31	33910552	The bladder tumour stage was pTa/pTis, pT1, and pT2a and prostate pT4a in one patient each, pT3a/b in 6 (31.6%) patients, and pT4a/b in 9 (47.4%) patients.	('pT3', 'Gene', '7694', (92, 95))	('pT4a', 'Var', (66, 70))	('pT3', 'Gene', (92, 95))	('bladder tumour', 'Disease', (4, 18))	('patient', 'Species', '9606', (78, 85))	('patient', 'Species', '9606', (112, 119))	('pTa', 'molecular_function', 'GO:0008959', ('29', '32'))	('bladder tumour', 'Phenotype', 'HP:0009725', (4, 18))	('patients', 'Species', '9606', (146, 154))	('patients', 'Species', '9606', (112, 120))	('pT1', 'Gene', '58492', (39, 42))	('pT2a', 'Disease', (48, 52))	('bladder tumour', 'Disease', 'MESH:D001749', (4, 18))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('patient', 'Species', '9606', (146, 153))	('pTa/pTis', 'Disease', (29, 37))	('pT1', 'Gene', (39, 42))
83	32957442	The protein products of individual CGB genes show amino acid differences at position 117.	('amino acid differences', 'Var', (50, 72))	('CGB', 'Gene', (35, 38))	('CGB', 'Gene', '93659', (35, 38))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
90	32957442	The insertion led to the deletion of a 52-base long segment of the proximal promoter, as well as the entire 5' untranslated region (5'UTR) region of the CGB gene.	(', as', 'Gene', '112935892', (84, 88))	('CGB', 'Gene', (153, 156))	('to', 'Gene', '6999', (18, 20))	('deletion', 'Var', (25, 33))	('CGB', 'Gene', '93659', (153, 156))
91	32957442	The consequence of this mutation was the creation of a new promoter sequence for CGB1 and CGB2, a new 5'UTR region with an alternative start codon, and a new first exon.	('CGB2', 'Gene', (90, 94))	('CGB1', 'Gene', (81, 85))	('CGB1', 'Gene', '114335', (81, 85))	('mutation', 'Var', (24, 32))	('CGB2', 'Gene', '114336', (90, 94))
125	32957442	It was also demonstrated that specific targeting of CGB1 and CGB2 with siRNA was much more effective in reducing cancer cell numbers than silencing other CGB genes.	('CGB', 'Gene', '93659', (154, 157))	('CGB', 'Gene', (52, 55))	('targeting', 'Var', (39, 48))	('CGB2', 'Gene', '114336', (61, 65))	('CGB', 'Gene', '93659', (61, 64))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('CGB', 'Gene', (154, 157))	('cancer', 'Disease', (113, 119))	('reducing', 'NegReg', (104, 112))	('CGB', 'Gene', (61, 64))	('CGB', 'Gene', '93659', (52, 55))	('CGB2', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CGB1', 'Gene', (52, 56))	('CGB1', 'Gene', '114335', (52, 56))
258	28137924	DNA Damage Response and Repair Gene Alterations Are Associated With Improved Survival In Patients With Platinum-Treated Advanced Urothelial Carcinoma Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage.	('Platinum', 'Chemical', 'MESH:D010984', (150, 158))	('Carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('Platinum', 'Chemical', 'MESH:D010984', (103, 111))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('Advanced Urothelial Carcinoma', 'Disease', (120, 149))	('advanced urothelial carcinoma', 'Disease', 'MESH:D020178', (213, 242))	('DNA Damage Response', 'biological_process', 'GO:0006974', ('0', '19'))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('inducing', 'PosReg', (246, 254))	('DNA', 'cellular_component', 'GO:0005574', ('255', '258'))	('Alterations', 'Var', (36, 47))	('Improved', 'PosReg', (68, 76))	('Patients', 'Species', '9606', (89, 97))	('DNA damage', 'MPA', (255, 265))	('Advanced Urothelial Carcinoma', 'Disease', 'MESH:D020178', (120, 149))	('advanced urothelial carcinoma', 'Disease', (213, 242))
259	28137924	We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy.	('improved', 'PosReg', (106, 114))	('alterations', 'Var', (28, 39))	('sensitivity to', 'MPA', (115, 129))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('DNA damage response', 'biological_process', 'GO:0006974', ('43', '62'))	('platinum', 'Chemical', 'MESH:D010984', (130, 138))	('DDR', 'Gene', (75, 78))
261	28137924	Patients were dichotomized based on presence/absence of alterations in a panel of 34 DDR genes.	('Patients', 'Species', '9606', (0, 8))	('DDR genes', 'Gene', (85, 94))	('alterations', 'Var', (56, 67))
263	28137924	Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log rank p=0.007) and overall survival (23.7 vs. 13.0 months, log rank p=0.006).	('improved', 'PosReg', (34, 42))	('alterations', 'Var', (18, 29))	('Patients', 'Species', '9606', (0, 8))	('DDR', 'Gene', (14, 17))	('overall survival', 'CPA', (112, 128))	('progression-free survival', 'CPA', (43, 68))
265	28137924	Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma.	('alteration', 'Var', (12, 22))	('platinum', 'Chemical', 'MESH:D010984', (72, 80))	('improved', 'PosReg', (42, 50))	('advanced urothelial carcinoma', 'Disease', (103, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('patients', 'Species', '9606', (89, 97))	('DDR', 'Gene', (8, 11))	('advanced urothelial carcinoma', 'Disease', 'MESH:D020178', (103, 132))
273	28137924	Inactivating alterations of genes involved in DNA repair pathways are frequently observed in cancer and the presence of somatic alterations in these genes have been reported to correlate with improved pathologic response following neoadjuvant cisplatin-based chemotherapy and possibly overall survival in urothelial carcinoma.	('improved', 'PosReg', (192, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('cancer', 'Disease', (93, 99))	('presence', 'Var', (108, 116))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('alterations', 'Var', (128, 139))	('Inactivating alterations', 'Var', (0, 24))	('DNA repair', 'biological_process', 'GO:0006281', ('46', '56'))	('urothelial carcinoma', 'Disease', (305, 325))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('pathologic response', 'CPA', (201, 220))	('cisplatin', 'Chemical', 'MESH:D002945', (243, 252))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (305, 325))
274	28137924	In this study, we sought to determine whether alterations of genes involved in DNA damage response and repair (DDR) are associated with improved sensitivity to platinum-based chemotherapy, as measured by objective response, progression free survival (PFS), and overall survival (OS) in patients with metastatic urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (311, 331))	('overall survival', 'CPA', (261, 277))	('DNA damage response', 'biological_process', 'GO:0006974', ('79', '98'))	('OS', 'Chemical', '-', (279, 281))	('sensitivity', 'MPA', (145, 156))	('platinum', 'Chemical', 'MESH:D010984', (160, 168))	('alterations', 'Var', (46, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('urothelial carcinoma', 'Disease', (311, 331))	('patients', 'Species', '9606', (286, 294))	('improved', 'PosReg', (136, 144))
278	28137924	We also explored the effect on these clinical endpoints by the number of individual DDR gene alterations in a given tumor identified on our institutional next generation sequencing platform and the number of DNA repair pathways involved on these endpoints.	('DNA repair', 'biological_process', 'GO:0006281', ('208', '218'))	('alterations', 'Var', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('DDR gene', 'Gene', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('DNA', 'cellular_component', 'GO:0005574', ('208', '211'))	('tumor', 'Disease', (116, 121))
279	28137924	Thirdly, we assessed the association of DDR gene alterations with both total tumor mutation and copy number alteration burden.	('alterations', 'Var', (49, 60))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('DDR gene', 'Gene', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
284	28137924	Based on previous work , all ERCC2 missense mutations within or near the helicase domains were considered deleterious.	('ERCC2', 'Gene', (29, 34))	('ERCC2', 'Gene', '2068', (29, 34))	('helicase', 'Protein', (73, 81))	('missense mutations', 'Var', (35, 53))
301	28137924	More patients were treated with cisplatin in the subgroup with DDR alterations (68.1% vs. 45.3%, p=0.027).	('patients', 'Species', '9606', (5, 13))	('DDR', 'Disease', (63, 66))	('alterations', 'Var', (67, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))
304	28137924	Patients with DDR alterations had significantly improved PFS of 9.3 months (95% CI: 7.3 - 13.4) compared to 6.0 months (95% CI 4.5 - 8.4) for those without DDR alterations (log rank p=0.007) (Figure 1A).	('alterations', 'Var', (18, 29))	('PFS', 'MPA', (57, 60))	('improved', 'PosReg', (48, 56))	('Patients', 'Species', '9606', (0, 8))	('DDR', 'Gene', (14, 17))
305	28137924	DDR alterations, performance status, platinum type, and prior peri-operative platinum were significantly associated with PFS in uni- and multivariable analyses(Table 2).	('alterations', 'Var', (4, 15))	('PFS', 'Disease', (121, 124))	('DDR', 'Gene', (0, 3))	('platinum', 'Chemical', 'MESH:D010984', (37, 45))	('platinum', 'Chemical', 'MESH:D010984', (77, 85))	('associated', 'Reg', (105, 115))
307	28137924	Patients with DDR alterations had significantly longer OS of 23.7 months (95% CI: 18.4 - not reached) compared to 13.0 months (95% CI: 10.7 - 19.2) for those without DDR alterations (log-rank p=0.006)(Figure 1B).	('alterations', 'Var', (18, 29))	('OS', 'Chemical', '-', (55, 57))	('longer', 'PosReg', (48, 54))	('Patients', 'Species', '9606', (0, 8))	('DDR', 'Gene', (14, 17))
313	28137924	Among the 47 patients with DDR alterations, 120 alterations were identified.	('DDR', 'Gene', (27, 30))	('patients', 'Species', '9606', (13, 21))	('alterations', 'Var', (31, 42))
314	28137924	Amongst the missense mutations, there were 95 unique mutations, of which only 13 were previously reported in COSMIC, published literature, or screening against a pan-cancer hotspot analysis of 11,119 tumors.	('missense mutations', 'Var', (12, 30))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('OS', 'Chemical', '-', (110, 112))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('mutations', 'Var', (53, 62))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Disease', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
315	28137924	There was no significant difference between those with deleterious and non-deleterious DDR alterations with regards to PFS (p=0.600) or OS (p=0.395).	('alterations', 'Var', (91, 102))	('DDR', 'Gene', (87, 90))	('OS', 'Chemical', '-', (136, 138))	('PFS', 'MPA', (119, 122))
316	28137924	There was no significant difference between those with deleterious and non-deleterious DDR alterations with regards to PFS (p=0.724) or OS (p=0.640).	('alterations', 'Var', (91, 102))	('DDR', 'Gene', (87, 90))	('OS', 'Chemical', '-', (136, 138))	('PFS', 'MPA', (119, 122))
317	28137924	(Supplemental figures 1C & 1D) When adjusted for other variables, those with deleterious DDR alterations demonstrated a trend towards improvement in PFS (HR 0.54, 95% CI 0.29 - 1.02, p=0.058) and statistically significant improvement in OS (HR 0.33, 95% CI 0.13 - 0.83, p=0.018) compared to those with wild type DDR genes.	('deleterious', 'Gene', (77, 88))	('towards', 'PosReg', (126, 133))	('DDR', 'Var', (89, 92))	('significant', 'PosReg', (210, 221))	('OS', 'Chemical', '-', (237, 239))
319	28137924	Compared to those without DDR alterations, patients with DDR alterations displayed a significantly higher number of mutations (Median 10 vs 7, p<0.001) and copy number alterations (median 3 vs 1, p<0.001) Patients were divided into four subgroups based upon the number of DDR alterations (0, 1, 2, and >=3).	('Patients', 'Species', '9606', (205, 213))	('higher', 'PosReg', (99, 105))	('patients', 'Species', '9606', (43, 51))	('mutations', 'MPA', (116, 125))	('alterations', 'Var', (61, 72))	('copy number alterations', 'Var', (156, 179))
320	28137924	Increasing number of total mutations showed a trend towards increased response rate (odds ratio 1.06, 95% CI 0.99 - 1.14, p=0.091) and PFS (HR 0.97, 95% CI 0.98 - 1.00, p=0.079), while showing statistically significant OS improvement (HR 0.93, 95% CI 0.88 - 0.98, p=0.010).	('mutations', 'Var', (27, 36))	('response', 'MPA', (70, 78))	('OS', 'Chemical', '-', (219, 221))	('PFS', 'MPA', (135, 138))	('increased', 'PosReg', (60, 69))
326	28137924	Alterations in different pathways exerted different magnitudes of effect on PFS and OS in exploratory analyses, most pronounced with POLE, damage response checkpoint and NER for PFS and POLE and NER for OS (Figures 3A, 3B).	('damage', 'MPA', (139, 145))	('NER', 'biological_process', 'GO:0006289', ('195', '198'))	('NER', 'biological_process', 'GO:0006289', ('170', '173'))	('Alterations', 'Var', (0, 11))	('OS', 'Chemical', '-', (84, 86))	('OS', 'Chemical', '-', (203, 205))
327	28137924	The first of these had six different POLE alterations, including a nonsense mutation (R114*) and a missense mutation (P436H) within the exonuclease domain.	('R114*', 'Var', (86, 91))	('R114*', 'SUBSTITUTION', 'None', (86, 91))	('P436H', 'Var', (118, 123))	('P436H', 'Mutation', 'p.P436H', (118, 123))
331	28137924	For those who were treated with radical cystectomy alone, DDR alteration status was not associated with both disease-free survival (hazard ratio 1.18, 95% CI 0.49 - 2.80, p=0.729) and OS (HR 0.77, 95% CI 0.42 - 1.42, p=0.408).	('DDR', 'Gene', (58, 61))	('alteration', 'Var', (62, 72))	('OS', 'Chemical', '-', (184, 186))
333	28137924	We examined the association between DDR alterations and clinical outcome in a cohort of urothelial carcinoma patients treated with first-line platinum-based chemotherapy.	('platinum', 'Chemical', 'MESH:D010984', (142, 150))	('patients', 'Species', '9606', (109, 117))	('urothelial carcinoma', 'Disease', (88, 108))	('alterations', 'Var', (40, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (88, 108))
334	28137924	We observed that 48% of tumors contained alterations in DDR genes, and that their presence was an independent indicator of improved PFS and OS.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('DDR genes', 'Gene', (56, 65))	('OS', 'Chemical', '-', (140, 142))	('PFS', 'CPA', (132, 135))	('improved', 'PosReg', (123, 131))	('alterations', 'Var', (41, 52))
335	28137924	Tumors with DDR gene alterations were also characterized by higher total mutation burden, lower rate of visceral metastases, and higher rate of nodal metastases.	('nodal metastases', 'Disease', (144, 160))	('visceral metastases', 'Disease', 'MESH:D009362', (104, 123))	('mutation burden', 'MPA', (73, 88))	('higher', 'PosReg', (60, 66))	('nodal metastases', 'Disease', 'MESH:D009362', (144, 160))	('DDR gene', 'Gene', (12, 20))	('lower', 'NegReg', (90, 95))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('visceral metastases', 'Disease', (104, 123))	('alterations', 'Var', (21, 32))
336	28137924	Dysregulation of DNA repair genes has long been implicated in both carcinogenesis and prognosis of urothelial carcinoma.	('carcinogenesis', 'Disease', 'MESH:D063646', (67, 81))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (99, 119))	('DNA repair genes', 'Gene', (17, 33))	('carcinogenesis', 'Disease', (67, 81))	('Dysregulation', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('urothelial carcinoma', 'Disease', (99, 119))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('implicated', 'Reg', (48, 58))	('DNA repair', 'biological_process', 'GO:0006281', ('17', '27'))
337	28137924	Polymorphisms in various DDR genes such as ERCC2 or NBN have previously been associated with the development of urothelial carcinoma and ERCC1 over-expression has been linked to poorer outcomes.	('ERCC1', 'Gene', (137, 142))	('over-expression', 'PosReg', (143, 158))	('NBN', 'Gene', '4683', (52, 55))	('ERCC1', 'Gene', '2067', (137, 142))	('DDR', 'Gene', (25, 28))	('NBN', 'Gene', (52, 55))	('Polymorphisms', 'Var', (0, 13))	('urothelial carcinoma', 'Disease', (112, 132))	('ERCC2', 'Gene', '2068', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('ERCC2', 'Gene', (43, 48))	('associated with', 'Reg', (77, 92))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (112, 132))
338	28137924	In a study of 50 patients treated with cisplatin-based neoadjuvant chemotherapy, ERCC2 mutation was significantly enriched in the subset with ypT0/ypTis disease.	('ypT0/ypTis disease', 'Disease', (142, 160))	('ERCC2', 'Gene', '2068', (81, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('patients', 'Species', '9606', (17, 25))	('ERCC2', 'Gene', (81, 86))	('mutation', 'Var', (87, 95))
339	28137924	Similarly, Plimack and colleagues demonstrated that alterations in one or more of the three DDR genes, ATM, RB1 and FANCC predicted increased likelihood of pathologic complete response following neoadjuvant cisplatin-based chemotherapy.	('alterations', 'Var', (52, 63))	('DDR', 'Gene', (92, 95))	('RB1', 'Gene', (108, 111))	('FANCC', 'Gene', '2176', (116, 121))	('ATM', 'Gene', '472', (103, 106))	('FANCC', 'Gene', (116, 121))	('FA', 'Phenotype', 'HP:0001994', (116, 118))	('RB1', 'Gene', '5925', (108, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (207, 216))	('ATM', 'Gene', (103, 106))
340	28137924	In our study cohort, mutations in ERCC2, ATM and FANCC were only detected in 5, 9 and 1% of patients and, individually they were not significantly associated with clinical outcomes (data not shown).	('associated', 'Reg', (147, 157))	('ERCC2', 'Gene', (34, 39))	('FA', 'Phenotype', 'HP:0001994', (49, 51))	('patients', 'Species', '9606', (92, 100))	('ATM', 'Gene', (41, 44))	('FANCC', 'Gene', '2176', (49, 54))	('FANCC', 'Gene', (49, 54))	('ERCC2', 'Gene', '2068', (34, 39))	('ATM', 'Gene', '472', (41, 44))	('mutations', 'Var', (21, 30))
341	28137924	Performing whole exome sequencing on 81 resected urothelial carcinoma cases with no prior neoadjuvant chemotherapy, Yap and colleagues observed an increased rate of mutations in ATM, ERCC2, FANCD2, PALB2, BRCA1 and BRCA2.	('PALB2', 'Gene', (198, 203))	('PALB2', 'Gene', '79728', (198, 203))	('FA', 'Phenotype', 'HP:0001994', (190, 192))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (49, 69))	('BRCA2', 'Gene', (215, 220))	('ERCC2', 'Gene', (183, 188))	('Yap', 'Gene', '10413', (116, 119))	('mutations', 'Var', (165, 174))	('ATM', 'Gene', '472', (178, 181))	('ERCC2', 'Gene', '2068', (183, 188))	('FANCD2', 'Gene', (190, 196))	('BRCA2', 'Gene', '675', (215, 220))	('Yap', 'Gene', (116, 119))	('FANCD2', 'Gene', '2177', (190, 196))	('BRCA1', 'Gene', '672', (205, 210))	('ATM', 'Gene', (178, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('urothelial carcinoma', 'Disease', (49, 69))	('BRCA1', 'Gene', (205, 210))
342	28137924	Tumors with mutation in at least one of these genes had significantly higher overall numbers of somatic mutations and longer recurrence-free survival.	('Tumors', 'Disease', (0, 6))	('mutation', 'Var', (12, 20))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('higher', 'PosReg', (70, 76))	('longer', 'PosReg', (118, 124))	('recurrence-free survival', 'CPA', (125, 149))
344	28137924	Furthermore, our data also showed that tumors with higher mutation load also demonstrated a trend toward superior response and OS, independent of DDR status.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('superior', 'PosReg', (105, 113))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mutation load', 'Var', (58, 71))	('OS', 'Chemical', '-', (127, 129))	('tumors', 'Disease', (39, 45))	('response', 'CPA', (114, 122))
346	28137924	Parallel phenomenon has been observed in microsatellite unstable colorectal cancer which is exquisitely sensitive to immune checkpoint inhibitors.	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('microsatellite unstable', 'Var', (41, 64))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('colorectal cancer', 'Disease', (65, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (65, 82))
349	28137924	Mutations in POLE were also observed in 5% of the TCGA bladder cancer cohort.	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('bladder cancer', 'Disease', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('Mutations', 'Var', (0, 9))	('POLE', 'Gene', (13, 17))	('observed', 'Reg', (28, 36))
350	28137924	To date, POLE mutations have been associated with 1.5 - 2% of unselected colorectal cancer cases and 5.6 - 9.7% of endometrial carcinoma.	('associated', 'Reg', (34, 44))	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (115, 136))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('endometrial carcinoma', 'Disease', (115, 136))	('colorectal cancer', 'Disease', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (115, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('mutations', 'Var', (14, 23))
352	28137924	Endometrial carcinomas with POLE mutations were found to contain significantly higher neoantigen load, a higher number of CD8+ tumor-infiltrating lymphocytes and over-expression of lymphocytic PD-1 as compared to tumors with microsatellite instability or wild-type tumors.	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('Endometrial carcinomas', 'Disease', 'MESH:D016889', (0, 22))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('PD-1', 'Gene', (193, 197))	('neoantigen load', 'MPA', (86, 101))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('PD-1', 'Gene', '5133', (193, 197))	('higher', 'PosReg', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('Endometrial carcinomas', 'Disease', (0, 22))	('tumors', 'Disease', (213, 219))	('tumor', 'Disease', (265, 270))	('CD8', 'Gene', (122, 125))	('over-expression', 'PosReg', (162, 177))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Disease', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('Endometrial carcinomas', 'Phenotype', 'HP:0012114', (0, 22))	('tumor', 'Disease', (127, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (12, 22))	('tumors', 'Disease', (265, 271))	('CD8', 'Gene', '925', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
353	28137924	Although not confirmed in bladder cancer, these findings suggested that POLE mutations might represent a subset of clinically unique disease with better prognosis and potentially enhanced response to both chemotherapy and immunotherapy.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('bladder cancer', 'Phenotype', 'HP:0009725', (26, 40))	('enhanced', 'PosReg', (179, 187))	('bladder cancer', 'Disease', 'MESH:D001749', (26, 40))	('bladder cancer', 'Disease', (26, 40))	('POLE mutations', 'Var', (72, 86))
354	28137924	Due to the retrospective nature of this analysis, we cannot distinguish between DDR alteration's prognostic role and their function as predictors of platinum sensitivity or resistance.	('platinum', 'Chemical', 'MESH:D010984', (149, 157))	('platinum sensitivity', 'CPA', (149, 169))	('alteration', 'Var', (84, 94))	('DDR', 'Gene', (80, 83))
358	28137924	Furthermore, since platinum-based chemotherapy is standard of care for metastatic urothelial carcinoma, it will require a prospective randomized trial involving a platinum-free chemotherapy arm to confirm the predictive role of DDR gene alterations.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('alterations', 'Var', (237, 248))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (82, 102))	('platinum', 'Chemical', 'MESH:D010984', (163, 171))	('platinum', 'Chemical', 'MESH:D010984', (19, 27))	('urothelial carcinoma', 'Disease', (82, 102))	('DDR', 'Gene', (228, 231))
361	28137924	In conclusion, our study demonstrates that defects in DDR genes are prevalent in advanced urothelial carcinoma and have significant impact upon sensitivity to platinum therapy.	('sensitivity to', 'MPA', (144, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('advanced urothelial carcinoma', 'Disease', 'MESH:D020178', (81, 110))	('prevalent', 'Reg', (68, 77))	('DDR genes', 'Gene', (54, 63))	('defects', 'Var', (43, 50))	('advanced urothelial carcinoma', 'Disease', (81, 110))	('impact', 'Reg', (132, 138))	('platinum', 'Chemical', 'MESH:D010984', (159, 167))
364	28137924	DDR gene alterations might also provide the missing link between platinum sensitivity and immunotherapy responsiveness via modulation of mutation burden, and further studies are required to further elucidate this relationship.	('platinum', 'Chemical', 'MESH:D010984', (65, 73))	('DDR', 'Gene', (0, 3))	('alterations', 'Var', (9, 20))
369	28137924	This can constitute the first step towards personalized treatment selection for patients with advanced urothelial carcinoma with a validated clinical sequencing platform, where only patients with defective DNA damage repair mechanism are offered platinum-based chemotherapy while clinical trials or immunotherapy can be considered for the other patients.	('patients', 'Species', '9606', (80, 88))	('DNA', 'Gene', (206, 209))	('defective', 'Var', (196, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('DNA', 'cellular_component', 'GO:0005574', ('206', '209'))	('advanced urothelial carcinoma', 'Disease', (94, 123))	('platinum', 'Chemical', 'MESH:D010984', (246, 254))	('patients', 'Species', '9606', (182, 190))	('advanced urothelial carcinoma', 'Disease', 'MESH:D020178', (94, 123))	('patients', 'Species', '9606', (345, 353))
513	21769321	Patients with confirmed pT1, G3 or Tis were considered eligible for immunotherapy provided that all visible tumors were resected and second look biopsies confirmed pT0.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('pT1', 'Gene', (24, 27))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('pT0', 'Var', (164, 167))	('pT1', 'Gene', '58492', (24, 27))
515	21769321	The outcome of patients with variant histology receiving BCG immunotherapy was compared to the outcome of patients with conventional high grade urothelial carcinoma treated with BCG immunotherapy.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('patients', 'Species', '9606', (15, 23))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (144, 164))	('variant', 'Var', (29, 36))	('patients', 'Species', '9606', (106, 114))	('urothelial carcinoma', 'Disease', (144, 164))
526	21769321	The outcome of patients with variant histology receiving BCG immunotherapy was compared to the outcome of 144 patients with conventional high grade urothelial carcinoma that were treated with BCG immunotherapy (Table 2 and Figure 2).	('patients', 'Species', '9606', (15, 23))	('urothelial carcinoma', 'Disease', (148, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('variant', 'Var', (29, 36))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (148, 168))	('patients', 'Species', '9606', (110, 118))
528	21769321	Median time of progress to muscle-invasive disease was significantly shorter in the patients with variant disease (19.8 vs 56 months, P=0001).	('patients', 'Species', '9606', (84, 92))	('shorter', 'NegReg', (69, 76))	('variant', 'Var', (98, 105))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (27, 50))	('muscle-invasive disease', 'Disease', (27, 50))
529	21769321	A total of 5/22 (22.7%) patients of the variant group and 13/144 (9.03%) of conventional group underwent cystectomy (P=0.068) during the course of disease follow-up.	('variant', 'Var', (40, 47))	('cystectomy', 'Disease', (105, 115))	('patients', 'Species', '9606', (24, 32))
535	21769321	The 2 and 5-year disease specific survival rates however, were not significantly different (97% and 91.43% for patients with conventional carcinoma and 94.74 % and 82% for patients with variant disease, P=0.33).	('carcinoma', 'Disease', 'MESH:D002277', (138, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('variant', 'Var', (186, 193))	('carcinoma', 'Disease', (138, 147))	('patients', 'Species', '9606', (172, 180))	('patients', 'Species', '9606', (111, 119))
579	33797188	In conclusion, this study first constructed an immune-related prognostic lncRNA signature, which consists of RP11-89, PSORS1C3, LINC02672 and MIR100HG and might shed lights on novel targets for individualized immunotherapy for BLCA patients.	('PSORS1C3', 'Gene', (118, 126))	('LINC02672', 'Chemical', '-', (128, 137))	('patients', 'Species', '9606', (232, 240))	('LINC02672', 'Var', (128, 137))	('MIR100HG', 'Gene', (142, 150))	('RP11', 'Gene', (109, 113))	('PSORS1C3', 'Gene', '100130889', (118, 126))	('RP11', 'Gene', '26121', (109, 113))	('BLCA', 'Phenotype', 'HP:0009725', (227, 231))	('MIR100HG', 'Gene', '399959', (142, 150))
641	33797188	Furthermore, we performed apoptosis analysis, which showed that RP11-89 depletion in 5637 cells induce cell early apoptosis (Figure 5C), while RP11-89 enrichment in T24 cells inhibited cell early apoptosis (P <.05).	('apoptosis', 'biological_process', 'GO:0006915', ('196', '205'))	('inhibited', 'NegReg', (175, 184))	('cell early apoptosis', 'CPA', (185, 205))	('apoptosis', 'biological_process', 'GO:0097194', ('196', '205'))	('RP11', 'Gene', (64, 68))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('depletion', 'Var', (72, 81))	('cell early apoptosis', 'CPA', (103, 123))	('RP11', 'Gene', (143, 147))	('apoptosis', 'biological_process', 'GO:0097194', ('114', '123'))	('apoptosis', 'biological_process', 'GO:0006915', ('114', '123'))	('RP11', 'Gene', '26121', (64, 68))	('RP11', 'Gene', '26121', (143, 147))
642	33797188	Transwell assay revealed that knock-down of RP11-89 significantly suppressed cell invasive capacity and overexpression significantly promoted cell invasive capacity compared with the respective controls.	('promoted', 'PosReg', (133, 141))	('cell invasive capacity', 'CPA', (77, 99))	('RP11', 'Gene', (44, 48))	('suppressed', 'NegReg', (66, 76))	('RP11', 'Gene', '26121', (44, 48))	('cell invasive capacity', 'CPA', (142, 164))	('knock-down', 'Var', (30, 40))
645	33797188	RT-qPCR result and Western blot analysis showed that 5637 cells transduced with sh-RP-1189 plasmid exhibited increased miR-27a-3p expression but decreased PPARgamma when compared to the cells treated with sh-RP-1189 control plasmid (Figure 6B, E) (P <.05).	('sh-RP-1189', 'Var', (80, 90))	('PPARgamma', 'Gene', '5468', (155, 164))	('expression', 'MPA', (130, 140))	('miR-27a-3p', 'Protein', (119, 129))	('decreased', 'NegReg', (145, 154))	('increased', 'PosReg', (109, 118))	('PPARgamma', 'Gene', (155, 164))
647	33797188	We performed bioinformatic method to analysis targeted genes of miR-27a-3p in starBase database (http://starbase.sysu.edu.cn/), which showed that miR-27a-3p was able to bind with PPARgamma in 3'-UTR region and caused the negative regulation of PPARgamma (Figure 6D).	('miR-27a-3p', 'Var', (146, 156))	('meth', 'Disease', 'None', (27, 31))	('regulation', 'biological_process', 'GO:0065007', ('230', '240'))	('PPARgamma', 'Gene', (179, 188))	('bind', 'Interaction', (169, 173))	('negative', 'NegReg', (221, 229))	('PPARgamma', 'Gene', (244, 253))	('meth', 'Disease', (27, 31))	('PPARgamma', 'Gene', '5468', (179, 188))	('PPARgamma', 'Gene', '5468', (244, 253))
654	33797188	LINC02672 was significantly correlated with the expression of IDO1, NRP1 and TNFSF4 in pan-cancers (Figure 6G), and it was significantly associated with the abundance of CD56 bright natural killer cells, mast cells, and immature dendritic cells in pan-cancers (Figure 8H).	('associated', 'Reg', (137, 147))	('IDO1', 'Gene', (62, 66))	('LINC02672', 'Chemical', '-', (0, 9))	('TNFSF4', 'Gene', (77, 83))	('-cancers', 'Disease', (251, 259))	('-cancers', 'Disease', 'MESH:D009369', (251, 259))	('CD56', 'Gene', (170, 174))	('IDO', 'molecular_function', 'GO:0033754', ('62', '65'))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('CD56', 'Gene', '4684', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('IDO1', 'Gene', '3620', (62, 66))	('NRP1', 'Gene', '8829', (68, 72))	('TNFSF4', 'Gene', '7292', (77, 83))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('-cancers', 'Disease', (90, 98))	('NRP1', 'Gene', (68, 72))	('IDO', 'molecular_function', 'GO:0047719', ('62', '65'))	('NRP', 'biological_process', 'GO:0085015', ('68', '71'))	('-cancers', 'Disease', 'MESH:D009369', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('LINC02672', 'Var', (0, 9))	('correlated', 'Reg', (28, 38))
675	33797188	In conclusion, this study first constructed an immune-related prognostic lncRNA signature (IRPLS), which consists of RP11-89, PSORS1C3, LINC02672 and MIR100HG.	('RP11', 'Gene', (117, 121))	('PSORS1C3', 'Gene', '100130889', (126, 134))	('MIR100HG', 'Gene', (150, 158))	('RP11', 'Gene', '26121', (117, 121))	('LINC02672', 'Chemical', '-', (136, 145))	('MIR100HG', 'Gene', '399959', (150, 158))	('LINC02672', 'Var', (136, 145))	('PSORS1C3', 'Gene', (126, 134))
714	30026844	On univariate analysis, patients with PNI < 40 had a significant shorter OS compared with those with PNI > 40 (9.6 vs. 17.6 months, HR 2.41, 95% CI 1.58 - 3.68, p < 0.0001; Figure 3).	('patients', 'Species', '9606', (24, 32))	('shorter', 'NegReg', (65, 72))	('PNI < 40', 'Var', (38, 46))
717	30026844	The PNI values were significantly lower in patients with visceral metastasis (p < 0.0001), liver metastasis (p = 0.05), lung metastasis (p = 0.006), bone metastasis (p = 0.007), leukocytosis (p = 0.006), and hemoglobin (Hb) < 10 g/dL (p < 0.0001, shown as Table 1).	('visceral metastasis', 'Disease', 'MESH:D009362', (57, 76))	('< 10 g/dL', 'Var', (224, 233))	('PNI values', 'MPA', (4, 14))	('lower', 'NegReg', (34, 39))	('patients', 'Species', '9606', (43, 51))	('leukocytosis', 'Disease', 'MESH:D007964', (178, 190))	('leukocytosis', 'Phenotype', 'HP:0001974', (178, 190))	('visceral metastasis', 'Disease', (57, 76))	('lung metastasis', 'Disease', 'MESH:D009362', (120, 135))	('bone metastasis', 'CPA', (149, 164))	('liver metastasis', 'Disease', 'MESH:D009362', (91, 107))	('lung metastasis', 'Disease', (120, 135))	('liver metastasis', 'Disease', (91, 107))	('leukocytosis', 'Disease', (178, 190))
719	30026844	Patients with a low PNI were highly associated with visceral metastasis, leukocytosis and anemia.	('anemia', 'Disease', 'MESH:D000740', (90, 96))	('leukocytosis', 'Disease', (73, 85))	('low', 'Var', (16, 19))	('visceral metastasis', 'Disease', (52, 71))	('anemia', 'Phenotype', 'HP:0001903', (90, 96))	('Patients', 'Species', '9606', (0, 8))	('visceral metastasis', 'Disease', 'MESH:D009362', (52, 71))	('PNI', 'Gene', (20, 23))	('associated', 'Reg', (36, 46))	('anemia', 'Disease', (90, 96))	('leukocytosis', 'Disease', 'MESH:D007964', (73, 85))	('leukocytosis', 'Phenotype', 'HP:0001974', (73, 85))
828	18823036	There was a trend toward superior overall survival (1.33 overall survival, 95% CI, 1.00-1.76) for MVAC-treated patients, with a 5-year survival of 57% compared with 43% for patients treated with surgery alone (P=.06).	('patients', 'Species', '9606', (173, 181))	('MVAC', 'Chemical', 'MESH:C044361', (98, 102))	('MVAC-treated', 'Var', (98, 110))	('superior', 'PosReg', (25, 33))	('overall survival', 'MPA', (34, 50))	('patients', 'Species', '9606', (111, 119))
900	18823036	Cisplatin dose intensity was slightly greater in patients receiving split-dose cisplatin (93%) compared with conventional single-dose cisplatin (88%).	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('Cisplatin', 'MPA', (0, 9))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('split-dose cisplatin', 'Var', (68, 88))	('patients', 'Species', '9606', (49, 57))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))
928	18823036	Although less responses in the primary tumors were seen after split-dose cisplatin than single-dose cisplatin (2/15 versus 13/27), the numbers of patients are too small to compare statistically or draw inferences.	('tumors', 'Disease', (39, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('split-dose', 'Var', (62, 72))	('patients', 'Species', '9606', (146, 154))
950	32161720	An elevated level of H2O2 may drive increased syntheses of various macromolecules with anti-oxidative properties such as polyunsaturated fatty acids.	('syntheses of various macromolecules', 'MPA', (46, 81))	('polyunsaturated fatty acids', 'MPA', (121, 148))	('increased', 'PosReg', (36, 45))	('H2O2', 'Chemical', 'MESH:D006861', (21, 25))	('H2O2', 'Var', (21, 25))	('polyunsaturated fatty acids', 'Chemical', 'MESH:D005231', (121, 148))
988	32161720	GAPDH is also one of the targets for modification during cancer reprogramming such as the methylation directed by coactivator-associated arginine methyltransferase 1 (CARM1 or PRMT4).	('methyltransferase 1', 'molecular_function', 'GO:0047152', ('146', '165'))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('coactivator-associated arginine methyltransferase 1', 'Gene', '10498', (114, 165))	('PRMT4', 'Gene', (176, 181))	('cancer', 'Disease', (57, 63))	('methylation', 'biological_process', 'GO:0032259', ('90', '101'))	('CARM1', 'Gene', (167, 172))	('methylation', 'Var', (90, 101))	('PRMT4', 'Gene', '10498', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('CARM1', 'Gene', '10498', (167, 172))	('GAPDH', 'Gene', '2597', (0, 5))	('GAPDH', 'Gene', (0, 5))
1049	32047140	Ten of these 11 lncRNAs (AC007406.3, AC019211.1, AC022613.1, AC112721.1, AL391704.1, LINC01602, ST8SIA6-AS1, LINC01929, LINC01971 and RNF144A-AS1) had hazard ratios (HRs) greater than 1, suggesting that their overexpression was associated with shorter OS.	('AC022613.1', 'Var', (49, 59))	('AC007406.3', 'Var', (25, 35))	('LINC01602', 'Gene', (85, 94))	('RNF144A-AS1', 'Gene', (134, 145))	('ST8SIA6-AS1', 'Gene', '100128098;338596;5729', (96, 107))	('OS', 'Chemical', '-', (252, 254))	('RNF144A-AS1', 'Gene', '386597', (134, 145))	('AL391704.1', 'Var', (73, 83))	('LINC01602', 'Gene', '100505477', (85, 94))	('AC019211.1', 'Var', (37, 47))	('LINC01929', 'Var', (109, 118))	('ST8SIA6-AS1', 'Gene', (96, 107))	('AC112721.1', 'Var', (61, 71))	('LINC01971', 'Var', (120, 129))
1057	32047140	The formula was as follows: Risk Score = (0.228 x ExpressionRNF144A-AS1) + (0.436 x ExpressionAC019211.1) + (0.116 x ExpressionST8SIA6-AS1).	('0.228', 'Var', (42, 47))	('RNF144A-AS1', 'Gene', (60, 71))	('ST8SIA6-AS1', 'Gene', '100128098;338596;5729', (127, 138))	('ST8SIA6-AS1', 'Gene', (127, 138))	('RNF144A-AS1', 'Gene', '386597', (60, 71))	('ExpressionAC019211.1', 'Var', (84, 104))
1097	32047140	After the knockdown of RNF144A-AS1, the expression of epithelial markers (E-cadherin and ZO-1) increased, while the expression of mesenchymal markers (N-cadherin and Vimentin) decreased in BCa cells (Figure 9G).	('BCa', 'Disease', (189, 192))	('decreased', 'NegReg', (176, 185))	('BCa', 'Disease', 'MESH:D001749', (189, 192))	('Vimentin', 'cellular_component', 'GO:0045099', ('166', '174'))	('Vimentin', 'Gene', '7431', (166, 174))	('ZO-1', 'Gene', '7082', (89, 93))	('cadherin', 'molecular_function', 'GO:0008014', ('76', '84'))	('Vimentin', 'Gene', (166, 174))	('ZO-1', 'Gene', (89, 93))	('knockdown', 'Var', (10, 19))	('expression', 'MPA', (40, 50))	('BCa', 'Phenotype', 'HP:0009725', (189, 192))	('Vimentin', 'cellular_component', 'GO:0045098', ('166', '174'))	('E-cadherin', 'Gene', (74, 84))	('E-cadherin', 'Gene', '999', (74, 84))	('RNF144A-AS1', 'Gene', (23, 34))	('RNF144A-AS1', 'Gene', '386597', (23, 34))	('expression', 'MPA', (116, 126))	('N-cadherin', 'Gene', (151, 161))	('N-cadherin', 'Gene', '1000', (151, 161))	('increased', 'PosReg', (95, 104))	('cadherin', 'molecular_function', 'GO:0008014', ('153', '161'))
1116	32047140	Transwell and wound-healing assays demonstrated that knocking down RNF144A-AS1 impaired the invasion and migration abilities of BCa cells.	('BCa', 'Phenotype', 'HP:0009725', (128, 131))	('wound-healing', 'biological_process', 'GO:0042060', ('14', '27'))	('BCa', 'Disease', (128, 131))	('RNF144A-AS1', 'Gene', (67, 78))	('RNF144A-AS1', 'Gene', '386597', (67, 78))	('BCa', 'Disease', 'MESH:D001749', (128, 131))	('knocking down', 'Var', (53, 66))	('impaired', 'NegReg', (79, 87))
1117	32047140	Knocking down RNF144A-AS1 also significantly inhibited the EMT, a key contributor to tumor invasion and metastasis, by inducing the expression of epithelial markers (E-cadherin and ZO-1) and suppressing the expression of mesenchymal markers (N-cadherin and Vimentin).	('E-cadherin', 'Gene', (166, 176))	('E-cadherin', 'Gene', '999', (166, 176))	('Vimentin', 'cellular_component', 'GO:0045099', ('257', '265'))	('N-cadherin', 'Gene', (242, 252))	('inhibited', 'NegReg', (45, 54))	('N-cadherin', 'Gene', '1000', (242, 252))	('tumor invasion', 'Disease', (85, 99))	('expression', 'MPA', (207, 217))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ZO-1', 'Gene', '7082', (181, 185))	('EMT', 'CPA', (59, 62))	('Vimentin', 'Gene', '7431', (257, 265))	('tumor invasion', 'Disease', 'MESH:D009361', (85, 99))	('Vimentin', 'cellular_component', 'GO:0045098', ('257', '265'))	('ZO-1', 'Gene', (181, 185))	('inducing', 'NegReg', (119, 127))	('Vimentin', 'Gene', (257, 265))	('RNF144A-AS1', 'Gene', (14, 25))	('suppressing', 'NegReg', (191, 202))	('EMT', 'biological_process', 'GO:0001837', ('59', '62'))	('Knocking down', 'Var', (0, 13))	('RNF144A-AS1', 'Gene', '386597', (14, 25))	('cadherin', 'molecular_function', 'GO:0008014', ('168', '176'))	('cadherin', 'molecular_function', 'GO:0008014', ('244', '252'))	('expression', 'MPA', (132, 142))
1118	32047140	Thus, silencing RNF144A-AS1 in BCa cells may prevent the EMT, thereby reducing tumor motility and invasiveness.	('BCa', 'Phenotype', 'HP:0009725', (31, 34))	('EMT', 'biological_process', 'GO:0001837', ('57', '60'))	('RNF144A-AS1', 'Gene', (16, 27))	('BCa', 'Disease', (31, 34))	('BCa', 'Disease', 'MESH:D001749', (31, 34))	('prevent', 'NegReg', (45, 52))	('reducing', 'NegReg', (70, 78))	('invasiveness', 'CPA', (98, 110))	('EMT', 'CPA', (57, 60))	('tumor motility', 'Disease', (79, 93))	('silencing', 'Var', (6, 15))	('RNF144A-AS1', 'Gene', '386597', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor motility', 'Disease', 'MESH:D015835', (79, 93))
1181	28978151	All patients with low hsa-miR-429 expression survived 5 years, while with high hsa-miR-429 expression, only 58% survived.	('hsa-miR-429', 'Gene', '554210', (22, 33))	('hsa-miR-429', 'Gene', (79, 90))	('hsa-miR-429', 'Gene', (22, 33))	('patients', 'Species', '9606', (4, 12))	('hsa-miR-429', 'Gene', '554210', (79, 90))	('low', 'Var', (18, 21))
1196	28978151	For example, there should be a positive relationship between high microRNA-200C expression and the risk of death from disease in muscle-invasive urothelial carcinoma of the bladder, as revealed by one published work.	('microRNA-200C', 'Protein', (66, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('high', 'Var', (61, 65))	('death', 'Disease', 'MESH:D003643', (107, 112))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (145, 180))	('muscle-invasive urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (129, 180))	('death', 'Disease', (107, 112))	('invasive urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (136, 180))
1197	28978151	We have identified that hsa-miR-125b decreased its target SIRT7 at both mRNA and protein levels through partial sequence pairing with the target sites.	('partial sequence pairing', 'Var', (104, 128))	('hsa-miR-125b', 'Var', (24, 36))	('SIRT7', 'Gene', (58, 63))	('SIRT7', 'Gene', '51547', (58, 63))	('decreased', 'NegReg', (37, 46))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))
1199	28978151	Deletion, mutation and hypermethylation of CDKN2B gene have been reported to lead to the loss of CDKN2B expression.	('CDKN2B', 'Gene', (97, 103))	('CDKN2B', 'Gene', '1030', (97, 103))	('CDKN2B', 'Gene', (43, 49))	('Deletion', 'Var', (0, 8))	('CDKN2B', 'Gene', '1030', (43, 49))	('mutation', 'Var', (10, 18))	('expression', 'MPA', (104, 114))	('hypermethylation', 'Var', (23, 39))	('loss', 'NegReg', (89, 93))
1212	28978151	For patients with low hsa-miR-429 expression, all survived 5 years after surgery, while for those with high hsa-miR-429 expression, only 58% survived.	('hsa-miR-429', 'Gene', '554210', (22, 33))	('hsa-miR-429', 'Gene', (108, 119))	('expression', 'Var', (34, 44))	('hsa-miR-429', 'Gene', (22, 33))	('patients', 'Species', '9606', (4, 12))	('hsa-miR-429', 'Gene', '554210', (108, 119))	('low', 'Var', (18, 21))
1260	28978151	The reporter vector CDKN2B 3'UTR-mutated-type (MUT) was created by mutating the hsa-miR-429 seed region binding site (seed sequence binding fragment 5'-AGTATT-3' changed to 5'-CCAGAA-3').	('hsa-miR-429', 'Gene', (80, 91))	('CDKN2B', 'Gene', (20, 26))	('mutating', 'Var', (67, 75))	('binding', 'molecular_function', 'GO:0005488', ('132', '139'))	('binding', 'molecular_function', 'GO:0005488', ('104', '111'))	('CDKN2B', 'Gene', '1030', (20, 26))	('hsa-miR-429', 'Gene', '554210', (80, 91))
1275	28977887	By utilizing the gene expression in The Cancer Genome Atlas (TCGA) dataset, and another two datasets, in GSE13507 and GSE31684, we constructed a risk score staging system with Cox multivariate regression to evaluate predict the outcome of BLCA patients.	('Cancer Genome Atlas', 'Disease', (40, 59))	('gene expression', 'biological_process', 'GO:0010467', ('17', '32'))	('BLCA', 'Phenotype', 'HP:0009725', (239, 243))	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (40, 59))	('BLCA', 'Disease', (239, 243))	('GSE13507', 'Var', (105, 113))	('Cox', 'Gene', '1351', (176, 179))	('Cox', 'Gene', (176, 179))	('patients', 'Species', '9606', (244, 252))	('GSE31684', 'Var', (118, 126))
1287	28977887	The patients with high risk score had a significantly shorter survival time than those with low risk score, and this finding was further validated in other two cohorts used for candidate gene selection (GSE13507 and GSE31684) and another two totally independent datasets (GSE40875 and E-TABM-4321).	('GSE13507', 'Var', (203, 211))	('survival time', 'CPA', (62, 75))	('GSE31684', 'Var', (216, 224))	('patients', 'Species', '9606', (4, 12))	('shorter', 'NegReg', (54, 61))	('GSE40875', 'Var', (272, 280))
1293	28977887	Multivariate cox regression analyses were performed and the risk scores were calculated as the following: It is noticed that the coefficient of ST3GAL5 is negative, indicating that the expression of this gene is positively related the survival time/rate of BLCA patients while the expression of RCOR1 and COL10A1 are negatively related.	('cox', 'Gene', '1351', (13, 16))	('patients', 'Species', '9606', (262, 270))	('RCOR1', 'Gene', '23186', (295, 300))	('COL10A1', 'Gene', (305, 312))	('RCOR1', 'Gene', (295, 300))	('expression', 'Var', (185, 195))	('BLCA', 'Disease', (257, 261))	('BLCA', 'Phenotype', 'HP:0009725', (257, 261))	('cox', 'Gene', (13, 16))	('related', 'Reg', (223, 230))	('COL10A1', 'Gene', '1300', (305, 312))	('survival time/rate', 'CPA', (235, 253))	('positively', 'PosReg', (212, 222))	('ST3GAL5', 'Gene', '8869', (144, 151))	('ST3GAL5', 'Gene', (144, 151))
1302	28977887	The overall survival rate of patients underwent radiation therapy (Figure 3C) with high risk score had a significantly shorter survival rate than these with low risk score.	('survival', 'MPA', (127, 135))	('shorter', 'NegReg', (119, 126))	('patients', 'Species', '9606', (29, 37))	('high', 'Var', (83, 87))
1330	28339163	For patients with matched tumor tissue, cytology specimens revealed all mutations detected in tissue as well as additional mutations, suggesting that urine may more effectively capture the full genetic heterogeneity of disease than an individual cystectomy.	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('mutations', 'Var', (123, 132))
1331	28339163	Alterations in multiple genes correlated with clinical and histopathological features including response to BCG treatment, flat versus papillary architecture, and smoking history.	('flat versus papillary architecture', 'CPA', (123, 157))	('flat versus papillary architecture', 'Phenotype', 'HP:0007482', (123, 157))	('Alterations', 'Var', (0, 11))	('correlated', 'Reg', (30, 40))	('BCG', 'Species', '33892', (108, 111))
1348	28339163	We analyzed the suitability of cytology specimens to replace FFPE material for genomic analysis and attempted to identify mutations or copy number alterations that might correlate with clinical features and response to BCG treatment.	('copy number alterations', 'Var', (135, 158))	('correlate', 'Reg', (170, 179))	('BCG', 'Species', '33892', (219, 222))
1374	28339163	In addition to mutations and copy number alterations, MSK-IMPACT was able to successfully detect chromosomal rearrangements in urine cytology specimens, including an intrachromosomal duplication producing the recurrent FGFR3-TACC3 gene fusion on chromosome 4 (Figure 3C).	('FGFR3', 'Gene', '2261', (219, 224))	('chromosome', 'cellular_component', 'GO:0005694', ('246', '256'))	('TACC3', 'Gene', '10460', (225, 230))	('FGFR3', 'Gene', (219, 224))	('TACC3', 'Gene', (225, 230))	('FGFR', 'molecular_function', 'GO:0005007', ('219', '223'))	('duplication', 'Var', (183, 194))
1379	28339163	The underrepresentation of deletions of CDKN2A and CDKN2B, adjacent genes on chromosome 9, could indicate a reduced sensitivity of our targeted sequencing assay for identifying deletions in particular, due in part to conservative thresholds for calling copy number alterations.	('CDKN2B', 'Gene', '1030', (51, 57))	('reduced', 'NegReg', (108, 115))	('chromosome', 'cellular_component', 'GO:0005694', ('77', '87'))	('CDKN2A', 'Gene', (40, 46))	('CDKN2A', 'Gene', '1029', (40, 46))	('deletions', 'Var', (27, 36))	('CDKN2B', 'Gene', (51, 57))
1381	28339163	FGFR3-TACC3 gene fusions were observed in both TCGA and our cohort at a 2% frequency.	('TACC3', 'Gene', '10460', (6, 11))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('TCGA', 'Disease', (47, 51))	('TACC3', 'Gene', (6, 11))	('FGFR3', 'Gene', (0, 5))	('fusions', 'Var', (17, 24))	('observed', 'Reg', (30, 38))	('FGFR3', 'Gene', '2261', (0, 5))
1382	28339163	Correlation of genetic alterations with response to BCG treatment demonstrated differences among the 2 patient categories (Response and Refractory).	('BCG', 'Species', '33892', (52, 55))	('genetic alterations', 'Var', (15, 34))	('differences', 'Reg', (79, 90))	('patient', 'Species', '9606', (103, 110))
1383	28339163	Genetic alterations in RMB10 and EPHA3 were statistically more frequent in the responder category when compared patients refractory to BCG (42% vs. 10%, p-value=0.04 and 25% vs. 0%, p-value=0.02).	('Genetic alterations', 'Var', (0, 19))	('BCG', 'Species', '33892', (135, 138))	('patients', 'Species', '9606', (112, 120))	('EPHA3', 'Gene', '2042', (33, 38))	('frequent', 'Reg', (63, 71))	('RMB10', 'Gene', (23, 28))	('EPHA3', 'Gene', (33, 38))
1385	28339163	We found that alterations in Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, which included genes ARID1A, ARID1B, and SMARCA4, were more common in flat tumor architecture compared to tumors with papillary architecture (59% vs. 21%, p-value=0.03).	('alterations', 'Var', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('Sucrose', 'Chemical', 'MESH:D013395', (36, 43))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('70', '90'))	('ARID1B', 'Gene', '57492', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('ARID1A', 'Gene', '8289', (121, 127))	('flat tumor', 'Disease', (170, 180))	('SMARCA4', 'Gene', (141, 148))	('ARID1A', 'Gene', (121, 127))	('tumors', 'Disease', (206, 212))	('SMARCA4', 'Gene', '6597', (141, 148))	('common', 'Reg', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('flat tumor', 'Disease', 'MESH:D005413', (170, 180))	('ARID1B', 'Gene', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('70', '98'))
1389	28339163	We also investigated alterations associated with smoking history and found that MDM2 amplifications (0% vs 32%, p-value=0.04) were exclusively found in patients who had a history of smoking.	('MDM2', 'Gene', (80, 84))	('amplifications', 'Var', (85, 99))	('patients', 'Species', '9606', (152, 160))	('found', 'Reg', (143, 148))	('MDM2', 'Gene', '4193', (80, 84))
1393	28339163	In 3/5 patients, at least 3 mutations present in urine were completely absent in FFPE tissue, including known oncogenic mutations in PIK3CA, TERT, and SMAD3 genes.	('PIK3CA', 'Gene', (133, 139))	('PIK3CA', 'Gene', '5290', (133, 139))	('SMAD3', 'Gene', '4088', (151, 156))	('SMAD3', 'Gene', (151, 156))	('mutations', 'Var', (120, 129))	('TERT', 'Gene', (141, 145))	('TERT', 'Gene', '7015', (141, 145))	('patients', 'Species', '9606', (7, 15))
1394	28339163	Altogether, we detected 31% more mutations in urine than in FFPE tissue, indicating that urine may more effectively capture the full genetic heterogeneity of a patient's cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('patient', 'Species', '9606', (160, 167))
1401	28339163	The incidence of mutations in the TERT promoter region in our cohort is very similar to a prior report of 74% in noninvasive urothelial neoplasms.	('TERT', 'Gene', (34, 38))	('neoplasms', 'Phenotype', 'HP:0002664', (136, 145))	('TERT', 'Gene', '7015', (34, 38))	('urothelial neoplasms', 'Disease', (125, 145))	('urothelial neoplasms', 'Disease', 'MESH:D014523', (125, 145))	('mutations', 'Var', (17, 26))
1402	28339163	The lower frequencies of alterations in CDKN2A and CDKN2B observed in our cohort may be explained by differential sensitivity for detecting deletions by MSK-IMPACT and array based methods used by TCGA.	('alterations', 'Var', (25, 36))	('CDKN2B', 'Gene', '1030', (51, 57))	('CDKN2A', 'Gene', (40, 46))	('deletions', 'Var', (140, 149))	('CDKN2A', 'Gene', '1029', (40, 46))	('CDKN2B', 'Gene', (51, 57))
1403	28339163	We cannot explain why ERBB2 alterations are detected more often in our cytological samples, though it is notable that some of these mutations occur in the Furin-like cysteine rich region and the protein tyrosine kinase domain, which are commonly mutated codons in ERBB2 in UCB.	('ERBB2', 'Gene', '2064', (22, 27))	('UCB', 'Phenotype', 'HP:0006740', (273, 276))	('ERBB2', 'Gene', (22, 27))	('cysteine', 'Chemical', 'MESH:D003545', (166, 174))	('mutations', 'Var', (132, 141))	('occur', 'Reg', (142, 147))	('ERBB2', 'Gene', (264, 269))	('ERBB2', 'Gene', '2064', (264, 269))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))
1410	28339163	Unsurprisingly, RMB10 alterations have been previously associated with less aggressive urothelial carcinomas when compared to higher grade or invasive UCBs.	('aggressive urothelial carcinomas', 'Disease', (76, 108))	('aggressive urothelial carcinomas', 'Disease', 'MESH:D001523', (76, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('associated', 'Reg', (55, 65))	('UCB', 'Phenotype', 'HP:0006740', (151, 154))	('alterations', 'Var', (22, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('less', 'Disease', (71, 75))	('RMB10', 'Gene', (16, 21))
1411	28339163	Our analysis showed that the presence of RMB10 alterations was 6 times more likely in patients who responded to BCG treatment (Odds ratio=6).	('alterations', 'Var', (47, 58))	('RMB10', 'Gene', (41, 46))	('BCG', 'Species', '33892', (112, 115))	('patients', 'Species', '9606', (86, 94))
1413	28339163	EPHA3 alterations are found in 5-10% of lung adenocarcinomas, and 3% in the TCGA study of urothelial carcinomas.	('alterations', 'Var', (6, 17))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (90, 111))	('EPHA3', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('lung adenocarcinomas', 'Disease', (40, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('found', 'Reg', (22, 27))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (40, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (40, 60))	('urothelial carcinomas', 'Disease', (90, 111))	('EPHA3', 'Gene', '2042', (0, 5))
1419	28339163	who described an association of ARID1A mutation with higher stage and grade in urothelial bladder tumors leading to a worse prognosis.	('urothelial bladder tumors', 'Disease', 'MESH:D001749', (79, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('mutation', 'Var', (39, 47))	('association', 'Interaction', (17, 28))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ARID1A', 'Gene', '8289', (32, 38))	('ARID1A', 'Gene', (32, 38))	('bladder tumors', 'Phenotype', 'HP:0009725', (90, 104))	('urothelial bladder tumors', 'Disease', (79, 104))
1421	28339163	The unaltered EP300 gene is believed to have a tumor suppressor gene role in bladder cancer, thus a mutation would silence its role as tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('EP300', 'Gene', '2033', (14, 19))	('tumor', 'Disease', (135, 140))	('EP300', 'Gene', (14, 19))	('bladder cancer', 'Disease', (77, 91))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mutation', 'Var', (100, 108))	('tumor suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor suppressor', 'biological_process', 'GO:0051726', ('135', '151'))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('135', '151'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
1423	28339163	Data reported by Cazier et al strongly suggest that loss of CDKN1A function promotes the growth of bladder carcinomas and may augment defects caused by inactivation of p53.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('loss', 'Var', (52, 56))	('CDKN1A', 'Gene', (60, 66))	('augment', 'NegReg', (126, 133))	('growth', 'MPA', (89, 95))	('p53', 'Gene', '7157', (168, 171))	('CDKN1A', 'Gene', '1026', (60, 66))	('defects', 'MPA', (134, 141))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (99, 117))	('promotes', 'PosReg', (76, 84))	('bladder carcinomas', 'Disease', (99, 117))	('p53', 'Gene', (168, 171))	('bladder carcinomas', 'Disease', 'MESH:D001749', (99, 117))
1424	28339163	The correlation of the genomic results with histological features support previous findings seen in papillary lesions, our results demonstrated a strong association of FGFR3 mutation with a papillary architecture (p-value=0.02).	('FGFR3', 'Gene', '2261', (168, 173))	('mutation', 'Var', (174, 182))	('papillary architecture', 'CPA', (190, 212))	('FGFR3', 'Gene', (168, 173))	('FGFR', 'molecular_function', 'GO:0005007', ('168', '172'))	('association', 'Interaction', (153, 164))	('papillary lesions', 'Phenotype', 'HP:0007482', (100, 117))
1425	28339163	These findings are in line with prior studies using tissue sections that showed the association of FGFR3 mutations and papillary architecture in UCB.	('association', 'Interaction', (84, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('FGFR3', 'Gene', (99, 104))	('mutations', 'Var', (105, 114))	('UCB', 'Phenotype', 'HP:0006740', (145, 148))	('FGFR3', 'Gene', '2261', (99, 104))	('papillary architecture', 'CPA', (119, 141))	('UCB', 'Disease', (145, 148))
1426	28339163	FGFR3 mutations in lesions with papillary architecture were first described by Billerey et al in tissue sections from low grade papillary UCB, but more recent studies in tissue sections have demonstrated FGFR3 mutations in both low grade and high grade papillary NMIUC.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('mutations', 'Var', (210, 219))	('lesions with papillary architecture', 'Phenotype', 'HP:0007482', (19, 54))	('FGFR3', 'Gene', (0, 5))	('FGFR3', 'Gene', '2261', (204, 209))	('UCB', 'Phenotype', 'HP:0006740', (138, 141))	('FGFR', 'molecular_function', 'GO:0005007', ('204', '208'))	('FGFR3', 'Gene', (204, 209))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
1429	28339163	One associated with FGFR3 alterations and papillary architecture and another one associated with flat architecture, alterations in the TP53 pathway and/or genetic alterations in the SWIF/SNF chromatin remodeling complex.	('FGFR3', 'Gene', '2261', (20, 25))	('papillary', 'Disease', (42, 51))	('associated', 'Reg', (4, 14))	('TP53', 'Gene', '7157', (135, 139))	('FGFR3', 'Gene', (20, 25))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('191', '211'))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('191', '219'))	('alterations', 'Var', (26, 37))	('TP53', 'Gene', (135, 139))	('alterations', 'Reg', (116, 127))	('associated', 'Reg', (81, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('20', '24'))
1430	28339163	Genetic alterations in FOXL2 and PTPRS were identified only in patients with pT1 disease and were absent in all non-invasive UCB in this cohort, suggesting that they might represent markers of progression in UCB.	('Genetic alterations', 'Var', (0, 19))	('UCB', 'Phenotype', 'HP:0006740', (208, 211))	('pT1', 'Gene', '58492', (77, 80))	('FOXL2', 'Gene', (23, 28))	('PTPRS', 'Gene', '5802', (33, 38))	('PTPRS', 'Gene', (33, 38))	('patients', 'Species', '9606', (63, 71))	('pT1', 'Gene', (77, 80))	('UCB', 'Phenotype', 'HP:0006740', (125, 128))	('FOXL2', 'Gene', '668', (23, 28))
1431	28339163	Although these genetic alterations have been previously described in urinary carcinoma, their relationship with stage has not been previously reported.	('described', 'Reg', (56, 65))	('urinary carcinoma', 'Disease', (69, 86))	('urinary carcinoma', 'Disease', 'MESH:D001749', (69, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('genetic alterations', 'Var', (15, 34))
1432	28339163	Correlation of the smoking history with the genomic results showed that alterations in 3 genes, MDM2, ATM, and SMARC4, were associated with smoking status.	('alterations', 'Var', (72, 83))	('MDM2', 'Gene', '4193', (96, 100))	('ATM', 'Gene', (102, 105))	('SMARC4', 'Gene', (111, 117))	('MDM2', 'Gene', (96, 100))	('associated', 'Reg', (124, 134))	('smoking status', 'Disease', (140, 154))	('ATM', 'Gene', '472', (102, 105))
1433	28339163	MDM2 amplifications were significantly associated with a history of smoking (p-value=0.04), while ATM and SMARC4A, were significantly more associated with a non-smoking history with p values of 0.01 and 0.03, respectively.	('amplifications', 'Var', (5, 19))	('ATM', 'Gene', (98, 101))	('MDM2', 'Gene', '4193', (0, 4))	('associated', 'Reg', (39, 49))	('MDM2', 'Gene', (0, 4))	('ATM', 'Gene', '472', (98, 101))
1435	28339163	Conversely, ATM mutations were significantly more common in non-smoker patients, a finding similar to the ones seen in prior studies evaluating lung and breast carcinoma.	('ATM', 'Gene', (12, 15))	('breast carcinoma', 'Disease', 'MESH:D001943', (153, 169))	('breast carcinoma', 'Phenotype', 'HP:0003002', (153, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('patients', 'Species', '9606', (71, 79))	('mutations', 'Var', (16, 25))	('common', 'Reg', (50, 56))	('ATM', 'Gene', '472', (12, 15))	('breast carcinoma', 'Disease', (153, 169))
1436	28339163	SMARC4A, another gene in the SWI/SNF chromatin remodeling complex, mutations have been reported in 75% of small cell carcinoma of the ovary; hypercalcemic type mutations but only 3.1% of carcinomas of the urinary tract (COSMIC).	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('SMARC4A', 'Gene', (0, 7))	('carcinomas of the urinary tract', 'Phenotype', 'HP:0010786', (187, 218))	('carcinoma of the ovary; hypercalcemic type', 'Disease', (117, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('reported', 'Reg', (87, 95))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (106, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('mutations', 'Var', (67, 76))	('carcinomas', 'Disease', 'MESH:D002277', (187, 197))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('37', '65'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('37', '57'))	('carcinomas', 'Disease', (187, 197))	('carcinoma of the ovary; hypercalcemic type', 'Disease', 'MESH:D010051', (117, 159))
1437	28339163	An area for potential future investigation is the use of targeted therapy in cases of high risk NMIUC as we identified several potentially actionable genetic alterations in ERBB2, CREBBP, and FGFR3 mutations among patients with refractory disease.	('ERBB2', 'Gene', (173, 178))	('patients', 'Species', '9606', (214, 222))	('CREBBP', 'Gene', '1387', (180, 186))	('FGFR3', 'Gene', (192, 197))	('mutations', 'Var', (198, 207))	('alterations', 'Var', (158, 169))	('FGFR', 'molecular_function', 'GO:0005007', ('192', '196'))	('ERBB2', 'Gene', '2064', (173, 178))	('CREBBP', 'Gene', (180, 186))	('FGFR3', 'Gene', '2261', (192, 197))
1438	28339163	These mutations were not solely found in patients with disease refractory to BCG, but can potentially play a therapeutic role in the event of refractoriness to BCG treatment.	('BCG', 'Species', '33892', (160, 163))	('BCG', 'Species', '33892', (77, 80))	('patients', 'Species', '9606', (41, 49))	('play', 'Reg', (102, 106))	('mutations', 'Var', (6, 15))
1439	28339163	For instance, ERBB2 mutations or amplifications were found in 24% of patients with refractory disease in our series.	('refractory disease', 'Disease', (83, 101))	('found', 'Reg', (53, 58))	('ERBB2', 'Gene', '2064', (14, 19))	('ERBB2', 'Gene', (14, 19))	('amplifications', 'Var', (33, 47))	('patients', 'Species', '9606', (69, 77))	('mutations', 'Var', (20, 29))
1444	28339163	Additionally, the presence of genomic alterations in the DNA repair-associated genes ATM and RB1, might predict response with cisplatin-based chemotherapy as demonstrated in muscle invasive bladder carcinomas by Plimack et al.	('presence', 'Var', (18, 26))	('predict', 'Reg', (104, 111))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (190, 208))	('ATM', 'Gene', (85, 88))	('invasive bladder', 'Phenotype', 'HP:0100645', (181, 197))	('RB1', 'Gene', (93, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('DNA repair', 'biological_process', 'GO:0006281', ('57', '67'))	('RB1', 'Gene', '5925', (93, 96))	('muscle invasive bladder carcinomas', 'Phenotype', 'HP:0006740', (174, 208))	('carcinomas', 'Phenotype', 'HP:0030731', (198, 208))	('ATM', 'Gene', '472', (85, 88))	('genomic alterations', 'Var', (30, 49))	('muscle invasive bladder carcinomas', 'Disease', 'MESH:D001749', (174, 208))	('muscle invasive bladder carcinomas', 'Disease', (174, 208))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))
1455	20939013	Pten, p27, phosAkt, phosS6 and 4E-BP1 expression correlated with pathologic stage (pT; p<0.03).	('Akt', 'Gene', '207', (15, 18))	('4E-BP1', 'Gene', (31, 37))	('correlated', 'Reg', (49, 59))	('phosS6', 'Chemical', '-', (20, 26))	('phosS6', 'Var', (20, 26))	('Pten', 'Gene', '5728', (0, 4))	('p27', 'Gene', (6, 9))	('Akt', 'Gene', (15, 18))	('4E-BP1', 'Gene', '1978', (31, 37))	('p27', 'Gene', '1027', (6, 9))	('Pten', 'Gene', (0, 4))
1459	20939013	In a multivariate analysis model that included: TNM stage grouping, divergent aggressive histology, concomitant CIS, phosS6 and c-Myc expression; phosS6 was an independent predictor of DSS (p=0.03; HR: -.19) while c-Myc was an independent predictor of progression (p=0.02; HR:-.38).	('c-Myc', 'Gene', '4609', (214, 219))	('c-Myc', 'Gene', '4609', (128, 133))	('phosS6', 'Chemical', '-', (117, 123))	('TNM', 'Gene', '10178', (48, 51))	('c-Myc', 'Gene', (128, 133))	('phosS6', 'Chemical', '-', (146, 152))	('TNM', 'Gene', (48, 51))	('DSS', 'Gene', (185, 188))	('c-Myc', 'Gene', (214, 219))	('DSS', 'Gene', '5376', (185, 188))	('phosS6', 'Var', (146, 152))
1460	20939013	In a second model substituting organ confined disease and lymph node status for TNM stage grouping, phosS6 and c-Myc remained independent predictors of DSS (p=0.03; HR: -.21) and progression (p=0.03; HR:-.34), respectively.	('TNM', 'Gene', (80, 83))	('c-Myc', 'Gene', '4609', (111, 116))	('DSS', 'Gene', '5376', (152, 155))	('c-Myc', 'Gene', (111, 116))	('phosS6', 'Chemical', '-', (100, 106))	('phosS6', 'Var', (100, 106))	('TNM', 'Gene', '10178', (80, 83))	('DSS', 'Gene', (152, 155))
1461	20939013	PhosS6 independently predicted DSS and c-Myc independently predicted progression.	('PhosS6', 'Var', (0, 6))	('predicted', 'Reg', (21, 30))	('c-Myc', 'Gene', '4609', (39, 44))	('DSS', 'Gene', (31, 34))	('c-Myc', 'Gene', (39, 44))	('DSS', 'Gene', '5376', (31, 34))
1463	20939013	While superficial papillary neoplasms are driven by gain-of-function mutations in oncogenes such as H-RAS and FGFR3, flat carcinoma in situ and muscle-invasive tumors usually carry loss-of-function mutations, affecting tumor suppressor genes such as p53 and phosphatase and tensine homologue (PTEN).	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (144, 166))	('tumor', 'Disease', (219, 224))	('FGFR', 'molecular_function', 'GO:0005007', ('110', '114'))	('muscle-invasive tumors', 'Disease', (144, 166))	('neoplasms', 'Phenotype', 'HP:0002664', (28, 37))	('papillary neoplasms', 'Disease', 'MESH:D002291', (18, 37))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('FGFR3', 'Gene', (110, 115))	('H-RAS', 'Gene', (100, 105))	('phosphatase', 'molecular_function', 'GO:0016791', ('258', '269'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('219', '235'))	('FGFR3', 'Gene', '2261', (110, 115))	('H-RAS', 'Gene', '3265', (100, 105))	('gain-of-function', 'PosReg', (52, 68))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (122, 139))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('mutations', 'Var', (69, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('219', '235'))	('tumor', 'Disease', (160, 165))	('flat carcinoma in situ', 'Disease', (117, 139))	('papillary neoplasms', 'Disease', (18, 37))	('PTEN', 'Gene', (293, 297))	('loss-of-function', 'NegReg', (181, 197))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('p53', 'Gene', (250, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('flat carcinoma in situ', 'Disease', 'MESH:D002278', (117, 139))
1464	20939013	Inactivation of PTEN tumor suppressor gene triggers the phosphatidil inositil-3 kinase (PI3K)-protein kinase B (AKT) pathway that leads to Akt phosphorylation and activation (phos Akt).	('phosphatidil inositil-3 kinase', 'Gene', '5294', (56, 86))	('activation', 'PosReg', (163, 173))	('Akt', 'Gene', '207', (139, 142))	('tumor', 'Disease', (21, 26))	('tumor suppressor', 'biological_process', 'GO:0051726', ('21', '37'))	('phosphorylation', 'MPA', (143, 158))	('Akt', 'Gene', (180, 183))	('Akt', 'Gene', (139, 142))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))	('phosphatidil inositil-3 kinase', 'Gene', (56, 86))	('PI3K', 'molecular_function', 'GO:0016303', ('88', '92'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('21', '37'))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('phosphorylation', 'biological_process', 'GO:0016310', ('143', '158'))	('Akt', 'Gene', '207', (180, 183))	('Inactivation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
1466	20939013	The current study evaluates the expression status and reciprocal interplay of six of the above biomarkers (Pten, phos Akt, phos S6, 4E-BP1, p27 and c-Myc) aiming to be the first to evaluate mTOR pathway status as it relates to outcome in a well characterized uniform cohort of UrCa treated by cystectomy.	('Pten', 'Gene', '5728', (107, 111))	('c-Myc', 'Gene', '4609', (148, 153))	('4E-BP1', 'Gene', (132, 138))	('p27', 'Gene', (140, 143))	('Akt', 'Gene', (118, 121))	('c-Myc', 'Gene', (148, 153))	('p27', 'Gene', '1027', (140, 143))	('UrCa', 'Disease', (277, 281))	('4E-BP1', 'Gene', '1978', (132, 138))	('Akt', 'Gene', '207', (118, 121))	('phos', 'Var', (123, 127))	('Pten', 'Gene', (107, 111))
1484	20939013	During multivariate analysis, a cut-off was used for phos S6 expression based on mean tumor H-score (H-score >= 27) and for c-MYC expression based on the 90th percentile tumor H-score (H-score >= 15).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('expression', 'MPA', (130, 140))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', (86, 91))	('c-MYC', 'Gene', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('expression', 'MPA', (61, 71))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('c-MYC', 'Gene', '4609', (124, 129))	('phos', 'Var', (53, 57))
1530	20939013	Among all six tested biomarkers, phos S6 was a significant predictor of DSS (p=0.001), OS (p=0.01) and disease progression (p=0.05) while c-Myc expression was a significant predictor of disease progression (p=0.01) but not of DSS or OS (p=NS) on univariate analysis (see Table 4).	('DSS', 'Gene', '5376', (72, 75))	('disease progression', 'CPA', (103, 122))	('c-Myc', 'Gene', '4609', (138, 143))	('c-Myc', 'Gene', (138, 143))	('DSS', 'Gene', (226, 229))	('DSS', 'Gene', '5376', (226, 229))	('phos S6', 'Var', (33, 40))	('DSS', 'Gene', (72, 75))
1531	20939013	In the first of two multivariate analysis models that included: TNM stage grouping, presence of divergent aggressive histology, concomitant CIS, phosS6 and c-Myc expression, phosS6 was an independent predictor of DSS (p=0.03; HR: -.19) while c-Myc was an independent predictor of progression (p=0.02; HR:-.38).	('phosS6', 'Chemical', '-', (174, 180))	('phosS6', 'Var', (174, 180))	('DSS', 'Gene', (213, 216))	('TNM', 'Gene', (64, 67))	('c-Myc', 'Gene', '4609', (242, 247))	('phosS6', 'Chemical', '-', (145, 151))	('c-Myc', 'Gene', '4609', (156, 161))	('DSS', 'Gene', '5376', (213, 216))	('c-Myc', 'Gene', (242, 247))	('c-Myc', 'Gene', (156, 161))	('TNM', 'Gene', '10178', (64, 67))
1535	20939013	The main downstream effectors of mTOR pathway (phos S6 and 4E-BP1) have been shown to be independent predictors of prognosis in several types of solid tumors including renal cell, ovarian, liver and mammary carcinomas.	('mTOR pathway', 'Pathway', (33, 45))	('4E-BP1', 'Gene', (59, 65))	('phos S6', 'Var', (47, 54))	('solid tumors', 'Disease', 'MESH:D009369', (145, 157))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (199, 216))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('liver', 'Disease', (189, 194))	('ovarian', 'Disease', (180, 187))	('4E-BP1', 'Gene', '1978', (59, 65))	('renal cell', 'Disease', (168, 178))	('solid tumors', 'Disease', (145, 157))	('carcinomas', 'Phenotype', 'HP:0030731', (207, 217))	('carcinomas', 'Disease', (207, 217))	('carcinomas', 'Disease', 'MESH:D002277', (207, 217))
1539	20939013	However, Yoo et al, using a mouse model that conditionally deletes PTEN in urogential epithelium, found AKT/mTOR pathway highly activated in prostate tumors, but not in bladder epithelium.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('AKT/mTOR pathway', 'Pathway', (104, 120))	('prostate tumors', 'Disease', 'MESH:D011471', (141, 156))	('mouse', 'Species', '10090', (28, 33))	('activated', 'PosReg', (128, 137))	('deletes', 'Var', (59, 66))	('PTEN', 'Gene', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('prostate tumors', 'Disease', (141, 156))
1555	20939013	In addition to promoting translation, phos S6 is recognized to repress PIK3-AKT pathway through the inhibition of insulin receptor substrates 1 and 2 (IRS1/IRS2).	('IRS1', 'Gene', (151, 155))	('PIK3', 'Gene', '5294', (71, 75))	('insulin', 'molecular_function', 'GO:0016088', ('114', '121'))	('IRS2', 'Gene', '8660', (156, 160))	('insulin receptor substrates 1 and 2', 'Gene', '3667;8660', (114, 149))	('repress', 'NegReg', (63, 70))	('phos S6', 'Var', (38, 45))	('promoting', 'PosReg', (15, 24))	('IRS1', 'Gene', '3667', (151, 155))	('IRS2', 'Gene', (156, 160))	('translation', 'biological_process', 'GO:0006412', ('25', '36'))	('PIK3', 'Gene', (71, 75))	('translation', 'MPA', (25, 36))	('inhibition', 'NegReg', (100, 110))
1556	20939013	Accordingly, we found phos S6 expression, but not 4E-BP1 to correlate with other AKT-regulated members: p27 and c-Myc.	('4E-BP1', 'Gene', (50, 56))	('c-Myc', 'Gene', '4609', (112, 117))	('p27', 'Gene', (104, 107))	('p27', 'Gene', '1027', (104, 107))	('c-Myc', 'Gene', (112, 117))	('phos S6', 'Var', (22, 29))	('4E-BP1', 'Gene', '1978', (50, 56))
1557	20939013	In fact, the strongest correlation among pathway members was between c-Myc and phos S6.	('correlation', 'Interaction', (23, 34))	('c-Myc', 'Gene', (69, 74))	('phos', 'Var', (79, 83))	('c-Myc', 'Gene', '4609', (69, 74))
1558	20939013	Furthermore, high c-Myc expression was an independent predictor of disease progression in our cohort.	('high', 'Var', (13, 17))	('c-Myc', 'Gene', (18, 23))	('c-Myc', 'Gene', '4609', (18, 23))
1561	20939013	Unlike some of the prior studies on p27 in UrCa, we did not find loss of p27 expression to be an unfavorable predictor of disease progression or DSS.	('expression', 'MPA', (77, 87))	('loss', 'Var', (65, 69))	('p27', 'Gene', (36, 39))	('p27', 'Gene', (73, 76))	('DSS', 'Gene', (145, 148))	('p27', 'Gene', '1027', (73, 76))	('DSS', 'Gene', '5376', (145, 148))	('p27', 'Gene', '1027', (36, 39))
1563	20939013	Interestingly, recent studies have pointed to a favorable effect on outcome for loss of p27 in UrCa especially in combination with other cell cycle markers.	('p27', 'Gene', '1027', (88, 91))	('loss', 'Var', (80, 84))	('UrCa', 'Disease', (95, 99))	('cell cycle', 'biological_process', 'GO:0007049', ('137', '147'))	('p27', 'Gene', (88, 91))
1566	20939013	Our intriguing novel findings of a statistically significant prognostic role for phos S6 and c-Myc in a multivariate model that included established clincopathologic prognostic parameters are promising and certainly warrant further confirmation in an independent cystectomy cohort, preferably in a prospective setting and in combination with cell cycle markers evaluation.	('c-Myc', 'Gene', '4609', (93, 98))	('c-Myc', 'Gene', (93, 98))	('significant', 'Reg', (49, 60))	('cell cycle', 'biological_process', 'GO:0007049', ('342', '352'))	('phos S6', 'Var', (81, 88))
1592	33291319	The vast majority of tRFs (~15-30 nt) are generated through Dicer-mediated cleavage of mature tRNAs within: (a) the D-loop and the anticodon stem, towards 5'-tRFs (harboring the 5'-end of tRNAs), (b) the TpsiC-loop, towards 3'-tRFs (harboring the 3'-end of tRNAs), and (c) internal sites, producing inter-tRFs (i-tRFs).	('TpsiC-loop', 'Disease', (204, 214))	('tRF', 'Gene', '7013', (313, 316))	('tRF', 'Gene', (305, 308))	('tRF', 'Gene', '7013', (227, 230))	('tRF', 'Gene', '7013', (21, 24))	('tRF', 'Gene', (158, 161))	('Dicer', 'Gene', '23405', (60, 65))	('Dicer', 'Gene', (60, 65))	('tRF', 'Gene', (21, 24))	('tRF', 'Gene', '7013', (305, 308))	('tRF', 'Gene', (313, 316))	('tRF', 'Gene', (227, 230))	('TpsiC-loop', 'Disease', 'MESH:D001765', (204, 214))	('cleavage', 'Var', (75, 83))	('tRF', 'Gene', '7013', (158, 161))
1668	33291319	Moreover, in the NMIBC cohort, higher 5'-tRF-LysCTT was observed in patients harboring T1HG compared with Ta and T1LG tumors, in EORTC high-risk patients as well as in TaT1 patients exhibiting recurrence at the FFC.	('patients', 'Species', '9606', (145, 153))	('TaT1', 'Gene', '117247', (168, 172))	('patients', 'Species', '9606', (173, 181))	('T1HG', 'Var', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('NMIBC', 'Chemical', '-', (17, 22))	('patients', 'Species', '9606', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('TaT1', 'Gene', (168, 172))	('tRF', 'Gene', (41, 44))	('tumors', 'Disease', (118, 124))	('tRF', 'Gene', '7013', (41, 44))	('higher', 'PosReg', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
1676	33291319	In the first studies of the role of tRFs in cancer progression, tRF-1001 (3'-tRF of tRNASerTGA) was correlated with increased cell proliferation, while tRF-1001 knockdown resulted in cell cycle arrest and accumulation of tumor cells in the G2 phase in prostate cancer cells.	('tRF', 'Gene', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('G2 phase', 'biological_process', 'GO:0051319', ('240', '248'))	('tRF', 'Gene', '7013', (36, 39))	('cell proliferation', 'biological_process', 'GO:0008283', ('126', '144'))	('increased', 'PosReg', (116, 125))	('tRF', 'Gene', (36, 39))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('knockdown', 'Var', (161, 170))	('cancer', 'Disease', (261, 267))	('arrest', 'Disease', (194, 200))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (183, 200))	('cell proliferation', 'CPA', (126, 144))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('tumor', 'Disease', (221, 226))	('tRF', 'Gene', '7013', (152, 155))	('prostate cancer', 'Disease', 'MESH:D011471', (252, 267))	('accumulation', 'PosReg', (205, 217))	('tRF', 'Gene', '7013', (64, 67))	('tRF-1001', 'Disease', 'None', (152, 160))	('prostate cancer', 'Phenotype', 'HP:0012125', (252, 267))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tRF', 'Gene', (152, 155))	('tRF-1001', 'Disease', 'None', (64, 72))	('tRF-1001', 'Disease', (152, 160))	('prostate cancer', 'Disease', (252, 267))	('arrest', 'Disease', 'MESH:D006323', (194, 200))	('tRF', 'Gene', (64, 67))	('cancer', 'Disease', (44, 50))	('tRF-1001', 'Disease', (64, 72))	('tRF', 'Gene', '7013', (77, 80))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('183', '200'))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
1678	33291319	highlighted that endogenous tRFs suppress breast cancer progression via displacement of YBX1, while the CU1276 (3'-tRF of from tRNAGlyGCC), which is significantly downregulated in lymphoma cell lines, was documented to suppress lymphoma cells' proliferation.	('YBX1', 'Gene', (88, 92))	('lymphoma', 'Disease', (180, 188))	('lymphoma', 'Disease', 'MESH:D008223', (180, 188))	('YBX1', 'Gene', '4904', (88, 92))	('lymphoma', 'Disease', (228, 236))	('tRF', 'Gene', '7013', (28, 31))	('lymphoma', 'Disease', 'MESH:D008223', (228, 236))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tRF', 'Gene', '7013', (115, 118))	('suppress', 'NegReg', (33, 41))	('tRF', 'Gene', (28, 31))	('CU1276', 'Var', (104, 110))	('tRF', 'Gene', (115, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('men', 'Species', '9606', (80, 83))	('lymphoma', 'Phenotype', 'HP:0002665', (180, 188))	('lymphoma', 'Phenotype', 'HP:0002665', (228, 236))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Disease', (42, 55))	('men', 'Species', '9606', (209, 212))	('suppress', 'NegReg', (219, 227))
1745	33402880	We observed that underweight was associated with inferior CSS (HR = 1.87, 95% CI: 1.54-2.26) in UTUC patients.	('patients', 'Species', '9606', (101, 109))	('inferior CSS', 'Disease', (49, 61))	('underweight', 'Var', (17, 28))
1789	33402880	revealed that both underweight and obesity were associated with inferior stage-specific survival in patients with small-cell lung cancer and non-small-cell lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('inferior', 'NegReg', (64, 72))	('obesity', 'Phenotype', 'HP:0001513', (35, 42))	('age', 'Gene', '5973', (75, 78))	('non-small-cell lung cancer', 'Disease', (141, 167))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (141, 167))	('underweight', 'Var', (19, 30))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (145, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('patients', 'Species', '9606', (100, 108))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (114, 136))	('obesity', 'Disease', 'MESH:D009765', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('age', 'Gene', (75, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('small-cell lung cancer', 'Disease', (114, 136))	('obesity', 'Disease', (35, 42))
1800	33402880	The results of our meta-analysis showed that overweight was associated with better CSS and RFS in UC patients treated with radical surgeries.	('patients', 'Species', '9606', (101, 109))	('overweight', 'Var', (45, 55))	('CSS', 'CPA', (83, 86))	('RFS', 'CPA', (91, 94))	('better', 'PosReg', (76, 82))	('overweight', 'Phenotype', 'HP:0025502', (45, 55))
1823	33033240	Interestingly, although the batch effect has been previously removed, cancer cells still showed a patient-specific expression pattern, which indicated extremely high heterogeneity that was probably caused by copy number variations (CNVs); this assumption was confirmed by InferCNV (Fig.	('patient', 'Species', '9606', (98, 105))	('copy number variations', 'Var', (208, 230))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('high heterogeneity', 'MPA', (161, 179))	('caused', 'Reg', (198, 204))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
1825	33033240	Despite the heterogeneity, almost all high-grade cancer cells possessed deletions from chromosomes 9 and 11 and amplifications in chromosomes 19 and 20.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('deletions', 'Var', (72, 81))
1831	33033240	In the TCGA BLCA cohort, a high level of IGF2 was significantly related to poor prognosis (Supplementary Fig.	('IGF2', 'Gene', (41, 45))	('IGF2', 'Gene', '3481', (41, 45))	('related', 'Reg', (64, 71))	('high level', 'Var', (27, 37))
1842	33033240	In the TCGA BLCA cohort, the LAMP3+ DC signature was highly positively correlated with the Treg signature and Th2 signature, which were both CCR4+, but there was not a high correlation with the CTL signature (Fig.	('Treg', 'MPA', (91, 95))	('LAMP3+', 'Var', (29, 35))	('Treg', 'Chemical', '-', (91, 95))	('Th2', 'Chemical', '-', (110, 113))	('CCR', 'molecular_function', 'GO:0043880', ('141', '144'))	('correlated', 'Interaction', (71, 81))	('Th2', 'MPA', (110, 113))
1843	33033240	LAMP3+ DCs were significantly enriched in tumor tissues (Supplementary Fig.	('LAMP3+ DCs', 'Var', (0, 10))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
1846	33033240	SCENIC analysis revealed that RELB and KDM2B motifs were highly activated in LAMP3+ DCs (Supplementary Fig.	('RELB', 'Gene', '5971', (30, 34))	('activated', 'PosReg', (64, 73))	('KDM2B', 'Gene', '84678', (39, 44))	('KDM2B', 'Gene', (39, 44))	('RELB', 'Gene', (30, 34))	('LAMP3+ DCs', 'Var', (77, 87))
1905	33033240	We found that LAMP3+ DCs were related to the recruitment of Tregs and other CCR4+ immune cells.	('LAMP3+', 'Var', (14, 20))	('related', 'Reg', (30, 37))	('recruitment', 'CPA', (45, 56))	('CCR', 'molecular_function', 'GO:0043880', ('76', '79'))	('Tregs', 'Chemical', '-', (60, 65))	('Tregs', 'CPA', (60, 65))
1939	33033240	The InferCNV package was used to detect the CNVs in EPCAM+ cells and to recognize real cancer cells with default parameters.	('EPCAM', 'Gene', '4072', (52, 57))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CNVs', 'Var', (44, 48))	('EPCAM', 'Gene', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
1952	33033240	The following antibodies were used: anti-CD31 (mouse, 1:300, BD, 566563), anti-CD45 (mouse, 1:100, BD, 555482), and anti-PDGFRA (mouse, 1:500, BD, 562799).	('mouse', 'Species', '10090', (85, 90))	('CD3', 'Gene', (41, 44))	('anti-PDGFRA', 'Var', (116, 127))	('anti-CD45', 'Var', (74, 83))	('CD3', 'Gene', '12501', (41, 44))	('mouse', 'Species', '10090', (129, 134))	('mouse', 'Species', '10090', (47, 52))
1966	32648580	In breast invasive carcinoma (BRCA) and liver hepatocellular carcinoma (LIHC), high YIF1B expression correlated with a poor disease-free interval (DFI), indicating a role in malignancy progression.	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (40, 70))	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('BRCA', 'Gene', (30, 34))	('malignancy', 'Disease', (174, 184))	('YIF1B', 'Gene', '90522', (84, 89))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (3, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('breast invasive carcinoma', 'Disease', (3, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (46, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('YIF1B', 'Gene', (84, 89))	('expression', 'MPA', (90, 100))	('high', 'Var', (79, 83))	('disease-free', 'MPA', (124, 136))	('liver hepatocellular carcinoma', 'Disease', (40, 70))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (3, 28))	('BRCA', 'Phenotype', 'HP:0003002', (30, 34))	('BRCA', 'Gene', '672', (30, 34))
2006	32648580	The following survival analyses, using patient data dichotomized for the median expression value in each cancer type (Figure 3), show that survival differences were all significant in OS-related cancer types, and that patients with high expression of YIF1B had worse outcomes (Figure 3).	('significant', 'Reg', (169, 180))	('patient', 'Species', '9606', (39, 46))	('YIF1B', 'Gene', (251, 256))	('patient', 'Species', '9606', (218, 225))	('patients', 'Species', '9606', (218, 226))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('YIF1B', 'Gene', '90522', (251, 256))	('high expression', 'Var', (232, 247))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
2010	32648580	In the following survival analysis, cancer types with high YIF1B expression again exhibited a worse prognosis in comparison with the low expression groups (Figure 5).	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('YIF1B', 'Gene', (59, 64))	('high', 'Var', (54, 58))	('cancer', 'Disease', (36, 42))	('YIF1B', 'Gene', '90522', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
2020	32648580	Their corresponding linear regression graphs show that high YIF1B expression is linked to a possible increased infiltration level by immune cells.	('infiltration level by immune cells', 'MPA', (111, 145))	('increased', 'PosReg', (101, 110))	('expression', 'MPA', (66, 76))	('YIF1B', 'Gene', '90522', (60, 65))	('high', 'Var', (55, 59))	('YIF1B', 'Gene', (60, 65))
2030	32648580	The coefficient values would indicate that YIF1B expression positively correlates with high mutation status in COAD, BLCA and LIHC, but low mutation in THYM, LAML and ESCA (particularly THYM).	('COAD', 'Disease', 'MESH:D029424', (111, 115))	('THYM', 'Phenotype', 'HP:0100522', (152, 156))	('YIF1B', 'Gene', '90522', (43, 48))	('COAD', 'Disease', (111, 115))	('high mutation status', 'Var', (87, 107))	('THYM', 'Phenotype', 'HP:0100522', (186, 190))	('YIF1B', 'Gene', (43, 48))	('ESCA', 'Phenotype', 'HP:0011459', (167, 171))
2036	32648580	Having established a correlation between YIF1B expression and the mutation indicators, TMB and MSI, further investigation of links between YIF1B expression and tumorigenesis mechanisms was warranted, in particular a relationship with MMR defects and methylation of specific tumor suppression genes.	('MMR defects', 'Disease', (234, 245))	('MMR defects', 'Disease', 'MESH:C536928', (234, 245))	('YIF1B', 'Gene', '90522', (139, 144))	('MMR', 'biological_process', 'GO:0006298', ('234', '237'))	('YIF1B', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('methylation', 'biological_process', 'GO:0032259', ('250', '261'))	('TMB', 'Chemical', '-', (87, 90))	('YIF1B', 'Gene', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('tumor', 'Disease', (160, 165))	('methylation', 'Var', (250, 261))	('YIF1B', 'Gene', '90522', (41, 46))
2046	32648580	In follow-on survival analysis, after dichotomizing patients according to their mean YIF1B expression value, patients in the high expression group had worse OS, which is consistent with in the results obtained using TCGA data (Supplementary Figure S1).	('YIF1B', 'Gene', (85, 90))	('patients', 'Species', '9606', (109, 117))	('YIF1B', 'Gene', '90522', (85, 90))	('high', 'Var', (125, 129))	('patients', 'Species', '9606', (52, 60))
2051	32648580	A correlation with disease progression rates was identified for LIHC and BRCA, for which patients with high YIF1B expression suffered from early recurrence of tumor.	('BRCA', 'Phenotype', 'HP:0003002', (73, 77))	('BRCA', 'Gene', '672', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('BRCA', 'Gene', (73, 77))	('YIF1B', 'Gene', (108, 113))	('tumor', 'Disease', (159, 164))	('LIHC', 'Disease', (64, 68))	('patients', 'Species', '9606', (89, 97))	('high', 'Var', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('expression', 'MPA', (114, 124))	('YIF1B', 'Gene', '90522', (108, 113))
2053	32648580	Previous research has shown that YIF1B is involved in anterograde vesicle traffic in cells, transporting 'cargo' proteins (including the serotonin receptor HTR1A) from the endoplasmic reticulum to the cell membrane via the Golgi apparatus; such cell membrane localization being accelerated upon knocking out YIF1B in HeLa cells.	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('172', '193'))	('vesicle', 'cellular_component', 'GO:0031982', ('66', '73'))	('YIF1B', 'Gene', '90522', (33, 38))	('cell membrane', 'cellular_component', 'GO:0005886', ('201', '214'))	('cell membrane', 'cellular_component', 'GO:0005886', ('245', '258'))	('cargo', 'molecular_function', 'GO:0140355', ('106', '111'))	('YIF1B', 'Gene', '90522', (308, 313))	('Golgi apparatus', 'cellular_component', 'GO:0005794', ('223', '238'))	("transporting 'cargo' proteins", 'MPA', (92, 121))	('serotonin', 'Chemical', 'MESH:D012701', (137, 146))	('knocking out', 'Var', (295, 307))	('YIF1B', 'Gene', (33, 38))	('localization', 'biological_process', 'GO:0051179', ('259', '271'))	('HTR1A', 'Gene', '3350', (156, 161))	('YIF1B', 'Gene', (308, 313))	('accelerated', 'PosReg', (278, 289))	('HeLa', 'CellLine', 'CVCL:0030', (317, 321))	('HTR1A', 'Gene', (156, 161))
2056	32648580	A link to signaling pathways via HTR receptors is the likely reason for association of YIF1B mutations with functional changes to specific proteins in neuronal cells, causing encephalopathy, epilepsy and movement disorder.	('HTR', 'Gene', (33, 36))	('signaling', 'biological_process', 'GO:0023052', ('10', '19'))	('movement disorder', 'Phenotype', 'HP:0100022', (204, 221))	('mutations', 'Var', (93, 102))	('specific proteins', 'MPA', (130, 147))	('YIF1B', 'Gene', (87, 92))	('link', 'Reg', (2, 6))	('association', 'Interaction', (72, 83))	('epilepsy and movement disorder', 'Disease', 'MESH:D004827', (191, 221))	('encephalopathy', 'Disease', 'MESH:D001927', (175, 189))	('epilepsy', 'Phenotype', 'HP:0001250', (191, 199))	('HTR', 'Gene', '7012', (33, 36))	('encephalopathy', 'Phenotype', 'HP:0001298', (175, 189))	('YIF1B', 'Gene', '90522', (87, 92))	('causing', 'Reg', (167, 174))	('encephalopathy', 'Disease', (175, 189))
2071	32648580	Furthermore, COAD patients with high MSI have demonstrated better checkpoint inhibitor responses and survival in both low and high clinical stages.	('COAD', 'Disease', (13, 17))	('high MSI', 'Var', (32, 40))	('better', 'PosReg', (59, 65))	('COAD', 'Disease', 'MESH:D029424', (13, 17))	('checkpoint inhibitor responses', 'MPA', (66, 96))	('patients', 'Species', '9606', (18, 26))	('survival', 'CPA', (101, 109))
2083	32648580	For example, protein activity might be affected in normal or cancer cells by post-transcription modification and/or regulated proteolysis.	('regulated proteolysis', 'MPA', (116, 137))	('proteolysis', 'biological_process', 'GO:0006508', ('126', '137'))	('affected', 'Reg', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('post-transcription modification', 'Var', (77, 108))	('cancer', 'Disease', (61, 67))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('transcription', 'biological_process', 'GO:0006351', ('82', '95'))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('activity', 'MPA', (21, 29))	('protein', 'Protein', (13, 20))
2094	32101536	Individualized genetic network analysis reveals new therapeutic vulnerabilities in 6,700 cancer genomes Tumor-specific genomic alterations allow systematic identification of genetic interactions that promote tumorigenesis and tumor vulnerabilities, offering novel strategies for development of targeted therapies for individual patients.	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('interactions', 'Interaction', (182, 194))	('patients', 'Species', '9606', (328, 336))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('Tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Disease', (89, 95))	('tumor', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('alterations', 'Var', (127, 138))	('promote', 'PosReg', (200, 207))	('tumor', 'Disease', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
2098	32101536	By analyzing drug pharmacogenomics profiles from the Genomics of Drug Sensitivity in Cancer database, we show that the network-predicted putative genetic interactions (e.g., BRCA2-TP53) are significantly correlated with sensitivity/resistance of multiple therapeutic agents.	('sensitivity/resistance', 'CPA', (220, 242))	('correlated', 'Reg', (204, 214))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (65, 81))	('Cancer', 'Disease', (85, 91))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('BRCA2-TP53', 'Gene', (174, 184))	('Cancer', 'Disease', 'MESH:D009369', (85, 91))	('interactions', 'Var', (154, 166))	('BRCA2-TP53', 'Gene', '7157;675', (174, 184))	('BRCA', 'Phenotype', 'HP:0003002', (174, 178))
2103	32101536	Tumor-specific genomic alterations derived from multi-center cancer genome projects allow identification of genetic interactions that promote tumor vulnerabilities, offering novel strategies for development of targeted cancer therapies.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('promote', 'PosReg', (134, 141))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('alterations', 'Var', (23, 34))	('cancer', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('multi-center cancer', 'Disease', (48, 67))	('multi-center cancer', 'Disease', 'MESH:D009369', (48, 67))
2107	32101536	By analyzing drug pharmacogenomics profiles, we showed that the network-predicted putative genetic interactions (e.g., BRCA2-TP53) were significantly correlated with sensitivity/resistance of anticancer drugs (e.g., afatinib) and we experimentally validated it in breast cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('afatinib', 'Chemical', 'MESH:D000077716', (216, 224))	('interactions', 'Var', (99, 111))	('sensitivity/resistance', 'MPA', (166, 188))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('breast cancer', 'Disease', 'MESH:D001943', (264, 277))	('BRCA2-TP53', 'Gene', (119, 129))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('breast cancer', 'Disease', (264, 277))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('cancer', 'Disease', (196, 202))	('correlated', 'Reg', (150, 160))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('BRCA2-TP53', 'Gene', '7157;675', (119, 129))	('BRCA', 'Phenotype', 'HP:0003002', (119, 123))	('cancer', 'Disease', (271, 277))	('genetic interactions', 'Var', (91, 111))
2111	32101536	Several multi-center cancer exome/genome projects, such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), have significantly improved our understanding of the landscape of somatic alterations that promote tumorigenesis and tumor evolution.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('multi-center cancer', 'Disease', (8, 27))	('Cancer', 'Disease', (112, 118))	('promote', 'PosReg', (236, 243))	('Cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Disease', (244, 249))	('multi-center cancer', 'Disease', 'MESH:D009369', (8, 27))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', (262, 267))	('Cancer', 'Disease', 'MESH:D009369', (63, 69))	('Cancer', 'Disease', (63, 69))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('alterations', 'Var', (219, 230))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (262, 267))
2113	32101536	Somatic alterations identified in tumor exomes/genomes are commonly grouped into two classes: gain-of-function mutations on oncogenes and loss-of-function mutations on tumor suppressor genes (TSGs).	('mutations', 'Var', (111, 120))	('oncogenes', 'Protein', (124, 133))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (168, 173))	('mutations', 'Var', (155, 164))	('tumor suppressor', 'biological_process', 'GO:0051726', ('168', '184'))	('loss-of-function', 'NegReg', (138, 154))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('168', '184'))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('gain-of-function', 'PosReg', (94, 110))
2117	32101536	A synthetic lethal interaction occurring between a tumor-specific somatic mutation and a gene that drives tumorigenesis and tumor progression offers an ideal therapeutic target in cancer.	('mutation', 'Var', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cancer', 'Disease', (180, 186))	('tumor', 'Disease', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
2122	32101536	For example, several computational approaches, such as MEMo and WeSME, were reported to identify mutually exclusive mutations in cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (116, 125))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))
2126	32101536	We computationally identified hundreds of new putative genetic interactions in multiple cancer types via INCM.	('cancer', 'Disease', (88, 94))	('genetic', 'Var', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))
2131	32101536	Previous studies have shown that gene pairs with high co-mutation rate in cancer populations and with the closest network topological distance in the human protein-protein interactome can have high likelihood to promote tumorigenesis and anticancer drug responses.	('human', 'Species', '9606', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('tumor', 'Disease', (220, 225))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('promote', 'PosReg', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('co-mutation', 'Var', (54, 65))
2158	32101536	We found that genes in the INCM-predicted putative genetic interactions were enriched to be in the CGC gene set (P < 0.01) across all 14 cancer types, in SMGs across 12 cancer types with the exception of BLCA and OV, in the DDR genes across 12 cancer types with the exception of PRAD and SKCM, and in the CRF genes across 8 cancer types with the exception of BLCA, BRCA, COAD, GBM, LAML and OV (Fig 3C and 3D).	('cancer', 'Disease', (169, 175))	('OV', 'Phenotype', 'HP:0012887', (391, 393))	('DDR', 'Gene', (224, 227))	('interactions', 'Var', (59, 71))	('COAD', 'Disease', 'MESH:D029424', (371, 375))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('BRCA', 'Gene', (365, 369))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('OV', 'Phenotype', 'HP:0012887', (213, 215))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Disease', (324, 330))	('COAD', 'Disease', (371, 375))	('BRCA', 'Phenotype', 'HP:0003002', (365, 369))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('CGC', 'Gene', (99, 102))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('BRCA', 'Gene', '672', (365, 369))	('cancer', 'Disease', 'MESH:D009369', (324, 330))
2166	32101536	Fig 4C reveals that melanoma patients harboring nonsynonymous somatic mutations on BACH2-KRAS have poor survival rate compared with the wild-type group (P = 0.001, log-rank test).	('patients', 'Species', '9606', (29, 37))	('BACH2', 'Gene', '60468', (83, 88))	('BACH2', 'Gene', (83, 88))	('poor', 'NegReg', (99, 103))	('survival rate', 'CPA', (104, 117))	('nonsynonymous', 'Var', (48, 61))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanoma', 'Disease', (20, 28))	('KRAS', 'Gene', (89, 93))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))	('KRAS', 'Gene', '3845', (89, 93))
2168	32101536	In addition to HRAS and KRAS, we also computationally identified several significantly mutated genetic interactions for new gene families, such as SEPT1-BRIP1 in melanoma (Fig 4D).	('genetic', 'Var', (95, 102))	('KRAS', 'Gene', '3845', (24, 28))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('HRAS', 'Gene', '3265', (15, 19))	('SEPT1', 'Gene', (147, 152))	('BRIP1', 'Gene', (153, 158))	('mutated', 'Reg', (87, 94))	('SEPT1', 'Gene', '1731', (147, 152))	('BRIP1', 'Gene', '83990', (153, 158))	('HRAS', 'Gene', (15, 19))	('KRAS', 'Gene', (24, 28))
2170	32101536	For BRCA, in total we identified 82 significantly mutated genetic interactions with adjusted P-value < 0.05 (S4 Table).	('mutated', 'Var', (50, 57))	('BRCA', 'Gene', (4, 8))	('BRCA', 'Gene', '672', (4, 8))	('BRCA', 'Phenotype', 'HP:0003002', (4, 8))
2175	32101536	Interestingly, breast cancer patients harboring nonsynonymous somatic mutations on BCL2L1-HRAS reveals poor survival rate compared to the wild-type status on both BCL2L1 and HRAS (P = 0, log-rank test, S6C Fig).	('BCL2L1', 'Gene', '598', (163, 169))	('patients', 'Species', '9606', (29, 37))	('BCL2L1', 'Gene', '598', (83, 89))	('HRAS', 'Gene', (174, 178))	('BCL2', 'molecular_function', 'GO:0015283', ('163', '167'))	('HRAS', 'Gene', '3265', (90, 94))	('BCL2', 'molecular_function', 'GO:0015283', ('83', '87'))	('HRAS', 'Gene', (90, 94))	('nonsynonymous somatic mutations', 'Var', (48, 79))	('survival rate', 'CPA', (108, 121))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))	('BCL2L1', 'Gene', (83, 89))	('poor', 'NegReg', (103, 107))	('breast cancer', 'Disease', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('BCL2L1', 'Gene', (163, 169))	('HRAS', 'Gene', '3265', (174, 178))
2188	32101536	By analyzing drug pharmacogenomic profiles across over 1,000 cancer cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) database (see Methods), we found that the network-predicted putative genetic interactions were highly correlated to sensitivity/resistance of multiple therapeutic agents (S7 Table).	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (100, 116))	('Cancer', 'Disease', (120, 126))	('Cancer', 'Disease', 'MESH:D009369', (120, 126))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('genetic interactions', 'Var', (203, 223))	('correlated', 'Reg', (236, 246))	('000 cancer', 'Disease', 'MESH:D009369', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('000 cancer', 'Disease', (57, 67))
2199	32101536	Fig 5A and 5D reveal that cancer cell lines have both somatic mutations on BRCA2 and TP53 (BRCA2-TP53) are sensitive to afatinib.	('TP53', 'Gene', (85, 89))	('afatinib', 'Chemical', 'MESH:D000077716', (120, 128))	('BRCA2-TP53', 'Gene', (91, 101))	('cancer', 'Disease', (26, 32))	('TP53', 'Gene', '7157', (97, 101))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('BRCA2', 'Gene', (91, 96))	('BRCA2', 'Gene', (75, 80))	('sensitive', 'Reg', (107, 116))	('TP53', 'Gene', (97, 101))	('BRCA2-TP53', 'Gene', '7157;675', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('BRCA', 'Phenotype', 'HP:0003002', (91, 95))	('BRCA', 'Phenotype', 'HP:0003002', (75, 79))	('BRCA2', 'Gene', '675', (91, 96))	('TP53', 'Gene', '7157', (85, 89))	('BRCA2', 'Gene', '675', (75, 80))	('mutations', 'Var', (62, 71))
2203	32101536	In addition, co-mutations on BRCA2 and TP53 (BRCA2-TP53) are sensitive to JQ1 (a BET inhibitor) compared to wild-type cell lines (Fig 5C).	('BRCA2', 'Gene', (45, 50))	('TP53', 'Gene', (51, 55))	('sensitive', 'MPA', (61, 70))	('BRCA2', 'Gene', '675', (45, 50))	('BRCA2', 'Gene', (29, 34))	('JQ1', 'MPA', (74, 77))	('BET', 'Gene', '92737', (81, 84))	('BRCA', 'Phenotype', 'HP:0003002', (45, 49))	('co-mutations', 'Var', (13, 25))	('BRCA', 'Phenotype', 'HP:0003002', (29, 33))	('BET', 'Gene', (81, 84))	('TP53', 'Gene', '7157', (39, 43))	('BRCA2-TP53', 'Gene', (45, 55))	('BRCA2', 'Gene', '675', (29, 34))	('BRCA2-TP53', 'Gene', '7157;675', (45, 55))	('TP53', 'Gene', '7157', (51, 55))	('TP53', 'Gene', (39, 43))
2204	32101536	Clinical studies showed that mutations on TP53 reduce responsiveness to first-line tyrosine kinase inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC) patients.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (126, 152))	('small cell lung cancer', 'Disease', (130, 152))	('TP53', 'Gene', '7157', (42, 46))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('reduce', 'NegReg', (47, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (29, 38))	('SCLC', 'Phenotype', 'HP:0030357', (155, 159))	('patients', 'Species', '9606', (161, 169))	('EGFR', 'Gene', '1956', (113, 117))	('small cell lung cancer', 'Disease', 'MESH:D055752', (130, 152))	('EGFR', 'Gene', (113, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (130, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('113', '117'))	('NSCLC', 'Disease', (154, 159))
2207	32101536	Collectively, INCM-predicted putative genetic interactions offer potential pharmacogenomics biomarkers for guiding personalized cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('genetic interactions', 'Var', (38, 58))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
2213	32101536	In addition, phosphorylation of centrin during the cell cycle process preceded centrosome duplication, and centrosome duplication played essential roles in genomic instability and cancer.	('centrosome', 'cellular_component', 'GO:0005813', ('107', '117'))	('centrosome duplication', 'biological_process', 'GO:0051298', ('79', '101'))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('phosphorylation', 'MPA', (13, 28))	('cell cycle process', 'biological_process', 'GO:0022402', ('51', '69'))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('centrosome duplication', 'biological_process', 'GO:0051298', ('107', '129'))	('roles', 'Reg', (147, 152))	('genomic instability', 'CPA', (156, 175))	('centrosome', 'cellular_component', 'GO:0005813', ('79', '89'))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))	('centrosome duplication', 'Var', (107, 129))
2214	32101536	Thus, network-based INCM analysis generates a hypothesis for a potential synthetic lethal interaction for CETN2 and CDK4 co-mutated ovarian cancer.	('ovarian cancer', 'Disease', (132, 146))	('CETN2', 'Gene', (106, 111))	('CDK', 'molecular_function', 'GO:0004693', ('116', '119'))	('co-mutated', 'Var', (121, 131))	('CETN2', 'Gene', '1069', (106, 111))	('CDK4', 'Gene', '1019', (116, 120))	('CDK4', 'Gene', (116, 120))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (132, 146))
2216	32101536	Here, we found that 159 samples have somatic mutations in both PTEN and PIK3CA (PIK3CA-PTEN [P < 1.0x10-4] by INCM analysis) in UCEC from TCGA.	('PTEN', 'Gene', '5728', (63, 67))	('PTEN', 'Gene', (87, 91))	('mutations', 'Var', (45, 54))	('PTEN', 'Gene', '5728', (87, 91))	('PIK3CA', 'Gene', (72, 78))	('PIK3CA', 'Gene', (80, 86))	('PIK3CA', 'Gene', '5290', (80, 86))	('PIK3CA', 'Gene', '5290', (72, 78))	('PTEN', 'Gene', (63, 67))
2217	32101536	In addition, the mutation burden is significantly increased in PIK3CA-PTEN co-mutated samples compared to tumors with single-mutant PTEN or PIK3CA alone in UCEC (Fig 6B).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('PTEN', 'Gene', (132, 136))	('co-mutated', 'Var', (75, 85))	('PIK3CA', 'Gene', (140, 146))	('PTEN', 'Gene', '5728', (132, 136))	('PTEN', 'Gene', (70, 74))	('tumors', 'Disease', (106, 112))	('mutant', 'Gene', '4594', (125, 131))	('PTEN', 'Gene', '5728', (70, 74))	('increased', 'PosReg', (50, 59))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('PIK3CA', 'Gene', '5290', (140, 146))	('PIK3CA', 'Gene', (63, 69))	('mutant', 'Gene', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PIK3CA', 'Gene', '5290', (63, 69))	('mutation burden', 'MPA', (17, 32))
2219	32101536	Thus, detection of co-mutations of both PIK3CA and PTEN may offer potential biomarkers or targets for individualized treatment of tumors in uterine cancer or other cancer types (Fig 6C).	('cancer', 'Disease', (148, 154))	('tumors', 'Disease', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('co-mutations', 'Var', (19, 31))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('PIK3CA', 'Gene', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('PIK3CA', 'Gene', '5290', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('uterine cancer', 'Phenotype', 'HP:0010784', (140, 154))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('PTEN', 'Gene', (51, 55))	('PTEN', 'Gene', '5728', (51, 55))
2221	32101536	Integrating large-scale somatic mutations with known genetic interaction networks, INCM can be used to build cancer type-specific genetic subnetworks which are significantly enriched in known cancer genes and well-established cancer pathways.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('mutations', 'Var', (32, 41))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
2232	32101536	The publicly available copy number variation profiles, gene fusions, and large-scale somatic mutations from TCGA pan-cancer project and ICGC project would significantly enhance the applications of INCM in the future.	('copy number variation', 'Var', (23, 44))	('TCGA', 'Gene', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('enhance', 'PosReg', (169, 176))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('applications', 'MPA', (181, 193))
2258	32101536	The reference C-score distribution was generated by calculating the C-score based on the reshuffled mutations for each individual tumor, and the process was independently repeated 10,000 times.	('mutations', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (130, 135))
2294	31908476	Epigenetic and genetic alterations of miRNAs are common events in cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Epigenetic', 'Var', (0, 10))	('genetic alterations', 'Var', (15, 34))	('miR', 'Gene', (38, 41))	('miR', 'Gene', '220972', (38, 41))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
2327	31908476	In 2013, Li and colleagues reported that miR-451 inhibits CRC cell growth by downregulating the P13K/AKT pathway.	('CRC', 'Phenotype', 'HP:0003003', (58, 61))	('AKT', 'Gene', '207', (101, 104))	('CRC', 'Disease', 'MESH:D015179', (58, 61))	('P13K', 'Var', (96, 100))	('inhibits', 'NegReg', (49, 57))	('miR', 'Gene', '220972', (41, 44))	('miR', 'Gene', (41, 44))	('AKT', 'Gene', (101, 104))	('P13K', 'SUBSTITUTION', 'None', (96, 100))	('downregulating', 'NegReg', (77, 91))	('CRC', 'Disease', (58, 61))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))
2363	31908476	In 2008, Martinez et al reported that miR-451 expression was lower in cell lines containing human papilloma virus-16 and/or -18 DNA than in normal cervical cells.	('human papilloma virus', 'Species', '10566', (92, 113))	('lower', 'NegReg', (61, 66))	('human papilloma virus-16', 'Var', (92, 116))	('papilloma', 'Phenotype', 'HP:0012740', (98, 107))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('expression', 'MPA', (46, 56))
2364	31908476	miR-451 expression was higher in the multidrug resistant (MDR) human cervical cancer cell line KB-3-1 than in its parental cell line KB-V1, and miR-451 antagomirs decreased P-glycoprotein expression and increased doxorubicin sensitivity in MDR cancer cells.	('P-glycoprotein', 'Gene', (173, 187))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('increased', 'PosReg', (203, 212))	('P-glycoprotein', 'molecular_function', 'GO:0008559', ('173', '187'))	('human', 'Species', '9606', (63, 68))	('higher', 'PosReg', (23, 29))	('P-glycoprotein', 'Gene', '5243', (173, 187))	('doxorubicin', 'Chemical', 'MESH:D004317', (213, 224))	('MDR', 'molecular_function', 'GO:0004745', ('58', '61'))	('expression', 'MPA', (8, 18))	('antagomirs', 'Var', (152, 162))	('KB-V1', 'CellLine', 'CVCL:2089', (133, 138))	('MDR', 'molecular_function', 'GO:0004745', ('240', '243'))	('cancer', 'Disease', (78, 84))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', '220972', (144, 147))	('multidrug resistant', 'Disease', (37, 56))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('miR', 'Gene', (0, 3))	('miR', 'Gene', (144, 147))	('decreased', 'NegReg', (163, 172))	('doxorubicin sensitivity', 'MPA', (213, 236))
2426	31908476	Phua et al found that fecal miR-451 had a sensitivity of 88% and specificity of 100% in detecting CRC.	('CRC', 'Disease', (98, 101))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('fecal', 'Var', (22, 27))	('CRC', 'Phenotype', 'HP:0003003', (98, 101))	('CRC', 'Disease', 'MESH:D015179', (98, 101))
2428	31908476	These data indicate that the abnormal expression of miR-451 is associated with the cancer disease state and that miR-451 has great clinical potential as a noninvasive diagnostic biomarker for numerous human cancers.	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('miR', 'Gene', '220972', (113, 116))	('cancer disease', 'Disease', (83, 97))	('miR', 'Gene', (113, 116))	('cancers', 'Disease', (207, 214))	('expression', 'MPA', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('associated', 'Reg', (63, 73))	('abnormal', 'Var', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('human', 'Species', '9606', (201, 206))	('miR', 'Gene', '220972', (52, 55))	('cancer disease', 'Disease', 'MESH:D009369', (83, 97))	('miR', 'Gene', (52, 55))
2437	31908476	In 2018, Wang et al reported that knockdown of long ncRNA TATDN1 increased the expression of miR-451 and improved cisplatin sensitivity of NSCLC in vitro and in vivo by targeting TRIM66.	('improved', 'PosReg', (105, 113))	('increased', 'PosReg', (65, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('expression', 'MPA', (79, 89))	('TATDN1', 'Gene', '83940', (58, 64))	('TRIM66', 'Gene', '9866', (179, 185))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('TATDN1', 'Gene', (58, 64))	('TRIM66', 'Gene', (179, 185))	('cisplatin sensitivity of NSCLC', 'MPA', (114, 144))	('miR', 'Gene', '220972', (93, 96))	('knockdown', 'Var', (34, 43))	('miR', 'Gene', (93, 96))	('targeting', 'Reg', (169, 178))	('SCLC', 'Phenotype', 'HP:0030357', (140, 144))
2449	31908476	In addition, they showed that dysregulation of miR-451/c-Myc-survivin/rad-51 signaling is responsible for radioresistance in DTX-resistant LAD cells.	('DTX', 'Chemical', 'MESH:C081705', (125, 128))	('c-Myc', 'Gene', '4609', (55, 60))	('dysregulation', 'Var', (30, 43))	('miR', 'Gene', '220972', (47, 50))	('LAD', 'Phenotype', 'HP:0030078', (139, 142))	('miR', 'Gene', (47, 50))	('c-Myc', 'Gene', (55, 60))	('rad-51', 'Gene', (70, 76))	('radioresistance', 'CPA', (106, 121))	('LAD', 'Disease', (139, 142))	('LAD', 'Disease', 'MESH:C538231', (139, 142))	('responsible', 'Reg', (90, 101))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))	('rad-51', 'Gene', '5888', (70, 76))	('rad', 'biological_process', 'GO:1990116', ('70', '73'))
2451	31908476	Zhang et al found that high miR-451 expression enhanced radiosensitivity in nasopharyngeal carcinoma cells by inhibiting the repair of irradiation-induced double-strand breaks and increasing cell apoptosis.	('apoptosis', 'biological_process', 'GO:0006915', ('196', '205'))	('enhanced', 'PosReg', (47, 55))	('high', 'Var', (23, 27))	('radiosensitivity', 'MPA', (56, 72))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (76, 100))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (47, 72))	('repair of irradiation-induced double-strand breaks', 'MPA', (125, 175))	('inhibiting', 'NegReg', (110, 120))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('miR', 'Gene', '220972', (28, 31))	('increasing', 'PosReg', (180, 190))	('miR', 'Gene', (28, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('apoptosis', 'biological_process', 'GO:0097194', ('196', '205'))	('carcinoma', 'Disease', (91, 100))
2459	31908476	Re-expression of miR-451 could reverse EMT to a mesenchymal-epithelial transition in vitro and in vivo and could inhibit invasion and metastasis of the two DTX-resistant LAD cells.	('reverse', 'NegReg', (31, 38))	('mesenchymal-epithelial transition', 'biological_process', 'GO:0060231', ('48', '81'))	('DTX', 'Chemical', 'MESH:C081705', (156, 159))	('EMT to a mesenchymal-epithelial transition', 'CPA', (39, 81))	('miR', 'Gene', '220972', (17, 20))	('LAD', 'Phenotype', 'HP:0030078', (170, 173))	('miR', 'Gene', (17, 20))	('EMT', 'biological_process', 'GO:0001837', ('39', '42'))	('inhibit', 'NegReg', (113, 120))	('Re-expression', 'Var', (0, 13))	('LAD', 'Disease', (170, 173))	('LAD', 'Disease', 'MESH:C538231', (170, 173))
2464	31908476	Tumor initiation and progression are complex processes involving consecutive gene mutations and changes in the fundamental biological behavior of cells caused by changes in their neighboring stroma.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('fundamental biological behavior of', 'MPA', (111, 145))	('mutations', 'Var', (82, 91))	('changes', 'Reg', (96, 103))	('men', 'Species', '9606', (116, 119))
2510	30552156	For patients administered vinflunine 280 mg/m2 (e.g., Eastern Cooperative Oncology Group performance status [ECOG PS] 1, creatinine clearance 40-60 mL/minute) in this study, the prognosis was most likely even worse than for the average second-line patient treated within the vinflunine registration trial.	('vinflunine', 'Chemical', 'MESH:C111217', (26, 36))	('Oncology', 'Phenotype', 'HP:0002664', (74, 82))	('creatinine', 'Chemical', 'MESH:D003404', (121, 131))	('patient', 'Species', '9606', (4, 11))	('creatinine clearance', 'MPA', (121, 141))	('vinflunine', 'Chemical', 'MESH:C111217', (275, 285))	('patients', 'Species', '9606', (4, 12))	('patient', 'Species', '9606', (248, 255))	('vinflunine', 'Var', (26, 36))
2531	30552156	Included patients were required to have an acceptable hematologic function: hemoglobin >=10 g/dL, absolute neutrophil count >=1.0x lower limit of normal, and platelets >=100 000 per muL; adequate hepatic function: bilirubin <1.5x upper limit of normal (ULN), and transaminases <2.5x ULN; renal function: creatinine clearance >=40 mL/minute (measured by iohexol or 51Cr-EDTA techniques).	('patients', 'Species', '9606', (9, 17))	('>=100 000', 'Var', (168, 177))	('iohexol', 'Chemical', 'MESH:D007472', (353, 360))	('bilirubin', 'MPA', (214, 223))	('51Cr-EDTA', 'Chemical', '-', (364, 373))	('bilirubin', 'Chemical', 'MESH:D001663', (214, 223))	('creatinine clearance', 'MPA', (304, 324))	('creatinine', 'Chemical', 'MESH:D003404', (304, 314))
2542	30552156	Investigator's Analysis Active and should be pursued further Drug 1   Generic/Working Name Vinflunine Trade Name Javlor Company Name Pierre Fabre Drug Type Small molecule Drug Class Tubulin/Microtubules targeting agent Dose 280 and 320 mg/m2 Route IV Schedule of Administration Day 1, Q3W Drug 2   Generic/Working Name Sorafenib Trade Name Nexavar Company Name Bayer Healthcare AG Drug Type Small molecule Drug Class Raf - BRAF Dose 400, 600, or 800 per day (200 + 200, 200 + 400, or 400 + 400) mg per flat dose Route p.o.	('Vinflunine', 'Chemical', 'MESH:C111217', (91, 101))	('Nexavar', 'Chemical', 'MESH:D000077157', (340, 347))	('Raf', 'Gene', '22882', (417, 420))	('200 + 200', 'Var', (459, 468))	('Raf', 'Gene', (417, 420))	('Sorafenib', 'Chemical', 'MESH:D000077157', (319, 328))
2570	30552156	Constipation and pain have more commonly been reported with vinflunine, whereas diarrhea is frequently seen with tyrosine kinase inhibitor therapies and fatigue with either [3], [4], [5], [6].	('pain', 'Disease', (17, 21))	('Constipation', 'Disease', 'MESH:D003248', (0, 12))	('vinflunine', 'Chemical', 'MESH:C111217', (60, 70))	('fatigue', 'Disease', 'MESH:D005221', (153, 160))	('Constipation', 'Disease', (0, 12))	('fatigue', 'Disease', (153, 160))	('pain', 'Phenotype', 'HP:0012531', (17, 21))	('Constipation', 'Phenotype', 'HP:0002019', (0, 12))	('diarrhea', 'Phenotype', 'HP:0002014', (80, 88))	('fatigue', 'Phenotype', 'HP:0012378', (153, 160))	('pain', 'Disease', 'MESH:D010146', (17, 21))	('diarrhea', 'Disease', (80, 88))	('vinflunine', 'Var', (60, 70))	('diarrhea', 'Disease', 'MESH:D003967', (80, 88))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('122', '138'))	('tyrosine kinase inhibitor', 'MPA', (113, 138))
2673	29221636	This hypothesis is strengthened by observations by Williamson and colleagues who have demonstrated that urothelial neoplasms in young patients harbor very few mutations in FGFR3 or TP53, which are found in a majority of older patients with urothelial carcinoma.	('neoplasms', 'Phenotype', 'HP:0002664', (115, 124))	('TP53', 'Gene', (181, 185))	('FGFR3', 'Gene', '2261', (172, 177))	('urothelial neoplasms', 'Disease', (104, 124))	('mutations', 'Var', (159, 168))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (240, 260))	('patients', 'Species', '9606', (134, 142))	('FGFR3', 'Gene', (172, 177))	('urothelial neoplasms', 'Disease', 'MESH:D014523', (104, 124))	('neoplasm', 'Phenotype', 'HP:0002664', (115, 123))	('patients', 'Species', '9606', (226, 234))	('urothelial carcinoma', 'Disease', (240, 260))	('TP53', 'Gene', '7157', (181, 185))	('FGFR', 'molecular_function', 'GO:0005007', ('172', '176'))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))
2674	29221636	A number of studies have examined the role of microsatellite instability in the pathogenesis of urothelial neoplasms in young patients.	('urothelial neoplasms', 'Disease', (96, 116))	('neoplasm', 'Phenotype', 'HP:0002664', (107, 115))	('microsatellite instability', 'Var', (46, 72))	('urothelial neoplasms', 'Disease', 'MESH:D014523', (96, 116))	('patients', 'Species', '9606', (126, 134))	('pathogenesis', 'biological_process', 'GO:0009405', ('80', '92'))	('neoplasms', 'Phenotype', 'HP:0002664', (107, 116))
2703	28929116	Except for the NAT2 genotype, also GSTM1 null genotype increased the risk of BC.	('GSTM1', 'Gene', (35, 40))	('increased', 'PosReg', (55, 64))	('BC', 'Phenotype', 'HP:0009725', (77, 79))	('null genotype', 'Var', (41, 54))	('GSTM1', 'Gene', '2944', (35, 40))
2705	28929116	Aromatic amines are permanently present in the environment (car pollution, tobacco smoke, and combustion products) and may also accumulate in the fatty tissue.	('accumulate', 'PosReg', (128, 138))	('Aromatic', 'Var', (0, 8))	('Aromatic amines', 'Chemical', '-', (0, 15))	('tobacco', 'Species', '4097', (75, 82))
2716	28929116	Primers used in the reaction had the sequences NAT2 F 5' GCT AGC GGG GGA TCC TCT TC 3' and NAT2 R 5' TTG GAT GGT TAC ACA ACA AGG G 3'.	('G 3', 'Gene', '7917', (129, 132))	("NAT2 F 5' GCT", 'Var', (47, 60))	('G 3', 'Gene', (129, 132))	('TCC', 'cellular_component', 'GO:0005579', ('73', '76'))	("NAT2 R 5' TTG GAT", 'Var', (91, 108))	('TAC', 'cellular_component', 'GO:0120121', ('113', '116'))
2726	28929116	People with two mutated alleles of the NAT2 gene are classified as slow acetylators.	('NAT2', 'Gene', (39, 43))	('People', 'Species', '9606', (0, 6))	('mutated', 'Var', (16, 23))
2732	28929116	The invasiveness of tumor (T2) and higher grade (G2/G3) result in a higher level of GSTpi.	('invasiveness of tumor', 'Disease', 'MESH:D009369', (4, 25))	('G2/G3', 'Var', (49, 54))	('higher', 'PosReg', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('invasiveness of tumor', 'Disease', (4, 25))	('GSTpi', 'MPA', (84, 89))
2738	27557492	In this study, we unveil a reverse regulatory mechanism contributing to bladder cancer progression; Foxp3 expression attenuates HIF-1alpha degradation.	('HIF-1alpha degradation', 'Disease', (128, 150))	('attenuates', 'NegReg', (117, 127))	('Foxp3', 'Gene', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('degradation', 'biological_process', 'GO:0009056', ('139', '150'))	('expression', 'Var', (106, 116))	('HIF-1alpha degradation', 'Disease', 'MESH:D055959', (128, 150))	('bladder cancer', 'Disease', 'MESH:D001749', (72, 86))	('bladder cancer', 'Disease', (72, 86))
2742	27557492	Knocking-down of Foxp3 expression blocks in vivo tumor growth in mice and prolongs mice's survival, which is associated with von Willebrand factor expression.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('Foxp3', 'Gene', (17, 22))	('blocks', 'NegReg', (34, 40))	('prolongs', 'NegReg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mice', 'Species', '10090', (65, 69))	('tumor', 'Disease', (49, 54))	('Knocking-down', 'Var', (0, 13))	('mice', 'Species', '10090', (83, 87))	('survival', 'CPA', (90, 98))
2759	27557492	In invasive human bladder cancer, Foxp3 expression is a worse prognostic factor for overall survival, in which the presence of Foxp3Delta3 isoform protein may contribute to in vitro spheroid formation in SW780 cells and larger tumor growth in mice, as well as chemoresistance.	('bladder cancer', 'Disease', 'MESH:D001749', (18, 32))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))	('tumor', 'Disease', (227, 232))	('bladder cancer', 'Disease', (18, 32))	('formation', 'biological_process', 'GO:0009058', ('191', '200'))	('presence', 'Var', (115, 123))	('chemoresistance', 'CPA', (260, 275))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('SW780', 'CellLine', 'CVCL:1728', (204, 209))	('human', 'Species', '9606', (12, 17))	('Foxp3Delta3', 'Var', (127, 138))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('contribute', 'Reg', (159, 169))	('bladder cancer', 'Phenotype', 'HP:0009725', (18, 32))	('larger', 'PosReg', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('mice', 'Species', '10090', (243, 247))
2762	27557492	The T24-B subline exhibited more glucose, lactate, and less ATP amounts than the other two sublines, which met with Warburg effect (Figure 1B), as well as higher VEGF121, VEGF165 and four GLUT member mRNA expressions (Figure 1C and 1D).	('glucose', 'MPA', (33, 40))	('lactate', 'MPA', (42, 49))	('VEGF', 'Gene', (162, 166))	('ATP', 'Chemical', 'MESH:D000255', (60, 63))	('VEGF', 'Gene', '7422', (171, 175))	('GLUT', 'Gene', (188, 192))	('glucose', 'Chemical', 'MESH:D005947', (33, 40))	('VEGF', 'Gene', '7422', (162, 166))	('T24-B', 'Var', (4, 9))	('more', 'PosReg', (28, 32))	('ATP amounts', 'MPA', (60, 71))	('lactate', 'Chemical', 'MESH:D019344', (42, 49))	('GLUT', 'Gene', '6513', (188, 192))	('VEGF', 'Gene', (171, 175))	('higher', 'PosReg', (155, 161))	('less', 'NegReg', (55, 59))
2763	27557492	After knocking-down Foxp3 expression in T24-B cells, glucose content and lactate production declined (Figure 1F).	('lactate production', 'MPA', (73, 91))	('glucose', 'Chemical', 'MESH:D005947', (53, 60))	('glucose content', 'MPA', (53, 68))	('declined', 'NegReg', (92, 100))	('expression', 'Protein', (26, 36))	('knocking-down', 'Var', (6, 19))	('lactate', 'Chemical', 'MESH:D019344', (73, 80))	('Foxp3', 'Gene', (20, 25))
2765	27557492	In contrast, both increased amount of glucose content and lactate production increased, and up-regulation of VEGF and GLUT mRNA were detected in the T24-P cells with ectopic expression of Foxp3.	('increased amount of glucose', 'Phenotype', 'HP:0003074', (18, 45))	('Foxp3', 'Gene', (188, 193))	('glucose', 'Chemical', 'MESH:D005947', (38, 45))	('increased', 'PosReg', (18, 27))	('regulation', 'biological_process', 'GO:0065007', ('95', '105'))	('GLUT', 'Gene', (118, 122))	('lactate', 'Chemical', 'MESH:D019344', (58, 65))	('VEGF', 'Gene', (109, 113))	('up-regulation', 'PosReg', (92, 105))	('GLUT', 'Gene', '6513', (118, 122))	('increased', 'PosReg', (77, 86))	('amount of glucose content', 'MPA', (28, 53))	('VEGF', 'Gene', '7422', (109, 113))	('ectopic expression', 'Var', (166, 184))	('lactate production', 'MPA', (58, 76))
2769	27557492	While knocking down Foxp3 expression in T24-B cells, the level of HIF-1alpha mRNA did not change regardless in normoxic or hypoxic conditions (Figure 3A) and HIF-1alpha protein expression is reduced under hypoxic condition (Figure 3B) or when cells treated with proteasome inhibitor MG132 (Figure 3C).	('hypoxic conditions', 'Disease', (123, 141))	('hypoxic condition', 'Disease', (205, 222))	('hypoxic condition', 'Disease', 'MESH:D009135', (205, 222))	('hypoxic conditions', 'Disease', 'MESH:D009135', (123, 141))	('proteasome', 'molecular_function', 'GO:0004299', ('262', '272'))	('proteasome', 'cellular_component', 'GO:0000502', ('262', '272'))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('reduced', 'NegReg', (191, 198))	('knocking down', 'Var', (6, 19))	('hypoxic condition', 'Disease', 'MESH:D009135', (123, 140))	('MG132', 'Chemical', 'MESH:C072553', (283, 288))	('Foxp3', 'Gene', (20, 25))
2771	27557492	Taken together, Foxp3 can be detected to be able to bind with HIF-1alpha protein, particularly upon hypoxia or MG132 treatment and enahnce HIF-1alpha protein expression through decreasing ubiquitin-mediated proteasomal degradation in human bladder cancer cells.	('bind', 'Interaction', (52, 56))	('ubiquitin', 'molecular_function', 'GO:0031386', ('188', '197'))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('men', 'Species', '9606', (122, 125))	('bladder cancer', 'Disease', 'MESH:D001749', (240, 254))	('bladder cancer', 'Disease', (240, 254))	('degradation', 'biological_process', 'GO:0009056', ('219', '230'))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('bladder cancer', 'Phenotype', 'HP:0009725', (240, 254))	('decreasing', 'NegReg', (177, 187))	('expression', 'MPA', (158, 168))	('ubiquitin-mediated proteasomal degradation', 'MPA', (188, 230))	('Foxp3', 'Gene', (16, 21))	('hypoxia', 'Disease', (100, 107))	('human', 'Species', '9606', (234, 239))	('HIF-1alpha protein', 'Var', (139, 157))	('MG132', 'Chemical', 'MESH:C072553', (111, 116))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))
2772	27557492	To investigate in vivo biological effect of Foxp3 expression in mice, female NOD-SCID mice were injected in the flank area subcutaneously with Foxp3 knocking-down T24-B cells or the control.	('knocking-down', 'Var', (149, 162))	('NOD-SCID', 'Disease', 'MESH:D020191', (77, 85))	('Foxp3', 'Gene', (143, 148))	('mice', 'Species', '10090', (86, 90))	('NOD-SCID', 'Disease', (77, 85))	('mice', 'Species', '10090', (64, 68))
2773	27557492	The results demonstrated that knocking-down of Foxp3 expression blocks in vivo tumor growth of T24-B cells in mice and prolongs the survival (p values, < 0.0001 and 0.0024, respectively) (Figure 4A and 4B).	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('blocks', 'NegReg', (64, 70))	('tumor', 'Disease', (79, 84))	('mice', 'Species', '10090', (110, 114))	('prolongs', 'PosReg', (119, 127))	('knocking-down', 'Var', (30, 43))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('survival', 'CPA', (132, 140))	('Foxp3', 'Gene', (47, 52))
2774	27557492	Consistently, the density of von Willebrand factor (vWF) immunostaining is decreased in the Foxp3-knokcking down tumor xenografts, as compared with the control (p = 0.020) (Figure 4C and 4D).	('tumor', 'Disease', (113, 118))	('vWF', 'Gene', '7450', (52, 55))	('Foxp3-knokcking down', 'Var', (92, 112))	('vWF', 'Gene', (52, 55))	('von', 'Protein', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('density', 'MPA', (18, 25))	('decreased', 'NegReg', (75, 84))
2779	27557492	Totally, 96 section slides were available for CD8 immunostaining, including 68 Foxp3 (-) and 28 Foxp3 (+) tumors.	('Foxp3', 'Var', (96, 101))	('CD8', 'Gene', '925', (46, 49))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('Foxp3', 'Disease', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('CD8', 'Gene', (46, 49))
2781	27557492	Tumors with Foxp3 expression exhibited less average number of CD8+TILs than did those without Foxp3 expression (p=0.01, unpaired t-test) (Figure 5H), as well as less frequency of higher CD8+ cells density (p=0.026, chi-square test) (Figure 5G).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD8', 'Gene', '925', (186, 189))	('Foxp3', 'Gene', (12, 17))	('CD8', 'Gene', (62, 65))	('less', 'NegReg', (39, 43))	('CD8', 'Gene', '925', (62, 65))	('Tumors', 'Disease', (0, 6))	('less', 'NegReg', (161, 165))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('higher', 'PosReg', (179, 185))	('CD8', 'Gene', (186, 189))	('expression', 'Var', (18, 28))
2790	27557492	To obtain the external validation, data mining from 2 published dataset GSE32548 (n=131) and GSE48075 (n=142) demonstrated Foxp3 mRNA expression is significantly associated with GLUT-4 (r = 0.261, p < 0.0001), GLUT-9 (r = 0.269, p<0.0001), VEGF-A (r = 0.147, p = 0.016), VEGF-B (r = 0.248, p<0.0001), and GLUT-D (r = 0.158, p = 0.0009), but not with HIF-1alpha (p > 0.05) (Table 3) (Figure 7).	('GLUT', 'Gene', '6513', (178, 182))	('GLUT-4', 'Gene', '6517', (178, 184))	('associated', 'Interaction', (162, 172))	('GLUT', 'Gene', '6513', (210, 214))	('Foxp3', 'Gene', (123, 128))	('VEGF-B', 'Gene', '7423', (271, 277))	('VEGF-A', 'Gene', (240, 246))	('mRNA expression', 'MPA', (129, 144))	('VEGF-A', 'Gene', '7422', (240, 246))	('GSE48075', 'Var', (93, 101))	('GLUT-4', 'Gene', (178, 184))	('VEGF-B', 'Gene', (271, 277))	('GLUT', 'Gene', (305, 309))	('GLUT', 'Gene', '6513', (305, 309))	('GLUT-9', 'Gene', (210, 216))	('GLUT-9', 'Gene', '56606', (210, 216))	('GLUT', 'Gene', (178, 182))	('GLUT', 'Gene', (210, 214))
2791	27557492	In the present study we demonstrated that Foxp3 expression is an independent predictor for disease progression in superficial bladder cancer patients, which is inversely associated with average number of CD8+TILs.	('CD8', 'Gene', '925', (204, 207))	('bladder cancer', 'Phenotype', 'HP:0009725', (126, 140))	('Foxp3', 'Gene', (42, 47))	('patients', 'Species', '9606', (141, 149))	('bladder cancer', 'Disease', 'MESH:D001749', (126, 140))	('bladder cancer', 'Disease', (126, 140))	('expression', 'Var', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('CD8', 'Gene', (204, 207))	('predictor', 'Reg', (77, 86))
2805	27557492	These tumor-derived factors can dysfunctionalize antigen-presenting cells and enhance regulatory T cells, which suppresses intraturmoral CD4+ and CD8+ T lymphocytes.	('CD4', 'Gene', (137, 140))	('enhance', 'PosReg', (78, 85))	('antigen-presenting', 'Protein', (49, 67))	('regulatory T cells', 'CPA', (86, 104))	('suppresses', 'NegReg', (112, 122))	('CD4', 'Gene', '920', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('dysfunctionalize', 'Var', (32, 48))	('CD8', 'Gene', (146, 149))	('CD8', 'Gene', '925', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
2816	27557492	Moreover, deletions and missense mutations of HIF-1alpha itself can increased its expression under nonhypoxic conditions by diminishing ubiquitination.	('hypoxic conditions', 'Disease', 'MESH:D009135', (102, 120))	('missense mutations', 'Var', (24, 42))	('diminishing', 'NegReg', (124, 135))	('HIF-1alpha', 'Gene', (46, 56))	('deletions', 'Var', (10, 19))	('increased', 'PosReg', (68, 77))	('hypoxic conditions', 'Disease', (102, 120))	('ubiquitination', 'MPA', (136, 150))
2848	27557492	Female (NOD-SCID, 6-8 weeks old) mice were subcutaneously injected with 1x106 Foxp3 knocking-down T24-B in 100 mul serum-free medium or its control.	('NOD-SCID', 'Disease', (8, 16))	('knocking-down', 'Var', (84, 97))	('T24-B', 'Gene', (98, 103))	('NOD-SCID', 'Disease', 'MESH:D020191', (8, 16))	('mice', 'Species', '10090', (33, 37))
2874	28139689	NF-kappaB suppresses apoptosis and promotes bladder cancer cell proliferation by upregulating survivin expression in vitro and in vivo Nuclear factor kappa-B (NF-kappaB) activation is a common phenomenon in cancers, which results in the aberrant expression of NF-kappaB target genes and leads to malignant transformation, metastatic dissemination, abnormal cell proliferation or resistance to cell death.	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (348, 375))	('bladder cancer', 'Phenotype', 'HP:0009725', (44, 58))	('cell proliferation', 'biological_process', 'GO:0008283', ('357', '375'))	('NF-kappaB', 'Gene', (0, 9))	('abnormal cell proliferation', 'CPA', (348, 375))	('cell death', 'biological_process', 'GO:0008219', ('393', '403'))	('NF-kappaB', 'Gene', (159, 168))	('leads to', 'Reg', (287, 295))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('NF-kappaB) activation', 'biological_process', 'GO:0051092', ('159', '180'))	('NF-kappaB', 'Gene', '4790', (0, 9))	('cancers', 'Disease', (207, 214))	('expression', 'MPA', (103, 113))	('promotes', 'PosReg', (35, 43))	('NF-kappaB', 'Gene', '4790', (159, 168))	('apoptosis', 'CPA', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('expression', 'MPA', (246, 256))	('suppresses', 'NegReg', (10, 20))	('metastatic dissemination', 'CPA', (322, 346))	('upregulating', 'PosReg', (81, 93))	('malignant transformation', 'CPA', (296, 320))	('NF-kappaB', 'Gene', (260, 269))	('aberrant', 'Var', (237, 245))	('survivin', 'Gene', (94, 102))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('resistance to cell death', 'CPA', (379, 403))	('NF-kappaB', 'Gene', '4790', (260, 269))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('survivin', 'Gene', '11799', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('21', '30'))	('bladder cancer', 'Disease', 'MESH:D001749', (44, 58))	('bladder cancer', 'Disease', (44, 58))	('Nuclear factor kappa-B', 'Gene', '4790', (135, 157))	('apoptosis', 'biological_process', 'GO:0006915', ('21', '30'))	('Nuclear factor kappa-B', 'Gene', (135, 157))
2880	28139689	Moreover, we found that YM-155 significantly induced apoptosis and decreased cellular proliferation as well as tumor growth in mice.	('mice', 'Species', '10090', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('apoptosis', 'CPA', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('induced', 'PosReg', (45, 52))	('cellular proliferation', 'CPA', (77, 99))	('tumor', 'Disease', (111, 116))	('YM-155', 'Chemical', 'MESH:C523798', (24, 30))	('YM-155', 'Var', (24, 30))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('decreased', 'NegReg', (67, 76))
2881	28139689	Our results demonstrate the carcinogenic function of the NF-kappaB/survivin pathway in bladder cancer and the role of YM-155 as a promising agent for the strategic treatment of bladder cancer.	('YM-155', 'Chemical', 'MESH:C523798', (118, 124))	('bladder cancer', 'Disease', 'MESH:D001749', (177, 191))	('bladder cancer', 'Disease', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('survivin', 'Gene', '11799', (67, 75))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('bladder cancer', 'Disease', 'MESH:D001749', (87, 101))	('survivin', 'Gene', (67, 75))	('bladder cancer', 'Disease', (87, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (177, 191))	('YM-155', 'Var', (118, 124))
2886	28139689	Alterations in apoptosis can lead to carcinogenesis (e.g., neoplastic cells that live longer and develop resistance to stress).	('apoptosis', 'CPA', (15, 24))	('carcinogenesis', 'Disease', 'MESH:D063646', (37, 51))	('lead to', 'Reg', (29, 36))	('carcinogenesis', 'Disease', (37, 51))	('Alterations', 'Var', (0, 11))	('apoptosis', 'biological_process', 'GO:0097194', ('15', '24'))	('apoptosis', 'biological_process', 'GO:0006915', ('15', '24'))	('neoplastic cells that live longer', 'CPA', (59, 92))
2902	28139689	We confirmed that NF-kappaB activation contributes to the upregulation of the survivin gene in bladder cancer, and we revealed that by upregulating survivin expression, NF-kappaB enhances the proliferation and suppresses the apoptosis of bladder cancer cell lines both in vitro and in vivo.	('proliferation', 'CPA', (192, 205))	('NF-kappaB', 'Var', (169, 178))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('18', '38'))	('suppresses', 'NegReg', (210, 220))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('bladder cancer', 'Disease', 'MESH:D001749', (238, 252))	('bladder cancer', 'Disease', (238, 252))	('bladder cancer', 'Disease', 'MESH:D001749', (95, 109))	('bladder cancer', 'Disease', (95, 109))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('bladder cancer', 'Phenotype', 'HP:0009725', (238, 252))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))	('survivin', 'Gene', (78, 86))	('apoptosis', 'CPA', (225, 234))	('survivin', 'Gene', '11799', (78, 86))	('survivin', 'Gene', (148, 156))	('upregulating', 'PosReg', (135, 147))	('apoptosis', 'biological_process', 'GO:0097194', ('225', '234'))	('survivin', 'Gene', '11799', (148, 156))	('apoptosis', 'biological_process', 'GO:0006915', ('225', '234'))	('expression', 'MPA', (157, 167))	('enhances', 'PosReg', (179, 187))	('upregulation', 'PosReg', (58, 70))
2912	28139689	2D) suggested a significant positive correlation between expression of survivin and p65/RelA in 40 bladder cancer tissue specimens (R = 0.6708, p < 0.01).	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('p65/RelA', 'Var', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('survivin', 'Gene', '11799', (71, 79))	('bladder cancer', 'Disease', (99, 113))	('survivin', 'Gene', (71, 79))
2923	28139689	Next, to avoid the influence that TNF-alpha or BAY 11-7082 may cause on survivin expression through other pathways rather than NF-kappaB, we knocked down p65/RelA with siRNA oligo, then the cells were treated with TNF-alpha in the same method.	('TNF-alpha', 'Gene', (34, 43))	('BAY 11-7082', 'Var', (47, 58))	('BAY 11-7082', 'Chemical', 'MESH:C434003', (47, 58))	('p65/RelA', 'Gene', (154, 162))	('TNF-alpha', 'Gene', '7124', (214, 223))	('survivin', 'Gene', (72, 80))	('knocked down', 'Var', (141, 153))	('TNF-alpha', 'Gene', (214, 223))	('TNF-alpha', 'Gene', '7124', (34, 43))	('survivin', 'Gene', '11799', (72, 80))
2926	28139689	Taken together, these results suggest that the activation of the NF-kappaB signaling pathway significantly contributes to the upregulation of survivin expression, whereas deactivation of NF-kappaB downregulates survivin expression.	('survivin', 'Gene', '11799', (211, 219))	('downregulates', 'NegReg', (197, 210))	('expression', 'MPA', (220, 230))	('survivin', 'Gene', (142, 150))	('expression', 'MPA', (151, 161))	('deactivation', 'Var', (171, 183))	('survivin', 'Gene', (211, 219))	('survivin', 'Gene', '11799', (142, 150))	('upregulation', 'PosReg', (126, 138))	('signaling pathway', 'biological_process', 'GO:0007165', ('75', '92'))	('NF-kappaB signaling pathway', 'Pathway', (65, 92))
2934	28139689	Figure 3H showed that TNF-alpha remarkably stimulated the luciferase activity of the cells received transfection of NCs, in contrast, survivin promoter luciferase activity of p65 knockdown cells could no longer be upregulated by TNF-alpha treatment.	('TNF-alpha', 'Gene', '7124', (22, 31))	('TNF-alpha', 'Gene', (22, 31))	('stimulated', 'PosReg', (43, 53))	('transfection', 'Var', (100, 112))	('luciferase activity', 'molecular_function', 'GO:0047077', ('58', '77'))	('survivin', 'Gene', (134, 142))	('luciferase activity', 'molecular_function', 'GO:0045289', ('58', '77'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('58', '77'))	('activity', 'MPA', (69, 77))	('luciferase activity', 'molecular_function', 'GO:0047077', ('152', '171'))	('survivin', 'Gene', '11799', (134, 142))	('luciferase activity', 'molecular_function', 'GO:0045289', ('152', '171'))	('luciferase', 'Enzyme', (58, 68))	('luciferase activity', 'molecular_function', 'GO:0047712', ('152', '171'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('58', '77'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('58', '77'))	('activity', 'MPA', (163, 171))	('TNF-alpha', 'Gene', '7124', (229, 238))	('TNF-alpha', 'Gene', (229, 238))	('luciferase activity', 'molecular_function', 'GO:0050248', ('152', '171'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('152', '171'))
2937	28139689	YM-155 has been confirmed to specifically decrease survivin expression and to induce apoptosis in many cancers.	('induce', 'Reg', (78, 84))	('expression', 'MPA', (60, 70))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('survivin', 'Gene', (51, 59))	('survivin', 'Gene', '11799', (51, 59))	('apoptosis', 'CPA', (85, 94))	('decrease', 'NegReg', (42, 50))	('YM-155', 'Var', (0, 6))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('YM-155', 'Chemical', 'MESH:C523798', (0, 6))	('cancers', 'Disease', (103, 110))
2939	28139689	However, few studies have reported the effects of YM-155 in bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('YM-155', 'Chemical', 'MESH:C523798', (50, 56))	('YM-155', 'Var', (50, 56))	('bladder cancer', 'Disease', 'MESH:D001749', (60, 74))	('bladder cancer', 'Disease', (60, 74))
2944	28139689	Similar to findings of previous studies, YM-155 specifically inhibited proliferation and induced apoptosis and the cycle arrest of bladder cancer cells.	('arrest of bladder cancer', 'Disease', 'MESH:D001749', (121, 145))	('inhibited', 'NegReg', (61, 70))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('induced', 'Reg', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('arrest of bladder cancer', 'Disease', (121, 145))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('bladder cancer', 'Phenotype', 'HP:0009725', (131, 145))	('YM-155', 'Var', (41, 47))	('proliferation', 'CPA', (71, 84))	('YM-155', 'Chemical', 'MESH:C523798', (41, 47))	('apoptosis', 'CPA', (97, 106))
2949	28139689	5C, YM-155 alone significantly induced apoptosis, and NF-kappaB overexpression combined with YM-155 reduced apoptosis compared with YM-155 treatment alone.	('apoptosis', 'CPA', (39, 48))	('YM-155', 'Chemical', 'MESH:C523798', (93, 99))	('YM-155', 'Chemical', 'MESH:C523798', (132, 138))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('reduced', 'NegReg', (100, 107))	('NF-kappaB', 'Protein', (54, 63))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('overexpression', 'PosReg', (64, 78))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('YM-155', 'Chemical', 'MESH:C523798', (4, 10))	('YM-155', 'Var', (93, 99))
2952	28139689	Our in vitro results suggested that YM-155 potently induced apoptosis and inhibited the proliferation of bladder cancer cell lines by downregulating survivin expression.	('inhibited', 'NegReg', (74, 83))	('survivin', 'Gene', '11799', (149, 157))	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('YM-155', 'Chemical', 'MESH:C523798', (36, 42))	('YM-155', 'Var', (36, 42))	('expression', 'MPA', (158, 168))	('induced', 'PosReg', (52, 59))	('apoptosis', 'CPA', (60, 69))	('bladder cancer', 'Disease', (105, 119))	('bladder cancer', 'Disease', 'MESH:D001749', (105, 119))	('downregulating', 'NegReg', (134, 148))	('survivin', 'Gene', (149, 157))	('proliferation', 'CPA', (88, 101))	('apoptosis', 'biological_process', 'GO:0097194', ('60', '69'))	('apoptosis', 'biological_process', 'GO:0006915', ('60', '69'))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
2960	28139689	The groups of mice with tumors established by Lv-NC-5637 or Lv-RelA-5637 were continuously infused with YM-155 at a dose of 5 mg/kg/day for 7 days; the other two groups of mice were infused with the vehicle control.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Lv-NC-5637', 'Var', (46, 56))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('mice', 'Species', '10090', (14, 18))	('mice', 'Species', '10090', (172, 176))	('YM-155', 'Gene', (104, 110))	('YM-155', 'Chemical', 'MESH:C523798', (104, 110))
2963	28139689	6A) showed that the tumors in the YM-155 plus Lv-NC-5637-treated mice grew significantly slower than those in the vehicle control plus Lv-NC-5637-treated mice.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('mice', 'Species', '10090', (154, 158))	('grew', 'CPA', (70, 74))	('Lv-NC-5637-treated', 'Var', (46, 64))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('slower', 'NegReg', (89, 95))	('mice', 'Species', '10090', (65, 69))	('YM-155', 'Chemical', 'MESH:C523798', (34, 40))	('YM-155', 'Var', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
2964	28139689	In contrast, in the NF-kappaB-overexpressing (Lv-RelA-5637) groups, the tumor growth inhibition resulting from YM-155 was significantly reduced, and the tumors in the mice treated with vehicle control plus Lv-RelA-5637 revealed the fastest growth rate among all of the groups.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('mice', 'Species', '10090', (167, 171))	('tumor', 'Disease', (72, 77))	('NF-kappaB-overexpressing', 'PosReg', (20, 44))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('reduced', 'NegReg', (136, 143))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('YM-155', 'Chemical', 'MESH:C523798', (111, 117))	('YM-155', 'Var', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
2968	28139689	Ki67 expression was also detected, and in accordance with the tumor growth, NF-kappaB overexpression without YM-155 treatment revealed the highest expression level of ki67, whereas YM-155 with vector significantly decreased ki67 expression and tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (244, 249))	('YM-155', 'Chemical', 'MESH:C523798', (109, 115))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('ki67', 'Protein', (224, 228))	('YM-155', 'Chemical', 'MESH:C523798', (181, 187))	('decreased', 'NegReg', (214, 223))	('ki67', 'Var', (167, 171))	('expression level', 'MPA', (147, 163))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('expression', 'MPA', (229, 239))
2978	28139689	In this study, we detected a significant increase in nuclear p65/RelA levels in bladder cancer tissues compared to that of adjacent normal tissues, and p65/RelA expression was also correlated with pathological progression of bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (80, 94))	('bladder cancer', 'Disease', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('bladder cancer', 'Disease', 'MESH:D001749', (225, 239))	('bladder cancer', 'Disease', (225, 239))	('correlated with', 'Reg', (181, 196))	('bladder cancer', 'Phenotype', 'HP:0009725', (80, 94))	('nuclear p65/RelA levels', 'MPA', (53, 76))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('increase', 'PosReg', (41, 49))	('p65/RelA', 'Var', (152, 160))	('bladder cancer', 'Phenotype', 'HP:0009725', (225, 239))
2988	28139689	In a study concerning the anti-tumor activities of YM-155 in a wide variety of human cancer cell lines and xenograft models, YM-155 was reported to elicit significant anti-tumor activity in a bladder cancer (UM-UC-3) xenograft model.	('tumor', 'Disease', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('bladder cancer', 'Disease', 'MESH:D001749', (192, 206))	('bladder cancer', 'Disease', (192, 206))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('YM-155', 'Var', (125, 131))	('human', 'Species', '9606', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('bladder cancer', 'Phenotype', 'HP:0009725', (192, 206))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('YM-155', 'Chemical', 'MESH:C523798', (125, 131))	('YM-155', 'Chemical', 'MESH:C523798', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('cancer', 'Disease', (200, 206))
2990	28139689	Our results showed that YM-155 potently suppresses xenograft tumor growth, as well as the expression of the survivin gene.	('survivin', 'Gene', (108, 116))	('suppresses', 'NegReg', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('YM-155', 'Chemical', 'MESH:C523798', (24, 30))	('expression', 'MPA', (90, 100))	('YM-155', 'Var', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('survivin', 'Gene', '11799', (108, 116))
3011	28139689	Cells in the logarithmic phase of growth were seeded into 96-well culture plates at 3 x 103 cells per well for 24 h. Next, the cells were differentially treated with TNF-alpha, BAY 11-7082 or YM-155.	('BAY 11-7082', 'Chemical', 'MESH:C434003', (177, 188))	('TNF-alpha', 'Gene', '7124', (166, 175))	('TNF-alpha', 'Gene', (166, 175))	('YM-155', 'Chemical', 'MESH:C523798', (192, 198))	('YM-155', 'Var', (192, 198))	('BAY 11-7082', 'Var', (177, 188))
3029	28139689	Each of the mice with xenograft tumors expressing Lv-RelA-5637 or Lv-NC-5637 were continuously infused with YM-155 at 5 mg/kg/day for 7 days; the other two groups of mice were infused with vehicle control.	('YM-155', 'Chemical', 'MESH:C523798', (108, 114))	('xenograft tumors', 'Disease', (22, 38))	('mice', 'Species', '10090', (12, 16))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mice', 'Species', '10090', (166, 170))	('Lv-RelA-5637', 'Var', (50, 62))	('xenograft tumors', 'Disease', 'MESH:D009369', (22, 38))	('Lv-NC-5637', 'Var', (66, 76))
3056	21924649	Broadly speaking, lesions can be classified into (i) well differentiated, non-invasive papillary cancers characterized by deletions in chromosome 9; (ii) poorly differentiated muscle-invasive tumors that show alterations in canonical tumor suppressors and oncogenes including p53, Rb and PTEN; and (iii) a distinct entity, carcinoma in situ (CIS) that, although confined to the urothelium, exists as a flat, non-papillary, poorly differentiated lesion displaying genetic alterations characteristic of both papillary and muscle-invasive tumors Importantly, the presence of CIS correlates strongly with the risk of invasive disease, demonstrating the close association between loss of urothelial differentiation and ultimate development of aggressive bladder cancer.	('tumor', 'Disease', (234, 239))	('non-invasive papillary cancers', 'Disease', (74, 104))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (323, 340))	('tumor', 'Disease', (536, 541))	('cancer', 'Phenotype', 'HP:0002664', (757, 763))	('CIS', 'Disease', (572, 575))	('bladder cancer', 'Phenotype', 'HP:0009725', (749, 763))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('carcinoma in situ', 'Disease', 'MESH:D002278', (323, 340))	('aggressive bladder cancer', 'Disease', (738, 763))	('tumor', 'Disease', 'MESH:D009369', (536, 541))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('deletions', 'Var', (122, 131))	('tumors', 'Phenotype', 'HP:0002664', (536, 542))	('chromosome', 'cellular_component', 'GO:0005694', ('135', '145'))	('PTEN', 'Gene', (288, 292))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', (192, 197))	('invasive disease', 'Disease', 'MESH:D009362', (613, 629))	('carcinoma', 'Phenotype', 'HP:0030731', (323, 332))	('tumor', 'Phenotype', 'HP:0002664', (536, 541))	('CIS', 'Phenotype', 'HP:0030075', (572, 575))	('CIS', 'Phenotype', 'HP:0030075', (342, 345))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (520, 542))	('PTEN', 'Gene', '5728', (288, 292))	('invasive disease', 'Disease', (613, 629))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('non-invasive papillary cancers', 'Disease', 'MESH:D000077273', (74, 104))	('muscle-invasive tumors', 'Disease', (520, 542))	('carcinoma in situ', 'Disease', (323, 340))	('aggressive bladder cancer', 'Disease', 'MESH:D001749', (738, 763))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (176, 198))	('muscle-invasive tumors', 'Disease', (176, 198))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
3064	21924649	In addition, aberrant expression and/or activity of ERBB receptors have been linked to urothelial carcinoma development and progression.	('ERBB', 'Gene', '1956', (52, 56))	('aberrant expression', 'Var', (13, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (87, 107))	('linked', 'Reg', (77, 83))	('activity', 'MPA', (40, 48))	('ERBB', 'Gene', (52, 56))	('urothelial carcinoma', 'Disease', (87, 107))
3072	21924649	Together, these findings suggest a receptor- independent mechanism whereby EGFR ligands can elicit tumor progression.	('tumor', 'Disease', (99, 104))	('elicit', 'Reg', (92, 98))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('ligands', 'Var', (80, 87))	('EGFR', 'Protein', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
3078	21924649	Somatic missense mutations in the FGFR3 gene have been shown to be more prevalent in low grade, Ta stage tumors, suggesting a possible association with early loss of differentiation.	('FGFR3', 'Gene', '2261', (34, 39))	('Ta stage tumors', 'Disease', (96, 111))	('association', 'Reg', (135, 146))	('low grade', 'CPA', (85, 94))	('FGFR3', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('Ta stage tumors', 'Disease', 'MESH:D062706', (96, 111))	('missense mutations', 'Var', (8, 26))	('prevalent', 'Reg', (72, 81))
3083	21924649	In a study of over 1600 human urothelial carcinoma samples, 11 members of the Shh family were genotyped for 177 single nucleotide polymorphisms (SNPs).	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('human', 'Species', '9606', (24, 29))	('urothelial carcinoma', 'Disease', (30, 50))	('Shh', 'Gene', (78, 81))	('single nucleotide polymorphisms', 'Var', (112, 143))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (30, 50))	('Shh', 'Gene', '6469', (78, 81))
3085	21924649	Importantly, two of these SNPs remained significant following statistical adjustment for multiple comparisons, suggesting that genetic alterations in the Shh pathway can influence response to therapy in patients with NMIBC.	('response to therapy', 'MPA', (180, 199))	('MIBC', 'Chemical', '-', (218, 222))	('Shh', 'Gene', (154, 157))	('patients', 'Species', '9606', (203, 211))	('NMIBC', 'Disease', (217, 222))	('Shh', 'Gene', '6469', (154, 157))	('genetic alterations', 'Var', (127, 146))	('influence', 'Reg', (170, 179))
3090	21924649	For instance, RARbeta mRNA levels are altered in bladder cancer, and mutations in highly conserved regions of the RARalpha gene have been detected in the immortalized urothelial cell line, HUC-BC, suggesting that retinoid signaling may be a frequent target of inactivation in bladder carcinogenesis.	('mutations', 'Var', (69, 78))	('bladder cancer', 'Disease', (49, 63))	('altered', 'Reg', (38, 45))	('bladder carcinogenesis', 'Disease', 'MESH:D063646', (276, 298))	('signaling', 'biological_process', 'GO:0023052', ('222', '231'))	('RARbeta', 'Gene', '5915', (14, 21))	('HUC', 'CellLine', 'CVCL:3798', (189, 192))	('bladder carcinogenesis', 'Disease', (276, 298))	('bladder cancer', 'Phenotype', 'HP:0009725', (49, 63))	('RARalpha', 'Gene', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('RARbeta', 'Gene', (14, 21))	('retinoid', 'Chemical', 'MESH:D012176', (213, 221))	('bladder cancer', 'Disease', 'MESH:D001749', (49, 63))	('RARalpha', 'Gene', '5914', (114, 122))
3095	21924649	However, treatment with retinoid analogues such as N-4-hydroxyphenyl-retinamide (Fenretinide or 4-HPR) and 6-[3-(1-adamantyl)-4 hydroxyphenyl]-2-napthalene carboxylic acid (CD437) resulted in apoptosis, G1 cell cycle arrest, and decreases in cell growth.	('CD437', 'Chemical', 'MESH:C099555', (173, 178))	('cell growth', 'CPA', (242, 253))	('N-4-hydroxyphenyl-retinamide', 'Chemical', 'MESH:D017313', (51, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('192', '201'))	('G1 cell cycle arrest', 'CPA', (203, 223))	('6-[3-(1-adamantyl)-4 hydroxyphenyl]-2-napthalene carboxylic acid', 'Chemical', '-', (107, 171))	('Fenretinide', 'Chemical', 'MESH:D017313', (81, 92))	('HPR', 'Gene', '3250', (98, 101))	('apoptosis', 'CPA', (192, 201))	('decreases', 'NegReg', (229, 238))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('206', '223'))	('apoptosis', 'biological_process', 'GO:0006915', ('192', '201'))	('cell growth', 'biological_process', 'GO:0016049', ('242', '253'))	('retinoid', 'Chemical', 'MESH:D012176', (24, 32))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (206, 223))	('N-4-hydroxyphenyl-retinamide', 'Var', (51, 79))	('HPR', 'Gene', (98, 101))
3097	21924649	However, subgroup analysis showed that high-risk patients receiving BCG and treated with 4-HPR were 1/3 as likely to develop recurrence as those administered placebo.	('BCG', 'Var', (68, 71))	('HPR', 'Gene', '3250', (91, 94))	('develop', 'PosReg', (117, 124))	('HPR', 'Gene', (91, 94))	('patients', 'Species', '9606', (49, 57))
3112	21924649	In addition, immunohistochemical analysis of PPARgamma expression in human bladder urothelium has demonstrated an association between attenuated nuclear localization and increasing histological grade in bladder carcinoma suggesting that loss of PPARgamma may be an important step in the progression of bladder cancer.	('bladder cancer', 'Disease', (302, 316))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (203, 220))	('PPARgamma', 'Gene', (245, 254))	('loss', 'Var', (237, 241))	('bladder carcinoma', 'Disease', (203, 220))	('nuclear localization', 'MPA', (145, 165))	('bladder carcinoma', 'Disease', 'MESH:D001749', (203, 220))	('human', 'Species', '9606', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('bladder cancer', 'Phenotype', 'HP:0009725', (302, 316))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('bladder cancer', 'Disease', 'MESH:D001749', (302, 316))	('attenuated', 'NegReg', (134, 144))	('PPARgamma', 'Gene', (45, 54))	('localization', 'biological_process', 'GO:0051179', ('153', '165'))
3114	21924649	Indeed, RXR-specific inhibitors have been shown to attenuate TZ-induced CK13 expression in NHU cell cultures suggesting a cooperative role of PPARgamma-RXR signaling in urothelial differentiation processes.	('RXR', 'Gene', '6256', (8, 11))	('expression', 'MPA', (77, 87))	('RXR', 'Gene', (8, 11))	('RXR', 'molecular_function', 'GO:0004879', ('8', '11'))	('RXR', 'Gene', (152, 155))	('attenuate', 'NegReg', (51, 60))	('inhibitors', 'Var', (21, 31))	('TZ', 'Chemical', 'MESH:D000077288', (61, 63))	('CK13', 'Gene', '3860', (72, 76))	('CK13', 'Gene', (72, 76))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('RXR', 'molecular_function', 'GO:0004879', ('152', '155'))	('RXR', 'Gene', '6256', (152, 155))
3116	21924649	These factors were induced upon TZ stimulation and formed transcriptional complexes on putative binding sites of UP1a, UP2, and UP3a promoter fragments while knockdown by transient siRNA of either FOXA1 or IRF-1 abrogated PPARgamma-induced uroplakin expression.	('UP3a', 'Gene', '7380', (128, 132))	('UP3a', 'Gene', (128, 132))	('binding', 'molecular_function', 'GO:0005488', ('96', '103'))	('UP2', 'Gene', '7379', (119, 122))	('IRF-1', 'Gene', '3659', (206, 211))	('UP2', 'Gene', (119, 122))	('UP1a', 'Gene', (113, 117))	('knockdown', 'Var', (158, 167))	('abrogated', 'NegReg', (212, 221))	('FOXA1', 'Gene', (197, 202))	('UP1a', 'Gene', '11045', (113, 117))	('TZ', 'Chemical', 'MESH:D000077288', (32, 34))	('formed', 'Reg', (51, 57))	('IRF-1', 'Gene', (206, 211))
3135	21924649	All 3 genes possess a second intronic promoter that yields N-terminally truncated variants that act as antagonists of the full-length proteins.	('variants', 'Var', (82, 90))	('All 3', 'Gene', (0, 5))	('All 3', 'Gene', '5079', (0, 5))	('N-terminally truncated', 'MPA', (59, 81))
3137	21924649	Subsequent identification and characterization of p63 and p73 variants, including the development and analysis of mice genetically modified for these isoforms has yielded a wealth of information regarding the redundant and tissue-specific functions of all three family members.	('p73 variants', 'Var', (58, 70))	('variants', 'Var', (62, 70))	('p63', 'Var', (50, 53))	('mice', 'Species', '10090', (114, 118))
3138	21924649	As the most commonly inactivated tumor suppressor in human tumors, it is not surprising that p53 has been functionally linked to the development of urothelial carcinoma, with a majority of bladder cancers displaying alterations in p53 expression.	('tumor', 'Disease', (59, 64))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('bladder cancers', 'Disease', 'MESH:D001749', (189, 204))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('bladder cancers', 'Disease', (189, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('p53', 'Gene', (231, 234))	('tumor', 'Disease', (33, 38))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('linked', 'Reg', (119, 125))	('alterations', 'Var', (216, 227))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('urothelial carcinoma', 'Disease', (148, 168))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('bladder cancer', 'Phenotype', 'HP:0009725', (189, 203))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('human', 'Species', '9606', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('bladder cancers', 'Phenotype', 'HP:0009725', (189, 204))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', (59, 65))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (148, 168))
3139	21924649	In marked contrast, mutations of p63 and p73 are rare in human tumors with differences in expression level and/or isoform expression appearing to be the dominant events in cancer.	('p73', 'Var', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('p63', 'Var', (33, 36))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('human', 'Species', '9606', (57, 62))	('expression level', 'MPA', (90, 106))
3141	21924649	Loss of p53 is necessary but not sufficient for development of urothelial tumors, requiring cooperation with oncogenes such as Ha-ras to elicit tumor formation.	('tumor', 'Disease', (144, 149))	('p53', 'Gene', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('urothelial tumors', 'Disease', 'MESH:D001749', (63, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('urothelial tumors', 'Disease', (63, 80))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('formation', 'biological_process', 'GO:0009058', ('150', '159'))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('Loss', 'Var', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
3147	21924649	Silencing of DeltaNp63 in keratinocytes led to marked downregulation of the genes encoding members of the claudin family, including claudin-1, -3 and -10.	('claudin-1, -3 and -10', 'Gene', '9076;1365;9071', (132, 153))	('DeltaNp63', 'Gene', (13, 22))	('Silencing', 'Var', (0, 9))	('downregulation', 'NegReg', (54, 68))
3155	21924649	A similar expression pattern was observed when p63 was assessed by immunohistochemical staining, although in that study the antibody used for analysis detected both full-length and truncated p63 variants such that the relative expression of DeltaNp63 in tumors could not be determined.	('antibody', 'molecular_function', 'GO:0003823', ('124', '132'))	('tumors', 'Disease', (254, 260))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('variants', 'Var', (195, 203))	('antibody', 'cellular_component', 'GO:0019815', ('124', '132'))	('antibody', 'cellular_component', 'GO:0042571', ('124', '132'))	('p63', 'Gene', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('antibody', 'cellular_component', 'GO:0019814', ('124', '132'))
3159	21924649	In human bladder cancer tissues, p63 was robustly expressed in non muscle-invasive lesions, with a subset (~15-30%) positive for DeltaNp63.	('positive', 'Reg', (116, 124))	('bladder cancer', 'Disease', 'MESH:D001749', (9, 23))	('bladder cancer', 'Disease', (9, 23))	('non muscle-invasive lesions', 'Disease', (63, 90))	('human', 'Species', '9606', (3, 8))	('DeltaNp63', 'Var', (129, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (9, 23))	('p63', 'Gene', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
3160	21924649	Furthermore, the extent of DeltaNp63 positivity was further increased in muscle-invasive specimens suggesting an association with DeltaNp63 expression and tumor aggressiveness.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (155, 175))	('association', 'Interaction', (113, 124))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('DeltaNp63', 'Gene', (27, 36))	('tumor aggressiveness', 'Disease', (155, 175))	('positivity', 'Var', (37, 47))	('aggressiveness', 'Phenotype', 'HP:0000718', (161, 175))	('muscle-invasive', 'Disease', (73, 88))
3164	21924649	Analysis of overall p73 mRNA levels revealed increased expression in invasive bladder cancers compared to normal bladder tissues, whereas evaluation of p73 protein levels, specifically the alpha isoform suggested loss of p73alpha was associated with tumor progression.	('p73alpha', 'Var', (221, 229))	('loss', 'NegReg', (213, 217))	('bladder cancers', 'Disease', 'MESH:D001749', (78, 93))	('associated', 'Reg', (234, 244))	('increased', 'PosReg', (45, 54))	('bladder cancer', 'Phenotype', 'HP:0009725', (78, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('expression', 'MPA', (55, 65))	('bladder cancers', 'Disease', (78, 93))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('invasive bladder', 'Phenotype', 'HP:0100645', (69, 85))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (69, 92))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('invasive bladder cancer', 'Disease', (69, 92))	('tumor', 'Disease', (250, 255))	('bladder cancers', 'Phenotype', 'HP:0009725', (78, 93))
3180	19948444	Although only a very small group of patients was analyzed in this study, the presence of CTCs seems to be correlated with an advanced tumor stage.	('patients', 'Species', '9606', (36, 44))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('presence', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('CTCs', 'Gene', (89, 93))	('correlated', 'Reg', (106, 116))
3256	19948444	Although only a very small group of patients was analyzed in this study, the presence of CTCs seems to be correlated with advanced tumor stage in patients with TCC.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('TCC', 'cellular_component', 'GO:0005579', ('160', '163'))	('tumor', 'Disease', (131, 136))	('presence', 'Var', (77, 85))	('CTCs', 'Gene', (89, 93))	('patients', 'Species', '9606', (146, 154))	('correlated', 'Reg', (106, 116))
3260	32962091	Deregulated FGFR signaling plays an important role in tumor development and progression in different cancer types.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('Deregulated', 'Var', (0, 11))	('FGFR', 'Protein', (12, 16))	('cancer', 'Disease', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', (54, 59))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))
3262	32962091	In this review, we describe the most frequent FGFR aberrations in human cancer.	('aberrations', 'Var', (51, 62))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('FGFR', 'Gene', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
3265	32962091	Mutations (single nucleotide variants, SNVs) of FGFRs have been described in different tumor types.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('FGFRs', 'Gene', (48, 53))	('tumor', 'Disease', (87, 92))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('described', 'Reg', (64, 73))
3268	32962091	The growing therapeutic relevance of FGFR alterations, including fusions, in different cancer types has greatly supported the development of a variety of novel agents along with the improvement of diagnostic tests.	('cancer', 'Disease', (87, 93))	('alterations', 'Var', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('FGFR', 'Gene', (37, 41))
3276	32962091	Alternative splicing in the D3 domain of FGFR1, 2, and 3, generates isoforms IIIb and IIIc with different FGF-binding specificity.	('FGF-binding', 'molecular_function', 'GO:0017134', ('106', '117'))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('FGFR1', 'Gene', (41, 46))	('FGFR1', 'Gene', '2260', (41, 46))	('Alternative splicing in', 'Var', (0, 23))	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))
3277	32962091	Alternative splicing and switching from epithelial to mesenchymal isoforms are involved in the epithelial-to-mesenchymal transition and in tumor progression.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('involved', 'Reg', (79, 87))	('epithelial-to-mesenchymal transition', 'CPA', (95, 131))	('Alternative splicing', 'Var', (0, 20))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('95', '131'))	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))
3278	32962091	However, no data on the involvement of this phenomenon in the growth of cancer addicted to FGFR fusions are available.	('FGFR', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('fusions', 'Var', (96, 103))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('FGFR', 'molecular_function', 'GO:0005007', ('91', '95'))	('cancer', 'Disease', (72, 78))
3288	32962091	Other pathways are activated by FGFRs, including JAK/STAT, p38MAPK, Jun N-terminal kinase, and RSK2.	('RSK2', 'Gene', (95, 99))	('JAK/STAT', 'Var', (49, 57))	('activated', 'PosReg', (19, 28))	('Jun N-terminal kinase', 'Gene', '5599', (68, 89))	('p38MAPK', 'Var', (59, 66))	('MAPK', 'molecular_function', 'GO:0004707', ('62', '66'))	('RSK2', 'Gene', '6197', (95, 99))	('FGFRs', 'Gene', (32, 37))	('JAK', 'molecular_function', 'GO:0004713', ('49', '52'))	('Jun N-terminal kinase', 'Gene', (68, 89))
3289	32962091	Deregulated FGFR signaling is observed in various tumor types.	('Deregulated', 'Var', (0, 11))	('FGFR', 'Protein', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))	('tumor', 'Disease', (50, 55))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))
3290	32962091	A recent study that analyzed the FGFR genomic alterations in 4853 tumor samples by next-generation sequencing (NGS), described the presence of FGFR alterations in 7.1% of cases.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('FGFR', 'Gene', (143, 147))	('alterations', 'Var', (148, 159))	('tumor', 'Disease', (66, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('143', '147'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('FGFR', 'Gene', (33, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))
3291	32962091	Genetic aberrations of FGFR1 are more frequently observed in human cancers (2.86%), followed by alterations in FGFR3 (2.21%), FGFR2 (1.77%), and FGFR4 (1.54%).	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('FGFR1', 'Gene', (23, 28))	('FGFR2', 'Gene', '2263', (126, 131))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('FGFR', 'molecular_function', 'GO:0005007', ('126', '130'))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('FGFR1', 'Gene', '2260', (23, 28))	('FGFR4', 'Gene', '2264', (145, 150))	('FGFR4', 'Gene', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('Genetic aberrations', 'Var', (0, 19))	('FGFR3', 'Gene', (111, 116))	('observed', 'Reg', (49, 57))	('FGFR2', 'Gene', (126, 131))	('human', 'Species', '9606', (61, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('145', '149'))
3292	32962091	Gene amplifications are the most frequent FGFR alterations reported in human cancers accounting for 66% of all FGFR aberrations.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('FGFR', 'Gene', (42, 46))	('Gene amplifications', 'Var', (0, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('human', 'Species', '9606', (71, 76))
3294	32962091	FGFR1 amplification is frequently observed in breast, lung, and colon cancer.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('colon cancer', 'Phenotype', 'HP:0003003', (64, 76))	('colon cancer', 'Disease', 'MESH:D015179', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('breast', 'Disease', (46, 52))	('colon cancer', 'Disease', (64, 76))	('observed', 'Reg', (34, 42))	('amplification', 'Var', (6, 19))	('lung', 'Disease', (54, 58))
3295	32962091	FGFR2 amplification is less frequent (0.34%) and has been described in some cancer types, including breast, gastric, and esophageal carcinoma.	('described', 'Reg', (58, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('breast', 'Disease', (100, 106))	('gastric', 'Disease', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('esophageal carcinoma', 'Disease', (121, 141))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (121, 141))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (121, 141))	('amplification', 'Var', (6, 19))	('FGFR2', 'Gene', (0, 5))	('cancer', 'Disease', (76, 82))	('FGFR2', 'Gene', '2263', (0, 5))
3298	32962091	FGFR mutations are less frequent than FGFR amplifications, representing 26% of the aberrations detected in FGFR-altered tumors.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('FGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))
3299	32962091	Mutations in FGFR1 have been observed in 1.12% of cases, with a prevalence in lung, colon, breast, endometrial adenocarcinoma, and glioblastoma multiforme.	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (131, 154))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (99, 125))	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('observed', 'Reg', (29, 37))	('prevalence', 'Reg', (64, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('FGFR1', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('FGFR1', 'Gene', '2260', (13, 18))	('endometrial adenocarcinoma', 'Disease', (99, 125))	('lung', 'Disease', (78, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('glioblastoma multiforme', 'Disease', (131, 154))	('breast', 'Disease', (91, 97))	('colon', 'Disease', (84, 89))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (99, 125))
3300	32962091	The most frequent FGFR1 activating mutation is the N546K (0.12%) in the kinase domain of the receptor that alters the tyrosine auto-phosphorylation with an increased kinase activation.	('kinase', 'MPA', (166, 172))	('activation', 'PosReg', (173, 183))	('activating', 'PosReg', (24, 34))	('tyrosine auto-phosphorylation', 'MPA', (118, 147))	('tyrosine', 'Chemical', 'MESH:D014443', (118, 126))	('N546K', 'Var', (51, 56))	('increased', 'PosReg', (156, 165))	('N546K', 'Mutation', 'rs779707422', (51, 56))	('FGFR1', 'Gene', (18, 23))	('alters', 'Reg', (107, 113))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('FGFR1', 'Gene', '2260', (18, 23))	('phosphorylation', 'biological_process', 'GO:0016310', ('132', '147'))
3301	32962091	Mutations in FGFR2 and FGFR3 are more frequent (1.36% and 1.83%, respectively).	('FGFR3', 'Gene', (23, 28))	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('Mutations', 'Var', (0, 9))	('FGFR2', 'Gene', '2263', (13, 18))	('FGFR2', 'Gene', (13, 18))
3302	32962091	The most common FGFR2 activating mutations are the S252W mutation in the extracellular domain (0.17%), the N549K mutation in the tyrosine kinase domain (0.06%), and the C382R mutation affecting the transmembrane domain of the receptor (0.06%).	('S252W', 'Var', (51, 56))	('C382R', 'Mutation', 'rs121913474', (169, 174))	('N549K', 'Var', (107, 112))	('N549K', 'Mutation', 'rs121913476', (107, 112))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('extracellular', 'cellular_component', 'GO:0005576', ('73', '86'))	('S252W', 'Mutation', 'rs79184941', (51, 56))	('C382R', 'Var', (169, 174))	('FGFR2', 'Gene', (16, 21))	('FGFR2', 'Gene', '2263', (16, 21))	('tyrosine', 'Chemical', 'MESH:D014443', (129, 137))	('affecting', 'Reg', (184, 193))	('transmembrane', 'cellular_component', 'GO:0044214', ('198', '211'))	('transmembrane', 'cellular_component', 'GO:0016021', ('198', '211'))	('activating', 'PosReg', (22, 32))
3303	32962091	The most frequent FGFR3 activating mutation is the S249C missense mutation that resides in the extracellular domain of the receptor (0.54%).	('extracellular', 'cellular_component', 'GO:0005576', ('95', '108'))	('activating', 'PosReg', (24, 34))	('FGFR3', 'Gene', (18, 23))	('S249C', 'Mutation', 'rs121913483', (51, 56))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('S249C missense', 'Var', (51, 65))
3304	32962091	The FGFR3 S249C mutation is relatively frequent in bladder cancer (66.6%).	('bladder cancer', 'Disease', (51, 65))	('frequent', 'Reg', (39, 47))	('S249C', 'Var', (10, 15))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('S249C', 'Mutation', 'rs121913483', (10, 15))	('FGFR3', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('bladder cancer', 'Disease', 'MESH:D001749', (51, 65))
3305	32962091	FGFR4-activating mutations are rare and are detected in some pediatric tumors, such as rhabdomyosarcoma.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR4', 'Gene', (0, 5))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (87, 103))	('detected', 'Reg', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('FGFR4', 'Gene', '2264', (0, 5))	('tumors', 'Disease', (71, 77))	('rhabdomyosarcoma', 'Disease', (87, 103))	('mutations', 'Var', (17, 26))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (87, 103))
3306	32962091	A novel oncogenic mutation of FGFR4 (G636C) has been recently discovered in gastric cancer.	('G636C', 'Mutation', 'c.636G>C', (37, 42))	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('FGFR4', 'Gene', (30, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('FGFR4', 'Gene', '2264', (30, 35))	('G636C', 'Var', (37, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('gastric cancer', 'Disease', (76, 90))
3307	32962091	FGFR fusions have been described in several tumor types, although the incidence is low (8%).	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'Gene', (0, 4))	('fusions', 'Var', (5, 12))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('described', 'Reg', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
3309	32962091	Fusion genes between FGFR1-2-3 and multiple partners have been identified in several tumor types (Table 1).	('Fusion genes', 'Var', (0, 12))	('tumor', 'Disease', (85, 90))	('identified', 'Reg', (63, 73))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('FGFR1', 'Gene', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('FGFR1', 'Gene', '2260', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
3311	32962091	FGFR1 fusions are rare in solid tumors.	('solid tumors', 'Disease', (26, 38))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('solid tumors', 'Disease', 'MESH:D009369', (26, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('fusions', 'Var', (6, 13))
3312	32962091	A FGFR1-HOOK3 gene fusion has been observed in gastrointestinal stromal tumor (GIST).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('fusion', 'Var', (19, 25))	('FGFR1', 'Gene', (2, 7))	('FGFR1', 'Gene', '2260', (2, 7))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (47, 77))	('HOOK3', 'Gene', (8, 13))	('gastrointestinal stromal tumor', 'Disease', (47, 77))	('GIST', 'Phenotype', 'HP:0100723', (79, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('2', '6'))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (47, 77))	('observed', 'Reg', (35, 43))	('HOOK3', 'Gene', '84376', (8, 13))
3314	32962091	These fusions involve the N-terminus of the FGFR1 protein and the coiled coil of the fusion partners to induce activation of the receptor and downstream signaling.	('activation', 'PosReg', (111, 121))	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('FGFR1', 'Gene', (44, 49))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('receptor', 'MPA', (129, 137))	('FGFR1', 'Gene', '2260', (44, 49))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('fusions', 'Var', (6, 13))
3317	32962091	FGFR2 fusions are the most frequent FGFR fusions.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))	('FGFR2', 'Gene', '2263', (0, 5))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
3318	32962091	As compared with the other member of the FGFR family, FGFR2 had several reported partners and FGFR2 fusions are particularly common in cholangiocarcinoma.	('fusions', 'Var', (100, 107))	('common', 'Reg', (125, 131))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('FGFR2', 'Gene', (94, 99))	('cholangiocarcinoma', 'Disease', (135, 153))	('FGFR2', 'Gene', '2263', (94, 99))	('FGFR2', 'Gene', (54, 59))	('FGFR2', 'Gene', '2263', (54, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('FGFR', 'molecular_function', 'GO:0005007', ('54', '58'))	('FGFR', 'molecular_function', 'GO:0005007', ('94', '98'))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (135, 153))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (135, 153))
3319	32962091	In this regard, FGFR2-AHCYL, FGFR2-BICC1, FGFR2-PPHLN1, and FGFR2-TACC3 fusions have been frequently described in patients with intrahepatic cholangiocarcinoma, although over 100 different FGFR2 partners have been reported in this disease.	('FGFR', 'molecular_function', 'GO:0005007', ('189', '193'))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('described', 'Reg', (101, 110))	('FGFR', 'molecular_function', 'GO:0005007', ('29', '33'))	('FGFR2', 'Gene', '2263', (29, 34))	('FGFR2', 'Gene', (60, 65))	('FGFR2', 'Gene', (42, 47))	('BICC1', 'Gene', '80114', (35, 40))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('FGFR2', 'Gene', '2263', (60, 65))	('BICC1', 'Gene', (35, 40))	('patients', 'Species', '9606', (114, 122))	('PPHLN1', 'Gene', (48, 54))	('FGFR2', 'Gene', '2263', (42, 47))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (128, 159))	('FGFR2', 'Gene', (16, 21))	('intrahepatic cholangiocarcinoma', 'Disease', (128, 159))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (141, 159))	('fusions', 'Var', (72, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('FGFR2', 'Gene', (189, 194))	('PPHLN1', 'Gene', '51535', (48, 54))	('FGFR2', 'Gene', (29, 34))	('FGFR2', 'Gene', '2263', (16, 21))	('FGFR2', 'Gene', '2263', (189, 194))
3320	32962091	The FGFR2-CCDC6 fusion has been demonstrated to induce cancer cell proliferation and tumorigenesis in vivo.	('tumor', 'Disease', (85, 90))	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('fusion', 'Var', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('FGFR2', 'Gene', '2263', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('induce', 'PosReg', (48, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('CCDC6', 'Gene', '8030', (10, 15))	('CCDC6', 'Gene', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('FGFR2', 'Gene', (4, 9))	('cancer', 'Disease', (55, 61))
3323	32962091	Two FGFR2-KIAA1598 fusions and other FGFR2 fusions with novel partners (CIT, ERC1, LZTFL1, POC1B, SORBS1, TP73, TXLNA) have been recently identified in a large cohort (n = 26054) of lung cancer patients.	('POC1B', 'Gene', (91, 96))	('ERC1', 'Gene', (77, 81))	('lung cancer', 'Disease', (182, 193))	('KIAA1598', 'Gene', '57698', (10, 18))	('FGFR2', 'Gene', '2263', (37, 42))	('CIT', 'Gene', '11113', (72, 75))	('FGFR2', 'Gene', '2263', (4, 9))	('TP73', 'Gene', (106, 110))	('POC1B', 'Gene', '282809', (91, 96))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('CIT', 'Gene', (72, 75))	('LZTFL1', 'Gene', '54585', (83, 89))	('patients', 'Species', '9606', (194, 202))	('KIAA1598', 'Gene', (10, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('fusions', 'Var', (19, 26))	('fusions', 'Var', (43, 50))	('CIT', 'biological_process', 'GO:0106106', ('72', '75'))	('SORBS1', 'Gene', '10580', (98, 104))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('TP73', 'Gene', '7161', (106, 110))	('SORBS1', 'Gene', (98, 104))	('TXLNA', 'Gene', '200081', (112, 117))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('ERC', 'cellular_component', 'GO:0055037', ('77', '80'))	('FGFR2', 'Gene', (37, 42))	('LZTFL1', 'Gene', (83, 89))	('ERC1', 'Gene', '23085', (77, 81))	('TXLNA', 'Gene', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('FGFR2', 'Gene', (4, 9))
3324	32962091	FGFR3 fusions are more commonly observed in glioblastoma, bladder, and lung cancer.	('glioblastoma', 'Disease', (44, 56))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('glioblastoma', 'Disease', 'MESH:D005909', (44, 56))	('observed', 'Reg', (32, 40))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('FGFR3', 'Gene', (0, 5))	('glioblastoma', 'Phenotype', 'HP:0012174', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('bladder', 'Disease', (58, 65))	('fusions', 'Var', (6, 13))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
3325	32962091	The majority of FGFR3 fusions are with transforming acidic coiled-coil 3 (TACC3) and result from the in-frame fusion of the FGFR3 N-terminus with the TACC3 C-terminus.	('FGFR3', 'Gene', (16, 21))	('transforming acidic coiled-coil 3', 'Gene', (39, 72))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('FGFR', 'molecular_function', 'GO:0005007', ('124', '128'))	('TACC3 C', 'Mutation', 'c.3TACC>C', (150, 157))	('fusions', 'Var', (22, 29))	('transforming acidic coiled-coil 3', 'Gene', '10460', (39, 72))	('FGFR3', 'Gene', (124, 129))
3326	32962091	FGFR3-TACC3 fusions have been described in different tumor types, including glioma, lung cancer, bladder cancer, head and neck squamous cancer, lung squamous cell carcinoma, and cervical cancer.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('glioma', 'Disease', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Disease', (105, 111))	('head and neck squamous cancer', 'Disease', 'MESH:D006258', (113, 142))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('squamous cancer', 'Phenotype', 'HP:0002860', (127, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('described', 'Reg', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('fusions', 'Var', (12, 19))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (144, 172))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('bladder cancer', 'Disease', 'MESH:D001749', (97, 111))	('bladder cancer', 'Disease', (97, 111))	('neck', 'cellular_component', 'GO:0044326', ('122', '126'))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('lung cancer', 'Disease', (84, 95))	('FGFR3-TACC3', 'Gene', (0, 11))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (144, 172))	('lung squamous cell carcinoma', 'Disease', (144, 172))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (187, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('head and neck squamous cancer', 'Phenotype', 'HP:0012288', (113, 142))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('tumor', 'Disease', (53, 58))
3329	32962091	The presence of the FGFR3-TACC3 fusion increased the proliferation of cancer cell lines and induced tumorigenesis in mice.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', (100, 105))	('induced', 'Reg', (92, 99))	('FGFR3-TACC3', 'Gene', (20, 31))	('mice', 'Species', '10090', (117, 121))	('increased', 'PosReg', (39, 48))	('fusion', 'Var', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Disease', (70, 76))	('FGFR', 'molecular_function', 'GO:0005007', ('20', '24'))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
3333	32962091	Recently, FGFR4 fusions (ANO3-FGFR4, NSD1-FGFR4) have been identified in NSCLC patients.	('FGFR4', 'Gene', '2264', (10, 15))	('identified', 'Reg', (59, 69))	('NSCLC', 'Disease', (73, 78))	('NSD1', 'Gene', (37, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('FGFR4', 'Gene', (42, 47))	('FGFR4', 'Gene', (10, 15))	('ANO3', 'Gene', '63982', (25, 29))	('ANO3', 'Gene', (25, 29))	('FGFR', 'molecular_function', 'GO:0005007', ('10', '14'))	('NSD1', 'Gene', '64324', (37, 41))	('FGFR4', 'Gene', '2264', (30, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('fusions', 'Var', (16, 23))	('patients', 'Species', '9606', (79, 87))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('FGFR4', 'Gene', (30, 35))	('FGFR4', 'Gene', '2264', (42, 47))
3336	32962091	Intrachromosomal rearrangements, which account for about 50% of FGFR2 fusions in intrahepatic cholangiocarcinoma, can also lead to false-negative results of FISH analysis.	('FGFR2', 'Gene', '2263', (64, 69))	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('false', 'biological_process', 'GO:0071878', ('131', '136'))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (81, 112))	('FGFR2', 'Gene', (64, 69))	('false', 'biological_process', 'GO:0071877', ('131', '136'))	('fusions', 'Var', (70, 77))	('intrahepatic cholangiocarcinoma', 'Disease', (81, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (94, 112))
3337	32962091	Recently, a novel RNA-FISH assay allowed the detection of FGFR3-TACC3 fusions in bladder cancer.	('FGFR3-TACC3', 'Gene', (58, 69))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('RNA', 'cellular_component', 'GO:0005562', ('18', '21'))	('bladder cancer', 'Disease', 'MESH:D001749', (81, 95))	('bladder cancer', 'Disease', (81, 95))	('bladder cancer', 'Phenotype', 'HP:0009725', (81, 95))	('fusions', 'Var', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
3341	32962091	Anchored multiplex PCR has been recently used to identify various FGFR2 fusions in cholangiocarcinoma clinical samples.	('FGFR2', 'Gene', (66, 71))	('FGFR2', 'Gene', '2263', (66, 71))	('cholangiocarcinoma', 'Disease', (83, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('fusions', 'Var', (72, 79))
3342	32962091	The improvement of diagnostic strategies for detection of FGFR alterations allowed the identification of a number of FGFR fusions that might potentially predict the outcome of cancer patients.	('alterations', 'Var', (63, 74))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('predict', 'Reg', (153, 160))	('FGFR', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('fusions', 'Var', (122, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('117', '121'))	('FGFR', 'Gene', (117, 121))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('patients', 'Species', '9606', (183, 191))
3344	32962091	In this regard, a study evaluated the presence of FGFR2 translocations in 152 cholangiocarcinoma and 4 intraductal papillary neoplasms of the bile duct by FISH.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('papillary neoplasms', 'Disease', (115, 134))	('FGFR2', 'Gene', (50, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('50', '54'))	('FGFR2', 'Gene', '2263', (50, 55))	('cholangiocarcinoma', 'Disease', (78, 96))	('neoplasms', 'Phenotype', 'HP:0002664', (125, 134))	('papillary neoplasms', 'Disease', 'MESH:D002291', (115, 134))	('translocations', 'Var', (56, 70))
3345	32962091	Thirteen specimens were positive for FGFR2 translocations.	('positive', 'Reg', (24, 32))	('FGFR2', 'Gene', (37, 42))	('translocations', 'Var', (43, 57))	('FGFR2', 'Gene', '2263', (37, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))
3346	32962091	The median cancer-specific survival interval for patients carrying FGFR2 translocations was significantly longer (123 months) than that for patients without FGFR2 translocations (37 months, P = 0.039).	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('translocations', 'Var', (73, 87))	('longer', 'PosReg', (106, 112))	('FGFR2', 'Gene', (67, 72))	('FGFR2', 'Gene', '2263', (67, 72))	('FGFR2', 'Gene', (157, 162))	('patients', 'Species', '9606', (140, 148))	('patients', 'Species', '9606', (49, 57))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))	('FGFR2', 'Gene', '2263', (157, 162))	('FGFR', 'molecular_function', 'GO:0005007', ('157', '161'))
3347	32962091	In a study in which 377 patients with biliary tract cancer were enrolled, 95 FGFR genetic alterations, including 63 FGFR2 fusions, were detected.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('116', '120'))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (38, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('patients', 'Species', '9606', (24, 32))	('genetic alterations', 'Var', (82, 101))	('FGFR2', 'Gene', (116, 121))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('FGFR2', 'Gene', '2263', (116, 121))	('cancer', 'Disease', (52, 58))	('FGFR', 'Gene', (77, 81))
3348	32962091	Patients with FGFR alterations experienced significantly longer overall survival (OS) than patients without FGFR aberrations (37 vs. 20 months; P <0.001).	('longer', 'PosReg', (57, 63))	('patients', 'Species', '9606', (91, 99))	('FGFR', 'Gene', (14, 18))	('overall survival', 'MPA', (64, 80))	('Patients', 'Species', '9606', (0, 8))	('alterations', 'Var', (19, 30))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))
3349	32962091	In a recent study in patients with fluke associated-intrahepatic cholangiocarcinoma, the presence of rare FGFR2 fusions indicated a trend toward better OS compared with that of fusion-negative tumors, although the difference was not statistically significant.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (52, 83))	('tumors', 'Disease', (193, 199))	('FGFR2', 'Gene', '2263', (106, 111))	('intrahepatic cholangiocarcinoma', 'Disease', (52, 83))	('fusions', 'Var', (112, 119))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('patients', 'Species', '9606', (21, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('better', 'PosReg', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('FGFR2', 'Gene', (106, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))	('presence', 'Var', (89, 97))
3350	32962091	The presence of FGFR genomic alterations, including FGFR2 fusions genes identified by NGS in 55 patients with intrahepatic cholangiocarcinoma, has been associated with an indolent disease course and prolonged survival.	('FGFR', 'Gene', (16, 20))	('fusions genes', 'Var', (58, 71))	('FGFR2', 'Gene', (52, 57))	('FGFR2', 'Gene', '2263', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (110, 141))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (123, 141))	('intrahepatic cholangiocarcinoma', 'Disease', (110, 141))	('patients', 'Species', '9606', (96, 104))	('associated with', 'Reg', (152, 167))	('presence', 'Var', (4, 12))
3352	32962091	Interestingly, one patient with an FGFR2-NOL4 fusion and a co-existing BAP1 mutation had a rapidly progressive course.	('patient', 'Species', '9606', (19, 26))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR2', 'Gene', (35, 40))	('FGFR2', 'Gene', '2263', (35, 40))	('fusion', 'Var', (46, 52))	('NOL4', 'Gene', '8715', (41, 45))	('BAP1', 'Gene', '8314', (71, 75))	('mutation', 'Var', (76, 84))	('BAP1', 'Gene', (71, 75))	('NOL4', 'Gene', (41, 45))
3354	32962091	In this study, KRAS and BRAF mutations were mutually exclusive with FGFR2 fusions.	('FGFR', 'molecular_function', 'GO:0005007', ('68', '72'))	('KRAS', 'Gene', (15, 19))	('mutations', 'Var', (29, 38))	('FGFR2', 'Gene', '2263', (68, 73))	('fusions', 'Var', (74, 81))	('BRAF', 'Gene', (24, 28))	('KRAS', 'Gene', '3845', (15, 19))	('BRAF', 'Gene', '673', (24, 28))	('FGFR2', 'Gene', (68, 73))
3355	32962091	The prognostic significance of FGFR1-3 fusions was explored in NSCLC.	('NSCLC', 'Disease', (63, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('fusions', 'Var', (39, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('FGFR1', 'Gene', (31, 36))	('FGFR1', 'Gene', '2260', (31, 36))
3361	32962091	Different clinical trials of non-selective TKIs are ongoing in patients with FGFR alterations (Table 3).	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('patients', 'Species', '9606', (63, 71))	('alterations', 'Var', (82, 93))	('FGFR', 'Gene', (77, 81))
3363	32962091	In this regard, in a study of dovitinib in 13 patients with Bacillus Calmette-Guerin (BCG)-refractory urothelial carcinoma and FGFR3 alterations, three patients had FGFR3 mutations.	('patients', 'Species', '9606', (46, 54))	('alterations', 'Var', (133, 144))	('FGFR', 'molecular_function', 'GO:0005007', ('165', '169'))	('FGFR3', 'Gene', (165, 170))	('dovitinib', 'Chemical', 'MESH:C500007', (30, 39))	('FGFR3', 'Gene', (127, 132))	('Bacillus Calmette-Guerin', 'Species', '33892', (60, 84))	('urothelial carcinoma', 'Disease', (102, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('FGFR', 'molecular_function', 'GO:0005007', ('127', '131'))	('BCG', 'Species', '33892', (86, 89))	('mutations', 'Var', (171, 180))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (102, 122))	('patients', 'Species', '9606', (152, 160))
3364	32962091	The response rate (RR) was 8% with only one complete response (CR) in a patient carrying the FGFR3 S249C mutation.	('S249C', 'Var', (99, 104))	('S249C', 'Mutation', 'rs121913483', (99, 104))	('patient', 'Species', '9606', (72, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('FGFR3', 'Gene', (93, 98))
3366	32962091	In a clinical study in FGFR2-mutant or wild-type endometrial cancer patients treated with dovitinib, the RR in the FGFR2 mutant group was 5% (11% for all patients); only 1/22 FGFR2 mutant patients achieved a partial response (PR).	('endometrial cancer', 'Disease', (49, 67))	('mutant', 'Var', (121, 127))	('FGFR2', 'Gene', (115, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('175', '179'))	('patients', 'Species', '9606', (188, 196))	('endometrial cancer', 'Disease', 'MESH:D016889', (49, 67))	('FGFR2', 'Gene', '2263', (115, 120))	('patients', 'Species', '9606', (68, 76))	('FGFR2', 'Gene', (175, 180))	('FGFR2', 'Gene', (23, 28))	('patients', 'Species', '9606', (154, 162))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('FGFR2', 'Gene', '2263', (175, 180))	('FGFR', 'molecular_function', 'GO:0005007', ('115', '119'))	('mutant', 'Var', (181, 187))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('endometrial cancer', 'Phenotype', 'HP:0012114', (49, 67))	('FGFR2', 'Gene', '2263', (23, 28))	('dovitinib', 'Chemical', 'MESH:C500007', (90, 99))
3367	32962091	Treatment with derazantinib produced an overall RR (ORR) of 20.7%, a disease control rate (DCR) of 82.8%, and a median progression-free survival (PFS) of 5.7 months in patients with advanced, unresectable intrahepatic cholangiocarcinoma and FGFR2 fusions who progressed after chemotherapy.	('DCR', 'Chemical', '-', (91, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('FGFR2', 'Gene', (241, 246))	('FGFR2', 'Gene', '2263', (241, 246))	('derazantinib', 'Chemical', 'MESH:C000621805', (15, 27))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (218, 236))	('fusions', 'Var', (247, 254))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (205, 236))	('disease control', 'Disease', (69, 84))	('patients', 'Species', '9606', (168, 176))	('FGFR', 'molecular_function', 'GO:0005007', ('241', '245'))	('intrahepatic cholangiocarcinoma', 'Disease', (205, 236))
3371	32962091	In particular, erdafitinib has been approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma with FGFR3 or FGFR2 genetic alterations, including R248C, S249C, G370C, and Y373C mutations and FGFR3-TACC3 fusions, on the basis of the BLC2001 trial.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (111, 131))	('FGFR2', 'Gene', (146, 151))	('Y373C', 'Mutation', 'rs121913485', (208, 213))	('S249C', 'Mutation', 'rs121913483', (190, 195))	('urothelial carcinoma', 'Disease', (111, 131))	('FGFR2', 'Gene', '2263', (146, 151))	('locally advanced', 'Disease', (80, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('137', '141'))	('FGFR', 'molecular_function', 'GO:0005007', ('228', '232'))	('erdafitinib', 'Chemical', 'MESH:C000604580', (15, 26))	('G370C', 'Var', (197, 202))	('FGFR', 'molecular_function', 'GO:0005007', ('146', '150'))	('R248C', 'Var', (183, 188))	('R248C', 'Mutation', 'rs121913482', (183, 188))	('Y373C mutations', 'Var', (208, 223))	('G370C', 'Mutation', 'rs199740841', (197, 202))	('patients', 'Species', '9606', (66, 74))	('FGFR3', 'Gene', (137, 142))	('S249C', 'Var', (190, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))
3374	32962091	Pemigatinib was granted FDA-accelerated approval in April 2020 for the treatment of cholangiocarcinoma patients with FGFR2 fusions or rearrangements.	('rearrangements', 'Var', (134, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('Pemigatinib', 'Chemical', '-', (0, 11))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('FGFR2', 'Gene', (117, 122))	('FGFR2', 'Gene', '2263', (117, 122))	('cholangiocarcinoma', 'Disease', (84, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('117', '121'))	('fusions', 'Var', (123, 130))	('patients', 'Species', '9606', (103, 111))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
3375	32962091	The efficacy of the drug was evaluated in the FIGHT-202 study in 107 patients with cholangiocarcinoma and FGFR2 gene fusions.	('cholangiocarcinoma', 'Disease', (83, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('FGFR2', 'Gene', '2263', (106, 111))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('gene fusions', 'Var', (112, 124))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('patients', 'Species', '9606', (69, 77))	('FGFR2', 'Gene', (106, 111))
3376	32962091	No CRs or PRs were observed in patients with other FGF/FGFR alterations or no FGF/FGFR alterations.	('PRs', 'CPA', (10, 13))	('FGFR', 'molecular_function', 'GO:0005007', ('82', '86'))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('patients', 'Species', '9606', (31, 39))	('alterations', 'Var', (60, 71))	('CRs', 'CPA', (3, 6))
3377	32962091	A number of different reversible competitive inhibitors directed against multiple FGFRs (e.g., erdafitinib, pemigatinib, infigratinib, rogaratinib, AZD4547, Debio1347) are in clinical development in patients with hematologic and solid tumors who carry FGFR alterations (Table 4).	('alterations', 'Var', (257, 268))	('hematologic', 'Disease', (213, 224))	('solid tumors', 'Disease', 'MESH:D009369', (229, 241))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('Debio1347', 'Chemical', 'MESH:C000602562', (157, 166))	('infigratinib', 'Chemical', 'MESH:C568950', (121, 133))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('FGFR', 'molecular_function', 'GO:0005007', ('252', '256'))	('AZD4547', 'Chemical', 'MESH:C572463', (148, 155))	('patients', 'Species', '9606', (199, 207))	('solid tumors', 'Disease', (229, 241))	('erdafitinib', 'Chemical', 'MESH:C000604580', (95, 106))	('pemigatinib', 'Chemical', '-', (108, 119))
3380	32962091	In a phase II trial of AZD4547 in patients with advanced cancers with FGFR1-3 aberrations, PRs were observed in 4 of 48 (8%) patients, including 2 patients with FGFR mutations and 2 with FGFR3-TACC3 fusions.	('PRs', 'Disease', (91, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('70', '74'))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('161', '165'))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('patients', 'Species', '9606', (147, 155))	('aberrations', 'Var', (78, 89))	('observed', 'Reg', (100, 108))	('FGFR1', 'Gene', (70, 75))	('patients', 'Species', '9606', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('187', '191'))	('AZD4547', 'Chemical', 'MESH:C572463', (23, 30))	('FGFR1', 'Gene', '2260', (70, 75))	('patients', 'Species', '9606', (125, 133))
3381	32962091	The 6-month PFS rate was low for patients with FGFR amplifications (0%) and for patients carrying FGFR mutations (6%) and higher for patients with FGFR fusions (56%).	('FGFR', 'Gene', (47, 51))	('mutations', 'Var', (103, 112))	('FGFR', 'Gene', (98, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (80, 88))	('higher', 'PosReg', (122, 128))	('patients', 'Species', '9606', (133, 141))	('PFS', 'Disease', (12, 15))	('amplifications', 'Var', (52, 66))	('low', 'NegReg', (25, 28))	('FGFR', 'molecular_function', 'GO:0005007', ('98', '102'))	('FGFR', 'molecular_function', 'GO:0005007', ('147', '151'))
3383	32962091	In a multicenter, open label, phase II study on infigratinib in chemotherapy-refractory advanced or metastatic cholangiocarcinoma with FGFR alterations, including 48 FGFR2 fusions, all responsive cases harbored FGFR2 fusions.	('FGFR', 'molecular_function', 'GO:0005007', ('211', '215'))	('cholangiocarcinoma', 'Disease', (111, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('166', '170'))	('FGFR2', 'Gene', (166, 171))	('FGFR2', 'Gene', '2263', (166, 171))	('infigratinib', 'Chemical', 'MESH:C568950', (48, 60))	('FGFR2', 'Gene', '2263', (211, 216))	('FGFR2', 'Gene', (211, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('alterations', 'Var', (140, 151))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 129))	('FGFR', 'Gene', (135, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('135', '139'))
3384	32962091	The RR was 14.8 % and the DCR 75.4% (18.8% and 83.3% for patients with FGFR2 fusions, respectively).	('DCR', 'Chemical', '-', (26, 29))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('patients', 'Species', '9606', (57, 65))	('fusions', 'Var', (77, 84))	('FGFR2', 'Gene', '2263', (71, 76))	('FGFR2', 'Gene', (71, 76))
3385	32962091	Reduced target lesion size in at least one disease evaluation was observed in 36/48 patients with tumors bearing FGFR2 fusions.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('FGFR', 'molecular_function', 'GO:0005007', ('113', '117'))	('patients', 'Species', '9606', (84, 92))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('FGFR2', 'Gene', '2263', (113, 118))	('Reduced', 'NegReg', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('fusions', 'Var', (119, 126))	('FGFR2', 'Gene', (113, 118))
3386	32962091	Only few studies with selective reversible FGFR-TKIs are planned in patients specifically carrying only FGFR fusions, presumably due to the low frequency of these alterations (Table 4).	('fusions', 'Var', (109, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('104', '108'))	('patients', 'Species', '9606', (68, 76))	('FGFR', 'Gene', (104, 108))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))
3387	32962091	In this regard, a study exploring the effects of AZD4547 is ongoing in patients with glioma and the FGFR3-TACC3 fusion (ClinicalTrials.gov Identifier: NCT02824133).	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('AZD4547', 'Var', (49, 56))	('AZD4547', 'Chemical', 'MESH:C572463', (49, 56))	('patients', 'Species', '9606', (71, 79))	('glioma', 'Disease', (85, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('100', '104'))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
3388	32962091	Infigratinib is under evaluation in a phase III study as first-line treatment for patients with cholangiocarcinoma and FGFR2 gene fusions/translocations (ClinicalTrials.gov Identifier: NCT03773302) and in a phase I study in patients with high-grade glioma and FGFR3-TACC3 translocations (ClinicalTrials.gov Identifier: NCT04424966).	('FGFR', 'molecular_function', 'GO:0005007', ('260', '264'))	('glioma', 'Disease', 'MESH:D005910', (249, 255))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('Infigratinib', 'Chemical', 'MESH:C568950', (0, 12))	('FGFR2', 'Gene', '2263', (119, 124))	('patients', 'Species', '9606', (82, 90))	('cholangiocarcinoma', 'Disease', (96, 114))	('gene fusions/translocations', 'Var', (125, 152))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))	('glioma', 'Disease', (249, 255))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 114))	('fusions/translocations', 'Var', (130, 152))	('patients', 'Species', '9606', (224, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('FGFR2', 'Gene', (119, 124))
3391	32962091	In a trial exploring futibatinib in previously treated cholangiocarcinoma patients with FGFR alterations, 20/28 patients carrying FGFR2 fusions experienced tumor shrinkage and 7/28 confirmed PR.	('FGFR', 'molecular_function', 'GO:0005007', ('130', '134'))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('alterations', 'Var', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('patients', 'Species', '9606', (74, 82))	('fusions', 'Var', (136, 143))	('cholangiocarcinoma', 'Disease', (55, 73))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('FGFR2', 'Gene', (130, 135))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (55, 73))	('tumor', 'Disease', (156, 161))	('FGFR2', 'Gene', '2263', (130, 135))	('FGFR', 'molecular_function', 'GO:0005007', ('88', '92'))	('futibatinib', 'Chemical', '-', (21, 32))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (55, 73))	('FGFR', 'Gene', (88, 92))
3393	32962091	The irreversible FGFR inhibitor futibatinib is currently under evaluation in a phase III clinical study in patients with advanced cholangiocarcinoma harboring FGFR2 gene rearrangements (ClinicalTrials.gov Identifier: NCT04093362).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (130, 148))	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('FGFR2', 'Gene', (159, 164))	('futibatinib', 'Chemical', '-', (32, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (130, 148))	('FGFR2', 'Gene', '2263', (159, 164))	('rearrangements', 'Var', (170, 184))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('cholangiocarcinoma', 'Disease', (130, 148))	('patients', 'Species', '9606', (107, 115))
3395	32962091	However, the results of clinical trials have clearly demonstrated that only tumors carrying genetic alterations of the FGFRs such as mutations or fusions might respond to treatment with FGFR inhibitors, at least when used as single agents.	('fusions', 'Var', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('FGFRs', 'Gene', (119, 124))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('mutations', 'Var', (133, 142))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('186', '190'))	('respond', 'Reg', (160, 167))
3397	32962091	In the last years, the rapid improvement in the development of drugs targeting FGFR alterations, including fusions, combined with the availability of ever more efficient diagnostic tests, allowed the selection of patients who might benefit from FGFR inhibitors.	('FGFR', 'molecular_function', 'GO:0005007', ('245', '249'))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('FGFR', 'Gene', (79, 83))	('alterations', 'Var', (84, 95))	('patients', 'Species', '9606', (213, 221))
3398	32962091	However, some issues should be considered, such as the need of adequate tools for the detection of FGFR genetic alterations, the identification of the mechanisms of resistance to FGFR inhibitors and the possibility of performing clinical trials specifically for patients with rare alterations.	('FGFR', 'Gene', (99, 103))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('FGFR', 'molecular_function', 'GO:0005007', ('179', '183'))	('patients', 'Species', '9606', (262, 270))	('alterations', 'Var', (112, 123))
3401	32962091	Analysis of cfDNA for the detection of FGFR fusions might also serve as a non-invasive tool for monitoring patients undergoing FGFR-targeted therapies and for the identification of biomarkers of resistance.	('FGFR', 'Gene', (39, 43))	('FGFR', 'molecular_function', 'GO:0005007', ('39', '43'))	('fusions', 'Var', (44, 51))	('FGFR', 'molecular_function', 'GO:0005007', ('127', '131'))	('patients', 'Species', '9606', (107, 115))
3404	32962091	Interestingly, one FGFR2 point mutation (p.V564F) was identified in all patients, suggesting a relevant role of this genomic alteration in the resistance to anti-FGFR agents.	('p.V564F', 'Mutation', 'p.V564F', (41, 48))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))	('FGFR2', 'Gene', '2263', (19, 24))	('FGFR2', 'Gene', (19, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('162', '166'))	('p.V564F', 'Var', (41, 48))	('patients', 'Species', '9606', (72, 80))
3405	32962091	A recent study in patients with fusion-positive intrahepatic cholangiocarcinoma who progressed on BGJ398 or Debio1347 revealed that treatment with the FGFR irreversible inhibitor futibatinib might overcome the acquired resistance to FGFR reversible inhibitors.	('Debio1347', 'Var', (108, 117))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (48, 79))	('BGJ398', 'Gene', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('151', '155'))	('intrahepatic cholangiocarcinoma', 'Disease', (48, 79))	('patients', 'Species', '9606', (18, 26))	('FGFR', 'molecular_function', 'GO:0005007', ('233', '237'))	('futibatinib', 'Chemical', '-', (179, 190))	('BGJ398', 'Chemical', 'MESH:C568950', (98, 104))	('Debio1347', 'Chemical', 'MESH:C000602562', (108, 117))
3409	32962091	Basket trials, in which a sufficient number of patients with specific genetic alterations can be enrolled, regardless of the tumor type, are required, in order to study the significance of these alterations in a larger population and to offer a personalized treatment to patients carrying these rare genomic aberrations.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Disease', (125, 130))	('alterations', 'Var', (78, 89))	('patients', 'Species', '9606', (271, 279))
3410	32962091	In conclusion, the awareness that FGFR alterations, including fusions, play an important role in cancer has greatly enhanced the clinical development of FGFR inhibitors together with the improvement of NGS-based molecular tests.	('enhanced', 'PosReg', (116, 124))	('cancer', 'Disease', (97, 103))	('FGFR', 'molecular_function', 'GO:0005007', ('153', '157'))	('FGFR', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('alterations', 'Var', (39, 50))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
3412	31920346	Identification of an Activating Mutation in the Extracellular Domain of HER2 Conferring Resistance to Pertuzumab The aberrant expression of HER2 is highly associated with tumour occurrence and metastasis, therefore HER2 is extensively targeted for tumour immunotherapy.	('HER2', 'Gene', (72, 76))	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('tumour', 'Disease', (248, 254))	('HER2', 'Gene', '2064', (72, 76))	('tumour', 'Disease', 'MESH:D009369', (171, 177))	('HER2', 'Gene', (215, 219))	('tumour', 'Disease', (171, 177))	('Mutation in', 'Var', (32, 43))	('aberrant expression', 'Var', (117, 136))	('HER2', 'Gene', '2064', (215, 219))	('Extracellular', 'cellular_component', 'GO:0005576', ('48', '61'))	('associated with', 'Reg', (155, 170))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('HER2', 'Gene', (140, 144))	('tumour', 'Disease', 'MESH:D009369', (248, 254))	('HER2', 'Gene', '2064', (140, 144))
3415	31920346	Then, the effect of the most frequent mutation (S310F) on the interaction between pertuzumab and HER2 was analysed by molecular modelling analysis.	('S310F', 'Var', (48, 53))	('interaction', 'Interaction', (62, 73))	('S310F', 'Mutation', 'rs1057519816', (48, 53))
3416	31920346	The effect of the S310F mutation was further evaluated through multiple in vitro binding experiments and antitumour activity assays.	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('S310F', 'Var', (18, 23))	('tumour', 'Disease', (109, 115))	('S310F', 'Mutation', 'rs1057519816', (18, 23))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
3418	31920346	The S310F mutation was shown to confer resistance of HER2-positive tumour cells to pertuzumab treatment.	('S310F', 'Var', (4, 9))	('resistance', 'MPA', (39, 49))	('tumour', 'Disease', (67, 73))	('S310F', 'Mutation', 'rs1057519816', (4, 9))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumour', 'Disease', 'MESH:D009369', (67, 73))
3419	31920346	With molecular modelling analysis, we confirmed the possibility that the S310F mutation might disrupt the interaction between pertuzumab and HER2 as a result of a significant change in the critical residue S310.	('change', 'Reg', (175, 181))	('interaction', 'Interaction', (106, 117))	('S310F', 'Mutation', 'rs1057519816', (73, 78))	('HER2', 'Protein', (141, 145))	('disrupt', 'NegReg', (94, 101))	('S310', 'Var', (206, 210))	('S310F', 'Var', (73, 78))
3420	31920346	Further functional analyses revealed that the S310F mutation completely abolished pertuzumab binding to HER2 receptor and inhibited pertuzumab antitumour efficacy.	('pertuzumab', 'MPA', (132, 142))	('inhibited', 'NegReg', (122, 131))	('abolished', 'NegReg', (72, 81))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('binding', 'molecular_function', 'GO:0005488', ('93', '100'))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('binding', 'Interaction', (93, 100))	('pertuzumab', 'Protein', (82, 92))	('S310F', 'Var', (46, 51))	('tumour', 'Disease', (147, 153))	('HER2 receptor', 'Protein', (104, 117))	('S310F', 'Mutation', 'rs1057519816', (46, 51))
3421	31920346	We demonstrated the loss-of-function mechanism underlying pertuzumab resistance in HER2-positive tumour cells bearing the S310F mutation.	('tumour', 'Disease', (97, 103))	('S310F', 'Var', (122, 127))	('loss-of-function', 'NegReg', (20, 36))	('S310F', 'Mutation', 'rs1057519816', (122, 127))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumour', 'Disease', 'MESH:D009369', (97, 103))
3424	31920346	HER2 amplification/overexpression is implicated in carcinogenesis and increased risk for progression, promoting its use as a promising target for immunotherapy across a variety of tumour types.	('amplification/overexpression', 'PosReg', (5, 33))	('implicated', 'Reg', (37, 47))	('amplification/overexpression', 'Var', (5, 33))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('carcinogenesis', 'Disease', 'MESH:D063646', (51, 65))	('carcinogenesis', 'Disease', (51, 65))	('HER2', 'Protein', (0, 4))	('tumour', 'Disease', (180, 186))
3427	31920346	Previous studies have reported that the drug resistance mechanisms of trastuzumab and pertuzumab include dysregulation of ErbB family receptors, loss of PTEN, and mutations of PI3KCA that result in the activation of the PI3K/Akt signal pathway.	('PI3', 'Gene', (176, 179))	('Akt', 'Gene', '207', (225, 228))	('mutations', 'Var', (163, 172))	('dysregulation', 'MPA', (105, 118))	('loss', 'NegReg', (145, 149))	('PTEN', 'Gene', (153, 157))	('Akt', 'Gene', (225, 228))	('PI3', 'Gene', '5266', (220, 223))	('PTEN', 'Gene', '5728', (153, 157))	('ErbB', 'Gene', (122, 126))	('drug resistance', 'biological_process', 'GO:0042493', ('40', '55'))	('drug resistance', 'biological_process', 'GO:0009315', ('40', '55'))	('ErbB', 'Gene', '1956', (122, 126))	('activation', 'PosReg', (202, 212))	('PI3', 'Gene', '5266', (176, 179))	('drug resistance', 'Phenotype', 'HP:0020174', (40, 55))	('PI3', 'Gene', (220, 223))	('PI3K', 'molecular_function', 'GO:0016303', ('220', '224'))
3428	31920346	As reported by Ou and colleagues, mutations at the amino acid residues V659 and G660 (located in the HER2 transmembrane domain) have been shown to reduce HER2 protein degradation and stabilize HER2 dimerization, thus these mutations are associated with resistance to trastuzumab.	('transmembrane', 'cellular_component', 'GO:0016021', ('106', '119'))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('associated', 'Reg', (237, 247))	('stabilize', 'MPA', (183, 192))	('dimerization', 'MPA', (198, 210))	('HER2', 'Protein', (193, 197))	('HER2 protein', 'Protein', (154, 166))	('reduce', 'NegReg', (147, 153))	('G660', 'Var', (80, 84))	('V659', 'Chemical', 'MESH:C418807', (71, 75))	('mutations', 'Var', (34, 43))	('transmembrane', 'cellular_component', 'GO:0044214', ('106', '119'))	('V659', 'Var', (71, 75))	('protein degradation', 'biological_process', 'GO:0030163', ('159', '178'))
3430	31920346	The S492R mutation in the EGFR extracellular domain was found to be the key factor in cetuximab treatment resistance.	('EGFR', 'Gene', (26, 30))	('S492R', 'Mutation', 'rs1057519860', (4, 9))	('extracellular', 'cellular_component', 'GO:0005576', ('31', '44'))	('S492R', 'Var', (4, 9))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))
3431	31920346	Tumours with a HER2 tyrosine kinase mutation (L755S, L755P, T798M or T798I) showed primary or acquired resistance to lapatinib.	('Tumours', 'Disease', (0, 7))	('resistance to lapatinib', 'MPA', (103, 126))	('L755P', 'Var', (53, 58))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('T798M', 'Var', (60, 65))	('L755S', 'Var', (46, 51))	('HER2', 'Protein', (15, 19))	('L755S', 'Mutation', 'rs121913470', (46, 51))	('T798M', 'Mutation', 'p.T798M', (60, 65))	('tyrosine', 'Chemical', 'None', (20, 28))	('Tumours', 'Disease', 'MESH:D009369', (0, 7))	('lapatinib', 'Chemical', 'MESH:C490728', (117, 126))	('L755P', 'Mutation', 'rs121913469', (53, 58))	('T798I', 'Mutation', 'p.T798I', (69, 74))	('T798I', 'Var', (69, 74))
3432	31920346	In this study, we analysed the frequency of somatic mutations across various tumour types based on TCGA and COSMIC databases and discovered that the S310F mutation, located in subdomain II of HER2 ECD, was the most frequent substitution among all tumour types and HER2 mutations.	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('frequent', 'Reg', (215, 223))	('S310F', 'Mutation', 'rs1057519816', (149, 154))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', (77, 83))	('tumour', 'Disease', 'MESH:D009369', (247, 253))	('tumour', 'Disease', (247, 253))	('S310F', 'Var', (149, 154))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
3433	31920346	We analysed the effect of the S310F mutation on the interaction between pertuzumab and HER2 by molecular modelling analysis.	('S310F', 'Var', (30, 35))	('interaction', 'Interaction', (52, 63))	('S310F', 'Mutation', 'rs1057519816', (30, 35))
3437	31920346	The missense mutations of tumour-associated genes that lead to altered amino acid property within the extracellular domain of membrane proteins were extracted by TMHMM (http://www.cbs.dtu.dk/services/TMHMM/), and further screening was carried out via UniProt (https://www.uniprot.org/) database.	('extracellular', 'cellular_component', 'GO:0005576', ('102', '115'))	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('tumour', 'Disease', (26, 32))	('altered', 'Reg', (63, 70))	('missense mutations', 'Var', (4, 22))	('amino acid property within the', 'MPA', (71, 101))	('membrane', 'cellular_component', 'GO:0016020', ('126', '134'))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))
3438	31920346	Then, the selected mutations were analysed by R software (https://www.r-project.org/) to depict the distribution across 33 cancer types.	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutations', 'Var', (19, 28))
3442	31920346	Using the X-ray structure of the HER2-pertuzumab complex (Protein Data Bank (PDB) ID: 1S78) as a template, the Ser310 of HER2 was mutated to Phe310 by PyMOL software (The PyMOL Molecular Graphics System, Schrodinger, LLC, NY, USA).	('Ser', 'cellular_component', 'GO:0005790', ('111', '114'))	('Phe310', 'Var', (141, 147))	('LLC', 'cellular_component', 'GO:0038045', ('217', '220'))	('Phe', 'Chemical', 'MESH:C026650', (141, 144))	('Ser310', 'Var', (111, 117))	('mutated', 'Var', (130, 137))	('Ser', 'Chemical', 'MESH:C530429', (111, 114))	('Ba', 'Chemical', 'MESH:D001464', (71, 73))	('HER2', 'Gene', (121, 125))
3447	31920346	WT and mutant HER2 cells (6x105) were harvested using 0.25% trypsin-EDTA solution and washed twice with ice-cold phosphate-buffered saline (PBS, pH 7.4).	('phosphate', 'Chemical', 'MESH:D010710', (113, 122))	('HER2', 'Gene', (14, 18))	('EDTA', 'Chemical', 'MESH:D004492', (68, 72))	('mutant', 'Var', (7, 13))
3460	31920346	SPR assay was performed on a Biacore 3000 instrument (GE Healthcare) at 25 C. WT and S310F-mutant HER2-ECD Fc-tagged proteins were immobilized on a CM5 sensor chip using the amine coupling reaction following the manufacturer's instructions.	('HER2-ECD', 'Gene', (98, 106))	('S310F-mutant', 'Var', (85, 97))	('S310F', 'Mutation', 'rs1057519816', (85, 90))	('amine', 'Chemical', 'MESH:D000588', (174, 179))
3461	31920346	The coupling density of HER2-ECD-WT/S310F Fc antigen was typically restricted to 300 response units (RU).	('Fc antigen', 'Protein', (42, 52))	('S310F', 'Mutation', 'rs1057519816', (36, 41))	('HER2-ECD-WT/S310F', 'Var', (24, 41))
3466	31920346	Then, the membranes were incubated with the following primary antibody: anti-phospho-HER2/ErbB2 (Y1221/1222) monoclonal antibody, anti-HER2/ErbB2 or anti-beta-actin polyclonal antibody (Beyotime) at 4 C overnight.	('ErbB2', 'Gene', '2064', (90, 95))	('antibody', 'cellular_component', 'GO:0019814', ('62', '70'))	('antibody', 'cellular_component', 'GO:0042571', ('176', '184'))	('ErbB2', 'Gene', (140, 145))	('antibody', 'molecular_function', 'GO:0003823', ('62', '70'))	('antibody', 'cellular_component', 'GO:0042571', ('120', '128'))	('antibody', 'cellular_component', 'GO:0019815', ('176', '184'))	('ErbB2', 'Gene', '2064', (140, 145))	('ErbB2', 'Gene', (90, 95))	('antibody', 'molecular_function', 'GO:0003823', ('176', '184'))	('antibody', 'cellular_component', 'GO:0042571', ('62', '70'))	('antibody', 'cellular_component', 'GO:0019815', ('120', '128'))	('antibody', 'cellular_component', 'GO:0019814', ('176', '184'))	('antibody', 'cellular_component', 'GO:0019815', ('62', '70'))	('antibody', 'cellular_component', 'GO:0019814', ('120', '128'))	('Y1221/1222', 'Var', (97, 107))	('antibody', 'molecular_function', 'GO:0003823', ('120', '128'))
3468	31920346	MCF7 cells and MCF7 cells expressing WT (MCF7-HER2 WT) or S310F-mutant (MCF7-HER2 S310F) HER2 were collected for the cellular activity test.	('S310F', 'Var', (82, 87))	('MCF7', 'CellLine', 'CVCL:0031', (72, 76))	('MCF7-HER2', 'CellLine', 'CVCL:3285', (41, 50))	('MCF7-HER2', 'CellLine', 'CVCL:3285', (72, 81))	('S310F', 'Mutation', 'rs1057519816', (82, 87))	('S310F', 'SUBSTITUTION', 'None', (82, 87))	('S310F', 'Var', (58, 63))	('MCF7', 'CellLine', 'CVCL:0031', (15, 19))	('MCF7', 'CellLine', 'CVCL:0031', (41, 45))	('MCF7', 'CellLine', 'CVCL:0031', (0, 4))	('S310F', 'Mutation', 'rs1057519816', (58, 63))	('S310F', 'SUBSTITUTION', 'None', (58, 63))	('HER2', 'Protein', (89, 93))
3469	31920346	MCF7, MCF7-HER2 WT and MCF7-HER2 S310F cells were seeded at a density of 3x103 cells per well into 96-well microtiter plates in DMEM culture medium with 1% FBS.	('MCF7', 'CellLine', 'CVCL:0031', (0, 4))	('MCF7-HER2', 'CellLine', 'CVCL:3285', (6, 15))	('S310F', 'SUBSTITUTION', 'None', (33, 38))	('MCF7', 'CellLine', 'CVCL:0031', (23, 27))	('MCF7-HER2', 'Gene', (23, 32))	('MCF7-HER2', 'CellLine', 'CVCL:3285', (23, 32))	('S310F', 'Var', (33, 38))	('MCF7', 'CellLine', 'CVCL:0031', (6, 10))
3470	31920346	According to the TCGA MC3 project, there were more than 1.5 million missense mutations in 10,033 cancer samples.	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', (97, 103))	('missense mutations', 'Var', (68, 86))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
3471	31920346	Among these mutations, we focused on the mutations with altered amino acid property, occurring in the extracellular domains of membrane proteins which are encoded by tumour-associated genes.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('extracellular', 'cellular_component', 'GO:0005576', ('102', '115'))	('tumour', 'Disease', (166, 172))	('mutations', 'Var', (12, 21))	('membrane', 'cellular_component', 'GO:0016020', ('127', '135'))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))
3473	31920346	HER2 S310F was the most frequent (n=43) among these mutations, followed by FGFR2 S252R (n=27) and EGFR G598V (n=15) (Figure 2A, Figure S1).	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('S310F', 'Mutation', 'rs1057519816', (5, 10))	('FGFR2', 'Gene', (75, 80))	('G598V', 'Mutation', 'rs139236063', (103, 108))	('HER2', 'Gene', (0, 4))	('FGFR2', 'Gene', '2263', (75, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('S310F', 'Var', (5, 10))	('S252R', 'Mutation', 'p.S252R', (81, 86))	('S252R', 'Var', (81, 86))
3474	31920346	Among all cancer types, bladder urothelial carcinoma (BLCA) and stomach adenocarcinoma (STAD) tended to have a higher probability of acquiring the S310F mutation (Figure S2A).	('bladder urothelial carcinoma', 'Disease', (24, 52))	('BLCA', 'Disease', (54, 58))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (24, 52))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (64, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('S310F', 'Var', (147, 152))	('stomach adenocarcinoma', 'Disease', (64, 86))	('STAD', 'Disease', 'MESH:D013274', (88, 92))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('STAD', 'Disease', (88, 92))	('BLCA', 'Disease', 'MESH:D001749', (54, 58))	('S310F', 'Mutation', 'rs1057519816', (147, 152))	('cancer', 'Disease', (10, 16))
3476	31920346	The S310F mutation turned out to be the most frequent mutation in STAD and BLCA, with 6 occurrences among the 440 cancer samples and 21 occurrences among the 412 cancer samples, respectively (Figure S2B-C).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('BLCA', 'Disease', 'MESH:D001749', (75, 79))	('S310F', 'Var', (4, 9))	('cancer', 'Disease', (162, 168))	('STAD', 'Disease', 'MESH:D013274', (66, 70))	('STAD', 'Disease', (66, 70))	('BLCA', 'Disease', (75, 79))	('S310F', 'Mutation', 'rs1057519816', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('S2B-C', 'Chemical', 'MESH:C079321', (199, 204))	('cancer', 'Disease', (114, 120))
3477	31920346	The S310F mutation did not show up in the mutation landscape of BRCA, with only 1 occurrence among the 986 cancer samples (Figure S2D).	('S310F', 'Var', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('BRCA', 'Gene', '672', (64, 68))	('BRCA', 'Phenotype', 'HP:0003002', (64, 68))	('S310F', 'Mutation', 'rs1057519816', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('BRCA', 'Gene', (64, 68))	('cancer', 'Disease', (107, 113))
3479	31920346	Similarly, the S310F mutation was also the most frequent mutation within all HER2 mutations in BLCA, STAD and BRCA (Figure S3A-C).	('S310F', 'Var', (15, 20))	('BRCA', 'Phenotype', 'HP:0003002', (110, 114))	('BRCA', 'Gene', '672', (110, 114))	('S310F', 'Mutation', 'rs1057519816', (15, 20))	('BLCA', 'Disease', 'MESH:D001749', (95, 99))	('BRCA', 'Gene', (110, 114))	('HER2', 'Gene', (77, 81))	('STAD', 'Disease', 'MESH:D013274', (101, 105))	('STAD', 'Disease', (101, 105))	('BLCA', 'Disease', (95, 99))
3480	31920346	Overall, we found that the S310F mutation of HER2 ECD was the most frequent mutation among all tumour types and HER2 mutations.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('frequent', 'Reg', (67, 75))	('S310F', 'Var', (27, 32))	('tumour', 'Disease', (95, 101))	('S310F', 'Mutation', 'rs1057519816', (27, 32))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
3481	31920346	The S310F mutation causes a substitution of serine to phenylalanine at amino acid 310, which maps to the pertuzumab epitope on HER2 (Figure 3A).	('causes', 'Reg', (19, 25))	('S310F', 'Var', (4, 9))	('substitution', 'Var', (28, 40))	('serine to phenylalanine at amino acid 310', 'Mutation', 'rs1057519816', (44, 85))	('S310F', 'Mutation', 'rs1057519816', (4, 9))	('serine to phenylalanine', 'MPA', (44, 67))
3482	31920346	We performed molecular modelling to predict the effect of the S310F mutation on pertuzumab binding to HER2.	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))	('S310F', 'Var', (62, 67))	('HER2', 'Protein', (102, 106))	('binding', 'Interaction', (91, 98))	('S310F', 'Mutation', 'rs1057519816', (62, 67))
3483	31920346	Compared to WT HER2, the S310F-mutant HER2 introduced a nonpolar side chain, which was predicted to decrease the interaction between pertuzumab and HER2 (Figure 3B).	('HER2', 'Protein', (148, 152))	('decrease', 'NegReg', (100, 108))	('S310F-mutant', 'Var', (25, 37))	('HER2', 'Gene', (38, 42))	('S310F', 'Mutation', 'rs1057519816', (25, 30))	('nonpolar side chain', 'MPA', (56, 75))	('interaction', 'Interaction', (113, 124))
3484	31920346	As shown in Figure 3C, the energy contribution of Ser310 ranked third and reached -5.26 kcal mol-1, mainly coming from the electrostatic potentials (-7.53 kcal mol-1), suggesting that the residue S310 was quite important for the formation of the HER2-pertuzumab complex.	('Ser310', 'Var', (50, 56))	('S310', 'Var', (196, 200))	('formation', 'biological_process', 'GO:0009058', ('229', '238'))	('Ser', 'Chemical', 'MESH:C530429', (50, 53))	('Ser', 'cellular_component', 'GO:0005790', ('50', '53'))
3486	31920346	We expressed WT or S310F-mutant HER2 in NIH3T3 cells to investigate the exact effect of the S310F mutation on pertuzumab binding affinity.	('S310F', 'Var', (92, 97))	('S310F-mutant', 'Var', (19, 31))	('S310F', 'Mutation', 'rs1057519816', (19, 24))	('S310F', 'Mutation', 'rs1057519816', (92, 97))	('HER2', 'Protein', (32, 36))	('binding', 'molecular_function', 'GO:0005488', ('121', '128'))	('NIH3T3', 'CellLine', 'CVCL:0594', (40, 46))
3487	31920346	As depicted in Figure 4A, pertuzumab could efficiently bind to cells expressing WT HER2 but not to cells that expressed S310F-mutant HER2.	('bind', 'Interaction', (55, 59))	('HER2', 'Protein', (83, 87))	('S310F-mutant', 'Var', (120, 132))	('S310F', 'Mutation', 'rs1057519816', (120, 125))	('HER2', 'Protein', (133, 137))
3488	31920346	Unlike pertuzumab, trastuzumab retained the ability to bind to both WT and S310F-mutant HER2 cells.	('bind', 'Interaction', (55, 59))	('S310F-mutant', 'Var', (75, 87))	('ability', 'MPA', (44, 51))	('S310F', 'Mutation', 'rs1057519816', (75, 80))	('HER2', 'Protein', (88, 92))
3490	31920346	Consistent with the abovementioned molecular modelling, the S310F mutation led to a significant reduction in pertuzumab binding relative to WT HER2.	('binding', 'molecular_function', 'GO:0005488', ('120', '127'))	('binding', 'Interaction', (120, 127))	('S310F', 'Var', (60, 65))	('S310F', 'Mutation', 'rs1057519816', (60, 65))	('pertuzumab', 'Protein', (109, 119))	('reduction', 'NegReg', (96, 105))
3492	31920346	WT and S310F-mutant HER2 ECD Fc-tagged proteins were successfully expressed by HEK293F cells and analysed by SDS-PAGE under reductive condition (Figure S4).	('HEK293F', 'CellLine', 'CVCL:6642', (79, 86))	('SDS', 'Chemical', 'MESH:C032259', (109, 112))	('S310F-mutant', 'Var', (7, 19))	('S310F', 'Mutation', 'rs1057519816', (7, 12))	('HER2', 'Protein', (20, 24))
3493	31920346	As shown in Figure 4C, the S310F-mutant HER2 ECD was selectively defective in binding pertuzumab but not trastuzumab.	('binding', 'Interaction', (78, 85))	('HER2', 'Protein', (40, 44))	('binding', 'molecular_function', 'GO:0005488', ('78', '85'))	('S310F-mutant', 'Var', (27, 39))	('defective', 'NegReg', (65, 74))	('S310F', 'Mutation', 'rs1057519816', (27, 32))	('4C', 'Chemical', 'MESH:C060809', (19, 21))
3494	31920346	The binding affinity of pertuzumab for S310F-mutant HER2 ECD was substantially unchanged with increasing antibody concentration.	('HER2', 'Protein', (52, 56))	('S310F-mutant', 'Var', (39, 51))	('binding', 'Interaction', (4, 11))	('S310F', 'Mutation', 'rs1057519816', (39, 44))	('antibody', 'cellular_component', 'GO:0042571', ('105', '113'))	('antibody', 'cellular_component', 'GO:0019814', ('105', '113'))	('antibody', 'cellular_component', 'GO:0019815', ('105', '113'))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))	('antibody', 'molecular_function', 'GO:0003823', ('105', '113'))
3495	31920346	An in vitro biochemical binding study proved once again that the S310F mutation interfered with the binding of pertuzumab to HER2.	('HER2', 'Protein', (125, 129))	('S310F', 'Var', (65, 70))	('binding', 'Interaction', (100, 107))	('interfered', 'NegReg', (80, 90))	('binding', 'molecular_function', 'GO:0005488', ('100', '107'))	('binding', 'molecular_function', 'GO:0005488', ('24', '31'))	('S310F', 'Mutation', 'rs1057519816', (65, 70))
3498	31920346	In addition, trastuzumab was still able to bind to the S310F-mutant HER2 antigen, with a high affinity (KD=1.64 nmol/L).	('S310F', 'Mutation', 'rs1057519816', (55, 60))	('KD', 'Disease', 'MESH:C537014', (104, 106))	('bind', 'Interaction', (43, 47))	('S310F-mutant', 'Var', (55, 67))	('HER2 antigen', 'Protein', (68, 80))
3499	31920346	Pertuzumab did not have any detectable binding to the S310F-mutant HER2 antigen, and the KD value could not be determined.	('HER2 antigen', 'Protein', (67, 79))	('S310F-mutant', 'Var', (54, 66))	('KD', 'Disease', 'MESH:C537014', (89, 91))	('binding', 'molecular_function', 'GO:0005488', ('39', '46'))	('S310F', 'Mutation', 'rs1057519816', (54, 59))	('binding', 'Interaction', (39, 46))
3500	31920346	The SPR results also showed that the S310F mutation disrupted the interaction between pertuzumab and HER2 receptor.	('interaction', 'Interaction', (66, 77))	('S310F', 'Mutation', 'rs1057519816', (37, 42))	('disrupted', 'NegReg', (52, 61))	('HER2 receptor', 'Protein', (101, 114))	('S310F', 'Var', (37, 42))
3503	31920346	We assessed the effect of the S310F mutation on pertuzumab-mediated inhibition of HER2 signalling via these two cell lines.	('signalling', 'biological_process', 'GO:0023052', ('87', '97'))	('S310F', 'Var', (30, 35))	('S310F', 'Mutation', 'rs1057519816', (30, 35))	('inhibition', 'NegReg', (68, 78))	('HER2 signalling', 'Pathway', (82, 97))
3505	31920346	In this assay, the intracellular phosphorylation signalling of WT or S310F-mutant HER2 was activated by HER3-ligand heregulin (HRG)-induced dimerization (Figure 5B).	('intracellular phosphorylation signalling', 'MPA', (19, 59))	('ligand', 'molecular_function', 'GO:0005488', ('109', '115'))	('intracellular', 'cellular_component', 'GO:0005622', ('19', '32'))	('signalling', 'biological_process', 'GO:0023052', ('49', '59'))	('activated', 'PosReg', (91, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('S310F-mutant', 'Var', (69, 81))	('HER2', 'Protein', (82, 86))	('S310F', 'Mutation', 'rs1057519816', (69, 74))
3506	31920346	However, there was no reduction in S310F-mutant HER2 signalling in response to pertuzumab.	('S310F', 'Mutation', 'rs1057519816', (35, 40))	('signalling', 'biological_process', 'GO:0023052', ('53', '63'))	('HER2', 'Protein', (48, 52))	('signalling', 'MPA', (53, 63))	('reduction', 'NegReg', (22, 31))	('S310F-mutant', 'Var', (35, 47))
3507	31920346	We further evaluated the in vitro efficacy of pertuzumab in the HER2-overexpressing breast cancer cell line bearing the S310F mutation.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('S310F', 'Var', (120, 125))	('S310F', 'Mutation', 'rs1057519816', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('breast cancer', 'Disease', (84, 97))
3511	31920346	The addition of HRG significantly increased the growth of MCF7, MCF7-HER2 WT and MCF7-HER2 S310F cells compared with that of the basal controls, which were incubated in the absence of HRG.	('MCF7-HER2', 'CellLine', 'CVCL:3285', (81, 90))	('S310F', 'Var', (91, 96))	('HRG', 'Gene', (16, 19))	('S310F', 'SUBSTITUTION', 'None', (91, 96))	('growth', 'MPA', (48, 54))	('MCF7', 'Gene', (58, 62))	('MCF7', 'CellLine', 'CVCL:0031', (81, 85))	('MCF7', 'CellLine', 'CVCL:0031', (64, 68))	('increased', 'PosReg', (34, 43))	('MCF7-HER2', 'CellLine', 'CVCL:3285', (64, 73))	('MCF7-HER2', 'Gene', (64, 73))	('MCF7', 'CellLine', 'CVCL:0031', (58, 62))
3512	31920346	In the presence of pertuzumab and HRG, the growth of MCF7-HER2 WT cells was significantly reduced to the basal level, while the cell viability of MCF7-HER2 S310F cell line was unaffected.	('growth', 'MPA', (43, 49))	('S310F', 'Var', (156, 161))	('reduced', 'NegReg', (90, 97))	('MCF7-HER2', 'CellLine', 'CVCL:3285', (146, 155))	('S310F', 'SUBSTITUTION', 'None', (156, 161))	('MCF7-HER2', 'Gene', (53, 62))	('MCF7-HER2', 'CellLine', 'CVCL:3285', (53, 62))
3513	31920346	In this study, we used bioinformatics to discover that S310F, an extracellular domain mutation of HER2, was the most frequent mutation within HER2 and among various tumours.	('S310F', 'Mutation', 'rs1057519816', (55, 60))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('extracellular', 'cellular_component', 'GO:0005576', ('65', '78'))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('tumours', 'Disease', 'MESH:D009369', (165, 172))	('S310F', 'Var', (55, 60))	('tumours', 'Disease', (165, 172))
3514	31920346	We also unexpectedly found that the S310F mutation alone completely abolished the binding ability of pertuzumab to HER2 ECD, which provides different insights into the important role of somatic mutations in the resistance mechanism of anti-HER2 antibodies.	('abolished', 'NegReg', (68, 77))	('S310F', 'Var', (36, 41))	('binding', 'molecular_function', 'GO:0005488', ('82', '89'))	('S310F', 'Mutation', 'rs1057519816', (36, 41))	('HER2 ECD', 'Protein', (115, 123))	('binding', 'Interaction', (82, 89))
3515	31920346	The S310F mutation disrupted the essential hydrogen bonds between residue S310 of HER2 and residue D31 of pertuzumab by introducing a hydrophobic benzene ring.	('disrupted', 'NegReg', (19, 28))	('essential hydrogen bonds', 'MPA', (33, 57))	('hydrogen', 'Chemical', 'MESH:D006859', (43, 51))	('introducing', 'Reg', (120, 131))	('S310F', 'Var', (4, 9))	('S310F', 'Mutation', 'rs1057519816', (4, 9))	('HER2', 'Protein', (82, 86))	('benzene', 'Chemical', 'MESH:D001554', (146, 153))	('hydrophobic benzene ring', 'MPA', (134, 158))
3516	31920346	also showed that these two hydrogen bonds play a major role in the interaction of pertuzumab and HER2, indicating that disruption of hydrogen bonds in key contacting residues could dramatically attenuate pertuzumab binding affinity.	('pertuzumab', 'Protein', (204, 214))	('hydrogen', 'Chemical', 'MESH:D006859', (133, 141))	('binding affinity', 'Interaction', (215, 231))	('hydrogen', 'Chemical', 'MESH:D006859', (27, 35))	('disruption', 'Var', (119, 129))	('binding', 'molecular_function', 'GO:0005488', ('215', '222'))	('interaction', 'Interaction', (67, 78))	('hydrogen bonds', 'MPA', (133, 147))	('attenuate', 'NegReg', (194, 203))
3517	31920346	Previous studies reported that the S310F is an activating mutation that has been considered an oncogenic driver, or a promoter of cancer cell growth.	('S310F', 'Mutation', 'rs1057519816', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('S310F', 'Var', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cell growth', 'biological_process', 'GO:0016049', ('137', '148'))
3518	31920346	showed that the S310F mutation exhibited a significant increase in HER2 phosphorylation signalling and was implicated in colony formation and oncogenic potency when studied in NIH3T3, AALE and Ba/F3 cell lines.	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('colony formation', 'CPA', (121, 137))	('S310F', 'Var', (16, 21))	('increase', 'PosReg', (55, 63))	('S310F', 'Mutation', 'rs1057519816', (16, 21))	('NIH3T3', 'CellLine', 'CVCL:0594', (176, 182))	('phosphorylation signalling', 'MPA', (72, 98))	('HER2', 'Protein', (67, 71))	('implicated', 'Reg', (107, 117))	('formation', 'biological_process', 'GO:0009058', ('128', '137'))	('signalling', 'biological_process', 'GO:0023052', ('88', '98'))	('Ba', 'Chemical', 'MESH:D001464', (193, 195))	('oncogenic potency', 'CPA', (142, 159))
3520	31920346	However, we discovered that an activating mutation S310F within the HER2 ECD conferred resistance to pertuzumab by abolishment of the binding.	('resistance to pertuzumab', 'MPA', (87, 111))	('activating', 'PosReg', (31, 41))	('S310F', 'Var', (51, 56))	('S310F', 'Mutation', 'rs1057519816', (51, 56))	('conferred', 'Reg', (77, 86))	('binding', 'molecular_function', 'GO:0005488', ('134', '141'))	('binding', 'Interaction', (134, 141))	('abolishment', 'NegReg', (115, 126))
3521	31920346	In addition to the S310F mutation, G309A/E and S310Y mutations that were also verified as activating mutations mapping to the pertuzumab epitopes on HER2, suggesting that tumours bearing these mutations may be refractory to pertuzumab.	('G309A', 'SUBSTITUTION', 'None', (35, 40))	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('G309A', 'Var', (35, 40))	('S310Y', 'Var', (47, 52))	('S310F', 'Mutation', 'rs1057519816', (19, 24))	('tumours', 'Phenotype', 'HP:0002664', (171, 178))	('tumours', 'Disease', 'MESH:D009369', (171, 178))	('tumours', 'Disease', (171, 178))	('S310Y', 'Mutation', 'rs1057519816', (47, 52))	('S310F', 'Var', (19, 24))
3527	31920346	However, our discovery confirmed that HER2-positive tumour cells bearing the S310F mutation were resistant to pertuzumab therapy, which provides a theoretical basis and a guide for clinically avoiding the irrational use of pertuzumab in patients with HER2-positive breast cancer bearing the S310F mutation.	('S310F', 'Var', (291, 296))	('S310F', 'Var', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('S310F', 'Mutation', 'rs1057519816', (291, 296))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('S310F', 'Mutation', 'rs1057519816', (77, 82))	('breast cancer', 'Disease', (265, 278))	('breast cancer', 'Disease', 'MESH:D001943', (265, 278))	('breast cancer', 'Phenotype', 'HP:0003002', (265, 278))	('tumour', 'Disease', (52, 58))	('patients', 'Species', '9606', (237, 245))
3530	31920346	Here, we found that the S310F mutation occurred more frequently in gastric cancer than other HER2 mutations, and its frequency in gastric cancer was almost 10 times higher than that in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('gastric cancer', 'Disease', (67, 81))	('gastric cancer', 'Disease', (130, 144))	('breast cancer', 'Disease', (185, 198))	('S310F', 'Var', (24, 29))	('gastric cancer', 'Disease', 'MESH:D013274', (67, 81))	('gastric cancer', 'Disease', 'MESH:D013274', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('S310F', 'Mutation', 'rs1057519816', (24, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
3531	31920346	Based on these data, thus we think that the S310F mutation is worthy to be considered in the clinical trial to classify gastric cancer patients more accurately, and it might be conducive to increasing the success rate of the clinical trial.	('S310F', 'Var', (44, 49))	('patients', 'Species', '9606', (135, 143))	('gastric cancer', 'Disease', (120, 134))	('Ba', 'Chemical', 'MESH:D001464', (0, 2))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('S310F', 'Mutation', 'rs1057519816', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))
3532	31920346	Many cancer-related genetic alterations, such as EGFR tyrosine kinase mutations L858R and T790M, have been included in clinical screening for treatment selection.	('T790M', 'Var', (90, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('tyrosine', 'Chemical', 'None', (54, 62))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('EGFR', 'Gene', (49, 53))	('cancer', 'Disease', (5, 11))	('L858R', 'Var', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('L858R', 'Mutation', 'rs121434568', (80, 85))	('T790M', 'Mutation', 'rs121434569', (90, 95))
3533	31920346	Considering its destructive effect on pertuzumab binding in this study, it is rational to perform S310F mutation screening in patients with HER2-positive tumours prior to antibody therapy.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('antibody', 'cellular_component', 'GO:0019814', ('171', '179'))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('S310F', 'Var', (98, 103))	('binding', 'Interaction', (49, 56))	('S310F', 'Mutation', 'rs1057519816', (98, 103))	('antibody', 'molecular_function', 'GO:0003823', ('171', '179'))	('tumours', 'Disease', 'MESH:D009369', (154, 161))	('tumours', 'Disease', (154, 161))	('patients', 'Species', '9606', (126, 134))	('antibody', 'cellular_component', 'GO:0042571', ('171', '179'))	('antibody', 'cellular_component', 'GO:0019815', ('171', '179'))	('binding', 'molecular_function', 'GO:0005488', ('49', '56'))
3534	31920346	Our study demonstrated the loss-of-function mechanism underlying pertuzumab resistance in HER2-positive tumour cells bearing the S310F mutation.	('loss-of-function', 'NegReg', (27, 43))	('S310F', 'Mutation', 'rs1057519816', (129, 134))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('tumour', 'Disease', (104, 110))	('S310F', 'Var', (129, 134))
3535	31920346	Our findings provide a molecular explanation for the potential clinical implications of the HER2 S310F mutation, and assist in identifying patients who would benefit from pertuzumab treatment.	('HER2', 'Protein', (92, 96))	('patients', 'Species', '9606', (139, 147))	('S310F', 'Mutation', 'rs1057519816', (97, 102))	('S310F', 'Var', (97, 102))
3559	28060759	Among these prognostic lncRNAs, the lncRNAs (AC005682.5 and CTD-2231H16.1) with higher expression profiles were associated with shorter survival (coefficient > 0), while the remaining two lncRNAs (CTB-92J24.2 and RP11-727F15.13) with higher expression profiles were associated with longer survival (coefficient < 0).	('RP11', 'Gene', '26121', (213, 217))	('CTB', 'Gene', (197, 200))	('CTD-2231H16.1', 'Gene', '153478', (60, 73))	('CTD-2231H16.1', 'Gene', (60, 73))	('CTB', 'Gene', '1486', (197, 200))	('AC005682.5', 'Var', (45, 55))	('shorter', 'NegReg', (128, 135))	('expression', 'MPA', (87, 97))	('higher', 'PosReg', (80, 86))	('RP11', 'Gene', (213, 217))
3561	28060759	Then we constructed a prognostic signature by integrating the expression profiles of the four lncRNAs and corresponding estimated regression coefficient derived from above multivariate Cox regression analysis as follows: Risk score = (0.371 x expression value of AC005682.5) + (0.175 x expression value of CTD-2231H16.1) + (-0.251 x expression value of CTB-92J24.2) + (-0.232 x expression value of RP11-727F15.13).	('RP11', 'Gene', (398, 402))	('CTD-2231H16.1', 'Gene', (306, 319))	('RP11', 'Gene', '26121', (398, 402))	('Cox', 'Gene', '1351', (185, 188))	('Cox', 'Gene', (185, 188))	('0.371 x', 'Var', (235, 242))	('CTB', 'Gene', (353, 356))	('CTB', 'Gene', '1486', (353, 356))	('CTD-2231H16.1', 'Gene', '153478', (306, 319))
3569	28060759	For patients with high risk scores, the expression profiles of lncRNAs (AC005682.5 and CTD-2231H16.1) are significantly up-regulated, while the remaining two lncRNAs (CTB-92J24.2 and RP11-727F15.13) were down-regulated.	('RP11', 'Gene', (183, 187))	('CTD-2231H16.1', 'Gene', (87, 100))	('RP11', 'Gene', '26121', (183, 187))	('CTB', 'Gene', (167, 170))	('AC005682.5', 'Var', (72, 82))	('expression profiles', 'MPA', (40, 59))	('CTB', 'Gene', '1486', (167, 170))	('patients', 'Species', '9606', (4, 12))	('down-regulated', 'NegReg', (204, 218))	('CTD-2231H16.1', 'Gene', '153478', (87, 100))	('up-regulated', 'PosReg', (120, 132))
3590	28060759	More recently, accumulated evidence indicates that dysregulated lncRNAs are implicated in various tumorigenesis processes including proliferation, invasion and apoptosis by acting as tumor oncogenes or suppressor, which has developed a new area for biomarkers.	('apoptosis', 'CPA', (160, 169))	('dysregulated', 'Var', (51, 63))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('lncRNAs', 'Protein', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('invasion', 'CPA', (147, 155))	('proliferation', 'CPA', (132, 145))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', (98, 103))	('implicated', 'Reg', (76, 86))
3591	28060759	Additionally, plenty of aberrant lncRNA expression in multiple cancers was discovered by the transcriptional profiling analyses, highlighting their potential roles as novel independent biomarkers for cancer prognosis.	('multiple cancers', 'Disease', (54, 70))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('aberrant', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lncRNA expression', 'Protein', (33, 50))	('multiple cancers', 'Disease', 'MESH:D009369', (54, 70))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', (200, 206))
3716	32915499	HNRNPM, HNRNPUL1, and HNRNPL showed high mutation frequencies, and most hnRNP genes were frequently mutated in uterine corpus endometrial carcinoma (UCEC).	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('mutated', 'Var', (100, 107))	('hnRNP', 'Gene', (72, 77))	('endometrial carcinoma', 'Disease', (126, 147))	('HNRNPM', 'Gene', (0, 6))	('HNRNPL', 'Gene', '3191', (22, 28))	('hnRNP', 'Gene', '3183', (72, 77))	('HNRNPUL1', 'Gene', '11100', (8, 16))	('HNRNPM', 'Gene', '4670', (0, 6))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (126, 147))	('HNRNPL', 'Gene', (22, 28))	('hnRNP', 'cellular_component', 'GO:0030530', ('72', '77'))	('hnRNP', 'molecular_function', 'GO:0008436', ('72', '77'))	('HNRNPUL1', 'Gene', (8, 16))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (126, 147))
3717	32915499	HNRNPA2B1 showed widespread copy number amplification across various cancer types.	('copy number amplification', 'Var', (28, 53))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('HNRNPA2B1', 'Gene', '3181', (0, 9))	('HNRNPA2B1', 'Gene', (0, 9))	('cancer', 'Disease', (69, 75))
3724	32915499	1 ,  2  Almost each transcript derived from human genes undergoes diverse patterns of alternative splicing (AS) including exclusion or inclusion of ''cassette'' exons, changes of AS sites, intron retentions, alternative promoter or terminator, and mutually exclusive exons.	('human', 'Species', '9606', (44, 49))	('as', 'Gene', '112935892', (151, 153))	('AS', 'Gene', '112935892', (179, 181))	('splicing', 'biological_process', 'GO:0045292', ('98', '106'))	('AS', 'Gene', '112935892', (108, 110))	('changes', 'Var', (168, 175))	('intron', 'MPA', (189, 195))	('alternative splicing', 'MPA', (86, 106))
3725	32915499	3 ,  4  Alternative splicing of pre-mRNA is responsible various aspects of biological processes and aberrant AS contribute to a series of disorders even cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('contribute', 'Reg', (112, 122))	('pre', 'molecular_function', 'GO:0003904', ('32', '35'))	('responsible', 'Reg', (44, 55))	('splicing', 'biological_process', 'GO:0045292', ('20', '28'))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('as', 'Gene', '112935892', (64, 66))	('disorders', 'Disease', (138, 147))	('Alternative splicing', 'Var', (8, 28))	('AS', 'Gene', '112935892', (109, 111))
3733	32915499	16  In pancreas cancer, hnRNP E1 cancer cell metastasis via controlling the alternative splicing of integrin beta1, a membrane receptor involved in cell adhesion, immune response and metastatic diffusion of cancer cells.	('cancer', 'Disease', (33, 39))	('as', 'Gene', '112935892', (186, 188))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('splicing', 'biological_process', 'GO:0045292', ('88', '96'))	('alternative splicing', 'Var', (76, 96))	('as', 'Gene', '112935892', (51, 53))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('hnRNP', 'cellular_component', 'GO:0030530', ('24', '29'))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('immune response', 'biological_process', 'GO:0006955', ('163', '178'))	('pancreas cancer', 'Disease', 'MESH:D010190', (7, 22))	('membrane', 'cellular_component', 'GO:0016020', ('118', '126'))	('pancreas cancer', 'Phenotype', 'HP:0002894', (7, 22))	('integrin beta1', 'Gene', '3688', (100, 114))	('as', 'Gene', '112935892', (48, 50))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('pancreas cancer', 'Disease', (7, 22))	('cell adhesion', 'biological_process', 'GO:0007155', ('148', '161'))	('hnRNP', 'molecular_function', 'GO:0008436', ('24', '29'))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('hnRNP E1', 'Gene', '5093', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('as', 'Gene', '112935892', (13, 15))	('hnRNP E1', 'Gene', (24, 32))	('integrin beta1', 'Gene', (100, 114))
3739	32915499	It is anticipated that the comprehensive pan-cancer analysis could shed light on the way alternative splicing lead to cancer.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('splicing', 'biological_process', 'GO:0045292', ('101', '109'))	('lead to', 'Reg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('alternative', 'Var', (89, 100))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
3743	32915499	All of the TCGA data including TPM (Transcripts Per Kilobase Million) expression, copy number variation, mutation and clinical information (survival status, stages, grades, survival time) were download from UCSC XENA (https://xenabrowser.net/).	('copy number variation', 'Var', (82, 103))	('as', 'Gene', '112935892', (57, 59))	('TCGA', 'Gene', (11, 15))	('TPM', 'Gene', (31, 34))
3762	32915499	The mutation frequency of hnRNP genes were analysed, and the results indicated that most hnRNP genes were frequently mutated in UCEC (Figure 2A).	('UCEC', 'Disease', (128, 132))	('hnRNP', 'cellular_component', 'GO:0030530', ('26', '31'))	('mutated', 'Var', (117, 124))	('hnRNP', 'molecular_function', 'GO:0008436', ('89', '94'))	('hnRNP', 'molecular_function', 'GO:0008436', ('26', '31'))	('hnRNP', 'cellular_component', 'GO:0030530', ('89', '94'))	('hnRNP', 'Gene', (26, 31))	('hnRNP', 'Gene', (89, 94))	('hnRNP', 'Gene', '3183', (26, 31))	('hnRNP', 'Gene', '3183', (89, 94))
3764	32915499	Several cancers such as THCA, PCPG and UVM demonstrated rare hnRNP gene mutations.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('mutations', 'Var', (72, 81))	('PCPG', 'Disease', (30, 34))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('hnRNP', 'cellular_component', 'GO:0030530', ('61', '66'))	('hnRNP', 'molecular_function', 'GO:0008436', ('61', '66'))	('THCA', 'Disease', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('hnRNP', 'Gene', '3183', (61, 66))	('hnRNP', 'Gene', (61, 66))	('UVM', 'Disease', (39, 42))	('as', 'Gene', '112935892', (21, 23))
3767	32915499	The results indicated that colorectal cancer and lung cancer cell lines suggested frequent mutations of most hnRNP genes.	('hnRNP', 'molecular_function', 'GO:0008436', ('109', '114'))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('colorectal cancer', 'Disease', (27, 44))	('lung cancer', 'Disease', (49, 60))	('mutations', 'Var', (91, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('hnRNP', 'Gene', (109, 114))	('hnRNP', 'cellular_component', 'GO:0030530', ('109', '114'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('hnRNP', 'Gene', '3183', (109, 114))	('colorectal cancer', 'Disease', 'MESH:D015179', (27, 44))
3768	32915499	In addition, the copy number variations of hnRNP genes were also investigated across different cancer types (Figure 2D): HNRNPA2B1 gene showed widespread copy number amplification across various cancer types whereas almost no CNV was detected in LAML.	('hnRNP', 'cellular_component', 'GO:0030530', ('43', '48'))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('HNRNPA2B1', 'Gene', '3181', (121, 130))	('HNRNPA2B1', 'Gene', (121, 130))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', (95, 101))	('copy number', 'Var', (154, 165))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('hnRNP', 'molecular_function', 'GO:0008436', ('43', '48'))	('hnRNP', 'Gene', (43, 48))	('as', 'Gene', '112935892', (231, 233))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('hnRNP', 'Gene', '3183', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('as', 'Gene', '112935892', (213, 215))
3792	32915499	20  In lung cancer, knockdown of HNRNPA1 suppressed the viability and growth as well as induced cell cycle arrest of lung cancer cells.	('lung cancer', 'Disease', (7, 18))	('viability', 'CPA', (56, 65))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('96', '113'))	('suppressed', 'NegReg', (41, 51))	('knockdown', 'Var', (20, 29))	('induced', 'Reg', (88, 95))	('arrest of lung cancer', 'Disease', (107, 128))	('lung cancer', 'Disease', 'MESH:D008175', (7, 18))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (96, 113))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('growth', 'CPA', (70, 76))	('HNRNPA1', 'Gene', '3178', (33, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (7, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('arrest of lung cancer', 'Disease', 'MESH:D012131', (107, 128))	('HNRNPA1', 'Gene', (33, 40))	('as', 'Gene', '112935892', (77, 79))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('as', 'Gene', '112935892', (85, 87))
3800	32915499	27  It is worth noting that most hnRNP genes were frequently mutated in UCEC, a certain type of cancer with high global mutation burden.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('hnRNP', 'cellular_component', 'GO:0030530', ('33', '38'))	('hnRNP', 'Gene', (33, 38))	('hnRNP', 'molecular_function', 'GO:0008436', ('33', '38'))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('mutated', 'Var', (61, 68))	('hnRNP', 'Gene', '3183', (33, 38))	('cancer', 'Disease', (96, 102))	('UCEC', 'Disease', (72, 76))
3801	32915499	28  Several cancers such as THCA, PCPG and UVM demonstrated rare hnRNP gene mutations.	('hnRNP', 'Gene', (65, 70))	('as', 'Gene', '112935892', (25, 27))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('PCPG', 'Disease', (34, 38))	('mutations', 'Var', (76, 85))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', (12, 19))	('THCA', 'Disease', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('hnRNP', 'cellular_component', 'GO:0030530', ('65', '70'))	('UVM', 'Disease', (43, 46))	('hnRNP', 'molecular_function', 'GO:0008436', ('65', '70'))	('hnRNP', 'Gene', '3183', (65, 70))
3802	32915499	Besides, human cancer cell lines analysis based on CCLE demonstrated that colorectal cancer and lung cancer cell lines possess frequent mutations of most hnRNP genes.	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('human', 'Species', '9606', (9, 14))	('as', 'Gene', '112935892', (43, 45))	('mutations', 'Var', (136, 145))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('hnRNP', 'molecular_function', 'GO:0008436', ('154', '159'))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('hnRNP', 'Gene', '3183', (154, 159))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', (85, 91))	('hnRNP', 'Gene', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (101, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('lung cancer', 'Disease', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('colorectal cancer', 'Disease', (74, 91))	('hnRNP', 'cellular_component', 'GO:0030530', ('154', '159'))
3803	32915499	Future investigations concerning the mutations of hnRNP genes in lung cancer and colorectal cancer might reveal critical evidence of contribution of hnRNPs in the development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('hnRNP', 'Gene', '3183', (149, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('colorectal cancer', 'Disease', (81, 98))	('hnRNP', 'Gene', (149, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('hnRNP', 'cellular_component', 'GO:0030530', ('50', '55'))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutations', 'Var', (37, 46))	('hnRNP', 'Gene', '3183', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('hnRNP', 'molecular_function', 'GO:0008436', ('50', '55'))	('lung cancer', 'Disease', (65, 76))	('cancer', 'Disease', (178, 184))	('hnRNP', 'Gene', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
3804	32915499	In addition, the copy number variations investigation revealed that HNRNPA2B1 gene showed widespread copy number amplification across various cancer types whereas almost no CNV was detected in LAML.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('HNRNPA2B1', 'Gene', '3181', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('copy number amplification', 'Var', (101, 126))	('as', 'Gene', '112935892', (160, 162))	('as', 'Gene', '112935892', (178, 180))	('HNRNPA2B1', 'Gene', (68, 77))	('cancer', 'Disease', (142, 148))
3820	32915499	Previously, high HNRNPUL2 expression has been reported to predict poor survival of multiple cancers.	('expression', 'MPA', (26, 36))	('high', 'Var', (12, 16))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('HNRNPUL2', 'Gene', '221092', (17, 25))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('HNRNPUL2', 'Gene', (17, 25))	('poor survival', 'CPA', (66, 79))	('as', 'Gene', '112935892', (38, 40))
3826	32915499	In summary, our study systematically demonstrated the expression, mutation, copy number variation, functional pathways and prognostic value of alternative splicing regulator hnRNPs across a series of cancers.	('hnRNP', 'Gene', '3183', (174, 179))	('splicing', 'biological_process', 'GO:0045292', ('155', '163'))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('copy number variation', 'Var', (76, 97))	('mutation', 'Var', (66, 74))	('hnRNP', 'Gene', (174, 179))
3890	32451768	Low albumin has been shown to reflect malnutrition, which is common among patients with cancer, leading to disruption of a number of human defense mechanisms, such as anatomic barriers, cellular and humoral immunity, and phagocyte function.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Low', 'Var', (0, 3))	('patients', 'Species', '9606', (74, 82))	('albumin', 'Gene', (4, 11))	('albumin', 'Gene', '213', (4, 11))	('malnutrition', 'Disease', (38, 50))	('malnutrition', 'Disease', 'MESH:D044342', (38, 50))	('Low albumin', 'Phenotype', 'HP:0003073', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('malnutrition', 'Phenotype', 'HP:0004395', (38, 50))	('human', 'Species', '9606', (133, 138))	('phagocyte function', 'CPA', (221, 239))
3901	32451768	Cancer and inflammation are linked through both extrinsic and intrinsic pathways, with the former being activated by infection or chronic inflammation, and the latter being driven by genetic changes, such as oncogene activation or tumor suppressor gene deactivation.	('inflammation', 'Disease', (11, 23))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('inflammation', 'Disease', (138, 150))	('tumor suppressor', 'biological_process', 'GO:0051726', ('231', '247'))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('oncogene', 'Gene', (208, 216))	('deactivation', 'Var', (253, 265))	('inflammation', 'biological_process', 'GO:0006954', ('138', '150'))	('inflammation', 'biological_process', 'GO:0006954', ('11', '23'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('231', '247'))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('infection', 'Disease', (117, 126))	('tumor', 'Disease', (231, 236))	('infection', 'Disease', 'MESH:D007239', (117, 126))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('inflammation', 'Disease', 'MESH:D007249', (138, 150))	('inflammation', 'Disease', 'MESH:D007249', (11, 23))
3916	32451768	In addition, low AGR had the highest HR, suggesting indirectly potentially stronger prognostic value than any other biomarkers.	('low', 'Var', (13, 16))	('AGR', 'Protein', (17, 20))	('AGR', 'Chemical', '-', (17, 20))
3926	31030230	Survival of AMP patients was similar to INLP and both were significantly better than INMP (P=0.002 and P=0.016).	('AMP', 'Chemical', '-', (12, 15))	('INMP', 'Chemical', '-', (85, 89))	('patients', 'Species', '9606', (16, 24))	('AMP', 'Var', (12, 15))	('MP', 'Phenotype', 'HP:0030936', (13, 15))	('better', 'PosReg', (73, 79))	('MP', 'Phenotype', 'HP:0030936', (87, 89))
3927	31030230	The great majority of patients with AMP on initial TURBT have advanced disease on RC and emphasizes the need for early repeat TURBT or even consideration of early cystectomy to lower the risk of worse pathological findings and to prolong survival.	('AMP', 'Chemical', '-', (36, 39))	('survival', 'MPA', (238, 246))	('advanced disease', 'Disease', (62, 78))	('patients', 'Species', '9606', (22, 30))	('MP', 'Phenotype', 'HP:0030936', (37, 39))	('AMP', 'Var', (36, 39))	('prolong', 'PosReg', (230, 237))
3944	31030230	In this study we report the RC findings and survival data on our cohort of cases diagnosed with bladder cancer and AMP on initial TURBT and compared them to cases with invasion into MP or lamina propria (LP) on initial TURBT.	('AMP', 'Chemical', '-', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('AMP', 'Var', (115, 118))	('bladder cancer', 'Phenotype', 'HP:0009725', (96, 110))	('MP', 'Phenotype', 'HP:0030936', (116, 118))	('MP', 'Phenotype', 'HP:0030936', (182, 184))	('bladder cancer', 'Disease', 'MESH:D001749', (96, 110))	('bladder cancer', 'Disease', (96, 110))
3971	31030230	The disease specific mortality was significantly higher on patients with INMP (117/296, 39.52%) than patients with INLP (30/102, 29.41%), and higher than patients with AMP (5/30, 16.67%; P=0.003).	('MP', 'Phenotype', 'HP:0030936', (169, 171))	('patients', 'Species', '9606', (101, 109))	('MP', 'Phenotype', 'HP:0030936', (75, 77))	('INMP', 'Chemical', '-', (73, 77))	('mortality', 'Disease', 'MESH:D003643', (21, 30))	('patients', 'Species', '9606', (154, 162))	('AMP', 'Chemical', '-', (168, 171))	('INMP', 'Var', (73, 77))	('patients', 'Species', '9606', (59, 67))	('higher', 'PosReg', (49, 55))	('mortality', 'Disease', (21, 30))	('higher', 'PosReg', (142, 148))
3974	31030230	In summary, patients diagnosed with AMP in pre-cystectomy TURBT have higher proportion of pT2 or pT3 tumors than INLP and similar to INMP on RC.	('AMP', 'Chemical', '-', (36, 39))	('patients', 'Species', '9606', (12, 20))	('INMP', 'Chemical', '-', (133, 137))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('pT2', 'Disease', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('MP', 'Phenotype', 'HP:0030936', (37, 39))	('pre', 'molecular_function', 'GO:0003904', ('43', '46'))	('AMP', 'Var', (36, 39))	('pT3', 'Gene', '7694', (97, 100))	('pT3', 'Gene', (97, 100))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('MP', 'Phenotype', 'HP:0030936', (135, 137))
3976	31030230	Mortality of AMP patients is significantly less than INMP patients and similar to INLP patients who undergo RC.	('MP', 'Phenotype', 'HP:0030936', (55, 57))	('MP', 'Phenotype', 'HP:0030936', (14, 16))	('AMP', 'Chemical', '-', (13, 16))	('Mortality', 'Disease', 'MESH:D003643', (0, 9))	('less', 'NegReg', (43, 47))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (58, 66))	('Mortality', 'Disease', (0, 9))	('patients', 'Species', '9606', (87, 95))	('AMP', 'Var', (13, 16))	('INMP', 'Chemical', '-', (53, 57))
3980	31030230	Infiltrating urothelial carcinoma can partially destroy or splay the MP leading to residual thin muscle bundles such that it is difficult to distinguish whether these thin muscle bundles represent the MM or altered MP.	('MP', 'Phenotype', 'HP:0030936', (69, 71))	('MP', 'Phenotype', 'HP:0030936', (215, 217))	('urothelial carcinoma', 'Disease', (13, 33))	('splay', 'Var', (59, 64))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (13, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))
3984	31030230	Absence of MP in TURBT with tumor has been associated with increased risk of residual disease, recurrence and understaging.	('tumor', 'Disease', (28, 33))	('understaging', 'CPA', (110, 122))	('recurrence', 'CPA', (95, 105))	('residual disease', 'CPA', (77, 93))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('MP', 'Phenotype', 'HP:0030936', (11, 13))	('Absence', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
3994	31030230	Although this overall delay in the surgery for these patients might have contributed to the high percentage of patients with pT2 or higher on their final pathologic staging, this delay in RC did not appear to affect the survival in these patients as their survival was not different from that of the INLP group and both groups had significantly better survival than the IMP group.	('patients', 'Species', '9606', (53, 61))	('IMP', 'cellular_component', 'GO:0042720', ('370', '373'))	('survival', 'MPA', (352, 360))	('MP', 'Phenotype', 'HP:0030936', (371, 373))	('better', 'PosReg', (345, 351))	('IMP', 'molecular_function', 'GO:0004244', ('370', '373'))	('pT2', 'Var', (125, 128))	('patients', 'Species', '9606', (238, 246))	('patients', 'Species', '9606', (111, 119))
4005	31030230	Researchers found that upstaging to pT2 among patients with high-grade T1 or CIS was associated with worse recurrence free survival (RFS) compared with patients with known muscle invasion before RC.	('pT2', 'Gene', (36, 39))	('recurrence free survival', 'MPA', (107, 131))	('patients', 'Species', '9606', (46, 54))	('CIS', 'Disease', (77, 80))	('patients', 'Species', '9606', (152, 160))	('high-grade', 'Var', (60, 70))	('upstaging', 'PosReg', (23, 32))
4016	31030230	The great majority of patients with AMP on pre-cystectomy TURBT will have muscle invasive disease or a higher pathological stage on RC but disease specific mortality that aligns with patients with INLP who undergo cystectomy.	('AMP', 'Chemical', '-', (36, 39))	('mortality', 'Disease', (156, 165))	('MP', 'Phenotype', 'HP:0030936', (37, 39))	('patients', 'Species', '9606', (22, 30))	('pre', 'molecular_function', 'GO:0003904', ('43', '46'))	('AMP', 'Var', (36, 39))	('muscle invasive disease', 'Disease', (74, 97))	('mortality', 'Disease', 'MESH:D003643', (156, 165))	('muscle invasive disease', 'Disease', 'MESH:D009362', (74, 97))	('patients', 'Species', '9606', (183, 191))
4023	31308746	The effects of either Nrf2 or TUG1 knockdown on the proliferation, invasion, apoptosis and adriamycin (ADM) resistance of UCB cells were evaluated by CCK-8 assay, transwell invasion assay and flow cytometry analysis.	('ADM', 'Chemical', 'MESH:D004317', (103, 106))	('knockdown', 'Var', (35, 44))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('adriamycin', 'Chemical', 'MESH:D004317', (91, 101))	('TUG1', 'Gene', (30, 34))	('apoptosis', 'CPA', (77, 86))	('invasion', 'CPA', (67, 75))	('Nrf2', 'Gene', (22, 26))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('si', 'Chemical', 'MESH:D012825', (177, 179))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('CCK-8', 'Chemical', 'MESH:D012844', (150, 155))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('TUG1', 'Gene', '55000', (30, 34))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('si', 'Chemical', 'MESH:D012825', (212, 214))	('Nrf2', 'Gene', '4780', (22, 26))
4027	31308746	Moreover, Nrf2 and TUG1 expression levels were higher in ADM-resistant cells compared with those in parental cells.	('ADM-resistant', 'Var', (57, 70))	('Nrf2', 'Gene', '4780', (10, 14))	('expression levels', 'MPA', (24, 41))	('higher', 'PosReg', (47, 53))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('TUG1', 'Gene', '55000', (19, 23))	('ADM', 'Chemical', 'MESH:D004317', (57, 60))	('Nrf2', 'Gene', (10, 14))	('TUG1', 'Gene', (19, 23))	('si', 'Chemical', 'MESH:D012825', (63, 65))
4031	31308746	Besides, knockdown of either Nrf2 or TUG1 inhibited tumor growth in the absence or presence of ADM in vivo.	('Nrf2', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('si', 'Chemical', 'MESH:D012825', (2, 4))	('knockdown', 'Var', (9, 18))	('ADM', 'Chemical', 'MESH:D004317', (95, 98))	('tumor', 'Disease', (52, 57))	('TUG1', 'Gene', '55000', (37, 41))	('inhibited', 'NegReg', (42, 51))	('Nrf2', 'Gene', '4780', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('TUG1', 'Gene', (37, 41))
4052	31308746	Aberrant expression of lncRNAs has been reported to confer tumor growth, cancer cell metastasis, apoptosis and chemoresistance.	('cancer', 'Disease', (73, 79))	('Aberrant expression', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('si', 'Chemical', 'MESH:D012825', (118, 120))	('tumor', 'Disease', (59, 64))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('chemoresistance', 'CPA', (111, 126))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('lncRNAs', 'Gene', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('apoptosis', 'CPA', (97, 106))
4058	31308746	Additionally, ADM-resistant acute myeloid leukemia tissues and HL60/ADR cells have been shown to express high levels of TUG1, and its knockdown facilitated the sensitivity of HL60/ADR cells to ADM by epigenetically promoting miR-34a expression.	('expression', 'MPA', (233, 243))	('TUG1', 'Gene', '55000', (120, 124))	('ADM', 'Chemical', 'MESH:D004317', (14, 17))	('si', 'Chemical', 'MESH:D012825', (239, 241))	('miR-34a', 'Gene', (225, 232))	('facilitated', 'PosReg', (144, 155))	('acute myeloid leukemia', 'Disease', (28, 50))	('sensitivity', 'MPA', (160, 171))	('HL60', 'CellLine', 'CVCL:0002', (175, 179))	('ADM', 'Chemical', 'MESH:D004317', (193, 196))	('miR-34a', 'Gene', '407040', (225, 232))	('HL60', 'CellLine', 'CVCL:0002', (63, 67))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (28, 50))	('TUG1', 'Gene', (120, 124))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('leukemia', 'Phenotype', 'HP:0001909', (42, 50))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (28, 50))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (34, 50))	('knockdown', 'Var', (134, 143))	('epigenetically', 'Var', (200, 214))	('promoting', 'PosReg', (215, 224))
4063	31308746	In this study, we hypothesized that aberrant expression of Nrf2 and TUG1 in UCB might drive a mechanism for ADM resistance, and found that Nrf2 induced the up-regulation of TUG1 to promote progression and ADM resistance in UCB.	('ADM', 'Chemical', 'MESH:D004317', (205, 208))	('si', 'Chemical', 'MESH:D012825', (114, 116))	('regulation', 'biological_process', 'GO:0065007', ('159', '169'))	('Nrf2', 'Gene', (59, 63))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('TUG1', 'Gene', (173, 177))	('TUG1', 'Gene', (68, 72))	('Nrf2', 'Gene', (139, 143))	('ADM', 'Chemical', 'MESH:D004317', (108, 111))	('ADM resistance', 'CPA', (205, 219))	('up-regulation', 'PosReg', (156, 169))	('TUG1', 'Gene', '55000', (173, 177))	('promote', 'PosReg', (181, 188))	('progression', 'CPA', (189, 200))	('aberrant', 'Var', (36, 44))	('si', 'Chemical', 'MESH:D012825', (196, 198))	('TUG1', 'Gene', '55000', (68, 72))	('Nrf2', 'Gene', '4780', (59, 63))	('si', 'Chemical', 'MESH:D012825', (211, 213))	('Nrf2', 'Gene', '4780', (139, 143))	('si', 'Chemical', 'MESH:D012825', (51, 53))
4070	31308746	Each round screened the surviving cells for the beginning of the next drug resistance concentration, until the cells surviving in 1 mug/ml were BIU-87/ADM and T24/ADM.	('mug', 'molecular_function', 'GO:0043739', ('132', '135'))	('BIU', 'Chemical', '-', (144, 147))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('BIU-87/ADM', 'Var', (144, 154))	('drug resistance', 'Phenotype', 'HP:0020174', (70, 85))	('T24/ADM', 'Var', (159, 166))	('drug resistance', 'biological_process', 'GO:0009315', ('70', '85'))	('ADM', 'Chemical', 'MESH:D004317', (151, 154))	('drug resistance', 'biological_process', 'GO:0042493', ('70', '85'))	('ADM', 'Chemical', 'MESH:D004317', (163, 166))
4071	31308746	Cells were incubated in RPMI-1640 medium (Solarbio, Beijing, China) supplemented with 10% fetal bovine serum (FBS; Solarbio), streptomycin (100 mg/ml; Solarbio) and penicillin (100 units/ml; Solarbio) and maintained in a humidified atmosphere of 95% air and 5% CO2 at 37 C. To knockdown Nrf2, BIU-87 and T24 cells were transfected with small interfering RNA (siRNA) specific for Nrf2 (si-Nrf2) or treated with ML385 (2 muM, a specific Nrf2 inhibitor).	('ML385', 'Chemical', '-', (410, 415))	('Nrf2', 'Gene', (435, 439))	('RNA', 'cellular_component', 'GO:0005562', ('354', '357'))	('Nrf2', 'Gene', '4780', (287, 291))	('bovine', 'Species', '9913', (96, 102))	('RPMI-1640 medium', 'Chemical', '-', (24, 40))	('Nrf2', 'Gene', '4780', (388, 392))	('Nrf2', 'Gene', (287, 291))	('FBS', 'Disease', (110, 113))	('Nrf2', 'Gene', '4780', (379, 383))	('penicillin', 'Chemical', 'MESH:D010406', (165, 175))	('FBS', 'Disease', 'MESH:D005198', (110, 113))	('CO2', 'Chemical', '-', (261, 264))	('Nrf2', 'Gene', '4780', (435, 439))	('muM', 'Gene', '56925', (419, 422))	('si-Nrf2', 'Gene', (385, 392))	('BIU', 'Chemical', '-', (293, 296))	('si-Nrf2', 'Gene', '4780', (385, 392))	('Nrf2', 'Gene', (388, 392))	('muM', 'Gene', (419, 422))	('knockdown', 'Var', (277, 286))	('streptomycin', 'Chemical', 'MESH:D013307', (126, 138))	('si', 'Chemical', 'MESH:D012825', (385, 387))	('Nrf2', 'Gene', (379, 383))	('si', 'Chemical', 'MESH:D012825', (359, 361))
4072	31308746	Similarly, si-TUG1 was used to knockdown TUG1.	('TUG1', 'Gene', (41, 45))	('TUG1', 'Gene', (14, 18))	('si', 'Chemical', 'MESH:D012825', (11, 13))	('TUG1', 'Gene', '55000', (41, 45))	('TUG1', 'Gene', '55000', (14, 18))	('knockdown', 'Var', (31, 40))
4109	31308746	The results of Western blot demonstrated that the expression of Nrf2 was remarkably increased in BIU-87/ADM and T24/ADM cells as compared to BIU-87 and T24 cells (Figure 2C).	('BIU', 'Chemical', '-', (141, 144))	('Nrf2', 'Gene', (64, 68))	('BIU', 'Chemical', '-', (97, 100))	('ADM', 'Chemical', 'MESH:D004317', (116, 119))	('increased', 'PosReg', (84, 93))	('Nrf2', 'Gene', '4780', (64, 68))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('ADM', 'Chemical', 'MESH:D004317', (104, 107))	('expression', 'MPA', (50, 60))	('BIU-87/ADM', 'Var', (97, 107))
4111	31308746	Meanwhile, the expression of TUG1 was higher in BIU-87/ADM and T24/ADM cells than that in BIU-87 and T24 cells, as evidenced by RT-PCR (Figure 2E).	('ADM', 'Chemical', 'MESH:D004317', (67, 70))	('BIU', 'Chemical', '-', (48, 51))	('BIU', 'Chemical', '-', (90, 93))	('TUG1', 'Gene', '55000', (29, 33))	('BIU-87/ADM', 'Var', (48, 58))	('ADM', 'Chemical', 'MESH:D004317', (55, 58))	('expression', 'MPA', (15, 25))	('TUG1', 'Gene', (29, 33))	('higher', 'PosReg', (38, 44))	('T24/ADM', 'Var', (63, 70))	('si', 'Chemical', 'MESH:D012825', (21, 23))
4115	31308746	Conversely, knockdown of Nrf2 by siRNA caused a marked decrease in TUG1 expression in BIU-87 and T24 cells (Figure 3E and F).	('BIU', 'Chemical', '-', (86, 89))	('Nrf2', 'Gene', '4780', (25, 29))	('si', 'Chemical', 'MESH:D012825', (33, 35))	('knockdown', 'Var', (12, 21))	('TUG1', 'Gene', '55000', (67, 71))	('expression', 'MPA', (72, 82))	('Nrf2', 'Gene', (25, 29))	('decrease', 'NegReg', (55, 63))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('TUG1', 'Gene', (67, 71))
4116	31308746	Similarly, treatment of BIU-87 and T24 cells with ML385 resulted in a dose-dependent reduction in TUG1 expression (Figure 3G and H).	('TUG1', 'Gene', (98, 102))	('BIU', 'Chemical', '-', (24, 27))	('ML385', 'Chemical', '-', (50, 55))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('reduction', 'NegReg', (85, 94))	('TUG1', 'Gene', '55000', (98, 102))	('ML385', 'Var', (50, 55))
4121	31308746	Meanwhile, knockdown of Nrf2 remarkably inhibited the invasion of BIU-87 and T24 cells and decreased the expression of MMP-2 and MMP-9 in BIU-87 and T24 cells.	('MMP-2', 'Gene', (119, 124))	('Nrf2', 'Gene', '4780', (24, 28))	('BIU', 'Chemical', '-', (66, 69))	('invasion', 'CPA', (54, 62))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('inhibited', 'NegReg', (40, 49))	('MMP-2', 'molecular_function', 'GO:0004228', ('119', '124'))	('BIU', 'Chemical', '-', (138, 141))	('MMP-9', 'molecular_function', 'GO:0004229', ('129', '134'))	('Nrf2', 'Gene', (24, 28))	('knockdown', 'Var', (11, 20))	('MMP-2', 'Gene', '4313', (119, 124))	('MMP-9', 'Gene', (129, 134))	('MMP-9', 'Gene', '4318', (129, 134))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('expression', 'MPA', (105, 115))	('decreased', 'NegReg', (91, 100))
4122	31308746	Intriguingly, TUG1 knockdown led to similar functional effects as those of Nrf2 knockdown in BIU-87 and T24 cells (Figure 4D-G).	('knockdown', 'Var', (80, 89))	('TUG1', 'Gene', (14, 18))	('BIU', 'Chemical', '-', (93, 96))	('knockdown', 'Var', (19, 28))	('Nrf2', 'Gene', (75, 79))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('TUG1', 'Gene', '55000', (14, 18))	('Nrf2', 'Gene', '4780', (75, 79))
4123	31308746	In parallel, Nrf2 knockdown conspicuously promoted the apoptosis of BIU-87 and T24 cells.	('knockdown', 'Var', (18, 27))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('Nrf2', 'Gene', (13, 17))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('apoptosis', 'CPA', (55, 64))	('promoted', 'PosReg', (42, 50))	('Nrf2', 'Gene', '4780', (13, 17))	('BIU', 'Chemical', '-', (68, 71))
4124	31308746	Also, TUG1 knockdown caused an increased rate of apoptotic cells in BIU-87 and T24 cells (Figure 4H and I).	('TUG1', 'Gene', (6, 10))	('apoptotic cells', 'CPA', (49, 64))	('knockdown', 'Var', (11, 20))	('BIU', 'Chemical', '-', (68, 71))	('TUG1', 'Gene', '55000', (6, 10))
4128	31308746	Identical conclusions were obtained in our study, the expression levels of p-gp protein and MDR1 mRNA were higher in BIU-87/ADM and T24/ADM cells as compared to BIU-87 and T24 cells (Figure 5A and B).To examine whether knockdown either Nrf2 or TUG1 restores the sensitivity of BIU-87/ADM and T24/ADM cells to ADM, BIU-87/ADM and T24/ADM cells were transfected with si-Nrf2, si-TUG1 or si-NC, followed by stimulation with increasing doses (0, 5, 10, 20 and 40 mug/ml) of ADM.	('MDR1', 'Gene', (92, 96))	('BIU', 'Chemical', '-', (117, 120))	('ADM', 'Chemical', 'MESH:D004317', (284, 287))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('Nrf2', 'Gene', (236, 240))	('TUG1', 'Gene', (244, 248))	('si', 'Chemical', 'MESH:D012825', (374, 376))	('Nrf2', 'Gene', (368, 372))	('ADM', 'Chemical', 'MESH:D004317', (124, 127))	('si', 'Chemical', 'MESH:D012825', (365, 367))	('TUG1', 'Gene', (377, 381))	('ADM', 'Chemical', 'MESH:D004317', (321, 324))	('MDR', 'molecular_function', 'GO:0004745', ('92', '95'))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('si-Nrf2', 'Gene', (365, 372))	('si-NC', 'Var', (385, 390))	('BIU', 'Chemical', '-', (314, 317))	('si-Nrf2', 'Gene', '4780', (365, 372))	('p-gp', 'Gene', (75, 79))	('ADM', 'Chemical', 'MESH:D004317', (296, 299))	('TUG1', 'Gene', '55000', (244, 248))	('BIU', 'Chemical', '-', (161, 164))	('si', 'Chemical', 'MESH:D012825', (427, 429))	('p-gp', 'Gene', '5243', (75, 79))	('MDR1', 'Gene', '5243', (92, 96))	('ADM', 'Chemical', 'MESH:D004317', (470, 473))	('TUG1', 'Gene', '55000', (377, 381))	('Nrf2', 'Gene', '4780', (236, 240))	('ADM', 'Chemical', 'MESH:D004317', (333, 336))	('Nrf2', 'Gene', '4780', (368, 372))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('mug', 'molecular_function', 'GO:0043739', ('459', '462'))	('ADM', 'Chemical', 'MESH:D004317', (136, 139))	('ADM', 'Chemical', 'MESH:D004317', (309, 312))	('si', 'Chemical', 'MESH:D012825', (265, 267))	('si', 'Chemical', 'MESH:D012825', (385, 387))	('BIU', 'Chemical', '-', (277, 280))
4130	31308746	In addition, Blocking either Nrf2 or TUG1 obviously downregulated the expression of p-gp in BIU-87/ADM and T24/ADM cells (Figure 5D and E).	('Blocking', 'Var', (13, 21))	('Nrf2', 'Gene', (29, 33))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('ADM', 'Chemical', 'MESH:D004317', (99, 102))	('p-gp', 'Gene', (84, 88))	('downregulated', 'NegReg', (52, 65))	('TUG1', 'Gene', '55000', (37, 41))	('expression', 'MPA', (70, 80))	('Nrf2', 'Gene', '4780', (29, 33))	('BIU', 'Chemical', '-', (92, 95))	('TUG1', 'Gene', (37, 41))	('p-gp', 'Gene', '5243', (84, 88))	('ADM', 'Chemical', 'MESH:D004317', (111, 114))
4131	31308746	Given the significance of Nrf2 and TUG1 in vitro, we further characterized whether knockdown either Nrf2 or TUG1 enhances the sensitivity of UCB cells to ADM in vivo.	('TUG1', 'Gene', '55000', (108, 112))	('Nrf2', 'Gene', '4780', (100, 104))	('Nrf2', 'Gene', (26, 30))	('enhances', 'PosReg', (113, 121))	('ADM', 'Chemical', 'MESH:D004317', (154, 157))	('sensitivity', 'MPA', (126, 137))	('TUG1', 'Gene', '55000', (35, 39))	('TUG1', 'Gene', (108, 112))	('si', 'Chemical', 'MESH:D012825', (129, 131))	('Nrf2', 'Gene', (100, 104))	('TUG1', 'Gene', (35, 39))	('Nrf2', 'Gene', '4780', (26, 30))	('knockdown', 'Var', (83, 92))	('si', 'Chemical', 'MESH:D012825', (10, 12))
4133	31308746	The results revealed that xenograft tumors from sh-Nrf2 or sh-TUG1 transfected T24/ADM cells grew slower than the tumors from sh-NC-transfected T24/ADM cells.	('TUG1', 'Gene', (62, 66))	('Nrf2', 'Gene', (51, 55))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('xenograft tumors', 'Disease', (26, 42))	('grew', 'CPA', (93, 97))	('ADM', 'Chemical', 'MESH:D004317', (148, 151))	('xenograft tumors', 'Disease', 'MESH:D009369', (26, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('TUG1', 'Gene', '55000', (62, 66))	('ADM', 'Chemical', 'MESH:D004317', (83, 86))	('slower', 'NegReg', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('Nrf2', 'Gene', '4780', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('transfected', 'Var', (67, 78))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (36, 42))
4134	31308746	Moreover, the tumor growth was slower in tumors from sh-Nrf2 or sh-TUG1 transfected T24/ADM cells than the tumors from sh-NC-transfected T24/ADM cells in the presence of ADM (Figure 6A).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (107, 112))	('tumors', 'Disease', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('transfected', 'Var', (72, 83))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('Nrf2', 'Gene', '4780', (56, 60))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('TUG1', 'Gene', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('ADM', 'Chemical', 'MESH:D004317', (170, 173))	('tumor', 'Disease', (41, 46))	('tumors', 'Disease', (107, 113))	('Nrf2', 'Gene', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('ADM', 'Chemical', 'MESH:D004317', (88, 91))	('TUG1', 'Gene', '55000', (67, 71))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('slower', 'NegReg', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('ADM', 'Chemical', 'MESH:D004317', (141, 144))
4136	31308746	The expression level of Nrf2 protein in the sh-Nrf2 group was lower than that in the sh-NC group (Figure 6C).The expression levels of TUG1, MDR1 mRNA and p-gp protein were obviously decreased in tumors from sh-Nrf2 or sh-TUG1 transfected T24/ADM cells as compared to the tumors from sh-NC-transfected T24/ADM cells (Figure 6D-F).	('TUG1', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('MDR1', 'Gene', (140, 144))	('tumors', 'Disease', (271, 277))	('MDR', 'molecular_function', 'GO:0004745', ('140', '143'))	('Nrf2', 'Gene', (210, 214))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('Nrf2', 'Gene', '4780', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('TUG1', 'Gene', '55000', (221, 225))	('ADM', 'Chemical', 'MESH:D004317', (242, 245))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('ADM', 'Chemical', 'MESH:D004317', (305, 308))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('TUG1', 'Gene', '55000', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('p-gp', 'Gene', (154, 158))	('Nrf2', 'Gene', '4780', (47, 51))	('tumors', 'Disease', (195, 201))	('decreased', 'NegReg', (182, 191))	('p-gp', 'Gene', '5243', (154, 158))	('Nrf2', 'Gene', (24, 28))	('expression levels', 'MPA', (113, 130))	('MDR1', 'Gene', '5243', (140, 144))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('Nrf2', 'Gene', '4780', (210, 214))	('Nrf2', 'Gene', (47, 51))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('TUG1', 'Gene', (221, 225))	('transfected', 'Var', (226, 237))
4140	31308746	For instance, inhibition of Nrf2 has been postulated to enhance the chemosensitivity of THP-1 cells to proteasome inhibitors.	('si', 'Chemical', 'MESH:D012825', (76, 78))	('THP-1', 'CellLine', 'CVCL:0006', (88, 93))	('Nrf2', 'Gene', '4780', (28, 32))	('proteasome', 'cellular_component', 'GO:0000502', ('103', '113'))	('proteasome', 'molecular_function', 'GO:0004299', ('103', '113'))	('enhance', 'PosReg', (56, 63))	('Nrf2', 'Gene', (28, 32))	('chemosensitivity', 'CPA', (68, 84))	('inhibition', 'Var', (14, 24))
4141	31308746	In addition, cisplatin-resistant RT112 cells have been shown to express high levels of Nrf2, and its knockdown partially restored the chemosensitivity to cisplatin.	('Nrf2', 'Gene', '4780', (87, 91))	('RT112', 'CellLine', 'CVCL:1670', (33, 38))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('restored', 'PosReg', (121, 129))	('Nrf2', 'Gene', (87, 91))	('chemosensitivity to cisplatin', 'MPA', (134, 163))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (154, 163))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('knockdown', 'Var', (101, 110))
4143	31308746	In vitro and in vivo experiments revealed that knockdown of Nrf2 increased the sensitivity of human lung cancer A549 cells to cisplatin, vinorelbine and carboplatin, as well as inhibited the growth of xenograft tumor, suggesting that overexpression of Nrf2 is a central contributor in the development of chemoresistance.	('Nrf2', 'Gene', (252, 256))	('Nrf2', 'Gene', (60, 64))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('si', 'Chemical', 'MESH:D012825', (311, 313))	('carboplatin', 'Chemical', 'MESH:D016190', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('A549', 'CellLine', 'CVCL:0023', (112, 116))	('lung cancer', 'Disease', (100, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('increased', 'PosReg', (65, 74))	('inhibited', 'NegReg', (177, 186))	('vinorelbine', 'MPA', (137, 148))	('sensitivity', 'MPA', (79, 90))	('human', 'Species', '9606', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('Nrf2', 'Gene', '4780', (60, 64))	('vinorelbine', 'Chemical', 'MESH:D000077235', (137, 148))	('xenograft tumor', 'Disease', (201, 216))	('Nrf2', 'Gene', '4780', (252, 256))	('si', 'Chemical', 'MESH:D012825', (244, 246))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('xenograft tumor', 'Disease', 'MESH:D009369', (201, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('knockdown', 'Var', (47, 56))
4145	31308746	Our study identified up-regulation of Nrf2 in ADM resistant UCB cells, and found that ADM resistant UCB cells were resensitized upon knockdown of Nrf2, fitting the established notion of Nrf2 as a key regulator in the development of chemoresistance and as a promising target to restore chemosensitivity.	('up-regulation', 'PosReg', (21, 34))	('si', 'Chemical', 'MESH:D012825', (262, 264))	('si', 'Chemical', 'MESH:D012825', (293, 295))	('Nrf2', 'Gene', '4780', (38, 42))	('ADM', 'Chemical', 'MESH:D004317', (46, 49))	('regulation', 'biological_process', 'GO:0065007', ('24', '34'))	('si', 'Chemical', 'MESH:D012825', (239, 241))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('Nrf2', 'Gene', (38, 42))	('knockdown', 'Var', (133, 142))	('Nrf2', 'Gene', '4780', (146, 150))	('Nrf2', 'Gene', '4780', (186, 190))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('ADM', 'Chemical', 'MESH:D004317', (86, 89))	('Nrf2', 'Gene', (146, 150))	('Nrf2', 'Gene', (186, 190))
4151	31308746	Moreover, TUG1 knockdown suppressed glucose consumption, lactate production and cell viability in osteosarcoma cells through up-regulation of hexokinase-2.	('glucose consumption', 'MPA', (36, 55))	('osteosarcoma', 'Phenotype', 'HP:0002669', (98, 110))	('regulation', 'biological_process', 'GO:0065007', ('128', '138'))	('osteosarcoma', 'Disease', 'MESH:D012516', (98, 110))	('knockdown', 'Var', (15, 24))	('up-regulation', 'PosReg', (125, 138))	('TUG1', 'Gene', (10, 14))	('lactate', 'Chemical', 'MESH:D019344', (57, 64))	('suppressed', 'NegReg', (25, 35))	('lactate production', 'MPA', (57, 75))	('cell viability', 'CPA', (80, 94))	('glucose', 'Chemical', 'MESH:D005947', (36, 43))	('hexokinase-2', 'Gene', '3099', (142, 154))	('hexokinase-2', 'Gene', (142, 154))	('TUG1', 'Gene', '55000', (10, 14))	('osteosarcoma', 'Disease', (98, 110))
4159	31308746	Therapeutic drug resistance is regarded as a dominant hindrance toward curative cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('Therapeutic', 'Var', (0, 11))	('drug resistance', 'Phenotype', 'HP:0020174', (12, 27))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('drug resistance', 'biological_process', 'GO:0009315', ('12', '27'))	('drug resistance', 'biological_process', 'GO:0042493', ('12', '27'))	('cancer', 'Disease', (80, 86))
4166	31308746	TUG1 depletion repressed cell proliferation and promoted cell apoptosis in BIU87 cells under radiation.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('depletion', 'Var', (5, 14))	('TUG1', 'Gene', (0, 4))	('cell apoptosis', 'CPA', (57, 71))	('BIU87', 'CellLine', 'CVCL:6881', (75, 80))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('cell proliferation', 'CPA', (25, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('25', '43'))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('promoted', 'PosReg', (48, 56))	('TUG1', 'Gene', '55000', (0, 4))
4168	31308746	In our study, up-regulation of p-gp and MDR was identified by us in ADM resistant UCB cells, and blocking either Nrf2 or TUG1 could downregulated the expression of p-gp, raising the possibility that targeting Nrf2 or TUG1 may be an effective approach for overcoming ADM resistance in UCB.	('p-gp', 'Gene', (31, 35))	('TUG1', 'Gene', '55000', (121, 125))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('p-gp', 'Gene', '5243', (31, 35))	('p-gp', 'Gene', (164, 168))	('si', 'Chemical', 'MESH:D012825', (185, 187))	('regulation', 'biological_process', 'GO:0065007', ('17', '27'))	('Nrf2', 'Gene', (113, 117))	('MDR', 'Gene', (40, 43))	('Nrf2', 'Gene', (209, 213))	('ADM', 'Chemical', 'MESH:D004317', (266, 269))	('p-gp', 'Gene', '5243', (164, 168))	('ADM', 'Chemical', 'MESH:D004317', (68, 71))	('expression', 'MPA', (150, 160))	('up-regulation', 'PosReg', (14, 27))	('TUG1', 'Gene', (217, 221))	('si', 'Chemical', 'MESH:D012825', (173, 175))	('downregulated', 'NegReg', (132, 145))	('TUG1', 'Gene', (121, 125))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('MDR', 'molecular_function', 'GO:0004745', ('40', '43'))	('Nrf2', 'Gene', '4780', (113, 117))	('si', 'Chemical', 'MESH:D012825', (272, 274))	('blocking', 'Var', (97, 105))	('TUG1', 'Gene', '55000', (217, 221))	('Nrf2', 'Gene', '4780', (209, 213))
4293	29625055	In the LGG marker paper, analysis of OS showed that patients diagnosed with an IDH1 and IDH2 (two very similar genes, hereafter referred to collectively as IDH) mutation with or without 1p/19q codeletion had substantially longer OS than did patients who had wild-type IDH, proving that IDH-1p/19q status represents a more robust survival predictor than LGG histologic subtype.	('IDH-1p', 'Gene', (286, 292))	('IDH', 'Gene', (88, 91))	('IDH1', 'Gene', (79, 83))	('IDH', 'Gene', (79, 82))	('mutation', 'Var', (161, 169))	('IDH', 'Gene', (286, 289))	('IDH', 'Gene', '3417', (88, 91))	('patients', 'Species', '9606', (52, 60))	('IDH1', 'Gene', '3417', (79, 83))	('IDH', 'Gene', (268, 271))	('IDH', 'Gene', '3417', (79, 82))	('IDH', 'Gene', (156, 159))	('OS', 'Chemical', '-', (229, 231))	('OS', 'Chemical', '-', (37, 39))	('IDH', 'Gene', '3417', (286, 289))	('patients', 'Species', '9606', (241, 249))	('longer', 'PosReg', (222, 228))	('IDH2', 'Gene', (88, 92))	('IDH-1p', 'Gene', '3417', (286, 292))	('IDH2', 'Gene', '3418', (88, 92))	('IDH', 'Gene', '3417', (268, 271))	('IDH', 'Gene', '3417', (156, 159))
4466	26901067	Frequent somatic CDH1 loss-of-function mutations in plasmacytoid-variant bladder cancer Plasmacytoid bladder cancer is an aggressive histologic variant with a high risk of disease-specific mortality.	('CDH1', 'Gene', '999', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('bladder cancer', 'Disease', (73, 87))	('loss-of-function', 'NegReg', (22, 38))	('bladder cancer', 'Disease', (101, 115))	('mutations', 'Var', (39, 48))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('CDH1', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))
4468	26901067	Consistent with the aggressive clinical behavior of plasmacytoid carcinomas, which frequently recur locally, CRISPR/Cas9-mediated knockout of CDH1 in bladder cancer cells enhanced cell migration.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('enhanced', 'PosReg', (171, 179))	('bladder cancer', 'Phenotype', 'HP:0009725', (150, 164))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (20, 48))	('carcinomas', 'Disease', (65, 75))	('CDH1', 'Gene', (142, 146))	('carcinomas', 'Disease', 'MESH:D002277', (65, 75))	('cell migration', 'CPA', (180, 194))	('CDH1', 'Gene', '999', (142, 146))	('bladder cancer', 'Disease', (150, 164))	('bladder cancer', 'Disease', 'MESH:D001749', (150, 164))	('cell migration', 'biological_process', 'GO:0016477', ('180', '194'))	('knockout', 'Var', (130, 138))	('Cas', 'cellular_component', 'GO:0005650', ('116', '119'))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
4473	26901067	Six plasmacytoid-variant bladder tumors were initially analyzed by whole exome sequencing and all 6 harbored nonsense mutations in CDH1, the gene encoding E-cadherin (Supplementary Figure 1).	('E-cadherin', 'Gene', '999', (155, 165))	('bladder tumor', 'Phenotype', 'HP:0009725', (25, 38))	('harbored', 'Reg', (100, 108))	('CDH1', 'Gene', (131, 135))	('men', 'Species', '9606', (173, 176))	('cadherin', 'molecular_function', 'GO:0008014', ('157', '165'))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('bladder tumors', 'Disease', (25, 39))	('bladder tumors', 'Disease', 'MESH:D001749', (25, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('nonsense mutations', 'Var', (109, 127))	('CDH1', 'Gene', '999', (131, 135))	('bladder tumors', 'Phenotype', 'HP:0009725', (25, 39))	('E-cadherin', 'Gene', (155, 165))
4475	26901067	To further confirm the association between CDH1 mutation and plasmacytoid-variant bladder cancer, we performed targeted exon capture and sequencing of 19 additional plasmacytoid-variant bladder tumors (Supplementary Table 1 and Figure 1a), 14 (74%) of which harbored CDH1 mutations.	('mutations', 'Var', (272, 281))	('bladder tumors', 'Disease', 'MESH:D001749', (186, 200))	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('bladder tumors', 'Phenotype', 'HP:0009725', (186, 200))	('bladder tumors', 'Disease', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('bladder tumor', 'Phenotype', 'HP:0009725', (186, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('men', 'Species', '9606', (208, 211))	('mutation', 'Var', (48, 56))	('bladder cancer', 'Disease', (82, 96))	('CDH1', 'Gene', (43, 47))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))	('CDH1', 'Gene', (267, 271))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('CDH1', 'Gene', '999', (267, 271))	('CDH1', 'Gene', '999', (43, 47))
4477	26901067	In this prospective cohort, CDH1 mutations were identified in 6 patients, all of whose tumors exhibited the plasmacytoid-variant histology, whereas no CDH1 alterations were observed in the 56 non-plasmacytoid-variant samples (Figure 1a).	('CDH1', 'Gene', (151, 155))	('identified', 'Reg', (48, 58))	('CDH1', 'Gene', '999', (151, 155))	('CDH1', 'Gene', (28, 32))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('exhibited', 'Reg', (94, 103))	('plasmacytoid-variant', 'Disease', (108, 128))	('mutations', 'Var', (33, 42))	('CDH1', 'Gene', '999', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
4478	26901067	With the exception of CDH1 alterations, the genomic profile of plasmacytoid-variant tumors was not substantially different from the 183 urothelial carcinoma, NOS tumors in the TCGA or Memorial Sloan Kettering prospective cohorts, with frequent mutations in the tumor suppressors TP53 and RB1, the chromatin remodeler ARID1A, and the targetable kinases ERBB2 and PIK3CA (Figures 1a and 1b).	('ERBB2', 'Gene', (352, 357))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('TP53', 'Gene', '7157', (279, 283))	('tumor', 'Disease', (162, 167))	('urothelial carcinoma', 'Disease', (136, 156))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('PIK3CA', 'Gene', (362, 368))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('ERBB2', 'Gene', '2064', (352, 357))	('CDH1', 'Gene', '999', (22, 26))	('NOS tumors', 'Disease', 'MESH:D009369', (158, 168))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', (84, 90))	('CDH1', 'Gene', (22, 26))	('mutations', 'Var', (244, 253))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (136, 156))	('TP53', 'Gene', (279, 283))	('RB1', 'Gene', (288, 291))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('ARID1A', 'Gene', (317, 323))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('NOS tumors', 'Disease', (158, 168))	('PIK3CA', 'Gene', '5290', (362, 368))	('chromatin', 'cellular_component', 'GO:0000785', ('297', '306'))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('tumor', 'Disease', (261, 266))	('tumor', 'Disease', (84, 89))	('ARID1A', 'Gene', '8289', (317, 323))	('tumors', 'Disease', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('RB1', 'Gene', '5925', (288, 291))
4481	26901067	Notably, this morphologic appearance shares similarities with lobular breast and diffuse gastric carcinomas, both of which frequently harbor CDH1 mutations (Figure 1c).	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('mutations', 'Var', (146, 155))	('CDH1', 'Gene', (141, 145))	('lobular breast', 'Disease', (62, 76))	('gastric carcinomas', 'Disease', 'MESH:D013274', (89, 107))	('gastric carcinomas', 'Disease', (89, 107))	('CDH1', 'Gene', '999', (141, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))
4482	26901067	In contrast to the germline point mutations in CDH1 that typify diffuse hereditary gastric cancers, we identified no germline CDH1 alterations in the plasmacytoid-variant bladder cancers.	('CDH1', 'Gene', (126, 130))	('bladder cancers', 'Phenotype', 'HP:0009725', (171, 186))	('CDH1', 'Gene', '999', (47, 51))	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('CDH1', 'Gene', '999', (126, 130))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('bladder cancers', 'Disease', 'MESH:D001749', (171, 186))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('alterations', 'Var', (131, 142))	('gastric cancers', 'Disease', (83, 98))	('gastric cancers', 'Disease', 'MESH:D013274', (83, 98))	('gastric cancers', 'Phenotype', 'HP:0012126', (83, 98))	('bladder cancers', 'Disease', (171, 186))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('CDH1', 'Gene', (47, 51))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))
4483	26901067	The co-mutation pattern of lobular breast and diffuse gastric cancers was also distinct from plasmacytoid-variant bladder carcinoma with the exception of CDH1 alterations (Supplementary Figure 2).	('CDH1', 'Gene', (154, 158))	('gastric cancers', 'Disease', (54, 69))	('CDH1', 'Gene', '999', (154, 158))	('gastric cancers', 'Phenotype', 'HP:0012126', (54, 69))	('lobular breast', 'Disease', (27, 41))	('alterations', 'Var', (159, 170))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('bladder carcinoma', 'Disease', (114, 131))	('bladder carcinoma', 'Disease', 'MESH:D001749', (114, 131))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('gastric cancers', 'Disease', 'MESH:D013274', (54, 69))	('men', 'Species', '9606', (178, 181))
4486	26901067	Both histologic regions shared mutations in CDKN1A (A45fs) and PIK3C2G (S48R), implying that these were truncal alterations occurring within a common precursor cell.	('A45fs', 'Var', (52, 57))	('CDKN1A', 'Gene', (44, 50))	('PIK3C2G', 'Gene', (63, 70))	('CDKN1A', 'Gene', '1026', (44, 50))	('A45fs', 'Mutation', 'p.A45fsX', (52, 57))	('PIK3C2G', 'Gene', '5288', (63, 70))	('S48R', 'Mutation', 'p.S48R', (72, 76))	('S48R', 'Var', (72, 76))
4487	26901067	A CDH1 Y68fs mutation alongside PTEN, NOTCH2, FAT4, and other gene mutations were, however, unique to the plasmacytoid component.	('CDH1', 'Gene', '999', (2, 6))	('NOTCH2', 'Gene', (38, 44))	('Y68fs', 'Var', (7, 12))	('FAT4', 'Gene', '79633', (46, 50))	('PTEN', 'Gene', (32, 36))	('FAT4', 'Gene', (46, 50))	('PTEN', 'Gene', '5728', (32, 36))	('NOTCH2', 'Gene', '4853', (38, 44))	('CDH1', 'Gene', (2, 6))	('Y68fs', 'Mutation', 'rs786202151', (7, 12))
4488	26901067	To confirm that the CDH1 alterations identified in the plasmacytoid-variant tumors resulted in loss of protein expression, we performed immunohistochemistry for E-cadherin.	('alterations', 'Var', (25, 36))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('CDH1', 'Gene', '999', (20, 24))	('plasmacytoid-variant', 'Disease', (55, 75))	('protein expression', 'MPA', (103, 121))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('E-cadherin', 'Gene', (161, 171))	('E-cadherin', 'Gene', '999', (161, 171))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('loss', 'NegReg', (95, 99))	('cadherin', 'molecular_function', 'GO:0008014', ('163', '171'))	('CDH1', 'Gene', (20, 24))
4491	26901067	CDH1 promoter hypermethylation was present in 4 of 5 CDH1 wild-type plasmacytoid tumors but in none of the CDH1 mutant or urothelial carcinoma, NOS specimens examined (Supplementary Figure 4).	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('CDH1', 'Gene', (107, 111))	('CDH1', 'Gene', '999', (0, 4))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (122, 142))	('present', 'Reg', (35, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('men', 'Species', '9606', (153, 156))	('CDH1', 'Gene', '999', (107, 111))	('urothelial carcinoma', 'Disease', (122, 142))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutant', 'Var', (112, 118))	('CDH1', 'Gene', (53, 57))	('men', 'Species', '9606', (174, 177))	('CDH1', 'Gene', '999', (53, 57))	('CDH1', 'Gene', (0, 4))
4493	26901067	In sum, the results indicate that loss of E-cadherin expression, most commonly as a result of somatic CDH1 mutation, is the defining molecular event in plasmacytoid-variant bladder cancers.	('CDH1', 'Gene', '999', (102, 106))	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('bladder cancers', 'Disease', 'MESH:D001749', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('bladder cancers', 'Disease', (173, 188))	('bladder cancer', 'Phenotype', 'HP:0009725', (173, 187))	('bladder cancers', 'Phenotype', 'HP:0009725', (173, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('E-cadherin', 'Gene', (42, 52))	('E-cadherin', 'Gene', '999', (42, 52))	('expression', 'MPA', (53, 63))	('loss', 'NegReg', (34, 38))	('mutation', 'Var', (107, 115))	('CDH1', 'Gene', (102, 106))
4494	26901067	Patients with plasmacytoid-variant bladder cancers display a higher cumulative incidence of local recurrence and cancer-specific mortality (Figure 2a-b) and more often exhibit a pattern of peritoneal spread than bladder tumors with pure urothelial carcinoma, NOS histology.	('local recurrence', 'CPA', (92, 108))	('bladder cancers', 'Phenotype', 'HP:0009725', (35, 50))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('bladder cancer', 'Phenotype', 'HP:0009725', (35, 49))	('cancer', 'Disease', (113, 119))	('bladder tumors', 'Disease', 'MESH:D001749', (212, 226))	('urothelial carcinoma', 'Disease', (237, 257))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('higher', 'PosReg', (61, 67))	('bladder cancers', 'Disease', 'MESH:D001749', (35, 50))	('Patients', 'Species', '9606', (0, 8))	('bladder cancers', 'Disease', (35, 50))	('exhibit', 'Reg', (168, 175))	('bladder tumors', 'Disease', (212, 226))	('plasmacytoid-variant', 'Var', (14, 34))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (237, 257))	('peritoneal spread', 'CPA', (189, 206))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('pure', 'molecular_function', 'GO:0034023', ('232', '236'))	('bladder tumors', 'Phenotype', 'HP:0009725', (212, 226))	('bladder tumor', 'Phenotype', 'HP:0009725', (212, 225))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
4495	26901067	To explore whether E-cadherin loss is the molecular basis for the distinct pattern of local invasion observed in patients with plasmacytoid-variant bladder cancers, we performed Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9-mediated knockout of CDH1 in two urothelial carcinoma cell lines (RT4 and MGHU4) (On-line Methods and Figure 2c).	('Cas', 'cellular_component', 'GO:0005650', ('244', '247'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (282, 302))	('cadherin', 'molecular_function', 'GO:0008014', ('21', '29'))	('knockout', 'Var', (258, 266))	('bladder cancers', 'Disease', 'MESH:D001749', (148, 163))	('bladder cancers', 'Disease', (148, 163))	('Short Palindromic Repeat', 'Disease', 'MESH:D000647', (210, 234))	('patients', 'Species', '9606', (113, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('E-cadherin', 'Gene', (19, 29))	('E-cadherin', 'Gene', '999', (19, 29))	('CDH1', 'Gene', '999', (270, 274))	('Short Palindromic Repeat', 'Disease', (210, 234))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('urothelial carcinoma', 'Disease', (282, 302))	('CDH1', 'Gene', (270, 274))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('bladder cancers', 'Phenotype', 'HP:0009725', (148, 163))	('bladder cancer', 'Phenotype', 'HP:0009725', (148, 162))
4496	26901067	Loss of E-cadherin expression resulted in increased migratory capability of MGHU4 cells (Figure 2d-e) and both RT4 and MGHU4 CDH1 knockouts displayed enhanced migration across a Boyden chamber membrane (Figure 2f) as compared to the parental lines.	('increased', 'PosReg', (42, 51))	('migratory capability', 'CPA', (52, 72))	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('enhanced', 'PosReg', (150, 158))	('membrane', 'cellular_component', 'GO:0016020', ('193', '201'))	('CDH1', 'Gene', (125, 129))	('CDH1', 'Gene', '999', (125, 129))	('Loss', 'NegReg', (0, 4))	('knockouts', 'Var', (130, 139))	('migration across a Boyden chamber membrane', 'CPA', (159, 201))	('cadherin', 'molecular_function', 'GO:0008014', ('10', '18'))
4497	26901067	These results suggest that somatic loss-of-function mutations in CDH1, with consequent E-cadherin loss, leads to the enhanced cellular migration and invasive properties characteristic of plasmacytoid-variant tumors.	('cellular migration', 'CPA', (126, 144))	('mutations', 'Var', (52, 61))	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', '999', (87, 97))	('CDH1', 'Gene', (65, 69))	('loss-of-function', 'NegReg', (35, 51))	('CDH1', 'Gene', '999', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('enhanced', 'PosReg', (117, 125))	('tumors', 'Disease', (208, 214))	('loss', 'NegReg', (98, 102))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('cadherin', 'molecular_function', 'GO:0008014', ('89', '97'))	('invasive properties', 'CPA', (149, 168))	('tumors', 'Disease', 'MESH:D009369', (208, 214))
4498	26901067	In summary, we report CDH1 alteration as the pathognomonic feature of plasmacytoid-variant bladder cancer, a disease subtype with an aggressive clinical behavior and poor prognosis.	('CDH1', 'Gene', '999', (22, 26))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (133, 161))	('bladder cancer', 'Disease', (91, 105))	('alteration', 'Var', (27, 37))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('CDH1', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
4499	26901067	Loss of E-cadherin expression, as a result of CDH1 somatic mutation or promoter hypermethylation, is associated with enhanced cellular migration, likely explaining the unique peritoneal pattern of disease dissemination and poor clinical outcome of patients with this disease.	('E-cadherin', 'Gene', (8, 18))	('cellular migration', 'CPA', (126, 144))	('E-cadherin', 'Gene', '999', (8, 18))	('expression', 'MPA', (19, 29))	('promoter hypermethylation', 'Var', (71, 96))	('CDH1', 'Gene', (46, 50))	('Loss', 'NegReg', (0, 4))	('enhanced', 'PosReg', (117, 125))	('mutation', 'Var', (59, 67))	('CDH1', 'Gene', '999', (46, 50))	('patients', 'Species', '9606', (248, 256))	('cadherin', 'molecular_function', 'GO:0008014', ('10', '18'))
4500	26901067	While inactivating mutations in CDH1 were found exclusively in plasmacytoid-variant tumors, the pattern of co-altered genes was similar to bladder cancers with uniformly urothelial carcinoma, NOS histology.	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('urothelial carcinoma', 'Disease', (170, 190))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('bladder cancers', 'Disease', 'MESH:D001749', (139, 154))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('plasmacytoid-variant', 'Disease', (63, 83))	('bladder cancers', 'Disease', (139, 154))	('CDH1', 'Gene', (32, 36))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('found', 'Reg', (42, 47))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (170, 190))	('CDH1', 'Gene', '999', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (139, 153))	('bladder cancers', 'Phenotype', 'HP:0009725', (139, 154))	('inactivating mutations', 'Var', (6, 28))
4501	26901067	This suggests that both histologic subtypes likely evolve from a common cell of origin, with CDH1 alterations demarcating a distinct evolutionary path.	('CDH1', 'Gene', '999', (93, 97))	('alterations', 'Var', (98, 109))	('CDH1', 'Gene', (93, 97))
4502	26901067	The frequent presence of clinically actionable alterations in genes such as ERBB2, PIK3CA, and TSC1 and the poor prognosis of patients with this disease imply that early use of targeted agents, as part of a multi-modality treatment approach, should be considered for patients with plasmacytoid-variant bladder cancers.	('cancers', 'Phenotype', 'HP:0002664', (310, 317))	('patients', 'Species', '9606', (267, 275))	('bladder cancers', 'Phenotype', 'HP:0009725', (302, 317))	('men', 'Species', '9606', (227, 230))	('TSC1', 'Gene', '7248', (95, 99))	('bladder cancers', 'Disease', 'MESH:D001749', (302, 317))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('TSC1', 'Gene', (95, 99))	('bladder cancer', 'Phenotype', 'HP:0009725', (302, 316))	('PIK3CA', 'Gene', (83, 89))	('patients', 'Species', '9606', (126, 134))	('PIK3CA', 'Gene', '5290', (83, 89))	('alterations', 'Var', (47, 58))	('ERBB2', 'Gene', (76, 81))	('bladder cancers', 'Disease', (302, 317))	('ERBB2', 'Gene', '2064', (76, 81))
4531	26901067	LentiCRISPR v2 plasmid deposited by Sanjana et al was obtained from Addgene (Cambridge, MA), and a D10A mutation was introduced in the Cas9 coding sequence to improve the specificity of genome editing.	('D10A', 'SUBSTITUTION', 'None', (99, 103))	('D10A', 'Var', (99, 103))	('Cas', 'cellular_component', 'GO:0005650', ('135', '138'))	('improve', 'PosReg', (159, 166))
4544	26091477	A subsequent immunohistochemical examination of 186 RCCs obtained in our patient series resulted in a strong diffuse positivity of BSND and ATP6V1G3 proteins (both of which are involved in the regulation of membrane transport) in all the chromophobe RCC specimens (23/23 cases, 100%) but not in the clear cell RCC specimens (0/153 cases, 0%) or the papillary RCC specimens (0/10 cases, 0%).	('BSND', 'Gene', (131, 135))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('papillary RCC', 'Disease', 'MESH:C538614', (349, 362))	('papillary RCC', 'Disease', (349, 362))	('RCC', 'Phenotype', 'HP:0005584', (310, 313))	('chromophobe RCC', 'Disease', 'MESH:C538614', (238, 253))	('ATP6V1G3', 'Var', (140, 148))	('RCC', 'Phenotype', 'HP:0005584', (359, 362))	('RCC', 'Phenotype', 'HP:0005584', (250, 253))	('regulation of membrane transport', 'biological_process', 'GO:0034762', ('193', '225'))	('proteins', 'Protein', (149, 157))	('patient', 'Species', '9606', (73, 80))	('chromophobe RCC', 'Disease', (238, 253))	('membrane', 'cellular_component', 'GO:0016020', ('207', '215'))
4545	26091477	BSND and ATP6V1G3 protein expressions were also detected in renal oncocytoma (13/14 cases, 92.9%) and in the distal nephron, including the collecting duct, in the normal kidney.	('detected', 'Reg', (48, 56))	('protein', 'Protein', (18, 25))	('renal oncocytoma', 'Disease', 'MESH:C537750', (60, 76))	('renal oncocytoma', 'Disease', (60, 76))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (60, 76))	('BSND', 'Gene', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('ATP6V1G3', 'Var', (9, 17))
4547	26091477	These results suggest that BSND and ATP6V1G3 are excellent novel immunohistochemical markers for differentiating between chromophobe RCC and other subtypes of RCC, including clear cell and papillary RCCs.	('chromophobe RCC', 'Disease', 'MESH:C538614', (121, 136))	('papillary RCC', 'Disease', 'MESH:C538614', (189, 202))	('papillary RCC', 'Disease', (189, 202))	('clear cell', 'Disease', (174, 184))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('chromophobe RCC', 'Disease', (121, 136))	('BSND', 'Gene', (27, 31))	('RCC', 'Phenotype', 'HP:0005584', (199, 202))	('ATP6V1G3', 'Var', (36, 44))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
4558	26091477	Next, we examined the expression statuses of these genes in 200 primary renal tumors and 85 primary lung carcinomas, and found that BSND and ATP6V1G3 were highly sensitive and specific markers of chromophobe RCC.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('renal tumors', 'Disease', (72, 84))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('chromophobe RCC', 'Disease', (196, 211))	('renal tumor', 'Phenotype', 'HP:0009726', (72, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('renal tumors', 'Phenotype', 'HP:0009726', (72, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('ATP6V1G3', 'Var', (141, 149))	('primary lung carcinomas', 'Disease', 'MESH:D008175', (92, 115))	('chromophobe RCC', 'Disease', 'MESH:C538614', (196, 211))	('renal tumors', 'Disease', 'MESH:D007674', (72, 84))	('primary lung carcinomas', 'Disease', (92, 115))
4559	26091477	Our study suggests that evaluating the expression levels of BSND and ATP6V1G3 could be of great value for distinguishing between chromophobe RCC and other subtypes of RCC.	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('chromophobe RCC', 'Disease', (129, 144))	('ATP6V1G3', 'Var', (69, 77))	('chromophobe RCC', 'Disease', 'MESH:C538614', (129, 144))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))
4581	26091477	Interestingly, strong diffuse positivity was observed in the immunohistochemical analyses for the BSND and ATP6V1G3 proteins in all the chromophobe RCC specimens (23/23 cases, 100%) but was not observed in the clear cell RCC specimens (0/153 cases, 0%) or the papillary RCC specimens (0/10 cases, 0%) (Figure 2A-L and Table 3).	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (221, 224))	('chromophobe RCC', 'Disease', (136, 151))	('papillary RCC', 'Disease', (260, 273))	('RCC', 'Phenotype', 'HP:0005584', (270, 273))	('BSND', 'Gene', (98, 102))	('ATP6V1G3', 'Var', (107, 115))	('chromophobe RCC', 'Disease', 'MESH:C538614', (136, 151))	('proteins', 'Protein', (116, 124))	('papillary RCC', 'Disease', 'MESH:C538614', (260, 273))
4582	26091477	None of the clear cell or papillary RCC specimens showed even a weak positivity for BSND immunostaining; on the other hand, weak diffuse or partial positivity for ATP6V1G3 was detected in some clear cell RCC specimens (8/153 cases, 5.2%) and 1 papillary RCC specimen (1/10 cases, 10%) (Figure 3 and Table 3).	('papillary RCC', 'Disease', (26, 39))	('papillary RCC', 'Disease', 'MESH:C538614', (244, 257))	('detected', 'Reg', (176, 184))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('papillary RCC', 'Disease', (244, 257))	('clear cell RCC', 'Disease', (193, 207))	('ATP6V1G3', 'Var', (163, 171))	('papillary RCC', 'Disease', 'MESH:C538614', (26, 39))	('RCC', 'Phenotype', 'HP:0005584', (254, 257))
4583	26091477	Thus, when calculating the sensitivity and specificity using the immunohistochemical results based only on strong diffuse positivity, the sensitivity of BSND or ATP6V1G3 expression for the diagnosis of chromophobe RCC was 100%, and the specificity was 100%.	('BSND', 'Gene', (153, 157))	('ATP6V1G3', 'Var', (161, 169))	('chromophobe RCC', 'Disease', (202, 217))	('RCC', 'Phenotype', 'HP:0005584', (214, 217))	('chromophobe RCC', 'Disease', 'MESH:C538614', (202, 217))
4585	26091477	These results suggested that both BSND and ATP6V1G3 are excellent immunohistochemical markers for differentiating between chromophobe RCC and other RCC subtypes.	('ATP6V1G3', 'Var', (43, 51))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('chromophobe RCC', 'Disease', (122, 137))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('chromophobe RCC', 'Disease', 'MESH:C538614', (122, 137))
4586	26091477	We next examined the expression status of BSND and ATP6V1G3 in renal oncocytoma, since this benign tumor often shares common morphological and immunophenotypic features with chromophobe RCC.	('tumor', 'Disease', (99, 104))	('renal oncocytoma', 'Disease', (63, 79))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('chromophobe RCC', 'Disease', (174, 189))	('ATP6V1G3', 'Var', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('renal oncocytoma', 'Disease', 'MESH:C537750', (63, 79))	('BSND', 'Gene', (42, 46))	('chromophobe RCC', 'Disease', 'MESH:C538614', (174, 189))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (63, 79))
4587	26091477	Immunohistochemical analysis for the BSND and ATP6V1G3 proteins revealed strong diffuse positivity for both in most of the renal oncocytoma specimens (13/14 cases, 92.9%, for both proteins) (Figure 2M-O and Table 3), suggesting that BSND and ATP6V1G3 are immunohistochemical markers for renal oncocytoma as well as chromophobe RCC.	('chromophobe RCC', 'Disease', (315, 330))	('RCC', 'Phenotype', 'HP:0005584', (327, 330))	('renal oncocytoma', 'Disease', 'MESH:C537750', (287, 303))	('renal oncocytoma', 'Disease', 'MESH:C537750', (123, 139))	('renal oncocytoma', 'Disease', (287, 303))	('renal oncocytoma', 'Disease', (123, 139))	('chromophobe RCC', 'Disease', 'MESH:C538614', (315, 330))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (287, 303))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (123, 139))	('ATP6V1G3', 'Var', (242, 250))
4588	26091477	In the immunohistochemical analyses of renal tumors, we found that some components of normal kidney tissue were also immunoreactive for BSND and ATP6V1G3.	('renal tumors', 'Disease', 'MESH:D007674', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('renal tumor', 'Phenotype', 'HP:0009726', (39, 50))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('BSND', 'Gene', (136, 140))	('renal tumors', 'Disease', (39, 51))	('renal tumors', 'Phenotype', 'HP:0009726', (39, 51))	('ATP6V1G3', 'Var', (145, 153))
4589	26091477	On the other hand, ATP6V1G3 was expressed at differential intensities in the nephrons: strong expression was observed in the distal convoluted tubule and collecting duct, while weak expression was observed in the proximal tubule and the thick ascending limb of the loop of Henle and very weak expression was observed in the thin limb of the loop of Henle (Figure 4E-H).	('ATP6V1G3', 'Var', (19, 27))	('nephrons', 'Disease', (77, 85))	('nephrons', 'Disease', 'MESH:D007683', (77, 85))
4590	26091477	These results suggested that BSND and ATP6V1G3 are variably expressed in normal kidney tissue, predominantly in the distal nephrons.	('nephrons', 'Disease', (123, 131))	('ATP6V1G3', 'Var', (38, 46))	('BSND', 'Gene', (29, 33))	('nephrons', 'Disease', 'MESH:D007683', (123, 131))
4591	26091477	Four CpG sites (cg27058889, cg00812246, cg19971655, and cg22162435) near the transcription start site (TSS) of BSND and 2 sites (cg12958813 and cg13100753) near the ATP6V1G3 TSS showed significantly lower DNA methylation levels (beta values) in chromophobe RCC than in clear cell RCC and papillary RCC; these median beta values of BSND or ATP6V1G3 in chromophobe RCC were lower than those in the other 2 RCCs by more than 0.25 (Figure 5A-C).	('chromophobe RCC', 'Disease', (351, 366))	('cg19971655', 'Var', (40, 50))	('RCC', 'Phenotype', 'HP:0005584', (298, 301))	('papillary RCC', 'Disease', 'MESH:C538614', (288, 301))	('RCC', 'Phenotype', 'HP:0005584', (257, 260))	('papillary RCC', 'Disease', (288, 301))	('cg22162435', 'Var', (56, 66))	('RCC', 'Phenotype', 'HP:0005584', (280, 283))	('transcription', 'biological_process', 'GO:0006351', ('77', '90'))	('cg13100753', 'Var', (144, 154))	('chromophobe RCC', 'Disease', 'MESH:C538614', (245, 260))	('DNA methylation levels', 'MPA', (205, 227))	('DNA methylation', 'biological_process', 'GO:0006306', ('205', '220'))	('cg00812246', 'Var', (28, 38))	('cg27058889', 'Var', (16, 26))	('lower', 'NegReg', (199, 204))	('lower', 'NegReg', (372, 377))	('DNA', 'cellular_component', 'GO:0005574', ('205', '208'))	('chromophobe RCC', 'Disease', 'MESH:C538614', (351, 366))	('chromophobe RCC', 'Disease', (245, 260))	('RCC', 'Phenotype', 'HP:0005584', (404, 407))	('RCC', 'Phenotype', 'HP:0005584', (363, 366))	('BSND and 2', 'Gene', '7809', (111, 121))	('cg12958813', 'Var', (129, 139))
4593	26091477	Thus, we examined the expression status of BSND and ATP6V1G3 proteins in lung carcinomas.	('BSND', 'Gene', (43, 47))	('lung carcinomas', 'Disease', (73, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('ATP6V1G3', 'Var', (52, 60))	('proteins', 'Protein', (61, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('examined', 'Reg', (9, 17))	('lung carcinomas', 'Disease', 'MESH:D008175', (73, 88))
4594	26091477	The results showed that BSND and ATP6V1G3 protein was not expressed in a total of 85 lung carcinomas, composed of 44 cases of squamous cell carcinoma of the lung and 41 cases of adenocarcinoma of the lung (Figure 6 and Table 3).	('ATP6V1G3', 'Var', (33, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('lung carcinomas', 'Disease', 'MESH:D008175', (85, 100))	('squamous cell carcinoma of the lung', 'Disease', (126, 161))	('adenocarcinoma of the lung', 'Disease', (178, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (183, 204))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (178, 204))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (126, 161))	('lung carcinomas', 'Disease', (85, 100))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (140, 161))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (126, 161))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))
4595	26091477	These results implied that BSND and ATP6V1G3 are excellent immunohistochemical markers for differentiating between chromophobe RCC that has metastasized to the lung and primary lung carcinoma.	('primary lung carcinoma', 'Disease', 'MESH:D008175', (169, 191))	('chromophobe RCC', 'Disease', 'MESH:C538614', (115, 130))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('primary lung carcinoma', 'Disease', (169, 191))	('ATP6V1G3', 'Var', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('chromophobe RCC', 'Disease', (115, 130))
4598	26091477	These results suggested that the expression levels of BSND and ATP6V1G3 were extremely low in various types of carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (111, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('BSND', 'Gene', (54, 58))	('carcinoma', 'Disease', (111, 120))	('ATP6V1G3', 'Var', (63, 71))	('expression levels', 'MPA', (33, 50))	('low', 'NegReg', (87, 90))
4601	26091477	Although weak positivity for ATP6V1G3 was detected in a subset of clear cell RCC (5.2%) and papillary RCC (10%), none of the clear cell or papillary RCC specimens showed even a weak positive signal for BSND.	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('clear', 'Disease', (66, 71))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('papillary RCC', 'Disease', 'MESH:C538614', (139, 152))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('papillary RCC', 'Disease', (139, 152))	('papillary RCC', 'Disease', 'MESH:C538614', (92, 105))	('ATP6V1G3', 'Var', (29, 37))	('papillary RCC', 'Disease', (92, 105))
4603	26091477	Regarding the expression levels of BSND and ATP6V1G3 in carcinomas other than RCC, lung carcinomas were negative (0%) for these protein expressions when examined using immunohistochemical analyses, and the TCGA data showed that the mRNA expression levels of both genes were extremely low in 12 types of carcinoma, including lung carcinoma.	('carcinoma', 'Disease', (329, 338))	('mRNA expression levels', 'MPA', (232, 254))	('lung carcinoma', 'Disease', (324, 338))	('lung carcinomas', 'Disease', (83, 98))	('carcinoma', 'Disease', (303, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('carcinomas', 'Disease', 'MESH:D002277', (88, 98))	('carcinoma', 'Disease', (88, 97))	('BSND', 'Gene', (35, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('carcinomas', 'Disease', 'MESH:D002277', (56, 66))	('carcinoma', 'Disease', (56, 65))	('carcinoma', 'Disease', 'MESH:D002277', (329, 338))	('carcinoma', 'Disease', 'MESH:D002277', (303, 312))	('ATP6V1G3', 'Var', (44, 52))	('lung carcinoma', 'Disease', 'MESH:D008175', (324, 338))	('low', 'NegReg', (284, 287))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('carcinoma', 'Disease', 'MESH:D002277', (88, 97))	('carcinomas', 'Disease', (88, 98))	('lung carcinoma', 'Disease', 'MESH:D008175', (83, 97))	('carcinoma', 'Disease', 'MESH:D002277', (56, 65))	('carcinomas', 'Disease', (56, 66))	('expression', 'MPA', (14, 24))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('lung carcinomas', 'Disease', 'MESH:D008175', (83, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (329, 338))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))
4604	26091477	These results suggest that BSND and ATP6V1G3 might be useful immunohistochemical markers for the differential diagnosis of chromophobe RCC.	('chromophobe RCC', 'Disease', (123, 138))	('ATP6V1G3', 'Var', (36, 44))	('chromophobe RCC', 'Disease', 'MESH:C538614', (123, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))
4606	26091477	In the current study, the sensitivity of BSND or ATP6V1G3 expression for the diagnosis of chromophobe RCC was 100%, and the specificity was 100%, when calculated based only on strong diffuse positivity.	('chromophobe RCC', 'Disease', 'MESH:C538614', (90, 105))	('ATP6V1G3', 'Var', (49, 57))	('chromophobe RCC', 'Disease', (90, 105))	('BSND', 'Gene', (41, 45))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))
4607	26091477	These values for BSND and ATP6V1G3 are superior or equal to those of any other immunohistochemical marker that has been used previously for the differential diagnosis of chromophobe RCC.	('ATP6V1G3', 'Var', (26, 34))	('chromophobe RCC', 'Disease', (170, 185))	('chromophobe RCC', 'Disease', 'MESH:C538614', (170, 185))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))
4612	26091477	In our analysis, renal oncocytoma was also found to be positive at a high frequency (92.9%) for BSND and ATP6V1G3 immunostaining.	('positive', 'Reg', (55, 63))	('renal oncocytoma', 'Disease', 'MESH:C537750', (17, 33))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (17, 33))	('BSND', 'Gene', (96, 100))	('renal oncocytoma', 'Disease', (17, 33))	('ATP6V1G3', 'Var', (105, 113))
4614	26091477	However, based on our results, BSND or ATP6V1G3 immunohistochemistry is not useful for differentiating between chromophobe RCC and renal oncocytoma.	('ATP6V1G3', 'Var', (39, 47))	('renal oncocytoma', 'Disease', 'MESH:C537750', (131, 147))	('renal oncocytoma', 'Disease', (131, 147))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (131, 147))	('chromophobe RCC', 'Disease', 'MESH:C538614', (111, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('chromophobe RCC', 'Disease', (111, 126))
4616	26091477	Germline mutations of the BSND gene cause Bartter syndrome type IV, which is an autosomal recessive disease characterized by salt loss, hypokalemia, metabolic alkalosis, and sensorineural deafness.	('Germline mutations', 'Var', (0, 18))	('hypokalemia', 'Disease', (136, 147))	('sensorineural deafness', 'Disease', (174, 196))	('metabolic alkalosis', 'Disease', (149, 168))	('BSND', 'Gene', (26, 30))	('hypokalemia', 'Phenotype', 'HP:0002900', (136, 147))	('autosomal recessive disease', 'Disease', (80, 107))	('metabolic alkalosis', 'Phenotype', 'HP:0200114', (149, 168))	('sensorineural deafness', 'Disease', 'MESH:D006313', (174, 196))	('salt loss', 'Phenotype', 'HP:0000127', (125, 134))	('hypokalemia', 'Disease', 'MESH:D007008', (136, 147))	('alkalosis', 'Phenotype', 'HP:0001948', (159, 168))	('salt', 'Chemical', 'MESH:D012492', (125, 129))	('Bartter syndrome type IV', 'Disease', 'MESH:C537653', (42, 66))	('metabolic alkalosis', 'Disease', 'MESH:D000471', (149, 168))	('deafness', 'Phenotype', 'HP:0000365', (188, 196))	('cause', 'Reg', (36, 41))	('Bartter syndrome type IV', 'Disease', (42, 66))	('autosomal recessive disease', 'Disease', 'MESH:D030342', (80, 107))	('sensorineural deafness', 'Phenotype', 'HP:0000407', (174, 196))
4617	26091477	At present, several research papers examining germline mutations of the BSND gene in the Bartter syndrome family have been reported; however, the expression of BSND protein in RCC has not been previously reported.	('BSND', 'Gene', (72, 76))	('Bartter syndrome', 'Disease', (89, 105))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('mutations', 'Var', (55, 64))	('Bartter syndrome', 'Disease', 'MESH:D001477', (89, 105))
4618	26091477	ATP6V1G3, another immunohistochemical marker identified in this study, is a subunit of vacuolar-H+ ATPase that couples ATP hydrolysis to proton pumping across membranes.	('ATP', 'Chemical', 'MESH:D000255', (99, 102))	('ATP', 'Chemical', 'MESH:D000255', (119, 122))	('couples ATP hydrolysis', 'MPA', (111, 133))	('ATP6V1G3', 'Var', (0, 8))	('vacuolar-H+ ATPase', 'Gene', '1769', (87, 105))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))	('vacuolar-H+ ATPase', 'Gene', (87, 105))	('ATP hydrolysis', 'biological_process', 'GO:0006200', ('119', '133'))
4620	26091477	Clinically, a reduction in the mRNA expression of ATP6V1G3 in clear cell RCC has been previously reported; however, its expression status in chromophobe RCC has not been previously reported.	('chromophobe RCC', 'Disease', 'MESH:C538614', (141, 156))	('clear cell RCC', 'Disease', (62, 76))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('chromophobe RCC', 'Disease', (141, 156))	('mRNA expression', 'MPA', (31, 46))	('ATP6V1G3', 'Var', (50, 58))	('reduction', 'NegReg', (14, 23))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
4627	26091477	We suspect that both BSND and ATP6V1G3 are members of the group of genes whose expressions are differentially influenced by the DNA methylation status between chromophobe RCC and other RCC subtypes, such as clear cell and papillary RCCs.	('influenced', 'Reg', (110, 120))	('papillary RCC', 'Disease', (222, 235))	('ATP6V1G3', 'Var', (30, 38))	('chromophobe RCC', 'Disease', 'MESH:C538614', (159, 174))	('RCC', 'Phenotype', 'HP:0005584', (232, 235))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('expressions', 'MPA', (79, 90))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('chromophobe RCC', 'Disease', (159, 174))	('DNA methylation', 'biological_process', 'GO:0006306', ('128', '143'))	('papillary RCC', 'Disease', 'MESH:C538614', (222, 235))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('clear cell', 'Disease', (207, 217))
4628	26091477	An examination of the mRNA expression data from the TCGA database also revealed that the mRNA expression levels of BSND and ATP6V1G3 were extremely low in various human carcinomas in this study.	('BSND', 'Gene', (115, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('mRNA expression levels', 'MPA', (89, 111))	('carcinomas', 'Disease', 'MESH:D002277', (169, 179))	('ATP6V1G3', 'Var', (124, 132))	('human', 'Species', '9606', (163, 168))	('carcinomas', 'Disease', (169, 179))	('low', 'NegReg', (148, 151))
4708	21918707	In a study of malignancies producing ectopic HCG, which included 2 bladder cancers, Crawford et al suggested that such expression may indicate chemosensitivity.	('bladder cancers', 'Disease', (67, 82))	('malignancies', 'Disease', 'MESH:D009369', (14, 26))	('ectopic', 'Var', (37, 44))	('HCG', 'Gene', '93659', (45, 48))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('bladder cancers', 'Phenotype', 'HP:0009725', (67, 82))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('malignancies', 'Disease', (14, 26))	('indicate', 'Reg', (134, 142))	('HCG', 'Gene', (45, 48))	('bladder cancers', 'Disease', 'MESH:D001749', (67, 82))
4721	21918707	Depression of cell-mediated immunity associated with the expression of beta=-HCG may be either generalised or specific, the latter being a form of immune tolerance.	('Depression', 'Disease', 'MESH:D000275', (0, 10))	('Depression', 'Disease', (0, 10))	('HCG', 'Gene', (77, 80))	('expression', 'Var', (57, 67))	('cell-mediated immunity', 'CPA', (14, 36))	('cell-mediated immunity', 'biological_process', 'GO:0002456', ('14', '36'))	('HCG', 'Gene', '93659', (77, 80))	('cell-mediated immunity', 'biological_process', 'GO:0002449', ('14', '36'))	('Depression', 'Phenotype', 'HP:0000716', (0, 10))
4723	21918707	Although it was observed that the expression of beta=-HCG was associated with inferior prognosis, there were a few beta=- HCG negative tumours that progressed resulting in the death of the patients.	('HCG', 'Gene', (54, 57))	('HCG', 'Gene', '93659', (122, 125))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('HCG', 'Gene', (122, 125))	('tumours', 'Disease', (135, 142))	('expression', 'Var', (34, 44))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('death', 'Disease', 'MESH:D003643', (176, 181))	('death', 'Disease', (176, 181))	('patients', 'Species', '9606', (189, 197))	('HCG', 'Gene', '93659', (54, 57))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))
4725	21918707	Considering the fact that the nodal status of the muscle-invasive tumours was not taken into consideration in this study there is the need to conduct another study Page number not for citation purposes 5 recruiting a large number of patients to investigate whether or not the inferior prognosis associated with the expression of beta=HCG is independent of the nodal status of the muscle-invasive urothelial carcinomas.	('muscle-invasive tumours', 'Disease', 'MESH:D009217', (50, 73))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (407, 416))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('HCG', 'Gene', '93659', (334, 337))	('expression', 'Var', (315, 325))	('muscle-invasive tumours', 'Disease', (50, 73))	('HCG', 'Gene', (334, 337))	('muscle-invasive urothelial carcinomas', 'Disease', 'MESH:D009217', (380, 417))	('carcinomas', 'Phenotype', 'HP:0030731', (407, 417))	('patients', 'Species', '9606', (233, 241))	('muscle-invasive urothelial carcinomas', 'Disease', (380, 417))
4755	21918707	The addition of antibodies to beta-hCG inhibited MTT reduction among high secretors but failed to inhibit MTT reduction in non-beta-hCG producers.	('beta-hCG', 'Protein', (30, 38))	('antibodies', 'Var', (16, 26))	('inhibited', 'NegReg', (39, 48))	('MTT', 'Chemical', 'MESH:C070243', (106, 109))	('MTT reduction', 'MPA', (49, 62))	('MTT', 'Chemical', 'MESH:C070243', (49, 52))
4804	21918707	In the case of patients with T2-T4 disease there was significant association with widespread metastasis (P < 0.01) and mortality, P = 0.07; Kaplan-Meier survival time analysis uncorrected for creatinine P = 0.027, corrected for creatinine P < 0.001).	('patients', 'Species', '9606', (15, 23))	('creatinine', 'Chemical', 'MESH:D003404', (192, 202))	('T2-T4', 'Var', (29, 34))	('creatinine', 'Chemical', 'MESH:D003404', (228, 238))	('widespread metastasis', 'CPA', (82, 103))
4805	21918707	Iles and associates concluded that although sample concentration was a serious confounding factor, after correcting for dilution using creatinine content, the elevated urinary levels of total beta-hCG indicated those T2-T4 lesions which were likely to metastasize and those patients likely to die early.	('T2-T4 lesions', 'Var', (217, 230))	('patients', 'Species', '9606', (274, 282))	('urinary levels of', 'MPA', (168, 185))	('creatinine', 'Chemical', 'MESH:D003404', (135, 145))	('metastasize', 'CPA', (252, 263))	('elevated', 'PosReg', (159, 167))
4806	21918707	However, for T2-T4 bladder tumours, an elevated pre-treatment level of urinary beta-hCG is a marker of poor prognosis and may prove useful in deciding appropriate therapy.	('pre', 'molecular_function', 'GO:0003904', ('48', '51'))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('elevated', 'PosReg', (39, 47))	('T2-T4', 'Var', (13, 18))	('bladder tumours', 'Disease', (19, 34))	('bladder tumour', 'Phenotype', 'HP:0009725', (19, 33))	('bladder tumours', 'Disease', 'MESH:D001749', (19, 34))
4814	21918707	Venyo and associates summarized their findings as follows: 1) 30% of all the urothelial carcinomas of all grades and stage were associated with raised serum levels of beta=-HCG, 2) Grades 1, 2 and 3 tumours were associated with raised levels of serum beta=-HCG in about 19%, 39%, and 47% of the tumours respectively and hence the higher the histological grade the higher the proportion of tumours associated with raised levels of serum beta=-HCG, 3)About 23% of the superficial tumours were associated with raised levels of serum beta=-HCG compared with about 47% of muscle-invasive urothelial tumours.	('HCG', 'Gene', (442, 445))	('muscle-invasive urothelial tumours', 'Disease', (567, 601))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('HCG', 'Gene', (257, 260))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('associated', 'Reg', (128, 138))	('HCG', 'Gene', '93659', (173, 176))	('HCG', 'Gene', (536, 539))	('tumours', 'Disease', (478, 485))	('tumours', 'Disease', (389, 396))	('associated', 'Reg', (491, 501))	('tumours', 'Phenotype', 'HP:0002664', (389, 396))	('tumours', 'Phenotype', 'HP:0002664', (478, 485))	('tumours', 'Disease', (295, 302))	('levels', 'MPA', (514, 520))	('tumours', 'Disease', (199, 206))	('serum levels', 'MPA', (151, 163))	('tumours', 'Disease', 'MESH:D009369', (389, 396))	('tumours', 'Disease', 'MESH:D009369', (478, 485))	('HCG', 'Gene', '93659', (442, 445))	('tumour', 'Phenotype', 'HP:0002664', (295, 301))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('tumours', 'Phenotype', 'HP:0002664', (295, 302))	('HCG', 'Gene', '93659', (257, 260))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('tumour', 'Phenotype', 'HP:0002664', (389, 395))	('tumour', 'Phenotype', 'HP:0002664', (478, 484))	('tumours', 'Disease', 'MESH:D009369', (295, 302))	('raised', 'Var', (507, 513))	('tumours', 'Disease', 'MESH:D009369', (199, 206))	('HCG', 'Gene', '93659', (536, 539))	('HCG', 'Gene', (173, 176))	('tumours', 'Disease', (594, 601))	('urothelial carcinomas', 'Disease', (77, 98))	('tumour', 'Phenotype', 'HP:0002664', (594, 600))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (77, 98))	('tumours', 'Phenotype', 'HP:0002664', (594, 601))	('tumours', 'Disease', 'MESH:D009369', (594, 601))	('muscle-invasive urothelial tumours', 'Disease', 'MESH:D009217', (567, 601))
4816	21918707	Muscle-invasive tumours associated with raised levels of serum beta=-HCG had inferior prognosis after radiotherapy and or cystectomy in comparison with muscle-invasive tumours associated with normal levels of serum beta=-HCG treated by radiotherapy or cystectomy.	('Muscle-invasive tumours', 'Disease', 'MESH:D009217', (0, 23))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('inferior', 'NegReg', (77, 85))	('tumours', 'Phenotype', 'HP:0002664', (168, 175))	('Muscle-invasive tumours', 'Disease', (0, 23))	('HCG', 'Gene', '93659', (69, 72))	('muscle-invasive tumours', 'Disease', (152, 175))	('HCG', 'Gene', (69, 72))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('HCG', 'Gene', '93659', (221, 224))	('raised', 'Var', (40, 46))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))	('HCG', 'Gene', (221, 224))	('prognosis', 'CPA', (86, 95))	('muscle-invasive tumours', 'Disease', 'MESH:D009217', (152, 175))
4817	21918707	Venyo and associates concluded that: 1) The serial measurement of serum =-HCG may prove to be a useful adjunct to the follow-up of patients whose tumours are associated with raised levels of beta=-HCG in their blood provided the elevation of the serum beta=-HCG level is due to production by the tumour, 2) The measurement of serum beta=-HCG in urothelial carcinoma may prove to be a method of identifying muscle-invasive tumours (T2-T4) which should be treated aggressively, perhaps, by adjuvant systemic chemotherapy, 3) the presence of beta=-HCG in urothelial tumours may add some prognostic information to the heterogenous biological behaviour of such tumours (usually aggressive tumours).	('tumour', 'Phenotype', 'HP:0002664', (656, 662))	('tumours', 'Disease', (146, 153))	('aggressive tumours', 'Disease', (673, 691))	('aggressive tumours', 'Disease', 'MESH:D001523', (673, 691))	('tumour', 'Disease', 'MESH:D009369', (656, 662))	('urothelial tumours', 'Disease', 'MESH:D014523', (552, 570))	('HCG', 'Gene', (258, 261))	('muscle-invasive tumours', 'Disease', (406, 429))	('tumour', 'Disease', (656, 662))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (345, 365))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('tumours', 'Disease', (422, 429))	('HCG', 'Gene', '93659', (197, 200))	('tumours', 'Disease', (684, 691))	('HCG', 'Gene', '93659', (545, 548))	('behaviour', 'biological_process', 'GO:0007610', ('638', '647'))	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('HCG', 'Gene', (74, 77))	('tumours', 'Phenotype', 'HP:0002664', (422, 429))	('tumour', 'Phenotype', 'HP:0002664', (296, 302))	('tumours', 'Disease', 'MESH:D009369', (422, 429))	('HCG', 'Gene', '93659', (338, 341))	('tumour', 'Disease', 'MESH:D009369', (296, 302))	('tumours', 'Phenotype', 'HP:0002664', (684, 691))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (356, 365))	('tumours', 'Disease', (563, 570))	('tumours', 'Disease', 'MESH:D009369', (684, 691))	('tumour', 'Disease', (296, 302))	('tumour', 'Disease', 'MESH:D009369', (146, 152))	('patients', 'Species', '9606', (131, 139))	('tumour', 'Phenotype', 'HP:0002664', (422, 428))	('tumour', 'Disease', (146, 152))	('tumours', 'Phenotype', 'HP:0002664', (563, 570))	('HCG', 'Gene', '93659', (258, 261))	('tumour', 'Disease', 'MESH:D009369', (422, 428))	('tumours', 'Disease', 'MESH:D009369', (563, 570))	('tumour', 'Disease', (422, 428))	('tumour', 'Disease', 'MESH:D009369', (684, 690))	('tumour', 'Disease', (684, 690))	('tumours', 'Disease', (656, 663))	('HCG', 'Gene', (197, 200))	('HCG', 'Gene', '93659', (74, 77))	('urothelial tumours', 'Disease', (552, 570))	('muscle-invasive tumours', 'Disease', 'MESH:D009217', (406, 429))	('tumour', 'Phenotype', 'HP:0002664', (563, 569))	('HCG', 'Gene', (545, 548))	('urothelial carcinoma', 'Disease', (345, 365))	('tumour', 'Disease', 'MESH:D009369', (563, 569))	('tumours', 'Phenotype', 'HP:0002664', (656, 663))	('tumour', 'Disease', (563, 569))	('tumours', 'Disease', 'MESH:D009369', (656, 663))	('HCG', 'Gene', (338, 341))	('presence', 'Var', (527, 535))
5072	31856727	For both datasets, the results using multi-omics data (all four data types combined) significantly outperform those using a single type of -omics data.	('a', 'Gene', '351', (10, 11))	('a', 'Gene', '351', (147, 148))	('a', 'Gene', '351', (93, 94))	('multi-omics', 'Var', (37, 48))	('a', 'Gene', '351', (55, 56))	('outperform', 'NegReg', (99, 109))	('a', 'Gene', '351', (52, 53))	('a', 'Gene', '351', (65, 66))	('a', 'Gene', '351', (149, 150))	('a', 'Gene', '351', (67, 68))	('a', 'Gene', '351', (12, 13))	('a', 'Gene', '351', (50, 51))	('a', 'Gene', '351', (122, 123))
5164	33260285	Reflecting this morphologic diversity, histologic variants have been proposed to define urothelial carcinoma with distinctive histomorphology that differs from that of conventional urothelial carcinoma.	('urothelial carcinoma', 'Disease', (88, 108))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (88, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('urothelial carcinoma', 'Disease', (181, 201))	('variants', 'Var', (50, 58))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (181, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
5231	33260285	Recognition of histologic variants is important because they commonly persist in metastatic tumors and represent the association between primary and corresponding metastatic tumors.	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumors', 'Disease', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('variants', 'Var', (26, 34))
5268	33231569	Results showed the upregulation of CTSL/B and ACE2 in Pancreatic adenocarcinoma (PAAD) and Stomach adenocarcinoma (STAD) and demonstrated a positive correlation between copy number alteration (CNA) and gene expression for CTSB in PAAD and STAD.	('CTSL', 'Gene', '1514', (35, 39))	('ACE2', 'Gene', '59272', (46, 50))	('CTSB', 'Gene', (222, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('CTSL', 'Gene', (35, 39))	('Pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (54, 79))	('CTSB', 'Gene', '1508', (222, 226))	('Stomach adenocarcinoma', 'Disease', (91, 113))	('PAAD', 'Phenotype', 'HP:0006725', (81, 85))	('upregulation', 'PosReg', (19, 31))	('PAAD', 'Phenotype', 'HP:0006725', (230, 234))	('Pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (54, 79))	('Pancreatic adenocarcinoma', 'Disease', (54, 79))	('gene expression', 'biological_process', 'GO:0010467', ('202', '217'))	('Stomach adenocarcinoma', 'Disease', 'MESH:D000230', (91, 113))	('ACE2', 'Gene', (46, 50))	('copy number', 'Var', (169, 180))
5269	33231569	Hypomethylation and a negative correlation of gene expression and methylation for CTSB were detected in PAAD.	('negative', 'NegReg', (22, 30))	('gene expression', 'biological_process', 'GO:0010467', ('46', '61'))	('methylation', 'MPA', (66, 77))	('Hypomethylation', 'Var', (0, 15))	('methylation', 'biological_process', 'GO:0032259', ('66', '77'))	('PAAD', 'Phenotype', 'HP:0006725', (104, 108))	('CTSB', 'Gene', '1508', (82, 86))	('expression', 'MPA', (51, 61))	('CTSB', 'Gene', (82, 86))
5291	33231569	CNA includes amplification, gain, diploidy, shallow deletion and deep deletion.	('gain', 'PosReg', (28, 32))	('shallow deletion', 'Var', (44, 60))	('diploidy', 'Disease', 'None', (34, 42))	('amplification', 'Var', (13, 26))	('deep deletion', 'Var', (65, 78))	('diploidy', 'Disease', (34, 42))
5292	33231569	c-BioPortal analysis based on The Cancer Genome Atlas (TCGA) data indicates that genomic amplification increased the gene expression of CTSB in STAD and PAAD (Figure 1E and Supplementary Figure 2, R>0.2, p<0.05).	('increased', 'PosReg', (103, 112))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Cancer', 'Disease', (34, 40))	('gene expression', 'biological_process', 'GO:0010467', ('117', '132'))	('gene expression', 'MPA', (117, 132))	('CTSB', 'Gene', '1508', (136, 140))	('Cancer', 'Disease', 'MESH:D009369', (34, 40))	('PAAD', 'Phenotype', 'HP:0006725', (153, 157))	('genomic amplification', 'Var', (81, 102))	('CTSB', 'Gene', (136, 140))
5296	33231569	For other types of tumors, the most frequent DNA alteration of the CTSL gene is DNA mutation in Uterine Corpus Endometrial Carcinoma (UCEC), ESCA, DLBC and Melanoma (Figure 1E), and followed by amplification in Sarcoma (SARC), Adrenocortical carcinoma (ACC), UCEC and ESCA.	('tumors', 'Disease', (19, 25))	('CTSL', 'Gene', '1514', (67, 71))	('ESCA', 'Phenotype', 'HP:0011459', (268, 272))	('ESCA', 'Phenotype', 'HP:0011459', (141, 145))	('SARC', 'Phenotype', 'HP:0100242', (220, 224))	('Adrenocortical carcinoma', 'Disease', (227, 251))	('Sarcoma', 'Disease', 'MESH:D012509', (211, 218))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (104, 132))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (111, 132))	('Melanoma', 'Disease', 'MESH:D008545', (156, 164))	('CTSL', 'Gene', (67, 71))	('Sarcoma', 'Disease', (211, 218))	('ACC', 'Phenotype', 'HP:0006744', (253, 256))	('Carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('ESCA', 'Disease', (268, 272))	('Sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('ESCA', 'Disease', (141, 145))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (227, 251))	('Melanoma', 'Disease', (156, 164))	('Corpus Endometrial Carcinoma', 'Disease', (104, 132))	('DNA', 'Gene', (80, 83))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('DLBC', 'Disease', (147, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('Melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (227, 251))	('mutation', 'Var', (84, 92))
5297	33231569	For CTSB, deep deletion in Uterine Carcinosarcoma (UCS), Liver hepatocellular carcinoma (LIHC), BLCA and OV, is the most frequent DNA alteration, followed by amplification in ESCA, STAD, PAAD and DLBC.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (63, 87))	('UCS', 'Phenotype', 'HP:0002891', (51, 54))	('CTSB', 'Gene', (4, 8))	('Liver hepatocellular carcinoma', 'Disease', (57, 87))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (57, 87))	('Carcinosarcoma', 'Disease', 'MESH:D002296', (35, 49))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('OV', 'Phenotype', 'HP:0012887', (105, 107))	('Carcinosarcoma', 'Disease', (35, 49))	('LIHC', 'Disease', (89, 93))	('CTSB', 'Gene', '1508', (4, 8))	('deep deletion', 'Var', (10, 23))	('PAAD', 'Phenotype', 'HP:0006725', (187, 191))	('Uterine Carcinosarcoma', 'Phenotype', 'HP:0002891', (27, 49))	('LIHC', 'Disease', 'None', (89, 93))	('ESCA', 'Phenotype', 'HP:0011459', (175, 179))
5298	33231569	For ACE2, the most frequent DNA alteration is mutation in UCEC, UCS, STAD and MEL (Supplementary Figure 1B).	('UCS', 'Disease', (64, 67))	('ACE2', 'Gene', (4, 8))	('STAD', 'Disease', (69, 73))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('ACE2', 'Gene', '59272', (4, 8))	('UCEC', 'Disease', (58, 62))	('UCS', 'Phenotype', 'HP:0002891', (64, 67))	('mutation', 'Var', (46, 54))
5320	32326336	Deleterious mutations in KDM6A occur in many human cancers, most frequently in urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (79, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('mutations', 'Var', (12, 21))	('KDM6A', 'Gene', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('human', 'Species', '9606', (45, 50))	('occur', 'Reg', (31, 36))	('KDM6A', 'Gene', '7403', (25, 30))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('urothelial carcinoma', 'Disease', (79, 99))
5322	32326336	UTX knockdown induced apoptosis and enriched KRT14high cells in the BFTC-905 papillary urothelial carcinoma cell line as well.	('apoptosis', 'biological_process', 'GO:0006915', ('22', '31'))	('BFTC-905 papillary urothelial carcinoma', 'Disease', (68, 107))	('apoptosis', 'CPA', (22, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (77, 107))	('BFTC-905 papillary urothelial carcinoma', 'Disease', 'MESH:D002291', (68, 107))	('induced', 'Reg', (14, 21))	('knockdown', 'Var', (4, 13))	('UTX', 'Gene', (0, 3))	('apoptosis', 'biological_process', 'GO:0097194', ('22', '31'))
5323	32326336	Our findings suggest an explanation for the frequent occurrence of KDM6A mutations across all stages and molecular subtypes of urothelial carcinoma, whereby loss of UTX function does not primarily impede later stages of urothelial differentiation, but favors the expansion of precursor populations to provide a reservoir of potential tumor-initiating cells.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (334, 339))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('KDM6A', 'Gene', '7403', (67, 72))	('favors', 'PosReg', (252, 258))	('tumor', 'Disease', (334, 339))	('urothelial carcinoma', 'Disease', (127, 147))	('KDM6A', 'Gene', (67, 72))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (127, 147))	('mutations', 'Var', (73, 82))	('loss', 'Var', (157, 161))
5325	32326336	KDM6A is frequently affected by deleterious mutations in urothelial carcinoma (UC) and other cancers.	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('urothelial carcinoma', 'Disease', (57, 77))	('affected', 'Reg', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('KDM6A', 'Gene', '7403', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('mutations', 'Var', (44, 53))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (57, 77))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('KDM6A', 'Gene', (0, 5))
5328	32326336	UTX has several molecular functions, including, prominently, a specific histone demethylase activity towards dimethylated or trimethylated lysine 27 of histone H3 (H3K27me2/3).	('lysine', 'Chemical', 'MESH:D008239', (139, 145))	('H3', 'Gene', '109741', (160, 162))	('histone demethylase activity', 'molecular_function', 'GO:0032452', ('72', '100'))	('dimethylated', 'MPA', (109, 121))	('H3', 'Gene', '109741', (164, 166))	('trimethylated lysine', 'Var', (125, 145))	('histone demethylase', 'Enzyme', (72, 91))	('activity', 'MPA', (92, 100))
5330	32326336	It is therefore plausible to assume that UTX inactivation in urothelial carcinoma might promote cancer development via aberrant urothelial differentiation.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('inactivation', 'Var', (45, 57))	('promote', 'PosReg', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('urothelial carcinoma', 'Disease', (61, 81))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (61, 81))	('UTX', 'Gene', (41, 44))	('cancer', 'Disease', (96, 102))
5332	32326336	For instance, loss of UTX in myeloid leukemia leads to dysregulation of transcription factor programs steering the differentiation of hematopoietic cells.	('dysregulation', 'MPA', (55, 68))	('loss', 'Var', (14, 18))	('myeloid leukemia', 'Disease', 'MESH:D007951', (29, 45))	('UTX', 'Gene', (22, 25))	('transcription factor', 'molecular_function', 'GO:0000981', ('72', '92'))	('myeloid leukemia', 'Disease', (29, 45))	('transcription', 'biological_process', 'GO:0006351', ('72', '85'))	('leukemia', 'Phenotype', 'HP:0001909', (37, 45))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (29, 45))
5334	32326336	However, KDM6A mutations are found across all molecular subtypes of invasive UC and are even frequent in well-differentiated papillary UC, as reviewed in.	('KDM6A', 'Gene', '7403', (9, 14))	('found', 'Reg', (29, 34))	('mutations', 'Var', (15, 24))	('well-differentiated papillary UC', 'Disease', (105, 137))	('KDM6A', 'Gene', (9, 14))	('invasive UC', 'Disease', 'MESH:D009361', (68, 79))	('invasive UC', 'Disease', (68, 79))	('frequent', 'Reg', (93, 101))
5336	32326336	Treatment with a PPARgamma agonist (troglitazone) and the EGF receptor inhibitor PD153035 (TZ/PD protocol) induces biochemical markers of urothelial differentiation, such as KRT20 and uroplakins, e.g., UPK2, while decreasing KRT14 and KRT5 expression.	('KRT5', 'Gene', (235, 239))	('PD153035', 'Chemical', 'MESH:C088860', (81, 89))	('UPK2', 'Gene', '7379', (202, 206))	('biochemical', 'MPA', (115, 126))	('PD153035', 'Var', (81, 89))	('decreasing', 'NegReg', (214, 224))	('KRT14', 'Gene', (225, 230))	('troglitazone', 'Chemical', 'MESH:D000077288', (36, 48))	('PPARgamma', 'Gene', '5468', (17, 26))	('EGF', 'molecular_function', 'GO:0005154', ('58', '61'))	('KRT20', 'Gene', (174, 179))	('induces', 'PosReg', (107, 114))	('UPK2', 'Gene', (202, 206))	('PPARgamma', 'Gene', (17, 26))	('urothelial differentiation', 'CPA', (138, 164))	('KRT20', 'Gene', '54474', (174, 179))
5339	32326336	Finally, we observed an analogous effect of UTX knockdown in the BFTC-905 urothelial carcinoma cell line, which also contains KRT14high and KRT14low cells.	('BFTC-905 urothelial carcinoma', 'Disease', 'MESH:D014523', (65, 94))	('UTX', 'Gene', (44, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('BFTC-905 urothelial carcinoma', 'Disease', (65, 94))	('knockdown', 'Var', (48, 57))
5341	32326336	In the T-24 cell line with a homozygous truncating KDM6A mutation, a weak band at approximately 100 kDa may correspond to the expected truncated protein.	('mutation', 'Var', (57, 65))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('KDM6A', 'Gene', (51, 56))	('KDM6A', 'Gene', '7403', (51, 56))
5342	32326336	Following CRISPR/Cas-mediated KDM6A knockout in the SW1710 cell line (as described in) UTX protein became undetectable (Figure S1b).	('knockout', 'Var', (36, 44))	('SW1710', 'CellLine', 'CVCL:1721', (52, 58))	('KDM6A', 'Gene', '7403', (30, 35))	('Cas', 'cellular_component', 'GO:0005650', ('17', '20'))	('UTX', 'MPA', (87, 90))	('undetectable', 'NegReg', (106, 118))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('KDM6A', 'Gene', (30, 35))
5348	32326336	The negative effect of UTX-knockdown on cell viability observed by microscopy was confirmed by MTT assays.	('UTX-knockdown', 'Gene', (23, 36))	('MTT', 'Chemical', 'MESH:C070243', (95, 98))	('UTX-knockdown', 'Var', (23, 36))	('negative', 'NegReg', (4, 12))
5355	32326336	Accordingly, the KRT14high/AldeFluorlow cells appear to increase in numbers, whereas KRT14low/AldeFluorhigh cells decrease, in a dynamic manner (Figure 5d).	('KRT14high/AldeFluorlow', 'Var', (17, 39))	('AldeFluor', 'Chemical', '-', (27, 36))	('increase', 'PosReg', (56, 64))	('AldeFluor', 'Chemical', '-', (94, 103))
5356	32326336	As observed via other parameters (see Figure 4), the KRT14low/AldeFluorhigh population was significantly diminished on day 4 after UTX knockdown but recovered thereafter.	('KRT14low/AldeFluorhigh population', 'CPA', (53, 86))	('AldeFluor', 'Chemical', '-', (62, 71))	('diminished', 'NegReg', (105, 115))	('knockdown', 'Var', (135, 144))
5366	32326336	Mutations inactivating UTX are found across all stages of urothelial carcinoma (UC), albeit more commonly in lower stage tumors, and intriguingly, across all molecular subtypes of muscle-invasive bladder cancers (MIBC).	('bladder cancers', 'Phenotype', 'HP:0009725', (196, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('Mutations inactivating', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('muscle-invasive bladder cancers', 'Disease', 'MESH:D001749', (180, 211))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (58, 78))	('bladder cancer', 'Phenotype', 'HP:0009725', (196, 210))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('UTX', 'Gene', (23, 26))	('MIBC', 'Chemical', '-', (213, 217))	('invasive bladder', 'Phenotype', 'HP:0100645', (187, 203))	('stage tumors', 'Disease', 'MESH:D007676', (115, 127))	('stage tumors', 'Disease', (115, 127))	('urothelial carcinoma', 'Disease', (58, 78))	('found', 'Reg', (31, 36))	('muscle-invasive bladder cancers', 'Disease', (180, 211))
5369	32326336	Therefore, it may seem a priori unlikely that UTX inactivation contributes to urothelial carcinogenesis by blocking the differentiation of basal to luminal cells, since in that case UTX mutations should be more prevalent in BASQ UC.	('differentiation', 'CPA', (120, 135))	('mutations', 'Var', (186, 195))	('blocking', 'NegReg', (107, 115))	('BASQ UC', 'Disease', (224, 231))	('prevalent', 'Reg', (211, 220))	('luminal', 'Chemical', 'MESH:D010634', (148, 155))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (78, 103))	('inactivation', 'Var', (50, 62))	('urothelial carcinogenesis', 'Disease', (78, 103))
5370	32326336	This assumption is borne out by our finding that UTX knockdown in models of urothelial differentiation, wherein cells with a basal phenotype differentiate into luminal cells, did not significantly inhibit differentiation.	('inhibit', 'NegReg', (197, 204))	('knockdown', 'Var', (53, 62))	('urothelial differentiation', 'Disease', (76, 102))	('luminal', 'Chemical', 'MESH:D010634', (160, 167))
5381	32326336	This argument also suggests that UTX inactivation might constitute an early event in urothelial carcinogenesis.	('urothelial carcinogenesis', 'Disease', (85, 110))	('inactivation', 'Var', (37, 49))	('UTX', 'Protein', (33, 36))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (85, 110))
5382	32326336	Additional mutations in p53 or growth factor receptors would then lead to cancer.	('mutations', 'Var', (11, 20))	('p53', 'Gene', (24, 27))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('lead to', 'Reg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
5383	32326336	For instance, activation of STAT3 in a mouse model of urothelial carcinoma was associated with expansion of KRT14high cells.	('STAT3', 'Gene', (28, 33))	('activation', 'PosReg', (14, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('KRT14high', 'Protein', (108, 117))	('urothelial carcinoma', 'Disease', (54, 74))	('expansion', 'Var', (95, 104))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (54, 74))	('mouse', 'Species', '10090', (39, 44))	('STAT3', 'Gene', '20848', (28, 33))
5385	32326336	In one study on four patients, intriguingly, KMT2D, another COMPASS component, was frequently mutated in morphologically normal urothelial tissue from cancer-carrying bladders.	('mutated', 'Var', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('patients', 'Species', '9606', (21, 29))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('KMT2D', 'Gene', '8085', (45, 50))	('KMT2D', 'Gene', (45, 50))
5386	32326336	An analogous scenario is established in the development of acute myeloid leukemia, which is often preceded by clonal hematopoiesis elicited by mutations in various genes, most often encoding epigenetic regulators like DNMT3A and TET2, which shift the balance between stem cells and differentiated progeny and displace normal with stem cells with mutants.	('DNMT3A', 'Gene', (218, 224))	('hematopoiesis', 'Disease', 'MESH:C536227', (117, 130))	('DNMT3A', 'Gene', '1788', (218, 224))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (59, 81))	('TET2', 'Gene', '54790', (229, 233))	('hematopoiesis', 'Disease', (117, 130))	('hematopoiesis', 'biological_process', 'GO:0030097', ('117', '130'))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (59, 81))	('TET2', 'Gene', (229, 233))	('leukemia', 'Phenotype', 'HP:0001909', (73, 81))	('shift', 'Reg', (241, 246))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (65, 81))	('acute myeloid leukemia', 'Disease', (59, 81))	('mutations', 'Var', (143, 152))
5387	32326336	Similarly, mutations inactivating KMT2D appear to increase the B-cell population at risk to develop lymphomas by further genetic alterations.	('mutations inactivating', 'Var', (11, 33))	('lymphomas', 'Disease', (100, 109))	('lymphomas', 'Disease', 'MESH:D008223', (100, 109))	('lymphomas', 'Phenotype', 'HP:0002665', (100, 109))	('increase', 'PosReg', (50, 58))	('KMT2D', 'Gene', (34, 39))	('KMT2D', 'Gene', '8085', (34, 39))
5404	32326336	The following siRNAs were purchased from ThermoFisher Scientific: ON-TARGETplus Human KDM6A siRNA (SMARTpool, Dharmacon, L-014140-01-0005, siRNA 01) with ON-TARGETplus Non-targeting Pool (Dharmacon, D-001810-10-05, siRNA 20) as a control, or Silencer  Select siRNA (4392420, Ambion, KDM6A, s14735) with Silencer  Select Negative Control No.	('KDM6A', 'Gene', (86, 91))	('Human', 'Species', '9606', (80, 85))	('KDM6A', 'Gene', (283, 288))	('KDM6A', 'Gene', '7403', (86, 91))	('4392420', 'Var', (266, 273))	('KDM6A', 'Gene', '7403', (283, 288))
5439	32326336	We suggest that loss of UTX function may promote the expansion of clonal cell populations in the urothelium that can generate tumors after acquiring additional mutations inactivating tumor suppressors, such as p53, or activating oncogenes, such as FGFR3.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('inactivating', 'Var', (170, 182))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('loss', 'Var', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('FGFR', 'molecular_function', 'GO:0005007', ('248', '252'))	('tumors', 'Disease', (126, 132))	('mutations inactivating', 'Var', (160, 182))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('FGFR3', 'Gene', (248, 253))	('tumor', 'Disease', (183, 188))	('activating', 'PosReg', (218, 228))	('generate', 'Reg', (117, 125))	('tumor', 'Disease', (126, 131))	('FGFR3', 'Gene', '2261', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('p53', 'Gene', (210, 213))	('UTX', 'Gene', (24, 27))
5444	30220708	Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes.	('mutations', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('copy number alterations', 'Var', (41, 64))	('cancer', 'Disease', (81, 87))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
5447	30220708	Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion.	('CR', 'Chemical', '-', (41, 43))	('TACC3', 'Gene', (134, 139))	('TSC1', 'Gene', '7248', (78, 82))	('patient', 'Species', '9606', (5, 12))	('patients', 'Species', '9606', (5, 13))	('TSC2', 'Gene', '7249', (83, 87))	('TSC2', 'Gene', (83, 87))	('FGFR3', 'Gene', (128, 133))	('TSC1', 'Gene', (78, 82))	('patient', 'Species', '9606', (106, 113))	('SD', 'Disease', 'MESH:D029461', (57, 59))	('FGFR', 'molecular_function', 'GO:0005007', ('128', '132'))	('FGFR3', 'Gene', '2261', (128, 133))	('mTOR', 'Gene', (91, 95))	('mTOR', 'Gene', '2475', (91, 95))	('TACC3', 'Gene', '10460', (134, 139))	('mutations', 'Var', (65, 74))
5454	30220708	Angiogenesis via VEGF is known to play a role in bladder cancer biology and disease progression and activation of mTOR has been shown to increase tumour cell proliferation and promote angiogenesis.	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('promote', 'PosReg', (176, 183))	('bladder cancer', 'Disease', 'MESH:D001749', (49, 63))	('bladder cancer', 'Disease', (49, 63))	('angiogenesis', 'CPA', (184, 196))	('VEGF', 'Gene', '7422', (17, 21))	('bladder cancer', 'Phenotype', 'HP:0009725', (49, 63))	('mTOR', 'Gene', (114, 118))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('VEGF', 'Gene', (17, 21))	('tumour', 'Disease', 'MESH:D009369', (146, 152))	('tumour', 'Disease', (146, 152))	('mTOR', 'Gene', '2475', (114, 118))	('increase', 'PosReg', (137, 145))	('cell proliferation', 'biological_process', 'GO:0008283', ('153', '171'))	('Angiogenesis', 'biological_process', 'GO:0001525', ('0', '12'))	('Angiogenesis', 'CPA', (0, 12))	('activation', 'Var', (100, 110))	('angiogenesis', 'biological_process', 'GO:0001525', ('184', '196'))
5468	30220708	Two dose levels (DLs) for everolimus (E) and three DLs for pazopanib (P) and its combinations (E/P) were evaluated as: E 5 mg daily + P 400 mg daily (DL-1); E 5 mg + P 600 mg (DL0); E 10 mg + P 600 mg (DL-1); E 10 mg + P 800 mg (DL2); and, E 5 mg daily + P 800 mg daily (DL2A, only used if the MTD was exceeded on DL2).	('DL-1', 'Gene', '28514', (202, 206))	('DL-1', 'Gene', '28514', (150, 154))	('pazopanib', 'Chemical', 'MESH:C516667', (59, 68))	('DL2', 'molecular_function', 'GO:0033904', ('271', '274'))	('everolimus', 'Chemical', 'MESH:D000068338', (26, 36))	('E 5', 'Var', (119, 122))	('DL-1', 'Gene', (150, 154))	('DL2', 'molecular_function', 'GO:0033904', ('229', '232'))	('DL-1', 'Gene', (202, 206))	('DL2', 'molecular_function', 'GO:0033904', ('314', '317'))
5484	30220708	Deep-targeted next-generation sequencing was performed using Dana-Farber Cancer Institute PROFILE test, a hybrid-capture and massively parallel sequencing assay surveying exonic DNA of 400 cancer genes as reported previously.	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('exonic DNA', 'Var', (171, 181))	('Cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('Cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (189, 195))
5512	30220708	Four patients that derived clinical benefit from combination treatment with E/P (one CR, two PR and one SD) had mutations in mTOR or TSC1/TSC2.	('patients', 'Species', '9606', (5, 13))	('mTOR', 'Gene', '2475', (125, 129))	('TSC1', 'Gene', '7248', (133, 137))	('SD', 'Disease', 'MESH:D029461', (104, 106))	('mTOR', 'Gene', (125, 129))	('TSC2', 'Gene', '7249', (138, 142))	('TSC2', 'Gene', (138, 142))	('TSC1', 'Gene', (133, 137))	('mutations', 'Var', (112, 121))	('CR', 'Chemical', '-', (85, 87))
5513	30220708	Specifically, the patient demonstrating CR had activating mTOR mutations (E2419K and E2014K); these findings have been reported in detail previously.	('E2014K)', 'Var', (85, 92))	('mTOR', 'Gene', (58, 62))	('E2419K', 'Var', (74, 80))	('E2014K', 'Mutation', 'rs1057519780', (85, 91))	('CR', 'Chemical', '-', (40, 42))	('patient', 'Species', '9606', (18, 25))	('E2419K', 'Mutation', 'rs587777900', (74, 80))	('activating', 'PosReg', (47, 57))	('mTOR', 'Gene', '2475', (58, 62))
5514	30220708	Two patients (one PR and one SD) were found to have separate mutations in TSC1 (patient with PR having c.1579C>T (p.Q527*), exon 15 in 27% of 209 reads; patient with SD having c.1237C>T (p.Q413*), exon 12 in 90% of 74 reads).	('c.1579C>T', 'Mutation', 'rs118203549', (103, 112))	('TSC1', 'Gene', '7248', (74, 78))	('p.Q527*', 'Mutation', 'rs118203549', (114, 121))	('TSC1', 'Gene', (74, 78))	('patient', 'Species', '9606', (4, 11))	('SD', 'Disease', 'MESH:D029461', (29, 31))	('SD', 'Disease', 'MESH:D029461', (166, 168))	('c.1237C>T (p.Q413*', 'Var', (176, 194))	('c.1579C>T (p.Q527*', 'Var', (103, 121))	('patient', 'Species', '9606', (153, 160))	('p.Q413*', 'Mutation', 'rs769299161', (187, 194))	('patients', 'Species', '9606', (4, 12))	('patient', 'Species', '9606', (80, 87))	('c.1237C>T', 'Mutation', 'rs769299161', (176, 185))
5515	30220708	Another patient with PR was shown to have molecular alterations in mTOR plus two DNA variants, EP300 (c.2050_2053+delTCTAG) and KDM6A (c.4187_4191delTACCA), as well as deletion in exon 1 of ARID1A and amplitude gains in MDM2 and CCNE1.	('CCNE1', 'Gene', (229, 234))	('KDM6A', 'Gene', '7403', (128, 133))	('c.2050_2053+delTCTAG', 'Mutation', 'c.2050del2053,TCTAG', (102, 122))	('EP300', 'Gene', (95, 100))	('amplitude', 'MPA', (201, 210))	('mTOR', 'Gene', (67, 71))	('MDM2', 'Gene', '4193', (220, 224))	('patient', 'Species', '9606', (8, 15))	('CCNE1', 'Gene', '898', (229, 234))	('deletion', 'Var', (168, 176))	('KDM6A', 'Gene', (128, 133))	('mTOR', 'Gene', '2475', (67, 71))	('ARID1A', 'Gene', (190, 196))	('c.2050_2053+delTCTAG', 'Var', (102, 122))	('alterations', 'Reg', (52, 63))	('gains', 'PosReg', (211, 216))	('c.4187_4191delTACCA', 'Var', (135, 154))	('c.4187_4191delTACCA', 'Mutation', 'c.4187_4191delTACCA', (135, 154))	('ARID1A', 'Gene', '8289', (190, 196))	('EP300', 'Gene', '2033', (95, 100))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('MDM2', 'Gene', (220, 224))
5516	30220708	In addition, molecular analysis on a fifth patient with clinical benefit from combination E/P treatment (PR) demonstrated the presence of an FGFR3-TACC3 fusion, without alterations in the mTOR pathway.	('TACC3', 'Gene', '10460', (147, 152))	('patient', 'Species', '9606', (43, 50))	('FGFR3', 'Gene', '2261', (141, 146))	('TACC3', 'Gene', (147, 152))	('mTOR', 'Gene', (188, 192))	('FGFR3', 'Gene', (141, 146))	('mTOR', 'Gene', '2475', (188, 192))	('fusion', 'Var', (153, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('141', '145'))
5529	30220708	The rationale for investigating targeted therapies in mUC is derived from the emerging data of molecular analysis that has helped further characterise this disease (https://www.mycancergenome.org/content/disease/bladder-cancer/).. Of particular interest are mutations in the mTOR pathway and the tyrosine-kinase fibroblast growth factor receptor (FGFR).	('mutations', 'Var', (258, 267))	('bladder-cancer', 'Disease', 'MESH:D001749', (212, 226))	('bladder-cancer', 'Phenotype', 'HP:0009725', (212, 226))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('bladder-cancer', 'Disease', (212, 226))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('312', '336'))	('FGFR', 'Gene', (347, 351))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('FGFR', 'molecular_function', 'GO:0005007', ('347', '351'))	('cancer', 'Disease', (220, 226))	('cancer', 'Disease', (179, 185))	('mTOR', 'Gene', (275, 279))	('mTOR', 'Gene', '2475', (275, 279))
5530	30220708	For example, in a study of comprehensive genomic profiling of recurrent or metastatic UC cases, TSC1 mutations were seen in up to 9.5% of samples and alterations of FGFR3 in up to 21%.	('metastatic UC', 'Disease', (75, 88))	('FGFR3', 'Gene', '2261', (165, 170))	('FGFR', 'molecular_function', 'GO:0005007', ('165', '169'))	('mutations', 'Var', (101, 110))	('FGFR3', 'Gene', (165, 170))	('to 9', 'Species', '1214577', (127, 131))	('alterations', 'Var', (150, 161))	('TSC1', 'Gene', '7248', (96, 100))	('TSC1', 'Gene', (96, 100))	('seen', 'Reg', (116, 120))
5531	30220708	In our study, five subjects that demonstrated clinical response carried mutations in the mTOR pathway, TSC1/TSC2, or were found to have FGFR3-TACC3 fusion (Table 4).	('mTOR', 'Gene', '2475', (89, 93))	('mutations', 'Var', (72, 81))	('FGFR3', 'Gene', '2261', (136, 141))	('TSC2', 'Gene', '7249', (108, 112))	('TACC3', 'Gene', '10460', (142, 147))	('FGFR3', 'Gene', (136, 141))	('FGFR', 'molecular_function', 'GO:0005007', ('136', '140'))	('TACC3', 'Gene', (142, 147))	('TSC2', 'Gene', (108, 112))	('TSC1', 'Gene', '7248', (103, 107))	('TSC1', 'Gene', (103, 107))	('mTOR', 'Gene', (89, 93))
5532	30220708	Mutations in the tumour suppressor genes TSC1 and TSC2 are well-described activating mutations in the kinase domain of the mTOR pathway.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('TSC2', 'Gene', '7249', (50, 54))	('TSC1', 'Gene', '7248', (41, 45))	('Mutations', 'Var', (0, 9))	('TSC1', 'Gene', (41, 45))	('tumour', 'Disease', (17, 23))	('TSC2', 'Gene', (50, 54))	('mTOR', 'Gene', '2475', (123, 127))	('mTOR', 'Gene', (123, 127))
5534	30220708	Inactivating mutations of TSC1/TSC2 result in mTOR pathway activation and these alterations have been shown, collectively, to confer sensitivity to mTOR inhibitors in patients with hamartomatous syndromes, such as tuberous sclerosis complex.	('sensitivity to', 'MPA', (133, 147))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('214', '240'))	('mTOR', 'Gene', (148, 152))	('mTOR', 'Gene', '2475', (148, 152))	('TSC2', 'Gene', '7249', (31, 35))	('mTOR', 'Gene', '2475', (46, 50))	('TSC1', 'Gene', '7248', (26, 30))	('hamartomatous syndromes', 'Disease', (181, 204))	('patients', 'Species', '9606', (167, 175))	('tuberous sclerosis', 'Disease', (214, 232))	('mTOR', 'Gene', (46, 50))	('Inactivating mutations', 'Var', (0, 22))	('TSC2', 'Gene', (31, 35))	('TSC1', 'Gene', (26, 30))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (214, 232))	('activation', 'PosReg', (59, 69))	('hamartomatous syndromes', 'Disease', 'MESH:C563621', (181, 204))
5535	30220708	These findings may explain the response to E/P seen in our mUC patients harbouring inactivating mutations in TSC1/TSC2 or activating mutations in mTOR.	('inactivating mutations', 'Var', (83, 105))	('mTOR', 'Gene', '2475', (146, 150))	('TSC1', 'Gene', '7248', (109, 113))	('mTOR', 'Gene', (146, 150))	('TSC1', 'Gene', (109, 113))	('TSC2', 'Gene', '7249', (114, 118))	('TSC2', 'Gene', (114, 118))	('activating mutations', 'Var', (122, 142))	('patients', 'Species', '9606', (63, 71))
5537	30220708	While the FGFR3 gene is one of the most frequent genetic alterations seen in bladder cancer, aberrant activation is also seen in chromosomal rearrangements of FGFR3 with potential fusion partners, such as TACC3 (transforming acid coiled coil 3).	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('FGFR3', 'Gene', '2261', (10, 15))	('transforming acid coiled coil 3', 'Gene', '10460', (212, 243))	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('10', '14'))	('transforming acid coiled coil 3', 'Gene', (212, 243))	('FGFR3', 'Gene', '2261', (159, 164))	('FGFR3', 'Gene', (10, 15))	('bladder cancer', 'Disease', (77, 91))	('activation', 'PosReg', (102, 112))	('fusion', 'Interaction', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('FGFR3', 'Gene', (159, 164))	('chromosomal rearrangements', 'Var', (129, 155))	('TACC3', 'Gene', '10460', (205, 210))	('TACC3', 'Gene', (205, 210))
5542	30220708	This may explain why our patient with FGFR3-TACC3 fusion was sensitive to combination E/P therapy and displayed a PR, despite having previously progressed on chemotherapy.	('FGFR3', 'Gene', '2261', (38, 43))	('FGFR3', 'Gene', (38, 43))	('patient', 'Species', '9606', (25, 32))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('TACC3', 'Gene', '10460', (44, 49))	('fusion', 'Var', (50, 56))	('TACC3', 'Gene', (44, 49))
5546	30220708	In conclusion, we demonstrate that combination therapy with E/P is well tolerated in patients with mUC and that genomically selected patients with mutations in the mTOR pathway or FGFR appear to derive significant clinical benefit.	('mutations', 'Var', (147, 156))	('benefit', 'PosReg', (223, 230))	('patients', 'Species', '9606', (133, 141))	('FGFR', 'molecular_function', 'GO:0005007', ('180', '184'))	('patients', 'Species', '9606', (85, 93))	('mTOR', 'Gene', '2475', (164, 168))	('FGFR', 'Gene', (180, 184))	('mTOR', 'Gene', (164, 168))	('mUC', 'Disease', (99, 102))
5556	23834155	Their aberrant expression has been found to be linked to the pathology of many diseases including cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('aberrant', 'Var', (6, 14))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('linked', 'Reg', (47, 53))
5561	23834155	A number of studies have shown that variations in components of the miRNA biogenesis pathways, particularly the aberrant expression of XPO5, increase the risk of developing cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('XPO5', 'Gene', (135, 139))	('miR', 'Gene', '220972', (68, 71))	('miR', 'Gene', (68, 71))	('cancer', 'Disease', (173, 179))	('XPO5', 'Gene', '57510', (135, 139))	('miRNA biogenesis', 'biological_process', 'GO:0035196', ('68', '84'))	('variations', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('increase', 'Reg', (141, 149))	('aberrant expression', 'Var', (112, 131))
5588	23834155	Over-expression of XPO5 has been shown to result in enhanced miRNA activity that competes with Dicer which suggests that XPO5-mediated nuclear export of pre-miRNAs may be a rate-limiting step in miRNA biogenesis.	('XPO5', 'Gene', (121, 125))	('XPO5', 'Gene', '57510', (121, 125))	('miR', 'Gene', '220972', (61, 64))	('miRNA biogenesis', 'biological_process', 'GO:0035196', ('195', '211'))	('miR', 'Gene', (61, 64))	('miR', 'Gene', '220972', (157, 160))	('XPO5', 'Gene', (19, 23))	('miR', 'Gene', (157, 160))	('XPO5', 'Gene', '57510', (19, 23))	('miR', 'Gene', '220972', (195, 198))	('nuclear export', 'biological_process', 'GO:0051168', ('135', '149'))	('enhanced', 'PosReg', (52, 60))	('miR', 'Gene', (195, 198))	('Dicer', 'Gene', '23405', (95, 100))	('Dicer', 'Gene', (95, 100))	('Over-expression', 'Var', (0, 15))	('pre', 'molecular_function', 'GO:0003904', ('153', '156'))
5590	23834155	The prognostic value of XPO5 in cancer is emerging and the importance of XPO5 in the miRNA pathway suggests that structural alterations in this transporter could potentially impact global miRNA expression, thereby altering an individual's risk of developing cancer.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (188, 191))	('miR', 'Gene', (85, 88))	('cancer', 'Disease', (32, 38))	('impact', 'Reg', (174, 180))	('miR', 'Gene', '220972', (188, 191))	('XPO5', 'Gene', '57510', (73, 77))	('structural alterations', 'Var', (113, 135))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('XPO5', 'Gene', (24, 28))	('cancer', 'Disease', (258, 264))	('XPO5', 'Gene', '57510', (24, 28))	('XPO5', 'Gene', (73, 77))	('altering', 'Reg', (214, 222))
5593	23834155	The authors also showed that nuclear to cytoplasmic transport could be inhibited by small interfering RNAs against CRM1, indicating that this pathway is shared by different classes of miRNAs.	('RNAs', 'Protein', (102, 106))	('miR', 'Gene', '220972', (184, 187))	('transport', 'biological_process', 'GO:0006810', ('52', '61'))	('miR', 'Gene', (184, 187))	('inhibited', 'NegReg', (71, 80))	('CRM1', 'Gene', (115, 119))	('nuclear', 'CPA', (29, 36))	('small interfering', 'Var', (84, 101))
5596	23834155	The RNA interference of these genes retarded heterochronic phenotypes similar to those observed for animals with mutations in the let-7 miRNA or core miRNA machinery genes.	('miR', 'Gene', '220972', (150, 153))	('miR', 'Gene', (150, 153))	('RNA interference', 'biological_process', 'GO:0016246', ('4', '20'))	('retarded heterochronic', 'Disease', 'MESH:D008607', (36, 58))	('core', 'cellular_component', 'GO:0019013', ('145', '149'))	('genes', 'Var', (30, 35))	('miR', 'Gene', '220972', (136, 139))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('miR', 'Gene', (136, 139))	('mutations', 'Var', (113, 122))	('retarded heterochronic', 'Disease', (36, 58))	('RNA interference', 'MPA', (4, 20))
5598	23834155	An involvement of XPO1 in miRNA biogenesis was found to be conserved in Drosophila, in which knockdown of XPO1 or its chemical inhibition through Leptomycin B (a CRM1 inhibitor) causes pri-miRNA accumulation.	('knockdown', 'Var', (93, 102))	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (26, 29))	('XPO1', 'Gene', (106, 110))	('miR', 'Gene', '220972', (189, 192))	('miRNA biogenesis', 'biological_process', 'GO:0035196', ('26', '42'))	('miR', 'Gene', (189, 192))	('Leptomycin B', 'Chemical', 'MESH:C038753', (146, 158))	('Drosophila', 'Species', '7227', (72, 82))
5603	23834155	Being a Ran dependent process, the XPO5:RanGTP complex was shown to form a glove (mitt) like structure in which N-terminal HEAT repeats 6-13 form the outer side of the glove and C-terminal HEAT repeats 14-21 form the thumb region of the glove.	('Ran', 'Gene', (40, 43))	('C-terminal HEAT repeats 14-21', 'Var', (178, 207))	('XPO5', 'Gene', (35, 39))	('RanGTP', 'Chemical', '-', (40, 46))	('Ran', 'Gene', '5901', (8, 11))	('XPO5', 'Gene', '57510', (35, 39))	('Ran', 'Gene', '5901', (40, 43))	('N-terminal HEAT repeats 6-13', 'Var', (112, 140))	('Ran', 'Gene', (8, 11))
5624	23834155	Their findings also suggested that XPO5 expression may also increase the pool of pre-miRNAs that are bound to be exported out of the nucleus.	('XPO5', 'Gene', (35, 39))	('XPO5', 'Gene', '57510', (35, 39))	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('expression', 'Var', (40, 50))	('pre', 'molecular_function', 'GO:0003904', ('81', '84'))	('increase', 'PosReg', (60, 68))	('nucleus', 'cellular_component', 'GO:0005634', ('133', '140'))
5631	23834155	They first genotyped two missense SNPs in XPO5, rs34324334 (S241N) and rs11544382 (M1115T), and evaluated the methylation levels in the XPO5 promoter region for blood DNA samples from a breast cancer case-control study.	('rs11544382', 'Var', (71, 81))	('rs34324334', 'Mutation', 'rs34324334', (48, 58))	('XPO5', 'Gene', '57510', (42, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('methylation', 'biological_process', 'GO:0032259', ('110', '121'))	('S241N', 'Mutation', 'rs34324334', (60, 65))	('M1115T', 'Mutation', 'rs11544382', (83, 89))	('methylation', 'MPA', (110, 121))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('XPO5', 'Gene', (136, 140))	('XPO5', 'Gene', '57510', (136, 140))	('DNA', 'cellular_component', 'GO:0005574', ('167', '170'))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Disease', (186, 199))	('XPO5', 'Gene', (42, 46))	('rs11544382', 'Mutation', 'rs11544382', (71, 81))	('rs34324334 (S241N', 'Var', (48, 65))
5632	23834155	Their primary findings included the capture of variant genotypes of rs11544382 that were associated with breast cancer risk compared to the homozygous commonly observed genotype.	('associated', 'Reg', (89, 99))	('rs11544382', 'Mutation', 'rs11544382', (68, 78))	('rs11544382', 'Var', (68, 78))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cap', 'Chemical', '-', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
5633	23834155	When stratified by menopausal status, the variant alleles of both rs11544382 and rs34324334 were found to be significantly associated with breast cancer risk in post-menopausal women.	('associated', 'Reg', (123, 133))	('rs34324334', 'Var', (81, 91))	('women', 'Species', '9606', (177, 182))	('rs11544382', 'Mutation', 'rs11544382', (66, 76))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('rs34324334', 'Mutation', 'rs34324334', (81, 91))	('rs11544382', 'Var', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', (139, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('menopausal status', 'Phenotype', 'HP:0008209', (19, 36))
5636	23834155	These findings support the hypothesis that variations in components of the miRNA biogenesis pathway, most importantly the XPO5, may affect an individual's risk of developing breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('affect', 'Reg', (132, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('miRNA biogenesis', 'biological_process', 'GO:0035196', ('75', '91'))	('XPO5', 'Gene', (122, 126))	('XPO5', 'Gene', '57510', (122, 126))	('variations', 'Var', (43, 53))
5639	23834155	As a proof of concept, the Inhibition of XPO5 induction was shown to interfere with global miRNA elevation that results in a G1/S dependent proliferation defect.	('miR', 'Gene', (91, 94))	('defect', 'NegReg', (154, 160))	('XPO5', 'Gene', '57510', (41, 45))	('G1/S dependent proliferation', 'CPA', (125, 153))	('interfere', 'NegReg', (69, 78))	('Inhibition', 'Var', (27, 37))	('XPO5', 'Gene', (41, 45))	('miR', 'Gene', '220972', (91, 94))
5642	23834155	Similarly, Han and colleagues investigated in urothelial carcinoma model the effect of expression patterns of Dicer, Drosha, and XPO5 on the cell proliferation inhibition and apoptosis induced by silencing these genes.	('cell proliferation inhibition', 'CPA', (141, 170))	('Dicer', 'Gene', '23405', (110, 115))	('urothelial carcinoma', 'Disease', (46, 66))	('Dicer', 'Gene', (110, 115))	('XPO5', 'Gene', (129, 133))	('Drosha', 'Gene', '29102', (117, 123))	('apoptosis', 'CPA', (175, 184))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('XPO5', 'Gene', '57510', (129, 133))	('cell proliferation', 'biological_process', 'GO:0008283', ('141', '159'))	('Drosha', 'Gene', (117, 123))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (46, 66))	('silencing', 'Var', (196, 205))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))
5645	23834155	Additionally, silencing Dicer, Drosha, and more specifically XPO5 induced cell proliferation inhibition and apoptosis in bladder urothelial carcinoma T24 and 5637 cells.	('Dicer', 'Gene', (24, 29))	('silencing', 'Var', (14, 23))	('Drosha', 'Gene', '29102', (31, 37))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (121, 149))	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))	('cell proliferation inhibition', 'CPA', (74, 103))	('bladder urothelial carcinoma', 'Disease', (121, 149))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('XPO5', 'Gene', (61, 65))	('XPO5', 'Gene', '57510', (61, 65))	('Drosha', 'Gene', (31, 37))	('Dicer', 'Gene', '23405', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('apoptosis', 'CPA', (108, 117))
5656	23834155	Their evidence suggests that copy-number driven over-expression of Drosha and consequent changes in miRNAs are likely to be important contributors to the selective advantage provided by 5p gain in cervical neo-plastic progression.	('Drosha', 'Gene', (67, 73))	('over-expression', 'PosReg', (48, 63))	('changes', 'Reg', (89, 96))	('miR', 'Gene', '220972', (100, 103))	('miR', 'Gene', (100, 103))	('Drosha', 'Gene', '29102', (67, 73))	('cervical', 'Disease', (197, 205))	('copy-number', 'Var', (29, 40))
5659	23834155	These drugs were designed with the idea that nuclear retention of major tumor suppressor proteins such as p53, FOXO, p27 and others can result in selective cancer cell death.	('p53', 'Gene', '7157', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('tumor suppressor', 'biological_process', 'GO:0051726', ('72', '88'))	('tumor', 'Disease', (72, 77))	('retention', 'biological_process', 'GO:0051235', ('53', '62'))	('result in', 'Reg', (136, 145))	('FOXO', 'Gene', (111, 115))	('cell death', 'biological_process', 'GO:0008219', ('163', '173'))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('p27', 'Gene', '3429', (117, 120))	('p27', 'Gene', (117, 120))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('72', '88'))	('nuclear', 'Var', (45, 52))	('p53', 'Gene', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
5669	23834155	One can only speculate that global retention of miRNAs is cancer or diseased cells that carry aberrant genetic material will be subject to cell genome surveillance while normal cells (carrying normal genome) will be protected from the adverse effects (Fig.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (58, 64))	('retention', 'biological_process', 'GO:0051235', ('35', '44'))	('aberrant genetic material', 'Var', (94, 119))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('miR', 'Gene', '220972', (48, 51))	('miR', 'Gene', (48, 51))
5685	33292100	The resulting uracil-induced mutations contribute to genomic variation, which may result in neutral, beneficial or harmful consequences for the cancer.	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('genomic variation', 'MPA', (53, 70))	('uracil', 'Chemical', 'MESH:D014498', (14, 20))	('mutations', 'Var', (29, 38))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
5690	33292100	It has long been known that cancer has a basis in somatic mutations that alter a diversity of cellular functions resulting in sustained proliferative signalling, evasion of growth suppressors and genome instability.	('mutations', 'Var', (58, 67))	('evasion', 'MPA', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('signalling', 'biological_process', 'GO:0023052', ('150', '160'))	('sustained proliferative signalling', 'MPA', (126, 160))	('growth suppressors', 'CPA', (173, 191))	('genome instability', 'CPA', (196, 214))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('alter', 'Reg', (73, 78))
5694	33292100	and Roberts et al.. Then, in 2013, the extensive resources generated by The Cancer Genome Atlas (TCGA) revealed APOBEC mutagenesis in multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutagenesis', 'biological_process', 'GO:0006280', ('119', '130'))	('APOBEC', 'cellular_component', 'GO:0030895', ('112', '118'))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))	('Cancer', 'Disease', (76, 82))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('mutagenesis', 'Var', (119, 130))	('APOBEC', 'Gene', (112, 118))
5695	33292100	There are seven APOBEC3 (A3) enzymes in humans (A3A-H, excluding E) that are capable of inducing DNA mutations through the deamination of cytosine to form promutagenic uracil on single-stranded (ss) DNA.	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('uracil', 'Chemical', 'MESH:D014498', (168, 174))	('mutations', 'Var', (101, 110))	('APOBEC3', 'Gene', '140564', (16, 23))	('APOBEC3', 'Gene', (16, 23))	('A3A', 'Gene', '200315', (48, 51))	('A3', 'Chemical', '-', (25, 27))	('A3A', 'Gene', (48, 51))	('A3', 'Chemical', '-', (48, 50))	('humans', 'Species', '9606', (40, 46))	('APOBEC', 'cellular_component', 'GO:0030895', ('16', '22'))	('DNA', 'cellular_component', 'GO:0005574', ('199', '202'))	('DNA', 'Gene', (97, 100))	('cytosine', 'Chemical', 'MESH:D003596', (138, 146))	('inducing', 'Reg', (88, 96))	('deamination', 'MPA', (123, 134))
5714	33292100	However, A3-mediated deamination of cytosines to uracils can also lead to C-to-T mutations directly through DNA replication using uracil as a template or other mutations by translesion synthesis (TLS) polymerases that insert incorrect bases opposite abasic sites after uracil removal.	('DNA replication', 'biological_process', 'GO:0006260', ('108', '123'))	('C-to-T', 'Gene', (74, 80))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('mutations', 'Var', (160, 169))	('translesion synthesis', 'biological_process', 'GO:0019985', ('173', '194'))	('uracil', 'Chemical', 'MESH:D014498', (49, 55))	('A3-mediated', 'Var', (9, 20))	('uracils', 'Chemical', 'MESH:D014498', (49, 56))	('uracil', 'Chemical', 'MESH:D014498', (269, 275))	('uracil', 'Chemical', 'MESH:D014498', (130, 136))	('lead to', 'Reg', (66, 73))	('mutations', 'Var', (81, 90))	('cytosines', 'Chemical', 'MESH:D003596', (36, 45))	('DNA', 'Disease', (108, 111))	('A3', 'Chemical', '-', (9, 11))
5715	33292100	According to yeast experiments, the observed C-to-G transversions that are linked to A3 deamination activity may be caused by TLS bypass over an abasic site by REV1 and DNA polymerase zeta after uracil base removal by UNG2.	('uracil', 'Chemical', 'MESH:D014498', (195, 201))	('UNG', 'Gene', (218, 221))	('A3', 'Chemical', '-', (85, 87))	('REV1', 'Gene', (160, 164))	('C-to-G', 'Var', (45, 51))	('DNA', 'cellular_component', 'GO:0005574', ('169', '172'))	('yeast', 'Species', '4932', (13, 18))	('caused by', 'Reg', (116, 125))	('transversions', 'Var', (52, 65))	('REV1', 'Gene', '854527', (160, 164))	('UNG', 'Gene', '7374', (218, 221))	('bypass over', 'PosReg', (130, 141))	('TLS', 'Gene', (126, 129))	('men', 'Species', '9606', (25, 28))
5724	33292100	A3G was the first A3 enzyme demonstrated to have restriction activity against HIV infection through G-to-A mutations in the sense DNA strand creating non-infectious virions when uracils in the anti-sense DNA were used as a template in DNA synthesis.	('DNA', 'cellular_component', 'GO:0005574', ('235', '238'))	('HIV infection', 'Disease', 'MESH:D015658', (78, 91))	('uracils', 'Chemical', 'MESH:D014498', (178, 185))	('mutations', 'Var', (107, 116))	('DNA', 'Gene', (130, 133))	('DNA', 'cellular_component', 'GO:0005574', ('204', '207'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('235', '248'))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('A3', 'Chemical', '-', (0, 2))	('HIV infection', 'Disease', (78, 91))	('A3G', 'Gene', (0, 3))	('A3', 'Chemical', '-', (18, 20))	('non-infectious virions', 'MPA', (150, 172))	('A3G', 'Gene', '60489', (0, 3))
5731	33292100	Otherwise, A3B would suppress viral replication through deamination of cytosines.	('viral replication', 'CPA', (30, 47))	('viral replication', 'biological_process', 'GO:0008166', ('30', '47'))	('A3B', 'Var', (11, 14))	('deamination of cytosines', 'MPA', (56, 80))	('cytosines', 'Chemical', 'MESH:D003596', (71, 80))	('suppress', 'NegReg', (21, 29))	('viral replication', 'biological_process', 'GO:0019058', ('30', '47'))	('viral replication', 'biological_process', 'GO:0019079', ('30', '47'))
5740	33292100	In general, these mutations occur randomly across the genome during our lifetime and sometimes the 'wrong combination' of somatic mutations can transform a normal cell into a tumoural cell.	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('mutations', 'Var', (130, 139))	('transform', 'Reg', (144, 153))	('tumoural', 'Disease', 'MESH:D009369', (175, 183))	('tumoural', 'Disease', (175, 183))
5741	33292100	Four members of A3 enzymes contain two zinc-coordinating domains (A3B, A3D, A3F and A3G) and three members contain one zinc-coordinating domain (A3A, A3C and A3H) with the consensus sequence His-X-Glu-X23-28-Pro-Cys-X2-4-Cys (figure 1a).	('A3', 'Chemical', '-', (158, 160))	('A3G', 'Gene', (84, 87))	('A3A', 'Gene', (145, 148))	('A3H', 'Gene', (158, 161))	('A3', 'Chemical', '-', (84, 86))	('A3H', 'Gene', '164668', (158, 161))	('A3', 'Chemical', '-', (76, 78))	('Glu', 'Chemical', 'MESH:D018698', (197, 200))	('A3', 'Chemical', '-', (150, 152))	('A3A', 'Gene', '200315', (145, 148))	('A3', 'Chemical', '-', (66, 68))	('zinc-coordinating', 'MPA', (39, 56))	('A3', 'Chemical', '-', (145, 147))	('His', 'Chemical', 'MESH:D006639', (191, 194))	('A3C', 'Mutation', 'c.3A>C', (150, 153))	('A3G', 'Gene', '60489', (84, 87))	('His-X-Glu-X23-28-Pro-Cys-X2-4-Cys', 'Var', (191, 224))	('A3', 'Chemical', '-', (71, 73))	('A3', 'Chemical', '-', (16, 18))
5744	33292100	The APOBEC enzymes induce mutations in a sequence-specific manner and the majority of A3 family members preferentially deaminate the central cytidine in 5'HTCW trinucleotide motifs (where H = A, C or T and W = A or T; the deaminated based is underlined) within ssDNA substrate, except A3G (5'CCCA) that deaminates cytidines in a different sequence motif.	('cytidines', 'Chemical', 'MESH:D003562', (314, 323))	('A3G', 'Gene', (285, 288))	('APOBEC', 'Gene', (4, 10))	('mutations', 'Var', (26, 35))	('A3', 'Chemical', '-', (86, 88))	('cytidine', 'Chemical', 'MESH:D003562', (141, 149))	('cytidine', 'Chemical', 'MESH:D003562', (314, 322))	('trinucleotide', 'Chemical', '-', (160, 173))	('A3', 'Chemical', '-', (285, 287))	('APOBEC', 'cellular_component', 'GO:0030895', ('4', '10'))	('A3G', 'Gene', '60489', (285, 288))
5746	33292100	A3D, A3G and A3F all bind cellular RNA and form a ribonucleoprotein high molecular weight molecule that is catalytically inactive in vitro unless treated with RNaseA.	('A3D', 'Var', (0, 3))	('A3', 'Chemical', '-', (13, 15))	('A3', 'Chemical', '-', (0, 2))	('A3G', 'Gene', (5, 8))	('A3G', 'Gene', '60489', (5, 8))	('RNA', 'Protein', (35, 38))	('cellular RNA', 'Protein', (26, 38))	('bind', 'Interaction', (21, 25))	('ribonucleoprotein', 'molecular_function', 'GO:0003733', ('50', '67'))	('A3F', 'Var', (13, 16))	('A3', 'Chemical', '-', (5, 7))	('RNA', 'cellular_component', 'GO:0005562', ('35', '38'))
5755	33292100	The deoxycytidine deaminase activity of A3A, A3B and A3H Hap I, as leading candidates, has been implicated in cancer and tumour evolution by providing the cells with a diverse pool of mutations.	('cancer', 'Disease', (110, 116))	('A3H', 'Gene', '164668', (53, 56))	('cytidine deaminase', 'Gene', '978', (9, 27))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('deoxycytidine deaminase activity', 'molecular_function', 'GO:0047844', ('4', '36'))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('A3H', 'Gene', (53, 56))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('A3A', 'Gene', (40, 43))	('A3B', 'Var', (45, 48))	('tumour', 'Disease', (121, 127))	('A3A', 'Gene', '200315', (40, 43))	('cytidine deaminase', 'Gene', (9, 27))	('implicated', 'Reg', (96, 106))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
5768	33292100	The processivity of several members of the AID/APOBEC family members on ssDNA has been reported and the results have implications for the finding that mutations associated with AID or A3s are often clustered.	('AID', 'Gene', (177, 180))	('A3s', 'Chemical', '-', (184, 187))	('AID', 'Gene', '57379', (177, 180))	('AID', 'Gene', '57379', (43, 46))	('AID', 'Gene', (43, 46))	('A3s', 'Gene', (184, 187))	('mutations', 'Var', (151, 160))	('APOBEC', 'cellular_component', 'GO:0030895', ('47', '53'))
5772	33292100	The ability to cycle between ssDNA substrates was important to not only quickly access the transiently ssDNA being replicated but also ssDNA bound by RPA, suggesting that the ability to compete for ssDNA rather than processivity was most important for A3s to induce 'off-target' deaminations.	('A3s', 'Chemical', '-', (252, 255))	('RPA', 'Gene', '6117', (150, 153))	('A3s', 'Var', (252, 255))	('deaminations', 'MPA', (279, 291))	('RPA', 'Gene', (150, 153))	("'off-target'", 'PosReg', (266, 278))	('RPA', 'cellular_component', 'GO:0005662', ('150', '153'))
5776	33292100	These results demonstrate that during replication stress where larger amounts of ssDNA accumulate, the protective RPA barrier is less effective against A3A, A3B and A3H Hap I.	('A3H', 'Gene', (165, 168))	('RPA', 'cellular_component', 'GO:0005662', ('114', '117'))	('less', 'NegReg', (129, 133))	('RPA', 'Gene', (114, 117))	('A3H', 'Gene', '164668', (165, 168))	('A3B', 'Var', (157, 160))	('A3A', 'Gene', '200315', (152, 155))	('A3A', 'Gene', (152, 155))	('RPA', 'Gene', '6117', (114, 117))
5780	33292100	For A3A, there was an association of mutations in a yeast system with the non-transcribed strand, but the majority of mutations correlated with the lagging strand of replication.	('correlated', 'Reg', (128, 138))	('A3A', 'Gene', '200315', (4, 7))	('A3A', 'Gene', (4, 7))	('mutations', 'Var', (118, 127))	('lagging strand of replication', 'MPA', (148, 177))	('mutations', 'Var', (37, 46))	('non-transcribed strand', 'MPA', (74, 96))	('association', 'Interaction', (22, 33))	('yeast', 'Species', '4932', (52, 57))
5781	33292100	No cellular studies examining A3H Hap I in this regard are available, but a study using a bioinformatics approach has suggested that A3H Hap I could act early in lung cancer mutations and possibly contribute to the APOBEC signature in A3B-null BRCA.	('BRCA', 'Gene', '672', (244, 248))	('contribute', 'Reg', (197, 207))	('A3H', 'Gene', '164668', (133, 136))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('A3H', 'Gene', '164668', (30, 33))	('APOBEC', 'cellular_component', 'GO:0030895', ('215', '221'))	('BRCA', 'Gene', (244, 248))	('A3H', 'Gene', (30, 33))	('lung cancer', 'Disease', (162, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('A3H', 'Gene', (133, 136))	('mutations', 'Var', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
5787	33292100	Genomic instability is one of the hallmarks of cancer that cause both aberrant chromosomal architecture and mutational changes at the single nucleotide level.	('mutational', 'Var', (108, 118))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('Genomic', 'Disease', (0, 7))	('cancer', 'Disease', (47, 53))	('cause', 'Reg', (59, 64))	('aberrant', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
5790	33292100	In addition to other endogenous mutational factors, now it is well known that some members of the A3 enzymes are an endogenous source of somatic mutations found in approximately 15% of sequenced human tumours such as, BRCA, bladder, cervix, lung (adenocarcinoma and squamous cell carcinoma), head and neck, myeloma, renal cell carcinoma, stomach and thyroid.	('carcinoma', 'Phenotype', 'HP:0030731', (327, 336))	('stomach', 'Disease', (338, 345))	('mutations', 'Var', (145, 154))	('tumours', 'Disease', (201, 208))	('tumours', 'Phenotype', 'HP:0002664', (201, 208))	('cervix', 'Disease', (233, 239))	('myeloma', 'Disease', (307, 314))	('tumours', 'Disease', 'MESH:D009369', (201, 208))	('thyroid', 'Disease', (350, 357))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (316, 336))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (247, 289))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('BRCA', 'Gene', '672', (218, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (266, 289))	('renal cell carcinoma', 'Disease', (316, 336))	('bladder', 'Disease', (224, 231))	('neck', 'cellular_component', 'GO:0044326', ('301', '305'))	('BRCA', 'Gene', (218, 222))	('A3', 'Chemical', '-', (98, 100))	('human', 'Species', '9606', (195, 200))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (316, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('myeloma', 'Disease', 'MESH:D009101', (307, 314))
5792	33292100	The APOBEC family of cytidine deaminases generates particular genome-wide mutational signatures and a signature of localized hypermutation called 'kataegis' or 'mutation clusters'.	('APOBEC family', 'Gene', (4, 17))	('mutational', 'Var', (74, 84))	('cytidine deaminase', 'Gene', (21, 39))	('APOBEC', 'cellular_component', 'GO:0030895', ('4', '10'))	('cytidine deaminase', 'Gene', '978', (21, 39))
5793	33292100	Two signatures characterized by C-to-T and/or C-to-G mutations at TpCpX trinucleotides were identified (the underlined base is the mutated base and X can be any base) in several cancer types and are among the most common mutational signatures found in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('C-to-G mutations', 'Var', (46, 62))	('trinucleotides', 'Chemical', '-', (72, 86))	('C-to-T', 'Var', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('TpCpX', 'Gene', (66, 71))	('cancer', 'Disease', (258, 264))	('human', 'Species', '9606', (252, 257))
5794	33292100	Signature 2 is composed predominantly of C-to-T transitions with fewer C-to-G transversions and Signature 13 is dominated by C-to-G transversions at a TpCpX sequence context and due to error-prone repair of APOBEC-induced uracils.	('uracils', 'Chemical', 'MESH:D014498', (222, 229))	('C-to-G transversions', 'Var', (125, 145))	('APOBEC', 'cellular_component', 'GO:0030895', ('207', '213'))	('transversions', 'Var', (132, 145))	('APOBEC-induced', 'Gene', (207, 221))
5803	33292100	The 'off-target' mutations in the host genome produced by members of the A3 family, that are the basis of its relationship to cancer, has been associated with cancer development, progression, metastasis and drug resistance.	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	("'off-target'", 'PosReg', (4, 16))	('associated', 'Reg', (143, 153))	('men', 'Species', '9606', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', (126, 132))	('progression', 'CPA', (179, 190))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('drug resistance', 'CPA', (207, 222))	('A3', 'Chemical', '-', (73, 75))	('drug resistance', 'Phenotype', 'HP:0020174', (207, 222))	('metastasis', 'CPA', (192, 202))	('drug resistance', 'biological_process', 'GO:0042493', ('207', '222'))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('drug resistance', 'biological_process', 'GO:0009315', ('207', '222'))	('mutations', 'Var', (17, 26))
5804	33292100	Most cancer cells and tumours show overexpression (20- to 60-fold) of A3B, A3A or A3H Hap I mRNA.	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('A3H', 'Gene', '164668', (82, 85))	('cancer', 'Disease', (5, 11))	('tumours', 'Disease', (22, 29))	('A3H', 'Gene', (82, 85))	('A3A', 'Gene', '200315', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('overexpression', 'PosReg', (35, 49))	('A3B', 'Var', (70, 73))	('A3A', 'Gene', (75, 78))
5807	33292100	Mutations captured in cancer genomes could have been generated by APOBEC deaminases over the lifetime of a cell lineage, whereas mRNA captures expression at the single time point of sample acquisition and not necessarily at the time of active mutagenesis.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('APOBEC', 'cellular_component', 'GO:0030895', ('66', '72'))	('cancer', 'Disease', (22, 28))	('APOBEC', 'Gene', (66, 72))	('Mutations', 'Var', (0, 9))	('mutagenesis', 'biological_process', 'GO:0006280', ('243', '254'))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
5812	33292100	Mutations are thought to be the key drivers of recurrence, metastasis and therapeutic resistance of cancer.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))
5813	33292100	The studies on the molecular origins of mutations in BRCA have implicated several mechanisms, including both spontaneous and enzyme catalysed deamination of DNA cytidine.	('cytidine', 'Chemical', 'MESH:D003562', (161, 169))	('BRCA', 'Gene', '672', (53, 57))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('mutations', 'Var', (40, 49))	('BRCA', 'Gene', (53, 57))	('deamination of DNA cytidine', 'MPA', (142, 169))
5818	33292100	In particular, A3A and A3B have been considered the main mutagenic enzymes that generate APOBEC-signature mutations in breast and other tumour types because overexpression of these enzymes triggers DNA damage responses and inflicts chromosomal mutations in hallmark trinucleotide contexts.	('chromosomal', 'Gene', (232, 243))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('DNA', 'cellular_component', 'GO:0005574', ('198', '201'))	('APOBEC', 'cellular_component', 'GO:0030895', ('89', '95'))	('tumour', 'Disease', (136, 142))	('trinucleotide', 'Chemical', '-', (266, 279))	('overexpression', 'PosReg', (157, 171))	('inflicts', 'Reg', (223, 231))	('mutations', 'Var', (106, 115))	('A3A', 'Gene', '200315', (15, 18))	('triggers', 'Reg', (189, 197))	('APOBEC-signature', 'Gene', (89, 105))	('A3A', 'Gene', (15, 18))	('DNA damage responses', 'MPA', (198, 218))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
5820	33292100	The analysis of the APOBEC-signature mutation load in cancer exons showed that it is statistically correlated with A3A and A3B transcript abundance.	('mutation load', 'Var', (37, 50))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('APOBEC', 'cellular_component', 'GO:0030895', ('20', '26'))	('cancer', 'Disease', (54, 60))	('APOBEC-signature', 'Gene', (20, 36))	('A3A', 'Gene', '200315', (115, 118))	('correlated', 'Reg', (99, 109))	('A3B transcript abundance', 'MPA', (123, 147))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('A3A', 'Gene', (115, 118))
5824	33292100	Multiple lines of evidence suggested that A3B, the only constitutively nuclear ssDNA deaminase, was the primary source of the mutations found in BRCA.	('BRCA', 'Gene', (145, 149))	('BRCA', 'Gene', '672', (145, 149))	('mutations', 'Var', (126, 135))
5826	33292100	The analysis of cell line and tumour datasets showing that A3B gene expression is upregulated in malignant versus normal tissues and epithelial cell lines have shown correlations between A3B expression and the presence of certain somatic mutations, particularly in TP53 and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) (figure 3).	('correlations', 'Reg', (166, 178))	('gene expression', 'biological_process', 'GO:0010467', ('63', '78'))	('expression', 'MPA', (68, 78))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('TP53', 'Gene', '7157', (265, 269))	('mutations', 'Var', (238, 247))	('upregulated', 'PosReg', (82, 93))	('PIK3CA', 'Gene', (347, 353))	('tumour', 'Disease', (30, 36))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('TP53', 'Gene', (265, 269))	('PIK3CA', 'Gene', '5290', (347, 353))	('phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha', 'Gene', '5290', (274, 345))	('A3B', 'Gene', (187, 190))	('A3B gene', 'Gene', (59, 67))
5833	33292100	They proposed that A3B expression is unlikely to account for APOBEC-mediated mutagenesis in breast tumours but might contribute to cancer development based on the possible mitogenic effect of A3B, a deamination-independent effect.	('cancer', 'Disease', (131, 137))	('APOBEC', 'cellular_component', 'GO:0030895', ('61', '67'))	('men', 'Species', '9606', (145, 148))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('mitogenic effect', 'CPA', (172, 188))	('breast tumours', 'Disease', 'MESH:D001943', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('A3B', 'Var', (192, 195))	('mutagenesis', 'biological_process', 'GO:0006280', ('77', '88'))	('contribute', 'Reg', (117, 127))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('breast tumours', 'Disease', (92, 106))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('breast tumour', 'Phenotype', 'HP:0100013', (92, 105))
5839	33292100	p53 controls the A3B expression and since ER- tumours are enriched for inactivating p53 mutations, this could contribute to elevated levels of A3B expression in this type of tumour that is significantly higher compared with ER+ breast tumours.	('tumours', 'Phenotype', 'HP:0002664', (235, 242))	('breast tumours', 'Disease', 'MESH:D001943', (228, 242))	('expression', 'MPA', (147, 157))	('tumours', 'Disease', 'MESH:D009369', (235, 242))	('tumour', 'Disease', (46, 52))	('mutations', 'Var', (88, 97))	('A3B', 'Protein', (17, 20))	('ER', 'Gene', '2069', (224, 226))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('p53', 'Gene', '7157', (0, 3))	('tumour', 'Disease', 'MESH:D009369', (235, 241))	('tumour', 'Disease', (235, 241))	('higher', 'PosReg', (203, 209))	('A3B', 'Protein', (143, 146))	('levels', 'MPA', (133, 139))	('breast tumours', 'Disease', (228, 242))	('p53', 'Gene', (0, 3))	('tumours', 'Disease', (46, 53))	('p53', 'Gene', '7157', (84, 87))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('expression', 'MPA', (21, 31))	('tumour', 'Disease', (174, 180))	('tumours', 'Disease', (235, 242))	('p53', 'Gene', (84, 87))	('ER', 'Gene', '2069', (42, 44))	('breast tumour', 'Phenotype', 'HP:0100013', (228, 241))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('elevated', 'PosReg', (124, 132))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
5847	33292100	The induction of A3B was found to be stronger in cell lines harbouring mutant TP53 than in those with wild-type TP53 (figure 3).	('stronger', 'PosReg', (37, 45))	('A3B', 'Protein', (17, 20))	('induction', 'MPA', (4, 13))	('mutant', 'Var', (71, 77))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', '7157', (112, 116))	('TP53', 'Gene', (78, 82))	('TP53', 'Gene', (112, 116))
5849	33292100	The role of DNA replication stress in mediating genomic instability could link the high level of somatic copy number aberrations and single nucleotide diversity caused by A3 activity that are both observed in human epidermal growth factor receptor 2 (HER2)+ tumours.	('tumours', 'Disease', (258, 265))	('human', 'Species', '9606', (209, 214))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('215', '238'))	('A3', 'Chemical', '-', (171, 173))	('tumour', 'Phenotype', 'HP:0002664', (258, 264))	('DNA replication', 'biological_process', 'GO:0006260', ('12', '27'))	('tumours', 'Phenotype', 'HP:0002664', (258, 265))	('HER2', 'Gene', (251, 255))	('HER2', 'Gene', '2064', (251, 255))	('tumours', 'Disease', 'MESH:D009369', (258, 265))	('DNA', 'cellular_component', 'GO:0005574', ('12', '15'))	('epidermal growth factor receptor 2', 'Gene', (215, 249))	('epidermal growth factor receptor 2', 'Gene', '2064', (215, 249))	('single nucleotide diversity', 'Var', (133, 160))
5852	33292100	The oncogenic signalling, cytotoxic drugs and genetic modulators of replication stress are all able to modulate A3 activity, although it has not been explored if there is a mechanistic connection between the underlying causes of chromosomal copy number aberrations and the generation of A3 mutagenesis in HER2+ BRCA.	('modulate', 'Reg', (103, 111))	('A3', 'Chemical', '-', (112, 114))	('BRCA', 'Gene', (311, 315))	('chromosomal', 'Var', (229, 240))	('activity', 'MPA', (115, 123))	('HER2', 'Gene', (305, 309))	('signalling', 'biological_process', 'GO:0023052', ('14', '24'))	('mutagenesis', 'Var', (290, 301))	('HER2', 'Gene', '2064', (305, 309))	('mutagenesis', 'biological_process', 'GO:0006280', ('290', '301'))	('A3', 'Chemical', '-', (287, 289))	('BRCA', 'Gene', '672', (311, 315))
5854	33292100	Despite all aforementioned findings, the importance of A3B in cancer has been questioned with the observation that APOBEC-signature mutations are still clearly evident in A3B-null breast tumours (figure 3).	('breast tumours', 'Disease', 'MESH:D001943', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('APOBEC', 'cellular_component', 'GO:0030895', ('115', '121'))	('APOBEC-signature', 'Gene', (115, 131))	('mutations', 'Var', (132, 141))	('breast tumour', 'Phenotype', 'HP:0100013', (180, 193))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('A3B-null', 'Gene', (171, 179))	('breast tumours', 'Disease', (180, 194))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))	('men', 'Species', '9606', (17, 20))
5855	33292100	A 29.5 kb deletion that removes the entire A3B coding sequence and fuses the 3' untranslated regions (UTR) of A3A and A3B forms a hybrid gene that is predicted to produce a transcript which is predominantly constituted of A3A sequence but replaces the A3A 3'UTR with the A3B 3' UTR and encodes a protein that has an identical amino acid sequence to A3A.	('produce', 'Reg', (163, 170))	('A3A', 'Gene', (349, 352))	('A3A', 'Gene', (222, 225))	('A3B', 'Gene', (43, 46))	('protein', 'cellular_component', 'GO:0003675', ('296', '303'))	('A3A', 'Gene', '200315', (110, 113))	('removes', 'NegReg', (24, 31))	('A3A', 'Gene', (110, 113))	('A3A', 'Gene', '200315', (252, 255))	('deletion', 'Var', (10, 18))	('replaces', 'NegReg', (239, 247))	('A3A', 'Gene', '200315', (222, 225))	('A3A', 'Gene', (252, 255))	('A3A', 'Gene', '200315', (349, 352))
5856	33292100	Some studies showed that the A3B deletion increases the risk of BRCA and increases tumour mutational burden.	('A3B', 'Gene', (29, 32))	('increases', 'PosReg', (42, 51))	('increases tumour', 'Disease', (73, 89))	('deletion', 'Var', (33, 41))	('BRCA', 'Gene', '672', (64, 68))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('increases tumour', 'Disease', 'MESH:D009369', (73, 89))	('BRCA', 'Gene', (64, 68))
5857	33292100	A genome-wide association study in the Chinese population demonstrated the A3B deletion is associated with BRCA (odds ratio (OR) 1.3 one-copy, 1.8 two-copy deletion, p = 2.0 x 10-24), which was replicated in a European population (OR 1.2 one-copy, 2.3 two-copy deletion, p = 0.005).	('odds ratio (OR) 1.3', 'Gene', (113, 132))	('A3B', 'Gene', (75, 78))	('BRCA', 'Gene', '672', (107, 111))	('BRCA', 'Gene', (107, 111))	('deletion', 'Var', (79, 87))	('odds ratio (OR) 1.3', 'Gene', '128360', (113, 132))	('associated', 'Reg', (91, 101))
5858	33292100	However, including familial BRCA for the first time, a later study showed a lack of association of the A3B deletion with BRCA risk, which was independently validated in three European cohorts (in total: 2972 cases and 3682 controls).	('association', 'Interaction', (84, 95))	('BRCA', 'Gene', '672', (28, 32))	('BRCA', 'Gene', '672', (121, 125))	('BRCA', 'Gene', (28, 32))	('BRCA', 'Gene', (121, 125))	('A3B', 'Gene', (103, 106))	('deletion', 'Var', (107, 115))
5859	33292100	This study provided direct evidence for the generation of the transcriptionally active hybrid gene A3A/A3B from the allele with the A3B deletion and confirmed the suggested structure of A3A/A3B transcript, which enabled A3A, A3B and A3A/A3B expression levels to be distinguished.	('A3A', 'Gene', '200315', (233, 236))	('A3A', 'Gene', '200315', (220, 223))	('A3A', 'Gene', (99, 102))	('A3A', 'Gene', (233, 236))	('A3A', 'Gene', (220, 223))	('deletion', 'Var', (136, 144))	('A3A', 'Gene', '200315', (186, 189))	('A3A', 'Gene', '200315', (99, 102))	('A3B', 'Gene', (132, 135))	('A3A', 'Gene', (186, 189))
5860	33292100	The knowledge of the exact structure of the hybrid transcript is vital for the design of comprehensive tests for analysis of the influence of the A3B deletion genotype on the expression of A3B, A3A and the A3A/A3B hybrid gene.	('A3A', 'Gene', '200315', (206, 209))	('A3A', 'Gene', (206, 209))	('deletion', 'Var', (150, 158))	('A3A', 'Gene', (194, 197))	('A3A', 'Gene', '200315', (194, 197))	('A3B', 'Gene', (146, 149))
5861	33292100	A recent study showed that the germline A3B deletion influenced the APOBEC mutational signature, neoantigen loads and relative immune cell compositions in BRCA.	('APOBEC', 'Gene', (68, 74))	('BRCA', 'Gene', '672', (155, 159))	('influenced', 'Reg', (53, 63))	('deletion', 'Var', (44, 52))	('BRCA', 'Gene', (155, 159))	('mutational signature', 'MPA', (75, 95))	('APOBEC', 'cellular_component', 'GO:0030895', ('68', '74'))	('neoantigen loads', 'MPA', (97, 113))
5863	33292100	As the homozygous carriers of the A3B deletion allele are predicted not to make any A3B protein, other APOBEC enzymes must contribute to APOBEC-signature mutations during tumour development.	('men', 'Species', '9606', (185, 188))	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('tumour', 'Disease', 'MESH:D009369', (171, 177))	('tumour', 'Disease', (171, 177))	('A3B', 'Gene', (34, 37))	('deletion', 'Var', (38, 46))	('APOBEC', 'cellular_component', 'GO:0030895', ('103', '109'))	('APOBEC', 'cellular_component', 'GO:0030895', ('137', '143'))
5864	33292100	In this regard, one study of APOBEC-induced mutations from A3B deleted BRCA tumours revealed that the only tumours displaying the APOBEC mutation signature also contained the nuclear A3H Hap I, providing correlative evidence that this protein may be the additional source of mutagenesis (figure 3).	('APOBEC', 'Gene', (130, 136))	('tumours', 'Disease', (107, 114))	('A3H', 'Gene', (183, 186))	('tumours', 'Disease', (76, 83))	('mutagenesis', 'biological_process', 'GO:0006280', ('275', '286'))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('APOBEC', 'cellular_component', 'GO:0030895', ('29', '35'))	('protein', 'cellular_component', 'GO:0003675', ('235', '242'))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('BRCA tumours', 'Disease', 'MESH:D009369', (71, 83))	('A3H', 'Gene', '164668', (183, 186))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('tumours', 'Disease', 'MESH:D009369', (107, 114))	('mutation', 'Var', (137, 145))	('BRCA tumours', 'Disease', (71, 83))	('A3B', 'Gene', (59, 62))	('APOBEC', 'cellular_component', 'GO:0030895', ('130', '136'))	('mutations', 'Var', (44, 53))
5868	33292100	Another study found the A3A mutational footprints in tumours, but no corresponding A3A expression and suggested that A3A is upregulated early, but later inactivated, perhaps due to being the most active deaminase that could cause cell death through its activity over time.	('cell death', 'biological_process', 'GO:0008219', ('230', '240'))	('A3A', 'Gene', '200315', (24, 27))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('A3A', 'Gene', '200315', (83, 86))	('A3A', 'Gene', '200315', (117, 120))	('A3A', 'Gene', (24, 27))	('A3A', 'Gene', (83, 86))	('A3A', 'Gene', (117, 120))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('mutational', 'Var', (28, 38))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))
5869	33292100	In addition, A3A and A3B can be differentiated by their different preferred tetranucleotide motifs, 5'YTCA and 5'RTCA (Y = T or C and R = G or A), respectively, when inducing mutations in a yeast model system.	('A3A', 'Gene', '200315', (13, 16))	('A3A', 'Gene', (13, 16))	('inducing', 'Reg', (166, 174))	('mutations', 'Var', (175, 184))	('TCA', 'Chemical', 'MESH:D014238', (103, 106))	('TCA', 'Chemical', 'MESH:D014238', (114, 117))	('yeast', 'Species', '4932', (190, 195))
5870	33292100	However, over-representation of mutations in the 5'YTCA motif predominates in a variety of cancers as well as among mutations actively acquired in BRCA cell lines, suggesting A3A may likewise contribute to cancer mutagenesis.	('A3A', 'Gene', '200315', (175, 178))	('A3A', 'Gene', (175, 178))	('BRCA', 'Gene', (147, 151))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancers', 'Disease', (91, 98))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('over-representation', 'PosReg', (9, 28))	('mutations', 'Var', (32, 41))	('contribute', 'Reg', (192, 202))	('mutagenesis', 'biological_process', 'GO:0006280', ('213', '224'))	('TCA', 'Chemical', 'MESH:D014238', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('BRCA', 'Gene', '672', (147, 151))
5871	33292100	A3A was often reported to have undetectable expression in BRCA lines, but more recently, some evidence indicates that A3A may be a major cause of APOBEC-induced mutation in BRCA and account for the majority of cytidine deaminase activity in extracts from multiple BRCA cell lines, despite higher A3B expression.	('A3A', 'Gene', '200315', (0, 3))	('cytidine deaminase', 'Gene', '978', (210, 228))	('cause', 'Reg', (137, 142))	('A3A', 'Gene', '200315', (118, 121))	('BRCA', 'Gene', '672', (173, 177))	('mutation', 'Var', (161, 169))	('cytidine deaminase', 'Gene', (210, 228))	('BRCA', 'Gene', (173, 177))	('APOBEC', 'cellular_component', 'GO:0030895', ('146', '152'))	('BRCA', 'Gene', '672', (264, 268))	('BRCA', 'Gene', '672', (58, 62))	('A3A', 'Gene', (0, 3))	('expression', 'MPA', (300, 310))	('A3A', 'Gene', (118, 121))	('higher', 'PosReg', (289, 295))	('BRCA', 'Gene', (58, 62))	('BRCA', 'Gene', (264, 268))	('cytidine deaminase activity', 'molecular_function', 'GO:0004126', ('210', '237'))	('APOBEC-induced', 'Gene', (146, 160))	('A3B', 'Protein', (296, 299))
5873	33292100	By contrast, a median 13.1-fold higher A3A mRNA expression level was observed in the APOBEC-mutated BRCA lines compared to non-APOBEC-mutated lines and the overall abundance of APOBEC-induced mutations linearly correlated with A3A expression.	('BRCA', 'Gene', '672', (100, 104))	('higher', 'PosReg', (32, 38))	('BRCA', 'Gene', (100, 104))	('A3A', 'Gene', '200315', (227, 230))	('APOBEC', 'cellular_component', 'GO:0030895', ('85', '91'))	('A3A', 'Gene', (227, 230))	('APOBEC', 'cellular_component', 'GO:0030895', ('127', '133'))	('APOBEC', 'cellular_component', 'GO:0030895', ('177', '183'))	('APOBEC-mutated', 'Gene', (85, 99))	('mutations', 'Var', (192, 201))	('A3A', 'Gene', '200315', (39, 42))	('expression', 'MPA', (231, 241))	('APOBEC-induced', 'Gene', (177, 191))	('A3A', 'Gene', (39, 42))
5875	33292100	A3A is more active biochemically than the next most potent somatic mutators A3B and A3H Hap I and RNA binding is known to inhibit the activity of A3B and partially inhibit the activity of A3H, but not A3A, suggesting that A3A may be a better candidate than A3H Hap I in causing the APOBEC mutation signature in A3B null BRCA.	('A3A', 'Gene', '200315', (0, 3))	('activity', 'MPA', (176, 184))	('A3A', 'Gene', (201, 204))	('mutation', 'Var', (289, 297))	('RNA binding', 'molecular_function', 'GO:0003723', ('98', '109'))	('A3A', 'Gene', '200315', (222, 225))	('inhibit', 'NegReg', (164, 171))	('activity', 'MPA', (134, 142))	('A3H', 'Gene', (188, 191))	('A3B', 'Gene', (311, 314))	('RNA', 'cellular_component', 'GO:0005562', ('98', '101'))	('A3H', 'Gene', '164668', (188, 191))	('BRCA', 'Gene', '672', (320, 324))	('A3A', 'Gene', (0, 3))	('A3A', 'Gene', '200315', (201, 204))	('A3H', 'Gene', (84, 87))	('A3H', 'Gene', (257, 260))	('A3H', 'Gene', '164668', (84, 87))	('A3A', 'Gene', (222, 225))	('APOBEC', 'cellular_component', 'GO:0030895', ('282', '288'))	('APOBEC', 'Gene', (282, 288))	('A3H', 'Gene', '164668', (257, 260))	('BRCA', 'Gene', (320, 324))	('inhibit', 'NegReg', (122, 129))
5878	33292100	In addition to mutagenesis linked to deamination of ssDNA, A3A as well as A3B have been reported to be involved in RNA editing.	('ssDNA', 'Gene', (52, 57))	('RNA editing', 'biological_process', 'GO:0009451', ('115', '126'))	('RNA editing', 'MPA', (115, 126))	('A3A', 'Gene', '200315', (59, 62))	('A3A', 'Gene', (59, 62))	('involved', 'Reg', (103, 111))	('mutagenesis', 'Var', (15, 26))	('mutagenesis', 'biological_process', 'GO:0006280', ('15', '26'))	('RNA', 'cellular_component', 'GO:0005562', ('115', '118'))
5882	33292100	developed a strategy using hotspot APOBEC-signature mutations in RNA stem-loops identified from A3A-positive tumours and droplet digital PCR to quantify the ongoing activity of A3A in tumours.	('mutations', 'Var', (52, 61))	('RNA', 'cellular_component', 'GO:0005562', ('65', '68'))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('A3A', 'Gene', '200315', (96, 99))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('tumours', 'Disease', 'MESH:D009369', (184, 191))	('tumours', 'Disease', (184, 191))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('A3A', 'Gene', (96, 99))	('tumours', 'Disease', (109, 116))	('APOBEC', 'cellular_component', 'GO:0030895', ('35', '41'))	('A3A', 'Gene', '200315', (177, 180))	('RNA', 'Gene', (65, 68))	('A3A', 'Gene', (177, 180))	('tumours', 'Phenotype', 'HP:0002664', (184, 191))	('APOBEC-signature', 'Gene', (35, 51))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
5883	33292100	They found that A3A expression and A3A-mediated DNA mutagenesis in tumours, but not those of A3B, correlate with APOBEC-signature mutations in RNA stem-loops.	('mutagenesis', 'biological_process', 'GO:0006280', ('52', '63'))	('A3A', 'Gene', '200315', (35, 38))	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('tumours', 'Disease', (67, 74))	('mutagenesis', 'Var', (52, 63))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('A3A', 'Gene', (35, 38))	('APOBEC-signature', 'Gene', (113, 129))	('mutations', 'Var', (130, 139))	('A3A', 'Gene', '200315', (16, 19))	('RNA', 'cellular_component', 'GO:0005562', ('143', '146'))	('A3A', 'Gene', (16, 19))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('APOBEC', 'cellular_component', 'GO:0030895', ('113', '119'))
5887	33292100	In line with this RNA-editing activity of the A3 enzymes, a recent bioinformatic study identified that A3-mediated RNA editing occurs in breast tumours and is positively associated with elevated immune activity and improved survival (figure 3).	('immune activity', 'CPA', (195, 210))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('RNA editing', 'biological_process', 'GO:0009451', ('115', '126'))	('breast tumours', 'Disease', (137, 151))	('RNA', 'cellular_component', 'GO:0005562', ('18', '21'))	('survival', 'CPA', (224, 232))	('A3', 'Chemical', '-', (103, 105))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('RNA', 'cellular_component', 'GO:0005562', ('115', '118'))	('RNA-editing', 'biological_process', 'GO:0009451', ('18', '29'))	('improved', 'PosReg', (215, 223))	('breast tumours', 'Disease', 'MESH:D001943', (137, 151))	('breast tumour', 'Phenotype', 'HP:0100013', (137, 150))	('A3', 'Chemical', '-', (46, 48))	('A3-mediated RNA editing', 'Var', (103, 126))	('elevated', 'PosReg', (186, 194))
5890	33292100	While they could detect C-to-U RNA-editing events in the tumours, the cellular origin of such events remains unclear.	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('RNA', 'cellular_component', 'GO:0005562', ('31', '34'))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('RNA-editing', 'biological_process', 'GO:0009451', ('31', '42'))	('tumours', 'Disease', (57, 64))	('C-to-U RNA-editing', 'Var', (24, 42))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))
5892	33292100	Further investigations implementing methods such as single-cell sequencing and isolation of sub-populations of cells from tumours are needed to definitively know if the editing occurs in cancerous epithelial or immune cells of breast tumours.	('cancerous epithelial', 'Disease', (187, 207))	('men', 'Species', '9606', (28, 31))	('breast tumour', 'Phenotype', 'HP:0100013', (227, 240))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('cancerous epithelial', 'Disease', 'MESH:D009369', (187, 207))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('tumours', 'Disease', (234, 241))	('tumours', 'Phenotype', 'HP:0002664', (234, 241))	('breast tumours', 'Disease', (227, 241))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast tumours', 'Disease', 'MESH:D001943', (227, 241))	('tumours', 'Disease', 'MESH:D009369', (234, 241))	('tumours', 'Disease', (122, 129))	('editing', 'Var', (169, 176))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
5893	33292100	The biological consequences of the editing events on cancer development, progression and immune response also remain unknown.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('men', 'Species', '9606', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('immune response', 'biological_process', 'GO:0006955', ('89', '104'))	('editing', 'Var', (35, 42))
5895	33292100	Also, it is important to elucidate which of the enzymes A3A, A3B and A3H Hap I are involved earlier in promoting cell transformation or later in promoting BRCA progression.	('A3H', 'Gene', (69, 72))	('promoting', 'PosReg', (103, 112))	('BRCA', 'Gene', '672', (155, 159))	('promoting', 'PosReg', (145, 154))	('A3B', 'Var', (61, 64))	('BRCA', 'Gene', (155, 159))	('A3A', 'Gene', '200315', (56, 59))	('A3H', 'Gene', '164668', (69, 72))	('A3A', 'Gene', (56, 59))	('cell transformation', 'CPA', (113, 132))
5901	33292100	In addition to smoking, one major cause of the heavy mutation load of NSCLC, the expression of APOBEC family members, especially A3B, was reported as a key source of mutations specifically in two subtypes of NSCLC: adenocarcinoma and squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (234, 257))	('SCLC', 'Phenotype', 'HP:0030357', (209, 213))	('mutations', 'Var', (166, 175))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (215, 257))	('NSCLC', 'Disease', (208, 213))	('APOBEC', 'cellular_component', 'GO:0030895', ('95', '101'))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('SCLC', 'Phenotype', 'HP:0030357', (71, 75))	('NSCLC', 'Disease', 'MESH:D002289', (208, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
5905	33292100	According to this endogenous mutational process driving subclonal expansions, mutations within an A3B context were found in driver genes such as PTPRD, PIK3CA, EP300, TGFBR1 and AKAP9 (figure 4).	('PIK3CA', 'Gene', '5290', (152, 158))	('AKAP9', 'Gene', (178, 183))	('TGFBR1', 'Gene', '7046', (167, 173))	('mutations', 'Var', (78, 87))	('TGFBR1', 'Gene', (167, 173))	('PTPRD', 'Gene', '5789', (145, 150))	('AKAP9', 'Gene', '10142', (178, 183))	('PTPRD', 'Gene', (145, 150))	('PIK3CA', 'Gene', (152, 158))	('EP300', 'Gene', (160, 165))	('EP300', 'Gene', '2033', (160, 165))
5906	33292100	Also, there was evidence for spatial heterogeneity in APOBEC activity; in one adeno squamous tumour, the APOBEC signature was found enriched in the adenocarcinoma branch, harbouring driver mutations in PTPRD and TGFBR1 within an APOBEC context, but not the squamous carcinoma branch.	('PTPRD', 'Gene', '5789', (202, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('squamous carcinoma branch', 'Disease', 'MESH:D002294', (257, 282))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('adenocarcinoma branch', 'Disease', (148, 169))	('squamous tumour', 'Disease', (84, 99))	('squamous tumour', 'Disease', 'MESH:D002294', (84, 99))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (257, 275))	('TGFBR1', 'Gene', (212, 218))	('TGFBR1', 'Gene', '7046', (212, 218))	('mutations', 'Var', (189, 198))	('squamous carcinoma branch', 'Disease', (257, 282))	('adenocarcinoma branch', 'Disease', 'MESH:D000230', (148, 169))	('APOBEC', 'cellular_component', 'GO:0030895', ('229', '235'))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('PTPRD', 'Gene', (202, 207))	('squamous tumour', 'Phenotype', 'HP:0002860', (84, 99))	('APOBEC', 'cellular_component', 'GO:0030895', ('54', '60'))	('APOBEC', 'cellular_component', 'GO:0030895', ('105', '111'))
5908	33292100	Most of these subclonal mutations were found in the PIK3CA helical domain (E545 K) that have been previously linked to APOBEC-mediated mutagenesis in cervical and head/neck tumours.	('head/neck tumours', 'Disease', 'MESH:D006258', (163, 180))	('cervical', 'Disease', (150, 158))	('E545 K', 'Mutation', 'rs104886003', (75, 81))	('head/neck tumours', 'Disease', (163, 180))	('neck', 'cellular_component', 'GO:0044326', ('168', '172'))	('PIK3CA', 'Gene', '5290', (52, 58))	('PIK3CA', 'Gene', (52, 58))	('mutagenesis', 'biological_process', 'GO:0006280', ('135', '146'))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('E545 K', 'Var', (75, 81))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('linked', 'Reg', (109, 115))	('APOBEC', 'cellular_component', 'GO:0030895', ('119', '125'))
5909	33292100	The importance of APOBEC later in tumour evolution is highlighted by the observation that this mutational process in lung adenocarcinoma and squamous carcinoma was found to be the major source of subclonal cancer gene mutations (figure 4) relative to clonal driver gene mutations, suggesting APOBEC is a mutagenic source, fuelling cancer heterogeneity and subclonal diversification.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (117, 136))	('APOBEC', 'cellular_component', 'GO:0030895', ('292', '298'))	('squamous carcinoma', 'Disease', 'MESH:D002294', (141, 159))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (117, 136))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', (34, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('cancer', 'Disease', (206, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('squamous carcinoma', 'Disease', (141, 159))	('APOBEC', 'cellular_component', 'GO:0030895', ('18', '24'))	('lung adenocarcinoma', 'Disease', (117, 136))	('cancer', 'Disease', (331, 337))	('mutations', 'Var', (218, 227))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (141, 159))
5910	33292100	In addition to A3B, a bioinformatics approach significantly associated the cytidine deaminase A3H Hap I with clonal APOBEC-signature mutations in lung adenocarcinoma (figure 4).	('A3H', 'Gene', (94, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('lung adenocarcinoma', 'Disease', (146, 165))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (146, 165))	('cytidine deaminase', 'Gene', '978', (75, 93))	('mutations', 'Var', (133, 142))	('APOBEC', 'cellular_component', 'GO:0030895', ('116', '122'))	('APOBEC-signature', 'Gene', (116, 132))	('A3H', 'Gene', '164668', (94, 97))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (146, 165))	('cytidine deaminase', 'Gene', (75, 93))
5911	33292100	Later, a computational study supported this idea and identified the association of SNP rs139298, that is correlated with lung cancer and creates a K121E mutation in A3H Hap I.	('K121E', 'Mutation', 'rs139298', (147, 152))	('A3H', 'Gene', (165, 168))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('K121E', 'Var', (147, 152))	('SNP', 'Gene', (83, 86))	('rs139298', 'Mutation', 'rs139298', (87, 95))	('correlated', 'Reg', (105, 115))	('A3H', 'Gene', '164668', (165, 168))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))
5914	33292100	However, the K121E mutation was shown to destabilize A3H Hap I in cells and supported the conclusion that the loss of A3H Hap I activity through the K121E variant may benefit the cancer and be detrimental to the host, suggesting that A3H Hap I deamination activity can induce tumour cell death or immune recognition.	('cell death', 'biological_process', 'GO:0008219', ('283', '293'))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumour cell death', 'Disease', 'MESH:D003643', (276, 293))	('K121E', 'Var', (149, 154))	('K121E', 'Var', (13, 18))	('K121E', 'Mutation', 'rs139298', (149, 154))	('A3H', 'Gene', (118, 121))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('K121E', 'Mutation', 'rs139298', (13, 18))	('A3H', 'Gene', '164668', (118, 121))	('benefit', 'PosReg', (167, 174))	('immune recognition', 'CPA', (297, 315))	('A3H', 'Gene', (53, 56))	('destabilize', 'NegReg', (41, 52))	('men', 'Species', '9606', (198, 201))	('tumour cell death', 'Disease', (276, 293))	('A3H', 'Gene', (234, 237))	('A3H', 'Gene', '164668', (53, 56))	('A3H', 'Gene', '164668', (234, 237))	('tumour', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Disease', (179, 185))
5915	33292100	These data emphasize that it is important to use additional genetic or clinical data for determining the beneficial or detrimental effects of A3-induced mutations.	('A3-induced', 'Gene', (142, 152))	('mutations', 'Var', (153, 162))	('A3', 'Chemical', '-', (142, 144))	('men', 'Species', '9606', (124, 127))
5918	33292100	When genomic sequences from lung adenocarcinomas were stratified by A3B and FHIT expression, those with high A3B and FHIT loss showed significantly higher A3 signature mutation loads than high A3B expressers with normal FHIT levels.	('FHIT', 'Gene', (220, 224))	('FHIT', 'Gene', (117, 121))	('FHIT loss', 'Disease', (117, 126))	('A3', 'Chemical', '-', (109, 111))	('FHIT loss', 'Disease', 'MESH:D014786', (117, 126))	('high A3B', 'Var', (104, 112))	('A3', 'Chemical', '-', (155, 157))	('FHIT', 'Gene', '2272', (220, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('FHIT', 'Gene', (76, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))	('higher', 'PosReg', (148, 154))	('FHIT', 'Gene', '2272', (117, 121))	('A3', 'Chemical', '-', (68, 70))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (28, 48))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('A3', 'Chemical', '-', (193, 195))	('FHIT', 'Gene', '2272', (76, 80))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (28, 48))	('lung adenocarcinomas', 'Disease', (28, 48))
5921	33292100	Also, evidence of preferential benefit from therapeutic approaches has emerged in patients with tumours with the highest mutational load.	('mutational load', 'Var', (121, 136))	('patients', 'Species', '9606', (82, 90))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('tumours', 'Disease', (96, 103))
5922	33292100	This suggests that the evolutionary trade-off for increased fitness brought about by an increased mutation rate is the risk of tumour neo-antigenic presentation and immune control (figure 4).	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('fitness', 'Disease', (60, 67))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('increased', 'PosReg', (50, 59))	('fitness', 'Disease', 'MESH:D012640', (60, 67))	('tumour', 'Disease', (127, 133))	('mutation rate', 'Var', (98, 111))
5928	33292100	It was demonstrated in advanced NSCLC, in patients treated with an antibody targeting PD-1, response rates of 17-21% with some responses being remarkably durable.	('antibody', 'cellular_component', 'GO:0019815', ('67', '75'))	('antibody', 'cellular_component', 'GO:0019814', ('67', '75'))	('antibody', 'Var', (67, 75))	('antibody', 'molecular_function', 'GO:0003823', ('67', '75'))	('NSCLC', 'Disease', (32, 37))	('PD-1', 'Gene', (86, 90))	('SCLC', 'Phenotype', 'HP:0030357', (33, 37))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('patients', 'Species', '9606', (42, 50))	('antibody', 'cellular_component', 'GO:0042571', ('67', '75'))
5936	33292100	This study implicates A3B and APOBEC mutational signatures as novel predictive biomarkers for checkpoint blockade immunotherapy response in NSCLC and suggests immunotherapy as a novel treatment option for A3B overexpressing NSCLC.	('A3B', 'Gene', (22, 25))	('APOBEC', 'Gene', (30, 36))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('men', 'Species', '9606', (189, 192))	('NSCLC', 'Disease', (224, 229))	('SCLC', 'Phenotype', 'HP:0030357', (141, 145))	('mutational', 'Var', (37, 47))	('NSCLC', 'Disease', 'MESH:D002289', (224, 229))	('overexpressing', 'PosReg', (209, 223))	('SCLC', 'Phenotype', 'HP:0030357', (225, 229))	('APOBEC', 'cellular_component', 'GO:0030895', ('30', '36'))	('NSCLC', 'Disease', (140, 145))
5943	33292100	About 80% of bladder tumours in the TCGA have an APOBEC mutation signature that is also frequently found in BRCA, lung, head and neck, and cervical cancers.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('neck', 'cellular_component', 'GO:0044326', ('129', '133'))	('BRCA', 'Gene', (108, 112))	('BRCA', 'Gene', '672', (108, 112))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('APOBEC', 'cellular_component', 'GO:0030895', ('49', '55'))	('found', 'Reg', (99, 104))	('APOBEC', 'Gene', (49, 55))	('lung', 'Disease', (114, 118))	('bladder tumours', 'Disease', (13, 28))	('mutation', 'Var', (56, 64))	('cervical cancers', 'Disease', (139, 155))	('bladder tumours', 'Disease', 'MESH:D001749', (13, 28))	('cervical cancers', 'Disease', 'MESH:D002583', (139, 155))
5946	33292100	Both A3A and A3B were induced in all cell lines by bleomycin, but the effect was more robust for A3B.	('A3B', 'Gene', (13, 16))	('bleomycin', 'Var', (51, 60))	('bleomycin', 'Chemical', 'MESH:D001761', (51, 60))	('A3A', 'Gene', '200315', (5, 8))	('A3A', 'Gene', (5, 8))
5949	33292100	The analysis of TCGA BLCA patient datasets revealed that a single nucleotide polymorphism, rs1014971, but not the germline A3A/A3B deletion, was associated with BLCA risk, increased A3B expression and enrichment with APOBEC-signature mutations in bladder tumours (figure 5).	('A3A', 'Gene', (123, 126))	('APOBEC-signature', 'Gene', (217, 233))	('patient', 'Species', '9606', (26, 33))	('rs1014971', 'Mutation', 'rs1014971', (91, 100))	('increased', 'PosReg', (172, 181))	('bladder tumours', 'Disease', 'MESH:D001749', (247, 262))	('APOBEC', 'cellular_component', 'GO:0030895', ('217', '223'))	('tumour', 'Phenotype', 'HP:0002664', (255, 261))	('rs1014971', 'Var', (91, 100))	('tumours', 'Phenotype', 'HP:0002664', (255, 262))	('men', 'Species', '9606', (207, 210))	('BLCA', 'Disease', (161, 165))	('increased A3B expression', 'Phenotype', 'HP:0032430', (172, 196))	('A3B', 'Protein', (182, 185))	('expression', 'MPA', (186, 196))	('bladder tumours', 'Disease', (247, 262))	('mutations', 'Var', (234, 243))	('A3A', 'Gene', '200315', (123, 126))
5950	33292100	Also, this group demonstrated that TCGA BLCA patients with increased APOBEC mutagenesis had significantly improved survival, and that the tumours from patients homozygous for the rs17000526-A allele were enriched for TP53 and PIK3CA mutations (figure 5).	('improved', 'PosReg', (106, 114))	('TP53', 'Gene', '7157', (217, 221))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('patients', 'Species', '9606', (45, 53))	('increased', 'PosReg', (59, 68))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('mutagenesis', 'Var', (76, 87))	('PIK3CA', 'Gene', (226, 232))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('APOBEC', 'cellular_component', 'GO:0030895', ('69', '75'))	('mutagenesis', 'biological_process', 'GO:0006280', ('76', '87'))	('TP53', 'Gene', (217, 221))	('rs17000526-A', 'Var', (179, 191))	('survival', 'CPA', (115, 123))	('rs17000526', 'Mutation', 'rs17000526', (179, 189))	('patients', 'Species', '9606', (151, 159))	('PIK3CA', 'Gene', '5290', (226, 232))	('APOBEC', 'Gene', (69, 75))	('tumours', 'Disease', (138, 145))
5952	33292100	When evaluating the effects of all A3 isoforms on survival, the effect of A3B expression was comparable to that of rs17000526 and similar in treated and untreated patients, while the effect of A3A expression was much stronger in treated compared to untreated patients suggesting that mutagenesis caused by A3B may represent a genetically regulated mechanism contributing to cancer initiation, while mutagenesis caused by A3A may represent events occurring in tumours and influenced by the tumour-specific environment, including treatment.	('tumour', 'Disease', 'MESH:D009369', (459, 465))	('tumour', 'Disease', (459, 465))	('men', 'Species', '9606', (512, 515))	('A3A', 'Gene', (193, 196))	('cancer initiation', 'Disease', 'MESH:D009369', (374, 391))	('cancer initiation', 'Disease', (374, 391))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('patients', 'Species', '9606', (259, 267))	('men', 'Species', '9606', (533, 536))	('contributing', 'Reg', (358, 370))	('A3', 'Chemical', '-', (306, 308))	('A3A', 'Gene', (421, 424))	('A3B', 'Var', (306, 309))	('mutagenesis', 'biological_process', 'GO:0006280', ('284', '295'))	('patients', 'Species', '9606', (163, 171))	('tumours', 'Disease', (459, 466))	('A3', 'Chemical', '-', (35, 37))	('A3A', 'Gene', '200315', (193, 196))	('A3', 'Chemical', '-', (193, 195))	('tumours', 'Phenotype', 'HP:0002664', (459, 466))	('A3', 'Chemical', '-', (74, 76))	('tumours', 'Disease', 'MESH:D009369', (459, 466))	('rs17000526', 'Mutation', 'rs17000526', (115, 125))	('mutagenesis', 'biological_process', 'GO:0006280', ('399', '410'))	('tumour', 'Phenotype', 'HP:0002664', (489, 495))	('A3A', 'Gene', '200315', (421, 424))	('tumour', 'Disease', 'MESH:D009369', (489, 495))	('A3', 'Chemical', '-', (421, 423))	('tumour', 'Phenotype', 'HP:0002664', (459, 465))	('tumour', 'Disease', (489, 495))
5953	33292100	Increased mutation loads, especially in DNA repair genes, were also associated with a response to neoadjuvant cisplatin-based treatment of MIBC (figure 5).	('DNA repair genes', 'Gene', (40, 56))	('MIBC', 'Chemical', '-', (139, 143))	('associated with', 'Reg', (68, 83))	('DNA repair', 'biological_process', 'GO:0006281', ('40', '50'))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('men', 'Species', '9606', (131, 134))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('mutation loads', 'Var', (10, 24))	('response', 'MPA', (86, 94))
5956	33292100	They confirmed that MIBCs show high overall mutation rates similar to those of melanoma and NSCLC, and these high rates are principally associated with mutation signatures from APOBEC enzymes.	('associated', 'Reg', (136, 146))	('mutation', 'Var', (44, 52))	('SCLC', 'Phenotype', 'HP:0030357', (93, 97))	('MIBC', 'Chemical', '-', (20, 24))	('NSCLC', 'Disease', (92, 97))	('APOBEC', 'cellular_component', 'GO:0030895', ('177', '183'))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
5957	33292100	Most BLCA mutations are clonal, suggesting that APOBEC's mutagenic activity occurs early in BLCA development.	('men', 'Species', '9606', (104, 107))	('APOBEC', 'Gene', (48, 54))	('BLCA', 'Gene', (5, 9))	('APOBEC', 'cellular_component', 'GO:0030895', ('48', '54'))	('mutations', 'Var', (10, 19))
5958	33292100	For instance, mutations in specific cancer genes as TP53 and ARID1A show a tendency to be clonal, but focusing on subclonal mutations in known cancer driver genes, in APOBEC-associated BLCA more than 45% of subclonal mutations in driver genes occurred in an APOBEC context.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('APOBEC', 'cellular_component', 'GO:0030895', ('167', '173'))	('APOBEC', 'cellular_component', 'GO:0030895', ('258', '264'))	('ARID1A', 'Gene', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('TP53', 'Gene', '7157', (52, 56))	('cancer', 'Disease', (36, 42))	('occurred', 'Reg', (243, 251))	('TP53', 'Gene', (52, 56))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('ARID1A', 'Gene', '8289', (61, 67))	('mutations', 'Var', (14, 23))
5964	33292100	Recently, several groups investigated the APOBEC mutational signature in the TCGA, Beijing Genomics Institute and Cancer Cell Line Encyclopedia BLCA datasets and its relationship with specific mutations, molecular subtype, gene expression and survival.	('Cancer', 'Disease', 'MESH:D009369', (114, 120))	('mutational', 'Var', (49, 59))	('APOBEC', 'Gene', (42, 48))	('gene expression', 'biological_process', 'GO:0010467', ('223', '238'))	('Cancer', 'Disease', (114, 120))	('APOBEC', 'cellular_component', 'GO:0030895', ('42', '48'))	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))
5966	33292100	They hypothesized that tumours with high levels of APOBEC-mediated mutagenesis would be enriched for mutations in DNA damage response genes and express genes related to activation of the immune system at higher levels, while tumours with low levels of APOBEC-mediated mutagenesis may have enrichments for oncogenes.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('mutations', 'Var', (101, 110))	('tumours', 'Disease', 'MESH:D009369', (225, 232))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('tumours', 'Disease', (225, 232))	('tumours', 'Disease', 'MESH:D009369', (23, 30))	('mutagenesis', 'biological_process', 'GO:0006280', ('67', '78'))	('DNA damage response', 'biological_process', 'GO:0006974', ('114', '133'))	('tumours', 'Disease', (23, 30))	('DNA damage response genes', 'Gene', (114, 139))	('men', 'Species', '9606', (295, 298))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('mutagenesis', 'biological_process', 'GO:0006280', ('268', '279'))	('tumours', 'Phenotype', 'HP:0002664', (225, 232))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('APOBEC', 'cellular_component', 'GO:0030895', ('252', '258'))	('APOBEC', 'cellular_component', 'GO:0030895', ('51', '57'))
5969	33292100	Tumours enriched for APOBEC mutagenesis had better survival and were more likely to have mutations in both DNA damage repair and chromatin-modifying genes such as TP53, PIK3CA (primarily at E542 K and E545 K), ATR, BRCA2, MLL, MLL3 and ARID1A (figure 5).	('ATR', 'Gene', '545', (210, 213))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('DNA damage repair', 'Gene', (107, 124))	('E545 K', 'Mutation', 'rs104886003', (201, 207))	('better', 'PosReg', (44, 50))	('MLL3', 'Gene', '58508', (227, 231))	('BRCA2', 'Gene', (215, 220))	('TP53', 'Gene', (163, 167))	('mutations', 'Reg', (89, 98))	('PIK3CA', 'Gene', (169, 175))	('E542 K', 'Var', (190, 196))	('APOBEC', 'cellular_component', 'GO:0030895', ('21', '27'))	('chromatin', 'cellular_component', 'GO:0000785', ('129', '138'))	('MLL', 'Gene', '4297', (222, 225))	('mutagenesis', 'Var', (28, 39))	('MLL', 'Gene', (222, 225))	('mutagenesis', 'biological_process', 'GO:0006280', ('28', '39'))	('survival', 'CPA', (51, 59))	('ATR', 'Gene', (210, 213))	('MLL3', 'Gene', (227, 231))	('BRCA2', 'Gene', '675', (215, 220))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('ARID1A', 'Gene', (236, 242))	('TP53', 'Gene', '7157', (163, 167))	('APOBEC', 'Gene', (21, 27))	('E545 K', 'Var', (201, 207))	('MLL', 'Gene', (227, 230))	('MLL', 'Gene', '4297', (227, 230))	('E542 K', 'Mutation', 'rs200491706', (190, 196))	('ARID1A', 'Gene', '8289', (236, 242))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('PIK3CA', 'Gene', '5290', (169, 175))
5970	33292100	Bladder tumours not enriched for APOBEC mutagenesis were more likely to have mutations in FGFR3 and the RAS family of oncogenes (KRAS/HRAS/NRAS), which are mutually exclusive, and these patients had poor overall survival.	('HRAS', 'Gene', (134, 138))	('NRAS', 'Gene', (139, 143))	('tumours', 'Disease', (8, 15))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))	('mutagenesis', 'biological_process', 'GO:0006280', ('40', '51'))	('FGFR3', 'Gene', '2261', (90, 95))	('NRAS', 'Gene', '4893', (139, 143))	('KRAS', 'Gene', (129, 133))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('mutations', 'Var', (77, 86))	('KRAS', 'Gene', '3845', (129, 133))	('APOBEC', 'cellular_component', 'GO:0030895', ('33', '39'))	('FGFR3', 'Gene', (90, 95))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('HRAS', 'Gene', '3265', (134, 138))	('patients', 'Species', '9606', (186, 194))	('tumours', 'Disease', 'MESH:D009369', (8, 15))
5974	33292100	It has been suggested that hypermutation could enhance the effectiveness of immune stimulation therapy to treat cancer, by means of the generation of tumour-specific neoantigens that might trigger targeted destruction by the immune system.	('enhance', 'PosReg', (47, 54))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Disease', (150, 156))	('effectiveness', 'MPA', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('hypermutation', 'Var', (27, 40))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))
5975	33292100	BLCA often has high levels of enrichment for APOBEC mutagenesis and A3A-like signatures.	('A3A', 'Gene', (68, 71))	('mutagenesis', 'biological_process', 'GO:0006280', ('52', '63'))	('mutagenesis', 'Var', (52, 63))	('men', 'Species', '9606', (36, 39))	('APOBEC', 'Protein', (45, 51))	('APOBEC', 'cellular_component', 'GO:0030895', ('45', '51'))	('A3A', 'Gene', '200315', (68, 71))
5979	33292100	At least 14 HPV types are carcinogenic, and these 'high-risk' (HR) types, among which HPV16 and HPV18 are the most studied, cause human cancers in the mucosal epithelia of several sites, including the cervix, vulva, vagina, penis, anus, and head and neck, especially those from the oropharynx that includes the tonsils and tongue base.	('HPV', 'Species', '10566', (96, 99))	('HPV', 'Species', '10566', (86, 89))	('carcinogenic', 'Disease', 'MESH:D063646', (26, 38))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('carcinogenic', 'Disease', (26, 38))	('types', 'Var', (67, 72))	('HPV1', 'Species', '12080', (96, 100))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('HPV1', 'Species', '12080', (86, 90))	('HPV', 'Species', '10566', (12, 15))	('HPV18', 'Var', (96, 101))	('HPV16', 'Species', '333760', (86, 91))	('cause', 'Reg', (124, 129))	('neck', 'cellular_component', 'GO:0044326', ('250', '254'))	('HPV16', 'Var', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('human', 'Species', '9606', (130, 135))
5985	33292100	The strong enrichment of the APOBEC signature in cervical cancer exomes and the previous evidence for A3 editing of HPV genomes in plantar warts and pre-cancerous cervical lesions suggest that the presence of HPV in cells might somehow induce or potentiate A3 activity, damaging the host genome and resulting in the observed enrichment of these mutational signatures in HPV-associated cancers.	('cancerous cervical lesions', 'Phenotype', 'HP:0030159', (153, 179))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (385, 391))	('mutational signatures', 'MPA', (345, 366))	('damaging', 'Reg', (270, 278))	('APOBEC', 'cellular_component', 'GO:0030895', ('29', '35'))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('pre', 'molecular_function', 'GO:0003904', ('149', '152'))	('HPV', 'Species', '10566', (209, 212))	('men', 'Species', '9606', (17, 20))	('HPV', 'Species', '10566', (116, 119))	('HPV', 'Species', '10566', (370, 373))	('A3', 'Chemical', '-', (102, 104))	('presence', 'Var', (197, 205))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (385, 391))	('cancers', 'Disease', 'MESH:D009369', (385, 392))	('potentiate', 'PosReg', (246, 256))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('HPV', 'Gene', (209, 212))	('cancerous cervical lesions', 'Disease', 'MESH:D002583', (153, 179))	('A3', 'Chemical', '-', (257, 259))	('cancerous cervical lesions', 'Disease', (153, 179))	('induce', 'PosReg', (236, 242))	('activity', 'MPA', (260, 268))	('cancers', 'Disease', (385, 392))	('warts', 'Phenotype', 'HP:0200043', (139, 144))	('men', 'Species', '9606', (331, 334))	('cancers', 'Phenotype', 'HP:0002664', (385, 392))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', (385, 391))
5987	33292100	Several studies indicate that NF-kappaB pathway activation, p53 inactivation by HPV oncoprotein E6 activation, or loss-of-function mutations in the TP53 gene and replication stress activation are responsible for transcriptional activation of APOBEC, in particular, A3B (figure 6).	('mutations', 'Var', (131, 140))	('APOBEC', 'Gene', (242, 248))	('NF-kappaB', 'Gene', '4790', (30, 39))	('activation', 'PosReg', (228, 238))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('HPV', 'Species', '10566', (80, 83))	('p53', 'Gene', (60, 63))	('NF-kappaB', 'Gene', (30, 39))	('loss-of-function', 'NegReg', (114, 130))	('activation', 'PosReg', (48, 58))	('APOBEC', 'cellular_component', 'GO:0030895', ('242', '248'))	('transcriptional', 'MPA', (212, 227))	('inactivation', 'NegReg', (64, 76))	('p53', 'Gene', '7157', (60, 63))
5989	33292100	The loss of p53 activity through mutations (e.g.	('mutations', 'Var', (33, 42))	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', (12, 15))	('activity', 'MPA', (16, 24))	('loss', 'NegReg', (4, 8))
5990	33292100	in BRCA) or HPV-16 E6/E7-mediated downregulation, causes A3B upregulation.	('BRCA', 'Gene', (3, 7))	('BRCA', 'Gene', '672', (3, 7))	('HPV-16', 'Species', '333760', (12, 18))	('downregulation', 'NegReg', (34, 48))	('upregulation', 'PosReg', (61, 73))	('A3B', 'Protein', (57, 60))	('HPV-16', 'Gene', (12, 18))	('E6/E7-mediated', 'Var', (19, 33))
5991	33292100	Thus, inactivation of p53 by viral protein E6 activation or loss of function of p53 mutations can activate A3B function, increase genome instability and promote tumour initiation.	('tumour initiation', 'Disease', (161, 178))	('tumour initiation', 'Disease', 'MESH:D009369', (161, 178))	('loss of function', 'NegReg', (60, 76))	('increase', 'PosReg', (121, 129))	('activate', 'PosReg', (98, 106))	('activation', 'PosReg', (46, 56))	('p53', 'Gene', (80, 83))	('p53', 'Gene', (22, 25))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('mutations', 'Var', (84, 93))	('function', 'MPA', (111, 119))	('p53', 'Gene', '7157', (80, 83))	('p53', 'Gene', '7157', (22, 25))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('promote', 'PosReg', (153, 160))	('genome instability', 'MPA', (130, 148))	('A3B', 'Protein', (107, 110))
5997	33292100	Translation of LINE1 results in neoantigen expression, so transcription of repetitive elements would put HR-HPV-infected cells at risk of extinction through adaptive immune responses.	('HR-HPV-infected', 'Disease', (105, 120))	('transcription', 'biological_process', 'GO:0006351', ('58', '71'))	('neoantigen expression', 'MPA', (32, 53))	('HR-HPV-infected', 'Disease', 'MESH:D030361', (105, 120))	('LINE1', 'Gene', (15, 20))	('men', 'Species', '9606', (89, 92))	('results in', 'Reg', (21, 31))	('Translation', 'Var', (0, 11))
6001	33292100	A3s target the ssDNA in R-loops and can thereby also activate the DNA damage response, which benefits virus replication (figure 6).	('benefits', 'PosReg', (93, 101))	('DNA damage response', 'biological_process', 'GO:0006974', ('66', '85'))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('R-loops', 'Protein', (24, 31))	('DNA', 'CPA', (66, 69))	('virus replication', 'MPA', (102, 119))	('A3s', 'Chemical', '-', (0, 3))	('A3s', 'Var', (0, 3))	('activate', 'PosReg', (53, 61))
6003	33292100	HPV16 or HPV18 induces A3B expression in cultured cells of BRCA and HNSCC, and the virus-encoded protein E6 directly binds the A3B promoter and triggers transcription.	('BRCA', 'Gene', '672', (59, 63))	('induces', 'Reg', (15, 22))	('HPV1', 'Species', '12080', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('BRCA', 'Gene', (59, 63))	('binds', 'Interaction', (117, 122))	('HPV16', 'Species', '333760', (0, 5))	('A3B', 'Protein', (23, 26))	('triggers', 'Reg', (144, 152))	('HPV16', 'Var', (0, 5))	('HPV1', 'Species', '12080', (9, 13))	('transcription', 'MPA', (153, 166))	('transcription', 'biological_process', 'GO:0006351', ('153', '166'))	('HPV18', 'Gene', (9, 14))
6005	33292100	E6-mediated p53 degradation, therefore, not only de-represses A3B transcription via the DREAM complex, but also results in increased levels of TEAD expression, further activating the A3B promoter (figure 6).	('increased', 'PosReg', (123, 132))	('activating', 'PosReg', (168, 178))	('transcription', 'biological_process', 'GO:0006351', ('66', '79'))	('degradation', 'biological_process', 'GO:0009056', ('16', '27'))	('TEAD expression', 'MPA', (143, 158))	('DREAM', 'Gene', '30818', (88, 93))	('transcription', 'MPA', (66, 79))	('p53', 'Gene', (12, 15))	('A3B', 'Gene', (62, 65))	('p53', 'Gene', '7157', (12, 15))	('degradation', 'Var', (16, 27))	('levels', 'MPA', (133, 139))	('de-represses', 'NegReg', (49, 61))	('DREAM', 'Gene', (88, 93))
6008	33292100	The distribution of PIK3CA-activating mutations is different in head and neck cancers, with exclusively helical domain C-to-T transitions observed in HPV-positive tumours and a combination of helical domain and kinase domain mutations in HPV-negative tumours.	('observed', 'Reg', (138, 146))	('HPV-positive tumours', 'Disease', (150, 170))	('HPV-negative tumours', 'Disease', 'MESH:D030361', (238, 258))	('head and neck cancers', 'Phenotype', 'HP:0012288', (64, 85))	('neck', 'cellular_component', 'GO:0044326', ('73', '77'))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('helical domain', 'MPA', (104, 118))	('PIK3CA', 'Gene', (20, 26))	('HPV-negative tumours', 'Disease', (238, 258))	('tumours', 'Phenotype', 'HP:0002664', (163, 170))	('tumours', 'Phenotype', 'HP:0002664', (251, 258))	('PIK3CA', 'Gene', '5290', (20, 26))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (38, 47))	('HPV-positive tumours', 'Disease', 'MESH:D030361', (150, 170))	('head and neck cancers', 'Disease', 'MESH:D006258', (64, 85))
6009	33292100	The HPV-positive tumours have 5'-TGA-to-TAA transitions (complementary strand 5'-TCA-to-TTA) that convert both helical domain Glu542 and Glu545 to Lys, whereas HPV-negative tumours often have a 5'-CAT-to-CGT transition mutation resulting in a kinase domain His1047 to Arg substitution.	('His1047 to Arg', 'Mutation', 'p.H1047R', (257, 271))	('TTA', 'Chemical', 'MESH:C062078', (88, 91))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('HPV-positive tumours', 'Disease', (4, 24))	('convert', 'Reg', (98, 105))	('TCA', 'Chemical', 'MESH:D014238', (81, 84))	('men', 'Species', '9606', (63, 66))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('HPV-positive tumours', 'Disease', 'MESH:D030361', (4, 24))	('CAT', 'molecular_function', 'GO:0004096', ('197', '200'))	('kinase', 'MPA', (243, 249))	('CGT', 'molecular_function', 'GO:0047801', ('204', '207'))	('HPV-negative tumours', 'Disease', (160, 180))	('CGT', 'Gene', '7368', (204, 207))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('Glu542 and Glu545 to Lys', 'Mutation', 'p.E,E542,545K', (126, 150))	('Glu545 to Lys', 'SUBSTITUTION', 'None', (137, 150))	('CGT', 'Gene', (204, 207))	('helical domain Glu542', 'MPA', (111, 132))	('Glu545 to Lys', 'Var', (137, 150))	('HPV-negative tumours', 'Disease', 'MESH:D030361', (160, 180))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))
6010	33292100	Similar helical domain biases have also been reported for PIK3CA mutations in other APOBEC-signature tumour types, implying as the common denominator the APOBEC mutagenesis and not viral infection.	('viral infection', 'Disease', 'MESH:D001102', (181, 196))	('APOBEC', 'cellular_component', 'GO:0030895', ('154', '160'))	('APOBEC-signature', 'Disease', (84, 100))	('tumour', 'Disease', (101, 107))	('APOBEC', 'cellular_component', 'GO:0030895', ('84', '90'))	('PIK3CA', 'Gene', (58, 64))	('viral infection', 'Disease', (181, 196))	('PIK3CA', 'Gene', '5290', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('viral infection', 'biological_process', 'GO:0016032', ('181', '196'))	('mutagenesis', 'biological_process', 'GO:0006280', ('161', '172'))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('helical domain biases', 'MPA', (8, 29))	('mutations', 'Var', (65, 74))
6012	33292100	The distinctive pattern of APOBEC-signature mutations in exon 9 of the PIK3CA proto-oncogene in HPV-positive HNSCC and in other cancer types displaying the APOBEC mutational signature implicates APOBEC activity in the generation of oncogenic driver events, findings that were confirmed by analysis of TCGA HPV-positive HNSCC cohorts.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('HPV', 'Species', '10566', (96, 99))	('APOBEC', 'cellular_component', 'GO:0030895', ('27', '33'))	('PIK3CA', 'Gene', '5290', (71, 77))	('cancer', 'Disease', (128, 134))	('APOBEC', 'cellular_component', 'GO:0030895', ('195', '201'))	('HPV', 'Species', '10566', (306, 309))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (44, 53))	('implicates', 'Reg', (184, 194))	('PIK3CA', 'Gene', (71, 77))	('APOBEC', 'cellular_component', 'GO:0030895', ('156', '162'))	('APOBEC-signature', 'Gene', (27, 43))
6017	33292100	It could be that when the mutations are occurring during development of these tumours, they are correlated with the expression of the A3 responsible, but that this relationship is lost following subsequent downregulation, possibly because of the role of A3s as transient hypermutators.	('correlated', 'Reg', (96, 106))	('A3', 'Chemical', '-', (134, 136))	('expression', 'MPA', (116, 126))	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('A3', 'Chemical', '-', (254, 256))	('tumours', 'Disease', (78, 85))	('mutations', 'Var', (26, 35))	('downregulation', 'NegReg', (206, 220))	('men', 'Species', '9606', (64, 67))	('lost', 'NegReg', (180, 184))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('A3s', 'Chemical', '-', (254, 257))
6018	33292100	The preponderance of A3-induced mutations in HPV-driven cervical cancer, together with the observation that A3-induced mutations are enriched in the HPV-associated subset of HNSCC, suggest a possible off-target response to the virus.	('A3-induced', 'Gene', (21, 31))	('HPV', 'Species', '10566', (45, 48))	('HPV', 'Species', '10566', (149, 152))	('A3', 'Chemical', '-', (21, 23))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('A3', 'Chemical', '-', (108, 110))	('mutations', 'Var', (32, 41))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
6021	33292100	Also, A3A expression is associated with HPV16 genome integration and hypermutations in oropharyngeal cancers.	('A3A', 'Gene', '200315', (6, 9))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('associated', 'Reg', (24, 34))	('HPV16', 'Species', '333760', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('HPV16', 'Gene', (40, 45))	('A3A', 'Gene', (6, 9))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('hypermutations', 'Var', (69, 83))
6024	33292100	The cervical epithelium is an oestrogen-responsive tissue; indeed, HPV E6/E7-driven cervical cancer development in transgenic mice can be promoted by oestradiol infusion over several months.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('transgenic mice', 'Species', '10090', (115, 130))	('men', 'Species', '9606', (107, 110))	('E6/E7-driven', 'Var', (71, 83))	('oestradiol', 'Chemical', 'MESH:D004958', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('HPV', 'Species', '10566', (67, 70))	('HPV', 'Gene', (67, 70))	('promoted', 'PosReg', (138, 146))
6025	33292100	Considering these factors, it is a possibility that A3B could also fuel cervical carcinogenesis via this non-mutagenic but nonetheless deaminase-dependent transcriptional activity.	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))	('carcinogenesis', 'Disease', (81, 95))	('A3B', 'Var', (52, 55))	('fuel', 'PosReg', (67, 71))	('deaminase-dependent transcriptional activity', 'MPA', (135, 179))
6027	33292100	first reported the evidence for APOBEC editing of HPV in human cells and noted that HPV1a DNA co-transfected with A3A, A3C and A3H but not A3B displayed evidence of cytidine deamination, and while low-risk HPV genomes isolated from warts display evidence of A3 editing, several tested low-risk E6 variants did not upregulate A3B in cultured keratinocytes.	('cytidine deamination', 'MPA', (165, 185))	('A3', 'Chemical', '-', (119, 121))	('A3', 'Chemical', '-', (127, 129))	('warts', 'Phenotype', 'HP:0200043', (232, 237))	('A3A', 'Gene', (114, 117))	('APOBEC', 'cellular_component', 'GO:0030895', ('32', '38'))	('HPV', 'Species', '10566', (84, 87))	('variants', 'Var', (297, 305))	('A3H', 'Gene', (127, 130))	('human', 'Species', '9606', (57, 62))	('A3H', 'Gene', '164668', (127, 130))	('A3', 'Chemical', '-', (139, 141))	('HPV', 'Species', '10566', (50, 53))	('HPV1', 'Species', '12080', (84, 88))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('cytidine', 'Chemical', 'MESH:D003562', (165, 173))	('A3A', 'Gene', '200315', (114, 117))	('A3', 'Chemical', '-', (258, 260))	('A3', 'Chemical', '-', (114, 116))	('cytidine deamination', 'biological_process', 'GO:0009972', ('165', '185'))	('HPV', 'Species', '10566', (206, 209))	('A3C', 'Mutation', 'c.3A>C', (119, 122))	('A3', 'Chemical', '-', (325, 327))
6029	33292100	The first hypothesis considered the possibility that the A3 response to HPV infection (mediated by A3A and/or A3C, A3H) is entirely separate from any role in host mutagenesis (mediated by A3B) during cancer development.	('A3H', 'Gene', '164668', (115, 118))	('A3', 'Chemical', '-', (188, 190))	('A3A', 'Gene', (99, 102))	('A3', 'Chemical', '-', (99, 101))	('mutagenesis', 'biological_process', 'GO:0006280', ('163', '174'))	('men', 'Species', '9606', (214, 217))	('HPV infection', 'Disease', 'MESH:D030361', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('A3H', 'Gene', (115, 118))	('A3C', 'Var', (110, 113))	('A3', 'Chemical', '-', (110, 112))	('HPV infection', 'Disease', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('A3A', 'Gene', '200315', (99, 102))	('A3', 'Chemical', '-', (115, 117))	('A3', 'Chemical', '-', (57, 59))	('cancer', 'Disease', (200, 206))	('A3C', 'Mutation', 'c.3A>C', (110, 113))
6033	33292100	Although further investigations will be necessary, these observations suggest A3A, rather than A3B, may be the major source of somatic mutations to the host genome in HPV-associated cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('mutations', 'Var', (135, 144))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('A3A', 'Gene', '200315', (78, 81))	('HPV', 'Species', '10566', (167, 170))	('A3A', 'Gene', (78, 81))
6038	33292100	This study showed that IFN-beta treatment upregulated A3A expression in cervical keratinocytes, and that knockdown of A3A expression reduced IFN-beta-induced hypermutation of the viral E2 gene (figure 6).	('IFN-beta', 'Gene', '3438', (23, 31))	('IFN-beta', 'Gene', (23, 31))	('expression', 'MPA', (58, 68))	('knockdown', 'Var', (105, 114))	('A3A', 'Gene', (54, 57))	('A3A', 'Gene', '200315', (118, 121))	('men', 'Species', '9606', (37, 40))	('A3A', 'Gene', (118, 121))	('upregulated', 'PosReg', (42, 53))	('IFN-beta', 'Gene', '3438', (141, 149))	('A3A', 'Gene', '200315', (54, 57))	('reduced', 'NegReg', (133, 140))	('IFN-beta', 'Gene', (141, 149))
6041	33292100	HPV restriction by A3A is deaminase-dependent, as a catalytically inactive mutant A3A was unable to restrict HPV infection.	('A3A', 'Gene', (82, 85))	('HPV', 'Species', '10566', (0, 3))	('HPV infection', 'Disease', (109, 122))	('mutant', 'Var', (75, 81))	('HPV infection', 'Disease', 'MESH:D030361', (109, 122))	('HPV', 'Species', '10566', (109, 112))	('A3A', 'Gene', '200315', (19, 22))	('A3A', 'Gene', (19, 22))	('A3A', 'Gene', '200315', (82, 85))
6050	33292100	The results obtained suggest that A3s activate BER in HNSCC, mediate repair of cisplatin ICLs and thereby, sensitize cells to cisplatin which likely contributes to the improved patient responses observed in HPV-infected patients.	('repair', 'MPA', (69, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('ICLs', 'Disease', 'None', (89, 93))	('mediate', 'Reg', (61, 68))	('HPV-infected', 'Disease', 'MESH:D030361', (207, 219))	('HPV-infected', 'Disease', (207, 219))	('HNSCC', 'Protein', (54, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('BER', 'biological_process', 'GO:0006284', ('47', '50'))	('patient', 'Species', '9606', (177, 184))	('activate', 'PosReg', (38, 46))	('patient', 'Species', '9606', (220, 227))	('patients', 'Species', '9606', (220, 228))	('ER', 'Gene', '2069', (48, 50))	('A3s', 'Chemical', '-', (34, 37))	('ICLs', 'Disease', (89, 93))	('A3s', 'Var', (34, 37))	('sensitize', 'Reg', (107, 116))
6051	33292100	Contrary to the idea that A3-mediated somatic mutations may drive HPV-positive cancer progression, recent cancer immunology studies have shown that high levels of somatic mutations favour anti-tumour immune responses that also coincide with better prognosis after immunotherapies.	('HPV', 'Species', '10566', (66, 69))	('tumour', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumour', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('mutations', 'Var', (171, 180))	('favour', 'PosReg', (181, 187))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('A3', 'Chemical', '-', (26, 28))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
6052	33292100	Tumour neoantigens are recognized as emerging targets for personalized cancer immunotherapies, implying that cancers with a high level of A3 mutation signatures may be beneficial for immunotherapies that induce robust anti-tumour T-cell responses specific to neoantigens generated by A3-mediated mutations.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancer', 'Disease', (71, 77))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('cancers', 'Disease', (109, 116))	('cancer', 'Disease', (109, 115))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('tumour', 'Disease', (223, 229))	('A3', 'Chemical', '-', (138, 140))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutation', 'Var', (141, 149))	('mutations', 'Var', (296, 305))	('A3', 'Chemical', '-', (284, 286))
6055	33292100	In this regard, A3-mediated mutations could be used beneficially to identify T-cell epitopes and treat HPV-positive cancer patients.	('cancer', 'Disease', (116, 122))	('HPV', 'Species', '10566', (103, 106))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('patients', 'Species', '9606', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('mutations', 'Var', (28, 37))	('A3', 'Chemical', '-', (16, 18))
6057	33292100	Thus, it would be interesting to investigate if A3 mutation loads in patients correlate to better outcome following current immunotherapies targeting immune checkpoint blockades, e.g.	('mutation loads', 'Var', (51, 65))	('better', 'PosReg', (91, 97))	('patients', 'Species', '9606', (69, 77))	('A3', 'Chemical', '-', (48, 50))
6059	33292100	Lastly, one study analysed the viral genomes of 5328 HPV16-positive case-control samples to investigate mutational signatures and the role of human A3-induced mutations in viral clearance and cervical carcinogenesis.	('HPV16', 'Species', '333760', (53, 58))	('carcinogenesis', 'Disease', (201, 215))	('mutations', 'Var', (159, 168))	('human', 'Species', '9606', (142, 147))	('A3', 'Chemical', '-', (148, 150))	('carcinogenesis', 'Disease', 'MESH:D063646', (201, 215))	('HPV16-positive', 'Gene', (53, 67))
6060	33292100	This analysis revealed that cervical infections with a greater burden of somatic HPV16 A3-induced mutations are more likely to be benign or subsequently clear (figure 6), suggesting they may reduce persistence, and thus progression, within the host.	('infections', 'Disease', 'MESH:D007239', (37, 47))	('persistence', 'MPA', (198, 209))	('HPV16', 'Species', '333760', (81, 86))	('infections', 'Disease', (37, 47))	('mutations', 'Var', (98, 107))	('HPV16 A3-induced', 'Gene', (81, 97))	('A3', 'Chemical', '-', (87, 89))	('reduce', 'NegReg', (191, 197))
6066	33292100	The leading candidates for inducing mutations in cancer are A3B, A3A and A3H Hap I.	('inducing', 'Reg', (27, 35))	('A3H', 'Gene', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('A3A', 'Gene', '200315', (65, 68))	('A3A', 'Gene', (65, 68))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('A3H', 'Gene', '164668', (73, 76))	('cancer', 'Disease', (49, 55))
6068	33292100	A3B, for example, could provide a mutation rate that is in some cases beneficial favouring immune responses following immunotherapy with a positive outcome for the cancer patients, but in other cases, it is related with poor clinical outcomes.	('beneficial', 'PosReg', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('mutation', 'Var', (34, 42))	('patients', 'Species', '9606', (171, 179))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('immune responses', 'CPA', (91, 107))
6074	33292100	Undoubtedly, knowledge of A3 mutagenesis in cancer may yield significant diagnostic and prognostic value and could open the doors towards new therapeutic opportunities.	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('mutagenesis', 'biological_process', 'GO:0006280', ('29', '40'))	('mutagenesis', 'Var', (29, 40))	('A3', 'Chemical', '-', (26, 28))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
6079	33292100	(ii) How and when can we avoid the off-target A3-induced mutations that results in poor clinical outcomes, and (iii) why does A3 overexpression sometimes have a clinical benefit for cancer patients?	('A3', 'Chemical', '-', (126, 128))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('overexpression', 'PosReg', (129, 143))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('mutations', 'Var', (57, 66))	('A3-induced', 'Gene', (46, 56))	('cancer', 'Disease', (182, 188))	('patients', 'Species', '9606', (189, 197))	('A3', 'Chemical', '-', (46, 48))
6089	33194662	Kaplan-Meier analysis demonstrated associations of high FBLN2 expression with worse DSS (p < 0.001) and MFS (p < 0.001).	('FBLN2', 'Gene', (56, 61))	('high', 'Var', (51, 55))	('worse DSS', 'Disease', (78, 87))	('DSS', 'Chemical', '-', (84, 87))	('MFS', 'Disease', 'MESH:D008382', (104, 107))	('MFS', 'Disease', (104, 107))
6090	33194662	Furthermore, multivariate analysis identified high FBLN2 expression as an independent predictive risk factor for DSS [hazard ratio (HR) in UBUC, 2.306, p = 0.014; in UTUC, 2.561, p = 0.012] and MFS (HR in UBUC, 2.493, p = 0.001; in UTUC, 2.837, p = 0.001).	('high', 'Var', (46, 50))	('MFS', 'Disease', 'MESH:D008382', (194, 197))	('MFS', 'Disease', (194, 197))	('FBLN2', 'Gene', (51, 56))	('DSS', 'Chemical', '-', (113, 116))	('DSS', 'Disease', (113, 116))
6121	33194662	As for positive controls, we included HT 1197 cell block sections known to express high FBLN2.	('FBLN2', 'Gene', (88, 93))	('high', 'Var', (83, 87))	('HT 1197', 'CellLine', 'CVCL:1291', (38, 45))
6128	33194662	We selected FBLN2 for further study, as the role of FBLN2 in cancer development is not straightforward; it may inhibit or promote tumorigenesis.	('inhibit', 'NegReg', (111, 118))	('FBLN2', 'Var', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('promote', 'PosReg', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (130, 135))
6137	33194662	In UTUC patients, high FBLN2 expression was significantly associated with advanced pathologic tumor stage, high histological grade, lymph node metastasis, VI, PNI, and high mitotic activity (all p < 0.001).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('high histological grade', 'CPA', (107, 130))	('lymph node metastasis', 'CPA', (132, 153))	('associated', 'Reg', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('PNI', 'Disease', (159, 162))	('high', 'Var', (18, 22))	('high mitotic activity', 'CPA', (168, 189))	('expression', 'MPA', (29, 39))	('FBLN2', 'Gene', (23, 28))	('patients', 'Species', '9606', (8, 16))
6138	33194662	Similarly, in UBUC patients, we found significant associations between high FBLN2 expression and advanced pT status (p < 0.001), high histological tumor grade (p = 0.003), lymph node metastasis (p = 0.001), VI (p < 0.001), PNI (p = 0.001), and high mitotic rate (p < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('advanced', 'Disease', (97, 105))	('patients', 'Species', '9606', (19, 27))	('high', 'Var', (71, 75))	('high mitotic rate', 'CPA', (244, 261))	('PNI', 'Disease', (223, 226))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('FBLN2', 'Gene', (76, 81))	('lymph node metastasis', 'CPA', (172, 193))
6143	33194662	Furthermore, 32.9% of high FBLN2-expressing tumors developed metastasis, whereas only 8.2% of the tumors with low FBLN2-expressing tumors did.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('developed', 'PosReg', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('metastasis', 'CPA', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumors', 'Disease', (131, 137))	('high FBLN2-expressing', 'Var', (22, 43))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
6144	33194662	Kaplan-Meier analysis showed a significant association of high FBLN2 expression with worse DSS (Figure 4A; p = 0.0001) and worse MFS (Figure 4B; p < 0.0001).	('MFS', 'Disease', 'MESH:D008382', (129, 132))	('FBLN2', 'Gene', (63, 68))	('MFS', 'Disease', (129, 132))	('high', 'Var', (58, 62))	('worse DSS', 'Disease', (85, 94))	('DSS', 'Chemical', '-', (91, 94))
6148	33194662	Following univariate analysis, we observed that advanced pT status, lymph node metastasis, high histological grade, VI, PNI, high mitotic activity, and high FBLN2 expression (Figures 4C,D; all p < 0.0001) were associated with worse DSS and MFS.	('high', 'Var', (91, 95))	('MFS', 'Disease', (240, 243))	('lymph node metastasis', 'CPA', (68, 89))	('expression', 'MPA', (163, 173))	('DSS', 'Chemical', '-', (232, 235))	('worse DSS', 'Disease', (226, 235))	('MFS', 'Disease', 'MESH:D008382', (240, 243))	('high mitotic activity', 'CPA', (125, 146))	('high FBLN2', 'Var', (152, 162))
6150	33194662	In addition, high FBLN2 expression (HR, 2.493; 95% CI, 1.427-4.353; p = 0.001), high pathologic stage, and high mitotic activity significantly correlated with worse MFS.	('expression', 'MPA', (24, 34))	('FBLN2', 'Gene', (18, 23))	('high', 'Var', (13, 17))	('MFS', 'Disease', 'MESH:D008382', (165, 168))	('MFS', 'Disease', (165, 168))
6161	33194662	In addition, high FBLN2 expression was significantly associated with adverse pathologic tumor characteristics, such as advanced pathologic tumor stage, high histological tumor grade, lymph node metastasis, VI, PNI, and high mitotic rate.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('lymph node metastasis', 'CPA', (183, 204))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('high', 'Var', (13, 17))	('expression', 'MPA', (24, 34))	('FBLN2', 'Gene', (18, 23))	('high mitotic rate', 'CPA', (219, 236))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('PNI', 'Disease', (210, 213))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('associated', 'Reg', (53, 63))	('tumor', 'Disease', (88, 93))
6165	33194662	Depending on the tissue context, FBLN2 may act as either a tumor promoter or a tumor suppressor in different cancer models.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('FBLN2', 'Var', (33, 38))	('cancer', 'Disease', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
6167	33194662	demonstrated that FBLN2 can drive malignant progression and promote tumor cell adherence to collagen and collagen cross-linking.	('tumor', 'Disease', (68, 73))	('promote', 'PosReg', (60, 67))	('FBLN2', 'Var', (18, 23))	('collagen', 'molecular_function', 'GO:0005202', ('92', '100'))	('collagen', 'molecular_function', 'GO:0005202', ('105', '113'))	('drive', 'PosReg', (28, 33))	('collagen cross-linking', 'CPA', (105, 127))	('malignant progression', 'CPA', (34, 55))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
6168	33194662	They found that FBLN2 was abundant in the ECM of human lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('human', 'Species', '9606', (49, 54))	('FBLN2', 'Var', (16, 21))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
6170	33194662	found that FBLN2 was a tumor suppressor and had antiangiogenic effects.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('antiangiogenic effects', 'CPA', (48, 70))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('tumor', 'Disease', (23, 28))	('FBLN2', 'Var', (11, 16))
6171	33194662	FBLN2 re-expression also inhibited tumor growth and angiogenesis in vivo.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('FBLN2', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('angiogenesis', 'biological_process', 'GO:0001525', ('52', '64'))	('tumor', 'Disease', (35, 40))	('re-expression', 'Var', (6, 19))	('inhibited', 'NegReg', (25, 34))
6172	33194662	In the present study, we demonstrated that high FBLN2 immunoexpression was significantly associated with aggressive UTUC and UBUC characteristics, such as high tumor stage and grade, PNI, VI, lymph node metastasis, and high mitotic rate, suggesting important roles of FBLN2 in UC progression and metastasis.	('associated', 'Reg', (89, 99))	('high tumor', 'Disease', (155, 165))	('high', 'Var', (43, 47))	('FBLN2', 'Gene', (48, 53))	('high mitotic rate', 'CPA', (219, 236))	('high tumor', 'Disease', 'MESH:D009369', (155, 165))	('grade', 'CPA', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('lymph node metastasis', 'CPA', (192, 213))	('aggressive', 'CPA', (105, 115))	('PNI', 'Disease', (183, 186))
6174	33194662	FBLN2 immunoexpression status may serve as a useful marker to classify these patients because high FBLN2 expression is significantly related to muscle invasiveness and high-grade UBUC.	('high-grade UBUC', 'Disease', (168, 183))	('FBLN2', 'Gene', (99, 104))	('related', 'Reg', (133, 140))	('patients', 'Species', '9606', (77, 85))	('muscle invasiveness', 'Disease', (144, 163))	('expression', 'MPA', (105, 115))	('high', 'Var', (94, 98))	('muscle invasiveness', 'Disease', 'MESH:D009362', (144, 163))
6175	33194662	However, in ureteroscopic biopsy tumors with high FBLN2 expression, radical nephroureterectomy with bladder cuff excision should be suggested.	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('high', 'Var', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('FBLN2', 'Gene', (50, 55))
6177	33194662	Here, we showed that UC patients with high FBLN2 expression and aggressive pathologic features were more likely to develop distant metastasis.	('high', 'Var', (38, 42))	('develop', 'PosReg', (115, 122))	('distant metastasis', 'CPA', (123, 141))	('patients', 'Species', '9606', (24, 32))	('FBLN2', 'Gene', (43, 48))
6180	33194662	In conclusion, we demonstrated that high FBLN2 immunoexpression is associated with aggressive tumor characteristics and independent prognostication of worse oncological outcomes in a large, well-characterized UC cohort.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('aggressive tumor', 'Disease', 'MESH:D001523', (83, 99))	('FBLN2', 'Gene', (41, 46))	('aggressive tumor', 'Disease', (83, 99))	('high', 'Var', (36, 40))
6184	32992842	High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro Aberrant hyperactivation of nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) is a common event in many tumour types and associates with resistance to therapy and poor patient prognosis; however, its relevance in colorectal tumours is not well-established.	('patient', 'Species', '9606', (319, 326))	('AT9283', 'Chemical', 'MESH:C535237', (122, 128))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (50, 67))	('tumours', 'Phenotype', 'HP:0002664', (375, 382))	('NRF2', 'Gene', (5, 9))	('Colorectal Cancer', 'Disease', (50, 67))	('hyperactivation', 'PosReg', (147, 162))	('nuclear factor erythroid 2', 'Gene', '4778', (166, 192))	('tumour', 'Phenotype', 'HP:0002664', (375, 381))	('NRF2', 'Gene', '4780', (223, 227))	('tumour', 'Disease', 'MESH:D009369', (375, 381))	('colorectal tumours', 'Disease', 'MESH:D015179', (364, 382))	('nuclear factor erythroid 2', 'Gene', (166, 192))	('tumour', 'Disease', (375, 381))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (50, 67))	('tumour', 'Phenotype', 'HP:0002664', (255, 261))	('tumour', 'Disease', 'MESH:D009369', (255, 261))	('tumour', 'Disease', (255, 261))	('NF-E2', 'Gene', (194, 199))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('NRF2', 'Gene', (223, 227))	('NRF2', 'Gene', '4780', (5, 9))	('Kinase Inhibitor', 'biological_process', 'GO:0033673', ('105', '121'))	('Patients', 'Species', '9606', (68, 76))	('Aberrant', 'Var', (138, 146))	('colorectal tumours', 'Disease', (364, 382))
6188	32992842	We identified AT9283, an Aurora kinase inhibitor, for its selectivity towards killing cancer cells with hyperactive NRF2 as a consequence to either genetic or pharmacological activation.	('AT9283', 'Chemical', 'MESH:C535237', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('hyperactive', 'Disease', (104, 115))	('NRF2', 'Gene', '4780', (116, 120))	('hyperactive', 'Disease', 'MESH:D006948', (104, 115))	('AT9283', 'Var', (14, 20))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('32', '48'))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('NRF2', 'Gene', (116, 120))	('cancer', 'Disease', (86, 92))
6193	32992842	Sustained activation of the NRF2 pathway is mainly due to either loss-of-function (LOF) mutations in KEAP1 or gain-of-function (GOF) mutations in NFE2L2.	('NRF2', 'Gene', (28, 32))	('KEAP1', 'Gene', '9817', (101, 106))	('mutations', 'Var', (88, 97))	('loss-of-function', 'NegReg', (65, 81))	('mutations', 'Var', (133, 142))	('NRF2', 'Gene', '4780', (28, 32))	('KEAP1', 'Gene', (101, 106))	('gain-of-function', 'PosReg', (110, 126))	('NFE2L2', 'Gene', '4780', (146, 152))	('activation', 'PosReg', (10, 20))	('NFE2L2', 'Gene', (146, 152))
6196	32992842	It is estimated that 34% LuSCC and 18% of LuAD patients harbour mutations in NRF2 or KEAP1, which correlates with poor survival.	('LuAD', 'Phenotype', 'HP:0030078', (42, 46))	('LuAD', 'Disease', (42, 46))	('KEAP1', 'Gene', (85, 90))	('LuAD', 'Disease', 'None', (42, 46))	('patients', 'Species', '9606', (47, 55))	('NRF2', 'Gene', '4780', (77, 81))	('mutations', 'Var', (64, 73))	('KEAP1', 'Gene', '9817', (85, 90))	('NRF2', 'Gene', (77, 81))
6197	32992842	Additionally, aberrant activation of NRF2 in cancer cells also occurs through alternative mechanisms, including the oncogene-induced transcription of NRF2 via KRAS, BRAF, MYC activation or epigenetic silencing of KEAP1.	('NRF2', 'Gene', (150, 154))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('NRF2', 'Gene', (37, 41))	('transcription', 'MPA', (133, 146))	('epigenetic silencing', 'Var', (189, 209))	('BRAF', 'Gene', '673', (165, 169))	('MYC', 'Gene', '4609', (171, 174))	('BRAF', 'Gene', (165, 169))	('KEAP1', 'Gene', '9817', (213, 218))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('KEAP1', 'Gene', (213, 218))	('KRAS', 'Gene', '3845', (159, 163))	('NRF2', 'Gene', '4780', (150, 154))	('cancer', 'Disease', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('KRAS', 'Gene', (159, 163))	('NRF2', 'Gene', '4780', (37, 41))	('activation', 'PosReg', (23, 33))	('MYC', 'Gene', (171, 174))
6198	32992842	Altogether, this shows that the aberrant activation of the NRF2 pathway might be a common pro-oncogenic event in many cancer types, and thus, the identification of ways to overcome the protection provided by NRF2 is a desirable goal.	('cancer', 'Disease', (118, 124))	('NRF2', 'Gene', (59, 63))	('NRF2', 'Gene', '4780', (208, 212))	('NRF2', 'Gene', '4780', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('NRF2', 'Gene', (208, 212))	('activation', 'PosReg', (41, 51))	('aberrant', 'Var', (32, 40))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
6207	32992842	This is in contrast with lung cancer, where, in addition to the existence of well-characterised cell lines harbouring mutant hyperactive NRF2 (e.g., the lung cancer cell line A549), several models have been developed to study NRF2 hyperactivation, and a number of associated vulnerabilities have been identified by using KEAP1-deficient or loss-of-function mutant models.	('KEAP1', 'Gene', (321, 326))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('NRF2', 'Gene', '4780', (137, 141))	('hyperactive', 'Disease', 'MESH:D006948', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('hyperactive', 'Disease', (125, 136))	('NRF2', 'Gene', (226, 230))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))	('A549', 'CellLine', 'CVCL:0023', (175, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('NRF2', 'Gene', (137, 141))	('mutant', 'Var', (118, 124))	('lung cancer', 'Disease', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('loss-of-function', 'NegReg', (340, 356))	('lung cancer', 'Disease', (25, 36))	('NRF2', 'Gene', '4780', (226, 230))	('KEAP1', 'Gene', '9817', (321, 326))
6211	32992842	Furthermore, we generated isogenic colorectal DLD1 cell lines harbouring gain-of-function (GOF) mutations in NRF2.	('NRF2', 'Gene', '4780', (109, 113))	('gain-of-function', 'PosReg', (73, 89))	('mutations', 'Var', (96, 105))	('NRF2', 'Gene', (109, 113))
6225	32992842	The primers used were obtained from Thermo Fisher Scientific (Waltham, MA, USA) as follows: NQO1 (Hs00168547_m1), AKR1B10 (Hs00252524_m1), NFE2L2 (Hs00975961_g1), HPRT1 (Hs02800695_m1) and beta-actin (Hs01060665_g1).	('HPRT', 'molecular_function', 'GO:0004422', ('163', '167'))	('Hs00252524_m1', 'Var', (123, 136))	('Hs00975961_g1', 'Var', (147, 160))	('Hs02800695_m1', 'Var', (170, 183))	('Hs00168547_m1', 'Var', (98, 111))	('NQO1', 'molecular_function', 'GO:0003955', ('92', '96'))	('NFE2L2', 'Gene', '4780', (139, 145))	('AKR1B10', 'Gene', (114, 121))	('AKR1B10', 'Gene', '57016', (114, 121))	('HPRT1', 'Gene', (163, 168))	('HPRT1', 'Gene', '3251', (163, 168))	('Hs01060665_g1', 'Var', (201, 214))	('NFE2L2', 'Gene', (139, 145))
6275	32992842	Indeed, high protein levels of nuclear NRF2, correlated with a decreased survival of colorectal cancer patients (p = 0.041) (Figure 1C), with a mean difference in cancer-specific survival of 17 months between those patients with high NRF2 expressions versus those with low NRF2 expressions.	('NRF2', 'Gene', '4780', (273, 277))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('high', 'Var', (229, 233))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))	('survival', 'MPA', (73, 81))	('NRF2', 'Gene', (234, 238))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('decreased', 'NegReg', (63, 72))	('expressions', 'Var', (239, 250))	('NRF2', 'Gene', (273, 277))	('protein levels', 'MPA', (13, 27))	('NRF2', 'Gene', '4780', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('cancer', 'Disease', (163, 169))	('patients', 'Species', '9606', (215, 223))	('colorectal cancer', 'Disease', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('NRF2', 'Gene', (39, 43))	('NRF2', 'Gene', '4780', (234, 238))	('patients', 'Species', '9606', (103, 111))
6276	32992842	In addition, nuclear NRF2 levels significantly correlated with both the proliferation index and defective DNA mismatch repair (MMR) status but not with other studied clinical factors (Supplementary Figure S1C).	('NRF2', 'Gene', (21, 25))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('proliferation index', 'CPA', (72, 91))	('defective', 'Var', (96, 105))	('correlated', 'Reg', (47, 57))	('MMR', 'biological_process', 'GO:0006298', ('127', '130'))	('mismatch repair', 'biological_process', 'GO:0006298', ('110', '125'))	('NRF2', 'Gene', '4780', (21, 25))
6280	32992842	This motif is one of the two KEAP1-binding motifs within NRF2, and thus, its deletion disrupts the functional interaction between NRF2 and KEAP1.	('KEAP1', 'Gene', (139, 144))	('NRF2', 'Gene', '4780', (57, 61))	('NRF2', 'Gene', '4780', (130, 134))	('deletion', 'Var', (77, 85))	('KEAP1', 'Gene', '9817', (139, 144))	('KEAP1', 'Gene', '9817', (29, 34))	('disrupts', 'NegReg', (86, 94))	('functional interaction', 'MPA', (99, 121))	('binding', 'molecular_function', 'GO:0005488', ('35', '42'))	('NRF2', 'Gene', (57, 61))	('NRF2', 'Gene', (130, 134))	('KEAP1', 'Gene', (29, 34))
6282	32992842	However, most of the cell clones in which the DNA is repaired in-frame will result in NRF2-GOF clones (as described in) due to a mutation or deletion of the KEAP1-binding sequence.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('KEAP1', 'Gene', (157, 162))	('deletion', 'Var', (141, 149))	('NRF2', 'Gene', '4780', (86, 90))	('mutation', 'Var', (129, 137))	('clones', 'Var', (95, 101))	('NRF2', 'Gene', (86, 90))	('binding', 'molecular_function', 'GO:0005488', ('163', '170'))	('result', 'Reg', (76, 82))	('KEAP1', 'Gene', '9817', (157, 162))
6283	32992842	These gain-of-function (GOF) deletions would functionally resemble some of the NRF2 mutations found in tumours.	('tumours', 'Disease', 'MESH:D009369', (103, 110))	('tumours', 'Disease', (103, 110))	('NRF2', 'Gene', (79, 83))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (84, 93))	('gain-of-function', 'PosReg', (6, 22))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('NRF2', 'Gene', '4780', (79, 83))	('deletions', 'Var', (29, 38))
6291	32992842	Altogether, using the CRISPR/Cas9 system, we generated stable DLD1 cells harbouring the constitutive activation of NRF2 by truncating one of the domains required for KEAP1 binding.	('binding', 'Interaction', (172, 179))	('KEAP1', 'Gene', '9817', (166, 171))	('NRF2', 'Gene', '4780', (115, 119))	('activation', 'PosReg', (101, 111))	('binding', 'molecular_function', 'GO:0005488', ('172', '179'))	('domains', 'MPA', (145, 152))	('truncating', 'Var', (123, 133))	('KEAP1', 'Gene', (166, 171))	('NRF2', 'Gene', (115, 119))	('Cas', 'cellular_component', 'GO:0005650', ('29', '32'))
6298	32992842	This analysis identified the Aurora kinase inhibitor AT9283 as the top candidate with selectivity against NRF2-GOF DLD1 cells (Figure 3A,B and Supplementary Figure S3A,B).	('AT9283', 'Chemical', 'MESH:C535237', (53, 59))	('NRF2', 'Gene', '4780', (106, 110))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('36', '52'))	('AT9283', 'Var', (53, 59))	('NRF2', 'Gene', (106, 110))
6299	32992842	AT9283 is a synthetic small heterocyclic molecule that potently inhibits several kinases, including Aurora A (3 nM), Aurora B (3 nM), JAK2 (1.2 nM), JAK3 (1.1 nM) and Abl (4.0 nM, T315I).	('JAK3', 'Gene', (149, 153))	('Aurora A', 'Gene', '6790', (100, 108))	('JAK', 'molecular_function', 'GO:0004713', ('149', '152'))	('JAK', 'molecular_function', 'GO:0004713', ('134', '137'))	('AT9283', 'Var', (0, 6))	('JAK2', 'Gene', '3717', (134, 138))	('kinases', 'Pathway', (81, 88))	('JAK3', 'Gene', '3718', (149, 153))	('Abl', 'Gene', (167, 170))	('Aurora B', 'Gene', '9212', (117, 125))	('JAK2', 'Gene', (134, 138))	('Aurora A', 'Gene', (100, 108))	('Aurora B', 'Gene', (117, 125))	('T315I', 'Mutation', 'rs121913459', (180, 185))	('Abl', 'Gene', '25', (167, 170))	('inhibits', 'NegReg', (64, 72))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))
6302	32992842	The drug screen also included other known Aurora kinase inhibitors (TAK 901, ENMD 2076, AZD A552-HQPA and MK-8745) that, although they did not pass the set threshold, displayed a selective trend against NRF2-GOF cells.	('NRF2', 'Gene', (203, 207))	('AZD A552-HQPA', 'Var', (88, 101))	('Aurora kinase', 'Enzyme', (42, 55))	('MK-8745', 'Chemical', 'MESH:C574019', (106, 113))	('AZD A552', 'Chemical', '-', (88, 96))	('NRF2', 'Gene', '4780', (203, 207))
6303	32992842	Altogether, these analyses suggest that AT9283 selectively kill DLD1 cells harbouring NRF2 hyperactivation through the inhibition of Aurora kinases.	('AT9283', 'Var', (40, 46))	('NRF2', 'Gene', '4780', (86, 90))	('NRF2', 'Gene', (86, 90))	('inhibition', 'NegReg', (119, 129))	('hyperactivation', 'PosReg', (91, 106))	('Aurora kinases', 'Enzyme', (133, 147))	('AT9283', 'Chemical', 'MESH:C535237', (40, 46))
6304	32992842	AT9283 showed antimyeloma, antilymphoma, antileukaemia and anticolorectal cancer activity in preclinical studies, and its safety and efficacy against myeloma, lymphoma and leukaemia has been tested in various Phase I and II clinical trials.	('leukaemia', 'Disease', (45, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('lymphoma', 'Phenotype', 'HP:0002665', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('antileukaemia', 'Disease', (41, 54))	('antileukaemia', 'Disease', 'None', (41, 54))	('AT9283', 'Var', (0, 6))	('myeloma', 'Disease', 'MESH:D009101', (18, 25))	('colorectal cancer', 'Disease', (63, 80))	('lymphoma', 'Phenotype', 'HP:0002665', (31, 39))	('myeloma', 'Disease', 'MESH:D009101', (150, 157))	('leukaemia', 'Disease', 'MESH:D007938', (172, 181))	('leukaemia', 'Disease', 'MESH:D007938', (45, 54))	('lymphoma', 'Disease', (159, 167))	('lymphoma', 'Disease', 'MESH:D008223', (159, 167))	('myeloma', 'Disease', (18, 25))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('lymphoma', 'Disease', (31, 39))	('myeloma', 'Disease', (150, 157))	('lymphoma', 'Disease', 'MESH:D008223', (31, 39))	('leukaemia', 'Disease', (172, 181))
6306	32992842	To validate the top hit from the screen, we tested the effect of AT9283 on the viability of NRF2-WT and NRF2-GOF DLD1 cells after three days, using the Alamar blue assay as the readout (Figure 4A).	('AT9283', 'Chemical', 'MESH:C535237', (65, 71))	('NRF2', 'Gene', (104, 108))	('NRF2', 'Gene', '4780', (92, 96))	('tested', 'Reg', (44, 50))	('AT9283', 'Var', (65, 71))	('NRF2', 'Gene', (92, 96))	('NRF2', 'Gene', '4780', (104, 108))	('Alamar blue', 'Chemical', 'MESH:C005843', (152, 163))
6307	32992842	This assay confirmed the increased (by ~10-fold) sensitivity of the NRF2-GOF compared to NRF2-WT cells: AT9283 had a half maximal inhibitory concentration (IC50) of 28 nM in NRF2-GOF cells versus an IC50 of 320 nM in NRF2-WT cells.	('AT9283', 'Chemical', 'MESH:C535237', (104, 110))	('NRF2', 'Gene', (217, 221))	('NRF2', 'Gene', (89, 93))	('AT9283', 'Var', (104, 110))	('NRF2', 'Gene', '4780', (68, 72))	('NRF2', 'Gene', '4780', (174, 178))	('NRF2', 'Gene', '4780', (217, 221))	('NRF2', 'Gene', '4780', (89, 93))	('NRF2', 'Gene', (68, 72))	('NRF2', 'Gene', (174, 178))
6309	32992842	This analysis showed that AT9283 successfully "discriminates" between cell lines based on their NRF2 activity, with cells with high levels of NRF2 activity (GOF) having an increased sensitivity to AT9283.	('NRF2', 'Gene', (96, 100))	('NRF2', 'Gene', (142, 146))	('activity', 'MPA', (101, 109))	('AT9283', 'Chemical', 'MESH:C535237', (26, 32))	('AT9283', 'Chemical', 'MESH:C535237', (197, 203))	('AT9283', 'Var', (26, 32))	('NRF2', 'Gene', '4780', (96, 100))	('NRF2', 'Gene', '4780', (142, 146))
6313	32992842	By contrast, HB229 is a nonelectrophilic small molecule that disrupts the KEAP1-NRF2 protein complex.	('HB229', 'CellLine', 'CVCL:3694', (13, 18))	('NRF2', 'Gene', '4780', (80, 84))	('disrupts', 'NegReg', (61, 69))	('NRF2', 'Gene', (80, 84))	('protein complex', 'cellular_component', 'GO:0032991', ('85', '100'))	('HB229', 'Var', (13, 18))	('KEAP1', 'Gene', '9817', (74, 79))	('KEAP1', 'Gene', (74, 79))
6315	32992842	Critically, the effect on cell viability was completely dependent on AT9283 acting together with the NRF2 activator, as, at these concentrations, neither AT9283 (Figure 4A,B) nor any of the NRF2 activators by themselves (Figure 4B, lower panel) affected the viability of the cells.	('AT9283', 'Var', (154, 160))	('Critically', 'Disease', (0, 10))	('NRF2', 'Gene', '4780', (101, 105))	('AT9283', 'Chemical', 'MESH:C535237', (69, 75))	('NRF2', 'Gene', '4780', (190, 194))	('NRF2', 'Gene', (101, 105))	('NRF2', 'Gene', (190, 194))	('AT9283', 'Chemical', 'MESH:C535237', (154, 160))	('Critically', 'Disease', 'MESH:D016638', (0, 10))
6317	32992842	Nevertheless, these results demonstrate that, similar to the genetic, the pharmacological activation of NRF2 also sensitises DLD1 cells towards AT9283-mediated killing and further suggests that AT9283 could be used in combination with an NRF2 activator to sensitise cells with normal NRF2 levels.	('activation', 'PosReg', (90, 100))	('NRF2', 'Gene', (104, 108))	('NRF2', 'Gene', '4780', (238, 242))	('AT9283', 'Chemical', 'MESH:C535237', (144, 150))	('AT9283', 'Chemical', 'MESH:C535237', (194, 200))	('NRF2', 'Gene', '4780', (284, 288))	('NRF2', 'Gene', (238, 242))	('sensitises', 'Reg', (114, 124))	('NRF2', 'Gene', (284, 288))	('AT9283', 'Var', (194, 200))	('NRF2', 'Gene', '4780', (104, 108))
6324	32992842	and Figure S4: NRF2-WT and GOF DLD1 cells were exposed to increasing concentrations of AT9283 as indicated.	('NRF2', 'Gene', (15, 19))	('AT9283', 'Var', (87, 93))	('AT9283', 'Chemical', 'MESH:C535237', (87, 93))	('NRF2', 'Gene', '4780', (15, 19))
6326	32992842	This work was supported by the Medical Research Institute of the University of Dundee, Cancer Research UK (C52419/A22869 and C20953/A18644) (L.d.l.V., A.J.	('C20953/A18644', 'Var', (125, 138))	('Cancer', 'Disease', 'MESH:D009369', (87, 93))	('C52419/A22869', 'Var', (107, 120))	('Cancer', 'Disease', (87, 93))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))
6420	31597922	Following activation in the cell by aquation, cisplatin forms monoadducts with guanine bases in DNA which react with adjacent purine bases to form intrastrand crosslinks, namely about 65% cis-Pt(NH3)2-d(GpG), 25% cis-Pt(NH3)2-d(ApG) 1,2-intrastrand adducts and 5-10% 1,3-intrastrand adducts.	('cis-Pt', 'Var', (188, 194))	('cis-Pt', 'Var', (213, 219))	('purine', 'Chemical', 'MESH:D011687', (126, 132))	('guanine', 'Chemical', 'MESH:D006147', (79, 86))	('cis-Pt(NH3)2-d', 'Chemical', 'MESH:C045230', (188, 202))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('cis-Pt(NH3)2-d', 'Chemical', 'MESH:C045230', (213, 227))
6431	31597922	Here, we report on the genomic differences between the parental RT-112, J82, 253J, and T-24 cell lines and their cisplatin-resistant LTT variants, as determined by whole exome sequencing (WES), array comparative genomic hybridization (aCGH) and karyotyping.	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('variants', 'Var', (137, 145))	('LTT', 'Gene', (133, 136))
6432	31597922	First, to which extent does cisplatin induce point mutations in bladder cancer cell lines?	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('bladder cancer', 'Phenotype', 'HP:0009725', (64, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('point mutations', 'Var', (45, 60))	('bladder cancer', 'Disease', (64, 78))	('bladder cancer', 'Disease', 'MESH:D001749', (64, 78))
6435	31597922	However, all parental cell lines contain mutations in genes significantly mutated in urothelial carcinoma (TCGA-SMG, where TCGA stands for The Cancer Genome Atlas), most of which have been documented in databases (see sheets TCGA SMG in Tables S1, S3, S5 and S7).	('mutations', 'Var', (41, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('TCGA-SMG', 'Chemical', 'MESH:C047031', (107, 115))	('S5', 'Chemical', 'MESH:D013455', (252, 254))	('urothelial carcinoma', 'Disease', (85, 105))	('Cancer', 'Phenotype', 'HP:0002664', (143, 149))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (85, 105))
6436	31597922	Compared to their parental lines, the LTTs acquired various additional mutations in TCGA-SMG, which are listed in Tables S9-S12.	('TCGA-SMG', 'Gene', (84, 92))	('S12', 'Gene', (124, 127))	('TCGA-SMG', 'Chemical', 'MESH:C047031', (84, 92))	('mutations', 'Var', (71, 80))	('S12', 'Gene', '6268', (124, 127))
6439	31597922	The mutation profiles in the three evaluable cell lines revealed an almost exact correspondence to the cisplatin-specific signature recently published by Boot et al., namely frequent C > A transversions preferentially in a ACC or GCC context, more frequent C > T transitions preferentially in CCC or CCT and less commonly in CCA or CCT contexts, with rarer transversions of C > G, predominantly in a GCC context and T > A, with a preceding C and any base following (Fig.	('C > T transitions', 'Var', (257, 274))	('CCC', 'cellular_component', 'GO:0030896', ('293', '296'))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('CCT', 'Gene', (332, 335))	('CCT', 'Gene', '907', (300, 303))	('transitions', 'Var', (263, 274))	('transversions', 'Var', (189, 202))	('CCT', 'Gene', '907', (332, 335))	('CCT', 'Gene', (300, 303))	('C >', 'Var', (183, 186))
6441	31597922	Among these genes, mutations likely to have a functional impact (nonsynonymous, stop-gain, or frameshift) were found in NRXN2, encoding the cell adhesion protein neurexin 2, HECW1, encoding the eponymous ubiquitin ligase (also known as NEDL1), FAM205A, encoding a poorly studied transmembrane protein, and ATP7B, a copper transporting ATPase.	('NEDL1', 'Gene', '23072', (236, 241))	('NEDL1', 'Gene', (236, 241))	('transmembrane', 'cellular_component', 'GO:0016021', ('279', '292'))	('NRXN2', 'Gene', (120, 125))	('NRXN2', 'Gene', '9379', (120, 125))	('ATP7B', 'Gene', (306, 311))	('transmembrane', 'cellular_component', 'GO:0044214', ('279', '292'))	('FAM205A', 'Gene', (244, 251))	('copper', 'Chemical', 'MESH:D003300', (315, 321))	('HECW1', 'Gene', '23072', (174, 179))	('protein', 'cellular_component', 'GO:0003675', ('293', '300'))	('cell adhesion', 'biological_process', 'GO:0007155', ('140', '153'))	('neurexin 2', 'Gene', (162, 172))	('FAM205A', 'Gene', '259308', (244, 251))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('ATP7B', 'Gene', '540', (306, 311))	('HECW1', 'Gene', (174, 179))	('mutations', 'Var', (19, 28))	('neurexin 2', 'Gene', '9379', (162, 172))	('ubiquitin', 'molecular_function', 'GO:0031386', ('204', '213'))
6442	31597922	This distribution is best explained by the assumption that in each LTT line some mutations occurred in a cell clone expanding during the initial selection process for cisplatin resistance, but others were acquired gradually during further expansion.	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('occurred', 'Reg', (91, 99))	('mutations', 'Var', (81, 90))
6443	31597922	Most interestingly, all LTTs contained missense mutations in ATP7B, and RT-112-LTT additionally contained mutations in ATP7A (Tables S13 and S14).	('ATP7A', 'Gene', '538', (119, 124))	('ATP7B', 'Gene', '540', (61, 66))	('contained', 'Reg', (96, 105))	('ATP7B', 'Gene', (61, 66))	('ATP7A', 'Gene', (119, 124))	('mutations', 'Var', (106, 115))	('S14', 'Gene', (141, 144))	('S14', 'Gene', '5714', (141, 144))	('missense mutations', 'Var', (39, 57))	('contained', 'Reg', (29, 38))
6445	31597922	The missense mutations in ATP7B are distributed throughout the protein at allelic frequencies of 0.45-1 (Fig.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('ATP7B', 'Gene', '540', (26, 31))	('ATP7B', 'Gene', (26, 31))	('missense mutations', 'Var', (4, 22))
6446	31597922	Similar to the mutations found in the TCGA data, mutations in ATP7B were mostly observed in the heavy metal-associated domains (HMA, Fig.	('observed', 'Reg', (80, 88))	('ATP7B', 'Gene', (62, 67))	('mutations', 'Var', (49, 58))	('ATP7B', 'Gene', '540', (62, 67))
6451	31597922	Most of the mutations found in NRXN2 were observed in the first three Laminin domains (Fig.	('mutations', 'Var', (12, 21))	('observed', 'Reg', (42, 50))	('NRXN2', 'Gene', '9379', (31, 36))	('NRXN2', 'Gene', (31, 36))
6457	31597922	The HECW1 mutations in the LTTs were found at allelic frequencies of 0.16-0.59 and, according to the TCGA data, in a commonly mutated region (Fig.	('mutations', 'Var', (10, 19))	('HECW1', 'Gene', '23072', (4, 9))	('HECW1', 'Gene', (4, 9))
6459	31597922	To exemplarily explore the impact of the mutations in ATP7B on cisplatin sensitivity, we used an siRNA mediated knockdown approach.	('mutations', 'Var', (41, 50))	('ATP7B', 'Gene', '540', (54, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('ATP7B', 'Gene', (54, 59))
6464	31597922	We therefore searched specifically for mutations in genes previously implicated in mechanisms of cisplatin resistance (abbreviated CRG here) as well as for TCGA-SMG.	('TCGA-SMG', 'Chemical', 'MESH:C047031', (156, 164))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('mutations', 'Var', (39, 48))	('CRG', 'Gene', (131, 134))	('CRG', 'Gene', '55636', (131, 134))	('cisplatin', 'MPA', (97, 106))
6465	31597922	Among the CRG, a KEAP1 mutation previously described in RT-112-LTT is very likely to contribute to NRF2 activation in this cell line, as KEAP1 negatively regulates NRF2.	('NRF2', 'Gene', (99, 103))	('NRF2', 'Gene', (164, 168))	('activation', 'PosReg', (104, 114))	('KEAP1', 'Gene', '9817', (17, 22))	('CRG', 'Gene', (10, 13))	('CRG', 'Gene', '55636', (10, 13))	('mutation', 'Var', (23, 31))	('KEAP1', 'Gene', (137, 142))	('regulates', 'Reg', (154, 163))	('KEAP1', 'Gene', (17, 22))	('NRF2', 'Gene', '4780', (99, 103))	('NRF2', 'Gene', '4780', (164, 168))	('KEAP1', 'Gene', '9817', (137, 142))
6466	31597922	A mutation in BACH1, albeit relatively conservative (A678G) might influence the same pathway.	('BACH1', 'Gene', (14, 19))	('mutation', 'Var', (2, 10))	('A678G', 'Var', (53, 58))	('A678G', 'Mutation', 'c.678A>G', (53, 58))	('BACH1', 'Gene', '571', (14, 19))	('influence', 'Reg', (66, 75))
6467	31597922	Mutations in three genes, CHUK (G289R), NFKB1 (nonframeshift substitution) and SIRT6 (G22A) might alter NFkappaB survival signaling.	('NFKB1', 'Gene', (40, 45))	('alter', 'Reg', (98, 103))	('CHUK', 'Gene', (26, 30))	('G289R', 'Mutation', 'p.G289R', (32, 37))	('G289R', 'Var', (32, 37))	('G22A', 'Mutation', 'c.22G>A', (86, 90))	('SIRT6', 'Gene', '51548', (79, 84))	('NFkappaB survival signaling', 'MPA', (104, 131))	('CHUK', 'molecular_function', 'GO:0008384', ('26', '30'))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('SIRT6', 'Gene', (79, 84))	('CHUK', 'Gene', '1147', (26, 30))	('NFKB1', 'Gene', '4790', (40, 45))
6469	31597922	Three LTT lines acquired mutations in HDAC6, a histone deacetylase involved in cell stress responses.	('HDAC6', 'Gene', (38, 43))	('mutations', 'Var', (25, 34))	('HDAC6', 'Gene', '10013', (38, 43))
6470	31597922	Most interestingly, all LTTs contained missense mutations in ATP7B, and RT-112-LTT additionally contained mutations in ATP7A, which encode copper transporters thought to support cisplatin extrusion (Table S13).	('ATP7B', 'Gene', '540', (61, 66))	('copper', 'Chemical', 'MESH:D003300', (139, 145))	('contained', 'Reg', (96, 105))	('ATP7B', 'Gene', (61, 66))	('ATP7A', 'Gene', (119, 124))	('mutations', 'Var', (106, 115))	('ATP7A', 'Gene', '538', (119, 124))	('missense mutations', 'Var', (39, 57))	('cisplatin', 'Chemical', 'MESH:D002945', (178, 187))
6471	31597922	Among the TCGA-SMG, RT-112-LTT gained likely functionally relevant mutations in TP53 (R198H), FOXA1 (A83T in the forkhead N-domain) at high allele frequency, ERCC2 (Y16N in the helicase domain), ARID1A (G406R and R1566K) and STAG2 (G667T) at presumable heterozygote frequency.	('R198H', 'Var', (86, 91))	('ARID1A', 'Gene', '8289', (195, 201))	('R1566K', 'Mutation', 'p.R1566K', (213, 219))	('FOXA1', 'Gene', '3169', (94, 99))	('TCGA-SMG', 'Chemical', 'MESH:C047031', (10, 18))	('G667T', 'Mutation', 'c.667G>T', (232, 237))	('R1566K', 'Var', (213, 219))	('TP53', 'Gene', '7157', (80, 84))	('FOXA1', 'Gene', (94, 99))	('ERCC2', 'Gene', (158, 163))	('STAG2', 'Gene', '10735', (225, 230))	('Y16N', 'Mutation', 'p.Y16N', (165, 169))	('R198H', 'Mutation', 'p.R198H', (86, 91))	('G406R', 'Mutation', 'p.G406R', (203, 208))	('ERCC2', 'Gene', '2068', (158, 163))	('G406R', 'Var', (203, 208))	('STAG2', 'Gene', (225, 230))	('ARID1A', 'Gene', (195, 201))	('G667T', 'Var', (232, 237))	('TP53', 'Gene', (80, 84))	('A83T', 'Mutation', 'c.83A>T', (101, 105))
6472	31597922	Interestingly, 253J-LTT acquired two mutations in ARID1A (R1566K and P1567A) as well, albeit at moderate allelic frequency.	('R1566K', 'Mutation', 'p.R1566K', (58, 64))	('R1566K', 'Var', (58, 64))	('P1567A', 'Chemical', 'MESH:C471426', (69, 75))	('P1567A', 'Var', (69, 75))	('ARID1A', 'Gene', '8289', (50, 56))	('ARID1A', 'Gene', (50, 56))
6473	31597922	All TCGA-SMG mutations in T-24-LTT occurred at relatively low variant allele frequencies and none were detected in J82-LTT (Table S13).	('mutations', 'Var', (13, 22))	('TCGA-SMG', 'Gene', (4, 12))	('T-24-LTT', 'Gene', (26, 34))	('TCGA-SMG', 'Chemical', 'MESH:C047031', (4, 12))
6476	31597922	6, a normally karyotypically relatively stable cell line with a near diploid chromosome number as revealed by conventional chromosome banding analysis (46,XX,add(1)(p34),del(3)(p12p21),i(4)(p10),i(8)(q10),add(11)(p15),add(17)(p12),del(18)(q21),i(21)(q10) in our variant (cf.).	('i(8)(q10', 'Var', (195, 203))	('del(18)(q21', 'Var', (231, 242))	('p12', 'Gene', '56655', (177, 180))	('46', 'Var', (152, 154))	('p12', 'Gene', (226, 229))	('p34', 'Gene', (165, 168))	('p10', 'Gene', (190, 193))	('p15', 'Gene', (213, 216))	('p15', 'Gene', '1030', (213, 216))	('chromosome', 'cellular_component', 'GO:0005694', ('77', '87'))	('p10', 'Gene', '6281', (190, 193))	('i(21)(q10', 'Var', (244, 253))	('p12', 'Gene', '56655', (226, 229))	('p12', 'Gene', (177, 180))	('p34', 'Gene', '340152', (165, 168))	('chromosome', 'cellular_component', 'GO:0005694', ('123', '133'))
6477	31597922	S5a,b; 68.2 +- 2.4 vs. 79.9 +- 4.0, p < 0.0001) and decreased on average in J82-LTT vs. J82 (Fig.	('J82-LTT', 'Var', (76, 83))	('decreased', 'NegReg', (52, 61))	('S5', 'Chemical', 'MESH:D013455', (0, 2))
6483	31597922	The KEAP1 copy number in the 19p13.3-q13.33 region appeared diminished in all cell lines, including RT-112 (Fig.	('diminished', 'NegReg', (60, 70))	('copy number', 'Var', (10, 21))	('KEAP1', 'Gene', (4, 9))	('KEAP1', 'Gene', '9817', (4, 9))
6484	31597922	The majority of the changes seen in the late passage LTTs were already established at the first available time point, but some changes accrued during further passages (Figs 8b, S6a-d and S7a-d, Tables S17 and S18).	('S17', 'Gene', '6218', (201, 204))	('S7a-d', 'Var', (187, 192))	('S6a-d', 'Var', (177, 182))	('S18', 'Gene', (209, 212))	('S17', 'Gene', (201, 204))	('S18', 'Gene', '6222', (209, 212))
6485	31597922	In four independent urothelial carcinoma (UC) cell lines selected for resistance to high concentrations of cisplatin, we observed a large number of mutations with distinctive characteristics by whole exome sequencing and pronounced chromosomal instability by aCGH.	('mutations', 'Var', (148, 157))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (20, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('chromosomal instability', 'MPA', (232, 255))	('urothelial carcinoma', 'Disease', (20, 40))	('UC', 'Disease', 'MESH:D014523', (42, 44))	('chromosomal instability', 'Phenotype', 'HP:0040012', (232, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
6495	31597922	The newly defined cisplatin mutational signature resembles the cisplatin mutation profile previously described in C. elegans, S. cerevisiae, and DT-40 chicken cells in its predominance of C > A and C > T changes, but the profiles differ in their base contexts, suggesting differences in cisplatin mutagenicity between species.	('S. cerevisiae', 'Species', '4932', (126, 139))	('cisplatin', 'Chemical', 'MESH:D002945', (18, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('chicken', 'Species', '9031', (151, 158))	('C > T changes', 'Var', (198, 211))	('C. elegans', 'Species', '6239', (114, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (287, 296))	('C > A', 'Var', (188, 193))
6496	31597922	Of note, in addition to the distinctive three-base contexts, we observed further characteristics of cisplatin mutagenesis in the LTTs, such as double-base replacements and single base deletions.	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('mutagenesis', 'MPA', (110, 121))	('mutagenesis', 'biological_process', 'GO:0006280', ('110', '121'))	('double-base replacements', 'Var', (143, 167))	('single base deletions', 'Var', (172, 193))	('cisplatin', 'MPA', (100, 109))
6498	31597922	Whereas the spectrum of cisplatin-induced point mutations observed in our study in urothelial carcinoma cell lines is very similar to that observed in UC tissues following neoadjuvant chemotherapy in vivo, the relative number of mutations differs strongly, as Liu et al.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (83, 103))	('point mutations', 'Var', (42, 57))	('UC', 'Disease', 'MESH:D014523', (151, 153))	('urothelial carcinoma', 'Disease', (83, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))
6501	31597922	in patient tissues, we did not observe APOBEC-related mutational signatures for the new variants in the LTTs, even though UC cell lines express APOBEC3B.	('UC cell lines', 'Disease', 'MESH:D002292', (122, 135))	('APOBEC3B', 'Gene', (144, 152))	('patient', 'Species', '9606', (3, 10))	('APOBEC', 'cellular_component', 'GO:0030895', ('144', '150'))	('APOBEC3B', 'Gene', '9582', (144, 152))	('LTTs', 'Gene', (104, 108))	('variants', 'Var', (88, 96))	('UC cell lines', 'Disease', (122, 135))	('APOBEC', 'cellular_component', 'GO:0030895', ('39', '45'))
6507	31597922	Most UC cell lines, however, are deficient in DNA damage checkpoint signaling due to inactivation of p53 and RB1 function, a defining property of almost all urothelial cancers, including those investigated by Liu et al..	('RB1', 'Gene', '5925', (109, 112))	('function', 'MPA', (113, 121))	('UC cell lines', 'Disease', 'MESH:D002292', (5, 18))	('inactivation', 'Var', (85, 97))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))	('p53', 'Gene', (101, 104))	('UC cell lines', 'Disease', (5, 18))	('p53', 'Gene', '7157', (101, 104))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('RB1', 'Gene', (109, 112))	('urothelial cancers', 'Disease', (157, 175))	('urothelial cancers', 'Disease', 'MESH:D014523', (157, 175))	('deficient', 'NegReg', (33, 42))	('DNA damage checkpoint', 'biological_process', 'GO:0000077', ('46', '67'))	('DNA damage checkpoint signaling', 'MPA', (46, 77))
6516	31597922	In such tumors, point mutations are more easily detected than copy number changes by current deep sequencing techniques.	('point mutations', 'Var', (16, 31))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))
6517	31597922	In addition to the previously reported KEAP1 mutation promoting NRF2 activation in RT-112-LTT, we detected mutations or copy number changes in genes related to NF-kappaB-signaling, DNA repair and cell survival regulation, among others.	('DNA', 'cellular_component', 'GO:0005574', ('181', '184'))	('KEAP1', 'Gene', (39, 44))	('mutations', 'Var', (107, 116))	('DNA repair', 'biological_process', 'GO:0006281', ('181', '191'))	('signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('NRF2', 'Gene', '4780', (64, 68))	('promoting', 'PosReg', (54, 63))	('KEAP1', 'Gene', '9817', (39, 44))	('regulation', 'biological_process', 'GO:0065007', ('210', '220'))	('mutation', 'Var', (45, 53))	('NRF2', 'Gene', (64, 68))	('copy number changes', 'Var', (120, 139))	('activation', 'PosReg', (69, 79))
6518	31597922	In addition, several point mutations affected large chromatin regulators like ARID1A, which are known to be relevant in UC in general and are important for transcriptional regulation of cell survival.	('affected', 'Reg', (37, 45))	('ARID1A', 'Gene', '8289', (78, 84))	('ARID1A', 'Gene', (78, 84))	('regulation', 'biological_process', 'GO:0065007', ('172', '182'))	('UC', 'Disease', 'MESH:D014523', (120, 122))	('point mutations', 'Var', (21, 36))	('chromatin', 'cellular_component', 'GO:0000785', ('52', '61'))
6519	31597922	Cases in point are the frequent missense mutations observed in the ATP7A and ATP7B metal ion transporters.	('missense mutations', 'Var', (32, 50))	('ATP7B', 'Gene', '540', (77, 82))	('ATP7B', 'Gene', (77, 82))	('ATP7A', 'Gene', (67, 72))	('ATP7A', 'Gene', '538', (67, 72))
6521	31597922	Specifically, mutations in ATP7B have been observed in patients with metastatic bladder cancer and may be predictive for the response to cisplatin-based chemotherapy.	('bladder cancer', 'Disease', 'MESH:D001749', (80, 94))	('bladder cancer', 'Disease', (80, 94))	('response to cisplatin', 'biological_process', 'GO:0072718', ('125', '146'))	('observed', 'Reg', (43, 51))	('predictive', 'Reg', (106, 116))	('bladder cancer', 'Phenotype', 'HP:0009725', (80, 94))	('ATP7B', 'Gene', '540', (27, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('patients', 'Species', '9606', (55, 63))	('mutations', 'Var', (14, 23))	('ATP7B', 'Gene', (27, 32))
6522	31597922	In the LTTs, expression of ATP7A and ATP7B is at most moderately changed, but the present findings raise the possibility that missense mutations, especially in ATP7B, might contribute to cisplatin resistance.	('contribute', 'Reg', (173, 183))	('ATP7A', 'Gene', (27, 32))	('ATP7A', 'Gene', '538', (27, 32))	('ATP7B', 'Gene', '540', (160, 165))	('missense mutations', 'Var', (126, 144))	('ATP7B', 'Gene', (37, 42))	('ATP7B', 'Gene', (160, 165))	('cisplatin resistance', 'MPA', (187, 207))	('cisplatin', 'Chemical', 'MESH:D002945', (187, 196))	('ATP7B', 'Gene', '540', (37, 42))
6523	31597922	These mutations are located within the HMA (heavy metal-associated) domains in the N-terminal metal-binding region where site-directed mutations have been demonstrated to influence cisplatin binding and ATPase activation.	('ATPase', 'Protein', (203, 209))	('binding', 'molecular_function', 'GO:0005488', ('191', '198'))	('mutations', 'Var', (135, 144))	('influence', 'Reg', (171, 180))	('activation', 'MPA', (210, 220))	('cisplatin', 'MPA', (181, 190))	('metal-binding', 'molecular_function', 'GO:0046872', ('94', '107'))	('binding', 'Interaction', (191, 198))	('cisplatin', 'Chemical', 'MESH:D002945', (181, 190))	('mutations', 'Var', (6, 15))
6524	31597922	Our data thus support the assumption that mutations in ATP7B may be a significant mechanism in the development of cisplatin resistance in UC.	('UC', 'Disease', 'MESH:D014523', (138, 140))	('ATP7B', 'Gene', (55, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('mechanism', 'Reg', (82, 91))	('cisplatin resistance', 'MPA', (114, 134))	('ATP7B', 'Gene', '540', (55, 60))	('mutations', 'Var', (42, 51))
6525	31597922	As a further support of their functional importance this idea, we observed that siRNA-mediated knockdown of ATP7B sensitized all four LTTs to cisplatin.	('ATP7B', 'Gene', (108, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('sensitized', 'Reg', (114, 124))	('knockdown', 'Var', (95, 104))	('ATP7B', 'Gene', '540', (108, 113))
6526	31597922	The precise effect of each missense mutation on cisplatin binding and extrusion would however need to be tested in appropriate models.	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('binding', 'Interaction', (58, 65))	('missense', 'Var', (27, 35))	('extrusion', 'MPA', (70, 79))	('binding', 'molecular_function', 'GO:0005488', ('58', '65'))
6527	31597922	In addition, the functional significance of mutations in HECW1 deserves further investigation.	('HECW1', 'Gene', (57, 62))	('mutations', 'Var', (44, 53))	('HECW1', 'Gene', '23072', (57, 62))
6532	31597922	In conclusion, our investigation demonstrates that the emergence of cisplatin-resistant UC cell lines in a continuous treatment model is accompanied by massive genomic changes, both point mutations and chromosomal alterations.	('chromosomal alterations', 'Var', (202, 225))	('UC cell lines', 'Disease', 'MESH:D002292', (88, 101))	('point mutations', 'Var', (182, 197))	('UC cell lines', 'Disease', (88, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
6552	31597922	2) Removal of improper oligo-nucleotides, flagged by the feature extraction software as having a too inhomogeneous distribution of pixel intensities throughout the spot representing the oligo (flags gIsFeatNonUnifOL = 1 or rIsFeatNonUnifOL = 1), or as being oversaturated (flags gIsSaturated = 1 or rIsSaturated = 1) or undersaturated or otherwise nonsensical (log-ratio set to zero).	('gIsFeatNonUnifOL = 1', 'Var', (199, 219))	('flags', 'Species', '34205', (273, 278))	('rIsFeatNonUnifOL = 1', 'Var', (223, 243))	('flags', 'Species', '34205', (193, 198))
6557	31597922	There are six classes of base substitution if all substitutions are referred to by the pyrimidine of the mutated base pair (C > A, C > G, C > T, T > A, T > C, and T > G).	('T > A', 'Var', (145, 150))	('T > G', 'Var', (163, 168))	('C > A', 'Var', (124, 129))	('T > C', 'Var', (152, 157))	('C > G', 'Var', (131, 136))	('pyrimidine', 'Chemical', 'MESH:C030986', (87, 97))	('C > T', 'Var', (138, 143))
6567	29515971	Using data from 10,355, primary tumor resection samples and 2,787 normal samples that we extracted from The Cancer Genome Atlas and Genotype-Tissue Expression project databases, we screened the variation of CYT across 32 different cancer types and 28 different normal tissue types.	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('Cancer Genome Atlas', 'Disease', (108, 127))	('tumor', 'Disease', (32, 37))	('screened', 'Reg', (181, 189))	('variation', 'Var', (194, 203))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (108, 127))	('CYT', 'Gene', (207, 210))
6596	29515971	Using the Genomic Data Commons (GDC) Data Portal (The Cancer Genome Atlas, TCGA program3) and the GTEx web portal (Genotype-Tissue Expression project4), we extracted data from a total of 10,355 tumor resection samples and 2,935 normal samples and screened the variation of CYT across these 32 different cancer types and 28 different normal solid tissue types.	('CYT', 'Gene', (273, 276))	('Cancer Genome Atlas', 'Disease', (54, 73))	('cancer', 'Disease', (303, 309))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('variation', 'Var', (260, 269))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (54, 73))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('screened', 'Reg', (247, 255))	('tumor', 'Disease', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
6613	29515971	GZMA was stained with an anti-GZMA antibody produced in rabbit (HPA054134, 1:200 dilution, Sigma-Aldrich) and PRF1 using two different antibodies produced in rabbit (either HPA037940, 1:29 dilution, or CAB002436, 1:10 dilution, Sigma-Aldrich).	('rabbit', 'Species', '9986', (56, 62))	('antibody', 'cellular_component', 'GO:0042571', ('35', '43'))	('antibody', 'cellular_component', 'GO:0019815', ('35', '43'))	('antibody', 'cellular_component', 'GO:0019814', ('35', '43'))	('CAB002436', 'Var', (202, 211))	('rabbit', 'Species', '9986', (158, 164))	('antibody', 'molecular_function', 'GO:0003823', ('35', '43'))	('GZMA', 'Gene', (30, 34))	('GZMA', 'Gene', (0, 4))	('GZMA', 'Gene', '3001', (30, 34))	('GZMA', 'Gene', '3001', (0, 4))
6630	29515971	Importantly, we show for the first time that DLBCL and testicular cancer also rank among the top cytolytic active tumors, with DLBCL exhibiting even higher cytolytic levels compared to KIRC (>100 TPM).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('testicular cancer', 'Phenotype', 'HP:0010788', (55, 72))	('testicular cancer', 'Disease', (55, 72))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('DLBCL', 'Disease', (45, 50))	('cytolytic levels', 'MPA', (156, 172))	('higher', 'PosReg', (149, 155))	('DLBCL', 'Var', (127, 132))	('testicular cancer', 'Disease', 'MESH:D013736', (55, 72))
6655	29515971	We next performed Kaplan-Meier survival analysis on 37 TCGA-datasets deriving from 25 different cancer types in order to estimate the risk of individual and/or simultaneous high (or low) PRF1 and GZMA expression on patient overall survival.	('high', 'Var', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('low', 'NegReg', (182, 185))	('GZMA', 'Gene', (196, 200))	('PRF1', 'Gene', (187, 191))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('GZMA', 'Gene', '3001', (196, 200))	('cancer', 'Disease', (96, 102))	('patient', 'Species', '9606', (215, 222))
6656	29515971	In TCGA-ACC, non-metastatic cutaneous melanoma ("m0" TCGA-SKCM), and bladder urothelial carcinoma (TCGA-BLCA but not the GSE32894 dataset), both individual and simultaneous high levels of PRF1 and GZMA were significantly associated with better prognosis.	('ACC', 'Phenotype', 'HP:0006744', (8, 11))	('non-metastatic cutaneous melanoma', 'Phenotype', 'HP:0012057', (13, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('bladder urothelial carcinoma', 'Disease', (69, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('high levels', 'Var', (173, 184))	('GZMA', 'Gene', (197, 201))	('GZMA', 'Gene', '3001', (197, 201))	('PRF1', 'Gene', (188, 192))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (69, 97))	('cutaneous melanoma', 'Disease', (28, 46))
6660	29515971	In TCGA-LIHC, only the individual high levels of PRF1 and GZMA were significantly associated with a positive effect on patient survival.	('GZMA', 'Gene', '3001', (58, 62))	('patient', 'Species', '9606', (119, 126))	('LIHC', 'Disease', (8, 12))	('PRF1', 'Gene', (49, 53))	('LIHC', 'Disease', 'None', (8, 12))	('high levels', 'Var', (34, 45))	('GZMA', 'Gene', (58, 62))
6661	29515971	A similar non-significant association of (individual or simultaneous) high GZMA and PRF1 expression with better effect on patient survival could also be observed in TCGA-MESO, ovarian cancer (GSE13876 and GSE49997), TCGA-STAD, TCGA-THCA, and TCGA-UCEC (Figure S1 in Supplementary Material).	('GZMA', 'Gene', '3001', (75, 79))	('patient', 'Species', '9606', (122, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('GSE49997', 'Var', (205, 213))	('TCGA-MESO', 'Disease', (165, 174))	('GSE13876', 'Var', (192, 200))	('TCGA-UCEC', 'Disease', (242, 251))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('GZMA', 'Gene', (75, 79))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('high', 'Var', (70, 74))	('TCGA-THCA', 'Disease', (227, 236))	('TCGA-STAD', 'Disease', (216, 225))	('ovarian cancer', 'Disease', (176, 190))	('PRF1', 'Gene', (84, 88))
6662	29515971	These data suggest that high CYT is widely associated with an improved prognosis among the above-mentioned cancer types.	('improved', 'PosReg', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('high CYT', 'Var', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
6663	29515971	On the contrary, across TCGA-LGG, BRCAs (GSE25066), and TCGA-THYM, both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both genes led to a significant shift toward positive effect (Figure 6B).	('BRCA', 'Gene', '672', (34, 38))	('GSE25066', 'Var', (41, 49))	('BRCA', 'Gene', (34, 38))	('GZMA', 'Gene', (115, 119))	('GZMA', 'Gene', '3001', (115, 119))	('PRF1', 'Gene', (124, 128))	('associated with', 'Reg', (148, 163))
6666	29515971	Analogous non-significant associations of (individual or simultaneous) high cytolytic levels with worse effect on patient survival were also observed in lung cancer (GSE30219, TCGA-LUAD, and TCGA-LUSC), TCGA-PAAD, TCGA-PRAD and GSE16560, and TCGA-READ (Figure S2 in Supplementary Material).	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('lung cancer', 'Disease', (153, 164))	('high cytolytic levels', 'MPA', (71, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('patient', 'Species', '9606', (114, 121))	('GSE30219', 'Var', (166, 174))	('PAAD', 'Phenotype', 'HP:0006725', (208, 212))
6668	29515971	Depending on the probe used, it seemed that a combination of high PRF1 and low GZMA levels yields a better patient outcome (GSE39582, TCGA-COAD, TCGA-COADREAD).	('COAD', 'Disease', (150, 154))	('low', 'NegReg', (75, 78))	('GZMA', 'Gene', '3001', (79, 83))	('PRF1', 'MPA', (66, 70))	('COAD', 'Disease', 'MESH:D029424', (139, 143))	('high', 'Var', (61, 65))	('COAD', 'Disease', 'MESH:D029424', (150, 154))	('COAD', 'Disease', (139, 143))	('patient', 'Species', '9606', (107, 114))	('GZMA', 'Gene', (79, 83))
6674	29515971	In DLBCL (GSE10846, and GSE32918), using various combinations of distinct molecular probes for the two cytolytic genes (PRF1, 214617_AT, 1553681_A_AT, or ILMN_1740633; GZMA, 205488_AT, or ILMN_1779324), we could not provide any significant association with patient survival.	('GSE32918', 'Var', (24, 32))	('GZMA', 'Gene', '3001', (168, 172))	('ILMN_1740633', 'Var', (154, 166))	('patient', 'Species', '9606', (257, 264))	('AT', 'Disease', 'None', (133, 135))	('AT', 'Disease', 'None', (147, 149))	('GSE10846', 'Var', (10, 18))	('PRF1', 'Var', (120, 124))	('AT', 'Disease', 'None', (181, 183))	('GZMA', 'Gene', (168, 172))
6675	29515971	A similar absence of significant associations was also detected in glioblastoma (GSE4271, GSE13041, and TCGA-GBM) and non-metastatic HNSCs.	('glioblastoma', 'Disease', (67, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('non-metastatic HNSCs', 'Disease', (118, 138))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('GSE13041', 'Var', (90, 98))	('GSE4271', 'Chemical', '-', (81, 88))	('GSE4271', 'Var', (81, 88))
6713	29515971	Among them, recurrent mutations in immune-related genes have been proposed, such as B2M, HLA-A, -B, and -C, and CASP8, as well as copy number aberrations in loci containing immunosuppressive factors, including the receptors PD-L1/2 and CTLA-4.	('B2M', 'Gene', (84, 87))	('CASP8', 'Gene', '841', (112, 117))	('B2M', 'Gene', '567', (84, 87))	('CTLA-4', 'Gene', '1493', (236, 242))	('copy number aberrations', 'Var', (130, 153))	('CTLA-4', 'Gene', (236, 242))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (89, 106))	('mutations', 'Var', (22, 31))	('PD-L1/2', 'Gene', '29126;80380', (224, 231))	('PD-L1/2', 'Gene', (224, 231))	('CASP8', 'Gene', (112, 117))
6718	29515971	Actually, recent clinical trials have demonstrated that blockage of this signaling can benefit patients with advanced melanoma, kidney, or non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (139, 165))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('non-small cell lung cancer', 'Disease', (139, 165))	('blockage', 'Var', (56, 64))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (139, 165))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (143, 165))	('kidney', 'Disease', (128, 134))
6726	29515971	Importantly, CTLA-4 blockade was reported to associate with bowel inflammation in melanoma patients, signifying that its signaling is crucial for the preservation of immune homeostasis in the gut.	('associate', 'Reg', (45, 54))	('patients', 'Species', '9606', (91, 99))	('signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('bowel inflammation', 'Phenotype', 'HP:0002037', (60, 78))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('CTLA-4', 'Gene', '1493', (13, 19))	('blockade', 'Var', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('bowel inflammation', 'Disease', 'MESH:D007249', (60, 78))	('inflammation', 'biological_process', 'GO:0006954', ('66', '78'))	('homeostasis', 'biological_process', 'GO:0042592', ('173', '184'))	('CTLA-4', 'Gene', (13, 19))	('bowel inflammation', 'Disease', (60, 78))
6732	29515971	Inhibition of both IDO and arginase can enhance intratumoral inflammation.	('IDO', 'Gene', '3620', (19, 22))	('inflammation', 'biological_process', 'GO:0006954', ('61', '73'))	('IDO', 'molecular_function', 'GO:0047719', ('19', '22'))	('IDO', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('enhance', 'PosReg', (40, 47))	('arginase', 'Protein', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('IDO', 'molecular_function', 'GO:0033754', ('19', '22'))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (53, 58))
6746	29515971	A very interesting improvement in the field was further made by Riaz et al., who showed that the mutation burden in melanoma patients decreases with successful anti-PD-1 blockade therapy, suggesting that the selection against mutant neoepitopes is a critical mechanism of action of this immunotherapy.	('Riaz', 'Gene', (64, 68))	('mutant', 'Var', (226, 232))	('mutation burden', 'MPA', (97, 112))	('PD-1', 'Gene', (165, 169))	('PD-1', 'Gene', '5133', (165, 169))	('Riaz', 'Gene', '23598', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('decreases', 'NegReg', (134, 143))	('patients', 'Species', '9606', (125, 133))
6750	29515971	Overall, it seems that CYT is part of an inflammatory environment in a premalignant state of certain tumor types, whereas, in others, oncogenic mutations, copy number aberrations, or viral infection can induce a tumor-promoting inflammatory microenvironment, within which complex interactions between different cell types regulate cancer development and metastasis.	('copy number aberrations', 'Var', (155, 178))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('induce', 'PosReg', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('viral infection', 'Disease', 'MESH:D001102', (183, 198))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('viral infection', 'biological_process', 'GO:0016032', ('183', '198'))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('viral infection', 'Disease', (183, 198))	('tumor', 'Disease', (212, 217))	('mutations', 'Var', (144, 153))
6757	29515971	In some tumor types (ACC, SKCM, BLCA, LIHC, MESO, OV, STAD, THCA, and UCEC), high CYT was associated with an improved outcome; whereas in others (LGG, BRCA, THYM, LUAD/LUSC, PAAD, PRAD, and READ) it is correlated with a worse outcome.	('BRCA', 'Gene', '672', (151, 155))	('THYM', 'Disease', (157, 161))	('LIHC', 'Disease', 'None', (38, 42))	('BRCA', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('MESO', 'Disease', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ACC', 'Phenotype', 'HP:0006744', (21, 24))	('PAAD', 'Phenotype', 'HP:0006725', (174, 178))	('PAAD', 'Disease', (174, 178))	('improved', 'PosReg', (109, 117))	('tumor', 'Disease', (8, 13))	('LUAD/LUSC', 'Disease', (163, 172))	('PRAD', 'Disease', (180, 184))	('LIHC', 'Disease', (38, 42))	('high CYT', 'Var', (77, 85))
6758	29515971	Among LGG, THYM, and BRCA, we showed that both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both cytolytic genes led to a significant shift toward a positive effect.	('GZMA', 'Gene', (90, 94))	('associated', 'Reg', (123, 133))	('BRCA', 'Gene', (21, 25))	('PRF1', 'Gene', (99, 103))	('high', 'Var', (75, 79))	('GZMA', 'Gene', '3001', (90, 94))	('BRCA', 'Gene', '672', (21, 25))
6799	28573130	The immunohistochemistry study revealed positivity to cytokeratin CK7, CK20, 34bE12 and CD138.	('CK7', 'Gene', '3855', (66, 69))	('CD138', 'Gene', '6382', (88, 93))	('CK20', 'Gene', (71, 75))	('CD138', 'Gene', (88, 93))	('CK20', 'Gene', '54474', (71, 75))	('CK7', 'Gene', (66, 69))	('34bE12', 'Var', (77, 83))
6810	28573130	Immunohistochemical profile of PVUC is characterized by positivity for CD138, a marker shared with myeloma cells.	('myeloma', 'Disease', (99, 106))	('positivity', 'Var', (56, 66))	('CD138', 'Gene', '6382', (71, 76))	('PVUC', 'Disease', (31, 35))	('myeloma', 'Disease', 'MESH:D009101', (99, 106))	('CD138', 'Gene', (71, 76))
6836	28167242	Epigenome-Wide DNA Methylation Profiling Identifies Differential Methylation Biomarkers in High-Grade Bladder Cancer1 Epigenetic changes, including CpG island hypermethylation, occur frequently in bladder cancer (BC) and may be exploited for BC detection and distinction between high-grade (HG) and low-grade (LG) disease.	('DNA Methylation', 'biological_process', 'GO:0006306', ('15', '30'))	('Methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('BC', 'Phenotype', 'HP:0009725', (242, 244))	('bladder cancer', 'Disease', 'MESH:D001749', (197, 211))	('bladder cancer', 'Disease', (197, 211))	('Epigenetic changes', 'Var', (118, 136))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('BC', 'Phenotype', 'HP:0009725', (213, 215))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('bladder cancer', 'Phenotype', 'HP:0009725', (197, 211))
6852	28167242	Among epigenetic mechanisms, DNA methylation is the best studied, and aberrant CpG island methylation has been shown to contribute to the development and progression of numerous cancer types including BC.	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('men', 'Species', '9606', (145, 148))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('BC', 'Phenotype', 'HP:0009725', (201, 203))	('DNA methylation', 'biological_process', 'GO:0006306', ('29', '44'))	('numerous cancer', 'Disease', (169, 184))	('contribute', 'Reg', (120, 130))	('aberrant', 'Var', (70, 78))	('methylation', 'biological_process', 'GO:0032259', ('90', '101'))	('numerous cancer', 'Disease', 'MESH:D009369', (169, 184))	('CpG', 'Gene', (79, 82))
6854	28167242	Therefore, identifying aberrant DNA methylation events that initiate and/or promote BC development can highlight biological markers for distinguishing LG from HG BC, improving diagnostic accuracy and treatment stratification.	('promote', 'PosReg', (76, 83))	('BC', 'Phenotype', 'HP:0009725', (162, 164))	('BC', 'Phenotype', 'HP:0009725', (84, 86))	('men', 'Species', '9606', (94, 97))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('men', 'Species', '9606', (205, 208))	('DNA methylation', 'biological_process', 'GO:0006306', ('32', '47'))	('aberrant', 'Var', (23, 31))
6863	28167242	Three regions (exon 7, 10, and 15) representing at least 99% of activating oncogenic FGFR3 mutations in BC were amplified by PCR.	('activating', 'PosReg', (64, 74))	('FGFR3', 'Gene', (85, 90))	('mutations', 'Var', (91, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('FGFR3', 'Gene', '2261', (85, 90))	('BC', 'Phenotype', 'HP:0009725', (104, 106))
6887	28167242	The top 32 genes, ranked by fold change, that were identified as significantly hyper- and hypomethylated in HG versus LG cancers are listed in Table 2.	('cancers', 'Disease', (121, 128))	('hypomethylated', 'Var', (90, 104))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('hyper-', 'PosReg', (79, 85))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
6891	28167242	Of the 32 DMGs, 19 showed hypermethylation and 13 hypomethylation in HG BC.	('DMGs', 'Chemical', '-', (10, 14))	('hypermethylation', 'Var', (26, 42))	('HG BC', 'Gene', (69, 74))	('BC', 'Phenotype', 'HP:0009725', (72, 74))	('hypomethylation', 'Var', (50, 65))
6894	28167242	The most frequently enriched biological processes as determined by gene ontology (GO) term analysis were anterior/posterior pattern specification (GO:0009952, GREAT Binom Raw P value = 5.8e-39), embryonic skeletal system development (GO:0048706, P value = 2.2e-28), and neuron fate commitment (GO:0048663, P value = 7.0e-24).	('embryonic skeletal system development', 'biological_process', 'GO:0048706', ('195', '232'))	('GO:0009952', 'Var', (147, 157))	('anterior/posterior pattern specification', 'biological_process', 'GO:0009952', ('105', '145'))	('embryonic skeletal system', 'Disease', 'MESH:C538496', (195, 220))	('anterior/posterior pattern specification', 'CPA', (105, 145))	('men', 'Species', '9606', (228, 231))	('embryonic skeletal system', 'Disease', (195, 220))	('gene ontology', 'biological_process', 'GO:0003673', ('67', '80'))	('men', 'Species', '9606', (288, 291))	('neuron fate commitment', 'biological_process', 'GO:0048663', ('270', '292'))	('neuron fate commitment', 'CPA', (270, 292))	('GO:0048706', 'Var', (234, 244))
6909	28167242	Next, we examined associations between several key prognostic molecular alterations in BC (FGFR3 mutations; expression of FGFR3, P53, and P27) and methylation patterns of the five DMGs.	('methylation', 'biological_process', 'GO:0032259', ('147', '158'))	('mutations', 'Var', (97, 106))	('FGFR3', 'Gene', (91, 96))	('BC', 'Phenotype', 'HP:0009725', (87, 89))	('FGFR', 'molecular_function', 'GO:0005007', ('122', '126'))	('associations', 'Interaction', (18, 30))	('P53', 'Gene', (129, 132))	('FGFR3', 'Gene', (122, 127))	('P53', 'Gene', '7157', (129, 132))	('P27', 'Gene', (138, 141))	('P27', 'Gene', '3429', (138, 141))	('FGFR3', 'Gene', '2261', (91, 96))	('examined', 'Reg', (9, 17))	('DMGs', 'Chemical', '-', (180, 184))	('FGFR', 'molecular_function', 'GO:0005007', ('91', '95'))	('FGFR3', 'Gene', '2261', (122, 127))
6910	28167242	FGFR3 mutation and expression are associated with LG BC and NMIBC, P53 expression is associated with LG BC, and P27 expression is associated with recurrence and progression.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('LG BC', 'Disease', (50, 55))	('P27', 'Gene', '3429', (112, 115))	('BC', 'Phenotype', 'HP:0009725', (104, 106))	('expression', 'MPA', (19, 29))	('P27', 'Gene', (112, 115))	('NMIBC', 'Disease', (60, 65))	('LG BC', 'Disease', (101, 106))	('associated', 'Reg', (85, 95))	('P53', 'Gene', (67, 70))	('BC', 'Phenotype', 'HP:0009725', (63, 65))	('expression', 'MPA', (71, 81))	('MIBC', 'Chemical', '-', (61, 65))	('BC', 'Phenotype', 'HP:0009725', (53, 55))	('associated', 'Reg', (130, 140))	('associated', 'Reg', (34, 44))	('expression', 'MPA', (116, 126))	('P53', 'Gene', '7157', (67, 70))	('FGFR3', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('FGFR3', 'Gene', '2261', (0, 5))
6913	28167242	The methylation of the remaining DMGs was not significantly different when stratified according to FGFR3 mutations or FGFR3, P53, and P27 expression.	('FGFR3', 'Gene', (118, 123))	('P53', 'Gene', '7157', (125, 128))	('FGFR', 'molecular_function', 'GO:0005007', ('118', '122'))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('FGFR3', 'Gene', (99, 104))	('P27', 'Gene', (134, 137))	('P27', 'Gene', '3429', (134, 137))	('mutations', 'Var', (105, 114))	('FGFR3', 'Gene', '2261', (118, 123))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('FGFR3', 'Gene', '2261', (99, 104))	('DMGs', 'Chemical', '-', (33, 37))	('P53', 'Gene', (125, 128))
6917	28167242	The combination of GP5 and ZSCAN12 methylation together achieved the highest AUC of any single gene or other genes combined, P = .006 and AUC = 0.679.	('ZSCAN12', 'Gene', (27, 34))	('GP5', 'Gene', (19, 22))	('AUC', 'MPA', (77, 80))	('ZSCAN12', 'Gene', '9753', (27, 34))	('methylation', 'Var', (35, 46))	('GP5', 'Gene', '2814', (19, 22))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))
6921	28167242	The loci FLJ46347, FLJ43870, and SHOX from our 32-gene panel were not represented on the 450K arrays.	('SHOX', 'Gene', '6473', (33, 37))	('FLJ46347', 'Var', (9, 17))	('SHOX', 'Gene', (33, 37))	('FLJ43870', 'Var', (19, 27))
6935	28167242	Among our 32-gene panel, we selected PAX6 and EOMES for independent validation because their methylation has previously been investigated in tumor as well as urine samples of BC patients, with EOMES methylation being associated with recurrence and higher grade.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('EOMES', 'Gene', '8320', (193, 198))	('recurrence', 'Disease', (233, 243))	('associated with', 'Reg', (217, 232))	('EOMES', 'Gene', (193, 198))	('PAX6', 'Gene', '5080', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('patients', 'Species', '9606', (178, 186))	('tumor', 'Disease', (141, 146))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('methylation', 'Var', (199, 210))	('EOMES', 'Gene', '8320', (46, 51))	('methylation', 'biological_process', 'GO:0032259', ('199', '210'))	('BC', 'Phenotype', 'HP:0009725', (175, 177))	('EOMES', 'Gene', (46, 51))	('PAX6', 'Gene', (37, 41))	('higher grade', 'CPA', (248, 260))
6936	28167242	Our study also identified novel hypermethylated loci for potential biomarkers such as GP5, TCF4, and ZSCAN12.	('hypermethylated', 'Var', (32, 47))	('GP5', 'Gene', '2814', (86, 89))	('ZSCAN12', 'Gene', (101, 108))	('TCF4', 'Gene', '6925', (91, 95))	('GP5', 'Gene', (86, 89))	('TCF4', 'Gene', (91, 95))	('ZSCAN12', 'Gene', '9753', (101, 108))
6951	28167242	The results of this study verify previous reports of EOMES hypermethylation in BC tissue and its association with HG disease.	('hypermethylation', 'Var', (59, 75))	('EOMES', 'Gene', (53, 58))	('association', 'Interaction', (97, 108))	('HG disease', 'Disease', (114, 124))	('EOMES', 'Gene', '8320', (53, 58))	('BC', 'Phenotype', 'HP:0009725', (79, 81))
6952	28167242	Additionally, EOMES hypermethylation has been detected in urine of BC patients and is associated with recurrence as well as HG BC.	('patients', 'Species', '9606', (70, 78))	('hypermethylation', 'Var', (20, 36))	('BC', 'Phenotype', 'HP:0009725', (67, 69))	('associated with', 'Reg', (86, 101))	('EOMES', 'Gene', '8320', (14, 19))	('EOMES', 'Gene', (14, 19))	('BC', 'Phenotype', 'HP:0009725', (127, 129))	('HG BC', 'Disease', (124, 129))	('recurrence', 'Disease', (102, 112))
6957	28167242	Despite previous studies showing significant methylation of the transcription factor PAX6 in BC, we did not find there to be any association between PAX6 methylation and tumor grade upon MethyLight analysis in 40 LG and 40 HG tumors.	('HG tumors', 'Disease', (223, 232))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Disease', (170, 175))	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('transcription', 'biological_process', 'GO:0006351', ('64', '77'))	('methylation', 'Var', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('transcription factor', 'molecular_function', 'GO:0000981', ('64', '84'))	('HG tumors', 'Disease', 'MESH:D009369', (223, 232))	('PAX6', 'Gene', (149, 153))	('PAX6', 'Gene', '5080', (149, 153))	('BC', 'Phenotype', 'HP:0009725', (93, 95))	('PAX6', 'Gene', (85, 89))	('PAX6', 'Gene', '5080', (85, 89))	('methylation', 'biological_process', 'GO:0032259', ('154', '165'))	('tumor', 'Disease', (226, 231))
6958	28167242	We also did not find any association between transcription factor TCF4 methylation and cancer, tumor grade, or other molecular characteristics of our BC cases when measured in a larger population.	('transcription factor', 'molecular_function', 'GO:0000981', ('45', '65'))	('cancer', 'Disease', (87, 93))	('methylation', 'Var', (71, 82))	('TCF4', 'Gene', (66, 70))	('TCF4', 'Gene', '6925', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('BC', 'Phenotype', 'HP:0009725', (150, 152))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('transcription', 'biological_process', 'GO:0006351', ('45', '58'))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('tumor', 'Disease', (95, 100))
6969	28167242	In addition, we validated hypermethylation marks in GP5, EOMES, and ZSCAN12 genes that should be further investigated as markers of BC detection in screening and differentiation of more aggressive disease.	('EOMES', 'Gene', '8320', (57, 62))	('ZSCAN12', 'Gene', '9753', (68, 75))	('aggressive disease', 'Disease', (186, 204))	('BC', 'Phenotype', 'HP:0009725', (132, 134))	('EOMES', 'Gene', (57, 62))	('GP5', 'Gene', '2814', (52, 55))	('hypermethylation marks', 'Var', (26, 48))	('aggressive disease', 'Disease', 'MESH:D001523', (186, 204))	('GP5', 'Gene', (52, 55))	('ZSCAN12', 'Gene', (68, 75))
7113	33173410	Genes encoding HNF1B transcription factors are prone to various types of mutations, causing the occurrence and progression of various diseases, including diabetes, renal insufficiency, and various malignant tumors.	('diabetes', 'Disease', (154, 162))	('malignant tumors', 'Disease', 'MESH:D009369', (197, 213))	('diabetes', 'Disease', 'MESH:D003920', (154, 162))	('renal insufficiency', 'Disease', (164, 183))	('HNF1B', 'Gene', '6928', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('transcription', 'biological_process', 'GO:0006351', ('21', '34'))	('HNF1B', 'Gene', (15, 20))	('renal insufficiency', 'Disease', 'MESH:D051437', (164, 183))	('renal insufficiency', 'Phenotype', 'HP:0000083', (164, 183))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('causing', 'Reg', (84, 91))	('malignant tumors', 'Disease', (197, 213))	('mutations', 'Var', (73, 82))
7114	33173410	In the present study, we evaluated expression and mutations of HNF1B in different types of cancer from The Cancer Genome Atlas (TCGA) database.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('HNF1B', 'Gene', '6928', (63, 68))	('Cancer', 'Disease', 'MESH:D009369', (107, 113))	('HNF1B', 'Gene', (63, 68))
7120	33173410	The cBio cancer genomics portal was used to explore mutations and copy-number alterations of HNF1B in the TCGA pan-cancer studies.	('mutations', 'Var', (52, 61))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', (115, 121))	('HNF1B', 'Gene', (93, 98))	('copy-number alterations', 'Var', (66, 89))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('HNF1B', 'Gene', '6928', (93, 98))
7134	33173410	As shown in Figure 2A, the mutation types of HNF1B included missense mutations, truncating mutations, in-frame mutations and other mutations.	('truncating', 'MPA', (80, 90))	('HNF1B', 'Gene', (45, 50))	('missense mutations', 'Var', (60, 78))	('in-frame mutations', 'Var', (102, 120))	('HNF1B', 'Gene', '6928', (45, 50))
7136	33173410	Additionally, cancer patients with HNF1B mutations are more susceptible to many other gene mutations, including TP53, TTN, MUC16, CSMD3, SYNE1, ZFHX4, LRP1B, XIRP2, PCLO, FLG, FAT4, DNAH5, HYDIN, PIK3CA, USH2A, HMCN1, RYR2, CSMD1, FAT3 and KMT2D (Figure 2C).	('ZFHX4', 'Gene', (144, 149))	('SYNE1', 'Gene', (137, 142))	('MUC16', 'Gene', '94025', (123, 128))	('HNF1B', 'Gene', (35, 40))	('DNAH5', 'Gene', '1767', (182, 187))	('PIK3CA', 'Gene', (196, 202))	('LRP1B', 'Gene', (151, 156))	('XIRP2', 'Gene', (158, 163))	('patients', 'Species', '9606', (21, 29))	('TP53', 'Gene', '7157', (112, 116))	('PCLO', 'Gene', (165, 169))	('HYDIN', 'Gene', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('FAT3', 'Gene', (231, 235))	('SYNE1', 'Gene', '23345', (137, 142))	('TTN', 'Gene', '7273', (118, 121))	('HMCN1', 'Gene', (211, 216))	('mutations', 'Var', (41, 50))	('FLG', 'Gene', (171, 174))	('ZFHX4', 'Gene', '79776', (144, 149))	('FAT4', 'Gene', '79633', (176, 180))	('TTN', 'Gene', (118, 121))	('CSMD3', 'Gene', '114788', (130, 135))	('KMT2D', 'Gene', '8085', (240, 245))	('MUC16', 'Gene', (123, 128))	('CSMD1', 'Gene', '64478', (224, 229))	('DNAH5', 'Gene', (182, 187))	('CSMD1', 'Gene', (224, 229))	('FAT3', 'Gene', '120114', (231, 235))	('LRP1B', 'Gene', '53353', (151, 156))	('FLG', 'Gene', '2312', (171, 174))	('USH2A', 'Gene', (204, 209))	('PIK3CA', 'Gene', '5290', (196, 202))	('RYR', 'cellular_component', 'GO:1990425', ('218', '221'))	('HMCN1', 'Gene', '83872', (211, 216))	('CSMD3', 'Gene', (130, 135))	('PCLO', 'Gene', '27445', (165, 169))	('TP53', 'Gene', (112, 116))	('cancer', 'Disease', (14, 20))	('XIRP2', 'Gene', '129446', (158, 163))	('FAT4', 'Gene', (176, 180))	('RYR2', 'Gene', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('HYDIN', 'Gene', '54768', (189, 194))	('KMT2D', 'Gene', (240, 245))	('RYR2', 'Gene', '6262', (218, 222))	('USH2A', 'Gene', '7399', (204, 209))	('HNF1B', 'Gene', '6928', (35, 40))
7154	33173410	As shown in Figure 6A, CD8+ T cell levels were negatively associated with overall survival in the low HNF1B expression group of kidney renal papillary cell carcinoma (KIRP, HR=3.76, P=0.00305) and uveal melanoma (UVM, HR=2.99, P=0.0479).	('CD8', 'Gene', (23, 26))	('kidney renal papillary cell carcinoma', 'Disease', (128, 165))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (135, 165))	('CD8', 'Gene', '925', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (128, 165))	('uveal melanoma', 'Phenotype', 'HP:0007716', (197, 211))	('uveal melanoma', 'Disease', 'MESH:C536494', (197, 211))	('low', 'Var', (98, 101))	('HNF1B', 'Gene', '6928', (102, 107))	('uveal melanoma', 'Disease', (197, 211))	('HNF1B', 'Gene', (102, 107))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('negatively', 'NegReg', (47, 57))	('overall', 'MPA', (74, 81))
7156	33173410	In the low HNF1B expression group of liver hepatocellular carcinoma (LIHC), CD8+ T cells were revealed to be positively associated with overall survival.	('associated', 'Reg', (120, 130))	('HNF1B', 'Gene', '6928', (11, 16))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (43, 67))	('HNF1B', 'Gene', (11, 16))	('low', 'Var', (7, 10))	('CD8', 'Gene', '925', (76, 79))	('CD8', 'Gene', (76, 79))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (37, 67))	('overall', 'MPA', (136, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('liver hepatocellular carcinoma', 'Disease', (37, 67))
7168	33173410	Moreover, it has been reported that the single nucleotide polymorphism (SNP) of HNF1B can affect the susceptibility of endometrial tumors.	('affect', 'Reg', (90, 96))	('endometrial tumors', 'Disease', 'MESH:D016889', (119, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('HNF1B', 'Gene', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('endometrial tumors', 'Disease', (119, 137))	('single nucleotide polymorphism', 'Var', (40, 70))	('HNF1B', 'Gene', '6928', (80, 85))
7169	33173410	conducted gene sequencing studies on endometrial cancer patients and control groups and found that HNF1B gene SNP (rs4430796, G A) can reduce the incidence of endometrial cancer.	('rs4430796', 'Var', (115, 124))	('patients', 'Species', '9606', (56, 64))	('rs4430796', 'Mutation', 'rs4430796', (115, 124))	('endometrial cancer', 'Disease', (159, 177))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('endometrial cancer', 'Disease', (37, 55))	('endometrial cancer', 'Phenotype', 'HP:0012114', (37, 55))	('HNF1B', 'Gene', '6928', (99, 104))	('endometrial cancer', 'Disease', 'MESH:D016889', (159, 177))	('endometrial cancer', 'Phenotype', 'HP:0012114', (159, 177))	('endometrial cancer', 'Disease', 'MESH:D016889', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('HNF1B', 'Gene', (99, 104))	('reduce', 'NegReg', (135, 141))
7172	33173410	Most HNF1B mutations are clustered in the first 4 exons of the gene.	('HNF1B', 'Gene', (5, 10))	('mutations', 'Var', (11, 20))	('HNF1B', 'Gene', '6928', (5, 10))
7174	33173410	A total of 106 HNF1B gene mutations, including gene deletion (34%), missense mutation (31%), frameshift deletion or insertion mutation (15%), nonsense mutation (11%) and splicing point mutation (8%) have been reported.	('frameshift deletion', 'Var', (93, 112))	('HNF1B', 'Gene', '6928', (15, 20))	('HNF1B', 'Gene', (15, 20))	('splicing', 'biological_process', 'GO:0045292', ('170', '178'))	('missense mutation', 'Var', (68, 85))	('insertion mutation', 'Var', (116, 134))	('splicing', 'MPA', (170, 178))	('nonsense mutation', 'Var', (142, 159))	('gene deletion', 'Var', (47, 60))
7175	33173410	According to these results, our study found that HNF1B mutations occurred widely in human cancers and that the most common type is missense mutations.	('cancers', 'Disease', (90, 97))	('mutations', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HNF1B', 'Gene', (49, 54))	('human', 'Species', '9606', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('missense mutations', 'Var', (131, 149))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('HNF1B', 'Gene', '6928', (49, 54))
7176	33173410	Additionally, patients with HNF1B mutations are more prone to mutations in other genes, such as TP53, TTN and MUC16.	('TTN', 'Gene', (102, 105))	('TP53', 'Gene', (96, 100))	('MUC16', 'Gene', (110, 115))	('TTN', 'Gene', '7273', (102, 105))	('prone', 'Reg', (53, 58))	('MUC16', 'Gene', '94025', (110, 115))	('mutations', 'Var', (34, 43))	('patients', 'Species', '9606', (14, 22))	('HNF1B', 'Gene', '6928', (28, 33))	('mutations', 'Var', (62, 71))	('TP53', 'Gene', '7157', (96, 100))	('HNF1B', 'Gene', (28, 33))
7188	33173410	HNF1B mutations are widely observed in tumors and interact with different genes in different cancer types, which may be the cause of the distinct prognostic values in cancers.	('interact', 'Reg', (50, 58))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancers', 'Disease', (167, 174))	('HNF1B', 'Gene', '6928', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('HNF1B', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Disease', (39, 45))	('mutations', 'Var', (6, 15))
7224	32021250	AA is derived from Aristolochic plants (fangchi and clematis) and is a potent carcinogen which causes codon 139 of p53 gene to be mutated leading to UTUC.	('UTUC', 'Disease', (149, 153))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('codon 139', 'Var', (102, 111))	('mutated', 'Var', (130, 137))	('UTUC', 'Disease', 'MESH:D012141', (149, 153))	('leading to', 'Reg', (138, 148))
7230	32021250	Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant genetic mutation that impairs DNA mismatch repair that is associated with a high risk of colon cancer as well as other cancers such as endometrial, ovarian, gastric and also urothelial cancers especially that of the upper tract.	('cancers', 'Disease', 'MESH:D009369', (278, 285))	('endometrial', 'Disease', 'MESH:D016889', (228, 239))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (18, 59))	('HNPCC', 'Disease', 'MESH:D003123', (61, 66))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (18, 59))	('ovarian', 'Disease', (241, 248))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('colon cancer', 'Phenotype', 'HP:0003003', (182, 194))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('impairs', 'NegReg', (115, 122))	('cancers', 'Disease', (278, 285))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('associated with', 'Reg', (151, 166))	('endometrial', 'Disease', (228, 239))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('gastric and also urothelial cancers', 'Disease', 'MESH:D013274', (250, 285))	('colon cancer', 'Disease', 'MESH:D015179', (182, 194))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Lynch syndrome', 'Disease', (0, 14))	('cancers', 'Disease', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('mismatch repair', 'biological_process', 'GO:0006298', ('127', '142'))	('hereditary nonpolyposis colorectal cancer', 'Disease', (18, 59))	('HNPCC', 'Disease', (61, 66))	('mutation', 'Var', (101, 109))	('colon cancer', 'Disease', (182, 194))	('DNA mismatch repair', 'MPA', (123, 142))
7234	32021250	Recently, Sfakianos et al used a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes in tumor and germline DNA from patients with UTUC (n=83) and bladder urothelial cancer (n=102).	('patients', 'Species', '9606', (193, 201))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', (242, 248))	('mutations', 'Var', (93, 102))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('DNA', 'cellular_component', 'GO:0005574', ('184', '187'))	('UTUC', 'Disease', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('copy number alterations', 'Var', (107, 130))	('UTUC', 'Disease', 'MESH:D012141', (207, 211))	('bladder urothelial cancer', 'Disease', (223, 248))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (223, 248))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Disease', (165, 170))
7236	32021250	In high-grade UTUC, there were more frequent mutations in FGFR3 and HRAS and less TP53 and RB1 as compared to high-grade bladder urothelial cancer.	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('UTUC', 'Disease', (14, 18))	('mutations', 'Var', (45, 54))	('FGFR3', 'Gene', '2261', (58, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('UTUC', 'Disease', 'MESH:D012141', (14, 18))	('FGFR3', 'Gene', (58, 63))	('HRAS', 'Gene', '3265', (68, 72))	('RB1', 'Gene', (91, 94))	('RB1', 'Gene', '5925', (91, 94))	('bladder urothelial cancer', 'Disease', (121, 146))	('HRAS', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (121, 146))
7239	32021250	High-grade UTUC as compared to low-grade UTUC had higher frequency of mutations in p53 and related interacting pathways with greater genomic instability, copy number alterations, and disruption of cell cycle and apoptotic pathways.	('UTUC', 'Disease', (11, 15))	('mutations', 'Var', (70, 79))	('copy', 'MPA', (154, 158))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('disruption', 'Reg', (183, 193))	('genomic instability', 'MPA', (133, 152))	('UTUC', 'Disease', 'MESH:D012141', (41, 45))	('cell cycle', 'biological_process', 'GO:0007049', ('197', '207'))	('UTUC', 'Disease', 'MESH:D012141', (11, 15))	('greater', 'PosReg', (125, 132))	('cell cycle', 'CPA', (197, 207))	('UTUC', 'Disease', (41, 45))
7242	32021250	Cluster 2 had 100% FGFR3 mutations, had more low-grade non-muscle invasive disease and no bladder recurrences.	('mutations', 'Var', (25, 34))	('FGFR3', 'Gene', '2261', (19, 24))	('muscle invasive disease', 'Disease', 'MESH:D019042', (59, 82))	('FGFR3', 'Gene', (19, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))	('muscle invasive disease', 'Disease', (59, 82))
7243	32021250	Cluster 3 also had 100% FGFR3 mutations; 71% PIK3CA and no TP53 mutations; and had high number of smokers and bladder recurrences.	('FGFR3', 'Gene', '2261', (24, 29))	('TP53', 'Gene', (59, 63))	('FGFR3', 'Gene', (24, 29))	('PIK3CA', 'Gene', (45, 51))	('mutations', 'Var', (30, 39))	('PIK3CA', 'Gene', '5290', (45, 51))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))	('TP53', 'Gene', '7157', (59, 63))
7245	32021250	Cluster 4 had KMT2D (62.5%), FGFR3 (50%) and TP53 (50%) mutations but no PIK3CA mutations; and had higher numbers of high grade, muscle invasive disease, smokers, carcinoma in situ and shorter survival.	('TP53', 'Gene', (45, 49))	('carcinoma in situ', 'Disease', (163, 180))	('FGFR', 'molecular_function', 'GO:0005007', ('29', '33'))	('FGFR3', 'Gene', (29, 34))	('PIK3CA', 'Gene', '5290', (73, 79))	('mutations', 'Var', (56, 65))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (163, 180))	('FGFR3', 'Gene', '2261', (29, 34))	('KMT2D', 'Gene', (14, 19))	('TP53', 'Gene', '7157', (45, 49))	('carcinoma in situ', 'Disease', 'MESH:D002278', (163, 180))	('shorter', 'NegReg', (185, 192))	('muscle invasive disease', 'Disease', 'MESH:D019042', (129, 152))	('smokers', 'CPA', (154, 161))	('high grade', 'CPA', (117, 127))	('PIK3CA', 'Gene', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('muscle invasive disease', 'Disease', (129, 152))	('KMT2D', 'Gene', '8085', (14, 19))
7251	32021250	An open-label Phase II trial (BLC2001) recruited 99 patients who had locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations and had a history of disease progression during or after at least 1 course of chemotherapy/immunotherapy.	('urothelial carcinoma', 'Disease', (117, 137))	('FGFR', 'Gene', (143, 147))	('alterations', 'Var', (148, 159))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (117, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('FGFR', 'molecular_function', 'GO:0005007', ('143', '147'))	('patients', 'Species', '9606', (52, 60))
7285	32021250	A recent review of 42 studies including 7554 patients who underwent open vs laparoscopic nephroureterectomy found no significant differences in oncologic outcomes in most series; however, 3 studies including the only randomized trial reported significantly poorer oncological outcomes among those who underwent laparoscopic RNU particularly in the subgroup of locally advanced (pT3/4) or high-grade UTUC patients.	('RNU', 'Disease', 'None', (324, 327))	('patients', 'Species', '9606', (404, 412))	('UTUC', 'Disease', (399, 403))	('pT3', 'Gene', '7694', (378, 381))	('poorer', 'NegReg', (257, 263))	('oncological outcomes', 'CPA', (264, 284))	('pT3', 'Gene', (378, 381))	('patients', 'Species', '9606', (45, 53))	('UTUC', 'Disease', 'MESH:D012141', (399, 403))	('RNU', 'Disease', (324, 327))	('laparoscopic', 'Var', (311, 323))
7307	32021250	In this trial, a single post-operative dose of MMC given at the time of catheter removal resulted in an absolute reduction in risk of intravesical recurrence in the first year by 11%; the relative reduction in risk was 40% and the number needed to treat to prevent one bladder tumor was 9.	('bladder tumor', 'Disease', 'MESH:D001749', (269, 282))	('bladder tumor', 'Phenotype', 'HP:0009725', (269, 282))	('MMC', 'Chemical', 'MESH:D016685', (47, 50))	('reduction', 'NegReg', (113, 122))	('bladder tumor', 'Disease', (269, 282))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('MMC', 'Var', (47, 50))
7378	31839882	Consistent with that study were previous publications showing that high expression of immune gene signatures was associated with favorable prognosis in breast and colorectal cancer.	('high', 'Var', (67, 71))	('breast and colorectal cancer', 'Disease', 'MESH:D001943', (152, 180))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('immune gene signatures', 'Gene', (86, 108))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
7403	31839882	CTNNB1 gene mutation has been shown to be associated with low immune response.	('CTNNB1', 'Gene', '1499', (0, 6))	('low immune response', 'CPA', (58, 77))	('low immune response', 'Phenotype', 'HP:0002721', (58, 77))	('CTNNB1', 'Gene', (0, 6))	('immune response', 'biological_process', 'GO:0006955', ('62', '77'))	('mutation', 'Var', (12, 20))
7404	31839882	On the other hand, patients with POLE gene mutations had higher immune activity and were associated with favorable prognosis compared with patients without POLE mutations.	('patients', 'Species', '9606', (19, 27))	('immune activity', 'MPA', (64, 79))	('higher', 'PosReg', (57, 63))	('patients', 'Species', '9606', (139, 147))	('mutations', 'Var', (43, 52))	('POLE gene', 'Gene', (33, 42))
7441	31839882	MHC class I molecules, including HLA-A, -B, and -C, present peptides from inside the cell to T lymphocytes, while MHC class II molecules (HLA-DP, -DM, -DO, -DQ, and -DR) present antigens from outside the cell.	('peptides', 'MPA', (60, 68))	('HLA-DP', 'Var', (138, 144))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (33, 50))
7524	24625776	Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs.	('patient', 'Species', '9606', (214, 221))	('mTOR', 'Gene', (11, 15))	('mTOR', 'Gene', '2475', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutations', 'Var', (16, 25))	('pazopanib', 'Chemical', 'MESH:C516667', (107, 116))	('improve', 'PosReg', (206, 213))	('everolimus', 'Chemical', 'MESH:D000068338', (92, 102))	('patient', 'Species', '9606', (31, 38))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('Activating', 'Reg', (0, 10))
7527	24625776	Whole exome sequencing of a patient with a 14-month complete response on this trial revealed two simultaneous mutations in mTOR, the target of everolimus.	('everolimus', 'Chemical', 'MESH:D000068338', (143, 153))	('mutations', 'Var', (110, 119))	('patient', 'Species', '9606', (28, 35))	('mTOR', 'Gene', '2475', (123, 127))	('mTOR', 'Gene', (123, 127))
7528	24625776	In vitro experiments demonstrate that both mutations are activating, suggesting a biological mechanism for exquisite sensitivity to everolimus in this patient.	('mutations', 'Var', (43, 52))	('patient', 'Species', '9606', (151, 158))	('everolimus', 'Chemical', 'MESH:D000068338', (132, 142))	('activating', 'PosReg', (57, 67))
7529	24625776	The use of precision (or "personalized") medicine approaches to screen cancer patients for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.	('mTOR', 'Gene', (110, 114))	('mTOR', 'Gene', '2475', (110, 114))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('mTOR', 'Gene', (221, 225))	('mTOR', 'Gene', '2475', (221, 225))	('cancer', 'Disease', (71, 77))	('patients', 'Species', '9606', (78, 86))	('alterations', 'Var', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('patients', 'Species', '9606', (155, 163))
7566	24625776	These findings suggest that the pharmacokinetics of pazopanib are unaffected by everolimus whereas the apparent oral clearance of everolimus is markedly diminished by pazopanib, resulting in increased concentrations of the drug in whole blood, when the two agents were given together on a continuous basis.	('everolimus', 'Chemical', 'MESH:D000068338', (80, 90))	('pazopanib', 'Var', (167, 176))	('concentrations', 'MPA', (201, 215))	('increased', 'PosReg', (191, 200))	('pazopanib', 'Chemical', 'MESH:C516667', (52, 61))	('everolimus', 'Chemical', 'MESH:D000068338', (130, 140))	('diminished', 'NegReg', (153, 163))	('apparent oral clearance', 'MPA', (103, 126))	('increased concentrations of the drug', 'Phenotype', 'HP:0020170', (191, 227))	('pazopanib', 'Chemical', 'MESH:C516667', (167, 176))
7572	24625776	Of these 340 alterations, 5 were in genes in the Cancer Gene Census (CGC), a curated catalogue of genes for which mutations have been causally implicated in cancer: PCM1, RANBP17, CTNNB1, FANCA, and TP53.	('PCM1', 'Gene', '5108', (165, 169))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('CTNNB1', 'Gene', '1499', (180, 186))	('TP53', 'Gene', (199, 203))	('RANBP17', 'Gene', '64901', (171, 178))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('PCM1', 'Gene', (165, 169))	('FANCA', 'Gene', '2175', (188, 193))	('CTNNB1', 'Gene', (180, 186))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Cancer', 'Disease', (49, 55))	('cancer', 'Disease', (157, 163))	('FANCA', 'Gene', (188, 193))	('alterations', 'Var', (13, 24))	('Cancer', 'Disease', 'MESH:D009369', (49, 55))	('RANBP17', 'Gene', (171, 178))	('TP53', 'Gene', '7157', (199, 203))
7575	24625776	Indels in PDGFRA, ATRX, NUP214, and CEBPA were all present at an AF of < 10%.	('NUP214', 'Gene', '8021', (24, 30))	('PDGFRA', 'Gene', '5156', (10, 16))	('PDGFRA', 'Gene', (10, 16))	('CEBPA', 'Gene', (36, 41))	('ATRX', 'Gene', '546', (18, 22))	('AF', 'Disease', 'MESH:D001281', (65, 67))	('ATRX', 'Gene', (18, 22))	('CEBPA', 'Gene', '1050', (36, 41))	('Indels', 'Var', (0, 6))	('NUP214', 'Gene', (24, 30))
7576	24625776	Examination of the sequencing data for biologically plausible mechanisms of sensitivity to everolimus or pazopanib revealed two mutations in mTOR, the target of everolimus (Figure 2).	('pazopanib', 'Chemical', 'MESH:C516667', (105, 114))	('mTOR', 'Gene', '2475', (141, 145))	('mTOR', 'Gene', (141, 145))	('mutations', 'Var', (128, 137))	('everolimus', 'Chemical', 'MESH:D000068338', (91, 101))	('everolimus', 'Chemical', 'MESH:D000068338', (161, 171))
7577	24625776	Although 96 somatic nonsynonymous mutations in mTOR have been reported in the COSMIC database to date, neither mutation identified in this patient has been previously reported in human cancer.	('human', 'Species', '9606', (179, 184))	('nonsynonymous mutations', 'Var', (20, 43))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mTOR', 'Gene', '2475', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('mTOR', 'Gene', (47, 51))	('cancer', 'Disease', (185, 191))	('patient', 'Species', '9606', (139, 146))
7580	24625776	There, a single mutation in Tor2, E2221K, was identified that conferred constitutive activation of TOR.	('E2221K', 'Var', (34, 40))	('TOR', 'MPA', (99, 102))	('Tor2', 'Gene', '853632', (28, 32))	('activation', 'PosReg', (85, 95))	('Tor2', 'Gene', (28, 32))	('E2221K', 'Mutation', 'p.E2221K', (34, 40))
7581	24625776	The homologous mutation in human mTOR, E2419K, was subsequently generated in human cell lines and shown to be constitutively activating through increased kinase activity and hyperactivation of the mTOR pathway.	('increased', 'PosReg', (144, 153))	('mTOR', 'Gene', '2475', (33, 37))	('human', 'Species', '9606', (27, 32))	('mTOR', 'Gene', (197, 201))	('activating', 'PosReg', (125, 135))	('mTOR', 'Gene', (33, 37))	('mTOR', 'Gene', '2475', (197, 201))	('kinase activity', 'molecular_function', 'GO:0016301', ('154', '169'))	('kinase activity', 'MPA', (154, 169))	('E2419K', 'Mutation', 'rs587777900', (39, 45))	('E2419K', 'Var', (39, 45))	('hyperactivation', 'PosReg', (174, 189))	('human', 'Species', '9606', (77, 82))
7585	24625776	In another study of potential hyperactivating mutations in mTOR, 2 FRB mutations, I2017T and A2020V, were shown to enhance kinase activity and cause hyperactivation of the mTOR pathway.	('mTOR', 'Gene', (172, 176))	('hyperactivation', 'PosReg', (149, 164))	('kinase activity', 'molecular_function', 'GO:0016301', ('123', '138'))	('A2020V', 'Mutation', 'p.A2020V', (93, 99))	('mTOR', 'Gene', '2475', (172, 176))	('kinase activity', 'MPA', (123, 138))	('I2017T', 'Var', (82, 88))	('enhance', 'PosReg', (115, 122))	('mTOR', 'Gene', '2475', (59, 63))	('I2017T', 'Mutation', 'p.I2017T', (82, 88))	('A2020V', 'Var', (93, 99))	('mTOR', 'Gene', (59, 63))
7586	24625776	Moreover, a mutant mTOR with both E2419K and I2017T exhibited higher activity of mTOR as compared to each individual mutation.	('I2017T', 'Mutation', 'p.I2017T', (45, 51))	('I2017T', 'Var', (45, 51))	('activity', 'MPA', (69, 77))	('E2419K', 'Var', (34, 40))	('mTOR', 'Gene', '2475', (19, 23))	('mTOR', 'Gene', (19, 23))	('higher', 'PosReg', (62, 68))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))	('E2419K', 'Mutation', 'rs587777900', (34, 40))
7587	24625776	To confirm that these mutations are activating, we assessed them using an established mTOR activity assay.	('mTOR', 'Gene', (86, 90))	('mutations', 'Var', (22, 31))	('mTOR', 'Gene', '2475', (86, 90))
7590	24625776	To determine if these mutations might exert additive activating effects, a variant of mTOR harboring both mutations was generated.	('mTOR', 'Gene', '2475', (86, 90))	('mTOR', 'Gene', (86, 90))	('mutations', 'Var', (22, 31))	('mutations', 'Var', (106, 115))
7592	24625776	The mTOR residues E2014 and E2419 are conserved throughout all eukaryotic TOR genes.	('E2419', 'Var', (28, 33))	('mTOR', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (4, 8))	('E2014', 'Var', (18, 23))
7594	24625776	Though functional experiments show E2014K and E2419K to be activating mutations, neither make contact with the mTOR activation loop (Figure 3, light yellow) and thus are not likely to directly change its conformation.	('E2014K', 'Mutation', 'rs1057519780', (35, 41))	('mTOR', 'Gene', '2475', (111, 115))	('mTOR', 'Gene', (111, 115))	('E2014K', 'Var', (35, 41))	('E2419K', 'Mutation', 'rs587777900', (46, 52))	('E2419K', 'Var', (46, 52))
7595	24625776	Similarly, neither mutation interfaces directly with bound rapamycin (Figure 3, cyan), and therefore would not be likely to directly alter binding to rapamycin or everolimus.	('mutation', 'Var', (19, 27))	('everolimus', 'Chemical', 'MESH:D000068338', (163, 173))	('interfaces', 'Reg', (28, 38))	('rapamycin', 'Chemical', 'MESH:D020123', (150, 159))	('rapamycin', 'Chemical', 'MESH:D020123', (59, 68))	('binding', 'molecular_function', 'GO:0005488', ('139', '146'))
7596	24625776	To test this, HEK-293T cells overexpressing wildtype or mutant mTOR were treated with rapamycin and the effect on S6K1 phosphorylation was assessed.	('mTOR', 'Gene', (63, 67))	('mutant', 'Var', (56, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('HEK-293T', 'CellLine', 'CVCL:0063', (14, 22))	('S6K1', 'Gene', (114, 118))	('S6K1', 'Gene', '6198', (114, 118))	('mTOR', 'Gene', '2475', (63, 67))	('rapamycin', 'Chemical', 'MESH:D020123', (86, 95))
7597	24625776	As shown in Figure 2C, treatment with 0.1 muM rapamycin completely abrogated S6K1 phosphorylation by both wildtype and mutant mTOR, suggesting that these mutations remain highly sensitive to allosteric inhibition.	('S6K1', 'Gene', '6198', (77, 81))	('rapamycin', 'Chemical', 'MESH:D020123', (46, 55))	('muM', 'Gene', '56925', (42, 45))	('abrogated', 'NegReg', (67, 76))	('muM', 'Gene', (42, 45))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))	('mTOR', 'Gene', (126, 130))	('mutant', 'Var', (119, 125))	('mTOR', 'Gene', '2475', (126, 130))	('S6K1', 'Gene', (77, 81))
7599	24625776	Taken together, these results are consistent with the notion that the occurrence of two activating mTOR mutations within the same bladder tumor might contribute to an exquisite dependency on mTOR signaling and therefore an exceptional response to mTOR inhibition.	('mutations', 'Var', (104, 113))	('mTOR', 'Gene', (191, 195))	('signaling', 'biological_process', 'GO:0023052', ('196', '205'))	('mTOR', 'Gene', '2475', (191, 195))	('bladder tumor', 'Disease', 'MESH:D001749', (130, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('activating', 'PosReg', (88, 98))	('mTOR', 'Gene', (247, 251))	('mTOR', 'Gene', '2475', (99, 103))	('mTOR', 'Gene', '2475', (247, 251))	('bladder tumor', 'Phenotype', 'HP:0009725', (130, 143))	('mTOR', 'Gene', (99, 103))	('bladder tumor', 'Disease', (130, 143))
7601	24625776	While we cannot rule out a direct contribution from pazopanib to the exquisite sensitivity in this patient, the doses of pazopanib required to overcome the effects of these mTOR mutations were more than 100-fold higher than those for rapamycin.	('patient', 'Species', '9606', (99, 106))	('mTOR', 'Gene', '2475', (173, 177))	('pazopanib', 'Chemical', 'MESH:C516667', (121, 130))	('pazopanib', 'Chemical', 'MESH:C516667', (52, 61))	('mTOR', 'Gene', (173, 177))	('rapamycin', 'Chemical', 'MESH:D020123', (234, 243))	('mutations', 'Var', (178, 187))
7603	24625776	Although PDGFRA is a target of pazopanib, the indel identified in this gene (p.Y102fs) was detected at an AF of 2%, and is therefore unlikely to be functionally relevant in this tumor.	('tumor', 'Disease', (178, 183))	('AF', 'Disease', 'MESH:D001281', (106, 108))	('PDGFRA', 'Gene', (9, 15))	('PDGFRA', 'Gene', '5156', (9, 15))	('pazopanib', 'Chemical', 'MESH:C516667', (31, 40))	('p.Y102fs', 'Var', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('p.Y102fs', 'Mutation', 'p.Y102fsX', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
7610	24625776	Whole exome sequencing revealed the presence of 2 simultaneous activating mTOR mutations in the urothelial carcinoma tumor sample, suggesting a biological mechanism for exquisite sensitivity to everolimus in this patient.	('urothelial carcinoma tumor', 'Disease', (96, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('patient', 'Species', '9606', (213, 220))	('urothelial carcinoma tumor', 'Disease', 'MESH:D009369', (96, 122))	('everolimus', 'Chemical', 'MESH:D000068338', (194, 204))	('activating', 'PosReg', (63, 73))	('mTOR', 'Gene', (74, 78))	('mTOR', 'Gene', '2475', (74, 78))	('mutations', 'Var', (79, 88))
7613	24625776	In hamartoma syndromes such as tuberous sclerosis complex and Peutz-Jeghers Syndrome, inactivating mutations in the tumor suppressor genes TSC1, TSC2, and STK11 (LKB1) result in mTOR pathway activation and are targetable by TOR inhibitors.	('tuberous sclerosis', 'Disease', (31, 49))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('116', '132'))	('STK11', 'Gene', (155, 160))	('STK11', 'molecular_function', 'GO:0033868', ('155', '160'))	('mTOR', 'Gene', (178, 182))	('TSC1', 'Gene', (139, 143))	('tumor suppressor', 'biological_process', 'GO:0051726', ('116', '132'))	('LKB1', 'Gene', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('31', '57'))	('hamartoma syndromes', 'Disease', 'MESH:D006222', (3, 22))	('STK11', 'Gene', '6794', (155, 160))	('mTOR', 'Gene', '2475', (178, 182))	('TSC1', 'Gene', '7248', (139, 143))	('hamartoma', 'Phenotype', 'HP:0010566', (3, 12))	('Peutz-Jeghers Syndrome', 'Disease', (62, 84))	('activation', 'PosReg', (191, 201))	('TSC2', 'Gene', '7249', (145, 149))	('hamartoma syndromes', 'Disease', (3, 22))	('inactivating mutations', 'Var', (86, 108))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (31, 49))	('TSC2', 'Gene', (145, 149))	('LKB1', 'Gene', '6794', (162, 166))	('tumor', 'Disease', (116, 121))
7615	24625776	In a recent phase II study of everolimus in chemotherapy refractory urothelial carcinoma, whole genome sequencing of a single patient who had a durable complete remission was found to have somatic TSC1 mutation (along with a somatic NF2 mutation).	('NF2', 'Gene', (233, 236))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (68, 88))	('TSC1', 'Gene', '7248', (197, 201))	('patient', 'Species', '9606', (126, 133))	('NF2', 'Gene', '4771', (233, 236))	('TSC1', 'Gene', (197, 201))	('mutation', 'Var', (202, 210))	('urothelial carcinoma', 'Disease', (68, 88))	('everolimus', 'Chemical', 'MESH:D000068338', (30, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))
7616	24625776	In addition, four of five additional patients with TSC1 mutations experienced tumor shrinkage with everolimus on that trial.	('mutations', 'Var', (56, 65))	('patients', 'Species', '9606', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('TSC1', 'Gene', '7248', (51, 55))	('everolimus', 'Chemical', 'MESH:D000068338', (99, 109))	('tumor', 'Disease', (78, 83))	('TSC1', 'Gene', (51, 55))
7618	24625776	Here, we describe the first activating mutations in mTOR found in a patient tumor that was exquisitely sensitive to mTOR inhibition.	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('patient', 'Species', '9606', (68, 75))	('activating', 'PosReg', (28, 38))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mutations', 'Var', (39, 48))	('mTOR', 'Gene', (116, 120))	('mTOR', 'Gene', '2475', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
7619	24625776	One of these constitutively activating mutations, mTORE2419K, had previously been evaluated in human tissue culture based on its homology to an activating mutation observed in yeast.	('human', 'Species', '9606', (95, 100))	('activating', 'PosReg', (28, 38))	('mTORE2419K', 'Var', (50, 60))	('yeast', 'Species', '4932', (176, 181))
7621	24625776	Indeed, very few activating mTOR mutations in human tumors have been described.	('mTOR', 'Gene', '2475', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mTOR', 'Gene', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('human', 'Species', '9606', (46, 51))
7623	24625776	Recurrent mutations include R2505P (N = 4), S2215Y (3), E1799K (2), T1977R (2), L1433S (2), C1483F (2), and L1460P (2).	('E1799K', 'Mutation', 'rs863225264', (56, 62))	('S2215Y', 'Mutation', 'rs587777894', (44, 50))	('L1460P', 'Var', (108, 114))	('L1460P', 'Mutation', 'rs1057519779', (108, 114))	('T1977R', 'Mutation', 'p.T1977R', (68, 74))	('R2505P', 'Mutation', 'rs1057519777', (28, 34))	('S2215Y', 'Var', (44, 50))	('R2505P', 'Var', (28, 34))	('L1433S', 'Var', (80, 86))	('E1799K', 'Var', (56, 62))	('T1977R', 'Var', (68, 74))	('C1483F', 'Mutation', 'rs786205165', (92, 98))	('C1483F', 'Var', (92, 98))	('L1433S', 'SUBSTITUTION', 'None', (80, 86))
7624	24625776	To date, 3 of these mTOR mutations found in human tumors have been shown to be activating in vitro.	('human', 'Species', '9606', (44, 49))	('mutations', 'Var', (25, 34))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('activating', 'MPA', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mTOR', 'Gene', '2475', (20, 24))	('tumors', 'Disease', (50, 56))	('mTOR', 'Gene', (20, 24))
7625	24625776	L1460P was identified as an activating mutation along with E2419K via the aforementioned fission yeast screen.	('fission yeast', 'Species', '4896', (89, 102))	('L1460P', 'Mutation', 'rs1057519779', (0, 6))	('L1460P', 'Var', (0, 6))	('E2419K', 'Mutation', 'rs587777900', (59, 65))	('E2419K', 'Var', (59, 65))
7626	24625776	More recently, additional mutations present in the COSMIC database were tested, and S2215Y and R2505P were shown to be activating in vitro.	('activating', 'MPA', (119, 129))	('S2215Y', 'Var', (84, 90))	('R2505P', 'Mutation', 'rs1057519777', (95, 101))	('R2505P', 'Var', (95, 101))	('S2215Y', 'Mutation', 'rs587777894', (84, 90))
7627	24625776	Notably, all 3 of these mutations remain sensitive to rapamycin exposure in vitro, though clinical information regarding the patients from whom these mutations were isolated is not available.	('sensitive', 'Reg', (41, 50))	('mutations', 'Var', (24, 33))	('rapamycin', 'Chemical', 'MESH:D020123', (54, 63))	('patients', 'Species', '9606', (125, 133))
7628	24625776	An additional mTOR mutation, L2431P, was recently identified in a patient with metastatic renal cell carcinoma and shown to be activating in vitro.	('mTOR', 'Gene', '2475', (14, 18))	('L2431P', 'Var', (29, 35))	('metastatic renal cell carcinoma', 'Disease', (79, 110))	('metastatic renal cell carcinoma', 'Disease', 'MESH:C538445', (79, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('activating', 'PosReg', (127, 137))	('patient', 'Species', '9606', (66, 73))	('L2431P', 'Mutation', 'rs1057524044', (29, 35))	('mTOR', 'Gene', (14, 18))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (90, 110))
7632	24625776	Moreover, if the mTOR mutation detected in the renal cell carcinoma was present at a low allelic fraction, a clinical response may not have been apparent.	('mutation', 'Var', (22, 30))	('renal cell carcinoma', 'Disease', (47, 67))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (47, 67))	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (47, 67))
7633	24625776	The case described here provides evidence that activating mTOR mutations can confer clinically significant sensitivity to mTOR inhibition.	('mutations', 'Var', (63, 72))	('mTOR', 'Gene', (58, 62))	('mTOR', 'Gene', (122, 126))	('mTOR', 'Gene', '2475', (122, 126))	('activating', 'PosReg', (47, 57))	('mTOR', 'Gene', '2475', (58, 62))
7636	24625776	Systematic functional analysis of mutations in mTOR, as well as other members of the mTOR pathway, may help to identify activating mutations a priori, generating a catalogue of activating mTOR-pathway alterations that may predict sensitivity to mTOR inhibition.	('mutations', 'Var', (131, 140))	('alterations', 'Var', (201, 212))	('mTOR', 'Gene', '2475', (245, 249))	('mTOR', 'Gene', (245, 249))	('mTOR', 'Gene', '2475', (47, 51))	('mTOR', 'Gene', (188, 192))	('activating', 'PosReg', (177, 187))	('mTOR', 'Gene', '2475', (188, 192))	('mTOR', 'Gene', (47, 51))	('mTOR', 'Gene', '2475', (85, 89))	('mTOR', 'Gene', (85, 89))	('mutations', 'Var', (34, 43))
7637	24625776	Furthermore, routine screening of cancer patients for these alterations may help to identify a subset of patients who may respond to targeted therapies against mTOR, including everolimus and other rapamycin analogues as well as direct mTOR kinase inhibitors now in clinical trials.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (105, 113))	('respond', 'Reg', (122, 129))	('mTOR', 'Gene', '2475', (160, 164))	('rapamycin', 'Chemical', 'MESH:D020123', (197, 206))	('mTOR', 'Gene', (235, 239))	('mTOR', 'Gene', (160, 164))	('mTOR', 'Gene', '2475', (235, 239))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('patients', 'Species', '9606', (41, 49))	('cancer', 'Disease', (34, 40))	('alterations', 'Var', (60, 71))	('everolimus', 'Chemical', 'MESH:D000068338', (176, 186))
7642	24625776	It has become increasingly clear that the spectrum of actionable cancer gene alterations exhibits a "long tail" pattern, in which the vast majority of cancer genes are mutated at frequencies of <5% within any given histologic tumor subtype.	('mutated', 'Var', (168, 175))	('long tail', 'Phenotype', 'HP:0002831', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('alterations', 'Var', (77, 88))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Disease', (226, 231))
7656	24625776	Transfections, mTOR activity assay, and immunoblot studies were performed using standard protocols (see Data Supplement).	('Transfections', 'Var', (0, 13))	('mTOR', 'Gene', (15, 19))	('mTOR', 'Gene', '2475', (15, 19))
7659	24625776	Here, we identify two activating mTOR mutations in a patient with exquisite sensitivity to everolimus and pazopanib, suggesting an approach to identifying patients who might benefit most from mTOR inhibitors.	('mTOR', 'Gene', '2475', (192, 196))	('mTOR', 'Gene', '2475', (33, 37))	('patient', 'Species', '9606', (155, 162))	('everolimus', 'Chemical', 'MESH:D000068338', (91, 101))	('mTOR', 'Gene', (33, 37))	('patients', 'Species', '9606', (155, 163))	('mTOR', 'Gene', (192, 196))	('mutations', 'Var', (38, 47))	('activating', 'PosReg', (22, 32))	('patient', 'Species', '9606', (53, 60))	('pazopanib', 'Chemical', 'MESH:C516667', (106, 115))
7720	30400878	Some studies also suggest that CDG mutations contribute to cancer-associated epigenomic and transcriptomic alterations across many cancer types.	('cancer', 'Disease', (131, 137))	('epigenomic', 'MPA', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('transcriptomic alterations', 'MPA', (92, 118))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('CDG', 'Gene', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('contribute', 'Reg', (45, 55))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('CDG', 'Chemical', '-', (31, 34))	('mutations', 'Var', (35, 44))
7721	30400878	Here we aim to improve our understanding of the connections between CDG mutations and altered cancer cell epigenomes and transcriptomes on pan-cancer level and how these connections contribute to the known association between epigenome and transcriptome.	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('CDG', 'Gene', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('CDG', 'Chemical', '-', (68, 71))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
7727	30400878	Cancer arises through accumulation of somatically acquired genetic and epigenetic aberrations that lead to malignant transformation.	('epigenetic aberrations', 'Var', (71, 93))	('lead to', 'Reg', (99, 106))	('malignant transformation', 'CPA', (107, 131))	('genetic', 'Var', (59, 66))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
7728	30400878	Comprehensive characterization of somatic mutations in cancer genomes using next-generation sequencing technology has led to discoveries of cancer driver genes (CDGs) in human cancers.	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('CDGs', 'Chemical', '-', (161, 165))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('human', 'Species', '9606', (170, 175))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (55, 61))
7729	30400878	Specifically, genome-wide change of DNA methylation was observed in patients with mutations in epigenetic regulators, affecting both the global levels of 5-methyl-cytosine (5mC) and the precise DNA methylation patterns in diverse regulatory sequences across the genome.	('affecting', 'Reg', (118, 127))	('5mC', 'Chemical', 'MESH:D044503', (173, 176))	('DNA', 'cellular_component', 'GO:0005574', ('194', '197'))	('5-methyl-cytosine', 'Chemical', 'MESH:D044503', (154, 171))	('DNA methylation', 'biological_process', 'GO:0006306', ('194', '209'))	('patients', 'Species', '9606', (68, 76))	('mutations', 'Var', (82, 91))	('DNA methylation patterns', 'MPA', (194, 218))	('DNA methylation', 'biological_process', 'GO:0006306', ('36', '51'))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('change', 'Reg', (26, 32))
7730	30400878	A recent study investigated associations between driver gene mutations and DNA methylation alterations across many cancer types, and identified associations between mutated driver genes and site-specific methylation changes as well as some genome-wide trends in specific cancer types.	('associations', 'Interaction', (144, 156))	('cancer', 'Disease', (115, 121))	('associations', 'Interaction', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('DNA methylation', 'biological_process', 'GO:0006306', ('75', '90'))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('methylation', 'biological_process', 'GO:0032259', ('204', '215'))	('DNA', 'Gene', (75, 78))	('cancer', 'Disease', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
7732	30400878	However, it remains largely unknown how the CDG mutations contribute to changes in cancer cell epigenomes on a pan-cancer level.	('cancer', 'Disease', (115, 121))	('CDG', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CDG', 'Chemical', '-', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('changes', 'Reg', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('mutations', 'Var', (48, 57))	('cancer', 'Disease', (83, 89))
7733	30400878	A better understanding of the connections between CDGs and altered cancer cell epigenomes is an important goal, particularly since mutations in epigenetic regulators could be novel targets for anti-cancer therapies.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('CDGs', 'Chemical', '-', (50, 54))
7735	30400878	An integrative analysis of DNA methylation data and gene expression data of various cancer types identified pan-cancer hypo- and hyper-methylated genes that are predictive of transcription as well as methylation-driven subgroups with clinical implications.	('hypo-', 'Var', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('methylation', 'biological_process', 'GO:0032259', ('200', '211'))	('hyper-methylated', 'Var', (129, 145))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('transcription', 'biological_process', 'GO:0006351', ('175', '188'))	('DNA methylation', 'biological_process', 'GO:0006306', ('27', '42'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('gene expression', 'biological_process', 'GO:0010467', ('52', '67'))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))
7737	30400878	Here we aim to improve our understanding of the connections between CDGs and altered cancer cell epigenomes and altered cancer cell transcriptome on pan-cancer level, and how these connections contribute to the known association between cancer epigenome and transcriptome.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('CDGs', 'Chemical', '-', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('CDGs', 'Var', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
7738	30400878	We used somatic mutation, DNA methylation, and gene expression data of 20 cancer types from The Cancer Genome Atlas (TCGA) project to identify CDGs that, when mutated, have strong associations with genome-wide methylation or expression changes across cancer types, which we refer as methylation driver genes (MDGs) or expression driver genes (EDGs).	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('DNA methylation', 'biological_process', 'GO:0006306', ('26', '41'))	('CDGs', 'Gene', (143, 147))	('EDG', 'Chemical', '-', (343, 346))	('methylation', 'biological_process', 'GO:0032259', ('283', '294'))	('gene expression', 'biological_process', 'GO:0010467', ('47', '62'))	('cancer', 'Disease', (74, 80))	('Cancer Genome Atlas', 'Disease', (96, 115))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('methylation', 'biological_process', 'GO:0032259', ('210', '221'))	('methylation', 'MPA', (210, 221))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('CDGs', 'Chemical', '-', (143, 147))	('expression changes', 'MPA', (225, 243))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('MDG', 'Gene', (309, 312))	('cancer', 'Disease', (251, 257))	('mutated', 'Var', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('associations', 'Interaction', (180, 192))	('MDG', 'Gene', '4350', (309, 312))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (96, 115))
7741	30400878	This finding shows that dysregulation of chromatin regulators is potentially an important mechanism that induces global change of DNA methylation and gene expression in tumor development.	('gene expression', 'biological_process', 'GO:0010467', ('150', '165'))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('DNA methylation', 'MPA', (130, 145))	('DNA methylation', 'biological_process', 'GO:0006306', ('130', '145'))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('dysregulation', 'Var', (24, 37))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('chromatin', 'cellular_component', 'GO:0000785', ('41', '50'))
7744	30400878	We then corrected for the type I/II probe bias using the BMIQ algorithm  We obtained level 2 somatic mutation data of the above-mentioned 20 tumor types from Broad Institute TCGA Genome Data Analysis Center Firehose and selected candidate CDGs using the MutSIG algorithm that tests how frequently a gene is mutated in a tumor type comparing to the background mutation rate.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('mutated', 'Var', (307, 314))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (320, 325))	('CDGs', 'Chemical', '-', (239, 243))
7749	30400878	To conduct pan-cancer analysis associating mutation and methylation/expression, within a tumor type, we selected CDGs that have mutations in at least 5 samples with matched methylation data or expression data in order to have not-too-sparse numbers in the mutated group.	('CDGs', 'Gene', (113, 117))	('cancer', 'Disease', (15, 21))	('mutations', 'Var', (128, 137))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('methylation', 'biological_process', 'GO:0032259', ('173', '184'))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('CDGs', 'Chemical', '-', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
7756	30400878	For the 422 CDGs, the number of tumor types in which a CDG is mutated in at least five samples varies from 1 to 14 (Additional file 2: Table S2), where TP53 and PTEN were mutated in 14 tumor types.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('TP53', 'Gene', '7157', (152, 156))	('CDGs', 'Chemical', '-', (12, 16))	('mutated', 'Var', (171, 178))	('CDG i', 'Chemical', '-', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('TP53', 'Gene', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('PTEN', 'Gene', (161, 165))	('tumor', 'Disease', (32, 37))	('PTEN', 'Gene', '5728', (161, 165))
7759	30400878	We then determine the hyper- or hypo-methylation status per CpG site by the mutation status of CDG i using the nonparametric Wilcoxon test.	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('CDG i', 'Chemical', '-', (95, 100))	('CDG i', 'Gene', (95, 100))	('hyper-', 'MPA', (22, 28))	('mutation', 'Var', (76, 84))
7762	30400878	To determine if mutation status of CDG i is significantly associated with genome-wide methylation changes in cancer type k, we calculate the p-value pi,k, which is the probability of observing the number of differentially (hyper- or hypo-) methylated sites  or more that are associated with the mutation status of CDG i in cancer type k under the null hypothesis that the mutation status of CDG i is not associated with genome-wide methylation changes.	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('mutation', 'Var', (16, 24))	('cancer', 'Disease', (323, 329))	('CDG i', 'Chemical', '-', (391, 396))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('methylation', 'biological_process', 'GO:0032259', ('432', '443'))	('mutation', 'Var', (295, 303))	('cancer', 'Disease', (109, 115))	('CDG i', 'Chemical', '-', (35, 40))	('methylation', 'biological_process', 'GO:0032259', ('86', '97'))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('CDG i', 'Chemical', '-', (314, 319))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('CDG i', 'Gene', (314, 319))
7773	30400878	We classify the effect of CDG i on genome-wide methylation in tumor type k as: To calculate the p-value, pi, testing if CDG i is significantly associated with genome-wide methylation changes across multiple cancer types, we compare , the observed total number of differentially methylated sites associated with CDG i summed over Ai cancer types, to B resampled values generated from the "methylation null pool" where we set B=one million.	('differentially', 'Var', (263, 277))	('CDG i', 'Chemical', '-', (311, 316))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cancer', 'Disease', (207, 213))	('CDG i', 'Gene', (311, 316))	('tumor', 'Disease', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('methylation', 'biological_process', 'GO:0032259', ('387', '398'))	('methylation', 'biological_process', 'GO:0032259', ('171', '182'))	('cancer', 'Disease', (332, 338))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('methylation', 'biological_process', 'GO:0032259', ('47', '58'))	('CDG i', 'Chemical', '-', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('CDG i', 'Chemical', '-', (26, 31))
7783	30400878	We first tested whether mutations in a CDG are significantly associated with changes in genome-wide methylation patterns in one cancer type.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('changes', 'Reg', (77, 84))	('genome-wide methylation patterns', 'MPA', (88, 120))	('CDG', 'Gene', (39, 42))	('CDG', 'Chemical', '-', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (24, 33))	('associated', 'Reg', (61, 71))	('methylation', 'biological_process', 'GO:0032259', ('100', '111'))	('cancer', 'Disease', (128, 134))
7785	30400878	We then used the number of genome-wide differentially methylated sites as the test statistic to measure degree of genome-wide methylation changes associated with the mutation status of a CDG for one cancer type.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('methylation', 'biological_process', 'GO:0032259', ('126', '137'))	('CDG', 'Chemical', '-', (187, 190))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('CDG', 'Gene', (187, 190))	('mutation', 'Var', (166, 174))
7786	30400878	To assess the significance of the genome-wide methylation changes by a CDG in one cancer type, we first generated an empirical null distribution with numbers of genome-wide differentially methylated sites by mutations of non-CDGs and then calculated the p-value pi,k for CDG i in cancer type k by comparing the number of genome-wide differentially methylated sites by the mutation of CDG i in cancer type k with the empirical null distribution.	('cancer', 'Disease', (393, 399))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('CDG i', 'Chemical', '-', (384, 389))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (280, 286))	('CDG i', 'Chemical', '-', (271, 276))	('cancer', 'Phenotype', 'HP:0002664', (393, 399))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CDG i', 'Gene', (384, 389))	('mutation', 'Var', (372, 380))	('CDGs', 'Chemical', '-', (225, 229))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('CDG i', 'Chemical', '-', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (393, 399))
7787	30400878	We then classify the effect of CDG i in tumor type k as hyper-methylated if pi,k<0.05 and the number of genome-wide hyper-methylated sites is greater than that of hypo-methylated sites or hypo-methylated if pi,k<0.05 and the number of genome-wide hypo-methylated sites is greater than that of hyper-methylated sites.	('k<0.05', 'Var', (79, 85))	('CDG i', 'Gene', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('CDG i', 'Chemical', '-', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
7794	30400878	For the complete list of CDGs whose mutation states were significantly associated with genome-wide methylation changes within each cancer type (gene i with pi,k<0.05 in the cancer type k), see Additional file 5: Table S4.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('CDGs', 'Chemical', '-', (25, 29))	('cancer', 'Disease', (173, 179))	('methylation', 'biological_process', 'GO:0032259', ('99', '110'))	('mutation', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CDGs', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('methylation changes', 'MPA', (99, 118))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('associated', 'Reg', (71, 81))
7796	30400878	They used Principal Component Analysis (PCA) to identify driver genes whose mutations are associated with the top five PCs within each cancer.	('cancer', 'Disease', (135, 141))	('mutations', 'Var', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('associated', 'Reg', (90, 100))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
7797	30400878	The 32 MDGs were mutated with different frequencies in each cancer types (Additional file 6: Figure S1) and the mutation status of the 32 MDGs is associated with different genome-wide number of hyper- and hypo-methylated sites (Fig.	('mutation', 'Var', (112, 120))	('MDG', 'Gene', (7, 10))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('MDG', 'Gene', '4350', (7, 10))	('MDG', 'Gene', (138, 141))	('cancer', 'Disease', (60, 66))	('MDG', 'Gene', '4350', (138, 141))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
7800	30400878	In CESC, LUSC, PAAD, and SARC tumor types, genome-wide methylation patterns were not significantly affected by mutations of any of the identified 32 MDGs, potentially due to small sample sizes or fewer number of CDGs.	('mutations', 'Var', (111, 120))	('SARC tumor', 'Disease', (25, 35))	('CDGs', 'Chemical', '-', (212, 216))	('SARC tumor', 'Phenotype', 'HP:0100242', (25, 35))	('MDG', 'Gene', (149, 152))	('SARC tumor', 'Disease', 'MESH:D009369', (25, 35))	('MDG', 'Gene', '4350', (149, 152))	('LUSC', 'Disease', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('methylation patterns', 'MPA', (55, 75))	('CESC', 'Disease', (3, 7))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
7801	30400878	TP53 mutations are associated with significant genome-wide methylation changes in 8 out of the 15 tumor types in which it was mutated in more than 5 samples (Table 1).	('TP53', 'Gene', '7157', (0, 4))	('methylation changes', 'MPA', (59, 78))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('15 tumor', 'Disease', (95, 103))	('15 tumor', 'Disease', 'MESH:C567447', (95, 103))
7802	30400878	Among these 8 tumor types, more CpG sites were hypo-methylated in all but LGG.	('hypo-methylated', 'Var', (47, 62))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
7803	30400878	Instead, in LGG, TP53 mutations are associated with more hyper-methylated CpG sites.	('hyper-methylated', 'MPA', (57, 73))	('mutations', 'Var', (22, 31))	('more', 'PosReg', (52, 56))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
7804	30400878	However, almost all LGG tumors with TP53 mutations also have IDH1 mutations (Additional file 6: Figure S1), which are known to lead to hyper-methylation in LGG.	('mutations', 'Var', (66, 75))	('LGG tumors', 'Disease', (20, 30))	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('lead', 'Reg', (127, 131))	('LGG tumors', 'Disease', 'MESH:D009369', (20, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('IDH1', 'Gene', '3417', (61, 65))	('TP53', 'Gene', '7157', (36, 40))	('IDH1', 'Gene', (61, 65))	('TP53', 'Gene', (36, 40))	('hyper-methylation', 'MPA', (135, 152))	('methylation', 'biological_process', 'GO:0032259', ('141', '152'))
7806	30400878	Given the prominent role of IDH1 in LGG, we stratified LGG tumor samples by the IDH1 mutation status and further examined the effect of the other 31 MDGs within the IDH1 mutation stratum and the IDH1 wild-type stratum and found that TP53 mutations are now significantly associated with more hypo-methylation genome-wide in each stratum (Additional file 3: Text S1).	('LGG tumor', 'Disease', 'MESH:D009369', (55, 64))	('IDH1', 'Gene', '3417', (28, 32))	('hypo-methylation', 'MPA', (291, 307))	('IDH1', 'Gene', '3417', (195, 199))	('associated', 'Reg', (270, 280))	('IDH1', 'Gene', (80, 84))	('mutations', 'Var', (238, 247))	('methylation', 'biological_process', 'GO:0032259', ('296', '307'))	('IDH1', 'Gene', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('more', 'PosReg', (286, 290))	('TP53', 'Gene', (233, 237))	('IDH1', 'Gene', '3417', (80, 84))	('MDG', 'Gene', (149, 152))	('IDH1', 'Gene', (195, 199))	('IDH1', 'Gene', '3417', (165, 169))	('IDH1', 'Gene', (28, 32))	('MDG', 'Gene', '4350', (149, 152))	('LGG tumor', 'Disease', (55, 64))	('TP53', 'Gene', '7157', (233, 237))
7807	30400878	Similar stratified analyses were conducted in all other tumor types whose genome-wide methylation patterns were significantly associated with mutations of the identified MDGs.	('mutations', 'Var', (142, 151))	('associated', 'Reg', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('methylation', 'biological_process', 'GO:0032259', ('86', '97'))	('MDG', 'Gene', (170, 173))	('MDG', 'Gene', '4350', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
7810	30400878	To test this hypothesis, we examined whether mutations of these 24 MDGs are associated with the expression changes of known epigenomic regulator genes across the 20 tumor types, where we used the exon level RNA-Seq data of the 20 tumor tissue types from TCGA.	('tumor', 'Disease', (230, 235))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('expression', 'MPA', (96, 106))	('associated', 'Reg', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('MDG', 'Gene', (67, 70))	('MDG', 'Gene', '4350', (67, 70))	('RNA', 'cellular_component', 'GO:0005562', ('207', '210'))	('tumor', 'Disease', (165, 170))
7815	30400878	For each of these 12 genes, we first identified genome-wide target genes whose expression levels were dysregulated by the mutation status commonly across tumor types.	('expression levels', 'MPA', (79, 96))	('mutation', 'Var', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
7822	30400878	For example, TP53 mutations are associated with upregulated KDM1A expression levels across all tumor types whose genome-wide methylation patterns are also significantly associated with TP53 mutations.	('methylation', 'biological_process', 'GO:0032259', ('125', '136'))	('TP53', 'Gene', (13, 17))	('TP53', 'Gene', (185, 189))	('expression levels', 'MPA', (66, 83))	('mutations', 'Var', (190, 199))	('KDM1A', 'Gene', '23028', (60, 65))	('TP53', 'Gene', '7157', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('KDM1A', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('upregulated', 'PosReg', (48, 59))	('TP53', 'Gene', '7157', (13, 17))	('tumor', 'Disease', (95, 100))	('mutations', 'Var', (18, 27))
7823	30400878	KDM1A is known to physically interact with TP53 and it demethylates histone lysine residues 9 of histone 3, which in turn leads to extensive hypo-methylation in that region.	('lysine', 'Chemical', 'MESH:D008239', (76, 82))	('hypo-methylation', 'MPA', (141, 157))	('leads to', 'Reg', (122, 130))	('TP53', 'Gene', '7157', (43, 47))	('KDM1A', 'Gene', '23028', (0, 5))	('demethylates', 'Var', (55, 67))	('KDM1A', 'Gene', (0, 5))	('TP53', 'Gene', (43, 47))	('methylation', 'biological_process', 'GO:0032259', ('146', '157'))
7824	30400878	This analysis suggests that KDM1A may play a role in the association between TP53 mutations and genome-wide hypo-methylation changes across tumor types.	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('KDM1A', 'Gene', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('mutations', 'Var', (82, 91))	('KDM1A', 'Gene', '23028', (28, 33))	('association', 'Interaction', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('tumor', 'Disease', (140, 145))
7830	30400878	We found only a small fraction of genes in list B whose expression and methylation levels are both associated with the mutation status of the MDGs (Table 2), which suggests that the differential expression of these target genes may be directly associated with mutations of these MDGs instead of being indirectly associated through changes in their methylation patterns.	('expression', 'MPA', (195, 205))	('methylation', 'biological_process', 'GO:0032259', ('348', '359'))	('MDG', 'Gene', (279, 282))	('MDG', 'Gene', '4350', (279, 282))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('expression', 'MPA', (56, 66))	('MDG', 'Gene', (142, 145))	('associated', 'Reg', (244, 254))	('MDG', 'Gene', '4350', (142, 145))	('mutations', 'Var', (260, 269))	('associated', 'Reg', (99, 109))
7831	30400878	We further investigated mutation status of genes in list B to examine if the mutations affect their expression or methylation levels directly and found that the majority of genes in list B were rarely mutated across tumor types (Additional file 8: Table S6).	('tumor', 'Disease', (216, 221))	('affect', 'Reg', (87, 93))	('list B', 'Gene', (182, 188))	('expression', 'MPA', (100, 110))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('methylation', 'biological_process', 'GO:0032259', ('114', '125'))	('methylation levels', 'MPA', (114, 132))
7832	30400878	Although CIC was not included in the above analyses since it was mutated only in LGG, due to its important role in LGG tumors, we examined how CIC regulates expressions of target genes and found that chromatin remodeling genes in list A were significantly enriched among dysregulated target genes, in both full LGG tumor samples and in stratified samples by IDH1 mutation status (Additional file 9: Table S7).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('chromatin', 'cellular_component', 'GO:0000785', ('200', '209'))	('LGG tumor', 'Disease', 'MESH:D009369', (115, 124))	('CIC', 'Gene', '23152', (9, 12))	('mutation', 'Var', (363, 371))	('LGG tumor', 'Disease', (311, 320))	('IDH1', 'Gene', '3417', (358, 362))	('LGG tumors', 'Disease', (115, 125))	('CIC', 'Gene', (9, 12))	('LGG tumor', 'Disease', 'MESH:D009369', (311, 320))	('CIC', 'Gene', '23152', (143, 146))	('LGG tumors', 'Disease', 'MESH:D009369', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('200', '220'))	('CIC', 'Gene', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('IDH1', 'Gene', (358, 362))
7835	30400878	The mutation status of these 29 EDGs is associated with different genome-wide number of up- and down-regulated genes (Fig.	('EDG', 'Chemical', '-', (32, 35))	('down-regulated', 'NegReg', (96, 110))	('up-', 'PosReg', (88, 91))	('mutation', 'Var', (4, 12))
7836	30400878	For the complete list of CDGs whose mutation states were significantly associated with genome-wide expression changes within each cancer type, see Additional file 10: Table S8.	('CDGs', 'Chemical', '-', (25, 29))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('associated', 'Reg', (71, 81))	('mutation', 'Var', (36, 44))
7838	30400878	To understand this high rate of overlap, within each cancer type, we examined the overlap between CDGs that are significantly associated with genome-wide methylation changes and CDGs that are significantly associated with genome-wide expression changes, and found they overlap highly.	('associated', 'Reg', (126, 136))	('CDGs', 'Disease', (98, 102))	('cancer', 'Disease', (53, 59))	('methylation changes', 'Var', (154, 173))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('CDGs', 'Chemical', '-', (178, 182))	('methylation', 'biological_process', 'GO:0032259', ('154', '165'))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('CDGs', 'Chemical', '-', (98, 102))
7841	30400878	A specific example of a target gene that is hypo-methylated and up-regulated by the mutation of TP53 is HSF1 gene.	('TP53', 'Gene', (96, 100))	('HSF1', 'Gene', (104, 108))	('HSF1', 'Gene', '3297', (104, 108))	('up-regulated', 'PosReg', (64, 76))	('TP53', 'Gene', '7157', (96, 100))	('mutation', 'Var', (84, 92))
7842	30400878	It is hypo-methylated and up-regulated by TP53 mutations across 9 tumor types.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('TP53', 'Gene', '7157', (42, 46))	('tumor', 'Disease', (66, 71))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('up-regulated', 'PosReg', (26, 38))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
7844	30400878	For each CDG, for every pair of tumor types in which it is mutated in more than five samples, we tested using a hypergeometric distribution if the number of overlapping target genes that are differentially methylated by the mutation of the CDG is larger than expected.	('tested', 'Reg', (97, 103))	('CDG', 'Chemical', '-', (240, 243))	('CDG', 'Chemical', '-', (9, 12))	('CDG i', 'Chemical', '-', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mutation', 'Var', (224, 232))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('CDG', 'Gene', (240, 243))	('tumor', 'Disease', (32, 37))
7848	30400878	Our findings on how CDG mutations contribute to pan-cancer-associated epigenomic alterations and transcriptomic alterations suggest that there are potentially three mechanisms (Fig.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('contribute', 'Reg', (34, 44))	('CDG', 'Gene', (20, 23))	('epigenomic alterations', 'MPA', (70, 92))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mutations', 'Var', (24, 33))	('CDG', 'Chemical', '-', (20, 23))
7849	30400878	We conducted a pan-cancer analysis to identify CDGs whose somatic mutations are associated with genome-wide methylation/expression changes across multiple cancer types.	('mutations', 'Var', (66, 75))	('methylation/expression', 'MPA', (108, 130))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('methylation', 'biological_process', 'GO:0032259', ('108', '119'))	('CDGs', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (19, 25))	('CDGs', 'Chemical', '-', (47, 51))	('associated', 'Reg', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
7850	30400878	We used a straightforward method to compare methylation/expression levels between mutated and non-mutated groups of each CDG.	('methylation/expression', 'MPA', (44, 66))	('methylation', 'biological_process', 'GO:0032259', ('44', '55'))	('mutated', 'Var', (82, 89))	('CDG', 'Chemical', '-', (121, 124))
7862	30400878	To identify TERT-independent TL regulation, they associated somatic alterations of 196 telomere-associated genes to TL ratio between matching tumor and normal samples and found alterations of ATRX, IDH1, TP53, BCOR, and RB1 were significantly associated with relative TL elongation under FDR<0.05.	('associated with', 'Reg', (243, 258))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('relative TL elongation', 'CPA', (259, 281))	('TP53', 'Gene', (204, 208))	('regulation', 'biological_process', 'GO:0065007', ('32', '42'))	('RB1', 'Gene', (220, 223))	('alterations', 'Var', (177, 188))	('IDH1', 'Gene', (198, 202))	('TERT', 'Gene', (12, 16))	('TERT', 'Gene', '7015', (12, 16))	('ATRX', 'Gene', (192, 196))	('RB1', 'Gene', '5925', (220, 223))	('tumor', 'Disease', (142, 147))	('ATRX', 'Gene', '546', (192, 196))	('TP53', 'Gene', '7157', (204, 208))	('IDH1', 'Gene', '3417', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('telomere', 'cellular_component', 'GO:0000781', ('87', '95'))	('BCOR', 'Gene', '54880', (210, 214))	('telomere', 'cellular_component', 'GO:0005696', ('87', '95'))	('BCOR', 'Gene', (210, 214))
7864	30400878	In a recent review by Feinberg et al., an epigenetic functional classification system was introduced that classifies epigenetic genes into three categories 1) "epigenetic mediators", which correspond to tumor progenitor genes that are targets of epigenetic modification; 2) "epigenetic modifiers", which modify DNA methylation or chromatin structure; and 3) "epigenetic modulators", which influence activities of epigenetic modifiers to destabilize epigenetic states.	('DNA', 'MPA', (311, 314))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('modifiers', 'Var', (286, 295))	('epigenetic states', 'MPA', (449, 466))	('modulators', 'Var', (370, 380))	('modify', 'Reg', (304, 310))	('activities', 'MPA', (399, 409))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('influence', 'Reg', (389, 398))
7866	30400878	Further analysis that examined whether mutations of 12 MDGs out of these 24 MDGs are associated with the expression of known epigenetic modifiers across cancer types supports our mechanistic hypothesis that some of these MDGs are the ones that regulate expression of chromatin regulators.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('expression', 'MPA', (253, 263))	('cancer', 'Disease', (153, 159))	('chromatin', 'cellular_component', 'GO:0000785', ('267', '276'))	('mutations', 'Var', (39, 48))	('MDG', 'Gene', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('MDG', 'Gene', (76, 79))	('regulate', 'Reg', (244, 252))	('MDG', 'Gene', '4350', (55, 58))	('MDG', 'Gene', '4350', (76, 79))	('MDG', 'Gene', '4350', (221, 224))	('MDG', 'Gene', (221, 224))	('associated', 'Reg', (85, 95))
7869	30400878	BRAF mutation is known to be tightly associated with a CpG island methylator phenotype (CIMP) and alteration of SWI/SNF chromatin remodeling pathway.	('SWI/SNF chromatin remodeling pathway', 'Pathway', (112, 148))	('chromatin', 'cellular_component', 'GO:0000785', ('120', '129'))	('BRAF', 'Gene', '673', (0, 4))	('alteration', 'Reg', (98, 108))	('associated', 'Reg', (37, 47))	('BRAF', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('120', '140'))
7881	30400878	Note that CIC mutations are associated with hyper-methylation in LGG both among IDH1 wild-type tumors and IDH1 mutated tumors.	('CIC', 'Gene', (10, 13))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('mutations', 'Var', (14, 23))	('IDH1', 'Gene', (80, 84))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('hyper-methylation', 'MPA', (44, 61))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('IDH1', 'Gene', '3417', (80, 84))	('methylation', 'biological_process', 'GO:0032259', ('50', '61'))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('IDH1', 'Gene', (106, 110))	('CIC', 'Gene', '23152', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('IDH1', 'Gene', '3417', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Disease', (95, 101))	('LGG', 'Gene', (65, 68))
7882	30400878	Further studies are needed to investigate if the observed clinical and biological impact of CIC mutations in LGG is through hyper-methylation of the epigenome.	('methylation', 'biological_process', 'GO:0032259', ('130', '141'))	('CIC', 'Gene', '23152', (92, 95))	('LGG', 'Gene', (109, 112))	('CIC', 'Gene', (92, 95))	('mutations', 'Var', (96, 105))
7883	30400878	In this study, we identified CDGs whose somatic mutations are associated with pan-cancer genome-wide methylation/expression changes by using a simple and straightforward method to compare methylation or expression levels between mutated and non-mutated groups of each CDG.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('CDG', 'Chemical', '-', (268, 271))	('methylation', 'biological_process', 'GO:0032259', ('188', '199'))	('associated', 'Reg', (62, 72))	('expression', 'MPA', (203, 213))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CDG', 'Chemical', '-', (29, 32))	('CDGs', 'Chemical', '-', (29, 33))	('methylation', 'biological_process', 'GO:0032259', ('101', '112'))	('mutations', 'Var', (48, 57))
7885	30400878	Our pan-cancer analysis examining connections between somatic mutation and DNA methylation/gene expression identified CDGs (32 MDGs and 29 EDGs) whose somatic mutations are associated with genome-wide methylation/expression changes across multiple cancer types.	('cancer', 'Disease', (248, 254))	('MDG', 'Gene', (127, 130))	('cancer', 'Disease', (8, 14))	('MDG', 'Gene', '4350', (127, 130))	('mutations', 'Var', (159, 168))	('EDG', 'Chemical', '-', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('methylation', 'biological_process', 'GO:0032259', ('201', '212'))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('gene expression', 'biological_process', 'GO:0010467', ('91', '106'))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('DNA methylation', 'biological_process', 'GO:0006306', ('75', '90'))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('CDGs', 'Chemical', '-', (118, 122))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
7888	30400878	These findings highlight that the dysregulation of chromatin regulation is an important mechanism that amplifies the impact of mutations in CDGs by global methylation and gene expression changes.	('gene expression', 'biological_process', 'GO:0010467', ('171', '186'))	('chromatin', 'cellular_component', 'GO:0000785', ('51', '60'))	('CDGs', 'Chemical', '-', (140, 144))	('dysregulation', 'Var', (34, 47))	('gene expression', 'MPA', (171, 186))	('CDGs', 'Gene', (140, 144))	('regulation', 'biological_process', 'GO:0065007', ('61', '71'))	('mutations', 'Var', (127, 136))	('methylation', 'biological_process', 'GO:0032259', ('155', '166'))	('changes', 'Reg', (187, 194))
7895	30279450	siRNA inhibition of nestin increases EC proliferation, and nestin expression is reduced in atherosclerotic plaque neovessels.	('nestin', 'Gene', (59, 65))	('EC proliferation', 'CPA', (37, 53))	('increases', 'PosReg', (27, 36))	('nestin', 'Gene', '10763', (20, 26))	('reduced', 'NegReg', (80, 87))	('expression', 'MPA', (66, 76))	('rat', 'Species', '10116', (47, 50))	('atherosclerotic', 'Disease', (91, 106))	('nestin', 'Gene', (20, 26))	('inhibition', 'Var', (6, 16))	('nestin', 'Gene', '10763', (59, 65))	('atherosclerotic', 'Disease', 'MESH:D050197', (91, 106))
7896	30279450	eQTL analysis reveals an association between SNPs linked to cardiovascular disease and reduced aortic EC nestin mRNA expression.	('cardiovascular disease', 'Phenotype', 'HP:0001626', (60, 82))	('aortic EC', 'MPA', (95, 104))	('nestin', 'Gene', '10763', (105, 111))	('reduced', 'NegReg', (87, 94))	('cardiovascular disease', 'Disease', 'MESH:D002318', (60, 82))	('nestin', 'Gene', (105, 111))	('SNPs', 'Var', (45, 49))	('cardiovascular disease', 'Disease', (60, 82))
7938	30279450	PECAM1 and CD34 mRNA were also elevated in GBM vs. normal brain, but to a lesser extent (Fig.	('PECAM1', 'Gene', '5175', (0, 6))	('GBM', 'Phenotype', 'HP:0012174', (43, 46))	('GBM', 'Var', (43, 46))	('PECAM1', 'Gene', (0, 6))	('CD34', 'Gene', (11, 15))	('elevated', 'PosReg', (31, 39))	('CD34', 'Gene', '947', (11, 15))
7962	30279450	EC cultured in low serum medium had reduced PCNA positivity (positive cells (mean %) +-SEM: 30.0 +- 6.7 vs. 68.5 +- 1.9, low serum vs. standard, respectively, P-value 0.02).	('PCNA', 'Gene', (44, 48))	('PCNA', 'Gene', '5111', (44, 48))	('PCNA', 'molecular_function', 'GO:0003892', ('44', '48'))	('reduced', 'NegReg', (36, 43))	('low', 'Var', (121, 124))
7965	30279450	To further examine EC nestin function, EC were transfected with 1 of 2 different siRNA sequences targeting NES ('N1' and 'N2') or a control scrambled siRNA sequence ('C').	('nestin', 'Gene', '10763', (22, 28))	('NES', 'Gene', '10763', (107, 110))	("'N1'", 'Var', (112, 116))	('nestin', 'Gene', (22, 28))	('NES', 'Gene', (107, 110))	("'N2'", 'Var', (121, 125))
7972	30279450	Taken together, these results indicate that inhibition of nestin increases cellular proliferation and thus, nestin expression inhibits the capacity for EC division.	('inhibits', 'NegReg', (126, 134))	('nestin', 'Gene', (108, 114))	('inhibition', 'Var', (44, 54))	('increases', 'PosReg', (65, 74))	('rat', 'Species', '10116', (91, 94))	('nestin', 'Gene', '10763', (58, 64))	('cellular proliferation', 'CPA', (75, 97))	('nestin', 'Gene', (58, 64))	('nestin', 'Gene', '10763', (108, 114))
7973	30279450	The cellular redistribution of nestin under flow and the effects of nestin knockdown on wound healing and proliferation led us to investigate nestin expression in the context of atherosclerosis.	('nestin', 'Gene', (142, 148))	('nestin', 'Gene', '10763', (68, 74))	('rat', 'Species', '10116', (113, 116))	('atherosclerosis', 'Disease', 'MESH:D050197', (178, 193))	('atherosclerosis', 'Phenotype', 'HP:0002621', (178, 193))	('knockdown', 'Var', (75, 84))	('nestin', 'Gene', (68, 74))	('nestin', 'Gene', '10763', (31, 37))	('atherosclerosis', 'Disease', (178, 193))	('nestin', 'Gene', (31, 37))	('nestin', 'Gene', '10763', (142, 148))	('wound healing', 'biological_process', 'GO:0042060', ('88', '101'))
7980	30279450	Two single nucleotide polymorphisms (SNPs) in the NES gene (rs3748570 and rs11582300) were previously reported as associated with early onset coronary heart disease (CHD), however no data linking these SNPs to nestin expression (cell type, or degree of) has been reported.	('coronary heart disease', 'Disease', 'MESH:D003324', (142, 164))	('nestin', 'Gene', '10763', (210, 216))	('CHD', 'Disease', 'None', (166, 169))	('rs11582300', 'Mutation', 'rs11582300', (74, 84))	('rs3748570', 'Var', (60, 69))	('NES', 'Gene', '10763', (50, 53))	('CHD', 'Phenotype', 'HP:0001677', (166, 169))	('associated', 'Reg', (114, 124))	('coronary heart disease', 'Disease', (142, 164))	('CHD', 'Disease', (166, 169))	('NES', 'Gene', (50, 53))	('coronary heart disease', 'Phenotype', 'HP:0001677', (142, 164))	('rs3748570', 'Mutation', 'rs3748570', (60, 69))	('nestin', 'Gene', (210, 216))	('rs11582300', 'Var', (74, 84))
7982	30279450	In a univariate analysis, both rs3748570 and rs11582300 were associated with NES expression (p = 1.19 * 10-3 and 5.29 * 10-3 respectively).	('rs3748570', 'Var', (31, 40))	('rs3748570', 'Mutation', 'rs3748570', (31, 40))	('NES', 'Gene', '10763', (77, 80))	('rs11582300', 'Var', (45, 55))	('rs11582300', 'Mutation', 'rs11582300', (45, 55))	('NES', 'Gene', (77, 80))	('associated', 'Reg', (61, 71))
7983	30279450	The strongest association was found for rs3935541 (p = 1.15 * 10-4), which is a SNP located approximately 50 kb upstream of the NES transcription start site.	('transcription', 'biological_process', 'GO:0006351', ('132', '145'))	('NES', 'Gene', '10763', (128, 131))	('NES', 'Gene', (128, 131))	('rs3935541', 'Mutation', 'rs3935541', (40, 49))	('rs3935541', 'Var', (40, 49))
7984	30279450	The rs3935541 is in strong LD with rs3748570 (r2 = 0.76, D' = 0.96) and rs11582300 (r2 = 0.57, D' = 0.90), according to the SNAP database (http://archive.broadinstitute.org/mpg/snap/index.php).	('rs3935541', 'Mutation', 'rs3935541', (4, 13))	('mpg', 'Gene', '4350', (173, 176))	('SNAP', 'molecular_function', 'GO:0005483', ('124', '128'))	('rs3935541', 'Var', (4, 13))	('rs3748570', 'Mutation', 'rs3748570', (35, 44))	('rs3748570', 'Var', (35, 44))	('rs11582300', 'Var', (72, 82))	('snap', 'molecular_function', 'GO:0005483', ('177', '181'))	('rs11582300', 'Mutation', 'rs11582300', (72, 82))	('mpg', 'Gene', (173, 176))
7987	30279450	The greatest, and the only significant (p = 0.023), decrease was observed for the AGC haplotype, the only haplotype carrying the minor allele of rs3935541.	('AGC', 'Gene', (82, 85))	('rs3935541', 'Mutation', 'rs3935541', (145, 154))	('rs3935541', 'Var', (145, 154))	('decrease', 'NegReg', (52, 60))
7988	30279450	Haplotype data were then compatible with the sole effect of the rs3935541 that explained ~4% of HAEC NES expression (p = 0,437 for rejecting this hypothesis).	('rs3935541', 'Var', (64, 73))	('NES', 'Gene', (101, 104))	('NES', 'Gene', '10763', (101, 104))	('rs3935541', 'Mutation', 'rs3935541', (64, 73))
8010	30279450	We found that silencing of the NES gene in in vitro increased EC proliferation, but did not affect migration.	('silencing', 'Var', (14, 23))	('rat', 'Species', '10116', (72, 75))	('increased', 'PosReg', (52, 61))	('NES', 'Gene', '10763', (31, 34))	('NES', 'Gene', (31, 34))	('rat', 'Species', '10116', (102, 105))	('EC proliferation', 'CPA', (62, 78))
8011	30279450	Previous studies also reported that NES silencing had no effect on EC migration, but reported inhibition of EC proliferation.	('inhibition', 'NegReg', (94, 104))	('rat', 'Species', '10116', (118, 121))	('EC migration', 'CPA', (67, 79))	('NES', 'Gene', '10763', (36, 39))	('EC proliferation', 'CPA', (108, 124))	('silencing', 'Var', (40, 49))	('NES', 'Gene', (36, 39))	('rat', 'Species', '10116', (73, 76))
8013	30279450	NES silencing can also increase proliferation capacity in terminally differentiated human podocytes, indicating that nestin may also influence cell cycle progression in other cell types where it is constitutively expressed.	('nestin', 'Gene', (117, 123))	('cell cycle progression', 'CPA', (143, 165))	('proliferation capacity', 'CPA', (32, 54))	('NES', 'Gene', (0, 3))	('influence', 'Reg', (133, 142))	('rat', 'Species', '10116', (39, 42))	('increase', 'PosReg', (23, 31))	('nestin', 'Gene', '10763', (117, 123))	('human', 'Species', '9606', (84, 89))	('cell cycle', 'biological_process', 'GO:0007049', ('143', '153'))	('silencing', 'Var', (4, 13))	('NES', 'Gene', '10763', (0, 3))
8034	30279450	Primary antibody against NES (HPA007007), CLEC14A (HPA039468), VWF (HPA001815), CD34 (HPA036722), PECAM1 (HPA004690), PCNA (HPA030522), MKI67 (HPA001164) (all Atlas Antibodies) and CDK2 (AHZ0142, BioSource) and a dextran polymer visualization system (UltraVision LP HRP polymer , Lab Vision) were incubated for 30 min each at room temperature and slides were developed for 10 minutes using Diaminobenzidine (Lab Vision) as the chromogen.	('CD34', 'Gene', '947', (80, 84))	('CLEC14A', 'Gene', '161198', (42, 49))	('PCNA', 'Gene', '5111', (118, 122))	('PECAM1', 'Gene', '5175', (98, 104))	('CDK', 'molecular_function', 'GO:0004693', ('181', '184'))	('NES', 'Gene', '10763', (25, 28))	('antibody', 'cellular_component', 'GO:0019815', ('8', '16'))	('VWF', 'Gene', '7450', (63, 66))	('PCNA', 'molecular_function', 'GO:0003892', ('118', '122'))	('HPA036722', 'Var', (86, 95))	('CD34', 'Gene', (80, 84))	('HPA007007', 'Var', (30, 39))	('antibody', 'cellular_component', 'GO:0019814', ('8', '16'))	('VWF', 'Gene', (63, 66))	('CDK2', 'Gene', '1017', (181, 185))	('PCNA', 'Gene', (118, 122))	('CDK2', 'Gene', (181, 185))	('PECAM1', 'Gene', (98, 104))	('MKI67', 'Gene', (136, 141))	('NES', 'Gene', (25, 28))	('CLEC14A', 'Gene', (42, 49))	('antibody', 'molecular_function', 'GO:0003823', ('8', '16'))	('MKI67', 'Gene', '4288', (136, 141))	('HPA004690', 'Var', (106, 115))	('rat', 'Species', '10116', (336, 339))	('antibody', 'cellular_component', 'GO:0042571', ('8', '16'))
8040	30279450	Endothelial cells were treated with two different siRNA sequences targeting nestin (s21141, s21142, Ambion) or a scrambled control (4390843, Ambion) using Lipofectamine RNAiMAX transfection reagent (Invitrogen) according to manufacturer instructions.	('nestin', 'Gene', (76, 82))	('Lipofectamine', 'Chemical', 'MESH:C086724', (155, 168))	('s21141', 'Var', (84, 90))	('s21142', 'Var', (92, 98))	('nestin', 'Gene', '10763', (76, 82))
8041	30279450	72 hours after transfection, nestin mRNA expression was inhibited by >75% compared to untransfected cells (Fig.	('nestin', 'Gene', (29, 35))	('mRNA expression', 'MPA', (36, 51))	('inhibited', 'NegReg', (56, 65))	('nestin', 'Gene', '10763', (29, 35))	('transfection', 'Var', (15, 27))
8049	30279450	cDNA was prepared using TaqMan Gene Expression Cells-to-Ct Kit (Ambion), and qPCR was subsequently performed using Taqman Fast Universal PCR Master Mix and 18 s rRNA reference primer (4319413E), with target primers for nestin (Hs04187831_g1) and vimentin (Hs00958111_m1) using a StepOnePlus Real-Time PCR System (all Applied Biosystems).	('Hs00958111_m1', 'Var', (256, 269))	('nestin', 'Gene', '10763', (219, 225))	('vimentin', 'cellular_component', 'GO:0045098', ('246', '254'))	('Mix', 'Gene', (148, 151))	('vimentin', 'Gene', '7431', (246, 254))	('Hs04187831_g1', 'Var', (227, 240))	('Mix', 'Gene', '83881', (148, 151))	('Gene Expression', 'biological_process', 'GO:0010467', ('31', '46'))	('vimentin', 'Gene', (246, 254))	('4319413E', 'Var', (184, 192))	('nestin', 'Gene', (219, 225))	('vimentin', 'cellular_component', 'GO:0045099', ('246', '254'))
8086	29136207	LinkedOmics contains multi-omics data for primary tumors from 32 TCGA cancer types and a total of 11 158 patients (Supplementary Table S1, Figure 1A), including mutation, copy number alteration (CNA), methylation, mRNA expression, miRNA expression and reverse phase protein array (RPPA) data at the gene level, mutation data at the site level, CNA data at the region-level, RPPA data at the analyte-level and clinical data.	('patients', 'Species', '9606', (105, 113))	('primary tumors', 'Disease', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutation', 'Var', (161, 169))	('protein', 'cellular_component', 'GO:0003675', ('266', '273'))	('primary tumors', 'Disease', 'MESH:D009369', (42, 56))	('methylation', 'biological_process', 'GO:0032259', ('201', '212'))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
8090	29136207	Associations between a query attribute and all target attributes in a user-defined search space, such as RB1 mutation versus mRNA expression in bladder cancer or ERBB2 amplification versus protein phosphorylation in breast cancer, are calculated using appropriate statistical tests depending on the data types of the two attributes.	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('bladder cancer', 'Phenotype', 'HP:0009725', (144, 158))	('protein phosphorylation', 'MPA', (189, 212))	('Associations', 'Interaction', (0, 12))	('RB1', 'Gene', '5925', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('breast cancer', 'Disease', (216, 229))	('protein phosphorylation', 'biological_process', 'GO:0006468', ('189', '212'))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('RB1', 'Gene', (105, 108))	('bladder cancer', 'Disease', 'MESH:D001749', (144, 158))	('bladder cancer', 'Disease', (144, 158))	('mRNA expression', 'MPA', (125, 140))	('ERBB2', 'Gene', '2064', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ERBB2', 'Gene', (162, 167))	('mutation', 'Var', (109, 117))
8098	29136207	Mutation in RB1 gene is a major cause of bladder cancer with mutation frequency of 16.5% observed in the TCGA BLCA (Bladder urothelial carcinoma) cohort.	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('Bladder urothelial carcinoma', 'Disease', (116, 144))	('RB1', 'Gene', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Mutation', 'Var', (0, 8))	('bladder cancer', 'Phenotype', 'HP:0009725', (41, 55))	('RB1', 'Gene', '5925', (12, 15))	('Bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (116, 144))	('bladder cancer', 'Disease', 'MESH:D001749', (41, 55))	('bladder cancer', 'Disease', (41, 55))	('cause', 'Reg', (32, 37))
8099	29136207	LinkFinder was used to study the association between RB1 mutation and mRNA expression in the TCGA BLCA cohort (n = 390).	('mRNA expression', 'MPA', (70, 85))	('mutation', 'Var', (57, 65))	('RB1', 'Gene', (53, 56))	('RB1', 'Gene', '5925', (53, 56))
8100	29136207	As shown in the volcano plot (Figure 2A), 1518 genes (dark red dots) had significant positive correlation with RB1 mutation, whereas 1294 genes (dark green dots) had significant negative correlation (FDR<0.01, t-test followed by multiple testing correction).	('negative', 'NegReg', (178, 186))	('RB1', 'Gene', (111, 114))	('positive', 'PosReg', (85, 93))	('RB1', 'Gene', '5925', (111, 114))	('mutation', 'Var', (115, 123))
8101	29136207	This result suggests a widespread impact of RB1 mutation on the transcriptome.	('RB1', 'Gene', (44, 47))	('mutation', 'Var', (48, 56))	('RB1', 'Gene', '5925', (44, 47))
8102	29136207	RB1 mutation showed a strong negative association with RB1 gene expression (negative rank #1, logFC[Fold Change] = -1.2, P = 2.2e-14).	('expression', 'MPA', (64, 74))	('RB1', 'Gene', (55, 58))	('RB1', 'Gene', '5925', (0, 3))	('RB1', 'Gene', '5925', (55, 58))	('mutation', 'Var', (4, 12))	('gene expression', 'biological_process', 'GO:0010467', ('59', '74'))	('negative', 'NegReg', (29, 37))	('RB1', 'Gene', (0, 3))
8103	29136207	RB1 mutation also showed strong positive associations with CDKN2A (positive rank #1, logFC = 4.4, P = 2.5e-49) and E2F1 (positive rank #22, logFC = 1.2, P = 1.7e-18), and a strong negative association with CCND1 (negative rank #29, logFC = -1.6, P = 1.4e-9) (Figure 2B).	('associations', 'Interaction', (41, 53))	('CCND1', 'Gene', (206, 211))	('E2F1', 'Gene', '1869', (115, 119))	('RB1', 'Gene', '5925', (0, 3))	('E2F1', 'Gene', (115, 119))	('CCND1', 'Gene', '595', (206, 211))	('mutation', 'Var', (4, 12))	('RB1', 'Gene', (0, 3))	('negative', 'NegReg', (180, 188))	('CDKN2A', 'Gene', (59, 65))	('positive', 'PosReg', (32, 40))	('CDKN2A', 'Gene', '1029', (59, 65))
8106	29136207	Using LinkInterpreter, we performed transcriptional factor target enrichment analysis for the 1518 genes with significant positive correlation with RB1 mutation (FDR < 0.01).	('RB1', 'Gene', (148, 151))	('RB1', 'Gene', '5925', (148, 151))	('mutation', 'Var', (152, 160))
8107	29136207	As shown in the result table (Figure 2C), transcriptional targets of E2F1 were significantly enriched among these genes, confirming the role of RB1 mutation in regulating E2F1-mediated transcriptional program.	('RB1', 'Gene', '5925', (144, 147))	('E2F1', 'Gene', '1869', (171, 175))	('E2F1', 'Gene', (171, 175))	('mutation', 'Var', (148, 156))	('E2F1', 'Gene', '1869', (69, 73))	('E2F1', 'Gene', (69, 73))	('RB1', 'Gene', (144, 147))
8108	29136207	LinkFinder was used to study the association between ERBB2 amplification and protein phosphorylation in the TCGA BRCA cohort (n = 105).	('ERBB2', 'Gene', '2064', (53, 58))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('BRCA', 'Phenotype', 'HP:0003002', (113, 117))	('protein phosphorylation', 'MPA', (77, 100))	('protein phosphorylation', 'biological_process', 'GO:0006468', ('77', '100'))	('amplification', 'Var', (59, 72))	('ERBB2', 'Gene', (53, 58))
8111	29136207	Over-phosphorylation of GRB7 in ERBB2 amplified tumors suggests its potential functional importance in Her2-positive breast cancer.	('GRB7', 'Gene', (24, 28))	('amplified', 'Var', (38, 47))	('Over-phosphorylation', 'MPA', (0, 20))	('ERBB2', 'Gene', (32, 37))	('Her2', 'Gene', '2064', (103, 107))	('ERBB2', 'Gene', '2064', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('GRB7', 'Gene', '2886', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('Her2', 'Gene', (103, 107))
8113	29136207	The strongest correlation was found between ERBB2 amplification and the phosphorylation level of ERBB2 protein at s1104 (Pearson's correlation = 0.76, P = 7.1e-20) (Figure 3B).	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('ERBB2', 'Gene', '2064', (44, 49))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('ERBB2', 'Gene', (44, 49))	('s1104', 'Var', (114, 119))	('phosphorylation level', 'MPA', (72, 93))	('ERBB2', 'Gene', '2064', (97, 102))	('ERBB2', 'Gene', (97, 102))
8116	29136207	Ovarian cancer is characterized by prevalent copy number alteration and has poor prognosis.	('Ovarian cancer', 'Disease', 'MESH:D010051', (0, 14))	('copy number alteration', 'Var', (45, 67))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Ovarian cancer', 'Disease', (0, 14))
8123	29136207	Figure 4C shows Kaplan-Meier survival curves for patients with above- (red) and below- (green) median ACTN4 copy number estimates (Hazard ratio [HR] = 1.235, P = 1.548e-04).	('ACTN4', 'Gene', '81', (102, 107))	('ACTN4', 'Gene', (102, 107))	('copy number', 'Var', (108, 119))	('patients', 'Species', '9606', (49, 57))
8152	27633916	conducted a multiplatform pan-cancer analysis across twelve cancer types and found a subtype consisting of lung squamous, head and neck, and a subset of bladder cancers, which are characterized by TP53 alterations, TP63 amplifications, and deregulation of immune and proliferation genes.	('TP63', 'Gene', (215, 219))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('bladder cancers', 'Phenotype', 'HP:0009725', (153, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancer', 'Disease', (161, 167))	('bladder cancer', 'Phenotype', 'HP:0009725', (153, 167))	('TP53', 'Gene', (197, 201))	('alterations', 'Var', (202, 213))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('neck', 'cellular_component', 'GO:0044326', ('131', '135'))	('TP63', 'Gene', '8626', (215, 219))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('lung squamous', 'Disease', (107, 120))	('bladder cancers', 'Disease', 'MESH:D001749', (153, 168))	('bladder cancers', 'Disease', (153, 168))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('TP53', 'Gene', '7157', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('deregulation', 'Var', (240, 252))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
8154	27633916	also employed a pan-cancer study to demonstrate universal patterns of epigenomic deregulation and distinct processes controlling genome-wide DNA hypo- and hyper-methylation across tumor lineages.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('hyper-methylation', 'Var', (155, 172))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('methylation', 'biological_process', 'GO:0032259', ('161', '172'))	('tumor', 'Disease', (180, 185))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))
8177	27633916	Generally, dysregulation of these cell cycle genes with defects of proteins RB and TP53 will permit persistent cell proliferation of cancer cells and promote tumor progression in the long term.	('defects of proteins RB', 'Disease', 'MESH:D012175', (56, 78))	('TP53', 'Gene', '7157', (83, 87))	('tumor', 'Disease', (158, 163))	('promote', 'PosReg', (150, 157))	('cell proliferation', 'biological_process', 'GO:0008283', ('111', '129'))	('TP53', 'Gene', (83, 87))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cell cycle', 'biological_process', 'GO:0007049', ('34', '44'))	('cancer', 'Disease', (133, 139))	('cell proliferation', 'CPA', (111, 129))	('dysregulation', 'Var', (11, 24))	('permit', 'PosReg', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('defects of proteins RB', 'Disease', (56, 78))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cell cycle genes', 'Gene', (34, 50))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
8178	27633916	From another perspective, alterations in cyclin-dependent kinase (CDK) activity often induce and regulate cell cycle defects in tumors.	('cyclin-dependent', 'Protein', (41, 57))	('induce', 'Reg', (86, 92))	('alterations', 'Var', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cyclin', 'molecular_function', 'GO:0016538', ('41', '47'))	('cell cycle defects', 'CPA', (106, 124))	('cell cycle', 'biological_process', 'GO:0007049', ('106', '116'))	('CDK) activity', 'molecular_function', 'GO:0004693', ('66', '79'))	('tumors', 'Disease', (128, 134))	('activity', 'MPA', (71, 79))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('regulate', 'Reg', (97, 105))	('cell cycle defects', 'Phenotype', 'HP:0011018', (106, 124))
8196	27633916	The deregulation of these functions remind us of the metastasizing features across different cancer types while the specific signatures of these subnetworks imply the distinct mechanisms of metastases.	('deregulation', 'Var', (4, 16))	('cancer', 'Disease', (93, 99))	('metastases', 'Disease', (190, 200))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('metastases', 'Disease', 'MESH:D009362', (190, 200))
8209	27633916	4A) tend to be ER, PR and HER2 negative ones and they have high frequency of TP53 mutations (Fig.	('HER2', 'Gene', (26, 30))	('mutations', 'Var', (82, 91))	('HER2', 'Gene', '2064', (26, 30))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
8218	27633916	Dysregulation of this gene may influence the remaining genes of this subnetwork, and further accelerates cell differentiation in basal-like tumors (Fig.	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('cell differentiation', 'biological_process', 'GO:0030154', ('105', '125'))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cell differentiation', 'CPA', (105, 125))	('influence', 'Reg', (31, 40))	('accelerates', 'PosReg', (93, 104))
8219	27633916	Previous studies have shown that malignant renal papillary cell carcinoma are marked by the trisomy of chromosomes 7, 16, 17 and the loss of Y chromosome.	('malignant renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (33, 73))	('loss', 'NegReg', (133, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('trisomy', 'Var', (92, 99))	('Y chromosome', 'cellular_component', 'GO:0000806', ('141', '153'))	('malignant renal papillary cell carcinoma', 'Disease', (33, 73))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (43, 73))
8230	27633916	We find that the ME scores of the THCA-specific subnetwork are strongly associated with the mutation status of BRAF, NRAS and HRAS, which have relatively high mutation frequency (Fig.	('ME', 'Chemical', '-', (17, 19))	('NRAS', 'Gene', (117, 121))	('HRAS', 'Gene', (126, 130))	('NRAS', 'Gene', '4893', (117, 121))	('THCA', 'Phenotype', 'HP:0002890', (34, 38))	('associated', 'Reg', (72, 82))	('HRAS', 'Gene', '3265', (126, 130))	('BRAF', 'Gene', '673', (111, 115))	('mutation status', 'Var', (92, 107))	('BRAF', 'Gene', (111, 115))
8235	27633916	This subnetwork is associated with FGFR3 mutations (Supplementary Figure S6B), which is a key marker of Ta pathway and therapeutic target of bladder cancer.	('mutations', 'Var', (41, 50))	('associated', 'Reg', (19, 29))	('bladder cancer', 'Disease', (141, 155))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR3', 'Gene', '2261', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (141, 155))	('FGFR3', 'Gene', (35, 40))	('bladder cancer', 'Disease', 'MESH:D001749', (141, 155))
8237	27633916	A recent study revealed a biological component relating to both Ta pathway and carcinoma in situ pathway, of which one biomarker is early TP53 mutation.	('TP53', 'Gene', '7157', (138, 142))	('carcinoma', 'Disease', (79, 88))	('mutation', 'Var', (143, 151))	('TP53', 'Gene', (138, 142))	('Ta pathway', 'Pathway', (64, 74))	('carcinoma', 'Disease', 'MESH:D002277', (79, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (79, 96))
8241	27633916	We also find 16 cancer type-specific subnetworks which demonstrate strong implications to somatic mutations, SCNAs, DNA methylation alterations and clinical outcomes in some specific cancers.	('cancers', 'Disease', (183, 190))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('cancer', 'Disease', (16, 22))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('implications', 'Reg', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('DNA methylation', 'biological_process', 'GO:0006306', ('116', '131'))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
8243	27633916	Not surprisingly, different cancer-specific subnetworks show very diverse implications to mutation status, SCNAs and others.	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutation status', 'Var', (90, 105))
8252	27633916	With the deepening of understanding of cancer, the nosogenesis is not only restricted to somatic mutations but also to SCNAs, some epigenomic deregulations and so on.	('cancer', 'Disease', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('epigenomic deregulations', 'Var', (131, 155))	('cancer', 'Disease', 'MESH:D009369', (39, 45))
8273	27633916	We download the mutation annotation files (MAF) of all 16 cancer types and the output of mutsig2cv which gives if a gene is significantly mutated or not from Broad Institute on July 24, 2015 (Supplementary Table S1).	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutated', 'Var', (138, 145))
8286	27633916	For each cancer, we use LIMMA to detect DEGs relative to normal samples with the TMM normalized data as input.	('DEGs', 'Var', (40, 44))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
8318	27197178	Burden of non-synonymous mutations among TCGA cancers and candidate immune checkpoint inhibitor responses Immune checkpoint inhibitor treatment represents a promising approach towards treating cancer and has been shown to be effective in a subset of melanoma, non-small cell lung cancer (NSCLC) and kidney cancers.	('cancers', 'Phenotype', 'HP:0002664', (306, 313))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Disease', (306, 313))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (280, 286))	('NSCLC', 'Phenotype', 'HP:0030358', (288, 293))	('kidney cancers', 'Phenotype', 'HP:0009726', (299, 313))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (264, 286))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (260, 286))	('melanoma', 'Disease', 'MESH:D008545', (250, 258))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', 'MESH:D009369', (306, 313))	('cancer', 'Disease', (46, 52))	('cancers', 'Disease', (46, 53))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (260, 286))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (306, 312))	('NSCLC', 'Disease', 'MESH:D002289', (288, 293))	('non-synonymous mutations', 'Var', (10, 34))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('lung cancer', 'Phenotype', 'HP:0100526', (275, 286))	('kidney cancers', 'Disease', (299, 313))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('non-small cell lung cancer', 'Disease', (260, 286))	('melanoma', 'Disease', (250, 258))	('kidney cancers', 'Disease', 'MESH:D007680', (299, 313))	('TCGA', 'Gene', (41, 45))	('NSCLC', 'Disease', (288, 293))
8319	27197178	Recent studies have suggested that the number of non-synonymous mutations (NsM) can be used to select melanoma and NSCLC patients most likely to benefit from checkpoint inhibitor treatment.	('non-synonymous mutations', 'Var', (49, 73))	('NSCLC', 'Disease', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('patients', 'Species', '9606', (121, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
8326	27197178	Recently, a new generation of immune therapeutics based on immune checkpoint inhibition, including anti-CTLA-4, anti-PD-1 and anti-PD1-L1, has emerged as a promising development in the treatment of select cancers.	('anti-CTLA-4', 'Var', (99, 110))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('cancers', 'Disease', (205, 212))	('PD1', 'Gene', (131, 134))	('PD1', 'Gene', '5133', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('anti-PD-1', 'Var', (112, 121))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
8329	27197178	Previously a series of studies have examined somatic alterations to identify possible predictive signatures; these have included studies of gene expression signature associated with immune infiltration, neoantigen load, NRAS mutation status and neoantigen-derived tetrapeptide signature.	('NRAS', 'Gene', '4893', (220, 224))	('gene expression', 'biological_process', 'GO:0010467', ('140', '155'))	('NRAS', 'Gene', (220, 224))	('mutation status', 'Var', (225, 240))
8330	27197178	Of these, the neoantigen load is most promising, particularly for treatment of melanoma and NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('neoantigen load', 'Var', (14, 29))	('NSCLC', 'Disease', (92, 97))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
8331	27197178	Non-synonymous somatic mutations can generate neoantigens, which, in turn, can be recognized by the immune system, triggering an anticancer immune response.	('Non-synonymous', 'Var', (0, 14))	('neoantigens', 'MPA', (46, 57))	('generate', 'Reg', (37, 45))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('triggering', 'Reg', (115, 125))	('immune response', 'biological_process', 'GO:0006955', ('140', '155'))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
8332	27197178	It has been observed that a higher number of non-synonymous mutations correlates with a response to checkpoint inhibitors in melanoma and NSCLC.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('NSCLC', 'Disease', (138, 143))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('non-synonymous mutations', 'Var', (45, 69))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('response to', 'MPA', (88, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))
8333	27197178	Here, we conducted an analysis of the non-synonymous mutation load across the 7,757 tumor samples drawn from 26 distinct cancers in The Cancer Genome Atlas (TCGA), to infer possible cancers that might be prioritized for subsequent study of immune checkpoint inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Disease', (121, 128))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('Cancer Genome Atlas', 'Disease', (136, 155))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (136, 155))	('Cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('tumor', 'Disease', (84, 89))	('non-synonymous mutation load', 'Var', (38, 66))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
8337	27197178	A literature search was performed in the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed, October 20, 2015) using combinations of the search terms: cancer, response, mutation, checkpoint inhibitor, CTLA4 and PD1.	('PD1', 'Gene', (212, 215))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('CTLA4', 'Gene', '1493', (202, 207))	('CTLA4', 'Gene', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('PD1', 'Gene', '5133', (212, 215))	('mutation', 'Var', (170, 178))
8363	27197178	In a comparison of the three published studies, using an ROC assessment for NsM against the checkpoint response rate, we observed similar cutoffs when comparing tumor types, but interestingly, the NSCLC study treated with anti-PD-1 had better AUC, which suggests perhaps better accuracy for NsM to predict immunotherapy response.	('NSCLC', 'Phenotype', 'HP:0030358', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('AUC', 'MPA', (243, 246))	('NSCLC', 'Disease', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('better', 'PosReg', (236, 242))	('tumor', 'Disease', (161, 166))	('anti-PD-1', 'Var', (222, 231))
8367	27197178	For anti-CTLA-4, plus dacarbazine, the range of 1 year survival is between 41.2 to 53.7% for melanoma patients, which is lower than our analysis predicts, however, anti-CTLA-4 appears to be less efficacious than anti-PD-1.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('anti-CTLA-4', 'Var', (164, 175))	('dacarbazine', 'Chemical', 'MESH:D003606', (22, 33))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('patients', 'Species', '9606', (102, 110))
8374	27197178	Alternatively, anti-CTLA-4 is active for adjuvant therapy in melanoma stage III patients which suggests that activity is not restricted to stage IV patients.	('anti-CTLA-4', 'Var', (15, 26))	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (80, 88))	('stage III', 'Disease', (70, 79))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))
8380	27197178	To the best of our knowledge, there are no published phase III clinical trials from colorectal cancer, however, some studies suggest that the subset of colorectal cancers with mismatch repair-deficient would have better immune checkpoint inhibition response.	('colorectal cancer', 'Disease', (84, 101))	('immune checkpoint inhibition response', 'MPA', (220, 257))	('mismatch repair-deficient', 'Var', (176, 201))	('mismatch repair', 'biological_process', 'GO:0006298', ('176', '191'))	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('better', 'PosReg', (213, 219))	('colorectal cancer', 'Disease', 'MESH:D015179', (84, 101))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('colorectal cancers', 'Disease', 'MESH:D015179', (152, 170))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('colorectal cancers', 'Disease', (152, 170))
8414	25106902	CIS only at bladder tumor TUR was associated with a higher likelihood of prostatic involvement compared to tumors in the overall cohort (57% vs 37%, p = 0.043).	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('men', 'Species', '9606', (90, 93))	('tumors', 'Disease', (107, 113))	('bladder tumor', 'Disease', 'MESH:D001749', (12, 25))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('CIS', 'Var', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('bladder tumor', 'Phenotype', 'HP:0009725', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('prostatic involvement', 'Disease', (73, 94))	('bladder tumor', 'Disease', (12, 25))
8428	25106902	The investigators reported that positive biopsy was associated with an increased risk of second primary tumors of the urethra more often than negative biopsy (11% vs 2%).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('positive biopsy', 'Var', (32, 47))
8503	25364421	The results showed that in normal bladder tissues, B7-H4 was not detected, but in the bladder urothelial carcinoma tissue samples, B7-H4 was detected in 24/49 (49.0%) specimens.	('B7-H4', 'Var', (131, 136))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (86, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('bladder urothelial carcinoma', 'Disease', (86, 114))
8507	25364421	Following the blockade of the B7-H4 antigen in BIU-87 cells, the cytotoxic activity of activated T cells against such BIU-87 cells was significantly enhanced compared with that against the control BIU-87 cells.	('B7-H4 antigen', 'Protein', (30, 43))	('BIU-87', 'Var', (47, 53))	('BIU-87', 'CellLine', 'CVCL:6881', (118, 124))	('enhanced', 'PosReg', (149, 157))	('BIU-87', 'CellLine', 'CVCL:6881', (197, 203))	('BIU-87', 'CellLine', 'CVCL:6881', (47, 53))	('cytotoxic activity', 'CPA', (65, 83))
8525	25364421	Subsequent to combining with the corresponding receptor, B7-H4 is involved in tumor immune escape by suppressing specific cellular and humoral immunity, and inducing specific T-cell apoptosis.	('B7-H4', 'Var', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('T-cell apoptosis', 'biological_process', 'GO:0070231', ('175', '191'))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('suppressing', 'NegReg', (101, 112))	('inducing', 'Reg', (157, 165))
8527	25364421	Studies have shown that tumor cells directly bind T-cell surface receptors through expressing B7-H4 protein or secreting soluble B7-H4 (sB7-H4) to inhibit the proliferation of CD4+ T cells, block the T-cell division cycle, and inhibit the release of antitumor cytokines and CD8+ T-cell cytotoxic activity against tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (313, 318))	('proliferation', 'CPA', (159, 172))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('soluble', 'cellular_component', 'GO:0005625', ('121', '128'))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('T-cell division cycle', 'CPA', (200, 221))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('tumor', 'Disease', (254, 259))	('tumor', 'Disease', (24, 29))	('CD8', 'Gene', '925', (274, 277))	('inhibit', 'NegReg', (147, 154))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('CD4', 'Gene', '920', (176, 179))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('inhibit', 'NegReg', (227, 234))	('sB7-H4', 'Chemical', '-', (136, 142))	('CD4', 'Gene', (176, 179))	('block', 'NegReg', (190, 195))	('cell division cycle', 'biological_process', 'GO:0007049', ('202', '221'))	('cell surface', 'cellular_component', 'GO:0009986', ('52', '64'))	('B7-H4', 'Var', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('CD8', 'Gene', (274, 277))
8577	25364421	Immunocytochemical analysis revealed positive B7-H4 expression in the BIU-87 cells incubated with B7-H4 mAbs, and negative expression in the control BIU-87 cells incubated with PBS instead of primary antibody (Fig.	('antibody', 'molecular_function', 'GO:0003823', ('200', '208'))	('B7-H4', 'Gene', (46, 51))	('PBS', 'Chemical', '-', (177, 180))	('BIU-87', 'CellLine', 'CVCL:6881', (70, 76))	('antibody', 'cellular_component', 'GO:0042571', ('200', '208'))	('B7-H4 mAbs', 'Var', (98, 108))	('expression', 'MPA', (52, 62))	('BIU-87', 'CellLine', 'CVCL:6881', (149, 155))	('antibody', 'cellular_component', 'GO:0019815', ('200', '208'))	('antibody', 'cellular_component', 'GO:0019814', ('200', '208'))
8585	25364421	Bladder urothelial carcinoma cells may inhibit T-cell activity and induce apoptosis in tumor antigen-specific cells due to B7-H4 combining with the corresponding T-cell surface receptor.	('apoptosis', 'CPA', (74, 83))	('urothelial carcinoma', 'Disease', (8, 28))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('inhibit', 'NegReg', (39, 46))	('B7-H4', 'Var', (123, 128))	('tumor', 'Disease', (87, 92))	('tumor antigen', 'molecular_function', 'GO:0008222', ('87', '100'))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (8, 28))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('cell surface', 'cellular_component', 'GO:0009986', ('164', '176'))	('induce', 'PosReg', (67, 73))	('T-cell activity', 'CPA', (47, 62))
8590	25364421	In the present study, no significant differences were identified between the rates of B7-H4 positive expression in newly diagnosed and recurrent BCa groups; however, B7-H4 expression was closely associated with TNM stage and histological grade.	('associated', 'Reg', (195, 205))	('TNM', 'Gene', (211, 214))	('BCa', 'Phenotype', 'HP:0009725', (145, 148))	('B7-H4', 'Var', (166, 171))	('expression', 'MPA', (172, 182))	('TNM', 'Gene', '10178', (211, 214))
8593	25364421	Tumor cells secrete sB7-H4, which restrains T-cell proliferation through blocking the cell cycle at the G0/G1 phase and further inhibits the T cell immune response by inducing T cell apoptosis.	('sB7-H4', 'Chemical', '-', (20, 26))	('inducing', 'Reg', (167, 175))	('T cell immune response', 'CPA', (141, 163))	('cell cycle at the G0/G1 phase', 'CPA', (86, 115))	('blocking', 'NegReg', (73, 81))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('immune response', 'biological_process', 'GO:0006955', ('148', '163'))	('inhibits', 'NegReg', (128, 136))	('T cell apoptosis', 'CPA', (176, 192))	('T-cell proliferation', 'biological_process', 'GO:0042098', ('44', '64'))	('sB7-H4', 'Var', (20, 26))	('G1 phase', 'biological_process', 'GO:0051318', ('107', '115'))	('cell cycle', 'biological_process', 'GO:0007049', ('86', '96'))	('T cell apoptosis', 'biological_process', 'GO:0070231', ('176', '192'))	('restrains', 'NegReg', (34, 43))	('T-cell proliferation', 'CPA', (44, 64))
8612	25364421	Therefore, altering B7-H4 protein expression in bladder urothelial carcinoma cells may enhance T-cell cytotoxicity to the cancer cells, and also promote and maintain a functional T cell immune response; thus the rate of BCa recurrence and progression may be reduced.	('BCa', 'Disease', (220, 223))	('expression', 'MPA', (34, 44))	('enhance', 'PosReg', (87, 94))	('B7-H4 protein', 'Protein', (20, 33))	('T cell immune response', 'CPA', (179, 201))	('bladder urothelial carcinoma', 'Disease', (48, 76))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('altering', 'Var', (11, 19))	('BCa', 'Phenotype', 'HP:0009725', (220, 223))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (48, 76))	('cytotoxicity', 'Disease', (102, 114))	('cytotoxicity', 'Disease', 'MESH:D064420', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (122, 128))	('immune response', 'biological_process', 'GO:0006955', ('186', '201'))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('protein', 'Protein', (26, 33))	('promote', 'PosReg', (145, 152))
8613	25364421	In conclusion, the results of the present study revealed that B7-H4 was upregulated in bladder urothelial carcinoma tissues and serum samples from patients, and was closely associated with TNM stage and histological grade.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (87, 115))	('bladder urothelial carcinoma', 'Disease', (87, 115))	('TNM', 'Gene', '10178', (189, 192))	('B7-H4', 'Var', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('patients', 'Species', '9606', (147, 155))	('associated', 'Reg', (173, 183))	('upregulated', 'PosReg', (72, 83))	('TNM', 'Gene', (189, 192))
8617	19340092	Genetic ablation of one or more uroplakin genes in mice causes severe retrograde vesicoureteral reflux, hydronephrosis and renal failure, conditions that mirror certain human congenital diseases.	('renal failure', 'Phenotype', 'HP:0000083', (123, 136))	('hydronephrosis', 'Phenotype', 'HP:0000126', (104, 118))	('uroplakin genes', 'Gene', (32, 47))	('mice', 'Species', '10090', (51, 55))	('retrograde vesicoureteral reflux', 'Disease', (70, 102))	('human', 'Species', '9606', (169, 174))	('causes', 'Reg', (56, 62))	('Genetic ablation', 'Var', (0, 16))	('congenital diseases', 'Disease', 'MESH:D030342', (175, 194))	('vesicoureteral reflux', 'Phenotype', 'HP:0000076', (81, 102))	('congenital diseases', 'Disease', (175, 194))	('hydronephrosis and renal failure', 'Disease', 'MESH:D051437', (104, 136))
8636	19340092	Third, transfection of 293T cells with single uroplakin cDNAs resulted in UPs being trapped in the ER (except UPIb which can exit by itself).	('293T', 'CellLine', 'CVCL:0063', (23, 27))	('single', 'Var', (39, 45))	('transfection', 'Var', (7, 19))	('N', 'Chemical', 'MESH:D009584', (58, 59))
8637	19340092	EM localization using the E. coli FimH adhesin, which specifically binds to UPIa, indicates that the UPIa/II pair occupies the inner subdomain, whereas the UP Ib/III pair occupies the outer subdomain Ref.	('adhesin', 'Gene', (39, 46))	('adhesin', 'Gene', '3654491', (39, 46))	('E. coli', 'Species', '562', (26, 33))	('UPIa/II', 'Var', (101, 108))	('localization', 'biological_process', 'GO:0051179', ('3', '15'))	('FimH', 'Chemical', '-', (34, 38))
8641	19340092	Furin-mediated removal of the pro-peptide in the TGN then triggers oligomerization to form a 16-nm particle in which UPIa/II and UPIb/IIIa are associated with the inner and outer subdomains, respectively , and to later form 2D crystals (Fig.	('UPIb/IIIa', 'Var', (129, 138))	('oligomerization', 'MPA', (67, 82))	('TGN', 'cellular_component', 'GO:0005802', ('49', '52'))	('form', 'Reg', (219, 223))	('UPIa/II', 'Var', (117, 124))	('Furin', 'Gene', '5045', (0, 5))	('associated', 'Interaction', (143, 153))	('Furin', 'Gene', (0, 5))	('triggers', 'Reg', (58, 66))	('N', 'Chemical', 'MESH:D009584', (51, 52))
8645	19340092	Mutations in such TMDs cause UPIb to aggregate, perhaps due to interactions with chaperone-like proteins that recognize improperly assembled TMDs resulting in their retention in the ER .	('aggregate', 'MPA', (37, 46))	('TMD', 'Disease', 'MESH:D049310', (141, 144))	('TMD', 'Disease', 'MESH:D049310', (18, 21))	('interactions', 'Interaction', (63, 75))	('retention', 'biological_process', 'GO:0051235', ('165', '174'))	('Mutations', 'Var', (0, 9))	('UPIb', 'MPA', (29, 33))	('TMD', 'Disease', (18, 21))	('TMD', 'Disease', (141, 144))	('retention', 'MPA', (165, 174))
8646	19340092	However, deletion of the N-linked oligosaccharide from UPIb or elimination of the disulfide bridges does not result in the ER-retention of UPIb.	('N-linked oligosaccharide', 'Chemical', '-', (25, 49))	('deletion', 'Var', (9, 17))	('disulfide', 'Chemical', 'MESH:D004220', (82, 91))	('retention', 'biological_process', 'GO:0051235', ('126', '135'))	('ER-retention', 'MPA', (123, 135))
8664	19340092	While experimental carcinogens like N-butyl-N-(4-hydroxybutyl)nitrosamine or N-nitrosomethylurea cause primarily urothelial carcinomas of the bladder , aristolochic acid, a mycotoxin contaminant in wheat and a component in certain Chinese herbal products, induces urothelial carcinomas of only the renal pelvis and the upper ureter .	('urothelial carcinomas of the bladder', 'Disease', (113, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('carcinomas', 'Phenotype', 'HP:0030731', (275, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('aristolochic acid', 'Var', (152, 169))	('N-nitrosomethylurea', 'Chemical', 'MESH:D008770', (77, 96))	('urothelial carcinomas of only the renal pelvis and the upper ureter', 'Disease', 'MESH:D014516', (264, 331))	('wheat', 'Species', '4565', (198, 203))	('N-butyl-N-(4-hydroxybutyl)nitrosamine', 'Chemical', 'MESH:D002085', (36, 73))	('urothelial carcinomas of the bladder', 'Disease', 'MESH:D001749', (113, 149))	('aristolochic acid', 'Chemical', 'MESH:C000228', (152, 169))	('cause', 'Reg', (97, 102))	('renal pelvis', 'Phenotype', 'HP:0000125', (298, 310))	('induces', 'Reg', (256, 263))
8665	19340092	A strategy was taken to ablate mouse genes encoding UPII or UPIIIa because inactivating these two UPs should abolish the formation of UPIa/II and UPIb/III pairs, respectively .	('formation', 'biological_process', 'GO:0009058', ('121', '130'))	('inactivating', 'Var', (75, 87))	('mouse', 'Species', '10090', (31, 36))	('abolish', 'NegReg', (109, 116))
8666	19340092	The retention of some plaques in the UPIIIa knockouts may be due to the presence of a minor UPIII isoform, UPIIIb, which was identified in a bovine urothelial subtraction cDNA library .	('N', 'Chemical', 'MESH:D009584', (173, 174))	('retention', 'biological_process', 'GO:0051235', ('4', '13'))	('UPIIIb', 'Gene', (107, 113))	('UPIII', 'Gene', (92, 97))	('UPIII', 'Gene', (37, 42))	('UPIII', 'Gene', '100336102', (107, 112))	('bovine', 'Species', '9913', (141, 147))	('knockouts', 'Var', (44, 53))	('UPIII', 'Gene', '100336102', (92, 97))	('UPIIIb', 'Gene', '282115', (107, 113))	('UPIII', 'Gene', '100336102', (37, 42))	('UPIII', 'Gene', (107, 112))
8673	19340092	In an attempt to determine whether UP defects might be involved in human VUR, we examined a panel of 76 well-documented VUR patients and 90 race-matched controls for single nucleotide polymorphisms (SNPs) of all four major UPs.	('VUR', 'Gene', (73, 76))	('patients', 'Species', '9606', (124, 132))	('VUR', 'Gene', '54113', (120, 123))	('single nucleotide polymorphisms', 'Var', (166, 197))	('VUR', 'Gene', (120, 123))	('human', 'Species', '9606', (67, 72))	('VUR', 'Gene', '54113', (73, 76))	('N', 'Chemical', 'MESH:D009584', (200, 201))
8677	19340092	More recent data indicate that certain UPIIIa mutations can be correlated with human renal hypodysplasia and adysplasia, which can lead to renal failure .	('correlated', 'Reg', (63, 73))	('renal failure', 'Disease', 'MESH:D051437', (139, 152))	('human', 'Species', '9606', (79, 84))	('mutations', 'Var', (46, 55))	('renal failure', 'Disease', (139, 152))	('adysplasia', 'Disease', (109, 119))	('renal hypodysplasia', 'Disease', 'MESH:C536482', (85, 104))	('renal failure', 'Phenotype', 'HP:0000083', (139, 152))	('renal hypodysplasia', 'Disease', (85, 104))	('UPIIIa', 'Gene', (39, 45))	('adysplasia', 'Disease', 'MESH:C563261', (109, 119))	('lead to', 'Reg', (131, 138))
8712	19340092	Finally, we have recently shown by using immunohistochemistry of arrayed human urothelial carcinomas that the absence of UPs expression was significantly associated with advanced pathologic stage, lymph node metastases, disease recurrence and bladder cancer-specific mortality in univariate analyses .	('metastases', 'Disease', (208, 218))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('bladder cancer', 'Phenotype', 'HP:0009725', (243, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('disease recurrence', 'CPA', (220, 238))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('urothelial carcinomas', 'Disease', (79, 100))	('human', 'Species', '9606', (73, 78))	('bladder cancer', 'Disease', 'MESH:D001749', (243, 257))	('bladder cancer', 'Disease', (243, 257))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (79, 100))	('advanced pathologic stage', 'CPA', (170, 195))	('metastases', 'Disease', 'MESH:D009362', (208, 218))	('absence', 'Var', (110, 117))	('associated', 'Reg', (154, 164))
8719	19340092	Using the mouse UPII promoter to express activated oncogenes and/or inactivate specific tumor suppressor genes in the urothelium, we have systematically evaluated whether specific molecular defects are capable of driving bladder tumorigenesis along divergent phenotypic pathways (Fig.	('mouse', 'Species', '10090', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('inactivate', 'Var', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('bladder tumor', 'Phenotype', 'HP:0009725', (221, 234))	('defects', 'Var', (190, 197))	('tumor', 'Disease', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('driving', 'Reg', (213, 220))	('tumor suppressor', 'biological_process', 'GO:0051726', ('88', '104'))	('tumor', 'Disease', (88, 93))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('88', '104'))
8722	19340092	The onset and time course of these lesions are, however, not affected by the concurrent deficiency of p16Ink4a and p19Arf - an event found to synergize with ras activation in a wide range of tissues .	('p16Ink4a', 'Gene', '1029', (102, 110))	('p19Arf', 'Gene', (115, 121))	('p19Arf', 'Gene', '1029', (115, 121))	('p16Ink4a', 'Gene', (102, 110))	('p19', 'cellular_component', 'GO:0070743', ('115', '118'))	('deficiency', 'Var', (88, 98))
8723	19340092	These results provide compelling experimental evidence indicating that deficiency of the INK4a gene, long-thought to be a critical event in urothelial tumor initiation , is unnecessary for urothelial tumor initiation; and that hyper-activation of ras per se is sufficient to trigger urothelial tumors.	('deficiency', 'Var', (71, 81))	('urothelial tumor initiation', 'Disease', 'MESH:D001749', (189, 216))	('INK4a', 'Gene', '1029', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('trigger', 'PosReg', (275, 282))	('urothelial tumors', 'Disease', (283, 300))	('INK4a', 'Gene', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('urothelial tumor initiation', 'Disease', (140, 167))	('hyper-activation', 'Var', (227, 243))	('ras', 'Protein', (247, 250))	('urothelial tumor initiation', 'Disease', (189, 216))	('urothelial tumor initiation', 'Disease', 'MESH:D001749', (140, 167))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('urothelial tumors', 'Disease', 'MESH:D001749', (283, 300))	('tumors', 'Phenotype', 'HP:0002664', (294, 300))
8724	19340092	The results obtained in mice are highly relevant to humans because ras activation via point mutations and over-expression occurs in 30% and 50%, respectively, of the human low-grade, superficial papillary bladder tumors .	('over-expression', 'PosReg', (106, 121))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('bladder tumors', 'Phenotype', 'HP:0009725', (205, 219))	('mice', 'Species', '10090', (24, 28))	('ras', 'Gene', (67, 70))	('bladder tumor', 'Phenotype', 'HP:0009725', (205, 218))	('activation', 'PosReg', (71, 81))	('human', 'Species', '9606', (166, 171))	('human', 'Species', '9606', (52, 57))	('papillary bladder tumors', 'Disease', (195, 219))	('point mutations', 'Var', (86, 101))	('papillary bladder tumors', 'Disease', 'MESH:D001749', (195, 219))	('humans', 'Species', '9606', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('low-grade', 'Disease', (172, 181))
8725	19340092	Interestingly, mutations of fibroblast growth factor receptor 3 (FGFR3), which can activate the ras signaling pathways, are found in up to 70% of these papillary tumors .	('fibroblast growth factor receptor 3', 'Gene', (28, 63))	('FGFR3', 'Gene', '2261', (65, 70))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('28', '52'))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('found', 'Reg', (124, 129))	('ras signaling pathways', 'Pathway', (96, 118))	('activate', 'PosReg', (83, 91))	('papillary tumors', 'Disease', (152, 168))	('mutations', 'Var', (15, 24))	('papillary tumors', 'Disease', 'MESH:D002291', (152, 168))	('FGFR3', 'Gene', (65, 70))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('fibroblast growth factor receptor 3', 'Gene', '2261', (28, 63))	('papillary tumors', 'Phenotype', 'HP:0007482', (152, 168))
8726	19340092	Given the fact that ras and FGFR3 mutations are almost always mutually exclusive , perhaps reflecting the fact that they function in the same signaling pathway, there is strong reason to believe that ras pathway activation, via ras mutation/overexpression or FGFR3 mutation/overexpression, occurs in an overwhelming majority of the low-grade, superficial papillary bladder tumors in humans (Refs.	('tumors', 'Phenotype', 'HP:0002664', (373, 379))	('ras pathway', 'Pathway', (200, 211))	('tumor', 'Phenotype', 'HP:0002664', (373, 378))	('FGFR3', 'Gene', (259, 264))	('bladder tumors', 'Phenotype', 'HP:0009725', (365, 379))	('mutation/overexpression', 'Var', (265, 288))	('ras', 'Gene', (228, 231))	('low-grade', 'Disease', (332, 341))	('mutation/overexpression', 'Var', (232, 255))	('FGFR3', 'Gene', (28, 33))	('FGFR3', 'Gene', '2261', (259, 264))	('FGFR', 'molecular_function', 'GO:0005007', ('259', '263'))	('FGFR3', 'Gene', '2261', (28, 33))	('bladder tumor', 'Phenotype', 'HP:0009725', (365, 378))	('papillary bladder tumors', 'Disease', (355, 379))	('signaling pathway', 'biological_process', 'GO:0007165', ('142', '159'))	('papillary bladder tumors', 'Disease', 'MESH:D001749', (355, 379))	('humans', 'Species', '9606', (383, 389))	('mutation/overexpression', 'PosReg', (232, 255))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('activation', 'PosReg', (212, 222))	('mutations', 'Var', (34, 43))
8727	19340092	Finally, patients with Costello syndrome, a genetic disease caused by germline mutations in the Ha-ras gene, frequently develop low-grade papillary bladder tumors , further supporting the relevance of ras pathway activation in this type of bladder tumors.	('bladder tumors', 'Disease', (240, 254))	('bladder tumors', 'Phenotype', 'HP:0009725', (240, 254))	('germline mutations', 'Var', (70, 88))	('bladder tumor', 'Phenotype', 'HP:0009725', (240, 253))	('bladder tumors', 'Disease', 'MESH:D001749', (148, 162))	('develop', 'PosReg', (120, 127))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('Ha-ras', 'Gene', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('bladder tumors', 'Disease', 'MESH:D001749', (240, 254))	('Costello syndrome', 'Disease', 'MESH:D056685', (23, 40))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('genetic disease', 'Disease', 'MESH:D030342', (44, 59))	('genetic disease', 'Disease', (44, 59))	('patients', 'Species', '9606', (9, 17))	('bladder tumors', 'Phenotype', 'HP:0009725', (148, 162))	('bladder tumor', 'Phenotype', 'HP:0009725', (148, 161))	('Costello syndrome', 'Disease', (23, 40))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('papillary bladder tumors', 'Disease', (138, 162))	('caused', 'Reg', (60, 66))	('papillary bladder tumors', 'Disease', 'MESH:D001749', (138, 162))
8731	19340092	Together, these results suggest that SV40T-mediated functional inactivation of the p53 and Rb tumor suppressors plays a critical role in bladder tumorigenesis along the high-grade, invasive pathway.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('inactivation', 'NegReg', (63, 75))	('Rb tumor', 'Disease', (91, 99))	('Rb tumor', 'Disease', 'MESH:D009369', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (145, 150))	('bladder tumor', 'Phenotype', 'HP:0009725', (137, 150))	('SV40T-mediated', 'Var', (37, 51))	('SV40T', 'Chemical', '-', (37, 42))
8732	19340092	Interestingly, in humans, defects affecting both p53 and Rb are rare in low-grade, superficial papillary bladder tumors but occur in over half of the high-grade, invasive bladder carcinomas .	('humans', 'Species', '9606', (18, 24))	('p53', 'Gene', (49, 52))	('papillary bladder tumors', 'Disease', (95, 119))	('invasive bladder carcinomas', 'Disease', (162, 189))	('p53', 'Gene', '7157', (49, 52))	('papillary bladder tumors', 'Disease', 'MESH:D001749', (95, 119))	('bladder tumors', 'Phenotype', 'HP:0009725', (105, 119))	('bladder tumor', 'Phenotype', 'HP:0009725', (105, 118))	('defects', 'Var', (26, 33))	('occur', 'Reg', (124, 129))	('invasive bladder carcinomas', 'Disease', 'MESH:D001749', (162, 189))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (171, 189))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('invasive bladder', 'Phenotype', 'HP:0100645', (162, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
8733	19340092	While the SV40T data from the transgenic mice are strongly supportive of the human data on p53 and Rb, one needs to be cautious because SV40T exerts wider oncogenic effects than simply inactivating p53 and Rb .	('SV40T', 'Chemical', '-', (136, 141))	('SV40T', 'Var', (136, 141))	('SV40T', 'Chemical', '-', (10, 15))	('transgenic mice', 'Species', '10090', (30, 45))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('inactivating', 'NegReg', (185, 197))	('p53', 'Gene', (198, 201))	('p53', 'Gene', '7157', (198, 201))	('oncogenic effects', 'CPA', (155, 172))	('human', 'Species', '9606', (77, 82))
8734	19340092	For this reason, specific inactivation of both p53 and Rb genes in urothelium should provide more insightful information regarding the role of these two genes in triggering muscle-invasive bladder tumors.	('invasive bladder', 'Phenotype', 'HP:0100645', (180, 196))	('invasive bladder tumors', 'Disease', (180, 203))	('inactivation', 'Var', (26, 38))	('invasive bladder tumors', 'Disease', 'MESH:D001749', (180, 203))	('bladder tumors', 'Phenotype', 'HP:0009725', (189, 203))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('p53', 'Gene', (47, 50))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('p53', 'Gene', '7157', (47, 50))	('bladder tumor', 'Phenotype', 'HP:0009725', (189, 202))
8739	19340092	We now know that uroplakins are the essential structural components of the urothelial apical surface whose deficiency compromises the urothelial permeability barrier and leads to global urinary tract anomalies.	('urinary tract anomalies', 'Disease', (186, 209))	('urinary tract anomalies', 'Phenotype', 'HP:0000079', (186, 209))	('compromises', 'NegReg', (118, 129))	('urothelial permeability barrier', 'MPA', (134, 165))	('urinary tract anomalies', 'Disease', 'MESH:D014552', (186, 209))	('deficiency', 'Var', (107, 117))	('leads to', 'Reg', (170, 178))
8830	32293345	Box plot of these scores clearly demonstrated the shared directionality in pathway dysregulation in SS and SLC, i.e., in both these conditions there was up-regulation of the pathway (Fig.	('SLC', 'Gene', '6366', (107, 110))	('SLC', 'Gene', (107, 110))	('up-regulation', 'PosReg', (153, 166))	('dysregulation', 'Var', (83, 96))	('regulation', 'biological_process', 'GO:0065007', ('156', '166'))	('SS', 'Phenotype', 'HP:0100806', (100, 102))
8869	32293345	It is worth mentioning that viral integration or bacterial infection in a setting of cancer has been reported to favour survival in SLC cancers of oropharynx, liver and kidney.	('bacterial infection', 'Phenotype', 'HP:0002718', (49, 68))	('SLC cancers', 'Disease', (132, 143))	('SLC cancers', 'Disease', 'MESH:D009369', (132, 143))	('liver', 'Disease', (159, 164))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('bacterial infection', 'Disease', 'MESH:D001424', (49, 68))	('survival', 'CPA', (120, 128))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('bacterial infection', 'Disease', (49, 68))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (85, 91))	('favour', 'PosReg', (113, 119))	('cancer', 'Disease', (136, 142))	('kidney', 'Disease', (169, 175))	('viral integration', 'Var', (28, 45))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
8870	32293345	Alteration of intestinal permeability is known in both sepsis and cancer.	('sepsis', 'Disease', 'MESH:D018805', (55, 61))	('Alteration', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('sepsis', 'Phenotype', 'HP:0100806', (55, 61))	('sepsis', 'Disease', (55, 61))	('intestinal permeability', 'MPA', (14, 37))	('cancer', 'Disease', (66, 72))
8926	29340065	In addition, we observed that the path:05215_1 from Prostate cancer displayed significantly higher activity in PRAD than other tumor types.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('higher', 'PosReg', (92, 98))	('Prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('tumor', 'Disease', (127, 132))	('Prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('PRAD', 'Enzyme', (111, 115))	('Prostate cancer', 'Disease', (52, 67))	('path:05215_1', 'Var', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('activity', 'MPA', (99, 107))
8928	29340065	For example, Path: 05219 (Bladder cancer) corresponded to BLCA, Path: 05223 (Non-small cell lung cancer) corresponded to LUAD and LUSC, and Path: 05215 (Prostate cancer) corresponded to PRAD.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Bladder cancer', 'Disease', (26, 40))	('Prostate cancer', 'Disease', 'MESH:D011471', (153, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (77, 103))	('Prostate cancer', 'Phenotype', 'HP:0012125', (153, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('PRAD', 'Disease', (186, 190))	('Path: 05215', 'Var', (140, 151))	('LUAD', 'Disease', (121, 125))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (81, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Bladder cancer', 'Phenotype', 'HP:0009725', (26, 40))	('Prostate cancer', 'Disease', (153, 168))	('Path: 05223', 'Var', (64, 75))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (77, 103))	('BLCA', 'Disease', (58, 62))	('Non-small cell lung cancer', 'Disease', (77, 103))	('Bladder cancer', 'Disease', 'MESH:D001749', (26, 40))	('Path: 05219', 'Var', (13, 24))
8933	29340065	As shown in Figure 2A, entire pathways displayed higher activities in tumor samples than normal samples, with P-value = 2.99e-07 in BLCA, P-value = 3.19e-04 in LUAD, P-value = 5.69e-11 in LUSC, and P-value = 7.87e-10 in PRAD.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('activities', 'MPA', (56, 66))	('tumor', 'Disease', (70, 75))	('P-value', 'Var', (138, 145))	('higher', 'PosReg', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('P-value', 'Var', (110, 117))
8935	29340065	In addition, the path:05223_8 and path:05215_8 displayed opposite subpathway patterns with higher activities in normal samples than tumor samples, showing that novel biological patterns were observed at the subpathway levels.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('activities', 'MPA', (98, 108))	('path:05215_8', 'Var', (34, 46))
9031	27279531	analyzed the data from 356 patients treated with radical cystectomy by univariate analysis which found that the presence of LVI was a risk for overall, cancer-specific and recurrence-free survival (p < 0.0001).	('cancer', 'Disease', (152, 158))	('LVI', 'Disease', (124, 127))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('presence', 'Var', (112, 120))	('patients', 'Species', '9606', (27, 35))	('recurrence-free survival', 'CPA', (172, 196))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('LVI', 'Chemical', '-', (124, 127))
9074	18971934	DNMT1 is associated with tumorigenesis through tumour suppressor gene hypermethylation.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('hypermethylation', 'Var', (70, 86))	('tumour', 'Disease', (47, 53))	('associated', 'Reg', (9, 19))	('DNMT1', 'Gene', (0, 5))	('DNMT1', 'Gene', '1786', (0, 5))	('tumorigenesis', 'CPA', (25, 38))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
9147	32963164	The clinical disease stage, according to the tumor-node-metastasis staging system of the Union for International Cancer Control, was T4N2M1, stage IV.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Cancer', 'Disease', (113, 119))	('tumor', 'Disease', (45, 50))	('Cancer', 'Disease', 'MESH:D009369', (113, 119))	('T4N2M1', 'Var', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
9195	33673611	The main focus hereby lies on chloroquine and hydroxychloroquine, which can inhibit autophagy by blocking the fusion of autophagosomes and lysosomes and are tested in combination studies with conventional chemotherapeutics.	('hydroxychloroquine', 'Chemical', 'MESH:D006886', (46, 64))	('inhibit', 'NegReg', (76, 83))	('autophagy', 'biological_process', 'GO:0006914', ('84', '93'))	('blocking', 'NegReg', (97, 105))	('hydroxychloroquine', 'Var', (46, 64))	('autophagy', 'CPA', (84, 93))	('chloroquine', 'Chemical', 'MESH:D002738', (53, 64))	('chloroquine', 'Chemical', 'MESH:D002738', (30, 41))	('autophagy', 'biological_process', 'GO:0016236', ('84', '93'))
9210	33673611	The cathepsin activities of RT-112 and RT-112res cells were measured using the fluorometric Cathepsin Activity Assay Kits (abcam, Cambridge, UK, #ab65300, #ab65302, #ab65306) according to the manufacturer's instructions and measured with a microplate reader (BioTek, Winooski, VT, USA, Synergy Mx).	('RT-112', 'Chemical', '-', (28, 34))	('#ab65306', 'Var', (165, 173))	('#ab65302', 'Var', (155, 163))	('RT-112', 'Chemical', '-', (39, 45))	('VT', 'Disease', 'MESH:D017180', (277, 279))	('#ab65300', 'Var', (145, 153))
9232	33673611	It is noteworthy that the IC50 value of prodigiosin in RT-112res cells was lower than in the sensitive RT-112 UCCs after both 24 h and 72 h, indicating an increased sensitivity of cisplatin-resistant cells against treatment with prodigiosin.	('lower', 'NegReg', (75, 80))	('men', 'Species', '9606', (219, 222))	('RT-112res', 'Var', (55, 64))	('sensitivity', 'MPA', (165, 176))	('increased', 'PosReg', (155, 164))	('IC50 value', 'MPA', (26, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (180, 189))	('RT-112', 'Chemical', '-', (103, 109))	('RT-112', 'Chemical', '-', (55, 61))	('prodigiosin', 'Chemical', 'MESH:D011353', (229, 240))	('prodigiosin', 'Chemical', 'MESH:D011353', (40, 51))
9245	33673611	As determined by immunoblotting, the basal levels of both LC3-II and SQSTM1 are upregulated in RT-112res cells compared to RT-112 cells (Figure 3C), which matches with previous observations and underlines the role of autophagy in the resistance mechanism of UCCs against cisplatin.	('autophagy', 'biological_process', 'GO:0016236', ('217', '226'))	('SQSTM1', 'Gene', '8878', (69, 75))	('LC3-II', 'Gene', '84557', (58, 64))	('RT-112', 'Chemical', '-', (123, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (271, 280))	('autophagy', 'biological_process', 'GO:0006914', ('217', '226'))	('LC3-II', 'Gene', (58, 64))	('RT-112res', 'Var', (95, 104))	('upregulated', 'PosReg', (80, 91))	('SQSTM1', 'Gene', (69, 75))	('RT-112', 'Chemical', '-', (95, 101))
9249	33673611	Taken together, these results suggest that RT-112res cells likely have a higher capacity for basal autophagy but that autophagy can still be modulated by prodigiosin treatment.	('autophagy', 'biological_process', 'GO:0006914', ('118', '127'))	('prodigiosin', 'Chemical', 'MESH:D011353', (154, 165))	('autophagy', 'biological_process', 'GO:0016236', ('99', '108'))	('autophagy', 'biological_process', 'GO:0006914', ('99', '108'))	('RT-112res', 'Var', (43, 52))	('autophagy', 'biological_process', 'GO:0016236', ('118', '127'))	('RT-112', 'Chemical', '-', (43, 49))	('men', 'Species', '9606', (171, 174))	('basal autophagy', 'CPA', (93, 108))	('higher', 'PosReg', (73, 79))
9252	33673611	In RT-112, there is no significant increase in cleaved PARP levels even after 48 h whereas in RT-112res, there is a time-dependent and significant increase in PARP cleavage after incubation with prodigiosin (Figure 4A,B), indicating apoptotic cell death in cisplatin-resistant UCCs upon this treatment.	('PARP', 'Gene', '142', (55, 59))	('RT-112', 'Chemical', '-', (3, 9))	('RT-112res', 'Var', (94, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (257, 266))	('PARP', 'Gene', '142', (159, 163))	('death', 'Disease', 'MESH:D003643', (248, 253))	('death', 'Disease', (248, 253))	('men', 'Species', '9606', (297, 300))	('PARP', 'Gene', (55, 59))	('RT-112', 'Chemical', '-', (94, 100))	('increase', 'PosReg', (147, 155))	('PARP', 'Gene', (159, 163))	('prodigiosin', 'Chemical', 'MESH:D011353', (195, 206))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('233', '253'))
9256	33673611	Whereas SQSTM1 accumulates in RT-112 over time, in RT-112res there is a decrease in protein level after 24 h and 48 h treatment with prodigiosin (Figure 4A,B).	('RT-112res', 'Var', (51, 60))	('SQSTM1', 'Gene', (8, 14))	('RT-112', 'Chemical', '-', (30, 36))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('SQSTM1', 'Gene', '8878', (8, 14))	('protein level', 'MPA', (84, 97))	('RT-112', 'Chemical', '-', (51, 57))	('decrease', 'NegReg', (72, 80))	('men', 'Species', '9606', (123, 126))	('prodigiosin', 'Chemical', 'MESH:D011353', (133, 144))
9259	33673611	Since modifications in both autophagy and apoptosis seem to contribute to cisplatin resistance in UCCs, we hypothesized that targeting these processes with prodigiosin might be beneficial to increase the efficiency of cisplatin treatment in BC.	('autophagy', 'CPA', (28, 37))	('modifications', 'Var', (6, 19))	('increase', 'PosReg', (191, 199))	('contribute', 'Reg', (60, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('apoptosis', 'CPA', (42, 51))	('prodigiosin', 'Chemical', 'MESH:D011353', (156, 167))	('autophagy', 'biological_process', 'GO:0006914', ('28', '37'))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('cisplatin', 'Chemical', 'MESH:D002945', (218, 227))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('autophagy', 'biological_process', 'GO:0016236', ('28', '37'))	('BC', 'Phenotype', 'HP:0009725', (241, 243))	('men', 'Species', '9606', (233, 236))
9270	33673611	In contrast to RT-112 cells, in which prodigiosin has no effect on PARP cleavage, prodigiosin treatment of RT-112res cells significantly induces apoptosis, which can be rescued by the caspase inhibitor QVD (Figure 6A,B).	('PARP', 'Gene', (67, 71))	('caspase', 'Gene', '839;841', (184, 191))	('caspase', 'Gene', (184, 191))	('induces', 'Reg', (137, 144))	('RT-112', 'Chemical', '-', (107, 113))	('PARP', 'Gene', '142', (67, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('prodigiosin', 'Var', (82, 93))	('men', 'Species', '9606', (99, 102))	('prodigiosin', 'Chemical', 'MESH:D011353', (82, 93))	('prodigiosin', 'Chemical', 'MESH:D011353', (38, 49))	('apoptosis', 'CPA', (145, 154))	('RT-112', 'Chemical', '-', (15, 21))
9273	33673611	Whereas in RT-112, prodigiosin treatment alone or in combination with cisplatin and QVD led to an increase in SQSTM1, indicating that autophagy was blocked in these cells, in RT-112res cells, the SQSTM1 levels decreased significantly upon all treatment regimens (Figure 6A,C).	('men', 'Species', '9606', (257, 260))	('SQSTM1', 'Gene', (110, 116))	('RT-112', 'Chemical', '-', (175, 181))	('men', 'Species', '9606', (248, 251))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('SQSTM1', 'Gene', '8878', (110, 116))	('RT-112', 'Chemical', '-', (11, 17))	('decreased', 'NegReg', (210, 219))	('men', 'Species', '9606', (36, 39))	('RT-112res', 'Var', (175, 184))	('increase', 'PosReg', (98, 106))	('SQSTM1', 'Gene', (196, 202))	('autophagy', 'biological_process', 'GO:0016236', ('134', '143'))	('prodigiosin', 'Chemical', 'MESH:D011353', (19, 30))	('autophagy', 'biological_process', 'GO:0006914', ('134', '143'))	('autophagy', 'CPA', (134, 143))	('SQSTM1', 'Gene', '8878', (196, 202))
9279	33673611	We observed reduced numbers but increased sizes of lysosomes in RT-112res cells (Figure 7A,B), indicating that acquired cisplatin resistance is accompanied with an altered lysosomal compartment in this cellular model.	('RT-112', 'Chemical', '-', (64, 70))	('men', 'Species', '9606', (189, 192))	('reduced', 'NegReg', (12, 19))	('RT-112res', 'Var', (64, 73))	('increased', 'PosReg', (32, 41))	('altered', 'Reg', (164, 171))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('sizes', 'MPA', (42, 47))
9285	33673611	The decreasing differences in the IC50 values of cisplatin in cisplatin-sensitive and -resistant cells reflect the different permanent cisplatin concentrations in the culture media of RT-112res, T24res, 253Jres and J82res, which are 12 microg/mL (39.9 microM), 7 microg/mL (23.3 microM), 2 microg/mL (6.6 microM) and 1 microg/mL (3.3 microM), respectively.	('IC50', 'MPA', (34, 38))	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('RT-112res', 'Var', (184, 193))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('253Jres', 'Var', (203, 210))	('RT-112', 'Chemical', '-', (184, 190))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('T24res', 'Var', (195, 201))	('J82res', 'Var', (215, 221))
9288	33673611	Whilst in T24 and T24res, effects were synergistic at all displayed EDs, the combination was rather additive to slightly synergistic in 253J, J82 and J82res.	('EDs', 'Disease', (68, 71))	('T24res', 'Var', (18, 24))	('EDs', 'Disease', 'MESH:C564542', (68, 71))	('J82', 'Var', (142, 145))	('J82res', 'Var', (150, 156))	('253J', 'Var', (136, 140))
9298	33673611	We also found that basal levels of autophagy-related proteins increased with cisplatin resistance.	('increased', 'PosReg', (62, 71))	('autophagy', 'biological_process', 'GO:0016236', ('35', '44'))	('autophagy', 'biological_process', 'GO:0006914', ('35', '44'))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('cisplatin resistance', 'Var', (77, 97))
9363	28958673	This includes a population of patients treated with modified regimens, such as split-dose cisplatin, which has been postulated to reduce renal toxicity.	('renal toxicity', 'Disease', 'MESH:D007674', (137, 151))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('patients', 'Species', '9606', (30, 38))	('renal toxicity', 'Disease', (137, 151))	('split-dose cisplatin', 'Var', (79, 99))
9389	28958673	Tables 1 and 2 present the demographic characteristics and hematologic toxicities, respectively, by high (>= 60 mL/min) and low (< 60 mL/min) baseline GFR groups.	('hematologic toxicities', 'Disease', 'MESH:D006402', (59, 81))	('low', 'NegReg', (124, 127))	('>=', 'Var', (106, 108))	('hematologic toxicities', 'Disease', (59, 81))
9390	28958673	There were no significant differences between groups, except that a greater percentage of patients with GFR < 60 mL/min had upper tract disease (P = .047).	('age', 'Gene', '5973', (83, 86))	('upper tract disease', 'Disease', 'MESH:D012141', (124, 143))	('< 60 mL/min', 'Var', (108, 119))	('age', 'Gene', (83, 86))	('upper tract disease', 'Disease', (124, 143))	('upper tract disease', 'Phenotype', 'HP:0002087', (124, 143))	('patients', 'Species', '9606', (90, 98))
9397	28958673	Hematologic toxicities were not greater in patients with baseline GFR < 60 mL/min compared to those with baseline GFR >= 60 mL/min.	('patients', 'Species', '9606', (43, 51))	('< 60', 'Var', (70, 74))	('Hematologic toxicities', 'Disease', 'MESH:D006402', (0, 22))	('Hematologic toxicities', 'Disease', (0, 22))
9417	28958673	In a meta-analysis comparing carboplatin-based regimens and cisplatin-based regimens in urothelial cancer, carboplatin-based regimens had a lower likelihood of achieving complete response and lower overall response.	('carboplatin-based', 'Var', (107, 124))	('lower', 'NegReg', (140, 145))	('carboplatin', 'Chemical', 'MESH:D016190', (29, 40))	('urothelial cancer', 'Disease', 'MESH:D014523', (88, 105))	('lower', 'NegReg', (192, 197))	('carboplatin', 'Chemical', 'MESH:D016190', (107, 118))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('complete response', 'MPA', (170, 187))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('urothelial cancer', 'Disease', (88, 105))	('overall response', 'MPA', (198, 214))
9420	28958673	These data fit with the Cleveland Clinic experience, in which 17 bladder cancer patients with GFR < 60 mL/min were found to have a similar rate of renal toxicity during neoadjuvant cisplatin chemotherapy compared to 74 with GFR >= 60 mL/min.	('bladder cancer', 'Disease', (65, 79))	('patients', 'Species', '9606', (80, 88))	('renal toxicity', 'Disease', 'MESH:D007674', (147, 161))	('GFR < 60 mL/min', 'Var', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('bladder cancer', 'Phenotype', 'HP:0009725', (65, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (181, 190))	('renal toxicity', 'Disease', (147, 161))	('bladder cancer', 'Disease', 'MESH:D001749', (65, 79))
9444	28958673	Hematologic toxicities were also not greater in patients with GFR < 60 mL/min compared to those with GFR >= 60 mL/min.	('patients', 'Species', '9606', (48, 56))	('< 60 mL/min', 'Var', (66, 77))	('Hematologic toxicities', 'Disease', 'MESH:D006402', (0, 22))	('Hematologic toxicities', 'Disease', (0, 22))
9452	32392182	In addition, gene set enrichment analysis demonstrated that PRMT5 knockdown leads to cell cycle G1/S arrest, deactivation of Akt, and mTOR phosphorylation in BUC cells.	('men', 'Species', '9606', (28, 31))	('S arrest', 'Disease', (99, 107))	('Akt', 'Gene', (125, 128))	('cell cycle', 'biological_process', 'GO:0007049', ('85', '95'))	('PRMT5', 'Gene', (60, 65))	('deactivation', 'NegReg', (109, 121))	('S arrest', 'Disease', 'MESH:D006323', (99, 107))	('mTOR', 'Gene', (134, 138))	('phosphorylation', 'biological_process', 'GO:0016310', ('139', '154'))	('mTOR', 'Gene', '2475', (134, 138))	('knockdown', 'Var', (66, 75))	('Akt', 'Gene', '207', (125, 128))
9463	32392182	One study demonstrated that overexpression and increased intranuclear accumulation of PRMT5 through methylation of Zn-finger protein were associated with a higher risk of defects in alternative splicing, leading to immortalized breast epithelial cells in humans.	('leading to', 'Reg', (204, 214))	('intranuclear accumulation', 'Phenotype', 'HP:0100304', (57, 82))	('splicing', 'biological_process', 'GO:0045292', ('194', '202'))	('immortalized breast epithelial cells in humans', 'CPA', (215, 261))	('methylation', 'MPA', (100, 111))	('increased', 'PosReg', (47, 56))	('alternative splicing', 'MPA', (182, 202))	('overexpression', 'PosReg', (28, 42))	('defects', 'Var', (171, 178))	('Zn-finger protein', 'Gene', (115, 132))	('humans', 'Species', '9606', (255, 261))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('PRMT5', 'Gene', (86, 91))	('Zn-finger protein', 'Gene', '10107', (115, 132))	('intranuclear', 'MPA', (57, 69))	('methylation', 'biological_process', 'GO:0032259', ('100', '111'))
9468	32392182	In addition, in the TCGA database, high PRMT5 expression was associated with poor overall and progression-free survival in BUC patients (Figure 1F, 1G).	('poor', 'NegReg', (77, 81))	('overall', 'CPA', (82, 89))	('progression-free survival', 'CPA', (94, 119))	('PRMT5', 'Gene', (40, 45))	('patients', 'Species', '9606', (127, 135))	('expression', 'MPA', (46, 56))	('high', 'Var', (35, 39))
9470	32392182	Figure 2E shows that patients with high PRMT5 expression had a worse prognosis compared with patients with low expression (5-year overall survival rates, 33.3% vs 58.2%, respectively; P = 0.0106).	('patients', 'Species', '9606', (21, 29))	('PRMT5', 'Gene', (40, 45))	('high', 'Var', (35, 39))	('patients', 'Species', '9606', (93, 101))
9471	32392182	The Kaplan-Meier curves also demonstrate poorer overall survival of patients with high PRMT5 expression, compared with those with low expression, with MIBC (T2-4) (P = 0.0360), absence of lymph node metastasis (P = 0.0298), and high-grade tumors (P = 0.0426; Figure 2F-2H).	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('high', 'Var', (82, 86))	('poorer', 'NegReg', (41, 47))	('overall', 'MPA', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('lymph node metastasis', 'CPA', (188, 209))	('MIBC', 'Chemical', '-', (151, 155))	('patients', 'Species', '9606', (68, 76))	('PRMT5', 'Gene', (87, 92))
9477	32392182	In the colony formation assay, both T24-siRNA and Biu87-siRNA cells formed fewer and smaller colonies than the negative control cells (P < 0.05, Figure 3D).	('Biu87-siRNA', 'Var', (50, 61))	('smaller', 'NegReg', (85, 92))	('fewer', 'NegReg', (75, 80))	('T24-siRNA', 'Var', (36, 45))	('formation', 'biological_process', 'GO:0009058', ('14', '23'))	('Biu87', 'Chemical', '-', (50, 55))
9481	32392182	The weight and size of the tumors were significantly reduced in the T24-shRNA group compared with the negative control group (P < 0.05, Figure 5C-5E).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))	('reduced', 'NegReg', (53, 60))	('T24-shRNA', 'Var', (68, 77))
9485	32392182	The proportion of cells in the G0/G1 phase significantly decreased after treatment with PRMT5 knockdown.	('knockdown', 'Var', (94, 103))	('G1 phase', 'biological_process', 'GO:0051318', ('34', '42'))	('PRMT5', 'Gene', (88, 93))	('men', 'Species', '9606', (78, 81))	('decreased', 'NegReg', (57, 66))
9493	32392182	Western blot analysis demonstrated that PRMT5 knockdown led to downregulation of PI3K, which deactivated Akt and mTOR phosphorylation.	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('Akt', 'Gene', '207', (105, 108))	('knockdown', 'Var', (46, 55))	('Akt', 'Gene', (105, 108))	('mTOR', 'Gene', (113, 117))	('deactivated', 'NegReg', (93, 104))	('mTOR', 'Gene', '2475', (113, 117))	('PRMT5', 'Gene', (40, 45))	('PI3K', 'Pathway', (81, 85))	('phosphorylation', 'biological_process', 'GO:0016310', ('118', '133'))	('downregulation', 'NegReg', (63, 77))
9499	32392182	Many novel oncogenes, such as chromosome 14 open reading frame 166, trimethylation of lysine 27 on histone H3, and maelstrom, promote malignant phenotypes in BUC.	('open reading frame 166', 'Var', (44, 66))	('lysine', 'Chemical', 'MESH:D008239', (86, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))	('histone H3', 'Protein', (99, 109))	('promote', 'PosReg', (126, 133))	('trimethylation', 'Var', (68, 82))	('malignant phenotypes', 'CPA', (134, 154))
9502	32392182	Arginine methylation is an important regulator of biological function, tumorigenesis, and tumor progression.	('Arginine', 'Chemical', 'MESH:D001120', (0, 8))	('tumor', 'Disease', (90, 95))	('Arginine', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
9504	32392182	PRMT5 and its substrate-binding partner WDR77 regulate alternative splicing through methylation of ZNF326 in breast cancer.	('regulate', 'Reg', (46, 54))	('breast cancer', 'Disease', (109, 122))	('methylation', 'Var', (84, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('WDR77', 'Gene', (40, 45))	('ZNF326', 'Gene', '284695', (99, 105))	('methylation', 'biological_process', 'GO:0032259', ('84', '95'))	('PRMT5', 'Gene', (0, 5))	('splicing', 'biological_process', 'GO:0045292', ('67', '75'))	('ZNF326', 'Gene', (99, 105))	('binding', 'molecular_function', 'GO:0005488', ('24', '31'))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('WDR77', 'Gene', '79084', (40, 45))	('alternative splicing', 'MPA', (55, 75))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
9506	32392182	These findings indicate that high PRMT5 expression promotes the proliferative and migratory processes of several types of solid cancer in humans.	('high', 'Var', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('humans', 'Species', '9606', (138, 144))	('promotes', 'PosReg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('PRMT5', 'Gene', (34, 39))	('cancer', 'Disease', (128, 134))
9512	32392182	PRMT5 upregulation results in increased proliferation and anchorage-independent colony growth, whereas cellular proliferation and colony formation in cancer are significantly inhibited by PRMT5 knockdown.	('knockdown', 'Var', (194, 203))	('inhibited', 'NegReg', (175, 184))	('anchorage-independent colony growth', 'CPA', (58, 93))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('formation', 'biological_process', 'GO:0009058', ('137', '146'))	('PRMT5', 'Gene', (0, 5))	('colony formation', 'CPA', (130, 146))	('increased', 'PosReg', (30, 39))	('PRMT5', 'Gene', (188, 193))	('cancer', 'Disease', (150, 156))	('upregulation', 'PosReg', (6, 18))	('cellular proliferation', 'CPA', (103, 125))	('proliferation', 'CPA', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
9514	32392182	In our experiments, PRMT5 knockdown resulted in significant inhibition of growth, migration, and invasion of BUC cells.	('migration', 'CPA', (82, 91))	('PRMT5', 'Gene', (20, 25))	('inhibition', 'NegReg', (60, 70))	('knockdown', 'Var', (26, 35))	('inhibition of growth', 'biological_process', 'GO:0045926', ('60', '80'))	('growth', 'CPA', (74, 80))	('men', 'Species', '9606', (13, 16))	('invasion of BUC cells', 'CPA', (97, 118))
9518	32392182	Specifically, PRMT5 inhibition markedly impaired the PI3K/Akt/ mTOR pathway.	('mTOR', 'Gene', (63, 67))	('inhibition', 'Var', (20, 30))	('impaired', 'NegReg', (40, 48))	('Akt', 'Gene', '207', (58, 61))	('PRMT5', 'Gene', (14, 19))	('PI3K', 'molecular_function', 'GO:0016303', ('53', '57'))	('Akt', 'Gene', (58, 61))	('mTOR', 'Gene', '2475', (63, 67))
9562	31312279	Nevertheless, variant histology, multiple, progressive and recurrent high-grade tumors are best treated with early radical cystectomy.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('variant', 'Var', (14, 21))
9627	31312279	Although several urine-based tumor markers have been investigated and developed (e.g., NMP22, BTA test, immunoCyt, microsatellite analysis, CYFRA21-1, fluorescence in situ hybridization (FISH), and Lewis-X), their low sensitivity and low specificity have prevented their application to NMIBC diagnosis and prognosis.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('BTA', 'Chemical', 'MESH:C012771', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('prevented', 'NegReg', (255, 264))	('tumor', 'Disease', (29, 34))	('NMIBC', 'Disease', (286, 291))	('NMP22', 'Gene', (87, 92))	('CYFRA21-1', 'Var', (140, 149))
9656	31312279	In a high-risk patient with newly diagnosed CIS, high-grade T1, or high-risk Ta urothelial carcinoma, a clinician should administer a 6-week induction course of BCG.	('patient', 'Species', '9606', (15, 22))	('high-grade', 'Var', (49, 59))	('Ta urothelial carcinoma', 'Phenotype', 'HP:0030409', (77, 100))	('Ta urothelial carcinoma', 'Disease', (77, 100))	('BCG', 'Species', '33892', (161, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('Ta urothelial carcinoma', 'Disease', 'MESH:D014526', (77, 100))
9660	31312279	Four meta-analyses (Shelley et al 2001; Han et al 2006, Shelley et al 2004, Bohle et al 2003) have confirmed that BCG after TUR is superior to TUR alone or TUR and chemotherapy for the prevention of recurrence of NMIBC in patients with Ta and T1 tumors.	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('patients', 'Species', '9606', (222, 230))	('BCG', 'Species', '33892', (114, 117))	('BCG', 'Var', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('NMIBC', 'Disease', (213, 218))	('tumors', 'Disease', (246, 252))	('tumors', 'Disease', 'MESH:D009369', (246, 252))
9672	31312279	Early radical cystectomy may be advised for very high-risk patients: T1 high grade with variant features; T1 high grade with lymphovascular invasion, multiple and/or large T1 high grade; T1 high grade with concomitant bladder/prostatic CIS; persistent T1 high grade on restaging TUR; early high-grade recurrence at 3 months; and invasive tumors involving bladder diverticula.	('bladder diverticula', 'Phenotype', 'HP:0000015', (355, 374))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('invasive tumors involving bladder diverticula', 'Disease', (329, 374))	('T1 high grade', 'Var', (187, 200))	('T1 high grade', 'Var', (252, 265))	('invasive tumors involving bladder diverticula', 'Disease', 'MESH:D001749', (329, 374))	('tumors', 'Phenotype', 'HP:0002664', (338, 344))	('patients', 'Species', '9606', (59, 67))	('bladder/prostatic CIS', 'CPA', (218, 239))
9691	26497743	Alterations of the fibroblast growth factor receptor (FGFR) pathway including amplification, mutations and overexpression are common in UC.	('mutations', 'Var', (93, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('54', '58'))	('FGF', 'Gene', (54, 57))	('amplification', 'Var', (78, 91))	('overexpression', 'PosReg', (107, 121))	('FGF', 'Gene', '2252', (54, 57))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('19', '43'))
9693	26497743	We present here the case of a patient with a metastatic UC of the renal pelvis with lymph node metastases treated with the selective FGFR inhibitor AZD4547.	('FGF', 'Gene', '2252', (133, 136))	('lymph node metastases', 'Disease', 'MESH:D009362', (84, 105))	('patient', 'Species', '9606', (30, 37))	('lymph node metastases', 'Disease', (84, 105))	('AZD4547', 'Var', (148, 155))	('FGF', 'Gene', (133, 136))	('renal pelvis', 'Phenotype', 'HP:0000125', (66, 78))	('AZD4547', 'Chemical', 'MESH:C572463', (148, 155))	('FGFR', 'molecular_function', 'GO:0005007', ('133', '137'))
9713	26497743	Genetic alterations of the FGFR genes including amplification, translocation and mutations promote cell proliferation, cell migration, anti-apoptosis and angiogenesis and have been described in a range of tumour types including urothelial cancers (Table 1).	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('cell proliferation', 'CPA', (99, 117))	('tumour', 'Disease', (205, 211))	('urothelial cancers', 'Disease', (228, 246))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('anti-apoptosis', 'CPA', (135, 149))	('mutations', 'Var', (81, 90))	('angiogenesis', 'CPA', (154, 166))	('cell migration', 'biological_process', 'GO:0016477', ('119', '133'))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('FGF', 'Gene', '2252', (27, 30))	('cell proliferation', 'biological_process', 'GO:0008283', ('99', '117'))	('anti-apoptosis', 'biological_process', 'GO:0043066', ('135', '149'))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('urothelial cancers', 'Disease', 'MESH:D014523', (228, 246))	('angiogenesis', 'biological_process', 'GO:0001525', ('154', '166'))	('FGF', 'Gene', (27, 30))	('cell migration', 'CPA', (119, 133))	('amplification', 'Var', (48, 61))	('promote', 'PosReg', (91, 98))	('translocation', 'Var', (63, 76))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('described', 'Reg', (181, 190))
9714	26497743	Amplifications of the FGFR1 gene have been found in 9-10 %, FGFR2 gene in 0.8 % and FGFR3 gene in 3-5 % of UC cases.	('FGFR1', 'Gene', '2260', (22, 27))	('found', 'Reg', (43, 48))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('Amplifications', 'Var', (0, 14))	('FGFR3', 'Gene', '2261', (84, 89))	('FGFR2', 'Gene', (60, 65))	('FGFR2', 'Gene', '2263', (60, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('84', '88'))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('FGFR1', 'Gene', (22, 27))	('FGFR3', 'Gene', (84, 89))
9717	26497743	In pre-clinical models, the presence of FGFR mutations, fusions and overexpression confers sensitivity to FGFR inhibitors.	('mutations', 'Var', (45, 54))	('FGF', 'Gene', '2252', (106, 109))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('FGF', 'Gene', (40, 43))	('sensitivity', 'MPA', (91, 102))	('FGF', 'Gene', (106, 109))	('pre', 'molecular_function', 'GO:0003904', ('3', '6'))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('FGF', 'Gene', '2252', (40, 43))
9740	26497743	Renal excretion of AZD4547 in these samples was 2.53 and 2.33 %, respectively.	('excretion', 'biological_process', 'GO:0007588', ('6', '15'))	('Renal excretion', 'Disease', (0, 15))	('AZD4547', 'Var', (19, 26))	('AZD4547', 'Chemical', 'MESH:C572463', (19, 26))	('Renal excretion', 'Disease', 'MESH:D007674', (0, 15))
9743	26497743	NanoString analysis of gene expression levels was performed on tumour samples from a total of 81 patients (15 patients dosed with AZD4547 plus an additional 66 patients pre-screened for the study).	('patients', 'Species', '9606', (160, 168))	('gene expression', 'biological_process', 'GO:0010467', ('23', '38'))	('patients', 'Species', '9606', (110, 118))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('AZD4547', 'Var', (130, 137))	('patients', 'Species', '9606', (97, 105))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('pre', 'molecular_function', 'GO:0003904', ('169', '172'))	('AZD4547', 'Chemical', 'MESH:C572463', (130, 137))	('tumour', 'Disease', (63, 69))
9747	26497743	Interestingly, this analysis failed to confirm the presence of FGFR1 gene amplification and detected the presence of an FGFR3 mutation (S236N).	('S236N', 'Mutation', 'rs200495316', (136, 141))	('FGFR3', 'Gene', (120, 125))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('FGFR1', 'Gene', (63, 68))	('FGFR1', 'Gene', '2260', (63, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('120', '124'))	('S236N', 'Var', (136, 141))	('FGFR3', 'Gene', '2261', (120, 125))
9749	26497743	In contrast to the known oncogenic FGFR3 mutations S249C, R248C and Y373C, expression of the S236N FGFR3 in MCF10 cells failed to induce anchorage-independent colony formation; hence, the functional significance of this mutation is unclear (data not shown).	('S236N', 'Var', (93, 98))	('R248C', 'Var', (58, 63))	('MCF10', 'CellLine', 'CVCL:5555', (108, 113))	('Y373C', 'Mutation', 'rs121913485', (68, 73))	('anchorage-independent colony formation', 'CPA', (137, 175))	('R248C', 'Mutation', 'rs121913482', (58, 63))	('FGFR3', 'Gene', (99, 104))	('FGFR3', 'Gene', '2261', (35, 40))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('S249C', 'Var', (51, 56))	('S249C', 'Mutation', 'rs121913483', (51, 56))	('formation', 'biological_process', 'GO:0009058', ('166', '175'))	('S236N', 'Mutation', 'rs200495316', (93, 98))	('FGFR3', 'Gene', (35, 40))	('induce', 'Reg', (130, 136))	('Y373C', 'Var', (68, 73))	('FGFR3', 'Gene', '2261', (99, 104))
9760	26497743	This report demonstrates for the first time that the FGFR inhibitor AZD4547 exhibits antitumour activity in a patient with metastatic UC.	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('FGF', 'Gene', (53, 56))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('patient', 'Species', '9606', (110, 117))	('AZD4547', 'Var', (68, 75))	('AZD4547', 'Chemical', 'MESH:C572463', (68, 75))	('FGF', 'Gene', '2252', (53, 56))
9763	26497743	AZD4547 is a potent selective inhibitor of the tyrosine-kinase activity of FGFR1, 2 and 3.	('FGFR1, 2 and 3', 'Gene', '2260;2263;2261', (75, 89))	('tyrosine-kinase activity', 'MPA', (47, 71))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('kinase activity', 'molecular_function', 'GO:0016301', ('56', '71'))	('AZD4547', 'Var', (0, 7))
9770	26497743	In phase 1 studies of FGFR inhibitors, an early efficacy signal has emerged in UC patients harbouring FGFR mutations or fusions.	('FGF', 'Gene', '2252', (102, 105))	('FGF', 'Gene', (22, 25))	('mutations', 'Var', (107, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('patients', 'Species', '9606', (82, 90))	('FGF', 'Gene', (102, 105))	('fusions', 'Var', (120, 127))	('FGF', 'Gene', '2252', (22, 25))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))
9772	26497743	A germ-line mutation in the FGFR3 extracellular binding domain was also detected, but in contrast to known hotspot FGFR3 mutations, this was not oncogenic when transfected into cells; hence, the functional significance is uncertain.	('FGFR', 'molecular_function', 'GO:0005007', ('115', '119'))	('mutations', 'Var', (121, 130))	('FGFR3', 'Gene', '2261', (28, 33))	('binding', 'molecular_function', 'GO:0005488', ('48', '55'))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('FGFR3', 'Gene', '2261', (115, 120))	('FGFR3', 'Gene', (28, 33))	('mutation', 'Var', (12, 20))	('extracellular', 'cellular_component', 'GO:0005576', ('34', '47'))	('FGFR3', 'Gene', (115, 120))
9773	26497743	This patient case highlights that, in addition to patients harbouring FGFR3 hotspot mutations or fusions in their tumour, there is potential for additional UC patients with high expression of FGFR pathway components such as FGFR, ligand and FRS2 to gain benefit from FGFR inhibitor therapy.	('gain benefit', 'PosReg', (249, 261))	('FGF', 'Gene', '2252', (70, 73))	('FGFR3', 'Gene', (70, 75))	('patient', 'Species', '9606', (159, 166))	('FGF', 'Gene', '2252', (267, 270))	('FGFR, ligand', 'molecular_function', 'GO:0005104', ('224', '236'))	('FGFR', 'molecular_function', 'GO:0005007', ('70', '74'))	('FGFR3', 'Gene', '2261', (70, 75))	('FRS2', 'Gene', (241, 245))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('FGF', 'Gene', (70, 73))	('tumour', 'Disease', (114, 120))	('FGF', 'Gene', '2252', (192, 195))	('patients', 'Species', '9606', (50, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('267', '271'))	('FGF', 'Gene', (267, 270))	('FGF', 'Gene', '2252', (224, 227))	('mutations', 'Var', (84, 93))	('FRS2', 'Gene', '10818', (241, 245))	('patients', 'Species', '9606', (159, 167))	('FGFR', 'molecular_function', 'GO:0005007', ('192', '196'))	('patient', 'Species', '9606', (5, 12))	('fusions', 'Var', (97, 104))	('FGF', 'Gene', (192, 195))	('FGF', 'Gene', (224, 227))	('patient', 'Species', '9606', (50, 57))
9774	26497743	Together, FGFR3 mutations, fusions or overexpression and FRS2 gene amplification occur in >50 % of urothelial cancer patients, and further work is required to determine the optimal patient selection criteria for defining the sensitive patient population.	('patient', 'Species', '9606', (235, 242))	('FGFR3', 'Gene', '2261', (10, 15))	('urothelial cancer', 'Disease', (99, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('10', '14'))	('patient', 'Species', '9606', (181, 188))	('FRS2', 'Gene', '10818', (57, 61))	('mutations', 'Var', (16, 25))	('FGFR3', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('overexpression', 'PosReg', (38, 52))	('FRS2', 'Gene', (57, 61))	('urothelial cancer', 'Disease', 'MESH:D014523', (99, 116))	('patient', 'Species', '9606', (117, 124))	('fusions', 'Var', (27, 34))	('patients', 'Species', '9606', (117, 125))
9775	26497743	Recently, encouraging clinical data has emerged for immunotherapies such as pembrolizumab and atezolizumab in advanced UC patients, and it will be interesting to understand the efficacy of these molecules in patients with FGFR pathway aberrations and the potential for combination with FGFR inhibitors.	('FGF', 'Gene', '2252', (222, 225))	('patients', 'Species', '9606', (208, 216))	('FGF', 'Gene', (222, 225))	('pembrolizumab', 'Chemical', 'MESH:C582435', (76, 89))	('aberrations', 'Var', (235, 246))	('patients', 'Species', '9606', (122, 130))	('FGF', 'Gene', '2252', (286, 289))	('atezolizumab', 'Chemical', 'MESH:C000594389', (94, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('286', '290'))	('FGF', 'Gene', (286, 289))	('FGFR', 'molecular_function', 'GO:0005007', ('222', '226'))
9776	26497743	To address this, a clinical trial is now planned to explore the efficacy of AZD4547, both in monotherapy and in combination with the anti-PDL1 antibody MEDI4736, in advanced UC patients with FGFR3 mutations or fusion-positive tumours, and a future opportunity might be to expand these studies to patients with elevated FGFR and/or ligand expression.	('FGF', 'Gene', (191, 194))	('FGFR3', 'Gene', (191, 196))	('tumours', 'Phenotype', 'HP:0002664', (226, 233))	('tumours', 'Disease', 'MESH:D009369', (226, 233))	('FGFR3', 'Gene', '2261', (191, 196))	('antibody', 'molecular_function', 'GO:0003823', ('143', '151'))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('antibody', 'cellular_component', 'GO:0042571', ('143', '151'))	('FGFR', 'molecular_function', 'GO:0005007', ('319', '323'))	('AZD4547', 'Gene', (76, 83))	('FGF', 'Gene', '2252', (319, 322))	('mutations', 'Var', (197, 206))	('antibody', 'cellular_component', 'GO:0019815', ('143', '151'))	('FGF', 'Gene', '2252', (191, 194))	('patients', 'Species', '9606', (296, 304))	('ligand', 'molecular_function', 'GO:0005488', ('331', '337'))	('FGF', 'Gene', (319, 322))	('patients', 'Species', '9606', (177, 185))	('AZD4547', 'Chemical', 'MESH:C572463', (76, 83))	('tumours', 'Disease', (226, 233))	('FGFR', 'molecular_function', 'GO:0005007', ('191', '195'))	('advanced', 'Disease', (165, 173))	('antibody', 'cellular_component', 'GO:0019814', ('143', '151'))
9779	26497743	Further work is required to optimise the predictive biomarkers of response to FGFR inhibitors in order to better select patients to clinical trials and ultimately provide them with a greater probability of deriving clinical benefit.	('FGF', 'Gene', '2252', (78, 81))	('FGFR', 'molecular_function', 'GO:0005007', ('78', '82'))	('FGF', 'Gene', (78, 81))	('patients', 'Species', '9606', (120, 128))	('inhibitors', 'Var', (83, 93))
9782	25096233	Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma Cisplatin-based chemotherapy is the standard of care for patients with muscle invasive urothelial carcinoma.	('muscle-invasive urothelial carcinoma', 'Disease', 'MESH:D009217', (64, 100))	('cisplatin sensitivity', 'MPA', (39, 60))	('muscle invasive urothelial carcinoma', 'Disease', 'MESH:D009217', (172, 208))	('muscle invasive urothelial carcinoma', 'Disease', (172, 208))	('ERCC2', 'Gene', '2068', (8, 13))	('muscle-invasive urothelial carcinoma', 'Disease', (64, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('ERCC2', 'Gene', (8, 13))	('patients', 'Species', '9606', (158, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('mutations', 'Var', (14, 23))	('Cisplatin', 'Chemical', 'MESH:D002945', (101, 110))
9786	25096233	Expression of representative ERCC2 mutations in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared to wild-type ERCC2.	('UV sensitivity', 'MPA', (108, 122))	('ERCC2-deficient', 'Disease', 'MESH:D007153', (51, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('ERCC2-deficient', 'Disease', (51, 66))	('ERCC2', 'Gene', (29, 34))	('cisplatin', 'MPA', (94, 103))	('mutations', 'Var', (35, 44))
9787	25096233	Lack of normal ERCC2 function may contribute to cisplatin sensitivity in urothelial cancer and somatic ERCC2 mutation status may inform cisplatin-containing regimen usage in muscle invasive urothelial carcinoma.	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('mutation', 'Var', (109, 117))	('ERCC2', 'Gene', (103, 108))	('contribute', 'Reg', (34, 44))	('urothelial cancer', 'Disease', (73, 90))	('inform', 'Reg', (129, 135))	('cisplatin sensitivity', 'MPA', (48, 69))	('urothelial cancer', 'Disease', 'MESH:D014523', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('muscle invasive urothelial carcinoma', 'Disease', 'MESH:D009217', (174, 210))	('muscle invasive urothelial carcinoma', 'Disease', (174, 210))
9795	25096233	Germline alterations in NER genes result in multiple recessive inherited disorders, including xeroderma pigmentosum (XP).	('inherited disorders', 'Disease', 'MESH:D030342', (63, 82))	('xeroderma pigmentosum', 'Disease', (94, 115))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (94, 115))	('NER', 'biological_process', 'GO:0006289', ('24', '27'))	('Germline alterations', 'Var', (0, 20))	('inherited disorders', 'Disease', (63, 82))	('result in', 'Reg', (34, 43))	('NER genes', 'Gene', (24, 33))
9799	25096233	These data suggest that tumors with loss of NER function may exhibit increased cisplatin sensitivity, and recent data has identified somatic ERCC2 mutations in 7-12% of urothelial carcinomas.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutations', 'Var', (147, 156))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (169, 190))	('increased', 'PosReg', (69, 78))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('NER', 'biological_process', 'GO:0006289', ('44', '47'))	('cisplatin sensitivity', 'MPA', (79, 100))	('ERCC2', 'Gene', (141, 146))	('urothelial carcinomas', 'Disease', (169, 190))
9806	25096233	A statistical assessment of the base mutations and short insertion/deletions across both responders and non-responders nominated four significantly altered genes previously implicated in urothelial carcinoma: TP53, RB1, KDM6A, and ARID1A (Fig.	('urothelial carcinoma', 'Disease', (187, 207))	('TP53', 'Gene', (209, 213))	('KDM6A', 'Gene', (220, 225))	('ARID1A', 'Gene', '8289', (231, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('altered', 'Reg', (148, 155))	('RB1', 'Gene', (215, 218))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (187, 207))	('KDM6A', 'Gene', '7403', (220, 225))	('TP53', 'Gene', '7157', (209, 213))	('base mutations', 'Var', (32, 46))	('RB1', 'Gene', '5925', (215, 218))	('insertion/deletions', 'Var', (57, 76))	('ARID1A', 'Gene', (231, 237))
9807	25096233	Although ERCC2 did not reach cohort-wide statistical significance, its known role in DNA repair and report of being recurrently mutated in bladder cancer raised the possibility that ERCC2 mutations might associate with cisplatin response.	('DNA repair', 'biological_process', 'GO:0006281', ('85', '95'))	('bladder cancer', 'Disease', 'MESH:D001749', (139, 153))	('bladder cancer', 'Disease', (139, 153))	('cisplatin', 'Chemical', 'MESH:D002945', (219, 228))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('ERCC2', 'Gene', (182, 187))	('associate with', 'Reg', (204, 218))	('cisplatin response', 'MPA', (219, 237))	('mutations', 'Var', (188, 197))	('bladder cancer', 'Phenotype', 'HP:0009725', (139, 153))
9808	25096233	Indeed, all ERCC2 non-synonymous somatic mutations occurred in the cisplatin sensitive tumors (P < 0.001; Fisher's exact test).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('non-synonymous', 'Var', (18, 32))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('ERCC2', 'Gene', (12, 17))	('tumors', 'Disease', (87, 93))	('occurred', 'Reg', (51, 59))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
9809	25096233	Towards this end, the median background mutation rate for ERCC2 mutant tumors (15.5 mutations per megabase) was significantly elevated compared to ERCC2 wild-type tumors (5.1 mutations per megabase) (P = 0.01; Mann-Whitney test) (Supplementary Fig.	('ERCC2', 'Gene', (58, 63))	('mutation', 'MPA', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('elevated', 'PosReg', (126, 134))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('mutant', 'Var', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
9811	25096233	When compared to these unselected populations, ERCC2 mutations were significantly enriched in the cisplatin responder cohort (36% of cases; P < 0.001; binomial test) (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('mutations', 'Var', (53, 62))	('cisplatin responder', 'MPA', (98, 117))	('ERCC2', 'Gene', (47, 52))
9812	25096233	To determine the relative abundance of somatic ERCC2 mutations in other tumor types, TCGA data from 19 tumor types (n = 4,429) was queried.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', (103, 108))	('mutations', 'Var', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('ERCC2', 'Gene', (47, 52))
9813	25096233	Somatic ERCC2 mutations were observed at low frequencies (< 4%) in 11 other tumor types (Fig.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('ERCC2', 'Gene', (8, 13))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
9814	25096233	Similarly, germline ERCC2 mutations in patients with XP (complementation group D) and XP with combined Cockayne syndrome (XP/CS), two disorders characterized by NER function, cluster within helicase domains (Fig.	('ERCC2', 'Gene', (20, 25))	('patients', 'Species', '9606', (39, 47))	('Cockayne syndrome', 'Disease', (103, 120))	('mutations', 'Var', (26, 35))	('NER', 'biological_process', 'GO:0006289', ('161', '164'))	('Cockayne syndrome', 'Disease', 'MESH:D003057', (103, 120))
9815	25096233	To test this hypothesis, the first five of the identified ERCC2 mutants were stably expressed in an immortalized ERCC2-deficient cell line derived from an XP patient, and the cisplatin sensitivity profile of each cell line was measured (Online Methods, Fig.	('ERCC2-deficient', 'Disease', (113, 128))	('ERCC2', 'Gene', (58, 63))	('patient', 'Species', '9606', (158, 165))	('mutants', 'Var', (64, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('ERCC2-deficient', 'Disease', 'MESH:D007153', (113, 128))
9817	25096233	The IC50 for the ERCC2WT-complemented cell line was significantly higher than the ERCC2-deficient parent cell line (P < 0.0001; ANOVA), whereas the IC50 for each ERCC2-mutant complemented cell line was not significantly different than the parent ERCC2-deficient parent cell line (Fig 4C).	('IC50', 'MPA', (4, 8))	('ERCC2-deficient', 'Disease', (82, 97))	('ERCC2-deficient', 'Disease', 'MESH:D007153', (246, 261))	('ERCC2-deficient', 'Disease', (246, 261))	('higher', 'PosReg', (66, 72))	('ERCC2-deficient', 'Disease', 'MESH:D007153', (82, 97))	('ERCC2WT-complemented', 'Var', (17, 37))
9819	25096233	The NER pathway repairs DNA lesions other than cisplatin adducts, so we also tested the effect of the identified ERCC2 mutations on NER-mediated repair of UV-induced DNA damage.	('DNA', 'cellular_component', 'GO:0005574', ('166', '169'))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('tested', 'Reg', (77, 83))	('NER', 'biological_process', 'GO:0006289', ('4', '7'))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('NER', 'biological_process', 'GO:0006289', ('132', '135'))	('mutations', 'Var', (119, 128))	('ERCC2', 'Gene', (113, 118))
9820	25096233	Whereas the ERCC2WT-complemented cell line rescued UV sensitivity, the UV sensitivities of the ERCC2-mutant complemented cell lines were not significantly different than that of the ERCC2-deficient parent cell line.	('rescued', 'PosReg', (43, 50))	('ERCC2-deficient', 'Disease', (182, 197))	('ERCC2-mutant', 'Var', (95, 107))	('ERCC2-deficient', 'Disease', 'MESH:D007153', (182, 197))	('ERCC2-mutant', 'Gene', (95, 107))	('UV sensitivity', 'MPA', (51, 65))
9821	25096233	Since the overall mutation rate was higher in ERCC2-mutated tumors, we hypothesized that ERCC2 mutations may be broadly contributing to genomic instability.	('mutation rate', 'MPA', (18, 31))	('contributing', 'Reg', (120, 132))	('higher', 'PosReg', (36, 42))	('genomic instability', 'MPA', (136, 155))	('ERCC2-mutated', 'Gene', (46, 59))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('mutations', 'Var', (95, 104))	('ERCC2', 'Gene', (89, 94))
9822	25096233	Thus, we measured rates of chromosomal aberrations in WT and mutant ERCC2 complemented cell lines before and after cisplatin treatment.	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (27, 50))	('ERCC2', 'Gene', (68, 73))	('mutant', 'Var', (61, 67))
9824	25096233	However, following cisplatin exposure, significantly fewer chromosomal aberrations were observed in the ERCC2WT-complemented cell line compared to the ERCC2-deficient parent cell line (P = 0.03; ANOVA), whereas expression of the ERCC2 mutants resulted in no rescue of chromosomal stability (P > 0.5) (Fig.	('ERCC2-deficient', 'Disease', (151, 166))	('chromosomal stability', 'CPA', (268, 289))	('fewer', 'NegReg', (53, 58))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (59, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('ERCC2', 'Gene', (229, 234))	('mutants', 'Var', (235, 242))	('ERCC2-deficient', 'Disease', 'MESH:D007153', (151, 166))	('chromosomal aberrations', 'CPA', (59, 82))
9825	25096233	These data suggest that the responder-associated ERCC2 mutations may contribute to overall genomic instability in these tumors.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('responder-associated', 'Disease', (28, 48))	('mutations', 'Var', (55, 64))	('ERCC2', 'Gene', (49, 54))	('genomic instability', 'CPA', (91, 110))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('contribute', 'Reg', (69, 79))
9827	25096233	However, in two responder tumors that did not have ERCC2 mutations, somatic nonsense (truncating) mutations were detected in the homologous recombination DNA repair genes BRCA1 and BRCA2 (Supplementary Table S2).	('BRCA2', 'Gene', '675', (181, 186))	('DNA', 'cellular_component', 'GO:0005574', ('154', '157'))	('DNA repair', 'biological_process', 'GO:0006281', ('154', '164'))	('BRCA1', 'Gene', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('ERCC2', 'Gene', (51, 56))	('mutations', 'Var', (98, 107))	('homologous recombination', 'biological_process', 'GO:0035825', ('129', '153'))	('mutations', 'Var', (57, 66))	('BRCA2', 'Gene', (181, 186))	('BRCA1', 'Gene', '672', (171, 176))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
9828	25096233	There were no nonsynonymous BRCA1 or BRCA2 mutations in the non-responders (Supplementary Table S2).	('BRCA1', 'Gene', '672', (28, 33))	('BRCA2', 'Gene', (37, 42))	('BRCA1', 'Gene', (28, 33))	('mutations', 'Var', (43, 52))	('BRCA2', 'Gene', '675', (37, 42))
9833	25096233	Using an extreme phenotype analysis, we have identified an association between somatic ERCC2 mutations and pathologic complete response to neoadjuvant cisplatin-based chemotherapy in muscle invasive urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('mutations', 'Var', (93, 102))	('ERCC2', 'Gene', (87, 92))	('muscle invasive urothelial carcinoma', 'Disease', 'MESH:D009217', (183, 219))	('muscle invasive urothelial carcinoma', 'Disease', (183, 219))
9834	25096233	While ERCC2 mutations occur in approximately 12% of unselected cases, 36% of cisplatin-based chemotherapy responders in our cohort harbored somatic ERCC2 non-synonymous mutations.	('ERCC2', 'Gene', (6, 11))	('mutations', 'Var', (12, 21))	('ERCC2', 'Gene', (148, 153))	('non-synonymous mutations', 'Var', (154, 178))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))
9835	25096233	Moreover, all ERCC2 mutant tumors responded to neoadjuvant chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('ERCC2', 'Gene', (14, 19))	('responded', 'Reg', (34, 43))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('mutant', 'Var', (20, 26))
9837	25096233	All ERCC2 mutations identified in this study occurred at conserved positions within or adjacent to these helicase domains, and the identified mutants all failed to complement cisplatin or UV sensitivity of an ERCC2-deficient cell line.	('ERCC2-deficient', 'Disease', (209, 224))	('ERCC2', 'Gene', (4, 9))	('complement cisplatin or UV sensitivity', 'MPA', (164, 202))	('failed', 'NegReg', (154, 160))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('mutations', 'Var', (10, 19))	('occurred', 'Reg', (45, 53))	('ERCC2-deficient', 'Disease', 'MESH:D007153', (209, 224))
9838	25096233	Together, these data suggest that the mutations result in loss of normal ERCC2 function, leading to increased tumor cell sensitivity to DNA-damaging agents such as cisplatin.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('loss', 'NegReg', (58, 62))	('increased', 'PosReg', (100, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('function', 'MPA', (79, 87))	('ERCC2', 'Gene', (73, 78))	('mutations', 'Var', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
9839	25096233	Therefore, the cisplatin sensitivity phenotype may result from a haploinsufficient or dominant negative effect of a heterozygous ERCC2 mutation, rather as a result of biallelic inactivating mutations (as in the traditional "two-hit" tumor suppressor model).	('negative', 'NegReg', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor suppressor', 'biological_process', 'GO:0051726', ('231', '247'))	('tumor', 'Disease', (233, 238))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('231', '247'))	('haploinsufficient', 'Disease', 'MESH:D058495', (65, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('result from', 'Reg', (51, 62))	('haploinsufficient', 'Disease', (65, 82))	('mutation', 'Var', (135, 143))	('ERCC2', 'Gene', (129, 134))	('cisplatin sensitivity', 'MPA', (15, 36))
9840	25096233	The driving force for heterozygous mutation of ERCC2 is unknown; however, the prevalence of ERCC2 mutations in this study and other cohorts (such as the TCGA) suggests that loss of normal ERCC2 function may provide a selective advantage for tumors.	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumors', 'Disease', (241, 247))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('mutations', 'Var', (98, 107))	('loss', 'NegReg', (173, 177))	('ERCC2', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
9843	25096233	Despite providing a potential growth advantage, mutation of one ERCC2 allele may render tumor cells susceptible to DNA damaging agent such as cisplatin if inadequate levels of WT ERCC2 are present to support NER (i.e.	('NER', 'biological_process', 'GO:0006289', ('208', '211'))	('render', 'Reg', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('mutation', 'Var', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('growth advantage', 'CPA', (30, 46))	('tumor', 'Disease', (88, 93))	('ERCC2', 'Gene', (64, 69))
9845	25096233	Alternatively, the mutated version of ERCC2 may bind but not efficiently repair damaged DNA, thereby preventing repair by an alternative DNA repair pathway and leading to a dominant-negative phenotype, as has been described for mutants of the yeast ERCC2 homolog, Rad3.	('alternative DNA', 'Pathway', (125, 140))	('ERCC2', 'Gene', (38, 43))	('Rad', 'biological_process', 'GO:1990116', ('264', '267'))	('leading to', 'Reg', (160, 170))	('preventing', 'NegReg', (101, 111))	('mutated', 'Var', (19, 26))	('Rad3', 'Gene', (264, 268))	('repair', 'MPA', (112, 118))	('dominant-negative phenotype', 'MPA', (173, 200))	('yeast', 'Species', '4932', (243, 248))	('DNA repair', 'biological_process', 'GO:0006281', ('137', '147'))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('Rad3', 'Gene', '856918', (264, 268))
9846	25096233	Further studies are necessary to explore the effects of ERCC2 loss on tumor growth, and the mechanism by which the identified ERCC2 mutations confer changes in tumor NER capacity.	('ERCC2', 'Gene', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('mutations', 'Var', (132, 141))	('ERCC2', 'Gene', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('NER', 'biological_process', 'GO:0006289', ('166', '169'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('changes', 'Reg', (149, 156))	('tumor', 'Disease', (160, 165))
9847	25096233	One possible explanation for the findings observed in this study is that somatic ERCC2 mutation is associated with good prognosis small tumors.	('good prognosis small tumors', 'Disease', 'MESH:D058405', (115, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('good prognosis small tumors', 'Disease', (115, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('ERCC2', 'Gene', (81, 86))	('mutation', 'Var', (87, 95))	('associated', 'Reg', (99, 109))
9850	25096233	While these data should not yet be used to justify avoiding cisplatin-based treatment in ERCC2 WT patients, our findings raise the possibility that somatic ERCC2 mutation status may provide a genetic means to select patients most likely to benefit from cisplatin-based chemotherapy, while directing other patients towards alternative therapeutic approaches.	('benefit', 'PosReg', (240, 247))	('mutation status', 'Var', (162, 177))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (305, 313))	('patients', 'Species', '9606', (216, 224))	('cisplatin', 'Chemical', 'MESH:D002945', (253, 262))	('ERCC2', 'Gene', (156, 161))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))
9852	25096233	Thus, this approach is distinct from genome-wide association studies that have examined germline ERCC1 or ERCC2 polymorphisms and their mixed impact on cisplatin sensitivity.	('ERCC2', 'Gene', (106, 111))	('polymorphisms', 'Var', (112, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (152, 161))	('ERCC1', 'Gene', (97, 102))	('ERCC1', 'Gene', '2067', (97, 102))	('cisplatin sensitivity', 'MPA', (152, 173))
9853	25096233	Broadly, these findings will require independent clinical validation in prospective trials to establish the clinical predictive power of somatic ERCC2 mutation status for cisplatin response.	('ERCC2', 'Gene', (145, 150))	('mutation', 'Var', (151, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))
9854	25096233	It is possible that some nonresponding urothelial tumors will harbor somatic ERCC2 mutations in larger cohorts; if observed, examination of the post-chemotherapy resistant tumor would be critical to understand whether tumor heterogeneity played a role in resistance.	('mutations', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('urothelial tumors', 'Disease', (39, 56))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('ERCC2', 'Gene', (77, 82))	('urothelial tumors', 'Disease', 'MESH:D001749', (39, 56))
9856	25096233	Since half of patients with bladder cancer are not candidates for cisplatin-based chemotherapy due to pre-existing comorbidities, less toxic carboplatin-based neoadjuvant therapies may warrant study for non-cisplatin eligible patients with ERCC2-mutant tumors To date, exceptional response genomic studies have informed genomic mechanisms of response to targeted therapies, such as response to everolimus in multiple disease contexts.	('tumors', 'Disease', (253, 259))	('tumors', 'Disease', 'MESH:D009369', (253, 259))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('ERCC2-mutant', 'Var', (240, 252))	('bladder cancer', 'Phenotype', 'HP:0009725', (28, 42))	('carboplatin', 'Chemical', 'MESH:D016190', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('ERCC2-mutant', 'Gene', (240, 252))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('patients', 'Species', '9606', (226, 234))	('cisplatin', 'Chemical', 'MESH:D002945', (207, 216))	('bladder cancer', 'Disease', 'MESH:D001749', (28, 42))	('bladder cancer', 'Disease', (28, 42))	('pre', 'molecular_function', 'GO:0003904', ('102', '105'))	('everolimus', 'Chemical', 'MESH:D000068338', (394, 404))	('patients', 'Species', '9606', (14, 22))
9859	25096233	epigenetic, expression-based) may mediate cisplatin sensitivity in these cases.	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('epigenetic', 'Var', (0, 10))	('mediate', 'Reg', (34, 41))	('cisplatin sensitivity', 'MPA', (42, 63))
9862	25096233	Finally, these results show that somatic genomic alterations may reveal the mechanistic underpinnings of anti-tumor response to conventional cytotoxic chemotherapy.	('alterations', 'Var', (49, 60))	('reveal', 'Reg', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
9881	25096233	Variants where there was inadequate sample for validation or insufficient sequencing reads in the validation data to interpret manually in IGV were listed as "Unavailable".	('Variants', 'Var', (0, 8))	('insufficient', 'Disease', (61, 73))	('insufficient', 'Disease', 'MESH:D000309', (61, 73))
9882	25096233	A site-directed PCR mutagenesis/BP recombination method was used to generate WT and mutant ERCC2 open reading frames (ORFs).	('mutant', 'Var', (84, 90))	('BP', 'Chemical', '-', (32, 34))	('ERCC2', 'Gene', (91, 96))	('mutagenesis', 'biological_process', 'GO:0006280', ('20', '31'))
9885	25096233	The expression plasmids harboring WT ERCC2, GFP (negative control), or mutant ERCC2s were expanded in E. coli TOP10 cells (Invitrogen) and purified using an anion exchange kit (Qiagen).	('E. coli', 'Species', '562', (102, 109))	('mutant', 'Var', (71, 77))	('ERCC2s', 'Gene', (78, 84))
9888	25096233	The 293T cell supernatants containing virus were collected after 48 hours, filtered twice (0.45 microm syringe filter, Millipore), then added directly to growing cultures of an SV40-transformed pseudodiploid ERCC2-deficient fibroblast cell line derived from an XP patient of genetic complementation group D (GM08207; Coriell Institute) The cell line is a compound heterozygote harboring ERCC2-R683W and ERCC2-DEL 36_61 mutations.	('293T', 'CellLine', 'CVCL:0063', (4, 8))	('R683W', 'Mutation', 'rs41556519', (393, 398))	('ERCC2-deficient', 'Disease', 'MESH:D007153', (208, 223))	('ERCC2-deficient', 'Disease', (208, 223))	('ERCC2-DEL 36_61', 'Gene', (403, 418))	('patient', 'Species', '9606', (264, 271))	('ERCC2-R683W', 'Var', (387, 398))
9903	25096233	Somatic ERCC2 mutations correlate with complete response to cisplatin-based chemosensitivity in muscle-invasive urothelial carcinoma and clinically identified mutations lead to cisplatin-sensitivity in vitro.	('response to cisplatin', 'biological_process', 'GO:0072718', ('48', '69'))	('muscle-invasive urothelial carcinoma', 'Disease', 'MESH:D009217', (96, 132))	('cisplatin-sensitivity', 'MPA', (177, 198))	('mutations', 'Var', (159, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('cisplatin', 'Chemical', 'MESH:D002945', (177, 186))	('muscle-invasive urothelial carcinoma', 'Disease', (96, 132))	('ERCC2', 'Gene', (8, 13))	('lead to', 'Reg', (169, 176))	('mutations', 'Var', (14, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))
9917	25811346	Smoking and chemical carcinogens such as aromatic amines, polycyclic hydrocarbons, and arsenic are associated with the development of urothelial carcinoma, and chronic infection with Schistosoma hematobium has been associated with squamous cell carcinoma of the bladder.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('squamous cell carcinoma of the bladder', 'Disease', (231, 269))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('associated', 'Reg', (215, 225))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (134, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('Schistosoma hematobium', 'Phenotype', 'HP:0001981', (183, 205))	('polycyclic hydrocarbons', 'Chemical', 'MESH:D006844', (58, 81))	('urothelial carcinoma', 'Disease', (134, 154))	('Schistosoma', 'Gene', (183, 194))	('chronic infection', 'Phenotype', 'HP:0031035', (160, 177))	('chronic infection', 'Disease', (160, 177))	('arsenic', 'Chemical', 'MESH:D001151', (87, 94))	('polycyclic hydrocarbons', 'Var', (58, 81))	('aromatic amines', 'Chemical', '-', (41, 56))	('associated', 'Reg', (99, 109))	('men', 'Species', '9606', (126, 129))	('squamous cell carcinoma of the bladder', 'Disease', 'MESH:D002294', (231, 269))	('chronic infection', 'Disease', 'MESH:D007239', (160, 177))
9941	25811346	In 2014, the FDA approved pembrolizumab and nivolumab for advanced melanoma and blinatumomab for acute lymphocytic leukemia, and granted breakthrough therapy designation for the immune checkpoint inhibitors MPDL3280A, an antiprogramed cell death protein ligand 1 (anti-PD-L1) antibody for metastatic urothelial bladder cancer and nivolumab, an anti-PD-1 antibody, for Hodgkin's lymphoma.	('blinatumomab for acute lymphocytic leukemia', 'Disease', (80, 123))	('pembrolizumab', 'Chemical', 'MESH:C582435', (26, 39))	('antibody', 'cellular_component', 'GO:0019815', ('354', '362'))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('antibody', 'molecular_function', 'GO:0003823', ('276', '284'))	('ligand', 'molecular_function', 'GO:0005488', ('254', '260'))	('bladder cancer', 'Phenotype', 'HP:0009725', (311, 325))	('antibody', 'cellular_component', 'GO:0042571', ('276', '284'))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (97, 123))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (207, 216))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('MPDL3280A', 'Var', (207, 216))	('cell death', 'biological_process', 'GO:0008219', ('235', '245'))	('antibody', 'cellular_component', 'GO:0019814', ('354', '362'))	('PD-L1', 'Gene', (269, 274))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (300, 325))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (368, 386))	('blinatumomab for acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (80, 123))	('PD-L1', 'Gene', '29126', (269, 274))	('antibody', 'cellular_component', 'GO:0019815', ('276', '284'))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (368, 386))	('urothelial bladder cancer', 'Disease', (300, 325))	('nivolumab', 'Chemical', 'MESH:D000077594', (330, 339))	('protein', 'cellular_component', 'GO:0003675', ('246', '253'))	('antibody', 'molecular_function', 'GO:0003823', ('354', '362'))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('nivolumab', 'Chemical', 'MESH:D000077594', (44, 53))	('melanoma', 'Disease', (67, 75))	('antibody', 'cellular_component', 'GO:0042571', ('354', '362'))	('lymphoma', 'Phenotype', 'HP:0002665', (378, 386))	('antibody', 'cellular_component', 'GO:0019814', ('276', '284'))	("Hodgkin's lymphoma", 'Disease', (368, 386))
9949	25811346	Recent clinical trials have shown durable antitumor responses following blockade of the PD-1/PD-L1 pathway, particularly in patients with PD-L1-expressing tumors or immune subsets.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('PD-L1', 'Gene', '29126', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('blockade', 'Var', (72, 80))	('PD-L1', 'Gene', (93, 98))	('PD-L1', 'Gene', (138, 143))	('patients', 'Species', '9606', (124, 132))	('PD-L1', 'Gene', '29126', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
9960	25811346	Overexpression of PD-L1 in urothelial carcinomas has been shown to correlate with high-grade tumors and worse clinical outcome.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (27, 48))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('urothelial carcinomas', 'Disease', (27, 48))	('Overexpression', 'Var', (0, 14))	('tumors', 'Disease', (93, 99))	('PD-L1', 'Gene', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))	('PD-L1', 'Gene', '29126', (18, 23))
9968	25811346	A phase-I multicohort study (PCD4989G) evaluates MPDL3280A, a high-affinity, humanized monoclonal IgG1 antibody against PD-L1, in advanced solid tumors.	('MPDL3280A', 'Chemical', 'MESH:C000594389', (49, 58))	('PCD', 'biological_process', 'GO:0012501', ('29', '32'))	('IgG1', 'Gene', '16017', (98, 102))	('solid tumors', 'Disease', 'MESH:D009369', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('IgG1 antibody', 'cellular_component', 'GO:0071736', ('98', '111'))	('PD-L1', 'Gene', (120, 125))	('PD-L1', 'Gene', '29126', (120, 125))	('MPDL3280A', 'Var', (49, 58))	('IgG1', 'Gene', (98, 102))	('CD4', 'Gene', (30, 33))	('solid tumors', 'Disease', (139, 151))	('CD4', 'Gene', '920', (30, 33))	('antibody', 'molecular_function', 'GO:0003823', ('103', '111'))	('human', 'Species', '9606', (77, 82))
9969	25811346	Because PD-L1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the fragment crystallizable (Fc) region that eliminates antibody-dependent cellular cytotoxicity to prevent depletion of T cells expressing PD-L1.	('MPDL3280A', 'Chemical', 'MESH:C000594389', (49, 58))	('cytotoxicity', 'Disease', 'MESH:D064420', (181, 193))	('PD-L1', 'Gene', '29126', (237, 242))	('PD-L1', 'Gene', (8, 13))	('depletion', 'MPA', (205, 214))	('antibody', 'cellular_component', 'GO:0042571', ('153', '161'))	('cytotoxicity', 'Disease', (181, 193))	('PD-L1', 'Gene', '29126', (8, 13))	('antibody-dependent cellular cytotoxicity', 'biological_process', 'GO:0001788', ('153', '193'))	('men', 'Species', '9606', (105, 108))	('antibody-dependent', 'Protein', (153, 171))	('MPDL3280A', 'Var', (49, 58))	('PD-L1', 'Gene', (237, 242))	('antibody', 'cellular_component', 'GO:0019815', ('153', '161'))	('eliminates', 'NegReg', (142, 152))	('antibody', 'cellular_component', 'GO:0019814', ('153', '161'))	('antibody', 'molecular_function', 'GO:0003823', ('153', '161'))
9992	25811346	In a murine model, B7-H3-deficient mice developed increased T helper type 1-mediated lung inflammation and autoimmune encephalomyelitis, suggesting B7-H3's role as a negative regulator of T helper type 1 responses.	('lung inflammation', 'Disease', (85, 102))	('autoimmune encephalomyelitis', 'Disease', 'MESH:D004681', (107, 135))	('B7-H3-deficient', 'Var', (19, 34))	('increased', 'PosReg', (50, 59))	('murine', 'Species', '10090', (5, 11))	('mice', 'Species', '10090', (35, 39))	('inflammation', 'biological_process', 'GO:0006954', ('90', '102'))	('lung inflammation', 'Disease', 'MESH:D011014', (85, 102))	('autoimmune encephalomyelitis', 'Disease', (107, 135))
9995	25811346	Expression of B7-H3 in urothelial bladder cancer was significantly increased compared with adjacent nontumor urothelium, as a median of 70% of tumor cells expressed B7-H3 compared with 20% of cells in nontumor specimens (P < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('B7-H3', 'Var', (165, 170))	('urothelial bladder cancer', 'Disease', (23, 48))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Expression', 'MPA', (0, 10))	('tumor', 'Disease', (103, 108))	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (23, 48))	('tumor', 'Disease', (204, 209))	('increased', 'PosReg', (67, 76))	('men', 'Species', '9606', (215, 218))	('B7-H3', 'Gene', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
10001	25811346	CTLA-4 blockade was associated with increased frequency of CD4+ICOShi T cells and increased perivascular infiltration of activated T cells in tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('CTLA-4', 'Gene', (0, 6))	('CD4', 'Gene', (59, 62))	('CD4', 'Gene', '920', (59, 62))	('tumor', 'Disease', (142, 147))	('perivascular infiltration of', 'CPA', (92, 120))	('increased', 'PosReg', (36, 45))	('CTLA-4', 'Gene', '1493', (0, 6))	('blockade', 'Var', (7, 15))	('increased', 'PosReg', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
10068	25811346	A preclinical study indicated that cabozantinib not only altered the phenotype of MC38-CEA murine tumor cells, rendering them more sensitive to immune-mediated killing, but also altered the frequency of immune subpopulations in the periphery and the tumor microenvironment, generating a more permissive immune environment.	('cabozantinib', 'Var', (35, 47))	('more', 'PosReg', (287, 291))	('cabozantinib', 'Chemical', 'MESH:C558660', (35, 47))	('men', 'Species', '9606', (317, 320))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('murine', 'Species', '10090', (91, 97))	('more', 'PosReg', (126, 130))	('men', 'Species', '9606', (268, 271))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', (98, 103))	('altered', 'Reg', (178, 185))	('sensitive', 'MPA', (131, 140))	('tumor', 'Disease', (250, 255))	('altered', 'Reg', (57, 64))
10089	31717704	Expression of Adenosine Receptors in Rodent Pancreas Adenosine regulates exocrine and endocrine secretions in the pancreas.	('Adenosine', 'Var', (53, 62))	('Pancreas', 'Disease', 'MESH:D010190', (44, 52))	('Adenosine', 'Chemical', 'MESH:D000241', (14, 23))	('regulates', 'Reg', (63, 72))	('Pancreas', 'Disease', (44, 52))	('Adenosine', 'Chemical', 'MESH:D000241', (53, 62))
10105	31717704	In endocrine cells, N6-L-phenyl-isopropyl-adenosine, an A1 adenosine receptor agonist, reduced glucose-induced insulin secretion from the perfused rat and mouse pancreas.	('adenosine', 'Chemical', 'MESH:D000241', (42, 51))	('insulin', 'molecular_function', 'GO:0016088', ('111', '118'))	('reduced', 'NegReg', (87, 94))	('mouse', 'Species', '10090', (155, 160))	('glucose', 'Chemical', 'MESH:D005947', (95, 102))	('N6-L-phenyl-isopropyl-adenosine', 'Chemical', 'MESH:C054123', (20, 51))	('rat', 'Species', '10116', (147, 150))	('insulin secretion', 'biological_process', 'GO:0030073', ('111', '128'))	('insulin', 'Gene', '100379579', (111, 118))	('N6-L-phenyl-isopropyl-adenosine', 'Var', (20, 51))	('adenosine', 'Chemical', 'MESH:D000241', (59, 68))	('insulin', 'Gene', (111, 118))
10108	31717704	Real-time PCR revealed that the rank order of the adenosine mRNA level was A2A > A2B >= A3 >> A1, where the level of A2A was at least five times higher than of other receptors in the rat pancreas.	('rat', 'Species', '10116', (183, 186))	('A2A', 'Var', (75, 78))	('A2B', 'Gene', '29316', (81, 84))	('adenosine', 'Chemical', 'MESH:D000241', (50, 59))	('A2B', 'Gene', (81, 84))	('adenosine mRNA level', 'MPA', (50, 70))
10120	31717704	In order to determine the cells that expressed A2A and A2B adenosine receptors, triple staining of adenosine receptors was performed with insulin and glucagon on paraffin sections of the rat pancreas.	('rat', 'Species', '10116', (187, 190))	('A2B', 'Gene', (55, 58))	('A2A', 'Var', (47, 50))	('insulin', 'molecular_function', 'GO:0016088', ('138', '145'))	('insulin', 'Gene', '100379579', (138, 145))	('A2B', 'Gene', '29316', (55, 58))	('insulin', 'Gene', (138, 145))	('adenosine', 'Chemical', 'MESH:D000241', (99, 108))	('adenosine', 'Chemical', 'MESH:D000241', (59, 68))
10142	31717704	We detected A2A (ADORA2A, 54 kDa) and A2B (ADORA2B, 55 kDa) adenosine receptors in the lysates of the isolated ducts (Figure 5; n = 2 rats).	('ADORA2A', 'Gene', (17, 24))	('A2B', 'Gene', (38, 41))	('rats', 'Species', '10116', (134, 138))	('ADORA2A', 'Gene', '25369', (17, 24))	('A2B', 'Gene', '29316', (47, 50))	('A2B', 'Gene', '29316', (38, 41))	('adenosine', 'Chemical', 'MESH:D000241', (60, 69))	('A2B', 'Gene', (47, 50))	('adenosine receptors', 'Protein', (60, 79))	('A2A', 'Var', (12, 15))
10162	31717704	Neither SCH-442416 nor PSB 603 led to an increase in the concentration of protein (Figure 7E,H) or had a significant effect on the HCO3- concentration (Figure 7C,F,I).	('SCH-442416', 'Var', (8, 18))	('HCO3- concentration', 'MPA', (131, 150))	('PSB 603', 'Gene', (23, 30))	('HCO3', 'Chemical', 'MESH:C504136', (131, 135))	('SCH-442416', 'Chemical', 'MESH:C416650', (8, 18))	('rat', 'Species', '10116', (64, 67))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('concentration of protein', 'MPA', (57, 81))	('rat', 'Species', '10116', (144, 147))	('increase', 'PosReg', (41, 49))
10166	31717704	In contrast, high expression of ADORA2B (A2B adenosine receptor) was associated with poor disease-free survival (Figure 8D; log-rank P = 0.0125).	('A2B', 'Gene', (41, 44))	('adenosine', 'Chemical', 'MESH:D000241', (45, 54))	('A2B', 'Gene', '29316', (36, 39))	('high', 'Var', (13, 17))	('A2B', 'Gene', '29316', (41, 44))	('A2B', 'Gene', (36, 39))	('poor', 'NegReg', (85, 89))	('disease-free survival', 'CPA', (90, 111))
10174	31717704	A2A and A2B adenosine receptors primarily signal via Gs proteins, resulting in the activation of adenylyl cyclase, an increase in cAMP production, activation of a membrane-associated isoform of protein kinase A (type II PKA), and subsequent activation of cAMP-activated Cl- channels (CFTR).	('increase', 'PosReg', (118, 126))	('A2B', 'Gene', (8, 11))	('activation', 'PosReg', (241, 251))	('adenylyl', 'MPA', (97, 105))	('A2B', 'Gene', '29316', (8, 11))	('PKA', 'cellular_component', 'GO:0005952', ('220', '223'))	('A2A', 'Var', (0, 3))	('adenosine', 'Chemical', 'MESH:D000241', (12, 21))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('CFTR', 'Gene', (284, 288))	('Gs proteins', 'Protein', (53, 64))	('membrane', 'cellular_component', 'GO:0016020', ('163', '171'))	('cAMP-activated Cl- channels', 'MPA', (255, 282))	('CFTR', 'Gene', '24255', (284, 288))	('activation', 'PosReg', (147, 157))	('cAMP production', 'MPA', (130, 145))	('PKA', 'molecular_function', 'GO:0004691', ('220', '223'))	('activation', 'PosReg', (83, 93))
10186	31717704	The effects of CGS 21680 and BAY 60-6583 were small compared to those of secretin in in vivo experiments (Figure 6).	('secretin', 'molecular_function', 'GO:0046659', ('73', '81'))	('secretin', 'Gene', (73, 81))	('BAY 60-6583', 'Chemical', 'MESH:C518875', (29, 40))	('CGS 21680', 'Var', (15, 24))	('secretin', 'molecular_function', 'GO:0008565', ('73', '81'))	('secretin', 'Gene', '24769', (73, 81))	('CGS 21680', 'Chemical', 'MESH:C061282', (15, 24))
10187	31717704	In the present study, ductal secretion was stimulated significantly more by CGS 21680 than BAY 60-6583 at the same concentration, indicating that A2A adenosine receptors were dominant in rat duct cells, whereas BAY 60-6583 showed a tendency to promote HCO3--rich fluid secretion (Figure 6E,F).	('HCO3', 'Chemical', 'MESH:C504136', (252, 256))	('rat', 'Species', '10116', (187, 190))	('stimulated', 'PosReg', (43, 53))	('BAY 60-6583', 'Chemical', 'MESH:C518875', (211, 222))	('A2A adenosine receptors', 'Protein', (146, 169))	('CGS 21680', 'Var', (76, 85))	('BAY 60-6583', 'Chemical', 'MESH:C518875', (91, 102))	('adenosine', 'Chemical', 'MESH:D000241', (150, 159))	('rat', 'Species', '10116', (122, 125))	('promote', 'PosReg', (244, 251))	('CGS 21680', 'Chemical', 'MESH:C061282', (76, 85))	('ductal secretion', 'MPA', (22, 38))	('HCO3--rich fluid secretion', 'MPA', (252, 278))	('secretion', 'biological_process', 'GO:0046903', ('269', '278'))	('secretion', 'biological_process', 'GO:0046903', ('29', '38'))
10191	31717704	Meanwhile, the affinity of A2B adenosine receptors for BAY 60-6583 was not altered by co-expression with A2A adenosine receptors.	('BAY 60-6583', 'Chemical', 'MESH:C518875', (55, 66))	('A2B', 'Gene', (27, 30))	('adenosine', 'Chemical', 'MESH:D000241', (31, 40))	('A2B', 'Gene', '29316', (27, 30))	('adenosine', 'Chemical', 'MESH:D000241', (109, 118))	('BAY', 'Var', (55, 58))
10201	31717704	The blockade of A2B adenosine receptors was shown to increase the sensitivity of mouse GL261 glioma cells to the chemotherapeutic drug temozolomide.	('A2B', 'Gene', '29316', (16, 19))	('glioma', 'Disease', (93, 99))	('sensitivity', 'MPA', (66, 77))	('blockade', 'Var', (4, 12))	('A2B', 'Gene', (16, 19))	('increase', 'PosReg', (53, 61))	('GL261', 'CellLine', 'CVCL:Y003', (87, 92))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('mouse', 'Species', '10090', (81, 86))	('adenosine', 'Chemical', 'MESH:D000241', (20, 29))	('temozolomide', 'Chemical', 'MESH:C047246', (135, 147))
10320	29487801	Radiotherapy for cervical cancer was associated with statistically significantly increased risks of several SMNs including bladder cancer.	('SMNs', 'Disease', (108, 112))	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('Radiotherapy', 'Var', (0, 12))	('SMNs', 'Chemical', '-', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cervical cancer', 'Disease', (17, 32))	('bladder cancer', 'Disease', 'MESH:D001749', (123, 137))	('cervical cancer', 'Disease', 'MESH:D002583', (17, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('bladder cancer', 'Disease', (123, 137))
10367	24987357	Because the biological behavior of a bladder tumor with variant histology differs from that of conventional UC, an accurate histological diagnosis is important for an optimal patient management.	('variant', 'Var', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('patient', 'Species', '9606', (175, 182))	('bladder tumor', 'Disease', 'MESH:D001749', (37, 50))	('bladder tumor', 'Phenotype', 'HP:0009725', (37, 50))	('man', 'Species', '9606', (183, 186))	('bladder tumor', 'Disease', (37, 50))
10387	24987357	Urothelial carcinomas with variant histological differentiation are more likely to present in an advanced stage and are associated with a worse prognosis.	('Urothelial carcinomas', 'Disease', (0, 21))	('Urothelial carcinomas', 'Disease', 'MESH:D014526', (0, 21))	('variant', 'Var', (27, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))
10397	24486590	Integrative analysis of 1q23.3 copy number gain in metastatic urothelial carcinoma Metastatic urothelial carcinoma (UC) of the bladder is associated with multiple somatic copy number alterations (SCNAs).	('Metastatic urothelial carcinoma', 'Disease', (83, 114))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (62, 82))	('Metastatic urothelial carcinoma', 'Disease', 'MESH:C538445', (83, 114))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (94, 114))	('copy number', 'Var', (31, 42))	('1q23.3', 'Gene', (24, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('gain', 'PosReg', (43, 47))	('urothelial carcinoma', 'Disease', (62, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
10402	24486590	The identification of the target of this copy number gain is ongoing, and exploration of this finding in other disease states may be useful for the early identification of poor risk UC patients.	('gain', 'PosReg', (53, 57))	('patients', 'Species', '9606', (185, 193))	('copy number', 'Var', (41, 52))
10422	24486590	The Genomic DNA ULS labeling kit for FFPE Samples (Agilent Technologies, Inc., Palo Alto, CA) was used to chemically label 500ng of DNA with either ULS-Cy5 (tumor) or ULS-Cy3 dye (normal/reference DNA) following the manufacturer's protocol.	('tumor', 'Disease', (157, 162))	('ULS-Cy3 dye', 'MPA', (167, 178))	('DNA', 'cellular_component', 'GO:0005574', ('197', '200'))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('ULS-Cy5', 'Var', (148, 155))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('DNA', 'cellular_component', 'GO:0005574', ('12', '15'))
10437	24486590	Threshold for copy number gain and loss was set so that approximately 99% of all segments in normal samples were below this threshold (+/- 0.15 for the Spanish and TCGA cohorts and +/- 0.25 for the DFCI cohort).	('loss', 'NegReg', (35, 39))	('DFCI', 'Chemical', '-', (198, 202))	('+/- 0.25', 'Var', (181, 189))	('copy number', 'Var', (14, 25))	('gain', 'PosReg', (26, 30))
10451	24486590	Validation of the 1q23.3 amplification showed it was significantly associated with overall survival after recurrence in the DFCI cohort (n = 33; adj.	('overall survival', 'MPA', (83, 99))	('DFCI', 'Chemical', '-', (124, 128))	('associated with', 'Reg', (67, 82))	('amplification', 'Var', (25, 38))	('1q23.3', 'Gene', (18, 24))
10452	24486590	Gain of 1q23.3 is often accompanied by gain of the MCL1 locus 1q21.2, one of the most frequent copy number alterations across all cancer types.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('Gain', 'PosReg', (0, 4))	('MCL1', 'Gene', '4170', (51, 55))	('MCL1', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('gain', 'PosReg', (39, 43))	('1q23.3', 'Var', (8, 14))
10457	24486590	Patients with 1q23.3 amplification often had high copy numbers in more than one peak (Figure S11).	('high copy', 'MPA', (45, 54))	('Patients', 'Species', '9606', (0, 8))	('amplification', 'Var', (21, 34))	('1q23.3 amplification', 'Var', (14, 34))
10459	24486590	Copy numbers of all genes in peak 1 were highly correlated with expression (FDR < 0.001).	('correlated', 'Interaction', (48, 58))	('expression', 'MPA', (64, 74))	('peak 1', 'Gene', '79834', (29, 35))	('Copy numbers', 'Var', (0, 12))	('peak 1', 'Gene', (29, 35))
10465	24486590	Finally, amplification of 1q23.3 was most frequent in peak 1 for the two large cohorts Spanish and TCGA (Figure 3b).	('peak 1', 'Gene', '79834', (54, 60))	('1q23.3', 'Gene', (26, 32))	('peak 1', 'Gene', (54, 60))	('amplification', 'Var', (9, 22))
10469	24486590	These high correlations of gene expression were only observed in Spanish and DFCI cohort patients with 1q23.3 copy number gain (Figure S16), implying that those MSKCC samples with correlated over-expression of all of these genes also had copy number gain of the 1q23.3 locus.	('copy number', 'Var', (238, 249))	('gene expression', 'biological_process', 'GO:0010467', ('27', '42'))	('over-expression', 'PosReg', (191, 206))	('patients', 'Species', '9606', (89, 97))	('DFCI', 'Chemical', '-', (77, 81))
10473	24486590	Gain of 1q23.3 is one of the most frequent copy number alterations in UC, is most prevalent in invasive tumors and is further observed in multiple other cancer types.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Disease', (153, 159))	('invasive tumors', 'Disease', (95, 110))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('Gain', 'PosReg', (0, 4))	('prevalent', 'Reg', (82, 91))	('invasive tumors', 'Disease', 'MESH:D009369', (95, 110))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('1q23.3', 'Var', (8, 14))
10474	24486590	The supporting data from the bladder cancer cohort of the TCGA identifies the same region showing significant copy number gains.	('bladder cancer', 'Disease', 'MESH:D001749', (29, 43))	('bladder cancer', 'Disease', (29, 43))	('bladder cancer', 'Phenotype', 'HP:0009725', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('copy number', 'Var', (110, 121))
10481	24486590	Similarly, CDKN2A deletion, and amplification of CDK4, cyclin D1, and E2F3 are potentially targetable by novel agents inhibiting CDK4.	('CDK4', 'Gene', (49, 53))	('amplification', 'MPA', (32, 45))	('cyclin D1', 'Gene', '595', (55, 64))	('E2F3', 'Gene', (70, 74))	('CDK4', 'Gene', (129, 133))	('cyclin D1', 'Gene', (55, 64))	('E2F3', 'Gene', '1871', (70, 74))	('CDK', 'molecular_function', 'GO:0004693', ('49', '52'))	('CDK', 'molecular_function', 'GO:0004693', ('129', '132'))	('CDK4', 'Gene', '1019', (129, 133))	('CDKN2A', 'Gene', (11, 17))	('inhibiting', 'NegReg', (118, 128))	('cyclin', 'molecular_function', 'GO:0016538', ('55', '61'))	('deletion', 'Var', (18, 26))	('CDKN2A', 'Gene', '1029', (11, 17))	('CDK4', 'Gene', '1019', (49, 53))
10482	24486590	While the association of 1q23.3 copy number gain with poor outcomes has been shown in unrelated cohorts in this study, the sample sizes for these validation cohorts were relatively small, treatments were non-uniform, and the tissue of origin (primary vs. metastatic) in the DFCI cohort was heterogeneous.	('DFCI', 'Chemical', '-', (274, 278))	('copy number', 'Var', (32, 43))	('gain', 'PosReg', (44, 48))
10487	24486590	Over-expression of DEDD has further been shown to decrease rates of apoptosis in vitro.	('DEDD', 'Gene', (19, 23))	('apoptosis', 'biological_process', 'GO:0097194', ('68', '77'))	('Over-expression', 'Var', (0, 15))	('apoptosis', 'biological_process', 'GO:0006915', ('68', '77'))	('DEDD', 'Gene', '9191', (19, 23))	('decrease', 'NegReg', (50, 58))
10489	24486590	PPOX, the protoporphyrinogen oxidase, is involved in heme biosynthesis, and its inactivation causes variegate porphyria.	('variegate porphyria', 'Disease', (100, 119))	('protoporphyrinogen oxidase', 'Gene', '5498', (10, 36))	('protoporphyrinogen oxidase', 'Gene', (10, 36))	('heme biosynthesis', 'biological_process', 'GO:0006783', ('53', '70'))	('heme', 'Chemical', 'MESH:D006418', (53, 57))	('PPOX', 'Gene', '5498', (0, 4))	('PPOX', 'Gene', (0, 4))	('inactivation', 'Var', (80, 92))	('causes', 'Reg', (93, 99))
10499	24486590	Somatic missense mutations of this gene have been observed in colon, ovarian and squamous cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('observed', 'Reg', (50, 58))	('colon, ovarian and squamous cell lung cancer', 'Disease', 'MESH:D002294', (62, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (81, 106))	('missense mutations', 'Var', (8, 26))
10500	24486590	While PVRL4 was not strongly associated with bladder cancer survival on the mRNA and protein level, suggesting that PVRL4 is not a primary target of 1q23.3 amplification, copy number gains and amplifications increased mRNA levels significantly (Figure S12).	('PVRL4', 'Gene', '81607', (6, 11))	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('bladder cancer', 'Disease', (45, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('PVRL4', 'Gene', (116, 121))	('increased', 'PosReg', (208, 217))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('PVRL4', 'Gene', (6, 11))	('mRNA levels', 'MPA', (218, 229))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('amplifications', 'Var', (193, 207))	('PVRL4', 'Gene', '81607', (116, 121))	('copy number gains', 'Var', (171, 188))
10502	24486590	High levels of this protein have been shown to be associated with poor survival in breast and lung cancer.	('breast and lung cancer', 'Disease', 'MESH:D001943', (83, 105))	('High levels', 'Var', (0, 11))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('poor', 'NegReg', (66, 70))
10509	24486590	Based on the results of this analysis, genes within 1q23.3 may lead to poor outcomes in a subset of patients with metastatic UC, and further exploration of this chromosomal region is warranted.	('chromosomal region', 'cellular_component', 'GO:0098687', ('161', '179'))	('patients', 'Species', '9606', (100, 108))	('metastatic UC', 'Disease', (114, 127))	('genes', 'Var', (39, 44))
10512	24486590	While many regions showed copy number gain and loss, gain of a short segment of chromosome 1q23.3, one of the most frequent alterations in UC, was determined to confer a poor prognosis independent of known prognostic factors, and externally validated in a cohort of primary and metastatic tumors.	('gain', 'PosReg', (38, 42))	('copy number', 'Var', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('chromosome', 'cellular_component', 'GO:0005694', ('80', '90'))	('loss', 'NegReg', (47, 51))	('tumors', 'Disease', (289, 295))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('gain', 'PosReg', (53, 57))
10578	22811704	IL-8-251 T > A polymorphism also seems to be a relevant susceptibility factor for bladder carcinoma development and to influence bladder cancer patients' outcome after BCG immunotherapy.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder carcinoma', 'Disease', (82, 99))	('IL-8-251', 'Gene', (0, 8))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('men', 'Species', '9606', (107, 110))	('bladder cancer', 'Disease', 'MESH:D001749', (129, 143))	('susceptibility', 'Reg', (56, 70))	('influence', 'Reg', (119, 128))	('patients', 'Species', '9606', (144, 152))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (82, 99))	('bladder cancer', 'Disease', (129, 143))	('polymorphism', 'Var', (15, 27))	('bladder carcinoma', 'Disease', 'MESH:D001749', (82, 99))	('IL-8', 'molecular_function', 'GO:0005153', ('0', '4'))
10602	22811704	As regards to BLCA-4, results show that its expression does not only provide bladder cancer cells with growth advantage but can also cause malignant cell transformation.	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('expression', 'Var', (44, 54))	('bladder cancer', 'Disease', (77, 91))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('malignant cell transformation', 'CPA', (139, 168))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('growth advantage', 'CPA', (103, 119))	('cause', 'Reg', (133, 138))
10608	31134149	Epigenetic-Mediated Downregulation of Zinc Finger Protein 671 (ZNF671) Predicts Poor Prognosis in Multiple Solid Tumors Zinc finger protein 671 (ZNF671) is a member of the largest transcription factor family in the human genome.	('Zinc Finger Protein 671', 'Gene', (38, 61))	('Epigenetic-Mediated', 'Var', (0, 19))	('transcription', 'biological_process', 'GO:0006351', ('180', '193'))	('Tumors', 'Disease', (113, 119))	('Tumors', 'Disease', 'MESH:D009369', (113, 119))	('Downregulation', 'NegReg', (20, 34))	('Tumors', 'Phenotype', 'HP:0002664', (113, 119))	('Zinc finger protein 671', 'Gene', '79891', (120, 143))	('ZNF671', 'Gene', (63, 69))	('Zinc finger protein 671', 'Gene', (120, 143))	('Zinc Finger Protein 671', 'Gene', '79891', (38, 61))	('ZNF671', 'Gene', (145, 151))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('transcription factor', 'molecular_function', 'GO:0000981', ('180', '200'))	('ZNF671', 'Gene', '79891', (63, 69))	('human', 'Species', '9606', (215, 220))	('ZNF671', 'Gene', '79891', (145, 151))
10617	31134149	Disruption of epigenetic processes can lead to activation of oncogenes and/or the inactivation of tumor suppressor pathways, and the accumulation of epigenetic changes in the molecular landscape is a hallmark of cancer.	('epigenetic', 'Var', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('hallmark of cancer', 'Disease', (200, 218))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('activation', 'PosReg', (47, 57))	('tumor suppressor', 'biological_process', 'GO:0051726', ('98', '114'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('oncogenes', 'CPA', (61, 70))	('hallmark of cancer', 'Disease', 'MESH:D009369', (200, 218))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('98', '114'))	('tumor', 'Disease', (98, 103))	('inactivation', 'NegReg', (82, 94))	('Disruption', 'Var', (0, 10))
10618	31134149	DNA methylation is an early event in tumorigenesis and plays a major role in tumor initiation and progression.	('tumor initiation', 'Disease', (77, 93))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('methylation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor initiation', 'Disease', 'MESH:D009369', (77, 93))	('tumor', 'Disease', (77, 82))
10626	31134149	Our results provide important insights into ZNF671 hypermethylation as a promising biomarker for eight solid tumors and thereby provide novel perspectives for the treatment of tumors.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('hypermethylation', 'Var', (51, 67))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Disease', (176, 182))	('solid tumors', 'Disease', 'MESH:D009369', (103, 115))	('ZNF671', 'Gene', '79891', (44, 50))	('solid tumors', 'Disease', (103, 115))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('ZNF671', 'Gene', (44, 50))
10648	31134149	The relationship between ZNF671 methylation, mRNA and protein expression, and prognosis among different cancer types is summarized in Table 1.	('methylation', 'Var', (32, 43))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ZNF671', 'Gene', (25, 31))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('ZNF671', 'Gene', '79891', (25, 31))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
10649	31134149	Overall, the results indicate that epigenetic-mediated downregulation of ZNF671 predicts poor survival in BRCA, CESC, HNSC, KIRP, LUAD, PAAD, UCEC, and SARC and that ZNF671 may play a tumor suppressor role in tumor progression, which is consistent with previous studies in HNSC, UCEC, and KIRP.	('ZNF671', 'Gene', '79891', (166, 172))	('HNSC', 'Phenotype', 'HP:0012288', (118, 122))	('BRCA', 'Phenotype', 'HP:0003002', (106, 110))	('downregulation', 'NegReg', (55, 69))	('tumor', 'Disease', (209, 214))	('PAAD', 'Phenotype', 'HP:0006725', (136, 140))	('HNSC', 'Phenotype', 'HP:0012288', (273, 277))	('CESC', 'Disease', (112, 116))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('BRCA', 'Gene', '672', (106, 110))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('184', '200'))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('poor', 'NegReg', (89, 93))	('ZNF671', 'Gene', (73, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('184', '200'))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('epigenetic-mediated', 'Var', (35, 54))	('BRCA', 'Gene', (106, 110))	('SARC', 'Phenotype', 'HP:0100242', (152, 156))	('ZNF671', 'Gene', '79891', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('HNSC', 'Disease', (118, 122))	('ZNF671', 'Gene', (166, 172))	('LUAD', 'Phenotype', 'HP:0030078', (130, 134))
10656	31134149	Our previous studies demonstrated that ZNF671 is a tumor suppressor that is epigenetically silenced by DNA methylation in nasopharyngeal carcinoma, but there is limited information regarding the role of ZNF671 methylation among different solid cancer types.	('nasopharyngeal carcinoma', 'Disease', (122, 146))	('ZNF671', 'Gene', (203, 209))	('ZNF671', 'Gene', '79891', (203, 209))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (122, 146))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('methylation', 'biological_process', 'GO:0032259', ('210', '221'))	('tumor', 'Disease', (51, 56))	('silenced', 'NegReg', (91, 99))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('51', '67'))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (122, 146))	('DNA methylation', 'biological_process', 'GO:0006306', ('103', '118'))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('51', '67'))	('ZNF671', 'Gene', (39, 45))	('methylation', 'Var', (107, 118))	('cancer', 'Disease', (244, 250))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('DNA', 'Var', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('ZNF671', 'Gene', '79891', (39, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))
10658	31134149	Functional assays and prognostic analysis found that high ZNF671 expression suppressed tumor cell proliferation, migration, and invasion, and downregulation of ZNF671 was associated with poor clinical prognosis in BRCA, CESC, HNSC, KIRP, LUAD, PAAD, and UCEC.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('HNSC', 'Phenotype', 'HP:0012288', (226, 230))	('BRCA', 'Gene', (214, 218))	('downregulation', 'NegReg', (142, 156))	('ZNF671', 'Gene', (58, 64))	('cell proliferation', 'biological_process', 'GO:0008283', ('93', '111'))	('LUAD', 'Phenotype', 'HP:0030078', (238, 242))	('ZNF671', 'Gene', '79891', (58, 64))	('invasion', 'CPA', (128, 136))	('high', 'Var', (53, 57))	('tumor', 'Disease', (87, 92))	('BRCA', 'Phenotype', 'HP:0003002', (214, 218))	('PAAD', 'Phenotype', 'HP:0006725', (244, 248))	('suppressed', 'NegReg', (76, 86))	('LUAD', 'Disease', (238, 242))	('ZNF671', 'Gene', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('CESC', 'Disease', (220, 224))	('ZNF671', 'Gene', '79891', (160, 166))	('BRCA', 'Gene', '672', (214, 218))	('UCEC', 'Disease', (254, 258))	('KIRP', 'Disease', (232, 236))	('migration', 'CPA', (113, 122))	('PAAD', 'Disease', (244, 248))	('HNSC', 'Disease', (226, 230))
10660	31134149	In this study, we found that the ZNF671 promoter is significantly methylated in 17 solid tumors, based on the TCGA datasets, which is consistent with studies in urothelial carcinoma, clear cell renal cell carcinomas, and cervical cancer.	('cervical cancer', 'Disease', 'MESH:D002583', (221, 236))	('cervical cancer', 'Disease', (221, 236))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (161, 181))	('solid tumors', 'Disease', (83, 95))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (183, 215))	('ZNF671', 'Gene', (33, 39))	('clear cell renal cell carcinomas', 'Disease', (183, 215))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (194, 215))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('ZNF671', 'Gene', '79891', (33, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (205, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('solid tumors', 'Disease', 'MESH:D009369', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('methylated', 'Var', (66, 76))	('urothelial carcinoma', 'Disease', (161, 181))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (183, 215))
10668	31134149	In conclusion, this is the first report to systematically evaluate the correlation between methylation of ZNF671 and prognosis among 18 solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('methylation', 'Var', (91, 102))	('solid tumors', 'Disease', (136, 148))	('ZNF671', 'Gene', (106, 112))	('ZNF671', 'Gene', '79891', (106, 112))	('solid tumors', 'Disease', 'MESH:D009369', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))
10669	31134149	The prognostic signature observed in our study was linked to hypermethylation of ZNF671.	('ZNF671', 'Gene', (81, 87))	('ZNF671', 'Gene', '79891', (81, 87))	('hypermethylation', 'Var', (61, 77))
10671	31134149	Further prognosis analysis indicated that high expression of ZNF671 was associated with longer overall survival (OS) and that ZNF671 expression is a favorable prognostic indicator in BRCA, CESC, HNSC, KIRP, LUAD, PAAD, SARC, and UCEC, but the mechanism remains unknown.	('HNSC', 'Disease', (195, 199))	('SARC', 'Disease', (219, 223))	('UCEC', 'Disease', (229, 233))	('ZNF671', 'Gene', '79891', (61, 67))	('LUAD', 'Phenotype', 'HP:0030078', (207, 211))	('overall survival', 'MPA', (95, 111))	('HNSC', 'Phenotype', 'HP:0012288', (195, 199))	('BRCA', 'Phenotype', 'HP:0003002', (183, 187))	('LUAD', 'Disease', (207, 211))	('SARC', 'Phenotype', 'HP:0100242', (219, 223))	('longer', 'PosReg', (88, 94))	('expression', 'MPA', (47, 57))	('KIRP', 'Disease', (201, 205))	('BRCA', 'Gene', '672', (183, 187))	('PAAD', 'Phenotype', 'HP:0006725', (213, 217))	('PAAD', 'Disease', (213, 217))	('CESC', 'Disease', (189, 193))	('ZNF671', 'Gene', (126, 132))	('BRCA', 'Gene', (183, 187))	('ZNF671', 'Gene', '79891', (126, 132))	('high', 'Var', (42, 46))	('ZNF671', 'Gene', (61, 67))
10676	28306559	This overview of checkpoint inhibitors in clinical trials focuses on novel immunotherapy combinations, predictive biomarkers including mutational load and neoantigen identification, and an evaluation of the future of bladder cancer immunotherapy.	('bladder cancer', 'Phenotype', 'HP:0009725', (217, 231))	('mutational load', 'Var', (135, 150))	('bladder cancer', 'Disease', 'MESH:D001749', (217, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('bladder cancer', 'Disease', (217, 231))
10701	28306559	Evidence that inhibition of the PD-1/PD-L1 pathway has clinical activity in patients with mUC opened the door to the investigation of additional immune therapies, either as single agents or in combination with a broad array of agents, in an effort to increase the number of patients who respond to T-cell checkpoint blockade.	('patients', 'Species', '9606', (76, 84))	('patients', 'Species', '9606', (274, 282))	('mUC', 'Disease', (90, 93))	('PD-1/PD-L1', 'Gene', (32, 42))	('inhibition', 'Var', (14, 24))
10717	28306559	Inhibition of immune escape mechanisms of the PD-1/PD-L1 pathway has demonstrated rapid, durable responses in multiple tumor types, including advanced urothelial carcinoma.	('tumor', 'Disease', (119, 124))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (151, 171))	('PD-1/PD-L1', 'Gene', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('Inhibition', 'Var', (0, 10))	('urothelial carcinoma', 'Disease', (151, 171))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
10726	28306559	Further studies of ipilimumab are currently in progress in combination with nivolumab (NCT01928394 and NCT02553642), nivolumab and cabozantinib (NCT02496208), and enoblituzumab, an mAb targeting B7-H3 (NCT02381314).	('NCT01928394', 'Var', (87, 98))	('NCT02496208', 'Var', (145, 156))	('cabozantinib', 'Chemical', 'MESH:C558660', (131, 143))	('B7-H3', 'Gene', (195, 200))	('B7-H3', 'Gene', '80381', (195, 200))	('nivolumab', 'Chemical', 'MESH:D000077594', (117, 126))	('enoblituzumab', 'Chemical', '-', (163, 176))	('ipilimumab', 'Chemical', 'MESH:D000074324', (19, 29))	('nivolumab', 'Chemical', 'MESH:D000077594', (76, 85))
10736	28306559	Nivolumab is currently being evaluated in urothelial carcinoma and other solid tumors in the metastatic second-line setting in combination with ipilimumab (NCT02553642 and NCT01928394), and with ipilimumab and cabozantinib (NCT02496208).	('ipilimumab', 'Chemical', 'MESH:D000074324', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('NCT02553642', 'Var', (156, 167))	('cabozantinib', 'Chemical', 'MESH:C558660', (210, 222))	('Nivolumab', 'Chemical', 'MESH:D000077594', (0, 9))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (42, 62))	('solid tumors', 'Disease', (73, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('NCT01928394', 'Var', (172, 183))	('urothelial carcinoma', 'Disease', (42, 62))	('solid tumors', 'Disease', 'MESH:D009369', (73, 85))	('ipilimumab', 'Chemical', 'MESH:D000074324', (195, 205))
10738	28306559	Further trials in urothelial carcinoma with nivolumab are currently in progress in combination with the oncolytic group B adenovirus vaccine enadenotucirev (NCT02636036); the personalized cancer vaccine NEO-PV-1 (NCT02897765); urelumab, a fully humanized IgG4 mAb against CD137, a tumor necrosis factor family receptor expressed primarily on activated T cells and activated NK cells (NCT02845323); and interferon-gamma (NCT02614456).	('necrosis', 'biological_process', 'GO:0001906', ('287', '295'))	('necrosis', 'Disease', 'MESH:D009336', (287, 295))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('402', '418'))	('necrosis', 'Disease', (287, 295))	('tumor', 'Disease', (281, 286))	('IgG4', 'cellular_component', 'GO:0071735', ('255', '259'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (18, 38))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('human', 'Species', '9606', (245, 250))	('necrosis', 'biological_process', 'GO:0008219', ('287', '295'))	('CD137', 'Gene', '3604', (272, 277))	('CD137', 'Gene', (272, 277))	('interferon-gamma', 'Gene', (402, 418))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('281', '302'))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('cancer', 'Disease', (188, 194))	('interferon-gamma', 'Gene', '3458', (402, 418))	('necrosis', 'biological_process', 'GO:0008220', ('287', '295'))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('NCT02614456', 'Var', (420, 431))	('nivolumab', 'Chemical', 'MESH:D000077594', (44, 53))	('necrosis', 'biological_process', 'GO:0070265', ('287', '295'))	('necrosis', 'biological_process', 'GO:0019835', ('287', '295'))	('urothelial carcinoma', 'Disease', (18, 38))
10739	28306559	Pembrolizumab is a humanized IgG4 mAb targeting PD-1 that is currently FDA-approved for the treatment of PD-L1+ metastatic melanoma and metastatic NSCLC [patients whose tumors have high PD-L1 expression (Tumor Proportion Score >=50%)].	('NSCLC', 'Disease', (147, 152))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('PD-L1+', 'Var', (105, 111))	('metastatic', 'Disease', (136, 146))	('men', 'Species', '9606', (97, 100))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('IgG4', 'cellular_component', 'GO:0071735', ('29', '33'))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('patients', 'Species', '9606', (154, 162))	('PD-1', 'Gene', (48, 52))	('Tumor', 'Phenotype', 'HP:0002664', (204, 209))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('human', 'Species', '9606', (19, 24))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))
10754	28306559	In the IMvigor 010 trial, atezolizumab is in a phase III study versus observation as adjuvant therapy in patients with PD-L1+, high-risk MIBC after cystectomy.	('patients', 'Species', '9606', (105, 113))	('atezolizumab', 'Chemical', 'MESH:C000594389', (26, 38))	('PD-L1+', 'Var', (119, 125))	('MIBC', 'Chemical', '-', (137, 141))	('MIBC', 'Disease', (137, 141))
10756	28306559	Combination studies include platinum-based chemotherapy (NCT02807636 and NCT02989584); novel immunotherapy agents, including CPI-444 [immune checkpoint inhibitor of the adenosine A2A receptor (ADORA2A) NCT02655822]; epacadostat [oral inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), NCT02298153]; varlilumab (mAb against CD27, NCT02543645); BCG (NCT02792192) for NMIBC; and versus physician's choice of chemotherapy for mUC (IMvigor 211; NCT02302807).	('NCT02792192', 'Var', (348, 359))	('adenosine A2A receptor', 'Gene', (169, 191))	('MIBC', 'Chemical', '-', (366, 370))	('BCG', 'Species', '33892', (343, 346))	('indoleamine 2,3-dioxygenase 1', 'Gene', '3620', (247, 276))	('IDO', 'molecular_function', 'GO:0033754', ('278', '281'))	('CPI-444', 'Chemical', '-', (125, 132))	('IDO', 'molecular_function', 'GO:0047719', ('278', '281'))	('CD27', 'Gene', '939', (323, 327))	('CD27', 'Gene', (323, 327))	('adenosine A2A receptor', 'Gene', '135', (169, 191))	('platinum', 'Chemical', 'MESH:D010984', (28, 36))
10760	28306559	Consequently, current trials with durvalumab are in combination with immunomodulatory agents, including tremelimumab in mUC (NCT02527434; allows for addition of durvalumab following disease progression); tremelimumab and polyICLC (a Toll-like receptor 3 agonist) for mUC (NCT02643303); tremelimumab in MIBC (NCT02812420); and in combination with radiotherapy for MIBC (NCT02891161, DUART).	('tremelimumab', 'Chemical', 'MESH:C520704', (204, 216))	('MIBC', 'Chemical', '-', (363, 367))	('NCT02643303', 'Var', (272, 283))	('durvalumab', 'Chemical', 'MESH:C000613593', (34, 44))	('durvalumab', 'Chemical', 'MESH:C000613593', (161, 171))	('tremelimumab', 'Chemical', 'MESH:C520704', (104, 116))	('MIBC', 'Chemical', '-', (302, 306))	('tremelimumab', 'Chemical', 'MESH:C520704', (286, 298))	('NCT02812420', 'Var', (308, 319))	('polyICLC', 'Chemical', 'MESH:C019531', (221, 229))
10763	28306559	There was a trend toward higher ORR and prolonged progression-free survival at 12 weeks in patients with PD-L1+ mUC [using a >=5% cutoff, ORR was 53.8% in PD-L1+ patients versus 9% in PD-L1- patients (2/22; P = 0.060)].	('prolonged', 'PosReg', (40, 49))	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (191, 199))	('progression-free survival', 'CPA', (50, 75))	('ORR', 'MPA', (32, 35))	('higher', 'PosReg', (25, 31))	('PD-L1+ mUC [', 'Var', (105, 117))
10764	28306559	A pooled analysis of the initial 44 patients and a larger cohort of 197 mUC patients reported an ORR of 17.6% [25% for PD-L1+ and 14.7% for PD-L1- tumors (P = 0.178)].	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('patients', 'Species', '9606', (76, 84))	('patients', 'Species', '9606', (36, 44))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('PD-L1+', 'Var', (119, 125))	('PD-L1- tumors', 'Disease', (140, 153))	('PD-L1- tumors', 'Disease', 'MESH:D010300', (140, 153))
10771	28306559	Solid tumors including bladder cancer are being studied in a phase I trial of adoptive transfer of autologous T cells engineered to recognize NY-ESO-1, MAGE-A4, PRAME, survivin, and SSX (NCT02239861).	('NY-ESO-1', 'Gene', '246100', (142, 150))	('bladder cancer', 'Disease', (23, 37))	('bladder cancer', 'Disease', 'MESH:D001749', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('NY-ESO-1', 'Gene', (142, 150))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('NCT02239861', 'Var', (187, 198))	('tumors', 'Disease', (6, 12))	('SSX', 'Gene', (182, 185))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('MAGE-A4', 'Gene', '4103', (152, 159))	('PRAME', 'Gene', '23532', (161, 166))	('SSX', 'Gene', '727837', (182, 185))	('MAGE-A4', 'Gene', (152, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (23, 37))	('PRAME', 'Gene', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
10785	28306559	Several nonimmunotherapy mAbs are also being investigated in multiple studies of solid tumors, including bladder cancer: anti-CEA antibody MK-6018 in advanced or recurrent cancers including bladder cancer (NCT02346955); antibody-drug conjugate HuMax targeting tissue factor (NCT02552121); anti-FGFR3 antibody B-701 (NCT02401542); and ramucirumab (Eli Lilly, Indianapolis, IN, USA), a VEGFR2 mAb, and chemotherapy (NCT02426125).	('antibody', 'cellular_component', 'GO:0019814', ('300', '308'))	('VEGFR2', 'Gene', (384, 390))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('FGFR3', 'Gene', (294, 299))	('NCT02552121', 'Var', (275, 286))	('bladder cancer', 'Disease', (105, 119))	('solid tumors', 'Disease', 'MESH:D009369', (81, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (105, 119))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('ramucirumab', 'Gene', (334, 345))	('VEGFR2', 'Gene', '3791', (384, 390))	('antibody', 'cellular_component', 'GO:0019815', ('220', '228'))	('FGFR3', 'Gene', '2261', (294, 299))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('bladder cancer', 'Disease', 'MESH:D001749', (190, 204))	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('antibody', 'molecular_function', 'GO:0003823', ('130', '138'))	('bladder cancer', 'Disease', (190, 204))	('antibody', 'molecular_function', 'GO:0003823', ('300', '308'))	('antibody', 'cellular_component', 'GO:0042571', ('130', '138'))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('bladder cancer', 'Phenotype', 'HP:0009725', (190, 204))	('antibody', 'cellular_component', 'GO:0042571', ('300', '308'))	('NCT02401542', 'Var', (316, 327))	('antibody', 'cellular_component', 'GO:0019814', ('220', '228'))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('antibody', 'cellular_component', 'GO:0019815', ('130', '138'))	('cancers', 'Disease', (172, 179))	('antibody', 'cellular_component', 'GO:0019815', ('300', '308'))	('antibody', 'molecular_function', 'GO:0003823', ('220', '228'))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('solid tumors', 'Disease', (81, 93))	('antibody', 'cellular_component', 'GO:0042571', ('220', '228'))	('FGFR', 'molecular_function', 'GO:0005007', ('294', '298'))	('NCT02346955', 'Var', (206, 217))	('antibody', 'cellular_component', 'GO:0019814', ('130', '138'))
10787	28306559	Inhibition of several members of the B7 family has been shown to have powerful antitumor effects in several solid tumor types.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (114, 119))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
10801	28306559	Among patients classified as positive for PD-L1 expression on infiltrating immune cells, 26% had tumor shrinkage versus 9.5% classified as negative for infiltrating immune-cell PD-L1 expression.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('patients', 'Species', '9606', (6, 14))	('expression', 'Var', (48, 58))	('PD-L1', 'Gene', (42, 47))	('positive', 'Var', (29, 37))
10806	28306559	It is interesting that mUC patients with tumors that had high PD-L1+ infiltrating immune cells had higher responses to monotherapy with atezolizumab if they had been previously treated with chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('atezolizumab', 'Chemical', 'MESH:C000594389', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('high', 'Var', (57, 61))	('higher', 'PosReg', (99, 105))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('patients', 'Species', '9606', (27, 35))	('responses', 'MPA', (106, 115))
10812	28306559	The correlation of higher mutational load and response to checkpoint inhibitor therapy has also been shown with CTLA-4 blockade in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('CTLA-4', 'Gene', '1493', (112, 118))	('higher', 'PosReg', (19, 25))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('CTLA-4', 'Gene', (112, 118))	('mutational', 'Var', (26, 36))
10813	28306559	have shown that in advanced melanoma and NSCLC patients treated with anti-CTLA-4 or anti-PD-1, a high tumor burden of clonal neoantigens correlated with higher levels of tumor-infiltrating lymphocytes and improved survival.	('melanoma', 'Disease', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('higher', 'PosReg', (153, 159))	('tumor', 'Disease', (102, 107))	('NSCLC', 'Disease', (41, 46))	('CTLA-4', 'Gene', '1493', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('patients', 'Species', '9606', (47, 55))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('improved', 'PosReg', (205, 213))	('tumor', 'Disease', (170, 175))	('survival', 'CPA', (214, 222))	('CTLA-4', 'Gene', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('anti-PD-1', 'Var', (84, 93))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
10814	28306559	When they analyzed the clonality of tumor neoantigen expression, almost every tumor with a high mutational load and low neoantigen subclonal fraction (<5% subclonal) demonstrated durable clinical benefit from anti-PD-1 therapy.	('benefit', 'PosReg', (196, 203))	('mutational load', 'Var', (96, 111))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', (36, 41))
10815	28306559	These data suggest that mutational burden and neoantigen expression may be predictive of response to immune checkpoint therapy in bladder cancer patients.	('patients', 'Species', '9606', (145, 153))	('bladder cancer', 'Disease', 'MESH:D001749', (130, 144))	('neoantigen', 'Protein', (46, 56))	('bladder cancer', 'Disease', (130, 144))	('mutational burden', 'Var', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('bladder cancer', 'Phenotype', 'HP:0009725', (130, 144))
10883	28127455	Invasive or large (T3/T4 and/or N+/M+) tumors are contraindications for laparoscopic RNU, until proven otherwise (authors think it depends on surgeon s experience).	('tumors', 'Disease', (39, 45))	('T3/T4', 'Var', (19, 24))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('RNU', 'Chemical', '-', (85, 88))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
10901	28127455	In the only meta-analysis published in the literature about the effect of lymph node dissection on the outcomes of UTUC, there was a better CSS in patients with muscle invasive UTUC receiving LDN vs. non-LDN (HR: 2.19) and better CSS in pN0 vs. pNx.	('better', 'PosReg', (133, 139))	('patients', 'Species', '9606', (147, 155))	('CSS', 'MPA', (140, 143))	('muscle invasive UTUC', 'Disease', (161, 181))	('CSS', 'Chemical', '-', (140, 143))	('CSS', 'Chemical', '-', (230, 233))	('LDN', 'Var', (192, 195))
10913	23777267	Overexpression of HSPA2 was significantly associated with primary tumor, TNM stage, lymph node metastases and recurrence, respectively (all, P <0.05).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('HSPA2', 'Gene', (18, 23))	('tumor', 'Disease', (66, 71))	('associated', 'Reg', (42, 52))	('TNM', 'Gene', '10178', (73, 76))	('metastases', 'Disease', (95, 105))	('Overexpression', 'Var', (0, 14))	('metastases', 'Disease', 'MESH:D009362', (95, 105))	('TNM', 'Gene', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('recurrence', 'CPA', (110, 120))
10923	23777267	Aberrant expression of HSPA2 in testes induced primary spermatocytes to arrest in meiosis I and undergo apoptosis, which was leading to male infertility .	('arrest', 'CPA', (72, 78))	('meiosis I', 'Disease', (82, 91))	('Aberrant expression', 'Var', (0, 19))	('leading to', 'Reg', (125, 135))	('meiosis I', 'biological_process', 'GO:0007127', ('82', '91'))	('infertility', 'Phenotype', 'HP:0000789', (141, 152))	('induced', 'Reg', (39, 46))	('infertility', 'Disease', (141, 152))	('male infertility', 'Phenotype', 'HP:0003251', (136, 152))	('meiosis I', 'Disease', 'MESH:C536875', (82, 91))	('HSPA2', 'Gene', (23, 28))	('apoptosis', 'CPA', (104, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('104', '113'))	('apoptosis', 'biological_process', 'GO:0006915', ('104', '113'))	('infertility', 'Disease', 'MESH:D007247', (141, 152))
10925	23777267	Some level of the HSPA2 gene activity was also observed in cell lines derived from several human cancers , while silencing of the HSPA2 gene in cancer cells led to growth arrest and decrease in tumorigenic potential .	('growth arrest', 'CPA', (164, 177))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('growth arrest', 'Phenotype', 'HP:0001510', (164, 177))	('cancers', 'Disease', (97, 104))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('decrease', 'NegReg', (182, 190))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (194, 199))	('silencing', 'Var', (113, 122))	('HSPA2', 'Gene', (130, 135))	('human', 'Species', '9606', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
10926	23777267	A HSPA2 mutation was recognized by cytotoxic T lymphocyte (CTL) on a human renal cell carcinoma .	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('renal cell carcinoma', 'Disease', (75, 95))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (75, 95))	('human', 'Species', '9606', (69, 74))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (75, 95))	('HSPA2', 'Gene', (2, 7))	('mutation', 'Var', (8, 16))
10927	23777267	Furthermore, polymorphism in the HSPA2 gene is associated with an increase in the risk of developing type 1 diabetes , non-Hodgkin's lymphoma , lung cancer , systemic lupus erythematosus (SLE) , rheumatoid arthritis  and inflammatory bowel diseases .	('polymorphism', 'Var', (13, 25))	('arthritis', 'Phenotype', 'HP:0001369', (206, 215))	('inflammatory bowel diseases', 'Disease', 'MESH:D015212', (221, 248))	('inflammatory bowel diseases', 'Disease', (221, 248))	('diabetes', 'Disease', 'MESH:D003920', (108, 116))	('systemic lupus erythematosus', 'Disease', (158, 186))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (119, 141))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (101, 116))	('rheumatoid arthritis', 'Disease', (195, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (119, 141))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (123, 141))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (158, 186))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (195, 215))	("non-Hodgkin's lymphoma", 'Disease', (119, 141))	('lymphoma', 'Phenotype', 'HP:0002665', (133, 141))	('diabetes', 'Disease', (108, 116))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (158, 186))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('inflammatory bowel diseases', 'Phenotype', 'HP:0002037', (221, 248))	('HSPA2', 'Gene', (33, 38))	('SLE', 'Disease', 'MESH:D008180', (188, 191))	('SLE', 'Disease', (188, 191))	('SLE', 'Phenotype', 'HP:0002725', (188, 191))	('lung cancer', 'Disease', (144, 155))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (195, 215))
10928	23777267	Overexpression of HSPA2 is correlated with increased cell proliferation, poor differentiation and lymph node metastases in human breast cancer, cervical cancer and bladder urothelial cancer .	('poor differentiation', 'CPA', (73, 93))	('human', 'Species', '9606', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cell proliferation', 'biological_process', 'GO:0008283', ('53', '71'))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('increased', 'PosReg', (43, 52))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (164, 189))	('HSPA2', 'Gene', (18, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('cell proliferation', 'CPA', (53, 71))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('metastases', 'Disease', 'MESH:D009362', (109, 119))	('breast cancer', 'Disease', (129, 142))	('cervical cancer', 'Disease', 'MESH:D002583', (144, 159))	('bladder urothelial cancer', 'Disease', (164, 189))	('cervical cancer', 'Disease', (144, 159))	('metastases', 'Disease', (109, 119))
10970	23777267	Overexpression of HSPA2 was significantly associated with primary tumor, TNM stage, lymph node metastases and recurrence respectively (all, P <0.05).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('associated', 'Reg', (42, 52))	('TNM', 'Gene', '10178', (73, 76))	('metastases', 'Disease', (95, 105))	('Overexpression', 'Var', (0, 14))	('metastases', 'Disease', 'MESH:D009362', (95, 105))	('TNM', 'Gene', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('recurrence', 'CPA', (110, 120))	('HSPA2', 'Protein', (18, 23))
10974	23777267	Kaplan-Meier curves of survival analysis demonstrated that patients with HSPA2-positive expression had a shorter overall survival than patients with HSPA2-negative expression (survival rate: 18.9% versus 66.7%, P <0.001) (Figure  3).	('patients', 'Species', '9606', (135, 143))	('HSPA2-positive expression', 'Var', (73, 98))	('overall survival', 'MPA', (113, 129))	('patients', 'Species', '9606', (59, 67))	('shorter', 'NegReg', (105, 112))
10979	23777267	The polymorphism of HSPA2 at position 1267 has been suggested to be associated with carcinogenesis in many malignant cancer tissues .	('HSPA2', 'Gene', (20, 25))	('associated', 'Reg', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('polymorphism', 'Var', (4, 16))
10982	23777267	Silencing the expression of the HSPA2 gene by RNA interference suggests that HSPA2 increases the growth rate and tumorigenic potential not only in the cell culture but also in tumor xenograft in mice .	('tumor', 'Disease', (113, 118))	('increases', 'PosReg', (83, 92))	('mice', 'Species', '10090', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('RNA', 'MPA', (46, 49))	('growth rate', 'CPA', (97, 108))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('RNA', 'cellular_component', 'GO:0005562', ('46', '49'))	('HSPA2', 'Gene', (32, 37))	('HSPA2', 'Gene', (77, 82))	('RNA interference', 'biological_process', 'GO:0016246', ('46', '62'))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
10985	23777267	During meiosis, spermatogenic cells synthesize HSPA2, knockout of HSPA2 in HSPA2 (-/-) male mice testes induce primary spermatocytes to arrest in meiosis I and undergo a dramatic increase in spermatocyte apoptosis, which was leading to male infertility .	('knockout', 'Var', (54, 62))	('HSPA2', 'Gene', (66, 71))	('male infertility', 'Phenotype', 'HP:0003251', (236, 252))	('meiosis I', 'Disease', 'MESH:C536875', (146, 155))	('infertility', 'Phenotype', 'HP:0000789', (241, 252))	('meiosis', 'biological_process', 'GO:0051321', ('7', '14'))	('infertility', 'Disease', (241, 252))	('leading to', 'Reg', (225, 235))	('meiosis I', 'biological_process', 'GO:0007127', ('146', '155'))	('apoptosis', 'biological_process', 'GO:0097194', ('204', '213'))	('apoptosis', 'biological_process', 'GO:0006915', ('204', '213'))	('meiosis I', 'Disease', (146, 155))	('HSPA2', 'Gene', (75, 80))	('increase', 'PosReg', (179, 187))	('mice', 'Species', '10090', (92, 96))	('spermatocyte apoptosis', 'CPA', (191, 213))	('infertility', 'Disease', 'MESH:D007247', (241, 252))
10987	23777267	The mechanism of a mutated HSPA2 chaperone has a dominant effect in tumor cells by triggering the G2/M phase transition during the mitotic cell cycle, which could explain the HSPA2 abnormal expression in somatic tumors.	('tumor', 'Disease', (68, 73))	('tumors', 'Disease', (212, 218))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('tumor', 'Disease', (212, 217))	('M phase', 'biological_process', 'GO:0000279', ('101', '108'))	('mutated', 'Var', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('G2/M phase transition during the', 'CPA', (98, 130))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('triggering', 'Reg', (83, 93))	('mitotic cell cycle', 'biological_process', 'GO:0000278', ('131', '149'))	('HSPA2', 'Protein', (27, 32))
11006	23777267	Overexpression of HSPA2 is correlated with poor therapeutic outcomes in human breast cancer, cervical cancer and bladder urothelial cancer; furthermore, it is now a valuable prognostic marker for breast cancer patients .	('cervical cancer', 'Disease', (93, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('bladder urothelial cancer', 'Disease', (113, 138))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (113, 138))	('breast cancer', 'Disease', (196, 209))	('human', 'Species', '9606', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (210, 218))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cervical cancer', 'Disease', 'MESH:D002583', (93, 108))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('HSPA2', 'Protein', (18, 23))	('breast cancer', 'Disease', (78, 91))
11007	23777267	The polymorphism of HSPA2 acts as an attractive susceptibility marker and independent prognostic indicator in Kangri cancer patients .	('HSPA2', 'Gene', (20, 25))	('Kangri cancer', 'Disease', (110, 123))	('Kangri cancer', 'Disease', 'MESH:D009369', (110, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (124, 132))	('polymorphism', 'Var', (4, 16))
11050	28749907	In murine models, expression of PD-L1 on the mastocytoma cell line increased apoptosis in active tumor-reactive T cells, suggesting a possible target for cancer immunotherapy.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('PD-L1', 'Gene', (32, 37))	('apoptosis', 'CPA', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('tumor', 'Disease', (97, 102))	('mastocytoma', 'Disease', 'MESH:D034801', (45, 56))	('increased', 'PosReg', (67, 76))	('murine', 'Species', '10090', (3, 9))	('mastocytoma', 'Disease', (45, 56))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('expression', 'Var', (18, 28))
11063	28749907	Second-line single-agent options derived from phase 2 studies show modest activity and include pemetrexed (Alimta, Lilly), docetaxel, ifosfamide, and nab-paclitaxel (Abraxane, Celgene), all of which produce ORRs of 28% or less.	('pemetrexed', 'Chemical', 'MESH:D000068437', (95, 105))	('nab', 'Chemical', '-', (150, 153))	('paclitaxel', 'Chemical', 'MESH:D017239', (154, 164))	('activity', 'MPA', (74, 82))	('nab-paclitaxel', 'Var', (150, 164))	('Celgene', 'Chemical', 'MESH:D013792', (176, 183))	('ORRs', 'MPA', (207, 211))	('ifosfamide', 'Chemical', 'MESH:D007069', (134, 144))	('docetaxel', 'Chemical', 'MESH:D000077143', (123, 132))
11126	28749907	Durvalumab (Imfinzi, AstraZeneca) is an engineered human IgG1 antibody against PD-L1, with mutations in the Fc domain to reduce ADCC and CDC.	('IgG1 antibody', 'cellular_component', 'GO:0071736', ('57', '70'))	('antibody', 'molecular_function', 'GO:0003823', ('62', '70'))	('ADCC', 'MPA', (128, 132))	('Durvalumab', 'Chemical', 'MESH:C000613593', (0, 10))	('human', 'Species', '9606', (51, 56))	('mutations', 'Var', (91, 100))	('Imfinzi', 'Chemical', 'MESH:C000613593', (12, 19))	('CDC', 'MPA', (137, 140))	('reduce', 'NegReg', (121, 127))	('ADCC', 'biological_process', 'GO:0001788', ('128', '132'))
11129	28749907	The ORR was 46% in the group with high PD-L1 expression (defined as >=25% staining in tumor cells or immune cells) compared with 0 in the 14 patients with a low rate of PD-L1 positivity (<25% staining).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('PD-L1', 'Gene', (39, 44))	('tumor', 'Disease', (86, 91))	('expression', 'MPA', (45, 55))	('high', 'Var', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('patients', 'Species', '9606', (141, 149))
11195	28749907	In urothelial cancer, several agents look promising, including AGS15E (also called ASG-15ME).	('AGS15E', 'Var', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('urothelial cancer', 'Disease', (3, 20))	('urothelial cancer', 'Disease', 'MESH:D014523', (3, 20))	('ASG-15ME', 'Chemical', 'MESH:C000620843', (83, 91))
11200	28749907	This trial will be expanded into a phase 2 trial of AGS15E in urothelial cancer at the maximum tolerated dose.	('urothelial cancer', 'Disease', 'MESH:D014523', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('AGS15E', 'Var', (52, 58))	('urothelial cancer', 'Disease', (62, 79))
11263	32596394	If  HRi > 1 and  betai > 0, the relevant genes are defined as risky candidate genes.	('HRi', 'Gene', '27102', (4, 7))	('HRi', 'Gene', (4, 7))	('betai > 0', 'Var', (17, 26))
11267	32596394	In the last step, to further screen the gene signature, proposed a sparse linear regression model (WLAD-SCAD), considering rp as a parameter of Xi, given by Equation (9) as follows: where Qnomega(gamman) is the objective function, plambda(.)	('WLAD-SCAD', 'Disease', (99, 108))	('Qnomega', 'Var', (188, 195))	('WLAD-SCAD', 'Disease', 'None', (99, 108))
11282	32596394	It is evident that fitness is better in which the value of R2 is 0.937 in GES13507 (Figure 1(a)) and 0.808 in TCGA-BLCA (Figure 1(b)), separately.	('fitness', 'Disease', (19, 26))	('fitness', 'Disease', 'MESH:D012640', (19, 26))	('0.808', 'Var', (101, 106))	('0.937', 'Var', (65, 70))	('BLCA', 'Phenotype', 'HP:0009725', (115, 119))
11289	32596394	The corresponding ROC curves present the accuracy (AUC) of th e17-gene signature up to values of 0.74 and 0.737 in GSE13507 and TCGA, respectively, as shown in Figures 3(c) and 3(f), which means the model has an effective performance for overall survival assessment.	('0.737', 'Var', (106, 111))	('GSE13507', 'Gene', (115, 123))	('men', 'Species', '9606', (261, 264))	('TCGA', 'Gene', (128, 132))
11325	32596394	Meanwhile, in breast cancer patients, 16q deletion is associated with survival, molecular subtypes, mRNA expression, and germline haplotypes, and the cell recognition gene CNTNAP4 is included.	('16q deletion', 'Var', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('CNTNAP4', 'Gene', (172, 179))	('cell recognition', 'biological_process', 'GO:0008037', ('150', '166'))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('CNTNAP4', 'Gene', '85445', (172, 179))	('breast cancer', 'Disease', (14, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('mRNA expression', 'MPA', (100, 115))	('patients', 'Species', '9606', (28, 36))	('associated', 'Reg', (54, 64))
11327	32596394	Mutations in this gene are known to cause Ewing sarcoma as well as neuroectodermal and various other tumors.	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('cause', 'Reg', (36, 41))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (42, 55))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Ewing sarcoma', 'Disease', (42, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('neuroectodermal', 'Disease', (67, 82))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (42, 55))	('tumors', 'Disease', (101, 107))
11328	32596394	The fusion of short fragments between EWSR1 and FLI1, contributing to the oncogenic gene to construct and maintain expression programs, is enough to recapitulate BAF complex retargeting and EWS-FLI1 activities.	('men', 'Species', '9606', (24, 27))	('EWS', 'Gene', (38, 41))	('EWS', 'Gene', '2130', (38, 41))	('FLI1', 'Gene', (48, 52))	('BAF', 'Gene', '8815', (162, 165))	('EWS', 'Gene', '2130', (190, 193))	('EWS', 'Gene', (190, 193))	('fusion', 'Var', (4, 10))	('EWSR1', 'Gene', '2130', (38, 43))	('FLI1', 'Gene', '2313', (48, 52))	('FLI1', 'Gene', (194, 198))	('FLI1', 'Gene', '2313', (194, 198))	('BAF', 'Gene', (162, 165))	('EWSR1', 'Gene', (38, 43))
11330	32596394	A mutation in this gene may be associated with increased risk for Barrett's esophagus and esophageal adenocarcinoma.	('mutation', 'Var', (2, 10))	('adenocarcinoma', 'Disease', 'MESH:D000230', (101, 115))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (90, 115))	('associated', 'Reg', (31, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	("Barrett's esophagus", 'Disease', (66, 85))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (66, 85))	('adenocarcinoma', 'Disease', (101, 115))
11342	32596394	Meanwhile, miR-1205 regulates the proliferation and migration of prostate epithelial cells, and loss of miR-1205 promotes a tumorigenic phenotype in prostate cancer.	('promotes', 'PosReg', (113, 121))	('proliferation', 'CPA', (34, 47))	('miR-1205', 'Gene', (11, 19))	('migration', 'CPA', (52, 61))	('loss', 'Var', (96, 100))	('miR-1205', 'Gene', (104, 112))	('prostate cancer', 'Disease', 'MESH:D011471', (149, 164))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('prostate cancer', 'Phenotype', 'HP:0012125', (149, 164))	('miR-1205', 'Gene', '100302161', (11, 19))	('tumor', 'Disease', (124, 129))	('miR-1205', 'Gene', '100302161', (104, 112))	('prostate cancer', 'Disease', (149, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
11354	32596394	And mutation of CRB1 is correlated with a severe form of retinitis pigmentosa and with Leber congenital amaurosis.	('Leber congenital amaurosis', 'Disease', (87, 113))	('CRB1', 'Gene', (16, 20))	('retinitis pigmentosa', 'Disease', 'MESH:C538365', (57, 77))	('mutation', 'Var', (4, 12))	('correlated with', 'Reg', (24, 39))	('retinitis', 'Phenotype', 'HP:0032118', (57, 66))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (57, 77))	('CRB1', 'Gene', '23418', (16, 20))	('retinitis pigmentosa', 'Disease', (57, 77))	('Leber congenital amaurosis', 'Disease', 'MESH:D057130', (87, 113))	('congenital amaurosis', 'Phenotype', 'HP:0007875', (93, 113))
11427	32414626	For high-grade NMIBC, progression to muscle invasion/metastases occurs in 15-40% and 10-20% of patients may die from BC.	('high-grade', 'Var', (4, 14))	('NMIBC', 'Disease', (15, 20))	('MIBC', 'Chemical', '-', (16, 20))	('patients', 'Species', '9606', (95, 103))	('metastases', 'Disease', (53, 63))	('BC', 'Phenotype', 'HP:0009725', (18, 20))	('metastases', 'Disease', 'MESH:D009362', (53, 63))	('BC', 'Phenotype', 'HP:0009725', (117, 119))
11434	32414626	RC should be considered in patients at low risk of COVID-19 mortality and with high-risk disease features, for example, presence of high-grade pT1 plus Tis, or tumors with lympho(vascular) invasion, variant histology (eg, micropapillary disease), residual grade 3/high-grade urothelial carcinoma on re-resection, or pT1 stage.	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('COVID-19', 'Disease', 'MESH:C000657245', (51, 59))	('tumors', 'Disease', (160, 166))	('COVID-19', 'Disease', (51, 59))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (275, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('patients', 'Species', '9606', (27, 35))	('mortality', 'Disease', (60, 69))	('variant', 'Var', (199, 206))	('urothelial carcinoma', 'Disease', (275, 295))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('micropapillary disease', 'Disease', 'MESH:D003141', (222, 244))	('micropapillary disease', 'Disease', (222, 244))	('pT1', 'Gene', '58492', (143, 146))	('pT1', 'Gene', '58492', (316, 319))	('pT1', 'Gene', (316, 319))	('pT1', 'Gene', (143, 146))	('mortality', 'Disease', 'MESH:D003643', (60, 69))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
11454	32414626	Specifically, if we look at the data relevant to the context of the current COVID-19 pandemic, Audenet and colleagues found that delays of >8 wk in NAC were associated with an increased risk of upstaging, but no harm in delays up to 6 mo from diagnosis to RC, assuming that NAC was administered in the meantime.	('COVID-19', 'Disease', 'MESH:C000657245', (76, 84))	('NAC', 'cellular_component', 'GO:0005854', ('274', '277'))	('COVID-19', 'Disease', (76, 84))	('delays', 'Var', (129, 135))	('NAC', 'Chemical', '-', (148, 151))	('NAC', 'cellular_component', 'GO:0005854', ('148', '151'))	('NAC', 'Gene', (148, 151))	('NAC', 'Chemical', '-', (274, 277))	('upstaging', 'MPA', (194, 203))
11484	32414626	However, metastasis-free survival (MFS) and PCa-specific survival are significantly worse for patients with Gleason 3 + 4 disease undergoing AS compared with those with Gleason 3 + 3 disease.	('Gleason 3 + 4 disease', 'Var', (108, 129))	('patients', 'Species', '9606', (94, 102))	('PCa', 'Phenotype', 'HP:0012125', (44, 47))	('MFS', 'Disease', 'MESH:D008382', (35, 38))	('worse', 'NegReg', (84, 89))	('metastasis-free survival', 'CPA', (9, 33))	('PCa-specific survival', 'CPA', (44, 65))	('MFS', 'Disease', (35, 38))
11492	32414626	For example, in men with localized intermediate-risk disease from Toronto, long-term deferral led to worsening in MFS (HR 3.14, 95% CI 1.51-6.53) and PCa-specific survival.	('MFS', 'Disease', (114, 117))	('deferral', 'Var', (85, 93))	('PCa', 'Phenotype', 'HP:0012125', (150, 153))	('men', 'Species', '9606', (16, 19))	('worsening', 'NegReg', (101, 110))	('PCa-specific', 'Disease', (150, 162))	('MFS', 'Disease', 'MESH:D008382', (114, 117))
11502	32414626	Meunier and colleagues found that there was an increased risk with delays of >90 and 60 d for patients with Gleason 3 + 4 disease and Gleason >=8 disease, respectively.	('Gleason', 'Disease', (108, 115))	('Gleason >=8', 'Var', (134, 145))	('patients', 'Species', '9606', (94, 102))
11521	32414626	Where radiotherapy is planned to be administered, a recent Cochrane Database systematic review and meta-analysis of 10 studies including 8278 patients demonstrated that for those with intermediate- and high-risk PCa, hypofractionation is associated with equivalent oncologic outcomes (MFS, disease-specific survival, and OS), as well as functional outcomes.	('PCa', 'Disease', (212, 215))	('PCa', 'Phenotype', 'HP:0012125', (212, 215))	('hypofractionation', 'Var', (217, 234))	('patients', 'Species', '9606', (142, 150))	('MFS', 'Disease', 'MESH:D008382', (285, 288))	('MFS', 'Disease', (285, 288))
11558	32414626	The Fox Chase Cancer Center group identified 61 patients with cT1b renal masses and seven with cT2 masses initially treated with AS, with 23 (34%) undergoing delayed intervention.	('cT1b', 'Var', (62, 66))	('renal masses', 'Phenotype', 'HP:0009726', (67, 79))	('cT2', 'Gene', (95, 98))	('cT2', 'Gene', '30848', (95, 98))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Cancer', 'Disease', (14, 20))	('patients', 'Species', '9606', (48, 56))	('Cancer', 'Disease', 'MESH:D009369', (14, 20))
11594	32414626	For poor-risk patients and those requiring treatment, there is no consensus regarding the optimal first-line therapy; however, VEGF targeted therapy is less likely to require toxicity-related hospitalization and/or glucocorticoids than immunotherapy regimens.	('VEGF', 'Gene', '7422', (127, 131))	('toxicity', 'Disease', 'MESH:D064420', (175, 183))	('men', 'Species', '9606', (254, 257))	('men', 'Species', '9606', (48, 51))	('targeted therapy', 'Var', (132, 148))	('toxicity', 'Disease', (175, 183))	('VEGF', 'Gene', (127, 131))	('patients', 'Species', '9606', (14, 22))
11645	32414626	As a result, it is important to prioritize the timely care of patients for whom delays are most likely to result in adverse outcomes, also taking into account the patient's age, comorbidities, symptoms, and life expectancy.	('patient', 'Species', '9606', (62, 69))	('result', 'Reg', (106, 112))	('delays', 'Var', (80, 86))	('patient', 'Species', '9606', (163, 170))	('patients', 'Species', '9606', (62, 70))
11712	30831560	While some studies described an association between high AR expression and increased tumor stage and grade as well as a worse survival, other studies reported that tumor progression is accompanied by decreased AR expression.	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('AR', 'Gene', '367', (57, 59))	('grade', 'CPA', (101, 106))	('decreased', 'NegReg', (200, 209))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('high', 'Var', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('increased', 'PosReg', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('AR', 'Gene', '367', (210, 212))
11718	30831560	In UCB, previous preclinical studies in UCB cell lines showed that GATA3 knockdown results in down-regulation of molecules that play a protective role in bladder tumorigenesis and up-regulation of oncogenic genes, thus suggesting a protective role of GATA3 in bladder cancer.	('tumor', 'Disease', (162, 167))	('oncogenic genes', 'Gene', (197, 212))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('down-regulation', 'NegReg', (94, 109))	('UCB', 'Phenotype', 'HP:0006740', (40, 43))	('bladder', 'Disease', (154, 161))	('regulation', 'biological_process', 'GO:0065007', ('99', '109'))	('knockdown', 'Var', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('up-regulation', 'PosReg', (180, 193))	('GATA3', 'Gene', '2625', (251, 256))	('bladder cancer', 'Disease', 'MESH:D001749', (260, 274))	('bladder cancer', 'Disease', (260, 274))	('regulation', 'biological_process', 'GO:0065007', ('183', '193'))	('GATA3', 'Gene', '2625', (67, 72))	('GATA3', 'Gene', (251, 256))	('bladder cancer', 'Phenotype', 'HP:0009725', (260, 274))	('UCB', 'Phenotype', 'HP:0006740', (3, 6))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('GATA3', 'Gene', (67, 72))	('molecules', 'Protein', (113, 122))
11732	30831560	TCGA subtypes): the subtypes I and II are described as luminal-like, with subtype I being defined by FGFR3 alterations and elevated FGFR3 expression, while subtype II is characterized by ERBB2 mutations and estrogen receptor beta (ESR2) enrichment.	('ERBB2', 'Gene', (187, 192))	('FGFR3', 'Gene', (132, 137))	('ESR2', 'Gene', (231, 235))	('FGFR', 'molecular_function', 'GO:0005007', ('132', '136'))	('alterations', 'Var', (107, 118))	('FGFR3', 'Gene', '2261', (101, 106))	('elevated', 'PosReg', (123, 131))	('estrogen receptor beta', 'Gene', '2100', (207, 229))	('mutations', 'Var', (193, 202))	('estrogen receptor beta', 'Gene', (207, 229))	('expression', 'MPA', (138, 148))	('ESR2', 'Gene', '2100', (231, 235))	('men', 'Species', '9606', (243, 246))	('FGFR3', 'Gene', '2261', (132, 137))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))	('FGFR3', 'Gene', (101, 106))	('ERBB2', 'Gene', '2064', (187, 192))
11763	30831560	Women with high AR mRNA expression >=2.83 had significantly worse DFS (P = .03) and OS (P = .02) than women with low AR mRNA expression <2.83.	('DFS', 'CPA', (66, 69))	('Women', 'Species', '9606', (0, 5))	('mRNA', 'Var', (19, 23))	('AR', 'Gene', '367', (16, 18))	('women', 'Species', '9606', (102, 107))	('high', 'Var', (11, 15))	('AR', 'Gene', '367', (117, 119))	('worse', 'NegReg', (60, 65))
11828	30195190	A distinct class of antioxidant response elements is consistently activated in tumors with NRF2 mutations NRF2 is a redox-responsive transcription factor that regulates expression of cytoprotective genes via its interaction with DNA sequences known as antioxidant response elements (AREs).	('interaction', 'Interaction', (212, 223))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('transcription factor', 'molecular_function', 'GO:0000981', ('133', '153'))	('NRF2', 'Gene', '4780', (91, 95))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('NRF2', 'Gene', '4780', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('expression', 'MPA', (169, 179))	('DNA', 'cellular_component', 'GO:0005574', ('229', '232'))	('activated', 'PosReg', (66, 75))	('NRF2', 'Gene', (91, 95))	('regulates', 'Reg', (159, 168))	('NRF2', 'Gene', (106, 110))	('mutations', 'Var', (96, 105))
11830	30195190	Mutations that disrupt the interaction between NRF2 and KEAP1, an inhibitor of NRF2, lead to NRF2 hyperactivation and promote oncogenesis.	('NRF2', 'Gene', '4780', (93, 97))	('NRF2', 'Gene', (79, 83))	('hyperactivation', 'PosReg', (98, 113))	('interaction', 'Interaction', (27, 38))	('oncogenesis', 'biological_process', 'GO:0007048', ('126', '137'))	('KEAP1', 'Gene', '9817', (56, 61))	('NRF2', 'Gene', (93, 97))	('oncogenesis', 'CPA', (126, 137))	('NRF2', 'Gene', '4780', (47, 51))	('Mutations', 'Var', (0, 9))	('KEAP1', 'Gene', (56, 61))	('NRF2', 'Gene', '4780', (79, 83))	('promote', 'PosReg', (118, 125))	('NRF2', 'Gene', (47, 51))
11832	30195190	We tested this possibility using an integrative genomics approach to get a precise view of the direct NRF2 target genes dysregulated in tumors with NRF2 hyperactivating mutations.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('NRF2', 'Gene', (148, 152))	('NRF2', 'Gene', '4780', (102, 106))	('hyperactivating mutations', 'Var', (153, 178))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('NRF2', 'Gene', (102, 106))	('NRF2', 'Gene', '4780', (148, 152))
11838	30195190	This NRF2 cancer target gene set also serves as a reliable proxy for NRF2 activity, and high NRF2 activity is associated with significant decreases in survival in multiple cancer types.	('high', 'Var', (88, 92))	('NRF2', 'Gene', '4780', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('decreases', 'NegReg', (138, 147))	('NRF2', 'Gene', (69, 73))	('multiple cancer', 'Disease', 'MESH:D009369', (163, 178))	('NRF2', 'Gene', '4780', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('NRF2', 'Gene', (93, 97))	('NRF2 cancer', 'Disease', 'MESH:D009369', (5, 16))	('multiple cancer', 'Disease', (163, 178))	('NRF2', 'Gene', (5, 9))	('NRF2 cancer', 'Disease', (5, 16))	('activity', 'MPA', (98, 106))	('survival', 'MPA', (151, 159))	('NRF2', 'Gene', '4780', (69, 73))
11863	30195190	Although NRF2 activity is cytoprotective, limitation of its activity by KEAP1 is crucial: mutations that impair KEAP1-mediated degradation of NRF2 are associated with tumorigenesis.	('KEAP1', 'Gene', (112, 117))	('mutations', 'Var', (90, 99))	('NRF2', 'Gene', '4780', (9, 13))	('KEAP1', 'Gene', '9817', (72, 77))	('NRF2', 'Gene', (142, 146))	('associated', 'Reg', (151, 161))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('NRF2', 'Gene', (9, 13))	('KEAP1', 'Gene', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('degradation', 'MPA', (127, 138))	('KEAP1', 'Gene', '9817', (112, 117))	('impair', 'NegReg', (105, 111))	('tumor', 'Disease', (167, 172))	('NRF2', 'Gene', '4780', (142, 146))	('degradation', 'biological_process', 'GO:0009056', ('127', '138'))
11864	30195190	KEAP1 mutations leading to constitutive NRF2 activity were first observed in lung cancer, and cancer-associated NRF2 mutations disrupting KEAP1's inhibition of NRF2 were identified shortly thereafter.	('cancer', 'Disease', (82, 88))	('KEAP1', 'Gene', '9817', (0, 5))	('lung cancer', 'Disease', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('KEAP1', 'Gene', (0, 5))	('NRF2', 'Gene', '4780', (40, 44))	('NRF2', 'Gene', '4780', (160, 164))	('disrupting', 'NegReg', (127, 137))	('NRF2', 'Gene', '4780', (112, 116))	('mutations', 'Var', (6, 15))	('cancer', 'Disease', (94, 100))	('activity', 'MPA', (45, 53))	('mutations', 'Var', (117, 126))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('NRF2', 'Gene', (40, 44))	('NRF2', 'Gene', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('NRF2', 'Gene', (112, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('KEAP1', 'Gene', '9817', (138, 143))	('KEAP1', 'Gene', (138, 143))	('inhibition', 'MPA', (146, 156))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
11866	30195190	Importantly, coding mutations in NRF2 or KEAP1 are not the only route to constitutive NRF2 activity.	('NRF2', 'Gene', '4780', (86, 90))	('coding mutations', 'Var', (13, 29))	('KEAP1', 'Gene', '9817', (41, 46))	('NRF2', 'Gene', '4780', (33, 37))	('NRF2', 'Gene', (86, 90))	('activity', 'MPA', (91, 99))	('KEAP1', 'Gene', (41, 46))	('NRF2', 'Gene', (33, 37))
11875	30195190	Specifically, we describe a set of direct NRF2 target genes consistently upregulated in tumors with oncogenic NRF2 mutations across multiple organ systems.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('mutations', 'Var', (115, 124))	('NRF2', 'Gene', (110, 114))	('NRF2', 'Gene', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('upregulated', 'PosReg', (73, 84))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('NRF2', 'Gene', '4780', (110, 114))	('NRF2', 'Gene', '4780', (42, 46))
11876	30195190	This functionally important subset of NRF2 targets includes many of the core cytoprotective genes of the NRF2-mediated antioxidant response, and the expression of these NRF2 "cancer targets" is associated with poor outcome across a number of cancers.	('NRF2', 'Gene', (38, 42))	('cancers', 'Disease', 'MESH:D009369', (242, 249))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('core', 'cellular_component', 'GO:0019013', ('72', '76'))	('cancer', 'Disease', (242, 248))	('cancers', 'Disease', (242, 249))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('NRF2', 'Gene', '4780', (105, 109))	('NRF2', 'Gene', '4780', (169, 173))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('NRF2', 'Gene', (105, 109))	('NRF2', 'Gene', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('NRF2', 'Gene', '4780', (38, 42))	('expression', 'Var', (149, 159))	('associated with', 'Reg', (194, 209))
11878	30195190	A recent analysis of transcriptome data from The Cancer Genome Atlas (TCGA) identified hundreds of gene expression changes that occur with cancer-associated NRF2 mutations that disrupt the NRF2-KEAP1 interaction interface.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('NRF2', 'Gene', (189, 193))	('mutations', 'Var', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('interaction', 'Interaction', (200, 211))	('KEAP1', 'Gene', '9817', (194, 199))	('Cancer Genome Atlas', 'Disease', (49, 68))	('cancer', 'Disease', (139, 145))	('disrupt', 'NegReg', (177, 184))	('NRF2', 'Gene', '4780', (157, 161))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (49, 68))	('KEAP1', 'Gene', (194, 199))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('gene expression', 'biological_process', 'GO:0010467', ('99', '114'))	('NRF2', 'Gene', '4780', (189, 193))	('NRF2', 'Gene', (157, 161))
11881	30195190	We used this differential cancer gene expression data to identify genes commonly dysregulated across cancers with NRF2 hyperactivating mutations.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancer', 'Disease', (26, 32))	('cancers', 'Disease', (101, 108))	('cancer', 'Disease', (101, 107))	('NRF2', 'Gene', '4780', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('hyperactivating mutations', 'Var', (119, 144))	('NRF2', 'Gene', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gene expression', 'biological_process', 'GO:0010467', ('33', '48'))
11882	30195190	To explore the tissue specificity of gene expression changes in cancers with mutated NRF2, we compared the differential gene expression lists from the four cancers analyzed in to identify shared up- or downregulated gene sets.	('NRF2', 'Gene', (85, 89))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('mutated', 'Var', (77, 84))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancers', 'Disease', (64, 71))	('NRF2', 'Gene', '4780', (85, 89))	('gene expression', 'biological_process', 'GO:0010467', ('37', '52'))	('gene expression', 'biological_process', 'GO:0010467', ('120', '135'))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
11884	30195190	Thus, consistent with NRF2's long-recognized role as a transcriptional activator, oncogenic NRF2 is associated with a consistent gene activation signature.	('oncogenic', 'Var', (82, 91))	('NRF2', 'Gene', '4780', (92, 96))	('NRF2', 'Gene', '4780', (22, 26))	('NRF2', 'Gene', (92, 96))	('NRF2', 'Gene', (22, 26))
11886	30195190	The above results highlight a gene set commonly upregulated with oncogenic NRF2 in cancers derived from a variety of organ systems, yet the data do not provide information indicating a direct role for NRF2 in regulating these genes.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('NRF2', 'Gene', '4780', (201, 205))	('NRF2', 'Gene', (201, 205))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('NRF2', 'Gene', '4780', (75, 79))	('oncogenic', 'Var', (65, 74))	('upregulated', 'PosReg', (48, 59))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('NRF2', 'Gene', (75, 79))	('cancers', 'Disease', (83, 90))
11889	30195190	We calculated the percent overlap between the ChIP-seq derived direct NRF2 targets and various groupings of the cancer upregulated genes (i.e., those upregulated with NRF2 mutation in 1-4 cancer types, 2-4 cancer types, etc.).	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('NRF2', 'Gene', '4780', (70, 74))	('cancer', 'Disease', (112, 118))	('upregulated', 'PosReg', (150, 161))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('NRF2', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutation', 'Var', (172, 180))	('NRF2', 'Gene', '4780', (167, 171))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('NRF2', 'Gene', (167, 171))
11895	30195190	And, as described multiple times above, KEAP1 is intimately linked to the NRF2 antioxidant pathway; KEAP1 is transcriptionally regulated by NRF2 as part of a negative feedback loop, but this feedback mechanism is broken in cancer cells carrying mutations that disrupt the NRF2-KEAP1 interaction interface.	('KEAP1', 'Gene', (40, 45))	('KEAP1', 'Gene', (277, 282))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('NRF2', 'Gene', (272, 276))	('mutations', 'Var', (245, 254))	('KEAP1', 'Gene', '9817', (100, 105))	('NRF2', 'Gene', '4780', (74, 78))	('interaction', 'Interaction', (283, 294))	('KEAP1', 'Gene', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('NRF2', 'Gene', '4780', (140, 144))	('cancer', 'Disease', (223, 229))	('KEAP1', 'Gene', '9817', (40, 45))	('KEAP1', 'Gene', '9817', (277, 282))	('NRF2', 'Gene', (74, 78))	('NRF2', 'Gene', '4780', (272, 276))	('NRF2', 'Gene', (140, 144))
11944	30195190	Indeed, a closer look at expression of these four classic NRF2 targets in tumors with no NFE2L2 mutation versus tumors with an NFE2L2 mutation reveals that HMOX1 is not as consistent in its activation by NFE2L2 mutation (Fig.	('NFE2L2', 'Gene', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('NRF2', 'Gene', '4780', (58, 62))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('NFE2L2', 'Gene', (204, 210))	('HMOX1', 'Gene', (156, 161))	('tumors', 'Disease', (112, 118))	('mutation', 'Var', (96, 104))	('activation', 'PosReg', (190, 200))	('NFE2L2', 'Gene', '4780', (89, 95))	('NRF2', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('NFE2L2', 'Gene', '4780', (127, 133))	('NFE2L2', 'Gene', (89, 95))	('HMOX1', 'Gene', '3162', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('NFE2L2', 'Gene', '4780', (204, 210))	('mutation', 'Var', (211, 219))	('tumors', 'Disease', (74, 80))
11949	30195190	Thus, ARE sequence and NRF2 binding strength are not sufficient to explain the less consistent induction of HMOX1 by oncogenic NRF2.	('HMOX1', 'Gene', (108, 113))	('HMOX1', 'Gene', '3162', (108, 113))	('NRF2', 'Gene', '4780', (23, 27))	('NRF2', 'Gene', '4780', (127, 131))	('oncogenic', 'Var', (117, 126))	('NRF2', 'Gene', (23, 27))	('NRF2', 'Gene', (127, 131))	('binding', 'molecular_function', 'GO:0005488', ('28', '35'))
11958	30195190	Taken together, these analyses suggest that oncogenic NRF2 is able to upregulate its cancer target genes in a variety of cell types because these genes contain fewer cell-specific repressive inputs, particularly in the chromatin environment surrounding their ARE-containing regulatory DNA regions.	('oncogenic', 'Var', (44, 53))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('chromatin', 'cellular_component', 'GO:0000785', ('219', '228'))	('NRF2', 'Gene', '4780', (54, 58))	('DNA', 'cellular_component', 'GO:0005574', ('285', '288'))	('cancer', 'Disease', (85, 91))	('fewer', 'NegReg', (160, 165))	('upregulate', 'PosReg', (70, 80))	('NRF2', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
11968	30195190	Thus, although the NRF2 cancer target genes were identified based on changes associated with NRF2 mutation in a limited number of tumors, our inferred activity data might identify additional genetic alterations driving high NRF2 activity.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('NRF2', 'Gene', '4780', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutation', 'Var', (98, 106))	('NRF2', 'Gene', (224, 228))	('NRF2', 'Gene', '4780', (19, 23))	('NRF2', 'Gene', (93, 97))	('NRF2 cancer', 'Disease', 'MESH:D009369', (19, 30))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('NRF2', 'Gene', (19, 23))	('NRF2 cancer', 'Disease', (19, 30))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('NRF2', 'Gene', '4780', (224, 228))
11969	30195190	To test this possibility, we used a receiver operating characteristic (ROC) based approach to ask which cancer driver mutations are enriched in tumors with high NRF2 activity.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('NRF2', 'Gene', (161, 165))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('activity', 'MPA', (166, 174))	('mutations', 'Var', (118, 127))	('NRF2', 'Gene', '4780', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
11974	30195190	To calculate the AUC for a given driver gene, ranked tumors were called 'positive' if they had a mutation in the gene, and 'negative' if they had no mutation in the gene.	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('mutation', 'Var', (97, 105))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
11975	30195190	For this analysis, AUC values closer to 1 correspond to enrichment (high NRF2 activity is a strong classifier for tumors with a mutation in given gene), 0.5 corresponds to no enrichment (random relationship between NRF2 activity and mutation), and values < 0.5 correspond to inverse relationships (low NRF2 activity identifies tumors with a mutation in given driver gene).	('NRF2', 'Gene', '4780', (73, 77))	('NRF2', 'Gene', '4780', (302, 306))	('tumors', 'Disease', 'MESH:D009369', (327, 333))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('NRF2', 'Gene', '4780', (215, 219))	('activity', 'MPA', (307, 315))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('NRF2', 'Gene', (73, 77))	('NRF2', 'Gene', (302, 306))	('NRF2', 'Gene', (215, 219))	('tumors', 'Disease', (327, 333))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('mutation', 'Var', (128, 136))	('activity', 'MPA', (78, 86))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('mutation', 'Var', (341, 349))	('tumors', 'Phenotype', 'HP:0002664', (327, 333))
11978	30195190	Using this method, the top three genes with mutations associated with high NRF2 activity were NFE2L2/NRF2 (AUC = 0.843), KEAP1 (AUC = 0.826), and CUL3 (AUC = 0.609) (Fig.	('NRF2', 'Gene', '4780', (101, 105))	('NRF2', 'Gene', (101, 105))	('KEAP1', 'Gene', '9817', (121, 126))	('activity', 'MPA', (80, 88))	('NRF2', 'Gene', '4780', (75, 79))	('NFE2L2', 'Gene', '4780', (94, 100))	('mutations', 'Var', (44, 53))	('CUL3', 'Gene', '8452', (146, 150))	('KEAP1', 'Gene', (121, 126))	('CUL3', 'Gene', (146, 150))	('NFE2L2', 'Gene', (94, 100))	('NRF2', 'Gene', (75, 79))
11979	30195190	Importantly, in addition to mutations, NFE2L2/NRF2 amplification (copy number gain) and KEAP1 or CUL3 deletion (copy number loss) are also associated with high inferred NRF2 activity (Fig.	('NFE2L2', 'Gene', (39, 45))	('NRF2', 'Gene', '4780', (46, 50))	('NRF2', 'Gene', '4780', (169, 173))	('deletion', 'Var', (102, 110))	('NRF2', 'Gene', (46, 50))	('NRF2', 'Gene', (169, 173))	('KEAP1', 'Gene', '9817', (88, 93))	('CUL3', 'Gene', '8452', (97, 101))	('NFE2L2', 'Gene', '4780', (39, 45))	('CUL3', 'Gene', (97, 101))	('activity', 'MPA', (174, 182))	('KEAP1', 'Gene', (88, 93))	('amplification', 'Var', (51, 64))
11980	30195190	Together, mutations in these three genes can account for many of the "high NRF2" tumors in multiple cancer types (Fig.	('NRF2"', 'Gene', (75, 80))	('multiple cancer', 'Disease', (91, 106))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('account for', 'Reg', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('multiple cancer', 'Disease', 'MESH:D009369', (91, 106))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutations', 'Var', (10, 19))	('NRF2"', 'Gene', '4780', (75, 80))
11990	30195190	No cancers showed a significant increase in overall survival with high NRF2 activity.	('increase', 'PosReg', (32, 40))	('activity', 'MPA', (76, 84))	('NRF2', 'Gene', '4780', (71, 75))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('overall', 'MPA', (44, 51))	('cancers', 'Disease', (3, 10))	('high', 'Var', (66, 70))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('NRF2', 'Gene', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
11994	30195190	We then looked for differences in overall survival between the high and low NRF2 tumor sets.	('NRF2', 'Gene', '4780', (76, 80))	('NRF2', 'Gene', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('high', 'Var', (63, 67))	('looked', 'Reg', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('low', 'NegReg', (72, 75))	('tumor', 'Disease', (81, 86))
11996	30195190	Again, high expression of the NRF2 cancer target genes is primarily associated with decreased overall survival (Supplemental Fig.	('overall survival', 'MPA', (94, 110))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('NRF2 cancer', 'Disease', 'MESH:D009369', (30, 41))	('high', 'Var', (7, 11))	('NRF2 cancer', 'Disease', (30, 41))	('decreased', 'NegReg', (84, 93))
11997	30195190	6), and 11 cancer types showed a significant decrease in overall survival in the high NRF2 group using this method.	('NRF2', 'Gene', '4780', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('high', 'Var', (81, 85))	('NRF2', 'Gene', (86, 90))	('overall survival', 'MPA', (57, 73))	('decrease', 'NegReg', (45, 53))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))
11999	30195190	Overall, this work implies that, at least for certain cancers, high expression of the NRF2 cancer target genes is associated with significantly shortened overall survival times.	('NRF2 cancer', 'Disease', (86, 97))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('shortened', 'NegReg', (144, 153))	('high', 'Var', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('overall survival times', 'CPA', (154, 176))	('NRF2 cancer', 'Disease', 'MESH:D009369', (86, 97))
12000	30195190	Dysregulation of transcription factor function is a common occurrence in cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('transcription', 'biological_process', 'GO:0006351', ('17', '30'))	('transcription factor', 'molecular_function', 'GO:0000981', ('17', '37'))	('transcription', 'Protein', (17, 30))
12002	30195190	Here, we focused on the transcription factor NRF2, which is often hyperactivated in cancer via mutations that disrupt the NRF2-KEAP1 interaction interface.	('hyperactivated', 'PosReg', (66, 80))	('interaction', 'Interaction', (133, 144))	('KEAP1', 'Gene', '9817', (127, 132))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('NRF2', 'Gene', (45, 49))	('cancer', 'Disease', (84, 90))	('transcription factor', 'molecular_function', 'GO:0000981', ('24', '44'))	('KEAP1', 'Gene', (127, 132))	('NRF2', 'Gene', '4780', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (95, 104))	('NRF2', 'Gene', '4780', (45, 49))	('NRF2', 'Gene', (122, 126))	('transcription', 'biological_process', 'GO:0006351', ('24', '37'))
12003	30195190	In fact, based on these mutations, NFE2L2 (which encodes NRF2) is considered a cancer driver gene in several cancer types, including carcinomas of the lung, bladder, head/neck, and uterus/endometrium; and KEAP1 is classified as a cancer driver in both lung carcinoma and adenocarcinoma.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('neck', 'cellular_component', 'GO:0044326', ('171', '175'))	('carcinomas of the lung', 'Disease', (133, 155))	('mutations', 'Var', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('NRF2', 'Gene', '4780', (57, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('NFE2L2', 'Gene', '4780', (35, 41))	('cancer', 'Disease', (230, 236))	('lung carcinoma and adenocarcinoma', 'Disease', 'MESH:D000077192', (252, 285))	('cancer', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', (109, 115))	('KEAP1', 'Gene', '9817', (205, 210))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('NRF2', 'Gene', (57, 61))	('NFE2L2', 'Gene', (35, 41))	('KEAP1', 'Gene', (205, 210))	('carcinomas of the lung', 'Disease', 'MESH:D008175', (133, 155))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
12004	30195190	To gain insight into the core oncogenic NRF2 regulatory network, we used an integrative genomics approach that combined our own ChIP-seq data with TCGA gene expression data to identify direct NRF2 target genes consistently upregulated by oncogenic NRF2 across multiple cancer contexts.	('oncogenic', 'Var', (238, 247))	('multiple cancer', 'Disease', (260, 275))	('NRF2', 'Gene', '4780', (40, 44))	('upregulated', 'PosReg', (223, 234))	('NRF2', 'Gene', (248, 252))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('NRF2', 'Gene', '4780', (192, 196))	('NRF2', 'Gene', (40, 44))	('multiple cancer', 'Disease', 'MESH:D009369', (260, 275))	('core', 'cellular_component', 'GO:0019013', ('25', '29'))	('NRF2', 'Gene', (192, 196))	('gene expression', 'biological_process', 'GO:0010467', ('152', '167'))	('NRF2', 'Gene', '4780', (248, 252))
12009	30195190	However, when we compared these potential NRF2 targets to gene expression changes associated with oncogenic NRF2 mutation in carcinomas of the lung, bladder, head/neck, or uterus/endometrium, only 32 direct target genes were upregulated by NRF2 in at least two cancer types.	('upregulated', 'PosReg', (225, 236))	('mutation', 'Var', (113, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('NRF2', 'Gene', (240, 244))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('NRF2', 'Gene', (108, 112))	('NRF2', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('NRF2', 'Gene', '4780', (240, 244))	('gene expression', 'biological_process', 'GO:0010467', ('58', '73'))	('carcinomas of the lung', 'Disease', 'MESH:D008175', (125, 147))	('neck', 'cellular_component', 'GO:0044326', ('163', '167'))	('NRF2', 'Gene', '4780', (108, 112))	('carcinomas of the lung', 'Disease', (125, 147))	('NRF2', 'Gene', '4780', (42, 46))
12012	30195190	HMOX1) share these features but fail to be consistently upregulated with oncogenic NRF2 mutations; thus, ARE sequence and NRF2 binding strength alone do not mechanistically differentiate NRF2-targeted cancer AREs from its non-cancer AREs.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('NRF2', 'Gene', '4780', (187, 191))	('cancer', 'Disease', (201, 207))	('NRF2', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('HMOX1', 'Gene', (0, 5))	('NRF2', 'Gene', '4780', (122, 126))	('NRF2', 'Gene', (187, 191))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('binding', 'molecular_function', 'GO:0005488', ('127', '134'))	('HMOX1', 'Gene', '3162', (0, 5))	('NRF2', 'Gene', (122, 126))	('NRF2', 'Gene', '4780', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
12022	30195190	We therefore used this expression signature to infer NRF2 activity across thousands of TCGA-profiled tumors, and test whether high NRF2 tumors are associated with the expected NRF2 pathway mutations.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('NRF2', 'Gene', '4780', (131, 135))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('NRF2', 'Gene', '4780', (176, 180))	('high NRF2 tumors', 'Disease', 'MESH:D009369', (126, 142))	('NRF2', 'Gene', '4780', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('NRF2', 'Gene', (131, 135))	('NRF2', 'Gene', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('NRF2', 'Gene', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (189, 198))	('high NRF2 tumors', 'Disease', (126, 142))	('tumors', 'Disease', (101, 107))
12024	30195190	As discussed previously, mutations that disrupt NRF2-KEAP1 interaction lead to constitutive NRF2 activity.	('NRF2', 'Gene', '4780', (48, 52))	('mutations', 'Var', (25, 34))	('lead', 'Reg', (71, 75))	('constitutive', 'MPA', (79, 91))	('interaction', 'Interaction', (59, 70))	('NRF2', 'Gene', (48, 52))	('activity', 'MPA', (97, 105))	('NRF2', 'Gene', '4780', (92, 96))	('KEAP1', 'Gene', '9817', (53, 58))	('NRF2', 'Gene', (92, 96))	('KEAP1', 'Gene', (53, 58))
12026	30195190	Mutations in CUL3 have previously been linked to NRF2 activation in papillary renal cell carcinoma, and our analysis confirms this, although we also see CUL3 mutation associated with high NRF2 activity in breast, esophageal, and head/neck cancer (see Fig.	('esophageal', 'Disease', (213, 223))	('neck cancer', 'Phenotype', 'HP:0012288', (234, 245))	('breast', 'Disease', (205, 211))	('neck', 'cellular_component', 'GO:0044326', ('234', '238'))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('NRF2', 'Gene', '4780', (49, 53))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (68, 98))	('CUL3', 'Gene', '8452', (13, 17))	('head/neck cancer', 'Disease', 'MESH:D006258', (229, 245))	('Mutations', 'Var', (0, 9))	('head/neck cancer', 'Disease', (229, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('CUL3', 'Gene', (153, 157))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (68, 98))	('NRF2', 'Gene', (49, 53))	('NRF2', 'Gene', '4780', (188, 192))	('CUL3', 'Gene', (13, 17))	('activity', 'MPA', (193, 201))	('papillary renal cell carcinoma', 'Disease', (68, 98))	('mutation', 'Var', (158, 166))	('activation', 'PosReg', (54, 64))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (78, 98))	('NRF2', 'Gene', (188, 192))	('associated', 'Reg', (167, 177))	('CUL3', 'Gene', '8452', (153, 157))
12027	30195190	Importantly, we also found copy number variation in the NRF2-KEAP1-CUL3 axis is linked to high NRF2 activity: NRF2 copy number gain (amplification) and KEAP1 or CUL3 copy number loss (deletion) are all associated with high NRF2 activity.	('copy number', 'Var', (115, 126))	('KEAP1', 'Gene', '9817', (152, 157))	('KEAP1', 'Gene', (152, 157))	('CUL3', 'Gene', (67, 71))	('CUL3', 'Gene', (161, 165))	('NRF2', 'Gene', '4780', (223, 227))	('NRF2', 'Gene', '4780', (110, 114))	('gain', 'PosReg', (127, 131))	('copy number', 'Var', (166, 177))	('NRF2', 'Gene', '4780', (56, 60))	('NRF2', 'Gene', '4780', (95, 99))	('KEAP1', 'Gene', '9817', (61, 66))	('activity', 'MPA', (228, 236))	('KEAP1', 'Gene', (61, 66))	('NRF2', 'Gene', (223, 227))	('CUL3', 'Gene', '8452', (67, 71))	('NRF2', 'Gene', (110, 114))	('NRF2', 'Gene', (56, 60))	('CUL3', 'Gene', '8452', (161, 165))	('NRF2', 'Gene', (95, 99))
12028	30195190	This is consistent with the prevailing model where gain of function variation in NRF2 and loss of function variation in KEAP1 or CUL3 drive high NRF2 activity, and highlights the potential broad oncogenic impact of copy number variation across the NRF2-KEAP1-CUL3 axis.	('CUL3', 'Gene', (259, 263))	('loss of function', 'NegReg', (90, 106))	('gain of function', 'PosReg', (51, 67))	('KEAP1', 'Gene', '9817', (120, 125))	('NRF2', 'Gene', '4780', (248, 252))	('CUL3', 'Gene', (129, 133))	('NRF2', 'Gene', '4780', (145, 149))	('KEAP1', 'Gene', (120, 125))	('NRF2', 'Gene', '4780', (81, 85))	('variation', 'Var', (107, 116))	('KEAP1', 'Gene', '9817', (253, 258))	('CUL3', 'Gene', '8452', (259, 263))	('activity', 'MPA', (150, 158))	('KEAP1', 'Gene', (253, 258))	('variation', 'Var', (68, 77))	('NRF2', 'Gene', (248, 252))	('NRF2', 'Gene', (145, 149))	('NRF2', 'Gene', (81, 85))	('CUL3', 'Gene', '8452', (129, 133))
12031	30195190	In general, when comparing high NRF2 tumors (top 10%) to all other tumors of a given cancer type, high inferred NRF2 activity is associated with poor survival, with significant decreases in overall survival in 11 cancer types.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('NRF2', 'Gene', '4780', (32, 36))	('overall survival', 'MPA', (190, 206))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('NRF2', 'Gene', '4780', (112, 116))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (213, 219))	('tumors', 'Disease', (37, 43))	('high NRF2 tumors', 'Disease', (27, 43))	('poor', 'NegReg', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('activity', 'MPA', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Disease', (85, 91))	('decreases', 'NegReg', (177, 186))	('NRF2', 'Gene', (32, 36))	('tumors', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('NRF2', 'Gene', (112, 116))	('high NRF2 tumors', 'Disease', 'MESH:D009369', (27, 43))	('high', 'Var', (98, 102))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
12033	30195190	High NRF2 is associated with significant decreases in overall survival in four of these cancers, and three of the four (KIRP, BLCA, and LIHC) were also deemed significant in the thresholding-based comparisons.	('High', 'Var', (0, 4))	('decreases', 'NegReg', (41, 50))	('NRF2', 'Gene', '4780', (5, 9))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('overall survival', 'MPA', (54, 70))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('BLCA', 'Disease', (126, 130))	('NRF2', 'Gene', (5, 9))	('LIHC', 'Disease', (136, 140))	('LIHC', 'Disease', 'None', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
12034	30195190	Thus, NRF2 hyperactivation is associated with decreased overall survival in multiple cancer types, and this relationship is especially evident for papillary renal cell carcinoma (KIRP), bladder carcinoma (BLCA), and hepatocellular carcinoma (LIHC).	('NRF2', 'Gene', (6, 10))	('hepatocellular carcinoma', 'Disease', (216, 240))	('LIHC', 'Disease', (242, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('bladder carcinoma', 'Disease', (186, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('overall survival', 'MPA', (56, 72))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (147, 177))	('LIHC', 'Disease', 'None', (242, 246))	('decreased', 'NegReg', (46, 55))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (216, 240))	('multiple cancer', 'Disease', 'MESH:D009369', (76, 91))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (147, 177))	('NRF2', 'Gene', '4780', (6, 10))	('bladder carcinoma', 'Disease', 'MESH:D001749', (186, 203))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (216, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (186, 203))	('multiple cancer', 'Disease', (76, 91))	('papillary renal cell carcinoma', 'Disease', (147, 177))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (157, 177))	('hyperactivation', 'Var', (11, 26))
12050	30195190	We obtained the full list of genes differentially expressed in NRF2 mutant tumors from Araya et al., Supplementary Table 11 (RNA-seq Differential Expression).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('NRF2', 'Gene', (63, 67))	('RNA', 'cellular_component', 'GO:0005562', ('125', '128'))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('NRF2', 'Gene', '4780', (63, 67))	('mutant', 'Var', (68, 74))
12068	30195190	To assess the usefulness, or accuracy, of our 32 target NRF2 activity signature in classifying NRF2-related mutations or variants, we employed a receiver operator characteristic (ROC) curve approach on TCGA gene expression and mutation (or copy number variation) data.	('NRF2', 'Gene', '4780', (56, 60))	('mutations', 'Var', (108, 117))	('NRF2', 'Gene', (56, 60))	('variants', 'Var', (121, 129))	('NRF2', 'Gene', '4780', (95, 99))	('gene expression', 'biological_process', 'GO:0010467', ('207', '222'))	('NRF2', 'Gene', (95, 99))
12271	25795707	Using mutant HRAS (HRAS*) as an oncogenic prototype, we obtained evidence in transgenic mice that RTK/RAS pathway activation in urothelial cells causes hyperplasia that neither progresses to frank carcinoma nor regresses to normal urothelium through a period of one year.	('activation', 'PosReg', (114, 124))	('HRAS', 'Gene', (13, 17))	('mutant', 'Var', (6, 12))	('hyperplasia', 'Disease', (152, 163))	('HRAS', 'Gene', '15461', (19, 23))	('transgenic mice', 'Species', '10090', (77, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('HRAS', 'Gene', '15461', (13, 17))	('HRAS', 'Gene', (19, 23))	('frank carcinoma', 'Disease', (191, 206))	('hyperplasia', 'Disease', 'MESH:D006965', (152, 163))	('frank carcinoma', 'Disease', 'MESH:D001946', (191, 206))
12275	25795707	Taken together, our results provide evidence for RTK/RAS pathway activation and p53 deficiency as a combinatorial theranostic biomarker which may inform the progression and treatment of urothelial carcinoma.	('inform', 'Reg', (146, 152))	('urothelial carcinoma', 'Disease', (186, 206))	('RTK/RAS pathway', 'Pathway', (49, 64))	('p53', 'Gene', (80, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (186, 206))	('deficiency', 'Var', (84, 94))	('activation', 'PosReg', (65, 75))
12281	25795707	Mutations of fibroblast growth factor 3 (FGFR3) and tuberous sclerosis 1 (TSC1) are prevalent along with alterations involving many other genes.	('TSC1', 'Gene', '64930', (74, 78))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('tuberous sclerosis 1', 'Gene', (52, 72))	('TSC1', 'Gene', (74, 78))	('FGFR3', 'Gene', '14174', (41, 46))	('Mutations', 'Var', (0, 9))	('fibroblast growth factor 3', 'Gene', (13, 39))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('13', '37'))	('FGFR3', 'Gene', (41, 46))	('fibroblast growth factor 3', 'Gene', '14174', (13, 39))	('tuberous sclerosis 1', 'Gene', '64930', (52, 72))
12283	25795707	Notably, the frequency of p53 mutations that characterize MIUCB in general does not differ significantly between the two major subtypes, although one study found RB1 pathway alterations to be more prevalent in the basal subtype than in the luminal subtype.	('prevalent', 'Reg', (197, 206))	('RB1 pathway', 'Pathway', (162, 173))	('MIUCB', 'Chemical', '-', (58, 63))	('alterations', 'Var', (174, 185))
12297	25795707	To begin to tackle some of these questions, we took an in-depth look of the effects of HRAS activation and p53 deficiency using a blend of in vitro and in vivo approaches.	('p53', 'Gene', (107, 110))	('deficiency', 'Var', (111, 121))	('HRAS', 'Gene', (87, 91))	('HRAS', 'Gene', '15461', (87, 91))
12299	25795707	This suggests that alterations affecting both signaling pathways could overlap, simply by chance, in at least 50% of the MIUCB.	('alterations', 'Var', (19, 30))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('MIUCB', 'Disease', (121, 126))	('MIUCB', 'Chemical', '-', (121, 126))
12300	25795707	One scenario is that this overlap is merely due to genetic drifting of two common events that do not necessarily cross-talk and are of no consequence to tumorigenesis.	('genetic', 'Var', (51, 58))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
12306	25795707	The third transgenic line harbored a "floxed" p53 allele (e.g., p53LOX) where loxP sites were inserted in introns 4 and 6, allowing deletion of exons 5 and 6 upon cre expression.	('LOX', 'Gene', '16948', (67, 70))	('deletion', 'Var', (132, 140))	('transgenic', 'Species', '10090', (10, 20))	('LOX', 'Gene', (67, 70))
12336	25795707	This corresponded well with elevated mitogenic signals including phosphorylated ERK and AKT (both T308 and S473) in the transgenic mice (Fig.	('S473', 'Var', (107, 111))	('ERK', 'Gene', '13844', (80, 83))	('mitogenic signals', 'MPA', (37, 54))	('ERK', 'Gene', (80, 83))	('AKT', 'Gene', '11651', (88, 91))	('T308', 'Var', (98, 102))	('AKT', 'Gene', (88, 91))	('transgenic mice', 'Species', '10090', (120, 135))	('elevated', 'PosReg', (28, 36))	('ERK', 'molecular_function', 'GO:0004707', ('80', '83'))
12338	25795707	Of the tumor-suppressive pathways surveyed, that of p53, including p19, p53 and p21, exhibited marked upregulation on mRNA (Fig.	('tumor', 'Disease', (7, 12))	('p19', 'Gene', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('p19', 'Gene', '12581', (67, 70))	('upregulation', 'PosReg', (102, 114))	('p21', 'Gene', (80, 83))	('p21', 'Gene', '12575', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('p19', 'cellular_component', 'GO:0070743', ('67', '70'))	('p53', 'Var', (72, 75))
12345	25795707	In contrast, knocking down p53 and expressing an oncogenic HRAS* resulted in a dramatic increase of cell migration and invasion of RT4 cells (Fig.	('knocking down', 'Var', (13, 26))	('cell migration', 'biological_process', 'GO:0016477', ('100', '114'))	('invasion of', 'CPA', (119, 130))	('cell migration', 'CPA', (100, 114))	('increase', 'PosReg', (88, 96))	('p53', 'Gene', (27, 30))	('RT4', 'CellLine', 'CVCL:0036', (131, 134))	('HRAS*', 'Gene', (59, 64))
12346	25795707	Thus, p53 deficiency and RAS activation appear to be synergistic in conferring the invasive property to human urothelial tumor cells and triggering the conversion of non-invasive human urothelial tumor cells into invasive ones.	('urothelial tumor', 'Disease', 'MESH:D001749', (185, 201))	('p53', 'Gene', (6, 9))	('activation', 'PosReg', (29, 39))	('human', 'Species', '9606', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('urothelial tumor', 'Disease', 'MESH:D001749', (110, 126))	('RAS', 'Protein', (25, 28))	('urothelial tumor', 'Disease', (185, 201))	('triggering', 'Reg', (137, 147))	('human', 'Species', '9606', (104, 109))	('urothelial tumor', 'Disease', (110, 126))	('invasive property', 'CPA', (83, 100))	('deficiency', 'Var', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
12347	25795707	To further define the interactive effects between oncogenic HRAS* and p53 deficiency in vivo, we developed compound mice by ablating p53 from urothelial cells expressing oncogenic HRAS*.	('p53', 'Gene', (133, 136))	('mice', 'Species', '10090', (116, 120))	('ablating', 'Var', (124, 132))
12351	25795707	In stark contrast, the compound line expressing oncogenic HRAS* and lacking p53 developed exclusively high-grade bladder tumors in the form of carcinoma-in-situ (CIS) and muscle-invasive tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('p53', 'Gene', (76, 79))	('muscle-invasive tumors', 'Disease', (171, 193))	('developed', 'PosReg', (80, 89))	('bladder tumors', 'Disease', 'MESH:D001749', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('bladder tumors', 'Phenotype', 'HP:0009725', (113, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('HRAS*', 'Var', (58, 63))	('bladder tumors', 'Disease', (113, 127))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('carcinoma-in-situ', 'Disease', 'MESH:D002278', (143, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('carcinoma-in-situ', 'Disease', (143, 160))	('bladder tumor', 'Phenotype', 'HP:0009725', (113, 126))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (171, 193))
12368	25795707	Interestingly, these ZEB2- and CD44-positive cells had a marked decrease of E-cadherin, an epithelial marker, and a marked increase of vimentin, a mesenchymal cell marker (Fig.	('vimentin', 'Gene', '22352', (135, 143))	('decrease', 'NegReg', (64, 72))	('cadherin', 'molecular_function', 'GO:0008014', ('78', '86'))	('vimentin', 'Gene', (135, 143))	('ZEB2', 'Gene', '24136', (21, 25))	('increase', 'PosReg', (123, 131))	('ZEB2', 'Gene', (21, 25))	('CD44-positive', 'Var', (31, 44))	('vimentin', 'cellular_component', 'GO:0045098', ('135', '143'))	('vimentin', 'cellular_component', 'GO:0045099', ('135', '143'))	('E-cadherin', 'Gene', '12550', (76, 86))	('E-cadherin', 'Gene', (76, 86))
12370	25795707	Whereas normal-appearing urothelial regions showed K14-positive cells which lacked ZEB2 labeling, areas with tumor morphology showed strong co-expression of ZEB2 and K14 (Fig.	('co-expression', 'Interaction', (140, 153))	('ZEB2', 'Gene', '24136', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('ZEB2', 'Gene', (157, 161))	('K14', 'Var', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('ZEB2', 'Gene', '24136', (83, 87))	('ZEB2', 'Gene', (83, 87))	('tumor', 'Disease', (109, 114))
12373	25795707	These results establish that urothelial tumor progenitor cells in our compound transgenic mice expressing oncogenic HRAS* and lacking p53 strongly express EMT drivers and their expression may play a central role in initiating muscle-invasive urothelial carcinoma.	('transgenic mice', 'Species', '10090', (79, 94))	('urothelial tumor', 'Disease', (29, 45))	('muscle-invasive urothelial carcinoma', 'Disease', 'MESH:D009217', (226, 262))	('EMT', 'biological_process', 'GO:0001837', ('155', '158'))	('HRAS*', 'Var', (116, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('muscle-invasive urothelial carcinoma', 'Disease', (226, 262))	('play', 'Reg', (192, 196))	('urothelial tumor', 'Disease', 'MESH:D001749', (29, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('initiating', 'Reg', (215, 225))
12376	25795707	The recent expansion of whole-genome and whole-exome sequencing into a broad range of human cancers has yielded unprecedented details about somatic gene mutations, making it possible to classify cancers in genomic terms and to devise target-specific, precision therapies.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('mutations', 'Var', (153, 162))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancers', 'Disease', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
12379	25795707	Up to 72% of the high-grade MIUCB harbored activation mutations in the FGFR3, EGFR, ERBB2, ERBB3, HRAS/NRAS and PIK3CA or inactivating mutations in NF1, PTEN, INPP4B, STK11, TSC1 and TSC2.	('FGFR3', 'Gene', (71, 76))	('ERBB3', 'Gene', (91, 96))	('FGFR3', 'Gene', '14174', (71, 76))	('PTEN', 'Gene', '19211', (153, 157))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('STK11', 'Gene', '20869', (167, 172))	('INPP4B', 'Gene', '234515', (159, 165))	('activation', 'PosReg', (43, 53))	('TSC1', 'Gene', '64930', (174, 178))	('inactivating mutations', 'Var', (122, 144))	('TSC2', 'Gene', '22084', (183, 187))	('mutations', 'Var', (54, 63))	('NF1', 'Gene', '18015', (148, 151))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('NRAS', 'Gene', (103, 107))	('PIK3CA', 'Gene', (112, 118))	('NRAS', 'Gene', '18176', (103, 107))	('HRAS', 'Gene', (98, 102))	('ERBB2', 'Gene', (84, 89))	('STK11', 'Gene', (167, 172))	('NF1', 'Gene', (148, 151))	('PTEN', 'Gene', (153, 157))	('INPP4B', 'Gene', (159, 165))	('STK11', 'molecular_function', 'GO:0033868', ('167', '172'))	('EGFR', 'Gene', (78, 82))	('EGFR', 'Gene', '13649', (78, 82))	('HRAS', 'Gene', '15461', (98, 102))	('ERBB2', 'Gene', '13866', (84, 89))	('MIUCB', 'Chemical', '-', (28, 33))	('TSC2', 'Gene', (183, 187))	('PIK3CA', 'Gene', '18706', (112, 118))	('TSC1', 'Gene', (174, 178))	('ERBB3', 'Gene', '13867', (91, 96))
12381	25795707	For instance, urothelial expression of an FGFR3 mutant (K644E) that constitutively activates the tyrosine kinase of FGFR3, either alone or in combination with KRAS and beta-catenin mutations or with PTEN deletion, in transgenic mice failed to elicit any urothelial carcinoma.	('KRAS', 'Gene', '16653', (159, 163))	('beta-catenin', 'Gene', '12387', (168, 180))	('K644E', 'Var', (56, 61))	('PTEN', 'Gene', '19211', (199, 203))	('urothelial carcinoma', 'Disease', (254, 274))	('beta-catenin', 'Gene', (168, 180))	('FGFR3', 'Gene', '14174', (116, 121))	('FGFR3', 'Gene', (116, 121))	('tyrosine kinase', 'MPA', (97, 112))	('activates', 'PosReg', (83, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('116', '120'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (254, 274))	('FGFR3', 'Gene', '14174', (42, 47))	('FGFR3', 'Gene', (42, 47))	('transgenic mice', 'Species', '10090', (217, 232))	('PTEN', 'Gene', (199, 203))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('KRAS', 'Gene', (159, 163))	('K644E', 'Mutation', 'p.K644E', (56, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))
12383	25795707	Furthermore, urothelium-specific expression in our transgenic mice of oncogenic HRAS* at a level comparable to the endogenous RAS elicited urothelial hyperplasia that only occasionally progressed to low-grade, papillary non-invasive UCB in aged mice (>12 months).	('elicited', 'Reg', (130, 138))	('transgenic mice', 'Species', '10090', (51, 66))	('mice', 'Species', '10090', (62, 66))	('urothelial hyperplasia', 'Disease', (139, 161))	('urothelial hyperplasia', 'Disease', 'MESH:D006965', (139, 161))	('HRAS', 'Gene', (80, 84))	('mice', 'Species', '10090', (245, 249))	('oncogenic', 'Var', (70, 79))
12385	25795707	The fact that gene mutations that activate the RTK/RAS pathway are highly prevalent in human high-grade MIUCB from the TCGA study raises an important question as to whether these mutations are tumor "drivers" or "passengers" and whether the mutations require additional genetic alterations to be tumorigenic.	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('activate', 'PosReg', (34, 42))	('human', 'Species', '9606', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', (296, 301))	('MIUCB', 'Chemical', '-', (104, 109))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', (193, 198))	('RTK/RAS pathway', 'Pathway', (47, 62))	('tumor', 'Disease', 'MESH:D009369', (296, 301))
12387	25795707	Although p53 deficiency by itself is also non-tumorigenic, it is highly synergistic with RAS activation, and these two alterations together are necessary and sufficient to initiate high-grade, carcinoma-in-situ (CIS) and MIUCB (Figs.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('deficiency', 'Var', (13, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('MIUCB', 'Chemical', '-', (221, 226))	('tumor', 'Disease', (46, 51))	('p53', 'Gene', (9, 12))	('carcinoma-in-situ', 'Disease', 'MESH:D002278', (193, 210))	('carcinoma-in-situ', 'Disease', (193, 210))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
12388	25795707	Of note, the MIUCB we observed in our double transgenic mice expressing oncogenic Ha-RAS and lacking p53 bear strong resemblance to the basal-subtype of MIUCB recently classified in patients in their (i) high expression of basal cell markers such as K5, K14 and CD44 (Figs.	('Ha-RAS', 'Gene', '15461', (82, 88))	('Ha-RAS', 'Gene', (82, 88))	('p53', 'Gene', (101, 104))	('CD44', 'Var', (262, 266))	('MIUCB', 'Chemical', '-', (153, 158))	('K14', 'Var', (254, 257))	('patients', 'Species', '9606', (182, 190))	('MIUCB', 'Chemical', '-', (13, 18))	('transgenic mice', 'Species', '10090', (45, 60))
12393	25795707	Our study therefore functionally defines RAS pathway activation and p53 deficiency as the highly synergistic co-drivers for the basal-subtype MIUCB, and it has several significant implications.	('activation', 'PosReg', (53, 63))	('MIUCB', 'Chemical', '-', (142, 147))	('deficiency', 'Var', (72, 82))	('RAS pathway', 'Pathway', (41, 52))	('p53', 'Gene', (68, 71))
12395	25795707	RAS pathway activation together with p53 deficiency could potentially serve as a new biomarker set for the genetic identification of the basal-subtype of MIUCB that may be associated with an unfavorable prognosis, hence requiring aggressive therapeutic modalities.	('activation', 'PosReg', (12, 22))	('deficiency', 'Var', (41, 51))	('p53', 'Gene', (37, 40))	('RAS pathway', 'Pathway', (0, 11))	('MIUCB', 'Chemical', '-', (154, 159))
12398	25795707	S3-S5), we also showed that introducing oncongenic HRAS* and knocking down p53 in cultured RT4 cells confer invasive properties to these otherwise non-invasive human UCB cells (Fig.	('RT4', 'CellLine', 'CVCL:0036', (91, 94))	('HRAS*', 'Gene', (51, 56))	('p53', 'Gene', (75, 78))	('invasive properties', 'CPA', (108, 127))	('knocking down', 'Var', (61, 74))	('human', 'Species', '9606', (160, 165))
12399	25795707	Perhaps it is not surprising that p53 alterations are not very predictive of UCB progression, based on data from genetically engineered mice indicating the lack of tumorigenicity by p53 deficiency alone (Fig.	('mice', 'Species', '10090', (136, 140))	('tumor', 'Disease', (164, 169))	('UCB', 'Disease', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('deficiency', 'Var', (186, 196))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('p53', 'Gene', (182, 185))
12400	25795707	It is possible, however, that a combination of RAS pathway activation and p53 deficiency, as we demonstrated here, are better biomarkers for UCB surveillance and prediction of tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('deficiency', 'Var', (78, 88))	('tumor', 'Disease', (176, 181))	('RAS pathway', 'Pathway', (47, 58))	('p53', 'Gene', (74, 77))	('activation', 'PosReg', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
12401	25795707	It is worth noting that ablation of both PTEN and p53 in mouse urothelia also led to MIUCB, consistent with the fact that PTEN acts in the RAS pathway and PTEN inactivation is functionally akin to RAS activation.	('RAS pathway', 'Pathway', (139, 150))	('PTEN', 'Gene', '19211', (155, 159))	('PTEN', 'Gene', (155, 159))	('mouse', 'Species', '10090', (57, 62))	('MIUCB', 'MPA', (85, 90))	('PTEN', 'Gene', '19211', (122, 126))	('p53', 'Gene', (50, 53))	('led to', 'Reg', (78, 84))	('PTEN', 'Gene', '19211', (41, 45))	('PTEN', 'Gene', (41, 45))	('PTEN', 'Gene', (122, 126))	('ablation', 'Var', (24, 32))	('MIUCB', 'Chemical', '-', (85, 90))
12406	25795707	From a mechanistic standpoint, RAS activation and p53 deficiency could synergize on several fronts to affect cellular processes that govern urothelial tumorigenesis and progression.	('deficiency', 'Var', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('urothelial tumor', 'Disease', 'MESH:D001749', (140, 156))	('urothelial tumor', 'Disease', (140, 156))	('RAS', 'Protein', (31, 34))	('p53', 'Gene', (50, 53))	('cellular processes', 'CPA', (109, 127))	('affect', 'Reg', (102, 108))	('activation', 'PosReg', (35, 45))
12412	25795707	In this regard, inhibiting RAS effectors that drive EMT and/or inhibiting EMT effectors such as MMPs may play a critical role in reducing chemoresistance that has been observed in the basal-type MIUCB.	('chemoresistance', 'CPA', (138, 153))	('MMPs', 'Gene', '17386;17390;17392;17395;17386', (96, 100))	('EMT', 'biological_process', 'GO:0001837', ('74', '77'))	('RAS', 'Protein', (27, 30))	('MMPs', 'Gene', (96, 100))	('inhibiting', 'NegReg', (63, 73))	('EMT', 'biological_process', 'GO:0001837', ('52', '55'))	('inhibiting', 'Var', (16, 26))	('reducing', 'NegReg', (129, 137))	('MIUCB', 'Chemical', '-', (195, 200))
12415	25795707	In summary, the data presented in this paper provide the first experimental evidence demonstrating that the loss of p53 is critical in allowing hyperplastic urothelial cells in vivo to bypass G2 arrest induced by activated HRAS and proceed to tumor formation; that RAS pathway activation and p53 pathway inactivation together confer invasive properties to non-invasive urothelial tumor cells and these two synergistic events are necessary and sufficient to convert carcinoma in situ to basal-subtype, muscle-invasive urothelial carcinoma of the bladder; and that activation of EMT and increased stemness in urothelial progenitor cells are crucial epigenetic events for invasive tumorigenesis.	('carcinoma', 'Disease', (528, 537))	('carcinoma', 'Disease', 'MESH:D002277', (465, 474))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (465, 482))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('tumor', 'Disease', (678, 683))	('EMT', 'CPA', (577, 580))	('tumor', 'Disease', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (678, 683))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('carcinoma', 'Disease', 'MESH:D002277', (528, 537))	('inactivation', 'Var', (304, 316))	('invasive urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (508, 552))	('carcinoma', 'Phenotype', 'HP:0030731', (465, 474))	('formation', 'biological_process', 'GO:0009058', ('249', '258'))	('tumor', 'Phenotype', 'HP:0002664', (678, 683))	('EMT', 'biological_process', 'GO:0001837', ('577', '580'))	('carcinoma', 'Disease', (465, 474))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('stemness', 'Disease', 'MESH:D020295', (595, 603))	('stemness', 'Disease', (595, 603))	('tumor', 'Disease', (380, 385))	('muscle-invasive urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (501, 552))	('HRAS', 'Gene', (223, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (528, 537))	('tumor', 'Disease', 'MESH:D009369', (380, 385))	('urothelial tumor', 'Disease', 'MESH:D001749', (369, 385))	('urothelial tumor', 'Disease', (369, 385))	('HRAS', 'Gene', '15461', (223, 227))
12425	22914978	Variant histology was associated with inferior 5-year DSS: 50% vs. 83% in pure TCC (p=0.02).	('DSS', 'Chemical', '-', (54, 57))	('inferior', 'NegReg', (38, 46))	('pure', 'molecular_function', 'GO:0034023', ('74', '78'))	('DSS', 'MPA', (54, 57))	('TCC', 'cellular_component', 'GO:0005579', ('79', '82'))	('Variant', 'Var', (0, 7))
12479	22914978	Down-staging correlated with 5-year overall survival (log-rank p <= 0.001): patients down-staged to <= pT1N0, pT2-3aN0, and >= pT3b or N+ tumors had an 87%, 67%, and 27% 5-year overall survival, respectively (Figure 1).	('pT1', 'Gene', '58492', (103, 106))	('patients', 'Species', '9606', (76, 84))	('pT1', 'Gene', (103, 106))	('pT2-3aN0', 'Var', (110, 118))	('tumors', 'Disease', (138, 144))	('>= pT3b', 'Var', (124, 131))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
12480	22914978	For patients completing 3 cycles of IAG prior to CGI, the pT0N0 and <=pT1N0, rates were 60 and 65%, respectively.	('pT1', 'Gene', '58492', (70, 73))	('pT1', 'Gene', (70, 73))	('CGI', 'Chemical', '-', (49, 52))	('pT0N0', 'Var', (58, 63))	('patients', 'Species', '9606', (4, 12))
12490	22914978	The presence of variant histology was associated with an inferior 5-year DSS of 50% (95% CI = 35-72%) as compared to 83% (95% CI = 71-96%) for pure transitional cell carcinoma (log-rank p= 0.02, Figure 3).	('carcinoma', 'Disease', 'MESH:D002277', (166, 175))	('variant', 'Var', (16, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (148, 175))	('pure', 'molecular_function', 'GO:0034023', ('143', '147'))	('carcinoma', 'Disease', (166, 175))	('DSS', 'MPA', (73, 76))	('DSS', 'Chemical', '-', (73, 76))
12491	22914978	The presence of micropapillary histology was associated with a 5-year OS and DSS of 54% (95% CI 33-89%).	('micropapillary histology', 'Var', (16, 40))	('DSS', 'CPA', (77, 80))	('DSS', 'Chemical', '-', (77, 80))
12527	22914978	On a previous clinical trial randomizing patients to either initial cystectomy or neoadjuvant chemotherapy, the presence of these high-risk features was associated with clinical up-staging in 86% of patients treated with initial surgery.	('patients', 'Species', '9606', (41, 49))	('presence', 'Var', (112, 120))	('patients', 'Species', '9606', (199, 207))	('up-staging', 'PosReg', (178, 188))
12560	33608980	Therefore, the present study reused multi-omics data obtained from public databases, including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), to uncover the influence of genetic and epigenetic alterations on different immune phenotypes in bladder cancer.	('epigenetic', 'Var', (201, 211))	('Cancer', 'Disease', 'MESH:D009369', (99, 105))	('Cancer', 'Disease', (99, 105))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (258, 272))	('Gene Expression', 'biological_process', 'GO:0010467', ('130', '145'))	('bladder cancer', 'Disease', 'MESH:D001749', (258, 272))	('bladder cancer', 'Disease', (258, 272))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))
12562	33608980	A total of five GEO data sets were identified, GSE87304  16  (305 bladder cancers), GSE128702  17  (256 bladder cancers), GSE31684  18  (93 bladder cancers), GSE13507  19  (165 bladder cancers) and GSE154261  20  (99 bladder cancers).	('bladder cancers', 'Disease', 'MESH:D001749', (140, 155))	('bladder cancers', 'Phenotype', 'HP:0009725', (217, 232))	('bladder cancers', 'Phenotype', 'HP:0009725', (66, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (66, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (217, 231))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('bladder cancers', 'Disease', (140, 155))	('bladder cancers', 'Phenotype', 'HP:0009725', (177, 192))	('GSE154261', 'Var', (198, 207))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('GSE13507  19', 'Var', (158, 170))	('bladder cancer', 'Phenotype', 'HP:0009725', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('bladder cancers', 'Disease', 'MESH:D001749', (217, 232))	('bladder cancers', 'Phenotype', 'HP:0009725', (104, 119))	('bladder cancers', 'Disease', 'MESH:D001749', (66, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('bladder cancers', 'Disease', (217, 232))	('GSE31684  18', 'Var', (122, 134))	('bladder cancers', 'Disease', 'MESH:D001749', (177, 192))	('bladder cancers', 'Disease', (66, 81))	('bladder cancers', 'Disease', (177, 192))	('bladder cancers', 'Disease', 'MESH:D001749', (104, 119))	('bladder cancers', 'Phenotype', 'HP:0009725', (140, 155))	('bladder cancers', 'Disease', (104, 119))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('GSE128702  17', 'Var', (84, 97))	('GSE87304', 'Var', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
12580	33608980	Six independent transcriptome data sets including 1329 bladder cancer patients, including TCGA-BLCA (n = 411), GSE87304  16  (n = 305), GSE128702  17  (n = 256), GSE31684  18  (n = 93), GSE13507  19  (n = 165) and GSE154261  20  (n = 99) were analysed by CIBERSORTx to evaluate portion of 22 immune cell types in bladder cancer patients.	('patients', 'Species', '9606', (70, 78))	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('bladder cancer', 'Disease', (55, 69))	('bladder cancer', 'Disease', (313, 327))	('bladder cancer', 'Phenotype', 'HP:0009725', (313, 327))	('GSE31684  18', 'Var', (162, 174))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (328, 336))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('GSE128702  17', 'Var', (136, 149))	('GSE87304  16', 'Var', (111, 123))	('bladder cancer', 'Disease', 'MESH:D001749', (313, 327))
12595	33608980	The analyses of concurrent and mutually exclusive mutations among the overall gene mutations in the TCGA-BLCA patients found that TP53 had concurrent mutations with RB1 and MUC16, and had mutually exclusive mutations with FGFR3, ATM and other genes (Figure 3C).	('FGFR3', 'Gene', (222, 227))	('ATM', 'Gene', (229, 232))	('RB1', 'Gene', '5925', (165, 168))	('patients', 'Species', '9606', (110, 118))	('MUC16', 'Gene', (173, 178))	('ATM', 'Gene', '472', (229, 232))	('mutations', 'Var', (150, 159))	('FGFR3', 'Gene', '2261', (222, 227))	('MUC16', 'Gene', '94025', (173, 178))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('RB1', 'Gene', (165, 168))	('TCGA-BLCA', 'Gene', (100, 109))	('FGFR', 'molecular_function', 'GO:0005007', ('222', '226'))
12596	33608980	We also found that the TTN gene had significant concurrent mutations with many genes, such as ERBB2, OBSCN, FAT4, ATM and KMT2C.	('FAT4', 'Gene', (108, 112))	('FAT4', 'Gene', '79633', (108, 112))	('OBSCN', 'Gene', '84033', (101, 106))	('TTN', 'Gene', '7273', (23, 26))	('ERBB2', 'Gene', (94, 99))	('ATM', 'Gene', '472', (114, 117))	('KMT2C', 'Gene', '58508', (122, 127))	('KMT2C', 'Gene', (122, 127))	('mutations', 'Var', (59, 68))	('OBSCN', 'Gene', (101, 106))	('ERBB2', 'Gene', '2064', (94, 99))	('ATM', 'Gene', (114, 117))	('TTN', 'Gene', (23, 26))
12598	33608980	The resultes of concurrent mutation analyses between clusters/subclusters showed that more genes had concurrent mutations with TP53 in cluster A compared with cluster B, and subcluster B1 had a lower frequency of concurrent mutation than subclusters A1 and A2.	('mutations', 'Var', (112, 121))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))
12599	33608980	Otherwise, the concurrent mutation frequency of TTN in subcluster B1 was higher than cluster A, especially relative to subcluster A1.	('TTN', 'Gene', '7273', (48, 51))	('TTN', 'Gene', (48, 51))	('higher', 'Reg', (73, 79))	('mutation', 'Var', (26, 34))
12600	33608980	The epigenetic-related methyltransferase gene KMT2D had a more concurrent mutation in cluster B1 than other subclusters.	('mutation', 'Var', (74, 82))	('KMT2D', 'Gene', (46, 51))	('KMT2D', 'Gene', '8085', (46, 51))
12602	33608980	In cluster A, there were more genes in subcluster A1 that had concurrent mutation with HMCN1 and BRCA2; however, there were more genes that had concurrent mutation with FAT4 and OBSCN in subcluster A2.	('BRCA2', 'Gene', (97, 102))	('OBSCN', 'Gene', (178, 183))	('FAT4', 'Gene', (169, 173))	('HMCN1', 'Gene', '83872', (87, 92))	('FAT4', 'Gene', '79633', (169, 173))	('BRCA2', 'Gene', '675', (97, 102))	('HMCN1', 'Gene', (87, 92))	('mutation', 'Var', (73, 81))	('OBSCN', 'Gene', '84033', (178, 183))
12603	33608980	But compared with cluster B, more genes had concurrent mutation with TP53 in the two subclusters A1 and A2.	('TP53', 'Gene', (69, 73))	('TP53', 'Gene', '7157', (69, 73))	('mutation', 'Var', (55, 63))
12620	33608980	Additionally, we found that six methylation probes (cg00137918, cg14951497, cg01085225, cg25856179, cg14768946 and cg15325732) were significantly different between bladder cancer and normal bladder (Figure S2).	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('bladder cancer', 'Phenotype', 'HP:0009725', (164, 178))	('cg01085225', 'Chemical', '-', (76, 86))	('different', 'Reg', (146, 155))	('cg01085225', 'Var', (76, 86))	('cg15325732', 'Chemical', '-', (115, 125))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('cg14768946', 'Chemical', '-', (100, 110))	('cg14951497', 'Chemical', '-', (64, 74))	('cg14768946', 'Var', (100, 110))	('cg25856179', 'Var', (88, 98))	('bladder cancer', 'Disease', (164, 178))	('bladder cancer', 'Disease', 'MESH:D001749', (164, 178))	('cg14951497', 'Var', (64, 74))	('cg00137918', 'Var', (52, 62))	('cg15325732', 'Var', (115, 125))	('cg25856179', 'Chemical', '-', (88, 98))	('normal bladder', 'Disease', (183, 197))
12621	33608980	Spearman's analysis suggested that cg00137918, cg14951497, cg01085225, cg25856179, cg14768946, cg00493400, cg11556416 and cg15325732 were negatively correlated with STAT1 gene expression with statistical significance (Figure S3).	('cg25856179', 'Chemical', '-', (71, 81))	('STAT1', 'Gene', (165, 170))	('cg00137918', 'Var', (35, 45))	('STAT1', 'Gene', '6772', (165, 170))	('gene expression', 'biological_process', 'GO:0010467', ('171', '186'))	('negatively', 'NegReg', (138, 148))	('cg15325732', 'Var', (122, 132))	('cg01085225', 'Chemical', '-', (59, 69))	('cg01085225', 'Var', (59, 69))	('cg14951497', 'Chemical', '-', (47, 57))	('cg00493400', 'Var', (95, 105))	('cg11556416', 'Var', (107, 117))	('cg14951497', 'Var', (47, 57))	('cg14768946', 'Chemical', '-', (83, 93))	('cg14768946', 'Var', (83, 93))	('cg25856179', 'Var', (71, 81))	('cg15325732', 'Chemical', '-', (122, 132))
12622	33608980	Multivariate Cox regression analysis suggested that cg14951497 was associated with an increased risk of overall survival in bladder cancer patients (Table S3).	('bladder cancer', 'Disease', 'MESH:D001749', (124, 138))	('bladder cancer', 'Disease', (124, 138))	('cg14951497', 'Var', (52, 62))	('patients', 'Species', '9606', (139, 147))	('overall', 'MPA', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (124, 138))	('cg14951497', 'Chemical', '-', (52, 62))
12641	33608980	The analyses of concurrent and mutually exclusive mutations found that TP53 had concurrent mutations with RB1 and MUC16, and had mutually exclusive mutations with FGFR3 and ATM.	('MUC16', 'Gene', (114, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('163', '167'))	('RB1', 'Gene', '5925', (106, 109))	('ATM', 'Gene', '472', (173, 176))	('FGFR3', 'Gene', '2261', (163, 168))	('mutations', 'Var', (91, 100))	('MUC16', 'Gene', '94025', (114, 119))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('FGFR3', 'Gene', (163, 168))	('RB1', 'Gene', (106, 109))	('ATM', 'Gene', (173, 176))
12665	32498352	Given the well-known activity of topical instillation of Bacillus of Calmette-Guerin (BCG) in high-risk, non-muscle invasive disease, UC immediately appeared as a suitable candidate for modern immunotherapy; moreover, UC is known to be a highly antigenic malignancy, given the high rates of DNA alterations and mutations leading to the formation of neoantigens, an element which further supports the application of ICIs in advanced or metastatic UC.	('DNA', 'cellular_component', 'GO:0005574', ('291', '294'))	('formation', 'MPA', (336, 345))	('non-muscle invasive disease', 'Disease', 'MESH:D000073296', (105, 132))	('malignancy', 'Disease', 'MESH:D009369', (255, 265))	('non-muscle invasive disease', 'Disease', (105, 132))	('formation', 'biological_process', 'GO:0009058', ('336', '345'))	('malignancy', 'Disease', (255, 265))	('mutations', 'Var', (311, 320))	('neoantigens', 'MPA', (349, 360))	('topical', 'molecular_function', 'GO:0003809', ('33', '40'))	('Calmette-Guerin', 'Chemical', '-', (69, 84))
12671	32498352	Interestingly, the magnitude of ORR and survival benefit was related to programmed death ligand-1 (PD-L1) expression: in fact, in patients with PD-L1 expression combined positive score (CPS) >= 10%, pembrolizumab resulted in improved survival, with a median OS of 18.5 months versus 11.5 months in overall cohort.	('PD-L1', 'Gene', '29126', (144, 149))	('programmed death ligand-1', 'Gene', '29126', (72, 97))	('ligand', 'molecular_function', 'GO:0005488', ('89', '95'))	('expression', 'Var', (150, 160))	('PD-L1', 'Gene', (99, 104))	('patients', 'Species', '9606', (130, 138))	('improved', 'PosReg', (225, 233))	('CPS', 'Chemical', '-', (186, 189))	('pembrolizumab', 'Disease', (199, 212))	('PD-L1', 'Gene', (144, 149))	('PD-L1', 'Gene', '29126', (99, 104))	('survival', 'MPA', (234, 242))	('pembrolizumab', 'Chemical', 'MESH:C582435', (199, 212))	('programmed death ligand-1', 'Gene', (72, 97))
12672	32498352	Finally, the CPS >= 10% population reported higher ORR (37%) compared to the CPS < 10% subgroup of patients (ORR = 18%).	('higher', 'PosReg', (44, 50))	('ORR', 'MPA', (51, 54))	('patients', 'Species', '9606', (99, 107))	('CPS', 'Chemical', '-', (77, 80))	('CPS', 'Chemical', '-', (13, 16))	('CPS >= 10%', 'Var', (13, 23))
12678	32498352	In these two trials, patients with low expression of PD-L1 receiving single-agent ICI experienced worse survival compared to patients receiving standard chemotherapy.	('PD-L1', 'Gene', (53, 58))	('survival', 'MPA', (104, 112))	('PD-L1', 'Gene', '29126', (53, 58))	('patients', 'Species', '9606', (21, 29))	('low expression', 'Var', (35, 49))	('worse', 'NegReg', (98, 103))	('patients', 'Species', '9606', (125, 133))
12696	32498352	With regard to PD-L1 expression, ORR was significantly higher in the subgroup of patients with PD-L1 expression >=5% (28.4%) compared to the PD-L1 >= 1% (23.8%) and the PD-L1 negative (16.1%) cohorts.	('PD-L1', 'Gene', (169, 174))	('PD-L1', 'Gene', (141, 146))	('PD-L1', 'Gene', '29126', (141, 146))	('PD-L1', 'Gene', (15, 20))	('PD-L1', 'Gene', '29126', (169, 174))	('patients', 'Species', '9606', (81, 89))	('expression >=5%', 'Var', (101, 116))	('PD-L1', 'Gene', (95, 100))	('>=5%', 'Var', (112, 116))	('PD-L1', 'Gene', '29126', (15, 20))	('PD-L1', 'Gene', '29126', (95, 100))	('higher', 'PosReg', (55, 61))	('ORR', 'MPA', (33, 36))
12706	32498352	Furthermore, this analysis showed that 69% of the tumors presented potential therapeutic targets, of which 42% regarded the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and 44% in the receptor tyrosine kinase/MAPK pathway, and identified an in-frame activating FGFR3-TACC3 fusion in three tumors.	('FGFR3', 'Gene', '2261', (302, 307))	('mammalian target of rapamycin', 'Gene', '2475', (165, 194))	('AKT', 'Gene', '207', (161, 164))	('receptor tyrosine kinase', 'Gene', '5979', (225, 249))	('fusion', 'Var', (314, 320))	('phosphatidylinositol-3-kinase', 'Gene', '5290', (124, 153))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (330, 336))	('MAPK', 'molecular_function', 'GO:0004707', ('250', '254'))	('PI3K', 'molecular_function', 'GO:0016303', ('155', '159'))	('mammalian target of rapamycin', 'Gene', (165, 194))	('receptor tyrosine kinase', 'Gene', (225, 249))	('phosphatidylinositol-3-kinase', 'Gene', (124, 153))	('activating', 'PosReg', (291, 301))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('FGFR', 'molecular_function', 'GO:0005007', ('302', '306'))	('tumors', 'Disease', (330, 336))	('TACC3', 'Gene', '10460', (308, 313))	('mTOR', 'Gene', (196, 200))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('TACC3', 'Gene', (308, 313))	('AKT', 'Gene', (161, 164))	('tumors', 'Disease', 'MESH:D009369', (330, 336))	('FGFR3', 'Gene', (302, 307))	('mTOR', 'Gene', '2475', (196, 200))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))
12707	32498352	Alterations in the PI3K/AKT/mTOR pathway consisted in point mutations in PIK3CA (17%), mutation or deletion of TSC1 or TSC2 (9%), and overexpression of AKT3 (10%).	('AKT', 'Gene', (24, 27))	('point mutations', 'Var', (54, 69))	('mTOR', 'Gene', (28, 32))	('mTOR', 'Gene', '2475', (28, 32))	('PIK3CA', 'Gene', '5290', (73, 79))	('AKT', 'Gene', '207', (152, 155))	('PI3K', 'molecular_function', 'GO:0016303', ('19', '23'))	('AKT', 'Gene', '207', (24, 27))	('AKT3', 'Gene', '10000', (152, 156))	('PIK3CA', 'Gene', (73, 79))	('TSC2', 'Gene', '7249', (119, 123))	('mutation', 'Var', (87, 95))	('TSC1', 'Gene', (111, 115))	('overexpression', 'PosReg', (134, 148))	('AKT3', 'Gene', (152, 156))	('AKT', 'Gene', (152, 155))	('deletion', 'Var', (99, 107))	('TSC2', 'Gene', (119, 123))	('TSC1', 'Gene', '7248', (111, 115))
12708	32498352	Alterations in the receptor tyrosine kinase/RAS pathway included activation of FGFR3 (17%), amplification of EGFR (9%), mutations of ERBB3 (6%), and mutation or amplification of ERBB2 (9%).	('FGFR3', 'Gene', '2261', (79, 84))	('ERBB3', 'Gene', '2065', (133, 138))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('receptor tyrosine kinase', 'Gene', '5979', (19, 43))	('FGFR3', 'Gene', (79, 84))	('ERBB2', 'Gene', '2064', (178, 183))	('EGFR', 'Gene', '1956', (109, 113))	('amplification', 'Var', (92, 105))	('ERBB2', 'Gene', (178, 183))	('mutations', 'Var', (120, 129))	('amplification', 'Var', (161, 174))	('receptor tyrosine kinase', 'Gene', (19, 43))	('EGFR', 'Gene', (109, 113))	('mutation', 'Var', (149, 157))	('activation', 'PosReg', (65, 75))	('ERBB3', 'Gene', (133, 138))	('EGFR', 'molecular_function', 'GO:0005006', ('109', '113'))
12713	32498352	Activating FGFR3 mutations are most common in NMIBC, being identified in approximately two-third of these early stage tumors, while their frequency in MIBC is lower (less than 25%), including amplifications, mutations, and fusions in FGFR gene.	('Activating', 'PosReg', (0, 10))	('FGFR3', 'Gene', '2261', (11, 16))	('FGFR', 'Gene', (234, 238))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutations', 'Var', (208, 217))	('FGFR3', 'Gene', (11, 16))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('11', '15'))	('fusions', 'Var', (223, 230))	('mutations', 'Var', (17, 26))	('FGFR', 'molecular_function', 'GO:0005007', ('234', '238'))	('NMIBC', 'Disease', (46, 51))
12714	32498352	The activating FGFR3 mutation leads to ligand-independent receptor dimerization and constitutive downstream signal transduction.	('FGFR3', 'Gene', (15, 20))	('signal transduction', 'biological_process', 'GO:0007165', ('108', '127'))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('activating', 'PosReg', (4, 14))	('mutation', 'Var', (21, 29))	('FGFR3', 'Gene', '2261', (15, 20))	('ligand-independent receptor dimerization', 'MPA', (39, 79))	('ligand', 'molecular_function', 'GO:0005488', ('39', '45'))	('constitutive downstream signal transduction', 'MPA', (84, 127))
12718	32498352	The luminal-papillary subtype of the consensus classification is characterized by a high rate of FGFR3 mutations and translocations, suggesting that these tumors may respond to FGFR inhibitors.	('mutations', 'Var', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('luminal', 'Chemical', 'MESH:D010634', (4, 11))	('FGFR3', 'Gene', '2261', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('FGFR', 'molecular_function', 'GO:0005007', ('97', '101'))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('luminal-papillary subtype', 'Disease', (4, 29))	('FGFR3', 'Gene', (97, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('177', '181'))	('translocations', 'Var', (117, 131))
12723	32498352	In this trial, 99 patients with locally advanced or metastatic UC with FGFR3 mutation or FGFR2/3 fusion and progressed to at least one previous chemotherapy or treatment naive if cisplatin ineligible were assigned to receive erdafitinib, 8 mg per day in a continuous regimen.	('FGFR3', 'Gene', (71, 76))	('FGFR2/3', 'Gene', '2263;2261', (89, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('mutation', 'Var', (77, 85))	('metastatic UC', 'Disease', (52, 65))	('locally advanced', 'Disease', (32, 48))	('FGFR2/3', 'Gene', (89, 96))	('FGFR3', 'Gene', '2261', (71, 76))	('fusion', 'Var', (97, 103))	('patients', 'Species', '9606', (18, 26))	('erdafitinib', 'Chemical', 'MESH:C000604580', (225, 236))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))
12726	32498352	FDA granted accelerated approval to erdafitinib for patients with FGFR3 or FGFR2 genetic alterations progressed during or following platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('platinum', 'Chemical', 'MESH:D010984', (132, 140))	('progressed', 'Reg', (101, 111))	('FGFR3', 'Gene', '2261', (66, 71))	('genetic alterations', 'Var', (81, 100))	('FGFR2', 'Gene', (75, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('FGFR3', 'Gene', (66, 71))	('platinum', 'Chemical', 'MESH:D010984', (220, 228))	('FGFR2', 'Gene', '2263', (75, 80))	('erdafitinib', 'Chemical', 'MESH:C000604580', (36, 47))	('patients', 'Species', '9606', (52, 60))
12793	32498352	Following the findings of a recent phase I trial where cabozantinib plus nivolumab plus ipilimumab yielded an ORR of 36% across all genitourinary cancers, this molecule is being evaluated in combination with pembrolizumab (NCT03534804), durvalumab (NCT03824691), atezolizumab (NCT03170960), and nivolumab plus ipilimumab (NCT03866382) in treatment-naive and previously treated patients.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cabozantinib', 'Chemical', 'MESH:C558660', (55, 67))	('NCT03824691', 'Var', (249, 260))	('pembrolizumab', 'Chemical', 'MESH:C582435', (208, 221))	('nivolumab', 'Chemical', 'MESH:D000077594', (295, 304))	('ipilimumab', 'Chemical', 'MESH:D000074324', (310, 320))	('ipilimumab', 'Chemical', 'MESH:D000074324', (88, 98))	('patients', 'Species', '9606', (377, 385))	('NCT03534804', 'Var', (223, 234))	('atezolizumab', 'Chemical', 'MESH:C000594389', (263, 275))	('durvalumab', 'Chemical', 'MESH:C000613593', (237, 247))	('nivolumab', 'Chemical', 'MESH:D000077594', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('NCT03170960', 'Var', (277, 288))	('NCT03866382', 'Var', (322, 333))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
12809	32498352	The novel anti-PD-L1 CK-301 (Cosibelimab) is being tested in a phase I trial (NCT03212404) on a number of advanced malignancies, including UC.	('PD-L1', 'Gene', (15, 20))	('PD-L1', 'Gene', '29126', (15, 20))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))	('CK-301', 'Var', (21, 27))	('malignancies', 'Disease', (115, 127))
12814	32498352	Despite early promising results, the combination of pembrolizumab plus the IDO-1 inhibitor epacadostat came up short against its primary endpoints of OS and PFS; thus, the two trials assessing the role of the anti-IDO-1 +- pembrolizumab in treatment-naive, cisplatin ineligible subjects (NCT03361865) and in platinum-refractory patients (NCT03374488) arrested recruitment.	('pembrolizumab', 'Chemical', 'MESH:C582435', (223, 236))	('IDO', 'molecular_function', 'GO:0033754', ('75', '78'))	('IDO-1', 'Gene', (214, 219))	('IDO-1', 'Gene', (75, 80))	('pembrolizumab', 'Chemical', 'MESH:C582435', (52, 65))	('IDO-1', 'Gene', '3620', (75, 80))	('IDO', 'molecular_function', 'GO:0047719', ('214', '217'))	('cisplatin', 'Chemical', 'MESH:D002945', (257, 266))	('patients', 'Species', '9606', (328, 336))	('IDO', 'molecular_function', 'GO:0047719', ('75', '78'))	('platinum', 'Chemical', 'MESH:D010984', (308, 316))	('NCT03361865', 'Var', (288, 299))	('NCT03374488', 'Var', (338, 349))	('epacadostat', 'Chemical', 'MESH:C000613752', (91, 102))	('IDO', 'molecular_function', 'GO:0033754', ('214', '217'))	('IDO-1', 'Gene', '3620', (214, 219))
12815	32498352	Currently, the safety of the combination of pembrolizumab plus KHK2455, a long-active selective IDO-1 inhibitor, is being evaluated in an ongoing Phase I study on platinum-refractory patients affected by metastatic UC (NCT03915405).	('pembrolizumab', 'Chemical', 'MESH:C582435', (44, 57))	('KHK2455', 'Gene', (63, 70))	('platinum', 'Chemical', 'MESH:D010984', (163, 171))	('IDO', 'molecular_function', 'GO:0033754', ('96', '99'))	('IDO', 'molecular_function', 'GO:0047719', ('96', '99'))	('IDO-1', 'Gene', (96, 101))	('KHK2455', 'Chemical', '-', (63, 70))	('IDO-1', 'Gene', '3620', (96, 101))	('metastatic UC', 'Disease', (204, 217))	('NCT03915405', 'Var', (219, 230))	('patients', 'Species', '9606', (183, 191))
12819	32498352	Preliminary results of this trial, which includes also a cohort of patients affected by UC, have shown an ORR of 5.4% across all cancer types; nevertheless, the promising 50% of ORR reported in the UC subgroup has led to the NCT03217747 and the Javelin Medley (NCT02554812) ongoing phase I/II trials which are evaluating the OX40 agonist PF-04518600 in combination with ICIs, radiation therapy, utomilumab, and cytotoxic chemotherapy.	('OX40', 'Gene', '7293', (325, 329))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('OX40', 'Gene', (325, 329))	('utomilumab', 'Chemical', 'MESH:C577122', (395, 405))	('patients', 'Species', '9606', (67, 75))	('PF-04518600', 'Var', (338, 349))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('PF-04518600', 'Chemical', '-', (338, 349))
12827	32498352	Other bispecific antibodies such as GEN1046, XmAb20717, XmAb22841, and XmAb23104 are currently under investigation in ongoing phase I (NCT03752398, NCT03849469, NCT03517488) and phase I/II (NCT03917381) trials.	('NCT03752398', 'Var', (135, 146))	('GEN1046', 'Chemical', '-', (36, 43))	('XmAb23104', 'Var', (71, 80))
12829	32498352	Thus, LAG-3 inhibitors as monotherapy or in combination with anti-PD-1 agents are currently being explored in several phase I and II trials in advanced malignancies, including pretreated UC (NCT03538028, NCT03250832).	('malignancies', 'Disease', 'MESH:D009369', (152, 164))	('PD-1', 'Gene', (66, 70))	('LAG-3', 'Gene', (6, 11))	('LAG-3', 'Gene', '3902', (6, 11))	('PD-1', 'Gene', '5133', (66, 70))	('NCT03538028', 'Var', (191, 202))	('NCT03250832', 'Var', (204, 215))	('malignancies', 'Disease', (152, 164))
12839	32498352	As regards UC, the majority of developing TVs concerns BCG-relapsing, non-muscle invasive disease, where neo-antigens are being studied in combination with immune-stimulating adjuvant agents, cytotoxic agents, and/or mTOR inhibitors (NCT01353222, NCT02015104, NCT01498172).	('NCT02015104', 'Var', (247, 258))	('mTOR', 'Gene', '2475', (217, 221))	('NCT01498172', 'Var', (260, 271))	('BCG-relapsing', 'Disease', (55, 68))	('non-muscle invasive disease', 'Disease', 'MESH:D000073296', (70, 97))	('non-muscle invasive disease', 'Disease', (70, 97))	('mTOR', 'Gene', (217, 221))	('NCT01353222', 'Var', (234, 245))
12842	32498352	One of the new promising therapeutic approaches is the use of Poly(ADP-ribose) polymerase (PARP) inhibitors that target DNA repair gene mutations and have been proven active in other type of cancer like ovarian, breast, and prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('DNA repair gene', 'Gene', (120, 135))	('mutations', 'Var', (136, 145))	('breast', 'Disease', (212, 218))	('cancer', 'Disease', (191, 197))	('ovarian', 'Disease', (203, 210))	('prostate cancer', 'Disease', 'MESH:D011471', (224, 239))	('Poly(ADP-ribose) polymerase', 'Gene', '142', (62, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (224, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('PARP', 'Gene', '142', (91, 95))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('prostate cancer', 'Disease', (224, 239))	('DNA repair', 'biological_process', 'GO:0006281', ('120', '130'))	('Poly(ADP-ribose) polymerase', 'Gene', (62, 89))	('PARP', 'Gene', (91, 95))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('ovarian', 'Disease', 'MESH:D010049', (203, 210))	('cancer', 'Disease', (233, 239))
12844	32498352	Moreover, patients with DNA damage response and repair (DDR) gene alterations treated with platinum based chemotherapy resulted to have better PFS and OS.	('better', 'PosReg', (136, 142))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('platinum', 'Chemical', 'MESH:D010984', (91, 99))	('PFS', 'CPA', (143, 146))	('DNA damage response', 'biological_process', 'GO:0006974', ('24', '43'))	('patients', 'Species', '9606', (10, 18))	('DDR', 'Gene', (56, 59))	('alterations', 'Var', (66, 77))
12845	32498352	In fact, in multiple tumors the presence of DDR gene aberrations correlates with an enhanced sensibility to platinum compounds.	('platinum', 'Chemical', 'MESH:D010984', (108, 116))	('tumors', 'Disease', (21, 27))	('presence', 'Var', (32, 40))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('DDR gene', 'Gene', (44, 52))	('sensibility to platinum compounds', 'MPA', (93, 126))	('enhanced', 'PosReg', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
12853	32498352	Two phase II trials are investigating the PARP inhibitor olaparib in monotherapy in chemotherapy naive cisplatin ineligible patients or progressed to first line treatment selected for DDR mutations (NCT03448718) and in patients with DNA-repair defects progressed to 1 or 2 prior treatment regimens (NCT03375307).	('mutations (NCT03448718', 'Var', (188, 210))	('olaparib', 'Chemical', 'MESH:C531550', (57, 65))	('DNA', 'cellular_component', 'GO:0005574', ('233', '236'))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('NCT03375307', 'Var', (299, 310))	('PARP', 'Gene', (42, 46))	('NCT03448718', 'Var', (199, 210))	('patients', 'Species', '9606', (219, 227))	('defects', 'Var', (244, 251))	('DNA-repair', 'biological_process', 'GO:0006281', ('233', '243'))	('PARP', 'Gene', '142', (42, 46))	('patients', 'Species', '9606', (124, 132))	('DDR', 'Gene', (184, 187))
12856	32498352	Indeed, the presence of alteration in DDR genes has been associated with higher mutational load and higher response to ICIs in patients with UC.	('response to ICIs', 'MPA', (107, 123))	('presence', 'Var', (12, 20))	('DDR genes', 'Gene', (38, 47))	('patients', 'Species', '9606', (127, 135))	('alteration', 'Var', (24, 34))	('higher', 'PosReg', (100, 106))	('mutational load', 'MPA', (80, 95))	('higher', 'PosReg', (73, 79))
12857	32498352	Based on these observations, several combinations of PARP inhibitors and PD-1/PD-L1 inhibitors are currently being tested: durvalumab plus olaparib (module B, NCT02546661, active not recruiting; NCT03459846, active not recruiting), rucaparib plus nivolumab (NCT03824704, active not recruiting), niraparib plus atezolizumab (NCT03869190, recruiting).	('PARP', 'Gene', (53, 57))	('niraparib plus atezolizumab', 'Disease', 'MESH:D007625', (295, 322))	('rucaparib', 'Chemical', 'MESH:C531549', (232, 241))	('PD-L1', 'Gene', (78, 83))	('durvalumab', 'Chemical', 'MESH:C000613593', (123, 133))	('PD-1', 'Gene', (73, 77))	('niraparib plus atezolizumab', 'Disease', (295, 322))	('NCT03824704', 'Var', (258, 269))	('NCT03869190', 'Var', (324, 335))	('NCT03459846', 'Var', (195, 206))	('PD-1', 'Gene', '5133', (73, 77))	('nivolumab', 'Chemical', 'MESH:D000077594', (247, 256))	('PD-L1', 'Gene', '29126', (78, 83))	('PARP', 'Gene', '142', (53, 57))	('olaparib', 'Chemical', 'MESH:C531550', (139, 147))
12859	32498352	Total of 391 patients were screened and NGS analysis showed the following absolute frequency of biomarkers: FGFR1-3 fusions or FGFR3 activating mutations in 21% of cases (83 patients in the AZD4547 arm/391), HRR deleterious gene alterations (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCI, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L) in 14% of cases (54 patients in the olaparib arm/391), RICTOR amplification and TSC1/TSC2 loss or inactivating mutations in 15% cases (60 patients in the Vistusertib arm/391).	('PALB2', 'Gene', (310, 315))	('RAD', 'biological_process', 'GO:1990116', ('333', '336'))	('FANCI', 'Gene', (296, 301))	('RAD51D', 'Gene', (333, 339))	('RAD51B', 'Gene', '5890', (317, 323))	('patients', 'Species', '9606', (13, 21))	('FGFR3', 'Gene', (127, 132))	('RAD51C', 'Gene', '5889', (325, 331))	('RAD', 'biological_process', 'GO:1990116', ('341', '344'))	('TSC2', 'Gene', '7249', (434, 438))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('FANCI', 'Gene', '55215', (296, 301))	('BARD1', 'Gene', '580', (247, 252))	('mutations', 'Var', (144, 153))	('BARD1', 'Gene', (247, 252))	('PALB2', 'Gene', '79728', (310, 315))	('RAD', 'biological_process', 'GO:1990116', ('317', '320'))	('FGFR3', 'Gene', '2261', (127, 132))	('HRR', 'biological_process', 'GO:0000724', ('208', '211'))	('RAD', 'biological_process', 'GO:1990116', ('325', '328'))	('ATM', 'Gene', '472', (242, 245))	('BRIP1', 'Gene', '83990', (268, 273))	('FANCL', 'Gene', (303, 308))	('CHEK2', 'Gene', (289, 294))	('AZD4547', 'Chemical', 'MESH:C572463', (190, 197))	('TSC2', 'Gene', (434, 438))	('RAD51C', 'Gene', (325, 331))	('FGFR', 'molecular_function', 'GO:0005007', ('127', '131'))	('FANCL', 'Gene', '55120', (303, 308))	('CDK12', 'Gene', (275, 280))	('loss', 'NegReg', (439, 443))	('FGFR1-3', 'Gene', '2260;2263;2261', (108, 115))	('BRCA2', 'Gene', (261, 266))	('BRCA1', 'Gene', '672', (254, 259))	('RAD51D', 'Gene', '5892', (333, 339))	('patients', 'Species', '9606', (369, 377))	('CHEK1', 'Gene', '1111', (282, 287))	('RAD51B', 'Gene', (317, 323))	('BRCA1', 'Gene', (254, 259))	('patients', 'Species', '9606', (487, 495))	('CHEK2', 'Gene', '11200', (289, 294))	('RICTOR', 'Gene', '253260', (404, 410))	('RAD54L', 'Gene', '8438', (341, 347))	('TSC1', 'Gene', (429, 433))	('CDK', 'molecular_function', 'GO:0004693', ('275', '278'))	('FGFR1-3', 'Gene', (108, 115))	('BRIP1', 'Gene', (268, 273))	('ATM', 'Gene', (242, 245))	('HRR', 'Gene', (208, 211))	('RAD54L', 'Gene', (341, 347))	('olaparib', 'Chemical', 'MESH:C531550', (385, 393))	('BRCA2', 'Gene', '675', (261, 266))	('RICTOR', 'Gene', (404, 410))	('CDK12', 'Gene', '51755', (275, 280))	('TSC1', 'Gene', '7248', (429, 433))	('patients', 'Species', '9606', (174, 182))	('CHEK1', 'Gene', (282, 287))
12860	32498352	The preliminary results available on 14 patients with homologous recombination repair genomic alterations treated with olaparib and durvalumab showed a high tumor mutation burden and a confirmed ORR of 35.7%, a 6-months PFS rate of 42%, 1-years OS rate of 54%.	('tumor', 'Disease', (157, 162))	('durvalumab', 'Chemical', 'MESH:C000613593', (132, 142))	('alterations', 'Var', (94, 105))	('patients', 'Species', '9606', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('PFS', 'CPA', (220, 223))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('homologous recombination', 'biological_process', 'GO:0035825', ('54', '78'))	('olaparib', 'Chemical', 'MESH:C531550', (119, 127))
12863	32498352	As already discussed, the FGFR inhibitor erdafitinib is a promising treatment strategy in patients with FGF/FGFR alterations.	('FGF/FGFR', 'Gene', (104, 112))	('erdafitinib', 'Chemical', 'MESH:C000604580', (41, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('alterations', 'Var', (113, 124))	('patients', 'Species', '9606', (90, 98))
12864	32498352	In these subgroup of patients, other therapies directed at inhibiting FGFR are currently being tested: PRN1371, a FGFR 1-4 inhibitor, in a phase I trial in previously treated patients (NCT02608125); Pemigatinib, a FGFR1-3 inhibitor, in phase II trial in patients progressed to at least one prior treatment (NCT02872714, FIGHT-201); Rogaratinib (BAY1163877), a FGFR 1-4 inhibitor, in a phase II/III trial in patients progressed to at least one platinum-containing regimen (NCT03410693).	('FGFR 1-4', 'Gene', (114, 122))	('FGFR 1-4', 'Gene', '2260;2263;2261;2264', (114, 122))	('FGFR', 'molecular_function', 'GO:0005007', ('214', '218'))	('patients', 'Species', '9606', (407, 415))	('FGFR', 'molecular_function', 'GO:0005007', ('70', '74'))	('FGFR1-3', 'Gene', '2260;2263;2261', (214, 221))	('FGFR', 'molecular_function', 'GO:0005007', ('114', '118'))	('FGFR1-3', 'Gene', (214, 221))	('BAY1163877', 'Var', (345, 355))	('patients', 'Species', '9606', (175, 183))	('patients', 'Species', '9606', (21, 29))	('FGFR', 'molecular_function', 'GO:0005007', ('360', '364'))	('platinum', 'Chemical', 'MESH:D010984', (443, 451))	('FGFR 1-4', 'Gene', (360, 368))	('FGFR 1-4', 'Gene', '2260;2263;2261;2264', (360, 368))	('patients', 'Species', '9606', (254, 262))
12871	32498352	Another interesting pathway being investigated is targeting human epidermal growth factor receptor 2 (HER2, ERBB2) considering that mutation or amplification of ERBB2 gene has been identified in 9% of MIBC.	('identified', 'Reg', (181, 191))	('MIBC', 'Disease', (201, 205))	('ERBB2', 'Gene', '2064', (161, 166))	('epidermal growth factor receptor 2', 'Gene', (66, 100))	('ERBB2', 'Gene', (161, 166))	('epidermal growth factor receptor 2', 'Gene', '2064', (66, 100))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('66', '89'))	('HER2', 'Gene', (102, 106))	('amplification', 'Var', (144, 157))	('HER2', 'Gene', '2064', (102, 106))	('ERBB2', 'Gene', '2064', (108, 113))	('human', 'Species', '9606', (60, 65))	('mutation', 'Var', (132, 140))	('ERBB2', 'Gene', (108, 113))
12874	32498352	RC48-ADC, an anti-HER2 monoclonal antibody, in under evaluation in two phase II trial in previously treated patients, one in HER2 negative (IHC 0 or 1+, NCT04073602) and one in HER2 overexpressed tumors (IHC 2+ or 3+, NCT03809013).	('HER2', 'Gene', (125, 129))	('antibody', 'cellular_component', 'GO:0019814', ('34', '42'))	('HER2', 'Gene', '2064', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('HER2', 'Gene', '2064', (125, 129))	('patients', 'Species', '9606', (108, 116))	('antibody', 'cellular_component', 'GO:0042571', ('34', '42'))	('tumors', 'Disease', (196, 202))	('HER2', 'Gene', (177, 181))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('HER2', 'Gene', '2064', (177, 181))	('antibody', 'cellular_component', 'GO:0019815', ('34', '42'))	('NCT04073602', 'Var', (153, 164))	('antibody', 'molecular_function', 'GO:0003823', ('34', '42'))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('HER2', 'Gene', (18, 22))
12877	32498352	Promising treatment approaches are FGFR inhibitors and enfortumab vedotin.	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('inhibitors', 'Var', (40, 50))	('enfortumab', 'Chemical', '-', (55, 65))	('vedotin', 'Chemical', '-', (66, 73))	('FGFR', 'Gene', (35, 39))
12879	32498352	The therapeutic approach to UC, which for many years has been dominated by platinum containing chemotherapy based on clinical and laboratory variable defining cisplatin eligibility, is now shifting toward a more personalized approach, based on the presence of molecular alteration (e.g., FGFR alterations) or PD-L1 expression.	('PD-L1', 'Gene', '29126', (309, 314))	('FGFR', 'molecular_function', 'GO:0005007', ('288', '292'))	('alterations', 'Var', (293, 304))	('cisplatin', 'Chemical', 'MESH:D002945', (159, 168))	('platinum', 'Chemical', 'MESH:D010984', (75, 83))	('PD-L1', 'Gene', (309, 314))	('FGFR', 'Gene', (288, 292))
12978	29333509	Adherence of uropathogenic Escherichia coli to uroplakin proteins on the apical surface of umbrella cells causes UTIs.	('uroplakin proteins', 'Disease', (47, 65))	('Adherence', 'Var', (0, 9))	('causes', 'Reg', (106, 112))	('Escherichia coli', 'Species', '562', (27, 43))	('uroplakin proteins', 'Disease', 'MESH:D011488', (47, 65))	('UTIs', 'Disease', (113, 117))
12998	28652266	Among ncRNAs, long ncRNAs (lncRNAs) that are >200 bases long have been reported to interact with DNA-binding proteins, such as chromatin-modifying complexes and transcription factors, and regulate gene expression through epigenetic alterations in the nucleus or to function as a molecular sponge in the cytoplasm.	('nucleus', 'cellular_component', 'GO:0005634', ('251', '258'))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('gene expression', 'MPA', (197, 212))	('cytoplasm', 'cellular_component', 'GO:0005737', ('303', '312'))	('epigenetic alterations', 'Var', (221, 243))	('transcription', 'biological_process', 'GO:0006351', ('161', '174'))	('interact', 'Interaction', (83, 91))	('rat', 'Species', '10116', (236, 239))	('regulate', 'Reg', (188, 196))	('gene expression', 'biological_process', 'GO:0010467', ('197', '212'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('97', '108'))	('chromatin', 'cellular_component', 'GO:0000785', ('127', '136'))
13009	28652266	The expression of both JHDM1D and JHDM1D-AS1 was decreased by deletion of common 5' promoter regions of JHDM1D and JHDM1D-AS1 using guide RNA (gRNA)-mediated genome editing (Fig.	('JHDM1D', 'Gene', '80853', (23, 29))	('JHDM1D', 'Gene', '80853', (34, 40))	('JHDM1D', 'Gene', (104, 110))	('JHDM1D', 'Gene', (115, 121))	('JHDM1D', 'Gene', '80853', (104, 110))	('expression', 'MPA', (4, 14))	('JHDM1D-AS1', 'Gene', '100134229', (34, 44))	('JHDM1D-AS1', 'Gene', (34, 44))	('decreased', 'NegReg', (49, 58))	('JHDM1D', 'Gene', '80853', (115, 121))	('JHDM1D-AS1', 'Gene', '100134229', (115, 125))	('RNA', 'cellular_component', 'GO:0005562', ('138', '141'))	('JHDM1D', 'Gene', (23, 29))	('deletion', 'Var', (62, 70))	('JHDM1D', 'Gene', (34, 40))	('JHDM1D-AS1', 'Gene', (115, 125))
13035	28652266	To investigate whether silencing of JHDM1D-AS1 small interfering RNAs (siRNAs) influences cancer cell growth in vitro and tumor growth in vivo, we knocked down JHDM1D-AS1 using siRNA (Fig.	('influences', 'Reg', (79, 89))	('JHDM1D-AS1', 'Gene', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cell growth', 'biological_process', 'GO:0016049', ('97', '108'))	('knocked down', 'Var', (147, 159))	('JHDM1D-AS1', 'Gene', (160, 170))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('JHDM1D-AS1', 'Gene', '100134229', (36, 46))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('JHDM1D-AS1', 'Gene', '100134229', (160, 170))	('cancer', 'Disease', (90, 96))	('tumor', 'Disease', (122, 127))
13037	28652266	4C) conditions in PANC-1 and AsPC-1 cells in vitro, inhibition of JHDM1D-AS1 significantly decreased the tumor growth of PANC-1 cells in vivo (Fig.	('PANC-1', 'Gene', (121, 127))	('AsPC-1', 'CellLine', 'CVCL:0152', (29, 35))	('JHDM1D-AS1', 'Gene', '100134229', (66, 76))	('PANC-1', 'Gene', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('inhibition', 'Var', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('PANC-1', 'Gene', '104066', (121, 127))	('JHDM1D-AS1', 'Gene', (66, 76))	('PANC-1', 'Gene', '104066', (18, 24))	('tumor', 'Disease', (105, 110))	('decreased', 'NegReg', (91, 100))
13073	28652266	A xenograft study revealed that JHDM1D-AS1 overexpression indeed increased tumor growth in vivo, accompanied by elevated blood vessel formation and macrophage infiltration.	('increased', 'PosReg', (65, 74))	('blood vessel formation', 'CPA', (121, 143))	('JHDM1D-AS1', 'Gene', (32, 42))	('rat', 'Species', '10116', (165, 168))	('formation', 'biological_process', 'GO:0009058', ('134', '143'))	('elevated', 'PosReg', (112, 120))	('macrophage infiltration', 'CPA', (148, 171))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('JHDM1D-AS1', 'Gene', '100134229', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('overexpression', 'Var', (43, 57))	('tumor', 'Disease', (75, 80))
13090	28652266	Based on these results, we suggest that inhibition of the nutrient starvation-responsive lncRNA JHDM1D-AS1 can be a potential therapeutic approach for cancer in the future.	('inhibition', 'Var', (40, 50))	('JHDM1D-AS1', 'Gene', '100134229', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('JHDM1D-AS1', 'Gene', (96, 106))
13108	28652266	Prewashed magnetic Dynabeads (Life Technologies, MA) were incubated with anti-H3K27ac antibody (Millipore, MA) or anti-SREBP2 antibody (Cayman, MI) in ChIP dilution buffer (20 mM Tris-HCl [pH 8.0], 150 mM NaCl, 1 mM EDTA, 1% Triton X-100, protease inhibitor cocktail [Roche, Basel, Switzerland]) for 6 h by wheel rotating at 4 C. Subsequently, sonicated cross-linked nuclear lysates were added and incubated overnight at 4 C by wheel rotating.	('SREBP2', 'Gene', (119, 125))	('antibody', 'cellular_component', 'GO:0019815', ('126', '134'))	('antibody', 'cellular_component', 'GO:0042571', ('86', '94'))	('antibody', 'cellular_component', 'GO:0019814', ('126', '134'))	('antibody', 'cellular_component', 'GO:0019815', ('86', '94'))	('anti-H3K27ac', 'Var', (73, 85))	('antibody', 'cellular_component', 'GO:0019814', ('86', '94'))	('antibody', 'molecular_function', 'GO:0003823', ('126', '134'))	('Triton X-100', 'Chemical', 'MESH:D017830', (225, 237))	('NaCl', 'Chemical', 'MESH:D012965', (205, 209))	('antibody', 'molecular_function', 'GO:0003823', ('86', '94'))	('Tris-HCl', 'Chemical', '-', (179, 187))	('SREBP2', 'Gene', '6721', (119, 125))	('antibody', 'cellular_component', 'GO:0042571', ('126', '134'))
13192	24137456	In a series of 196 patients, bladder recurrence was lower in those who received mitomycin C or epirubicin compared with those who did not received anything (29.0, 25.9 and 41.3%, respectively).	('patients', 'Species', '9606', (19, 27))	('lower', 'NegReg', (52, 57))	('bladder recurrence', 'CPA', (29, 47))	('mitomycin C', 'Chemical', 'MESH:D016685', (80, 91))	('epirubicin', 'Chemical', 'MESH:D015251', (95, 105))	('mitomycin', 'Var', (80, 89))
13214	23403633	The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell cycle progression in malignant bladder cancer cells in vitro and in vivo Despite over 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities.	('malignant bladder cancer', 'Disease', 'MESH:D001749', (118, 142))	('cell cycle progression', 'CPA', (92, 114))	('defects', 'NegReg', (62, 69))	('advanced disease', 'Disease', (263, 279))	('malignant bladder cancer', 'Disease', (118, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('MLN8237', 'Var', (46, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (128, 142))	('cell viability', 'CPA', (73, 87))	('Aurora kinase A', 'Gene', '6790', (20, 35))	('cell cycle', 'biological_process', 'GO:0007049', ('92', '102'))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('MLN8237', 'Chemical', 'MESH:C550258', (46, 53))	('patients', 'Species', '9606', (249, 257))	('bladder cancer', 'Disease', 'MESH:D001749', (203, 217))	('bladder cancer', 'Disease', (203, 217))	('Aurora kinase A', 'Gene', (20, 35))	('advanced disease', 'Disease', 'MESH:D020178', (263, 279))	('bladder cancer', 'Phenotype', 'HP:0009725', (203, 217))	('men', 'Species', '9606', (322, 325))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('malignant bladder', 'Phenotype', 'HP:0009725', (118, 135))
13217	23403633	Effects of the Aurora kinase A inhibitor MLN8237 (Millennium) on cell dynamics in malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells were evaluated in vitro and in vivo in a mouse xenograft model.	('mouse', 'Species', '10090', (189, 194))	('RT4', 'CellLine', 'CVCL:0036', (130, 133))	('papilloma', 'Phenotype', 'HP:0012740', (112, 121))	('Aurora kinase A', 'Gene', (15, 30))	('MLN8237', 'Chemical', 'MESH:C550258', (41, 48))	('papilloma', 'Disease', (112, 121))	('MLN8237', 'Var', (41, 48))	('papilloma', 'Disease', 'MESH:D010212', (112, 121))	('Aurora kinase A', 'Gene', '6790', (15, 30))
13219	23403633	The Aurora kinase A inhibitor MLN8237 induced cell cycle arrest, aneuploidy, mitotic spindle failure, and apoptosis in the human bladder cancer cell lines T24 and UM-UC-3.	('human', 'Species', '9606', (123, 128))	('bladder cancer', 'Disease', 'MESH:D001749', (129, 143))	('arrest', 'Disease', 'MESH:D006323', (57, 63))	('aneuploidy', 'Disease', 'MESH:D000782', (65, 75))	('bladder cancer', 'Disease', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('MLN8237', 'Var', (30, 37))	('Aurora kinase A', 'Gene', '6790', (4, 19))	('aneuploidy', 'Disease', (65, 75))	('MLN8237', 'Chemical', 'MESH:C550258', (30, 37))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (46, 63))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('46', '63'))	('apoptosis', 'CPA', (106, 115))	('mitotic spindle failure', 'Disease', 'MESH:D002277', (77, 100))	('induced', 'Reg', (38, 45))	('arrest', 'Disease', (57, 63))	('Aurora kinase A', 'Gene', (4, 19))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('77', '92'))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('mitotic spindle failure', 'Disease', (77, 100))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))
13220	23403633	MLN8237 also arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model.	('bladder cancer', 'Phenotype', 'HP:0009725', (84, 98))	('bladder cancer', 'Disease', 'MESH:D001749', (84, 98))	('bladder cancer', 'Disease', (84, 98))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('MLN8237', 'Var', (0, 7))	('arrested tumor', 'Disease', 'MESH:D006323', (13, 27))	('arrested tumor', 'Disease', (13, 27))	('tumor growth', 'Disease', (22, 34))	('mouse', 'Species', '10090', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor growth', 'Disease', 'MESH:D006130', (22, 34))
13223	23403633	Given our demonstration of the ability of the Aurora A inhibitor MLN8237 to inhibit growth of bladder cancer in vitro and in vivo, we conclude that Aurora kinase inhibitors warrant further therapeutic investigation in bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('bladder cancer', 'Disease', 'MESH:D001749', (218, 232))	('inhibit', 'NegReg', (76, 83))	('bladder cancer', 'Disease', (218, 232))	('growth', 'CPA', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('MLN8237', 'Chemical', 'MESH:C550258', (65, 72))	('MLN8237', 'Var', (65, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (218, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
13228	23403633	Both overexpression and gene amplification of Aurora A have been characterized in human tumors, and have been shown to correlate with tumor proliferation rates and prognostic markers.	('gene amplification', 'Var', (24, 42))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('human', 'Species', '9606', (82, 87))	('correlate', 'Reg', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (134, 139))	('Aurora A', 'Gene', (46, 54))
13232	23403633	In particular, MLN8237 is a novel, orally bioavailable, second generation selective inhibitor of Aurora A. MLN8237 and its predecessor MLN8054 have exhibited efficacy against solid tumors and hematologic malignancies in preclinical models and are currently undergoing evaluation in hematological and solid cancers.	('cancers', 'Phenotype', 'HP:0002664', (306, 313))	('MLN8237', 'Var', (107, 114))	('solid cancers', 'Disease', 'MESH:D009369', (300, 313))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('hematologic malignancies', 'Disease', (192, 216))	('hematologic malignancies', 'Disease', 'MESH:D019337', (192, 216))	('hematological', 'Disease', (282, 295))	('MLN8237', 'Chemical', 'MESH:C550258', (107, 114))	('solid cancers', 'Disease', (300, 313))	('MLN8237', 'Chemical', 'MESH:C550258', (15, 22))
13237	23403633	We hypothesize that this can be exploited therapeutically with Aurora kinase inhibition, and we test the antitumor activity of the selective Aurora A inhibitor MLN8237 in vitro in bladder cancer cell lines and in vivo in a mouse xenograft model.	('MLN8237', 'Chemical', 'MESH:C550258', (160, 167))	('bladder cancer', 'Disease', 'MESH:D001749', (180, 194))	('MLN8237', 'Var', (160, 167))	('bladder cancer', 'Disease', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('mouse', 'Species', '10090', (223, 228))	('bladder cancer', 'Phenotype', 'HP:0009725', (180, 194))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
13252	23403633	Drugs evaluated included the Aurora kinase A inhibitor MLN8237 (a kind gift from Millennium Pharmaceuticals), paclitaxel (Sigma), and gemcitabine (Sigma).	('paclitaxel', 'Chemical', 'MESH:D017239', (110, 120))	('Aurora kinase A', 'Gene', (29, 44))	('MLN8237', 'Chemical', 'MESH:C550258', (55, 62))	('Aurora kinase A', 'Gene', '6790', (29, 44))	('gemcitabine', 'Chemical', 'MESH:C056507', (134, 145))	('MLN8237', 'Var', (55, 62))
13257	23403633	Blots were blocked with 1% bovine serum albumin diluted in TBS-T for P-Aurora A-T288 and P-Histone-H3 antibodies, or in 5% Carnation instant milk in TBS-T for remaining antibodies, for 1 hour at room temperature.	('TBS-T', 'Chemical', '-', (149, 154))	('TBS-T', 'Chemical', '-', (59, 64))	('bovine', 'Species', '9913', (27, 33))	('Carnation', 'Species', '3570', (123, 132))	('P-Histone-H3 antibodies', 'Var', (89, 112))	('TBS-T for P-Aurora A-T288', 'Disease', 'MESH:C000656865', (59, 84))	('TBS-T for P-Aurora A-T288', 'Disease', (59, 84))
13264	23403633	For live cell time-lapse microscopy, cells were plated in 6-well plates, treated with MLN8237 or DMSO, imaged for 48 h with phase-contrast images taken every 10 min using a Leica DMIRB Inverted microscope (Leica) with CoolSNAP HQ Cooled CCD camera (Princeton Instruments), and processed using LAS-AF (Leica) software.	('men', 'Species', '9606', (265, 268))	('MLN8237', 'Chemical', 'MESH:C550258', (86, 93))	('DMSO', 'Var', (97, 101))	('MLN8237', 'Var', (86, 93))	('DMSO', 'Chemical', 'MESH:D004121', (97, 101))
13270	23403633	In vivo antitumor capacity of MLN8237 was evaluated in a mouse xenograft model of bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('MLN8237', 'Chemical', 'MESH:C550258', (30, 37))	('MLN8237', 'Var', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))	('bladder cancer', 'Disease', (82, 96))	('tumor', 'Disease', (12, 17))	('mouse', 'Species', '10090', (57, 62))
13290	23403633	We used the Aurora A-specific inhibitor MLN8237 to evaluate the effects of Aurora A inhibition on the human urothelial carcinoma cell lines T24 and UM-UC-3, which were derived from high-grade urothelial carcinoma and have acquired mutations in TP53.	('urothelial carcinoma', 'Disease', (108, 128))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (192, 212))	('mutations', 'Var', (231, 240))	('MLN8237', 'Var', (40, 47))	('TP53', 'Gene', (244, 248))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (108, 128))	('urothelial carcinoma', 'Disease', (192, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('MLN8237', 'Chemical', 'MESH:C550258', (40, 47))	('human', 'Species', '9606', (102, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('TP53', 'Gene', '7157', (244, 248))
13292	23403633	Application of 10 nM to 1 muM MLN8237 resulted in a loss of phospho-Aurora A at the mitotic spindle (Figure 2A) and a dose-dependent reduction in phosphorylation of Aurora A (Figure 2B).	('phospho-Aurora', 'MPA', (60, 74))	('MLN8237', 'Chemical', 'MESH:C550258', (30, 37))	('loss', 'NegReg', (52, 56))	('MLN8237', 'Var', (30, 37))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('84', '99'))	('Aurora A', 'Protein', (165, 173))	('reduction', 'NegReg', (133, 142))	('phosphorylation', 'biological_process', 'GO:0016310', ('146', '161'))	('phosphorylation', 'MPA', (146, 161))
13293	23403633	Application of MLN8237 did not affect total Aurora A levels, and did not appear to alter Aurora B status within the cells as measured by phospho-histone-H3 expression as an indicator of Aurora B function (Figure 2B).	('MLN8237', 'Var', (15, 22))	('Aurora B', 'Gene', (89, 97))	('Aurora B', 'Gene', '9212', (89, 97))	('alter', 'Reg', (83, 88))	('Aurora B', 'Gene', '9212', (186, 194))	('Aurora A levels', 'MPA', (44, 59))	('Aurora B', 'Gene', (186, 194))	('MLN8237', 'Chemical', 'MESH:C550258', (15, 22))
13294	23403633	Next, we used flow cytometry to assess the effect of MLN8237 on cell cycle dynamics.	('cell cycle', 'biological_process', 'GO:0007049', ('64', '74'))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('MLN8237', 'Var', (53, 60))	('cell cycle', 'CPA', (64, 74))
13295	23403633	Treatment of T24, UM-UC-3, and RT4 cells with 10 nM to 1 muM MLN8237 for 48 h induced significant cell cycle arrest in a dose-dependent manner (Figure 2C).	('cell cycle arrest', 'biological_process', 'GO:0007050', ('98', '115'))	('MLN8237', 'Chemical', 'MESH:C550258', (61, 68))	('MLN8237', 'Var', (61, 68))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (98, 115))	('arrest', 'Disease', 'MESH:D006323', (109, 115))	('RT4', 'CellLine', 'CVCL:0036', (31, 34))	('men', 'Species', '9606', (5, 8))	('arrest', 'Disease', (109, 115))
13298	23403633	Moreover, MLN8237 induced a significant increase in aneuploidy in the malignant T24 and UM-UC-3 cell lines, but no increase in aneuploidy in the benign RT4 cell line.	('aneuploidy', 'Disease', (52, 62))	('increase', 'PosReg', (40, 48))	('aneuploidy', 'Disease', 'MESH:D000782', (127, 137))	('MLN8237', 'Chemical', 'MESH:C550258', (10, 17))	('aneuploidy', 'Disease', 'MESH:D000782', (52, 62))	('MLN8237', 'Var', (10, 17))	('RT4', 'CellLine', 'CVCL:0036', (152, 155))	('aneuploidy', 'Disease', (127, 137))
13300	23403633	To further characterize the phenotype of Aurora A inhibition, we used microscopy to visualize the cellular phenotype and mitotic spindle during cell cycle arrest induced by MLN8237.	('MLN8237', 'Var', (173, 180))	('arrest', 'Disease', 'MESH:D006323', (155, 161))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('121', '136'))	('arrest', 'Disease', (155, 161))	('MLN8237', 'Chemical', 'MESH:C550258', (173, 180))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('144', '161'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (144, 161))
13301	23403633	Treatment of malignant T24 cells with 100 nM MLN8237 for 24 h resulted in a significant increase in cell size, whereas treatment of RT4 cells had no apparent effect on cell size (Figure 3A).	('men', 'Species', '9606', (124, 127))	('increase', 'PosReg', (88, 96))	('MLN8237', 'Chemical', 'MESH:C550258', (45, 52))	('MLN8237', 'Var', (45, 52))	('cell size', 'CPA', (100, 109))	('men', 'Species', '9606', (5, 8))	('RT4', 'CellLine', 'CVCL:0036', (132, 135))
13303	23403633	Both cell lines demonstrated disruption of the mitotic spindle and formation of aberrant multipolar spindle apparatuses following MLN8237 treatment (Figure 3B).	('spindle', 'cellular_component', 'GO:0005819', ('100', '107'))	('MLN8237', 'Chemical', 'MESH:C550258', (130, 137))	('MLN8237 treatment', 'Var', (130, 147))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('47', '62'))	('formation', 'biological_process', 'GO:0009058', ('67', '76'))	('men', 'Species', '9606', (143, 146))	('mitotic spindle', 'CPA', (47, 62))
13306	23403633	MLN8237-treated T24 cells demonstrated markedly increased DNA content and CENP-A staining per cell, whereas RT4 cells did not (Figure 3C).	('increased', 'PosReg', (48, 57))	('staining', 'MPA', (81, 89))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('CENP-A', 'Gene', '1058', (74, 80))	('DNA content', 'MPA', (58, 69))	('RT4', 'CellLine', 'CVCL:0036', (108, 111))	('CENP-A', 'Gene', (74, 80))	('MLN8237-treated', 'Var', (0, 15))
13307	23403633	These results are consistent with the flow cytometry analysis that showed increases in aneuploidy with MLN8237 treatment in the malignant T24 cell line.	('aneuploidy', 'Disease', (87, 97))	('MLN8237 treatment', 'Var', (103, 120))	('increases', 'PosReg', (74, 83))	('MLN8237', 'Chemical', 'MESH:C550258', (103, 110))	('aneuploidy', 'Disease', 'MESH:D000782', (87, 97))	('men', 'Species', '9606', (116, 119))
13309	23403633	However, inhibition of Aurora A activity with 100 nM MLN8237 resulted in enhanced expression of Aurora A in the malignant T24 cells only, with augmentation of Aurora A expression both at the mitotic spindle and within the cytoplasm, although the mechanism behind this finding is unclear.	('inhibition', 'NegReg', (9, 19))	('augmentation', 'PosReg', (143, 155))	('MLN8237', 'Var', (53, 60))	('expression', 'MPA', (82, 92))	('expression', 'MPA', (168, 178))	('men', 'Species', '9606', (146, 149))	('activity', 'MPA', (32, 40))	('Aurora A', 'Gene', (96, 104))	('enhanced', 'PosReg', (73, 81))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('191', '206'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('222', '231'))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))
13310	23403633	Finally, time-lapse microscopy was performed to further visualize cell division dynamics following MLN8237 treatment.	('cell division', 'CPA', (66, 79))	('MLN8237', 'Chemical', 'MESH:C550258', (99, 106))	('MLN8237', 'Var', (99, 106))	('men', 'Species', '9606', (112, 115))	('cell division', 'biological_process', 'GO:0051301', ('66', '79'))
13311	23403633	T24 cells treated with 100 nM MLN8237 exhibited repeated attempts at mitosis within a 24 h period with no increase in cell number over time (i.e.	('mitosis', 'Disease', 'None', (69, 76))	('MLN8237', 'Chemical', 'MESH:C550258', (30, 37))	('MLN8237', 'Var', (30, 37))	('attempts', 'CPA', (57, 65))	('mitosis', 'biological_process', 'GO:0000278', ('69', '76'))	('mitosis', 'Disease', (69, 76))
13313	23403633	Taken together, these results demonstrate that repeated cell cycle progressions despite failure in separation of daughter cells in malignant T24 cells, but not benign RT4 cells, account for the development of aneuploidy in the former cell line following MLN8237 treatment.	('MLN8237 treatment', 'Var', (254, 271))	('aneuploidy', 'Disease', 'MESH:D000782', (209, 219))	('RT4', 'CellLine', 'CVCL:0036', (167, 170))	('men', 'Species', '9606', (201, 204))	('cell cycle', 'CPA', (56, 66))	('MLN8237', 'Chemical', 'MESH:C550258', (254, 261))	('cell cycle', 'biological_process', 'GO:0007049', ('56', '66'))	('men', 'Species', '9606', (267, 270))	('aneuploidy', 'Disease', (209, 219))
13314	23403633	Given the dramatic cell cycle arrest caused by MLN8237, we sought to quantify growth inhibition induced by this compound in our cell lines.	('MLN8237', 'Chemical', 'MESH:C550258', (47, 54))	('MLN8237', 'Var', (47, 54))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (19, 36))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('19', '36'))	('arrest', 'Disease', 'MESH:D006323', (30, 36))	('arrest', 'Disease', (30, 36))
13316	23403633	MLN8237 was most potent in T24 and UM-UC-3 cells (IC50 of 31 nM and 45 nM, respectively), and least potent in RT4 cells (IC50 of 120 nM).	('T24', 'CPA', (27, 30))	('MLN8237', 'Var', (0, 7))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('RT4', 'CellLine', 'CVCL:0036', (110, 113))
13318	23403633	Application of 100 nM MLN8237 resulted in an increase in PARP cleavage expression in RT4 and T24 cells by 24 h. RT4 cell lines, which contain wildtype p53, demonstrated a peak in p53 expression at 24 h after initiation of MLN8237 treatment, with a subsequent increase in the expression of p21, a downstream mediator of p53, through 72 h (Figure 4B).	('p53', 'Gene', (179, 182))	('p53', 'Gene', (319, 322))	('p53', 'Gene', '7157', (151, 154))	('RT4', 'CellLine', 'CVCL:0036', (112, 115))	('increase', 'PosReg', (259, 267))	('MLN8237', 'Var', (222, 229))	('expression', 'MPA', (183, 193))	('PARP', 'Gene', '1302', (57, 61))	('p53', 'Gene', (151, 154))	('MLN8237', 'Chemical', 'MESH:C550258', (22, 29))	('RT4', 'CellLine', 'CVCL:0036', (85, 88))	('MLN8237', 'Chemical', 'MESH:C550258', (222, 229))	('p53', 'Gene', '7157', (179, 182))	('PARP', 'Gene', (57, 61))	('p21', 'Gene', (289, 292))	('expression', 'MPA', (275, 285))	('p21', 'Gene', '644914', (289, 292))	('men', 'Species', '9606', (235, 238))	('p53', 'Gene', '7157', (319, 322))
13319	23403633	In contrast, T24 cells contain mutated p53; in this cell line an increase in p73 expression was apparent at 24 h, whereas p53 and p21 expression remained unaltered.	('increase', 'PosReg', (65, 73))	('p21', 'Gene', (130, 133))	('p21', 'Gene', '644914', (130, 133))	('p53', 'Gene', '7157', (122, 125))	('p73', 'Gene', '7161', (77, 80))	('p53', 'Gene', (39, 42))	('p73', 'Gene', (77, 80))	('p53', 'Gene', '7157', (39, 42))	('mutated', 'Var', (31, 38))	('p53', 'Gene', (122, 125))
13321	23403633	Both cell lines demonstrated an increase in the apoptotic cell population starting at 24 h after initiation of MLN8237 treatment, although this population was greater in the T24 cells (Figure 4C).	('men', 'Species', '9606', (124, 127))	('apoptotic cell population', 'CPA', (48, 73))	('MLN8237', 'Chemical', 'MESH:C550258', (111, 118))	('MLN8237', 'Var', (111, 118))
13322	23403633	Thus, T24 cells appear to be more sensitive to MLN8237 as demonstrated by the combination of a lower IC50 and a more sizeable apoptotic response as measured by annexin V staining (Figure 4A,C).	('lower', 'NegReg', (95, 100))	('apoptotic response', 'CPA', (126, 144))	('annexin V', 'Gene', '308', (160, 169))	('MLN8237', 'Chemical', 'MESH:C550258', (47, 54))	('MLN8237', 'Var', (47, 54))	('annexin V', 'Gene', (160, 169))	('IC50', 'MPA', (101, 105))
13325	23403633	To assess the capacity of MLN8237 to reduce tumor growth in vivo, nude mice were inoculated with T24 cells in the subcutaneous flank tissue to induce growth of tumors (N=8 for treatment group, N=8 for control group).	('reduce', 'NegReg', (37, 43))	('MLN8237', 'Var', (26, 33))	('induce', 'PosReg', (143, 149))	('growth of tumors', 'Disease', 'MESH:D006130', (150, 166))	('tumor growth', 'Disease', (44, 56))	('growth of tumors', 'Disease', (150, 166))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor growth', 'Disease', 'MESH:D006130', (44, 56))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('nude mice', 'Species', '10090', (66, 75))	('men', 'Species', '9606', (181, 184))	('MLN8237', 'Chemical', 'MESH:C550258', (26, 33))
13326	23403633	When tumor sizes reached 250 mm3, a 4 week regimen of MLN8237 30 mg/kg orally 5 times weekly was initiated.	('MLN8237', 'Var', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('men', 'Species', '9606', (47, 50))	('MLN8237', 'Chemical', 'MESH:C550258', (54, 61))
13328	23403633	Mice treated with MLN8237 exhibited arrest of tumor growth compared to the control group (Wilcoxon rank-sum P < 0.05), and showed no statistically significant difference in tumor size between initiation of treatment and completion of the 4 week regimen (t-test P > 0.05; Figure 5A).	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tween', 'Chemical', 'MESH:D011136', (186, 191))	('tumor growth', 'Disease', (46, 58))	('tumor', 'Disease', (46, 51))	('tumor growth', 'Disease', 'MESH:D006130', (46, 58))	('men', 'Species', '9606', (211, 214))	('tumor', 'Disease', (173, 178))	('arrest', 'Disease', 'MESH:D006323', (36, 42))	('MLN8237', 'Chemical', 'MESH:C550258', (18, 25))	('men', 'Species', '9606', (249, 252))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('Mice', 'Species', '10090', (0, 4))	('arrest', 'Disease', (36, 42))	('MLN8237', 'Var', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
13331	23403633	To further illustrate the antitumor activity of MLN8237 in vivo, tumors were harvested and stained with hematoxylin/eosin, Ki67, and TUNEL.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('Ki67', 'Gene', (123, 127))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('hematoxylin', 'Chemical', 'MESH:D006416', (104, 115))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('eosin', 'Chemical', 'MESH:D004801', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('MLN8237', 'Chemical', 'MESH:C550258', (48, 55))	('Ki67', 'Gene', '17345', (123, 127))	('MLN8237', 'Var', (48, 55))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
13332	23403633	Tumors treated with MLN8237 showed decreased cellularity compared to tumors from control mice, as well as regions of cell death and fibrosis (Figure 5B).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cellularity', 'CPA', (45, 56))	('mice', 'Species', '10090', (89, 93))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('decreased', 'NegReg', (35, 44))	('Tumors', 'Disease', (0, 6))	('MLN8237', 'Chemical', 'MESH:C550258', (20, 27))	('MLN8237', 'Var', (20, 27))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('fibrosis', 'Disease', 'MESH:D005355', (132, 140))	('fibrosis', 'Disease', (132, 140))	('cell death', 'biological_process', 'GO:0008219', ('117', '127'))
13333	23403633	The MLN8237 treated group also exhibited a 50% decrease in percentage of cells staining positive for Ki67 and a 10-fold increase in percentage of cells staining positive for TUNEL (t-test P < 0.05; Figure 5B).	('Ki67', 'Gene', (101, 105))	('decrease', 'NegReg', (47, 55))	('Ki67', 'Gene', '17345', (101, 105))	('MLN8237', 'Chemical', 'MESH:C550258', (4, 11))	('MLN8237', 'Var', (4, 11))	('increase', 'PosReg', (120, 128))
13334	23403633	Finally, we evaluated the response of the T24 bladder cancer cell line to MLN8237 in combination with either paclitaxel or gemcitabine - two agents currently used for the treatment of advanced bladder cancer.	('MLN8237', 'Chemical', 'MESH:C550258', (74, 81))	('gemcitabine', 'Chemical', 'MESH:C056507', (123, 134))	('bladder cancer', 'Disease', 'MESH:D001749', (193, 207))	('MLN8237', 'Var', (74, 81))	('men', 'Species', '9606', (176, 179))	('bladder cancer', 'Disease', (193, 207))	('bladder cancer', 'Disease', (46, 60))	('bladder cancer', 'Disease', 'MESH:D001749', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('bladder cancer', 'Phenotype', 'HP:0009725', (46, 60))	('paclitaxel', 'Chemical', 'MESH:D017239', (109, 119))	('bladder cancer', 'Phenotype', 'HP:0009725', (193, 207))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
13337	23403633	Sequential administration of MLN8237 followed by either paclitaxel or gemcitabine resulted in synergistic interactions, most prominently at lower concentrations of the second drug (Figure 6).	('synergistic interactions', 'MPA', (94, 118))	('paclitaxel', 'Chemical', 'MESH:D017239', (56, 66))	('MLN8237', 'Var', (29, 36))	('gemcitabine', 'Chemical', 'MESH:C056507', (70, 81))	('resulted in', 'Reg', (82, 93))	('MLN8237', 'Chemical', 'MESH:C550258', (29, 36))
13338	23403633	For example, when paclitaxel was administered alone, 1.6 nM paclitaxel produced 30% of maximal reduction in cell viability, but when paclitaxel was administered after 100 nM MLN8237, 1.6 nM paclitaxel achieved 70% of maximal reduction in cell viability.	('reduction', 'NegReg', (225, 234))	('paclitaxel', 'Chemical', 'MESH:D017239', (18, 28))	('MLN8237', 'Chemical', 'MESH:C550258', (174, 181))	('paclitaxel', 'Chemical', 'MESH:D017239', (190, 200))	('MLN8237', 'Var', (174, 181))	('cell viability', 'CPA', (108, 122))	('cell viability', 'CPA', (238, 252))	('paclitaxel', 'Chemical', 'MESH:D017239', (60, 70))	('paclitaxel', 'Chemical', 'MESH:D017239', (133, 143))
13339	23403633	Likewise, 4 nM gemcitabine along produced 48% of maximal reduction in cell viability, whereas 4 nM gemcitabine administered sequentially following 100 nM MLN8237 was able to achieve 87% of maximal reduction in cell viability.	('MLN8237', 'Chemical', 'MESH:C550258', (154, 161))	('reduction', 'NegReg', (57, 66))	('cell viability', 'CPA', (70, 84))	('MLN8237', 'Var', (154, 161))	('gemcitabine', 'Chemical', 'MESH:C056507', (15, 26))	('gemcitabine', 'Chemical', 'MESH:C056507', (99, 110))
13345	23403633	For both MLN8237/paclitaxel and MLN8237/gemcitabine combinations, sequential dosing regimens produced the most significant extent of cell cycle arrest, while simultaneous dosing regimens were the least effective in causing additional cell cycle arrest (Figure S2).	('MLN8237/gemcitabine', 'Var', (32, 51))	('MLN8237', 'Chemical', 'MESH:C550258', (9, 16))	('MLN8237/paclitaxel', 'Var', (9, 27))	('MLN8237', 'Chemical', 'MESH:C550258', (32, 39))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('133', '150'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (133, 150))	('arrest', 'Disease', 'MESH:D006323', (245, 251))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('234', '251'))	('men', 'Species', '9606', (88, 91))	('arrest', 'Disease', 'MESH:D006323', (144, 150))	('gemcitabine', 'Chemical', 'MESH:C056507', (40, 51))	('paclitaxel', 'Chemical', 'MESH:D017239', (17, 27))	('arrest', 'Disease', (245, 251))	('men', 'Species', '9606', (182, 185))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (234, 251))	('arrest', 'Disease', (144, 150))
13346	23403633	For example, sequential administrations of MLN8237 and paclitaxel produced a broad aneuploid cell population with no predominance of a single ploidy, whereas simultaneous MLN8237 and paclitaxel administration resulted in a cell cycle profile indistinguishable from that of MLN8237 treatment alone.	('cell cycle', 'biological_process', 'GO:0007049', ('223', '233'))	('MLN8237', 'Chemical', 'MESH:C550258', (273, 280))	('MLN8237', 'Chemical', 'MESH:C550258', (171, 178))	('MLN8237', 'Chemical', 'MESH:C550258', (43, 50))	('cell cycle', 'CPA', (223, 233))	('men', 'Species', '9606', (286, 289))	('paclitaxel', 'Chemical', 'MESH:D017239', (55, 65))	('paclitaxel', 'Chemical', 'MESH:D017239', (183, 193))	('MLN8237', 'Var', (43, 50))
13350	23403633	With the goal of exploiting this pathway as anticancer therapy, we evaluated the impact of the Aurora kinase A inhibitor MLN8237 on bladder cancer cells in vitro.	('Aurora kinase A', 'Gene', '6790', (95, 110))	('MLN8237', 'Var', (121, 128))	('bladder cancer', 'Disease', 'MESH:D001749', (132, 146))	('bladder cancer', 'Disease', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('Aurora kinase A', 'Gene', (95, 110))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('bladder cancer', 'Phenotype', 'HP:0009725', (132, 146))	('MLN8237', 'Chemical', 'MESH:C550258', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
13351	23403633	Application of MLN8237 to papilloma-derived RT4 cells and malignant T24 and UM-UC-3 urothelial carcinoma cells resulted in cell cycle arrest, mitotic spindle failure, and eventual apoptotic cell death.	('arrest', 'Disease', (134, 140))	('RT4', 'CellLine', 'CVCL:0036', (44, 47))	('mitotic spindle failure', 'Disease', 'MESH:D002277', (142, 165))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('142', '157'))	('MLN8237', 'Var', (15, 22))	('urothelial carcinoma', 'Disease', (84, 104))	('papilloma', 'Phenotype', 'HP:0012740', (26, 35))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('123', '140'))	('mitotic spindle failure', 'Disease', (142, 165))	('MLN8237', 'Chemical', 'MESH:C550258', (15, 22))	('arrest', 'Disease', 'MESH:D006323', (134, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('papilloma', 'Disease', (26, 35))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('180', '200'))	('papilloma', 'Disease', 'MESH:D010212', (26, 35))	('apoptotic cell death', 'CPA', (180, 200))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (123, 140))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (84, 104))
13355	23403633	Our results are consistent with a previous report of p73-dependent apoptosis following Aurora A inhibition in p53 mutant cells.	('p53', 'Gene', (110, 113))	('p53', 'Gene', '7157', (110, 113))	('mutant', 'Var', (114, 120))	('p73', 'Gene', '7161', (53, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('67', '76'))	('p73', 'Gene', (53, 56))	('apoptosis', 'biological_process', 'GO:0006915', ('67', '76'))	('inhibition', 'NegReg', (96, 106))
13356	23403633	Given the high incidence of p53 mutations in human bladder cancer, activation of an alternate apoptotic pathway following Aurora A inhibition constitutes an important mechanism for achieving cell death.	('bladder cancer', 'Disease', (51, 65))	('p53', 'Gene', (28, 31))	('activation', 'PosReg', (67, 77))	('p53', 'Gene', '7157', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('human', 'Species', '9606', (45, 50))	('cell death', 'biological_process', 'GO:0008219', ('191', '201'))	('mutations', 'Var', (32, 41))	('bladder cancer', 'Disease', 'MESH:D001749', (51, 65))
13361	23403633	These results suggest that the induction of spindle checkpoint dysfunction by MLN8237 can potentiate the ability of paclitaxel and gemcitabine to induce cell cycle arrest, and underscore the potential of MLN8237 as either an independent or concurrent agent in bladder cancer.	('spindle', 'MPA', (44, 51))	('bladder cancer', 'Phenotype', 'HP:0009725', (260, 274))	('MLN8237', 'Chemical', 'MESH:C550258', (78, 85))	('spindle', 'cellular_component', 'GO:0005819', ('44', '51'))	('arrest', 'Disease', (164, 170))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (153, 170))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('153', '170'))	('MLN8237', 'Var', (78, 85))	('bladder cancer', 'Disease', (260, 274))	('bladder cancer', 'Disease', 'MESH:D001749', (260, 274))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('potentiate', 'PosReg', (90, 100))	('paclitaxel', 'Chemical', 'MESH:D017239', (116, 126))	('arrest', 'Disease', 'MESH:D006323', (164, 170))	('gemcitabine', 'Chemical', 'MESH:C056507', (131, 142))	('spindle checkpoint', 'biological_process', 'GO:0031577', ('44', '62'))	('MLN8237', 'Chemical', 'MESH:C550258', (204, 211))
13362	23403633	Finally, we demonstrated the in vivo capacity of MLN8237 to arrest tumor growth in a mouse xenograft model of bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (110, 124))	('bladder cancer', 'Disease', (110, 124))	('mouse', 'Species', '10090', (85, 90))	('arrest tumor', 'Disease', 'MESH:D006323', (60, 72))	('arrest tumor', 'Disease', (60, 72))	('MLN8237', 'Chemical', 'MESH:C550258', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (110, 124))	('MLN8237', 'Var', (49, 56))	('tumor growth', 'Disease', (67, 79))	('tumor growth', 'Disease', 'MESH:D006130', (67, 79))
13363	23403633	In other studies, MLN8237 has been shown to have similar antitumor activity in animal models and in early clinical testing, but has not been evaluated specifically in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (167, 181))	('bladder cancer', 'Disease', 'MESH:D001749', (167, 181))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('bladder cancer', 'Disease', (167, 181))	('MLN8237', 'Chemical', 'MESH:C550258', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MLN8237', 'Var', (18, 25))	('tumor', 'Disease', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
13364	23403633	Our demonstration of decreased tumor size, associated with cell drop-out and reduced proliferation index, following MLN8237 administration in a mouse xenograft model of bladder cancer is consistent with current published findings of tumor response to this drug.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('bladder cancer', 'Disease', 'MESH:D001749', (169, 183))	('proliferation index', 'CPA', (85, 104))	('mouse', 'Species', '10090', (144, 149))	('cell drop-out', 'CPA', (59, 72))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('MLN8237', 'Chemical', 'MESH:C550258', (116, 123))	('tumor', 'Disease', (233, 238))	('bladder cancer', 'Disease', (169, 183))	('tumor', 'Disease', (31, 36))	('MLN8237', 'Var', (116, 123))	('reduced', 'NegReg', (77, 84))	('decreased tumor', 'Disease', 'MESH:D009369', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('bladder cancer', 'Phenotype', 'HP:0009725', (169, 183))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('decreased tumor', 'Disease', (21, 36))
13369	23403633	Targeting this pathway with the Aurora A inhibitor MLN8237 induced cell cycle arrest, aneuploidy, spindle abnormalities, and apoptosis in bladder cancer cell lines, and arrested tumor growth in a mouse xenograft model.	('bladder cancer', 'Disease', 'MESH:D001749', (138, 152))	('bladder cancer', 'Disease', (138, 152))	('arrested tumor', 'Disease', (169, 183))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (67, 84))	('arrest', 'Disease', 'MESH:D006323', (169, 175))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('apoptosis', 'CPA', (125, 134))	('arrest', 'Disease', (78, 84))	('arrested tumor', 'Disease', 'MESH:D006323', (169, 183))	('aneuploidy', 'Disease', 'MESH:D000782', (86, 96))	('tumor growth', 'Disease', 'MESH:D006130', (178, 190))	('mouse', 'Species', '10090', (196, 201))	('apoptosis', 'biological_process', 'GO:0097194', ('125', '134'))	('apoptosis', 'biological_process', 'GO:0006915', ('125', '134'))	('arrest', 'Disease', 'MESH:D006323', (78, 84))	('MLN8237', 'Var', (51, 58))	('arrest', 'Disease', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('spindle', 'cellular_component', 'GO:0005819', ('98', '105'))	('spindle abnormalities', 'CPA', (98, 119))	('aneuploidy', 'Disease', (86, 96))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('67', '84'))	('MLN8237', 'Chemical', 'MESH:C550258', (51, 58))	('tumor growth', 'Disease', (178, 190))
13372	23403633	We sought to identify pathways in human bladder cancer that could be exploited with targeted therapies, leading us to identify mitotic spindle checkpoint dysfunction and to evaluate the effects of the Aurora kinase A inhibitor MLN8237 in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('human', 'Species', '9606', (34, 39))	('Aurora kinase A', 'Gene', (201, 216))	('bladder cancer', 'Disease', (238, 252))	('bladder cancer', 'Disease', 'MESH:D001749', (238, 252))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('MLN8237', 'Chemical', 'MESH:C550258', (227, 234))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('Aurora kinase A', 'Gene', '6790', (201, 216))	('bladder cancer', 'Phenotype', 'HP:0009725', (238, 252))	('MLN8237', 'Var', (227, 234))	('mitotic spindle checkpoint', 'biological_process', 'GO:0071174', ('127', '153'))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('127', '142'))
13374	23403633	Based on our mechanism-based hypothesis of the efficacy of Aurora kinase inhibition in bladder cancer, as well as our validation of in vitro findings using a mouse xenograft study and our demonstration of schedule-dependent synergistic effects between MLN8237 and gemcitabine and paclitaxel, we feel strongly that this pathway warrants further therapeutic investigation in bladder cancer.	('MLN8237', 'Chemical', 'MESH:C550258', (252, 259))	('mouse', 'Species', '10090', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('bladder cancer', 'Phenotype', 'HP:0009725', (373, 387))	('inhibition', 'NegReg', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('MLN8237', 'Var', (252, 259))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('gemcitabine', 'Chemical', 'MESH:C056507', (264, 275))	('Aurora kinase', 'Enzyme', (59, 72))	('tween', 'Chemical', 'MESH:D011136', (246, 251))	('paclitaxel', 'Chemical', 'MESH:D017239', (280, 290))	('bladder cancer', 'Disease', 'MESH:D001749', (373, 387))	('bladder cancer', 'Disease', (373, 387))	('bladder cancer', 'Disease', 'MESH:D001749', (87, 101))	('bladder cancer', 'Disease', (87, 101))
13376	34046088	Approval was based on a phase II single-arm trial that demonstrated significant activity of erdafitinib in patients with tumors harboring FGFR2/3 alterations.	('FGFR2/3', 'Gene', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('alterations', 'Var', (146, 157))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('activity', 'MPA', (80, 88))	('FGFR2/3', 'Gene', '2263;2261', (138, 145))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('erdafitinib', 'Chemical', 'MESH:C000604580', (92, 103))	('patients', 'Species', '9606', (107, 115))	('FGFR', 'molecular_function', 'GO:0005007', ('138', '142'))
13380	34046088	Patients with FGFR2/3 alterations were selected to receive erdafitinib at the standard dosing schedule and were followed prospectively to evaluate the efficacy and safety outcomes.	('erdafitinib', 'Chemical', 'MESH:C000604580', (59, 70))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('FGFR2/3', 'Gene', '2263;2261', (14, 21))	('Patients', 'Species', '9606', (0, 8))	('alterations', 'Var', (22, 33))	('FGFR2/3', 'Gene', (14, 21))
13381	34046088	From 19 April 2019, through 13 March 2020, 47 patients with mUC from 10 Brazilian centers were tested for FGFR2/3 alterations.	('patients', 'Species', '9606', (46, 54))	('alterations', 'Var', (114, 125))	('FGFR2/3', 'Gene', '2263;2261', (106, 113))	('FGFR2/3', 'Gene', (106, 113))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))
13382	34046088	Alterations in FGFR2/3 were found in 12 patients (25.5%) and all of them were eligible for the EAP.	('patients', 'Species', '9606', (40, 48))	('Alterations', 'Var', (0, 11))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('FGFR2/3', 'Gene', (15, 22))	('FGFR2/3', 'Gene', '2263;2261', (15, 22))	('found', 'Reg', (28, 33))	('EAP', 'Chemical', '-', (95, 98))
13395	34046088	FGFR genetic alterations (mutations and fusions) are associated with neoplastic progression of many tumors including urothelial carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('urothelial carcinoma', 'Disease', (117, 137))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'Gene', (0, 4))	('fusions', 'Var', (40, 47))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (117, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('tumors', 'Disease', (100, 106))	('genetic alterations', 'Var', (5, 24))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('associated with', 'Reg', (53, 68))	('neoplastic progression', 'CPA', (69, 91))
13396	34046088	At least 20% of advanced urothelial carcinoma have been shown to harbor FGFR2/3 alterations and have been associated with worse outcomes.	('alterations', 'Var', (80, 91))	('associated', 'Reg', (106, 116))	('FGFR2/3', 'Gene', '2263;2261', (72, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('urothelial carcinoma', 'Disease', (25, 45))	('FGFR2/3', 'Gene', (72, 79))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (25, 45))
13398	34046088	Erdafitinib was the first targeted therapy approved for the treatment of patients with metastatic urothelial carcinoma (mUC) based on a phase II single-arm trial, including 99 patients that demonstrated significant activity with ORR of 40% in heavily treated patients with tumors harboring FGFR2/3 alterations.	('patients', 'Species', '9606', (176, 184))	('FGFR2/3', 'Gene', '2263;2261', (290, 297))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (0, 11))	('patients', 'Species', '9606', (259, 267))	('FGFR', 'molecular_function', 'GO:0005007', ('290', '294'))	('activity', 'MPA', (215, 223))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('urothelial carcinoma', 'Disease', (98, 118))	('FGFR2/3', 'Gene', (290, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (98, 118))	('tumors', 'Disease', 'MESH:D009369', (273, 279))	('alterations', 'Var', (298, 309))	('patients', 'Species', '9606', (73, 81))	('tumors', 'Disease', (273, 279))
13402	34046088	Patients with FGFR2/3 alterations identified from April 2019 to March 2020 who received erdafitinib at the recommended dosing schedule of 8 mg daily were followed prospectively during the program to evaluate the effectiveness and safety of the treatment.	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('FGFR2/3', 'Gene', '2263;2261', (14, 21))	('Patients', 'Species', '9606', (0, 8))	('alterations', 'Var', (22, 33))	('FGFR2/3', 'Gene', (14, 21))	('erdafitinib', 'Chemical', 'MESH:C000604580', (88, 99))
13406	34046088	The analysis for FGFR2/3 gene alterations was performed in formalin-fixed paraffin-embedded tumor samples using a custom reverse transcriptase polymerase chain reaction (RT-PCR) amplified in real time with the therascreen  FGFR RGQ RT-PCR kit (QIAGEN).	('transcriptase', 'molecular_function', 'GO:0003899', ('129', '142'))	('transcriptase', 'molecular_function', 'GO:0003968', ('129', '142'))	('FGFR2/3', 'Gene', '2263;2261', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('transcriptase', 'molecular_function', 'GO:0034062', ('129', '142'))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('alterations', 'Var', (30, 41))	('paraffin', 'Chemical', 'MESH:D010232', (74, 82))	('FGFR2/3', 'Gene', (17, 24))	('formalin', 'Chemical', 'MESH:D005557', (59, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('FGFR', 'molecular_function', 'GO:0005007', ('223', '227'))
13407	34046088	The specific gene alterations evaluated were: two-point mutations in exon 7 [p.R248C (c.742C > T) and p.S249C (c.746C > G)], two-point mutations in exon 10 [p.G370C (c.1108G > T) and p.Y373C (c.1118A > G)], and three fusions in the FGFR3 gene (FGFR3-TACC3v1, FGFR3-TACC3v3 and FGFR3-BAIAP2L1) as well as two fusions in the FGFR2 gene (FGFR2-BICC1 and FGFR2-CASP7).	('p.Y373C', 'Mutation', 'rs121913485', (183, 190))	('FGFR2', 'Gene', '2263', (323, 328))	('FGFR3', 'Gene', (277, 282))	('FGFR', 'molecular_function', 'GO:0005007', ('244', '248'))	('CASP7', 'Gene', (357, 362))	('FGFR3', 'Gene', (244, 249))	('FGFR3', 'Gene', '2261', (277, 282))	('p.R248C', 'Mutation', 'rs121913482', (77, 84))	('BAIAP2L1', 'Gene', '55971', (283, 291))	('FGFR', 'molecular_function', 'GO:0005007', ('351', '355'))	('CASP7', 'Gene', '840', (357, 362))	('FGFR', 'molecular_function', 'GO:0005007', ('323', '327'))	('FGFR', 'molecular_function', 'GO:0005007', ('335', '339'))	('FGFR3', 'Gene', (259, 264))	('FGFR3', 'Gene', '2261', (244, 249))	('FGFR2', 'Gene', (351, 356))	('c.746C > G', 'Mutation', 'rs121913483', (111, 121))	('FGFR3', 'Gene', '2261', (259, 264))	('FGFR', 'molecular_function', 'GO:0005007', ('259', '263'))	('FGFR2', 'Gene', (335, 340))	('c.742C > T', 'Mutation', 'rs121913482', (86, 96))	('FGFR2', 'Gene', '2263', (351, 356))	('BICC1', 'Gene', '80114', (341, 346))	('p.G370C', 'Mutation', 'rs121913479', (157, 164))	('p.S249C', 'Var', (102, 109))	('c.1118A > G', 'Mutation', 'rs121913485', (192, 203))	('FGFR', 'molecular_function', 'GO:0005007', ('232', '236'))	('c.1108G > T', 'Mutation', 'rs121913479', (166, 177))	('BICC1', 'Gene', (341, 346))	('BAIAP2L1', 'Gene', (283, 291))	('FGFR2', 'Gene', '2263', (335, 340))	('FGFR3', 'Gene', (232, 237))	('FGFR2', 'Gene', (323, 328))	('FGFR3', 'Gene', '2261', (232, 237))	('p.S249C', 'Mutation', 'rs121913483', (102, 109))	('FGFR', 'molecular_function', 'GO:0005007', ('277', '281'))
13411	34046088	From 9 April 2019, through March 13, 2020, 47 patients with mUC from 10 Brazilian centers were tested for FGFR2/3 alterations.	('patients', 'Species', '9606', (46, 54))	('alterations', 'Var', (114, 125))	('FGFR2/3', 'Gene', '2263;2261', (106, 113))	('FGFR2/3', 'Gene', (106, 113))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))
13412	34046088	Alterations in FGFR2/3 were found in 12 patients (25.5%) and all of them were eligible for erdafitinib treatment in the EAP.	('EAP', 'Chemical', '-', (120, 123))	('patients', 'Species', '9606', (40, 48))	('Alterations', 'Var', (0, 11))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('FGFR2/3', 'Gene', (15, 22))	('erdafitinib', 'Chemical', 'MESH:C000604580', (91, 102))	('FGFR2/3', 'Gene', '2263;2261', (15, 22))
13415	34046088	All evaluated patients were found to have tumors harboring FGFR3 alterations, and the most common one was p.S249c, present in nine patients (75%), two patients had FGFR3 p.R248C mutation and one patient had p.Y373C.	('p.S249c', 'Mutation', 'rs121913483', (106, 113))	('p.Y373C', 'Mutation', 'rs121913485', (207, 214))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('patients', 'Species', '9606', (14, 22))	('FGFR3', 'Gene', (59, 64))	('patient', 'Species', '9606', (151, 158))	('FGFR3', 'Gene', (164, 169))	('FGFR3', 'Gene', '2261', (164, 169))	('patients', 'Species', '9606', (131, 139))	('FGFR3', 'Gene', '2261', (59, 64))	('alterations', 'Var', (65, 76))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('patient', 'Species', '9606', (14, 21))	('p.R248C', 'Mutation', 'rs121913482', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('p.R248C', 'Var', (170, 177))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('tumors', 'Disease', (42, 48))	('patient', 'Species', '9606', (195, 202))	('FGFR', 'molecular_function', 'GO:0005007', ('164', '168'))	('p.S249c', 'Var', (106, 113))	('patients', 'Species', '9606', (151, 159))	('patient', 'Species', '9606', (131, 138))
13420	34046088	The baseline clinical characteristics, details of prior treatment and FGFR3 alterations of all patients are summarized in Table 1.	('alterations', 'Var', (76, 87))	('FGFR', 'molecular_function', 'GO:0005007', ('70', '74'))	('FGFR3', 'Gene', '2261', (70, 75))	('patients', 'Species', '9606', (95, 103))	('FGFR3', 'Gene', (70, 75))
13426	34046088	All subjects who had an PR or SD carried the p.S249C mutation on the FGFR3 gene.	('FGFR3', 'Gene', '2261', (69, 74))	('FGFR', 'molecular_function', 'GO:0005007', ('69', '73'))	('p.S249C', 'Var', (45, 52))	('FGFR3', 'Gene', (69, 74))	('p.S249C', 'Mutation', 'rs121913483', (45, 52))
13443	34046088	All patients included in this analysis had FGFR3 mutations.	('mutations', 'Var', (49, 58))	('FGFR3', 'Gene', (43, 48))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('FGFR3', 'Gene', '2261', (43, 48))	('patients', 'Species', '9606', (4, 12))
13452	34046088	Regarding the daily clinical practice and the applicability of erdafitinib, it is worth discussing what types of sample (tumor tissue and/or blood sample) and methods to use to identify the FGFR2/3 alterations.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('FGFR2/3', 'Gene', (190, 197))	('erdafitinib', 'Chemical', 'MESH:C000604580', (63, 74))	('tumor', 'Disease', (121, 126))	('alterations', 'Var', (198, 209))	('FGFR', 'molecular_function', 'GO:0005007', ('190', '194'))	('FGFR2/3', 'Gene', '2263;2261', (190, 197))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
13453	34046088	While the evaluation of DNA with next-generation sequence (NGS) techniques seems to be more versatile to identify FGFR2/3 alterations, able to be used in both tumor tissue (tumor DNA) and blood samples (cell-free DNA), the high cost and low availability of the use of these tests and the lack of health insurance coverage limit the use of DNA-based NGS tests.	('FGFR2/3', 'Gene', (114, 121))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('DNA', 'cellular_component', 'GO:0005574', ('339', '342'))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('FGFR', 'molecular_function', 'GO:0005007', ('114', '118'))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', (159, 164))	('FGFR2/3', 'Gene', '2263;2261', (114, 121))	('DNA', 'cellular_component', 'GO:0005574', ('213', '216'))	('alterations', 'Var', (122, 133))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('DNA', 'cellular_component', 'GO:0005574', ('179', '182'))
13454	34046088	Furthermore, data suggest that DNA-based techniques can miss some FGFR2/3 alterations (fusion and/or mutation).	('FGFR2/3', 'Gene', '2263;2261', (66, 73))	('miss', 'NegReg', (56, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('alterations', 'Var', (74, 85))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('mutation', 'Var', (101, 109))	('FGFR2/3', 'Gene', (66, 73))
13457	34046088	Another interesting finding in our analysis was the incidence rate of 25.5% of FGFR2/3 mutations.	('FGFR2/3', 'Gene', '2263;2261', (79, 86))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('mutations', 'Var', (87, 96))	('FGFR2/3', 'Gene', (79, 86))
13458	34046088	This cohort was probably overestimated as some patients had already been tested and were found to have FGFR mutations before entering the program.	('FGFR', 'molecular_function', 'GO:0005007', ('103', '107'))	('patients', 'Species', '9606', (47, 55))	('FGFR', 'Gene', (103, 107))	('mutations', 'Var', (108, 117))
13460	34046088	In addition, there are data showing an incidence rate up to 37% of FGFR3 mutations in upper urinary tract tumors.	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('FGFR3', 'Gene', (67, 72))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('upper urinary tract tumors', 'Phenotype', 'HP:0010935', (86, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('FGFR3', 'Gene', '2261', (67, 72))	('urinary tract tumors', 'Phenotype', 'HP:0010786', (92, 112))	('mutations', 'Var', (73, 82))
13464	34046088	Second, patients usually required a few weeks to evaluate eligibility with the FGFR alteration and receive erdafitinib, which could have caused tumor progression and decrease in the performance status.	('tumor', 'Disease', (144, 149))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('FGFR', 'Gene', (79, 83))	('performance status', 'MPA', (182, 200))	('erdafitinib', 'Chemical', 'MESH:C000604580', (107, 118))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('alteration', 'Var', (84, 94))	('caused', 'Reg', (137, 143))	('decrease', 'NegReg', (166, 174))	('patients', 'Species', '9606', (8, 16))
13469	34046088	Our data confirm the activity demonstrated in the BLC2001 trial and support the approval of erdafitinib in Brazil for the treatment of patients with mUC harboring FGFR2/3 alterations.	('FGFR2/3', 'Gene', (163, 170))	('patients', 'Species', '9606', (135, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('163', '167'))	('FGFR2/3', 'Gene', '2263;2261', (163, 170))	('activity', 'MPA', (21, 29))	('erdafitinib', 'Chemical', 'MESH:C000604580', (92, 103))	('alterations', 'Var', (171, 182))
13472	34046088	These results support erdafitinib as a new treatment option for patients with mUC harboring FGFR alterations in addition to standard treatment options.	('FGFR', 'Gene', (92, 96))	('patients', 'Species', '9606', (64, 72))	('alterations', 'Var', (97, 108))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('erdafitinib', 'Chemical', 'MESH:C000604580', (22, 33))
13575	24685646	Four ongoing trials in BCG-refractory patients are assessing ALT-801 (Altor Bioscience) [interleukin 2 (IL-2)/T-cell receptor fusion protein that targets p53] combined with intravesical gemcitabine, everolimus [mammalian target of rapamycin (mTOR) inhibitor] in combination with intravesical gemcitabine, recombinant adenovirus mediated interferon (antiangiogenic and immunomodulatory), and dovitinib [fibroblast growth factor receptor 3 (FGFR-3) inhibitor] in tumors positive for FGFR-3 mutation or overexpression.	('FGFR-3', 'Gene', '2261', (439, 445))	('FGFR-3', 'Gene', (481, 487))	('tumor', 'Phenotype', 'HP:0002664', (461, 466))	('tumors', 'Disease', (461, 467))	('BCG', 'Species', '33892', (23, 26))	('mTOR', 'Gene', (242, 246))	('FGFR', 'molecular_function', 'GO:0005007', ('439', '443'))	('mutation', 'Var', (488, 496))	('gemcitabine', 'Chemical', 'MESH:C056507', (186, 197))	('patients', 'Species', '9606', (38, 46))	('FGFR-3', 'Gene', (439, 445))	('mammalian target of rapamycin', 'Gene', '2475', (211, 240))	('interleukin 2', 'Gene', (89, 102))	('interleukin 2', 'Gene', '3558', (89, 102))	('ALT', 'molecular_function', 'GO:0004021', ('61', '64'))	('tumors', 'Disease', 'MESH:D009369', (461, 467))	('IL-2', 'Gene', (104, 108))	('IL-2', 'molecular_function', 'GO:0005134', ('104', '108'))	('mTOR', 'Gene', '2475', (242, 246))	('mammalian target of rapamycin', 'Gene', (211, 240))	('gemcitabine', 'Chemical', 'MESH:C056507', (292, 303))	('fibroblast growth factor receptor 3', 'Gene', (402, 437))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('p53', 'Gene', '7157', (154, 157))	('IL-2', 'Gene', '3558', (104, 108))	('overexpression', 'PosReg', (500, 514))	('tumors', 'Phenotype', 'HP:0002664', (461, 467))	('FGFR-3', 'Gene', '2261', (481, 487))	('everolimus', 'Chemical', 'MESH:C107135', (199, 209))	('dovitinib', 'Chemical', 'MESH:C500007', (391, 400))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('402', '426'))	('p53', 'Gene', (154, 157))	('fibroblast growth factor receptor 3', 'Gene', '2261', (402, 437))	('FGFR', 'molecular_function', 'GO:0005007', ('481', '485'))
13620	24685646	VEGFR inhibition has been shown to decrease proliferation and invasion of urothelial carcinoma cells, leading to the investigation of VEGF-targeted agents in urothelial carcinoma.	('VEGFR', 'Gene', '3791', (0, 5))	('VEGF', 'Gene', '7422', (134, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('VEGF', 'Gene', '7422', (0, 4))	('urothelial carcinoma', 'Disease', (74, 94))	('decrease', 'NegReg', (35, 43))	('VEGFR', 'Gene', (0, 5))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (74, 94))	('urothelial carcinoma', 'Disease', (158, 178))	('inhibition', 'Var', (6, 16))	('VEGF', 'Gene', (134, 138))	('invasion', 'CPA', (62, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (158, 178))	('VEGF', 'Gene', (0, 4))	('proliferation', 'CPA', (44, 57))
13660	24685646	PI3K mutations are found in urothelial carcinoma, and this pathway is a potential therapeutic target.	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (28, 48))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('PI3K mutations', 'Var', (0, 14))	('urothelial carcinoma', 'Disease', (28, 48))
13674	24685646	PSCA is a novel therapeutic target for urothelial carcinoma in carriers of the rs2294008-T allele.	('rs2294008-T', 'Var', (79, 90))	('PSCA', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('urothelial carcinoma', 'Disease', (39, 59))	('rs2294008', 'Mutation', 'rs2294008', (79, 88))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (39, 59))	('PSCA', 'Gene', '8000', (0, 4))
13675	24685646	A genetic variant (rs2294008) discovered by urothelial carcinoma genome-wide association studies is a strong predictor of PSCA protein expression in bladder tumors.	('predictor', 'Reg', (109, 118))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('bladder tumors', 'Phenotype', 'HP:0009725', (149, 163))	('PSCA', 'Gene', (122, 126))	('bladder tumors', 'Disease', (149, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('urothelial carcinoma', 'Disease', (44, 64))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('expression', 'MPA', (135, 145))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (44, 64))	('rs2294008', 'Var', (19, 28))	('PSCA', 'Gene', '8000', (122, 126))	('rs2294008', 'Mutation', 'rs2294008', (19, 28))	('bladder tumors', 'Disease', 'MESH:D001749', (149, 163))
13676	24685646	Carriers of the T allele have been shown to be at higher risk of urothelial carcinoma, and urothelial carcinoma patients with the T allele have higher expression of PSCA mRNA and protein in tumors.	('PSCA', 'Gene', '8000', (165, 169))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (65, 85))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('T allele', 'Var', (130, 138))	('PSCA', 'Gene', (165, 169))	('expression', 'MPA', (151, 161))	('urothelial carcinoma', 'Disease', (91, 111))	('higher', 'PosReg', (144, 150))	('patients', 'Species', '9606', (112, 120))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (91, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('tumors', 'Disease', (190, 196))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('urothelial carcinoma', 'Disease', (65, 85))
13682	24685646	In addition, tumor cells can adapt to targeted therapies by developing resistance, usually through mutations in target enzymes and cell-death pathways, or by developing new methods of drug efflux.	('cell-death', 'CPA', (131, 141))	('tumor', 'Disease', (13, 18))	('efflux', 'biological_process', 'GO:0140115', ('189', '195'))	('resistance', 'MPA', (71, 81))	('efflux', 'biological_process', 'GO:0140352', ('189', '195'))	('mutations', 'Var', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('developing', 'PosReg', (60, 70))	('cell-death', 'biological_process', 'GO:0008219', ('131', '141'))
13686	24685646	The analysis also showed that mutations in chromatin-modifying genes were enriched, and that the chromatin-modifying genes MLL2, ARID1A, and KDM6A were inactivated at high frequency in uro-thelial carcinoma.	('chromatin', 'cellular_component', 'GO:0000785', ('97', '106'))	('ARID1A', 'Gene', '8289', (129, 135))	('MLL2', 'Gene', '9757', (123, 127))	('ARID1A', 'Gene', (129, 135))	('chromatin', 'cellular_component', 'GO:0000785', ('43', '52'))	('carcinoma', 'Disease', 'MESH:D002277', (197, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('KDM6A', 'Gene', (141, 146))	('inactivated', 'NegReg', (152, 163))	('mutations', 'Var', (30, 39))	('MLL2', 'Gene', (123, 127))	('carcinoma', 'Disease', (197, 206))	('KDM6A', 'Gene', '7403', (141, 146))
13688	24685646	A study that analyzed 97 high-grade bladder tumors identified several genomic alterations in molecular pathways that could be potential drug targets.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('genomic alterations', 'Var', (70, 89))	('bladder tumors', 'Disease', 'MESH:D001749', (36, 50))	('bladder tumors', 'Phenotype', 'HP:0009725', (36, 50))	('bladder tumors', 'Disease', (36, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('molecular pathways', 'Pathway', (93, 111))
13689	24685646	In this study, 61% of the tumors analyzed had potential actionable drug targets due to mutations in the RTK-RAS-RAF and PI3K/AKT/mTOR pathways.	('AKT', 'Gene', '207', (125, 128))	('PI3K', 'molecular_function', 'GO:0016303', ('120', '124'))	('AKT', 'Gene', (125, 128))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('mTOR', 'Gene', '2475', (129, 133))	('mTOR', 'Gene', (129, 133))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('RAF', 'Gene', (112, 115))	('RAF', 'Gene', '22882', (112, 115))	('mutations', 'Var', (87, 96))	('tumors', 'Disease', (26, 32))
13690	24685646	Tumors with high burden of DNA copy number alterations were found to have more mutations in TP53 and RB1.	('RB1', 'Gene', (101, 104))	('copy number alterations', 'Var', (31, 54))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TP53', 'Gene', '7157', (92, 96))	('RB1', 'Gene', '5925', (101, 104))	('TP53', 'Gene', (92, 96))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))	('mutations', 'Var', (79, 88))
13692	24685646	TSC1 (tuberous sclerosis complex 1), which codes for TSC1 protein, a regulator of mTOR signaling, has been shown to be mutated in some bladder cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('TSC1', 'Gene', '7248', (53, 57))	('signaling', 'biological_process', 'GO:0023052', ('87', '96'))	('tuberous sclerosis complex 1', 'Gene', '7248', (6, 34))	('bladder cancers', 'Disease', (135, 150))	('TSC1', 'Gene', '7248', (0, 4))	('TSC1', 'Gene', (53, 57))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('6', '32'))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('mTOR', 'Gene', (82, 86))	('mutated', 'Var', (119, 126))	('TSC1', 'Gene', (0, 4))	('tuberous sclerosis complex 1', 'Gene', (6, 34))	('mTOR', 'Gene', '2475', (82, 86))	('bladder cancers', 'Phenotype', 'HP:0009725', (135, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (135, 149))	('bladder cancers', 'Disease', 'MESH:D001749', (135, 150))
13693	24685646	In this study, two of three patients with nonsense mutations in TSC1 gene had some degree of response to everolimus, one patient with missense mutation in TSC1, which is of unknown functional significance, had some tumor response to everolimus, and eight of nine patients with progressive disease were TSC1 wild-type.	('TSC1', 'Gene', (155, 159))	('patient', 'Species', '9606', (263, 270))	('TSC1', 'Gene', '7248', (64, 68))	('nonsense mutations', 'Var', (42, 60))	('response to everolimus', 'MPA', (93, 115))	('TSC1', 'Gene', '7248', (302, 306))	('patients', 'Species', '9606', (263, 271))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('everolimus', 'Chemical', 'MESH:C107135', (105, 115))	('TSC1', 'Gene', (64, 68))	('patient', 'Species', '9606', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('everolimus', 'Chemical', 'MESH:C107135', (233, 243))	('tumor', 'Disease', (215, 220))	('TSC1', 'Gene', '7248', (155, 159))	('patient', 'Species', '9606', (121, 128))	('patients', 'Species', '9606', (28, 36))	('TSC1', 'Gene', (302, 306))
13694	24685646	The data obtained from these studies can help target therapies more specifically to tumors based on a large panel of mutational analysis and possibly predict responsiveness to targeted therapies based on the presence of specific mutations - a possible future direction for targeted therapy for urothelial carcinoma.	('mutational', 'Var', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mutations', 'Var', (229, 238))	('urothelial carcinoma', 'Disease', (294, 314))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (294, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
13707	24685646	Genomic studies reveal that urothelial carcinoma is a heterogeneous disease with a large number of somatic mutations that may provide targets for therapy and predict response to specific targeted agents.	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (28, 48))	('urothelial carcinoma', 'Disease', (28, 48))	('mutations', 'Var', (107, 116))
13708	26965579	High prevalence of TERT promoter mutations in primary squamous cell carcinoma of the urinary bladder TERT promoter mutations (TERT-mut) are detectable in the majority of urothelial carcinomas.	('TERT', 'Gene', '7015', (101, 105))	('TERT', 'Gene', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('TERT', 'Gene', '7015', (19, 23))	('TERT', 'Gene', (126, 130))	('mutations', 'Var', (33, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('TERT', 'Gene', '7015', (126, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 77))	('urothelial carcinomas', 'Disease', (170, 191))	('TERT', 'Gene', (101, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('squamous cell carcinoma', 'Disease', (54, 77))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (170, 191))
13716	26965579	TERT promoter mutations, commonly found in conventional urothelial carcinoma, are also highly prevalent in urinary bladder squamous cell carcinoma suggesting a common tumorigenesis and potential utility as a molecular urine-based-screening assay.	('urothelial carcinoma', 'Disease', (56, 76))	('prevalent', 'Reg', (94, 103))	('urinary bladder squamous cell carcinoma', 'Disease', (107, 146))	('TERT', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('TERT', 'Gene', '7015', (0, 4))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (56, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('urinary bladder squamous cell carcinoma', 'Disease', 'MESH:D001749', (107, 146))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (167, 172))
13718	26965579	High rates of activating mutations in the upstream promoter of the TERT gene (TERT-mut) have been found in several solid tumor types.	('mutations', 'Var', (25, 34))	('TERT', 'Gene', (67, 71))	('TERT', 'Gene', (78, 82))	('TERT', 'Gene', '7015', (67, 71))	('TERT', 'Gene', '7015', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('activating', 'PosReg', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
13719	26965579	Mutations tend to occur in 'hot spots', particularly g.1295228C> T and g.129525OC> T. These mutations generate a CCGGAA/T or GGAA/T motif, thereby altering the binding site for Ets transcription factor, thereby increasing TERT promoter activity.	('altering', 'Reg', (147, 155))	('increasing', 'PosReg', (211, 221))	('g.129525OC> T.', 'Var', (71, 85))	('TERT', 'Gene', (222, 226))	('binding', 'molecular_function', 'GO:0005488', ('160', '167'))	('TERT', 'Gene', '7015', (222, 226))	('g.1295228C', 'Var', (53, 63))	('transcription factor', 'molecular_function', 'GO:0000981', ('181', '201'))	('mutations', 'Var', (92, 101))	('g.1295228C> T', 'Mutation', 'g.1295228C>T', (53, 66))	('Ets', 'Protein', (177, 180))	('binding', 'Interaction', (160, 167))	('transcription', 'biological_process', 'GO:0006351', ('181', '194'))
13721	26965579	In the study by Kinde et al, 66% of muscle invasive and 74% of non-muscle invasive bladder lesions were shown to harbor these alterations.	('invasive bladder lesions', 'Disease', (74, 98))	('invasive bladder lesions', 'Disease', 'MESH:D001745', (74, 98))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (63, 90))	('muscle invasive', 'Disease', (36, 51))	('alterations', 'Var', (126, 137))	('invasive bladder', 'Phenotype', 'HP:0100645', (74, 90))
13732	26965579	Safe-SeqS amplification primers were designed to amplify segments containing the region of the TERT promoter previously shown to harbor mutations in melanomas and other tumors (Figure 1).	('melanomas', 'Disease', 'MESH:D008545', (149, 158))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('TERT', 'Gene', (95, 99))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('TERT', 'Gene', '7015', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('harbor', 'Reg', (129, 135))	('mutations', 'Var', (136, 145))	('men', 'Species', '9606', (60, 63))	('melanomas', 'Disease', (149, 158))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))
13748	26965579	Of all the patients with TERT-mut, 2 (17%) were g.129525OC> T and the remaining 10 (83%) were a g.1295228C> T alteration (Table 2).	('g.1295228C> T', 'Var', (96, 109))	('g.1295228C> T', 'Mutation', 'g.1295228C>T', (96, 109))	('TERT', 'Gene', (25, 29))	('g.129525OC> T', 'Var', (48, 61))	('TERT', 'Gene', '7015', (25, 29))	('patients', 'Species', '9606', (11, 19))
13754	26965579	Subsequently, the same mutations were discovered by our group and others in numerous solid cancers, including urothelial carcinoma, gliomas and hepato-cellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('gliomas', 'Disease', (132, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (110, 130))	('mutations', 'Var', (23, 32))	('numerous solid cancers', 'Disease', (76, 98))	('discovered', 'Reg', (38, 48))	('hepato-cellular carcinoma', 'Disease', (144, 169))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('hepato-cellular carcinoma', 'Disease', 'MESH:D020065', (144, 169))	('hepato-cellular carcinoma', 'Phenotype', 'HP:0001402', (144, 169))	('numerous solid cancers', 'Disease', 'MESH:D009369', (76, 98))	('urothelial carcinoma', 'Disease', (110, 130))
13755	26965579	High rates of TERT-mut have been conspicuously absent in colorectal and lung carcinomas.	('colorectal and lung carcinomas', 'Disease', 'MESH:D015179', (57, 87))	('TERT-mut', 'Var', (14, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('absent', 'NegReg', (47, 53))
13760	26965579	All mutations were from previously published hotspots, with the majority of cases (83%) having the g.1295228C> T mutation, whereas the remainder had a g.1295250C> T mutation.	('g.1295228C> T', 'Mutation', 'g.1295228C>T', (99, 112))	('g.1295250C> T', 'Mutation', 'g.1295250C>T', (151, 164))	('g.1295250C> T', 'Var', (151, 164))	('g.1295228C> T', 'Var', (99, 112))
13771	26965579	In summary, TERT promoter mutations, commonly found in conventional urothelial carcinoma, are also highly prevalent in urinary bladder squamous cell carcinoma, suggesting a common tumorigenesis and potential utility as a molecular urine-based-screening assay.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (68, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('urinary bladder squamous cell carcinoma', 'Disease', (119, 158))	('TERT', 'Gene', '7015', (12, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('urinary bladder squamous cell carcinoma', 'Disease', 'MESH:D001749', (119, 158))	('mutations', 'Var', (26, 35))	('urothelial carcinoma', 'Disease', (68, 88))	('prevalent', 'Reg', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('TERT', 'Gene', (12, 16))
13801	28160564	Five candidate miRNAs (miR-155-5p, miR-15a-5p, miR-21-5p, miR-132-3p and miR-31-5p) were all significantly expressed more highly in urinary EVs of UC patients compared to those of the control (all, p<0.0001) (Figure 3A).	('miR-155', 'Gene', (23, 30))	('miR-31', 'Gene', '407035', (73, 79))	('miR-132-3p', 'Gene', (58, 68))	('more highly', 'PosReg', (117, 128))	('miR-31', 'Gene', (73, 79))	('miR-21-5p', 'Gene', (47, 56))	('patients', 'Species', '9606', (150, 158))	('miR-155', 'Gene', '406947', (23, 30))	('miR-132-3p', 'Gene', '100302255', (58, 68))	('miR-21-5p', 'Gene', '406997', (47, 56))	('miR-15a-5p', 'Var', (35, 45))
13808	28160564	We also examined EVs from carcinoma in situ (CIS, n=3), and miR-21-5p was significantly overexpressed in urinary EVs from CIS compared to the control (p=0.0151).	('carcinoma in situ', 'Disease', 'MESH:D002278', (26, 43))	('CIS', 'Var', (122, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('overexpressed', 'PosReg', (88, 101))	('carcinoma in situ', 'Disease', (26, 43))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (26, 43))	('miR-21-5p', 'Gene', (60, 69))	('miR-21-5p', 'Gene', '406997', (60, 69))
13863	28160564	The following antibodies were used for immunological analysis in this study: CD9 (1:1000, 12A12, Shionogi, Osaka, Japan) and CD63 (1:1000, ab59479, Abcam, Cambridge, UK).	('CD9', 'Gene', '928', (77, 80))	('CD63', 'Gene', '967', (125, 129))	('CD9', 'Gene', (77, 80))	('CD63', 'Gene', (125, 129))	('1:1000', 'Var', (131, 137))
13919	28166762	The primary antibodies were anti-CLASP2, anti-E-cadherin, anti-vimentin (Cell Signaling Technology, USA) and anti-GAPDH (Santa Cruz Biotechnology, USA).	('cadherin', 'molecular_function', 'GO:0008014', ('48', '56'))	('E-cadherin', 'Gene', (46, 56))	('vimentin', 'Gene', (63, 71))	('vimentin', 'cellular_component', 'GO:0045099', ('63', '71'))	('E-cadherin', 'Gene', '999', (46, 56))	('Signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('GAPDH', 'Gene', '2597', (114, 119))	('GAPDH', 'Gene', (114, 119))	('vimentin', 'cellular_component', 'GO:0045098', ('63', '71'))	('anti-CLASP2', 'Var', (28, 39))	('vimentin', 'Gene', '7431', (63, 71))
13980	28166762	In present study, we confirmed that manipulation of expression of CLASP2 could change the status of EMT in bladder cancer cell lines in vitro.	('bladder cancer', 'Disease', 'MESH:D001749', (107, 121))	('bladder cancer', 'Disease', (107, 121))	('status of EMT in', 'CPA', (90, 106))	('manipulation', 'Var', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (107, 121))	('change', 'Reg', (79, 85))	('CLASP2', 'Gene', (66, 72))	('EMT', 'biological_process', 'GO:0001837', ('100', '103'))
14003	28166762	In our study, univariable and multivariable analysis suggested that high expressions of CLASP2 in tumor and urine cells were risk factors for progression within 2 years.	('high', 'Var', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('CLASP2', 'Gene', (88, 94))
14081	25733301	There was no difference in high CD8 density among tumors with positive PD-L1 and negative PD-L1 expression (50% vs 13%, respectively; P = .27).	('CD8', 'Gene', '925', (32, 35))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('PD-L1', 'Gene', '29126', (90, 95))	('positive', 'Var', (62, 70))	('PD-L1', 'Gene', (71, 76))	('PD-L1', 'Gene', '29126', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('CD8', 'Gene', (32, 35))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('PD-L1', 'Gene', (90, 95))
14088	25733301	High CD8 density was associated with improved OS (P = .02) and DSS (P = .02) in invasive UC.	('CD8', 'Gene', (5, 8))	('CD8', 'Gene', '925', (5, 8))	('invasive UC', 'Disease', (80, 91))	('High', 'Var', (0, 4))	('OS', 'Chemical', '-', (46, 48))	('improved', 'PosReg', (37, 45))	('DSS', 'Gene', (63, 66))	('DSS', 'Gene', '5376', (63, 66))
14104	25733301	Although several large retrospective studies suggested PD-L1 expression to be associated with more aggressive disease in solid tumors, including bladder cancer, other reports have failed to show such association.	('associated with', 'Reg', (78, 93))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('PD-L1', 'Gene', '29126', (55, 60))	('solid tumors', 'Disease', 'MESH:D009369', (121, 133))	('aggressive disease', 'Disease', 'MESH:D001523', (99, 117))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('expression', 'Var', (61, 71))	('aggressive disease', 'Disease', (99, 117))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('solid tumors', 'Disease', (121, 133))	('PD-L1', 'Gene', (55, 60))	('bladder cancer', 'Disease', 'MESH:D001749', (145, 159))	('bladder cancer', 'Disease', (145, 159))
14105	25733301	In fact, a more recent study seems to point to a correlation between PD-L1 expression and improved survival as well as influx of lymphocytes into the tumor micro-environment.	('PD-L1', 'Gene', '29126', (69, 74))	('survival', 'CPA', (99, 107))	('expression', 'Var', (75, 85))	('improved', 'PosReg', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('PD-L1', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
14113	25733301	We found no difference in CD8 density between tumors with positive and negative PD-L1 expression.	('PD-L1', 'Gene', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CD8', 'Gene', '925', (26, 29))	('PD-L1', 'Gene', '29126', (80, 85))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('positive', 'Var', (58, 66))	('tumors', 'Disease', (46, 52))	('CD8', 'Gene', (26, 29))	('negative', 'NegReg', (71, 79))
14146	25886613	In contrast to inverted urothelial papilloma, inverted PUNLMP focally showed expanded and rounded cords and nests, which were composed of architecturally and cytologically bland and uniform urothelium, and showed only rare mitoses as illustrated in Figure 2.	('inverted', 'Var', (46, 54))	('papilloma', 'Phenotype', 'HP:0012740', (35, 44))	('urothelial papilloma', 'Disease', (24, 44))	('urothelial papilloma', 'Disease', 'MESH:D010212', (24, 44))
14206	32182788	Disrupting microtubule dynamics is one of the most successful and widely considered targets of cancer chemotherapy agents.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('microtubule dynamics', 'biological_process', 'GO:0000226', ('11', '31'))	('cancer', 'Disease', (95, 101))	('Disrupting', 'Var', (0, 10))	('microtubule', 'cellular_component', 'GO:0005874', ('11', '22'))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
14214	32182788	As shown in Figure 1c,d, the MAP1B transcripts level was significantly higher among tumors with high pT status (pT2-pT4) than in noninvasive tumors (pTa-pT1) in both the UTUC and UBUC groups (both p < 0.01).	('higher', 'PosReg', (71, 77))	('MAP1B', 'Gene', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('pT1', 'Gene', '58492', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('MAP', 'molecular_function', 'GO:0004239', ('29', '32'))	('high pT status', 'Var', (96, 110))	('pT1', 'Gene', (153, 156))	('tumors', 'Disease', (84, 90))	('transcripts level', 'MPA', (35, 52))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('pTa', 'molecular_function', 'GO:0008959', ('149', '152'))
14216	32182788	We found, in UTUC cases, that high MAP1B expression was markedly associated with synchronous multiple tumors (p = 0.024), advanced pT status (p = 0.005) (Figure 2A-C), positive lymph node metastasis (p = 0.002), the presence of vascular invasion (p < 0.001), and an increased mitotic rate (p < 0.001) (Table 2 and Figure 2D).	('positive lymph node metastasis', 'CPA', (168, 198))	('mitotic rate', 'CPA', (276, 288))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('expression', 'MPA', (41, 51))	('synchronous multiple tumors', 'Disease', 'MESH:D009378', (81, 108))	('high', 'Var', (30, 34))	('associated', 'Reg', (65, 75))	('vascular invasion', 'CPA', (228, 245))	('advanced pT status', 'Disease', (122, 140))	('synchronous multiple tumors', 'Disease', (81, 108))	('increased', 'PosReg', (266, 275))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('MAP', 'molecular_function', 'GO:0004239', ('35', '38'))	('MAP1B', 'Gene', (35, 40))
14219	32182788	During univariate analysis, we observed that multifocal tumors, advanced pathological tumor stage, positive lymph node metastasis, high histological tumor grade, the presence of vascular invasion, perineural invasion, and high MAP1B expression (Figure 3A,B) were associated with worse disease-specific survival (DSS) and metastasis-free survival (MFS) (all p < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('expression', 'MPA', (233, 243))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('high', 'Var', (222, 226))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('MAP1B', 'Gene', (227, 232))	('vascular invasion', 'CPA', (178, 195))	('multifocal tumors', 'Disease', 'None', (45, 62))	('tumor', 'Disease', (56, 61))	('perineural invasion', 'CPA', (197, 216))	('metastasis-free survival', 'CPA', (321, 345))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('DSS', 'Chemical', '-', (312, 315))	('multifocal tumors', 'Disease', (45, 62))	('positive lymph node metastasis', 'CPA', (99, 129))	('tumor', 'Disease', (86, 91))	('disease-specific survival', 'CPA', (285, 310))	('worse', 'NegReg', (279, 284))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('MAP', 'molecular_function', 'GO:0004239', ('227', '230'))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
14222	32182788	During univariate analysis, we determined that advanced pT status, positive lymph node metastasis, high histological tumor grade, the presence of vascular invasion, perineural invasion, an increased mitotic rate, and increment of MAP1B expression (Figure 3C,D) were associated with worse DSS and MFS (all p < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('MAP', 'molecular_function', 'GO:0004239', ('230', '233'))	('vascular invasion', 'CPA', (146, 163))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('MAP1B', 'Gene', (230, 235))	('MFS', 'Disease', (296, 299))	('mitotic rate', 'CPA', (199, 211))	('positive lymph node metastasis', 'CPA', (67, 97))	('increment', 'Var', (217, 226))	('perineural invasion', 'CPA', (165, 184))	('DSS', 'Chemical', '-', (288, 291))	('expression', 'MPA', (236, 246))	('DSS', 'Disease', (288, 291))	('increased', 'PosReg', (189, 198))
14225	32182788	We next successfully knocked down MAP1B in both the RTCC1 (Figure 4B, left) and J82 (Figure 4B, right) cell lines using short hairpin RNA (shRNA).	('MAP', 'molecular_function', 'GO:0004239', ('34', '37'))	('RNA', 'cellular_component', 'GO:0005562', ('134', '137'))	('knocked', 'Var', (21, 28))	('MAP1B', 'Gene', (34, 39))	('J82', 'CellLine', 'CVCL:0359', (80, 83))
14227	32182788	MAP1B knockdown significantly decreased the migratory and invasive abilities of RTCC1 (Figure 4C3,C5) and J82 (Figure 4C4,C6) cells.	('RTCC1', 'Gene', (80, 85))	('J82', 'CellLine', 'CVCL:0359', (106, 109))	('MAP1B', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('MAP', 'molecular_function', 'GO:0004239', ('0', '3'))	('decreased', 'NegReg', (30, 39))
14228	32182788	Flow cytometric analysis of stable MAP1B knockdown RTCC1 and J82 cell lines showed stable MAP1B knockdown significantly increased the sub-G1 population, indicating induced cell apoptosis (Figure 5 and Figure 6).	('knockdown', 'Var', (96, 105))	('apoptosis', 'biological_process', 'GO:0097194', ('177', '186'))	('sub-G1 population', 'CPA', (134, 151))	('J82', 'CellLine', 'CVCL:0359', (61, 64))	('induced', 'Reg', (164, 171))	('MAP', 'molecular_function', 'GO:0004239', ('90', '93'))	('cell apoptosis', 'CPA', (172, 186))	('apoptosis', 'biological_process', 'GO:0006915', ('177', '186'))	('increased', 'PosReg', (120, 129))	('MAP1B', 'Gene', (90, 95))	('MAP', 'molecular_function', 'GO:0004239', ('35', '38'))
14230	32182788	In the independent UBUC patient cohort receiving adjuvant chemotherapy, Kaplan-Meier survival analysis showed high MAP1B expression correlated with inferior DFS (Figure 9), further supporting the role of MAP1B in chemoresistance.	('expression', 'MPA', (121, 131))	('patient', 'Species', '9606', (24, 31))	('high', 'Var', (110, 114))	('MAP', 'molecular_function', 'GO:0004239', ('204', '207'))	('inferior', 'NegReg', (148, 156))	('MAP', 'molecular_function', 'GO:0004239', ('115', '118'))	('MAP1B', 'Gene', (115, 120))
14258	32182788	For example, Ras-association domain family 1 isoform A (RASSF1A), a tumor suppressor whose inactivation is implicated in the development of many human cancers, interacts with MAP1B to influence microtubule dynamics in the cell cycle and is involved in the inhibition of cancer cell growth.	('MAP', 'molecular_function', 'GO:0004239', ('175', '178'))	('cell cycle', 'biological_process', 'GO:0007049', ('222', '232'))	('involved', 'Reg', (240, 248))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('68', '84'))	('human', 'Species', '9606', (145, 150))	('interacts', 'Var', (160, 169))	('microtubule dynamics', 'biological_process', 'GO:0000226', ('194', '214'))	('Ras-association domain family 1 isoform A', 'Gene', '11186', (13, 54))	('tumor', 'Disease', (68, 73))	('tumor suppressor', 'biological_process', 'GO:0051726', ('68', '84'))	('cancer', 'Disease', (270, 276))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Disease', (151, 157))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('cancers', 'Disease', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('microtubule', 'cellular_component', 'GO:0005874', ('194', '205'))	('RASSF1A', 'Gene', '11186', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('microtubule dynamics in the cell cycle', 'MPA', (194, 232))	('Ras-association domain family 1 isoform A', 'Gene', (13, 54))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('RASSF1A', 'Gene', (56, 63))	('MAP1B', 'Gene', (175, 180))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cell growth', 'biological_process', 'GO:0016049', ('277', '288'))	('influence', 'Reg', (184, 193))
14260	32182788	In addition, it has been proposed that the accumulation of C19ORF5 results in microtubule hyperstability, which may be involved in the tumor suppression activity of RASSF1A.	('C19ORF5', 'Gene', '55201', (59, 66))	('RASSF1A', 'Gene', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('microtubule hyperstability', 'MPA', (78, 104))	('tumor', 'Disease', (135, 140))	('C19ORF5', 'Gene', (59, 66))	('results', 'Reg', (67, 74))	('RASSF1A', 'Gene', '11186', (165, 172))	('microtubule', 'cellular_component', 'GO:0005874', ('78', '89'))	('accumulation', 'Var', (43, 55))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
14284	32182788	Predesigned TaqMan assay reagents (Applied Biosystems, Waltham, MA, USA) were used to assess the mRNA abundance of MAP1B (Hs00195485_m1) using the ABI StepOnePlus  system (Applied Biosystems, Waltham, MA, USA), for which POLR2A (Hs01108291_m1) was used as the internal control for normalization.	('POLR2A', 'Gene', (221, 227))	('POLR2A', 'Gene', '5430', (221, 227))	('MAP', 'molecular_function', 'GO:0004239', ('115', '118'))	('MAP1B', 'Gene', (115, 120))	('Hs00195485_m1', 'Var', (122, 135))
14298	32182788	Stable pools of MAP1B knockdown versus the corresponding shLacZ control of the RTCC1 and J82 cell lines were pelleted and fixed overnight in 75% cold ethanol at -20  C. The cells were washed twice using cold phosphate-buffered saline with 10 mg/mL of DNase-free RNase.	('MAP1B', 'Gene', (16, 21))	('knockdown', 'Var', (22, 31))	('ethanol', 'Chemical', 'MESH:D000431', (150, 157))	('MAP', 'molecular_function', 'GO:0004239', ('16', '19'))	('phosphate-buffered saline', 'Chemical', '-', (208, 233))	('J82', 'CellLine', 'CVCL:0359', (89, 92))
14300	32182788	Cell apoptosis was evaluated by plating RTCC1 and J82 cells (105 cells each) with shLacZ or shMAP1B for 24 h, followed by 15 min of incubation using an Annexin V-FITC kit (BD Biosciences, Franklin Lakes, NJ, USA) that contained propidium iodide.	('apoptosis', 'biological_process', 'GO:0097194', ('5', '14'))	('apoptosis', 'biological_process', 'GO:0006915', ('5', '14'))	('shMAP1B', 'Var', (92, 99))	('propidium iodide', 'Chemical', 'MESH:D011419', (228, 244))	('Annexin V', 'Gene', '308', (152, 161))	('Annexin V', 'Gene', (152, 161))	('J82', 'CellLine', 'CVCL:0359', (50, 53))
14307	32182788	The following are available online at , Table S1: Urothelial carcinoma enrolled to explore potential MAP1B mutation, Table S2: MAP1B mutations validated and primer sets, Table S3: Characters of independent UBUC patient cohorts receiving postoperative adjuvant chemotherapy.	('Urothelial carcinoma', 'Disease', 'MESH:D014523', (50, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('MAP', 'molecular_function', 'GO:0004239', ('127', '130'))	('MAP', 'molecular_function', 'GO:0004239', ('101', '104'))	('MAP1B', 'Gene', (101, 106))	('Urothelial carcinoma', 'Disease', (50, 70))	('mutation', 'Var', (107, 115))	('patient', 'Species', '9606', (211, 218))
14308	32182788	KMU-TP104E31, KMU-TP105G00, KMU-TP105G01, and KMU-TP105G02; the Health and Welfare Surcharge of Tobacco Products, Ministry of Health and Welfare, grant no.	('KMU-TP104E31', 'Var', (0, 12))	('Tobacco', 'Species', '4097', (96, 103))	('KMU-TP105G02', 'Var', (46, 58))	('G01', 'CellLine', 'CVCL:4V47', (37, 40))	('KMU-TP105G00', 'Var', (14, 26))	('KMU-TP105G01', 'Var', (28, 40))
14322	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))
14324	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))
14327	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))
14343	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))
14354	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))	('aging acceleration-associated', 'Disease', (203, 232))
14366	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))	('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))
14380	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))
14388	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))
14406	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))	('P-value', 'Var', (246, 253))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
14433	30526555	In the NMIBC patient group, as many as 50 to 80% of cases with low grade pTa-pT1 will recur, and up to 40 to 50% of cases with high grade/G3 pTa-pT1 or associated Cis will progress within 5 years to a higher tumour stage or metastatic disease.	('high grade/G3', 'Var', (127, 140))	('pTa', 'Gene', '171558', (141, 144))	('pT1', 'Gene', '58492', (145, 148))	('MIBC', 'Chemical', '-', (8, 12))	('pTa', 'molecular_function', 'GO:0008959', ('141', '144'))	('Cis', 'Phenotype', 'HP:0030075', (163, 166))	('pT1', 'Gene', (145, 148))	('progress', 'PosReg', (172, 180))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('tumour', 'Disease', 'MESH:D009369', (208, 214))	('tumour', 'Disease', (208, 214))	('patient', 'Species', '9606', (13, 20))	('pTa', 'Gene', (73, 76))	('pTa', 'Gene', (141, 144))	('pT1', 'Gene', '58492', (77, 80))	('metastatic disease', 'CPA', (224, 242))	('Cis', 'Disease', (163, 166))	('pTa', 'Gene', '171558', (73, 76))	('pTa', 'molecular_function', 'GO:0008959', ('73', '76'))	('pT1', 'Gene', (77, 80))
14470	30526555	Antigen retrieval was performed by using 0.5% H2O2 for 30 min, followed by unmasking in citrate buffer (pH 6.0) for 20 min at high temperature, and then blocked with 0.5% bovine serum albumin (BSA).	('H2O2', 'Chemical', 'MESH:D006861', (46, 50))	('H2O2', 'Var', (46, 50))	('albumin', 'Gene', (184, 191))	('albumin', 'Gene', '213', (184, 191))	('citrate', 'Chemical', 'MESH:D019343', (88, 95))	('bovine', 'Species', '9913', (171, 177))
14541	30526555	In addition, the univariate survival analysis showed that A-FABP positivity was associated with a better prognosis for EFS and OS.	('EFS', 'Disease', (119, 122))	('OS', 'Gene', '17451', (127, 129))	('positivity', 'Var', (65, 75))	('A-FABP', 'Gene', (58, 64))
14542	30526555	Finally, our data demonstrated that the presence of A-FABP was predictive of the absence of any event (recurrence, progression or death) and that loss of A-FABP expression in resected primary pTa UC, and pTa/pT1 group was a higher risk factor of progression.	('pTa', 'Gene', (192, 195))	('pTa', 'molecular_function', 'GO:0008959', ('192', '195'))	('death', 'Disease', 'MESH:D003643', (130, 135))	('pT1', 'Gene', '58492', (208, 211))	('death', 'Disease', (130, 135))	('pTa', 'Gene', '171558', (192, 195))	('pTa', 'molecular_function', 'GO:0008959', ('204', '207'))	('loss', 'Var', (146, 150))	('pTa', 'Gene', (204, 207))	('A-FABP', 'Protein', (154, 160))	('pT1', 'Gene', (208, 211))	('pTa', 'Gene', '171558', (204, 207))
14548	30526555	Thus, contrary to what we have demonstrated in bladder cancer, where strong expression of A-FABP was associated with a good prognosis, high A-FABP expression was significantly associated with shorter disease-free survival and OS in breast cancer patients.	('breast cancer', 'Disease', (232, 245))	('shorter', 'NegReg', (192, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (232, 245))	('patients', 'Species', '9606', (246, 254))	('bladder cancer', 'Disease', 'MESH:D001749', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('bladder cancer', 'Phenotype', 'HP:0009725', (47, 61))	('bladder cancer', 'Disease', (47, 61))	('high A-FABP', 'Var', (135, 146))	('disease-free survival', 'CPA', (200, 221))	('breast cancer', 'Disease', 'MESH:D001943', (232, 245))	('OS', 'Gene', '17451', (226, 228))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
14552	30526555	In addition, the protein knock-down with a specific siRNA prevented the proliferation of several SCC cell lines.	('protein', 'Protein', (17, 24))	('prevented', 'NegReg', (58, 67))	('proliferation', 'CPA', (72, 85))	('knock-down', 'Var', (25, 35))	('SCC', 'Gene', (97, 100))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('SCC', 'Gene', '6317', (97, 100))
14553	30526555	Overexpression of FABP4 has also been reported in glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('reported', 'Reg', (38, 46))	('FABP4', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('glioblastoma', 'Disease', (50, 62))	('FABP4', 'Gene', '2167', (18, 23))
14557	30526555	All of these investigations revealed downregulation of A-FABP in invasive UC, and good association of loss of A-FABP with tumour stage and grade.	('downregulation', 'NegReg', (37, 51))	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('invasive UC', 'Disease', (65, 76))	('tumour', 'Disease', (122, 128))	('loss', 'Var', (102, 106))	('A-FABP', 'Gene', (110, 116))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('A-FABP', 'Gene', (55, 61))
14561	30526555	Unlike the studies described above reporting the expression of A-FABP protein by immunohistochemical or two-dimensional electrophoresis analyses, we show on a long-term follow-up of patients that high expression of A-FABP was associated with a good prognosis and that the decrease of A-FABP expression is a tumor progression marker of pTa and pTa/pT1 group.	('expression', 'MPA', (291, 301))	('pTa', 'Gene', '171558', (343, 346))	('pTa', 'Gene', '171558', (335, 338))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('A-FABP', 'Gene', (215, 221))	('men', 'Species', '9606', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('pT1', 'Gene', (347, 350))	('high', 'Var', (196, 200))	('decrease', 'NegReg', (272, 280))	('tumor', 'Disease', (307, 312))	('patients', 'Species', '9606', (182, 190))	('pTa', 'molecular_function', 'GO:0008959', ('335', '338'))	('pTa', 'Gene', (343, 346))	('pTa', 'Gene', (335, 338))	('pTa', 'molecular_function', 'GO:0008959', ('343', '346'))	('pT1', 'Gene', '58492', (347, 350))
14563	30526555	In triple-negative breast cancer, a single nucleotide polymorphism (SNP) of the 3'-UTR region of a-fabp gene has been shown to be associated with significantly lower expression of the protein.	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('single nucleotide polymorphism', 'Var', (36, 66))	('a-fabp', 'Gene', '2167', (97, 103))	('protein', 'cellular_component', 'GO:0003675', ('184', '191'))	('a-fabp', 'Gene', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('protein', 'Protein', (184, 191))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('expression', 'MPA', (166, 176))	('breast cancer', 'Disease', (19, 32))	('lower', 'NegReg', (160, 165))
14566	30526555	In particular, hypermethylation was associated with tumour suppressor gene silencing.	('gene silencing', 'biological_process', 'GO:0016458', ('70', '84'))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('hypermethylation', 'Var', (15, 31))	('tumour', 'Disease', (52, 58))	('associated', 'Reg', (36, 46))
14568	30526555	Thus, hypermethylation of the CpG islands around the human FABP4 promoter could be involved in the loss of FABP4 expression.	('expression', 'MPA', (113, 123))	('FABP4', 'Gene', (59, 64))	('hypermethylation', 'Var', (6, 22))	('FABP4', 'Gene', '2167', (107, 112))	('FABP4', 'Gene', (107, 112))	('human', 'Species', '9606', (53, 58))	('loss', 'NegReg', (99, 103))	('FABP4', 'Gene', '2167', (59, 64))
14572	30526555	which found that high FABP4 expression was associated with pTa UC progression.	('pTa', 'Gene', (59, 62))	('high', 'Var', (17, 21))	('expression', 'MPA', (28, 38))	('pTa', 'Gene', '171558', (59, 62))	('FABP4', 'Gene', '2167', (22, 27))	('associated', 'Reg', (43, 53))	('FABP4', 'Gene', (22, 27))	('pTa', 'molecular_function', 'GO:0008959', ('59', '62'))
14574	30526555	In our pathological practice, A-FABP could be a helpful prognostic marker for bladder UC, easy to detect on formalin-fixed paraffin embedded tumour sections.	('A-FABP', 'Var', (30, 36))	('bladder UC', 'Disease', (78, 88))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('paraffin', 'Chemical', 'MESH:D010232', (123, 131))	('tumour', 'Disease', (141, 147))	('formalin', 'Chemical', 'MESH:D005557', (108, 116))
14575	30526555	Importantly, we demonstrated that loss of A-FABP expression was predictive of a higher risk of progression in pTa UC.	('loss', 'Var', (34, 38))	('pTa', 'Gene', '171558', (110, 113))	('pTa', 'Gene', (110, 113))	('pTa', 'molecular_function', 'GO:0008959', ('110', '113'))	('A-FABP', 'Protein', (42, 48))
14595	29464864	A further case study in breast invasive carcinoma (BRCA) found that DRCE expression was consistent with the drug response pattern and the aberrant expression of the two NEAT1-related DRCEs may lead to poor response to tamoxifen therapy for patients with TP53 mutations.	('poor', 'NegReg', (201, 205))	('BRCA', 'Gene', '672', (51, 55))	('TP53', 'Gene', '7157', (254, 258))	('tamoxifen', 'Chemical', 'MESH:D013629', (218, 227))	('TP53', 'Gene', (254, 258))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (24, 49))	('breast invasive carcinoma', 'Disease', (24, 49))	('BRCA', 'Gene', (51, 55))	('mutations', 'Var', (259, 268))	('BRCA', 'Phenotype', 'HP:0003002', (51, 55))	('aberrant', 'Var', (138, 146))	('response to tamoxifen therapy', 'MPA', (206, 235))	('lead to', 'Reg', (193, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('patients', 'Species', '9606', (240, 248))	('NEAT1', 'Gene', '283131', (169, 174))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (24, 49))	('NEAT1', 'Gene', (169, 174))
14611	29464864	A patient-drug two-layer integrated network and a linear weighting method were used to predict drug responses, and the dysregulation of DRCE expression was inferred to trigger functions and pathways associated with differences in the response to drugs.	('DRCE', 'Gene', (136, 140))	('dysregulation', 'Var', (119, 132))	('patient', 'Species', '9606', (2, 9))
14681	29464864	Epidermal growth factor receptor (EGFR) mutations are prevalent and well characterized in lung cancer and were shown by Gazdar (2009) to be associated with sensitivity and resistance to lung cancer treatment.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('associated', 'Reg', (140, 150))	('EGFR', 'Gene', (34, 38))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('0', '23'))	('lung cancer', 'Disease', (90, 101))	('mutations', 'Var', (40, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (186, 197))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('EGFR', 'Gene', '1956', (34, 38))
14691	29464864	In addition, we compared the correlation of simvastatin's drug activities with the expression of DRCEs and non-DRCEs and found DRCEs had a significantly higher correlation with simvastatin's drug activities than non-DRCEs (t-test P < 0.001, Fig.	('simvastatin', 'Chemical', 'MESH:D019821', (44, 55))	('higher', 'PosReg', (153, 159))	('correlation', 'Interaction', (160, 171))	('DRCEs', 'Var', (127, 132))	('simvastatin', 'Chemical', 'MESH:D019821', (177, 188))
14734	29464864	TP53 mutation is the most frequent genetic alteration in BRCA, and in the 304 patients, ER and PR negative patients with a TP53 mutation had a high DRS to carboplatin, clodronic acid, and letrozole, indicating that the three drugs might be given treatment priority.	('patients', 'Species', '9606', (107, 115))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('clodronic acid', 'Chemical', 'MESH:D004002', (168, 182))	('carboplatin', 'Chemical', 'MESH:D016190', (155, 166))	('patients', 'Species', '9606', (78, 86))	('BRCA', 'Phenotype', 'HP:0003002', (57, 61))	('BRCA', 'Gene', '672', (57, 61))	('TP53', 'Gene', '7157', (123, 127))	('PR', 'Gene', '5241', (95, 97))	('mutation', 'Var', (128, 136))	('ER', 'Gene', '2099', (88, 90))	('letrozole', 'Chemical', 'MESH:D000077289', (188, 197))	('BRCA', 'Gene', (57, 61))	('DRS to carboplatin', 'MPA', (148, 166))	('TP53', 'Gene', (123, 127))
14737	29464864	As tamoxifen can target TP53, previous studies found that TP53 mutation can result in tamoxifen resistance in BRCA (Elledge et al., 1995).	('BRCA', 'Phenotype', 'HP:0003002', (110, 114))	('BRCA', 'Gene', '672', (110, 114))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (24, 28))	('BRCA', 'Gene', (110, 114))	('TP53', 'Gene', (58, 62))	('mutation', 'Var', (63, 71))	('tamoxifen', 'Chemical', 'MESH:D013629', (3, 12))	('result in', 'Reg', (76, 85))	('tamoxifen', 'Chemical', 'MESH:D013629', (86, 95))	('tamoxifen resistance', 'MPA', (86, 106))	('TP53', 'Gene', '7157', (24, 28))
14741	29464864	Consistent with this report, TP53 mutation triggered down-regulation of NEAT1 expression and resulted in poor response to tamoxifen (Fig.	('down-regulation', 'NegReg', (53, 68))	('tamoxifen', 'Chemical', 'MESH:D013629', (122, 131))	('mutation', 'Var', (34, 42))	('TP53', 'Gene', '7157', (29, 33))	('NEAT1', 'Gene', (72, 77))	('TP53', 'Gene', (29, 33))	('NEAT1', 'Gene', '283131', (72, 77))	('response to tamoxifen', 'MPA', (110, 131))	('regulation', 'biological_process', 'GO:0065007', ('58', '68'))
14749	29464864	The expression dysregulated DRCEs NEAT1_hsa-miR-130b_TP53INP1 and NEAT1_hsa-miR-18a_NBR1 are thus likely to lead to poor response to tamoxifen therapy for patients carrying TP53 mutations.	('NBR1', 'Gene', '4077', (84, 88))	('NEAT1', 'Gene', (34, 39))	('poor', 'NegReg', (116, 120))	('NEAT1', 'Gene', (66, 71))	('lead to', 'Reg', (108, 115))	('patients', 'Species', '9606', (155, 163))	('TP53', 'Gene', (173, 177))	('hsa-miR-18a', 'Gene', '406953', (72, 83))	('TP53INP1', 'Gene', (53, 61))	('response', 'MPA', (121, 129))	('TP53', 'Gene', (53, 57))	('tamoxifen', 'Chemical', 'MESH:D013629', (133, 142))	('hsa-miR-18a', 'Gene', (72, 83))	('NBR1', 'Gene', (84, 88))	('NEAT1', 'Gene', '283131', (34, 39))	('NEAT1', 'Gene', '283131', (66, 71))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', '7157', (173, 177))	('TP53INP1', 'Gene', '94241', (53, 61))	('miR-130b', 'Gene', (44, 52))	('miR-130b', 'Gene', '406920', (44, 52))	('mutations', 'Var', (178, 187))
14753	29464864	7D), indicating that NEAT1 expression could impact on drug response of BRCA patients.	('patients', 'Species', '9606', (76, 84))	('NEAT1', 'Gene', '283131', (21, 26))	('impact', 'Reg', (44, 50))	('NEAT1', 'Gene', (21, 26))	('BRCA', 'Phenotype', 'HP:0003002', (71, 75))	('BRCA', 'Gene', '672', (71, 75))	('expression', 'Var', (27, 37))	('drug', 'MPA', (54, 58))	('BRCA', 'Gene', (71, 75))
14761	29464864	Furthermore, we focused on cisplatin which is widely used to treat a variety of cancers and kills cells by directly or indirectly inducing apoptosis, DNA damage, and cell cycle arrest (Siddik, 2003).	('inducing', 'Reg', (130, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('apoptosis', 'biological_process', 'GO:0097194', ('139', '148'))	('apoptosis', 'biological_process', 'GO:0006915', ('139', '148'))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('cell cycle arrest', 'CPA', (166, 183))	('DNA damage', 'MPA', (150, 160))	('DNA', 'cellular_component', 'GO:0005574', ('150', '153'))	('cisplatin', 'Var', (27, 36))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('166', '183'))	('apoptosis', 'CPA', (139, 148))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
14765	29464864	Two DRCEs, NEAT1_hsa-miR-130b_TP53INP1 and NEAT1_hsa-miR-18a_NBR1, were found that may modulate the effect of tamoxifen therapy in BRCA patients with TP53 mutation.	('TP53INP1', 'Gene', (30, 38))	('TP53', 'Gene', (150, 154))	('NEAT1', 'Gene', (43, 48))	('NBR1', 'Gene', '4077', (61, 65))	('BRCA', 'Phenotype', 'HP:0003002', (131, 135))	('NEAT1', 'Gene', (11, 16))	('hsa-miR-18a', 'Gene', '406953', (49, 60))	('TP53', 'Gene', (30, 34))	('BRCA', 'Gene', '672', (131, 135))	('hsa-miR-18a', 'Gene', (49, 60))	('TP53', 'Gene', '7157', (150, 154))	('tamoxifen', 'Chemical', 'MESH:D013629', (110, 119))	('NEAT1', 'Gene', '283131', (43, 48))	('NBR1', 'Gene', (61, 65))	('NEAT1', 'Gene', '283131', (11, 16))	('BRCA', 'Gene', (131, 135))	('miR-130b', 'Gene', '406920', (21, 29))	('TP53', 'Gene', '7157', (30, 34))	('miR-130b', 'Gene', (21, 29))	('modulate', 'Reg', (87, 95))	('TP53INP1', 'Gene', '94241', (30, 38))	('patients', 'Species', '9606', (136, 144))	('mutation', 'Var', (155, 163))
14782	29625048	These integrated subtypes shared mutations, copy-number alterations, pathway commonalities, and micro-environment characteristics that appeared influential in the new molecular taxonomy, beyond any phenotypic contributions from tumor stage or tissue of origin.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))	('copy-number alterations', 'Var', (44, 67))
14796	29625048	Using aneuploidy (AN), CpG hypermethylation (METH), mRNA (MRNA), miRNA (MIR), and protein (P), the resultant number of groups ranged from 10 to 25 (Figure 1).	('hypermethylation', 'Var', (27, 43))	('METH', 'Chemical', '-', (45, 49))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('miRNA', 'MPA', (65, 70))	('mRNA', 'MPA', (52, 56))	('METH', 'molecular_function', 'GO:0008705', ('45', '49'))	('aneuploidy', 'Var', (6, 16))
14800	29625048	Over one-third of the samples displayed relatively sparse aneuploidy in AN7; these were enriched for THCA, LAML, PRAD, and THYM.	('aneuploidy', 'Var', (58, 68))	('amp', 'Chemical', 'MESH:D000249', (23, 26))	('AN7', 'Gene', (72, 75))	('THCA', 'Disease', (101, 105))
14803	29625048	Consistent with previous results, squamous (lung, head and neck, and esophageal) tumors clustered together by aneuploidy patterns, particularly 3p loss and 3q gain (AN3).	('3p loss', 'Var', (144, 151))	('3q gain', 'Var', (156, 163))	('esophageal) tumors clustered', 'Disease', 'MESH:D004938', (69, 97))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('neck', 'cellular_component', 'GO:0044326', ('59', '63'))
14805	29625048	Despite the exclusion of loci known to be involved in tissue-specific DNA methylation, tumors originating from the same organ often aggregated by cancer-type-specific hypermethylation (Figure 1B; Table S2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('DNA methylation', 'biological_process', 'GO:0006306', ('70', '85'))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('hypermethylation', 'Var', (167, 183))
14821	29625048	We used clustering of cluster assignments (COCA) algorithm to assess the overlap of platform-specific memberships from each of the five molecular platforms (aneuploidy, mRNA, miRNA, DNA methylation, and RPPA) (Figure 2A).	('COCA', 'Species', '289672', (43, 47))	('miRNA', 'MPA', (175, 180))	('mRNA', 'MPA', (169, 173))	('DNA', 'MPA', (182, 185))	('aneuploidy', 'Var', (157, 167))	('DNA methylation', 'biological_process', 'GO:0006306', ('182', '197'))	('DNA', 'cellular_component', 'GO:0005574', ('182', '185'))
14832	29625048	Eight iClusters were dominated by a single tumor type (C24:LAML, C11:LGG [IDH1 mut], C6:OV, C8:UCEC, C12:THCA, C16:PRAD, C26:LIHC, C14:LUAD).	('C26', 'CellLine', 'CVCL:0240', (121, 124))	('IDH1', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('C11', 'Gene', '51728', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('C24:', 'Var', (55, 59))	('IDH1', 'Gene', '3417', (74, 78))	('C12:THCA', 'Var', (101, 109))	('tumor', 'Disease', (43, 48))	('C11', 'Gene', (65, 68))
14833	29625048	Others contained tumors from similar or related cells or tissues: C28:pan-kidney (KIRC, KIRP), C15:SKCM/UVM-melanoma of the skin (SKCM) and eye (UVM), C23:GBM/LGG (IDH1wt), and C5:CNS/ endocrine.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('C15', 'Gene', '51316', (95, 98))	('C23:GBM/LGG', 'Gene', '4691', (151, 162))	('UVM-melanoma of the skin', 'Disease', (104, 128))	('IDH1', 'Gene', (164, 168))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('C15', 'Gene', (95, 98))	('IDH1', 'Gene', '3417', (164, 168))	('C28', 'Var', (66, 69))	('UVM-melanoma of the skin', 'Disease', 'MESH:D008545', (104, 128))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('C23:GBM/LGG', 'Gene', (151, 162))
14837	29625048	C4:pan-GI (CRC) was predominantly COAD and READ with chromosomal instability (CIN) and a distinct aneuploidy profile (Figure 2B).	('CIN', 'Disease', (78, 81))	('COAD', 'Disease', (34, 38))	('pan-GI', 'Var', (3, 9))	('CIN', 'Disease', 'MESH:D007674', (78, 81))	('COAD', 'Disease', 'MESH:D029424', (34, 38))	('chromosomal instability', 'Phenotype', 'HP:0040012', (53, 76))	('chromosomal instability', 'Disease', (53, 76))
14838	29625048	The pan-squamous cohort formed three iClusters (C10, C25, and C27).	('C10', 'Gene', '3226', (48, 51))	('C10', 'Gene', (48, 51))	('C25', 'Var', (53, 56))	('C27', 'Var', (62, 65))
14840	29625048	Even though all squamous iClusters were characterized by chromosome 3q amplification, unique features defined C10:pan-SCC (9p deletion) and C25:pan-SCC (Chr11 amp) (Figure 2B).	('amp', 'Chemical', 'MESH:D000249', (71, 74))	('SCC', 'Gene', (118, 121))	('C10', 'Gene', (110, 113))	('chromosome', 'cellular_component', 'GO:0005694', ('57', '67'))	('SCC', 'Gene', (148, 151))	('C10', 'Gene', '3226', (110, 113))	('SCC', 'Gene', '6317', (118, 121))	('SCC', 'Gene', '6317', (148, 151))	('amp', 'Chemical', 'MESH:D000249', (159, 162))	('9p deletion', 'Var', (123, 134))
14841	29625048	Among mixed tumor type iClusters, three were defined by copy-number alterations.	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('copy-number alterations', 'Var', (56, 79))
14842	29625048	C7:mixed was characterized by chr9 deletion, C2:BRCA (HER2 amp) mainly consisted of ERBB2-amplified tumors (BRCA, BLCA, and STAD), and C13:mixed (Chr8 del) contained highly aneuploid tumors, including a mixture of BRCA-Basal, UCEC (CN-high subtype), UCS, and BLCA.	('BRCA', 'Gene', '672', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('BRCA', 'Gene', (48, 52))	('amp', 'Chemical', 'MESH:D000249', (59, 62))	('amp', 'Chemical', 'MESH:D000249', (90, 93))	('BRCA', 'Gene', (214, 218))	('tumors', 'Disease', (183, 189))	('BLCA', 'Disease', (259, 263))	('aneuploid tumors', 'Disease', 'MESH:D000782', (173, 189))	('BRCA', 'Gene', (108, 112))	('UCEC', 'Disease', (226, 230))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('HER2', 'Gene', '2064', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('ERBB2', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('C13', 'Gene', (135, 138))	('tumors', 'Disease', (100, 106))	('deletion', 'Var', (35, 43))	('ERBB2', 'Gene', '2064', (84, 89))	('UCS', 'Disease', (250, 253))	('C13', 'Gene', '3229', (135, 138))	('BRCA', 'Gene', '672', (48, 52))	('HER2', 'Gene', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('BRCA', 'Gene', '672', (214, 218))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('aneuploid tumors', 'Disease', (173, 189))
14850	29625048	The silhouette widths ranged from -0.05 to 0.59, with the highest silhouette widths belonging to single-cancer-type-dominant iClusters (C11:LGG [IDH1 mut], C12:THCA, C16:PRAD, and C24:LAML).	('IDH1', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('IDH1', 'Gene', '3417', (145, 149))	('C11', 'Gene', '51728', (136, 139))	('C24:LAML', 'Var', (180, 188))	('C16:PRAD', 'Var', (166, 174))	('cancer', 'Disease', (104, 110))	('C12:THCA', 'Var', (156, 164))	('C11', 'Gene', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
14851	29625048	Interestingly, 6 of the 7 pan-organ system iClusters (pan-GI: C1, C4, C18; pan-SCC: C25, C27, and pan-kidney: C28) had similar ranges of silhouette widths to those of single cancer-type dominant iClusters, suggesting that these were as robust as the cancer-type-dominant iClusters.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('C27', 'Var', (89, 92))	('SCC', 'Gene', (79, 82))	('C18', 'Gene', (70, 73))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', (174, 180))	('SCC', 'Gene', '6317', (79, 82))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('C18', 'Gene', '27241', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
14852	29625048	iClusters driven by a shared specific chromosomal alteration (e.g., C13:mixed [chr8 del]) tended to compose multiple tumor types and appeared to have among the lowest silhouette widths, suggesting substantial molecular heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mixed [chr8 del]', 'Var', (72, 88))	('tumor', 'Disease', (117, 122))	('C13', 'Gene', (68, 71))	('C13', 'Gene', '3229', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
14869	29625048	Melanomas and lung adenocarcinomas have been shown to have relatively high mutation rates, and we observed similar results with C15:SKCM/UVM and C14:LUAD.	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('C15', 'Gene', (128, 131))	('C14:LUAD', 'Var', (145, 153))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (14, 34))	('mutation', 'MPA', (75, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('Melanomas and lung adenocarcinomas', 'Disease', 'MESH:D000077192', (0, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('C15', 'Gene', '51316', (128, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
14870	29625048	Mutation frequencies varied widely within the two iClusters with the most diverse tumor compositions: C3:mesenchymal (immune) and C20:mixed (stromal/immune).	('C20', 'Var', (130, 133))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
14877	29625048	Despite having very different cancer type compositions, the pan-squamous iClusters C10:pan-SCC, C25:pan-SCC (chr11 amp), and C27:pan-SCC (HPV) shared many pathway characteristics.	('amp', 'Chemical', 'MESH:D000249', (115, 118))	('SCC', 'Gene', '6317', (133, 136))	('HPV', 'Species', '10566', (138, 141))	('C10', 'Gene', (83, 86))	('SCC', 'Gene', '6317', (91, 94))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('SCC', 'Gene', (104, 107))	('C10', 'Gene', '3226', (83, 86))	('C25', 'Var', (96, 99))	('SCC', 'Gene', (91, 94))	('SCC', 'Gene', '6317', (104, 107))	('SCC', 'Gene', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('C27', 'Var', (125, 128))
14881	29625048	In addition, C20:mixed (stromal/immune) contained 32% Pan-GI samples and also displayed strong immune-related signaling.	('amp', 'Chemical', 'MESH:D000249', (62, 65))	('C20:mixed', 'Var', (13, 22))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))	('Pan-GI', 'Protein', (54, 60))
14882	29625048	Beta-catenin/cell-cell adhesion signaling appeared high in C4:pan-GI (CRC), C18:pan-GI (MSI), and C20:mixed (stromal/immune), but not in the smaller C1:STAD (EBV-CIMP).	('SI', 'Disease', 'None', (89, 91))	('C18', 'Gene', (76, 79))	('C4:pan-GI', 'Var', (59, 68))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('Beta-catenin/cell-cell adhesion signaling', 'MPA', (0, 41))	('C20:mixed', 'Var', (98, 107))	('C18', 'Gene', '27241', (76, 79))	('EBV', 'Species', '10376', (158, 161))	('high', 'PosReg', (51, 55))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('13', '31'))
14900	29625048	Interrogation of individual iClusters for their differentiating PARADIGM pathway features, canonical pathways, and gene programs amenable to drug targeting identified strong immune-related signaling features for both C3:mesenchymal (immune) and C20:mixed (stromal/immune) tumors, suggesting that they may share potential susceptibility to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('C20', 'Var', (245, 248))	('tumors', 'Disease', (272, 278))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('C3', 'Var', (217, 219))	('immune-related signaling', 'MPA', (174, 198))	('signaling', 'biological_process', 'GO:0023052', ('189', '198'))	('AR', 'Gene', '367', (65, 67))
14903	29625048	Compared to the seemingly discohesive groupings of the 17 heterogeneous iClusters, the 11 most homogeneous iClusters (C6:OV, C8:UCEC, C11:LGG [IDH1 mut], C12:THCA, C14:LUAD, C15:SKCM/UVM, C16:PRAD, C19:BRCA [luminal], C21:DLBC, C24:LAML, C26:LIHC) had higher silhouette widths, uniform tumor types, and histopathologies, but showed surprising degrees of spatial discohesion in the TumorMap.	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('C21', 'Gene', (218, 221))	('IDH1', 'Gene', (143, 147))	('C11', 'Gene', (134, 137))	('C24:LAML', 'Var', (228, 236))	('higher', 'PosReg', (252, 258))	('Tumor', 'Phenotype', 'HP:0002664', (381, 386))	('C16:PRAD', 'Var', (188, 196))	('C21', 'Gene', '79718', (218, 221))	('C19:BRCA', 'Gene', (198, 206))	('IDH1', 'Gene', '3417', (143, 147))	('tumor', 'Disease', (286, 291))	('C15', 'Gene', '51316', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('C15', 'Gene', (174, 177))	('C26', 'CellLine', 'CVCL:0240', (238, 241))	('silhouette widths', 'CPA', (259, 276))	('C11', 'Gene', '51728', (134, 137))	('C19:BRCA', 'Gene', '672', (198, 206))
14906	29625048	However, exceptions that challenge this concept have also become apparent from such notable examples as the unpredictable clinical responses to a potent BRAF inhibitor across diverse malignancies all expressing the same BRAF mutation.	('BRAF', 'Gene', '673', (153, 157))	('BRAF', 'Gene', (153, 157))	('BRAF', 'Gene', '673', (220, 224))	('malignancies', 'Disease', 'MESH:D009369', (183, 195))	('BRAF', 'Gene', (220, 224))	('amp', 'Chemical', 'MESH:D000249', (94, 97))	('mutation', 'Var', (225, 233))	('malignancies', 'Disease', (183, 195))
14931	29625048	Cervical squamous tumors clustered in high aneuploidy clusters AN1 and AN5.	('squamous tumors', 'Disease', (9, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('squamous tumors', 'Disease', 'MESH:D002294', (9, 24))	('AN1', 'Var', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
14932	29625048	These clusters were also enriched for other Pan-gyn tumors, including ovarian, high-copy number endometrial, and uterine carcinosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('high-copy number', 'Var', (79, 95))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('carcinosarcoma', 'Disease', 'MESH:D002296', (121, 135))	('ovarian', 'Disease', (70, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (113, 135))	('carcinosarcoma', 'Disease', (121, 135))
14933	29625048	Gynecologic tumors with fewer copy-number alterations including Luminal breast cancers and other endometrial tumors grouped separately in low aneuploidy clusters AN7 and AN8, respectively.	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('low aneuploidy clusters', 'Disease', 'MESH:D000782', (138, 161))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('copy-number alterations', 'Var', (30, 53))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('low aneuploidy clusters', 'Disease', (138, 161))	('breast cancers', 'Disease', 'MESH:D001943', (72, 86))	('breast cancers', 'Disease', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('endometrial tumors', 'Disease', 'MESH:D016889', (97, 115))	('tumors', 'Disease', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('breast cancers', 'Phenotype', 'HP:0003002', (72, 86))	('AN7', 'Var', (162, 165))	('endometrial tumors', 'Disease', (97, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
14944	29625048	To minimize the influence of variable tumor purity levels on a clustering result, we dichotomized the data using a beta-value of >= 0.3 to define positive DNA methylation and < 0.3 to specify lack of methylation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('positive DNA methylation', 'Var', (146, 170))	('DNA', 'cellular_component', 'GO:0005574', ('155', '158'))	('methylation', 'biological_process', 'GO:0032259', ('200', '211'))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('DNA methylation', 'biological_process', 'GO:0006306', ('155', '170'))
14946	29625048	For clustering analysis of tumors, we selected 3,139 CpG sites that were methylated at a beta-value of >= 0.3 in more than 10% of tumors within any of the 33 cancer types.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('methylated', 'Var', (73, 83))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
14949	29625048	The heatmap was generated using the original beta-values for the top one-third (n = 1,035) of the most variability methylated CpGs across tumors (Figure 1B).	('CpGs', 'Gene', (126, 130))	('methylated', 'Var', (115, 125))	('tumors', 'Disease', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
14950	29625048	We noted that a fraction of ESCA and STAD was found in METH9 with LUAD and PAAD, a result that may be related to the low tumor cellularity of the cancers in this cluster.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('METH', 'Chemical', '-', (55, 59))	('low tumor', 'Disease', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('ESCA', 'Disease', (28, 32))	('METH9', 'Var', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('METH', 'molecular_function', 'GO:0008705', ('55', '59'))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('low tumor', 'Disease', 'MESH:D009800', (117, 126))
14974	29625048	MIR5 contained OV, MIR8 BRCA, MIR12 LGG, MIR13 LIHC, MIR14 THCA, and MIR15 PRAD.	('MIR1', 'Gene', '79187', (69, 73))	('MIR1', 'Gene', (69, 73))	('BRCA', 'Gene', '672', (24, 28))	('MIR12', 'Gene', (30, 35))	('BRCA', 'Gene', (24, 28))	('MIR8', 'Var', (19, 23))	('MIR1', 'Gene', '79187', (53, 57))	('MIR12', 'Gene', '406905', (30, 35))	('MIR1', 'Gene', (53, 57))	('MIR1', 'Gene', '79187', (41, 45))	('MIR1', 'Gene', '79187', (30, 34))	('MIR1', 'Gene', (41, 45))	('MIR1', 'Gene', (30, 34))
14982	29625048	MIR6, the Pan-GI group, was largely COAD and STAD, but also had substantial PAAD, READ and ESCA, with smaller numbers of CHOL and LIHC.	('MIR6', 'Var', (0, 4))	('COAD', 'Disease', (36, 40))	('COAD', 'Disease', 'MESH:D029424', (36, 40))
15031	29254181	Pathological downstagings of the primary tumor and lymphovascular invasion were significantly improved in the NAC than in the Ctrl groups.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('NAC', 'Var', (110, 113))	('NAC', 'Chemical', '-', (110, 113))	('NAC', 'cellular_component', 'GO:0005854', ('110', '113'))	('improved', 'PosReg', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('lymphovascular invasion', 'CPA', (51, 74))
15033	29254181	Multivariate Cox regression analysis using an inverse probability of treatment weighted (IPTW) method showed that NAC was selected as an independent predictor for prolonged recurrence-free and cancer-specific survival.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('Cox', 'Gene', (13, 16))	('cancer', 'Disease', (193, 199))	('NAC', 'Var', (114, 117))	('NAC', 'Chemical', '-', (114, 117))	('NAC', 'cellular_component', 'GO:0005854', ('114', '117'))	('recurrence-free', 'CPA', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('prolonged', 'PosReg', (163, 172))	('IPTW', 'Chemical', '-', (89, 93))	('Cox', 'Gene', '1351', (13, 16))
15059	29254181	Additionally, the number of patients with lymphovascular invasion (LVI) was significantly lower in the NAC (n = 26, 26%) than in the Ctrl (n = 61, 46%) groups (P = 0.004).	('NAC', 'Var', (103, 106))	('NAC', 'Chemical', '-', (103, 106))	('NAC', 'cellular_component', 'GO:0005854', ('103', '106'))	('lower', 'NegReg', (90, 95))	('lymphovascular invasion', 'CPA', (42, 65))	('patients', 'Species', '9606', (28, 36))
15066	29254181	Due to the patients' selection for cisplatin-eligibility, the median estimated glomerular filtration rates (eGFRs) were significantly lower in patients who received GCarbo NAC than in those who received GCis therapy (67 vs. 55 mL/min/1.73 m2, respectively).	('lower', 'NegReg', (134, 139))	('NAC', 'Chemical', '-', (172, 175))	('GCarbo NAC', 'Var', (165, 175))	('eGFR', 'Gene', (108, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('NAC', 'cellular_component', 'GO:0005854', ('172', '175'))	('patients', 'Species', '9606', (143, 151))	('min/1', 'Gene', '966', (230, 235))	('estimated glomerular filtration rates', 'MPA', (69, 106))	('GCarbo', 'Chemical', '-', (165, 171))	('patients', 'Species', '9606', (11, 19))	('eGFR', 'Gene', '1956', (108, 112))	('GCis', 'Chemical', '-', (203, 207))	('glomerular filtration', 'biological_process', 'GO:0003094', ('79', '100'))	('min/1', 'Gene', (230, 235))
15070	29254181	Multivariate Cox regression analysis using an inverse probability of treatment weighting (IPTW) model revealed that the impact of NAC on intravesical RFS (P = 0.023; hazards ratio [HR], 0.52), visceral RFS (P = 0.021; HR, 0.57) and CSS (P = 0.016; HR, 0.48) was significant, whereas the impact on OS (P = 0.081; HR, 0.62) was not significant (Table 2, lower row).	('NAC', 'Var', (130, 133))	('CSS', 'MPA', (232, 235))	('NAC', 'Chemical', '-', (130, 133))	('IPTW', 'Chemical', '-', (90, 94))	('Cox', 'Gene', (13, 16))	('RFS', 'Chemical', '-', (150, 153))	('CSS', 'Chemical', '-', (232, 235))	('RFS', 'Chemical', '-', (202, 205))	('OS', 'Chemical', '-', (297, 299))	('intravesical', 'MPA', (137, 149))	('NAC', 'cellular_component', 'GO:0005854', ('130', '133'))	('Cox', 'Gene', '1351', (13, 16))
15082	29254181	Firstly, we thought that the rate of other cause of death might be higher in the NAC group.	('NAC', 'cellular_component', 'GO:0005854', ('81', '84'))	('death', 'Disease', 'MESH:D003643', (52, 57))	('death', 'Disease', (52, 57))	('NAC', 'Var', (81, 84))	('NAC', 'Chemical', '-', (81, 84))
15149	28152158	Among LN-positive (pN+) patients, there was no association between total LN yield and OS; however, positive and negative LN counts were independent predictors of OS (HR 1.27 per five positive LN, 95% CI 1.16, 1.39, p<0.001; HR 0.90 per five negative LN, 95% CI 0.82, 1.00, p=0.049).	('negative', 'NegReg', (112, 120))	('positive', 'Var', (99, 107))	('OS', 'Chemical', '-', (162, 164))	('OS', 'Chemical', '-', (86, 88))	('OS', 'Disease', (86, 88))	('patients', 'Species', '9606', (24, 32))
15189	28152158	Subgroup analyses confirmed that higher LN yield was associated with higher OS among pN0 patients (HR 0.86 per five LN, 95% CI 0.79, 0.94, p=0.001) but not pN+ patients (HR 1.01 per five LN, 95% CI 0.94, 1.08, p=0.89).	('patients', 'Species', '9606', (160, 168))	('higher', 'PosReg', (33, 39))	('OS', 'Chemical', '-', (76, 78))	('patients', 'Species', '9606', (89, 97))	('pN0', 'Var', (85, 88))	('LN yield', 'MPA', (40, 48))	('higher', 'PosReg', (69, 75))
15191	28152158	Increasing LN density was likewise an independent predictor of lower OS among the pN+ subgroup (HR 1.04 per 10% increase, 95% CI 1.01, 1.07, p=0.005).	('OS', 'Chemical', '-', (69, 71))	('increase', 'PosReg', (112, 120))	('lower OS', 'Disease', (63, 71))	('pN+', 'Var', (82, 85))
15205	28152158	Although LN density has been previously established to be an important prognostic factor in patients with pN+ urothelial carcinoma of the bladder, this concept has yet to be validated in the setting of UTUC.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (110, 145))	('patients', 'Species', '9606', (92, 100))	('urothelial carcinoma of the bladder', 'Disease', (110, 145))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (110, 145))	('pN+', 'Var', (106, 109))
15206	28152158	Previously, a small series showed that LN density >=30% was an independent predictor of higher cancer-specific mortality, although this finding was not replicated in a follow-up study.	('higher', 'PosReg', (88, 94))	('LN density >=30%', 'Var', (39, 55))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('>=30%', 'Var', (50, 55))
15209	28152158	Patients in our study with LN metastases were more likely to receive adjuvant chemotherapy, and while there is currently no level one evidence for a benefit of perioperative chemotherapy in patients with UTUC undergoing RNU, we did find an association between receipt of adjuvant chemotherapy and higher OS among pN+ but not pN0 patients.	('pN+', 'Var', (313, 316))	('patients', 'Species', '9606', (190, 198))	('Patients', 'Species', '9606', (0, 8))	('higher OS', 'Disease', (297, 306))	('metastases', 'Disease', (30, 40))	('patients', 'Species', '9606', (329, 337))	('OS', 'Chemical', '-', (304, 306))	('metastases', 'Disease', 'MESH:D009362', (30, 40))	('RNU', 'Chemical', '-', (220, 223))
15256	27785428	Recently, in a cohort of 236 consecutive Chinese patients treated with RNU, preoperative underweight was identified as an independent predictor of worse recurrence-free survivals (RFS) and CSS.	('CSS', 'Gene', (189, 192))	('RFS', 'Disease', 'MESH:D005198', (180, 183))	('worse', 'NegReg', (147, 152))	('RNU', 'Chemical', '-', (71, 74))	('CSS', 'Gene', '55907', (189, 192))	('RFS', 'Disease', (180, 183))	('patients', 'Species', '9606', (49, 57))	('underweight', 'Var', (89, 100))
15260	27785428	Similarly, a higher risk of recurrence should be considered in patients with specific risk factors for UTUC, such as hereditary nonpolyposis colorectal carcinoma (HNPCC) syndrome, and aristolochic acid or analgesic phenacetin exposure.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('UTUC', 'Disease', (103, 107))	('hereditary nonpolyposis colorectal carcinoma (HNPCC) syndrome', 'Disease', 'MESH:D003123', (117, 178))	('HNPCC', 'Phenotype', 'HP:0006716', (163, 168))	('phenacetin', 'Chemical', 'MESH:D010615', (215, 225))	('aristolochic acid', 'Chemical', 'MESH:C000228', (184, 201))	('aristolochic acid', 'Var', (184, 201))	('patients', 'Species', '9606', (63, 71))	('hereditary nonpolyposis colorectal carcinoma', 'Phenotype', 'HP:0006716', (117, 161))
15278	27785428	Ureteroscopy can help to appreciate tumor architecture (papillary vs. sessile) and biopsies can provide information regarding concomitant carcinoma in situ (CIS), variant histology, LVI or tumor necrosis.	('variant histology', 'Var', (163, 180))	('tumor necrosis', 'Disease', (189, 203))	('necrosis', 'biological_process', 'GO:0008220', ('195', '203'))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (36, 41))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (138, 155))	('necrosis', 'biological_process', 'GO:0070265', ('195', '203'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('necrosis', 'biological_process', 'GO:0019835', ('195', '203'))	('necrosis', 'biological_process', 'GO:0001906', ('195', '203'))	('carcinoma in situ', 'Disease', 'MESH:D002278', (138, 155))	('concomitant', 'Disease', (126, 137))	('LVI', 'Disease', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('tumor', 'Disease', (189, 194))	('necrosis', 'biological_process', 'GO:0008219', ('195', '203'))	('CIS', 'Phenotype', 'HP:0030075', (157, 160))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor necrosis', 'Disease', 'MESH:D009336', (189, 203))	('carcinoma in situ', 'Disease', (138, 155))
15286	27785428	demonstrated that MSI positive status was associated with better outcomes in T2-T3N0M0 UTUC patients.	('T2-T3N0M0', 'Var', (77, 86))	('better', 'PosReg', (58, 64))	('MSI', 'Disease', 'None', (18, 21))	('patients', 'Species', '9606', (92, 100))	('MSI', 'Disease', (18, 21))
15287	27785428	Epigenetic changes are common events in cancer and DNA methylation is usually responsible for the repression of gene transcription.	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('cancer', 'Disease', (40, 46))	('DNA methylation', 'biological_process', 'GO:0006306', ('51', '66'))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Epigenetic changes', 'Var', (0, 18))
15289	27785428	also demonstrated that low methylation of VIM promoter predicted worse CSS.	('VIM', 'Gene', (42, 45))	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('CSS', 'Gene', '55907', (71, 74))	('methylation', 'MPA', (27, 38))	('low', 'Var', (23, 26))	('VIM', 'Gene', '7431', (42, 45))	('CSS', 'Gene', (71, 74))
15290	27785428	Conversely, in a panel of different genes, the methylation of promoters predicted higher T stage, higher grade, LN metastases, bladder recurrence and worse CSS in a large cohort of 687 UTUC patients.	('CSS', 'Gene', '55907', (156, 159))	('metastases', 'Disease', (115, 125))	('T stage', 'CPA', (89, 96))	('CSS', 'Gene', (156, 159))	('patients', 'Species', '9606', (190, 198))	('metastases', 'Disease', 'MESH:D009362', (115, 125))	('methylation', 'Var', (47, 58))	('higher', 'PosReg', (82, 88))	('higher grade', 'CPA', (98, 110))	('methylation', 'biological_process', 'GO:0032259', ('47', '58'))	('bladder recurrence', 'CPA', (127, 145))
15291	27785428	Fibroblast growth factor receptor 3 (FGFR3) and TP53 mutations are the most frequent somatic mutations observed in urothelial carcinoma.	('FGFR3', 'Gene', (37, 42))	('Fibroblast growth factor', 'molecular_function', 'GO:0005104', ('0', '24'))	('TP53', 'Gene', '7157', (48, 52))	('urothelial carcinoma', 'Disease', (115, 135))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('FGFR3', 'Gene', '2261', (37, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('Fibroblast growth factor receptor 3', 'Gene', (0, 35))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (115, 135))	('Fibroblast growth factor receptor 3', 'Gene', '2261', (0, 35))
15292	27785428	FGFR3 mutations occur in 50% of all primary bladder tumours and are associated with low stage and grade tumors as well as a good prognosis.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('associated', 'Reg', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('FGFR3', 'Gene', (0, 5))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('bladder tumours', 'Disease', (44, 59))	('low', 'Disease', (84, 87))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('bladder tumours', 'Disease', 'MESH:D001749', (44, 59))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
15293	27785428	confirmed that in UTUC these mutations were also associated with lower stage and better survival in patients with invasive tumors.	('survival', 'CPA', (88, 96))	('invasive tumors', 'Disease', (114, 129))	('better', 'PosReg', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('invasive tumors', 'Disease', 'MESH:D009369', (114, 129))	('mutations', 'Var', (29, 38))	('lower', 'NegReg', (65, 70))	('patients', 'Species', '9606', (100, 108))	('stage', 'CPA', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
15302	27785428	Preoperative neutrophil to lymphocyte ratio was significantly associated with worse pathological features and was an independent risk factor of disease recurrence and cancer-specific mortality.	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('neutrophil', 'Var', (13, 23))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (167, 173))
15340	27785428	A high risk of UTUC recurrence is predictable in active smokers and patients with UTUC risk factors such as HNPCC syndrome, and aristolochic acid or analgesic phenacetin exposure.	('HNPCC syndrome', 'Disease', (108, 122))	('phenacetin', 'Chemical', 'MESH:D010615', (159, 169))	('HNPCC', 'Phenotype', 'HP:0006716', (108, 113))	('aristolochic acid', 'Var', (128, 145))	('HNPCC syndrome', 'Disease', 'MESH:D013577', (108, 122))	('aristolochic acid', 'Chemical', 'MESH:C000228', (128, 145))	('patients', 'Species', '9606', (68, 76))	('UTUC', 'Disease', (15, 19))
15396	21792316	Overexpression of P53 detected by immunohistochemistry (IHC) which infers mutation of TP53 gene has been demonstrated to be a predictor of poor survival in patients with advanced bladder cancer.	('patients', 'Species', '9606', (156, 164))	('bladder cancer', 'Phenotype', 'HP:0009725', (179, 193))	('mutation', 'Var', (74, 82))	('TP53', 'Gene', '7157', (86, 90))	('TP53', 'Gene', (86, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (179, 193))	('bladder cancer', 'Disease', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('P53', 'Gene', (18, 21))	('P53', 'Gene', '7157', (18, 21))	('P53', 'Gene', (87, 90))	('P53', 'Gene', '7157', (87, 90))
15397	21792316	In a report of 90 patients undergoing neoadjuvant M-VAC chemotherapy, those who harbored mutant P53 were three times more likely to die from their disease than those with wild-type P53.	('M-VAC', 'Chemical', '-', (50, 55))	('P53', 'Gene', (96, 99))	('P53', 'Gene', (181, 184))	('P53', 'Gene', '7157', (181, 184))	('patients', 'Species', '9606', (18, 26))	('P53', 'Gene', '7157', (96, 99))	('mutant', 'Var', (89, 95))
15401	21792316	A recent report from a German group on the gene expression analysis of chemotherapy response modifiers multidrug resistance gene 1 (MDR1) and excision repair cross-complementing 1 (ERCC1) performed on tumor samples from patients undergoing adjuvant chemotherapy for locally advanced bladder cancer showed that expression of MDR1 and ERCC1 were independently associated with overall progression-free survival (PFS) with relative risk of 2.9 and 2.24, respectively.	('associated', 'Reg', (358, 368))	('patients', 'Species', '9606', (220, 228))	('progression-free', 'Disease', (382, 398))	('excision repair cross-complementing 1', 'Gene', '2067', (142, 179))	('tumor', 'Disease', (201, 206))	('MDR1', 'Gene', '5243', (132, 136))	('MDR1', 'Gene', '5243', (324, 328))	('gene expression', 'biological_process', 'GO:0010467', ('43', '58'))	('ERCC1', 'Gene', '2067', (333, 338))	('ERCC1', 'Gene', '2067', (181, 186))	('bladder cancer', 'Disease', 'MESH:D001749', (283, 297))	('excision repair cross-complementing 1', 'Gene', (142, 179))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('MDR', 'molecular_function', 'GO:0004745', ('132', '135'))	('bladder cancer', 'Disease', (283, 297))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('bladder cancer', 'Phenotype', 'HP:0009725', (283, 297))	('ERCC1', 'Gene', (333, 338))	('ERCC1', 'Gene', (181, 186))	('expression', 'Var', (310, 320))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('MDR1', 'Gene', (132, 136))	('MDR', 'molecular_function', 'GO:0004745', ('324', '327'))	('MDR1', 'Gene', (324, 328))
15402	21792316	In another study of 57 patients with advanced bladder cancer treated with cisplatin-based regimen, the median survival was significantly longer in patients with low ERCC1 levels.	('ERCC1', 'Gene', '2067', (165, 170))	('ERCC1', 'Gene', (165, 170))	('patients', 'Species', '9606', (23, 31))	('men', 'Species', '9606', (94, 97))	('longer', 'PosReg', (137, 143))	('bladder cancer', 'Disease', 'MESH:D001749', (46, 60))	('bladder cancer', 'Disease', (46, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('patients', 'Species', '9606', (147, 155))	('low', 'Var', (161, 164))	('bladder cancer', 'Phenotype', 'HP:0009725', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
15426	21792316	The most recent update, after 8 years of follow-up, showed a statistically significant 16% reduction in the risk for death in patients who received neoadjuvant CMV prior to radiotherapy and/or cystectomy; this corresponds to an increase in 3-year survival from 50% to 56%, an increase in 10-year survival from 30% to 36%, and an increase in median survival time of 7 months (from 37 to 44 months) in CMV-treated patients compared with those treated with local therapy only.	('CMV', 'Chemical', '-', (400, 403))	('CMV', 'Chemical', '-', (160, 163))	('increase', 'PosReg', (276, 284))	('increase', 'PosReg', (228, 236))	('reduction', 'NegReg', (91, 100))	('death', 'Disease', 'MESH:D003643', (117, 122))	('death', 'Disease', (117, 122))	('patients', 'Species', '9606', (126, 134))	('increase', 'PosReg', (329, 337))	('patients', 'Species', '9606', (412, 420))	('CMV', 'Var', (160, 163))	('CMV-treated', 'Var', (400, 411))
15439	21792316	In this Phase II trial, 27 eligible patients with T2-T4, N0, or any T, N1-3 bladder cancer were treated with three cycles of nab-paclitaxel along with gemcitabine and carboplatin, followed by cystectomy.	('bladder cancer', 'Disease', (76, 90))	('nab', 'Chemical', '-', (125, 128))	('gemcitabine', 'Chemical', 'MESH:C056507', (151, 162))	('patients', 'Species', '9606', (36, 44))	('carboplatin', 'Chemical', 'MESH:D016190', (167, 178))	('T2-T4', 'Var', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('paclitaxel', 'Chemical', 'MESH:D017239', (129, 139))	('nab-paclitaxel', 'Var', (125, 139))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))
15468	21792316	In an Italian multicenter randomized Phase III trial, patients with pT2G3, pT3-4, N0-2 transitional cell bladder carcinoma, after radical cystectomy, were assigned to four cycles of GC or observation followed by same chemotherapy at progression.	('GC', 'Chemical', '-', (182, 184))	('patients', 'Species', '9606', (54, 62))	('pT2G3', 'Var', (68, 73))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (105, 122))	('transitional cell bladder carcinoma', 'Phenotype', 'HP:0006740', (87, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('bladder carcinoma', 'Disease', (105, 122))	('bladder carcinoma', 'Disease', 'MESH:D001749', (105, 122))
15478	21792316	At a median follow-up of 51 months, there was a statistically significant increase in OS with chemotherapy compared with observation.	('OS', 'Chemical', '-', (86, 88))	('increase', 'PosReg', (74, 82))	('chemotherapy', 'Var', (94, 106))
15483	21792316	In patients with pT2, N0 urothelial bladder cancer, following cystectomy with observation seems to be a rational approach while for those patients with pT3-4 and/or node-positive disease, following cystectomy with four cycles of chemotherapy with M-VAC or GC appears reasonable since these regimens have shown significant activity in metastatic setting.	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('bladder cancer', 'Phenotype', 'HP:0009725', (36, 50))	('pT2', 'Var', (17, 20))	('M-VAC', 'Chemical', '-', (247, 252))	('patients', 'Species', '9606', (3, 11))	('urothelial bladder cancer', 'Disease', (25, 50))	('men', 'Species', '9606', (294, 297))	('GC', 'Chemical', '-', (256, 258))	('nab', 'Chemical', '-', (272, 275))	('patients', 'Species', '9606', (138, 146))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (25, 50))
15493	21792316	M-VAC regimen was associated with a greater toxicity, particularly leukopenia, mucositis, neutropenic fever, and drug-related mortality.	('leukopenia', 'Phenotype', 'HP:0001882', (67, 77))	('men', 'Species', '9606', (10, 13))	('mucositis', 'Disease', 'MESH:D052016', (79, 88))	('M-VAC', 'Chemical', '-', (0, 5))	('leukopenia', 'Disease', (67, 77))	('M-VAC', 'Var', (0, 5))	('neutropenic fever', 'Disease', 'MESH:D005334', (90, 107))	('fever', 'Phenotype', 'HP:0001945', (102, 107))	('leukopenia', 'Disease', 'MESH:D007970', (67, 77))	('neutropenic fever', 'Disease', (90, 107))	('toxicity', 'Disease', 'MESH:D064420', (44, 52))	('mucositis', 'Disease', (79, 88))	('toxicity', 'Disease', (44, 52))
15494	21792316	Response rates were superior in the M-VAC arm compared with the single-agent cisplatin arm (39% vs 12%) PFS (10.0 vs 4.3 months) and OS (12.5 vs 8.2 months) were significantly greater for the combined therapy arm.	('M-VAC', 'Chemical', '-', (36, 41))	('M-VAC', 'Var', (36, 41))	('greater', 'PosReg', (176, 183))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('OS', 'Chemical', '-', (133, 135))
15495	21792316	In another randomized trial with 110 patients, M-VAC was compared with a regimen consisting of cisplatin, cyclophosphamide, and doxorubin (CISCA); M-VAC arm showed significantly higher response rate (65% vs 46%) and median survival (48 vs 36 weeks) compared with CISCA.	('M-VAC', 'Chemical', '-', (47, 52))	('patients', 'Species', '9606', (37, 45))	('M-VAC', 'Chemical', '-', (147, 152))	('men', 'Species', '9606', (77, 80))	('higher', 'PosReg', (178, 184))	('doxorubin', 'Chemical', 'MESH:D004317', (128, 137))	('M-VAC', 'Var', (147, 152))	('response', 'CPA', (185, 193))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (106, 122))	('CISCA', 'Chemical', '-', (139, 144))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('CISCA', 'Chemical', '-', (263, 268))
15499	21792316	In the subsequent update with more than 7 years of follow-up, high dose M-VAC showed a border-line statistically significant relative reduction in the risk of death at 5 years (21.8% vs 13.5%; hazard ratio = 0.76) compared with M-VAC.	('M-VAC', 'Chemical', '-', (228, 233))	('high dose', 'Var', (62, 71))	('reduction', 'NegReg', (134, 143))	('death', 'Disease', 'MESH:D003643', (159, 164))	('M-VAC', 'Chemical', '-', (72, 77))	('death', 'Disease', (159, 164))
15626	33181667	Thus, high expression of TGF-beta2 not only facilitates the prognosis in CRC patients, but also may provide a new target for the treatment of CRC.	('CRC', 'Disease', (73, 76))	('TGF-beta2', 'Gene', '7042', (25, 34))	('patients', 'Species', '9606', (77, 85))	('high', 'Var', (6, 10))	('prognosis', 'CPA', (60, 69))	('facilitates', 'PosReg', (44, 55))	('TGF-beta2', 'Gene', (25, 34))	('CRC', 'Disease', (142, 145))
15629	33181667	Immunotherapy has provided antitumor effects in malignant melanoma and non-small cell lung cancer by targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4), and inhibitors of programmed death 1 (PD-1) receptor, and programmed death ligand 1 (PD-L1).	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (71, 97))	('PD-1', 'Gene', (202, 206))	('PD-1', 'Gene', '5133', (202, 206))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (75, 97))	('inhibitors', 'Var', (168, 178))	('lung cancer', 'Disease', (86, 97))	('malignant melanoma', 'Phenotype', 'HP:0002861', (48, 66))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('programmed death 1', 'Gene', '5133', (182, 200))	('programmed death ligand 1', 'Gene', (222, 247))	('malignant melanoma', 'Disease', 'MESH:D008545', (48, 66))	('programmed death 1', 'Gene', (182, 200))	('CTLA4', 'Gene', '1493', (156, 161))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', (111, 154))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', '1493', (111, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('ligand', 'molecular_function', 'GO:0005488', ('239', '245'))	('CTLA4', 'Gene', (156, 161))	('PD-L1', 'Gene', (249, 254))	('programmed death ligand 1', 'Gene', '29126', (222, 247))	('tumor', 'Disease', (31, 36))	('malignant melanoma', 'Disease', (48, 66))	('PD-L1', 'Gene', '29126', (249, 254))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
15641	33181667	Inhibition of TGF-beta signaling prevents metastasis or further development of certain advanced tumors such as CRC and gastric cancer, while TGF-beta1 can impair immune cell responsiveness and promote angiogenesis.	('promote', 'PosReg', (193, 200))	('angiogenesis', 'CPA', (201, 213))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TGF-beta', 'Gene', (14, 22))	('tumors', 'Disease', (96, 102))	('gastric cancer', 'Disease', (119, 133))	('TGF-beta', 'Gene', (141, 149))	('angiogenesis', 'biological_process', 'GO:0001525', ('201', '213'))	('impair', 'NegReg', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('TGF-beta1', 'Gene', (141, 150))	('immune cell responsiveness', 'CPA', (162, 188))	('Inhibition', 'Var', (0, 10))	('metastasis', 'CPA', (42, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('prevents', 'NegReg', (33, 41))	('CRC', 'Disease', (111, 114))	('TGF-beta1', 'Gene', '7040', (141, 150))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('TGF-beta', 'Gene', '7039', (14, 22))	('TGF-beta', 'Gene', '7039', (141, 149))	('signaling', 'biological_process', 'GO:0023052', ('23', '32'))	('further development', 'CPA', (56, 75))
15676	33181667	This analysis documented that upregulation of TGF- beta2 was strongly related to the poor prognosis of patients with gastric cancer (OS HR = 1.88 (95%CI: 1.57-2.24), P < .0001; PPS HR = 2.51 (95%CI: 2.01-3.15), P < .0001; 209908_s_at), breast cancer (OS HR = 0.77 (95%CI: 0.61-0.99), P = .039; no-distance survival HR = 0.78 (95%CI: 0.62-0.99), P = .043; 209908_s_at) (2K-L), lung cancer (OS HR = 1.23 (1.08-1.4), P = .0013, 220407_s_at; PPS HR = 1.34 (1.04-1.73), P = .025, 220406_at), and Ovarian cancer (OS HR = 1.18 (1.04-1.34), P = .013, 209909_s_at; progression-free survival, progression-free survival, HR = 1.22 (1.07-1.39), P = .0036, 220407_s_at;) (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (376, 387))	('TGF- beta2', 'Gene', '7042', (46, 56))	('patients', 'Species', '9606', (103, 111))	('gastric cancer', 'Disease', (117, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (376, 387))	('220407_s_at', 'Var', (644, 655))	('breast cancer', 'Phenotype', 'HP:0003002', (236, 249))	('209909_s_at', 'Var', (543, 554))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (491, 505))	('TGF- beta2', 'Gene', (46, 56))	('cancer', 'Disease', (381, 387))	('cancer', 'Disease', (125, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('breast cancer', 'Disease', 'MESH:D001943', (236, 249))	('cancer', 'Disease', (499, 505))	('breast cancer', 'Disease', (236, 249))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (499, 505))	('upregulation', 'PosReg', (30, 42))	('lung cancer', 'Disease', (376, 387))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (499, 505))
15677	33181667	Conversely, the expression of TGF-beta2 appeared as a protective factor in the prostate, breast cancer, colorectal, blood cancer, brain, gastric, lung, and ovarian cancers.	('ovarian cancers', 'Phenotype', 'HP:0100615', (156, 171))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('breast cancer', 'Disease', (89, 102))	('TGF-beta2', 'Gene', (30, 39))	('prostate', 'Disease', (79, 87))	('gastric', 'Disease', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('TGF-beta2', 'Gene', '7042', (30, 39))	('blood cancer', 'Phenotype', 'HP:0001909', (116, 128))	('ovarian cancers', 'Disease', (156, 171))	('ovarian cancers', 'Disease', 'MESH:D010051', (156, 171))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('expression', 'Var', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung', 'Disease', (146, 150))	('brain', 'Disease', (130, 135))	('colorectal, blood cancer', 'Disease', 'MESH:D015179', (104, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
15695	33181667	Data on the expression of markers of DCs (CD1C, NRP1, and ITGAX) indicate that high TGF-beta2 expression increases DC infiltration in COAD.	('CD1C', 'Gene', '911', (42, 46))	('DC infiltration', 'MPA', (115, 130))	('TGF-beta2', 'Gene', '7042', (84, 93))	('TGF-beta2', 'Gene', (84, 93))	('ITGAX', 'Gene', (58, 63))	('NRP', 'biological_process', 'GO:0085015', ('48', '51'))	('NRP1', 'Gene', '8829', (48, 52))	('NRP1', 'Gene', (48, 52))	('high', 'Var', (79, 83))	('ITGAX', 'Gene', '3687', (58, 63))	('CD1C', 'Gene', (42, 46))	('increases', 'PosReg', (105, 114))
15700	33181667	The present work demonstrated that TGF-beta2 expression correlates with the prognosis of patients with multiple types of cancer, and particularly strong correlation is present between high TGF-beta2 expression and the prognosis of CRC patients.	('TGF-beta2', 'Gene', '7042', (35, 44))	('TGF-beta2', 'Gene', (35, 44))	('expression', 'MPA', (199, 209))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('patients', 'Species', '9606', (235, 243))	('CRC', 'Disease', (231, 234))	('patients', 'Species', '9606', (89, 97))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('TGF-beta2', 'Gene', '7042', (189, 198))	('cancer', 'Disease', (121, 127))	('TGF-beta2', 'Gene', (189, 198))	('high', 'Var', (184, 188))
15708	33181667	Variations in TGF-beta2 expression in a range of different cancers may be related to discrepancies in data collection methods between individual studies or differences in underlying biological mechanisms.	('related', 'Reg', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Variations', 'Var', (0, 10))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('TGF-beta2', 'Gene', (14, 23))	('cancers', 'Disease', (59, 66))	('TGF-beta2', 'Gene', '7042', (14, 23))
15709	33181667	In the database used in the current work, a correlation between high TGF-beta2 expression and poor prognosis of CRC was observed.	('high', 'Var', (64, 68))	('expression', 'MPA', (79, 89))	('CRC', 'Disease', (112, 115))	('TGF-beta2', 'Gene', '7042', (69, 78))	('TGF-beta2', 'Gene', (69, 78))
15771	31278255	We identified FGFR3 mutations in 11/37 (29.7%) (Fig.	('FGFR3', 'Gene', (14, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('mutations', 'Var', (20, 29))	('FGFR3', 'Gene', '2261', (14, 19))
15772	31278255	In contrast, we found no significant difference in the prevalence of mutations in chromatin modifying (KMT2D, ARID1A, KDM6A), receptor tyrosine kinase pathway (PIK3CA, HRAS), transcription factor (RXRA, KLF5, ELF3), and cell cycle regulation (TP53, RB1, CDKN1A, CDKN2A) genes between our UTUC and TCGA UCB cohorts (Fig.	('CDKN2A', 'Gene', '1029', (262, 268))	('RXRA', 'Gene', (197, 201))	('KLF5', 'Gene', '688', (203, 207))	('tyrosine', 'Chemical', 'MESH:D014443', (135, 143))	('transcription factor', 'molecular_function', 'GO:0000981', ('175', '195'))	('TP53', 'Gene', (243, 247))	('KMT2D', 'Gene', (103, 108))	('ELF3', 'Gene', (209, 213))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('220', '241'))	('KLF5', 'Gene', (203, 207))	('PIK3CA', 'Gene', '5290', (160, 166))	('KDM6A', 'Gene', '7403', (118, 123))	('CDKN1A', 'Gene', (254, 260))	('CDKN1A', 'Gene', '1026', (254, 260))	('transcription', 'biological_process', 'GO:0006351', ('175', '188'))	('mutations', 'Var', (69, 78))	('RB1', 'Gene', (249, 252))	('chromatin', 'cellular_component', 'GO:0000785', ('82', '91'))	('ARID1A', 'Gene', (110, 116))	('KDM6A', 'Gene', (118, 123))	('TP53', 'Gene', '7157', (243, 247))	('KMT2D', 'Gene', '8085', (103, 108))	('HRAS', 'Gene', '3265', (168, 172))	('CDKN2A', 'Gene', (262, 268))	('PIK3CA', 'Gene', (160, 166))	('RXRA', 'Gene', '6256', (197, 201))	('HRAS', 'Gene', (168, 172))	('ARID1A', 'Gene', '8289', (110, 116))	('ELF3', 'Gene', '1999', (209, 213))	('RB1', 'Gene', '5925', (249, 252))
15774	31278255	This signature is characterized by high numbers of small indels at mono/polynucleotide repeats and is associated with defective MMR (Fig.	('associated', 'Reg', (102, 112))	('MMR', 'Disease', (128, 131))	('mono', 'Chemical', 'MESH:C106553', (67, 71))	('polynucleotide', 'Chemical', 'MESH:D011119', (72, 86))	('mono/polynucleotide repeats', 'Var', (67, 94))	('MMR', 'biological_process', 'GO:0006298', ('128', '131'))
15775	31278255	The association between germline mutations in MMR genes that cause microsatellite instability (MSI) and Lynch syndrome and increased susceptibility to the development of UTUC is well established.	('cause', 'Reg', (61, 66))	('Lynch syndrome', 'Disease', (104, 118))	('MSI', 'Disease', (95, 98))	('Lynch syndrome', 'Disease', 'MESH:D003123', (104, 118))	('susceptibility', 'Reg', (133, 147))	('germline mutations', 'Var', (24, 42))	('MSI', 'Disease', 'None', (95, 98))	('MMR', 'biological_process', 'GO:0006298', ('46', '49'))	('microsatellite', 'MPA', (67, 81))	('MMR genes', 'Gene', (46, 55))
15802	31278255	We detected outlier FGFR3 mRNA expression in 14/32 (43.7%) of the tumors in our UTUC (WCM, BCM-MDA) cohorts (Fig.	('FGFR3', 'Gene', '2261', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('FGFR3', 'Gene', (20, 25))	('tumors', 'Disease', (66, 72))	('mRNA', 'Var', (26, 30))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('FGFR', 'molecular_function', 'GO:0005007', ('20', '24'))
15803	31278255	We identified nine activating missense mutations in these tumors.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('missense mutations', 'Var', (30, 48))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('activating', 'Reg', (19, 29))
15808	31278255	We reanalyzed a previously published dataset of mRNA expression from the RT-112 UC cell line following doxycycline (dox)-inducible short hairpin RNA (shRNA) knockdown of FGFR3.	('doxycycline', 'Chemical', 'MESH:D004318', (103, 114))	('dox', 'Chemical', 'MESH:D004318', (103, 106))	('FGFR3', 'Gene', '2261', (170, 175))	('FGFR3', 'Gene', (170, 175))	('knockdown', 'Var', (157, 166))	('dox', 'Chemical', 'MESH:D004318', (116, 119))	('mRNA expression', 'MPA', (48, 63))	('RNA', 'cellular_component', 'GO:0005562', ('145', '148'))	('FGFR', 'molecular_function', 'GO:0005007', ('170', '174'))
15809	31278255	We found that several IFNG response genes including BST2, MX2, IRF9, GBP2 were upregulated after FGFR3 knockdown (Fig.	('GBP2', 'Gene', '2634', (69, 73))	('MX2', 'Gene', '4600', (58, 61))	('BST2', 'Gene', (52, 56))	('IRF9', 'Gene', (63, 67))	('IFNG', 'Gene', '3458', (22, 26))	('FGFR3', 'Gene', '2261', (97, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('97', '101'))	('IFNG', 'Gene', (22, 26))	('MX2', 'Gene', (58, 61))	('FGFR3', 'Gene', (97, 102))	('upregulated', 'PosReg', (79, 90))	('IRF9', 'Gene', '10379', (63, 67))	('BST2', 'Gene', '684', (52, 56))	('knockdown', 'Var', (103, 112))	('GBP2', 'Gene', (69, 73))
15813	31278255	These cell lines harbor FGFR3 fusions (RT-112, RT-4: FGFR3-TACC3; SW780: FGFR3-BAIAP2L1) resulting in constitutively activated FGFR3 signaling.	('TACC3', 'Gene', '10460', (59, 64))	('FGFR3', 'Gene', '2261', (24, 29))	('TACC3', 'Gene', (59, 64))	('fusions', 'Var', (30, 37))	('FGFR3', 'Gene', '2261', (73, 78))	('FGFR3', 'Gene', (127, 132))	('FGFR3', 'Gene', (53, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('BAIAP2L1', 'Gene', (79, 87))	('FGFR3', 'Gene', '2261', (127, 132))	('signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('FGFR3', 'Gene', '2261', (53, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('127', '131'))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))	('activated', 'PosReg', (117, 126))	('FGFR', 'molecular_function', 'GO:0005007', ('73', '77'))	('BAIAP2L1', 'Gene', '55971', (79, 87))	('FGFR3', 'Gene', (24, 29))	('SW780', 'CellLine', 'CVCL:1728', (66, 71))	('FGFR3', 'Gene', (73, 78))
15817	31278255	Previous studies identified a link between Lynch syndrome caused by germline mutations in MMR genes and UTUC.	('caused', 'Reg', (58, 64))	('MMR', 'Gene', (90, 93))	('Lynch syndrome', 'Disease', (43, 57))	('germline mutations', 'Var', (68, 86))	('MMR', 'biological_process', 'GO:0006298', ('90', '93'))	('Lynch syndrome', 'Disease', 'MESH:D003123', (43, 57))	('UTUC', 'Disease', (104, 108))
15829	31278255	We observed a consistent increase in BST2 following pharmacologic FGFR3 inhibition in three different UC cell lines that harbor activating FGFR3 fusions.	('increase', 'PosReg', (25, 33))	('FGFR3', 'Gene', '2261', (66, 71))	('BST2', 'Gene', '684', (37, 41))	('activating', 'PosReg', (128, 138))	('inhibition', 'NegReg', (72, 82))	('FGFR3', 'Gene', '2261', (139, 144))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('FGFR3', 'Gene', (66, 71))	('BST2', 'Gene', (37, 41))	('fusions', 'Var', (145, 152))	('FGFR', 'molecular_function', 'GO:0005007', ('139', '143'))	('FGFR3', 'Gene', (139, 144))
15830	31278255	BST2 is a viral restriction factor which is canonically induced by interferon.This is also consistent with the role of FGFR3 in blocking the Y701 tyrosine phosphorylation required for STAT1 activation.	('BST2', 'Gene', (0, 4))	('blocking', 'NegReg', (128, 136))	('phosphorylation', 'biological_process', 'GO:0016310', ('155', '170'))	('tyrosine', 'Chemical', 'MESH:D014443', (146, 154))	('FGFR3', 'Gene', (119, 124))	('STAT1', 'Gene', (184, 189))	('Y701', 'Var', (141, 145))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))	('BST2', 'Gene', '684', (0, 4))	('STAT1', 'Gene', '6772', (184, 189))	('FGFR3', 'Gene', '2261', (119, 124))
15831	31278255	Taken together, these findings provide putative mechanistic links between FGFR3 and IFNG signaling and suggest that FGFR3 inhibition potentially remodels the immune contexture of UTUC by upregulating interferon response genes to reverse its T-cell-depleted phenotype.	('FGFR3', 'Gene', (74, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('116', '120'))	('IFNG', 'Gene', '3458', (84, 88))	('inhibition', 'Var', (122, 132))	('interferon', 'Gene', (200, 210))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('FGFR3', 'Gene', (116, 121))	('IFNG', 'Gene', (84, 88))	('FGFR3', 'Gene', '2261', (74, 79))	('upregulating', 'PosReg', (187, 199))	('remodels', 'Reg', (145, 153))	('FGFR3', 'Gene', '2261', (116, 121))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))
15832	31278255	Our observations also provide a rationale for combining FGFR3 inhibitors with PD-1/PD-L1 inhibitors as a targeted therapeutic strategy to modulate the T-cell-depleted phenotype of UTUC.	('PD-L1', 'Gene', '29126', (83, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('56', '60'))	('FGFR3', 'Gene', '2261', (56, 61))	('UTUC', 'Disease', (180, 184))	('FGFR3', 'Gene', (56, 61))	('PD-L1', 'Gene', (83, 88))	('inhibitors', 'Var', (62, 72))
15834	31278255	Erdafitinib was granted  accelerated approval by the FDA in relapsed/refractory metastatic bladder cancer on the basis of phase 2 trial results showing a response rate of 32.2% in 87 patients with tumors that harbored actionable FGFR alterations.	('alterations', 'Var', (234, 245))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (0, 11))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('229', '233'))	('bladder cancer', 'Disease', (91, 105))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('FGFR', 'Gene', (229, 233))	('patients', 'Species', '9606', (183, 191))
15835	31278255	Our findings suggest that clinical trials of FGFR3 inhibitors as single agents or in combination with immune checkpoint blockade as a UTUC-targeted therapeutic strategy is warranted.	('FGFR3', 'Gene', (45, 50))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('inhibitors', 'Var', (51, 61))	('FGFR3', 'Gene', '2261', (45, 50))
15836	31278255	This strategy is also potentially applicable to other tumor types harboring FGFR3-activating molecular alterations.	('alterations', 'Var', (103, 114))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('FGFR3', 'Gene', '2261', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('FGFR3', 'Gene', (76, 81))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))
15875	31278255	To study the role of FGFR3 in up-regulation of the interferon response, we obtained the publicly available Affymetrix microarray dataset from the RT-112 bladder cancer cell line, with or without shRNA-mediated knockdown of FGFR3.	('knockdown', 'Var', (210, 219))	('FGFR3', 'Gene', '2261', (21, 26))	('bladder cancer', 'Disease', 'MESH:D001749', (153, 167))	('bladder cancer', 'Disease', (153, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('FGFR3', 'Gene', '2261', (223, 228))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('FGFR3', 'Gene', (21, 26))	('FGFR3', 'Gene', (223, 228))	('bladder cancer', 'Phenotype', 'HP:0009725', (153, 167))	('regulation', 'biological_process', 'GO:0065007', ('33', '43'))	('FGFR', 'molecular_function', 'GO:0005007', ('223', '227'))
15880	31278255	A pre-ranked gene set enrichment analysis (GSEA) was applied to the differentially expressed genes, ordered based on their log-fold change values, to identify the cellular pathways significantly altered after shRNA-mediated knockdown of FGFR3.	('altered', 'Reg', (195, 202))	('cellular pathways', 'Pathway', (163, 180))	('FGFR3', 'Gene', '2261', (237, 242))	('FGFR3', 'Gene', (237, 242))	('GSEA', 'Chemical', '-', (43, 47))	('pre', 'molecular_function', 'GO:0003904', ('2', '5'))	('FGFR', 'molecular_function', 'GO:0005007', ('237', '241'))	('knockdown', 'Var', (224, 233))
15910	28040424	CIS has been shown to have a 54% to 83% risk of progression to MIUC if left untreated.	('CIS', 'Var', (0, 3))	('MIUC', 'Disease', (63, 67))	('CIS', 'Phenotype', 'HP:0030075', (0, 3))	('MIUC', 'Chemical', '-', (63, 67))
15941	28040424	Furthermore, a significantly greater frequency of pTisN0M0 stage was observed at cystectomy in patients with CIS found on TURBT (19.0% vs. 3.2%; P < .01).	('CIS', 'Phenotype', 'HP:0030075', (109, 112))	('cystectomy', 'Disease', (81, 91))	('patients', 'Species', '9606', (95, 103))	('pTisN0M0', 'Var', (50, 58))
15946	28040424	As depicted in Figure 4, the median PFS was 139.9 and 104.5 months (P = .055) and the median OS was 152.3 and 104.5 months (P = .091) for pCR and pTisN0M0 patients, respectively.	('pCR', 'Disease', (138, 141))	('pTisN0M0', 'Var', (146, 154))	('patients', 'Species', '9606', (155, 163))
15951	28040424	Additional factors affecting the risk of relapse in patients with MIUC that are not considered in the current staging system include primary tumor location at the bladder neck or ureterovesical junction (especially with associated hydroureteronephrosis), sarcomatoid, small cell, or micropapillary variant histologic features, and an abnormal immunophenotype for p53, Rb, or vascular endothelial growth factor.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('neck', 'cellular_component', 'GO:0044326', ('171', '175'))	('sarcomatoid', 'Disease', 'MESH:C538614', (255, 266))	('hydroureteronephrosis', 'Disease', 'None', (231, 252))	('hydroureteronephrosis', 'Disease', (231, 252))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('MIUC', 'Chemical', '-', (66, 70))	('p53', 'Gene', '7157', (363, 366))	('ureterovesical junction', 'Disease', (179, 202))	('micropapillary', 'Var', (283, 297))	('patients', 'Species', '9606', (52, 60))	('p53', 'Gene', (363, 366))	('vascular endothelial growth factor', 'Gene', '7422', (375, 409))	('sarcomatoid', 'Disease', (255, 266))	('tumor location at the bladder', 'Phenotype', 'HP:0009725', (141, 170))	('tumor', 'Disease', (141, 146))	('ureterovesical junction', 'Disease', 'MESH:D020511', (179, 202))	('vascular endothelial growth factor', 'Gene', (375, 409))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('375', '409'))
15952	28040424	The presence of CIS on pre-NAC TURBT could be another potential risk-modifying feature in MIUC, because it has been shown to have negative prognostic implications in studies of UC, as discussed previously.	('CIS', 'Phenotype', 'HP:0030075', (16, 19))	('NAC', 'Chemical', '-', (27, 30))	('pre', 'molecular_function', 'GO:0003904', ('23', '26'))	('NAC', 'cellular_component', 'GO:0005854', ('27', '30'))	('MIUC', 'Disease', (90, 94))	('presence', 'Var', (4, 12))	('MIUC', 'Chemical', '-', (90, 94))
15958	28040424	Interestingly, the survival analysis showed that patients with TURBT CIS had numerically greater median PFS and OS outcomes; however, the differences were not statistically significant.	('TURBT', 'Var', (63, 68))	('OS outcomes', 'CPA', (112, 123))	('CIS', 'Phenotype', 'HP:0030075', (69, 72))	('PFS', 'CPA', (104, 107))	('patients', 'Species', '9606', (49, 57))	('greater', 'PosReg', (89, 96))
15966	28040424	However, if pTisN0M0 truly results in prolonged survival, this is a critical finding, given that the current standard endpoint in NAC clinical trials is the pCR.	('survival', 'MPA', (48, 56))	('NAC', 'Chemical', '-', (130, 133))	('prolonged', 'PosReg', (38, 47))	('pTisN0M0', 'Var', (12, 20))	('NAC', 'cellular_component', 'GO:0005854', ('130', '133'))
15976	28040424	Two such techniques include blue light and narrow band cystoscopy, both of which have been shown to improve the detection of CIS in NMIUC compared with traditional white light cystoscopy.	('CIS', 'Phenotype', 'HP:0030075', (125, 128))	('MIUC', 'Chemical', '-', (133, 137))	('CIS', 'Var', (125, 128))	('improve', 'PosReg', (100, 107))	('detection', 'MPA', (112, 121))
15978	28040424	Our study identified a significant association between the presence of CIS within the pretreatment TURBT sample of MIUC patients treated with NAC and decreased pCR rates at cystectomy.	('CIS', 'Phenotype', 'HP:0030075', (71, 74))	('NAC', 'Chemical', '-', (142, 145))	('patients', 'Species', '9606', (120, 128))	('decreased pCR rates', 'Phenotype', 'HP:0005165', (150, 169))	('pCR', 'Disease', (160, 163))	('NAC', 'cellular_component', 'GO:0005854', ('142', '145'))	('decreased', 'NegReg', (150, 159))	('MIUC', 'Chemical', '-', (115, 119))	('presence', 'Var', (59, 67))
15979	28040424	Furthermore, the finding of pTisN0M0 at cystectomy is common in patients with CIS found on pre-NAC TURBT samples.	('pTisN0M0', 'Var', (28, 36))	('NAC', 'cellular_component', 'GO:0005854', ('95', '98'))	('patients', 'Species', '9606', (64, 72))	('CIS', 'Phenotype', 'HP:0030075', (78, 81))	('pre', 'molecular_function', 'GO:0003904', ('91', '94'))	('CIS', 'Disease', (78, 81))	('NAC', 'Chemical', '-', (95, 98))
15983	28040424	CIS identified in pretreatment biopsy samples of patients treated with NAC results in decreased pCR rates at cystectomy; however, no significant differences in median PFS or OS were found.	('decreased pCR rates', 'Phenotype', 'HP:0005165', (86, 105))	('pCR rates at', 'CPA', (96, 108))	('decreased', 'NegReg', (86, 95))	('NAC', 'Var', (71, 74))	('NAC', 'Chemical', '-', (71, 74))	('CIS', 'Phenotype', 'HP:0030075', (0, 3))	('patients', 'Species', '9606', (49, 57))	('NAC', 'cellular_component', 'GO:0005854', ('71', '74'))
15990	26013764	Based largely on differences in biogenesis and structure, small RNAs can be broadly divided into three groups: small interfering RNAs (siRNAs), microRNAs (miRNAs) and PIWI-interacting RNA (piRNAs).	('PIWI', 'Gene', '34521', (167, 171))	('PIWI', 'Gene', (167, 171))	('small interfering', 'Var', (111, 128))	('RNA', 'cellular_component', 'GO:0005562', ('184', '187'))
16017	26013764	While expression of some mt-piRNAs such as FR015567 were highly variable across tumour-types, with particularly low expression levels in COAD, THCA and UCEC, other mt-piRNAs such as FR043670, were highly expressed across almost all tumour types (Fig.	('tumour', 'Disease', (80, 86))	('tumour-type', 'Disease', (80, 91))	('tumour', 'Disease', (232, 238))	('tumour-type', 'Disease', 'MESH:D009369', (80, 91))	('COAD', 'Disease', 'MESH:D029424', (137, 141))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (232, 238))	('FR015567', 'Var', (43, 51))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('expression levels', 'MPA', (116, 133))	('COAD', 'Disease', (137, 141))
16019	26013764	Additionally, we assessed tumour piRNA expression data derived from independent cancer cohorts, including bladder (GSE31616, n = 10), breast (GSE29173 and GSE28884, n = 167), colon (GSE63119, n = 50), lung (GEO Accession numbers pending; adenocarcinoma subtype, n = 30, squamous cell carcinoma subtype, n = 30) and stomach (GSE36968, n = 25) tumours.	('adenocarcinoma subtype', 'Disease', (238, 260))	('GSE28884', 'Var', (155, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (270, 293))	('GSE63119', 'Var', (182, 190))	('cancer', 'Disease', (80, 86))	('GSE36968', 'Var', (324, 332))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GSE29173', 'Var', (142, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('squamous cell carcinoma subtype', 'Disease', 'MESH:D002294', (270, 301))	('tumours', 'Disease', (342, 349))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('tumour', 'Phenotype', 'HP:0002664', (342, 348))	('tumour', 'Disease', 'MESH:D009369', (342, 348))	('squamous cell carcinoma subtype', 'Disease', (270, 301))	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('tumours', 'Phenotype', 'HP:0002664', (342, 349))	('colon', 'Disease', (175, 180))	('tumour', 'Disease', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('tumour', 'Disease', (342, 348))	('tumours', 'Disease', 'MESH:D009369', (342, 349))	('bladder', 'Disease', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('adenocarcinoma subtype', 'Disease', 'MESH:D000230', (238, 260))	('GSE31616', 'Var', (115, 123))	('lung', 'Disease', (201, 205))	('breast', 'Disease', (134, 140))
16032	26013764	For KIRC, we assessed whether metastasis, nodal status, stage and presence of Von Hippel-Lindau (VHL) mutation :a common mutation in kidney cancer: were significantly different across the three distinct tumour clusters (Fig.	('kidney cancer', 'Disease', (133, 146))	('VHL', 'Gene', '7428', (97, 100))	('Von Hippel-Lindau', 'Gene', '7428', (78, 95))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('Von Hippel-Lindau', 'Gene', (78, 95))	('mutation', 'Var', (102, 110))	('tumour clusters', 'Disease', 'MESH:D003027', (203, 218))	('kidney cancer', 'Disease', 'MESH:D007680', (133, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('kidney cancer', 'Phenotype', 'HP:0009726', (133, 146))	('VHL', 'Gene', (97, 100))	('tumour clusters', 'Disease', (203, 218))
16046	26013764	high levels of FR004819 associated with poorer patient survival in STAD, BLCA, THCA), or had opposite associations in different tumour types.	('poorer', 'NegReg', (40, 46))	('tumour', 'Disease', (128, 134))	('patient', 'Species', '9606', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('patient survival', 'CPA', (47, 63))	('FR004819', 'Var', (15, 23))	('BLCA', 'Disease', (73, 77))	('STAD', 'Disease', (67, 71))	('tumour', 'Disease', 'MESH:D009369', (128, 134))
16047	26013764	For example, high expression of FR090905 is associated with poor patient survival in KIRC, and improved survival in UCEC.	('survival', 'MPA', (104, 112))	('poor', 'NegReg', (60, 64))	('patient', 'Species', '9606', (65, 72))	('improved', 'PosReg', (95, 103))	('FR090905', 'Var', (32, 40))
16048	26013764	Notably, FR090905 was significantly associated with survival in three different tumour types (KIRC, HNSC, and UCEC), and was nearly significant in LUSC (p value = 0.065, after false discovery rate correction for multiple testing), highlighting the potential importance of this piRNA in multiple tumour types.	('tumour', 'Disease', (80, 86))	('HNSC', 'Disease', (100, 104))	('tumour', 'Disease', 'MESH:D009369', (295, 301))	('false', 'biological_process', 'GO:0071878', ('176', '181'))	('tumour', 'Disease', (295, 301))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('false', 'biological_process', 'GO:0071877', ('176', '181'))	('associated with', 'Reg', (36, 51))	('FR090905', 'Var', (9, 17))	('tumour', 'Phenotype', 'HP:0002664', (295, 301))
16050	26013764	Indeed, two piRNAs associated with survival in the TCGA breast cancer cohort (FR378984 and FR025321) validated in this external cohort (Supplementary Table 5).	('FR378984', 'Var', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('FR025321', 'Var', (91, 99))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('associated with', 'Reg', (19, 34))
16059	26013764	This is expected, since piRNAs and PIWI proteins play critical roles in germline development and gametogenesis, including germline determination, stem cell maintenance, meiosis, spermatogenesis, and transposon silencing.	('transposon silencing', 'Var', (199, 219))	('meiosis', 'CPA', (169, 176))	('gametogenesis', 'biological_process', 'GO:0048229', ('97', '110'))	('PIWI', 'Gene', (35, 39))	('gametogenesis', 'biological_process', 'GO:0007276', ('97', '110'))	('meiosis', 'biological_process', 'GO:0051321', ('169', '176'))	('stem cell maintenance', 'CPA', (146, 167))	('PIWI', 'Gene', '34521', (35, 39))	('spermatogenesis', 'biological_process', 'GO:0007283', ('178', '193'))	('spermatogenesis', 'CPA', (178, 193))
16088	26013764	A full description of a per-tissue processing can be found in the Synapse archive (www.synapse.org) within the following accessions: syn1461149 (BLCA), syn1461151 (BRCA), syn1461155 (COAD), syn1461156 (HNSC), syn1461159 (KIRC), syn1461166 (LUAD), syn1461168 (LUSC), syn1461171 (OV), syn1461173 (PRAD), syn1461177 (STAD), syn1461178 (THCA), syn1461180 (UCEC).	('syn1461159', 'Var', (209, 219))	('syn1461173', 'Var', (283, 293))	('BRCA', 'Gene', (164, 168))	('syn1461168', 'Var', (247, 257))	('syn1461151', 'Var', (152, 162))	('syn1461180', 'Var', (340, 350))	('syn1461166', 'Var', (228, 238))	('synapse', 'cellular_component', 'GO:0045202', ('87', '94'))	('COAD', 'Disease', (183, 187))	('syn1461156', 'Var', (190, 200))	('syn1461155', 'Var', (171, 181))	('syn1461171', 'Var', (266, 276))	('COAD', 'Disease', 'MESH:D029424', (183, 187))	('syn1461178', 'Var', (321, 331))	('syn1461177', 'Var', (302, 312))	('Synapse', 'cellular_component', 'GO:0045202', ('66', '73'))	('BRCA', 'Gene', '672', (164, 168))	('syn1461149', 'Var', (133, 143))
16228	29415874	Since mainly patients with high-grade or high-volume low-grade tumor will qualify for radical treatment, selection bias could be a risk.	('tumor', 'Disease', (63, 68))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('low-grade', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
16284	27785423	Low density of CD3 cells within tumor tissue was statistically highly significantly associated with worse cancer-specific survival.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('worse', 'NegReg', (100, 105))	('Low density', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Disease', (106, 112))	('associated', 'Reg', (84, 94))	('tumor', 'Disease', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
16289	27785423	in this study could be verified in 60 patients with stage pT1 bladder cancer that showed better cancer-sepcific survival in case of high density of CD3 cells in the tumour.	('pT1', 'Gene', (58, 61))	('better', 'PosReg', (89, 95))	('high density', 'Var', (132, 144))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('patients', 'Species', '9606', (38, 46))	('bladder cancer', 'Phenotype', 'HP:0009725', (62, 76))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('pT1', 'Gene', '58492', (58, 61))	('tumour', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('bladder cancer', 'Disease', 'MESH:D001749', (62, 76))	('bladder cancer', 'Disease', (62, 76))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (96, 102))
16308	27785423	The ligands PD-L1 (B7-H1) and PD-L2 (B7-DC) are mainly expressed by tumor cells and stromal cells.	('tumor', 'Disease', (68, 73))	('PD-L1', 'Gene', (12, 17))	('PD-L2', 'Var', (30, 35))	('PD-L1', 'Gene', '29126', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('B7-H1', 'Gene', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('B7-H1', 'Gene', '29126', (19, 24))
16309	27785423	Interaction of PD-1 and the immunosuppressive ligand PD-L1 (B7-H1) or PD-L2 (B7-DC) takes place in peripheral tissues and results in a suppression of T-cell activation and thus mediates immune resistance in the tumor microenvironment.	('PD-1', 'Gene', '5133', (15, 19))	('PD-L1', 'Gene', (53, 58))	('Interaction', 'Interaction', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('PD-L1', 'Gene', '29126', (53, 58))	('suppression', 'NegReg', (135, 146))	('PD-L2', 'Var', (70, 75))	('men', 'Species', '9606', (229, 232))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('T-cell activation', 'CPA', (150, 167))	('mediates', 'Reg', (177, 185))	('ligand', 'molecular_function', 'GO:0005488', ('46', '52'))	('T-cell activation', 'biological_process', 'GO:0042110', ('150', '167'))	('B7-H1', 'Gene', (60, 65))	('PD-1', 'Gene', (15, 19))	('B7-H1', 'Gene', '29126', (60, 65))
16322	27785423	could show that MPDL3280A (a PD-L1 antibody) can induce rapid and durable responses especially in patients with high expression of PD-L1 in immunohistochemistry, while being well-tolerated.	('antibody', 'cellular_component', 'GO:0042571', ('35', '43'))	('PD-L1', 'Gene', (29, 34))	('PD-L1', 'Gene', '29126', (131, 136))	('antibody', 'cellular_component', 'GO:0019815', ('35', '43'))	('MPDL3280A', 'Var', (16, 25))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (16, 25))	('patients', 'Species', '9606', (98, 106))	('antibody', 'cellular_component', 'GO:0019814', ('35', '43'))	('PD-L1', 'Gene', '29126', (29, 34))	('antibody', 'molecular_function', 'GO:0003823', ('35', '43'))	('PD-L1', 'Gene', (131, 136))
16324	27785423	What all the ongoing trials could show, is an improved efficacy in tumors with high PD-1 or PD-L1 expression, suggesting a patient tailored therapy.	('patient', 'Species', '9606', (123, 130))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('PD-L1', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('improved', 'PosReg', (46, 54))	('high', 'Var', (79, 83))	('PD-L1', 'Gene', '29126', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('efficacy', 'MPA', (55, 63))	('PD-1', 'Gene', (84, 88))	('tumors', 'Disease', (67, 73))	('PD-1', 'Gene', '5133', (84, 88))	('expression', 'MPA', (98, 108))
16383	33786632	The proliferation and survival of urothelial carcinoma cell lines treated with a combination of both Z-VAD-FMK as a pan-caspase inhibitor and ABT-737 were assessed in vitro.	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('ABT-737', 'Chemical', 'MESH:C501332', (142, 149))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (101, 110))	('Z-VAD-FMK', 'Var', (101, 110))	('caspase', 'Gene', (120, 127))	('urothelial carcinoma', 'Disease', (34, 54))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (34, 54))	('caspase', 'Gene', '841;842', (120, 127))
16413	33786632	ABT-737 is a Bcl-2 homology (BH)3-mimetic drug, and an inhibitor of Bcl-2, Bcl-xL and Bcl-w. ABT-737 competes with Bim to bind Bcl-2, leading to the release of Bim and triggering Bax/Bak-mediated apoptosis.	('Bak', 'Gene', (183, 186))	('Bcl-w', 'Gene', (86, 91))	('Bcl-xL', 'Gene', (75, 81))	('Bax', 'Gene', '581', (179, 182))	('Bcl-2', 'Gene', (13, 18))	('Bcl-xL', 'Gene', '598', (75, 81))	('Bcl-2', 'Gene', '596', (127, 132))	('Bcl-2', 'molecular_function', 'GO:0015283', ('127', '132'))	('ABT-737', 'Var', (93, 100))	('ABT-737', 'Chemical', 'MESH:C501332', (93, 100))	('Bcl-2', 'molecular_function', 'GO:0015283', ('13', '18'))	('leading to', 'Reg', (134, 144))	('Bcl-2', 'Gene', (68, 73))	('Bim', 'Gene', '10018', (115, 118))	('Bcl-2', 'Gene', '596', (13, 18))	('Bcl-2', 'molecular_function', 'GO:0015283', ('68', '73'))	('Bak', 'Gene', '578', (183, 186))	('Bcl-2', 'Gene', (127, 132))	('Bcl-w', 'Gene', '599', (86, 91))	('apoptosis', 'biological_process', 'GO:0097194', ('196', '205'))	('Bim', 'Gene', (115, 118))	('apoptosis', 'biological_process', 'GO:0006915', ('196', '205'))	('Bcl-2', 'Gene', '596', (68, 73))	('Bim', 'Gene', '10018', (160, 163))	('triggering', 'Reg', (168, 178))	('Bax', 'Gene', (179, 182))	('ABT-737', 'Chemical', 'MESH:C501332', (0, 7))	('release', 'MPA', (149, 156))	('Bim', 'Gene', (160, 163))
16441	33786632	MAB9187; 1:1,000; R&D Systems, Inc.) and anti-GAPDH (cat.	('GAPDH', 'Gene', '2597', (46, 51))	('cat', 'molecular_function', 'GO:0004096', ('53', '56'))	('and', 'Var', (37, 40))	('GAPDH', 'Gene', (46, 51))
16471	33786632	The current study knocked down RIP1 in the UMUC3 and 5637 cell lines using siRNA.	('knocked', 'Var', (18, 25))	('RIP1', 'Gene', (31, 35))	('RIP1', 'Gene', '8737', (31, 35))
16488	33786632	In another experiment, the role of RIP3 in necrosis was examined by knocking down the RIP3 gene in UMUC3 and 5637 cells.	('RIP3', 'Gene', (86, 90))	('RIP3', 'Gene', (35, 39))	('necrosis', 'Disease', 'MESH:D009336', (43, 51))	('necrosis', 'biological_process', 'GO:0070265', ('43', '51'))	('necrosis', 'biological_process', 'GO:0008219', ('43', '51'))	('necrosis', 'biological_process', 'GO:0019835', ('43', '51'))	('necrosis', 'Disease', (43, 51))	('RIP3', 'Gene', '11035', (35, 39))	('RIP3', 'Gene', '11035', (86, 90))	('necrosis', 'biological_process', 'GO:0008220', ('43', '51'))	('knocking', 'Var', (68, 76))	('necrosis', 'biological_process', 'GO:0001906', ('43', '51'))	('men', 'Species', '9606', (17, 20))
16496	33786632	These results verified that RIP3 knockdown can counteract the ABT-737-induced necrosis of bladder cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('necrosis of bladder cancer', 'Disease', (78, 104))	('ABT-737', 'Chemical', 'MESH:C501332', (62, 69))	('knockdown', 'Var', (33, 42))	('necrosis', 'biological_process', 'GO:0070265', ('78', '86'))	('necrosis of bladder cancer', 'Disease', 'MESH:D001749', (78, 104))	('necrosis', 'biological_process', 'GO:0008219', ('78', '86'))	('RIP3', 'Gene', '11035', (28, 32))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('necrosis', 'biological_process', 'GO:0019835', ('78', '86'))	('necrosis', 'biological_process', 'GO:0008220', ('78', '86'))	('RIP3', 'Gene', (28, 32))	('necrosis', 'biological_process', 'GO:0001906', ('78', '86'))
16581	32592351	In all, 7 (6.6%) cases were stage pTa, 13 (12.3%) stage pT1 , 6 (5.7%) stage pT2a, 14 (13.2%) stage pT2b, 48 (45%) stage pT3, and 19 (17.9%) were stage pT4 (Figure 1-2).	('pT1', 'Gene', '58492', (56, 59))	('stage pT2b', 'Var', (94, 104))	('pT3', 'Gene', '7694', (121, 124))	('pT1', 'Gene', (56, 59))	('pTa', 'molecular_function', 'GO:0008959', ('34', '37'))	('pT3', 'Gene', (121, 124))
16596	32592351	Survival analysis  As shown in Table 3, high tumor grade, advanced stage, LVI, LNM , PNI, and positive CD10 expression in both tumor and CAF (Figure 2) were significantly associated with poor OS.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('CD10', 'Gene', (103, 107))	('high tumor', 'Disease', 'MESH:D009369', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('CD10', 'Gene', '4311', (103, 107))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (45, 50))	('CAF', 'Gene', (137, 140))	('high tumor', 'Disease', (40, 50))	('LVI', 'Disease', (74, 77))	('poor OS', 'Disease', (187, 194))	('expression', 'MPA', (108, 118))	('positive', 'Var', (94, 102))	('CAF', 'Gene', '8850', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('CD10', 'molecular_function', 'GO:0004245', ('103', '107'))	('associated', 'Reg', (171, 181))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
16646	32592351	With regard to survival analysis, we observed that high tumor grade, advanced stage, LVI, LNM, PNI, and positive CD10 expression in both tumor and stromal cells were associated with shorter OS.	('high tumor', 'Disease', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('positive', 'Var', (104, 112))	('CD10', 'Gene', '4311', (113, 117))	('high tumor', 'Disease', 'MESH:D009369', (51, 61))	('CD10', 'Gene', (113, 117))	('LVI', 'Disease', (85, 88))	('shorter OS', 'Disease', (182, 192))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('CD10', 'molecular_function', 'GO:0004245', ('113', '117'))
16686	33035117	Bladder urothelial carcinoma (BLCA) patients with COL1A2, COL5A1, and COL5A2 alterations showed poor disease-free survival rates, while BLCA patients with COL1A1 and LUM alterations showed poor overall survival rates.	('COL1A1', 'Gene', (155, 161))	('patients', 'Species', '9606', (36, 44))	('COL1A1', 'Gene', '1277', (155, 161))	('LUM', 'Gene', (166, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('Bladder urothelial carcinoma', 'Disease', (0, 28))	('COL5A1', 'Gene', (58, 64))	('COL5A2', 'Gene', '1290', (70, 76))	('COL5A2', 'Gene', (70, 76))	('alterations', 'Var', (77, 88))	('LUM', 'Gene', '4060', (166, 169))	('COL5A1', 'Gene', '1289', (58, 64))	('COL1A2', 'Gene', (50, 56))	('poor', 'NegReg', (96, 100))	('COL1A2', 'Gene', '1278', (50, 56))	('disease-free survival rates', 'CPA', (101, 128))	('Bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (0, 28))	('patients', 'Species', '9606', (141, 149))
16689	33035117	It was evident that BLCA patients with an elevated high combined gene expression had significantly shorter overall survival and relapse-free survival than those with low combined gene expression using PROGgeneV2.	('shorter', 'NegReg', (99, 106))	('gene expression', 'biological_process', 'GO:0010467', ('179', '194'))	('overall survival', 'CPA', (107, 123))	('gene expression', 'biological_process', 'GO:0010467', ('65', '80'))	('BLCA', 'Disease', (20, 24))	('high', 'Var', (51, 55))	('patients', 'Species', '9606', (25, 33))	('relapse-free survival', 'CPA', (128, 149))
16702	33035117	Four gene expression profiles (GSE7476, GSE37317, GSE48075, and GSE120736) were downloaded from GEO; the four datasets contained both NMIBC and MIBC tissue samples (6 vs 3; 8 vs 10; 69 vs 73; and 78 vs 61, respectively) ( Table 1 ).	('GSE7476', 'Var', (31, 38))	('GSE7476', 'Chemical', '-', (31, 38))	('GSE120736', 'Var', (64, 73))	('gene expression', 'biological_process', 'GO:0010467', ('5', '20'))	('MIBC', 'Chemical', '-', (144, 148))	('MIBC', 'Chemical', '-', (135, 139))	('GSE48075', 'Var', (50, 58))	('GSE37317', 'Var', (40, 48))
16717	33035117	After acquiring four different gene expression profiles, we identified a large number of DEGs (1156 in GSE7476, 746 in GSE120736, 1093 in GSE48075, and 604 in GSE37317).	('GSE7476', 'Var', (103, 110))	('GSE120736', 'Var', (119, 128))	('GSE48075', 'Var', (138, 146))	('GSE7476', 'Chemical', '-', (103, 110))	('1156', 'Var', (95, 99))	('gene expression', 'biological_process', 'GO:0010467', ('31', '46'))
16727	33035117	BLCA patients with COL1A2, COL5A1, COL5A2 alterations were associated with poor disease-free survival (Fig.	('patients', 'Species', '9606', (5, 13))	('alterations', 'Var', (42, 53))	('COL5A1', 'Gene', (27, 33))	('poor', 'NegReg', (75, 79))	('COL5A2', 'Gene', '1290', (35, 41))	('COL5A1', 'Gene', '1289', (27, 33))	('COL5A2', 'Gene', (35, 41))	('COL1A2', 'Gene', (19, 25))	('COL1A2', 'Gene', '1278', (19, 25))	('disease-free survival', 'CPA', (80, 101))
16735	33035117	Analyzing the GSE13507 gene array dataset, from the study of Wun-Jae Kim et al., revealed that patients with high combined gene expression had significantly shorter overall survival than those with low combined gene expression in bladder cancer.	('gene expression', 'biological_process', 'GO:0010467', ('211', '226'))	('bladder cancer', 'Phenotype', 'HP:0009725', (230, 244))	('shorter', 'NegReg', (157, 164))	('high', 'Var', (109, 113))	('patients', 'Species', '9606', (95, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (230, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('bladder cancer', 'Disease', (230, 244))	('overall survival', 'MPA', (165, 181))	('gene expression', 'biological_process', 'GO:0010467', ('123', '138'))
16736	33035117	indicated that high combined gene expression was associated with poor relapse-free survival in bladder cancer.	('high', 'Var', (15, 19))	('relapse-free survival', 'CPA', (70, 91))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('bladder cancer', 'Disease', 'MESH:D001749', (95, 109))	('bladder cancer', 'Disease', (95, 109))	('gene expression', 'biological_process', 'GO:0010467', ('29', '44'))	('poor', 'NegReg', (65, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))
16749	33035117	Kaplan-Meier estimation revealed that BLCA patients with COL1A2, COL5A1, and COL5A2 alterations were linked to poor disease-free survival, whereas, BLCA patients having COL1A1 and LUM alterations were associated with poor overall survival.	('COL5A2', 'Gene', (77, 83))	('disease-free survival', 'CPA', (116, 137))	('patients', 'Species', '9606', (153, 161))	('COL1A1', 'Gene', (169, 175))	('LUM', 'Gene', (180, 183))	('patients', 'Species', '9606', (43, 51))	('COL1A1', 'Gene', '1277', (169, 175))	('COL5A1', 'Gene', (65, 71))	('LUM', 'Gene', '4060', (180, 183))	('COL1A2', 'Gene', (57, 63))	('COL1A2', 'Gene', '1278', (57, 63))	('alterations', 'Var', (84, 95))	('COL5A1', 'Gene', '1289', (65, 71))	('COL5A2', 'Gene', '1290', (77, 83))	('poor', 'NegReg', (111, 115))
16753	33035117	Furthermore, high expression of COL1A1, COL1A2, COL3A1, and COL5A2 led to a shorter overall survival of BLCA patients, as per data retrieved from TCGAportal online tool.	('BLCA', 'Disease', (104, 108))	('COL1A2', 'Gene', (40, 46))	('COL5A2', 'Gene', '1290', (60, 66))	('COL5A2', 'Gene', (60, 66))	('patients', 'Species', '9606', (109, 117))	('high', 'Var', (13, 17))	('COL3A1', 'Gene', (48, 54))	('COL1A1', 'Gene', '1277', (32, 38))	('COL1A1', 'Gene', (32, 38))	('overall survival', 'MPA', (84, 100))	('COL1A2', 'Gene', '1278', (40, 46))	('shorter', 'NegReg', (76, 83))	('COL3A1', 'Gene', '1281', (48, 54))
16756	33035117	previously revealed that the expression of COL1A1 was increased in colorectal adenocarcinoma and that COL1A1 silencing significantly inhibited cell proliferation, migration, and invasion and promoted apoptosis.	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (67, 92))	('promoted', 'PosReg', (191, 199))	('invasion', 'CPA', (178, 186))	('COL1A1', 'Gene', '1277', (102, 108))	('COL1A1', 'Gene', '1277', (43, 49))	('COL1A1', 'Gene', (102, 108))	('silencing', 'Var', (109, 118))	('cell proliferation', 'biological_process', 'GO:0008283', ('143', '161'))	('cell proliferation', 'CPA', (143, 161))	('migration', 'CPA', (163, 172))	('COL1A1', 'Gene', (43, 49))	('colorectal adenocarcinoma', 'Disease', (67, 92))	('expression', 'MPA', (29, 39))	('apoptosis', 'CPA', (200, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('200', '209'))	('inhibited', 'NegReg', (133, 142))	('apoptosis', 'biological_process', 'GO:0006915', ('200', '209'))	('increased', 'PosReg', (54, 63))
16758	33035117	showed that the loss of BMP1 promotes the expression of COL1A1 and EMT progression in colon cancer; COL1A1 may be a novel prognostic biomarker and a promising therapeutic target for breast cancer, malignant astrocytoma, colorectal cancer, and gastric cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (220, 237))	('expression', 'MPA', (42, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('loss', 'Var', (16, 20))	('EMT', 'biological_process', 'GO:0001837', ('67', '70'))	('promotes', 'PosReg', (29, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (243, 257))	('COL1A1', 'Gene', '1277', (100, 106))	('colon cancer', 'Disease', (86, 98))	('breast cancer', 'Disease', 'MESH:D001943', (182, 195))	('EMT', 'CPA', (67, 70))	('breast cancer', 'Disease', (182, 195))	('malignant astrocytoma', 'Disease', 'MESH:D020339', (197, 218))	('colorectal cancer', 'Disease', 'MESH:D015179', (220, 237))	('astrocytoma', 'Phenotype', 'HP:0009592', (207, 218))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('BMP1', 'Gene', (24, 28))	('COL1A1', 'Gene', (100, 106))	('colorectal cancer', 'Disease', (220, 237))	('gastric cancer', 'Disease', (243, 257))	('BMP1', 'Gene', '649', (24, 28))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('malignant astrocytoma', 'Disease', (197, 218))	('COL1A1', 'Gene', '1277', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('BMP1', 'molecular_function', 'GO:0017026', ('24', '28'))	('gastric cancer', 'Disease', 'MESH:D013274', (243, 257))	('colon cancer', 'Disease', 'MESH:D015179', (86, 98))	('COL1A1', 'Gene', (56, 62))
16761	33035117	Interestingly, miR-25 silencing increased the expression of COL1A2 and inhibited the expression of E-cadherin, revealing the inhibitory effect of mir-25 on diffuse gastric cancer.	('expression', 'MPA', (85, 95))	('mir-25', 'Gene', (146, 152))	('mir-25', 'Gene', '407014', (146, 152))	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cadherin', 'molecular_function', 'GO:0008014', ('101', '109'))	('inhibited', 'NegReg', (71, 80))	('miR-25', 'Gene', (15, 21))	('COL1A2', 'Gene', '1278', (60, 66))	('E-cadherin', 'Gene', (99, 109))	('silencing', 'Var', (22, 31))	('E-cadherin', 'Gene', '999', (99, 109))	('gastric cancer', 'Disease', 'MESH:D013274', (164, 178))	('increased', 'PosReg', (32, 41))	('gastric cancer', 'Disease', (164, 178))	('COL1A2', 'Gene', (60, 66))	('expression', 'MPA', (46, 56))	('miR-25', 'Gene', '407014', (15, 21))
16765	33035117	reported that abnormal expression of miR-29a/b in nasopharyngeal carcinoma tissue may regulate COL3A1 expression and contribute to migration and invasion, while Su et al.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('COL3A1', 'Gene', (95, 101))	('migration', 'CPA', (131, 140))	('expression', 'MPA', (102, 112))	('carcinoma', 'Disease', (65, 74))	('abnormal', 'Var', (14, 22))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (50, 74))	('COL3A1', 'Gene', '1281', (95, 101))	('carcinoma', 'Disease', 'MESH:D009369', (65, 74))	('invasion', 'CPA', (145, 153))	('contribute', 'Reg', (117, 127))	('miR-29a/b', 'Gene', (37, 46))	('regulate', 'Reg', (86, 94))	('miR-29a/b', 'Gene', '407021', (37, 46))
16767	33035117	COL5A2, collagen type V alpha 2 chain, encodes an alpha chain that composes one of the low abundance fibrillar collagens, and mutations in this gene are associated with the Ehlers-Danlos syndrome.	('collagen', 'molecular_function', 'GO:0005202', ('8', '16'))	('COL5A2', 'Gene', '1290', (0, 6))	('COL5A2', 'Gene', (0, 6))	('collagen type V alpha 2', 'Gene', (8, 31))	('associated', 'Reg', (153, 163))	('collagen type V alpha 2', 'Gene', '1290', (8, 31))	('mutations', 'Var', (126, 135))	('Ehlers-Danlos syndrome', 'Disease', 'MESH:D004535', (173, 195))	('Ehlers-Danlos syndrome', 'Disease', (173, 195))
16782	32192274	In conclusion, multicentric genetic changes, in line with the field-cancerization effect, may result in SV involvement by CIS of the bladder.	('result in', 'Reg', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('multicentric', 'Var', (15, 27))	('SV involvement', 'Disease', (104, 118))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('CIS', 'Phenotype', 'HP:0030075', (122, 125))	('CIS', 'Disease', (122, 125))
16809	32192274	We used the MuTect to detect somatic single nucleotide variants (SNVs), and the Strelka to detect somatic small insertions and deletions (InDels), and copy number variations (CNVs) in the tumor samples.	('tumor', 'Disease', (188, 193))	('deletions', 'Var', (127, 136))	('small insertions', 'Var', (106, 122))	('single nucleotide variants', 'Var', (37, 63))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('copy number variations', 'Var', (151, 173))
16813	32192274	Notably, we found significant differences in the genomic changes between bladder and SV tumor cells, including the SNVs (S1 and S2 Tables), the InDels (S3 and S4 Tables), and the CNVs (S5 and S6 Tables).	('differences', 'Reg', (30, 41))	('SV tumor', 'Disease', (85, 93))	('SV tumor', 'Disease', 'MESH:D009369', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('InDels', 'Var', (144, 150))
16821	32192274	For example, among somatic SNVs frequently detected in BC, TP53 (one of tumor suppressor genes) and KDM6A (one of most commonly mutated, chromatin-modifying genes in BC) mutations were present in bladder CIS, but absent in SV CIS (S1 and S2 Tables).	('BC', 'Phenotype', 'HP:0009725', (55, 57))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('TP53', 'Gene', (59, 63))	('BC', 'Phenotype', 'HP:0009725', (166, 168))	('CIS', 'Phenotype', 'HP:0030075', (204, 207))	('chromatin', 'cellular_component', 'GO:0000785', ('137', '146'))	('tumor', 'Disease', (72, 77))	('mutations', 'Var', (170, 179))	('KDM6A', 'Gene', (100, 105))	('tumor suppressor', 'biological_process', 'GO:0051726', ('72', '88'))	('CIS', 'Phenotype', 'HP:0030075', (226, 229))	('KDM6A', 'Gene', '7403', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('72', '88'))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('TP53', 'Gene', '7157', (59, 63))
16822	32192274	Meanwhile, ZDHHC21, PGGHG, and USP7 mutations, which were reported to be associated with BC, were present in SV CIS only, not in bladder CIS.	('USP7', 'Gene', '7874', (31, 35))	('CIS', 'Phenotype', 'HP:0030075', (112, 115))	('USP', 'molecular_function', 'GO:0051748', ('31', '34'))	('mutations', 'Var', (36, 45))	('BC', 'Phenotype', 'HP:0009725', (89, 91))	('ZDHHC21', 'Gene', (11, 18))	('ZDHHC21', 'Gene', '340481', (11, 18))	('SV CIS only', 'Disease', (109, 120))	('CIS', 'Phenotype', 'HP:0030075', (137, 140))	('PGGHG', 'Gene', (20, 25))	('SV CIS only', 'Disease', 'MESH:D054331', (109, 120))	('USP7', 'Gene', (31, 35))
16834	32550918	Additionally, transcriptomic analysis showed immune activation in the high-M1 subgroup, whereas it showed steroid and drug metabolism reprograming in the M1-deficient subset, which characterized the limited sensitivity to ICB therapy.	('steroid', 'Chemical', 'MESH:D013256', (106, 113))	('drug metabolism', 'biological_process', 'GO:0017144', ('118', '133'))	('high-M1', 'Var', (70, 77))	('ICB', 'Chemical', '-', (222, 225))	('immune', 'MPA', (45, 51))
16835	32550918	Notably, investigation of the corresponding intrinsic genomic profiles highlighted the significance of TP53 and FGFR alterations.	('alterations', 'Var', (117, 128))	('TP53', 'Gene', '7157', (103, 107))	('FGFR', 'Gene', (112, 116))	('TP53', 'Gene', (103, 107))	('FGFR', 'molecular_function', 'GO:0005007', ('112', '116'))
16836	32550918	Innate immunity activation involving macrophage polarization remodeling and anti-FGFR mutations may be promising strategies for synergy with anti-PD-L1 treatments and may help prolong the clinical survival of patients with mUC.	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('mutations', 'Var', (86, 95))	('Innate immunity', 'biological_process', 'GO:0045087', ('0', '15'))	('PD-L1', 'Gene', '29126', (146, 151))	('prolong', 'PosReg', (176, 183))	('macrophage polarization', 'biological_process', 'GO:0042116', ('37', '60'))	('mUC', 'Disease', (223, 226))	('patients', 'Species', '9606', (209, 217))	('anti-FGFR', 'Gene', (76, 85))	('PD-L1', 'Gene', (146, 151))
16843	32550918	Intriguingly, a recent study found FGFR3 mutation status is not a biomarker of resistance to ICBs, despite its significant association with T-cell exclusion.	('association', 'Interaction', (123, 134))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('T-cell exclusion', 'Disease', (140, 156))	('FGFR3', 'Gene', '2261', (35, 40))	('ICBs', 'Chemical', '-', (93, 97))	('mutation', 'Var', (41, 49))	('FGFR3', 'Gene', (35, 40))
16845	32550918	For instance, high PD-L1 and CD8 expression had a significantly higher TMB or neoantigens in bladder urothelial carcinoma.	('PD-L1', 'Gene', (19, 24))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (93, 121))	('CD8', 'Gene', '925', (29, 32))	('higher', 'PosReg', (64, 70))	('bladder urothelial carcinoma', 'Disease', (93, 121))	('PD-L1', 'Gene', '29126', (19, 24))	('TMB', 'MPA', (71, 74))	('high', 'Var', (14, 18))	('neoantigens', 'MPA', (78, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('expression', 'MPA', (33, 43))	('TMB', 'Chemical', '-', (71, 74))	('CD8', 'Gene', (29, 32))
16854	32550918	In the low-M1 subset, we detected elevated expression of steroid metabolic and drug metabolic pathways, which characterize a poor immunotherapeutic sensitivity.	('steroid', 'Chemical', 'MESH:D013256', (57, 64))	('drug metabolic pathways', 'Pathway', (79, 102))	('low-M1', 'Var', (7, 13))	('steroid metabolic', 'Pathway', (57, 74))	('elevated', 'PosReg', (34, 42))	('expression', 'MPA', (43, 53))
16897	32550918	Intensive investigation into the genetic profile demonstrated that M1-macrophage levels were significantly elevated in FBXW7 and TP53 mutation settings (Mann Whitney U test, p = 3.2e-5, p = 6.9e-4, respectively; Figure 5A-B;Table S6).	('FBXW7', 'Gene', '55294', (119, 124))	('M1-macrophage levels', 'MPA', (67, 87))	('mutation settings', 'Var', (134, 151))	('FBXW7', 'Gene', (119, 124))	('TP53', 'Gene', '7157', (129, 133))	('TP53', 'Gene', (129, 133))	('elevated', 'PosReg', (107, 115))
16900	32550918	However, a decrease in M1-macrophage infiltration was observed in patients with FGFR mutation, compared with that in the wild type (Mann Whitney U test, p = 0.001; Figure 5C).	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('mutation', 'Var', (85, 93))	('decrease', 'NegReg', (11, 19))	('M1-macrophage', 'CPA', (23, 36))	('FGFR', 'Gene', (80, 84))	('patients', 'Species', '9606', (66, 74))
16902	32550918	FGFR alterations have been recognized as a biomarker of resistance to ICBs with anti-FGFR agents approved by the FDA.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'Gene', (0, 4))	('ICBs', 'Chemical', '-', (70, 74))	('alterations', 'Var', (5, 16))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))
16903	32550918	In line with this, the current work demonstrated that FGFR mutated cases had a more deserted immune phenotype than the wild type (Figure 5D), as well as a lower Immunoscore and higher tumor purity (Mann Whitney U test, p = 3.1e-11, p = 9.9e-13, respectively; Figure 5E-F).	('deserted immune phenotype', 'MPA', (84, 109))	('higher', 'PosReg', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('Immunoscore', 'MPA', (161, 172))	('tumor', 'Disease', (184, 189))	('lower', 'NegReg', (155, 160))	('FGFR', 'molecular_function', 'GO:0005007', ('54', '58'))	('mutated', 'Var', (59, 66))	('FGFR', 'Gene', (54, 58))
16904	32550918	Consistent with previous studies, FGFR pathway alteration was associated with alternative immune mechanisms, such as downregulated immune checkpoint pathways and elevated drug-resistance metabolism, especially steroid metabolism (Figure 5G, S8A-B), which collectively suggest that combination of FGFR inhibition and PD-L1 blockade may hold promise in elevating antitumor immunity.	('drug-resistance', 'Phenotype', 'HP:0020174', (171, 186))	('drug-resistance metabolism', 'MPA', (171, 197))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('metabolism', 'biological_process', 'GO:0008152', ('187', '197'))	('elevated', 'PosReg', (162, 170))	('drug-resistance', 'biological_process', 'GO:0009315', ('171', '186'))	('PD-L1', 'Gene', (316, 321))	('steroid metabolism', 'biological_process', 'GO:0008202', ('210', '228'))	('PD-L1', 'Gene', '29126', (316, 321))	('elevating', 'PosReg', (351, 360))	('steroid metabolism', 'MPA', (210, 228))	('drug-resistance', 'biological_process', 'GO:0042493', ('171', '186'))	('tumor', 'Disease', (365, 370))	('downregulated', 'NegReg', (117, 130))	('immune checkpoint pathways', 'Pathway', (131, 157))	('FGFR', 'molecular_function', 'GO:0005007', ('296', '300'))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('tumor', 'Disease', 'MESH:D009369', (365, 370))	('FGFR pathway', 'Gene', (34, 46))	('alteration', 'Var', (47, 57))	('FGFR', 'Gene', (296, 300))	('steroid', 'Chemical', 'MESH:D013256', (210, 217))
16905	32550918	However, a trend toward a better response to anti-PD-L1 therapy was observed in FGFR mutated patients, although statistical significance was not attained (Figure S8 C-D; p = 0.1399, p = 0.2691, respectively).	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('PD-L1', 'Gene', (50, 55))	('mutated', 'Var', (85, 92))	('PD-L1', 'Gene', '29126', (50, 55))	('FGFR', 'Gene', (80, 84))	('patients', 'Species', '9606', (93, 101))	('better', 'PosReg', (26, 32))
16906	32550918	Additionally, external validation of M1 macrophage related DEGs mutations (comprising FGFR3, TP53, and FBXW7) versus wild type in TCGA were also described (Figure S8 E-G).	('TC', 'Chemical', '-', (130, 132))	('FBXW7', 'Gene', '55294', (103, 108))	('TP53', 'Gene', '7157', (93, 97))	('FGFR3', 'Gene', '2261', (86, 91))	('TP53', 'Gene', (93, 97))	('FBXW7', 'Gene', (103, 108))	('mutations', 'Var', (64, 73))	('FGFR3', 'Gene', (86, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('86', '90'))
16921	32550918	Furthermore, DEGs, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) demonstrated that tumors with M1-deficient subtype have dramatically higher activation in steroid metabolism, xenobiotics metabolism, and TGF-beta signaling pathway, which were previously reported to develop immunosuppressive activity.	('metabolism', 'biological_process', 'GO:0008152', ('217', '227'))	('M1-deficient', 'Var', (125, 137))	('xenobiotics metabolism', 'Disease', (205, 227))	('TGF-beta', 'Gene', (233, 241))	('steroid metabolism', 'biological_process', 'GO:0008202', ('185', '203'))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('steroid', 'Chemical', 'MESH:D013256', (185, 192))	('TGF-beta', 'Gene', '7039', (233, 241))	('xenobiotics metabolism', 'Disease', 'MESH:D008659', (205, 227))	('higher activation', 'PosReg', (164, 181))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('steroid metabolism', 'MPA', (185, 203))	('signaling pathway', 'biological_process', 'GO:0007165', ('242', '259'))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
16928	32550918	Our data revealed that a TP53 mutation was associated with a more pro-inflammatory phenotype of macrophages in the IMvigor210 and TCGA cohorts.	('TC', 'Chemical', '-', (130, 132))	('TP53', 'Gene', (25, 29))	('mutation', 'Var', (30, 38))	('more', 'PosReg', (61, 65))	('associated', 'Reg', (43, 53))	('TP53', 'Gene', '7157', (25, 29))
16929	32550918	Conversely, the infiltration of M1 macrophages was markedly lower in tumors with FGFR pathway deficiency.	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('infiltration of M1 macrophages', 'CPA', (16, 46))	('lower', 'NegReg', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('deficiency', 'Var', (94, 104))	('FGFR pathway', 'Pathway', (81, 93))
16930	32550918	Consistently with previous research, FGFR pathway mutations were not statistically correlated with anti-PD-L1 response, but were markedly enriched in desert-immune subtype and high tumor purity.	('tumor', 'Disease', (181, 186))	('mutations', 'Var', (50, 59))	('PD-L1', 'Gene', '29126', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('FGFR pathway', 'Gene', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('PD-L1', 'Gene', (104, 109))
16931	32550918	The observation that FGFR pathway mutation is significantly associated with steroid metabolism activation, insulin receptor signaling pathway upregulation, cell cycle activation, and immune exclusion phenotype, inspired a rational hypothesis that anti-FGFR mutation may offer a way to tackle immune cell exclusion (including cytotoxic T cells and M1 macrophages) from the tumor center to boost tumor destruction via immunotherapy.	('tumor', 'Disease', (394, 399))	('cell cycle', 'biological_process', 'GO:0007049', ('156', '166'))	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('mutation', 'Var', (257, 265))	('tumor', 'Disease', 'MESH:D009369', (394, 399))	('FGFR pathway', 'Gene', (21, 33))	('upregulation', 'PosReg', (142, 154))	('mutation', 'Var', (34, 42))	('insulin receptor', 'Gene', '3643', (107, 123))	('boost', 'PosReg', (388, 393))	('tumor', 'Phenotype', 'HP:0002664', (394, 399))	('steroid metabolism', 'biological_process', 'GO:0008202', ('76', '94'))	('insulin receptor', 'Gene', (107, 123))	('tumor', 'Disease', (372, 377))	('insulin', 'molecular_function', 'GO:0016088', ('107', '114'))	('steroid', 'MPA', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (372, 377))	('insulin receptor signaling pathway', 'biological_process', 'GO:0008286', ('107', '141'))	('steroid', 'Chemical', 'MESH:D013256', (76, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('252', '256'))
16961	31493109	T1 m, or pT1 m (micro infiltration) was a single focus of lamina propria invasion with a maximum depth of 0.5 mm (within one high power field; objective x 40).	('T1 m', 'Var', (0, 4))	('pT1', 'Gene', '58492', (9, 12))	('pT1', 'Gene', (9, 12))
16962	31493109	T1e or pT1/e (extensive infiltration) was defined as a larger area with invasion or multiple micro-invasive areas.	('pT1/e', 'Gene', '58492', (7, 12))	('pT1/e', 'Gene', (7, 12))	('T1e', 'Var', (0, 3))
16989	31493109	Indeed, patients harboring T1b/c or T1e in substaging system may benefit from early radical cystectomy as their tumor carries the biologic and clinical behavior of muscle-invasive bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('T1b/c', 'Var', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('T1e', 'Var', (36, 39))	('invasive bladder', 'Phenotype', 'HP:0100645', (171, 187))	('bladder cancer', 'Phenotype', 'HP:0009725', (180, 194))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (164, 194))	('muscle-invasive bladder cancer', 'Disease', (164, 194))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('patients', 'Species', '9606', (8, 16))
17014	30444046	Simultaneously, tumor suppressor genes (TSGs) can be inactivated by promoter hypermethylation (Llinas-Arias and Esteller, 2017).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor suppressor', 'biological_process', 'GO:0051726', ('16', '32'))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('promoter hypermethylation', 'Var', (68, 93))	('Llinas-Arias', 'Disease', (95, 107))	('tumor', 'Disease', (16, 21))	('inactivated', 'NegReg', (53, 64))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('16', '32'))	('Llinas-Arias', 'Disease', 'MESH:D005878', (95, 107))
17015	30444046	CpG island hypermethylation in cancer cells is associated with a decrease in histone active marks: histone H3 and H4 acetylation, H3K4 trimethylation, and gain of repressive marks: H3K9me3 and H3K27me3 (Llinas-Arias and Esteller, 2017).	('H3K27me3', 'Var', (193, 201))	('H3K4', 'Protein', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('hypermethylation', 'Var', (11, 27))	('histone H3', 'Protein', (99, 109))	('H3K9me3', 'Protein', (181, 188))	('Llinas-Arias', 'Disease', 'MESH:D005878', (203, 215))	('gain', 'PosReg', (155, 159))	('histone', 'MPA', (77, 84))	('decrease', 'NegReg', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('repressive', 'MPA', (163, 173))	('cancer', 'Disease', (31, 37))	('Llinas-Arias', 'Disease', (203, 215))
17030	30444046	This KRAB-ZNF is upregulated in bladder cancer, while its knockdown induces apoptosis and reduces the viability of cancer cells in in vitro and in vivo experiments (Kawahara et al., 2016).	('induces', 'Reg', (68, 75))	('cancer', 'Disease', (115, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('bladder cancer', 'Disease', (32, 46))	('upregulated', 'PosReg', (17, 28))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('reduces', 'NegReg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ZNF', 'Gene', (10, 13))	('apoptosis', 'CPA', (76, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('knockdown', 'Var', (58, 67))	('ZNF', 'Gene', '284390', (10, 13))
17060	30444046	For breast cancer, we used nine different cell lines representing distinct molecular subtypes: luminal A (MCF7, T47D), luminal B (BT474), basal (BT20, BT549, HS578T, MDA-MB231, MDA-MB468), and HER2 positive (SKBR3).	('T47D', 'CellLine', 'CVCL:0553', (112, 116))	('HER2', 'Gene', (193, 197))	('MDA-MB231', 'CellLine', 'CVCL:0062', (166, 175))	('MDA-MB231', 'Var', (166, 175))	('BT549', 'CellLine', 'CVCL:1092', (151, 156))	('MDA-MB468', 'Var', (177, 186))	('HER2', 'Gene', '2064', (193, 197))	('HS578T', 'CellLine', 'CVCL:0332', (158, 164))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('MDA-MB468', 'CellLine', 'CVCL:0419', (177, 186))	('SKBR3', 'CellLine', 'CVCL:0033', (208, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('MCF7', 'CellLine', 'CVCL:0031', (106, 110))	('BT20', 'Var', (145, 149))	('HS578T', 'Var', (158, 164))
17082	30444046	Interestingly, the majority of the KRAB-ZNFs with an altered mRNA level exhibited reduced expression, while only a small but distinct cluster of 16 KRAB-ZNFs showed upregulation in multiple cancer types (Fig.	('ZNFs', 'Chemical', '-', (40, 44))	('multiple cancer', 'Disease', (181, 196))	('altered', 'Var', (53, 60))	('reduced', 'NegReg', (82, 89))	('expression', 'MPA', (90, 100))	('ZNFs', 'Chemical', '-', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('upregulation', 'PosReg', (165, 177))	('mRNA level', 'MPA', (61, 71))	('multiple cancer', 'Disease', 'MESH:D009369', (181, 196))
17116	30444046	As aberrant splicing is a frequent event in carcinogenesis, we wanted to explore the isoform signature for cancer-associated KRAB-ZNFs in TCGA datasets.	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('carcinogenesis', 'Disease', (44, 58))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('aberrant splicing', 'Var', (3, 20))	('cancer', 'Disease', (107, 113))	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))	('ZNFs', 'Chemical', '-', (130, 134))
17119	30444046	As expected, we found that a majority of splicing variants (84.5%) were overexpressed in cancer tissues compared to their normal counterparts (Fig.	('splicing variants', 'Var', (41, 58))	('splicing', 'biological_process', 'GO:0045292', ('41', '49'))	('overexpressed', 'PosReg', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
17120	30444046	Out of 490 significant isoforms, 21 variants (4.3%) showed expression only in cancer tissues, 220 variants (44.9%) were strongly overexpressed in cancer compared to normal (>= 2-fold overexpression, with the highest level reaching 652-fold change), and 173 variants (35.3%) showed mild overexpression (FC < 2 and >= 1.2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('expression', 'MPA', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('variants', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('overexpression', 'PosReg', (286, 300))	('overexpressed', 'PosReg', (129, 142))	('variants', 'Var', (98, 106))
17121	30444046	It is of note that 21 isoforms that fell below the detection threshold in normal samples included mainly truncated and nonsense variants of ZNF695.	('ZNF695', 'Gene', '57116', (140, 146))	('nonsense', 'Var', (119, 127))	('ZNF695', 'Gene', (140, 146))
17126	30444046	ZNF273, the isoform with a 5' partial deletion of the KRAB domain, was switched to three other isoforms, which could be translated to a full-length protein, a variant with a C-terminal partial deletion of the KRAB domain, and a protein devoid of the zinc finger domain.	('protein', 'cellular_component', 'GO:0003675', ('228', '235'))	('partial deletion', 'Var', (30, 46))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('ZNF273', 'Gene', (0, 6))	('ZNF273', 'Gene', '10793', (0, 6))
17131	30444046	Four out of five ZNF273 variants (Fig.	('ZNF273', 'Gene', '10793', (17, 23))	('ZNF273', 'Gene', (17, 23))	('variants', 'Var', (24, 32))
17189	30444046	Finally, our survival analysis indicated that the expression of KRAB-ZNFs may act as a risk factor.	('KRAB-ZNFs', 'Gene', (64, 73))	('ZNFs', 'Chemical', '-', (69, 73))	('expression', 'Var', (50, 60))
17190	30444046	Patients with high expression of five out of 10 analyzed KRAB-ZNFs presented significantly shorter overall survival than those with low expression (Fig.	('ZNFs', 'Chemical', '-', (62, 66))	('overall survival', 'MPA', (99, 115))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('KRAB-ZNFs', 'Gene', (57, 66))	('shorter', 'NegReg', (91, 98))
17192	30444046	In contrast, high expression was associated with better prognosis in the case of ZNF205 (P < 0.001, hazard ratio = 0.5), ZNF707 (P = 0.001, hazard ratio = 0.5), and ZNF789 (P = 0.017, hazard ratio = 0.5) (Fig.	('ZNF205', 'Gene', (81, 87))	('high', 'Var', (13, 17))	('ZNF707', 'Gene', '286075', (121, 127))	('ZNF789', 'Gene', (165, 171))	('ZNF789', 'Gene', '285989', (165, 171))	('better', 'PosReg', (49, 55))	('ZNF205', 'Gene', '7755', (81, 87))	('ZNF707', 'Gene', (121, 127))
17207	30444046	We observed that the majority of variants was detected both in normal and cancer tissues, but as expected, they had a higher level in tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('variants', 'Var', (33, 41))
17208	30444046	The differential expression of KRAB-ZNF splicing isoforms in cancer was reported only by Juarez-Mendez and colleagues (Juarez-Mendez et al., 2013), who demonstrated a specific increase of ZNF695 variants in ovarian cancer compared to normal cells.	('ZNF', 'Gene', (36, 39))	('variants', 'Var', (195, 203))	('increase', 'PosReg', (176, 184))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('splicing', 'biological_process', 'GO:0045292', ('40', '48'))	('ovarian cancer', 'Disease', (207, 221))	('cancer', 'Disease', (61, 67))	('ZNF', 'Gene', (188, 191))	('ZNF', 'Gene', '284390', (36, 39))	('ZNF695', 'Gene', '57116', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ZNF', 'Gene', '284390', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ovarian cancer', 'Disease', 'MESH:D010051', (207, 221))	('ovarian cancer', 'Phenotype', 'HP:0100615', (207, 221))	('ZNF695', 'Gene', (188, 194))
17219	30444046	Furthermore, we have previously shown that ZNF695 was upregulated in pluripotent stem cells compared to more specialized cell types, whereas its knockdown resulted in the loss of self-renewal properties and differentiation of pluripotent stem cells (Oleksiewicz et al., 2017).	('ZNF695', 'Gene', '57116', (43, 49))	('knockdown', 'Var', (145, 154))	('upregulated', 'PosReg', (54, 65))	('self-renewal properties', 'CPA', (179, 202))	('differentiation', 'CPA', (207, 222))	('ZNF695', 'Gene', (43, 49))	('loss', 'NegReg', (171, 175))
17237	30233553	However, L1 knockdown diminished proliferation of a UC cell line exhibiting robust endogenous L1 expression, but had little impact on a cell line with low L1 expression levels.	('diminished', 'NegReg', (22, 32))	('proliferation', 'CPA', (33, 46))	('knockdown', 'Var', (12, 21))	('a UC', 'CellLine', 'CVCL:F801', (50, 54))
17248	30233553	In contrast, the frequent occurrence of a characteristic mutational A3 signature in urothelial carcinoma (UC) is puzzling, as these tumors are thought to be caused predominantly by chemical carcinogens rather than viral infections.	('viral infections', 'Disease', (214, 230))	('viral infections', 'Disease', 'MESH:D001102', (214, 230))	('urothelial carcinoma', 'Disease', (84, 104))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mutational', 'Var', (57, 67))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (84, 104))
17250	30233553	For instance, the role of A3B in intracellular defense against transposable element activity was recently demonstrated by a twofold to fourfold increase in retrotransposition efficiency of an engineered human L1 reporter after shRNA-based knockdown of A3B in hESCs.	('A3B', 'Gene', (26, 29))	('retrotransposition', 'MPA', (156, 174))	('human', 'Species', '9606', (203, 208))	('knockdown', 'Var', (239, 248))	('retrotransposition', 'biological_process', 'GO:0032197', ('156', '174'))	('A3B', 'Gene', '9582', (252, 255))	('intracellular', 'cellular_component', 'GO:0005622', ('33', '46'))	('A3B', 'Gene', '9582', (26, 29))	('increase', 'PosReg', (144, 152))	('A3B', 'Gene', (252, 255))
17253	30233553	However, L1Hs elements were reported to be particularly strongly hypomethylated in UCs, full-length L1 (FL-L1) transcript levels are increased and L1 ORF1 protein (ORF1p) can be detected in UC tissues.	('UCs', 'Disease', (83, 86))	('hypomethylated', 'Var', (65, 79))	('ORF1', 'Gene', (164, 168))	('transcript levels', 'MPA', (111, 128))	('ORF1', 'Gene', '55354', (150, 154))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('ORF1p', 'Gene', '55354', (164, 169))	('ORF1p', 'Gene', (164, 169))	('increased', 'PosReg', (133, 142))	('ORF1', 'Gene', (150, 154))	('ORF1', 'Gene', '55354', (164, 168))
17260	30233553	Our experiments provide evidence that there is only some minor effect of L1Hs expression on A3B promoter activity, which alone cannot explain the extensive upregulation of A3B expression in UC tissues and cell lines.	('A3B', 'Gene', (92, 95))	('A3B', 'Gene', (172, 175))	('A3B', 'Gene', '9582', (92, 95))	('A3B', 'Gene', '9582', (172, 175))	('L1Hs', 'Var', (73, 77))
17284	30233553	In order to knockdown expression of functional endogenous L1 elements, cells were transfected for 72 h with 20 nmol of either L1_siRNA#1 (5'-GAGAACGCCACAAAGAUACtt-3') or L1_siRNA#2 (5'-GAAAUGAAGCGAGAAGGGAAGUUUA-3') targeting specifically nucleotide positions 1512-1531 or 1287-1312 of the L1.3 reference sequence (acc.no: L19088.1), respectively, (Supplementary Table 2) or a non-specific control (Silencer select negative control siRNA 1; Life Technologies, Darmstadt, Germany).	('1287-1312', 'Var', (272, 281))	('L1.3', 'Gene', '28929', (289, 293))	('L1.3', 'Gene', (289, 293))	('nucleotide', 'Var', (238, 248))
17292	30233553	UC cells 5637 and VM-CUB1 were plated in 24-well dishes and cotransfected with either pA3B-120 or pA3B-1200 and either pJM101/L1RP or pAJG101/L1RP on the next day using X-tremeGENE 9 DNA transfection reagent (Roche).	('A3B', 'Gene', (99, 102))	('A3B', 'Gene', '9582', (87, 90))	('pJM101/L1RP', 'Var', (119, 130))	('pAJG101/L1RP', 'Var', (134, 146))	('A3B', 'Gene', '9582', (99, 102))	('DNA', 'cellular_component', 'GO:0005574', ('183', '186'))	('A3B', 'Gene', (87, 90))
17293	30233553	The cells were cotransfected with each A3B-promoter-luciferase reporter construct or the DeltaHOX plasmid, containing a frameshifted HOXB13 cDNA in pcDNA/TO4, as a MOCK-transfection control.	('A3B', 'Gene', (39, 42))	('HOXB13', 'Gene', '10481', (133, 139))	('frameshifted', 'Var', (120, 132))	('HOXB13', 'Gene', (133, 139))	('A3B', 'Gene', '9582', (39, 42))
17307	30233553	Amplified fragments were subjected to direct Sanger sequencing and results were analyzed for the highly polymorphic SNP rs139297 and the adjacent SNPs rs139298/rs139299.	('rs139297', 'Var', (120, 128))	('rs139298', 'Mutation', 'rs139298', (151, 159))	('rs139299', 'Mutation', 'rs139299', (160, 168))	('rs139297', 'Mutation', 'rs139297', (120, 128))	('SNP', 'Gene', (116, 119))
17311	30233553	A3C, D, and F transcripts were detectable at moderate levels in all tested UPs and the majority of UCCs, but a few UCCs expressed A3C and A3D at extremely low or undetectable levels (Figure 1 and Supplementary Figure 3).	('A3C', 'Var', (130, 133))	('A3C', 'Gene', (0, 3))	('A3C', 'Mutation', 'c.3A>C', (130, 133))	('A3C', 'Mutation', 'c.3A>C', (0, 3))	('A3D', 'Var', (138, 141))
17317	30233553	Because A3H was expressed in several UPs and A3H haplotype I (A3H-I), a specific allele of A3H, has been implicated in breast and lung carcinogenesis, we additionally determined the A3H genotype at SNPs rs139297, rs139298 and rs139299 in UCCs (Supplementary Table 3).	('SNPs', 'Var', (198, 202))	('A3H', 'Gene', (8, 11))	('rs139299', 'Mutation', 'rs139299', (226, 234))	('A3H', 'Gene', '164668', (8, 11))	('A3H', 'Gene', (62, 65))	('A3H', 'Gene', (182, 185))	('rs139297', 'Var', (203, 211))	('rs139298', 'Mutation', 'rs139298', (213, 221))	('A3H', 'Gene', '164668', (182, 185))	('implicated', 'Reg', (105, 115))	('A3H', 'Gene', '164668', (62, 65))	('rs139298', 'Var', (213, 221))	('A3H', 'Gene', (45, 48))	('rs139299', 'Var', (226, 234))	('A3H', 'Gene', (91, 94))	('rs139297', 'Mutation', 'rs139297', (203, 211))	('A3H', 'Gene', '164668', (45, 48))	('A3H', 'Gene', '164668', (91, 94))	('breast and lung carcinogenesis', 'Disease', 'MESH:D063646', (119, 149))
17318	30233553	Approximately two thirds of the tested UCCs harbor the G105/K121 allele associated with the A3H-I haplotype in a homozygous (6/18) or heterozygous (7/18) manner.	('G105/K121', 'Var', (55, 64))	('A3H', 'Gene', (92, 95))	('A3H', 'Gene', '164668', (92, 95))
17320	30233553	This finding implies A3H as a possible but unlikely source of A3 mutations in several but not all UCCs.	('A3H', 'Gene', '164668', (21, 24))	('A3H', 'Gene', (21, 24))	('mutations', 'Var', (65, 74))
17324	30233553	More moderate but still detectable L1 ORF1p levels were present in J82, SW-I710, UMUC6, 253J, 5637, 639-V, 647-V, HT-1376, T24, and UMUC3 cells (Supplementary Figure 4).	('HT-1376', 'CellLine', 'CVCL:1292', (114, 121))	('5637', 'Var', (94, 98))	('639-V', 'Var', (100, 105))	('ORF1p', 'Gene', '55354', (38, 43))	('SW', 'CellLine', 'CVCL:R777', (72, 74))	('253J', 'Var', (88, 92))	('ORF1p', 'Gene', (38, 43))
17331	30233553	Since the partial mRNA knockdown observed in these cell lines nevertheless resulted in a highly efficient L1 ORF1p depletion (Figures 2A-D), this observation indicates that the siRNAs target most if not all intact protein-coding L1 elements harboring an intact ORF1 efficiently.	('ORF1', 'Gene', '55354', (261, 265))	('ORF1p', 'Gene', '55354', (109, 114))	('ORF1', 'Gene', (261, 265))	('knockdown', 'Var', (23, 32))	('ORF1', 'Gene', '55354', (109, 113))	('ORF1p', 'Gene', (109, 114))	('ORF1', 'Gene', (109, 113))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))
17332	30233553	In contrast, non-functional FL-L1 elements with mutations in ORF1 that differ from the L1.3 reference sequence were targeted less efficiently.	('L1.3', 'Gene', (87, 91))	('L1.3', 'Gene', '28929', (87, 91))	('ORF1', 'Gene', '55354', (61, 65))	('mutations', 'Var', (48, 57))	('ORF1', 'Gene', (61, 65))
17340	30233553	L1_siRNA#2-mediated knockdown of ORF1p-expressing endogenous L1 elements was associated with a strong increase of A3G transcript levels in three UCCs ranging from 50% in the SD line to fourfold in VM-CUB1 cells but had no consequences for A3F expression in 5637 cells, and no noteworthy effect on 5637 cells (Figures 2E-H).	('A3G', 'Gene', (114, 117))	('A3G', 'Gene', '60489', (114, 117))	('ORF1p', 'Gene', (33, 38))	('increase', 'PosReg', (102, 110))	('knockdown', 'Var', (20, 29))	('ORF1p', 'Gene', '55354', (33, 38))
17341	30233553	In summary, knockdown of functional L1 elements with L1_siRNA#2 resulted in a general increase of A3C, D, F, and G transcript levels in three out of four analyzed UCCs, while L1_siRNA#1-mediated knockdown was associated with a comparable major increase in A3C, A3D, and A3F transcript levels only in 639-V cells and a minor increase in VM-CUB1 cells.	('A3C', 'Mutation', 'c.3A>C', (256, 259))	('increase', 'PosReg', (244, 252))	('increase', 'PosReg', (86, 94))	('A3C', 'Mutation', 'c.3A>C', (98, 101))	('knockdown', 'Var', (12, 21))	('L1_siRNA#2', 'Var', (53, 63))	('A3C', 'MPA', (256, 259))	('A3F transcript levels', 'MPA', (270, 291))	('A3C', 'MPA', (98, 101))	('A3D', 'MPA', (261, 264))
17342	30233553	To investigate the consequences of ectopic overexpression of retrotransposition-competent L1 elements on endogenous A3B and A3G transcript levels in UCC lines, we next transfected either of the L1 expression plasmids pJM101/L1RP and pAJG101/L1RP (Supplementary Figure 1) into the cell lines VM-CUB1 and 5637, which are characterized by relatively high and low endogenous L1 transcript levels, respectively (Figure 1).	('A3B', 'Gene', (116, 119))	('pJM101/L1RP', 'Var', (217, 228))	('A3G', 'Gene', (124, 127))	('retrotransposition', 'biological_process', 'GO:0032197', ('61', '79'))	('A3B', 'Gene', '9582', (116, 119))	('A3G', 'Gene', '60489', (124, 127))
17344	30233553	We found that expression of A3B and A3G was slightly increased in VM-CUB1 UCC after transfection with pAJG101/L1RP, but only A3B expression changes reached the level of significance (Figures 3A,B).	('A3B', 'Gene', (125, 128))	('A3B', 'Gene', '9582', (28, 31))	('A3G', 'Gene', (36, 39))	('A3G', 'Gene', '60489', (36, 39))	('A3B', 'Gene', '9582', (125, 128))	('pAJG101/L1RP', 'Var', (102, 114))	('expression', 'MPA', (14, 24))	('increased', 'PosReg', (53, 62))	('A3B', 'Gene', (28, 31))	('VM-CUB1', 'Gene', (66, 73))
17347	30233553	Activity of the A3B promoter encoded by pA3B-1200 increased by ~36% - 42% and 64% - 80%, respectively, after co-transfection of the luciferase reporter construct with pJM101/L1RP or pAJG101/L1RP into VM-CUB1 and 5637 cells relative to the effect of the control vector (Figures 3C,D).	('pJM101/L1RP', 'Var', (167, 178))	('increased', 'PosReg', (50, 59))	('A3B', 'Gene', '9582', (16, 19))	('Activity', 'MPA', (0, 8))	('A3B', 'Gene', (41, 44))	('pAJG101/L1RP', 'Var', (182, 194))	('A3B', 'Gene', '9582', (41, 44))	('A3B', 'Gene', (16, 19))
17353	30233553	Therefore, to determine whether A3B or A3G is responsible for any potential deamination activity in these cancer cell lines, A3B and A3G were knocked down separately in different cultures or simultaneously in the same culture.	('A3B', 'Gene', (125, 128))	('A3B', 'Gene', '9582', (125, 128))	('A3B', 'Gene', '9582', (32, 35))	('A3G', 'Gene', (133, 136))	('deamination activity', 'MPA', (76, 96))	('A3G', 'Gene', (39, 42))	('A3G', 'Gene', '60489', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('A3G', 'Gene', '60489', (133, 136))	('knocked', 'Var', (142, 149))	('A3B', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
17369	30233553	Importantly, as expected from the CCCA substrate specificity of A3G, siRNA-mediated knockdown of A3G affected product formation in the CCCA assay more efficiently than in the TTCA assay (Figure 4C).	('A3G', 'Gene', (97, 100))	('A3G', 'Gene', '60489', (97, 100))	('product formation', 'MPA', (110, 127))	('knockdown', 'Var', (84, 93))	('A3G', 'Gene', (64, 67))	('A3G', 'Gene', '60489', (64, 67))	('formation', 'biological_process', 'GO:0009058', ('118', '127'))	('affected', 'Reg', (101, 109))
17370	30233553	Using the CCCA substrate, A3B downregulation slightly reduced product formation, whereas simultaneous knockdown of A3B and A3G abolished detectable deaminase activity.	('abolished', 'NegReg', (127, 136))	('A3B', 'Gene', (26, 29))	('product formation', 'MPA', (62, 79))	('deaminase activity', 'molecular_function', 'GO:0019239', ('148', '166'))	('deaminase activity', 'MPA', (148, 166))	('downregulation', 'NegReg', (30, 44))	('A3B', 'Gene', '9582', (115, 118))	('knockdown', 'Var', (102, 111))	('A3G', 'Gene', (123, 126))	('A3G', 'Gene', '60489', (123, 126))	('reduced', 'NegReg', (54, 61))	('A3B', 'Gene', '9582', (26, 29))	('formation', 'biological_process', 'GO:0009058', ('70', '79'))	('A3B', 'Gene', (115, 118))
17371	30233553	Conversely, using the TTCA substrate, A3B knockdown, but not A3G knockdown resulted in complete loss of detectable deaminase activity (Figure 4C, TTCA panel).	('A3B', 'Gene', '9582', (38, 41))	('deaminase activity', 'MPA', (115, 133))	('A3B', 'Gene', (38, 41))	('deaminase activity', 'molecular_function', 'GO:0019239', ('115', '133'))	('A3G', 'Gene', (61, 64))	('A3G', 'Gene', '60489', (61, 64))	('loss', 'NegReg', (96, 100))	('knockdown', 'Var', (42, 51))
17372	30233553	Taken together, these data confirm that A3G favors the CCCA sequence motif and A3B prefers the TTCA motif, but also indicate that A3B might mutate CCCA sequences on ssDNA substrates with a low frequency.	('mutate', 'Var', (140, 146))	('A3G', 'Gene', (40, 43))	('A3B', 'Gene', (130, 133))	('A3G', 'Gene', '60489', (40, 43))	('CCCA sequences', 'Gene', (147, 161))	('A3B', 'Gene', (79, 82))	('A3B', 'Gene', '9582', (130, 133))	('A3B', 'Gene', '9582', (79, 82))
17377	30233553	Caspase 3/7 activity, measured as an indicator of apoptosis, decreased to 43% and 8% in VM-CUB1 cells after L1_siRNA#1 and L1_siRNA#2 treatment, respectively (Figure 5B).	('apoptosis', 'biological_process', 'GO:0006915', ('50', '59'))	('L1_siRNA#1', 'Var', (108, 118))	('L1_siRNA', 'Var', (123, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('50', '59'))	('activity', 'MPA', (12, 20))	('Caspase 3', 'Gene', (0, 9))	('Caspase 3', 'Gene', '836', (0, 9))	('decreased', 'NegReg', (61, 70))
17379	30233553	Mutations induced by misdirected activity of A3 proteins have been implicated in several cancer types.	('implicated', 'Reg', (67, 77))	('misdirected activity', 'Var', (21, 41))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (89, 95))	('A3 proteins', 'Protein', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
17380	30233553	Following viral replication or in the context of other genomic disturbances, A3 proteins can act as endogenous sources of mutations that can promote genomic instability in cancer evolution.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('viral replication', 'biological_process', 'GO:0019079', ('10', '27'))	('viral replication', 'biological_process', 'GO:0019058', ('10', '27'))	('A3 proteins', 'Protein', (77, 88))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('mutations', 'Var', (122, 131))	('promote', 'PosReg', (141, 148))	('viral replication', 'biological_process', 'GO:0008166', ('10', '27'))	('cancer', 'Disease', (172, 178))	('genomic instability', 'MPA', (149, 168))
17382	30233553	Indeed, in a recently published molecular characterization of muscle-invasive bladder cancer, it was calculated that APOBEC3-mediated mutagenesis contributes 67% of all single nucleotide variants (SNVs).	('APOBEC3-mediated', 'Gene', (117, 133))	('mutagenesis', 'biological_process', 'GO:0006280', ('134', '145'))	('bladder cancer', 'Phenotype', 'HP:0009725', (78, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('single nucleotide variants', 'Var', (169, 195))	('invasive bladder', 'Phenotype', 'HP:0100645', (69, 85))	('APOBEC', 'cellular_component', 'GO:0030895', ('117', '123'))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (62, 92))	('muscle-invasive bladder cancer', 'Disease', (62, 92))
17390	30233553	Thus, our results rather argue for the enzymatic activity of A3B being responsible for the observed mutations, at least in the context of UCC lines.	('A3B', 'Gene', '9582', (61, 64))	('mutations', 'Var', (100, 109))	('A3B', 'Gene', (61, 64))
17395	30233553	Of note, the general DNA motif reported to be recognized by APOBEC proteins to introduce somatic mutations in cancer is "TC" (the A3B-specific motif in our assay here is TTCA).	('mutations', 'Var', (97, 106))	('cancer', 'Disease', (110, 116))	('A3B', 'Gene', (130, 133))	('APOBEC', 'cellular_component', 'GO:0030895', ('60', '66'))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('A3B', 'Gene', '9582', (130, 133))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
17401	30233553	Expression of functional endogenous L1 elements seems a plausible cause for A3 activation, because in urothelial cancer cells, L1 promoter sequences are frequently hypomethylated, and FL-L1 expression is increased even more than in other cancer types.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('increased', 'PosReg', (204, 213))	('urothelial cancer', 'Disease', 'MESH:D014523', (102, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('FL-L1', 'Gene', (184, 189))	('expression', 'MPA', (190, 200))	('hypomethylated', 'Var', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('urothelial cancer', 'Disease', (102, 119))
17407	30233553	Knocking down the expression of endogenous FL-L1 elements with two different siRNAs targeting the intact ORF1 coding region resulted in the efficient depletion of endogenous L1 ORF1p.	('ORF1p', 'Gene', '55354', (177, 182))	('ORF1p', 'Gene', (177, 182))	('ORF1', 'Gene', '55354', (177, 181))	('ORF1', 'Gene', '55354', (105, 109))	('ORF1', 'Gene', (177, 181))	('ORF1', 'Gene', (105, 109))	('FL-L1 elements', 'Gene', (43, 57))	('Knocking', 'Var', (0, 8))
17410	30233553	In particular, efficient knockdown of ORF1p expressing FL-L1 elements by siRNAs diminished proliferation of UCCs with higher L1 expression levels (such as VM-CUB1), but had less effect on UCCs exhibiting lower L1 expression levels (such as 5637 cells).	('ORF1p', 'Gene', '55354', (38, 43))	('proliferation', 'CPA', (91, 104))	('FL-L1 elements', 'Gene', (55, 69))	('ORF1p', 'Gene', (38, 43))	('diminished', 'NegReg', (80, 90))	('knockdown', 'Var', (25, 34))
17411	30233553	These results are in good agreement with previous reports that L1 knockdown causes a loss of proliferative ability in tumor cells independent from apoptosis, ultimately leading to senescence.	('proliferative ability', 'CPA', (93, 114))	('leading to', 'Reg', (169, 179))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('apoptosis', 'biological_process', 'GO:0097194', ('147', '156'))	('senescence', 'MPA', (180, 190))	('tumor', 'Disease', (118, 123))	('loss', 'NegReg', (85, 89))	('apoptosis', 'biological_process', 'GO:0006915', ('147', '156'))	('senescence', 'biological_process', 'GO:0010149', ('180', '190'))	('knockdown', 'Var', (66, 75))
17413	30233553	There is growing evidence suggesting that expression and retrotransposition of LINE-1 in neoplasms affects transcription initiation of oncogenes.	('neoplasms', 'Disease', (89, 98))	('LINE-1', 'Gene', (79, 85))	('retrotransposition', 'Var', (57, 75))	('affects', 'Reg', (99, 106))	('retrotransposition', 'biological_process', 'GO:0032197', ('57', '75'))	('transcription', 'biological_process', 'GO:0006351', ('107', '120'))	('transcription initiation', 'MPA', (107, 131))	('neoplasms', 'Disease', 'MESH:D009369', (89, 98))
17415	30233553	Indeed, L1 expression is linked to the activation of epithelial-mesenchymal transition (EMT) and was shown to affect the expression of miRNA genes (let-7 miRNA family) specifically regulating tumor suppressor expression.	('miRNA genes', 'Gene', (135, 146))	('tumor', 'Disease', (192, 197))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('53', '86'))	('activation', 'PosReg', (39, 49))	('affect', 'Reg', (110, 116))	('expression', 'MPA', (121, 131))	('tumor suppressor', 'biological_process', 'GO:0051726', ('192', '208'))	('EMT', 'biological_process', 'GO:0001837', ('88', '91'))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('192', '208'))	('expression', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('epithelial-mesenchymal transition', 'CPA', (53, 86))
17420	30233553	A3-high tumors demonstrated higher expression of relevant immune marker genes.	('A3-high', 'Var', (0, 7))	('expression', 'MPA', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('higher', 'PosReg', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
17422	30233553	Most advanced muscle-invasive UCs contain mutations inactivating p53, which are rare in non-muscle invasive UC.	('muscle-invasive UCs', 'Disease', (14, 33))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('mutations inactivating', 'Var', (42, 64))
17424	30233553	In particular, loss of p53 or overexpression of gain-of-function mutants leads to upregulation of A3B.	('mutants', 'Var', (65, 72))	('A3B', 'Gene', (98, 101))	('overexpression', 'PosReg', (30, 44))	('loss', 'NegReg', (15, 19))	('upregulation', 'PosReg', (82, 94))	('p53', 'Gene', (23, 26))	('gain-of-function', 'PosReg', (48, 64))	('A3B', 'Gene', '9582', (98, 101))	('p53', 'Gene', '7157', (23, 26))
17437	25431765	Chinese Herbs Containing Aristolochic Acid Associated with Renal Failure and Urothelial Carcinoma: A Review from Epidemiologic Observations to Causal Inference Herbal remedies containing aristolochic acid (AA) have been designated to be a strong carcinogen.	('Urothelial Carcinoma', 'Disease', (77, 97))	('Aristolochic Acid', 'Chemical', 'MESH:C000228', (25, 42))	('Associated', 'Reg', (43, 53))	('Renal Failure', 'Phenotype', 'HP:0000083', (59, 72))	('aristolochic acid', 'Chemical', 'MESH:C000228', (187, 204))	('aristolochic acid', 'Var', (187, 204))	('Aristolochic Acid', 'Var', (25, 42))	('Renal Failure', 'Disease', 'MESH:D051437', (59, 72))	('Renal Failure', 'Disease', (59, 72))	('Carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('Urothelial Carcinoma', 'Disease', 'MESH:D014526', (77, 97))
17468	25431765	subsequently analyzed the urothelial lesions of kidneys and ureters removed during renal transplantation from 10 patients, overexpressed TP53 was observed, which suggested that a TP53 gene mutation plays a role for the carcinogenic effect.	('TP53', 'Gene', (179, 183))	('ureter', 'Disease', (60, 66))	('urothelial lesions of kidneys', 'Disease', (26, 55))	('patients', 'Species', '9606', (113, 121))	('urothelial lesions of kidneys', 'Disease', 'MESH:D007674', (26, 55))	('mutation', 'Var', (189, 197))	('carcinogenic', 'Disease', 'MESH:D063646', (219, 231))	('carcinogenic', 'Disease', (219, 231))	('TP53', 'Gene', '7157', (137, 141))	('ureter', 'Disease', 'MESH:D014516', (60, 66))	('TP53', 'Gene', '7157', (179, 183))	('TP53', 'Gene', (137, 141))
17470	25431765	AL-DNA adducts and TP53 mutations were verified in tumor tissues of most patients.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('DNA', 'cellular_component', 'GO:0005574', ('3', '6'))	('tumor', 'Disease', (51, 56))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('AL', 'Chemical', 'MESH:D000535', (0, 2))	('mutations', 'Var', (24, 33))	('patients', 'Species', '9606', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
17472	25431765	investigated the chromosomal aberrations of UTUC specimens from seven dialysis patients in Taiwan by conventional comparative genomic hybridization and results showed that gains at 5p, 7, and 19q and losses at 4q, 9p, and 15q are common in UTUC of ESRD patients.	('losses', 'NegReg', (200, 206))	('gains at 5p', 'Var', (172, 183))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (17, 40))	('patients', 'Species', '9606', (253, 261))	('ESRD', 'Disease', (248, 252))	('rat', 'Species', '10116', (119, 122))	('rat', 'Species', '10116', (33, 36))	('patients', 'Species', '9606', (79, 87))	('ESRD', 'Disease', 'MESH:D007676', (248, 252))
17474	25431765	found a high somatic mutation rate and the AA-induced mutations were also significantly enriched at splice sites, suggesting a role for splice-site mutations in UTUC pathogenesis.	('pathogenesis', 'biological_process', 'GO:0009405', ('166', '178'))	('mutations', 'Var', (54, 63))	('somatic mutation rate', 'CPA', (13, 34))	('rat', 'Species', '10116', (30, 33))
17475	25431765	analyzed 151 UTUC patients in a medical center of Taiwan and found that AL-DNA adducts were present in the renal cortex of 83% of patients with A : T to T : A mutations in TP53, FGFR3, or HRAS.	('HRAS', 'Gene', (188, 192))	('TP53', 'Gene', '7157', (172, 176))	('mutations', 'Var', (159, 168))	('TP53', 'Gene', (172, 176))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('FGFR3', 'Gene', (178, 183))	('patients', 'Species', '9606', (130, 138))	('HRAS', 'Gene', '3265', (188, 192))	('AL', 'Chemical', 'MESH:D000535', (72, 74))	('patients', 'Species', '9606', (18, 26))	('FGFR', 'molecular_function', 'GO:0005007', ('178', '182'))	('FGFR3', 'Gene', '2261', (178, 183))
17479	25431765	Because human urothelial tissue is rich in peroxidases, the aristolactams activated by peroxidase may result in the formation of the AL-DNA adducts in urothelial tissue and lead to A : T to T : A transverse mutations in the TP53 tumor suppression gene, as demonstrated by overexpression of TP53 protein in patients with AAN and urothelial carcinoma.	('lead to', 'Reg', (173, 180))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('rat', 'Species', '10116', (263, 266))	('TP53', 'Gene', (290, 294))	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (328, 348))	('mutations', 'Var', (207, 216))	('aristolactams', 'Chemical', '-', (60, 73))	('human', 'Species', '9606', (8, 13))	('patients', 'Species', '9606', (306, 314))	('TP53', 'Gene', (224, 228))	('tumor', 'Disease', (229, 234))	('TP53', 'Gene', '7157', (290, 294))	('formation', 'biological_process', 'GO:0009058', ('116', '125'))	('carcinoma', 'Phenotype', 'HP:0030731', (339, 348))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('result in', 'Reg', (102, 111))	('AAN', 'Chemical', '-', (320, 323))	('AL', 'Chemical', 'MESH:D000535', (133, 135))	('urothelial carcinoma', 'Disease', (328, 348))	('protein', 'cellular_component', 'GO:0003675', ('295', '302'))	('TP53', 'Gene', '7157', (224, 228))
17491	25431765	Based on a study including 39 patients with AAN who underwent prophylactic surgery, a cumulative dose of more than 200 g of Guang Fang Ji was associated with a higher risk of urothelial carcinoma.	('Guang', 'Var', (124, 129))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (175, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('patients', 'Species', '9606', (30, 38))	('urothelial carcinoma', 'Disease', (175, 195))	('AAN', 'Chemical', '-', (44, 47))
17501	25431765	The carcinogenesis of AA is associated with specific A : T to T : A mutations in the TP53 tumor-suppressor gene.	('TP53', 'Gene', (85, 89))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('90', '106'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('TP53', 'Gene', '7157', (85, 89))	('mutations', 'Var', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('90', '106'))
17502	25431765	To verify the exposure to AA, ultra-high-performance liquid chromatography-multistage fragmentation mass spectrometry can be applied to determine the presence of aristolochic acid I (AA I) and aristolochic acid II (AA II) in herbal dietary supplements.	('aristolochic acid', 'Var', (162, 179))	('aristolochic acid II', 'Var', (193, 213))	('aristolochic acid I', 'Chemical', 'MESH:C000228', (193, 212))	('aristolochic acid I', 'Chemical', 'MESH:C000228', (162, 181))
17587	33488701	Among human keratins, the recent consensus nomenclature comprises the type I keratins K9-K10, K12-K28, and K31-K40 and type II keratins K1-K8 and K71-K86.	('human', 'Species', '9606', (6, 11))	('K71', 'Gene', '112802', (146, 149))	('K28', 'Gene', (98, 101))	('K12', 'Gene', (94, 97))	('K71', 'Gene', (146, 149))	('K10', 'Gene', '3858', (89, 92))	('K10', 'Gene', (89, 92))	('K12', 'Gene', '3859', (94, 97))	('K86', 'Gene', '3892', (150, 153))	('K86', 'Gene', (150, 153))	('K28', 'Gene', '162605', (98, 101))	('K31-K40', 'Var', (107, 114))
17589	33488701	It is thought that the two cytokeratin subfamilies arose through gene duplication and subsequent divergence of the CK8 and CK18.	('CK', 'Gene', '51727', (115, 117))	('CK18', 'Gene', '3875', (123, 127))	('gene duplication', 'Var', (65, 81))	('CK', 'Gene', '51727', (123, 125))	('CK18', 'Gene', (123, 127))
17709	26372038	Several single-agent trials with PD-1/PD-L1 inhibitors are ongoing in both locally advanced and metastatic bladder cancer (NCT02108652, NCT01848834, and NCT01375842).	('NCT02108652', 'Var', (123, 134))	('bladder cancer', 'Disease', (107, 121))	('bladder cancer', 'Disease', 'MESH:D001749', (107, 121))	('NCT01375842', 'Var', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (107, 121))	('PD-1/PD-L1', 'Gene', (33, 43))	('NCT01848834', 'Var', (136, 147))	('locally advanced', 'Disease', (75, 91))	('NCT01848834', 'Chemical', 'MESH:C079985', (136, 147))
17713	26372038	Randomized phase III trials of MPDL3280A and pembrolizumab in the second-line setting compared with chemotherapy are ongoing (NCT02302807 and NCT02256436).	('MPDL3280A', 'Var', (31, 40))	('NCT02302807', 'Chemical', 'MESH:C079985', (126, 137))	('NCT02302807', 'Var', (126, 137))
17723	26372038	Clinical trials of agonistic anti-OX40 antibody in patients with advanced or metastatic solid tumors, including bladder cancer, are ongoing (NCT02219724 and NCT02221960).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('antibody', 'molecular_function', 'GO:0003823', ('39', '47'))	('OX40', 'Gene', '7293', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('NCT02219724', 'Var', (141, 152))	('bladder cancer', 'Disease', 'MESH:D001749', (112, 126))	('bladder cancer', 'Disease', (112, 126))	('OX40', 'Gene', (34, 38))	('solid tumors', 'Disease', 'MESH:D009369', (88, 100))	('antibody', 'cellular_component', 'GO:0019815', ('39', '47'))	('antibody', 'cellular_component', 'GO:0042571', ('39', '47'))	('metastatic', 'CPA', (77, 87))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('patients', 'Species', '9606', (51, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))	('advanced', 'Disease', (65, 73))	('solid tumors', 'Disease', (88, 100))	('antibody', 'cellular_component', 'GO:0019814', ('39', '47'))
17736	26372038	The presence of TILs has been shown to correlate with improved clinical outcome in many cancer types, including bladder.	('TILs', 'Gene', (16, 20))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('bladder', 'Disease', (112, 119))	('improved', 'PosReg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('presence', 'Var', (4, 12))
17745	26372038	Antigen expression in cancer cells differs from normal cells because of genetic and epigenetic variations.	('epigenetic variations', 'Var', (84, 105))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('differs', 'Reg', (35, 42))
17747	26372038	A recent study revealed that immune checkpoint inhibitors target mutant tumor antigen-specific T cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor antigen', 'molecular_function', 'GO:0008222', ('72', '85'))	('tumor', 'Disease', (72, 77))	('mutant', 'Var', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
17748	26372038	used whole-exome sequencing of nonsmall cell lung cancer (NSCLC) tumors treated with pembrolizumab to reveal the relationship between the number of mutations in a tumor and response to pembrolizumab.	('nonsmall cell lung cancer (NSCLC) tumors', 'Disease', 'MESH:D002289', (31, 71))	('mutations', 'Var', (148, 157))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', (65, 70))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (31, 56))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', (163, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
17749	26372038	The study demonstrated that a higher non-synonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival (PFS).	('progression-free survival', 'CPA', (157, 182))	('objective response', 'CPA', (107, 125))	('non-synonymous mutation burden', 'Var', (37, 67))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('improved', 'PosReg', (98, 106))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
17752	26372038	This study revealed that mutational load is associated with degree of clinical benefit, suggesting that monitoring mutations in tumor cells may provide a predictive biomarker of response to immune checkpoint therapies.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mutational load', 'Var', (25, 40))	('mutations', 'Var', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))
17794	26372038	Recent results from a phase I study in patients with stage III or IV melanoma suggest that combination therapy with blockades of CTLA-4 and PD-1 may be more effective than either agent alone.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('patients', 'Species', '9606', (39, 47))	('combination', 'Interaction', (91, 102))	('PD-1', 'Gene', (140, 144))	('blockades', 'Var', (116, 125))	('CTLA-4', 'Gene', (129, 135))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
17801	26372038	A number of trials of PD-1/PD-L1 blockade in combination with other drugs, including anti-LAG-3 antibody (NCT01968109), anti-CD40 agonistic antibody (NCT02304393), MEK inhibitor (NCT01988896), 4-1BB agonistic antibody (NCT02179918), anti-KIR antibody (NCT01714739), and ID01 inhibitor (NCT02178722), are under way in patients with advanced urothelial cancer.	('CD40', 'Gene', '958', (125, 129))	('antibody', 'cellular_component', 'GO:0042571', ('209', '217'))	('MEK', 'Gene', '5609', (164, 167))	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('antibody', 'cellular_component', 'GO:0019815', ('242', '250'))	('NCT01988896', 'Var', (179, 190))	('antibody', 'molecular_function', 'GO:0003823', ('96', '104'))	('KIR', 'Gene', '3805', (238, 241))	('antibody', 'cellular_component', 'GO:0019815', ('140', '148'))	('KIR', 'Gene', (238, 241))	('antibody', 'cellular_component', 'GO:0042571', ('96', '104'))	('MEK', 'Gene', (164, 167))	('antibody', 'cellular_component', 'GO:0019815', ('209', '217'))	('NCT02304393', 'Chemical', 'MESH:C079985', (150, 161))	('PD-1/PD-L1', 'Gene', (22, 32))	('antibody', 'cellular_component', 'GO:0019814', ('242', '250'))	('advanced urothelial cancer', 'Disease', 'MESH:D014523', (331, 357))	('advanced urothelial cancer', 'Disease', (331, 357))	('NCT01714739', 'Var', (252, 263))	('antibody', 'cellular_component', 'GO:0019814', ('140', '148'))	('NCT02178722', 'Var', (286, 297))	('antibody', 'cellular_component', 'GO:0019815', ('96', '104'))	('NCT02179918', 'Var', (219, 230))	('antibody', 'cellular_component', 'GO:0019814', ('209', '217'))	('antibody', 'molecular_function', 'GO:0003823', ('242', '250'))	('antibody', 'cellular_component', 'GO:0042571', ('242', '250'))	('antibody', 'molecular_function', 'GO:0003823', ('140', '148'))	('CD40', 'Gene', (125, 129))	('NCT01714739', 'Chemical', 'MESH:C079985', (252, 263))	('NCT02178722', 'Chemical', 'MESH:C079985', (286, 297))	('NCT02304393', 'Var', (150, 161))	('antibody', 'cellular_component', 'GO:0042571', ('140', '148'))	('antibody', 'cellular_component', 'GO:0019814', ('96', '104'))	('NCT01968109', 'Var', (106, 117))	('antibody', 'molecular_function', 'GO:0003823', ('209', '217'))	('patients', 'Species', '9606', (317, 325))
17816	29681821	We describe here 2 clinical cases with a histological diagnosis of an invasive sarcomatoid and a poorly differentiated carcinoma favoring urothelial with some neuroendocrine differentiation, two of the rarer types of urothelial cancers, which were evaluated for mutations in 212 genes for single-nucleotide variants and copy-number variants and 53 genes for fusions associated with solid tumors.	('single-nucleotide variants', 'Var', (289, 315))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('carcinoma', 'Disease', (119, 128))	('copy-number variants', 'Var', (320, 340))	('invasive sarcomatoid', 'Disease', 'MESH:C538614', (70, 90))	('solid tumors', 'Disease', 'MESH:D009369', (382, 394))	('tumors', 'Phenotype', 'HP:0002664', (388, 394))	('invasive sarcomatoid', 'Disease', (70, 90))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('urothelial cancers', 'Disease', 'MESH:D014523', (217, 235))	('urothelial cancers', 'Disease', (217, 235))	('solid tumors', 'Disease', (382, 394))	('carcinoma', 'Disease', 'MESH:D002277', (119, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('mutations', 'Var', (262, 271))	('tumor', 'Phenotype', 'HP:0002664', (388, 393))
17817	29681821	In both cases, we identified variants in 2 genes, ARID1A and CDKN2A, indicative of the role of dysregulation of chromatin remodeling and cell cycle control as being common features of bladder cancer, consistent with the proposed model of tumorigenesis in these rare, highly aggressive pathological subtypes.	('chromatin', 'cellular_component', 'GO:0000785', ('112', '121'))	('cell cycle control', 'biological_process', 'GO:1901987', ('137', '155'))	('bladder cancer', 'Disease', (184, 198))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('CDKN2A', 'Gene', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('112', '132'))	('CDKN2A', 'Gene', '1029', (61, 67))	('variants', 'Var', (29, 37))	('tumor', 'Disease', (238, 243))	('bladder cancer', 'Phenotype', 'HP:0009725', (184, 198))	('ARID1A', 'Gene', '8289', (50, 56))	('bladder cancer', 'Disease', 'MESH:D001749', (184, 198))	('ARID1A', 'Gene', (50, 56))
17818	29681821	The presence of a KRAS mutation in the poorly differentiated cancer and a TP53 mutation in the sarcomatoid tumor is indicative of a distinctive profile and adds a potential layer of molecular stratification to these rarer histological subtypes.	('sarcomatoid tumor', 'Disease', (95, 112))	('KRAS', 'Gene', (18, 22))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('mutation', 'Var', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('KRAS', 'Gene', '3845', (18, 22))	('cancer', 'Disease', (61, 67))	('TP53', 'Gene', '7157', (74, 78))	('mutation', 'Var', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('poorly differentiated', 'Disease', (39, 60))	('TP53', 'Gene', (74, 78))	('sarcomatoid tumor', 'Disease', 'MESH:C538614', (95, 112))	('sarcomatoid tumor', 'Phenotype', 'HP:0100242', (95, 112))
17842	29681821	Two genes were mutated in both cases; actionable variants were identified in ARID1A (p.Q1172* - PDUC and p. H782Tfs*51 - sarcomatoid) and CDKN2A (p. N42Kfs*77 - PDUC and p. W110* - sarcomatoid).	('ARID1A', 'Gene', '8289', (77, 83))	('CDKN2A', 'Gene', (138, 144))	('p. N42Kfs*77 - PDUC', 'Var', (146, 165))	('sarcomatoid', 'Disease', (121, 132))	('ARID1A', 'Gene', (77, 83))	('p.Q1172* - PDUC', 'Var', (85, 100))	('p. N42Kfs', 'Mutation', 'p.N42KfsX', (146, 155))	('CDKN2A', 'Gene', '1029', (138, 144))	('p.Q1172*', 'Mutation', 'p.Q1172*', (85, 93))	('sarcomatoid', 'Disease', 'MESH:C538614', (181, 192))	('W110*', 'SUBSTITUTION', 'None', (173, 178))	('p. H782Tfs', 'Mutation', 'p.H782TfsX', (105, 115))	('sarcomatoid', 'Disease', 'MESH:C538614', (121, 132))	('p. H782Tfs*51 -', 'Var', (105, 120))	('W110*', 'Var', (173, 178))	('sarcomatoid', 'Disease', (181, 192))
17843	29681821	Additionally, we identified an actionable KRAS (p.G12D) variant in the PDUC and 2 actionable variants in the tumor suppressors TP53 (p. R273C) and FBXW7 (p. R465C) in the sarcomatoid cancer.	('KRAS', 'Gene', (42, 46))	('sarcomatoid cancer', 'Disease', (171, 189))	('KRAS', 'Gene', '3845', (42, 46))	('FBXW7', 'Gene', '55294', (147, 152))	('p.G12D', 'Mutation', 'rs121913529', (48, 54))	('R465C', 'SUBSTITUTION', 'None', (157, 162))	('sarcomatoid cancer', 'Disease', 'MESH:C538614', (171, 189))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('R465C', 'Var', (157, 162))	('FBXW7', 'Gene', (147, 152))	('R273C', 'Var', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('R273C', 'SUBSTITUTION', 'None', (136, 141))	('tumor', 'Disease', (109, 114))	('sarcomatoid cancer', 'Phenotype', 'HP:0100242', (171, 189))
17844	29681821	While no variants of uncertain significance were identified in the PDUC, we did identify 1 variant of uncertain significance in NFE2L2 (p.E82V) in the sarcomatoid tumor (Table 1).	('sarcomatoid tumor', 'Phenotype', 'HP:0100242', (151, 168))	('sarcomatoid tumor', 'Disease', 'MESH:C538614', (151, 168))	('p.E82V', 'Mutation', 'p.E82V', (136, 142))	('sarcomatoid tumor', 'Disease', (151, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('NFE2L2', 'Gene', '4780', (128, 134))	('NFE2L2', 'Gene', (128, 134))	('p.E82V', 'Var', (136, 142))
17846	29681821	While there were no FDA-approved targeted therapies identified for urothelial tumors in any of the relevant drug classes, FDA-approved drugs for these mutations in other cancers (metastatic or locally advanced solid tumors) were listed in the genomic testing report as potential options for off-label use, consistent with the AMP/ASCO guidelines for reporting of somatic variants.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('urothelial tumors', 'Disease', (67, 84))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('solid tumors', 'Disease', (210, 222))	('AMP', 'Chemical', 'MESH:D000249', (326, 329))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ASCO', 'Chemical', '-', (330, 334))	('solid tumors', 'Disease', 'MESH:D009369', (210, 222))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('mutations', 'Var', (151, 160))	('urothelial tumors', 'Disease', 'MESH:D001749', (67, 84))
17862	29681821	Mutations in 2 genes, ARID1A and CDKN2A, were identified in both our cases and they have been shown to occur in 25 and 5% of urothelial carcinomas, respectively, indicative of the role of dysregulation of chromatin remodeling and cell cycle control in these rare, highly aggressive pathological subtypes.	('cell cycle control', 'biological_process', 'GO:1901987', ('230', '248'))	('CDKN2A', 'Gene', (33, 39))	('chromatin', 'cellular_component', 'GO:0000785', ('205', '214'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('205', '225'))	('CDKN2A', 'Gene', '1029', (33, 39))	('occur', 'Reg', (103, 108))	('Mutations', 'Var', (0, 9))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (125, 146))	('urothelial carcinomas', 'Disease', (125, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('ARID1A', 'Gene', '8289', (22, 28))	('ARID1A', 'Gene', (22, 28))
17864	29681821	In addition, we identified a mutation in KRAS in 1 of the 2 cases (PDUC).	('mutation', 'Var', (29, 37))	('KRAS', 'Gene', (41, 45))	('KRAS', 'Gene', '3845', (41, 45))
17865	29681821	Mutations in the RAS oncogenes (HRAS, KRAS, and NRAS) are found in ~11-13% of bladder tumors and occur in all stages and grades, with mutations in KRAS being the least frequent.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('KRAS', 'Gene', '3845', (38, 42))	('NRAS', 'Gene', '4893', (48, 52))	('HRAS', 'Gene', '3265', (32, 36))	('occur', 'Reg', (97, 102))	('bladder tumors', 'Disease', 'MESH:D001749', (78, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('bladder tumors', 'Phenotype', 'HP:0009725', (78, 92))	('Mutations', 'Var', (0, 9))	('HRAS', 'Gene', (32, 36))	('bladder tumor', 'Phenotype', 'HP:0009725', (78, 91))	('bladder tumors', 'Disease', (78, 92))	('KRAS', 'Gene', (147, 151))	('NRAS', 'Gene', (48, 52))	('KRAS', 'Gene', '3845', (147, 151))	('KRAS', 'Gene', (38, 42))
17866	29681821	Profiling of urothelial cancers across multiple studies have not identified co-occurrence of KRAS with CDKN2A mutations, however, a single study has reported the co-occurrence of a KRAS substitution with an ARID1A truncation mutation in a stage IV high-grade urothelial carcinoma in a 51-year-old male indicative of the rarity of this genomic profile.	('substitution', 'Var', (186, 198))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('KRAS', 'Gene', (93, 97))	('urothelial carcinoma', 'Disease', (259, 279))	('KRAS', 'Gene', '3845', (93, 97))	('urothelial cancers', 'Disease', 'MESH:D014523', (13, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('ARID1A', 'Gene', '8289', (207, 213))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (259, 279))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('CDKN2A', 'Gene', (103, 109))	('urothelial cancers', 'Disease', (13, 31))	('ARID1A', 'Gene', (207, 213))	('KRAS', 'Gene', (181, 185))	('CDKN2A', 'Gene', '1029', (103, 109))	('KRAS', 'Gene', '3845', (181, 185))
17868	29681821	In contrast to the PDUC, the sarcomatoid urothelial carcinoma had actionable mutations in 3 other genes (TP53, FBXW7, and NFE2L2) known to harbor aberration in bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('bladder cancer', 'Disease', 'MESH:D001749', (160, 174))	('sarcomatoid urothelial carcinoma', 'Disease', (29, 61))	('NFE2L2', 'Gene', (122, 128))	('bladder cancer', 'Disease', (160, 174))	('FBXW7', 'Gene', '55294', (111, 116))	('sarcomatoid urothelial carcinoma', 'Disease', 'MESH:C538614', (29, 61))	('mutations', 'Var', (77, 86))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('FBXW7', 'Gene', (111, 116))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('NFE2L2', 'Gene', '4780', (122, 128))
17870	29681821	Mutations in TP53 have been shown to co-occur with either ARID1A or CDKN2A with aberration in the CDK pathway genes being the second most common mutation across most cancers next to TP53.	('TP53', 'Gene', (13, 17))	('CDK', 'Gene', '1019;1021', (68, 71))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('TP53', 'Gene', (182, 186))	('ARID1A', 'Gene', (58, 64))	('CDKN2A', 'Gene', (68, 74))	('CDK', 'Gene', (98, 101))	('aberration', 'Var', (80, 90))	('CDK', 'Gene', '1019;1021', (98, 101))	('ARID1A', 'Gene', '8289', (58, 64))	('Mutations', 'Var', (0, 9))	('CDKN2A', 'Gene', '1029', (68, 74))	('TP53', 'Gene', '7157', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancers', 'Disease', (166, 173))	('TP53', 'Gene', '7157', (182, 186))	('common', 'Reg', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('CDK', 'Gene', (68, 71))	('CDK', 'molecular_function', 'GO:0004693', ('98', '101'))
17871	29681821	Mutations in FBXW7 are observed in 10% of bladder cancers across all stages and mutations in NFE2L2 are observed in ~8-11% of bladder tumors, particularly the basal subtype, based on samples in TCGA suggesting a potential role for the oxidative stress pathway in progression of bladder cancer.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('FBXW7', 'Gene', '55294', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('bladder tumors', 'Disease', (126, 140))	('NFE2L2', 'Gene', '4780', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('bladder cancer', 'Disease', 'MESH:D001749', (278, 292))	('bladder cancer', 'Disease', (278, 292))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('observed', 'Reg', (23, 31))	('bladder cancers', 'Disease', 'MESH:D001749', (42, 57))	('bladder cancer', 'Phenotype', 'HP:0009725', (278, 292))	('bladder tumors', 'Phenotype', 'HP:0009725', (126, 140))	('Mutations', 'Var', (0, 9))	('bladder cancers', 'Disease', (42, 57))	('oxidative stress', 'Phenotype', 'HP:0025464', (235, 251))	('NFE2L2', 'Gene', (93, 99))	('FBXW7', 'Gene', (13, 18))	('bladder tumor', 'Phenotype', 'HP:0009725', (126, 139))	('bladder tumors', 'Disease', 'MESH:D001749', (126, 140))	('bladder cancer', 'Disease', 'MESH:D001749', (42, 56))	('bladder cancers', 'Phenotype', 'HP:0009725', (42, 57))	('observed', 'Reg', (104, 112))
17872	29681821	While co-occurrence of FBXW7 mutations with TP53 has been reported in a single case report, of a high-grade, advanced-stage tumor from a 71-year-old woman, from the lymph node metastasis specimen which had a micropapillary architecture, mutations in NFE2L2 have not been shown to co-occur with TP53 mutations across a comprehensive study evaluating ~400 bladder cancers, contributing to the novelty of this genomic profile and providing further insight into the possible genomic changes involved in the development and evolution of sarcomatoid urothelial carcinoma.	('tumor', 'Disease', (124, 129))	('bladder cancers', 'Disease', 'MESH:D001749', (354, 369))	('TP53', 'Gene', '7157', (294, 298))	('NFE2L2', 'Gene', '4780', (250, 256))	('sarcomatoid urothelial carcinoma', 'Disease', 'MESH:C538614', (532, 564))	('TP53', 'Gene', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('bladder cancers', 'Disease', (354, 369))	('woman', 'Species', '9606', (149, 154))	('FBXW7', 'Gene', (23, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (555, 564))	('sarcomatoid urothelial carcinoma', 'Disease', (532, 564))	('mutations', 'Var', (237, 246))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('NFE2L2', 'Gene', (250, 256))	('mutations', 'Var', (29, 38))	('TP53', 'Gene', '7157', (44, 48))	('FBXW7', 'Gene', '55294', (23, 28))	('TP53', 'Gene', (294, 298))	('cancers', 'Phenotype', 'HP:0002664', (362, 369))	('bladder cancers', 'Phenotype', 'HP:0009725', (354, 369))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('bladder cancer', 'Phenotype', 'HP:0009725', (354, 368))
17876	29681821	Most noteworthy is a trial listed for the ARID1A and KRAS mutations (NCT02576444) which is a phase II study of the PARP inhibitor olaparib (AZD2281) alone and in combination with AZD1775, AZD5363, or AZD2014 in advanced solid tumors across different molecular profiles including any mutation in ARID1A, as well as protocol-defined mutations in KRAS and TP53.	('mutation', 'Var', (283, 291))	('olaparib', 'Chemical', 'MESH:C531550', (130, 138))	('solid tumors', 'Disease', (220, 232))	('ARID1A', 'Gene', (42, 48))	('AZD5363', 'Chemical', 'MESH:C575618', (188, 195))	('PARP', 'Gene', '1302', (115, 119))	('KRAS', 'Gene', (53, 57))	('TP53', 'Gene', (353, 357))	('ARID1A', 'Gene', (295, 301))	('AZD1775', 'Chemical', 'MESH:C549567', (179, 186))	('ARID1A', 'Gene', '8289', (42, 48))	('AZD2014', 'Chemical', 'MESH:C585537', (200, 207))	('KRAS', 'Gene', '3845', (344, 348))	('solid tumors', 'Disease', 'MESH:D009369', (220, 232))	('PARP', 'Gene', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('ARID1A', 'Gene', '8289', (295, 301))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('KRAS', 'Gene', (344, 348))	('AZD5363', 'Var', (188, 195))	('AZD2281', 'Chemical', 'MESH:C531550', (140, 147))	('TP53', 'Gene', '7157', (353, 357))	('KRAS', 'Gene', '3845', (53, 57))
17877	29681821	The TP53 mutation identified in the sarcomatoid case did not fit inclusion criteria, but the mutations in ARID1A and KRAS were eligible, resulting in the inclusion of this trial in the genomic testing report.	('KRAS', 'Gene', (117, 121))	('sarcomatoid', 'Disease', 'MESH:C538614', (36, 47))	('mutations', 'Var', (93, 102))	('TP53', 'Gene', (4, 8))	('ARID1A', 'Gene', '8289', (106, 112))	('ARID1A', 'Gene', (106, 112))	('KRAS', 'Gene', '3845', (117, 121))	('sarcomatoid', 'Disease', (36, 47))	('TP53', 'Gene', '7157', (4, 8))
17880	29681821	The identification of the co-occurring combinations of ARID1A/KRAS in the PDUC and the TP53/FBXW7 in the sarcomatoid subtype adds a layer of potential stratification across these two histological subtypes.	('FBXW7', 'Gene', (92, 97))	('KRAS', 'Gene', (62, 66))	('TP53', 'Gene', '7157', (87, 91))	('KRAS', 'Gene', '3845', (62, 66))	('sarcomatoid subtype', 'Disease', 'MESH:C538614', (105, 124))	('sarcomatoid subtype', 'Disease', (105, 124))	('TP53', 'Gene', (87, 91))	('ARID1A', 'Gene', '8289', (55, 61))	('ARID1A', 'Gene', (55, 61))	('combinations', 'Var', (39, 51))	('FBXW7', 'Gene', '55294', (92, 97))
17885	27885740	 ASP5878, a selective FGFR inhibitor, to treat FGFR3-dependent urothelial cancer with or without chemoresistance FGF/FGFR gene aberrations such as amplification, mutation and fusion are associated with many types of human cancers including urothelial cancer.	('FGFR3', 'Gene', (47, 52))	('human', 'Species', '9606', (216, 221))	('cancer', 'Disease', (74, 80))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('amplification', 'Var', (147, 160))	('FGFR3', 'Gene', '2261', (47, 52))	('mutation', 'Var', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (222, 228))	('FGFR', 'molecular_function', 'GO:0005007', ('117', '121'))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('urothelial cancer', 'Disease', 'MESH:D014523', (240, 257))	('FGF/FGFR', 'Gene', (113, 121))	('fusion', 'Var', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('urothelial cancer', 'Disease', (240, 257))	('cancers', 'Disease', (222, 229))	('associated', 'Reg', (186, 196))	('urothelial cancer', 'Disease', 'MESH:D014523', (63, 80))	('cancer', 'Disease', (251, 257))	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('urothelial cancer', 'Disease', (63, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('ASP5878', 'Chemical', 'MESH:C000615784', (1, 8))
17886	27885740	ASP5878, a selective inhibitor of FGFR1, 2, 3 and 4 under clinical investigation, selectively inhibited cell proliferation of urothelial cancer cell lines harboring FGFR3 point mutation or fusion (UM-UC-14, RT-112, RT4 and SW 780) among 23 urothelial cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('165', '169'))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('RT-112', 'CellLine', 'CVCL:1670', (207, 213))	('FGFR3', 'Gene', (165, 170))	('cell proliferation', 'CPA', (104, 122))	('FGFR1', 'Gene', (34, 39))	('FGFR1', 'Gene', '2260', (34, 39))	('cell proliferation', 'biological_process', 'GO:0008283', ('104', '122'))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('inhibited', 'NegReg', (94, 103))	('point mutation', 'Var', (171, 185))
17887	27885740	Furthermore, ASP5878 inhibited cell proliferation of adriamycin-resistant UM-UC-14 cell line harboring MDR1 overexpression and gemcitabine-resistant RT-112 cell line.	('adriamycin', 'Chemical', 'MESH:D004317', (53, 63))	('gemcitabine', 'Chemical', 'MESH:C056507', (127, 138))	('MDR1', 'Gene', '5243', (103, 107))	('cell proliferation', 'CPA', (31, 49))	('MDR', 'molecular_function', 'GO:0004745', ('103', '106'))	('ASP5878', 'Var', (13, 20))	('MDR1', 'Gene', (103, 107))	('inhibited', 'NegReg', (21, 30))	('overexpression', 'PosReg', (108, 122))	('cell proliferation', 'biological_process', 'GO:0008283', ('31', '49'))
17897	27885740	In a variety of human cancers, aberrant activation of FGF/FGFR signaling promotes cellular proliferation, migration/invasion and angiogenesis.6 Five different FGFR3 point mutations such as R248C, S249C, G372C, Y375C, and K652E account for more than 90% of the point mutations of FGFR3, and S249C is the most common (48%) in bladder cancer.7 The frequency of FGFR3 point mutation in muscle-invasive bladder cancer is lower than that in non-muscle invasive bladder cancer [15% (7/47): invasive, 58% (58/100): non-invasive].7 Another report shows that the frequencies of FGFR3 point mutations in primary muscle invasive urothelial tumors and metastases are 2% (2/161) and 9% (3/33), respectively.8 Recently, it has been also reported that FGFR3-TACC3 and FGFR3-BAIAP2L1, fusion genes were identified in some urothelial cancer cell lines and cancer tissue samples.9, 10 FGFR3 fusion genes are observed in 3% (3/114) of muscle-invasive urothelial cancer.11 Therefore, clinical trials of FGFR inhibitors in urothelial cancer harboring FGFR3 fusion genes or point mutations are ongoing.12 The clinical relevance of FGFR3-TACC3 has been suggested by the clinical report of JNJ-42756493, a pan-FGFR inhibitor, which exerts three out of four partial responses among patients with tumors harboring FGFR3-TACC3 fusion genes.13 In a subset of urothelial cancer patients harboring FGFR3 gene alternation (FGFR3 fusion gene and point mutation) treated with BGJ398, the overall response rate in 25 evaluable patients was 36% and included one unconfirmed complete response and eight partial responses.14 In light of these reports, FGFR3 has been considered as an attractive target for novel therapy in urothelial bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (463, 469))	('FGFR', 'molecular_function', 'GO:0005007', ('1029', '1033'))	('TACC3', 'Gene', '10460', (742, 747))	('FGFR', 'molecular_function', 'GO:0005007', ('752', '756'))	('urothelial bladder cancer', 'Disease', (1685, 1710))	('TACC3', 'Gene', (742, 747))	('S249C', 'SUBSTITUTION', 'None', (196, 201))	('FGFR', 'molecular_function', 'GO:0005007', ('736', '740'))	('FGFR', 'molecular_function', 'GO:0005007', ('866', '870'))	('TACC3', 'Gene', '10460', (1114, 1119))	('muscle invasive urothelial tumors', 'Disease', 'MESH:D009217', (601, 634))	('TACC3', 'Gene', (1114, 1119))	('BAIAP2L1', 'Gene', '55971', (758, 766))	('BGJ398', 'Chemical', 'MESH:C568950', (1442, 1448))	('bladder cancer', 'Phenotype', 'HP:0009725', (455, 469))	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('FGFR', 'molecular_function', 'GO:0005007', ('1614', '1618'))	('S249C', 'Var', (196, 201))	('S249C', 'SUBSTITUTION', 'None', (290, 295))	('-muscle invasive bladder cancer', 'Phenotype', 'HP:0006740', (438, 469))	('invasive bladder', 'Phenotype', 'HP:0100645', (446, 462))	('bladder cancer', 'Phenotype', 'HP:0009725', (398, 412))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('FGFR', 'molecular_function', 'GO:0005007', ('358', '362'))	('FGFR', 'molecular_function', 'GO:0005007', ('568', '572'))	('invasive bladder', 'Phenotype', 'HP:0100645', (389, 405))	('K652E', 'Mutation', 'rs78311289', (221, 226))	('cancer', 'Phenotype', 'HP:0002664', (406, 412))	('FGFR', 'molecular_function', 'GO:0005007', ('1367', '1371'))	('muscle-invasive urothelial cancer', 'Disease', (915, 948))	('S249C', 'Var', (290, 295))	('muscle invasive urothelial tumors', 'Disease', (601, 634))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (435, 462))	('cancer', 'Phenotype', 'HP:0002664', (816, 822))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('S249C', 'Mutation', 'rs121913483', (196, 201))	('FGFR', 'molecular_function', 'GO:0005007', ('982', '986'))	('muscle-invasive urothelial cancer', 'Disease', 'MESH:D009217', (915, 948))	('bladder cancer', 'Phenotype', 'HP:0009725', (324, 338))	('TACC3', 'Gene', '10460', (1293, 1298))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('FGFR', 'molecular_function', 'GO:0005007', ('1185', '1189'))	('TACC3', 'Gene', (1293, 1298))	('BAIAP2L1', 'Gene', (758, 766))	('metastases', 'Disease', 'MESH:D009362', (639, 649))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('G372C', 'Mutation', 'rs121913479', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (1270, 1276))	('S249C', 'Mutation', 'rs121913483', (290, 295))	('bladder cancer', 'Phenotype', 'HP:0009725', (1696, 1710))	('tumors', 'Phenotype', 'HP:0002664', (628, 634))	('FGFR', 'molecular_function', 'GO:0005007', ('1287', '1291'))	('FGFR', 'molecular_function', 'GO:0005007', ('1391', '1395'))	('R248C', 'Mutation', 'rs121913482', (189, 194))	('angiogenesis', 'biological_process', 'GO:0001525', ('129', '141'))	('metastases', 'Disease', (639, 649))	('FGFR', 'molecular_function', 'GO:0005007', ('279', '283'))	('FGFR', 'molecular_function', 'GO:0005007', ('1108', '1112'))	('tumor', 'Phenotype', 'HP:0002664', (1270, 1275))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (1685, 1710))	('Y375C', 'Mutation', 'rs121913485', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (628, 633))
17907	27885740	Phosphorylated and total FGFR3 were measured by sandwich ELISA assay (DYC2719 and DYC766; R&D Systems, Minneapolis, MN, USA).	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('DYC2719', 'Var', (70, 77))	('FGFR3', 'Gene', (25, 30))	('MN', 'CellLine', 'CVCL:U508', (116, 118))	('DYC766', 'Var', (82, 88))
17911	27885740	ASP5878 potently inhibited the tyrosine kinase activities of recombinant FGFR 1, 2, 3 and 4 with IC50 values of, 0.47, 0.60 0.74 and 3.5 nmol/L, respectively (Table S1).	('tyrosine kinase activities', 'MPA', (31, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('73', '77'))	('FGFR 1', 'Gene', '2260', (73, 79))	('inhibited', 'NegReg', (17, 26))	('ASP5878', 'Var', (0, 7))	('FGFR 1', 'Gene', (73, 79))
17913	27885740	Additionally, ASP5878 also inhibited cell proliferation of NCI-H1581 [FGFR1 amplification, lung;18], HSC-39 [FGFR2 amplification, stomach;19], and Hep3B2.1-7 [FGF19 amplification, liver;20] which is known as a FGF19/FGFR4-dependent cell line (Table S3, Appendix S1).	('NCI-H1581', 'Gene', (59, 68))	('cell proliferation', 'biological_process', 'GO:0008283', ('37', '55'))	('NCI-H1581', 'CellLine', 'CVCL:1479', (59, 68))	('FGFR2', 'Gene', '2263', (109, 114))	('FGFR4', 'Gene', (216, 221))	('ASP5878', 'Var', (14, 21))	('FGFR', 'molecular_function', 'GO:0005007', ('70', '74'))	('FGFR', 'molecular_function', 'GO:0005007', ('109', '113'))	('FGFR', 'molecular_function', 'GO:0005007', ('216', '220'))	('inhibited', 'NegReg', (27, 36))	('Hep3B2.1-7', 'CellLine', 'CVCL:0326', (147, 157))	('FGF19', 'Gene', (210, 215))	('FGF19', 'Gene', '9965', (210, 215))	('HSC', 'cellular_component', 'GO:0035301', ('101', '104'))	('cell proliferation', 'CPA', (37, 55))	('FGF19', 'Gene', '9965', (159, 164))	('FGF19', 'Gene', (159, 164))	('FGFR2', 'Gene', (109, 114))	('FGFR4', 'Gene', '2264', (216, 221))
17915	27885740	On the other hand, it has been reported that c-MYC expression was decreased by PD173074, an FGFR inhibitor, in lung cancer cell lines harboring FGFR1 overexpression.30 Activated ERK, a downstream molecule of FGFR, stabilizes c-MYC in melanoma cells.31 In the present study, ASP5878 also inhibited ERK phosphorylation and induced c-MYC down-regulation in urothelial cancer cell line harboring FGFR3 gene alternation independent on gemcitabine resistant status (Fig.	('c-MYC', 'MPA', (329, 334))	('phosphorylation', 'biological_process', 'GO:0016310', ('301', '316'))	('lung cancer', 'Disease', (111, 122))	('regulation', 'biological_process', 'GO:0065007', ('340', '350'))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))	('alternation', 'Var', (403, 414))	('FGFR', 'molecular_function', 'GO:0005007', ('392', '396'))	('FGFR', 'molecular_function', 'GO:0005007', ('208', '212'))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('ASP5878', 'Var', (274, 281))	('FGFR3', 'Gene', (392, 397))	('inhibited', 'NegReg', (287, 296))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('ERK', 'Protein', (297, 300))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('melanoma', 'Disease', (234, 242))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('down-regulation', 'NegReg', (335, 350))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('ERK', 'molecular_function', 'GO:0004707', ('297', '300'))	('ERK', 'molecular_function', 'GO:0004707', ('178', '181'))
17916	27885740	Recently, FGFR inhibitors such as BGJ398 and CH5183284/Debio1347 have been reported to have an antitumor effect in FGFR3-dependent urothelial cancer models.32, 33 And also several FGFR inhibitors including BGJ398, CH5183284/Debio1347, JNJ-42756493 and AZD4547 are being developed for treatment of urothelial cancer.	('CH5183284', 'Chemical', 'MESH:C000602562', (45, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('115', '119'))	('BGJ398', 'Var', (206, 212))	('FGFR', 'molecular_function', 'GO:0005007', ('10', '14'))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('CH5183284', 'Chemical', 'MESH:C000602562', (214, 223))	('FGFR', 'molecular_function', 'GO:0005007', ('180', '184'))	('AZD4547', 'Var', (252, 259))	('AZD4547', 'Chemical', 'MESH:C572463', (252, 259))	('JNJ-42756493', 'Var', (235, 247))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('FGFR', 'Gene', (180, 184))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('urothelial cancer', 'Disease', (297, 314))	('CH5183284/Debio1347', 'Var', (214, 233))
17918	27885740	Patient-derived xenograft models are thought to be useful to make sure the efficacy of ASP5878 in urothelial cancer harboring FGFR3 gene alternation.	('urothelial cancer', 'Disease', (98, 115))	('FGFR3', 'Gene', (126, 131))	('gene alternation', 'Var', (132, 148))	('FGFR', 'molecular_function', 'GO:0005007', ('126', '130'))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Patient', 'Species', '9606', (0, 7))
17921	27885740	These findings suggest that ASP5878, which is currently being evaluated in phase I clinical trials, has therapeutic potential against urothelial bladder cancers harboring FGFR3-TACC3, FGFR3-BAIAP2L1 or FGFR3 point mutation after the acquisition of gemcitabine- or adriamycin- resistance.	('FGFR3-TACC3', 'Gene', (171, 182))	('urothelial bladder cancers', 'Disease', (134, 160))	('bladder cancers', 'Phenotype', 'HP:0009725', (145, 160))	('FGFR3-BAIAP2L1', 'Gene', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('point mutation', 'Var', (208, 222))	('FGFR3', 'Gene', (202, 207))	('urothelial bladder cancers', 'Disease', 'MESH:D001749', (134, 160))	('FGFR', 'molecular_function', 'GO:0005007', ('184', '188'))	('FGFR', 'molecular_function', 'GO:0005007', ('202', '206'))	('FGFR', 'molecular_function', 'GO:0005007', ('171', '175'))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
18021	23781380	This significant difference between the two regions is due in part to aristolochic acid, a substance in a Chinese herb which is known as an important risk factor of urothelial carcinoma and was present as a risk factor in 16/27 (59,3%) of the RTRs diagnosed of TCC.	('TCC', 'cellular_component', 'GO:0005579', ('261', '264'))	('aristolochic acid', 'Chemical', 'MESH:C000228', (70, 87))	('aristolochic acid', 'Var', (70, 87))	('TCC', 'Phenotype', 'HP:0006740', (261, 264))	('urothelial carcinoma', 'Disease', (165, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
18037	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))
18040	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))
18088	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))
18093	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))
18107	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))
18108	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))
18109	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))
18126	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))
18141	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))
18170	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))
18172	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))
18209	32219034	In the KM plotter database, high NFIA and NFIX expression predicted better OS and disease-specific survival (DSS) in liver cancer patients.	('DSS', 'Chemical', '-', (109, 112))	('NFIX', 'Protein', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('disease-specific survival', 'CPA', (82, 107))	('better', 'PosReg', (68, 74))	('liver cancer', 'Phenotype', 'HP:0002896', (117, 129))	('liver cancer', 'Disease', 'MESH:D006528', (117, 129))	('OS', 'Chemical', '-', (75, 77))	('liver cancer', 'Disease', (117, 129))	('NFIA', 'Protein', (33, 37))	('high', 'Var', (28, 32))
18227	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))
18228	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))
18232	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))
18233	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))
18235	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))
18237	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))
18243	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))
18249	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))
18252	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))
18254	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))
18269	31130821	The CHIP-silencing significantly enhanced the AGS cell proliferation capability likely due to the induced phosphorylation of ERK.	('ERK', 'Gene', '5594', (125, 128))	('phosphorylation', 'biological_process', 'GO:0016310', ('106', '121'))	('phosphorylation', 'MPA', (106, 121))	('ERK', 'molecular_function', 'GO:0004707', ('125', '128'))	('ERK', 'Gene', (125, 128))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('CHIP-silencing', 'Var', (4, 18))	('AGS cell proliferation capability', 'CPA', (46, 79))	('enhanced', 'PosReg', (33, 41))
18270	31130821	The CHIP-silencing significantly inhibited apoptosis due to increased expression of Bcl-2.	('apoptosis', 'CPA', (43, 52))	('Bcl-2', 'Gene', (84, 89))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('increased', 'PosReg', (60, 69))	('Bcl-2', 'Gene', '596', (84, 89))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('expression', 'MPA', (70, 80))	('CHIP-silencing', 'Var', (4, 18))	('inhibited', 'NegReg', (33, 42))	('Bcl-2', 'molecular_function', 'GO:0015283', ('84', '89'))
18271	31130821	The CHIP-silencing promoted the AGS cell migration and invasion abilities, likely by regulating the expression of Integrin beta-1.	('promoted', 'PosReg', (19, 27))	('cell migration', 'biological_process', 'GO:0016477', ('36', '50'))	('regulating', 'Reg', (85, 95))	('invasion abilities', 'CPA', (55, 73))	('Integrin beta-1', 'Gene', '3688', (114, 129))	('expression', 'MPA', (100, 110))	('CHIP-silencing', 'Var', (4, 18))	('Integrin beta-1', 'Gene', (114, 129))	('AGS cell migration', 'CPA', (32, 50))
18278	31130821	Lower CHIP or higher TRAF2 was significantly linked to shorter overall survival in gastric cancer patients.	('overall survival', 'MPA', (63, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('shorter', 'NegReg', (55, 62))	('patients', 'Species', '9606', (98, 106))	('TRAF2', 'Gene', '7186', (21, 26))	('gastric cancer', 'Disease', (83, 97))	('Lower CHIP', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('TRAF2', 'Gene', (21, 26))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))
18366	31130821	AP6413B, Abgent, San Diego, CA, USA) and TRAF2 primary Abs (Cat Nr.	('TRAF2', 'Gene', (41, 46))	('TRAF2', 'Gene', '7186', (41, 46))	('AP6413B', 'Var', (0, 7))	('Cat', 'molecular_function', 'GO:0004096', ('60', '63'))
18381	31130821	However, the CHIP-silencing in the AGS cells led to significant induction of p-ERK, indicating of the activation of the ERK signaling (Fig.	('ERK', 'Gene', (79, 82))	('induction', 'PosReg', (64, 73))	('ERK', 'molecular_function', 'GO:0004707', ('120', '123'))	('signaling', 'biological_process', 'GO:0023052', ('124', '133'))	('activation', 'PosReg', (102, 112))	('ERK', 'Gene', '5594', (120, 123))	('ERK', 'molecular_function', 'GO:0004707', ('79', '82'))	('CHIP-silencing', 'Var', (13, 27))	('p-ERK', 'Gene', '9451', (77, 82))	('p-ERK', 'Gene', (77, 82))	('ERK', 'Gene', '5594', (79, 82))	('ERK', 'Gene', (120, 123))
18382	31130821	Therefore, the CHIP-silencing significantly enhanced the AGS cell proliferation capability likely due to the induced phosphorylation of ERK.	('AGS cell proliferation capability', 'CPA', (57, 90))	('phosphorylation', 'biological_process', 'GO:0016310', ('117', '132'))	('ERK', 'molecular_function', 'GO:0004707', ('136', '139'))	('ERK', 'Gene', '5594', (136, 139))	('phosphorylation', 'MPA', (117, 132))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('ERK', 'Gene', (136, 139))	('enhanced', 'PosReg', (44, 52))	('CHIP-silencing', 'Var', (15, 29))
18386	31130821	Therefore, the CHIP-silencing significantly inhibited the AGS apoptosis due to increased expression of Bcl-2.	('Bcl-2', 'Gene', '596', (103, 108))	('increased', 'PosReg', (79, 88))	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('expression', 'MPA', (89, 99))	('CHIP-silencing', 'Var', (15, 29))	('inhibited', 'NegReg', (44, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('AGS apoptosis', 'CPA', (58, 71))	('Bcl-2', 'molecular_function', 'GO:0015283', ('103', '108'))	('Bcl-2', 'Gene', (103, 108))
18417	31130821	The relative luciferase activities in the cell viability assay were 112347.30 +- 3341.51, 166221.00 +- 8858.15, and 164306.00 +- 3278.85 in the sictrl cells, while 51296.00 +- 2631.062, 68389.25 +- 6703.21, and 65559.50 +- 6339.22 in the siTRAF2 cells at 24, 48, and 72 h, respectively (Fig.	('166221.00 +- 8858.15', 'Var', (90, 110))	('activities', 'MPA', (24, 34))	('TRAF2', 'Gene', '7186', (240, 245))	('164306.00 +- 3278.85', 'Var', (116, 136))	('luciferase', 'Enzyme', (13, 23))	('112347.30 +- 3341.51', 'Var', (68, 88))	('TRAF2', 'Gene', (240, 245))	('68389.25 +- 6703.21', 'Var', (186, 205))	('65559.50 +- 6339.22', 'Var', (211, 230))	('51296.00 +- 2631.062', 'Var', (164, 184))
18449	31130821	Kaplan-Meier analyses indicated that GC patients with high-CHIP expression were significantly correlated with a better OS than those with low-CHIP expression (p = 0.01, Fig.	('low-CHIP', 'Disease', 'MESH:D009800', (138, 146))	('high-CHIP expression', 'Var', (54, 74))	('low-CHIP', 'Disease', (138, 146))	('patients', 'Species', '9606', (40, 48))	('better', 'Disease', (112, 118))	('GC', 'Phenotype', 'HP:0012126', (37, 39))	('OS', 'Chemical', '-', (119, 121))
18464	31130821	In the current study, we found that the CHIP-silencing in the AGS gastric cancer cells significantly enhanced cell growth, owing to elevated cell proliferative activity, less apoptosis, and promoted G1/S phase transition.	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))	('AGS gastric cancer', 'Disease', 'MESH:D013274', (62, 80))	('elevated', 'PosReg', (132, 140))	('S phase', 'biological_process', 'GO:0051320', ('202', '209'))	('less', 'NegReg', (170, 174))	('G1/S phase transition', 'CPA', (199, 220))	('apoptosis', 'CPA', (175, 184))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('CHIP-silencing', 'Var', (40, 54))	('AGS gastric cancer', 'Disease', (62, 80))	('cell proliferative activity', 'CPA', (141, 168))	('enhanced', 'PosReg', (101, 109))	('cell growth', 'biological_process', 'GO:0016049', ('110', '121'))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cell growth', 'CPA', (110, 121))	('promoted', 'PosReg', (190, 198))
18465	31130821	The CHIP-silencing in the AGS cells activated the ERK signaling rather than the AKT signaling, contributing to the enhanced cell proliferation capability.	('signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('AKT', 'Gene', '207', (80, 83))	('ERK', 'Gene', '5594', (50, 53))	('AKT signaling', 'biological_process', 'GO:0043491', ('80', '93'))	('ERK', 'Gene', (50, 53))	('activated', 'PosReg', (36, 45))	('cell proliferation capability', 'CPA', (124, 153))	('cell proliferation', 'biological_process', 'GO:0008283', ('124', '142'))	('AKT', 'Gene', (80, 83))	('enhanced', 'PosReg', (115, 123))	('CHIP-silencing', 'Var', (4, 18))	('ERK', 'molecular_function', 'GO:0004707', ('50', '53'))
18466	31130821	The CHIP-silencing inhibited the AGS cell apoptosis due to increased expression of Bcl-2, which is in line the previous report that CHIP-knockdown can regulate the Bcl-2 expression level in breast cancer.	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('increased', 'PosReg', (59, 68))	('Bcl-2', 'Gene', (164, 169))	('Bcl-2', 'molecular_function', 'GO:0015283', ('83', '88'))	('inhibited', 'NegReg', (19, 28))	('Bcl-2', 'Gene', (83, 88))	('AGS cell apoptosis', 'CPA', (33, 51))	('Bcl-2', 'Gene', '596', (83, 88))	('Bcl-2', 'Gene', '596', (164, 169))	('Bcl-2', 'molecular_function', 'GO:0015283', ('164', '169'))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('expression level', 'MPA', (170, 186))	('regulate', 'Reg', (151, 159))	('expression', 'MPA', (69, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('CHIP-silencing', 'Var', (4, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
18467	31130821	The CHIP-silencing notably promoted the G1/S phase transition and entry into the S-phase, which was due to the dysregulated Cyclin D1, Cyclin D3, and p53.	('Cyclin D3', 'Gene', (135, 144))	('G1/S phase transition', 'CPA', (40, 61))	('S-phase', 'biological_process', 'GO:0051320', ('81', '88'))	('Cyclin D1', 'Gene', (124, 133))	('Cyclin', 'molecular_function', 'GO:0016538', ('135', '141'))	('promoted', 'PosReg', (27, 35))	('dysregulated', 'PosReg', (111, 123))	('p53', 'Gene', (150, 153))	('p53', 'Gene', '7157', (150, 153))	('entry', 'CPA', (66, 71))	('Cyclin D3', 'Gene', '896', (135, 144))	('Cyclin', 'molecular_function', 'GO:0016538', ('124', '130'))	('CHIP-silencing', 'Var', (4, 18))	('Cyclin D1', 'Gene', '595', (124, 133))	('S phase', 'biological_process', 'GO:0051320', ('43', '50'))
18468	31130821	In addition, the CHIP-silencing clearly enhanced the abilities of migration and invasion of the AGS cells, which was associated with the increased expression of Integrin beta-1.	('expression', 'MPA', (147, 157))	('Integrin beta-1', 'Gene', (161, 176))	('CHIP-silencing', 'Var', (17, 31))	('increased', 'PosReg', (137, 146))	('Integrin beta-1', 'Gene', '3688', (161, 176))	('enhanced', 'PosReg', (40, 48))	('invasion of the AGS cells', 'CPA', (80, 105))
18476	31130821	The most common genetic alterations of TRAF2 are deep deletion, gene amplification, and mutation.	('TRAF2', 'Gene', '7186', (39, 44))	('mutation', 'Var', (88, 96))	('deep deletion', 'Var', (49, 62))	('TRAF2', 'Gene', (39, 44))	('gene amplification', 'Var', (64, 82))
18477	31130821	Truncation and fusion of TRAF2 are relatively rare but also detected in human cancers.	('fusion', 'Var', (15, 21))	('TRAF2', 'Gene', (25, 30))	('Truncation', 'Var', (0, 10))	('human', 'Species', '9606', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('detected', 'Reg', (60, 68))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('TRAF2', 'Gene', '7186', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
18478	31130821	Genetic alterations of TRAF2 are detected in 1-2% of human hepatocellular carcinoma (HCC).	('Genetic alterations', 'Var', (0, 19))	('hepatocellular carcinoma', 'Disease', (59, 83))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (59, 83))	('TRAF2', 'Gene', (23, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('HCC', 'Gene', '619501', (85, 88))	('HCC', 'Phenotype', 'HP:0001402', (85, 88))	('detected', 'Reg', (33, 41))	('human', 'Species', '9606', (53, 58))	('TRAF2', 'Gene', '7186', (23, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (59, 83))	('HCC', 'Gene', (85, 88))
18488	31130821	GC patients with TRAF2 hypomethylation live much shorter than those with TRAF2 hypermethylation.	('GC', 'Phenotype', 'HP:0012126', (0, 2))	('TRAF2', 'Gene', (73, 78))	('shorter', 'NegReg', (49, 56))	('TRAF2', 'Gene', '7186', (17, 22))	('patients', 'Species', '9606', (3, 11))	('TRAF2', 'Gene', '7186', (73, 78))	('TRAF2', 'Gene', (17, 22))	('hypomethylation', 'Var', (23, 38))
18489	31130821	Cox regression analysis reveals that TRAF2 hypomethylation, lymph node metastasis, distant metastasis, as well as differentiation are vital prognostic factors in GC.	('hypomethylation', 'Var', (43, 58))	('TRAF2', 'Gene', (37, 42))	('TRAF2', 'Gene', '7186', (37, 42))	('GC', 'Phenotype', 'HP:0012126', (162, 164))
18490	31130821	Therefore, TRAF2 expression is increased in GC patients by DNA hypomethylation and this methylation could be an independent diagnostic and prognostic indicator in GC.	('DNA hypomethylation', 'Var', (59, 78))	('increased', 'PosReg', (31, 40))	('expression', 'MPA', (17, 27))	('TRAF2', 'Gene', '7186', (11, 16))	('patients', 'Species', '9606', (47, 55))	('GC', 'Phenotype', 'HP:0012126', (163, 165))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('59', '78'))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('GC', 'Phenotype', 'HP:0012126', (44, 46))	('TRAF2', 'Gene', (11, 16))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
18492	31130821	High TRAF2 expression can enhance NF-kappaB activation and subsequent IL-8 expression in GC cells.	('High', 'Var', (0, 4))	('TRAF2', 'Gene', (5, 10))	('NF-kappaB', 'Gene', '4790', (34, 43))	('activation', 'PosReg', (44, 54))	('NF-kappaB', 'Gene', (34, 43))	('GC', 'Phenotype', 'HP:0012126', (89, 91))	('IL-8', 'Gene', '3576', (70, 74))	('IL-8', 'molecular_function', 'GO:0005153', ('70', '74'))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('34', '54'))	('IL-8', 'Gene', (70, 74))	('expression', 'MPA', (75, 85))	('enhance', 'PosReg', (26, 33))	('TRAF2', 'Gene', '7186', (5, 10))
18494	31130821	In MDA-MB-231 breast cancer cells, TRAF2 has been found to be a substrate for CHIP and that, consequently, CHIP regulates cell invasion via ubiquitination and degradation of TRAF2 and further inhibition of the NF-kappaB activation.	('NF-kappaB', 'Gene', '4790', (210, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('TRAF2', 'Gene', '7186', (35, 40))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('210', '230'))	('cell invasion', 'CPA', (122, 135))	('CHIP', 'Var', (107, 111))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (3, 13))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('breast cancer', 'Disease', (14, 27))	('TRAF2', 'Gene', (174, 179))	('regulates', 'Reg', (112, 121))	('TRAF2', 'Gene', '7186', (174, 179))	('degradation', 'biological_process', 'GO:0009056', ('159', '170'))	('ubiquitination', 'MPA', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('degradation', 'MPA', (159, 170))	('inhibition', 'NegReg', (192, 202))	('NF-kappaB', 'Gene', (210, 219))	('TRAF2', 'Gene', (35, 40))
18512	31130821	Lower CHIP or higher TRAF2 was significantly linked to shorter OS in GC patients.	('shorter OS', 'Disease', (55, 65))	('OS', 'Chemical', '-', (63, 65))	('GC', 'Phenotype', 'HP:0012126', (69, 71))	('TRAF2', 'Gene', '7186', (21, 26))	('Lower CHIP', 'Var', (0, 10))	('TRAF2', 'Gene', (21, 26))	('patients', 'Species', '9606', (72, 80))
18526	29379740	His final pathology demonstrated a T3aNxM0 papillary renal cell carcinoma, clear cell subtype, Fuhrman Grade 2-3, with negative margins.	('papillary renal cell carcinoma', 'Disease', (43, 73))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (53, 73))	('T3aNxM0', 'Var', (35, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (43, 73))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (43, 73))
18542	29379740	Carcinogenic compounds in tobacco smoke induce mutations in tumor suppressor genes (e.g.	('tobacco', 'Species', '4097', (26, 33))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('mutations', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))
18561	28416766	Notch3 knockdown resulted in decreased proliferation of urothelial cancer cells in vitro and decreased xenograft tumor growth in vivo.	('tumor', 'Disease', (113, 118))	('decreased', 'NegReg', (93, 102))	('Notch3', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('proliferation', 'CPA', (39, 52))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('decreased', 'NegReg', (29, 38))	('urothelial cancer', 'Disease', (56, 73))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('knockdown', 'Var', (7, 16))	('urothelial cancer', 'Disease', 'MESH:D014523', (56, 73))
18562	28416766	In addition, Notch3 knockdown rendered urothelial cancer cells more sensitive to cisplatin.	('sensitive to cisplatin', 'MPA', (68, 90))	('Notch3', 'Gene', (13, 19))	('urothelial cancer', 'Disease', 'MESH:D014523', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('more', 'PosReg', (63, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('knockdown', 'Var', (20, 29))	('urothelial cancer', 'Disease', (39, 56))
18576	28416766	Overexpression of Notch3 is associated with chemoresistance and poor overall survival of human ovarian cancer patients and induced resistance to carboplatin in ovarian cancer cells.	('Overexpression', 'Var', (0, 14))	('carboplatin', 'Chemical', 'MESH:D016190', (145, 156))	('human', 'Species', '9606', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('overall survival', 'CPA', (69, 85))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('chemoresistance', 'CPA', (44, 59))	('ovarian cancer', 'Disease', 'MESH:D010051', (160, 174))	('associated', 'Reg', (28, 38))	('ovarian cancer', 'Disease', 'MESH:D010051', (95, 109))	('poor', 'NegReg', (64, 68))	('resistance to carboplatin', 'MPA', (131, 156))	('ovarian cancer', 'Disease', (160, 174))	('ovarian cancer', 'Disease', (95, 109))	('induced', 'Reg', (123, 130))	('Notch3', 'Gene', (18, 24))	('ovarian cancer', 'Phenotype', 'HP:0100615', (160, 174))	('patients', 'Species', '9606', (110, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))
18579	28416766	In this study, we found that high expression of Notch3 was associated with poor patient survival, and may serve as a prognostic marker for urothelial cancer.	('urothelial cancer', 'Disease', 'MESH:D014523', (139, 156))	('high expression', 'Var', (29, 44))	('Notch3', 'Gene', (48, 54))	('poor', 'NegReg', (75, 79))	('patient survival', 'CPA', (80, 96))	('urothelial cancer', 'Disease', (139, 156))	('patient', 'Species', '9606', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
18588	28416766	Notch3 was detected in 55 out of 59 samples (93.2%) of bladder tumor tissues (Figure 2A).	('bladder tumor', 'Disease', 'MESH:D001749', (55, 68))	('bladder tumor', 'Phenotype', 'HP:0009725', (55, 68))	('Notch3', 'Var', (0, 6))	('bladder tumor', 'Disease', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
18590	28416766	Clinical and pathological analyses showed that high Notch3 levels (strong staining) were not significantly associated with tumor size and stage (Table 1), but the Kaplan-Meier analysis indicated that patients with high Notch3 levels had significantly shorter overall survival than those with low levels (Figure 2B, P < 0.001).	('shorter', 'NegReg', (251, 258))	('tumor', 'Disease', (123, 128))	('patients', 'Species', '9606', (200, 208))	('high Notch3', 'Var', (214, 225))	('overall survival', 'MPA', (259, 275))	('Notch3', 'Var', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
18591	28416766	To determine whether Notch3 contributes to urothelial cancer cell proliferation and disease progression, specific shRNAs against Notch3 (shRNA-Notch3-1 and shRNA-Notch3-2) were used to knockdown Notch3 in the human urothelial cancer cell lines T24 and J82.	('human', 'Species', '9606', (209, 214))	('Notch3', 'Gene', (195, 201))	('urothelial cancer', 'Disease', (43, 60))	('urothelial cancer', 'Disease', 'MESH:D014523', (215, 232))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('urothelial cancer', 'Disease', 'MESH:D014523', (43, 60))	('shRNA-Notch3-2', 'Gene', (156, 170))	('knockdown', 'Var', (185, 194))	('urothelial cancer', 'Disease', (215, 232))	('J82', 'CellLine', 'CVCL:0359', (252, 255))	('shRNA-Notch3-2', 'Gene', '4854', (156, 170))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
18593	28416766	We found that Notch3 expression in cells was dramatically reduced after treatment with both Notch3-shRNAs.	('Notch3-shRNAs', 'Var', (92, 105))	('expression', 'MPA', (21, 31))	('men', 'Species', '9606', (77, 80))	('Notch3', 'Gene', (14, 20))	('reduced', 'NegReg', (58, 65))
18596	28416766	These data indicated that reduced urothelial cancer growth induced by Notch3 knockdown was due to reduced cell proliferation.	('cell proliferation', 'CPA', (106, 124))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('urothelial cancer', 'Disease', (34, 51))	('knockdown', 'Var', (77, 86))	('Notch3', 'Gene', (70, 76))	('reduced', 'NegReg', (26, 33))	('urothelial cancer', 'Disease', 'MESH:D014523', (34, 51))	('reduced', 'NegReg', (98, 105))	('cell proliferation', 'biological_process', 'GO:0008283', ('106', '124'))
18599	28416766	Four weeks after establishment of the xenograft models, tumors generated from T24 and J82 cells with Notch3 knockdown were smaller than those generated by control T24 and J82 cells (Figure 4A and 4B).	('J82', 'CellLine', 'CVCL:0359', (171, 174))	('knockdown', 'Var', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('smaller', 'NegReg', (123, 130))	('J82', 'CellLine', 'CVCL:0359', (86, 89))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('men', 'Species', '9606', (26, 29))	('Notch3', 'Gene', (101, 107))
18600	28416766	In addition, Notch3 knockdown decreased tumor weight compared to control values (Figure 4C).	('Notch3', 'Gene', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('knockdown', 'Var', (20, 29))	('tumor', 'Disease', (40, 45))	('decreased', 'NegReg', (30, 39))
18601	28416766	In agreement, Notch3 silencing resulted in reduced Ki-67 levels in urothelial cancer cells in vivo (Figure 4D).	('men', 'Species', '9606', (8, 11))	('urothelial cancer', 'Disease', 'MESH:D014523', (67, 84))	('Ki-67 levels', 'MPA', (51, 63))	('Notch3', 'Gene', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('reduced', 'NegReg', (43, 50))	('urothelial cancer', 'Disease', (67, 84))	('silencing', 'Var', (21, 30))
18604	28416766	To determine whether Notch3 knockdown increases the sensitivity of urothelial cancer cells to cisplatin, T24 cells were treated with cisplatin after Notch3 knockdown.	('increases', 'PosReg', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('knockdown', 'Var', (156, 165))	('urothelial cancer', 'Disease', 'MESH:D014523', (67, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('Notch3', 'Gene', (21, 27))	('sensitivity', 'MPA', (52, 63))	('Notch3', 'Gene', (149, 155))	('knockdown', 'Var', (28, 37))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('urothelial cancer', 'Disease', (67, 84))
18605	28416766	As shown in Figure 5A, both Notch3 knockdown and treatment with cisplatin (5 muM) decreased cell viability of T24 cells, but the reduction was more pronounced in Notch3 knockdown cells treated with cisplatin.	('knockdown', 'Var', (35, 44))	('muM', 'Gene', (77, 80))	('knockdown', 'Var', (169, 178))	('Notch3', 'Gene', (28, 34))	('Notch3 knockdown', 'Var', (162, 178))	('cisplatin', 'Chemical', 'MESH:D002945', (198, 207))	('men', 'Species', '9606', (54, 57))	('muM', 'Gene', '56925', (77, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('decreased', 'NegReg', (82, 91))	('cell viability of T24 cells', 'CPA', (92, 119))
18606	28416766	Colony formation assay showed similar results, with almost complete elimination of cisplatin-resistant colonies observed in Notch3 knockdown T24 cells (Figure 5B).	('knockdown', 'Var', (131, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('formation', 'biological_process', 'GO:0009058', ('7', '16'))	('elimination', 'NegReg', (68, 79))	('Notch3', 'Gene', (124, 130))	('cisplatin-resistant colonies', 'MPA', (83, 111))
18607	28416766	These findings indicated that inhibition of Notch3 expression could sensitize urothelial cancer cells to cisplatin.	('urothelial cancer', 'Disease', (78, 95))	('Notch3', 'Gene', (44, 50))	('inhibition', 'Var', (30, 40))	('urothelial cancer', 'Disease', 'MESH:D014523', (78, 95))	('sensitize', 'Reg', (68, 77))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
18612	28416766	In addition, co-immunoprecipitation demonstrated that SAHA (10 muM) increased the levels of acetylated Notch3 compared to DMSO (vehicle control) (Figure 6C).	('10', 'Var', (60, 62))	('muM', 'Gene', '56925', (63, 66))	('SAHA', 'Chemical', 'MESH:D000077337', (54, 58))	('muM', 'Gene', (63, 66))	('DMSO', 'Chemical', 'MESH:D004121', (122, 126))	('increased', 'PosReg', (68, 77))	('acetylated Notch3', 'MPA', (92, 109))	('levels', 'MPA', (82, 88))
18618	28416766	Taken together, these findings demonstrated that acetylation regulated NOTCH3 ubiquitination, proteasomal degradation, and function.	('ubiquitination', 'MPA', (78, 92))	('NOTCH3', 'Gene', '4854', (71, 77))	('degradation', 'biological_process', 'GO:0009056', ('106', '117'))	('acetylation', 'Var', (49, 60))	('proteasomal degradation', 'MPA', (94, 117))	('NOTCH3', 'Gene', (71, 77))	('function', 'MPA', (123, 131))
18623	28416766	Importantly, high Notch3 levels in urothelial cancer tissues were associated with poor prognosis and short overall survival in patients with urothelial cancer.	('urothelial cancer', 'Disease', 'MESH:D014523', (35, 52))	('urothelial cancer', 'Disease', 'MESH:D014523', (141, 158))	('high', 'Var', (13, 17))	('Notch3 levels', 'MPA', (18, 31))	('urothelial cancer', 'Disease', (35, 52))	('patients', 'Species', '9606', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('urothelial cancer', 'Disease', (141, 158))
18629	28416766	In this study, combining Notch3 knockdown and cisplatin completely abolished drug-resistant colonies of urothelial cancer cells.	('knockdown', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Notch3', 'Gene', (25, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('urothelial cancer', 'Disease', (104, 121))	('abolished', 'NegReg', (67, 76))	('urothelial cancer', 'Disease', 'MESH:D014523', (104, 121))
18630	28416766	These findings corroborate the observation that inhibition of Notch activity prevents the development of drug resistance in cancer cells.	('cancer', 'Disease', (124, 130))	('drug resistance', 'biological_process', 'GO:0009315', ('105', '120'))	('drug resistance', 'biological_process', 'GO:0042493', ('105', '120'))	('men', 'Species', '9606', (97, 100))	('Notch', 'Gene', (62, 67))	('prevents', 'NegReg', (77, 85))	('inhibition', 'Var', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('drug resistance', 'Phenotype', 'HP:0020174', (105, 120))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
18638	28416766	showed that genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract of mice.	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('genetic inactivation', 'Var', (12, 32))	('mice', 'Species', '10090', (136, 140))	('resulting in', 'Reg', (85, 97))	('Erk1/2', 'Gene', (61, 67))	('phosphorylation', 'MPA', (68, 83))	('Erk1', 'molecular_function', 'GO:0004707', ('61', '65'))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('Notch signaling', 'Gene', (36, 51))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('phosphorylation', 'biological_process', 'GO:0016310', ('68', '83'))	('Erk1/2', 'Gene', '26417;26413', (61, 67))	('tumor', 'Disease', (98, 103))
18642	28416766	found in liver cancer that decreased Notch3 expression could increase the p53 levels, inducing DNA damage, increasing adriamycin-induced apoptosis, and blocking cell cycle progression in liver cancer cells; these findings suggested associations of high Notch3 expression and tumor metastasis, vascular invasion, and satellite focus.	('expression', 'MPA', (44, 54))	('decreased', 'NegReg', (27, 36))	('tumor metastasis', 'Disease', (275, 291))	('vascular invasion', 'CPA', (293, 310))	('liver cancer', 'Phenotype', 'HP:0002896', (187, 199))	('p53', 'Gene', (74, 77))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('liver cancer', 'Disease', (187, 199))	('Notch3', 'Gene', (37, 43))	('Notch3', 'Gene', (253, 259))	('adriamycin', 'Chemical', 'MESH:D004317', (118, 128))	('satellite focus', 'CPA', (316, 331))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('blocking', 'NegReg', (152, 160))	('increasing', 'PosReg', (107, 117))	('associations', 'Interaction', (232, 244))	('increase', 'PosReg', (61, 69))	('liver cancer', 'Disease', 'MESH:D006528', (9, 21))	('adriamycin-induced apoptosis', 'MPA', (118, 146))	('cell cycle', 'biological_process', 'GO:0007049', ('161', '171'))	('cell cycle progression', 'CPA', (161, 183))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('DNA damage', 'MPA', (95, 105))	('inducing', 'Reg', (86, 94))	('liver cancer', 'Phenotype', 'HP:0002896', (9, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('liver cancer', 'Disease', (9, 21))	('expression', 'MPA', (260, 270))	('tumor metastasis', 'Disease', 'MESH:D009362', (275, 291))	('liver cancer', 'Disease', 'MESH:D006528', (187, 199))	('p53', 'Gene', '7157', (74, 77))	('high', 'Var', (248, 252))
18643	28416766	Inhibiting Notch3 promotes GSK313 phosphorylation and downregulates p21, increasing the toxic effects of sorafenib on liver cancer cells.	('downregulates', 'NegReg', (54, 67))	('phosphorylation', 'MPA', (34, 49))	('Inhibiting', 'Var', (0, 10))	('p21', 'Gene', '644914', (68, 71))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('GSK313', 'Chemical', '-', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Notch3', 'Gene', (11, 17))	('liver cancer', 'Phenotype', 'HP:0002896', (118, 130))	('liver cancer', 'Disease', 'MESH:D006528', (118, 130))	('promotes', 'PosReg', (18, 26))	('toxic effects', 'MPA', (88, 101))	('GSK', 'molecular_function', 'GO:0050321', ('27', '30'))	('increasing', 'PosReg', (73, 83))	('liver cancer', 'Disease', (118, 130))	('sorafenib', 'Chemical', 'MESH:D000077157', (105, 114))	('p21', 'Gene', (68, 71))	('GSK313', 'Protein', (27, 33))
18664	28416766	The following sequences were used for shNotch3 and control cells: Scrambled shRNA, 5'-CGT ACG CGG AAT ACT TCG A-3'; Notch3 shRNA1, 5'-GCA TGA AGA ACA TGG CCA A-3'; Notch3 shRNA2, 5'-ATG CCT AGA CCT GGT GGA CAA-3'.	('AAT', 'molecular_function', 'GO:0004069', ('98', '101'))	('CCT', 'Gene', '907', (194, 197))	('CCT', 'Gene', '907', (186, 189))	('Notch3 shRNA1', 'Var', (116, 129))	('CGT', 'molecular_function', 'GO:0047801', ('86', '89'))	('GCA', 'molecular_function', 'GO:0033968', ('134', '137'))	('Notch3 shRNA2', 'Var', (164, 177))	('CCT', 'Gene', (194, 197))	('CCT', 'Gene', (186, 189))
18678	28416766	Mouse experiments were approved by the Institutional Animal Care and Use Committee at the Third Military Medical University; 2 x 106 T24 and J82 cells, respectively, treated with Notch3-shRNA or scrambled shRNA, were resuspended in serum-free medium, and subcutaneously injected into the right flank of NOD/SCID mice.	('Notch3-shRNA', 'Var', (179, 191))	('NOD', 'Gene', (303, 306))	('men', 'Species', '9606', (12, 15))	('J82', 'CellLine', 'CVCL:0359', (141, 144))	('Mouse', 'Species', '10090', (0, 5))	('SCID', 'Disease', 'MESH:D053632', (307, 311))	('SCID', 'Disease', (307, 311))	('mice', 'Species', '10090', (312, 316))	('NOD', 'Gene', '1822', (303, 306))
18695	15999101	The aim of our study was to investigate whether LBC could improve p53 immunolabelling, and to assess whether urinary p53 could have a prognostic value.	('p53', 'Gene', '7157', (66, 69))	('p53', 'Gene', (117, 120))	('improve', 'PosReg', (58, 65))	('p53', 'Gene', '7157', (117, 120))	('LBC', 'Var', (48, 51))	('p53', 'Gene', (66, 69))
18697	15999101	After antigen retrieval, cells were labelled with a monoclonal antibody that recognises both wild-type and mutant form of the p53 protein (Clone DO-7, Dako), 1/1000.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('p53', 'Gene', '7157', (126, 129))	('mutant', 'Var', (107, 113))	('antibody', 'cellular_component', 'GO:0042571', ('63', '71'))	('DO-7', 'Chemical', '-', (145, 149))	('antibody', 'cellular_component', 'GO:0019815', ('63', '71'))	('antibody', 'cellular_component', 'GO:0019814', ('63', '71'))	('antibody', 'molecular_function', 'GO:0003823', ('63', '71'))	('p53', 'Gene', (126, 129))
18709	15999101	Mutations and loss of heterozygosity (LOH) commonly induce p53 inactivation, which correlates with protein accumulation in the nuclei of tumour cells.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('induce', 'Reg', (52, 58))	('inactivation', 'NegReg', (63, 75))	('protein', 'MPA', (99, 106))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('loss of heterozygosity', 'Var', (14, 36))	('accumulation', 'PosReg', (107, 119))	('tumour', 'Disease', (137, 143))	('Mutations', 'Var', (0, 9))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
18710	15999101	Numerous studies have shown a clear correlation between p53 gene mutation and the tumour stage and grade of bladder tumours (Brandau and Bohle, 2001).	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('bladder tumours', 'Disease', (108, 123))	('p53', 'Gene', (56, 59))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('bladder tumour', 'Phenotype', 'HP:0009725', (108, 122))	('tumour', 'Disease', (116, 122))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('p53', 'Gene', '7157', (56, 59))	('bladder tumours', 'Disease', 'MESH:D001749', (108, 123))	('tumour', 'Disease', (82, 88))	('mutation', 'Var', (65, 73))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
18711	15999101	Deletions of 17p have been observed in more than 60% of patients with high-grade urothelial carcinomas, as well as in those who recur with muscle infiltration (Friedrich et al, 2001).	('patients', 'Species', '9606', (56, 64))	('urothelial carcinomas', 'Disease', (81, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (81, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('observed', 'Reg', (27, 35))	('Deletions', 'Var', (0, 9))
18733	15999101	This antibody recognises both wild-type and mutant forms of the p53 protein.	('antibody', 'cellular_component', 'GO:0019814', ('5', '13'))	('antibody', 'cellular_component', 'GO:0019815', ('5', '13'))	('antibody', 'molecular_function', 'GO:0003823', ('5', '13'))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('antibody', 'cellular_component', 'GO:0042571', ('5', '13'))	('p53', 'Gene', (64, 67))	('mutant', 'Var', (44, 50))	('protein', 'Protein', (68, 75))	('p53', 'Gene', '7157', (64, 67))
18764	15999101	The eight cases with low-grade urothelial tumours but positive, high-grade cytology findings showed positivity for p53 immunostaining.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('urothelial tumours', 'Disease', (31, 49))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('positivity', 'Var', (100, 110))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('urothelial tumours', 'Disease', 'MESH:D014523', (31, 49))
18781	15999101	Most patients with allelic loss of 17p or p53 mutation have positive p53 immunoreactivity, as well as patients with LOH of the p16 locus located on 9p21 (Sourvinos et al, 2001).	('p53', 'Gene', (42, 45))	('positive', 'PosReg', (60, 68))	('p53', 'Gene', (69, 72))	('patients', 'Species', '9606', (5, 13))	('p53', 'Gene', '7157', (69, 72))	('p16', 'Gene', (127, 130))	('p53', 'Gene', '7157', (42, 45))	('patients', 'Species', '9606', (102, 110))	('17p', 'Gene', (35, 38))	('p16', 'Gene', '1029', (127, 130))	('mutation', 'Var', (46, 54))	('loss', 'NegReg', (27, 31))
18783	15999101	In bladder tumours, a number of studies have shown a positive correlation between p53 overexpression and mutation detection by DNA sequencing (Stadler et al, 2001; Hopman et al, 2002).	('bladder tumour', 'Phenotype', 'HP:0009725', (3, 17))	('bladder tumours', 'Disease', 'MESH:D001749', (3, 18))	('mutation', 'Var', (105, 113))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('overexpression', 'PosReg', (86, 100))	('bladder tumours', 'Disease', (3, 18))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))
18785	15999101	The first studies of p53 alterations in the urine used a cloning approach followed by sequencing to confirm the presence of mutations (Sidransky et al, 1991).	('alterations', 'Var', (25, 36))	('p53', 'Gene', (21, 24))	('p53', 'Gene', '7157', (21, 24))	('mutations', 'Var', (124, 133))
18786	15999101	Thereafter, several reports have compared mutations in tissue samples with those found in the urine: p53 gene mutation in the urine has been shown to correlate with tumour recurrence or residual (Sachs et al, 2000).	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('mutation', 'Var', (110, 118))	('tumour', 'Disease', (165, 171))	('residual', 'CPA', (186, 194))
18787	15999101	Voided urine specimens and bladder wash specimens have >90% accuracy in detecting p53 mutations compared with tumour tissue and show the same mutations after sequencing (Prescott et al, 2001).	('mutations', 'Var', (86, 95))	('men', 'Species', '9606', (45, 48))	('men', 'Species', '9606', (18, 21))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('detecting', 'Var', (72, 81))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))
18788	15999101	Some authors have shown that a number of microsatellite alterations on p16, p53 and RB1 regions found in cytological urine specimens were not detectable in the corresponding tumour biopsies (Sourvinos et al, 2001).	('p16', 'Gene', (71, 74))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('microsatellite', 'Var', (41, 55))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('men', 'Species', '9606', (128, 131))	('RB1', 'Gene', (84, 87))	('p16', 'Gene', '1029', (71, 74))	('tumour', 'Disease', (174, 180))	('RB1', 'Gene', '5925', (84, 87))
18803	15999101	Although some studies have addressed the detection of mutated p53 in urine, none to our knowledge has studied the impact of LBC processing on p53 immunoreactivity.	('p53', 'Gene', (142, 145))	('p53', 'Gene', '7157', (142, 145))	('p53', 'Gene', (62, 65))	('mutated', 'Var', (54, 61))	('p53', 'Gene', '7157', (62, 65))
18815	15999101	Both data illustrate that p53 mutation detection has limited clinical utility for the detection of bladder tumours, but that voided urine specimens provide a good material for studying p53 in a prognostic attempt.	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('p53', 'Gene', (185, 188))	('p53', 'Gene', '7157', (185, 188))	('mutation', 'Var', (30, 38))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (26, 29))	('bladder tumours', 'Disease', (99, 114))	('men', 'Species', '9606', (143, 146))	('bladder tumour', 'Phenotype', 'HP:0009725', (99, 113))	('bladder tumours', 'Disease', 'MESH:D001749', (99, 114))
18823	31872572	Importantly, these NaCl-induced changes also significantly increased UT-B protein abundance (p < .01, n = 7, ANOVA), whereas mannitol-induced changes in external osmolality had no effect (NS, n = 4, ANOVA).	('NaCl', 'Chemical', 'MESH:D012965', (19, 23))	('mannitol', 'Chemical', 'MESH:D008353', (125, 133))	('abundance', 'MPA', (82, 91))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('UT-B protein', 'Protein', (69, 81))	('increased', 'PosReg', (59, 68))	('changes', 'Var', (32, 39))
18834	31872572	Importantly, although no link has been reported between UT-B and human kidney disease (Capriolli, Visentainer, & Sell, 2017), UT-B allelic variation has been shown to affect bladder cancer risk levels (Garcia-Closas et al., 2011; Rafnar et al., 2011).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('kidney disease', 'Phenotype', 'HP:0000112', (71, 85))	('UT-B allelic', 'Var', (126, 138))	('affect', 'MPA', (167, 173))	('Garcia-Closas', 'Disease', 'MESH:C536767', (202, 215))	('bladder cancer', 'Phenotype', 'HP:0009725', (174, 188))	('human kidney disease', 'Disease', 'MESH:D007674', (65, 85))	('Garcia-Closas', 'Disease', (202, 215))	('bladder cancer', 'Disease', 'MESH:D001749', (174, 188))	('bladder cancer', 'Disease', (174, 188))	('human kidney disease', 'Disease', (65, 85))
18836	31872572	More recently, UT-B expression has also been shown to be downregulated in bladder urothelial cancer (Hou, Alemozaffar, et al., 2017a; Li et al., 2014) and a mutated UT-B transporter has been reported in this disease (Hou, Alemozaffar, et al., 2017a).	('UT-B transporter', 'MPA', (165, 181))	('downregulated', 'NegReg', (57, 70))	('expression', 'MPA', (20, 30))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (74, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('UT-B', 'Gene', (15, 19))	('mutated', 'Var', (157, 164))	('bladder urothelial cancer', 'Disease', (74, 99))
18891	31872572	However, the RT4 cells did not contain the 24 nucleotide in-frame, exon 4 deletion mutant recently reported in bladder cancer cells (Hou, Alemozaffar, et al., 2017a).	('bladder cancer', 'Disease', (111, 125))	('RT4', 'CellLine', 'CVCL:0036', (13, 16))	('deletion mutant', 'Var', (74, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (111, 125))	('bladder cancer', 'Disease', 'MESH:D001749', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
18925	31872572	Chronic increases in external osmolality, either through NaCl or urea, lead to a significant increase in glycosylated UT-B protein abundance.	('urea', 'Var', (65, 69))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('NaCl', 'Chemical', 'MESH:D012965', (57, 61))	('increase', 'PosReg', (93, 101))	('glycosylated UT-B protein abundance', 'MPA', (105, 140))	('NaCl', 'Var', (57, 61))	('external osmolality', 'MPA', (21, 40))	('increases', 'PosReg', (8, 17))	('urea', 'Chemical', 'MESH:D014508', (65, 69))
18931	31488176	Clinical data shows that blockade of this PD-1 signaling significantly enhance antitumor immunity, produce durable clinical responses, and prolong survival.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('survival', 'CPA', (147, 155))	('tumor', 'Disease', (83, 88))	('blockade', 'Var', (25, 33))	('prolong', 'PosReg', (139, 146))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('clinical responses', 'CPA', (115, 133))	('enhance', 'PosReg', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
18952	31488176	PD-1 ligation inhibits the induction of the cell survival factor Bcl-xL as well as the expression of transcription factors associated with effector cell function, including GATA-3, Tbet, and Eomes, and limit autoimmunity at the time of inflammatory response to infections.	('inflammatory response', 'biological_process', 'GO:0006954', ('236', '257'))	('autoimmunity', 'Phenotype', 'HP:0002960', (208, 220))	('inhibits', 'NegReg', (14, 22))	('PD-1', 'Gene', (0, 4))	('Tbet', 'Gene', '30009', (181, 185))	('ligation', 'Var', (5, 13))	('autoimmunity', 'Disease', (208, 220))	('Bcl-xL', 'Gene', '598', (65, 71))	('Tbet', 'Gene', (181, 185))	('GATA-3', 'Gene', '2625', (173, 179))	('transcription', 'biological_process', 'GO:0006351', ('101', '114'))	('expression', 'MPA', (87, 97))	('induction', 'MPA', (27, 36))	('Bcl-xL', 'Gene', (65, 71))	('GATA-3', 'Gene', (173, 179))	('autoimmunity', 'Disease', 'MESH:D001327', (208, 220))
18960	31488176	By innate immune resistance, PD-L1 expression is upregulated in some tumor cells by constitutive oncogenic signaling through aberrant activation of the PI3K-AKT pathway or chromosomal alterations and amplifications which is found in Hodgkin lymphoma, independent of inflammatory signals in the tumor microenvironment.	('Hodgkin lymphoma', 'Disease', (233, 249))	('tumor', 'Disease', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('PD-L1', 'Gene', (29, 34))	('tumor', 'Disease', (69, 74))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (233, 249))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (233, 249))	('PI3K', 'molecular_function', 'GO:0016303', ('152', '156'))	('expression', 'MPA', (35, 45))	('activation', 'PosReg', (134, 144))	('upregulated', 'PosReg', (49, 60))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('PI3K-AKT pathway', 'Pathway', (152, 168))	('lymphoma', 'Phenotype', 'HP:0002665', (241, 249))	('chromosomal alterations', 'Var', (172, 195))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
18972	31488176	Inhibitors of PD-1 and PD-L1 disrupt PD-1 axis thereby reverses T cell suppression and enhances endogenous antitumor immunity to unleash long-term antitumor responses for patients with a wide range of cancers.	('T cell suppression', 'MPA', (64, 82))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancers', 'Disease', (201, 208))	('reverses', 'NegReg', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (151, 156))	('Inhibitors', 'Var', (0, 10))	('PD-1', 'Gene', (14, 18))	('PD-1 axis', 'Disease', (37, 46))	('tumor', 'Disease', (111, 116))	('patients', 'Species', '9606', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('PD-1 axis', 'Disease', 'MESH:D010300', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('enhances', 'PosReg', (87, 95))
19007	31488176	The phase III IMpower130 study met its co-primary endpoint of progression-free survival and overall survival with atezolizumab plus chemotherapy (carboplatin plus nab-paclitaxel) compared to chemotherapy alone as the first-line treatment of patients with stage IV non-squamous non-small cell lung cancer and no ALK or EGFR mutations.	('EGFR', 'molecular_function', 'GO:0005006', ('318', '322'))	('mutations', 'Var', (323, 332))	('ALK', 'Gene', (311, 314))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (277, 303))	('lung cancer', 'Phenotype', 'HP:0100526', (292, 303))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (281, 303))	('EGFR', 'Gene', '1956', (318, 322))	('non-small cell lung cancer', 'Disease', (277, 303))	('atezolizumab', 'Chemical', 'MESH:C000594389', (114, 126))	('ALK', 'Gene', '238', (311, 314))	('carboplatin', 'Chemical', 'MESH:D016190', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('paclitaxel', 'Chemical', 'MESH:D017239', (167, 177))	('EGFR', 'Gene', (318, 322))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (277, 303))	('patients', 'Species', '9606', (241, 249))
19021	31488176	Recent studies suggest that targeted therapy enhance antitumor immune responses by releasing new antigens and provide a basis for immunotherapy combined with targeted therapy.	('releasing', 'PosReg', (83, 92))	('enhance', 'PosReg', (45, 52))	('targeted', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
19034	31488176	Responses were early, durable, and observed regardless of PD-L1 expression with higher ORR of 27.6% in patients with high and low expression of PD-L1 compared to 5.1% in patients with negative expression of PD-L1.	('patients', 'Species', '9606', (170, 178))	('expression', 'MPA', (130, 140))	('low', 'NegReg', (126, 129))	('PD-L1', 'Gene', (144, 149))	('high', 'Var', (117, 121))	('patients', 'Species', '9606', (103, 111))	('higher', 'PosReg', (80, 86))
19085	31488176	Based on these results, a phase II study for microsatellite instability-high (MSI-H) advanced solid tumors and a phase III trial for patients with biliary tract carcinoma (cholangiocarcinoma) have been initiated in China.	('MSI-H', 'Disease', (78, 83))	('microsatellite', 'Var', (45, 59))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cholangiocarcinoma', 'Disease', (172, 190))	('solid tumors', 'Disease', 'MESH:D009369', (94, 106))	('patients', 'Species', '9606', (133, 141))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (172, 190))	('biliary tract carcinoma', 'Disease', 'MESH:D001661', (147, 170))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (172, 190))	('MSI-H', 'Disease', 'MESH:D000848', (78, 83))	('biliary tract carcinoma', 'Disease', (147, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('solid tumors', 'Disease', (94, 106))
19091	31488176	Similar to avelumab, CK-301 has functional Fc domain and is capable of inducing ADCC and complement-dependent cytotoxicity (CDC)-mediated killing of PD-L1+ cell lines, including lymphoma cells.	('ADCC', 'CPA', (80, 84))	('CK-301', 'Chemical', '-', (21, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (110, 122))	('lymphoma', 'Disease', (178, 186))	('complement-dependent cytotoxicity', 'biological_process', 'GO:0097278', ('89', '122'))	('lymphoma', 'Disease', 'MESH:D008223', (178, 186))	('lymphoma', 'Phenotype', 'HP:0002665', (178, 186))	('ADCC', 'biological_process', 'GO:0001788', ('80', '84'))	('Fc domain', 'Protein', (43, 52))	('avelumab', 'Chemical', 'MESH:C000609138', (11, 19))	('inducing', 'PosReg', (71, 79))	('cytotoxicity', 'Disease', (110, 122))	('CK-301', 'Var', (21, 27))
19099	31488176	Additionally, there are two pivotal phase II studies for patients with relapsed/refractory extranodal natural killer/T cell lymphoma (NKTL) (NCT03595657) and relapsed/refractory classical Hodgkin lymphoma (rr-cHL)(NCT03505996) and two phase III studies for patients with stage IV non-small cell lung cancer (NCT03789604) and locally advanced/unresectable (stage III) non-small cell lung cancer that has not progressed after prior concurrent/sequential chemoradiotherapy (NCT03728556) have been initiated in China.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (280, 306))	('cell lymphoma', 'Phenotype', 'HP:0012191', (119, 132))	('T cell lymphoma', 'Disease', 'MESH:D016399', (117, 132))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (367, 393))	('Hodgkin lymphoma', 'Disease', (188, 204))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (117, 132))	('T cell lymphoma', 'Disease', (117, 132))	('non-small cell lung cancer', 'Disease', (280, 306))	('patients', 'Species', '9606', (257, 265))	('non-small cell lung cancer', 'Disease', (367, 393))	('lung cancer', 'Phenotype', 'HP:0100526', (382, 393))	('NCT03595657', 'Var', (141, 152))	('NCT03728556', 'Var', (471, 482))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (188, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (295, 306))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (188, 204))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('lymphoma', 'Phenotype', 'HP:0002665', (196, 204))	('NCT03789604', 'Var', (308, 319))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (280, 306))	('lymphoma', 'Phenotype', 'HP:0002665', (124, 132))	('NCT03505996', 'Var', (214, 225))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (367, 393))	('cancer', 'Phenotype', 'HP:0002664', (387, 393))	('patients', 'Species', '9606', (57, 65))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (284, 306))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (371, 393))
19105	31488176	With these promising preclinical data, CBT-502 is undergoing clinical development to assess its safety and tolerability in patients with advanced tumors (NCT03825705, NCT03800706, NCT03855384).	('advanced tumors', 'Disease', 'MESH:D020178', (137, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('CBT-502', 'Gene', (39, 46))	('NCT03855384', 'Var', (180, 191))	('patients', 'Species', '9606', (123, 131))	('advanced tumors', 'Disease', (137, 152))	('NCT03800706', 'Var', (167, 178))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('NCT03825705', 'Var', (154, 165))
19141	31412916	High risk patients included stage T1, grade 3 (WHO73), concurrent or later carcinoma in situ (pTis), three or more separate tumours diagnosed within 18 months or recurrences at multiple sites at first or second follow-up.	('stage T1', 'Disease', (28, 36))	('carcinoma in situ', 'Disease', 'MESH:D002278', (75, 92))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('carcinoma in situ', 'Disease', (75, 92))	('WHO73', 'Var', (47, 52))	('concurrent', 'Disease', (55, 65))	('patients', 'Species', '9606', (10, 18))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (75, 92))	('tumours', 'Disease', 'MESH:D009369', (124, 131))	('tumours', 'Disease', (124, 131))
19149	31412916	All specimens were evaluated by three pathologists, focusing on grading criteria of the individual features, one at a time, for both WHO73 and WHO04.	('WHO04', 'Var', (143, 148))	('WHO73', 'Var', (133, 138))	('men', 'Species', '9606', (9, 12))
19191	25759655	The pathological diagnosis was focal-type lymphoepithelioma-like carcinoma containing a component of urothelial carcinoma G3>G2.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('component of urothelial carcinoma', 'Disease', (88, 121))	('G3>G2', 'Var', (122, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('component of urothelial carcinoma', 'Disease', 'MESH:C562869', (88, 121))	('focal-type lymphoepithelioma-like carcinoma', 'Disease', 'MESH:D005490', (31, 74))	('focal-type lymphoepithelioma-like carcinoma', 'Disease', (31, 74))
19207	25759655	The pathological diagnosis was focal-type LELC containing a component of urothelial carcinoma G3>G2, infiltrative-type.	('focal-type LELC', 'Disease', (31, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('component of urothelial carcinoma', 'Disease', 'MESH:C562869', (60, 93))	('G3>G2', 'Var', (94, 99))	('component of urothelial carcinoma', 'Disease', (60, 93))
19237	31998552	Kaplan-Meier curves and Cox analysis revealed that the high expression of MEX3A was significantly associated with poor survival (OS and RFS) (p < 0.001).	('poor', 'NegReg', (114, 118))	('Cox', 'Gene', '1351', (24, 27))	('MEX3A', 'Gene', '92312', (74, 79))	('Cox', 'Gene', (24, 27))	('high', 'Var', (55, 59))	('MEX3A', 'Gene', (74, 79))
19273	31998552	Chi-square tests were used to analyze clinical variables between the two groups, in which high MEX3A expression was associated with cancer related mortality (p = 0.001; Table 2).	('cancer', 'Disease', (132, 138))	('MEX3A', 'Gene', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('expression', 'MPA', (101, 111))	('high', 'Var', (90, 94))	('MEX3A', 'Gene', '92312', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('associated', 'Reg', (116, 126))
19274	31998552	High MEX3A expression was also associated with a deterioration in liver tumor histopathology (p < 0.001; Table 2).	('MEX3A', 'Gene', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('liver tumor', 'Phenotype', 'HP:0002896', (66, 77))	('MEX3A', 'Gene', '92312', (5, 10))	('liver tumor', 'Disease', 'MESH:D008113', (66, 77))	('deterioration', 'NegReg', (49, 62))	('liver tumor', 'Disease', (66, 77))
19275	31998552	Kaplan-Meier curves showed that patients with high MEX3A expression were more likely to have a poor OS (p < 0.0001; Fig.	('high', 'Var', (46, 50))	('patients', 'Species', '9606', (32, 40))	('MEX3A', 'Gene', '92312', (51, 56))	('MEX3A', 'Gene', (51, 56))	('poor', 'Disease', (95, 99))
19287	31998552	A strong correlation between high MEX3A expression and liver malignancy was also observed.	('high', 'Var', (29, 33))	('expression', 'MPA', (40, 50))	('MEX3A', 'Gene', '92312', (34, 39))	('liver malignancy', 'Phenotype', 'HP:0002896', (55, 71))	('MEX3A', 'Gene', (34, 39))	('malignancy', 'Disease', 'MESH:D009369', (61, 71))	('malignancy', 'Disease', (61, 71))
19293	31998552	found that MEX3A silencing significantly inhibits the proliferation of bladder cancer cells and promotes apoptosis.	('inhibits', 'NegReg', (41, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('105', '114'))	('bladder cancer', 'Disease', 'MESH:D001749', (71, 85))	('MEX3A', 'Gene', '92312', (11, 16))	('apoptosis', 'CPA', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('promotes', 'PosReg', (96, 104))	('MEX3A', 'Gene', (11, 16))	('bladder cancer', 'Disease', (71, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('105', '114'))	('proliferation', 'CPA', (54, 67))	('silencing', 'Var', (17, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))
19294	31998552	similarly reported that MEX3A silencing delays the cell cycle progression of gastric cancer cells.	('MEX3A', 'Gene', '92312', (24, 29))	('gastric cancer', 'Disease', (77, 91))	('MEX3A', 'Gene', (24, 29))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('cell cycle', 'biological_process', 'GO:0007049', ('51', '61'))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('silencing', 'Var', (30, 39))	('cell cycle progression of', 'CPA', (51, 76))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('delays', 'NegReg', (40, 46))
19295	31998552	MEX3A silencing significantly inhibited cell migration and anchorage-independent growth.	('cell migration', 'biological_process', 'GO:0016477', ('40', '54'))	('MEX3A', 'Gene', (0, 5))	('inhibited', 'NegReg', (30, 39))	('MEX3A', 'Gene', '92312', (0, 5))	('silencing', 'Var', (6, 15))
19344	30497361	showed aberrant expression of TSC gene in breast cancer that it is related to clinical outcome in this cancer tissue.	('related', 'Reg', (67, 74))	('TSC', 'Gene', (30, 33))	('TSC', 'Gene', '7248', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('aberrant', 'Var', (7, 15))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('expression', 'MPA', (16, 26))	('cancer', 'Disease', (49, 55))
19363	30497361	In that field, protein-protein interaction (PPI) networks can provide much information about the comprehension of biological processes in an organism, and their aberrant interaction networks are the basis of multiple aggregation-related diseases, such as Creutzfeldt-Jakob, Alzheimer's diseases, and may also lead to cancer.	('aberrant', 'Var', (161, 169))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('Creutzfeldt-Jakob', 'Disease', (255, 272))	('interaction', 'MPA', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	("Alzheimer's diseases", 'Disease', 'MESH:D000544', (274, 294))	('PPI', 'biological_process', 'GO:0060134', ('44', '47'))	('lead to', 'Reg', (309, 316))	("Alzheimer's diseases", 'Disease', (274, 294))	('basis', 'Reg', (199, 204))	('cancer', 'Disease', (317, 323))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
19438	30008848	Non-papillary, flat tumor growth was statistically significantly strongly associated with tumor muscle invasion (OR 31.00, 95% CI 66.24-153.95).	('flat tumor', 'Disease', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('Non-papillary', 'Var', (0, 13))	('associated', 'Reg', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('flat tumor', 'Disease', 'MESH:D005413', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
19499	32449280	Furthermore, SLC12A5 expression was suppressed by miR-133a-3p.	('suppressed', 'NegReg', (36, 46))	('miR-133a-3p', 'Chemical', '-', (50, 61))	('miR-133a-3p', 'Var', (50, 61))	('expression', 'MPA', (21, 31))	('SLC12A5', 'Gene', (13, 20))
19503	32449280	High SLC12A5 expression was associated with poor survival of patients with bladder urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('SLC12A5', 'Gene', (5, 12))	('High', 'Var', (0, 4))	('expression', 'MPA', (13, 23))	('poor', 'NegReg', (44, 48))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (75, 103))	('patients', 'Species', '9606', (61, 69))	('bladder urothelial carcinoma', 'Disease', (75, 103))
19505	32449280	SLC12A5 expression was suppressed by miR-133a-3p.	('suppressed', 'NegReg', (23, 33))	('miR-133a-3p', 'Var', (37, 48))	('miR-133a-3p', 'Chemical', '-', (37, 48))	('SLC12A5', 'Gene', (0, 7))	('expression', 'MPA', (8, 18))
19511	32449280	However, recent studies have shown that mutation and abnormal expression of SLC12A5 is involved in the tumorigenesis and progression of some human cancers.	('SLC12A5', 'Gene', (76, 83))	('mutation', 'Var', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Disease', (103, 108))	('expression', 'MPA', (62, 72))	('involved', 'Reg', (87, 95))	('progression', 'CPA', (121, 132))	('human', 'Species', '9606', (141, 146))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
19512	32449280	7 ,  8 ,  9 ,  10 ,  11 ,  12  Recently, we found that high expression of SLC12A5 is an independent molecular marker for shortened survival of patients with BUC.	('SLC12A5', 'Gene', (74, 81))	('patients', 'Species', '9606', (143, 151))	('shortened', 'NegReg', (121, 130))	('high', 'Var', (55, 59))	('survival', 'CPA', (131, 139))
19540	32449280	Primary antibodies comprised: anti-SLC12A5 (1:1000 dilution, Abcam), anti-SOX18 (1:1000 dilution, Cell Signaling Technology), anti-MMP7 (1:1000 dilution, Abcam), anti-MMP2 (1:800 dilution, Abcam), anti-MMP9 (1:1000 dilution, Abcam), and anti-GAPDH (1:5000 dilution, Cell Signaling Technology).	('MMP7', 'Gene', '4316', (131, 135))	('MMP9', 'molecular_function', 'GO:0004229', ('202', '206'))	('Signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('MMP7', 'molecular_function', 'GO:0004235', ('131', '135'))	('SOX18', 'Gene', (74, 79))	('MMP2', 'Gene', '4313', (167, 171))	('anti-SLC12A5', 'Var', (30, 42))	('GAPDH', 'Gene', '2597', (242, 247))	('Signaling', 'biological_process', 'GO:0023052', ('271', '280'))	('MMP2', 'molecular_function', 'GO:0004228', ('167', '171'))	('SOX18', 'Gene', '54345', (74, 79))	('MMP7', 'Gene', (131, 135))	('GAPDH', 'Gene', (242, 247))	('MMP2', 'Gene', (167, 171))	('MMP9', 'Gene', '4318', (202, 206))	('MMP9', 'Gene', (202, 206))
19542	32449280	Primary antibodies comprised: anti-SLC12A5 (1:100 dilution, Abcam), anti-SOX18 (1:200 dilution, Cell Signaling Technology), and anti-MMP7 (1:1000 dilution, Abcam).	('MMP7', 'Gene', (133, 137))	('SOX18', 'Gene', (73, 78))	('MMP7', 'Gene', '4316', (133, 137))	('anti-SLC12A5', 'Var', (30, 42))	('Signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('SOX18', 'Gene', '54345', (73, 78))	('MMP7', 'molecular_function', 'GO:0004235', ('133', '137'))
19568	32449280	In the learning and validation cohorts, univariate analysis showed that poor OS for patients with BUC correlated with high SLC12A5 expression (P < .001 and P = .002, respectively; Figure 1E,F; Table S1).	('high', 'Var', (118, 122))	('expression', 'MPA', (131, 141))	('SLC12A5', 'Gene', (123, 130))	('patients', 'Species', '9606', (84, 92))
19574	32449280	However, Boyden chamber assays demonstrated that SLC12A5 increased the migration of 5637 and UM-UC-3 cells across the Transwell membrane by 3-fold to 4-fold (Figure 2E).	('migration', 'CPA', (71, 80))	('UM-UC-3', 'CellLine', 'CVCL:1783', (93, 100))	('membrane', 'cellular_component', 'GO:0016020', ('128', '136'))	('SLC12A5', 'Var', (49, 56))	('increased', 'PosReg', (57, 66))
19575	32449280	Similarly, the numbers of 5637 and UM-UC-3 cells that invaded through Matrigel in the Transwell insert were also significantly increased by SLC12A5 overexpression (Figure 2F).	('SLC12A5', 'Gene', (140, 147))	('increased', 'PosReg', (127, 136))	('UM-UC-3', 'CellLine', 'CVCL:1783', (35, 42))	('overexpression', 'Var', (148, 162))
19583	32449280	In BUC cells, the expression level of SOX18 mRNA was unaffected by SLC12A5 overexpression (Figure 3A); however, in 5637 and UM-UC-3 cells, overexpression of SLC12A5 increased the SOX18 protein level; in T24 cells, SLC12A5 knockdown had the opposite effect (Figure 3B).	('SOX18', 'Gene', '54345', (179, 184))	('SOX18', 'Gene', '54345', (38, 43))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('UM-UC-3', 'CellLine', 'CVCL:1783', (124, 131))	('SLC12A5', 'Var', (157, 164))	('SOX18', 'Gene', (179, 184))	('SOX18', 'Gene', (38, 43))	('increased', 'PosReg', (165, 174))
19584	32449280	Thus, SLC12A5 functions to increase the SOX18 protein level.	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('SOX18', 'Gene', (40, 45))	('SLC12A5', 'Var', (6, 13))	('SOX18', 'Gene', '54345', (40, 45))	('increase', 'PosReg', (27, 35))
19593	32449280	Importantly, high expression of SOX18 was associated with poor OS in these 2 cohorts (P < .001 and P = .007, respectively; Figure S2).	('SOX18', 'Gene', (32, 37))	('poor OS', 'Disease', (58, 65))	('high expression', 'Var', (13, 28))	('SOX18', 'Gene', '54345', (32, 37))
19594	32449280	Short hairpin RNA (shRNA) was used to knockdown SLC12A5 expression to determine whether SLC12A5 modulates SOX18 levels.	('SOX18', 'Gene', '54345', (106, 111))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('modulates', 'Reg', (96, 105))	('SOX18', 'Gene', (106, 111))	('SLC12A5', 'Gene', (48, 55))	('knockdown', 'Var', (38, 47))
19596	32449280	Inhibition of protein synthesis by CHX for different times, followed by analysis using western blotting, suggested that SOX18 half-life was markedly extended after SLC12A5 knockdown (Figure S5).	('SOX18', 'Gene', '54345', (120, 125))	('extended', 'PosReg', (149, 157))	('SLC12A5', 'Gene', (164, 171))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('protein synthesis', 'biological_process', 'GO:0006412', ('14', '31'))	('SOX18', 'Gene', (120, 125))	('protein synthesis', 'MPA', (14, 31))	('knockdown', 'Var', (172, 181))
19602	32449280	However, MMP7 expression was significantly attenuated by SLC12A5 knockdown in T24 cells (Figure 4C,D).	('MMP7', 'Gene', '4316', (9, 13))	('SLC12A5', 'Gene', (57, 64))	('MMP7', 'molecular_function', 'GO:0004235', ('9', '13'))	('expression', 'MPA', (14, 24))	('attenuated', 'NegReg', (43, 53))	('knockdown', 'Var', (65, 74))	('MMP7', 'Gene', (9, 13))
19608	32449280	Moreover, in 5637 and UM-UC-3 cells that overexpressed SLC12A5, SOX18 knockdown led to rescued SOX18 levels (Figure S7A).	('SOX18', 'Gene', '54345', (95, 100))	('knockdown', 'Var', (70, 79))	('SOX18', 'Gene', (64, 69))	('SOX18', 'Gene', (95, 100))	('SLC12A5', 'Gene', (55, 62))	('rescued', 'PosReg', (87, 94))	('UM-UC-3', 'CellLine', 'CVCL:1783', (22, 29))	('SOX18', 'Gene', '54345', (64, 69))
19610	32449280	In addition, MMP7 knockdown rescued the ability of SLC12A5 overexpression to promote 5637 and UM-UC-3 cell migration and invasion (Figure S7D,E).	('promote', 'PosReg', (77, 84))	('MMP7', 'Gene', (13, 17))	('overexpression', 'Var', (59, 73))	('MMP7', 'Gene', '4316', (13, 17))	('UM-UC-3', 'CellLine', 'CVCL:1783', (94, 101))	('SLC12A5', 'Gene', (51, 58))	('invasion', 'CPA', (121, 129))	('MMP7', 'molecular_function', 'GO:0004235', ('13', '17'))	('cell migration', 'biological_process', 'GO:0016477', ('102', '116'))
19614	32449280	A putative binding site for miR-133a-3p in the SLC12A5 3' untranslated region (UTR) was identified (Figure 5A).	('binding', 'Interaction', (11, 18))	('SLC12A5', 'Gene', (47, 54))	('binding', 'molecular_function', 'GO:0005488', ('11', '18'))	('miR-133a-3p', 'Var', (28, 39))	('miR-133a-3p', 'Chemical', '-', (28, 39))
19615	32449280	In T24 and 5637cells, miR-133a-3p overexpression markedly reduced the protein and mRNA levels of SLC12A5 (Figure 5B-D).	('mRNA levels of SLC12A5', 'MPA', (82, 104))	('miR-133a-3p', 'Var', (22, 33))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('miR-133a-3p', 'Chemical', '-', (22, 33))	('protein', 'MPA', (70, 77))	('reduced', 'NegReg', (58, 65))
19617	32449280	The activity of the wild-type 3'UTR of SLC12A5 was attenuated by miR-133a-3p overexpression, but it had no effect on the activity of the mutant 3'UTR, as shown by dual-luciferase reporter assay (Figure 5E).	('SLC12A5', 'Gene', (39, 46))	('attenuated', 'NegReg', (51, 61))	('overexpression', 'Var', (77, 91))	('miR-133a-3p', 'Chemical', '-', (65, 76))	('activity', 'MPA', (4, 12))	('miR-133a-3p', 'Var', (65, 76))
19620	32449280	Our results validated previous reports 25 ,  26  that miR-133a-3p functions as a tumor suppressor in BUC (Figure 5G,H).	('tumor suppressor', 'biological_process', 'GO:0051726', ('81', '97'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('81', '97'))	('miR-133a-3p', 'Var', (54, 65))	('miR-133a-3p', 'Chemical', '-', (54, 65))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
19622	32449280	SLC12A5 overexpression in miR-133a-3p-BUC cells abrogated miR-133a-3p-induced suppression of BUC cell migration and invasion (Figure 5G,H).	('overexpression', 'PosReg', (8, 22))	('abrogated', 'NegReg', (48, 57))	('miR-133a-3p', 'Chemical', '-', (26, 37))	('miR-133a-3p-induced', 'Var', (58, 77))	('SLC12A5', 'Gene', (0, 7))	('miR-133a-3p', 'Chemical', '-', (58, 69))	('suppression', 'NegReg', (78, 89))	('cell migration', 'biological_process', 'GO:0016477', ('97', '111'))
19624	32449280	Taken together, these results implied that SLC12A5 participates in miR-133a-3p's tumor suppressive activity.	('miR-133a-3p', 'Var', (67, 78))	('miR-133a-3p', 'Chemical', '-', (67, 78))	('SLC12A5', 'Gene', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
19625	32449280	In accordance with the results reported in our previous study, 13  our data suggested that SLC12A5 overexpression markedly increased BUC cells' migratory ability through their expression of SOX18, which then transcriptionally activates expression of its downstream target MMP7.	('increased', 'PosReg', (123, 132))	('SLC12A5', 'Gene', (91, 98))	('SOX18', 'Gene', (190, 195))	('MMP7', 'Gene', (272, 276))	('MMP7', 'molecular_function', 'GO:0004235', ('272', '276'))	('SOX18', 'Gene', '54345', (190, 195))	('activates', 'PosReg', (226, 235))	('MMP7', 'Gene', '4316', (272, 276))	('expression', 'MPA', (236, 246))	('overexpression', 'Var', (99, 113))
19637	32449280	Cell migration could be markedly inhibited by miR-133a-3p overexpression, however this effect was attenuated markedly after SLC12A5 overexpression.	('overexpression', 'Var', (58, 72))	('Cell migration', 'biological_process', 'GO:0016477', ('0', '14'))	('Cell migration', 'CPA', (0, 14))	('miR-133a-3p', 'Chemical', '-', (46, 57))	('miR-133a-3p overexpression', 'Var', (46, 72))	('inhibited', 'NegReg', (33, 42))
19638	32449280	The results also indicated that miR-133a-3p caused a reduction in SLC12A5 expression by suppressing SLC12A5 promoter activity.	('expression', 'MPA', (74, 84))	('miR-133a-3p', 'Var', (32, 43))	('suppressing', 'NegReg', (88, 99))	('miR-133a-3p', 'Chemical', '-', (32, 43))	('reduction', 'NegReg', (53, 62))	('SLC12A5', 'Gene', (66, 73))	('SLC12A5 promoter activity', 'MPA', (100, 125))
19639	32449280	Previous studies have reported the role of miR-133a-3p in BUC.	('BUC', 'Disease', (58, 61))	('miR-133a-3p', 'Var', (43, 54))	('miR-133a-3p', 'Chemical', '-', (43, 54))
19644	32449280	In BUC tissues, downregulation of miR-133a-3p results in SLC12A5 upregulation, and poor patient prognosis is associated with SLC12A5 overexpression.	('patient', 'Species', '9606', (88, 95))	('downregulation', 'NegReg', (16, 30))	('SLC12A5', 'Gene', (57, 64))	('miR-133a-3p', 'Var', (34, 45))	('miR-133a-3p', 'Chemical', '-', (34, 45))	('upregulation', 'PosReg', (65, 77))
19654	31395079	The high expression of ANLN was associated with tumor size, tumor differentiation, TNM stage, lymph node metastasis, distant metastasis and poor prognosis in pancreatic cancer.	('pancreatic cancer', 'Disease', (158, 175))	('lymph node metastasis', 'CPA', (94, 115))	('tumor', 'Disease', (48, 53))	('pancreatic cancer', 'Disease', 'MESH:D010190', (158, 175))	('expression', 'Species', '29278', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (158, 175))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('high', 'Var', (4, 8))	('associated', 'Reg', (32, 42))	('distant metastasis', 'CPA', (117, 135))	('tumor', 'Disease', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('ANLN', 'Gene', (23, 27))
19656	31395079	Meanwhile, we found that ANLN knockdown inhibited several cell-cell adhesion related genes, including the gene encoding LIM and SH3 protein 1 (LASP1).	('LASP1', 'Gene', '3927', (143, 148))	('inhibited', 'NegReg', (40, 49))	('LIM and SH3 protein 1', 'Gene', '3927', (120, 141))	('LASP1', 'Gene', (143, 148))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('knockdown', 'Var', (30, 39))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('58', '76'))	('cell-cell adhesion related genes', 'Gene', (58, 90))
19658	31395079	Moreover, we found that ANLN downregulation induced the expression of miR-218-5p which inhibited LASP1 expression through binding to its 3'UTR.	('downregulation', 'NegReg', (29, 43))	('miR-218-5p', 'Var', (70, 80))	('expression', 'Species', '29278', (103, 113))	('binding', 'Interaction', (122, 129))	('binding', 'molecular_function', 'GO:0005488', ('122', '129'))	('expression', 'MPA', (103, 113))	('expression', 'Species', '29278', (56, 66))	('LASP1', 'Gene', '3927', (97, 102))	('expression', 'MPA', (56, 66))	('inhibited', 'NegReg', (87, 96))	('miR-218-5p', 'Chemical', '-', (70, 80))	('LASP1', 'Gene', (97, 102))
19661	31395079	ANLN contributed to pancreatic cancer progression by regulating EZH2/miR-218-5p/LASP1 signaling axis.	('regulating', 'Reg', (53, 63))	('pancreatic cancer', 'Disease', 'MESH:D010190', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('contributed', 'Reg', (5, 16))	('miR-218-5p', 'Chemical', '-', (69, 79))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('LASP1', 'Gene', '3927', (80, 85))	('LASP1', 'Gene', (80, 85))	('ANLN', 'Var', (0, 4))	('EZH2', 'Gene', (64, 68))	('pancreatic cancer', 'Disease', (20, 37))	('EZH2', 'Gene', '2146', (64, 68))
19671	31395079	For example, ANLN knockdown inhibited cell proliferation and metastasis and induced G2/M arrest in bladder urothelial carcinoma.	('knockdown', 'Var', (18, 27))	('ANLN', 'Gene', (13, 17))	('M arrest', 'Disease', (87, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (99, 127))	('inhibited', 'NegReg', (28, 37))	('cell proliferation', 'biological_process', 'GO:0008283', ('38', '56'))	('bladder urothelial carcinoma', 'Disease', (99, 127))	('M arrest', 'Disease', 'MESH:D006323', (87, 95))	('induced', 'Reg', (76, 83))
19681	31395079	Among these miRNAs, miR-218-5p was found to play pivotal roles in many malignant tumors.	('malignant tumors', 'Disease', (71, 87))	('miR-218-5p', 'Chemical', '-', (20, 30))	('roles', 'Reg', (57, 62))	('malignant tumors', 'Disease', 'MESH:D018198', (71, 87))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('miR-218-5p', 'Var', (20, 30))
19682	31395079	For example, miR-218-5p upregulation repressed gastric cancer growth and metastasis by directly regulating CDK6/CyclinD1.	('metastasis', 'CPA', (73, 83))	('gastric cancer', 'Disease', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('miR-218-5p', 'Chemical', '-', (13, 23))	('regulating', 'Reg', (96, 106))	('repressed', 'NegReg', (37, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('miR-218-5p', 'Var', (13, 23))	('upregulation', 'PosReg', (24, 36))	('CDK6/CyclinD1', 'Gene', (107, 120))	('CDK', 'molecular_function', 'GO:0004693', ('107', '110'))
19687	31395079	Thus, it is necessary to study the roles of miR-218-5p in ANLN-induced pancreatic cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('miR-218-5p', 'Chemical', '-', (44, 54))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('miR-218-5p', 'Var', (44, 54))	('pancreatic cancer', 'Disease', (71, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (71, 88))
19690	31395079	In pancreatic cancer, EZH2 downregulation induced the expression of miR-139-5p via H3K27me3, thereby repressing the progression of pancreatic cancer.	('expression', 'MPA', (54, 64))	('5p', 'Chemical', '-', (76, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('EZH2', 'Gene', (22, 26))	('pancreatic cancer', 'Disease', (3, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('repressing', 'NegReg', (101, 111))	('miR-139-5p', 'Var', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('pancreatic cancer', 'Disease', (131, 148))	('H3K27me3', 'Protein', (83, 91))	('downregulation', 'NegReg', (27, 41))	('expression', 'Species', '29278', (54, 64))	('EZH2', 'Gene', '2146', (22, 26))
19714	31395079	The pCMV3-LASP1 CDS (NM_006148) and pCMV3-EZH2 CDS (NM_004456) expression plasmids were acquired from Sino Biological Inc. (Beijing, China).	('NM_004456', 'Var', (52, 61))	('expression', 'Species', '29278', (63, 73))	('LASP1', 'Gene', '3927', (10, 15))	('EZH2', 'Gene', '2146', (42, 46))	('EZH2', 'Gene', (42, 46))	('CDS', 'Chemical', 'MESH:D002104', (16, 19))	('LASP1', 'Gene', (10, 15))	('NM_006148', 'Var', (21, 30))	('CDS', 'Chemical', 'MESH:D002104', (47, 50))
19745	31395079	The partial wild-type sequence of the LASP1 3'-untranslated region (UTR) (2262 bp) containing the three putative miR-218-5p binding sites (Site1:686-692, Site2: 1587-1593 and Site3 2080-2087) or the sequences having mutations of the miR-218-5p putative binding sites in LASP1 3'UTR were cloned into the downstream of the luciferase gene in the psiCHECK-2 vector (Promega, Madison, WI, USA).	('LASP1', 'Gene', (270, 275))	('miR-218-5p', 'Chemical', '-', (113, 123))	('LASP1', 'Gene', '3927', (38, 43))	('miR-218-5p', 'Chemical', '-', (233, 243))	('LASP1', 'Gene', (38, 43))	('luciferase', 'Gene', (321, 331))	('mutations', 'Var', (216, 225))	('binding', 'molecular_function', 'GO:0005488', ('124', '131'))	('LASP1', 'Gene', '3927', (270, 275))	('binding', 'molecular_function', 'GO:0005488', ('253', '260'))
19751	31395079	Moreover, fewer ANLN shallow deletion and high-level ANLN gene amplification (amplification) and more ANLN diploid and low-level ANLN gene amplification (gain) were observed in two pancreatic cancer datasets (Pancreatic Adenocarcinoma-TCGA, PanCancer Atlas and Pancreatic Adenocarcinoma-TCGA, Provisional) (Fig.	('pancreatic cancer', 'Disease', 'MESH:D010190', (181, 198))	('ANLN', 'Gene', (53, 57))	('pancreatic cancer', 'Disease', (181, 198))	('fewer', 'NegReg', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('Pancreatic Adenocarcinoma-TCGA, PanCancer Atlas and Pancreatic Adenocarcinoma-TCGA', 'Disease', 'MESH:D010190', (209, 291))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (181, 198))	('Cancer', 'Phenotype', 'HP:0002664', (244, 250))	('Pancreatic Adenocarcinoma', 'Phenotype', 'HP:0006725', (209, 234))	('ANLN shallow deletion', 'Var', (16, 37))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('Pancreatic Adenocarcinoma', 'Phenotype', 'HP:0006725', (261, 286))
19752	31395079	The ANLN mRNA expression in the pancreatic cancer samples with low-level ANLN gene amplification (gain) was markedly increased compared with that in the pancreatic cancer samples with ANLN diploids (Fig.	('low-level', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('increased', 'PosReg', (117, 126))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (153, 170))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (32, 49))	('ANLN', 'Gene', (73, 77))	('expression', 'Species', '29278', (14, 24))	('ANLN mRNA expression', 'MPA', (4, 24))	('pancreatic cancer', 'Disease', (153, 170))	('pancreatic cancer', 'Disease', (32, 49))	('pancreatic cancer', 'Disease', 'MESH:D010190', (153, 170))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('pancreatic cancer', 'Disease', 'MESH:D010190', (32, 49))
19767	31395079	Moreover, the xenograft tumor volumes of the LV-ANLN shRNA group were obviously reduced when compared with those of the LV-NC group (P < 0.01, Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('xenograft tumor', 'Disease', 'MESH:D009369', (14, 29))	('LV-ANLN', 'Var', (45, 52))	('reduced', 'NegReg', (80, 87))	('xenograft tumor', 'Disease', (14, 29))
19774	31395079	Further investigation showed that LASP1 restoration partially reversed the effects of ANLN knockdown on pancreatic cancer cell proliferation (Additional file 5: Figure S1C).	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('LASP1', 'Gene', '3927', (34, 39))	('cell proliferation', 'biological_process', 'GO:0008283', ('122', '140'))	('pancreatic cancer', 'Disease', (104, 121))	('LASP1', 'Gene', (34, 39))	('knockdown', 'Var', (91, 100))	('ANLN', 'Gene', (86, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))
19779	31395079	In addition, the CCK-8 and colony formation assays indicated that the suppressive effects of ANLN knockdown on pancreatic cancer cell growth were restored by LASP1 re-expression (Fig.	('LASP1', 'Gene', '3927', (158, 163))	('LASP1', 'Gene', (158, 163))	('knockdown', 'Var', (98, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (111, 128))	('pancreatic cancer', 'Disease', (111, 128))	('cell growth', 'biological_process', 'GO:0016049', ('129', '140'))	('ANLN', 'Gene', (93, 97))	('expression', 'Species', '29278', (167, 177))	('re-expression', 'Var', (164, 177))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('formation', 'biological_process', 'GO:0009058', ('34', '43'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (111, 128))
19780	31395079	Moreover, LASP1 re-expression partially reversed the effect of ANLN knockdown on pancreatic cancer cell migration and invasion (Fig.	('ANLN', 'Gene', (63, 67))	('LASP1', 'Gene', '3927', (10, 15))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('LASP1', 'Gene', (10, 15))	('knockdown', 'Var', (68, 77))	('cell migration', 'biological_process', 'GO:0016477', ('99', '113'))	('invasion', 'CPA', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('expression', 'Species', '29278', (19, 29))	('pancreatic cancer', 'Disease', (81, 98))
19783	31395079	By combining the gene expression profiles and Targetscan (http://www.targetscan.org/), three miRNAs (miR-145-5p, miR-218-5p and miR-9-5p) were found both upregulated in ANLN downregulated BxPC-3 cells and contained binding sites of the 3'UTR of LASP1 (Additional file 6: Figure S2B).	('LASP1', 'Gene', (245, 250))	('upregulated', 'PosReg', (154, 165))	('5p', 'Chemical', '-', (121, 123))	('miR-218-5p', 'Chemical', '-', (113, 123))	('gene expression', 'biological_process', 'GO:0010467', ('17', '32'))	('downregulated', 'NegReg', (174, 187))	('miR-145-5p', 'Var', (101, 111))	('5p', 'Chemical', '-', (134, 136))	('5p', 'Chemical', '-', (109, 111))	('LASP1', 'Gene', '3927', (245, 250))	('binding', 'molecular_function', 'GO:0005488', ('215', '222'))	('miR-9-5p', 'Var', (128, 136))	('expression', 'Species', '29278', (22, 32))	('miR-218-5p', 'Var', (113, 123))	('BxPC-3', 'CellLine', 'CVCL:0186', (188, 194))	('binding', 'Interaction', (215, 222))
19784	31395079	To determine the effect of miR-145-5p, miR-218-5p and miR-9-5p on LASP1 expression, miR-145-5p, miR-218-5p and miR-9-5p mimics were transfected into BxPC-3 cells, respectively.	('miR-145-5p', 'Var', (84, 94))	('5p', 'Chemical', '-', (104, 106))	('miR-218-5p', 'Chemical', '-', (39, 49))	('BxPC-3', 'CellLine', 'CVCL:0186', (149, 155))	('expression', 'Species', '29278', (72, 82))	('5p', 'Chemical', '-', (60, 62))	('LASP1', 'Gene', '3927', (66, 71))	('LASP1', 'Gene', (66, 71))	('miR-218-5p', 'Chemical', '-', (96, 106))	('5p', 'Chemical', '-', (92, 94))	('5p', 'Chemical', '-', (47, 49))	('5p', 'Chemical', '-', (117, 119))	('5p', 'Chemical', '-', (35, 37))
19785	31395079	We found that the expression of miR-145-5p, miR-218-5p and miR-9-5p in transfected cells was significantly upregulated (Additional file 6: Figure S2C).	('miR-218-5p', 'Chemical', '-', (44, 54))	('miR-145-5p', 'Var', (32, 42))	('5p', 'Chemical', '-', (40, 42))	('expression', 'Species', '29278', (18, 28))	('miR-9-5p', 'Var', (59, 67))	('miR-218-5p', 'Var', (44, 54))	('expression', 'MPA', (18, 28))	('upregulated', 'PosReg', (107, 118))	('5p', 'Chemical', '-', (65, 67))	('5p', 'Chemical', '-', (52, 54))
19786	31395079	Additional qRT-PCR showed that only miR-218-5p upregulation significantly repressed LASP1 mRNA expression in BxPC-3 cells (Additional file 6: Figure S2D).	('miR-218-5p', 'Chemical', '-', (36, 46))	('repressed', 'NegReg', (74, 83))	('BxPC-3', 'CellLine', 'CVCL:0186', (109, 115))	('miR-218-5p', 'Var', (36, 46))	('expression', 'Species', '29278', (95, 105))	('LASP1', 'Gene', '3927', (84, 89))	('LASP1', 'Gene', (84, 89))
19788	31395079	5a, the expression of miR-218-5p in transfected cells was significantly upregulated.	('miR-218-5p', 'Chemical', '-', (22, 32))	('miR-218-5p', 'Var', (22, 32))	('expression', 'Species', '29278', (8, 18))	('upregulated', 'PosReg', (72, 83))	('expression', 'MPA', (8, 18))
19789	31395079	Moreover, miR-218-5p upregulation significantly suppressed LASP1 protein expression in BxPC-3 and SW1990 cells (Fig.	('miR-218-5p', 'Var', (10, 20))	('BxPC-3', 'CellLine', 'CVCL:0186', (87, 93))	('LASP1', 'Gene', '3927', (59, 64))	('protein', 'Protein', (65, 72))	('SW1990', 'CellLine', 'CVCL:1723', (98, 104))	('expression', 'Species', '29278', (73, 83))	('LASP1', 'Gene', (59, 64))	('suppressed', 'NegReg', (48, 58))	('upregulation', 'PosReg', (21, 33))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('miR-218-5p', 'Chemical', '-', (10, 20))
19791	31395079	We found that the luciferase activity of miR-218-5p-transfected cells was significantly inhibited compared with that of the con-transfected cells.	('miR-218-5p-transfected', 'Var', (41, 63))	('inhibited', 'NegReg', (88, 97))	('luciferase activity', 'molecular_function', 'GO:0047712', ('18', '37'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('18', '37'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('18', '37'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('18', '37'))	('activity', 'MPA', (29, 37))	('miR-218-5p', 'Chemical', '-', (41, 51))	('luciferase', 'Enzyme', (18, 28))	('luciferase activity', 'molecular_function', 'GO:0047077', ('18', '37'))
19792	31395079	In addition, site-directed mutagenesis of the miRNA binding sequences in the 3'UTR of LASP1 showed a slightly different trend.	('miRNA', 'Protein', (46, 51))	('mutagenesis', 'Var', (27, 38))	('mutagenesis', 'biological_process', 'GO:0006280', ('27', '38'))	('LASP1', 'Gene', '3927', (86, 91))	('LASP1', 'Gene', (86, 91))	('miRNA binding', 'molecular_function', 'GO:0035198', ('46', '59'))
19793	31395079	The conserved miRNA binding site (Site3) appeared to be slightly more effective in miR-218b-5p-induced luciferase activity repression because mutation of this site significantly reversed a decrease in the luciferase signal (Fig.	('luciferase activity', 'molecular_function', 'GO:0047077', ('103', '122'))	('mutation', 'Var', (142, 150))	('miRNA binding', 'molecular_function', 'GO:0035198', ('14', '27'))	('activity', 'MPA', (114, 122))	('luciferase activity', 'molecular_function', 'GO:0047712', ('103', '122'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('103', '122'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('103', '122'))	('luciferase signal', 'MPA', (205, 222))	('miR-218b-5p-induced', 'Gene', (83, 102))	('luciferase activity', 'molecular_function', 'GO:0050248', ('103', '122'))	('decrease', 'NegReg', (189, 197))	('5p', 'Chemical', '-', (92, 94))	('luciferase', 'Enzyme', (103, 113))	('miR-218', 'Chemical', '-', (83, 90))
19794	31395079	However, the miR-218-5p-mediated repression of luciferase activity was abolished by mutating the three binding sequences (triple mutation) of the LASP1 3'UTR (Fig.	('activity', 'MPA', (58, 66))	('luciferase activity', 'molecular_function', 'GO:0047077', ('47', '66'))	('luciferase', 'Enzyme', (47, 57))	('binding', 'Interaction', (103, 110))	('miR-218-5p', 'Chemical', '-', (13, 23))	('binding', 'molecular_function', 'GO:0005488', ('103', '110'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('47', '66'))	('mutating', 'Var', (84, 92))	('luciferase activity', 'molecular_function', 'GO:0045289', ('47', '66'))	('LASP1', 'Gene', '3927', (146, 151))	('LASP1', 'Gene', (146, 151))	('luciferase activity', 'molecular_function', 'GO:0050248', ('47', '66'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('47', '66'))	('abolished', 'NegReg', (71, 80))
19796	31395079	5e, LASP1 protein expression in miR-218-5p-transfected cells was restored by LASP1 plasmid.	('LASP1', 'Gene', '3927', (77, 82))	('LASP1', 'Gene', (77, 82))	('protein', 'Protein', (10, 17))	('LASP1', 'Gene', '3927', (4, 9))	('LASP1', 'Gene', (4, 9))	('restored', 'PosReg', (65, 73))	('miR-218-5p-transfected', 'Var', (32, 54))	('expression', 'Species', '29278', (18, 28))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('miR-218-5p', 'Chemical', '-', (32, 42))
19799	31395079	In this study, we showed that miR-218-5p upregulation inhibited pancreatic cancer cell growth, migration and invasion by directly regulating LASP1 expression.	('LASP1', 'Gene', (141, 146))	('inhibited', 'NegReg', (54, 63))	('invasion', 'CPA', (109, 117))	('expression', 'Species', '29278', (147, 157))	('regulating', 'Reg', (130, 140))	('miR-218-5p', 'Chemical', '-', (30, 40))	('expression', 'MPA', (147, 157))	('cell growth', 'biological_process', 'GO:0016049', ('82', '93'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('miR-218-5p', 'Var', (30, 40))	('LASP1', 'Gene', '3927', (141, 146))	('pancreatic cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('pancreatic cancer', 'Disease', 'MESH:D010190', (64, 81))	('upregulation', 'PosReg', (41, 53))
19800	31395079	Moreover, ANLN knockdown significantly induced the expression of miR-218-5p.	('miR-218-5p', 'Var', (65, 75))	('knockdown', 'Var', (15, 24))	('ANLN', 'Gene', (10, 14))	('expression', 'Species', '29278', (51, 61))	('expression', 'MPA', (51, 61))	('miR-218-5p', 'Chemical', '-', (65, 75))	('induced', 'PosReg', (39, 46))
19801	31395079	Thus, ANLN may regulate LASP1 expression and pancreatic cancer progression by miR-218-5p.	('expression', 'MPA', (30, 40))	('pancreatic cancer', 'Disease', (45, 62))	('miR-218-5p', 'Chemical', '-', (78, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('LASP1', 'Gene', '3927', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('LASP1', 'Gene', (24, 29))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))	('miR-218-5p', 'Var', (78, 88))	('expression', 'Species', '29278', (30, 40))	('regulate', 'Reg', (15, 23))
19802	31395079	To determine whether miR-218-5p was involved in ANLN-induced LASP1 expression and pancreatic cancer cell growth, migration and invasion, miR-218-5p inhibitor (anti-miR-218) was used to reverse the expression of miR-218-5p upregulation caused by ANLN knockdown.	('miR-218-5p', 'Chemical', '-', (211, 221))	('LASP1', 'Gene', (61, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (82, 99))	('expression', 'Species', '29278', (197, 207))	('miR-218-5p', 'Gene', (211, 221))	('knockdown', 'Var', (250, 259))	('upregulation', 'PosReg', (222, 234))	('expression', 'Species', '29278', (67, 77))	('miR-218-5p', 'Chemical', '-', (137, 147))	('miR-218', 'Chemical', '-', (164, 171))	('miR-218', 'Chemical', '-', (21, 28))	('pancreatic cancer', 'Disease', 'MESH:D010190', (82, 99))	('miR-218', 'Chemical', '-', (211, 218))	('pancreatic cancer', 'Disease', (82, 99))	('LASP1', 'Gene', '3927', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('miR-218-5p', 'Chemical', '-', (21, 31))	('miR-218', 'Chemical', '-', (137, 144))	('cell growth', 'biological_process', 'GO:0016049', ('100', '111'))
19804	31395079	In addition, the LASP1 protein levels were restored in the cells cotransfected with ANLN RNAi and anti-miR-218 compared with the protein levels in the cells cotransfected with ANLN RNAi and inhibitor control (anti-con) (Fig.	('anti-miR-218', 'Var', (98, 110))	('RNAi', 'biological_process', 'GO:0016246', ('181', '185'))	('restored', 'PosReg', (43, 51))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('LASP1', 'Gene', '3927', (17, 22))	('LASP1', 'Gene', (17, 22))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('ANLN RNAi', 'Var', (84, 93))	('RNAi', 'biological_process', 'GO:0016246', ('89', '93'))	('miR-218', 'Chemical', '-', (103, 110))
19805	31395079	In functional assays, miR-218-5p knockdown in pancreatic cancer cells transfected with ANLN RNAi rescued the inhibition of cell proliferation, colony formation, cell migration and cell invasion caused by ANLN knockdown (Fig.	('miR-218-5p', 'Chemical', '-', (22, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (46, 63))	('cell proliferation', 'CPA', (123, 141))	('RNAi', 'biological_process', 'GO:0016246', ('92', '96'))	('cell migration', 'CPA', (161, 175))	('pancreatic cancer', 'Disease', (46, 63))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('109', '141'))	('cell invasion', 'CPA', (180, 193))	('pancreatic cancer', 'Disease', 'MESH:D010190', (46, 63))	('inhibition', 'NegReg', (109, 119))	('colony formation', 'CPA', (143, 159))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('formation', 'biological_process', 'GO:0009058', ('150', '159'))	('cell migration', 'biological_process', 'GO:0016477', ('161', '175'))	('ANLN knockdown', 'Var', (204, 218))
19806	31395079	Collectively, these results demonstrated that ANLN promotes pancreatic cancer cell growth, migration and invasion by regulating miR-218-5p/LASP1 signaling axis.	('invasion', 'CPA', (105, 113))	('LASP1', 'Gene', (139, 144))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('cell growth', 'biological_process', 'GO:0016049', ('78', '89'))	('ANLN', 'Var', (46, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('promotes', 'PosReg', (51, 59))	('regulating', 'Reg', (117, 127))	('pancreatic cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('migration', 'CPA', (91, 100))	('LASP1', 'Gene', '3927', (139, 144))	('miR-218-5p', 'Chemical', '-', (128, 138))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))
19808	31395079	In this study, the result of gene expression profiles showed that ANLN knockdown significantly inhibited the expression of EZH2 (Additional file 7: Figure S3A).	('EZH2', 'Gene', (123, 127))	('expression', 'MPA', (109, 119))	('inhibited', 'NegReg', (95, 104))	('knockdown', 'Var', (71, 80))	('EZH2', 'Gene', '2146', (123, 127))	('expression', 'Species', '29278', (34, 44))	('gene expression', 'biological_process', 'GO:0010467', ('29', '44'))	('ANLN knockdown', 'Var', (66, 80))	('expression', 'Species', '29278', (109, 119))
19809	31395079	To further confirm the effect of ANLN knockdown on EZH2, qRT-PCR and Western blot analysis was performed.	('knockdown', 'Var', (38, 47))	('EZH2', 'Gene', (51, 55))	('EZH2', 'Gene', '2146', (51, 55))
19810	31395079	Our results showed that ANLN knockdown significantly repressed the expression of EZH2 mRNA and protein (Additional file 7: Figure S3B and C).	('EZH2', 'Gene', (81, 85))	('EZH2', 'Gene', '2146', (81, 85))	('knockdown', 'Var', (29, 38))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('expression', 'Species', '29278', (67, 77))	('expression', 'MPA', (67, 77))
19811	31395079	Therefore, ANLN may promote pancreatic cancer cell progression and miR-218-5p/LASP1 signaling axis by mediating EZH2.	('LASP1', 'Gene', (78, 83))	('ANLN', 'Var', (11, 15))	('pancreatic cancer', 'Disease', (28, 45))	('EZH2', 'Gene', (112, 116))	('EZH2', 'Gene', '2146', (112, 116))	('pancreatic cancer', 'Disease', 'MESH:D010190', (28, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('promote', 'PosReg', (20, 27))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (28, 45))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('miR-218-5p', 'Chemical', '-', (67, 77))	('LASP1', 'Gene', '3927', (78, 83))
19815	31395079	7b, anti-miR-218 obviously reversed the EZH2 knockdown-induced miR-218-5p expression.	('knockdown-induced', 'Var', (45, 62))	('miR-218', 'Chemical', '-', (9, 16))	('miR-218-5p', 'Chemical', '-', (63, 73))	('miR-218-5p expression', 'MPA', (63, 84))	('EZH2', 'Gene', (40, 44))	('EZH2', 'Gene', '2146', (40, 44))	('expression', 'Species', '29278', (74, 84))	('miR-218', 'Chemical', '-', (63, 70))
19816	31395079	Moreover, the LASP1 protein levels were restored in the cells cotransfected with EZH2 RNAi and anti-miR-218 compared with the protein levels in the cells cotransfected with EZH2 RNAi and inhibitor control (anti-con) (Fig.	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('EZH2', 'Gene', (81, 85))	('EZH2', 'Gene', '2146', (81, 85))	('RNAi', 'biological_process', 'GO:0016246', ('86', '90'))	('RNAi', 'biological_process', 'GO:0016246', ('178', '182'))	('EZH2', 'Gene', '2146', (173, 177))	('LASP1', 'Gene', '3927', (14, 19))	('LASP1', 'Gene', (14, 19))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('restored', 'PosReg', (40, 48))	('anti-miR-218', 'Var', (95, 107))	('EZH2', 'Gene', (173, 177))	('miR-218', 'Chemical', '-', (100, 107))
19817	31395079	To further determine whether EZH2 was involved in ANLN-induced LASP1 expression and the inhibition of miR-218-5p, EZH2 expression plasmid vectors were used to rescue the inhibition of EZH2 caused by ANLN knockdown.	('EZH2', 'Gene', '2146', (114, 118))	('knockdown', 'Var', (204, 213))	('LASP1', 'Gene', '3927', (63, 68))	('LASP1', 'Gene', (63, 68))	('expression', 'Species', '29278', (69, 79))	('inhibition', 'NegReg', (170, 180))	('miR-218-5p', 'Chemical', '-', (102, 112))	('EZH2', 'Gene', '2146', (184, 188))	('EZH2', 'Gene', (184, 188))	('EZH2', 'Gene', (29, 33))	('EZH2', 'Gene', '2146', (29, 33))	('expression', 'Species', '29278', (119, 129))	('EZH2', 'Gene', (114, 118))
19818	31395079	7d, the ectopic expression of EZH2 reversed the upregulation of miR-218-5p expression caused by ANLN knockdown.	('miR-218-5p', 'Gene', (64, 74))	('EZH2', 'Gene', '2146', (30, 34))	('EZH2', 'Gene', (30, 34))	('miR-218-5p', 'Chemical', '-', (64, 74))	('ANLN knockdown', 'Var', (96, 110))	('expression', 'Species', '29278', (16, 26))	('expression', 'Species', '29278', (75, 85))	('upregulation', 'PosReg', (48, 60))
19819	31395079	In addition, EZH2 re-expression reversed the inhibition of LASP1 caused by ANLN knockdown (Fig.	('inhibition', 'NegReg', (45, 55))	('EZH2', 'Gene', (13, 17))	('knockdown', 'Var', (80, 89))	('ANLN', 'Gene', (75, 79))	('EZH2', 'Gene', '2146', (13, 17))	('LASP1', 'Gene', '3927', (59, 64))	('expression', 'Species', '29278', (21, 31))	('LASP1', 'Gene', (59, 64))
19820	31395079	In functional assays, EZH2 restoration in pancreatic cancer cells transfected with ANLN RNAi rescued the inhibition of cell proliferation, colony formation, cell migration and cell invasion caused by ANLN knockdown (Fig.	('EZH2', 'Gene', (22, 26))	('pancreatic cancer', 'Disease', (42, 59))	('cell proliferation', 'CPA', (119, 137))	('cell migration', 'CPA', (157, 171))	('pancreatic cancer', 'Disease', 'MESH:D010190', (42, 59))	('inhibition', 'NegReg', (105, 115))	('colony formation', 'CPA', (139, 155))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('105', '137'))	('RNAi', 'biological_process', 'GO:0016246', ('88', '92'))	('knockdown', 'Var', (205, 214))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cell invasion', 'CPA', (176, 189))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (42, 59))	('formation', 'biological_process', 'GO:0009058', ('146', '155'))	('cell migration', 'biological_process', 'GO:0016477', ('157', '171'))	('EZH2', 'Gene', '2146', (22, 26))
19822	31395079	IHC staining showed that the levels of EZH2 and LASP1 expression were repressed after ANLN knockdown (Fig.	('LASP1', 'Gene', '3927', (48, 53))	('LASP1', 'Gene', (48, 53))	('knockdown', 'Var', (91, 100))	('expression', 'Species', '29278', (54, 64))	('EZH2', 'Gene', (39, 43))	('EZH2', 'Gene', '2146', (39, 43))
19823	31395079	Consistent with these findings, Western blot results also showed that the levels of EZH2 and LASP1 expression were significantly inhibited in the LV-ANLN-shRNA group when compared to the LV-NC group (Fig.	('inhibited', 'NegReg', (129, 138))	('expression', 'MPA', (99, 109))	('LV-ANLN-shRNA', 'Var', (146, 159))	('LASP1', 'Gene', '3927', (93, 98))	('LASP1', 'Gene', (93, 98))	('levels', 'MPA', (74, 80))	('EZH2', 'Gene', '2146', (84, 88))	('expression', 'Species', '29278', (99, 109))	('EZH2', 'Gene', (84, 88))
19824	31395079	Taken together, ANLN may promote pancreatic cancer cell growth, migration and invasion by regulating EZH2/miR-218-5p/LASP1 signaling axis (Fig.	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('cell growth', 'biological_process', 'GO:0016049', ('51', '62'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (33, 50))	('invasion', 'CPA', (78, 86))	('LASP1', 'Gene', '3927', (117, 122))	('miR-218-5p', 'Chemical', '-', (106, 116))	('EZH2', 'Gene', (101, 105))	('promote', 'PosReg', (25, 32))	('LASP1', 'Gene', (117, 122))	('ANLN', 'Var', (16, 20))	('pancreatic cancer', 'Disease', (33, 50))	('EZH2', 'Gene', '2146', (101, 105))	('migration', 'CPA', (64, 73))	('pancreatic cancer', 'Disease', 'MESH:D010190', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
19831	31395079	ANLN expression was increased in pancreatic cancer, and high ANLN expression was associated with a poor prognosis in the pancreatic ductal adenocarcinoma TCGA database.	('increased', 'PosReg', (20, 29))	('pancreatic ductal adenocarcinoma', 'Disease', (121, 153))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (121, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (33, 50))	('expression', 'Species', '29278', (66, 76))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (121, 153))	('ANLN expression', 'MPA', (0, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('pancreatic cancer', 'Disease', (33, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (33, 50))	('high ANLN', 'Var', (56, 65))	('expression', 'Species', '29278', (5, 15))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
19833	31395079	Moreover, ANLN could serve as an independent predictor for overall survival of pancreatic cancer patients.	('ANLN', 'Var', (10, 14))	('pancreatic cancer', 'Disease', 'MESH:D010190', (79, 96))	('pancreatic cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (79, 96))	('patients', 'Species', '9606', (97, 105))
19835	31395079	Consistent with our results, ANLN knockdown significantly repressed cell proliferation, migration and invasion in bladder urothelial carcinoma.	('repressed', 'NegReg', (58, 67))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (114, 142))	('cell proliferation', 'CPA', (68, 86))	('invasion', 'CPA', (102, 110))	('bladder urothelial carcinoma', 'Disease', (114, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('migration', 'CPA', (88, 97))	('knockdown', 'Var', (34, 43))	('ANLN', 'Gene', (29, 33))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))
19836	31395079	ANLN knockdown significantly inhibited the proliferation and migration and invasion of pancreatic cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('inhibited', 'NegReg', (29, 38))	('ANLN', 'Gene', (0, 4))	('pancreatic cancer', 'Disease', (87, 104))	('invasion', 'CPA', (75, 83))	('knockdown', 'Var', (5, 14))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))
19844	31395079	Further investigation showed that only LASP1 restoration partially reversed the effects of ANLN knockdown on pancreatic cancer cell proliferation, colony formation, cell migration and cell invasion (Additional file 5: Figure S1C and Fig.	('knockdown', 'Var', (96, 105))	('ANLN', 'Gene', (91, 95))	('LASP1', 'Gene', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cell proliferation', 'biological_process', 'GO:0008283', ('127', '145'))	('cell migration', 'CPA', (165, 179))	('formation', 'biological_process', 'GO:0009058', ('154', '163'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('cell migration', 'biological_process', 'GO:0016477', ('165', '179'))	('cell invasion', 'CPA', (184, 197))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('colony formation', 'CPA', (147, 163))	('pancreatic cancer', 'Disease', (109, 126))	('LASP1', 'Gene', '3927', (39, 44))
19846	31395079	By combining the gene expression profiles and Targetscan (http://www.targetscan.org/), three miRNAs, including miR-145-5p, miR-218-5p and miR-9-5p, were selected and were found upregulated in ANLN downregulated BxPC-3 cells and contained binding sites of the 3'UTR of LASP1 (Additional file 6: Figure S2B), and mostly acted as tumor suppressors.	('miR-218-5p', 'Chemical', '-', (123, 133))	('expression', 'Species', '29278', (22, 32))	('5p', 'Chemical', '-', (131, 133))	('gene expression', 'biological_process', 'GO:0010467', ('17', '32'))	('tumor', 'Disease', (327, 332))	('miR-218-5p', 'Var', (123, 133))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('upregulated', 'PosReg', (177, 188))	('binding', 'molecular_function', 'GO:0005488', ('238', '245'))	('LASP1', 'Gene', '3927', (268, 273))	('BxPC-3', 'CellLine', 'CVCL:0186', (211, 217))	('5p', 'Chemical', '-', (144, 146))	('binding', 'Interaction', (238, 245))	('miR-145-5p', 'Var', (111, 121))	('downregulated', 'NegReg', (197, 210))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('miR-9-5p', 'Var', (138, 146))	('LASP1', 'Gene', (268, 273))	('5p', 'Chemical', '-', (119, 121))
19847	31395079	However, further investigation showed that only miR-218-5p upregulation significantly repressed LASP1 mRNA expression in BxPC-3 cells (Additional file 6: Figure S2D).	('BxPC-3', 'CellLine', 'CVCL:0186', (121, 127))	('repressed', 'NegReg', (86, 95))	('expression', 'Species', '29278', (107, 117))	('LASP1', 'Gene', '3927', (96, 101))	('mRNA expression', 'MPA', (102, 117))	('miR-218-5p', 'Chemical', '-', (48, 58))	('LASP1', 'Gene', (96, 101))	('miR-218-5p', 'Var', (48, 58))
19849	31395079	In the present study, we showed that miR-218-5p upregulation repressed pancreatic cancer cell growth, migration and invasion by directly regulating LASP1 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cell growth', 'biological_process', 'GO:0016049', ('89', '100'))	('miR-218-5p', 'Chemical', '-', (37, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('invasion', 'CPA', (116, 124))	('repressed', 'NegReg', (61, 70))	('miR-218-5p', 'Var', (37, 47))	('regulating', 'Reg', (137, 147))	('LASP1', 'Gene', '3927', (148, 153))	('LASP1', 'Gene', (148, 153))	('migration', 'CPA', (102, 111))	('pancreatic cancer', 'Disease', (71, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (71, 88))	('upregulation', 'PosReg', (48, 60))
19850	31395079	In line with our results, miR-218-5p upregulation inhibited prostate cancer cell migration and invasion by directly regulating LASP1 expression.	('expression', 'MPA', (133, 143))	('regulating', 'Reg', (116, 126))	('miR-218-5p', 'Chemical', '-', (26, 36))	('prostate cancer', 'Disease', (60, 75))	('LASP1', 'Gene', '3927', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('upregulation', 'PosReg', (37, 49))	('LASP1', 'Gene', (127, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('miR-218-5p', 'Var', (26, 36))	('cell migration', 'biological_process', 'GO:0016477', ('76', '90'))	('expression', 'Species', '29278', (133, 143))	('inhibited', 'NegReg', (50, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))
19851	31395079	Moreover, miR-218-5p downregulation partially reversed the inhibition of LASP1 expression, cell proliferation, colony formation, cell migration and cell invasion caused by ANLN knockdown (Fig.	('inhibition', 'NegReg', (59, 69))	('expression', 'Species', '29278', (79, 89))	('colony formation', 'CPA', (111, 127))	('expression', 'MPA', (79, 89))	('LASP1', 'Gene', '3927', (73, 78))	('cell invasion', 'CPA', (148, 161))	('downregulation', 'NegReg', (21, 35))	('knockdown', 'Var', (177, 186))	('formation', 'biological_process', 'GO:0009058', ('118', '127'))	('cell proliferation', 'biological_process', 'GO:0008283', ('91', '109'))	('cell migration', 'biological_process', 'GO:0016477', ('129', '143'))	('miR-218-5p', 'Chemical', '-', (10, 20))	('LASP1', 'Gene', (73, 78))	('cell proliferation', 'CPA', (91, 109))	('cell migration', 'CPA', (129, 143))
19852	31395079	These results suggested that ANLN induces the expression of LASP1 by repressing the expression of miR-218-5p, resulting in pancreatic cancer cell progression.	('LASP1', 'Gene', '3927', (60, 65))	('LASP1', 'Gene', (60, 65))	('miR-218-5p', 'Chemical', '-', (98, 108))	('pancreatic cancer', 'Disease', (123, 140))	('pancreatic cancer', 'Disease', 'MESH:D010190', (123, 140))	('ANLN', 'Var', (29, 33))	('miR-218-5p', 'Var', (98, 108))	('resulting in', 'Reg', (110, 122))	('expression', 'Species', '29278', (84, 94))	('expression', 'Species', '29278', (46, 56))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (123, 140))	('expression', 'MPA', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('expression', 'MPA', (46, 56))
19853	31395079	Additionally, EZH2-mediated H3K27 trimethylation is involved in epigenetic silencing of miR-218.	('miR-218', 'Gene', (88, 95))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('epigenetic silencing', 'MPA', (64, 84))	('miR-218', 'Chemical', '-', (88, 95))	('involved', 'Reg', (52, 60))	('trimethylation', 'Var', (34, 48))	('H3K27', 'Protein', (28, 33))
19855	31395079	Interestingly, our results showed that ANLN knockdown significantly inhibited the expression of EZH2 in (Additional file 7: Figure S3).	('expression', 'Species', '29278', (82, 92))	('expression', 'MPA', (82, 92))	('EZH2', 'Gene', '2146', (96, 100))	('EZH2', 'Gene', (96, 100))	('inhibited', 'NegReg', (68, 77))	('knockdown', 'Var', (44, 53))
19856	31395079	Moreover, miR-218-5p downregulation partially reversed the inhibition of LASP1 expression induced by EZH2 knockdown (Fig.	('inhibition', 'NegReg', (59, 69))	('expression', 'Species', '29278', (79, 89))	('expression', 'MPA', (79, 89))	('LASP1', 'Gene', '3927', (73, 78))	('downregulation', 'NegReg', (21, 35))	('knockdown', 'Var', (106, 115))	('EZH2', 'Gene', (101, 105))	('EZH2', 'Gene', '2146', (101, 105))	('miR-218-5p', 'Chemical', '-', (10, 20))	('LASP1', 'Gene', (73, 78))
19857	31395079	Thus, we hypothesized that ANLN may induce the silencing of miR-218-5p by mediating EZH2 in pancreatic cancer progression.	('miR-218-5p', 'Gene', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('miR-218-5p', 'Chemical', '-', (60, 70))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('mediating', 'Reg', (74, 83))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))	('pancreatic cancer', 'Disease', (92, 109))	('EZH2', 'Gene', '2146', (84, 88))	('ANLN', 'Var', (27, 31))	('silencing', 'MPA', (47, 56))	('EZH2', 'Gene', (84, 88))
19858	31395079	Our results support this, as we found that EZH2 restoration obviously reversed the upregulation of miR-218-5p and the inhibition of LASP1 expression, cell proliferation, colony formation, cell migration and cell invasion caused by ANLN knockdown (Fig.	('EZH2', 'Gene', (43, 47))	('cell migration', 'CPA', (188, 202))	('upregulation', 'PosReg', (83, 95))	('colony formation', 'CPA', (170, 186))	('cell proliferation', 'CPA', (150, 168))	('miR-218-5p', 'Gene', (99, 109))	('inhibition', 'NegReg', (118, 128))	('miR-218-5p', 'Chemical', '-', (99, 109))	('expression', 'Species', '29278', (138, 148))	('knockdown', 'Var', (236, 245))	('cell migration', 'biological_process', 'GO:0016477', ('188', '202'))	('cell invasion', 'CPA', (207, 220))	('expression', 'MPA', (138, 148))	('cell proliferation', 'biological_process', 'GO:0008283', ('150', '168'))	('EZH2', 'Gene', '2146', (43, 47))	('LASP1', 'Gene', '3927', (132, 137))	('LASP1', 'Gene', (132, 137))	('formation', 'biological_process', 'GO:0009058', ('177', '186'))
19859	31395079	We further demonstrated that ANLN knockdown significantly inhibited the levels of EZH2 and LASP1 expression in xenograft tumor models (Fig.	('EZH2', 'Gene', (82, 86))	('EZH2', 'Gene', '2146', (82, 86))	('LASP1', 'Gene', '3927', (91, 96))	('LASP1', 'Gene', (91, 96))	('levels', 'MPA', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('xenograft tumor', 'Disease', 'MESH:D009369', (111, 126))	('expression', 'Species', '29278', (97, 107))	('inhibited', 'NegReg', (58, 67))	('knockdown', 'Var', (34, 43))	('ANLN', 'Gene', (29, 33))	('expression', 'MPA', (97, 107))	('xenograft tumor', 'Disease', (111, 126))
19918	28830196	Hydronephrosis grade was significantly higher in the high-grade group than in the low-grade group (p < 0.001 for both readers).	('Hydronephrosis', 'Disease', 'MESH:D006869', (0, 14))	('higher', 'PosReg', (39, 45))	('Hydronephrosis', 'Phenotype', 'HP:0000126', (0, 14))	('high-grade', 'Var', (53, 63))	('Hydronephrosis', 'Disease', (0, 14))
19951	28830196	Preoperative clinical factors associated with low-risk UTUC include low-grade ureteroscopic biopsy, low-grade cytology, tumour size <1 cm, no invasive features on cross-sectional imaging, unifocal disease, and the availability of feasible close follow-up.	('UTUC', 'Disease', (55, 59))	('unifocal disease', 'Disease', (188, 204))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('low-grade cytology', 'Var', (100, 118))	('tumour', 'Disease', (120, 126))	('low-grade', 'Var', (68, 77))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
19967	26230923	The combination of both these protein biomarkers detected by IHC in biopsy specimens along with the relevant clinical parameters resulted in a prediction model able to significantly stratify the likelihood of NAC resistance in our cohort (n = 37) into two well separated halves: low-26% n = 19 and high-89% n = 18, Fisher's exact p = 0.0002).	('low-26% n', 'Var', (279, 288))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('stratify', 'Reg', (182, 190))	('NAC', 'cellular_component', 'GO:0005854', ('209', '212'))	('high-89% n', 'Var', (298, 308))	('NAC', 'Chemical', '-', (209, 212))
19980	26230923	Recent investigations have identified molecular signatures of these two concepts primarily via microarray based high-throughput gene expression profiling technologies, including a prior study by an author of this study that identified a molecular signature able to identify MIBC likely to exhibit lymph node metastases at cystectomy.	('MIBC', 'Chemical', '-', (274, 278))	('exhibit', 'PosReg', (289, 296))	('metastases', 'Disease', (308, 318))	('MIBC', 'Var', (274, 278))	('gene expression', 'biological_process', 'GO:0010467', ('128', '143'))	('metastases', 'Disease', 'MESH:D009362', (308, 318))
19999	26230923	In addition to these 6 antibodies, we also characterized our TMA MIBC cohort with respect to Ki67 staining, a semi-quantitative index of proliferation, and p53 mutation status, as detected by IHC.	('mutation', 'Var', (160, 168))	('TMA', 'Disease', (61, 64))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('MIBC', 'Chemical', '-', (65, 69))	('TMA', 'Disease', 'MESH:D000783', (61, 64))
20003	26230923	As shown in Fig 3B, positive GDPD3 protein expression is associated with response to GC NAC while positive SPRED1 protein expression is associated GC NAC resistance.	('associated', 'Reg', (136, 146))	('NAC', 'cellular_component', 'GO:0005854', ('88', '91'))	('GC', 'Chemical', '-', (147, 149))	('protein', 'Protein', (35, 42))	('GDPD3', 'Gene', '79153', (29, 34))	('NAC', 'Chemical', '-', (150, 153))	('GDPD3', 'Gene', (29, 34))	('positive', 'Var', (20, 28))	('SPRED1', 'Gene', (107, 113))	('NAC', 'cellular_component', 'GO:0005854', ('150', '153'))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('SPRED1', 'Gene', '161742', (107, 113))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('response to GC NAC', 'MPA', (73, 91))	('GC', 'Chemical', '-', (85, 87))	('NAC', 'Chemical', '-', (88, 91))	('associated', 'Reg', (57, 67))
20006	26230923	Since the mRNA and protein changes were concordantly associated to response, we examined GDPD3 and SPRED1 gene expression data in three publically available data sets of non-NAC treated MIBC (GSE48075, GSE32894, and GSE31684).	('SPRED1', 'Gene', '161742', (99, 105))	('SPRED1', 'Gene', (99, 105))	('NAC', 'Chemical', '-', (174, 177))	('gene expression', 'biological_process', 'GO:0010467', ('106', '121'))	('GSE31684', 'Var', (216, 224))	('GDPD3', 'Gene', '79153', (89, 94))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))	('GSE32894', 'Var', (202, 210))	('GDPD3', 'Gene', (89, 94))	('NAC', 'cellular_component', 'GO:0005854', ('174', '177'))	('MIBC', 'Chemical', '-', (186, 190))	('mRNA', 'MPA', (10, 14))	('GSE48075', 'Var', (192, 200))
20016	26230923	A combined multivariate classification tree, incorporating both of these models together, resulted in a prediction model able to significantly stratify the likelihood of NAC resistance in our cohort (n = 37) into two well separated halves: low-26% n = 19 and high-89% n = 18 (Fisher's exact test, p = 0.0002).	('high-89% n = 18', 'Var', (259, 274))	('stratify', 'Reg', (143, 151))	('NAC', 'cellular_component', 'GO:0005854', ('170', '173'))	('NAC', 'Chemical', '-', (170, 173))	('low-26% n', 'Var', (240, 249))
20046	26230923	However, with the completion of the TCGA sequencing efforts in MIBC and a subsequent exome level sequencing in a NAC MIBC cohort, we anticipate that somatic mutations (such as ERCC2, ATM, RB1, FANCC, and others) in urothelial carcinoma will likely also play a role in identifying patients likely to derive benefit from platinum based NAC in MIBC.	('urothelial carcinoma', 'Disease', (215, 235))	('FANCC', 'Gene', (193, 198))	('ERCC2', 'Gene', (176, 181))	('MIBC', 'Chemical', '-', (63, 67))	('MIBC', 'Chemical', '-', (341, 345))	('RB1', 'Gene', (188, 191))	('NAC', 'cellular_component', 'GO:0005854', ('334', '337'))	('ATM', 'Gene', (183, 186))	('NAC', 'cellular_component', 'GO:0005854', ('113', '116'))	('ERCC2', 'Gene', '2068', (176, 181))	('NAC MIBC', 'Chemical', '-', (113, 121))	('mutations', 'Var', (157, 166))	('MIBC', 'Chemical', '-', (117, 121))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (215, 235))	('NAC', 'Chemical', '-', (113, 116))	('platinum', 'Chemical', 'MESH:D010984', (319, 327))	('patients', 'Species', '9606', (280, 288))	('RB1', 'Gene', '5925', (188, 191))	('NAC', 'Chemical', '-', (334, 337))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('FANCC', 'Gene', '2176', (193, 198))	('ATM', 'Gene', '472', (183, 186))
20069	25408144	Importantly, we identified that low protein expression of ALDH2 while high CCNE1 and SMAD3 were novel independent predictors of adverse outcome in patients with UTUC.	('low', 'NegReg', (32, 35))	('SMAD3', 'Gene', '4088', (85, 90))	('SMAD3', 'Gene', (85, 90))	('ALDH2', 'Gene', '217', (58, 63))	('CCNE1', 'Gene', (75, 80))	('CCNE1', 'Gene', '898', (75, 80))	('ALDH', 'molecular_function', 'GO:0004030', ('58', '62'))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('ALDH2', 'Gene', (58, 63))	('patients', 'Species', '9606', (147, 155))	('high', 'Var', (70, 74))	('protein expression', 'MPA', (36, 54))	('UTUC', 'Disease', (161, 165))
20098	25408144	Genes that specifically dysregulated in UTUC were associated with metabolic disorders (e.g.	('dysregulated', 'Var', (24, 36))	('metabolic disorder', 'Phenotype', 'HP:0001939', (66, 84))	('metabolic disorders', 'Disease', 'MESH:D008659', (66, 85))	('metabolic disorders', 'Disease', (66, 85))	('associated', 'Reg', (50, 60))
20115	25408144	Taken together, the deregulation of CCNE1, SMAD3 and ALDH2 may lead to the disruptions of cellular functions of cell cycle control, tumor growth and metabolism.	('SMAD3', 'Gene', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('ALDH2', 'Gene', (53, 58))	('CCNE1', 'Gene', (36, 41))	('CCNE1', 'Gene', '898', (36, 41))	('cell cycle control', 'biological_process', 'GO:1901987', ('112', '130'))	('metabolism', 'biological_process', 'GO:0008152', ('149', '159'))	('metabolism', 'CPA', (149, 159))	('cellular functions', 'MPA', (90, 108))	('deregulation', 'Var', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('lead to', 'Reg', (63, 70))	('ALDH2', 'Gene', '217', (53, 58))	('SMAD3', 'Gene', '4088', (43, 48))	('ALDH', 'molecular_function', 'GO:0004030', ('53', '57'))	('disruptions', 'MPA', (75, 86))
20120	25408144	Low ALDH2, high CCNE1 and SMAD3 were significantly associated with increase in tumor depth (T1, T2 and T3; P <0.05, chi-square test).	('ALDH2', 'Gene', '217', (4, 9))	('SMAD3', 'Gene', (26, 31))	('CCNE1', 'Gene', (16, 21))	('tumor depth', 'Disease', 'MESH:D007222', (79, 90))	('ALDH2', 'Gene', (4, 9))	('tumor depth', 'Disease', (79, 90))	('increase', 'PosReg', (67, 75))	('ALDH', 'molecular_function', 'GO:0004030', ('4', '8'))	('high', 'Var', (11, 15))	('SMAD3', 'Gene', '4088', (26, 31))	('CCNE1', 'Gene', '898', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('Low', 'Var', (0, 3))
20123	25408144	As shown in Figure 4A-C, low expression of ALDH2 was significantly associated with an adverse outcome, whereas high CCNE1 and SMAD3 were associated with adverse outcomes (all ***P <0.0001, log-rank test).	('SMAD3', 'Gene', '4088', (126, 131))	('CCNE1', 'Gene', '898', (116, 121))	('ALDH2', 'Gene', (43, 48))	('SMAD3', 'Gene', (126, 131))	('CCNE1', 'Gene', (116, 121))	('low expression', 'Var', (25, 39))	('ALDH', 'molecular_function', 'GO:0004030', ('43', '47'))	('associated', 'Reg', (67, 77))	('ALDH2', 'Gene', '217', (43, 48))
20124	25408144	In addition, the predictive powers of ALDH2, CCNE1 and SMAD3 alone, and the combined marker (low ALDH2, high CCNE1 and high SMAD3, Figure 4D) were similar, which may in part be explained by their significant associations with each other (Table 1).	('CCNE1', 'Gene', '898', (109, 114))	('CCNE1', 'Gene', (109, 114))	('ALDH2', 'Gene', '217', (38, 43))	('SMAD3', 'Gene', '4088', (124, 129))	('ALDH2', 'Gene', (38, 43))	('SMAD3', 'Gene', '4088', (55, 60))	('SMAD3', 'Gene', (55, 60))	('associations', 'Interaction', (208, 220))	('high', 'Var', (104, 108))	('CCNE1', 'Gene', (45, 50))	('CCNE1', 'Gene', '898', (45, 50))	('SMAD3', 'Gene', (124, 129))	('ALDH2', 'Gene', '217', (97, 102))	('ALDH', 'molecular_function', 'GO:0004030', ('97', '101'))	('ALDH', 'molecular_function', 'GO:0004030', ('38', '42'))	('low', 'Var', (93, 96))	('ALDH2', 'Gene', (97, 102))
20144	25408144	One of its functions is to break down acetaldehyde metabolized from ethanol, inhibition of ALDH2 therefore may result in the build-up of acetaldehyde, which is a highly toxic and carcinogenic compound.	('result in', 'Reg', (111, 120))	('inhibition', 'Var', (77, 87))	('acetaldehyde', 'Chemical', 'MESH:D000079', (137, 149))	('ALDH2', 'Gene', (91, 96))	('carcinogenic', 'Disease', 'MESH:D063646', (179, 191))	('break down', 'Phenotype', 'HP:0001061', (27, 37))	('carcinogenic', 'Disease', (179, 191))	('break down acetaldehyde', 'Phenotype', 'HP:0003533', (27, 50))	('acetaldehyde', 'Chemical', 'MESH:D000079', (38, 50))	('ethanol', 'Chemical', 'MESH:D000431', (68, 75))	('acetaldehyde', 'MPA', (137, 149))	('acetaldehyde metabolized', 'MPA', (38, 62))	('build-up', 'MPA', (125, 133))	('ALDH', 'molecular_function', 'GO:0004030', ('91', '95'))	('ALDH2', 'Gene', '217', (91, 96))
20173	32365627	The carcinogenic effects of As include oxidative damage, epigenetic effects, and interference with DNA repair, all implicated in the development of urinary tract cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (148, 168))	('cancer', 'Disease', (162, 168))	('interference', 'NegReg', (81, 93))	('carcinogenic', 'Disease', 'MESH:D063646', (4, 16))	('As', 'Chemical', 'MESH:D001151', (28, 30))	('carcinogenic', 'Disease', (4, 16))	('epigenetic effects', 'Var', (57, 75))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('oxidative damage', 'MPA', (39, 55))	('DNA repair', 'Protein', (99, 109))	('DNA repair', 'biological_process', 'GO:0006281', ('99', '109'))
20248	30760718	Here we comprehensively analyze the genomic alterations of the genes encoding histone acetylation modulator proteins (HAMPs) in the Cancer Genome Atlas cohort and observe that HAMPs have a high frequency of focal copy number alterations and recurrent mutations, whereas transcript fusions of HAMPs are relatively rare genomic events in common adult cancers.	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('mutations', 'Var', (251, 260))	('histone acetylation', 'biological_process', 'GO:0016573', ('78', '97'))	('Cancer Genome Atlas cohort', 'Disease', 'MESH:D009369', (132, 158))	('cancers', 'Phenotype', 'HP:0002664', (349, 356))	('Cancer Genome Atlas cohort', 'Disease', (132, 158))	('focal', 'MPA', (207, 212))	('adult cancers', 'Disease', (343, 356))	('HAMP', 'Gene', '57817', (292, 296))	('adult cancers', 'Disease', 'MESH:C535836', (343, 356))	('HAMP', 'Gene', (292, 296))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('HAMP', 'Gene', '57817', (176, 180))	('HAMP', 'Gene', '57817', (118, 122))	('HAMP', 'Gene', (176, 180))	('HAMP', 'Gene', (118, 122))
20250	30760718	For example, the recurrent focal amplification of BRD9 is observed in 9 cancer types and genetic depletion of BRD9 inhibits tumor growth.	('genetic depletion', 'Var', (89, 106))	('BRD9', 'Gene', '65980', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('BRD9', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (124, 129))	('BRD9', 'Gene', (50, 54))	('inhibits', 'NegReg', (115, 123))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('BRD9', 'Gene', '65980', (110, 114))	('cancer', 'Disease', (72, 78))
20298	30760718	BRD9, BRD4, KAT6A, ATAD2, CLOCK, ASH1L, and BPTF showed high overall G-scores for copy number gain, whereas HDAC4, BRD1, SIRT3, HDAC10, SP100, SP140L, SP110, and PBRM1 had high overall G-scores for copy number loss (overall G-score > 0.9; Fig.	('KAT', 'molecular_function', 'GO:0003988', ('12', '15'))	('BRD4', 'Gene', '23476', (6, 10))	('BPTF', 'Gene', (44, 48))	('SP140L', 'Gene', (143, 149))	('SP110', 'Gene', '3431', (151, 156))	('ATAD2', 'Gene', (19, 24))	('KAT6A', 'Gene', '7994', (12, 17))	('HDAC10', 'Gene', '83933', (128, 134))	('SIRT3', 'Gene', (121, 126))	('ASH1L', 'Gene', (33, 38))	('SIRT3', 'Gene', '23410', (121, 126))	('BRD9', 'Gene', '65980', (0, 4))	('copy number gain', 'Disease', 'MESH:D015430', (82, 98))	('CLOCK', 'Gene', '9575', (26, 31))	('CLOCK', 'Gene', (26, 31))	('BRD1', 'Gene', (115, 119))	('HDAC4', 'Gene', '9759', (108, 113))	('copy number', 'Var', (198, 209))	('ASH1L', 'Gene', '55870', (33, 38))	('copy number gain', 'Disease', (82, 98))	('KAT6A', 'Gene', (12, 17))	('SP110', 'Gene', (151, 156))	('SP100', 'Gene', '6672', (136, 141))	('BRD4', 'Gene', (6, 10))	('SP140L', 'Gene', '93349', (143, 149))	('BRD9', 'Gene', (0, 4))	('ATAD2', 'Gene', '29028', (19, 24))	('PBRM1', 'Gene', '55193', (162, 167))	('BRD1', 'Gene', '23774', (115, 119))	('HDAC10', 'Gene', (128, 134))	('HDAC4', 'Gene', (108, 113))	('BPTF', 'Gene', '2186', (44, 48))	('PBRM1', 'Gene', (162, 167))	('SP100', 'Gene', (136, 141))
20300	30760718	3b); in contrast, high-level alterations (GISTIC status = - 2) were markedly less frequent in HAMPs with copy number loss (0.8-9.4%; Fig.	('HAMP', 'Gene', (94, 98))	('HAMP', 'Gene', '57817', (94, 98))	('copy number loss', 'Var', (105, 121))
20304	30760718	The mutation call set was generated via an ensemble calling strategy by the MC3 (Multi-Center Mutation Calling in Multiple Cancers) project, then we integrated five complementary methods to identify the genes with mutations that have significant signs of positive selection during tumor evolution (Fig.	('Multiple Cancers', 'Disease', (114, 130))	('MC3', 'Gene', (76, 79))	('Multiple Cancers', 'Disease', 'MESH:D009369', (114, 130))	('MC3', 'Gene', '4159', (76, 79))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Cancers', 'Phenotype', 'HP:0002664', (123, 130))	('mutations', 'Var', (214, 223))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Disease', (281, 286))
20305	30760718	Collectively, across 33 cancer types, we identified 34 HAMPs that have recurrent mutations in at least one cancer type (Fig.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (24, 30))	('HAMP', 'Gene', '57817', (55, 59))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('HAMP', 'Gene', (55, 59))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', (107, 113))
20307	30760718	3b), the recurrent mutations of HAMPs were largely cancer type-specific (Fig.	('HAMP', 'Gene', '57817', (32, 36))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('HAMP', 'Gene', (32, 36))
20308	30760718	4b): 17 of 34 (50%) HAMPs with recurrent mutations were only observed in one cancer type and no recurrent mutation of HAMPs was found in more than 7 cancer types.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('HAMP', 'Gene', '57817', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('HAMP', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('HAMP', 'Gene', '57817', (118, 122))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('HAMP', 'Gene', (118, 122))
20310	30760718	UCEC (n = 20), SKCM (n = 8), BLCA (n = 6), cervical squamous cell carcinoma, and endocervical adenocarcinoma (CESC; n = 6), and HNSC (n = 6) had the largest numbers of recurrent mutations in HAMPs, whereas ACC, DLBC, ESCA, KICH, LAML, LGG, mesothelioma (MESO), OV, PAAD, PCPG, READ, SARC, TGCT, THCA, THYM, UCS, and UVM had none (Fig.	('READ', 'Disease', 'None', (277, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('KICH', 'Disease', (223, 227))	('PAAD', 'Phenotype', 'HP:0006725', (265, 269))	('cervical squamous cell carcinoma', 'Disease', (43, 75))	('UCS', 'Phenotype', 'HP:0002891', (307, 310))	('OV', 'Phenotype', 'HP:0012887', (261, 263))	('mesothelioma', 'Disease', (240, 252))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (81, 108))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 75))	('HAMP', 'Gene', '57817', (191, 195))	('mesothelioma', 'Disease', 'MESH:D008654', (240, 252))	('ACC', 'Phenotype', 'HP:0006744', (206, 209))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('ESCA', 'Phenotype', 'HP:0011459', (217, 221))	('READ', 'Disease', (277, 281))	('KICH', 'Disease', 'None', (223, 227))	('HAMP', 'Gene', (191, 195))	('THYM', 'Phenotype', 'HP:0100522', (301, 305))	('THCA', 'Phenotype', 'HP:0002890', (295, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('mutations', 'Var', (178, 187))	('endocervical adenocarcinoma', 'Disease', (81, 108))
20311	30760718	Among the three types of HAMPs, BRD proteins and HATs had the highest frequencies of recurrent mutations and HDACs had few recurrent events (Fig.	('HAMP', 'Gene', '57817', (25, 29))	('HDAC', 'Gene', (109, 113))	('HAMP', 'Gene', (25, 29))	('HDAC', 'Gene', '9734', (109, 113))	('mutations', 'Var', (95, 104))
20313	30760718	Among eight HAMPs with M-scores > 0.4, EP300, PBRM1, and CREBBP had the largest overall M-scores across the 33 cancer types (Fig.	('CREBBP', 'Gene', (57, 63))	('HAMP', 'Gene', '57817', (12, 16))	('HAMP', 'Gene', (12, 16))	('M-scores', 'MPA', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CREBBP', 'Gene', '1387', (57, 63))	('PBRM1', 'Gene', (46, 51))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('EP300', 'Gene', (39, 44))	('EP300', 'Gene', '2033', (39, 44))	('PBRM1', 'Gene', '55193', (46, 51))	('M-scores > 0.4', 'Var', (23, 37))
20315	30760718	At a pan-cancer level, except for PBRM1, the most common mutation category of HAMPs was missense mutation (53.0-77.5%; Fig.	('cancer', 'Disease', (9, 15))	('HAMP', 'Gene', (78, 82))	('PBRM1', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('PBRM1', 'Gene', '55193', (34, 39))	('missense mutation', 'Var', (88, 105))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('HAMP', 'Gene', '57817', (78, 82))
20316	30760718	In contrast, PBRM1 was most commonly affected by truncating mutations (49.1%; Fig.	('truncating mutations', 'Var', (49, 69))	('PBRM1', 'Gene', (13, 18))	('PBRM1', 'Gene', '55193', (13, 18))	('affected', 'Reg', (37, 45))
20317	30760718	Using the ABSOLUTE algorithm, we also determined the timing of the mutational processes and the clonal statuses of the mutations in HAMPs.	('HAMP', 'Gene', (132, 136))	('mutations', 'Var', (119, 128))	('HAMP', 'Gene', '57817', (132, 136))
20318	30760718	More than 50% of mutations in HAMPs were early genomic events (Fig.	('HAMP', 'Gene', '57817', (30, 34))	('mutations', 'Var', (17, 26))	('HAMP', 'Gene', (30, 34))
20319	30760718	5d and Supplementary Data 15) and more than 65% of mutations in HAMPs were clonal mutations (Fig.	('HAMP', 'Gene', (64, 68))	('mutations', 'Var', (51, 60))	('HAMP', 'Gene', '57817', (64, 68))
20321	30760718	We also analyzed the distributions of the mutations across the gene bodies and found that mutations in HAMPs were widely spatially distributed along the entire coding sequences, not concentrated within a specific local region (Fig.	('HAMP', 'Gene', '57817', (103, 107))	('mutations', 'Var', (90, 99))	('HAMP', 'Gene', (103, 107))
20324	30760718	Notably, we observed that PBRM1 mutations showed a unique pattern in KIRC and cholangiocarcinoma (CHOL).	('CHOL', 'Phenotype', 'HP:0030153', (98, 102))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('mutations', 'Var', (32, 41))	('KIRC', 'Disease', (69, 73))	('cholangiocarcinoma', 'Disease', (78, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
20325	30760718	Compared with other cancer types, KIRC and CHOL showed higher frequencies of PBRM1 mutations (40.1% in KIRC and 19.4% in CHOL vs. an average of 2.3% among other cancer types).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (83, 92))	('PBRM1', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('PBRM1', 'Gene', '55193', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('CHOL', 'Phenotype', 'HP:0030153', (121, 125))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', (161, 167))	('CHOL', 'Phenotype', 'HP:0030153', (43, 47))
20326	30760718	Importantly, the dominant PBRM1 mutation category and type in KIRC and CHOL were truncating (83.9% and 85.7%, respectively) and homozygous (85.2% and 71.4%, respectively) mutations, which were remarkably higher than the averages in other cancer types (30.3% and 19.4%, respectively).	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('truncating', 'MPA', (81, 91))	('mutation', 'Var', (32, 40))	('CHOL', 'Phenotype', 'HP:0030153', (71, 75))
20327	30760718	Interestingly, we observed that, in both the CREBBP and EP300 genes, the most frequent mutations were located within the catalytic domain, although the mutations were not statistically significant hotspot mutations at the individual gene level based on OncodriveCLUST analysis (Fig.	('CREBBP', 'Gene', '1387', (45, 51))	('EP300', 'Gene', (56, 61))	('EP300', 'Gene', '2033', (56, 61))	('CREBBP', 'Gene', (45, 51))	('mutations', 'Var', (87, 96))
20334	30760718	6a and Supplementary Data 18), which suggests that transcript fusion is a rare genetic alteration compared with SCNAs and mutations in HAMPs in common adult cancers.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('adult cancers', 'Disease', 'MESH:C535836', (151, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('adult cancers', 'Disease', (151, 164))	('transcript fusion', 'Var', (51, 68))	('HAMP', 'Gene', '57817', (135, 139))	('HAMP', 'Gene', (135, 139))
20338	30760718	KAT6B-ADK (n = 6), BPTF-PITPNC1 (n = 5), and NCOA3-EYA2 (n = 5) were the most frequent fusions among the common cancer types examined in our study (Fig.	('NCOA3', 'Gene', (45, 50))	('fusions', 'Var', (87, 94))	('PITPNC1', 'Gene', '26207', (24, 31))	('BPTF', 'Gene', (19, 23))	('cancer', 'Disease', (112, 118))	('BPTF', 'Gene', '2186', (19, 23))	('NCOA3', 'Gene', '8202', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('EYA2', 'Gene', '2139', (51, 55))	('EYA2', 'Gene', (51, 55))	('KAT', 'molecular_function', 'GO:0003988', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('PITPNC1', 'Gene', (24, 31))
20342	30760718	Taken together, these results suggest that, although certain HAMP transcript fusions may be actionable for clinical cancer care, transcript fusion is a rare genomic alteration compared with SCNAs and mutations of HAMPs in common cancers.	('HAMP', 'Gene', '57817', (61, 65))	('transcript fusion', 'Var', (129, 146))	('HAMP', 'Gene', (61, 65))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('cancers', 'Disease', (229, 236))	('HAMP', 'Gene', '57817', (213, 217))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('HAMP', 'Gene', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
20346	30760718	Across the different lineages of cancers, three types of alterations were observed: (1) consistent, putative gain-of-function (such as for KAT6A and CLOCK, which were focally amplified in six and five cancer types, respectively); (2) consistent, putative loss-of-function (such as for PBRM1, which is mutated in four and focally deleted in five cancer types, and for CREBBP, which is mutated in four and focally deleted in two cancer types); and (3) diverse alterations (such as for ATAD2, which is mutated in three and focally amplified in five cancer types, and for BPTF, which is mutated in three and focally amplified in five cancer types).	('gain-of-function', 'PosReg', (109, 125))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', (630, 636))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (427, 433))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('KAT6A', 'Gene', '7994', (139, 144))	('ATAD2', 'Gene', '29028', (483, 488))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('loss-of-function', 'NegReg', (255, 271))	('cancers', 'Disease', (33, 40))	('CREBBP', 'Gene', (367, 373))	('cancer', 'Disease', (546, 552))	('PBRM1', 'Gene', '55193', (285, 290))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (630, 636))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', (427, 433))	('KAT6A', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (546, 552))	('ATAD2', 'Gene', (483, 488))	('PBRM1', 'Gene', (285, 290))	('cancer', 'Phenotype', 'HP:0002664', (427, 433))	('BPTF', 'Gene', '2186', (568, 572))	('CREBBP', 'Gene', '1387', (367, 373))	('cancer', 'Disease', (345, 351))	('CLOCK', 'Gene', '9575', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('KAT', 'molecular_function', 'GO:0003988', ('139', '142'))	('CLOCK', 'Gene', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (546, 552))	('BPTF', 'Gene', (568, 572))	('deleted', 'Var', (329, 336))
20347	30760718	This suggests that a large fraction of HAMP alterations may be commonly shared by multiple cancer types, whereas others may be tumor-lineage dependent.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('HAMP', 'Gene', (39, 43))	('HAMP', 'Gene', '57817', (39, 43))	('multiple cancer', 'Disease', (82, 97))	('tumor', 'Disease', (127, 132))	('alterations', 'Var', (44, 55))	('multiple cancer', 'Disease', 'MESH:D009369', (82, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
20376	30760718	Consistent with the GBA prediction, knocking down BRD9 expression dramatically inhibited cancer cell growth in vitro (Fig.	('BRD9', 'Gene', '65980', (50, 54))	('cell growth', 'biological_process', 'GO:0016049', ('96', '107'))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('BRD9', 'Gene', (50, 54))	('expression', 'MPA', (55, 65))	('cancer', 'Disease', (89, 95))	('inhibited', 'NegReg', (79, 88))	('knocking down', 'Var', (36, 49))	('GBA', 'Chemical', '-', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
20377	30760718	Finally, we demonstrated that the expression of BRD9 shRNAs significantly suppressed the growth of subcutaneous tumors formed by MDA-MB-231 or OVCAR8 cells in nude mice (Fig.	('subcutaneous tumors', 'Disease', (99, 118))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (129, 139))	('BRD9', 'Gene', (48, 52))	('nude mice', 'Species', '10090', (159, 168))	('OV', 'Phenotype', 'HP:0012887', (143, 145))	('suppressed', 'NegReg', (74, 84))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (99, 118))	('expression', 'Var', (34, 44))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (99, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('growth', 'CPA', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('BRD9', 'Gene', '65980', (48, 52))
20378	30760718	Collectively, our results demonstrate that genetic depletion of BDR9 expression significantly represses tumor cell growth in vitro and in vivo, suggesting that small molecular compounds targeting BRD9 may have strong clinical application potentials.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('BDR9', 'Gene', (64, 68))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('represses', 'NegReg', (94, 103))	('BRD9', 'Gene', '65980', (196, 200))	('cell growth', 'biological_process', 'GO:0016049', ('110', '121'))	('BRD9', 'Gene', (196, 200))	('genetic depletion', 'Var', (43, 60))
20386	30760718	A HAMP with a high score indicates its recurrent alterations are common genomic events across multiple adult cancer types.	('HAMP', 'Gene', '57817', (2, 6))	('alterations', 'Var', (49, 60))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('HAMP', 'Gene', (2, 6))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
20399	30760718	Furthermore, genetic depletion of HDACs in tumor cells leads to cell cycle arrest, apoptosis, and senescence, suggesting that HDACs are required for the survival and growth of tumor cells.	('tumor', 'Disease', (43, 48))	('HDAC', 'Gene', (34, 38))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('64', '81'))	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('genetic depletion', 'Var', (13, 30))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('apoptosis', 'CPA', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('HDAC', 'Gene', '9734', (126, 130))	('senescence', 'CPA', (98, 108))	('senescence', 'biological_process', 'GO:0010149', ('98', '108'))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('HDAC', 'Gene', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cell cycle arrest', 'CPA', (64, 81))	('HDAC', 'Gene', '9734', (34, 38))
20402	30760718	For example, CREBBP and EP300 were widely mutated across multiple cancer types at relatively low frequencies; most of these mutations were heterozygous missense mutations.	('mutations', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('EP300', 'Gene', (24, 29))	('EP300', 'Gene', '2033', (24, 29))	('multiple cancer', 'Disease', 'MESH:D009369', (57, 72))	('CREBBP', 'Gene', (13, 19))	('multiple cancer', 'Disease', (57, 72))	('CREBBP', 'Gene', '1387', (13, 19))
20403	30760718	In contrast, PBRM1 showed high-frequency, cancer type-specific mutations in KIRC (40.1%).	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('PBRM1', 'Gene', (13, 18))	('PBRM1', 'Gene', '55193', (13, 18))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
20409	30760718	Collectively, our comprehensive genomic analysis identified 63 putative cancer-causing HAMPs driven by SCNAs and/or mutations (recurrent score >= 1).	('SCNAs', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (116, 125))	('HAMP', 'Gene', '57817', (87, 91))	('HAMP', 'Gene', (87, 91))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
20412	30760718	For example, the breast and ovarian cancer patients with BRD4 amplifications may be potential candidates for treatment with BET inhibitors that have been successfully developed to the preclinical stage.	('BET', 'Gene', '92737', (124, 127))	('BET', 'Gene', (124, 127))	('ovarian cancer', 'Phenotype', 'HP:0100615', (28, 42))	('patients', 'Species', '9606', (43, 51))	('BRD4', 'Gene', (57, 61))	('amplifications', 'Var', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('BRD4', 'Gene', '23476', (57, 61))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (17, 42))
20413	30760718	In addition, eight HAMPs focally lost copy numbers (overall G-score > 0.9) and eight HAMPs showed high frequencies of mutations (overall M-score > 0.4), which indicates that their functions may be reduced and/or deficient due to partial loss of wild-type alleles during cancer development.	('HAMP', 'Gene', (19, 23))	('deficient', 'NegReg', (212, 221))	('copy', 'MPA', (38, 42))	('HAMP', 'Gene', '57817', (85, 89))	('functions', 'MPA', (180, 189))	('mutations', 'Var', (118, 127))	('HAMP', 'Gene', (85, 89))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('lost', 'NegReg', (33, 37))	('HAMP', 'Gene', '57817', (19, 23))
20415	30760718	For example, mutations of the BRD-containing protein SMARCA4 in tumor cells results in a unique functional dependence on SMARCA2.	('tumor', 'Disease', (64, 69))	('functional dependence', 'MPA', (96, 117))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('SMARCA4', 'Gene', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mutations', 'Var', (13, 22))	('SMARCA2', 'Gene', (121, 128))	('SMARCA2', 'Gene', '6595', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('results in', 'Reg', (76, 86))	('SMARCA4', 'Gene', '6597', (53, 60))
20417	30760718	Notably, very few homozygous deletions or mutations of HAMPs (except for PBRM1) were observed in cancer, suggesting that HAMPs may be essential for tumor growth, and that complete loss may be lethal.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', (148, 153))	('HAMP', 'Gene', '57817', (55, 59))	('PBRM1', 'Gene', '55193', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('HAMP', 'Gene', (55, 59))	('HAMP', 'Gene', '57817', (121, 125))	('HAMP', 'Gene', (121, 125))	('PBRM1', 'Gene', (73, 78))	('deletions', 'Var', (29, 38))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
20431	30760718	Our genomic and functional studies demonstrated that: (1) BRD9 is recurrently and focally amplified in nine cancer types with the highest recurrent score; (2) the expression of BRD9 is significantly increased in cancer specimens compared with that in corresponding normal tissues; (3) computational prediction suggests that BRD9 expression is associated with cell cycle, DNA damage repair, and RNA metabolic pathways in cancer; and (4) genetic depletion of BRD9 by shRNAs reduced cancer cell growth in vitro and in vivo.	('associated', 'Reg', (343, 353))	('cell growth', 'biological_process', 'GO:0016049', ('487', '498'))	('genetic depletion', 'Var', (436, 453))	('BRD9', 'Gene', (324, 328))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (480, 486))	('cancer', 'Disease', (420, 426))	('BRD9', 'Gene', '65980', (324, 328))	('BRD9', 'Gene', (457, 461))	('cancer', 'Phenotype', 'HP:0002664', (420, 426))	('BRD9', 'Gene', '65980', (457, 461))	('BRD9', 'Gene', (58, 62))	('RNA', 'cellular_component', 'GO:0005562', ('394', '397'))	('BRD9', 'Gene', (177, 181))	('cancer', 'Disease', (212, 218))	('cell cycle', 'biological_process', 'GO:0007049', ('359', '369'))	('DNA', 'cellular_component', 'GO:0005574', ('371', '374'))	('BRD9', 'Gene', '65980', (58, 62))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (420, 426))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Disease', (480, 486))	('reduced', 'NegReg', (472, 479))	('BRD9', 'Gene', '65980', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (480, 486))
20437	30760718	Taken together, our functional studies on BRD9 are the proof-of-concept for the HAMP candidates identified in our study and strongly suggest the clinical potential of targeting BRD9 in common adult solid cancers.	('BRD9', 'Gene', (42, 46))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('targeting', 'Var', (167, 176))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('BRD9', 'Gene', '65980', (177, 181))	('BRD9', 'Gene', (177, 181))	('HAMP', 'Gene', '57817', (80, 84))	('HAMP', 'Gene', (80, 84))	('BRD9', 'Gene', '65980', (42, 46))
20442	30760718	The gene expression data of 2012 cancer cell lines were downloaded through the Expression Atlas (https://www.ebi.ac.uk/gxa/download.html) under the accessions E-MTAB-2770, E-MTAB-3983, and E-MTAB-2706.	('E-MTAB-2770', 'Var', (159, 170))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('MTAB', 'molecular_function', 'GO:0047152', ('161', '165'))	('MTAB-2706', 'CellLine', 'CVCL:A552', (191, 200))	('MTAB', 'molecular_function', 'GO:0047152', ('191', '195'))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('E-MTAB-2706', 'Var', (189, 200))	('MTAB', 'molecular_function', 'GO:0047152', ('174', '178'))	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))
20466	30760718	ABSOLUTE calculated the purity, ploidy, and absolute DNA copy numbers from the segmented copy number alterations and mutation profiles of tumor samples.	('tumor', 'Disease', (138, 143))	('alterations', 'Var', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
20469	30760718	The cancer cell fraction of each somatic single-nucleotide variant was extracted from the output.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('single-nucleotide variant', 'Var', (41, 66))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cell fraction', 'cellular_component', 'GO:0000267', ('11', '24'))	('cancer', 'Disease', (4, 10))
20526	30417057	ORR was numerically higher in patients with ,,1% tumor PD-L1 treated with NIVO1IPI3 (58%), and efficacy was observed across PD-L1 expression levels in all treatment arms.	('PD-L1', 'Gene', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('PD-L1', 'Gene', '29126', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('NIVO1IPI3', 'Var', (74, 83))	('higher', 'PosReg', (20, 26))	('ORR', 'MPA', (0, 3))	('PD-L1', 'Gene', '29126', (124, 129))	('tumor', 'Disease', (49, 54))	('patients', 'Species', '9606', (30, 38))	('PD-L1', 'Gene', (55, 60))
20626	30684035	The most prevalent CLE features between low-grade and high-grade UTUCs were: organization versus disorganization of the cellular architecture; monomorphism versus pleomorphism of cells; and cohesiveness versus discohesion of cells.	('cohesiveness', 'CPA', (190, 202))	('UTUC', 'Disease', (65, 69))	('CLE', 'Disease', (19, 22))	('UTUC', 'Disease', 'MESH:D012141', (65, 69))	('monomorphism', 'Var', (143, 155))
20693	30773067	In addition, a stage wise comparison analysis revealed that cyclooxygenase (COX), lipoxygenase (LOX) signaling, heme catabolism, and nicotinamide adenine dinucleotide (NAD+) synthesis were enhanced in MIBC compared to NMIBC.	('cyclooxygenase', 'MPA', (60, 74))	('heme catabolism', 'biological_process', 'GO:0042167', ('112', '127'))	('enhanced', 'PosReg', (189, 197))	('NAD+) synthesis', 'biological_process', 'GO:0009435', ('168', '183'))	('heme', 'Chemical', 'MESH:D006418', (112, 116))	('heme catabolism', 'MPA', (112, 127))	('MIBC', 'Var', (201, 205))	('NAD+', 'Chemical', 'MESH:D009243', (168, 172))	('nicotinamide adenine dinucleotide', 'Chemical', 'MESH:D009243', (133, 166))	('MIBC', 'Chemical', '-', (219, 223))	('lipoxygenase', 'MPA', (82, 94))	('MIBC', 'Chemical', '-', (201, 205))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))
20716	30773067	In addition, evaluation of serum specimens in pre-operative and post-operative BLCA settings revealed aberrant downregulation of S10089, S100A9, S100A4, CA I and upregulation of Annexin V in post-operative BLCA.	('S100A4', 'Gene', '6275', (145, 151))	('Annexin V', 'Gene', '308', (178, 187))	('S100A9', 'Gene', '6280', (137, 143))	('upregulation', 'PosReg', (162, 174))	('S100A9', 'Gene', (137, 143))	('pre', 'molecular_function', 'GO:0003904', ('46', '49'))	('Annexin V', 'Gene', (178, 187))	('BLCA', 'Phenotype', 'HP:0009725', (206, 210))	('BLCA', 'Phenotype', 'HP:0009725', (79, 83))	('S10089', 'Var', (129, 135))	('CA I', 'Gene', '759', (153, 157))	('downregulation', 'NegReg', (111, 125))	('S100A4', 'Gene', (145, 151))	('CA I', 'Gene', (153, 157))
20723	30773067	It was suggested that perturbations in phospholipid metabolism are associated with many cancers.	('phospholipid', 'Chemical', 'MESH:D010743', (39, 51))	('phospholipid metabolism', 'MPA', (39, 62))	('perturbations', 'Var', (22, 35))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('phospholipid metabolism', 'biological_process', 'GO:0006644', ('39', '62'))	('cancers', 'Disease', (88, 95))	('associated', 'Reg', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
20742	30773067	In our study, smokers with BLCA, and BLCA cell lines treated with NNK and BaP showed increased expression of Y-H2AX and check-point kinase 2 (Chk2) in comparison to non-smokers.	('Chk2', 'Gene', (142, 146))	('Y-H2AX', 'Var', (109, 115))	('check-point kinase 2', 'Gene', (120, 140))	('BLCA', 'Phenotype', 'HP:0009725', (37, 41))	('BLCA', 'Phenotype', 'HP:0009725', (27, 31))	('check-point kinase 2', 'Gene', '11200', (120, 140))	('BaP', 'Chemical', '-', (74, 77))	('increased', 'PosReg', (85, 94))	('Chk2', 'Gene', '11200', (142, 146))	('expression', 'MPA', (95, 105))
20743	30773067	Hence, we postulate that smoking causes DNA damage when erroneous DNA repair causes mutations and chromosomal aberrations leading to activation of oncogenes and loss of tumor suppressor genes which in turn may cause more aggressive BLCA.	('oncogenes', 'Protein', (147, 156))	('BLCA', 'Phenotype', 'HP:0009725', (232, 236))	('DNA repair', 'biological_process', 'GO:0006281', ('66', '76'))	('chromosomal aberrations', 'Var', (98, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('169', '185'))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (98, 121))	('aggressive BLCA', 'Disease', (221, 236))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('loss of tumor', 'Disease', 'MESH:D009369', (161, 174))	('mutations', 'Var', (84, 93))	('activation', 'PosReg', (133, 143))	('erroneous DNA', 'Var', (56, 69))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('cause', 'Reg', (210, 215))	('loss of tumor', 'Disease', (161, 174))	('tumor suppressor', 'biological_process', 'GO:0051726', ('169', '185'))
20750	30773067	In our study, we found that BLCA smokers and BLCA cell lines treated with NNK and BaP also show very high DNMT1 expression compared to nonsmokers with BLCA which further supports the role of DNMT1 in BLCA development.	('BLCA', 'Phenotype', 'HP:0009725', (200, 204))	('DNMT1', 'Gene', (191, 196))	('BLCA', 'Phenotype', 'HP:0009725', (45, 49))	('BaP', 'Var', (82, 85))	('DNMT1', 'Gene', (106, 111))	('BLCA', 'Phenotype', 'HP:0009725', (151, 155))	('BLCA', 'Phenotype', 'HP:0009725', (28, 32))	('DNMT1', 'Gene', '1786', (191, 196))	('DNMT1', 'Gene', '1786', (106, 111))	('BaP', 'Chemical', '-', (82, 85))	('expression', 'MPA', (112, 122))
20751	30773067	DNMT1 inhibitors are currently being investigated as epigenetic therapeutics for the treatment of cancer,, and our findings further strengthen the evidence that DNMT inhibitors may serve as potential therapeutics for smokers with BLCA.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('DNMT', 'Gene', '1786', (161, 165))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('BLCA', 'Phenotype', 'HP:0009725', (230, 234))	('BLCA', 'Disease', (230, 234))	('cancer', 'Disease', (98, 104))	('DNMT1', 'Gene', (0, 5))	('inhibitors', 'Var', (6, 16))	('DNMT1', 'Gene', '1786', (0, 5))	('DNMT', 'Gene', '1786', (0, 4))	('DNMT', 'Gene', (161, 165))	('DNMT', 'Gene', (0, 4))
20752	30773067	The amino acid methionine is a principal source of a methyl group for the DNMT1 mediated epigenetic modification.	('DNMT1', 'Gene', (74, 79))	('epigenetic modification', 'Var', (89, 112))	('DNMT1', 'Gene', '1786', (74, 79))	('methyl', 'Chemical', 'MESH:C051224', (53, 59))	('methionine', 'Chemical', 'MESH:D008715', (15, 25))
20753	30773067	Isotope-labeled methionine flux studies on DNMT1 knockdown BLCA cells treated with NNK, BaP show higher levels of methionine and SAM, lower levels of SAH, methylated metabolites, and DNA adducts which further confirms that tobacco smoke-induced DNMT1 plays a major role in inducing epigenetic changes that lead to more aggressive BLCA.	('levels', 'MPA', (104, 110))	('higher', 'PosReg', (97, 103))	('DNMT1', 'Gene', (245, 250))	('BLCA', 'Phenotype', 'HP:0009725', (59, 63))	('DNMT1', 'Gene', '1786', (43, 48))	('aggressive BLCA', 'Disease', (319, 334))	('BaP', 'Chemical', '-', (88, 91))	('methionine', 'Chemical', 'MESH:D008715', (114, 124))	('DNA', 'cellular_component', 'GO:0005574', ('183', '186'))	('methylated', 'MPA', (155, 165))	('lead to', 'Reg', (306, 313))	('DNMT1', 'Gene', (43, 48))	('epigenetic changes', 'Var', (282, 300))	('DNMT1', 'Gene', '1786', (245, 250))	('methionine', 'MPA', (114, 124))	('lower', 'NegReg', (134, 139))	('methionine', 'Chemical', 'MESH:D008715', (16, 26))	('methyl', 'Chemical', 'MESH:C051224', (155, 161))	('BLCA', 'Phenotype', 'HP:0009725', (330, 334))	('tobacco', 'Species', '4097', (223, 230))	('more', 'PosReg', (314, 318))
20796	30588098	A few studies have also reported a relationship between MTDH/AEG-1 and BUC, as MTDH/AEG-1 is upregulated in BUC and high expression of MTDH/AEG-1 shows a relationship with poor prognosis.	('AEG-1', 'Gene', '92140', (140, 145))	('AEG-1', 'Gene', (140, 145))	('high', 'Var', (116, 120))	('AEG-1', 'Gene', '92140', (84, 89))	('AEG-1', 'Gene', (84, 89))	('AEG-1', 'Gene', '92140', (61, 66))	('upregulated', 'PosReg', (93, 104))	('poor prognosis', 'CPA', (172, 186))	('AEG-1', 'Gene', (61, 66))
20828	30588098	The results were determined by measuring the signals from the absolute number of viable cells (Hoechst 33342 positive/PI negative), necrotic cells (PI positive), early apoptotic cells (Hoechst 33342 positive/PI negative, blue fragmentations), late apoptotic cells (Hoechst 33342 positive/PI positive, red fragmentations), and debris.	('Hoechst 33342', 'Chemical', 'MESH:C017807', (95, 108))	('necrotic', 'Disease', (132, 140))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (185, 198))	('Hoechst', 'Var', (265, 272))	('Hoechst', 'Var', (185, 192))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (265, 278))	('necrotic', 'Disease', 'MESH:D009336', (132, 140))	('blue fragmentations', 'CPA', (221, 240))
20842	30588098	We selected 13 clip datasets (GSE30522, GSE76211, GSE65635, GSE38264, GSE52519, GSE40355, GSE37815, GSE31189, GSE24152, GSE13507, GSE7476, GSE3167, and E-MTAB-1940) to measure the expression of MTDH/AEG-1 according to GEO and ArrayExpress.	('AEG-1', 'Gene', '92140', (199, 204))	('AEG-1', 'Gene', (199, 204))	('MTAB', 'molecular_function', 'GO:0047152', ('154', '158'))	('GSE3167', 'Chemical', '-', (139, 146))	('GSE40355', 'Var', (80, 88))	('GSE38264', 'Var', (60, 68))	('GSE65635', 'Var', (50, 58))	('GSE24152', 'Var', (110, 118))	('GSE13507', 'Var', (120, 128))	('GSE52519', 'Var', (70, 78))	('GSE7476', 'Chemical', '-', (130, 137))	('GSE37815', 'Var', (90, 98))	('GSE31189', 'Var', (100, 108))
20843	30588098	Comparison of MTDH/AEG-1 expression in BUC and normal bladder using Student's t-test indicated a clear upregulation of MTDH/AEG-1 expression in BUC in GSE7476 and GSE3167 (Figure 1H and I), whereas no obvious associations were evident in the other datasets.	('GSE7476', 'Var', (151, 158))	('expression', 'MPA', (130, 140))	('upregulation', 'PosReg', (103, 115))	('GSE3167', 'Var', (163, 170))	('GSE7476', 'Chemical', '-', (151, 158))	('AEG-1', 'Gene', '92140', (124, 129))	('AEG-1', 'Gene', (124, 129))	('GSE3167', 'Chemical', '-', (163, 170))	('AEG-1', 'Gene', '92140', (19, 24))	('AEG-1', 'Gene', (19, 24))
20853	30588098	MTDH/AEG-1 expression was also markedly enhanced in the group with a high Ki-67, PCNA, and p53 LI expression (P<0.001, Figure 5, Table 4).	('high Ki-67', 'Var', (69, 79))	('expression', 'MPA', (11, 21))	('p53', 'Gene', (91, 94))	('Ki-67', 'Var', (74, 79))	('p53', 'Gene', '7157', (91, 94))	('PCNA', 'molecular_function', 'GO:0003892', ('81', '85'))	('AEG-1', 'Gene', '92140', (5, 10))	('AEG-1', 'Gene', (5, 10))	('enhanced', 'PosReg', (40, 48))	('PCNA', 'Var', (81, 85))
20855	30588098	The meta-analysis included 976 cases from three sources (12 datasets in GEO [GSE30522, GSE76211, GSE65635, GSE38264, GSE52519, GSE40355, GSE37815, GSE31189, GSE24152, GSE13507, GSE7476, and GSE3167], one data set in ArrayExpress [E-MTAB-1940], and the original data in TCGA).	('GSE37815', 'Var', (137, 145))	('GSE76211', 'Var', (87, 95))	('MTAB', 'molecular_function', 'GO:0047152', ('232', '236'))	('GSE38264', 'Var', (107, 115))	('GSE65635', 'Var', (97, 105))	('GSE24152', 'Var', (157, 165))	('GSE7476', 'Var', (177, 184))	('GSE13507', 'Var', (167, 175))	('GSE52519', 'Var', (117, 125))	('GSE3167', 'Chemical', '-', (190, 197))	('GSE7476', 'Chemical', '-', (177, 184))	('GSE31189', 'Var', (147, 155))	('GSE40355', 'Var', (127, 135))	('GSE3167]', 'Var', (190, 198))
20862	30588098	The pooled sensitivity and specificity were assessed to confirm the accuracy of MTDH/AEG-1 for the detection of BUC.	('AEG-1', 'Gene', '92140', (85, 90))	('AEG-1', 'Gene', (85, 90))	('BUC', 'Var', (112, 115))
20872	30588098	Caspase-3/7 activity was clearly enhanced by transfection with MTDH/AEG-1 siRNA in all three BUC cell lines, especially at 96 hours (Figure 10A-C).	('Caspase-3', 'Gene', (0, 9))	('AEG-1', 'Gene', (68, 73))	('AEG-1', 'Gene', '92140', (68, 73))	('activity', 'MPA', (12, 20))	('transfection', 'Var', (45, 57))	('enhanced', 'PosReg', (33, 41))	('Caspase-3', 'Gene', '836', (0, 9))
20875	30588098	A search of the top 1,500 genes co-expressed with MTDH/AEG-1 in five different probe sets (212251_AT, 212248_AT, 227277_AT, 212250_AT, and 1559822_S_At) of the MEM database revealed 173 genes that were overlapped by all five probe sets.	('AEG-1', 'Gene', '92140', (55, 60))	('AT', 'Disease', 'None', (109, 111))	('AT', 'Disease', 'None', (120, 122))	('AEG-1', 'Gene', (55, 60))	('AT', 'Disease', 'None', (98, 100))	('1559822_S_At', 'Var', (139, 151))	('AT', 'Disease', 'None', (131, 133))
20894	30588098	MTDH/AEG-1 expression has previously been reported to promote invasion and metastasis through the activation of nuclear factor-kappaB (NF-kappaB), interleukin-8, and matrix metalloproteinase-9.	('promote', 'PosReg', (54, 61))	('matrix metalloproteinase-9', 'Gene', '4318', (166, 192))	('AEG-1', 'Gene', '92140', (5, 10))	('activation', 'PosReg', (98, 108))	('interleukin-8', 'Gene', (147, 160))	('matrix metalloproteinase-9', 'Gene', (166, 192))	('nuclear', 'Protein', (112, 119))	('invasion', 'CPA', (62, 70))	('AEG-1', 'Gene', (5, 10))	('expression', 'Var', (11, 21))	('interleukin-8', 'Gene', '3576', (147, 160))
20897	30588098	Ki-67 and PCNA are classical markers of cell proliferation and are routinely used by pathologists, whereas p53 is related to DNA repair and apoptosis.	('Ki-67', 'Var', (0, 5))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('PCNA', 'Disease', (10, 14))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('DNA repair', 'biological_process', 'GO:0006281', ('125', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('cell proliferation', 'biological_process', 'GO:0008283', ('40', '58'))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))	('PCNA', 'molecular_function', 'GO:0003892', ('10', '14'))
20922	30598907	Although the causal relationship between HPV and urothelial carcinoma of the bladder has been evaluated by several groups, the findings are widely divergent showing the presence of HPV DNA in 0% to 35%-52% of bladder cancers.	('DNA', 'cellular_component', 'GO:0005574', ('185', '188'))	('bladder cancers', 'Disease', 'MESH:D001749', (209, 224))	('bladder cancer', 'Phenotype', 'HP:0009725', (209, 223))	('HPV', 'Gene', (181, 184))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (49, 84))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (49, 84))	('presence', 'Var', (169, 177))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('bladder cancers', 'Disease', (209, 224))	('urothelial carcinoma of the bladder', 'Disease', (49, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('DNA', 'Var', (185, 188))	('bladder cancers', 'Phenotype', 'HP:0009725', (209, 224))
21017	25087173	A single-institution series of Indiana pouches had complications in up to 90% of patients, the most common being incontinence caused by problems with the valve.	('incontinence', 'Disease', (113, 125))	('incontinence', 'Disease', 'MESH:D014549', (113, 125))	('patients', 'Species', '9606', (81, 89))	('to 9', 'Species', '1214577', (71, 75))	('Indiana pouches', 'Phenotype', 'HP:0000384', (31, 46))	('problems', 'Var', (136, 144))
21037	25087173	reported the results of the SWOG 8710 study that evaluated a four-drug combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) in 307 patients with MIBC (T2N0M0 to T4aN0M0).	('MVAC', 'Chemical', '-', (141, 145))	('methotrexate', 'Chemical', 'MESH:D008727', (86, 98))	('doxorubicin', 'Chemical', 'MESH:D004317', (113, 124))	('patients', 'Species', '9606', (154, 162))	('MIBC', 'Chemical', '-', (168, 172))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('T2N0M0', 'Var', (174, 180))	('T4aN0M0', 'Var', (184, 191))	('vinblastine', 'Chemical', 'MESH:D014747', (100, 111))	('MIBC', 'Disease', (168, 172))
21044	25087173	The Advanced Bladder Cancer Meta-Analysis Collaboration analyzed 2688 patients from ten clinical trials and found that cisplatin-based combination neoadjuvant chemotherapy was associated with a significant overall survival benefit (HR 0.87; P = 0.016), although the HR for all trials, including those using single-agent cisplatin, was not significant (HR 0.91; P = 0.084).	('patients', 'Species', '9606', (70, 78))	('benefit', 'PosReg', (223, 230))	('cisplatin-based', 'Var', (119, 134))	('Bladder Cancer', 'Disease', (13, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (320, 329))	('Bladder Cancer', 'Disease', 'MESH:D001749', (13, 27))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (13, 27))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))
21053	25087173	Patients receiving MVAC showed higher pT0 rates than patients receiving GC (31% vs. 25%, respectively), which was not statistically significant (P = 0.645), and there was no difference in overall survival between the two regimens (HR 1.3; P = 0.33).	('GC', 'Chemical', '-', (72, 74))	('patients', 'Species', '9606', (53, 61))	('MVAC', 'Chemical', '-', (19, 23))	('men', 'Species', '9606', (225, 228))	('Patients', 'Species', '9606', (0, 8))	('higher', 'PosReg', (31, 37))	('pT0 rates', 'CPA', (38, 47))	('MVAC', 'Var', (19, 23))
21056	25087173	In the EORTC study by Sternberg et al., ddMVAC given every two weeks with growth-factor support resulted in a higher response rate with fewer dose delays and less toxicity compared to the standard schedule of MVAC given over four weeks in advanced metastatic bladder cancer.	('response', 'MPA', (117, 125))	('bladder cancer', 'Disease', 'MESH:D001749', (259, 273))	('bladder cancer', 'Disease', (259, 273))	('ddMVAC', 'Var', (40, 46))	('ddMVAC', 'Chemical', '-', (40, 46))	('bladder cancer', 'Phenotype', 'HP:0009725', (259, 273))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('toxicity', 'Disease', 'MESH:D064420', (163, 171))	('MVAC', 'Chemical', '-', (209, 213))	('higher', 'PosReg', (110, 116))	('toxicity', 'Disease', (163, 171))	('MVAC', 'Chemical', '-', (42, 46))
21097	25087173	Results also showed a prolonged five-year overall survival in the PCG arm (60%) compared to observation (31%) (P < 0.0009).	('PCG', 'Chemical', '-', (66, 69))	('prolonged', 'PosReg', (22, 31))	('overall survival', 'CPA', (42, 58))	('PCG', 'Var', (66, 69))
21105	25087173	It has been suggested that p53 positivity is associated with a high recurrence rate in patients with organ-confined bladder cancer, especially in early-stage disease (T1/T2N0).	('confined bladder', 'Phenotype', 'HP:0100645', (107, 123))	('bladder cancer', 'Phenotype', 'HP:0009725', (116, 130))	('bladder cancer', 'Disease', 'MESH:D001749', (116, 130))	('bladder cancer', 'Disease', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('positivity', 'Var', (31, 41))	('p53', 'Gene', (27, 30))	('patients', 'Species', '9606', (87, 95))	('p53', 'Gene', '7157', (27, 30))
21106	25087173	p53 positivity has also been suggested as a predictive marker for cisplatin-based chemotherapy in bladder cancer.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('positivity', 'Var', (4, 14))	('bladder cancer', 'Disease', (98, 112))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
21165	25087173	The largest series reporting the outcomes of radiotherapy alone in patients with urothelial carcinoma of the bladder was from Scotland, where the institutional policy was primary radiotherapy as the sole treatment in patients with T1-T4 urothelial carcinoma of the bladder.	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (237, 272))	('patients', 'Species', '9606', (67, 75))	('urothelial carcinoma of the bladder', 'Disease', (237, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('T1-T4', 'Var', (231, 236))	('men', 'Species', '9606', (209, 212))	('patients', 'Species', '9606', (217, 225))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (81, 116))	('urothelial carcinoma of the bladder', 'Disease', (81, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
21246	25087173	Advances in molecular technologies that allow more rapid and extensive analyses have identified various genetic and epigenetic changes and aberrant protein expressions associated with urothelial carcinoma.	('associated', 'Reg', (168, 178))	('epigenetic changes', 'Var', (116, 134))	('urothelial carcinoma', 'Disease', (184, 204))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('protein', 'Protein', (148, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (184, 204))	('aberrant', 'Var', (139, 147))
21247	25087173	Deletion, mutation, or aberrant methylation of tumor suppressor genes such as TP53, RB1, CDKN2A, and PTEN and activation, mutation, or overexpression of oncogenes such as FGFR3, Her2, and CCND1 are commonly associated with MIBC.	('PTEN', 'Gene', (101, 105))	('MIBC', 'Chemical', '-', (223, 227))	('associated', 'Reg', (207, 217))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('FGFR3', 'Gene', (171, 176))	('mutation', 'Var', (122, 130))	('PTEN', 'Gene', '5728', (101, 105))	('RB1', 'Gene', (84, 87))	('mutation', 'Var', (10, 18))	('CDKN2A', 'Gene', (89, 95))	('TP53', 'Gene', '7157', (78, 82))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('FGFR3', 'Gene', '2261', (171, 176))	('Deletion', 'Var', (0, 8))	('CCND1', 'Gene', (188, 193))	('aberrant methylation', 'Var', (23, 43))	('tumor suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('CDKN2A', 'Gene', '1029', (89, 95))	('RB1', 'Gene', '5925', (84, 87))	('tumor', 'Disease', (47, 52))	('overexpression', 'PosReg', (135, 149))	('Her2', 'Gene', '2064', (178, 182))	('CCND1', 'Gene', '595', (188, 193))	('activation', 'PosReg', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('171', '175'))	('Her2', 'Gene', (178, 182))	('TP53', 'Gene', (78, 82))	('MIBC', 'Disease', (223, 227))
21248	25087173	Some of these alterations seem to play a critical role in tumorigenesis, disease progression, and development of treatment resistance.	('alterations', 'Var', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('disease progression', 'CPA', (73, 92))	('role', 'Reg', (50, 54))	('men', 'Species', '9606', (118, 121))	('men', 'Species', '9606', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('play', 'Reg', (34, 38))
21260	25087173	Mutations, copy number alterations, or RNA expression changes affecting the PI3K/AKT/mTOR pathway were observed in 42% of tumors, including activating point mutations in PIK3CA (17%), mutation or deletion of TSC1 or TSC2 (9%), and overexpression of AKT3 (10%).	('PIK3CA', 'Gene', '5290', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('AKT', 'Gene', '207', (81, 84))	('AKT', 'Gene', '207', (249, 252))	('copy number alterations', 'Var', (11, 34))	('mTOR', 'Gene', '2475', (85, 89))	('changes affecting', 'Reg', (54, 71))	('Mutations', 'Var', (0, 9))	('AKT3', 'Gene', '10000', (249, 253))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('PIK3CA', 'Gene', (170, 176))	('TSC2', 'Gene', '7249', (216, 220))	('activating', 'PosReg', (140, 150))	('mutation', 'Var', (184, 192))	('PI3K', 'molecular_function', 'GO:0016303', ('76', '80'))	('RNA expression', 'MPA', (39, 53))	('TSC1', 'Gene', (208, 212))	('AKT3', 'Gene', (249, 253))	('AKT', 'Gene', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('AKT', 'Gene', (249, 252))	('TSC2', 'Gene', (216, 220))	('TSC1', 'Gene', '7248', (208, 212))	('tumors', 'Disease', (122, 128))	('overexpression', 'PosReg', (231, 245))	('RNA', 'cellular_component', 'GO:0005562', ('39', '42'))	('mTOR', 'Gene', (85, 89))
21261	25087173	ERBB2 mutation or amplification was detected in 9% of tumors, which is approximately as frequent as in TCGA breast cancers, but with fewer amplifications and more mutations.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('ERBB2', 'Gene', '2064', (0, 5))	('breast cancers', 'Phenotype', 'HP:0003002', (108, 122))	('detected', 'Reg', (36, 44))	('ERBB2', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('breast cancers', 'Disease', 'MESH:D001943', (108, 122))	('breast cancers', 'Disease', (108, 122))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
21262	25087173	Other genetic alterations with potential therapeutic implications include amplification of EGFR (9%) and FGFR3 mutation.	('FGFR3', 'Gene', (105, 110))	('EGFR', 'Gene', (91, 95))	('amplification', 'Var', (74, 87))	('EGFR', 'molecular_function', 'GO:0005006', ('91', '95'))	('FGFR3', 'Gene', '2261', (105, 110))	('mutation', 'Var', (111, 119))	('EGFR', 'Gene', '1956', (91, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))
21263	25087173	FGFR3 mutation, commonly found in low-grade NMIBC, was found at a lower frequency in high-grade MIBC (17%) and is strongly associated with papillary morphology.	('associated with', 'Reg', (123, 138))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('papillary morphology', 'Phenotype', 'HP:0007482', (139, 159))	('MIBC', 'Chemical', '-', (45, 49))	('MIBC', 'Chemical', '-', (96, 100))	('papillary morphology', 'Disease', (139, 159))	('FGFR3', 'Gene', '2261', (0, 5))
21264	25087173	Of the tumors analyzed, 76% had an inactivating mutation in one or more chromatin-regulatory genes, which could potentially be targeted by newly developed agents that target chromatin modifications.	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Disease', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('chromatin-regulatory genes', 'Gene', (72, 98))	('inactivating mutation', 'Var', (35, 56))	('chromatin', 'cellular_component', 'GO:0000785', ('72', '81'))	('chromatin', 'cellular_component', 'GO:0000785', ('174', '183'))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
21315	25087173	Mutations, copy number alterations, or RNA expression changes affecting the PI3K/Akt/mTOR pathway are commonly found in various malignancies, including bladder cancer.	('found', 'Reg', (111, 116))	('RNA expression', 'MPA', (39, 53))	('Akt', 'Gene', '207', (81, 84))	('bladder cancer', 'Disease', 'MESH:D001749', (152, 166))	('bladder cancer', 'Disease', (152, 166))	('copy number alterations', 'Var', (11, 34))	('malignancies', 'Disease', 'MESH:D009369', (128, 140))	('Akt', 'Gene', (81, 84))	('affecting', 'Reg', (62, 71))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('mTOR', 'Gene', '2475', (85, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (152, 166))	('malignancies', 'Disease', (128, 140))	('RNA', 'cellular_component', 'GO:0005562', ('39', '42'))	('mTOR', 'Gene', (85, 89))	('PI3K', 'molecular_function', 'GO:0016303', ('76', '80'))
21316	25087173	Data from Memorial Sloan-Kettering showed mutations or copy number gains/losses of genes in the PI3K/Akt/mTOR pathway, including PIK3CA, PIK3R1, TSC1, PTEN, and the AKT3 isoforms in 26 of 95 patients (27%) with high-grade MIBC.	('mTOR', 'Gene', (105, 109))	('PIK3CA', 'Gene', '5290', (129, 135))	('MIBC', 'Disease', (222, 226))	('AKT3', 'Gene', (165, 169))	('MIBC', 'Chemical', '-', (222, 226))	('Akt', 'Gene', (101, 104))	('gains/losses', 'PosReg', (67, 79))	('mTOR', 'Gene', '2475', (105, 109))	('copy number', 'Var', (55, 66))	('PI3K', 'molecular_function', 'GO:0016303', ('96', '100'))	('Akt', 'Gene', '207', (101, 104))	('PIK3R1', 'Gene', (137, 143))	('TSC1', 'Gene', (145, 149))	('PIK3CA', 'Gene', (129, 135))	('TSC1', 'Gene', '7248', (145, 149))	('PTEN', 'Gene', (151, 155))	('patients', 'Species', '9606', (191, 199))	('gains/losses', 'NegReg', (67, 79))	('mutations', 'Var', (42, 51))	('PIK3R1', 'Gene', '5295', (137, 143))	('AKT3', 'Gene', '10000', (165, 169))	('PTEN', 'Gene', '5728', (151, 155))
21319	25087173	However, some genetic alterations, such as TSC1 mutation or mTOR activation mutations (E2419K and E2014K), have been identified by whole-genome sequencing in a subset of patients.	('patients', 'Species', '9606', (170, 178))	('TSC1', 'Gene', '7248', (43, 47))	('E2014K', 'Var', (98, 104))	('TSC1', 'Gene', (43, 47))	('mTOR', 'Gene', '2475', (60, 64))	('E2419K', 'Mutation', 'rs587777900', (87, 93))	('E2014K', 'Mutation', 'rs1057519780', (98, 104))	('mTOR', 'Gene', (60, 64))	('E2419K', 'Var', (87, 93))
21320	25087173	These alterations are associated with exceptional responses to everolimus, which validates the clinical value of next-generation molecular techniques in achieving more precise and personalized therapy.	('alterations', 'Var', (6, 17))	('responses', 'MPA', (50, 59))	('everolimus', 'Chemical', 'MESH:D000068338', (63, 73))
21325	25087173	In small studies, positive PET/CT prior to planned cystectomy in patients with no evidence of metastatic disease by conventional staging methods has been associated with poor survival.	('positive PET/CT', 'Var', (18, 33))	('poor', 'NegReg', (170, 174))	('patients', 'Species', '9606', (65, 73))
21343	33243261	We used the Bioconductor R package Maftools to efficiently and comprehensively analyze somatic variants of muscle-invasive bladder cancer (MIBC) from The Cancer Genome Atlas (TCGA).	('MIBC', 'Chemical', '-', (139, 143))	('Cancer', 'Disease', (154, 160))	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('Cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Cancer', 'Phenotype', 'HP:0002664', (154, 160))	('invasive bladder', 'Phenotype', 'HP:0100645', (114, 130))	('variants', 'Var', (95, 103))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (107, 137))	('muscle-invasive bladder cancer', 'Disease', (107, 137))
21344	33243261	We then used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and explored its correlation with clinical parameters as well as mutational subtypes.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('mutant-allele', 'Var', (15, 28))	('tumor', 'Disease', 'MESH:D009369', (29, 34))
21346	33243261	There was a strong correlation between higher MATH value and presence of TP53 mutations (p = 0.008), as well as between lower MATH value and presence of FGFR3 mutations (p = 0.006).	('lower', 'NegReg', (120, 125))	('higher', 'PosReg', (39, 45))	('TP53', 'Gene', '7157', (73, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('153', '157'))	('mutations', 'Var', (159, 168))	('lower MATH', 'Phenotype', 'HP:0001249', (120, 130))	('TP53', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('FGFR3', 'Gene', '2261', (153, 158))	('FGFR3', 'Gene', (153, 158))
21347	33243261	Patients with FGFR3 mutation and low MATH value exhibit longer overall survival time than that of all BLCA patients (p = 0.044), which was replicated in another bladder cancer database composed of 109 BLCA patients.	('overall survival', 'MPA', (63, 79))	('FGFR3', 'Gene', '2261', (14, 19))	('BLCA', 'Phenotype', 'HP:0009725', (102, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (161, 175))	('mutation', 'Var', (20, 28))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (56, 62))	('FGFR3', 'Gene', (14, 19))	('patients', 'Species', '9606', (206, 214))	('bladder cancer', 'Disease', 'MESH:D001749', (161, 175))	('low MATH', 'Phenotype', 'HP:0001249', (33, 41))	('BLCA', 'Phenotype', 'HP:0009725', (201, 205))	('low MATH value', 'Var', (33, 47))	('patients', 'Species', '9606', (107, 115))	('bladder cancer', 'Disease', (161, 175))
21349	33243261	Low MATH value was an independent risk factor that predicted better prognosis for patients with FGFR3 mutation compared to all BLCA patients.	('better', 'PosReg', (61, 67))	('Low MATH', 'Phenotype', 'HP:0001249', (0, 8))	('FGFR3', 'Gene', '2261', (96, 101))	('mutation', 'Var', (102, 110))	('patients', 'Species', '9606', (82, 90))	('BLCA', 'Phenotype', 'HP:0009725', (127, 131))	('FGFR3', 'Gene', (96, 101))	('patients', 'Species', '9606', (132, 140))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))
21362	33243261	FGFR3 and TP53 mutations are the most common mutations in MIBC but are mutually exclusive events.	('MIBC', 'Disease', (58, 62))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', '2261', (0, 5))	('TP53', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('FGFR3', 'Gene', (0, 5))	('MIBC', 'Chemical', '-', (58, 62))	('TP53', 'Gene', '7157', (10, 14))
21363	33243261	Usually, FGFR3 mutations are accompanied by fewer molecular alterations than are found in FGFR3 wild-type tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('mutations', 'Var', (15, 24))	('FGFR3', 'Gene', '2261', (9, 14))	('FGFR3', 'Gene', '2261', (90, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('9', '13'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('FGFR3', 'Gene', (9, 14))	('FGFR3', 'Gene', (90, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))
21365	33243261	Interestingly, FGFR3 mutations have been predominantly found in genetically stable bladder cancers with favorable prognoses.	('found', 'Reg', (55, 60))	('FGFR3', 'Gene', (15, 20))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('bladder cancers', 'Phenotype', 'HP:0009725', (83, 98))	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('bladder cancers', 'Disease', 'MESH:D001749', (83, 98))	('FGFR3', 'Gene', '2261', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('bladder cancers', 'Disease', (83, 98))	('mutations', 'Var', (21, 30))
21369	33243261	In the present study, we downloaded somatic variants of MIBC in Mutation Annotation Format from the Cancer Genome Atlas (TCGA), and used Maftools to efficiently and comprehensively analyze somatic variants in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (209, 223))	('MIBC', 'Chemical', '-', (56, 60))	('MIBC', 'Gene', (56, 60))	('bladder cancer', 'Disease', (209, 223))	('bladder cancer', 'Disease', 'MESH:D001749', (209, 223))	('Cancer', 'Disease', 'MESH:D009369', (100, 106))	('Cancer', 'Disease', (100, 106))	('Cancer', 'Phenotype', 'HP:0002664', (100, 106))	('variants', 'Var', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
21370	33243261	We then used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and explore its correlation with clinical parameters.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('mutant-allele', 'Var', (15, 28))	('tumor', 'Disease', 'MESH:D009369', (29, 34))
21385	33243261	MATH values are calculated from the median absolute deviation (MAD) and the median of its mutant-allele fractions of tumor-specific mutated loci, so the precision of MATH values depends on the sampling of loci and of mutant vs. reference alleles [19].	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutant', 'Var', (217, 223))	('tumor', 'Disease', (117, 122))	('MAD', 'biological_process', 'GO:0072671', ('63', '66'))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
21395	33243261	MATH value was higher in the high-grade group than in the low-grade group (p < 0.05), which suggests that MATH value may be useful in differentiating such patients.	('patients', 'Species', '9606', (155, 163))	('MATH value', 'MPA', (0, 10))	('higher', 'PosReg', (15, 21))	('high-grade', 'Var', (29, 39))
21398	33243261	Although MATH value was not related to the overall mutation rate, we hypothesized that different driver gene mutations may direct different routes of tumor evolution, resulting in variable intratumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('direct', 'Reg', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (194, 199))	('mutations', 'Var', (109, 118))	('tumor', 'Disease', (150, 155))
21399	33243261	We observed mutually exclusive variants in FGFR3 vs. TP53 (q < 0.003) and FGFR3 vs. RB1 (q < 0.02).	('FGFR3', 'Gene', (74, 79))	('variants', 'Var', (31, 39))	('FGFR3', 'Gene', (43, 48))	('RB1', 'Gene', (84, 87))	('FGFR3', 'Gene', '2261', (74, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('TP53', 'Gene', '7157', (53, 57))	('FGFR3', 'Gene', '2261', (43, 48))	('RB1', 'Gene', '5925', (84, 87))	('TP53', 'Gene', (53, 57))
21400	33243261	Similar analyses identified co-occurrence of variants in TP53 vs. RB1, RYR1 vs. AHNAK, BIRC6 vs. ADGRV1, SYNE1 vs. AHNAK, FGFR3 vs. STAG2, KDM6A vs. STAG2, MUC16 vs. BIRC6, and TTN vs. MUC16 (q < 0.005).	('MUC16', 'Gene', '94025', (185, 190))	('SYNE1', 'Gene', '23345', (105, 110))	('TP53', 'Gene', '7157', (57, 61))	('FGFR', 'molecular_function', 'GO:0005007', ('122', '126'))	('BIRC6', 'Gene', '57448', (87, 92))	('AHNAK', 'Gene', '79026', (115, 120))	('ADGRV1', 'Gene', (97, 103))	('BIRC6', 'Gene', '57448', (166, 171))	('STAG2', 'Gene', '10735', (149, 154))	('MUC16', 'Gene', (156, 161))	('RYR1', 'Gene', '6261', (71, 75))	('MUC16', 'Gene', (185, 190))	('AHNAK', 'Gene', (115, 120))	('RB1', 'Gene', (66, 69))	('KDM6A', 'Gene', '7403', (139, 144))	('FGFR3', 'Gene', (122, 127))	('STAG2', 'Gene', (149, 154))	('BIRC6', 'Gene', (166, 171))	('RYR1', 'Gene', (71, 75))	('BIRC6', 'Gene', (87, 92))	('STAG2', 'Gene', '10735', (132, 137))	('TP53', 'Gene', (57, 61))	('FGFR3', 'Gene', '2261', (122, 127))	('TTN', 'Gene', '7273', (177, 180))	('ADGRV1', 'Gene', '84059', (97, 103))	('AHNAK', 'Gene', '79026', (80, 85))	('STAG2', 'Gene', (132, 137))	('variants', 'Var', (45, 53))	('RB1', 'Gene', '5925', (66, 69))	('RYR', 'cellular_component', 'GO:1990425', ('71', '74'))	('KDM6A', 'Gene', (139, 144))	('TTN', 'Gene', (177, 180))	('SYNE1', 'Gene', (105, 110))	('MUC16', 'Gene', '94025', (156, 161))	('AHNAK', 'Gene', (80, 85))
21401	33243261	In the BLCA cohort, TP53 was mutated in > 47% of the samples, and FGFR3 was mutated in > 14% of the samples.	('TP53', 'Gene', (20, 24))	('FGFR3', 'Gene', '2261', (66, 71))	('mutated', 'Var', (76, 83))	('BLCA', 'Phenotype', 'HP:0009725', (7, 11))	('mutated', 'Var', (29, 36))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('FGFR3', 'Gene', (66, 71))	('TP53', 'Gene', '7157', (20, 24))
21402	33243261	FGFR3 and TP53 mutation are potential survival prediction biomarkers of MIBC.	('mutation', 'Var', (15, 23))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', '2261', (0, 5))	('TP53', 'Gene', (10, 14))	('MIBC', 'Disease', (72, 76))	('FGFR3', 'Gene', (0, 5))	('MIBC', 'Chemical', '-', (72, 76))	('TP53', 'Gene', '7157', (10, 14))
21403	33243261	The known role of the p53, as a guardian of the genome stability, supports the general hypothesis that TP53 mutations lead to increased ITH.	('TP53', 'Gene', '7157', (103, 107))	('mutations', 'Var', (108, 117))	('TP53', 'Gene', (103, 107))	('p53', 'Gene', (22, 25))	('p53', 'Gene', '7157', (22, 25))	('ITH', 'Disease', (136, 139))	('increased', 'PosReg', (126, 135))
21404	33243261	Thus, we first aimed to validate the hypothesis that TP53 mutations, rather than FGFR3 mutations, was associated with greater ITH in BLCA.	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('mutations', 'Var', (58, 67))	('BLCA', 'Phenotype', 'HP:0009725', (133, 137))	('FGFR3', 'Gene', (81, 86))	('associated', 'Reg', (102, 112))	('TP53', 'Gene', '7157', (53, 57))	('FGFR3', 'Gene', '2261', (81, 86))	('ITH', 'Disease', (126, 129))	('TP53', 'Gene', (53, 57))
21405	33243261	Based on the presence of somatic mutations in TP53 and FGFR3, we divided the BLCA cohort into three groups: TP53-mutant, FGFR3-mutant, and no TP53 and FGFR3-mutant.	('BLCA', 'Phenotype', 'HP:0009725', (77, 81))	('FGFR', 'molecular_function', 'GO:0005007', ('121', '125'))	('FGFR3', 'Gene', '2261', (151, 156))	('FGFR3', 'Gene', '2261', (121, 126))	('TP53', 'Gene', (108, 112))	('TP53', 'Gene', (142, 146))	('FGFR3', 'Gene', '2261', (55, 60))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', '7157', (142, 146))	('mutations', 'Var', (33, 42))	('TP53', 'Gene', '7157', (46, 50))	('FGFR', 'molecular_function', 'GO:0005007', ('151', '155'))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('FGFR3', 'Gene', (151, 156))	('TP53', 'Gene', (46, 50))	('FGFR3', 'Gene', (121, 126))	('FGFR3', 'Gene', (55, 60))
21406	33243261	Consistent with our hypothesis, TP53 mutations were specifically associated with higher MATH values.	('TP53', 'Gene', '7157', (32, 36))	('higher', 'PosReg', (81, 87))	('associated', 'Reg', (65, 75))	('mutations', 'Var', (37, 46))	('TP53', 'Gene', (32, 36))
21407	33243261	MATH values were higher in the BLCA cases with TP53 mutations than in those with FGFR3-mutant (Fig.	('mutations', 'Var', (52, 61))	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('FGFR3', 'Gene', (81, 86))	('MATH values', 'MPA', (0, 11))	('TP53', 'Gene', (47, 51))	('higher', 'PosReg', (17, 23))	('BLCA', 'Phenotype', 'HP:0009725', (31, 35))	('TP53', 'Gene', '7157', (47, 51))	('FGFR3', 'Gene', '2261', (81, 86))	('BLCA', 'Disease', (31, 35))
21409	33243261	MATH values were lowest in BLCA cases with FGFR3 mutations (Fig.	('mutations', 'Var', (49, 58))	('FGFR3', 'Gene', (43, 48))	('MATH values', 'MPA', (0, 11))	('BLCA', 'Phenotype', 'HP:0009725', (27, 31))	('lowest', 'NegReg', (17, 23))	('BLCA', 'Disease', (27, 31))	('FGFR3', 'Gene', '2261', (43, 48))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))
21415	33243261	5d, p = 0.925), which indicated that the better survival of patients was specifically correlated with patients carrying FGFR3 mutation with lower MATH value.	('lower', 'NegReg', (140, 145))	('FGFR3', 'Gene', (120, 125))	('patients', 'Species', '9606', (60, 68))	('patients', 'Species', '9606', (102, 110))	('lower MATH', 'Phenotype', 'HP:0001249', (140, 150))	('mutation', 'Var', (126, 134))	('better', 'PosReg', (41, 47))	('survival', 'CPA', (48, 56))	('FGFR', 'molecular_function', 'GO:0005007', ('120', '124'))	('MATH', 'MPA', (146, 150))	('FGFR3', 'Gene', '2261', (120, 125))
21419	33243261	Taken together, we found that low MATH value was an independent favorable prognostic biomarker in FGFR3-mutant patients.	('FGFR3', 'Gene', (98, 103))	('MATH value', 'MPA', (34, 44))	('low', 'Var', (30, 33))	('FGFR', 'molecular_function', 'GO:0005007', ('98', '102'))	('low MATH', 'Phenotype', 'HP:0001249', (30, 38))	('FGFR3', 'Gene', '2261', (98, 103))	('patients', 'Species', '9606', (111, 119))
21421	33243261	First, to verify that FGFR3 mutations, rather than TP53 mutations, were associated with lower ITH in BLCA, we divided the 109 samples into three groups: TP53-mutant, FGFR3-mutant, and no TP53 and FGFR3-mutant.	('ITH in BLCA', 'MPA', (94, 105))	('FGFR3', 'Gene', '2261', (166, 171))	('TP53', 'Gene', '7157', (153, 157))	('TP53', 'Gene', (187, 191))	('FGFR3', 'Gene', (22, 27))	('TP53', 'Gene', (51, 55))	('FGFR3', 'Gene', (196, 201))	('FGFR', 'molecular_function', 'GO:0005007', ('196', '200'))	('FGFR3', 'Gene', '2261', (22, 27))	('lower', 'NegReg', (88, 93))	('FGFR3', 'Gene', '2261', (196, 201))	('TP53', 'Gene', '7157', (187, 191))	('TP53', 'Gene', (153, 157))	('mutations', 'Var', (28, 37))	('TP53', 'Gene', '7157', (51, 55))	('FGFR', 'molecular_function', 'GO:0005007', ('166', '170'))	('FGFR3', 'Gene', (166, 171))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('BLCA', 'Phenotype', 'HP:0009725', (101, 105))
21422	33243261	Although there was no significant difference between them (p > 0.05), probably due to the small sample size in this cohort, the overall trend of the median MATH values showed that MATH values were greater in BLCA patients with TP53 mutations than in those with FGFR3 mutations (Fig.	('TP53', 'Gene', '7157', (227, 231))	('FGFR', 'molecular_function', 'GO:0005007', ('261', '265'))	('BLCA', 'Disease', (208, 212))	('FGFR3', 'Gene', '2261', (261, 266))	('TP53', 'Gene', (227, 231))	('mutations', 'Var', (232, 241))	('greater', 'PosReg', (197, 204))	('MATH', 'MPA', (180, 184))	('FGFR3', 'Gene', (261, 266))	('patients', 'Species', '9606', (213, 221))	('BLCA', 'Phenotype', 'HP:0009725', (208, 212))
21423	33243261	6a, p = 0.074) and MATH values were lowest in BLCA cases with FGFR3 mutations (Fig.	('lowest', 'NegReg', (36, 42))	('FGFR3', 'Gene', '2261', (62, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('FGFR3', 'Gene', (62, 67))	('mutations', 'Var', (68, 77))	('BLCA', 'Phenotype', 'HP:0009725', (46, 50))	('MATH', 'MPA', (19, 23))	('BLCA', 'Disease', (46, 50))
21429	33243261	Taken together, we verified that low MATH value was an independent favorable prognostic biomarker in FGFR3-mutant patients in another bladder cancer cohort.	('bladder cancer', 'Disease', 'MESH:D001749', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('low', 'Var', (33, 36))	('FGFR3', 'Gene', '2261', (101, 106))	('low MATH', 'Phenotype', 'HP:0001249', (33, 41))	('bladder cancer', 'Disease', (134, 148))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))	('patients', 'Species', '9606', (114, 122))	('FGFR3', 'Gene', (101, 106))	('MATH value', 'MPA', (37, 47))	('bladder cancer', 'Phenotype', 'HP:0009725', (134, 148))
21434	33243261	ITH is the result of temporal acquisition of mutations and corresponding tumor evolution.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('mutations', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (73, 78))
21436	33243261	High genetic heterogeneity is thought to contribute to risk of poor survival in patients with bladder cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('patients', 'Species', '9606', (80, 88))	('bladder cancers', 'Disease', (94, 109))	('bladder cancers', 'Phenotype', 'HP:0009725', (94, 109))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('bladder cancers', 'Disease', 'MESH:D001749', (94, 109))	('High genetic heterogeneity', 'Var', (0, 26))
21442	33243261	Different driver gene mutations may direct different routes of tumor evolution which may affect the prognosis of bladder cancer patients.	('tumor', 'Disease', (63, 68))	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('direct', 'Reg', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (113, 127))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mutations', 'Var', (22, 31))	('bladder cancer', 'Disease', (113, 127))	('affect', 'Reg', (89, 95))	('patients', 'Species', '9606', (128, 136))
21445	33243261	Therefore, we combined FGFR3 and TP53 mutations and MATH value to analyze the prognosis of bladder cancer patients.	('FGFR3', 'Gene', (23, 28))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('TP53', 'Gene', '7157', (33, 37))	('bladder cancer', 'Disease', (91, 105))	('patients', 'Species', '9606', (106, 114))	('FGFR3', 'Gene', '2261', (23, 28))	('TP53', 'Gene', (33, 37))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('mutations', 'Var', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
21446	33243261	FGFR3 mutation is usually accompanied by fewer molecular alterations than wild-type FGFR3.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('FGFR3', 'Gene', (84, 89))	('FGFR3', 'Gene', '2261', (84, 89))	('FGFR', 'molecular_function', 'GO:0005007', ('84', '88'))	('FGFR3', 'Gene', '2261', (0, 5))
21447	33243261	The p53 protein functions as a guardian of the genome stability, which supports the hypothesis that mutations in TP53 result in increased ITH.	('mutations', 'Var', (100, 109))	('p53', 'Gene', '7157', (4, 7))	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('increased', 'PosReg', (128, 137))	('TP53', 'Gene', '7157', (113, 117))	('ITH', 'CPA', (138, 141))	('TP53', 'Gene', (113, 117))	('p53', 'Gene', (4, 7))
21448	33243261	We examined the relationship between heterogeneity (using MATH value) with FGFR3 and/or TP53 mutations and found that FGFR3 mutations were associated with lower ITH.	('FGFR3', 'Gene', (118, 123))	('FGFR3', 'Gene', (75, 80))	('mutations', 'Var', (124, 133))	('mutations', 'Var', (93, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('FGFR', 'molecular_function', 'GO:0005007', ('118', '122'))	('TP53', 'Gene', '7157', (88, 92))	('lower', 'NegReg', (155, 160))	('FGFR3', 'Gene', '2261', (118, 123))	('FGFR3', 'Gene', '2261', (75, 80))	('TP53', 'Gene', (88, 92))
21449	33243261	The administration of neoadjuvant chemotherapy preceding radical cystectomy improves overall survival of patients with MIBC, and FGFR3 mutations in MIBCs are potential predictive biomarkers of the response to neoadjuvant.	('FGFR3', 'Gene', (129, 134))	('patients', 'Species', '9606', (105, 113))	('MIBC', 'Chemical', '-', (119, 123))	('mutations', 'Var', (135, 144))	('MIBCs', 'Gene', (148, 153))	('FGFR', 'molecular_function', 'GO:0005007', ('129', '133'))	('FGFR3', 'Gene', '2261', (129, 134))	('MIBC', 'Disease', (119, 123))	('MIBC', 'Chemical', '-', (148, 152))	('overall survival', 'MPA', (85, 101))	('improves', 'PosReg', (76, 84))	('MIBCs', 'Chemical', '-', (148, 153))
21452	33243261	We also assessed the prognostic value of MATH with TP53 or FGFR3 mutations and found that a low MATH value was an independent risk factor that predicted better survival in the FGFR3-mutant patients.	('survival', 'CPA', (160, 168))	('FGFR3', 'Gene', '2261', (59, 64))	('TP53', 'Gene', (51, 55))	('FGFR3', 'Gene', '2261', (176, 181))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('FGFR', 'molecular_function', 'GO:0005007', ('176', '180'))	('FGFR3', 'Gene', (59, 64))	('low MATH', 'Phenotype', 'HP:0001249', (92, 100))	('better', 'PosReg', (153, 159))	('FGFR3', 'Gene', (176, 181))	('patients', 'Species', '9606', (189, 197))	('TP53', 'Gene', '7157', (51, 55))	('mutations', 'Var', (65, 74))
21462	33243261	Here, we show that patients with FGFR3 mutations and low MATH value tend to exhibit favorable prognosis.	('MATH value', 'MPA', (57, 67))	('low', 'NegReg', (53, 56))	('patients', 'Species', '9606', (19, 27))	('mutations', 'Var', (39, 48))	('FGFR3', 'Gene', '2261', (33, 38))	('low MATH', 'Phenotype', 'HP:0001249', (53, 61))	('FGFR3', 'Gene', (33, 38))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))
21466	33243261	BLCA Bladder cancer ITH Intratumor heterogeneity MAF Mutant-allele fraction MATH Mutant-allele tumor heterogeneity MIBC Muscle-invasive bladder cancer NMIBC Non-muscle-invasive bladder cancer TCGA The Cancer Genome Atlas ZJ, HY, and YT conceived the research, acquired the data, and drafted the manuscript.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('Non-muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (157, 191))	('Mutant-allele', 'Var', (53, 66))	('Non-muscle-invasive bladder cancer', 'Disease', (157, 191))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Bladder cancer', 'Phenotype', 'HP:0009725', (5, 19))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (177, 191))	('Cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Cancer', 'Disease', (201, 207))	('invasive bladder', 'Phenotype', 'HP:0100645', (127, 143))	('Muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (120, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('BLCA', 'Phenotype', 'HP:0009725', (0, 4))	('Muscle-invasive bladder cancer', 'Disease', (120, 150))	('cancer', 'Disease', (13, 19))	('invasive bladder', 'Phenotype', 'HP:0100645', (168, 184))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('Cancer', 'Disease', 'MESH:D009369', (201, 207))	('tumor', 'Disease', (95, 100))	('MIBC', 'Chemical', '-', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (29, 34))	('MIBC', 'Chemical', '-', (152, 156))
21532	30949449	Consequently, our females have a higher risk of exposure to a potent carcinogen, aristolochic acid, which is present in certain herbal medicines and has been well-known to cause UTUC.	('UTUC', 'Disease', (178, 182))	('aristolochic acid', 'Chemical', 'MESH:C000228', (81, 98))	('herbal medicine', 'Species', '1407750', (128, 143))	('cause', 'Reg', (172, 177))	('exposure', 'MPA', (48, 56))	('aristolochic acid', 'Var', (81, 98))
21574	30717708	Immunohistochemistry (IHC)-based quantification of expressed CD133 protein levels has been proposed as a GC prognostic marker and CD133 positivity indicates poor prognosis as well as chemoresistance and disease progression of GC.	('positivity', 'Var', (136, 146))	('GC', 'Phenotype', 'HP:0012126', (226, 228))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('chemoresistance', 'CPA', (183, 198))	('CD133', 'Gene', (61, 66))	('CD133', 'Gene', (130, 135))	('CD133', 'Gene', '8842', (130, 135))	('CD133', 'Gene', '8842', (61, 66))	('poor prognosis', 'CPA', (157, 171))	('GC', 'Phenotype', 'HP:0012126', (105, 107))
21578	30717708	In this study, we performed microarray-based transcriptome analyses of CD133+ vs. CD133- cells obtained by cell sorting from three GC cell lines (KATO-III, SNU216 and SNU601).	('GC', 'Phenotype', 'HP:0012126', (131, 133))	('CD133', 'Gene', '8842', (82, 87))	('CD133', 'Gene', (82, 87))	('SNU601', 'Var', (167, 173))	('CD133', 'Gene', '8842', (71, 76))	('CD133', 'Gene', (71, 76))	('SNU216', 'Var', (156, 162))	('SNU216', 'CellLine', 'CVCL:3946', (156, 162))
21603	30717708	To evaluate the gene expression associated with the CD133 stem cell marker in GCs, we performed gene expression profiling of three gastric cancer cell lines (KATO-III, SNU216, and SNU601).	('gastric cancer', 'Disease', 'MESH:D013274', (131, 145))	('CD133', 'Gene', (52, 57))	('CD133', 'Gene', '8842', (52, 57))	('SNU601', 'Var', (180, 186))	('SNU216', 'CellLine', 'CVCL:3946', (168, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('gene expression', 'biological_process', 'GO:0010467', ('96', '111'))	('gene expression', 'biological_process', 'GO:0010467', ('16', '31'))	('GCs', 'Phenotype', 'HP:0012126', (78, 81))	('GC', 'Phenotype', 'HP:0012126', (78, 80))	('gastric cancer', 'Disease', (131, 145))
21641	30717708	Among the major mutations of GC, mutations of TP53, PIK3CA, KRAS, ARID1A, and RHOA were evaluated, whereas only ARID1A mutations were significantly associated with CD133 expression signature (P = 0.0007; Fig.	('ARID1A', 'Gene', (112, 118))	('CD133', 'Gene', '8842', (164, 169))	('RHOA', 'Gene', '387', (78, 82))	('TP53', 'Gene', '7157', (46, 50))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (52, 58))	('ARID1A', 'Gene', '8289', (66, 72))	('ARID1A', 'Gene', (66, 72))	('KRAS', 'Gene', (60, 64))	('GC', 'Phenotype', 'HP:0012126', (29, 31))	('RHOA', 'Gene', (78, 82))	('associated', 'Reg', (148, 158))	('TP53', 'Gene', (46, 50))	('KRAS', 'Gene', '3845', (60, 64))	('PIK3CA', 'Gene', '5290', (52, 58))	('ARID1A', 'Gene', '8289', (112, 118))	('CD133', 'Gene', (164, 169))
21693	30717708	In general, IHC-based CD133 positivity in GC has been regarded as a feature associated with high-stage and high-grade tumors with poor prognosis.	('GC', 'Phenotype', 'HP:0012126', (42, 44))	('positivity', 'Var', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('associated', 'Reg', (76, 86))	('CD133', 'Gene', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('CD133', 'Gene', '8842', (22, 27))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
21707	29617660	SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation.	('methylation', 'Var', (115, 126))	('SCC', 'Gene', (0, 3))	('inflammation', 'Disease', (348, 360))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('squamous cell stemness', 'Disease', (225, 247))	('mutations', 'Var', (88, 97))	('SCC', 'Gene', '6317', (0, 3))	('aberrant methylation', 'Var', (106, 126))	('methylation', 'biological_process', 'GO:0032259', ('115', '126'))	('squamous cell stemness', 'Disease', 'MESH:D002294', (225, 247))	('inflammation', 'biological_process', 'GO:0006954', ('348', '360'))	('DNA', 'Gene', (84, 87))	('inflammation', 'Disease', 'MESH:D007249', (348, 360))
21708	29617660	Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules.	('RAS-MAPK pathways', 'Pathway', (190, 207))	('repression', 'NegReg', (67, 77))	('MAPK', 'molecular_function', 'GO:0004707', ('194', '198'))	('mutations', 'Var', (163, 172))	('TET1', 'Gene', '80312', (81, 85))	('FANCF', 'Gene', (102, 107))	('chromatin', 'cellular_component', 'GO:0000785', ('209', '218'))	('SCC', 'Gene', (8, 11))	('SCC', 'Gene', (148, 151))	('HPV', 'Species', '10566', (26, 29))	('hypermethylation', 'MPA', (45, 61))	('CASP8', 'Gene', '841', (183, 188))	('FANCF', 'Gene', '2188', (102, 107))	('TET1', 'Gene', (81, 85))	('SCC', 'Gene', '6317', (8, 11))	('CASP8', 'Gene', (183, 188))	('affecting', 'Reg', (173, 182))	('SCC', 'Gene', '6317', (148, 151))
21709	29617660	We uncovered hypomethylation of the alternative promoter that drives expression of the DeltaNp63 oncogene and embedded miR944.	('hypomethylation', 'Var', (13, 28))	('DeltaNp63', 'Chemical', '-', (87, 96))	('DeltaNp63', 'Gene', (87, 96))	('drives', 'PosReg', (62, 68))	('expression', 'MPA', (69, 79))	('miR944', 'Gene', (119, 125))	('miR944', 'Gene', '100126340', (119, 125))
21710	29617660	reveal that squamous cell cancers from different tissue sites may be distinguished from other cancers and subclassified molecularly by recurrent alterations in chromosomes, DNA methylation, messenger and microRNA expression, or by mutations.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('alterations', 'Reg', (145, 156))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('mutations', 'Var', (231, 240))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('squamous cell cancers', 'Disease', (12, 33))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (12, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('DNA methylation', 'biological_process', 'GO:0006306', ('173', '188'))	('DNA', 'cellular_component', 'GO:0005574', ('173', '176'))	('chromosomes', 'MPA', (160, 171))	('squamous cell cancers', 'Disease', 'MESH:D002294', (12, 33))	('cancers', 'Disease', (94, 101))	('DNA', 'MPA', (173, 176))
21720	29617660	Further, these tools uncovered broader and subtype-related genetic and epigenetic alterations that distinguish SCCs from other cancers and from one another.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('epigenetic alterations', 'Var', (71, 93))	('SCC', 'Gene', (111, 114))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('SCC', 'Gene', '6317', (111, 114))
21722	29617660	These identified recurrent chromosomal alterations and CpG methylation strongly correlated with the expression of multiple genes that converge on pathways and functions relevant to SCC biology and therapeutics.	('correlated', 'Reg', (80, 90))	('chromosomal alterations', 'Var', (27, 50))	('SCC', 'Gene', (181, 184))	('SCC', 'Gene', '6317', (181, 184))	('expression', 'MPA', (100, 110))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('methylation', 'Var', (59, 70))
21727	29617660	To identify a molecular signature-based classification, we conducted an integrated TM and iC analysis of 9,759 tumor samples from PanCancer-33 cancers for which DNA copy-number alteration (CNA), methylation, mRNA, microRNA (miRNA), and a smaller set of protein expression profiles were available.	('copy-number alteration', 'Var', (165, 187))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('methylation', 'MPA', (195, 206))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('protein', 'cellular_component', 'GO:0003675', ('253', '260'))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('microRNA', 'MPA', (214, 222))	('mRNA', 'MPA', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('cancers', 'Disease', (143, 150))	('methylation', 'biological_process', 'GO:0032259', ('195', '206'))
21731	29617660	All three major SCC-related clusters included significant chromosome 3q and 5p copy gains (Figures 1E and 1F; Table S1A).	('chromosome', 'Var', (58, 68))	('SCC', 'Gene', '6317', (16, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))	('SCC', 'Gene', (16, 19))
21732	29617660	Many iC10/25 HPV(-) SCC tumors were associated with higher DNA CNA and broad hypomethylation, with corresponding patterns of increased mRNA and miRNA expression (Figures 1F-1I).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('increased', 'PosReg', (125, 134))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('iC10/25 HPV(-', 'Var', (5, 18))	('miRNA expression', 'MPA', (144, 160))	('higher', 'PosReg', (52, 58))	('SCC tumors', 'Disease', 'MESH:D009369', (20, 30))	('DNA CNA', 'MPA', (59, 66))	('SCC tumors', 'Disease', (20, 30))	('HPV', 'Species', '10566', (13, 16))	('broad hypomethylation', 'MPA', (71, 92))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
21734	29617660	These observations suggest that most SCCs are driven by a combination of recurrent CN and other alterations, while HPV, epigenetic, or other alterations may have a greater role in subtypes with fewer CNAs.	('SCC', 'Gene', '6317', (37, 40))	('alterations', 'Var', (96, 107))	('driven by', 'Reg', (46, 55))	('HPV', 'Species', '10566', (115, 118))	('SCC', 'Gene', (37, 40))
21745	29617660	Unexpectedly, the CN/expression correlation for TP63 was lower than for other nearby genes, and it was associated with predominant expression of the DeltaNp63alpha isoform for all 5 sites (Figure 2H), consistent with epigenetic regulation of these alternatively transcribed isoforms discovered below.	('DeltaNp63alpha', 'Var', (149, 163))	('CN/expression correlation', 'MPA', (18, 43))	('DeltaNp63', 'Chemical', '-', (149, 158))	('regulation', 'biological_process', 'GO:0065007', ('228', '238'))	('TP63', 'Gene', (48, 52))	('TP63', 'Gene', '8626', (48, 52))	('lower', 'NegReg', (57, 62))
21748	29617660	These observations suggest that 3q26 or 11q22 CNAs could be alternative drivers orchestrating deregulation of ACTLA6/TP63 differentiation and Hippo growth pathway YAP1 gene expression in SCC subtypes.	('TP63', 'Gene', (117, 121))	('deregulation', 'MPA', (94, 106))	('SCC', 'Gene', (187, 190))	('3q26', 'Var', (32, 36))	('SCC', 'Gene', '6317', (187, 190))	('YAP1', 'Gene', (163, 167))	('YAP1', 'Gene', '10413', (163, 167))	('TP63', 'Gene', '8626', (117, 121))	('gene expression', 'biological_process', 'GO:0010467', ('168', '183'))
21753	29617660	Together, alteration of 5p genes with these functions is consistent with the generation of increased CNAs found in most SCCs.	('5p genes', 'Gene', (24, 32))	('SCC', 'Gene', '6317', (120, 123))	('increased', 'PosReg', (91, 100))	('alteration', 'Var', (10, 20))	('CNAs', 'Gene', (101, 105))	('SCC', 'Gene', (120, 123))
21761	29617660	Copy loss of TNFR-associated factor TRAF3 has recently been implicated as a tumor suppressor of NF-kappaB gene expression and HPV infection, and it is a marker for HPV(+) HNSC tumors with better prognosis.	('gene expression', 'biological_process', 'GO:0010467', ('106', '121'))	('TRAF3', 'Gene', (36, 41))	('tumor', 'Disease', (76, 81))	('NF-kappaB', 'Gene', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (176, 181))	('TNFR', 'Gene', '7132', (13, 17))	('NF-kappaB', 'Gene', '4790', (96, 105))	('HPV infection', 'Disease', 'MESH:D030361', (126, 139))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('Copy loss', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('TNFR', 'Gene', (13, 17))	('HPV infection', 'Disease', (126, 139))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('HNSC tumors', 'Disease', 'MESH:D009369', (171, 182))	('TRAF3', 'Gene', '7187', (36, 41))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('76', '92'))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('HNSC tumors', 'Disease', (171, 182))	('tumor suppressor', 'biological_process', 'GO:0051726', ('76', '92'))	('HPV', 'Species', '10566', (164, 167))	('HPV', 'Species', '10566', (126, 129))
21765	29617660	Together, the significance of these CN alterations, distinguishing major subsets of SCC by iC (Figure 1B; Table S1A), and strongly correlated expression by MVisAGe (Figure 2), support their roles as important drivers of SCC.	('SCC', 'Gene', '6317', (84, 87))	('SCC', 'Gene', (220, 223))	('SCC', 'Gene', '6317', (220, 223))	('alterations', 'Var', (39, 50))	('SCC', 'Gene', (84, 87))
21766	29617660	Integration of unsupervised hierarchical clustering of significant CNAs, available for 1,386 samples of squamous histology, HPV status, and significant mutations, helped resolve different candidate drivers of high- and low-copy-number variation (CNV) subtypes (Figures 3A, 3B, and S2A-S2C).	('low-copy-number', 'NegReg', (219, 234))	('high-', 'Var', (209, 214))	('HPV', 'Species', '10566', (124, 127))
21768	29617660	C1-4 with higher CNAs displayed 5p amplification and the highest frequency of deleterious mutations of TP53, consistent with their function in maintaining genomic integrity.	('TP53', 'Gene', '7157', (103, 107))	('TP53', 'Gene', (103, 107))	('mutations', 'Var', (90, 99))	('5p amplification', 'MPA', (32, 48))
21769	29617660	Mutations in NFE2L2 and KEAP1, important in oxidative damage, were also enriched in C1-3.	('KEAP1', 'Gene', '9817', (24, 29))	('NFE2L2', 'Gene', '4780', (13, 19))	('KEAP1', 'Gene', (24, 29))	('NFE2L2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))
21770	29617660	Low-CNA C5A and B tumors were enriched for mutations in (1) epigenetic modifiers EP300, MLL4, and CTCF; (2) mitogen pathway components EPHA2, HRAS, MAPK1, and RAC1; and (3) cell death mediator caspase CASP8 (Figures 1A, 1B, and S2B).	('CASP8', 'Gene', '841', (201, 206))	('tumors', 'Disease', (18, 24))	('caspase', 'Gene', (193, 200))	('CTCF', 'Gene', (98, 102))	('CASP8', 'Gene', (201, 206))	('C5A', 'Gene', (8, 11))	('EPHA2', 'Gene', '1969', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('EP300', 'Gene', '2033', (81, 86))	('MAPK1', 'Gene', '5594', (148, 153))	('RAC1', 'Gene', (159, 163))	('caspase', 'Gene', '841', (193, 200))	('cell death', 'biological_process', 'GO:0008219', ('173', '183'))	('MLL4', 'Gene', '8085', (88, 92))	('C5A', 'Gene', '728', (8, 11))	('MLL4', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('EP300', 'Gene', (81, 86))	('HRAS', 'Gene', '3265', (142, 146))	('RAC1', 'Gene', '5879', (159, 163))	('MAPK', 'molecular_function', 'GO:0004707', ('148', '152'))	('CTCF', 'Gene', '10664', (98, 102))	('HRAS', 'Gene', (142, 146))	('mutations', 'Var', (43, 52))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('EPHA2', 'Gene', (135, 140))	('MAPK1', 'Gene', (148, 153))
21772	29617660	Mutations in EPHA2, HRAS, MAPK1, and RAC1 cumulatively affected ~27% and 46% of C5 and C5A tumors, with EPHA2 and HRAS mutations tending toward mutual exclusivity across all C5 samples (Figure S2B; p = 0.037).	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('RAC1', 'Gene', '5879', (37, 41))	('affected', 'Reg', (55, 63))	('MAPK1', 'Gene', '5594', (26, 31))	('HRAS', 'Gene', '3265', (20, 24))	('HRAS', 'Gene', (20, 24))	('EPHA2', 'Gene', '1969', (104, 109))	('EPHA2', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('C5A', 'Gene', (87, 90))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('MAPK1', 'Gene', (26, 31))	('HRAS', 'Gene', '3265', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('HRAS', 'Gene', (114, 118))	('MAPK', 'molecular_function', 'GO:0004707', ('26', '30'))	('EPHA2', 'Gene', '1969', (13, 18))	('tumors', 'Disease', (91, 97))	('RAC1', 'Gene', (37, 41))	('EPHA2', 'Gene', (104, 109))	('C5A', 'Gene', '728', (87, 90))
21773	29617660	EPHA2 mutations were enriched for truncating alterations, consistent with evidence that it serves as a negative regulator of RAS pathway signaling.	('EPHA2', 'Gene', '1969', (0, 5))	('EPHA2', 'Gene', (0, 5))	('signaling', 'biological_process', 'GO:0023052', ('137', '146'))	('truncating alterations', 'MPA', (34, 56))	('mutations', 'Var', (6, 15))
21774	29617660	Conversely, HRAS, MAPK1, and RAC1 showed missense hotspot mutations (Figure S2C), implicated in signal activation.	('MAPK1', 'Gene', '5594', (18, 23))	('RAC1', 'Gene', '5879', (29, 33))	('missense', 'Var', (41, 49))	('MAPK1', 'Gene', (18, 23))	('RAC1', 'Gene', (29, 33))	('HRAS', 'Gene', '3265', (12, 16))	('HRAS', 'Gene', (12, 16))	('MAPK', 'molecular_function', 'GO:0004707', ('18', '22'))
21776	29617660	C5A SCC displayed mutations of HLA-A and -B and deletions of B2M, implicated in immune escape (Figure 3B).	('SCC', 'Gene', (4, 7))	('B2M', 'Gene', (61, 64))	('B2M', 'Gene', '567', (61, 64))	('SCC', 'Gene', '6317', (4, 7))	('HLA-A and -B', 'Gene', '3105;3106', (31, 43))	('deletions', 'Var', (48, 57))	('C5A', 'Gene', '728', (0, 3))	('C5A', 'Gene', (0, 3))	('mutations', 'Var', (18, 27))
21779	29617660	CN and mutations inactivating FAT1 trended toward mutual exclusivity with amplification of YAP1 (p = 0.08), consistent with a role of FAT1 as a negative regulator of Hippo growth pathway.	('mutations inactivating', 'Var', (7, 29))	('mutual', 'MPA', (50, 56))	('FAT1', 'Gene', '2195', (30, 34))	('FAT1', 'Gene', '2195', (134, 138))	('YAP1', 'Gene', '10413', (91, 95))	('FAT1', 'Gene', (30, 34))	('FAT1', 'Gene', (134, 138))	('YAP1', 'Gene', (91, 95))
21780	29617660	Interestingly, these were exclusive of amplifications of 3q gene PIK3CA (p = 0.005) or mutations of PTEN (p = 0.002), which could potentially enhance AKT signaling implicated in YAP1 inactivation via cytoplasmic sequestration.	('PTEN', 'Gene', (100, 104))	('PTEN', 'Gene', '5728', (100, 104))	('YAP1', 'Gene', (178, 182))	('YAP1', 'Gene', '10413', (178, 182))	('AKT', 'Gene', '207', (150, 153))	('PIK3CA', 'Gene', (65, 71))	('enhance', 'PosReg', (142, 149))	('AKT', 'Gene', (150, 153))	('PIK3CA', 'Gene', '5290', (65, 71))	('mutations', 'Var', (87, 96))	('AKT signaling', 'biological_process', 'GO:0043491', ('150', '163'))
21781	29617660	Inactivating deletions or mutations of TP63 and ZNF750 support possible alternative mechanisms for deregulation of the TP63-ZNF750 differentiation pathways (Figures 2D, 2E, S2D, and S2E).	('Inactivating deletions', 'Var', (0, 22))	('ZNF750', 'Gene', '79755', (124, 130))	('TP63', 'Gene', '8626', (119, 123))	('TP63', 'Gene', (39, 43))	('deregulation', 'MPA', (99, 111))	('ZNF750', 'Gene', (48, 54))	('TP63', 'Gene', '8626', (39, 43))	('mutations', 'Var', (26, 35))	('TP63', 'Gene', (119, 123))	('ZNF750', 'Gene', (124, 130))	('ZNF750', 'Gene', '79755', (48, 54))
21784	29617660	Notably, hypermethylated C2 enriched for HPV(+) CESC and HNSC (p < 2.2E-16) predominantly overlapped the low-CNA cluster C5A (Figures 4A, 4B, and S3A; Fisher's exact test for CNV-MethylMix Clusters, p = 1E-5).	('HPV', 'Species', '10566', (41, 44))	('hypermethylated', 'Var', (9, 24))	('S3A', 'Gene', (146, 149))	('S3A', 'Gene', '6189', (146, 149))	('C5A', 'Gene', '728', (121, 124))	('C5A', 'Gene', (121, 124))
21786	29617660	Among 28/51 genes significantly mutated and differentially distributed among the methylation clusters in SCC (Table S2L), hypermethylated HPV-enriched C2 also harbored fewer mutations in HRAS, CDKN2A(p16), CASP8, NFE2L2, NSD1, and TP53 than did clusters with predominantly HPV(-) SCC (Figures 4A and S3B).	('methylation', 'biological_process', 'GO:0032259', ('81', '92'))	('HRAS', 'Gene', '3265', (187, 191))	('NFE2L2', 'Gene', (213, 219))	('TP53', 'Gene', '7157', (231, 235))	('HRAS', 'Gene', (187, 191))	('SCC', 'Gene', '6317', (280, 283))	('SCC', 'Gene', '6317', (105, 108))	('NSD1', 'Gene', '64324', (221, 225))	('CDKN2A', 'Gene', (193, 199))	('HPV', 'Species', '10566', (138, 141))	('CASP8', 'Gene', '841', (206, 211))	('SCC', 'Gene', (280, 283))	('SCC', 'Gene', (105, 108))	('HPV', 'Species', '10566', (273, 276))	('mutations', 'Var', (174, 183))	('p16', 'Gene', (200, 203))	('p16', 'Gene', '1029', (200, 203))	('CDKN2A', 'Gene', '1029', (193, 199))	('CASP8', 'Gene', (206, 211))	('TP53', 'Gene', (231, 235))	('fewer', 'NegReg', (168, 173))	('NFE2L2', 'Gene', '4780', (213, 219))	('NSD1', 'Gene', (221, 225))
21787	29617660	Strikingly, hypomethylation in C5 was linked to inactivating mutations in the H3K36 histone methyltransferase NSD1, defining a distinct subtype across SCC tissue sites previously observed in HNSC.	('NSD1', 'Gene', '64324', (110, 114))	('linked', 'Reg', (38, 44))	('inactivating mutations', 'Var', (48, 70))	('SCC', 'Gene', '6317', (151, 154))	('NSD1', 'Gene', (110, 114))	('hypomethylation', 'MPA', (12, 27))	('H3K36', 'Gene', (78, 83))	('SCC', 'Gene', (151, 154))
21790	29617660	TET1 is a demethylase whose inactivation is implicated in sustaining CpG hypermethylation in cancer, consistent with hypermethylation found in C2 and C4.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('hypermethylation', 'Var', (73, 89))	('TET1', 'Gene', '80312', (0, 4))	('inactivation', 'Var', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('CpG', 'Protein', (69, 72))	('TET1', 'Gene', (0, 4))
21792	29617660	A broader analysis of FANC and DNA damage repair pathway genes revealed an unexpectedly high frequency (~12%) of somatic methylation, CNAs, and mutations affecting FANC-BRCA genes in SCC (Figure 4E), suggesting that acquired as well as germline alterations in this pathway may contribute to the development of a subset of SCC.	('methylation', 'biological_process', 'GO:0032259', ('121', '132'))	('FANC', 'Gene', (164, 168))	('SCC', 'Gene', '6317', (322, 325))	('contribute', 'Reg', (277, 287))	('SCC', 'Gene', (183, 186))	('FANC-BRCA', 'Gene', '672', (164, 173))	('FANC-BRCA', 'Gene', (164, 173))	('FANC', 'Gene', '2188;5888;672', (22, 26))	('SCC', 'Gene', '6317', (183, 186))	('mutations', 'Var', (144, 153))	('SCC', 'Gene', (322, 325))	('FANC', 'Gene', (22, 26))	('FANC', 'Gene', '2188;5888;672', (164, 168))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))
21793	29617660	Of these, FANCF methylation is more often observed in Pan-SCC than other PanCan-33 tumors (Figures 4F and S3C; chi-square, p < 2.2E-16).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('SCC', 'Gene', (58, 61))	('methylation', 'biological_process', 'GO:0032259', ('16', '27'))	('tumors', 'Disease', (83, 89))	('SCC', 'Gene', '6317', (58, 61))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('methylation', 'Var', (16, 27))	('FANCF', 'Gene', (10, 15))	('observed', 'Reg', (42, 50))	('FANCF', 'Gene', '2188', (10, 15))
21815	29617660	C1 was enriched for amplification of MAPK1 (p = 0.001) and deletion of NF-kappaB negative regulator TRAF3 (p = 3E-05), relative to other clusters.	('MAPK', 'molecular_function', 'GO:0004707', ('37', '41'))	('TRAF3', 'Gene', '7187', (100, 105))	('NF-kappaB', 'Gene', (71, 80))	('MAPK1', 'Gene', '5594', (37, 42))	('deletion', 'Var', (59, 67))	('MAPK1', 'Gene', (37, 42))	('NF-kappaB', 'Gene', '4790', (71, 80))	('TRAF3', 'Gene', (100, 105))
21816	29617660	In contrast, C2, with predominantly LUSC and ESCA, showed higher inferred activation of proliferation-related cell cycle components, with enrichment for CDK6 amplification (p = 1.3E-08), CDKN2A deletion (3.6E-07), a decreased immune signature, and a lower proportion of cases with amplification of immune checkpoint PDL1 (p = 0.0003).	('CDK6', 'Gene', (153, 157))	('deletion', 'Var', (194, 202))	('decreased', 'NegReg', (216, 225))	('CDKN2A', 'Gene', (187, 193))	('CDKN2A', 'Gene', '1029', (187, 193))	('CDK6', 'Gene', '1021', (153, 157))	('immune signature', 'MPA', (226, 242))	('PDL1', 'Gene', '29126', (316, 320))	('activation', 'PosReg', (74, 84))	('proliferation-related cell cycle components', 'CPA', (88, 131))	('PDL1', 'Gene', (316, 320))	('cell cycle', 'biological_process', 'GO:0007049', ('110', '120'))	('CDK', 'molecular_function', 'GO:0004693', ('153', '156'))
21817	29617660	C3 with HNSC showed MAPK-JUN-FOS, TP53/63/73, and proliferation signatures and lower immune signatures, associated with amplifications of EGFR, IGF1R, and PDGFA (p <= 0.005).	('PDGFA', 'Gene', '5154', (155, 160))	('FOS', 'Gene', '2353', (29, 32))	('amplifications', 'Var', (120, 134))	('TP53', 'Gene', (34, 38))	('EGFR', 'Gene', '1956', (138, 142))	('MAPK', 'molecular_function', 'GO:0004707', ('20', '24'))	('lower', 'NegReg', (79, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('138', '142'))	('EGFR', 'Gene', (138, 142))	('proliferation signatures', 'CPA', (50, 74))	('IGF1R', 'Gene', (144, 149))	('PDGFA', 'Gene', (155, 160))	('IGF1R', 'Gene', '3480', (144, 149))	('FOS', 'Gene', (29, 32))	('TP53', 'Gene', '7157', (34, 38))
21818	29617660	C4 and C5, with HPV+ CESC and some HPV(-) tumors, shared high proliferation-related features, but they had a lower proportion of cases with amplifications of MAPK1 (p <= 6.4E-0.05) and FGFR1 (p = 0.0006).	('lower', 'NegReg', (109, 114))	('amplifications', 'Var', (140, 154))	('FGFR', 'molecular_function', 'GO:0005007', ('185', '189'))	('HPV', 'Species', '10566', (35, 38))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('MAPK1', 'Gene', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('HPV', 'Species', '10566', (16, 19))	('FGFR1', 'Gene', (185, 190))	('MAPK', 'molecular_function', 'GO:0004707', ('158', '162'))	('MAPK1', 'Gene', '5594', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
21819	29617660	C4, which contains higher MYB/MYC negative regulator FBXW7 mutations (p = 0.04), displayed low inferred activation of immune features, while C5 was enriched for PDL1 (CD274) amplification (p = 0.0009), differentiating these HPV(+) SCC subsets.	('FBXW7', 'Gene', (53, 58))	('CD274', 'Gene', '29126', (167, 172))	('SCC', 'Gene', '6317', (231, 234))	('PDL1', 'Gene', '29126', (161, 165))	('HPV', 'Species', '10566', (224, 227))	('CD274', 'Gene', (167, 172))	('PDL1', 'Gene', (161, 165))	('mutations', 'Var', (59, 68))	('SCC', 'Gene', (231, 234))
21820	29617660	LUSC enriched cluster C6, which contained a higher proportion of cases with CDK6 amplifications (p = 1.9E-05) and exhibited higher proliferation-related signature but lower JUN/FOS and TP53/63/73 pathway activation.	('FOS', 'Gene', '2353', (177, 180))	('activation', 'PosReg', (204, 214))	('lower', 'NegReg', (167, 172))	('amplifications', 'Var', (81, 95))	('TP53', 'Gene', (185, 189))	('proliferation-related signature', 'MPA', (131, 162))	('FOS', 'Gene', (177, 180))	('CDK', 'molecular_function', 'GO:0004693', ('76', '79'))	('higher', 'PosReg', (124, 130))	('CDK6', 'Gene', (76, 80))	('TP53', 'Gene', '7157', (185, 189))	('CDK6', 'Gene', '1021', (76, 80))
21826	29617660	Notably, a C2 arm and C3 with mostly HPV(+) CESC and C4 and C5 with LUSC, ESCA, CESC, and BLCA were enriched for growth factor and rapamycin-sensitive mTORC1 target P70S6KpT389 and RAD51 DNA damage factor.	('P70S6KpT389', 'Var', (165, 176))	('RAD51', 'Gene', '5888', (181, 186))	('DNA', 'cellular_component', 'GO:0005574', ('187', '190'))	('mTORC1', 'cellular_component', 'GO:0031931', ('151', '157'))	('mTORC1', 'Gene', '382056', (151, 157))	('RAD', 'biological_process', 'GO:1990116', ('181', '184'))	('HPV', 'Species', '10566', (37, 40))	('mTORC1', 'Gene', (151, 157))	('RAD51', 'Gene', (181, 186))
21829	29617660	However, C1 was enriched for activated EGFRpY1068/1173 and HER2pY1248, as potential therapeutic targets for this subset.	('EGFR', 'Gene', (39, 43))	('HER2pY1248', 'Var', (59, 69))	('EGFR', 'Gene', '1956', (39, 43))
21830	29617660	AKTp473/T308 and GSK3p21S9 were enriched in C4 arm 1 and C6.	('AKT', 'Gene', (0, 3))	('GSK', 'molecular_function', 'GO:0050321', ('17', '20'))	('GSK3p21S9', 'Var', (17, 26))	('AKT', 'Gene', '207', (0, 3))
21831	29617660	We found positive Pearson's correlations between upstream MAPKpT202Y204 and JUN phospho-proteins, between AKT and mTOR, and among GSK3alphabeta, GSK3p21S9, and NF-kappaBpS536 (Figure 6B).	('AKT', 'Gene', (106, 109))	('NF-kappaB', 'Gene', (160, 169))	('GSK', 'molecular_function', 'GO:0050321', ('145', '148'))	('GSK', 'molecular_function', 'GO:0050321', ('130', '133'))	('mTOR', 'Gene', '2475', (114, 118))	('JUN phospho-proteins', 'MPA', (76, 96))	('mTOR', 'Gene', (114, 118))	('AKT', 'Gene', '207', (106, 109))	('NF-kappaB', 'Gene', '4790', (160, 169))	('MAPKpT202Y204', 'Var', (58, 71))	('correlations', 'Interaction', (28, 40))
21840	29617660	Of these, we highlight the two with the largest positive fold changes in SCC, miR-205-5p and miR-944, and a set that included miRs-200a-c-5/3p, 141-5/3p, and 429, which we observed to exhibit decreased expression linked with an increased EMT score in miRNA C2 and C3 (Figures 7A and S7A, EMT score track).	('EMT', 'biological_process', 'GO:0001837', ('238', '241'))	('decreased', 'NegReg', (192, 201))	('miR-944', 'Gene', (93, 100))	('miR-205', 'Gene', (78, 85))	('SCC', 'Gene', (73, 76))	('miRs-200a-c-5/3p', 'Var', (126, 142))	('expression', 'MPA', (202, 212))	('EMT', 'Gene', (238, 241))	('miR-205', 'Gene', '406988', (78, 85))	('increased EMT', 'Phenotype', 'HP:0008151', (228, 241))	('increased', 'PosReg', (228, 237))	('EMT', 'Gene', '3702', (238, 241))	('EMT', 'biological_process', 'GO:0001837', ('288', '291'))	('EMT', 'Gene', (288, 291))	('SCC', 'Gene', '6317', (73, 76))	('EMT', 'Gene', '3702', (288, 291))	('miR-944', 'Gene', '100126340', (93, 100))
21841	29617660	Notably, miR-205-5p as well as miR-200/141 and 429 were anti-correlated (rho <= -0.4) to the EMT-related transcription factors ZEB1 and ZEB2 (Figures 7C and S7C).	('EMT', 'biological_process', 'GO:0001837', ('93', '96'))	('miR-205', 'Gene', (9, 16))	('ZEB2', 'Gene', '9839', (136, 140))	('miR-205', 'Gene', '406988', (9, 16))	('ZEB2', 'Gene', (136, 140))	('EMT', 'Gene', (93, 96))	('ZEB1', 'Gene', '6935', (127, 131))	('EMT', 'Gene', '3702', (93, 96))	('ZEB1', 'Gene', (127, 131))	('transcription', 'biological_process', 'GO:0006351', ('105', '118'))	('miR-200/141', 'Var', (31, 42))
21843	29617660	The EMT-related mRNAs ZEB2, CTGF, and CYR61 were observed to cluster together above in a branch of mRNA C1 with LUSC and C6 with HNSC that overlap miRNA C2 and C3 with decreased expression of these miRs (Figure S7A, mRNA track).	('miRNA', 'Var', (147, 152))	('CTGF', 'Gene', '1490', (28, 32))	('EMT', 'Gene', (4, 7))	('CYR61', 'Gene', '3491', (38, 43))	('CTGF', 'Gene', (28, 32))	('EMT', 'Gene', '3702', (4, 7))	('decreased', 'NegReg', (168, 177))	('expression', 'MPA', (178, 188))	('ZEB2', 'Gene', (22, 26))	('CYR61', 'Gene', (38, 43))	('EMT', 'biological_process', 'GO:0001837', ('4', '7'))	('ZEB2', 'Gene', '9839', (22, 26))
21852	29617660	The cg06520450 site with lowest methylation was most significantly correlated with overall expression of TP63 and miR-944 (Tables S5A and S5B).	('S5A', 'Gene', (130, 133))	('expression', 'MPA', (91, 101))	('miR-944', 'Gene', '100126340', (114, 121))	('cg06520450', 'Var', (4, 14))	('TP63', 'Gene', '8626', (105, 109))	('correlated', 'Reg', (67, 77))	('TP63', 'Gene', (105, 109))	('miR-944', 'Gene', (114, 121))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('S5B', 'Gene', '5711', (138, 141))	('methylation', 'MPA', (32, 43))	('lowest', 'NegReg', (25, 31))	('S5B', 'Gene', (138, 141))	('S5A', 'Gene', '5710', (130, 133))
21857	29617660	We uncovered a significant mutually exclusive relationship between gains in 3q or 11q22 affecting the majority of SCCs (Figure S1C; Table S2A).	('11q22', 'Gene', (82, 87))	('SCC', 'Gene', (114, 117))	('SCC', 'Gene', '6317', (114, 117))	('gains', 'Var', (67, 72))
21860	29617660	In that study, DeltaNp63 and AKT inhibition were shown to modulate YAP1.	('DeltaNp63', 'Var', (15, 24))	('AKT', 'Gene', '207', (29, 32))	('inhibition', 'NegReg', (33, 43))	('YAP1', 'Gene', (67, 71))	('DeltaNp63', 'Chemical', '-', (15, 24))	('AKT', 'Gene', (29, 32))	('modulate', 'Reg', (58, 66))	('YAP1', 'Gene', '10413', (67, 71))
21863	29617660	A correlation between overall TP63 expression and miR-944 due to hypomethylation of the same TSS CpG island is supported by a recent genome-wide analysis, but the link with the differential methylation of the alternative TSSs for TA/DeltaN isoforms was unrecognized.	('methylation', 'biological_process', 'GO:0032259', ('190', '201'))	('miR-944', 'Gene', '100126340', (50, 57))	('hypomethylation', 'Var', (65, 80))	('miR-944', 'Gene', (50, 57))	('TP63', 'Gene', (30, 34))	('TP63', 'Gene', '8626', (30, 34))
21866	29617660	These observations suggest that methylation and PI3K inhibitors could modulate TA/DeltaNp63 to inhibit SCC.	('modulate', 'Reg', (70, 78))	('methylation', 'Var', (32, 43))	('SCC', 'Gene', (103, 106))	('inhibit', 'NegReg', (95, 102))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('PI3K', 'molecular_function', 'GO:0016303', ('48', '52'))	('DeltaNp63', 'Chemical', '-', (82, 91))	('SCC', 'Gene', '6317', (103, 106))	('TA/DeltaNp63', 'Gene', (79, 91))
21867	29617660	Indeed, PI3K-AKT-mTOR-eIF signaling appears to be a common pathway in which recurrent 3q26 CNAs (69%; Table S2) and PIK3CA mutations (11%-27%; Figure S2A) are observed.	('PIK3CA', 'Gene', (116, 122))	('PI3K', 'molecular_function', 'GO:0016303', ('8', '12'))	('PIK3CA', 'Gene', '5290', (116, 122))	('AKT', 'Gene', '207', (13, 16))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))	('3q26', 'Gene', (86, 90))	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (17, 21))	('mutations', 'Var', (123, 132))	('AKT', 'Gene', (13, 16))
21868	29617660	Consistent with this, we observed increases in a variety of PI3K, AKT, mTOR, eIF components, and phospho-proteins and greater correlation scores for signaling downstream of mTOR than PI3K detected by RPPA.	('signaling', 'biological_process', 'GO:0023052', ('149', '158'))	('AKT', 'Gene', (66, 69))	('signaling', 'MPA', (149, 158))	('PI3K', 'molecular_function', 'GO:0016303', ('183', '187'))	('PI3K', 'molecular_function', 'GO:0016303', ('60', '64'))	('mTOR', 'Gene', '2475', (173, 177))	('mTOR', 'Gene', '2475', (71, 75))	('greater', 'PosReg', (118, 125))	('mTOR', 'Gene', (173, 177))	('mTOR', 'Gene', (71, 75))	('correlation scores', 'MPA', (126, 144))	('AKT', 'Gene', '207', (66, 69))	('PI3K', 'Var', (60, 64))	('increases', 'PosReg', (34, 43))
21870	29617660	SCCs are enriched for P70S6KpT389, RICTORpT1135, and RAD51 DNA damage proteins, which are associated with growth factor and rapamycin sensitivity.	('SCC', 'Gene', (0, 3))	('RICTOR', 'Gene', '253260', (35, 41))	('RAD', 'biological_process', 'GO:1990116', ('53', '56'))	('proteins', 'Protein', (70, 78))	('SCC', 'Gene', '6317', (0, 3))	('associated', 'Reg', (90, 100))	('RAD51', 'Gene', (53, 58))	('RAD51', 'Gene', '5888', (53, 58))	('P70S6KpT389', 'Var', (22, 33))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('RICTOR', 'Gene', (35, 41))
21872	29617660	CNAs or mutations that enhance expression and activation of receptors and kinases activating PI3K-AKT and MAPK signal axes were observed and supported by RPPA.	('MAPK', 'molecular_function', 'GO:0004707', ('106', '110'))	('activation', 'PosReg', (46, 56))	('PI3K', 'molecular_function', 'GO:0016303', ('93', '97'))	('mutations', 'Var', (8, 17))	('AKT', 'Gene', '207', (98, 101))	('expression', 'MPA', (31, 41))	('AKT', 'Gene', (98, 101))	('enhance', 'PosReg', (23, 30))
21877	29617660	FANC-BRCA defects are associated with increased sensitivity to standard DNA-damaging therapies, potentially helping explain the relative sensitivity of some HPV+ tumors to chemoradiotherapy and potential for their de-escalation.	('HPV', 'Species', '10566', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('FANC-BRCA', 'Gene', (0, 9))	('FANC-BRCA', 'Gene', '672', (0, 9))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('defects', 'Var', (10, 17))
21878	29617660	Targeted agents, such as WEE1 inhibitors that prevent G2 checkpoint arrest and DNA repair, may warrant investigation in SCCs with these defects or those with TP53 mutations.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('arrest', 'Disease', (68, 74))	('mutations', 'Var', (163, 172))	('SCC', 'Gene', '6317', (120, 123))	('DNA repair', 'biological_process', 'GO:0006281', ('79', '89'))	('DNA repair', 'MPA', (79, 89))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('WEE1', 'Gene', '7465', (25, 29))	('arrest', 'Disease', 'MESH:D006323', (68, 74))	('WEE1', 'Gene', (25, 29))	('SCC', 'Gene', (120, 123))
21880	29617660	Lastly, the prevalence of 11q13/22 with FADD/IAP alterations in >30% of HPV(-) HNSC, LUSC, and ESCA subtypes and their sensitivity to IAP inhibitors plus radiotherapy in recent preclinical studies support the investigation of IAP antagonists in those tumors.	('alterations', 'Var', (49, 60))	('clinical', 'Species', '191496', (180, 188))	('IAP', 'Gene', (226, 229))	('tumors', 'Disease', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('HPV', 'Species', '10566', (72, 75))	('IAP', 'Gene', '961', (134, 137))	('IAP', 'Gene', '961', (226, 229))	('11q13/22', 'Gene', (26, 34))	('IAP', 'Gene', (134, 137))	('IAP', 'Gene', (45, 48))	('IAP', 'Gene', '961', (45, 48))
21897	29617660	Significantly mutated genes were identified for each tumor type and for the combined PanSCC cohort using MutSig2CV, which combines p values from tests for high mutational frequency relative to the background mutation rate (pCV), clustering of mutations within the gene (pCL), and enrichment of mutations within evolutionarily conserved sites (pFN).	('SCC', 'Gene', '6317', (88, 91))	('pCL', 'Gene', (270, 273))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (243, 252))	('pCV', 'Species', '28355', (223, 226))	('SCC', 'Gene', (88, 91))	('tumor', 'Disease', (53, 58))	('mutations', 'Var', (294, 303))	('pCL', 'Gene', '2324', (270, 273))
21906	29617660	Therefore, the silencing status for p16 was called with probe cg13601799 on HM450 as previously described, with a beta value of 0.2 or above considered as epigenetic silencing.	('silencing', 'NegReg', (15, 24))	('cg13601799', 'Var', (62, 72))	('HM450', 'Chemical', '-', (76, 81))	('p16', 'Gene', '1029', (36, 39))	('HM450', 'Enzyme', (76, 81))	('p16', 'Gene', (36, 39))
21907	29617660	MethylMix was applied to CpG cluster data available for 1408 SCC tumors to identify CpG clusters (hereafter referred to as 'genes') that are abnormally methylated in all or a subset of cancers compared with adjacent normal tissue, where this abnormal methylation state is associated with decreased RNA expression of the same gene, as previously described.	('decreased', 'NegReg', (288, 297))	('CpG clusters', 'Gene', (84, 96))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('methylation', 'Var', (251, 262))	('methylation', 'biological_process', 'GO:0032259', ('251', '262'))	('SCC tumors', 'Disease', 'MESH:D009369', (61, 71))	('RNA expression', 'MPA', (298, 312))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('RNA', 'cellular_component', 'GO:0005562', ('298', '301'))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('SCC tumors', 'Disease', (61, 71))	('cancers', 'Disease', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
21909	29617660	We aimed to identify genes that were aberrantly methylated in cancer versus 125 normal adjacent tissue samples available across multiple SCC types, i.e., pan-cancer abnormally methylated genes.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('abnormally methylated', 'Var', (165, 186))	('SCC', 'Gene', '6317', (137, 140))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('SCC', 'Gene', (137, 140))
21921	29617660	For example, TET1 and FANCF are specifically hypermethylated in HPV+ subtype 2, while SYK is hypomethylated in HNSC, LUSC, and CESC within all subtypes.	('TET1', 'Gene', '80312', (13, 17))	('FANCF', 'Gene', (22, 27))	('HPV+', 'Gene', (64, 68))	('FANCF', 'Gene', '2188', (22, 27))	('SYK', 'Gene', (86, 89))	('hypermethylated', 'Var', (45, 60))	('TET1', 'Gene', (13, 17))	('SYK', 'Gene', '6850', (86, 89))	('HPV', 'Species', '10566', (64, 67))
21922	29617660	For each of the 905 abnormally methylated genes in SCC, MethylMix ascribed differential methylation (DM) values, a categorical variable indicating the methylation state for that gene (normal, hypomethylated or hypermethylated, relative to normal tissue) in each cancer.	('cancer', 'Disease', (262, 268))	('SCC', 'Gene', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('SCC', 'Gene', '6317', (51, 54))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('hypermethylated', 'Var', (210, 225))	('methylation', 'MPA', (88, 99))	('hypomethylated', 'Var', (192, 206))	('DM', 'Disease', 'MESH:D009223', (101, 103))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('methylation', 'biological_process', 'GO:0032259', ('151', '162'))
21927	29617660	Review of this gene list confirms that it includes many of the most significant and novel cancer related genes and signatures associated with iC, CNAs, mutations, methylation, miRNAs, paradigm analysis, and RPPA analyses found in the present study.	('mutations', 'Var', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('CNAs', 'Disease', (146, 150))	('methylation', 'biological_process', 'GO:0032259', ('163', '174'))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
21935	29617660	Gene alterations were called based on mutation, methylation, and deep copy number deletions from PanCan 33 dataset for 1409 Pan-SCC, and the top 10 are presented as an oncoprint, and compared with 8350 other cancers.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('SCC', 'Gene', (128, 131))	('cancers', 'Disease', (208, 215))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('SCC', 'Gene', '6317', (128, 131))	('PanCan', 'Gene', (97, 103))	('deep copy number deletions', 'Var', (65, 91))
21947	29617660	SCCs show chromosome or methylation alterations affecting multiple related genes These regulate squamous stemness, differentiation, growth, survival, and inflammation Copy-quiet SCCs have hypermethylated (FANCF, TET1) or mutated (CASP8, MAPK-RAS) genes Potential targets include DeltaNp63, WEE1, IAPs, PI3K-mTOR/MAPK, and immune responses	('SCC', 'Gene', '6317', (178, 181))	('mTOR', 'Gene', '2475', (307, 311))	('CASP8', 'Gene', '841', (230, 235))	('DeltaNp63', 'Chemical', '-', (279, 288))	('alterations', 'Var', (36, 47))	('mutated', 'Var', (221, 228))	('MAPK', 'molecular_function', 'GO:0004707', ('312', '316'))	('WEE1', 'Gene', (290, 294))	('SCC', 'Gene', (178, 181))	('TET1', 'Gene', '80312', (212, 216))	('PI3K', 'molecular_function', 'GO:0016303', ('302', '306'))	('CASP8', 'Gene', (230, 235))	('FANCF', 'Gene', (205, 210))	('chromosome', 'cellular_component', 'GO:0005694', ('10', '20'))	('inflammation', 'Disease', 'MESH:D007249', (154, 166))	('hypermethylated', 'MPA', (188, 203))	('WEE1', 'Gene', '7465', (290, 294))	('SCC', 'Gene', '6317', (0, 3))	('inflammation', 'biological_process', 'GO:0006954', ('154', '166'))	('TET1', 'Gene', (212, 216))	('inflammation', 'Disease', (154, 166))	('MAPK', 'molecular_function', 'GO:0004707', ('237', '241'))	('SCC', 'Gene', (0, 3))	('squamous stemness', 'Disease', (96, 113))	('mTOR', 'Gene', (307, 311))	('squamous stemness', 'Disease', 'MESH:D002294', (96, 113))	('FANCF', 'Gene', '2188', (205, 210))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('IAP', 'Gene', '961', (296, 299))	('IAP', 'Gene', (296, 299))
21948	29557778	Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy Current non-invasive approaches for detection of urothelial cancers are suboptimal.	('urothelial cancer', 'Disease', (26, 43))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('aneuploidy', 'Disease', (94, 104))	('urothelial cancer', 'Disease', 'MESH:D014523', (26, 43))	('urothelial cancers', 'Disease', 'MESH:D014523', (154, 172))	('urothelial cancers', 'Disease', (154, 172))	('urothelial cancer', 'Disease', 'MESH:D014523', (154, 171))	('aneuploidy', 'Disease', 'MESH:D000782', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))
21950	29557778	UroSEEK incorporates massive parallel sequencing assays for mutations in 11 genes and copy number changes on 39 chromosome arms.	('mutations', 'Var', (60, 69))	('UroSEEK', 'Chemical', '-', (0, 7))	('copy number changes', 'Var', (86, 105))	('chromosome', 'cellular_component', 'GO:0005694', ('112', '122'))
21961	29557778	The annual incidence of these upper tract urothelial carcinomas (UTUC) in Western countries is 1-2 cases per 100,000, but the disease occurs at a much higher rate in populations exposed to aristolochic acid (AA).	('upper tract urothelial carcinomas', 'Disease', (30, 63))	('aristolochic acid', 'Chemical', 'MESH:C000228', (189, 206))	('aristolochic acid', 'Var', (189, 206))	('upper tract urothelial carcinomas', 'Disease', 'MESH:D012141', (30, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))
21967	29557778	TERT promoter mutations predominantly affect two hot spots, g.1295228 C > T and g.1295250 C > T. These mutations generate CCGGAA/T or GGAA/T motifs that alter the binding site for ETS transcription factors and subsequently stimulate increased TERT promoter activity.	('ETS', 'Protein', (180, 183))	('mutations', 'Var', (103, 112))	('alter', 'Reg', (153, 158))	('TERT', 'Gene', (243, 247))	('TERT', 'Gene', '7015', (243, 247))	('stimulate increased', 'PosReg', (223, 242))	('transcription', 'biological_process', 'GO:0006351', ('184', '197'))	('g.1295228 C > T', 'Mutation', 'g.1295228C>T', (60, 75))	('TERT', 'Gene', (0, 4))	('binding', 'Interaction', (163, 170))	('TERT', 'Gene', '7015', (0, 4))	('binding', 'molecular_function', 'GO:0005488', ('163', '170'))	('mutations', 'Var', (14, 23))	('g.1295250 C > T', 'Mutation', 'g.1295250C>T', (80, 95))
21968	29557778	TERT promoter mutations occur in up to 80% of invasive urothelial carcinomas of the bladder and in several of their histologic variants.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('occur', 'Reg', (24, 29))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('invasive urothelial carcinomas of the bladder', 'Phenotype', 'HP:0006740', (46, 91))	('mutations', 'Var', (14, 23))	('invasive urothelial carcinomas of the bladder', 'Disease', (46, 91))	('invasive urothelial carcinomas of the bladder', 'Disease', 'MESH:D001749', (46, 91))
21969	29557778	Moreover, TERT promoter mutations occur in 60-80% of BC precursors, including papillary urothelial neoplasms of low malignant potential, non-invasive low-grade papillary urothelial carcinoma, non-invasive high-grade papillary urothelial carcinoma and 'flat' carcinoma in situ (CIS), as well as in urinary cells from a subset of these patients.	('carcinoma in situ', 'Phenotype', 'HP:0030075', (258, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('papillary urothelial neoplasms', 'Disease', 'MESH:D002291', (78, 108))	('TERT', 'Gene', (10, 14))	('patients', 'Species', '9606', (334, 342))	('papillary urothelial neoplasms', 'Disease', (78, 108))	('papillary urothelial carcinoma', 'Disease', (160, 190))	("papillary urothelial carcinoma and 'flat' carcinoma", 'Disease', 'MESH:D002291', (216, 267))	('papillary urothelial carcinoma', 'Disease', 'MESH:D002291', (160, 190))	('neoplasms', 'Phenotype', 'HP:0002664', (99, 108))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (160, 190))	('TERT', 'Gene', '7015', (10, 14))	('papillary urothelial carcinoma', 'Disease', (216, 246))	('papillary urothelial carcinoma', 'Disease', 'MESH:D002291', (216, 246))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (216, 246))	('mutations', 'Var', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
21971	29557778	Other important oncogene-activating mutations include those in FGFR3, RAS and PIK3CA genes, which occur in a high fraction of non-muscle invasive bladder cancers.	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (126, 153))	('PIK3CA', 'Gene', (78, 84))	('FGFR3', 'Gene', '2261', (63, 68))	('invasive bladder', 'Phenotype', 'HP:0100645', (137, 153))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (137, 161))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('RAS', 'Gene', (70, 73))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('PIK3CA', 'Gene', '5290', (78, 84))	('mutations', 'Var', (36, 45))	('FGFR3', 'Gene', (63, 68))	('bladder cancers', 'Phenotype', 'HP:0009725', (146, 161))	('invasive bladder cancers', 'Disease', (137, 161))	('bladder cancer', 'Phenotype', 'HP:0009725', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('occur', 'Reg', (98, 103))
21972	29557778	In muscle-invasive bladder cancers, mutations in the TP53, CDKN2A, MLL and ERBB2 genes are also frequently found.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('ERBB2', 'Gene', (75, 80))	('ERBB2', 'Gene', '2064', (75, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (19, 33))	('invasive bladder', 'Phenotype', 'HP:0100645', (10, 26))	('mutations', 'Var', (36, 45))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('muscle-invasive bladder cancers', 'Disease', (3, 34))	('TP53', 'Gene', '7157', (53, 57))	('found', 'Reg', (107, 112))	('MLL', 'Gene', '4297', (67, 70))	('CDKN2A', 'Gene', (59, 65))	('bladder cancers', 'Phenotype', 'HP:0009725', (19, 34))	('MLL', 'Gene', (67, 70))	('muscle-invasive bladder cancers', 'Disease', 'MESH:D001749', (3, 34))	('TP53', 'Gene', (53, 57))	('CDKN2A', 'Gene', '1029', (59, 65))
21980	29557778	UroSEEK has three components: detection of intragenic mutations in regions of ten genes (FGFR3, TP53, CDKN2A, ERBB2, HRAS, KRAS, PIK3CA, MET, VHL and MLL) frequently mutated in urothelial tumors; detection of mutations in the TERT promoter; and detection of aneuploidy.	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('mutated', 'Var', (166, 173))	('MET', 'Gene', (137, 140))	('HRAS', 'Gene', '3265', (117, 121))	('VHL', 'Disease', 'MESH:D006623', (142, 145))	('PIK3CA', 'Gene', '5290', (129, 135))	('HRAS', 'Gene', (117, 121))	('CDKN2A', 'Gene', '1029', (102, 108))	('KRAS', 'Gene', (123, 127))	('urothelial tumors', 'Disease', 'MESH:D001749', (177, 194))	('MLL', 'Gene', (150, 153))	('MLL', 'Gene', '4297', (150, 153))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('TERT', 'Gene', (226, 230))	('mutations', 'Var', (54, 63))	('TERT', 'Gene', '7015', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('ERBB2', 'Gene', (110, 115))	('PIK3CA', 'Gene', (129, 135))	('TP53', 'Gene', (96, 100))	('aneuploidy', 'Disease', 'MESH:D000782', (258, 268))	('VHL', 'Disease', (142, 145))	('ERBB2', 'Gene', '2064', (110, 115))	('UroSEEK', 'Chemical', '-', (0, 7))	('FGFR3', 'Gene', (89, 94))	('CDKN2A', 'Gene', (102, 108))	('urothelial tumors', 'Disease', (177, 194))	('mutations', 'Var', (209, 218))	('KRAS', 'Gene', '3845', (123, 127))	('aneuploidy', 'Disease', (258, 268))	('TP53', 'Gene', '7157', (96, 100))	('FGFR3', 'Gene', '2261', (89, 94))
21985	29557778	A small fraction (4% to 5%) of patients with microscopic hematuria later develops urothelial malignancy , so the decision as to which patients should undergo cystoscopy is often difficult.	('hematuria', 'Disease', 'MESH:D006417', (57, 66))	('develops', 'PosReg', (73, 81))	('patients', 'Species', '9606', (134, 142))	('microscopic hematuria', 'Phenotype', 'HP:0002907', (45, 66))	('patients', 'Species', '9606', (31, 39))	('microscopic', 'Var', (45, 56))	('urothelial malignancy', 'Disease', (82, 103))	('hematuria', 'Phenotype', 'HP:0000790', (57, 66))	('urothelial malignancy', 'Disease', 'MESH:D009369', (82, 103))	('hematuria', 'Disease', (57, 66))
22001	29557778	First, we evaluated mutations in selected regions of ten genes that have been shown to be frequently altered in urothelial tumors (Figure 3 and Supplementary file 3).	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('urothelial tumors', 'Disease', (112, 129))	('altered', 'Reg', (101, 108))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('mutations', 'Var', (20, 29))	('urothelial tumors', 'Disease', 'MESH:D001749', (112, 129))
22006	29557778	The most commonly altered genes were TP53 (45% of the total mutations) and FGFR3 (20% of the total mutations; Figure 3).	('FGFR3', 'Gene', (75, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('mutations', 'Var', (60, 69))	('altered', 'Reg', (18, 25))	('TP53', 'Gene', '7157', (37, 41))	('FGFR3', 'Gene', '2261', (75, 80))	('TP53', 'Gene', (37, 41))
22008	29557778	Mutations in the TERT promoter were detected in 57% of the 175 urinary cell samples from the patients who developed cancer during the study interval (95% CI, 49% to 64%; Table 1a and Supplementary file 6).	('TERT', 'Gene', (17, 21))	('cancer', 'Disease', (116, 122))	('detected', 'Reg', (36, 44))	('TERT', 'Gene', '7015', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('patients', 'Species', '9606', (93, 101))
22013	29557778	Of the 395 patients in this cohort who did not develop BC during the course of the study, only 4% had a detectable mutation in the TERT promoter.	('patients', 'Species', '9606', (11, 19))	('mutation', 'Var', (115, 123))	('TERT', 'Gene', (131, 135))	('TERT', 'Gene', '7015', (131, 135))
22014	29557778	Finally, only one of the 188 urinary samples from healthy individuals harbored a TERT promoter mutation.	('TERT', 'Gene', (81, 85))	('TERT', 'Gene', '7015', (81, 85))	('mutation', 'Var', (95, 103))
22023	29557778	We identified a mutation in at least one of the 11 genes in 62% of the primary tumors from patients with false negative urine tests (Supplementary file 3 and 8).	('mutation', 'Var', (16, 24))	('patients', 'Species', '9606', (91, 99))	('false', 'biological_process', 'GO:0071877', ('105', '110'))	('negative urine', 'Phenotype', 'HP:0100519', (111, 125))	('false', 'biological_process', 'GO:0071878', ('105', '110'))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('primary tumors', 'Disease', (71, 85))	('primary tumors', 'Disease', 'MESH:D009369', (71, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('negative urine tests', 'Phenotype', 'HP:0500110', (111, 131))
22026	29557778	In samples without TERT promoter mutations (n = 45), mutations in one of the other ten genes were detected (Figure 4 and Supplementary file 5).	('TERT', 'Gene', (19, 23))	('detected', 'Reg', (98, 106))	('TERT', 'Gene', '7015', (19, 23))	('mutations', 'Var', (53, 62))
22032	29557778	On average, UroSEEK positivity preceded the diagnosis of BC by 2.3 months, and in eight cases, by >one year (Figure 5 and Supplementary file 2).	('UroSEEK', 'Chemical', '-', (12, 19))	('UroSEEK', 'Protein', (12, 19))	('positivity', 'Var', (20, 30))
22046	29557778	The most commonly altered genes were TP53 (n = 33, 58% of the 57 mutations) and FGFR3 (n = 9, 16% of the 57 mutations; Figure 3).	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('altered', 'Reg', (18, 25))	('FGFR3', 'Gene', '2261', (80, 85))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('FGFR3', 'Gene', (80, 85))	('mutations', 'Var', (65, 74))
22047	29557778	Mutations in the TERT promoter were detected in 16 of the 56 urinary cell samples from UTUC patients (29%, 95% CI, 18% to 42%; Table 2 and Supplementary file 11).	('TERT', 'Gene', (17, 21))	('detected', 'Reg', (36, 44))	('TERT', 'Gene', '7015', (17, 21))	('patients', 'Species', '9606', (92, 100))	('Mutations', 'Var', (0, 9))
22053	29557778	The distribution of mutant genes in primary tumors (Supplementary file 14) was consistent with findings from some but not all, exome-wide and targeted sequencing studies of UTUCs.	('primary tumors', 'Disease', 'MESH:D009369', (36, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('mutant genes', 'Var', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('primary tumors', 'Disease', (36, 50))
22054	29557778	In the present study, TP53 mutations were found only in high-grade UTUCs, while FGFR3 mutations dominated in low-grade tumors (present in 5/6).	('mutations', 'Var', (27, 36))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('TP53', 'Gene', (22, 26))	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('FGFR3', 'Gene', '2261', (80, 85))	('TP53', 'Gene', '7157', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('FGFR3', 'Gene', (80, 85))
22055	29557778	However, the overall frequency of FGFR3 mutations in our UTUC cohort (21%) was relatively low compared to values reported by (74%) and (54%), but was comparable to values reported by (8%) and (13%).	('FGFR3', 'Gene', '2261', (34, 39))	('FGFR3', 'Gene', (34, 39))	('mutations', 'Var', (40, 49))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('low', 'NegReg', (90, 93))
22056	29557778	We attribute this difference to the race/ethnicity profile of the cohorts under comparison, as FGFR3 mutation levels are relatively low in UTUCs from Han Chinese patients (3-9%) compared to Western patients (36-60%), as reported by.	('low', 'NegReg', (132, 135))	('patients', 'Species', '9606', (162, 170))	('FGFR', 'molecular_function', 'GO:0005007', ('95', '99'))	('patients', 'Species', '9606', (198, 206))	('FGFR3', 'Gene', (95, 100))	('FGFR3', 'Gene', '2261', (95, 100))	('mutation', 'Var', (101, 109))
22059	29557778	In 35 (90%) of these 39 cases, at least one of the mutations identified in the urine sample (Supplementary file 10 and 11) was also identified in the corresponding tumor DNA sample (Supplementary file 14 and 15).	('tumor', 'Disease', (164, 169))	('mutations', 'Var', (51, 60))	('identified', 'Reg', (132, 142))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))
22067	29557778	Overall, 96% of the chromosomal gains or losses observed in the urinary cells were also observed in the primary tumors (Supplementary file 13).	('primary tumors', 'Disease', (104, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('primary tumors', 'Disease', 'MESH:D009369', (104, 118))	('losses', 'NegReg', (41, 47))	('chromosomal gains', 'Var', (20, 37))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
22069	29557778	Evaluation of the corresponding 56 tumors with the same assay demonstrated that all but three were aneuploid.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('aneuploid', 'Var', (99, 108))
22072	29557778	Mutations in one of the other ten genes were detected in 23 samples without TERT promoter mutations (Figure 4).	('TERT', 'Gene', '7015', (76, 80))	('Mutations', 'Var', (0, 9))	('TERT', 'Gene', (76, 80))
22077	29557778	These three tumors were aneuploid, thus enabling their detection through copy number variations in the urinary cell samples.	('copy number variations', 'Var', (73, 95))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('enabling', 'PosReg', (40, 48))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
22089	29557778	Moreover, the A > T signature mutation associated with AA was highly represented in the mutational spectra of TP53 (18/32 A > T) and HRAS (2/2 A > T) found in urinary cells (Supplementary file 10).	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('2 A > T', 'Mutation', 'rs193920817', (141, 148))	('32 A > T', 'Mutation', 'rs370502517', (119, 127))	('HRAS', 'Gene', '3265', (133, 137))	('HRAS', 'Gene', (133, 137))	('A > T', 'Var', (14, 19))	('2 A > T', 'Mutation', 'rs193920817', (120, 127))
22091	29557778	Tumor tissue was thus generally available, and in most such tumors, a mutation was identified.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutation', 'Var', (70, 78))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
22092	29557778	We evaluated a total of 322 patients with a BC tumor containing a mutation in at least one of the 11 genes and a urine sample collected within 0-5 years after surgery.	('BC tumor', 'Disease', (44, 52))	('BC tumor', 'Disease', 'MESH:D009369', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutation', 'Var', (66, 74))	('patients', 'Species', '9606', (28, 36))
22097	29557778	The multiplex assay detected mutations in 52% of the urinary cell samples from patients who developed recurrent BC during the study interval (95% CI, 45% to 60%; Supplementary file 16 and Supplementary file 17).	('detected', 'Reg', (20, 28))	('mutations', 'Var', (29, 38))	('patients', 'Species', '9606', (79, 87))
22098	29557778	The most commonly altered genes were FGFR3 (43% of the 134 mutations) and TP53 (30% of the 134 mutations; Figure 3).	('FGFR3', 'Gene', (37, 42))	('altered', 'Reg', (18, 25))	('TP53', 'Gene', '7157', (74, 78))	('FGFR3', 'Gene', '2261', (37, 42))	('mutations', 'Var', (59, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('TP53', 'Gene', (74, 78))
22100	29557778	Mutations in the TERT promoter were detected in 57% of the urinary cell samples from patients who developed recurrent BC during the study interval (95% CI 44% to 58%; (Table 1b and Supplementary file 18).	('patients', 'Species', '9606', (85, 93))	('TERT', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('TERT', 'Gene', '7015', (17, 21))
22101	29557778	The median TERT MAF in the urinary cells with detectable mutations was 5% (5.02%).	('mutations', 'Var', (57, 66))	('TERT', 'Gene', (11, 15))	('TERT', 'Gene', '7015', (11, 15))
22107	29557778	Thirty-two samples without TERT promoter mutations were detected by mutations in one of the other ten genes (Figure 4 and Supplementary file 17).	('mutations', 'Var', (68, 77))	('TERT', 'Gene', (27, 31))	('TERT', 'Gene', '7015', (27, 31))
22112	29557778	On average, UroSEEK positivity preceded the diagnosis of BC by 7 months, and in 47 cases, by >one year (Figure 4 and Supplementary file 16).	('UroSEEK', 'Chemical', '-', (12, 19))	('UroSEEK', 'Protein', (12, 19))	('positivity', 'Var', (20, 30))
22138	29557778	First, we cannot be certain that the patients whose urinary cells harbored genetic alterations did not have cancer.	('patients', 'Species', '9606', (37, 45))	('genetic alterations', 'Var', (75, 94))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
22141	29557778	Clonal proliferations may also be the basis for any discordance between mutations in urinary cells and in the primary tumors of the same patients.	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('patients', 'Species', '9606', (137, 145))	('primary tumors', 'Disease', (110, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('primary tumors', 'Disease', 'MESH:D009369', (110, 124))
22142	29557778	Although in the majority of cases, at least one of the mutations identified in the urine was also present in the primary tumor, this was not true in 22% of the cases in the BC early detection cohort.	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('mutations', 'Var', (55, 64))
22152	29557778	In addition, some of the mutations in the 11 genes queried, such as large insertions or deletions or complex changes, might be undetectable by mutation-based assays, but such samples might still score positive in a test for aneuploidy.	('deletions', 'Var', (88, 97))	('aneuploidy', 'Disease', (224, 234))	('positive', 'Reg', (201, 209))	('aneuploidy', 'Disease', 'MESH:D000782', (224, 234))
22179	29557778	As noted in the main text, the primary tumors from these patients harbored mutations in at least one of the 11 genes assessed through the multiplex or singleplex assays.	('patients', 'Species', '9606', (57, 65))	('primary tumors', 'Disease', (31, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('primary tumors', 'Disease', 'MESH:D009369', (31, 45))	('mutations', 'Var', (75, 84))	('harbored', 'Reg', (66, 74))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
22199	29557778	First, a multiplex PCR was used to detect mutations in regions of ten genes commonly mutated in urologic malignancies: CDKN2A, ERBB2, FGFR3, HRAS, KRAS, MET, MLL, PIK3CA, TP53, and VHL.	('urologic malignancies', 'Disease', (96, 117))	('FGFR3', 'Gene', (134, 139))	('HRAS', 'Gene', '3265', (141, 145))	('HRAS', 'Gene', (141, 145))	('PIK3CA', 'Gene', (163, 169))	('FGFR3', 'Gene', '2261', (134, 139))	('KRAS', 'Gene', (147, 151))	('MET', 'Gene', (153, 156))	('TP53', 'Gene', (171, 175))	('MLL', 'Gene', '4297', (158, 161))	('MLL', 'Gene', (158, 161))	('VHL', 'Disease', 'MESH:D006623', (181, 184))	('ERBB2', 'Gene', (127, 132))	('urologic malignancies', 'Disease', 'MESH:D014570', (96, 117))	('FGFR', 'molecular_function', 'GO:0005007', ('134', '138'))	('CDKN2A', 'Gene', (119, 125))	('ERBB2', 'Gene', '2064', (127, 132))	('PIK3CA', 'Gene', '5290', (163, 169))	('TP53', 'Gene', '7157', (171, 175))	('VHL', 'Disease', (181, 184))	('CDKN2A', 'Gene', '1029', (119, 125))	('mutations', 'Var', (42, 51))	('KRAS', 'Gene', '3845', (147, 151))
22201	29557778	A single amplification primer was used to amplify a 73 bp segment containing the region of the TERT promoter known to harbor mutations in BC and UTUC.	('TERT', 'Gene', (95, 99))	('TERT', 'Gene', '7015', (95, 99))	('mutations', 'Var', (125, 134))
22214	29557778	Thank you for submitting your article "Non-invasive detection of bladder cancer through the analysis of driver gene mutations and aneuploidy" for consideration by eLife.	('bladder cancer', 'Disease', (65, 79))	('aneuploidy', 'Disease', 'MESH:D000782', (130, 140))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('bladder cancer', 'Phenotype', 'HP:0009725', (65, 79))	('mutations', 'Var', (116, 125))	('aneuploidy', 'Disease', (130, 140))	('bladder cancer', 'Disease', 'MESH:D001749', (65, 79))
22216	29557778	UroSEEK combines three assessments including mutations from exons in 11 genes, TERT mutations, and aneuploidy.	('mutations', 'Var', (45, 54))	('aneuploidy', 'Disease', 'MESH:D000782', (99, 109))	('UroSEEK', 'Chemical', '-', (0, 7))	('TERT', 'Gene', (79, 83))	('TERT', 'Gene', '7015', (79, 83))	('aneuploidy', 'Disease', (99, 109))
22223	29557778	The message is the same - urinary cell mutation testing has potential to detect urothelial and bladder cancers.	('mutation', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('detect', 'Reg', (73, 79))	('bladder cancers', 'Disease', (95, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))	('bladder cancers', 'Phenotype', 'HP:0009725', (95, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('urothelial and bladder cancer', 'Disease', 'MESH:D001749', (80, 109))	('bladder cancers', 'Disease', 'MESH:D001749', (95, 110))
22227	29557778	The authors indicate that one reason for false negatives was due to discordant mutations on the gene panel and the tumor.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('false', 'biological_process', 'GO:0071878', ('41', '46'))	('false', 'biological_process', 'GO:0071877', ('41', '46'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('mutations', 'Var', (79, 88))
22265	28789622	The 5-year cancer specific survival rates were 69% for squamous differentiation-positive patients and 91% for squamous differentiation-negative patients (p < 0.001).	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('squamous differentiation-positive', 'Var', (55, 88))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (89, 97))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))
22299	28789622	The tumor multiplicity rate was significantly different between squamous differentiation-positive patients (115 patients, 51%) and squamous differentiation-negative patients (615 patients, 42%) (p = 0.02).	('tumor', 'Disease', (4, 9))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('different', 'Reg', (46, 55))	('patients', 'Species', '9606', (179, 187))	('patients', 'Species', '9606', (165, 173))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('squamous differentiation-positive', 'Var', (64, 97))
22306	28789622	Furthermore, the 5 year cancer specific survival rates were 69% for squamous differentiation-positive patients and 91% for squamous differentiation-negative patients (p < 0.001, Fig.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (157, 165))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('squamous differentiation-positive', 'Var', (68, 101))
22364	28686671	Thus far, the majority of ctDNA studies have focused on detection of tumor-specific point mutations after cancer diagnosis for the purpose of post-treatment surveillance.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('point mutations', 'Var', (84, 99))	('tumor', 'Disease', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
22376	28686671	A series of studies have demonstrated the ability to detect tumor derived genetic aberrations in circulating free DNA (cfDNA).	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('genetic aberrations', 'Var', (74, 93))	('tumor', 'Disease', (60, 65))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))
22381	28686671	Copy number variations (CNVs), like point mutations, are common and causal for a large proportion of cancer types.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('causal', 'Reg', (68, 74))	('cancer', 'Disease', (101, 107))	('Copy number variations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('point mutations', 'Disease', (36, 51))
22397	28686671	Cancer CNVs, especially amplifications, often exceed a single copy gained or lost.	('lost', 'NegReg', (77, 81))	('amplifications', 'Var', (24, 38))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
22418	28686671	The random forest was also readily capable of detecting the presence of cancer as expected: TPR of 0.854 and PPV of 0.997 at 100 Mb ctDNA CNV resolution and TPR of 0.895 and PPV of 0.995 at 5 Mb resolution (Fig 4B).	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('TPR', 'Var', (92, 95))	('cancer', 'Disease', (72, 78))
22427	28686671	Most cancer types demonstrate a PPV of >80% at even coarse grain resolution (100Mb) outpacing the PPV of diagnostic tests currently used in clinical practice.	('100Mb', 'Var', (77, 82))	('cancer', 'Disease', (5, 11))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
22445	28686671	However, the unbiased nature of ctDNA sequencing can create challenges for clinical follow-up given that individual cancer mutations, especially point mutations, are not quite as cancer type specific as serum tumor markers.	('tumor', 'Disease', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('point mutations', 'Var', (145, 160))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('mutations', 'Var', (123, 132))
22446	28686671	Since there is a large degree of overlap in the recurrent point mutations that drive common cancer types, point mutations tend to be the least useful molecular determinant of tissue of origin.	('point mutations', 'Var', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))
22519	27070449	We next assessed the percentage of tumors that highly expressed MAGE-A (staining of >50% of tumor cells) and found that the majority of malignancies that expressed MAGE-A were indeed high expressers (Table 2).	('MAGE-A', 'Chemical', '-', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('MAGE-A', 'Var', (164, 170))	('MAGE-A', 'Chemical', '-', (164, 170))	('malignancies', 'Disease', 'MESH:D009369', (136, 148))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('malignancies', 'Disease', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Disease', (92, 97))
22529	27070449	In summary, the expression patterns of MAGE-A and NY-ESO-1 in metastatic lesions are similar to the staining patterns seen in primary lesions with MAGE-A expression being significantly higher than NY-ESO-1 in multiple primary and metastatic malignancies (Table 1, 2, and 3).	('MAGE-A', 'Var', (147, 153))	('MAGE-A', 'Chemical', '-', (147, 153))	('NY-ESO-1', 'Gene', (197, 205))	('malignancies', 'Disease', 'MESH:D009369', (241, 253))	('NY-ESO-1', 'Gene', '246100', (197, 205))	('NY-ESO-1', 'Gene', '246100', (50, 58))	('MAGE-A', 'Chemical', '-', (39, 45))	('NY-ESO-1', 'Gene', (50, 58))	('higher', 'PosReg', (185, 191))	('malignancies', 'Disease', (241, 253))	('expression', 'MPA', (154, 164))
22651	30073111	Abnormalities of p53 regulation were also suggested for having a role in the pathogenesis of LELCB.	('role', 'Reg', (65, 69))	('Abnormalities', 'Var', (0, 13))	('regulation', 'biological_process', 'GO:0065007', ('21', '31'))	('pathogenesis', 'biological_process', 'GO:0009405', ('77', '89'))	('LELCB', 'Disease', (93, 98))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
22656	29697365	Population-based statistical inference for temporal sequence of somatic mutations in cancer genomes It is well recognized that accumulation of somatic mutations in cancer genomes plays a role in carcinogenesis; however, the temporal sequence and evolutionary relationship of somatic mutations remain largely unknown.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('carcinogenesis', 'Disease', 'MESH:D063646', (195, 209))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('carcinogenesis', 'Disease', (195, 209))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (151, 160))
22659	29697365	The most common ancestors identified in pairwise comparison of somatic mutations were TP53 mutations in breast, head/neck, and lung cancers.	('lung cancers', 'Disease', (127, 139))	('TP53', 'Gene', '7157', (86, 90))	('head/neck', 'Disease', (112, 121))	('lung cancers', 'Disease', 'MESH:D008175', (127, 139))	('breast', 'Disease', (104, 110))	('neck', 'cellular_component', 'GO:0044326', ('117', '121'))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('TP53', 'Gene', (86, 90))	('lung cancers', 'Phenotype', 'HP:0100526', (127, 139))	('mutations', 'Var', (91, 100))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
22660	29697365	The known relationship of KRAS to TP53 mutations in colorectal cancers was identified, as well as potential ancestors of TP53 mutation such as NOTCH1, EGFR, and PTEN mutations in head/neck, lung and endometrial cancers, respectively.	('head/neck', 'Disease', (179, 188))	('TP53', 'Gene', '7157', (121, 125))	('NOTCH1', 'Gene', (143, 149))	('mutations', 'Var', (166, 175))	('endometrial cancers', 'Disease', (199, 218))	('endometrial cancers', 'Disease', 'MESH:D016889', (199, 218))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('neck', 'cellular_component', 'GO:0044326', ('184', '188'))	('mutations', 'Var', (39, 48))	('lung', 'Disease', (190, 194))	('NOTCH1', 'Gene', '4851', (143, 149))	('colorectal cancers', 'Disease', (52, 70))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('PTEN', 'Gene', (161, 165))	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('KRAS', 'Gene', '3845', (26, 30))	('TP53', 'Gene', (34, 38))	('EGFR', 'Gene', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('TP53', 'Gene', (121, 125))	('KRAS', 'Gene', (26, 30))	('PTEN', 'Gene', '5728', (161, 165))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('colorectal cancers', 'Disease', 'MESH:D015179', (52, 70))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('TP53', 'Gene', '7157', (34, 38))	('EGFR', 'Gene', '1956', (151, 155))
22661	29697365	We also identified apoptosis-related genes enriched with ancestor mutations in lung cancers and a relationship between APC hotspot mutations and TP53 mutations in colorectal cancers.	('APC', 'Disease', 'MESH:D011125', (119, 122))	('APC', 'cellular_component', 'GO:0005680', ('119', '122'))	('APC', 'Disease', (119, 122))	('TP53', 'Gene', '7157', (145, 149))	('apoptosis', 'biological_process', 'GO:0097194', ('19', '28'))	('apoptosis', 'biological_process', 'GO:0006915', ('19', '28'))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('mutations', 'Var', (150, 159))	('lung cancers', 'Disease', 'MESH:D008175', (79, 91))	('colorectal cancers', 'Disease', (163, 181))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('lung cancers', 'Disease', (79, 91))	('TP53', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lung cancers', 'Phenotype', 'HP:0100526', (79, 91))	('apoptosis-related genes', 'Gene', (19, 42))	('mutations', 'Var', (131, 140))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('colorectal cancers', 'Disease', 'MESH:D015179', (163, 181))
22666	29697365	Recent advances in high-throughput sequencing technologies have enabled screening of cancer genomes for well-known cancer-related genomic aberrations such as somatic mutations, DNA copy number alterations, and chromosomal translocations.	('chromosomal translocations', 'Var', (210, 236))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('DNA', 'cellular_component', 'GO:0005574', ('177', '180'))	('cancer', 'Disease', (85, 91))	('mi', 'Chemical', 'MESH:C011506', (134, 136))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
22670	29697365	proposed a mathematical approach to determine the sequential order of APC, KRAS, and TP53 mutations in 70 colorectal cancer samples.	('TP53', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('colorectal cancer', 'Disease', (106, 123))	('APC', 'Disease', 'MESH:D011125', (70, 73))	('APC', 'cellular_component', 'GO:0005680', ('70', '73'))	('KRAS', 'Gene', (75, 79))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('TP53', 'Gene', '7157', (85, 89))	('APC', 'Disease', (70, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('mi', 'Chemical', 'MESH:C011506', (41, 43))	('KRAS', 'Gene', '3845', (75, 79))
22685	29697365	The CCF is defined as the proportion of cancer cells harboring the mutations for each variant, and can be estimated using a method outlined by Landau et al..	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', (40, 46))
22696	29697365	A mean number of 120 somatic mutations (nonsilent SNVs; missense, nonsense and splice site mutations) were observed (1 to 1597 mutations per case; median of 59 mutations; Table 1).	('missense', 'Var', (56, 64))	('mi', 'Chemical', 'MESH:C011506', (56, 58))	('nonsense and splice site mutations', 'Var', (66, 100))
22700	29697365	The gene pairs with high SCORE-CO include TTN and MUC16 whose frequent mutations are largely due to their large gene size (36,800 and 14,500 amino acids, respectively) rather than their functional significance.	('mi', 'Chemical', 'MESH:C011506', (142, 144))	('MUC16', 'Gene', (50, 55))	('TTN', 'Gene', (42, 45))	('mutations', 'Var', (71, 80))	('TTN', 'Gene', '7273', (42, 45))	('MUC16', 'Gene', '94025', (50, 55))
22701	29697365	Thus, we focused on mutations in known cancer-related genes or the Cancer Gene Census (CGC) (Fig.	('Cancer', 'Disease', 'MESH:D009369', (67, 73))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Cancer', 'Disease', (67, 73))	('mutations', 'Var', (20, 29))
22702	29697365	The co-occurring mutation gene pairs with high SCORE-CO were tumor type-specific, e.g., gene pairs of TP53 and PIK3CA were highly ranked in BLCA, BRCA, COADREAD, HNSC, LUSC, UCEC (SCORE-CO = 0.089 for 8 cases with the co-occurrence / total 90 patients, 0.055 for 40 cases, 0.085 for 21 cases, 0.083 for 22 cases, 0.085 for 10 cases, 0.106 for 18 cases, respectively) and to a lesser extent in LUAD (SCORE-CO =0.024 for 7 cases).	('LUSC', 'Phenotype', 'HP:0030359', (168, 172))	('TP53', 'Gene', (102, 106))	('BRCA', 'Phenotype', 'HP:0003002', (146, 150))	('patients', 'Species', '9606', (243, 251))	('BRCA', 'Gene', '672', (146, 150))	('PIK3CA', 'Gene', (111, 117))	('BRCA', 'Gene', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('BLCA', 'Disease', (140, 144))	('0.083', 'Var', (293, 298))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('UCEC', 'Disease', (174, 178))	('TP53', 'Gene', '7157', (102, 106))	('PIK3CA', 'Gene', '5290', (111, 117))	('tumor', 'Disease', (61, 66))
22704	29697365	LRP1B mutants frequently co-occurred with TP53 mutants in HNSC, LUAD and LUSC.	('TP53', 'Gene', '7157', (42, 46))	('mutants', 'Var', (6, 13))	('LUSC', 'Disease', (73, 77))	('LRP1B', 'Gene', (0, 5))	('HNSC', 'Disease', (58, 62))	('TP53', 'Gene', (42, 46))	('co-occurred', 'Reg', (25, 36))	('LRP1B', 'Gene', '53353', (0, 5))	('LUAD', 'Disease', (64, 68))	('mutants', 'Var', (47, 54))	('LUSC', 'Phenotype', 'HP:0030359', (73, 77))
22706	29697365	In addition, some of the mutation occurrences were tumor type-specific, e.g., PIK3CA mutations showed co-occurrence with FAT4 mutations with a high frequency in BLCA, but mainly co-occurred with PTEN mutations in UCEC.	('PIK3CA', 'Gene', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('FAT4', 'Gene', (121, 125))	('FAT4', 'Gene', '79633', (121, 125))	('tumor', 'Disease', (51, 56))	('PIK3CA', 'Gene', '5290', (78, 84))	('BLCA', 'Disease', (161, 165))	('co-occurrence', 'Reg', (102, 115))	('mutations', 'Var', (85, 94))	('mutations', 'Var', (126, 135))	('PTEN', 'Gene', (195, 199))	('PTEN', 'Gene', '5728', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
22714	29697365	For example, a frequently co-occurred mutation pair of TP53 and LRP1B (Fig.	('LRP1B', 'Gene', (64, 69))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('LRP1B', 'Gene', '53353', (64, 69))	('mutation', 'Var', (38, 46))	('co-occurred', 'Reg', (26, 37))
22716	29697365	In addition, KMT2C mutation was consistently observed as a descendant of TP53 mutations (TP53  KMT2C) in HNSC and LUAD (P value =3.0*10-5 and 5.0*10-5, respectively).	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (89, 93))	('TP53', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('KMT2C', 'Gene', '58508', (95, 100))	('KMT2C', 'Gene', (95, 100))	('KMT2C', 'Gene', '58508', (13, 18))	('KMT2C', 'Gene', (13, 18))
22718	29697365	The hierarchy of the three genes (TP53  PIK3CA  CDH1) in BRCA suggests that TP53 mutations represent early events that are followed by subsequent PIK3CA mutations (P value =0.034), then CDH1 mutations (P value =3.0*10-5).	('PIK3CA', 'Gene', '5290', (146, 152))	('PIK3CA', 'Gene', (40, 46))	('TP53', 'Gene', (34, 38))	('CDH1', 'Gene', (48, 52))	('mutations', 'Var', (153, 162))	('PIK3CA', 'Gene', '5290', (40, 46))	('TP53', 'Gene', '7157', (76, 80))	('mutations', 'Var', (191, 200))	('CDH1', 'Gene', (186, 190))	('CDH1', 'Gene', '999', (48, 52))	('TP53', 'Gene', (76, 80))	('CDH1', 'Gene', '999', (186, 190))	('BRCA', 'Gene', '672', (57, 61))	('mutations', 'Var', (81, 90))	('BRCA', 'Phenotype', 'HP:0003002', (57, 61))	('PIK3CA', 'Gene', (146, 152))	('BRCA', 'Gene', (57, 61))	('TP53', 'Gene', '7157', (34, 38))
22719	29697365	This mutation sequence can be functionally interpreted as follows: genomic integrity is disrupted with TP53 mutations followed by cancer cell proliferation stimulated by PIK3CA mutations and the acquisition of later invasive/metastatic potential with CDH1 mutations.	('PIK3CA', 'Gene', '5290', (170, 176))	('TP53', 'Gene', '7157', (103, 107))	('invasive/metastatic potential', 'CPA', (216, 245))	('CDH1', 'Gene', '999', (251, 255))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('mutations', 'Var', (108, 117))	('disrupted', 'NegReg', (88, 97))	('cancer', 'Disease', (130, 136))	('TP53', 'Gene', (103, 107))	('mutations', 'Var', (177, 186))	('genomic integrity', 'CPA', (67, 84))	('mi', 'Chemical', 'MESH:C011506', (71, 73))	('cell proliferation', 'biological_process', 'GO:0008283', ('137', '155'))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('PIK3CA', 'Gene', (170, 176))	('CDH1', 'Gene', (251, 255))
22722	29697365	The elevated mutation abundance (mean of 211 mutations per LUAD case vs. mean of 120 mutations for total cases) and the relatively large size of the cohort (290 cases) may explain this number, but only one mutation pair was observed in LUSC with similar mutation abundance (average 221 mutations per cases) and a smaller number of cohorts (118 cases).	('mutations', 'Var', (45, 54))	('mi', 'Chemical', 'MESH:C011506', (248, 250))	('elevated', 'PosReg', (4, 12))	('LUSC', 'Phenotype', 'HP:0030359', (236, 240))	('mutation abundance', 'MPA', (13, 31))
22723	29697365	TP53 mutation appeared as a hub in the 16 edge-based network of LUAD and was identified as ancestor in most mutation pairs.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
22724	29697365	TP53 mutations have been implicated in tumor development and progression across many tumor types.	('tumor', 'Disease', (85, 90))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Disease', (39, 44))	('implicated', 'Reg', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
22725	29697365	Our analysis also suggests that EGFR mutations may be earlier genomic events among the mutations in the LUAD pathogenesis.	('EGFR', 'Gene', '1956', (32, 36))	('mutations', 'Var', (37, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('EGFR', 'Gene', (32, 36))	('mi', 'Chemical', 'MESH:C011506', (66, 68))	('pathogenesis', 'biological_process', 'GO:0009405', ('109', '121'))
22726	29697365	A substantial fraction of EGFR mutations in LUAD are considered to be early addicted targets of targeted therapy, suggesting that they represent early genomic aberrations together with TP53 mutations.	('EGFR', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('mi', 'Chemical', 'MESH:C011506', (155, 157))	('TP53', 'Gene', (185, 189))	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))	('TP53', 'Gene', '7157', (185, 189))
22728	29697365	In HNSC, NOTCH1 mutations may be earlier events than TP53 mutations.	('HNSC', 'Disease', (3, 7))	('mutations', 'Var', (16, 25))	('NOTCH1', 'Gene', '4851', (9, 15))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))	('NOTCH1', 'Gene', (9, 15))
22731	29697365	Colorectal carcinogenesis is one of the well-established stepwise cancer progression models and involves sequential acquisition of APC, KRAS, and TP53 mutations at colorectal dysplasia, adenoma, and carcinoma stages, respectively.	('colorectal dysplasia', 'Disease', 'MESH:D015179', (164, 184))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Colorectal carcinogenesis', 'Disease', (0, 25))	('adenoma', 'Disease', 'MESH:D000236', (186, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('cancer', 'Disease', (66, 72))	('colorectal dysplasia', 'Disease', (164, 184))	('carcinoma', 'Disease', (199, 208))	('TP53', 'Gene', (146, 150))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('mutations', 'Var', (151, 160))	('KRAS', 'Gene', '3845', (136, 140))	('Colorectal carcinogenesis', 'Disease', 'MESH:D063646', (0, 25))	('KRAS', 'Gene', (136, 140))	('APC', 'Disease', 'MESH:D011125', (131, 134))	('carcinoma', 'Disease', 'MESH:D002277', (199, 208))	('APC', 'Disease', (131, 134))	('TP53', 'Gene', '7157', (146, 150))	('APC', 'cellular_component', 'GO:0005680', ('131', '134'))	('adenoma', 'Disease', (186, 193))
22732	29697365	Our inferred hierarchy from somatic mutations suggested that KRAS mutations were the earliest events in colorectal carcinogenesis.	('mutations', 'Var', (66, 75))	('events', 'Reg', (94, 100))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (104, 129))	('KRAS', 'Gene', (61, 65))	('colorectal carcinogenesis', 'Disease', (104, 129))	('KRAS', 'Gene', '3845', (61, 65))
22733	29697365	Given that our statistical model only considered the SNV, tumor suppressors that can be inactivated by chromosomal deletions, such as APC, may not be adequately assessed for order of mutation.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('APC', 'Disease', 'MESH:D011125', (134, 137))	('APC', 'Disease', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('APC', 'cellular_component', 'GO:0005680', ('134', '137'))	('deletions', 'Var', (115, 124))
22741	29697365	For this tumor type, TP53 mutation was marked as a descendant for PIK3CA and PTEN mutations.	('TP53', 'Gene', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('mutation', 'Var', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PIK3CA', 'Gene', (66, 72))	('PTEN', 'Gene', (77, 81))	('tumor', 'Disease', (9, 14))	('PTEN', 'Gene', '5728', (77, 81))	('PIK3CA', 'Gene', '5290', (66, 72))	('TP53', 'Gene', '7157', (21, 25))
22742	29697365	It was also noted that TP53 mutations were also observed as descendants of KRAS mutations in COADREAD.	('mutations', 'Var', (80, 89))	('KRAS', 'Gene', (75, 79))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('KRAS', 'Gene', '3845', (75, 79))
22746	29697365	On C2cp gene sets (canonical pathway in MSigDB), the results for the positively ranked genes or functions enriched with high SCORE-AN were also obviously enriched for cancer-related functionalities (Additional file 7: Table S6) but no gene sets with statistical significance were observed for genes with low SCORE-AN (Additional file 8: Table S7).	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('high SCORE-AN', 'Var', (120, 133))
22747	29697365	It has been previously reported that APC mutations may initiate the process of colon cancer development as one of the earliest genomic aberrations, but we did not obtain clear results for the early occurrence of APC mutations in the gene-level experiments shown in the previous section.	('mutations', 'Var', (41, 50))	('colon cancer', 'Disease', (79, 91))	('APC', 'cellular_component', 'GO:0005680', ('212', '215'))	('APC', 'cellular_component', 'GO:0005680', ('37', '40'))	('mi', 'Chemical', 'MESH:C011506', (131, 133))	('APC', 'Disease', (37, 40))	('APC', 'Disease', 'MESH:D011125', (212, 215))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('APC', 'Disease', (212, 215))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('APC', 'Disease', 'MESH:D011125', (37, 40))
22749	29697365	The APC non-hotspot mutations showed relatively low CCF values compared with the APC hotspot mutations (Additional file 9: Figure S2(a)).	('APC', 'Disease', (81, 84))	('CCF values', 'MPA', (52, 62))	('APC', 'cellular_component', 'GO:0005680', ('81', '84'))	('APC', 'Disease', 'MESH:D011125', (4, 7))	('APC', 'Disease', (4, 7))	('low', 'NegReg', (48, 51))	('APC', 'cellular_component', 'GO:0005680', ('4', '7'))	('mutations', 'Var', (20, 29))	('APC', 'Disease', 'MESH:D011125', (81, 84))
22750	29697365	When we further examined four cases harboring both APC:Q1387 hotspot mutations and TP53 mutations, the APC:Q1387 hotspot mutations had higher CCF values compared with TP53 mutation, and it is reasonable to assume that the APC:Q1387 mutations would be an ancestor of the TP53 mutations in these cases (Additional file 9: Figure S2(b)).	('mutations', 'Var', (121, 130))	('mutations', 'Var', (88, 97))	('TP53', 'Gene', '7157', (270, 274))	('TP53', 'Gene', '7157', (167, 171))	('APC', 'Disease', 'MESH:D011125', (103, 106))	('APC', 'Disease', (103, 106))	('APC', 'cellular_component', 'GO:0005680', ('51', '54'))	('APC', 'Disease', 'MESH:D011125', (222, 225))	('TP53', 'Gene', (83, 87))	('APC', 'Disease', (222, 225))	('APC', 'cellular_component', 'GO:0005680', ('222', '225'))	('APC', 'cellular_component', 'GO:0005680', ('103', '106'))	('mutations', 'Var', (69, 78))	('APC', 'Disease', 'MESH:D011125', (51, 54))	('APC', 'Disease', (51, 54))	('TP53', 'Gene', (270, 274))	('CCF', 'MPA', (142, 145))	('TP53', 'Gene', (167, 171))	('TP53', 'Gene', '7157', (83, 87))	('mi', 'Chemical', 'MESH:C011506', (19, 21))	('higher', 'PosReg', (135, 141))
22753	29697365	Early- and late-occurring somatic mutations have different biological and clinical implications-the early addicted somatic mutations may serve as appropriate targets for therapeutic intervention while late-occurring cancer drivers have been associated with therapeutic resistance or disease progression.	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('mutations', 'Var', (123, 132))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))
22763	29697365	Among the tumor types examined, we identified TP53 mutations as a recurrently observed hub connected with other cancer-related genes, consistent with its prevalent and known roles in tumorigenesis across multiple cancer types.	('mi', 'Chemical', 'MESH:C011506', (25, 27))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (112, 118))	('tumor', 'Disease', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('TP53', 'Gene', '7157', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('TP53', 'Gene', (46, 50))	('tumor', 'Disease', (183, 188))	('cancer', 'Disease', (213, 219))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
22766	29697365	Inactivation of LRP1B increased the invasive potential in an in vitro setting, implicating a role of LRP1B mutations in the later stages of carcinogenesis.	('LRP1B', 'Gene', (16, 21))	('LRP1B', 'Gene', '53353', (101, 106))	('mutations', 'Var', (107, 116))	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('LRP1B', 'Gene', '53353', (16, 21))	('carcinogenesis', 'Disease', (140, 154))	('increased', 'PosReg', (22, 31))	('LRP1B', 'Gene', (101, 106))	('Inactivation', 'Var', (0, 12))	('invasive potential', 'CPA', (36, 54))
22767	29697365	Whether the mutations in epigenetic modifiers are early or late events drivers is a subject of debate, with lines of evidence supporting early events for TET2 mutations or late events for SETD2 mutations.	('mutations', 'Var', (159, 168))	('mutations', 'Var', (194, 203))	('SETD2', 'Gene', '29072', (188, 193))	('TET2', 'Gene', '54790', (154, 158))	('SETD2', 'Gene', (188, 193))	('TET2', 'Gene', (154, 158))
22768	29697365	Our results suggest that KMT2C mutations are descendant genomic events relative to TP53 mutations in LUAD and HNSC, but further experimental validation in terms of multiregion sequencing or other method is required.	('TP53', 'Gene', '7157', (83, 87))	('mutations', 'Var', (31, 40))	('TP53', 'Gene', (83, 87))	('mi', 'Chemical', 'MESH:C011506', (60, 62))	('KMT2C', 'Gene', '58508', (25, 30))	('KMT2C', 'Gene', (25, 30))
22770	29697365	For example, USH2A mutation was frequently observed in several tumor types as shown in Fig.	('tumor', 'Disease', (63, 68))	('mutation', 'Var', (19, 27))	('USH2A', 'Gene', '7399', (13, 18))	('observed', 'Reg', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('USH2A', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
22774	29697365	In the case of APC, chromosomal deletions or frameshifting indels may be also responsible for APC inactivation and our methods may not adequately evaluate the genetic hierarchy of tumor suppressors such as APC.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('APC', 'cellular_component', 'GO:0005680', ('94', '97'))	('APC', 'Disease', (15, 18))	('APC', 'cellular_component', 'GO:0005680', ('206', '209'))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('responsible', 'Reg', (78, 89))	('APC', 'Disease', 'MESH:D011125', (206, 209))	('APC', 'cellular_component', 'GO:0005680', ('15', '18'))	('tumor', 'Disease', (180, 185))	('APC', 'Disease', (206, 209))	('chromosomal deletions', 'Var', (20, 41))	('APC', 'Disease', 'MESH:D011125', (94, 97))	('APC', 'Disease', (94, 97))	('APC', 'Disease', 'MESH:D011125', (15, 18))	('frameshifting indels', 'Var', (45, 65))
22775	29697365	When we limit the APC mutations to those on a known mutation hotspot (APC:Q1387) accompanying TP53 mutations (four COADREAD cases), the CCF values of APC mutations were higher than those of TP53 mutations suggesting that APC mutation may have occurred earlier than TP53 mutation in those cases.	('APC', 'Disease', 'MESH:D011125', (150, 153))	('mi', 'Chemical', 'MESH:C011506', (10, 12))	('APC', 'Disease', (150, 153))	('TP53', 'Gene', '7157', (265, 269))	('TP53', 'Gene', (94, 98))	('APC', 'Disease', 'MESH:D011125', (221, 224))	('APC', 'Disease', (221, 224))	('APC', 'cellular_component', 'GO:0005680', ('70', '73'))	('TP53', 'Gene', '7157', (190, 194))	('APC', 'Disease', 'MESH:D011125', (70, 73))	('APC', 'Disease', (70, 73))	('TP53', 'Gene', '7157', (94, 98))	('CCF', 'MPA', (136, 139))	('TP53', 'Gene', (265, 269))	('APC', 'cellular_component', 'GO:0005680', ('150', '153'))	('higher', 'PosReg', (169, 175))	('mutations', 'Var', (99, 108))	('TP53', 'Gene', (190, 194))	('APC', 'Disease', 'MESH:D011125', (18, 21))	('APC', 'cellular_component', 'GO:0005680', ('221', '224'))	('APC', 'Disease', (18, 21))	('mutations', 'Var', (154, 163))	('APC', 'cellular_component', 'GO:0005680', ('18', '21'))
22781	29697365	Furthermore, the study on mutation hotspot information may be more robust in that the hotspot mutations represent functionally relevant cancer drivers as shown in the example of APC mutations in COADREAD.	('APC', 'Disease', 'MESH:D011125', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('APC', 'cellular_component', 'GO:0005680', ('178', '181'))	('mutations', 'Var', (94, 103))	('APC', 'Disease', (178, 181))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('mutations', 'Var', (182, 191))
22788	25482946	The silencing of M2 receptor by siRNA in T24 and 5637 cell lines showed the inability of Arecaidine (100 muM) to inhibit cell proliferation after 48 hours, whereas the use of M1 and M3 antagonists in T24 appeared not to counteract the Arecaidine effect, suggesting that the inhibition of cell proliferation was directly dependent on M2 receptor activation.	('M2 receptor', 'Protein', (17, 28))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('274', '306'))	('cell proliferation', 'biological_process', 'GO:0008283', ('121', '139'))	('Arecaidine', 'Chemical', 'MESH:C015688', (235, 245))	('Arecaidine', 'Chemical', 'MESH:C015688', (89, 99))	('inhibit', 'NegReg', (113, 120))	('cell proliferation', 'CPA', (121, 139))	('muM', 'Gene', '56925', (105, 108))	('muM', 'Gene', (105, 108))	('silencing', 'Var', (4, 13))
22818	25482946	3D), although the silencing step caused per se an inevitable decrease in cell number (see Control bar), possibly due to the lipofectamine toxicity, however the additional treatment with (100 muM) Arecaidine after M2 receptor silencing, was ineffective to inhibit T24 cell viability compared with control (P > 0.05).	('lipofectamine', 'Chemical', 'MESH:C086724', (124, 137))	('silencing', 'Var', (18, 27))	('lipofectamine', 'MPA', (124, 137))	('decrease', 'NegReg', (61, 69))	('silencing', 'NegReg', (225, 234))	('T24 cell', 'CPA', (263, 271))	('toxicity', 'Disease', 'MESH:D064420', (138, 146))	('Arecaidine', 'Chemical', 'MESH:C015688', (196, 206))	('muM', 'Gene', '56925', (191, 194))	('toxicity', 'Disease', (138, 146))	('cell number', 'CPA', (73, 84))	('muM', 'Gene', (191, 194))
22819	25482946	To further confirm the involvement of M2 receptors in the decrease of cell proliferation, we treated the T24 cell line with the M1 or M3 antagonists (10-6M pirenzepine and 10-8M 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide [4-DAMP], respectively).	('pirenzepine', 'Chemical', 'MESH:D010890', (156, 167))	('cell proliferation', 'biological_process', 'GO:0008283', ('70', '88'))	('cell proliferation', 'CPA', (70, 88))	('10-6M', 'Var', (150, 155))	('4-DAMP', 'Chemical', 'MESH:C042375', (229, 235))	('1,1-dimethyl-4-diphenylacetoxypiperidinium iodide', 'Chemical', 'MESH:C042375', (178, 227))
22856	25482946	In fact, after siRNA transfection the M2 receptor expression was completely abolished in T24 cells, and the T24 cell proliferation appeared unmodified after Arecaidine treatment.	('M2 receptor', 'Protein', (38, 49))	('transfection', 'Var', (21, 33))	('abolished', 'NegReg', (76, 85))	('Arecaidine', 'Chemical', 'MESH:C015688', (157, 167))	('cell proliferation', 'biological_process', 'GO:0008283', ('112', '130'))	('expression', 'MPA', (50, 60))
22858	25482946	Interestingly, in presence of M3 antagonist we observed that the Arecaidine effect was enhanced, suggesting either that high doses of Arecaidine bind a lesser extend M3 receptors and that on the other the block of the M3 receptor enhances the Arecaidine mediated effect.	('Arecaidine', 'Chemical', 'MESH:C015688', (134, 144))	('Arecaidine', 'Chemical', 'MESH:C015688', (243, 253))	('enhances', 'PosReg', (230, 238))	('Arecaidine', 'Chemical', 'MESH:C015688', (65, 75))	('M3 receptors', 'Protein', (166, 178))	('Arecaidine mediated effect', 'MPA', (243, 269))	('block', 'Var', (205, 210))
22916	26539377	No atypical or malignant cells are seen in three consecutive specimen of urine for cytology His renal function tests were markedly deranged, with blood urea 346 mg/dl, serum creatinine 25 mg/dl and deranged electrolytes.	('creatinine', 'Chemical', 'MESH:D003404', (174, 184))	('deranged', 'Reg', (131, 139))	('deranged electrolytes', 'Phenotype', 'HP:0003111', (198, 219))	('urea', 'Chemical', 'MESH:D014508', (152, 156))	('346 mg/dl', 'Var', (157, 166))	('electrolytes', 'MPA', (207, 219))	('deranged', 'Reg', (198, 206))	('blood urea', 'MPA', (146, 156))	('renal function tests', 'MPA', (96, 116))	('serum creatinine', 'MPA', (168, 184))
22923	26539377	Immunohistochemistry was done for CD138, cytokeratin (CK) CK7, leukocyte common antigen (LCA), kappa and lambda light chain, with positivity for CK7, CD138 [Figures 2 and 3] and negative for other markers.	('positivity', 'Var', (130, 140))	('CK7', 'Gene', '3855', (145, 148))	('CD138', 'Gene', (34, 39))	('CD138', 'Gene', '6382', (150, 155))	('CK7', 'Gene', (58, 61))	('CD138', 'Gene', '6382', (34, 39))	('CK7', 'Gene', '3855', (58, 61))	('CK7', 'Gene', (145, 148))	('CD138', 'Gene', (150, 155))
22959	23870731	Immunostaining for cytokeratin (CK) 7, CK20 and Ki-67 confirmed that CK7: (-), CK20: (+) and Ki-67: (<=30%) in villous adenoma while CK7: (+), CK20: (+), and Ki-67: (70%) in urothelial carcinoma.	('CK7', 'Gene', '3855', (69, 72))	('Ki-67', 'Chemical', '-', (158, 163))	('urothelial carcinoma', 'Disease', (174, 194))	('Ki-67', 'Chemical', '-', (93, 98))	('CK20', 'Gene', (143, 147))	('CK20', 'Gene', (79, 83))	('villous adenoma', 'Disease', 'MESH:D018253', (111, 126))	('CK20', 'Gene', (39, 43))	('CK20', 'Gene', '54474', (143, 147))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (174, 194))	('villous adenoma', 'Disease', (111, 126))	('CK20', 'Gene', '54474', (79, 83))	('Ki-67', 'Var', (93, 98))	('CK7', 'Gene', (133, 136))	('cytokeratin (CK) 7', 'Gene', '3855', (19, 37))	('CK7', 'Gene', (69, 72))	('CK20', 'Gene', '54474', (39, 43))	('cytokeratin (CK) 7', 'Gene', (19, 37))	('Ki-67', 'Chemical', '-', (48, 53))	('CK7', 'Gene', '3855', (133, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
23005	23870731	Ki-67 is associated with the growth fraction of a given human cell subset.	('Ki-67', 'Var', (0, 5))	('Ki-67', 'Chemical', '-', (0, 5))	('growth fraction', 'CPA', (29, 44))	('human', 'Species', '9606', (56, 61))	('associated', 'Reg', (9, 19))
23009	23870731	reported that Ki-67 and CK20 could be potential prognostic markers improving the risk stratification of pT1 bladder tumors.	('bladder tumors', 'Phenotype', 'HP:0009725', (108, 122))	('CK20', 'Gene', (24, 28))	('bladder tumors', 'Disease', (108, 122))	('CK20', 'Gene', '54474', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('Ki-67', 'Var', (14, 19))	('pT1', 'Gene', (104, 107))	('Ki-67', 'Chemical', '-', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('bladder tumors', 'Disease', 'MESH:D001749', (108, 122))	('pT1', 'Gene', '58492', (104, 107))
23039	33865196	His history was remarkable for bladder urothelial carcinoma cTisN0M0, high grade status post-transurethral resection of a bladder tumor and two-times instillation chemotherapy with intravesical 81 mg Bacillus Calmette-Guerin once a week 2 years earlier.	('bladder tumor', 'Disease', (122, 135))	('bladder urothelial carcinoma', 'Disease', (31, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('Bacillus Calmette-Guerin', 'Species', '33892', (200, 224))	('bladder tumor', 'Disease', 'MESH:D001749', (122, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('bladder tumor', 'Phenotype', 'HP:0009725', (122, 135))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (31, 59))	('cTisN0M0', 'Var', (60, 68))
23077	33430305	Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1, MSH2, MSH6, and PMS2, and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis.	('men', 'Species', '9606', (145, 148))	('MLH1', 'Gene', '4292', (64, 68))	('MMR', 'biological_process', 'GO:0006298', ('17', '20'))	('variants', 'Var', (52, 60))	('PMS2', 'Gene', (86, 90))	('Mismatch repair', 'biological_process', 'GO:0006298', ('0', '15'))	('microsatellite', 'MPA', (96, 110))	('MSH2', 'Gene', (70, 74))	('carcinogenesis', 'Disease', (184, 198))	('Lynch syndrome', 'Disease', (153, 167))	('MSH6', 'Gene', (76, 80))	('PMS2', 'Gene', '5395', (86, 90))	('MSH6', 'Gene', '2956', (76, 80))	('deficiency', 'Disease', 'MESH:D007153', (22, 32))	('MSH2', 'Gene', '4436', (70, 74))	('carcinogenesis', 'Disease', 'MESH:D063646', (184, 198))	('MLH1', 'Gene', (64, 68))	('Lynch syndrome', 'Disease', 'MESH:D003123', (153, 167))	('deficiency', 'Disease', (22, 32))
23079	33430305	The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers.	('cancer', 'Disease', (148, 154))	('mutation', 'Var', (215, 223))	('MMR', 'Gene', (51, 54))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('loss', 'NegReg', (101, 105))	('developing UC', 'Disease', (193, 206))	('MSH2', 'Gene', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('MSH2', 'Gene', '4436', (210, 214))	('MMR', 'biological_process', 'GO:0006298', ('51', '54'))	('function', 'MPA', (92, 100))
23084	33430305	The following medical subject heading terms were used to identify the results suitable to our review topic: Lynch syndrome, urothelial cancer, upper urinary tract, mismatch repair genes, microsatellite instability, immunotherapy, checkpoint inhibitor.	('Lynch syndrome', 'Disease', (108, 122))	('Lynch syndrome', 'Disease', 'MESH:D003123', (108, 122))	('mismatch repair genes', 'Gene', (164, 185))	('microsatellite instability', 'Var', (187, 213))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('urothelial cancer', 'Disease', (124, 141))	('upper urinary tract', 'Disease', (143, 162))	('mismatch repair', 'biological_process', 'GO:0006298', ('164', '179'))	('urothelial cancer', 'Disease', 'MESH:D014523', (124, 141))
23085	33430305	Sporadic colon cancer is often linked to point mutations in tumor suppressor genes such as p53 and APC, which are less represented in LS.	('APC', 'Disease', 'MESH:D011125', (99, 102))	('colon cancer', 'Phenotype', 'HP:0003003', (9, 21))	('Sporadic colon cancer', 'Disease', 'MESH:D015179', (0, 21))	('linked', 'Reg', (31, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('APC', 'Disease', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('point mutations', 'Var', (41, 56))	('Sporadic colon cancer', 'Disease', (0, 21))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('APC', 'cellular_component', 'GO:0005680', ('99', '102'))	('tumor', 'Disease', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))
23086	33430305	After the onset of MMR in LS, mutations in the KRAS gene commonly occur, followed by APC mutations.	('APC', 'Disease', 'MESH:D011125', (85, 88))	('APC', 'Disease', (85, 88))	('occur', 'Reg', (66, 71))	('MMR', 'biological_process', 'GO:0006298', ('19', '22'))	('mutations', 'Var', (30, 39))	('KRAS', 'Gene', (47, 51))	('KRAS', 'Gene', '3845', (47, 51))	('APC', 'cellular_component', 'GO:0005680', ('85', '88'))
23088	33430305	Its underlying mechanism is a germline variant of DNA mismatch repair (MMR) genes, which are found in 88% to 95% of patients diagnosed with this disorder.	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('patients', 'Species', '9606', (116, 124))	('MMR) genes', 'Gene', (71, 81))	('germline variant', 'Var', (30, 46))	('mismatch repair', 'biological_process', 'GO:0006298', ('54', '69'))	('MMR', 'biological_process', 'GO:0006298', ('71', '74'))	('DNA', 'Gene', (50, 53))
23089	33430305	Additionally, EPCAM, which is a gene adjacent to MSH2 that when mutated can cause the MSH2 to be inactivated, constitutes for about 3% of LS cases.	('inactivated', 'MPA', (97, 108))	('MSH2', 'Gene', '4436', (86, 90))	('MSH2', 'Gene', (49, 53))	('MSH2', 'Gene', (86, 90))	('EPCAM', 'Gene', (14, 19))	('MSH2', 'Gene', '4436', (49, 53))	('mutated', 'Var', (64, 71))	('EPCAM', 'Gene', '4072', (14, 19))
23090	33430305	MMR is one of the essential factors in preventing cancer development in a biological system, as it corrects miss-paired DNA insertions and replication errors and serves as a checkpoint to maintain vital genomic stability by restoring improperly assembled single-base matches during replication.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('miss-paired', 'Var', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('men', 'Species', '9606', (64, 67))	('MMR', 'biological_process', 'GO:0006298', ('0', '3'))	('improperly assembled single-base matches', 'MPA', (234, 274))	('restoring', 'PosReg', (224, 233))
23096	33430305	MutLalpha then promotes the excision of the mismatched locus, which is performed by proteins such as exonuclease-1 and DNA polymerase, and DNA ligase resynthesize and ligate the DNA strand.	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('exonuclease-1', 'Gene', (101, 114))	('exonuclease-1', 'Gene', '9156', (101, 114))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('MutLalpha', 'Var', (0, 9))	('excision', 'MPA', (28, 36))	('mismatched', 'Var', (44, 54))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('promotes', 'PosReg', (15, 23))
23097	33430305	Any defect in these proteins results in an inactive DNA repair process, which increases pathogenic alteration rates in genes of the cell growth cycle, leading to defects in tumor suppressor genes and oncogenes, followed by an elevated cancer risk.	('elevated cancer', 'Disease', 'MESH:D006973', (226, 241))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('oncogenes', 'Gene', (200, 209))	('defects', 'NegReg', (162, 169))	('cell growth', 'biological_process', 'GO:0016049', ('132', '143'))	('genes of', 'Gene', (119, 127))	('tumor suppressor', 'biological_process', 'GO:0051726', ('173', '189'))	('elevated cancer', 'Disease', (226, 241))	('tumor', 'Disease', (173, 178))	('inactive', 'MPA', (43, 51))	('pathogenic alteration rates', 'MPA', (88, 115))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('173', '189'))	('increases', 'PosReg', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('defect', 'Var', (4, 10))	('DNA repair', 'biological_process', 'GO:0006281', ('52', '62'))
23098	33430305	Insufficient MMR and subsequent variation in the number of nucleotides in a microsatellite region, defined as small repetitive DNA sequences, is referred to as microsatellite instability (MSI), which is present in approximately 95% for of all tumors associated with LS.	('variation', 'Var', (32, 41))	('tumors', 'Disease', (243, 249))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))	('MMR', 'biological_process', 'GO:0006298', ('13', '16'))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
23102	33430305	Interestingly, current findings from the prospective LS database confirmed distinct gene and gender-specific patterns of cancer risk depending on the affected MMR pathogenic variant carrier in LS patients.	('MMR', 'Gene', (159, 162))	('carrier', 'molecular_function', 'GO:0005215', ('182', '189'))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('patients', 'Species', '9606', (196, 204))	('variant', 'Var', (174, 181))	('MMR', 'biological_process', 'GO:0006298', ('159', '162'))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
23103	33430305	In detail, MSH2 pathogenic variant carriers confirmed a higher risk of UC of the UUT.	('MSH2', 'Gene', '4436', (11, 15))	('variant', 'Var', (27, 34))	('MSH2', 'Gene', (11, 15))
23105	33430305	Interestingly, neither urinary tract cancers, nor colorectal or endometrial cancer (EC), were observed before the age of 50 in carriers of a PMS2 variant.	('variant', 'Var', (146, 153))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (23, 43))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('PMS2', 'Gene', (141, 145))	('cancers', 'Disease', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('carriers', 'Reg', (127, 135))	('EC', 'Phenotype', 'HP:0012114', (84, 86))	('PMS2', 'Gene', '5395', (141, 145))	('endometrial cancer', 'Phenotype', 'HP:0012114', (64, 82))	('colorectal or endometrial cancer', 'Disease', (50, 82))	('colorectal or endometrial cancer', 'Disease', 'MESH:D015179', (50, 82))
23106	33430305	At older age, it has been shown that germline pathological variants of MSH2 and MLH1 are even more associated with urinary tract cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('associated with', 'Reg', (99, 114))	('MSH2', 'Gene', '4436', (71, 75))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (115, 135))	('variants', 'Var', (59, 67))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('MLH1', 'Gene', '4292', (80, 84))	('MLH1', 'Gene', (80, 84))	('MSH2', 'Gene', (71, 75))
23108	33430305	Additionally, the MSH6 pathogenic variant seems to be a gender-specific factor in cancer susceptibility with higher EC risk, but only a low risk of colon cancer in both sexes.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('colon cancer', 'Disease', (148, 160))	('MSH6', 'Gene', (18, 22))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('MSH6', 'Gene', '2956', (18, 22))	('variant', 'Var', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('colon cancer', 'Phenotype', 'HP:0003003', (148, 160))	('colon cancer', 'Disease', 'MESH:D015179', (148, 160))	('EC', 'Phenotype', 'HP:0012114', (116, 118))
23109	33430305	The findings result in cumulative incidences at an age of 75 years for urinary tract cancers with MLH1, MSH2, and MSH6 variants in 8%, 25%, and 11%, respectively, suggesting that MSH2 pathogenic variant carriers were at significant increased risk of developing UC compared with individuals with pathogenic germline variants in MLH1 or MSH6.	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('MSH6', 'Gene', '2956', (335, 339))	('MSH2', 'Gene', '4436', (104, 108))	('variants', 'Var', (119, 127))	('MSH2', 'Gene', (179, 183))	('MLH1', 'Gene', (98, 102))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('MLH1', 'Gene', (327, 331))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (71, 91))	('MLH1', 'Gene', '4292', (98, 102))	('MSH2', 'Gene', '4436', (179, 183))	('MSH6', 'Gene', (114, 118))	('MSH2', 'Gene', (104, 108))	('variant', 'Var', (195, 202))	('MLH1', 'Gene', '4292', (327, 331))	('MSH6', 'Gene', '2956', (114, 118))	('MSH6', 'Gene', (335, 339))
23112	33430305	Additionally, it has been demonstrated that tumors with MSI due to defects in MMR proteins often present with high Th1 type T-cell infiltration.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('MMR proteins', 'Protein', (78, 90))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('defects', 'Var', (67, 74))	('MMR', 'biological_process', 'GO:0006298', ('78', '81'))	('present', 'Reg', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
23114	33430305	A detailed overview of incidence rates of LS-associated cancers at 75 years depending on the involved MMR gene mutation is presented in Figure 3.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('mutation', 'Var', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('MMR', 'biological_process', 'GO:0006298', ('102', '105'))	('MMR', 'Gene', (102, 105))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
23126	33430305	However, IHC cannot differentiate between dysfunctional proteins deriving from either missense mutations or polypeptides.	('dysfunctional proteins', 'Disease', 'MESH:D001796', (42, 64))	('dysfunctional proteins', 'Disease', (42, 64))	('missense mutations', 'Var', (86, 104))
23130	33430305	Pathogenic variants in MSH2 will result in disintegration to missense of both MSH2 and MSH6.	('MSH2', 'Gene', (78, 82))	('MSH2', 'Gene', (23, 27))	('MSH6', 'Gene', (87, 91))	('MSH2', 'Gene', '4436', (78, 82))	('MSH2', 'Gene', '4436', (23, 27))	('result in', 'Reg', (33, 42))	('variants', 'Var', (11, 19))	('Pathogenic', 'Reg', (0, 10))	('MSH6', 'Gene', '2956', (87, 91))	('missense', 'MPA', (61, 69))	('disintegration', 'MPA', (43, 57))
23131	33430305	On the other hand, pathogenic variants in the secondary genes MSH6 and PMS2 result in selective loss of only these genes, as additionally summarized in Table 4.	('variants', 'Var', (30, 38))	('MSH6', 'Gene', (62, 66))	('PMS2', 'Gene', '5395', (71, 75))	('MSH6', 'Gene', '2956', (62, 66))	('PMS2', 'Gene', (71, 75))	('loss', 'NegReg', (96, 100))
23132	33430305	IHC should therefore include antibodies of all four proteins in order to detect as many as MLH1 and MSH2 abnormalities as possible.	('detect', 'Reg', (73, 79))	('MLH1', 'Gene', '4292', (91, 95))	('abnormalities', 'Var', (105, 118))	('MSH2', 'Gene', (100, 104))	('MLH1', 'Gene', (91, 95))	('MSH2', 'Gene', '4436', (100, 104))
23133	33430305	IHC for MMR proteins should not replace MSI testing to detect LS, encouraging a so called 'combined diagnostic molecular concept', as IHC interpretation may be difficult due to inter- and intraobserver variability, missense mutations, or low or absent intensity of nuclear staining in tumors and normal tissue.	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('missense mutations', 'Var', (215, 233))	('MMR', 'biological_process', 'GO:0006298', ('8', '11'))	('tumors', 'Disease', 'MESH:D009369', (285, 291))	('tumors', 'Disease', (285, 291))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))
23137	33430305	Currently, in addition to MLH1 and MSH2, whose testing was introduced in 1990s, mutations in the genes MSH6, PMS2, and EPCAM are now also included in testing of individuals suspected to have LS.	('MSH6', 'Gene', (103, 107))	('mutations', 'Var', (80, 89))	('MLH1', 'Gene', '4292', (26, 30))	('MLH1', 'Gene', (26, 30))	('EPCAM', 'Gene', (119, 124))	('MSH6', 'Gene', '2956', (103, 107))	('PMS2', 'Gene', (109, 113))	('MSH2', 'Gene', (35, 39))	('EPCAM', 'Gene', '4072', (119, 124))	('MSH2', 'Gene', '4436', (35, 39))	('PMS2', 'Gene', '5395', (109, 113))
23141	33430305	Combined testing allows the simultaneous diagnosis of LS and describes atypical IHC patterns in patients where germline pathogenic variants were not concordant with specific protein expression, e.g., double somatic mutations, which explain IHC staining in addition to a germline mutation in a different LS gene.	('variants', 'Var', (131, 139))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('double somatic mutations', 'Var', (200, 224))	('patients', 'Species', '9606', (96, 104))
23142	33430305	Moreover, solely tumor sequencing for germline screening is limited in detecting exon-level somatic copy number variants in regions with significant pseudogene homology such as the PMS2 pseudogene region.	('PMS2', 'Gene', (181, 185))	('tumor', 'Disease', (17, 22))	('PMS2', 'Gene', '5395', (181, 185))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('variants', 'Var', (112, 120))
23151	33430305	Comparison of next-generation sequencing of high-grade UUT cancer with high-grade UC of the bladder identified similar pathogenic germline variants in both cancer types, but at different frequencies, confirming a higher prevalence of fibroblast growth factor receptor 3 (FGFR3), HRAS and CDKN2B mutated genes in high-grade UUT cancers, and TP53 and RB1 in high-grade UC of the bladder.	('TP53', 'Gene', (340, 344))	('FGFR3', 'Gene', '2261', (271, 276))	('higher', 'PosReg', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('CDKN2B', 'Gene', '1030', (288, 294))	('variants', 'Var', (139, 147))	('cancers', 'Phenotype', 'HP:0002664', (327, 334))	('fibroblast growth factor receptor 3', 'Gene', '2261', (234, 269))	('cancer', 'Disease', (327, 333))	('RB1', 'Gene', '5925', (349, 352))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('high-grade UC', 'Disease', (356, 369))	('UUT cancers', 'Disease', 'MESH:D009369', (323, 334))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('TP53', 'Gene', '7157', (340, 344))	('UUT cancers', 'Disease', (323, 334))	('HRAS', 'Gene', '3265', (279, 283))	('HRAS', 'Gene', (279, 283))	('FGFR', 'molecular_function', 'GO:0005007', ('271', '275'))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('234', '258'))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('cancer', 'Disease', (156, 162))	('fibroblast growth factor receptor 3', 'Gene', (234, 269))	('CDKN2B', 'Gene', (288, 294))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('FGFR3', 'Gene', (271, 276))	('RB1', 'Gene', (349, 352))	('cancer', 'Disease', (59, 65))
23154	33430305	Whereas sporadic low-grade UC of the UUT is FGFR3 mutated in over 90%, high-grade UC of the UUT is associated with TP53/MDM2 mutations.	('high-grade UC', 'Disease', (71, 84))	('mutations', 'Var', (125, 134))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('FGFR3', 'Gene', (44, 49))	('TP53', 'Gene', '7157', (115, 119))	('MDM2', 'Gene', '4193', (120, 124))	('MDM2', 'Gene', (120, 124))	('mutated', 'Var', (50, 57))	('TP53', 'Gene', (115, 119))	('FGFR3', 'Gene', '2261', (44, 49))	('low-grade UC of the UUT', 'Disease', (17, 40))	('associated', 'Reg', (99, 109))
23156	33430305	MMR protein loss has been shown to be present in 7% of all UUT cancer cases and 30% in LS-related UC of the UUT, in this cohort of patients with UUT urothelial cancers and verified loss of mismatch repair protein expression, up to 86% were affected in loss of MSH2 and MSH6, with the remaining 14% showing isolated loss of MSH6.	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('UUT urothelial cancers', 'Disease', (145, 167))	('cancer', 'Disease', (160, 166))	('MSH6', 'Gene', (323, 327))	('loss', 'NegReg', (12, 16))	('MSH6', 'Gene', (269, 273))	('MSH6', 'Gene', '2956', (323, 327))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('MSH6', 'Gene', '2956', (269, 273))	('loss', 'Var', (252, 256))	('MMR', 'biological_process', 'GO:0006298', ('0', '3'))	('cancer', 'Disease', (63, 69))	('patients', 'Species', '9606', (131, 139))	('MSH2', 'Gene', (260, 264))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('affected', 'Reg', (240, 248))	('UUT urothelial cancers', 'Disease', 'MESH:D014523', (145, 167))	('MSH2', 'Gene', '4436', (260, 264))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('mismatch repair', 'biological_process', 'GO:0006298', ('189', '204'))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
23157	33430305	Cases with MSH2 variants were shown to have the highest risk of developing UC, with an odds ratio of 4.6 (p = 0.001).	('MSH2', 'Gene', '4436', (11, 15))	('variants', 'Var', (16, 24))	('MSH2', 'Gene', (11, 15))
23161	33430305	Generally, it has been shown that bladder cancer generally was more common in MSH2 variant families than in the general population.	('variant', 'Var', (83, 90))	('MSH2', 'Gene', (78, 82))	('MSH2', 'Gene', '4436', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('bladder cancer', 'Disease', 'MESH:D001749', (34, 48))	('bladder cancer', 'Disease', (34, 48))	('common', 'Reg', (68, 74))
23163	33430305	Especially amongst patients with MSH2 pathogenic variants, the incidence not only for UC of the UUT, but also for bladder cancer, has shown to be increased.	('bladder cancer', 'Disease', 'MESH:D001749', (114, 128))	('bladder cancer', 'Disease', (114, 128))	('patients', 'Species', '9606', (19, 27))	('variants', 'Var', (49, 57))	('increased', 'PosReg', (146, 155))	('UC of the UUT', 'Disease', (86, 99))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('bladder cancer', 'Phenotype', 'HP:0009725', (114, 128))	('MSH2', 'Gene', (33, 37))	('MSH2', 'Gene', '4436', (33, 37))
23165	33430305	confirmed an increased risk of UC of both the UUT and the bladder in patients with LS carrying a germline MSH2 variant.	('patients', 'Species', '9606', (69, 77))	('variant', 'Var', (111, 118))	('MSH2', 'Gene', (106, 110))	('MSH2', 'Gene', '4436', (106, 110))
23166	33430305	The cumulative risk of bladder cancer alone until the age of 70 years in MSH2 pathogenic variant carriers and first-degree relatives was 12.3% for men and 2.6% for women.	('bladder cancer', 'Disease', 'MESH:D001749', (23, 37))	('bladder cancer', 'Disease', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('men', 'Species', '9606', (166, 169))	('MSH2', 'Gene', (73, 77))	('variant', 'Var', (89, 96))	('MSH2', 'Gene', '4436', (73, 77))	('women', 'Species', '9606', (164, 169))	('bladder cancer', 'Phenotype', 'HP:0009725', (23, 37))	('men', 'Species', '9606', (147, 150))
23167	33430305	The overall cumulative risk for urinary tract cancer, including bladder and UUT, in MSH2 germline variant carriers and first-degree relatives was 18.2% in men and 8.4% in women.	('men', 'Species', '9606', (155, 158))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('women', 'Species', '9606', (171, 176))	('men', 'Species', '9606', (173, 176))	('bladder', 'Disease', (64, 71))	('variant', 'Var', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('UUT', 'Disease', (76, 79))	('MSH2', 'Gene', (84, 88))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (32, 52))	('MSH2', 'Gene', '4436', (84, 88))
23172	33430305	In patients who underwent nephroureterectomy due to invasive UC of the UUT, a high MSI incidence (17%) was an independent positive prognostic factor for survival, especially in patients younger than 71 years with tumor stage T2-T3N0M0.	('tumor', 'Disease', (213, 218))	('T2-T3N0M0', 'Var', (225, 234))	('patients', 'Species', '9606', (177, 185))	('invasive UC', 'Disease', (52, 63))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))
23173	33430305	Five-year and 10-year survival rates for LS-associated bladder cancer with germline pathogenic variants in any of the four MMR genes were very promising with 93% and 81%, respectively.	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('bladder cancer', 'Disease', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('MMR', 'Gene', (123, 126))	('variants', 'Var', (95, 103))	('MMR', 'biological_process', 'GO:0006298', ('123', '126'))
23177	33430305	Furthermore, specific histopathological features, such as pleomorphism, inverted growth, and intratumoral lymphocytes, were associated with the presence of LS.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('associated', 'Reg', (124, 134))	('pleomorphism', 'Var', (58, 70))	('inverted growth', 'CPA', (72, 87))	('tumor', 'Disease', (98, 103))
23187	33430305	European guidelines for managing patients with MMR mutations recommend sonography and urine analysis every one to two years from the age of 30 only in family constellations of two or more UC of the UUT cases.	('men', 'Species', '9606', (66, 69))	('mutations', 'Var', (51, 60))	('patients', 'Species', '9606', (33, 41))	('MMR', 'Gene', (47, 50))	('MMR', 'biological_process', 'GO:0006298', ('47', '50'))
23193	33430305	Special attention should be put on surveillance of UC of the bladder in patients with a verified MSH2 variant, as the association between MSH2 and UC has evolved in the past.	('MSH2', 'Gene', (138, 142))	('variant', 'Var', (102, 109))	('MSH2', 'Gene', (97, 101))	('MSH2', 'Gene', '4436', (138, 142))	('MSH2', 'Gene', '4436', (97, 101))	('patients', 'Species', '9606', (72, 80))
23194	33430305	In literature, recommendations for UC surveillance in LS are defined as ultrasound of the bladder and UUT with urine cytology and sediment in every MSH2 mutation carrier starting at age 40 and above, performed every one to two years.	('MSH2', 'Gene', (148, 152))	('MSH2', 'Gene', '4436', (148, 152))	('carrier', 'molecular_function', 'GO:0005215', ('162', '169'))	('men', 'Species', '9606', (20, 23))	('mutation', 'Var', (153, 161))	('men', 'Species', '9606', (134, 137))
23226	33430305	With the knowledge that MSH6 expression can be retained in absence of MSH2 staining and given the clinical suspicion for LS, this patient was assigned to germline testing:confirming a germline MSH2 mutation, and therefore LS.	('MSH6', 'Gene', (24, 28))	('patient', 'Species', '9606', (130, 137))	('MSH6', 'Gene', '2956', (24, 28))	('MSH2', 'Gene', (70, 74))	('MSH2', 'Gene', (193, 197))	('MSH2', 'Gene', '4436', (70, 74))	('MSH2', 'Gene', '4436', (193, 197))	('mutation', 'Var', (198, 206))
23235	33430305	Urological surveillance in LS should include imaging of the UUT, urine analysis, cytology, and cystoscopy, especially in patients with MSH2 germline variants.	('MSH2', 'Gene', (135, 139))	('MSH2', 'Gene', '4436', (135, 139))	('patients', 'Species', '9606', (121, 129))	('germline', 'Var', (140, 148))
23248	30918102	Patients who with high UCA1 expression suffered from an increased risk of LNM (OR = 2.50; 95% CI: 1.93-3.25).	('UCA1', 'Gene', '652995', (23, 27))	('UCA1', 'Gene', (23, 27))	('LNM', 'Disease', (74, 77))	('Patients', 'Species', '9606', (0, 8))	('high', 'Var', (18, 22))
23251	30918102	Conclusion: High expression of UCA1 was linked with poor clinical outcome.	('linked', 'Reg', (40, 46))	('High', 'Var', (12, 16))	('UCA1', 'Gene', '652995', (31, 35))	('UCA1', 'Gene', (31, 35))
23265	30918102	Studies have shown that the dysregulation of UCA1 is closely associated with the clinicopathological characteristics of cancer, such as lymph node metastasis (LNM) and overall survival (OS).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lymph node metastasis', 'Disease', (136, 157))	('overall survival', 'CPA', (168, 184))	('OS', 'Chemical', '-', (186, 188))	('cancer', 'Disease', (120, 126))	('dysregulation', 'Var', (28, 41))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('UCA1', 'Gene', '652995', (45, 49))	('UCA1', 'Gene', (45, 49))	('associated', 'Reg', (61, 71))
23283	30918102	The result indicated that patients with high UCA1 expression in cancer tissues were more susceptible to LNM.	('high', 'Var', (40, 44))	('LNM', 'Disease', (104, 107))	('susceptible', 'Reg', (89, 100))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('patients', 'Species', '9606', (26, 34))	('UCA1', 'Gene', '652995', (45, 49))	('UCA1', 'Gene', (45, 49))	('expression', 'MPA', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
23284	30918102	A total of 36 studies including 3146 patients were assessed for the correlation between UCA1 and OS (Table 2), High UCA1 expression was significantly correlated with poor prognosis, compared with low UCA1 expression in a pooled analysis of all studies (HR = 2.05; 95% CI: 1.77-2.38; P<0.00001) (Figure 3).	('UCA1', 'Gene', '652995', (200, 204))	('patients', 'Species', '9606', (37, 45))	('UCA1', 'Gene', (200, 204))	('UCA1', 'Gene', '652995', (88, 92))	('expression', 'MPA', (121, 131))	('UCA1', 'Gene', (88, 92))	('OS', 'Chemical', '-', (97, 99))	('High', 'Var', (111, 115))	('UCA1', 'Gene', '652995', (116, 120))	('UCA1', 'Gene', (116, 120))
23285	30918102	In other words, high UCA1 expression group shortened the OS compared with low UCA1 expression group.	('shortened', 'NegReg', (43, 52))	('high', 'Var', (16, 20))	('UCA1', 'Gene', '652995', (78, 82))	('UCA1', 'Gene', (78, 82))	('OS', 'Chemical', '-', (57, 59))	('UCA1', 'Gene', '652995', (21, 25))	('UCA1', 'Gene', (21, 25))
23288	30918102	Subgroup analysis by sample size explored that high UCA1 expression status was related to high LNM numbers both in big (n>=100, OR = 1.99, 95% CI: 1.50-2.65, P<0.0001) and small sample size group (n<100, OR = 2.71, 95% CI: 2.12-3.47, P<0.00001).	('UCA1', 'Gene', '652995', (52, 56))	('expression', 'MPA', (57, 67))	('UCA1', 'Gene', (52, 56))	('high LNM numbers', 'CPA', (90, 106))	('high', 'Var', (47, 51))	('related', 'Reg', (79, 86))
23290	30918102	However, when conducting subgroup analyses on tumor type, we found no significant correlation between high UCA1 expression and LNM among the studies in respiratory system (OR = 2.54, 95% CI: 0.70-9.23, P=0.16).	('UCA1', 'Gene', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('expression', 'MPA', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('high', 'Var', (102, 106))	('tumor', 'Disease', (46, 51))	('UCA1', 'Gene', '652995', (107, 111))	('LNM', 'Disease', (127, 130))
23293	30918102	Subgroup analysis by sample size, cut-off value, follow-up time, analysis method and reference control all revealed that high UCA1 expression was significantly associated with poor OS in each groups.	('OS', 'Chemical', '-', (181, 183))	('high', 'Var', (121, 125))	('expression', 'MPA', (131, 141))	('poor OS', 'Disease', (176, 183))	('UCA1', 'Gene', '652995', (126, 130))	('UCA1', 'Gene', (126, 130))	('associated', 'Reg', (160, 170))
23294	30918102	However, when conducting subgroup analyses on tumor type, we found high UCA1 expression was remarkably related to poor OS among respiratory system, digestive system, reproductive system and other systems but no significant correlation between high UCA1 expression and OS among the studies in urinary system (HR = 1.54, 95% CI: 0.98-2.40, P=0.06).	('UCA1', 'Gene', '652995', (72, 76))	('expression', 'MPA', (77, 87))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('UCA1', 'Gene', (72, 76))	('high', 'Var', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('OS', 'Chemical', '-', (268, 270))	('tumor', 'Disease', (46, 51))	('OS', 'Chemical', '-', (119, 121))	('UCA1', 'Gene', '652995', (248, 252))	('UCA1', 'Gene', (248, 252))
23306	30918102	Several literatures established a statistically significant relationship between high UCA1 expression and lymph node metastasis or prognosis.	('UCA1', 'Gene', '652995', (86, 90))	('expression', 'MPA', (91, 101))	('UCA1', 'Gene', (86, 90))	('high', 'Var', (81, 85))	('lymph node metastasis', 'CPA', (106, 127))	('significant', 'Reg', (48, 59))	('prognosis', 'CPA', (131, 140))
23307	30918102	Nevertheless, some studies showed no statistical impact of UCA1 dysregulation on cancer metastasis and prognosis.	('dysregulation', 'Var', (64, 77))	('cancer metastasis', 'Disease', 'MESH:D009362', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('UCA1', 'Gene', '652995', (59, 63))	('UCA1', 'Gene', (59, 63))	('cancer metastasis', 'Disease', (81, 98))
23310	30918102	The results of the current study demonstrated that high UCA1 expression level was positively related to increasing the risk of LNM in cancer patients.	('UCA1', 'Gene', '652995', (56, 60))	('UCA1', 'Gene', (56, 60))	('patients', 'Species', '9606', (141, 149))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('high', 'Var', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('expression', 'MPA', (61, 71))	('LNM', 'Disease', (127, 130))
23311	30918102	Moreover, we also identified that there was a significantly positive correlation between high UCA1 expression and short OS in cancer patients.	('UCA1', 'Gene', '652995', (94, 98))	('expression', 'MPA', (99, 109))	('positive', 'PosReg', (60, 68))	('UCA1', 'Gene', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('patients', 'Species', '9606', (133, 141))	('short OS', 'Disease', (114, 122))	('short OS', 'Disease', 'MESH:C567932', (114, 122))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('high', 'Var', (89, 93))
23329	30918102	Third, UCA1 overexpression could promote cancer metastasis by activation of metastasis-related genes including GRK2/ERK-MMP9, EZH2/AKT, p21/E-cadherin, iASPP, KLF4-KRT6/13, FGFR1/ERK and ZEB1/2-FSCN1.	('AKT', 'Gene', '207', (131, 134))	('FGFR1', 'Gene', '2260', (173, 178))	('E-cadherin', 'Gene', (140, 150))	('E-cadherin', 'Gene', '999', (140, 150))	('cadherin', 'molecular_function', 'GO:0008014', ('142', '150'))	('GRK2', 'molecular_function', 'GO:0047696', ('111', '115'))	('ERK', 'Gene', (116, 119))	('overexpression', 'Var', (12, 26))	('UCA1', 'Gene', '652995', (7, 11))	('KLF4', 'Gene', (159, 163))	('UCA1', 'Gene', (7, 11))	('ERK', 'Gene', (179, 182))	('cancer metastasis', 'Disease', (41, 58))	('GRK2', 'Gene', (111, 115))	('iASPP', 'Gene', '10848', (152, 157))	('p21', 'Gene', (136, 139))	('ZEB1', 'Gene', (187, 191))	('promote', 'PosReg', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('p21', 'Gene', '644914', (136, 139))	('MMP9', 'molecular_function', 'GO:0004229', ('120', '124'))	('FGFR', 'molecular_function', 'GO:0005007', ('173', '177'))	('ERK', 'molecular_function', 'GO:0004707', ('179', '182'))	('FSCN1', 'Gene', (194, 199))	('KRT6', 'Gene', '140807', (164, 168))	('ERK', 'Gene', '2048', (116, 119))	('ERK', 'Gene', '2048', (179, 182))	('GRK2', 'Gene', '156', (111, 115))	('FGFR1', 'Gene', (173, 178))	('EZH2', 'Gene', '2146', (126, 130))	('cancer metastasis', 'Disease', 'MESH:D009362', (41, 58))	('KRT6', 'Gene', (164, 168))	('EZH2', 'Gene', (126, 130))	('AKT', 'Gene', (131, 134))	('KLF4', 'Gene', '9314', (159, 163))	('activation', 'PosReg', (62, 72))	('iASPP', 'Gene', (152, 157))	('ZEB1', 'Gene', '6935', (187, 191))	('metastasis-related genes', 'Gene', (76, 100))	('FSCN1', 'Gene', '6624', (194, 199))	('MMP9', 'Gene', '4318', (120, 124))	('ERK', 'molecular_function', 'GO:0004707', ('116', '119'))	('MMP9', 'Gene', (120, 124))
23330	30918102	UCA1 overexpression could increase the metastatic ability of GC cells through regulating GRK2 protein stability by promoting Cbl-c-mediated GRK2 ubiquitination and degradation, thus activate the ERK-MMP9 signaling pathway.	('MMP9', 'Gene', '4318', (199, 203))	('MMP9', 'Gene', (199, 203))	('metastatic ability', 'CPA', (39, 57))	('degradation', 'biological_process', 'GO:0009056', ('164', '175'))	('ERK', 'molecular_function', 'GO:0004707', ('195', '198'))	('signaling pathway', 'biological_process', 'GO:0007165', ('204', '221'))	('activate', 'PosReg', (182, 190))	('ubiquitination', 'MPA', (145, 159))	('GRK2', 'Gene', (89, 93))	('degradation', 'MPA', (164, 175))	('overexpression', 'Var', (5, 19))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))	('ERK', 'Gene', (195, 198))	('promoting', 'PosReg', (115, 124))	('Cbl', 'Gene', (125, 128))	('protein', 'Protein', (94, 101))	('GRK2', 'Gene', '156', (89, 93))	('GC', 'Phenotype', 'HP:0012126', (61, 63))	('ERK', 'Gene', '2048', (195, 198))	('GRK2', 'Gene', (140, 144))	('Cbl', 'Gene', '867', (125, 128))	('MMP9', 'molecular_function', 'GO:0004229', ('199', '203'))	('GRK2', 'molecular_function', 'GO:0047696', ('140', '144'))	('GRK2', 'molecular_function', 'GO:0047696', ('89', '93'))	('GRK2', 'Gene', '156', (140, 144))	('UCA1', 'Gene', '652995', (0, 4))	('UCA1', 'Gene', (0, 4))	('increase', 'PosReg', (26, 34))
23331	30918102	Mechanically, UCA1 promoted the cell proliferation and metastasis of GBC by recruiting enhancer of zeste homolog 2 (EZH2) to the promoter of p21 and E-cadherin, and epigenetically suppressing their transcript.	('transcript', 'MPA', (198, 208))	('EZH2', 'Gene', (116, 120))	('promoted', 'PosReg', (19, 27))	('metastasis', 'CPA', (55, 65))	('EZH2', 'Gene', '2146', (116, 120))	('UCA1', 'Gene', '652995', (14, 18))	('enhancer of zeste homolog 2', 'Gene', '2146', (87, 114))	('p21', 'Gene', (141, 144))	('cell proliferation', 'biological_process', 'GO:0008283', ('32', '50'))	('E-cadherin', 'Gene', '999', (149, 159))	('p21', 'Gene', '644914', (141, 144))	('epigenetically', 'Var', (165, 179))	('enhancer of zeste homolog 2', 'Gene', (87, 114))	('cadherin', 'molecular_function', 'GO:0008014', ('151', '159'))	('cell proliferation', 'CPA', (32, 50))	('E-cadherin', 'Gene', (149, 159))	('UCA1', 'Gene', (14, 18))
23341	30918102	Meanwhile, shorter OS may be observed in the patients with high UCA1 expression.	('UCA1', 'Gene', '652995', (64, 68))	('high', 'Var', (59, 63))	('UCA1', 'Gene', (64, 68))	('patients', 'Species', '9606', (45, 53))	('OS', 'Chemical', '-', (19, 21))
23349	27322140	A synthetic androgen R1881 significantly reduced CDDP sensitivity in UMUC3, 647V-AR, or 5637-AR cells, and the addition of an anti-androgen hydroxyflutamide inhibited the effect of R1881.	('reduced', 'NegReg', (41, 48))	('CDDP sensitivity', 'MPA', (49, 65))	('AR', 'Gene', '367', (93, 95))	('hydroxyflutamide', 'Chemical', 'MESH:C014290', (140, 156))	('AR', 'Gene', '367', (81, 83))	('R1881', 'Var', (21, 26))	('CDDP', 'Chemical', '-', (49, 53))
23350	27322140	In these AR-positive cells, R1881 treatment also induced the expression levels of NF-kappaB, which is known to involve CDDP resistance, and its phosphorylated form, as well as nuclear translocation of NF-kappaB.	('NF-kappaB', 'Gene', (201, 210))	('induced', 'PosReg', (49, 56))	('NF-kappaB', 'Gene', (82, 91))	('AR', 'Gene', '367', (9, 11))	('nuclear translocation', 'MPA', (176, 197))	('CDDP', 'Chemical', '-', (119, 123))	('NF-kappaB', 'Gene', '4790', (201, 210))	('R1881', 'Var', (28, 33))	('NF-kappaB', 'Gene', '4790', (82, 91))	('expression levels', 'MPA', (61, 78))
23366	27322140	In addition, we have recently demonstrated, in bladder cancer cells, that androgens up-regulate ELK1, a transcription factor whose downstream target is c-fos proto-oncogene, and that ELK1 inactivation results in enhancement of the cytotoxic activity of CDDP.	('ELK1', 'Gene', '2002', (96, 100))	('transcription factor', 'molecular_function', 'GO:0000981', ('104', '124'))	('ELK1', 'Gene', '2002', (183, 187))	('cytotoxic activity', 'CPA', (231, 249))	('inactivation', 'Var', (188, 200))	('bladder cancer', 'Disease', 'MESH:D001749', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('bladder cancer', 'Phenotype', 'HP:0009725', (47, 61))	('bladder cancer', 'Disease', (47, 61))	('CDDP', 'Chemical', '-', (253, 257))	('enhancement', 'PosReg', (212, 223))	('up-regulate', 'PosReg', (84, 95))	('transcription', 'biological_process', 'GO:0006351', ('104', '117'))	('ELK1', 'Gene', (96, 100))	('ELK1', 'Gene', (183, 187))
23386	27322140	Similarly, in AR-positive cells, R1881 increased the expression of AR as well as that of NF-kappaB and its active form, phospho-NF-kappaB (p-NF-kappaB), and HF at least partially abolished the effect of R1881 on their expression (Figure 5).	('HF', 'Chemical', 'MESH:C014290', (157, 159))	('AR', 'Gene', '367', (14, 16))	('NF-kappaB', 'Gene', (128, 137))	('R1881', 'Var', (33, 38))	('NF-kappaB', 'Gene', '4790', (89, 98))	('AR', 'Gene', '367', (67, 69))	('NF-kappaB', 'Gene', (89, 98))	('NF-kappaB', 'Gene', '4790', (141, 150))	('increased', 'PosReg', (39, 48))	('expression', 'MPA', (53, 63))	('NF-kappaB', 'Gene', '4790', (128, 137))	('NF-kappaB', 'Gene', (141, 150))
23387	27322140	More remarkably, immunofluorescence that was performed to determine the localization of NF-kappaB showed its distribution predominantly in the cytoplasm of mock-treated cells and induction of its nuclear translocation by R1881 treatment in AR-positive cells, but not in AR-negative cells (Figure 6).	('nuclear translocation', 'MPA', (196, 217))	('induction', 'Reg', (179, 188))	('NF-kappaB', 'Gene', (88, 97))	('localization', 'biological_process', 'GO:0051179', ('72', '84'))	('AR', 'Gene', '367', (270, 272))	('cytoplasm', 'cellular_component', 'GO:0005737', ('143', '152'))	('AR', 'Gene', '367', (240, 242))	('NF-kappaB', 'Gene', '4790', (88, 97))	('R1881 treatment', 'Var', (221, 236))
23397	27322140	More strikingly, there was a strong correlation between p-NF-kappaB positivity and chemotherapy resistance (54% of responders vs. 81% of non-responders; P = 0.044).	('chemotherapy resistance', 'CPA', (83, 106))	('NF-kappaB', 'Gene', '4790', (58, 67))	('positivity', 'Var', (68, 78))	('NF-kappaB', 'Gene', (58, 67))
23405	27322140	Preclinical findings have suggested that ADT inhibits the growth of AR-positive bladder cancer [5-10, 13, 14, 16-18].	('ADT', 'Chemical', '-', (41, 44))	('bladder cancer', 'Disease', 'MESH:D001749', (80, 94))	('bladder cancer', 'Disease', (80, 94))	('inhibits', 'NegReg', (45, 53))	('ADT', 'cellular_component', 'GO:0030956', ('41', '44'))	('growth', 'MPA', (58, 64))	('AR', 'Gene', '367', (68, 70))	('bladder cancer', 'Phenotype', 'HP:0009725', (80, 94))	('ADT', 'Var', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('positive bladder', 'Phenotype', 'HP:0100645', (71, 87))
23429	27322140	Inhibitors, including dehydroxymethylepoxyquinomicin that prevents nuclear translocation of NF-kappaB and its binding to DNA, have indeed been reported to not only exhibit anti-cancer activity but also confer sensitization to CDDP in CR cells.	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('CR', 'Chemical', '-', (234, 236))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('NF-kappaB', 'Gene', (92, 101))	('dehydroxymethylepoxyquinomicin', 'Var', (22, 52))	('binding', 'molecular_function', 'GO:0005488', ('110', '117'))	('NF-kappaB', 'Gene', '4790', (92, 101))	('sensitization', 'biological_process', 'GO:0046960', ('209', '222'))	('binding', 'Interaction', (110, 117))	('prevents', 'NegReg', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('nuclear translocation', 'MPA', (67, 88))	('CDDP', 'Chemical', '-', (226, 230))	('sensitization', 'MPA', (209, 222))	('dehydroxymethylepoxyquinomicin', 'Chemical', 'MESH:C464444', (22, 52))
23437	27322140	Using the same models for bladder cancer for assessing cytotoxicity of CDDP, we investigated the role of AR signals in sensitivity of gemcitabine and found no significant effects of AR overexpression or silencing (data not shown).	('silencing', 'Var', (203, 212))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('bladder cancer', 'Phenotype', 'HP:0009725', (26, 40))	('AR', 'Gene', '367', (105, 107))	('bladder cancer', 'Disease', (26, 40))	('bladder cancer', 'Disease', 'MESH:D001749', (26, 40))	('CDDP', 'Chemical', '-', (71, 75))	('cytotoxicity', 'Disease', (55, 67))	('AR', 'Gene', '367', (182, 184))	('gemcitabine', 'Chemical', 'MESH:C056507', (134, 145))	('cytotoxicity', 'Disease', 'MESH:D064420', (55, 67))
23460	27322140	Briefly, cells plated onto chamber slides (8-well Nunc Lab-Tek, Thermo Scientific) were cultured in medium containing ethanol or R1881 for 24 h, and the adherent cells were fixed with 4% paraformaldehyde.	('paraformaldehyde', 'Chemical', 'MESH:C003043', (187, 203))	('Tek', 'Gene', '7010', (59, 62))	('ethanol', 'Chemical', 'MESH:D000431', (118, 125))	('R1881', 'Var', (129, 134))	('Tek', 'Gene', (59, 62))
23508	26317352	Mutations in specific genes including FGFR3, p53, and Rb have been associated with both UTUC and UCB.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('UCB', 'Disease', (97, 100))	('FGFR3', 'Gene', '2261', (38, 43))	('FGFR3', 'Gene', (38, 43))	('Mutations', 'Var', (0, 9))	('UTUC', 'Disease', (88, 92))	('associated', 'Reg', (67, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('UCB', 'Phenotype', 'HP:0006740', (97, 100))
23514	26317352	This group went on to create a mouse model with a PTEN deletion which resulted in increased AKT/mTOR signaling in upper tract urothelial carcinoma.	('AKT/mTOR signaling', 'MPA', (92, 110))	('PTEN', 'Gene', '19211', (50, 54))	('mouse', 'Species', '10090', (31, 36))	('PTEN', 'Gene', (50, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (114, 146))	('increased', 'PosReg', (82, 91))	('deletion', 'Var', (55, 63))	('upper tract urothelial carcinoma', 'Disease', (114, 146))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))
23517	26317352	The recently published Cancer Genome Atlas Research Network study of muscle invasive UCB showed recurrent mutations in 32 unique genes as well as a wide variety of copy number alterations, confirming that muscle invasive UCB is indeed a molecularly heterogeneous disease.	('UCB', 'Phenotype', 'HP:0006740', (221, 224))	('Cancer', 'Disease', (23, 29))	('UCB', 'Phenotype', 'HP:0006740', (85, 88))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('copy', 'Var', (164, 168))	('muscle invasive UCB', 'Disease', (205, 224))	('mutations', 'Var', (106, 115))
23527	26317352	Given our analysis compared the relative expression of UCB and UTUC and this gene was found to be over-expressed in UTUC relative to UCB, AGS15E may be a good drug candidate for patients with locally advanced or metastatic UTUC who otherwise have limited treatment options.	('AGS15E', 'Var', (138, 144))	('UCB', 'Phenotype', 'HP:0006740', (133, 136))	('metastatic UTUC', 'Disease', (212, 227))	('patients', 'Species', '9606', (178, 186))	('UCB', 'Phenotype', 'HP:0006740', (55, 58))	('over-expressed', 'PosReg', (98, 112))	('locally advanced', 'Disease', (192, 208))
23535	32443727	Among six high-affinity IGFBPs, which are IGFBP-1 through 6, IGFBP-3 is the most extensively investigated IGFBP species with respect to its IGF/IGF-I receptor (IGF-IR)-independent biological actions beyond its endocrine/paracrine/autocrine role in modulating IGF action in cancer.	('IGF-IR', 'Gene', '3480', (160, 166))	('IGFBPs', 'Gene', (24, 30))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('IGFBPs', 'Gene', '3485;3486;16009;24484', (24, 30))	('IGF-I receptor', 'Gene', '3480', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('IGFBP-3', 'Var', (61, 68))	('IGF-I receptor', 'Gene', (144, 158))	('IGF-IR', 'Gene', (160, 166))
23536	32443727	Disruption of IGFBP-3 at transcriptional and post-translational levels has been implicated in the pathophysiology of many different types of cancer including breast, prostate, and lung cancer.	('prostate', 'Disease', (166, 174))	('implicated', 'Reg', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('IGFBP-3', 'Gene', (14, 21))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('lung cancer', 'Disease', (180, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('breast', 'Disease', (158, 164))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', (141, 147))	('Disruption', 'Var', (0, 10))
23542	32443727	Dysregulation of the IGF system attributes to pathophysiology of a variety of human diseases such as cancer, diabetes, chronic inflammatory disease, and malnutrition.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('malnutrition', 'Phenotype', 'HP:0004395', (153, 165))	('cancer', 'Disease', (101, 107))	('Dysregulation', 'Var', (0, 13))	('inflammatory disease', 'Disease', (127, 147))	('inflammatory disease', 'Disease', 'MESH:D007249', (127, 147))	('diabetes', 'Disease', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('diabetes', 'Disease', 'MESH:D003920', (109, 117))	('human', 'Species', '9606', (78, 83))	('malnutrition', 'Disease', (153, 165))
23571	32443727	Further studies using p53 mutants have revealed a link between p53's activation of IGFBP-3 transcription and its induction of apoptosis by showing that the mutants that lost the ability to activate IGFBP-3 could not induce apoptosis.	('transcription', 'MPA', (91, 104))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('IGFBP-3', 'Gene', (83, 90))	('transcription', 'biological_process', 'GO:0006351', ('91', '104'))	('p53', 'Gene', (22, 25))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('113', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('223', '232'))	('mutants', 'Var', (156, 163))	('apoptosis', 'CPA', (223, 232))	('mutants', 'Var', (26, 33))	('p53', 'Gene', '7157', (22, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('223', '232'))	('activation', 'PosReg', (69, 79))
23572	32443727	Further research also demonstrated that the transfection of doxycycline-inducible p53 plasmids resulted in increased expression of p53 and IGFBP-3 and, subsequently, induced apoptosis in p53-negative PC-3 prostate cancer cells.	('p53', 'Gene', (131, 134))	('apoptosis', 'CPA', (174, 183))	('doxycycline', 'Chemical', 'MESH:D004318', (60, 71))	('IGFBP-3', 'Gene', (139, 146))	('p53', 'Gene', (82, 85))	('PC-3', 'CellLine', 'CVCL:0035', (200, 204))	('increased', 'PosReg', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('induced', 'Reg', (166, 173))	('transfection', 'Var', (44, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('174', '183'))	('apoptosis', 'biological_process', 'GO:0006915', ('174', '183'))	('expression', 'MPA', (117, 127))	('prostate cancer', 'Disease', 'MESH:D011471', (205, 220))	('p53', 'Gene', '7157', (187, 190))	('prostate cancer', 'Phenotype', 'HP:0012125', (205, 220))	('prostate cancer', 'Disease', (205, 220))	('p53', 'Gene', (187, 190))	('p53', 'Gene', '7157', (131, 134))	('p53', 'Gene', '7157', (82, 85))
23573	32443727	This p53-depedent induction of apoptosis was inhibited by treating with IGF-I, IGFBP-3 blocking antibodies, and IGFBP-3 antisense oligonucleotides, which demonstrated p53-dependent IGFBP-3's proapoptotic function.	('IGFBP-3', 'Gene', (79, 86))	('oligonucleotides', 'Chemical', 'MESH:D009841', (130, 146))	('IGF-I', 'Gene', '3479', (72, 77))	('p53', 'Gene', (5, 8))	('p53', 'Gene', '7157', (5, 8))	('p53', 'Gene', '7157', (167, 170))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('18', '40'))	('antisense oligonucleotides', 'Var', (120, 146))	('inhibited', 'NegReg', (45, 54))	('IGF-I', 'Gene', (72, 77))	('IGFBP-3', 'Gene', (112, 119))	('apoptosis', 'CPA', (31, 40))	('p53', 'Gene', (167, 170))
23575	32443727	It appears that DeltaNp63alpha binds the p53 binding sites, Box A and Box B, in the IGFBP-3 gene, and, thereby, inhibits p53-dependent IGFBP-3 expression and presumably suppresses IGFBP-3-induced apoptosis.	('suppresses', 'NegReg', (169, 179))	('p53', 'Gene', '7157', (41, 44))	('DeltaNp63alpha', 'Var', (16, 30))	('expression', 'MPA', (143, 153))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('p53 binding', 'molecular_function', 'GO:0002039', ('41', '52'))	('IGFBP-3', 'Gene', (135, 142))	('IGFBP-3', 'Gene', (84, 91))	('inhibits', 'NegReg', (112, 120))	('apoptosis', 'biological_process', 'GO:0097194', ('196', '205'))	('apoptosis', 'biological_process', 'GO:0006915', ('196', '205'))	('p53', 'Gene', (41, 44))
23604	32443727	Humanin is a mitochondrial-derived peptide that inhibits neuronal cell death induced by mutant genes in Alzheimer's disease.	('Human', 'Species', '9606', (0, 5))	('death', 'Disease', 'MESH:D003643', (71, 76))	('death', 'Disease', (71, 76))	('mutant genes', 'Var', (88, 100))	('inhibits', 'NegReg', (48, 56))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (104, 123))	('neuronal cell death', 'biological_process', 'GO:0070997', ('57', '76'))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (104, 123))	("Alzheimer's disease", 'Disease', (104, 123))
23619	32443727	On the contrary, IGFBP-3 has been shown to enhance the survival of cells subjected to glucose starvation and hypoxia by inducing autophagy in a GRP78-dependent manner in human breast cancer cells, which suggests that IGFBP-3 may play a key role in mediating an autophagic survival response.	('GRP78', 'Gene', (144, 149))	('inducing', 'Reg', (120, 128))	('hypoxia', 'Disease', (109, 116))	('hypoxia', 'Disease', 'MESH:D000860', (109, 116))	('autophagy', 'biological_process', 'GO:0016236', ('129', '138'))	('survival', 'CPA', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('autophagy', 'biological_process', 'GO:0006914', ('129', '138'))	('autophagy', 'CPA', (129, 138))	('IGFBP-3', 'Var', (17, 24))	('human', 'Species', '9606', (170, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('breast cancer', 'Disease', (176, 189))	('glucose', 'Chemical', 'MESH:D005947', (86, 93))	('GRP78', 'Gene', '3309', (144, 149))	('enhance', 'PosReg', (43, 50))
23626	32443727	However, recent studies also showed that IGFBP-3 mutants that failed to translocate to the nucleus and lost binding ability to RXR-alpha, still induced apoptosis in breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('breast cancer', 'Disease', (165, 178))	('mutants', 'Var', (49, 56))	('IGFBP-3', 'Gene', (41, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('binding', 'Interaction', (108, 115))	('RXR', 'molecular_function', 'GO:0004879', ('127', '130'))	('binding', 'molecular_function', 'GO:0005488', ('108', '115'))	('RXR-alpha', 'Gene', '6256', (127, 136))	('induced', 'Reg', (144, 151))	('nucleus', 'cellular_component', 'GO:0005634', ('91', '98'))	('apoptosis', 'CPA', (152, 161))	('RXR-alpha', 'Gene', (127, 136))
23640	32443727	Additionally, IGFBP-3R activates caspase-8-induced apoptosis in unconventional ways: (1) IGFBP-3R and inactive procaspase-8 is pre-complexed at the resting stage, and IGFBP-3 binding to IGFBP-3R releases procaspase-8, and, thereby, activates caspase-8-dependent apoptosis, and (2) IGFBP-3R complexes with procasepase-8 without involvement of a typical death domain (DD) sequence.	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('caspase-8', 'Gene', (242, 251))	('caspase-8', 'Gene', '841', (207, 216))	('releases', 'PosReg', (195, 203))	('caspase-8', 'Gene', (33, 42))	('caspase-8', 'Gene', (114, 123))	('binding', 'molecular_function', 'GO:0005488', ('175', '182'))	('death', 'Disease', 'MESH:D003643', (352, 357))	('caspase-8', 'Gene', (207, 216))	('IGFBP-3', 'Var', (167, 174))	('caspase-8', 'Gene', '841', (242, 251))	('pre', 'molecular_function', 'GO:0003904', ('127', '130'))	('binding', 'Interaction', (175, 182))	('activates', 'PosReg', (232, 241))	('apoptosis', 'biological_process', 'GO:0097194', ('262', '271'))	('apoptosis', 'biological_process', 'GO:0006915', ('262', '271'))	('caspase-8', 'Gene', '841', (33, 42))	('caspase-8', 'Gene', '841', (114, 123))	('death', 'Disease', (352, 357))
23651	32443727	This inhibitory action of IGFBP-3 was IGF/IGF-IR-independent since the IGFBP-3 mutant devoid of IGF binding affinity had a similar inhibitory effect.	('mutant', 'Var', (79, 85))	('IGF-IR', 'Gene', (42, 48))	('IGFBP-3', 'Gene', (71, 78))	('IGF-IR', 'Gene', '3480', (42, 48))	('IGF binding', 'molecular_function', 'GO:0005520', ('96', '107'))
23682	32443727	Survival in pan-kidney cohort (KICH+KIRC+KIRP), lower grade glioma, mesothelioma, colorectal adenocarcinoma was similarly affected by IGFBP-3 to a lesser extent (FDR = 1.74 10-6 (HR = 2.73), 1.25 10-5 (HR = 2.36), 1.22 10-3 (HR = 2.98), 3.87 10-3 (HR = 2.20), respectively) (Figure 6B,C).	('mesothelioma', 'Disease', (68, 80))	('colorectal adenocarcinoma', 'Disease', (82, 107))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (82, 107))	('KICH+KIRC+KIRP', 'Disease', 'None', (31, 45))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('affected', 'Reg', (122, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('IGFBP-3', 'Var', (134, 141))	('glioma', 'Disease', (60, 66))	('KICH+KIRC+KIRP', 'Disease', (31, 45))
23685	32443727	Of note, the observed dichotomy of IGFBP-3 expression and patients' survival in various cancers may be attributed to other factors such as IGF-1/IGF-2 expression, IGFBP-3 polymorphism status, tumor suppressor p53 family status, tumor metabolic characteristics, and others.	('IGFBP-3', 'Gene', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('polymorphism', 'Var', (171, 183))	('IGF-1', 'Gene', (139, 144))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('cancers', 'Disease', (88, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('192', '208'))	('IGF-1', 'Gene', '3479', (139, 144))	('tumor', 'Disease', (192, 197))	('tumor suppressor', 'biological_process', 'GO:0051726', ('192', '208'))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('patients', 'Species', '9606', (58, 66))	('p53', 'Gene', '7157', (209, 212))	('IGF-2', 'Gene', (145, 150))	('IGFBP-3', 'Gene', (163, 170))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('IGF-2', 'Gene', '3481', (145, 150))	('tumor', 'Disease', (228, 233))	('p53', 'Gene', (209, 212))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
23700	32443727	Similar results were observed for clinical subgroups in mesothelioma, the pan-kidney cohort, rectum adenocarcinoma, colorectal adenocarcinoma, and colon adenocarcinoma cancers, where low expression of IGFBP-3 was similarly associated with better survival outcome.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colon adenocarcinoma cancers', 'Disease', 'MESH:D015179', (147, 175))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (116, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('rectum adenocarcinoma', 'Disease', (93, 114))	('associated', 'Reg', (223, 233))	('colon adenocarcinoma cancers', 'Disease', (147, 175))	('IGFBP-3', 'Gene', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (93, 114))	('mesothelioma', 'Disease', (56, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('low expression', 'Var', (183, 197))	('colorectal adenocarcinoma', 'Disease', (116, 141))	('mesothelioma', 'Disease', 'MESH:D008654', (56, 68))
23701	32443727	These results confirm previous observations that the expression of IGFBP-3 may affect survival in glioma, mesothelioma, kidney, and colorectal cancers.	('affect', 'Reg', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mesothelioma', 'Disease', (106, 118))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('expression', 'Var', (53, 63))	('kidney', 'Disease', (120, 126))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))	('colorectal cancers', 'Disease', 'MESH:D015179', (132, 150))	('survival', 'CPA', (86, 94))	('glioma', 'Disease', (98, 104))	('IGFBP-3', 'Gene', (67, 74))	('colorectal cancers', 'Disease', (132, 150))
23702	32443727	Further analyses of the effect of IGFBP-3 and TMEM219 expression in specific clinical subgroups revealed that kidney renal papillary cell carcinoma is the only cancer where the expression of both IGFBP-3 and TMEM219 is marginally associated with survival in "race-black or the African-American" subgroup.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (110, 147))	('cancer', 'Disease', (160, 166))	('expression', 'Var', (177, 187))	('associated', 'Reg', (230, 240))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (117, 147))	('TMEM219', 'Gene', '124446', (46, 53))	('TMEM219', 'Gene', '124446', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('kidney renal papillary cell carcinoma', 'Disease', (110, 147))	('IGFBP-3', 'Gene', (196, 203))	('TMEM219', 'Gene', (46, 53))	('TMEM219', 'Gene', (208, 215))
23709	32443727	Of note were race-specific survival effects with high expression of IGFBP-3 being beneficial in the "race-black or African-American" subgroup (FDR = 2.01 10-1 (HR = 0.42), Figure 10E) and TMEM219 high expression being beneficial in the "race-Asian" subgroup (FDR = 1.16 10-1 (HR = 0.00), Figure 10D).	('TMEM219', 'Gene', (188, 195))	('high expression', 'Var', (49, 64))	('TMEM219', 'Gene', '124446', (188, 195))	('beneficial', 'PosReg', (82, 92))	('IGFBP-3', 'Gene', (68, 75))
23710	32443727	Confirming our previous observations, the survival benefits of IGFBP-3 expression in breast cancer were consistently associated with high IGFBP-3 expression, while the effect of TMEM219 was more diverse and subgroup-specific.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('IGFBP-3', 'Gene', (63, 70))	('TMEM219', 'Gene', (178, 185))	('breast cancer', 'Disease', (85, 98))	('high', 'Var', (133, 137))	('IGFBP-3', 'Gene', (138, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('TMEM219', 'Gene', '124446', (178, 185))	('expression', 'MPA', (146, 156))	('benefits', 'PosReg', (51, 59))	('high IGFBP', 'Phenotype', 'HP:0030269', (133, 143))
23716	32443727	Given the fact that IGFBP-3/IGFBP-3R (TMEM219) axis is impaired and shown to have great impact on the survival outcome in specific cancers, IGFBP-3 and TMEM219 may serve as new diagnostic and prognostic biomarkers in specific cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('impact', 'Reg', (88, 94))	('TMEM219', 'Gene', '124446', (38, 45))	('cancers', 'Disease', (131, 138))	('TMEM219', 'Gene', '124446', (152, 159))	('TMEM219', 'Gene', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('cancers', 'Disease', (226, 233))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('IGFBP-3', 'Var', (140, 147))	('IGFBP-3/IGFBP-3R', 'Gene', (20, 36))	('TMEM219', 'Gene', (152, 159))	('impaired', 'NegReg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
23730	31867319	Some of these differential methylation sites were associated with cancer survival.	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('methylation', 'Var', (27, 38))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('associated', 'Reg', (50, 60))	('cancer', 'Disease', (66, 72))
23737	31867319	DNA methylation could modulate gene expression during development and cancer progression (Wang et al.,; Zhang et al.,).	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('development', 'CPA', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('modulate', 'Reg', (22, 30))	('methylation', 'Var', (4, 15))	('gene expression', 'MPA', (31, 46))	('men', 'Species', '9606', (61, 64))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('gene expression', 'biological_process', 'GO:0010467', ('31', '46'))
23746	31867319	Methylation of SLFN11 is a biomarker for poor prognosis in colorectal cancer and methylations of SLIT1, SLIT2, and SLIT3 are abnormal in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('SLIT2', 'Gene', (104, 109))	('SLIT3', 'Gene', '6586', (115, 120))	('SLIT3', 'Gene', (115, 120))	('gastric cancer', 'Disease', 'MESH:D013274', (137, 151))	('methylations', 'MPA', (81, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('Methylation', 'Var', (0, 11))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('SLIT2', 'Gene', '9353', (104, 109))	('abnormal', 'Reg', (125, 133))	('SLIT1', 'Gene', (97, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SLFN11', 'Gene', (15, 21))	('SLIT1', 'Gene', '6585', (97, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))	('colorectal cancer', 'Disease', (59, 76))	('gastric cancer', 'Disease', (137, 151))	('SLFN11', 'Gene', '91607', (15, 21))
23747	31867319	F2RL3 methylation is recently identified as a biomarker closely reflecting both current and past smoking exposure, causing lung cancer (Yan et al.,; Kim et al.,; He et al.,).	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('F2RL3', 'Gene', (0, 5))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('causing', 'Reg', (115, 122))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('methylation', 'Var', (6, 17))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('F2RL3', 'Gene', '9002', (0, 5))
23754	31867319	For each cancer type, we detected a series of methylation sites, which could influence m-age compared to healthy samples.	('cancer', 'Disease', (9, 15))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('influence', 'Reg', (77, 86))	('m-age', 'CPA', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('methylation sites', 'Var', (46, 63))
23783	31867319	According to the least Mean-Squared Error (MSE, reflect the degree of difference between the estimator and true value, the smaller the MSE, the better the model fit) of LASSO linear regression model, we found that the value beta0 of the model was 34.63 when the adjustment parameter was 0.1419941 (Figure 2C).	('MSE', 'Gene', (135, 138))	('MSE', 'Gene', '101180900', (135, 138))	('0.1419941', 'Var', (287, 296))	('men', 'Species', '9606', (268, 271))	('MSE', 'Gene', (43, 46))	('MSE', 'Gene', '101180900', (43, 46))
23784	31867319	Among the 282 methylation characteristics in the construction of model, the levels of cg08461576, cg05923914, cg27641628, cg13221458, cg05632420, and cg07103722 were significantly and negatively correlated with sample age, and the linear model coefficients of the six sites above were negative as well (Figure 2D).	('cg27641628', 'Var', (110, 120))	('cg13221458', 'Var', (122, 132))	('cg08461576', 'Chemical', '-', (86, 96))	('negatively', 'NegReg', (184, 194))	('cg05923914', 'Chemical', '-', (98, 108))	('cg05632420', 'Chemical', '-', (134, 144))	('cg27641628', 'Chemical', '-', (110, 120))	('cg08461576', 'Var', (86, 96))	('cg05923914', 'Var', (98, 108))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('cg07103722', 'Var', (150, 160))	('cg05632420', 'Var', (134, 144))	('cg13221458', 'Chemical', '-', (122, 132))
23785	31867319	Gene Ontology (GO) analysis of the genes for the 282 model characteristics revealed that these genes were associated with some GO terms such as "lysine catabolic process" (GO:0006554) and "lysine metabolic process" (GO:0006553) (Figure 3A).	('GO:0006553', 'Var', (216, 226))	('lysine', 'Chemical', 'MESH:D008239', (189, 195))	('lysine', 'Chemical', 'MESH:D008239', (145, 151))	('associated', 'Reg', (106, 116))	('metabolic process', 'MPA', (196, 213))	('Gene Ontology', 'biological_process', 'GO:0003673', ('0', '13'))
23786	31867319	These results indicated that age-related methylation sites could alter many important biology processes (Supplementary Table S5).	('sites', 'Var', (53, 58))	('men', 'Species', '9606', (111, 114))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('methylation sites', 'Var', (41, 58))	('alter', 'Reg', (65, 70))
23788	31867319	In addition, we found that most methylation sites were enriched in human acute leukemia [-log10 (p) > 50] (Figure 3C, Supplementary Table S6).	('men', 'Species', '9606', (124, 127))	('methylation sites', 'Var', (32, 49))	('acute leukemia', 'Disease', (73, 87))	('acute leukemia', 'Phenotype', 'HP:0002488', (73, 87))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('sites', 'Var', (44, 49))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('acute leukemia', 'Disease', 'MESH:D015470', (73, 87))	('human', 'Species', '9606', (67, 72))
23803	31867319	It is suggested that hyper-methylation of these age-related differences may lead to changes in m-age and cancer development.	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('lead to changes', 'Reg', (76, 91))	('men', 'Species', '9606', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('hyper-methylation', 'Var', (21, 38))	('m-age', 'CPA', (95, 100))
23807	31867319	In most cancer types, these differential methylation sites in age-related samples were associated with survival (Figure 5).	('survival', 'MPA', (103, 111))	('differential methylation', 'Var', (28, 52))	('cancer', 'Disease', (8, 14))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('methylation', 'Var', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('associated with', 'Reg', (87, 102))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
23809	31867319	The results indicated that differential methylation sites of age-related samples maybe could be an effective prognostic biomarker for cancers.	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('differential methylation sites', 'Var', (27, 57))	('cancers', 'Disease', (134, 141))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
23819	31867319	Previous study also showed that epigenetic age acceleration is associated with colorectal cancer molecular characteristics and can be a significant predictor of overall survival, as well as age and tumor stage (Zheng et al.,).	('epigenetic age', 'Var', (32, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('associated', 'Reg', (63, 73))	('colorectal cancer', 'Disease', (79, 96))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('acceleration', 'PosReg', (47, 59))	('tumor', 'Disease', (198, 203))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))
23828	31867319	We further discovered the differential methylation sites between age-related cancer samples and normal samples.	('methylation', 'Var', (39, 50))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
23829	31867319	These differential methylation sites were associated with survival in cancers.	('methylation sites', 'Var', (19, 36))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('associated with', 'Reg', (42, 57))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
23834	31329578	Aberrant DNA methylation defines isoform usage in cancer, with functional implications Alternative transcript isoforms are common in tumors and act as potential drivers of cancer.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('Aberrant', 'Var', (0, 8))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('cancer', 'Disease', (172, 178))
23839	31329578	Finally, methylation-correlated isoforms were enriched for oncogenes, tumor suppressors, and cancer-related pathways.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('oncogenes', 'Gene', (59, 68))	('methylation-correlated', 'Var', (9, 31))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
23840	31329578	These findings provide new insights into the functional impact of dysregulated DNA methylation in cancer and highlight the relationship between the epigenome and transcriptome.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('DNA', 'Protein', (79, 82))	('dysregulated', 'Var', (66, 78))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('cancer', 'Disease', (98, 104))	('DNA methylation', 'biological_process', 'GO:0006306', ('79', '94'))
23842	31329578	Given that dysregulation of DNA methylation is a cancer hallmark, we suspect the same regulation holds in cancer and contributes to cancer progression.	('cancer', 'Disease', (132, 138))	('DNA', 'Protein', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('cancer', 'Disease', (106, 112))	('dysregulation', 'Var', (11, 24))	('DNA methylation', 'biological_process', 'GO:0006306', ('28', '43'))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
23846	31329578	This finding could help us to better understand the functional impact of DNA methylation alterations via regulation of isoform expression in tumorigenesis and to further improve the cancer treatment.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('isoform expression', 'MPA', (119, 137))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('DNA methylation', 'biological_process', 'GO:0006306', ('73', '88'))	('tumor', 'Disease', (141, 146))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('regulation', 'MPA', (105, 115))	('cancer', 'Disease', (182, 188))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('alterations', 'Var', (89, 100))	('improve', 'PosReg', (170, 177))	('regulation', 'biological_process', 'GO:0065007', ('105', '115'))
23850	31329578	To date, researchers seeking to learn more about the mechanisms underlying aberrant isoform activity in cancer have primarily focused on mutations in splicing regulatory sites or altered/deregulated splicing factors.	('splicing factor', 'Gene', (199, 214))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('splicing', 'biological_process', 'GO:0045292', ('199', '207'))	('splicing', 'biological_process', 'GO:0045292', ('150', '158'))	('mutations', 'Var', (137, 146))	('splicing factor', 'Gene', '10569', (199, 214))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
23851	31329578	For example, we now know that mutations in the tumor suppressor gene BRCA1 cause inappropriate exon skipping and inactivation of BRCA1, whereas upregulation of NUMA1 splice isoforms in breast cancer cause increased cell proliferation.	('inactivation', 'MPA', (113, 125))	('increased', 'PosReg', (205, 214))	('BRCA1', 'Gene', '672', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('upregulation', 'PosReg', (144, 156))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('BRCA1', 'Gene', (129, 134))	('NUMA1', 'Gene', (160, 165))	('NUMA1', 'Gene', '4926', (160, 165))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('cell proliferation', 'biological_process', 'GO:0008283', ('215', '233'))	('cell proliferation', 'CPA', (215, 233))	('tumor suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (47, 52))	('exon', 'MPA', (95, 99))	('BRCA1', 'Gene', '672', (69, 74))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('breast cancer', 'Disease', (185, 198))	('BRCA1', 'Gene', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
23855	31329578	Moreover, intragenic DNAm within exons or near exon boundaries can regulate alternative splicing outcomes by (1) preventing access of the DNA-binding protein CTCF, whose presence mediates local RNA polymerase II pausing for inclusion of weak exons or (2) facilitating access of the DNA-binding protein MeCP2, involved in inclusion of alternatively spliced exons.	('alternative splicing', 'MPA', (76, 96))	('regulate', 'Reg', (67, 75))	('CTCF', 'Gene', (158, 162))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('facilitating', 'PosReg', (255, 267))	('protein', 'cellular_component', 'GO:0003675', ('294', '301'))	('CTCF', 'Gene', '10664', (158, 162))	('DNA-binding', 'molecular_function', 'GO:0003677', ('138', '149'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('282', '293'))	('DNAm', 'Var', (21, 25))	('MeCP2', 'Gene', '4204', (302, 307))	('splicing', 'biological_process', 'GO:0045292', ('88', '96'))	('preventing', 'NegReg', (113, 123))	('access', 'MPA', (124, 130))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('RNA', 'cellular_component', 'GO:0005562', ('194', '197'))	('MeCP2', 'Gene', (302, 307))	('DNA', 'cellular_component', 'GO:0005574', ('282', '285'))
23856	31329578	Affecting differential use of transcription termination sites, CGI methylation directs imprinting of murine H13 isoforms between paternal and maternal alleles.	('directs', 'Reg', (79, 86))	('imprinting', 'MPA', (87, 97))	('murine', 'Species', '10090', (101, 107))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('transcription', 'biological_process', 'GO:0006351', ('30', '43'))	('methylation', 'Var', (67, 78))
23858	31329578	In this study, recent advances in transcriptome sequencing and DNAm analysis, coupled with expansive collections of tumor samples, enabled us to test the hypothesis that DNAm dysregulation in cancers can disrupt isoform usage and contribute to tumorigenesis, as a common phenomenon.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('DNAm', 'Gene', (170, 174))	('dysregulation', 'Var', (175, 188))	('tumor', 'Disease', (244, 249))	('isoform usage', 'MPA', (212, 225))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancers', 'Disease', (192, 199))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('disrupt', 'NegReg', (204, 211))	('contribute', 'Reg', (230, 240))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Disease', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
23860	31329578	Based on a comprehensive analysis of data for 18 cancer types from The Cancer Genome Atlas (TCGA), we report that, within 11 cancer types, DNAm in the top 25% of variable methylated sites is associated with isoform switching, and this isoform switching is predicted to have functional consequences for tumorigenesis, involving 10-21% of genes.	('Cancer Genome Atlas', 'Disease', (71, 90))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))	('isoform switching', 'MPA', (207, 224))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (71, 90))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', (302, 307))	('methylated sites', 'Var', (171, 187))	('associated', 'Reg', (191, 201))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', (49, 55))	('DNAm', 'Var', (139, 143))
23866	31329578	To further investigate the connection between DNAm and isoform usage, for each cancer type we identified methylation probes with the most variable values, which were most likely to behave differently across samples (i.e., those whose standard deviation across tumors fell within the top 25% for all sites).	('methylation', 'Var', (105, 116))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('methylation', 'biological_process', 'GO:0032259', ('105', '116'))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (260, 266))
23875	31329578	We found negative correlations enriched among probes within OSRs, compared to other regions, in 9 out of 11 cancer types (#gene = 232) (Fig 1C) whereas the same enrichment was seen for CGIs in only 6 out of 11 cancer types, suggesting that TSS-correlated DNAm need not be confined to CGIs to impact transcription initiation.	('transcription', 'biological_process', 'GO:0006351', ('299', '312'))	('probes', 'Var', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('transcription initiation', 'MPA', (299, 323))	('impact', 'Reg', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('negative', 'NegReg', (9, 17))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
23877	31329578	These findings suggest that, across most cancer types, DNAm at isoform positions > = exon 4 correlates with inclusion of distal exons in the gene body, indicative of transcriptional elongation.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('DNAm', 'Var', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (41, 47))
23882	31329578	For example, the very long terminal exon in BHLHE41 contains two internal methylation sites positively correlated with the inclusion of a long terminal exon but negatively correlated with the shorter isoform (Fig 3C).	('BHLHE41', 'Gene', '79365', (44, 51))	('negatively', 'NegReg', (161, 171))	('inclusion', 'Var', (123, 132))	('correlated', 'Reg', (103, 113))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))	('BHLHE41', 'Gene', (44, 51))
23896	31329578	To determine whether these subtype-discerning, isoform switching-linked DNAm alterations could impact tumorigenesis, we analyzed the functional outcomes of isoform switching among BRCA subtype samples, and also in normal breast tissue samples, using software designed for this purpose, IsoformSwitchAnalyzeR.	('impact', 'Reg', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('BRCA', 'Gene', (180, 184))	('alterations', 'Var', (77, 88))	('BRCA', 'Gene', '672', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
23905	31329578	Nevertheless, the overrepresentation remained statistically significant across all n values (hypergeometric test; p < 1E-2) (S1 Table), suggesting DNAm-correlated isoform alterations may be positively selected in cancer-related genes, consistent with our hypothesis.	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('alterations', 'Var', (171, 182))	('cancer', 'Disease', (213, 219))
23910	31329578	Thus, alteration of the DNAm of these genes may correspond to alteration of their functional domains and influence pathway functions in many types of cancer.	('DNAm', 'MPA', (24, 28))	('influence', 'Reg', (105, 114))	('pathway functions', 'CPA', (115, 132))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('functional domains', 'MPA', (82, 100))	('cancer', 'Disease', (150, 156))	('alteration', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('alteration', 'Reg', (62, 72))
23914	31329578	Thus, this study shows that DNAm-correlated isoform usage alterations are common, could functionally contribute to cancer processes, and represent a new paradigm in the cancer epigenomic landscape.	('contribute', 'Reg', (101, 111))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (169, 175))	('isoform usage', 'MPA', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('alterations', 'Var', (58, 69))
23916	31329578	These correlations suggest a potential blueprint for DNAm-regulated isoform activities worthy of further experimental elucidation while controlling for other isoform-regulating mechanisms such as aforementioned splicing factor alterations and recently reported regulation via miRNA binding at 3'UTRs.	('miRNA', 'Protein', (276, 281))	('splicing factor', 'Gene', '10569', (211, 226))	('splicing', 'biological_process', 'GO:0045292', ('211', '219'))	('miRNA binding', 'molecular_function', 'GO:0035198', ('276', '289'))	('splicing factor', 'Gene', (211, 226))	('regulation', 'biological_process', 'GO:0065007', ('261', '271'))	('alterations', 'Var', (227, 238))
23918	31329578	First, the main functional role established for cancer-associated DNAm alterations is gene silencing via promoter CGI methylation.	('gene', 'MPA', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('gene silencing', 'biological_process', 'GO:0016458', ('86', '100'))	('alterations', 'Var', (71, 82))	('methylation', 'biological_process', 'GO:0032259', ('118', '129'))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('promoter', 'MPA', (105, 113))
23919	31329578	Thus, most cancer studies have focused on causal relationships between aberrant promoter hypermethylation and tumor suppressor gene silencing, paying less attention to the functional consequences of intragenic DNAm alterations.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('silencing', 'NegReg', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('promoter', 'MPA', (80, 88))	('paying less attention', 'Phenotype', 'HP:0000736', (143, 164))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('gene silencing', 'biological_process', 'GO:0016458', ('127', '141'))	('aberrant', 'Var', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
23922	31329578	Integrative analysis of these factors (using ChIP-Seq datasets, for example) coupled with exon-level expression data may provide insights into a mechanistic link between DNAm alterations and deleterious alternative splicing in cancer.	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('splicing', 'biological_process', 'GO:0045292', ('215', '223'))	('DNAm', 'MPA', (170, 174))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('alterations', 'Var', (175, 186))
23933	31329578	The following types of probes were removed from the analysis: (i) probes on the X and Y chromosomes, (ii) cross-reactive probes, (iii) probes near single nucleotide polymorphisms, and (iv) probes with missing rates >= 90% across all samples for a given cancer type.	('single nucleotide polymorphisms', 'Var', (147, 178))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('probes', 'Var', (135, 141))
23965	19197366	We base the present manuscript on the observation that in rats, toxicity of dual-acting PPARalpha+gamma agonists appears to target cells coexpressing PPARalpha and PPARgamma, resulting in a qualitatively different target organ profile from that of selective PPARalpha and PPARgamma agonists (Table 1).	('PPARgamma', 'Var', (164, 173))	('rats', 'Species', '10116', (58, 62))	('target organ profile', 'MPA', (214, 234))	('PPARalpha', 'Gene', (150, 159))	('different', 'Reg', (204, 213))	('toxicity', 'Disease', 'MESH:D064420', (64, 72))	('toxicity', 'Disease', (64, 72))
24034	19197366	These effects were independent of p38 or pERK activation and were not seen with fenofibrate (PPARalpha), L165041 (PPARbeta), or rosiglitazone (PPARgamma).	('ERK', 'Gene', (42, 45))	('p38', 'Gene', '81649', (34, 37))	('ERK', 'Gene', '24338', (42, 45))	('L165041', 'Var', (105, 112))	('fenofibrate', 'Chemical', 'MESH:D011345', (80, 91))	('rosiglitazone', 'Chemical', 'MESH:D000077154', (128, 141))	('L165041', 'Chemical', 'MESH:C520164', (105, 112))	('p38', 'Gene', (34, 37))	('PPARbeta', 'Gene', (114, 122))	('PPARbeta', 'Gene', '25682', (114, 122))
24039	19197366	Interestingly, PPAR agonists associated with hepatotoxicity and carcinogenicity in vivo also exhibited the most severe cytotoxicity profile in vitro, comprising apoptosis and sustained increases in intracellular calcium.	('intracellular', 'cellular_component', 'GO:0005622', ('198', '211'))	('increases', 'PosReg', (185, 194))	('carcinogenic', 'Disease', 'MESH:D063646', (64, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('161', '170'))	('cytotoxicity', 'Disease', (119, 131))	('carcinogenic', 'Disease', (64, 76))	('apoptosis', 'biological_process', 'GO:0006915', ('161', '170'))	('PPAR', 'Gene', (15, 19))	('hepatotoxicity', 'Disease', 'MESH:D056486', (45, 59))	('cytotoxicity', 'Disease', 'MESH:D064420', (119, 131))	('calcium', 'Chemical', 'MESH:D002118', (212, 219))	('intracellular calcium', 'MPA', (198, 219))	('agonists', 'Var', (20, 28))	('hepatotoxicity', 'Disease', (45, 59))
24053	19197366	Technically, this could, for example, be done by, in urothelial cells, separately monitoring expression of genes known to be activated by PPARalpha on one hand, and genes known to be activated by PPARgamma, on the other (PPAR-regulated genes listed in).	('rat', 'Species', '10116', (75, 78))	('expression', 'MPA', (93, 103))	('PPARalpha', 'Var', (138, 147))	('activated', 'PosReg', (125, 134))
24054	19197366	Nevertheless, the findings in Table 1 suggest that while agonists with a high degree of PPARgamma selectivity (i.e., specific PPARgamma agonists) can cause bladder cancer in rats, they may be less prone to do so than are agonists with a lower degree of PPARgamma selectivity (i.e., dual-acting PPARalpha+gamma agonists).	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cause', 'Reg', (150, 155))	('rats', 'Species', '10116', (174, 178))	('bladder cancer', 'Disease', 'MESH:D001749', (156, 170))	('bladder cancer', 'Disease', (156, 170))	('PPARgamma selectivity', 'Var', (88, 109))	('bladder cancer', 'Phenotype', 'HP:0009725', (156, 170))
24057	19197366	We have a different interpretation of the available data: it is clear that activation of PPARalpha can cause tumours in rats and mice (Table 1), and while more controversial, activation of PPARgamma can at least in some cases cause cancer in rats and mice (Table 1).	('rats', 'Species', '10116', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('mice', 'Species', '10090', (251, 255))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('cancer', 'Disease', (232, 238))	('cause', 'Reg', (226, 231))	('mice', 'Species', '10090', (129, 133))	('tumours', 'Disease', (109, 116))	('PPARalpha', 'Gene', (89, 98))	('cause', 'Reg', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('rats', 'Species', '10116', (242, 246))	('activation', 'Var', (75, 85))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
24059	19197366	Thus, it is plausible that the carcinogenic effect of dual-acting PPARalpha+gamma agonists in cells coexpressing PPARalpha and PPARgamma (Table 1) may be due to receptor-mediated mechanisms (exaggerated pharmacology).	('rat', 'Species', '10116', (197, 200))	('PPARgamma', 'Var', (127, 136))	('PPARalpha', 'Var', (113, 122))	('carcinogenic', 'Disease', 'MESH:D063646', (31, 43))	('carcinogenic', 'Disease', (31, 43))
24060	19197366	Thus, the hypothesis of receptor-mediated carcinogenicity (carcinogenicity due to exaggerated pharmacology) would predict that in rat tissue coexpressing PPARalpha and PPARgamma, dual-acting PPARalpha+gamma agonists may have a higher propensity for carcinogenic effect than selective PPARalpha and PPARgamma agonists alone, which in fact appears to be the case (Table 1).	('carcinogenic', 'Disease', (249, 261))	('rat', 'Species', '10116', (88, 91))	('PPARgamma', 'Var', (168, 177))	('PPARalpha', 'Var', (154, 163))	('carcinogenic', 'Disease', 'MESH:D063646', (42, 54))	('carcinogenic', 'Disease', 'MESH:D063646', (59, 71))	('carcinogenic', 'Disease', (42, 54))	('carcinogenic', 'Disease', (59, 71))	('rat', 'Species', '10116', (130, 133))	('carcinogenic', 'Disease', 'MESH:D063646', (249, 261))
24073	19197366	Adding 1% NH4Cl to rat feed induces systemic acidosis, measurable directly by reduced blood pH, reduced blood [HCO3 -], and increased blood [H+] as well as indirectly by, for example, increased urinary Ca++ and phosphorus excretion due to bone resorption.	('HCO3', 'Chemical', 'MESH:D001639', (111, 115))	('systemic acidosis', 'Disease', 'MESH:D000138', (36, 53))	('bone resorption', 'biological_process', 'GO:0045453', ('239', '254'))	('reduced', 'NegReg', (96, 103))	('increased', 'PosReg', (124, 133))	('blood [HCO3 -]', 'MPA', (104, 118))	('4Cl', 'molecular_function', 'GO:0016207', ('12', '15'))	('systemic acidosis', 'Disease', (36, 53))	('excretion', 'biological_process', 'GO:0007588', ('222', '231'))	('acidosis', 'Phenotype', 'HP:0001941', (45, 53))	('phosphorus', 'Chemical', 'MESH:D010758', (211, 221))	('NH4Cl', 'Chemical', 'MESH:D000643', (10, 15))	('increased', 'PosReg', (184, 193))	('blood pH', 'MPA', (86, 94))	('reduced', 'NegReg', (78, 85))	('blood [H+]', 'MPA', (134, 144))	('NH4Cl', 'Var', (10, 15))	('bone resorption', 'Phenotype', 'HP:0002797', (239, 254))	('rat', 'Species', '10116', (19, 22))	('bone resorption', 'CPA', (239, 254))
24075	19197366	However, urine acidification by feeding rats NH4Cl has also been reported to reduce the occurence of bladder tumours, where the mechanism is not thought to be urolith-mediated, and NH4Cl feeding of rats can also influence the occurrence of tumours outside of the urinary bladder.	('bladder tumours', 'Disease', (101, 116))	('urine acidification', 'Phenotype', 'HP:0031033', (9, 28))	('tumours', 'Disease', (240, 247))	('NH4Cl', 'Var', (181, 186))	('reduce', 'NegReg', (77, 83))	('NH4Cl', 'Chemical', 'MESH:D000643', (45, 50))	('acidification', 'biological_process', 'GO:0045851', ('15', '28'))	('influence', 'Reg', (212, 221))	('urine acidification', 'MPA', (9, 28))	('tumours', 'Phenotype', 'HP:0002664', (240, 247))	('bladder tumour', 'Phenotype', 'HP:0009725', (101, 115))	('bladder tumours', 'Disease', 'MESH:D001749', (101, 116))	('tumours', 'Disease', 'MESH:D009369', (240, 247))	('rats', 'Species', '10116', (40, 44))	('NH4Cl', 'Chemical', 'MESH:D000643', (181, 186))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('tumours', 'Disease', (109, 116))	('rats', 'Species', '10116', (198, 202))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('4Cl', 'molecular_function', 'GO:0016207', ('183', '186'))	('4Cl', 'molecular_function', 'GO:0016207', ('47', '50'))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
24076	19197366	In fact, systemic acidosis induced by NH4Cl would be expected to have profound effects on cellular and organ function in the whole organism, including the bladder.	('acidosis', 'Phenotype', 'HP:0001941', (18, 26))	('NH4Cl', 'Var', (38, 43))	('systemic acidosis', 'Disease', 'MESH:D000138', (9, 26))	('NH4Cl', 'Chemical', 'MESH:D000643', (38, 43))	('4Cl', 'molecular_function', 'GO:0016207', ('40', '43'))	('effects', 'Reg', (79, 86))	('systemic acidosis', 'Disease', (9, 26))
24200	31652725	The interactions promote the aggressive phenotypes of certain cancers, such as those of the bladder, endometrium, lung, urinary bladder, and breast cancer through programming the epithelial-mesenchymal transition (EMT).	('EMT', 'biological_process', 'GO:0001837', ('214', '217'))	('programming', 'Reg', (163, 174))	('epithelial-mesenchymal transition', 'CPA', (179, 212))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('interactions', 'Var', (4, 16))	('promote', 'PosReg', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('179', '212'))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('endometrium', 'Disease', (101, 112))	('bladder', 'Disease', (92, 99))	('breast cancer', 'Disease', (141, 154))	('lung', 'Disease', (114, 118))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('urinary bladder', 'Disease', (120, 135))
24213	31652725	Similar to EMPs, the atypical activity of PMP22 is correlated with metastatic progression in certain cancers.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('metastatic progression', 'CPA', (67, 89))	('correlated with', 'Reg', (51, 66))	('atypical', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('PMP22', 'Gene', (42, 47))
24218	31652725	In a retinal epithelial cell line, EMP2 induces intracellular collagen gel contraction through the activation of focal adhesion kinase (FAK) at two phosphorylation sites Tyr576 and Tyr577.	('induces', 'Reg', (40, 47))	('Tyr576', 'Chemical', '-', (170, 176))	('intracellular collagen gel contraction', 'CPA', (48, 86))	('focal adhesion', 'cellular_component', 'GO:0005925', ('113', '127'))	('Tyr577', 'Var', (181, 187))	('FAK', 'Gene', (136, 139))	('activation', 'PosReg', (99, 109))	('FAK', 'Gene', '5747', (136, 139))	('focal adhesion kinase', 'Gene', '5747', (113, 134))	('Tyr577', 'Chemical', '-', (181, 187))	('EMP2', 'Gene', (35, 39))	('FAK', 'molecular_function', 'GO:0004717', ('136', '139'))	('phosphorylation', 'biological_process', 'GO:0016310', ('148', '163'))	('intracellular', 'cellular_component', 'GO:0005622', ('48', '61'))	('collagen', 'molecular_function', 'GO:0005202', ('62', '70'))	('focal adhesion kinase', 'Gene', (113, 134))	('Tyr576', 'Var', (170, 176))
24223	31652725	In contrast, knockdown of EMP3 expression enhances the induction of CTLs, secretion of interferon-gamma, and the expression of IL-2 receptor alpha by CD8+ T cells.	('expression', 'MPA', (113, 123))	('CD8', 'Gene', (150, 153))	('CD8', 'Gene', '925', (150, 153))	('induction', 'MPA', (55, 64))	('IL-2 receptor alpha', 'Gene', '3559', (127, 146))	('IL-2 receptor alpha', 'Gene', (127, 146))	('IL-2', 'molecular_function', 'GO:0005134', ('127', '131'))	('interferon-gamma', 'Gene', '3458', (87, 103))	('enhances', 'PosReg', (42, 50))	('EMP3', 'Gene', (26, 30))	('secretion', 'biological_process', 'GO:0046903', ('74', '83'))	('knockdown', 'Var', (13, 22))	('CTLs', 'MPA', (68, 72))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('87', '103'))	('interferon-gamma', 'Gene', (87, 103))
24235	31652725	Silencing EMP1 expression in glioblastoma cells inhibits their proliferation and invasiveness, as well as the expression of CD44 and matrix metalloprotease (MMP)-2.	('glioblastoma', 'Disease', 'MESH:D005909', (29, 41))	('proliferation', 'CPA', (63, 76))	('CD44', 'Gene', (124, 128))	('inhibits', 'NegReg', (48, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('MMP)-2', 'molecular_function', 'GO:0004228', ('157', '163'))	('expression', 'MPA', (110, 120))	('invasiveness', 'CPA', (81, 93))	('EMP1', 'Gene', (10, 14))	('CD44', 'Gene', '960', (124, 128))	('Silencing', 'Var', (0, 9))	('glioblastoma', 'Disease', (29, 41))
24238	31652725	Other consequences of the inhibition of dysregulated CD44 by silencing EMP1 expression include the suppression of the activities of transcription factors such as OCT4, SOX2, and Nanog.	('OCT4', 'Gene', '5460', (162, 166))	('SOX2', 'Gene', '6657', (168, 172))	('OCT4', 'Gene', (162, 166))	('transcription', 'biological_process', 'GO:0006351', ('132', '145'))	('SOX2', 'Gene', (168, 172))	('CD44', 'Gene', '960', (53, 57))	('dysregulated', 'Var', (40, 52))	('inhibition', 'NegReg', (26, 36))	('activities', 'MPA', (118, 128))	('silencing', 'NegReg', (61, 70))	('CD44', 'Gene', (53, 57))	('transcription', 'MPA', (132, 145))	('expression', 'MPA', (76, 86))	('EMP1', 'Gene', (71, 75))	('Nanog', 'Gene', '79923', (178, 183))	('suppression', 'NegReg', (99, 110))	('Nanog', 'Gene', (178, 183))
24250	31652725	Silencing EMP1 expression in prednisolone-resistant leukemic cell lines induces apoptosis, suppresses cell migration and adhesion, decreases the proliferation rate, and sensitizes cells to prednisolone.	('sensitizes', 'Reg', (169, 179))	('suppresses', 'NegReg', (91, 101))	('induces', 'Reg', (72, 79))	('prednisolone', 'Chemical', 'MESH:D011239', (189, 201))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('proliferation rate', 'CPA', (145, 163))	('decreases', 'NegReg', (131, 140))	('prednisolone', 'Chemical', 'MESH:D011239', (29, 41))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('EMP1', 'Gene', (10, 14))	('Silencing', 'Var', (0, 9))	('apoptosis', 'CPA', (80, 89))	('cell migration', 'biological_process', 'GO:0016477', ('102', '116'))
24294	31652725	Transcriptional profiling analyses detected the dysregulation of EMP2 mRNA expression in breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (89, 103))	('breast cancers', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('EMP2', 'Gene', (65, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('dysregulation', 'Var', (48, 61))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('mRNA expression', 'MPA', (70, 85))	('N', 'Chemical', 'MESH:D009584', (72, 73))	('breast cancers', 'Phenotype', 'HP:0003002', (89, 103))
24308	31652725	Ectopic expression of EMP2 in nasopharynx cancer cells in vitro impairs cell growth, enhances the efficiency of radiotherapy, induces cell cycle arrest at S phase, and increases apoptosis at both early and late stages.	('arrest', 'Disease', 'MESH:D006323', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('178', '187'))	('apoptosis', 'biological_process', 'GO:0006915', ('178', '187'))	('cell growth', 'CPA', (72, 83))	('induces', 'Reg', (126, 133))	('Ectopic expression', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('S phase', 'biological_process', 'GO:0051320', ('155', '162'))	('increases', 'PosReg', (168, 177))	('arrest', 'Disease', (145, 151))	('apoptosis', 'CPA', (178, 187))	('nasopharynx cancer', 'Phenotype', 'HP:0100630', (30, 48))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (134, 151))	('EMP2', 'Gene', (22, 26))	('impairs', 'NegReg', (64, 71))	('cancer', 'Disease', (42, 48))	('enhances', 'PosReg', (85, 93))	('cell growth', 'biological_process', 'GO:0016049', ('72', '83'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('134', '151'))
24312	31652725	EMP2 protein expression inversely correlates with the histologic grades of uroepithelial cancer cells, and overexpression of EMP2 impairs cancer cell proliferation and inhibits tumor development.	('impairs cancer', 'Disease', (130, 144))	('cell proliferation', 'biological_process', 'GO:0008283', ('145', '163'))	('inhibits', 'NegReg', (168, 176))	('overexpression', 'Var', (107, 121))	('EMP2', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('uroepithelial cancer', 'Disease', 'MESH:D009369', (75, 95))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('EMP2', 'Gene', (125, 129))	('impairs cancer', 'Disease', 'MESH:D009369', (130, 144))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('uroepithelial cancer', 'Disease', (75, 95))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('protein', 'Protein', (5, 12))	('tumor', 'Disease', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
24318	31652725	The overall survival rates of GBM patients with high EMP3 levels are reduced compared with those with low EMP3 levels.	('reduced', 'NegReg', (69, 76))	('survival rates', 'CPA', (12, 26))	('patients', 'Species', '9606', (34, 42))	('high', 'Var', (48, 52))	('GBM', 'Disease', (30, 33))
24323	31652725	The expression of EMP3 is likely modulated by miR-765 in oral squamous carcinoma cells, and the depletion of EMP3 markedly stimulates the expression of p66Shc to impair the migratory activity of the cells.	('p66Shc', 'Var', (152, 158))	('stimulates', 'PosReg', (123, 133))	('migratory activity of the cells', 'CPA', (173, 204))	('oral squamous carcinoma', 'Disease', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('miR-765', 'Gene', '768220', (46, 53))	('EMP3', 'Gene', (109, 113))	('oral squamous carcinoma', 'Disease', 'MESH:D002294', (57, 80))	('depletion', 'Var', (96, 105))	('expression', 'MPA', (138, 148))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (62, 80))	('impair', 'NegReg', (162, 168))	('miR-765', 'Gene', (46, 53))
24328	31652725	The knockdown enhances the expression of cyclin-dependent kinase inhibitors p21 and p27, and reduces the levels of cyclins E and D1.	('cyclin-dependent', 'Protein', (41, 57))	('p27', 'Gene', (84, 87))	('reduces', 'NegReg', (93, 100))	('p21', 'Gene', (76, 79))	('expression', 'MPA', (27, 37))	('cyclin', 'molecular_function', 'GO:0016538', ('41', '47'))	('enhances', 'PosReg', (14, 22))	('knockdown', 'Var', (4, 13))	('p21', 'Gene', '644914', (76, 79))	('p27', 'Gene', '3429', (84, 87))
24329	31652725	The effects of high EMP3 expression on the malignant phenotype of HCC cells are associated with the increment of cell migration and invasion, as well as the proteolytic activities of MMP-9 and urokinase.	('high', 'Var', (15, 19))	('EMP3', 'Gene', (20, 24))	('malignant phenotype', 'CPA', (43, 62))	('urokinase', 'Protein', (193, 202))	('MMP-9', 'Gene', (183, 188))	('MMP-9', 'Gene', '4318', (183, 188))	('increment', 'PosReg', (100, 109))	('cell migration', 'biological_process', 'GO:0016477', ('113', '127'))	('proteolytic activities', 'MPA', (157, 179))	('MMP-9', 'molecular_function', 'GO:0004229', ('183', '188'))	('invasion', 'CPA', (132, 140))
24337	31652725	These findings highlight the importance of the EMP3-ErbB2 association as a potential indicator of progression and metastasis of upper urinary tract urothelial carcinoma.	('association', 'Var', (58, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('upper urinary tract urothelial carcinoma', 'Disease', (128, 168))	('ErbB2', 'Gene', (52, 57))	('upper urinary tract urothelial carcinoma', 'Disease', 'MESH:D014571', (128, 168))	('ErbB2', 'Gene', '2064', (52, 57))
24345	31652725	The level of miR-663a is augmented in human gallbladder cancer tissues, and knockdown of this miRNA reciprocally increases EMP3 expression.	('human', 'Species', '9606', (38, 43))	('knockdown', 'Var', (76, 85))	('miR-663a', 'Gene', (13, 21))	('miR-663a', 'Gene', '724033', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('gallbladder cancer', 'Disease', 'MESH:D005706', (44, 62))	('gallbladder cancer', 'Disease', (44, 62))	('EMP3', 'Gene', (123, 127))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('increases', 'PosReg', (113, 122))
24351	31652725	Although mutations and loss of functions of PMP22 are related to demyelinating peripheral neuropathies, PMP22 is also reported to increase the aggressiveness of various types of cancers.	('aggressiveness', 'Disease', 'MESH:D001523', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('demyelinating peripheral neuropathies', 'Phenotype', 'HP:0007108', (65, 102))	('mutations', 'Var', (9, 18))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('PMP22', 'Gene', (44, 49))	('aggressiveness', 'Disease', (143, 157))	('loss of functions', 'NegReg', (23, 40))	('demyelinating peripheral neuropathies', 'Disease', (65, 102))	('cancers', 'Disease', (178, 185))	('increase', 'PosReg', (130, 138))	('aggressiveness', 'Phenotype', 'HP:0000718', (143, 157))	('peripheral neuropathies', 'Phenotype', 'HP:0009830', (79, 102))	('demyelinating peripheral neuropathies', 'Disease', 'MESH:D010523', (65, 102))	('PMP22', 'Gene', (104, 109))
24365	31652725	In an animal model using BALB/c mice, anti-EMP2 treatment actually reduces the number of metastatic lesions generated by xenografted mammary gland tumor cells that express high levels of EMP2.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('anti-EMP2', 'Var', (38, 47))	('mice', 'Species', '10090', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('reduces', 'NegReg', (67, 74))
24401	31440865	All patients reported the following questionnaires weekly electronically or by paper: EORTC QLQ-C30, EORTC QLQ-BLM30, HADS, PRO-CTCAE QF1 and 3 general health questions, a total of 161 questions weekly by each patient throughout the course of chemotherapy.	('HADS', 'Chemical', 'MESH:C018209', (118, 122))	('EORTC QLQ-C30', 'Disease', (86, 99))	('patient', 'Species', '9606', (4, 11))	('patient', 'Species', '9606', (210, 217))	('EORTC QLQ-BLM30', 'Var', (101, 116))	('patients', 'Species', '9606', (4, 12))	('EORTC', 'Chemical', '-', (86, 91))	('EORTC', 'Chemical', '-', (101, 106))
24474	29541581	UCB is typically caused by environmental factors such as cigarette smoking, occupational exposures, e.g., aromatic amines, and intravesical chronic inflammation.	('inflammation', 'Disease', 'MESH:D007249', (148, 160))	('inflammation', 'Disease', (148, 160))	('UCB', 'Chemical', '-', (0, 3))	('UCB', 'Phenotype', 'HP:0006740', (0, 3))	('aromatic amines', 'Chemical', '-', (106, 121))	('aromatic', 'Var', (106, 114))	('inflammation', 'biological_process', 'GO:0006954', ('148', '160'))	('UCB', 'Disease', (0, 3))	('caused', 'Reg', (17, 23))
24482	29541581	CK20 is a sensitive marker for urothelial differentiation in superficial bladder tumors, and abnormal CK20 staining is likely to be associated with a high recurrence rate.	('bladder tumors', 'Phenotype', 'HP:0009725', (73, 87))	('bladder tumors', 'Disease', (73, 87))	('CK20', 'Gene', '54474', (0, 4))	('abnormal', 'Var', (93, 101))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('associated', 'Reg', (132, 142))	('CK20', 'Gene', '54474', (102, 106))	('bladder tumors', 'Disease', 'MESH:D001749', (73, 87))	('CK20', 'Gene', (102, 106))	('CK20', 'Gene', (0, 4))
24506	29126388	Furthermore, expression of RNY1 and RNY3 was predictive for BCA patients' overall (also RNY4) and cancer-specific survival as estimated using Kaplan-Meier and univariate (but not multivariate) Cox regression analyses.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('patients', 'Species', '9606', (64, 72))	('BCA', 'Disease', (60, 63))	('RNY4', 'Gene', (88, 92))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('RNY3', 'Gene', '6085', (36, 40))	('expression', 'Var', (13, 23))	('RNY1', 'Gene', (27, 31))	('cancer', 'Disease', (98, 104))	('RNY1', 'Gene', '6084', (27, 31))	('RNY3', 'Gene', (36, 40))	('RNY4', 'Gene', '6086', (88, 92))
24544	29126388	siRNA mediated knock-down of RNY1 and RNY3 reduced the number proportion of S phase cells in the HeLa cells; degradation of RNY3 reduced also the number S-phase cells in EJ30 bladder cancer cells.	('bladder cancer', 'Disease', 'MESH:D001749', (175, 189))	('S phase', 'biological_process', 'GO:0051320', ('76', '83'))	('bladder cancer', 'Disease', (175, 189))	('reduced', 'NegReg', (129, 136))	('reduced', 'NegReg', (43, 50))	('HeLa', 'CellLine', 'CVCL:0030', (97, 101))	('RNY3', 'Gene', '6085', (38, 42))	('RNY1', 'Gene', '6084', (29, 33))	('bladder cancer', 'Phenotype', 'HP:0009725', (175, 189))	('RNY3', 'Gene', '6085', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('S-phase', 'biological_process', 'GO:0051320', ('153', '160'))	('degradation', 'Var', (109, 120))	('degradation', 'biological_process', 'GO:0009056', ('109', '120'))	('RNY1', 'Gene', (29, 33))	('RNY3', 'Gene', (38, 42))	('RNY3', 'Gene', (124, 128))	('knock-down', 'Var', (15, 25))	('EJ30', 'CellLine', 'CVCL:7039', (170, 174))
24571	28143426	Remarkably, inhibition of p53 by gene silencing or pifithrin-alpha pretreatment, as well as caspase inhibition, did not suppress apoptotic activity of frondoside A, while cisplatin activity, in contrast, was significantly decreased.	('gene silencing', 'Var', (33, 47))	('frondoside A', 'Gene', '8061', (151, 163))	('inhibition', 'NegReg', (12, 22))	('caspase', 'Gene', (92, 99))	('cisplatin activity', 'MPA', (171, 189))	('frondoside A', 'Gene', (151, 163))	('p53', 'Gene', (26, 29))	('caspase', 'Gene', '841;842', (92, 99))	('gene silencing', 'biological_process', 'GO:0016458', ('33', '47'))	('apoptotic activity', 'CPA', (129, 147))	('p53', 'Gene', '7157', (26, 29))	('pifithrin-alpha', 'Chemical', 'MESH:C121565', (51, 66))	('suppress', 'NegReg', (120, 128))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))	('decreased', 'NegReg', (222, 231))
24581	28143426	Furthermore, p53 deficiency or inactivation is a known mechanism of drug resistance in human malignancies.	('deficiency', 'Disease', (17, 27))	('drug resistance', 'Phenotype', 'HP:0020174', (68, 83))	('deficiency', 'Disease', 'MESH:D007153', (17, 27))	('inactivation', 'Var', (31, 43))	('human', 'Species', '9606', (87, 92))	('malignancies', 'Disease', 'MESH:D009369', (93, 105))	('drug resistance', 'biological_process', 'GO:0009315', ('68', '83'))	('p53', 'Gene', (13, 16))	('drug resistance', 'biological_process', 'GO:0042493', ('68', '83'))	('malignancies', 'Disease', (93, 105))	('p53', 'Gene', '7157', (13, 16))
24584	28143426	Therefore, pharmacological inhibitors of autophagy may prevent development of resistance and enhance cytotoxic activity of known anticancer drugs.	('autophagy', 'CPA', (41, 50))	('cytotoxic activity', 'CPA', (101, 119))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('autophagy', 'biological_process', 'GO:0016236', ('41', '50'))	('enhance', 'PosReg', (93, 100))	('cancer', 'Disease', (133, 139))	('pharmacological inhibitors', 'Var', (11, 37))	('autophagy', 'biological_process', 'GO:0006914', ('41', '50'))	('prevent', 'NegReg', (55, 62))	('development of resistance', 'CPA', (63, 88))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
24589	28143426	In this study we examined the effect of the triterpene glycoside FrA in human UC cells bearing either wild-type or mutant p53.	('triterpene glycoside', 'Chemical', '-', (44, 64))	('mutant', 'Var', (115, 121))	('p53', 'Gene', '7157', (122, 125))	('human', 'Species', '9606', (72, 77))	('FrA', 'Gene', (65, 68))	('FrA', 'Gene', '8061', (65, 68))	('p53', 'Gene', (122, 125))
24593	28143426	The human urothelial cancer cell lines RT4 (p53 wild type), HT-1197 (p53 wild type), TCC-SUP (mutant p53), T-24 (mutant p53), were purchased from ATCC (Manassas, VA, USA).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('TCC', 'cellular_component', 'GO:0005579', ('85', '88'))	('human', 'Species', '9606', (4, 9))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('p53', 'Gene', '7157', (120, 123))	('HT-1197', 'CellLine', 'CVCL:1291', (60, 67))	('urothelial cancer', 'Disease', (10, 27))	('TC', 'Chemical', 'MESH:D013667', (85, 87))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('p53', 'Gene', (44, 47))	('TC', 'Chemical', 'MESH:D013667', (147, 149))	('p53', 'Gene', '7157', (44, 47))	('mutant', 'Var', (113, 119))	('p53', 'Gene', (120, 123))	('urothelial cancer', 'Disease', 'MESH:D014523', (10, 27))
24604	28143426	Silencing of p53 gene was performed using siRNA transfection technique and Lipofectamine  RNAiMAX Transfection Reagent (Invitrogen, UK).	('Silencing', 'Var', (0, 9))	('Lipofectamine', 'Chemical', 'MESH:C086724', (75, 88))	('p53', 'Gene', '7157', (13, 16))	('p53', 'Gene', (13, 16))
24634	28143426	Silencing of the p53 gene expression using specific siRNA resulted in a substantial reduction of p53 protein level in RT112 cells (Fig.	('p53', 'Gene', (97, 100))	('reduction', 'NegReg', (84, 93))	('Silencing', 'Var', (0, 9))	('p53', 'Gene', '7157', (97, 100))	('RT112', 'CellLine', 'CVCL:1670', (118, 123))	('gene expression', 'biological_process', 'GO:0010467', ('21', '36'))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
24638	28143426	3e) suggesting that FrA remains active in human cancer cells bearing mutated non-functional p53.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('human', 'Species', '9606', (42, 47))	('mutated non-functional', 'Var', (69, 91))	('cancer', 'Disease', (48, 54))	('p53', 'Gene', (92, 95))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('FrA', 'Gene', (20, 23))	('p53', 'Gene', '7157', (92, 95))	('non-functional', 'Var', (77, 91))	('FrA', 'Gene', '8061', (20, 23))
24644	28143426	Combining FrA and SP600125 clearly showed synergistic cytotoxic effects in MTT-based Chou-Talalay assays (Fig.	('SP600125', 'Var', (18, 26))	('MTT', 'Chemical', 'MESH:C070243', (75, 78))	('MTT-based Chou-Talalay assays', 'CPA', (75, 104))	('SP600125', 'Chemical', 'MESH:C432165', (18, 26))	('FrA', 'Gene', (10, 13))	('FrA', 'Gene', '8061', (10, 13))
24662	28143426	This process was associated with the alteration of several pro-apoptotic factors, like cleaved caspases-3, -8, and -9, cleaved PARP, Bax and p21, leading to dose-dependent DNA fragmentation and phosphatidylserine externalization.	('phosphatidylserine externalization', 'MPA', (194, 228))	('caspases', 'Gene', (95, 103))	('PARP', 'Gene', (127, 131))	('p21', 'Gene', (141, 144))	('Bax', 'Gene', (133, 136))	('alteration', 'Reg', (37, 47))	('p21', 'Gene', '644914', (141, 144))	('caspases', 'Gene', '841;842', (95, 103))	('DNA fragmentation', 'MPA', (172, 189))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('cleaved', 'Var', (119, 126))	('DNA fragmentation', 'biological_process', 'GO:0006309', ('172', '189'))	('PARP', 'Gene', '1302', (127, 131))	('Bax', 'Gene', '581', (133, 136))
24668	28143426	Overexpression of endogenous caspase inhibitors, mutations in caspase genes and genes coding up- or downstream molecules, as well as low expression of these genes were found to be causative.	('mutations', 'Var', (49, 58))	('caspase', 'Gene', (29, 36))	('caspase', 'Gene', '841;842', (62, 69))	('caspase', 'Gene', (62, 69))	('caspase', 'Gene', '841;842', (29, 36))
24669	28143426	In addition, more than 50% of all human tumors (and >60% of UC neoplasms) harbor mutant p53 with abrogated tumor suppressive function.	('human', 'Species', '9606', (34, 39))	('neoplasms', 'Disease', 'MESH:D009369', (63, 72))	('neoplasms', 'Disease', (63, 72))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('abrogated', 'NegReg', (97, 106))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (88, 91))	('neoplasms', 'Phenotype', 'HP:0002664', (63, 72))	('mutant', 'Var', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (40, 45))	('tumors', 'Disease', (40, 46))
24674	28143426	More importantly, using two different independent methods, namely p53 gene silencing and inhibition of p53 activity by pifithrin-alpha, we have demonstrated that FrA-induced apoptosis could not be abolished by p53 alterations.	('p53', 'Gene', '7157', (210, 213))	('FrA', 'Gene', (162, 165))	('p53', 'Gene', '7157', (66, 69))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('activity', 'MPA', (107, 115))	('gene silencing', 'biological_process', 'GO:0016458', ('70', '84'))	('FrA', 'Gene', '8061', (162, 165))	('apoptosis', 'biological_process', 'GO:0097194', ('174', '183'))	('apoptosis', 'biological_process', 'GO:0006915', ('174', '183'))	('pifithrin-alpha', 'Chemical', 'MESH:C121565', (119, 134))	('gene', 'Var', (70, 74))	('inhibition', 'NegReg', (89, 99))	('p53', 'Gene', (210, 213))	('p53', 'Gene', (66, 69))
24675	28143426	In line with these results, FrA was active in UC cells bearing both wild-type (RT112, RT4, and HT-1197 cells) and mutant (T-24 and TCC-SUP cells) p53.	('FrA', 'Gene', '8061', (28, 31))	('HT-1197', 'CellLine', 'CVCL:1291', (95, 102))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('TCC', 'cellular_component', 'GO:0005579', ('131', '134'))	('mutant', 'Var', (114, 120))	('RT112', 'CellLine', 'CVCL:1670', (79, 84))	('TC', 'Chemical', 'MESH:D013667', (131, 133))	('FrA', 'Gene', (28, 31))
24676	28143426	Interestingly, FrA appeared to be even slightly more effective in RT112 cells with silenced or inhibited p53.	('RT112', 'CellLine', 'CVCL:1670', (66, 71))	('FrA', 'Gene', (15, 18))	('silenced', 'Var', (83, 91))	('FrA', 'Gene', '8061', (15, 18))	('inhibited', 'NegReg', (95, 104))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))
24677	28143426	In contrast, in both experiments cisplatin was significantly less active in cells with either silenced or inhibited p53, demonstrating a p53-dependence of cytotoxicity of this classical anti-cancer agent.	('inhibited', 'Var', (106, 115))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('p53', 'Gene', '7157', (137, 140))	('cytotoxicity', 'Disease', (155, 167))	('p53', 'Gene', '7157', (116, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('p53', 'Gene', (137, 140))	('cytotoxicity', 'Disease', 'MESH:D064420', (155, 167))	('p53', 'Gene', (116, 119))
24699	27218105	Aberrantly expressed miRNAs have been shown to be associated with many types of cancers.	('Aberrantly expressed', 'Var', (0, 20))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('miRNAs', 'Protein', (21, 27))	('associated', 'Reg', (50, 60))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
24700	27218105	A number of studies have investigated the expression of microRNAs in urothelial carcinoma, mainly on urothelial bladder cancer, and only a few have included patients with UTUC.	('microRNAs', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (101, 126))	('patients', 'Species', '9606', (157, 165))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (69, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))	('urothelial carcinoma', 'Disease', (69, 89))	('urothelial bladder cancer', 'Disease', (101, 126))
24711	27218105	Disrupting any of the three systems that contribute to epigenetic alterations can cause abnormal activation or silencing of genes.	('epigenetic alterations', 'Var', (55, 77))	('silencing', 'NegReg', (111, 120))	('cause', 'Reg', (82, 87))	('rat', 'Species', '10116', (70, 73))	('Disrupting', 'Var', (0, 10))	('activation', 'MPA', (97, 107))	('genes', 'Gene', (124, 129))
24714	27218105	Aberrantly expressed miRNAs have been shown to be associated with many types of cancers, functioning as regulatory molecules, acting as oncogenes or tumor suppressors.	('Aberrantly expressed', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('miRNAs', 'Protein', (21, 27))	('tumor', 'Disease', (149, 154))	('associated', 'Reg', (50, 60))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
24749	27218105	R Bioconductor analysis included moderated t-test for differential expression of the miRNAs with log fold change >2 and P value < 0.05, while GeneSpring statistics included one-way ANOVA, followed by moderated t-test, also set at P value < 0.05, and log fold change >2.	('log fold change', 'Var', (97, 112))	('rat', 'Species', '10116', (204, 207))	('rat', 'Species', '10116', (37, 40))	('expression', 'MPA', (67, 77))	('differential', 'Reg', (54, 66))
24764	27218105	In patients with BEN-UTUC we determined three downregulated miRNAs, that is, hsa-miR-127-3p, hsa-miR-154-5p, and hsa-miR-30a-5p.	('miR-127', 'Gene', (81, 88))	('miR-127', 'Gene', '406914', (81, 88))	('patients', 'Species', '9606', (3, 11))	('downregulated', 'NegReg', (46, 59))	('miRNAs', 'MPA', (60, 66))	('miR-154', 'Gene', (97, 104))	('miR-154', 'Gene', '406946', (97, 104))	('hsa-miR-30a-5p', 'Var', (113, 127))
24766	27218105	Hsa-miR-30a-5p was found to be downregulated in lung and colorectal and upregulated in ovarian cancer.	('Hsa-miR-30a-5p', 'Var', (0, 14))	('colorectal', 'Disease', 'MESH:D015179', (57, 67))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('lung', 'Disease', (48, 52))	('colorectal', 'Disease', (57, 67))	('ovarian cancer', 'Disease', 'MESH:D010051', (87, 101))	('downregulated', 'NegReg', (31, 44))	('upregulated', 'PosReg', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ovarian cancer', 'Disease', (87, 101))
24768	27218105	Recently a few studies that investigated microRNA profile in nephropathies caused by aristolochic acid in humans and rats have been published.	('nephropathies', 'Disease', (61, 74))	('aristolochic acid', 'Chemical', 'MESH:C000228', (85, 102))	('nephropathies', 'Phenotype', 'HP:0000112', (61, 74))	('rats', 'Species', '10116', (117, 121))	('humans', 'Species', '9606', (106, 112))	('nephropathies', 'Disease', 'MESH:D007674', (61, 74))	('aristolochic acid', 'Var', (85, 102))
24780	27218105	Two studies investigated the toxicity of aristolochic acid in rat models, making direct comparison not quite suitable.	('toxicity', 'Disease', 'MESH:D064420', (29, 37))	('aristolochic acid', 'Chemical', 'MESH:C000228', (41, 58))	('investigated', 'Reg', (12, 24))	('rat', 'Species', '10116', (62, 65))	('toxicity', 'Disease', (29, 37))	('aristolochic', 'Var', (41, 53))
24784	27218105	We found 15 differentially expressed microRNAs among non-BEN-UTUC samples, of which only hsa-miR-663b was downregulated and 14 were upregulated (hsa-miR-1260a, hsa-miR-141-3p, hsa-miR-149-5p, hsa-miR-182-5p, hsa-miR-183-5p, hsa-miR-197-3p, hsa-miR-200c-3p, hsa-miR-203a-3p, hsa-miR-205-5p, hsa-miR-205-3p, hsa-miR-210-3p, hsa-miR-224-5p, hsa-miR-224-3p, and hsa-miR-96-5p).	('miR-149', 'Gene', '406941', (180, 187))	('miR-205', 'Gene', '406988', (278, 285))	('miR-210', 'Gene', (310, 317))	('downregulated', 'NegReg', (106, 119))	('hsa-miR-663b', 'Gene', (89, 101))	('miR-197', 'Gene', (228, 235))	('upregulated', 'PosReg', (132, 143))	('miR-200c', 'Gene', (244, 252))	('miR-182', 'Gene', (196, 203))	('miR-205', 'Gene', (294, 301))	('miR-182', 'Gene', '406958', (196, 203))	('miR-205', 'Gene', (278, 285))	('hsa-miR-663b', 'Gene', '100313824', (89, 101))	('miR-197', 'Gene', '406974', (228, 235))	('miR-183', 'Gene', '406959', (212, 219))	('miR-141', 'Gene', '406933', (164, 171))	('miR-149', 'Gene', (180, 187))	('miR-224', 'Gene', '407009', (342, 349))	('miR-203a', 'Gene', (261, 269))	('miR-203a', 'Gene', '406986', (261, 269))	('miR-210', 'Gene', '406992', (310, 317))	('miR-141', 'Gene', (164, 171))	('miR-224', 'Gene', (342, 349))	('miR-183', 'Gene', (212, 219))	('miR-224', 'Gene', (326, 333))	('hsa-miR-1260a', 'Var', (145, 158))	('miR-205', 'Gene', '406988', (294, 301))	('miR-224', 'Gene', '407009', (326, 333))	('miR-200c', 'Gene', '406985', (244, 252))
24786	27218105	They found several microRNAs (miRNA-96, miRNA-182, miRNA-183, miRNA-141, miRNA-30b, miRNA-21, and miRNA-200c) that were overexpressed in high grade UCC.	('miRNA-200c', 'Var', (98, 108))	('miRNA-96', 'Gene', '407053', (30, 38))	('miRNA-21', 'Gene', '406991', (84, 92))	('miRNA-30b', 'Var', (73, 82))	('miRNA-182', 'Gene', '406958', (40, 49))	('miRNA-96', 'Gene', (30, 38))	('miRNA-183', 'Gene', '406959', (51, 60))	('miRNA-21', 'Gene', (84, 92))	('miRNA-183', 'Gene', (51, 60))	('miRNA-141', 'Var', (62, 71))	('miRNA-182', 'Gene', (40, 49))
24790	27218105	Furthermore, numerous studies have shown that alterations in surface glycans play pivotal roles in cancer initiation and progression.	('glycans', 'Chemical', 'MESH:D011134', (69, 76))	('rat', 'Species', '10116', (50, 53))	('surface glycans', 'Protein', (61, 76))	('cancer initiation', 'Disease', 'MESH:D009369', (99, 116))	('alterations', 'Var', (46, 57))	('cancer initiation', 'Disease', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
24908	33542239	It was previously reported that inhibin beta A (INHBA) production by cancer cells helps to induce CAFs, and ablating INHBA decreases the CAF phenotype both in vitro and in vivo.	('decreases', 'NegReg', (123, 132))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('CAF', 'Gene', '8850', (137, 140))	('CAF', 'Gene', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ablating', 'Var', (108, 116))	('CAF', 'Gene', (137, 140))	('INHBA', 'Gene', '3624', (48, 53))	('CAF', 'Gene', '8850', (98, 101))	('INHBA', 'Gene', '3624', (117, 122))	('inhibin', 'molecular_function', 'GO:0016916', ('32', '39'))	('INHBA', 'Gene', (48, 53))	('inhibin beta A', 'cellular_component', 'GO:0048183', ('32', '46'))	('inhibin', 'molecular_function', 'GO:0005160', ('32', '39'))	('INHBA', 'Gene', (117, 122))	('cancer', 'Disease', (69, 75))
24915	33542239	The calculation of the IFN-gamma/IMS ratio provides a self-normalization method that directly measures the balance between contradicting biological processes within the tumor microenvironment, thus providing a selection process that is more robust to the confounding factor of intersample gene expression variations to identify genes that contribute negatively to the outcome of immunotherapy.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('IMS', 'Chemical', '-', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('gene expression', 'biological_process', 'GO:0010467', ('289', '304'))	('IFN-gamma', 'Gene', '3458', (23, 32))	('IFN-gamma', 'Gene', (23, 32))	('tumor', 'Disease', (169, 174))	('variations', 'Var', (305, 315))
24924	33542239	Currently, clinical trials are assessing the efficacy of combining anti-PD-1 therapy with medicines that target at normalization of immune suppressive TME including the CSF1R inhibitor Cabrilizumab for the treatment of resectable biliary tract cancer (NCT03768531), CCR2 inhibitor plozalizumab for the treatment of melanoma (NCT02723006), the FAP inhibitor RO6874281 for the treatment of metastatic head and neck, esophageal or cervical cancers (NCT03386721) and metastatic melanoma (NCT03875079), and the TGF-beta inhibitor galunisertib (LY2157299) for the treatment of advanced-stage NSCLC or hepatocellular carcinoma (NCT02423343) and metastatic pancreatic cancer (NCT02734160).	('neck', 'cellular_component', 'GO:0044326', ('408', '412'))	('NSCLC or hepatocellular carcinoma', 'Disease', (586, 619))	('FAP', 'Gene', (343, 346))	('TGF-beta', 'Gene', (506, 514))	('pancreatic cancer', 'Disease', 'MESH:D010190', (649, 666))	('NCT03386721', 'Var', (446, 457))	('CSF1', 'molecular_function', 'GO:0005011', ('169', '173'))	('melanoma', 'Disease', 'MESH:D008545', (315, 323))	('CCR2', 'Gene', '729230', (266, 270))	('cancer', 'Disease', (660, 666))	('PD-1', 'Gene', '9825', (72, 76))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (230, 250))	('cancers', 'Phenotype', 'HP:0002664', (437, 444))	('pancreatic cancer', 'Disease', (649, 666))	('cancer', 'Disease', (437, 443))	('cancer', 'Phenotype', 'HP:0002664', (660, 666))	('carcinoma', 'Phenotype', 'HP:0030731', (610, 619))	('cancer', 'Phenotype', 'HP:0002664', (437, 443))	('LY2157299', 'CellLine', 'CVCL:2097', (539, 548))	('CSF1R', 'Gene', '1436', (169, 174))	('FAP', 'Gene', '2191', (343, 346))	('LY2157299', 'Var', (539, 548))	('melanoma', 'Phenotype', 'HP:0002861', (474, 482))	('melanoma', 'Disease', (474, 482))	('cervical cancers', 'Disease', (428, 444))	('cervical cancers', 'Disease', 'MESH:D002583', (428, 444))	('CSF1R', 'Gene', (169, 174))	('CCR', 'molecular_function', 'GO:0043880', ('266', '269'))	('TGF-beta', 'Gene', '7039', (506, 514))	('PD-1', 'Gene', (72, 76))	('cancer', 'Disease', 'MESH:D009369', (660, 666))	('melanoma', 'Phenotype', 'HP:0002861', (315, 323))	('melanoma', 'Disease', (315, 323))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (649, 666))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (437, 443))	('NSCLC or hepatocellular carcinoma', 'Disease', 'MESH:D006528', (586, 619))	('NCT03875079', 'Var', (484, 495))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (595, 619))	('NCT02734160', 'Var', (668, 679))	('NCT02423343', 'Var', (621, 632))	('melanoma', 'Disease', 'MESH:D008545', (474, 482))	('CCR2', 'Gene', (266, 270))
25039	31770212	Testicular mass may be metastatic tumor during follow-up for patients who were diagnosed as BC, especially for TCC with variant histology.	('Testicular mass', 'Phenotype', 'HP:0032404', (0, 15))	('tumor', 'Disease', (34, 39))	('TCC', 'cellular_component', 'GO:0005579', ('111', '114'))	('TCC', 'Disease', (111, 114))	('BC', 'Disease', 'MESH:D001749', (92, 94))	('patients', 'Species', '9606', (61, 69))	('BC', 'Phenotype', 'HP:0009725', (92, 94))	('variant', 'Var', (120, 127))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('Testicular mass', 'Disease', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
25066	31770212	Mohamed et al analyzed the characteristics of 120 patients who received adjuvant radiotherapy plus chemotherapy or chemotherapy alone; this study revealed that the combination of adjuvant radiotherapy and chemotherapy was associated with a significant improvement in the local recurrence-free survival and marginal improvements in the disease-free survival.	('adjuvant', 'Var', (179, 187))	('disease-free survival', 'CPA', (335, 356))	('local recurrence-free survival', 'CPA', (271, 301))	('patients', 'Species', '9606', (50, 58))	('improvement', 'PosReg', (252, 263))	('men', 'Species', '9606', (259, 262))	('men', 'Species', '9606', (322, 325))
25078	31770212	CK5/6 is a basal cytokeratin, which is expressed in urothelial carcinoma and positivity signifies adverse prognostic features such as high-grade and muscularis propria invasion.	('urothelial carcinoma', 'Disease', (52, 72))	('high-grade', 'CPA', (134, 144))	('positivity', 'Var', (77, 87))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (52, 72))	('muscularis propria', 'Phenotype', 'HP:0030936', (149, 167))	('CK5/6', 'Gene', '3852', (0, 5))	('CK5/6', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
25095	31216997	Univariable COX regression analysis revealed high TOP2A expression was significantly associated with poorer cancer-specific, progression-free and recurrence-free survival, but not independently of clinical characteristics in the multivariable models.	('COX', 'Gene', '1351', (12, 15))	('clinical', 'Species', '191496', (197, 205))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('expression', 'MPA', (56, 66))	('high', 'Var', (45, 49))	('recurrence-free', 'CPA', (146, 161))	('COX', 'Gene', (12, 15))	('poorer', 'NegReg', (101, 107))	('TOP2A', 'Gene', (50, 55))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
25097	31216997	Furthermore, migration and invasion capacity of BLCA cells were strongly suppressed after TOP2A knockdown.	('knockdown', 'Var', (96, 105))	('invasion capacity of BLCA cells', 'CPA', (27, 58))	('BLCA', 'Chemical', '-', (48, 52))	('TOP2A', 'Gene', (90, 95))	('suppressed', 'NegReg', (73, 83))
25098	31216997	Moreover, flow cytometry suggested TOP2A had anti-apoptotic function, and knockdown of TOP2A could induce resistance to doxorubicin in J82 cells.	('induce', 'PosReg', (99, 105))	('resistance to doxorubicin', 'MPA', (106, 131))	('TOP2A', 'Gene', (87, 92))	('knockdown', 'Var', (74, 83))	('doxorubicin', 'Chemical', 'MESH:D004317', (120, 131))	('anti-apoptotic function', 'CPA', (45, 68))	('J82', 'CellLine', 'CVCL:0359', (135, 138))
25104	31216997	Identification of recurrent genetic alteration in BLCA is critical for discovering genes that drive BLCA and identifying prognostic biomarkers for stratification of patients with different risks of prognosis.	('BLCA', 'Chemical', '-', (100, 104))	('genetic alteration', 'Var', (28, 46))	('BLCA', 'Chemical', '-', (50, 54))	('BLCA', 'Disease', (100, 104))	('patients', 'Species', '9606', (165, 173))
25150	31216997	We found that the TOP2A expression was significantly higher in MIBC compared with NMIBC in GSE31684 dataset, which included 93 patients with high-risk BLCA from Memorial Sloan-Kettering Cancer Center (MSKCC, Fig.	('higher', 'PosReg', (53, 59))	('MIBC', 'Var', (63, 67))	('Memorial Sloan-Kettering Cancer', 'Disease', (161, 192))	('expression', 'MPA', (24, 34))	('Memorial Sloan-Kettering Cancer', 'Disease', 'MESH:D008569', (161, 192))	('TOP2A', 'Protein', (18, 23))	('patients', 'Species', '9606', (127, 135))	('MIBC', 'Chemical', '-', (63, 67))	('MIBC', 'Chemical', '-', (83, 87))	('Cancer', 'Phenotype', 'HP:0002664', (186, 192))	('BLCA', 'Chemical', '-', (151, 155))
25157	31216997	With a median follow-up of 27.9 months (range, 10 to 95 months), patients with high TOP2A expression showed significantly poorer cancer-specific survival (CSS, Fig.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('CSS', 'Gene', (155, 158))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('high', 'Var', (79, 83))	('patients', 'Species', '9606', (65, 73))	('expression', 'Var', (90, 100))	('TOP2A', 'Gene', (84, 89))	('CSS', 'Gene', '55907', (155, 158))	('poorer', 'NegReg', (122, 128))
25173	31216997	The level of TOP2A mRNA and protein were significantly down-regulated after siRNA transfection in J82 and 5637 cells, while TOP2B expression was not influenced (Additional file 2: Figure S2).	('TOP2A', 'Gene', (13, 18))	('J82', 'CellLine', 'CVCL:0359', (98, 101))	('transfection', 'Var', (82, 94))	('level', 'MPA', (4, 9))	('TOP2B', 'Gene', '7155', (124, 129))	('down-regulated', 'NegReg', (55, 69))	('TOP2B', 'Gene', (124, 129))	('siRNA', 'Gene', (76, 81))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
25175	31216997	4b, cell proliferation rate was significantly inhibited 5 days after TOP2A knockdown in J82 and 5637 cells.	('b, cell proliferation', 'biological_process', 'GO:0042100', ('1', '22'))	('TOP2A', 'Gene', (69, 74))	('cell proliferation rate', 'CPA', (4, 27))	('knockdown', 'Var', (75, 84))	('inhibited', 'NegReg', (46, 55))	('J82', 'CellLine', 'CVCL:0359', (88, 91))
25179	31216997	The difference of tumor volume between TOP2A knockdown group and control group was statistically significant 6 weeks after tumor cells implantation (Fig.	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', (18, 23))	('TOP2A', 'Gene', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('knockdown', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
25184	31216997	We performed flow cytometry to compare cell cycle phases and apoptosis in J82 and 5637 cells between TOP2A knockdown and control cells.	('knockdown', 'Var', (107, 116))	('cell cycle', 'biological_process', 'GO:0007049', ('39', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('TOP2A', 'Gene', (101, 106))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('J82', 'CellLine', 'CVCL:0359', (74, 77))
25185	31216997	We found no significant changes in cell cycle phase distribution after TOP2A knockdown in J82 and 5637 cells (Additional file 3: Figure S3).	('cell cycle phase', 'biological_process', 'GO:0022403', ('35', '51'))	('cell cycle phase', 'CPA', (35, 51))	('J82', 'CellLine', 'CVCL:0359', (90, 93))	('knockdown', 'Var', (77, 86))	('TOP2A', 'Gene', (71, 76))
25186	31216997	In terms of apoptosis, knockdown of TOP2A showed a significant increase of early and late apoptosis in both J82 cells and cells after induction of apoptosis by gemcitabine treatment for 24 h (Fig.	('increase', 'PosReg', (63, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('knockdown', 'Var', (23, 32))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('134', '156'))	('J82', 'CellLine', 'CVCL:0359', (108, 111))	('gemcitabine', 'Chemical', 'MESH:C056507', (160, 171))	('apoptosis', 'biological_process', 'GO:0006915', ('12', '21'))	('TOP2A', 'Gene', (36, 41))	('apoptosis', 'biological_process', 'GO:0097194', ('12', '21'))
25194	31216997	J82 cells exhibited relatively resistance to doxorubicin after TOP2A knockdown.	('J82', 'CellLine', 'CVCL:0359', (0, 3))	('TOP2A', 'Gene', (63, 68))	('doxorubicin', 'Chemical', 'MESH:D004317', (45, 56))	('resistance to doxorubicin', 'MPA', (31, 56))	('knockdown', 'Var', (69, 78))
25207	31216997	reported that TOP2A and HER-2 expression was co-amplified in BLCA, and TOP2A amplification were associated with advanced tumor stage and high grade, but they also found no independent prognostic value of TOP2A amplification or protein expression in multivariable COX regression analysis.	('protein', 'cellular_component', 'GO:0003675', ('227', '234'))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('associated', 'Reg', (96, 106))	('TOP2A', 'Gene', (14, 19))	('COX', 'Gene', '1351', (263, 266))	('tumor', 'Disease', (121, 126))	('amplification', 'Var', (77, 90))	('high grade', 'CPA', (137, 147))	('BLCA', 'Chemical', '-', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('HER-2', 'Gene', '2064', (24, 29))	('TOP2A', 'Gene', (71, 76))	('HER-2', 'Gene', (24, 29))	('COX', 'Gene', (263, 266))
25209	31216997	Subgroup analysis of the prognostic value of TOP2A in MIBC and NMIBC in the present study further revealed that TOP2A had better prognostic value for patients with MIBC rather than NMIBC.	('MIBC', 'Chemical', '-', (64, 68))	('MIBC', 'Chemical', '-', (54, 58))	('MIBC', 'Chemical', '-', (164, 168))	('MIBC', 'Chemical', '-', (182, 186))	('patients', 'Species', '9606', (150, 158))	('MIBC', 'Disease', (164, 168))	('TOP2A', 'Var', (112, 117))
25216	31216997	revealed high TOP2A expression correlated with worse cancer prognosis, but no relationship between amplification of TOP2A gene and prognosis of cancer in the meta-analysis of 25 studies.	('TOP2A', 'Gene', (116, 121))	('expression', 'MPA', (20, 30))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('TOP2A', 'Gene', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('high', 'Var', (9, 13))
25218	31216997	Although TOP2A alteration was closely associated with prognosis of BLCA, the oncogenic function of TOP2A in BLCA has not been studied previously.	('associated', 'Reg', (38, 48))	('BLCA', 'Disease', (67, 71))	('BLCA', 'Chemical', '-', (108, 112))	('TOP2A', 'Gene', (9, 14))	('BLCA', 'Chemical', '-', (67, 71))	('alteration', 'Var', (15, 25))
25220	31216997	In the present study, we found that knockdown of TOP2A could significantly inhibit the proliferation of bladder cancer cells and non-cancerous urothelial cells, which revealed the essential role of TOP2A in cell proliferation.	('bladder cancer', 'Disease', (104, 118))	('non-cancerous urothelial', 'Disease', 'MESH:D014523', (129, 153))	('cell proliferation', 'biological_process', 'GO:0008283', ('207', '225'))	('proliferation', 'CPA', (87, 100))	('inhibit', 'NegReg', (75, 82))	('TOP2A', 'Gene', (49, 54))	('knockdown', 'Var', (36, 45))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('non-cancerous urothelial', 'Disease', (129, 153))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('bladder cancer', 'Disease', 'MESH:D001749', (104, 118))
25221	31216997	In addition, knockdown of TOP2A strongly suppressed the migration and invasion capacity of J82 and 5637 cells.	('invasion capacity', 'CPA', (70, 87))	('suppressed', 'NegReg', (41, 51))	('knockdown', 'Var', (13, 22))	('J82', 'CellLine', 'CVCL:0359', (91, 94))	('TOP2A', 'Gene', (26, 31))
25224	31216997	reported that TOP2A was overexpressed in adrenocortical carcinoma and might influence tumor progression, as knockdown of TOP2A in adrenocortical carcinoma cells decreased cell proliferation, and invasion.	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (130, 154))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (41, 65))	('knockdown', 'Var', (108, 117))	('cell proliferation', 'CPA', (171, 189))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (130, 154))	('decreased', 'NegReg', (161, 170))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (41, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('cell proliferation', 'biological_process', 'GO:0008283', ('171', '189'))	('adrenocortical carcinoma', 'Disease', (130, 154))	('TOP2A', 'Gene', (121, 126))	('invasion', 'CPA', (195, 203))	('adrenocortical carcinoma', 'Disease', (41, 65))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('influence', 'Reg', (76, 85))
25225	31216997	found TOP2A was overexpressed in liposarcoma, and knockdown of TOP2A in liposarcoma cell lines reduced proliferation, invasiveness and increased apoptosis.	('liposarcoma', 'Phenotype', 'HP:0012034', (72, 83))	('liposarcoma', 'Disease', 'MESH:D008080', (72, 83))	('proliferation', 'CPA', (103, 116))	('liposarcoma', 'Disease', (33, 44))	('TOP2A', 'Gene', (63, 68))	('knockdown', 'Var', (50, 59))	('invasiveness', 'CPA', (118, 130))	('liposarcoma', 'Disease', 'MESH:D008080', (33, 44))	('increased', 'PosReg', (135, 144))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('liposarcoma', 'Disease', (72, 83))	('liposarcoma', 'Phenotype', 'HP:0012034', (33, 44))	('reduced', 'NegReg', (95, 102))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('apoptosis', 'CPA', (145, 154))
25229	31216997	In the present study, we showed that TOP2A knockdown induced doxorubicin resistance in J82 cells, however, the sensitivity of different bladder cancer cell lines to doxorubicin was not significantly correlated with the expression level of TOP2A.	('induced', 'Reg', (53, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('doxorubicin', 'Chemical', 'MESH:D004317', (61, 72))	('knockdown', 'Var', (43, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (136, 150))	('bladder cancer', 'Disease', (136, 150))	('doxorubicin', 'Chemical', 'MESH:D004317', (165, 176))	('J82', 'CellLine', 'CVCL:0359', (87, 90))	('TOP2A', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('doxorubicin resistance', 'MPA', (61, 83))
25281	27409828	Similarly, when 48 metastatic urothelial cancer patients were treated with nanoparticle albumin-bound paclitaxel at three-week intervals, a 28% ORR was achieved.	('paclitaxel', 'Chemical', 'MESH:D017239', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('urothelial cancer', 'Disease', (30, 47))	('urothelial cancer', 'Disease', 'MESH:D014523', (30, 47))	('nanoparticle', 'Var', (75, 87))	('patients', 'Species', '9606', (48, 56))
25440	32363111	While the increase in B7-H4 expression within the bladder by CD11b+ monocytes is shared with human cancers, B7-H4 expression has not been previously identified in other murine cancer models.	('murine', 'Species', '10090', (169, 175))	('B7-H4', 'Gene', (22, 27))	('expression', 'MPA', (28, 38))	('human', 'Species', '9606', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancer', 'Disease', (99, 105))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('CD11b+', 'Var', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('increase', 'PosReg', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
25442	32363111	Evaluation of B7-H4 by single-cell RNA-Seq and immune mass cytometry of human bladder tumors found that B7-H4 is expressed in both the epithelium of urothelial carcinoma and CD68+ macrophages within the tumor.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('urothelial carcinoma', 'Disease', (149, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('tumor', 'Disease', (86, 91))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (149, 169))	('human', 'Species', '9606', (72, 77))	('bladder tumors', 'Disease', 'MESH:D001749', (78, 92))	('bladder tumors', 'Phenotype', 'HP:0009725', (78, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('bladder tumor', 'Phenotype', 'HP:0009725', (78, 91))	('B7-H4', 'Var', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('bladder tumors', 'Disease', (78, 92))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('RNA', 'cellular_component', 'GO:0005562', ('35', '38'))
25445	32363111	Furthermore, treatment with a combination of anti-PD-1 and anti-B7-H4 antibodies resulted in a significant reduction in tumor stage, a reduction in tumor size, and an increased level of tumor necrosis.	('necrosis', 'biological_process', 'GO:0008219', ('192', '200'))	('anti-PD-1', 'Var', (45, 54))	('tumor', 'Disease', (186, 191))	('reduction', 'NegReg', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('necrosis', 'biological_process', 'GO:0008220', ('192', '200'))	('tumor necrosis', 'Disease', 'MESH:D009336', (186, 200))	('tumor necrosis', 'Disease', (186, 200))	('tumor', 'Disease', (120, 125))	('necrosis', 'biological_process', 'GO:0070265', ('192', '200'))	('necrosis', 'biological_process', 'GO:0019835', ('192', '200'))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('necrosis', 'biological_process', 'GO:0001906', ('192', '200'))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('increased', 'PosReg', (167, 176))	('reduction', 'NegReg', (135, 144))	('tumor', 'Disease', (148, 153))	('anti-B7-H4', 'Var', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
25447	32363111	Genetic alterations result in the expression of neoantigens that may be recognized by cells of the innate and adaptive immune system, which in turn generate the anti-tumor immune response.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('Genetic alterations', 'Var', (0, 19))	('generate', 'Reg', (148, 156))	('expression', 'MPA', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('immune response', 'biological_process', 'GO:0006955', ('172', '187'))	('tumor', 'Disease', (166, 171))	('neoantigens', 'Protein', (48, 59))	('result in', 'Reg', (20, 29))
25450	32363111	While CTLA-4 and PD-L1 are the most well-described checkpoint proteins, B7-H4 (B7S1, B7x, VTCN1), a B7-family member expressed on antigen-presenting cells and/or tumors, can inhibit T cell-mediated inflammatory responses.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('B7x', 'Gene', '242122', (85, 88))	('CTLA-4', 'Gene', (6, 12))	('B7x', 'Gene', (85, 88))	('VTCN1', 'Gene', '242122', (90, 95))	('inhibit', 'NegReg', (174, 181))	('B7-H4', 'Var', (72, 77))	('VTCN1', 'Gene', (90, 95))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('CTLA-4', 'Gene', '12477', (6, 12))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('B7S1', 'Gene', (79, 83))	('T cell-mediated inflammatory responses', 'CPA', (182, 220))	('B7S1', 'Gene', '242122', (79, 83))
25452	32363111	Data show that B7-H4 functionally decreases inflammatory CD4+ T cells directly and indirectly via B7-H4-induced increases in both the number and function of regulatory CD4+ T cells (Tregs).	('inflammatory CD4+ T cells', 'CPA', (44, 69))	('decreases', 'NegReg', (34, 43))	('Tregs', 'Chemical', '-', (182, 187))	('B7-H4-induced', 'Var', (98, 111))	('increases', 'PosReg', (112, 121))	('B7-H4', 'Var', (15, 20))	('regulatory CD4+ T cells', 'CPA', (157, 180))
25455	32363111	Therefore, inhibition of B7-H4 may be an alternative strategy to reinvigorate tumor-specific T cell responses.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('B7-H4', 'Protein', (25, 30))	('inhibition', 'Var', (11, 21))	('tumor', 'Disease', (78, 83))
25461	32363111	Tumor specimen was minced and enzymatically dissociated DMEM supplemented with Liberase TM (0.0625 mg/ml) and DNase I (Sigma, D5025, 0.2 mg/mL) for 30 min.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('DNase I', 'Gene', '13419', (110, 117))	('DMEM', 'Chemical', '-', (56, 60))	('DNase I', 'Gene', (110, 117))	('0.0625 mg/ml', 'Var', (92, 104))	('DNase I', 'molecular_function', 'GO:0004530', ('110', '117'))	('D5025', 'Chemical', '-', (126, 131))
25475	32363111	After 20 weeks of exposure, mice were randomized to therapy which included treatment with IgG (200 mug/kg, BioXcell), anti-PD1 (200 mug/kg, BioXcell), and/or anti-B7-H4 (200 mug/mouse, from Amplimmune).	('PD1', 'Gene', '18566', (123, 126))	('200', 'Var', (128, 131))	('mouse', 'Species', '10090', (178, 183))	('mug', 'molecular_function', 'GO:0043739', ('132', '135'))	('anti-B7-H4', 'Var', (158, 168))	('mice', 'Species', '10090', (28, 32))	('mug', 'molecular_function', 'GO:0043739', ('99', '102'))	('mug', 'molecular_function', 'GO:0043739', ('174', '177'))	('PD1', 'Gene', (123, 126))
25489	32363111	Four micron thick sections were used for IHC staining for CD8 (1:1000, #MA5-13263, Invitrogen) and Foxp3 (1:400, #12653, Cell Signaling).	('Foxp3', 'Gene', (99, 104))	('CD8', 'Gene', (58, 61))	('1:1000', 'Var', (63, 69))	('1:400', 'Var', (106, 111))	('CD8', 'Gene', '925', (58, 61))	('Foxp3', 'Gene', '20371', (99, 104))	('Signaling', 'biological_process', 'GO:0023052', ('126', '135'))
25504	32363111	PLP139-151/CFA Induced EAE and DTH.	('Induced', 'Reg', (15, 22))	('PLP139-151/CFA', 'Var', (0, 14))	('PLP139', 'Chemical', '-', (0, 6))	('DTH', 'Disease', (31, 34))	('EAE', 'Disease', (23, 26))	('CFA', 'Chemical', '-', (11, 14))
25528	32363111	For example, markers of T cell exhaustion (PD-1, LAG-3, and Tim-3) and regulation (Foxp3 and Nrp-1) increased by 2 weeks, and B7-H4, a protein expressed by APCs that is known to inhibit T cell function via both direct and indirect mechanisms, was significantly increased by 4 weeks and corresponded to a decrease in CD8 and CD4 transcripts present within the bladder (Figure 1a).	('APCs', 'Gene', '20219', (156, 160))	('increased', 'PosReg', (261, 270))	('CD4', 'Gene', (324, 327))	('Foxp3', 'Gene', (83, 88))	('Nrp', 'biological_process', 'GO:0085015', ('93', '96'))	('CD8', 'Gene', '925', (316, 319))	('LAG-3', 'Gene', '16768', (49, 54))	('Tim-3', 'Gene', '171285', (60, 65))	('increased', 'PosReg', (100, 109))	('regulation', 'biological_process', 'GO:0065007', ('71', '81'))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('LAG-3', 'Gene', (49, 54))	('decrease', 'NegReg', (304, 312))	('Foxp3', 'Gene', '20371', (83, 88))	('inhibit', 'NegReg', (178, 185))	('CD8', 'Gene', (316, 319))	('Tim-3', 'Gene', (60, 65))	('Nrp-1', 'Gene', (93, 98))	('B7-H4', 'Var', (126, 131))	('Nrp-1', 'Gene', '18186', (93, 98))	('APCs', 'Gene', (156, 160))
25530	32363111	Patients with high expression of B7-H4 had significantly worse overall survival compared to those with lower expression (21.85 vs 34.03 months, p = .03) (Figure 1b).	('overall survival', 'MPA', (63, 79))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('B7-H4', 'Protein', (33, 38))	('worse', 'NegReg', (57, 62))
25531	32363111	Unlike other immune checkpoints (such as PD-1, PD-L1, and CTLA-4), expression of B7-H4 does not appear to correlate with neoantigens, total mutation burden, APOBEC mutations, or gene signatures (Supplemental Figure 1).	('APOBEC', 'cellular_component', 'GO:0030895', ('157', '163'))	('correlate', 'Reg', (106, 115))	('B7-H4', 'Gene', (81, 86))	('APOBEC', 'Gene', (157, 163))	('CTLA-4', 'Gene', '12477', (58, 64))	('mutations', 'Var', (164, 173))	('APOBEC', 'Gene', '80287', (157, 163))	('CTLA-4', 'Gene', (58, 64))
25535	32363111	Using immunohistochemistry, we found expression of B7-H4 localized to immune cells present within healthy human bladder, with increased expression of B7-H4 in higher grade urothelial tumors as compared to low-grade urothelial tumors (Figure 1d, left and middle panels).	('human', 'Species', '9606', (106, 111))	('expression', 'MPA', (136, 146))	('B7-H4', 'Var', (150, 155))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('urothelial tumors', 'Disease', (215, 232))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('urothelial tumors', 'Disease', 'MESH:D001749', (172, 189))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('urothelial tumors', 'Disease', 'MESH:D001749', (215, 232))	('increased', 'PosReg', (126, 135))	('urothelial tumors', 'Disease', (172, 189))
25536	32363111	While most mouse tumor in vivo models do not contain B7-H4 expressing cells, our data show that B7-H4 is expressed in the BBN mouse model, and B7-H4 expression co-localized with CD11b+ myeloid cells (Figure 1d, right; Supplemental Figure 2).	('mouse', 'Species', '10090', (126, 131))	('mouse', 'Species', '10090', (11, 16))	('tumor', 'Disease', (17, 22))	('B7-H4', 'Var', (143, 148))	('BBN', 'Chemical', 'MESH:D002085', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
25555	32363111	To functionally demonstrate that anti-B7-H4 can inhibit the regulatory function of B7-H4, we tested the ability of anti-B7-H4 to block the immunoregulatory function of human B7-H4Ig (hB7-H4Ig).	('human', 'Species', '9606', (168, 173))	('regulatory function', 'MPA', (60, 79))	('anti-B7-H4', 'Var', (33, 43))	('tested', 'Reg', (93, 99))	('inhibit', 'NegReg', (48, 55))
25556	32363111	SJL/J lymph node cells (5x105 cells/well) were labeled with CFSE, and stimulated with anti-CD3 (1 mug/ml) plus control Ig, hB7-H4Ig, and/or anti-B7-H4 (10 mug/ml) (Figure 3a).	('hB7-H4Ig', 'Var', (123, 131))	('anti-B7-H4', 'Var', (140, 150))	('mug', 'molecular_function', 'GO:0043739', ('98', '101'))	('CD3', 'Gene', (91, 94))	('mug', 'molecular_function', 'GO:0043739', ('155', '158'))	('CD3', 'Gene', '28134', (91, 94))
25558	32363111	The level of 3H-TdR incorporation (counts per minute, CPM) confirmed that anti-B7-H4 blocked the inhibitory function of human B7-H4Ig (Figure 3a).	('3H', 'Chemical', 'MESH:D014316', (13, 15))	('human', 'Species', '9606', (120, 125))	('anti-B7-H4', 'Var', (74, 84))	('blocked', 'NegReg', (85, 92))	('inhibitory function', 'MPA', (97, 116))
25560	32363111	Mice were observed for paralytic disease symptoms, as we previously reported, hB7-H4Ig treatment significantly decreased disease severity (Figure 3b).	('hB7-H4Ig', 'Var', (78, 86))	('decreased', 'NegReg', (111, 120))	('paralytic disease', 'Disease', 'MESH:D007418', (23, 40))	('disease severity', 'MPA', (121, 137))	('paralytic disease', 'Disease', (23, 40))	('Mice', 'Species', '10090', (0, 4))
25561	32363111	In addition, anti-B7-H4 blocked the hB7-H4Ig-induced decrease in in vivo CD4+ T cell function as measured by delayed-type hypersensitivity (DTH) responses to ear challenge with PLP139-151.	('delayed-type hypersensitivity', 'biological_process', 'GO:0001806', ('109', '138'))	('decrease', 'NegReg', (53, 61))	('hB7-H4Ig-induced', 'Var', (36, 52))	('hypersensitivity', 'Disease', (122, 138))	('CD4+ T cell function', 'MPA', (73, 93))	('hypersensitivity', 'Disease', 'MESH:D004342', (122, 138))	('PLP139', 'Chemical', '-', (177, 183))
25566	32363111	Therefore, we cultured monocytes with IL-10 and IL-6 for 3 days prior to co-culture with CD4 + T cell or CD8 + T cells in the presence of anti-CD3, control, or anti-B7-H4 antibody.	('CD8', 'Gene', (105, 108))	('antibody', 'cellular_component', 'GO:0019814', ('171', '179'))	('CD8', 'Gene', '925', (105, 108))	('IL-6', 'Gene', '3569', (48, 52))	('CD3', 'Gene', (143, 146))	('IL-10', 'molecular_function', 'GO:0005141', ('38', '43'))	('CD3', 'Gene', '28134', (143, 146))	('antibody', 'molecular_function', 'GO:0003823', ('171', '179'))	('antibody', 'cellular_component', 'GO:0042571', ('171', '179'))	('IL-6', 'molecular_function', 'GO:0005138', ('48', '52'))	('IL-6', 'Gene', (48, 52))	('antibody', 'cellular_component', 'GO:0019815', ('171', '179'))	('anti-B7-H4', 'Var', (160, 170))
25567	32363111	While the addition of anti-B7-H4 did not significantly enhance proliferation of CD4+ (Figure 4b) or CD8+ T cells (Figure 4d), anti-B7-H4 induced a significant increase in the production of IFN-gamma by both CD4+ and CD8+ T cells (Figure 4c,e).	('anti-B7-H4', 'Var', (126, 136))	('CD8', 'Gene', (216, 219))	('CD8', 'Gene', (100, 103))	('CD8', 'Gene', '925', (216, 219))	('CD8', 'Gene', '925', (100, 103))	('production of IFN-gamma', 'MPA', (175, 198))	('increase', 'PosReg', (159, 167))
25569	32363111	After confirmation of the functional activity of our B7-H4 antibody, we investigated if anti-B7-H4 could modulate tumor development in the BBN bladder cancer model.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('antibody', 'cellular_component', 'GO:0019815', ('59', '67'))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('bladder cancer', 'Phenotype', 'HP:0009725', (143, 157))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('antibody', 'cellular_component', 'GO:0019814', ('59', '67'))	('modulate', 'Reg', (105, 113))	('antibody', 'molecular_function', 'GO:0003823', ('59', '67'))	('antibody', 'cellular_component', 'GO:0042571', ('59', '67'))	('tumor', 'Disease', (114, 119))	('BBN bladder cancer', 'Disease', 'MESH:D001749', (139, 157))	('anti-B7-H4', 'Var', (88, 98))	('BBN bladder cancer', 'Disease', (139, 157))
25570	32363111	Mice were given BBN for 4 months followed by normal drinking water during treatment with a species and isotype-matched control antibody, anti-PD-1, or anti-B7-H4 once weekly for four total treatments (Figure 5a).	('BBN', 'Chemical', 'MESH:D002085', (16, 19))	('antibody', 'cellular_component', 'GO:0019815', ('127', '135'))	('antibody', 'cellular_component', 'GO:0019814', ('127', '135'))	('water', 'Chemical', 'MESH:D014867', (61, 66))	('antibody', 'molecular_function', 'GO:0003823', ('127', '135'))	('anti-B7-H4', 'Var', (151, 161))	('Mice', 'Species', '10090', (0, 4))	('anti-PD-1', 'Var', (137, 146))	('antibody', 'cellular_component', 'GO:0042571', ('127', '135'))
25571	32363111	Treatment with the anti-B7-H4 antibody led to a decrease in the number of advanced tumors (50% stage 3 or greater compared to 70% in controls), and a significant increase in the number of CD8+ bladder-infiltrating T cells (Figure 5b,c).	('anti-B7-H4', 'Var', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('antibody', 'cellular_component', 'GO:0042571', ('30', '38'))	('increase', 'PosReg', (162, 170))	('CD8', 'Gene', (188, 191))	('CD8', 'Gene', '925', (188, 191))	('antibody', 'cellular_component', 'GO:0019815', ('30', '38'))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('antibody', 'cellular_component', 'GO:0019814', ('30', '38'))	('decrease', 'NegReg', (48, 56))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('antibody', 'molecular_function', 'GO:0003823', ('30', '38'))
25572	32363111	In contrast, anti-B7-H4 treatment decreased the number of Foxp3+ Tregs (Figure 5b,d), indicating that anti-B7-H4 treatment shifted the CD8+ T cell to Treg ratio in favor of an anti-tumor response (Supplemental Figure 3).	('CD8', 'Gene', '925', (135, 138))	('Foxp3', 'Gene', (58, 63))	('tumor', 'Disease', (181, 186))	('Foxp3', 'Gene', '20371', (58, 63))	('anti-B7-H4', 'Var', (102, 112))	('Tregs', 'Chemical', '-', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('CD8', 'Gene', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
25573	32363111	While treatment of mice with anti-PD-1 or anti-B7-H4 did not alter the number of total splenic CD45hi cells, CD4+ T cells, or CD8+ T cells present within the spleen (Figure 5e), both anti-PD-1 and anti-B7-H4 treatments significantly increased the number of CD8+/IFN-gamma+ cells present within the spleen compared to control Ab-treated mice (figure 5f).	('anti-B7-H4', 'Var', (197, 207))	('mice', 'Species', '10090', (336, 340))	('CD8', 'Gene', (126, 129))	('CD8', 'Gene', (257, 260))	('CD8', 'Gene', '925', (126, 129))	('CD8', 'Gene', '925', (257, 260))	('anti-PD-1', 'Var', (183, 192))	('CD45', 'Gene', '19264', (95, 99))	('CD45', 'Gene', (95, 99))	('mice', 'Species', '10090', (19, 23))	('increased', 'PosReg', (233, 242))
25575	32363111	Splenocytes from anti-B7-H4-treated mice secreted significantly higher levels of IFN-gamma in response to anti-CD3 stimulation, as compared to T cells from control Ab or anti-PD-1 treated mice (Figure 5g).	('mice', 'Species', '10090', (188, 192))	('higher', 'PosReg', (64, 70))	('mice', 'Species', '10090', (36, 40))	('CD3', 'Gene', (111, 114))	('CD3', 'Gene', '28134', (111, 114))	('levels of IFN-gamma', 'MPA', (71, 90))	('anti-B7-H4-treated', 'Var', (17, 35))
25578	32363111	Most prominently, the response to B7-H4 was associated with decreased expression of the oncogenes Hoxb9, H19, and Egln3.	('decreased', 'NegReg', (60, 69))	('B7-H4', 'Var', (34, 39))	('H19', 'Gene', '14955', (105, 108))	('Egln3', 'Gene', (114, 119))	('Hoxb9', 'Gene', (98, 103))	('expression', 'MPA', (70, 80))	('H19', 'Gene', (105, 108))	('Egln3', 'Gene', '112407', (114, 119))	('Hoxb9', 'Gene', '15417', (98, 103))
25580	32363111	These findings indicate that anti-B7-H4 treatment of BBN mice induced an increase in CD8+ T cell infiltration into the bladder and increased the level of IFN-gamma secreted per splenic CD8+ T cell, while decreasing the number of Tregs present within the bladder.	('mice', 'Species', '10090', (57, 61))	('level of IFN-gamma secreted', 'MPA', (145, 172))	('CD8', 'Gene', (85, 88))	('increased', 'PosReg', (131, 140))	('increase', 'PosReg', (73, 81))	('BBN', 'Chemical', 'MESH:D002085', (53, 56))	('Tregs', 'Chemical', '-', (229, 234))	('CD8', 'Gene', '925', (85, 88))	('CD8', 'Gene', (185, 188))	('CD8', 'Gene', '925', (185, 188))	('anti-B7-H4', 'Var', (29, 39))	('decreasing', 'NegReg', (204, 214))
25581	32363111	Lastly, we showed that anti-B7-H4 therapy synergized with anti-PD-1 therapy, which is the current standard of care for metastatic and chemotherapy-resistant bladder cancer.	('anti-B7-H4', 'Var', (23, 33))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Disease', 'MESH:D001749', (157, 171))	('bladder cancer', 'Disease', (157, 171))
25582	32363111	The co-treatment of mice with anti-B7-H4 and anti-PD-1 resulted in a significant reduction in advanced stage tumors (80% in vehicle-treated mice vs. 60% in anti-B7-H4 treated mice; and 40% in combination treated mice (Figure 5h) (p = .017), decreased tumor area (51% tumor in vehicle vs. 19%, p < .009), and a trend toward increased tumor necrosis (6% in vehicle vs. 28%, p < .07) (Figure 5j).	('tumor', 'Disease', (251, 256))	('mice', 'Species', '10090', (212, 216))	('increased', 'PosReg', (323, 332))	('necrosis', 'biological_process', 'GO:0070265', ('339', '347'))	('tumor necrosis', 'Disease', (333, 347))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('necrosis', 'biological_process', 'GO:0019835', ('339', '347'))	('anti-PD-1', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('necrosis', 'biological_process', 'GO:0001906', ('339', '347'))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('mice', 'Species', '10090', (140, 144))	('decreased tumor', 'Disease', 'MESH:D002303', (241, 256))	('mice', 'Species', '10090', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('decreased tumor', 'Disease', (241, 256))	('anti-B7-H4', 'Var', (30, 40))	('necrosis', 'biological_process', 'GO:0008219', ('339', '347'))	('reduction', 'NegReg', (81, 90))	('tumor', 'Disease', (333, 338))	('mice', 'Species', '10090', (175, 179))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('necrosis', 'biological_process', 'GO:0008220', ('339', '347'))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('tumor', 'Disease', (267, 272))	('tumor necrosis', 'Disease', 'MESH:D009336', (333, 347))	('tumor', 'Disease', (109, 114))
25591	32363111	In our evaluation of MIBC, we found that B7-H4 is expressed in higher levels in luminal and luminal papillary tumors.	('luminal papillary tumors', 'Disease', (92, 116))	('MIBC', 'Chemical', '-', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('B7-H4', 'Var', (41, 46))	('luminal', 'Chemical', 'MESH:D010634', (80, 87))	('papillary tumors', 'Phenotype', 'HP:0007482', (100, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('luminal papillary tumors', 'Disease', 'MESH:D002291', (92, 116))	('luminal', 'Chemical', 'MESH:D010634', (92, 99))	('higher', 'PosReg', (63, 69))
25599	32363111	Across the various types of solid human tumors, the expression of B7-H4 is associated with worse patient survival.	('human', 'Species', '9606', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('B7-H4', 'Var', (66, 71))	('patient survival', 'CPA', (97, 113))	('patient', 'Species', '9606', (97, 104))	('expression', 'Var', (52, 62))	('worse', 'NegReg', (91, 96))	('tumors', 'Disease', (40, 46))
25601	32363111	Mechanistic investigation of B7-H4 in liver cancer identified that targeting B7-H4 genetically resulted in increased proliferation of CD8+ T cells with decreased levels of exhaustion transcription factors.	('targeting', 'Var', (67, 76))	('liver cancer', 'Phenotype', 'HP:0002896', (38, 50))	('proliferation', 'CPA', (117, 130))	('liver cancer', 'Disease', 'MESH:D006528', (38, 50))	('B7-H4', 'Gene', (77, 82))	('increased', 'PosReg', (107, 116))	('CD8', 'Gene', (134, 137))	('CD8', 'Gene', '925', (134, 137))	('decreased', 'NegReg', (152, 161))	('liver cancer', 'Disease', (38, 50))	('levels of exhaustion transcription factors', 'MPA', (162, 204))	('transcription', 'biological_process', 'GO:0006351', ('183', '196'))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
25602	32363111	In the current study, we confirmed that anti-B7-H4 treatment increased CD8+ T cell activation as a mechanism of immune activation.	('CD8', 'Gene', '925', (71, 74))	('anti-B7-H4', 'Var', (40, 50))	('increased', 'PosReg', (61, 70))	('T cell activation', 'biological_process', 'GO:0042110', ('76', '93'))	('CD8', 'Gene', (71, 74))
25603	32363111	Additionally, we found lower numbers of Foxp3+ Tregs present within the bladders of mice receiving anti-B7-H4 treatment, thereby indicating that a regulatory phenotype of the TILs had shifted toward an anti-tumor phenotype.	('anti-B7-H4', 'Var', (99, 109))	('mice', 'Species', '10090', (84, 88))	('Tregs', 'Chemical', '-', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('Foxp3', 'Gene', (40, 45))	('Foxp3', 'Gene', '20371', (40, 45))	('lower', 'NegReg', (23, 28))
25604	32363111	In addition to effects on Tregs, receptor ligation by the immune modulatory molecules, such as B7-H4, have been suggested to directly alter the phenotype of CD4+ T cells.	('alter', 'Reg', (134, 139))	('B7-H4', 'Gene', (95, 100))	('Tregs', 'Chemical', '-', (26, 31))	('CD4+ T cells', 'CPA', (157, 169))	('receptor ligation', 'Var', (33, 50))
25605	32363111	Co-culture of CD4+ T cells with IL-10/TGF-beta treated macrophages expressing B7-H4 decreased CD4+ T cell proliferation and increased the number of Foxp3+ CD4+ T cells.	('TGF-beta', 'Gene', (38, 46))	('TGF-beta', 'Gene', '21802', (38, 46))	('CD4+ T cell proliferation', 'CPA', (94, 119))	('increased', 'PosReg', (124, 133))	('Foxp3', 'Gene', (148, 153))	('Foxp3', 'Gene', '20371', (148, 153))	('T cell proliferation', 'biological_process', 'GO:0042098', ('99', '119'))	('IL-10', 'molecular_function', 'GO:0005141', ('32', '37'))	('decreased', 'NegReg', (84, 93))	('B7-H4', 'Var', (78, 83))
25606	32363111	The present data show that B7-H4 also directly interacts with a functional B7-H4 receptor on CD8 + T cells, as the addition of anti-B7-H4 to monocyte/CD8+ T cell co-cultures induced a significant increase in the level of secreted IFN-gamma (Figure 4e).	('level of secreted IFN-gamma', 'MPA', (212, 239))	('CD8', 'Gene', (150, 153))	('CD8', 'Gene', '925', (150, 153))	('addition', 'Interaction', (115, 123))	('anti-B7-H4', 'Var', (127, 137))	('CD8', 'Gene', (93, 96))	('increase', 'PosReg', (196, 204))	('CD8', 'Gene', '925', (93, 96))
25607	32363111	This is supported by our previous findings showing that hB7-H4Ig can down-regulate IL-17 and IFN-gamma production of mouse T cells in the absence of Tregs.	('Tregs', 'Chemical', '-', (149, 154))	('IL-17', 'Gene', (83, 88))	('IL-17', 'molecular_function', 'GO:0030367', ('83', '88'))	('down-regulate', 'NegReg', (69, 82))	('mouse T', 'CellLine', 'CVCL:0594', (117, 124))	('IL-17', 'Gene', '16171', (83, 88))	('hB7-H4Ig', 'Var', (56, 64))
25611	32363111	While the present data show the functionality of anti-B7-H4 treatment in the presence of monocyte expressed B7-H4, B7-H4 expression by tumor cells is also a putative mechanism by which these cells evade anti-tumor immune responses.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('B7-H4', 'Var', (115, 120))	('tumor', 'Disease', (208, 213))	('evade', 'NegReg', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
25613	32363111	Additionally, tumor tissues from breast, uterus, ovary, colon, and pancreas showed a statistically significant increase in the percentage of cells expressing B7-H4.	('increase', 'PosReg', (111, 119))	('tumor', 'Disease', (14, 19))	('B7-H4', 'Var', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
25615	32363111	Based on these findings, expression of B7-H4 within the tumor microenvironment, either by the tumor cells and/or by infiltrating monocytes, is hypothesized to promote immune evasion.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('immune evasion', 'MPA', (167, 181))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (56, 61))	('immune evasion', 'biological_process', 'GO:0042783', ('167', '181'))	('tumor', 'Disease', (94, 99))	('immune evasion', 'biological_process', 'GO:0051842', ('167', '181'))	('promote', 'PosReg', (159, 166))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('B7-H4', 'Var', (39, 44))
25616	32363111	In support of this hypothesis, published data show that stimulation of the B7-H4 receptor complex via hB7-H4Ig treatment in the PLP139-151/CFA model of relapsing-remitting EAE increased the number and function of Tregs.	('relapsing-remitting EAE', 'Disease', (152, 175))	('hB7-H4Ig', 'Var', (102, 110))	('increased', 'PosReg', (176, 185))	('number', 'CPA', (190, 196))	('receptor complex', 'cellular_component', 'GO:0043235', ('81', '97'))	('B7-H4 receptor complex', 'Protein', (75, 97))	('Tregs', 'Chemical', '-', (213, 218))	('function', 'CPA', (201, 209))	('CFA', 'Chemical', '-', (139, 142))	('stimulation', 'PosReg', (56, 67))	('PLP139', 'Chemical', '-', (128, 134))
25618	32363111	The present data show that the treatment of C57BL/6 male mice receiving BBN containing water with anti-B7-H4 increases the number of CD8+ T cells and decreases the number of Tregs present within the bladder (Figure 5k).	('mice', 'Species', '10090', (57, 61))	('water', 'Chemical', 'MESH:D014867', (87, 92))	('CD8', 'Gene', (133, 136))	('BBN', 'Chemical', 'MESH:D002085', (72, 75))	('CD8', 'Gene', '925', (133, 136))	('Tregs', 'Chemical', '-', (174, 179))	('increases', 'PosReg', (109, 118))	('decreases', 'NegReg', (150, 159))	('anti-B7-H4', 'Var', (98, 108))
25619	32363111	The anti-B7-H4 treatment-induced skewing of the CD8+ T cell to Treg ratio within the bladder correlated with a decrease in the bladder cancer stage score.	('bladder cancer', 'Phenotype', 'HP:0009725', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('CD8', 'Gene', (48, 51))	('anti-B7-H4', 'Var', (4, 14))	('bladder cancer', 'Disease', 'MESH:D001749', (127, 141))	('bladder cancer', 'Disease', (127, 141))	('decrease', 'NegReg', (111, 119))	('CD8', 'Gene', '925', (48, 51))
25620	32363111	Additionally, co-treatment of mice with both anti-B7-H4 and anti-PD-1 further decreased bladder cancer stage score, and such combination therapy may be considered a target for future therapeutic trials in patients with bladder cancer.	('decreased bladder cancer', 'Disease', 'MESH:D001749', (78, 102))	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))	('mice', 'Species', '10090', (30, 34))	('patients', 'Species', '9606', (205, 213))	('anti-PD-1', 'Var', (60, 69))	('bladder cancer', 'Disease', 'MESH:D001749', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('bladder cancer', 'Phenotype', 'HP:0009725', (219, 233))	('anti-B7-H4', 'Var', (45, 55))	('decreased bladder', 'Phenotype', 'HP:0005343', (78, 95))	('bladder cancer', 'Disease', 'MESH:D001749', (219, 233))	('decreased bladder cancer', 'Disease', (78, 102))	('bladder cancer', 'Disease', (219, 233))
25627	28723398	However, a fairly large proportion of patients with PDL1-negative tumors also benefit from PD1/PDL1 inhibition.	('PDL1', 'Gene', '29126', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('PDL1', 'Gene', '29126', (52, 56))	('PDL1', 'Gene', (95, 99))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('PD1', 'Gene', (91, 94))	('PD1', 'Gene', '5133', (91, 94))	('inhibition', 'Var', (100, 110))	('PDL1', 'Gene', (52, 56))	('patients', 'Species', '9606', (38, 46))	('benefit', 'PosReg', (78, 85))
25635	28723398	A biomarker study using paired biopsies from patients receiving MPDL3280A, a PDL1 inhibitor, demonstrated that treatment with MPDL3280A increased CD8 tumor immune infiltrates and PDL1 expression on tumor-infiltrating immune cells and tumor cells in patients with radiologic responses.	('tumor', 'Disease', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('patients', 'Species', '9606', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('expression', 'MPA', (184, 194))	('CD8', 'Gene', (146, 149))	('PDL1', 'Gene', (77, 81))	('PDL1', 'Gene', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('PDL1', 'Gene', '29126', (77, 81))	('PDL1', 'Gene', '29126', (179, 183))	('MPDL3280A', 'Var', (126, 135))	('patients', 'Species', '9606', (249, 257))	('increased', 'PosReg', (136, 145))	('tumor', 'Disease', (198, 203))	('CD8', 'Gene', '925', (146, 149))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('MPDL3280A', 'Chemical', 'MESH:C434123', (64, 73))	('MPDL3280A', 'Chemical', 'MESH:C434123', (126, 135))
25668	31363310	The response rate was highest in patients with tumours expressing PD-L1.	('highest', 'Reg', (22, 29))	('patients', 'Species', '9606', (33, 41))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('tumours', 'Disease', (47, 54))	('PD-L1', 'Var', (66, 71))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
25671	31363310	Although the data are incomplete, overall survival was 20 months in those with high PD-L1 expression and 8.1 months in other patients.	('expression', 'MPA', (90, 100))	('high', 'Var', (79, 83))	('PD-L1', 'Gene', (84, 89))	('patients', 'Species', '9606', (125, 133))
25689	30275714	Many previous studies have reported that MUTYH is directly related to hereditary adenomatous polyposis and colorectal cancer and is also associated with other cancers.	('hereditary adenomatous polyposis', 'Disease', (70, 102))	('cancers', 'Disease', (159, 166))	('associated', 'Reg', (137, 147))	('hereditary adenomatous polyposis', 'Disease', 'MESH:D011125', (70, 102))	('MUTYH', 'Var', (41, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('colorectal cancer', 'Disease', (107, 124))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (81, 102))	('related', 'Reg', (59, 66))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))
25693	30275714	The level of MUTYH was stably downregulated by lentivirus-mediated vector in SW780 cells.	('lentivirus-mediated', 'Var', (47, 66))	('downregulated', 'NegReg', (30, 43))	('SW780', 'CellLine', 'CVCL:1728', (77, 82))
25697	30275714	MUTYH knockdown inhibited the proliferation and migration and induced apoptosis in SW780 cells.	('inhibited', 'NegReg', (16, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('MUTYH', 'Gene', (0, 5))	('SW780', 'CellLine', 'CVCL:1728', (83, 88))	('induced', 'Reg', (62, 69))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('apoptosis', 'CPA', (70, 79))	('knockdown', 'Var', (6, 15))
25703	30275714	According to the results, we demonstrated that MUTYH was upregulated in BC tissues and cell line (SW780).	('SW780', 'CellLine', 'CVCL:1728', (98, 103))	('BC', 'Phenotype', 'HP:0009725', (72, 74))	('MUTYH', 'Var', (47, 52))	('upregulated', 'PosReg', (57, 68))
25704	30275714	Our data show that MUTYH is a powerful tumor marker, and highlight its potential clinical application as a promising prognostic marker and therapeutic target.	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('MUTYH', 'Var', (19, 24))	('tumor', 'Disease', (39, 44))
25706	30275714	The SV-HUC-1 cells were cultured in F12K (Thermo Fisher Scientific, Waltham, MA, USA) plus 1% antibiotics (100 U/mL penicillin and 100 microg/mL streptomycin sulfate) and 10% FBS.	('FBS', 'Disease', (175, 178))	('penicillin', 'Chemical', 'MESH:D010406', (116, 126))	('SV-HUC-1', 'CellLine', 'CVCL:3798', (4, 12))	('FBS', 'Disease', 'MESH:D005198', (175, 178))	('F12K', 'SUBSTITUTION', 'None', (36, 40))	('F12K', 'Var', (36, 40))	('streptomycin sulfate', 'Chemical', 'MESH:D013307', (145, 165))
25751	30275714	The EdU assay also demonstrated that the number of EdU-positive SW780 cells was significantly decreased in the MUTYH shRNA group compared with the shRNA negative control group (Figure 3B).	('EdU', 'Chemical', '-', (51, 54))	('SW780', 'CellLine', 'CVCL:1728', (64, 69))	('MUTYH shRNA', 'Var', (111, 122))	('decreased', 'NegReg', (94, 103))	('SW780', 'Gene', (64, 69))	('EdU', 'Chemical', '-', (4, 7))
25753	30275714	These data demonstrated that MUTYH knockdown significantly inhibited the proliferation of SW780 cells.	('proliferation', 'CPA', (73, 86))	('inhibited', 'NegReg', (59, 68))	('SW780', 'CellLine', 'CVCL:1728', (90, 95))	('MUTYH knockdown', 'Var', (29, 44))
25755	30275714	These results suggest that MUTYH knockdown inhibits the migration of SW780 cells.	('migration of SW780 cells', 'CPA', (56, 80))	('MUTYH knockdown', 'Var', (27, 42))	('knockdown', 'Var', (33, 42))	('SW780', 'CellLine', 'CVCL:1728', (69, 74))	('inhibits', 'NegReg', (43, 51))
25756	30275714	To investigate whether MUTYH induces apoptosis of BC cells, a caspase-3 ELISA was performed to measure the relative caspase-3 activity of SW780 cells stably transfected with MUTYH shRNA or shRNA negative control.	('MUTYH', 'Var', (174, 179))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('116', '134'))	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('caspase-3', 'Gene', '836', (62, 71))	('SW780', 'CellLine', 'CVCL:1728', (138, 143))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('116', '134'))	('caspase-3', 'Gene', (116, 125))	('BC', 'Phenotype', 'HP:0009725', (50, 52))	('caspase-3', 'Gene', '836', (116, 125))	('caspase-3', 'Gene', (62, 71))
25757	30275714	From the results shown in Figure 5, we found that the relative activity of caspase-3 was significantly increased in the MUTYH shRNA group compared with the negative control group (P<0.01).	('caspase-3', 'Gene', '836', (75, 84))	('activity', 'MPA', (63, 71))	('increased', 'PosReg', (103, 112))	('caspase-3', 'Gene', (75, 84))	('MUTYH shRNA', 'Var', (120, 131))
25758	30275714	These results indicated that MUTYH knockdown induces apoptosis of SW780 cells.	('apoptosis', 'CPA', (53, 62))	('SW780', 'CellLine', 'CVCL:1728', (66, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('MUTYH knockdown', 'Var', (29, 44))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))
25759	30275714	Differences in coding gene expression result in different functional proteins, which participate in a variety of biological actions, including tumor development.	('Differences', 'Var', (0, 11))	('tumor', 'Disease', (143, 148))	('participate', 'Reg', (85, 96))	('result in', 'Reg', (38, 47))	('gene expression', 'biological_process', 'GO:0010467', ('22', '37'))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('functional proteins', 'MPA', (58, 77))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
25761	30275714	MUTYH is a post-replicative DNA glycosylase that is highly conserved throughout the evolution process and is involved in the correction of mismatching caused by the misreplication of 8-hydroxyguanine.	('8-hydroxyguanine', 'Chemical', 'MESH:C024829', (183, 199))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('misreplication', 'Var', (165, 179))	('glycosylase', 'molecular_function', 'GO:0016798', ('32', '43'))	('involved', 'Reg', (109, 117))
25762	30275714	Several MUTYH mutations have been found to be responsible for mutyh-related polyposis, an autosomal recessive genetic disease characterized by the susceptibility of adenomatous polyps in the colon and rectum.	('polyposis', 'Disease', 'MESH:D011125', (76, 85))	('adenomatous polyps in the colon', 'Disease', (165, 196))	('mutations', 'Var', (14, 23))	('autosomal recessive genetic disease', 'Disease', 'MESH:D030342', (90, 125))	('responsible', 'Reg', (46, 57))	('mutyh', 'Gene', (62, 67))	('adenomatous polyps in the colon', 'Disease', 'MESH:D018256', (165, 196))	('mutyh', 'Gene', '4595', (62, 67))	('autosomal recessive genetic disease', 'Disease', (90, 125))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (165, 183))	('polyposis', 'Disease', (76, 85))	('MUTYH', 'Gene', (8, 13))
25763	30275714	It is known that mutation of mismatched repair genes will increase the susceptibility to cancer in organs other than the colon, and previous studies have found that MUTYH is highly related to colorectal cancer, breast cancer, lung adenocarcinoma, and gastric cancer, but the relationship between MUTYH and BC has not been revealed.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('colorectal cancer', 'Disease', (192, 209))	('gastric cancer', 'Phenotype', 'HP:0012126', (251, 265))	('susceptibility', 'MPA', (71, 85))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('related', 'Reg', (181, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))	('lung adenocarcinoma', 'Disease', (226, 245))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('mutation', 'Var', (17, 25))	('breast cancer', 'Disease', 'MESH:D001943', (211, 224))	('gastric cancer', 'Disease', (251, 265))	('colorectal cancer', 'Phenotype', 'HP:0003003', (192, 209))	('breast cancer', 'Disease', (211, 224))	('cancer', 'Disease', (259, 265))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (226, 245))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (226, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('cancer', 'Disease', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('mismatched', 'Var', (29, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (251, 265))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('BC', 'Phenotype', 'HP:0009725', (306, 308))	('increase', 'PosReg', (58, 66))	('cancer', 'Disease', (218, 224))	('colorectal cancer', 'Disease', 'MESH:D015179', (192, 209))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
25768	30275714	The results showed that MUTYH knockdown, in the MUTYH shRNA group, significantly inhibited cell proliferation and migration and induced apoptosis of BC SW780 cells compared with the shRNA negative control group, suggesting that inhibition of MUTYH expression could suppress the development and progression of BC.	('inhibition', 'Var', (228, 238))	('suppress', 'NegReg', (265, 273))	('BC', 'Phenotype', 'HP:0009725', (309, 311))	('progression', 'CPA', (294, 305))	('BC', 'Phenotype', 'HP:0009725', (149, 151))	('apoptosis', 'CPA', (136, 145))	('inhibited', 'NegReg', (81, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('SW780', 'CellLine', 'CVCL:1728', (152, 157))	('cell proliferation', 'biological_process', 'GO:0008283', ('91', '109'))	('development', 'CPA', (278, 289))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))	('induced', 'Reg', (128, 135))	('cell proliferation', 'CPA', (91, 109))
25771	30275714	In our future work, we will focus on mouse tumor formation experiments to verify whether the findings are consistent at the whole body level, and whether the tumor growth can be inhibited after knocking down MUTYH.	('MUTYH', 'Gene', (208, 213))	('tumor', 'Disease', (158, 163))	('formation', 'biological_process', 'GO:0009058', ('49', '58'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('knocking down', 'Var', (194, 207))	('inhibited', 'NegReg', (178, 187))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mouse', 'Species', '10090', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (43, 48))
25773	30275714	This study demonstrated that MUTYH is upregulated in BC, and that high MUTYH expression is associated with advanced stage and high-grade carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('expression', 'MPA', (77, 87))	('carcinomas', 'Disease', (137, 147))	('advanced stage', 'CPA', (107, 121))	('carcinomas', 'Disease', 'MESH:D002277', (137, 147))	('BC', 'Phenotype', 'HP:0009725', (53, 55))	('upregulated', 'PosReg', (38, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('high MUTYH', 'Var', (66, 76))	('associated', 'Reg', (91, 101))
25783	26952546	Exploratory analyses showed TCGA subtypes and mutation load to be independently predictive for response to atezolizumab.	('predictive', 'Reg', (80, 90))	('mutation load', 'Var', (46, 59))	('atezolizumab', 'Chemical', 'MESH:C000594389', (107, 119))	('TCGA', 'Gene', (28, 32))
25792	26952546	Because T lymphocytes play a central role in mediating acquired antitumoral immunity, expression of PD-L1 in the tumor microenvironment endows tumors with a mechanism to evade eradication by the host immune system.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (113, 118))	('endows tumors', 'Disease', (136, 149))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', (143, 148))	('PD-L1', 'Gene', '29126', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('expression', 'Var', (86, 96))	('endows tumors', 'Disease', 'MESH:D009369', (136, 149))	('PD-L1', 'Gene', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
25793	26952546	PD-L1 is broadly expressed across a wide range of malignancies, including urothelial carcinoma, and blockade of the PD-L1/PD-1 pathway has been shown to produce overall survival benefits in non-small cell lung cancer, melanoma and renal cell carcinoma.	('malignancies', 'Disease', (50, 62))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (194, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('PD-L1', 'Gene', (0, 5))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (74, 94))	('PD-L1', 'Gene', '29126', (0, 5))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (190, 216))	('PD-1', 'Gene', (122, 126))	('PD-1', 'Gene', '5133', (122, 126))	('benefits', 'PosReg', (178, 186))	('melanoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (218, 251))	('non-small cell lung cancer', 'Disease', (190, 216))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (231, 251))	('PD-L1', 'Gene', (116, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('PD-L1', 'Gene', '29126', (116, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('urothelial carcinoma', 'Disease', (74, 94))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('blockade', 'Var', (100, 108))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (190, 216))	('malignancies', 'Disease', 'MESH:D009369', (50, 62))
25795	26952546	Emerging data from The Cancer Genome Atlas (TCGA) indicated that urothelial carcinoma carried the third highest mutation rate and that gene expression signatures could be used to separate the disease into luminal and basal subtypes.	('mutation', 'Var', (112, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('Cancer Genome Atlas', 'Disease', (23, 42))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (23, 42))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (65, 85))	('gene expression', 'biological_process', 'GO:0010467', ('135', '150'))	('urothelial carcinoma', 'Disease', (65, 85))
25796	26952546	Additional mechanisms such as increased prevalence of non-synonymous mutations, higher neoantigen load, higher antigen binding affinity, and select T effector signatures, have all been identified as factors that may predict for durable clinical benefit in patients treated with immune checkpoint inhibitors consistent with the hypothesis that mutations may create neoantigens that are recognized by anti-tumor T cells.	('mutations', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (404, 409))	('tumor', 'Phenotype', 'HP:0002664', (404, 409))	('patients', 'Species', '9606', (256, 264))	('antigen binding', 'molecular_function', 'GO:0003823', ('111', '126'))	('tumor', 'Disease', (404, 409))	('antigen', 'MPA', (111, 118))	('neoantigen load', 'MPA', (87, 102))	('mutations', 'Var', (343, 352))	('non-synonymous mutations', 'Var', (54, 78))	('higher', 'PosReg', (104, 110))	('higher', 'PosReg', (80, 86))	('neoantigens', 'MPA', (364, 375))
25808	26952546	Exploratory analyses included the association between gene expression profiling, CD8+ T cell infiltration, and mutation load with IRF-assessed objective response.	('association', 'Interaction', (34, 45))	('CD8', 'Gene', (81, 84))	('CD8', 'Gene', '925', (81, 84))	('mutation load', 'Var', (111, 124))	('gene expression', 'biological_process', 'GO:0010467', ('54', '69'))
25839	26952546	The primary analysis demonstrated that treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each pre-specified IC group [IC2/3, 27% (95% CI 19 to 37), p<0 0001; IC1/2/3, 18% (95% CI 13 to 24), p=0 0004; and all patients, 15% (95% CI, 11 to 20), p=0 0058] compared to a historical control overall response rate of 10% (table 2, appendix).	('patients', 'Species', '9606', (263, 271))	('improved', 'PosReg', (95, 103))	('IC2/3', 'Gene', (173, 178))	('pre', 'molecular_function', 'GO:0003904', ('149', '152'))	('RECIST v1.1 objective response rate', 'MPA', (104, 139))	('IC2/3', 'Gene', '1781', (173, 178))	('atezolizumab', 'Chemical', 'MESH:C000594389', (54, 66))	('atezolizumab', 'Var', (54, 66))
25895	26952546	In addition to PD-L1 immunohistochemistry expression on immune cells, response to atezolizumab was strongly correlated with mutation load.	('response', 'MPA', (70, 78))	('correlated', 'Reg', (108, 118))	('atezolizumab', 'Chemical', 'MESH:C000594389', (82, 94))	('PD-L1', 'Gene', (15, 20))	('mutation load', 'Var', (124, 137))	('PD-L1', 'Gene', '29126', (15, 20))
25897	26952546	Although this targeted approach interrogated a much smaller fraction of the exome than typically used for mutation load estimation, a re-analysis of TCGA bladder urothelial carcinoma mutation data showed that whole-exome results were well-correlated with those obtained from only the FoundationOne regions (figure 10, appendix).	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (154, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('bladder urothelial carcinoma', 'Disease', (154, 182))	('mutation', 'Var', (183, 191))
25898	26952546	Moreover, the correlation of mutational load and response to atezolizumab is consistent with the pattern observed in other malignancies, and reinforces the concept that the multiple mutations that occur in cancer create novel epitopes against which protective T cell responses are directed.	('malignancies', 'Disease', 'MESH:D009369', (123, 135))	('atezolizumab', 'Chemical', 'MESH:C000594389', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('mutational', 'Var', (29, 39))	('malignancies', 'Disease', (123, 135))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('mutations', 'Var', (182, 191))
25904	26952546	While PD-L1 IC status clearly is associated with atezolizumab response, incorporation of TCGA gene expression subtype, mutation load, or both of these novel biomarkers into a model based on PD-L1 IC staining significantly improved the association with response (figure 9, appendix).	('mutation', 'Var', (119, 127))	('PD-L1', 'Gene', (190, 195))	('gene expression', 'biological_process', 'GO:0010467', ('94', '109'))	('PD-L1', 'Gene', '29126', (190, 195))	('atezolizumab', 'Chemical', 'MESH:C000594389', (49, 61))	('response', 'MPA', (252, 260))	('PD-L1', 'Gene', (6, 11))	('associated', 'Reg', (33, 43))	('TCGA', 'Gene', (89, 93))	('improved', 'PosReg', (222, 230))	('association', 'Interaction', (235, 246))	('PD-L1', 'Gene', '29126', (6, 11))
25905	26952546	Thus, disease subtype and mutation load do not simply recapitulate the information already provided by PD-L1 expression in immune cells, but rather, they provide independent and complementary information.	('PD-L1', 'Gene', '29126', (103, 108))	('PD-L1', 'Gene', (103, 108))	('mutation', 'Var', (26, 34))
25913	25874217	The use of aristolochic acid contaminated Chinese herbal medicine has been reported to be associated with the high incidence of upper urinary tract urothelial carcinoma (UUT-UC) in Taiwan.	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('aristolochic acid', 'Var', (11, 28))	('upper urinary tract urothelial carcinoma', 'Disease', (128, 168))	('aristolochic acid', 'Chemical', 'MESH:C000228', (11, 28))	('aristolochic', 'Chemical', '-', (11, 23))	('herbal medicine', 'Species', '1407750', (50, 65))
25937	24478461	Large deletions encompassing both BRCA1 and BECN1, and deletions of only BRCA1 but not BECN1, were found in breast and ovarian cancers, consistent with BRCA1 loss being a primary driver mutation in these cancers.	('ovarian cancer', 'Phenotype', 'HP:0100615', (119, 133))	('found', 'Reg', (99, 104))	('BRCA', 'Phenotype', 'HP:0003002', (34, 38))	('BRCA1', 'Gene', '672', (34, 39))	('BRCA', 'Phenotype', 'HP:0003002', (73, 77))	('BRCA', 'Phenotype', 'HP:0003002', (152, 156))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('BRCA1', 'Gene', '672', (152, 157))	('BECN1', 'Gene', (44, 49))	('BRCA1', 'Gene', (34, 39))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('BRCA1', 'Gene', (152, 157))	('cancers', 'Disease', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('BRCA1 loss', 'Disease', 'MESH:D015431', (152, 162))	('ovarian cancers', 'Phenotype', 'HP:0100615', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('BRCA1', 'Gene', '672', (73, 78))	('BRCA1', 'Gene', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (108, 134))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('deletions', 'Var', (55, 64))	('BRCA1 loss', 'Disease', (152, 162))
25938	24478461	Furthermore, there was no evidence for BECN1 mutation or loss in any other cancer, casting doubt on whether BECN1 is a tumor suppressor in most human cancers.	('tumor', 'Disease', (119, 124))	('BECN1', 'Gene', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('human', 'Species', '9606', (144, 149))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('tumor suppressor', 'biological_process', 'GO:0051726', ('119', '135'))	('cancers', 'Disease', (150, 157))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('119', '135'))	('cancer', 'Disease', (150, 156))	('mutation', 'Var', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
25941	24478461	Monoallelic disruption of BECN1 on chromosome 17q21 has been reported in 40 to 75% of human breast, ovarian, and prostate tumors, suggesting that autophagy is a tumor suppression mechanism.	('prostate tumors', 'Disease', (113, 128))	('ovarian', 'Disease', (100, 107))	('breast', 'Disease', (92, 98))	('prostate tumors', 'Disease', 'MESH:D011471', (113, 128))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('chromosome', 'cellular_component', 'GO:0005694', ('35', '45'))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('autophagy', 'biological_process', 'GO:0016236', ('146', '155'))	('BECN1', 'Gene', (26, 31))	('autophagy', 'CPA', (146, 155))	('human', 'Species', '9606', (86, 91))	('Monoallelic disruption', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('autophagy', 'biological_process', 'GO:0006914', ('146', '155'))	('reported', 'Reg', (61, 69))
25942	24478461	BECN1 allelic loss was also found in 9 out of 22 breast cancer cell lines by fluorescence in situ hybridization (FISH) analysis, although no coding or splice site mutations were found.	('BECN1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('allelic', 'Var', (6, 13))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('loss', 'NegReg', (14, 18))
25945	24478461	BRCA1 is a critical regulator of DNA repair by homologous recombination (HR) and its loss causes DNA repair defects and cancer predisposition.	('loss', 'Var', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('DNA repair', 'biological_process', 'GO:0006281', ('33', '43'))	('BRCA1', 'Gene', (0, 5))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('DNA repair', 'biological_process', 'GO:0006281', ('97', '107'))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('homologous recombination', 'biological_process', 'GO:0035825', ('47', '71'))	('causes', 'Reg', (90, 96))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('DNA repair', 'MPA', (97, 107))
25948	24478461	In support of the concept that autophagy is a tumor suppression mechanism and that allelic loss of BECN1 promotes cancer, Beclin1+/- mice are prone to mammary hyperplasia, liver and lung carcinomas and lymphomas.	('hyperplasia', 'Disease', (159, 170))	('liver and lung carcinomas and lymphomas', 'Disease', 'MESH:D006528', (172, 211))	('mice', 'Species', '10090', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('hyperplasia', 'Disease', 'MESH:D006965', (159, 170))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Beclin1', 'Gene', '56208', (122, 129))	('autophagy', 'biological_process', 'GO:0016236', ('31', '40'))	('Beclin1', 'Gene', (122, 129))	('BECN1', 'Gene', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('promotes', 'PosReg', (105, 113))	('autophagy', 'biological_process', 'GO:0006914', ('31', '40'))	('mammary hyperplasia', 'Phenotype', 'HP:0010313', (151, 170))	('tumor', 'Disease', (46, 51))	('lymphomas', 'Phenotype', 'HP:0002665', (202, 211))	('loss', 'Var', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('prone', 'Reg', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (202, 210))	('cancer', 'Disease', (114, 120))
25949	24478461	However, mosaic whole body knock out of the essential autophagy gene Atg5, or liver-specific knock out of the essential autophagy gene Atg7, produces only benign liver hepatomas and no other neoplasms.	('autophagy', 'biological_process', 'GO:0006914', ('120', '129'))	('autophagy', 'biological_process', 'GO:0006914', ('54', '63'))	('benign liver hepatomas', 'Disease', (155, 177))	('neoplasms', 'Phenotype', 'HP:0002664', (191, 200))	('Atg5', 'Gene', (69, 73))	('Atg7', 'Gene', (135, 139))	('benign liver hepatomas', 'Disease', 'MESH:D018248', (155, 177))	('knock out', 'Var', (27, 36))	('neoplasm', 'Phenotype', 'HP:0002664', (191, 199))	('neoplasms', 'Disease', 'MESH:D009369', (191, 200))	('neoplasms', 'Disease', (191, 200))	('knock out', 'Var', (93, 102))	('autophagy', 'biological_process', 'GO:0016236', ('120', '129'))	('autophagy', 'biological_process', 'GO:0016236', ('54', '63'))
25952	24478461	The vast majority of germline mutations in BRCA1 are loss-of-function mutations (frameshift, indels, nonsense mutations, or missense), or focal deletions, not gross deletions in the BRCA1 locus at 17q21 that extend to encompass BECN1.	('BRCA1', 'Gene', (43, 48))	('BRCA1', 'Gene', '672', (182, 187))	('deletions', 'Var', (144, 153))	('missense', 'Var', (124, 132))	('BRCA1', 'Gene', (182, 187))	('frameshift', 'Var', (81, 91))	('nonsense mutations', 'Var', (101, 119))	('germline mutations', 'Var', (21, 39))	('BRCA', 'Phenotype', 'HP:0003002', (43, 47))	('BRCA1', 'Gene', '672', (43, 48))	('BRCA', 'Phenotype', 'HP:0003002', (182, 186))	('loss-of-function', 'NegReg', (53, 69))
25956	24478461	Without autophagy tumors accumulate defective mitochondria, have growth and metabolic defects, and progresses to a more benign fate.	('progresses', 'PosReg', (99, 109))	('defective', 'Var', (36, 45))	('growth', 'CPA', (65, 71))	('metabolic defects', 'Disease', (76, 93))	('autophagy tumors', 'Disease', (8, 24))	('more benign fate', 'CPA', (115, 131))	('autophagy tumors', 'Disease', 'MESH:C564093', (8, 24))	('metabolic defects', 'Disease', 'MESH:D008659', (76, 93))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('autophagy', 'biological_process', 'GO:0016236', ('8', '17'))	('mitochondria', 'cellular_component', 'GO:0005739', ('46', '58'))	('autophagy', 'biological_process', 'GO:0006914', ('8', '17'))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
25958	24478461	Germline mutations in BRCA1, BRCA2, and PALB2, predispose to hereditary breast cancer and the three proteins function together to maintain genome stability by promoting faithful repair of double strand breaks by HR.	('Germline mutations', 'Var', (0, 18))	('PALB2', 'Gene', (40, 45))	('PALB2', 'Gene', '79728', (40, 45))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (61, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('genome', 'MPA', (139, 145))	('maintain', 'PosReg', (130, 138))	('BRCA2', 'Gene', (29, 34))	('faithful repair', 'MPA', (169, 184))	('predispose', 'Reg', (47, 57))	('hereditary breast cancer', 'Disease', (61, 85))	('promoting', 'PosReg', (159, 168))	('BRCA', 'Phenotype', 'HP:0003002', (29, 33))	('function', 'Reg', (109, 117))	('BRCA1', 'Gene', '672', (22, 27))	('BRCA2', 'Gene', '675', (29, 34))	('BRCA', 'Phenotype', 'HP:0003002', (22, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('BRCA1', 'Gene', (22, 27))
25959	24478461	Mammary epithelial cell-specific knockout of Palb2 causes mammary tumorigenesis with long latency that is suppressed by allelic loss of Becnl, suggesting that autophagy is tumor-promoting.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('knockout', 'Var', (33, 41))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (172, 177))	('autophagy', 'biological_process', 'GO:0016236', ('159', '168'))	('Palb2', 'Gene', '79728', (45, 50))	('causes', 'Reg', (51, 57))	('autophagy', 'biological_process', 'GO:0006914', ('159', '168'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('Palb2', 'Gene', (45, 50))
25960	24478461	Deletion of Trp53 abrogates tumorigenesis impairment upon allelic loss of Becnl in Pa/fr2-deficient mammary tumors, thus the combination of autophagy defect and loss of a critical DNA repair mechanism augments the p53 anti-tumor response.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('DNA', 'cellular_component', 'GO:0005574', ('180', '183'))	('Pa/fr2-deficient mammary tumors', 'Disease', (83, 114))	('autophagy', 'biological_process', 'GO:0016236', ('140', '149'))	('impairment', 'NegReg', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('Pa/fr2-deficient mammary tumors', 'Disease', 'MESH:D015674', (83, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('p53', 'Gene', '7157', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('abrogates', 'NegReg', (18, 27))	('augments', 'PosReg', (201, 209))	('Deletion', 'Var', (0, 8))	('autophagy', 'biological_process', 'GO:0006914', ('140', '149'))	('tumor', 'Disease', (223, 228))	('p53', 'Gene', '7157', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('p53', 'Gene', (214, 217))	('Trp53', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('Trp53', 'Gene', '7157', (12, 17))	('p53', 'Gene', (14, 17))	('DNA repair', 'biological_process', 'GO:0006281', ('180', '190'))	('autophagy defect and loss', 'Disease', 'MESH:C564093', (140, 165))
25961	24478461	Since loss of both Palb2 and autophagy promote DNA damage and p53 activation,, this explains enhanced p53 activity and why autophagy suppresses the p53 response and mammary tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('p53', 'Gene', '7157', (62, 65))	('activation', 'PosReg', (66, 76))	('loss', 'Var', (6, 10))	('autophagy', 'CPA', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (62, 65))	('autophagy', 'biological_process', 'GO:0016236', ('123', '132'))	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('autophagy', 'biological_process', 'GO:0016236', ('29', '38'))	('promote', 'PosReg', (39, 46))	('Palb2', 'Gene', (19, 24))	('p53', 'Gene', '7157', (148, 151))	('DNA damage', 'MPA', (47, 57))	('enhanced', 'PosReg', (93, 101))	('Palb2', 'Gene', '79728', (19, 24))	('p53', 'Gene', (102, 105))	('p53', 'Gene', (148, 151))	('autophagy', 'biological_process', 'GO:0006914', ('123', '132'))	('autophagy', 'biological_process', 'GO:0006914', ('29', '38'))	('suppresses', 'NegReg', (133, 143))	('tumor', 'Disease', (173, 178))	('activity', 'MPA', (106, 114))
25962	24478461	The important unanswered question here is whether mutations in essential autophagy genes are found in human cancers using current genomic information, and if they are found, are they loss- or gain-of-function mutations?	('loss-', 'NegReg', (183, 188))	('mutations', 'Var', (50, 59))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('gain-of-function', 'PosReg', (192, 208))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('autophagy', 'biological_process', 'GO:0006914', ('73', '82'))	('autophagy', 'biological_process', 'GO:0016236', ('73', '82'))	('autophagy genes', 'Gene', (73, 88))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))	('human', 'Species', '9606', (102, 107))
25965	24478461	We first assessed BECN1 for single nucleotide variations (SNVs) and copy number variations (CNVs) in human breast, ovarian and prostate cancer genome sequences.	('prostate cancer', 'Phenotype', 'HP:0012125', (127, 142))	('human', 'Species', '9606', (101, 106))	('single nucleotide variations', 'Var', (28, 56))	('copy number variations', 'Var', (68, 90))	('ovarian and prostate cancer', 'Disease', 'MESH:D010051', (115, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
25966	24478461	Since BECN1 is adjacent to BRCA1, we specifically looked for deletions of BECN1 that do not encompass BRCA1.	('BRCA1', 'Gene', (102, 107))	('BECN1', 'Gene', (74, 79))	('deletions', 'Var', (61, 70))	('BRCA1', 'Gene', '672', (27, 32))	('BRCA1', 'Gene', (27, 32))	('BRCA', 'Phenotype', 'HP:0003002', (102, 106))	('BRCA1', 'Gene', '672', (102, 107))	('BRCA', 'Phenotype', 'HP:0003002', (27, 31))
25967	24478461	We found enrichment for truncating mutations of BRCA1, deletion of the chromosomal region that included BRCA1 only, and deletions affecting both BRCA1 and BECN1, but not truncating mutations of BECN1 or deletions of only BECN1.	('BRCA1', 'Gene', '672', (48, 53))	('deletions', 'Var', (120, 129))	('BRCA', 'Phenotype', 'HP:0003002', (48, 52))	('BRCA1', 'Gene', '672', (104, 109))	('BRCA', 'Phenotype', 'HP:0003002', (145, 149))	('BRCA1', 'Gene', (48, 53))	('BRCA1', 'Gene', '672', (145, 150))	('BRCA1', 'Gene', (104, 109))	('chromosomal region', 'cellular_component', 'GO:0098687', ('71', '89'))	('BRCA1', 'Gene', (145, 150))	('deletion', 'Var', (55, 63))	('truncating', 'MPA', (24, 34))	('BECN1', 'Gene', (155, 160))	('BRCA', 'Phenotype', 'HP:0003002', (104, 108))
25968	24478461	Analysis of all other cancers that lack BRCA1 deletion indicated no significant recurrence of SNVs or CNVs in BECN1.	('deletion', 'Var', (46, 54))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('cancers', 'Disease', (22, 29))	('BRCA', 'Phenotype', 'HP:0003002', (40, 44))	('BRCA1', 'Gene', '672', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('SNVs', 'Disease', (94, 98))	('BRCA1', 'Gene', (40, 45))
25975	24478461	We test the sensitivity of our method by finding the previously reported CNV (amplifications in PIK3CA, EGFR, FOXA1 and HER2; de/etions in MLL3, PTEN, RB1 and MAP2K4) in breast invasive cancer.	('MAP2K4', 'Gene', '6416', (159, 165))	('MAP2K4', 'Gene', (159, 165))	('HER2', 'Gene', '2064', (120, 124))	('PIK3CA', 'Gene', '5290', (96, 102))	('FOXA1', 'Gene', '3169', (110, 115))	('EGFR', 'Gene', (104, 108))	('RB1', 'Gene', '5925', (151, 154))	('MAP2K', 'molecular_function', 'GO:0004708', ('159', '164'))	('MLL3', 'Gene', '58508', (139, 143))	('FOXA1', 'Gene', (110, 115))	('de/etions', 'Var', (126, 135))	('PTEN', 'Gene', (145, 149))	('HER2', 'Gene', (120, 124))	('PIK3CA', 'Gene', (96, 102))	('EGFR', 'Gene', '1956', (104, 108))	('MLL3', 'Gene', (139, 143))	('PTEN', 'Gene', '5728', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))	('breast invasive cancer', 'Disease', 'MESH:D001943', (170, 192))	('breast invasive cancer', 'Disease', (170, 192))	('RB1', 'Gene', (151, 154))
25980	24478461	We extracted the somatic mutations for BECN1 and BRCA1 and indicated their type as missense, nonsense, silent, splice site, and insertion or deletion resulting in frame shift or in frame (Table S3 and Table S4).	('BRCA', 'Phenotype', 'HP:0003002', (49, 53))	('nonsense', 'Var', (93, 101))	('deletion', 'Var', (141, 149))	('BECN1', 'Gene', (39, 44))	('missense', 'Var', (83, 91))	('BRCA1', 'Gene', '672', (49, 54))	('frame', 'MPA', (163, 168))	('BRCA1', 'Gene', (49, 54))	('insertion', 'Var', (128, 137))
25984	24478461	CNVs were classified into three groups defined by whether the CNV overlapped with BECN1 but not BRCA1, overlapped with BRCA1 but not BECN1, or overlapped with both BECN1 and BRCA1 (Table 1).	('BRCA', 'Phenotype', 'HP:0003002', (96, 100))	('BRCA1', 'Gene', (174, 179))	('BRCA1', 'Gene', (119, 124))	('BRCA1', 'Gene', '672', (96, 101))	('BRCA1', 'Gene', (96, 101))	('BRCA', 'Phenotype', 'HP:0003002', (119, 123))	('BRCA', 'Phenotype', 'HP:0003002', (174, 178))	('BRCA1', 'Gene', '672', (174, 179))	('BRCA1', 'Gene', '672', (119, 124))	('overlapped', 'Var', (103, 113))
25986	24478461	As expected, breast and ovarian tumors were significantly enriched for having deletions in the locus containing both BECN1 and BRCA1 (Table 1).	('BRCA1', 'Gene', '672', (127, 132))	('breast and ovarian tumors', 'Disease', 'MESH:D001943', (13, 38))	('BRCA1', 'Gene', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('BRCA', 'Phenotype', 'HP:0003002', (127, 131))	('ovarian tumor', 'Phenotype', 'HP:0100615', (24, 37))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('BECN1', 'Gene', (117, 122))	('ovarian tumors', 'Phenotype', 'HP:0100615', (24, 38))	('deletions', 'Var', (78, 87))
25987	24478461	Other tumor types that exhibited significant enrichment for deletions in both BECN1 and BRCA1 include kidney chromophobe and uterine corpus endometrioid carcinoma (Table 1).	('BRCA1', 'Gene', (88, 93))	('kidney chromophobe', 'Disease', 'MESH:D000238', (102, 120))	('corpus endometrioid carcinoma', 'Disease', (133, 162))	('corpus endometrioid carcinoma', 'Disease', 'MESH:D016889', (133, 162))	('BECN1', 'Gene', (78, 83))	('deletions', 'Var', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('BRCA', 'Phenotype', 'HP:0003002', (88, 92))	('kidney chromophobe', 'Disease', (102, 120))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('BRCA1', 'Gene', '672', (88, 93))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (140, 162))	('tumor', 'Disease', (6, 11))
25989	24478461	Closer examination found that the CNVs in kidney chromophobe and kidney renal papillary cell carcinoma are whole chromosome deletions and amplifications, respectively, which are consistent with known loss and gain of chromosome 17 for these two types of tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('tumors', 'Disease', (254, 260))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('chromosome', 'cellular_component', 'GO:0005694', ('217', '227'))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (72, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('113', '123'))	('CNVs', 'Var', (34, 38))	('kidney chromophobe and kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007674', (42, 102))
25990	24478461	CNVs that overlap BRCA1 but not BECN1 were enriched for deletions in breast and ovarian tumors, while CNVs that overlap BECN1 but not BRCA1 were not enriched for deletions in any tumor (Table 1).	('BRCA', 'Phenotype', 'HP:0003002', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('BRCA1', 'Gene', '672', (18, 23))	('BRCA1', 'Gene', (134, 139))	('ovarian tumors', 'Phenotype', 'HP:0100615', (80, 94))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('ovarian tumor', 'Phenotype', 'HP:0100615', (80, 93))	('BECN1', 'Gene', (120, 125))	('BRCA1', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('deletions', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('BRCA', 'Phenotype', 'HP:0003002', (134, 138))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('breast and ovarian tumors', 'Disease', 'MESH:D001943', (69, 94))	('BRCA1', 'Gene', '672', (134, 139))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (179, 184))
25991	24478461	These results are consistent with the loss of BRCA1 being the driver mutation in breast and ovarian tumors.	('loss', 'Var', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('BRCA1', 'Gene', '672', (46, 51))	('ovarian tumors', 'Phenotype', 'HP:0100615', (92, 106))	('ovarian tumor', 'Phenotype', 'HP:0100615', (92, 105))	('BRCA', 'Phenotype', 'HP:0003002', (46, 50))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('breast and ovarian tumors', 'Disease', 'MESH:D001943', (81, 106))	('BRCA1', 'Gene', (46, 51))
25993	24478461	Loss of chromosome 17q21 and BRCA1 has been reported in prostate cancer only very infrequently (0.45%).	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('BRCA', 'Phenotype', 'HP:0003002', (29, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('BRCA1', 'Gene', '672', (29, 34))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('BRCA1', 'Gene', (29, 34))	('Loss', 'Var', (0, 4))	('prostate cancer', 'Disease', (56, 71))
25994	24478461	For prostate adenocarcinoma, we found 9 deletions (covering both BECN1 and BRCA1) and no amplifications (Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('BRCA1', 'Gene', (75, 80))	('prostate adenocarcinoma', 'Disease', (4, 27))	('deletions', 'Var', (40, 49))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (4, 27))	('BECN1', 'Gene', (65, 70))	('BRCA', 'Phenotype', 'HP:0003002', (75, 79))	('BRCA1', 'Gene', '672', (75, 80))
25995	24478461	Prostate adenocarcinoma is a heterogeneous disease and the fraction of this disease where loss of 17q21 is a driver mutation is small compared to breast or ovarian cancer.	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (146, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (0, 23))	('17q21', 'Gene', (98, 103))	('breast or ovarian cancer', 'Disease', (146, 170))	('Prostate adenocarcinoma', 'Disease', (0, 23))	('ovarian cancer', 'Phenotype', 'HP:0100615', (156, 170))	('loss of', 'Var', (90, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
25996	24478461	It is clear, however, that in contrast to previous reports, BECN1 deletions do not significantly occur in the absence of BRCA1 deletion.	('BRCA', 'Phenotype', 'HP:0003002', (121, 125))	('BECN1', 'Gene', (60, 65))	('BRCA1', 'Gene', '672', (121, 126))	('BRCA1', 'Gene', (121, 126))	('deletions', 'Var', (66, 75))
25997	24478461	There are 169 and 32 (ratio of 5.28) mutations found in BRCA1 and BECN1 respectively across all tumor samples (6632) and the numbers are 137 and 31 (ratio of 4.42) if we exclude breast and ovarian tumors where BRCA1 is known to be a tumor suppressor (Table S2).	('BRCA', 'Phenotype', 'HP:0003002', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('ovarian tumor', 'Phenotype', 'HP:0100615', (189, 202))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('ovarian tumors', 'Phenotype', 'HP:0100615', (189, 203))	('tumor', 'Disease', (233, 238))	('BRCA1', 'Gene', '672', (210, 215))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('233', '249'))	('BRCA1', 'Gene', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('BECN1', 'Gene', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('BRCA1', 'Gene', '672', (56, 61))	('BRCA', 'Phenotype', 'HP:0003002', (56, 60))	('tumor suppressor', 'biological_process', 'GO:0051726', ('233', '249'))	('tumor', 'Disease', (96, 101))	('BRCA1', 'Gene', (56, 61))	('mutations', 'Var', (37, 46))	('breast and ovarian tumors', 'Disease', 'MESH:D001943', (178, 203))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (197, 202))
25999	24478461	None of the mutations found in BECN1 were nonsense or splice site mutations (Table S3) with the potential to alter function and that are frequently found tumor suppressor mutations.	('alter', 'Reg', (109, 114))	('mutations', 'Var', (12, 21))	('tumor suppressor', 'biological_process', 'GO:0051726', ('154', '170'))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('154', '170'))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('BECN1', 'Gene', (31, 36))	('function', 'MPA', (115, 123))	('tumor', 'Disease', (154, 159))
26000	24478461	If we restrict analysis to breast and ovarian cancer, there is only one mutation found in BECN1 and it is a missense mutation in an ovarian tumor.	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (27, 52))	('ovarian cancer', 'Phenotype', 'HP:0100615', (38, 52))	('ovarian tumor', 'Phenotype', 'HP:0100615', (132, 145))	('ovarian tumor', 'Disease', 'MESH:D010051', (132, 145))	('missense mutation', 'Var', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('BECN1', 'Gene', (90, 95))	('ovarian tumor', 'Disease', (132, 145))
26001	24478461	In contrast, there are 32 mutations in BRCA1 of which 23 are nonsense, splice site or frame shift mutations all of which lead to truncation of BRCA1 (Table S4).	('BRCA1', 'Gene', '672', (143, 148))	('truncation', 'MPA', (129, 139))	('BRCA1', 'Gene', (143, 148))	('BRCA', 'Phenotype', 'HP:0003002', (143, 147))	('BRCA', 'Phenotype', 'HP:0003002', (39, 43))	('mutations', 'Var', (26, 35))	('BRCA1', 'Gene', '672', (39, 44))	('lead to', 'Reg', (121, 128))	('frame shift', 'Var', (86, 97))	('BRCA1', 'Gene', (39, 44))
26002	24478461	Across all cancer data from TCGA, there are 30 missense, 0 nonsense, 0 splice site and 11 silent mutations for BECN1 and 135 missense, 20 nonsense, 12 splice site and 39 silent mutations for BRCA1.	('BRCA1', 'Gene', (191, 196))	('missense', 'Var', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BRCA', 'Phenotype', 'HP:0003002', (191, 195))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('missense', 'Var', (125, 133))	('BRCA1', 'Gene', '672', (191, 196))	('cancer', 'Disease', (11, 17))	('BECN1', 'Gene', (111, 116))
26003	24478461	To find statistical enrichment of missense, nonsense or splice site mutations compared to silent mutations, we use as null model the aggregate of mutations across all samples in breast cancer (778 tumors) yielding 31861 missense, 2339 nonsense, 1075 splice site and 11677 silent mutations.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('missense', 'Var', (220, 228))	('nonsense', 'Var', (235, 243))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('breast cancer', 'Disease', (178, 191))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))
26004	24478461	Since the vast majority of mutations detected in tumors are passenger mutations with little or no selective advantage to the tumors, the ratio of missense to silent mutations (2.73), nonsense to silent mutations (0.20), and splice site to silent mutations (0.09) are good approximations for little or no selection of missense, nonsense or splice site over silent mutations.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))
26006	24478461	There is statistically significant enrichment for ratio of nonsense to silent and splice site to silent mutations for BRCA1 (2.6 and 3.4 fold enrichment with p-value of 0.0008 and 0.0003 using two-tailed Chi-square test with Yate's correction).	('BRCA1', 'Gene', (118, 123))	('nonsense', 'Var', (59, 67))	('BRCA', 'Phenotype', 'HP:0003002', (118, 122))	('BRCA1', 'Gene', '672', (118, 123))
26007	24478461	There is no significant enrichment for missense over silent mutations for BRCA1 and BECN1, and no enrichment of nonsense and splice site over silent mutations in BECN1.	('BECN1', 'Gene', (84, 89))	('BRCA1', 'Gene', (74, 79))	('BRCA1', 'Gene', '672', (74, 79))	('BRCA', 'Phenotype', 'HP:0003002', (74, 78))	('BECN1', 'Gene', (162, 167))	('missense', 'Var', (39, 47))
26011	24478461	Despite reports indicating allelic loss of BECN1 in some human cancers, this appears to be explained solely by the proximity of BECN1 to BRCA1.	('BRCA1', 'Gene', '672', (137, 142))	('loss', 'NegReg', (35, 39))	('BECN1', 'Gene', (43, 48))	('BRCA1', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('allelic', 'Var', (27, 34))	('BRCA', 'Phenotype', 'HP:0003002', (137, 141))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('human', 'Species', '9606', (57, 62))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
26014	24478461	Furthermore, there is no finding of nonsense or splice site mutations in BECN1 in any other cancers.	('nonsense or splice site mutations', 'Var', (36, 69))	('BECN1', 'Gene', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
26016	24478461	In these cancers, the majority of the deletions are large and take out both genes and a hundred others.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('deletions', 'Var', (38, 47))
26017	24478461	While focal deletions and somatic, predicted loss of function mutations (missense, nonsense, frame shift and splice site mutations) are found in BRCA1, they are not found in BECN1.	('BRCA', 'Phenotype', 'HP:0003002', (145, 149))	('BRCA1', 'Gene', '672', (145, 150))	('loss of function', 'NegReg', (45, 61))	('BRCA1', 'Gene', (145, 150))	('nonsense', 'Var', (83, 91))	('frame shift', 'Var', (93, 104))
26018	24478461	Furthermore, there are no significant germline mutation or allelic loss of BECN1 in breast and ovarian cancer patients, nor are there inactivating mutations in the absence of BRCA1 mutation or loss.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BRCA1', 'Gene', (175, 180))	('BECN1', 'Gene', (75, 80))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))	('loss', 'NegReg', (67, 71))	('mutation', 'Var', (181, 189))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (84, 109))	('BRCA', 'Phenotype', 'HP:0003002', (175, 179))	('patients', 'Species', '9606', (110, 118))	('BRCA1', 'Gene', '672', (175, 180))
26020	24478461	Indeed, allelic loss of Becnl suppresses rather than promotes mammary tumorgenesis mediated by Palb2 deficiency.	('promotes', 'PosReg', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Palb2', 'Gene', '79728', (95, 100))	('Becnl', 'Gene', (24, 29))	('suppresses', 'NegReg', (30, 40))	('tumor', 'Disease', (70, 75))	('Palb2', 'Gene', (95, 100))	('deficiency', 'Var', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
26023	24478461	Mice with allelic loss of Becnl, or bi-allelic deletion of Atg5 or Atg7 in liver are prone to liver tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('bi-allelic deletion', 'Var', (36, 55))	('loss', 'NegReg', (18, 22))	('Atg5', 'Gene', (59, 63))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('Atg7', 'Gene', (67, 71))	('liver tumors', 'Disease', 'MESH:D008113', (94, 106))	('Mice', 'Species', '10090', (0, 4))	('prone', 'Reg', (85, 90))	('liver tumors', 'Phenotype', 'HP:0002896', (94, 106))	('liver tumors', 'Disease', (94, 106))
26025	24478461	Indeed, deletion of Atg7 diverts progression of lung adenocarcinomas to benign oncocytomas.	('lung adenocarcinomas to benign oncocytomas', 'Disease', (48, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))	('progression', 'MPA', (33, 44))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (48, 68))	('diverts', 'NegReg', (25, 32))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('lung adenocarcinomas to benign oncocytomas', 'Disease', 'MESH:D018249', (48, 90))	('deletion', 'Var', (8, 16))	('Atg7', 'Gene', (20, 24))
26031	23842986	We identified 139 patients treated with neoadjuvant cisplatin-based chemotherapy followed by RC for T2-4aN0M0 bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (110, 124))	('bladder cancer', 'Disease', (110, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('T2-4aN0M0', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('bladder cancer', 'Phenotype', 'HP:0009725', (110, 124))	('patients', 'Species', '9606', (18, 26))
26081	23842986	Several groups have reported that pathologic responders have improved overall survival over those with residual muscle-invasive disease, with the best outcomes experienced by those with complete response (pT0).	('improved', 'PosReg', (61, 69))	('overall survival', 'MPA', (70, 86))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (112, 135))	('pathologic responders', 'Var', (34, 55))	('muscle-invasive disease', 'Disease', (112, 135))
26090	23842986	These components promote tumor formation through direct DNA damage, mutating oncogenes and tumor suppressors, or by modifying key signal transduction pathways.	('signal transduction', 'biological_process', 'GO:0007165', ('130', '149'))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('key signal transduction pathways', 'Pathway', (126, 158))	('direct DNA damage', 'CPA', (49, 66))	('tumor', 'Disease', (25, 30))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('promote', 'PosReg', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('oncogenes', 'Protein', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mutating', 'Var', (68, 76))	('formation', 'biological_process', 'GO:0009058', ('31', '40'))	('modifying', 'Reg', (116, 125))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
26092	23842986	For example, STAT3, a transcription factor involved in cell growth and apoptosis, is activated by nicotine and leads to chemoresistance, while inhibition of STAT3 restores chemosensitivity in vitro.	('cell growth', 'biological_process', 'GO:0016049', ('55', '66'))	('chemoresistance', 'MPA', (120, 135))	('transcription factor', 'molecular_function', 'GO:0000981', ('22', '42'))	('leads to', 'Reg', (111, 119))	('STAT3', 'Gene', '6774', (157, 162))	('nicotine', 'Chemical', 'MESH:D009538', (98, 106))	('activated', 'PosReg', (85, 94))	('inhibition', 'Var', (143, 153))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('STAT3', 'Gene', (157, 162))	('STAT3', 'Gene', '6774', (13, 18))	('chemosensitivity', 'MPA', (172, 188))	('transcription', 'biological_process', 'GO:0006351', ('22', '35'))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('STAT3', 'Gene', (13, 18))
26095	23842986	Importantly, in oral cancer cell lines exposed to nicotine, treatment with the PI3K pathway inhibitor LY294002 restored cisplatin-mediated apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('nicotine', 'Chemical', 'MESH:D009538', (50, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('139', '148'))	('apoptosis', 'biological_process', 'GO:0006915', ('139', '148'))	('cisplatin-mediated apoptosis', 'MPA', (120, 148))	('LY294002', 'Chemical', 'MESH:C085911', (102, 110))	('restored', 'PosReg', (111, 119))	('oral cancer', 'Disease', 'MESH:D009062', (16, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('PI3K', 'molecular_function', 'GO:0016303', ('79', '83'))	('oral cancer', 'Disease', (16, 27))	('LY294002', 'Var', (102, 110))
26142	23927752	Frozen section evaluation of a biopsy sample showed atypical urothelial cells, findings consistent with a urothelial carcinoma.	('atypical', 'Var', (52, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (106, 126))	('urothelial carcinoma', 'Disease', (106, 126))
26237	33332422	A heatmap of the 52 tumors from the UNC-Training dataset supervised by distance to the basal centroid in the Nanostring BASE47 classifier demonstrated that there were very distinct basal and luminal nodes of BASE47 genes, consistent with previous analyses of genes in the Transcriptome BASE47 classifier (Fig 3A).	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('genes', 'Var', (215, 220))	('luminal', 'Chemical', 'MESH:D010634', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('BASE47', 'Gene', (208, 214))
26267	33038052	 CDK12 and HER2 coamplification in two urothelial carcinomas with rapid and aggressive clinical progression Cyclin-dependent kinase 12 (CDK12), one of the key factors associated with DNA damage response pathways, is located on chromosome 17 proximal to Erb-B2 receptor tyrosine kinase 2 (ERBB2).	('ERBB2', 'Gene', (288, 293))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (39, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('CDK', 'molecular_function', 'GO:0004693', ('1', '4'))	('CDK12', 'Gene', '51755', (1, 6))	('CDK', 'molecular_function', 'GO:0004693', ('136', '139'))	('CDK12', 'Gene', '51755', (136, 141))	('chromosome', 'cellular_component', 'GO:0005694', ('227', '237'))	('ERBB2', 'Gene', '2064', (288, 293))	('Erb-B2', 'Gene', (253, 259))	('Cyclin-dependent kinase 12', 'Gene', '51755', (108, 134))	('Cyclin', 'molecular_function', 'GO:0016538', ('108', '114'))	('HER2', 'Gene', (11, 15))	('DNA', 'cellular_component', 'GO:0005574', ('183', '186'))	('urothelial carcinomas', 'Disease', (39, 60))	('Erb-B2', 'Gene', '2064', (253, 259))	('coamplification', 'Var', (16, 31))	('CDK12', 'Gene', (1, 6))	('Cyclin-dependent kinase 12', 'Gene', (108, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('DNA damage response', 'biological_process', 'GO:0006974', ('183', '202'))	('CDK12', 'Gene', (136, 141))	('HER2', 'Gene', '2064', (11, 15))
26270	33038052	Our results suggest that CDK12 coamplification with ERBB2 might be associated with tumor aggressiveness and contribution to cancer pathogenesis.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Disease', (124, 130))	('pathogenesis', 'biological_process', 'GO:0009405', ('131', '143'))	('CDK12', 'Protein', (25, 30))	('tumor aggressiveness', 'Disease', (83, 103))	('aggressiveness', 'Phenotype', 'HP:0000718', (89, 103))	('coamplification', 'Var', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('ERBB2', 'Gene', '2064', (52, 57))	('associated', 'Reg', (67, 77))	('CDK', 'molecular_function', 'GO:0004693', ('25', '28'))	('ERBB2', 'Gene', (52, 57))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (83, 103))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
26272	33038052	BCG Bacillus Calmette-Guerin CDK12 cyclin-dependent kinase 12 CN copy number CT computed tomography DDR DNA damage response ERBB2 Erb-b2 receptor tyrosine kinase 2 HER2 human epidermal growth factor receptor 2 PARP poly (ADP-ribose) polymerase PSA prostate-specific antigen SNV single nucleotide variant TMB tumor mutation burden TURBT transurethral resection of the bladder tumor VUS variant of unknown significance Cyclin-dependent kinase 12 is an important kinase necessary for modulating transcription in various cellular processes, including DDR, cell growth regulation, and differentiation, similar to HER2.	('DNA damage response', 'biological_process', 'GO:0006974', ('104', '123'))	('Erb-b2', 'Gene', '2064', (130, 136))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('175', '198'))	('cell growth', 'biological_process', 'GO:0016049', ('552', '563'))	('single', 'Var', (278, 284))	('DDR', 'Chemical', '-', (547, 550))	('human', 'Species', '9606', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('bladder tumor', 'Phenotype', 'HP:0009725', (367, 380))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('PARP', 'Gene', '142', (210, 214))	('DDR', 'Disease', (547, 550))	('DDR', 'Chemical', '-', (100, 103))	('PSA', 'Gene', (244, 247))	('PARP', 'Gene', (210, 214))	('cyclin', 'molecular_function', 'GO:0016538', ('35', '41'))	('tumor', 'Disease', (375, 380))	('transcription', 'biological_process', 'GO:0006351', ('492', '505'))	('Cyclin-dependent kinase 12', 'Gene', '51755', (417, 443))	('TMB', 'Chemical', '-', (304, 307))	('regulation', 'biological_process', 'GO:0065007', ('564', '574'))	('bladder tumor', 'Disease', (367, 380))	('tumor', 'Disease', 'MESH:D009369', (375, 380))	('Cyclin', 'molecular_function', 'GO:0016538', ('417', '423'))	('bladder tumor', 'Disease', 'MESH:D001749', (367, 380))	('tumor', 'Disease', (308, 313))	('ERBB2', 'Gene', (124, 129))	('Erb-b2', 'Gene', (130, 136))	('differentiation', 'CPA', (580, 595))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('PSA', 'Gene', '354', (244, 247))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('Cyclin-dependent kinase 12', 'Gene', (417, 443))	('cell growth', 'CPA', (552, 563))	('ERBB2', 'Gene', '2064', (124, 129))	('CDK', 'molecular_function', 'GO:0004693', ('29', '32'))
26274	33038052	CDK12 mutation could predict sensitivity to targeted treatments against BRCA-mutant tumors, such as PARP1 inhibitors.	('PARP1', 'Gene', '142', (100, 105))	('PARP1', 'Gene', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CDK', 'molecular_function', 'GO:0004693', ('0', '3'))	('mutation', 'Var', (6, 14))	('CDK12', 'Gene', (0, 5))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('predict', 'Reg', (21, 28))
26276	33038052	5  However, CDK12 and ERBB2 coamplification in urological cancers remains unreported.	('ERBB2', 'Gene', '2064', (22, 27))	('CDK', 'molecular_function', 'GO:0004693', ('12', '15'))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ERBB2', 'Gene', (22, 27))	('CDK12', 'Gene', (12, 17))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('coamplification', 'Var', (28, 43))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))
26277	33038052	In this study, we report on two patients with urothelial carcinoma showing CDK12 and ERBB2 coamplification.	('patients', 'Species', '9606', (32, 40))	('urothelial carcinoma', 'Disease', (46, 66))	('CDK', 'molecular_function', 'GO:0004693', ('75', '78'))	('ERBB2', 'Gene', (85, 90))	('ERBB2', 'Gene', '2064', (85, 90))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (46, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('CDK12', 'Gene', (75, 80))	('coamplification', 'Var', (91, 106))
26288	33038052	Furthermore, we detected TP53 somatic point mutation (p.F113C) with LOH as an actionable variant in the tumor, and EP300 somatic point mutations (p.G672R and p.T2391M) as VUS.	('EP300', 'Gene', '2033', (115, 120))	('TP53', 'Gene', (25, 29))	('p.G672R', 'Var', (146, 153))	('p.F113C', 'Var', (54, 61))	('p.F113C', 'Mutation', 'p.F113C', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('p.G672R', 'Mutation', 'p.G672R', (146, 153))	('tumor', 'Disease', (104, 109))	('p.T2391M', 'Mutation', 'rs139279818', (158, 166))	('EP300', 'Gene', (115, 120))	('p.T2391M', 'Var', (158, 166))	('TP53', 'Gene', '7157', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
26302	33038052	Two VUS point mutations (p.S633F and p.A763D) were additionally detected in the ERBB2 gene.	('p.S633F', 'Var', (25, 32))	('p.A763D', 'Var', (37, 44))	('p.A763D', 'Mutation', 'p.A763D', (37, 44))	('ERBB2', 'Gene', '2064', (80, 85))	('p.S633F', 'Mutation', 'rs199726056', (25, 32))	('ERBB2', 'Gene', (80, 85))
26303	33038052	Furthermore, TP53 somatic frameshift mutation (p.Y236*), FANCD2 VUS mutation, and LOH without mutation in WT1, SMAD4, KDM6A, FANCA, PBRM1, BAP1, and SETD2 were detected in the sample.	('SMAD4', 'Gene', (111, 116))	('TP53', 'Gene', (13, 17))	('p.Y236*', 'Var', (47, 54))	('KDM6A', 'Gene', '7403', (118, 123))	('WT1', 'Gene', (106, 109))	('SMAD4', 'Gene', '4089', (111, 116))	('FANCD2', 'Gene', (57, 63))	('TP53', 'Gene', '7157', (13, 17))	('FANCA', 'Gene', '2175', (125, 130))	('WT1', 'Gene', '7490', (106, 109))	('p.Y236*', 'Mutation', 'p.Y236*', (47, 54))	('BAP1', 'Gene', '8314', (139, 143))	('FANCD2', 'Gene', '2177', (57, 63))	('KDM6A', 'Gene', (118, 123))	('SETD2', 'Gene', (149, 154))	('PBRM1', 'Gene', '55193', (132, 137))	('FANCA', 'Gene', (125, 130))	('PBRM1', 'Gene', (132, 137))	('BAP1', 'Gene', (139, 143))	('SETD2', 'Gene', '29072', (149, 154))
26309	33038052	Cyclin-dependent kinase alteration is reportedly associated with PARP inhibitors, 3 ,  4  which are effective in patients with DDR mutation-positive prostate cancer according to a well described synthetically lethal effect.	('Cyclin-dependent', 'Enzyme', (0, 16))	('DDR', 'Chemical', '-', (127, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (149, 164))	('DDR', 'Gene', (127, 130))	('patients', 'Species', '9606', (113, 121))	('prostate cancer', 'Phenotype', 'HP:0012125', (149, 164))	('PARP', 'Gene', '142', (65, 69))	('PARP', 'Gene', (65, 69))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('prostate cancer', 'Disease', (149, 164))	('alteration', 'Reg', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('mutation-positive', 'Var', (131, 148))
26310	33038052	6  However, CDK12-altered prostate cancer is an aggressive subtype that poorly responds to PARP inhibitors or to hormonal and taxane therapies.	('CDK', 'molecular_function', 'GO:0004693', ('12', '15'))	('PARP', 'Gene', (91, 95))	('prostate cancer', 'Disease', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CDK12-altered', 'Var', (12, 25))	('PARP', 'Gene', '142', (91, 95))	('taxane', 'Chemical', 'MESH:C080625', (126, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (26, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (26, 41))
26315	33038052	10 ,  11 ,  12  However, the effectiveness of anti-HER2 therapy for breast cancers with CDK12 and ERBB2 coamplification is still unconfirmed.	('ERBB2', 'Gene', '2064', (98, 103))	('breast cancers', 'Disease', 'MESH:D001943', (68, 82))	('ERBB2', 'Gene', (98, 103))	('breast cancers', 'Disease', (68, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('CDK', 'molecular_function', 'GO:0004693', ('88', '91'))	('CDK12', 'Gene', (88, 93))	('coamplification', 'Var', (104, 119))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('breast cancers', 'Phenotype', 'HP:0003002', (68, 82))
26316	33038052	13 ,  14  For these patients, anti-CDK12 therapy will be effective because it induces self-renewal of breast cancers and reduces susceptibility to anti-HER2 therapy.	('breast cancers', 'Disease', 'MESH:D001943', (102, 116))	('breast cancers', 'Disease', (102, 116))	('susceptibility to', 'MPA', (129, 146))	('induces', 'Reg', (78, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('CDK', 'molecular_function', 'GO:0004693', ('35', '38'))	('reduces', 'NegReg', (121, 128))	('self-renewal', 'CPA', (86, 98))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('anti-CDK12', 'Var', (30, 40))	('breast cancers', 'Phenotype', 'HP:0003002', (102, 116))
26323	33038052	Anti-HER2 therapy might not be effective for treating patients with CDK12 and ERBB2 coamplification, and therapy targeting CDK12 can be a therapeutic option for these patients.	('ERBB2', 'Gene', '2064', (78, 83))	('CDK', 'molecular_function', 'GO:0004693', ('123', '126'))	('ERBB2', 'Gene', (78, 83))	('patients', 'Species', '9606', (54, 62))	('CDK', 'molecular_function', 'GO:0004693', ('68', '71'))	('patients', 'Species', '9606', (167, 175))	('CDK12', 'Gene', (68, 73))	('coamplification', 'Var', (84, 99))
26324	33038052	To the best of our knowledge, CDK12 and ERBB2 coamplification in urothelial carcinoma has not been reported.	('CDK', 'molecular_function', 'GO:0004693', ('30', '33'))	('ERBB2', 'Gene', '2064', (40, 45))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (65, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('ERBB2', 'Gene', (40, 45))	('CDK12', 'Gene', (30, 35))	('coamplification', 'Var', (46, 61))	('urothelial carcinoma', 'Disease', (65, 85))
26325	33038052	Our results suggest that CDK12 coamplification with ERBB2 could be associated with tumor aggressiveness and could contribute to cancer pathogenesis.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Disease', (128, 134))	('CDK12', 'Protein', (25, 30))	('pathogenesis', 'biological_process', 'GO:0009405', ('135', '147'))	('tumor aggressiveness', 'Disease', (83, 103))	('aggressiveness', 'Phenotype', 'HP:0000718', (89, 103))	('coamplification', 'Var', (31, 46))	('ERBB2', 'Gene', '2064', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('associated', 'Reg', (67, 77))	('CDK', 'molecular_function', 'GO:0004693', ('25', '28'))	('ERBB2', 'Gene', (52, 57))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (83, 103))	('contribute', 'Reg', (114, 124))
26350	31058186	In recent reports, relatively high prevalence of UTUC with aristolochic acid (AA) mutational signatures was found in Taiwan.	('aristolochic acid', 'Chemical', 'MESH:C000228', (59, 76))	('mutational signatures', 'Var', (82, 103))	('aristolochic', 'Disease', (59, 71))
26351	31058186	Aristolochic acid-related UTUC is associated with a specific oncologic pattern, namely, aristolochic acid nephropathy, which is a toxic interstitial nephropathy caused by ingestion of plants containing aristolochic acids (AA) as part of traditional phytotherapies (formerly known as Chinese herb nephropathy).	('nephropathy', 'Disease', 'MESH:D007674', (149, 160))	('Aristolochic acid', 'Chemical', 'MESH:C000228', (0, 17))	('nephropathy', 'Phenotype', 'HP:0000112', (106, 117))	('nephropathy', 'Disease', (106, 117))	('nephropathy', 'Disease', 'MESH:D007674', (296, 307))	('aristolochic acid', 'Chemical', 'MESH:C000228', (202, 219))	('nephropathy', 'Phenotype', 'HP:0000112', (296, 307))	('nephropathy', 'Disease', (296, 307))	('nephropathy', 'Disease', (149, 160))	('acid nephropathy', 'Phenotype', 'HP:0001947', (101, 117))	('nephropathy', 'Phenotype', 'HP:0000112', (149, 160))	('nephropathy', 'Disease', 'MESH:D007674', (106, 117))	('interstitial nephropathy', 'Phenotype', 'HP:0001970', (136, 160))	('aristolochic', 'Var', (202, 214))	('aristolochic acids', 'Chemical', 'MESH:D034341', (202, 220))	('interstitial nephropathy', 'Disease', (136, 160))	('interstitial nephropathy', 'Disease', 'MESH:D007674', (136, 160))	('aristolochic acid', 'Chemical', 'MESH:C000228', (88, 105))
26437	30212968	As we known, renal insufficiency could not only contribute to the poor outcomes of urothelial carcinoma but also related to causing anemia due to erythropoietin deficiency, uremic-induced inhibitors of erythropoiesis, shortened erythrocyte survival, and iron deficiency.	('uremic', 'Disease', 'MESH:D006463', (173, 179))	('uremic', 'Disease', (173, 179))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (83, 103))	('erythropoietin deficiency', 'Phenotype', 'HP:0010972', (146, 171))	('anemia', 'Disease', 'MESH:D000740', (132, 138))	('shortened', 'NegReg', (218, 227))	('erythropoietin', 'Gene', (146, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('erythropoietin', 'molecular_function', 'GO:0005128', ('146', '160'))	('shortened erythrocyte survival', 'Phenotype', 'HP:0025066', (218, 248))	('renal insufficiency', 'Disease', (13, 32))	('erythrocyte survival', 'CPA', (228, 248))	('erythropoietin', 'Gene', '2056', (146, 160))	('anemia', 'Phenotype', 'HP:0001903', (132, 138))	('urothelial carcinoma', 'Disease', (83, 103))	('iron deficiency', 'Disease', 'MESH:C562385', (254, 269))	('anemia', 'Disease', (132, 138))	('iron deficiency', 'Disease', (254, 269))	('deficiency', 'Var', (161, 171))	('renal insufficiency', 'Disease', 'MESH:D051437', (13, 32))	('erythropoiesis', 'biological_process', 'GO:0030218', ('202', '216'))	('renal insufficiency', 'Phenotype', 'HP:0000083', (13, 32))
26471	28753846	Little is known, however, about how the level of genetic alteration across an entire cancer genome affects tumor grade or stage or survival.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('affects', 'Reg', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('genetic alteration', 'Var', (49, 67))	('stage', 'CPA', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('survival', 'CPA', (131, 139))
26481	28753846	Cancers with higher levels of genomic alterations are associated with worse pathologic features and survival.	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('genomic alterations', 'Var', (30, 49))
26485	28753846	Much less is known about how the level of genetic alteration across an entire cancer genome affects the natural history of an individual malignancy.	('malignancy', 'Disease', (137, 147))	('affects', 'Reg', (92, 99))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('genetic alteration', 'Var', (42, 60))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('malignancy', 'Disease', 'MESH:D009369', (137, 147))
26487	28753846	While some studies have shown clustering of mutations that are associated with grade and stage, the effect that genomic alterations have on tumor grade and stage on histopathologic analysis has not been fully elucidated.	('associated', 'Reg', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
26488	28753846	With the publication of whole cancer genomes as part of The Cancer Genome Atlas (TCGA) and International Cancer Genome consortium, the association of whole-genome alterations such as mutation count (MC) and copy number variation (CNV) can now be correlated with clinicopathologic characteristics, survival outcomes, and therapeutic response.	('Cancer', 'Disease', (105, 111))	('Cancer Genome Atlas', 'Disease', (60, 79))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('Cancer', 'Disease', 'MESH:D009369', (105, 111))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (60, 79))	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (30, 36))	('correlated', 'Reg', (246, 256))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('MC', 'Chemical', '-', (199, 201))	('copy number variation', 'Var', (207, 228))	('mutation count', 'Disease', (183, 197))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
26498	28753846	For tumors types with substaging (eg, T2a and T2b in BLCA), substages were combined for analysis.	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('T2b', 'Var', (46, 49))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
26519	28753846	There was no association with Fuhrman grade and MC for a four-tier (p = 0.27) or a two-tier system; however, CNV was associated with higher Fuhrman grade in both four-tier (p = 0.0006) and two-tier (p = 0.0001) systems.	('Fuhrman grade', 'CPA', (140, 153))	('CNV', 'Var', (109, 112))	('MC', 'Chemical', '-', (48, 50))	('higher', 'PosReg', (133, 139))
26527	28753846	PRAD had the third lowest MC and the lowest CNV.	('lowest', 'NegReg', (37, 43))	('lowest', 'NegReg', (19, 25))	('MC', 'Chemical', '-', (26, 28))	('CNV', 'MPA', (44, 47))	('PRAD', 'Var', (0, 4))
26540	28753846	Genetic instability has largely been studied in terms of microsatellite instability and chromosomal instability, and has been linked to adverse pathology and survival in colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (170, 182))	('colon cancer', 'Disease', 'MESH:D015179', (170, 182))	('colon cancer', 'Disease', (170, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('microsatellite', 'Var', (57, 71))	('linked', 'Reg', (126, 132))	('chromosomal instability', 'Phenotype', 'HP:0040012', (88, 111))
26541	28753846	One theory, described by Kinzler and Vogelstein, is that mutations in "caretaker" genes that maintain the integrity of the genome is an early event in cancer development that accelerates the accumulation of additional mutations that eventually lead to neoplasia.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutations', 'Var', (218, 227))	('accelerates', 'PosReg', (175, 186))	('neoplasia', 'Phenotype', 'HP:0002664', (252, 261))	('neoplasia', 'Disease', (252, 261))	('mutations', 'Var', (57, 66))	('lead to', 'Reg', (244, 251))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('neoplasia', 'Disease', 'MESH:D009369', (252, 261))
26542	28753846	Our data support the role of genetic instability in the progression to higher grade and/or higher stage cancer for some genitourinary malignancies.	('cancer for some genitourinary malignancies', 'Phenotype', 'HP:0007379', (104, 146))	('genetic instability', 'Var', (29, 48))	('higher grade', 'Disease', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('genitourinary malignancies', 'Disease', 'MESH:D014564', (120, 146))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('genitourinary malignancies', 'Disease', (120, 146))
26543	28753846	High MC has previously been associated with greater response to checkpoint inhibitors in melanoma, non-small cell lung cancer, and renal cell carcinoma.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (99, 125))	('renal cell carcinoma', 'Disease', (131, 151))	('MC', 'Chemical', '-', (5, 7))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (99, 125))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (131, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('non-small cell lung cancer', 'Disease', (99, 125))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (131, 151))	('High MC', 'Var', (0, 7))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (103, 125))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('response', 'MPA', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
26587	28680882	More the mutation board, more likely this kind of antigens is expressed in tumor microenvironment.	('mutation', 'Var', (9, 17))	('tumor', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))
26600	28680882	ORR was 28% (95% CI; 14-47) in patients with high PD-L1 expression and 21% (95% CI; 9-36) in patients PD-L1 negative.	('PD-L1', 'Gene', (50, 55))	('PD-L1', 'Gene', (102, 107))	('high', 'Var', (45, 49))	('patients', 'Species', '9606', (31, 39))	('PD-L1', 'Gene', '29126', (50, 55))	('PD-L1', 'Gene', '29126', (102, 107))	('patients', 'Species', '9606', (93, 101))
26603	28680882	In both cohorts, responses were more frequent in the Luminal II subtype and in patients with higher mutation load, irrespective of PD-L1 expression.	('responses', 'MPA', (17, 26))	('PD-L1', 'Gene', '29126', (131, 136))	('mutation load', 'Var', (100, 113))	('more frequent', 'PosReg', (32, 45))	('patients', 'Species', '9606', (79, 87))	('Luminal II', 'Disease', (53, 63))	('PD-L1', 'Gene', (131, 136))
26626	28680882	Based on a >=5% PD-L1 expression cutoff assessed prospectively on tumor cells, ORR was significantly higher in PD-L1 positive patients (25.0%; 95% CI, 14.4-38.4) compared with PD-L1 negative subgroup (14.7%; 95% CI, 7.6-24.7; p = 0.178).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('higher', 'PosReg', (101, 107))	('PD-L1', 'Gene', '29126', (111, 116))	('tumor', 'Disease', (66, 71))	('PD-L1', 'Gene', (16, 21))	('PD-L1', 'Gene', '29126', (176, 181))	('positive', 'Var', (117, 125))	('PD-L1', 'Gene', '29126', (16, 21))	('patients', 'Species', '9606', (126, 134))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('PD-L1', 'Gene', (111, 116))	('expression', 'MPA', (22, 32))	('PD-L1', 'Gene', (176, 181))
26636	28680882	Confirmed ORR was 19.6% (95% CI, 15.0-24.9) for all patients, 28.4% for patients with PD-L1 expression of 5% or greater, 23.8% for patients with PD-L1 expression of 1% or greater, and 16.1% for patients with PD-L1 expression of less than 1%.	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (194, 202))	('expression', 'Var', (92, 102))	('PD-L1', 'Gene', (208, 213))	('PD-L1', 'Gene', '29126', (86, 91))	('PD-L1', 'Gene', '29126', (145, 150))	('PD-L1', 'Gene', '29126', (208, 213))	('PD-L1', 'Gene', (86, 91))	('PD-L1', 'Gene', (145, 150))	('patients', 'Species', '9606', (52, 60))	('patients', 'Species', '9606', (72, 80))
26654	28680882	The only data available have been presented at ESMO 2016 Congress: ORR was 36.7% (95% CI, 19.9-56.1) in patients with 10% or greater PD-L1 expression (Table 1).	('PD-L1', 'Gene', (133, 138))	('PD-L1', 'Gene', '29126', (133, 138))	('patients', 'Species', '9606', (104, 112))	('expression', 'Var', (139, 149))
26665	28680882	Immunotherapy includes treatments that work in different ways, not only limited to anti-PD-1, anti-PD-L1, or anti-CTL A4 antibodies.	('PD-1', 'Gene', '5133', (88, 92))	('PD-L1', 'Gene', (99, 104))	('anti-CTL', 'Var', (109, 117))	('PD-L1', 'Gene', '29126', (99, 104))	('PD-1', 'Gene', (88, 92))
26691	28680882	Human epidermal growth factor receptor 2 (HER2), also known as CD340, is a member of a big receptor family, encoded by a protooncogene whose alterations (almost amplification and overexpression) are common not only in breast and gastric, but also in urothelial cancer.	('HER2', 'Gene', '2064', (42, 46))	('Human epidermal growth factor receptor 2', 'Gene', (0, 40))	('CD340', 'Gene', '2064', (63, 68))	('alterations', 'Var', (141, 152))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('6', '29'))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('urothelial cancer', 'Disease', 'MESH:D014523', (250, 267))	('overexpression', 'PosReg', (179, 193))	('Human epidermal growth factor receptor 2', 'Gene', '2064', (0, 40))	('CD340', 'Gene', (63, 68))	('breast', 'Disease', (218, 224))	('HER2', 'Gene', (42, 46))	('gastric', 'Disease', (229, 236))	('common', 'Reg', (199, 205))	('urothelial cancer', 'Disease', (250, 267))
26695	28680882	Other clinical trials are still ongoing in these patients, testing other HER2 inhibitors, like trastuzumab emtansine (NCT02999672) and Lapatinib (NCT00949455, NCT02342587).	('HER2', 'Gene', '2064', (73, 77))	('NCT02342587', 'Var', (159, 170))	('trastuzumab emtansine', 'Chemical', 'MESH:C550911', (95, 116))	('NCT02999672', 'Var', (118, 129))	('NCT00949455', 'Var', (146, 157))	('Lapatinib', 'Chemical', 'MESH:D000077341', (135, 144))	('patients', 'Species', '9606', (49, 57))	('HER2', 'Gene', (73, 77))
26717	28680882	Two phase I trials (NCT02457650 and NCT02869217) are currently recruiting participants with NY-ESO-1-expressing malignancies to evaluate the safety and feasibility of the administration of anti-NY-ESO-1 TCR engineered autologous T-cells.	('TCR', 'Gene', (203, 206))	('participants', 'Species', '9606', (74, 86))	('malignancies', 'Disease', (112, 124))	('NCT02869217', 'Var', (36, 47))	('NCT02457650', 'Var', (20, 31))	('TCR', 'Gene', '6962', (203, 206))	('NY-ESO-1', 'Gene', '246100', (194, 202))	('TCR', 'cellular_component', 'GO:0042101', ('203', '206'))	('NY-ESO-1', 'Gene', '246100', (92, 100))	('NY-ESO-1', 'Gene', (194, 202))	('NY-ESO-1', 'Gene', (92, 100))	('TCR', 'biological_process', 'GO:0006283', ('203', '206'))	('malignancies', 'Disease', 'MESH:D009369', (112, 124))
26870	21816094	The present meta-analysis showed that CTC+ bladder/urothelial cancer patients are significantly more likely to have extra-organ and/or metastatic disease; this key finding was consistently observed throughout subsequent subgroup analyses.	('extra-organ and/or metastatic disease', 'CPA', (116, 153))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('bladder/urothelial cancer', 'Disease', (43, 68))	('CTC+', 'Var', (38, 42))	('patients', 'Species', '9606', (69, 77))	('bladder/urothelial cancer', 'Disease', 'MESH:D001749', (43, 68))
26901	20646741	Treatment with bevacizumab may have a direct anti-angiogenic effect, but other data suggest that bevacizumab leads to "normalization" of disorganized tumor blood vessels, leading to better chemotherapy delivery.	('bevacizumab', 'Chemical', 'MESH:D000068258', (97, 108))	('better', 'PosReg', (182, 188))	('bevacizumab', 'Chemical', 'MESH:D000068258', (15, 26))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('bevacizumab', 'Var', (97, 108))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('chemotherapy delivery', 'MPA', (189, 210))
26966	26629935	Suppression of Cellular Proliferation and Invasion by HMGB1 Knockdown in Bladder Urothelial Carcinoma Cells HMGB1, which acts as a DNA chaperone to help maintain nuclear homeostasis, was reported to play a prominent role in cancer progression, angiogenesis, invasion, and metastasis development.	('invasion', 'CPA', (258, 266))	('Suppression', 'NegReg', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))	('cancer', 'Disease', (224, 230))	('Carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('HMGB1', 'Gene', (54, 59))	('HMGB1', 'Gene', '3146', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('angiogenesis', 'biological_process', 'GO:0001525', ('244', '256'))	('HMGB1', 'Gene', (108, 113))	('Invasion', 'CPA', (42, 50))	('HMGB1', 'Gene', '3146', (108, 113))	('Knockdown', 'Var', (60, 69))	('Cellular Proliferation', 'CPA', (15, 37))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('angiogenesis', 'CPA', (244, 256))	('Urothelial Carcinoma', 'Disease', 'MESH:D014523', (81, 101))	('Urothelial Carcinoma', 'Disease', (81, 101))	('homeostasis', 'biological_process', 'GO:0042592', ('170', '181'))	('metastasis development', 'CPA', (272, 294))
26970	26629935	In order to investigate the role of HMGB1 in BUC cells, RNA interference and Talen-mediated gene knockout (KO) were used to knockdown and knockout HMGB1, respectively, in BUC cell lines BIU-87 and T24.	('knockdown', 'Var', (124, 133))	('RNA interference', 'biological_process', 'GO:0016246', ('56', '72'))	('HMGB1', 'Gene', (147, 152))	('BIU', 'Chemical', '-', (186, 189))	('knockout', 'Var', (138, 146))	('RNA', 'cellular_component', 'GO:0005562', ('56', '59'))
26971	26629935	The decrease in cell viability caused by HMGB1 knockdown/out was due to an increase in apoptosis via Bax/Bcl-2, both of which were important molecules involved in the apoptotic pathway.	('Bax', 'Gene', (101, 104))	('decrease', 'NegReg', (4, 12))	('knockdown/out', 'Var', (47, 60))	('Bcl-2', 'Gene', (105, 110))	('HMGB1', 'Gene', (41, 46))	('apoptosis', 'CPA', (87, 96))	('Bcl-2', 'Gene', '596', (105, 110))	('Bax', 'Gene', '581', (101, 104))	('cell viability', 'CPA', (16, 30))	('increase', 'PosReg', (75, 83))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('105', '110'))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))
26972	26629935	We then investigated the effect of HMGB1 knockdown/out on the sensitivity of BUC cells treated with the anticancer drug cisplatin.	('investigated', 'Reg', (8, 20))	('HMGB1', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('knockdown/out', 'Var', (41, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
26973	26629935	Knockdown or knockout of HMGB1 rendered BUC cells more sensitive to cisplatin.	('sensitive to cisplatin', 'MPA', (55, 77))	('knockout', 'Var', (13, 21))	('HMGB1', 'Gene', (25, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('more', 'PosReg', (50, 54))
26979	26629935	Many factors, such as chromosomal anomalies, genetic polymorphisms, genetic and epigenetic alterations, contribute to tumorigenesis and progression of urothelial carcinoma of the bladder.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('progression', 'CPA', (136, 147))	('epigenetic alterations', 'Var', (80, 102))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (151, 186))	('urothelial carcinoma of the bladder', 'Disease', (151, 186))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (151, 186))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('chromosomal anomalies', 'Disease', 'MESH:D002869', (22, 43))	('tumor', 'Disease', (118, 123))	('chromosomal anomalies', 'Disease', (22, 43))	('contribute', 'Reg', (104, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
26991	26629935	We also investigated the effect of HMGB1 knockdown/out on the sensitivity of BUC cells treated with the anticancer drug cisplatin, and its probable mechanism was also discussed.	('investigated', 'Reg', (8, 20))	('HMGB1', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('knockdown/out', 'Var', (41, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
27029	26629935	The effect of HMGB1 knockdown/out on proliferation of BUC cells was tested by MTT assay.	('knockdown/out', 'Var', (20, 33))	('HMGB1', 'Gene', (14, 19))	('MTT', 'Chemical', 'MESH:C070243', (78, 81))
27030	26629935	To determine whether the decrease in cell viability caused by HMGB1 knockdown/out was due to an increase in apoptosis, we determined the number of early apoptotic cells in BUC cell lines with annexin V-FITC and PI labeling followed by fluorescence-activated cell sorting (FACS).	('annexin V', 'Gene', (192, 201))	('decrease', 'NegReg', (25, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('HMGB1', 'Gene', (62, 67))	('FITC', 'Chemical', 'MESH:D016650', (202, 206))	('knockdown/out', 'Var', (68, 81))	('cell viability', 'CPA', (37, 51))	('annexin V', 'Gene', '308', (192, 201))
27031	26629935	The data showed that after siRNA transfection for 48 h, the number of apoptotic cells was increased significantly in both BIU-87 and T24 cells compared with control groups (Fig.	('increased', 'PosReg', (90, 99))	('transfection', 'Var', (33, 45))	('BIU', 'Chemical', '-', (122, 125))
27034	26629935	We then analyzed the effects of HMGB1 knockdown/out cell cycle of T24 BUC cell line by using flow cytometry.	('cell cycle', 'biological_process', 'GO:0007049', ('52', '62'))	('knockdown/out', 'Var', (38, 51))	('T24 BUC', 'CellLine', 'CVCL:G691', (66, 73))	('HMGB1', 'Gene', (32, 37))
27035	26629935	As HMGB1 knockdown/out induced cell cycle arrest, we investigated the expression of G1/S phase-related molecules, particularly PCNA and cyclin D1 by using Western blotting, both of which were significantly lower in HMGB1 knockdown/out BUC cells, compared to controls (Fig.	('HMGB1', 'Gene', (215, 220))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (31, 48))	('PCNA', 'molecular_function', 'GO:0003892', ('127', '131'))	('knockdown/out', 'Var', (9, 22))	('knockdown/out', 'Var', (221, 234))	('arrest', 'Disease', (42, 48))	('PCNA', 'Gene', (127, 131))	('cyclin', 'molecular_function', 'GO:0016538', ('136', '142'))	('induced', 'Reg', (23, 30))	('S phase', 'biological_process', 'GO:0051320', ('87', '94'))	('HMGB1', 'Gene', (3, 8))	('lower', 'NegReg', (206, 211))	('cyclin D1', 'Gene', '595', (136, 145))	('PCNA', 'Gene', '5111', (127, 131))	('cyclin D1', 'Gene', (136, 145))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('31', '48'))	('arrest', 'Disease', 'MESH:D006323', (42, 48))
27038	26629935	Whether knockdown/out of HMGB1 might affect cisplatin sensitivity in BUC cells aroused our great interest.	('cisplatin sensitivity', 'MPA', (44, 65))	('knockdown/out', 'Var', (8, 21))	('HMGB1', 'Gene', (25, 30))	('affect', 'Reg', (37, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))
27041	26629935	CCK assay demonstrated that knockdown or KO of HMGB1 in BUC cells rendered them significantly more sensitive to cisplatin (Fig.	('HMGB1', 'Gene', (47, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('CCK', 'Gene', (0, 3))	('knockdown', 'Var', (28, 37))	('CCK', 'Gene', '885', (0, 3))	('sensitive to cisplatin', 'MPA', (99, 121))	('more', 'PosReg', (94, 98))
27046	26629935	The expression of LC3-II in HMGB1 knockdown/out BUC cells after treatment with cisplatin was also elevated; however, the increased levels were much slighter (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('LC3', 'Gene', '84557', (18, 21))	('expression', 'MPA', (4, 14))	('LC3', 'Gene', (18, 21))	('HMGB1', 'Gene', (28, 33))	('elevated', 'PosReg', (98, 106))	('knockdown/out', 'Var', (34, 47))
27054	26629935	We evaluated Bcl-2 and Bax after HMGB1 knockdown/out and found that Bax increased sharply and Bcl-2 acted in the opposite way when compared with those of controls.	('increased', 'PosReg', (72, 81))	('knockdown/out', 'Var', (39, 52))	('Bcl-2', 'Gene', (94, 99))	('Bcl-2', 'molecular_function', 'GO:0015283', ('13', '18'))	('Bcl-2', 'Gene', '596', (94, 99))	('Bax', 'Gene', (23, 26))	('Bax', 'Gene', (68, 71))	('Bcl-2', 'molecular_function', 'GO:0015283', ('94', '99'))	('HMGB1', 'Gene', (33, 38))	('Bax', 'Gene', '581', (23, 26))	('Bax', 'Gene', '581', (68, 71))	('Bcl-2', 'Gene', (13, 18))	('Bcl-2', 'Gene', '596', (13, 18))
27055	26629935	These findings suggest that the Bcl-2 and Bax are involved in apoptosis in HMGB1 knockdown/out BUC cells.	('HMGB1', 'Gene', (75, 80))	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('32', '37'))	('Bax', 'Gene', '581', (42, 45))	('Bcl-2', 'Gene', (32, 37))	('knockdown/out', 'Var', (81, 94))	('Bcl-2', 'Gene', '596', (32, 37))	('Bax', 'Gene', (42, 45))	('involved', 'Reg', (50, 58))
27060	26629935	We found that the expressions of cyclin D1 and PCNA were significantly increased in the BUC cells, which, however, could be significantly inhibited by HMGB1 knockdown/out.	('PCNA', 'Gene', (47, 51))	('cyclin D1', 'Gene', '595', (33, 42))	('cyclin D1', 'Gene', (33, 42))	('PCNA', 'Gene', '5111', (47, 51))	('HMGB1', 'Gene', (151, 156))	('cyclin', 'molecular_function', 'GO:0016538', ('33', '39'))	('PCNA', 'molecular_function', 'GO:0003892', ('47', '51'))	('knockdown/out', 'Var', (157, 170))	('expressions', 'MPA', (18, 29))	('inhibited', 'NegReg', (138, 147))	('increased', 'PosReg', (71, 80))
27061	26629935	Moreover, our experimental data demonstrated that HMGB1 knockdown/out significantly enhanced chemotherapy sensitivity, suggesting that HMGB1 might be considered as a potential therapeutic target for bladder cancer.	('HMGB1', 'Gene', (50, 55))	('bladder cancer', 'Phenotype', 'HP:0009725', (199, 213))	('chemotherapy sensitivity', 'CPA', (93, 117))	('bladder cancer', 'Disease', 'MESH:D001749', (199, 213))	('bladder cancer', 'Disease', (199, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('enhanced', 'PosReg', (84, 92))	('knockdown/out', 'Var', (56, 69))
27062	26629935	Our results were in line with previous prospective studies that knockdown of HMGB1 by RNA interference increased the sensitivity of leukemia cells to chemotherapeutic agents.	('RNA interference', 'biological_process', 'GO:0016246', ('86', '102'))	('increased', 'PosReg', (103, 112))	('sensitivity', 'MPA', (117, 128))	('RNA', 'cellular_component', 'GO:0005562', ('86', '89'))	('leukemia', 'Disease', 'MESH:D007938', (132, 140))	('leukemia', 'Disease', (132, 140))	('knockdown', 'Var', (64, 73))	('RNA interference', 'MPA', (86, 102))	('leukemia', 'Phenotype', 'HP:0001909', (132, 140))	('HMGB1', 'Gene', (77, 82))
27071	26629935	Here we found that knockdown or KO of HMGB1 decreased the expression levels of LC3-II and Beclin 1, which reflects the decreased levels of autophagy.	('expression levels', 'MPA', (58, 75))	('decreased', 'NegReg', (119, 128))	('Beclin 1', 'Gene', (90, 98))	('knockdown', 'Var', (19, 28))	('HMGB1', 'Gene', (38, 43))	('LC3', 'Gene', (79, 82))	('LC3', 'Gene', '84557', (79, 82))	('autophagy', 'biological_process', 'GO:0016236', ('139', '148'))	('levels', 'MPA', (129, 135))	('autophagy', 'biological_process', 'GO:0006914', ('139', '148'))	('decreased', 'NegReg', (44, 53))
27072	26629935	In addition, knockdown/out of HMGB1 rendered BUC cells more sensitive to the anticancer drug cisplatin.	('HMGB1', 'Gene', (30, 35))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('cancer', 'Disease', (81, 87))	('knockdown/out', 'Var', (13, 26))	('more', 'PosReg', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
27076	32376723	To explore the contextual prognostic value of cancer immune phenotypes, we applied a multimodal pan-cancer analysis among 31 different histologies (9282 patients), encompassing immune and oncogenic transcriptomic analysis, mutational and neoantigen load and copy number variations.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('patients', 'Species', '9606', (153, 161))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (100, 106))	('copy number variations', 'Var', (258, 280))
27078	32376723	WNT-beta catenin, barrier molecules, Notch, hedgehog, mismatch repair, telomerase activity and AMPK signaling were the pathways most coherently associated with an immune silent phenotype together with mutations of driver genes including IDH1/2, FOXA2, HDAC3, PSIP1, MAP3K1, KRAS, NRAS, EGFR, FGFR3, WNT5A and IRF7.	('NRAS', 'Gene', (280, 284))	('associated', 'Reg', (144, 154))	('EGFR', 'Gene', '1956', (286, 290))	('IDH1/2', 'Gene', '3417;3418', (237, 243))	('telomerase activity', 'molecular_function', 'GO:0003720', ('71', '90'))	('AMPK', 'molecular_function', 'GO:0050405', ('95', '99'))	('FOXA2', 'Gene', '3170', (245, 250))	('beta catenin', 'Gene', '1499', (4, 16))	('FGFR3', 'Gene', (292, 297))	('KRAS', 'Gene', (274, 278))	('beta catenin', 'Gene', (4, 16))	('IDH1/2', 'Gene', (237, 243))	('mismatch repair', 'biological_process', 'GO:0006298', ('54', '69'))	('HDAC3', 'Gene', (252, 257))	('FGFR3', 'Gene', '2261', (292, 297))	('EGFR', 'molecular_function', 'GO:0005006', ('286', '290'))	('MAP3K', 'molecular_function', 'GO:0004709', ('266', '271'))	('AMPK', 'molecular_function', 'GO:0004691', ('95', '99'))	('WNT5A', 'Gene', (299, 304))	('NRAS', 'Gene', '4893', (280, 284))	('EGFR', 'Gene', (286, 290))	('FGFR', 'molecular_function', 'GO:0005007', ('292', '296'))	('HDAC3', 'Gene', '8841', (252, 257))	('AMPK', 'molecular_function', 'GO:0047322', ('95', '99'))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('MAP3K1', 'Gene', (266, 272))	('IRF7', 'Gene', '3665', (309, 313))	('mutations', 'Var', (201, 210))	('MAP3K1', 'Gene', '4214', (266, 272))	('AMPK', 'Gene', '5564', (95, 99))	('FOXA2', 'Gene', (245, 250))	('WNT5A', 'Gene', '7474', (299, 304))	('PSIP1', 'Gene', (259, 264))	('AMPK', 'Gene', (95, 99))	('KRAS', 'Gene', '3845', (274, 278))	('IRF7', 'Gene', (309, 313))	('PSIP1', 'Gene', '11168', (259, 264))
27087	32376723	In breast cancer, a positive association between survival and density of tumor infiltrating lymphocytes, as estimated by transcriptomic data, was restricted to tumors displaying a high mutational load or an aggressive/high proliferative phenotype.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('high mutational load', 'Var', (180, 200))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('breast cancer', 'Disease', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('tumor', 'Disease', (160, 165))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
27093	32376723	In particular, we reported that transcriptional dysregulation of the MAPK pathways sustained by genetic alterations (ie, MAP3K1 and MAP2K4 mutations) are enriched in immune silent tumors.	('genetic alterations', 'Var', (96, 115))	('alterations', 'Var', (104, 115))	('MAP2K4', 'Gene', '6416', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('mutations', 'Var', (139, 148))	('silent tumors', 'Disease', 'MESH:C566065', (173, 186))	('MAP3K', 'molecular_function', 'GO:0004709', ('121', '126'))	('MAPK pathways', 'Pathway', (69, 82))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('MAP2K', 'molecular_function', 'GO:0004708', ('132', '137'))	('MAP2K4', 'Gene', (132, 138))	('MAP3K1', 'Gene', (121, 127))	('MAPK', 'molecular_function', 'GO:0004707', ('69', '73'))	('silent tumors', 'Disease', (173, 186))	('transcriptional dysregulation', 'MPA', (32, 61))	('MAP3K1', 'Gene', '4214', (121, 127))
27105	32376723	Raw fastq files of datasets GSE78220 and GSE78220 were downloaded from National Center for Biotechnology Information (NCBI) storage replication adapter (SRA) servers, quality control and adapter trimming was performed using Trim_Galore (https://github.com/FelixKrueger/TrimGalore).	('GSE78220', 'Var', (41, 49))	('FelixKrueger', 'Disease', 'None', (256, 268))	('GSE78220', 'Var', (28, 36))	('storage', 'biological_process', 'GO:0051235', ('124', '131'))	('FelixKrueger', 'Disease', (256, 268))
27121	32376723	Factors added in the multivariate analyzes (overall and stratified according to the ICR-enabling categories) include representative oncogenic pathways (proliferation and transforming growth factor beta (TGF-ss) signaling), mutation rate, aneuploidy, stage or histological grade.	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('170', '201'))	('transforming growth factor beta', 'Gene', '7124', (170, 201))	('transforming growth factor beta', 'Gene', (170, 201))	('aneuploidy', 'Disease', (238, 248))	('signaling', 'biological_process', 'GO:0023052', ('211', '220'))	('mutation', 'Var', (223, 231))	('oncogenic pathways', 'Pathway', (132, 150))	('aneuploidy', 'Disease', 'MESH:D000782', (238, 248))
27126	32376723	Finally, several pathways were added that have previously been hypothesized to associate with cancer immune phenotypes, including Hypoxia/Adenosine Immune Cell Suppression, immunogenic cell death, NOS1 Signature, PI3Kgamma signature and SHC1/pSTAT3 signatures as described by Lu et al, barrier genes as described by Salerno et al, the proliferation metagene as described by Miller et al  and genes upregulated in MAPK mutated breast cancer.	('SHC1', 'Gene', '6464', (237, 241))	('cancer', 'Disease', 'MESH:D009369', (433, 439))	('mutated', 'Var', (418, 425))	('death', 'Disease', (190, 195))	('PI3Kgamma', 'Gene', (213, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (426, 439))	('MAPK', 'Gene', (413, 417))	('MAPK', 'molecular_function', 'GO:0004707', ('413', '417'))	('STAT3', 'Gene', '20848', (243, 248))	('cancer', 'Disease', (94, 100))	('NOS1', 'Gene', '4842', (197, 201))	('Hypoxia', 'Disease', (130, 137))	('Adenosine', 'Chemical', 'MESH:D000241', (138, 147))	('breast cancer', 'Disease', 'MESH:D001943', (426, 439))	('upregulated', 'PosReg', (398, 409))	('breast cancer', 'Disease', (426, 439))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('NOS1', 'Gene', (197, 201))	('cancer', 'Disease', (433, 439))	('cell death', 'biological_process', 'GO:0008219', ('185', '195'))	('STAT3', 'Gene', (243, 248))	('death', 'Disease', 'MESH:D003643', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (433, 439))	('SHC1', 'Gene', (237, 241))	('PI3Kgamma', 'Gene', '5294', (213, 222))	('Hypoxia', 'Disease', 'MESH:D000860', (130, 137))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
27129	32376723	An elastic net regularized model was built to predict the ICR score as function of mutations in each sample and using the tumor-type as a covariate.	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))
27131	32376723	A ratio >1 implies that the ICR score is higher in the mutated group compared with WT, while a ratio <1 implies that the ICR score is higher in subset of tumors without mutation.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('mutated', 'Var', (55, 62))	('ICR score', 'MPA', (28, 37))	('higher', 'PosReg', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))
27133	32376723	For PTEN deletion, CNV-low versus CNV-high categories were also defined using a Log R ratio cut-off of -0.4, previously optimized in melanoma.	('PTEN', 'Gene', '5728', (4, 8))	('deletion', 'Var', (9, 17))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('PTEN', 'Gene', (4, 8))
27214	32376723	To define the association of specific oncogenic mutations with ICR immune phenotypes, we first selected a set of 470 frequently mutated genes in cancer, then trained an elastic net model to predict the ICR score as function of mutations in each sample and using the tumor type as covariate.	('cancer', 'Disease', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Disease', (266, 271))	('mutations', 'Var', (227, 236))
27215	32376723	The use of tumor type as covariate tends to limit the effect of the enrichment of mutations in specific cancer types and their correlation with ICR score.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (11, 16))	('mutations', 'Var', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
27218	32376723	Interestingly MAP3K1 mutations, whose effect on ICR low has been described in breast cancer, were also associated to ICR low tumors pan-cancer.	('low tumors pan-cancer', 'Disease', (121, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('low tumors pan-cancer', 'Disease', 'MESH:D009369', (121, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('associated', 'Reg', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('MAP3K1', 'Gene', '4214', (14, 20))	('MAP3K', 'molecular_function', 'GO:0004709', ('14', '19'))	('MAP3K1', 'Gene', (14, 20))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))	('mutations', 'Var', (21, 30))
27219	32376723	The top genes of which mutations positively correlate with ICR reflect immune-evasion mechanisms that follow immunological pressure such as mutations of antigen-presenting machinery transcripts previously described (ie, B2M, HLA-A, HLA-B and CASP8).	('immune-evasion', 'biological_process', 'GO:0051842', ('71', '85'))	('ICR', 'Disease', (59, 62))	('B2M', 'Gene', (220, 223))	('B2M', 'Gene', '567', (220, 223))	('HLA-B', 'Gene', (232, 237))	('immune-evasion', 'biological_process', 'GO:0042783', ('71', '85'))	('mutations', 'Var', (23, 32))	('HLA-A', 'Gene', '3105', (225, 230))	('HLA-B', 'Gene', '3106', (232, 237))	('mutations', 'Var', (140, 149))	('CASP8', 'Gene', (242, 247))	('HLA-A', 'Gene', (225, 230))	('CASP8', 'Gene', '841', (242, 247))
27220	32376723	To better compare the association between specific mutations and ICR groups within individual cancer types, we calculated, for each of the identified genes, the mean ICR score in the mutated group divided by the mean ICR score in the WT within each individual cancer type.	('mutated', 'Var', (183, 190))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
27223	32376723	While for most cancer types, ICR score is indeed lower in the mutated group, results for cancer types COAD, UCEC and STAD show the reverse (figure 4A-B, right panels).	('COAD', 'Disease', (102, 106))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('COAD', 'Disease', 'MESH:D029424', (102, 106))	('cancer', 'Disease', (89, 95))	('lower', 'NegReg', (49, 54))	('mutated', 'Var', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('ICR score', 'MPA', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('UCEC', 'Disease', (108, 112))
27226	32376723	Mutated genes were frequently part of multiple pathways, suggesting impact on various tumor biological systems (online supplementary figure 11).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Mutated genes', 'Var', (0, 13))	('part', 'Reg', (30, 34))	('tumor', 'Disease', (86, 91))	('impact', 'Reg', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
27227	32376723	PTEN and CTNNB1 somatic alterations (either mutations or CNVs) have been associated with differential response to immunotherapy (PTEN) and intratumoral immune response (PTEN  and CTNNB1).	('tumor', 'Disease', (144, 149))	('CTNNB1', 'Gene', '1499', (179, 185))	('CTNNB1', 'Gene', '1499', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('PTEN', 'Gene', (169, 173))	('PTEN', 'Gene', '5728', (169, 173))	('associated', 'Reg', (73, 83))	('PTEN', 'Gene', (129, 133))	('response', 'CPA', (102, 110))	('CTNNB1', 'Gene', (179, 185))	('PTEN', 'Gene', '5728', (129, 133))	('mutations', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('CTNNB1', 'Gene', (9, 15))	('immune response', 'biological_process', 'GO:0006955', ('152', '167'))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
27229	32376723	PTEN mutations, however, were associated with higher ICR score in four individual cancer types (LGG, BRCA, COAD and Lung Adenocarcinoma (LUAD)) and in the pan-cancer analysis (online supplementary figure 12).	('LGG', 'Disease', (96, 99))	('cancer', 'Disease', (82, 88))	('Lung Adenocarcinoma', 'Disease', (116, 135))	('BRCA', 'Disease', (101, 105))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('higher', 'PosReg', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('COAD', 'Disease', 'MESH:D029424', (107, 111))	('ICR score', 'MPA', (53, 62))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (116, 135))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('PTEN', 'Gene', (0, 4))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (116, 135))	('COAD', 'Disease', (107, 111))	('PTEN', 'Gene', '5728', (0, 4))
27230	32376723	As for CTNNB1, a significant association between higher copy number and lower ICR was found in five cancer types (KIRP, Ovarian Cancer (OV), BLCA STAD and TGCT).	('higher copy number', 'Var', (49, 67))	('BLCA STAD', 'Disease', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lower', 'NegReg', (72, 77))	('CTNNB1', 'Gene', (7, 13))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (120, 134))	('Cancer', 'Disease', (128, 134))	('Cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('ICR', 'MPA', (78, 81))	('Cancer', 'Disease', 'MESH:D009369', (128, 134))	('CTNNB1', 'Gene', '1499', (7, 13))
27232	32376723	CTNNB1 mutations (either in all positions or in exon 3) were associated with lower ICR in ACC, with a non-significant trend in SKCM, PRAD and LGG (online supplementary figure 13).	('lower', 'NegReg', (77, 82))	('CTNNB1', 'Gene', '1499', (0, 6))	('ICR', 'MPA', (83, 86))	('CTNNB1', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
27241	32376723	As anticipated, pan-cancer survival analysis of all samples that formed a cluster along with samples of the ICR-disabled cancer types, named the ICR non-beneficial cluster, revealed no survival benefit of a high ICR expression.	('high', 'Var', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
27271	32376723	In tumor types with medium/high mutational burden, the mutational or neoantigenic load tended to be higher in hot (ICR high) versus cold (ICR low) tumors while this association was not observed within cancer types with overall low mutational burden.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('tumor', 'Disease', (147, 152))	('mutational burden', 'Var', (32, 49))	('tumor', 'Disease', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('cancer', 'Disease', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('neoantigenic load', 'MPA', (69, 86))	('mutational', 'MPA', (55, 65))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('higher', 'PosReg', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
27272	32376723	By adding granularity to previous observations that described an overall weak correlation between immunologic correlates of antitumor immune response and mutational load, we demonstrated here that the differences in term of mutational load was especially evident in tumors types known to be constituted by a significant proportion of microsatellite instable cases, such as COAD, STAD and UCEC.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mutational', 'Var', (224, 234))	('COAD', 'Disease', (373, 377))	('microsatellite', 'Var', (334, 348))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('COAD', 'Disease', 'MESH:D029424', (373, 377))	('immune response', 'biological_process', 'GO:0006955', ('134', '149'))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('STAD', 'Disease', (379, 383))	('UCEC', 'Disease', (388, 392))	('tumor', 'Disease', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumor', 'Disease', (266, 271))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('tumors', 'Disease', (266, 272))
27275	32376723	The top pathways associated with the absence of the Th-1/hot immune phenotype included, barriers genes, WNT-ss catenin, mismatch repair, telomerase extension by telomerase, Notch, Hedgehog and AMPK signaling pathways.	('AMPK', 'molecular_function', 'GO:0050405', ('193', '197'))	('AMPK', 'Gene', '5564', (193, 197))	('signaling', 'biological_process', 'GO:0023052', ('198', '207'))	('mismatch', 'Var', (120, 128))	('AMPK', 'molecular_function', 'GO:0004691', ('193', '197'))	('WNT-ss', 'Gene', (104, 110))	('Notch', 'Pathway', (173, 178))	('AMPK', 'molecular_function', 'GO:0047322', ('193', '197'))	('mismatch repair', 'biological_process', 'GO:0006298', ('120', '135'))	('barriers genes', 'Gene', (88, 102))	('AMPK', 'Gene', (193, 197))
27279	32376723	CTNNB1 somatic alterations leading to WNT-ss catenin activation (ie, amplifications and somatic mutations preventing proteolytic ss-catenin degradations) have been associated with a non-T cell inflamed immune phenotype in melanoma and across different tumor types.	('CTNNB1', 'Gene', '1499', (0, 6))	('associated with', 'Reg', (164, 179))	('activation', 'PosReg', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('CTNNB1', 'Gene', (0, 6))	('alterations', 'Var', (15, 26))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('melanoma', 'Disease', (222, 230))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('WNT-ss catenin', 'MPA', (38, 52))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))	('tumor', 'Disease', (252, 257))
27280	32376723	Interestingly, neither the elastic model nor the single-gene level analysis selected CTNNB1 mutations in relationship to ICR expression, while associations between CTNNB1 amplifications and low ICR score were observed across several cancer types.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('CTNNB1', 'Gene', (85, 91))	('ICR expression', 'MPA', (121, 135))	('CTNNB1', 'Gene', (164, 170))	('cancer', 'Disease', (233, 239))	('mutations', 'Var', (92, 101))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('CTNNB1', 'Gene', '1499', (85, 91))	('CTNNB1', 'Gene', '1499', (164, 170))	('associations', 'Interaction', (143, 155))
27281	32376723	Similarly, no associations between CTNNB1 mutations and intratumoral immune response were detected by two pan-cancer studies assessing an immune signature closely related to ICR and the level of cytolytic activity (PRF1 and GZMA).	('ICR', 'Disease', (174, 177))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('immune response', 'biological_process', 'GO:0006955', ('69', '84'))	('cancer', 'Disease', (110, 116))	('CTNNB1', 'Gene', '1499', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CTNNB1', 'Gene', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('PRF1', 'Gene', (215, 219))	('PRF1', 'Gene', '5551', (215, 219))	('GZMA', 'Gene', (224, 228))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', (61, 66))	('GZMA', 'Gene', '3001', (224, 228))
27282	32376723	Interestingly, in addition to a negative (although modest) correlation between ICR score and mutations of APC (an inhibitor of the WNT-ss catenin pathway), we detected a stronger correlation between WNT5A mutations and decreased ICR score.	('APC', 'cellular_component', 'GO:0005680', ('106', '109'))	('ICR', 'Disease', (79, 82))	('mutations', 'Var', (93, 102))	('decreased', 'NegReg', (219, 228))	('APC', 'Disease', 'MESH:D011125', (106, 109))	('mutations', 'Var', (205, 214))	('APC', 'Disease', (106, 109))	('WNT5A', 'Gene', '7474', (199, 204))	('ICR', 'Disease', (229, 232))	('WNT5A', 'Gene', (199, 204))
27284	32376723	However, associations between the WNT5A mutations and decreased intratumoral immune response were not previously checked in WNT-ss catenin-focused analyzes.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('WNT5A', 'Gene', '7474', (34, 39))	('tumor', 'Disease', (69, 74))	('mutations', 'Var', (40, 49))	('immune response', 'biological_process', 'GO:0006955', ('77', '92'))	('decreased', 'NegReg', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('WNT5A', 'Gene', (34, 39))
27285	32376723	The correlation between WNT5A mutations and immune suppression might deserve mechanistic investigation considering the complexity of this pathway.	('WNT5A', 'Gene', (24, 29))	('WNT5A', 'Gene', '7474', (24, 29))	('mutations', 'Var', (30, 39))
27287	32376723	Loss of PTEN (a negative regulator of the PI3K-AKT pathway), due to somatic mutations or deletions has been associated with decreased response to checkpoint blockade in melanoma, glioblastoma, lung cancer and uterine sarcoma.	('lung cancer', 'Disease', 'MESH:D008175', (193, 204))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (209, 224))	('melanoma', 'Disease', (169, 177))	('glioblastoma', 'Disease', 'MESH:D005909', (179, 191))	('PTEN', 'Gene', '5728', (8, 12))	('response to checkpoint blockade', 'MPA', (134, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))	('AKT', 'Gene', (47, 50))	('glioblastoma', 'Disease', (179, 191))	('sarcoma', 'Disease', 'MESH:D012509', (217, 224))	('Loss', 'NegReg', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('sarcoma', 'Disease', (217, 224))	('PI3K', 'molecular_function', 'GO:0016303', ('42', '46'))	('deletions', 'Var', (89, 98))	('AKT', 'Gene', '207', (47, 50))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('lung cancer', 'Disease', (193, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('mutations', 'Var', (76, 85))	('PTEN', 'Gene', (8, 12))	('decreased', 'NegReg', (124, 133))
27288	32376723	In melanoma, PTEN deletions have been associated with reduced T-cell infiltration.	('reduced', 'NegReg', (54, 61))	('T-cell infiltration', 'CPA', (62, 81))	('reduced T-cell', 'Phenotype', 'HP:0005403', (54, 68))	('deletions', 'Var', (18, 27))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('PTEN', 'Gene', (13, 17))	('melanoma', 'Disease', (3, 11))	('PTEN', 'Gene', '5728', (13, 17))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
27290	32376723	Paradoxically, PTEN mutations have not been associated with decreased intratumoral immune infiltration but rather with an increased leukocyte fraction across tumors, and an increased expression of immune-suppressive signature in glioblastoma.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('glioblastoma', 'Phenotype', 'HP:0012174', (229, 241))	('PTEN', 'Gene', '5728', (15, 19))	('leukocyte fraction', 'MPA', (132, 150))	('increased', 'PosReg', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (75, 80))	('tumors', 'Disease', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('expression', 'MPA', (183, 193))	('increased leukocyte', 'Phenotype', 'HP:0001974', (122, 141))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutations', 'Var', (20, 29))	('glioblastoma', 'Disease', 'MESH:D005909', (229, 241))	('tumor', 'Disease', (158, 163))	('PTEN', 'Gene', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('glioblastoma', 'Disease', (229, 241))
27291	32376723	Consistently, PTEN mutations were found to be associated with higher ICR score across cancers when PTEN mutational status was evaluated as a single variable.	('PTEN', 'Gene', (14, 18))	('PTEN', 'Gene', '5728', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (19, 28))	('ICR score', 'MPA', (69, 78))	('higher', 'PosReg', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('PTEN', 'Gene', (99, 103))	('cancers', 'Disease', (86, 93))	('PTEN', 'Gene', '5728', (99, 103))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
27292	32376723	The lack of selection of PTEN mutations by the elastic model might be explained by the co-occurrence with mutations in other genes with higher coefficient selected by the model.	('PTEN', 'Gene', (25, 29))	('mutations', 'Var', (30, 39))	('PTEN', 'Gene', '5728', (25, 29))
27293	32376723	Overall, these findings suggest a differential immune-regulatory role of PTEN mutations and deletions.	('PTEN', 'Gene', (73, 77))	('PTEN', 'Gene', '5728', (73, 77))	('deletions', 'Var', (92, 101))	('mutations', 'Var', (78, 87))
27298	32376723	As for the Hedgehog pathway, in breast cancer models, inhibition of this signaling induces a marked reduction in immune-suppressive innate and adaptive cells paralleled with an enrichment of cytotoxic immune cells.	('reduction', 'NegReg', (100, 109))	('breast cancer', 'Disease', (32, 45))	('inhibition', 'Var', (54, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))
27300	32376723	In lung cancer mouse models, the deletion of Lkb1, an upstream modulator of AMPK pathway, was associated with decrease T-cell tumor infiltration, and impaired production of pro-inflammatory cytokines, which was mediated by induction of STAT3 and IL-6 secretion.	('Lkb1', 'Gene', '20869', (45, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('deletion', 'Var', (33, 41))	('STAT3', 'Gene', '20848', (236, 241))	('AMPK', 'molecular_function', 'GO:0050405', ('76', '80'))	('IL-6', 'Gene', (246, 250))	('mouse', 'Species', '10090', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('production of pro-inflammatory cytokines', 'MPA', (159, 199))	('AMPK', 'Gene', (76, 80))	('AMPK', 'Gene', '5564', (76, 80))	('decrease T-cell tumor', 'Disease', (110, 131))	('decrease T-cell', 'Phenotype', 'HP:0005403', (110, 125))	('AMPK', 'molecular_function', 'GO:0004691', ('76', '80'))	('IL-6', 'Gene', '16193', (246, 250))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('STAT3', 'Gene', (236, 241))	('impaired', 'NegReg', (150, 158))	('lung cancer', 'Disease', (3, 14))	('Lkb1', 'Gene', (45, 49))	('AMPK', 'molecular_function', 'GO:0047322', ('76', '80'))	('IL-6 secretion', 'biological_process', 'GO:0072604', ('246', '260'))	('IL-6', 'molecular_function', 'GO:0005138', ('246', '250'))	('decrease T-cell tumor', 'Disease', 'MESH:D016399', (110, 131))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
27306	32376723	Interestingly, MAP3K1 mutations were previously associated with low ICR in breast cancer in our previous work.	('ICR', 'MPA', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MAP3K', 'molecular_function', 'GO:0004709', ('15', '20'))	('breast cancer', 'Disease', (75, 88))	('MAP3K1', 'Gene', (15, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('MAP3K1', 'Gene', '4214', (15, 21))	('mutations', 'Var', (22, 31))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
27307	32376723	Remarkably, mutations of other genes of the RAS/MAPK pathways such as FGFR3 (previously associated with T-cell exclusion in bladder cancer and diminished leukocyte infiltration pan-cancer), EGFR, NRAS and KRAS were associated with a low ICR score, substantiating their potential role in mediating immune exclusion.	('EGFR', 'Gene', '1956', (190, 194))	('diminished leukocyte', 'Phenotype', 'HP:0001882', (143, 163))	('FGFR3', 'Gene', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('NRAS', 'Gene', '4893', (196, 200))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('MAPK', 'molecular_function', 'GO:0004707', ('48', '52'))	('FGFR', 'molecular_function', 'GO:0005007', ('70', '74'))	('FGFR3', 'Gene', '2261', (70, 75))	('KRAS', 'Gene', '3845', (205, 209))	('NRAS', 'Gene', (196, 200))	('EGFR', 'Gene', (190, 194))	('cancer', 'Disease', (181, 187))	('bladder cancer', 'Disease', 'MESH:D001749', (124, 138))	('bladder cancer', 'Disease', (124, 138))	('cancer', 'Disease', (132, 138))	('KRAS', 'Gene', (205, 209))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('mutations', 'Var', (12, 21))	('EGFR', 'molecular_function', 'GO:0005006', ('190', '194'))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (124, 138))	('associated', 'Reg', (88, 98))	('ICR', 'Disease', (237, 240))
27310	32376723	Other mutations associated with the immune silent phenotype include WNT5A, corroborating the immune-suppressive role of the WNT ss catenin pathway  and GATA3, which was also previously associated with low leukocyte infiltration.	('GATA3', 'Gene', (152, 157))	('GATA3', 'Gene', '2625', (152, 157))	('WNT5A', 'Gene', '7474', (68, 73))	('low leukocyte', 'Phenotype', 'HP:0001882', (201, 214))	('associated', 'Reg', (16, 26))	('mutations', 'Var', (6, 15))	('WNT5A', 'Gene', (68, 73))
27311	32376723	Mutations of FKBP5, MAT2A, PPP2R5A, MECOM, SMAD2, MED17, ADAM10, PRKAR1A, DIS3, PRRX1, MFNG, TNPO1, KDM6A, IRF7, SUZ12, RPSAP58 and SF3B1 represent additional novel findings.	('ADAM10', 'Gene', (57, 63))	('PRRX1', 'Gene', '5396', (80, 85))	('RPSAP58', 'Gene', '388524', (120, 127))	('DIS3', 'Gene', (74, 78))	('MAT2A', 'Gene', (20, 25))	('MFNG', 'Gene', '4242', (87, 91))	('FKBP5', 'Gene', '2289', (13, 18))	('PRKAR1A', 'Gene', (65, 72))	('FKBP5', 'Gene', (13, 18))	('ADAM10', 'Gene', '102', (57, 63))	('SMAD2', 'Gene', (43, 48))	('PPP2R5A', 'Gene', (27, 34))	('SF3B1', 'Gene', '23451', (132, 137))	('IRF7', 'Gene', '3665', (107, 111))	('FKBP', 'molecular_function', 'GO:0030051', ('13', '17'))	('MFNG', 'Gene', (87, 91))	('Mutations', 'Var', (0, 9))	('TNPO1', 'Gene', (93, 98))	('KDM6A', 'Gene', '7403', (100, 105))	('MAT', 'molecular_function', 'GO:0004314', ('20', '23'))	('MED17', 'Gene', (50, 55))	('PRKAR1A', 'Gene', '5573', (65, 72))	('PRRX1', 'Gene', (80, 85))	('DIS3', 'Gene', '22894', (74, 78))	('IRF7', 'Gene', (107, 111))	('MED17', 'Gene', '9440', (50, 55))	('PPP2R5A', 'Gene', '5525', (27, 34))	('MAT2A', 'Gene', '4144', (20, 25))	('SUZ12', 'Gene', (113, 118))	('RPSAP58', 'Gene', (120, 127))	('MECOM', 'Gene', (36, 41))	('KDM6A', 'Gene', (100, 105))	('SMAD2', 'Gene', '4087', (43, 48))	('MECOM', 'Gene', '2122', (36, 41))	('SF3B1', 'Gene', (132, 137))	('TNPO1', 'Gene', '3842', (93, 98))	('SUZ12', 'Gene', '23512', (113, 118))
27313	32376723	B2M mutations have been associated with disease progression following immune checkpoint therapy.	('B2M', 'Gene', (0, 3))	('disease', 'Disease', (40, 47))	('B2M', 'Gene', '567', (0, 3))	('associated with', 'Reg', (24, 39))	('mutations', 'Var', (4, 13))
27315	32376723	The occurrence of B2M mutations might indicate an early phase of immune editing, which however did not completely compromise the protective effect of the immunological pressure at this early phase of tumor evolution.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('B2M', 'Gene', '567', (18, 21))	('mutations', 'Var', (22, 31))	('B2M', 'Gene', (18, 21))
27316	32376723	This is consistent with recent observations in colon cancer, in which immune-edited metastases have a decrease risk of relapse as compared with the non-immune edited ones.	('colon cancer', 'Phenotype', 'HP:0003003', (47, 59))	('metastases', 'Disease', (84, 94))	('decrease', 'NegReg', (102, 110))	('immune-edited', 'Var', (70, 83))	('colon cancer', 'Disease', 'MESH:D015179', (47, 59))	('relapse', 'CPA', (119, 126))	('metastases', 'Disease', 'MESH:D009362', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('colon cancer', 'Disease', (47, 59))
27321	32376723	To compare cancer types based on the prognostic value of ICR, we categorized them into two groups: one for which ICR high was associated with increased OS and one for which ICR was associated with worse OS.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('increased', 'PosReg', (142, 151))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('ICR high', 'Var', (113, 121))	('cancer', 'Disease', (11, 17))
27336	32376723	The pan-cancer survival analysis of samples of ICR-neutral cancer types showed that for samples that coclustered with samples of ICR-enabled cancer types (the ICR beneficial cluster), ICR high was associated with significant prolonged survival.	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('ICR high', 'Var', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('prolonged', 'PosReg', (225, 234))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
27337	32376723	In fact, the positive prognostic role of ICR was present also in a subset of samples with low proliferation and high mutational load but absent only in tumors with both low proliferation and low mutational load.	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('high mutational load', 'Var', (112, 132))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
27339	32376723	We hypothesize that, in tumor with high mutational burden and/or high proliferative capacity, the high level of ICR captures a true protective antitumoral immune response, while in the other cases, such as in tumors dominated by cancer signaling, the high ICR captures a bystander, or heavily suppressed, lymphocyte infiltration with no protective effect.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (209, 215))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', (209, 214))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Disease', (229, 235))	('tumor', 'Disease', (24, 29))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('signaling', 'biological_process', 'GO:0023052', ('236', '245'))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('mutational', 'Var', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('immune response', 'biological_process', 'GO:0006955', ('155', '170'))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
27351	28294568	Systems Pharmacology-Based Discovery of Natural Products for Precision Oncology Through Targeting Cancer Mutated Genes Massive cancer genomics data have facilitated the rapid revolution of a novel oncology drug discovery paradigm through targeting clinically relevant driver genes or mutations for the development of precision oncology.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Oncology', 'Phenotype', 'HP:0002664', (71, 79))	('mutations', 'Var', (284, 293))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('oncology', 'Phenotype', 'HP:0002664', (327, 335))	('cancer', 'Disease', (127, 133))	('oncology', 'Phenotype', 'HP:0002664', (197, 205))
27354	28294568	In case studies, we computationally identified novel anticancer indications for several US Food and Drug Administration-approved or clinically investigational natural products (e.g., resveratrol, quercetin, genistein, and fisetin) through targeting significantly mutated genes in multiple cancer types.	('multiple cancer', 'Disease', (280, 295))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('multiple cancer', 'Disease', 'MESH:D009369', (280, 295))	('quercetin', 'Chemical', 'MESH:D011794', (196, 205))	('resveratrol', 'Chemical', 'MESH:D000077185', (183, 194))	('mutated', 'Var', (263, 270))	('genes', 'Gene', (271, 276))	('fisetin', 'Chemical', 'MESH:C017875', (222, 229))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('genistein', 'Chemical', 'MESH:D019833', (207, 216))	('cancer', 'Disease', (289, 295))
27356	28294568	Massive cancer genomic data has facilitated the revolution of a novel oncology drug discovery paradigm through targeting clinically relevant driver genes or mutations for the development of precision oncology.	('cancer', 'Disease', (8, 14))	('mutations', 'Var', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('oncology', 'Phenotype', 'HP:0002664', (70, 78))	('oncology', 'Phenotype', 'HP:0002664', (200, 208))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
27359	28294568	WHAT THIS STUDY ADDS TO OUR KNOWLEDGE    This study demonstrates that a systems pharmacology framework that integrates drug-target interaction network of natural products and cancer mutant genes from the cancer genome projects would be useful for the development of novel targeted cancer therapies.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('mutant', 'Var', (182, 188))
27360	28294568	In the past several decades, traditional oncology drug discovery that focused on synthesized compounds has shown high risk in clinical trials.1 A recent study revealed that ~7.5% of the oncology drugs were able to enter phase I trials and only 33.2% of the drugs that entered phase III trials were eventually approved.1 Compared with traditional oncology drugs, natural products are better templates with ideal pharmacokinetics/pharmacodynamics (PK/PD) properties, of which scaffolds are repeatedly considered "privileged" in drug discovery.2 So far, more than half of the new drugs introduced after 1990 could be traced to naturally derived products or their analogs.3, 4 Since natural products possess enormous structural and chemical diversity and are abundant, they have served as great inspiration for the next generation of cancer therapeutics.5, 6  With rapidly growing, revolutionary next-generation sequencing technologies, several large-scale cancer genome projects, such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), have generated massive amounts of somatic mutation profiles.7 Such massive amounts of cancer genomic data have helped us better understand cancer biology and improve cancer prognosis, diagnosis, and treatment.8, 9 For most solid tumors, their genomes harbor hundreds of DNA-level genetic alterations, which are composed of massive bystander mutations ("passenger mutations") with no oncogenic potential and few cancer-driving genomic aberrations ("driver mutations").10 Driver mutations represent mutations that have a selective growth advantage in tumor cells, further contributing to tumor initiation, progression, and drug resistance via activating oncogenes or inactivating tumor suppressor genes.11 Therefore, cancer drugs that target clinically relevant driver mutations, such as kinase inhibitors, have shown high selectivity on tumor cells and demonstrated valuable opportunities for precision oncology.12 For example, BCR-ABL mutations have been found to predict clinical responses to imatinib, the first US Food and Drug Administration (FDA)-approved targeted agent, in chronic myelogenous leukemia (CML).	('cancer', 'Disease', 'MESH:D009369', (1482, 1488))	('cancer', 'Disease', 'MESH:D009369', (1237, 1243))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (2159, 2179))	('oncology', 'Phenotype', 'HP:0002664', (1973, 1981))	('oncology', 'Phenotype', 'HP:0002664', (346, 354))	('tumor', 'Disease', 'MESH:D009369', (1657, 1662))	('cancer', 'Disease', 'MESH:D009369', (830, 836))	('tumor', 'Disease', 'MESH:D009369', (1300, 1305))	('tumor', 'Disease', (1749, 1754))	('predict', 'Reg', (2035, 2042))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (2151, 2179))	('solid tumors', 'Disease', 'MESH:D009369', (1294, 1306))	('cancer', 'Disease', (1786, 1792))	('tumors', 'Phenotype', 'HP:0002664', (1300, 1306))	('cancer', 'Disease', 'MESH:D009369', (1210, 1216))	('oncology', 'Phenotype', 'HP:0002664', (186, 194))	('tumor', 'Disease', 'MESH:D009369', (1749, 1754))	('oncology', 'Phenotype', 'HP:0002664', (41, 49))	('BCR-ABL', 'Gene', '25', (1998, 2005))	('tumor', 'Phenotype', 'HP:0002664', (1657, 1662))	('cancer', 'Disease', (953, 959))	('tumor', 'Disease', (1907, 1912))	('cancer', 'Disease', (1157, 1163))	('tumor', 'Phenotype', 'HP:0002664', (1300, 1305))	('tumor', 'Disease', (1620, 1625))	('cancer', 'Phenotype', 'HP:0002664', (953, 959))	('cancer', 'Phenotype', 'HP:0002664', (1157, 1163))	('drug resistance', 'Phenotype', 'HP:0020174', (1692, 1707))	('mutations', 'Var', (2006, 2015))	('cancer', 'Disease', (1482, 1488))	('cancer', 'Disease', (1237, 1243))	('tumor', 'Disease', 'MESH:D009369', (1907, 1912))	('tumor', 'Phenotype', 'HP:0002664', (1749, 1754))	('cancer', 'Disease', (830, 836))	('tumor', 'Disease', 'MESH:D009369', (1620, 1625))	('DNA', 'cellular_component', 'GO:0005574', ('1339', '1342'))	('CML', 'Disease', 'MESH:D015464', (2181, 2184))	('chronic myelogenous leukemia', 'Disease', (2151, 2179))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (2151, 2179))	('leukemia', 'Phenotype', 'HP:0001909', (2171, 2179))	('cancer', 'Phenotype', 'HP:0002664', (1237, 1243))	('cancer', 'Disease', 'MESH:D009369', (1786, 1792))	('CML', 'Disease', (2181, 2184))	('cancer', 'Disease', (1210, 1216))	('cancer', 'Phenotype', 'HP:0002664', (830, 836))	('Cancer', 'Phenotype', 'HP:0002664', (1038, 1044))	('PD', 'Disease', 'MESH:D010300', (449, 451))	('tumor initiation', 'Disease', 'MESH:D009369', (1657, 1673))	('solid tumors', 'Disease', (1294, 1306))	('Cancer', 'Phenotype', 'HP:0002664', (989, 995))	('BCR-ABL', 'Gene', (1998, 2005))	('cancer', 'Disease', 'MESH:D009369', (953, 959))	('cancer', 'Phenotype', 'HP:0002664', (1210, 1216))	('tumor', 'Phenotype', 'HP:0002664', (1907, 1912))	('tumor initiation', 'Disease', (1657, 1673))	('tumor', 'Phenotype', 'HP:0002664', (1620, 1625))	('cancer', 'Disease', 'MESH:D009369', (1157, 1163))	('tumor', 'Disease', (1657, 1662))	('tumor', 'Disease', (1300, 1305))
27383	28294568	The alternative hypothesis asserts that cancer drug target proteins are more likely to be protein products of SMGs than other proteins for a natural product that has a potential anticancer indication.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('SMGs', 'Var', (110, 114))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
27388	28294568	Among the 409 FDA-approved or clinically investigational natural products, eight are linked by over 100 target proteins: DB04077 (glycerol), DB04216 (quercetin), DB02709 (resveratrol), DB00396 (progesterone), DB04272 (citric acid), DB07352 (apigenin), DB01645 (genistein), and DB00131 (adenosine monophosphate).	('DB00131', 'Gene', (277, 284))	('resveratrol', 'Chemical', 'MESH:D000077185', (171, 182))	('adenosine monophosphate', 'Chemical', 'MESH:D000249', (286, 309))	('DB07352', 'Var', (232, 239))	('apigenin', 'Chemical', 'MESH:D047310', (241, 249))	('progesterone', 'Chemical', 'MESH:D011374', (194, 206))	('DB01645', 'Var', (252, 259))	('DB04272', 'Var', (209, 216))	('DB04077', 'Var', (121, 128))	('DB00396', 'Var', (185, 192))	('DB07352', 'Chemical', '-', (232, 239))	('DB04077', 'Chemical', '-', (121, 128))	('quercetin', 'Chemical', 'MESH:D011794', (150, 159))	('DB04216', 'Chemical', '-', (141, 148))	('DB04272', 'Chemical', '-', (209, 216))	('DB00396', 'Chemical', '-', (185, 192))	('DB02709', 'Var', (162, 169))	('DB02709', 'Chemical', '-', (162, 169))	('genistein', 'Chemical', 'MESH:D019833', (261, 270))	('citric acid', 'Chemical', 'MESH:D019343', (218, 229))	('glycerol', 'Chemical', 'MESH:D005990', (130, 138))	('DB04216', 'Var', (141, 148))	('DB01645', 'Chemical', '-', (252, 259))	('DB00131', 'Chemical', '-', (277, 284))
27397	28294568	We further developed an integrated statistical systems pharmacology framework with the permutation test for prioritizing new anticancer indications of natural products via targeting cancer relevant mutations and mutant genes.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutant genes', 'Var', (212, 224))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', (182, 188))
27400	28294568	Resveratrol is a non-flavonoid polyphenol in grape skin and has been reported to have antioxidative and proapoptotic effects in several cancer cell lines.31 Several ongoing or completed clinical trials (http://clinicaltrials.gov/) for resveratrol are being conducted to treat various cancers, such as colon cancer (NCT00256334), neuroendocrine tumor (NCT01476592), and liver cancer (NCT02261844).	('NCT02261844', 'Var', (383, 394))	('Resveratrol', 'Chemical', 'MESH:D000077185', (0, 11))	('cancers', 'Disease', 'MESH:D009369', (284, 291))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('neuroendocrine tumor', 'Disease', (329, 349))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('colon cancer', 'Disease', (301, 313))	('cancer', 'Disease', (136, 142))	('flavonoid', 'Chemical', 'MESH:D005419', (21, 30))	('liver cancer', 'Disease', 'MESH:D006528', (369, 381))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (329, 349))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('NCT00256334', 'Var', (315, 326))	('liver cancer', 'Phenotype', 'HP:0002896', (369, 381))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (329, 349))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('liver cancer', 'Disease', (369, 381))	('colon cancer', 'Phenotype', 'HP:0003003', (301, 313))	('cancers', 'Phenotype', 'HP:0002664', (284, 291))	('cancer', 'Disease', (284, 290))	('cancers', 'Disease', (284, 291))	('NCT01476592', 'Var', (351, 362))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('cancer', 'Disease', (307, 313))	('colon cancer', 'Disease', 'MESH:D015179', (301, 313))	('polyphenol', 'Chemical', 'MESH:D059808', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('resveratrol', 'Chemical', 'MESH:D000077185', (235, 246))	('cancer', 'Disease', (375, 381))
27405	28294568	Recently, several clinical trials for quercetin to treat or prevent various cancers are ongoing or completed, including prostate cancer (NCT01912820), colorectal cancer (NCT00003365), renal cell carcinoma (NCT02446795), and advanced pancreatic cancer (NCT01879878).	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('NCT01912820', 'Var', (137, 148))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (184, 204))	('NCT00003365', 'Var', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (151, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('colorectal cancer', 'Disease', (151, 168))	('prostate cancer', 'Disease', 'MESH:D011471', (120, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (120, 135))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('pancreatic cancer', 'Disease', 'MESH:D010190', (233, 250))	('renal cell carcinoma', 'Disease', (184, 204))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (184, 204))	('prostate cancer', 'Disease', (120, 135))	('quercetin', 'Chemical', 'MESH:D011794', (38, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (151, 168))	('pancreatic cancer', 'Disease', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('NCT02446795', 'Var', (206, 217))
27409	28294568	Figure 4 c shows that genistein is predicted to have potential anticancer indications for 11 cancer types, such as BLCA (Z = 6.24, q < 1.0 x 10-5), BRCA (Z = 7.03, q < 1.0 x 10-5), and LUAD (Z = 9.74, q < 1.0 x 10-5).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('LUAD', 'Disease', (185, 189))	('cancer', 'Disease', (67, 73))	('BRCA', 'Gene', '672', (148, 152))	('BRCA', 'Gene', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BLCA', 'Chemical', '-', (115, 119))	('genistein', 'Var', (22, 31))	('BLCA', 'Disease', (115, 119))	('genistein', 'Chemical', 'MESH:D019833', (22, 31))
27410	28294568	A recent study has reported that genistein acted as a chemotherapeutic agent against different types of cancers via altering apoptosis, cell cycle, and angiogenesis or inhibiting metastasis.39 In addition, genistein has been widely used and tested in several clinical cancer studies, such as breast cancer (NCT00244933), bladder cancer (NCT00118040), prostate cancer (NCT01325311), and lung cancer (NCT01628471).	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('prostate cancer', 'Disease', 'MESH:D011471', (351, 366))	('prostate cancer', 'Phenotype', 'HP:0012125', (351, 366))	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('cancer', 'Disease', (391, 397))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('prostate cancer', 'Disease', (351, 366))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('cancers', 'Disease', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('NCT01325311', 'Var', (368, 379))	('breast cancer', 'Disease', 'MESH:D001943', (292, 305))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('cancer', 'Disease', 'MESH:D009369', (360, 366))	('breast cancer', 'Disease', (292, 305))	('cell cycle', 'biological_process', 'GO:0007049', ('136', '146'))	('genistein', 'Chemical', 'MESH:D019833', (33, 42))	('NCT00118040', 'Var', (337, 348))	('lung cancer', 'Disease', (386, 397))	('apoptosis', 'biological_process', 'GO:0097194', ('125', '134'))	('apoptosis', 'biological_process', 'GO:0006915', ('125', '134'))	('bladder cancer', 'Phenotype', 'HP:0009725', (321, 335))	('cancer', 'Disease', 'MESH:D009369', (391, 397))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('cancer', 'Disease', (268, 274))	('lung cancer', 'Disease', 'MESH:D008175', (386, 397))	('bladder cancer', 'Disease', 'MESH:D001749', (321, 335))	('bladder cancer', 'Disease', (321, 335))	('cancer', 'Disease', (329, 335))	('cancer', 'Disease', (360, 366))	('NCT00244933', 'Var', (307, 318))	('genistein', 'Chemical', 'MESH:D019833', (206, 215))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('angiogenesis', 'biological_process', 'GO:0001525', ('152', '164'))	('lung cancer', 'Phenotype', 'HP:0100526', (386, 397))
27419	28294568	Data quality and data incompleteness of the cancer mutant genes may be influenced by the limited cohorts of cancer genome projects and tumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('mutant', 'Var', (51, 57))	('cancer', 'Disease', (44, 50))	('tumor', 'Disease', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Disease', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
27422	28294568	Fourth, it is commonly known that most cancer significantly mutated genes are not targetable by current small molecular drugs, owing to the "undruggable" properties of certain cancer mutant genes (e.g., KRAS).	('KRAS', 'Gene', (203, 207))	('KRAS', 'Gene', '3845', (203, 207))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('mutant', 'Var', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
27469	27725621	In previous studies, the rates of 2+/3+ HER2 IHC in UUTUC ranged from 14% to 18%.	('HER2', 'Gene', '2064', (40, 44))	('HER2', 'Gene', (40, 44))	('2+/3+', 'Var', (34, 39))
27471	27725621	The high pTNM stage, high ISUP grade, and high HER2 expression group, as classified by the FDA criteria, showed significantly shorter cancer-specific survival, whereas HER2 expression classified using the ASCO/CAP 2013 criteria did not show a significant association with shorter cancer-specific survival.	('HER2', 'Gene', '2064', (168, 172))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('shorter', 'NegReg', (126, 133))	('cancer', 'Disease', (280, 286))	('cancer', 'Disease', (134, 140))	('HER2', 'Gene', (47, 51))	('expression', 'MPA', (52, 62))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('HER2', 'Gene', '2064', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('high', 'Var', (42, 46))	('high ISUP grade', 'Var', (21, 36))	('HER2', 'Gene', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
27474	27725621	Some studies have tried to clarify the association between HER2 status and the prognosis of urothelial carcinoma, and the results were diverse.	('status', 'Var', (64, 70))	('urothelial carcinoma', 'Disease', (92, 112))	('HER2', 'Gene', (59, 63))	('HER2', 'Gene', '2064', (59, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (92, 112))	('association', 'Interaction', (39, 50))
27483	27725621	There have been some studies reporting good correlation between HER2 protein overexpression and gene amplification in UUTUC.	('overexpression', 'PosReg', (77, 91))	('gene amplification', 'Var', (96, 114))	('HER2', 'Gene', (64, 68))	('HER2', 'Gene', '2064', (64, 68))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))
27569	30325609	On multivariate analysis, the presence of moderate or severe LUTS was an independent predictor of tumor recurrence (OR: 19.1, 95% confidence interval [CI]: 2.86 - 127; p = 0.002) in addition to pathological tumor stage (p < 0.05) (Table-3).	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('moderate', 'Var', (42, 50))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (207, 212))
27580	30325609	In the typical age group that men develop bladder cancer (60 - 80 years), BPH can cause significant LUTS, such as urinary frequency, urgency, and hesitancy because of obstruction of the bladder.	('LUTS', 'Disease', (100, 104))	('cause', 'Reg', (82, 87))	('bladder cancer', 'Disease', 'MESH:D001749', (42, 56))	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('men', 'Species', '9606', (30, 33))	('urgency', 'Disease', (133, 140))	('obstruction of the bladder', 'Disease', 'MESH:D001749', (167, 193))	('obstruction of the bladder', 'Disease', (167, 193))	('urinary frequency', 'Disease', (114, 131))	('BPH', 'Phenotype', 'HP:0008711', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('hesitancy', 'Disease', (146, 155))	('bladder cancer', 'Disease', (42, 56))	('BPH', 'Var', (74, 77))	('obstruction of the bladder', 'Phenotype', 'HP:0041047', (167, 193))
27591	30325609	A similar study from Europe corroborated this finding, showing a reduced 5 - year recurrence rate (56% vs. 80%, p < 0.01) in men diagnosed with Tis, Ta, or T1 urothelial carcinoma of the bladder and BPH / BOO who underwent TURBT and TURP in the same setting versus TURBT alone.	('BOO', 'Phenotype', 'HP:0041047', (205, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('reduced', 'NegReg', (65, 72))	('BPH', 'Phenotype', 'HP:0008711', (199, 202))	('men', 'Species', '9606', (125, 128))	('Tis', 'Var', (144, 147))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (159, 194))	('urothelial carcinoma of the bladder', 'Disease', (159, 194))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (159, 194))
27607	30592142	Inhibition of stearoyl CoA desaturase-1 activity suppresses tumour progression and improves prognosis in human bladder cancer Urinary bladder neoplasm is one of the most common cancers worldwide.	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('prognosis', 'CPA', (92, 101))	('bladder neoplasm', 'Disease', (134, 150))	('activity', 'MPA', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('human', 'Species', '9606', (105, 110))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('bladder cancer', 'Disease', 'MESH:D001749', (111, 125))	('bladder cancer', 'Disease', (111, 125))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Disease', (60, 66))	('bladder neoplasm', 'Disease', 'MESH:D001749', (134, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (111, 125))	('stearoyl CoA desaturase', 'Gene', '6319', (14, 37))	('improves', 'PosReg', (83, 91))	('suppresses', 'NegReg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('Inhibition', 'Var', (0, 10))	('stearoyl CoA desaturase', 'Gene', (14, 37))	('neoplasm', 'Phenotype', 'HP:0002664', (142, 150))
27612	30592142	Loss-of-function experiments further revealed that the SCD inhibitor A939572 and SCD gene interference reduced cell proliferation and invasion.	('cell proliferation', 'biological_process', 'GO:0008283', ('111', '129'))	('reduced', 'NegReg', (103, 110))	('A939572', 'Chemical', '-', (69, 76))	('SCD', 'Gene', (55, 58))	('SCD', 'Gene', '6319', (81, 84))	('cell proliferation', 'CPA', (111, 129))	('men', 'Species', '9606', (23, 26))	('SCD', 'Gene', '6319', (55, 58))	('A939572', 'Var', (69, 76))	('SCD', 'Gene', (81, 84))
27683	30592142	As shown by the Kaplan-Meier curve, patients with high SCD mRNA expression displayed a significantly lower overall survival than patients with low SCD mRNA expression in both programs (Figure 2A).	('mRNA expression', 'Var', (59, 74))	('SCD', 'Gene', (147, 150))	('overall survival', 'MPA', (107, 123))	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (129, 137))	('SCD', 'Gene', '6319', (147, 150))	('SCD', 'Gene', (55, 58))	('lower', 'NegReg', (101, 106))	('SCD', 'Gene', '6319', (55, 58))
27684	30592142	High PI3 expression was found to be significantly correlated with worse patient survival in one group cut-off program (Figure 2B).	('PI3', 'Gene', '5266', (5, 8))	('High', 'Var', (0, 4))	('worse', 'NegReg', (66, 71))	('PI3', 'Gene', (5, 8))	('patient', 'Species', '9606', (72, 79))	('patient survival', 'CPA', (72, 88))
27705	30592142	As shown in Figure 4A, the growth curve revealed that after treatment with 3.2 or 25.6 microg/mL A939572, the inhibition of SCD activity significantly decreased the growth of UMUC3 and RT4 cells compared to that of the DMSO (0.25%) control.	('inhibition', 'NegReg', (110, 120))	('men', 'Species', '9606', (65, 68))	('A939572', 'Chemical', '-', (97, 104))	('SCD', 'Gene', (124, 127))	('decreased', 'NegReg', (151, 160))	('growth', 'MPA', (165, 171))	('DMSO', 'Chemical', 'MESH:D004121', (219, 223))	('SCD', 'Gene', '6319', (124, 127))	('A939572', 'Var', (97, 104))
27708	30592142	After 2 weeks of treatment at a concentration of 1.6 microg/mL A939572, we observed that UMUC3 and RT4 cells notably lost their sphere formation ability (Figure 4C).	('formation', 'biological_process', 'GO:0009058', ('135', '144'))	('A939572', 'Chemical', '-', (63, 70))	('men', 'Species', '9606', (22, 25))	('lost', 'NegReg', (117, 121))	('A939572', 'Var', (63, 70))	('sphere formation ability', 'CPA', (128, 152))
27711	30592142	As shown in Figure 4D,E, compared with the DMSO-treated group or the normal control, SCD inhibition using either A939572 or two siRNAs significantly decreased the EdU values.	('SCD', 'Gene', (85, 88))	('SCD', 'Gene', '6319', (85, 88))	('DMSO', 'Chemical', 'MESH:D004121', (43, 47))	('EdU values', 'MPA', (163, 173))	('A939572', 'Var', (113, 120))	('decreased', 'NegReg', (149, 158))	('A939572', 'Chemical', '-', (113, 120))	('EdU', 'Chemical', 'MESH:C031086', (163, 166))
27722	30592142	In summary, SCD inhibition was capable of decreasing the migration and invasion abilities of bladder cancer cell lines in vitro.	('bladder cancer', 'Disease', 'MESH:D001749', (93, 107))	('bladder cancer', 'Disease', (93, 107))	('SCD', 'Gene', '6319', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('decreasing', 'NegReg', (42, 52))	('bladder cancer', 'Phenotype', 'HP:0009725', (93, 107))	('invasion abilities', 'CPA', (71, 89))	('SCD', 'Gene', (12, 15))	('inhibition', 'Var', (16, 26))
27723	30592142	Many studies reported that pharmacologic or genetic interference with SCD remarkably accelerated the process of cellular apoptosis in different types of cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cellular apoptosis', 'CPA', (112, 130))	('cancer', 'Disease', (153, 159))	('accelerated', 'PosReg', (85, 96))	('SCD', 'Gene', (70, 73))	('SCD', 'Gene', '6319', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('apoptosis', 'biological_process', 'GO:0097194', ('121', '130'))	('genetic interference', 'Var', (44, 64))	('apoptosis', 'biological_process', 'GO:0006915', ('121', '130'))
27727	30592142	In addition, A939572 treatment alone had no effect on cell survival (Figure 5C).	('A939572', 'Var', (13, 20))	('men', 'Species', '9606', (26, 29))	('A939572', 'Chemical', '-', (13, 20))	('cell survival', 'CPA', (54, 67))
27728	30592142	When combined with A939572 at concentrations of 3.2 and 25.6 microg/mL, the inhibitory effect of pirarubicin in UMUC3 or RT4 cells did not increase (Figure 5D).	('A939572', 'Chemical', '-', (19, 26))	('A939572', 'Var', (19, 26))	('pirarubicin', 'Chemical', 'MESH:C027260', (97, 108))	('inhibitory', 'MPA', (76, 86))
27732	30592142	Taken together, the above data suggested that the SCD inhibitor was unable to reduce cell survival in 2D cultured cells, but in bladder CSCs, cell apoptosis was enhanced after treatment with A939572.	('cell apoptosis', 'CPA', (142, 156))	('enhanced', 'PosReg', (161, 169))	('A939572', 'Var', (191, 198))	('men', 'Species', '9606', (181, 184))	('apoptosis', 'biological_process', 'GO:0097194', ('147', '156'))	('SCD', 'Gene', '6319', (50, 53))	('A939572', 'Chemical', '-', (191, 198))	('apoptosis', 'biological_process', 'GO:0006915', ('147', '156'))	('SCD', 'Gene', (50, 53))
27741	30592142	Thus, we conclude that high SCD expression indicates poor prognosis in patients with bladder urothelial cancer, and the blockade of SCD gene activity significantly inhibits the proliferation and invasion of bladder cancer cells.	('patients', 'Species', '9606', (71, 79))	('SCD', 'Gene', (28, 31))	('invasion', 'CPA', (195, 203))	('SCD', 'Gene', '6319', (28, 31))	('bladder cancer', 'Disease', 'MESH:D001749', (207, 221))	('high', 'Var', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('bladder cancer', 'Disease', (207, 221))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (85, 110))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('bladder cancer', 'Phenotype', 'HP:0009725', (207, 221))	('expression', 'MPA', (32, 42))	('inhibits', 'NegReg', (164, 172))	('activity', 'MPA', (141, 149))	('blockade', 'Var', (120, 128))	('bladder urothelial cancer', 'Disease', (85, 110))	('SCD', 'Gene', (132, 135))	('SCD', 'Gene', '6319', (132, 135))	('proliferation', 'CPA', (177, 190))
27755	30592142	In xenograft tumours deriving from MF-438 cells, treatment with the SCD inhibitor A939572 had no virtual antitumour impacts but suppressed tumour growth when carfilzomib was used.37 In our study, the results suggested that treatment with A939572 did not cause apoptosis in parental bladder cancer cell lines.	('SCD', 'Gene', (68, 71))	('SCD', 'Gene', '6319', (68, 71))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('MF-438', 'CellLine', 'CVCL:V770', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('parental bladder cancer', 'Disease', (273, 296))	('parental bladder cancer', 'Disease', 'MESH:D001749', (273, 296))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('tumour', 'Disease', (109, 115))	('A939572', 'Chemical', '-', (238, 245))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('tumour', 'Disease', (13, 19))	('suppressed', 'NegReg', (128, 138))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('xenograft tumours', 'Disease', 'MESH:D009369', (3, 20))	('tumour', 'Disease', (139, 145))	('A939572', 'Var', (238, 245))	('xenograft tumours', 'Disease', (3, 20))	('men', 'Species', '9606', (228, 231))	('carfilzomib', 'Chemical', 'MESH:C524865', (158, 169))	('men', 'Species', '9606', (54, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('260', '269'))	('apoptosis', 'biological_process', 'GO:0006915', ('260', '269'))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('bladder cancer', 'Phenotype', 'HP:0009725', (282, 296))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('A939572', 'Chemical', '-', (82, 89))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
27809	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))	('18F-FDG PET/CT', 'Var', (77, 91))	('superior', 'PosReg', (105, 113))	('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))
27828	28948154	Initial exam revealed a patient in moderate respiratory distress and tachypnea with a RR of 22, tachycardia with a HR of 104 and hypotension with a BP of 84/55, with an SpO2 94% and temp of 96.4F.	('tachycardia', 'Phenotype', 'HP:0001649', (96, 107))	('hypotension', 'Disease', 'MESH:D007022', (129, 140))	('patient', 'Species', '9606', (24, 31))	('tachycardia', 'Disease', 'MESH:D013610', (96, 107))	('tachypnea', 'Disease', (69, 78))	('tachycardia', 'Disease', (96, 107))	('tachypnea', 'Disease', 'MESH:D059246', (69, 78))	('respiratory distress', 'Phenotype', 'HP:0002098', (44, 64))	('hypotension', 'Disease', (129, 140))	('tachypnea', 'Phenotype', 'HP:0002789', (69, 78))	('RR of', 'Var', (86, 91))	('hypotension', 'Phenotype', 'HP:0002615', (129, 140))	('HR of 104', 'Var', (115, 124))
27862	24363758	HLA-A24/survivin-2B80-88 tetramer analysis and ELISPOT assay revealed a significant increase in the frequency of the peptide-specific CTLs after vaccination in nine patients.	('peptide-specific', 'Var', (117, 133))	('HLA-A', 'Gene', '3105', (0, 5))	('HLA-A', 'Gene', (0, 5))	('increase', 'PosReg', (84, 92))	('patients', 'Species', '9606', (165, 173))
27873	24363758	Immunization with peptides derived from cancer-specific antigen induces antitumor cytotoxic T lymphocytes (CTLs).	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('cancer', 'Disease', (40, 46))	('peptides', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
27928	24363758	The vaccination group had significantly better OS than the control group (P = 0.0009), as shown in Figure 4.	('better', 'PosReg', (40, 46))	('OS', 'Chemical', '-', (47, 49))	('vaccination', 'Var', (4, 15))
27980	24129236	Active TB was defined by at least two ambulatory visits or one in-patient record with a compatible diagnosis (ICD-9-CM codes 010-018 and A-codes A020-A022, A025), prescriptions consisting of at least two anti-TB drugs simultaneously for >=120 days of a 180-day period, and at least one prescription consisting of three or more anti-TB drugs.	('Active TB', 'Disease', (0, 9))	('prescriptions', 'Var', (163, 176))	('patient', 'Species', '9606', (66, 73))
27987	24129236	The urinary tract cancer was identified by compatible ICD-9-CM codes (188 and 189) or A-codes (A126 and A129) from the Registry for Catastrophic Illness Patient Database, a separate section of the NHIRD that required histologic confirmation.	('A129', 'Var', (104, 108))	('Patient', 'Species', '9606', (153, 160))	('188', 'Var', (70, 73))	('urinary tract cancer', 'Disease', 'MESH:D014571', (4, 24))	('A126', 'Var', (95, 99))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (4, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('urinary tract cancer', 'Disease', (4, 24))
27994	24129236	Urinary tract infections were identified by diagnostic codes (ICD-9-CM codes 590, 595, 597, and 599.0 and A-codes A351, A353, and A359) within 1 month prior to or after the index date.	('A359', 'Var', (130, 134))	('Urinary tract infections', 'Disease', 'MESH:D014552', (0, 24))	('A353', 'Var', (120, 124))	('Urinary tract infections', 'Phenotype', 'HP:0000010', (0, 24))	('A351', 'Var', (114, 118))	('Urinary tract infections', 'Disease', (0, 24))
27995	24129236	Obstructive uropathy was identified by compatible diagnostic codes (ICD-9-CM codes 591, 592, 594, 596, 598, 599.3, and 599.6, and A-codes A352 and A359) prior to the index date.	('A-codes A352', 'Var', (130, 142))	('uropathy', 'Disease', (12, 20))	('A359', 'Var', (147, 151))	('A352', 'Var', (138, 142))	('uropathy', 'Disease', 'MESH:C536483', (12, 20))	('599.6', 'Var', (119, 124))
28019	24129236	Patients with UTB were older and had significantly higher risk of developing urothelial carcinoma than those without UTB (1.3% vs 0.4%, P<0.001, by chi2-square test) (Table 1).	('urothelial carcinoma', 'Disease', 'MESH:D014526', (77, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('UTB', 'Chemical', '-', (117, 120))	('Patients', 'Species', '9606', (0, 8))	('urothelial carcinoma', 'Disease', (77, 97))	('UTB', 'Var', (14, 17))	('UTB', 'Chemical', '-', (14, 17))
28028	24129236	In sub-population analysis of male and female patients separately, urinary TB remained an independent risk factor for developing urothelial carcinoma in both sexes, but the magnitude of association was higher among female patients than among male patients or the overall TB population (Table 6).	('urothelial carcinoma', 'Disease', 'MESH:D014526', (129, 149))	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (222, 230))	('urinary', 'Var', (67, 74))	('urothelial carcinoma', 'Disease', (129, 149))	('patients', 'Species', '9606', (247, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
28035	24129236	Delays in TB diagnosis and in the initiation of anti-TB treatment may increase the duration and severity of urinary tract inflammation and organ fibrosis, thus making the patient more vulnerable to urinary tract cancer.	('urinary tract cancer', 'Phenotype', 'HP:0010786', (198, 218))	('inflammation', 'biological_process', 'GO:0006954', ('122', '134'))	('increase', 'PosReg', (70, 78))	('patient', 'Species', '9606', (171, 178))	('urinary tract inflammation', 'Disease', 'MESH:D014570', (108, 134))	('men', 'Species', '9606', (61, 64))	('fibrosis', 'Disease', 'MESH:D005355', (145, 153))	('fibrosis', 'Disease', (145, 153))	('urinary tract cancer', 'Disease', (198, 218))	('Delays', 'Var', (0, 6))	('urinary tract cancer', 'Disease', 'MESH:D014571', (198, 218))	('urinary tract inflammation', 'Disease', (108, 134))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
28047	24129236	However, in the sub-population analyses restricted to female and male patients separately, urinary TB remained an independent risk factor for urothelial carcinoma among the female patients, the predominantly non-smoking population, with a hazard ratio higher than that of male patients and the overall TB population.	('patients', 'Species', '9606', (70, 78))	('urothelial carcinoma', 'Disease', (142, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('patients', 'Species', '9606', (277, 285))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (142, 162))	('urinary', 'Var', (91, 98))	('patients', 'Species', '9606', (180, 188))
28060	24129236	Such infections have been reported to cause aggressive urinary bladder urothelial carcinomas with adenocarcinomatous or micropapillary differentiation.	('adenocarcinomatous', 'Disease', 'None', (98, 116))	('adenocarcinomatous', 'Disease', (98, 116))	('aggressive urinary bladder urothelial carcinomas', 'Disease', 'MESH:D001749', (44, 92))	('cause', 'Reg', (38, 43))	('aggressive urinary bladder urothelial carcinomas', 'Disease', (44, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('infections', 'Var', (5, 15))
28065	24129236	The Aristolochia acts as a common confounding factor for ESRD and urothelial carcinoma.	('urothelial carcinoma', 'Disease', (66, 86))	('ESRD', 'Disease', 'MESH:D007676', (57, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (66, 86))	('Aristolochia', 'Var', (4, 16))	('ESRD', 'Disease', (57, 61))
28071	24129236	Urinary TB poses a high risk of developing urothelial carcinoma even after adjusting for other known risk factors such as age, sex, ESRD, obstructive uropathy, and arsenic intoxication.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (43, 63))	('arsenic intoxication', 'Disease', (164, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('urothelial carcinoma', 'Disease', (43, 63))	('ESRD', 'Disease', (132, 136))	('obstructive uropathy', 'Disease', (138, 158))	('developing', 'PosReg', (32, 42))	('obstructive uropathy', 'Disease', 'MESH:C536483', (138, 158))	('arsenic intoxication', 'Disease', 'MESH:D014869', (164, 184))	('Urinary', 'Var', (0, 7))	('ESRD', 'Disease', 'MESH:D007676', (132, 136))
28087	34020650	In our study, VWCE expression was associated with a better prognosis and was immune infiltration in breast cancer.	('VWCE expression', 'Var', (14, 29))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('better', 'PosReg', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('VWCE', 'Chemical', '-', (14, 18))
28116	34020650	We analyzed the expression level of VWCE based on various classification parameters, such as the estrogen receptor (ER) and progesterone receptor (PR) expression, human epidermal growth factor receptor-2 (HER2) status (ER+ /ER-, PR+ /PR-, and HER2+ /HER2-), nodal status (N+ /N-), age (Y21-40, Y40-70, and Y70-97), and subtypes (basal-like, HER2-E, luminal A, luminal B, and normal basal-like).	('ER', 'Gene', '2099', (224, 226))	('human epidermal growth factor receptor-2', 'Gene', '2064', (163, 203))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('169', '192'))	('HER2', 'Gene', (243, 247))	('estrogen receptor', 'Gene', '2099', (97, 114))	('nodal', 'Gene', (258, 263))	('nodal', 'Gene', '4838', (258, 263))	('ER', 'Gene', '2099', (206, 208))	('HER2', 'Gene', '2064', (341, 345))	('VWCE', 'Chemical', '-', (36, 40))	('HER2', 'Gene', '2064', (205, 209))	('HER2', 'Gene', (250, 254))	('PR', 'Gene', '5241', (229, 231))	('ER', 'Gene', '2099', (116, 118))	('ER', 'Gene', '2099', (219, 221))	('ER', 'Gene', '2099', (251, 253))	('ER', 'Gene', '2099', (244, 246))	('luminal', 'Chemical', 'MESH:D010634', (360, 367))	('Y70-97', 'Var', (306, 312))	('estrogen receptor', 'Gene', (97, 114))	('HER2', 'Gene', '2064', (243, 247))	('luminal', 'Chemical', 'MESH:D010634', (349, 356))	('HER2', 'Gene', (341, 345))	('Y40-70', 'Var', (294, 300))	('PR', 'Gene', '5241', (147, 149))	('PR', 'Gene', '5241', (234, 236))	('progesterone receptor', 'Gene', (124, 145))	('progesterone receptor', 'Gene', '5241', (124, 145))	('HER2', 'Gene', (205, 209))	('human epidermal growth factor receptor-2', 'Gene', (163, 203))	('HER2', 'Gene', '2064', (250, 254))	('ER', 'Gene', '2099', (342, 344))
28156	34020650	GO analysis results demonstrated that the biological processes of these proteins were mainly involved in positive regulation of pathway-restricted SMAD protein phosphorylation (GO: 0010862), positive regulation of bone mineralization (GO: 0030501), and regulation of pathway-restricted SMAD protein phosphorylation (GO: 0060393).	('SMAD', 'Gene', (286, 290))	('bone mineralization', 'CPA', (214, 233))	('positive', 'PosReg', (105, 113))	('SMAD', 'Gene', '4086', (147, 151))	('pathway-restricted SMAD protein', 'molecular_function', 'GO:0030618', ('267', '298'))	('SMAD', 'Gene', '4086', (286, 290))	('regulation of pathway-restricted SMAD protein phosphorylation', 'biological_process', 'GO:0060393', ('253', '314'))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('GO: 0010862', 'Var', (177, 188))	('SMAD', 'Gene', (147, 151))	('pathway-restricted SMAD protein', 'molecular_function', 'GO:0030618', ('128', '159'))	('positive regulation of bone mineralization', 'biological_process', 'GO:0030501', ('191', '233'))	('pathway-restricted', 'Pathway', (128, 146))	('positive regulation of pathway-restricted SMAD protein phosphorylation', 'biological_process', 'GO:0010862', ('105', '175'))	('GO: 0030501', 'Var', (235, 246))	('protein', 'cellular_component', 'GO:0003675', ('291', '298'))
28157	34020650	Molecular function (MF) were mainly enhanced in BMP receptor binding (GO: 0070700), BMP receptor activity (GO: 0098821), and transmembrane receptor protein serine/threonine kinase binding (GO: 0070696).	('GO: 0098821', 'Var', (107, 118))	('BMP receptor activity', 'molecular_function', 'GO:0098821', ('84', '105'))	('Molecular function', 'molecular_function', 'GO:0003674', ('0', '18'))	('BMP receptor binding', 'molecular_function', 'GO:0070700', ('48', '68'))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('BMP', 'Gene', (48, 51))	('BMP', 'Gene', '649', (84, 87))	('transmembrane', 'cellular_component', 'GO:0044214', ('125', '138'))	('BMP', 'Gene', (84, 87))	('transmembrane receptor protein serine/threonine kinase binding', 'molecular_function', 'GO:0070696', ('125', '187'))	('enhanced', 'PosReg', (36, 44))	('BMP', 'Gene', '649', (48, 51))	('serine', 'Chemical', 'MESH:D012694', (156, 162))	('GO: 0070700', 'Var', (70, 81))	('transmembrane', 'cellular_component', 'GO:0016021', ('125', '138'))	('Molecular function', 'CPA', (0, 18))
28158	34020650	Cell component was significantly enriched in the spanning component of the plasma membrane (GO: 0044214), HFE-transferrin receptor complex (GO: 1990712), and spanning component of membrane (GO: 0089717).	('HFE', 'Gene', '3077', (106, 109))	('plasma membrane', 'cellular_component', 'GO:0005886', ('75', '90'))	('HFE', 'Gene', (106, 109))	('HFE-transferrin receptor complex', 'cellular_component', 'GO:1990712', ('106', '138'))	('GO: 0044214', 'Var', (92, 103))	('spanning component of membrane', 'cellular_component', 'GO:0089717', ('158', '188'))
28161	34020650	Among them, the variant types of VWCE, RANBP3, and ZNF114 are missense mutations and frame-shift-Del.	('ZNF114', 'Gene', '163071', (51, 57))	('ZNF114', 'Gene', (51, 57))	('frame-shift-Del', 'Var', (85, 100))	('VWCE', 'Chemical', '-', (33, 37))	('missense mutations', 'Var', (62, 80))	('RANBP3', 'Gene', (39, 45))	('RANBP3', 'Gene', '8498', (39, 45))
28162	34020650	Thus, these data indicate that VWCE mutations are associated with its expression.	('VWCE', 'Chemical', '-', (31, 35))	('expression', 'MPA', (70, 80))	('VWCE', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))
28165	34020650	However, the EMT pathway mainly is activated by TWSG1, THSD1, and GDF5 expression.	('TWSG1', 'Gene', (48, 53))	('EMT', 'Gene', '3702', (13, 16))	('TWSG1', 'Gene', '57045', (48, 53))	('EMT', 'biological_process', 'GO:0001837', ('13', '16'))	('GDF5', 'Gene', '8200', (66, 70))	('GDF5', 'Gene', (66, 70))	('THSD1', 'Gene', (55, 60))	('expression', 'Var', (71, 81))	('activated', 'PosReg', (35, 44))	('EMT', 'Gene', (13, 16))	('THSD1', 'Gene', '55901', (55, 60))
28168	34020650	6a, the high expression of VWCE was associated with better prognosis (HR = 0.67, p = 0.015).	('high expression', 'Var', (8, 23))	('VWCE', 'Protein', (27, 31))	('VWCE', 'Chemical', '-', (27, 31))
28171	34020650	SCNA module provides the comparison of tumor infiltration levels among tumors with different somatic copy number alterations for a given gene.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('copy number alterations', 'Var', (101, 124))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', (39, 44))	('tumors', 'Disease', (71, 77))	('tumor', 'Disease', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
28229	34020650	Notably, we found VWCE expression mainly inhibited the apoptosis pathway.	('apoptosis pathway', 'Pathway', (55, 72))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('VWCE', 'Var', (18, 22))	('inhibited', 'NegReg', (41, 50))	('VWCE', 'Chemical', '-', (18, 22))
28236	34020650	Therefore, we hypothesized that VWCE expression is associated with immune infiltration in breast cancer, and is a potential marker of the tumor immune microenvironment.	('immune infiltration', 'CPA', (67, 86))	('tumor', 'Disease', (138, 143))	('VWCE', 'Chemical', '-', (32, 36))	('VWCE expression', 'Var', (32, 47))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('associated', 'Reg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
28250	34020650	High serum TGFbeta1 level predicts better survival in breast cancer.	('breast cancer', 'Disease', (54, 67))	('High', 'Var', (0, 4))	('survival', 'CPA', (42, 50))	('better', 'PosReg', (35, 41))	('TGFbeta1', 'Gene', '7040', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('TGFbeta1', 'Gene', (11, 19))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('High serum TGFbeta1', 'Phenotype', 'HP:0030269', (0, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
28289	32030476	One of the central methods through which tumors resist elimination by endogenous tumor-specific T cells is upregulation of PD-L1 expression, since PD-L1 suppresses T-cell migration/proliferation and also restricts cancer cell killing by prevention of binding to T-cell receptors.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('binding', 'Interaction', (251, 258))	('tumors', 'Disease', (41, 47))	('cell killing', 'biological_process', 'GO:0001906', ('221', '233'))	('T-cell migration', 'biological_process', 'GO:0072678', ('164', '180'))	('binding', 'molecular_function', 'GO:0005488', ('251', '258'))	('suppresses', 'NegReg', (153, 163))	('cancer', 'Disease', (214, 220))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('restricts', 'NegReg', (204, 213))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('T-cell migration/proliferation', 'CPA', (164, 194))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('upregulation', 'PosReg', (107, 119))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('T-cell', 'Protein', (262, 268))	('PD-L1', 'Gene', (123, 128))	('PD-L1', 'Var', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
28293	32030476	Several recent clinical trials that targeted the PD-1/PD-L1 pathway using anti-PD-1 or anti-PD-L1 antibodies have demonstrated the benefit of such treatments for patients with advanced UC, with these agents subsequently being approved by the Food and Drug Administration in the United States.	('patients', 'Species', '9606', (162, 170))	('anti-PD-L1', 'Var', (87, 97))	('PD-1', 'Gene', (49, 53))	('advanced UC', 'Disease', (176, 187))	('PD-1', 'Gene', '5133', (49, 53))	('men', 'Species', '9606', (152, 155))	('PD-1', 'Gene', (79, 83))	('PD-1', 'Gene', '5133', (79, 83))
28325	32030476	, i.e., type I (high PD-L1 expression and high TILD), type II (low PD-L1 expression and low TILD), type III (high PD-L1 expression and low TILD), and type IV (low PD-L1 expression and high TILD).	('PD-L1', 'Gene', (114, 119))	('TIL', 'Gene', '7096', (189, 192))	('expression', 'MPA', (120, 130))	('high', 'Var', (109, 113))	('TIL', 'Gene', (139, 142))	('TIL', 'Gene', (92, 95))	('high', 'Var', (16, 20))	('PD-L1', 'Gene', (67, 72))	('TIL', 'Gene', (47, 50))	('TIL', 'Gene', (189, 192))	('PD-L1', 'Gene', (21, 26))	('low', 'NegReg', (63, 66))	('TIL', 'Gene', '7096', (139, 142))	('TIL', 'Gene', '7096', (47, 50))	('TIL', 'Gene', '7096', (92, 95))
28356	32030476	In addition, it has been reported that UC of the bladder (BUC) patients with high PD-L1 expression tends to have advanced cancer and a poor prognosis, but there have been conflicting reports that high PD-L1 expression is associated with a better prognosis.	('PD-L1', 'Gene', (82, 87))	('high', 'Var', (77, 81))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('patients', 'Species', '9606', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
28379	32030476	These changes could trigger immunosuppression as a result of crosstalk between tumor cells and TIICs in the tumor microenvironment, because PD-L1 suppresses T-cell migration/proliferation and also prevents cancer cell killing by binding to T-cell receptors.	('prevents', 'NegReg', (197, 205))	('tumor', 'Disease', (108, 113))	('T-cell migration', 'biological_process', 'GO:0072678', ('157', '173'))	('cell killing', 'biological_process', 'GO:0001906', ('213', '225'))	('suppresses', 'NegReg', (146, 156))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('T-cell migration/proliferation', 'CPA', (157, 187))	('cancer', 'Disease', (206, 212))	('T-cell', 'Protein', (240, 246))	('tumor', 'Disease', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PD-L1', 'Var', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('men', 'Species', '9606', (126, 129))	('binding', 'molecular_function', 'GO:0005488', ('229', '236'))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('binding', 'Interaction', (229, 236))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
28389	32030476	During the development of adaptive immune resistance, macrophages are activated by interferons and kill tumor cells, but the same macrophages may also protect the tumor against attack from infiltrating T cells by expressing inhibitory PD-L1.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('men', 'Species', '9606', (18, 21))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('PD-L1', 'Protein', (235, 240))	('tumor', 'Disease', (163, 168))	('inhibitory', 'Var', (224, 234))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
28406	32030476	It is generally thought that the effects of immunotherapy depend on the following three factors: (1) elevated expression of PD-L1 by tumor cells; (2) a higher tumor mutational burden associated with targeting by mutation-associated neoantigen-specific T cells, and (3) greater tumor infiltration by TILs.	('PD-L1', 'Gene', (124, 129))	('higher', 'PosReg', (152, 158))	('elevated', 'PosReg', (101, 109))	('TIL', 'Gene', '7096', (299, 302))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('expression', 'MPA', (110, 120))	('tumor', 'Disease', (133, 138))	('TIL', 'Gene', (299, 302))	('tumor', 'Disease', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('mutation-associated', 'Var', (212, 231))
28455	30719143	In subgroup analyses by race, high pretreatment fibrinogen levels predicted worse OS in both Asian (fixed effect model, pooled HR=2.07, 95% CI=1.73-2.49, P<0.001) and Caucasian (random effect model, pooled HR=2.52, 95% CI=1.93-3.25, P<0.001) populations (Fig 2C).	('fibrinogen', 'cellular_component', 'GO:0005577', ('48', '58'))	('fibrinogen', 'molecular_function', 'GO:0008001', ('48', '58'))	('high', 'Var', (30, 34))	('OS', 'Chemical', '-', (82, 84))	('high pretreatment fibrinogen levels', 'Phenotype', 'HP:0011899', (30, 65))	('fibrinogen', 'Gene', '2244', (48, 58))	('fibrinogen', 'Gene', (48, 58))
28457	30719143	Subgroup analyses by tumor type showed that high pretreatment fibrinogen levels were associated with reduced CSS in PCa (fixed effect model, pooled HR=2.42, 95% CI=1.44-4.07, P=0.001), RCC (fixed effect model, pooled HR=2.99, 95% CI=2.29-3.89, P<0.001) and UTUC (fixed effect model, pooled HR=2.43, 95% CI=1.84-3.20, P<0.001) patients (Fig 3B, Table 3).	('RCC', 'Disease', (185, 188))	('high', 'Var', (44, 48))	('RCC', 'Disease', 'MESH:C538614', (185, 188))	('tumor', 'Disease', (21, 26))	('PCa', 'Disease', (116, 119))	('CSS', 'Disease', (109, 112))	('patients', 'Species', '9606', (326, 334))	('reduced', 'NegReg', (101, 108))	('fibrinogen', 'cellular_component', 'GO:0005577', ('62', '72'))	('CSS', 'Chemical', '-', (109, 112))	('fibrinogen', 'molecular_function', 'GO:0008001', ('62', '72'))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('high pretreatment fibrinogen levels', 'Phenotype', 'HP:0011899', (44, 79))	('fibrinogen', 'Gene', '2244', (62, 72))	('fibrinogen', 'Gene', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
28476	30719143	Fibrinogen is also a critical determinant of tumor growth with plasminogen in the tumor microenvironment and can increase the metastatic potential of malignant tumors.	('malignant tumors', 'Disease', (150, 166))	('plasminogen', 'Var', (63, 74))	('Fibrinogen', 'Gene', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('malignant tumors', 'Disease', 'MESH:D018198', (150, 166))	('Fibrinogen', 'molecular_function', 'GO:0008001', ('0', '10'))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('Fibrinogen', 'Gene', '2244', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('increase', 'PosReg', (113, 121))	('Fibrinogen', 'cellular_component', 'GO:0005577', ('0', '10'))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
28477	30719143	suggested that fibrinogen deficiency reduced the incidence of spontaneous metastasis in aggressive tumors via both hematogenous and lymphatic routes.	('deficiency', 'Var', (26, 36))	('fibrinogen', 'Gene', '2244', (15, 25))	('fibrinogen', 'Gene', (15, 25))	('aggressive tumors', 'Disease', 'MESH:D001523', (88, 105))	('spontaneous metastasis', 'CPA', (62, 84))	('fibrinogen deficiency', 'Phenotype', 'HP:0011900', (15, 36))	('aggressive tumors', 'Disease', (88, 105))	('fibrinogen', 'cellular_component', 'GO:0005577', ('15', '25'))	('reduced', 'NegReg', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('fibrinogen', 'molecular_function', 'GO:0008001', ('15', '25'))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
28511	27883053	However, their DNA replication system malfunctions, often in cancer, and leaves de novo mutational signatures, furthermore copy number alterations (CNA) and loss of heterozygosity (LOH).	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('copy number alterations', 'Var', (123, 146))	('malfunctions', 'Reg', (38, 50))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('cancer', 'Disease', (61, 67))	('DNA replication', 'biological_process', 'GO:0006260', ('15', '30'))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('loss of', 'NegReg', (157, 164))
28576	27883053	We measured tITH of 11 time point data with first time point data (MCF10A), MCF10A-HRAS, XT1-XT8, M1 and M2, and compared with reported number of clones from original research (Fig.	('MCF10A', 'CellLine', 'CVCL:0598', (76, 82))	('MCF10A-HRAS', 'CellLine', 'CVCL:0598', (76, 87))	('MCF10A-HRAS', 'Var', (76, 87))	('XT1', 'Gene', (89, 92))	('MCF10A', 'CellLine', 'CVCL:0598', (67, 73))	('XT1', 'Gene', '64131', (89, 92))
28578	27883053	However, we observed the abrupt elevation of tITH between MCF10A-HRAS and XT1 (from 0.109 to 0.346).	('MCF10A-HRAS', 'Var', (58, 69))	('tITH', 'MPA', (45, 49))	('elevation', 'PosReg', (32, 41))	('XT1', 'Gene', (74, 77))	('XT1', 'Gene', '64131', (74, 77))	('MCF10A-HRAS', 'CellLine', 'CVCL:0598', (58, 69))
28580	27883053	The divergence of major clones occurred at MCF10A-HRAS   XT1, XT2   XT3, XT5   XT6, and XT8   M. tITH values steadily increased as the number of subclones increased (Fig.	('MCF10A-HRAS', 'Var', (43, 54))	('increased', 'PosReg', (118, 127))	('XT1', 'Gene', (57, 60))	('XT1', 'Gene', '64131', (57, 60))	('MCF10A-HRAS', 'CellLine', 'CVCL:0598', (43, 54))
28581	27883053	tITH increased at MCF10A-HRAS   XT1 (from 0.109 to 0.346), XT2   XT3 (from 0.349 to 0.350), XT5   XT6 (from 0.349 to 0.356) and XT8   M (from 0.358 to 0.384 at M1, and 0.371 at M2).	('XT1', 'Gene', (32, 35))	('MCF10A-HRAS', 'CellLine', 'CVCL:0598', (18, 29))	('XT1', 'Gene', '64131', (32, 35))	('increased', 'PosReg', (5, 14))	('XT8   M', 'Var', (128, 135))
28586	27883053	Cell cycle and central dogma related pathways such as Parkinson's disease, Ribosome, mRNA surveillance pathway, Cell cycle, and DNA replication were at the top of the positively correlated pathway list in HRAS mutated cell lines (Fig.	('mutated', 'Var', (210, 217))	('HRAS', 'Gene', '3265', (205, 209))	("Parkinson's disease", 'Disease', (54, 73))	('Ribosome', 'cellular_component', 'GO:0005840', ('75', '83'))	('DNA replication', 'biological_process', 'GO:0006260', ('128', '143'))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	("Parkinson's disease", 'Disease', 'MESH:D010300', (54, 73))	('mRNA surveillance pathway', 'Pathway', (85, 110))	('HRAS', 'Gene', (205, 209))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('Ribosome', 'Pathway', (75, 83))	('Cell cycle', 'biological_process', 'GO:0007049', ('112', '122'))
28587	27883053	This finding was confirmed in a study that reports the central dogma and cell cycle related pathways became more heterogeneous as the mutated HRAS activated MAP kinase cascades downstream and effects on transcriptional control and cell growth.	('MAP', 'molecular_function', 'GO:0004239', ('157', '160'))	('HRAS', 'Gene', '3265', (142, 146))	('transcriptional', 'MPA', (203, 218))	('MAP kinase cascades downstream', 'Pathway', (157, 187))	('cell cycle', 'biological_process', 'GO:0007049', ('73', '83'))	('HRAS', 'Gene', (142, 146))	('mutated', 'Var', (134, 141))	('transcriptional control', 'biological_process', 'GO:0006355', ('203', '226'))	('cell growth', 'biological_process', 'GO:0016049', ('231', '242'))	('activated', 'PosReg', (147, 156))	('effects', 'Reg', (192, 199))	('cell cycle related pathways', 'Pathway', (73, 100))
28596	27883053	In the original study, missense mutations on RAD54B and PMS1 were reported, and they were connected by direct edges to Fanconni anemia pathway in STRING PIN (PMS1-FAN1 and RAD51-RAD54B).	('RAD', 'biological_process', 'GO:1990116', ('45', '48'))	('RAD54B', 'Gene', (45, 51))	('FAN1', 'Gene', (163, 167))	('PMS1', 'Gene', (56, 60))	('PMS1', 'Gene', '5378', (56, 60))	('anemia', 'Phenotype', 'HP:0001903', (128, 134))	('Fanconni anemia', 'Disease', (119, 134))	('RAD', 'biological_process', 'GO:1990116', ('178', '181'))	('PMS1', 'Gene', (158, 162))	('missense mutations', 'Var', (23, 41))	('RAD54B', 'Gene', (178, 184))	('PMS1', 'Gene', '5378', (158, 162))	('FAN1', 'Gene', '22909', (163, 167))	('PIN', 'Gene', (153, 156))	('Fanconni anemia', 'Disease', 'MESH:D000740', (119, 134))	('RAD54B', 'Gene', '25788', (45, 51))	('RAD51', 'Gene', (172, 177))	('RAD', 'biological_process', 'GO:1990116', ('172', '175'))	('RAD51', 'Gene', '5888', (172, 177))	('PIN', 'Gene', '8655', (153, 156))	('RAD54B', 'Gene', '25788', (178, 184))
28675	31514337	However, significantly increased TGFBI was predominantly found in muscle invasive (14,411.7 pg/mg creatinine), high-grade (8190.7 pg/mg) and de novo UC (1856.7 pg/mg; all p < 0.0001).	('TGFBI', 'Gene', '7045', (33, 38))	('TGFBI', 'Gene', (33, 38))	('muscle invasive', 'Disease', (66, 81))	('8190.7', 'Var', (123, 129))	('increased', 'PosReg', (23, 32))	('1856.7', 'Var', (153, 159))	('creatinine', 'Chemical', 'MESH:D003404', (98, 108))
28732	31514337	Therefore, we investigated the role of TGFBI on tumor cell proliferation by siRNA mediated gene silencing of TGFBI.	('TGFBI', 'Gene', '7045', (39, 44))	('tumor', 'Disease', (48, 53))	('TGFBI', 'Gene', (39, 44))	('gene silencing', 'Var', (91, 105))	('TGFBI', 'Gene', '7045', (109, 114))	('investigated', 'Reg', (14, 26))	('TGFBI', 'Gene', (109, 114))	('cell proliferation', 'biological_process', 'GO:0008283', ('54', '72'))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('gene silencing', 'biological_process', 'GO:0016458', ('91', '105'))	('rat', 'Species', '10116', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
28738	31514337	Knockdown of TGFBI resulted in a significant decrease of TGFBI concentration in the cell supernatant in comparison to negative control (Figure 5B).	('TGFBI', 'Gene', '7045', (57, 62))	('rat', 'Species', '10116', (70, 73))	('Knockdown', 'Var', (0, 9))	('TGFBI', 'Gene', (57, 62))	('TGFBI', 'Gene', '7045', (13, 18))	('decrease', 'NegReg', (45, 53))	('TGFBI', 'Gene', (13, 18))
28740	31514337	On day 4 (96 h) TGFBI-siRNA transfected cells significantly increased their G1 and G2/M phase populations by 19.9% (p = 0.0273) and 7.6% (p <= 0.0066) compared to negative control.	('TGFBI', 'Gene', '7045', (16, 21))	('transfected', 'Var', (28, 39))	('TGFBI', 'Gene', (16, 21))	('M phase', 'biological_process', 'GO:0000279', ('86', '93'))	('increased', 'PosReg', (60, 69))
28742	31514337	Together, these results indicate that TGFBI-deficient 5637 bladder cancer cells have a disrupted cell cycle with, most likely, erroneous G1/S transitioning and S phase regulation.	('bladder cancer', 'Phenotype', 'HP:0009725', (59, 73))	('cell cycle', 'biological_process', 'GO:0007049', ('97', '107'))	('disrupted', 'Reg', (87, 96))	('TGFBI', 'Gene', '7045', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('S phase', 'biological_process', 'GO:0051320', ('160', '167'))	('bladder cancer', 'Disease', 'MESH:D001749', (59, 73))	('TGFBI', 'Gene', (38, 43))	('erroneous', 'Var', (127, 136))	('cell cycle', 'CPA', (97, 107))	('S phase regulation', 'CPA', (160, 178))	('regulation', 'biological_process', 'GO:0065007', ('168', '178'))	('bladder cancer', 'Disease', (59, 73))
28793	31514337	The silencing of TGFBI in glioma and gastrointestinal cancer decreased local tumor growth and metastasis.	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (37, 60))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TGFBI', 'Gene', '7045', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('TGFBI', 'Gene', (17, 22))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('silencing', 'Var', (4, 13))	('glioma and gastrointestinal cancer decreased local tumor', 'Disease', 'MESH:D005770', (26, 82))
28880	30208947	Molecular testing of the primary tumor using a targeted next-generation sequencing assay (SNaPshot V1) revealed a single nucleotide variant in TP53 (Arg282Trp).	('TP53', 'Gene', (143, 147))	('primary tumor', 'Disease', (25, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('primary tumor', 'Disease', 'MESH:D009369', (25, 38))	('TP53', 'Gene', '7157', (143, 147))	('Arg282Trp', 'Var', (149, 158))	('Arg282Trp', 'SUBSTITUTION', 'None', (149, 158))
28923	29259653	One of these tests is fluorescence - in situ hybridization (UroVyison ) for the detection of chromosomal aberrations; loss of the 9p21 locus, which is the site of the p16 tumor suppressor gene, has been identified as a common chromosomal aberration in patients with UC.	('chromosomal aberration', 'Phenotype', 'HP:0040012', (93, 115))	('patients', 'Species', '9606', (252, 260))	('p16', 'Gene', (167, 170))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('loss', 'Var', (118, 122))	('9p21', 'Gene', (130, 134))	('p16', 'Gene', '1029', (167, 170))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (226, 248))	('tumor suppressor', 'biological_process', 'GO:0051726', ('171', '187'))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (93, 116))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('171', '187'))
28932	29259653	CK20 is normally expressed only in umbrella cells, and dysregulation of CK20 is an early event of carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (98, 112))	('carcinogenesis', 'Disease', (98, 112))	('CK20', 'Gene', '54474', (0, 4))	('CK20', 'Gene', (72, 76))	('CK20', 'Gene', '54474', (72, 76))	('dysregulation', 'Var', (55, 68))	('CK20', 'Gene', (0, 4))
28933	29259653	Abnormal expression beyond superficial layers has been used as a marker for the diagnosis of urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (93, 113))	('Abnormal', 'Var', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('urothelial carcinoma', 'Disease', (93, 113))
28935	29259653	Mutation of the p53 gene prolongs the half-life of the protein resulting in nuclear p53 accumulation, which is detectable by immunohistochemistry.	('p53', 'Gene', (16, 19))	('Mutation', 'Var', (0, 8))	('p53', 'Gene', '7157', (16, 19))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('prolongs', 'PosReg', (25, 33))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('accumulation', 'PosReg', (88, 100))	('half-life of the protein', 'MPA', (38, 62))
28973	28978023	Here, we investigated 11 mucin expressing cancers for DNA mutations, mRNA expression, copy number, methylation, and the impacts these genomic features may have on patient survival by utilizing The Cancer Genome Atlas dataset.	('cancers', 'Disease', (42, 49))	('mutations', 'Var', (58, 67))	('Cancer', 'Disease', (197, 203))	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('mucin', 'Gene', '100508689', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Cancer', 'Disease', 'MESH:D009369', (197, 203))	('methylation', 'biological_process', 'GO:0032259', ('99', '110'))	('mucin', 'Gene', (25, 30))	('patient', 'Species', '9606', (163, 170))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))
28974	28978023	We demonstrate that mucin DNA mutations have a significant rate, pattern, and impact on cancer patient survival depending on the tissue of origin.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patient', 'Species', '9606', (95, 102))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('impact', 'Reg', (78, 84))	('mucin', 'Gene', (20, 25))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mucin', 'Gene', '100508689', (20, 25))
28975	28978023	This includes a frequent T112P mutation in MUC1 that is seen in half of the pancreatic MUC1 mutations, as well as being present in other cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('T112P', 'Mutation', 'rs753286956', (25, 30))	('pancreatic', 'Disease', (76, 86))	('MUC1', 'Gene', (43, 47))	('mutations', 'Var', (92, 101))	('MUC1', 'Gene', '4582', (43, 47))	('T112P', 'Var', (25, 30))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('MUC1', 'Gene', (87, 91))	('MUC1', 'Gene', '4582', (87, 91))	('pancreatic', 'Disease', 'MESH:D010195', (76, 86))
28981	28978023	Thus, our study presents a comprehensive analysis of genomic alterations in mucins and their corresponding roles in cancer progression.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('mucin', 'Gene', '100508689', (76, 81))	('genomic alterations', 'Var', (53, 72))	('roles', 'Reg', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('mucin', 'Gene', (76, 81))
29014	28978023	Hence, we undertook a pan-mucin genomic study across multiple cancers to investigate potential new avenues and to discover new alterations that may impact the mucin functions in cancers.	('impact', 'Reg', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mucin', 'Gene', (26, 31))	('mucin', 'Gene', '100508689', (159, 164))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('multiple cancers', 'Disease', (53, 69))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('alterations', 'Var', (127, 138))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('mucin', 'Gene', (159, 164))	('mucin', 'Gene', '100508689', (26, 31))	('cancers', 'Disease', (62, 69))	('multiple cancers', 'Disease', 'MESH:D009369', (53, 69))
29018	28978023	The rate of mutations varies from mucin to mucin depending on the histological cohort (Figures 1A, 1B, and Supplementary Dataset 1).	('mucin', 'Gene', (43, 48))	('mutations', 'Var', (12, 21))	('mucin', 'Gene', (34, 39))	('mucin', 'Gene', '100508689', (43, 48))	('mucin', 'Gene', '100508689', (34, 39))
29019	28978023	Kidney papillary cell carcinoma (KIRP) shows the largest relative mutation rate for MUC2, while no other histological subtypes appear to favor MUC2 mutations to a similar degree (Figure 1C).	('MUC2', 'Gene', (143, 147))	('Kidney papillary cell carcinoma', 'Disease', (0, 31))	('mutations', 'Var', (148, 157))	('MUC2', 'Gene', '4583', (143, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('mutation', 'Var', (66, 74))	('MUC2', 'Gene', (84, 88))	('MUC2', 'Gene', '4583', (84, 88))	('Kidney papillary cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))
29021	28978023	Like KIRP, kidney clear cell carcinoma (KIRC) trends with lower rate of mucin mutations, except for MUC4, which shows a cluster of in-frame deletions for KIRC (Figure 1D).	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('MUC4', 'Gene', (100, 104))	('mucin', 'Gene', '100508689', (72, 77))	('mutations', 'Var', (78, 87))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (11, 38))	('mucin', 'Gene', (72, 77))	('MUC4', 'Gene', '4585', (100, 104))	('kidney clear cell carcinoma', 'Disease', (11, 38))
29022	28978023	Uterine corpus endometrioid endometrial adenocarcinoma (UEC) appears to acquire more mutations in multiple mucins, including MUC5B and MUC17, which becomes very prominent in stage III (Figures 1A, 1B, and Supplementary Dataset 1).	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (28, 54))	('mucin', 'Gene', '100508689', (107, 112))	('mutations', 'Var', (85, 94))	('endometrioid endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (15, 54))	('MUC5B', 'Gene', '727897', (125, 130))	('endometrioid endometrial adenocarcinoma', 'Disease', (15, 54))	('mucin', 'Gene', (107, 112))	('MUC5B', 'Gene', (125, 130))	('MUC17', 'Gene', '140453', (135, 140))	('MUC17', 'Gene', (135, 140))
29023	28978023	UEC tumors also have mutations in other mucins, such as MUC4 and MUC16, however, the mutation rates are much lower (Figure 1D and 1E).	('MUC4', 'Gene', '4585', (56, 60))	('MUC16', 'Gene', '94025', (65, 70))	('mucin', 'Gene', (40, 45))	('UEC', 'Disease', (0, 3))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('MUC4', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mucin', 'Gene', '100508689', (40, 45))	('MUC16', 'Gene', (65, 70))	('mutations', 'Var', (21, 30))
29026	28978023	Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) share MUC16 and MUC17 mutations at a similar rate between the histological subtypes.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (40, 59))	('MUC16', 'Gene', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('MUC17', 'Gene', '140453', (83, 88))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 28))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (0, 28))	('MUC16', 'Gene', '94025', (73, 78))	('lung adenocarcinoma', 'Disease', (40, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('mutations', 'Var', (89, 98))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (40, 59))	('squamous cell carcinoma', 'Disease', (5, 28))	('MUC17', 'Gene', (83, 88))	('LUSC', 'Phenotype', 'HP:0030359', (30, 34))	('LUAD', 'Phenotype', 'HP:0030078', (61, 65))
29027	28978023	Lastly, despite many cancers observed not to harbor mutations in MUC12 and MUC19, breast cancer appears to have a unique profile.	('mutations', 'Var', (52, 61))	('breast cancer', 'Disease', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('MUC12', 'Gene', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('MUC19', 'Gene', '283463', (75, 80))	('MUC12', 'Gene', '10071', (65, 70))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancers', 'Disease', (21, 28))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('MUC19', 'Gene', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
29028	28978023	Furthermore, location specific mutations may indicate a significant role of the residue or protein domain(s) in cancer pathogenesis.	('mutations', 'Var', (31, 40))	('pathogenesis', 'biological_process', 'GO:0009405', ('119', '131'))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('protein', 'Protein', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
29030	28978023	A total of five tissues were observed with MUC1 mutations (Supplementary Table 2).	('mutations', 'Var', (48, 57))	('MUC1', 'Gene', (43, 47))	('MUC1', 'Gene', '4582', (43, 47))
29031	28978023	Non-papillary bladder cancer, pancreatic ductal adenocarcinomas (PDAC), and stomach intestinal adenocarcinoma not otherwise specified (SIA NOS) were the only tissues that were observed to have MUC1 mutation(s) at stage II cancer (Figures 2A and Supplementary Table 2).	('II cancer', 'Disease', 'MESH:D009369', (219, 228))	('Non-papillary bladder cancer', 'Disease', (0, 28))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('II cancer', 'Disease', (219, 228))	('PDAC', 'Chemical', '-', (65, 69))	('MUC1', 'Gene', (193, 197))	('MUC1', 'Gene', '4582', (193, 197))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (30, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('pancreatic ductal adenocarcinomas', 'Disease', (30, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('stomach intestinal adenocarcinoma', 'Disease', 'MESH:D013274', (76, 109))	('mutation', 'Var', (198, 206))	('SIA', 'Disease', (135, 138))	('stomach intestinal adenocarcinoma', 'Disease', (76, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('SIA', 'Disease', 'None', (135, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (14, 28))	('Non-papillary bladder cancer', 'Disease', 'MESH:D001749', (0, 28))
29032	28978023	Half of stage II PDAC MUC1 mutations are T112P.	('mutations', 'Var', (27, 36))	('T112P', 'Mutation', 'rs753286956', (41, 46))	('MUC1', 'Gene', (22, 26))	('MUC1', 'Gene', '4582', (22, 26))	('T112P', 'Var', (41, 46))	('PDAC', 'Chemical', '-', (17, 21))
29033	28978023	Altogether, 5/8 of stage II MUC1 mutations are T112P and 31.25% of MUC1 mutations observed in all stages were T112P.	('MUC1', 'Gene', '4582', (28, 32))	('T112P', 'Var', (47, 52))	('T112P', 'Mutation', 'rs753286956', (110, 115))	('MUC1', 'Gene', (67, 71))	('MUC1', 'Gene', '4582', (67, 71))	('mutations', 'Var', (33, 42))	('T112P', 'Mutation', 'rs753286956', (47, 52))	('T112P', 'Var', (110, 115))	('MUC1', 'Gene', (28, 32))
29034	28978023	MUC2 mutations increase with the increasing disease stage in KIRP, appearing in 9.5% of stage I KIRP (n = 95) and up to 50% of stage IV KIRP cancers (n = 10).	('MUC2', 'Gene', (0, 4))	('MUC2', 'Gene', '4583', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (5, 14))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))	('stage I KIRP', 'Disease', (88, 100))
29035	28978023	MUC2 shows a large cluster of mutations with a Gaussian distribution across tissues with the mode at T1538 (Figure 2B).	('mutations', 'Var', (30, 39))	('T1538', 'Var', (101, 106))	('MUC2', 'Gene', (0, 4))	('MUC2', 'Gene', '4583', (0, 4))
29036	28978023	Many of the multiple mutations appear to target threonine and appear to include multiple silent mutations, perhaps suggesting a role of the region in regulating transcription, mRNA stability, or non-coding RNAs.	('threonine', 'MPA', (48, 57))	('transcription', 'MPA', (161, 174))	('threonine', 'Chemical', 'MESH:D013912', (48, 57))	('transcription', 'biological_process', 'GO:0006351', ('161', '174'))	('mRNA stability', 'MPA', (176, 190))	('target', 'Reg', (41, 47))	('mutations', 'Var', (21, 30))
29037	28978023	Amino acid changes observed in more than one patient in the cluster spanning from residues 1353-1652 target the threonine codon in over 85% of the cases.	('Amino acid changes', 'Var', (0, 18))	('target', 'Reg', (101, 107))	('threonine codon', 'MPA', (112, 127))	('patient', 'Species', '9606', (45, 52))	('threonine', 'Chemical', 'MESH:D013912', (112, 121))
29038	28978023	Within this dense cluster, three non-damaging T1488P mutations are observed in KIRP, while three T1568M mutations are observed once in KIRP, rectal adenocarcinoma (READ), and uterine endometrioid endometrial adenocarcinoma (UEC).	('EA', 'Chemical', '-', (165, 167))	('T1488P', 'Var', (46, 52))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (196, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('T1488P', 'Mutation', 'rs149562922', (46, 52))	('rectal adenocarcinoma', 'Disease', (141, 162))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (141, 162))	('endometrioid endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (183, 222))	('endometrioid endometrial adenocarcinoma', 'Disease', (183, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('T1568M', 'Mutation', 'rs78684063', (97, 103))
29039	28978023	UEC has a large percent of the MUC3A mutations with 11 out of the 35 of the mutations in MUC3A, of which, over a third of the UEC mutations occur at S207, with two in-frame insertions and one non-synonymous mutation (Supplementary Table 2 and Supplementary Dataset 2).	('MUC3A', 'Gene', '4584', (31, 36))	('UEC', 'Gene', (126, 129))	('MUC3A', 'Gene', (89, 94))	('mutations', 'Var', (130, 139))	('MUC3A', 'Gene', '4584', (89, 94))	('MUC3A', 'Gene', (31, 36))
29042	28978023	Furthermore, compared to silent mutations, non-damaging MUC4 mutations are drastically increased in KIRC, resulting in amino acid changing mutations to be 19.8% in stage I (n = 197), 35.0% in stage II (n = 40), 32.2% in stage III (n = 112), and 44.1% in stage IV (n = 68).	('MUC4', 'Gene', '4585', (56, 60))	('mutations', 'Var', (139, 148))	('mutations', 'Var', (61, 70))	('MUC4', 'Gene', (56, 60))	('amino acid changing', 'MPA', (119, 138))
29043	28978023	UEC also has an increased rate of non-damaging mutations for MUC4 that increase with the increasing stages, ultimately resulting in 41.4% single nucleotide variation (SNVs) mutations in stage III (n = 29) (Figure 1D).	('MUC4', 'Gene', (61, 65))	('single nucleotide variation', 'Var', (138, 165))	('mutations', 'Var', (47, 56))	('mutations', 'Var', (173, 182))	('MUC4', 'Gene', '4585', (61, 65))	('resulting in', 'Reg', (119, 131))
29044	28978023	This dataset reveals all 10 H4205Q MUC4 mutations occur as 10 G < C; half of which are from KIRC, three from bladder cancer, and two from LUAD (Figure 2C and Supplementary Table 2).	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('MUC4', 'Gene', '4585', (35, 39))	('LUAD', 'Phenotype', 'HP:0030078', (138, 142))	('bladder cancer', 'Disease', 'MESH:D001749', (109, 123))	('MUC4', 'Gene', (35, 39))	('bladder cancer', 'Disease', (109, 123))	('H4205Q', 'Mutation', 'rs369326402', (28, 34))	('H4205Q', 'Var', (28, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))
29045	28978023	In KIRC, high rates of in-frame deletions occur compared to other tissues for MUC4 (Figure 2C).	('MUC4', 'Gene', '4585', (78, 82))	('deletions', 'Var', (32, 41))	('MUC4', 'Gene', (78, 82))
29048	28978023	Lastly, multiple positions in MUC4 had at least two mutations at the same position, which overall suggests a role of mutations in MUC4, especially in KIRC.	('MUC4', 'Gene', (30, 34))	('mutations', 'Var', (117, 126))	('role', 'Reg', (109, 113))	('MUC4', 'Gene', '4585', (130, 134))	('MUC4', 'Gene', '4585', (30, 34))	('MUC4', 'Gene', (130, 134))
29051	28978023	MUC6 has a relatively high mutation rate in stage II PDAC, where 9.6% (n = 114) of the mutations caused amino acid changes, while no silent mutations were discovered.	('MUC6', 'Gene', '4588', (0, 4))	('caused', 'Reg', (97, 103))	('MUC6', 'Gene', (0, 4))	('amino', 'MPA', (104, 109))	('PDAC', 'Chemical', '-', (53, 57))	('mutations', 'Var', (87, 96))
29052	28978023	Furthermore, breast invasive carcinoma (BRCA) harbors three frameshift insertions at L2241, while KIRC has two at P1570.	('L2241', 'Var', (85, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('breast invasive carcinoma (BRCA', 'Gene', (13, 44))	('BRCA', 'Phenotype', 'HP:0003002', (40, 44))	('breast invasive carcinoma (BRCA)', 'Gene', '672', (13, 45))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (13, 38))
29054	28978023	Three of the seven non-damaging UEC stage I (n = 149) mutations were found to be S336L in MUC7.	('S336L', 'Var', (81, 86))	('S336L', 'Mutation', 'p.S336L', (81, 86))	('UEC stage I', 'Gene', (32, 43))	('MUC7', 'Gene', '4589', (90, 94))	('MUC7', 'Gene', (90, 94))
29056	28978023	A wide range of mutations in MUC12 have been found to associate with many BRCA histological subtypes as well as UEC.	('UEC', 'Disease', (112, 115))	('MUC12', 'Gene', (29, 34))	('MUC12', 'Gene', '10071', (29, 34))	('associate', 'Reg', (54, 63))	('mutations', 'Var', (16, 25))	('BRCA', 'Phenotype', 'HP:0003002', (74, 78))	('BRCA', 'Gene', '672', (74, 78))	('BRCA', 'Gene', (74, 78))
29057	28978023	Most striking is estrogen-receptor and progesterone-receptor-positive BRCA - stage II (n = 279) with 12.2% patient tumors having amino acid altering mutations.	('estrogen-receptor', 'Gene', (17, 34))	('BRCA', 'Phenotype', 'HP:0003002', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('BRCA', 'Gene', '672', (70, 74))	('tumors', 'Disease', (115, 121))	('patient', 'Species', '9606', (107, 114))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('BRCA', 'Gene', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('progesterone-receptor', 'Gene', '5241', (39, 60))	('amino acid altering mutations', 'Var', (129, 158))	('progesterone-receptor', 'Gene', (39, 60))	('estrogen-receptor', 'Gene', '2099', (17, 34))
29058	28978023	Most strikingly, multiple mutations appear to target arginine (R) in BRCA, where it is converted into either cysteine (C) or histidine (H).	('histidine', 'Chemical', 'MESH:D006639', (125, 134))	('BRCA', 'Phenotype', 'HP:0003002', (69, 73))	('target', 'Reg', (46, 52))	('BRCA', 'Gene', '672', (69, 73))	('arginine', 'Chemical', 'MESH:D001120', (53, 61))	('cysteine', 'MPA', (109, 117))	('arginine', 'MPA', (53, 61))	('BRCA', 'Gene', (69, 73))	('mutations', 'Var', (26, 35))	('cysteine', 'Chemical', 'MESH:D003545', (109, 117))
29060	28978023	Another event is seen at R2777 in BRCA, in which two mutations result in histidine and one becomes cysteine.	('BRCA', 'Gene', '672', (34, 38))	('BRCA', 'Gene', (34, 38))	('R2777', 'Var', (25, 30))	('cysteine', 'Chemical', 'MESH:D003545', (99, 107))	('histidine', 'MPA', (73, 82))	('result in', 'Reg', (63, 72))	('histidine', 'Chemical', 'MESH:D006639', (73, 82))	('BRCA', 'Phenotype', 'HP:0003002', (34, 38))
29061	28978023	Lastly, three A1933 frame shift insertions and three P4621T mutations and were observed in BRCA.	('BRCA', 'Gene', (91, 95))	('P4621T mutations', 'Var', (53, 69))	('A1933 frame shift', 'Var', (14, 31))	('BRCA', 'Phenotype', 'HP:0003002', (91, 95))	('P4621T', 'Mutation', 'p.P4621T', (53, 59))	('BRCA', 'Gene', '672', (91, 95))
29063	28978023	MUC16 is a very large transmembrane protein whose mutation rate is relatively high in colon adenocarcinoma (COAD) and colon mucinous adenocarcinoma (COMA) cancers, LUAD, bladder urothelial carcinoma (BLCA), PDAC, and UEC (Figure 1E).	('COMA', 'Phenotype', 'HP:0001259', (149, 153))	('LUAD', 'Disease', (164, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('colon mucinous adenocarcinoma (COMA) cancers', 'Disease', 'MESH:C537423', (118, 162))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (170, 198))	('BLCA', 'Chemical', '-', (200, 204))	('mutation', 'Var', (50, 58))	('PDAC', 'Disease', (207, 211))	('COAD', 'Disease', 'MESH:D029424', (108, 112))	('colon adenocarcinoma', 'Disease', (86, 106))	('MUC16', 'Gene', '94025', (0, 5))	('transmembrane', 'cellular_component', 'GO:0016021', ('22', '35'))	('UEC', 'Disease', (217, 220))	('high', 'Reg', (78, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('transmembrane', 'cellular_component', 'GO:0044214', ('22', '35'))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('COAD', 'Disease', (108, 112))	('PDAC', 'Chemical', '-', (207, 211))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('MUC16', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (86, 106))	('LUAD', 'Phenotype', 'HP:0030078', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('bladder urothelial carcinoma', 'Disease', (170, 198))
29064	28978023	Non-damaging nonsynonymous mutations occur in 62.5% of stage II COAD, which is 3.3-fold higher than silent mutations.	('nonsynonymous mutations', 'Var', (13, 36))	('COAD', 'Disease', (64, 68))	('COAD', 'Disease', 'MESH:D029424', (64, 68))
29067	28978023	LUAD shows a trend of increased nonsense mutations in MUC16.	('MUC16', 'Gene', '94025', (54, 59))	('nonsense mutations', 'Var', (32, 50))	('MUC16', 'Gene', (54, 59))	('LUAD', 'Phenotype', 'HP:0030078', (0, 4))
29068	28978023	In the case of PDAC, 43.0% of specimens have amino acid altering mutations, with 14.9% of these mutations resulting in frameshifts or deletions.	('deletions', 'Var', (134, 143))	('amino acid altering mutations', 'Var', (45, 74))	('frameshifts', 'MPA', (119, 130))	('PDAC', 'Chemical', '-', (15, 19))	('resulting', 'Reg', (106, 115))
29070	28978023	In other cancers, R8606 has four amino acid changing mutations (Supplementary Table 2).	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('R8606', 'Var', (18, 23))
29071	28978023	MUC20 mutations do not appear to be common, only three A515 frameshift deletions standout (Supplementary Table 2 and Supplementary Figure 1).	('A515 frameshift deletions', 'Var', (55, 80))	('MUC20', 'Gene', (0, 5))	('MUC20', 'Gene', '200958', (0, 5))
29072	28978023	MUC13 also has a very low mutation profile with three R324W SNVs and two S185 amino acid altering mutations predicted to be damaging.	('S185 amino acid altering', 'Var', (73, 97))	('R324W', 'Mutation', 'p.R324W', (54, 59))	('MUC13', 'Gene', '56667', (0, 5))	('R324W', 'Var', (54, 59))	('MUC13', 'Gene', (0, 5))
29074	28978023	Since half of the MUC1 mutations in stage II PDAC specimens had mutations at T112P in MUC1 (Figure 2A), we examined the mutational impact on survival in the cohort.	('MUC1', 'Gene', (86, 90))	('MUC1', 'Gene', '4582', (86, 90))	('PDAC', 'Chemical', '-', (45, 49))	('mutations', 'Var', (23, 32))	('mutations at T112P', 'Var', (64, 82))	('T112P', 'Mutation', 'rs753286956', (77, 82))	('MUC1', 'Gene', (18, 22))	('MUC1', 'Gene', '4582', (18, 22))
29077	28978023	Despite high occurrences, these mutations appear to improve survival of the patient in stage III KIRC (Figure 3B).	('survival', 'MPA', (60, 68))	('mutations', 'Var', (32, 41))	('improve', 'PosReg', (52, 59))	('patient', 'Species', '9606', (76, 83))
29078	28978023	Further examination of the impact of MUC4 mutations on patient survival highlights that not all mutations in a gene are potentially beneficial to the patient.	('patient', 'Species', '9606', (150, 157))	('MUC4', 'Gene', '4585', (37, 41))	('patient', 'Species', '9606', (55, 62))	('mutations', 'Var', (42, 51))	('MUC4', 'Gene', (37, 41))	('mutations', 'Var', (96, 105))
29079	28978023	A nearly significant (p = 0.0795) in-frame mutation at 4045 is associated with increased aggressive behavior of the tumor, while all other mutations appeared to have improved survival compared to patients without MUC4 mutations in KIRC stage I patients (Figure 3C).	('in-frame mutation at 4045', 'Var', (34, 59))	('increased', 'PosReg', (79, 88))	('aggressive behavior', 'biological_process', 'GO:0002118', ('89', '108'))	('survival', 'CPA', (175, 183))	('aggressive behavior', 'Disease', (89, 108))	('MUC4', 'Gene', (213, 217))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('aggressive behavior', 'Disease', 'MESH:D001523', (89, 108))	('patients', 'Species', '9606', (196, 204))	('improved', 'PosReg', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('aggressive behavior', 'Phenotype', 'HP:0000718', (89, 108))	('patients', 'Species', '9606', (244, 252))	('MUC4', 'Gene', '4585', (213, 217))	('tumor', 'Disease', (116, 121))
29109	28978023	Here we report frequent copy number gains in MUC1 and the locus 3q29 containing MUC4 and MUC20 (Figure 6A and 6B).	('copy number gains', 'Var', (24, 41))	('MUC4', 'Gene', '4585', (80, 84))	('MUC1', 'Gene', '4582', (45, 49))	('MUC4', 'Gene', (80, 84))	('MUC1', 'Gene', (45, 49))	('MUC20', 'Gene', (89, 94))	('MUC20', 'Gene', '200958', (89, 94))
29113	28978023	After adjusting for multiple hypothesis testing within each histology, only MUC1 in KIRP was found to significantly impact patient survival for both univariate (HR = 20.1; q = 5.8E-6) and multivariate (HR = 12.9; q = 0.01), indicating a possible negative role of MUC1 copy number increase in patient survival (Supplementary Table 5).	('MUC1', 'Gene', (76, 80))	('MUC1', 'Gene', '4582', (76, 80))	('impact', 'Reg', (116, 122))	('patient', 'Species', '9606', (123, 130))	('increase', 'PosReg', (280, 288))	('MUC1', 'Gene', (263, 267))	('patient', 'Species', '9606', (292, 299))	('MUC1', 'Gene', '4582', (263, 267))	('copy number', 'Var', (268, 279))	('patient survival', 'CPA', (123, 139))	('negative', 'NegReg', (246, 254))
29127	28978023	The MUC15 promoter methylation has strong impact on patient survival with LUAD; it was discovered to have a significant (q = 0.0001) astounding HR of 64.1 when corrected by a multiple regression analysis and a univariate HR of 30.2 (q = 0.0017) (Supplementary Table 6).	('methylation', 'Var', (19, 30))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('MUC15', 'Gene', (4, 9))	('impact', 'Reg', (42, 48))	('patient', 'Species', '9606', (52, 59))	('LUAD', 'Phenotype', 'HP:0030078', (74, 78))	('MUC15', 'Gene', '143662', (4, 9))
29130	28978023	To further understand the genomic significance of mucins, 37 histological subtypes across 12 cancers were examined for mutations, mRNA, copy number, methylation profile, de novo expression and silencing, and the impact on survival.	('methylation', 'biological_process', 'GO:0032259', ('149', '160'))	('cancers', 'Disease', (93, 100))	('mucin', 'Gene', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('expression', 'MPA', (178, 188))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mRNA', 'MPA', (130, 134))	('mucin', 'Gene', '100508689', (50, 55))	('silencing', 'MPA', (193, 202))	('mutations', 'Var', (119, 128))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
29135	28978023	MUC1 is overexpressed in more than 90% of breast carcinomas and we hereby report that copy number might play a significant role in this tissue, as copy gain was frequently seen in breast cancer (Figure 6A and 6B).	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (49, 59))	('breast carcinomas', 'Disease', 'MESH:D001943', (42, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('breast carcinomas', 'Disease', (42, 59))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('copy', 'Var', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', (180, 193))	('breast carcinomas', 'Phenotype', 'HP:0003002', (42, 59))	('MUC1', 'Gene', (0, 4))	('MUC1', 'Gene', '4582', (0, 4))
29136	28978023	These observations are further supported by a significant correlation of MUC1 mRNA in breast cancer with copy number (q = 3.65E-09) (Supplementary Table 7), but not with methylation (Supplementary Table 8), after correcting for multiple hypotheses.	('MUC1', 'Gene', (73, 77))	('MUC1', 'Gene', '4582', (73, 77))	('methylation', 'biological_process', 'GO:0032259', ('170', '181'))	('correlation', 'Interaction', (58, 69))	('copy number', 'Var', (105, 116))	('mRNA', 'Var', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))
29137	28978023	Furthermore, we report that only a few cancer subtypes carry MUC1 mutations, where extracellular region point mutation T112P was commonly seen and responsible for 50% of the MUC1 mutations observed in PDAC (Figure 1 and Supplementary Table 2).	('mutations', 'Var', (66, 75))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('extracellular region', 'cellular_component', 'GO:0005576', ('83', '103'))	('MUC1', 'Gene', (61, 65))	('PDAC', 'Chemical', '-', (201, 205))	('MUC1', 'Gene', '4582', (61, 65))	('MUC1', 'Gene', (174, 178))	('MUC1', 'Gene', '4582', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutations', 'Var', (179, 188))	('T112P', 'Mutation', 'rs753286956', (119, 124))
29139	28978023	However, the only cohort with enough mutations to test survival was in stage II PDAC, in which the corresponding patients were too newly enrolled to obtain any meaningful statistics for survival comparisons (Figure 3A).	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (113, 121))	('PDAC', 'Disease', (80, 84))	('PDAC', 'Chemical', '-', (80, 84))
29144	28978023	Furthermore, MUC2 is seen to have a Gaussian distribution of mutations around T1538 (Figure 2B), many of which are threonine, a key component for glycosylation.	('MUC2', 'Gene', (13, 17))	('T1538', 'Gene', (78, 83))	('glycosylation', 'biological_process', 'GO:0070085', ('146', '159'))	('threonine', 'Chemical', 'MESH:D013912', (115, 124))	('mutations', 'Var', (61, 70))	('MUC2', 'Gene', '4583', (13, 17))
29148	28978023	If there is truly low abundance of mRNA, it is rather unclear why mutations in MUC2 appear to cluster together in KIRP.	('mutations', 'Var', (66, 75))	('MUC2', 'Gene', '4583', (79, 83))	('MUC2', 'Gene', (79, 83))
29157	28978023	Copy number alterations may contribute significantly to MUC4 expression, as the genomic segment containing MUC4 and MUC20 demonstrates copy gains in over 50% of the specimens in all stages of LUSC, later stages of OSC, and in USEC.	('copy', 'Var', (135, 139))	('OSC', 'molecular_function', 'GO:0000250', ('214', '217'))	('MUC4', 'Gene', '4585', (56, 60))	('MUC4', 'Gene', '4585', (107, 111))	('MUC4', 'Gene', (56, 60))	('MUC4', 'Gene', (107, 111))	('MUC20', 'Gene', (116, 121))	('LUSC', 'Phenotype', 'HP:0030359', (192, 196))	('MUC20', 'Gene', '200958', (116, 121))	('OSC', 'Phenotype', 'HP:0012887', (214, 217))
29158	28978023	Positive significant correlations between mRNA and copy number were seen in breast and pancreatic cancer histological subtypes (r = 0.14 and r = 0.38, respectively) (Supplementary Table 7).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast and pancreatic cancer', 'Disease', 'MESH:D010190', (76, 104))	('copy number', 'Var', (51, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('mRNA', 'MPA', (42, 46))
29159	28978023	Here we also shed light on the significance of mutations in MUC4, especially in KIRC.	('MUC4', 'Gene', (60, 64))	('MUC4', 'Gene', '4585', (60, 64))	('mutations', 'Var', (47, 56))
29160	28978023	Although MUC4 is a rather large gene, repeated mutations and matching in-frame deletions in the same position where seen, especially H4205Q, which we believe should be further investigated.	('H4205Q', 'Mutation', 'rs369326402', (133, 139))	('MUC4', 'Gene', '4585', (9, 13))	('H4205Q', 'Var', (133, 139))	('MUC4', 'Gene', (9, 13))
29178	28978023	This study reveals demethylations of mucin CpG are very frequent in cancer (Figure 7).	('demethylations', 'Var', (19, 33))	('mucin', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('mucin', 'Gene', '100508689', (37, 42))	('cancer', 'Disease', (68, 74))	('frequent', 'Reg', (56, 64))
29181	28978023	Lastly, MUC15 and MUC20 methylation also appears to be of interest beyond renal carcinomas (Figure 7).	('renal carcinomas', 'Disease', 'MESH:C538614', (74, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('MUC15', 'Gene', (8, 13))	('MUC20', 'Gene', '200958', (18, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('renal carcinoma', 'Phenotype', 'HP:0005584', (74, 89))	('methylation', 'Var', (24, 35))	('renal carcinomas', 'Disease', (74, 90))	('MUC15', 'Gene', '143662', (8, 13))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('renal carcinomas', 'Phenotype', 'HP:0005584', (74, 90))	('MUC20', 'Gene', (18, 23))
29185	28978023	Lastly, despite not being of kidney origin, LUAD MUC15 methylation was associated with a multiple regression HR of 64.1 (q = 0.0001) and a univariate HR of 30.2 (q = 0.0017) (Supplementary Table 6).	('LUAD', 'Gene', (44, 48))	('MUC15', 'Gene', '143662', (49, 54))	('methylation', 'Var', (55, 66))	('LUAD', 'Phenotype', 'HP:0030078', (44, 48))	('MUC15', 'Gene', (49, 54))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
29187	28978023	Furthermore, within KIRP, MUC1 copy number had a large impact on survival for both univariate (HR = 20.1; q = 5.8E-6) and multivariate (HR = 12.9; q = 0.01) analyses (Supplementary Table 5).	('MUC1', 'Gene', (26, 30))	('MUC1', 'Gene', '4582', (26, 30))	('copy number', 'Var', (31, 42))	('impact', 'Reg', (55, 61))	('survival', 'MPA', (65, 73))
29189	28978023	Many significantly aberrant mRNA expression levels were observed in conjunction with histological subtypes favoring certain mucin mutations as well as location specific mutations.	('aberrant', 'Reg', (19, 27))	('mucin', 'Gene', '100508689', (124, 129))	('mutations', 'Var', (130, 139))	('mRNA expression levels', 'MPA', (28, 50))	('mucin', 'Gene', (124, 129))
29217	28978023	Both the univariate and multivariate Cox-proportional hazard regressions were used to evaluate the associations between the copy number, methylation, log2 scaled mRNA expression levels with the survival of each patient.	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('methylation', 'Var', (137, 148))	('log2', 'MPA', (150, 154))	('copy number', 'Var', (124, 135))	('associations', 'Interaction', (99, 111))	('mRNA expression levels', 'MPA', (162, 184))	('patient', 'Species', '9606', (211, 218))	('Cox', 'Gene', '1351', (37, 40))	('Cox', 'Gene', (37, 40))
29222	27531258	Previous studies from our laboratory have shown that the environmental pollutants arsenite and cadmium can cause malignant transformation of the immortalized urothelial cell line UROtsa.	('arsenite', 'Chemical', 'MESH:C015001', (82, 90))	('cause', 'Reg', (107, 112))	('cadmium', 'Var', (95, 102))	('cadmium', 'Chemical', 'MESH:D002104', (95, 102))	('malignant transformation', 'CPA', (113, 137))
29238	27531258	The remaining cancers contain aberrant differentiation which can occur in approximately 10-60% of the patients (Lopez-Beltram et al., 2007,).	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('aberrant', 'Var', (30, 38))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancers', 'Disease', 'MESH:D009369', (14, 21))
29250	27531258	Recently it was shown that high expression of Cx43 in bladder cancer was associated with poor patient prognosis.	('bladder cancer', 'Phenotype', 'HP:0009725', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('bladder cancer', 'Disease', 'MESH:D001749', (54, 68))	('bladder cancer', 'Disease', (54, 68))	('high', 'Var', (27, 31))	('patient', 'Species', '9606', (94, 101))	('Cx43', 'Protein', (46, 50))
29339	27531258	Cx43 expression was negative for 6 of the 7 samples of invasive, high grade urothelial cancers, with one specimen showing a few scattered cells that stained positive for the Cx43protein, but such cell profiles were very rare (Fig.	('urothelial cancers', 'Disease', (76, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Cx43protein', 'Var', (174, 185))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('urothelial cancers', 'Disease', 'MESH:D014523', (76, 94))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))
29373	27531258	This finding suggests that Cx43 expression in human urothelial cancer is a rare event.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Cx43', 'Var', (27, 31))	('human', 'Species', '9606', (46, 51))	('urothelial cancer', 'Disease', (52, 69))	('urothelial cancer', 'Disease', 'MESH:D014523', (52, 69))
29450	24885603	Possibilities include rearrangement of the G-CSF gene occurring within one of the alleles and intrinsic activation of nuclear factors that work on the promoter region of the G-CSF gene.	('G-CSF', 'Gene', (43, 48))	('activation', 'PosReg', (104, 114))	('G-CSF', 'Gene', '1440', (174, 179))	('G-CSF', 'Gene', (174, 179))	('rearrangement', 'Var', (22, 35))	('G-CSF', 'Gene', '1440', (43, 48))
29532	31444589	Enfortumab vedotin is an antibody-drug conjugate composed of an anti-Nectin-4 humanized monoclonal antibody linked to the microtubule disrupting agent, monomethyl auristatin E. In this phase I study (NCT03070990), Japanese patients with locally advanced/metastatic urothelial cancer treated with prior chemotherapy, or ineligible for cisplatin, were randomized 1:1 to receive 1.0 mg/kg (Arm A) or 1.25 mg/kg (Arm B) enfortumab vedotin on Days 1, 8, and 15 of each 28-day cycle.	('monomethyl auristatin E', 'Chemical', 'MESH:C495575', (152, 175))	('Enfortumab', 'Chemical', '-', (0, 10))	('1.25 mg/kg', 'Var', (397, 407))	('antibody', 'cellular_component', 'GO:0019814', ('99', '107'))	('antibody', 'cellular_component', 'GO:0019815', ('25', '33'))	('cisplatin', 'Chemical', 'MESH:D002945', (334, 343))	('human', 'Species', '9606', (78, 83))	('urothelial cancer', 'Disease', 'MESH:D014523', (265, 282))	('microtubule', 'cellular_component', 'GO:0005874', ('122', '133'))	('vedotin', 'Chemical', '-', (427, 434))	('antibody', 'molecular_function', 'GO:0003823', ('99', '107'))	('enfortumab', 'Chemical', '-', (416, 426))	('enfortumab', 'Gene', (416, 426))	('antibody', 'cellular_component', 'GO:0042571', ('99', '107'))	('antibody', 'cellular_component', 'GO:0019814', ('25', '33'))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('urothelial cancer', 'Disease', (265, 282))	('Nectin-4', 'Gene', '81607', (69, 77))	('antibody', 'molecular_function', 'GO:0003823', ('25', '33'))	('Nectin-4', 'Gene', (69, 77))	('vedotin', 'Chemical', '-', (11, 18))	('patients', 'Species', '9606', (223, 231))	('antibody', 'cellular_component', 'GO:0019815', ('99', '107'))	('antibody', 'cellular_component', 'GO:0042571', ('25', '33'))
29560	31444589	Across the 112 patients with metastatic UC treated with EV 1.25 mg/kg, the observed response rate and durability were promising with an investigator-assessed confirmed ORR of 43% and a median duration of response (DoR) of 7.4 months.	('EV 1.25 mg/kg', 'Var', (56, 69))	('patients', 'Species', '9606', (15, 23))	('metastatic UC', 'Disease', (29, 42))
29661	32209086	We sought to identify gene expression patterns associated with two primary types of canine iUC tumors: those that express a common somatic mutation in the BRAF gene, and those that do not.	('BRAF', 'Gene', (155, 159))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('mutation', 'Var', (139, 147))	('canine', 'Species', '9615', (84, 90))	('iUC tumor', 'Disease', (91, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('gene expression', 'biological_process', 'GO:0010467', ('22', '37'))	('BRAF', 'Gene', '475526', (155, 159))	('tumors', 'Disease', (95, 101))	('iUC tumor', 'Disease', 'MESH:D009369', (91, 100))
29663	32209086	Analysis of differential expression and clustering, and positional and individual expression was used to develop gene set enrichment profiles distinguishing iUC tumors with and without BRAFV595E mutations, as well as genomic regions harboring excessive numbers of dysregulated genes.	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('iUC tumor', 'Disease', (157, 166))	('BRAF', 'Gene', '475526', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mutations', 'Var', (195, 204))	('BRAF', 'Gene', (185, 189))	('iUC tumor', 'Disease', 'MESH:D009369', (157, 166))
29699	32209086	One matched normal sample that displayed mutant alleles at this position and one tumor that conflicted with original genotype results were excluded from further analysis.	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutant alleles', 'Var', (41, 55))	('tumor', 'Disease', (81, 86))
29702	32209086	To perform a replication analysis we selected a comparable dataset of 12 tumors, eight with and four without BRAFV595E mutations, and four normal tissue samples available from previously published data.	('BRAF', 'Gene', '475526', (109, 113))	('BRAF', 'Gene', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('mutations', 'Var', (119, 128))
29746	32209086	We, and others, had previously defined a mutation in the BRAF gene and encoded protein in over 80% of canine iUC (BRAFV595E), that corresponds to the common BRAFV600E variant observed in humans.	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '475526', (57, 61))	('humans', 'Species', '9606', (187, 193))	('BRAF', 'Gene', '475526', (157, 161))	('BRAF', 'Gene', (57, 61))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('mutation', 'Var', (41, 49))	('BRAF', 'Gene', (157, 161))	('canine', 'Species', '9615', (102, 108))	('BRAFV600E', 'Mutation', 'rs113488022', (157, 166))	('BRAF', 'Gene', '475526', (114, 118))
29753	32209086	This is likely due to the overabundance (up to 87%) of BRAFV595E mutations in canine iUC, thus skewing all lumped results toward the pattern of BRAFV595E tumors.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('BRAF', 'Gene', '475526', (144, 148))	('skewing', 'Reg', (95, 102))	('canine', 'Species', '9615', (78, 84))	('BRAF', 'Gene', '475526', (55, 59))	('BRAF', 'Gene', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('BRAF', 'Gene', (55, 59))	('mutations', 'Var', (65, 74))
29756	32209086	EGFR and FGFR1 appear to work together to increase tumorgenicity in lung cancer, and active FGFR1 can increase resistance to EGFR targeted therapies.	('FGFR1', 'Gene', (92, 97))	('resistance', 'MPA', (111, 121))	('FGFR1', 'Gene', '475582', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('active', 'Var', (85, 91))	('tumorgenicity in lung cancer', 'Disease', (51, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('FGFR1', 'Gene', '475582', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('9', '13'))	('tumorgenicity in lung cancer', 'Disease', 'MESH:D008175', (51, 79))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('increase', 'PosReg', (102, 110))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('FGFR1', 'Gene', (9, 14))	('increase', 'PosReg', (42, 50))
29769	32209086	For instance, FGFR3 mutations are found primarily in the luminal-papillary cluster of human iUC tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('FGFR3', 'Gene', '2261', (14, 19))	('iUC tumor', 'Disease', (92, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('human', 'Species', '9606', (86, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('FGFR3', 'Gene', (14, 19))	('iUC tumor', 'Disease', 'MESH:D009369', (92, 101))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('found', 'Reg', (34, 39))	('mutations', 'Var', (20, 29))
29773	32209086	Further investigation of BRAFwt tumors may reveal early mutations that initiate tumorigenesis, making them particularly good targets for therapy.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('mutations', 'Var', (56, 65))	('BRAFwt tumors', 'Disease', (25, 38))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('BRAFwt tumors', 'Disease', 'MESH:D009369', (25, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', (32, 37))
29782	32209086	Antagonists of CCR5 are currently being assessed for their anti-tumor activity in aggressive tumors that express the gene.	('Antagonists', 'Var', (0, 11))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('CCR', 'molecular_function', 'GO:0043880', ('15', '18'))	('aggressive tumors', 'Disease', 'MESH:D001523', (82, 99))	('tumor', 'Disease', (93, 98))	('CCR5', 'Gene', '1234', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('aggressive tumors', 'Disease', (82, 99))	('CCR5', 'Gene', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
29783	32209086	Positional analysis of expression data highlights syntenic human genome regions that harbor common somatic copy number variants important in tumor development.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('human', 'Species', '9606', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('copy number variants', 'Var', (107, 127))	('variants', 'Var', (119, 127))
29784	32209086	Ten chromosomal regions in our study correspond to sites of recurring copy number amplification in a study of 11 different human tumor types, including bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (152, 166))	('bladder cancer', 'Disease', (152, 166))	('human', 'Species', '9606', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('copy number amplification', 'Var', (70, 95))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('bladder cancer', 'Phenotype', 'HP:0009725', (152, 166))	('tumor', 'Disease', (129, 134))
29786	32209086	Fluorescence in situ hybridization analysis reveals amplification of the entirety of chromosome 13 in canine iUCs, as does the expression level of individual genes in the region.	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('amplification', 'Var', (52, 65))	('expression level', 'MPA', (127, 143))	('canine', 'Species', '9615', (102, 108))
29794	32209086	These findings suggest there are different functional outcomes related to amplification at the 8q24.3 locus within canine iUCs.	('8q24.3', 'Gene', (95, 101))	('canine', 'Species', '9615', (115, 121))	('amplification', 'Var', (74, 87))
29806	32209086	Notably, many of these regions highlight syntenic regions in the human genome that are associated with initiation or progression of human tumors, as well as long term and often deleterious outcomes.	('human', 'Species', '9606', (65, 70))	('associated', 'Reg', (87, 97))	('initiation', 'Disease', (103, 113))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('human', 'Species', '9606', (132, 137))	('initiation', 'Disease', 'MESH:D007319', (103, 113))	('syntenic regions', 'Var', (41, 57))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
29841	26884756	Therefore in our study, the percentage of pT1 high grade tumour among urothelial cancers was 16.5% and is closer to the findings of a study done at NHSL in 2010 which was 18%.	('urothelial cancers', 'Disease', (70, 88))	('pT1 high grade', 'Var', (42, 56))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('urothelial cancers', 'Disease', 'MESH:D014523', (70, 88))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))
29907	26149529	For all criteria used for tumor evaluation, selection of target lesions followed RECIST 1.1 parameters (2 lesions/organ, 5 total/patient/exam; >= 1.0 cm in long axis for solid tumors and >= 1.5 cm in short axis for lymphadenopathy; absolute change of >= 5 mm).	('lymphadenopathy', 'Phenotype', 'HP:0002716', (215, 230))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('solid tumors', 'Disease', 'MESH:D009369', (170, 182))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('>= 1.0 cm', 'Var', (143, 152))	('lymphadenopathy', 'Disease', (215, 230))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('>= 1.5 cm', 'Var', (187, 196))	('tumor', 'Disease', (26, 31))	('solid tumors', 'Disease', (170, 182))	('lymphadenopathy', 'Disease', 'MESH:D008206', (215, 230))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('patient', 'Species', '9606', (129, 136))
29921	26149529	Combining automated segmentation capability with a tool for assessing volumetric density (voxels of attenuation) creates histograms of attenuation that are partitioned into thresholds of a less perfused tumor (0-50 HU, or VTV-low) and a more viable tumor (50-180 HU, or VTV-high).	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('VTV', 'Chemical', '-', (270, 273))	('tumor', 'Disease', (249, 254))	('men', 'Species', '9606', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('VTV', 'Chemical', '-', (222, 225))	('less', 'NegReg', (189, 193))	('50-180', 'Var', (256, 262))	('segmentation', 'biological_process', 'GO:0035282', ('20', '32'))
29940	26149529	When time to classification of PR was evaluated as a time-varying covariate, low-attenuation VTV change demonstrated a trend toward an association with OS (p = 0.087; hazard ratio [HR] 0.16; 95% CI on HR: 0.02-1.30).	('low-attenuation', 'Var', (77, 92))	('change', 'Var', (97, 103))	('VTV', 'Chemical', '-', (93, 96))	('VTV', 'Gene', (93, 96))
29971	26149529	Typical segmentation outline edits using a freeform segmentation tool exclude nontumoral components.	('men', 'Species', '9606', (55, 58))	('men', 'Species', '9606', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('exclude', 'NegReg', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('segmentation', 'biological_process', 'GO:0035282', ('52', '64'))	('tumor', 'Disease', (81, 86))	('segmentation', 'biological_process', 'GO:0035282', ('8', '20'))	('edits', 'Var', (29, 34))
29991	26148869	Cancer largely results from various molecular aberrations comprising somatic mutational events such as single nucleotide mutations, copy number changes and DNA methylations.	('copy number changes', 'Var', (132, 151))	('results from', 'Reg', (15, 27))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('DNA methylations', 'Var', (156, 172))	('single nucleotide mutations', 'Var', (103, 130))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
29995	26148869	Similarly, endometrial cancers have also been classified into four categories (POLE ultramutated, microsatellite instability hypermutated, copy-number low, and serous-like) through a comprehensive, multiplatform analysis, and glioblastoma multiformae was stratified into four distinct molecular subtypes (proneural, neural, classical, and mesenchymal) based on the CpG island methylation phenotype.	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('glioblastoma', 'Disease', (226, 238))	('glioblastoma', 'Disease', 'MESH:D005909', (226, 238))	('endometrial cancers', 'Disease', 'MESH:D016889', (11, 30))	('copy-number low', 'Var', (139, 154))	('endometrial cancers', 'Disease', (11, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (226, 238))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('methylation', 'biological_process', 'GO:0032259', ('376', '387'))
30013	26148869	KIRC has been reported to have a high frequency of Von Hippel-Lindau (VHL) mutation and show distinct exclusivity from other 11 cancer types.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('mutation', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('VHL', 'Disease', (70, 73))	('VHL', 'Disease', 'MESH:D006623', (70, 73))	('Von Hippel-Lindau', 'Gene', '7428', (51, 68))	('Von Hippel-Lindau', 'Gene', (51, 68))	('cancer', 'Disease', (128, 134))
30015	26148869	The similarity of these tumors has been implicated in the mutation or amplification of ERBB2-HER2.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('HER2', 'Gene', '2064', (93, 97))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('implicated', 'Reg', (40, 50))	('mutation', 'Var', (58, 66))	('ERBB2', 'Gene', (87, 92))	('ERBB2', 'Gene', '2064', (87, 92))	('HER2', 'Gene', (93, 97))	('amplification', 'Var', (70, 83))
30040	26148869	The relationship between mutations of VHL and KIRC has been established for decades and the association between VHL and tumor stage, tumor-cell proliferation, and patient prognosis has also been well studied.	('VHL', 'Disease', (112, 115))	('mutations', 'Var', (25, 34))	('VHL', 'Disease', 'MESH:D006623', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('VHL', 'Disease', 'MESH:D006623', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cell proliferation', 'biological_process', 'GO:0008283', ('139', '157'))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('VHL', 'Disease', (38, 41))	('patient', 'Species', '9606', (163, 170))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
30041	26148869	Besides VHL, other genetic alterations in subgroup-5 involve the mutation of the chromatin remodeling gene PBRM1, the mutation of the histone methyltransferase gene SETD2, which has been identified as a tumor suppressor in KIRC and high methylation rate of GSTP1 (Fig.	('tumor suppressor', 'biological_process', 'GO:0051726', ('203', '219'))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('GSTP1', 'Gene', '2950', (257, 262))	('GSTP1', 'Gene', (257, 262))	('VHL', 'Disease', (8, 11))	('mutation', 'Var', (65, 73))	('histone methyltransferase', 'Gene', '56979', (134, 159))	('methylation', 'biological_process', 'GO:0032259', ('237', '248'))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('SETD2', 'Gene', (165, 170))	('mutation', 'Var', (118, 126))	('chromatin', 'cellular_component', 'GO:0000785', ('81', '90'))	('PBRM1', 'Gene', '55193', (107, 112))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('203', '219'))	('SETD2', 'Gene', '29072', (165, 170))	('VHL', 'Disease', 'MESH:D006623', (8, 11))	('PBRM1', 'Gene', (107, 112))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('81', '101'))	('histone methyltransferase', 'Gene', (134, 159))
30045	26148869	Both PTEN and PIK3CA alterations were reported to have strong relationships with UCEC and COADREAD, and the loss of PTEN expression is also observed to be associated with PIK3CA mutations in metastatic colorectal cancer.	('PIK3CA', 'Gene', (171, 177))	('PTEN', 'Gene', (5, 9))	('expression', 'MPA', (121, 131))	('colorectal cancer', 'Disease', (202, 219))	('relationships', 'Reg', (62, 75))	('PIK3CA', 'Gene', (14, 20))	('PTEN', 'Gene', (116, 120))	('COADREAD', 'Disease', (90, 98))	('loss', 'Var', (108, 112))	('PTEN', 'Gene', '5728', (5, 9))	('PTEN', 'Gene', '5728', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('PIK3CA', 'Gene', '5290', (171, 177))	('associated', 'Reg', (155, 165))	('PIK3CA', 'Gene', '5290', (14, 20))	('UCEC', 'Disease', (81, 85))	('mutations', 'Var', (178, 187))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))
30046	26148869	Altered PTEN expression was viewed as a diagnostic marker for early detection of UCEC, and is associated with favorable clinical and pathologic characteristics.	('PTEN', 'Gene', (8, 12))	('UCEC', 'Disease', (81, 85))	('Altered', 'Var', (0, 7))	('PTEN', 'Gene', '5728', (8, 12))
30047	26148869	In addition, PIK3CA mutations were reported to be present in approximately 25 % of breast cancers, particularly the estrogen receptor-positive subtypes, while they are absent in the basal-type breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('breast cancers', 'Phenotype', 'HP:0003002', (83, 97))	('basal-type breast cancer', 'Disease', 'MESH:D001943', (182, 206))	('PIK3CA', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancers', 'Disease', 'MESH:D001943', (83, 97))	('breast cancers', 'Disease', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('basal-type breast cancer', 'Disease', (182, 206))	('PIK3CA', 'Gene', '5290', (13, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('present', 'Reg', (50, 57))	('mutations', 'Var', (20, 29))
30049	26148869	The mutation of PTEN and PIK3CA together with other alterations of genes affects a common biological network, which reflects the major similarities among subgroup-1 tumors (Fig.	('common biological network', 'Pathway', (83, 108))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('mutation', 'Var', (4, 12))	('PIK3CA', 'Gene', (25, 31))	('PTEN', 'Gene', (16, 20))	('PIK3CA', 'Gene', '5290', (25, 31))	('PTEN', 'Gene', '5728', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('affects', 'Reg', (73, 80))
30051	26148869	Finally, many subgroup-1-specific altered genes including PIK3CA show significant differential expression in subgroup-1 compared to all other patients (Fig.	('differential', 'Reg', (82, 94))	('PIK3CA', 'Gene', (58, 64))	('PIK3CA', 'Gene', '5290', (58, 64))	('patients', 'Species', '9606', (142, 150))	('subgroup-1', 'Var', (109, 119))	('expression', 'MPA', (95, 105))
30052	26148869	Subgroup-6 was mainly characterized by frequent promoter hypermethylation of MGMT and mutations of APC, KRAS, FLT3, and NPM1 (Fig.	('mutations', 'Var', (86, 95))	('APC', 'Disease', 'MESH:D011125', (99, 102))	('FLT3', 'Gene', (110, 114))	('KRAS', 'Gene', '3845', (104, 108))	('APC', 'Disease', (99, 102))	('NPM1', 'Gene', (120, 124))	('promoter hypermethylation', 'MPA', (48, 73))	('APC', 'cellular_component', 'GO:0005680', ('99', '102'))	('NPM1', 'Gene', '4869', (120, 124))	('MGMT', 'Gene', '4255', (77, 81))	('MGMT', 'Gene', (77, 81))	('FLT3', 'Gene', '2322', (110, 114))	('MGMT', 'molecular_function', 'GO:0003908', ('77', '81'))	('KRAS', 'Gene', (104, 108))
30056	26148869	Thus, hypermethylation of MGMT, inhibiting the expression of this gene, is of clinical interest for LAML.	('inhibiting', 'NegReg', (32, 42))	('hypermethylation', 'Var', (6, 22))	('MGMT', 'molecular_function', 'GO:0003908', ('26', '30'))	('MGMT', 'Gene', (26, 30))	('MGMT', 'Gene', '4255', (26, 30))	('expression', 'MPA', (47, 57))
30057	26148869	Moreover, the methylation of MGMT was also reported as a valuable molecular marker for the early detection of colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('MGMT', 'Gene', '4255', (29, 33))	('MGMT', 'Gene', (29, 33))	('methylation', 'Var', (14, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('colorectal cancer', 'Disease', (110, 127))	('MGMT', 'molecular_function', 'GO:0003908', ('29', '33'))
30058	26148869	Therefore, the alteration of MGMT would provide potential implications for targeted and shared therapy across these two malignancies.	('implications', 'Reg', (58, 70))	('malignancies', 'Disease', 'MESH:D009369', (120, 132))	('MGMT', 'Gene', '4255', (29, 33))	('malignancies', 'Disease', (120, 132))	('MGMT', 'Gene', (29, 33))	('alteration', 'Var', (15, 25))	('MGMT', 'molecular_function', 'GO:0003908', ('29', '33'))
30061	26148869	For example, mutations of tumor suppressor gene APC were only presented in COADREAD, while mutations of FLT3 and NPM1 are exclusive to LAML.	('NPM1', 'Gene', (113, 117))	('FLT3', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('APC', 'cellular_component', 'GO:0005680', ('48', '51'))	('NPM1', 'Gene', '4869', (113, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('26', '42'))	('APC', 'Disease', 'MESH:D011125', (48, 51))	('tumor', 'Disease', (26, 31))	('FLT3', 'Gene', '2322', (104, 108))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('26', '42'))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mutations', 'Var', (13, 22))	('APC', 'Disease', (48, 51))
30065	26148869	This subgroup demonstrates a typical cross-cancer similarity phenomenon that subsets of samples from different tumor types are characterized by the same genomic alterations on chromosome 9.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('chromosome', 'cellular_component', 'GO:0005694', ('176', '186'))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cross-cancer', 'Disease', (37, 49))	('cross-cancer', 'Disease', 'MESH:C537866', (37, 49))	('alterations', 'Var', (161, 172))
30066	26148869	The associations of the deletion of tumor suppressor genes CDKN2A, CDKN2B, and MTAP with the four significant enriched cancer types in this subgroup have been widely investigated and reported.	('MTAP', 'Gene', '4507', (79, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('CDKN2B', 'Gene', (67, 73))	('CDKN2B', 'Gene', '1030', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cancer', 'Disease', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('deletion', 'Var', (24, 32))	('CDKN2A', 'Gene', (59, 65))	('tumor', 'Disease', (36, 41))	('MTAP', 'Gene', (79, 83))	('associations', 'Interaction', (4, 16))	('CDKN2A', 'Gene', '1029', (59, 65))
30075	26148869	The lack of expression due to the deletion of IFNAs may be responsible for the HPV infection in carcinogenesis of these cancers; however, their relationships need to be further investigated.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('IFNA', 'Gene', '3440', (46, 50))	('HPV infection', 'Disease', 'MESH:D030361', (79, 92))	('IFNA', 'Gene', (46, 50))	('lack', 'NegReg', (4, 8))	('HPV infection', 'Disease', (79, 92))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('deletion', 'Var', (34, 42))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('expression', 'MPA', (12, 22))
30078	26148869	The largest patient group, subgroup-3 enriched with BRCA-basal, UCEC-serous, and OV tumors, was characterized by multiple recurrent chromosomal gains and losses (in Additional file 1: Figure S6A).	('BRCA', 'Phenotype', 'HP:0003002', (52, 56))	('OV', 'Phenotype', 'HP:0012887', (81, 83))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('BRCA', 'Gene', (52, 56))	('chromosomal gains', 'Var', (132, 149))	('BRCA', 'Gene', '672', (52, 56))	('OV tumors', 'Disease', 'MESH:D009369', (81, 90))	('losses', 'NegReg', (154, 160))	('OV tumors', 'Disease', (81, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('patient', 'Species', '9606', (12, 19))	('UCEC-serous', 'Disease', (64, 75))
30079	26148869	BRCA-basal, UCEC-serous, and OV patients in this cohort are associated with a high mutation rate of TP53 (88.4 %) (in Additional file 1: Figure S6B), which was consistent with previous observations.	('TP53', 'Gene', '7157', (100, 104))	('patients', 'Species', '9606', (32, 40))	('BRCA', 'Gene', (0, 4))	('TP53', 'Gene', (100, 104))	('mutation', 'Var', (83, 91))	('OV', 'Phenotype', 'HP:0012887', (29, 31))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('BRCA', 'Gene', '672', (0, 4))
30080	26148869	Amplification of 11q13 involving CCND1, ORAOV1, and ANO1 was dominated in subgroup-4, mainly consisting of luminal BRCA and HNSC (in Additional file 1: Figure S7).	('Amplification', 'Var', (0, 13))	('CCND1', 'Gene', (33, 38))	('CCND1', 'Gene', '595', (33, 38))	('OV', 'Phenotype', 'HP:0012887', (43, 45))	('BRCA', 'Phenotype', 'HP:0003002', (115, 119))	('ANO1', 'Gene', (52, 56))	('BRCA', 'Gene', '672', (115, 119))	('ORAOV1', 'Gene', '220064', (40, 46))	('ORAOV1', 'Gene', (40, 46))	('BRCA', 'Gene', (115, 119))	('ANO1', 'Gene', '55107', (52, 56))	('HNSC', 'Phenotype', 'HP:0012288', (124, 128))
30082	26148869	Amplification and overexpression of CCND1 would alter cell cycle progression and contribute to tumorigenesis.	('Amplification', 'Var', (0, 13))	('contribute', 'Reg', (81, 91))	('tumor', 'Disease', (95, 100))	('cell cycle', 'biological_process', 'GO:0007049', ('54', '64'))	('CCND1', 'Gene', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('alter', 'Reg', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('CCND1', 'Gene', '595', (36, 41))	('cell cycle progression', 'CPA', (54, 76))	('overexpression', 'PosReg', (18, 32))
30083	26148869	Previous studies have shown that luminal cancers harbor recurrent amplifications and overexpression of CCND1, whereas basal-like tumors harbor recurrent deletions and down-regulation of it.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('regulation', 'biological_process', 'GO:0065007', ('172', '182'))	('overexpression', 'PosReg', (85, 99))	('CCND1', 'Gene', '595', (103, 108))	('amplifications', 'Var', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('down-regulation', 'NegReg', (167, 182))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('luminal cancers', 'Disease', 'MESH:D009369', (33, 48))	('CCND1', 'Gene', (103, 108))	('deletions', 'Var', (153, 162))	('luminal cancers', 'Disease', (33, 48))
30084	26148869	Subgroup-8, mainly consisting of LUSC, HNSC, and OV tumors, was characterized by 100 % copy number gain on chromosome 3q26 involving genes PIK3CA, KCNMB3, KCNMB2, MFN1, GNB4, MECOM, ZMAT3, SOX2, and KCNJ13 (in Additional file 1: Figure S11).	('ZMAT3', 'Gene', '64393', (182, 187))	('S11', 'Gene', '6267', (236, 239))	('LUSC', 'Phenotype', 'HP:0030359', (33, 37))	('MECOM', 'Gene', (175, 180))	('OV', 'Phenotype', 'HP:0012887', (49, 51))	('KCNMB3', 'Gene', '27094', (147, 153))	('PIK3CA', 'Gene', (139, 145))	('GNB4', 'Gene', '59345', (169, 173))	('MECOM', 'Gene', '2122', (175, 180))	('gain', 'PosReg', (99, 103))	('MFN1', 'Gene', (163, 167))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('KCNJ13', 'Gene', (199, 205))	('S11', 'Gene', (236, 239))	('KCNJ13', 'Gene', '3769', (199, 205))	('KCNMB2', 'Gene', '10242', (155, 161))	('copy number', 'Var', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('KCNMB3', 'Gene', (147, 153))	('KCNMB2', 'Gene', (155, 161))	('GNB4', 'Gene', (169, 173))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('HNSC', 'Disease', (39, 43))	('OV tumors', 'Disease', 'MESH:D009369', (49, 58))	('MFN1', 'Gene', '55669', (163, 167))	('SOX2', 'Gene', '6657', (189, 193))	('PIK3CA', 'Gene', '5290', (139, 145))	('SOX2', 'Gene', (189, 193))	('OV tumors', 'Disease', (49, 58))	('HNSC', 'Phenotype', 'HP:0012288', (39, 43))	('LUSC', 'Disease', (33, 37))	('ZMAT3', 'Gene', (182, 187))
30085	26148869	Subgroup-9, mainly consisting of HNSC, OV, and COADREAD, was characterized by a distinct TP53 mutation rate (98.6 %, in Additional file 1: Figure S12).	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('HNSC', 'Phenotype', 'HP:0012288', (33, 37))	('OV', 'Phenotype', 'HP:0012887', (39, 41))	('S12', 'Gene', (146, 149))	('S12', 'Gene', '6268', (146, 149))	('mutation', 'Var', (94, 102))
30096	26148869	Both studies reported the loss of CDKN2A in this patient cohort; however, our subgroup-7 was characterized by the copy number deletion on chromosome 9p21 with nearly 100 % frequency.	('chromosome', 'cellular_component', 'GO:0005694', ('138', '148'))	('patient', 'Species', '9606', (49, 56))	('CDKN2A', 'Gene', '1029', (34, 40))	('CDKN2A', 'Gene', (34, 40))	('copy number deletion', 'Var', (114, 134))
30100	26148869	such as the hypermethylation of MGMT and other genetic characteristics shared by subsets of LAML and UCEC in subgroup-6 and the 100 % copy number gain on chromosome 3q26 in fractional OV, LUSC, and HNSC in subgroup-8 (in Additional file 1: Figure S13).	('chromosome', 'cellular_component', 'GO:0005694', ('154', '164'))	('HNSC', 'Phenotype', 'HP:0012288', (198, 202))	('hypermethylation', 'Var', (12, 28))	('copy number', 'Var', (134, 145))	('MGMT', 'Gene', '4255', (32, 36))	('gain', 'PosReg', (146, 150))	('MGMT', 'Gene', (32, 36))	('OV', 'Phenotype', 'HP:0012887', (184, 186))	('LUSC', 'Phenotype', 'HP:0030359', (188, 192))	('MGMT', 'molecular_function', 'GO:0003908', ('32', '36'))
30111	26148869	These data contain 479 functional genetic alterations, including 116 copy number gains, 151 copy number losses, 199 recurrently mutated genes, and 13 epigenetically silenced genes recorded across 3299 tumor samples from 12 cancer types (Additional file 1: Table S1).	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('copy number gains', 'Var', (69, 86))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('copy number', 'Var', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('tumor', 'Disease', (201, 206))	('cancer', 'Disease', (223, 229))
30115	26148869	Briefly, the NBS applies a network propagation method to spread the influence of each mutation over its network neighborhood and produce a network-smoothed profile to reflect the effect of each genetic alteration on network module or pathway levels with a continuous value.	('NBS', 'Disease', (13, 16))	('NBS', 'Disease', 'MESH:D049932', (13, 16))	('mutation', 'Var', (86, 94))
30188	24900993	APF was also shown to decrease cell secretion of heparin-binding epithelial growth factor-like growth factor (HB-EGF), as well as an enzyme that cleaves pro-HB-EGF with release of active HB-EGF-matrix metalloproteinase-2 (MMP-2).	('HB-EGF', 'Gene', '1839', (110, 116))	('HB-EGF', 'Gene', '1839', (157, 163))	('MMP-2', 'Gene', (222, 227))	('heparin-binding', 'molecular_function', 'GO:0008201', ('49', '64'))	('decrease', 'NegReg', (22, 30))	('matrix metalloproteinase-2', 'Gene', '4313', (194, 220))	('HB-EGF', 'Gene', '1839', (187, 193))	('cell secretion', 'MPA', (31, 45))	('secretion', 'biological_process', 'GO:0046903', ('36', '45'))	('HB-EGF', 'Gene', (110, 116))	('EGF', 'molecular_function', 'GO:0005154', ('113', '116'))	('APF', 'Var', (0, 3))	('HB-EGF', 'Gene', (157, 163))	('EGF', 'molecular_function', 'GO:0005154', ('160', '163'))	('EGF', 'molecular_function', 'GO:0005154', ('190', '193'))	('epithelia', 'Disease', 'None', (65, 74))	('HB-EGF', 'Gene', (187, 193))	('matrix metalloproteinase-2', 'Gene', (194, 220))	('MMP-2', 'Gene', '4313', (222, 227))	('MMP-2', 'molecular_function', 'GO:0004228', ('222', '227'))	('epithelia', 'Disease', (65, 74))
30194	24900993	In addition to abnormal expression of those gene products mentioned above, abnormal expression in BPS/IC bladder cells also appears to extend to the production of various cell signaling molecules and signaling receptors, as well as ultimate downstream modification of certain target proteins/enzymes.	('BPS/IC', 'Disease', (98, 104))	('cell signaling molecules', 'MPA', (171, 195))	('modification', 'Reg', (252, 264))	('extend', 'Reg', (135, 141))	('signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('signaling', 'biological_process', 'GO:0023052', ('200', '209'))	('production of', 'MPA', (149, 162))	('expression', 'MPA', (84, 94))	('BPS/IC', 'Disease', 'MESH:C564874', (98, 104))	('abnormal', 'Var', (75, 83))
30211	24900993	The resultant abnormalities of bladder urothelial cell proliferation, gene expression, and signaling by these abnormally differentiated bladder urothelial cells could ultimately result in bladder urothelial thinning or ulceration, leakiness, and altered downstream afferent neuronal cell activation, causing increased urinary frequency, urgency, and pain which characterizes BPS/IC.	('abnormalities', 'Var', (14, 27))	('ulcer', 'Disease', 'MESH:D014456', (219, 224))	('causing', 'Reg', (300, 307))	('BPS/IC', 'Disease', (375, 381))	('altered', 'Reg', (246, 253))	('urinary frequency', 'Disease', (318, 335))	('urothelial cell proliferation', 'biological_process', 'GO:0050674', ('39', '68'))	('pain', 'Disease', (350, 354))	('abnormalities of bladder', 'Phenotype', 'HP:0000014', (14, 38))	('BPS/IC', 'Disease', 'MESH:C564874', (375, 381))	('ulcer', 'Disease', (219, 224))	('activation', 'PosReg', (288, 298))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('result in', 'Reg', (178, 187))	('pain', 'Phenotype', 'HP:0012531', (350, 354))	('urgency', 'Disease', (337, 344))	('cell activation', 'biological_process', 'GO:0001775', ('283', '298'))	('pain', 'Disease', 'MESH:D010146', (350, 354))	('leakiness', 'Disease', (231, 240))	('increased', 'PosReg', (308, 317))	('gene expression', 'biological_process', 'GO:0010467', ('70', '85'))	('bladder urothelial thinning', 'CPA', (188, 215))	('leakiness', 'Disease', 'MESH:C535298', (231, 240))
30227	24900993	Studies have shown that a major source of NGF comes from smooth muscle of the bladder in addition to the urothelium, and altered NGF levels may contribute to altered neural excitability and emergence of bladder pain.	('neural', 'CPA', (166, 172))	('pain', 'Phenotype', 'HP:0012531', (211, 215))	('altered', 'Var', (121, 128))	('bladder pain', 'Disease', 'MESH:D018856', (203, 215))	('contribute', 'Reg', (144, 154))	('levels', 'MPA', (133, 139))	('altered', 'Reg', (158, 165))	('bladder pain', 'Disease', (203, 215))	('bladder pain', 'Phenotype', 'HP:0032171', (203, 215))
30236	24900993	It is likely that many of these alterations could contribute to epithelial hypersensitivity and barrier dysfunction that often occur in patients with functional and inflammatory urological as well as gastrointestinal esophageal symptoms.	('barrier dysfunction', 'Disease', (96, 115))	('contribute', 'Reg', (50, 60))	('gastrointestinal esophageal symptoms', 'Disease', 'MESH:D012817', (200, 236))	('hypersensitivity', 'Disease', 'MESH:D004342', (75, 91))	('gastrointestinal esophageal symptoms', 'Disease', (200, 236))	('alterations', 'Var', (32, 43))	('epithelia', 'Disease', (64, 73))	('patients', 'Species', '9606', (136, 144))	('epithelia', 'Disease', 'None', (64, 73))	('hypersensitivity', 'biological_process', 'GO:0002524', ('75', '91'))	('epithelial hypersensitivity', 'Phenotype', 'HP:0100326', (64, 91))	('hypersensitivity', 'Disease', (75, 91))
30247	24900993	Recently, transgenic animals with alterations specifically targeting the urothelium (urothelial restriction or conditional transgenics) have been developed to test the hypothesis that urothelial dysfunction can drive altered bladder function.	('transgenic', 'Species', '10090', (10, 20))	('bladder function', 'Disease', (225, 241))	('altered bladder function', 'Phenotype', 'HP:0000009', (217, 241))	('transgenic', 'Species', '10090', (123, 133))	('urothelial dysfunction', 'Disease', (184, 206))	('urothelial dysfunction', 'Disease', 'MESH:D014522', (184, 206))	('alterations', 'Var', (34, 45))
30263	24900993	The ATP receptor, P2X3, when constitutively knocked out resulted in a hyporeflexive (hyposensitive) bladder.	('ATP receptor', 'Gene', '5024', (4, 16))	('resulted in', 'Reg', (56, 67))	('P2X3', 'Var', (18, 22))	('ATP receptor', 'Gene', (4, 16))
30276	24900993	Interestingly, the urothelium from this transgenic animal also had a 2-fold increase in urinary ATP concentration compared to wild-type animals.	('urinary ATP concentration', 'MPA', (88, 113))	('increase', 'PosReg', (76, 84))	('ATP', 'Chemical', 'MESH:D000255', (96, 99))	('transgenic', 'Species', '10090', (40, 50))	('transgenic', 'Var', (40, 50))	('urothelium', 'CPA', (19, 29))
30277	24900993	These findings suggest that urothelial integrins are important for regulating bladder mechanosensory transduction, and loss of the beta1-integrin recapitulates an OAB phenotype.	('bladder mechanosensory transduction', 'MPA', (78, 113))	('transduction', 'biological_process', 'GO:0009293', ('101', '113'))	('beta1-integrin', 'Gene', '3688', (131, 145))	('OAB', 'Disease', 'MESH:D053201', (163, 166))	('beta1-integrin', 'Gene', (131, 145))	('OAB', 'Disease', (163, 166))	('loss', 'Var', (119, 123))	('OAB', 'Phenotype', 'HP:0000012', (163, 166))
30281	24900993	This suggested that polyamines can modulate the mRNA levels of these tight junction proteins.	('polyamines', 'Chemical', 'MESH:D011073', (20, 30))	('modulate', 'Reg', (35, 43))	('polyamines', 'Var', (20, 30))	('tight junction', 'cellular_component', 'GO:0070160', ('69', '83'))	('mRNA levels of', 'MPA', (48, 62))
30290	24900993	As presented in the prior section on polyamine signaling, OXO, a muscarinic agonist, caused OAB urothelial cells to have higher maximal response in terms of intracellular calcium rise, compared to control urothelial cells.	('OAB', 'Disease', (92, 95))	('polyamine', 'Chemical', 'MESH:D011073', (37, 46))	('OXO', 'Var', (58, 61))	('intracellular calcium rise', 'Phenotype', 'HP:0003575', (157, 183))	('OAB', 'Phenotype', 'HP:0000012', (92, 95))	('maximal response', 'MPA', (128, 144))	('OXO', 'Chemical', 'MESH:D010095', (58, 61))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('calcium', 'Chemical', 'MESH:D002118', (171, 178))	('intracellular', 'cellular_component', 'GO:0005622', ('157', '170'))	('higher', 'PosReg', (121, 127))	('OAB', 'Disease', 'MESH:D053201', (92, 95))	('intracellular calcium rise', 'MPA', (157, 183))
30311	24900993	However, in a different study, investigators did not find a difference in frequency of bladder contractions on cystometry between the TRPV1 knockout versus the wild-type animals, though nonvoiding contractions were not calculated.	('knockout', 'Var', (140, 148))	('bladder contractions', 'Disease', 'MESH:D001745', (87, 107))	('bladder contractions', 'Disease', (87, 107))	('TRPV1', 'Gene', (134, 139))
30321	24900993	However, a recent investigation found that while human bladder urothelium expressed mRNA for TRPV1, cultured human bladder urothelial cells did not respond to capsaicin, as measured by intracellular calcium rise, unless a very high dose (10-100 muM) of capsaicin was used.	('human', 'Species', '9606', (109, 114))	('mRNA', 'Var', (84, 88))	('human', 'Species', '9606', (49, 54))	('intracellular', 'cellular_component', 'GO:0005622', ('185', '198'))	('muM', 'Gene', '56925', (245, 248))	('capsaicin', 'Chemical', 'MESH:D002211', (159, 168))	('intracellular calcium rise', 'Phenotype', 'HP:0003575', (185, 211))	('calcium', 'Chemical', 'MESH:D002118', (199, 206))	('capsaicin', 'Chemical', 'MESH:D002211', (253, 262))	('muM', 'Gene', (245, 248))	('TRPV1', 'Gene', (93, 98))
30326	24900993	Another trial, which was open label, using a different subject phenotype including those with neurogenic OAB, found a beneficial effect of 50 nM RTX.	('OAB', 'Phenotype', 'HP:0000012', (105, 108))	('RTX', 'Chemical', 'MESH:C024353', (145, 148))	('beneficial', 'PosReg', (118, 128))	('50 nM', 'Var', (139, 144))	('OAB', 'Disease', 'MESH:D053201', (105, 108))	('OAB', 'Disease', (105, 108))
30333	24900993	Animal models, specifically urothelially restricted transgenics, are valuable tools to test the hypothesis that perturbations in urothelial function results in altered bladder function, but the relevance of animal models to the human illness must be established.	('altered bladder function', 'Phenotype', 'HP:0000009', (160, 184))	('perturbations', 'Var', (112, 125))	('altered', 'Reg', (160, 167))	('human', 'Species', '9606', (228, 233))	('bladder function', 'MPA', (168, 184))	('transgenic', 'Species', '10090', (52, 62))
30472	32198650	In BAC, in addition to known alterations in TP53, Wnt, MAP kinase and MTOR pathway, mutations in SMAD4, ARID1A and BRAF were identified.	('MTOR', 'Gene', (70, 74))	('SMAD4', 'Gene', (97, 102))	('BRAF', 'Gene', '673', (115, 119))	('BRAF', 'Gene', (115, 119))	('MTOR', 'Gene', '2475', (70, 74))	('MAP', 'molecular_function', 'GO:0004239', ('55', '58'))	('SMAD4', 'Gene', '4089', (97, 102))	('mutations', 'Var', (84, 93))	('MAP kinase', 'Pathway', (55, 65))	('ARID1A', 'Gene', '8289', (104, 110))	('ARID1A', 'Gene', (104, 110))	('TP53', 'Gene', '7157', (44, 48))	('BAC', 'Phenotype', 'HP:0002862', (3, 6))	('TP53', 'Gene', (44, 48))
30478	32198650	Alterations of TERT and FBXW7 in single cases of intestinal metaplasia further point towards a possible precancerous character in line with previous reports.	('TERT', 'Gene', '7015', (15, 19))	('intestinal metaplasia', 'Disease', (49, 70))	('FBXW7', 'Gene', '55294', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Alterations', 'Var', (0, 11))	('FBXW7', 'Gene', (24, 29))	('metaplasia', 'biological_process', 'GO:0036074', ('60', '70'))	('TERT', 'Gene', (15, 19))
30486	32198650	Next-generation sequencing (NGS) data have improved our knowledge of genetic driver alterations in urothelial carcinomas and CORAD, and first NGS data are now available for rare BAC and UAC.	('CORAD', 'Disease', (125, 130))	('BAC', 'Phenotype', 'HP:0002862', (178, 181))	('urothelial carcinomas', 'Disease', (99, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('UAC', 'Phenotype', 'HP:0012618', (186, 189))	('alterations', 'Var', (84, 95))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (99, 120))
30493	32198650	Additionally, tumours were screened for TERT promoter mutations and analysed immunohistochemically for DNA mismatch repair (MMR) deficiency, loss of SWI/SNF complex expression and PD-L1 expression.	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('mismatch repair', 'biological_process', 'GO:0006298', ('107', '122'))	('MMR', 'biological_process', 'GO:0006298', ('124', '127'))	('deficiency', 'Disease', 'MESH:D007153', (129, 139))	('mutations', 'Var', (54, 63))	('PD-L1', 'Gene', (180, 185))	('deficiency', 'Disease', (129, 139))	('PD-L1', 'Gene', '29126', (180, 185))	('loss of SWI', 'Disease', 'MESH:D014786', (141, 152))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('tumours', 'Disease', (14, 21))	('TERT', 'Gene', (40, 44))	('TERT', 'Gene', '7015', (40, 44))	('expression', 'MPA', (165, 175))	('loss of SWI', 'Disease', (141, 152))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('149', '164'))	('expression', 'MPA', (186, 196))	('tumours', 'Disease', 'MESH:D009369', (14, 21))
30497	32198650	In addition, n = 8 CG and n = 7 IM samples with low material were analysed only with SNapShot  for TERT promoter mutations.	('mutations', 'Var', (113, 122))	('TERT', 'Gene', (99, 103))	('TERT', 'Gene', '7015', (99, 103))
30504	32198650	SNapShot  Multiplex System assay (Applied Biosystems, Foster City, USA) was used to simultaneously screen for 11 known activating FGFR3 point mutations (R248C, S249C, G372C, S373C, Y375C, G382R, A393E, K652E, K652M, K652Q and K652T,) and for TERT promoter mutations at positions -124 (C228T) and -146 (C250T).	('K652M', 'Mutation', 'rs121913105', (209, 214))	('C228T', 'Mutation', 'rs750304263', (285, 290))	('G372C', 'Mutation', 'rs121913479', (167, 172))	('K652M', 'Var', (209, 214))	('K652Q', 'Var', (216, 221))	('K652T', 'Var', (226, 231))	('S249C', 'Mutation', 'rs121913483', (160, 165))	('FGFR', 'molecular_function', 'GO:0005007', ('130', '134'))	('activating', 'PosReg', (119, 129))	('K652Q', 'Mutation', 'rs78311289', (216, 221))	('Y375C', 'Mutation', 'rs121913485', (181, 186))	('R248C', 'Var', (153, 158))	('R248C', 'Mutation', 'rs121913482', (153, 158))	('TERT', 'Gene', (242, 246))	('TERT', 'Gene', '7015', (242, 246))	('S373C', 'Var', (174, 179))	('K652E', 'Var', (202, 207))	('K652E', 'Mutation', 'rs1228165704', (202, 207))	('FGFR3', 'Gene', (130, 135))	('G382R', 'Mutation', 'rs28931614', (188, 193))	('C250T', 'Mutation', 'rs1064793519', (302, 307))	('FGFR3', 'Gene', '2261', (130, 135))	('S373C', 'Mutation', 'rs121913484', (174, 179))	('K652T', 'Mutation', 'rs121913105', (226, 231))	('A393E', 'Mutation', 'rs28931615', (195, 200))	('Y375C', 'Var', (181, 186))	('G372C', 'Var', (167, 172))	('A393E', 'Var', (195, 200))	('S249C', 'Var', (160, 165))	('G382R', 'Var', (188, 193))
30508	32198650	Since all oncogenic hotspots except for FGFR3 were sufficiently covered, 11 activating FGFR3 mutations were additionally sequenced with SNaPshot  analysis.	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('mutations', 'Var', (93, 102))	('FGFR3', 'Gene', '2261', (87, 92))	('FGFR3', 'Gene', (40, 45))	('FGFR3', 'Gene', (87, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('FGFR3', 'Gene', '2261', (40, 45))
30513	32198650	We detected two mutations of CTNNB1 (1/12 BAC; 1/13 UAC) and six mutations of APC (3/12 BAC; 2/13 UAC; 1/11 UCg); however, CTNNB1 mutations were not common activation hotspot mutations and no nuclear beta-catenin staining was detected in subsequent immunohistochemistry (see Table 2).	('BAC', 'Phenotype', 'HP:0002862', (42, 45))	('APC (3/12 BAC; 2/13 UAC; 1/11 UCg', 'Gene', '996', (78, 111))	('CTNNB1', 'Gene', (123, 129))	('CTNNB1', 'Gene', '1499', (29, 35))	('UAC', 'Phenotype', 'HP:0012618', (52, 55))	('beta-catenin', 'Gene', (200, 212))	('BAC', 'Phenotype', 'HP:0002862', (88, 91))	('mutations', 'Var', (130, 139))	('CTNNB1', 'Gene', '1499', (123, 129))	('beta-catenin', 'Gene', '1499', (200, 212))	('CTNNB1', 'Gene', (29, 35))	('UAC', 'Phenotype', 'HP:0012618', (98, 101))	('APC', 'cellular_component', 'GO:0005680', ('78', '81'))
30524	32198650	3b) associated with a truncating ARID1A mutation and additional loss of the non-mutated allele in the tumour tissue (Fig.	('mutation', 'Var', (40, 48))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('truncating', 'MPA', (22, 32))	('associated', 'Reg', (4, 14))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Disease', (102, 108))	('loss', 'NegReg', (64, 68))	('ARID1A', 'Gene', '8289', (33, 39))	('ARID1A', 'Gene', (33, 39))
30527	32198650	Due to the known heterogeneous performance of currently available anti-PD-L1 antibodies, all available samples (12 BAC, 3 UAC and 10 UCg) were stained with four different anti-PD-L1 antibody clones (28-8, SP142, SP263, 22C3).	('antibody', 'cellular_component', 'GO:0042571', ('182', '190'))	('BAC', 'Phenotype', 'HP:0002862', (115, 118))	('PD-L1', 'Gene', '29126', (176, 181))	('antibody', 'cellular_component', 'GO:0019815', ('182', '190'))	('PD-L1', 'Gene', (71, 76))	('SP142', 'Var', (205, 210))	('antibody', 'cellular_component', 'GO:0019814', ('182', '190'))	('PD-L1', 'Gene', '29126', (71, 76))	('antibody', 'molecular_function', 'GO:0003823', ('182', '190'))	('SP263', 'Var', (212, 217))	('28-8', 'Var', (199, 203))	('UAC', 'Phenotype', 'HP:0012618', (122, 125))	('PD-L1', 'Gene', (176, 181))
30536	32198650	The three sequenced CG cases showed neither oncogenic SNV nor CNA in any of the 20 genes, but in the IM sample, a FBXW7 alteration (R505G) predicting loss of function was identified (Supplementary Tables 2 and 3).	('R505G', 'Mutation', 'rs149680468', (132, 137))	('alteration (R505G', 'Var', (120, 137))	('R505G', 'Var', (132, 137))	('FBXW7', 'Gene', '55294', (114, 119))	('loss', 'NegReg', (150, 154))	('FBXW7', 'Gene', (114, 119))
30543	32198650	described APC and CTNNB1 mutations and nuclear ss-catenin expression (alterations of Wnt signaling) to be involved in BAC development.	('mutations', 'Var', (25, 34))	('CTNNB1', 'Gene', '1499', (18, 24))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('involved', 'Reg', (106, 114))	('BAC', 'Phenotype', 'HP:0002862', (118, 121))	('APC', 'cellular_component', 'GO:0005680', ('10', '13'))	('APC', 'Disease', 'MESH:D011125', (10, 13))	('APC', 'Disease', (10, 13))	('CTNNB1', 'Gene', (18, 24))
30545	32198650	We also revealed variants in the Wnt pathway-regulating gene SMAD4, which have not been described to be altered in BAC so far.	('BAC', 'Phenotype', 'HP:0002862', (115, 118))	('variants', 'Var', (17, 25))	('SMAD4', 'Gene', (61, 66))	('SMAD4', 'Gene', '4089', (61, 66))
30546	32198650	SMAD4 is a tumour suppressor, and transcription factor of the TGF-ss pathway and loss of function alterations have been shown to cause, for instance, impaired response to chemotherapy in colorectal cancer.	('colorectal cancer', 'Disease', (187, 204))	('SMAD4', 'Gene', '4089', (0, 5))	('loss of function', 'NegReg', (81, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (187, 204))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('SMAD4', 'Gene', (0, 5))	('alterations', 'Var', (98, 109))	('tumour', 'Disease', 'MESH:D009369', (11, 17))	('transcription', 'biological_process', 'GO:0006351', ('34', '47'))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('transcription factor', 'molecular_function', 'GO:0000981', ('34', '54'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (187, 204))	('impaired', 'NegReg', (150, 158))	('TGF-ss', 'Gene', (62, 68))	('tumour', 'Disease', (11, 17))	('response to chemotherapy', 'MPA', (159, 183))
30548	32198650	However, functional SMAD4 inactivation alone is not sufficient for tumour initiation, but it is thought to promote tumour progression in conjunction with additional alterations, e.g.	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('inactivation', 'Var', (26, 38))	('SMAD4', 'Gene', '4089', (20, 25))	('tumour', 'Disease', (67, 73))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('SMAD4', 'Gene', (20, 25))	('tumour initiation', 'Disease', 'MESH:D009369', (67, 84))	('tumour', 'Disease', 'MESH:D009369', (67, 73))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('promote', 'PosReg', (107, 114))	('tumour initiation', 'Disease', (67, 84))	('tumour', 'Disease', (115, 121))
30549	32198650	activating KRAS (pancreatic duct adenocarcinoma) or inactivating APC alterations (colorectal cancer).	('pancreatic duct adenocarcinoma', 'Disease', (17, 47))	('colorectal cancer', 'Disease', (82, 99))	('KRAS', 'Gene', (11, 15))	('activating', 'Var', (0, 10))	('APC', 'Disease', 'MESH:D011125', (65, 68))	('KRAS', 'Gene', '3845', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('pancreatic duct adenocarcinoma', 'Disease', 'MESH:D010190', (17, 47))	('APC', 'cellular_component', 'GO:0005680', ('65', '68'))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('APC', 'Disease', (65, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('inactivating', 'Var', (52, 64))
30551	32198650	and ours, and alterations of FBXW7 (no hotspot variants but cases with loss of function through either mutation or deletion detected) were similar.	('mutation', 'Var', (103, 111))	('deletion', 'Var', (115, 123))	('FBXW7', 'Gene', '55294', (29, 34))	('FBXW7', 'Gene', (29, 34))
30553	32198650	reported PIK3CA mutations as a potential druggable target in BAC, which we also confirmed in two samples.	('BAC', 'Phenotype', 'HP:0002862', (61, 64))	('PIK3CA', 'Gene', '5290', (9, 15))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (9, 15))
30554	32198650	Furthermore, we identified two cases with BRAF mutations of which one (sample AEM-1) exhibited a hotspot V600E variant.	('BRAF', 'Gene', '673', (42, 46))	('V600E', 'Mutation', 'rs113488022', (105, 110))	('mutations', 'Var', (47, 56))	('V600E', 'Var', (105, 110))	('BRAF', 'Gene', (42, 46))
30556	32198650	was the absence of any SNV or CNA in BAC with mucinous histology; however, both analysed mucinous BAC cases in our cohort exhibited several mutations in KRAS, TP53 and ARID1A, SMAD4, TP53, respectively.	('TP53', 'Gene', '7157', (183, 187))	('SMAD4', 'Gene', '4089', (176, 181))	('ARID1A', 'Gene', '8289', (168, 174))	('KRAS', 'Gene', (153, 157))	('TP53', 'Gene', (183, 187))	('ARID1A', 'Gene', (168, 174))	('TP53', 'Gene', (159, 163))	('KRAS', 'Gene', '3845', (153, 157))	('TP53', 'Gene', '7157', (159, 163))	('BAC', 'Phenotype', 'HP:0002862', (98, 101))	('BAC', 'Phenotype', 'HP:0002862', (37, 40))	('mutations', 'Var', (140, 149))	('SMAD4', 'Gene', (176, 181))	('exhibited', 'Reg', (122, 131))
30558	32198650	detected TERT promoter mutations only in non-enteric BAC and Roy et al.	('mutations', 'Var', (23, 32))	('BAC', 'Phenotype', 'HP:0002862', (53, 56))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (9, 13))
30564	32198650	BRAF mutations, single cases of MET, ERBB2 and EGFR amplification) while exome-wide studies revealed recurrent alterations in TP53, Wnt/TGF-ss and MAP kinase pathways similar to those detected in our study including 13 UAC samples.	('ERBB2', 'Gene', (37, 42))	('UAC', 'Phenotype', 'HP:0012618', (219, 222))	('ERBB2', 'Gene', '2064', (37, 42))	('alterations', 'Reg', (111, 122))	('TP53', 'Gene', (126, 130))	('MAP kinase pathways', 'Pathway', (147, 166))	('EGFR', 'molecular_function', 'GO:0005006', ('47', '51'))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('EGFR', 'Gene', '1956', (47, 51))	('MAP', 'molecular_function', 'GO:0004239', ('147', '150'))	('BRAF', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (126, 130))	('EGFR', 'Gene', (47, 51))
30566	32198650	Bearing in mind that SMAD4 function is thought to be a characteristic of adenocarcinomas, triggering tumour progression in close association with further mutational drivers such as activating KRAS, involvement of comparable molecular pathways driving tumourigenesis of adenocarcinomas like BAC, UAC and CORAD could be suggested independently of the tissue origin.	('function', 'Var', (27, 35))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('tumour', 'Disease', 'MESH:D009369', (251, 257))	('BAC', 'Phenotype', 'HP:0002862', (290, 293))	('tumour', 'Disease', (251, 257))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('KRAS', 'Gene', '3845', (192, 196))	('tumour', 'Disease', (101, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('KRAS', 'Gene', (192, 196))	('SMAD4', 'Gene', (21, 26))	('UAC', 'Disease', (295, 298))	('adenocarcinomas', 'Disease', 'MESH:D000230', (73, 88))	('BAC', 'Disease', (290, 293))	('adenocarcinomas', 'Disease', (73, 88))	('triggering', 'Reg', (90, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('CORAD', 'Disease', (303, 308))	('SMAD4', 'Gene', '4089', (21, 26))	('adenocarcinomas', 'Disease', 'MESH:D000230', (269, 284))	('adenocarcinomas', 'Disease', (269, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('carcinomas', 'Phenotype', 'HP:0030731', (274, 284))	('UAC', 'Phenotype', 'HP:0012618', (295, 298))	('activating', 'Var', (181, 191))
30571	32198650	We furthermore identified a TERT promoter mutation and a missense FBXW7 variant in one of the tested glandular preinvasive lesions (IM sample).	('FBXW7', 'Gene', '55294', (66, 71))	('TERT', 'Gene', (28, 32))	('TERT', 'Gene', '7015', (28, 32))	('FBXW7', 'Gene', (66, 71))	('variant', 'Var', (72, 79))
30572	32198650	The detected FBXW7 R505G mutation is located in the WD repeat domain at a recurrently altered hotspot (R505) with R505L and R505C associated with a loss of function through disruption of substrate binding.	('loss', 'NegReg', (148, 152))	('R505C', 'Mutation', 'rs149680468', (124, 129))	('FBXW7', 'Gene', '55294', (13, 18))	('R505L', 'Mutation', 'rs1057519896', (114, 119))	('disruption', 'Reg', (173, 183))	('FBXW7', 'Gene', (13, 18))	('R505G', 'Mutation', 'rs149680468', (19, 24))	('R505C', 'Var', (124, 129))	('R505L', 'Var', (114, 119))	('R505G', 'Var', (19, 24))	('substrate binding', 'Interaction', (187, 204))	('binding', 'molecular_function', 'GO:0005488', ('197', '204'))
30573	32198650	The tumour suppressor FBXW7 binds to proto-oncogenes mediating degradation, while dysregulation leads to chromosomal instability and tumourigenesis due to accumulation of oncoproteins.	('oncoproteins', 'Protein', (171, 183))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('dysregulation', 'Var', (82, 95))	('FBXW7', 'Gene', (22, 27))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('accumulation', 'PosReg', (155, 167))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('leads to', 'Reg', (96, 104))	('chromosomal instability', 'MPA', (105, 128))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (133, 139))	('degradation', 'biological_process', 'GO:0009056', ('63', '74'))	('tumour', 'Disease', (4, 10))	('FBXW7', 'Gene', '55294', (22, 27))	('chromosomal instability', 'Phenotype', 'HP:0040012', (105, 128))
30574	32198650	In line with previous analysis of TERT promoter mutations in glandular bladder tumours including 25 benign glandular lesions of the bladder (with 5 CG samples amongst Brunn nests, cystitis cystica and nephrogenic adenoma), we did not detect any TERT variants in the tested CG samples.	('cystitis cystica', 'Disease', (180, 196))	('glandular bladder tumours', 'Disease', (61, 86))	('cystitis cystica', 'Disease', 'MESH:D003556', (180, 196))	('TERT', 'Gene', '7015', (245, 249))	('nephrogenic adenoma', 'Disease', 'MESH:D000236', (201, 220))	('TERT', 'Gene', (34, 38))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('glandular bladder tumours', 'Disease', 'MESH:D001749', (61, 86))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('TERT', 'Gene', '7015', (34, 38))	('nephrogenic adenoma', 'Disease', (201, 220))	('TERT', 'Gene', (245, 249))	('mutations', 'Var', (48, 57))
30578	32198650	Single SWI/SNF alterations (ARID1A loss in one BAC sample; no alterations in the two analysed UAC samples; two UCg cases with loss of either SMARCA2 or PBMR1 expression) can be found predominantly in the urothelial glandular tumours, with currently no therapeutic consequences.	('urothelial glandular tumours', 'Disease', 'MESH:D002277', (204, 232))	('loss', 'NegReg', (35, 39))	('urothelial glandular tumours', 'Disease', (204, 232))	('ARID1A', 'Gene', '8289', (28, 34))	('ARID1A', 'Gene', (28, 34))	('tumours', 'Phenotype', 'HP:0002664', (225, 232))	('UAC', 'Phenotype', 'HP:0012618', (94, 97))	('alterations', 'Var', (15, 26))	('loss', 'NegReg', (126, 130))	('SMARCA2', 'Gene', (141, 148))	('SMARCA2', 'Gene', '6595', (141, 148))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('BAC', 'Phenotype', 'HP:0002862', (47, 50))	('PBMR1', 'Gene', (152, 157))	('SWI/SNF', 'Gene', (7, 14))
30604	31475242	Additionally, the methods for calculating TMB are inconsistent, especially the inclusion or exclusion of synonymous mutations.	('TMB', 'Chemical', '-', (42, 45))	('synonymous mutations', 'Var', (105, 125))	('TMB', 'MPA', (42, 45))
30627	31475242	For example, the TMB for prostate cancer in TCGA ranged from 0.03 mutations/Mb to 14.13 mutations/Mb, with a mean of 1.23 mutations/Mb (n = 326).	('mutations/Mb', 'Var', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('TMB', 'Chemical', '-', (17, 20))	('prostate cancer', 'Disease', 'MESH:D011471', (25, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (25, 40))	('prostate cancer', 'Disease', (25, 40))
30628	31475242	However, the TMB for bladder cancer in TCGA ranged from 0.04 mutations/Mb to 99.68 mutations/Mb with a mean of 6.92 mutations/Mb (n = 375).	('bladder cancer', 'Phenotype', 'HP:0009725', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('mutations/Mb', 'Var', (61, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (21, 35))	('bladder cancer', 'Disease', (21, 35))	('TMB', 'Chemical', '-', (13, 16))
30640	31475242	UCEC also showed significantly improved survival for TMB high patients compared to TMB low when using Chalmers et al (log-rank p-value = 0.023), but did not reach significance when using WCM (log-rank p-value = 0.055) (Supplemental Figure 6).	('improved', 'PosReg', (31, 39))	('high', 'Var', (57, 61))	('TMB', 'Disease', (53, 56))	('TMB', 'Chemical', '-', (83, 86))	('survival', 'MPA', (40, 48))	('patients', 'Species', '9606', (62, 70))	('TMB', 'Chemical', '-', (53, 56))	('WCM', 'Chemical', '-', (187, 190))
30672	31475242	Additionally, patients with low TMB and stage III bladder cancer had the lowest survival rate.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (50, 64))	('survival rate', 'CPA', (80, 93))	('bladder cancer', 'Disease', (50, 64))	('TMB', 'Chemical', '-', (32, 35))	('lowest', 'NegReg', (73, 79))	('low', 'Var', (28, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (50, 64))	('patients', 'Species', '9606', (14, 22))
30676	31475242	For example, the Chalmers et al cutoff of 20 mutations/Mb is higher than the maximum TMB seen within TCGA prostate cancer (14.13 mutations/Mb), however using a lower threshold might be too lenient for TCGA bladder cancer (maximum TMB of 99.68 mutations/Mb).	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('TMB', 'Chemical', '-', (230, 233))	('bladder cancer', 'Phenotype', 'HP:0009725', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('prostate cancer', 'Disease', (106, 121))	('bladder cancer', 'Disease', 'MESH:D001749', (206, 220))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))	('mutations/Mb', 'Var', (45, 57))	('bladder cancer', 'Disease', (206, 220))	('TMB', 'Chemical', '-', (85, 88))
30695	31475242	Mutational signatures for these samples showed a cluster of patients with POLE deficiency, which leads to a large number of mutations and a TMB distribution with a large IQR, causing the cancer-specific threshold to be strict in this case.	('POLE deficiency', 'Disease', (74, 89))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('POLE deficiency', 'Disease', 'MESH:D007153', (74, 89))	('TMB', 'Chemical', '-', (140, 143))	('mutations', 'Var', (124, 133))	('cancer', 'Disease', (187, 193))	('patients', 'Species', '9606', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
30702	31475242	A recent study has shown that melanoma and NSCLC patients with heterozygous HLA class I exhibit improved survival than patients who are homozygous.	('improved', 'PosReg', (96, 104))	('heterozygous', 'Var', (63, 75))	('patients', 'Species', '9606', (119, 127))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('patients', 'Species', '9606', (49, 57))	('melanoma', 'Disease', (30, 38))	('NSCLC', 'Disease', (43, 48))	('survival', 'CPA', (105, 113))	('HLA class', 'Gene', (76, 85))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
30706	31151482	Mismatch repair pathways play a vital role in identifying and repairing mismatched bases during DNA replication and genetic recombination in normal and cancer cells.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Mismatch repair', 'biological_process', 'GO:0006298', ('0', '15'))	('DNA replication', 'biological_process', 'GO:0006260', ('96', '111'))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mismatched bases', 'Var', (72, 88))
30707	31151482	Defects in DNA mismatch repair proteins and subsequent microsatellite instability-high lead to the accumulation of mutation loads in cancer-related genes and the generation of neoantigens, which stimulate the anti-tumor immune response of the host.	('Defects', 'NegReg', (0, 7))	('neoantigens', 'MPA', (176, 187))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('DNA mismatch repair proteins', 'Protein', (11, 39))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('stimulate', 'PosReg', (195, 204))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('microsatellite', 'MPA', (55, 69))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('cancer', 'Disease', (133, 139))	('immune response', 'biological_process', 'GO:0006955', ('220', '235'))	('tumor', 'Disease', (214, 219))	('lead', 'Reg', (87, 91))	('mutation', 'Var', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mismatch repair', 'biological_process', 'GO:0006298', ('15', '30'))
30708	31151482	Mismatch repair deficiency/microsatellite instability-high represents a good prognosis in early colorectal cancer settings without adjuvant treatment and a poor prognosis in patients with metastasis.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Mismatch repair', 'biological_process', 'GO:0006298', ('0', '15'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('patients', 'Species', '9606', (174, 182))	('deficiency', 'Disease', (16, 26))	('colorectal cancer', 'Disease', (96, 113))	('deficiency', 'Disease', 'MESH:D007153', (16, 26))	('Mismatch', 'Var', (0, 8))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
30709	31151482	Several clinical trials have demonstrated that mismatch repair deficiency or microsatellite instability-high is significantly associated with long-term immunotherapy-related responses and better prognosis in colorectal and noncolorectal malignancies treated with immune checkpoint inhibitors.	('mismatch repair', 'Protein', (47, 62))	('associated', 'Reg', (126, 136))	('colorectal and noncolorectal malignancies', 'Disease', 'MESH:D009369', (208, 249))	('deficiency', 'Disease', (63, 73))	('mismatch repair', 'biological_process', 'GO:0006298', ('47', '62'))	('deficiency', 'Disease', 'MESH:D007153', (63, 73))	('microsatellite instability-high', 'Var', (77, 108))
30710	31151482	To date, the anti-programmed cell death-1 inhibitor pembrolizumab has been approved for mismatch repair deficiency/microsatellite instability-high refractory or metastatic solid tumors, and nivolumab has been approved for colorectal cancer patients with mismatch repair deficiency/microsatellite instability-high.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('nivolumab', 'Chemical', 'MESH:D000077594', (190, 199))	('mismatch repair', 'biological_process', 'GO:0006298', ('88', '103'))	('colorectal cancer', 'Disease', 'MESH:D015179', (222, 239))	('deficiency', 'Disease', 'MESH:D007153', (104, 114))	('solid tumors', 'Disease', (172, 184))	('deficiency', 'Disease', 'MESH:D007153', (270, 280))	('colorectal cancer', 'Disease', (222, 239))	('deficiency', 'Disease', (104, 114))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('refractory', 'Disease', (147, 157))	('patients', 'Species', '9606', (240, 248))	('deficiency', 'Disease', (270, 280))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('programmed cell death', 'biological_process', 'GO:0012501', ('18', '39'))	('mismatch repair', 'biological_process', 'GO:0006298', ('254', '269'))	('solid tumors', 'Disease', 'MESH:D009369', (172, 184))	('pembrolizumab', 'Chemical', 'MESH:C582435', (52, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (222, 239))	('mismatch', 'Var', (88, 96))
30712	31151482	This review summarizes the features of mismatch repair deficiency/microsatellite instability-high, its relationship with programmed death-ligand 1/programmed cell death-1, and the recent advances in predicting immunotherapy efficacy.	('ligand', 'molecular_function', 'GO:0005488', ('138', '144'))	('mismatch repair', 'biological_process', 'GO:0006298', ('39', '54'))	('deficiency', 'Disease', (55, 65))	('deficiency', 'Disease', 'MESH:D007153', (55, 65))	('programmed cell death', 'biological_process', 'GO:0012501', ('147', '168'))	('mismatch', 'Var', (39, 47))
30726	31151482	MSH2/MSH6 heterodimers are responsible for binding to the initial DNA mismatched base errors (including single-base mismatch and incorrect insertion or deletion loop mismatch) by conformational changes, and MLH1/PMS2 heterodimers are in charge of the excision and synthesis of corrected DNA chains in the mismatch site (see Fig.	('synthesis', 'biological_process', 'GO:0009058', ('264', '273'))	('DNA', 'cellular_component', 'GO:0005574', ('287', '290'))	('deletion', 'Var', (152, 160))	('binding', 'Interaction', (43, 50))	('MSH2', 'Gene', (0, 4))	('PMS2', 'Gene', '5395', (212, 216))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('mismatched', 'Var', (70, 80))	('MSH6', 'Gene', (5, 9))	('MSH2', 'Gene', '4436', (0, 4))	('mismatch', 'Var', (166, 174))	('incorrect insertion', 'Var', (129, 148))	('binding', 'molecular_function', 'GO:0005488', ('43', '50'))	('MLH1', 'Gene', '4292', (207, 211))	('PMS2', 'Gene', (212, 216))	('MSH6', 'Gene', '2956', (5, 9))	('MLH1', 'Gene', (207, 211))
30729	31151482	The dysfunction of MLH1 or MSH2 leads to the inactivation of MLH1/PMS2 or MSH2/MSH6 and the degradation of PMS2 or MSH6 (see Fig.	('MSH2', 'Gene', '4436', (74, 78))	('MSH6', 'Gene', '2956', (79, 83))	('degradation', 'biological_process', 'GO:0009056', ('92', '103'))	('PMS2', 'Gene', '5395', (66, 70))	('MLH1', 'Gene', (61, 65))	('dysfunction', 'Var', (4, 15))	('PMS2', 'Gene', (107, 111))	('degradation', 'MPA', (92, 103))	('MLH1', 'Gene', (19, 23))	('MLH1', 'Gene', '4292', (61, 65))	('MSH6', 'Gene', (115, 119))	('MSH2', 'Gene', (27, 31))	('PMS2', 'Gene', (66, 70))	('MSH6', 'Gene', '2956', (115, 119))	('MLH1', 'Gene', '4292', (19, 23))	('MSH2', 'Gene', (74, 78))	('inactivation', 'NegReg', (45, 57))	('MSH2', 'Gene', '4436', (27, 31))	('PMS2', 'Gene', '5395', (107, 111))	('MSH6', 'Gene', (79, 83))
30730	31151482	Lynch syndrome is a common hereditary disease that is characterized by germline mutations in MMR genes.	('MMR', 'Gene', (93, 96))	('hereditary disease', 'Disease', (27, 45))	('germline mutations', 'Var', (71, 89))	('hereditary disease', 'Disease', 'MESH:D030342', (27, 45))	('Lynch syndrome', 'Disease', (0, 14))	('MMR', 'biological_process', 'GO:0006298', ('93', '96'))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))
30732	31151482	A lack of MSH2, substantial mutations in the MLH1 or MSH2 genes, MLH1-methylation inactivation, and transcriptional silencing lead to Lynch syndrome.	('MSH2', 'Gene', (53, 57))	('MSH2', 'Gene', '4436', (53, 57))	('methylation', 'biological_process', 'GO:0032259', ('70', '81'))	('Lynch syndrome', 'Disease', 'MESH:D003123', (134, 148))	('MSH2', 'Gene', (10, 14))	('silencing', 'NegReg', (116, 125))	('MLH1', 'Gene', '4292', (45, 49))	('MLH1', 'Gene', '4292', (65, 69))	('MSH2', 'Gene', '4436', (10, 14))	('MLH1', 'Gene', (45, 49))	('lead to', 'Reg', (126, 133))	('MLH1', 'Gene', (65, 69))	('Lynch syndrome', 'Disease', (134, 148))	('lack', 'NegReg', (2, 6))	('mutations', 'Var', (28, 37))
30733	31151482	Deletion mutations in MLH1 and MSH2 account for 42-50% and 33-39%; however, MSH6 and PMS2 mutations account for only 7-18% and less than 7%, respectively.	('PMS2', 'Gene', (85, 89))	('PMS2', 'Gene', '5395', (85, 89))	('MLH1', 'Gene', '4292', (22, 26))	('MLH1', 'Gene', (22, 26))	('MSH6', 'Gene', (76, 80))	('MSH6', 'Gene', '2956', (76, 80))	('MSH2', 'Gene', (31, 35))	('MSH2', 'Gene', '4436', (31, 35))	('Deletion mutations', 'Var', (0, 18))
30734	31151482	A hypothesis that heterozygous germline deletions in the epithelial cell adhesion molecule (EPCAM) gene as one factor that leads to MSH2 defects has been confirmed, and the addition of EPCAM to the diagnostic panel for Lynch syndrome in MSH2-defective tumors has been advised.	('defects', 'Var', (137, 144))	('EPCAM', 'Gene', '4072', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('epithelial cell adhesion molecule', 'Gene', (57, 90))	('epithelial cell adhesion molecule', 'Gene', '4072', (57, 90))	('EPCAM', 'Gene', (92, 97))	('Lynch syndrome', 'Disease', (219, 233))	('MSH2', 'Gene', (237, 241))	('MSH2', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('68', '90'))	('Lynch syndrome', 'Disease', 'MESH:D003123', (219, 233))	('EPCAM', 'Gene', (185, 190))	('MSH2', 'Gene', '4436', (237, 241))	('MSH2', 'Gene', '4436', (132, 136))	('leads to', 'Reg', (123, 131))	('cell adhesion', 'biological_process', 'GO:0007155', ('68', '81'))	('MSH2-defective tumors', 'Disease', (237, 258))	('EPCAM', 'Gene', '4072', (92, 97))	('MSH2-defective tumors', 'Disease', 'MESH:D009369', (237, 258))
30735	31151482	The inactivation of MMR genes and MMR protein dysfunction may be the results of germline mutations or spontaneous hypermutation alterations, which may induce microsatellite instability (MSI).	('protein dysfunction', 'Disease', 'MESH:D011488', (38, 57))	('inactivation', 'Var', (4, 16))	('MMR', 'biological_process', 'GO:0006298', ('34', '37'))	('induce', 'Reg', (151, 157))	('protein dysfunction', 'Disease', (38, 57))	('MMR genes', 'Gene', (20, 29))	('MMR', 'biological_process', 'GO:0006298', ('20', '23'))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('MMR', 'Gene', (34, 37))	('microsatellite instability', 'MPA', (158, 184))
30736	31151482	Two mononucleotide repeats (BAT25 and BAT26) and three dinucleotide repeats (D5S346, D2S123, and D17S250) are the standard sites in panels for MSI testing, as recommended by the National Cancer Institute in 1998.	('Cancer', 'Disease', 'MESH:D009369', (187, 193))	('BAT26', 'Var', (38, 43))	('Cancer', 'Disease', (187, 193))	('dinucleotide', 'Chemical', 'MESH:D015226', (55, 67))	('D5S346', 'Var', (77, 83))	('mononucleotide', 'Chemical', '-', (4, 18))	('D2S123', 'Var', (85, 91))	('BAT25', 'Var', (28, 33))	('Cancer', 'Phenotype', 'HP:0002664', (187, 193))	('D17S250', 'Var', (97, 104))
30757	31151482	In general, dMMR is correlated with an improved median overall survival (mOS) in most tumors other than head and neck cancer and pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('mOS', 'Gene', (73, 76))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('overall survival', 'MPA', (55, 71))	('tumors', 'Disease', (86, 92))	('mOS', 'Gene', '17451', (73, 76))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('improved', 'PosReg', (39, 47))	('dMMR', 'Chemical', '-', (12, 16))	('head and neck cancer', 'Phenotype', 'HP:0012288', (104, 124))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('neck cancer', 'Disease', 'MESH:D006258', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('dMMR', 'Var', (12, 16))	('neck cancer', 'Disease', (113, 124))	('pancreatic cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('neck', 'cellular_component', 'GO:0044326', ('113', '117'))
30764	31151482	Most results indicated that dMMR is a positive prognostic factor in early-stage (II/III) rather than late-stage (IV).	('early-stage', 'Disease', (68, 79))	('dMMR', 'Var', (28, 32))	('dMMR', 'Chemical', '-', (28, 32))
30767	31151482	They pooled the data and showed that MSS patients treated with 5-fluorouracil had a better prognosis but that the benefit was not obvious for MSI-H CRC patients (OR 0.52, 95% CI 0.4-0.6, P < 0.0001 versus OR 0.69, 95% CI 0.3-1.5, P = 0.10).	('patients', 'Species', '9606', (41, 49))	('5-fluorouracil', 'Var', (63, 77))	('CRC', 'Phenotype', 'HP:0003003', (148, 151))	('MSI-H', 'Disease', (142, 147))	('better', 'PosReg', (84, 90))	('patients', 'Species', '9606', (152, 160))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (63, 77))	('MSI-H', 'Disease', 'MESH:D000848', (142, 147))
30768	31151482	also concluded that patients with stages II-III CRC with pMMR exhibited improved DFS (hazard ratio [HR] 0.67, 95% CI 0.48-0.93, P = 0.02) resulting from adjuvant therapy compared with those who underwent surgery alone.	('DFS', 'MPA', (81, 84))	('pMMR', 'Var', (57, 61))	('pMMR', 'Chemical', '-', (57, 61))	('improved', 'PosReg', (72, 80))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('patients', 'Species', '9606', (20, 28))
30772	31151482	A meta-analysis confirmed that mCRC patients with dMMR had poorer survival compared with pMMR patients, which might be due to a BRAF V600E mutation.	('survival', 'MPA', (66, 74))	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (36, 44))	('poorer', 'NegReg', (59, 65))	('V600E', 'Mutation', 'rs113488022', (133, 138))	('CRC', 'Phenotype', 'HP:0003003', (32, 35))	('pMMR', 'Chemical', '-', (89, 93))	('V600E', 'Var', (133, 138))	('BRAF', 'Gene', '673', (128, 132))	('dMMR', 'Chemical', '-', (50, 54))	('BRAF', 'Gene', (128, 132))
30837	31151482	A higher number of mutations in DNA coding sequences in MSI-H tumors have more potential to stimulate the host to generate neoantigens and trigger immune activation.	('immune activation', 'MPA', (147, 164))	('stimulate', 'PosReg', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('MSI-H tumors', 'Disease', 'MESH:D009369', (56, 68))	('generate neoantigens', 'MPA', (114, 134))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('MSI-H tumors', 'Disease', (56, 68))	('mutations', 'Var', (19, 28))	('DNA', 'Gene', (32, 35))
30843	31151482	In the CheckMate 568 trial, the ORR was 4%, 10%, 44%, and 39% when the TMB cutoffs were < 5, < 10, >= 10, and >= 15 mut/Mb in NSCLC patients treated with nivolumab plus ipilimumab as a first-line therapy.	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('< 10', 'Var', (93, 97))	('mut/Mb', 'Gene', (116, 122))	('>= 15', 'Var', (110, 115))	('nivolumab', 'Chemical', 'MESH:D000077594', (154, 163))	('< 5', 'Var', (88, 91))	('>= 10', 'Var', (99, 104))	('ipilimumab', 'Chemical', 'MESH:D000074324', (169, 179))	('CheckMate', 'Chemical', 'MESH:C049437', (7, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('TMB', 'Chemical', '-', (71, 74))	('SCLC', 'Phenotype', 'HP:0030357', (127, 131))	('patients', 'Species', '9606', (132, 140))	('NSCLC', 'Disease', (126, 131))
30845	31151482	The prospective phase III trial confirmed that nivolumab plus ipilimumab resulted in a significantly longer PFS and higher ORR only in high TMB patients with stage IV or recurrent NSCLC compared with chemotherapy (mPFS 7.2 months vs 5.5 months; ORR 45.3% vs 26.9%).	('ORR', 'MPA', (123, 126))	('longer', 'PosReg', (101, 107))	('SCLC', 'Phenotype', 'HP:0030357', (181, 185))	('TMB', 'Chemical', '-', (140, 143))	('ipilimumab', 'Chemical', 'MESH:D000074324', (62, 72))	('nivolumab', 'Chemical', 'MESH:D000077594', (47, 56))	('NSCLC', 'Disease', (180, 185))	('PFS', 'MPA', (108, 111))	('high TMB', 'Var', (135, 143))	('patients', 'Species', '9606', (144, 152))	('NSCLC', 'Disease', 'MESH:D002289', (180, 185))	('ipilimumab', 'Gene', (62, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (180, 185))
30847	31151482	The CheckMate 032 trial demonstrated better clinical benefit in high TMB (TMB >= 248 mutations) patients with SCLC.	('SCLC', 'Phenotype', 'HP:0030357', (110, 114))	('CheckMate', 'Chemical', 'MESH:C049437', (4, 13))	('TMB', 'Chemical', '-', (69, 72))	('patients', 'Species', '9606', (96, 104))	('TMB', 'Chemical', '-', (74, 77))	('SCLC', 'Disease', (110, 114))	('high TMB', 'Var', (64, 72))	('SCLC', 'Disease', 'MESH:D018288', (110, 114))
30853	31151482	In clinical validation, 50 patients with NSCLC with high bTMB (>= 6 mut/Mb) was associated with prolonged mPFS and higher ORR than patients with low bTMB (< 6 mut/Mb) (mPFS not reach vs 2.9 m; ORR 39.3% vs 9.1%) when treated with anti-PD-1/PD-L1 therapies (see Table 5).	('patients', 'Species', '9606', (131, 139))	('PD-1', 'Gene', '5133', (235, 239))	('NSCLC', 'Disease', (41, 46))	('SCLC', 'Phenotype', 'HP:0030357', (42, 46))	('ORR', 'MPA', (122, 125))	('mPFS', 'CPA', (106, 110))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('patients', 'Species', '9606', (27, 35))	('high', 'Var', (52, 56))	('PD-L1', 'Gene', (240, 245))	('bTMB', 'Chemical', '-', (149, 153))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('PD-L1', 'Gene', '29126', (240, 245))	('PD-1', 'Gene', (235, 239))	('bTMB', 'Chemical', '-', (57, 61))
30858	31151482	Patients with high-TMB and positive PD-L1 expression had the highest rate of durable clinical benefit than that with only one or neither variable presence (50% vs. 18.2-35.5%).	('PD-L1', 'Gene', (36, 41))	('Patients', 'Species', '9606', (0, 8))	('expression', 'Var', (42, 52))	('PD-L1', 'Gene', '29126', (36, 41))	('TMB', 'Chemical', '-', (19, 22))	('high-TMB', 'Var', (14, 22))
30897	29065504	For example, H2O2 has been shown to stimulate an activating mutation of the proto-oncogene, c-Ha-ras-1, whereas it inhibits the function of the tumor-suppressor gene, p53.	('c-Ha-ras-1', 'Gene', (92, 102))	('tumor', 'Disease', (144, 149))	('stimulate', 'PosReg', (36, 45))	('H2O2', 'Chemical', 'MESH:D006861', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('c-Ha-ras-1', 'Gene', '3265', (92, 102))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('144', '160'))	('function', 'MPA', (128, 136))	('p53', 'Gene', '7157', (167, 170))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('inhibits', 'NegReg', (115, 123))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('144', '160'))	('p53', 'Gene', (167, 170))	('H2O2', 'Var', (13, 17))	('activating mutation', 'MPA', (49, 68))
30898	29065504	In addition to such genetic changes, ROS are known to stimulate carcinogenesis via various epigenetic alterations.	('ROS', 'Gene', (37, 40))	('carcinogenesis', 'Disease', 'MESH:D063646', (64, 78))	('epigenetic alterations', 'Var', (91, 113))	('carcinogenesis', 'Disease', (64, 78))	('rat', 'Species', '10116', (106, 109))	('ROS', 'Chemical', 'MESH:D017382', (37, 40))	('stimulate', 'PosReg', (54, 63))
30899	29065504	The methylation of tumor-suppressor genes is the most representative epigenetic alteration in oxidative stress-induced carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (119, 133))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('rat', 'Species', '10116', (84, 87))	('methylation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('carcinogenesis', 'Disease', (119, 133))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('19', '35'))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('19', '35'))	('tumor', 'Disease', (19, 24))	('oxidative stress', 'Phenotype', 'HP:0025464', (94, 110))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
30900	29065504	For example, H2O2 has been reported to hypermethylate tumor-suppressor genes, such as retinoblastoma, Von Hippel-Lindau, and breast cancer 1.	('retinoblastoma', 'Disease', 'MESH:D012175', (86, 100))	('retinoblastoma', 'Disease', (86, 100))	('hypermethylate', 'Var', (39, 53))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (102, 119))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('54', '70'))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('H2O2', 'Gene', (13, 17))	('Von Hippel-Lindau', 'Disease', (102, 119))	('retinoblastoma', 'Phenotype', 'HP:0009919', (86, 100))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('54', '70'))	('breast cancer', 'Disease', (125, 138))	('tumor', 'Disease', (54, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('H2O2', 'Chemical', 'MESH:D006861', (13, 17))
30901	29065504	Furthermore, the activities of various proteins and signaling molecules, such as mitogen-activated protein kinase (MAPK) and extracellular regulated kinase (Erk)1/2 (associated with cell proliferation), nuclear factor kappaB (NFkappaB) (involved in cell proliferation and the cell cycle), and 3-phosphoinositide-dependent kinase (PDK)-1 (involved in cell proliferation and apoptosis), are affected by ROS.	('3-phosphoinositide-dependent kinase (PDK)-1', 'Gene', '5163', (293, 336))	('nuclear factor kappaB', 'Gene', '4790', (203, 224))	('ROS', 'Var', (401, 404))	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('PDK)-1', 'molecular_function', 'GO:0004740', ('330', '336'))	('NFkappaB', 'Gene', '4790', (226, 234))	('extracellular', 'cellular_component', 'GO:0005576', ('125', '138'))	('MAPK', 'Gene', (115, 119))	('rat', 'Species', '10116', (261, 264))	('extracellular regulated kinase (Erk)1/2', 'Gene', '5595;5594', (125, 164))	('NFkappaB', 'Gene', (226, 234))	('cell proliferation', 'biological_process', 'GO:0008283', ('249', '267'))	('cell proliferation', 'biological_process', 'GO:0008283', ('350', '368'))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('activities', 'MPA', (17, 27))	('rat', 'Species', '10116', (362, 365))	('apoptosis', 'biological_process', 'GO:0097194', ('373', '382'))	('Erk)1', 'molecular_function', 'GO:0004707', ('157', '162'))	('apoptosis', 'biological_process', 'GO:0006915', ('373', '382'))	('MAPK', 'molecular_function', 'GO:0004707', ('115', '119'))	('ROS', 'Chemical', 'MESH:D017382', (401, 404))	('rat', 'Species', '10116', (194, 197))	('nuclear factor kappaB', 'Gene', (203, 224))	('cell proliferation', 'biological_process', 'GO:0008283', ('182', '200'))	('cell cycle', 'biological_process', 'GO:0007049', ('276', '286'))	('MAPK', 'Gene', '5595;5594;5595', (115, 119))	('affected', 'Reg', (389, 397))	('proteins', 'Protein', (39, 47))
30902	29065504	Phosphoinositide 3-kinase (PI3K)/Akt (protein kinase B) signaling, implicated in cancer cell proliferation, is also modulated by ROS.	('PI3K', 'molecular_function', 'GO:0016303', ('27', '31'))	('Akt', 'Gene', '207', (33, 36))	('protein kinase B', 'Gene', '2185', (38, 54))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('Phosphoinositide 3-kinase', 'Gene', (0, 25))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('Phosphoinositide 3-kinase', 'Gene', '5294', (0, 25))	('cancer', 'Disease', (81, 87))	('ROS', 'Var', (129, 132))	('modulated', 'Reg', (116, 125))	('protein kinase B) signaling', 'biological_process', 'GO:0043491', ('38', '65'))	('Akt', 'Gene', (33, 36))	('cell proliferation', 'biological_process', 'GO:0008283', ('88', '106'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ROS', 'Chemical', 'MESH:D017382', (129, 132))	('rat', 'Species', '10116', (100, 103))	('protein kinase B', 'Gene', (38, 54))
30903	29065504	Interestingly, ROS can suppress the activity of phosphatase and tensin homolog (PTEN), recognized as inhibitor of PI3K/Akt signaling.	('PTEN', 'Gene', (80, 84))	('PI3K', 'molecular_function', 'GO:0016303', ('114', '118'))	('PTEN', 'Gene', '5728', (80, 84))	('Akt', 'Gene', '207', (119, 122))	('activity', 'MPA', (36, 44))	('suppress', 'NegReg', (23, 31))	('Akt', 'Gene', (119, 122))	('ROS', 'Chemical', 'MESH:D017382', (15, 18))	('Akt signaling', 'biological_process', 'GO:0043491', ('119', '132'))	('ROS', 'Var', (15, 18))	('phosphatase', 'molecular_function', 'GO:0016791', ('48', '59'))	('phosphatase', 'Protein', (48, 59))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('48', '78'))
30911	29065504	Interestingly, tissue inhibitors of metalloproteinases (TIMPs), endogenous inhibitors of MMPs, are downregulated by ROS.	('ROS', 'Var', (116, 119))	('MMPs', 'Gene', '4312', (89, 93))	('tissue inhibitors', 'MPA', (15, 32))	('ROS', 'Chemical', 'MESH:D017382', (116, 119))	('downregulated', 'NegReg', (99, 112))	('MMPs', 'Gene', (89, 93))
30930	29065504	NOX-mediated ROS are reported to stimulate various pro-oncogenes, such as Src and Ras, and to inhibit tumor suppressors, such as p53 and PTEN.	('ROS', 'Var', (13, 16))	('pro-oncogenes', 'MPA', (51, 64))	('tumor', 'Disease', (102, 107))	('Src', 'Gene', '6714', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('pro-oncogenes', 'Protein', (51, 64))	('NOX-mediated', 'Var', (0, 12))	('p53', 'Gene', (129, 132))	('PTEN', 'Gene', (137, 141))	('p53', 'Gene', '7157', (129, 132))	('PTEN', 'Gene', '5728', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Ras', 'Gene', (82, 85))	('inhibit', 'NegReg', (94, 101))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))	('Src', 'Gene', (74, 77))	('stimulate', 'PosReg', (33, 42))
30942	29065504	From this finding, it has been suggested that inhibition of ROS, induced by reflux, could be a useful strategy for preventing DNA damage and decreasing the risk of tumorigenic transformation caused by gastroesophageal reflux disease, which is the greatest risk factor for esophageal adenocarcinoma.	('ROS', 'Protein', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('inhibition', 'Var', (46, 56))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (272, 297))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (201, 224))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (201, 232))	('gastroesophageal reflux disease', 'Disease', (201, 232))	('preventing', 'NegReg', (115, 125))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('esophageal adenocarcinoma', 'Disease', (272, 297))	('DNA damage', 'MPA', (126, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('decreasing', 'NegReg', (141, 151))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (272, 297))	('ROS', 'Chemical', 'MESH:D017382', (60, 63))	('rat', 'Species', '10116', (104, 107))
30952	29065504	In addition, NOX4 stimulates angiogenesis through the upregulation of vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor (HIF)-1alpha in a variety of cancers, and siRNA-mediated knockdown of NOX4 inhibited VEGF-induced endothelial cell migration and proliferation.	('inhibited', 'NegReg', (218, 227))	('knockdown', 'Var', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('angiogenesis', 'CPA', (29, 41))	('endothelial cell migration', 'biological_process', 'GO:0043542', ('241', '267'))	('hypoxia-inducible factor (HIF)-1alpha', 'Gene', '3091', (118, 155))	('upregulation', 'PosReg', (54, 66))	('angiogenesis', 'biological_process', 'GO:0001525', ('29', '41'))	('vascular endothelial growth factor', 'Gene', (70, 104))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('70', '104'))	('cancers', 'Disease', (172, 179))	('stimulates', 'PosReg', (18, 28))	('vascular endothelial growth factor', 'Gene', '7422', (70, 104))	('rat', 'Species', '10116', (261, 264))	('rat', 'Species', '10116', (279, 282))	('NOX4', 'Gene', (13, 17))
30964	29065504	In contrast, in one report, the reintroduction of functional DUOX1 into lung cancer cell lines increased cell migration and wound repair, without affecting cell growth.	('cell migration', 'biological_process', 'GO:0016477', ('105', '119'))	('reintroduction', 'Var', (32, 46))	('DUOX1', 'Gene', '53905', (61, 66))	('rat', 'Species', '10116', (113, 116))	('cell growth', 'biological_process', 'GO:0016049', ('156', '167'))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('DUOX1', 'Gene', (61, 66))	('wound repair', 'CPA', (124, 136))	('increased', 'PosReg', (95, 104))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
30998	29065504	Interestingly, in rat prostate cancer, castration results in dramatic increases in NOX1, NOX2, and NOX4.	('rat', 'Species', '10116', (18, 21))	('prostate cancer', 'Disease', (22, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('NOX1', 'Enzyme', (83, 87))	('increases', 'PosReg', (70, 79))	('NOX4', 'Enzyme', (99, 103))	('rat', 'Species', '10116', (43, 46))	('prostate cancer', 'Disease', 'MESH:D011471', (22, 37))	('prostate cancer', 'Phenotype', 'HP:0012125', (22, 37))	('castration', 'Var', (39, 49))	('NOX2', 'Enzyme', (89, 93))
31047	29065504	For example, the silencing of ALKBH8, a member of the human AlkB family of DNA repair molecules, leads to a decrease in ROS production, via the downregulation of NOX1 in urothelial cancer and to apoptosis resistance, resulting in bladder cancer development.	('AlkB', 'Gene', '8846', (60, 64))	('apoptosis', 'biological_process', 'GO:0006915', ('195', '204'))	('AlkB', 'molecular_function', 'GO:0043734', ('60', '64'))	('resulting in', 'Reg', (217, 229))	('bladder cancer', 'Disease', 'MESH:D001749', (230, 244))	('bladder cancer', 'Disease', (230, 244))	('decrease', 'NegReg', (108, 116))	('bladder cancer', 'Phenotype', 'HP:0009725', (230, 244))	('urothelial cancer', 'Disease', 'MESH:D014523', (170, 187))	('ROS', 'Chemical', 'MESH:D017382', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('urothelial cancer', 'Disease', (170, 187))	('ALKBH8', 'Gene', '91801', (30, 36))	('apoptosis resistance', 'CPA', (195, 215))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('DNA repair', 'biological_process', 'GO:0006281', ('75', '85'))	('human', 'Species', '9606', (54, 59))	('NOX1', 'Enzyme', (162, 166))	('AlkB', 'Gene', (60, 64))	('ROS production', 'MPA', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('downregulation', 'NegReg', (144, 158))	('ALKBH8', 'Gene', (30, 36))	('silencing', 'Var', (17, 26))	('apoptosis', 'biological_process', 'GO:0097194', ('195', '204'))
31048	29065504	In addition, other reports have shown that the knockdown of NOX1 reduces ROS production and apoptosis by FK228, a histone deacetylase inhibitor, in a human bladder cancer cell line (J82 cells).	('human', 'Species', '9606', (150, 155))	('J82', 'CellLine', 'CVCL:0359', (182, 185))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('apoptosis', 'CPA', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('FK228', 'Chemical', 'MESH:C087123', (105, 110))	('bladder cancer', 'Disease', 'MESH:D001749', (156, 170))	('reduces', 'NegReg', (65, 72))	('bladder cancer', 'Disease', (156, 170))	('FK228', 'Gene', (105, 110))	('ROS', 'Chemical', 'MESH:D017382', (73, 76))	('NOX1', 'Gene', (60, 64))	('knockdown', 'Var', (47, 56))	('ROS production', 'MPA', (73, 87))	('reduces ROS production', 'Phenotype', 'HP:0025464', (65, 87))	('bladder cancer', 'Phenotype', 'HP:0009725', (156, 170))
31057	29065504	Regarding apoptosis, NOX4 gene silencing did induce a change in the apoptotic activity of urothelial cancer cells.	('NOX4', 'Gene', (21, 25))	('gene silencing', 'Var', (26, 40))	('apoptosis', 'biological_process', 'GO:0097194', ('10', '19'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gene silencing', 'biological_process', 'GO:0016458', ('26', '40'))	('urothelial cancer', 'Disease', (90, 107))	('apoptotic activity', 'CPA', (68, 86))	('apoptosis', 'biological_process', 'GO:0006915', ('10', '19'))	('urothelial cancer', 'Disease', 'MESH:D014523', (90, 107))
31095	29065504	Cis-dichlorodiammineplatinum has been reported to increase ROS production in the urothelial cancer cell lines, T24, KU-1, and KU-19-19.	('urothelial cancer', 'Disease', (81, 98))	('Cis-dichlorodiammineplatinum', 'Chemical', 'MESH:D002945', (0, 28))	('ROS', 'Chemical', 'MESH:D017382', (59, 62))	('Cis-dichlorodiammineplatinum', 'Var', (0, 28))	('ROS production', 'MPA', (59, 73))	('increase', 'PosReg', (50, 58))	('KU-1, and KU-19-19', 'Disease', 'MESH:C567026', (116, 134))	('urothelial cancer', 'Disease', 'MESH:D014523', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('increase ROS production', 'Phenotype', 'HP:0025464', (50, 73))
31099	29065504	The knockdown of ALKBH3 led to the downregulation of angiogenesis, ROS production, and VEGF expression in bladder cancer, in vitro and in vivo, in an orthotopic mouse model.	('ALKBH3', 'Gene', (17, 23))	('VEGF', 'Protein', (87, 91))	('mouse', 'Species', '10090', (161, 166))	('angiogenesis', 'CPA', (53, 65))	('downregulation of angiogenesis', 'biological_process', 'GO:0016525', ('35', '65'))	('bladder cancer', 'Disease', 'MESH:D001749', (106, 120))	('bladder cancer', 'Disease', (106, 120))	('ROS', 'Chemical', 'MESH:D017382', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('downregulation', 'NegReg', (35, 49))	('knockdown', 'Var', (4, 13))	('ROS production', 'MPA', (67, 81))	('expression', 'MPA', (92, 102))	('bladder cancer', 'Phenotype', 'HP:0009725', (106, 120))
31105	29065504	Apoptosis via the caspase cascade can be also stimulated by the ligation of tumor necrosis factor (TNF)-alpha and TNF-related apoptosis-inducing ligand (TRAIL) to their respective receptors, such as TNF receptor and death receptors.	('TNF-related apoptosis-inducing ligand', 'Gene', (114, 151))	('stimulated', 'PosReg', (46, 56))	('TRAIL', 'Gene', '8743', (153, 158))	('necrosis', 'biological_process', 'GO:0008220', ('82', '90'))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('necrosis', 'biological_process', 'GO:0070265', ('82', '90'))	('tumor necrosis factor (TNF)-alpha', 'Gene', '7124', (76, 109))	('necrosis', 'biological_process', 'GO:0019835', ('82', '90'))	('necrosis', 'biological_process', 'GO:0001906', ('82', '90'))	('caspase', 'Gene', (18, 25))	('TRAIL', 'Gene', (153, 158))	('ligation', 'Var', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('TNF-related apoptosis-inducing ligand', 'Gene', '8743', (114, 151))	('Apoptosis', 'CPA', (0, 9))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('76', '97'))	('ligand', 'molecular_function', 'GO:0005488', ('145', '151'))	('caspase', 'Gene', '841', (18, 25))	('necrosis', 'biological_process', 'GO:0008219', ('82', '90'))
31117	29065504	Furthermore, treatment with WZ35, a chemical analog of curcumin, induced apoptosis in two prostate cancer cell lines (RM-1 and DU145), and this anti-cancer effect depended on ROS production.	('WZ35', 'Chemical', '-', (28, 32))	('cancer', 'Disease', (149, 155))	('ROS', 'Chemical', 'MESH:D017382', (175, 178))	('curcumin', 'Chemical', 'MESH:D003474', (55, 63))	('prostate cancer', 'Disease', 'MESH:D011471', (90, 105))	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', (99, 105))	('apoptosis', 'CPA', (73, 82))	('WZ35', 'Var', (28, 32))	('DU145', 'CellLine', 'CVCL:0105', (127, 132))	('prostate cancer', 'Disease', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
31122	29065504	For example, treatment with JS-K, a glutathione S transferase-activated nitric oxide donor prodrug, for 24 h, increased the proportion of apoptotic cells, by inducing ROS production in prostate cancer cells (22RV1, C4-2, LNCaP, and PC-3).	('JS-K', 'Var', (28, 32))	('ROS production', 'MPA', (167, 181))	('nitric oxide', 'Chemical', 'MESH:D009569', (72, 84))	('prostate cancer', 'Disease', 'MESH:D011471', (185, 200))	('C4-2', 'CellLine', 'CVCL:J641', (215, 219))	('increased', 'PosReg', (110, 119))	('LNCaP', 'CellLine', 'CVCL:0395', (221, 226))	('prostate cancer', 'Phenotype', 'HP:0012125', (185, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('donor', 'Species', '9606', (85, 90))	('prostate cancer', 'Disease', (185, 200))	('inducing', 'PosReg', (158, 166))	('ROS', 'Chemical', 'MESH:D017382', (167, 170))
31136	29065504	For example, the anti-hepatitis drug, bicyclol (4,4'-dimethoxy-5,6,5',6'-bis(methylenedioxy)-2-hydroxymethy-l-2'-methoxy-carbonyl biphenyl, reportedly induces apoptosis and cell-cycle arrest, which depended on ROS production in RCC cells.	('bicyclol', 'Var', (38, 46))	('bicyclol', 'Chemical', 'MESH:C477843', (38, 46))	('arrest', 'Disease', 'MESH:D006323', (184, 190))	('apoptosis', 'biological_process', 'GO:0097194', ('159', '168'))	("4,4'-dimethoxy-5,6,5',6'-bis(methylenedioxy)-2-hydroxymethy-l-2'-methoxy-carbonyl biphenyl", 'Chemical', '-', (48, 138))	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('RCC', 'Disease', (228, 231))	('ROS', 'Chemical', 'MESH:D017382', (210, 213))	('bis', 'molecular_function', 'GO:0033815', ('73', '76'))	('arrest', 'Disease', (184, 190))	('induces', 'Reg', (151, 158))	('apoptosis', 'biological_process', 'GO:0006915', ('159', '168'))	('hepatitis', 'Phenotype', 'HP:0012115', (22, 31))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('173', '190'))	('apoptosis', 'CPA', (159, 168))
31137	29065504	Furthermore, niclosamide, an anthelmintic drug, especially used for the treatment of tapeworm infection, can inhibit cell proliferation and induce apoptosis in RCC cell lines, and Wnt/beta-catenin activities are associated with these anti-cancer effects.	('induce', 'Reg', (140, 146))	('inhibit', 'NegReg', (109, 116))	('niclosamide', 'Var', (13, 24))	('cell proliferation', 'CPA', (117, 135))	('RCC', 'Disease', (160, 163))	('rat', 'Species', '10116', (129, 132))	('beta-catenin', 'Gene', (184, 196))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('cancer', 'Disease', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('apoptosis', 'biological_process', 'GO:0097194', ('147', '156'))	('beta-catenin', 'Gene', '1499', (184, 196))	('apoptosis', 'CPA', (147, 156))	('cell proliferation', 'biological_process', 'GO:0008283', ('117', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('147', '156'))	('niclosamide', 'Chemical', 'MESH:D009534', (13, 24))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
31138	29065504	The study also showed that niclosamide induces mitochondrial dysfunction, resulting in increased ROS levels.	('increased', 'PosReg', (87, 96))	('niclosamide', 'Chemical', 'MESH:D009534', (27, 38))	('increased ROS levels', 'Phenotype', 'HP:0025464', (87, 107))	('mitochondrial dysfunction', 'MPA', (47, 72))	('niclosamide', 'Var', (27, 38))	('ROS levels', 'MPA', (97, 107))	('ROS', 'Chemical', 'MESH:D017382', (97, 100))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (47, 72))	('induces', 'Reg', (39, 46))
31153	29065504	Furthermore, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one has been reported to induce apoptosis, via the activation of caspases and increased ROS production.	('induce', 'PosReg', (82, 88))	('apoptosis', 'CPA', (89, 98))	('increased ROS production', 'Phenotype', 'HP:0025464', (135, 159))	('caspases', 'Gene', (122, 130))	('ROS', 'Chemical', 'MESH:D017382', (145, 148))	('caspases', 'Gene', '841', (122, 130))	('5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one', 'Chemical', 'MESH:C572758', (13, 60))	('ROS production', 'MPA', (145, 159))	('increased', 'PosReg', (135, 144))	('5-bromo-3-', 'Var', (13, 23))	('apoptosis', 'biological_process', 'GO:0097194', ('89', '98'))	('apoptosis', 'biological_process', 'GO:0006915', ('89', '98'))	('activation', 'PosReg', (108, 118))
31174	28146082	Among these herbs, the causative nephrotoxic agent was identified as aristolochic acid (AA) and this renal disease is now worldwide recognized as aristolochic acid nephropathy (AAN).	('nephropathy', 'Phenotype', 'HP:0000112', (164, 175))	('nephropathy', 'Disease', (164, 175))	('aristolochic acid', 'Chemical', 'MESH:C000228', (69, 86))	('nephrotoxic', 'Disease', 'MESH:D007674', (33, 44))	('acid nephropathy', 'Phenotype', 'HP:0001947', (159, 175))	('nephropathy', 'Disease', 'MESH:D007674', (164, 175))	('aristolochic acid', 'Chemical', 'MESH:C000228', (146, 163))	('AAN', 'Chemical', '-', (177, 180))	('nephrotoxic', 'Disease', (33, 44))	('renal disease', 'Disease', (101, 114))	('renal disease', 'Disease', 'MESH:D007674', (101, 114))	('aristolochic', 'Var', (69, 81))	('renal disease', 'Phenotype', 'HP:0000112', (101, 114))
31176	28146082	Indeed, in Asian countries, traditional medicines are very popular and the complexity of the pharmacopoeia represents a high risk of AA-induced nephropathy due to the frequent use of Aristolochia species thereby increasing the potential risk of substitutions between botanical products.	('Aristolochia', 'Var', (183, 195))	('nephropathy', 'Disease', (144, 155))	('nephropathy', 'Phenotype', 'HP:0000112', (144, 155))	('nephropathy', 'Disease', 'MESH:D007674', (144, 155))	('Aristolochia', 'Species', '212733', (183, 195))
31192	28146082	In Spain, investigators reported a case of rapidly progressive renal failure in a man who had ingested a homemade mixture infusion containing mint and Aristolochia pistolochia.	('pain', 'Disease', 'MESH:D010146', (4, 8))	('pain', 'Disease', (4, 8))	('renal failure', 'Phenotype', 'HP:0000083', (63, 76))	('Aristolochia pistolochia', 'Species', '212733', (151, 175))	('man', 'Species', '9606', (82, 85))	('progressive renal failure', 'Phenotype', 'HP:0012622', (51, 76))	('progressive renal failure', 'Disease', (51, 76))	('progressive renal failure', 'Disease', 'MESH:D058186', (51, 76))	('pain', 'Phenotype', 'HP:0012531', (4, 8))	('Aristolochia', 'Var', (151, 163))
31244	28146082	Further analysis also revealed that cumulative dose of ingested Aristolochia was a significant risk factor in developing urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('Aristolochia', 'Species', '212733', (64, 76))	('Aristolochia', 'Var', (64, 76))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (121, 141))	('urothelial carcinoma', 'Disease', (121, 141))
31249	28146082	AAN is certain in any individual who suffers from renal failure, in combination with at least two of the following three criteria: (i) a renal histology displaying interstitial fibrosis with a corticomedullary gradient; (ii) a history of consumption of herbal products which demonstrated the presence of AA; and (iii) the presence of AA-DNA adducts (or the specific A:T   T:A transversion in p53 gene) in a kidney tissue sample or of a urothelial tumor.	('p53 gene', 'Gene', (392, 400))	('renal failure', 'Disease', 'MESH:D051437', (50, 63))	('DNA', 'cellular_component', 'GO:0005574', ('337', '340'))	('rat', 'Species', '10116', (282, 285))	('renal failure', 'Disease', (50, 63))	('urothelial tumor', 'Disease', 'MESH:D001749', (436, 452))	('AAN', 'Chemical', '-', (0, 3))	('interstitial fibrosis', 'Disease', (164, 185))	('transversion', 'Var', (376, 388))	('urothelial tumor', 'Disease', (436, 452))	('renal failure', 'Phenotype', 'HP:0000083', (50, 63))	('interstitial fibrosis', 'Disease', 'MESH:D005355', (164, 185))	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (164, 185))	('tumor', 'Phenotype', 'HP:0002664', (447, 452))
31314	28146082	Particularly, AA have been found to modify guanosine at significantly higher frequencies than adenosine suggesting that guanosine is a major target of AA and that guanosine adducts might constitute a critical factor in AA-induced nephrotoxicity and carcinogenicity.	('carcinogenic', 'Disease', (249, 261))	('nephrotoxicity', 'Disease', (230, 244))	('guanosine', 'Chemical', 'MESH:D006151', (163, 172))	('adenosine', 'Chemical', 'MESH:D000241', (94, 103))	('modify', 'Reg', (36, 42))	('guanosine', 'Chemical', 'MESH:D006151', (43, 52))	('guanosine', 'Chemical', 'MESH:D006151', (120, 129))	('nephrotoxicity', 'Disease', 'MESH:D007674', (230, 244))	('adducts', 'Var', (173, 180))	('guanosine', 'MPA', (43, 52))	('guanosine', 'Var', (163, 172))	('carcinogenic', 'Disease', 'MESH:D063646', (249, 261))
31332	28146082	In AAN patients, an overexpression of p53 protein was observed suggesting a mutation in the tumor suppressor gene; p53.	('AAN', 'Chemical', '-', (3, 6))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('92', '108'))	('p53 protein', 'Protein', (38, 49))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('overexpression', 'PosReg', (20, 34))	('p53', 'Gene', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('mutation', 'Var', (76, 84))	('patients', 'Species', '9606', (7, 15))	('tumor suppressor', 'biological_process', 'GO:0051726', ('92', '108'))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))
31334	28146082	Interestingly, the same neighboring bases were observed in the mutated base adenine in codon 139 of the p53 gene and in codon 61 of the H-ras gene suggesting a sequence specific mechanism during mutation induction.	('mutated', 'Var', (63, 70))	('p53', 'Gene', (104, 107))	('H-ras', 'Gene', (136, 141))	('adenine', 'Chemical', 'MESH:D000225', (76, 83))	('H-ras', 'Gene', '3265', (136, 141))
31335	28146082	Later, it has been described that A:T   T:A transversions constitute 58% of p53 sequence changes found in UUC linked to AA exposure while it represents less than 2% in UUC patients with no suspected exposure to AA.	('UUC', 'Phenotype', 'HP:0010935', (106, 109))	('p53', 'Gene', (76, 79))	('changes', 'Var', (89, 96))	('transversions', 'Var', (44, 57))	('linked', 'Reg', (110, 116))	('patients', 'Species', '9606', (172, 180))	('UUC', 'Phenotype', 'HP:0010935', (168, 171))
31336	28146082	Moreover, these mutations described in AA-induced UUC have been found to be almost exclusively positioned on the non-transcribed strand which is rather unique hallmark because in other human cancers, A:T   T:A transversions do not present this pattern.	('human', 'Species', '9606', (185, 190))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Disease', (191, 198))	('mutations', 'Var', (16, 25))	('UUC', 'Phenotype', 'HP:0010935', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('rat', 'Species', '10116', (145, 148))
31337	28146082	Another recent study reported an unusually high prevalence of G   T transversions in the p53 binding site in UUC of non-smoking AA-intoxicated women in Belgium (n = 5).	('p53 binding', 'molecular_function', 'GO:0002039', ('89', '100'))	('G   T transversions', 'Var', (62, 81))	('p53', 'Gene', (89, 92))	('women', 'Species', '9606', (143, 148))	('UUC', 'Phenotype', 'HP:0010935', (109, 112))
31392	28146082	Indeed, Smad3 has emerged as a key factor that has been tightly linked to matrix accumulation and deletion of Smad3 has been demonstrated to protect against several kidney disease, including AAN.	('kidney disease', 'Disease', (165, 179))	('Smad3', 'Gene', (8, 13))	('rat', 'Species', '10116', (132, 135))	('deletion', 'Var', (98, 106))	('Smad3', 'Gene', '4088', (110, 115))	('kidney disease', 'Disease', 'MESH:D007674', (165, 179))	('kidney disease', 'Phenotype', 'HP:0000112', (165, 179))	('Smad3', 'Gene', '4088', (8, 13))	('AAN', 'Chemical', '-', (191, 194))	('Smad3', 'Gene', (110, 115))	('protect', 'NegReg', (141, 148))
31401	28146082	The inhibition of p-Smad2/3 signaling pathway by neutralizing anti-TGF-beta antibody (1D11) administered during the acute phase of the rat model of AAN significantly reduced the score of acute tubular necrosis and interstitial inflammation, but also the extent of peritubular capillaritis and of PDGFRbeta+ pericytes derived myofibroblasts accumulation.	('tubular necrosis', 'Phenotype', 'HP:0008682', (193, 209))	('necrosis', 'biological_process', 'GO:0070265', ('201', '209'))	('acute tubular necrosis', 'Disease', (187, 209))	('necrosis', 'biological_process', 'GO:0019835', ('201', '209'))	('inflammation', 'biological_process', 'GO:0006954', ('227', '239'))	('necrosis', 'biological_process', 'GO:0001906', ('201', '209'))	('antibody', 'cellular_component', 'GO:0019815', ('76', '84'))	('rat', 'Species', '10116', (135, 138))	('signaling pathway', 'biological_process', 'GO:0007165', ('28', '45'))	('capillaritis', 'Disease', (276, 288))	('acute tubular necrosis', 'Phenotype', 'HP:0008682', (187, 209))	('acute tubular necrosis', 'Disease', 'MESH:D007683', (187, 209))	('antibody', 'cellular_component', 'GO:0019814', ('76', '84'))	('reduced', 'NegReg', (166, 173))	('necrosis', 'biological_process', 'GO:0008219', ('201', '209'))	('neutralizing', 'Var', (49, 61))	('interstitial inflammation', 'Disease', (214, 239))	('AAN', 'Chemical', '-', (148, 151))	('interstitial inflammation', 'Disease', 'MESH:D007249', (214, 239))	('inhibition', 'NegReg', (4, 14))	('antibody', 'molecular_function', 'GO:0003823', ('76', '84'))	('p-Smad2/3 signaling pathway', 'Pathway', (18, 45))	('capillaritis', 'Disease', 'None', (276, 288))	('antibody', 'cellular_component', 'GO:0042571', ('76', '84'))	('necrosis', 'biological_process', 'GO:0008220', ('201', '209'))
31419	26235332	High CRP yielded a worse survival in renal cell carcinoma, prostate cancer, bladder cancer, and upper urinary tract urothelial carcinoma.	('bladder cancer', 'Disease', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (37, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('High', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('CRP', 'Gene', (5, 8))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('renal cell carcinoma', 'Disease', (37, 57))	('CRP', 'Gene', '1401', (5, 8))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (37, 57))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('prostate cancer', 'Disease', (59, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('upper urinary tract urothelial carcinoma', 'Disease', 'MESH:D014552', (96, 136))	('upper urinary tract urothelial carcinoma', 'Disease', (96, 136))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))
31460	26235332	Subgroup analyses by race showed that high CRP predicted a worse CSS (Caucasian: random-effects model; [HR] = 1.92, 95% CI = 1.34-2.75; p < 0.01; Asian: random -effects model; [HR] = 1.87, 95% CI = 1.55-2.26; p < 0.01).	('CSS', 'Chemical', '-', (65, 68))	('CRP', 'Gene', (43, 46))	('high', 'Var', (38, 42))	('CRP', 'Gene', '1401', (43, 46))	('CSS', 'Disease', (65, 68))
31515	24262005	BIU-87, J82, and UM-UC-3 bladder cancer cells were transfected with eIF5A2 siRNA or negative control siRNA before incubation with doxorubicin alone or doxorubicin plus GC7 for 48 h. Doxorubicin cytotoxicity was enhanced by GC7 in BIU-87, J82, and UM-UC-3 cells.	('GC7', 'Chemical', '-', (223, 226))	('GC7', 'Var', (223, 226))	('BIU-87', 'CellLine', 'CVCL:6881', (230, 236))	('doxorubicin', 'Chemical', 'MESH:D004317', (130, 141))	('BIU-87', 'CellLine', 'CVCL:6881', (0, 6))	('cytotoxicity', 'Disease', 'MESH:D064420', (194, 206))	('bladder cancer', 'Disease', 'MESH:D001749', (25, 39))	('bladder cancer', 'Phenotype', 'HP:0009725', (25, 39))	('doxorubicin', 'Chemical', 'MESH:D004317', (151, 162))	('Doxorubicin', 'Chemical', 'MESH:D004317', (182, 193))	('GC7', 'Chemical', '-', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('enhanced', 'PosReg', (211, 219))	('Doxorubicin', 'MPA', (182, 193))	('cytotoxicity', 'Disease', (194, 206))	('bladder cancer', 'Disease', (25, 39))
31534	24262005	Chromosomal aberrations are one of the most frequent events during the progress of cancer.	('Chromosomal aberrations', 'Var', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
31535	24262005	This includes the amplification of 3q, which has been detected in bladder, liver, and ovarian cancer.	('ovarian cancer', 'Disease', (86, 100))	('liver', 'Disease', (75, 80))	('detected', 'Reg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (86, 100))	('amplification', 'Var', (18, 31))	('bladder', 'Disease', (66, 73))
31540	24262005	These facts imply that aberrant eIF5A2 expression is a response to the malignant behavior of cancer cells.	('cancer', 'Disease', (93, 99))	('eIF5A2', 'Gene', (32, 38))	('response', 'Reg', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('malignant behavior of', 'CPA', (71, 92))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('aberrant', 'Var', (23, 31))
31542	24262005	Hence, it is important to exploit the underlying mechanism that eIF5A2 exerts and predict the oncogenic pathway, the benefit of which may be improvement of the prognosis for patients with bladder cancer.	('eIF5A2', 'Var', (64, 70))	('improvement', 'PosReg', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('bladder cancer', 'Phenotype', 'HP:0009725', (188, 202))	('oncogenic pathway', 'Pathway', (94, 111))	('exerts', 'Reg', (71, 77))	('patients', 'Species', '9606', (174, 182))	('bladder cancer', 'Disease', 'MESH:D001749', (188, 202))	('bladder cancer', 'Disease', (188, 202))
31578	24262005	Hence, GC7 significantly sensitized bladder cancer cells to doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (60, 71))	('bladder cancer', 'Phenotype', 'HP:0009725', (36, 50))	('sensitized', 'Reg', (25, 35))	('bladder cancer', 'Disease', 'MESH:D001749', (36, 50))	('bladder cancer', 'Disease', (36, 50))	('GC7', 'Var', (7, 10))	('GC7', 'Chemical', '-', (7, 10))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
31583	24262005	In addition to its therapeutic effects, emerging evidence suggests that doxorubicin also induces EMT and enhances malignant properties of cancer cells, such as chemoresistance and metastasis.	('cancer', 'Disease', (138, 144))	('metastasis', 'CPA', (180, 190))	('EMT', 'biological_process', 'GO:0001837', ('97', '100'))	('doxorubicin', 'Var', (72, 83))	('enhances', 'PosReg', (105, 113))	('EMT', 'CPA', (97, 100))	('chemoresistance', 'CPA', (160, 175))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('doxorubicin', 'Chemical', 'MESH:D004317', (72, 83))	('induces', 'PosReg', (89, 96))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
31585	24262005	After 48 h of incubation, doxorubicin transformed cobblestone-like BIU-87 cells to a spindle-like phenotype and led to loss of cell-cell adhesion, which are the hallmarks of mesenchymal cells (Fig.	('doxorubicin', 'Chemical', 'MESH:D004317', (26, 37))	('cell-cell adhesion', 'CPA', (127, 145))	('spindle', 'cellular_component', 'GO:0005819', ('85', '92'))	('doxorubicin', 'Var', (26, 37))	('BIU-87', 'CellLine', 'CVCL:6881', (67, 73))	('loss', 'NegReg', (119, 123))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('127', '145'))
31586	24262005	We next investigated the changes of underlying molecular markers of EMT and found that doxorubicin significantly decreased E-cadherin expression and upregulated the mesenchymal marker vimentin in BIU-87 cells (Fig.	('mesenchymal marker', 'CPA', (165, 183))	('BIU-87', 'CellLine', 'CVCL:6881', (196, 202))	('expression', 'MPA', (134, 144))	('vimentin', 'cellular_component', 'GO:0045099', ('184', '192'))	('doxorubicin', 'Var', (87, 98))	('EMT', 'biological_process', 'GO:0001837', ('68', '71'))	('vimentin', 'cellular_component', 'GO:0045098', ('184', '192'))	('cadherin', 'molecular_function', 'GO:0008014', ('125', '133'))	('E-cadherin', 'Protein', (123, 133))	('upregulated', 'PosReg', (149, 160))	('decreased', 'NegReg', (113, 122))	('doxorubicin', 'Chemical', 'MESH:D004317', (87, 98))
31593	24262005	To investigate whether GC7 could regulate doxorubicin-induced EMT, we examined morphologic changes and expressions of EMT markers in bladder cancer cells treated by GC7 with or without doxorubicin.	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('EMT', 'biological_process', 'GO:0001837', ('118', '121'))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('GC7', 'Chemical', '-', (23, 26))	('EMT', 'biological_process', 'GO:0001837', ('62', '65'))	('doxorubicin', 'Chemical', 'MESH:D004317', (185, 196))	('bladder cancer', 'Disease', 'MESH:D001749', (133, 147))	('bladder cancer', 'Disease', (133, 147))	('GC7', 'Chemical', '-', (165, 168))	('doxorubicin', 'Chemical', 'MESH:D004317', (42, 53))	('GC7', 'Var', (165, 168))
31597	24262005	Hence, these results indicated that GC7 reverses doxorubicin-induced EMT in epithelial bladder cancer cells.	('GC7', 'Var', (36, 39))	('EMT', 'biological_process', 'GO:0001837', ('69', '72'))	('EMT', 'CPA', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('epithelial bladder cancer', 'Disease', (76, 101))	('GC7', 'Chemical', '-', (36, 39))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('reverses', 'NegReg', (40, 48))	('epithelial bladder cancer', 'Disease', 'MESH:D001749', (76, 101))	('doxorubicin', 'Chemical', 'MESH:D004317', (49, 60))
31598	24262005	Moreover, although doxorubicin alone did not affect the mesenchymal phenotype of J82 and UM-UC-3 cells, GC7 promoted development of cell-cell contacts and reversed their epithelial/mesenchymal ratio (Fig.	('GC7', 'Chemical', '-', (104, 107))	('development of cell-cell contacts', 'CPA', (117, 150))	('doxorubicin', 'Chemical', 'MESH:D004317', (19, 30))	('promoted', 'PosReg', (108, 116))	('epithelial/mesenchymal ratio', 'CPA', (170, 198))	('GC7', 'Var', (104, 107))	('reversed', 'PosReg', (155, 163))
31599	24262005	These results suggested that treatment with GC7 leads to MET in mesenchymal bladder cancer cells and contributes to the sensitization of bladder cancer cells to doxorubicin.	('mesenchymal bladder cancer', 'Disease', 'MESH:D001749', (64, 90))	('sensitization', 'biological_process', 'GO:0046960', ('120', '133'))	('bladder cancer', 'Phenotype', 'HP:0009725', (137, 151))	('GC7', 'Var', (44, 47))	('MET', 'CPA', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('doxorubicin', 'Chemical', 'MESH:D004317', (161, 172))	('GC7', 'Chemical', '-', (44, 47))	('bladder cancer', 'Disease', 'MESH:D001749', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('sensitization', 'MPA', (120, 133))	('bladder cancer', 'Disease', (137, 151))	('mesenchymal bladder cancer', 'Disease', (64, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))
31600	24262005	In addition, we tested the expression of eIF5A2 after incubation with GC7 or GC7 plus doxorubicin and found that GC7 did not affect expression of eIF5A2 in the presence or absence of doxorubicin, however, GC7 significantly reduced formation of mature eIF5A2 (Fig.	('GC7', 'Var', (205, 208))	('doxorubicin', 'Chemical', 'MESH:D004317', (183, 194))	('GC7', 'Chemical', '-', (70, 73))	('GC7', 'Chemical', '-', (205, 208))	('formation', 'biological_process', 'GO:0009058', ('231', '240'))	('reduced', 'NegReg', (223, 230))	('GC7', 'Chemical', '-', (113, 116))	('GC7', 'Chemical', '-', (77, 80))	('doxorubicin', 'Chemical', 'MESH:D004317', (86, 97))	('formation of mature', 'MPA', (231, 250))
31605	24262005	Next, we explored the sensitivity change to doxorubicin in Twist-1 siRNA-treated BIU-87 cells and found that Twist-1 siRNA significantly enhanced the cytotoxicity of doxorubicin (Fig.	('enhanced', 'PosReg', (137, 145))	('doxorubicin', 'Chemical', 'MESH:D004317', (166, 177))	('doxorubicin', 'Chemical', 'MESH:D004317', (44, 55))	('cytotoxicity', 'Disease', (150, 162))	('Twist-1 siRNA', 'Var', (109, 122))	('cytotoxicity', 'Disease', 'MESH:D064420', (150, 162))	('BIU-87', 'CellLine', 'CVCL:6881', (81, 87))
31610	24262005	Thus, to ascertain the role of eIF5A2 in doxorubicin-induced EMT, we used RNAi to knockdown eIF5A2 expression in bladder cancer cells.	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('eIF5A2', 'Gene', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (113, 127))	('knockdown', 'Var', (82, 91))	('RNAi', 'biological_process', 'GO:0016246', ('74', '78'))	('doxorubicin', 'Chemical', 'MESH:D004317', (41, 52))	('bladder cancer', 'Disease', (113, 127))	('EMT', 'biological_process', 'GO:0001837', ('61', '64'))
31611	24262005	The siRNA-transfected bladder cancer cells were incubated with doxorubicin or doxorubicin plus GC7 for 48 h. The CCK8 assay and EdU incorporation assay revealed that the eIF5A2 siRNA significantly enhanced the cytotoxicity of doxorubicin in bladder cancer cells (Fig.	('cytotoxicity', 'Disease', 'MESH:D064420', (210, 222))	('doxorubicin', 'Chemical', 'MESH:D004317', (63, 74))	('bladder cancer', 'Disease', 'MESH:D001749', (22, 36))	('bladder cancer', 'Disease', 'MESH:D001749', (241, 255))	('GC7', 'Chemical', '-', (95, 98))	('doxorubicin', 'Chemical', 'MESH:D004317', (78, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (22, 36))	('bladder cancer', 'Phenotype', 'HP:0009725', (241, 255))	('doxorubicin', 'Chemical', 'MESH:D004317', (226, 237))	('bladder cancer', 'Disease', (22, 36))	('cytotoxicity', 'Disease', (210, 222))	('enhanced', 'PosReg', (197, 205))	('eIF5A2', 'Var', (170, 176))	('bladder cancer', 'Disease', (241, 255))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
31624	24262005	We confirmed that GC7 significantly sensitized BIU-87, J82, and UM-UC-3 bladder cancer cells to doxorubicin in vitro and identified the molecular mechanism mediating the chemoresistance of bladder cancer cells to doxorubicin.	('GC7', 'Chemical', '-', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('doxorubicin', 'Chemical', 'MESH:D004317', (213, 224))	('bladder cancer', 'Phenotype', 'HP:0009725', (189, 203))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('doxorubicin', 'Chemical', 'MESH:D004317', (96, 107))	('bladder cancer', 'Disease', 'MESH:D001749', (72, 86))	('bladder cancer', 'Disease', 'MESH:D001749', (189, 203))	('bladder cancer', 'Disease', (189, 203))	('GC7', 'Var', (18, 21))	('BIU-87', 'CellLine', 'CVCL:6881', (47, 53))	('sensitized', 'Reg', (36, 46))	('bladder cancer', 'Disease', (72, 86))
31626	24262005	Recently, several studies have reported that aberrant gene expression was closely associated to chemoresistance in diverse tumor types.	('chemoresistance', 'CPA', (96, 111))	('associated', 'Reg', (82, 92))	('tumor', 'Disease', (123, 128))	('aberrant gene expression', 'Var', (45, 69))	('gene expression', 'biological_process', 'GO:0010467', ('54', '69'))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
31637	24262005	Hence, we showed that GC7 reversed the expression pattern of EMT markers in mesenchymal cells and induced MET in J82 and UM-UC-3 cells.	('GC7', 'Var', (22, 25))	('GC7', 'Chemical', '-', (22, 25))	('MET', 'MPA', (106, 109))	('EMT', 'biological_process', 'GO:0001837', ('61', '64'))	('expression', 'MPA', (39, 49))	('induced', 'PosReg', (98, 105))
31638	24262005	To ascertain the mechanism of action of GC7 in combination with doxorubicin, we silenced eIF5A2 in the three cell lines using RNAi.	('doxorubicin', 'Chemical', 'MESH:D004317', (64, 75))	('GC7', 'Chemical', '-', (40, 43))	('eIF5A2', 'Gene', (89, 95))	('RNAi', 'biological_process', 'GO:0016246', ('126', '130'))	('silenced', 'Var', (80, 88))
31640	24262005	In addition, eIF5A2 knockdown significantly downregulated expression of Twist-1 in doxorubicin-treated bladder cancer cells, which further confirms that eIF5A2 may function as an upstream factor in the Twist-1 EMT molecular pathways regulating EMT in bladder cancer.	('downregulated', 'NegReg', (44, 57))	('bladder cancer', 'Phenotype', 'HP:0009725', (251, 265))	('EMT', 'biological_process', 'GO:0001837', ('210', '213'))	('expression', 'MPA', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('bladder cancer', 'Phenotype', 'HP:0009725', (103, 117))	('bladder cancer', 'Disease', (251, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('EMT', 'biological_process', 'GO:0001837', ('244', '247'))	('Twist-1', 'Gene', (72, 79))	('doxorubicin', 'Chemical', 'MESH:D004317', (83, 94))	('bladder cancer', 'Disease', 'MESH:D001749', (103, 117))	('bladder cancer', 'Disease', 'MESH:D001749', (251, 265))	('knockdown', 'Var', (20, 29))	('bladder cancer', 'Disease', (103, 117))
31645	24262005	Consistent with these observations, our data also proved that inhibition of EMT enhanced sensitivity of bladder cancer cells to doxorubicin.	('bladder cancer', 'Disease', (104, 118))	('sensitivity', 'MPA', (89, 100))	('EMT', 'Gene', (76, 79))	('EMT', 'biological_process', 'GO:0001837', ('76', '79'))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('inhibition', 'Var', (62, 72))	('enhanced', 'PosReg', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('doxorubicin', 'Chemical', 'MESH:D004317', (128, 139))	('bladder cancer', 'Disease', 'MESH:D001749', (104, 118))
31655	33649388	Tumor volume was significantly smaller in sbVTP-treated animals than in controls (135 mm3 vs. 1222 mm3, P < 0.0001) on the day of surgery.	('Tumor volume', 'CPA', (0, 12))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('sbVTP-treated', 'Var', (42, 55))	('smaller', 'NegReg', (31, 38))	('sbVTP', 'Chemical', '-', (42, 47))
31673	33649388	Upon illumination within tissues, WST11 vascular-targeted photodynamic therapy (VTP) produces localized, soft-tissue ablation mediated by cytotoxic-reactive oxygen species and destroys malignant cells.	('soft-tissue ablation', 'CPA', (105, 125))	('oxygen', 'Chemical', 'MESH:D010100', (157, 163))	('destroys', 'NegReg', (176, 184))	('VTP', 'Chemical', '-', (80, 83))	('malignant cells', 'CPA', (185, 200))	('WST11', 'Var', (34, 39))	('cytotoxic-reactive oxygen species', 'MPA', (138, 171))
31674	33649388	In contrast to former photodynamic therapies, VTP is confined to the vasculature of the tumor, arresting the tumor's blood supply by rapid occlusion and causing profound tumor necrosis within 48 h. WST11-VTP of tumor-bearing solid organs was found to be safe and effective in prostate cancer clinical trials.	('necrosis', 'biological_process', 'GO:0008220', ('176', '184'))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', (211, 216))	('necrosis', 'biological_process', 'GO:0070265', ('176', '184'))	('necrosis', 'biological_process', 'GO:0019835', ('176', '184'))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('necrosis', 'biological_process', 'GO:0001906', ('176', '184'))	('tumor necrosis', 'Disease', 'MESH:D009336', (170, 184))	('WST11-VTP', 'Var', (198, 207))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor necrosis', 'Disease', (170, 184))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('VTP', 'Chemical', '-', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('prostate cancer', 'Disease', 'MESH:D011471', (276, 291))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('prostate cancer', 'Phenotype', 'HP:0012125', (276, 291))	('necrosis', 'biological_process', 'GO:0008219', ('176', '184'))	('prostate cancer', 'Disease', (276, 291))	('VTP', 'Chemical', '-', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (109, 114))
31689	33649388	OS and MFS were significantly longer in the early sbVTP group compared to control (P < 0.05), but shorter than in the early surgery group (P < 0.001).	('longer', 'PosReg', (30, 36))	('early sbVTP', 'Var', (44, 55))	('sbVTP', 'Chemical', '-', (50, 55))	('MFS', 'CPA', (7, 10))	('shorter', 'NegReg', (98, 105))
31710	33649388	At day of surgery tumor volume for sbVTP-treated animals (i.e., sbVTP and sbVTP + surgery at day 31[VTPS]) was 135 mm3 (SE, 35; 95% CI, 66-204 mm3) and for non-sbVTP-treated animals (i.e., control and surgery only) was 1222 mm3 (SE, 125; 95% CI, 976-1468 mm3) (P < 0.0001).	('tumor', 'Disease', (18, 23))	('sbVTP', 'Chemical', '-', (74, 79))	('VTPS', 'Disease', 'None', (100, 104))	('SE', 'Disease', 'None', (120, 122))	('SE', 'Disease', 'None', (229, 231))	('sbVTP', 'Chemical', '-', (160, 165))	('VTPS', 'Disease', (100, 104))	('sbVTP-treated', 'Var', (35, 48))	('sbVTP', 'Chemical', '-', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('sbVTP', 'Chemical', '-', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
31748	33649388	Similarly, our model showed that animals treated with sbVTP prior to surgical resection have higher rates of tumor regression and lower rates of systemic progression prior surgery (Table 1) translated in to longer PFS and OS.	('lower', 'NegReg', (130, 135))	('longer', 'PosReg', (207, 213))	('higher', 'PosReg', (93, 99))	('PFS', 'CPA', (214, 217))	('tumor', 'Disease', (109, 114))	('sbVTP', 'Chemical', '-', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('systemic progression', 'MPA', (145, 165))	('sbVTP', 'Var', (54, 59))
31753	33649388	These findings confirm published literature defining immune response as one of the main mechanisms by which PDT destroys tumor cells and initiates the long-term systemic immune response that follows.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('PDT', 'Var', (108, 111))	('initiates', 'Reg', (137, 146))	('immune response', 'biological_process', 'GO:0006955', ('53', '68'))	('destroys', 'NegReg', (112, 120))	('immune response', 'biological_process', 'GO:0006955', ('170', '185'))	('systemic immune response', 'CPA', (161, 185))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
31754	33649388	In the long term, sbVTP produced superior PFS compared to all other treatments.	('men', 'Species', '9606', (73, 76))	('superior', 'PosReg', (33, 41))	('sbVTP', 'Var', (18, 23))	('PFS', 'MPA', (42, 45))	('sbVTP', 'Chemical', '-', (18, 23))
31767	33649388	Our flow analysis showed APCs increasing in the early phase after sbVTP throughout all three systemic foci (spleen, lungs, and peripheral blood) (Fig.	('APCs', 'MPA', (25, 29))	('increasing', 'PosReg', (30, 40))	('sbVTP', 'Var', (66, 71))	('sbVTP', 'Chemical', '-', (66, 71))
31780	33649388	On top of our findings that sbVTP improves survival and regression rates, our finding that sbVTP has a long-lasting systemic effect can potentially benefit UC patients by lowering recurrence rates.	('sbVTP', 'Var', (91, 96))	('sbVTP', 'Chemical', '-', (91, 96))	('recurrence rates', 'MPA', (180, 196))	('lowering', 'NegReg', (171, 179))	('sbVTP', 'Chemical', '-', (28, 33))	('patients', 'Species', '9606', (159, 167))
31787	33649388	VTP may enhance the neoadjuvant arsenal by offering a similar, if not superior, long-term effect at a considerably lower toxicity than existing treatments.	('neoadjuvant arsenal', 'CPA', (20, 39))	('VTP', 'Var', (0, 3))	('men', 'Species', '9606', (149, 152))	('toxicity', 'Disease', 'MESH:D064420', (121, 129))	('enhance', 'PosReg', (8, 15))	('toxicity', 'Disease', (121, 129))	('VTP', 'Chemical', '-', (0, 3))
31798	33649388	Our focus, however, was primarily on the systemic effects associated with partial treatment as well as on the effects in the tumor microenvironment under these conditions.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('men', 'Species', '9606', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('partial treatment', 'Var', (74, 91))	('men', 'Species', '9606', (143, 146))
31845	33649388	Samples were incubated with fluorophore conjugated CD4, CD8, CD25, CD62L, CD44, CD45, CD11c, Ly6G, Ly6C, MHC II, CD86, CD11b, and TGFbeta for 20-30 min and then washed three times with FACS buffer.	('CD4', 'Gene', '12504', (74, 77))	('CD25', 'Var', (61, 65))	('CD4', 'Gene', (80, 83))	('Ly6G', 'Gene', '546644', (93, 97))	('CD8', 'Gene', '925', (56, 59))	('MHC II', 'Gene', '111364', (105, 111))	('Ly6C', 'Gene', '17067', (99, 103))	('Ly6G', 'Gene', (93, 97))	('CD8', 'Gene', (113, 116))	('MHC II', 'Gene', (105, 111))	('CD11c', 'Gene', (86, 91))	('Ly6C', 'Gene', (99, 103))	('CD4', 'Gene', '12504', (80, 83))	('TGFbeta', 'Gene', '21802', (130, 137))	('TGFbeta', 'Gene', (130, 137))	('CD4', 'Gene', (51, 54))	('CD11c', 'Gene', '16411', (86, 91))	('CD8', 'Gene', (56, 59))	('CD4', 'Gene', (74, 77))	('CD62L', 'Gene', (67, 72))	('CD8', 'Gene', '925', (113, 116))	('CD4', 'Gene', '12504', (51, 54))	('CD62L', 'Gene', '20343', (67, 72))
31877	33649388	and A.S. animals' experiments S.B., S.M., S.L.R, A.S. histology analysis B.R., K.K., A.S., J.A.C.	('men', 'Species', '9606', (24, 27))	('J.A.C', 'Var', (91, 96))	('A.S.', 'Var', (85, 89))
31911	26700620	Then, we validated the three best performing combinations and POU4F2 in another 72 UCC, 21 IUC, 26 KC and 22 PC, and 23 HV urine samples.	('PC', 'Phenotype', 'HP:0012125', (109, 111))	('KC', 'Phenotype', 'HP:0009726', (99, 101))	('POU4F2', 'Gene', (62, 68))	('combinations', 'Var', (45, 57))	('POU4F2', 'Gene', '5458', (62, 68))
31912	26700620	The combination of POU4F2/PCDH17 has yielded the highest sensitivity and specificity of 90.00% and 93.96% in all the 312 individuals, showing the capability of detecting BlCa effectively among pathologically varied sample groups.	('PCDH17', 'Gene', (26, 32))	('POU4F2', 'Gene', '5458', (19, 25))	('BlCa', 'Phenotype', 'HP:0009725', (170, 174))	('combination', 'Var', (4, 15))	('POU4F2', 'Gene', (19, 25))	('PCDH17', 'Gene', '27253', (26, 32))	('PC', 'Phenotype', 'HP:0012125', (26, 28))	('detecting', 'Reg', (160, 169))
31937	26700620	The alterations in the state of DNA methylation usually happen more frequently than the mutations in the DNA sequence, especially as a result of changes in the microenvironment.	('alterations', 'Var', (4, 15))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('mutations', 'Var', (88, 97))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('changes', 'Reg', (145, 152))	('DNA methylation', 'biological_process', 'GO:0006306', ('32', '47'))	('men', 'Species', '9606', (172, 175))	('DNA sequence', 'Gene', (105, 117))
31948	26700620	The low success rate due to the lysis of the exfoliated cells caused by body temperature and long ex situ exposure time could be one of the reasons that caused the undervaluation of epigenetic detecting for bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (207, 221))	('bladder cancer', 'Disease', (207, 221))	('lysis', 'biological_process', 'GO:0019835', ('32', '37'))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('bladder cancer', 'Phenotype', 'HP:0009725', (207, 221))	('epigenetic', 'Var', (182, 192))
31960	26700620	DNA of the urine sediments and the bladder cancer cell lines were achieved respectively by using TIANamp Micro DNA Kit DP316 (TianGen) and TIANamp Blood/Tissue/Cell DNA Kit DP304 (TianGen) and according to the protocol provided.	('DP304', 'Var', (173, 178))	('bladder cancer', 'Disease', (35, 49))	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('bladder cancer', 'Phenotype', 'HP:0009725', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('bladder cancer', 'Disease', 'MESH:D001749', (35, 49))	('DP316', 'Var', (119, 124))	('men', 'Species', '9606', (21, 24))
31976	15890073	Our group has demonstrated that BCG mediated cross-linking of alpha51 integrin receptors present on the tumor surface elicits a complex biologic response involving AP1 and NF-kappaB signaling as well as the transactivation of immediate early genes.	('alpha51 integrin receptors', 'Protein', (62, 88))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('signaling', 'biological_process', 'GO:0023052', ('182', '191'))	('immediate early genes', 'Gene', (226, 247))	('AP1', 'Gene', (164, 167))	('BCG', 'Species', '33892', (32, 35))	('tumor', 'Disease', (104, 109))	('transactivation', 'biological_process', 'GO:2000144', ('207', '222'))	('transactivation', 'MPA', (207, 222))	('elicits', 'Reg', (118, 125))	('AP1', 'Gene', '3726', (164, 167))	('cross-linking', 'Var', (45, 58))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('AP1', 'cellular_component', 'GO:0005907', ('164', '167'))
31977	15890073	This study evaluated the direct biologic effect of cross-linking alpha5beta1 integrin on cell cycle progression and apoptosis in two human urothelial carcinoma cell lines.	('beta1', 'Gene', '15129', (71, 76))	('apoptosis', 'CPA', (116, 125))	('urothelial carcinoma', 'Disease', (139, 159))	('beta1', 'Gene', (71, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (139, 159))	('human', 'Species', '9606', (133, 138))	('cell cycle', 'biological_process', 'GO:0007049', ('89', '99'))	('cross-linking', 'Var', (51, 64))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('cell cycle progression', 'CPA', (89, 111))
31981	15890073	Results demonstrate that integrin cross-linking by BCG, or antibody mediated crosslinking of alpha5beta1 resulted in a decrease in proliferating cell number.	('decrease', 'NegReg', (119, 127))	('antibody', 'cellular_component', 'GO:0019815', ('59', '67'))	('proliferating cell number', 'CPA', (131, 156))	('beta1', 'Gene', '15129', (99, 104))	('cross-linking', 'Var', (34, 47))	('antibody', 'cellular_component', 'GO:0019814', ('59', '67'))	('antibody', 'molecular_function', 'GO:0003823', ('59', '67'))	('BCG', 'Species', '33892', (51, 54))	('beta1', 'Gene', (99, 104))	('antibody', 'cellular_component', 'GO:0042571', ('59', '67'))	('crosslinking', 'Var', (77, 89))	('integrin', 'Protein', (25, 33))
31986	15890073	Cell cycle arrest at the G1/S interface is a mechanism by which BCG inhibits cellular proliferation.	('Cell cycle arrest at the G1/S interface', 'CPA', (0, 39))	('cellular proliferation', 'CPA', (77, 99))	('BCG', 'Species', '33892', (64, 67))	('Cell cycle arrest', 'Phenotype', 'HP:0011018', (0, 17))	('inhibits', 'NegReg', (68, 76))	('BCG', 'Var', (64, 67))	('Cell cycle arrest', 'biological_process', 'GO:0007050', ('0', '17'))
31996	15890073	We have shown that this response is mediated via signal transduction initiated as a consequence of BCG induced cross-linking of alpha5beta1 integrins present on the surface membrane of urothelial carcinoma cells.	('membrane', 'cellular_component', 'GO:0016020', ('173', '181'))	('signal transduction', 'biological_process', 'GO:0007165', ('49', '68'))	('beta1', 'Gene', '15129', (134, 139))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (185, 205))	('BCG', 'Species', '33892', (99, 102))	('beta1', 'Gene', (134, 139))	('urothelial carcinoma', 'Disease', (185, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('cross-linking', 'Var', (111, 124))
32003	15890073	Our results show that BCG decreases cell proliferation as measured by two separate assays of cell viability.	('BCG', 'Species', '33892', (22, 25))	('cell proliferation', 'biological_process', 'GO:0008283', ('36', '54'))	('BCG', 'Var', (22, 25))	('decreases', 'NegReg', (26, 35))	('cell proliferation', 'CPA', (36, 54))
32043	15890073	Cross-linking decreased viability as measured by the MTT assay to 78% and 77% of untreated controls in the 253J and T24 lines at 3 days.	('MTT', 'Chemical', 'MESH:C070243', (53, 56))	('decreased', 'NegReg', (14, 23))	('viability', 'CPA', (24, 33))	('Cross-linking', 'Var', (0, 13))	('MTT assay', 'CPA', (53, 62))
32075	15890073	Rather than constituting a passive interaction, our prior reports have shown that FN mediated BCG adherence to the urothelial carcinoma surface has a pharmacogenetic effect as exemplified by transactivation of IL-6.	('IL-6', 'Gene', '3569', (210, 214))	('adherence', 'CPA', (98, 107))	('urothelial carcinoma', 'Disease', (115, 135))	('FN', 'Gene', '2335', (82, 84))	('IL-6', 'molecular_function', 'GO:0005138', ('210', '214'))	('IL-6', 'Gene', (210, 214))	('transactivation', 'biological_process', 'GO:2000144', ('191', '206'))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (115, 135))	('transactivation', 'Var', (191, 206))	('BCG', 'Species', '33892', (94, 97))
32085	15890073	The failure of simple integrin ligation to simulate the BCG response, the ability of antibody mediated crosslinking of alpha5beta1 integrin to duplicate the BCG response, the central role of FN in the biologic response to BCG, together with the predominance of alpha5beta1 as the principal FN binding integrin on urothelial cells, strongly supports a model in which the biologic response of the tumor cell to BCG occurs as a consequence of BCG crosslinking of alpha5beta1 integrin receptors.	('FN', 'Gene', '2335', (191, 193))	('BCG', 'Species', '33892', (222, 225))	('crosslinking', 'Var', (444, 456))	('BCG', 'Species', '33892', (157, 160))	('antibody', 'cellular_component', 'GO:0019815', ('85', '93'))	('tumor', 'Phenotype', 'HP:0002664', (395, 400))	('beta1', 'Gene', (125, 130))	('beta1', 'Gene', (267, 272))	('beta1', 'Gene', (466, 471))	('BCG', 'Species', '33892', (409, 412))	('BCG', 'Species', '33892', (440, 443))	('antibody', 'cellular_component', 'GO:0019814', ('85', '93'))	('binding', 'molecular_function', 'GO:0005488', ('293', '300'))	('FN', 'Gene', '2335', (290, 292))	('beta1', 'Gene', '15129', (125, 130))	('antibody', 'molecular_function', 'GO:0003823', ('85', '93'))	('beta1', 'Gene', '15129', (267, 272))	('tumor', 'Disease', (395, 400))	('beta1', 'Gene', '15129', (466, 471))	('antibody', 'cellular_component', 'GO:0042571', ('85', '93'))	('tumor', 'Disease', 'MESH:D009369', (395, 400))	('BCG', 'Species', '33892', (56, 59))
32094	33227989	Assessment of ARID1A, SMARCA2, SMARCA4, SMARCB1/INI1, SMARCC1, SMARCC2 and PBRM1 mutations in a TCGA data set of sq-BLCA (n = 45) revealed that ARID1A was the most frequently altered SWI/SNF gene (15%) while being associated with protein downregulation.	('downregulation', 'NegReg', (238, 252))	('SMARCA2', 'Gene', (22, 29))	('PBRM1', 'Gene', (75, 80))	('SMARCA2', 'Gene', '6595', (22, 29))	('SMARCC1', 'Gene', '6599', (54, 61))	('ARID1A', 'Gene', '8289', (14, 20))	('mutations', 'Var', (81, 90))	('altered', 'Reg', (175, 182))	('SMARCC1', 'Gene', (54, 61))	('ARID1A', 'Gene', (144, 150))	('SMARCA4', 'Gene', (31, 38))	('SMARCC2', 'Gene', (63, 70))	('protein', 'MPA', (230, 237))	('ARID1A', 'Gene', '8289', (144, 150))	('SMARCB1', 'Gene', '6598', (40, 47))	('SWI/SNF', 'Gene', (183, 190))	('SMARCC2', 'Gene', '6601', (63, 70))	('SMARCB1', 'Gene', (40, 47))	('INI1', 'Gene', (48, 52))	('INI1', 'Gene', '6598', (48, 52))	('men', 'Species', '9606', (6, 9))	('PBRM1', 'Gene', '55193', (75, 80))	('SMARCA4', 'Gene', '6597', (31, 38))	('ARID1A', 'Gene', (14, 20))	('protein', 'cellular_component', 'GO:0003675', ('230', '237'))
32095	33227989	Genetic alterations and loss of ARID1A were confirmed by Targeted Next Generation Sequencing (NGS) (3/6) and immunohistochemistry (6/116).	('ARID1A', 'Gene', '8289', (32, 38))	('Genetic alterations', 'Var', (0, 19))	('ARID1A', 'Gene', (32, 38))	('loss', 'NegReg', (24, 28))
32096	33227989	Correlation with further mutational data and PD-L1 expression revealed co-occurrence of ARID1A loss and TP53 mutations, while positive correlations with other driver mutations such as PIK3CA were not observed.	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('PD-L1', 'Gene', '29126', (45, 50))	('mutations', 'Var', (109, 118))	('PIK3CA', 'Gene', (184, 190))	('loss', 'NegReg', (95, 99))	('PIK3CA', 'Gene', '5290', (184, 190))	('ARID1A', 'Gene', (88, 94))	('PD-L1', 'Gene', (45, 50))	('ARID1A', 'Gene', '8289', (88, 94))
32102	33227989	Over 90% of bladder cancers are urothelial carcinomas with distinct molecular characteristics for muscle-invasive bladder cancers (MIBCs) such as TP53 mutations or non-muscle-invasive bladder cancers (NMIBCs) including activating FGFR3 mutations or PIK3CA alterations.	('non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (164, 191))	('PIK3CA', 'Gene', '5290', (249, 255))	('bladder cancers', 'Phenotype', 'HP:0009725', (114, 129))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('bladder cancer', 'Phenotype', 'HP:0009725', (184, 198))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('230', '234'))	('bladder cancer', 'Phenotype', 'HP:0009725', (114, 128))	('bladder cancers', 'Disease', 'MESH:D001749', (12, 27))	('urothelial carcinomas', 'Disease', (32, 53))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('invasive bladder', 'Phenotype', 'HP:0100645', (105, 121))	('bladder cancers', 'Disease', (12, 27))	('TP53', 'Gene', (146, 150))	('bladder cancers', 'Disease', 'MESH:D001749', (114, 129))	('bladder cancers', 'Phenotype', 'HP:0009725', (184, 199))	('mutations', 'Var', (151, 160))	('PIK3CA', 'Gene', (249, 255))	('invasive bladder', 'Phenotype', 'HP:0100645', (175, 191))	('activating', 'PosReg', (219, 229))	('muscle-invasive bladder cancers', 'Disease', (98, 129))	('muscle-invasive bladder cancers', 'Disease', (168, 199))	('alterations', 'Reg', (256, 267))	('mutations', 'Var', (236, 245))	('muscle-invasive bladder cancers', 'Disease', 'MESH:D001749', (98, 129))	('muscle-invasive bladder cancers', 'Disease', 'MESH:D001749', (168, 199))	('bladder cancers', 'Disease', 'MESH:D001749', (184, 199))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('TP53', 'Gene', '7157', (146, 150))	('FGFR3', 'Gene', (230, 235))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (32, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('bladder cancers', 'Phenotype', 'HP:0009725', (12, 27))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('bladder cancer', 'Phenotype', 'HP:0009725', (12, 26))	('FGFR3', 'Gene', '2261', (230, 235))
32103	33227989	Only 5% of all bladder cancers are squamous cell carcinomas (SCCs) characterized by low frequent alterations of ERBB genes but frequent TP53 mutations, while alterations of the FGFR3 gene are rare but associated with worse patients' outcome.	('bladder cancers', 'Disease', 'MESH:D001749', (15, 30))	('bladder cancers', 'Disease', (15, 30))	('TP53', 'Gene', '7157', (136, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (49, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (15, 29))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (35, 59))	('FGFR', 'molecular_function', 'GO:0005007', ('177', '181'))	('SCCs', 'Phenotype', 'HP:0002860', (61, 65))	('mutations', 'Var', (141, 150))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (35, 59))	('ERBB', 'Gene', (112, 116))	('bladder cancers', 'Phenotype', 'HP:0009725', (15, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('ERBB', 'Gene', '1956', (112, 116))	('TP53', 'Gene', (136, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))	('FGFR3', 'Gene', (177, 182))	('squamous cell carcinomas', 'Disease', (35, 59))	('FGFR3', 'Gene', '2261', (177, 182))	('patients', 'Species', '9606', (223, 231))
32113	33227989	Furthermore, mutations and loss of expression of central SWI/SNF proteins were found in over 20% of different neoplasms, such as oesophageal adenocarcinoma, lung cancer, ovarian clear cell and endometrioid cancers as well as uterine endometrioid carcinomas.	('neoplasms', 'Phenotype', 'HP:0002664', (110, 119))	('central SWI/SNF', 'Gene', (49, 64))	('loss of expression', 'NegReg', (27, 45))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('ovarian clear cell and endometrioid cancers', 'Disease', 'MESH:D008649', (170, 213))	('endometrioid carcinomas', 'Disease', (233, 256))	('lung cancer', 'Disease', (157, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('carcinomas', 'Phenotype', 'HP:0030731', (246, 256))	('neoplasms', 'Disease', 'MESH:D009369', (110, 119))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('found', 'Reg', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (233, 256))	('proteins', 'Protein', (65, 73))	('neoplasms', 'Disease', (110, 119))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (129, 155))	('mutations', 'Var', (13, 22))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('oesophageal adenocarcinoma', 'Disease', (129, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (233, 256))
32116	33227989	Among the identified subunits to date, the AT-rich interactive domain-containing protein 1A (ARID1A) is the most frequently mutated SWI/SNF component in urothelial bladder cancer.	('SNF component in urothelial bladder cancer', 'Disease', 'MESH:D001749', (136, 178))	('AT-rich interactive domain-containing protein 1A', 'Gene', (43, 91))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('mutated', 'Var', (124, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (164, 178))	('AT-rich interactive domain-containing protein 1A', 'Gene', '8289', (43, 91))	('ARID1A', 'Gene', '8289', (93, 99))	('SNF component in urothelial bladder cancer', 'Disease', (136, 178))	('ARID1A', 'Gene', (93, 99))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))
32126	33227989	For stainings of further components of the SWI/SNF complex, the BenchMark ULTRA system (Ventana Medical Systems Inc, 1910 Innovation Park Drive, Tucson, AZ, USA) and antibodies against the following antigens were used: anti-SMARCB1 (INI1) (ZSI1, 1:50, Zytomed), anti-SMARCA2 (polyclonal antibody, 1:100, Atlas Antibodies AB, Stockholm, Sweden), anti-SMARCA4 (anti-BRG1 antibody, clone EPNCIR111A, 1:100, Abcam; Cambridge, UK), anti-SMARCC1 (HPA026853, 1:50, Atlas Antibodies AB), anti-SMARCC2 (HPA021213, 1:50, Atlas Antibodies AB) and anti-PBRM1 (clone CL0331, dilution 1:50, Atlas Antibodies AB).	('SMARCC2', 'Gene', (485, 492))	('antibody', 'molecular_function', 'GO:0003823', ('287', '295'))	('antibody', 'cellular_component', 'GO:0019814', ('369', '377'))	('PBRM1', 'Gene', '55193', (541, 546))	('antibody', 'cellular_component', 'GO:0042571', ('287', '295'))	('SMARCA4', 'Gene', (350, 357))	('SMARCA2', 'Gene', (267, 274))	('PBRM1', 'Gene', (541, 546))	('SMARCA2', 'Gene', '6595', (267, 274))	('SMARCC2', 'Gene', '6601', (485, 492))	('INI1', 'Gene', (233, 237))	('INI1', 'Gene', '6598', (233, 237))	('antibody', 'molecular_function', 'GO:0003823', ('369', '377'))	('SMARCB1', 'Gene', '6598', (224, 231))	('SMARCC1', 'Gene', '6599', (432, 439))	('HPA026853', 'Var', (441, 450))	('HPA021213', 'Var', (494, 503))	('SMARCB1', 'Gene', (224, 231))	('antibody', 'cellular_component', 'GO:0042571', ('369', '377'))	('antibody', 'cellular_component', 'GO:0019815', ('287', '295'))	('SMARCC1', 'Gene', (432, 439))	('BRG1', 'Gene', '6597', (364, 368))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('43', '58'))	('antibody', 'cellular_component', 'GO:0019815', ('369', '377'))	('SMARCA4', 'Gene', '6597', (350, 357))	('antibody', 'cellular_component', 'GO:0019814', ('287', '295'))	('BRG1', 'Gene', (364, 368))
32130	33227989	PIK3CA and FGFR3 mutational analyses were performed using the SNaPshot method for the simultaneous detection of hotspot mutations according to Hurst et al.	('FGFR3', 'Gene', '2261', (11, 16))	('PIK3CA', 'Gene', (0, 6))	('FGFR3', 'Gene', (11, 16))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (120, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('11', '15'))
32144	33227989	In order to give first insights into the mutational status of (putative) key components of the SWI/SNF complex in squamous bladder cancers (for study design see Supplementary Figure S1), carcinomas with histologically squamous differentiation (n = 3 pure SCC and n = 42 MIX) of The Cancer Genome Atlas (TCGA) were analyzed for genetic alterations of seven frequently affected subunits of the SWI/SNF complexes BAF and PBAF.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('95', '110'))	('Cancer', 'Disease', (282, 288))	('squamous bladder cancers', 'Disease', (114, 138))	('BAF', 'Gene', (419, 422))	('genetic alterations', 'Var', (327, 346))	('Cancer', 'Disease', 'MESH:D009369', (282, 288))	('carcinomas', 'Disease', (187, 197))	('BAF', 'Gene', (410, 413))	('men', 'Species', '9606', (167, 170))	('pure', 'molecular_function', 'GO:0034023', ('250', '254'))	('squamous bladder cancers', 'Disease', 'MESH:D001749', (114, 138))	('BAF', 'Gene', '8815', (419, 422))	('carcinomas', 'Disease', 'MESH:D009369', (187, 197))	('MIX', 'Gene', '83881', (270, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('BAF', 'Gene', '8815', (410, 413))	('Cancer', 'Phenotype', 'HP:0002664', (282, 288))	('MIX', 'Gene', (270, 273))	('bladder cancers', 'Phenotype', 'HP:0009725', (123, 138))
32145	33227989	Alterations of the BAF-specific component ARID1A were the most frequent events (15.2%, 7/46), comprising one deep deletion, four truncating mutations and two missense mutations indicating impaired protein function (Figure 1A,B).	('missense mutations', 'Var', (158, 176))	('Alterations', 'Var', (0, 11))	('ARID1A', 'Gene', '8289', (42, 48))	('ARID1A', 'Gene', (42, 48))	('truncating', 'MPA', (129, 139))	('protein', 'Protein', (197, 204))	('BAF', 'Gene', '8815', (19, 22))	('BAF', 'Gene', (19, 22))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))
32147	33227989	The gene encoding the PBAF-specific subunit PBRM1 was mutated in 4.3% of samples (2/46) (Figure 1A).	('PBRM1', 'Gene', (44, 49))	('PBRM1', 'Gene', '55193', (44, 49))	('BAF', 'Gene', '8815', (23, 26))	('mutated', 'Var', (54, 61))	('BAF', 'Gene', (23, 26))
32148	33227989	Determining the ARID1A protein level in dependency of its mutational status, we confirmed a significantly lower expression in tumors with genetic alterations of the ARID1A gene including missense mutations (Figure 1C):i.e., frequent ARID1A mutations correlate with loss of ARID1A protein in TCGA Sq-BLCA.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('ARID1A', 'Gene', (233, 239))	('ARID1A', 'Gene', '8289', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('ARID1A', 'Gene', '8289', (273, 279))	('expression', 'MPA', (112, 122))	('lower', 'NegReg', (106, 111))	('tumors', 'Disease', (126, 132))	('ARID1A', 'Gene', '8289', (233, 239))	('ARID1A', 'Gene', (16, 22))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('loss', 'NegReg', (265, 269))	('ARID1A', 'Gene', '8289', (16, 22))	('ARID1A', 'Gene', (165, 171))	('protein', 'cellular_component', 'GO:0003675', ('280', '287'))	('protein', 'Protein', (280, 287))	('mutations', 'Var', (240, 249))	('ARID1A', 'Gene', (273, 279))
32149	33227989	As genetic alterations of SWI/SNF components are known to be associated with patients' outcome, we correlated SWI/SNF mutations with clinico-pathological parameters and analyzed recurrence-free (RFS) and overall survival (OS) as an indicator of potential prognostic impact.	('RFS', 'Disease', (195, 198))	('mutations', 'Var', (118, 127))	('SWI/SNF', 'Gene', (110, 117))	('patients', 'Species', '9606', (77, 85))	('RFS', 'Disease', 'MESH:D005198', (195, 198))	('associated', 'Reg', (61, 71))
32150	33227989	We focused on patients with at least one genetic alteration in one or more of the analyzed components as well as on those harboring ARID1A mutations (missense vs. nonsense).	('ARID1A', 'Gene', '8289', (132, 138))	('patients', 'Species', '9606', (14, 22))	('ARID1A', 'Gene', (132, 138))	('missense vs.', 'Var', (150, 162))
32151	33227989	Using a Fisher's exact test, no associations of SWI/SNF mutations or ARID1A mutations with clinico-pathological characteristics were observed (Supplementary Tables S2-S4).	('mutations', 'Var', (56, 65))	('mutations', 'Var', (76, 85))	('men', 'Species', '9606', (149, 152))	('SWI/SNF', 'Gene', (48, 55))	('associations', 'Interaction', (32, 44))	('ARID1A', 'Gene', '8289', (69, 75))	('ARID1A', 'Gene', (69, 75))
32152	33227989	Kaplan-Meier analysis did not show any association of mutated SWI/SNF components and/or ARID1A mutations with RFS and OS (Supplementary Figure S2).	('men', 'Species', '9606', (128, 131))	('RFS', 'Disease', (110, 113))	('mutations', 'Var', (95, 104))	('RFS', 'Disease', 'MESH:D005198', (110, 113))	('SWI/SNF components', 'Gene', (62, 80))	('ARID1A', 'Gene', (88, 94))	('ARID1A', 'Gene', '8289', (88, 94))
32164	33227989	Novel PIK3CA mutational analyses were performed by SNaPshot according to Hurst et al., while PCR-amplification and Sanger sequencing was performed for CDKN2A as specified in 2016.	('PIK3CA', 'Gene', (6, 12))	('CDKN2A', 'Gene', (151, 157))	('PIK3CA', 'Gene', '5290', (6, 12))	('mutational', 'Var', (13, 23))	('CDKN2A', 'Gene', '1029', (151, 157))
32170	33227989	ARID1A expression was further significantly associated with TP53 mutations (p < 0.05) (Table 3).	('associated', 'Reg', (44, 54))	('ARID1A', 'Gene', '8289', (0, 6))	('ARID1A', 'Gene', (0, 6))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
32171	33227989	Interestingly, ARID1A expression loss was not observed in tumors with genetic alterations of FGFR3 or PIK3CA.	('ARID1A', 'Gene', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('PIK3CA', 'Gene', (102, 108))	('tumors', 'Disease', (58, 64))	('FGFR3', 'Gene', '2261', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('ARID1A', 'Gene', '8289', (15, 21))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('PIK3CA', 'Gene', '5290', (102, 108))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('FGFR3', 'Gene', (93, 98))	('genetic alterations', 'Var', (70, 89))
32172	33227989	Since ARID1A loss seems to be associated with advanced tumor stages, we focused on this important SWI/SNF component with therapeutic potential to confirm that ARID1A protein loss results from genetic ARID1A gene alterations.	('associated', 'Reg', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('ARID1A', 'Gene', '8289', (159, 165))	('ARID1A', 'Gene', '8289', (6, 12))	('protein', 'Protein', (166, 173))	('ARID1A', 'Gene', (6, 12))	('ARID1A', 'Gene', (159, 165))	('ARID1A', 'Gene', '8289', (200, 206))	('loss', 'NegReg', (13, 17))	('ARID1A', 'Gene', (200, 206))	('alterations', 'Var', (212, 223))	('loss', 'NegReg', (174, 178))
32174	33227989	Three out of the six ARID1A-deficient samples showed ARID1A mutations (c.1001C>A, p.(Ser334Ter), allele frequency (AF) 20%; c.1753C>T, p.(Gln585Ter), AF 23%; c.4005-2A>G, p.(?	('c.4005-2A>G', 'Var', (158, 169))	('c.1753C>T', 'Mutation', 'rs759993319', (124, 133))	('c.1001C>A', 'Mutation', 'c.1001C>A', (71, 80))	('p.(Ser334Ter)', 'Mutation', 'p.S334X', (82, 95))	('c.1001C>A', 'Var', (71, 80))	('ARID1A', 'Gene', '8289', (21, 27))	('p.(Gln585Ter)', 'Mutation', 'rs754735230', (135, 148))	('ARID1A', 'Gene', (21, 27))	('Ter', 'cellular_component', 'GO:0097047', ('144', '147'))	('c.1753C>T', 'Var', (124, 133))	('AF', 'Disease', 'MESH:D001281', (115, 117))	('Ter', 'cellular_component', 'GO:0097047', ('91', '94'))	('Ser', 'cellular_component', 'GO:0005790', ('85', '88'))	('ARID1A', 'Gene', '8289', (53, 59))	('c.4005-2A>G', 'Mutation', 'c.4005-2A>G', (158, 169))	('AF', 'Disease', 'MESH:D001281', (150, 152))	('ARID1A', 'Gene', (53, 59))
32177	33227989	To our knowledge, none of the three mutations has been previously described in the literature, but all three mutations are annotated in the COSMIC database v92 (; c.1001C>T (p.Ser334Ter/COSM6983737): n = 1, pancreatic carcinoid-endocrine tumor [P-0012246-T01-IM5]; c.1753C>T (p.Gln585Ter/COSM1133047): n = 2, breast carcinoma [H_KU-1186-1186_A2_core], Burkitt lymphoma BL-6; c.4005-2A>G (COSM6925751): n = 1, transitional cell bladder carcinoma [P-0003024-T01-IM3]).	('pancreatic carcinoid-endocrine tumor', 'Phenotype', 'HP:0030405', (207, 243))	('Burkitt lymphoma BL-6', 'Disease', (352, 373))	('Ter', 'cellular_component', 'GO:0097047', ('182', '185'))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('COSM6983737', 'Chemical', '-', (186, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (360, 368))	('p.Ser334Ter', 'SUBSTITUTION', 'None', (174, 185))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (352, 368))	('carcinoid', 'Phenotype', 'HP:0100570', (218, 227))	('c.1001C>T', 'Mutation', 'rs773457718', (163, 172))	('core', 'cellular_component', 'GO:0019013', ('345', '349'))	('Ser', 'cellular_component', 'GO:0005790', ('176', '179'))	('p.Gln585Ter', 'SUBSTITUTION', 'None', (276, 287))	('transitional cell bladder carcinoma', 'Disease', 'MESH:D001749', (409, 444))	('breast carcinoma', 'Disease', 'MESH:D001943', (309, 325))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('c.1753C>T', 'Mutation', 'rs759993319', (265, 274))	('pancreatic carcinoid-endocrine tumor', 'Disease', 'MESH:D002276', (207, 243))	('pancreatic carcinoid-endocrine tumor', 'Disease', (207, 243))	('Burkitt lymphoma BL-6', 'Disease', 'MESH:D002051', (352, 373))	('c.1753C>T', 'Var', (265, 274))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (427, 444))	('carcinoma', 'Phenotype', 'HP:0030731', (435, 444))	('p.Gln585Ter', 'Var', (276, 287))	('breast carcinoma', 'Phenotype', 'HP:0003002', (309, 325))	('p.Ser334Ter', 'Var', (174, 185))	('transitional cell bladder carcinoma', 'Phenotype', 'HP:0006740', (409, 444))	('Ter', 'cellular_component', 'GO:0097047', ('284', '287'))	('breast carcinoma', 'Disease', (309, 325))	('c.4005-2A>G', 'Mutation', 'c.4005-2A>G', (375, 386))	('; c.1001C>T', 'Var', (161, 172))	('transitional cell bladder carcinoma', 'Disease', (409, 444))	('endocrine tumor', 'Phenotype', 'HP:0100568', (228, 243))
32178	33227989	Two of the three mutations are also (redundantly) listed in the cBioPortal database v3.4.13 (; c.1001C>T: n = 1, pancreatic neuroendocrine tumor [P-0012246-T01-IM5], classification: likely oncogenic; c.4005-2A>G: n = 1, bladder urothelial carcinoma [P-0003024-T01-IM3], classification: likely oncogenic).	('bladder urothelial carcinoma', 'Disease', (220, 248))	('; c.1001C>T', 'Var', (93, 104))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (124, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('c.4005-2A>G', 'Mutation', 'c.4005-2A>G', (200, 211))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (113, 144))	('c.4005-2A>G', 'Var', (200, 211))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('pancreatic neuroendocrine tumor', 'Disease', (113, 144))	('c.1001C>T', 'Mutation', 'rs773457718', (95, 104))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (220, 248))	('pancreatic neuroendocrine tumor', 'Disease', 'MESH:D018358', (113, 144))	('endocrine tumor', 'Phenotype', 'HP:0100568', (129, 144))
32179	33227989	The mutation c.4005-2A>G affects the canonical splice site and leads to loss of the acceptor splice site according to distinct prediction tools.	('c.4005-2A>G', 'Var', (13, 24))	('c.4005-2A>G', 'Mutation', 'c.4005-2A>G', (13, 24))	('loss', 'NegReg', (72, 76))	('canonical splice site', 'MPA', (37, 58))	('affects', 'Reg', (25, 32))	('acceptor splice site', 'MPA', (84, 104))
32184	33227989	To date, dysfunction of the components of the SWI/SNF complex has been shown for various cancer entities including urothelial cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Disease', (89, 95))	('urothelial cancer', 'Disease', (115, 132))	('dysfunction', 'Var', (9, 20))	('shown', 'Reg', (71, 76))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('46', '61'))	('urothelial cancer', 'Disease', 'MESH:D014523', (115, 132))
32186	33227989	Most ARID1A mutations are inactivating truncating mutations :e.g., 63% of ARID1A gene alterations in urothelial carcinomas or over 90% of ARID1A mutations in ovarian clear cell carcinoma.	('ARID1A', 'Gene', '8289', (5, 11))	('ARID1A', 'Gene', (74, 80))	('ARID1A', 'Gene', (5, 11))	('ovarian clear cell carcinoma', 'Disease', (158, 186))	('mutations', 'Var', (145, 154))	('mutations', 'Var', (12, 21))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (101, 122))	('ARID1A', 'Gene', '8289', (74, 80))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (158, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('ARID1A', 'Gene', '8289', (138, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('ARID1A', 'Gene', (138, 144))	('urothelial carcinomas', 'Disease', (101, 122))	('alterations', 'Var', (86, 97))
32187	33227989	ARID1A mutated carcinomas are associated with poor prognosis, and for instance, in breast cancer patients, inactivated ARID1A suggests a tumor suppressive function.	('tumor', 'Disease', (137, 142))	('ARID1A', 'Gene', '8289', (119, 125))	('carcinomas', 'Disease', 'MESH:D009369', (15, 25))	('ARID1A', 'Gene', '8289', (0, 6))	('ARID1A', 'Gene', (119, 125))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('carcinomas', 'Phenotype', 'HP:0030731', (15, 25))	('breast cancer', 'Disease', (83, 96))	('carcinomas', 'Disease', (15, 25))	('ARID1A', 'Gene', (0, 6))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('mutated', 'Var', (7, 14))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('patients', 'Species', '9606', (97, 105))
32188	33227989	Recently, we revealed frequent genetic alterations of genes encoding for SWI/SNF subunits including ARID1A with a frequency of 26% in urothelial bladder cancer.	('SWI/SNF', 'Gene', (73, 80))	('ARID1A', 'Gene', '8289', (100, 106))	('urothelial bladder cancer', 'Disease', (134, 159))	('ARID1A', 'Gene', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (134, 159))	('genetic alterations', 'Var', (31, 50))
32189	33227989	In line with this, we identified ARID1A mutations in 15% of sq-BLCA of the TCGA data set.	('mutations', 'Var', (40, 49))	('ARID1A', 'Gene', '8289', (33, 39))	('sq-BLCA', 'Disease', (60, 67))	('ARID1A', 'Gene', (33, 39))
32190	33227989	The pathological/functional significance of identified missense mutations remains elusive; however, by stratifying the mutations we significantly observed reduced ARID1A protein levels for both:i.e., for nonsense mutations as well as for the combined group of nonsense and missense mutations.	('reduced', 'NegReg', (155, 162))	('nonsense mutations', 'Var', (204, 222))	('ARID1A', 'Gene', '8289', (163, 169))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('ARID1A', 'Gene', (163, 169))	('mutations', 'Var', (119, 128))	('missense mutations', 'Var', (273, 291))
32191	33227989	Wu and colleagues showed, for instance, that heterozygous ARID1A mutations correlated with loss of protein expression:i.e., 73% of tumors with heterozygous ARID1A mutations lacked protein expression :suggesting a second hit on the remaining allele.	('mutations', 'Var', (163, 172))	('ARID1A', 'Gene', '8289', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('ARID1A', 'Gene', (58, 64))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('protein expression', 'MPA', (180, 198))	('ARID1A', 'Gene', '8289', (156, 162))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('protein expression', 'MPA', (99, 117))	('lacked', 'NegReg', (173, 179))	('mutations', 'Var', (65, 74))	('ARID1A', 'Gene', (156, 162))
32192	33227989	Considering that, we confirmed missense and nonsense mutations of ARID1A in both pure and mixed SCC samples which were characterized by ARID1A protein loss.	('ARID1A', 'Gene', '8289', (136, 142))	('missense', 'Var', (31, 39))	('ARID1A', 'Gene', (136, 142))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('ARID1A', 'Gene', '8289', (66, 72))	('ARID1A', 'Gene', (66, 72))	('pure', 'molecular_function', 'GO:0034023', ('81', '85'))	('nonsense mutations', 'Var', (44, 62))
32199	33227989	In endometrial carcinomas, ARID1A mutations are associated with mismatch repair deficiency and normal p53 expression.	('mismatch repair', 'biological_process', 'GO:0006298', ('64', '79'))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (3, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (15, 25))	('associated', 'Reg', (48, 58))	('p53', 'Gene', '7157', (102, 105))	('expression', 'MPA', (106, 116))	('ARID1A', 'Gene', '8289', (27, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('ARID1A', 'Gene', (27, 33))	('endometrial carcinomas', 'Disease', (3, 25))	('p53', 'Gene', (102, 105))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (3, 25))	('deficiency', 'NegReg', (80, 90))	('mutations', 'Var', (34, 43))	('mismatch repair', 'Protein', (64, 79))
32200	33227989	Bosse and colleagues showed a nearly mutual exclusivity of ARID1A loss and mutant-like TP53 expression, while alterations of the PI3K-AKT pathway were more frequent when ARID1A expression was lost.	('AKT', 'Gene', (134, 137))	('loss', 'NegReg', (66, 70))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('ARID1A', 'Gene', '8289', (59, 65))	('PI3K', 'molecular_function', 'GO:0016303', ('129', '133'))	('ARID1A', 'Gene', (59, 65))	('AKT', 'Gene', '207', (134, 137))	('mutant-like', 'Var', (75, 86))	('ARID1A', 'Gene', '8289', (170, 176))	('expression', 'MPA', (92, 102))	('ARID1A', 'Gene', (170, 176))
32201	33227989	Coexistence of PIK3CA and ARID1A mutations has been shown before, whereas association of both events was not observed in our SCC/MIX samples of the urinary bladder.	('ARID1A', 'Gene', (26, 32))	('PIK3CA', 'Gene', '5290', (15, 21))	('MIX', 'Gene', '83881', (129, 132))	('mutations', 'Var', (33, 42))	('PIK3CA', 'Gene', (15, 21))	('MIX', 'Gene', (129, 132))	('ARID1A', 'Gene', '8289', (26, 32))
32203	33227989	Thus, a hypothesized causal and functional link between both events (e.g., PIK3CA and ARID1A mutations/expression) seems unlikely in squamous bladder cancer.	('PIK3CA', 'Gene', (75, 81))	('PIK3CA', 'Gene', '5290', (75, 81))	('mutations/expression', 'Var', (93, 113))	('ARID1A', 'Gene', '8289', (86, 92))	('ARID1A', 'Gene', (86, 92))	('bladder cancer', 'Phenotype', 'HP:0009725', (142, 156))	('squamous bladder cancer', 'Disease', 'MESH:D001749', (133, 156))	('squamous bladder cancer', 'Disease', (133, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
32205	33227989	However, accumulating studies propose the involvement of functional ARID1A loss in synthetic lethality, which contributes to the response to various classical and novel therapeutic options, including immune checkpoint inhibitors (ICI).	('men', 'Species', '9606', (49, 52))	('ARID1A', 'Gene', '8289', (68, 74))	('ARID1A', 'Gene', (68, 74))	('synthetic lethality', 'MPA', (83, 102))	('loss', 'NegReg', (75, 79))	('functional', 'Var', (57, 67))
32206	33227989	Goswami and colleagues have recently shown that ARID1A mutation in combination with immune cytokine CXCL13 expression predicts response to immune checkpoint inhibitors in metastasized bladder cancers.	('CXCL13', 'Gene', (100, 106))	('response to immune checkpoint inhibitors', 'MPA', (127, 167))	('ARID1A', 'Gene', '8289', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('ARID1A', 'Gene', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('CXCL13', 'Gene', '10563', (100, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (184, 198))	('metastasized bladder cancers', 'Disease', 'MESH:D001749', (171, 199))	('mutation', 'Var', (55, 63))	('bladder cancers', 'Phenotype', 'HP:0009725', (184, 199))	('metastasized bladder cancers', 'Disease', (171, 199))	('predicts', 'Reg', (118, 126))
32208	33227989	However, a correlation between ARID1A mutations and increased PD-L1 expression as previously reported could not be confirmed in sq-BLCA.	('PD-L1', 'Gene', '29126', (62, 67))	('increased', 'PosReg', (52, 61))	('expression', 'MPA', (68, 78))	('ARID1A', 'Gene', '8289', (31, 37))	('ARID1A', 'Gene', (31, 37))	('increased PD', 'Phenotype', 'HP:0008151', (52, 64))	('PD-L1', 'Gene', (62, 67))	('mutations', 'Var', (38, 47))
32209	33227989	The co-occurrence was rare, and only a subgroup of patients with ARID1A mutations may benefit from ICI treatment.	('mutations', 'Var', (72, 81))	('men', 'Species', '9606', (108, 111))	('ARID1A', 'Gene', '8289', (65, 71))	('ARID1A', 'Gene', (65, 71))	('patients', 'Species', '9606', (51, 59))
32213	33227989	Further clinical trials may be necessary to prove the possible synergistic effect of both HDAC- and PD-L1-inhibitors on squamous bladder cancer cells with ARID1A mutation.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('PD-L1', 'Gene', '29126', (100, 105))	('mutation', 'Var', (162, 170))	('ARID1A', 'Gene', '8289', (155, 161))	('ARID1A', 'Gene', (155, 161))	('squamous bladder cancer', 'Disease', 'MESH:D001749', (120, 143))	('squamous bladder cancer', 'Disease', (120, 143))	('PD-L1', 'Gene', (100, 105))
32216	33227989	Supplementary Tables S2-S4: Clinico-pathological parameters of the TCGA sq-BLCA data set in relation to SWI/SNF/ARID1A mutations.	('ARID1A', 'Gene', (112, 118))	('mutations', 'Var', (119, 128))	('ARID1A', 'Gene', '8289', (112, 118))	('men', 'Species', '9606', (6, 9))
32217	33227989	Supplementary Table S5: Overlap of ARID1A mutations/expression loss with PD-L1 expression.	('PD-L1', 'Gene', '29126', (73, 78))	('mutations/expression', 'Var', (42, 62))	('ARID1A', 'Gene', '8289', (35, 41))	('ARID1A', 'Gene', (35, 41))	('mutations/expression', 'MPA', (42, 62))	('loss', 'NegReg', (63, 67))	('PD-L1', 'Gene', (73, 78))	('men', 'Species', '9606', (6, 9))
32220	33227989	Supplementary Figure S2: Prognostic impact of SWI/SNF and ARID1A mutations on tumor patients' survival.	('ARID1A', 'Gene', '8289', (58, 64))	('patients', 'Species', '9606', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('ARID1A', 'Gene', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('SWI/SNF', 'Gene', (46, 53))	('tumor', 'Disease', (78, 83))	('mutations', 'Var', (65, 74))	('men', 'Species', '9606', (6, 9))
32222	31192134	Somatic Mutations Profile of a Young Patient With Metastatic Urothelial Carcinoma Reveals Mutations in Genes Involved in Ion Channels Background: Urothelial carcinoma is the most common malignancy of the bladder and is primarily considered as a disease of the elderly.	('Mutations', 'Var', (90, 99))	('Metastatic Urothelial Carcinoma', 'Disease', (50, 81))	('Metastatic Urothelial Carcinoma', 'Disease', 'MESH:C538445', (50, 81))	('Ion Channels', 'molecular_function', 'GO:0022831', ('121', '133'))	('Urothelial carcinoma', 'Disease', 'MESH:D014526', (146, 166))	('Carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('Patient', 'Species', '9606', (37, 44))	('malignancy of the bladder', 'Disease', (186, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('Urothelial carcinoma', 'Disease', (146, 166))	('malignancy of the bladder', 'Disease', 'MESH:D001749', (186, 211))	('malignancy of the bladder', 'Phenotype', 'HP:0009725', (186, 211))
32228	31192134	Result: We predicted eight potential driver mutations (TP53 p.V157L, RB1 c.1498+1G>T, MED23 p.L1127P, CTNND1 p.S713C, NSD1 p.P2212A, MED17 p.G556V, DPYD p.Q814K, and SPEN p.S1078*).	('c.1498+1G>T', 'Var', (73, 84))	('p.G556V', 'Mutation', 'p.G556V', (139, 146))	('NSD1', 'Gene', (118, 122))	('RB1', 'Gene', (69, 72))	('c.1498+1G>T', 'Mutation', 'c.1498+1G>T', (73, 84))	('p.L1127P', 'Mutation', 'rs981694966', (92, 100))	('TP53', 'Gene', '7157', (55, 59))	('p.V157L', 'Var', (60, 67))	('p.S1078*', 'Mutation', 'p.S1078*', (171, 179))	('MED23', 'Gene', '9439', (86, 91))	('MED23', 'Gene', (86, 91))	('RB1', 'Gene', '5925', (69, 72))	('NSD1', 'Gene', '64324', (118, 122))	('p.P2212A', 'Mutation', 'p.P2212A', (123, 131))	('p.L1127P', 'Var', (92, 100))	('p.Q814K', 'Var', (153, 160))	('p.S713C', 'Mutation', 'p.S713C', (109, 116))	('CTNND1', 'Gene', (102, 108))	('CTNND1', 'Gene', '1500', (102, 108))	('p.S1078*', 'Var', (171, 179))	('MED17', 'Gene', (133, 138))	('p.V157L', 'Mutation', 'p.V157L', (60, 67))	('MED17', 'Gene', '9440', (133, 138))	('p.G556V', 'Var', (139, 146))	('p.S713C', 'Var', (109, 116))	('TP53', 'Gene', (55, 59))	('p.Q814K', 'Mutation', 'p.Q814K', (153, 160))	('p.P2212A', 'Var', (123, 131))
32229	31192134	In addition, we predicted deleterious mutations in genes involved in the ion channels (CACNA1S p.E1581K, CACNG1 p.P71T, CACNG8 p.G404W, GRIN2B p.A1096T, KCNC1 p.G16V, KCNH4 p.E874K, KCNK9 p.R131S, P2RX7 p.A296D, and SCN8A p.R558H).	('p.R131S', 'Var', (188, 195))	('CACNG1', 'Gene', '786', (105, 111))	('GRIN2B', 'Gene', (136, 142))	('p.R558H', 'Var', (222, 229))	('p.G404W', 'Var', (127, 134))	('p.E874K', 'Mutation', 'p.E874K', (173, 180))	('p.G404W', 'Mutation', 'p.G404W', (127, 134))	('p.A1096T', 'Mutation', 'rs777047940', (143, 151))	('KCNK9', 'Gene', (182, 187))	('p.G16V', 'Var', (159, 165))	('p.E1581K', 'Mutation', 'p.E1581K', (95, 103))	('GRIN2B', 'Gene', '2904', (136, 142))	('SCN8A', 'Gene', (216, 221))	('P2RX7', 'Gene', (197, 202))	('KCNK9', 'Gene', '51305', (182, 187))	('SCN8A', 'Gene', '6334', (216, 221))	('CACNG1', 'Gene', (105, 111))	('p.P71T', 'Mutation', 'p.P71T', (112, 118))	('CACNA1S', 'Gene', '779', (87, 94))	('p.G16V', 'Mutation', 'p.G16V', (159, 165))	('ion channels', 'molecular_function', 'GO:0022831', ('73', '85'))	('KCNC1', 'Gene', (153, 158))	('p.P71T', 'Var', (112, 118))	('p.R131S', 'Mutation', 'rs1373479176', (188, 195))	('p.A1096T', 'Var', (143, 151))	('CACNA1S', 'Gene', (87, 94))	('p.A296D', 'Var', (203, 210))	('p.A296D', 'Mutation', 'rs200947358', (203, 210))	('CACNG8', 'Gene', (120, 126))	('p.R558H', 'Mutation', 'rs770777288', (222, 229))	('p.E1581K', 'Var', (95, 103))	('KCNC1', 'Gene', '3746', (153, 158))	('CACNG8', 'Gene', '59283', (120, 126))	('P2RX7', 'Gene', '5027', (197, 202))
32230	31192134	Conclusions: Most likely, mutations in genes involved in ion channels may be responsible for the aggressive behavior of a tumor.	('aggressive behavior', 'Phenotype', 'HP:0000718', (97, 116))	('aggressive behavior', 'biological_process', 'GO:0002118', ('97', '116'))	('responsible', 'Reg', (77, 88))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mutations', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('ion channels', 'molecular_function', 'GO:0022831', ('57', '69'))
32252	31192134	Thirty mutations are reported in COSMIC database including in genes, such as TP53, ABL1, ARID5B, and P2RX7 (Supplementary Table 1).	('ABL1', 'Gene', '25', (83, 87))	('ABL1', 'Gene', (83, 87))	('ARID5B', 'Gene', '84159', (89, 95))	('ARID5B', 'Gene', (89, 95))	('P2RX7', 'Gene', (101, 106))	('P2RX7', 'Gene', '5027', (101, 106))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('mutations', 'Var', (7, 16))
32253	31192134	In addition, using Cancer Genome Interpreter, we predicted eight potential driver mutations among all the somatic mutations detected in this rare tumor.	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Cancer', 'Disease', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Cancer', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Disease', (146, 151))	('mutations', 'Var', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
32254	31192134	These predicted driver mutations including loss-of-function mutations in TP53, RB1, MED23, CTNND1 and activating mutations in NSD1and MED17 (Table 1).	('loss-of-function', 'NegReg', (43, 59))	('RB1', 'Gene', (79, 82))	('NSD1', 'Gene', (126, 130))	('TP53', 'Gene', '7157', (73, 77))	('activating', 'PosReg', (102, 112))	('RB1', 'Gene', '5925', (79, 82))	('MED17', 'Gene', '9440', (134, 139))	('TP53', 'Gene', (73, 77))	('MED23', 'Gene', '9439', (84, 89))	('CTNND1', 'Gene', (91, 97))	('CTNND1', 'Gene', '1500', (91, 97))	('MED23', 'Gene', (84, 89))	('NSD1', 'Gene', '64324', (126, 130))	('mutations', 'Var', (60, 69))	('MED17', 'Gene', (134, 139))
32255	31192134	The TP53 p.V157L a known oncogenic mutation was identified as a recurrent hotspot in various cancer types.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('TP53', 'Gene', (4, 8))	('p.V157L', 'Var', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('p.V157L', 'Mutation', 'p.V157L', (9, 16))	('TP53', 'Gene', '7157', (4, 8))
32257	31192134	The RB1 c.1498+1G>T alteration is likely oncogenic.	('c.1498+1G>T', 'Mutation', 'c.1498+1G>T', (8, 19))	('c.1498+1G>T', 'Var', (8, 19))	('RB1', 'Gene', '5925', (4, 7))	('RB1', 'Gene', (4, 7))
32258	31192134	Mutations in RB1 is associated with poor overall survival in patients with urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('RB1', 'Gene', '5925', (13, 16))	('overall', 'MPA', (41, 48))	('poor', 'NegReg', (36, 40))	('urothelial carcinoma', 'Disease', (75, 95))	('patients', 'Species', '9606', (61, 69))	('Mutations', 'Var', (0, 9))	('RB1', 'Gene', (13, 16))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (75, 95))
32259	31192134	Given that the above predicted driver mutations are in the genes that are limited to already known/predicted cancer driver genes, we carried out a network analysis of 347 genes that harbor a missense mutation using the STRING database.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('missense mutation', 'Var', (191, 208))	('mutations', 'Var', (38, 47))
32264	31192134	A typical tumor exhibits two to five driver genes, however our sequencing analysis of the primary tumor identified eight predicted somatic driver mutations as well as the predicted deleterious somatic mutations in genes involved in ion channels, such as CACNA1S, KCNK9, SCN8A, and P2RX7.	('P2RX7', 'Gene', '5027', (281, 286))	('SCN8A', 'Gene', '6334', (270, 275))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('CACNA1S', 'Gene', '779', (254, 261))	('mutations', 'Var', (146, 155))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('KCNK9', 'Gene', '51305', (263, 268))	('KCNK9', 'Gene', (263, 268))	('ion channels', 'molecular_function', 'GO:0022831', ('232', '244'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('SCN8A', 'Gene', (270, 275))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('P2RX7', 'Gene', (281, 286))	('CACNA1S', 'Gene', (254, 261))
32271	31192134	For example, inhibition of CACNA1S has been reported to block invasion in breast cancer cell lines and pancreatic cancer.	('CACNA1S', 'Gene', '779', (27, 34))	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('block', 'NegReg', (56, 61))	('pancreatic cancer', 'Disease', (103, 120))	('inhibition', 'Var', (13, 23))	('pancreatic cancer', 'Disease', 'MESH:D010190', (103, 120))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('invasion', 'CPA', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('CACNA1S', 'Gene', (27, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
32272	31192134	The blocking of voltage gated potassium channels in small cell lung cancer, melanoma cells, breast cancer cells, and prostate cancer cells with therapeutic agents have also been reported to reduce the cell proliferation.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (52, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cell proliferation', 'biological_process', 'GO:0008283', ('201', '219'))	('cell proliferation', 'CPA', (201, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('small cell lung cancer', 'Disease', 'MESH:D055752', (52, 74))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('breast cancer', 'Disease', (92, 105))	('blocking', 'Var', (4, 12))	('voltage', 'Protein', (16, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('small cell lung cancer', 'Disease', (52, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('prostate cancer', 'Disease', (117, 132))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('melanoma', 'Disease', (76, 84))	('reduce', 'NegReg', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
32274	31192134	Our results underpin the value of WES in revealing the somatic mutations in the known cancerdriver genes and genes involved in ion channels in a patient.	('mutations', 'Var', (63, 72))	('ion channels', 'molecular_function', 'GO:0022831', ('127', '139'))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('patient', 'Species', '9606', (145, 152))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
32297	30275913	PC0020) and ECL Plus Super-Enhanced chemiluminescence detection reagent (PE0010-100; Beijing Solarbio, China); Multiskan MK3 microplate reader, STP 120 tissue processor, and 171 tissue embedding station (Thermo Scientific); Leica RM2125 rotary manual microtome and Leica TK-218 thermostatic slice spreading and baking machine (Hubei Taiva Medical Technology, China); and Nikon Eclipse 80i biologic microscope (Shanghai Jiangwen Information Technology, China).	('PE0010-100;', 'Var', (73, 84))	('MK3', 'Gene', '7867', (121, 124))	('MK3', 'Gene', (121, 124))
32318	29039894	Hydronephrosis was also significantly higher in patients with orifice involved BC, due to the orifice obstruction caused by the tumor (33.3% vs. 13.9%, p<0.05).	('Hydronephrosis', 'Disease', 'MESH:D006869', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Hydronephrosis', 'Phenotype', 'HP:0000126', (0, 14))	('BC', 'Phenotype', 'HP:0009725', (79, 81))	('nephrosis', 'Phenotype', 'HP:0000100', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('higher', 'PosReg', (38, 44))	('tumor', 'Disease', (128, 133))	('orifice involved', 'Var', (62, 78))	('patients', 'Species', '9606', (48, 56))	('Hydronephrosis', 'Disease', (0, 14))
32321	29039894	Transurethral resection (TUR) of the ureteral orifice is necessary during treatment of these cases and TUR of the ureteral orifice is suggested to cause vesicoureteral reflux (VUR), due to the destruction of the muscle fibers, which leads to upper tract urothelial carcinoma (UTUC) development.	('VUR', 'Gene', (176, 179))	('leads to', 'Reg', (233, 241))	('VUR', 'Phenotype', 'HP:0000076', (176, 179))	('cause', 'Reg', (147, 152))	('TUR of', 'Var', (103, 109))	('vesicoureteral reflux', 'Gene', '54113', (153, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))	('vesicoureteral reflux', 'Phenotype', 'HP:0000076', (153, 174))	('vesicoureteral reflux', 'Gene', (153, 174))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (242, 274))	('VUR', 'Gene', '54113', (176, 179))	('upper tract urothelial carcinoma', 'Disease', (242, 274))
32368	29039894	Our data indicate that resection of the ureteral orifice resulted in resolution of hydro-nephrosis in 10 of the 27 patients that have hydronephrosis prior to resection.	('patients', 'Species', '9606', (115, 123))	('hydronephrosis', 'Disease', (134, 148))	('nephrosis', 'Phenotype', 'HP:0000100', (139, 148))	('hydro-nephrosis', 'Disease', 'MESH:D009401', (83, 98))	('hydronephrosis', 'Phenotype', 'HP:0000126', (134, 148))	('resection', 'Var', (23, 32))	('nephrosis', 'Phenotype', 'HP:0000100', (89, 98))	('hydro-nephrosis', 'Disease', (83, 98))	('hydronephrosis', 'Disease', 'MESH:D006869', (134, 148))
32437	28035323	Several groups have assessed the prognostic ability of PD-L1 expression in urothelial cancer and described the expression of PD-L1 on tumor cells to be associated with a shorter survival after cystectomy.	('urothelial cancer', 'Disease', (75, 92))	('expression', 'Var', (111, 121))	('PD-L1', 'Gene', '29126', (55, 60))	('PD-L1', 'Gene', '29126', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('urothelial cancer', 'Disease', 'MESH:D014523', (75, 92))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('shorter', 'NegReg', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('PD-L1', 'Gene', (55, 60))	('PD-L1', 'Gene', (125, 130))	('tumor', 'Disease', (134, 139))
32445	28035323	The underlying hypothesis was that patients with a higher PD-L1 expression have a better response to adjuvant treatment and thus better outcome.	('PD-L1', 'Gene', '29126', (58, 63))	('expression', 'MPA', (64, 74))	('better', 'PosReg', (82, 88))	('response', 'CPA', (89, 97))	('higher', 'Var', (51, 57))	('PD-L1', 'Gene', (58, 63))	('patients', 'Species', '9606', (35, 43))
32472	28035323	For the preoperative sample, chi-square tests were performed to assess the association between PD1 status and preoperative chemotherapy response, and CD8 status and response.	('CD8', 'Gene', (150, 153))	('CD8', 'Gene', '925', (150, 153))	('status', 'Var', (99, 105))	('PD1', 'Gene', '5133', (95, 98))	('PD1', 'Gene', (95, 98))	('association', 'Interaction', (75, 86))
32485	28035323	Also, there was no significant evidence of a difference in survival between patients with pN+ (n = 29) or pN0 (n = 13) disease (p = 0.54).	('pN0', 'Var', (106, 109))	('patients', 'Species', '9606', (76, 84))	('pN+', 'Var', (90, 93))
32522	28035323	Also in breast cancer, patients with a high PD-L1 expression were more likely to have a pathologically complete response after preoperative treatment.	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('high', 'Var', (39, 43))	('patients', 'Species', '9606', (23, 31))	('PD-L1', 'Gene', (44, 49))	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('PD-L1', 'Gene', '29126', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (8, 21))
32534	32344886	Moreover, increased EZH2 expression and H3K27me3 deposition in E-Cadherin promoter was found in sh-SIRT7 cells.	('E-Cadherin', 'Gene', '999', (63, 73))	('EZH2', 'Gene', '2146', (20, 24))	('expression', 'MPA', (25, 35))	('H3K27me3', 'Var', (40, 48))	('EZH2', 'Gene', (20, 24))	('Cadherin', 'molecular_function', 'GO:0008014', ('65', '73'))	('E-Cadherin', 'Gene', (63, 73))	('increased', 'PosReg', (10, 19))
32581	32344886	Moreover, EZH2 protein levels were significantly increased in sh-SIRT7 5637 cells (chosen because it showed differences in all phenotypic assays), compared to sh-CTRL cells (MW p< 0.01, Figure 5C).	('EZH2', 'Gene', '2146', (10, 14))	('increased', 'PosReg', (49, 58))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('EZH2', 'Gene', (10, 14))	('SIRT7 5637', 'CellLine', 'CVCL:0126', (65, 75))	('sh-SIRT7', 'Var', (62, 70))
32583	32344886	Firstly, PLA assay showed that EZH2 and SIRT7 physically interact in sh-CTRL 5637 cells (p < 0.0001; Figure 5D), and that sh-SIRT7 cells showed more H3K27me3 mark (p < 0.001; Figure 5D).	('EZH2', 'Gene', '2146', (31, 35))	('more', 'PosReg', (144, 148))	('EZH2', 'Gene', (31, 35))	('sh-SIRT7', 'Var', (122, 130))	('H3K27me3', 'Protein', (149, 157))
32585	32344886	Lastly, a ChIP assay was performed to assess the deposition of H3K27me3 mark at CDH1 promoter region in all transfected cell lines.	('CDH1', 'Gene', (80, 84))	('H3K27me3 mark', 'Var', (63, 76))	('CDH1', 'Gene', '999', (80, 84))
32586	32344886	As expected, increased H3K27me3 was observed across the CDH1 promoter in sh-SIRT7 cells, with a significant increase in both MGHU3 and J82 cells (2-way ANOVA p = 0.01; Figure 5F), suggesting that CDH1 repression associated with SIRT7 downregulation occurs through EZH2 overexpression.	('repression', 'NegReg', (201, 211))	('CDH1', 'Gene', '999', (196, 200))	('H3K27me3', 'Var', (23, 31))	('CDH1', 'Gene', (56, 60))	('EZH2', 'Gene', (264, 268))	('CDH1', 'Gene', '999', (56, 60))	('EZH2', 'Gene', '2146', (264, 268))	('downregulation', 'NegReg', (234, 248))	('CDH1', 'Gene', (196, 200))	('increased', 'PosReg', (13, 22))	('overexpression', 'PosReg', (269, 283))
32603	32344886	This hypothesis was confirmed as SIRT7 knockdown significantly associated with decreased E-Cadherin expression and augmented expression of a mesenchymal marker (N-Cadherin), and EMT-inducing transcription factors (SLUG and SNAIL), in the modulated BlCa cells.	('EMT', 'Gene', '3702', (178, 181))	('Cadherin', 'molecular_function', 'GO:0008014', ('91', '99'))	('SLUG', 'Gene', '6591', (214, 218))	('SLUG', 'Gene', (214, 218))	('decreased', 'NegReg', (79, 88))	('EMT', 'biological_process', 'GO:0001837', ('178', '181'))	('Cadherin', 'molecular_function', 'GO:0008014', ('163', '171'))	('N-Cadherin', 'Gene', (161, 171))	('E-Cadherin', 'Gene', (89, 99))	('N-Cadherin', 'Gene', '1000', (161, 171))	('expression', 'MPA', (125, 135))	('transcription', 'biological_process', 'GO:0006351', ('191', '204'))	('SNAIL', 'Gene', '6615', (223, 228))	('SNAIL', 'Gene', (223, 228))	('knockdown', 'Var', (39, 48))	('augmented', 'PosReg', (115, 124))	('expression', 'MPA', (100, 110))	('SIRT7', 'Gene', (33, 38))	('E-Cadherin', 'Gene', '999', (89, 99))	('EMT', 'Gene', (178, 181))
32604	32344886	Although only a few studies investigated the relationship between sirtuins and EMT, SIRT7 depletion in PC3 prostate cancer cell line was shown to impair migration and invasiveness, reprograming neoplastic cells towards epithelial gene expression.	('prostate cancer', 'Disease', (107, 122))	('EMT', 'biological_process', 'GO:0001837', ('79', '82'))	('EMT', 'Gene', (79, 82))	('EMT', 'Gene', '3702', (79, 82))	('migration', 'CPA', (153, 162))	('prostate cancer', 'Disease', 'MESH:D011471', (107, 122))	('reprograming', 'Reg', (181, 193))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('invasiveness', 'CPA', (167, 179))	('SIRT7', 'Gene', (84, 89))	('PC3', 'CellLine', 'CVCL:0035', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('depletion', 'Var', (90, 99))	('gene expression', 'biological_process', 'GO:0010467', ('230', '245'))	('impair', 'NegReg', (146, 152))
32611	32344886	Thus, when SIRT7 is downregulated, EZH2 activity might be enhanced by acetylation, contributing to CDH1 transcription repression through H3K27me3 deposition in its promoter, as previously reported.	('H3K27me3 deposition', 'Var', (137, 156))	('repression', 'NegReg', (118, 128))	('CDH1', 'Gene', '999', (99, 103))	('transcription', 'MPA', (104, 117))	('EZH2', 'Gene', (35, 39))	('EZH2', 'Gene', '2146', (35, 39))	('CDH1', 'Gene', (99, 103))	('transcription', 'biological_process', 'GO:0006351', ('104', '117'))
32622	32344886	Although the mechanism of SIRT7 deregulation in BlCa remains elusive, it is tempting to speculate whether it might be due to epigenetic mechanisms, which allow for the suggested plasticity of SIRT7 gene expression during carcinogenesis and tumor progression.	('SIRT7', 'Gene', (192, 197))	('tumor', 'Disease', (240, 245))	('gene expression', 'biological_process', 'GO:0010467', ('198', '213'))	('carcinogenesis', 'Disease', (221, 235))	('deregulation', 'Var', (32, 44))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('carcinogenesis', 'Disease', 'MESH:D063646', (221, 235))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('SIRT7', 'Gene', (26, 31))
32656	32344886	After incubation with primary antibodies for SIRT7 (1:350, HPA053669, Sigma-Aldrich) or EZH2 (1:500, NCL-L-EZH2, Leica Biosystems) for 1 h 30 min at RT, the membranes were washed in TBS/T and incubated with s ondary antibody coupled with horseradish peroxidase for 1 h at RT.	('EZH2', 'Gene', (88, 92))	('1:350', 'Var', (52, 57))	('antibody', 'cellular_component', 'GO:0019815', ('216', '224'))	('horseradish', 'Species', '3704', (238, 249))	('antibody', 'cellular_component', 'GO:0019814', ('216', '224'))	('EZH2', 'Gene', '2146', (107, 111))	('antibody', 'molecular_function', 'GO:0003823', ('216', '224'))	('EZH2', 'Gene', (107, 111))	('TBS', 'Chemical', 'MESH:D013725', (182, 185))	('EZH2', 'Gene', '2146', (88, 92))	('antibody', 'cellular_component', 'GO:0042571', ('216', '224'))
32660	32344886	After overnight SIRT7 (1:500, HPA053669, Sigma-Aldrich), ECAD (1:150, #3195, Cell Signaling Technology) and/or NCAD (1:50, #13116, Cell Signaling Technology) incubation at RT, cells were incubated with s ondary antibody anti-rabbit IgG-TRITC (1:500, T6778, Sigma-Aldrich) during 1 h at RT.	('antibody', 'cellular_component', 'GO:0019814', ('211', '219'))	('NCAD', 'Gene', (111, 115))	('antibody', 'molecular_function', 'GO:0003823', ('211', '219'))	('Signaling', 'biological_process', 'GO:0023052', ('136', '145'))	('NCAD', 'Gene', '1000', (111, 115))	('HPA053669', 'Var', (30, 39))	('TRITC', 'Chemical', 'MESH:C009434', (236, 241))	('Signaling', 'biological_process', 'GO:0023052', ('82', '91'))	('antibody', 'cellular_component', 'GO:0042571', ('211', '219'))	('ECAD', 'Gene', (57, 61))	('antibody', 'cellular_component', 'GO:0019815', ('211', '219'))	('ECAD', 'Gene', '999', (57, 61))
32670	32344886	The antibodies used were Histone H3 (ab1791, Abcam, Cambridge, UK), tri-methylation of Lysine 27 of Histone H3 (H3K27me3, 07-449, Millipore), SIRT7 (HPA053669, Sigma-Aldrich) and EZH2 (NCL-L-EZH2, Leica Biosystems).	('EZH2', 'Gene', (179, 183))	('EZH2', 'Gene', '2146', (179, 183))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('EZH2', 'Gene', (191, 195))	('EZH2', 'Gene', '2146', (191, 195))	('Lysine', 'Chemical', 'MESH:D008239', (87, 93))	('HPA053669', 'Var', (149, 158))
32744	30915526	When using the 2004 WHO classification, low-grade tumors are more likely to be regarded as superficial, whereas it is likely that high-grade tumors will be identified as invasive.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('low-grade', 'Var', (40, 49))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
32756	30915526	Low-grade tumors have a large proportion of FGFR3 alterations (80%).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('FGFR3', 'Gene', (44, 49))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('alterations', 'Var', (50, 61))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('FGFR3', 'Gene', '2261', (44, 49))
32764	30915526	observed that only two alterations were uniformly related to high-grade and advanced disease: TP53/MDM2 alterations, associated with poor prognosis; and FGFR3 mutations, associated with more favorable outcome.	('alterations', 'Var', (104, 115))	('FGFR', 'molecular_function', 'GO:0005007', ('153', '157'))	('MDM2', 'Gene', '4193', (99, 103))	('mutations', 'Var', (159, 168))	('MDM2', 'Gene', (99, 103))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('FGFR3', 'Gene', '2261', (153, 158))	('FGFR3', 'Gene', (153, 158))
32769	30915526	High IRP can result in forniceal rupture and potentially also perirenal tumor seeding.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('High IRP', 'Var', (0, 8))	('tumor', 'Disease', (72, 77))	('result in', 'Reg', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('forniceal rupture', 'CPA', (23, 40))
32861	25065704	Although it is most commonly activated by mutation in low-grade noninvasive bladder tumors (>70%), a significant number of invasive tumors also exhibit this mutation (~ 15%), and 40% to 50% of these show up-regulated expression of nonmutant protein.	('activated', 'PosReg', (29, 38))	('nonmutant', 'Protein', (231, 240))	('bladder tumor', 'Phenotype', 'HP:0009725', (76, 89))	('bladder tumors', 'Disease', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('expression', 'MPA', (217, 227))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('up-regulated', 'PosReg', (204, 216))	('invasive tumors', 'Disease', (123, 138))	('mutation', 'Var', (42, 50))	('bladder tumors', 'Phenotype', 'HP:0009725', (76, 90))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('protein', 'cellular_component', 'GO:0003675', ('241', '248'))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('invasive tumors', 'Disease', 'MESH:D009361', (123, 138))	('Al', 'Chemical', 'MESH:D000535', (0, 2))	('invasive bladder', 'Phenotype', 'HP:0100645', (67, 83))	('bladder tumors', 'Disease', 'MESH:D001749', (76, 90))
32864	25065704	Strikingly, bladder tumor cell lines containing FGFR3 fusions are extremely sensitive to small molecules and antibodies that target FGFR3.	('FGFR3', 'Gene', (132, 137))	('FGFR3', 'Gene', '2261', (48, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('132', '136'))	('fusions', 'Var', (54, 61))	('bladder tumor', 'Disease', 'MESH:D001749', (12, 25))	('FGFR3', 'Gene', (48, 53))	('bladder tumor', 'Phenotype', 'HP:0009725', (12, 25))	('FGFR3', 'Gene', '2261', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('bladder tumor', 'Disease', (12, 25))
32865	25065704	Taken together, preclinical studies indicate that the presence of point mutations in FGFR3, up-regulated expression of nonmutant protein, or the presence of a fusion protein may be useful biomarkers for predicting sensitivity to FGFR inhibitors.	('Ta', 'Chemical', 'MESH:D013635', (0, 2))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('FGFR3', 'Gene', (85, 90))	('expression', 'MPA', (105, 115))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('point mutations', 'Var', (66, 81))	('up-regulated', 'PosReg', (92, 104))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('nonmutant protein', 'Protein', (119, 136))	('FGFR3', 'Gene', '2261', (85, 90))	('fusion', 'Interaction', (159, 165))	('FGFR', 'molecular_function', 'GO:0005007', ('229', '233'))
32867	25065704	Conversely, inhibition of EGFR signaling leads to up-regulated expression of FGFR3.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('EGFR', 'Gene', (26, 30))	('FGFR3', 'Gene', (77, 82))	('inhibition', 'Var', (12, 22))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('expression', 'MPA', (63, 73))	('up-regulated', 'PosReg', (50, 62))	('FGFR3', 'Gene', '2261', (77, 82))	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))
32891	25065704	Promising biomarkers of response and outcome to bladder-sparing radiation-based therapy involved in DNA repair, apoptosis, proliferation, angiogenesis, and hypoxia, such as high MRE11, normal HER2, low ERCC1, high XRCC1/APE1, and low vascular endothelial growth factor-B, need further validation.	('hypoxia', 'Disease', 'MESH:D000860', (156, 163))	('XRCC1', 'Gene', (214, 219))	('ERCC1', 'Gene', '2067', (202, 207))	('APE1', 'Gene', (220, 224))	('angiogenesis', 'biological_process', 'GO:0001525', ('138', '150'))	('vascular endothelial growth factor-B', 'Gene', (234, 270))	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('ERCC1', 'Gene', (202, 207))	('low', 'NegReg', (230, 233))	('XRCC1', 'Gene', '7515', (214, 219))	('HER2', 'Gene', (192, 196))	('MRE11', 'Gene', (178, 183))	('vascular endothelial growth factor-B', 'Gene', '7423', (234, 270))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('MRE11', 'Gene', '4361', (178, 183))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('234', '268'))	('DNA repair', 'biological_process', 'GO:0006281', ('100', '110'))	('hypoxia', 'Disease', (156, 163))	('low', 'Var', (198, 201))	('HER2', 'Gene', '2064', (192, 196))	('APE1', 'Gene', '328', (220, 224))
32896	25065704	Using an experimental mouse model, it was shown that depletion of T cells before the third BCG instillation abrogated the inflammatory response.	('depletion', 'Var', (53, 62))	('abrogated', 'NegReg', (108, 117))	('men', 'Species', '9606', (15, 18))	('inflammatory response', 'biological_process', 'GO:0006954', ('122', '143'))	('inflammatory response', 'CPA', (122, 143))	('mouse', 'Species', '10090', (22, 27))	('depletion of T cells', 'Phenotype', 'HP:0005403', (53, 73))
33005	29023197	We identified 281 RBPs to be enriched for mutations (GEMs) in at least one cancer type.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('GEMs', 'cellular_component', 'GO:0015030', ('53', '57'))	('cancer', 'Disease', (75, 81))	('RBP', 'Gene', (18, 21))	('RBP', 'Gene', '57794', (18, 21))	('GEMs', 'cellular_component', 'GO:0097504', ('53', '57'))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (42, 51))
33006	29023197	GEM RBPs were found to undergo frequent frameshift and inframe deletions as well as missense, nonsense and silent mutations when compared to those that are not enriched for mutations.	('nonsense', 'Var', (94, 102))	('RBP', 'Gene', (4, 7))	('RBP', 'Gene', '57794', (4, 7))	('frameshift', 'Var', (40, 50))	('missense', 'Var', (84, 92))
33008	29023197	Using the OncodriveFM framework, we also identified more than 200 candidate driver RBPs that were found to accumulate functionally impactful mutations in at least one cancer.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('mutations', 'Var', (141, 150))	('cancer', 'Disease', (167, 173))	('RBP', 'Gene', (83, 86))	('RBP', 'Gene', '57794', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
33017	29023197	Given the importance of regulatory molecules like RBPs in controlling gene expression, it is evident that any deviation from normal function of these proteins can lead to various disorders including cancer.	('RBP', 'Gene', '57794', (50, 53))	('deviation', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('various disorders', 'Disease', (171, 188))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('gene expression', 'biological_process', 'GO:0010467', ('70', '85'))	('cancer', 'Disease', (199, 205))	('RBP', 'Gene', (50, 53))	('lead to', 'Reg', (163, 170))	('various disorders', 'Disease', 'MESH:C566351', (171, 188))
33022	29023197	An increased expression of this protein facilitates the inclusion of exon5 in the pre-mRNA of CD44 - a cell surface protein involved in cancer proliferation.	('increased', 'PosReg', (3, 12))	('CD44', 'Gene', (94, 98))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('expression', 'MPA', (13, 23))	('exon5', 'Protein', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cell surface', 'cellular_component', 'GO:0009986', ('103', '115'))	('pre', 'molecular_function', 'GO:0003904', ('82', '85'))	('cancer', 'Disease', (136, 142))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('CD44', 'Gene', '960', (94, 98))	('facilitates', 'PosReg', (40, 51))	('inclusion', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
33029	29023197	Mutational analysis of all the genes in the human genome across 12 cancer types identified SF3B1, U2AF1 and PCBP1 - RBPs involved in splicing to be significantly mutated in multiple cancers suggesting their role in causing cancer phenotypes.	('human', 'Species', '9606', (44, 49))	('SF3B1', 'Gene', (91, 96))	('PCBP1', 'Gene', (108, 113))	('splicing', 'biological_process', 'GO:0045292', ('133', '141'))	('U2AF1', 'Gene', (98, 103))	('cancer', 'Disease', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('RBP', 'Gene', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('SF3B1', 'Gene', '23451', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('U2AF1', 'Gene', '7307', (98, 103))	('multiple cancers', 'Disease', 'MESH:D009369', (173, 189))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('mutated', 'Var', (162, 169))	('PCBP1', 'Gene', '5093', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (67, 73))	('multiple cancers', 'Disease', (173, 189))	('U2AF', 'cellular_component', 'GO:0089701', ('98', '102'))	('RBP', 'Gene', '57794', (116, 119))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
33030	29023197	Furthermore, APOBEC3B - an important protein in the RNA editing mechanism was found to be upregulated and frequently mutated in cancers of bladder, cervix, lung, head and neck and breast.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('mutated', 'Var', (117, 124))	('cancers of bladder', 'Disease', (128, 146))	('cervix', 'Disease', (148, 154))	('cancers of bladder', 'Disease', 'MESH:D001749', (128, 146))	('neck', 'cellular_component', 'GO:0044326', ('171', '175'))	('APOBEC3B', 'Gene', (13, 21))	('APOBEC3B', 'Gene', '9582', (13, 21))	('breast', 'Disease', (180, 186))	('lung', 'Disease', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('APOBEC', 'cellular_component', 'GO:0030895', ('13', '19'))	('upregulated', 'PosReg', (90, 101))	('RNA editing', 'biological_process', 'GO:0009451', ('52', '63'))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))
33031	29023197	Also notable are the mutations in the gene coding for RBM10 in lung cancer which was found to misregulate the alternative splicing of NUMB protein- a critical regulator of the Notch pathway and hence leading to irregular cell proliferation in lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('lung cancers', 'Phenotype', 'HP:0100526', (243, 255))	('lung cancer', 'Disease', (63, 74))	('RBM10', 'Gene', '8241', (54, 59))	('splicing', 'biological_process', 'GO:0045292', ('122', '130'))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('alternative splicing', 'MPA', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('NUMB', 'Gene', (134, 138))	('irregular cell proliferation', 'CPA', (211, 239))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('misregulate', 'Var', (94, 105))	('mutations', 'Var', (21, 30))	('irregular cell proliferation', 'Phenotype', 'HP:0031377', (211, 239))	('NUMB', 'Gene', '8650', (134, 138))	('lung cancers', 'Disease', 'MESH:D008175', (243, 255))	('cell proliferation', 'biological_process', 'GO:0008283', ('221', '239'))	('lung cancer', 'Disease', 'MESH:D008175', (243, 254))	('RBM10', 'Gene', (54, 59))	('lung cancers', 'Disease', (243, 255))	('leading to', 'Reg', (200, 210))
33033	29023197	Hence, to expand the current understanding of mutations in these genes, we performed a systematic analyses of somatic mutations occurring in ~1300 RBPs in ~6000 tumor samples across 26 cancer types.	('tumor', 'Disease', (161, 166))	('RBP', 'Gene', (147, 150))	('RBP', 'Gene', '57794', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutations', 'Var', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
33035	29023197	We then analyzed the exome sequencing data of 26 cancer types to identify candidate drivers and integrated their transcriptome profiles to assess alterations in their expression due to mutation.	('expression', 'MPA', (167, 177))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mutation', 'Var', (185, 193))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
33039	29023197	Secondly, we identify Genes Enriched for Mutations (GEMs) in a given cancer using a Fisher's exact test that calculates the probability of observing mutations in a given gene against a genomic background (Fig.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('GEMs', 'cellular_component', 'GO:0015030', ('52', '56'))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('GEMs', 'cellular_component', 'GO:0097504', ('52', '56'))	('Mutations', 'Var', (41, 50))	('cancer', 'Disease', (69, 75))
33040	29023197	Finally, we identify RBPs that accumulate high functionally-impactful mutations using OncodriveFM approach (Fig.	('RBP', 'Gene', (21, 24))	('mutations', 'Var', (70, 79))	('RBP', 'Gene', '57794', (21, 24))
33041	29023197	1C) (See Materials and Methods) that relies on SIFT, PPH2 and Mutation Assessor to estimate the functional impact of individual mutations.	('SIFT', 'Disease', 'None', (47, 51))	('mutations', 'Var', (128, 137))	('PPH', 'molecular_function', 'GO:0033978', ('53', '56'))	('SIFT', 'Disease', (47, 51))	('PPH', 'molecular_function', 'GO:0004238', ('53', '56'))
33042	29023197	It does so by computing the bias towards the accumulation of high-impact mutations across the cancer in the cohort as a signal of their involvement in tumorogenesis.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('mutations', 'Var', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
33046	29023197	Overall, we find the mutational frequency of Non-RBPs to be significantly higher than that of RBPs in ~70% of the cancer types studied (Fig.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('higher', 'PosReg', (74, 80))	('RBP', 'Gene', (49, 52))	('RBP', 'Gene', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('RBP', 'Gene', '57794', (49, 52))	('RBP', 'Gene', '57794', (94, 97))	('mutational', 'Var', (21, 31))	('cancer', 'Disease', (114, 120))
33062	29023197	S1D), suggesting that these observations could reveal common mechanisms of dysregulation at post-transcriptional level with in members of these cancer type clusters due to mutations in RBPs.	('mutations', 'Var', (172, 181))	('cancer type clusters', 'Disease', (144, 164))	('RBP', 'Gene', (185, 188))	('RBP', 'Gene', '57794', (185, 188))	('cancer type clusters', 'Disease', 'MESH:D003027', (144, 164))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
33064	29023197	1B to identify Genes Enriched for Mutations (GEMs) in a given cancer type (see Materials and Methods).	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Mutations', 'Var', (34, 43))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('GEMs', 'cellular_component', 'GO:0015030', ('45', '49'))	('GEMs', 'cellular_component', 'GO:0097504', ('45', '49'))
33065	29023197	This identified 281 genes encoding for RBPs to be significantly enriched for mutations in at least one cancer (see Fig.	('RBP', 'Gene', '57794', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('RBP', 'Gene', (39, 42))
33066	29023197	3A for RBPs enriched for mutations in at least 4 cancers and Fig.	('mutations', 'Var', (25, 34))	('RBP', 'Gene', (7, 10))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('RBP', 'Gene', '57794', (7, 10))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))
33068	29023197	Comparison of GEM and non-GEM RBPs with corresponding gene sets for non-RBPs, for differences in the GC content and exome length, revealed that while GC content does not contribute to the extent of mutations in RBPs (p = 0.496, Wilcoxon test), it was found to be significantly different (p = 4.21e-08, Wilcoxon test) between GEM and non-GEM groups for non-RBPs (Fig.	('RBP', 'Gene', '57794', (30, 33))	('RBP', 'Gene', (356, 359))	('RBP', 'Gene', '57794', (72, 75))	('RBP', 'Gene', '57794', (356, 359))	('mutations', 'Var', (198, 207))	('RBP', 'Gene', (72, 75))	('RBP', 'Gene', (211, 214))	('RBP', 'Gene', '57794', (211, 214))	('different', 'Reg', (277, 286))	('RBP', 'Gene', (30, 33))
33070	29023197	These observations suggest that while GC content has no significant influence on the extent of mutations in RBPs, exome length might be higher for GEM RBPs, however it does not necessarily determine whether a gene is a GEM since non-RBPs GEMs exhibited significantly lower exome lengths.	('RBP', 'Gene', (233, 236))	('RBP', 'Gene', (151, 154))	('higher', 'PosReg', (136, 142))	('exome length', 'MPA', (114, 126))	('exome lengths', 'MPA', (273, 286))	('RBP', 'Gene', '57794', (151, 154))	('RBP', 'Gene', '57794', (233, 236))	('RBP', 'Gene', (108, 111))	('RBP', 'Gene', '57794', (108, 111))	('GEMs', 'cellular_component', 'GO:0015030', ('238', '242'))	('mutations', 'Var', (95, 104))	('lower', 'NegReg', (267, 272))	('GEMs', 'cellular_component', 'GO:0097504', ('238', '242'))
33071	29023197	Among the GEM RBPs, we identified KMT2C (MLL3), a histone 3- lysine 4 methyltransferase with tumor-suppressor properties that belongs to a family of chromatin regulator genes, to be enriched for mutations in 40% of the cancer types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('93', '109'))	('RBP', 'Gene', (14, 17))	('MLL3', 'Gene', (41, 45))	('tumor', 'Disease', (93, 98))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('93', '109'))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('chromatin', 'cellular_component', 'GO:0000785', ('149', '158'))	('mutations', 'Var', (195, 204))	('RBP', 'Gene', '57794', (14, 17))	('cancer', 'Disease', (219, 225))	('KMT2C', 'Gene', (34, 39))	('KMT2C', 'Gene', '58508', (34, 39))	('MLL3', 'Gene', '58508', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
33073	29023197	Furthermore, PLEC (plectin) - an abundantly expressed versatile protein that links different elements of the cytoskeleton was also seen to be enriched for mutations in 11 cancer types including lung, head and neck, bladder and pancreas.	('plectin', 'Gene', '5339', (19, 26))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('109', '121'))	('mutations', 'Var', (155, 164))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('neck', 'cellular_component', 'GO:0044326', ('209', '213'))	('cancer', 'Disease', (171, 177))	('PLEC', 'Gene', '5339', (13, 17))	('lung', 'Disease', (194, 198))	('PLEC', 'Gene', (13, 17))	('plectin', 'Gene', (19, 26))	('bladder and pancreas', 'Disease', 'MESH:D001749', (215, 235))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
33076	29023197	Also notable is the gene encoding for EPPK1 which was seen to be mutated in ~40% of the cancers including cancers of cervix, colon, head and neck, pancreas etc.	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('pancreas', 'Disease', (147, 155))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (88, 95))	('EPPK1', 'Gene', '83481', (38, 43))	('neck', 'cellular_component', 'GO:0044326', ('141', '145'))	('cancers', 'Disease', (106, 113))	('EPPK1', 'Gene', (38, 43))	('colon', 'Disease', (125, 130))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutated', 'Var', (65, 72))
33078	29023197	Further, functional analysis of RBPs enriched for mutations identified diverse pathways including translation, mRNA splicing and apoptosis to be over-represented (p < 0.01, Fig.	('mRNA splicing', 'biological_process', 'GO:0000373', ('111', '124'))	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('mRNA splicing', 'biological_process', 'GO:0006371', ('111', '124'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('111', '124'))	('translation', 'biological_process', 'GO:0006412', ('98', '109'))	('apoptosis', 'CPA', (129, 138))	('mRNA splicing', 'biological_process', 'GO:0000394', ('111', '124'))	('mutations', 'Var', (50, 59))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('mRNA splicing', 'biological_process', 'GO:0000372', ('111', '124'))	('translation', 'MPA', (98, 109))	('over-represented', 'PosReg', (145, 161))	('RBP', 'Gene', (32, 35))	('mRNA splicing', 'biological_process', 'GO:0000374', ('111', '124'))	('mRNA splicing', 'MPA', (111, 124))	('RBP', 'Gene', '57794', (32, 35))
33080	29023197	As different genes are susceptible to undergo different kinds of mutations at varied frequency, we aimed to identify mutation types that RBPs enriched for mutations (GEM-RBPs) frequently undergo when compared to RBPs that are not enriched for mutations (NonGEM-RBPs) (See Materials and Methods).	('mutations', 'Var', (155, 164))	('RBP', 'Gene', (212, 215))	('RBP', 'Gene', (137, 140))	('RBP', 'Gene', '57794', (212, 215))	('RBP', 'Gene', (261, 264))	('RBP', 'Gene', '57794', (137, 140))	('RBP', 'Gene', '57794', (261, 264))	('RBP', 'Gene', (170, 173))	('RBP', 'Gene', '57794', (170, 173))
33081	29023197	In particular, we quantified the mutation frequencies of nine different classes of mutations namely Frameshift mutations - Deletion and Insertion, Inframe Deletion, Inframe Insertion, Missense, Nonsense, Nonstop, Silent and Splice Site for all the RBPs across cancer samples (Materials and Methods, Table S2).	('Inframe Deletion', 'Var', (147, 163))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('RBP', 'Gene', (248, 251))	('cancer', 'Disease', (260, 266))	('Nonstop', 'Var', (204, 211))	('Missense', 'Var', (184, 192))	('RBP', 'Gene', '57794', (248, 251))	('Insertion', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('Nonsense', 'Var', (194, 202))	('Frameshift mutations - Deletion', 'Var', (100, 131))
33082	29023197	Our analysis clearly revealed that RBPs frequently and significantly undergo Frameshift deletion, Inframe deletion, Missense, Nonsense and Silent mutations (Fig.	('Frameshift deletion', 'Var', (77, 96))	('Silent mutations', 'Var', (139, 155))	('Inframe deletion', 'Var', (98, 114))	('RBP', 'Gene', (35, 38))	('RBP', 'Gene', '57794', (35, 38))	('Missense', 'Var', (116, 124))	('undergo', 'Reg', (69, 76))
33084	29023197	Abundance of Frameshift deletions in GEM-RBPs clearly indicates that deletion mutations causing change in reading frame thereby resulting in different translation than the original polypeptide, could be a frequent mechanism of dysregulation.	('deletion mutations', 'Var', (69, 87))	('RBP', 'Gene', (41, 44))	('RBP', 'Gene', '57794', (41, 44))	('Frameshift deletions', 'Var', (13, 33))	('resulting in different', 'Reg', (128, 150))	('translation', 'MPA', (151, 162))	('translation', 'biological_process', 'GO:0006412', ('151', '162'))	('reading frame', 'MPA', (106, 119))
33085	29023197	Also, a significant difference in the frequency of nonsense mutations - which introduce a premature termination codon (PTC) in the gene; between the two groups indicate the importance of these mutations in triggering the mechanism of nonsense mediate decay (NMD) of RBPs enriched for mutations in several cancers.	('cancers', 'Disease', 'MESH:D009369', (305, 312))	('cancers', 'Phenotype', 'HP:0002664', (305, 312))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('cancers', 'Disease', (305, 312))	('mutations', 'Var', (193, 202))	('RBP', 'Gene', (266, 269))	('RBP', 'Gene', '57794', (266, 269))
33087	29023197	This study showed that mutations that change the reading frame and introduce a premature termination codon cause a severe form of the disease as the whole transcript is eliminated by NMD, whereas mutations that did not give rise to a PTC resulted in a milder form of muscular dystrophy.	('muscular dystrophy', 'Disease', (267, 285))	('muscular dystrophy', 'Disease', 'MESH:D009136', (267, 285))	('cause', 'Reg', (107, 112))	('mutations', 'Var', (23, 32))	('premature termination codon', 'MPA', (79, 106))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (267, 285))	('eliminated', 'NegReg', (169, 179))
33088	29023197	A similar mechanism could be leading to the dysregulation of RBPs that are enriched for mutations in several cancer phenotypes, due to the higher mutational rate of nonsense mutations in GEM-RBPs (Fig.	('nonsense mutations', 'Var', (165, 183))	('RBP', 'Gene', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('RBP', 'Gene', '57794', (61, 64))	('mutational rate', 'MPA', (146, 161))	('cancer', 'Disease', (109, 115))	('dysregulation', 'MPA', (44, 57))	('RBP', 'Gene', (191, 194))	('RBP', 'Gene', '57794', (191, 194))	('higher', 'PosReg', (139, 145))
33089	29023197	Likewise, missense mutations that result in a change in the amino acid composition and inframe deletions which although do not change the frame of transcription but can result in a dysfunctional protein form could contribute to the loss of function phenotypes in RBPs enriched for mutations.	('dysfunctional', 'Disease', (181, 194))	('dysfunctional', 'Disease', 'MESH:D006331', (181, 194))	('protein form', 'MPA', (195, 207))	('amino acid composition', 'MPA', (60, 82))	('change', 'Reg', (46, 52))	('transcription', 'biological_process', 'GO:0006351', ('147', '160'))	('missense mutations', 'Var', (10, 28))	('RBP', 'Gene', '57794', (263, 266))	('RBP', 'Gene', (263, 266))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))	('result', 'Reg', (169, 175))
33090	29023197	In addition to identifying Genes Enriched for Mutations (GEMs), which can comprise of both synonymous and nonsynonymous somatic mutations in a cancer genome, we aimed to uncover RBPs that exhibit a bias towards the accumulation of nonsynonymous mutations with high functional impact during tumorigenesis, as a means to uncover likely driver RBPs.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('GEMs', 'cellular_component', 'GO:0015030', ('57', '61'))	('RBP', 'Gene', (178, 181))	('RBP', 'Gene', '57794', (178, 181))	('GEMs', 'cellular_component', 'GO:0097504', ('57', '61'))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('cancer', 'Disease', (143, 149))	('RBP', 'Gene', (341, 344))	('nonsynonymous mutations', 'Var', (231, 254))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('RBP', 'Gene', '57794', (341, 344))	('accumulation', 'PosReg', (215, 227))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Disease', (290, 295))
33091	29023197	Driver genes are known to provide a significant growth advantage to cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('genes', 'Var', (7, 12))	('growth advantage', 'CPA', (48, 64))
33093	29023197	A significant trend towards the accumulation of such functional mutations is calculated as FM bias - signal of positive selection during cancer development (See Materials and Methods).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (137, 143))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (137, 143))
33100	29023197	We predict AHNAK to be a candidate driver in 12 cancers including head and neck squamous carcinoma, lung adenocarcinoma, lung squamous carcinoma, breast cancers (See Table S3) suggesting the impact of nonsynonymous mutations on protein function and thus misregulating pathways responsible for cellular growth and hence leading to a cancer phenotype.	('lung squamous carcinoma', 'Disease', (121, 144))	('lung adenocarcinoma', 'Disease', (100, 119))	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (75, 98))	('cancer', 'Disease', (153, 159))	('cancers', 'Disease', (153, 160))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('leading to', 'Reg', (319, 329))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (100, 119))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('protein', 'cellular_component', 'GO:0003675', ('228', '235'))	('nonsynonymous mutations', 'Var', (201, 224))	('pathways', 'Pathway', (268, 276))	('protein', 'Protein', (228, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('breast cancers', 'Disease', 'MESH:D001943', (146, 160))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (100, 119))	('breast cancers', 'Disease', (146, 160))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancers', 'Disease', (48, 55))	('misregulating', 'Reg', (254, 267))	('AHNAK', 'Gene', '79026', (11, 16))	('impact', 'Reg', (191, 197))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('cancer', 'Disease', (332, 338))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('AHNAK', 'Gene', (11, 16))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (80, 98))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('cellular growth', 'biological_process', 'GO:0016049', ('293', '308'))	('neck squamous carcinoma', 'Disease', (75, 98))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (126, 144))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('neck', 'cellular_component', 'GO:0044326', ('75', '79'))
33101	29023197	Another striking example is AGO2 which was found to accumulate functional mutations in cancers of breast, skin, lung and stomach.	('AGO2', 'Gene', '27161', (28, 32))	('cancers of breast', 'Disease', 'MESH:D001943', (87, 104))	('stomach', 'Disease', (121, 128))	('mutations', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('skin', 'Disease', (106, 110))	('AGO2', 'Gene', (28, 32))	('cancers of breast', 'Disease', (87, 104))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('lung', 'Disease', (112, 116))
33108	29023197	Interestingly, we find the gene encoding SF3B1 - an important splicing factor to be frequently mutated and accumulating functional mutations in uveal melanoma (UVM) which is in accordance with a study that showed the impact of SF3B1 mutations on alternative splicing in uveal melanomas.	('uveal melanomas', 'Disease', (270, 285))	('uveal melanomas', 'Phenotype', 'HP:0007716', (270, 285))	('melanomas', 'Phenotype', 'HP:0002861', (276, 285))	('splicing', 'biological_process', 'GO:0045292', ('258', '266'))	('SF3B1', 'Gene', '23451', (227, 232))	('splicing factor', 'Gene', (62, 77))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('SF3B1', 'Gene', (41, 46))	('uveal melanoma', 'Disease', 'MESH:C536494', (144, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('uveal melanoma', 'Disease', (144, 158))	('splicing factor', 'Gene', '10569', (62, 77))	('uveal melanomas', 'Disease', 'MESH:C536494', (270, 285))	('uveal melanoma', 'Disease', 'MESH:C536494', (270, 284))	('uveal melanoma', 'Phenotype', 'HP:0007716', (144, 158))	('SF3B1', 'Gene', '23451', (41, 46))	('mutations', 'Var', (131, 140))	('splicing', 'biological_process', 'GO:0045292', ('62', '70'))	('SF3B1', 'Gene', (227, 232))	('uveal melanoma', 'Phenotype', 'HP:0007716', (270, 284))	('mutations', 'Var', (233, 242))
33109	29023197	Furthermore, recurrent missense mutation at R625 in patients with uveal melanoma was observed suggesting an oncogenic role of this mutation (Fig.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('missense mutation at R625', 'Var', (23, 48))	('patients', 'Species', '9606', (52, 60))
33112	29023197	Also, recurrent missense mutations at S34 in the zf-CCCH domain was observed to be highly recurrent in patients with LAML (Fig.	('missense mutations at S34', 'Var', (16, 41))	('patients', 'Species', '9606', (103, 111))	('LAML', 'Disease', (117, 121))
33113	29023197	To identify if mutations in an RBP gene affects its RNA levels, we performed pan-cancer expression analysis for all the candidate RBP drivers between patient cohorts containing these mutations and cohorts that don't carry such mutations (See Materials and Methods).	('RBP', 'Gene', (130, 133))	('patient', 'Species', '9606', (150, 157))	('mutations', 'Var', (183, 192))	('affects', 'Reg', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('RBP', 'Gene', '57794', (130, 133))	('mutations', 'Var', (15, 24))	('cancer', 'Disease', (81, 87))	('RBP', 'Gene', (31, 34))	('RBP', 'Gene', '57794', (31, 34))	('RNA levels', 'MPA', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))
33115	29023197	Of these, CDKN2A, a cyclin-dependent kinase inhibitor 2A known to stabilize the tumor suppressor protein p53 was observed to have higher levels of RNA in mutated samples when compared to the non-mutated samples (Fold change = 3.9, p = 1.26E-11, Wilcox test).	('kinase inhibitor', 'biological_process', 'GO:0033673', ('37', '53'))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('p53', 'Gene', (105, 108))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (20, 56))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('mutated', 'Var', (154, 161))	('CDKN2A', 'Gene', (10, 16))	('RNA', 'MPA', (147, 150))	('higher', 'PosReg', (130, 136))	('tumor', 'Disease', (80, 85))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('20', '53'))	('RNA', 'cellular_component', 'GO:0005562', ('147', '150'))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('CDKN2A', 'Gene', '1029', (10, 16))	('p53', 'Gene', '7157', (105, 108))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (20, 56))	('levels', 'MPA', (137, 143))
33116	29023197	Additionally, two distinct RNA helicases - DDX5 and DHX9 were found to have significantly different expression profiles between mutated and non-mutated cohorts.	('RNA helicases', 'Protein', (27, 40))	('expression profiles', 'MPA', (100, 119))	('mutated', 'Var', (128, 135))	('RNA', 'cellular_component', 'GO:0005562', ('27', '30'))	('different', 'Reg', (90, 99))	('DDX5', 'Gene', (43, 47))	('DHX9', 'Gene', (52, 56))	('DDX5', 'Gene', '1655', (43, 47))	('DHX9', 'Gene', '1660', (52, 56))
33118	29023197	RBM10 was seen to be 2 fold down regulated in mutated samples when compared to the non-mutated samples.	('mutated', 'Var', (46, 53))	('down regulated', 'NegReg', (28, 42))	('RBM10', 'Gene', (0, 5))	('RBM10', 'Gene', '8241', (0, 5))
33119	29023197	We hypothesize that the lower expression in the mutated samples could be a result of the presence of truncated transcripts due to several non-sense mutations in the gene encoding for RBM10 (Fig.	('mutations', 'Var', (148, 157))	('expression', 'MPA', (30, 40))	('lower', 'NegReg', (24, 29))	('RBM10', 'Gene', '8241', (183, 188))	('RBM10', 'Gene', (183, 188))
33120	29023197	Hence, mutations in the RBP gene might not only lead to abnormal subcellular localization, defective binding to RNA but also lead to altered protein-protein interactions and thus conferring a cancer phenotype.	('conferring', 'Reg', (179, 189))	('defective', 'NegReg', (91, 100))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('protein-protein interactions', 'MPA', (141, 169))	('cancer', 'Disease', (192, 198))	('binding', 'Interaction', (101, 108))	('abnormal', 'Reg', (56, 64))	('lead', 'Reg', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('subcellular localization', 'MPA', (65, 89))	('RBP', 'Gene', '57794', (24, 27))	('mutations', 'Var', (7, 16))	('altered', 'Reg', (133, 140))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('localization', 'biological_process', 'GO:0051179', ('77', '89'))	('RNA', 'Protein', (112, 115))	('RNA', 'cellular_component', 'GO:0005562', ('112', '115'))	('RBP', 'Gene', (24, 27))	('lead', 'Reg', (48, 52))
33130	29023197	Higher degree, betweenness and closeness of drivers when compared to the non-drivers indicates that they form an integral part of the protein-protein interaction network of RBPs and thus mutations in them could significantly contribute to causing lethal phenotypes by potentially disrupting the formation of RNP complexes.	('disrupting', 'NegReg', (280, 290))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('contribute', 'Reg', (225, 235))	('formation', 'MPA', (295, 304))	('RNP', 'Gene', (308, 311))	('mutations', 'Var', (187, 196))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('RNP', 'Gene', '55599', (308, 311))	('RBP', 'Gene', (173, 176))	('causing', 'Reg', (239, 246))	('RBP', 'Gene', '57794', (173, 176))	('RNP', 'cellular_component', 'GO:1990904', ('308', '311'))	('formation', 'biological_process', 'GO:0009058', ('295', '304'))
33133	29023197	Hence, mutations in them may not only affect the expression, defective binding to RNA but can also lead to altered protein-protein interactions and thus conferring a cancer phenotype.	('RNA', 'cellular_component', 'GO:0005562', ('82', '85'))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('cancer', 'Disease', (166, 172))	('defective', 'NegReg', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('RNA', 'Protein', (82, 85))	('lead to altered', 'Reg', (99, 114))	('expression', 'MPA', (49, 59))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('conferring', 'Reg', (153, 163))	('binding', 'Interaction', (71, 78))	('protein-protein interactions', 'MPA', (115, 143))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('affect', 'Reg', (38, 44))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))	('mutations', 'Var', (7, 16))
33141	29023197	This RBP interacts with CDC5L and SF3A1 in LUAD whereas it interacts with SNRNP300 and SF3B3 in COAD suggesting that different combinations of RBP mutated complexes could be contributing to disruption in different post-transcriptional sub-networks leading to varying cancer phenotypes.	('COAD', 'Disease', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('disruption', 'Reg', (190, 200))	('LUAD', 'Disease', (43, 47))	('RBP', 'Gene', (5, 8))	('leading to', 'Reg', (248, 258))	('RBP', 'Gene', '57794', (143, 146))	('CDC5L', 'Gene', (24, 29))	('post-transcriptional sub-networks', 'Pathway', (214, 247))	('SNRNP', 'cellular_component', 'GO:0030532', ('74', '79'))	('SF3B3', 'Gene', (87, 92))	('mutated', 'Var', (147, 154))	('contributing', 'Reg', (174, 186))	('CDC5L', 'Gene', '988', (24, 29))	('interacts', 'Reg', (9, 18))	('cancer', 'Disease', (267, 273))	('SF3B3', 'Gene', '23450', (87, 92))	('SF3A1', 'Gene', '10291', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('COAD', 'Disease', 'MESH:D029424', (96, 100))	('RBP', 'Gene', '57794', (5, 8))	('RNP', 'Gene', '55599', (76, 79))	('RBP', 'Gene', (143, 146))	('SNRNP', 'molecular_function', 'GO:0003734', ('74', '79'))	('SF3A1', 'Gene', (34, 39))	('RNP', 'Gene', (76, 79))
33145	29023197	Hence, to understand if the mutations in these proteins are truly deleterious and/or can have a phenotypic impact in breast cancer, we choose SF3B1 and PRPF8 to study their effect on breast cancer cell lines.	('PRPF8', 'Gene', (152, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('SF3B1', 'Gene', '23451', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('SF3B1', 'Gene', (142, 147))	('breast cancer', 'Disease', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('PRPF8', 'Gene', '10594', (152, 157))	('breast cancer', 'Disease', (183, 196))	('mutations', 'Var', (28, 37))
33149	29023197	Despite inefficient knockdown of SF3B1 (Fig.	('knockdown', 'Var', (20, 29))	('SF3B1', 'Gene', (33, 38))	('SF3B1', 'Gene', '23451', (33, 38))
33150	29023197	8A), CD44+/CD24+ cells were reproducibly reduced upon SF3B1 knockdown (Fig.	('CD24', 'Gene', (11, 15))	('reduced', 'NegReg', (41, 48))	('SF3B1', 'Gene', (54, 59))	('CD44', 'Gene', (5, 9))	('SF3B1', 'Gene', '23451', (54, 59))	('knockdown', 'Var', (60, 69))	('CD24', 'Gene', '100133941', (11, 15))	('CD44', 'Gene', '960', (5, 9))
33151	29023197	By contrast, SF3B1 knockdown cells displayed elevated levels of CD24 compared with control luciferase siRNA transfected cells (Fig.	('CD24', 'Gene', '100133941', (64, 68))	('SF3B1', 'Gene', (13, 18))	('knockdown', 'Var', (19, 28))	('CD24', 'Gene', (64, 68))	('SF3B1', 'Gene', '23451', (13, 18))	('elevated', 'PosReg', (45, 53))	('levels', 'MPA', (54, 60))
33152	29023197	Similar results were obtained upon knockdown of PRPF8 in these cells (Fig.	('knockdown', 'Var', (35, 44))	('PRPF8', 'Gene', '10594', (48, 53))	('PRPF8', 'Gene', (48, 53))
33153	29023197	Interestingly, SF3B1 or PRPF8 knockdown in MDA-MB-231 cell line, which represents mesenchymal stem like triple negative breast cancer, had no effect on CD44+/CD24- status (Fig.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('CD44', 'Gene', (152, 156))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('SF3B1', 'Gene', '23451', (15, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('CD24', 'Gene', '100133941', (158, 162))	('CD24', 'Gene', (158, 162))	('PRPF8', 'Gene', '10594', (24, 29))	('PRPF8', 'Gene', (24, 29))	('knockdown', 'Var', (30, 39))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (43, 53))	('SF3B1', 'Gene', (15, 20))	('CD44', 'Gene', '960', (152, 156))
33157	29023197	Consistent with this possibility, recent studies have demonstrated SF3B1 mutation (K700E) in breast cancer, preferentially in estrogen receptor positive breast cancer, to be a driver mutation.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('SF3B1', 'Gene', '23451', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('SF3B1', 'Gene', (67, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('K700E', 'Mutation', 'rs559063155', (83, 88))	('K700E', 'Var', (83, 88))	('breast cancer', 'Disease', (153, 166))
33161	29023197	Dysregulation of these proteins has been implicated in several disorders including cancer although the causes of such dysregulation is poorly understood.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('implicated', 'Reg', (41, 51))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
33163	29023197	Our computational analysis revealed that RBPs have an average of ~3 mutations per Mb across 26 cancers and enabled the identification of 281 RBPs to be enriched for mutations in at least one cancer type.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('RBP', 'Gene', (41, 44))	('cancers', 'Disease', (95, 102))	('cancer', 'Disease', (95, 101))	('RBP', 'Gene', '57794', (41, 44))	('RBP', 'Gene', (141, 144))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('RBP', 'Gene', '57794', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('mutations', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
33164	29023197	Among these, genes encoding for EPPK1, KMT2C, AHNAK and PLEC were found to be enriched for mutations in at least 10 cancers suggesting common players in mediating cancer phenotypes in different tissues.	('PLEC', 'Gene', '5339', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('EPPK1', 'Gene', '83481', (32, 37))	('PLEC', 'Gene', (56, 60))	('EPPK1', 'Gene', (32, 37))	('AHNAK', 'Gene', '79026', (46, 51))	('KMT2C', 'Gene', '58508', (39, 44))	('cancer', 'Disease', (116, 122))	('KMT2C', 'Gene', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('mutations', 'Var', (91, 100))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('cancer', 'Disease', (163, 169))	('AHNAK', 'Gene', (46, 51))
33165	29023197	GC content and exome length were not found to play a major role in contributing to the mutational frequency of RBPs in majority of the studied cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutational', 'Var', (87, 97))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('RBP', 'Gene', (111, 114))	('RBP', 'Gene', '57794', (111, 114))
33168	29023197	Our analyses also revealed that RBPs enriched for mutations in atleast one cancer type were seen to be undergoing frequent Frameshift and Inframe deletions, missense, nonsense and silent mutations when compared to those that are not enriched, revealing the abundance of these variant types in mutated RBPs as significant contributor for malfunction in cancer genomes.	('cancer', 'Disease', 'MESH:D009369', (352, 358))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (352, 358))	('cancer', 'Disease', (75, 81))	('atleast', 'Gene', (63, 70))	('RBP', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('RBP', 'Gene', (301, 304))	('RBP', 'Gene', '57794', (301, 304))	('missense', 'Var', (157, 165))	('RBP', 'Gene', '57794', (32, 35))
33172	29023197	We show that the presence of non-synonymous mutations correlate with change in the RNA levels of a significant fraction of driver RBPs (15% of the drivers), when cancer samples are grouped by the presence of mutations in an RBP irrespective of the cancer type.	('cancer', 'Disease', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('RBP', 'Gene', (130, 133))	('RNA', 'cellular_component', 'GO:0005562', ('83', '86'))	('RBP', 'Gene', '57794', (130, 133))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('RBP', 'Gene', (224, 227))	('RBP', 'Gene', '57794', (224, 227))	('change', 'Reg', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('presence', 'Var', (17, 25))	('non-synonymous mutations', 'Var', (29, 53))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('RNA levels', 'MPA', (83, 93))
33175	29023197	Our knock down experiments indicated that deletion of either of these RBPs resulted in MCF7 cells, which are estrogen receptor positive, to exhibit reduced stem cell features.	('MCF7', 'CellLine', 'CVCL:0031', (87, 91))	('stem cell features', 'CPA', (156, 174))	('reduced', 'NegReg', (148, 155))	('RBP', 'Gene', (70, 73))	('RBP', 'Gene', '57794', (70, 73))	('MCF7', 'Gene', (87, 91))	('deletion', 'Var', (42, 50))
33183	29023197	This analysis should form a foundation to help us uncover the mutational spectrum of RBPs and their wiring dynamics in different cancer types thereby leading to dysregulation of post-transcriptional regulatory networks and also emphasizes the potential of various proteins of the splicesomal machinery as possible drug targets in cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutational', 'Var', (62, 72))	('RBP', 'Gene', (85, 88))	('RBP', 'Gene', '57794', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('leading to', 'Reg', (150, 160))	('cancer', 'Disease', (129, 135))	('dysregulation', 'MPA', (161, 174))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('post-transcriptional', 'Pathway', (178, 198))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('cancer', 'Disease', (330, 336))
33192	29023197	Genes with corrected p < 0.01 and odds ratio < 1 were classified as Genes Enriched in Mutations (GEMs) in a given cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('GEMs', 'cellular_component', 'GO:0015030', ('97', '101'))	('Mutations', 'Var', (86, 95))	('GEMs', 'cellular_component', 'GO:0097504', ('97', '101'))
33194	29023197	We then obtained the mutation frequency of these genes in each cancer type for nine different variant classes viz - Inframe deletion, Inframe insertion, Frameshift deletion, Frameshift Insertion, Missense mutation, Nonsense mutation, Nonstop mutation, Silent and Splice Site mutations.	('Inframe insertion', 'Var', (134, 151))	('Frameshift deletion', 'Var', (153, 172))	('Nonsense mutation', 'Var', (215, 232))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('Nonstop mutation', 'Var', (234, 250))	('Frameshift Insertion', 'Var', (174, 194))	('cancer', 'Disease', (63, 69))	('Missense mutation', 'Var', (196, 213))
33195	29023197	Variants were classified into the above mentioned categories based on the annotations provided in the downloaded MAF files.	('MAF', 'Gene', '4094', (113, 116))	('MAF', 'Gene', (113, 116))	('Variants', 'Var', (0, 8))
33197	29023197	Upon obtaining the mutation frequencies in each cancer type for all the variant classes, we pooled the mutational frequencies of RBPs enriched for mutations across the cancers into one bin named as GEM-RBPs (Fig.	('RBP', 'Gene', (129, 132))	('mutations', 'Var', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('RBP', 'Gene', '57794', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('RBP', 'Gene', (202, 205))	('RBP', 'Gene', '57794', (202, 205))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancer', 'Disease', (48, 54))	('cancers', 'Disease', (168, 175))	('cancer', 'Disease', (168, 174))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
33213	29023197	Further, genes were categorized as drivers - if they are predicted to be candidate drivers in at least two cancer types and the remaining RBPs are termed nondrivers.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('RBP', 'Gene', (138, 141))	('RBP', 'Gene', '57794', (138, 141))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('genes', 'Var', (9, 14))	('cancer', 'Disease', (107, 113))
33224	29023197	Antibodies against SF3B1 (cat# 14434S, Cell Signaling), PRPF8 (Cat#Ab190347, Abcam), CD24 (Cat#555428, BD Biosciences) and CD44 (Cat#559942, BD Biosciences) were used as per instructions from manufacturers.	('Cat', 'molecular_function', 'GO:0004096', ('91', '94'))	('Signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('Cat#Ab190347', 'Var', (63, 75))	('Cat', 'molecular_function', 'GO:0004096', ('129', '132'))	('CD44', 'Gene', '960', (123, 127))	('SF3B1', 'Gene', '23451', (19, 24))	('cat# 14434S', 'Var', (26, 37))	('Cat', 'molecular_function', 'GO:0004096', ('63', '66'))	('CD24', 'Gene', '100133941', (85, 89))	('CD24', 'Gene', (85, 89))	('CD44', 'Gene', (123, 127))	('SF3B1', 'Gene', (19, 24))	('PRPF8', 'Gene', '10594', (56, 61))	('PRPF8', 'Gene', (56, 61))	('cat', 'molecular_function', 'GO:0004096', ('26', '29'))
33254	27376133	Rationale: JNJ-42756493 is a selective and potent orally administered pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor with demonstrated activity in patients with solid tumors with alterations in the FGFR pathway including urothelial carcinoma (Tabernero J et al., ASCO 2015), indicating the potential to be a new therapeutic option for these patients.	('alterations', 'Reg', (203, 214))	('patients', 'Species', '9606', (365, 373))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('74', '98'))	('activity', 'MPA', (159, 167))	('urothelial carcinoma', 'Disease', (245, 265))	('solid tumors', 'Disease', (185, 197))	('FGFR', 'molecular_function', 'GO:0005007', ('109', '113'))	('JNJ-42756493', 'Var', (11, 23))	('patients', 'Species', '9606', (171, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('124', '140'))	('FGFR pathway', 'Pathway', (222, 234))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (245, 265))	('solid tumors', 'Disease', 'MESH:D009369', (185, 197))	('FGFR', 'molecular_function', 'GO:0005007', ('222', '226'))
33276	32459456	The UroVysion  FISH test detects the aneuploidy of chromosomes 3, 7 and 17, and loss of both 9p21 loci in malignant urothelial cells, showing a diagnostic sensitivity of 87.3% and specificity of 71.4%.	('p21', 'Gene', (94, 97))	('aneuploidy', 'Disease', (37, 47))	('loss', 'Var', (80, 84))	('p21', 'Gene', '644914', (94, 97))	('aneuploidy', 'Disease', 'MESH:D000782', (37, 47))
33349	32459456	CCND1 amplification status and CyclinD1 expression were independent risk factors in BC metastasis, and high nuclear CyclinD1 expression in lymph node metastases predicted favorable response to chemotherapy.	('risk', 'Reg', (68, 72))	('BC', 'Phenotype', 'HP:0009725', (84, 86))	('CyclinD1', 'Gene', (116, 124))	('CyclinD1', 'Gene', (31, 39))	('metastases', 'Disease', (150, 160))	('CCND1', 'Gene', (0, 5))	('metastases', 'Disease', 'MESH:D009362', (150, 160))	('high nuclear', 'Var', (103, 115))	('CyclinD1', 'Gene', '595', (116, 124))	('CyclinD1', 'Gene', '595', (31, 39))	('CCND1', 'Gene', '595', (0, 5))
33367	32459456	The proteomics of T24 BC cell line identified overexpression of cullin-3 (CUL3), a protein involved in ubiquitination, whose silencing leads to decreased cell proliferation and migration.	('cell proliferation', 'CPA', (154, 172))	('CUL3', 'Gene', '8452', (74, 78))	('cullin-3', 'Gene', '8452', (64, 72))	('overexpression', 'PosReg', (46, 60))	('decreased', 'NegReg', (144, 153))	('CUL3', 'Gene', (74, 78))	('silencing', 'Var', (125, 134))	('BC', 'Phenotype', 'HP:0009725', (22, 24))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))	('cullin-3', 'Gene', (64, 72))
33376	33567603	Our analysis indicates that uc.8+ can localize both in the cytoplasm and nucleus of bladder cells at early stages of tumorigenesis, while in tumors at advanced stages, uc.8+ has a prevalent cytoplasmic localization.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('nucleus', 'cellular_component', 'GO:0005634', ('73', '80'))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('localization', 'biological_process', 'GO:0051179', ('202', '214'))	('tumor', 'Disease', (117, 122))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumor', 'Disease', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('uc.8+', 'Var', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('cytoplasm', 'cellular_component', 'GO:0005737', ('59', '68'))
33383	33567603	The analysis of subcellular localization indicated the simultaneous presence of uc.8+ in the cytoplasm and nucleus of cells from the Low-Grade group, whereas a prevalent cytoplasmic localization was observed in samples from the High-Grade group, supporting the hypothesis of uc.8+ nuclear-to-cytoplasmic translocation in most malignant tumor forms.	('malignant tumor', 'Disease', 'MESH:D009369', (326, 341))	('cytoplasm', 'cellular_component', 'GO:0005737', ('93', '102'))	('nucleus', 'cellular_component', 'GO:0005634', ('107', '114'))	('localization', 'biological_process', 'GO:0051179', ('28', '40'))	('uc.8+', 'Var', (80, 85))	('malignant tumor', 'Disease', (326, 341))	('localization', 'biological_process', 'GO:0051179', ('182', '194'))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))
33385	33567603	Our model suggests uc.8+ subcellular localization as a potential prognostic biomarker for bladder cancer.	('bladder cancer', 'Disease', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('localization', 'biological_process', 'GO:0051179', ('37', '49'))	('uc.8+', 'Var', (19, 24))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))
33409	33567603	The mean survival times for BlCa pts were 42.8 and 31.4 months for uc.8+ HI-s and LI-s, respectively.	('BlCa', 'Phenotype', 'HP:0009725', (28, 32))	('LI-s', 'Var', (82, 86))	('pts', 'Species', '9606', (33, 36))	('uc.8+ HI-s', 'Var', (67, 77))	('HI-s', 'Chemical', '-', (73, 77))	('LI-s', 'Chemical', '-', (82, 86))
33410	33567603	Kaplan-Meier curve shows that low level of uc.8+ is associated with a worst overall survival in BlCa pts dataset.	('pts', 'Species', '9606', (101, 104))	('worst', 'NegReg', (70, 75))	('overall', 'MPA', (76, 83))	('uc.8+', 'Var', (43, 48))	('BlCa', 'Phenotype', 'HP:0009725', (96, 100))
33411	33567603	In fact, the prognosis of BlCa pts with LI-s of uc.8+ was significantly poorer than that of BlCa pts with HI-s of uc.8+ (HI-s/LI-s hazard ratio 0.24, 95% CI; 0.07-0.8; LI-s/HI-s hazard ratio 4.2, 95% CI; 1.3-13.8; p < 0.05) (Figure 1B).	('rat', 'Species', '10116', (138, 141))	('HI-s', 'Chemical', '-', (106, 110))	('LI-s', 'Chemical', '-', (168, 172))	('LI-s', 'Chemical', '-', (40, 44))	('HI-s', 'Chemical', '-', (121, 125))	('poorer', 'NegReg', (72, 78))	('pts', 'Species', '9606', (31, 34))	('prognosis', 'CPA', (13, 22))	('BlCa', 'Phenotype', 'HP:0009725', (26, 30))	('BlCa', 'Phenotype', 'HP:0009725', (92, 96))	('LI-s of uc.8+', 'Var', (40, 53))	('HI-s', 'Chemical', '-', (173, 177))	('LI-s', 'Chemical', '-', (126, 130))	('rat', 'Species', '10116', (185, 188))	('pts', 'Species', '9606', (97, 100))
33413	33567603	In addition, by using the multiple logistic regression model on n = 73 patients, we found a significant association between uc.8+ intensity and the tumor grade (p value = 0.00365) after correcting for age and sex.	('uc.8+ intensity', 'Var', (124, 139))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('patients', 'Species', '9606', (71, 79))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
33427	33567603	We observed a significant increase in uc.8+ intensity in the stroma of HG compared to LG, suggesting a possible role of uc.8+ not only in early phases of tumorigenesis inside cancer cells, but also in the tumor microenvironment and in tumor invasiveness.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('men', 'Species', '9606', (223, 226))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor invasiveness', 'Disease', (235, 253))	('uc.8+', 'MPA', (38, 43))	('uc.8+', 'Var', (120, 125))	('tumor', 'Disease', (235, 240))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor invasiveness', 'Disease', 'MESH:D009361', (235, 253))	('increase', 'PosReg', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Disease', (154, 159))
33428	33567603	In most of the stroma biopsies analyzed, we measured a cytoplasm-restricted localization for uc.8+ in about 54% of the HI-s group and 56% of the LI-s group.	('HI-s', 'Disease', (119, 123))	('localization', 'biological_process', 'GO:0051179', ('76', '88'))	('LI-s', 'Chemical', '-', (145, 149))	('cytoplasm', 'cellular_component', 'GO:0005737', ('55', '64'))	('HI-s', 'Chemical', '-', (119, 123))	('uc.8+', 'Var', (93, 98))
33433	33567603	The same data plotted against the BlCa stage highlighted the prevalent cytosol localization of uc.8+ in the stroma of LG and HG pts, also an increase in the number of LG pts with very low or absent uc.8+ expression, was observed (Figure 4D).	('pts', 'Species', '9606', (170, 173))	('increase', 'PosReg', (141, 149))	('localization', 'biological_process', 'GO:0051179', ('79', '91'))	('cytosol localization', 'MPA', (71, 91))	('cytosol', 'cellular_component', 'GO:0005829', ('71', '78'))	('uc.8+', 'Var', (95, 100))	('pts', 'Species', '9606', (128, 131))	('BlCa', 'Phenotype', 'HP:0009725', (34, 38))
33434	33567603	These results suggest that, as described for other lncRNAs species, uc.8+ may undergo nucleus-cytoplasm shuttling, at higher extent in tumor cells rather than in the surrounding stroma.	('undergo', 'Reg', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('nucleus-cytoplasm shuttling', 'CPA', (86, 113))	('tumor', 'Disease', (135, 140))	('rat', 'Species', '10116', (147, 150))	('uc.8+', 'Var', (68, 73))	('cytoplasm', 'cellular_component', 'GO:0005737', ('94', '103'))	('nucleus', 'cellular_component', 'GO:0005634', ('86', '93'))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
33435	33567603	In particular, the long U-repeats (6-7 nucleotides) in multibranched loop are predicted to interact with proteins involved in the transport of RNA from the nucleus to the cytoplasm, such as an ATP-dependent RNA helicase (DDX19B), which is associated with nuclear pore complex cytoplasmic fibrils and involved in mRNA export from the nucleus.	('cytoplasm', 'cellular_component', 'GO:0005737', ('171', '180'))	('transport', 'MPA', (130, 139))	('long U-repeats', 'Var', (19, 33))	('transport', 'biological_process', 'GO:0006810', ('130', '139'))	('DDX19B', 'Gene', '11269', (221, 227))	('DDX19B', 'Gene', (221, 227))	('nucleus', 'cellular_component', 'GO:0005634', ('156', '163'))	('RNA', 'cellular_component', 'GO:0005562', ('207', '210'))	('RNA', 'cellular_component', 'GO:0005562', ('143', '146'))	('nuclear pore complex', 'cellular_component', 'GO:0005643', ('255', '275'))	('nucleus', 'cellular_component', 'GO:0005634', ('333', '340'))	('mRNA export', 'MPA', (312, 323))	('interact', 'Reg', (91, 99))
33457	33567603	Furthermore, the analysis of tumor-surrounding stroma showed a significant increase in uc.8+ ISH signal intensity in the stroma of HG compared to LG, suggesting a possible role of uc.8+ not only in cancer cells in the early phases of tumorigenesis but also in tumor microenvironment and tumor invasiveness.	('tumor', 'Disease', (260, 265))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('uc.8+ ISH signal intensity', 'MPA', (87, 113))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('tumor invasiveness', 'Disease', (287, 305))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('uc.8+', 'Var', (180, 185))	('cancer', 'Disease', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('men', 'Species', '9606', (278, 281))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('tumor invasiveness', 'Disease', 'MESH:D009361', (287, 305))	('increase', 'PosReg', (75, 83))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Disease', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))
33458	33567603	In addition, in tumor-surrounding stroma, the uc.8+ signal showed a prevalent cytoplasmic localization, suggesting that uc.8+ might undergo nuclear-cytoplasmic shuttling at higher extent in tumor cells rather than in the surrounding stroma.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('localization', 'biological_process', 'GO:0051179', ('90', '102'))	('nuclear-cytoplasmic', 'CPA', (140, 159))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('uc.8+', 'Var', (120, 125))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', (16, 21))	('undergo', 'Reg', (132, 139))	('rat', 'Species', '10116', (202, 205))
33463	33567603	Differently, the exclusive subcellular localization of uc.8+ in the cytosol represents a more dramatic event, because involving the entire pathway of displacement and affecting the nuclear function of the lncRNA.	('uc.8+', 'Var', (55, 60))	('affecting', 'Reg', (167, 176))	('nuclear', 'MPA', (181, 188))	('cytosol', 'cellular_component', 'GO:0005829', ('68', '75'))	('localization', 'biological_process', 'GO:0051179', ('39', '51'))	('involving', 'Reg', (118, 127))	('men', 'Species', '9606', (158, 161))
33527	33567603	The analysis of uc.8+ in bladder cancer tissues, linked its accumulation and subcellular distribution to clinical phenotype.	('bladder cancer', 'Phenotype', 'HP:0009725', (25, 39))	('uc.8+', 'Var', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('bladder cancer', 'Disease', 'MESH:D001749', (25, 39))	('bladder cancer', 'Disease', (25, 39))
33530	33567603	Fluorescence microscopy of J82 bladder cancer control cells (first lane, Mock) after transfection with PNA-TO scramble-R8 (second lane, scramble PNA) or with TO-PNA1-R8, complementary to uc.8+ sequence (third lane, uc.8+ PNA).	('PNA-TO scramble-R8', 'Var', (103, 121))	('J82', 'CellLine', 'CVCL:0359', (27, 30))	('men', 'Species', '9606', (176, 179))	('PNA', 'Chemical', 'MESH:D020135', (161, 164))	('bladder cancer', 'Phenotype', 'HP:0009725', (31, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('PNA', 'Chemical', 'MESH:D020135', (103, 106))	('PNA', 'Chemical', 'MESH:D020135', (145, 148))	('PNA', 'Chemical', 'MESH:D020135', (221, 224))	('bladder cancer', 'Disease', 'MESH:D001749', (31, 45))	('bladder cancer', 'Disease', (31, 45))
33542	32145825	We recruited patients with UTUC after nephroureterectomy staged as either pT2-T4 pN0-N3 M0 or pTany N1-3 M0.	('pTany N1-3 M0', 'Var', (94, 107))	('UTUC', 'Disease', (27, 31))	('patients', 'Species', '9606', (13, 21))
33604	32145825	The trial was designed to detect a hazard ratio (HR) of 0 65 in favour of chemotherapy, equivalent to a 15% absolute improvement in 3-year disease-free survival (from 40% to 55%, which was chosen to correspond with the magnitude of benefit noted for chemotherapy in muscle-invasive bladder cancer), with a two-sided significance of 5% and 80% power.	('invasive bladder', 'Phenotype', 'HP:0100645', (273, 289))	('improvement', 'PosReg', (117, 128))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (266, 296))	('muscle-invasive bladder cancer', 'Disease', (266, 296))	('bladder cancer', 'Phenotype', 'HP:0009725', (282, 296))	('disease-free', 'Disease', (139, 151))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('chemotherapy', 'Var', (74, 86))
33653	32145825	Chemotherapy was also associated with improved metastasis-free survival, with acceptable acute toxic effects consistent with existing data, and with no more than a transient effect on patient-reported quality of life.	('metastasis-free survival', 'CPA', (47, 71))	('improved', 'PosReg', (38, 46))	('Chemotherapy', 'Var', (0, 12))	('patient', 'Species', '9606', (184, 191))
33655	32145825	Findings of a meta-analysis of outcomes of patients with advanced urothelial carcinoma treated with platinum-based chemotherapy showed superior tumour response rates in trials of cisplatin compared with those of carboplatin.	('urothelial carcinoma', 'Disease', (66, 86))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (66, 86))	('carboplatin', 'Chemical', 'MESH:D016190', (212, 223))	('patients', 'Species', '9606', (43, 51))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('cisplatin', 'Var', (179, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('tumour', 'Disease', (144, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))	('platinum', 'Chemical', 'MESH:D010984', (100, 108))
33680	32145825	Higher proportions of FGFR alterations and luminal-like urothelial cancer signatures have been noted in UTUC than in bladder cancer.	('FGFR', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (117, 131))	('urothelial cancer', 'Disease', 'MESH:D014523', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('urothelial cancer', 'Disease', (56, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (117, 131))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('luminal', 'Chemical', 'MESH:D010634', (43, 50))	('bladder cancer', 'Disease', (117, 131))	('UTUC', 'Disease', (104, 108))	('alterations', 'Var', (27, 38))
33681	32145825	Because FGFR alterations are associated with high response rates to FGFR inhibitors and luminal-like urothelial cancer signatures with low response rates to chemotherapy in advanced urothelial cancers, investigation of orally bioavailable FGFR inhibitors (eg, erdafitinib alone or in combination with gemcitabine-platinum regimens) in molecularly selected patient cohorts might have particular value.	('platinum', 'Chemical', 'MESH:D010984', (313, 321))	('FGFR', 'molecular_function', 'GO:0005007', ('239', '243'))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('FGFR', 'molecular_function', 'GO:0005007', ('68', '72'))	('patient', 'Species', '9606', (356, 363))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('FGFR', 'molecular_function', 'GO:0005007', ('8', '12'))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('urothelial cancers', 'Disease', 'MESH:D014523', (182, 200))	('urothelial cancers', 'Disease', (182, 200))	('alterations', 'Var', (13, 24))	('urothelial cancer', 'Disease', (101, 118))	('urothelial cancer', 'Disease', 'MESH:D014523', (182, 199))	('FGFR', 'Gene', (8, 12))	('gemcitabine', 'Chemical', 'MESH:C056507', (301, 312))	('luminal', 'Chemical', 'MESH:D010634', (88, 95))	('erdafitinib', 'Chemical', 'MESH:C000604580', (260, 271))	('urothelial cancer', 'Disease', 'MESH:D014523', (101, 118))
33682	32145825	Efficacy of checkpoint inhibitors (eg, pembrolizumab and atezolizumab) in advanced urothelial carcinoma has prompted trials of immunotherapy in the perioperative setting as monotherapy and in combination with cytotoxic chemotherapy for urothelial carcinomas of the bladder (eg, NCT02365766 and NCT03661320).	('atezolizumab', 'Chemical', 'MESH:C000594389', (57, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('urothelial carcinomas of the bladder', 'Disease', 'MESH:D001749', (236, 272))	('NCT03661320', 'Var', (294, 305))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (83, 103))	('NCT02365766', 'Var', (278, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('pembrolizumab', 'Chemical', 'MESH:C582435', (39, 52))	('urothelial carcinoma', 'Disease', (83, 103))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (236, 256))	('urothelial carcinomas of the bladder', 'Disease', (236, 272))	('carcinomas', 'Phenotype', 'HP:0030731', (247, 257))
33694	30216763	Overexpression of sorcin has been reported to be associated with different cancers such as breast cancer, colorectal cancer, gastric cancer, leukemia, lung cancer, nasopharyngeal cancer, ovarian cancer, etc.	('ovarian cancer', 'Disease', 'MESH:D010051', (187, 201))	('colorectal cancer', 'Disease', (106, 123))	('associated', 'Reg', (49, 59))	('lung cancer', 'Disease', (151, 162))	('Overexpression', 'Var', (0, 14))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (164, 185))	('gastric cancer', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('ovarian cancer', 'Disease', (187, 201))	('leukemia', 'Phenotype', 'HP:0001909', (141, 149))	('ovarian cancer', 'Phenotype', 'HP:0100615', (187, 201))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('sorcin', 'Protein', (18, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (164, 185))	('leukemia', 'Disease', 'MESH:D007938', (141, 149))	('leukemia', 'Disease', (141, 149))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('breast cancer', 'Disease', (91, 104))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('nasopharyngeal cancer', 'Disease', (164, 185))
33697	30216763	Sorcin was also found to regulate apoptosis, as silencing of the same resulted in increased levels of proapoptotic genes and induced mitochondrial apoptotic pathway in cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('silencing', 'Var', (48, 57))	('apoptosis', 'biological_process', 'GO:0006915', ('34', '43'))	('levels of proapoptotic genes', 'MPA', (92, 120))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('mitochondrial apoptotic pathway', 'Pathway', (133, 164))	('cancer', 'Disease', (168, 174))	('increased', 'PosReg', (82, 91))	('induced', 'PosReg', (125, 132))	('apoptosis', 'biological_process', 'GO:0097194', ('34', '43'))
33698	30216763	Interestingly, mutations in the sorcin gene have been closely linked with poor overall survival in bladder cancer, brain lower-grade glioma, glioblastoma, glioblastoma multiforme, kidney renal clear cell carcinoma, and stomach adenocarcinoma.	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioblastoma', 'Disease', (155, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('glioblastoma', 'Disease', (141, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('poor', 'NegReg', (74, 78))	('mutations', 'Var', (15, 24))	('glioblastoma multiforme', 'Disease', (155, 178))	('stomach adenocarcinoma', 'Disease', (219, 241))	('linked', 'Reg', (62, 68))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (155, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (180, 213))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (219, 241))	('glioma', 'Disease', (133, 139))	('bladder cancer', 'Disease', (99, 113))	('sorcin', 'Gene', (32, 38))	('kidney renal clear cell carcinoma', 'Disease', (180, 213))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('glioblastoma', 'Disease', 'MESH:D005909', (141, 153))
33714	30216763	In addition, silencing of this protein resulted in apoptosis and reverted MDR of cancer cells, and additionally, sorcin depletion reduced the levels of various proteins involved in angiogenesis, invasion, and metastasis.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('levels of various proteins', 'MPA', (142, 168))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('angiogenesis', 'biological_process', 'GO:0001525', ('181', '193'))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('cancer', 'Disease', (81, 87))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('reduced', 'NegReg', (130, 137))	('depletion', 'MPA', (120, 129))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('MDR of', 'CPA', (74, 80))	('apoptosis', 'CPA', (51, 60))	('MDR', 'molecular_function', 'GO:0004745', ('74', '77'))	('silencing', 'Var', (13, 22))
33725	30216763	These five EF-hands were found to pair with each other (EF1 with EF2 and EF3 with EF4).	('EF2', 'Gene', '1938', (65, 68))	('EF4', 'Gene', '60558', (82, 85))	('EF2', 'Gene', (65, 68))	('EF3', 'Var', (73, 76))	('EF4', 'Gene', (82, 85))
33742	30216763	Calcium (Ca2+) plays significant roles in neurons, including synaptic plasticity and apoptosis, and deregulation of this neuronal calcium signaling was known to be one of the central mechanisms of different neurodegenerative diseases such as Alzheimer's disease (AD).	('AD', 'Phenotype', 'HP:0002511', (263, 265))	('deregulation', 'Var', (100, 112))	('AD', 'Disease', 'MESH:D000544', (263, 265))	('AD', 'Disease', (263, 265))	('calcium', 'Chemical', 'MESH:D002118', (130, 137))	('neurodegenerative diseases', 'Disease', (207, 233))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (242, 261))	('calcium signaling', 'biological_process', 'GO:0019722', ('130', '147'))	('Calcium', 'Chemical', 'MESH:D002118', (0, 7))	("Alzheimer's disease", 'Disease', (242, 261))	('Ca2+', 'Chemical', 'MESH:D000069285', (9, 13))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (207, 233))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (242, 261))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (207, 233))
33744	30216763	Sorcin expression enhances the concentration of calcium in endoplasmic reticulum (ER), inhibits ER stress, and induces the resistance to apoptosis.	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('59', '80'))	('calcium', 'Chemical', 'MESH:D002118', (48, 55))	('concentration of calcium', 'MPA', (31, 55))	('Sorcin', 'Gene', (0, 6))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('induces', 'Reg', (111, 118))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('inhibits', 'NegReg', (87, 95))	('expression', 'Var', (7, 17))	('resistance to apoptosis', 'CPA', (123, 146))	('ER stress', 'MPA', (96, 105))	('enhances', 'PosReg', (18, 26))
33745	30216763	Apart from calcium homeostasis, sorcin was also found to have a key role in the activation of mitosis and cytokinesis as loss of sorcin highly compromised the normal process of mitosis and cytokinesis.	('mitosis', 'Disease', 'None', (94, 101))	('activation of mitosis', 'biological_process', 'GO:0045840', ('80', '101'))	('compromised', 'NegReg', (143, 154))	('mitosis', 'Disease', (177, 184))	('mitosis', 'biological_process', 'GO:0000278', ('177', '184'))	('loss', 'Var', (121, 125))	('mitosis', 'Disease', 'None', (177, 184))	('homeostasis', 'biological_process', 'GO:0042592', ('19', '30'))	('cytokinesis', 'biological_process', 'GO:0000910', ('189', '200'))	('calcium', 'Chemical', 'MESH:D002118', (11, 18))	('cytokinesis', 'biological_process', 'GO:0000910', ('106', '117'))	('sorcin', 'Protein', (129, 135))	('mitosis', 'Disease', (94, 101))
33750	30216763	Apart from this, sorcin also targets the sarcolemmal NCX1 (sodium/ calcium exchanger) and induces its expression in the cardiac muscles, and silencing of sorcin by miR-1 helps to regulate the myocardial contraction through calcium signaling.	('calcium', 'Chemical', 'MESH:D002118', (223, 230))	('sorcin', 'Gene', (154, 160))	('silencing', 'Var', (141, 150))	('calcium', 'Chemical', 'MESH:D002118', (67, 74))	('expression', 'MPA', (102, 112))	('induces', 'PosReg', (90, 97))	('calcium signaling', 'biological_process', 'GO:0019722', ('223', '240'))	('myocardial contraction', 'CPA', (192, 214))	('NCX1', 'Gene', (53, 57))	('sodium/ calcium exchanger', 'molecular_function', 'GO:0005432', ('59', '84'))	('regulate', 'Reg', (179, 187))	('miR-1', 'Gene', '79187', (164, 169))	('NCX1', 'Gene', '6546', (53, 57))	('calcium signaling', 'MPA', (223, 240))	('miR-1', 'Gene', (164, 169))
33763	30216763	As observed from the cBioPortal for Cancer Genomics data, several mutations of sorcin protein are associated with different kind of cancers including bladder cancer, colorectal adenocarcinoma, prostate adenocarcinoma, skin cutaneous melanoma, sarcoma, and uterine corpus endometrial carcinoma, etc.	('mutations', 'Var', (66, 75))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (223, 241))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('colorectal adenocarcinoma, prostate adenocarcinoma', 'Disease', 'MESH:D000230', (166, 216))	('sorcin', 'Gene', (79, 85))	('Cancer', 'Disease', (36, 42))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('endometrial carcinoma', 'Disease', (271, 292))	('protein', 'Protein', (86, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('bladder cancer', 'Disease', 'MESH:D001749', (150, 164))	('bladder cancer', 'Disease', (150, 164))	('sarcoma', 'Disease', 'MESH:D012509', (243, 250))	('sarcoma', 'Disease', (243, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('bladder cancer', 'Phenotype', 'HP:0009725', (150, 164))	('Cancer', 'Disease', 'MESH:D009369', (36, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (271, 292))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (218, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('skin cutaneous melanoma', 'Disease', (218, 241))	('associated', 'Reg', (98, 108))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (271, 292))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))
33764	30216763	In line with this, RNA sequencing analysis of patient samples revealed amplification of SRI gene to be associated with various cancers, which was evident from the TCGA cBioPortal database.	('patient', 'Species', '9606', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('associated', 'Reg', (103, 113))	('amplification', 'Var', (71, 84))	('SRI', 'Gene', (88, 91))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('RNA', 'cellular_component', 'GO:0005562', ('19', '22'))	('SRI', 'Gene', '6717', (88, 91))	('cancers', 'Disease', (127, 134))
33767	30216763	In addition to gene amplification, different mutations of SRI gene were also reported in the TCGA database, and frequency of SRI gene mutation observed in different cancers is as follows: colorectal cancer 0.16%, uterine cancer 0.36%, prostate cancer 0.4%, and sarcoma 0.38%.	('sarcoma', 'Disease', (261, 268))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('prostate cancer', 'Disease', (235, 250))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', (199, 205))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (261, 268))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('uterine cancer', 'Phenotype', 'HP:0010784', (213, 227))	('colorectal cancer', 'Disease', (188, 205))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('SRI', 'Gene', '6717', (125, 128))	('cancer', 'Disease', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('cancer', 'Disease', (244, 250))	('SRI', 'Gene', '6717', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('mutation', 'Var', (134, 142))	('SRI', 'Gene', (125, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))	('SRI', 'Gene', (58, 61))	('prostate cancer', 'Disease', 'MESH:D011471', (235, 250))	('sarcoma', 'Disease', 'MESH:D012509', (261, 268))	('prostate cancer', 'Phenotype', 'HP:0012125', (235, 250))
33769	30216763	As mentioned earlier, according to the TCGA database, sorcin shows different mutations in different cancers such as X84_splice (splice mutation) in bladder cancer, D157N (missense mutation) in colorectal adenocarcinoma, A161T (missense mutation) & Q48*(nonsense mutation) in prostate adenocarcinoma, P28L (missense mutation) & C162F (missense mutation) in skin cutaneous melanoma, Y13Tfs *30(FS del mutation) in sarcoma, and A161T (missense mutation) & R106I (missense mutation) in uterine corpus endometrial carcinoma.	('D157N', 'Var', (164, 169))	('A161T', 'Mutation', 'rs1457132903', (220, 225))	('P28L', 'Mutation', 'p.P28L', (300, 304))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (275, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('A161T', 'Mutation', 'rs1457132903', (425, 430))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (412, 419))	('C162F', 'Mutation', 'p.C162F', (327, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (509, 518))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (193, 218))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (497, 518))	('colorectal adenocarcinoma', 'Disease', (193, 218))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (497, 518))	('melanoma', 'Phenotype', 'HP:0002861', (371, 379))	('X84_splice', 'Var', (116, 126))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (356, 379))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (361, 379))	('skin cutaneous melanoma', 'Disease', (356, 379))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('P28', 'cellular_component', 'GO:0070744', ('300', '303'))	('R106I', 'Mutation', 'p.R106I', (453, 458))	('cancers', 'Disease', (100, 107))	('prostate adenocarcinoma', 'Disease', (275, 298))	('bladder cancer', 'Disease', 'MESH:D001749', (148, 162))	('bladder cancer', 'Disease', (148, 162))	('D157N', 'Mutation', 'rs754279084', (164, 169))	('A161T', 'Var', (220, 225))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('sarcoma', 'Disease', 'MESH:D012509', (412, 419))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('bladder cancer', 'Phenotype', 'HP:0009725', (148, 162))	('endometrial carcinoma', 'Disease', (497, 518))	('sarcoma', 'Disease', (412, 419))	('Y13Tfs *30(FS del', 'Mutation', 'p.13,FSdelT', (381, 398))
33772	30216763	However, in some of the cancers, patients with altered sorcin showed more median month survival such as breast cancer (163.1 months), esophageal carcinoma (44.71 months), head and neck squamous cell carcinoma (71.16 months), ovarian serous cystadenocarcinoma (50.33 months), and skin cutaneous melanoma (297.67 months) (Table 1).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (279, 302))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (134, 154))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (225, 258))	('breast cancer', 'Disease', (104, 117))	('skin cutaneous melanoma', 'Disease', (279, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('neck', 'cellular_component', 'GO:0044326', ('180', '184'))	('altered', 'Var', (47, 54))	('esophageal carcinoma', 'Disease', (134, 154))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (284, 302))	('cancers', 'Disease', (24, 31))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (134, 154))	('neck squamous cell carcinoma', 'Disease', (180, 208))	('more', 'PosReg', (69, 73))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (180, 208))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (225, 258))	('patients', 'Species', '9606', (33, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('ovarian serous cystadenocarcinoma', 'Disease', (225, 258))
33778	30216763	Cancer cells acquire MDR through ABC transporter family, resistance to apoptosis induction, autophagy, cancer stem cells, miRNA, hypoxia, DNA damage and repair, and epigenetic regulation.	('epigenetic', 'Var', (165, 175))	('hypoxia', 'Disease', (129, 136))	('ABC transporter', 'molecular_function', 'GO:0140359', ('33', '48'))	('MDR', 'molecular_function', 'GO:0004745', ('21', '24'))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', (103, 109))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('hypoxia', 'Disease', 'MESH:D000860', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('autophagy', 'biological_process', 'GO:0016236', ('92', '101'))	('autophagy', 'CPA', (92, 101))	('MDR', 'Gene', (21, 24))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('autophagy', 'biological_process', 'GO:0006914', ('92', '101'))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('regulation', 'biological_process', 'GO:0065007', ('176', '186'))	('Cancer', 'Disease', (0, 6))
33785	30216763	Silencing of sorcin resulted in the downregulation of these genes in addition to p-Akt and NF-kappaB levels inducing chemoresistance in myeloma cells (Figure 3).	('downregulation', 'NegReg', (36, 50))	('sorcin', 'Gene', (13, 19))	('NF-kappaB', 'Gene', '4790', (91, 100))	('NF-kappaB', 'Gene', (91, 100))	('myeloma', 'Disease', (136, 143))	('inducing', 'Reg', (108, 116))	('p-Akt', 'MPA', (81, 86))	('Silencing', 'Var', (0, 9))	('myeloma', 'Disease', 'MESH:D009101', (136, 143))	('chemoresistance', 'CPA', (117, 132))
33788	30216763	Likewise, chemoresistance to cisplatin in MDR cells is also associated with the co-amplification of sorcin.	('MDR', 'molecular_function', 'GO:0004745', ('42', '45'))	('sorcin', 'Protein', (100, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('chemoresistance', 'CPA', (10, 25))	('co-amplification', 'Var', (80, 96))	('associated', 'Reg', (60, 70))
33790	30216763	Similarly, co-amplification of sorcin and MDR1 gene observed in leukemia can be taken as a good indicator of clinical drug resistance and prognosis of the disease.	('leukemia', 'Disease', (64, 72))	('MDR', 'molecular_function', 'GO:0004745', ('42', '45'))	('sorcin', 'Gene', (31, 37))	('drug resistance', 'Phenotype', 'HP:0020174', (118, 133))	('MDR1', 'Gene', (42, 46))	('drug resistance', 'biological_process', 'GO:0009315', ('118', '133'))	('co-amplification', 'Var', (11, 27))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('MDR1', 'Gene', '5243', (42, 46))	('leukemia', 'Disease', 'MESH:D007938', (64, 72))	('drug resistance', 'biological_process', 'GO:0042493', ('118', '133'))
33791	30216763	Further proving the importance of sorcin in MDR, overexpression of sorcin in K562 cells by gene transfection led to the increase in drug resistance, from 4.1- to 22.5-fold, to various chemotherapeutic drugs such as doxorubicin, etoposide, homoharringtonine, and vincristine.	('drug resistance', 'biological_process', 'GO:0042493', ('132', '147'))	('K562', 'CellLine', 'CVCL:0004', (77, 81))	('doxorubicin', 'Chemical', 'MESH:D004317', (215, 226))	('drug resistance', 'MPA', (132, 147))	('increase', 'PosReg', (120, 128))	('etoposide', 'Chemical', 'MESH:D005047', (228, 237))	('gene transfection', 'Var', (91, 108))	('vincristine', 'Chemical', 'MESH:D014750', (262, 273))	('drug resistance', 'Phenotype', 'HP:0020174', (132, 147))	('homoharringtonine', 'Chemical', 'MESH:D000077863', (239, 256))	('overexpression', 'PosReg', (49, 63))	('drug resistance', 'biological_process', 'GO:0009315', ('132', '147'))	('MDR', 'molecular_function', 'GO:0004745', ('44', '47'))
33804	30216763	Upregulation of sorcin in malignant cells significantly induces the cell proliferation, migration, and invasion, and knockdown of the same diminished the proliferation, migration, and invasion of cancer cells, revealing the importance of sorcin in the development and progression of cancer.	('Upregulation', 'PosReg', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('cell proliferation', 'CPA', (68, 86))	('migration', 'CPA', (169, 178))	('cancer', 'Disease', (283, 289))	('induces', 'PosReg', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('migration', 'CPA', (88, 97))	('cancer', 'Disease', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('sorcin', 'Gene', (16, 22))	('diminished', 'NegReg', (139, 149))	('invasion', 'CPA', (103, 111))	('knockdown', 'Var', (117, 126))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))
33807	30216763	TCGA data analysis also showed alteration status of sorcin gene to be significantly associated with survival of cancer patients, suggesting the prognostic value of this protein.	('sorcin gene', 'Gene', (52, 63))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('patients', 'Species', '9606', (119, 127))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('survival', 'Disease', (100, 108))	('associated', 'Reg', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('alteration status', 'Var', (31, 48))
33813	25940704	Mutagenesis on either or both cAMP-responsive element(s) dramatically decreased the EMP2 promoter activity with, without genistein treatment or exogenous CREB1 expression, respectively.	('Mutagenesis', 'biological_process', 'GO:0006280', ('0', '11'))	('Mutagenesis', 'Var', (0, 11))	('decreased', 'NegReg', (70, 79))	('genistein', 'Chemical', 'MESH:D019833', (121, 130))	('cAMP', 'Chemical', 'MESH:D000242', (30, 34))	('EMP2', 'Gene', (84, 88))
33815	25940704	Genistein treatments, knockdown of EMP2 gene and double knockdown of CREB1 and EMP2 genes significantly inhibited tumor growth and notably downregulated CREB1 and EMP2 protein levels in the mice xenograft models.	('EMP2 gene', 'Gene', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('CREB1', 'Gene', (69, 74))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mice', 'Species', '10090', (190, 194))	('EMP2 genes', 'Gene', (79, 89))	('tumor', 'Disease', (114, 119))	('knockdown', 'Var', (22, 31))	('downregulated', 'NegReg', (139, 152))	('double knockdown', 'Var', (49, 65))	('inhibited', 'NegReg', (104, 113))	('Genistein', 'Chemical', 'MESH:D019833', (0, 9))
33823	25940704	Cell cycle dysregulation resulting in uncontrolled cell proliferation has been associated with UBUC development.	('associated', 'Reg', (79, 89))	('cell proliferation', 'biological_process', 'GO:0008283', ('51', '69'))	('uncontrolled', 'MPA', (38, 50))	('Cell cycle dysregulation', 'Phenotype', 'HP:0011018', (0, 24))	('Cell cycle', 'CPA', (0, 10))	('dysregulation', 'Var', (11, 24))	('UBUC', 'Chemical', '-', (95, 99))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('UBUC development', 'Disease', (95, 111))
33830	25940704	Of 14 candidate transcripts, only downregulation of EMP2 significantly predicts inferior overall survival (Supplementary Table S1, Figure S1), suggesting that EMP2 plays a potential tumor suppressor role in UBUC.	('tumor', 'Disease', (182, 187))	('UBUC', 'Chemical', '-', (207, 211))	('downregulation', 'Var', (34, 48))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor suppressor', 'biological_process', 'GO:0051726', ('182', '198'))	('EMP2', 'Gene', (52, 56))	('overall survival', 'MPA', (89, 105))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('182', '198'))	('inferior', 'NegReg', (80, 88))	('UBUC', 'Disease', (207, 211))
33840	25940704	The EMP2 mRNA and protein levels are notably higher expressed in HUC and RT4 than those in TSGH8301 and J82 cells (Supplementary Figure S2).	('RT4', 'Var', (73, 76))	('J82', 'CellLine', 'CVCL:0359', (104, 107))	('HUC', 'Var', (65, 68))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('higher', 'PosReg', (45, 51))	('RT4', 'CellLine', 'CVCL:0036', (73, 76))	('expressed', 'MPA', (52, 61))
33843	25940704	Conversely, as shown in Figure 1I-1N, stable knockdown of EMP2 gene in RT4 cells inhibited EMP2 mRNA (p < 0.001) and protein (p < 0.01) levels, induced cell cycle progression to G0/G1 (p < 0.05) and S (p < 0.01) phases, increased cell viability (p < 0.01), cell proliferation (p < 0.001) and colony formation/anchorage-independent cell growth (p < 0.01; see also Supplementary Figure S3B).	('increased', 'PosReg', (220, 229))	('RT4', 'CellLine', 'CVCL:0036', (71, 74))	('induced', 'PosReg', (144, 151))	('cell proliferation', 'biological_process', 'GO:0008283', ('257', '275'))	('formation', 'biological_process', 'GO:0009058', ('299', '308'))	('inhibited', 'NegReg', (81, 90))	('cell cycle', 'biological_process', 'GO:0007049', ('152', '162'))	('cell proliferation', 'CPA', (257, 275))	('cell cycle progression', 'CPA', (152, 174))	('EMP2', 'Gene', (58, 62))	('colony formation/anchorage-independent cell growth', 'CPA', (292, 342))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('cell growth', 'biological_process', 'GO:0016049', ('331', '342'))	('cell viability', 'CPA', (230, 244))	('knockdown', 'Var', (45, 54))
33848	25940704	In contrast, stable knockdown of CREB1 gene in RT4 cells downregulated CREB1 (p < 0.001) and EMP2 (p < 0.001) mRNA (Figure 2F); CREB1, pCREB1(S133) and EMP2 protein (Figure 2G) levels.	('downregulated', 'NegReg', (57, 70))	('RT4', 'CellLine', 'CVCL:0036', (47, 50))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('EMP2 protein', 'MPA', (152, 164))	('CREB1', 'Gene', (33, 38))	('EMP2', 'Gene', (93, 97))	('CREB1', 'Gene', (71, 76))	('knockdown', 'Var', (20, 29))
33851	25940704	The promoter activity of EMP2 gene was further diminished when double mutations (pGL3-C/dmCREs) were incorporated, compared to either single mutant (p < 0.05) (Figure 2K).	('pGL3', 'Gene', '6391', (81, 85))	('pGL', 'molecular_function', 'GO:0004598', ('81', '84'))	('diminished', 'NegReg', (47, 57))	('double mutations', 'Var', (63, 79))	('promoter activity', 'MPA', (4, 21))	('pGL3', 'Gene', (81, 85))	('EMP2 gene', 'Gene', (25, 34))
33854	25940704	Therefore, genistein induced EMP2 transcription via upregulation of CREB1 mRNA, CREB1 and pCREB1(S133) protein levels, as well as enhancement of the interaction between pCREB1(S133) and CREs on the EMP2 proximal promoter region.	('protein levels', 'MPA', (103, 117))	('S133', 'Var', (176, 180))	('upregulation', 'PosReg', (52, 64))	('EMP2 transcription', 'Gene', (29, 47))	('pCREB1', 'Gene', (169, 175))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('interaction', 'Interaction', (149, 160))	('genistein', 'Chemical', 'MESH:D019833', (11, 20))	('enhancement', 'PosReg', (130, 141))	('transcription', 'biological_process', 'GO:0006351', ('34', '47'))
33858	25940704	Kaplan-Meier plots revealed that low EMP2 immunointensity predicted worse DSS (p < 0.000) and MFS (p = 0.006) (Figure 3C, 3D).	('EMP2 immunointensity', 'Protein', (37, 57))	('low', 'Var', (33, 36))	('MFS', 'CPA', (94, 97))	('DSS', 'Chemical', '-', (74, 77))	('DSS', 'Disease', (74, 77))
33866	25940704	In NOD/SCID mice, xenografts with EMP2 stable knocked down RT4 cells showed larger tumors, compared to the control group (*, p < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('larger', 'PosReg', (76, 82))	('RT4', 'Gene', (59, 62))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('RT4', 'CellLine', 'CVCL:0036', (59, 62))	('SCID', 'Disease', 'MESH:D053632', (7, 11))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('SCID', 'Disease', (7, 11))	('NOD', 'Gene', '1822', (3, 6))	('mice', 'Species', '10090', (12, 16))	('knocked down', 'Var', (46, 58))	('NOD', 'Gene', (3, 6))
33868	25940704	In this study, we found that a high EMP2 protein level could be an independent prognostic factor for DSS in UBUC patients, suggesting that loss of EMP2 expression plays a crucial role in the mortality of UBUC, similar to its role in nasopharyngeal carcinoma and UTUC observed in our earlier studies.	('nasopharyngeal carcinoma', 'Disease', (233, 257))	('UBUC', 'Chemical', '-', (108, 112))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (233, 257))	('EMP2', 'Gene', (147, 151))	('patients', 'Species', '9606', (113, 121))	('UBUC', 'Chemical', '-', (204, 208))	('loss', 'Var', (139, 143))	('DSS', 'Chemical', '-', (101, 104))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (233, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
33869	25940704	Based on our unpublished cohort containing 60 UBUCs analyzed by Affymetrix  Human SNP Assay 6.0, the EMP2 locus is infrequently altered, suggesting the possibilities of epigenetic and/or transcriptional regulation of EMP2 gene (Supplementary Figure S4).	('epigenetic', 'Var', (169, 179))	('EMP2', 'Gene', (217, 221))	('UBUC', 'Chemical', '-', (46, 50))	('EMP2', 'Gene', (101, 105))	('regulation', 'biological_process', 'GO:0065007', ('203', '213'))	('Human', 'Species', '9606', (76, 81))
33881	25940704	Moreover, it has been found that an histone deacetylase (HDAC) inhibitor, valproic acid, caused an increase in transcription of a DNA damage recognition gene, the xeroderma pigmentosum, complementation group C (XPC) via increasing binding of both CREB1 and SP1 transcription factors in both HTB4 and HTB9 UBUC-derived cell lines.	('valproic', 'Var', (74, 82))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('SP1', 'Gene', (257, 260))	('XPC', 'Gene', (211, 214))	('binding', 'molecular_function', 'GO:0005488', ('231', '238'))	('transcription', 'MPA', (111, 124))	('increasing', 'PosReg', (220, 230))	('UBUC', 'Chemical', '-', (305, 309))	('transcription', 'biological_process', 'GO:0006351', ('111', '124'))	('transcription', 'biological_process', 'GO:0006351', ('261', '274'))	('XPC', 'Gene', '7508', (211, 214))	('binding', 'Interaction', (231, 238))	('increase', 'PosReg', (99, 107))	('xeroderma pigmentosum, complementation group C', 'Gene', '7508', (163, 209))	('valproic acid', 'Chemical', 'MESH:D014635', (74, 87))
33888	25940704	In addition to the activation by cyclins, CDK1 activity can be negatively regulated by phosphorylation of two inhibitory residues, Y14 and Y15.	('activity', 'MPA', (47, 55))	('Y14', 'Gene', '9939', (131, 134))	('CDK', 'molecular_function', 'GO:0004693', ('42', '45'))	('negatively', 'NegReg', (63, 73))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))	('CDK1', 'Protein', (42, 46))	('phosphorylation', 'MPA', (87, 102))	('Y14', 'Gene', (131, 134))	('Y15', 'Var', (139, 142))
33893	25940704	During interphase growth and under DNA damage or stress, CDC25C is prevented from entering the nucleus (inactive) owing to S216 phosphorylation and interaction with tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, theta (YWHAQ or 14-3-3).	('YWHAQ or 14-3-3', 'Gene', '10971', (244, 259))	('phosphorylation', 'biological_process', 'GO:0016310', ('128', '143'))	('protein', 'cellular_component', 'GO:0003675', ('228', '235'))	('CDC25C', 'Gene', '995', (57, 63))	('interaction', 'Interaction', (148, 159))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('YWHAQ or 14-3-3', 'Gene', (244, 259))	('nucleus', 'cellular_component', 'GO:0005634', ('95', '102'))	('CDC25C', 'Gene', (57, 63))	('interphase', 'biological_process', 'GO:0051325', ('7', '17'))	('S216', 'Var', (123, 127))
33895	25940704	In distinct UBUC-derived cell lines, EMP2 expression induces G2/M cell cycle arrest via regulation of G2/M checkpoints, WEE1, pCDK(Y15) and pCDC25C(S216), and subsequently decreases cell viability, proliferation and colony formation/anchorage-independent cell growth.	('EMP2', 'Gene', (37, 41))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (66, 83))	('formation', 'biological_process', 'GO:0009058', ('223', '232'))	('cell viability', 'CPA', (182, 196))	('decreases', 'NegReg', (172, 181))	('colony formation/anchorage-independent cell growth', 'CPA', (216, 266))	('UBUC', 'Chemical', '-', (12, 16))	('CDC25C', 'Gene', (141, 147))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('66', '83'))	('WEE1', 'Gene', '7465', (120, 124))	('regulation', 'biological_process', 'GO:0065007', ('88', '98'))	('G2/M cell cycle arrest', 'CPA', (61, 83))	('expression', 'Var', (42, 52))	('cell growth', 'biological_process', 'GO:0016049', ('255', '266'))	('WEE1', 'Gene', (120, 124))	('CDC25C', 'Gene', '995', (141, 147))	('induces', 'Reg', (53, 60))
33905	25940704	Quantitative RT-PCR assay was applied to quantify the expression levels of EMP2 and cAMP responsive element binding protein 1 (CREB1) transcripts using predesigned TaqMan  assay reagents [EMP2: Hs00171315_m1, 88 bp; CREB1: Hs00231713_m1, 75 bp; polymerase (RNA) II (DNA directed) polypeptide A (POLR2A): Hs00172187_m1, 61 bp, internal control), StepOnePlus  Real-Time PCR System (Life Technologies) and DeltaDeltaCT calculation.	('POLR2A', 'Gene', '5430', (295, 301))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('cAMP responsive element binding', 'molecular_function', 'GO:0035497', ('84', '115'))	('cAMP responsive element binding protein 1', 'Gene', '1385', (84, 125))	('Hs00172187_m1', 'Var', (304, 317))	('RNA', 'cellular_component', 'GO:0005562', ('257', '260'))	('POLR2A', 'Gene', (295, 301))	('cAMP responsive element binding protein 1', 'Gene', (84, 125))	('DNA', 'cellular_component', 'GO:0005574', ('266', '269'))
33915	25940704	Plasmids shEMP2#1 (TRCN0000072386: 5'-CAACACGAATTGCACAGTCAT-3'), shEMP2#2 (TRCN0000072387: 5'-GTTTGTCCTAACCTCCAT CAT-3'), shCREB1#1 (TRCN0000011085: 5'-CAG TGGATAGTGTAACTGATT-3') and shCREB1#3 (TRCN0000007309: 5'-GCAAACATTAACCATGACC AA-3) were used for knockdown of EMP2 and CREB1 genes and shLuc (TRCN0000072243:5'-CTTCGAAATGTCCGTTCGGTT-3)' was used as a negative control clone.	('CREB1 genes', 'Gene', (275, 286))	('CAT-3', 'Species', '717647', (113, 118))	('CAT', 'molecular_function', 'GO:0004096', ('113', '116'))	('knockdown', 'Var', (253, 262))	('CAT-3', 'Species', '717647', (56, 61))	('EMP2', 'Gene', (266, 270))
33918	25940704	Flow cytometric, 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), bromodeoxyuridine (BrdU) and soft agar assays were used to determine alternations of cell cycle distribution, cell viability, cell proliferation and colony formation/anchorage-independent cell growth after exogenous expression or knockdown of EMP2 and/or CREB1 genes in vitro.	('MTT', 'Chemical', 'MESH:C070243', (81, 84))	('cell proliferation', 'biological_process', 'GO:0008283', ('213', '231'))	('3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (17, 79))	('BrdU', 'Chemical', 'MESH:D001973', (106, 110))	('bromodeoxyuridine', 'Chemical', 'MESH:D001973', (87, 104))	('cell proliferation', 'CPA', (213, 231))	('formation', 'biological_process', 'GO:0009058', ('243', '252'))	('EMP2', 'Gene', (330, 334))	('cell growth', 'biological_process', 'GO:0016049', ('275', '286'))	('cell cycle', 'biological_process', 'GO:0007049', ('172', '182'))	('CREB1', 'Gene', (342, 347))	('cell cycle distribution', 'CPA', (172, 195))	('cell viability', 'CPA', (197, 211))	('colony formation/anchorage-independent cell growth', 'CPA', (236, 286))	('knockdown', 'Var', (317, 326))
33919	25940704	For cell cycle analysis, 1 x 106 cells were collected, washed with ice-cold PBS, fixed with 70% ethanol and stored at -20 C after stable transfection of pCMV6-Entry, pCMV6-EMP2 or pCMV6-CREB1 plasmid, or infection with shEMP2#1, shEMP2#1, shCREB1#1, shCREB#3, shCREB1#3 and shEMP1#1, or shLuc lentiviral particles.	('pCMV6-EMP2', 'Var', (166, 176))	('CREB', 'Gene', '1385', (252, 256))	('cell cycle', 'biological_process', 'GO:0007049', ('4', '14'))	('CREB', 'Gene', (262, 266))	('infection', 'Disease', (204, 213))	('CREB', 'Gene', (241, 245))	('CREB', 'Gene', (186, 190))	('infection', 'Disease', 'MESH:D007239', (204, 213))	('CREB', 'Gene', '1385', (262, 266))	('ethanol', 'Chemical', 'MESH:D000431', (96, 103))	('PBS', 'Chemical', 'MESH:D007854', (76, 79))	('CREB', 'Gene', '1385', (241, 245))	('CREB', 'Gene', '1385', (186, 190))	('CREB', 'Gene', (252, 256))
33920	25940704	Before analysis, fixed cells were washed with ice-cold PBS for three times and treatments with 200 mug/mL RNase A (#R6513, Sigma-Aldrich) and 20 mug/mL propidium iodide (#P4170, Sigma-Aldrich).	('propidium iodide', 'Chemical', 'MESH:D011419', (152, 168))	('RNase A', 'Gene', '6035', (106, 113))	('mug', 'molecular_function', 'GO:0043739', ('99', '102'))	('#P4170', 'Var', (170, 176))	('PBS', 'Chemical', 'MESH:D007854', (55, 58))	('#R6513', 'Var', (115, 121))	('mug', 'molecular_function', 'GO:0043739', ('145', '148'))	('RNase A', 'Gene', (106, 113))
33927	25940704	CytoSelect  96-well in vitro tumor sensitivity assay (soft agar colony formation, CBA-150-5, CELL BIOLABS, INC) was used to analyze whether stable expression and knockdown of EMP2 affected anchorage-independent cell growth.	('EMP2', 'Gene', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('CytoSelect', 'Chemical', '-', (0, 10))	('anchorage-independent cell growth', 'CPA', (189, 222))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('cell growth', 'biological_process', 'GO:0016049', ('211', '222'))	('formation', 'biological_process', 'GO:0009058', ('71', '80'))	('affected', 'Reg', (180, 188))	('knockdown', 'Var', (162, 171))
33943	25940704	Cisplatin-based post-operative adjuvant chemotherapy was performed in those with pT3 or pT4 status or nodal involvement.	('pT3', 'Gene', '7694', (81, 84))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('pT4 status', 'Var', (88, 98))	('pT3', 'Gene', (81, 84))
34001	25364228	Margulis et al reported that the 5-year survival rates of patients with positive lymph nodes were 35.3% for patients with pT2 disease, 74.7% for patients with pT3 disease, and 54% for those with pT4 disease.	('patients', 'Species', '9606', (145, 153))	('patients', 'Species', '9606', (108, 116))	('pT3', 'Gene', '7694', (159, 162))	('pT2', 'Var', (122, 125))	('pT3', 'Gene', (159, 162))	('patients', 'Species', '9606', (58, 66))
34015	25364228	In our study, we found that patients >65 years, patients with a BMI >25 kg/m2, patients with a contralateral kidney length <10 cm, and patients without ipsilateral hydronephrosis are at significant risk of decreased renal function after surgery.	('patients', 'Species', '9606', (135, 143))	('decreased renal function', 'Disease', 'MESH:D051437', (206, 230))	('>25 kg/m2', 'Var', (68, 77))	('hydronephrosis', 'Phenotype', 'HP:0000126', (164, 178))	('ipsilateral hydronephrosis', 'Disease', (152, 178))	('patients', 'Species', '9606', (79, 87))	('ipsilateral hydronephrosis', 'Disease', 'MESH:D006869', (152, 178))	('patients', 'Species', '9606', (28, 36))	('patients', 'Species', '9606', (48, 56))	('decreased renal function', 'Disease', (206, 230))
34119	33032610	In addition, immunohistochemically, the expression of ZEB1 reduced E-cadherin expression in the sarcomatous component of other cancers.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('reduced', 'NegReg', (59, 66))	('E-cadherin', 'Gene', (67, 77))	('expression', 'Var', (40, 50))	('E-cadherin', 'Gene', '999', (67, 77))	('ZEB1', 'Gene', (54, 58))	('ZEB1', 'Gene', '6935', (54, 58))	('cadherin', 'molecular_function', 'GO:0008014', ('69', '77'))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('sarcomatous component of other cancers', 'Disease', (96, 134))	('sarcomatous component of other cancers', 'Disease', 'MESH:D009369', (96, 134))
34152	33032610	The expression of ZEB1 has been reported in various human cancers and increases the resistance of cancer cells to chemotherapy and radiation therapy, indicating that ZEB1 is a transcription factor not only involved in the tumorigenesis of cancers but also in the prognosis for cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ZEB1', 'Gene', (166, 170))	('patients', 'Species', '9606', (284, 292))	('cancer', 'Disease', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('ZEB1', 'Gene', '6935', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('cancer', 'Disease', (277, 283))	('cancers', 'Disease', (239, 246))	('cancer', 'Disease', (239, 245))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('expression', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('ZEB1', 'Gene', '6935', (166, 170))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', (222, 227))	('cancer', 'Disease', (58, 64))	('transcription', 'biological_process', 'GO:0006351', ('176', '189'))	('transcription factor', 'molecular_function', 'GO:0000981', ('176', '196'))	('ZEB1', 'Gene', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('increases', 'PosReg', (70, 79))	('human', 'Species', '9606', (52, 57))	('cancers', 'Disease', 'MESH:D009369', (239, 246))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', (58, 65))
34153	33032610	The results of this case suggest that ZEB1 expression in plasmacytoid tumor cells may be associated with a poor prognosis as regards plasmacytoid urothelial carcinomas.	('associated', 'Reg', (89, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (146, 167))	('expression', 'Var', (43, 53))	('tumor', 'Disease', (70, 75))	('plasmacytoid tumor', 'Phenotype', 'HP:0011857', (57, 75))	('urothelial carcinomas', 'Disease', (146, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('ZEB1', 'Gene', '6935', (38, 42))	('ZEB1', 'Gene', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
34180	30699951	Molecular subtypes showed differences in prognosis, responsiveness to neoadjuvant chemotherapy, and targetable mutations; therefore, they would significantly influence MIBC treatment.	('mutations', 'Var', (111, 120))	('treatment', 'CPA', (173, 182))	('influence', 'Reg', (158, 167))	('MIBC', 'Chemical', '-', (168, 172))	('MIBC', 'Disease', (168, 172))
34184	30699951	In another study on stage Ta urinary bladder carcinoma, cancers were segregated by copy number alteration profiles into two subtypes which varied in mammalian target of rapamycin complex 1 activity, metabolic pathways, and mutations.	('cancers', 'Disease', (56, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('mutations', 'Var', (223, 232))	('mammalian', 'Species', '9606', (149, 158))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (37, 54))	('urinary bladder carcinoma', 'Disease', 'MESH:D001749', (29, 54))	('urinary bladder carcinoma', 'Disease', (29, 54))	('varied', 'Reg', (139, 145))	('metabolic pathways', 'CPA', (199, 217))	('activity', 'MPA', (189, 197))	('target of rapamycin complex', 'cellular_component', 'GO:0038201', ('159', '186'))
34187	30699951	UTUC was revealed to have comparable types of mutations as urinary bladder carcinoma by targeted sequencing, but with different prevalence.	('mutations', 'Var', (46, 55))	('urinary bladder carcinoma', 'Disease', 'MESH:D001749', (59, 84))	('urinary bladder carcinoma', 'Disease', (59, 84))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (67, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))
34189	30699951	It was also reported that UTUC was more enriched with luminal type genes compared with urinary bladder carcinoma.	('luminal', 'Var', (54, 61))	('urinary bladder carcinoma', 'Disease', 'MESH:D001749', (87, 112))	('urinary bladder carcinoma', 'Disease', (87, 112))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (95, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
34192	30699951	In MIBC, positivity for CK5/6 and negativity for CK20 were correlated with poor survival.	('CK20', 'Gene', (49, 53))	('CK20', 'Gene', '54474', (49, 53))	('MIBC', 'Chemical', '-', (3, 7))	('negativity', 'Var', (34, 44))	('positivity', 'Var', (9, 19))	('CK5/6', 'Gene', '3852', (24, 29))	('MIBC', 'Disease', (3, 7))	('CK5/6', 'Gene', (24, 29))
34201	30699951	Among these characteristics, only WHO grade showed a significant association with IHC profiles: high WHO grade was associated with low CK5/6 (p = 0.004) and CD44 (p = 0.048), marginally with high CK20 (p = 0.083) and p53 (p = 0.051) expression, but not with CK14 (p = 1.000), GATA3 (p = 0.339), and FOXA1 (p = 0.778) staining (Figure 1A and Figure S1).	('CK5/6', 'Gene', '3852', (135, 140))	('GATA3', 'Gene', (276, 281))	('p53', 'Gene', (217, 220))	('high', 'Var', (191, 195))	('expression', 'MPA', (233, 243))	('CD44', 'Gene', '960', (157, 161))	('FOXA1', 'Gene', (299, 304))	('CK5/6', 'Gene', (135, 140))	('p53', 'Gene', '7157', (217, 220))	('GATA3', 'Gene', '2625', (276, 281))	('CD44', 'Gene', (157, 161))	('CK14', 'Gene', '3861', (258, 262))	('FOXA1', 'Gene', '3169', (299, 304))	('CK20', 'Gene', '54474', (196, 200))	('CK20', 'Gene', (196, 200))	('low', 'NegReg', (131, 134))	('CK14', 'Gene', (258, 262))
34231	30699951	First, we showed that immunoreactions of low CK5/6, high CK20, low CD44, and high p53 were predictive of high WHO grade in non-muscle-invasive papillary UTUC.	('CK5/6', 'Gene', '3852', (45, 50))	('CD44', 'Gene', '960', (67, 71))	('CK5/6', 'Gene', (45, 50))	('CD44', 'Gene', (67, 71))	('non-muscle-invasive papillary UTUC', 'Disease', (123, 157))	('low', 'Var', (41, 44))	('CK20', 'Gene', (57, 61))	('p53', 'Gene', (82, 85))	('high', 'Var', (52, 56))	('low', 'Var', (63, 66))	('CK20', 'Gene', '54474', (57, 61))	('p53', 'Gene', '7157', (82, 85))
34250	30699951	This was also substantiated by the results showing that the alteration of the genes observed in group 3 have been reported to promote invasion of and to be associated with the poor prognoses of urothelial carcinoma and other various malignancies, including downregulation of CLCA2, SPINK5, SHC1, LGALS8, COL7A1, FAT2, WNT5A, and NRXN3, and upregulation of CLDN4, PKN1, FREM2, XBP1, PKP2, ANG, and PFN1.	('PKN1', 'Gene', '5585', (363, 367))	('CLDN4', 'Gene', '1364', (356, 361))	('malignancies', 'Disease', 'MESH:D009369', (233, 245))	('SHC1', 'Gene', '6464', (290, 294))	('FREM2', 'Gene', '341640', (369, 374))	('WNT5A', 'Gene', (318, 323))	('CLCA2', 'Gene', '9635', (275, 280))	('NRXN3', 'Gene', (329, 334))	('LGALS8', 'Gene', '3964', (296, 302))	('malignancies', 'Disease', (233, 245))	('ANG', 'Gene', (388, 391))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (194, 214))	('FAT2', 'Gene', '2196', (312, 316))	('XBP1', 'Gene', '7494', (376, 380))	('alteration', 'Var', (60, 70))	('PKN1', 'Gene', (363, 367))	('CLDN4', 'Gene', (356, 361))	('PFN1', 'Gene', (397, 401))	('upregulation', 'PosReg', (340, 352))	('WNT5A', 'Gene', '7474', (318, 323))	('COL7A1', 'Gene', (304, 310))	('PFN1', 'Gene', '5216', (397, 401))	('COL7A1', 'Gene', '1294', (304, 310))	('PKP2', 'Gene', (382, 386))	('FAT2', 'Gene', (312, 316))	('promote', 'PosReg', (126, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('XBP1', 'Gene', (376, 380))	('downregulation', 'NegReg', (257, 271))	('ANG', 'Gene', '283', (388, 391))	('PKP2', 'Gene', '5318', (382, 386))	('SPINK5', 'Gene', '11005', (282, 288))	('CLCA2', 'Gene', (275, 280))	('urothelial carcinoma', 'Disease', (194, 214))	('invasion', 'CPA', (134, 142))	('SHC1', 'Gene', (290, 294))	('FREM2', 'Gene', (369, 374))	('LGALS8', 'Gene', (296, 302))	('NRXN3', 'Gene', '9369', (329, 334))	('SPINK5', 'Gene', (282, 288))
34333	30457576	Atezolizumab (1200 mg IV q3w) resulted in an ORR (primary end point) of 16%, including 7% of complete response (CR) in all patients; the ORR reached up to 28%, including 15% CR in IC2/3 patients.	('complete', 'Disease', (93, 101))	('IC2/3', 'Gene', (180, 185))	('Atezolizumab', 'Chemical', 'MESH:C000594389', (0, 12))	('1200', 'Var', (14, 18))	('patients', 'Species', '9606', (123, 131))	('IC2/3', 'Gene', '1781', (180, 185))	('CR', 'Chemical', '-', (112, 114))	('CR', 'Chemical', '-', (174, 176))	('patients', 'Species', '9606', (186, 194))
34340	30457576	The primary efficacy end point OS was to be tested in a successive fashion in study populations defined by IC PD-L1 expression, starting with high (IC2/3) PD-L1 expression, followed by those with any level of PD-L1 expression (IC1/2/3), and followed by the overall study population (intention-to-treat [ITT]).	('PD-L1', 'Gene', (110, 115))	('OS', 'Chemical', '-', (31, 33))	('expression', 'MPA', (161, 171))	('IC2/3', 'Gene', (148, 153))	('IC1/2/3', 'Gene', '105259599;1781', (227, 234))	('IC2/3', 'Gene', '1781', (148, 153))	('high', 'Var', (142, 146))	('PD-L1', 'Gene', (155, 160))	('IC1/2/3', 'Gene', (227, 234))
34363	30457576	After median follow-up of 14.1 months, OS in all patients was significantly improved with pembrolizumab compared with chemotherapy (10.3 vs 7.4 months, respectively; p = 0.002;).	('pembrolizumab', 'Var', (90, 103))	('pembrolizumab', 'Chemical', 'MESH:C582435', (90, 103))	('improved', 'PosReg', (76, 84))	('OS', 'Chemical', '-', (39, 41))	('patients', 'Species', '9606', (49, 57))
34368	30457576	In the pembrolizumab arm, high PD-L1 expression was even associated with a lower OS (8 months) compared with that of all pembrolizumab-treated patients, suggesting that this biomarker could highlight a poor-prognosis group.	('lower', 'NegReg', (75, 80))	('pembrolizumab', 'Chemical', 'MESH:C582435', (121, 134))	('pembrolizumab', 'Chemical', 'MESH:C582435', (7, 20))	('high', 'Var', (26, 30))	('patients', 'Species', '9606', (143, 151))	('OS', 'Chemical', '-', (81, 83))	('expression', 'MPA', (37, 47))	('PD-L1', 'Gene', (31, 36))
34380	30457576	The median PFS was 1.5 months in the entire population and was higher in PD-L1 high patients (2.1 months) compared with low or negative patients (1.4 months).	('patients', 'Species', '9606', (84, 92))	('PFS', 'MPA', (11, 14))	('patients', 'Species', '9606', (136, 144))	('high', 'Var', (79, 83))	('higher', 'PosReg', (63, 69))	('PD-L1', 'Gene', (73, 78))
34381	30457576	The median OS was 18.2 months in the entire population and was also higher in PD-L1 high (20.0 months) compared with low or negative patients (8.1 months).	('OS', 'Chemical', '-', (11, 13))	('high', 'Var', (84, 88))	('PD-L1', 'Gene', (78, 83))	('patients', 'Species', '9606', (133, 141))	('higher', 'PosReg', (68, 74))
34384	30457576	Compared with durvalumab and atezolizumab, avelumab can, in addition to PD-L1 inhibition, induce antibody-dependent cell-mediated cytotoxicity, which results in a direct lysis of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('antibody', 'cellular_component', 'GO:0019814', ('97', '105'))	('lysis', 'biological_process', 'GO:0019835', ('170', '175'))	('antibody', 'cellular_component', 'GO:0042571', ('97', '105'))	('avelumab', 'Var', (43, 51))	('cytotoxicity', 'Disease', (130, 142))	('antibody', 'molecular_function', 'GO:0003823', ('97', '105'))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('induce', 'PosReg', (90, 96))	('cytotoxicity', 'Disease', 'MESH:D064420', (130, 142))	('durvalumab', 'Chemical', 'MESH:C000613593', (14, 24))	('atezolizumab', 'Chemical', 'MESH:C000594389', (29, 41))	('antibody', 'cellular_component', 'GO:0019815', ('97', '105'))	('avelumab', 'Chemical', 'MESH:C000609138', (43, 51))	('tumor', 'Disease', (179, 184))
34389	30457576	The confirmed ORR increased to 53.8% in PD-L1-positive tumors and was 4.2% in PD-L1-negative tumors.	('increased', 'PosReg', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('PD-L1-positive', 'Var', (40, 54))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (93, 99))
34402	30457576	Conversely to cohort 1, high PD-L1 expression was not associated with high ORR or OS.	('high ORR', 'Disease', (70, 78))	('OS', 'Chemical', '-', (82, 84))	('high', 'Var', (24, 28))	('PD-L1', 'Gene', (29, 34))
34419	30457576	Some studies measured PD-L1 in the tumor, some measure PD-L1 in immune-infiltrating cells and some measure both, all with different PD-L1 antibodies (SP142, 22C3, 28-8 and 5H1).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('SP142', 'Var', (150, 155))
34425	30457576	High PD-L1 and high tGE were associated with improved outcomes with both chemotherapy and atezolizumab.	('high', 'Var', (15, 19))	('High', 'Var', (0, 4))	('improved', 'PosReg', (45, 53))	('PD-L1', 'Gene', (5, 10))	('tGE', 'Gene', (20, 23))	('atezolizumab', 'Chemical', 'MESH:C000594389', (90, 102))
34436	30457576	The rates of Grade 3/4 AEs were similar in each group, at 30.8 and 31.7%, for the N1/I3 and N3/N1 arms, respectively, compared with 28% observed in the nivolumab arm.	('N1/I3', 'Var', (82, 87))	('N3/N1', 'Var', (92, 97))	('nivolumab', 'Chemical', 'MESH:D000077594', (152, 161))
34452	28978000	On 27 paired samples, IC1/2/3 score on TCs was homogeneous distributed with 59.3% in primary tumors and metastases, but with a high discordance rate of 44.4% of PD-L1 positivity on ICs.	('metastases', 'Disease', (104, 114))	('primary tumors', 'Disease', 'MESH:D009369', (85, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('IC1/2/3', 'Gene', (22, 29))	('IC1/2/3', 'Gene', '105259599;1781', (22, 29))	('metastases', 'Disease', 'MESH:D009362', (104, 114))	('TCs', 'Chemical', '-', (39, 42))	('primary tumors', 'Disease', (85, 99))	('PD-L1', 'Gene', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('ICs', 'Chemical', '-', (181, 184))	('PD-L1', 'Gene', '29126', (161, 166))	('positivity', 'Var', (167, 177))
34454	28978000	PD-L1 expression on TCs in primary tumors (IC2/3 vs. IC0, median: 3.2 vs. 13.8 months, p=0.019) and metastatic sites (IC2/3 vs. IC0, median: 6.1 vs. 21.8 months, p=0.014) was associated with poor chemo-response, represented by significant shortened DSS.	('IC2/3', 'Gene', '1781', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('primary tumors', 'Disease', (27, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('TCs', 'Chemical', '-', (20, 23))	('shortened DSS', 'Disease', (239, 252))	('DSS', 'Chemical', '-', (249, 252))	('PD-L1', 'Gene', (0, 5))	('IC2/3', 'Gene', '1781', (118, 123))	('primary tumors', 'Disease', 'MESH:D009369', (27, 41))	('IC2/3', 'Gene', (118, 123))	('PD-L1', 'Gene', '29126', (0, 5))	('expression', 'Var', (6, 16))	('IC2/3', 'Gene', (43, 48))
34461	28978000	Furthermore, immune gene expression profiling identified three molecular pathways (B-catenin overexpression, FGF3 mutations and PPAR-g activation) linked to a non-T cell-inflamed tumor microenvironment, being responsible for intrinsic resistance to immunotherapies, Supplementary Figure 1.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('men', 'Species', '9606', (272, 275))	('FGF3', 'Gene', (109, 113))	('gene expression', 'biological_process', 'GO:0010467', ('20', '35'))	('mutations', 'Var', (114, 123))	('B-catenin', 'Gene', '1499', (83, 92))	('men', 'Species', '9606', (197, 200))	('PPAR-g', 'Gene', (128, 134))	('B-catenin', 'Gene', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('FGF3', 'Gene', '2248', (109, 113))	('PPAR-g', 'Gene', '5468', (128, 134))	('overexpression', 'PosReg', (93, 107))	('tumor', 'Disease', (179, 184))
34462	28978000	On the contrary, a T-cell inflamed tumor microenvironment is associated with increased CD8+ T cell infiltration (Supplementary Figure 1), higher amount of tumor-infiltrating lymphocyte (TIL) clonality, which correlates with higher PD-L1 expression, higher mutation load and consecutive radiographic response to checkpoint inhibitors such as atezolizumab, supporting an adaptive immune response-mechanism.	('PD-L1', 'Gene', (231, 236))	('tumor', 'Disease', (155, 160))	('PD-L1', 'Gene', '29126', (231, 236))	('adaptive immune response', 'biological_process', 'GO:0002250', ('369', '393'))	('increased', 'PosReg', (77, 86))	('CD8', 'Gene', '925', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (35, 40))	('atezolizumab', 'Chemical', 'MESH:C000594389', (341, 353))	('men', 'Species', '9606', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mutation', 'Var', (256, 264))	('expression', 'MPA', (237, 247))	('CD8', 'Gene', (87, 90))	('higher', 'PosReg', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('higher', 'PosReg', (249, 255))	('men', 'Species', '9606', (53, 56))	('higher', 'PosReg', (224, 230))
34491	28978000	Interestingly, patients with histologic variants of urothelial cancer (median [95% CI] DSS 3.1 [0.6-5.6] months) responded less to platinum-based chemotherapy with a shorter DSS than those patients with pure urothelial cancer (median [95% CI] DSS 11.4 [5.3-17.6] months, p=0.013), Figure 5F.	('DSS', 'Chemical', '-', (243, 246))	('patients', 'Species', '9606', (15, 23))	('DSS', 'Chemical', '-', (174, 177))	('pure urothelial cancer', 'Disease', 'MESH:D014523', (203, 225))	('platinum', 'Chemical', 'MESH:D010984', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('urothelial cancer', 'Disease', 'MESH:D014523', (208, 225))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('pure urothelial cancer', 'Disease', (203, 225))	('less', 'NegReg', (123, 127))	('DSS', 'Chemical', '-', (87, 90))	('urothelial cancer', 'Disease', (52, 69))	('pure', 'molecular_function', 'GO:0034023', ('203', '207'))	('patients', 'Species', '9606', (189, 197))	('variants', 'Var', (40, 48))	('responded', 'MPA', (113, 122))	('urothelial cancer', 'Disease', 'MESH:D014523', (52, 69))
34492	28978000	Univariate Cox regression analysis revealed that histological variants of urothelial cancers [HR = 2.35; 95% CI: 1.17-4.71; p=0.016], and a high IC2/3 PD-L1 expression on TCs of primary tumor [HR=2.53; 95% CI: 1.27-5.03; p=0.008] as well as of metastatic sites [HR=3.55; 95% CI: 1.15-10.89; p=0.027] were associated with a higher risk of poor DSS after recurrence.	('DSS', 'Chemical', '-', (343, 346))	('primary tumor', 'Disease', (178, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('primary tumor', 'Disease', 'MESH:D009369', (178, 191))	('urothelial cancers', 'Disease', 'MESH:D014523', (74, 92))	('variants', 'Var', (62, 70))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('urothelial cancers', 'Disease', (74, 92))	('TCs', 'Chemical', '-', (171, 174))	('IC2/3 PD-L1', 'Gene', (145, 156))	('poor DSS', 'Disease', (338, 346))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('IC2/3 PD-L1', 'Gene', '1781', (145, 156))
34496	28978000	Patients with a IC0 score (median [95% CI] OS 32.6 [..] months) had a significant better OS than patients with a IC1 score (median [95% CI] OS 23.3 [10.5-36.2] months) or IC2/3 score (median [95% CI] OS 11.1 [6.4-15.8] months; p=0.042), Figure 6B.	('IC2/3', 'Gene', '1781', (171, 176))	('better', 'PosReg', (82, 88))	('IC0 score', 'Var', (16, 25))	('OS', 'Chemical', '-', (200, 202))	('IC1', 'Gene', (113, 116))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (43, 45))	('OS', 'Chemical', '-', (89, 91))	('OS', 'Chemical', '-', (140, 142))	('IC1', 'Gene', '105259599', (113, 116))	('IC2/3', 'Gene', (171, 176))	('patients', 'Species', '9606', (97, 105))
34499	28978000	Univariate analysis confirmed a significant positive association between IC2/3 score on TCs of primary tumor [HR=2.25; 95% CI: 1.15-4.41; p=0.019], histological variants of urothelial cancer [HR=2.48; 95% CI: 1.23-5.01; p=0.011] and lower OS.	('variants', 'Var', (161, 169))	('primary tumor', 'Disease', 'MESH:D009369', (95, 108))	('urothelial cancer', 'Disease', 'MESH:D014523', (173, 190))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('TCs', 'Chemical', '-', (88, 91))	('lower OS', 'Disease', (233, 241))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('IC2/3', 'Gene', '1781', (73, 78))	('IC2/3', 'Gene', (73, 78))	('OS', 'Chemical', '-', (239, 241))	('urothelial cancer', 'Disease', (173, 190))	('primary tumor', 'Disease', (95, 108))
34511	28978000	Inhibition of CTLA-4 proved to induce long-term responses, however more frequent immune related adverse events were reported compared to the inhibition of PD-1/PD-L1 axis.	('CTLA-4', 'Gene', (14, 20))	('PD-L1', 'Gene', (160, 165))	('PD-1', 'Gene', (155, 159))	('PD-L1', 'Gene', '29126', (160, 165))	('PD-1', 'Gene', '5133', (155, 159))	('Inhibition', 'Var', (0, 10))	('CTLA-4', 'Gene', '1493', (14, 20))
34522	28978000	We show a tendency towards a positive correlation of PD-L1 positivity between TCs and ICs, in primary tumor as well as in metastasis.	('PD-L1', 'Gene', (53, 58))	('positivity', 'Var', (59, 69))	('TCs', 'Disease', (78, 81))	('primary tumor', 'Disease', (94, 107))	('PD-L1', 'Gene', '29126', (53, 58))	('TCs', 'Chemical', '-', (78, 81))	('primary tumor', 'Disease', 'MESH:D009369', (94, 107))	('ICs', 'Chemical', '-', (86, 89))	('ICs', 'Disease', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
34530	28978000	In line with our results on the prognostic role of PD-L1 positivity on TCs it has been reported that PD-L1 expression was associated with a shorter survival after RC, whereas other trials showed no influence on RFS and OS.	('OS', 'Chemical', '-', (219, 221))	('shorter', 'NegReg', (140, 147))	('survival', 'MPA', (148, 156))	('TCs', 'Chemical', '-', (71, 74))	('PD-L1', 'Gene', '29126', (101, 106))	('PD-L1', 'Gene', '29126', (51, 56))	('PD-L1', 'Gene', (101, 106))	('expression', 'Var', (107, 117))	('PD-L1', 'Gene', (51, 56))
34532	28978000	Moreover, knockdown of PD-L1 expression increased chemo-response to cisplatin in vivo and in vitro.	('chemo-response to cisplatin', 'MPA', (50, 77))	('PD-L1', 'Gene', (23, 28))	('PD-L1', 'Gene', '29126', (23, 28))	('response to cisplatin', 'biological_process', 'GO:0072718', ('56', '77'))	('increased', 'PosReg', (40, 49))	('knockdown', 'Var', (10, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
34534	28978000	In mammary epithelial cells, MERTK overexpression a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases, promotes chemo-resistance and induces consecutive PD-L1 overexpression.	('MERTK', 'Gene', (87, 92))	('induces', 'PosReg', (151, 158))	('TYRO3', 'Gene', '7301', (71, 76))	('MERTK', 'Gene', '10461', (29, 34))	('overexpression', 'PosReg', (177, 191))	('AXL', 'Gene', '558', (78, 81))	('PD-L1', 'Gene', (171, 176))	('overexpression', 'Var', (35, 49))	('MERTK', 'Gene', (29, 34))	('chemo-resistance', 'CPA', (130, 146))	('promotes', 'PosReg', (121, 129))	('AXL', 'Gene', (78, 81))	('TYRO3', 'Gene', (71, 76))	('PD-L1', 'Gene', '29126', (171, 176))	('MERTK', 'Gene', '10461', (87, 92))
34535	28978000	Vice versa MERTK knockdown significantly reduced PD-L1 expression levels in highly invasive breast cancer cells MDA-MB 231.	('reduced', 'NegReg', (41, 48))	('MDA-MB', 'CellLine', 'CVCL:0062', (112, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('PD-L1', 'Gene', '29126', (49, 54))	('knockdown', 'Var', (17, 26))	('reduced PD', 'Phenotype', 'HP:0032198', (41, 51))	('PD-L1', 'Gene', (49, 54))	('MERTK', 'Gene', '10461', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('MERTK', 'Gene', (11, 16))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
34537	28978000	A possible explanation for poor prognosis of FGF-2 expressing bladder cancers is the association with epithelial to mesenchymal transition (EMT), high proliferation, low mutation load and high expression of CTLA-4, PD-1 and PD-L1, thus being more sensitive to immune checkpoint inhibition.	('expression', 'MPA', (193, 203))	('FGF-2', 'Gene', (45, 50))	('PD-L1', 'Gene', (224, 229))	('PD-L1', 'Gene', '29126', (224, 229))	('epithelial to mesenchymal transition', 'CPA', (102, 138))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('EMT', 'biological_process', 'GO:0001837', ('140', '143'))	('FGF-2', 'Gene', '2247', (45, 50))	('PD-1', 'Gene', (215, 219))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('102', '138'))	('bladder cancers', 'Phenotype', 'HP:0009725', (62, 77))	('PD-1', 'Gene', '5133', (215, 219))	('CTLA-4', 'Gene', '1493', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CTLA-4', 'Gene', (207, 213))	('bladder cancer', 'Phenotype', 'HP:0009725', (62, 76))	('high proliferation', 'CPA', (146, 164))	('low', 'Var', (166, 169))	('bladder cancers', 'Disease', 'MESH:D001749', (62, 77))	('bladder cancers', 'Disease', (62, 77))
34538	28978000	In line with these in-vitro findings, we are able to show that those patients with histological subtypes of urothelial cancer (including approximately 70% with squamous differentiation, in which FGFR alterations are well known) had significant increased PD-L1 expression, but decreased survival outcomes compared to pure urothelial cancers.	('patients', 'Species', '9606', (69, 77))	('PD-L1', 'Gene', (254, 259))	('PD-L1', 'Gene', '29126', (254, 259))	('urothelial cancer', 'Disease', 'MESH:D014523', (108, 125))	('alterations', 'Var', (200, 211))	('urothelial cancer', 'Disease', 'MESH:D014523', (321, 338))	('urothelial cancers', 'Disease', (321, 339))	('decreased', 'NegReg', (276, 285))	('urothelial cancer', 'Disease', (108, 125))	('pure', 'molecular_function', 'GO:0034023', ('316', '320'))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('survival', 'MPA', (286, 294))	('pure urothelial cancer', 'Disease', 'MESH:D014523', (316, 338))	('cancers', 'Phenotype', 'HP:0002664', (332, 339))	('increased PD', 'Phenotype', 'HP:0008151', (244, 256))	('FGFR', 'molecular_function', 'GO:0005007', ('195', '199'))	('expression', 'MPA', (260, 270))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('pure urothelial cancer', 'Disease', (316, 338))	('urothelial cancers', 'Disease', 'MESH:D014523', (321, 339))	('increased', 'PosReg', (244, 253))
34567	28978000	Expression on TCs was evaluated as positive or negative and the exact percentage (%) of positive TCs was noted; in addition, a semi-quantitative score for the PD-L1 expression status on TCs in the tumor microenvironment was applied for statistical analysis and defined by the percentage of PD-L1-positive TCs as published previously: < 1%= Score 0 (IC0), >=1% but <5% = Score 1 (IC1), >=5 % = Score 2/3 (IC2/3) in primary tumors (n=61) as well as at the metastatic site (n=27).	('>=1%', 'Var', (355, 359))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('primary tumors', 'Disease', (414, 428))	('IC2/3', 'Gene', (404, 409))	('PD-L1', 'Gene', (159, 164))	('TCs', 'Chemical', '-', (14, 17))	('PD-L1', 'Gene', '29126', (159, 164))	('TCs', 'Chemical', '-', (305, 308))	('IC1', 'Gene', '105259599', (379, 382))	('men', 'Species', '9606', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('primary tumors', 'Disease', 'MESH:D009369', (414, 428))	('IC2/3', 'Gene', '1781', (404, 409))	('tumor', 'Disease', (422, 427))	('TCs', 'Chemical', '-', (186, 189))	('tumor', 'Disease', 'MESH:D009369', (422, 427))	('>=5 % =', 'Var', (385, 392))	('TCs', 'Chemical', '-', (97, 100))	('tumors', 'Phenotype', 'HP:0002664', (422, 428))	('PD-L1', 'Gene', (290, 295))	('PD-L1', 'Gene', '29126', (290, 295))	('tumor', 'Phenotype', 'HP:0002664', (422, 427))	('tumor', 'Disease', (197, 202))	('IC1', 'Gene', (379, 382))
34577	28978000	High PD-L1 expression was associated with histologic subtypes of urothelial cancers and had a negative predictive value for response to first-line chemotherapy.	('urothelial cancers', 'Disease', (65, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('High', 'Var', (0, 4))	('PD-L1', 'Gene', (5, 10))	('expression', 'MPA', (11, 21))	('PD-L1', 'Gene', '29126', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('urothelial cancers', 'Disease', 'MESH:D014523', (65, 83))	('associated', 'Reg', (26, 36))
34578	28978000	Furthermore, high PD-L1 expression on TCs was also a negative prognostic marker for DSS and OS.	('high', 'Var', (13, 17))	('expression', 'MPA', (24, 34))	('TCs', 'Chemical', '-', (38, 41))	('OS', 'Chemical', '-', (92, 94))	('DSS', 'Chemical', '-', (84, 87))	('PD-L1', 'Gene', (18, 23))	('DSS', 'Disease', (84, 87))	('PD-L1', 'Gene', '29126', (18, 23))
34602	28149931	This finding, which is being tested in the ongoing SWOG 1011 trial randomizing patients to extensive versus standard lymphadenectomy, suggests that eradicating occult nodal disease may improve survival by decreasing distant as well as local failure.	('decreasing', 'NegReg', (205, 215))	('occult nodal disease', 'Disease', 'MESH:D005596', (160, 180))	('local failure', 'CPA', (235, 248))	('improve', 'PosReg', (185, 192))	('eradicating', 'Var', (148, 159))	('distant', 'CPA', (216, 223))	('patients', 'Species', '9606', (79, 87))	('survival', 'CPA', (193, 201))	('occult nodal disease', 'Disease', (160, 180))
34679	28149931	For pT3 and pT4 patients, 2 year LF rates were 8% and 11% for the common iliac nodal region, 6% and 15% for the external/internal iliac region, 7% and 19% for the obturator nodal region, 4% and 6% for the cystectomy bed, respectively.	('iliac region', 'Phenotype', 'HP:0009780', (130, 142))	('pT3', 'Gene', '7694', (4, 7))	('patients', 'Species', '9606', (16, 24))	('pT3', 'Gene', (4, 7))	('iliac nodal region', 'Phenotype', 'HP:0009780', (73, 91))	('pT4', 'Var', (12, 15))
34695	27385897	Molecular imaging of prostate cancer with Ga-68 prostate-specific membrane antigen.	('membrane', 'cellular_component', 'GO:0016020', ('66', '74'))	('prostate cancer', 'Disease', 'MESH:D011471', (21, 36))	('Ga', 'Chemical', 'MESH:D005708', (42, 44))	('prostate-specific membrane antigen', 'molecular_function', 'GO:0043275', ('48', '82'))	('prostate-specific membrane antigen', 'Gene', '2346', (48, 82))	('prostate cancer', 'Phenotype', 'HP:0012125', (21, 36))	('prostate-specific membrane antigen', 'Gene', (48, 82))	('prostate cancer', 'Disease', (21, 36))	('Ga-68', 'Var', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
34700	27385897	(0.51.ng/ml) and referred for Ga-68 PSMA PET-CT, which showed a positive enlarged left supraclavicular lymph node.	('PSMA', 'Gene', (36, 40))	('PSMA', 'Gene', '2346', (36, 40))	('0.51.ng/ml', 'Var', (1, 11))	('PSMA', 'molecular_function', 'GO:0043275', ('36', '40'))	('Ga', 'Chemical', 'MESH:D005708', (30, 32))
34711	27385897	A 72-year-old male treated earlier with transurethral resection of prostate and the right open radical nephroureterectomy in 2013 for synchronous double malignancy (high-grade invasive papillary urothelial carcinoma right ureter and adenocarcinoma prostate Gleason 4+4) presented with rising PSA (0.59 ng/ml) with PSA doubling time of <6 months on routine follow-up.	('high-grade', 'Var', (165, 175))	('synchronous double malignancy', 'Disease', 'MESH:D009378', (134, 163))	('rising', 'PosReg', (285, 291))	('invasive papillary urothelial carcinoma right ureter and adenocarcinoma prostate Gleason', 'Disease', 'MESH:D000231', (176, 264))	('PSA', 'Gene', (292, 295))	('PSA', 'Gene', '354', (292, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('synchronous double malignancy', 'Disease', (134, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('PSA', 'Gene', '354', (314, 317))	('PSA', 'Gene', (314, 317))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (185, 215))
34753	23870412	In addition, it was reported that transgenic mice with liver-specific YAP 1 overexpression showed a dramatic increase in liver size and eventually developed tumors.	('liver size', 'CPA', (121, 131))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('overexpression', 'Var', (76, 90))	('increase', 'PosReg', (109, 117))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('increase in liver size', 'Phenotype', 'HP:0002240', (109, 131))	('transgenic mice', 'Species', '10090', (34, 49))	('YAP 1', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
34754	23870412	To date, however, abnormalities in YAP 1 and their clinicopathologic/prognostic implication in UCBs have not been explored.	('UCB', 'Phenotype', 'HP:0006740', (95, 98))	('UCBs', 'Disease', (95, 99))	('UCBs', 'Chemical', '-', (95, 99))	('YAP 1', 'Gene', (35, 40))	('abnormalities', 'Var', (18, 31))
34795	23870412	Moreover, expression of YAP 1 was found to be a prognostic factor in UCB patients having grades 2 and 3 tumors (P = 0.005 and 0.046, respectively, Figure 2, Table 2), pT1 (P = 0.013), pT2-4 (P = 0.002) and pN- (P < 0.001) (Figure 2, Table 2).	('pT1', 'Gene', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('YAP 1', 'Gene', (24, 29))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('pT2-4', 'Var', (184, 189))	('pT1', 'Gene', '58492', (167, 170))	('UCB', 'Phenotype', 'HP:0006740', (69, 72))	('patients', 'Species', '9606', (73, 81))	('UCB', 'Disease', (69, 72))
34796	23870412	In addition, survival analysis with regard to YAP 1 expression and a subset of pT2-4 UCB patients without lymph node metastasis (pT2-4/pN-, n = 64) showed that expression of YAP1 was also a significant prognostic factor (P = 0.004, Figure 2, Table 2).	('lymph node metastasis', 'Disease', (106, 127))	('lymph node metastasis', 'Disease', 'MESH:D009362', (106, 127))	('YAP1', 'Gene', (174, 178))	('YAP1', 'Gene', '10413', (174, 178))	('UCB', 'Phenotype', 'HP:0006740', (85, 88))	('expression', 'Var', (160, 170))	('pT2-4', 'Gene', (79, 84))	('patients', 'Species', '9606', (89, 97))	('YAP 1', 'Gene', (46, 51))
34798	23870412	The results showed that the expression of YAP 1 was an independent prognostic factor for overall patient survival (relative risk: 3.553, CI: 1.561-8.086, P = 0.003, Table 3).	('YAP 1', 'Gene', (42, 47))	('expression', 'Var', (28, 38))	('patient', 'Species', '9606', (97, 104))
34801	23870412	In our UCB cohorts, the mean LI value of Ki-67 for all 213 UCB tumor samples was 31.2%, thus, the mean value of 31.2% was used as a cutoff value to define low Ki-67 LI (LI<31.2%) and high Ki-67 LI (LI 31.2%).	('low Ki-67 LI', 'Var', (155, 167))	('tumor', 'Disease', (63, 68))	('UCB', 'Phenotype', 'HP:0006740', (7, 10))	('UCB', 'Phenotype', 'HP:0006740', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
34807	23870412	Overexpression of YAP 1 has been implicated in tumor progression in various human cancers, such as liver, colon, ovarian and lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('colon', 'Disease', (106, 111))	('implicated', 'Reg', (33, 43))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('liver', 'Disease', (99, 104))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('YAP 1', 'Gene', (18, 23))	('tumor', 'Disease', (47, 52))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('human', 'Species', '9606', (76, 81))	('ovarian and lung cancers', 'Disease', 'MESH:D010051', (113, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancers', 'Phenotype', 'HP:0100526', (125, 137))
34814	23870412	In 92 cases of non-small-cell lung carcinoma, positive expression YAP 1 was observed in 66.3% of the cases, and it was significantly correlated with lymph node metastasis and later clinical stages, and it was a poor prognostic predictor of the patients.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('positive expression', 'Var', (46, 65))	('lung carcinoma', 'Disease', 'MESH:D008175', (30, 44))	('lung carcinoma', 'Disease', (30, 44))	('YAP 1', 'Gene', (66, 71))	('correlated', 'Reg', (133, 143))	('lymph node metastasis', 'Disease', (149, 170))	('patients', 'Species', '9606', (244, 252))	('lymph node metastasis', 'Disease', 'MESH:D009362', (149, 170))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (19, 44))
34816	23870412	Importantly, positive expression of YAP 1 was a strong and independent predictor of short overall survival of UCB patients, as evidenced by the Kaplan-Meier curves and multivariate Cox proportional hazards regression analysis.	('YAP 1', 'Gene', (36, 41))	('positive expression', 'Var', (13, 32))	('short', 'NegReg', (84, 89))	('patients', 'Species', '9606', (114, 122))	('UCB', 'Disease', (110, 113))	('UCB', 'Phenotype', 'HP:0006740', (110, 113))	('overall survival', 'MPA', (90, 106))
34821	23870412	Moreover, YAP 1 overexpression stimulates proliferation and increases the saturation cell density in monolayer cultures of NIH-3T3 cells.	('proliferation', 'CPA', (42, 55))	('NIH-3T3', 'CellLine', 'CVCL:0594', (123, 130))	('YAP 1', 'Gene', (10, 15))	('saturation cell density', 'CPA', (74, 97))	('overexpression', 'Var', (16, 30))	('stimulates', 'PosReg', (31, 41))	('increases', 'PosReg', (60, 69))
34844	33006377	6 ,  8  Figure 1 summarizes all detected genomic alterations; single-nucleotide variants (SNVs), indels, allelic imbalance (AI), amplifications and homozygous deletions.	('homozygous deletions', 'Var', (148, 168))	('indels', 'Var', (97, 103))	('amplifications', 'Var', (129, 143))	('allelic imbalance', 'Disease', (105, 122))	('single-nucleotide', 'Chemical', '-', (62, 79))	('imbalance', 'Phenotype', 'HP:0002172', (113, 122))	('single-nucleotide variants', 'Var', (62, 88))
34853	33006377	The frequencies of hotspot mutations in TERT promoter (pTERT) have not been included in the TCGA data set.	('mutations', 'Var', (27, 36))	('TERT', 'Gene', '7015', (40, 44))	('TERT', 'Gene', (56, 60))	('TERT', 'Gene', (40, 44))	('TERT', 'Gene', '7015', (56, 60))
34854	33006377	We completed the data set by adding reported frequencies of pTERT C228T (64%) and C250T (13%) mutations from a study by Allory et al.	('C228T', 'Mutation', 'rs755521855', (66, 71))	('C228T', 'Var', (66, 71))	('TERT', 'Gene', (61, 65))	('TERT', 'Gene', '7015', (61, 65))	('C250T', 'Mutation', 'rs80358515', (82, 87))	('C250T', 'Var', (82, 87))
34859	33006377	Patient XIII, diagnosed with Lynch syndrome (LS), only shared a Fibroblast Growth Factor Receptor (FGFR)-3 mutation (p.R248C; c.742C>T) between both tumors.	('p.R248C; c.742C>T', 'Var', (117, 134))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('FGFR)-3', 'Gene', (99, 106))	('Lynch syndrome', 'Disease', (29, 43))	('p.R248C', 'Mutation', 'rs121913482', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Lynch syndrome', 'Disease', 'MESH:D003123', (29, 43))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('Fibroblast Growth Factor', 'molecular_function', 'GO:0005104', ('64', '88'))	('c.742C>T', 'Mutation', 'rs121913482', (126, 134))	('Patient', 'Species', '9606', (0, 7))
34865	33006377	Exposure to aristocholic acid was linked to tumor development in all five patients, which possibly affected the entire urothelium leading to field cancerization.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('patients', 'Species', '9606', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('aristocholic acid', 'Chemical', '-', (12, 29))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('linked to', 'Reg', (34, 43))	('cancer', 'Disease', (147, 153))	('tumor', 'Disease', (44, 49))	('aristocholic', 'Var', (12, 24))
34871	33006377	Pertinently, recent work proposed enrichment of the FGFR3 p.R248C amino acid substitution in LS-linked UTUC, and so it is debatable whether this shared alteration alone indicates a clonal relationship in Patient XIII.	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('Patient', 'Species', '9606', (204, 211))	('FGFR3', 'Gene', (52, 57))	('p.R248C amino acid', 'Var', (58, 76))	('p.R248C', 'Mutation', 'rs121913482', (58, 65))
34928	33115513	Following MYC inactivation, tumors undergo various proliferative arrests, cell differentiation, and apoptosis, thus inhibiting tumor occurrence.	('inhibiting', 'NegReg', (116, 126))	('tumor', 'Disease', (28, 33))	('inactivation', 'Var', (14, 26))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('MYC', 'Gene', (10, 13))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('cell differentiation', 'biological_process', 'GO:0030154', ('74', '94'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('apoptosis', 'CPA', (100, 109))	('proliferative arrests', 'CPA', (51, 72))	('tumors', 'Disease', (28, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('MYC', 'Gene', '4609', (10, 13))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('tumor', 'Disease', (127, 132))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('cell differentiation', 'CPA', (74, 94))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
34930	33115513	have demonstrated that MYC inactivation triggers stem cell differentiation, while its reactivation can restore their tumor characteristics.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('stem cell differentiation', 'biological_process', 'GO:0048863', ('49', '74'))	('inactivation', 'Var', (27, 39))	('triggers', 'Reg', (40, 48))	('tumor', 'Disease', (117, 122))	('MYC', 'Gene', '4609', (23, 26))	('MYC', 'Gene', (23, 26))	('stem cell differentiation', 'CPA', (49, 74))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
34931	33115513	Therefore, although the inactivation of oncogenes restores normal cells, some cells retain their potential of becoming cancerous, possibly existing in a tumor dormant state.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('cancerous', 'Disease', 'MESH:D009369', (119, 128))	('inactivation', 'Var', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('normal cells', 'MPA', (59, 71))	('cancerous', 'Disease', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
34934	33115513	KMT1A protein directly catalyzes the trimethylation modification (H3K9me3) of the 9th lysine of histone H3 in the promoter region of the GATA3 gene (- 1351 to approximately - 1172), thereby inhibiting its transcription.	('GATA3', 'Gene', '2625', (137, 142))	('KMT1A', 'Gene', (0, 5))	('lysine', 'Chemical', 'MESH:D008239', (86, 92))	('KMT1A', 'Gene', '6839', (0, 5))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('- 1351 to approximately - 1172', 'Var', (149, 179))	('transcription', 'MPA', (205, 218))	('GATA3', 'Gene', (137, 142))	('inhibiting', 'NegReg', (190, 200))	('trimethylation modification', 'MPA', (37, 64))	('transcription', 'biological_process', 'GO:0006351', ('205', '218'))
34935	33115513	The GATA3 protein can directly bind to the promoter region (- 1710 to approximately - 1530) of the STAT3 gene inhibiting its transcription.	('STAT3', 'Gene', '6774', (99, 104))	('transcription', 'MPA', (125, 138))	('transcription', 'biological_process', 'GO:0006351', ('125', '138'))	('inhibiting', 'NegReg', (110, 120))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('- 1710', 'Var', (60, 66))	('STAT3', 'Gene', (99, 104))	('GATA3', 'Gene', (4, 9))	('GATA3', 'Gene', '2625', (4, 9))
35002	33115513	Inactivation, mutations, and deletions of TP53 and RB1 are one of the primary causes of BLCA.	('TP53', 'Gene', '7157', (42, 46))	('RB1', 'Gene', (51, 54))	('BLCA', 'Phenotype', 'HP:0009725', (88, 92))	('causes', 'Reg', (78, 84))	('BLCA', 'Disease', (88, 92))	('TP53', 'Gene', (42, 46))	('RB1', 'Gene', '5925', (51, 54))	('deletions', 'Var', (29, 38))	('mutations', 'Var', (14, 23))	('Inactivation', 'Var', (0, 12))
35004	33115513	However, the mutation frequency of STAG2, one of the most commonly mutated genes in BLCA, in SCE_L (24%) was significantly higher than that of SCE_M (11%) and SCE_H (9%).	('SCE_L', 'Gene', (93, 98))	('SCE_L', 'Gene', '8796', (93, 98))	('BLCA', 'Phenotype', 'HP:0009725', (84, 88))	('STAG2', 'Gene', (35, 40))	('SCE_H', 'Gene', (159, 164))	('STAG2', 'Gene', '10735', (35, 40))	('SCE_H', 'Gene', '1892', (159, 164))	('mutation', 'Var', (13, 21))	('higher', 'PosReg', (123, 129))
35005	33115513	In the identified EMT pathways, the mutation frequency of COL6A3, LRP1, and FBN2 in SCE_L (12%, 12%, and 13%, respectively) was significantly higher than that of SCE_M (3%, 6%, and 5%, respectively) and SCE_H (7%, 4%, and 4%, respectively).	('SCE_H', 'Gene', '1892', (203, 208))	('COL6A3', 'Gene', (58, 64))	('EMT', 'CPA', (18, 21))	('SCE_L', 'Gene', (84, 89))	('FBN2', 'Gene', '2201', (76, 80))	('LRP1', 'Gene', (66, 70))	('COL6A3', 'Gene', '1293', (58, 64))	('SCE_L', 'Gene', '8796', (84, 89))	('SCE_H', 'Gene', (203, 208))	('FBN2', 'Gene', (76, 80))	('LRP1', 'Gene', '4035', (66, 70))	('EMT', 'biological_process', 'GO:0001837', ('18', '21'))	('higher', 'PosReg', (142, 148))	('mutation', 'Var', (36, 44))
35006	33115513	In the hypoxia pathway, no MYH9 mutation was observed in SCE_L (0%), while the mutation frequencies in SCE_M and SCE_H were 5% and 8%, respectively.	('MYH9', 'Gene', '4627', (27, 31))	('hypoxia', 'Disease', 'MESH:D000860', (7, 14))	('SCE_L', 'Gene', (57, 62))	('hypoxia', 'Disease', (7, 14))	('MYH9', 'Gene', (27, 31))	('SCE_H', 'Gene', (113, 118))	('SCE_L', 'Gene', '8796', (57, 62))	('SCE_H', 'Gene', '1892', (113, 118))	('mutation', 'Var', (32, 40))
35007	33115513	In addition, the mutation frequencies of CDKN1A in SCE_L, SCE_M, and SCE_H were 13%, 11%, and 6%, respectively, and in the KRAS signaling pathway, the mutation frequencies of RELN in SCE_L, SCE_M, and SCE_H were 12%, 6%, and 5%, respectively (Fig.	('RELN', 'Gene', '5649', (175, 179))	('RELN', 'Gene', (175, 179))	('SCE_L', 'Gene', '8796', (51, 56))	('SCE_H', 'Gene', '1892', (69, 74))	('SCE_L', 'Gene', (183, 188))	('SCE_L', 'Gene', '8796', (183, 188))	('SCE_H', 'Gene', (201, 206))	('mutation', 'Var', (17, 25))	('signaling pathway', 'biological_process', 'GO:0007165', ('128', '145'))	('CDKN1A', 'Gene', '1026', (41, 47))	('CDKN1A', 'Gene', (41, 47))	('KRAS', 'Gene', (123, 127))	('SCE_H', 'Gene', '1892', (201, 206))	('KRAS', 'Gene', '3845', (123, 127))	('SCE_H', 'Gene', (69, 74))	('SCE_L', 'Gene', (51, 56))
35048	33115513	COL6A3 silencing inhibits cell proliferation and angiopoiesis, which is consistent with COL6A3 having a lower mutation rate in SCE_H and SCE_M, and a higher mutation rate in SCE_L.	('inhibits', 'NegReg', (17, 25))	('COL6A3', 'Gene', (0, 6))	('higher', 'PosReg', (150, 156))	('cell proliferation', 'biological_process', 'GO:0008283', ('26', '44'))	('COL6A3', 'Gene', '1293', (0, 6))	('angiopoiesis', 'CPA', (49, 61))	('SCE_L', 'Gene', '8796', (174, 179))	('lower', 'NegReg', (104, 109))	('COL6A3', 'Gene', (88, 94))	('COL6A3', 'Gene', '1293', (88, 94))	('SCE_L', 'Gene', (174, 179))	('cell proliferation', 'CPA', (26, 44))	('SCE_H', 'Gene', (127, 132))	('silencing', 'Var', (7, 16))	('mutation', 'MPA', (110, 118))	('SCE_H', 'Gene', '1892', (127, 132))
35098	32009946	The cluster analysis showed that regimens such as cisplatin, MCAVI, CP, LC, and DC had fewer SAEs but were also less effective.	('MCAVI', 'Disease', (61, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('cisplatin', 'Var', (50, 59))
35134	32009946	However, after classification by Hsp27 level, subgrouped patients with <5.7 ng/ml and < = 20.5% exhibited an obvious survival benefit after apatorsen treatment.	('Hsp27', 'Gene', (33, 38))	('benefit', 'PosReg', (126, 133))	('<5.7 ng/ml', 'Var', (71, 81))	('patients', 'Species', '9606', (57, 65))	('survival', 'CPA', (117, 125))	('Hsp27', 'Gene', '3315', (33, 38))
35189	30961555	The Kaplan-Meier method was used to estimate renal survival rates of the histological GGS normal and abnormal groups and test the difference between these two groups by log-rank test.	('GGS', 'Phenotype', 'HP:0004737', (86, 89))	('abnormal', 'Var', (101, 109))	('renal survival', 'CPA', (45, 59))	('rat', 'Species', '10116', (60, 63))
35208	30961555	Competitive survival regression analysis after stepwise selection showed hypertension (p = 0.004), pre-existing CKD (p = 0.019), or abnormal GGS rate (p = 0.041) were risk factors associated with adverse renal outcomes (Table 3).	('CKD', 'Phenotype', 'HP:0012622', (112, 115))	('abnormal', 'Var', (132, 140))	('hypertension', 'Disease', 'MESH:D006973', (73, 85))	('pre', 'molecular_function', 'GO:0003904', ('99', '102'))	('hypertension', 'Disease', (73, 85))	('rat', 'Species', '10116', (145, 148))	('GGS', 'Phenotype', 'HP:0004737', (141, 144))	('hypertension', 'Phenotype', 'HP:0000822', (73, 85))
35212	30961555	Patients with hypertension, pre-existing CKD before unilateral nephrectomy and abnormal GGS rates had a higher risk of creatinine doubling or developing ESRD within 5 years in not only UTUC but RCC patients.	('creatinine', 'Chemical', 'MESH:D003404', (119, 129))	('creatinine doubling', 'MPA', (119, 138))	('patients', 'Species', '9606', (198, 206))	('ESRD', 'Disease', 'MESH:D007676', (153, 157))	('pre', 'molecular_function', 'GO:0003904', ('28', '31'))	('hypertension', 'Disease', 'MESH:D006973', (14, 26))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('RCC', 'Disease', (194, 197))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('rat', 'Species', '10116', (92, 95))	('Patients', 'Species', '9606', (0, 8))	('ESRD', 'Disease', (153, 157))	('GGS', 'Phenotype', 'HP:0004737', (88, 91))	('hypertension', 'Disease', (14, 26))	('CKD', 'Phenotype', 'HP:0012622', (41, 44))	('hypertension', 'Phenotype', 'HP:0000822', (14, 26))	('CKD', 'Var', (41, 44))	('ESRD', 'Phenotype', 'HP:0003774', (153, 157))
35231	30961555	Aristolochic acid (AA), a compound that is known to cause chronic kidney disease and urothelial carcinoma, has been purposed as a possible cause.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('Aristolochic acid', 'Chemical', 'MESH:C000228', (0, 17))	('chronic kidney disease', 'Disease', 'MESH:D051436', (58, 80))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (85, 105))	('kidney disease', 'Phenotype', 'HP:0000112', (66, 80))	('urothelial carcinoma', 'Disease', (85, 105))	('cause', 'Reg', (52, 57))	('Aristolochic', 'Var', (0, 12))	('chronic kidney disease', 'Disease', (58, 80))	('chronic kidney', 'Phenotype', 'HP:0012622', (58, 72))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (58, 80))
35260	30961555	According to our results, the UTUC patients frequently suffered from pre-existing CKD and TI nephropathy than RCC ones, but UTUC ones with worse renal function had higher risk of abnormal GGS rate, and abnormal GGS Rate is histopathological predictor of creatinine doubling or dialysis within 5 years in not only UTUC patients but RCC ones.	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('RCC', 'Disease', (331, 334))	('RCC', 'Phenotype', 'HP:0005584', (331, 334))	('GGS', 'Phenotype', 'HP:0004737', (211, 214))	('suffered from', 'Reg', (55, 68))	('creatinine doubling', 'Disease', (254, 273))	('nephropathy', 'Phenotype', 'HP:0000112', (93, 104))	('pre', 'molecular_function', 'GO:0003904', ('69', '72'))	('CKD', 'Disease', (82, 85))	('RCC', 'Disease', 'MESH:C538614', (331, 334))	('CKD', 'Phenotype', 'HP:0012622', (82, 85))	('patients', 'Species', '9606', (35, 43))	('abnormal', 'Var', (202, 210))	('nephropathy', 'Disease', (93, 104))	('RCC', 'Disease', (110, 113))	('nephropathy', 'Disease', 'MESH:D007674', (93, 104))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('creatinine', 'Chemical', 'MESH:D003404', (254, 264))	('patients', 'Species', '9606', (318, 326))	('rat', 'Species', '10116', (192, 195))	('GGS', 'Phenotype', 'HP:0004737', (188, 191))	('dialysis', 'Disease', (277, 285))	('abnormal GGS rate', 'MPA', (179, 196))
35270	30961555	Conceived and designed the experiments: S-WN, M-CK, W-JW, L-TC and S-JH.	('men', 'Species', '9606', (33, 36))	('L-TC', 'Var', (58, 62))	('M-CK', 'Gene', (46, 50))	('M-CK', 'Gene', '1158', (46, 50))	('S-JH', 'Var', (67, 71))	('L-TC', 'Chemical', 'MESH:D017997', (58, 62))
35272	30961555	Performed the experiments, contributed reagents/materials/analysis tools and histopathologic analysis: S-WN, S-MY and P-IL.	('S-MY', 'Var', (109, 113))	('P-IL', 'Gene', (118, 122))	('P-IL', 'Gene', '390502', (118, 122))	('men', 'Species', '9606', (20, 23))
35294	30565086	Non-muscle-invasive urothelial carcinomas characterized by activation of the receptor tyrosine kinase-Ras pathway, activating mutations in HRAS or fibroblast growth factor receptor 3 (FGFR3) genes.	('tyrosine', 'Chemical', 'MESH:D014443', (86, 94))	('fibroblast growth factor receptor 3', 'Gene', (147, 182))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('147', '171'))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('FGFR3', 'Gene', '2261', (184, 189))	('HRAS', 'Gene', '3265', (139, 143))	('Non-muscle-invasive urothelial carcinomas', 'Disease', 'MESH:D009217', (0, 41))	('activating', 'PosReg', (115, 125))	('HRAS', 'Gene', (139, 143))	('mutations', 'Var', (126, 135))	('FGFR3', 'Gene', (184, 189))	('fibroblast growth factor receptor 3', 'Gene', '2261', (147, 182))	('FGFR', 'molecular_function', 'GO:0005007', ('184', '188'))	('activation', 'PosReg', (59, 69))	('Non-muscle-invasive urothelial carcinomas', 'Disease', (0, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
35298	30565086	From a normal urothelium, loss of heterozygosity (LOH) of chromosome 9 has been associated with most urothelial cancers with two main pathways for their development: Fifty-eight genes were significantly mutated; these genes included TP53, KTDM2D, KDM6A, PIK3CA, RB1, and FGFR3.	('RB1', 'Gene', (262, 265))	('FGFR3', 'Gene', '2261', (271, 276))	('PIK3CA', 'Gene', '5290', (254, 260))	('associated', 'Reg', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('KDM6A', 'Gene', (247, 252))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('KTDM2D', 'Gene', (239, 245))	('urothelial cancers', 'Disease', (101, 119))	('RB1', 'Gene', '5925', (262, 265))	('men', 'Species', '9606', (160, 163))	('TP53', 'Gene', (233, 237))	('PIK3CA', 'Gene', (254, 260))	('FGFR', 'molecular_function', 'GO:0005007', ('271', '275'))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))	('urothelial cancers', 'Disease', 'MESH:D014523', (101, 119))	('loss of heterozygosity', 'Var', (26, 48))	('FGFR3', 'Gene', (271, 276))	('KDM6A', 'Gene', '7403', (247, 252))	('TP53', 'Gene', '7157', (233, 237))
35299	30565086	Mutations in the p53/RB tumor suppressor pathway were seen in nearly 90% of tumors and alterations in the PI3K/AKT/mTOR and RTK/RAS signaling pathways were observed in 71%.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('RB tumor', 'Disease', (21, 29))	('alterations', 'Reg', (87, 98))	('mTOR', 'Gene', (115, 119))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('AKT', 'Gene', (111, 114))	('p53', 'Gene', (17, 20))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('mTOR', 'Gene', '2475', (115, 119))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('Mutations', 'Var', (0, 9))	('AKT', 'Gene', '207', (111, 114))	('RTK/RAS signaling pathways', 'Pathway', (124, 150))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('RB tumor', 'Disease', 'MESH:D012175', (21, 29))	('tumors', 'Disease', (76, 82))	('PI3K', 'molecular_function', 'GO:0016303', ('106', '110'))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('p53', 'Gene', '7157', (17, 20))
35300	30565086	MIBC exhibits high overall mutation rates, which appears to be associated with mutation signatures for an endogenous mutagenic enzyme, APOBEC cytidine deaminase.	('MIBC', 'Gene', (0, 4))	('cytidine deaminase', 'Gene', '978', (142, 160))	('MIBC', 'Chemical', '-', (0, 4))	('mutation', 'Var', (27, 35))	('APOBEC', 'cellular_component', 'GO:0030895', ('135', '141'))	('cytidine deaminase', 'Gene', (142, 160))
35302	30565086	Epigenetic changes were observed in nearly 90% of tumors.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('observed', 'Reg', (24, 32))	('tumors', 'Disease', (50, 56))	('Epigenetic changes', 'Var', (0, 18))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
35310	30565086	The Lund group identified two major molecular subtypes, designated MS1 and MS2, displaying differences in the number of genomic alterations, including FGFR3 and TP53 mutations.	('TP53', 'Gene', (161, 165))	('mutations', 'Var', (166, 175))	('FGFR3', 'Gene', '2261', (151, 156))	('MS2', 'Gene', '100271694', (75, 78))	('FGFR', 'molecular_function', 'GO:0005007', ('151', '155'))	('MS1', 'Gene', '4397', (67, 70))	('MS1', 'Gene', (67, 70))	('FGFR3', 'Gene', (151, 156))	('MS2', 'Gene', (75, 78))	('TP53', 'Gene', '7157', (161, 165))
35311	30565086	Luminal-papillary enriched with FGFR3 alterations; papillary histology.	('FGFR3', 'Gene', (32, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('FGFR3', 'Gene', '2261', (32, 37))	('alterations', 'Var', (38, 49))	('papillary histology', 'Phenotype', 'HP:0007482', (51, 70))
35315	30565086	The TCGA study identified five expression subtypes: In conclusion, the TCGA study confirmed the existence of luminal (KRT20+, GATA3+, FOXA1+) and basal (KRT5,6,14+, GATA3-, FOXA1-) transcriptional subtypes, as well as identifying luminal and neuronal subtypes.	('KRT20', 'Gene', (118, 123))	('KRT5,6,14+', 'Var', (153, 163))	('FOXA1', 'Gene', '3169', (173, 178))	('GATA3', 'Gene', '2625', (165, 170))	('CG', 'Chemical', '-', (72, 74))	('GATA3', 'Gene', '2625', (126, 131))	('TCGA', 'Gene', (71, 75))	('FOXA1', 'Gene', '3169', (134, 139))	('GATA3', 'Gene', (126, 131))	('KRT20', 'Gene', '54474', (118, 123))	('FOXA1', 'Gene', (173, 178))	('CG', 'Chemical', '-', (5, 7))	('GATA3', 'Gene', (165, 170))	('FOXA1', 'Gene', (134, 139))
35335	30565086	In retrospective studies, CG (cisplatin/gemcitabine) has demonstrated complete pathological response (pCR) rates similar to those of MVAC, albeit with a better toxicity profile, and ddMVAC provides higher (pCR) and improved survival rates with respect to CG.	('CG', 'Chemical', '-', (255, 257))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('survival', 'CPA', (224, 232))	('MVAC', 'Chemical', '-', (184, 188))	('CR', 'Chemical', 'MESH:D002857', (207, 209))	('toxicity', 'Disease', 'MESH:D064420', (160, 168))	('MVAC', 'Chemical', '-', (133, 137))	('ddMVAC', 'Chemical', '-', (182, 188))	('CG', 'Chemical', '-', (26, 28))	('improved', 'PosReg', (215, 223))	('gemcitabine', 'Chemical', 'MESH:C056507', (40, 51))	('ddMVAC', 'Var', (182, 188))	('toxicity', 'Disease', (160, 168))	('higher', 'PosReg', (198, 204))	('CR', 'Chemical', 'MESH:D002857', (103, 105))
35425	30565086	Aberrant activity of the pathway is associated with developmental defects that disrupt organogenesis, impair the response to injury, and result in metabolic disorders, and cancer.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('impair', 'NegReg', (102, 108))	('disrupt', 'NegReg', (79, 86))	('developmental defects', 'Disease', (52, 73))	('developmental defects', 'Disease', 'MESH:D003147', (52, 73))	('organogenesis', 'MPA', (87, 100))	('metabolic disorders', 'Disease', 'MESH:D008659', (147, 166))	('Aberrant activity', 'Var', (0, 17))	('result in', 'Reg', (137, 146))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('metabolic disorders', 'Disease', (147, 166))	('associated', 'Reg', (36, 46))	('organogenesis', 'biological_process', 'GO:0048513', ('87', '100'))	('response to', 'CPA', (113, 124))
35426	30565086	In the open-label, phase II study BLC2001 presented at the 2018 ASCO Annual Symposium, erdafitinib, an oral pan-FGFR tyrosine kinase inhibitor, was tested in 96 patients with metastatic or unresectable urothelial carcinoma and FGFR alterations (mutation in FGFR3 or fusion in FGFR2 or FGFR3).	('urothelial carcinoma', 'Disease', 'MESH:D014526', (202, 222))	('FGFR', 'molecular_function', 'GO:0005007', ('285', '289'))	('FGFR', 'molecular_function', 'GO:0005007', ('112', '116'))	('FGFR', 'molecular_function', 'GO:0005007', ('257', '261'))	('FGFR3', 'Gene', (285, 290))	('fusion', 'Var', (266, 272))	('tyrosine', 'Chemical', 'MESH:D014443', (117, 125))	('FGFR3', 'Gene', '2261', (285, 290))	('erdafitinib', 'Chemical', 'MESH:C000604580', (87, 98))	('FGFR', 'molecular_function', 'GO:0005007', ('227', '231'))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('FGFR2', 'Gene', (276, 281))	('FGFR', 'molecular_function', 'GO:0005007', ('276', '280'))	('patients', 'Species', '9606', (161, 169))	('FGFR3', 'Gene', (257, 262))	('urothelial carcinoma', 'Disease', (202, 222))	('mutation', 'Var', (245, 253))	('FGFR3', 'Gene', '2261', (257, 262))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('126', '142'))	('FGFR2', 'Gene', '2263', (276, 281))
35454	28588243	We develop a novel method called mCGfinder to efficiently detect mutated cancer genes in tumour samples with inter-patient heterogeneity.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', (89, 95))	('patient', 'Species', '9606', (115, 122))	('mutated', 'Var', (65, 72))
35456	28588243	All the results demonstrate that mCGfinder is an efficient method in detecting mutated cancer genes.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutated', 'Var', (79, 86))
35462	28588243	These mutated cancer genes are not likely to display significant mutational recurrence due to inter-patient heterogeneity, and consequently they may be underestimated by the frequency-based methods.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('patient', 'Species', '9606', (100, 107))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('mutated', 'Var', (6, 13))
35463	28588243	A prominent explanation of inter-patient heterogeneity is that the behavior of key pathways of tumour samples is perturbed by mutated cancer genes, and only a subset of genes in these pathways are mutated in a given sample.	('patient', 'Species', '9606', (33, 40))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('perturbed', 'Reg', (113, 122))	('cancer', 'Disease', (134, 140))	('tumour', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('behavior', 'MPA', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mutated', 'Var', (126, 133))
35468	28588243	Despite the success achieved by the aforementioned approaches, another important aspect contributing to inter-patient heterogeneity is that some cancer genes in different perturbed pathways are mutated in different subsets of samples, which has been observed in recent studies.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('patient', 'Species', '9606', (110, 117))	('mutated', 'Var', (194, 201))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
35470	28588243	If some mutated cancer genes are associated with only a subset of samples, these genes may not exhibit significant mutational recurrence in all samples even in consideration of the mutational influence from their network context.	('mutated', 'Var', (8, 15))	('cancer', 'Disease', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
35477	28588243	Notably, mCGfinder yields substantially smaller p-values (e.g., p-value = 1.24e-17 for breast cancer) than other existing network-based approaches across all investigated cancers.	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('p-values', 'MPA', (48, 56))	('mCGfinder', 'Var', (9, 18))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancers', 'Disease', (171, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('smaller', 'NegReg', (40, 47))
35479	28588243	All the results indicate the efficiency of mCGfinder in detecting mutated cancer genes in heterogeneous tumour samples.	('mutated', 'Var', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumour', 'Disease', (104, 110))
35489	28588243	Taking BRCA as an example, HotNet2 and ReMIC obtain p-values of 1.08e-05 (8 CGC genes) and 1.04e-03 (5 CGC genes) respectively, which suggest that these results are significantly different than random selection.	('BRCA', 'Phenotype', 'HP:0003002', (7, 11))	('BRCA', 'Gene', (7, 11))	('BRCA', 'Gene', '672', (7, 11))	('1.04e-03', 'Var', (91, 99))
35492	28588243	Literature survey shows that AKT1 gene is implicated as significantly mutated gene in breast cancer in a previous study, and mutations of BRCA2 gene are reported to be involved in the primary events of breast carcinogenesis.	('mutations', 'Var', (125, 134))	('BRCA2', 'Gene', '675', (138, 143))	('breast carcinogenesis', 'Disease', (202, 223))	('BRCA', 'Phenotype', 'HP:0003002', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (202, 223))	('involved', 'Reg', (168, 176))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('AKT1', 'Gene', '207', (29, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('BRCA2', 'Gene', (138, 143))	('AKT1', 'Gene', (29, 33))
35493	28588243	In the three other types of cancers, mCGfinder also provides high enrichment for CGC genes, with associated p-values of 1.91e-08 in BLCA (8 CGC genes), 4.91e-14 in GBM (12 CGC genes), 1.46e-08 in HNSC (9 CGC genes) and 5.57e-16 in LAML (10 CGC genes).	('cancers', 'Disease', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('CGC genes', 'Gene', (81, 90))	('BLCA', 'Chemical', '-', (132, 136))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('BLCA', 'Disease', (132, 136))	('4.91e-14', 'Var', (152, 160))	('1.46e-08', 'Var', (184, 192))
35523	28588243	Developing efficient methods to detect cancer genes from inter-patient heterogeneous tumour samples is an challenging task, and a major obstacle is the fact that some cancer genes are mutated in perturbed pathways associated with only a subset of samples.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Disease', (85, 91))	('cancer', 'Disease', (167, 173))	('mutated', 'Var', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('patient', 'Species', '9606', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
35525	28588243	In this paper, based on the combination of matrix decomposition framework and information from gene interaction network, we propose a novel method which is capable of detecting mutated cancer genes in a subset of samples.	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('mutated', 'Var', (177, 184))
35532	28588243	These results suggest that it may be worth using both mCGfinder and the existing methods to maximize the detection rate of mutated cancer genes.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutated', 'Var', (123, 130))
35536	28588243	Furthermore, a promising expansion to the mCGfinder in future work would be to integrate information from not only gene interactions, but also different types of information such as copy number alternation, gene expression and DNA methylation, which would offer an opportunity to comprehensively understand cancer events from a multi-omics view.	('cancer', 'Disease', (307, 313))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('DNA methylation', 'biological_process', 'GO:0006306', ('227', '242'))	('DNA', 'cellular_component', 'GO:0005574', ('227', '230'))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('copy', 'Var', (182, 186))	('gene expression', 'biological_process', 'GO:0010467', ('207', '222'))
35538	28588243	Altogether, mutational profile analysis from mCGfinder and further experimental follow-up may help take a step forward to a more comprehensive knowledge of the cancer genome.	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('mutational', 'Var', (12, 22))
35592	26555878	This multicenter retrospective study identified four independent prognostic factors of poorer overall survival: high PS, presence of visceral metastases, abnormal levels of hemoglobin and early PD.	('abnormal levels of hemoglobin', 'Phenotype', 'HP:0011902', (154, 183))	('PD', 'Disease', 'MESH:D010300', (194, 196))	('high PS', 'Disease', (112, 119))	('visceral metastases', 'Disease', (133, 152))	('visceral metastases', 'Disease', 'MESH:D009362', (133, 152))	('abnormal', 'Var', (154, 162))
35722	32201516	Siglec-15 mutations are widely observed in tumors and interact with different genes in different cancer types.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('interact', 'Reg', (54, 62))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('mutations', 'Var', (10, 19))	('Siglec-15', 'Gene', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
35744	32201516	It has a collection of data on millions of coding mutations, noncoding mutations, genomic rearrangements, fusion genes, copy number abnormalities and gene expression variants in the human genome all in one database so that researchers can explore these data more easily.	('gene expression', 'biological_process', 'GO:0010467', ('150', '165'))	('human', 'Species', '9606', (182, 187))	('copy number abnormalities', 'Disease', 'MESH:D007674', (120, 145))	('copy number abnormalities', 'Disease', (120, 145))	('variants', 'Var', (166, 174))
35745	32201516	In this study, COSMIC was used to investigate the mutations of Siglec-15 in human cancers, and the results are depicted in pie charts.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Siglec-15', 'Gene', (63, 72))	('mutations', 'Var', (50, 59))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('human', 'Species', '9606', (76, 81))	('cancers', 'Disease', 'MESH:D009369', (82, 89))
35758	32201516	COSMIC provided information on Siglec-15 mutations in different cancers, which included substitution missense, nonsense and synonymous mutations, and the results are depicted in pie charts.	('mutations', 'Var', (41, 50))	('Siglec-15', 'Gene', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('substitution missense', 'Var', (88, 109))	('nonsense', 'Var', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
35759	32201516	Nonsense substitutions were found in biliary tract cancer (33.33%), breast cancer (25%) and lung cancer (16.67%), while substitution missense mutations were observed in biliary tract cancer (33.33%), breast cancer (75%), central nervous system cancer (33.33%), hematopoietic and lymphoid cancer (100%), endometrial cancer (100%), large intestine cancer (68.42%), liver cancer (25%), lung cancer (83.33%), esophageal cancer (75%), prostate cancer (100%), skin cancer (100%), stomach cancer (75%), thyroid cancer (100%) and upper aerodigestive tract cancer (60%).	('cancer', 'Disease', 'MESH:D009369', (459, 465))	('endometrial cancer', 'Disease', (303, 321))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('stomach cancer', 'Disease', (474, 488))	('lung cancer', 'Phenotype', 'HP:0100526', (383, 394))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('biliary tract cancer', 'Disease', (37, 57))	('cancer', 'Disease', 'MESH:D009369', (504, 510))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (388, 394))	('lymphoid cancer', 'Phenotype', 'HP:0002665', (279, 294))	('missense mutations', 'Var', (133, 151))	('cancer', 'Disease', (315, 321))	('central nervous system cancer', 'Phenotype', 'HP:0100006', (221, 250))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (37, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('biliary tract cancer', 'Disease', 'MESH:D001661', (37, 57))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', (504, 510))	('breast cancer', 'Disease', (200, 213))	('cancer', 'Disease', (416, 422))	('liver cancer', 'Phenotype', 'HP:0002896', (363, 375))	('liver cancer', 'Disease', (363, 375))	('lymphoid cancer', 'Disease', 'MESH:D009369', (279, 294))	('cancer', 'Disease', 'MESH:D009369', (482, 488))	('upper aerodigestive tract cancer', 'Disease', (522, 554))	('cancer', 'Disease', (288, 294))	('thyroid cancer', 'Disease', (496, 510))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('prostate cancer', 'Disease', 'MESH:D011471', (430, 445))	('prostate cancer', 'Phenotype', 'HP:0012125', (430, 445))	('cancer', 'Disease', (97, 103))	('central nervous system cancer', 'Disease', (221, 250))	('thyroid cancer', 'Disease', 'MESH:D013964', (496, 510))	('biliary tract cancer', 'Disease', (169, 189))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', (482, 488))	('cancer', 'Disease', (459, 465))	('nervous system cancer', 'Phenotype', 'HP:0004375', (229, 250))	('esophageal cancer', 'Disease', (405, 422))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (369, 375))	('substitutions', 'Var', (9, 22))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (169, 189))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('endometrial cancer', 'Phenotype', 'HP:0012114', (303, 321))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancer', 'Disease', 'MESH:D009369', (548, 554))	('skin cancer', 'Disease', 'MESH:D012878', (454, 465))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (51, 57))	('biliary tract cancer', 'Disease', 'MESH:D001661', (169, 189))	('cancer', 'Disease', 'MESH:D009369', (346, 352))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (522, 554))	('cancer', 'Disease', (548, 554))	('cancer', 'Disease', 'MESH:D009369', (439, 445))	('skin cancer', 'Disease', (454, 465))	('prostate cancer', 'Disease', (430, 445))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('stomach cancer', 'Disease', 'MESH:D013274', (474, 488))	('lymphoid cancer', 'Disease', (279, 294))	('lung cancer', 'Disease', (92, 103))	('large intestine cancer', 'Phenotype', 'HP:0100834', (330, 352))	('stomach cancer', 'Phenotype', 'HP:0012126', (474, 488))	('cancer', 'Disease', (346, 352))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('thyroid cancer', 'Phenotype', 'HP:0002890', (496, 510))	('central nervous system cancer', 'Disease', 'MESH:D002494', (221, 250))	('cancer', 'Disease', 'MESH:D009369', (388, 394))	('cancer', 'Disease', (439, 445))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('lung cancer', 'Disease', 'MESH:D008175', (383, 394))	('endometrial cancer', 'Disease', 'MESH:D016889', (303, 321))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (416, 422))	('esophageal cancer', 'Disease', 'MESH:D004938', (405, 422))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('skin cancer', 'Phenotype', 'HP:0008069', (454, 465))	('hematopoietic and', 'Disease', (261, 278))	('lung cancer', 'Disease', (383, 394))	('liver cancer', 'Disease', 'MESH:D006528', (363, 375))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('breast cancer', 'Disease', (68, 81))
35760	32201516	Additionally, synonymous substitution mutations appeared in biliary tract cancer (33.33%), central nervous system cancer (66.67%), large intestine cancer (36.84%), liver cancer (75%), esophageal cancer (25%), parathyroid cancer (100%), stomach cancer (25%) and upper aerodigestive tract cancer (40%).	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', (170, 176))	('liver cancer', 'Disease', 'MESH:D006528', (164, 176))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('upper aerodigestive tract cancer', 'Disease', (261, 293))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('thyroid cancer', 'Phenotype', 'HP:0002890', (213, 227))	('synonymous substitution mutations', 'Var', (14, 47))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('nervous system cancer', 'Phenotype', 'HP:0004375', (99, 120))	('liver cancer', 'Phenotype', 'HP:0002896', (164, 176))	('biliary tract cancer', 'Disease', (60, 80))	('liver cancer', 'Disease', (164, 176))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (261, 293))	('stomach cancer', 'Disease', 'MESH:D013274', (236, 250))	('stomach cancer', 'Phenotype', 'HP:0012126', (236, 250))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (184, 201))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('parathyroid cancer', 'Disease', 'MESH:D010282', (209, 227))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('large intestine cancer', 'Phenotype', 'HP:0100834', (131, 153))	('parathyroid cancer', 'Disease', (209, 227))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (195, 201))	('esophageal cancer', 'Disease', (184, 201))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (60, 80))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('central nervous system cancer', 'Disease', (91, 120))	('biliary tract cancer', 'Disease', 'MESH:D001661', (60, 80))	('parathyroid cancer', 'Phenotype', 'HP:0006780', (209, 227))	('appeared', 'Reg', (48, 56))	('central nervous system cancer', 'Phenotype', 'HP:0100006', (91, 120))	('cancer', 'Disease', (147, 153))	('stomach cancer', 'Disease', (236, 250))	('central nervous system cancer', 'Disease', 'MESH:D002494', (91, 120))	('cancer', 'Disease', (114, 120))
35761	32201516	C>T and G>A mutations were most common in the Siglec-15 coding strand, both of which were observed in eleven cancer types.	('G>A mutations', 'Var', (8, 21))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('C>T', 'Var', (0, 3))	('cancer', 'Disease', (109, 115))	('common', 'Reg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
35762	32201516	A>T and T>A mutations in Siglec-15 were not found in the TCGA cancer samples.	('T>A', 'Var', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Siglec-15', 'Gene', (25, 34))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
35763	32201516	Other types of base mutations occurred sporadically in different cancers (Figure 3a).	('base mutations', 'Var', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('occurred', 'Reg', (30, 38))	('cancers', 'Disease', (65, 72))
35777	32201516	Several lines of evidence have shown that interactions with sialic acid-binding receptors can influence cancer progression; for example, hypersialylation can induce changes in the physical properties of tumor cells and potentiate the evasion of apoptosis in cancer cells.	('tumor', 'Disease', (203, 208))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cancer', 'Disease', (104, 110))	('hypersialylation', 'Var', (137, 153))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('apoptosis', 'biological_process', 'GO:0097194', ('245', '254'))	('interactions', 'Interaction', (42, 54))	('apoptosis', 'biological_process', 'GO:0006915', ('245', '254'))	('influence', 'Reg', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('cancer', 'Disease', (258, 264))	('induce changes', 'Reg', (158, 172))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('potentiate', 'PosReg', (219, 229))	('sialic acid', 'Chemical', 'MESH:D019158', (60, 71))	('sialic acid-binding', 'molecular_function', 'GO:0033691', ('60', '79'))	('evasion', 'MPA', (234, 241))
35785	32201516	Additionally, knockdown of Siglec-15 expression did not cause obvious physical abnormalities but did inhibit tumor growth.	('Siglec-15', 'Gene', (27, 36))	('inhibit', 'NegReg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('knockdown', 'Var', (14, 23))	('tumor', 'Disease', (109, 114))
35786	32201516	Since no previous studies have focused on Siglec-15 mutations in human cancers, we explored this topic with the help of COSMIC and cBioPortal.	('mutations', 'Var', (52, 61))	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('Siglec-15', 'Gene', (42, 51))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
35787	32201516	As shown in Figure 3, the results from TCGA demonstrated that Siglec-15 mutations occurred widely in human cancers.	('mutations', 'Var', (72, 81))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Siglec-15', 'Gene', (62, 71))	('occurred', 'Reg', (82, 90))	('human', 'Species', '9606', (101, 106))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
35788	32201516	The most common type of Siglec-15 mutation was missense substitution, which could be observed in all tumors with mutations.	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Siglec-15', 'Gene', (24, 33))	('missense substitution', 'Var', (47, 68))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))
35789	32201516	At the base-pair level, C>T and G>A mutations were the most widely observed in tumors.	('observed', 'Reg', (67, 75))	('C>T', 'Var', (24, 27))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('G>A mutations', 'Var', (32, 45))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
35793	32201516	Alterations in the expression of Siglec-15 may cause a variety of gene changes across different cancers, which could lead to remarkably different results.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cause', 'Reg', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Alterations', 'Var', (0, 11))	('gene changes', 'MPA', (66, 78))	('Siglec-15', 'Gene', (33, 42))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))
35797	32201516	For cutaneous melanoma patients, high Siglec-15 expression indicates a high risk of tumor aggressiveness and adverse clinical outcomes.	('high', 'Var', (33, 37))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (84, 104))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('expression', 'MPA', (48, 58))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('Siglec-15', 'Protein', (38, 47))	('tumor aggressiveness', 'Disease', (84, 104))	('cutaneous melanoma', 'Disease', (4, 22))	('aggressiveness', 'Phenotype', 'HP:0000718', (90, 104))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (4, 22))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (4, 22))
35825	31927310	By correlating TP63 isoform expression with clinical outcomes, we find that while the DNp63 isoforms correlated with improved patient prognosis, the TAp63 isoforms correlated with worse patient prognosis in bladder, breast and lung cancers.	('TP63', 'Gene', '8626', (15, 19))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('bladder', 'Disease', (207, 214))	('breast and lung cancers', 'Disease', 'MESH:D001943', (216, 239))	('TAp63', 'Var', (149, 154))	('TP63', 'Gene', (15, 19))	('worse', 'NegReg', (180, 185))	('improved', 'PosReg', (117, 125))	('patient', 'Species', '9606', (126, 133))	('DNp63', 'Gene', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('patient', 'Species', '9606', (186, 193))	('lung cancers', 'Phenotype', 'HP:0100526', (227, 239))
35845	31927310	In MIBC, TP63 expression has been shown to be correlated with induction of EMT and worse patient outcomes and expression of DNp63 was shown to identify basal-subtype bladder cancers with aggressive clinical courses and poor prognosis.	('TP63', 'Gene', '8626', (9, 13))	('bladder cancers', 'Disease', (166, 181))	('MIBC', 'Disease', (3, 7))	('patient', 'Species', '9606', (89, 96))	('EMT', 'Gene', '3702', (75, 78))	('TP63', 'Gene', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('correlated', 'Reg', (46, 56))	('MIBC', 'Disease', 'MESH:D001749', (3, 7))	('bladder cancers', 'Phenotype', 'HP:0009725', (166, 181))	('EMT', 'biological_process', 'GO:0001837', ('75', '78'))	('bladder cancer', 'Phenotype', 'HP:0009725', (166, 180))	('DNp63', 'Gene', (124, 129))	('EMT', 'Gene', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('bladder cancers', 'Disease', 'MESH:D001749', (166, 181))	('expression', 'Var', (110, 120))
35849	31927310	Using previously annotated, as well as, un-annotated TP63 isoforms, we show that DNp63 is the most commonly expressed isoform type in bladder cancer and most other cancer types in the TCGA and find that high expression is generally associated with improved patient outcomes.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('improved', 'PosReg', (248, 256))	('TP63', 'Gene', '8626', (53, 57))	('bladder cancer', 'Disease', 'MESH:D001749', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patient', 'Species', '9606', (257, 264))	('TP63', 'Gene', (53, 57))	('bladder cancer', 'Disease', (134, 148))	('DNp63', 'Var', (81, 86))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('bladder cancer', 'Phenotype', 'HP:0009725', (134, 148))	('C', 'Chemical', 'MESH:D002244', (185, 186))	('cancer', 'Disease', (142, 148))
35850	31927310	Conversely, although less commonly expressed, TAp63 is associated with worse patient outcomes in bladder and other tumor types.	('TAp63', 'Var', (46, 51))	('bladder', 'Disease', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('patient', 'Species', '9606', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
35851	31927310	In bladder cancers, the favorable association of DNp63 was selectively observed in luminal tumors, whereas, the negative association of TAp63 was observed specifically in basal squamous tumor subtypes.	('squamous tumor', 'Disease', (177, 191))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('DNp63', 'Var', (49, 54))	('luminal tumors', 'Disease', 'MESH:D009369', (83, 97))	('bladder cancers', 'Disease', 'MESH:D001749', (3, 18))	('basal squamous tumor', 'Phenotype', 'HP:0002671', (171, 191))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('squamous tumor', 'Phenotype', 'HP:0002860', (177, 191))	('bladder cancers', 'Disease', (3, 18))	('luminal tumors', 'Disease', (83, 97))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('squamous tumor', 'Disease', 'MESH:D002294', (177, 191))	('bladder cancers', 'Phenotype', 'HP:0009725', (3, 18))
35870	31927310	For example, TAp63 isoform expression was calculated by adding together all TPM values for all TP63 isoforms with a 5p trans-activation domain (TAp63alpha, TAp63alphaP, TAp63beta, TAp63gamma, TAp63delta).	('TAp63gamma', 'Var', (180, 190))	('p63alpha', 'Gene', '8626', (158, 166))	('p63alpha', 'Gene', (158, 166))	('p63alpha', 'Gene', '8626', (146, 154))	('TP63', 'Gene', '8626', (95, 99))	('p63alpha', 'Gene', (146, 154))	('TAp63delta', 'Var', (192, 202))	('TAp63beta', 'Var', (169, 178))	('TP63', 'Gene', (95, 99))
35872	31927310	Initial investigation using Cox regression showed evidence of an association with survival in BLCA, BRCA, and LUSC patient cohorts with expression of TP63, DNp63, and TAp63 isoforms.	('C', 'Chemical', 'MESH:D002244', (28, 29))	('BLCA', 'Disease', (94, 98))	('C', 'Chemical', 'MESH:D002244', (96, 97))	('BRCA', 'Gene', '672', (100, 104))	('C', 'Chemical', 'MESH:D002244', (102, 103))	('BRCA', 'Gene', (100, 104))	('association', 'Interaction', (65, 76))	('Cox', 'Gene', '1351', (28, 31))	('TAp63', 'Var', (167, 172))	('Cox', 'Gene', (28, 31))	('TP63', 'Gene', (150, 154))	('DNp63', 'Var', (156, 161))	('TP63', 'Gene', '8626', (150, 154))	('BLCA', 'Disease', 'MESH:D001749', (94, 98))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('patient', 'Species', '9606', (115, 122))
35874	31927310	Genes were rank-ordered by negative log10 p-value from a Wilcoxon test to quantify differences in patient gene expression for patients with high or low TP63 isoform expression with negative fold changes represented as a negative score for ranking.	('TP63', 'Gene', (152, 156))	('patient', 'Species', '9606', (98, 105))	('TP63', 'Gene', '8626', (152, 156))	('gene expression', 'biological_process', 'GO:0010467', ('106', '121'))	('high', 'Var', (140, 144))	('patient', 'Species', '9606', (126, 133))	('patients', 'Species', '9606', (126, 134))	('low', 'NegReg', (148, 151))
35916	31927310	These un-annotated isoform variants are closely related to DNp63alpha and DNp63beta but harbor a 4 amino acid alternative splice junction acceptor site at the 3' end of exon 8 resulting in an alternative exon 8-9 junction (Fig.	('variants', 'Var', (27, 35))	('amino', 'Chemical', 'MESH:D000596', (99, 104))	('alternative exon 8-9 junction', 'MPA', (192, 221))	('p63alpha', 'Gene', '8626', (61, 69))	('p63alpha', 'Gene', (61, 69))
35917	31927310	This alternative exon 8-9 junction is present in TAp63alpha and DNp63delta (NM_001329148 and NM_001329149) forms, but is not present in Refgene or Encode gene definitions as a variant of DNp63alpha or DNp63beta isoforms.	('p63alpha', 'Gene', '8626', (189, 197))	('p63alpha', 'Gene', '8626', (51, 59))	('p63alpha', 'Gene', (189, 197))	('NM_001329148', 'Var', (76, 88))	('p63alpha', 'Gene', (51, 59))	('NM_001329149', 'Var', (93, 105))
35918	31927310	Here we will refer to these isoforms as DNp63alphaP (DNp63alpha prime) and DNp63betaP (DNp63beta prime).	('p63alpha', 'Gene', '8626', (42, 50))	('p63alpha', 'Gene', (42, 50))	('p63alpha', 'Gene', '8626', (55, 63))	('p63alpha', 'Gene', (55, 63))	('DNp63betaP', 'Var', (75, 85))
35919	31927310	To confirm that the DNp63alphaP and DNp63betaP isoforms were truly expressed in human bladder cancer, we designed PCR primers specific to their unique 8a-9 or 8b-9 exon junctions and the exon 12-13 junction (unique to alpha isoforms), exon 12-14 junction (beta isoforms) and for the exon 11b-14 junction (delta isoforms) (Fig.	('bladder cancer', 'Disease', (86, 100))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))	('C', 'Chemical', 'MESH:D002244', (115, 116))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('exon 11b-14', 'Var', (283, 294))	('human', 'Species', '9606', (80, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('p63alpha', 'Gene', (22, 30))	('p63alpha', 'Gene', '8626', (22, 30))
35921	31927310	PCR products for both p63alpha, p63beta and p63delta non-prime and prime isoforms were detectable in UM-UC14 and UM-UC5 but not 253J or UM-UC10 control bladder cancer cells (Fig.	('C', 'Chemical', 'MESH:D002244', (117, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (152, 166))	('p63beta', 'Var', (32, 39))	('bladder cancer', 'Disease', (152, 166))	('C', 'Chemical', 'MESH:D002244', (1, 2))	('p63delta', 'Var', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('bladder cancer', 'Phenotype', 'HP:0009725', (152, 166))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('p63alpha', 'Gene', (22, 30))	('C', 'Chemical', 'MESH:D002244', (140, 141))	('p63alpha', 'Gene', '8626', (22, 30))
35927	31927310	In bladder cancer, TP63 expression was dominated by DNp63 group isoforms (DNp63alpha, DNp63alphaP, DNp63beta, and DNp63betaP, DNp63gamma, DNp63delta, DNp63 deltaP) whereas TAp63 group isoforms (TAp63alpha, TAp63alphaP, TAp63beta, TAp63gamma and TAp63delta) were expressed in only a minority of patients (Fig.	('DNp63betaP', 'Var', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('TP63', 'Gene', '8626', (19, 23))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('p63alpha', 'Gene', '8626', (88, 96))	('p63alpha', 'Gene', '8626', (208, 216))	('DNp63beta', 'Var', (99, 108))	('p63alpha', 'Gene', (76, 84))	('DNp63delta', 'Var', (138, 148))	('p63alpha', 'Gene', '8626', (196, 204))	('p63alpha', 'Gene', (88, 96))	('p63alpha', 'Gene', (208, 216))	('DNp63gamma', 'Var', (126, 136))	('patients', 'Species', '9606', (294, 302))	('p63alpha', 'Gene', '8626', (76, 84))	('TP63', 'Gene', (19, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('p63alpha', 'Gene', (196, 204))
35929	31927310	In all three data sets, prime versions of DNp63alpha and DNp63beta demonstrated slightly less expression than non-prime analogs, although they were among the most highly expressed transcripts.	('DNp63beta', 'Var', (57, 66))	('p63alpha', 'Gene', '8626', (44, 52))	('expression', 'MPA', (94, 104))	('p63alpha', 'Gene', (44, 52))	('less', 'NegReg', (89, 93))
35941	31927310	Diseases with the highest TP63 gene level expression had, on average, the highest amounts of DNp63alpha, DNp63alphaP, DNp63beta and DNp63betaP with lower to moderate expression of TAp63 isoforms (Fig.	('expression', 'MPA', (42, 52))	('p63alpha', 'Gene', '8626', (107, 115))	('DNp63betaP', 'Var', (132, 142))	('p63alpha', 'Gene', (107, 115))	('TP63', 'Gene', (26, 30))	('TP63', 'Gene', '8626', (26, 30))	('p63alpha', 'Gene', (95, 103))	('p63alpha', 'Gene', '8626', (95, 103))	('expression', 'MPA', (166, 176))	('DNp63beta', 'Var', (118, 127))
35955	31927310	Stratification of BLCA patients into those with TAp63 isoform expression (5%) and those without (95%) demonstrated that patients with high TAp63 or TAp63beta expressing tumors had significantly worse OS than those with low/no expression (median OS 13.4 mos.	('TAp63beta expressing', 'Var', (148, 168))	('high TAp63', 'Var', (134, 144))	('patients', 'Species', '9606', (23, 31))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('BLCA', 'Disease', 'MESH:D001749', (18, 22))	('worse', 'NegReg', (194, 199))	('patients', 'Species', '9606', (120, 128))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('BLCA', 'Disease', (18, 22))	('tumors', 'Disease', (169, 175))
35958	31927310	Similarly, DNp63 expression was significantly associated with reduced hazard in luminal patients (HR = 0.89, CI 0.80-0.99, Cox p = 0.034), but did not show a significant association in patients with a basal squamous subtype (HR = 1.00, CI 0.91-1.10, Cox p = 0.95) (Fig.	('Cox', 'Gene', (250, 253))	('Cox', 'Gene', '1351', (123, 126))	('Cox', 'Gene', (123, 126))	('patients', 'Species', '9606', (88, 96))	('C', 'Chemical', 'MESH:D002244', (236, 237))	('C', 'Chemical', 'MESH:D002244', (250, 251))	('C', 'Chemical', 'MESH:D002244', (109, 110))	('DNp63 expression', 'Var', (11, 27))	('patients', 'Species', '9606', (185, 193))	('Cox', 'Gene', '1351', (250, 253))	('C', 'Chemical', 'MESH:D002244', (123, 124))	('reduced', 'NegReg', (62, 69))
35959	31927310	TAp63 was significantly associated with increased hazard in basal squamous subtype patients (HR = 2.35, CI 1.64-3.37, Cox p < 0.0001), but not in patients with luminal tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('luminal tumors', 'Disease', (160, 174))	('basal squamous subtype', 'Disease', (60, 82))	('C', 'Chemical', 'MESH:D002244', (104, 105))	('C', 'Chemical', 'MESH:D002244', (118, 119))	('Cox', 'Gene', '1351', (118, 121))	('luminal tumors', 'Disease', 'MESH:D009369', (160, 174))	('TAp63', 'Var', (0, 5))	('patients', 'Species', '9606', (83, 91))	('Cox', 'Gene', (118, 121))	('patients', 'Species', '9606', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
35960	31927310	Taken together, these results suggest that DNp63 plays a protective role in luminal bladder cancer patients whereas TAp63 is associated with poor risk in basal bladder cancers (Fig.	('bladder cancer', 'Phenotype', 'HP:0009725', (84, 98))	('luminal bladder cancer', 'Disease', (76, 98))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('luminal bladder cancer', 'Disease', 'MESH:D001749', (76, 98))	('basal bladder cancers', 'Disease', (154, 175))	('patients', 'Species', '9606', (99, 107))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('bladder cancers', 'Phenotype', 'HP:0009725', (160, 175))	('DNp63', 'Var', (43, 48))	('TAp63', 'Var', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('basal bladder cancers', 'Disease', 'MESH:D001749', (154, 175))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))
35961	31927310	To determine if the prognostic importance of TAp63 or DNp63 was independent of other known factors associated with bladder cancer patient prognosis, we performed multivariable Cox regression to adjust for potentially relevant clinical attributes (age, gender, grade, pathologic stage).	('bladder cancer', 'Disease', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('patient', 'Species', '9606', (130, 137))	('DNp63', 'Var', (54, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('Cox', 'Gene', '1351', (176, 179))	('Cox', 'Gene', (176, 179))	('bladder cancer', 'Disease', 'MESH:D001749', (115, 129))
35963	31927310	Multivariable Cox regression analysis confirmed that high DNp63 expression continued to trend with increased survival when controlling for age and pathologic stage (HR 0.68, CI 0.45-1.0, Cox p = 0.062) (Fig.	('C', 'Chemical', 'MESH:D002244', (14, 15))	('expression', 'MPA', (64, 74))	('high', 'Var', (53, 57))	('DNp63', 'Gene', (58, 63))	('survival', 'MPA', (109, 117))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('C', 'Chemical', 'MESH:D002244', (187, 188))	('increased', 'PosReg', (99, 108))	('Cox', 'Gene', (187, 190))	('Cox', 'Gene', '1351', (187, 190))	('C', 'Chemical', 'MESH:D002244', (174, 175))
35964	31927310	Likewise, high TAp63 expression was significantly associated with an increased risk of death when controlling for age and pathologic stage (HR 2.7, CI 1.6-4.6, Cox p = 0.0002).	('Cox', 'Gene', (160, 163))	('C', 'Chemical', 'MESH:D002244', (148, 149))	('expression', 'MPA', (21, 31))	('death', 'Disease', 'MESH:D003643', (87, 92))	('TAp63', 'Gene', (15, 20))	('high', 'Var', (10, 14))	('C', 'Chemical', 'MESH:D002244', (160, 161))	('death', 'Disease', (87, 92))	('Cox', 'Gene', '1351', (160, 163))	('associated', 'Reg', (50, 60))
35969	31927310	Likewise, these analyses confirmed that TAp63 was associated with reduced survival for BLCA (HR 1.8, CI 1.4-2.4, Cox p = 0.0002).	('Cox', 'Gene', (113, 116))	('reduced', 'NegReg', (66, 73))	('C', 'Chemical', 'MESH:D002244', (101, 102))	('BLCA', 'Disease', 'MESH:D001749', (87, 91))	('survival', 'MPA', (74, 82))	('TAp63', 'Var', (40, 45))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('BLCA', 'Disease', (87, 91))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('Cox', 'Gene', '1351', (113, 116))
35971	31927310	1(b)), the isoform level DNp63 expression was associated with worse survival (HR 1.2, CI 1.1-1.4, Cox p = 0.0003) and TAp63 associated with improved survival (HR 0.70, CI 0.51-0.96, Cox p = 0.020) which was also in the opposite direction of BLCA, BRCA and LUSC.	('Cox', 'Gene', (182, 185))	('worse', 'NegReg', (62, 67))	('C', 'Chemical', 'MESH:D002244', (249, 250))	('C', 'Chemical', 'MESH:D002244', (98, 99))	('C', 'Chemical', 'MESH:D002244', (243, 244))	('BRCA', 'Gene', '672', (247, 251))	('C', 'Chemical', 'MESH:D002244', (168, 169))	('Cox', 'Gene', '1351', (98, 101))	('TAp63', 'Var', (118, 123))	('DNp63', 'Gene', (25, 30))	('BLCA', 'Disease', (241, 245))	('C', 'Chemical', 'MESH:D002244', (182, 183))	('improved', 'PosReg', (140, 148))	('Cox', 'Gene', (98, 101))	('BRCA', 'Gene', (247, 251))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('Cox', 'Gene', '1351', (182, 185))	('survival', 'MPA', (149, 157))	('C', 'Chemical', 'MESH:D002244', (259, 260))	('BLCA', 'Disease', 'MESH:D001749', (241, 245))	('survival', 'MPA', (68, 76))
35974	31927310	To investigate this hypothesis, we grouped entire TCGA tumor cohorts together and plotted the average proportion of TAp63 or DNp63 over total TP63 for each population vs. TP63 HR for the entire cohort (Fig.	('TP63', 'Gene', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('DNp63', 'Var', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('C', 'Chemical', 'MESH:D002244', (51, 52))	('tumor', 'Disease', (55, 60))	('TP63', 'Gene', '8626', (171, 175))	('TP63', 'Gene', (171, 175))	('TP63', 'Gene', '8626', (142, 146))
35978	31927310	These results suggest that the relative proportion of TAp63 or DNp63 vs. total TP63 associates with clinical outcome regardless of tumor type.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('TP63', 'Gene', (79, 83))	('TAp63', 'Var', (54, 59))	('TP63', 'Gene', '8626', (79, 83))	('DNp63', 'Var', (63, 68))	('clinical outcome', 'MPA', (100, 116))
35980	31927310	had previously shown that DNp63 and TAp63 promoted transcriptional programs of prognostic significance in various tumor types including bladder cancer.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('bladder cancer', 'Disease', 'MESH:D001749', (136, 150))	('bladder cancer', 'Disease', (136, 150))	('tumor', 'Disease', (114, 119))	('transcriptional programs', 'MPA', (51, 75))	('DNp63', 'Var', (26, 31))	('promoted', 'PosReg', (42, 50))	('TAp63', 'Gene', (36, 41))
35981	31927310	Contrasting isoform-specific associations with patient survival observed across multiple diseases lead us to investigate transcriptional signaling programs that distinguish patient populations with high levels of DNp63 or TAp63.	('patient', 'Species', '9606', (47, 54))	('signaling', 'biological_process', 'GO:0023052', ('137', '146'))	('TAp63', 'Gene', (222, 227))	('patient', 'Species', '9606', (173, 180))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('DNp63', 'Var', (213, 218))
35983	31927310	Patients with tumors with high levels of DNp63 enriched for gene sets related to epidermal cell differentiation, keratinization, and skin development (Fig.	('DNp63', 'Var', (41, 46))	('keratinization', 'biological_process', 'GO:0031424', ('113', '127'))	('skin development', 'biological_process', 'GO:0043588', ('133', '149'))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('epidermal cell differentiation', 'biological_process', 'GO:0009913', ('81', '111'))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('skin development', 'CPA', (133, 149))
35998	31927310	In this context, DNp63 isoforms appear to be the predominate cancer-associated isoform.	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('DNp63', 'Var', (17, 22))
36004	31927310	Genome-wide association studies (GWAS) have found that bladder cancer risk is associated with a sequence variant of an enhancer specifically controlling DNp63 expression.	('associated', 'Reg', (78, 88))	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('sequence variant', 'Var', (96, 112))	('bladder cancer', 'Disease', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('expression', 'MPA', (159, 169))	('DNp63', 'Gene', (153, 158))
36005	31927310	In contrast, DNp63 in NMIBC did not correlate with tumor risk of relapse and was associated with reduced risk of invasive progression in T1 bladder tumors.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('bladder tumor', 'Phenotype', 'HP:0009725', (140, 153))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (51, 56))	('reduced', 'NegReg', (97, 104))	('bladder tumors', 'Disease', 'MESH:D001749', (140, 154))	('bladder tumors', 'Phenotype', 'HP:0009725', (140, 154))	('MIBC', 'Disease', (23, 27))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('MIBC', 'Disease', 'MESH:D001749', (23, 27))	('bladder tumors', 'Disease', (140, 154))	('DNp63', 'Var', (13, 18))	('invasive progression', 'CPA', (113, 133))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
36012	31927310	Finally, we hypothesize that patient prognosis may be determined by the proportion of TP63 that is expressed as DNp63 vs. TAp63.	('TP63', 'Gene', '8626', (86, 90))	('DNp63', 'Var', (112, 117))	('patient', 'Species', '9606', (29, 36))	('TP63', 'Gene', (86, 90))
36020	31927310	Although prime variant isoforms have previously been described, here we characterize two commonly expressed variants, DNp63alphaP and DNp63betaP, which are not currently part of the TP63 isoform definitions present in Refgene and Gencode.	('p63alpha', 'Gene', (120, 128))	('DNp63betaP', 'Var', (134, 144))	('TP63', 'Gene', '8626', (182, 186))	('TP63', 'Gene', (182, 186))	('p63alpha', 'Gene', '8626', (120, 128))
36074	31359955	A 74-year-old male had the histories of diabetes mellitus (hemoglobin A1c: 6.5%), hypertension, chronic kidney disease Stage 2 (eGFR: 77 mL/min/1.73 m2), bladder urothelial carcinoma, papillary, noninvasive, high grade, cTaN0M0, status posttransurethral resection of bladder tumor, and chemotherapy.	('cTaN0M0', 'Var', (220, 227))	('hemoglobin A1c', 'Phenotype', 'HP:0040217', (59, 73))	('chronic kidney disease', 'Disease', (96, 118))	('bladder tumor', 'Disease', (267, 280))	('hypertension', 'Disease', 'MESH:D006973', (82, 94))	('hypertension', 'Disease', (82, 94))	('bladder tumor', 'Disease', 'MESH:D001749', (267, 280))	('diabetes mellitus', 'Disease', (40, 57))	('min/1', 'Gene', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('chronic kidney disease', 'Disease', 'MESH:D051436', (96, 118))	('hypertension', 'Phenotype', 'HP:0000822', (82, 94))	('diabetes mellitus', 'Disease', 'MESH:D003920', (40, 57))	('bladder urothelial carcinoma', 'Disease', (154, 182))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (96, 118))	('papillary', 'Disease', (184, 193))	('min/1', 'Gene', '966', (140, 145))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (40, 57))	('bladder tumor', 'Phenotype', 'HP:0009725', (267, 280))	('kidney disease', 'Phenotype', 'HP:0000112', (104, 118))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (154, 182))	('eGFR', 'molecular_function', 'GO:0005006', ('128', '132'))
36089	31359955	We supposed that in cancer patients, high probability of BBB disruption may render the brain more vulnerable to metronidazole-induced toxic-metabolic process and lead to cerebral axonal swelling and demyelination.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('demyelination', 'Phenotype', 'HP:0011096', (199, 212))	('disruption', 'Var', (61, 71))	('metronidazole', 'Chemical', 'MESH:D008795', (112, 125))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('demyelination', 'Disease', (199, 212))	('cerebral axonal swelling', 'Disease', (170, 194))	('vulnerable', 'MPA', (98, 108))	('toxic-metabolic process', 'MPA', (134, 157))	('cerebral axonal swelling', 'Disease', 'MESH:D001929', (170, 194))	('cancer', 'Disease', (20, 26))	('demyelination', 'Disease', 'MESH:D003711', (199, 212))	('patients', 'Species', '9606', (27, 35))	('metabolic process', 'biological_process', 'GO:0008152', ('140', '157'))	('lead to', 'Reg', (162, 169))	('BBB', 'Protein', (57, 60))
36129	30524881	In this setting, considerable attention is currently attracted by mutational burden (MuB), which is generally assessed by whole-exon DNA-seq, and PD-L1 expression levels, which are normally monitored by immunohistochemistry (IHC).	('PD-L1', 'Gene', (146, 151))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('PD-L1', 'Gene', '29126', (146, 151))	('mutational', 'Var', (66, 76))
36162	29765151	Patients with baseline Hsp27 levels <5.7 ng/mL had improved OS compared to those with levels >=5.7 ng/mL.	('Hsp27', 'Gene', '3315', (23, 28))	('improved', 'PosReg', (51, 59))	('<5.7 ng/mL', 'Var', (36, 46))	('Patients', 'Species', '9606', (0, 8))	('Hsp27', 'Gene', (23, 28))
36167	29765151	Hsp27 also stabilises mutated or inappropriately activated oncoproteins that contribute to the initiation, growth, and metastasis of human cancers.	('metastasis of human cancers', 'Disease', (119, 146))	('oncoproteins', 'Protein', (59, 71))	('Hsp27', 'Gene', (0, 5))	('Hsp27', 'Gene', '3315', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('inappropriately', 'Var', (33, 48))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('stabilises', 'MPA', (11, 21))	('mutated', 'Var', (22, 29))	('metastasis of human cancers', 'Disease', 'MESH:D009362', (119, 146))
36179	29765151	Patients whose tumours contained variant histological features were eligible if the tumour was not considered a pure histologic variant; however, patients with any amount of small cell carcinoma were not eligible.	('small cell carcinoma', 'Phenotype', 'HP:0030357', (174, 194))	('tumour', 'Disease', (84, 90))	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumours', 'Disease', 'MESH:D009369', (15, 22))	('tumour', 'Disease', (15, 21))	('tumours', 'Disease', (15, 22))	('pure', 'molecular_function', 'GO:0034023', ('112', '116'))	('variant', 'Var', (33, 40))	('Patients', 'Species', '9606', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('small cell carcinoma', 'Disease', (174, 194))	('small cell carcinoma', 'Disease', 'MESH:D018288', (174, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('patients', 'Species', '9606', (146, 154))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))
36196	29765151	This phase II study was designed to have 90% power with one-sided 0.10 significance level to detect a 33% reduction in the OS hazard rate with docetaxel and apatorsen compared with docetaxel alone [hazard ratio (docetaxel and apatorsen/docetaxel) = 0.667], assuming an exponential distribution of OS, and median OS of 6 months on docetaxel alone.	('docetaxel', 'Chemical', 'MESH:D000077143', (330, 339))	('apatorsen', 'Var', (157, 166))	('apatorsen', 'Chemical', 'MESH:C000595177', (226, 235))	('apatorsen', 'Chemical', 'MESH:C000595177', (157, 166))	('reduction', 'NegReg', (106, 115))	('docetaxel', 'Chemical', 'MESH:D000077143', (236, 245))	('docetaxel', 'Chemical', 'MESH:D000077143', (181, 190))	('docetaxel', 'Chemical', 'MESH:D000077143', (212, 221))	('docetaxel', 'Chemical', 'MESH:D000077143', (143, 152))
36239	29765151	Treatment with docetaxel and apatorsen improved survival in both groups of patients with either baseline Hsp27 level <5.7 ng/mL (HR: 0.71, 80% CI: 0.50-1.00) or >=5.7 ng/mL (HR: 0.67, 80% CI: 0.48-0.92; two-sided P = 0.87 for interaction) compared to docetaxel alone.	('survival', 'MPA', (48, 56))	('docetaxel', 'Chemical', 'MESH:D000077143', (251, 260))	('Hsp27', 'Gene', (105, 110))	('Hsp27', 'Gene', '3315', (105, 110))	('>=5.7 ng/mL', 'Var', (161, 172))	('patients', 'Species', '9606', (75, 83))	('docetaxel', 'Chemical', 'MESH:D000077143', (15, 24))	('men', 'Species', '9606', (5, 8))	('improved', 'PosReg', (39, 47))	('apatorsen', 'Chemical', 'MESH:C000595177', (29, 38))
36293	26094807	Retrospective multi-institutional study of 73 patients with N+M0 UTUC undergoing template lymphadenectomy during nephroureterectomy.	('nephroureterectomy', 'Disease', (113, 131))	('nephroureterectomy', 'Disease', 'None', (113, 131))	('patients', 'Species', '9606', (46, 54))	('N+M0', 'Var', (60, 64))
36327	26094807	On the right side, patients with renal pelvis tumors had high frequency LNM to the hilum, paracaval, retrocaval, and interaortocaval regions (table 2 and figure 1).	('patients', 'Species', '9606', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('renal pelvis tumors', 'Disease', 'MESH:D010386', (33, 52))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('LNM', 'Var', (72, 75))	('renal pelvis', 'Phenotype', 'HP:0000125', (33, 45))	('renal pelvis tumors', 'Disease', (33, 52))
36426	33024233	Inclusion criteria included the following: patients with a primary site labeled as "C65.9 Renal pelvis, or C66.9 Ureter", and the histology codes of transitional cell carcinoma including: 8120/2, 8120/3, 8122/3, 8130/2, 8130/3, and 8131/3 (Detailed definition of ICD-O-3 SEER Site/Histology Validation List [https://seer.cancer.gov/icd-o-3/]).	('8131/3', 'Var', (232, 238))	('8120/2', 'Var', (188, 194))	('transitional cell carcinoma', 'Disease', (149, 176))	('cancer', 'Disease', 'MESH:D009369', (321, 327))	('8122/3', 'Var', (204, 210))	('8130/2', 'Var', (212, 218))	('Renal pelvis', 'Phenotype', 'HP:0000125', (90, 102))	('cancer', 'Disease', (321, 327))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('C66.9', 'Var', (107, 112))	('Renal pelvis', 'Disease', 'MESH:D007680', (90, 102))	('transitional cell carcinoma', 'Disease', 'MESH:D002295', (149, 176))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (149, 176))	('Renal pelvis', 'Disease', (90, 102))
36449	33024233	First, Chinese analyses of subsequent contralateral UTUC after an initial diagnosis often include many patients with renal insufficiency commonly caused by the consumption of Chinese herbs containing aristolochic acid which was an independent risk factor of metachronous contralateral UTUC, but aristolochic acid-induced UTUC was not common in the American population.	('caused by', 'Reg', (146, 155))	('aristolochic acid', 'Chemical', 'MESH:C000228', (295, 312))	('renal insufficiency', 'Disease', (117, 136))	('renal insufficiency', 'Disease', 'MESH:D051437', (117, 136))	('aristolochic acid', 'Chemical', 'MESH:C000228', (200, 217))	('aristolochic acid', 'Var', (200, 217))	('renal insufficiency', 'Phenotype', 'HP:0000083', (117, 136))
36479	29081218	Notably, multivariate analyses revealed that NSAIDs significantly increased the risk of prostate cancer (hazard ratio [HR], 1.35).	('increased', 'PosReg', (66, 75))	('prostate cancer', 'Disease', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))	('NSAIDs', 'Var', (45, 51))
36493	29081218	We screened data with the code C61, C64, and C65-67, indicating prostate, kidney, and urothelial cancers, respectively, according to the National Center for Health Statistics International Classification of Diseases and Related Health Problems, 10th edition (ICD-10).	('C65-67', 'Var', (45, 51))	('urothelial cancers', 'Disease', (86, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('kidney', 'Disease', (74, 80))	('C61', 'Var', (31, 34))	('prostate', 'Disease', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('C64', 'Var', (36, 39))	('urothelial cancers', 'Disease', 'MESH:D014523', (86, 104))
36516	29081218	The key finding of the current study was that NSAIDs were associated with increased risk of PCa (HR, 1.35), and aspirin (HR, 1.28) and statin (HR, 1.55), were associated with a higher risk of kidney cancer in the multivariate Cox regression analyses.	('aspirin', 'Chemical', 'MESH:D001241', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('kidney cancer', 'Phenotype', 'HP:0009726', (192, 205))	('kidney cancer', 'Disease', 'MESH:D007680', (192, 205))	('PCa', 'Phenotype', 'HP:0012125', (92, 95))	('kidney cancer', 'Disease', (192, 205))	('NSAIDs', 'Var', (46, 52))	('PCa', 'Disease', (92, 95))
36518	29081218	Mechanistically, NSAIDs inhibited cancer cell growth and induced apoptotic cell death via suppression of AKT signaling pathway and cell cycle (G1) arrest in LNCaP and PC3 cells.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('suppression', 'NegReg', (90, 101))	('AKT', 'Gene', '207', (105, 108))	('cell cycle', 'biological_process', 'GO:0007049', ('131', '141'))	('signaling pathway', 'biological_process', 'GO:0007165', ('109', '126'))	('PC3', 'CellLine', 'CVCL:0035', (167, 170))	('AKT signaling', 'biological_process', 'GO:0043491', ('105', '118'))	('LNCaP', 'CellLine', 'CVCL:0395', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('inhibited', 'NegReg', (24, 33))	('AKT', 'Gene', (105, 108))	('apoptotic cell death', 'CPA', (65, 85))	('cancer', 'Disease', (34, 40))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('65', '85'))	('NSAIDs', 'Var', (17, 23))	('cell growth', 'biological_process', 'GO:0016049', ('41', '52'))
36558	31190871	The ACPI was confirmed in datasets of GSE13507 (HR=7.389, 95% CI=3.645-14.980, P<0.001) and GSE31684 (HR=1.665, 95% CI=0.872-3.179, P=0.122).	('GSE31684', 'Var', (92, 100))	('ACPI', 'Chemical', '-', (4, 8))	('GSE13507', 'Var', (38, 46))
36606	31190871	The formula of PI is as follows: PI=(0.1643 x expression value of JUN)+(0.1555 x expression value of MYC)+(-0.1505 x expression value of ITGA3).	('0.1643', 'Var', (37, 43))	('MYC', 'Gene', '4609', (101, 104))	('ITGA3', 'Gene', '3675', (137, 142))	('MYC', 'Gene', (101, 104))	('ITGA3', 'Gene', (137, 142))
36622	31190871	The prognostic value of ACPI was also validated by GSE13507 and GSE31684.	('GSE31684', 'Var', (64, 72))	('ACPI', 'Chemical', '-', (24, 28))	('GSE13507', 'Var', (51, 59))
36625	31190871	A total of 19 eligible studies were involved, including Blaveri Bladder 2, Modlich Bladder, Sanchez Carbayo Bladder 2, TCGA, GSE3167, GSE13507, GSE76211, GSE2109, GSE7476, GSE30522, GSE31189, GSE37815, GSE52519, GSE65635, GSE37817, GSE100926, GSE24152, GSE19915 (GPL3883 and GPL5186), and GSE40355.	('GSE2109', 'Chemical', '-', (154, 161))	('GSE24152', 'Var', (243, 251))	('GSE100926', 'Var', (232, 241))	('GSE7476', 'Var', (163, 170))	('GSE52519', 'Var', (202, 210))	('GSE7476', 'Chemical', '-', (163, 170))	('GPL5186', 'Var', (275, 282))	('GSE2109', 'Var', (154, 161))	('GSE37817', 'Var', (222, 230))	('GSE65635', 'Var', (212, 220))	('GSE76211', 'Var', (144, 152))
36628	31190871	Among the 19 studies involved in meta-analysis, only two microarrays (GSE37137 and GSE35824) and TCGA contained gene expression data from non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) tissues.	('BC', 'Phenotype', 'HP:0009725', (177, 179))	('MIBC', 'Chemical', '-', (175, 179))	('GSE35824', 'Var', (83, 91))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (142, 172))	('bladder cancer', 'Phenotype', 'HP:0009725', (201, 215))	('gene expression', 'biological_process', 'GO:0010467', ('112', '127'))	('invasive bladder', 'Phenotype', 'HP:0100645', (192, 208))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('bladder cancer', 'Phenotype', 'HP:0009725', (158, 172))	('muscle invasive bladder cancer', 'Disease', (185, 215))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('BC', 'Phenotype', 'HP:0009725', (219, 221))	('-muscle invasive bladder cancer', 'Phenotype', 'HP:0006740', (141, 172))	('GSE37137', 'Var', (70, 78))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (185, 215))	('MIBC', 'Chemical', '-', (217, 221))	('muscle invasive bladder cancer', 'Disease', (142, 172))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (138, 165))	('invasive bladder', 'Phenotype', 'HP:0100645', (149, 165))
36638	31190871	Initially, the tumor-suppressive role of autophagy in cancers was proposed for autophagy inhibited by activation of mutations in oncogenes or inactivation of tumor suppressor genes.	('autophagy', 'CPA', (79, 88))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('autophagy', 'biological_process', 'GO:0016236', ('41', '50'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('autophagy', 'biological_process', 'GO:0016236', ('79', '88'))	('autophagy', 'biological_process', 'GO:0006914', ('41', '50'))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('inhibited', 'NegReg', (89, 98))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('158', '174'))	('oncogenes', 'Protein', (129, 138))	('tumor', 'Disease', (15, 20))	('mutations', 'Var', (116, 125))	('autophagy', 'biological_process', 'GO:0006914', ('79', '88'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor suppressor', 'biological_process', 'GO:0051726', ('158', '174'))	('activation', 'PosReg', (102, 112))	('inactivation', 'Var', (142, 154))	('tumor', 'Disease', 'MESH:D009369', (158, 163))
36648	31190871	In addition, several studies found that c-Myc knockdown could inhibit proliferation, migration, and invasion of bladder cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('knockdown', 'Var', (46, 55))	('bladder cancer', 'Disease', 'MESH:D001749', (112, 126))	('bladder cancer', 'Disease', (112, 126))	('proliferation', 'CPA', (70, 83))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))	('c-Myc', 'Gene', '4609', (40, 45))	('invasion', 'CPA', (100, 108))	('migration', 'CPA', (85, 94))	('inhibit', 'NegReg', (62, 69))	('c-Myc', 'Gene', (40, 45))
36664	31190871	The microarray data of GSE13507, GSE31684, GSE76211, GSE2109, GSE7476, GSE30522, GSE31189, GSE37815, GSE52519, GSE65635, GSE37817, GSE100926, GSE24152, GSE19915 (GPL3883 and GPL5186), and GSE40355 can be acquired from the Gene Expression Omnibus (GEO) database.	('GSE7476', 'Var', (62, 69))	('GSE31684', 'Var', (33, 41))	('GSE30522', 'Var', (71, 79))	('GSE37817', 'Var', (121, 129))	('GSE65635', 'Var', (111, 119))	('GSE7476', 'Chemical', '-', (62, 69))	('GSE2109', 'Var', (53, 60))	('Gene Expression', 'biological_process', 'GO:0010467', ('222', '237'))	('GSE13507', 'Var', (23, 31))	('GSE40355', 'Var', (188, 196))	('GSE31189', 'Var', (81, 89))	('GSE76211', 'Var', (43, 51))	('GSE100926', 'Var', (131, 140))	('GSE37815', 'Var', (91, 99))	('GSE2109', 'Chemical', '-', (53, 60))	('GSE52519', 'Var', (101, 109))
36685	31048858	The largest cluster (#0) has 16 members, a silhouette value of 0.789 and is labeled as carcinogenic aristolochic acid by LLR (log-likelihood ratio).	('carcinogenic', 'Disease', (87, 99))	('aristolochic acid', 'Chemical', 'MESH:C000228', (100, 117))	('aristolochic acid', 'Var', (100, 117))	('carcinogenic', 'Disease', 'MESH:D063646', (87, 99))
36721	31048858	found that AA-related carcinogenesis was associated with the overexpression of p53.	('p53', 'Gene', '7157', (79, 82))	('p53', 'Gene', (79, 82))	('associated', 'Reg', (41, 51))	('carcinogenesis', 'Disease', (22, 36))	('overexpression', 'Var', (61, 75))	('carcinogenesis', 'Disease', 'MESH:D063646', (22, 36))
36727	31048858	published a study that utilized computational modeling to provide a plausible structural explanation for the experimentally observed differential global genome repair propensity of the ALII-N-2-dG and ALII-N-6-dA DNA adducts of AA II.	('ALII-N-2-dG', 'Chemical', '-', (185, 196))	('adducts', 'Var', (217, 224))	('ALII-N-6-dA', 'Chemical', '-', (201, 212))	('global genome repair propensity', 'MPA', (146, 177))	('DNA', 'cellular_component', 'GO:0005574', ('213', '216'))
36758	30988298	Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer.	('hypermethylation', 'Var', (164, 180))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', (57, 63))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))	('DNA methylation', 'MPA', (127, 142))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('loss', 'NegReg', (119, 123))	('DNA methylation', 'biological_process', 'GO:0006306', ('127', '142'))
36766	30988298	In cancer, global DNA methylation loss and CpG island hypermethylation are commonly observed.	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('DNA methylation', 'biological_process', 'GO:0006306', ('18', '33'))	('CpG island', 'Var', (43, 53))	('cancer', 'Disease', (3, 9))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('global', 'Protein', (11, 17))	('loss', 'NegReg', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
36767	30988298	Here, in breast cancer the authors find that hyper-variability of partially methylated domains is the prime source of DNA methylation variation and that these domains fuel CpG island hypermethylation.	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('variation', 'Var', (134, 143))	('hypermethylation', 'Var', (183, 199))	('DNA methylation', 'biological_process', 'GO:0006306', ('118', '133'))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('breast cancer', 'Disease', (9, 22))	('DNA methylation', 'MPA', (118, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))
36773	30988298	PMDs have been shown to harbor focal sites of hypermethylation that largely overlap with CGIs.	('hypermethylation', 'Var', (46, 62))	('PMD', 'Disease', 'MESH:D020371', (0, 3))	('PMD', 'Disease', (0, 3))
36791	30988298	Given the variation between tumors, we asked whether the patterns of methylation loss were associated with distribution of copy-number variations (CNVs) throughout the genome.	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumors', 'Disease', (28, 34))	('methylation', 'biological_process', 'GO:0032259', ('69', '80'))	('methylation', 'Var', (69, 80))	('loss', 'NegReg', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
36793	30988298	Finally, we assessed whether mean PMD methylation was associated with the fraction of aberrant cells within the sample (ASCAT).	('PMD', 'Disease', (34, 37))	('methylation', 'Var', (38, 49))	('PMD', 'Disease', 'MESH:D020371', (34, 37))	('associated', 'Reg', (54, 64))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))
36831	30988298	In the 25 overlapping cases between our WGBS cohort and the WGS cohort, substitutions, insertions, and deletions occur more frequently within than outside PMDs (p < 0.0005 for each mutation type, logistic regression), with a (slight) increase in highly frequent PMDs (p < 2.2e-16 for substitutions, p = 0.37 for insertions, p = 1.6e-05 for deletions, logistic regression, Fig.	('substitutions', 'Var', (72, 85))	('PMD', 'Disease', (262, 265))	('PMD', 'Disease', (155, 158))	('substitutions', 'Var', (284, 297))	('PMD', 'Disease', 'MESH:D020371', (262, 265))	('PMD', 'Disease', 'MESH:D020371', (155, 158))
36832	30988298	In contrast, rearrangements are more abundant outside of PMDs (p = 1.1e-09, logistic regression), in keeping with the hypothesis that regions with higher transcriptional activity are more susceptible to translocations.	('PMD', 'Disease', 'MESH:D020371', (57, 60))	('rearrangements', 'Var', (13, 27))	('PMD', 'Disease', (57, 60))
36835	30988298	Importantly, in addition to epigenomic instability, breast cancer PMDs also tolerate transcriptomic variability and genomic instability.	('transcriptomic', 'MPA', (85, 99))	('genomic instability', 'Var', (116, 135))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer PMDs', 'Disease', 'MESH:D001943', (52, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('breast cancer PMDs', 'Disease', (52, 70))
36839	30988298	This has been described also as focal hypermethylation inside PMDs.	('PMD', 'Disease', (62, 65))	('focal hypermethylation', 'Var', (32, 54))	('PMD', 'Disease', 'MESH:D020371', (62, 65))
36844	30988298	Thus, incognizant deposition of DNA methylation inside PMDs results in extensive hypermethylation of virtually all PMD-CGIs.	('PMD', 'Disease', 'MESH:D020371', (115, 118))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('PMD', 'Disease', (55, 58))	('hypermethylation', 'MPA', (81, 97))	('PMD', 'Disease', (115, 118))	('PMD', 'Disease', 'MESH:D020371', (55, 58))	('DNA methylation', 'biological_process', 'GO:0006306', ('32', '47'))	('methylation', 'Var', (36, 47))
36845	30988298	Concurrent hypermethylation of CGIs in cancer has been termed CIMP, and in breast cancer this phenomenon has been termed B-CIMP.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('hypermethylation', 'Var', (11, 27))	('B-CIMP', 'Chemical', '-', (121, 127))	('CIMP', 'Chemical', '-', (62, 66))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CIMP', 'Chemical', '-', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('CGIs', 'Protein', (31, 35))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
36854	30988298	To assess whether widespread hypermethylation of CGI-promoters within PMDs instigates gene repression we analyzed expression as a function of gene location inside or outside of PMDs.	('PMD', 'Disease', 'MESH:D020371', (70, 73))	('instigates', 'Reg', (75, 85))	('PMD', 'Disease', 'MESH:D020371', (177, 180))	('gene', 'MPA', (86, 90))	('PMD', 'Disease', (70, 73))	('PMD', 'Disease', (177, 180))	('hypermethylation', 'Var', (29, 45))
36863	30988298	Given the widely accepted model of hypermethylated promoter-CGIs causing repression of tumor suppressor genes (TSGs) we determined whether breast cancer PMDs overlap with these genes to instigate such repression.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('causing', 'Reg', (65, 72))	('breast cancer PMDs', 'Disease', 'MESH:D001943', (139, 157))	('repression', 'MPA', (73, 83))	('TSG', 'Gene', (111, 114))	('tumor', 'Disease', (87, 92))	('tumor suppressor', 'biological_process', 'GO:0051726', ('87', '103'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('87', '103'))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('TSG', 'Gene', '57045', (111, 114))	('hypermethylated', 'Var', (35, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('breast cancer PMDs', 'Disease', (139, 157))
36868	30988298	Similarly, from our previously identified set of genes containing breast cancer driver mutations: 86/93 (92%) were located outside of PMDs (p = 2.0e-11, hypergeometric test).	('PMD', 'Disease', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('PMD', 'Disease', 'MESH:D020371', (134, 137))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('mutations', 'Var', (87, 96))
36872	30988298	Among the downregulated genes in PMDs are EGFR (epidermal growth factor receptor) and PDGFRA (platelet-derived growth factor receptor alpha) that have tumor promoting mutations (Supplementary Fig.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('48', '71'))	('EGFR', 'Gene', '1956', (42, 46))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (94, 139))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('PDGFRA', 'Gene', '5156', (86, 92))	('PDGFRA', 'Gene', (86, 92))	('platelet-derived growth factor receptor alpha', 'Gene', (94, 139))	('EGFR', 'Gene', (42, 46))	('tumor', 'Disease', (151, 156))	('epidermal growth factor receptor', 'Gene', (48, 80))	('mutations', 'Var', (167, 176))	('PMD', 'Disease', 'MESH:D020371', (33, 36))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('94', '124'))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('PMD', 'Disease', (33, 36))	('epidermal growth factor receptor', 'Gene', '1956', (48, 80))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
36874	30988298	Taken together, despite the large number of hypermethylated CpG islands inside breast cancer PMDs (13,013 CGIs; 47%, Fig.	('hypermethylated', 'Var', (44, 59))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer PMDs', 'Disease', 'MESH:D001943', (79, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('breast cancer PMDs', 'Disease', (79, 97))
36908	30988298	Directly linked to this is the concurrent CGI hypermethylation, which inside PMDs affects 92% of all CGIs.	('PMD', 'Disease', 'MESH:D020371', (77, 80))	('affects', 'Reg', (82, 89))	('hypermethylation', 'Var', (46, 62))	('CGIs', 'Disease', (101, 105))	('PMD', 'Disease', (77, 80))
36911	30988298	Inside PMDs the accumulation of breast cancer mutations is higher than outside of them.	('breast cancer', 'Disease', (32, 45))	('PMD', 'Disease', (7, 10))	('mutations', 'Var', (46, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('PMD', 'Disease', 'MESH:D020371', (7, 10))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))
36917	30988298	In effect such approaches are biased towards CGIs due to their design and consequently, the hypermethylation groups represent tumors in which PMDs are highly abundant (e.g., see refs.	('PMD', 'Disease', 'MESH:D020371', (142, 145))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('PMD', 'Disease', (142, 145))	('hypermethylation groups', 'Var', (92, 115))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
36918	30988298	It is very likely that for some tumor types hypermethylation groups associate with clinicopathological features, amongst which a positive association with tumor cellularity is recurrent.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (155, 160))	('hypermethylation groups', 'Var', (44, 67))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('associate', 'Reg', (68, 77))	('tumor', 'Disease', (32, 37))
36920	30988298	This makes hypermethylated CGIs useful diagnostic markers but less likely informative as prognostic markers informing about tumor state, progression and outcome.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('CGIs', 'Protein', (27, 31))	('tumor', 'Disease', (124, 129))	('hypermethylated', 'Var', (11, 26))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
37018	29953738	Among these urological cancers, T24 is a metastatic UCC cell line and has better drug sensitivity to niclosamide and B17.	('better', 'PosReg', (74, 80))	('urological cancers', 'Disease', (12, 30))	('urological cancers', 'Disease', 'MESH:D014571', (12, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('niclosamide', 'Chemical', 'MESH:D009534', (101, 112))	('B17', 'Gene', '4712', (117, 120))	('drug sensitivity to niclosamide', 'MPA', (81, 112))	('drug sensitivity', 'Phenotype', 'HP:0020174', (81, 97))	('B17', 'Gene', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('T24', 'Var', (32, 35))
37020	29953738	DU145 and PC-3 are androgen resistant PCa18 and DU145 has better drug sensitivity to niclosamide and B17.	('better', 'PosReg', (58, 64))	('DU145', 'CellLine', 'CVCL:0105', (0, 5))	('DU145', 'Var', (48, 53))	('niclosamide', 'Chemical', 'MESH:D009534', (85, 96))	('DU145', 'CellLine', 'CVCL:0105', (48, 53))	('B17', 'Gene', '4712', (101, 104))	('drug sensitivity', 'Phenotype', 'HP:0020174', (65, 81))	('B17', 'Gene', (101, 104))	('drug sensitivity to niclosamide', 'MPA', (65, 96))
37035	29953738	Meanwhile, apoptotic cells were slightly increased after niclosamide (14.1%) and B17 (7.2%) treatment than control group (2.0%) in Caki-1 RCC cells, and they were slightly increased after niclosamide (7.4%) and B17 (8.4%) treatment than control group (2.2%) in DU145 PCa cells.	('B17', 'Gene', (211, 214))	('B17', 'Gene', (81, 84))	('apoptotic cells', 'CPA', (11, 26))	('increased', 'PosReg', (41, 50))	('niclosamide', 'Chemical', 'MESH:D009534', (57, 68))	('B17', 'Gene', '4712', (81, 84))	('B17', 'Gene', '4712', (211, 214))	('niclosamide', 'Chemical', 'MESH:D009534', (188, 199))	('DU145 PCa', 'CellLine', 'CVCL:0105', (261, 270))	('niclosamide', 'Var', (57, 68))
37039	29953738	The SubG1 phase was not significantly changed after niclosamide (2.8%) and B17 (2.2%) treatment when compared to control (3.6%) in Caki-1 RCC cells, and it was not significantly changed after niclosamide (1.7%) and B17 (0.5%) treatment when compared to control (2.6%) in DU145 PCa cells too.	('B17', 'Gene', (75, 78))	('B17', 'Gene', (215, 218))	('niclosamide', 'Chemical', 'MESH:D009534', (52, 63))	('DU145 PCa', 'CellLine', 'CVCL:0105', (271, 280))	('B17', 'Gene', '4712', (215, 218))	('niclosamide', 'Var', (52, 63))	('B17', 'Gene', '4712', (75, 78))	('niclosamide', 'Chemical', 'MESH:D009534', (192, 203))
37046	29953738	Caspase-3 expression was dramatically decreased in IC50 of niclosamide (0.68 +- 0.06, P < .001) and IC50 and IC75 of B17 (0.78 +- 0.07, P = .006 and 0.87 +- 0.08, P = .044) than IC75 of niclosamide (0.92 +- 0.08, P = .131) treatment and control for 72 hours in Caki-1 RCC cells.	('Caspase-3', 'Gene', (0, 9))	('IC50', 'Var', (51, 55))	('decreased', 'NegReg', (38, 47))	('Caspase-3', 'Gene', '836', (0, 9))	('IC75', 'Var', (109, 113))	('expression', 'MPA', (10, 20))	('niclosamide', 'Chemical', 'MESH:D009534', (186, 197))	('B17', 'Gene', '4712', (117, 120))	('B17', 'Gene', (117, 120))	('niclosamide', 'Chemical', 'MESH:D009534', (59, 70))	('IC50', 'Var', (100, 104))
37049	29953738	PARP and caspase-3 expression were only decreased in IC50 of niclosamide (0.59 +- 0.16, P = .011 and 0.72 +- 0.08, P = .003) treatment when compared to control group in DU145 PCa cells.	('DU145 PCa', 'CellLine', 'CVCL:0105', (169, 178))	('expression', 'MPA', (19, 29))	('caspase-3', 'Gene', (9, 18))	('PARP', 'Gene', (0, 4))	('IC50', 'Var', (53, 57))	('caspase-3', 'Gene', '836', (9, 18))	('niclosamide', 'Chemical', 'MESH:D009534', (61, 72))	('decreased', 'NegReg', (40, 49))	('PARP', 'Gene', '142', (0, 4))
37111	28690772	Immunohistochemical markers for prostate carcinoma, including PSA, PAP and P501S, were all negative.	('PSA', 'Gene', (62, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('P501S', 'Var', (75, 80))	('prostate carcinoma', 'Disease', 'MESH:D011472', (32, 50))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (32, 50))	('prostate carcinoma', 'Disease', (32, 50))	('PAP', 'Disease', (67, 70))	('PAP', 'molecular_function', 'GO:0043751', ('67', '70'))	('P501S', 'Mutation', 'p.P501S', (75, 80))	('PSA', 'Gene', '354', (62, 65))
37362	33445605	The UroVysion FISH test detects genetic markers, specifically aneuploidy for chromosomes 3, 7, and 17, and loss of 9p21 locus.	('aneuploidy', 'Disease', (62, 72))	('et', 'Gene', '79157', (25, 27))	('9p21 locus', 'Gene', (115, 125))	('et', 'Gene', '79157', (35, 37))	('loss', 'Var', (107, 111))	('aneuploidy', 'Disease', 'MESH:D000782', (62, 72))	('of', 'Gene', '6688', (112, 114))
37391	33445605	A meta-analysis of 30 published studies involving 2161 UC patients showed that CTC positivity was significantly associated with tumor stage, histological grade, metastasis, and lymph node metastasis.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('et', 'Gene', '79157', (3, 5))	('patients', 'Species', '9606', (58, 66))	('et', 'Gene', '79157', (189, 191))	('et', 'Gene', '79157', (162, 164))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('positivity', 'Var', (83, 93))	('histological grade', 'CPA', (141, 159))	('tumor', 'Disease', (128, 133))	('of', 'Gene', '6688', (16, 18))	('associated', 'Reg', (112, 122))	('CTC', 'Gene', (79, 82))
37421	33445605	UroSEEK is a novel, non-invasive urine-based biomarker that is measured by applying massively parallel sequencing to cellular DNA to detect UC mutations involving the TERT gene promoter and 10 other genes (FGFR3, TP53, CDKN2A, ERBB2, HRAS, KRAS, PIK3CA, MET, VHL, and MLL) combined with aneuploidy assessment.	('TERT', 'Gene', (167, 171))	('aneuploidy', 'Disease', 'MESH:D000782', (287, 297))	('TP53', 'Gene', (213, 217))	('UroSEEK', 'Chemical', '-', (0, 7))	('TERT', 'Gene', '7015', (167, 171))	('CDKN2A', 'Gene', (219, 225))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('FGFR', 'molecular_function', 'GO:0005007', ('206', '210'))	('FGFR3', 'Gene', (206, 211))	('men', 'Species', '9606', (304, 307))	('aneuploidy', 'Disease', (287, 297))	('et', 'Gene', '79157', (134, 136))	('ERBB2', 'Gene', (227, 232))	('mutations', 'Var', (143, 152))
37426	33445605	AssureMDX is a laboratory-developed test that identifies DNA mutations in three genes (FGFR3, TERT, and HRAS) and methylation in another three genes (OTX1, ONECUT2, and TWIST1) in urine samples.	('methylation', 'biological_process', 'GO:0032259', ('114', '125'))	('mutations', 'Var', (61, 70))	('et', 'Gene', '79157', (115, 117))	('FGFR3', 'Gene', (87, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('TERT', 'Gene', (94, 98))	('TERT', 'Gene', '7015', (94, 98))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))
37467	33445605	The dysregulation of Fas-mediated apoptosis is hypothesized to lead to UC progression and development.	('apoptosis', 'biological_process', 'GO:0006915', ('34', '43'))	('Fas-mediated', 'Protein', (21, 33))	('dysregulation', 'Var', (4, 17))	('men', 'Species', '9606', (97, 100))	('of', 'Gene', '6688', (18, 20))	('development', 'CPA', (90, 101))	('lead', 'Reg', (63, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('34', '43'))
37474	33445605	Changes in CD44 expression levels are commonly associated with tumor invasion and metastasis.	('tumor', 'Disease', (63, 68))	('et', 'Gene', '79157', (83, 85))	('CD44', 'Gene', '960', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Changes', 'Var', (0, 7))	('expression levels', 'MPA', (16, 33))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('associated', 'Reg', (47, 57))	('CD44', 'Gene', (11, 15))
37560	32454461	and Salzman et al., a covalently linked 668-nt circRNA termed circZNF139 is generated by splicing exons 2 and 3 of ZNF139 together.	('ZNF139', 'Gene', '7586', (115, 121))	('circZNF139', 'Chemical', '-', (62, 72))	('ZNF139', 'Gene', (66, 72))	('ZNF139', 'Gene', (115, 121))	('splicing', 'biological_process', 'GO:0045292', ('89', '97'))	('splicing exons', 'Var', (89, 103))	('ZNF139', 'Gene', '7586', (66, 72))
37572	32454461	The results demonstrated that cases with alteration in query gene (namely ZNF139) had evidently worse disease-free survival than cases without alteration in ZNF139 (Figure 1C) and high expression of ZNF139 was associated with worse disease free survival (Figure 1D).	('disease-free survival', 'CPA', (102, 123))	('ZNF139', 'Gene', (157, 163))	('ZNF139', 'Gene', (199, 205))	('worse', 'NegReg', (96, 101))	('ZNF139', 'Gene', '7586', (199, 205))	('disease free survival', 'CPA', (232, 253))	('ZNF139', 'Gene', '7586', (74, 80))	('alteration', 'Var', (41, 51))	('ZNF139', 'Gene', '7586', (157, 163))	('high', 'Var', (180, 184))	('si', 'Chemical', '-', (191, 193))	('ZNF139', 'Gene', (74, 80))
37606	32454461	In addition, ZNF139 or circZNF139 overexpression obviously facilitated cell migration and invasion in UC3 and 5637 cells (Figure 6E-H).	('circZNF139', 'Chemical', '-', (23, 33))	('overexpression', 'Var', (34, 48))	('si', 'Chemical', '-', (44, 46))	('ZNF139', 'Gene', (27, 33))	('ZNF139', 'Gene', '7586', (13, 19))	('facilitated', 'PosReg', (59, 70))	('cell migration', 'biological_process', 'GO:0016477', ('71', '85'))	('ZNF139', 'Gene', '7586', (27, 33))	('si', 'Chemical', '-', (94, 96))	('cell migration', 'CPA', (71, 85))	('invasion', 'CPA', (90, 98))	('ZNF139', 'Gene', (13, 19))
37607	32454461	Conversely, ZNF139 or circZNF139 knockdown evidently suppressed cell migration and invasion in UC3 and 5637 cells (Figure 6E-H).	('ZNF139', 'Gene', '7586', (12, 18))	('ZNF139', 'Gene', '7586', (26, 32))	('knockdown', 'Var', (33, 42))	('ZNF139', 'Gene', (26, 32))	('si', 'Chemical', '-', (87, 89))	('cell migration', 'biological_process', 'GO:0016477', ('64', '78'))	('ZNF139', 'Gene', (12, 18))	('circZNF139', 'Chemical', '-', (22, 32))	('suppressed', 'NegReg', (53, 63))	('cell migration', 'CPA', (64, 78))
37764	32188929	Cancers can be caused by an accumulation of genetic mutations in oncogenes or tumor suppressors.	('caused by', 'Reg', (15, 24))	('Cancers', 'Disease', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('genetic mutations', 'Var', (44, 61))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', (78, 83))	('oncogenes', 'Protein', (65, 74))
37765	32188929	These mutations are known as "driver" mutations and they are under positive selection; however, only a very small fraction of somatic mutations in a tumor sample are expected to be drivers.	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (149, 154))
37769	32188929	For example, deleterious mutations in POLE, POLD1, and the MMR system defects may lead to a hypermutated phenotype.	('mutations', 'Var', (25, 34))	('POLE', 'Gene', (38, 42))	('lead to', 'Reg', (82, 89))	('hypermutated phenotype', 'MPA', (92, 114))	('system defects', 'Disease', 'MESH:D009421', (63, 77))	('system defects', 'Disease', (63, 77))	('POLD1', 'Gene', '5424', (44, 49))	('MMR', 'biological_process', 'GO:0006298', ('59', '62'))	('POLD1', 'Gene', (44, 49))
37774	32188929	Microsatellite instability (MSI) is a phenotype of an accumulation of deletions/insertions in repetitive DNA tracts, called microsatellites.	('Microsatellite instability', 'Disease', (0, 26))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('deletions/insertions', 'Var', (70, 90))
37778	32188929	The major challenge is that even though the current well-accepted TMB measurement requires counting the non-synonymous somatic mutations in a paired tumor-normal sample using whole-exome sequencing (WES), current diagnostics based on sequencing technologies still rely heavily on targeted panel sequencing.	('TMB', 'Chemical', '-', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('mutations', 'Var', (127, 136))
37782	32188929	For example, Foundation Medicine used COSMIC to filter out driver mutations and added synonymous mutations to reach an agreement with WES-based TMB.	('mutations', 'Var', (66, 75))	('synonymous mutations', 'Var', (86, 106))	('TMB', 'Chemical', '-', (144, 147))
37794	32188929	The mutation predictions for MUC16 and TTN then became much closer to the observed values (Supplementary Fig.	('TTN', 'Gene', '7273', (39, 42))	('MUC16', 'Gene', (29, 34))	('mutation', 'Var', (4, 12))	('MUC16', 'Gene', '94025', (29, 34))	('TTN', 'Gene', (39, 42))
37795	32188929	In addition, the observed number of non-synonymous mutations in well-known cancer-specific driver genes, such as TP53, KRAS, and PIK3CA, were much higher than the predicted background ones due to positive selection (Supplementary Fig.	('PIK3CA', 'Gene', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('PIK3CA', 'Gene', '5290', (129, 135))	('TP53', 'Gene', '7157', (113, 117))	('KRAS', 'Gene', (119, 123))	('non-synonymous mutations', 'Var', (36, 60))	('higher', 'PosReg', (147, 153))	('KRAS', 'Gene', '3845', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('TP53', 'Gene', (113, 117))
37810	32188929	In contrast, ecTMB predictions, using both synonymous and non-synonymous mutations, not only improved correlation coefficients with WES-based TMB, but also reduced MSE, RMSE, sigma, and biases while keeping the slope close to 1.	('correlation coefficients', 'MPA', (102, 126))	('improved', 'PosReg', (93, 101))	('sigma', 'MPA', (175, 180))	('TMB', 'Chemical', '-', (142, 145))	('reduced', 'NegReg', (156, 163))	('RMSE', 'MPA', (169, 173))	('biases', 'MPA', (186, 192))	('TMB', 'Chemical', '-', (15, 18))	('mutations', 'Var', (73, 82))	('MSE', 'MPA', (164, 167))
37811	32188929	As an example, for the predictions of the TST170 panel, ecTMB improved R from 0.71 to 0.77, reduced MAE from 7.05 to 3.21, and decreased sigma from 6.04 to 4.13 if compared with the counting method without filtering (Fig.	('TMB', 'Chemical', '-', (58, 61))	('decreased', 'NegReg', (127, 136))	('improved', 'PosReg', (62, 70))	('sigma', 'MPA', (137, 142))	('ecTMB', 'Var', (56, 61))	('reduced', 'NegReg', (92, 99))	('MAE', 'MPA', (100, 103))
37813	32188929	These performance metrics demonstrated that TMB prediction by ecTMB has a higher agreement with WES-based TMB.	('tri', 'Chemical', '-', (20, 23))	('TMB', 'Chemical', '-', (106, 109))	('TMB', 'Chemical', '-', (64, 67))	('TMB', 'Disease', (44, 47))	('ecTMB', 'Var', (62, 67))	('TMB', 'Chemical', '-', (44, 47))
37818	32188929	ecTMB prediction had pretty good sensitivity and also high precision, leading to higher overall accuracy when comparing to the other 2 methods (Fig.	('ecTMB', 'Var', (0, 5))	('higher', 'PosReg', (81, 87))	('TMB', 'Chemical', '-', (2, 5))	('accuracy', 'MPA', (96, 104))
37826	32188929	We found that a large fraction (92%) of TMB-extreme samples possessed at least one non-synonymous mutation in POLE in aggregated colorectal, endometrial, and stomach cancer samples, among which we detected a high recurrence of 2 known POLE driver mutations (P286R and V411L) (Supplementary Fig.	('stomach cancer', 'Disease', (158, 172))	('P286R', 'Var', (258, 263))	('V411L', 'Mutation', 'rs1196350669', (268, 273))	('TMB-extreme', 'Gene', (40, 51))	('stomach cancer', 'Disease', 'MESH:D013274', (158, 172))	('TMB', 'Chemical', '-', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('V411L', 'Var', (268, 273))	('stomach cancer', 'Phenotype', 'HP:0012126', (158, 172))	('P286R', 'Mutation', 'p.P286R', (258, 263))	('tri', 'Chemical', '-', (147, 150))
37828	32188929	The comparison of non-synonymous mutations in seven MMR genes between TMB-high samples against the rest revealed 2 highly recurred mutations: N674lfs*6 in MLH3 and K383Rfs*32 in MSH3, which have not been reported as driver mutation before (Supplementary Fig.	('K383Rfs*32', 'Mutation', 'rs587776701', (164, 174))	('MMR', 'biological_process', 'GO:0006298', ('52', '55'))	('N674lfs*6', 'Var', (142, 151))	('MLH3', 'Gene', '27030', (155, 159))	('TMB', 'Chemical', '-', (70, 73))	('MSH3', 'Gene', (178, 182))	('K383Rfs*32', 'Var', (164, 174))	('MLH3', 'Gene', (155, 159))	('MSH3', 'Gene', '4437', (178, 182))
37829	32188929	We also found that TMB-high samples generally had a significantly higher fraction (~17%) of INDEL mutations than what was observed in both TMB-low (~5%) and TMB-extreme (~1%) samples (Fig.	('TMB', 'Chemical', '-', (157, 160))	('INDEL mutations', 'Var', (92, 107))	('higher', 'PosReg', (66, 72))	('TMB', 'Chemical', '-', (19, 22))	('TMB', 'Chemical', '-', (139, 142))
37830	32188929	These distinct mutation profiles suggest that defective MMR system could be the likely cause for TMB-high whereas mutated POLE system for TMB-extreme.	('TMB', 'Chemical', '-', (138, 141))	('TMB', 'Chemical', '-', (97, 100))	('TMB-high', 'Disease', (97, 105))	('MMR', 'Protein', (56, 59))	('defective', 'Var', (46, 55))	('MMR', 'biological_process', 'GO:0006298', ('56', '59'))
37841	32188929	First, ecTMB improves the consistency of TMB prediction among assays through systematic correction of panel design biases.	('consistency', 'MPA', (26, 37))	('TMB', 'Chemical', '-', (41, 44))	('improves', 'PosReg', (13, 21))	('ecTMB', 'Var', (7, 12))	('TMB', 'Chemical', '-', (9, 12))	('TMB', 'MPA', (41, 44))
37844	32188929	Although there are other factors influencing the consistency of TMB among assays, such as sequencing depth and choice of somatic mutation caller, we have demonstrated that ecTMB can help to improve the stability of TMB measurement when those factors are fixed.	('TMB', 'Chemical', '-', (64, 67))	('stability', 'MPA', (202, 211))	('TMB', 'MPA', (215, 218))	('ecTMB', 'Var', (172, 177))	('TMB', 'Chemical', '-', (215, 218))	('improve', 'PosReg', (190, 197))	('TMB', 'Chemical', '-', (174, 177))
37849	32188929	Although multiple studies have observed a better prognosis in MSI-H patients, we showed that TMB-extreme caused by dysfunctional POLE showed even better overall survival outcomes compared to TMB-high (MSI-H).	('patients', 'Species', '9606', (68, 76))	('dysfunctional POLE', 'Var', (115, 133))	('TMB', 'Chemical', '-', (93, 96))	('TMB-extreme', 'Disease', (93, 104))	('TMB', 'Chemical', '-', (191, 194))	('better', 'PosReg', (146, 152))
37850	32188929	Similar to our result, studies have reported that mutations in POLE proofreading domain are associated with improved prognosis in several cancer types, including high-grade glioma, lung adenocarcinoma, endometrial cancer, and colorectal cancer.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (226, 243))	('cancer', 'Disease', (214, 220))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (181, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (181, 200))	('cancer', 'Disease', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('endometrial cancer', 'Phenotype', 'HP:0012114', (202, 220))	('improved', 'PosReg', (108, 116))	('colorectal cancer', 'Disease', 'MESH:D015179', (226, 243))	('endometrial cancer', 'Disease', (202, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('colorectal cancer', 'Disease', (226, 243))	('mutations', 'Var', (50, 59))	('glioma', 'Disease', (173, 179))	('endometrial cancer', 'Disease', 'MESH:D016889', (202, 220))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('lung adenocarcinoma', 'Disease', (181, 200))
37852	32188929	The TMB-extreme subtype can also be potentially detected with an assay targeting only mutations in the POLE's proofreading domain.	('mutations', 'Var', (86, 95))	('TMB', 'Chemical', '-', (4, 7))	('TMB-extreme', 'Disease', (4, 15))	('detected', 'Reg', (48, 56))
37864	32188929	Different proportions of non-synonymous mutations can be used for TMB prediction.	('non-synonymous mutations', 'Var', (25, 49))	('TMB', 'Chemical', '-', (66, 69))	('TMB', 'Disease', (66, 69))
37865	32188929	In BLCA, SKCM, LUSC, and LUAD, which are known to harbor somatic mutations caused by environmental factors, the prediction accuracy increased as a higher proportion of non-synonymous mutations were included (Supplementary Fig.	('LUAD', 'Disease', (25, 29))	('SKCM', 'Disease', (9, 13))	('BLCA', 'Disease', 'MESH:D001749', (3, 7))	('LUSC', 'Disease', 'MESH:D002294', (15, 19))	('increased', 'PosReg', (132, 141))	('LUAD', 'Disease', 'MESH:D000077192', (25, 29))	('LUSC', 'Disease', (15, 19))	('BLCA', 'Disease', (3, 7))	('SKCM', 'Disease', 'MESH:C562393', (9, 13))	('non-synonymous mutations', 'Var', (168, 192))	('LUAD', 'Phenotype', 'HP:0030078', (25, 29))
37892	30327565	The knockdown of CD24 attenuated cancer stemness properties.	('attenuated cancer stemness', 'Disease', (22, 48))	('CD24', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('knockdown', 'Var', (4, 13))	('attenuated cancer stemness', 'Disease', 'MESH:D009369', (22, 48))
37956	30327565	Furthermore, we determined that CD24 knockdown significantly attenuated the anti-apoptotic ability against CDDP treatment in spheroid cells (Fig.	('CD24', 'Gene', (32, 36))	('CDDP', 'Chemical', 'MESH:D002945', (107, 111))	('knockdown', 'Var', (37, 46))	('anti-apoptotic ability', 'CPA', (76, 98))	('attenuated', 'NegReg', (61, 71))
37962	30327565	Seven and eight tumours were developed in a total of ten flanks of five mice injected with spheroid CD24-Ctrl BFTC 909 and CD24-Ctrl BFTC 905 cells, respectively, within a 70-day follow-up period after cell injection.	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('tumours', 'Disease', (16, 23))	('CD24-Ctrl BFTC', 'Var', (123, 137))	('mice', 'Species', '10090', (72, 76))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))
37963	30327565	In contrast, the spheroid CD24-sh cells showed decreased tumour initiation frequency (development of three and four tumours per ten flanks of mice for CD24-sh BFTC 909 and CD24-sh BFTC 905 cells, respectively; Fig.	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('decreased tumour initiation frequency', 'Disease', 'MESH:C565121', (47, 84))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('mice', 'Species', '10090', (142, 146))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('tumours', 'Disease', (116, 123))	('CD24-sh BFTC', 'Var', (172, 184))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('CD24-sh BFTC 909', 'Var', (151, 167))	('decreased tumour initiation frequency', 'Disease', (47, 84))
37965	30327565	In addition, the link of CD24 with CD133, YAP1, and ABCG2 was solidified by our observation of high expression of these molecules in PDX-derived high-CD24-expressing cells, as compared with low-CD24-expressing cells (Fig.	('CD133', 'Gene', (35, 40))	('YAP1', 'Gene', (42, 46))	('ABCG2', 'Gene', (52, 57))	('high-CD24-expressing', 'Var', (145, 165))	('CD133', 'Gene', '8842', (35, 40))	('YAP1', 'Gene', '10413', (42, 46))	('ABCG2', 'Gene', '9429', (52, 57))	('expression', 'MPA', (100, 110))
37966	30327565	Furthermore, the high-CD24-expressing cells grew faster and generated larger tumours than the low-CD24-expressing cells after subcutaneous injection of 1 x 104 cells per flank into NSG mice (Fig.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('larger', 'PosReg', (70, 76))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('faster', 'PosReg', (49, 55))	('tumours', 'Disease', (77, 84))	('mice', 'Species', '10090', (185, 189))	('grew', 'CPA', (44, 48))	('high-CD24-expressing', 'Var', (17, 37))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
37976	30327565	By determining the optimal cut-off using ROC curves for each molecule, the individual sensitivity and specificity of these six molecules (NANOG, CD49f, LGR5, DeltaNp63, SOX2, and CD24) for cancer detection ranged from 29.2% to 62.5% and 83.3 to 100%, respectively (Supplementary Table S2).	('CD49f', 'Gene', (145, 150))	('LGR5', 'Gene', '8549', (152, 156))	('SOX2', 'Gene', '6657', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('NANOG', 'Gene', '79923', (138, 143))	('SOX2', 'Gene', (169, 173))	('NANOG', 'Gene', (138, 143))	('CD49f', 'Gene', '3655', (145, 150))	('CD24', 'Gene', (179, 183))	('DeltaNp63', 'Var', (158, 167))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('LGR5', 'Gene', (152, 156))	('cancer', 'Disease', (189, 195))
37977	30327565	When combination of CD24, CD49f, and NANOG was considered, a high UCB detection accuracy was achieved, with a sensitivity of 83.3% and specificity of 87.5% (Fig.	('NANOG', 'Gene', (37, 42))	('CD24', 'Var', (20, 24))	('UCB', 'Phenotype', 'HP:0006740', (66, 69))	('CD49f', 'Gene', (26, 31))	('NANOG', 'Gene', '79923', (37, 42))	('CD49f', 'Gene', '3655', (26, 31))
37979	30327565	The expression levels of these three molecules (CD24, CD49f, and NANOG) in primary tumour tissues were significantly higher in subjects with positive expression in urine samples than in those with negative urine expression (Supplementary Fig.	('tumour', 'Disease', (83, 89))	('expression levels', 'MPA', (4, 21))	('CD49f', 'Gene', (54, 59))	('NANOG', 'Gene', '79923', (65, 70))	('CD24', 'Var', (48, 52))	('NANOG', 'Gene', (65, 70))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('negative urine', 'Phenotype', 'HP:0100519', (197, 211))	('higher', 'PosReg', (117, 123))	('CD49f', 'Gene', '3655', (54, 59))
37980	30327565	The concordance rate between primary tumours and the matched urine samples (analytical sensitivity) was 77.8% (7/9) for CD24, 70.0% (7/10) for CD49f, and 64.3% (9/14) for NANOG (Fig.	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('CD49f', 'Gene', '3655', (143, 148))	('CD24', 'Var', (120, 124))	('NANOG', 'Gene', (171, 176))	('primary tumours', 'Disease', 'MESH:D009369', (29, 44))	('CD49f', 'Gene', (143, 148))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('primary tumours', 'Disease', (29, 44))	('NANOG', 'Gene', '79923', (171, 176))
37985	30327565	Using the same cut-off as of training cohort, the individual sensitivity and specificity for cancer detection were 35.0% (21/60) and 91.3% (167/183) for CD24, 35.0% (21/60) and 83.6% (153/183) for CD49f, and 51.7% (31/60) and 88.5% (162/183) for NANOG, respectively (Table 2).	('cancer', 'Disease', (93, 99))	('NANOG', 'Gene', (246, 251))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('CD49f', 'Gene', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('NANOG', 'Gene', '79923', (246, 251))	('CD24', 'Var', (153, 157))	('CD49f', 'Gene', '3655', (197, 202))
37987	30327565	Finally, we assessed the UCB detection accuracy by three markers (CD24, CD49f, and NANOG) panel urine testing by combining training and validation cohorts (total 84 and 207 urine samples from UCB and control subjects, respectively).	('CD49f', 'Gene', '3655', (72, 77))	('UCB', 'Phenotype', 'HP:0006740', (192, 195))	('NANOG', 'Gene', '79923', (83, 88))	('CD24', 'Var', (66, 70))	('NANOG', 'Gene', (83, 88))	('UCB', 'Phenotype', 'HP:0006740', (25, 28))	('UCB', 'Disease', (25, 28))	('CD49f', 'Gene', (72, 77))
37995	30327565	demonstrated that treatment with an anti-CD24 monoclonal antibody led to reduced tumour growth and metastasis, resulting in prolonged survival in UCB xenograft model.	('antibody', 'cellular_component', 'GO:0042571', ('57', '65'))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('anti-CD24', 'Gene', (36, 45))	('anti-CD24', 'Var', (36, 45))	('antibody', 'cellular_component', 'GO:0019815', ('57', '65'))	('survival', 'CPA', (134, 142))	('reduced', 'NegReg', (73, 80))	('antibody', 'cellular_component', 'GO:0019814', ('57', '65'))	('tumour', 'Disease', (81, 87))	('antibody', 'molecular_function', 'GO:0003823', ('57', '65'))	('prolonged', 'PosReg', (124, 133))	('UCB', 'Phenotype', 'HP:0006740', (146, 149))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
37997	30327565	We observed the downregulation of several CSC-related molecules such as CD133, ABCG2, and YAP1 in CD24-sh cells and expression level of these molecules were higher in high-CD24-expressing cells, indicating a potential crosstalk between CD24 and these CSC-related molecules.	('ABCG2', 'Gene', (79, 84))	('downregulation', 'NegReg', (16, 30))	('CD133', 'Gene', (72, 77))	('ABCG2', 'Gene', '9429', (79, 84))	('CD133', 'Gene', '8842', (72, 77))	('YAP1', 'Gene', (90, 94))	('YAP1', 'Gene', '10413', (90, 94))	('higher', 'PosReg', (157, 163))	('expression level', 'MPA', (116, 132))	('high-CD24-expressing', 'Var', (167, 187))
38005	30327565	In this study, the combination panel (CD24, CD49f, and NANOG) yielded high sensitivity for cancer detection not only for NMIBC (80.9%), but also for low-grade UCB (80.0%).	('MIBC', 'Disease', 'MESH:D001749', (122, 126))	('cancer', 'Disease', (91, 97))	('CD24', 'Var', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('CD49f', 'Gene', (44, 49))	('UCB', 'Phenotype', 'HP:0006740', (159, 162))	('MIBC', 'Disease', (122, 126))	('NANOG', 'Gene', '79923', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NANOG', 'Gene', (55, 60))	('CD49f', 'Gene', '3655', (44, 49))
38009	30327565	Thus, all the three molecules (CD24, CD49f, and NANOG) act as biologically relevant CSC factors in UCB.	('UCB', 'Phenotype', 'HP:0006740', (99, 102))	('NANOG', 'Gene', '79923', (48, 53))	('CD49f', 'Gene', (37, 42))	('UCB', 'Disease', (99, 102))	('CD24', 'Var', (31, 35))	('NANOG', 'Gene', (48, 53))	('CD49f', 'Gene', '3655', (37, 42))
38060	28649990	A pan-cancer genome-wide analysis reveals tumour dependencies by induction of nonsense-mediated decay Nonsense-mediated decay (NMD) eliminates transcripts with premature termination codons.	('nonsense-mediated decay', 'MPA', (78, 101))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('tumour dependencies', 'Disease', (42, 61))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('transcripts with premature termination codons', 'MPA', (143, 188))	('Nonsense-mediated', 'Var', (102, 119))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('tumour dependencies', 'Disease', 'MESH:D009369', (42, 61))	('eliminates', 'NegReg', (132, 142))
38063	28649990	NMD-elicit mutations in tumour suppressor genes (TSGs) are associated with significant reduction in gene expression.	('mutations', 'Var', (11, 20))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('gene expression', 'biological_process', 'GO:0010467', ('100', '115'))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('TSGs', 'Gene', (49, 53))	('tumour', 'Disease', (24, 30))	('gene expression', 'MPA', (100, 115))	('reduction', 'NegReg', (87, 96))
38066	28649990	Half of hypermutated stomach adenocarcinomas are associated with NMD-elicit mutations of the translation initiators LARP4B and EIF5B.	('stomach adenocarcinomas', 'Disease', (21, 44))	('mutations', 'Var', (76, 85))	('associated', 'Reg', (49, 59))	('EIF5B', 'Gene', '9669', (127, 132))	('translation', 'biological_process', 'GO:0006412', ('93', '104'))	('LARP4B', 'Gene', (116, 122))	('LARP4B', 'Gene', '23185', (116, 122))	('stomach adenocarcinomas', 'Disease', 'MESH:D013274', (21, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('EIF5B', 'Gene', (127, 132))
38067	28649990	Our results unravel strong therapeutic opportunities by targeting tumour dependencies on NMD-elicit mutations.	('mutations', 'Var', (100, 109))	('tumour dependencies', 'Disease', 'MESH:D009369', (66, 85))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumour dependencies', 'Disease', (66, 85))	('NMD-elicit', 'Gene', (89, 99))
38068	28649990	Nonsense-mediated decay (NMD) eliminates transcripts with premature stop codons and has been linked to cancer genesis.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('eliminates', 'NegReg', (30, 40))	('transcripts', 'MPA', (41, 52))	('Nonsense-mediated', 'Var', (0, 17))	('linked', 'Reg', (93, 99))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
38069	28649990	Here, the authors develop an algorithm to predict NMD and perform a pan-cancer analysis that finds that some hypermutated cancers are dependent on mutations that elicit NMD.	('mutations', 'Var', (147, 156))	('dependent', 'Reg', (134, 143))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('hypermutated', 'Disease', (109, 121))	('elicit', 'Reg', (162, 168))	('cancer', 'Disease', (72, 78))
38071	28649990	An example of this is how the inactivation of tumour suppressor genes (TSGs) harbouring PTCs through NMD is thought to contribute to cancer initiation.	('inactivation', 'Var', (30, 42))	('contribute', 'Reg', (119, 129))	('tumour', 'Disease', (46, 52))	('cancer initiation', 'Disease', 'MESH:D009369', (133, 150))	('cancer initiation', 'Disease', (133, 150))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
38074	28649990	Recent work has validated the previously known rules for predicting whether a mutation is likely to elicit NMD (NMD-elicit) or not (NMD-escape), but the global impact of NMD-elicit mutations on cancer has remained unexplored.	('cancer', 'Disease', (194, 200))	('mutation', 'Var', (78, 86))	('NMD', 'Disease', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('elicit', 'Reg', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
38075	28649990	The analysis of over 1 million somatic mutations across 24 cancers from The Cancer Genome Atlas (TCGA) predicts 73,855 NMD-elicit mutations and provides a comprehensive landscape of NMD targeting in 7,725 genomes and corresponding transcriptomes.	('cancers', 'Disease', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (39, 48))	('mutations', 'Var', (130, 139))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('Cancer Genome Atlas', 'Disease', (76, 95))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (76, 95))
38076	28649990	NMD compromises the expression of mutated TSGs, which may facilitate the initiation or progression of cancers.	('facilitate', 'PosReg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('expression', 'MPA', (20, 30))	('cancers', 'Disease', (102, 109))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('compromises', 'NegReg', (4, 15))	('TSGs', 'Protein', (42, 46))	('progression', 'CPA', (87, 98))	('mutated', 'Var', (34, 41))
38077	28649990	We applied our prediction algorithm to all reported somatic mutations from 24 cancers and predicted 73,855 (6%) NMD-elicit mutations (Supplementary Data 1).	('NMD-elicit', 'Disease', (112, 122))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (123, 132))
38078	28649990	Importantly, NMD-escape mutations were not associated with a reduction in the expression of the affected genes compared to silent mutations (median ratio of REV=1, P=0.1, one-side t-test).	('expression', 'MPA', (78, 88))	('REV=1', 'Gene', (157, 162))	('NMD-escape', 'Gene', (13, 23))	('reduction', 'NegReg', (61, 70))	('mutations', 'Var', (24, 33))	('REV=1', 'Gene', '51455', (157, 162))
38079	28649990	Of note, stomach adenocarcinoma (STAD), kidney cancer (KIRP) and colon cancer (COAD) had a disproportionately higher number of NMD-elicit mutations, compared to other cancers with similar mutation frequency (P<0.007, by generalized linear regression; Fig.	('colon cancer', 'Disease', (65, 77))	('stomach adenocarcinoma', 'Disease', (9, 31))	('kidney cancer', 'Disease', (40, 53))	('COAD', 'Disease', (79, 83))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('colon cancer', 'Phenotype', 'HP:0003003', (65, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cancers', 'Disease', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colon cancer', 'Disease', 'MESH:D015179', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (9, 31))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('kidney cancer', 'Disease', 'MESH:D007680', (40, 53))	('COAD', 'Disease', 'MESH:D029424', (79, 83))	('kidney cancer', 'Phenotype', 'HP:0009726', (40, 53))	('mutations', 'Var', (138, 147))
38081	28649990	For example, the two genes that were most widely affected by NMD-elicit mutations were the TSGs TP53 (23 cancer types affected) and NF1 (22 cancer types affected).	('mutations', 'Var', (72, 81))	('NF1', 'Gene', '4763', (132, 135))	('TP53', 'Gene', (96, 100))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('NMD-elicit', 'Gene', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('TP53', 'Gene', '7157', (96, 100))	('NF1', 'Gene', (132, 135))
38082	28649990	For example, NMD-elicit TP53 mutations occurred in 8.8% of all cancer samples (n=7,725), while missense non-synonymous mutations in the same gene occurred in 22.2% of samples.	('TP53', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (29, 38))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('TP53', 'Gene', '7157', (24, 28))
38083	28649990	NMD-elicit mutations in these genes are associated with a significant reduction in gene expression (median ratio of REV=0.07 for NF1, 0.06 for TP53; P<2.2e-16, one-side Mann-Whitney-Wilcoxon (MWW) test and Fig.	('TP53', 'Gene', (143, 147))	('reduction', 'NegReg', (70, 79))	('mutations', 'Var', (11, 20))	('NF1', 'Gene', (129, 132))	('NF1', 'Gene', '4763', (129, 132))	('gene expression', 'biological_process', 'GO:0010467', ('83', '98'))	('gene expression', 'MPA', (83, 98))	('TP53', 'Gene', '7157', (143, 147))
38084	28649990	We conducted a global analysis of all reported mutations in TCGA and observed that the NMD-elicit mutations that had the lowest z-scores (highest magnitude of reduction) and the most frequency tended to occur in known TSGs or the previously reported significantly mutated genes (SMGs) in cancer (Supplementary Fig.	('occur', 'Reg', (203, 208))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('mutations', 'Var', (47, 56))	('TCGA', 'Gene', (60, 64))	('mutations', 'Var', (98, 107))	('cancer', 'Disease', (288, 294))	('TSGs', 'Disease', (218, 222))	('z-scores', 'MPA', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))
38085	28649990	In uterine corpus endometrioid carcinoma (UCEC), bladder urothelial carcinoma (BLCA) and stomach cancer (STAD), more than half of cases had NMD-elicit mutations within TSGs (Fig.	('stomach cancer', 'Disease', (89, 103))	('bladder urothelial carcinoma', 'Disease', (49, 77))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (18, 40))	('TSGs', 'Gene', (168, 172))	('corpus endometrioid carcinoma', 'Disease', (11, 40))	('stomach cancer', 'Disease', 'MESH:D013274', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (49, 77))	('stomach cancer', 'Phenotype', 'HP:0012126', (89, 103))	('corpus endometrioid carcinoma', 'Disease', 'MESH:D016889', (11, 40))	('mutations', 'Var', (151, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
38086	28649990	The list of TSGs or SMGs with highly frequent NMD-elicit mutations varied according to the tumour types (Fig.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('tumour', 'Disease', (91, 97))	('NMD-elicit', 'Gene', (46, 56))	('mutations', 'Var', (57, 66))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
38087	28649990	For example, the ATRX gene frequently harbours NMD-elicit mutations in low grade glioma and sarcoma.	('mutations', 'Var', (58, 67))	('ATRX', 'Gene', (17, 21))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('ATRX', 'Gene', '546', (17, 21))	('glioma', 'Disease', (81, 87))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('sarcoma', 'Disease', (92, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
38088	28649990	APC is often affected by NMD-elicit mutations in colon cancer (COAD) and rectal cancer (READ).	('colon cancer', 'Disease', 'MESH:D015179', (49, 61))	('COAD', 'Disease', 'MESH:D029424', (63, 67))	('COAD', 'Disease', (63, 67))	('APC', 'cellular_component', 'GO:0005680', ('0', '3'))	('affected', 'Reg', (13, 21))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('READ', 'Disease', (88, 92))	('mutations', 'Var', (36, 45))	('rectal cancer', 'Disease', 'MESH:D012004', (73, 86))	('colon cancer', 'Phenotype', 'HP:0003003', (49, 61))	('APC', 'Disease', (0, 3))	('rectal cancer', 'Disease', (73, 86))	('rectal cancer', 'Phenotype', 'HP:0100743', (73, 86))	('READ', 'Disease', 'None', (88, 92))	('colon cancer', 'Disease', (49, 61))
38089	28649990	Of particular note is that BLCA is uniquely affected by KDM6A NMD-elicit mutations when compared with other tumour types.	('tumour', 'Disease', (108, 114))	('NMD-elicit', 'Gene', (62, 72))	('affected', 'Reg', (44, 52))	('KDM6A', 'Gene', (56, 61))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('BLCA', 'Disease', (27, 31))	('KDM6A', 'Gene', '7403', (56, 61))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('mutations', 'Var', (73, 82))
38090	28649990	While single mutations of that type are unlikely to have important functional consequences, several mutations targeting a particular pathway could collectively be selected for to promote tumour survival.	('mutations', 'Var', (100, 109))	('tumour', 'Disease', (187, 193))	('promote', 'PosReg', (179, 186))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('tumour', 'Disease', 'MESH:D009369', (187, 193))
38094	28649990	For example, there was a significant enrichment in NMD-elicit mutations in genes involved in chromatin remodelling/modification, such as SMARCAD1, CHD1, CHD8, HDAC4, BRD3 and TTF1 (FDR<5e-05).	('HDAC4', 'Gene', (159, 164))	('BRD3', 'Gene', (166, 170))	('TTF1', 'Gene', (175, 179))	('CHD1', 'Gene', (147, 151))	('CHD1', 'Gene', '1105', (147, 151))	('TTF1', 'Gene', '7270', (175, 179))	('chromatin', 'cellular_component', 'GO:0000785', ('93', '102'))	('CHD8', 'Gene', (153, 157))	('SMARCAD1', 'Gene', '56916', (137, 145))	('SMARCAD1', 'Gene', (137, 145))	('CHD8', 'Gene', '57680', (153, 157))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('93', '114'))	('mutations', 'Var', (62, 71))	('HDAC4', 'Gene', '9759', (159, 164))	('BRD3', 'Gene', '8019', (166, 170))
38095	28649990	Most notably, there were frequent NMD-elicit mutations in genes such as LARP4B, YTHDC1 and EIF5B (FDR<5e-05 and Fig.	('mutations', 'Var', (45, 54))	('LARP4B', 'Gene', (72, 78))	('YTHDC1', 'Gene', (80, 86))	('LARP4B', 'Gene', '23185', (72, 78))	('EIF5B', 'Gene', (91, 96))	('YTHDC1', 'Gene', '91746', (80, 86))	('NMD-elicit', 'Disease', (34, 44))	('EIF5B', 'Gene', '9669', (91, 96))
38097	28649990	Further analysis revealed an unexpected enrichment of NMD-elicit mutations in LARP4B (22/54 compared) and EIF5B (12/54) in hypermutated stomach adenocarcinoma cases.	('EIF5B', 'Gene', '9669', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (136, 158))	('EIF5B', 'Gene', (106, 111))	('stomach adenocarcinoma', 'Disease', (136, 158))	('LARP4B', 'Gene', (78, 84))	('LARP4B', 'Gene', '23185', (78, 84))	('mutations', 'Var', (65, 74))
38099	28649990	Compared to other cancers, there was a significant enrichment of NMD-elicit mutations in the PTEN of hypermutated STADs (P=4e-05).	('PTEN', 'Gene', (93, 97))	('cancers', 'Disease', (18, 25))	('mutations', 'Var', (76, 85))	('PTEN', 'Gene', '5728', (93, 97))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancers', 'Disease', 'MESH:D009369', (18, 25))
38100	28649990	Interestingly, 21 out of the hypermutated samples, that also had high MSI, with NMD-elicit mutations in LARP4B occurred because of deletion or insertion of a T at position chr10:890939, hg19 in the LARP4B gene.	('LARP4B', 'Gene', (104, 110))	('LARP4B', 'Gene', '23185', (104, 110))	('LARP4B', 'Gene', (198, 204))	('insertion', 'Var', (143, 152))	('MSI', 'Disease', 'None', (70, 73))	('hg19', 'Var', (186, 190))	('mutations', 'Var', (91, 100))	('LARP4B', 'Gene', '23185', (198, 204))	('MSI', 'Disease', (70, 73))	('deletion', 'Var', (131, 139))
38101	28649990	As expected, NMD-elicit mutations in LARP4B were associated with a modest but significant reduction in expression in STAD (median ratio of REV=0.15, FDR=0.017, one-side MWW test).	('reduction', 'NegReg', (90, 99))	('expression', 'MPA', (103, 113))	('STAD', 'MPA', (117, 121))	('LARP4B', 'Gene', (37, 43))	('NMD-elicit', 'Disease', (13, 23))	('LARP4B', 'Gene', '23185', (37, 43))	('mutations', 'Var', (24, 33))
38102	28649990	Similarly, 8 out of 12 NMD-elicit mutations in PTEN occurred because of a deletion of an A (chr10:89717770-A, hg19).	('occurred', 'Reg', (52, 60))	('deletion', 'Var', (74, 82))	('PTEN', 'Gene', (47, 51))	('PTEN', 'Gene', '5728', (47, 51))	('mutations', 'Var', (34, 43))
38103	28649990	NMD-elicit mutations in PTEN were associated with a profound and significant reduction in PTEN expression (median ratio of REV=0.02, FDR=8.7e-05, one-side MWW test).	('expression', 'MPA', (95, 105))	('PTEN', 'Gene', '5728', (24, 28))	('mutations', 'Var', (11, 20))	('PTEN', 'Gene', (90, 94))	('reduction', 'NegReg', (77, 86))	('PTEN', 'Gene', '5728', (90, 94))	('PTEN', 'Gene', (24, 28))
38104	28649990	This revealed that 4 out of 10 cancers with MSI had mutations that would induce PTCs in LARP4B and three of those mutations occurred at the same site mentioned in TCGA data (chr10:890939-T, hg19).	('mutations', 'Var', (52, 61))	('MSI', 'Disease', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('LARP4B', 'Gene', (88, 94))	('LARP4B', 'Gene', '23185', (88, 94))	('induce', 'Reg', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('MSI', 'Disease', 'None', (44, 47))	('cancers', 'Disease', (31, 38))	('cancers', 'Disease', 'MESH:D009369', (31, 38))	('PTCs', 'MPA', (80, 84))
38105	28649990	Two out of the ten MSI samples had frameshift mutations in EIF5B.	('MSI', 'Disease', (19, 22))	('frameshift mutations', 'Var', (35, 55))	('EIF5B', 'Gene', '9669', (59, 64))	('EIF5B', 'Gene', (59, 64))	('MSI', 'Disease', 'None', (19, 22))
38107	28649990	These results indicate that NMD-elicit mutations in these genes play a permissive role and are, therefore, potential therapeutic targets for hypermutated STADs with MSI.	('permissive role', 'MPA', (71, 86))	('MSI', 'Disease', (165, 168))	('MSI', 'Disease', 'None', (165, 168))	('mutations', 'Var', (39, 48))
38109	28649990	We show a global enrichment of NMD-elicit mutations in genes involved in DNA repair, chromatin modifications and RNA stabilization in hypermutated tumours.	('RNA stabilization', 'biological_process', 'GO:0043489', ('113', '130'))	('tumours', 'Phenotype', 'HP:0002664', (147, 154))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumours', 'Disease', 'MESH:D009369', (147, 154))	('tumours', 'Disease', (147, 154))	('chromatin', 'cellular_component', 'GO:0000785', ('85', '94'))	('RNA', 'cellular_component', 'GO:0005562', ('113', '116'))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('mutations', 'Var', (42, 51))	('DNA repair', 'biological_process', 'GO:0006281', ('73', '83'))
38110	28649990	We speculate that this enrichment plays a permissive role to allow the survival of cancer cells with hypermutation and MSI.	('hypermutation', 'Var', (101, 114))	('MSI', 'Disease', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))	('MSI', 'Disease', 'None', (119, 122))
38112	28649990	We found that NMD-elicit mutations target certain TSGs (for example, TP53 and NF1) across all cancer types, which is consistent with previous studies.	('mutations', 'Var', (25, 34))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('NF1', 'Gene', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('NF1', 'Gene', '4763', (78, 81))	('target', 'Reg', (35, 41))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
38113	28649990	We speculate that NMD-elicit mutations would occur less frequently than other LoF mutations in some genes such as TP53, but that they are associated with significant LoF because of reduction in expression particularly in TSGs.	('mutations', 'Var', (29, 38))	('TSGs', 'Disease', (221, 225))	('TP53', 'Gene', '7157', (114, 118))	('mutations', 'Var', (82, 91))	('reduction', 'NegReg', (181, 190))	('expression', 'MPA', (194, 204))	('TP53', 'Gene', (114, 118))	('NMD-elicit', 'Disease', (18, 28))
38114	28649990	The association between NMD-elicit mutations in TSGs and the very low expression level further supports the viewpoint that NMD is a promising target for cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('expression level', 'MPA', (70, 86))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('TSGs', 'Gene', (48, 52))	('NMD-elicit', 'Gene', (24, 34))	('mutations', 'Var', (35, 44))
38117	28649990	It is noteworthy that certain tumours (UCEC, BLCA and STAD) appear to have a higher load of NMD-elicit mutations, suggesting that they may be particularly sensitive to therapeutic targeting of NMD.	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('mutations', 'Var', (103, 112))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('NMD-elicit', 'Gene', (92, 102))	('tumours', 'Disease', (30, 37))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
38119	28649990	In addition, further analysis of the impact of cancer-specific mutational partterns and signatures on potential enrichment of NMD-elicit mutations in particular pathways might provide important insights into the possible dependencies of these tumours on NMD.	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('tumours', 'Phenotype', 'HP:0002664', (243, 250))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('tumours', 'Disease', 'MESH:D009369', (243, 250))	('mutations', 'Var', (137, 146))	('tumours', 'Disease', (243, 250))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
38120	28649990	We observed that NMD-elicit mutations in 'cancer-unrelated' genes caused a modest reduction in expression but clustered in particular pathways presumably to permit the emergence of certain tumour phenotypes.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('reduction', 'NegReg', (82, 91))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('clustered', 'Reg', (110, 119))	('cancer', 'Disease', (42, 48))	('NMD-elicit', 'Disease', (17, 27))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumour', 'Disease', (189, 195))	('mutations', 'Var', (28, 37))	('expression', 'MPA', (95, 105))
38121	28649990	This is reminiscent to the concept of BRCAness, where the dysfunction of many different genes can perturb homologous recombination repair in a relatively large proportion of patients.	('perturb', 'Reg', (98, 105))	('BRCAness', 'Disease', (38, 46))	('dysfunction', 'Var', (58, 69))	('patients', 'Species', '9606', (174, 182))	('homologous recombination', 'biological_process', 'GO:0035825', ('106', '130'))	('homologous recombination repair', 'MPA', (106, 137))
38123	28649990	Moreover, we found that stomach adenocarcinoma (STAD) tends to have disproportionately higher number of NMD-elicit mutations and a mutator phenotype that selects for NMD-elicit mutations in LARP4B, EIF5B and PTEN.	('EIF5B', 'Gene', (198, 203))	('LARP4B', 'Gene', (190, 196))	('PTEN', 'Gene', (208, 212))	('mutations', 'Var', (177, 186))	('LARP4B', 'Gene', '23185', (190, 196))	('PTEN', 'Gene', '5728', (208, 212))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (24, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('EIF5B', 'Gene', '9669', (198, 203))	('stomach adenocarcinoma', 'Disease', (24, 46))
38125	28649990	It is conceivable that NMD-mediated hypofunction of LARP4B or EIF5B permits the hypermutated cancer cells to cope with a high mutation load by delaying translation.	('LARP4B', 'Gene', (52, 58))	('hypofunction of LARP4B', 'Phenotype', 'HP:0045044', (36, 58))	('cancer', 'Disease', (93, 99))	('translation', 'MPA', (152, 163))	('LARP4B', 'Gene', '23185', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('translation', 'biological_process', 'GO:0006412', ('152', '163'))	('delaying', 'NegReg', (143, 151))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('EIF5B', 'Gene', '9669', (62, 67))	('EIF5B', 'Gene', (62, 67))	('hypofunction', 'Var', (36, 48))
38126	28649990	Although the rules that we used to predict NMD-elicit mutation are known to have a significant effect on mRNA levels, other potentially important factors may have been overlooked because of the incomplete understanding of the mechanisms of NMD in humans.	('mRNA levels', 'MPA', (105, 116))	('mutation', 'Var', (54, 62))	('effect', 'Reg', (95, 101))	('humans', 'Species', '9606', (247, 253))
38132	28649990	The first type is the mutations of genes without Entrez gene IDs or with multiple corresponding Entrez gene IDs.	('Entrez gene IDs', 'Disease', 'MESH:C535742', (96, 111))	('Entrez gene IDs', 'Disease', 'MESH:C535742', (49, 64))	('mutations', 'Var', (22, 31))	('Entrez gene IDs', 'Disease', (96, 111))	('Entrez gene IDs', 'Disease', (49, 64))
38138	28649990	We defined the top NMD-affected genes for each cancer as the genes harbouring NMD mutations within over 5% samples.	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (82, 91))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
38168	26657291	In this study, we applied the National Heart, Lung, and Blood Institute's BMI categories of underweight (BMI<18.5), normal weight (18.5 <= BMI < 25), overweight (25 <= BMI < 30), and obesity (BMI >= 30).	('obesity', 'Disease', (183, 190))	('25 <= BMI < 30', 'Var', (162, 176))	('overweight', 'Phenotype', 'HP:0025502', (150, 160))	('obesity', 'Phenotype', 'HP:0001513', (183, 190))	('overweight', 'Disease', (150, 160))	('18.5 <= BMI < 25', 'Var', (131, 147))	('obesity', 'Disease', 'MESH:D009765', (183, 190))
38173	26657291	In addition, cox regression analysis also confirmed the lower mortality in grade 1 obesity (HR=0.76, 95%CI, 0.58-0.99, P = 0.049), grade 2 and grade 3 obesity (HR=0.63, 95%CI, 0.46-0.85, P < 0.001), but not in the overweight group (HR=0.87, 95%CI, 0.70-1.08, P = 0.19), or in the underweight group (HR=1.50, 95%CI, 0.91-2.47, P = 0.115).	('overweight', 'Phenotype', 'HP:0025502', (214, 224))	('obesity', 'Phenotype', 'HP:0001513', (151, 158))	('obesity', 'Phenotype', 'HP:0001513', (83, 90))	('grade 2', 'Var', (131, 138))	('lower', 'NegReg', (56, 61))	('grade 3 obesity', 'Phenotype', 'HP:0025501', (143, 158))	('obesity', 'Disease', 'MESH:D009765', (151, 158))	('grade 1 obesity', 'Phenotype', 'HP:0025499', (75, 90))	('obesity', 'Disease', 'MESH:D009765', (83, 90))	('grade 2 and grade 3 obesity', 'Phenotype', 'HP:0025500', (131, 158))	('obesity', 'Disease', (151, 158))	('obesity', 'Disease', (83, 90))	('mortality', 'MPA', (62, 71))
38297	33668963	Mutations in TERT promoter has been proposed as a good discriminator between nested carcinoma and their mimickers, but this approach is not always available everywhere.	('carcinoma', 'Disease', 'MESH:D009369', (84, 93))	('TERT', 'Gene', (13, 17))	('TERT', 'Gene', '7015', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Disease', (84, 93))
38300	33668963	IGG4 simulates malignancy everywhere since it develops tumor masses that are detectable on radiological exams.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('malignancy', 'Disease', 'MESH:D009369', (15, 25))	('IGG4', 'Var', (0, 4))	('tumor', 'Disease', (55, 60))	('malignancy', 'Disease', (15, 25))	('IGG4', 'cellular_component', 'GO:0071735', ('0', '4'))
38306	33668963	Allelic loss of the TSC2 locus in 16p13 has been detected in PEC and angiomyolipomas, suggesting a common etiopathogenetic pathway of these entities, and, more interestingly, a hypothetical common therapeutic approach.	('TSC2', 'Gene', '7249', (20, 24))	('detected', 'Reg', (49, 57))	('TSC2', 'Gene', (20, 24))	('EC', 'Chemical', '-', (62, 64))	('Allelic loss', 'Var', (0, 12))	('PEC', 'Disease', (61, 64))	('angiomyolipomas', 'Disease', 'MESH:D018207', (69, 84))	('angiomyolipomas', 'Disease', (69, 84))
38376	33546237	Low grade papillary urothelial carcinoma Ta, Hematoxylin and eosin, x100 Low grade papillary urothelial carcinoma Ta, Sema3A, x100 Cells in the basal layer of the mucosa show light Sema3A staining.	('Sema3A', 'Gene', (181, 187))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (83, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('Sema3A', 'Gene', (118, 124))	('x100', 'Var', (126, 130))	('papillary urothelial carcinoma Ta', 'Disease', (10, 43))	('papillary urothelial carcinoma Ta', 'Disease', (83, 116))	('Sema3A', 'Gene', '10371', (181, 187))	('Hematoxylin', 'Chemical', 'MESH:D006416', (45, 56))	('eosin', 'Chemical', 'MESH:D004801', (61, 66))	('papillary urothelial carcinoma Ta', 'Disease', 'MESH:D002291', (10, 43))	('papillary urothelial carcinoma Ta', 'Disease', 'MESH:D002291', (83, 116))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (10, 40))	('Sema3A', 'Gene', '10371', (118, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
38377	33546237	High grade urothelial carcinoma Ta, Hematoxylin and eosin, x200 High grade urothelial carcinoma Ta, Sema3A, x200 Sama3A staining is intense in the entire thickness of the mucosa without any change in stain intensity between the different urothelial layers.	('urothelial carcinoma Ta', 'Disease', (75, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('Hematoxylin', 'Chemical', 'MESH:D006416', (36, 47))	('urothelial carcinoma Ta', 'Disease', 'MESH:D014523', (11, 34))	('Sema3A', 'Gene', (100, 106))	('eosin', 'Chemical', 'MESH:D004801', (52, 57))	('urothelial carcinoma Ta', 'Disease', (11, 34))	('x200', 'Var', (59, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('x200 Sama3A', 'Var', (108, 119))	('Sema3A', 'Gene', '10371', (100, 106))	('urothelial carcinoma Ta', 'Disease', 'MESH:D014523', (75, 98))
38378	33546237	Carcinoma in situ, Hematoxylin and eosin, x200 Carcinoma in situ, Sema3A, x200 The urothelial mucosa was roughly divided into three layers: basal, intermediate, and apical.	('Carcinoma', 'Disease', 'MESH:D009369', (0, 9))	('x200', 'Var', (74, 78))	('Carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('Hematoxylin', 'Chemical', 'MESH:D006416', (19, 30))	('eosin', 'Chemical', 'MESH:D004801', (35, 40))	('Sema3A', 'Gene', (66, 72))	('Carcinoma', 'Phenotype', 'HP:0030731', (0, 9))	('Carcinoma in situ', 'Phenotype', 'HP:0030075', (47, 64))	('Carcinoma', 'Disease', (47, 56))	('x200', 'Var', (42, 46))	('Carcinoma in situ', 'Phenotype', 'HP:0030075', (0, 17))	('Sema3A', 'Gene', '10371', (66, 72))	('Carcinoma', 'Disease', 'MESH:D009369', (47, 56))	('Carcinoma', 'Disease', (0, 9))
38380	33546237	Results showed high expression of Sema3A in the basal (1506.3 +- 914.7), intermediate (1768.1 +- 917.3), and apical (1909.1 +- 961.8) layers of HGUC.	('1768.1', 'Var', (87, 93))	('Sema3A', 'Gene', (34, 40))	('Sema3A', 'Gene', '10371', (34, 40))
38401	33546237	A number of studies showed that low levels of Sema3A were associated with non-small cell lung carcinoma and melanoma.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (78, 103))	('low', 'Var', (32, 35))	('Sema3A', 'Gene', '10371', (46, 52))	('associated', 'Reg', (58, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('low levels of Sema3A', 'Phenotype', 'HP:0032429', (32, 52))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (74, 103))	('lung carcinoma', 'Disease', (89, 103))	('Sema3A', 'Gene', (46, 52))	('lung carcinoma', 'Disease', 'MESH:D008175', (89, 103))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
38421	32498593	It is well known that not only genomic but also epigenomic alterations participate in carcinogenesis in various human organs.	('carcinogenesis', 'Disease', (86, 100))	('participate', 'Reg', (71, 82))	('epigenomic alterations', 'Var', (48, 70))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('human', 'Species', '9606', (112, 117))
38422	32498593	DNA methylation alterations are one of the most important epigenomic changes resulting in chromosomal instability and aberrant expression of tumour-related genes.	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'Gene', (0, 3))	('expression', 'MPA', (127, 137))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('chromosomal instability', 'Phenotype', 'HP:0040012', (90, 113))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('resulting in', 'Reg', (77, 89))	('tumour', 'Disease', (141, 147))	('chromosomal instability', 'CPA', (90, 113))	('methylation alterations', 'Var', (4, 27))
38424	32498593	Moreover, since DNA methylation alterations during carcinogenesis are stably maintained on the DNA double-strand by covalent bonding through a maintenance methylation mechanism involving DNA methyltransferase (DNMT1), such alterations can be regarded as a stable indicator for cancer diagnostics, differing from abnormalities of mRNA or protein expression that are easily affected by the microenvironment of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (408, 414))	('protein', 'cellular_component', 'GO:0003675', ('337', '344'))	('DNMT1', 'Gene', '1786', (210, 215))	('DNA methylation', 'biological_process', 'GO:0006306', ('16', '31'))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('DNA', 'cellular_component', 'GO:0005574', ('187', '190'))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('cancer', 'Disease', 'MESH:D009369', (408, 414))	('methylation', 'biological_process', 'GO:0032259', ('155', '166'))	('carcinogenesis', 'Disease', 'MESH:D063646', (51, 65))	('cancer', 'Disease', (408, 414))	('alterations', 'Var', (223, 234))	('carcinogenesis', 'Disease', (51, 65))	('DNMT1', 'Gene', (210, 215))
38431	32498593	Although we intended to technically verify the DNA methylation levels of the 18 candidate marker CpG sites based on Infinium assay using pyrosequencing, optimization of the PCR conditions was very difficult for pyrosequencing of 5 of the 18 CpG sites (cg05492975, cg10216717, cg16529477, cg18077971, and cg26132774).	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('cg05492975', 'Var', (252, 262))	('DNA methylation', 'biological_process', 'GO:0006306', ('47', '62'))	('cg26132774', 'Var', (304, 314))	('cg10216717', 'Var', (264, 274))	('cg18077971', 'Var', (288, 298))	('Infinium', 'Chemical', '-', (116, 124))	('cg16529477', 'Var', (276, 286))
38432	32498593	In addition, for 3 of the remaining 13 CpG sites (cg01227537, cg08070771, and cg16705627), the measured values did not completely agree with the theoretical values during the optimization procedure.	('cg01227537', 'Var', (50, 60))	('cg08070771', 'Var', (62, 72))	('cg16705627', 'Var', (78, 88))	('cg08070771', 'Chemical', '-', (62, 72))	('cg16705627', 'Chemical', '-', (78, 88))	('cg01227537', 'Chemical', '-', (50, 60))
38433	32498593	On the other hand, the PCR conditions for pyrosequencing were successfully optimized for verification of the remaining 10 candidate marker CpG sites (cg01921432, cg07197785, cg07418387, cg08364561, cg10256242, cg10874111, cg14302471, cg14851578, cg15822765, and cg24035245) (Table S1): linearity of the measured values and consistency of them with the theoretical values for each of the CpG sites are shown in Figure S1.	('cg10256242', 'Chemical', '-', (198, 208))	('cg07418387', 'Var', (174, 184))	('cg07197785', 'Var', (162, 172))	('cg15822765', 'Var', (246, 256))	('cg08364561', 'Var', (186, 196))	('cg14302471', 'Var', (222, 232))	('cg10874111', 'Var', (210, 220))
38445	32498593	It is well known that aberrant DNA methylation participates in even the early and precancerous stages in different organs.	('aberrant', 'Var', (22, 30))	('participates', 'Reg', (47, 59))	('DNA methylation', 'biological_process', 'GO:0006306', ('31', '46'))	('cancerous', 'Disease', (85, 94))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('DNA methylation', 'Protein', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancerous', 'Disease', 'MESH:D009369', (85, 94))
38446	32498593	In particular, we have revealed that DNA methylation levels at numerous CpG sites were actually altered in non-cancerous urothelia showing no marked histological changes, but which were clearly at the precancerous stage due to field cancerization, compared to normal urothelia; thus, DNA methylation abnormalities at the precancerous stage can predict future risk or urothelial carcinogenesis.	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('urothelial carcinogenesis', 'Disease', (367, 392))	('altered', 'Reg', (96, 103))	('cancerous', 'Disease', (204, 213))	('cancerous', 'Disease', (324, 333))	('abnormalities', 'Var', (300, 313))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancerous urothelia', 'Disease', 'MESH:D009369', (111, 130))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (367, 392))	('cancer', 'Disease', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('predict', 'Reg', (344, 351))	('cancerous', 'Disease', 'MESH:D009369', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', (324, 330))	('DNA methylation', 'biological_process', 'GO:0006306', ('284', '299'))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('cancerous', 'Disease', 'MESH:D009369', (204, 213))	('cancerous', 'Disease', 'MESH:D009369', (324, 333))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('DNA', 'cellular_component', 'GO:0005574', ('284', '287'))	('cancerous urothelia', 'Disease', (111, 130))	('cancerous', 'Disease', (111, 120))	('DNA methylation', 'biological_process', 'GO:0006306', ('37', '52'))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (324, 330))
38455	32498593	DNA hypermethylation around the TSS of the BARHL2 gene has been reported in human gastric adenocarcinoma, lung squamous cell carcinoma and astrocytoma.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('reported', 'Reg', (64, 72))	('BARHL2', 'Gene', (43, 49))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (106, 134))	('lung squamous cell carcinoma', 'Disease', (106, 134))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (82, 104))	('gastric adenocarcinoma', 'Disease', (82, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('BARHL2', 'Gene', '343472', (43, 49))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('human', 'Species', '9606', (76, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('astrocytoma', 'Disease', 'MESH:D001254', (139, 150))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('0', '20'))	('astrocytoma', 'Disease', (139, 150))	('astrocytoma', 'Phenotype', 'HP:0009592', (139, 150))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (106, 134))	('hypermethylation', 'Var', (4, 20))
38459	32498593	By analogy, BARHL2 DNA hypermethylation may not only be regarded as a marker of UTUC but may also participate in the development of UTUC by silencing BARHL2.	('BARHL2', 'Gene', (12, 18))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('19', '39'))	('BARHL2', 'Gene', '343472', (12, 18))	('BARHL2', 'Gene', (150, 156))	('silencing', 'NegReg', (140, 149))	('BARHL2', 'Gene', '343472', (150, 156))	('participate', 'Reg', (98, 109))	('hypermethylation', 'Var', (23, 39))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
38467	32498593	Knockdown of the RADIL gene has been reported to efficiently block migration and invasion of breast cancer cell lines in vitro and breast cancer metastasis in a mouse model.	('Knockdown', 'Var', (0, 9))	('RADIL', 'Gene', (17, 22))	('invasion', 'CPA', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer metastasis', 'Disease', 'MESH:D001943', (131, 155))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('migration', 'CPA', (67, 76))	('breast cancer', 'Disease', (93, 106))	('breast cancer metastasis', 'Disease', (131, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('block', 'NegReg', (61, 66))	('mouse', 'Species', '10090', (161, 166))
38468	32498593	In UCs deposited in the TCGA database, the DNA methylation level of the Infinium probe CpG (cg10256242) in the gene body was positively correlated with the level of mRNA expression (r = 0.482, P = 3.60 x 10-26), suggesting that DNA hypomethylation may result in reduced expression.	('cg10256242', 'Chemical', '-', (92, 102))	('DNA', 'cellular_component', 'GO:0005574', ('228', '231'))	('Infinium', 'Chemical', '-', (72, 80))	('reduced', 'NegReg', (262, 269))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('228', '247'))	('mRNA expression', 'MPA', (165, 180))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('DNA methylation', 'biological_process', 'GO:0006306', ('43', '58'))	('hypomethylation', 'Var', (232, 247))	('expression', 'MPA', (270, 280))
38469	32498593	However, to our knowledge, aberrant expression due to DNA methylation alteration of the RADIL gene has never been reported in any human cancers.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('DNA methylation', 'biological_process', 'GO:0006306', ('54', '69'))	('DNA', 'Var', (54, 57))	('RADIL', 'Gene', (88, 93))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('expression', 'MPA', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('human', 'Species', '9606', (130, 135))
38470	32498593	However, if a system for quantification of DNA methylation (such as high-performance liquid chromatography [HPLC]) was able to discriminate diseased cells with DNA methylation abnormalities from contaminating cells, even if the proportion of diseased cells is low; then, our marker might be useful for UTUC diagnosis in patients with haematuria but without any obvious lesion detected by cystoscopy in the urinary bladder.	('haematuria', 'Disease', 'MESH:D006417', (334, 344))	('abnormalities', 'Var', (176, 189))	('DNA methylation', 'biological_process', 'GO:0006306', ('160', '175'))	('DNA', 'cellular_component', 'GO:0005574', ('160', '163'))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('DNA methylation', 'biological_process', 'GO:0006306', ('43', '58'))	('haematuria', 'Disease', (334, 344))	('patients', 'Species', '9606', (320, 328))
38549	33653340	2, a high expression of TUBA1C was significantly associated with the following parameters: different disease states (Tumor or Normal) (P < 0.05), pathological stage (P = 1.82e-04), overall survival (P = 3.8e-05), and disease-free survival (P = 0.047).	('TUBA1C', 'Gene', '84790', (24, 30))	('high', 'Var', (5, 9))	('Tumor', 'Phenotype', 'HP:0002664', (117, 122))	('disease-free survival', 'CPA', (217, 238))	('associated', 'Reg', (49, 59))	('overall survival', 'CPA', (181, 197))	('TUBA1C', 'Gene', (24, 30))
38558	33653340	In particular, activated CD4 T cell, effector memory CD8 T cell, gamma-delta T cell, memory B cell, natural killer T cell, and regulatory T cell were present in higher proportions in the high expression group than in others.	('high expression', 'Var', (187, 202))	('CD8', 'Gene', (53, 56))	('memory', 'biological_process', 'GO:0007613', ('85', '91'))	('CD8', 'Gene', '925', (53, 56))	('CD4', 'Gene', '920', (25, 28))	('memory', 'biological_process', 'GO:0007613', ('46', '52'))	('gamma-delta T cell', 'CPA', (65, 83))	('CD4', 'Gene', (25, 28))
38559	33653340	Moreover, activated B cell, central memory CD4 T cell, eosinophils, immature B cell, mast cell, and type 2 T -helper cell were also present in higher proportion in the high expression group (Fig.	('high expression', 'Var', (168, 183))	('memory', 'biological_process', 'GO:0007613', ('36', '42'))	('CD4', 'Gene', (43, 46))	('CD4', 'Gene', '920', (43, 46))
38602	33653340	These studies have reported that CD4 + Th1 cells and activated CD8 + T cells often elicited type I immune responses, which indicate a favorable prognosis of LUAD; however, Th2, Th17, and Foxp3 + regulatory T (Treg) cells were found to be associated with tumor progression and unfavorable prognosis.	('Th2', 'Var', (172, 175))	('LUAD', 'Phenotype', 'HP:0030078', (157, 161))	('tumor', 'Disease', (254, 259))	('elicited', 'Reg', (83, 91))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('Foxp3', 'Gene', '50943', (187, 192))	('Foxp3', 'Gene', (187, 192))	('CD8', 'Gene', (63, 66))	('Th17', 'CPA', (177, 181))	('type I immune responses', 'MPA', (92, 115))	('associated', 'Reg', (238, 248))	('CD4', 'Gene', (33, 36))	('CD8', 'Gene', '925', (63, 66))	('CD4', 'Gene', '920', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('LUAD', 'Disease', (157, 161))
38672	31277094	As shown in Table 1, the expression of IMP3 was highly related to advanced tumor stage (P < 0.001), advanced tumor grade (P = .004), and tumor recurrence (P < .001) in non-muscle-invasive urothelial carcinomas of the bladder.	('advanced tumor', 'Disease', 'MESH:D020178', (100, 114))	('muscle-invasive urothelial carcinomas', 'Disease', (172, 209))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('advanced tumor', 'Disease', (100, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('tumor', 'Disease', (75, 80))	('advanced tumor', 'Disease', 'MESH:D020178', (66, 80))	('IMP', 'cellular_component', 'GO:0042720', ('39', '42'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('IMP', 'molecular_function', 'GO:0004244', ('39', '42'))	('advanced tumor', 'Disease', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('urothelial carcinomas of the bladder', 'Disease', (188, 224))	('IMP3', 'Gene', (39, 43))	('tumor', 'Disease', (137, 142))	('IMP3', 'Gene', '55272', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('expression', 'Var', (25, 35))	('muscle-invasive urothelial carcinomas', 'Disease', 'MESH:D009217', (172, 209))	('urothelial carcinomas of the bladder', 'Disease', 'MESH:D001749', (188, 224))	('related', 'Reg', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', (109, 114))
38831	29744750	Cisplatin is known to cause nephrotoxicity, neurotoxicity, and ototoxicity.	('neurotoxicity', 'Disease', 'MESH:D020258', (44, 57))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('ototoxicity', 'Disease', (63, 74))	('ototoxicity', 'Disease', 'MESH:D006311', (63, 74))	('Cisplatin', 'Var', (0, 9))	('neurotoxicity', 'Disease', (44, 57))	('nephrotoxicity', 'Disease', (28, 42))	('nephrotoxicity', 'Disease', 'MESH:D007674', (28, 42))
38842	29744750	PD-L1 expression also causes peripheral tolerance of tissue to the immune system.	('PD-L1', 'Gene', (0, 5))	('PD-L1', 'Gene', '29126', (0, 5))	('expression', 'Var', (6, 16))	('causes', 'Reg', (22, 28))
38860	29744750	Immune-mediated adverse events (including colitis, pneumonitis, and transaminitis) occurred in 7% of patients who received atezolizumab following cisplatin therapy and 12% of patients who received atezolizumab as first line therapy.	('pneumonitis', 'Disease', (51, 62))	('patients', 'Species', '9606', (101, 109))	('colitis', 'Disease', 'MESH:D003092', (42, 49))	('atezolizumab', 'Chemical', 'MESH:C000594389', (123, 135))	('colitis', 'Disease', (42, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (146, 155))	('atezolizumab', 'Var', (123, 135))	('Immune-mediated adverse events', 'Disease', (0, 30))	('pneumonitis', 'Disease', 'MESH:D011014', (51, 62))	('patients', 'Species', '9606', (175, 183))	('colitis', 'Phenotype', 'HP:0002583', (42, 49))	('atezolizumab', 'Chemical', 'MESH:C000594389', (197, 209))
38873	29744750	An analysis of the correlation of response to PD-L1 status, demonstrated that patients with >5% PD-L1 expression had an ORR of 28.4%, >1% PD-L1 expression had an ORR of 23.8%, and <1% PD-L1 expression had an ORR of 16.1%.	('PD-L1', 'Gene', (46, 51))	('PD-L1', 'Gene', (184, 189))	('PD-L1', 'Gene', '29126', (96, 101))	('PD-L1', 'Gene', '29126', (184, 189))	('PD-L1', 'Gene', '29126', (46, 51))	('patients', 'Species', '9606', (78, 86))	('expression', 'Var', (102, 112))	('PD-L1', 'Gene', (96, 101))	('PD-L1', 'Gene', (138, 143))	('PD-L1', 'Gene', '29126', (138, 143))
38972	30015865	MicroRNA-665 suppresses the growth and migration of ovarian cancer cells by targeting HOXA10 Ovarian cancer is the most lethal gynecological cancer and its metastasis leads to a poor prognosis.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('migration of ovarian cancer', 'Disease', 'MESH:D010051', (39, 66))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('ovarian cancer', 'Phenotype', 'HP:0100615', (52, 66))	('Ovarian cancer', 'Disease', (93, 107))	('suppresses', 'NegReg', (13, 23))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Ovarian cancer', 'Disease', 'MESH:D010051', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('MicroRNA-665', 'Var', (0, 12))	('HOXA10', 'Gene', (86, 92))	('migration of ovarian cancer', 'Disease', (39, 66))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
38983	30015865	A number of miRs are associated with ovarian cancer, and may regulate tumor progression, function as potential prognostic markers and contribute to drug resistance.	('ovarian cancer', 'Disease', 'MESH:D010051', (37, 51))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('regulate', 'Reg', (61, 69))	('ovarian cancer', 'Disease', (37, 51))	('tumor', 'Disease', (70, 75))	('associated', 'Reg', (21, 31))	('contribute', 'Reg', (134, 144))	('drug resistance', 'Phenotype', 'HP:0020174', (148, 163))	('drug resistance', 'biological_process', 'GO:0009315', ('148', '163'))	('miRs', 'Var', (12, 16))	('ovarian cancer', 'Phenotype', 'HP:0100615', (37, 51))	('drug resistance', 'biological_process', 'GO:0042493', ('148', '163'))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
38988	30015865	For example, by targeting cyclin dependent kinase (CDK1), miR-490-3p inhibits the proliferation, migration and invasion of EOC cells.	('targeting', 'Reg', (16, 25))	('CDK', 'molecular_function', 'GO:0004693', ('51', '54'))	('migration', 'CPA', (97, 106))	('cyclin', 'molecular_function', 'GO:0016538', ('26', '32'))	('inhibits', 'NegReg', (69, 77))	('CDK1', 'Gene', (51, 55))	('miR-490-3p', 'Var', (58, 68))	('CDK1', 'Gene', '983', (51, 55))	('proliferation', 'CPA', (82, 95))	('EOC', 'Phenotype', 'HP:0025318', (123, 126))	('invasion', 'CPA', (111, 119))
39034	30015865	Western blotting was performed to confirm the downregulation of the HOXA10 protein following the miR-665 transfection in HO8910 and OVCAR-3 EOC cells.	('miR-665', 'Gene', (97, 104))	('downregulation', 'NegReg', (46, 60))	('transfection', 'Var', (105, 117))	('HOXA10', 'Gene', '3206', (68, 74))	('EOC', 'Phenotype', 'HP:0025318', (140, 143))	('miR-665', 'Gene', '100126315', (97, 104))	('HOXA10', 'Gene', (68, 74))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('OVCAR-3', 'CellLine', 'CVCL:0465', (132, 139))	('HO8910', 'CellLine', 'CVCL:6868', (121, 127))
39045	30015865	The colony formation capacity of HO8910 and OVCAR-3 cells transfected with miR-665 mimic was significantly inhibited compared with the miR-NC group (P<0.05; Fig.	('miR-665', 'Gene', (75, 82))	('HO8910', 'CellLine', 'CVCL:6868', (33, 39))	('miR-665', 'Gene', '100126315', (75, 82))	('colony formation capacity', 'CPA', (4, 29))	('mimic', 'Var', (83, 88))	('formation', 'biological_process', 'GO:0009058', ('11', '20'))	('OVCAR-3', 'CellLine', 'CVCL:0465', (44, 51))	('inhibited', 'NegReg', (107, 116))
39054	30015865	miR-490-3p overexpression inhibits the proliferation, migration and invasion of tumor cells by directly targeting CDK1.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('inhibits', 'NegReg', (26, 34))	('CDK1', 'Gene', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('migration', 'CPA', (54, 63))	('proliferation', 'CPA', (39, 52))	('miR-490-3p', 'Var', (0, 10))	('targeting', 'Reg', (104, 113))	('overexpression', 'PosReg', (11, 25))	('CDK', 'molecular_function', 'GO:0004693', ('114', '117'))	('CDK1', 'Gene', '983', (114, 118))
39067	30015865	Aberrant HOX gene expression has been reported in several types of cancer, including glioblastoma, oral cancer and gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('oral cancer', 'Disease', 'MESH:D009062', (99, 110))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('oral cancer', 'Disease', (99, 110))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('glioblastoma', 'Disease', (85, 97))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('expression', 'MPA', (18, 28))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('gastric cancer', 'Disease', (115, 129))	('gene expression', 'biological_process', 'GO:0010467', ('13', '28'))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('HOX gene', 'Gene', (9, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('cancer', 'Disease', (67, 73))	('reported', 'Reg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (123, 129))
39159	29731977	Interestingly, the FH gene has not been described as an anticancer target but as a tumor suppressor gene whose loss of function due to germ line mutations results in hereditary leiomyomatosis and renal cell cancer (HLRCC) due to the accumulation of fumarate and succinate.	('tumor suppressor', 'biological_process', 'GO:0051726', ('83', '99'))	('tumor', 'Disease', (83, 88))	('mutations', 'Var', (145, 154))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('HLRCC', 'Disease', (215, 220))	('succinate', 'Chemical', 'MESH:D019802', (262, 271))	('cancer', 'Disease', (207, 213))	('accumulation', 'PosReg', (233, 245))	('fumarate', 'MPA', (249, 257))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('HLRCC', 'Disease', 'MESH:C535516', (215, 220))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (166, 213))	('renal cell cancer', 'Phenotype', 'HP:0005584', (196, 213))	('loss of function', 'NegReg', (111, 127))	('FH', 'Gene', '2271', (19, 21))	('fumarate', 'Chemical', 'MESH:D005650', (249, 257))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('results', 'Reg', (155, 162))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('83', '99'))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
39160	29731977	Renal cancers with non-functional FH genes have been shown to be more dependent on glycolysis and particularly sensitive to its inhibition, which is fully consistent with our predictions.	('glycolysis', 'MPA', (83, 93))	('inhibition', 'NegReg', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Renal cancers', 'Disease', (0, 13))	('dependent', 'MPA', (70, 79))	('Renal cancers', 'Disease', 'MESH:D007680', (0, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('non-functional', 'Var', (19, 33))	('FH', 'Gene', '2271', (34, 36))	('glycolysis', 'biological_process', 'GO:0006096', ('83', '93'))
39172	29731977	High expression of AQP5 has been linked to higher proliferation and metastasis in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('High', 'Var', (0, 4))	('higher', 'PosReg', (43, 49))	('metastasis in lung cancer', 'Disease', (68, 93))	('AQP5', 'Gene', '362', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('metastasis in lung cancer', 'Disease', 'MESH:D009362', (68, 93))	('AQP5', 'Gene', (19, 23))
39284	27884605	Phospho-Ser271 CREB showed facilitated interaction with the TFIID subunit coactivator TAF4 assessed by immunoprecipitation.	('Ser', 'cellular_component', 'GO:0005790', ('8', '11'))	('TAF4', 'Gene', '6874', (86, 90))	('Phospho-Ser271', 'Var', (0, 14))	('TAF4', 'Gene', (86, 90))	('facilitated', 'PosReg', (27, 38))	('interaction', 'Interaction', (39, 50))	('Ser271', 'Chemical', '-', (8, 14))
39288	27884605	Dysfunction and deregulation of CREB can cause cancer development and loss of long-term memory due to disorder of cell proliferation and neuronal plasticity.	('cell proliferation', 'biological_process', 'GO:0008283', ('114', '132'))	('long-term memory', 'CPA', (78, 94))	('Dysfunction', 'Var', (0, 11))	('loss', 'NegReg', (70, 74))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('deregulation', 'Var', (16, 28))	('cause', 'Reg', (41, 46))	('CREB', 'Protein', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('neuronal plasticity', 'CPA', (137, 156))	('long-term memory', 'biological_process', 'GO:0007616', ('78', '94'))
39289	27884605	For instance, CREB overexpression promotes leukemia cell growth and survival, and mutations in RSK2 (ribosomal S6 kinase 2) responsible for CREB phosphorylation or a coactivator of CREB, CBP (CREB binding protein) cause physical abnormalities and mental retardation, Coffin-Lowry syndrome and Rubinstein-Taybi syndrome, respectively.	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('Rubinstein-Taybi syndrome', 'Disease', (293, 318))	('leukemia', 'Disease', (43, 51))	('CBP', 'Gene', (187, 190))	('phosphorylation', 'biological_process', 'GO:0016310', ('145', '160'))	('RSK2', 'Gene', '6197', (95, 99))	('abnormalities and mental retardation', 'Disease', 'MESH:D008607', (229, 265))	('cause', 'Reg', (214, 219))	('CREB binding', 'molecular_function', 'GO:0008140', ('192', '204'))	('ribosomal S6 kinase 2', 'Gene', (101, 122))	('survival', 'CPA', (68, 76))	('CREB binding protein', 'Gene', (192, 212))	('cell growth', 'biological_process', 'GO:0016049', ('52', '63'))	('Rubinstein-Taybi syndrome', 'Disease', 'MESH:D012415', (293, 318))	('Coffin-Lowry syndrome', 'Disease', (267, 288))	('mental retardation', 'Phenotype', 'HP:0001249', (247, 265))	('leukemia', 'Phenotype', 'HP:0001909', (43, 51))	('Coffin-Lowry syndrome', 'Disease', 'MESH:D038921', (267, 288))	('RSK2', 'Gene', (95, 99))	('CBP', 'molecular_function', 'GO:0008140', ('187', '190'))	('CREB binding protein', 'Gene', '1387', (192, 212))	('mutations', 'Var', (82, 91))	('ribosomal S6 kinase 2', 'Gene', '6197', (101, 122))	('leukemia', 'Disease', 'MESH:D007938', (43, 51))
39290	27884605	Furthermore, deficiency of CREB in mouse impairs early development and disrupts neuron survival leading to neurodegeneration.	('CREB', 'Protein', (27, 31))	('neurodegeneration', 'Disease', (107, 124))	('disrupts', 'NegReg', (71, 79))	('deficiency', 'Var', (13, 23))	('neurodegeneration', 'Disease', 'MESH:D019636', (107, 124))	('neuron survival', 'biological_process', 'GO:0043524', ('80', '95'))	('mouse', 'Species', '10090', (35, 40))	('impairs', 'NegReg', (41, 48))	('early development', 'CPA', (49, 66))	('neurodegeneration', 'Phenotype', 'HP:0002180', (107, 124))	('neuron survival', 'CPA', (80, 95))
39295	27884605	Disruption of phosphorylation at Ser133 by expressing a CREB mutant containing a Ser133 to Ala substitution in mice caused somatotroph hypoplasia and dwarfism and dilated cardiomyopathy.	('Ser', 'cellular_component', 'GO:0005790', ('33', '36'))	('Ser', 'cellular_component', 'GO:0005790', ('81', '84'))	('somatotroph hypoplasia', 'Disease', (123, 145))	('somatotroph hypoplasia', 'Phenotype', 'HP:0000824', (123, 145))	('Ser133', 'Gene', (81, 87))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (171, 185))	('dilated cardiomyopathy', 'Disease', (163, 185))	('Ser133', 'Chemical', '-', (33, 39))	('Disruption', 'Var', (0, 10))	('somatotroph hypoplasia', 'Disease', 'MESH:D049912', (123, 145))	('Ser133', 'Chemical', '-', (81, 87))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (163, 185))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('caused', 'Reg', (116, 122))	('dwarfism', 'Phenotype', 'HP:0003510', (150, 158))	('substitution', 'Var', (95, 107))	('Ser133 to Ala', 'Mutation', 'rs746682028', (81, 94))	('mice', 'Species', '10090', (111, 115))	('dwarfism', 'CPA', (150, 158))	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (163, 185))
39301	27884605	In order to characterize the roles of HIPK2 and other nuclear HIPK family members in CREB and ATF1 regulation, we developed rabbit polyclonal antibodies that recognize the region containing the human phospho-Ser271 CREB and phospho-Ser198 ATF1 (Fig.	('phospho-Ser271', 'Var', (200, 214))	('rabbit', 'Species', '9986', (124, 130))	('Ser', 'cellular_component', 'GO:0005790', ('232', '235'))	('phospho-Ser198', 'Var', (224, 238))	('Ser', 'cellular_component', 'GO:0005790', ('208', '211'))	('human', 'Species', '9606', (194, 199))	('Ser271', 'Chemical', '-', (208, 214))	('regulation', 'biological_process', 'GO:0065007', ('99', '109'))	('Ser198', 'Chemical', '-', (232, 238))
39304	27884605	First, to verify the specificity of our phospho-Ser271 CREB and phospho-Ser198 ATF1 antibodies, we transiently cotransfected HIPK2 (wild type (wt) or kinase dead) with CREB [wt, Ser133 to Ala mutant (S133A), Ser271 to Ala mutant (S271A)] or ATF1 [wt or Ser198 to Ala mutant (S198A)] into HEK293 cells, and phosphorylated CREB was detected by Western blotting with these phospho-specific antibodies.	('HEK293', 'CellLine', 'CVCL:0045', (288, 294))	('Ser271 to Ala', 'Mutation', 'p.S271A', (208, 221))	('Ser133', 'Var', (178, 184))	('Ser271 to', 'Var', (208, 217))	('S133A', 'Mutation', 'rs746682028', (200, 205))	('S198A', 'Mutation', 'p.S198A', (275, 280))	('Ser', 'cellular_component', 'GO:0005790', ('208', '211'))	('Ser198', 'Chemical', '-', (72, 78))	('Ser', 'cellular_component', 'GO:0005790', ('72', '75'))	('Ser271', 'Chemical', '-', (208, 214))	('S271A', 'Var', (230, 235))	('Ser271', 'Chemical', '-', (48, 54))	('Ser198 to Ala', 'Mutation', 'p.S198A', (253, 266))	('Ser133 to Ala', 'Mutation', 'rs746682028', (178, 191))	('Ser', 'cellular_component', 'GO:0005790', ('253', '256'))	('Ser', 'cellular_component', 'GO:0005790', ('48', '51'))	('Ser198', 'Chemical', '-', (253, 259))	('S271A', 'Mutation', 'p.S271A', (230, 235))	('Ser', 'cellular_component', 'GO:0005790', ('178', '181'))
39306	27884605	The phosphorylation of CREB Ser271 was enhanced by cotransfection of wt HIPK2 (lane 3) but not by kinase dead HIPK2 (lane 6).	('phosphorylation', 'MPA', (4, 19))	('Ser271', 'Chemical', '-', (28, 34))	('Ser271', 'Var', (28, 34))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('Ser', 'cellular_component', 'GO:0005790', ('28', '31'))	('enhanced', 'PosReg', (39, 47))
39307	27884605	S133A mutant CREB was also efficiently phosphorylated by HIPK2 (lane 4) but S271A mutant CREB was not phosphorylated (lane 5).	('S133A', 'Var', (0, 5))	('S271A', 'Mutation', 'p.S271A', (76, 81))	('S133A', 'Mutation', 'rs746682028', (0, 5))	('S271A', 'Var', (76, 81))
39309	27884605	1c, lanes 5), while S198A mutant ATF1 was not phosphorylated (Fig.	('S198A', 'Mutation', 'p.S198A', (20, 25))	('S198A', 'Var', (20, 25))	('ATF1', 'Gene', (33, 37))
39311	27884605	To verify HIPK2 is a direct CREB and ATF1 kinase as well as to address whether HIPK2 and PKA share the phosphorylation sites in CREB and ATF1, recombinant HIPK2 or PKA was incubated with His-tagged CREB (wt, S133A, or S271A, Fig.	('PKA', 'molecular_function', 'GO:0004691', ('164', '167'))	('S271A', 'Mutation', 'p.S271A', (218, 223))	('S133A', 'Var', (208, 213))	('S271A', 'Var', (218, 223))	('PKA', 'molecular_function', 'GO:0004691', ('89', '92'))	('phosphorylation', 'biological_process', 'GO:0016310', ('103', '118'))	('PKA', 'cellular_component', 'GO:0005952', ('164', '167'))	('PKA', 'cellular_component', 'GO:0005952', ('89', '92'))	('S133A', 'Mutation', 'rs746682028', (208, 213))
39319	27884605	This is also true in ATF1 phosphorylation, in which HIPK2 phosphorylated Ser198 of ATF1 wt and S63A but not S198A (Fig.	('S63A', 'Var', (95, 99))	('Ser', 'cellular_component', 'GO:0005790', ('73', '76'))	('S198A', 'Mutation', 'p.S198A', (108, 113))	('Ser198', 'Var', (73, 79))	('phosphorylation', 'biological_process', 'GO:0016310', ('26', '41'))	('S63A', 'Mutation', 'p.S63A', (95, 99))	('Ser198', 'Chemical', '-', (73, 79))
39323	27884605	First, we performed in vitro kinase assay by incubating His-tagged CREB or ATF1 protein (wt or phosphorylation-deficient Ser to Ala mutants) with recombinant HIPK1, HIPK2, HIPK3, or PKA, followed by Western blotting with our phospho-Ser271 CREB or Ser198 ATF1 antibody.	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('mutants', 'Var', (132, 139))	('Ser', 'Chemical', 'MESH:D012694', (233, 236))	('antibody', 'cellular_component', 'GO:0019815', ('260', '268'))	('Ser', 'cellular_component', 'GO:0005790', ('248', '251'))	('Ser271', 'Chemical', '-', (233, 239))	('phosphorylation', 'biological_process', 'GO:0016310', ('95', '110'))	('HIPK3', 'Gene', '10114', (172, 177))	('Ser198', 'Chemical', '-', (248, 254))	('HIPK1', 'Gene', '204851', (158, 163))	('Ala', 'Chemical', 'MESH:D000409', (128, 131))	('Ser', 'Chemical', 'MESH:D012694', (248, 251))	('antibody', 'cellular_component', 'GO:0019814', ('260', '268'))	('Ser', 'Chemical', 'MESH:D012694', (121, 124))	('PKA', 'cellular_component', 'GO:0005952', ('182', '185'))	('HIPK3', 'Gene', (172, 177))	('Ser', 'cellular_component', 'GO:0005790', ('121', '124'))	('Ser', 'cellular_component', 'GO:0005790', ('233', '236'))	('antibody', 'molecular_function', 'GO:0003823', ('260', '268'))	('PKA', 'molecular_function', 'GO:0004691', ('182', '185'))	('antibody', 'cellular_component', 'GO:0042571', ('260', '268'))	('HIPK1', 'Gene', (158, 163))
39324	27884605	1f, all three HIPKs phosphorylated wt and S133A mutant CREB but failed to phosphorylate CREB S271A mutant.	('CREB', 'Protein', (55, 59))	('S133A mutant', 'Var', (42, 54))	('S133A', 'Mutation', 'rs746682028', (42, 47))	('S271A', 'Mutation', 'p.S271A', (93, 98))
39325	27884605	Likewise, wt and S63A mutant ATF1, but not S198A mutant ATF1, were phosphorylated by HIPK1 and HIPK2 (Fig.	('S63A', 'Var', (17, 21))	('S63A', 'Mutation', 'p.S63A', (17, 21))	('HIPK1', 'Gene', '204851', (85, 90))	('HIPK1', 'Gene', (85, 90))	('S198A', 'Mutation', 'p.S198A', (43, 48))
39335	27884605	Four genes, CCNA1 (cyclin A1), PTGS2, JUNB, and SGK1, were commonly upregulated in CREB transfection and cotransfection with HIPK2 (Fig.	('transfection', 'Var', (88, 100))	('cyclin A1', 'Gene', '8900', (19, 28))	('upregulated', 'PosReg', (68, 79))	('JUNB', 'Gene', '3726', (38, 42))	('PTGS2', 'Gene', (31, 36))	('CCNA1', 'Gene', (12, 17))	('SGK1', 'Gene', (48, 52))	('cyclin A1', 'Gene', (19, 28))	('PTGS2', 'Gene', '5743', (31, 36))	('JUNB', 'Gene', (38, 42))	('PTGS', 'biological_process', 'GO:0016441', ('31', '35'))	('CCNA1', 'Gene', '8900', (12, 17))	('SGK1', 'Gene', '6446', (48, 52))	('cyclin', 'molecular_function', 'GO:0016538', ('19', '25'))
39336	27884605	Among commonly upregulated 4 genes, CCNA1 mRNA was significantly increased by cotransfection of CREB and HIPK2 compared to CREB alone transfection.	('increased', 'PosReg', (65, 74))	('HIPK2', 'Gene', (105, 110))	('CCNA1', 'Gene', (36, 41))	('cotransfection', 'Var', (78, 92))	('CCNA1', 'Gene', '8900', (36, 41))	('mRNA', 'MPA', (42, 46))
39340	27884605	These results suggest that Ser271-phosphorylated CREB induced by HIPK2 has target genes for transcriptional activation.	('Ser', 'cellular_component', 'GO:0005790', ('27', '30'))	('HIPK2', 'Gene', (65, 70))	('Ser271', 'Chemical', '-', (27, 33))	('Ser271-phosphorylated', 'Var', (27, 48))
39357	27884605	To address whether phosphorylation of endogenous CREB at Ser271 and ATF1 at Ser198 is actually induced by xenobiotic stress, SW480 cells were treated with sodium arsenite (Fig.	('Ser271', 'Chemical', '-', (57, 63))	('xenobiotic stress', 'Disease', (106, 123))	('phosphorylation', 'biological_process', 'GO:0016310', ('19', '34'))	('Ser198', 'Var', (76, 82))	('Ser', 'cellular_component', 'GO:0005790', ('76', '79'))	('xenobiotic stress', 'Disease', 'MESH:D004194', (106, 123))	('SW480', 'CellLine', 'CVCL:0546', (125, 130))	('sodium arsenite', 'Chemical', 'MESH:C017947', (155, 170))	('Ser', 'cellular_component', 'GO:0005790', ('57', '60'))	('Ser198', 'Chemical', '-', (76, 82))
39359	27884605	Phosphorylation of CREB at Ser271 was induced by 10 muM sodium arsenite, and the higher concentration of sodium arsenite induced ATF1 phosphorylation at Ser198 along with phosphorylation of CREB at Ser133 and ATF1 at Ser63 (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('171', '186'))	('Ser271', 'Var', (27, 33))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('sodium arsenite', 'Chemical', 'MESH:C017947', (56, 71))	('Ser198', 'Chemical', '-', (153, 159))	('induced', 'Reg', (121, 128))	('phosphorylation', 'MPA', (134, 149))	('Ser', 'cellular_component', 'GO:0005790', ('153', '156'))	('Ser271', 'Chemical', '-', (27, 33))	('phosphorylation', 'biological_process', 'GO:0016310', ('134', '149'))	('Ser', 'cellular_component', 'GO:0005790', ('217', '220'))	('Ser133', 'Chemical', '-', (198, 204))	('Ser', 'cellular_component', 'GO:0005790', ('27', '30'))	('Ser63', 'Chemical', '-', (217, 222))	('induced', 'Reg', (38, 45))	('ATF1', 'Gene', (129, 133))	('Ser198', 'Var', (153, 159))	('sodium arsenite', 'Chemical', 'MESH:C017947', (105, 120))	('Ser', 'cellular_component', 'GO:0005790', ('198', '201'))	('Phosphorylation', 'MPA', (0, 15))
39362	27884605	Arsenic treatment caused 3-fold increase in wt CREB-mediated luciferase expression, while S271A mutation partially impaired CREB activation by arsenic treatment (Fig.	('activation', 'MPA', (129, 139))	('arsenic', 'Chemical', 'MESH:D001151', (143, 150))	('increase', 'PosReg', (32, 40))	('impaired', 'NegReg', (115, 123))	('Arsenic', 'Chemical', 'MESH:D001151', (0, 7))	('S271A', 'Mutation', 'p.S271A', (90, 95))	('expression', 'MPA', (72, 82))	('S271A mutation', 'Var', (90, 104))
39364	27884605	S133A mutant CREB also showed partial impairment of CREB activation (Fig.	('impairment', 'NegReg', (38, 48))	('S133A', 'Var', (0, 5))	('S133A', 'Mutation', 'rs746682028', (0, 5))	('CREB activation', 'CPA', (52, 67))
39368	27884605	4b), and knockdown of HIPK1-3 strongly reduced CREB-mediated luciferase expression (Fig.	('knockdown', 'Var', (9, 18))	('reduced', 'NegReg', (39, 46))	('HIPK1-3', 'Gene', '204851;28996;10114', (22, 29))	('CREB-mediated luciferase', 'Enzyme', (47, 71))	('HIPK1-3', 'Gene', (22, 29))
39370	27884605	CREB transcriptional activity is regulated by coactivators such as CBP through Ser133 phosphorylation and TAF4 through a Q2 glutamine-rich domain.	('TAF4', 'Gene', '6874', (106, 110))	('phosphorylation', 'biological_process', 'GO:0016310', ('86', '101'))	('regulated', 'Reg', (33, 42))	('TAF4', 'Gene', (106, 110))	('glutamine', 'Chemical', 'MESH:D005973', (124, 133))	('CREB', 'Gene', (0, 4))	('Ser133', 'Var', (79, 85))	('CBP', 'Gene', (67, 70))	('Ser', 'cellular_component', 'GO:0005790', ('79', '82'))	('Ser133', 'Chemical', '-', (79, 85))	('CBP', 'molecular_function', 'GO:0008140', ('67', '70'))	('transcriptional activity', 'MPA', (5, 29))
39371	27884605	To address whether these interactions are affected by phosphorylation of CREB at Ser271, we cotransfected CREB (wt, S271E and S133E phosphomimetic mutants) and CBP or TAF4 in HEK293 cells and performed immunoprecipitation/Western blotting to assess their interactions.	('S271E', 'Var', (116, 121))	('S133E', 'Mutation', 'p.S133E', (126, 131))	('TAF4', 'Gene', '6874', (167, 171))	('TAF4', 'Gene', (167, 171))	('CREB', 'Gene', (106, 110))	('S133E', 'Var', (126, 131))	('HEK293', 'CellLine', 'CVCL:0045', (175, 181))	('Ser271', 'Chemical', '-', (81, 87))	('Ser', 'cellular_component', 'GO:0005790', ('81', '84'))	('S271E', 'Mutation', 'p.S271E', (116, 121))	('CBP', 'molecular_function', 'GO:0008140', ('160', '163'))	('CBP', 'Gene', (160, 163))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))
39372	27884605	First, to characterize whether S271E CREB is a conformational mimic of phosphor-Ser271 CREB, we transiently transfected wt or S271E CREB and carried out immunoprecipitation with the phospho-Ser271 CREB antibody.	('Ser', 'cellular_component', 'GO:0005790', ('80', '83'))	('antibody', 'cellular_component', 'GO:0019814', ('202', '210'))	('S271E', 'Var', (126, 131))	('antibody', 'molecular_function', 'GO:0003823', ('202', '210'))	('S271E', 'Var', (31, 36))	('antibody', 'cellular_component', 'GO:0042571', ('202', '210'))	('S271E', 'Mutation', 'p.S271E', (126, 131))	('Ser', 'cellular_component', 'GO:0005790', ('190', '193'))	('Ser271', 'Chemical', '-', (80, 86))	('antibody', 'cellular_component', 'GO:0019815', ('202', '210'))	('S271E', 'Mutation', 'p.S271E', (31, 36))	('Ser271', 'Chemical', '-', (190, 196))
39377	27884605	This fact did not allow us to compare S271E CREB to S133E CREB for their interactions with CBP or TAF4.	('TAF4', 'Gene', '6874', (98, 102))	('S133E', 'Mutation', 'p.S133E', (52, 57))	('S271E', 'Var', (38, 43))	('S133E', 'Var', (52, 57))	('interactions', 'Interaction', (73, 85))	('CBP', 'molecular_function', 'GO:0008140', ('91', '94'))	('S271E', 'Mutation', 'p.S271E', (38, 43))	('TAF4', 'Gene', (98, 102))
39380	27884605	Although phosphomimetic S271E CREB showed no changes in its interaction with CBP compared to wt CREB (Fig.	('interaction', 'Interaction', (60, 71))	('CBP', 'molecular_function', 'GO:0008140', ('77', '80'))	('S271E', 'Mutation', 'p.S271E', (24, 29))	('S271E', 'Var', (24, 29))
39385	27884605	HIPK2 cotransfection induced phosphorylation of CREB at Ser271 and increased immunoprecipitation of TAF4 (Fig.	('cotransfection', 'Var', (6, 20))	('Ser', 'cellular_component', 'GO:0005790', ('56', '59'))	('TAF4', 'Gene', '6874', (100, 104))	('TAF4', 'Gene', (100, 104))	('CREB', 'Protein', (48, 52))	('immunoprecipitation', 'MPA', (77, 96))	('phosphorylation', 'biological_process', 'GO:0016310', ('29', '44'))	('HIPK2', 'Gene', (0, 5))	('increased', 'PosReg', (67, 76))	('Ser271', 'Chemical', '-', (56, 62))	('phosphorylation', 'MPA', (29, 44))
39386	27884605	These results suggest that phosphorylation of CREB at Ser271 may utilize distinct mechanisms of CREB activation from Ser133 phosphorylation through different interactions with coactivators.	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('Ser271', 'Chemical', '-', (54, 60))	('Ser271', 'Var', (54, 60))	('activation', 'PosReg', (101, 111))	('interactions', 'Interaction', (158, 170))	('Ser133', 'Chemical', '-', (117, 123))	('Ser', 'cellular_component', 'GO:0005790', ('54', '57'))	('Ser', 'cellular_component', 'GO:0005790', ('117', '120'))	('phosphorylation', 'biological_process', 'GO:0016310', ('124', '139'))
39389	27884605	HIPK phosphorylation sites of CREB at Ser271 and ATF1 at Ser198 are adjacent to the C-terminal from these KID phosphorylation clusters and localized between the second glutamine-rich (Q2) and basic/b-zip domains.	('Ser198', 'Chemical', '-', (57, 63))	('KID', 'Disease', 'MESH:C536168', (106, 109))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('glutamine', 'Chemical', 'MESH:D005973', (168, 177))	('Ser', 'cellular_component', 'GO:0005790', ('38', '41'))	('Ser271', 'Chemical', '-', (38, 44))	('Ser271', 'Var', (38, 44))	('Ser', 'cellular_component', 'GO:0005790', ('57', '60'))	('Ser198', 'Var', (57, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('110', '125'))	('KID', 'Disease', (106, 109))
39390	27884605	Recently, phosphorylation of CREB at Ser270 and Ser271 by cyclin-dependent kinase 1 (CDK1) during cell cycle G2/M was reported.	('Ser270', 'Chemical', '-', (37, 43))	('cyclin-dependent kinase 1', 'Gene', (58, 83))	('Ser270', 'Var', (37, 43))	('cyclin-dependent kinase 1', 'Gene', '983', (58, 83))	('phosphorylation', 'biological_process', 'GO:0016310', ('10', '25'))	('Ser', 'cellular_component', 'GO:0005790', ('48', '51'))	('cyclin', 'molecular_function', 'GO:0016538', ('58', '64'))	('phosphorylation', 'MPA', (10, 25))	('CDK1', 'Gene', (85, 89))	('cell cycle', 'biological_process', 'GO:0007049', ('98', '108'))	('CDK1', 'Gene', '983', (85, 89))	('Ser271', 'Chemical', '-', (48, 54))	('Ser271', 'Var', (48, 54))	('Ser', 'cellular_component', 'GO:0005790', ('37', '40'))	('CDK', 'molecular_function', 'GO:0004693', ('85', '88'))
39391	27884605	This seems to be a little different from CREB phosphorylation by HIPK2 because we previously shown that HIPK2 is able to phosphorylate CREB only at Ser271 (ATF1 only at Ser198).	('phosphorylation', 'biological_process', 'GO:0016310', ('46', '61'))	('HIPK2', 'Gene', (104, 109))	('Ser', 'cellular_component', 'GO:0005790', ('148', '151'))	('Ser', 'cellular_component', 'GO:0005790', ('169', '172'))	('phosphorylate', 'MPA', (121, 134))	('Ser271', 'Var', (148, 154))	('Ser198', 'Chemical', '-', (169, 175))	('Ser271', 'Chemical', '-', (148, 154))
39392	27884605	No phosphorylation of CREB at Ser270 by HIPK2 is consistent with the fact that HIPK2 belongs to the DYRK (dual-specificity tyrosine-regulated kinase) family that preferentially phosphorylates Ser/Thr flanked by Pro.	('preferentially', 'PosReg', (162, 176))	('DYRK', 'Gene', '1859', (100, 104))	('Ser270', 'Chemical', '-', (30, 36))	('Ser', 'Chemical', 'MESH:D012694', (192, 195))	('Ser270', 'Var', (30, 36))	('DYRK', 'Gene', (100, 104))	('HIPK2', 'Gene', (40, 45))	('dual-specificity tyrosine-regulated kinase', 'Gene', '1859', (106, 148))	('Thr', 'Chemical', 'MESH:D013912', (196, 199))	('dual-specificity tyrosine-regulated kinase', 'Gene', (106, 148))	('phosphorylation', 'biological_process', 'GO:0016310', ('3', '18'))	('Ser', 'cellular_component', 'GO:0005790', ('30', '33'))	('Ser', 'cellular_component', 'GO:0005790', ('192', '195'))	('Ser', 'Chemical', 'MESH:D012694', (30, 33))
39398	27884605	Catalytic activity of HIPK2 is regulated by autophosphorylation of Tyr354 in mouse HIPK2 (equivalent to Tyr361 in human HIPK2) in the activation loop and Thr880/Ser882 (in human HIPK2), along with HIPK2 protein stability via the ubiquitin E3 ligase Siah1 and WSB-1.	('autophosphorylation', 'MPA', (44, 63))	('WSB-1', 'Gene', '26118', (259, 264))	('Tyr354', 'Var', (67, 73))	('human', 'Species', '9606', (114, 119))	('Thr880', 'Chemical', '-', (154, 160))	('Thr880/Ser882', 'Var', (154, 167))	('Catalytic activity', 'MPA', (0, 18))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('WSB-1', 'Gene', (259, 264))	('Ser882', 'Chemical', '-', (161, 167))	('ubiquitin', 'molecular_function', 'GO:0031386', ('229', '238'))	('Tyr354', 'Chemical', '-', (67, 73))	('Tyr361', 'Chemical', '-', (104, 110))	('Catalytic activity', 'molecular_function', 'GO:0003824', ('0', '18'))	('mouse', 'Species', '10090', (77, 82))	('HIPK2', 'Gene', (83, 88))	('Ser', 'cellular_component', 'GO:0005790', ('161', '164'))	('human', 'Species', '9606', (172, 177))	('Siah1', 'Gene', (249, 254))	('Siah1', 'Gene', '6477', (249, 254))
39404	27884605	The autophosphorylated human HIPK2 Tyr361 in the activation loop is highly conserved in HIPK1 (Tyr352) and HIPK3 (Tyr359) and shares the mechanism of kinase activation via autophosphorylation.	('HIPK2', 'Gene', (29, 34))	('Tyr359', 'Chemical', '-', (114, 120))	('Tyr352', 'Chemical', '-', (95, 101))	('Tyr359', 'Var', (114, 120))	('Tyr361', 'Var', (35, 41))	('HIPK1', 'Gene', '204851', (88, 93))	('HIPK3', 'Gene', '10114', (107, 112))	('HIPK1', 'Gene', (88, 93))	('HIPK3', 'Gene', (107, 112))	('human', 'Species', '9606', (23, 28))	('Tyr352', 'Var', (95, 101))	('Tyr361', 'Chemical', '-', (35, 41))
39407	27884605	Our phosphomimetic CREB S271E was indistinguishable from HIPK2-phosphorylated CREB at Ser271 in terms of its retarded migration in SDS-PAGE and successful immunoprecipitation and Western blotting with the phospho-Ser271 CREB antibody (Fig.	('retarded migration', 'Disease', 'MESH:D014085', (109, 127))	('SDS', 'Chemical', 'MESH:D012967', (131, 134))	('antibody', 'molecular_function', 'GO:0003823', ('225', '233'))	('Ser', 'cellular_component', 'GO:0005790', ('213', '216'))	('S271E', 'Var', (24, 29))	('Ser271', 'Chemical', '-', (213, 219))	('retarded migration', 'Disease', (109, 127))	('Ser', 'cellular_component', 'GO:0005790', ('86', '89'))	('antibody', 'cellular_component', 'GO:0042571', ('225', '233'))	('Ser271', 'Chemical', '-', (86, 92))	('antibody', 'cellular_component', 'GO:0019815', ('225', '233'))	('S271E', 'Mutation', 'p.S271E', (24, 29))	('antibody', 'cellular_component', 'GO:0019814', ('225', '233'))
39409	27884605	Later we realized that the Ser133 to Glu substitution in CREB was previously characterized as harboring a more flexible KID and is conformationally different from phosphorylated CREB at Ser133.	('KID', 'Disease', 'MESH:C536168', (120, 123))	('more', 'PosReg', (106, 110))	('Ser', 'cellular_component', 'GO:0005790', ('27', '30'))	('Ser', 'cellular_component', 'GO:0005790', ('186', '189'))	('Ser133', 'Chemical', '-', (186, 192))	('KID', 'Disease', (120, 123))	('Ser133', 'Chemical', '-', (27, 33))	('Ser133 to Glu', 'Var', (27, 40))	('Ser133 to Glu', 'Mutation', 'p.S133E', (27, 40))
39410	27884605	Therefore, we compared S271E with wt CREB for their interactions with CBP and TAF4, in which S271E CREB exhibited no significant changes for interaction with CBP but enhanced interaction with TAF4 (Fig.	('interaction', 'Interaction', (175, 186))	('TAF4', 'Gene', '6874', (192, 196))	('S271E', 'Mutation', 'p.S271E', (93, 98))	('TAF4', 'Gene', (192, 196))	('CBP', 'molecular_function', 'GO:0008140', ('70', '73'))	('S271E', 'Mutation', 'p.S271E', (23, 28))	('CBP', 'molecular_function', 'GO:0008140', ('158', '161'))	('S271E', 'Var', (93, 98))	('enhanced', 'PosReg', (166, 174))	('TAF4', 'Gene', '6874', (78, 82))	('TAF4', 'Gene', (78, 82))
39411	27884605	This was confirmed by the interaction between HIPK2-induced Ser271 phosphorylated CREB and TAF4 (Fig.	('TAF4', 'Gene', (91, 95))	('Ser271', 'Chemical', '-', (60, 66))	('Ser271 phosphorylated', 'Var', (60, 81))	('Ser', 'cellular_component', 'GO:0005790', ('60', '63'))	('interaction', 'Interaction', (26, 37))	('TAF4', 'Gene', '6874', (91, 95))
39414	27884605	Although we did not observe enhanced interaction between CREB S271E and CBP in transfected cells, activation of HIPK2 by arsenic and DNA stress may not only facilitate CREB-TAF4 interaction but also activate p300/CBP through multiple sites of phosphorylation as reported.	('interaction', 'Interaction', (178, 189))	('CBP', 'molecular_function', 'GO:0008140', ('72', '75'))	('HIPK2', 'Gene', (112, 117))	('activate', 'PosReg', (199, 207))	('activation', 'PosReg', (98, 108))	('p300', 'Gene', '2033', (208, 212))	('S271E', 'Mutation', 'p.S271E', (62, 67))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('S271E', 'Var', (62, 67))	('arsenic', 'Chemical', 'MESH:D001151', (121, 128))	('CBP', 'molecular_function', 'GO:0008140', ('213', '216'))	('p300', 'Gene', (208, 212))	('TAF4', 'Gene', '6874', (173, 177))	('phosphorylation', 'biological_process', 'GO:0016310', ('243', '258'))	('TAF4', 'Gene', (173, 177))	('facilitate', 'PosReg', (157, 167))
39430	27884605	The potential mechanism of the transcriptional activation of CREB via Ser271 phosphorylation is its enhanced interaction with TAF4 and associated TFIID complex.	('Ser', 'cellular_component', 'GO:0005790', ('70', '73'))	('Ser271 phosphorylation', 'Var', (70, 92))	('TAF4', 'Gene', '6874', (126, 130))	('TAF4', 'Gene', (126, 130))	('transcriptional', 'MPA', (31, 46))	('enhanced', 'PosReg', (100, 108))	('activation', 'PosReg', (47, 57))	('activation of CREB', 'biological_process', 'GO:0032793', ('47', '65'))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('Ser271', 'Chemical', '-', (70, 76))	('interaction', 'Interaction', (109, 120))
39443	27884605	Mixture of pFR-Luc, pFA2 or pFA2-CREB (wt, S133A, or S271A), and pRL-SV40 as a transfection internal control, was simultaneously transfected into SW480 cells in a 24-well plate.	('S133A', 'Mutation', 'rs746682028', (43, 48))	('pFA2', 'Var', (20, 24))	('S271A', 'Mutation', 'p.S271A', (53, 58))	('pFR', 'cellular_component', 'GO:0097740', ('11', '14'))	('S271A', 'Var', (53, 58))	('SW480', 'CellLine', 'CVCL:0546', (146, 151))	('pFA2-CREB', 'Var', (28, 37))
39454	27884605	His-tagged wt or mutant CREB/ATF-1 proteins were expressed in E. coli and purified through Ni-NTA agarose according to the instructions of pQE vector system (Qiagen).	('agarose', 'Chemical', 'MESH:D012685', (98, 105))	('ATF-1', 'Gene', (29, 34))	('E. coli', 'Species', '562', (62, 69))	('ATF-1', 'Gene', '466', (29, 34))	('Ni-NTA', 'Chemical', '-', (91, 97))	('mutant', 'Var', (17, 23))
39462	27884605	cDNAs were mixed with iTaq Universal SYBR Green Supermix (Bio-Rad) and specific primers for human HIPK2 (QT00051485, Qiagen), human beta-actin and GAPDH (HHK-1, Real Time Primers, LLC, PA), or the other primers as listed below (Sigma).	('Rad', 'biological_process', 'GO:1990116', ('62', '65'))	('GAPDH', 'Gene', '2597', (147, 152))	('human', 'Species', '9606', (126, 131))	('GAPDH', 'Gene', (147, 152))	('QT00051485', 'Var', (105, 115))	('HHK-1', 'Gene', (154, 159))	('HHK-1', 'Gene', '51361', (154, 159))	('Rad', 'Gene', (62, 65))	('LLC', 'cellular_component', 'GO:0038045', ('180', '183'))	('human', 'Species', '9606', (92, 97))	('Rad', 'Gene', '6236', (62, 65))
39465	27884605	Many of these genes are regulated by PKA-induced phosphorylation of CREB at Ser133 signaling to cAMP-response element along with serum-response element and calcium-response element.	('PKA', 'cellular_component', 'GO:0005952', ('37', '40'))	('calcium', 'Chemical', 'MESH:D002118', (156, 163))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('Ser', 'cellular_component', 'GO:0005790', ('76', '79'))	('cAMP', 'Gene', (96, 100))	('cAMP', 'Gene', '820', (96, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('49', '64'))	('regulated', 'Reg', (24, 33))	('Ser133', 'Chemical', '-', (76, 82))	('PKA', 'molecular_function', 'GO:0004691', ('37', '40'))	('phosphorylation', 'Var', (49, 64))
39466	27884605	This PCR array was employed to identify the genes that are also regulated and even further activated by HIPK2-induced phosphorylation of CREB at Ser271.	('phosphorylation', 'Var', (118, 133))	('activated', 'PosReg', (91, 100))	('Ser271', 'Chemical', '-', (145, 151))	('phosphorylation', 'biological_process', 'GO:0016310', ('118', '133'))	('Ser', 'cellular_component', 'GO:0005790', ('145', '148'))
39467	27884605	Total RNA was purified using TRI reagent RT (Molecular Research Center, Cincinnati, OH) 24 hr after transfection of pCMVCREB alone, pCMVFlag-HIPK2 alone, or both of pCMVCREB and pCMVFlag-HIPK2 into HEK293 cells.	('pCMVFlag-HIPK2', 'Var', (132, 146))	('HEK293', 'CellLine', 'CVCL:0045', (198, 204))	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('pCMVFlag-HIPK2', 'Var', (178, 192))
39475	27884605	Phosphorylation of CREB at Ser271 enhances transcription of CREB-target genes.	('Phosphorylation', 'Var', (0, 15))	('Ser', 'cellular_component', 'GO:0005790', ('27', '30'))	('Ser271', 'Var', (27, 33))	('enhances', 'PosReg', (34, 42))	('transcription', 'biological_process', 'GO:0006351', ('43', '56'))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('Ser271', 'Chemical', '-', (27, 33))	('transcription', 'MPA', (43, 56))
39476	27884605	Phosphorylation of CREB at Ser271 facilitates interaction with TAF4.	('TAF4', 'Gene', '6874', (63, 67))	('Ser', 'cellular_component', 'GO:0005790', ('27', '30'))	('TAF4', 'Gene', (63, 67))	('Phosphorylation', 'MPA', (0, 15))	('Ser271', 'Var', (27, 33))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('Ser271', 'Chemical', '-', (27, 33))	('interaction', 'Interaction', (46, 57))	('facilitates', 'PosReg', (34, 45))
39482	16891811	In clear cell RCC, MET expression was positively correlated with high nuclear grade, presence of infiltrative growth, tumoral necrosis, papillary architecture, sarcomatoid component, tumoral involvement of the renal pelvis or ureter, involvement of the calyx, and lymphatic invasion.	('RCC', 'Disease', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumoral necrosis', 'Phenotype', 'HP:0010885', (118, 134))	('necrosis', 'biological_process', 'GO:0008219', ('126', '134'))	('tumoral necrosis', 'Disease', 'MESH:D009336', (118, 134))	('lymphatic invasion', 'CPA', (264, 282))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('rat', 'Species', '10116', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumoral involvement of the renal pelvis or ureter', 'Disease', (183, 232))	('tumoral necrosis', 'Disease', (118, 134))	('correlated', 'Reg', (49, 59))	('tumoral involvement of the renal pelvis or ureter', 'Disease', 'MESH:D014516', (183, 232))	('necrosis', 'biological_process', 'GO:0008220', ('126', '134'))	('renal pelvis', 'Phenotype', 'HP:0000125', (210, 222))	('necrosis', 'biological_process', 'GO:0070265', ('126', '134'))	('necrosis', 'biological_process', 'GO:0019835', ('126', '134'))	('necrosis', 'biological_process', 'GO:0001906', ('126', '134'))	('papillary architecture', 'Disease', (136, 158))	('MET expression', 'MPA', (19, 33))	('sarcomatoid component, tumoral involvement of the renal pelvis', 'Disease', 'MESH:C538614', (160, 222))	('high', 'Var', (65, 69))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
39487	16891811	The evidences implicating the mutation of met in the development of hereditary papillary renal carcinoma have been obtained.	('hereditary papillary renal carcinoma', 'Disease', (68, 104))	('mutation', 'Var', (30, 38))	('met', 'Gene', (42, 45))	('renal carcinoma', 'Phenotype', 'HP:0005584', (89, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (79, 104))	('hereditary papillary renal carcinoma', 'Disease', 'MESH:D007681', (68, 104))
39488	16891811	A gene associated with the hereditary papillary renal carcinoma and a small proportion of sporadic papillary RCC was mapped to a region encompassing the met locus, and the sequencing revealed germline met mutations in affected individuals.	('hereditary papillary renal carcinoma', 'Disease', 'MESH:D007681', (27, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('hereditary papillary renal carcinoma', 'Disease', (27, 63))	('associated', 'Reg', (7, 17))	('germline met mutations', 'Var', (192, 214))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (38, 63))	('renal carcinoma', 'Phenotype', 'HP:0005584', (48, 63))
39525	16891811	Papillary RCC was characterized by trisomy of chromosomes 7, 16, 17 and loss of Y chromosome in male patients in cytogenetics.	('patients', 'Species', '9606', (101, 109))	('loss', 'NegReg', (72, 76))	('trisomy', 'Var', (35, 42))	('Papillary RCC', 'Disease', 'MESH:C538614', (0, 13))	('Papillary RCC', 'Disease', (0, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('Y chromosome', 'cellular_component', 'GO:0000806', ('80', '92'))
39526	16891811	A germline mutation of met gene of 7q31 has been detected in patients with hereditary papillary renal carcinoma as well as a small portion of sporadic papillary RCC.	('met', 'Gene', (23, 26))	('renal carcinoma', 'Phenotype', 'HP:0005584', (96, 111))	('detected', 'Reg', (49, 57))	('germline mutation', 'Var', (2, 19))	('patients', 'Species', '9606', (61, 69))	('RCC', 'Disease', (161, 164))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('hereditary papillary renal carcinoma', 'Disease', 'MESH:D007681', (75, 111))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (86, 111))	('hereditary papillary renal carcinoma', 'Disease', (75, 111))
39527	16891811	In present study, the over expression of MET was detected in 90% of sporadic papillary RCC by the method of immunohistochemistry, which was much higher than the result of the previous study using molecular method that identified met mutations in 13% of sporadic RCC.	('over expression', 'PosReg', (22, 37))	('RCC', 'Disease', 'MESH:C538614', (262, 265))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('sporadic', 'Disease', (68, 76))	('RCC', 'Disease', (262, 265))	('MET', 'Var', (41, 44))	('RCC', 'Phenotype', 'HP:0005584', (262, 265))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
39529	16891811	Trisomy of chromosome 7 has been reported in 95% of sporadic RCC, and it may result in an increased met mRNA copy number, as described by Glukhova et al..	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('increased', 'PosReg', (90, 99))	('chromosome', 'cellular_component', 'GO:0005694', ('11', '21'))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('Trisomy of chromosome', 'Var', (0, 21))	('met mRNA copy number', 'MPA', (100, 120))
39536	16891811	In the study by Lubensky et al., all 6 sporadic RCC with met mutations demonstrated type 1, whereas 10 papillary RCC without met mutations demonstrated both types equally.	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('rat', 'Species', '10116', (146, 149))	('mutations', 'Var', (61, 70))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('rat', 'Species', '10116', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('RCC', 'Disease', (48, 51))	('met mutations', 'Var', (57, 70))
39538	16891811	It is of interest that the diffuse and strong expression of MET was observed in all cases of collecting duct carcinoma, while the majority of chromophobe RCC and all oncocytomas did lack in the expression of MET.	('chromophobe RCC', 'Disease', 'MESH:C538614', (142, 157))	('observed', 'Reg', (68, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('chromophobe RCC', 'Disease', (142, 157))	('MET', 'Var', (60, 63))	('duct carcinoma', 'Disease', (104, 118))	('duct carcinoma', 'Disease', 'MESH:D021441', (104, 118))	('oncocytomas', 'Disease', (166, 177))	('oncocytomas', 'Disease', 'MESH:D018249', (166, 177))
39548	16891811	We demonstrated that MET expression in clear cell RCC were correlated with several clinicopathological parameters, such as infiltrative growth pattern, tumoral necrosis, pelvic or ureteral involvement, calyceal involvement, and lymphatic invasion, which were thought to be related to the invasiveness or aggressiveness of the tumor (Table 2).	('necrosis', 'biological_process', 'GO:0070265', ('160', '168'))	('necrosis', 'biological_process', 'GO:0019835', ('160', '168'))	('MET expression', 'Var', (21, 35))	('rat', 'Species', '10116', (10, 13))	('growth pattern', 'biological_process', 'GO:0040007', ('136', '150'))	('necrosis', 'biological_process', 'GO:0001906', ('160', '168'))	('calyceal involvement', 'Disease', (202, 222))	('aggressiveness of the tumor', 'Disease', (304, 331))	('correlated', 'Reg', (59, 69))	('tumoral necrosis', 'Disease', (152, 168))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('aggressiveness', 'Phenotype', 'HP:0000718', (304, 318))	('RCC', 'Disease', (50, 53))	('aggressiveness of the tumor', 'Disease', 'MESH:D001523', (304, 331))	('infiltrative growth pattern', 'Disease', (123, 150))	('necrosis', 'biological_process', 'GO:0008219', ('160', '168'))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('rat', 'Species', '10116', (129, 132))	('growth pattern', 'biological_process', 'GO:0007150', ('136', '150'))	('necrosis', 'biological_process', 'GO:0008220', ('160', '168'))	('lymphatic', 'Disease', (228, 237))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('tumoral necrosis', 'Phenotype', 'HP:0010885', (152, 168))	('pelvic or ureteral involvement', 'Disease', (170, 200))	('tumoral necrosis', 'Disease', 'MESH:D009336', (152, 168))
39626	33376528	Kaplan-Meier survival analysis demonstrated that high P4HB expression was associated with low OS and RFS.	('P4HB', 'Gene', '5034', (54, 58))	('as', 'Gene', '112935892', (71, 73))	('high', 'Var', (49, 53))	('P4HB', 'Gene', (54, 58))	('as', 'Gene', '112935892', (74, 76))	('RFS', 'Disease', (101, 104))	('low OS', 'Disease', (90, 96))
39719	33376528	The results of IHC demonstrated that high pathological N stage and P4HB protein levels were significantly associated with a poorer RFS by univariate and multivariate analyses (Table II).	('high', 'Var', (37, 41))	('P4HB', 'Gene', '5034', (67, 71))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('RFS', 'MPA', (131, 134))	('poorer', 'NegReg', (124, 130))	('P4HB', 'Gene', (67, 71))	('as', 'Gene', '112935892', (106, 108))
39729	33376528	High P4HB expression was associated with several significant processes that promote tumorigenesis, including N-glycan biosynthesis, pathways in cancer and primary immunodeficiency (Fig.	('promote', 'PosReg', (76, 83))	('N-glycan biosynthesis', 'biological_process', 'GO:0006487', ('109', '130'))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('P4HB', 'Gene', '5034', (5, 9))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('immunodeficiency', 'Phenotype', 'HP:0002721', (163, 179))	('N-glycan biosynthesis', 'MPA', (109, 130))	('High', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('P4HB', 'Gene', (5, 9))	('pathways', 'MPA', (132, 140))	('as', 'Gene', '112935892', (25, 27))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('primary immunodeficiency', 'Disease', (155, 179))	('primary immunodeficiency', 'Disease', 'MESH:D000081207', (155, 179))	('tumor', 'Disease', (84, 89))	('as', 'Gene', '112935892', (22, 24))	('N-glycan', 'Chemical', '-', (109, 117))
39734	33376528	P4HB may catalyze the oxidation, reduction and isomerization of disulfide bonds in the ER, which is essential to maintain homeostasis of the ER.	('P4HB', 'Gene', (0, 4))	('oxidation, reduction', 'biological_process', 'GO:0055114', ('22', '42'))	('isomerization', 'Var', (47, 60))	('homeostasis', 'biological_process', 'GO:0042592', ('122', '133'))	('as', 'Gene', '112935892', (129, 131))	('oxidation', 'MPA', (22, 31))	('P4HB', 'Gene', '5034', (0, 4))	('ER', 'Gene', '2069', (141, 143))	('ER', 'Gene', '2069', (87, 89))	('disulfide', 'Chemical', 'MESH:D004220', (64, 73))
39747	33376528	Furthermore, based on immunohistochemical staining analysis, it was revealed that the expression of P4HB was an independent risk factor for OS and RFS.	('as', 'Gene', '112935892', (14, 16))	('as', 'Gene', '112935892', (65, 67))	('risk factor', 'Reg', (124, 135))	('P4HB', 'Gene', (100, 104))	('RFS', 'Disease', (147, 150))	('P4HB', 'Gene', '5034', (100, 104))	('expression', 'Var', (86, 96))	('as', 'Gene', '112935892', (106, 108))
39758	33376528	In summary, the results of the present study demonstrated that P4HB may be a promising biomarker as it was overexpressed in BLCA and high expression of P4HB was associated with a poor prognosis.	('P4HB', 'Gene', '5034', (152, 156))	('as', 'Gene', '112935892', (161, 163))	('as', 'Gene', '112935892', (104, 106))	('P4HB', 'Gene', (63, 67))	('high', 'Var', (133, 137))	('overexpressed', 'PosReg', (107, 120))	('as', 'Gene', '112935892', (97, 99))	('P4HB', 'Gene', (152, 156))	('P4HB', 'Gene', '5034', (63, 67))	('BLCA', 'Phenotype', 'HP:0009725', (124, 128))	('as', 'Gene', '112935892', (158, 160))
39781	33451333	However, only about ten clinical trials using inhibitors specifically targeting AURKB and most of them are still in phase I stage.	('inhibitors', 'Var', (46, 56))	('AURKB', 'Gene', (80, 85))	('AURKB', 'Gene', '9212', (80, 85))
39785	33451333	Gene amplification, transcriptional activation and inhibition of protein degradation could contribute to the elevated levels of AURKA expression in cancer tissues.	('cancer', 'Disease', (148, 154))	('inhibition', 'NegReg', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('protein degradation', 'biological_process', 'GO:0030163', ('65', '84'))	('expression', 'MPA', (134, 144))	('levels', 'MPA', (118, 124))	('protein degradation', 'MPA', (65, 84))	('elevated', 'PosReg', (109, 117))	('contribute', 'Reg', (91, 101))	('AURKA', 'Gene', '6790', (128, 133))	('activation', 'PosReg', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Gene amplification', 'Var', (0, 18))	('AURKA', 'Gene', (128, 133))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))
39787	33451333	Given that overexpression and gene amplification of AURKA have been identified in diverse cancers, small molecule kinase inhibitors of AURKA have attracted considerable interest.	('AURKA', 'Gene', '6790', (52, 57))	('cancers', 'Disease', (90, 97))	('AURKA', 'Gene', '6790', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('AURKA', 'Gene', (52, 57))	('AURKA', 'Gene', (135, 140))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('overexpression', 'PosReg', (11, 25))	('gene amplification', 'Var', (30, 48))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
39788	33451333	A series of AURKA kinase inhibitors (AKIs) have been produced over the past decades; inhibition of the expression or activity of AURKA by AKIs suppresses cancer cell proliferation, migration and invasion.	('AKIs suppresses cancer', 'Disease', 'MESH:D009369', (138, 160))	('activity', 'MPA', (117, 125))	('cell proliferation', 'biological_process', 'GO:0008283', ('161', '179'))	('expression', 'MPA', (103, 113))	('inhibition', 'Var', (85, 95))	('AURKA', 'Gene', '6790', (129, 134))	('AURKA', 'Gene', '6790', (12, 17))	('AURKA', 'Gene', (129, 134))	('AURKA', 'Gene', (12, 17))	('AKIs suppresses cancer', 'Disease', (138, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
39807	33451333	There is overwhelming evidence of overexpression and gene amplification of AURKA in a wide range of cancers.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('overexpression', 'PosReg', (34, 48))	('AURKA', 'Gene', '6790', (75, 80))	('gene amplification', 'Var', (53, 71))	('AURKA', 'Gene', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
39808	33451333	The underlying mechanisms for AURKA upregulation in cancer include gene amplification, gene mutation, microRNA regulation, transcriptional or posttranscriptional modification, and others.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('microRNA regulation', 'MPA', (102, 121))	('upregulation', 'PosReg', (36, 48))	('regulation', 'biological_process', 'GO:0065007', ('111', '121'))	('AURKA', 'Gene', '6790', (30, 35))	('gene amplification', 'Var', (67, 85))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('gene mutation', 'Var', (87, 100))	('cancer', 'Disease', (52, 58))	('AURKA', 'Gene', (30, 35))
39835	33451333	Likewise, NEDD9 and PUM2 not only stimulate autophosphorylation and autoactivation of AURKA but also stabilize AURKA protein expression through disassociation from cdh.	('disassociation', 'Var', (144, 158))	('AURKA', 'Gene', '6790', (111, 116))	('AURKA', 'Gene', '6790', (86, 91))	('stabilize', 'PosReg', (101, 110))	('PUM2', 'Gene', (20, 24))	('autophosphorylation', 'MPA', (44, 63))	('cdh', 'Protein', (164, 167))	('AURKA', 'Gene', (111, 116))	('AURKA', 'Gene', (86, 91))	('autoactivation', 'MPA', (68, 82))	('stimulate', 'PosReg', (34, 43))	('expression', 'MPA', (125, 135))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('NEDD9', 'Gene', (10, 15))	('PUM2', 'Gene', '23369', (20, 24))	('NEDD9', 'Gene', '4739', (10, 15))
39838	33451333	These regulators are usually tumor suppressors, and inhibition of AURKA is one of the mechanisms explaining their tumor-suppressive functions.	('AURKA', 'Gene', '6790', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('AURKA', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (114, 119))	('inhibition', 'Var', (52, 62))	('tumor', 'Disease', (29, 34))
39846	33451333	GSK-3beta interacts with AURKA and phosphorylates AURKA at Ser290/291 in vitro, after which autophosphorylation occurs at Ser349, which is an AURKA activity-inhibiting phosphorylation site.	('Ser349', 'Chemical', '-', (122, 128))	('AURKA', 'Gene', '6790', (25, 30))	('AURKA', 'Gene', '6790', (142, 147))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('Ser349', 'Var', (122, 128))	('autophosphorylation', 'MPA', (92, 111))	('Ser290', 'Chemical', '-', (59, 65))	('AURKA', 'Gene', (25, 30))	('AURKA', 'Gene', (142, 147))	('AURKA', 'Gene', '6790', (50, 55))	('Ser', 'cellular_component', 'GO:0005790', ('122', '125'))	('Ser', 'cellular_component', 'GO:0005790', ('59', '62'))	('interacts', 'Interaction', (10, 19))	('GSK-3beta', 'Gene', '2931', (0, 9))	('AURKA', 'Gene', (50, 55))	('GSK-3beta', 'Gene', (0, 9))	('phosphorylation', 'biological_process', 'GO:0016310', ('168', '183'))
39854	33451333	Phosphorylation of AURKA by IKK2 targets it for beta-TRCP-mediated degradation and serves to maintain appropriate levels of AURKA to assure proper bipolar spindle assembly and mitotic progression.	('IKK2', 'Gene', (28, 32))	('levels', 'MPA', (114, 120))	('AURKA', 'Gene', '6790', (124, 129))	('AURKA', 'Gene', '6790', (19, 24))	('beta-TRCP', 'Gene', '8945', (48, 57))	('Phosphorylation', 'Var', (0, 15))	('beta-TRCP', 'Gene', (48, 57))	('targets', 'Reg', (33, 40))	('spindle assembly', 'biological_process', 'GO:0051225', ('155', '171'))	('IKK2', 'molecular_function', 'GO:0008384', ('28', '32'))	('degradation', 'biological_process', 'GO:0009056', ('67', '78'))	('AURKA', 'Gene', (124, 129))	('AURKA', 'Gene', (19, 24))	('mitotic progression', 'CPA', (176, 195))	('IKK2', 'Gene', '3551', (28, 32))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('bipolar spindle assembly', 'CPA', (147, 171))	('spindle', 'cellular_component', 'GO:0005819', ('155', '162'))
39860	33451333	VHL is an E3 ligase that multi-monoubiquitinates AURKA in quiescent cells and targets it for proteasome-mediated degradation under both normoxic and hypoxic conditions.	('AURKA', 'Gene', '6790', (49, 54))	('degradation', 'biological_process', 'GO:0009056', ('113', '124'))	('AURKA', 'Gene', (49, 54))	('proteasome-mediated degradation', 'MPA', (93, 124))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (149, 167))	('hypoxic conditions', 'Disease', (149, 167))	('VHL', 'Gene', (0, 3))	('proteasome', 'molecular_function', 'GO:0004299', ('93', '103'))	('proteasome', 'cellular_component', 'GO:0000502', ('93', '103'))	('VHL', 'Gene', '7428', (0, 3))	('multi-monoubiquitinates', 'Var', (25, 48))
39871	33451333	Many of the substrates regulated by AURKA coordinate with AURKA to control mitotic progression, and aberrant expression of AURKA in a variety of human cancers has been linked with mitotic defects.	('linked', 'Reg', (168, 174))	('AURKA', 'Gene', (123, 128))	('AURKA', 'Gene', '6790', (58, 63))	('mitotic progression', 'CPA', (75, 94))	('AURKA', 'Gene', (58, 63))	('mitotic defects', 'Disease', (180, 195))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('human', 'Species', '9606', (145, 150))	('AURKA', 'Gene', '6790', (36, 41))	('aberrant expression', 'Var', (100, 119))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('AURKA', 'Gene', '6790', (123, 128))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('AURKA', 'Gene', (36, 41))	('cancers', 'Disease', (151, 158))	('mitotic defects', 'Disease', 'MESH:C536987', (180, 195))
39878	33451333	ASAP is also a spindle-associated protein, deregulation of which induces severe mitotic defects.	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('ASAP', 'Gene', '79884', (0, 4))	('ASAP', 'Gene', (0, 4))	('induces', 'Reg', (65, 72))	('spindle', 'cellular_component', 'GO:0005819', ('15', '22'))	('mitotic defects', 'Disease', 'MESH:C536987', (80, 95))	('deregulation', 'Var', (43, 55))	('mitotic defects', 'Disease', (80, 95))
39880	33451333	The AURKA activator TPX2 is an AURKA substrate with phosphorylation sites at Ser121 and Ser125.	('Ser121', 'Var', (77, 83))	('AURKA', 'Gene', (4, 9))	('AURKA', 'Gene', '6790', (31, 36))	('Ser', 'cellular_component', 'GO:0005790', ('88', '91'))	('Ser125', 'Chemical', '-', (88, 94))	('AURKA', 'Gene', (31, 36))	('TPX2', 'Gene', (20, 24))	('Ser', 'cellular_component', 'GO:0005790', ('77', '80'))	('Ser121', 'Chemical', '-', (77, 83))	('Ser125', 'Var', (88, 94))	('AURKA', 'Gene', '6790', (4, 9))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('TPX2', 'Gene', '22974', (20, 24))
39890	33451333	Research has shown that AURKA phosphorylation of Twist at Ser123, Thr148 and Ser184 facilitates Twist-mediated promotion of EMT and chemoresistance in pancreatic cancer cells.	('Twist', 'Gene', '7291', (96, 101))	('Twist', 'Gene', '7291', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('facilitates', 'PosReg', (84, 95))	('Ser', 'cellular_component', 'GO:0005790', ('58', '61'))	('promotion', 'PosReg', (111, 120))	('EMT', 'biological_process', 'GO:0001837', ('124', '127'))	('Ser', 'cellular_component', 'GO:0005790', ('77', '80'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('Ser123', 'Chemical', '-', (58, 64))	('AURKA', 'Gene', '6790', (24, 29))	('AURKA', 'Gene', (24, 29))	('Thr148', 'Var', (66, 72))	('Twist', 'Gene', (96, 101))	('Twist', 'Gene', (49, 54))	('Ser184', 'Chemical', '-', (77, 83))	('pancreatic cancer', 'Disease', 'MESH:D010190', (151, 168))	('Thr148', 'Chemical', '-', (66, 72))	('phosphorylation', 'biological_process', 'GO:0016310', ('30', '45'))	('Ser184', 'Var', (77, 83))	('pancreatic cancer', 'Disease', (151, 168))
39899	33451333	Phosphorylation of LDHB by AURKA at Ser162 amplifies its activity in reducing pyruvate to lactate, thus promoting glycolysis and biosynthesis and promoting tumor growth.	('Ser162', 'Chemical', '-', (36, 42))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('tumor', 'Disease', (156, 161))	('AURKA', 'Gene', '6790', (27, 32))	('reducing pyruvate to lactate', 'MPA', (69, 97))	('promoting', 'PosReg', (146, 155))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('AURKA', 'Gene', (27, 32))	('Ser162', 'Var', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('glycolysis', 'biological_process', 'GO:0006096', ('114', '124'))	('lactate', 'Chemical', 'MESH:D019344', (90, 97))	('pyruvate', 'Chemical', 'MESH:D019289', (78, 86))	('glycolysis', 'MPA', (114, 124))	('biosynthesis', 'MPA', (129, 141))	('promoting', 'PosReg', (104, 113))	('Ser', 'cellular_component', 'GO:0005790', ('36', '39'))	('Phosphorylation', 'MPA', (0, 15))	('LDHB', 'Gene', (19, 23))	('biosynthesis', 'biological_process', 'GO:0009058', ('129', '141'))	('LDHB', 'Gene', '3945', (19, 23))
39900	33451333	Recently, our research has indicated that phosphorylation of the scaffold and oncogenic protein SDCBP by AURKA maintains its protein stability and pro-proliferative functions.	('SDCBP', 'Gene', (96, 101))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('pro-proliferative functions', 'CPA', (147, 174))	('maintains', 'PosReg', (111, 120))	('protein stability', 'MPA', (125, 142))	('SDCBP', 'Gene', '6386', (96, 101))	('AURKA', 'Gene', '6790', (105, 110))	('phosphorylation', 'Var', (42, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('AURKA', 'Gene', (105, 110))
39903	33451333	HURP protein stability and serum-independent growth are enhanced after phosphorylation.	('phosphorylation', 'Var', (71, 86))	('HURP', 'Gene', '9787', (0, 4))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))	('enhanced', 'PosReg', (56, 64))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('serum-independent growth', 'CPA', (27, 51))	('HURP', 'Gene', (0, 4))
39907	33451333	AURKA regulates LIMK2 kinase activity, subcellular localization and protein levels by directly phosphorylating LIMK2 at Ser283, Thr494 and Thr505.	('LIMK2', 'Gene', '3985', (111, 116))	('LIMK2', 'Gene', '3985', (16, 21))	('AURKA', 'Gene', '6790', (0, 5))	('AURKA', 'Gene', (0, 5))	('Ser', 'cellular_component', 'GO:0005790', ('120', '123'))	('activity', 'MPA', (29, 37))	('localization', 'biological_process', 'GO:0051179', ('51', '63'))	('Thr505', 'Var', (139, 145))	('Thr494', 'Chemical', '-', (128, 134))	('protein levels', 'MPA', (68, 82))	('Ser283', 'Chemical', '-', (120, 126))	('subcellular localization', 'MPA', (39, 63))	('LIMK2', 'Gene', (111, 116))	('Ser283', 'Var', (120, 126))	('LIMK2', 'Gene', (16, 21))	('regulates', 'Reg', (6, 15))	('Thr494', 'Var', (128, 134))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('Thr505', 'Chemical', '-', (139, 145))	('kinase activity', 'molecular_function', 'GO:0016301', ('22', '37'))
39908	33451333	The small GTPase RalA is also a target of AURKA; phosphorylation of RalA at Ser194 enhances cell migration and anchorage-independent growth.	('cell migration', 'biological_process', 'GO:0016477', ('92', '106'))	('anchorage-independent growth', 'CPA', (111, 139))	('AURKA', 'Gene', (42, 47))	('RalA', 'Gene', (68, 72))	('RalA', 'Gene', (17, 21))	('Ser194', 'Chemical', '-', (76, 82))	('Ser', 'cellular_component', 'GO:0005790', ('76', '79'))	('RalA', 'Gene', '5898', (68, 72))	('phosphorylation', 'biological_process', 'GO:0016310', ('49', '64'))	('enhances', 'PosReg', (83, 91))	('AURKA', 'Gene', '6790', (42, 47))	('cell migration', 'CPA', (92, 106))	('RalA', 'Gene', '5898', (17, 21))	('phosphorylation', 'Var', (49, 64))
39909	33451333	ALDH1A1 is an AURKA substrate enzyme whose phosphorylation by AURKA at Thr267, Thr442 and Thr493 regulates ALDH1A1 protein stability, enhancing the role of this protein in the process of EMT.	('Thr267', 'Chemical', '-', (71, 77))	('Thr442', 'Chemical', '-', (79, 85))	('phosphorylation', 'MPA', (43, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('ALDH', 'molecular_function', 'GO:0004030', ('0', '4'))	('ALDH1A1', 'Gene', '216', (107, 114))	('ALDH1A1', 'Gene', (0, 7))	('enhancing', 'PosReg', (134, 143))	('regulates', 'Reg', (97, 106))	('Thr493', 'Var', (90, 96))	('ALDH1A1', 'Gene', '216', (0, 7))	('Thr493', 'Chemical', '-', (90, 96))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('AURKA', 'Gene', '6790', (14, 19))	('AURKA', 'Gene', '6790', (62, 67))	('AURKA', 'Gene', (14, 19))	('AURKA', 'Gene', (62, 67))	('ALDH1A1', 'Gene', (107, 114))	('EMT', 'biological_process', 'GO:0001837', ('187', '190'))	('protein stability', 'MPA', (115, 132))	('ALDH', 'molecular_function', 'GO:0004030', ('107', '111'))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))
39912	33451333	However, Ser106 residue phosphorylation by AURKA has the opposite effect.	('phosphorylation', 'biological_process', 'GO:0016310', ('24', '39'))	('Ser', 'cellular_component', 'GO:0005790', ('9', '12'))	('Ser106', 'Chemical', '-', (9, 15))	('AURKA', 'Gene', '6790', (43, 48))	('AURKA', 'Gene', (43, 48))	('Ser106 residue', 'Var', (9, 23))
39914	33451333	Another study has revealed that the p53 Ser215 site is phosphorylated by AURKA.	('AURKA', 'Gene', '6790', (73, 78))	('Ser', 'cellular_component', 'GO:0005790', ('40', '43'))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('AURKA', 'Gene', (73, 78))	('Ser215', 'Var', (40, 46))	('Ser215', 'Chemical', '-', (40, 46))
39917	33451333	Phosphorylation of RASSF1A by AURKA at Ser203 and Thr202 removes the ability of RASSF1A to interact with microtubules and induce M-phase cell cycle arrest.	('Thr202', 'Var', (50, 56))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('137', '154'))	('RASSF1A', 'Gene', '11186', (19, 26))	('Phosphorylation', 'Var', (0, 15))	('interact', 'Interaction', (91, 99))	('arrest', 'Disease', (148, 154))	('Ser203', 'Chemical', '-', (39, 45))	('RASSF1A', 'Gene', (19, 26))	('Ser', 'cellular_component', 'GO:0005790', ('39', '42'))	('Thr202', 'Chemical', '-', (50, 56))	('microtubules', 'Protein', (105, 117))	('removes', 'NegReg', (57, 64))	('RASSF1A', 'Gene', '11186', (80, 87))	('arrest', 'Disease', 'MESH:D006323', (148, 154))	('RASSF1A', 'Gene', (80, 87))	('AURKA', 'Gene', '6790', (30, 35))	('M-phase', 'biological_process', 'GO:0000279', ('129', '136'))	('induce', 'Reg', (122, 128))	('ability', 'MPA', (69, 76))	('AURKA', 'Gene', (30, 35))
39921	33451333	Phosphorylation of LKB1 at Ser299 causes LKB1 to dissociate from AMPK, resulting in impairment of the AMPK signaling pathway and facilitating non-small-cell lung cancer (NSCLC) growth and migration.	('LKB1', 'Gene', '6794', (19, 23))	('LKB1', 'Gene', '6794', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('AMPK', 'molecular_function', 'GO:0047322', ('102', '106'))	('Phosphorylation', 'Var', (0, 15))	('AMPK', 'molecular_function', 'GO:0050405', ('65', '69'))	('facilitating', 'PosReg', (129, 141))	('signaling pathway', 'biological_process', 'GO:0007165', ('107', '124'))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (146, 168))	('AMPK', 'Gene', (65, 69))	('LKB1', 'Gene', (19, 23))	('AMPK', 'Gene', '5564', (65, 69))	('small-cell lung cancer', 'Disease', (146, 168))	('Ser299', 'Var', (27, 33))	('LKB1', 'Gene', (41, 45))	('AMPK', 'molecular_function', 'GO:0050405', ('102', '106'))	('Ser', 'cellular_component', 'GO:0005790', ('27', '30'))	('NSCLC', 'Disease', (170, 175))	('AMPK', 'molecular_function', 'GO:0004691', ('65', '69'))	('Ser299', 'Chemical', '-', (27, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('AMPK', 'Gene', (102, 106))	('impairment', 'NegReg', (84, 94))	('AMPK', 'Gene', '5564', (102, 106))	('AMPK', 'molecular_function', 'GO:0004691', ('102', '106'))	('AMPK', 'molecular_function', 'GO:0047322', ('65', '69'))
39928	33451333	Once YY1 is phosphorylated by AURKA at Ser365, its DNA-binding activity and transcriptional activity are abolished.	('YY1', 'Gene', '7528', (5, 8))	('DNA-binding', 'Interaction', (51, 62))	('YY1', 'Gene', (5, 8))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('51', '62'))	('Ser365', 'Var', (39, 45))	('transcriptional activity', 'MPA', (76, 100))	('AURKA', 'Gene', '6790', (30, 35))	('Ser365', 'Chemical', '-', (39, 45))	('abolished', 'NegReg', (105, 114))	('Ser', 'cellular_component', 'GO:0005790', ('39', '42'))	('AURKA', 'Gene', (30, 35))
39931	33451333	AURKA-mediated phosphorylation of CHIP at Ser273 promotes androgen degradation in castration-resistant prostate cancer.	('AURKA', 'Gene', (0, 5))	('Ser', 'cellular_component', 'GO:0005790', ('42', '45'))	('phosphorylation', 'Var', (15, 30))	('prostate cancer', 'Disease', 'MESH:D011471', (103, 118))	('promotes', 'PosReg', (49, 57))	('Ser273', 'Chemical', '-', (42, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('AURKA', 'Gene', '6790', (0, 5))	('phosphorylation', 'biological_process', 'GO:0016310', ('15', '30'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('androgen degradation', 'MPA', (58, 78))	('prostate cancer', 'Disease', (103, 118))	('androgen degradation', 'biological_process', 'GO:0006710', ('58', '78'))
39933	33451333	Phosphorylation by AURKA at Ser243 may account for the cancer-promoting effects of KCTD12.	('KCTD12', 'Gene', '115207', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('AURKA', 'Gene', '6790', (19, 24))	('Ser243', 'Chemical', '-', (28, 34))	('Ser243', 'Var', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Phosphorylation', 'MPA', (0, 15))	('AURKA', 'Gene', (19, 24))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('KCTD12', 'Gene', (83, 89))	('Ser', 'cellular_component', 'GO:0005790', ('28', '31'))	('cancer', 'Disease', (55, 61))
39943	33451333	In recent years, several small molecules that selectively target AURKA have been identified with anticancer activity in preclinical studies including LY3295668, BPR1K0609S1, LDD970, MK-8745, AKI603 and CYC3.	('BPR1K0609S1', 'Var', (161, 172))	('AURKA', 'Gene', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('LDD970', 'Var', (174, 180))	('LDD970', 'CellLine', 'CVCL:7312', (174, 180))	('MK-8745', 'Var', (182, 189))	('AKI603', 'Var', (191, 197))	('LY3295668', 'Var', (150, 159))	('LY3295668', 'Chemical', '-', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('AURKA', 'Gene', '6790', (65, 70))
39945	33451333	The common dose-limiting toxicity of specific AKIs, including MLN8237 and ENMD-2076, are neutropenia, somnolence and mucisitis.	('neutropenia', 'Phenotype', 'HP:0001875', (89, 100))	('neutropenia', 'Disease', 'MESH:D009503', (89, 100))	('toxicity', 'Disease', 'MESH:D064420', (25, 33))	('toxicity', 'Disease', (25, 33))	('somnolence', 'Disease', (102, 112))	('MLN8237', 'Chemical', 'MESH:C550258', (62, 69))	('somnolence', 'Disease', 'MESH:D006970', (102, 112))	('mucisitis', 'Disease', (117, 126))	('MLN8237', 'Var', (62, 69))	('neutropenia', 'Disease', (89, 100))
39946	33451333	MLN8237 is a highly selective small molecule inhibitor of AURKA with an IC50 of 1 nM.	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('MLN8237', 'Var', (0, 7))	('AURKA', 'Gene', '6790', (58, 63))	('AURKA', 'Gene', (58, 63))
39947	33451333	MLN8237 was developed as an enhancement of its predecessor, MLN8054, development of which was terminated after phase I studies due to central nervous system side effects, including dose-limiting somnolence.	('somnolence', 'Disease', (195, 205))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('somnolence', 'Disease', 'MESH:D006970', (195, 205))	('MLN8237', 'Var', (0, 7))	('MLN8054', 'Chemical', 'MESH:C518940', (60, 67))
39948	33451333	MLN8237 has been shown to inhibit cell proliferation by impairing mitosis, inducing cell cycle arrest and autophagy, and accelerating cancer cell apoptosis and senescence in multiple cancer types.	('cell proliferation', 'CPA', (34, 52))	('senescence', 'CPA', (160, 170))	('MLN8237', 'Var', (0, 7))	('impairing mitosis', 'Disease', 'MESH:D060825', (56, 73))	('inducing', 'PosReg', (75, 83))	('cancer', 'Disease', (183, 189))	('impairing mitosis', 'Disease', (56, 73))	('mitosis', 'biological_process', 'GO:0000278', ('66', '73'))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('cancer', 'Disease', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('accelerating', 'PosReg', (121, 133))	('senescence', 'biological_process', 'GO:0010149', ('160', '170'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('autophagy', 'biological_process', 'GO:0016236', ('106', '115'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('84', '101'))	('autophagy', 'CPA', (106, 115))	('cell proliferation', 'biological_process', 'GO:0008283', ('34', '52'))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('autophagy', 'biological_process', 'GO:0006914', ('106', '115'))	('inhibit', 'NegReg', (26, 33))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('apoptosis', 'biological_process', 'GO:0097194', ('146', '155'))	('apoptosis', 'biological_process', 'GO:0006915', ('146', '155'))	('arrest', 'Disease', (95, 101))
39949	33451333	The EMT process is also impeded by MLN8237 treatment in human epithelial ovarian and pancreatic cancer cells.	('epithelial ovarian and pancreatic cancer', 'Disease', 'MESH:D010195', (62, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MLN8237', 'Chemical', 'MESH:C550258', (35, 42))	('human', 'Species', '9606', (56, 61))	('EMT process', 'CPA', (4, 15))	('MLN8237 treatment', 'Var', (35, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('impeded', 'NegReg', (24, 31))	('EMT', 'biological_process', 'GO:0001837', ('4', '7'))
39950	33451333	Importantly, MLN8237 significantly increases the sensitivity of tumor cells to chemotherapy drugs or radiation.	('tumor', 'Disease', (64, 69))	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('increases', 'PosReg', (35, 44))	('sensitivity', 'MPA', (49, 60))	('MLN8237', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
39951	33451333	Mechanistic studies have revealed that MLN8237 induces proteasomal degradation of N-myc in childhood neuroblastoma.	('MLN8237', 'Chemical', 'MESH:C550258', (39, 46))	('induces', 'Reg', (47, 54))	('MLN8237', 'Var', (39, 46))	('neuroblastoma', 'Disease', (101, 114))	('proteasomal degradation', 'MPA', (55, 78))	('degradation', 'biological_process', 'GO:0009056', ('67', '78'))	('N-myc', 'Gene', '4613', (82, 87))	('neuroblastoma', 'Phenotype', 'HP:0003006', (101, 114))	('N-myc', 'Gene', (82, 87))	('neuroblastoma', 'Disease', 'MESH:D009447', (101, 114))
39952	33451333	In THCA cells, MLN8237 disrupts c-Myc/AURKA complex formation, and c-Myc is a major determinant of MLN8237 responsiveness both in vitro and in vivo.	('MLN8237', 'Chemical', 'MESH:C550258', (99, 106))	('formation', 'biological_process', 'GO:0009058', ('52', '61'))	('AURKA', 'Gene', (38, 43))	('MLN8237', 'Var', (15, 22))	('THCA', 'Phenotype', 'HP:0002890', (3, 7))	('c-Myc', 'Gene', '4609', (32, 37))	('c-Myc', 'Gene', '4609', (67, 72))	('c-Myc', 'Gene', (32, 37))	('c-Myc', 'Gene', (67, 72))	('AURKA', 'Gene', '6790', (38, 43))	('disrupts', 'NegReg', (23, 31))	('MLN8237', 'Chemical', 'MESH:C550258', (15, 22))
39953	33451333	MLN8237 has demonstrated efficacy in cell-derived and patient-derived xenograft (PDX) models of numerous tumor types, including glioblastoma, bladder cancer, esophageal adenocarcinoma, multiple myeloma, neuroblastoma and colon cancer.	('multiple myeloma', 'Disease', (185, 201))	('numerous tumor', 'Disease', (96, 110))	('MLN8237', 'Var', (0, 7))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (158, 183))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (158, 183))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('esophageal adenocarcinoma', 'Disease', (158, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('numerous tumor', 'Disease', 'MESH:D009369', (96, 110))	('colon cancer', 'Phenotype', 'HP:0003003', (221, 233))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('multiple myeloma', 'Phenotype', 'HP:0006775', (185, 201))	('patient', 'Species', '9606', (54, 61))	('bladder cancer', 'Disease', 'MESH:D001749', (142, 156))	('bladder cancer', 'Disease', (142, 156))	('glioblastoma', 'Disease', (128, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (142, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))	('multiple myeloma', 'Disease', 'MESH:D009101', (185, 201))	('neuroblastoma', 'Phenotype', 'HP:0003006', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('neuroblastoma and colon cancer', 'Disease', 'MESH:D015179', (203, 233))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
39954	33451333	Due to its potent efficiency in preclinical studies, MLN8237 has been tested in clinical trials for multiple cancers and is the only AURKA inhibitor that has proceeded to phase III evaluation.	('MLN8237', 'Var', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('AURKA', 'Gene', '6790', (133, 138))	('AURKA', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))
39958	33451333	One phase II trial of MLN8237 in patients with ovarian cancer, fallopian tube cancer, peritoneal carcinoma, acute myelogenous leukemia and high-grade myelodysplastic syndrome showed that MLN8237 has modest single-agent antitumor activity.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('acute myelogenous leukemia', 'Disease', (108, 134))	('fallopian tube cancer', 'Disease', (63, 84))	('myelodysplastic syndrome', 'Disease', (150, 174))	('peritoneal carcinoma', 'Disease', (86, 106))	('MLN8237', 'Var', (22, 29))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (108, 134))	('peritoneal carcinoma', 'Disease', 'MESH:D010534', (86, 106))	('MLN8237', 'Chemical', 'MESH:C550258', (22, 29))	('MLN8237', 'Var', (187, 194))	('ovarian cancer', 'Disease', 'MESH:D010051', (47, 61))	('fallopian tube cancer', 'Disease', 'MESH:D005185', (63, 84))	('tumor', 'Disease', (223, 228))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (114, 134))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (150, 174))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('MLN8237', 'Chemical', 'MESH:C550258', (187, 194))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (150, 174))	('patients', 'Species', '9606', (33, 41))	('ovarian cancer', 'Disease', (47, 61))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (108, 134))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))
39959	33451333	In a multicenter phase II study, MLN8237 treatment obtained an objective response in 18% of 49 women with breast cancer and 21% of 48 participants with small-cell lung cancer.	('small-cell lung cancer', 'Disease', (152, 174))	('MLN8237', 'Chemical', 'MESH:C550258', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('participants', 'Species', '9606', (134, 146))	('women', 'Species', '9606', (95, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('MLN8237 treatment', 'Var', (33, 50))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (152, 174))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
39960	33451333	In another phase II study of MLN8237 in advanced/metastatic sarcoma, occasional responses and prolonged stable disease were observed, and progression-free survival (PFS) was promising.	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('MLN8237', 'Var', (29, 36))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('MLN8237', 'Chemical', 'MESH:C550258', (29, 36))
39961	33451333	In castration-resistant neuroendocrine prostate cancer patients, those with AURKA and N-myc activation achieve significant clinical benefit from single-agent MLN8237 treatment.	('MLN8237 treatment', 'Var', (158, 175))	('AURKA', 'Gene', '6790', (76, 81))	('activation', 'PosReg', (92, 102))	('MLN8237', 'Chemical', 'MESH:C550258', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('AURKA', 'Gene', (76, 81))	('benefit', 'PosReg', (132, 139))	('N-myc', 'Gene', (86, 91))	('neuroendocrine prostate cancer', 'Disease', (24, 54))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (24, 54))	('patients', 'Species', '9606', (55, 63))	('prostate cancer', 'Phenotype', 'HP:0012125', (39, 54))	('N-myc', 'Gene', '4613', (86, 91))
39962	33451333	Another phase II study has shown that in relapsed or refractory peripheral T-cell NHL (PTCL) patients, MLN8237 has antitumor activity with an overall response rate of 30%.	('tumor', 'Disease', (119, 124))	('NHL', 'Gene', '51750', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('MLN8237', 'Chemical', 'MESH:C550258', (103, 110))	('MLN8237', 'Var', (103, 110))	('NHL', 'Gene', (82, 85))	('patients', 'Species', '9606', (93, 101))
39963	33451333	In a recently reported phase III study conducted in patients with PTCL, although MLN8237 did not demonstrate superior efficacy over comparators, it did show antitumor activity and acceptable tolerability and safety.	('MLN8237', 'Chemical', 'MESH:C550258', (81, 88))	('MLN8237', 'Var', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('patients', 'Species', '9606', (52, 60))
39964	33451333	All these encouraging outcomes make MLN8237 a promising agent for cancer treatment.	('MLN8237', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('MLN8237', 'Chemical', 'MESH:C550258', (36, 43))	('cancer', 'Disease', (66, 72))
39965	33451333	ENMD-2076, a novel, orally bioavailable multitarget inhibitor whose main targets are FLT3 (IC50 = 3 nM) and AURKA (IC50 = 14 nM), exhibits much greater potency against AURKA than against AURKB (IC50 = 350 nM).	('AURKA', 'Gene', (168, 173))	('ENMD-2076', 'Var', (0, 9))	('greater', 'PosReg', (144, 151))	('AURKA', 'Gene', '6790', (108, 113))	('FLT3', 'Gene', '2322', (85, 89))	('AURKB', 'Gene', '9212', (187, 192))	('AURKA', 'Gene', (108, 113))	('AURKA', 'Gene', '6790', (168, 173))	('FLT3', 'Gene', (85, 89))	('potency', 'MPA', (152, 159))	('AURKB', 'Gene', (187, 192))
39966	33451333	Because of its multitarget properties, ENMD-2076 inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines, with IC50 values ranging from 0.025 to 0.7 muM.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('growth', 'CPA', (62, 68))	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (100, 105))	('inhibits', 'NegReg', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('human', 'Species', '9606', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('ENMD-2076', 'Var', (39, 48))
39967	33451333	ENMD-2076 shows antitumor activity in colorectal cancer, multiple myeloma and triple-negative breast cancer both in vitro and in vivo.	('ENMD-2076', 'Var', (0, 9))	('multiple myeloma', 'Disease', (57, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (38, 55))	('multiple myeloma', 'Phenotype', 'HP:0006775', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colorectal cancer', 'Disease', (38, 55))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('multiple myeloma', 'Disease', 'MESH:D009101', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (38, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('tumor', 'Disease', (20, 25))
39969	33451333	MK-5108 is a novel small molecule that shows robust selectivity for AURKA over AURKB (220-fold greater selectivity) and AURKC (190-fold greater selectivity).	('AURKC', 'Gene', (120, 125))	('AURKA', 'Gene', (68, 73))	('AURKB', 'Gene', '9212', (79, 84))	('AURKB', 'Gene', (79, 84))	('AURKC', 'Gene', '6795', (120, 125))	('MK-5108', 'Var', (0, 7))	('MK-5108', 'Chemical', 'MESH:C547876', (0, 7))	('AURKA', 'Gene', '6790', (68, 73))
39971	33451333	In EOC stem cells, MK-5108 induces cell cycle arrest by affecting the NF-kB pathway.	('MK-5108', 'Var', (19, 26))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('35', '52'))	('arrest', 'Disease', 'MESH:D006323', (46, 52))	('induces', 'Reg', (27, 34))	('NF-kB pathway', 'Pathway', (70, 83))	('affecting', 'Reg', (56, 65))	('MK-5108', 'Chemical', 'MESH:C547876', (19, 26))	('arrest', 'Disease', (46, 52))
39972	33451333	MK-5108 also decreases the rate of proliferation and increases intratumoral apoptosis in uterine leiomyosarcoma xenografts.	('decreases', 'NegReg', (13, 22))	('tumor', 'Disease', (68, 73))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (97, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (97, 111))	('MK-5108', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (89, 111))	('MK-5108', 'Chemical', 'MESH:C547876', (0, 7))	('increases', 'PosReg', (53, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('leiomyosarcoma', 'Disease', (97, 111))
39975	33451333	Even though the selective AURKA inhibitors might be less toxic than pan-inhibitors, it may also lead to drug resistance more easily, so it is necessary to develop broad Aurora kinase inhibitors to obtain drugs with greater potency for cancer treatment.	('inhibitors', 'Var', (32, 42))	('drug', 'MPA', (104, 108))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('drug resistance', 'biological_process', 'GO:0009315', ('104', '119'))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('AURKA', 'Gene', '6790', (26, 31))	('lead to', 'Reg', (96, 103))	('drug resistance', 'biological_process', 'GO:0042493', ('104', '119'))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('AURKA', 'Gene', (26, 31))
39976	33451333	AT9283 exhibits strong activity against several kinases.	('kinases', 'Pathway', (48, 55))	('AT9283', 'Var', (0, 6))	('activity', 'MPA', (23, 31))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))
39977	33451333	The ability of AT9283 to inhibit the growth and survival of tumor cells as well as xenografts has been demonstrated in imatinib-resistant BCR-ABL-positive leukemic cells, aggressive B-cell lymphoma and medulloblastoma.	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (182, 197))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (182, 197))	('tumor', 'Disease', (60, 65))	('medulloblastoma', 'Disease', 'MESH:D008527', (202, 217))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cell lymphoma', 'Phenotype', 'HP:0012191', (184, 197))	('AT9283', 'Chemical', 'MESH:C535237', (15, 21))	('medulloblastoma', 'Phenotype', 'HP:0002885', (202, 217))	('imatinib', 'Chemical', 'MESH:D000068877', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('growth', 'CPA', (37, 43))	('inhibit', 'NegReg', (25, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (189, 197))	('BCR-ABL', 'Gene', '25', (138, 145))	('AT9283', 'Var', (15, 21))	('medulloblastoma', 'Disease', (202, 217))	('B-cell lymphoma', 'Disease', (182, 197))	('BCR-ABL', 'Gene', (138, 145))
39980	33451333	MK-0457, a pyrazoloquinazoline compound, inhibits all three Aurora kinases and inhibits FLT-3 and Abl kinases.	('Abl', 'Gene', '25', (98, 101))	('pyrazoloquinazoline', 'Chemical', '-', (11, 30))	('inhibits', 'NegReg', (41, 49))	('MK-0457', 'Chemical', 'MESH:C484810', (0, 7))	('inhibits', 'NegReg', (79, 87))	('MK-0457', 'Var', (0, 7))	('Abl', 'Gene', (98, 101))	('FLT-3', 'Gene', (88, 93))	('FLT-3', 'Gene', '2322', (88, 93))	('Aurora', 'Enzyme', (60, 66))
39983	33451333	MK-0457 induces accumulation of cells with >=4 N DNA content, inhibits cell cycle progression and induces apoptosis of anaplastic THCA cells.	('THCA', 'Phenotype', 'HP:0002890', (130, 134))	('induces', 'Reg', (98, 105))	('inhibits', 'NegReg', (62, 70))	('MK-0457', 'Chemical', 'MESH:C484810', (0, 7))	('cells with >=4 N DNA content', 'MPA', (32, 60))	('apoptosis', 'CPA', (106, 115))	('MK-0457', 'Var', (0, 7))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('cell cycle progression', 'CPA', (71, 93))	('cell cycle', 'biological_process', 'GO:0007049', ('71', '81'))	('accumulation', 'PosReg', (16, 28))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))
39985	33451333	The activity of MK-0457 was also assessed in two other phase I/II studies, both of which showed promising outcomes in patients with BCR-ABL T315I leukemia.	('BCR-ABL', 'Gene', (132, 139))	('BCR-ABL', 'Gene', '25', (132, 139))	('T315I', 'Var', (140, 145))	('T315I', 'Mutation', 'rs121913459', (140, 145))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('leukemia', 'Disease', 'MESH:D007938', (146, 154))	('MK-0457', 'Chemical', 'MESH:C484810', (16, 23))	('leukemia', 'Disease', (146, 154))	('patients', 'Species', '9606', (118, 126))
39987	33451333	PHA-739358 exhibits strong antiproliferative activity in BCR-ABL-positive leukemia cells, including those harboring the T315I mutation.	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))	('T315I', 'Var', (120, 125))	('T315I', 'Mutation', 'rs121913459', (120, 125))	('BCR-ABL', 'Gene', '25', (57, 64))	('BCR-ABL', 'Gene', (57, 64))	('leukemia', 'Disease', (74, 82))	('antiproliferative activity', 'MPA', (27, 53))	('leukemia', 'Disease', 'MESH:D007938', (74, 82))
39988	33451333	The crystal structure of the Abl-T315I-PHA-739358 complex provides a possible structural explanation for the activity of PHA-739358 on the T315I mutation.	('Abl', 'Gene', (29, 32))	('activity', 'MPA', (109, 117))	('T315I', 'Var', (139, 144))	('Abl', 'Gene', '25', (29, 32))	('T315I', 'Mutation', 'rs121913459', (33, 38))	('T315I', 'Mutation', 'rs121913459', (139, 144))
39989	33451333	PHA-739358 also induces cell cycle arrest, apoptosis and autophagy and suppresses the EMT process.	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('apoptosis', 'CPA', (43, 52))	('suppresses', 'NegReg', (71, 81))	('PHA-739358', 'Var', (0, 10))	('autophagy', 'biological_process', 'GO:0016236', ('57', '66'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('24', '41'))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('arrest', 'Disease', (35, 41))	('autophagy', 'biological_process', 'GO:0006914', ('57', '66'))	('EMT process', 'CPA', (86, 97))	('autophagy', 'CPA', (57, 66))	('induces', 'Reg', (16, 23))	('EMT', 'biological_process', 'GO:0001837', ('86', '89'))
39990	33451333	In one study, PHA-739358 inhibited liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model.	('metastases', 'Disease', 'MESH:D009362', (41, 51))	('PHA-739358', 'Var', (14, 24))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', (57, 101))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', 'MESH:C535650', (57, 101))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (80, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('inhibited', 'NegReg', (25, 34))	('metastases', 'Disease', (41, 51))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
39991	33451333	In another study, PHA-739358 inhibited early-stage bone metastases based on an ex vivo model named the 'bone-in-culture array'.	('metastases', 'Disease', 'MESH:D009362', (56, 66))	('inhibited', 'NegReg', (29, 38))	('PHA-739358', 'Var', (18, 28))	('metastases', 'Disease', (56, 66))
39992	33451333	Several phase I/II clinical evaluations have been performed on PHA-739358 due to its encouraging antitumor effects.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('PHA-739358', 'Var', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
39993	33451333	Other drugs including AMG900, AS703569, BI-847325, CYC116, PF-03814735, and SNS-314 are also in phase I clinical trials.	('SNS-314', 'Chemical', 'MESH:C532454', (76, 83))	('AMG900', 'Chemical', 'MESH:C555658', (22, 28))	('PF-03814735', 'Chemical', 'MESH:C550549', (59, 70))	('CYC116', 'Var', (51, 57))	('PF-03814735', 'Var', (59, 70))	('BI-847325', 'Var', (40, 49))	('BI-847325', 'Chemical', 'MESH:C000606531', (40, 49))	('AS703569', 'Var', (30, 38))	('AS703569', 'Chemical', 'MESH:C000592140', (30, 38))
39994	33451333	AURKA inhibitors have been shown to have great potential for enhancing the efficacy of multiple established therapeutic agents in both preclinical and clinical studies.	('AURKA', 'Gene', (0, 5))	('efficacy', 'MPA', (75, 83))	('inhibitors', 'Var', (6, 16))	('AURKA', 'Gene', '6790', (0, 5))	('enhancing', 'PosReg', (61, 70))
40001	33451333	In patients with solid tumors, AS703569 in combination with the standard dose of gemcitabine produces preliminary signs of efficacy.	('solid tumors', 'Disease', (17, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patients', 'Species', '9606', (3, 11))	('AS703569', 'Var', (31, 39))	('solid tumors', 'Disease', 'MESH:D009369', (17, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('AS703569', 'Chemical', 'MESH:C000592140', (31, 39))	('gemcitabine', 'Chemical', 'MESH:C056507', (81, 92))
40004	33451333	In addition, MLN8237 has a synergistic effect in association with vincristine and rituximab in aggressive B-cell NHL.	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('vincristine', 'Chemical', 'MESH:D014750', (66, 77))	('NHL', 'Gene', '51750', (113, 116))	('MLN8237', 'Var', (13, 20))	('NHL', 'Gene', (113, 116))	('rituximab', 'Chemical', 'MESH:D000069283', (82, 91))
40008	33451333	In a study on Myc-overexpressing lymphoma xenografts, a combination of cyclophosphamide and MLN8237 induced complete tumor regression in all mice, leading to improvements in survival.	('lymphoma', 'Disease', 'MESH:D008223', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('MLN8237', 'Chemical', 'MESH:C550258', (92, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (33, 41))	('survival', 'CPA', (174, 182))	('tumor', 'Disease', (117, 122))	('MLN8237', 'Var', (92, 99))	('Myc', 'Gene', (14, 17))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (71, 87))	('Myc', 'Gene', '17869', (14, 17))	('mice', 'Species', '10090', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('improvements', 'PosReg', (158, 170))	('lymphoma', 'Disease', (33, 41))
40011	33451333	Combined treatment with MLN8237 and eribulin leads to a synergistic increase in apoptosis in mammary tumors as well as cytotoxic autophagy in metastases through the LC3B/p62 axis and Akt pathway.	('MLN8237', 'Var', (24, 31))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('autophagy', 'biological_process', 'GO:0016236', ('129', '138'))	('MLN8237', 'Chemical', 'MESH:C550258', (24, 31))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('increase', 'PosReg', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('metastases', 'Disease', 'MESH:D009362', (142, 152))	('p62', 'Gene', '23636', (170, 173))	('autophagy', 'biological_process', 'GO:0006914', ('129', '138'))	('p62', 'Gene', (170, 173))	('apoptosis', 'CPA', (80, 89))	('tumors', 'Disease', (101, 107))	('LC3B', 'Gene', (165, 169))	('Akt', 'Gene', (183, 186))	('metastases', 'Disease', (142, 152))	('LC3B', 'Gene', '81631', (165, 169))	('Akt', 'Gene', '207', (183, 186))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
40012	33451333	In multiple myeloma, studies on combined treatment with AT9283 and lenalidomide have shown significant synergistic antitumor effects of this regimen both in vitro and in vivo.	('AT9283', 'Chemical', 'MESH:C535237', (56, 62))	('multiple myeloma', 'Disease', (3, 19))	('tumor', 'Disease', (119, 124))	('AT9283', 'Var', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('lenalidomide', 'Chemical', 'MESH:D000077269', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('multiple myeloma', 'Phenotype', 'HP:0006775', (3, 19))	('multiple myeloma', 'Disease', 'MESH:D009101', (3, 19))
40015	33451333	PHA680632 treatment prior to radiation treatment leads to an additive effect in cancer cells, especially in p53-deficient cells in vitro or in vivo.	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('additive effect', 'MPA', (61, 76))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('PHA680632', 'Chemical', 'MESH:C524543', (0, 9))	('PHA680632', 'Var', (0, 9))	('cancer', 'Disease', (80, 86))
40016	33451333	Another AURKA inhibitor, MLN8054, sensitizes androgen-insensitive prostate cancer to radiation; this sensitization is associated with sustained DNA double-strand breaks.	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('MLN8054', 'Chemical', 'MESH:C518940', (25, 32))	('AURKA', 'Gene', '6790', (8, 13))	('sensitizes', 'Reg', (34, 44))	('prostate cancer', 'Disease', (66, 81))	('sensitization', 'biological_process', 'GO:0046960', ('101', '114'))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('AURKA', 'Gene', (8, 13))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('MLN8054', 'Var', (25, 32))
40017	33451333	Two other AURKA inhibitors, MLN8237 and ENMD-2076, also enhance radiation sensitivity in cancer cells.	('ENMD-2076', 'Var', (40, 49))	('AURKA', 'Gene', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('enhance', 'PosReg', (56, 63))	('MLN8237', 'Chemical', 'MESH:C550258', (28, 35))	('cancer', 'Disease', (89, 95))	('MLN8237', 'Var', (28, 35))	('AURKA', 'Gene', '6790', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
40022	33451333	In addition, vorinostat and MK-0457 or MK-5108 combination treatment enhances lymphoma cell killing with reductions in c-Myc, hTERT, and microRNA levels.	('lymphoma', 'Disease', (78, 86))	('hTERT', 'Gene', (126, 131))	('vorinostat', 'Chemical', 'MESH:D000077337', (13, 23))	('MK-5108', 'Gene', (39, 46))	('MK-0457', 'Chemical', 'MESH:C484810', (28, 35))	('lymphoma', 'Disease', 'MESH:D008223', (78, 86))	('cell killing', 'biological_process', 'GO:0001906', ('87', '99'))	('MK-0457', 'Var', (28, 35))	('lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	('microRNA levels', 'MPA', (137, 152))	('reductions', 'NegReg', (105, 115))	('MK-5108', 'Chemical', 'MESH:C547876', (39, 46))	('enhances', 'PosReg', (69, 77))	('c-Myc', 'Gene', '4609', (119, 124))	('hTERT', 'Gene', '7015', (126, 131))	('c-Myc', 'Gene', (119, 124))
40026	33451333	EGFR inhibitors have been a major breakthrough for NSCLC treatment.	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (51, 56))	('inhibitors', 'Var', (5, 15))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))
40030	33451333	Both BRD4 and AURKA are regulators of the MYC gene at the translational and posttranslational levels, respectively, and targeting both of them simultaneously may produce synergistic antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('produce', 'Reg', (162, 169))	('BRD4', 'Gene', (5, 9))	('AURKA', 'Gene', (14, 19))	('MYC', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('targeting', 'Var', (120, 129))	('tumor', 'Disease', (186, 191))	('BRD4', 'Gene', '23476', (5, 9))	('MYC', 'Gene', '4609', (42, 45))	('AURKA', 'Gene', '6790', (14, 19))
40031	33451333	JQ1 treatment to repress BRD4 activity together with MLN8237 treatment synergistically promotes cell death in c-Myc expressing human glioblastoma cells.	('glioblastoma', 'Disease', (133, 145))	('BRD4', 'Gene', '23476', (25, 29))	('human', 'Species', '9606', (127, 132))	('MLN8237', 'Var', (53, 60))	('c-Myc', 'Gene', '4609', (110, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('cell death', 'biological_process', 'GO:0008219', ('96', '106'))	('BRD4', 'Gene', (25, 29))	('c-Myc', 'Gene', (110, 115))	('death', 'Disease', 'MESH:D003643', (101, 106))	('death', 'Disease', (101, 106))	('promotes', 'PosReg', (87, 95))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('activity', 'MPA', (30, 38))
40034	33451333	One study showed that AURKA and MDM2 antagonism with MLN8237 and Nutlin-3 halted melanoma growth by inducing growth arrest and senescence, limiting the lifespans of senescent cells, and enhancing tumor immune infiltration and clearance.	('tumor', 'Disease', (196, 201))	('growth arrest', 'Disease', (109, 122))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('senescence', 'CPA', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('Nutlin-3', 'Chemical', 'MESH:C482205', (65, 73))	('lifespans', 'CPA', (152, 161))	('MLN8237', 'Var', (53, 60))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('MDM2', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('halted', 'NegReg', (74, 80))	('growth arrest', 'Phenotype', 'HP:0001510', (109, 122))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('enhancing', 'PosReg', (186, 195))	('MDM2', 'Gene', '4193', (32, 36))	('clearance', 'CPA', (226, 235))	('inducing', 'PosReg', (100, 108))	('growth arrest', 'Disease', 'MESH:D006323', (109, 122))	('AURKA', 'Gene', '6790', (22, 27))	('limiting', 'NegReg', (139, 147))	('AURKA', 'Gene', (22, 27))	('senescence', 'biological_process', 'GO:0010149', ('127', '137'))
40035	33451333	The other study showed that combined MK-0457 and Nutlin-3 treatment activated p53-dependent postmitotic checkpoints at pseudo-G1 phase and induced proapoptotic p53 signaling and mitochondrial apoptosis in AML.	('MK-0457', 'Var', (37, 44))	('G1 phase', 'biological_process', 'GO:0051318', ('126', '134'))	('apoptosis', 'biological_process', 'GO:0097194', ('192', '201'))	('mitochondrial apoptosis', 'CPA', (178, 201))	('postmitotic checkpoints at pseudo-G1 phase', 'CPA', (92, 134))	('p53', 'Gene', (160, 163))	('AML', 'Disease', (205, 208))	('activated', 'PosReg', (68, 77))	('p53', 'Gene', (78, 81))	('induced', 'PosReg', (139, 146))	('p53', 'Gene', '7157', (160, 163))	('apoptosis', 'biological_process', 'GO:0006915', ('192', '201'))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))	('Nutlin-3', 'Chemical', 'MESH:C482205', (49, 57))	('p53', 'Gene', '7157', (78, 81))	('MK-0457', 'Chemical', 'MESH:C484810', (37, 44))	('AML', 'Disease', 'MESH:D015470', (205, 208))
40038	33451333	In human neuroblastoma cells, MK-5108 increases the efficacy of an anti-ganglioside (GD2) 14G2a antibody, which is related to a reduction in N-Myc expression and an increase in PHLDA1 and p53 protein levels.	('MK-5108', 'Var', (30, 37))	('neuroblastoma', 'Disease', (9, 22))	('human', 'Species', '9606', (3, 8))	('expression', 'MPA', (147, 157))	('neuroblastoma', 'Phenotype', 'HP:0003006', (9, 22))	('ganglioside', 'Chemical', 'MESH:D005732', (72, 83))	('antibody', 'molecular_function', 'GO:0003823', ('96', '104'))	('neuroblastoma', 'Disease', 'MESH:D009447', (9, 22))	('efficacy', 'MPA', (52, 60))	('increase', 'PosReg', (165, 173))	('antibody', 'cellular_component', 'GO:0042571', ('96', '104'))	('PHLDA1', 'Gene', '22822', (177, 183))	('N-Myc', 'Gene', (141, 146))	('p53', 'Gene', '7157', (188, 191))	('GD2', 'Gene', (85, 88))	('N-Myc', 'Gene', '4613', (141, 146))	('antibody', 'cellular_component', 'GO:0019815', ('96', '104'))	('p53', 'Gene', (188, 191))	('protein', 'cellular_component', 'GO:0003675', ('192', '199'))	('increases', 'PosReg', (38, 47))	('PHLDA1', 'Gene', (177, 183))	('reduction', 'NegReg', (128, 137))	('MK-5108', 'Chemical', 'MESH:C547876', (30, 37))	('antibody', 'cellular_component', 'GO:0019814', ('96', '104'))
40039	33451333	In addition, combined treatment with an anti-GD2 14G2a antibody and MK-5108 leads to enhancement of the autophagy process in IMR-32 neuroblastoma cells.	('antibody', 'cellular_component', 'GO:0042571', ('55', '63'))	('neuroblastoma', 'Disease', (132, 145))	('MK-5108', 'Gene', (68, 75))	('autophagy', 'biological_process', 'GO:0016236', ('104', '113'))	('antibody', 'cellular_component', 'GO:0019815', ('55', '63'))	('autophagy process', 'CPA', (104, 121))	('IMR-32', 'CellLine', 'CVCL:0346', (125, 131))	('neuroblastoma', 'Phenotype', 'HP:0003006', (132, 145))	('autophagy', 'biological_process', 'GO:0006914', ('104', '113'))	('neuroblastoma', 'Disease', 'MESH:D009447', (132, 145))	('MK-5108', 'Chemical', 'MESH:C547876', (68, 75))	('enhancement', 'PosReg', (85, 96))	('antibody', 'molecular_function', 'GO:0003823', ('55', '63'))	('antibody', 'cellular_component', 'GO:0019814', ('55', '63'))	('combined', 'Interaction', (13, 21))	('anti-GD2 14G2a', 'Var', (40, 54))	('anti-GD2', 'Gene', (40, 48))
40040	33451333	A death receptor 5 agonist antibody has been found to initiate significant apoptosis in tumor cells undergoing therapy-induced senescence induced by MLN8237 treatment.	('antibody', 'cellular_component', 'GO:0042571', ('27', '35'))	('death receptor 5', 'Gene', '8795', (2, 18))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('apoptosis', 'biological_process', 'GO:0006915', ('75', '84'))	('antibody', 'cellular_component', 'GO:0019815', ('27', '35'))	('MLN8237', 'Chemical', 'MESH:C550258', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('antibody', 'cellular_component', 'GO:0019814', ('27', '35'))	('MLN8237 treatment', 'Var', (149, 166))	('death receptor 5', 'Gene', (2, 18))	('antibody', 'molecular_function', 'GO:0003823', ('27', '35'))	('tumor', 'Disease', (88, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('75', '84'))	('senescence', 'biological_process', 'GO:0010149', ('127', '137'))
40058	33451333	This drug delivery technology has been applied to MLN8237 and the polysaccharide nanovesicle efficiently delivers low concentrations of MLN8237 to inhibit AURKA and disrupt the anchorage-independent growth of MCF-7 cell than free MLN8237.	('AURKA', 'Gene', '6790', (155, 160))	('disrupt', 'NegReg', (165, 172))	('polysaccharide', 'Chemical', 'MESH:D011134', (66, 80))	('MLN8237', 'Chemical', 'MESH:C550258', (136, 143))	('MCF-7', 'CellLine', 'CVCL:0031', (209, 214))	('AURKA', 'Gene', (155, 160))	('MLN8237', 'Var', (136, 143))	('MLN8237', 'Chemical', 'MESH:C550258', (230, 237))	('inhibit', 'NegReg', (147, 154))	('anchorage-independent growth', 'CPA', (177, 205))	('MLN8237', 'Chemical', 'MESH:C550258', (50, 57))
40067	33451333	Furthermore, due to the fact that AURKA exerts its function through specific substrates in certain cancers, inhibition of AURKA substrates instead of targeting AURKA kinase activity may decrease the adverse effects.	('AURKA', 'Gene', (34, 39))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('function', 'MPA', (51, 59))	('kinase activity', 'molecular_function', 'GO:0016301', ('166', '181'))	('cancers', 'Disease', (99, 106))	('AURKA', 'Gene', '6790', (160, 165))	('AURKA', 'Gene', '6790', (122, 127))	('AURKA', 'Gene', '6790', (34, 39))	('inhibition', 'Var', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('AURKA', 'Gene', (160, 165))	('AURKA', 'Gene', (122, 127))
40071	33451333	Furthermore, in the triple-negative breast cancer cells, cell lines with a p53 mutation and increased p53 expression are more sensitive to ENMD-2076 than cell lines with decreased p53 expression.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (180, 183))	('expression', 'MPA', (106, 116))	('p53', 'Gene', '7157', (180, 183))	('sensitive', 'MPA', (126, 135))	('increased', 'PosReg', (92, 101))	('p53', 'Gene', (75, 78))	('mutation', 'Var', (79, 87))	('p53', 'Gene', '7157', (75, 78))	('p53', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
40098	30425004	The miR-5p and miR-3p represent 5' mature miRNA and 3' mature miRNA, respectively, as shown in Fig.	('miR-5p', 'Var', (4, 10))	('miR-5p', 'Chemical', '-', (4, 10))	('miR-3p', 'Var', (15, 21))
40104	30425004	Moreover, some cancer-related studies have integrated miR-5p and miR-3p together.	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('miR-5p', 'Var', (54, 60))	('miR-5p', 'Chemical', '-', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
40105	30425004	For example, miR-193a-5p and miR-193a-3p were found significantly increased in breast cancer and revealed that strand expression preference may be a means of modulating miRNA function.	('miR-193a-3p', 'Var', (29, 40))	('increased', 'PosReg', (66, 75))	('modulating', 'Reg', (158, 168))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('miR-193a-5p', 'Var', (13, 24))	('miRNA function', 'MPA', (169, 183))
40107	30425004	miR-5p and miR-3p have been found that co-express and cross-target in colon cancer cells.	('miR-5p', 'Chemical', '-', (0, 6))	('colon cancer', 'Disease', (70, 82))	('miR-3p', 'Var', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('colon cancer', 'Phenotype', 'HP:0003003', (70, 82))	('colon cancer', 'Disease', 'MESH:D015179', (70, 82))	('miR-5p', 'Gene', (0, 6))
40108	30425004	Moreover, dysregulation of miR-5p/miR-3p specific miRNAs were found in gastric cancer in a TCGA data set.	('gastric cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('miR-5p/miR-3p', 'Var', (27, 40))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('miR-5p', 'Chemical', '-', (27, 33))
40125	30425004	The ratio was adopted as a measure of the arm selection, where 1 >= ratio > 0.5 indicates miR-5p dominant expression, and 0.5 > ratio >=0 indicates miR-3p dominant expression.	('miR-5p', 'Var', (90, 96))	('miR-5p', 'Chemical', '-', (90, 96))	('0.5 > ratio >', 'Var', (122, 135))
40127	30425004	We then defined an arm switching event between normal and tumour samples by finding a transformation between miR-5p and miR-3p dominant expression.	('miR-3p', 'Var', (120, 126))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('miR-5p', 'Var', (109, 115))	('tumour', 'Disease', (58, 64))	('miR-5p', 'Chemical', '-', (109, 115))
40141	30425004	In order to explore the arm switching effect of the 51 pre-miRNAs, we performed GO and KEGG enrichment analysis for miR-3p and miR-5p arms, respectively.	('miR-5p', 'Var', (127, 133))	('pre', 'molecular_function', 'GO:0003904', ('55', '58'))	('miR-5p', 'Chemical', '-', (127, 133))	('miR-3p', 'Var', (116, 122))
40147	30425004	As a tumour promoter, miR-29-3p mediates epithelial-mesenchymal transition (EMT) and promotes metastasis in breast cancer and colon cancer.	('tumour', 'Disease', 'MESH:D009369', (5, 11))	('metastasis', 'CPA', (94, 104))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('41', '74'))	('epithelial-mesenchymal transition', 'CPA', (41, 74))	('miR-29-3p', 'Var', (22, 31))	('tumour', 'Disease', (5, 11))	('promotes', 'PosReg', (85, 93))	('mediates', 'Reg', (32, 40))	('colon cancer', 'Disease', 'MESH:D015179', (126, 138))	('colon cancer', 'Phenotype', 'HP:0003003', (126, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('EMT', 'biological_process', 'GO:0001837', ('76', '79'))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('colon cancer', 'Disease', (126, 138))	('breast cancer', 'Disease', (108, 121))
40154	30425004	In most miRNAs, we could observe three patterns: miR-5p preference, miR-3p preference, and not expressed in tumours compared to others.	('tumours', 'Disease', (108, 115))	('miR-5p', 'Var', (49, 55))	('miR-5p', 'Chemical', '-', (49, 55))	('miR-3p', 'MPA', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('tumours', 'Disease', 'MESH:D009369', (108, 115))
40158	30425004	Some of the miRNAs were associated with increased survival in more than one cancer.	('miRNAs', 'Var', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('increased', 'PosReg', (40, 49))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
40174	30425004	They were serum miRNAs: miR-369-5p, miR-30e-5p, and miR-423-3p and plasma miRNAs: miR-671-3p, miR-483-3p, and miR-744-5p.	('miR-483', 'Gene', (94, 101))	('miR-30e', 'Gene', '407034', (36, 43))	('miR-483', 'Gene', '619552', (94, 101))	('miR-744', 'Gene', '100126313', (110, 117))	('miR-369-5p', 'Var', (24, 34))	('miR-30e', 'Gene', (36, 43))	('miR-423-3p', 'Var', (52, 62))	('miR-671-3p', 'Var', (82, 92))	('miR-744', 'Gene', (110, 117))
40191	28928878	The Kaplan-Meier survival analysis showed significantly decreased 5-year recurrence-free survival (RFS) (50.3% vs. 74.6%, log-rank test, p=0.014) in the noninvasive LGPUC group compared to the PUNLMP group.	('PUC', 'Phenotype', 'HP:0006766', (167, 170))	('LGPUC', 'Chemical', '-', (165, 170))	('noninvasive', 'Var', (153, 164))	('decreased', 'NegReg', (56, 65))	('recurrence-free survival', 'CPA', (73, 97))
40230	28928878	In the total study cohort, the Kaplan-Meier survival analysis showed significantly decreased 5-year RFS (50.3% vs. 74.6%, log-rank test, p=0.014) in the noninvasive LGPUC group compared to the PUNLMP group (Fig.	('PUC', 'Phenotype', 'HP:0006766', (167, 170))	('RFS', 'MPA', (100, 103))	('LGPUC', 'Chemical', '-', (165, 170))	('noninvasive', 'Var', (153, 164))	('decreased', 'NegReg', (83, 92))
40231	28928878	Subsequently, the Kaplan-Meier survival analysis was conducted, and consistently showed significantly decreased 5-year RFS (31.0% vs. 74.6%, log-rank test, p<0.001) in the noninvasive LGPUC group compared to the PUNLMP group (Fig.	('LGPUC', 'Chemical', '-', (184, 189))	('RFS', 'MPA', (119, 122))	('noninvasive', 'Var', (172, 183))	('decreased', 'NegReg', (102, 111))	('PUC', 'Phenotype', 'HP:0006766', (186, 189))
40248	28928878	The Kaplan-Meier survival analysis also showed significantly decreased 5-year RFS (50.3% vs. 74.6%, log-rank test, p=0.014) in noninvasive LGPUC group compared to the PUNLMP group (Fig.	('PUC', 'Phenotype', 'HP:0006766', (141, 144))	('LGPUC', 'Chemical', '-', (139, 144))	('RFS', 'MPA', (78, 81))	('decreased', 'NegReg', (61, 70))	('noninvasive LGPUC', 'Var', (127, 144))
40250	28928878	In addition, median time to first recurrence were even shorter in PUNLMP group than noninvasive LGPUC group (9 vs. 11 months).	('PUNLMP', 'Var', (66, 72))	('LGPUC', 'Chemical', '-', (96, 101))	('PUC', 'Phenotype', 'HP:0006766', (98, 101))	('shorter', 'NegReg', (55, 62))
40269	28767070	Effects of siRNA-mediated NRF2 knockdown on chemosensitivity were analysed by viability assays, gammaH2AX immunofluorescence, and flow cytometry.	('NRF2', 'Gene', (26, 30))	('knockdown', 'Var', (31, 40))	('gammaH2AX', 'Chemical', '-', (96, 105))
40272	28767070	NRF2 knockdown resulted in downregulation of cytoprotective enzymes and resensitised 3/4 LTTs towards cisplatin as demonstrated by reduced IC50 values, increased gammaH2AX foci formation, and elevated number of apoptotic cells.	('formation', 'biological_process', 'GO:0009058', ('177', '186'))	('NRF2', 'Gene', (0, 4))	('elevated number of apoptotic cells', 'Phenotype', 'HP:0030887', (192, 226))	('knockdown', 'Var', (5, 14))	('increased', 'PosReg', (152, 161))	('elevated', 'PosReg', (192, 200))	('reduced', 'NegReg', (131, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('downregulation', 'NegReg', (27, 41))	('gammaH2AX', 'Protein', (162, 171))	('IC50 values', 'MPA', (139, 150))	('gammaH2AX', 'Chemical', '-', (162, 171))	('cytoprotective enzymes', 'Enzyme', (45, 67))
40274	28767070	Accordingly, inhibition of NRF2 can be used to resensitise UC cells to cisplatin, but responses in patients may likewise be variable.	('patients', 'Species', '9606', (99, 107))	('NRF2', 'Gene', (27, 31))	('inhibition', 'Var', (13, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (71, 80))
40283	28767070	Under resting conditions it is polyubiquitinated by the Kelch-like ECH-associated protein 1 (KEAP1)-Cullin 3 (CUL3) E3 ligase complex which leads to its degradation.	('ECH', 'molecular_function', 'GO:0004300', ('67', '70'))	('leads to', 'Reg', (140, 148))	('Cullin 3', 'Gene', (100, 108))	('degradation', 'MPA', (153, 164))	('KEAP1', 'Gene', '9817', (93, 98))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('Cullin 3', 'Gene', '8452', (100, 108))	('KEAP1', 'Gene', (93, 98))	('Kelch-like ECH-associated protein 1', 'Gene', (56, 91))	('polyubiquitinated', 'Var', (31, 48))	('CUL3', 'Gene', '8452', (110, 114))	('CUL3', 'Gene', (110, 114))	('Kelch-like ECH-associated protein 1', 'Gene', '9817', (56, 91))	('degradation', 'biological_process', 'GO:0009056', ('153', '164'))
40289	28767070	In particular, the association between elevated cellular levels of GSH and cisplatin resistance suggests that conjugation with GSH can be an important step in cisplatin inactivation in MCF7, U87MG, U251MG, and U138MG cell lines.	('GSH', 'Chemical', 'MESH:D005978', (127, 130))	('U87MG', 'CellLine', 'CVCL:0022', (191, 196))	('conjugation', 'biological_process', 'GO:0000746', ('110', '121'))	('U251MG', 'Var', (198, 204))	('U138MG', 'CellLine', 'CVCL:0020', (210, 216))	('cisplatin', 'Chemical', 'MESH:D002945', (159, 168))	('GSH', 'Chemical', 'MESH:D005978', (67, 70))	('U87MG', 'Var', (191, 196))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))	('conjugation', 'MPA', (110, 121))	('MCF7', 'CellLine', 'CVCL:0031', (185, 189))	('U251MG', 'CellLine', 'CVCL:0021', (198, 204))
40292	28767070	As in some other cancer types, a significant fraction of UC contain mutations in the NFE2L2 gene, typically missense mutations in the Neh2 domain required for KEAP1 interaction that are expected to cause NRF2 overexpression.	('cause', 'Reg', (198, 203))	('KEAP1', 'Gene', '9817', (159, 164))	('NFE2L2', 'Gene', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('Neh2', 'Gene', '252969', (134, 138))	('missense mutations in', 'Var', (108, 129))	('cancer', 'Disease', (17, 23))	('KEAP1', 'Gene', (159, 164))	('mutations', 'Var', (68, 77))	('NFE2L2', 'Gene', '4780', (85, 91))	('Neh2', 'Gene', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
40293	28767070	Likewise, as in other cancers, high NRF2 expression is associated with poor prognosis in UC.	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('expression', 'MPA', (41, 51))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('cancers', 'Disease', (22, 29))	('NRF2', 'Gene', (36, 40))	('high', 'Var', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
40294	28767070	Experimentally, cisplatin resistance was linked to NRF2 activation in the UC cell line RT-112 which was likely caused by loss of KEAP1.	('NRF2', 'Gene', (51, 55))	('loss', 'Var', (121, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (16, 25))	('KEAP1', 'Gene', '9817', (129, 134))	('cisplatin resistance', 'MPA', (16, 36))	('activation', 'PosReg', (56, 66))	('KEAP1', 'Gene', (129, 134))
40299	28767070	KEAP1 protein was only diminished in J82-LTT, which also overexpressed p62/SQSTM1.	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('KEAP1', 'Gene', (0, 5))	('diminished', 'NegReg', (23, 33))	('J82-LTT', 'Var', (37, 44))	('KEAP1', 'Gene', '9817', (0, 5))
40306	28767070	According to the TCGA data on UC, missense mutations in NRF2/NFE2L2 are usually located in exon 2 and were detected in 14 (11%) of 126 sequenced UC.	('detected', 'Reg', (107, 115))	('NFE2L2', 'Gene', (61, 67))	('missense mutations', 'Var', (34, 52))	('NFE2L2', 'Gene', '4780', (61, 67))
40307	28767070	KEAP1 was altered in 10 (7%) of 126 sequenced cases/patients, with 4 missense and 1 truncating mutation (Figure S2a).	('truncating', 'MPA', (84, 94))	('altered', 'Reg', (10, 17))	('KEAP1', 'Gene', (0, 5))	('missense', 'Var', (69, 77))	('KEAP1', 'Gene', '9817', (0, 5))	('patients', 'Species', '9606', (52, 60))
40308	28767070	Deletion of NFE2L2 exon 2 represents an alternative mechanism for activation of NRF2 in a subset of squamous lung and head-and-neck cancers.	('NFE2L2', 'Gene', '4780', (12, 18))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('NFE2L2', 'Gene', (12, 18))	('squamous lung', 'Disease', 'MESH:D002294', (100, 113))	('neck', 'cellular_component', 'GO:0044326', ('127', '131'))	('Deletion', 'Var', (0, 8))	('NRF2', 'Gene', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('squamous lung', 'Disease', (100, 113))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('activation', 'PosReg', (66, 76))
40309	28767070	Somatic mutations of the KEAP1 gene, especially in the BTB domain encoded by exon 2 have been identified in several solid cancers, e.g., NSCLC and gastric adenocarcinoma.	('NSCLC', 'Disease', (137, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('KEAP1', 'Gene', '9817', (25, 30))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('identified', 'Reg', (94, 104))	('gastric adenocarcinoma', 'Disease', (147, 169))	('mutations', 'Var', (8, 17))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (147, 169))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('KEAP1', 'Gene', (25, 30))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('BTB domain', 'molecular_function', 'GO:0031208', ('55', '65'))
40311	28767070	Sanger sequencing revealed no changes in NFE2L2 exon 2 (data not shown), but a non-silent missense mutation in KEAP1 exon 2, namely c. 334A>T (T112S), in RT-112-LTT, which was not present in the parental cell line (Figure S2c).	('T112S', 'Mutation', 'p.T112S', (143, 148))	('KEAP1', 'Gene', '9817', (111, 116))	('NFE2L2', 'Gene', '4780', (41, 47))	('334A>T', 'Var', (135, 141))	('KEAP1', 'Gene', (111, 116))	('NFE2L2', 'Gene', (41, 47))	('334A>T', 'SUBSTITUTION', 'None', (135, 141))
40313	28767070	Despite introducing a serine residue this previously unreported mutation is not predicted to change phosphorylation by in silico analysis, but according to the KEAP1 crystal structure (data not shown, PDB ID 5NLB), the amino acid change could lead to a conformational change impairing KEAP1 binding to Cullin-3 and thereby interfere with NRF2 degradation.	('PDB ID', 'Disease', 'MESH:C537985', (201, 207))	('phosphorylation', 'biological_process', 'GO:0016310', ('100', '115'))	('NRF2 degradation', 'MPA', (338, 354))	('interfere', 'NegReg', (323, 332))	('binding', 'molecular_function', 'GO:0005488', ('291', '298'))	('conformational change', 'MPA', (253, 274))	('binding', 'Interaction', (291, 298))	('Cullin-3', 'Gene', '8452', (302, 310))	('lead to', 'Reg', (243, 250))	('degradation', 'biological_process', 'GO:0009056', ('343', '354'))	('KEAP1', 'Gene', '9817', (160, 165))	('NLB', 'cellular_component', 'GO:1990934', ('209', '212'))	('PDB ID', 'Disease', (201, 207))	('Cullin-3', 'Gene', (302, 310))	('KEAP1', 'Gene', (160, 165))	('amino acid change', 'Var', (219, 236))	('KEAP1', 'Gene', '9817', (285, 290))	('KEAP1', 'Gene', (285, 290))	('impairing', 'NegReg', (275, 284))	('serine', 'Chemical', 'MESH:D012694', (22, 28))
40314	28767070	Two additional cisplatin-resistant cell lines derived by pulse-treatment, RT-112-R and J82-R contained no alternations in exons 2 of NFE2L2 and KEAP1 (Figure S2d).	('KEAP1', 'Gene', '9817', (144, 149))	('NFE2L2', 'Gene', '4780', (133, 139))	('KEAP1', 'Gene', (144, 149))	('NFE2L2', 'Gene', (133, 139))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))	('J82-R', 'Var', (87, 92))
40315	28767070	Significantly increased expression of the cytoprotective enzyme genes GSR, NQO1, GPX1, GPX2, GSTM1, and GSTP1 was observed in RT-112-LTT compared to their parental cells (Figure 2a) and, except for GSTM1, also in T-24-LTT (Figure 2d).	('increased', 'PosReg', (14, 23))	('GPX2', 'Gene', (87, 91))	('GSTM1', 'Gene', (93, 98))	('GSTM1', 'Gene', '2944', (198, 203))	('RT-112-LTT', 'Var', (126, 136))	('GSTP1', 'Gene', '2950', (104, 109))	('expression', 'MPA', (24, 34))	('NQO1', 'molecular_function', 'GO:0003955', ('75', '79'))	('NQO1', 'Gene', (75, 79))	('GSTM1', 'Gene', (198, 203))	('GSR', 'Gene', (70, 73))	('GSTP1', 'Gene', (104, 109))	('NQO1', 'Gene', '1728', (75, 79))	('GSTM1', 'Gene', '2944', (93, 98))	('GPX2', 'Gene', '2877', (87, 91))	('GPX1', 'Gene', '2876', (81, 85))	('GPX1', 'Gene', (81, 85))
40317	28767070	The mRNA of the SLC3A2 transporter was significantly elevated in RT-112-LTT, J82-LTT, and T-24-LTT compared to their parental cell lines.	('elevated', 'PosReg', (53, 61))	('SLC3A2', 'Gene', (16, 22))	('J82-LTT', 'Var', (77, 84))	('RT-112-LTT', 'Var', (65, 75))	('SLC3A2', 'Gene', '6520', (16, 22))	('mRNA', 'MPA', (4, 8))
40318	28767070	Total GSH was significantly increased in J82-LTT and T-24-LTT, but not in RT-112-LTT and 253J-LTT (Figure 2f).	('increased', 'PosReg', (28, 37))	('J82-LTT', 'Var', (41, 48))	('GSH', 'Chemical', 'MESH:D005978', (6, 9))	('GSH', 'MPA', (6, 9))	('T-24-LTT', 'Var', (53, 61))
40320	28767070	Moreover, compared to their parental cell lines, significantly lower intracellular ROS concentrations were detected after cisplatin treatment in J82-LTT, 253J-LTT and T-24-LTT, but not in RT-112-LTT, where significantly higher levels were observed after cisplatin treatment (Figure 2g and Figure S3).	('cisplatin', 'Chemical', 'MESH:D002945', (254, 263))	('intracellular ROS concentrations', 'MPA', (69, 101))	('lower', 'NegReg', (63, 68))	('J82-LTT', 'Var', (145, 152))	('intracellular', 'cellular_component', 'GO:0005622', ('69', '82'))	('ROS', 'Chemical', 'MESH:D017382', (83, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))
40322	28767070	Cisplatin sensitivity increased, with statistically significant changes in the IC50 values for cisplatin in RT-112-LTT, 253J-LTT, and T-24-LTT, albeit not in J82-LTT (Figure 3g).	('T-24-LTT', 'Var', (134, 142))	('IC50 values for cisplatin', 'MPA', (79, 104))	('changes', 'Reg', (64, 71))	('253J-LTT', 'Var', (120, 128))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('Cisplatin sensitivity', 'MPA', (0, 21))	('increased', 'PosReg', (22, 31))	('RT-112-LTT', 'Var', (108, 118))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))
40325	28767070	Notably, following NRF2 knockdown in T-24-LTT, apoptosis was increased and clonogenicity was diminished even in the absence of cisplatin treatment (Figure 4c,d).	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('apoptosis', 'CPA', (47, 56))	('increased', 'PosReg', (61, 70))	('NRF2', 'Gene', (19, 23))	('knockdown', 'Var', (24, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))	('diminished', 'NegReg', (93, 103))	('clonogenicity', 'CPA', (75, 88))
40328	28767070	Further, IKKalpha and NF-kappaB p65 mRNA expression was significantly decreased in J82-LTT and 253J-LTT compared to their parental cell lines (Figure 5c, Table S1).	('IKKalpha', 'Gene', '1147', (9, 17))	('IKKalpha', 'Gene', (9, 17))	('J82-LTT', 'Var', (83, 90))	('decreased', 'NegReg', (70, 79))	('NF-kappaB p65', 'Gene', (22, 35))	('NF-kappaB p65', 'Gene', '5970', (22, 35))
40335	28767070	SiRNA-mediated knockdown of NRF2 decreased IC50 values for cisplatin in RT-112-LTT, 253J-LTT, and T-24-LTT and this sensitisation was paralleled by increased gammaH2AX foci formation, in line with the presumed functions of NRF2.	('knockdown', 'Var', (15, 24))	('increased', 'PosReg', (148, 157))	('NRF2', 'Gene', (28, 32))	('gammaH2AX', 'Protein', (158, 167))	('gammaH2AX', 'Chemical', '-', (158, 167))	('formation', 'biological_process', 'GO:0009058', ('173', '182'))	('decreased', 'NegReg', (33, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('IC50 values for cisplatin', 'MPA', (43, 68))
40336	28767070	Concordantly with our results, NRF2 knockdown sensitised the lung carcinoma cell line A549 to cisplatin, whereas its stable overexpression enhanced cisplatin resistance of breast adenocarcinoma and neuroblastoma cells MDA-MB-231 and SH-SY5Y.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (172, 193))	('NRF2', 'Gene', (31, 35))	('lung carcinoma', 'Disease', (61, 75))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (233, 240))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (218, 228))	('breast adenocarcinoma', 'Disease', (172, 193))	('neuroblastoma', 'Disease', (198, 211))	('knockdown', 'Var', (36, 45))	('neuroblastoma', 'Phenotype', 'HP:0003006', (198, 211))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (172, 193))	('overexpression enhanced', 'PosReg', (124, 147))	('neuroblastoma', 'Disease', 'MESH:D009447', (198, 211))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('lung carcinoma', 'Disease', 'MESH:D008175', (61, 75))	('A549', 'CellLine', 'CVCL:0023', (86, 90))	('cisplatin resistance', 'MPA', (148, 168))	('sensitised', 'Reg', (46, 56))
40337	28767070	Similarly, inhibition of KEAP1 stabilised NRF2 expression in SCC stem cells and rendered them resistant to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('NRF2', 'Gene', (42, 46))	('KEAP1', 'Gene', '9817', (25, 30))	('resistant', 'MPA', (94, 103))	('KEAP1', 'Gene', (25, 30))	('inhibition', 'Var', (11, 21))	('expression', 'MPA', (47, 57))	('stabilised', 'Reg', (31, 41))
40339	28767070	The deletion of NFE2L2 exon 2 represents an alternative mechanism for activation of NRF2 in squamous carcinomas.	('NFE2L2', 'Gene', (16, 22))	('squamous carcinomas', 'Disease', 'MESH:D002294', (92, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('squamous carcinomas', 'Disease', (92, 111))	('deletion', 'Var', (4, 12))	('NFE2L2', 'Gene', '4780', (16, 22))	('NRF2', 'Gene', (84, 88))	('activation', 'PosReg', (70, 80))
40340	28767070	In hepatocarcinogenesis most NRF2 mutations are located in the regions coding for the DLG or ETGE motives, which bind to the Kelch domain in KEAP1.	('hepatocarcinogenesis', 'Disease', (3, 23))	('KEAP1', 'Gene', '9817', (141, 146))	('NRF2', 'Gene', (29, 33))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (3, 23))	('KEAP1', 'Gene', (141, 146))	('mutations', 'Var', (34, 43))
40341	28767070	Instead, we detected a mutation near the BTB domain of KEAP1, c. 334A>T (T112S), in RT-112-LTT, which, despite the newly introduced serine, likely does not affect protein phosphorylation.	('KEAP1', 'Gene', '9817', (55, 60))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('334A>T', 'Var', (65, 71))	('T112S', 'Mutation', 'p.T112S', (73, 78))	('KEAP1', 'Gene', (55, 60))	('serine', 'Chemical', 'MESH:D012694', (132, 138))	('BTB domain', 'molecular_function', 'GO:0031208', ('41', '51'))	('334A>T', 'SUBSTITUTION', 'None', (65, 71))	('protein phosphorylation', 'biological_process', 'GO:0006468', ('163', '186'))
40342	28767070	Nevertheless, the T112 side chain interacts with the neighbouring amino acid backbone to stabilise a protein loop, and its replacement by a serine could impair interaction with Cullin 3.	('serine', 'Chemical', 'MESH:D012694', (140, 146))	('impair', 'NegReg', (153, 159))	('T112', 'Var', (18, 22))	('Cullin 3', 'Gene', '8452', (177, 185))	('protein', 'Protein', (101, 108))	('stabilise a', 'MPA', (89, 100))	('Cullin 3', 'Gene', (177, 185))	('interaction', 'Interaction', (160, 171))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))
40345	28767070	In other cancer types, KEAP1 mutations in the first Kelch domain (e.g., G333C in A549 cells) and in the intervention region (IVR, D236H in H460 cells) modified NRF2 signalling and influenced platinum sensitivity.	('cancer', 'Disease', (9, 15))	('influenced', 'Reg', (180, 190))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('G333C', 'Mutation', 'c.333G>C', (72, 77))	('G333C', 'Var', (72, 77))	('platinum', 'Chemical', 'MESH:D010984', (191, 199))	('mutations', 'Var', (29, 38))	('D236H', 'Mutation', 'p.D236H', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('platinum sensitivity', 'CPA', (191, 211))	('KEAP1', 'Gene', '9817', (23, 28))	('NRF2 signalling', 'Pathway', (160, 175))	('signalling', 'biological_process', 'GO:0023052', ('165', '175'))	('H460', 'CellLine', 'CVCL:0459', (139, 143))	('modified', 'Reg', (151, 159))	('KEAP1', 'Gene', (23, 28))	('A549', 'CellLine', 'CVCL:0023', (81, 85))
40349	28767070	Moreover, some UCCs, including RT-112, do not express functional p21 because of frameshift mutations.	('frameshift mutations', 'Var', (80, 100))	('p21', 'Gene', (65, 68))	('p21', 'Gene', '1026', (65, 68))
40351	28767070	In most LTTs, though, NRF2 knockdown diminished mRNA expression of downstream cytoprotective enzymes, such as GSR, NQO1, HMOX1, and GSTP1, as well as the NRF2 target p62/SQSTM1.	('NQO1', 'molecular_function', 'GO:0003955', ('115', '119'))	('NQO1', 'Gene', (115, 119))	('knockdown', 'Var', (27, 36))	('HMOX1', 'Gene', '3162', (121, 126))	('GSTP1', 'Gene', '2950', (132, 137))	('NQO1', 'Gene', '1728', (115, 119))	('GSR', 'Gene', (110, 113))	('mRNA expression', 'MPA', (48, 63))	('GSTP1', 'Gene', (132, 137))	('NRF2', 'Gene', (22, 26))	('diminished', 'NegReg', (37, 47))	('HMOX1', 'Gene', (121, 126))
40355	28767070	In our study, elevated GSH content and decreased intracellular ROS production was found in J82-LTT and especially in 253J-LTT and T-24-LTT, compared to their respective parental lines.	('intracellular', 'cellular_component', 'GO:0005622', ('49', '62'))	('ROS', 'Chemical', 'MESH:D017382', (63, 66))	('decreased', 'NegReg', (39, 48))	('intracellular ROS production', 'MPA', (49, 77))	('J82-LTT', 'Var', (91, 98))	('GSH', 'Chemical', 'MESH:D005978', (23, 26))	('GSH content', 'MPA', (23, 34))	('elevated', 'PosReg', (14, 22))
40357	28767070	Surprisingly, total GSH levels remained unchanged and intracellular oxidative stress was increased in RT-112-LTT compared to its parental cell line.	('GSH', 'Chemical', 'MESH:D005978', (20, 23))	('oxidative stress', 'Phenotype', 'HP:0025464', (68, 84))	('RT-112-LTT', 'Var', (102, 112))	('intracellular', 'cellular_component', 'GO:0005622', ('54', '67'))	('GSH levels', 'MPA', (20, 30))	('increased', 'PosReg', (89, 98))	('intracellular oxidative stress', 'MPA', (54, 84))
40361	28767070	In that study, the combination of low miRNA-27a and high SLC7A11 was also observed in cancer tissues, but in a relatively low fraction of cases.	('SLC7A11', 'Gene', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('low', 'NegReg', (34, 37))	('high', 'Var', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))	('miRNA-27a', 'Protein', (38, 47))
40363	28767070	Nevertheless, efficient siRNA-mediated knockdown of NRF2 had minimal effects on cisplatin sensitivity in this resistant subline.	('cisplatin sensitivity', 'MPA', (80, 101))	('knockdown', 'Var', (39, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('NRF2', 'Gene', (52, 56))
40364	28767070	Indeed, expression of cytoprotective enzymes and of genes involved in GSH transport and biosynthesis was largely unchanged in J82-LTT compared to its parental line.	('transport', 'biological_process', 'GO:0006810', ('74', '83'))	('GSH', 'Chemical', 'MESH:D005978', (70, 73))	('biosynthesis', 'biological_process', 'GO:0009058', ('88', '100'))	('expression', 'MPA', (8, 18))	('unchanged', 'Reg', (113, 122))	('J82-LTT', 'Var', (126, 133))
40365	28767070	As nuclear immunofluorescence staining of NRF2 was not as prominent in J82-LTT as in RT-112-LTT and 253J-LTT, we suspect that NRF2 might be prevented from activating its target genes in a KEAP1 independent manner.	('KEAP1', 'Gene', (188, 193))	('J82-LTT', 'Var', (71, 78))	('KEAP1', 'Gene', '9817', (188, 193))
40369	28767070	However, the low amount of NRF2 present proved essential in this cell line, as siNRF2 knockdown not only sensitised T-24-LTT to cisplatin, but also induced apoptosis and decreased clonogenicity in the absence of cisplatin especially in this cell line.	('knockdown', 'Var', (86, 95))	('sensitised', 'Reg', (105, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('clonogenicity', 'CPA', (180, 193))	('decreased', 'NegReg', (170, 179))	('apoptosis', 'biological_process', 'GO:0097194', ('156', '165'))	('siNRF2', 'Gene', (79, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('156', '165'))	('cisplatin', 'Chemical', 'MESH:D002945', (212, 221))	('induced', 'Reg', (148, 155))	('apoptosis', 'CPA', (156, 165))
40370	28767070	Suppression of cell proliferation by complete siNRF2-mediated knockdown has also been observed in the cholangiocarcinoma cell lines KKU-156 and KKU-100 and was similarly enhanced by cisplatin treatment.	('cisplatin', 'Chemical', 'MESH:D002945', (182, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('siNRF2-mediated', 'Gene', (46, 61))	('cell proliferation', 'biological_process', 'GO:0008283', ('15', '33'))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (102, 120))	('cell proliferation', 'CPA', (15, 33))	('Suppression', 'NegReg', (0, 11))	('cholangiocarcinoma cell lines KKU-156 and KKU-100', 'Disease', 'MESH:D018281', (102, 151))	('knockdown', 'Var', (62, 71))
40371	28767070	The sensitivity of T-24-LTT to NRF2 knockdown may of course relate to the downregulation of cytoprotective and GSH biosynthetic enzymes by the treatment.	('GSH biosynthetic enzymes', 'Enzyme', (111, 135))	('cytoprotective', 'Enzyme', (92, 106))	('downregulation', 'NegReg', (74, 88))	('NRF2', 'Gene', (31, 35))	('GSH', 'Chemical', 'MESH:D005978', (111, 114))	('knockdown', 'Var', (36, 45))
40377	28767070	Following its activation by phosphorylation at Ser276, p65 suppresses transcription of ARE-dependent genes by depriving NRF2 of CBP.	('Ser', 'cellular_component', 'GO:0005790', ('47', '50'))	('CBP', 'Gene', (128, 131))	('CBP', 'molecular_function', 'GO:0008140', ('128', '131'))	('Ser276', 'Chemical', '-', (47, 53))	('CBP', 'Gene', '1387', (128, 131))	('transcription', 'MPA', (70, 83))	('p65', 'Gene', (55, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('28', '43'))	('p65', 'Gene', '5970', (55, 58))	('suppresses', 'NegReg', (59, 69))	('ARE-dependent genes', 'Gene', (87, 106))	('Ser276', 'Var', (47, 53))	('transcription', 'biological_process', 'GO:0006351', ('70', '83'))	('NRF2', 'Gene', (120, 124))	('depriving', 'NegReg', (110, 119))
40381	28767070	There, YAP1 knockdown in T-24 cells increased sensitivity towards cisplatin by increasing DNA damage accumulation leading to apoptosis.	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('YAP1', 'Gene', (7, 11))	('DNA damage accumulation', 'MPA', (90, 113))	('sensitivity towards cisplatin', 'MPA', (46, 75))	('knockdown', 'Var', (12, 21))	('increasing', 'PosReg', (79, 89))	('apoptosis', 'biological_process', 'GO:0097194', ('125', '134'))	('apoptosis', 'biological_process', 'GO:0006915', ('125', '134'))	('increased', 'PosReg', (36, 45))	('apoptosis', 'CPA', (125, 134))
40386	28767070	For short-term experiments (STT) a single IC50 dose cisplatin was added for 72 h. As previously reported, long-term treated (LTT) UCCs were generated by adding cisplatin after every passage at escalating doses over months with constant end concentrations of 50, 3.3, 6.6, and 23 microM in RT-112-LTT, J82-LTT, 253J-LTT, and T-24-LTT, respectively.	('253J-LTT', 'Var', (310, 318))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('STT', 'Chemical', '-', (28, 31))	('J82-LTT', 'Var', (301, 308))	('cisplatin', 'Chemical', 'MESH:D002945', (160, 169))	('RT-112-LTT', 'Var', (289, 299))
40388	28767070	For siRNA-mediated knockdown, UCCs and LTTs were transfected with 10 nmol/L siNRF2 or a non-targeting control (#L-003755-00 and #D-001810-10-05, both Dharmacon, Lafayette, CO, USA) using Lipofectamine RNAiMAX Reagent (Thermo Fisher, Waltham, MA, USA) according to the manufacturer's protocol.	('knockdown', 'Var', (19, 28))	('siNRF2', 'Gene', (76, 82))	('Lipofectamine', 'Chemical', 'MESH:C086724', (187, 200))
40403	28767070	Total protein was extracted by lysis for 30 min on ice in RIPA buffer pH 7.6 (150 mM NaCL, 1% Nonidet P-40, 0.5% sodium deoxycholate, 1% Triton X-100, 0.1% SDS, 1 mM EDTA, 50 mM Tris pH 7.6, 1% protease inhibitor cocktail (#P8340) and 1% phosphatase inhibitor (#P0044, both Sigma-Aldrich).	('SDS', 'Chemical', 'MESH:D012967', (156, 159))	('Triton X-100', 'Chemical', 'MESH:D017830', (137, 149))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('Tris', 'Chemical', '-', (178, 182))	('phosphatase', 'molecular_function', 'GO:0016791', ('238', '249'))	('EDTA', 'Chemical', 'MESH:D004492', (166, 170))	('#P0044', 'Var', (261, 267))	('P-40', 'cellular_component', 'GO:0070743', ('102', '106'))	('sodium deoxycholate', 'Chemical', 'MESH:D003840', (113, 132))	('NaCL', 'Chemical', 'MESH:D012965', (85, 89))	('#P8340', 'Var', (223, 229))	('Nonidet P-40', 'Chemical', 'MESH:C010615', (94, 106))	('lysis', 'biological_process', 'GO:0019835', ('31', '36'))	('P-40', 'cellular_component', 'GO:0043514', ('102', '106'))
40404	28767070	Primary antibodies were used against NRF2 (1:1000, ab62352; Abcam, Cambridge, UK), KEAP1 (sc-365626), p62/SQSTM1 (sc-28359), YAP (sc-398182; all 1:1000; Santa Cruz Biotechnology, Heidelberg, Germany), NF-kappaB p65 (#610868) and IKKalpha (#556532; both BD Bioscience, San Jose, CA, USA, 1:1000).	('KEAP1', 'Gene', '9817', (83, 88))	('IKKalpha', 'Gene', '1147', (229, 237))	('IKKalpha', 'Gene', (229, 237))	('YAP', 'Gene', '10413', (125, 128))	('NF-kappaB p65', 'Gene', (201, 214))	('#556532;', 'Var', (239, 247))	('YAP', 'Gene', (125, 128))	('#610868', 'Var', (216, 223))	('KEAP1', 'Gene', (83, 88))	('NF-kappaB p65', 'Gene', '5970', (201, 214))
40408	28767070	NRF2/NFE2L2 and KEAP1 mutations in 413 bladder urothelial carcinoma samples (TCGA) were analysed using the cBioPortal for Cancer Genomics.	('Cancer', 'Disease', (122, 128))	('NFE2L2', 'Gene', (5, 11))	('Cancer', 'Disease', 'MESH:D009369', (122, 128))	('Cancer', 'Phenotype', 'HP:0002664', (122, 128))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (39, 67))	('bladder urothelial carcinoma', 'Disease', (39, 67))	('mutations', 'Var', (22, 31))	('KEAP1', 'Gene', '9817', (16, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('NFE2L2', 'Gene', '4780', (5, 11))	('KEAP1', 'Gene', (16, 21))
40419	27224422	The finding that the cells expressing N-cadherin gave rise to tumors with no expression of N-cadherin is in agreement with the classical view of epithelial to mesenchymal transition.	('gave rise', 'Reg', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('N-cadherin', 'Var', (38, 48))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('145', '181'))	('cadherin', 'molecular_function', 'GO:0008014', ('93', '101'))	('cadherin', 'molecular_function', 'GO:0008014', ('40', '48'))
40444	27224422	Using this cell line, it was shown that Cd+2 and As+3 can cause the malignant transformation of urothelial cells as evidence by colony formation in soft agar and tumor formation in athymic mice.	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('formation', 'biological_process', 'GO:0009058', ('135', '144'))	('colony formation in soft agar', 'CPA', (128, 157))	('mice', 'Species', '10090', (189, 193))	('tumor', 'Disease', (162, 167))	('cause', 'Reg', (58, 63))	('Cd', 'Chemical', 'MESH:D002104', (40, 42))	('As+3', 'Chemical', '-', (49, 53))	('formation', 'biological_process', 'GO:0009058', ('168', '177'))	('malignant transformation of urothelial cells', 'CPA', (68, 112))	('Cd+2', 'Var', (40, 44))
40447	27224422	The UROtsa cell line was used in the present study to determine if exposure to, or malignant transformation by, As+3 or Cd+2 would alter the expression of E- or N-cadherin in-vitro and in-vivo.	('E- or N-cadherin', 'Protein', (155, 171))	('malignant transformation', 'CPA', (83, 107))	('Cd+2', 'Var', (120, 124))	('Cd', 'Chemical', 'MESH:D002104', (120, 122))	('expression', 'MPA', (141, 151))	('cadherin', 'molecular_function', 'GO:0008014', ('163', '171'))	('alter', 'Reg', (131, 136))	('As+3', 'Chemical', '-', (112, 116))
40486	27224422	In contrast, N-cadherin mRNA expression was significantly elevated in 5 of the 6 As+3-transformed cell lines (Fig 1A) and in all 7 of the Cd+2- transformed cell lines (Fig 1B).	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('Cd', 'Chemical', 'MESH:D002104', (138, 140))	('As+3', 'Chemical', '-', (81, 85))	('N-cadherin', 'Protein', (13, 23))	('elevated', 'PosReg', (58, 66))	('As+3-transformed', 'Var', (81, 97))
40506	27224422	For E-cadherin, the results showed that all the tumor transplants produced by the As+3- (Fig 5A) and Cd+2-(Fig 5B) transformed cells expressed E-cadherin mRNA at levels equal to or greater than that found in the parental UROtsa cell line.	('As+3', 'Chemical', '-', (82, 86))	('E-cadherin', 'Gene', '999', (4, 14))	('cadherin', 'molecular_function', 'GO:0008014', ('6', '14'))	('Cd+2-', 'Var', (101, 106))	('tumor', 'Disease', (48, 53))	('Cd', 'Chemical', 'MESH:D002104', (101, 103))	('E-cadherin', 'Gene', (143, 153))	('cadherin', 'molecular_function', 'GO:0008014', ('145', '153'))	('E-cadherin', 'Gene', (4, 14))	('E-cadherin', 'Gene', '999', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
40507	27224422	The level of E-cadherin mRNA was similar in all the tumors produced by the Cd+2-transformed cell lines, however the levels were higher and more variable in tumors produced from the 6 As+3-transformed cell lines.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('Cd', 'Chemical', 'MESH:D002104', (75, 77))	('tumors', 'Disease', (52, 58))	('As+3', 'Chemical', '-', (183, 187))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('Cd+2-transformed', 'Var', (75, 91))	('tumors', 'Disease', (156, 162))
40534	27224422	The initial goal of this study was to show that N-cadherin expression was increased in UROtsa cells malignantly transformed by As+3 and Cd+2, providing evidence that the transformed cells were undergoing EMT.	('As+3', 'Chemical', '-', (127, 131))	('Cd', 'Chemical', 'MESH:D002104', (136, 138))	('EMT', 'biological_process', 'GO:0001837', ('204', '207'))	('Cd+2', 'Var', (136, 140))	('cadherin', 'molecular_function', 'GO:0008014', ('50', '58'))	('N-cadherin', 'Protein', (48, 58))	('increased', 'PosReg', (74, 83))	('expression', 'MPA', (59, 69))	('As+3', 'Var', (127, 131))
40574	23657946	Fibroblast Growth Factor Receptor 3 is a Rational Therapeutic Target in Bladder Cancer Activating mutations of Fibroblast growth factor receptor-3 (FGFR3) have been described in approximately 75% of low-grade papillary bladder tumors.	('Fibroblast growth factor receptor-3', 'Gene', (111, 146))	('papillary bladder tumors', 'Disease', (209, 233))	('papillary bladder tumors', 'Disease', 'MESH:D001749', (209, 233))	('FGFR3', 'Gene', (148, 153))	('Fibroblast growth factor', 'molecular_function', 'GO:0005104', ('111', '135'))	('Cancer', 'Disease', 'MESH:D009369', (80, 86))	('Fibroblast Growth Factor Receptor 3', 'Gene', '2261', (0, 35))	('Fibroblast Growth Factor Receptor 3', 'Gene', (0, 35))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('FGFR3', 'Gene', '2261', (148, 153))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('Fibroblast Growth Factor', 'molecular_function', 'GO:0005104', ('0', '24'))	('Cancer', 'Disease', (80, 86))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (72, 86))	('bladder tumors', 'Phenotype', 'HP:0009725', (219, 233))	('Fibroblast growth factor receptor-3', 'Gene', '2261', (111, 146))	('mutations', 'Var', (98, 107))	('FGFR', 'molecular_function', 'GO:0005007', ('148', '152'))	('described', 'Reg', (165, 174))
40575	23657946	In muscle invasive disease, FGFR3 mutations are found in 20% of tumors, but overexpression of FGFR3 is observed in about half of cases.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('ser', 'Chemical', 'MESH:D012694', (105, 108))	('FGFR3', 'Gene', '2261', (28, 33))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('FGFR3', 'Gene', '2261', (94, 99))	('FGFR3', 'Gene', (28, 33))	('found', 'Reg', (48, 53))	('FGFR3', 'Gene', (94, 99))	('muscle invasive disease', 'Disease', (3, 26))	('FGFR', 'molecular_function', 'GO:0005007', ('94', '98'))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mutations', 'Var', (34, 43))
40588	23657946	Activating FGFR3 mutations have been described in approximately 75% of low-grade papillary bladder tumors.	('Activating', 'PosReg', (0, 10))	('papillary bladder tumors', 'Disease', 'MESH:D001749', (81, 105))	('papillary bladder tumors', 'Disease', (81, 105))	('FGFR3', 'Gene', '2261', (11, 16))	('bladder tumors', 'Phenotype', 'HP:0009725', (91, 105))	('FGFR3', 'Gene', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('FGFR', 'molecular_function', 'GO:0005007', ('11', '15'))	('mutations', 'Var', (17, 26))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
40590	23657946	The most common mutation (S249C), located on exon 7, results in the substitution of serine at codon 249 with a cysteine residue.	('S249C', 'Var', (26, 31))	('serine at codon 249 with a cysteine', 'Mutation', 'rs121913483', (84, 119))	('S249C', 'Mutation', 'rs121913483', (26, 31))	('results in', 'Reg', (53, 63))	('serine', 'MPA', (84, 90))
40592	23657946	These small molecule inhibitors, including BGJ398 (Novartis), TKI258/CHIR258 (Dovitinib, Novartis), AZD4547 (Astra Zeneca) PD173074 (Pfizer, Groton, CT), and BMS-582664 (Brivanib, Bristol Myers Squibb), generally target all members of the FGFR family, VEGFR2 and other tyrosine kinases.	('VEGFR2', 'Gene', (252, 258))	('FGFR', 'molecular_function', 'GO:0005007', ('239', '243'))	('PD173074', 'Var', (123, 131))	('AZD4547', 'Var', (100, 107))	('tyrosine', 'Chemical', 'MESH:D014443', (269, 277))	('AZD4547', 'Chemical', 'MESH:C572463', (100, 107))	('Dovitinib', 'Chemical', 'MESH:C500007', (78, 87))	('target', 'Reg', (213, 219))	('BGJ398', 'Chemical', 'MESH:C568950', (43, 49))	('VEGFR2', 'Gene', '3791', (252, 258))	('FGFR family', 'Gene', (239, 250))	('BGJ398', 'Gene', (43, 49))	('Brivanib', 'Chemical', 'MESH:C509922', (170, 178))	('TKI258/CHIR258', 'Gene', (62, 76))
40596	23657946	Disruption of this pathway with pan-FGFR inhibitors leads to hyperphosphatemia and deposit of calcium phosphorous in the soft tissues, including the vasculature, smooth muscle, and renal tubules.	('deposit of calcium phosphorous in the soft tissues', 'Phenotype', 'HP:0003761', (83, 133))	('Disruption', 'Var', (0, 10))	('calcium phosphorous', 'Chemical', '-', (94, 113))	('inhibitors', 'Var', (41, 51))	('hyperphosphatemia', 'Disease', 'MESH:D054559', (61, 78))	('leads to', 'Reg', (52, 60))	('hyperphosphatemia', 'Phenotype', 'HP:0002905', (61, 78))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))	('deposit of calcium phosphorous', 'MPA', (83, 113))	('hyperphosphatemia', 'Disease', (61, 78))
40599	23657946	Most recently, an inhibitory monoclonal antibody targeting FGFR3 specifically (R3Mab) has been developed and undergone preliminary testing in pre-clinical subcutaneous models of bladder cancer, where it has demonstrated activity on both wild type and mutated FGFR3.	('FGFR3', 'Gene', '2261', (59, 64))	('FGFR3', 'Gene', (259, 264))	('bladder cancer', 'Phenotype', 'HP:0009725', (178, 192))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('antibody', 'cellular_component', 'GO:0042571', ('40', '48'))	('pre', 'molecular_function', 'GO:0003904', ('142', '145'))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('FGFR3', 'Gene', (59, 64))	('FGFR3', 'Gene', '2261', (259, 264))	('antibody', 'cellular_component', 'GO:0019814', ('40', '48'))	('antibody', 'cellular_component', 'GO:0019815', ('40', '48'))	('bladder cancer', 'Disease', 'MESH:D001749', (178, 192))	('bladder cancer', 'Disease', (178, 192))	('FGFR', 'molecular_function', 'GO:0005007', ('259', '263'))	('antibody', 'molecular_function', 'GO:0003823', ('40', '48'))	('mutated', 'Var', (251, 258))	('activity', 'MPA', (220, 228))
40603	23657946	We have measured FGFR3 mutation and expression in an American cohort of patients with bladder cancer and have demonstrated R3Mab activity in an orthotopic xenograft model of bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('bladder cancer', 'Disease', (86, 100))	('FGFR3', 'Gene', '2261', (17, 22))	('mutation', 'Var', (23, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (174, 188))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('FGFR3', 'Gene', (17, 22))	('bladder cancer', 'Disease', 'MESH:D001749', (174, 188))	('activity', 'MPA', (129, 137))	('bladder cancer', 'Disease', (174, 188))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))	('expression', 'MPA', (36, 46))	('patients', 'Species', '9606', (72, 80))
40605	23657946	A panel of 19 human bladder cancer cell lines was kindly provided by the Pathology Core of the Bladder Cancer SPORE at MD Anderson Cancer Center, including UM-UC1, UM-UC3, UM-UC4, UM-UC5, UM-UC6, UM-UC7, UM-UC10, UM-UC11, UM-UC12, UM-UC13, UM-UC14, UM-UC15, UM-UC16, UM-UC17, 253J-P, 253J-BV, RT4v6 and RT112.	('Bladder Cancer', 'Disease', 'MESH:D001749', (95, 109))	('Bladder Cancer', 'Disease', (95, 109))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('human', 'Species', '9606', (14, 19))	('bladder cancer', 'Phenotype', 'HP:0009725', (20, 34))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (95, 109))	('Cancer', 'Disease', (103, 109))	('bladder cancer', 'Disease', 'MESH:D001749', (20, 34))	('Cancer', 'Disease', 'MESH:D009369', (103, 109))	('Cancer', 'Disease', (131, 137))	('Cancer', 'Phenotype', 'HP:0002664', (103, 109))	('bladder cancer', 'Disease', (20, 34))	('Cancer', 'Phenotype', 'HP:0002664', (131, 137))	('UM-UC16', 'Var', (258, 265))	('Cancer', 'Disease', 'MESH:D009369', (131, 137))	('UM-UC15', 'Var', (249, 256))
40612	23657946	Antibodies detecting p-FGFR (#3471), p-FRS2 (#3864), p42/44MAPK (#4965), phospho-p42/44-MAPK (#4370), AKT (#9272), phosphor-AKT (ser 473; # 9271S), ZEB-1 (#3396), and cleaved caspase-3 (#9661) were purchased from Cell Signaling (Danvers, MA).	('caspase-3', 'Gene', '836', (175, 184))	('#3864', 'Var', (45, 50))	('FRS2', 'Gene', '10818', (39, 43))	('caspase-3', 'Gene', (175, 184))	('#4965', 'Var', (65, 70))	('AKT', 'Gene', (102, 105))	('#9661', 'Var', (186, 191))	('p42', 'Gene', (53, 56))	('AKT', 'Gene', (124, 127))	('ser', 'cellular_component', 'GO:0005790', ('129', '132'))	('#9272', 'Var', (107, 112))	('p42', 'Gene', '23552', (53, 56))	('p42', 'Gene', (81, 84))	('MAPK', 'molecular_function', 'GO:0004707', ('88', '92'))	('MAPK', 'molecular_function', 'GO:0004707', ('59', '63'))	('ZEB-1', 'Gene', (148, 153))	('#3396', 'Var', (155, 160))	('AKT', 'Gene', '207', (102, 105))	('FRS2', 'Gene', (39, 43))	('ZEB-1', 'Gene', '6935', (148, 153))	('Signaling', 'biological_process', 'GO:0023052', ('218', '227'))	('AKT', 'Gene', '207', (124, 127))	('#4370', 'Var', (94, 99))	('p42', 'Gene', '23552', (81, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('ser', 'Chemical', 'MESH:D012694', (129, 132))	('#3471', 'Var', (29, 34))
40613	23657946	Anti-phospho-tyrosine 4G10 was obtained from EMD Millipore (Bedford, MA) and E-cadherin antibody (#610181) from BD Biosciences (Mississauga, ON).	('Anti-phospho-tyrosine 4G10', 'Var', (0, 26))	('cadherin', 'molecular_function', 'GO:0008014', ('79', '87'))	('antibody', 'cellular_component', 'GO:0019815', ('88', '96'))	('E-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (77, 87))	('antibody', 'cellular_component', 'GO:0019814', ('88', '96'))	('antibody', 'molecular_function', 'GO:0003823', ('88', '96'))	('tyrosine', 'Chemical', 'MESH:D014443', (13, 21))	('antibody', 'cellular_component', 'GO:0042571', ('88', '96'))	('#610181', 'Var', (98, 105))
40663	23657946	170 fresh frozen samples from an independent cohort of patients with urothelial carcinoma of the bladder were analyzed for mutations in the FGFR3 gene by direct sequencing.	('FGFR', 'molecular_function', 'GO:0005007', ('140', '144'))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('FGFR3', 'Gene', (140, 145))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (69, 104))	('urothelial carcinoma of the bladder', 'Disease', (69, 104))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (69, 104))	('patients', 'Species', '9606', (55, 63))	('FGFR3', 'Gene', '2261', (140, 145))	('mutations', 'Var', (123, 132))
40666	23657946	FGFR3 mutations in exon 7 or exon 10 were found in 26% of all samples and 56% of low-grade tumors.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mutations in', 'Var', (6, 18))	('found', 'Reg', (42, 47))	('FGFR3', 'Gene', '2261', (0, 5))
40667	23657946	Low grade, non-invasive tumors showed more than a fourfold increased rate of FGFR3 mutation compared to high grade, invasive tumors (Tab.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('FGFR3', 'Gene', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('invasive tumors', 'Disease', (15, 30))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('mutation', 'Var', (83, 91))	('invasive tumors', 'Disease', 'MESH:D009369', (15, 30))	('invasive tumors', 'Disease', (116, 131))	('FGFR3', 'Gene', '2261', (77, 82))	('invasive tumors', 'Disease', 'MESH:D009369', (116, 131))
40668	23657946	Similar analysis revealed a S249C mutation (exon 7) in 5 of 19 cell lines and a Y375C (exon 10) mutation in one cell line.	('Y375C', 'Var', (80, 85))	('S249C', 'Var', (28, 33))	('Y375C', 'Mutation', 'rs121913485', (80, 85))	('S249C', 'Mutation', 'rs121913483', (28, 33))
40678	23657946	A similar experiment was performed in UM-UC14, which harbors an S249C mutation in exon 7 of FGFR3, but here an immune-precipitation was performed with anti-FGFR3 and subsequent blotting with anti-phospho-tyrosine as an alternative method to demonstrate FGFR3 phosphorylation (Fig.	('FGFR3', 'Gene', (156, 161))	('S249C', 'Var', (64, 69))	('FGFR3', 'Gene', (92, 97))	('S249C', 'Mutation', 'rs121913483', (64, 69))	('tyrosine', 'Chemical', 'MESH:D014443', (204, 212))	('men', 'Species', '9606', (16, 19))	('FGFR3', 'Gene', '2261', (253, 258))	('FGFR3', 'Gene', '2261', (156, 161))	('phosphorylation', 'biological_process', 'GO:0016310', ('259', '274'))	('FGFR', 'molecular_function', 'GO:0005007', ('253', '257'))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('FGFR3', 'Gene', '2261', (92, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('156', '160'))	('FGFR3', 'Gene', (253, 258))
40679	23657946	Treatment with R3Mab in regular growth medium resulted in a concentration-dependent growth inhibition in three out of four different tumor cell lines in a crystal violet assay (Fig.	('growth inhibition', 'CPA', (84, 101))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('R3Mab', 'Var', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('men', 'Species', '9606', (5, 8))	('crystal violet', 'Chemical', 'MESH:D005840', (155, 169))
40688	23657946	The IgG1 had no effect on tumor growth, while mice treated with R3Mab showed a reduction in tumor growth by 59.2 % compared to IgG and 57.2% compared to saline controls (Fig.	('IgG1', 'Gene', (4, 8))	('saline', 'Chemical', 'MESH:D012965', (153, 159))	('IgG1', 'cellular_component', 'GO:0071735', ('4', '8'))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('IgG1', 'Gene', '105243590', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Disease', (92, 97))	('R3Mab', 'Var', (64, 69))	('tumor', 'Disease', (26, 31))	('reduction', 'NegReg', (79, 88))
40689	23657946	In vivo, UM-UC1 tumors orthotopically injected into the bladder of nude mice showed a reduction in tumor growth of 83.9% when treated with R3Mab compared to mice injected with IgG and 84,1 % compared to saline controls (Fig.	('reduction', 'NegReg', (86, 95))	('tumor', 'Disease', (99, 104))	('saline', 'Chemical', 'MESH:D012965', (203, 209))	('mice', 'Species', '10090', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('nude mice', 'Species', '10090', (67, 76))	('R3Mab', 'Var', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (16, 21))	('mice', 'Species', '10090', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (16, 22))
40694	23657946	We have demonstrated a high rate of FGFR3 mutation and over-expression in an American cohort of patients.	('FGFR3', 'Gene', (36, 41))	('over-expression', 'MPA', (55, 70))	('mutation', 'Var', (42, 50))	('patients', 'Species', '9606', (96, 104))	('FGFR3', 'Gene', '2261', (36, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
40697	23657946	We see a lower rate of FGFR3 mutations in low grade tumors and a higher rate of FGFR3 overexpression in high grade tumors compared to prior reports.	('FGFR3', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (29, 38))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('FGFR3', 'Gene', '2261', (80, 85))	('FGFR3', 'Gene', '2261', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('FGFR3', 'Gene', (80, 85))	('overexpression', 'MPA', (86, 100))
40701	23657946	Although we possess bladder cancer cell lines with FGFR3 mutations, these mutations are found only in highly invasive cell lines that are not representative of non-muscle invasive disease.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('FGFR3', 'Gene', '2261', (51, 56))	('bladder cancer', 'Phenotype', 'HP:0009725', (20, 34))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('bladder cancer', 'Disease', 'MESH:D001749', (20, 34))	('mutations', 'Var', (57, 66))	('bladder cancer', 'Disease', (20, 34))	('FGFR3', 'Gene', (51, 56))
40707	23657946	While it would seem logical to target the activating mutations in non-muscle invasive disease, it will be challenging to give systemic therapy to this patient population, especially since FGFR3 mutations indicate a favorable prognosis.	('FGFR3', 'Gene', '2261', (188, 193))	('FGFR', 'molecular_function', 'GO:0005007', ('188', '192'))	('patient', 'Species', '9606', (151, 158))	('mutations', 'Var', (194, 203))	('FGFR3', 'Gene', (188, 193))	('mutations', 'Var', (53, 62))	('non-muscle invasive disease', 'Disease', (66, 93))
40713	23657946	Whether FGFR3 mutations are relevant in the context of muscle invasive bladder cancer remains to be shown.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('invasive bladder', 'Phenotype', 'HP:0100645', (62, 78))	('FGFR3', 'Gene', '2261', (8, 13))	('FGFR', 'molecular_function', 'GO:0005007', ('8', '12'))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (55, 85))	('muscle invasive bladder cancer', 'Disease', (55, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))	('mutations', 'Var', (14, 23))	('FGFR3', 'Gene', (8, 13))
40714	23657946	Our cell line investigations reveal little drug activity in invasive cells with FGFR3 mutations, with the exception of UM-UC14.	('mutations', 'Var', (86, 95))	('FGFR3', 'Gene', '2261', (80, 85))	('FGFR3', 'Gene', (80, 85))	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))
40720	23657946	We have confirmed the results of prior reports on FGFR3 mutation and expression patterns in urothelial carcinoma of the bladder: FGFR3 is frequently mutated in non-invasive bladder cancer and frequently over-expressed in both non-invasive and invasive bladder cancer.	('invasive bladder', 'Phenotype', 'HP:0100645', (243, 259))	('mutated', 'Var', (149, 156))	('over-expressed', 'PosReg', (203, 217))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (164, 187))	('invasive bladder', 'Phenotype', 'HP:0100645', (164, 180))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (92, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (243, 266))	('invasive bladder cancer', 'Disease', (164, 187))	('FGFR', 'molecular_function', 'GO:0005007', ('129', '133'))	('FGFR3', 'Gene', (129, 134))	('invasive bladder cancer', 'Disease', (243, 266))	('FGFR3', 'Gene', '2261', (129, 134))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (92, 127))	('bladder cancer', 'Phenotype', 'HP:0009725', (173, 187))	('bladder cancer', 'Phenotype', 'HP:0009725', (252, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('FGFR3', 'Gene', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('non-invasive', 'Disease', (226, 238))	('FGFR', 'molecular_function', 'GO:0005007', ('50', '54'))	('urothelial carcinoma of the bladder', 'Disease', (92, 127))	('FGFR3', 'Gene', '2261', (50, 55))
40729	33608012	Subgroup analysis by cancer type revealed that high CONUT score associated with worse OS in renal cell carcinoma (RCC) and urothelial cancer (UC) (HR: 3.05, 95% CI 2.07-4.50, p < 0.001; HR: 1.58, 95% CI 1.32-1.89, p < 0.001).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('high', 'Var', (47, 51))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('CONUT', 'Gene', (52, 57))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (92, 112))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('renal cell carcinoma (RCC) and urothelial cancer', 'Disease', 'MESH:C538614', (92, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
40731	33608012	These results illustrated that the high CONUT score may predict worse survival for patients suffering from urological cancers.	('worse', 'NegReg', (64, 69))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('patients', 'Species', '9606', (83, 91))	('urological cancers', 'Disease', (107, 125))	('urological cancers', 'Disease', 'MESH:D014571', (107, 125))	('high', 'Var', (35, 39))
40765	33608012	Finally, among Asian populations, high CONUT score could be a negative predictor for OS in urological cancers (HR: 1.73, 95% CI 1.46-2.04, p < 0.001).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('urological cancers', 'Disease', 'MESH:D014571', (91, 109))	('urological cancers', 'Disease', (91, 109))	('negative', 'NegReg', (62, 70))	('high', 'Var', (34, 38))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))
40767	33608012	A combined analysis demonstrated that high CONUT score were significantly positively correlated with shortened CSS (HR: 2.14, 95% CI 1.55-2.97, p < 0.001), with moderate heterogeneity identified between studies (I2 = 51.6%, p = 0.035; Fig.	('CSS', 'Chemical', '-', (111, 114))	('high', 'Var', (38, 42))	('shortened CSS', 'CPA', (101, 114))
40784	33608012	A stratified analysis demonstrated that high CONUT score were significantly correlated with decreased OS, CSS and RFS/DFS/PFS, irrespective of the cancer type, cancer stage, treatment methods, sample size and cut-off value.	('RFS', 'Gene', '65211', (114, 117))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (160, 166))	('RFS', 'Gene', (114, 117))	('decreased', 'NegReg', (92, 101))	('CSS', 'Disease', (106, 109))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', (147, 153))	('high CONUT', 'Var', (40, 50))	('CSS', 'Chemical', '-', (106, 109))
40789	33608012	Our results confirmed that high COUNT score was associated with worse OS, CSS and RFS/DFS/PFS and CONUT score was an effective prognostic biomarker for RCC.	('CSS', 'Disease', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('high', 'Var', (27, 31))	('RFS', 'Gene', '65211', (82, 85))	('worse OS', 'Disease', (64, 72))	('CSS', 'Chemical', '-', (74, 77))	('RFS', 'Gene', (82, 85))
40793	33608012	However, there are several reasons to explain why a high CONUT score is associated with poor outcomes in urological cancers.	('urological cancers', 'Disease', 'MESH:D014571', (105, 123))	('urological cancers', 'Disease', (105, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('high', 'Var', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
40799	33608012	Thus, high CONUT score is typically associated with the invasion and metastasis of tumour cells and it can lead to poor survival.	('tumour', 'Disease', (83, 89))	('poor', 'NegReg', (115, 119))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('high', 'Var', (6, 10))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('lead', 'Reg', (107, 111))	('associated', 'Reg', (36, 46))	('invasion', 'CPA', (56, 64))
40805	33499282	In Silico Inference of Synthetic Cytotoxic Interactions from Paclitaxel Responses To exploit negatively interacting pairs of cancer somatic mutations in chemotherapy responses or synthetic cytotoxicity (SC), we systematically determined mutational pairs that had significantly lower paclitaxel half maximal inhibitory concentration (IC50) values.	('Paclitaxel', 'Chemical', 'MESH:D017239', (61, 71))	('paclitaxel half maximal inhibitory concentration', 'MPA', (283, 331))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutational pairs', 'Var', (237, 253))	('paclitaxel', 'Chemical', 'MESH:D017239', (283, 293))	('cytotoxicity', 'Disease', (189, 201))	('cytotoxicity', 'Disease', 'MESH:D064420', (189, 201))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('lower', 'NegReg', (277, 282))
40819	33499282	(2014) performed a series of yeast experiments, including synthetic genetic and plate assays, to show that digenic disruption due to the TEL1/ATM mutation leads to SC with camptothecin, a topoisomerase I inhibitor.	('ATM', 'Gene', '472', (142, 145))	('TEL1', 'Gene', (137, 141))	('camptothecin', 'Chemical', 'MESH:D002166', (172, 184))	('leads to', 'Reg', (155, 163))	('topoisomerase', 'molecular_function', 'GO:0003917', ('188', '201'))	('TEL1', 'Gene', '852190', (137, 141))	('topoisomerase', 'molecular_function', 'GO:0003918', ('188', '201'))	('digenic disruption', 'MPA', (107, 125))	('mutation', 'Var', (146, 154))	('yeast', 'Species', '4932', (29, 34))	('ATM', 'Gene', (142, 145))
40821	33499282	Here, we focused on the chemotherapeutic agent paclitaxel, and using Genomics of Drug Sensitivity in Cancer (GDSC) cell line data, we identified SC mutational pairs that increase the anticancer effect of paclitaxel via conditional synthetic lethality.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('Cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (187, 193))	('increase', 'PosReg', (170, 178))	('paclitaxel', 'Chemical', 'MESH:D017239', (204, 214))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('conditional synthetic lethality', 'CPA', (219, 250))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('paclitaxel', 'Chemical', 'MESH:D017239', (47, 57))	('mutational pairs', 'Var', (148, 164))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (81, 97))	('Cancer', 'Disease', (101, 107))
40828	33499282	An SC interaction was defined as a better response to paclitaxel (i.e., lower IC50 value) when both genes in an interacting pair were disrupted (details in method section).	('lower', 'NegReg', (72, 77))	('disrupted', 'Var', (134, 143))	('paclitaxel', 'Chemical', 'MESH:D017239', (54, 64))	('response', 'MPA', (42, 50))	('response to paclitaxel', 'biological_process', 'GO:1901555', ('42', '64'))
40834	33499282	When both TP53 and SYNE2 were disrupted, the response to paclitaxel was significantly better compared with that of the other three cases (p < 0.05, Wilcoxon test; Figure 5a).	('response to paclitaxel', 'MPA', (45, 67))	('TP53', 'Gene', (10, 14))	('better', 'PosReg', (86, 92))	('disrupted', 'Var', (30, 39))	('paclitaxel', 'Chemical', 'MESH:D017239', (57, 67))	('SYNE2', 'Gene', (19, 24))	('response to paclitaxel', 'biological_process', 'GO:1901555', ('45', '67'))	('SYNE2', 'Gene', '23224', (19, 24))	('TP53', 'Gene', '7157', (10, 14))
40846	33499282	Patients with bladder urothelial carcinoma were divided into four groups according to the mutations in SYNE2 and TP53.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (14, 42))	('mutations', 'Var', (90, 99))	('bladder urothelial carcinoma', 'Disease', (14, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('SYNE2', 'Gene', (103, 108))	('Patients', 'Species', '9606', (0, 8))	('SYNE2', 'Gene', '23224', (103, 108))	('TP53', 'Gene', '7157', (113, 117))	('TP53', 'Gene', (113, 117))
40847	33499282	There were 48 patients with mutations in SYNE2 and TP53, 88 patients with mutations in SYNE2, 150 patients with mutations in TP53, and 184 patients with wild-type versions of both genes (Figure 6a).	('TP53', 'Gene', (51, 55))	('SYNE2', 'Gene', (87, 92))	('patients', 'Species', '9606', (139, 147))	('TP53', 'Gene', '7157', (125, 129))	('SYNE2', 'Gene', (41, 46))	('patients', 'Species', '9606', (60, 68))	('mutations', 'Var', (74, 83))	('patients', 'Species', '9606', (98, 106))	('TP53', 'Gene', (125, 129))	('SYNE2', 'Gene', '23224', (87, 92))	('SYNE2', 'Gene', '23224', (41, 46))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (28, 37))	('TP53', 'Gene', '7157', (51, 55))
40848	33499282	Cox regression with Firth's penalized likelihood method was used for patients with mutations in SYNE2 and TP53, as this was the reference group.	('mutations', 'Var', (83, 92))	('SYNE2', 'Gene', (96, 101))	('SYNE2', 'Gene', '23224', (96, 101))	('patients', 'Species', '9606', (69, 77))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
40849	33499282	Compared with the group with mutations in SYNE2 and TP53, the hazard ratio and p-value of wild-type, TP53 mutant, and SYNE2 mutant groups were 2.40 and 0.047, 2.67 and 0.021, and 2.68 and 0.092, respectively.	('mutant', 'Var', (106, 112))	('SYNE2', 'Gene', (42, 47))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', '7157', (101, 105))	('mutant', 'Var', (124, 130))	('SYNE2', 'Gene', '23224', (42, 47))	('TP53', 'Gene', (52, 56))	('TP53', 'Gene', (101, 105))	('SYNE2', 'Gene', (118, 123))	('SYNE2', 'Gene', '23224', (118, 123))
40854	33499282	With the SON and TP53 mutant group as the reference, the hazard ratios of the wild-type group were 4.51 (p = 0.184) and 8.43 (p = 0.033), respectively, for the TP53 mutant group, and 9.54 (p = 0.041) for the SYNE2 mutant group.	('mutant', 'Var', (165, 171))	('TP53', 'Gene', '7157', (160, 164))	('mutant', 'Var', (214, 220))	('TP53', 'Gene', (160, 164))	('SYNE2', 'Gene', (208, 213))	('TP53', 'Gene', '7157', (17, 21))	('SYNE2', 'Gene', '23224', (208, 213))	('TP53', 'Gene', (17, 21))
40855	33499282	Figure 7 illustrates the Kaplan-Meier curves for the patients with bladder urothelial (Figure 7a,b) and uterine corpus endometrial (Figure 7c,d) carcinoma, according to the cumulative disruption of SYNE2 and SON with (Figure 7a,c) and without (Figure 7b,d) TP53 mutation.	('SYNE2', 'Gene', '23224', (198, 203))	('carcinoma', 'Disease', 'MESH:D009369', (145, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('TP53', 'Gene', (257, 261))	('patients', 'Species', '9606', (53, 61))	('mutation', 'Var', (262, 270))	('carcinoma', 'Disease', (145, 154))	('bladder urothelial', 'Disease', 'MESH:D001745', (67, 85))	('bladder urothelial', 'Disease', (67, 85))	('SYNE2', 'Gene', (198, 203))	('TP53', 'Gene', '7157', (257, 261))
40856	33499282	Red lines represent wild-type SYNE2 and SON, green lines indicate a mutation in one of the genes, and blue lines indicate disruption of both genes.	('mutation', 'Var', (68, 76))	('disruption', 'NegReg', (122, 132))	('SYNE2', 'Gene', '23224', (30, 35))	('SYNE2', 'Gene', (30, 35))
40857	33499282	While the TP53 mutations (Figure 7a,c) were noted in both cancer types, accumulation of SYNE2 and SON SC pairs showed better prognosis according to the results of Cox regression with Firth's penalized likelihood method (p < 0.05).	('SYNE2', 'Gene', '23224', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('TP53', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('accumulation', 'PosReg', (72, 84))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('SYNE2', 'Gene', (88, 93))	('cancer', 'Disease', (58, 64))	('better', 'PosReg', (118, 124))	('TP53', 'Gene', '7157', (10, 14))
40862	33499282	Only TP53 mutant patients with an SC burden consistent with the univariate analysis showed significant results for survival analysis.	('mutant', 'Var', (10, 16))	('patients', 'Species', '9606', (17, 25))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))
40863	33499282	In TP53 mutant bladder cancer, the p value of the SC burden was 0.031 and the hazard ratio was 0.397, while in TP53 mutant uterine cancer, the p value of the SC burden was 0.035 and the hazard ratio was 0.237.	('cancer', 'Disease', (131, 137))	('TP53', 'Gene', '7157', (3, 7))	('TP53', 'Gene', (3, 7))	('bladder cancer', 'Disease', 'MESH:D001749', (15, 29))	('bladder cancer', 'Disease', (15, 29))	('TP53', 'Gene', '7157', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutant', 'Var', (8, 14))	('cancer', 'Disease', (23, 29))	('TP53', 'Gene', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('bladder cancer', 'Phenotype', 'HP:0009725', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('mutant', 'Var', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('uterine cancer', 'Phenotype', 'HP:0010784', (123, 137))
40884	33499282	The TP53 mutation is an important biomarker for tumor recurrence, progression, and prognosis in urogenital cancer.	('mutation', 'Var', (9, 17))	('urogenital cancer', 'Disease', 'MESH:D014565', (96, 113))	('tumor', 'Disease', (48, 53))	('TP53', 'Gene', (4, 8))	('urogenital cancer', 'Disease', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('TP53', 'Gene', '7157', (4, 8))
40886	33499282	However, SC exploits the highly mutated TP53 in an unconventional way that allows for the development of novel therapeutic strategies by exploiting other genes.	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('mutated', 'Var', (32, 39))
40887	33499282	For response to paclitaxel, both SON and SYNE2 genes were found to increase the drug cytotoxicity when disrupted with the TP53 gene.	('TP53', 'Gene', (122, 126))	('genes', 'Var', (47, 52))	('SON', 'Gene', (33, 36))	('drug cytotoxicity', 'Disease', 'MESH:D064420', (80, 97))	('drug cytotoxicity', 'Disease', (80, 97))	('SYNE2', 'Gene', (41, 46))	('SYNE2', 'Gene', '23224', (41, 46))	('response to paclitaxel', 'biological_process', 'GO:1901555', ('4', '26'))	('paclitaxel', 'Chemical', 'MESH:D017239', (16, 26))	('increase', 'PosReg', (67, 75))	('disrupted', 'NegReg', (103, 112))	('TP53', 'Gene', '7157', (122, 126))
40908	33499282	To validate SC effects for gene pairs computationally inferred from the cell line database derived from GDSC, we confirmed the prognostic effect in the real patient database from TCGA for the SC pairs that improved the response to paclitaxel.	('patient', 'Species', '9606', (157, 164))	('improved', 'PosReg', (206, 214))	('response to paclitaxel', 'biological_process', 'GO:1901555', ('219', '241'))	('paclitaxel', 'Chemical', 'MESH:D017239', (231, 241))	('pairs', 'Var', (195, 200))	('response to paclitaxel', 'MPA', (219, 241))
40910	33499282	Patients were divided into two groups, with and without TP53 mutations.	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', (56, 60))	('TP53', 'Gene', '7157', (56, 60))	('mutations', 'Var', (61, 70))
40911	33499282	For each group, patients were subdivided according to the burden of the mutation forming SC with TP53.	('TP53', 'Gene', (97, 101))	('patients', 'Species', '9606', (16, 24))	('TP53', 'Gene', '7157', (97, 101))	('mutation', 'Var', (72, 80))
40912	33499282	Finally, Cox regression with Firth's penalized likelihood method was used based on the burden of the mutation, and the hazard ratio of the burden was compared between the TP53 mutant and nonmutant groups to confirm the prognostic effect of the SC pair.	('TP53', 'Gene', (171, 175))	('mutant', 'Var', (176, 182))	('TP53', 'Gene', '7157', (171, 175))	('mutation', 'Var', (101, 109))
40917	32330187	This study investigates the BRAF V595E allele concentration in circulating cell-free DNA (cfDNA) and assesses the clinical significance of BRAF-mutated ctDNA levels in canines with urothelial carcinoma.	('canines', 'Species', '9615', (168, 175))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('V595E', 'Mutation', 'p.V595E', (33, 38))	('urothelial carcinoma', 'Disease', (181, 201))	('BRAF', 'Gene', (28, 32))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (181, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('V595E', 'Var', (33, 38))
40919	32330187	BRAF mutations were detected in 11 (73%) of the 15 tested tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('BRAF', 'Gene', (0, 4))
40920	32330187	BRAF-mutated ctDNA concentrations were significantly higher in dogs with the BRAF mutation (14.05 +- 13.51 ng/ml) than in wild-type dogs (0.21 +- 0.41 ng/ml) (p = 0.031).	('higher', 'PosReg', (53, 59))	('mutation', 'Var', (82, 90))	('dogs', 'Species', '9615', (63, 67))	('dogs', 'Species', '9615', (132, 136))	('BRAF', 'Gene', (77, 81))	('BRAF-mutated ctDNA concentrations', 'MPA', (0, 33))
40921	32330187	Our results show that BRAF-mutated ctDNA can be detected using allele-specific real-time PCR in plasma samples of canines with urothelial carcinoma with the BRAF V595E mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('V595E', 'Mutation', 'p.V595E', (162, 167))	('BRAF V595E', 'Var', (157, 167))	('canines', 'Species', '9615', (114, 121))	('urothelial carcinoma', 'Disease', (127, 147))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (127, 147))
40933	32330187	CtDNAs with PIK3CA, EGFR, KRAS, or BRAF mutations have been detected in human patients, and the levels of these ctDNAs have been shown to be useful for the monitoring of disease progression.	('BRAF', 'Gene', (35, 39))	('PIK3CA', 'Gene', '5290', (12, 18))	('EGFR', 'Gene', (20, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('20', '24'))	('human', 'Species', '9606', (72, 77))	('patients', 'Species', '9606', (78, 86))	('mutations', 'Var', (40, 49))	('KRAS', 'Gene', (26, 30))	('KRAS', 'Gene', '3845', (26, 30))	('EGFR', 'Gene', '1956', (20, 24))	('PIK3CA', 'Gene', (12, 18))
40935	32330187	In humans, approximately 50% of patients with melanoma have the BRAF V600E mutation, and BRAF-mutated ctDNA levels have been shown to serve as specific biomarkers in these patients.	('V600E', 'Var', (69, 74))	('patients', 'Species', '9606', (32, 40))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('BRAF', 'Gene', (64, 68))	('V600E', 'Mutation', 'rs113488022', (69, 74))	('humans', 'Species', '9606', (3, 9))	('patients', 'Species', '9606', (172, 180))
40936	32330187	In veterinary medicine, testing for the presence of the BRAF mutation using urine or tissue samples is a sensitive and noninvasive method for the diagnosis of canine urothelial carcinoma.	('canine', 'Species', '9615', (159, 165))	('urothelial carcinoma', 'Disease', (166, 186))	('mutation', 'Var', (61, 69))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (166, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('BRAF', 'Gene', (56, 60))
40944	32330187	The BRAF mutation status was available for all dogs and was obtained from DNA from biopsy or surgical specimens using the QIAamp DNA Mini Kit (QIAGEN, Hilden, Germany).	('mutation', 'Var', (9, 17))	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('DNA', 'cellular_component', 'GO:0005574', ('129', '132'))	('BRAF', 'Gene', (4, 8))	('dogs', 'Species', '9615', (47, 51))
40945	32330187	Sequencing was performed at Eurofins Genomics (https://www.eurofinsgenomics.jp/), and data were analyzed for the presence of the cBRAF V595E mutation using Sequencher (Sequencher  version 4.7 DNA sequence analysis software, Gene Codes Corporation, Ann Arbor, MI, USA).	('cBRAF', 'Gene', (129, 134))	('V595E', 'Mutation', 'p.V595E', (135, 140))	('V595E', 'Var', (135, 140))	('DNA', 'cellular_component', 'GO:0005574', ('192', '195'))
40947	32330187	The standard curve for the BRAF mutation consisted of six dilutions (100%, 50%, 20%, 10%, 1%, and 0% of BRAF mutated samples) obtained by mixing DNA from a mutant transitional cell carcinoma cell line (LC-TCC) and wild-type genomic DNA obtained from peripheral blood leukocytes of a healthy dog (Fig 2).	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('DNA', 'cellular_component', 'GO:0005574', ('145', '148'))	('carcinoma', 'Disease', 'MESH:D009369', (181, 190))	('DNA', 'cellular_component', 'GO:0005574', ('232', '235'))	('dog', 'Species', '9615', (291, 294))	('mutant', 'Var', (156, 162))	('BRAF', 'Gene', (27, 31))	('TCC', 'cellular_component', 'GO:0005579', ('205', '208'))	('mutation', 'Var', (32, 40))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (163, 190))	('carcinoma', 'Disease', (181, 190))
40948	32330187	Because canine TCC is heterozygous for the BRAF mutation, mutated BRAF concentrations were calculated as follows: mutated BRAF ctDNA (ng/ml) = (% mutated BRAF x total cfDNA)/100/2.	('BRAF', 'Gene', (122, 126))	('TCC', 'cellular_component', 'GO:0005579', ('15', '18'))	('mutation', 'Var', (48, 56))	('canine', 'Species', '9615', (8, 14))
40954	32330187	BRAF mutations were detected in 11 (73%) of the 15 tested tumor tissue or urine samples (S1 Fig).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('BRAF', 'Gene', (0, 4))
40962	32330187	The mean percentage of the BRAF mutation in cfDNA was 2.18 +- 2.15% in dogs with the BRAF mutation and 0.11 +- 0.22% in wild-type dogs (p = 0.022).	('cfDNA', 'Disease', (44, 49))	('BRAF', 'Gene', (27, 31))	('mutation', 'Var', (90, 98))	('mutation', 'Var', (32, 40))	('dogs', 'Species', '9615', (71, 75))	('dogs', 'Species', '9615', (130, 134))
40963	32330187	BRAF-mutated ctDNA concentration was significantly higher in dogs with the BRAF mutation (14.05 +- 13.51 ng/ml) than in wild-type dogs (0.21 +- 0.41 ng/ml) (p = 0.031) (Fig 4).	('mutation', 'Var', (80, 88))	('BRAF', 'Gene', (75, 79))	('higher', 'PosReg', (51, 57))	('BRAF-mutated ctDNA concentration', 'MPA', (0, 32))	('dogs', 'Species', '9615', (130, 134))	('dogs', 'Species', '9615', (61, 65))
40964	32330187	We compared the BRAF-mutated ctDNA concentrations in 11 dogs with the BRAF mutation with different tumor stages.	('tumor', 'Disease', (99, 104))	('mutation', 'Var', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('dogs', 'Species', '9615', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
40968	32330187	In several patients, the concentration of BRAF-mutated ctDNA in plasma increased with disease progression and responded to the treatment.	('concentration', 'MPA', (25, 38))	('ctDNA', 'Gene', (55, 60))	('increased', 'PosReg', (71, 80))	('patients', 'Species', '9606', (11, 19))	('BRAF-mutated', 'Var', (42, 54))
40986	32330187	The 11 patients who tested positive for the BRAF mutation in their primary tumor were divided into two groups according to their plasma concentrations of BRAF-mutated ctDNA (< 8.3 ng/ml vs. >= 8.3 ng/ml) at first sampling.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('mutation', 'Var', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('BRAF-mutated', 'Var', (154, 166))	('patients', 'Species', '9606', (7, 15))	('tumor', 'Disease', (75, 80))
40988	32330187	CtDNAs carrying tumor-specific mutations have been found in the bloodstream.	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (31, 40))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (16, 21))
40990	32330187	Recently, studies have reported that the canine BRAF V595E mutation, a single nucleotide T to A transversion at nucleotide 1349, is detectable in 80% of canines with urothelial carcinomas.	('V595E', 'Var', (53, 58))	('canine', 'Species', '9615', (153, 159))	('T to A transversion at nucleotide 1349', 'Mutation', 'c.1349T>A', (89, 127))	('canines', 'Species', '9615', (153, 160))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (166, 187))	('V595E', 'Mutation', 'p.V595E', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('urothelial carcinomas', 'Disease', (166, 187))	('BRAF', 'Gene', (48, 52))	('canine', 'Species', '9615', (41, 47))
40994	32330187	CtDNAs with mutations in several genes have been detected in human patients with cancer, and ctDNA analysis provides critical clinical information to improve diagnosis in these patients.	('patients', 'Species', '9606', (67, 75))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('patients', 'Species', '9606', (177, 185))	('mutations', 'Var', (12, 21))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('human', 'Species', '9606', (61, 66))
40995	32330187	Mutated BRAF ctDNA was detected in 9 of these 11 patients' plasma at the time of the first blood collection.	('BRAF', 'Gene', (8, 12))	('Mutated', 'Var', (0, 7))	('patients', 'Species', '9606', (49, 57))
40997	32330187	This study suggests that the quantification of mutated BRAF ctDNA in plasma may represent a useful biomarker for the noninvasive diagnosis of canine urothelial carcinoma when the tumor has the BRAF mutation.	('urothelial carcinoma', 'Disease', (149, 169))	('canine', 'Species', '9615', (142, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (149, 169))	('BRAF ctDNA', 'Gene', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('mutated', 'Var', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
41001	32330187	Furthermore, it is possible that ctDNA in plasma of the dog could be indicative of a BRAF mutation originating from other neoplasms that have been undiagnosed because BRAF V595E mutation has been detected in not only urothelial carcinoma but also many other neoplasms.	('neoplasms', 'Disease', (122, 131))	('V595E', 'Mutation', 'p.V595E', (172, 177))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (217, 237))	('dog', 'Species', '9615', (56, 59))	('neoplasms', 'Disease', (258, 267))	('detected', 'Reg', (196, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('BRAF', 'Gene', (167, 171))	('neoplasms', 'Disease', 'MESH:D009369', (258, 267))	('neoplasms', 'Phenotype', 'HP:0002664', (122, 131))	('V595E', 'Var', (172, 177))	('neoplasms', 'Phenotype', 'HP:0002664', (258, 267))	('urothelial carcinoma', 'Disease', (217, 237))	('neoplasms', 'Disease', 'MESH:D009369', (122, 131))
41002	32330187	In addition, recently, study has reported that low levels of common cancer gene mutations may be present even in healthy individuals.	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', (68, 74))	('mutations', 'Var', (80, 89))
41005	32330187	Detection of mutated BRAF cfDNA in plasma may be a potentially useful biomarker for noninvasive follow-up of canines with urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (122, 142))	('BRAF cfDNA', 'Gene', (21, 31))	('cfDNA', 'Gene', (26, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('follow-up of canines', 'Phenotype', 'HP:0012738', (96, 116))	('urothelial carcinoma', 'Disease', (122, 142))	('canines', 'Species', '9615', (109, 116))	('mutated', 'Var', (13, 20))
41013	32330187	The method has already been used to detect BRAF mutations in plasma samples of human patients with melanoma.	('human', 'Species', '9606', (79, 84))	('BRAF', 'Gene', (43, 47))	('patients', 'Species', '9606', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('mutations', 'Var', (48, 57))
41018	32330187	Further research is required to establish the true clinical value of plasma mutated BRAF ctDNA as a biomarker for canine urothelial carcinoma.	('plasma mutated', 'Var', (69, 83))	('canine', 'Species', '9615', (114, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (121, 141))	('BRAF ctDNA', 'Gene', (84, 94))	('urothelial carcinoma', 'Disease', (121, 141))
41020	28139702	However, the same 'actionable mutation' impacts distinct context-specific gene regulatory programs and signalling networks:and interacts with different genetic backgrounds of co-occurring alterations:in different cancers.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('signalling', 'biological_process', 'GO:0023052', ('103', '113'))	('impacts', 'Reg', (40, 47))	('context-specific', 'MPA', (57, 73))	('mutation', 'Var', (30, 38))	('signalling networks', 'Pathway', (103, 122))	('cancers', 'Disease', 'MESH:D009369', (213, 220))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('cancers', 'Disease', (213, 220))	('interacts', 'Reg', (127, 136))
41022	28139702	Our analysis predicts distinct dysregulated transcriptional regulators downstream of somatic alterations in different cancers, and we validate the context-specific differential activity of TFs associated to mutant PIK3CA in isogenic cancer cell line models.	('cancer', 'Disease', (118, 124))	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (233, 239))	('mutant', 'Var', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('dysregulated transcriptional regulators', 'MPA', (31, 70))	('PIK3CA', 'Gene', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('PIK3CA', 'Gene', '5290', (214, 220))
41025	28139702	Large-scale cancer genomics projects such as The Cancer Genome Atlas (TCGA) have generated a comprehensive catalogue of somatic mutations and copy number aberrations across many tumour types.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (12, 18))	('mutations', 'Var', (128, 137))	('copy number aberrations', 'Var', (142, 165))	('tumour type', 'Disease', (178, 189))	('tumour type', 'Disease', 'MESH:D009369', (178, 189))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))
41030	28139702	To this end, we applied a computational strategy for exploiting parallel (phospho)proteomic and mRNA sequencing data for large tumour sets by linking the dysregulation of upstream signalling pathways with altered transcriptional response through the transcriptional circuitry.	('dysregulation', 'Var', (154, 167))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('upstream signalling pathways', 'Pathway', (171, 199))	('signalling', 'biological_process', 'GO:0023052', ('180', '190'))	('transcriptional response', 'MPA', (213, 237))	('tumour', 'Disease', (127, 133))
41034	28139702	By stratifying tumours by inferred TF activities rather than gene expression patterns, we identified known and previously unlinked TFs that are differentially active in HPV(+) versus HPV(-) head and neck squamous cancer, and we uncovered a subtype of endometrioid uterine cancer harbouring mutant beta-catenin with altered TF activities.	('uterine cancer', 'Phenotype', 'HP:0010784', (264, 278))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('squamous cancer', 'Phenotype', 'HP:0002860', (204, 219))	('neck squamous cancer', 'Disease', 'MESH:D006258', (199, 219))	('head and neck squamous cancer', 'Phenotype', 'HP:0012288', (190, 219))	('HPV', 'Species', '10566', (169, 172))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('activities', 'MPA', (326, 336))	('cancer', 'Disease', (213, 219))	('gene expression', 'biological_process', 'GO:0010467', ('61', '76'))	('HPV', 'Disease', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('expression', 'Species', '29278', (66, 76))	('tumours', 'Disease', (15, 22))	('HPV', 'Species', '10566', (183, 186))	('neck squamous cancer', 'Disease', (199, 219))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))	('tumours', 'Disease', 'MESH:D009369', (15, 22))	('neck', 'cellular_component', 'GO:0044326', ('199', '203'))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('beta-catenin', 'Gene', (297, 309))	('cancer', 'Disease', (272, 278))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('mutant', 'Var', (290, 296))	('beta-catenin', 'Gene', '1499', (297, 309))
41036	28139702	This analysis identified key regulators associated with the major mutations in renal clear-cell carcinoma.	('mutations', 'Var', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('renal clear-cell carcinoma', 'Phenotype', 'HP:0006770', (79, 105))	('renal clear-cell carcinoma', 'Disease', 'MESH:C538614', (79, 105))	('renal clear-cell carcinoma', 'Disease', (79, 105))
41038	28139702	In particular, we associated PIK3CA activating mutations with altered activities of distinct sets of TFs in different cancers.	('cancers', 'Disease', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('activities', 'MPA', (70, 80))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('TFs', 'Gene', (101, 104))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (29, 35))	('activating', 'PosReg', (36, 46))
41039	28139702	Notably, in isogenic cell line models of breast cancer and head and neck cancer, we validated the altered activity of several TFs in the presence of mutant PIK3CA by measuring promoter occupancy and expression of target genes, confirming the context-specific predictions of our model.	('neck', 'cellular_component', 'GO:0044326', ('68', '72'))	('expression', 'Species', '29278', (199, 209))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('promoter occupancy', 'MPA', (176, 194))	('head and neck cancer', 'Phenotype', 'HP:0012288', (59, 79))	('expression', 'MPA', (199, 209))	('PIK3CA', 'Gene', '5290', (156, 162))	('breast cancer', 'Disease', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mutant', 'Var', (149, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('head and neck cancer', 'Disease', 'MESH:D006258', (59, 79))	('activity', 'MPA', (106, 114))	('altered', 'Reg', (98, 105))	('PIK3CA', 'Gene', (156, 162))
41068	28139702	Head and neck squamous cancer is frequently associated with human papillomavirus (HPV) infection and mutations in TP53.	('associated', 'Reg', (44, 54))	('papillomavirus (HPV) infection', 'Disease', 'MESH:D030361', (66, 96))	('neck squamous cancer', 'Disease', (9, 29))	('mutations', 'Var', (101, 110))	('neck', 'cellular_component', 'GO:0044326', ('9', '13'))	('TP53', 'Gene', '7157', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('neck squamous cancer', 'Disease', 'MESH:D006258', (9, 29))	('TP53', 'Gene', (114, 118))	('squamous cancer', 'Phenotype', 'HP:0002860', (14, 29))	('human', 'Species', '9606', (60, 65))
41077	28139702	As described previously, mutant TP53 tends to be mutually exclusive with HPV(+) status, but inferred TP53 TF activity and inferred p53 protein activity were not significantly different between HPV(+) and HPV(-) patients (t-test P=0.477 and P=0.741, respectively).	('mutant', 'Var', (25, 31))	('patients', 'Species', '9606', (211, 219))	('TP53', 'Gene', '7157', (101, 105))	('TP53', 'Gene', '7157', (32, 36))	('HPV', 'Species', '10566', (73, 76))	('p53', 'Gene', (131, 134))	('HPV', 'Species', '10566', (193, 196))	('p53', 'Gene', '7157', (131, 134))	('HPV', 'Species', '10566', (204, 207))	('TP53', 'Gene', (101, 105))	('TP53', 'Gene', (32, 36))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))
41082	28139702	Serous-like endometrial tumours are hormone receptor negative, mostly copy number high, and harbour mutations in TP53, whereas endometrioid tumours are hormone receptor positive, copy number low, and have a high frequency of PI3K-AKT (phosphatidylinositol 3-kinase-AKT) pathway alterations.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('AKT', 'Gene', (230, 233))	('alterations', 'Reg', (278, 289))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('hormone receptor', 'Gene', (152, 168))	('hormone receptor', 'Gene', '3164', (36, 52))	('endometrioid tumours', 'Disease', 'MESH:D016889', (127, 147))	('AKT', 'Gene', '207', (230, 233))	('TP53', 'Gene', (113, 117))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('endometrial tumours', 'Disease', (12, 31))	('AKT', 'Gene', (265, 268))	('PI3K', 'molecular_function', 'GO:0016303', ('225', '229'))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('hormone receptor', 'Gene', (36, 52))	('endometrioid tumours', 'Disease', (127, 147))	('hormone receptor', 'Gene', '3164', (152, 168))	('mutations', 'Var', (100, 109))	('endometrial tumours', 'Disease', 'MESH:D016889', (12, 31))	('TP53', 'Gene', '7157', (113, 117))	('AKT', 'Gene', '207', (265, 268))
41084	28139702	Importantly, clustering by TF activities revealed subclasses of tumours within each histological subtype that sometimes correlated with mutation status.	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('mutation', 'Var', (136, 144))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('correlated', 'Reg', (120, 130))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
41085	28139702	In particular, endometrioid tumours with a CTNNB1 mutation form a distinct cluster based on inferred TF activity profiles that was not observed by clustering TF mRNA expression levels directly (Supplementary Fig.	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('endometrioid tumours', 'Disease', (15, 35))	('endometrioid tumours', 'Disease', 'MESH:D016889', (15, 35))	('mutation', 'Var', (50, 58))	('CTNNB1', 'Gene', '1499', (43, 49))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('expression', 'Species', '29278', (166, 176))	('CTNNB1', 'Gene', (43, 49))
41086	28139702	Moreover, clustering based on inferred TF activity was better able to stratify patients by CTNNB1 mutation status (P<10-17, two-sided chi2 test for all tests) compared to reported TCGA mRNA clusters (P<0.01) and TCGA integrated clusters (P<10-6) (Supplementary Tables 9 and 10).	('CTNNB1', 'Gene', '1499', (91, 97))	('mutation', 'Var', (98, 106))	('patients', 'Species', '9606', (79, 87))	('CTNNB1', 'Gene', (91, 97))
41087	28139702	Significant inferred TF activity differences between CTNNB1 mutant and WT patients (satisfying FDR-corrected P<0.01, t-test) associated CTNNB1 mutant status with altered activity of TFs involved in WNT signalling, epithelial-mesenchymal transition and cancer stem cell transition including TCF4 (transcriptional factor 4), NFATC4, JUN, TP53, MAX, MYC, STAT3 and KLF12 (Fig.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('KLF12', 'Gene', (362, 367))	('STAT3', 'Gene', '6774', (352, 357))	('NFATC4', 'Gene', (323, 329))	('CTNNB1', 'Gene', '1499', (136, 142))	('KLF12', 'Gene', '11278', (362, 367))	('MYC', 'Gene', '4609', (347, 350))	('TCF4', 'Gene', '6925', (290, 294))	('signalling', 'biological_process', 'GO:0023052', ('202', '212'))	('TP53', 'Gene', (336, 340))	('mutant', 'Var', (143, 149))	('CTNNB1', 'Gene', (136, 142))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('214', '247'))	('cancer', 'Disease', (252, 258))	('patients', 'Species', '9606', (74, 82))	('CTNNB1', 'Gene', '1499', (53, 59))	('transcriptional factor 4', 'Gene', (296, 320))	('transcriptional factor 4', 'Gene', '6925', (296, 320))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('TCF4', 'Gene', (290, 294))	('epithelial-mesenchymal transition', 'CPA', (214, 247))	('MYC', 'Gene', (347, 350))	('activity', 'MPA', (170, 178))	('mutant', 'Var', (60, 66))	('altered', 'Reg', (162, 169))	('STAT3', 'Gene', (352, 357))	('NFATC4', 'Gene', '4776', (323, 329))	('TP53', 'Gene', '7157', (336, 340))	('CTNNB1', 'Gene', (53, 59))
41088	28139702	We confirmed these results in an independent data set of 203 endometrial RPPA profiles along with mutation and clinical data compiled by MDACC, using the UCEC TCGA-trained AR model to infer TF activities, and replicated many of the TFs associated with mutant CTNBB1 (P<10-5, Mann-Whitney test; Fig.	('CTNBB1', 'Gene', (259, 265))	('mutant', 'Var', (252, 258))	('P<10-5', 'Gene', (267, 273))	('P<10-5', 'Gene', '4790', (267, 273))
41089	28139702	Interestingly, another study performed customized consensus clustering on TCGA UCEC expression data and did identify a cluster enriched with beta-catenin mutations, and GSEA (gene set enrichment analysis) suggested an association with WNT signalling, consistent with our analysis.	('association', 'Interaction', (218, 229))	('WNT signalling', 'Pathway', (235, 249))	('beta-catenin', 'Gene', (141, 153))	('GSEA', 'Chemical', '-', (169, 173))	('expression', 'Species', '29278', (84, 94))	('beta-catenin', 'Gene', '1499', (141, 153))	('signalling', 'biological_process', 'GO:0023052', ('239', '249'))	('mutations', 'Var', (154, 163))
41090	28139702	Encouraged by our findings for mutant CTNBB1 endometrioid tumours, we developed a systematic statistical approach for modelling the impact of somatic alterations on regulator activity in each tumour type, with the eventual goal of deciphering cancer-specific downstream effects of targeted therapies and potentially discovering secondary targets for combination drug strategies.	('CTNBB1', 'Gene', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('mutant', 'Var', (31, 37))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (243, 249))	('tumour type', 'Disease', (192, 203))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('tumour type', 'Disease', 'MESH:D009369', (192, 203))	('endometrioid tumours', 'Disease', (45, 65))	('endometrioid tumours', 'Disease', 'MESH:D016889', (45, 65))
41093	28139702	Combining these results identified a set of regulators predicted to be significantly dysregulated by each somatic alteration in each TCGA cancer study.	('cancer', 'Disease', (138, 144))	('TCGA', 'Disease', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('alteration', 'Var', (114, 124))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
41094	28139702	Our model identified mutations in VHL (von Hippel-Lindau), PBMR1, BAP1, MTOR, ATM, SETD2, KDM5C and PTEN (phosphatase and tensin homolog), as well as copy number changes in MLH1, DUSP1 and RANDBP17 as significantly associated with various TF activity changes across tumours.	('PTEN', 'Gene', (100, 104))	('DUSP1', 'Gene', '1843', (179, 184))	('tumours', 'Disease', 'MESH:D009369', (266, 273))	('BAP1', 'Gene', (66, 70))	('SETD2', 'Gene', '29072', (83, 88))	('phosphatase', 'molecular_function', 'GO:0016791', ('106', '117'))	('ATM', 'Gene', '472', (78, 81))	('tumour', 'Phenotype', 'HP:0002664', (266, 272))	('associated', 'Reg', (215, 225))	('PTEN', 'Gene', '5728', (100, 104))	('MLH1', 'Gene', (173, 177))	('KDM5C', 'Gene', '8242', (90, 95))	('von Hippel-Lindau', 'Gene', '7428', (39, 56))	('PBMR1', 'Gene', (59, 64))	('copy number changes', 'Var', (150, 169))	('DUSP1', 'Gene', (179, 184))	('MLH1', 'Gene', '4292', (173, 177))	('MTOR', 'Gene', (72, 76))	('ATM', 'Gene', (78, 81))	('activity', 'MPA', (242, 250))	('MTOR', 'Gene', '2475', (72, 76))	('VHL', 'Gene', (34, 37))	('mutations', 'Var', (21, 30))	('KDM5C', 'Gene', (90, 95))	('BAP1', 'Gene', '8314', (66, 70))	('tumours', 'Disease', (266, 273))	('RANDBP17', 'Gene', (189, 197))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('106', '136'))	('SETD2', 'Gene', (83, 88))	('von Hippel-Lindau', 'Gene', (39, 56))	('VHL', 'Gene', '7428', (34, 37))	('tumours', 'Phenotype', 'HP:0002664', (266, 273))
41095	28139702	KIRC is characterized by a high-frequency inactivating mutation in the VHL gene found in ~54% of tumours in TCGA and likely more prevalent.	('tumours', 'Disease', (97, 104))	('VHL', 'Gene', (71, 74))	('inactivating mutation', 'Var', (42, 63))	('VHL', 'Gene', '7428', (71, 74))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumours', 'Disease', 'MESH:D009369', (97, 104))
41096	28139702	Mutually exclusive mutations in PBRM1, a subunit of the PBAF SWI/SNF chromatin remodelling complex, and in histone deubiquitinase BAP1 define two genetic subtypes of KIRC, while recurrent mutations in the histone methyltransferase SETD2 also occur.	('PBRM1', 'Gene', (32, 37))	('BAP1', 'Gene', (130, 134))	('PBRM1', 'Gene', '55193', (32, 37))	('SETD2', 'Gene', (231, 236))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('115', '129'))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('69', '90'))	('mutations', 'Var', (19, 28))	('BAP1', 'Gene', '8314', (130, 134))	('chromatin remodelling complex', 'cellular_component', 'GO:0016585', ('69', '98'))	('SETD2', 'Gene', '29072', (231, 236))
41097	28139702	KIRC samples with PBMR1 and BAP1 mutations showed distinct patterns of TF and protein activities (Fig.	('BAP1', 'Gene', '8314', (28, 32))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('PBMR1', 'Gene', (18, 23))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))
41098	28139702	PBMR1 mutant tumours are associated with increased activity of TFs/(phospho)proteins that have roles in interleukin signalling and MYC, while regulators with increased activity in BAP1 mutant tumours are involved in DNA damage response, apoptosis, insulin signalling and mTOR signalling.	('TFs/', 'Protein', (63, 67))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('MYC', 'Gene', (131, 134))	('tumours', 'Disease', (192, 199))	('mTOR', 'Gene', (271, 275))	('insulin', 'Gene', '3630', (248, 255))	('tumours', 'Phenotype', 'HP:0002664', (192, 199))	('signalling', 'biological_process', 'GO:0023052', ('256', '266'))	('BAP1', 'Gene', '8314', (180, 184))	('tumours', 'Disease', 'MESH:D009369', (192, 199))	('apoptosis', 'biological_process', 'GO:0097194', ('237', '246'))	('insulin', 'molecular_function', 'GO:0016088', ('248', '255'))	('mTOR', 'Gene', '2475', (271, 275))	('apoptosis', 'biological_process', 'GO:0006915', ('237', '246'))	('MYC', 'Gene', '4609', (131, 134))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('DNA damage response', 'biological_process', 'GO:0006974', ('216', '235'))	('tumours', 'Disease', (13, 20))	('BAP1', 'Gene', (180, 184))	('signalling', 'biological_process', 'GO:0023052', ('116', '126'))	('insulin', 'Gene', (248, 255))	('activity', 'MPA', (51, 59))	('mutant', 'Var', (6, 12))	('increased', 'PosReg', (41, 50))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('PBMR1', 'Gene', (0, 5))	('DNA', 'cellular_component', 'GO:0005574', ('216', '219'))	('signalling', 'biological_process', 'GO:0023052', ('276', '286'))	('tumours', 'Disease', 'MESH:D009369', (13, 20))
41099	28139702	Notably, NFE2L2 TF activity was significantly higher in BAP1 mutant tumours than PBMR1 mutant tumours.	('tumours', 'Disease', (94, 101))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('higher', 'PosReg', (46, 52))	('BAP1', 'Gene', '8314', (56, 60))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('activity', 'MPA', (19, 27))	('tumours', 'Disease', (68, 75))	('BAP1', 'Gene', (56, 60))	('NFE2L2', 'Gene', '4780', (9, 15))	('mutant', 'Var', (61, 67))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('NFE2L2', 'Gene', (9, 15))	('tumours', 'Disease', 'MESH:D009369', (94, 101))
41101	28139702	Mutations in KEAP1, NFE2L2 (Nrf2), CUL3 or RBX1 are the most common mechanisms that impair KEAP1-mediated degradation of NFE2L2 and thereby activate the transcriptional effects of NFE2L2.	('KEAP1', 'Gene', (91, 96))	('NFE2L2', 'Gene', '4780', (20, 26))	('RBX1', 'Gene', '9978', (43, 47))	('Nrf2', 'Gene', (28, 32))	('impair', 'NegReg', (84, 90))	('NFE2L2', 'Gene', (180, 186))	('activate', 'PosReg', (140, 148))	('NFE2L2', 'Gene', '4780', (121, 127))	('NFE2L2', 'Gene', (20, 26))	('Mutations', 'Var', (0, 9))	('CUL3', 'Gene', (35, 39))	('degradation', 'biological_process', 'GO:0009056', ('106', '117'))	('RBX1', 'Gene', (43, 47))	('NFE2L2', 'Gene', (121, 127))	('degradation', 'MPA', (106, 117))	('KEAP1', 'Gene', '9817', (13, 18))	('transcriptional effects', 'MPA', (153, 176))	('KEAP1', 'Gene', (13, 18))	('Nrf2', 'Gene', '4780', (28, 32))	('NFE2L2', 'Gene', '4780', (180, 186))	('KEAP1', 'Gene', '9817', (91, 96))	('CUL3', 'Gene', '8452', (35, 39))
41102	28139702	Inferred TF activity of NFE2L2 was increased in mutant versus WT KEAP1 or NFE2L2 lung cancers; these differences are not observed at the gene expression level (Supplementary Fig.	('NFE2L2', 'Gene', '4780', (74, 80))	('increased', 'PosReg', (35, 44))	('mutant', 'Var', (48, 54))	('TF activity', 'MPA', (9, 20))	('NFE2L2', 'Gene', '4780', (24, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('KEAP1', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancers', 'Disease', 'MESH:D008175', (81, 93))	('NFE2L2', 'Gene', (74, 80))	('NFE2L2', 'Gene', (24, 30))	('lung cancers', 'Phenotype', 'HP:0100526', (81, 93))	('expression', 'Species', '29278', (142, 152))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('lung cancers', 'Disease', (81, 93))	('gene expression', 'biological_process', 'GO:0010467', ('137', '152'))	('KEAP1', 'Gene', '9817', (65, 70))
41103	28139702	In samples where VHL was comutated with PBMR1, SMAD1 (interaction P<0.0003) and KLF12 (interaction P<0.05) activity were significantly decreased.	('SMAD1', 'Gene', (47, 52))	('PBMR1', 'Gene', (40, 45))	('activity', 'MPA', (107, 115))	('comutated', 'Var', (25, 34))	('KLF12', 'Gene', '11278', (80, 85))	('VHL', 'Gene', (17, 20))	('decreased', 'NegReg', (135, 144))	('VHL', 'Gene', '7428', (17, 20))	('KLF12', 'Gene', (80, 85))	('SMAD1', 'Gene', '4086', (47, 52))
41105	28139702	The PI3K pathway controls proliferation, metabolism, survival and motility and is frequently activated in many cancers, often via mutations in PIK3CA, which encodes the alpha-isoform of the p110 catalytic subunit of PI3K (PI3Kalpha); loss of PTEN, which antagonizes PI3K function; and overexpression of membrane-bound receptor tyrosine kinase.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('PI3K', 'molecular_function', 'GO:0016303', ('216', '220'))	('motility', 'CPA', (66, 74))	('PI3Kalpha', 'Gene', (222, 231))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('PTEN', 'Gene', (242, 246))	('PIK3CA', 'Gene', '5290', (143, 149))	('PI3K pathway', 'Pathway', (4, 16))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('loss', 'Var', (234, 238))	('cancers', 'Disease', (111, 118))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('membrane', 'cellular_component', 'GO:0016020', ('303', '311'))	('PTEN', 'Gene', '5728', (242, 246))	('expression', 'Species', '29278', (289, 299))	('metabolism', 'biological_process', 'GO:0008152', ('41', '51'))	('PI3Kalpha', 'Gene', '5290', (222, 231))	('PI3K', 'molecular_function', 'GO:0016303', ('266', '270'))	('PIK3CA', 'Gene', (143, 149))	('mutations', 'Var', (130, 139))	('activated', 'PosReg', (93, 102))	('proliferation', 'CPA', (26, 39))	('overexpression', 'PosReg', (285, 299))
41109	28139702	Mutations often occur in one of three hotspot locations (E545K, E542K and H1047) and promote constitutive signalling though the pathway.	('E542K', 'Mutation', 'rs121913273', (64, 69))	('E545K', 'Var', (57, 62))	('promote', 'PosReg', (85, 92))	('H1047', 'Var', (74, 79))	('signalling', 'biological_process', 'GO:0023052', ('106', '116'))	('E542K', 'Var', (64, 69))	('E545K', 'Mutation', 'rs104886003', (57, 62))	('constitutive signalling', 'MPA', (93, 116))
41110	28139702	In UCEC, ~66% of tumours have PTEN inactivating mutations, ~50% have PIK3CA activating mutations and ~35% have a comutation of PTEN and PIK3CA.	('PIK3CA', 'Gene', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('activating', 'PosReg', (76, 86))	('PIK3CA', 'Gene', '5290', (136, 142))	('PIK3CA', 'Gene', '5290', (69, 75))	('inactivating', 'NegReg', (35, 47))	('PIK3CA', 'Gene', (69, 75))	('tumours', 'Disease', (17, 24))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('PTEN', 'Gene', (127, 131))	('PTEN', 'Gene', (30, 34))	('comutation', 'Var', (113, 123))	('PTEN', 'Gene', '5728', (127, 131))	('PTEN', 'Gene', '5728', (30, 34))
41112	28139702	Notably, the number of TFs dysregulated by PI3K pathway alterations varied widely across different cancers (9 in HNSC, 65 in BRCA and 63 in UCEC), with striking changes in ErbB/MAPK, mTOR, HIF-1, VEGF and PI3K-Akt pathways.	('PI3K', 'Gene', (43, 47))	('BRCA', 'Gene', '672', (125, 129))	('HNSC', 'Disease', (113, 117))	('mTOR', 'Gene', (183, 187))	('MAPK', 'molecular_function', 'GO:0004707', ('177', '181'))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('PI3K', 'molecular_function', 'GO:0016303', ('43', '47'))	('BRCA', 'Gene', (125, 129))	('ErbB', 'Gene', '1956', (172, 176))	('Akt', 'Gene', (210, 213))	('HIF-1', 'Gene', (189, 194))	('mTOR', 'Gene', '2475', (183, 187))	('HIF-1', 'Gene', '29072', (189, 194))	('Akt', 'Gene', '207', (210, 213))	('VEGF', 'Gene', '7422', (196, 200))	('alterations', 'Var', (56, 67))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('changes', 'Reg', (161, 168))	('cancers', 'Disease', (99, 106))	('VEGF', 'Gene', (196, 200))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('PI3K', 'molecular_function', 'GO:0016303', ('205', '209'))	('ErbB', 'Gene', (172, 176))
41113	28139702	Only ELK1, a TF downstream of the MAPK/ERK pathway, is dysregulated by PIK3CA or PTEN mutations in all three cancers.	('mutations', 'Var', (86, 95))	('MAPK', 'molecular_function', 'GO:0004707', ('34', '38'))	('PIK3CA', 'Gene', '5290', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('PTEN', 'Gene', '5728', (81, 85))	('ELK1', 'Gene', (5, 9))	('cancers', 'Disease', (109, 116))	('ERK', 'Gene', '2048', (39, 42))	('ELK1', 'Gene', '2002', (5, 9))	('ERK', 'Gene', (39, 42))	('PTEN', 'Gene', (81, 85))	('ERK', 'molecular_function', 'GO:0004707', ('39', '42'))	('dysregulated', 'Reg', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('PIK3CA', 'Gene', (71, 77))
41116	28139702	Interestingly, many TF activities were associated with mutant PTEN irrespective of PIK3CA status in endometrial cancer (Supplementary Fig.	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('endometrial cancer', 'Disease', (100, 118))	('endometrial cancer', 'Phenotype', 'HP:0012114', (100, 118))	('mutant', 'Var', (55, 61))	('endometrial cancer', 'Disease', 'MESH:D016889', (100, 118))	('associated', 'Reg', (39, 49))	('PIK3CA', 'Gene', (83, 89))	('PIK3CA', 'Gene', '5290', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('activities', 'MPA', (23, 33))
41117	28139702	19), consistent with a recent preclinical study, while PIK3CA mutations were only significantly associated with a single TF, CREB1.	('CREB1', 'Gene', '1385', (125, 130))	('associated', 'Reg', (96, 106))	('CREB1', 'Gene', (125, 130))	('PIK3CA', 'Gene', (55, 61))	('PIK3CA', 'Gene', '5290', (55, 61))	('mutations', 'Var', (62, 71))
41118	28139702	Therefore, PTEN and PIK3CA appear to have distinct consequences for PI3K activation in UCEC.	('PTEN', 'Gene', (11, 15))	('activation', 'PosReg', (73, 83))	('PTEN', 'Gene', '5728', (11, 15))	('PI3K', 'molecular_function', 'GO:0016303', ('68', '72'))	('PIK3CA', 'Gene', (20, 26))	('PIK3CA', 'Gene', '5290', (20, 26))	('PI3K', 'Var', (68, 72))	('UCEC', 'Disease', (87, 91))
41119	28139702	PI3K pathway inhibition is known to alter STAT5 (ref.	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('STAT5', 'Gene', (42, 47))	('inhibition', 'Var', (13, 23))	('PI3K pathway', 'Pathway', (0, 12))	('STAT5', 'Gene', '6776', (42, 47))
41123	28139702	We also examined protein microarray-based AKT1 kinase assay and SILAC-based phosphoproteomic data from isogenic knock-in breast cell lines harbouring mutations of PIK3CA (see Methods section).	('AKT1', 'Gene', '207', (42, 46))	('AKT1', 'Gene', (42, 46))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('PIK3CA', 'Gene', (163, 169))	('mutations', 'Var', (150, 159))	('PIK3CA', 'Gene', '5290', (163, 169))
41124	28139702	Of 11 TFs represented in the phosphoproteomic data and associated with mutant PIK3CA in BRCA, eight of them:ADD1, FOXO3, HMGA1, HSF1, JUND, NF1, POU2F1, STAT3:showed protein abundance change in isogenic cell line systems (see Methods section and Supplementary Table 12).	('PIK3CA', 'Gene', (78, 84))	('STAT3', 'Gene', '6774', (153, 158))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('ADD1', 'Gene', (108, 112))	('POU2F1', 'Gene', (145, 151))	('HMGA1', 'Gene', (121, 126))	('BRCA', 'Gene', (88, 92))	('FOXO3', 'Gene', '2309', (114, 119))	('ADD1', 'Gene', '118', (108, 112))	('mutant', 'Var', (71, 77))	('HSF1', 'Gene', '3297', (128, 132))	('NF1', 'Gene', '4763', (140, 143))	('HSF1', 'Gene', (128, 132))	('JUND', 'Gene', (134, 138))	('PIK3CA', 'Gene', '5290', (78, 84))	('NF1', 'Gene', (140, 143))	('JUND', 'Gene', '3727', (134, 138))	('change', 'Reg', (184, 190))	('BRCA', 'Gene', '672', (88, 92))	('STAT3', 'Gene', (153, 158))	('POU2F1', 'Gene', '5451', (145, 151))	('FOXO3', 'Gene', (114, 119))	('HMGA1', 'Gene', '3159', (121, 126))	('protein abundance', 'MPA', (166, 183))
41125	28139702	Moreover, of the six TFs represented in the AKT1 kinase assay and associated with mutant PIK3CA in BRCA, four of them:ETS1, ATF6, SOX9 and TEAD1:were identified as AKT substrates (Supplementary Table 13).	('PIK3CA', 'Gene', '5290', (89, 95))	('AKT1', 'Gene', '207', (44, 48))	('ETS1', 'Gene', (118, 122))	('mutant', 'Var', (82, 88))	('AKT', 'Gene', (164, 167))	('AKT', 'Gene', (44, 47))	('BRCA', 'Gene', '672', (99, 103))	('SOX9', 'Gene', (130, 134))	('AKT1', 'Gene', (44, 48))	('PIK3CA', 'Gene', (89, 95))	('ATF6', 'Gene', (124, 128))	('AKT', 'Gene', '207', (164, 167))	('TEAD1', 'Gene', (139, 144))	('BRCA', 'Gene', (99, 103))	('SOX9', 'Gene', '6662', (130, 134))	('AKT', 'Gene', '207', (44, 47))	('TEAD1', 'Gene', '7003', (139, 144))	('ETS1', 'Gene', '2113', (118, 122))	('ATF6', 'Gene', '22926', (124, 128))
41126	28139702	Our analysis associated mutant PIK3CA with ELK1 and TCF4 activity in both breast and head and neck cancer, and with FOXO1 activity in BRCA but not in head and neck cancer.	('BRCA', 'Gene', '672', (134, 138))	('head and neck cancer', 'Disease', 'MESH:D006258', (150, 170))	('ELK1', 'Gene', (43, 47))	('activity', 'MPA', (57, 65))	('mutant', 'Var', (24, 30))	('head and neck cancer', 'Phenotype', 'HP:0012288', (85, 105))	('FOXO1', 'Gene', '2308', (116, 121))	('BRCA', 'Gene', (134, 138))	('PIK3CA', 'Gene', '5290', (31, 37))	('neck', 'cellular_component', 'GO:0044326', ('159', '163'))	('FOXO1', 'Gene', (116, 121))	('TCF4', 'Gene', '6925', (52, 56))	('head and neck cancer', 'Disease', 'MESH:D006258', (85, 105))	('ELK1', 'Gene', '2002', (43, 47))	('breast', 'Disease', (74, 80))	('head and neck cancer', 'Phenotype', 'HP:0012288', (150, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('TCF4', 'Gene', (52, 56))	('neck', 'cellular_component', 'GO:0044326', ('94', '98'))	('PIK3CA', 'Gene', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('activity', 'MPA', (122, 130))
41128	28139702	First, we used the parental MCF7 cell line carrying the PIK3CA E545K mutation and an MCF7 PIK3CA WT cell line in which the mutation was corrected using gene targeting.	('MCF7', 'CellLine', 'CVCL:0031', (28, 32))	('E545K', 'Mutation', 'rs104886003', (63, 68))	('E545K', 'Var', (63, 68))	('PIK3CA', 'Gene', (56, 62))	('PIK3CA', 'Gene', (90, 96))	('MCF7', 'CellLine', 'CVCL:0031', (85, 89))	('PIK3CA', 'Gene', '5290', (56, 62))	('PIK3CA', 'Gene', '5290', (90, 96))
41131	28139702	), WNK1, PAPLN, FOXP4 and DDX27 confirmed significant increases in mRNA levels in the parental PIK3CA mutant cells compared to PIK3CA WT cells, with the exception of PAPLN, where we observed a significant decrease (Fig.	('mutant', 'Var', (102, 108))	('WNK1', 'Gene', (3, 7))	('PAPLN', 'Gene', (166, 171))	('PIK3CA', 'Gene', (95, 101))	('DDX27', 'Gene', '55661', (26, 31))	('PAPLN', 'Gene', (9, 14))	('PIK3CA', 'Gene', '5290', (95, 101))	('DDX27', 'Gene', (26, 31))	('mRNA levels', 'MPA', (67, 78))	('PIK3CA', 'Gene', (127, 133))	('FOXP4', 'Gene', '116113', (16, 21))	('PIK3CA', 'Gene', '5290', (127, 133))	('increases', 'PosReg', (54, 63))	('FOXP4', 'Gene', (16, 21))	('WNK1', 'Gene', '65125', (3, 7))	('PAPLN', 'Gene', '89932', (166, 171))	('PAPLN', 'Gene', '89932', (9, 14))
41132	28139702	Moreover, ChIP-qPCR experiments confirmed that ELK1 binding to all five target gene promoters was significantly increased in the PIK3CA mutant MCF7 compared to WT cells, showing that mutant PIK3CA enhances ELK1 transcriptional activity in BRCA cells (Fig.	('enhances', 'PosReg', (197, 205))	('PIK3CA', 'Gene', '5290', (190, 196))	('PIK3CA', 'Gene', (129, 135))	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('mutant', 'Var', (183, 189))	('PIK3CA', 'Gene', '5290', (129, 135))	('binding', 'Interaction', (52, 59))	('ELK1', 'Gene', (47, 51))	('transcriptional activity', 'MPA', (211, 235))	('increased', 'PosReg', (112, 121))	('ELK1', 'Gene', '2002', (47, 51))	('PIK3CA', 'Gene', (190, 196))	('BRCA', 'Gene', '672', (239, 243))	('MCF7', 'CellLine', 'CVCL:0031', (143, 147))	('ELK1', 'Gene', (206, 210))	('mutant', 'Var', (136, 142))	('ELK1', 'Gene', '2002', (206, 210))	('BRCA', 'Gene', (239, 243))
41133	28139702	Well-known TCF4 target genes such as WNT10B, APC, FBXW11 and PPP2R5E were differentially regulated by the PIK3CA E545K mutation in MCF7 cells (Fig.	('WNT10B', 'Gene', (37, 43))	('PPP2R5E', 'Gene', '5529', (61, 68))	('E545K', 'Mutation', 'rs104886003', (113, 118))	('E545K', 'Var', (113, 118))	('FBXW11', 'Gene', (50, 56))	('WNT10B', 'Gene', '7480', (37, 43))	('PIK3CA', 'Gene', (106, 112))	('PPP2R5E', 'Gene', (61, 68))	('TCF4', 'Gene', (11, 15))	('TCF4', 'Gene', '6925', (11, 15))	('MCF7', 'CellLine', 'CVCL:0031', (131, 135))	('PIK3CA', 'Gene', '5290', (106, 112))	('APC', 'cellular_component', 'GO:0005680', ('45', '48'))	('FBXW11', 'Gene', '23291', (50, 56))	('regulated', 'Reg', (89, 98))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('APC', 'Disease', (45, 48))
41134	28139702	21b), and ChIP-qPCR analysis confirmed enhanced binding of TCF4 to their promoters in mutant PIK3CA cells (Fig.	('TCF4', 'Gene', (59, 63))	('TCF4', 'Gene', '6925', (59, 63))	('PIK3CA', 'Gene', '5290', (93, 99))	('binding', 'molecular_function', 'GO:0005488', ('48', '55'))	('mutant', 'Var', (86, 92))	('binding', 'Interaction', (48, 55))	('PIK3CA', 'Gene', (93, 99))	('enhanced', 'PosReg', (39, 47))
41136	28139702	mRNA confirmed that their mRNA levels were differentially regulated by the PIK3CA E545K mutation (Fig.	('PIK3CA', 'Gene', (75, 81))	('E545K', 'Var', (82, 87))	('PIK3CA', 'Gene', '5290', (75, 81))	('mRNA levels', 'MPA', (26, 37))	('regulated', 'Reg', (58, 67))	('E545K', 'Mutation', 'rs104886003', (82, 87))
41139	28139702	Control, PIK3CA WT or PIK3CA E545K vectors were overexpressed in Cal27, and ChIP-qPCR and RT-qPCR expression experiments were performed to investigate the activity of ELK1, TCF4 and FOXO1.	('PIK3CA', 'Gene', '5290', (22, 28))	('PIK3CA', 'Gene', '5290', (9, 15))	('FOXO1', 'Gene', (182, 187))	('FOXO1', 'Gene', '2308', (182, 187))	('ELK1', 'Gene', (167, 171))	('TCF4', 'Gene', '6925', (173, 177))	('ELK1', 'Gene', '2002', (167, 171))	('PIK3CA', 'Gene', (9, 15))	('Cal27', 'CellLine', 'CVCL:1107', (65, 70))	('expression', 'Species', '29278', (98, 108))	('TCF4', 'Gene', (173, 177))	('PIK3CA', 'Gene', (22, 28))	('E545K', 'Mutation', 'rs104886003', (29, 34))	('E545K', 'Var', (29, 34))
41141	28139702	Like in the MCF7 BRCA model, RT-qPCR analysis demonstrated an increase in the mRNA levels of four known ELK1 target genes, ACTR3, PSMB4, WNK1 and DDX27, in Cal27 cells transfected with PIK3CA E545K compared to Cal27 cells transfected with WT PIK3CA and control cells (Fig.	('E545K', 'Var', (192, 197))	('PIK3CA', 'Gene', '5290', (185, 191))	('PIK3CA', 'Gene', (242, 248))	('ELK1', 'Gene', (104, 108))	('increase', 'PosReg', (62, 70))	('PSMB4', 'Gene', (130, 135))	('MCF7', 'CellLine', 'CVCL:0031', (12, 16))	('ACTR3', 'Gene', (123, 128))	('BRCA', 'Gene', '672', (17, 21))	('Cal27', 'CellLine', 'CVCL:1107', (156, 161))	('mRNA levels', 'MPA', (78, 89))	('PIK3CA', 'Gene', (185, 191))	('WNK1', 'Gene', (137, 141))	('DDX27', 'Gene', (146, 151))	('PSMB4', 'Gene', '5692', (130, 135))	('ELK1', 'Gene', '2002', (104, 108))	('BRCA', 'Gene', (17, 21))	('E545K', 'Mutation', 'rs104886003', (192, 197))	('Cal27', 'CellLine', 'CVCL:1107', (210, 215))	('PIK3CA', 'Gene', '5290', (242, 248))	('ACTR3', 'Gene', '10096', (123, 128))	('WNK1', 'Gene', '65125', (137, 141))	('DDX27', 'Gene', '55661', (146, 151))
41142	28139702	Increased occupancy of ELK1 at target promoters was confirmed by ChIP-qPCR assays only when cells were transfected with the PIK3CA E545K vector (Fig.	('ELK1', 'Gene', (23, 27))	('PIK3CA', 'Gene', (124, 130))	('E545K', 'Mutation', 'rs104886003', (131, 136))	('ELK1', 'Gene', '2002', (23, 27))	('E545K', 'Var', (131, 136))	('PIK3CA', 'Gene', '5290', (124, 130))
41143	28139702	Thus, ELK1 transcriptional activity is enhanced by mutant PIK3CA in both head and neck and BRCA models.	('transcriptional activity', 'MPA', (11, 35))	('BRCA', 'Gene', (91, 95))	('neck', 'cellular_component', 'GO:0044326', ('82', '86'))	('mutant', 'Var', (51, 57))	('PIK3CA', 'Gene', (58, 64))	('PIK3CA', 'Gene', '5290', (58, 64))	('ELK1', 'Gene', (6, 10))	('BRCA', 'Gene', '672', (91, 95))	('ELK1', 'Gene', '2002', (6, 10))	('enhanced', 'PosReg', (39, 47))
41144	28139702	RT-qPCR analysis demonstrated an increase in the mRNA levels of four TCF4 target genes in Cal27 cells with PIK3CA E545K compared to WT Cal27 and control cells (Fig.	('mRNA levels of', 'MPA', (49, 63))	('Cal27', 'CellLine', 'CVCL:1107', (90, 95))	('Cal27', 'CellLine', 'CVCL:1107', (135, 140))	('TCF4', 'Gene', '6925', (69, 73))	('TCF4', 'Gene', (69, 73))	('increase', 'PosReg', (33, 41))	('PIK3CA', 'Gene', (107, 113))	('PIK3CA', 'Gene', '5290', (107, 113))	('E545K', 'Mutation', 'rs104886003', (114, 119))	('E545K', 'Var', (114, 119))
41145	28139702	Increased occupancy of TCF4 at the promoters of these genes was confirmed by ChIP assays only when cells were transfected with the PIK3CA E545K vector (Fig.	('E545K', 'Mutation', 'rs104886003', (138, 143))	('E545K', 'Var', (138, 143))	('PIK3CA', 'Gene', (131, 137))	('PIK3CA', 'Gene', '5290', (131, 137))	('TCF4', 'Gene', (23, 27))	('TCF4', 'Gene', '6925', (23, 27))
41146	28139702	Thus, mutant PIK3CA enhances TCF4 transcriptional activity in head and neck as well as BRCA models.	('mutant', 'Var', (6, 12))	('PIK3CA', 'Gene', (13, 19))	('BRCA', 'Gene', '672', (87, 91))	('transcriptional activity', 'MPA', (34, 58))	('BRCA', 'Gene', (87, 91))	('enhances', 'PosReg', (20, 28))	('PIK3CA', 'Gene', '5290', (13, 19))	('TCF4', 'Gene', (29, 33))	('TCF4', 'Gene', '6925', (29, 33))	('neck', 'cellular_component', 'GO:0044326', ('71', '75'))
41147	28139702	FOXO1 activity was not associated with mutant PIK3CA in our HNSC model.	('activity', 'MPA', (6, 14))	('PIK3CA', 'Gene', '5290', (46, 52))	('FOXO1', 'Gene', (0, 5))	('FOXO1', 'Gene', '2308', (0, 5))	('mutant', 'Var', (39, 45))	('PIK3CA', 'Gene', (46, 52))
41149	28139702	Further, no change in occupancy of FOXO1 at the promoters of TNFSF10 and RUNX1 was shown by ChIP assays when cells were transfected with the PIK3CA E545K vector (Fig.	('PIK3CA', 'Gene', '5290', (141, 147))	('RUNX1', 'Gene', (73, 78))	('occupancy', 'MPA', (22, 31))	('RUNX1', 'Gene', '861', (73, 78))	('FOXO1', 'Gene', '2308', (35, 40))	('PIK3CA', 'Gene', (141, 147))	('E545K', 'Mutation', 'rs104886003', (148, 153))	('E545K', 'Var', (148, 153))	('TNFSF10', 'Gene', (61, 68))	('FOXO1', 'Gene', (35, 40))	('TNFSF10', 'Gene', '8743', (61, 68))
41152	28139702	Our computational and experimental results suggest that a potential mechanism for ELK1 activation is through an activating PIK3CA mutation.	('activation', 'PosReg', (87, 97))	('mutation', 'Var', (130, 138))	('PIK3CA', 'Gene', (123, 129))	('PIK3CA', 'Gene', '5290', (123, 129))	('ELK1', 'Gene', (82, 86))	('ELK1', 'Gene', '2002', (82, 86))	('activating', 'PosReg', (112, 122))
41154	28139702	Our analyses confirm that TCF4 activation may result from an activating PIK3CA mutation.	('PIK3CA', 'Gene', (72, 78))	('mutation', 'Var', (79, 87))	('activation', 'PosReg', (31, 41))	('PIK3CA', 'Gene', '5290', (72, 78))	('TCF4', 'Gene', (26, 30))	('TCF4', 'Gene', '6925', (26, 30))	('activating', 'PosReg', (61, 71))
41156	28139702	Since we demonstrated altered transcriptional activity of TCF4 downstream of mutant PIK3CA in breast and head and neck cancer cells, targeting TCF4 might be new therapeutic strategy in PIK3CA mutant patients.	('PIK3CA', 'Gene', '5290', (84, 90))	('transcriptional activity', 'MPA', (30, 54))	('neck', 'cellular_component', 'GO:0044326', ('114', '118'))	('head and neck cancer', 'Disease', 'MESH:D006258', (105, 125))	('TCF4', 'Gene', (58, 62))	('TCF4', 'Gene', '6925', (58, 62))	('PIK3CA', 'Gene', (185, 191))	('altered', 'Reg', (22, 29))	('head and neck cancer', 'Phenotype', 'HP:0012288', (105, 125))	('PIK3CA', 'Gene', (84, 90))	('PIK3CA', 'Gene', '5290', (185, 191))	('patients', 'Species', '9606', (199, 207))	('mutant', 'Var', (77, 83))	('TCF4', 'Gene', (143, 147))	('TCF4', 'Gene', '6925', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
41159	28139702	Specifically, we showed that an activating PIK3CA mutation altered FOXO1 activity in the BRCA model but not in the head and neck cancer model, consistent with the context-specific predictions of our algorithm.	('neck', 'cellular_component', 'GO:0044326', ('124', '128'))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('FOXO1', 'Gene', (67, 72))	('FOXO1', 'Gene', '2308', (67, 72))	('PIK3CA', 'Gene', '5290', (43, 49))	('BRCA', 'Gene', (89, 93))	('activity', 'MPA', (73, 81))	('head and neck cancer', 'Disease', 'MESH:D006258', (115, 135))	('head and neck cancer', 'Phenotype', 'HP:0012288', (115, 135))	('BRCA', 'Gene', '672', (89, 93))	('activating', 'PosReg', (32, 42))	('mutation', 'Var', (50, 58))	('PIK3CA', 'Gene', (43, 49))
41160	28139702	This shows one example of how a clinically relevant 'actionable mutation' impacts regulatory programs in a cancer-specific manner, giving clues about druggability across tumour types.	('tumour type', 'Disease', 'MESH:D009369', (170, 181))	('regulatory programs', 'MPA', (82, 101))	('impacts', 'Reg', (74, 81))	("mutation'", 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('clues', 'Reg', (138, 143))	('tumour type', 'Disease', (170, 181))
41162	28139702	For example, activating mutations and amplifications of PIK3CA are targetable by PI3K inhibitors, which are in active clinical assessment in combination therapies with RTK inhibitors and antioestrogen therapies in BRCA, antiandrogen therapy in PRAD and MEK inhibitors in many solid tumours.	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('solid tumours', 'Disease', 'MESH:D009369', (276, 289))	('tumour', 'Phenotype', 'HP:0002664', (282, 288))	('amplifications', 'Var', (38, 52))	('activating', 'PosReg', (13, 23))	('solid tumours', 'Disease', (276, 289))	('MEK', 'Gene', '5604;5605', (253, 256))	('PIK3CA', 'Gene', (56, 62))	('BRCA', 'Gene', '672', (214, 218))	('tumours', 'Phenotype', 'HP:0002664', (282, 289))	('BRCA', 'Gene', (214, 218))	('MEK', 'Gene', (253, 256))	('PIK3CA', 'Gene', '5290', (56, 62))
41169	28139702	Linking mutant beta-catenin to putative downstream TF effectors could inform future mechanistic studies:for example, short hairpin RNA or CRISPR/Cas screening to identify TFs whose deletion/knockdown leads to changes in proliferation:to develop new therapeutic strategies.	('proliferation', 'MPA', (220, 233))	('TFs', 'Gene', (171, 174))	('RNA', 'cellular_component', 'GO:0005562', ('131', '134'))	('changes', 'Reg', (209, 216))	('mutant', 'Var', (8, 14))	('beta-catenin', 'Gene', (15, 27))	('Cas', 'cellular_component', 'GO:0005650', ('145', '148'))	('beta-catenin', 'Gene', '1499', (15, 27))	('deletion/knockdown', 'Var', (181, 199))
41170	28139702	Several recent studies have integrated TF binding site or occupancy data to identify cancer-associated TFs, for example, combining tumour-specific DNA methylation changes in distal enhancers, mRNA sequencing and cis-regulatory sequences mediating effects on target genes or integrating ENCODE TF ChIP-seq profiles with the pancancer TCGA expression data.	('changes', 'Var', (163, 170))	('TF binding', 'molecular_function', 'GO:0008134', ('39', '49'))	('tumour', 'Disease', (131, 137))	('DNA methylation', 'biological_process', 'GO:0006306', ('147', '162'))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('expression', 'Species', '29278', (338, 348))	('cancer', 'Disease', (85, 91))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', (326, 332))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
41184	28139702	We obtained SILAC-based quantitative phosphoproteomic data set of a spontaneously immortalized non-tumorigenic breast epithelial cell line MCF10A along with two isogenic derivatives generated by knock-in of mutant alleles:one bearing the E545K mutation and the other bearing the H1047R mutation of the PIK3CA gene:from the originally published Supplementary Data.	('MCF10A', 'CellLine', 'CVCL:0598', (139, 145))	('H1047R', 'Mutation', 'rs121913279', (279, 285))	('PIK3CA', 'Gene', (302, 308))	('PIK3CA', 'Gene', '5290', (302, 308))	('H1047R', 'Var', (279, 285))	('E545K', 'Var', (238, 243))	('E545K', 'Mutation', 'rs104886003', (238, 243))
41210	28139702	The BRCA cell line, MCF7, which has a PIK3CA E545K mutation, and the targeted correction of the E545K mutation to WT PIK3CA were obtained from the Lauring Lab.	('BRCA', 'Gene', '672', (4, 8))	('BRCA', 'Gene', (4, 8))	('PIK3CA', 'Gene', (38, 44))	('E545K mutation', 'Var', (45, 59))	('PIK3CA', 'Gene', (117, 123))	('E545K', 'Mutation', 'rs104886003', (96, 101))	('E545K', 'Var', (96, 101))	('PIK3CA', 'Gene', '5290', (38, 44))	('E545K', 'Mutation', 'rs104886003', (45, 50))	('PIK3CA', 'Gene', '5290', (117, 123))	('MCF7', 'CellLine', 'CVCL:0031', (20, 24))
41214	28139702	Cal27 cell lines were transfected with pbabe control vector, pbabe WT PIK3CA and pbabe E545K PIK3CA vectors (Addgene) using Lipofectamine 3000 according to the manufacturer's instructions.	('PIK3CA', 'Gene', '5290', (93, 99))	('E545K', 'Mutation', 'rs104886003', (87, 92))	('E545K', 'Var', (87, 92))	('PIK3CA', 'Gene', (70, 76))	('Cal27', 'CellLine', 'CVCL:1107', (0, 5))	('PIK3CA', 'Gene', (93, 99))	('PIK3CA', 'Gene', '5290', (70, 76))	('Lipofectamine', 'Chemical', 'MESH:C086724', (124, 137))
41219	28139702	Sheared chromatin was incubated overnight with 2 mug of rabbit monoclonal ChIP grade antibody to ELK1 (E277, ab32106; Abcam) as has been previously used by Zhang et al.	('antibody', 'molecular_function', 'GO:0003823', ('85', '93'))	('rabbit', 'Species', '9986', (56, 62))	('chromatin', 'cellular_component', 'GO:0000785', ('8', '17'))	('mug', 'molecular_function', 'GO:0043739', ('49', '52'))	('ELK1', 'Gene', (97, 101))	('ELK1', 'Gene', '2002', (97, 101))	('antibody', 'cellular_component', 'GO:0042571', ('85', '93'))	('E277', 'Var', (103, 107))	('antibody', 'cellular_component', 'GO:0019814', ('85', '93'))	('antibody', 'cellular_component', 'GO:0019815', ('85', '93'))
41267	24478941	Twenty two subjects, with either hematuria or a positive NMP22, FISH or Cyt test accepted the option of PDD instead of white light cystoscopy and took part in the present sub-study.	('hematuria', 'Disease', 'MESH:D006417', (33, 42))	('hematuria', 'Phenotype', 'HP:0000790', (33, 42))	('NMP22', 'Gene', (57, 62))	('Cyt test', 'Gene', (72, 80))	('positive', 'Var', (48, 56))	('hematuria', 'Disease', (33, 42))	('NMP22', 'Gene', '4926', (57, 62))
41367	29617668	To demonstrate proof of concept, we showed that perturbations targeting OIP5-AS1 (an inferred tumor suppressor) and TUG1 and WT1-AS (inferred onco-lncRNAs) dysregulated cancer genes and altered proliferation of breast and gynecologic cancer cells.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('WT1-AS', 'Gene', (125, 131))	('OIP5-AS1', 'Gene', '729082;11339;5729', (72, 80))	('TUG1', 'Gene', (116, 120))	('OIP5-AS1', 'Gene', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('dysregulated', 'Reg', (156, 168))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('94', '110'))	('proliferation', 'CPA', (194, 207))	('TUG1', 'Gene', '55000', (116, 120))	('WT1-AS', 'Gene', '51352', (125, 131))	('tumor suppressor', 'biological_process', 'GO:0051726', ('94', '110'))	('tumor', 'Disease', (94, 99))	('altered', 'Reg', (186, 193))	('perturbations', 'Var', (48, 61))	('cancer', 'Disease', (234, 240))
41371	29617668	They suggest that the dysregulation of hundreds of lncRNAs target and alter the expression of cancer genes and pathways in each tumor context.	('dysregulation', 'Var', (22, 35))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('pathways', 'Pathway', (111, 119))	('alter', 'Reg', (70, 75))	('expression', 'MPA', (80, 90))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
41373	29617668	Most cancers exhibit long noncoding RNA (lncRNA) dysregulation by copy number gains and losses.	('losses', 'NegReg', (88, 94))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('RNA', 'cellular_component', 'GO:0005562', ('36', '39'))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('gains', 'PosReg', (78, 83))	('copy number', 'Var', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
41379	29617668	Our approach was to predict lncRNA targets using models for lncRNA regulation that could be populated using RNA expression profiles and then implicate dysregulated lncRNAs in cancer-relevant activity based on their inferred targets.	('dysregulated', 'Var', (151, 163))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('implicate', 'Reg', (141, 150))	('RNA', 'cellular_component', 'GO:0005562', ('108', '111'))	('regulation', 'biological_process', 'GO:0065007', ('67', '77'))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
41384	29617668	As a proof of principle, we used biochemical assays to test the predictive effects of four lncRNAs, which were chosen to include predicted pan-cancer lncRNAs, a tumor-suppressor lncRNA, onco-lncRNAs, antisense lncRNAs, and intergenic lncRNAs.	('antisense', 'Var', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('a tumor', 'Disease', (159, 166))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('161', '177'))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('161', '177'))	('a tumor', 'Disease', 'MESH:D009369', (159, 166))
41386	29617668	Our results, although underpowered, suggest good accuracy for our inferred lncNETs, which provide a framework for inferring trans effects for copy number gains and losses at lncRNA loci in cancer.	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('copy number gains', 'Var', (142, 159))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('losses', 'NegReg', (164, 170))	('cancer', 'Disease', (189, 195))
41397	29617668	TUG1 and WT1-AS were predicted onco- lncRNAs; their silencing in ovarian serous carcinoma cell lines downregulated oncogenes and reduced proliferation in vitro.	('proliferation', 'CPA', (137, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('silencing', 'Var', (52, 61))	('TUG1', 'Gene', (0, 4))	('oncogenes', 'Protein', (115, 124))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (65, 89))	('reduced', 'NegReg', (129, 136))	('ovarian serous carcinoma', 'Disease', (65, 89))	('downregulated', 'NegReg', (101, 114))	('TUG1', 'Gene', '55000', (0, 4))	('WT1-AS', 'Gene', (9, 15))	('WT1-AS', 'Gene', '51352', (9, 15))
41402	29617668	These data suggest that alterations at lncRNA loci account for a significant proportion of the observed dysregulation of dozens of cancer genes in most tested tumor contexts.	('cancer', 'Disease', (131, 137))	('alterations', 'Var', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Disease', (159, 164))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('dysregulation', 'MPA', (104, 117))
41404	29617668	Similar to observations for TF binding sites, lncBS multiplicity in core promoters was an indicator of predicted interactions (Figure 3B) and was predictive of lncRNA-target co-expression (Figure 3C).	('lncBS', 'Chemical', '-', (46, 51))	('TF binding', 'molecular_function', 'GO:0008134', ('28', '38'))	('lncRNA-target', 'MPA', (160, 173))	('lncBS multiplicity', 'Var', (46, 64))	('core', 'cellular_component', 'GO:0019013', ('68', '72'))	('interactions', 'Interaction', (113, 125))
41412	29617668	Some of these predictions, including modulation of FOXA1 and ZEB1 by OIP5-AS1, were biochemically verified in cell lines.	('FOXA1', 'Gene', (51, 56))	('ZEB1', 'Gene', '6935', (61, 65))	('modulation', 'Var', (37, 47))	('ZEB1', 'Gene', (61, 65))	('OIP5-AS1', 'Gene', '729082;11339;5729', (69, 77))	('OIP5-AS1', 'Gene', (69, 77))	('FOXA1', 'Gene', '3169', (51, 56))
41418	29617668	lncRNAs whose predicted targets were enriched in more than 10 HGS pathways across tumor types are presented in Figure 4B; this selection identified pan-cancer lncRNAs that potentially affect multiple biological functions in tumors.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('lncRNAs', 'Var', (159, 166))	('affect', 'Reg', (184, 190))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
41436	29617668	These targets, including PTEN, are known to play key roles in each of the three tumor types, and they were downregulated following RNAi-mediated silencing of OIP5-AS1 in premalignant (Figure 6A), claudin-low triple-negative (Figure 6B), and basal-like (Figure 6C) BRCA cell lines, and in ovarian (Figures 6D and 6E) and endometrial (Figures 6F and 6G) cancer cell lines.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (352, 358))	('BRCA', 'Gene', '672', (264, 268))	('silencing', 'Var', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Disease', (352, 358))	('BRCA', 'Gene', (264, 268))	('tumor', 'Disease', (80, 85))	('downregulated', 'NegReg', (107, 120))	('OIP5-AS1', 'Gene', '729082;11339;5729', (158, 166))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('PTEN', 'Gene', (25, 29))	('OIP5-AS1', 'Gene', (158, 166))	('PTEN', 'Gene', '5728', (25, 29))	('RNAi', 'biological_process', 'GO:0016246', ('131', '135'))
41438	29617668	Focusing on PTEN, we showed that siRNA (si)OIP5-AS1 downregulated PTEN-protein expression (Figures 6H-6J) and that siOIP5-AS1 phenocopied siPTEN transfections and upregulated cell growth estimates of MDA-MB-231 (Figure 6K), OVCAR-3 (Figure 6L), and ECC-1 (Figure 6M), supporting its effects on tumor proliferation in all three tumor contexts.	('siOIP5-AS1', 'Gene', (115, 125))	('upregulated', 'PosReg', (163, 174))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('PTEN', 'Gene', (140, 144))	('tumor', 'Disease', (327, 332))	('PTEN', 'Gene', (12, 16))	('siOIP5-AS1', 'Gene', '5729', (115, 125))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (200, 210))	('OIP5-AS1', 'Gene', '729082;11339;5729', (117, 125))	('cell growth', 'CPA', (175, 186))	('PTEN', 'Gene', '5728', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('OIP5-AS1', 'Gene', (117, 125))	('PTEN', 'Gene', (66, 70))	('transfections', 'Var', (145, 158))	('PTEN', 'Gene', '5728', (12, 16))	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('tumor', 'Disease', (294, 299))	('cell growth', 'biological_process', 'GO:0016049', ('175', '186'))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('OIP5-AS1', 'Gene', '729082;11339;5729', (43, 51))	('PTEN', 'Gene', '5728', (66, 70))	('OIP5-AS1', 'Gene', (43, 51))	('downregulated', 'NegReg', (52, 65))	('tumor', 'Disease', 'MESH:D009369', (294, 299))
41440	29617668	Our analysis, presented in Figure S1, suggested a significant enrichment for predicted OIP5-AS1 post-transcriptional targets among genes that were downregulated following siOIP5-AS1 transfections.	('downregulated', 'NegReg', (147, 160))	('OIP5-AS1', 'Gene', '729082;11339;5729', (173, 181))	('OIP5-AS1', 'Gene', (173, 181))	('transfections', 'Var', (182, 195))	('OIP5-AS1', 'Gene', '729082;11339;5729', (87, 95))	('siOIP5-AS1', 'Gene', (171, 181))	('siOIP5-AS1', 'Gene', '5729', (171, 181))	('OIP5-AS1', 'Gene', (87, 95))
41445	29617668	RNAi-mediated silencing of LINC01184 downregulated its predicted targets in the breast cancer cell lines MDA-MB-231 and MDA-MB-468 (Figures 7E and 7F), and WT1-AS and TUG1 silencing in ovarian cell lines downregulated their predicted targets in SK-OV-3 and OVCAR-3 (Figures 7G-7J).	('silencing', 'Var', (14, 23))	('downregulated', 'NegReg', (37, 50))	('WT1-AS', 'Gene', (156, 162))	('WT1-AS', 'Gene', '51352', (156, 162))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (120, 130))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('LINC01184', 'Gene', (27, 36))	('SK-OV-3', 'Disease', (245, 252))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('TUG1', 'Gene', (167, 171))	('RNAi', 'biological_process', 'GO:0016246', ('0', '4'))	('TUG1', 'Gene', '55000', (167, 171))	('breast cancer', 'Disease', (80, 93))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (105, 115))	('LINC01184', 'Gene', '644873', (27, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('downregulated', 'NegReg', (204, 217))	('silencing', 'Var', (172, 181))
41448	29617668	While only a handful of lncRNAs are known to be relevant in cancer, our results suggest that the dysregulation of hundreds of lncRNAs may alter cancer pathophysiology in each tumor context.	('tumor', 'Disease', (175, 180))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', (144, 150))	('alter', 'Reg', (138, 143))	('dysregulation', 'Var', (97, 110))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('lncRNAs', 'Gene', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
41454	29617668	These observations, particularly our interpretation of the function of alterations that target lncRNA loci in cancer, suggest that lncNETs can be a valuable resource for studying lncRNA regulation and the effects of lncRNAs on tumor etiology in a multitude of cancer contexts.	('cancer', 'Disease', (110, 116))	('regulation', 'biological_process', 'GO:0065007', ('186', '196'))	('tumor', 'Disease', (227, 232))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (260, 266))	('alterations', 'Var', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
41457	29617668	Furthermore, we biochemically tested the effects of silencing each of three lncRNAs on both their target expression and cancer cell growth.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('silencing', 'Var', (52, 61))	('cancer', 'Disease', (120, 126))	('tested', 'Reg', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cell growth', 'biological_process', 'GO:0016049', ('127', '138'))
41458	29617668	RNAi-mediated silencing of OIP5-AS1 in breast, ovarian, and endometrial cancer cell lines downregulated tumor suppressors in these tumor contexts and accelerated cell growth, supporting its predicted role as a tumor suppressor.	('cell growth', 'CPA', (162, 173))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cell growth', 'biological_process', 'GO:0016049', ('162', '173'))	('accelerated', 'PosReg', (150, 161))	('tumor', 'Disease', (131, 136))	('downregulated', 'NegReg', (90, 103))	('tumor suppressor', 'biological_process', 'GO:0051726', ('210', '226'))	('silencing', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('a tumor', 'Disease', 'MESH:D009369', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('endometrial cancer', 'Phenotype', 'HP:0012114', (60, 78))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (104, 109))	('OIP5-AS1', 'Gene', '729082;11339;5729', (27, 35))	('a tumor', 'Disease', (208, 215))	('endometrial cancer', 'Disease', (60, 78))	('OIP5-AS1', 'Gene', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('endometrial cancer', 'Disease', 'MESH:D016889', (60, 78))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('RNAi', 'biological_process', 'GO:0016246', ('0', '4'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('210', '226'))
41459	29617668	In contrast, TUG1 and WT1-AS were inferred as pan-cancer and OV-specific onco-lncRNAs, respectively, and their silencing downregulated oncogenes and reduced ovarian cancer cell growth, supporting their predicted roles in OV.	('oncogenes', 'Gene', (135, 144))	('WT1-AS', 'Gene', '51352', (22, 28))	('cancer', 'Disease', (50, 56))	('silencing', 'Var', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('WT1-AS', 'Gene', (22, 28))	('ovarian cancer', 'Disease', 'MESH:D010051', (157, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	('cell growth', 'biological_process', 'GO:0016049', ('172', '183'))	('reduced', 'NegReg', (149, 156))	('TUG1', 'Gene', '55000', (13, 17))	('cancer', 'Disease', (165, 171))	('downregulated', 'NegReg', (121, 134))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('ovarian cancer', 'Disease', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('TUG1', 'Gene', (13, 17))
41588	29617668	We identified lncRNA modulation of TF and RBP expression to further improve lncRNA-target prediction.	('modulation', 'Var', (21, 31))	('RBP', 'Gene', (42, 45))	('improve', 'PosReg', (68, 75))	('RBP', 'Gene', '84549', (42, 45))
41630	29344166	A total of 4 sub-pathways of cysteine and methionine metabolism were obtained, including paths 00270_4 (P=4.11x10-4), 00270_1 (P=6.16x10-4), 00270_2 (P=5.40x10-3) and 00270_5 (P=6.26x10-3).	('methionine metabolism', 'biological_process', 'GO:0006555', ('42', '63'))	('00270_4', 'Var', (95, 102))	('cysteine', 'Chemical', 'MESH:D003545', (29, 37))	('methionine', 'Chemical', 'MESH:D008715', (42, 52))	('00270_2', 'Var', (141, 148))	('00270_1', 'Var', (118, 125))	('00270_5', 'Var', (167, 174))
41634	29344166	Finally, 4 pathways, including path00270_4, path00270_1, path00270_2 and path00270_5, were obtained and enriched by 4 target genes, DNMT3A DNMT3B, MAT2A and SMS.	('DNMT3A DNMT3B', 'Gene', '1789', (132, 145))	('MAT', 'molecular_function', 'GO:0004314', ('147', '150'))	('SMS', 'Gene', (157, 160))	('DNMT3A DNMT3B', 'Gene', (132, 145))	('MAT2A', 'Gene', '4144', (147, 152))	('path00270_5', 'Var', (73, 84))	('path00270_2', 'Var', (57, 68))	('MAT2A', 'Gene', (147, 152))	('path00270_4', 'Var', (31, 42))	('SMS', 'Gene', '6611', (157, 160))	('path00270_1', 'Var', (44, 55))
41636	29344166	hsa-miR-29a is a microRNA member of the miR-29 family, the dysregulation of which has been demonstrated to affect DNMT3A expression in the HL1 cell line.	('hsa-miR-29a', 'Gene', '407021', (0, 11))	('affect', 'Reg', (107, 113))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('miR', 'Gene', (4, 7))	('expression', 'MPA', (121, 131))	('dysregulation', 'Var', (59, 72))	('miR', 'Gene', '220972', (4, 7))	('HL1', 'CellLine', 'CVCL:0303', (139, 142))	('DNMT3A', 'Gene', (114, 120))	('DNMT3A', 'Gene', '1788', (114, 120))	('hsa-miR-29a', 'Gene', (0, 11))
41637	29344166	Notably, in the DNMT3A mutation samples, DNA methylation patterns were altered.	('DNMT3A', 'Gene', '1788', (16, 22))	('DNMT3A', 'Gene', (16, 22))	('mutation', 'Var', (23, 31))	('altered', 'Reg', (71, 78))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('DNA methylation', 'biological_process', 'GO:0006306', ('41', '56'))	('DNA methylation patterns', 'MPA', (41, 65))
41638	29344166	In other types of cancer, including lung cancer, the miR-29 family reversed biological processes of aberrant DNA methylation and was associated with a poor prognosis in cancer.	('miR', 'Gene', '220972', (53, 56))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('DNA methylation', 'biological_process', 'GO:0006306', ('109', '124'))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', (18, 24))	('miR', 'Gene', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('associated', 'Reg', (133, 143))	('lung cancer', 'Disease', (36, 47))	('reversed', 'NegReg', (67, 75))	('DNA methylation', 'MPA', (109, 124))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('aberrant', 'Var', (100, 108))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('biological processes', 'MPA', (76, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))
41655	27157475	FGFR3b Extracellular Loop Mutation Lacks Tumorigenicity In Vivo but Collaborates with p53/pRB Deficiency to Induce High-grade Papillary Urothelial Carcinoma Missense mutations of fibroblast growth factor receptor 3 (FGFR3) occur in up to 80% of low-grade papillary urothelial carcinoma of the bladder (LGP-UCB) suggesting that these mutations are tumor drivers, although direct experimental evidence is lacking.	('papillary urothelial carcinoma of the bladder', 'Disease', (255, 300))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('Papillary Urothelial Carcinoma', 'Disease', 'MESH:D002291', (126, 156))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (255, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('FGFR', 'molecular_function', 'GO:0005007', ('216', '220'))	('Extracellular', 'cellular_component', 'GO:0005576', ('7', '20'))	('p53', 'Gene', (86, 89))	('Missense mutations', 'Var', (157, 175))	('fibroblast growth factor receptor 3', 'Gene', (179, 214))	('Papillary Urothelial Carcinoma', 'Phenotype', 'HP:0006766', (126, 156))	('FGFR3', 'Gene', (216, 221))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (265, 300))	('Carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('179', '203'))	('FGFR3', 'Gene', '14184', (216, 221))	('pRB Deficiency', 'Disease', (90, 104))	('tumor', 'Disease', (347, 352))	('FGFR3', 'Gene', '14184', (0, 5))	('FGFR3', 'Gene', (0, 5))	('fibroblast growth factor receptor 3', 'Gene', '14184', (179, 214))	('Papillary Urothelial Carcinoma', 'Disease', (126, 156))	('men', 'Species', '9606', (384, 387))	('pRB Deficiency', 'Disease', 'MESH:D007153', (90, 104))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('UCB', 'Phenotype', 'HP:0006740', (306, 309))	('papillary urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (255, 300))	('p53', 'Gene', '22059', (86, 89))
41656	27157475	Here we show that forced expression of FGFR3b-S249C, the most prevalent FGFR3 mutation in human LGP-UCB, in cultured urothelial cells resulted in slightly reduced surface translocation than wild-type FGFR3b, but nearly twice as much proliferation.	('surface translocation', 'MPA', (163, 184))	('FGFR3b-S249C', 'Var', (39, 51))	('FGFR', 'molecular_function', 'GO:0005007', ('39', '43'))	('expression', 'Species', '29278', (25, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('200', '204'))	('reduced', 'NegReg', (155, 162))	('human', 'Species', '9606', (90, 95))	('UCB', 'Phenotype', 'HP:0006740', (100, 103))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('FGFR3', 'Gene', (72, 77))	('S249C', 'Mutation', 'rs121913483', (46, 51))
41657	27157475	When we expressed a mouse equivalent of this mutant (FGFR3b-S243C) in urothelia of adult transgenic mice in a tissue-specific and inducible manner, we observed significant activation of AKT and MAPK pathways.	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('MAPK', 'molecular_function', 'GO:0004707', ('194', '198'))	('AKT', 'Gene', '11651', (186, 189))	('transgenic mice', 'Species', '10090', (89, 104))	('AKT', 'Gene', (186, 189))	('S243C', 'Mutation', 'p.S243C', (60, 65))	('MAPK pathways', 'Pathway', (194, 207))	('activation', 'PosReg', (172, 182))	('FGFR3b-S243C', 'Var', (53, 65))	('mouse', 'Species', '10090', (20, 25))
41659	27157475	Indeed, expressing FGFR3b-S249C in cultured human urothelial cells expressing SV40T, which functionally inactivates pRB/p53, markedly accelerated proliferation and cell-cycle progression.	('human', 'Species', '9606', (44, 49))	('FGFR3b-S249C', 'Var', (19, 31))	('SV40T', 'Var', (78, 83))	('inactivates', 'NegReg', (104, 115))	('S249C', 'Mutation', 'rs121913483', (26, 31))	('proliferation', 'CPA', (146, 159))	('accelerated', 'PosReg', (134, 145))	('cell-cycle progression', 'CPA', (164, 186))	('pRB/p53', 'Gene', (116, 123))	('cell-cycle', 'biological_process', 'GO:0007049', ('164', '174'))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))
41660	27157475	Furthermore, expressing FGFR3b-S243C in transgenic mouse urothelium expressing SV40T converted carcinoma-in-situ to high-grade papillary urothelial carcinoma.	('carcinoma', 'Disease', (95, 104))	('S243C', 'Mutation', 'p.S243C', (31, 36))	('FGFR3b-S243C', 'Var', (24, 36))	('carcinoma', 'Disease', (148, 157))	('mouse', 'Species', '10090', (51, 56))	('transgenic', 'Species', '10090', (40, 50))	('carcinoma', 'Disease', 'MESH:D002277', (95, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('SV40T', 'Var', (79, 84))	('papillary urothelial carcinoma', 'Disease', (127, 157))	('papillary urothelial carcinoma', 'Disease', 'MESH:D002291', (127, 157))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (127, 157))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))	('converted', 'Reg', (85, 94))	('carcinoma', 'Disease', 'MESH:D002277', (148, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
41661	27157475	Together, our study provides new experimental evidence indicating that the FGFR3 mutations have very limited urothelial tumorigenicity and that these mutations must collaborate with other genetic events to drive urothelial tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('FGFR3', 'Gene', (75, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('urothelial tumor', 'Disease', (212, 228))	('limited', 'NegReg', (101, 108))	('drive', 'PosReg', (206, 211))	('mutations', 'Var', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('men', 'Species', '9606', (39, 42))	('urothelial tumor', 'Disease', 'MESH:D001749', (109, 125))	('urothelial tumor', 'Disease', 'MESH:D001749', (212, 228))	('urothelial tumor', 'Disease', (109, 125))
41665	27157475	Among the genetic alterations identified to date in LGP-UCB, mutations involving the fibroblast growth factor receptor 3 (FGFR3) gene are by far the most common, occurring in up to 80% of all the tumors.	('FGFR', 'molecular_function', 'GO:0005007', ('122', '126'))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('FGFR3', 'Gene', (122, 127))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('mutations', 'Var', (61, 70))	('fibroblast growth factor receptor 3', 'Gene', '14184', (85, 120))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('85', '109'))	('common', 'Reg', (154, 160))	('occurring', 'Reg', (162, 171))	('UCB', 'Phenotype', 'HP:0006740', (56, 59))	('fibroblast growth factor receptor 3', 'Gene', (85, 120))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
41666	27157475	Interestingly, the cysteine-altering mutations, i.e., mutations that either abrogate an original cysteine or create a new one, dominate the extracellular loop mutations.	('cysteine', 'MPA', (97, 105))	('abrogate', 'NegReg', (76, 84))	('extracellular', 'cellular_component', 'GO:0005576', ('140', '153'))	('cysteine', 'Chemical', 'MESH:D003545', (97, 105))	('mutations', 'Var', (54, 63))	('cysteine-altering', 'Disease', (19, 36))	('cysteine', 'Chemical', 'MESH:D003545', (19, 27))	('mutations', 'Var', (37, 46))
41667	27157475	It has been suggested that these mutations can lead to the mispairing of the cysteines between two FGFR3 protein molecules and, consequently, ligand-independent receptor dimerization and activation.	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('mispairing of the cysteines', 'MPA', (59, 86))	('ligand', 'molecular_function', 'GO:0005488', ('142', '148'))	('cysteines', 'Chemical', 'MESH:D003545', (77, 86))	('FGFR3', 'Gene', (99, 104))	('lead to', 'Reg', (47, 54))	('activation', 'PosReg', (187, 197))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('mutations', 'Var', (33, 42))	('dimerization', 'Interaction', (170, 182))	('protein', 'Protein', (105, 112))
41668	27157475	Whether these cysteine-altering FGFR mutants become misfolded and trapped in the endoplasmic reticulum entirely and activate downstream signals intracellularly, or some of them can still translocate to the cell surface and be partially ligand-dependent during urothelial transformation and tumorigenesis remains unresolved.	('ligand', 'molecular_function', 'GO:0005488', ('236', '242'))	('activate', 'PosReg', (116, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('cysteine', 'Chemical', 'MESH:D003545', (14, 22))	('cell surface', 'cellular_component', 'GO:0009986', ('206', '218'))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('FGFR', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('translocate', 'MPA', (187, 198))	('mutants', 'Var', (37, 44))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('81', '102'))	('tumor', 'Disease', (290, 295))
41669	27157475	On the other hand, non-cysteine mutations in the transmembrane and cytoplasmic domains of FGFR3 are believed to change the conformational structure of the kinase domains, leading to their constitutive activation.	('constitutive activation', 'MPA', (188, 211))	('transmembrane', 'cellular_component', 'GO:0016021', ('49', '62'))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))	('cysteine', 'Chemical', 'MESH:D003545', (23, 31))	('non-cysteine mutations', 'Var', (19, 41))	('conformational structure', 'MPA', (123, 147))	('FGFR3', 'Gene', (90, 95))	('transmembrane', 'cellular_component', 'GO:0044214', ('49', '62'))	('change', 'Reg', (112, 118))
41670	27157475	The sheer abundance of the FGFR3 mutations in LGP-UCB implies that they may play an important role in urothelial tumorigenesis, although direct experimental evidence remains scarce.	('urothelial tumor', 'Disease', 'MESH:D001749', (102, 118))	('play', 'Reg', (76, 80))	('UCB', 'Phenotype', 'HP:0006740', (50, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('urothelial tumor', 'Disease', (102, 118))	('role', 'Reg', (94, 98))	('mutations', 'Var', (33, 42))	('FGFR3', 'Gene', (27, 32))	('men', 'Species', '9606', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
41671	27157475	On the one hand, enforced expression of various FGFR3 mutants in cultured urothelial cells could activate MAPK pathway and promote cell proliferation and survival, effects that are known to be conducive to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('cell proliferation', 'biological_process', 'GO:0008283', ('131', '149'))	('MAPK', 'molecular_function', 'GO:0004707', ('106', '110'))	('expression', 'Species', '29278', (26, 36))	('tumor', 'Disease', (206, 211))	('survival', 'CPA', (154, 162))	('promote', 'PosReg', (123, 130))	('activate', 'PosReg', (97, 105))	('mutants', 'Var', (54, 61))	('cell proliferation', 'CPA', (131, 149))	('FGFR3', 'Gene', (48, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('MAPK pathway', 'Pathway', (106, 118))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
41672	27157475	On the other hand, expression of a kinase mutant (K652E) of FGFR3 in the urothelium of transgenic mice failed to elicit urothelial proliferation, let alone tumor formation after 18 months, thus refuting a tumorigenic role of this particular mutation.	('K652E', 'Mutation', 'rs78311289', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('elicit', 'Reg', (113, 119))	('FGFR3', 'Gene', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('transgenic mice', 'Species', '10090', (87, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('urothelial proliferation', 'CPA', (120, 144))	('expression', 'Species', '29278', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('K652E', 'Var', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', (156, 161))	('formation', 'biological_process', 'GO:0009058', ('162', '171'))	('failed', 'NegReg', (103, 109))
41673	27157475	The tumorigenicity or, the lack thereof, of the more prevalent, cysteine-altering extracellular loop mutations in an in vivo physiologically relevant system has not been addressed.	('tumor', 'Disease', (4, 9))	('mutations', 'Var', (101, 110))	('cysteine', 'Chemical', 'MESH:D003545', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('extracellular', 'cellular_component', 'GO:0005576', ('82', '95'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
41674	27157475	In the present study, we examined the tumorigenic potential of a cysteine-altering mutant of FGFR3 (e.g., S249C), the most prevalent FGFR3 mutation in human LGP-UCB, using a combination of cultured cells and transgenic mice.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('transgenic mice', 'Species', '10090', (208, 223))	('S249C', 'Mutation', 'rs121913483', (106, 111))	('cysteine', 'Chemical', 'MESH:D003545', (65, 73))	('human', 'Species', '9606', (151, 156))	('UCB', 'Phenotype', 'HP:0006740', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('FGFR3', 'Gene', (93, 98))	('FGFR', 'molecular_function', 'GO:0005007', ('133', '137'))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('S249C', 'Var', (106, 111))
41675	27157475	We further tested the effects of suppressing the anti-proliferative responses elicited by the mutated FGFR3 on urothelial tumor formation.	('anti-proliferative responses', 'CPA', (49, 77))	('suppressing', 'NegReg', (33, 44))	('mutated', 'Var', (94, 101))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('FGFR3', 'Gene', (102, 107))	('urothelial tumor', 'Disease', 'MESH:D001749', (111, 127))	('tested', 'Reg', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('formation', 'biological_process', 'GO:0009058', ('128', '137'))	('urothelial tumor', 'Disease', (111, 127))
41676	27157475	Our results provide direct in vivo evidence indicating that FGFR3 mutations by themselves have very limited tumorigenic activity and they require specific collaborative events, particularly deficiencies in one or more tumor suppressive pathways, in order to initiate urothelial tumors.	('mutations', 'Var', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('FGFR3', 'Gene', (60, 65))	('tumor', 'Disease', (278, 283))	('urothelial tumors', 'Disease', (267, 284))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('limited', 'NegReg', (100, 107))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('tumor', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))	('initiate', 'PosReg', (258, 266))	('urothelial tumors', 'Disease', 'MESH:D001749', (267, 284))
41677	27157475	Based on the data presented here and those published previously, we provide an integral view of the role of RTK/RAS pathway components in the genesis and progression of major phenotypic variants of urothelial carcinoma of the bladder.	('urothelial carcinoma of the bladder', 'Disease', (198, 233))	('variants', 'Var', (186, 194))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (198, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (198, 233))
41680	27157475	The detection of the FGFR3-S249C mutant was facilitated by the insertion of an Influenza virus hemagglutinin (HA) tag between amino acid residues 27 and 28, a region preceding the extracellular loop domains of FGFR3b (Fig.	('Influenza virus', 'Species', '11309', (79, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('210', '214'))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('facilitated', 'PosReg', (44, 55))	('S249C', 'Mutation', 'rs121913483', (27, 32))	('insertion', 'Var', (63, 72))	('FGFR3-S249C', 'Var', (21, 32))	('extracellular', 'cellular_component', 'GO:0005576', ('180', '193'))	('FGFR3b', 'Gene', (210, 216))
41681	27157475	While the enforced expression of the wild-type FGFR3b cDNA only slightly increased the proliferation of UMUC3 cells over the vector control, that of the FGFR3b-S249C mutant increased the proliferation by nearly 2-fold (p < 0.001; Fig.	('FGFR3b-S249C', 'Var', (153, 165))	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('FGFR', 'molecular_function', 'GO:0005007', ('153', '157'))	('expression', 'Species', '29278', (19, 29))	('FGFR3b', 'Gene', (47, 53))	('increased', 'PosReg', (173, 182))	('proliferation', 'CPA', (187, 200))	('UMUC3', 'CellLine', 'CVCL:1783', (104, 109))	('S249C', 'Mutation', 'rs121913483', (160, 165))
41682	27157475	Immunofluorescent staining using anti-HA of transfected, non-permeabilized UMUC3 cells (that were therefore negative for intracellular beta-actin staining) showed cell surface labeling for the wild-type FGFR3b and less so for the FGFR3b-S249C mutant (Fig.	('cell surface', 'cellular_component', 'GO:0009986', ('163', '175'))	('UMUC3', 'CellLine', 'CVCL:1783', (75, 80))	('FGFR3b-S249C', 'Var', (230, 242))	('cell surface', 'CPA', (163, 175))	('S249C', 'Mutation', 'rs121913483', (237, 242))	('FGFR', 'molecular_function', 'GO:0005007', ('230', '234'))	('intracellular', 'cellular_component', 'GO:0005622', ('121', '134'))	('FGFR', 'molecular_function', 'GO:0005007', ('203', '207'))
41685	27157475	To determine the in vivo tumorigenic potential of the FGFR3b mutant, we engineered the FGFR3b mutant cDNA downstream of a tetracycline responsive element (TRE-FGFR3b*), and then crossed the transgenic mice with another transgenic line that we generated previously that expressed a modified tetracycline transactivator under the control of a mouse uroplakin II promoter (UPII-rtTA-M2) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('uroplakin II', 'Gene', (347, 359))	('UPII', 'Gene', (370, 374))	('mouse', 'Species', '10090', (341, 346))	('uroplakin II', 'Gene', '22269', (347, 359))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('tetracycline', 'Chemical', 'MESH:D013752', (122, 134))	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('transgenic mice', 'Species', '10090', (190, 205))	('FGFR', 'molecular_function', 'GO:0005007', ('54', '58'))	('FGFR3b', 'Gene', (87, 93))	('men', 'Species', '9606', (149, 152))	('transgenic', 'Species', '10090', (190, 200))	('tumor', 'Disease', (25, 30))	('mutant', 'Var', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tetracycline', 'Chemical', 'MESH:D013752', (290, 302))	('transgenic', 'Species', '10090', (219, 229))	('UPII', 'Gene', '22269', (370, 374))
41686	27157475	We again devised an isogenic system, i.e., expression of a mouse version of HA-tagged FGFR3b mutant (S243C) in mice (Fig.	('FGFR3b', 'Gene', (86, 92))	('mouse', 'Species', '10090', (59, 64))	('S243C', 'Mutation', 'p.S243C', (101, 106))	('S243C', 'Var', (101, 106))	('mice', 'Species', '10090', (111, 115))	('expression', 'Species', '29278', (43, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('86', '90'))
41689	27157475	Direct sequencing of the RT-PCR products confirmed the presence of the mutation on codon 243 converting the wild-type serine to cysteine, only in doxycycline-treated mice (Fig.	('doxycycline', 'Chemical', 'MESH:D004318', (146, 157))	('cysteine', 'Chemical', 'MESH:D003545', (128, 136))	('mutation', 'Var', (71, 79))	('mice', 'Species', '10090', (166, 170))	('converting', 'Reg', (93, 103))	('serine', 'Chemical', 'MESH:D012694', (118, 124))	('wild-type', 'MPA', (108, 117))
41697	27157475	We surmised that the compensatory induction of tumor barriers via an overexpression of tumor suppressor genes may contribute to the lack of tumorigenicity by the FGFR3 mutation, and therefore surveyed a number of such targets using real-time quantitative PCR.	('overexpression', 'PosReg', (69, 83))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (87, 92))	('lack', 'NegReg', (132, 136))	('expression', 'Species', '29278', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor suppressor', 'biological_process', 'GO:0051726', ('87', '103'))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('FGFR', 'molecular_function', 'GO:0005007', ('162', '166'))	('mutation', 'Var', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('87', '103'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('FGFR3', 'Gene', (162, 167))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', (140, 145))
41698	27157475	We found genes operative in the p16-pRb and p19-p53-p21 pathways to be significantly upregulated on mRNA and protein levels in urothelial cells expressing the FGFR3b-S243C mutant, but not in non-expressing controls (Fig.	('S243C', 'Mutation', 'p.S243C', (166, 171))	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('p19', 'cellular_component', 'GO:0070743', ('44', '47'))	('upregulated', 'PosReg', (85, 96))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('p16', 'Gene', '12578', (32, 35))	('FGFR3b-S243C', 'Var', (159, 171))	('p21', 'Gene', (52, 55))	('p21', 'Gene', '12575', (52, 55))	('p19', 'Gene', (44, 47))	('p16', 'Gene', (32, 35))	('p19', 'Gene', '12581', (44, 47))
41699	27157475	These results raised the interesting possibility that the oncogenic effects of the FGFR3b mutant in urothelial cells may be negated by the secondary tumor defenses, thus rendering the FGFR3b non-tumorigenic.	('FGFR3b', 'Gene', (83, 89))	('negated', 'NegReg', (124, 131))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('mutant', 'Var', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('FGFR', 'molecular_function', 'GO:0005007', ('83', '87'))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('FGFR', 'molecular_function', 'GO:0005007', ('184', '188'))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
41700	27157475	If the upregulation of the molecular players in the p16-pRb and p19-p53-p21 pathways indeed acted as tumor barriers in urothelial cells expressing the FGFR3 mutant, their removal should then enhance urothelial proliferation or even induce urothelial tumor formation.	('FGFR3', 'Gene', (151, 156))	('p16', 'Gene', (52, 55))	('p19', 'Gene', (64, 67))	('p19', 'cellular_component', 'GO:0070743', ('64', '67'))	('tumor', 'Disease', (250, 255))	('urothelial tumor', 'Disease', 'MESH:D001749', (239, 255))	('induce', 'PosReg', (232, 238))	('urothelial tumor', 'Disease', (239, 255))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('p21', 'Gene', (72, 75))	('p19', 'Gene', '12581', (64, 67))	('upregulation', 'PosReg', (7, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('151', '155'))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('mutant', 'Var', (157, 163))	('p16', 'Gene', '12578', (52, 55))	('formation', 'biological_process', 'GO:0009058', ('256', '265'))	('tumor', 'Disease', (101, 106))	('urothelial proliferation', 'CPA', (199, 223))	('p21', 'Gene', '12575', (72, 75))	('enhance', 'PosReg', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
41701	27157475	To test this hypothesis, we first transfected a mammalian expression vector containing the human FGFR3b-S249C mutant cDNA into human urothelial cells that were immortalized with the SV40T antigen (the latter of which is known to bind and functionally inactivate both p53 and pRb;).	('mammalian', 'Species', '9606', (48, 57))	('expression', 'Species', '29278', (58, 68))	('pRb', 'Protein', (275, 278))	('human', 'Species', '9606', (127, 132))	('FGFR3b-S249C', 'Gene', (97, 109))	('SV40T antigen', 'molecular_function', 'GO:0016887', ('182', '195'))	('bind', 'Interaction', (229, 233))	('p53', 'Protein', (267, 270))	('mutant', 'Var', (110, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('97', '101'))	('inactivate', 'NegReg', (251, 261))	('S249C', 'Mutation', 'rs121913483', (104, 109))	('human', 'Species', '9606', (91, 96))
41702	27157475	While the expression of the wild-type FGFR3b did not promote cell proliferation beyond the non-transfected or vector-transfected controls in UROtsa cells, the FGFR3-S249C mutant markedly increased cell proliferation (Fig.	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('S249C', 'Mutation', 'rs121913483', (165, 170))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('expression', 'Species', '29278', (10, 20))	('FGFR3-S249C', 'Var', (159, 170))	('increased', 'PosReg', (187, 196))	('cell proliferation', 'biological_process', 'GO:0008283', ('197', '215'))	('cell proliferation', 'CPA', (197, 215))
41704	27157475	After additional crosses among the siblings, the resultant double (UPII-rtTA-M2 and TRE-FGFR3b-S243C) and triple (UPII-rtTA-M2, TRE-FGFR3b-S243C and UPII-SV40T) transgenic mice (Fig.	('UPII', 'Gene', (67, 71))	('TRE-FGFR3b-S243C', 'Var', (128, 144))	('FGFR', 'molecular_function', 'GO:0005007', ('132', '136'))	('UPII', 'Gene', '22269', (149, 153))	('S243C', 'Mutation', 'p.S243C', (139, 144))	('UPII', 'Gene', '22269', (114, 118))	('UPII', 'Gene', '22269', (67, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('88', '92'))	('transgenic mice', 'Species', '10090', (161, 176))	('S243C', 'Mutation', 'p.S243C', (95, 100))	('UPII', 'Gene', (114, 118))	('UPII', 'Gene', (149, 153))
41709	27157475	Without doxycycline treatment (e.g., without FGFR3b-S243C expression), the triple transgenic mice bearing UPII-rtTA-M2, TRE-FGFR3b-S243C and UPII-SV40T transgenes exhibited high-grade carcinoma-in-situ lesions in the bladder (Fig.	('carcinoma-in-situ lesions', 'Disease', 'MESH:D002278', (184, 209))	('carcinoma-in-situ lesions', 'Disease', (184, 209))	('S243C', 'Mutation', 'p.S243C', (52, 57))	('doxycycline', 'Chemical', 'MESH:D004318', (8, 19))	('S243C', 'Mutation', 'p.S243C', (131, 136))	('expression', 'Species', '29278', (58, 68))	('UPII', 'Gene', '22269', (141, 145))	('UPII', 'Gene', (106, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('FGFR', 'molecular_function', 'GO:0005007', ('124', '128'))	('exhibited', 'Reg', (163, 172))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('UPII', 'Gene', '22269', (106, 110))	('high-grade', 'CPA', (173, 183))	('transgenic mice', 'Species', '10090', (82, 97))	('UPII', 'Gene', (141, 145))	('TRE-FGFR3b-S243C', 'Var', (120, 136))	('men', 'Species', '9606', (25, 28))
41712	27157475	It seems clear therefore that the functional inactivation of pRb and p53 by SV40T could collaborate with FGFR3b mutation to trigger urothelial tumors in vivo.	('urothelial tumors', 'Disease', (132, 149))	('inactivation', 'NegReg', (45, 57))	('p53', 'Gene', (69, 72))	('mutation', 'Var', (112, 120))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('FGFR3b', 'Gene', (105, 111))	('trigger', 'PosReg', (124, 131))	('urothelial tumors', 'Disease', 'MESH:D001749', (132, 149))	('pRb', 'Gene', (61, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('SV40T', 'Var', (76, 81))
41714	27157475	This suggested that the inactivation of pRb and p53 allowed the downstream signals of FGFR3b to overactivate, helping fuel urothelial proliferation and tumor formation.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('FGFR3b', 'Gene', (86, 92))	('p53', 'Gene', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('inactivation', 'Var', (24, 36))	('pRb', 'Gene', (40, 43))	('urothelial proliferation', 'CPA', (123, 147))	('tumor', 'Disease', (152, 157))	('helping fuel', 'PosReg', (110, 122))	('FGFR', 'molecular_function', 'GO:0005007', ('86', '90'))	('formation', 'biological_process', 'GO:0009058', ('158', '167'))
41715	27157475	A key finding of our present study was that the urothelium-specific and time-controlled expression of an FGFR3b mutant (S243C) alone in transgenic mice was insufficient to trigger urothelial tumorigenesis (Fig.	('insufficient', 'Disease', (156, 168))	('FGFR3b', 'Gene', (105, 111))	('urothelial tumor', 'Disease', 'MESH:D001749', (180, 196))	('transgenic mice', 'Species', '10090', (136, 151))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('expression', 'Species', '29278', (88, 98))	('S243C', 'Mutation', 'p.S243C', (120, 125))	('insufficient', 'Disease', 'MESH:D000309', (156, 168))	('S243C', 'Var', (120, 125))	('urothelial tumor', 'Disease', (180, 196))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))
41716	27157475	This was largely unexpected because the mutant we chose is by far the most prevalent among all the FGFR3b mutations in human urothelial carcinoma of the bladder (UCB); because the mutant is considered ligand-independent and constitutively active; and because the mutant exerted significant pro-proliferative effects in cultured urothelial cells as shown here (Fig.	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (125, 160))	('urothelial carcinoma of the bladder', 'Disease', (125, 160))	('pro-proliferative effects', 'MPA', (290, 315))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (125, 160))	('FGFR3b', 'Gene', (99, 105))	('prevalent', 'Reg', (75, 84))	('mutant', 'Var', (263, 269))	('UCB', 'Phenotype', 'HP:0006740', (162, 165))	('mutations', 'Var', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('ligand', 'molecular_function', 'GO:0005488', ('201', '207'))	('human', 'Species', '9606', (119, 124))
41717	27157475	Our results, coupled with those showing that a kinase mutant of FGFR3b (K652E) alone also failed to cause urothelial tumor formation in transgenic mice, strongly suggests that the mutational activation of FGFR3b by itself lacks significant tumorigenicity in urothelial cells in vivo.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('FGFR', 'molecular_function', 'GO:0005007', ('205', '209'))	('tumor', 'Disease', (240, 245))	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('tumor', 'Disease', (117, 122))	('urothelial tumor', 'Disease', (106, 122))	('FGFR3b', 'Gene', (205, 211))	('mutational activation', 'Var', (180, 201))	('K652E', 'Var', (72, 77))	('transgenic mice', 'Species', '10090', (136, 151))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('K652E', 'Mutation', 'rs78311289', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('lacks', 'NegReg', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('urothelial tumor', 'Disease', 'MESH:D001749', (106, 122))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))
41718	27157475	These two independent studies, both based on biologically relevant systems, therefore do not support the conventional belief that, since FGFR3b mutations are extremely prevalent in human UCB, they are the molecular drivers for these tumors.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('human', 'Species', '9606', (181, 186))	('tumors', 'Disease', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('FGFR', 'molecular_function', 'GO:0005007', ('137', '141'))	('FGFR3b', 'Gene', (137, 143))	('UCB', 'Phenotype', 'HP:0006740', (187, 190))	('mutations', 'Var', (144, 153))	('prevalent', 'Reg', (168, 177))	('UCB', 'Disease', (187, 190))
41719	27157475	It should be emphasized that the lack of tumorigenicity of the FGFR3b mutant in vivo was not due to the lack of growth-promoting/oncogenic activities of the mutant per se.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('mutant', 'Var', (70, 76))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('FGFR3b', 'Gene', (63, 69))
41720	27157475	As we found out, the FGFR3b S249C mutant actually significantly activated both MAPK and AKT (Figs 1 and 3), signals critical for tumorigenesis in urothelial as well as non-urothelial cells.	('S249C', 'Var', (28, 33))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('MAPK', 'molecular_function', 'GO:0004707', ('79', '83'))	('AKT', 'Gene', '11651', (88, 91))	('S249C', 'Mutation', 'rs121913483', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('activated', 'PosReg', (64, 73))	('AKT', 'Gene', (88, 91))	('tumor', 'Disease', (129, 134))	('MAPK', 'Pathway', (79, 83))	('FGFR3b', 'Gene', (21, 27))
41721	27157475	It is, however, the compensatory tumor defense of the urothelial cells that counteracted the growth-promoting effects of the FGFR3 mutant, rendering the mutant non-tumorigenic.	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('mutant', 'Var', (131, 137))	('FGFR', 'molecular_function', 'GO:0005007', ('125', '129'))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mutant', 'Var', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', (33, 38))	('FGFR3', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
41722	27157475	In particular, key components of the p16-pRB and p19-p53-p21 tumor suppressor pathways, that were barely detectable in normal urothelial cells, were strongly upregulated in FGFR3b mutant-expressing cells (Fig.	('p19', 'Gene', (49, 52))	('p21', 'Gene', '12575', (57, 60))	('upregulated', 'PosReg', (158, 169))	('FGFR', 'molecular_function', 'GO:0005007', ('173', '177'))	('FGFR3b', 'Gene', (173, 179))	('p19', 'Gene', '12581', (49, 52))	('mutant-expressing', 'Var', (180, 197))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('p16', 'Gene', '12578', (37, 40))	('tumor suppressor', 'biological_process', 'GO:0051726', ('61', '77'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('p19', 'cellular_component', 'GO:0070743', ('49', '52'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('61', '77'))	('p21', 'Gene', (57, 60))	('tumor', 'Disease', (61, 66))	('p16', 'Gene', (37, 40))
41725	27157475	In direct support of our tumor-defense line of reasoning, functional inactivation of both p16-pRB and p19-p53-p21 pathways by urothelial expression of SV40 large T antigen induced high-grade papillary urothelial carcinoma of the bladder (HGP-UCB) in double transgenic mice that simultaneously expressed the FGFR3b mutant in the urothelium (Figs 3, 4, 5, 6).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('SV40 large', 'Var', (151, 161))	('p19', 'cellular_component', 'GO:0070743', ('102', '105'))	('papillary urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (191, 236))	('papillary urothelial carcinoma of the bladder', 'Disease', (191, 236))	('p16', 'Gene', (90, 93))	('FGFR', 'molecular_function', 'GO:0005007', ('307', '311'))	('p21', 'Gene', (110, 113))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (191, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('p19', 'Gene', (102, 105))	('tumor', 'Disease', (25, 30))	('induced', 'Reg', (172, 179))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (201, 236))	('transgenic mice', 'Species', '10090', (257, 272))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('UCB', 'Phenotype', 'HP:0006740', (242, 245))	('expression', 'Species', '29278', (137, 147))	('p19', 'Gene', '12581', (102, 105))	('p16', 'Gene', '12578', (90, 93))	('inactivation', 'NegReg', (69, 81))	('p21', 'Gene', '12575', (110, 113))	('high-grade', 'Disease', (180, 190))
41726	27157475	Thus, FGFR3b mutation and pRb/p53 deficiency apparently act synergistically as combinatorial genetic drivers of HGP-UCB in our experimental system.	('deficiency', 'Var', (34, 44))	('mutation', 'Var', (13, 21))	('UCB', 'Phenotype', 'HP:0006740', (116, 119))	('men', 'Species', '9606', (133, 136))	('FGFR', 'molecular_function', 'GO:0005007', ('6', '10'))	('FGFR3b', 'Gene', (6, 12))	('pRb/p53', 'Gene', (26, 33))
41727	27157475	Since single transgenic mice expressing SV40T-only consistently developed carcinoma in situ, the formation of HGP-UCB in the double transgenic mice could be a result of the acquisition of increased growth potential conferred by the FGFR3 mutant, which was missing in the SV40T single transgenic mice.	('FGFR3', 'Gene', (232, 237))	('developed', 'Reg', (64, 73))	('transgenic mice', 'Species', '10090', (132, 147))	('formation', 'biological_process', 'GO:0009058', ('97', '106'))	('carcinoma', 'Disease', 'MESH:D002277', (74, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('232', '236'))	('transgenic mice', 'Species', '10090', (284, 299))	('mutant', 'Var', (238, 244))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (74, 91))	('transgenic mice', 'Species', '10090', (13, 28))	('carcinoma', 'Disease', (74, 83))	('UCB', 'Phenotype', 'HP:0006740', (114, 117))	('increased', 'PosReg', (188, 197))	('growth', 'MPA', (198, 204))
41728	27157475	Interestingly, similar collaborative relationships existed between SV40T and overexpressed EGFR, and between SV40T and activated HRAS.	('SV40T', 'Var', (67, 72))	('EGFR', 'Gene', (91, 95))	('SV40T', 'Var', (109, 114))	('EGFR', 'molecular_function', 'GO:0005006', ('91', '95'))	('HRAS', 'Gene', '15461', (129, 133))	('HRAS', 'Gene', (129, 133))	('overexpressed', 'PosReg', (77, 90))	('EGFR', 'Gene', '13649', (91, 95))
41731	27157475	A limited number of studies found that HGP-UCB harbor significantly more chromosomal abnormalities (e.g., gains and deletions) than the low-grade counterpart, suggesting that HGP-UCB are more genomically unstable and prone to progress.	('gains', 'Var', (106, 111))	('UCB', 'Phenotype', 'HP:0006740', (43, 46))	('deletions', 'Var', (116, 125))	('HGP-UCB', 'Var', (175, 182))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (73, 98))	('chromosomal abnormalities', 'Disease', (73, 98))	('UCB', 'Phenotype', 'HP:0006740', (179, 182))
41732	27157475	Results from our present study therefore offer potential leads to further studying whether a combination of activation of receptor tyrosine kinase/RAS pathway and inactivation of pRb/p53 also plays an important role in the genesis of HGP-UCB in humans.	('pRb/p53', 'Gene', (179, 186))	('humans', 'Species', '9606', (245, 251))	('HGP-UCB', 'Gene', (234, 241))	('activation', 'PosReg', (108, 118))	('inactivation', 'Var', (163, 175))	('UCB', 'Phenotype', 'HP:0006740', (238, 241))	('receptor tyrosine kinase/RAS pathway', 'Pathway', (122, 158))
41738	27157475	The fact that even a genetic alteration as prevalent as FGFR3 mutation is by itself incapable of causing urothelial carcinoma in vivo, as we demonstrated here, illustrates the need to validate the molecular profiling data from human tumors using experimental systems.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('FGFR', 'molecular_function', 'GO:0005007', ('56', '60'))	('urothelial carcinoma', 'Disease', (105, 125))	('tumors', 'Disease', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('human', 'Species', '9606', (227, 232))	('men', 'Species', '9606', (252, 255))	('causing', 'Reg', (97, 104))	('FGFR3', 'Gene', (56, 61))	('mutation', 'Var', (62, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (105, 125))
41748	27157475	After 16 h, the attached cells were transfected using Lipofectamine 2000 (Invitrogen) with the vector only, that containing wild-type FGFR3b or that containing FGFR3b-S249C.	('S249C', 'Mutation', 'rs121913483', (167, 172))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (54, 72))	('FGFR3b', 'Gene', (134, 140))	('FGFR', 'molecular_function', 'GO:0005007', ('160', '164'))	('FGFR', 'molecular_function', 'GO:0005007', ('134', '138'))	('FGFR3b-S249C', 'Var', (160, 172))
41755	27157475	Cells in both conditions were incubated with primary (anti-HA tag and anti-beta-actin) followed by fluorescein-conjugated secondary antibodies.	('anti-HA', 'Var', (54, 61))	('fluorescein', 'Chemical', 'MESH:D019793', (99, 110))	('anti-beta-actin', 'Var', (70, 85))
41766	27157475	The primary antibodies used in this study were anti-HA (Abcam, Inc., 1:1,000), anti-beta-actin (Sigma, 1:2,000), anti-E-cadherin (SCBT Inc., 1:400), anti-p-MAPK (Thr202/Tyr204; Cell Signaling Technology, Inc., 1:2,000) anti-p-AKT (Ser473; Cell Signaling Technology, Inc., 1:200), anti-p-S6 (Ser235/Ser236; Cell Signaling Technology, Inc., 1:400) and anti-p-STAT (Tyr705; Cell Signaling Technology, Inc., 1:400).	('AKT', 'Gene', (226, 229))	('MAPK', 'molecular_function', 'GO:0004707', ('156', '160'))	('cadherin', 'molecular_function', 'GO:0008014', ('120', '128'))	('AKT', 'Gene', '11651', (226, 229))	('Signaling', 'biological_process', 'GO:0023052', ('311', '320'))	('anti-E-cadherin', 'Gene', (113, 128))	('Ser473', 'Chemical', '-', (231, 237))	('Signaling', 'biological_process', 'GO:0023052', ('182', '191'))	('Ser', 'cellular_component', 'GO:0005790', ('231', '234'))	('Ser', 'cellular_component', 'GO:0005790', ('298', '301'))	('Signaling', 'biological_process', 'GO:0023052', ('244', '253'))	('anti-p-S6', 'Var', (280, 289))	('Ser', 'cellular_component', 'GO:0005790', ('291', '294'))	('anti-E-cadherin', 'Gene', '12550', (113, 128))	('Signaling', 'biological_process', 'GO:0023052', ('376', '385'))
41769	27157475	The primary antibodies used (all from Cell Signaling Technology, Inc., unless otherwise noted or differ from the immunohistochemistry) were: anti-HA (1:1,000), anti-p-MAPK (1:3,000), anti-MAPK (1:2,000), anti-p-AKT (S473; 1:1,000), anti-AKT (1:1,000), anti-p16 (Abcam, Inc., 1:1,000), anti-p19 (EMD Millipore, 1:500), anti-p53 (SCBT Inc., 1:500) and anti-p21 (Abcam, Inc., 1:500).	('AKT', 'Gene', (237, 240))	('anti-p53', 'Var', (318, 326))	('Signaling', 'biological_process', 'GO:0023052', ('43', '52'))	('MAPK', 'molecular_function', 'GO:0004707', ('167', '171'))	('AKT', 'Gene', '11651', (211, 214))	('p16', 'Gene', (257, 260))	('p21', 'Gene', (355, 358))	('HA (1', 'cellular_component', 'GO:0030121', ('146', '151'))	('MAPK', 'molecular_function', 'GO:0004707', ('188', '192'))	('p19', 'Gene', (290, 293))	('AKT', 'Gene', (211, 214))	('p21', 'Gene', '12575', (355, 358))	('AKT', 'Gene', '11651', (237, 240))	('p19', 'Gene', '12581', (290, 293))	('p19', 'cellular_component', 'GO:0070743', ('290', '293'))	('p16', 'Gene', '12578', (257, 260))
41771	27157475	Student t test (two-tailed) was employed for evaluating the statistical significances in (i) the growth-promotion capacities in UMUC3 cells between FGFR3b-S249C and wild-type FGFR3b; (ii) the expression levels of p16 and p19 between doxycycline-treated mice expressing FGFR3b-S249C and untreated mice not expressing FGFR3b-S249C; and (iii) the frequency of high-grade, papillary urothelial carcinoma between doxycycline-treated and untreated triple transgenic mice.	('p19', 'cellular_component', 'GO:0070743', ('221', '224'))	('carcinoma', 'Phenotype', 'HP:0030731', (390, 399))	('FGFR', 'molecular_function', 'GO:0005007', ('175', '179'))	('FGFR3b-S249C', 'Var', (148, 160))	('doxycycline', 'Chemical', 'MESH:D004318', (233, 244))	('S249C', 'Mutation', 'rs121913483', (276, 281))	('doxycycline', 'Chemical', 'MESH:D004318', (408, 419))	('p16', 'Gene', '12578', (213, 216))	('UMUC3', 'CellLine', 'CVCL:1783', (128, 133))	('papillary urothelial carcinoma', 'Disease', (369, 399))	('papillary urothelial carcinoma', 'Disease', 'MESH:D002291', (369, 399))	('p19', 'Gene', (221, 224))	('S249C', 'Mutation', 'rs121913483', (323, 328))	('FGFR', 'molecular_function', 'GO:0005007', ('316', '320'))	('p16', 'Gene', (213, 216))	('mice', 'Species', '10090', (296, 300))	('S249C', 'Mutation', 'rs121913483', (155, 160))	('transgenic mice', 'Species', '10090', (449, 464))	('p19', 'Gene', '12581', (221, 224))	('FGFR', 'molecular_function', 'GO:0005007', ('269', '273'))	('mice', 'Species', '10090', (460, 464))	('expression', 'Species', '29278', (192, 202))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (369, 399))	('growth-promotion capacities', 'CPA', (97, 124))	('high-grade', 'Disease', (357, 367))	('FGFR', 'molecular_function', 'GO:0005007', ('148', '152'))	('mice', 'Species', '10090', (253, 257))
41772	27157475	FGFR3b Extracellular Loop Mutation Lacks Tumorigenicity In Vivo but Collaborates with p53/pRB Deficiency to Induce High-grade Papillary Urothelial Carcinoma.	('Papillary Urothelial Carcinoma', 'Phenotype', 'HP:0006766', (126, 156))	('Papillary Urothelial Carcinoma', 'Disease', 'MESH:D002291', (126, 156))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('Mutation', 'Var', (26, 34))	('Extracellular', 'cellular_component', 'GO:0005576', ('7', '20'))	('Papillary Urothelial Carcinoma', 'Disease', (126, 156))	('Carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('Induce', 'Reg', (108, 114))	('pRB Deficiency', 'Disease', 'MESH:D007153', (90, 104))	('FGFR3b', 'Gene', (0, 6))	('pRB Deficiency', 'Disease', (90, 104))
41775	29396293	The most frequently altered genes across the patient cohort were consistent with the urothelial carcinoma-associated alterations identified in a cohort of 130 RNU specimens previously sequenced at our center, including mutations in the TERT promoter (64%), hotspot activating mutations in FGFR3 (64%), and frequent mutations in chromatin remodeling genes.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (85, 105))	('TERT', 'Gene', (236, 240))	('altered', 'Reg', (20, 27))	('mutations', 'Var', (276, 285))	('TERT', 'Gene', '7015', (236, 240))	('chromatin', 'cellular_component', 'GO:0000785', ('328', '337'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('328', '348'))	('mutations', 'Reg', (315, 324))	('activating', 'PosReg', (265, 275))	('urothelial carcinoma', 'Disease', (85, 105))	('FGFR3', 'Gene', '2261', (289, 294))	('patient', 'Species', '9606', (45, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('289', '293'))	('mutations', 'Var', (219, 228))	('FGFR3', 'Gene', (289, 294))	('RNU', 'Chemical', '-', (159, 162))
41784	29396293	We previously identified genetic signatures in RNU specimens that are associated with adverse pathologic features.	('RNU', 'Chemical', '-', (47, 50))	('genetic signatures', 'Var', (25, 43))	('associated', 'Reg', (70, 80))
41793	29396293	The version of MSK-IMPACT used was capable of identifying missense mutations, small insertions and deletions, copy number alterations (CNAs), and select fusions (including FGFR3:TACC3) in 410 cancer-related genes.	('TACC3', 'Gene', '10460', (178, 183))	('FGFR3', 'Gene', '2261', (172, 177))	('TACC3', 'Gene', (178, 183))	('deletions', 'Var', (99, 108))	('copy number alterations', 'Var', (110, 133))	('FGFR3', 'Gene', (172, 177))	('missense mutations', 'Var', (58, 76))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('insertions', 'Var', (84, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('172', '176'))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
41797	29396293	Consistent with prior studies, chromatin remodeling genes including KMT2D (56%), KDM6A (47%), KMT2C (33%), ARID1A (31%), and CREBBP (31%) were commonly mutated, with most mutations in these genes predicted to result in protein inactivation.	('KMT2C', 'Gene', '58508', (94, 99))	('KMT2C', 'Gene', (94, 99))	('CREBBP', 'Gene', '1387', (125, 131))	('inactivation', 'NegReg', (227, 239))	('mutated', 'Var', (152, 159))	('KDM6A', 'Gene', '7403', (81, 86))	('ARID1A', 'Gene', '8289', (107, 113))	('ARID1A', 'Gene', (107, 113))	('KMT2D', 'Gene', '8085', (68, 73))	('chromatin', 'cellular_component', 'GO:0000785', ('31', '40'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('31', '51'))	('KMT2D', 'Gene', (68, 73))	('CREBBP', 'Gene', (125, 131))	('mutations', 'Var', (171, 180))	('KDM6A', 'Gene', (81, 86))	('chromatin remodeling genes', 'Gene', (31, 57))	('protein', 'cellular_component', 'GO:0003675', ('219', '226'))	('protein', 'Protein', (219, 226))
41798	29396293	Alteration of TP53 was found in 25% of cases.	('Alteration', 'Var', (0, 10))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))
41806	29396293	For the patients who received NAC, the concordance was lower (53% and 62% for all and likely pathogenic mutations, respectively), and may have been the result of outgrowth of a drug-resistant population under the selective pressure of chemotherapy.	('mutations', 'Var', (104, 113))	('lower', 'NegReg', (55, 60))	('NAC', 'Chemical', '-', (30, 33))	('NAC', 'cellular_component', 'GO:0005854', ('30', '33'))	('patients', 'Species', '9606', (8, 16))
41897	30521479	Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2.	('Dihydrotestosterone', 'Chemical', 'MESH:D013196', (0, 19))	('positive bladder', 'Phenotype', 'HP:0100645', (36, 52))	('transcriptional', 'MPA', (163, 178))	('AR', 'Gene', '367', (33, 35))	('nuclear translocation', 'CPA', (137, 158))	('men', 'Species', '9606', (25, 28))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('ERK', 'molecular_function', 'GO:0004707', ('122', '125'))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('phospho-ATF2', 'Var', (97, 109))	('expression', 'MPA', (83, 93))	('ERK', 'Gene', '5594', (122, 125))	('induced', 'PosReg', (71, 78))	('ERK', 'Gene', (122, 125))	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('bladder cancer', 'Disease', (45, 59))
41898	30521479	Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively.	('decreases', 'NegReg', (213, 222))	('cell cycle phase', 'biological_process', 'GO:0022403', ('245', '261'))	('apoptosis', 'biological_process', 'GO:0097194', ('226', '235'))	('apoptosis', 'biological_process', 'GO:0006915', ('226', '235'))	('ATF2', 'Gene', (11, 15))	('AR', 'Gene', '367', (115, 117))	('apoptosis', 'CPA', (226, 235))	('cell viability', 'CPA', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('M phase', 'biological_process', 'GO:0000279', ('274', '281'))	('bladder cancer', 'Disease', 'MESH:D001749', (127, 141))	('bladder cancer', 'Disease', (127, 141))	('decreases', 'NegReg', (60, 69))	('increases', 'PosReg', (199, 208))	('bladder cancer', 'Phenotype', 'HP:0009725', (127, 141))	('S or G2/M phase', 'CPA', (266, 281))	('invasion', 'CPA', (103, 111))	('G0/G1 cell cycle phase', 'CPA', (239, 261))	('knockdown', 'Var', (16, 25))	('positive bladder', 'Phenotype', 'HP:0100645', (118, 134))	('AR', 'Gene', '367', (157, 159))	('migration', 'CPA', (89, 98))
41899	30521479	Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors.	('retarded', 'Disease', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('growth', 'CPA', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('retarded', 'Disease', 'MESH:D008607', (99, 107))	('mice', 'Species', '10090', (90, 94))	('ATF2-shRNA', 'Var', (58, 68))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('AR', 'Gene', '367', (28, 30))	('tumors', 'Disease', (40, 46))
41900	30521479	ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/cyclin-A2/cyclin-D1/JUN/MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells.	('Bcl-2', 'molecular_function', 'GO:0015283', ('168', '173'))	('cyclin', 'molecular_function', 'GO:0016538', ('174', '180'))	('knockdown', 'Var', (5, 14))	('3-methylcholanthrene', 'Chemical', 'MESH:D008748', (117, 137))	('MMP-2', 'Gene', (198, 203))	('cyclin-D1', 'Gene', '595', (184, 193))	('cyclin-D1', 'Gene', (184, 193))	('MMP-2', 'molecular_function', 'GO:0004228', ('198', '203'))	('AR', 'Gene', '367', (287, 289))	('human', 'Species', '9606', (221, 226))	('ATF2', 'Gene', (0, 4))	('neoplastic transformation', 'CPA', (58, 83))	('cyclin-A2', 'Gene', (174, 183))	('inhibition', 'NegReg', (44, 54))	('cyclin-A2', 'Gene', '890', (174, 183))	('Bcl-2', 'Gene', (168, 173))	('MMP-2', 'Gene', '4313', (198, 203))	('cyclin', 'molecular_function', 'GO:0016538', ('184', '190'))	('AR', 'Gene', '367', (275, 277))	('Bcl-2', 'Gene', '596', (168, 173))	('expression', 'MPA', (154, 164))
41902	30521479	Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR) = 2.956, P = 0.045) and cancer-specific mortality of muscle-invasive tumors (HR = 5.317, P = 0.012), respectively.	('tumors', 'Disease', (158, 164))	('tumors', 'Disease', (253, 259))	('tumors', 'Disease', 'MESH:D009369', (253, 259))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Disease', (208, 214))	('ATF2', 'Gene', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (237, 259))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('muscle-invasive tumors', 'Disease', (237, 259))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('moderate/strong', 'Var', (42, 57))
41955	30521479	IHC was performed on the 5 microm sections, using a primary antibody to ATF2 (dilution 1:500), p-ATF2 (dilution 1:250) or p-ERK (dilution 1:1000), as we described previously.	('p-ERK', 'Gene', (122, 127))	('antibody', 'molecular_function', 'GO:0003823', ('60', '68'))	('ATF2', 'Gene', (72, 76))	('ERK', 'molecular_function', 'GO:0004707', ('124', '127'))	('p-ATF2', 'Var', (95, 101))	('antibody', 'cellular_component', 'GO:0042571', ('60', '68'))	('antibody', 'cellular_component', 'GO:0019815', ('60', '68'))	('p-ERK', 'Gene', '9451', (122, 127))	('antibody', 'cellular_component', 'GO:0019814', ('60', '68'))
41975	30521479	ATF2 knockdown resulted in significant decreases in the cell/colony number of AR-positive lines.	('ATF2', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('AR', 'Gene', '367', (78, 80))	('decreases', 'NegReg', (39, 48))
41976	30521479	By contrast, ATF2 knockdown did not significantly affect the growth of AR-negative cells.	('knockdown', 'Var', (18, 27))	('AR', 'Gene', '367', (71, 73))	('ATF2', 'Gene', (13, 17))
41980	30521479	Similar to the above findings, ATF2 knockdown demonstrated marked decreases in the migration/invasion ability of AR-positive cells, but not in that of AR-negative cells.	('ATF2', 'Gene', (31, 35))	('decreases', 'NegReg', (66, 75))	('migration/invasion ability', 'CPA', (83, 109))	('knockdown', 'Var', (36, 45))	('AR', 'Gene', '367', (113, 115))	('AR', 'Gene', '367', (151, 153))
41981	30521479	Next, we used mouse xenograft models to assess the effects of ATF2 knockdown on bladder tumor outgrowth in vivo.	('ATF2', 'Gene', (62, 66))	('bladder tumor', 'Disease', 'MESH:D001749', (80, 93))	('mouse', 'Species', '10090', (14, 19))	('bladder tumor', 'Phenotype', 'HP:0009725', (80, 93))	('knockdown', 'Var', (67, 76))	('bladder tumor', 'Disease', (80, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
41984	30521479	The inoculated ATF2-shRNA tumors were found to be smaller than control-shRNA tumors, especially at day 10 or after (Fig.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', (26, 32))	('ATF2-shRNA', 'Var', (15, 25))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('smaller', 'NegReg', (50, 57))
41992	30521479	In all the three assays, ATF2 knockdown in MCA-SVHUC-AR cells resulted in significant inhibition of their neoplastic transformation.	('AR', 'Gene', '367', (53, 55))	('MCA', 'Chemical', 'MESH:D008748', (43, 46))	('knockdown', 'Var', (30, 39))	('ATF2', 'Gene', (25, 29))	('neoplastic transformation', 'CPA', (106, 131))	('inhibition', 'NegReg', (86, 96))
41993	30521479	By contrast, ATF2 knockdown did not significantly have an impact on neoplastic transformation of AR-negative MCA-SVHUC cells.	('knockdown', 'Var', (18, 27))	('AR', 'Gene', '367', (97, 99))	('MCA', 'Chemical', 'MESH:D008748', (109, 112))	('neoplastic transformation', 'CPA', (68, 93))	('ATF2', 'Gene', (13, 17))
41995	30521479	In accordance with the above findings, ATF2 knockdown resulted in striking delay in the formation of xenograft tumors (Fig.	('delay', 'NegReg', (75, 80))	('formation', 'biological_process', 'GO:0009058', ('88', '97'))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('xenograft tumors', 'Disease', 'MESH:D009369', (101, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('ATF2', 'Gene', (39, 43))	('knockdown', 'Var', (44, 53))	('xenograft tumors', 'Disease', (101, 117))
41997	30521479	In SVHUC-AR cells with MCA exposure, ATF2 knockdown significantly downregulated the expression of Bcl-2, cyclin A2, cyclin D1, JUN and MMP-2 (Fig.	('cyclin', 'molecular_function', 'GO:0016538', ('105', '111'))	('downregulated', 'NegReg', (66, 79))	('MMP-2', 'Gene', (135, 140))	('cyclin', 'molecular_function', 'GO:0016538', ('116', '122'))	('Bcl-2', 'Gene', (98, 103))	('knockdown', 'Var', (42, 51))	('JUN', 'MPA', (127, 130))	('AR', 'Gene', '367', (9, 11))	('cyclin A2', 'Gene', (105, 114))	('cyclin D1', 'Gene', (116, 125))	('Bcl-2', 'Gene', '596', (98, 103))	('expression', 'MPA', (84, 94))	('cyclin A2', 'Gene', '890', (105, 114))	('MMP-2', 'Gene', '4313', (135, 140))	('MCA', 'Chemical', 'MESH:D008748', (23, 26))	('cyclin D1', 'Gene', '595', (116, 125))	('ATF2', 'Gene', (37, 41))	('MMP-2', 'molecular_function', 'GO:0004228', ('135', '140'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('98', '103'))
41999	30521479	Finally, we stained immunohistochemically for ATF2, p-ATF2 and p-ERK in the bladder TMAs consisting of 129 urothelial neoplasms and corresponding 85-86 non-neoplastic bladder tissues.	('neoplasms', 'Phenotype', 'HP:0002664', (118, 127))	('ERK', 'molecular_function', 'GO:0004707', ('65', '68'))	('TMAs', 'Chemical', 'MESH:C071868', (84, 88))	('p-ERK', 'Gene', (63, 68))	('neoplasm', 'Phenotype', 'HP:0002664', (118, 126))	('urothelial neoplasms', 'Disease', (107, 127))	('p-ATF2', 'Var', (52, 58))	('urothelial neoplasms', 'Disease', 'MESH:D014523', (107, 127))	('p-ERK', 'Gene', '9451', (63, 68))	('neoplastic bladder', 'Phenotype', 'HP:0009725', (156, 174))
42003	30521479	The rate of moderate to strong (0/1+ vs 2+/3+) or strong (0/1+/2+ vs 3+) ATF2 expression was significantly higher in high-grade tumors (53 (67%) or 11 (14%)) than in lower grade tumors (22 (44%) or 1 (2%)).	('ATF2', 'Gene', (73, 77))	('expression', 'MPA', (78, 88))	('0/1+/2+ vs 3+', 'Var', (58, 71))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('higher', 'PosReg', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
42004	30521479	Positivity (0 vs 1+/2+/3+) or moderate/strong positivity (0/1+ vs 2+/3+) of ATF2 also tended to be more often seen in muscle-invasive tumors (47 (92%) or 35 (69%)) than in non-muscle-invasive tumors (61 (78%) or 40 (52%)).	('seen', 'Reg', (110, 114))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('ATF2', 'Gene', (76, 80))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (176, 198))	('0/1+ vs 2+/3+', 'Var', (58, 71))	('muscle-invasive tumors', 'Disease', (176, 198))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (118, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('muscle-invasive tumors', 'Disease', (118, 140))
42006	30521479	In tumors, the expression levels of p-ATF2 vs p-ERK were correlated (all cases; CC = 0.449, P < 0.001) (Supplementary Table 5).	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('p-ATF2', 'Var', (36, 42))	('men', 'Species', '9606', (110, 113))	('tumors', 'Disease', (3, 9))	('p-ERK', 'Gene', (46, 51))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('p-ERK', 'Gene', '9451', (46, 51))	('expression levels', 'MPA', (15, 32))	('ERK', 'molecular_function', 'GO:0004707', ('48', '51'))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
42012	30521479	Moreover, as suggested (P = 0.071) in our previous study involving 91 muscle-invasive tumors, AR positivity was significantly (P = 0.013) associated with disease progression in the 51 muscle-invasive tumors (Table 1).	('AR', 'Gene', '367', (94, 96))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('muscle-invasive tumors', 'Disease', (184, 206))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (70, 92))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (184, 206))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('associated with', 'Reg', (138, 153))	('muscle-invasive tumors', 'Disease', (70, 92))	('positivity', 'Var', (97, 107))	('disease progression', 'CPA', (154, 173))
42014	30521479	In muscle-invasive tumors, p-ATF2 positivity was strongly associated with a lower CSS rate (HR = 5.317, P = 0.012).	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (3, 25))	('CSS rate', 'CPA', (82, 90))	('positivity', 'Var', (34, 44))	('muscle-invasive tumors', 'Disease', (3, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('lower', 'NegReg', (76, 81))	('CSS', 'Chemical', '-', (82, 85))	('p-ATF2', 'Protein', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
42015	30521479	p-ERK positivity also showed a trend toward significance for disease progression (HR = 2.727, P = 0.066).	('p-ERK', 'Gene', (0, 5))	('ERK', 'molecular_function', 'GO:0004707', ('2', '5'))	('positivity', 'Var', (6, 16))	('disease progression', 'CPA', (61, 80))	('p-ERK', 'Gene', '9451', (0, 5))
42016	30521479	Additionally, in 50 cases of low grade tumors, moderate/strong expression of ATF2 was strongly associated with the risk of tumor recurrence in both univariate (P = 0.034) and multivariate (HR = 2.956, P = 0.045) settings.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('moderate/strong expression', 'Var', (47, 73))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('ATF2', 'Gene', (77, 81))	('tumor', 'Disease', (39, 44))	('associated', 'Reg', (95, 105))	('tumors', 'Disease', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
42025	30521479	We here demonstrated that ATF2 knockdown significantly reduced cell proliferation by modulating apoptosis and cell cycle, as well as cell migration/invasion and the growth of inoculated xenografts in mice, of bladder cancer lines possessing a functional AR.	('bladder cancer', 'Phenotype', 'HP:0009725', (209, 223))	('knockdown', 'Var', (31, 40))	('cell cycle', 'biological_process', 'GO:0007049', ('110', '120'))	('cell migration/invasion', 'CPA', (133, 156))	('ATF2', 'Gene', (26, 30))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))	('cell migration', 'biological_process', 'GO:0016477', ('133', '147'))	('reduced', 'NegReg', (55, 62))	('cell cycle', 'CPA', (110, 120))	('cell proliferation', 'CPA', (63, 81))	('mice', 'Species', '10090', (200, 204))	('AR', 'Gene', '367', (254, 256))	('growth', 'CPA', (165, 171))	('modulating', 'Reg', (85, 95))	('bladder cancer', 'Disease', 'MESH:D001749', (209, 223))	('bladder cancer', 'Disease', (209, 223))	('apoptosis', 'CPA', (96, 105))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
42029	30521479	Additionally, in SVHUC normal urothelial cells, treatment with arsenic, a bladder carcinogen, induced the expression of ATF2 and p-ATF2, which was inhibited by JNK or p38 inhibitors.	('JNK', 'molecular_function', 'GO:0004705', ('160', '163'))	('p38', 'Gene', '5594', (167, 170))	('p-ATF2', 'Var', (129, 135))	('expression', 'MPA', (106, 116))	('arsenic', 'Chemical', 'MESH:D001151', (63, 70))	('men', 'Species', '9606', (53, 56))	('ATF2', 'Gene', (120, 124))	('p38', 'Gene', (167, 170))
42031	30521479	In SVHUC-AR cells with carcinogen challenge, ATF2 knockdown resulted in significant decreases in the expression levels of oncogenic molecules.	('AR', 'Gene', '367', (9, 11))	('knockdown', 'Var', (50, 59))	('expression levels of oncogenic molecules', 'MPA', (101, 141))	('decreases', 'NegReg', (84, 93))	('ATF2', 'Gene', (45, 49))
42037	30521479	Several immunohistochemical studies have determined the expression levels of ATF2, p-ATF2 and/or p-ERK in human tumor specimens.	('human', 'Species', '9606', (106, 111))	('p-ERK', 'Gene', '9451', (97, 102))	('p-ATF2', 'Var', (83, 89))	('ERK', 'molecular_function', 'GO:0004707', ('99', '102'))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('p-ERK', 'Gene', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('ATF2', 'Gene', (77, 81))	('tumor', 'Disease', (112, 117))	('men', 'Species', '9606', (123, 126))
42038	30521479	In particular, ATF2 and/or p-ATF2 were found to be significantly elevated in pancreatic cancer, prostate cancer and spindle cell carcinoma of the skin, compared with respective normal/benign controls.	('ATF2', 'Var', (15, 19))	('prostate cancer', 'Disease', 'MESH:D011471', (96, 111))	('carcinoma of the skin', 'Disease', (129, 150))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('carcinoma of the skin', 'Disease', 'MESH:D012878', (129, 150))	('spindle', 'cellular_component', 'GO:0005819', ('116', '123'))	('p-ATF2', 'Var', (27, 33))	('spindle cell carcinoma', 'Disease', (116, 138))	('prostate cancer', 'Disease', (96, 111))	('elevated', 'PosReg', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('pancreatic cancer', 'Disease', (77, 94))	('spindle cell carcinoma', 'Disease', 'MESH:D002277', (116, 138))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
42040	30521479	Using IHC in our bladder TMAs, we found significant increases in the expression levels of ATF2, p-ATF2 and p-ERK in bladder cancers, compared with corresponding non-neoplastic urothelial tissues.	('p-ERK', 'Gene', '9451', (107, 112))	('expression levels', 'MPA', (69, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (116, 130))	('ATF2', 'Gene', (90, 94))	('increases', 'PosReg', (52, 61))	('p-ERK', 'Gene', (107, 112))	('bladder cancers', 'Disease', 'MESH:D001749', (116, 131))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('bladder cancers', 'Disease', (116, 131))	('TMAs', 'Chemical', 'MESH:C071868', (25, 29))	('p-ATF2', 'Var', (96, 102))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('ERK', 'molecular_function', 'GO:0004707', ('109', '112'))	('bladder cancers', 'Phenotype', 'HP:0009725', (116, 131))
42042	30521479	Prognostic analysis of the expression of these proteins further revealed that overexpression of ATF2, p-ATF2 and p-ERK was an independent predictor of recurrence of low grade tumors, cancer-specific mortality of muscle-invasive tumors and disease progression of muscle-invasive tumors, respectively.	('tumors', 'Disease', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumors', 'Disease', (278, 284))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (262, 284))	('muscle-invasive tumors', 'Disease', (262, 284))	('overexpression', 'PosReg', (78, 92))	('p-ATF2', 'Var', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('p-ERK', 'Gene', '9451', (113, 118))	('ATF2', 'Gene', (96, 100))	('p-ERK', 'Gene', (113, 118))	('ERK', 'molecular_function', 'GO:0004707', ('115', '118'))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Disease', (183, 189))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', (228, 234))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (212, 234))	('muscle-invasive tumors', 'Disease', (212, 234))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('low', 'Disease', (165, 168))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
42044	30521479	Meanwhile, there were significant positive correlations between the expression levels of p-ATF2 and p-ERK, ATF2 and AR (high-grade non-muscle-invasive tumors only) and p-ATF2 and AR.	('p-ERK', 'Gene', '9451', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('p-ERK', 'Gene', (100, 105))	('expression', 'MPA', (68, 78))	('ATF2', 'Gene', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('AR', 'Gene', '367', (116, 118))	('p-ATF2', 'Var', (89, 95))	('ERK', 'molecular_function', 'GO:0004707', ('102', '105'))	('p-ATF2', 'Var', (168, 174))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (135, 157))	('muscle-invasive tumors', 'Disease', (135, 157))	('AR', 'Gene', '367', (179, 181))
42120	29333514	Deactivation of the device prior to instrumentation and use of small caliber instruments appears to mitigate the risk of traumatic urethral erosion.	('mitigate', 'NegReg', (100, 108))	('men', 'Species', '9606', (42, 45))	('Deactivation', 'Var', (0, 12))	('men', 'Species', '9606', (83, 86))	('traumatic urethral erosion', 'Disease', 'MESH:D014526', (121, 147))	('traumatic urethral erosion', 'Disease', (121, 147))
42131	25596753	The pre-miR-9 could up-regulate the miR-9 expression and down-regulate CBX7 protein expression.	('up-regulate', 'PosReg', (20, 31))	('expression', 'MPA', (42, 52))	('CBX7', 'Gene', (71, 75))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('miR-9', 'Gene', (36, 41))	('CBX7', 'Gene', '23492', (71, 75))	('pre-miR-9', 'Var', (4, 13))	('pre', 'molecular_function', 'GO:0003904', ('4', '7'))	('down-regulate', 'NegReg', (57, 70))
42132	25596753	The luciferase activities assay verified that CBX7 gene was a direct and specific target gene of miR-9.	('CBX7', 'Gene', '23492', (46, 50))	('miR-9', 'Var', (97, 102))	('CBX7', 'Gene', (46, 50))
42134	25596753	Aberrantly expressed miR-9 contributes to T24 cells invasion, partly through directly down-regulating CBX7 protein expression in TCC.	('Aberrantly expressed', 'Var', (0, 20))	('T24 cells invasion', 'CPA', (42, 60))	('contributes', 'Reg', (27, 38))	('CBX7', 'Gene', (102, 106))	('TCC', 'Phenotype', 'HP:0006740', (129, 132))	('TCC', 'cellular_component', 'GO:0005579', ('129', '132'))	('expression', 'MPA', (115, 125))	('miR-9', 'Gene', (21, 26))	('CBX7', 'Gene', '23492', (102, 106))	('down-regulating', 'NegReg', (86, 101))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
42146	25596753	Our previous microarray assays found that miR-9 had higher expression in TCC samples than in controls, suggesting that miR-9 might be an oncogene in tumorigenesis of bladder carcinoma.	('TCC', 'Disease', (73, 76))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (166, 183))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('miR-9', 'Var', (119, 124))	('bladder carcinoma', 'Disease', 'MESH:D001749', (166, 183))	('expression', 'MPA', (59, 69))	('tumor', 'Disease', (149, 154))	('higher', 'PosReg', (52, 58))	('bladder carcinoma', 'Disease', (166, 183))	('TCC', 'cellular_component', 'GO:0005579', ('73', '76'))	('TCC', 'Phenotype', 'HP:0006740', (73, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('miR-9', 'Gene', (42, 47))
42178	25596753	These results verified that miR-9 could inhibit the expression of CBX7 at the post-translational level.	('inhibit', 'NegReg', (40, 47))	('CBX7', 'Gene', '23492', (66, 70))	('expression', 'MPA', (52, 62))	('miR-9', 'Var', (28, 33))	('CBX7', 'Gene', (66, 70))
42183	25596753	The expression of target genes related to various tumor cellular activities, such as apoptosis, invasion, and malignant proliferation, are inhibited by miRNAs.	('miRNAs', 'Var', (152, 158))	('malignant proliferation', 'CPA', (110, 133))	('expression', 'MPA', (4, 14))	('apoptosis', 'CPA', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('invasion', 'CPA', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('tumor', 'Disease', (50, 55))	('inhibited', 'NegReg', (139, 148))
42187	25596753	Aberrant miRNA expression can regulate critical biological processes, including cell proliferation and invasion, which may promote TCC development and lead to poor prognosis.	('men', 'Species', '9606', (142, 145))	('Aberrant', 'Var', (0, 8))	('TCC', 'Disease', (131, 134))	('promote', 'PosReg', (123, 130))	('TCC', 'cellular_component', 'GO:0005579', ('131', '134'))	('regulate', 'Reg', (30, 38))	('cell proliferation', 'CPA', (80, 98))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('miRNA expression', 'Protein', (9, 25))	('invasion', 'CPA', (103, 111))	('TCC', 'Phenotype', 'HP:0006740', (131, 134))
42192	25596753	Moreover, further studies have shown that the correlation of the loss of CBX7 with a highly malignant phenotype and a consequent poor prognosis is a general event in oncology.	('oncology', 'Phenotype', 'HP:0002664', (166, 174))	('CBX7', 'Gene', (73, 77))	('CBX7', 'Gene', '23492', (73, 77))	('loss', 'Var', (65, 69))
42199	25596753	Secondly, the nonsense point mutations at seed zone of 3'UTR of CBX7 could be restored by the inhibitive effect of miR-9 enhancement.	('CBX7', 'Gene', (64, 68))	('nonsense point mutations', 'Var', (14, 38))	('men', 'Species', '9606', (128, 131))	('CBX7', 'Gene', '23492', (64, 68))
42203	25596753	All these results indicate the following: miR-9 functions as an endogenous siRNA for CBX7 in TCC, up-regulation of miR-9 in TCC could inhibit the expression of CBX7, and low-expression of CBX7 lost its inhibitive effects on invasion.	('CBX7', 'Gene', (160, 164))	('miR-9', 'Gene', (115, 120))	('CBX7', 'Gene', '23492', (188, 192))	('TCC', 'cellular_component', 'GO:0005579', ('124', '127'))	('inhibit', 'NegReg', (134, 141))	('CBX7', 'Gene', (188, 192))	('CBX7', 'Gene', '23492', (160, 164))	('low-expression', 'Var', (170, 184))	('TCC', 'Phenotype', 'HP:0006740', (93, 96))	('up-regulation', 'PosReg', (98, 111))	('invasion', 'CPA', (224, 232))	('CBX7', 'Gene', (85, 89))	('regulation', 'biological_process', 'GO:0065007', ('101', '111'))	('CBX7', 'Gene', '23492', (85, 89))	('expression', 'MPA', (146, 156))	('TCC', 'Phenotype', 'HP:0006740', (124, 127))	('TCC', 'cellular_component', 'GO:0005579', ('93', '96'))
42255	24575145	CK20 positivity was most frequently observed in the cytoplasm of normal superficial cells identified as medium to large sized urothelial cells with rounded luminal surfaces, scalloped borders, abundant cytoplasm and often multiple nuclei.	('observed', 'Reg', (36, 44))	('positivity', 'Var', (5, 15))	('CK20', 'Gene', (0, 4))	('cytoplasm', 'cellular_component', 'GO:0005737', ('202', '211'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('52', '61'))	('CK20', 'Gene', '54474', (0, 4))
42315	24575145	Our data is comparable and shows CK20 positivity in 33/42 cases (79%) of carcinoma and negativity in 9/42 cases (21%) [Table 1] yielding specificity of 80%.	('positivity', 'Var', (38, 48))	('carcinoma', 'Disease', (73, 82))	('CK20', 'Gene', (33, 37))	('CK20', 'Gene', '54474', (33, 37))	('carcinoma', 'Disease', 'MESH:D002277', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
42317	24575145	Nuclear overexpression by immunohistochemistry has been shown to correlate with p53 mutations, which are a common event in urothelial carcinomas.	('p53', 'Gene', (80, 83))	('urothelial carcinomas', 'Disease', (123, 144))	('mutations', 'Var', (84, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('p53', 'Gene', '7157', (80, 83))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (123, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))
42321	24575145	Our results with p53 immunostaining alone show positivity in 28/42 (67%) of carcinoma cases and negativity in 14/42 (33%) [Table 1] resulting in a sensitivity of 67% and specificity of 85%.	('carcinoma', 'Disease', 'MESH:D002277', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Disease', (76, 85))	('p53', 'Gene', (17, 20))	('positivity', 'Var', (47, 57))	('p53', 'Gene', '7157', (17, 20))
42369	33047430	6   Dysregulation of the programmed cell death protein-1/programmed death ligand 1 (PD-1/PD-L1) axis can allow cancer cells to evade the immune system 7 ,  8  and PD-L1 overexpression by tumors is associated with poor outcomes for patients with melanoma, ovarian cancer, and lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('cancer', 'Disease', (263, 269))	('cancer', 'Disease', (280, 286))	('programmed death ligand 1', 'Gene', (57, 82))	('programmed death ligand 1', 'Gene', '574058', (57, 82))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('cancer', 'Disease', (111, 117))	('ligand', 'molecular_function', 'GO:0005488', ('74', '80'))	('programmed cell death protein-1', 'Gene', (25, 56))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('overexpression', 'PosReg', (169, 183))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('Dysregulation', 'Var', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('lung cancers', 'Disease', 'MESH:D008175', (275, 287))	('tumors', 'Disease', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('PD-L1', 'Gene', (163, 168))	('programmed cell death protein-1', 'Gene', '100533201', (25, 56))	('melanoma, ovarian cancer', 'Disease', 'MESH:D008545', (245, 269))	('patients', 'Species', '9606', (231, 239))	('lung cancers', 'Disease', (275, 287))	('ovarian cancer', 'Phenotype', 'HP:0100615', (255, 269))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('programmed cell death', 'biological_process', 'GO:0012501', ('25', '46'))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('lung cancers', 'Phenotype', 'HP:0100526', (275, 287))
42377	33047430	17 ,  18 ,  19 ,  20  In the global, phase 1A/1B first-in-human study (BGB-A317-001; NCT02407990), tislelizumab treatment across multiple tumor types resulted in an ORR of 13%.	('human', 'Species', '9606', (58, 63))	('tumor', 'Disease', (138, 143))	('tislelizumab', 'Var', (99, 111))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
42380	33047430	21  Similar results were observed in an open-label phase 1/2 study conducted in China (BGB-A317-102; NCT04068519), which found that treatment with tislelizumab resulted in an ORR of 18% across all tumor types.	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tislelizumab', 'Var', (147, 159))
42453	33171596	In 2017, pembrolizumab, an anti-PD-1 antibody, was granted the first agnostic indication by the U.S.A's FDA for patients with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors.	('mismatch repair', 'biological_process', 'GO:0006298', ('179', '194'))	('pembrolizumab', 'Chemical', 'MESH:C582435', (9, 22))	('antibody', 'cellular_component', 'GO:0019815', ('37', '45'))	('MSI-H', 'Chemical', '-', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('patients', 'Species', '9606', (112, 120))	('antibody', 'cellular_component', 'GO:0019814', ('37', '45'))	('antibody', 'molecular_function', 'GO:0003823', ('37', '45'))	('tumors', 'Disease', (208, 214))	('deficient mismatch', 'Var', (169, 187))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('microsatellite instability-high', 'Var', (126, 157))	('antibody', 'cellular_component', 'GO:0042571', ('37', '45'))
42462	33171596	CIN involves intratumor heterogenicity, cancer evaluation, host immunity, and gene mutation, which can be immunogenic, as well as increased immune evasion.	('immune evasion', 'biological_process', 'GO:0042783', ('140', '154'))	('gene mutation', 'Var', (78, 91))	('immune evasion', 'MPA', (140, 154))	('tumor', 'Disease', (18, 23))	('CIN', 'Disease', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('immune evasion', 'biological_process', 'GO:0051842', ('140', '154'))	('cancer', 'Disease', (40, 46))	('CIN', 'Disease', 'MESH:D007674', (0, 3))	('increased', 'PosReg', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('CIN', 'Phenotype', 'HP:0040012', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
42476	33171596	TMB-H and a high CIN70 were associated with a poor progression-free survival (PFS) and overall survival (OS); in contrast, MSI-H was marginally associated with a favorable PFS, but not OS (Figure 2D-I).	('poor', 'NegReg', (46, 50))	('high', 'Var', (12, 16))	('overall survival', 'CPA', (87, 103))	('progression-free survival', 'CPA', (51, 76))	('CIN', 'Disease', (17, 20))	('CIN', 'Disease', 'MESH:D007674', (17, 20))	('TMB-H', 'Chemical', '-', (0, 5))	('CIN', 'Phenotype', 'HP:0040012', (17, 20))	('MSI-H', 'Chemical', '-', (123, 128))
42481	33171596	Among the 25 cancer types with MSI-H samples, the CIN70 scores were significantly higher in the MSI-H group than non-MSI-H group within only three cancer types (breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), and stomach adenocarcinoma (STAD); Figure 3, Supplementary Figure S2).	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('MSI-H', 'Chemical', '-', (117, 122))	('MSI-H', 'Chemical', '-', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('CIN', 'Disease', 'MESH:D007674', (50, 53))	('MSI-H', 'Var', (96, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (228, 250))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (161, 186))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (195, 215))	('stomach adenocarcinoma', 'Disease', (228, 250))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('CIN', 'Disease', (50, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('cancer', 'Disease', (13, 19))	('colon adenocarcinoma', 'Disease', (195, 215))	('breast invasive carcinoma', 'Disease', (161, 186))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('MSI-H', 'Chemical', '-', (96, 101))	('higher', 'PosReg', (82, 88))	('CIN', 'Phenotype', 'HP:0040012', (50, 53))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (161, 186))	('cancer', 'Disease', (147, 153))
42483	33171596	Regarding PFS, TMB is significantly associated with a PFS difference in 9 out of 32 cancer types (Figure 3, Supplementary Figure S4; Supplementary Table S1).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('PFS difference', 'Var', (54, 68))	('cancer', 'Disease', (84, 90))	('TMB', 'Disease', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TMB', 'Chemical', '-', (15, 18))	('associated', 'Reg', (36, 46))	('difference', 'Var', (58, 68))
42484	33171596	In most cancer types, patients with TMB-H had a significantly shorter PFS than patients without TMB-H, indicating TMB-H is an unfavorable prognostic factor in such cancers.	('TMB-H', 'Chemical', '-', (96, 101))	('shorter', 'NegReg', (62, 69))	('cancer', 'Disease', (8, 14))	('TMB-H', 'Chemical', '-', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('patients', 'Species', '9606', (22, 30))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancers', 'Disease', (164, 171))	('cancer', 'Disease', (164, 170))	('PFS', 'MPA', (70, 73))	('TMB-H', 'Chemical', '-', (36, 41))	('patients', 'Species', '9606', (79, 87))	('TMB-H', 'Var', (36, 41))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
42485	33171596	However, patients with TMB-H had a significantly longer PFS than the patients without TMB-H in three cancer types (bladder urothelial carcinoma (BLCA), STAD, and uterine corpus endometrial carcinoma (UCEC); Supplementary Figure S4).	('patients', 'Species', '9606', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (177, 198))	('cancer', 'Disease', (101, 107))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (115, 143))	('TMB-H', 'Chemical', '-', (23, 28))	('bladder urothelial carcinoma', 'Disease', (115, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (177, 198))	('TMB-H', 'Var', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('longer', 'PosReg', (49, 55))	('PFS', 'MPA', (56, 59))	('patients', 'Species', '9606', (69, 77))	('endometrial carcinoma', 'Disease', (177, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('TMB-H', 'Chemical', '-', (86, 91))
42488	33171596	Using the median of CIN70, we performed the survival analysis, comparing the high CIN70 and low CIN70 patients in each cancer type.	('CIN', 'Disease', (82, 85))	('high', 'Var', (77, 81))	('CIN', 'Disease', (20, 23))	('patients', 'Species', '9606', (102, 110))	('CIN', 'Disease', (96, 99))	('CIN', 'Disease', 'MESH:D007674', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', (119, 125))	('CIN', 'Disease', 'MESH:D007674', (20, 23))	('CIN', 'Disease', 'MESH:D007674', (96, 99))	('CIN', 'Phenotype', 'HP:0040012', (20, 23))	('CIN', 'Phenotype', 'HP:0040012', (82, 85))	('CIN', 'Phenotype', 'HP:0040012', (96, 99))
42492	33171596	Specifically, the patients with TMB-H had a shorter OS than those without TMB-H in six cancers.	('cancers', 'Disease', (87, 94))	('TMB-H', 'Chemical', '-', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('TMB-H', 'Chemical', '-', (32, 37))	('TMB-H', 'Var', (32, 37))	('patients', 'Species', '9606', (18, 26))	('shorter', 'NegReg', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
42493	33171596	On the other hand, patients with TMB-H had a longer OS than those without TMB-H in four cancers (BLCA, ovarian serous cystadenocarcinoma (OV), skin cutaneous melanoma (SKCM), and testicular germ cell tumors (TGCT); Supplementary Figure S7).	('TMB-H', 'Chemical', '-', (33, 38))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (103, 136))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (143, 166))	('skin cutaneous melanoma', 'Disease', (143, 166))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('germ cell tumors', 'Phenotype', 'HP:0100728', (190, 206))	('ovarian serous cystadenocarcinoma', 'Disease', (103, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('patients', 'Species', '9606', (19, 27))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (103, 136))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (148, 166))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('TMB-H', 'Chemical', '-', (74, 79))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('TMB-H', 'Var', (33, 38))	('tumors', 'Disease', (200, 206))
42494	33171596	In 25 cancer types with MSI-H samples, MSI status was significantly associated with OS in three cancer types (Figure 3, Supplementary Figure S8; Supplementary Table S2).	('MSI status', 'Var', (39, 49))	('MSI-H', 'Chemical', '-', (24, 29))	('associated with', 'Reg', (68, 83))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (6, 12))	('cancer', 'Disease', (96, 102))
42496	33171596	However, MSI-H patients had a longer OS than the non-MSI-H patients in UCEC (Supplementary Figure S8).	('patients', 'Species', '9606', (15, 23))	('UCEC', 'Disease', (71, 75))	('MSI-H', 'Chemical', '-', (9, 14))	('MSI-H', 'Chemical', '-', (53, 58))	('MSI-H', 'Var', (9, 14))	('patients', 'Species', '9606', (59, 67))
42499	33171596	However, unlike the prognostic value of CIN70, PFS showing CIN70 is a universally poor prognostic factor, and patients with a high CIN70 had a favorable OS in two cancer types (cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and THYM; Supplementary Figure S9).	('CIN', 'Disease', 'MESH:D007674', (131, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('THYM', 'Disease', (253, 257))	('CIN', 'Phenotype', 'HP:0040012', (40, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('CIN', 'Disease', 'MESH:D007674', (40, 43))	('CIN', 'Disease', (59, 62))	('high', 'Var', (126, 130))	('CIN', 'Disease', (131, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (186, 209))	('cancer', 'Disease', (163, 169))	('CIN', 'Disease', (40, 43))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (177, 241))	('CIN', 'Phenotype', 'HP:0040012', (59, 62))	('CIN', 'Phenotype', 'HP:0040012', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('CIN', 'Disease', 'MESH:D007674', (59, 62))	('patients', 'Species', '9606', (110, 118))
42508	33171596	Multiple genetic alterations contribute to CIN, such as genes involving DNA damage and repair, mitotic checkpoint, chromosome condensation and segregation from mutational inactivation of STAG2, and possibly sister chromatid cohesion (hSecurin).	('contribute', 'Reg', (29, 39))	('mitotic checkpoint', 'CPA', (95, 113))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('207', '232'))	('CIN', 'Disease', 'MESH:D007674', (43, 46))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('chromatid', 'cellular_component', 'GO:0005694', ('214', '223'))	('chromatid', 'cellular_component', 'GO:0005695', ('214', '223'))	('segregation', 'CPA', (143, 154))	('CIN', 'Disease', (43, 46))	('mutational inactivation', 'Var', (160, 183))	('hSecurin', 'Gene', '9232', (234, 242))	('chromosome', 'cellular_component', 'GO:0005694', ('115', '125'))	('STAG2', 'Gene', '10735', (187, 192))	('mitotic checkpoint', 'biological_process', 'GO:0007093', ('95', '113'))	('chromosome condensation', 'CPA', (115, 138))	('chromosome condensation', 'biological_process', 'GO:0030261', ('115', '138'))	('STAG2', 'Gene', (187, 192))	('CIN', 'Phenotype', 'HP:0040012', (43, 46))	('hSecurin', 'Gene', (234, 242))
42540	33171596	Therefore, TMB was determined by counting the number of mutations in the TCGA MC3 data.	('TMB', 'Chemical', '-', (11, 14))	('mutations', 'Var', (56, 65))	('TCGA MC3', 'Gene', (73, 81))
42547	33171596	), the Ministry of Science and Technology (105-2314-B-182A-041-MY2 and 107-2314-B-182A-134-MY3 to C.-N.Y., 106-2221-E-010-019-MY3 and 109-2221-E-010-013-MY3 to Y.-C.W., 109-2314-B-182A-148 -MY3 to C.-E.W., and 104-2314-B-075-064-MY2 to M.-H.C.), and the Taipei Veterans General Hospital (V109C-028 to M.-H.C.).	('104-2314-B-075-064-MY2 to', 'Var', (210, 235))	('V109C-028', 'Var', (288, 297))	('V109C', 'Mutation', 'p.V109C', (288, 293))	('109-2314-B-182A-148 -MY3', 'Var', (169, 193))
42591	31791304	Pazopanib had less ORR events compared to ramucirumab plus docetaxel (ln OR: -1.97; 95% CI: - 3.40, - 0.54) and vinflunine (ln OR: -2.27; 95% CI: - 4.32, - 0.21).	('vinflunine', 'Chemical', 'MESH:C111217', (112, 122))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('ramucirumab', 'Chemical', 'MESH:C543333', (42, 53))	('ORR events', 'MPA', (19, 29))	('less', 'NegReg', (14, 18))	('Pazopanib', 'Var', (0, 9))	('docetaxel', 'Chemical', 'MESH:D000077143', (59, 68))
42625	31791304	However, the IMvigor211 trial showed that in the PD-L1 expression rate in tumor-infiltrating immune cells in more than 5% of the population, atezolizumab did not provide significant benefits in patient survival.	('patient', 'Species', '9606', (194, 201))	('PD-L1', 'Gene', '29126', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('atezolizumab', 'Chemical', 'MESH:C000594389', (141, 153))	('PD-L1', 'Gene', (49, 54))	('expression', 'Var', (55, 65))
42654	31231212	Histamine acts through four different receptor subtypes: H1, H2, H3, and H4 receptors (H1R, H2R, H3R, and H4R).	('H3R', 'Gene', (97, 100))	('H1R', 'Gene', (87, 90))	('Histamine', 'Chemical', 'MESH:D006632', (0, 9))	('H2R', 'Gene', '3274', (92, 95))	('H3R', 'Gene', '11255', (97, 100))	('H4 receptors', 'Protein', (73, 85))	('H4R', 'Var', (106, 109))	('H2R', 'Gene', (92, 95))	('H1R', 'Gene', '3269', (87, 90))
42664	31231212	The discovery of the first selective and potent H4R antagonist JNJ7777120 by Johnson & Johnson Research and Development (now Janssen Pharmaceuticals, Inc.) was essential for evaluating the role of H4R in pathophysiology, including immune reaction-associated pruritus and inflammation.	('pruritus', 'Phenotype', 'HP:0000989', (258, 266))	('inflammation', 'biological_process', 'GO:0006954', ('271', '283'))	('including immune reaction-associated', 'Disease', (221, 257))	('men', 'Species', '9606', (115, 118))	('and', 'Disease', (267, 270))	('pruritus', 'Disease', 'MESH:D011537', (258, 266))	('pruritus', 'Disease', (258, 266))	('inflammation', 'Disease', 'MESH:D007249', (271, 283))	('JNJ7777120', 'Var', (63, 73))	('inflammation', 'Disease', (271, 283))	('JNJ7777120', 'Chemical', 'MESH:C484309', (63, 73))
42667	31231212	Recently, the compound JNJ39758979 was developed as a more potent and selective H4R antagonist than JNJ7777120 and it also shows preclinical anti-inflammatory and antipruritic effects.	('JNJ7777120', 'Chemical', 'MESH:C484309', (100, 110))	('anti-inflammatory', 'CPA', (141, 158))	('antipruritic', 'CPA', (163, 175))	('JNJ39758979', 'Var', (23, 34))	('H4R antagonist', 'Protein', (80, 94))
42671	31231212	JNJ39758979 was also tested in a phase 2a trial in adults with uncontrolled asthma without reaching the primary efficacy endpoint.	('asthma', 'Disease', (76, 82))	('asthma', 'Disease', 'MESH:D001249', (76, 82))	('JNJ39758979', 'Var', (0, 11))	('asthma', 'Phenotype', 'HP:0002099', (76, 82))
42678	31231212	A recent phase 2a clinical trial was carried out with the selective H4R antagonist ZPL-3893787, administered orally in patients with moderate to severe atopic dermatitis.	('patients', 'Species', '9606', (119, 127))	('H4R', 'Protein', (68, 71))	('ZPL-3893787', 'Var', (83, 94))	('dermatitis', 'Phenotype', 'HP:0011123', (159, 169))	('rat', 'Species', '10116', (137, 140))	('atopic dermatitis', 'Disease', 'MESH:D003876', (152, 169))	('atopic dermatitis', 'Phenotype', 'HP:0001047', (152, 169))	('ZPL-3893787', 'Chemical', '-', (83, 94))	('atopic dermatitis', 'Disease', (152, 169))
42696	31231212	Patients with high protein expression of H4R in tumor cells exhibited a larger primary tumor size and a greater number of lymph node metastases than those with lower expression.	('larger', 'PosReg', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (48, 53))	('high protein expression', 'Var', (14, 37))	('H4R', 'Protein', (41, 44))	('tumor', 'Disease', (87, 92))	('Patients', 'Species', '9606', (0, 8))	('metastases', 'Disease', (133, 143))	('greater number of lymph node', 'Phenotype', 'HP:0032536', (104, 132))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('metastases', 'Disease', 'MESH:D009362', (133, 143))
42706	31231212	Furthermore, authors demonstrated that deletion and downregulation of H4R gene take place in the progression but not the initiation of stomach cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('H4R', 'Gene', (70, 73))	('stomach cancer', 'Phenotype', 'HP:0012126', (135, 149))	('initiation of stomach cancer', 'Disease', (121, 149))	('deletion', 'Var', (39, 47))	('downregulation', 'NegReg', (52, 66))	('initiation of stomach cancer', 'Disease', 'MESH:D013274', (121, 149))	('rat', 'Species', '10116', (28, 31))
42715	31231212	On the other hand, a previous study showed that JNJ7777120 inhibited histamine-induced cell growth of human CRC cell lines.	('cell growth', 'biological_process', 'GO:0016049', ('87', '98'))	('histamine', 'Chemical', 'MESH:D006632', (69, 78))	('inhibited', 'NegReg', (59, 68))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('JNJ7777120', 'Var', (48, 58))	('JNJ7777120', 'Chemical', 'MESH:C484309', (48, 58))	('human', 'Species', '9606', (102, 107))
42718	31231212	In addition, it was reported that histidine decarboxylase (HDC) deficiency promoted inflammation-associated CRC.	('HDC', 'Gene', (59, 62))	('histidine decarboxylase', 'Gene', '3067', (34, 57))	('deficiency', 'Var', (64, 74))	('inflammation', 'Disease', 'MESH:D007249', (84, 96))	('promoted', 'PosReg', (75, 83))	('inflammation', 'biological_process', 'GO:0006954', ('84', '96'))	('inflammation', 'Disease', (84, 96))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('HDC', 'Gene', '3067', (59, 62))	('histidine decarboxylase', 'Gene', (34, 57))
42721	31231212	Administration of L. reuteri and not of an isogenic HDC-deficient L. reuteri mutant that was unable to generate histamine, suppressed carcinogenesis, cancer-associated cytokines, and decreased the relative number of splenic CD11b+Gr-1+ immature myeloid cells, which confirmed the potential antitumorigenic effect of histamine.	('carcinogenesis', 'Disease', 'MESH:D063646', (134, 148))	('rat', 'Species', '10116', (8, 11))	('HDC', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('CD11b', 'Gene', '3684', (224, 229))	('CD11b', 'Gene', (224, 229))	('decreased', 'NegReg', (183, 192))	('cancer', 'Disease', (150, 156))	('HDC', 'Gene', '3067', (52, 55))	('histamine', 'Chemical', 'MESH:D006632', (112, 121))	('L. reuteri', 'Species', '1598', (66, 76))	('L. reuteri', 'Gene', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('mutant', 'Var', (77, 83))	('rat', 'Species', '10116', (107, 110))	('tumor', 'Disease', (294, 299))	('L. reuteri', 'Species', '1598', (18, 28))	('suppressed', 'NegReg', (123, 133))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('carcinogenesis', 'Disease', (134, 148))	('histamine', 'Chemical', 'MESH:D006632', (316, 325))	('tumor', 'Disease', 'MESH:D009369', (294, 299))
42736	31231212	To confirm the exclusive participation of the H4R in these processes, studies were performed in cells with genetic knockdown of the H3R and overexpression of H4R.	('overexpression', 'PosReg', (140, 154))	('H3R', 'Gene', '11255', (132, 135))	('H3R', 'Gene', (132, 135))	('knockdown', 'Var', (115, 124))
42747	31231212	It is important to highlight that high expression of H4R in tumor specimens was associated with increased OS in pancreatic cancer (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('H4R', 'Protein', (53, 56))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('high expression', 'Var', (34, 49))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('men', 'Species', '9606', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('pancreatic cancer', 'Disease', (112, 129))	('tumor', 'Disease', (60, 65))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))	('OS', 'Chemical', '-', (106, 108))
42785	31231212	Further supporting the critical role of H4R in breast cancer development and progression, He and coworkers demonstrated the presence of polymorphisms of the H4R gene (rs623590, rs11662595, and rs1421125 genotypes of H4R gene) in Chinese Han population, which were associated with the risk of developing breast cancer and the malignant degree of the tumor.	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('rs11662595', 'Var', (177, 187))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('rs623590', 'Var', (167, 175))	('breast cancer', 'Disease', (47, 60))	('rs11662595', 'Mutation', 'rs11662595', (177, 187))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('H4R', 'Gene', (157, 160))	('rs623590', 'Mutation', 'rs623590', (167, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', (349, 354))	('rat', 'Species', '10116', (114, 117))	('associated', 'Reg', (264, 274))	('rs1421125', 'Mutation', 'rs1421125', (193, 202))	('breast cancer', 'Disease', (303, 316))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('rs1421125', 'Var', (193, 202))	('men', 'Species', '9606', (68, 71))
42787	31231212	All the studies, using different H4R ligands and also genetic down-regulation of H4R, demonstrated that the principal receptor subtype involved in the histamine-induced reduction of proliferation was the H4R.	('proliferation', 'CPA', (182, 195))	('H4R', 'Protein', (81, 84))	('H4R', 'Protein', (204, 207))	('reduction', 'NegReg', (169, 178))	('histamine', 'Chemical', 'MESH:D006632', (151, 160))	('down-regulation', 'NegReg', (62, 77))	('regulation', 'biological_process', 'GO:0065007', ('67', '77'))	('rat', 'Species', '10116', (189, 192))	('genetic', 'Var', (54, 61))	('rat', 'Species', '10116', (93, 96))
42788	31231212	The in vivo administration of histamine or H4R agonists (e.g., JNJ28610244) diminished the tumor growth of human triple negative breast cancer (TNBC) developed in immune-deficient nude mice with MDA-MB-231 cells.	('breast cancer', 'Disease', (129, 142))	('nude mice', 'Species', '10090', (180, 189))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (195, 205))	('histamine', 'Chemical', 'MESH:D006632', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('human', 'Species', '9606', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('JNJ28610244', 'Var', (63, 74))	('rat', 'Species', '10116', (20, 23))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('tumor', 'Disease', (91, 96))	('TNBC', 'Disease', 'None', (144, 148))	('TNBC', 'Disease', (144, 148))	('diminished', 'NegReg', (76, 86))
42789	31231212	On the other hand, tumor doubling time was not significantly modified while mean survival was reduced after the treatment with the H4R antagonist JNJ10191584.	('JNJ10191584', 'Chemical', 'MESH:C506811', (146, 157))	('JNJ10191584', 'Var', (146, 157))	('reduced', 'NegReg', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('men', 'Species', '9606', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('mean survival', 'CPA', (76, 89))
42805	31231212	Furthermore, patients with tumors showing low/medium H4R expression presented a higher OS compared to those with high expression levels (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('H4R', 'Protein', (53, 56))	('low/medium', 'Var', (42, 52))	('patients', 'Species', '9606', (13, 21))	('OS', 'Chemical', '-', (87, 89))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('higher', 'PosReg', (80, 86))
42819	31231212	Likewise, results described in breast cancer, genetic variations of H4R gene were found in a large number of Chinese NSCLC patients.	('NSCLC', 'Disease', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('found', 'Reg', (82, 87))	('genetic variations', 'Var', (46, 64))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('patients', 'Species', '9606', (123, 131))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('H4R', 'Gene', (68, 71))	('breast cancer', 'Disease', (31, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))
42820	31231212	In particular, the loss-of-function polymorphism rs11662595, associated to a higher invasive behavior, was linked to the prognosis, the degree of malignancy, and the metastatic potential of NSCLC.	('rs11662595', 'Mutation', 'rs11662595', (49, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (190, 195))	('invasive behavior', 'CPA', (84, 101))	('higher', 'PosReg', (77, 83))	('metastatic potential', 'CPA', (166, 186))	('malignancy', 'Disease', 'MESH:D009369', (146, 156))	('rs11662595', 'Var', (49, 59))	('NSCLC', 'Disease', (190, 195))	('NSCLC', 'Disease', 'MESH:D002289', (190, 195))	('malignancy', 'Disease', (146, 156))	('loss-of-function', 'NegReg', (19, 35))
42842	31231212	Antagonist JNJ7777120, as mentioned before, shows high selectivity for the human, mouse and rat H4R.	('JNJ7777120', 'Chemical', 'MESH:C484309', (11, 21))	('rat', 'Species', '10116', (92, 95))	('JNJ7777120', 'Var', (11, 21))	('H4R', 'Protein', (96, 99))	('men', 'Species', '9606', (26, 29))	('human', 'Species', '9606', (75, 80))	('mouse', 'Species', '10090', (82, 87))
42849	31231212	Human H4R isoforms are the result of alternative splicing.	('alternative splicing', 'Var', (37, 57))	('Human H4R', 'Protein', (0, 9))	('splicing', 'biological_process', 'GO:0045292', ('49', '57'))	('Human', 'Species', '9606', (0, 5))
42852	31231212	Some polymorphisms of H4R have been reported in cancer, which were associated to malignancy of the disease in a Chinese Han population.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('H4R', 'Gene', (22, 25))	('reported', 'Reg', (36, 44))	('cancer', 'Disease', (48, 54))	('associated', 'Reg', (67, 77))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('malignancy of the disease', 'Disease', 'MESH:D009369', (81, 106))	('malignancy of the disease', 'Disease', (81, 106))	('polymorphisms', 'Var', (5, 18))
42854	31231212	In addition, the study of the alteration frequency of H4R gene in the main cancer types, with available data from cBioPortal, indicated that H4R gene alterations occurred in different percentage depending on cancer type.	('cancer', 'Disease', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('H4R gene', 'Gene', (141, 149))	('rat', 'Species', '10116', (154, 157))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('alterations', 'Var', (150, 161))	('rat', 'Species', '10116', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
42855	31231212	Amplifications and mutations comprised the major types of H4R gene alterations (Figure 3).	('Amplifications', 'Var', (0, 14))	('H4R', 'Gene', (58, 61))	('mutations', 'Var', (19, 28))	('rat', 'Species', '10116', (71, 74))
42868	31231212	In this context, H4R gene alterations (e.g., mutation, deletions, and amplifications) in different cancer types should be studied.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('rat', 'Species', '10116', (30, 33))	('cancer', 'Disease', (99, 105))	('H4R', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('deletions', 'Var', (55, 64))
42880	31231212	H4R ligands exhibit a complex pharmacology, which is related to numerous factors including tissue variability in histamine-induced signaling pathways, functional selectivity, intra and interspecies differences in potency and selectivity, structural homology with H3R, splice variant isoforms, and polymorphisms that could preclude H4R function, together with impairment expression in pathological conditions.	('histamine', 'Chemical', 'MESH:D006632', (113, 122))	('polymorphisms', 'Var', (297, 310))	('men', 'Species', '9606', (365, 368))	('H3R', 'Gene', (263, 266))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('H3R', 'Gene', '11255', (263, 266))
42976	29541392	The genes are upregulated in glioblastoma relative to normal brain and lower grade glioma samples; they are also hypo-methylated in glioblastoma relative to lower grade glioma tumors.	('glioma', 'Disease', (83, 89))	('glioblastoma', 'Disease', 'MESH:D005909', (29, 41))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('glioma', 'Disease', (169, 175))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('glioma tumors', 'Disease', (169, 182))	('hypo-methylated', 'Var', (113, 128))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('glioma tumors', 'Disease', 'MESH:D005910', (169, 182))	('upregulated', 'PosReg', (14, 25))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('glioblastoma', 'Disease', (132, 144))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('glioblastoma', 'Disease', (29, 41))
42978	29541392	Furthermore, high expression of these genes is associated with decreased survival across each glioblastoma subtype.	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('glioblastoma subtype', 'Disease', 'MESH:D005909', (94, 114))	('high', 'Var', (13, 17))	('decreased', 'NegReg', (63, 72))	('glioblastoma subtype', 'Disease', (94, 114))
42984	29541392	There are known monogenic GBM biomarkers that include mutations in the IDH1 and PDGFRalpha loci.	('PDGFRalpha', 'Gene', '5156', (80, 90))	('mutations', 'Var', (54, 63))	('IDH1', 'Gene', (71, 75))	('PDGFRalpha', 'Gene', (80, 90))	('IDH1', 'Gene', '3417', (71, 75))
43030	29541392	The mutual exclusivity of PIK3R1 mutations in GBM is of particular interest; PIK3R1 knockdown decreases invasion, proliferation, and migration in GBM.	('knockdown', 'Var', (84, 93))	('mutations', 'Var', (33, 42))	('decreases', 'NegReg', (94, 103))	('migration', 'CPA', (133, 142))	('PIK3R1', 'Gene', '5295', (26, 32))	('invasion', 'CPA', (104, 112))	('PIK3R1', 'Gene', '5295', (77, 83))	('PIK3R1', 'Gene', (26, 32))	('PIK3R1', 'Gene', (77, 83))
43031	29541392	IDH1 mutations were neither mutually exclusive nor co-occurring with alterations in the 22 shared genes.	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', '3417', (0, 4))
43032	29541392	This is consistent with Figure 7; the proneural GBM subtype, which exhibits low expression for these 22 genes, is often defined by IDH1 or PDGFRA mutation.	('IDH1', 'Gene', (131, 135))	('IDH1', 'Gene', '3417', (131, 135))	('PDGFRA', 'Gene', '5156', (139, 145))	('PDGFRA', 'Gene', (139, 145))	('mutation', 'Var', (146, 154))
43050	29541392	Transcript counts were indexed as 209086 Ensembl hg38 transcript IDs resulted in a 209086 x 204 GEM.	('GEM', 'Gene', (96, 99))	('hg38', 'Gene', (49, 53))	('209086', 'Var', (83, 89))	('hg38', 'Gene', '8549', (49, 53))	('GEM', 'Gene', '2669', (96, 99))
43055	29541392	The KS test (DN > 0.15) removed 211 datasets, resulting in a 209086 x 1793 GEM.	('GEM', 'Gene', (75, 78))	('209086 x 1793', 'Var', (61, 74))	('GEM', 'Gene', '2669', (75, 78))	('KS', 'Chemical', '-', (4, 6))
43056	29541392	From this 209086 x 1793 preprocessed GEM, 49 transcripts mapped to the genes present in Module 0214 identified in the TCGA Network.	('209086', 'Var', (10, 16))	('GEM', 'Gene', (37, 40))	('GEM', 'Gene', '2669', (37, 40))
43161	27498249	Compared to normal kidneys, kidneys with fusion anomalies have a higher risk of developing nephroblastomas, and the risk of developing urothelial carcinoma is 3-4 times higher, possibly due to embryopathogenic mechanisms or urinary stasis.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('anomalies', 'Var', (48, 57))	('nephroblastoma', 'Phenotype', 'HP:0002667', (91, 105))	('urothelial carcinoma', 'Disease', (135, 155))	('nephroblastomas', 'Disease', 'MESH:D009396', (91, 106))	('kidneys with fusion', 'Phenotype', 'HP:0004736', (28, 47))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (135, 155))	('nephroblastomas', 'Disease', (91, 106))	('nephroblastomas', 'Phenotype', 'HP:0002667', (91, 106))
43194	27498249	In a previous report from our institution, partial nephrectomy for kidneys without an anomaly was associated with a median estimated blood loss of 350 mL and low overall and major complication rates of 19% and 4%, respectively.	('partial nephrectomy', 'Var', (43, 62))	('blood loss', 'Disease', 'MESH:D006473', (133, 143))	('anomaly', 'Disease', 'MESH:D000014', (86, 93))	('blood loss', 'Disease', (133, 143))	('anomaly', 'Disease', (86, 93))
43266	33834191	Higher RBP4 expression was associated with better overall survival time in HCC patients, and we identified a deletion-mutation rate of 1.4% in RBP4.	('deletion-mutation', 'Var', (109, 126))	('RBP4', 'Gene', (143, 147))	('RBP4', 'Gene', '5950', (143, 147))	('HCC', 'Gene', '619501', (75, 78))	('RBP4', 'Gene', '5950', (7, 11))	('RBP4', 'Gene', (7, 11))	('patients', 'Species', '9606', (79, 87))	('expression', 'MPA', (12, 22))	('HCC', 'Gene', (75, 78))
43288	33834191	Studies have indicated that high serum RBP4 in HCC combined with metabolic syndrome patients were closely associated with poor prognosis.	('RBP4', 'Gene', '5950', (39, 43))	('HCC', 'Gene', (47, 50))	('metabolic syndrome', 'Disease', (65, 83))	('associated', 'Reg', (106, 116))	('patients', 'Species', '9606', (84, 92))	('HCC', 'Gene', '619501', (47, 50))	('metabolic syndrome', 'Disease', 'MESH:D024821', (65, 83))	('high', 'Var', (28, 32))	('RBP4', 'Gene', (39, 43))
43300	33834191	The online CBioPortal site (https://www.cbioportal.org/) and LinkedOmics were used to access data for RBP4 gene mutations, co-expressed genes, and mutations related to protein expression.	('mutations', 'Var', (112, 121))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('RBP4', 'Gene', '5950', (102, 106))	('RBP4', 'Gene', (102, 106))
43315	33834191	For DSS, high RBP4 expression was also associated with better outcomes (HR = 0.32, 95% CI: 0.2-0.51), (log rank P = 2.8e-07, Figure 2J).	('expression', 'MPA', (19, 29))	('RBP4', 'Gene', (14, 18))	('DSS', 'Chemical', '-', (4, 7))	('RBP4', 'Gene', '5950', (14, 18))	('high', 'Var', (9, 13))
43317	33834191	Deletion mutations accounted for 1.4% of total RBP4 mutations, and five proteins were changed because of RBP4 related somatic mutations (T41l, RBP4-GPC3, IGHG1-RBP4, AMBP-RBP4, and CLU-RBP4) (Figure 3A).	('RBP4', 'Gene', (143, 147))	('CLU', 'Gene', (181, 184))	('RBP4', 'Gene', (47, 51))	('RBP4', 'Gene', '5950', (171, 175))	('CLU', 'Gene', '1191', (181, 184))	('IGHG1', 'Gene', '3500', (154, 159))	('Deletion mutations', 'Var', (0, 18))	('T41l', 'Var', (137, 141))	('RBP4', 'Gene', '5950', (105, 109))	('RBP4', 'Gene', (171, 175))	('RBP4', 'Gene', '5950', (185, 189))	('IGHG1', 'Gene', (154, 159))	('GPC3', 'Gene', (148, 152))	('RBP4', 'Gene', '5950', (160, 164))	('RBP4', 'Gene', (105, 109))	('AMBP', 'Gene', '259', (166, 170))	('mutations', 'Var', (52, 61))	('RBP4', 'Gene', '5950', (143, 147))	('changed', 'Reg', (86, 93))	('GPC3', 'Gene', '2719', (148, 152))	('AMBP', 'Gene', (166, 170))	('proteins', 'Protein', (72, 80))	('RBP4', 'Gene', (185, 189))	('RBP4', 'Gene', (160, 164))	('RBP4', 'Gene', '5950', (47, 51))
43318	33834191	The different types of RBP4 mutations also affected RBP4 m RNA expression (F-value = 9.969, P<0.001, Figure 3B).	('affected', 'Reg', (43, 51))	('RBP4', 'Gene', '5950', (23, 27))	('RBP4', 'Gene', (52, 56))	('RBP4', 'Gene', '5950', (52, 56))	('RNA', 'cellular_component', 'GO:0005562', ('59', '62'))	('mutations', 'Var', (28, 37))	('RBP4', 'Gene', (23, 27))
43319	33834191	The RBP4 mutation types were also correlated with immune cell infiltration levels, especially for neutrophils with deep-deletion and arm-level gain types of mutations (Figure 3C).	('deep-deletion', 'Var', (115, 128))	('RBP4', 'Gene', '5950', (4, 8))	('RBP4', 'Gene', (4, 8))	('mutations', 'Var', (157, 166))	('arm-level', 'MPA', (133, 142))	('immune cell infiltration levels', 'MPA', (50, 81))	('gain', 'PosReg', (143, 147))
43321	33834191	Collectively, RBP4 expression and mutations were associated with immune cell infiltration characteristics.	('RBP4', 'Gene', (14, 18))	('associated', 'Reg', (49, 59))	('RBP4', 'Gene', '5950', (14, 18))	('mutations', 'Var', (34, 43))	('immune cell infiltration characteristics', 'CPA', (65, 105))
43352	33834191	We determined that RBP4 mutations were negatively correlated with immune cell infiltration, indicating that RBP4 expression is closely related to immune cell bioactivity in preclinical and clinical models.	('RBP4', 'Gene', (108, 112))	('negatively', 'NegReg', (39, 49))	('RBP4', 'Gene', '5950', (108, 112))	('RBP4', 'Gene', '5950', (19, 23))	('mutations', 'Var', (24, 33))	('RBP4', 'Gene', (19, 23))	('immune cell infiltration', 'CPA', (66, 90))
43408	20142235	Effects of ALDH1A1 knock-down on tumorigenicity/clonal growth of these bladder cancer cells were investigated using the above assays.	('ALDH1A1', 'Gene', (11, 18))	('bladder cancer', 'Disease', 'MESH:D001749', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('bladder cancer', 'Disease', (71, 85))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('ALDH', 'molecular_function', 'GO:0004030', ('11', '15'))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))	('knock-down', 'Var', (19, 29))
43409	20142235	ALDH1A1+, ALDH1A1-, ALDH1A1+/CD44+, ALDH1A1+/CD44-, ALDH1A1-/CD44+, ALDH1A1-/CD44-, CD44+, CD44-, and unsorted cancer cells were subcutaneously inoculated in 10 athymic Swiss nu/nu mice per each cell type at different dose (Table 1).	('mice', 'Species', '10090', (181, 185))	('ALDH', 'molecular_function', 'GO:0004030', ('0', '4'))	('ALDH', 'molecular_function', 'GO:0004030', ('52', '56'))	('Ta', 'Chemical', 'MESH:D013635', (224, 226))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ALDH', 'molecular_function', 'GO:0004030', ('68', '72'))	('ALDH', 'molecular_function', 'GO:0004030', ('10', '14'))	('CD44+', 'Var', (84, 89))	('ALDH1A1-/CD44-', 'Var', (68, 82))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('ALDH1A1+/CD44-', 'Var', (36, 50))	('cancer', 'Disease', (111, 117))	('ALDH1A1-/CD44+', 'Var', (52, 66))	('ALDH', 'molecular_function', 'GO:0004030', ('20', '24'))	('ALDH', 'molecular_function', 'GO:0004030', ('36', '40'))
43437	20142235	16.5% (16.8+-2.3%), 14.8% (13.1+-3.1%), and 12.6% (12.8+-2.9%) of CD44+ HTB-2, HTB-8, and HTB-4 cells were also positive for ALDH1A1, respectively.	('positive', 'Reg', (112, 120))	('CD44+', 'Var', (66, 71))	('HTB-2', 'CellLine', 'CVCL:1901', (72, 77))	('ALDH', 'molecular_function', 'GO:0004030', ('125', '129'))	('ALDH1A1', 'Gene', (125, 132))	('HTB-4', 'CellLine', 'CVCL:7377', (90, 95))
43440	20142235	The ALDH1A1+ HTB-2, HTB-9, and HTB-4 cells displayed significantly higher colony-forming efficiency by forming larger and more clones (P < 0.0001) compared with the ALDH1A1- isogenic cells at the end of the clonal assays.	('higher', 'PosReg', (67, 73))	('more clones', 'CPA', (122, 133))	('ALDH', 'molecular_function', 'GO:0004030', ('165', '169'))	('ALDH', 'molecular_function', 'GO:0004030', ('4', '8'))	('colony-forming efficiency', 'CPA', (74, 99))	('ALDH1A1+', 'Var', (4, 12))	('HTB-4', 'CellLine', 'CVCL:7377', (31, 36))	('HTB-2', 'CellLine', 'CVCL:1901', (13, 18))
43443	20142235	2A, the ALDH1A1+ HTB-2 cells generated at least 10 times as many colonies as the ALDH1A1- HTB-2 cells.	('ALDH', 'molecular_function', 'GO:0004030', ('81', '85'))	('colonies', 'CPA', (65, 73))	('HTB-2', 'CellLine', 'CVCL:1901', (90, 95))	('ALDH', 'molecular_function', 'GO:0004030', ('8', '12'))	('ALDH1A1+', 'Var', (8, 16))	('HTB-2', 'CellLine', 'CVCL:1901', (17, 22))
43444	20142235	Furthermore, the colonies from the ALDH1A1+ HTB-2 cells were larger in size compared with ones from the ALDH1A1- cells (all p<0.01).	('ALDH', 'molecular_function', 'GO:0004030', ('35', '39'))	('ALDH', 'molecular_function', 'GO:0004030', ('104', '108'))	('larger', 'PosReg', (61, 67))	('HTB-2', 'CellLine', 'CVCL:1901', (44, 49))	('ALDH1A1+', 'Var', (35, 43))	('HTB-2', 'Gene', (44, 49))
43445	20142235	Similarly, the ALDH1A1+ HTB-9 and HTB-4 cells also resulted in more than 10 times as many colonies as did the ALDH1A1- cells.	('ALDH', 'molecular_function', 'GO:0004030', ('15', '19'))	('HTB-4', 'CellLine', 'CVCL:7377', (34, 39))	('ALDH1A1+ HTB-9', 'Var', (15, 29))	('ALDH', 'molecular_function', 'GO:0004030', ('110', '114'))	('colonies', 'CPA', (90, 98))	('resulted in', 'Reg', (51, 62))	('HTB-4', 'Gene', (34, 39))
43449	20142235	Therefore, these in vitro observations indicate that ALDH1A1+ bladder cancer cells present higher survival, proliferation, and tumorigenicity compared with the isogenic ALDH1A1- and CD44+ cells.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('ALDH', 'molecular_function', 'GO:0004030', ('169', '173'))	('survival', 'CPA', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('higher', 'PosReg', (91, 97))	('tumor', 'Disease', (127, 132))	('ALDH1A1+', 'Var', (53, 61))	('bladder cancer', 'Phenotype', 'HP:0009725', (62, 76))	('proliferation', 'CPA', (108, 121))	('bladder cancer', 'Disease', 'MESH:D001749', (62, 76))	('bladder cancer', 'Disease', (62, 76))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('ALDH', 'molecular_function', 'GO:0004030', ('53', '57'))
43452	20142235	Furthermore, soft agar assay showed that the ALDH1A1+ HTB-2 cells, after the ALDH1A1 was reduced, generated much less colonies compared with the enriched ALDH1A1+ HTB-2 cells without reduced ALDH1A1 expression (P < 0.0001).	('less', 'NegReg', (113, 117))	('colonies', 'CPA', (118, 126))	('ALDH', 'molecular_function', 'GO:0004030', ('77', '81'))	('HTB-2', 'CellLine', 'CVCL:1901', (163, 168))	('agar', 'Chemical', 'MESH:D000362', (18, 22))	('ALDH', 'molecular_function', 'GO:0004030', ('45', '49'))	('ALDH', 'molecular_function', 'GO:0004030', ('154', '158'))	('ALDH1A1', 'Gene', (77, 84))	('reduced', 'NegReg', (89, 96))	('ALDH', 'molecular_function', 'GO:0004030', ('191', '195'))	('ALDH1A1+', 'Var', (45, 53))	('HTB-2', 'CellLine', 'CVCL:1901', (54, 59))
43454	20142235	Altogether, the data demonstrates that high ALDH1A1 expression could directly contribute to tumorigenicity in bladder cancer cells.	('bladder cancer', 'Disease', 'MESH:D001749', (110, 124))	('bladder cancer', 'Disease', (110, 124))	('high', 'Var', (39, 43))	('ALDH', 'molecular_function', 'GO:0004030', ('44', '48'))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('contribute', 'Reg', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'MPA', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('ALDH1A1', 'Gene', (44, 51))	('bladder cancer', 'Phenotype', 'HP:0009725', (110, 124))	('tumor', 'Disease', (92, 97))
43455	20142235	We implanted ALDH1A1+, ALDH1A1-, ALDH1A1+/CD44+, ALDH1A1+/CD44-, ALDH1A1-/CD44+, CD44+, CD44-, and unsorted HTB-2 cells into 10 mice, respectively.	('ALDH', 'molecular_function', 'GO:0004030', ('23', '27'))	('CD44+', 'Var', (81, 86))	('ALDH', 'molecular_function', 'GO:0004030', ('33', '37'))	('ALDH1A1+/CD44-', 'Var', (49, 63))	('ALDH1A1+/CD44+', 'Var', (33, 47))	('HTB-2', 'CellLine', 'CVCL:1901', (108, 113))	('ALDH1A1-/CD44+', 'Var', (65, 79))	('ALDH', 'molecular_function', 'GO:0004030', ('65', '69'))	('ALDH1A1+', 'Var', (13, 21))	('mice', 'Species', '10090', (128, 132))	('ALDH', 'molecular_function', 'GO:0004030', ('49', '53'))	('ALDH1A1-', 'Var', (23, 31))	('ALDH', 'molecular_function', 'GO:0004030', ('13', '17'))
43459	20142235	Therefore, the ALDH1A1+ bladder cancer cells were 100 times more potential in inducing in vivo tumorigenicity compared with the ALDH1A1- cells.	('ALDH1A1+', 'Var', (15, 23))	('ALDH', 'molecular_function', 'GO:0004030', ('15', '19'))	('bladder cancer', 'Phenotype', 'HP:0009725', (24, 38))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('bladder cancer', 'Disease', 'MESH:D001749', (24, 38))	('bladder cancer', 'Disease', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('ALDH', 'molecular_function', 'GO:0004030', ('128', '132'))	('tumor', 'Disease', (95, 100))
43460	20142235	1 x 103 ALDH1A1+/CD44+ HTB-2 bladder cancer cells and ALDH1A1+/CD44- HTB-2 bladder cancer cells created tumors of average 20+-1.3 mm3 and 19+-1.1 mm3, respectively, in 8 of the mice, which had no statistical difference from the tumors generated by ALDH1A1+ cells alone (P>0.05).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('ALDH', 'molecular_function', 'GO:0004030', ('248', '252'))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Disease', (228, 234))	('ALDH', 'molecular_function', 'GO:0004030', ('54', '58'))	('bladder cancer', 'Disease', 'MESH:D001749', (29, 43))	('bladder cancer', 'Disease', (29, 43))	('ALDH1A1+/CD44-', 'Var', (54, 68))	('HTB-2', 'CellLine', 'CVCL:1901', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('bladder cancer', 'Phenotype', 'HP:0009725', (29, 43))	('mice', 'Species', '10090', (177, 181))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('HTB-2', 'CellLine', 'CVCL:1901', (69, 74))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('ALDH', 'molecular_function', 'GO:0004030', ('8', '12'))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))
43470	20142235	The data imply that the CD44+ cells that have tumorigenity, when lacking ALDH1A1+ in the population, will have reduced potential to create xenograft tumors.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('xenograft tumors', 'Disease', (139, 155))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('CD44+', 'Var', (24, 29))	('lacking', 'NegReg', (65, 72))	('tumor', 'Disease', (46, 51))	('xenograft tumors', 'Disease', 'MESH:D009369', (139, 155))	('reduced', 'NegReg', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('ALDH', 'molecular_function', 'GO:0004030', ('73', '77'))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Disease', (149, 154))	('ALDH1A1+', 'Gene', (73, 81))
43491	20142235	In the follow-up period, 32% (45 of 140) of tumors with high ALDH1A1 expression recurred compared with 15% (11 of 76) tumors with low ALDH1A1 expression having recurrence (P = 0.007) (Table 2).	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('expression', 'Var', (69, 79))	('ALDH', 'molecular_function', 'GO:0004030', ('61', '65'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Ta', 'Chemical', 'MESH:D013635', (184, 186))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ALDH', 'molecular_function', 'GO:0004030', ('134', '138'))	('tumors', 'Disease', (118, 124))	('ALDH1A1', 'Gene', (61, 68))	('high', 'Var', (56, 60))
43492	20142235	Furthermore, 55% (38 of 69) of tumors with high ALDH1A1 expression showed progression, as compared with only 12% (18 of 147) of tumors with low ALDH1A1 expression having progression (P = 0.001).	('ALDH', 'molecular_function', 'GO:0004030', ('144', '148'))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('high', 'Var', (43, 47))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('ALDH1A1', 'Gene', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('ALDH', 'molecular_function', 'GO:0004030', ('48', '52'))
43494	20142235	Kaplan-Meier plots and log-rank tests showed that the bladder cancer patients with high ALDH1A1 expression in their tumor tissues had statistically significant shorter cancer-specific survival, as compared with those whose tumors had low ALDH1A1 expression (P = 0.027; Fig.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('ALDH', 'molecular_function', 'GO:0004030', ('238', '242'))	('ALDH1A1', 'Gene', (88, 95))	('cancer', 'Disease', (168, 174))	('patients', 'Species', '9606', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Disease', (62, 68))	('tumor', 'Disease', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('bladder cancer', 'Disease', 'MESH:D001749', (54, 68))	('bladder cancer', 'Disease', (54, 68))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('high', 'Var', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('shorter', 'NegReg', (160, 167))	('ALDH', 'molecular_function', 'GO:0004030', ('88', '92'))	('expression', 'Var', (96, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (54, 68))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Disease', (116, 121))
43495	20142235	Moreover, patients with high ALDH1A1 positive staining in their tumors had statistically significantly shorter overall survival rate compared with those whose tumors had low ALDH1A1 expression (P = 0.030; Fig.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('overall survival', 'MPA', (111, 127))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('ALDH', 'molecular_function', 'GO:0004030', ('29', '33'))	('shorter', 'NegReg', (103, 110))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('ALDH1A1', 'Gene', (29, 36))	('high', 'Var', (24, 28))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('patients', 'Species', '9606', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('ALDH', 'molecular_function', 'GO:0004030', ('174', '178'))
43505	20142235	First, the in vitro assays revealed that ALDH1A1+ cancer cells had higher clone formation efficiency than did ALDH1A1- cancer cells.	('higher', 'PosReg', (67, 73))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('clone formation efficiency', 'CPA', (74, 100))	('ALDH', 'molecular_function', 'GO:0004030', ('41', '45'))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('ALDH', 'molecular_function', 'GO:0004030', ('110', '114'))	('cancer', 'Disease', (119, 125))	('formation', 'biological_process', 'GO:0009058', ('80', '89'))	('ALDH1A1+', 'Var', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
43518	20142235	Furthermore, our and their data showed that CD44+ bladder cancer cells had higher in vitro and in vivo tumorigenity compared with CD44- cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('bladder cancer', 'Phenotype', 'HP:0009725', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (50, 64))	('tumor', 'Disease', (103, 108))	('higher', 'PosReg', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('bladder cancer', 'Disease', (50, 64))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('CD44+', 'Var', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
43520	20142235	The in vitro observation is supported by subsequent in vivo findings, in which, although displaying higher tumorigenicity compared with CD44- cells, the CD44+ cells had lower potential to create tumor compared with ALDH1A1+ cells.	('ALDH', 'molecular_function', 'GO:0004030', ('215', '219'))	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('CD44+', 'Var', (153, 158))	('higher', 'PosReg', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('lower', 'NegReg', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
43521	20142235	Both in vitro and in vivo experiments also showed that ALDH1A1+/CD44+ did not exhibit higher tumor-initiating capability than did ALDH1A1+ and ALDH1A1+/CD44- cells.	('ALDH1A1+/CD44+', 'Var', (55, 69))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ALDH', 'molecular_function', 'GO:0004030', ('130', '134'))	('tumor', 'Disease', (93, 98))	('ALDH', 'molecular_function', 'GO:0004030', ('143', '147'))	('ALDH', 'molecular_function', 'GO:0004030', ('55', '59'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
43526	20142235	The result was also consistent with a recent study of colon carcinomas, in which, ALDH1A1+/CD44+ colon cancer cells did not display statistically better efficiency in generating tumors than did isogenic ALDH1A1+ cells.	('colon cancer', 'Disease', 'MESH:D015179', (97, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('colon cancer', 'Disease', (97, 109))	('colon carcinomas', 'Disease', (54, 70))	('ALDH1A1+/CD44+', 'Var', (82, 96))	('colon carcinomas', 'Disease', 'MESH:D015179', (54, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('ALDH', 'molecular_function', 'GO:0004030', ('82', '86'))	('colon cancer', 'Phenotype', 'HP:0003003', (97, 109))	('ALDH', 'molecular_function', 'GO:0004030', ('203', '207'))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
43608	27191498	CisPt resistant RT-112R and J-82R variants revealed a 2-3-fold increased CisPt resistance as compared to their corresponding parental counterparts.	('CisPt', 'Chemical', 'MESH:D002945', (73, 78))	('increased', 'PosReg', (63, 72))	('variants', 'Var', (34, 42))	('CisPt resistance', 'MPA', (73, 89))	('CisPt', 'Chemical', 'MESH:D002945', (0, 5))
43624	27191498	DSBs are potent triggers of cell death and can be repaired by DNA double-strand break repair (homologous recombination (HR) or non-homologous end joining (NHEJ)).	('DSBs', 'Var', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('cell death', 'CPA', (28, 38))	('cell death', 'biological_process', 'GO:0008219', ('28', '38'))	('double-strand break repair', 'biological_process', 'GO:0006302', ('66', '92'))	('homologous recombination', 'biological_process', 'GO:0035825', ('94', '118'))	('DSBs', 'Chemical', '-', (0, 4))	('NHEJ', 'biological_process', 'GO:0006303', ('155', '159'))
43631	27191498	In case of error prone repair of DSBs, genomic instability of bladder carcinomas is favoured.	('bladder carcinomas', 'Phenotype', 'HP:0002862', (62, 80))	('bladder carcinomas', 'Disease', (62, 80))	('error prone', 'Var', (11, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('DSBs', 'Chemical', '-', (33, 37))	('bladder carcinomas', 'Disease', 'MESH:D001749', (62, 80))	('favoured', 'PosReg', (84, 92))	('genomic instability', 'CPA', (39, 58))
43645	27191498	Proliferation rate was higher in RT-112 as compared to J-82 cells (Figure 1C).	('Proliferation rate', 'CPA', (0, 18))	('higher', 'PosReg', (23, 29))	('rat', 'Species', '10116', (7, 10))	('rat', 'Species', '10116', (14, 17))	('RT-112', 'Var', (33, 39))
43667	27191498	The formation of nuclear gammaH2AX foci and 53BP1 foci is part of the DNA damage response (DDR) and is believed to reflect predominantly the formation of DNA double-strand breaks (DSBs).	('DNA', 'cellular_component', 'GO:0005574', ('154', '157'))	('53BP1', 'Gene', (44, 49))	('53BP1', 'Gene', '7158', (44, 49))	('DNA damage response', 'biological_process', 'GO:0006974', ('70', '89'))	('DSBs', 'Chemical', '-', (180, 184))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('formation', 'biological_process', 'GO:0009058', ('141', '150'))	('formation', 'biological_process', 'GO:0009058', ('4', '13'))	('gammaH2AX', 'Chemical', '-', (25, 34))	('gammaH2AX', 'Var', (25, 34))
43677	27191498	The data obtained uncover large variations in the activation of DDR mechanisms already in J-82 versus RT-112 parental cells, as reflected on the levels of gammaH2AX, p-Chk1, p-p53 and p-Kap1 (Figure 6A-6B).	('gammaH2AX', 'Var', (155, 164))	('Kap1', 'Gene', '1033', (186, 190))	('p53', 'Gene', (176, 179))	('Kap1', 'Gene', (186, 190))	('p53', 'Gene', '7157', (176, 179))	('Chk1', 'Gene', (168, 172))	('Chk1', 'Gene', '1111', (168, 172))	('gammaH2AX', 'Chemical', '-', (155, 164))
43678	27191498	Comparative analyses of J-82 cells versus CisPt resistant J-82R cells showed lower phosphorylation levels of H2AX, Chk1, p53 and Kap1 in the CisPt resistant variants (Figure 6A).	('lower', 'NegReg', (77, 82))	('Chk1', 'Gene', '1111', (115, 119))	('Kap1', 'Gene', '1033', (129, 133))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('CisPt', 'Chemical', 'MESH:D002945', (141, 146))	('H2AX', 'Gene', '3014', (109, 113))	('Kap1', 'Gene', (129, 133))	('rat', 'Species', '10116', (5, 8))	('H2AX', 'Gene', (109, 113))	('phosphorylation', 'biological_process', 'GO:0016310', ('83', '98'))	('phosphorylation levels', 'MPA', (83, 105))	('CisPt', 'Chemical', 'MESH:D002945', (42, 47))	('Chk1', 'Gene', (115, 119))	('variants', 'Var', (157, 165))
43684	27191498	Hence, the two types of CisPt resistant UC cell variants were characterized by an increased mRNA expression of XAF1.	('XAF1', 'Gene', '54739', (111, 115))	('XAF1', 'Gene', (111, 115))	('mRNA expression', 'MPA', (92, 107))	('variants', 'Var', (48, 56))	('increased', 'PosReg', (82, 91))	('CisPt', 'Chemical', 'MESH:D002945', (24, 29))
43687	27191498	Correspondingly, high XAF1 level was suggested as predictive marker in pancreatic cancer associated with better overall survival.	('better', 'PosReg', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('high', 'Var', (17, 21))	('XAF1', 'Gene', '54739', (22, 26))	('XAF1', 'Gene', (22, 26))	('pancreatic cancer', 'Disease', (71, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (71, 88))
43702	27191498	J-82R cells turned out to be slightly more sensitive to treatment with the pan Chk inhibitor AZD-7762 (Figure 8A) and showed a significantly enhanced sensitivity to the Chk1-specific inhibitor LY2603618 as compared to parental cells (Figure 8B).	('sensitivity', 'MPA', (150, 161))	('Chk1', 'Gene', '1111', (169, 173))	('sensitive', 'MPA', (43, 52))	('more', 'PosReg', (38, 42))	('AZD-7762', 'Var', (93, 101))	('AZD-7762', 'Chemical', 'MESH:C532363', (93, 101))	('enhanced', 'PosReg', (141, 149))	('LY2603618', 'Chemical', 'MESH:C582547', (193, 202))	('Chk1', 'Gene', (169, 173))
43703	27191498	The J-82R cells also revealed a tendentially enhanced sensitivity to the Wee1 kinase inhibitor MK-1775 (Figure 8C) but not to the CDK inhibitor roscovitine (Figure 8D).	('kinase inhibitor', 'biological_process', 'GO:0033673', ('78', '94'))	('roscovitine', 'Chemical', 'MESH:D000077546', (144, 155))	('Wee1', 'Gene', (73, 77))	('enhanced', 'PosReg', (45, 53))	('Wee1', 'Gene', '7465', (73, 77))	('MK-1775', 'Var', (95, 102))	('MK-1775', 'Chemical', 'MESH:C549567', (95, 102))	('CDK inhibitor', 'molecular_function', 'GO:0004861', ('130', '143'))	('sensitivity', 'MPA', (54, 65))
43704	27191498	The pronounced loss of cell viability of J-82R cells following Chk1 inhibition seems to be specific as it was not observed upon inhibition of ATM/ATR kinase or the DNA repair factors RAD51 and PARP-1 (Table 1).	('ATM', 'Gene', '472', (142, 145))	('ATR', 'Gene', '545', (146, 149))	('RAD', 'biological_process', 'GO:1990116', ('183', '186'))	('inhibition', 'Var', (68, 78))	('PARP-1', 'Gene', (193, 199))	('RAD51', 'Gene', (183, 188))	('loss', 'NegReg', (15, 19))	('PARP-1', 'Gene', '142', (193, 199))	('Chk1', 'Gene', (63, 67))	('cell viability', 'CPA', (23, 37))	('RAD51', 'Gene', '5888', (183, 188))	('DNA repair', 'biological_process', 'GO:0006281', ('164', '174'))	('DNA', 'cellular_component', 'GO:0005574', ('164', '167'))	('Chk1', 'Gene', '1111', (63, 67))	('ATM', 'Gene', (142, 145))	('ATR', 'Gene', (146, 149))
43705	27191498	Pre-treatment of J-82R cells with low non-toxic concentration of Chk inhibitors increased their sensitivity to CisPt (Figure 8E-8F), indicating that targeting of Chk might be particular useful to overcome acquired CisPt resistance of some subtypes of UC cells.	('CisPt', 'Chemical', 'MESH:D002945', (111, 116))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('CisPt', 'Chemical', 'MESH:D002945', (214, 219))	('sensitivity to CisPt', 'MPA', (96, 116))	('increased', 'PosReg', (80, 89))	('Chk', 'Gene', (65, 68))	('inhibitors', 'Var', (69, 79))	('rat', 'Species', '10116', (55, 58))
43715	27191498	Importantly, inhibitors of Chk might be useful to handle CisPt resistance in UC cells.	('Chk', 'Gene', (27, 30))	('inhibitors', 'Var', (13, 23))	('CisPt', 'Chemical', 'MESH:D002945', (57, 62))
43716	27191498	Forthcoming in vivo studies are required to scrutinize the potency of Chk1 specific inhibitors to work against the non-responsiveness of urothelial carcinoma cells to CisPt-based anticancer therapy in a clincally relevant setting.	('inhibitors', 'Var', (84, 94))	('Chk1', 'Gene', '1111', (70, 74))	('cancer', 'Disease', (183, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('CisPt', 'Chemical', 'MESH:D002945', (167, 172))	('urothelial carcinoma', 'Disease', (137, 157))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('non-responsiveness', 'MPA', (115, 133))	('Chk1', 'Gene', (70, 74))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (137, 157))
43719	27191498	The following antibodies were used: antibodies detecting Ser139 phosphorylated histone H2AX (gammaH2AX), H2AX (Millipore (Billerica, MA, USA)), beta-actin (Santa Cruz Biotechnology (Santa Cruz, CA, USA)), 53BP1, p-p53, p-Chk1, p-p38 (Cell Signaling (Denvers, MA, USA)), p-Chk2 (Abcam (Cambridge, UK)), p-RPA32 and p-KAP1 (Bethyl Laboratories (Montgomery, AL, USA)).	('Chk1', 'Gene', '1111', (221, 225))	('Signaling', 'biological_process', 'GO:0023052', ('239', '248'))	('rat', 'Species', '10116', (333, 336))	('H2AX', 'Gene', (105, 109))	('Ser', 'cellular_component', 'GO:0005790', ('57', '60'))	('beta-actin', 'Gene', '728378', (144, 154))	('KAP1', 'Gene', '1033', (316, 320))	('H2AX', 'Gene', (98, 102))	('53BP1', 'Gene', (205, 210))	('p-p38', 'Var', (227, 232))	('H2AX', 'Gene', '3014', (105, 109))	('H2AX', 'Gene', '3014', (98, 102))	('RPA32', 'Gene', (304, 309))	('Chk2', 'Gene', (272, 276))	('p53', 'Gene', '7157', (214, 217))	('histone H2AX', 'Gene', (79, 91))	('gammaH2AX', 'Chemical', '-', (93, 102))	('H2AX', 'Gene', (87, 91))	('KAP1', 'Gene', (316, 320))	('RPA32', 'Gene', '6118', (304, 309))	('p53', 'Gene', (214, 217))	('beta-actin', 'Gene', (144, 154))	('histone H2AX', 'Gene', '3014', (79, 91))	('H2AX', 'Gene', '3014', (87, 91))	('RPA', 'cellular_component', 'GO:0005662', ('304', '307'))	('Chk2', 'Gene', '11200', (272, 276))	('53BP1', 'Gene', '7158', (205, 210))	('Chk1', 'Gene', (221, 225))
43755	27191498	Expression of CisPt specific resistance factors differs between urothelial carcinoma cells lines Selection of CisPt resistant UC cell variants promotes an EMT-like phenotype Aquired CisPt resistance of epithelial-like RT-112 UC cells is related to a lower frequency of apoptosis CisPt resistant mesenchymal-like J-82 UC cells are characterized by reduced formation of DNA damage and attenuated DDR Acquired CisPt resistance is reversible by pharmacological inhibition of Chk1.	('CisPt', 'Chemical', 'MESH:D002945', (110, 115))	('EMT', 'biological_process', 'GO:0001837', ('155', '158'))	('urothelial carcinoma', 'Disease', (64, 84))	('formation of DNA damage', 'MPA', (355, 378))	('DDR', 'MPA', (394, 397))	('apoptosis', 'biological_process', 'GO:0097194', ('269', '278'))	('apoptosis', 'biological_process', 'GO:0006915', ('269', '278'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (64, 84))	('CisPt', 'Chemical', 'MESH:D002945', (407, 412))	('DNA', 'cellular_component', 'GO:0005574', ('368', '371'))	('Chk1', 'Gene', (471, 475))	('Chk1', 'Gene', '1111', (471, 475))	('CisPt', 'Chemical', 'MESH:D002945', (279, 284))	('variants', 'Var', (134, 142))	('reduced', 'NegReg', (347, 354))	('J-82 UC', 'CellLine', 'CVCL:0359', (312, 319))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('CisPt', 'Chemical', 'MESH:D002945', (14, 19))	('CisPt', 'Chemical', 'MESH:D002945', (182, 187))	('formation', 'biological_process', 'GO:0009058', ('355', '364'))
43805	26918061	Both univariate and multivariate analysis revealed that poor DSS was significantly associated with multifocality (P=0.0042 and P=0.006, respectively), advanced pT (P<0.0001 and P=0.010, respectively), lymph node metastasis (P<0.0001 and P<0.0001, respectively), high histological grade (P=0.0171 and P=0.044, respectively), perineurial invasion (P<0.0001 and P=0.002, respectively), and high SPOCK1 expression (P<0.0001 and P=0.031, respectively).	('SPOCK1', 'Gene', (392, 398))	('high', 'Var', (387, 391))	('DSS', 'Gene', (61, 64))	('DSS', 'Gene', '5376', (61, 64))	('perineurial invasion', 'CPA', (324, 344))	('expression', 'MPA', (399, 409))	('lymph node metastasis', 'Disease', (201, 222))	('lymph node metastasis', 'Disease', 'MESH:D009362', (201, 222))	('poor', 'Var', (56, 60))	('multifocality', 'CPA', (99, 112))	('high histological grade', 'CPA', (262, 285))	('advanced pT', 'CPA', (151, 162))
43810	26918061	In the univariate analyses (Table 3), patients with UTUC showing high SPOCK1 expression had significantly worse DSS (P<0.0001, Fig.	('worse', 'NegReg', (106, 111))	('DSS', 'Gene', (112, 115))	('DSS', 'Gene', '5376', (112, 115))	('high', 'Var', (65, 69))	('patients', 'Species', '9606', (38, 46))	('SPOCK1', 'Gene', (70, 76))
43820	26918061	A study showed that a de novo missense change in SPOCK1 identified by whole exon sequencing might relate to developmental delay, microcephaly and agenesis of the corpus callosum, leading to the hypothesis that SPOCK1 plays a critical role in neurogenesis.	('microcephaly', 'Disease', (129, 141))	('agenesis of the corpus callosum', 'CPA', (146, 177))	('neurogenesis', 'biological_process', 'GO:0022008', ('242', '254'))	('agenesis of the corpus callosum', 'Phenotype', 'HP:0001274', (146, 177))	('relate', 'Reg', (98, 104))	('microcephaly', 'Disease', 'MESH:D008831', (129, 141))	('developmental delay', 'CPA', (108, 127))	('missense change', 'Var', (30, 45))	('microcephaly', 'Phenotype', 'HP:0000252', (129, 141))	('developmental delay', 'Phenotype', 'HP:0001263', (108, 127))	('SPOCK1', 'Gene', (49, 55))
43825	26918061	The clinical significance of SPOCK1 in lung cancer was correlated with metastasis and silencing of SPOCK1 in cell study inhibited lung cancer cell invasion in vitro .	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('silencing', 'Var', (86, 95))	('lung cancer', 'Disease', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('inhibited', 'NegReg', (120, 129))	('SPOCK1', 'Gene', (99, 105))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('lung cancer', 'Disease', (130, 141))
43833	26918061	In vivo studies of lung cancer demonstrated that SPOCK1 is not only associated with metastasis and also induces EMT.	('lung cancer', 'Phenotype', 'HP:0100526', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('associated', 'Reg', (68, 78))	('induces', 'PosReg', (104, 111))	('metastasis', 'CPA', (84, 94))	('SPOCK1', 'Var', (49, 55))	('lung cancer', 'Disease', 'MESH:D008175', (19, 30))	('EMT', 'CPA', (112, 115))	('EMT', 'biological_process', 'GO:0001837', ('112', '115'))	('lung cancer', 'Disease', (19, 30))
43991	22754656	While gemcitabine and cisplatin (GC) does not improve overall survival compared with the combination of methotrexate, vinblastine, doxorubidin and cisplatin (MVAC), MVAC is associated with increased toxicity, including granulocytopenia, nausea, and vomiting.	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('toxicity', 'Disease', 'MESH:D064420', (199, 207))	('GC', 'Chemical', '-', (33, 35))	('MVAC', 'Var', (165, 169))	('vinblastine', 'Chemical', 'MESH:D014747', (118, 129))	('nausea', 'Phenotype', 'HP:0002018', (237, 243))	('granulocytopenia', 'Phenotype', 'HP:0001913', (219, 235))	('toxicity', 'Disease', (199, 207))	('MVAC', 'Chemical', '-', (165, 169))	('MVAC', 'Chemical', '-', (158, 162))	('doxorubidin', 'Chemical', '-', (131, 142))	('nausea', 'Disease', (237, 243))	('vomiting', 'Disease', 'MESH:D014839', (249, 257))	('granulocytopenia', 'Disease', (219, 235))	('cisplatin', 'Chemical', 'MESH:D002945', (22, 31))	('granulocytopenia', 'Disease', 'MESH:D000380', (219, 235))	('vomiting', 'Phenotype', 'HP:0002013', (249, 257))	('methotrexate', 'Chemical', 'MESH:D008727', (104, 116))	('vomiting', 'Disease', (249, 257))	('gemcitabine', 'Chemical', 'MESH:C056507', (6, 17))	('nausea', 'Disease', 'MESH:D009325', (237, 243))
43996	22754656	A well-described signature of chromosomal aberrations exists between low-grade, non-invasive, papillary hyperplasia variants and high-grade, muscle-invasive disease.	('non-invasive', 'Disease', (80, 92))	('variants', 'Var', (116, 124))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (30, 53))	('papillary hyperplasia', 'Disease', (94, 115))	('papillary hyperplasia variants', 'Phenotype', 'HP:0007482', (94, 124))	('papillary hyperplasia', 'Disease', 'MESH:D006965', (94, 115))	('low-grade', 'Disease', (69, 78))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (141, 164))	('muscle-invasive disease', 'Disease', (141, 164))
43999	22754656	The most frequent activating mutations detected in low-grade tumors constitutively up-regulate the activity of receptor-tyrosine kinase-Ras pathway and include over-expression of fibroblast growth factor receptor-3 (FGFR-3) in up to 70% of tumors, HRAS in 30-40% and PIK3CA in 10%.	('up-regulate', 'PosReg', (83, 94))	('tumors', 'Disease', (240, 246))	('activating', 'PosReg', (18, 28))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('FGFR-3', 'Gene', '2261', (216, 222))	('FGFR', 'molecular_function', 'GO:0005007', ('216', '220'))	('fibroblast growth factor receptor-3', 'Gene', (179, 214))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Disease', (61, 67))	('HRAS', 'Gene', '3265', (248, 252))	('FGFR-3', 'Gene', (216, 222))	('PIK3CA', 'Gene', '5290', (267, 273))	('HRAS', 'Gene', (248, 252))	('mutations', 'Var', (29, 38))	('receptor-tyrosine kinase-Ras pathway', 'Pathway', (111, 147))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('179', '203'))	('over-expression', 'PosReg', (160, 175))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('fibroblast growth factor receptor-3', 'Gene', '2261', (179, 214))	('PIK3CA', 'Gene', (267, 273))	('activity', 'MPA', (99, 107))
44000	22754656	Chromosome 9 loss is seen in both low-grade and high-grade tumors.	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('Chromosome', 'Var', (0, 10))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('loss', 'NegReg', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
44001	22754656	The deletion or mutation of tumor suppressor genes p53 and pRB, both critical cell cycle regulators, are the most frequent abnormalities in high-grade tumors and contribute to tumor progression.	('p53', 'Gene', (51, 54))	('tumor', 'Disease', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('contribute', 'Reg', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumor', 'Disease', (176, 181))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('pRB', 'Gene', '5925', (59, 62))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('pRB', 'Gene', (59, 62))	('deletion', 'Var', (4, 12))	('tumor suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('mutation', 'Var', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cell cycle', 'biological_process', 'GO:0007049', ('78', '88'))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
44003	22754656	Finally, changes in the microenvironment also promote invasion and progression though aberrant N- and E-cadherin expression and production of vascular endothelial growth factor.	('cadherin', 'molecular_function', 'GO:0008014', ('104', '112'))	('progression', 'CPA', (67, 78))	('expression', 'MPA', (113, 123))	('promote', 'PosReg', (46, 53))	('changes', 'Var', (9, 16))	('invasion', 'CPA', (54, 62))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('142', '176'))	('vascular endothelial growth factor', 'Gene', (142, 176))	('men', 'Species', '9606', (36, 39))	('E-cadherin', 'Gene', (102, 112))	('E-cadherin', 'Gene', '999', (102, 112))	('production', 'MPA', (128, 138))	('vascular endothelial growth factor', 'Gene', '7422', (142, 176))
44005	22754656	Despite the identification of genetic alterations thought to drive high-grade, muscle-invasive disease, these aberrations have not successfully predicted response to targeted treatment.	('muscle-invasive disease', 'Disease', (79, 102))	('high-grade', 'Disease', (67, 77))	('men', 'Species', '9606', (180, 183))	('genetic alterations', 'Var', (30, 49))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (79, 102))
44029	22754656	recently reported the disappointing results that ZD1839 (gefitinib), an oral EGFR TKI, was ineffective as second-line therapy for metastatic transitional cell carcinoma based on the results of their Southwest Oncology Group phase II study (S0031) (Table 2).	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('ZD1839', 'Chemical', 'MESH:D000077156', (49, 55))	('ZD1839', 'Var', (49, 55))	('cell carcinoma', 'Disease', (154, 168))	('Oncology', 'Phenotype', 'HP:0002664', (209, 217))	('EGFR', 'Gene', '1956', (77, 81))	('cell carcinoma', 'Disease', 'MESH:C538614', (154, 168))	('gefitinib', 'Chemical', 'MESH:D000077156', (57, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('EGFR', 'Gene', (77, 81))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (141, 168))
44046	22754656	Trastuzumab is being studied together with paclitaxel and radiation for patients ineligible for cystectomy (NCT00238420) and studies of a novel Fc-optimized monoclonal antibody that targets HER2, MGAH22, are in phase I trials (NCT01195935, NCT01148849) (Table 2).	('antibody', 'cellular_component', 'GO:0019814', ('168', '176'))	('HER2', 'Gene', (190, 194))	('HER2', 'Gene', '2064', (190, 194))	('antibody', 'molecular_function', 'GO:0003823', ('168', '176'))	('paclitaxel', 'Chemical', 'MESH:D017239', (43, 53))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (0, 11))	('antibody', 'cellular_component', 'GO:0042571', ('168', '176'))	('antibody', 'cellular_component', 'GO:0019815', ('168', '176'))	('NCT01195935', 'Var', (227, 238))	('patients', 'Species', '9606', (72, 80))
44049	22754656	examined 11 urothelial bladder cancer cell lines and 75 patient tumors for the presence of mutations within the kinase domain and expression of EGFRvIII expression, which have been reported to affect patient response to gefitinib.	('gefitinib', 'Chemical', 'MESH:D000077156', (220, 229))	('tumors', 'Disease', (64, 70))	('EGFR', 'Gene', (144, 148))	('urothelial bladder cancer', 'Disease', (12, 37))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('bladder cancer', 'Phenotype', 'HP:0009725', (23, 37))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (12, 37))	('affect', 'Reg', (193, 199))	('mutations', 'Var', (91, 100))	('patient', 'Species', '9606', (56, 63))	('EGFR', 'Gene', '1956', (144, 148))	('patient', 'Species', '9606', (200, 207))
44057	22754656	TKI12458 from Novartis is currently being studied in a phase II trial (NCT00790426) of second and third-line therapy for patients with FGFR-3 mutated and wild type urothelial carcinoma after it demonstrated activity in preclinical models (Table 2).	('type urothelial carcinoma', 'Disease', (159, 184))	('mutated', 'Var', (142, 149))	('FGFR-3', 'Gene', (135, 141))	('FGFR-3', 'Gene', '2261', (135, 141))	('type urothelial carcinoma', 'Disease', 'MESH:D014526', (159, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('patients', 'Species', '9606', (121, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('135', '139'))
44063	22754656	Down-regulation of PTEN is seen in over 20% of muscle-invasive bladder tumors and in up to 40% of tumors in the presence of p53 mutations, and inactivation of this pathways results in loss of control of the mTOR signaling cascade.	('tumors', 'Disease', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('regulation', 'biological_process', 'GO:0065007', ('5', '15'))	('tumors', 'Disease', (71, 77))	('mTOR', 'Gene', (207, 211))	('control', 'MPA', (192, 199))	('mutations', 'Var', (128, 137))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('PTEN', 'Gene', (19, 23))	('Down-regulation', 'NegReg', (0, 15))	('signaling cascade', 'biological_process', 'GO:0007165', ('212', '229'))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('muscle-invasive bladder tumors', 'Disease', (47, 77))	('bladder tumors', 'Phenotype', 'HP:0009725', (63, 77))	('bladder tumor', 'Phenotype', 'HP:0009725', (63, 76))	('mTOR', 'Gene', '2475', (207, 211))	('loss', 'NegReg', (184, 188))	('PTEN', 'Gene', '5728', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('muscle-invasive bladder tumors', 'Disease', 'MESH:D001749', (47, 77))	('invasive bladder', 'Phenotype', 'HP:0100645', (54, 70))	('p53', 'Gene', (124, 127))	('inactivation', 'Var', (143, 155))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
44069	22754656	Based on this data, and the relatively low toxicity profile, two phase II trials at Baylor are assessing tamoxifen in the second-line setting for advanced urothelial cell carcinoma (NCT00589017 and NCT00710970).	('toxicity', 'Disease', (43, 51))	('urothelial cell carcinoma', 'Disease', 'MESH:C538614', (155, 180))	('tamoxifen', 'Chemical', 'MESH:D013629', (105, 114))	('NCT00710970', 'Var', (198, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('NCT00589017', 'Var', (182, 193))	('urothelial cell carcinoma', 'Disease', (155, 180))	('toxicity', 'Disease', 'MESH:D064420', (43, 51))
44074	22754656	They then retrospectively correlated the frequency of CD4+ICOShi T cells with clinical benefit in a cohort of metastatic melanoma patients and found that increased frequency of CD4+ICOShi T cells in tumor tissues and systemic circulation correlated with increased likelihood of overall survival.	('tumor', 'Disease', (199, 204))	('increased', 'PosReg', (254, 263))	('melanoma', 'Disease', (121, 129))	('overall survival', 'CPA', (278, 294))	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('CD4+ICOShi T', 'Var', (177, 189))	('patients', 'Species', '9606', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
44094	22754656	While the intention-to-treat analysis showed only a trend towards improved survival with vinflunine compared with BSC, multivariate Cox analysis adjusted for prognostic factors confirmed a reduction in the risk of death by 23% and a statistically significant increase in overall survival with vinflunine.	('death', 'Disease', (214, 219))	('vinflunine', 'Chemical', 'MESH:C111217', (89, 99))	('increase', 'PosReg', (259, 267))	('improved', 'PosReg', (66, 74))	('Cox', 'Gene', '1351', (132, 135))	('overall survival', 'MPA', (271, 287))	('Cox', 'Gene', (132, 135))	('reduction', 'NegReg', (189, 198))	('vinflunine', 'Chemical', 'MESH:C111217', (293, 303))	('vinflunine', 'Var', (89, 99))	('death', 'Disease', 'MESH:D003643', (214, 219))
44096	22754656	Eribulin (E7389) was subsequently developed as a synthetic analog of halichondrin B, and it inhibits microtubule growth resulting in cell cycle arrest.	('microtubule growth', 'MPA', (101, 119))	('halichondrin B', 'Chemical', 'MESH:C070519', (69, 83))	('microtubule', 'cellular_component', 'GO:0005874', ('101', '112'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('133', '150'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (133, 150))	('E7389', 'Var', (10, 15))	('inhibits', 'NegReg', (92, 100))	('cell cycle arrest', 'CPA', (133, 150))
44102	22754656	Epothilones are a novel class of antineoplastic agents with activity against cells that have acquired resistance to taxanes through beta-tubulin mutation or overexpression by enhanced microtubule stability via tubulin polymerization, which leads to cell cycle arrest at the G2/M transition and ultimately apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('305', '314'))	('apoptosis', 'biological_process', 'GO:0006915', ('305', '314'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('249', '266'))	('enhanced', 'PosReg', (175, 183))	('apoptosis', 'CPA', (305, 314))	('beta-tubulin', 'Protein', (132, 144))	('leads to', 'Reg', (240, 248))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (249, 266))	('tubulin', 'MPA', (210, 217))	('microtubule stability', 'MPA', (184, 205))	('overexpression', 'PosReg', (157, 171))	('taxanes', 'Chemical', 'MESH:D043823', (116, 123))	('cell cycle arrest at the G2/M transition', 'CPA', (249, 289))	('microtubule', 'cellular_component', 'GO:0005874', ('184', '195'))	('Epothilones', 'Chemical', 'MESH:D034261', (0, 11))	('mutation', 'Var', (145, 153))
44114	22754656	Platinums bind to DNA and form monoadducts, which usually react to create intra- and inter-strand crosslinks that contort the conformation of the double helix.	('bind', 'Interaction', (10, 14))	('Platinums', 'Chemical', 'MESH:D010984', (0, 9))	('crosslinks', 'Var', (98, 108))	('conformation of the double helix', 'MPA', (126, 158))	('contort', 'Reg', (114, 121))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))
44115	22754656	These DNA lesions ultimately block transcription and replication and activate signaling cascades, including caspases, thus resulting in cytotoxicity via apoptosis.	('resulting in', 'Reg', (123, 135))	('transcription', 'CPA', (35, 48))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('activate', 'PosReg', (69, 77))	('signaling cascades', 'Pathway', (78, 96))	('cytotoxicity', 'Disease', (136, 148))	('DNA', 'cellular_component', 'GO:0005574', ('6', '9'))	('transcription', 'biological_process', 'GO:0006351', ('35', '48'))	('apoptosis', 'biological_process', 'GO:0006915', ('153', '162'))	('block', 'NegReg', (29, 34))	('lesions', 'Var', (10, 17))	('apoptosis', 'biological_process', 'GO:0097194', ('153', '162'))	('cytotoxicity', 'Disease', 'MESH:D064420', (136, 148))	('replication', 'CPA', (53, 64))	('caspases', 'Pathway', (108, 116))	('apoptosis', 'CPA', (153, 162))
44117	22754656	While defects in any one of these pathways can cause mutations, genomic instability and predispose to the development of malignancy, sensitivity of tumor cells to chemotherapy relies upon the same pathways.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mutations', 'MPA', (53, 62))	('cause', 'Reg', (47, 52))	('malignancy', 'Disease', 'MESH:D009369', (121, 131))	('genomic instability', 'MPA', (64, 83))	('tumor', 'Disease', (148, 153))	('malignancy', 'Disease', (121, 131))	('predispose', 'Reg', (88, 98))	('men', 'Species', '9606', (113, 116))	('defects', 'Var', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
44122	22754656	Furthermore, chemosensitivity can be restored in cisplatin-resistant ovarian cancer cell lines with elevated levels of ERCC1 via antisense RNA inhibition of ERCC1.	('ovarian cancer', 'Disease', (69, 83))	('antisense RNA', 'molecular_function', 'GO:0009388', ('129', '142'))	('ERCC1', 'Gene', '2067', (157, 162))	('ERCC1', 'Gene', '2067', (119, 124))	('RNA', 'cellular_component', 'GO:0005562', ('139', '142'))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('chemosensitivity', 'MPA', (13, 29))	('antisense', 'Var', (129, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ovarian cancer', 'Disease', 'MESH:D010051', (69, 83))	('ERCC1', 'Gene', (157, 162))	('restored', 'PosReg', (37, 45))	('ERCC1', 'Gene', (119, 124))
44123	22754656	ERCC1 was shown to predict response to cisplatin-based chemotherapy in advanced bladder cancer patients treated with gemcitabine plus cisplatin; patients with low levels of ERCC1 mRNA expression had a median survival of 25.4 months versus 15.4 months in those with high levels of expression.	('patients', 'Species', '9606', (145, 153))	('ERCC1', 'Gene', (0, 5))	('ERCC1', 'Gene', '2067', (0, 5))	('bladder cancer', 'Disease', (80, 94))	('bladder cancer', 'Disease', 'MESH:D001749', (80, 94))	('response to cisplatin', 'biological_process', 'GO:0072718', ('27', '48'))	('patients', 'Species', '9606', (95, 103))	('gemcitabine', 'Chemical', 'MESH:C056507', (117, 128))	('bladder cancer', 'Phenotype', 'HP:0009725', (80, 94))	('mRNA expression', 'MPA', (179, 194))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('ERCC1', 'Gene', '2067', (173, 178))	('ERCC1', 'Gene', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('low', 'Var', (159, 162))
44128	22754656	Similar to NER, MMR is also initiated by the detection of DNA damage and results in the excision of mismatched nucleotides or insertion/deletion loops, followed by resynthesis of the missing portion by DNA polymerase.	('excision', 'MPA', (88, 96))	('mismatched nucleotides', 'Var', (100, 122))	('DNA', 'cellular_component', 'GO:0005574', ('202', '205'))	('MMR', 'biological_process', 'GO:0006298', ('16', '19'))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('ER', 'Gene', '2099', (12, 14))	('NER', 'biological_process', 'GO:0006289', ('11', '14'))	('insertion/deletion loops', 'Var', (126, 150))
44130	22754656	While a predictive biomarker involved in the MMR pathway has not been identified and tested in the setting of urothelial carcinoma, a new report suggests that mutations in mismatch repair genes known to cause Lynch syndrome, which is associated with upper tract transitional cell carcinomas, may also pose an increased risk of bladder cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (262, 289))	('MMR', 'biological_process', 'GO:0006298', ('45', '48'))	('carcinomas', 'Phenotype', 'HP:0030731', (280, 290))	('carcinomas', 'Disease', 'MESH:D002277', (280, 290))	('urothelial carcinoma', 'Disease', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('cell carcinoma', 'Disease', 'MESH:C538614', (275, 289))	('bladder cancer', 'Disease', 'MESH:D001749', (327, 341))	('bladder cancer', 'Disease', (327, 341))	('mutations', 'Var', (159, 168))	('Lynch syndrome', 'Disease', (209, 223))	('bladder cancer', 'Phenotype', 'HP:0009725', (327, 341))	('cause', 'Reg', (203, 208))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (110, 130))	('mismatch repair', 'biological_process', 'GO:0006298', ('172', '187'))	('transitional cell carcinomas', 'Phenotype', 'HP:0006740', (262, 290))	('carcinomas', 'Disease', (280, 290))	('Lynch syndrome', 'Disease', 'MESH:D003123', (209, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('cell carcinoma', 'Disease', (275, 289))
44131	22754656	Furthermore, it has been hypothesized that defects in the DNA repair pathway, including MMR, may mediate the increased risk of bladder cancer secondary to the known carcinogenic effects of tobacco use.	('MMR', 'biological_process', 'GO:0006298', ('88', '91'))	('tobacco', 'Species', '4097', (189, 196))	('carcinogenic', 'Disease', 'MESH:D063646', (165, 177))	('bladder cancer', 'Phenotype', 'HP:0009725', (127, 141))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('carcinogenic', 'Disease', (165, 177))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('MMR', 'Gene', (88, 91))	('bladder cancer', 'Disease', 'MESH:D001749', (127, 141))	('bladder cancer', 'Disease', (127, 141))	('DNA repair pathway', 'Pathway', (58, 76))	('defects', 'Var', (43, 50))	('DNA repair', 'biological_process', 'GO:0006281', ('58', '68'))
44132	22754656	Therefore, in addition to likely mediating cisplatin resistance in urothelial carcinomas, defects in the MMR pathway may be involved in pathogenesis as well.	('pathogenesis', 'biological_process', 'GO:0009405', ('136', '148'))	('defects', 'Var', (90, 97))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (67, 88))	('MMR', 'biological_process', 'GO:0006298', ('105', '108'))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('involved', 'Reg', (124, 132))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('MMR pathway', 'Pathway', (105, 116))	('urothelial carcinomas', 'Disease', (67, 88))
44133	22754656	The tumor suppressor gene p53 has long been hypothesized to be a key player in the pathogenesis of invasive urothelial carcinoma, and preclinical studies support the role of p53 inactivation in urothelial proliferation and invasion.	('inactivation', 'Var', (178, 190))	('tumor', 'Disease', (4, 9))	('urothelial proliferation', 'CPA', (194, 218))	('pathogenesis', 'biological_process', 'GO:0009405', ('83', '95'))	('invasive urothelial carcinoma', 'Disease', (99, 128))	('p53', 'Gene', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor suppressor', 'biological_process', 'GO:0051726', ('4', '20'))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (99, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('invasion', 'CPA', (223, 231))	('p53', 'Gene', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('4', '20'))
44136	22754656	In contrast, a recent report of over 3,000 patients demonstrated that p53 had predictive value in advanced bladder cancer but in not superficial (Ta) disease.	('bladder cancer', 'Disease', 'MESH:D001749', (107, 121))	('p53', 'Var', (70, 73))	('bladder cancer', 'Disease', (107, 121))	('patients', 'Species', '9606', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (107, 121))
44139	22754656	The tumor suppressor gene breast-cancer-susceptibility gene 1 (BRCA1) together with proteins mutated in Fanconi's anemia (FA proteins), a rare inherited condition of chromosomal instability, are involved in the DNA repair pathway of homologous recombination (HR), which causes resistance to DNA inter-strand cross-links.	('tumor', 'Disease', (4, 9))	('homologous recombination', 'biological_process', 'GO:0035825', ('233', '257'))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('breast-cancer-susceptibility gene 1', 'Gene', (26, 61))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('4', '20'))	('mutated', 'Var', (93, 100))	('DNA', 'cellular_component', 'GO:0005574', ('211', '214'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('4', '20'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('chromosomal instability', 'Phenotype', 'HP:0040012', (166, 189))	('BRCA1', 'Gene', '672', (63, 68))	('DNA', 'cellular_component', 'GO:0005574', ('291', '294'))	('BRCA1', 'Gene', (63, 68))	("Fanconi's anemia", 'Disease', 'MESH:D005199', (104, 120))	('breast-cancer-susceptibility gene 1', 'Gene', '672', (26, 61))	('involved', 'Reg', (195, 203))	('anemia', 'Phenotype', 'HP:0001903', (114, 120))	("Fanconi's anemia", 'Disease', (104, 120))	('DNA repair', 'biological_process', 'GO:0006281', ('211', '221'))	("Fanconi's anemia", 'Phenotype', 'HP:0001994', (104, 120))
44169	22754656	Emerging data suggests that alterations in DNA repair pathways, specifically homologous recombination, nucleotide excision repair, and mismatch repair, may mediate resistance to platinum agents in urothelial carcinoma.	('resistance', 'CPA', (164, 174))	('mismatch repair', 'biological_process', 'GO:0006298', ('135', '150'))	('urothelial carcinoma', 'Disease', (197, 217))	('alterations', 'Var', (28, 39))	('mismatch repair', 'MPA', (135, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('DNA repair', 'biological_process', 'GO:0006281', ('43', '53'))	('nucleotide excision repair', 'MPA', (103, 129))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('103', '129'))	('DNA', 'Enzyme', (43, 46))	('homologous recombination', 'MPA', (77, 101))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('platinum', 'Chemical', 'MESH:D010984', (178, 186))	('mediate', 'Reg', (156, 163))	('homologous recombination', 'biological_process', 'GO:0035825', ('77', '101'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (197, 217))
44172	22754656	Low-grade urothelial cancers often have "gain-of-function" oncogene mutations.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (68, 77))	('urothelial cancers', 'Disease', 'MESH:D014523', (10, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('urothelial cancers', 'Disease', (10, 28))	('oncogene', 'Gene', (59, 67))
44173	22754656	High-grade urothelial cancers are characterized by "loss-of-function" mutations in tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutations', 'Var', (70, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('81', '97'))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('tumor', 'Disease', (83, 88))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('81', '97'))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('urothelial cancers', 'Disease', 'MESH:D014523', (11, 29))	('urothelial cancers', 'Disease', (11, 29))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
44192	21627811	Patient had also a transurethral resection of prostate due to urinary obstruction complicated by multiple tract infections one year prior to his current presentation.	('infections', 'Disease', 'MESH:D007239', (112, 122))	('urinary obstruction', 'Disease', (62, 81))	('infections', 'Disease', (112, 122))	('urinary obstruction', 'Disease', 'MESH:D001748', (62, 81))	('transurethral', 'Var', (19, 32))	('Patient', 'Species', '9606', (0, 7))
44208	21627811	Immunohistochemistry studies, using a battery of prostate specific antibodies, showed viable neoplastic cells staining positive for racemace/AMACR (Figure 4A) and negative for Prostate specific antigen (PSA), Prostate specific membrane antigen (PSMA), Prostate specific acid phosphatase (PSAP) and P501S (553-amino acid protein that is localized to the Golgi complex and expressed in both benign and neoplastic prostate tissues).	('PSA', 'Gene', '354', (203, 206))	('AMACR', 'Gene', '23600', (141, 146))	('Prostate specific membrane antigen', 'molecular_function', 'GO:0043275', ('209', '243'))	('Golgi complex', 'cellular_component', 'GO:0005794', ('353', '366'))	('P501S', 'Var', (298, 303))	('PSA', 'Gene', '354', (288, 291))	('PSMA', 'molecular_function', 'GO:0043275', ('245', '249'))	('Prostate specific antigen', 'Gene', (176, 201))	('phosphatase', 'molecular_function', 'GO:0016791', ('275', '286'))	('P501S', 'Mutation', 'p.P501S', (298, 303))	('Prostate specific membrane antigen', 'Gene', (209, 243))	('protein', 'cellular_component', 'GO:0003675', ('320', '327'))	('PSA', 'Gene', (203, 206))	('PSMA', 'Gene', '2346', (245, 249))	('PSA', 'Gene', (288, 291))	('Prostate specific antigen', 'Gene', '354', (176, 201))	('neoplastic prostate', 'Phenotype', 'HP:0100787', (400, 419))	('Prostate specific membrane antigen', 'Gene', '2346', (209, 243))	('PSMA', 'Gene', (245, 249))	('neoplastic prostate', 'Disease', (400, 419))	('AMACR', 'Gene', (141, 146))	('neoplastic prostate', 'Disease', 'MESH:D011471', (400, 419))	('membrane', 'cellular_component', 'GO:0016020', ('227', '235'))
44242	21627811	In concordance with prior reports, the neoplastic cells were negative for PSA, PSAP, PSMA, P501S but showed cytoplasmic staining with AMACR.	('P501S', 'Mutation', 'p.P501S', (91, 96))	('PSA', 'Gene', '354', (79, 82))	('PSA', 'Gene', (79, 82))	('P501S', 'Var', (91, 96))	('PSMA', 'Gene', (85, 89))	('PSMA', 'molecular_function', 'GO:0043275', ('85', '89'))	('PSA', 'Gene', '354', (74, 77))	('AMACR', 'Gene', '23600', (134, 139))	('AMACR', 'Gene', (134, 139))	('PSA', 'Gene', (74, 77))	('PSMA', 'Gene', '2346', (85, 89))
44245	21627811	Wei Li proved that high AMACR in the cytoplasm of hepatocellular carcinoma tumor cells was significantly associated with venous invasion, suggesting an important role of this enzyme in tumor invasiveness.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('AMACR', 'Gene', '23600', (24, 29))	('high', 'Var', (19, 23))	('tumor invasiveness', 'Disease', 'MESH:D009369', (185, 203))	('cytoplasm', 'cellular_component', 'GO:0005737', ('37', '46'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (50, 74))	('hepatocellular carcinoma tumor', 'Disease', 'MESH:D006528', (50, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor invasiveness', 'Disease', (185, 203))	('associated', 'Reg', (105, 115))	('AMACR', 'Gene', (24, 29))	('hepatocellular carcinoma tumor', 'Disease', (50, 80))	('venous', 'Disease', (121, 127))
44246	21627811	Molecular studies showed that squamous malignant cells can be either diploid (one case of adenosquamous carcinoma reported by Devaney, with well differentiated squamous component), or aneuploid or tetraploid (one case of adenosquamous carcinoma reported by Bassler with moderately differentiated squamous component).	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('adenosquamous carcinoma', 'Disease', (221, 244))	('tetraploid', 'Var', (197, 207))	('aneuploid', 'Disease', 'MESH:D000782', (184, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (226, 244))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (95, 113))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (90, 113))	('adenosquamous carcinoma', 'Disease', (90, 113))	('aneuploid', 'Disease', (184, 193))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (221, 244))
44254	33842332	Genome-Wide Analyses of Prognostic and Therapeutic Alternative Splicing Signatures in Bladder Urothelial Carcinoma Alternative splicing (AS) is an indispensable post-transcriptional modification applied during the maturation of mRNA, and AS defects have been associated with many cancers.	('Carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('AS', 'Gene', '112935892', (137, 139))	('Splicing', 'biological_process', 'GO:0045292', ('63', '71'))	('as', 'Gene', '112935892', (259, 261))	('cancers', 'Disease', (280, 287))	('cancers', 'Disease', 'MESH:D009369', (280, 287))	('splicing', 'biological_process', 'GO:0045292', ('127', '135'))	('AS', 'Gene', '112935892', (238, 240))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('Bladder Urothelial Carcinoma', 'Disease', 'MESH:D001749', (86, 114))	('Alternative splicing', 'Disease', (115, 135))	('Bladder Urothelial Carcinoma', 'Disease', (86, 114))	('defects', 'Var', (241, 248))
44265	33842332	The present findings revealed that DASEs and splicing factors tended to impact BLCA patient survival and sensitivity to chemotherapy drugs, which may provide novel prospects for BLCA therapies.	('BLCA', 'Chemical', '-', (178, 182))	('BLCA', 'Chemical', '-', (79, 83))	('sensitivity to chemotherapy drugs', 'MPA', (105, 138))	('splicing', 'biological_process', 'GO:0045292', ('45', '53'))	('patient', 'Species', '9606', (84, 91))	('BLCA', 'Disease', (79, 83))	('impact', 'Reg', (72, 78))	('AS', 'Gene', '112935892', (36, 38))	('splicing factors', 'Var', (45, 61))
44272	33842332	Aberrations in splicing events and their regulators, which are known as splicing factors (SFs), can lead to the development and progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('splicing', 'MPA', (15, 23))	('as', 'Gene', '112935892', (69, 71))	('development', 'CPA', (112, 123))	('Aberrations', 'Var', (0, 11))	('cancer', 'Disease', (143, 149))	('lead to', 'Reg', (100, 107))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('progression', 'CPA', (128, 139))	('splicing', 'biological_process', 'GO:0045292', ('72', '80'))	('splicing', 'biological_process', 'GO:0045292', ('15', '23'))
44361	33842332	Among these, the driving gene TP53 was mutated in 192 samples (accounting for > 47%), but no significant difference was observed for the TP53 distribution across the AS clusters (Chi-square test, P-values > 0.05;  Figure 8D ).	('as', 'Gene', '112935892', (117, 119))	('TP53', 'Gene', (30, 34))	('mutated', 'Var', (39, 46))	('AS', 'Gene', '112935892', (166, 168))	('as', 'Gene', '112935892', (36, 38))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', '7157', (30, 34))	('TP53', 'Gene', (137, 141))
44371	33842332	Changes in AS events can have significant effects on oncogenesis and tumor progression.	('oncogenesis', 'biological_process', 'GO:0007048', ('53', '64'))	('oncogenesis', 'CPA', (53, 64))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('effects', 'Reg', (42, 49))	('tumor', 'Disease', (69, 74))	('AS', 'Gene', '112935892', (11, 13))	('Changes', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
44373	33842332	Similarly, many recent studies have shown that DASEs regulated by differentially expressed SFs have effects on tumorigenesis, the epithelial-mesenchymal transition, and lymphatic metastasis.	('differentially expressed', 'Var', (66, 90))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('epithelial-mesenchymal transition', 'CPA', (130, 163))	('AS', 'Gene', '112935892', (48, 50))	('effects', 'Reg', (100, 107))	('as', 'Gene', '112935892', (185, 187))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('130', '163'))	('tumor', 'Disease', (111, 116))	('SFs', 'Gene', (91, 94))	('as', 'Gene', '112935892', (182, 184))
44382	33842332	reported that single-nucleotide polymorphisms can influence specific splicing events and are associated with BLCA risk scores.	('single-nucleotide polymorphisms', 'Var', (14, 45))	('as', 'Gene', '112935892', (93, 95))	('splicing', 'biological_process', 'GO:0045292', ('69', '77'))	('BLCA risk scores', 'Disease', (109, 125))	('BLCA', 'Chemical', '-', (109, 113))	('specific splicing events', 'MPA', (60, 84))	('influence', 'Reg', (50, 59))
44392	33842332	Based on the differential AS genes, we constructed a PPI network to display how differential protein variants interact in BLCA ( Figure 4 ).	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('BLCA', 'Disease', (122, 126))	('PPI', 'biological_process', 'GO:0060134', ('53', '56'))	('as', 'Gene', '112935892', (1, 3))	('variants', 'Var', (101, 109))	('interact', 'Reg', (110, 118))	('AS', 'Gene', '112935892', (26, 28))	('BLCA', 'Chemical', '-', (122, 126))
44417	33842332	We then used a submap algorithm to predict whether differences could be identified in response to anti-PD-1 and anti-CTAL-4 between the low- and high-risk groups.	('PD-1', 'Gene', '5133', (103, 107))	('anti-CTAL-4', 'Var', (112, 123))	('PD-1', 'Gene', (103, 107))
44442	33712636	Moreover, about two thirds of BLCA are exposed to APOBEC mutagenesis, which increases the mutational diversity within each individual tumor during development.	('APOBEC', 'cellular_component', 'GO:0030895', ('50', '56'))	('mutational diversity', 'MPA', (90, 110))	('BLCA', 'Phenotype', 'HP:0009725', (30, 34))	('increases', 'PosReg', (76, 85))	('mutagenesis', 'biological_process', 'GO:0006280', ('57', '68'))	('mutagenesis', 'Var', (57, 68))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('APOBEC', 'Gene', (50, 56))	('tumor', 'Disease', (134, 139))
44447	33712636	Variant calling from the 412 patients` tumor genomes resulted in an unfiltered variant count (UVC) of 201,937 genomic variations.	('patients', 'Species', '9606', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Variant calling', 'Var', (0, 15))	('tumor', 'Disease', (39, 44))
44448	33712636	Before DGIdb-based filtering, tumor samples showed a wide range of mutational load from 1 to 7320 SNVs (median 293).	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('mutational', 'Var', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (30, 35))
44450	33712636	Manual curation and the CIViC ("Clinical Interpretation of Variants in Cancer"; https://civicdb.org) query created a final total "drug load" of 0-66 drugs (median 27) per sample (Fig.	('Cancer', 'Disease', (71, 77))	('Variants', 'Var', (59, 67))	('Cancer', 'Disease', 'MESH:D009369', (71, 77))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
44452	33712636	A SENSITIVITY for veliparib is predicted by our algorithm, amongst others, in case of an ATM mutation due to the work of Subhash et al..	('ATM', 'Gene', '472', (89, 92))	('ATM', 'Gene', (89, 92))	('mutation', 'Var', (93, 101))
44453	33712636	In their study on gastric cancer they identified sensitivity for veliparib in case of ATM loss-of-function mutations of ATM.	('gastric cancer', 'Disease', (18, 32))	('gastric cancer', 'Disease', 'MESH:D013274', (18, 32))	('mutations', 'Var', (107, 116))	('ATM', 'Gene', '472', (86, 89))	('loss-of-function', 'NegReg', (90, 106))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('ATM', 'Gene', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('ATM', 'Gene', (86, 89))	('ATM', 'Gene', '472', (120, 123))
44456	33712636	An non-curated DGI for FGFR3 and ponatinib was called on the results of the study "Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models" by Gozgit et al..	('FGFR3', 'Gene', (23, 28))	('FGFR2', 'Gene', (196, 201))	('ponatinib', 'Chemical', 'MESH:C545373', (33, 42))	('mTOR', 'Gene', (115, 119))	('FGFR3', 'Gene', '2261', (23, 28))	('FGFR2', 'Gene', '2263', (196, 201))	('tumor', 'Disease', (178, 183))	('mTOR', 'Gene', '2475', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('FGFR2', 'Gene', (105, 110))	('endometrial cancer', 'Phenotype', 'HP:0012114', (209, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('FGFR2', 'Gene', '2263', (105, 110))	('endometrial cancer', 'Disease', (209, 227))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('endometrial cancer', 'Disease', 'MESH:D016889', (209, 227))	('ponatinib', 'Chemical', 'MESH:C545373', (123, 132))	('mutant', 'Var', (202, 208))
44460	33712636	While being tested in solid tumor basket trials or other solid tumor entities, at the time of our investigation 17 of the listed drugs have not been tested in explicit BLCA trials yet (ceritinib; CUDC-907 (fimepinostat); dacomitinib; DS-7423; entrectinib; gedatolisib; idelalisib; letrozole; margetuximab; MK-2206; PD-0325901 (mirdametinib); PF-04691502; pictilisib; ponatinib; rigosertib; rociletinib; VS-5584).	('tumor', 'Disease', (63, 68))	('PD-0325901', 'Disease', 'MESH:D010300', (315, 325))	('tumor', 'Disease', (28, 33))	('ponatinib', 'Chemical', 'MESH:C545373', (367, 376))	('PD-0325901', 'Disease', (315, 325))	('BLCA', 'Phenotype', 'HP:0009725', (168, 172))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('gedatolisib', 'Chemical', 'MESH:C549060', (256, 267))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('PF-04691502', 'Var', (342, 353))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
44477	33712636	BRAF mutations in melanoma or HER2 mutations in breast cancer.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('HER2', 'Gene', '2064', (30, 34))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('mutations', 'Var', (5, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('BRAF', 'Gene', '673', (0, 4))	('breast cancer', 'Disease', (48, 61))	('HER2', 'Gene', (30, 34))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))	('mutations', 'Var', (35, 44))
44487	33712636	Its mutations are described in many cancer entities.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('described', 'Reg', (18, 27))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('mutations', 'Var', (4, 13))
44488	33712636	In BLCA, mutated DNMT3A is known to cause hypermethylation and thereby silence promoters of tumor suppressor genes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('92', '108'))	('cause', 'Reg', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('mutated', 'Var', (9, 16))	('DNMT3A', 'Gene', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('DNMT3A', 'Gene', '1788', (17, 23))	('promoters', 'MPA', (79, 88))	('BLCA', 'Phenotype', 'HP:0009725', (3, 7))	('tumor', 'Disease', (92, 97))	('hypermethylation', 'MPA', (42, 58))	('silence', 'NegReg', (71, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('92', '108'))
44489	33712636	In the case of DNMT3A activating mutations, our algorithm acknowledged this pathogenetic mechanism and suggested use of the DNA methyltransferase inhibitor decitabine.	('DNMT3A', 'Gene', (15, 21))	('DNMT3A', 'Gene', '1788', (15, 21))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('mutations', 'Var', (33, 42))	('decitabine', 'Chemical', 'MESH:D000077209', (156, 166))	('activating', 'PosReg', (22, 32))
44490	33712636	In case of a PIK3CA mutation, our algorithm suggested CDK4/CDK6-inhibitor palbociclib.	('CDK', 'molecular_function', 'GO:0004693', ('59', '62'))	('PIK3CA', 'Gene', (13, 19))	('CDK4', 'Gene', (54, 58))	('mutation', 'Var', (20, 28))	('CDK6', 'Gene', (59, 63))	('CDK4', 'Gene', '1019', (54, 58))	('CDK6', 'Gene', '1021', (59, 63))	('PIK3CA', 'Gene', '5290', (13, 19))	('palbociclib', 'Chemical', 'MESH:C500026', (74, 85))	('CDK', 'molecular_function', 'GO:0004693', ('54', '57'))
44492	33712636	in breast cancer models, manual curation suggested PI3K-inhibition in combination with palbociclib in case of PIK3CA mutation.	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('PIK3CA', 'Gene', '5290', (110, 116))	('palbociclib', 'Chemical', 'MESH:C500026', (87, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('mutation', 'Var', (117, 125))	('PIK3CA', 'Gene', (110, 116))	('PI3K-inhibition', 'Var', (51, 66))
44505	33712636	Despite achieving a superior overall response rate with the combination of durvalumab and the PARP inhibitor olaparib in case of an DNA-damage-repair gene alteration, compared to durvalumab monotherapy none of the study arms could reach the threshold for a positive study result.	('durvalumab', 'Chemical', 'MESH:C000613593', (75, 85))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('durvalumab', 'Chemical', 'MESH:C000613593', (179, 189))	('PARP', 'Gene', '1302', (94, 98))	('alteration', 'Var', (155, 165))	('PARP', 'Gene', (94, 98))	('olaparib', 'Chemical', 'MESH:C531550', (109, 117))
44512	33712636	Based on the whole exome sequencing (WES) information, variants in the tumor genome have been identified and linked to their potentially targeting drugs.	('variants', 'Var', (55, 63))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
44513	33712636	We prioritized variants and drugs according to their clinical relevance and prevalence in bladder cancer patients.	('bladder cancer', 'Disease', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('patients', 'Species', '9606', (105, 113))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('variants', 'Var', (15, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))
44519	33712636	To investigate the genomic landscape of the 412 bladder cancer patients, we performed somatic variant calling for the identification of single nucleotide variants (SNVs), as well as copy number calling to identify copy number variants (CNVs).	('bladder cancer', 'Disease', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('single nucleotide variants', 'Var', (136, 162))	('patients', 'Species', '9606', (63, 71))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))
44521	33712636	Variants were annotated using SNPeff and SNPsift and enriched with information on their presence in ClinVar, COSMIC, and dbSNP, as well as their overall mutation impact (e.g.	('SNPsift', 'Disease', (41, 48))	('Variants', 'Var', (0, 8))	('SNPsift', 'Disease', 'None', (41, 48))	('dbSNP', 'Gene', (121, 126))
44522	33712636	We used the CNV caller Facets to call copy number variants on the matched tumor and normal samples for each patient.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('copy number variants', 'Var', (38, 58))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('patient', 'Species', '9606', (108, 115))
44528	33712636	Furthermore, we prioritized variants that occur more frequently across the TCGA-BLCA cohort, to obtain a final selection that is not only likely to be of clinical relevance, but also likely to have at least one targetable variant present in BLCA patients.	('patients', 'Species', '9606', (246, 254))	('variants', 'Var', (28, 36))	('TCGA-BLCA', 'Gene', (75, 84))	('BLCA', 'Phenotype', 'HP:0009725', (241, 245))	('BLCA', 'Phenotype', 'HP:0009725', (80, 84))
44532	33712636	In experimental studies, response "SENSITIVITY" was defined as deteriorated growth or decreased survival of the tumor model under administration of the drug, in case of mutated gene compared to wild type.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutated gene', 'Var', (169, 181))	('decreased', 'NegReg', (86, 95))	('tumor', 'Disease', (112, 117))	('growth', 'MPA', (76, 82))
44533	33712636	Response "RESISTANCE" was defined as accelerated growth or increased survival of the tumor model under administration of the drug, in case of mutated gene compared to wild type.	('tumor', 'Disease', (85, 90))	('growth', 'CPA', (49, 55))	('mutated gene', 'Var', (142, 154))	('accelerated', 'PosReg', (37, 48))	('survival', 'CPA', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('increased', 'PosReg', (59, 68))
44534	33712636	Response "UNKNOWN" was defined as no significant difference of clinical outcome or tumor model reaction when comparing mutant to wild type.	('tumor', 'Disease', (83, 88))	('mutant', 'Var', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))
44538	30387298	Silencing circular RNA UVRAG inhibits bladder cancer growth and metastasis by targeting the microRNA-223/fibroblast growth factor receptor 2 axis Circular RNA UVRAG (circUVRAG), a type of non-coding RNA, is derived and cyclized by part of the exon from the UVRAG gene.	('UVRAG', 'Gene', '7405', (159, 164))	('RNA', 'cellular_component', 'GO:0005562', ('155', '158'))	('Silencing', 'Var', (0, 9))	('UVRAG', 'Gene', '7405', (23, 28))	('UVRAG', 'Gene', (159, 164))	('circUVRAG', 'Chemical', '-', (166, 175))	('UVRAG', 'Gene', (23, 28))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('105', '129'))	('bladder cancer', 'Disease', 'MESH:D001749', (38, 52))	('bladder cancer', 'Disease', (38, 52))	('inhibits', 'NegReg', (29, 37))	('bladder cancer', 'Phenotype', 'HP:0009725', (38, 52))	('RNA', 'cellular_component', 'GO:0005562', ('19', '22'))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('UVRAG', 'Gene', '7405', (170, 175))	('UVRAG', 'Gene', (170, 175))	('RNA', 'cellular_component', 'GO:0005562', ('199', '202'))	('UVRAG', 'Gene', '7405', (257, 262))	('UVRAG', 'Gene', (257, 262))
44550	30387298	Taken together, silencing circular RNA UVRAG inhibited bladder cancer growth and metastasis by targeting the miR-223/FGFR2 axis, which may provide a potential biomarker and therapeutic target for the management of BLCA.	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('bladder cancer', 'Disease', (55, 69))	('UVRAG', 'Gene', (39, 44))	('FGFR2', 'Gene', (117, 122))	('UVRAG', 'Gene', '7405', (39, 44))	('FGFR2', 'Gene', '2263', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('targeting', 'Reg', (95, 104))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('silencing', 'Var', (16, 25))	('FGFR', 'molecular_function', 'GO:0005007', ('117', '121'))	('inhibited', 'NegReg', (45, 54))	('BLCA', 'Phenotype', 'HP:0009725', (214, 218))	('RNA', 'cellular_component', 'GO:0005562', ('35', '38'))
44551	30387298	BLCA bladder cancer circUVRAG circular RNA UVRAG FGFR2 fibroblast growth factor receptor 2 miR-223 micro RNA-223 miRNA micro RNA sicircUVRAG small interfering circular RNA UVRAG Bladder cancer is a common malignant tumor of the urinary system.	('RNA', 'cellular_component', 'GO:0005562', ('105', '108'))	('RNA', 'cellular_component', 'GO:0005562', ('168', '171'))	('RNA', 'cellular_component', 'GO:0005562', ('125', '128'))	('UVRAG', 'Gene', '7405', (24, 29))	('malignant tumor', 'Disease', (205, 220))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor of the urinary system', 'Phenotype', 'HP:0010786', (215, 242))	('UVRAG', 'Gene', (24, 29))	('UVRAG', 'Gene', '7405', (135, 140))	('Bladder cancer', 'Phenotype', 'HP:0009725', (178, 192))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('55', '79'))	('UVRAG', 'Gene', (135, 140))	('malignant tumor', 'Disease', 'MESH:D018198', (205, 220))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('FGFR2', 'Gene', (49, 54))	('UVRAG', 'Gene', '7405', (172, 177))	('BLCA', 'Phenotype', 'HP:0009725', (0, 4))	('circUVRAG', 'Chemical', '-', (20, 29))	('Bladder cancer', 'Disease', 'MESH:D001749', (178, 192))	('UVRAG', 'Gene', (172, 177))	('circUVRAG', 'Chemical', '-', (131, 140))	('UVRAG', 'Gene', '7405', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('Bladder cancer', 'Disease', (178, 192))	('UVRAG', 'Gene', (43, 48))	('FGFR2', 'Gene', '2263', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('bladder cancer', 'Disease', 'MESH:D001749', (5, 19))	('bladder cancer', 'Disease', (5, 19))	('small interfering circular', 'Var', (141, 167))	('RNA', 'cellular_component', 'GO:0005562', ('39', '42'))	('bladder cancer', 'Phenotype', 'HP:0009725', (5, 19))
44588	30387298	Results showed that the expression of circUVRAG was significantly decreased after silencing of circUVRAG (Figure 2A).	('circUVRAG', 'Gene', (38, 47))	('expression', 'Species', '29278', (24, 34))	('expression', 'MPA', (24, 34))	('decreased', 'NegReg', (66, 75))	('silencing', 'Var', (82, 91))	('circUVRAG', 'Chemical', '-', (95, 104))	('circUVRAG', 'Chemical', '-', (38, 47))	('circUVRAG', 'Gene', (95, 104))
44591	30387298	qRT-PCR assays showed that the expression of miR-223 was increased after knockdown of circUVRAG in tumor tissues (Figure 2F).	('tumor', 'Disease', (99, 104))	('circUVRAG', 'Chemical', '-', (86, 95))	('miR-223', 'Gene', (45, 52))	('expression', 'Species', '29278', (31, 41))	('circUVRAG', 'Gene', (86, 95))	('expression', 'MPA', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('increased', 'PosReg', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('knockdown', 'Var', (73, 82))
44592	30387298	Western blot analyses showed that silencing of circUVRAG suppressed FGFR2 expression (Figure 2G,H).	('expression', 'MPA', (74, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('68', '72'))	('FGFR2', 'Gene', '2263', (68, 73))	('circUVRAG', 'Chemical', '-', (47, 56))	('expression', 'Species', '29278', (74, 84))	('silencing', 'Var', (34, 43))	('FGFR2', 'Gene', (68, 73))	('circUVRAG', 'Gene', (47, 56))	('suppressed', 'NegReg', (57, 67))
44600	30387298	CCK-8 and cloning formation assays showed that circUVRAG knockdown suppressed the proliferation of UM-UC-3 cells, but treatment with the miR-223 inhibitor rescued the suppression effect of circUVRAG silencing.	('UM-UC-3', 'CellLine', 'CVCL:1783', (99, 106))	('miR-223', 'Gene', (137, 144))	('proliferation of UM-UC-3 cells', 'CPA', (82, 112))	('formation', 'biological_process', 'GO:0009058', ('18', '27'))	('knockdown', 'Var', (57, 66))	('circUVRAG', 'Chemical', '-', (47, 56))	('circUVRAG', 'Chemical', '-', (189, 198))	('suppressed', 'NegReg', (67, 77))
44606	30387298	To further confirm the relationship between FGFR2 and miR-223, UM-UC-3 cells were transfected with miR-223 mimics combined with or without a FGFR2 overexpression vector.	('miR-223', 'Gene', (99, 106))	('expression', 'Species', '29278', (151, 161))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('FGFR2', 'Gene', (141, 146))	('FGFR2', 'Gene', '2263', (141, 146))	('UM-UC-3', 'CellLine', 'CVCL:1783', (63, 70))	('mimics', 'Var', (107, 113))	('FGFR2', 'Gene', '2263', (44, 49))	('FGFR2', 'Gene', (44, 49))	('FGFR', 'molecular_function', 'GO:0005007', ('141', '145'))
44613	30387298	To confirm the relationships among miR-223, circUVRAG, and FGFR2, bioinformatics analyses showed that circUVRAG targeted miR-223.	('FGFR2', 'Gene', (59, 64))	('FGFR2', 'Gene', '2263', (59, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('circUVRAG', 'Chemical', '-', (102, 111))	('circUVRAG', 'Chemical', '-', (44, 53))	('miR-223', 'Gene', (121, 128))	('circUVRAG', 'Var', (102, 111))	('targeted', 'Reg', (112, 120))
44617	30387298	The results suggested that silencing circUVRAG inhibited bladder cancer metastasis and growth by targeting the miR-223/FGFR2 axis.	('inhibited', 'NegReg', (47, 56))	('silencing', 'Var', (27, 36))	('FGFR2', 'Gene', '2263', (119, 124))	('circUVRAG', 'Chemical', '-', (37, 46))	('bladder cancer metastasis', 'Disease', 'MESH:D009362', (57, 82))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('growth', 'CPA', (87, 93))	('bladder cancer metastasis', 'Disease', (57, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))	('targeting', 'Reg', (97, 106))	('circUVRAG', 'Gene', (37, 46))	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))	('FGFR2', 'Gene', (119, 124))
44621	30387298	Recent studies have reported that UVRAG not only promotes Beclin-1-mediated autophagy, but it also facilitates endosome/autophagosome maturation.18, 19 Activation of autophagy can increase chemo- and radiotherapy resistance in bladder cancer.20, 21, 22 We also found that high expression of UVRAG predicted poor prognosis, which was consistent with the role of circUVRAG.	('high expression', 'Var', (272, 287))	('UVRAG', 'Gene', '7405', (365, 370))	('UVRAG', 'Gene', (365, 370))	('autophagy', 'biological_process', 'GO:0016236', ('76', '85'))	('autophagosome maturation', 'biological_process', 'GO:0097352', ('120', '144'))	('UVRAG', 'Gene', '7405', (291, 296))	('UVRAG', 'Gene', (291, 296))	('autophagy', 'biological_process', 'GO:0006914', ('76', '85'))	('autophagy', 'biological_process', 'GO:0016236', ('166', '175'))	('endosome', 'cellular_component', 'GO:0005768', ('111', '119'))	('bladder cancer', 'Disease', 'MESH:D001749', (227, 241))	('bladder cancer', 'Disease', (227, 241))	('circUVRAG', 'Chemical', '-', (361, 370))	('autophagosome', 'cellular_component', 'GO:0005776', ('120', '133'))	('UVRAG', 'Gene', '7405', (34, 39))	('poor prognosis', 'CPA', (307, 321))	('bladder cancer', 'Phenotype', 'HP:0009725', (227, 241))	('UVRAG', 'Gene', (34, 39))	('expression', 'Species', '29278', (277, 287))	('autophagy', 'biological_process', 'GO:0006914', ('166', '175'))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
44623	30387298	Previous studies have reported that miR-223 acts as a suppressor and as a potential therapeutic target for glioblastoma,23 colorectal cancer,24 lung cancer,25 colon adenocarcinoma,26 and bladder cancer.27 In the present study, we also found that downregulation of circUVRAG promoted miR-223 expression.	('colon adenocarcinoma', 'Disease', (159, 179))	('colorectal cancer', 'Disease', (123, 140))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (107, 119))	('expression', 'Species', '29278', (291, 301))	('glioblastoma', 'Disease', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('miR-223', 'Gene', (283, 290))	('downregulation', 'Var', (246, 260))	('promoted', 'PosReg', (274, 282))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (159, 179))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('expression', 'MPA', (291, 301))	('bladder cancer', 'Disease', 'MESH:D001749', (187, 201))	('lung cancer', 'Disease', (144, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('bladder cancer', 'Disease', (187, 201))	('bladder cancer', 'Phenotype', 'HP:0009725', (187, 201))	('circUVRAG', 'Chemical', '-', (264, 273))	('colorectal cancer', 'Disease', 'MESH:D015179', (123, 140))
44624	30387298	Bioinformatics analysis found that circUVRAG interacted with several miRNAs including miR-507, miR-508, and miR-653, but miR-223 has more conservative binding sites.	('circUVRAG', 'Chemical', '-', (35, 44))	('interacted', 'Interaction', (45, 55))	('binding', 'Interaction', (151, 158))	('miR-653', 'Var', (108, 115))	('miR-508', 'Var', (95, 102))	('miR-507', 'Var', (86, 93))	('binding', 'molecular_function', 'GO:0005488', ('151', '158'))
44627	30387298	Our data also showed that miR-223 interacted with the 3'-UTR of FGFR and suppressed FGFR2 expression on a post-transcriptional level.	('FGFR', 'Gene', (64, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('FGFR2', 'Gene', (84, 89))	('FGFR2', 'Gene', '2263', (84, 89))	('expression', 'Species', '29278', (90, 100))	('miR-223', 'Var', (26, 33))	('expression', 'MPA', (90, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('84', '88'))	('suppressed', 'NegReg', (73, 83))	('interacted', 'Interaction', (34, 44))
44631	30387298	Collectively, our study showed for the first time that silencing circUVRAG suppressed the proliferation and metastasis abilities of BLCA cells by targeting the miR-223/FGFR2 axis, which indicated that circUVRAG could be used as a potential biomarker for the prognosis of BLCA.	('FGFR2', 'Gene', (168, 173))	('suppressed', 'NegReg', (75, 85))	('FGFR2', 'Gene', '2263', (168, 173))	('circUVRAG', 'Gene', (65, 74))	('proliferation', 'CPA', (90, 103))	('silencing', 'Var', (55, 64))	('BLCA', 'Phenotype', 'HP:0009725', (271, 275))	('FGFR', 'molecular_function', 'GO:0005007', ('168', '172'))	('targeting', 'Reg', (146, 155))	('BLCA', 'Phenotype', 'HP:0009725', (132, 136))	('circUVRAG', 'Chemical', '-', (65, 74))	('circUVRAG', 'Chemical', '-', (201, 210))	('metastasis abilities of BLCA', 'CPA', (108, 136))
44641	30428884	Overexpression of cytoplasmic REDD1 in ovarian cancer was significantly associated with serous carcinoma (P < 0.001), late-stage disease (P < 0.001), ascites (P < 0.001), and partial or non-response to chemotherapy (P < 0.001).	('late-stage disease', 'Disease', (118, 136))	('ascites', 'Disease', 'MESH:D001201', (150, 157))	('ascites', 'Phenotype', 'HP:0001541', (150, 157))	('cytoplasmic', 'Var', (18, 29))	('REDD1 in ovarian cancer', 'Disease', 'MESH:D010051', (30, 53))	('serous carcinoma', 'Disease', (88, 104))	('associated', 'Reg', (72, 82))	('ascites', 'Disease', (150, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (39, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('Overexpression', 'Var', (0, 14))	('serous carcinoma', 'Disease', 'MESH:D018284', (88, 104))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('late-stage disease', 'Disease', 'MESH:D062706', (118, 136))	('REDD1 in ovarian cancer', 'Disease', (30, 53))
44642	30428884	High cytoplasmic expression of REDD1 was correlated with poorer overall survival (P < 0.001) and disease-free survival (P < 0.001).	('REDD1', 'Gene', '54541', (31, 36))	('REDD1', 'Gene', (31, 36))	('disease-free survival', 'CPA', (97, 118))	('overall survival', 'CPA', (64, 80))	('poorer', 'NegReg', (57, 63))	('High cytoplasmic', 'Var', (0, 16))
44643	30428884	The multivariate Cox proportional hazards regression analysis indicated that patients with high cytoplasmic REDD1 expression had a high risk of death (P < 0.001) and high risk of an event (i.e., recurrence, progression, or death) (P < 0.001).	('high cytoplasmic', 'Var', (91, 107))	('Cox', 'Gene', '1351', (17, 20))	('REDD1', 'Gene', '54541', (108, 113))	('Cox', 'Gene', (17, 20))	('death', 'Disease', 'MESH:D003643', (144, 149))	('REDD1', 'Gene', (108, 113))	('death', 'Disease', (144, 149))	('death', 'Disease', 'MESH:D003643', (223, 228))	('death', 'Disease', (223, 228))	('patients', 'Species', '9606', (77, 85))	('progression', 'CPA', (207, 218))	('recurrence', 'Disease', (195, 205))
44687	30428884	The REDD1 primary antibody for immunoblotting (10638-1-AP) was obtained from Proteintech.	('antibody', 'cellular_component', 'GO:0019814', ('18', '26'))	('10638-1-AP', 'Var', (47, 57))	('antibody', 'molecular_function', 'GO:0003823', ('18', '26'))	('antibody', 'cellular_component', 'GO:0042571', ('18', '26'))	('REDD1', 'Gene', '54541', (4, 9))	('antibody', 'cellular_component', 'GO:0019815', ('18', '26'))	('REDD1', 'Gene', (4, 9))
44688	30428884	Anti-rabbit (cs-7074) and anti-mouse (cs-7076) secondary antibodies bound to HRP were obtained from Cell Signaling Technology (Massachusetts, US).	('cs-7074', 'Var', (13, 20))	('bound', 'Interaction', (68, 73))	('HRP', 'Protein', (77, 80))	('Signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('cs', 'Chemical', 'MESH:D002586', (38, 40))	('cs', 'Chemical', 'MESH:D002586', (13, 15))	('mouse', 'Species', '10090', (31, 36))	('cs-7076', 'Var', (38, 45))	('rabbit', 'Species', '9986', (5, 11))
44693	30428884	The Kaplan-Meier method was used to estimate the probability of overall survival and disease-free survival, and the log-rank test was used to compare the overall survival or disease-free survival between different comparison groups, such as patients with low or high REDD1 expression.	('REDD1', 'Gene', '54541', (267, 272))	('low', 'Var', (255, 258))	('REDD1', 'Gene', (267, 272))	('high', 'Var', (262, 266))	('patients', 'Species', '9606', (241, 249))	('expression', 'MPA', (273, 283))
44713	30428884	Cytoplasmic and nuclear staining in cancer cells were analyzed, and high cytoplasmic REDD1 expression was associated with serous carcinoma (P < 0.001), late-stage disease (P < 0.001) (the cut- off for early vs. late stage is I-II vs. III-IV), and ascites (P < 0.001).	('late-stage disease', 'Disease', 'MESH:D062706', (152, 170))	('late-stage disease', 'Disease', (152, 170))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('associated', 'Reg', (106, 116))	('ascites', 'Disease', 'MESH:D001201', (247, 254))	('ascites', 'Disease', (247, 254))	('ascites', 'Phenotype', 'HP:0001541', (247, 254))	('cancer', 'Disease', (36, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('REDD1', 'Gene', '54541', (85, 90))	('serous carcinoma', 'Disease', (122, 138))	('serous carcinoma', 'Disease', 'MESH:D018284', (122, 138))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('REDD1', 'Gene', (85, 90))	('high cytoplasmic', 'Var', (68, 84))
44721	30428884	High nuclear REDD1 expression was associated with clear cell carcinoma (P = 0.043).	('associated', 'Reg', (34, 44))	('expression', 'MPA', (19, 29))	('High nuclear', 'Var', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('clear cell carcinoma', 'Disease', (50, 70))	('REDD1', 'Gene', '54541', (13, 18))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (50, 70))	('REDD1', 'Gene', (13, 18))
44728	30428884	Patients with high REDD1 expression had worse overall survival rates (P < 0.001) (Fig.	('REDD1', 'Gene', '54541', (19, 24))	('overall survival', 'MPA', (46, 62))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('REDD1', 'Gene', (19, 24))
44731	30428884	Patients with high REDD1 expression had worse overall survival rate (P < 0.05) and disease free survival rate (P < 0.05) than patients with low REDD1 expression (Fig.	('disease free survival rate', 'CPA', (83, 109))	('REDD1', 'Gene', (144, 149))	('worse', 'NegReg', (40, 45))	('REDD1', 'Gene', '54541', (19, 24))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('REDD1', 'Gene', (19, 24))	('patients', 'Species', '9606', (126, 134))	('REDD1', 'Gene', '54541', (144, 149))	('overall survival rate', 'CPA', (46, 67))
44737	30428884	High REDD1 expression was found to be an independent prognostic factor for poor OS and DFS.	('High', 'Var', (0, 4))	('OS', 'Chemical', '-', (80, 82))	('expression', 'MPA', (11, 21))	('REDD1', 'Gene', '54541', (5, 10))	('REDD1', 'Gene', (5, 10))	('DFS', 'Disease', (87, 90))	('poor OS', 'Disease', (75, 82))
44740	30428884	Because our data showed that high REDD1 expression correlated with poor ovarian cancer patient prognosis, we explored the effect of REDD1 on the migration and invasion of ovarian cancer cells.	('expression', 'MPA', (40, 50))	('high', 'Var', (29, 33))	('REDD1', 'Gene', (34, 39))	('ovarian cancer', 'Disease', 'MESH:D010051', (171, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('ovarian cancer', 'Phenotype', 'HP:0100615', (171, 185))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('REDD1', 'Gene', '54541', (132, 137))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('ovarian cancer', 'Disease', (171, 185))	('patient', 'Species', '9606', (87, 94))	('ovarian cancer', 'Disease', 'MESH:D010051', (72, 86))	('REDD1', 'Gene', '54541', (34, 39))	('REDD1', 'Gene', (132, 137))	('ovarian cancer', 'Disease', (72, 86))	('correlated', 'Reg', (51, 61))
44749	30428884	reported that high REDD1 expression was correlated with a shorter DFS and OS in 100 ovarian cancer specimens by Kaplan Meier survival analysis; however, multivariate factor analysis was not performed to evaluate the value of REDD1 expression for ovarian cancer prognoses, and REDD1 expression in different locations (cytoplasm and nuclear) was not discretely correlated with the clinical pathologic factors and patient survival.	('REDD1', 'Gene', (276, 281))	('OS in 100 ovarian cancer', 'Disease', (74, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('cytoplasm', 'cellular_component', 'GO:0005737', ('317', '326'))	('OS in 100 ovarian cancer', 'Disease', 'MESH:C567932', (74, 98))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('shorter', 'NegReg', (58, 65))	('REDD1', 'Gene', '54541', (276, 281))	('expression', 'MPA', (25, 35))	('high', 'Var', (14, 18))	('ovarian cancer', 'Disease', 'MESH:D010051', (246, 260))	('patient', 'Species', '9606', (411, 418))	('DFS', 'MPA', (66, 69))	('REDD1', 'Gene', (19, 24))	('REDD1', 'Gene', (225, 230))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('REDD1', 'Gene', '54541', (225, 230))	('REDD1', 'Gene', '54541', (19, 24))	('ovarian cancer', 'Disease', (246, 260))	('ovarian cancer', 'Phenotype', 'HP:0100615', (246, 260))
44753	30428884	Our data showed that high cytoplasmic rather than nuclear expression of REDD1 was associated with serous carcinoma, late-stage disease, and partial or no chemotherapy response.	('REDD1', 'Gene', '54541', (72, 77))	('late-stage disease', 'Disease', 'MESH:D062706', (116, 134))	('associated', 'Reg', (82, 92))	('late-stage disease', 'Disease', (116, 134))	('high cytoplasmic', 'Var', (21, 37))	('REDD1', 'Gene', (72, 77))	('serous carcinoma', 'Disease', (98, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('serous carcinoma', 'Disease', 'MESH:D018284', (98, 114))
44757	30428884	Here, we noted that high nuclear REDD1 expression was more common in clear cell carcinoma than in the other ovarian cancer histotypes.	('expression', 'MPA', (39, 49))	('common', 'Reg', (59, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('REDD1', 'Gene', '54541', (33, 38))	('carcinoma than in the other ovarian cancer', 'Disease', 'MESH:D010051', (80, 122))	('high nuclear', 'Var', (20, 32))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (69, 89))	('clear cell carcinoma', 'Disease', (69, 89))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('REDD1', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('carcinoma than in the other ovarian cancer', 'Disease', (80, 122))
44770	30428884	On the other hand, multivariate Cox proportional hazards regression analysis showed that cytoplasmic REDD1 expression was strongly associated with overall survival and disease-free survival (P < 0.001 and P < 0.001, respectively) and also adjusted by other variables (age, histologic type, response to chemotherapy, and stage).	('REDD1', 'Gene', '54541', (101, 106))	('disease-free survival', 'CPA', (168, 189))	('cytoplasmic', 'Var', (89, 100))	('associated', 'Reg', (131, 141))	('REDD1', 'Gene', (101, 106))	('Cox', 'Gene', '1351', (32, 35))	('Cox', 'Gene', (32, 35))	('overall survival', 'CPA', (147, 163))
44778	30428884	High REDD1 expression is associated with a poor prognosis for ovarian cancer patients, and might be a predictor of chemotherapy response for ovarian cancer patients.	('patients', 'Species', '9606', (156, 164))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('expression', 'MPA', (11, 21))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('REDD1', 'Gene', '54541', (5, 10))	('ovarian cancer', 'Disease', 'MESH:D010051', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('patients', 'Species', '9606', (77, 85))	('ovarian cancer', 'Phenotype', 'HP:0100615', (141, 155))	('REDD1', 'Gene', (5, 10))	('ovarian cancer', 'Disease', 'MESH:D010051', (141, 155))	('ovarian cancer', 'Disease', (62, 76))	('ovarian cancer', 'Disease', (141, 155))
44827	29593429	The final Arp2 expression score was calculated using the value of the proportion of positive cell score multiplied by the staining intensity score as "-" (score, 0-1), "+" (score, 2-3), "++" (score, 4-5), or "+++" (score, >=6).	('Arp2', 'Gene', (10, 14))	('++" (score, 4-5', 'Var', (187, 202))	('+" (score, 2-3', 'Var', (169, 183))	('Arp2', 'Gene', '10109', (10, 14))
44845	29593429	The results indicated that the 5-year RFS of the BUC patients was significantly associated with an increased Arp2 expression and multiple clinical features, including tumor size, clinical T stage, and lymph node metastasis (P < 0.05; Table 5).	('lymph node metastasis', 'CPA', (201, 222))	('patients', 'Species', '9606', (53, 61))	('clinical', 'Species', '191496', (138, 146))	('Arp2', 'Gene', (109, 113))	('Arp2', 'Gene', '10109', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('increased', 'PosReg', (99, 108))	('expression', 'MPA', (114, 124))	('RFS', 'Var', (38, 41))	('tumor', 'Disease', (167, 172))	('clinical', 'Species', '191496', (179, 187))
44867	29593429	Since it has been revealed that the risk of lymph node metastasis in patients with an increased expression of Arp2 is 1.66-fold higher than that of patients without an increased expression of Arp2, it is clinically reasonable to conclude that Arp2 could function as a potential indicator for predicting lymph node metastasis.	('patients', 'Species', '9606', (148, 156))	('Arp2', 'Gene', (243, 247))	('clinical', 'Species', '191496', (204, 212))	('Arp2', 'Gene', (192, 196))	('Arp2', 'Gene', '10109', (243, 247))	('lymph node metastasis', 'CPA', (44, 65))	('Arp2', 'Gene', '10109', (192, 196))	('Arp2', 'Gene', (110, 114))	('patients', 'Species', '9606', (69, 77))	('Arp2', 'Gene', '10109', (110, 114))	('expression', 'Var', (96, 106))
44871	29593429	Several potential mechanisms could be involved to explain the association between expression of Arp2 and BUC carcinogenesis.	('BUC carcinogenesis', 'Disease', 'MESH:D063646', (105, 123))	('association', 'Interaction', (62, 73))	('BUC carcinogenesis', 'Disease', (105, 123))	('expression', 'Var', (82, 92))	('Arp2', 'Gene', (96, 100))	('Arp2', 'Gene', '10109', (96, 100))
44875	29593429	The migration ability was partly activated by the Arp2 expression in BUC cell carcinogenesis.	('Arp2', 'Gene', (50, 54))	('activated', 'PosReg', (33, 42))	('migration ability', 'CPA', (4, 21))	('Arp2', 'Gene', '10109', (50, 54))	('BUC cell carcinogenesis', 'Disease', (69, 92))	('expression', 'Var', (55, 65))
44978	28761743	The objective RR was 31%; 46.6% in the PD-L1 positive, 0% in the PD-L1 negative.	('PD-L1', 'Gene', (39, 44))	('positive', 'Var', (45, 53))	('PD-L1', 'Gene', '29126', (39, 44))	('PD-L1', 'Gene', (65, 70))	('PD-L1', 'Gene', '29126', (65, 70))
45037	28761743	Preclinical models have demonstrated that VEGF inhibitors can antagonise immunosupression and form potent antitumour T-cells.	('inhibitors', 'Var', (47, 57))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('VEGF', 'Gene', '7422', (42, 46))	('antagonise', 'NegReg', (62, 72))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('immunosupression', 'CPA', (73, 89))	('VEGF', 'Gene', (42, 46))	('tumour', 'Disease', (110, 116))
45054	28761743	Grade 3 and 4 toxicities occurred in 19 patients (43%); 5 in the N3I1 and 14 in the N1I3 group.	('patients', 'Species', '9606', (40, 48))	('toxicities', 'Disease', 'MESH:D064420', (14, 24))	('N3I1', 'Var', (65, 69))	('toxicities', 'Disease', (14, 24))
45059	28761743	The PSA decline was reported in 13.1% of the patients treated with ipilimumab and in 5.3% of the patients on placebo.	('ipilimumab', 'Var', (67, 77))	('decline', 'NegReg', (8, 15))	('ipilimumab', 'Chemical', 'MESH:D000074324', (67, 77))	('patients', 'Species', '9606', (45, 53))	('PSA', 'Disease', (4, 7))	('patients', 'Species', '9606', (97, 105))
45072	28761743	In cohort 2 of the IMvigor210 study, the patients with the PD-L1 expression >=5% had the ORR of 26%, in comparison with the patients with <1% expression who responded in 8% of cases.	('expression >=5%', 'Var', (65, 80))	('>=5%', 'Var', (76, 80))	('PD-L1', 'Gene', (59, 64))	('patients', 'Species', '9606', (41, 49))	('PD-L1', 'Gene', '29126', (59, 64))	('patients', 'Species', '9606', (124, 132))
45076	28761743	In this study, the cut-off value for the PD-L1 positivity was significantly higher than in other trials.	('higher', 'PosReg', (76, 82))	('PD-L1', 'Gene', (41, 46))	('positivity', 'Var', (47, 57))	('PD-L1', 'Gene', '29126', (41, 46))
45078	28761743	Patients treated with pembrolizumab in the KEYNOTE-045 had shorter survival in the group with the expression >=10% CPS, although pembrolizumab did result in benefits in both groups.	('CPS', 'Var', (115, 118))	('shorter', 'NegReg', (59, 66))	('survival', 'MPA', (67, 75))	('pembrolizumab', 'Chemical', 'MESH:C582435', (129, 142))	('CPS', 'Chemical', '-', (115, 118))	('Patients', 'Species', '9606', (0, 8))	('pembrolizumab', 'Chemical', 'MESH:C582435', (22, 35))
45088	28761743	In cohort 1, the mutational load was a much better predictor of response than PD-L1 expression.	('PD-L1', 'Gene', (78, 83))	('mutational load', 'Var', (17, 32))	('PD-L1', 'Gene', '29126', (78, 83))
45101	25088195	Comparison of gene expression patterns across twelve tumor types identifies a cancer supercluster characterized by TP53 mutations and cell cycle defects Transcriptional profile based subtypes of cancer are often viewed as identifying different diseases from the same tissue origin.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('TP53', 'Gene', '7157', (115, 119))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cell cycle', 'biological_process', 'GO:0007049', ('134', '144'))	('gene expression', 'biological_process', 'GO:0010467', ('14', '29'))	('TP53', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))	('tumor', 'Disease', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cell cycle defects', 'Phenotype', 'HP:0011018', (134, 152))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
45103	25088195	One of the largest superclusters was determined by the upregulation of a proliferation signature, significant enrichment in TP53 mutations, genomic loss of CDKN2A (p16ARF), evidence of increased numbers of DNA double strand breaks and high expression of cyclin B1 protein.	('cyclin B1', 'Gene', (254, 263))	('CDKN2A', 'Gene', (156, 162))	('TP53', 'Gene', '7157', (124, 128))	('loss', 'NegReg', (148, 152))	('protein', 'cellular_component', 'GO:0003675', ('264', '271'))	('DNA', 'cellular_component', 'GO:0005574', ('206', '209'))	('mutations', 'Var', (129, 138))	('CDKN2A', 'Gene', '1029', (156, 162))	('TP53', 'Gene', (124, 128))	('expression', 'MPA', (240, 250))	('increased', 'PosReg', (185, 194))	('cyclin', 'molecular_function', 'GO:0016538', ('254', '260'))	('upregulation', 'PosReg', (55, 67))	('cyclin B1', 'Gene', '891', (254, 263))
45104	25088195	These correlations suggested that abrogation of the P53 mediated apoptosis response to DNA damage results in activation of cell cycle pathways and represents a common theme in cancer.	('P53', 'Gene', '7157', (52, 55))	('cell', 'Pathway', (123, 127))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('activation', 'PosReg', (109, 119))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('apoptosis', 'CPA', (65, 74))	('abrogation', 'Var', (34, 44))	('P53', 'Gene', (52, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cell cycle', 'biological_process', 'GO:0007049', ('123', '133'))
45110	25088195	Furthermore, molecular subtypes are frequently found to associate with somatic alterations, such as EGFR abnormalities in the classical subtype of glioblastoma, or the enrichment of NF1 deletions and mutations in the primitive group of lung squamous carcinoma.	('associate', 'Reg', (56, 65))	('EGFR', 'Gene', '1956', (100, 104))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (236, 259))	('mutations', 'Var', (200, 209))	('glioblastoma', 'Disease', (147, 159))	('glioblastoma', 'Disease', 'MESH:D005909', (147, 159))	('EGFR', 'Gene', (100, 104))	('abnormalities', 'Var', (105, 118))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('lung squamous carcinoma', 'Disease', (236, 259))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('NF1', 'Gene', (182, 185))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (241, 259))	('NF1', 'Gene', '4763', (182, 185))	('deletions', 'Var', (186, 195))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (236, 259))
45144	25088195	As expected, both stromal and immune scores were significantly higher in supercluster 1 compared to other superclusters (stromal score, posthoc maximum P = 0.00065; immune score, posthoc maximum P = 1.3E-15) (Figure 4).	('stroma', 'Disease', (121, 127))	('immune scores', 'CPA', (30, 43))	('stroma', 'Disease', (18, 24))	('supercluster 1', 'Var', (73, 87))	('stroma', 'Disease', 'None', (121, 127))	('higher', 'PosReg', (63, 69))	('stroma', 'Disease', 'None', (18, 24))
45148	25088195	We used reverse phase protein array (RPPA) profiles available for a subset of samples and found that the protein expression levels of mitotic cycle marker cyclin B1 (CCNB1) was significantly up-regulated in supercluster 5 relative to other superclusters (P = 1.56E-8) (Supplementary Figure 4).	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('protein expression levels', 'MPA', (105, 130))	('CCNB1', 'Gene', '891', (166, 171))	('cyclin B1', 'Gene', (155, 164))	('cyclin B1', 'Gene', '891', (155, 164))	('up-regulated', 'PosReg', (191, 203))	('supercluster', 'Var', (207, 219))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('cyclin', 'molecular_function', 'GO:0016538', ('155', '161'))	('CCNB1', 'Gene', (166, 171))
45151	25088195	Interestingly, a higher number of mutations in the apoptosis and cell cycle regulator TP53 were observed in supercluster 5 (77% of samples; Figure 5a), which may explain why cells are not entering apoptosis despite a high level of DNA damage.	('apoptosis', 'biological_process', 'GO:0097194', ('197', '206'))	('apoptosis', 'biological_process', 'GO:0006915', ('197', '206'))	('DNA', 'cellular_component', 'GO:0005574', ('231', '234'))	('TP53', 'Gene', '7157', (86, 90))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('65', '85'))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('TP53', 'Gene', (86, 90))	('apoptosis', 'Gene', (51, 60))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('65', '85'))	('mutations', 'Var', (34, 43))
45152	25088195	In addition, all subtypes except OV_Proliferative in supercluster 5 harbored deletions of cyclin-dependent kinase inhibitor 2A (CDKN2A) in more than 10% of samples (Supplementary Figure 6, Supplementary Table 6 and 7).	('harbored', 'Reg', (68, 76))	('deletions', 'Var', (77, 86))	('CDKN2A', 'Gene', (128, 134))	('CDKN2A', 'Gene', '1029', (128, 134))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('90', '123'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('107', '123'))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (90, 126))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (90, 126))
45154	25088195	The association between TP53 mutation and CDKN2A deletion showed a trend towards mutually exclusivity (Fisher's exact test, P = 0.10).	('mutation', 'Var', (29, 37))	('association', 'Interaction', (4, 15))	('TP53', 'Gene', (24, 28))	('CDKN2A', 'Gene', (42, 48))	('deletion', 'Var', (49, 57))	('CDKN2A', 'Gene', '1029', (42, 48))	('TP53', 'Gene', '7157', (24, 28))
45168	25088195	The role of the tumor microenvironment is increasingly being appreciated, most prominently as immunotherapeutics such as anti-PD1 and anti-CTL4A that have shown efficacy in advanced melanoma and other tumor types.	('PD1', 'Gene', (126, 129))	('PD1', 'Gene', '9825', (126, 129))	('anti-CTL4A', 'Var', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', (201, 206))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('melanoma', 'Disease', (182, 190))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
45172	25088195	A second large supercluster, plus a third smaller supercluster, unified the cell cycle and apoptosis pathways, through combined presence of an increased level of DNA double strand breaks, mutations in TP53, loss of CDKN2A, and cell cycle protein levels.	('apoptosis pathways', 'Pathway', (91, 109))	('increased', 'PosReg', (143, 152))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('CDKN2A', 'Gene', (215, 221))	('cell cycle', 'Pathway', (76, 86))	('loss', 'NegReg', (207, 211))	('TP53', 'Gene', '7157', (201, 205))	('DNA', 'cellular_component', 'GO:0005574', ('162', '165'))	('CDKN2A', 'Gene', '1029', (215, 221))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('cell cycle protein levels', 'MPA', (227, 252))	('cell cycle', 'biological_process', 'GO:0007049', ('227', '237'))	('TP53', 'Gene', (201, 205))	('DNA double strand breaks', 'MPA', (162, 186))	('cell cycle', 'biological_process', 'GO:0007049', ('76', '86'))	('mutations', 'Var', (188, 197))	('protein', 'cellular_component', 'GO:0003675', ('238', '245'))
45173	25088195	While TP53 mutations are frequent across cancer lineages and may generally serve an anti-apoptotic role, we speculate that in the context of the proliferation transcriptomic signature, these mutations were selected to negate the apoptotic signals resulting from high levels of DNA damage.	('DNA', 'cellular_component', 'GO:0005574', ('277', '280'))	('mutations', 'Var', (11, 20))	('TP53', 'Gene', '7157', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('TP53', 'Gene', (6, 10))	('mutations', 'Var', (191, 200))	('negate', 'NegReg', (218, 224))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('apoptotic', 'CPA', (229, 238))
45185	25088195	To identify a squamous signature specifically related to the presence of squamous cell carcinoma, four microarray data sets were obtained from the Gene Expression Omnibus (GSE10245, lung cancer; GSE28571, lung cancer; GSE26886, esophageal cancer; and GSE27388, cervical cancer).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('lung cancer', 'Disease', (182, 193))	('Gene Expression', 'biological_process', 'GO:0010467', ('147', '162'))	('esophageal cancer', 'Disease', (228, 245))	('cervical cancer', 'Disease', 'MESH:D002583', (261, 276))	('lung cancer', 'Disease', (205, 216))	('GSE26886', 'Var', (218, 226))	('cervical cancer', 'Disease', (261, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 96))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('GSE28571', 'Var', (195, 203))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('lung cancer', 'Disease', 'MESH:D008175', (205, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('squamous cell carcinoma', 'Disease', (73, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('GSE10245', 'Var', (172, 180))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('GSE27388', 'Var', (251, 259))	('esophageal cancer', 'Disease', 'MESH:D004938', (228, 245))
45217	33658791	Apart from that, it was observed that TRPM2-AS knockdown significantly inhibited the viability, proliferation and colony formation of BCLA cells, but it promoted the apoptosis of the BCLA cells.	('viability', 'CPA', (85, 94))	('promoted', 'PosReg', (153, 161))	('apoptosis', 'biological_process', 'GO:0097194', ('166', '175'))	('inhibited', 'NegReg', (71, 80))	('proliferation', 'CPA', (96, 109))	('TRPM2-AS', 'Gene', (38, 46))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('apoptosis', 'biological_process', 'GO:0006915', ('166', '175'))	('knockdown', 'Var', (47, 56))	('si', 'Chemical', 'MESH:D012825', (172, 174))	('formation', 'biological_process', 'GO:0009058', ('121', '130'))	('apoptosis', 'CPA', (166, 175))	('TRPM2-AS', 'Gene', '101928607', (38, 46))	('colony formation of BCLA cells', 'CPA', (114, 144))
45220	33658791	As well as discovering that GINS2 mRNA was a downstream target of miR-22-3p and was significantly upregulated in BLCA, experimental results also indicated that the knockdown of GINS2 suppressed BLCA cell phenotypes.	('miR-22-3p', 'Gene', '407008', (66, 75))	('BLCA', 'Phenotype', 'HP:0009725', (113, 117))	('GINS2', 'Gene', (177, 182))	('BLCA', 'Disease', (194, 198))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('upregulated', 'PosReg', (98, 109))	('GINS2', 'Gene', '51659', (28, 33))	('GINS2', 'Gene', (28, 33))	('knockdown', 'Var', (164, 173))	('suppressed', 'NegReg', (183, 193))	('miR-22-3p', 'Gene', (66, 75))	('GINS2', 'Gene', '51659', (177, 182))	('BLCA', 'Phenotype', 'HP:0009725', (194, 198))
45233	33658791	Besides, in the last 10 years, research has demonstrated that small RNAs could participate in the progression of human neoplasms.	('si', 'Chemical', 'MESH:D012825', (2, 4))	('neoplasms', 'Disease', 'MESH:D009369', (119, 128))	('small', 'Var', (62, 67))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('neoplasms', 'Phenotype', 'HP:0002664', (119, 128))	('participate', 'Reg', (79, 90))	('human', 'Species', '9606', (113, 118))	('neoplasms', 'Disease', (119, 128))
45259	33658791	Genomics materials were acquired from GeneCopoeia (Guangzhou, China), such as negative control (NC) plasmids, miR-22-3p inhibitor, and small interfering RNAs for TRPM2-AS (si-TRPM2-AS) and GINS2 (si-GINS2).	('miR-22-3p', 'Gene', (110, 119))	('si-TRPM2-AS', 'Gene', '101928607', (172, 183))	('TRPM2-AS', 'Gene', (175, 183))	('si-TRPM2-AS', 'Gene', (172, 183))	('miR-22-3p', 'Gene', '407008', (110, 119))	('TRPM2-AS', 'Gene', '101928607', (162, 170))	('GINS2', 'Gene', '51659', (199, 204))	('GINS2', 'Gene', '51659', (189, 194))	('small', 'Var', (135, 140))	('GINS2', 'Gene', (199, 204))	('GINS2', 'Gene', (189, 194))	('TRPM2-AS', 'Gene', (162, 170))	('si', 'Chemical', 'MESH:D012825', (196, 198))	('si', 'Chemical', 'MESH:D012825', (172, 174))	('TRPM2-AS', 'Gene', '101928607', (175, 183))
45278	33658791	The plasmids containing the wild strains and mutants of TRPM2-AS and GINS2 mRNA, with and without the predicted binding sequences, were constructed by and purchased from GeneCopoeia (China).	('TRPM2-AS', 'Gene', '101928607', (56, 64))	('mutants', 'Var', (45, 52))	('TRPM2-AS', 'Gene', (56, 64))	('GINS2', 'Gene', '51659', (69, 74))	('binding', 'molecular_function', 'GO:0005488', ('112', '119'))	('GINS2', 'Gene', (69, 74))
45293	33658791	The total protein was subsequently transferred onto the PVDF membranes (Millipore, MA, USA) with 5.0% evaporated milk at 37  C for 1 h. Next, the PVDF membranes were incubated with the primary antibodies against GINS2 (1:500, Cat#: ab197123, Abcam, UK), Bcl-2 (1:2000, Cat#: ab182858, Abcam, UK), Bax (1:5000, Cat#: ab32503, Abcam, UK), Cleaved caspase-3 (1:500, Cat#: ab32042, Abcam, UK) and GAPDH (1:5000, Cat#: ab175781, Abcam, UK) at 4 C overnight.	('PVDF', 'Chemical', 'MESH:C024865', (146, 150))	('GINS2', 'Gene', (212, 217))	('GAPDH', 'Gene', (393, 398))	('Bcl-2', 'molecular_function', 'GO:0015283', ('254', '259'))	('1:5000', 'Var', (400, 406))	('Cat', 'molecular_function', 'GO:0004096', ('310', '313'))	('Cat', 'molecular_function', 'GO:0004096', ('408', '411'))	('Cat', 'molecular_function', 'GO:0004096', ('269', '272'))	('Cat', 'molecular_function', 'GO:0004096', ('226', '229'))	('Cat', 'molecular_function', 'GO:0004096', ('363', '366'))	('PVDF', 'Chemical', 'MESH:C024865', (56, 60))	('caspase-3', 'Gene', '836', (345, 354))	('Bcl-2', 'Gene', (254, 259))	('Bax', 'Gene', (297, 300))	('1:500', 'Var', (356, 361))	('caspase-3', 'Gene', (345, 354))	('GINS2', 'Gene', '51659', (212, 217))	('Bax', 'Gene', '581', (297, 300))	('GAPDH', 'Gene', '2597', (393, 398))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('Bcl-2', 'Gene', '596', (254, 259))
45325	33658791	This outcome further indicated that TRM2-AS knockdown promoted the apoptosis of BLCA cells (Figure 3C).	('promoted', 'PosReg', (54, 62))	('si', 'Chemical', 'MESH:D012825', (73, 75))	('TRM2', 'Gene', '7210', (36, 40))	('TRM2', 'Gene', (36, 40))	('apoptosis', 'biological_process', 'GO:0097194', ('67', '76'))	('knockdown', 'Var', (44, 53))	('BLCA', 'Phenotype', 'HP:0009725', (80, 84))	('apoptosis', 'biological_process', 'GO:0006915', ('67', '76'))	('apoptosis of BLCA cells', 'CPA', (67, 90))
45341	33658791	Equally important, the cell apoptosis rate in the co-transfection group was found to be the same as that in blank group (Figure 6A).	('cell apoptosis', 'CPA', (23, 37))	('co-transfection', 'Var', (50, 65))	('apoptosis', 'biological_process', 'GO:0097194', ('28', '37'))	('apoptosis', 'biological_process', 'GO:0006915', ('28', '37'))	('si', 'Chemical', 'MESH:D012825', (34, 36))
45347	33658791	The fluorescence intensity was discovered to be reduced in the GINS2-wild type and miR-22-3p mimic co-transfection group, while no differences in T24 and 5637 cell lines were observed in other groups (Figure 7B).	('fluorescence intensity', 'MPA', (4, 26))	('co-transfection', 'Var', (99, 114))	('GINS2', 'Gene', '51659', (63, 68))	('reduced', 'NegReg', (48, 55))	('miR-22-3p', 'Gene', '407008', (83, 92))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('GINS2', 'Gene', (63, 68))	('miR-22-3p', 'Gene', (83, 92))
45358	33658791	The results of the colony formation assay showed that the knockdown of GINS2 reduced the number of colonies of T24 and 5637 cells, but the co-transfection of miR-22-3p inhibitor impaired the influence of si-GINS2 on the colony formation of BLCA cell lines (Figure 8E).	('si', 'Chemical', 'MESH:D012825', (204, 206))	('GINS2', 'Gene', (207, 212))	('miR-22-3p', 'Gene', '407008', (158, 167))	('formation', 'biological_process', 'GO:0009058', ('227', '236'))	('influence', 'MPA', (191, 200))	('GINS2', 'Gene', (71, 76))	('BLCA', 'Phenotype', 'HP:0009725', (240, 244))	('impaired', 'NegReg', (178, 186))	('formation', 'biological_process', 'GO:0009058', ('26', '35'))	('reduced', 'NegReg', (77, 84))	('miR-22-3p', 'Gene', (158, 167))	('GINS2', 'Gene', '51659', (207, 212))	('GINS2', 'Gene', '51659', (71, 76))	('knockdown', 'Var', (58, 67))	('colony formation of', 'CPA', (220, 239))
45370	33658791	Apart from the fact that TRPM2-AS was found to stimulate the progression of prostate cancer, the knockout of TRPM2-AS was documented to induce cell apoptosis by strengthening cell stress and cell cycle arrest.	('strengthening', 'PosReg', (161, 174))	('TRPM2-AS', 'Gene', '101928607', (25, 33))	('TRPM2-AS', 'Gene', (109, 117))	('cell stress', 'CPA', (175, 186))	('induce', 'PosReg', (136, 142))	('stimulate', 'PosReg', (47, 56))	('knockout', 'Var', (97, 105))	('progression', 'CPA', (61, 72))	('arrest', 'Disease', (202, 208))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (191, 208))	('TRPM2-AS', 'Gene', '101928607', (109, 117))	('cell apoptosis', 'CPA', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('apoptosis', 'biological_process', 'GO:0097194', ('148', '157'))	('TRPM2-AS', 'Gene', (25, 33))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('apoptosis', 'biological_process', 'GO:0006915', ('148', '157'))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('191', '208'))	('si', 'Chemical', 'MESH:D012825', (154, 156))	('prostate cancer', 'Disease', (76, 91))	('arrest', 'Disease', 'MESH:D006323', (202, 208))
45404	33658791	In addition to that, we found that the effects of the GINS2 knockdown on BLCA cell phenotypes could be attenuated via miR-22-3p inhibition.	('GINS2', 'Gene', '51659', (54, 59))	('attenuated', 'NegReg', (103, 113))	('miR-22-3p', 'Gene', (118, 127))	('GINS2', 'Gene', (54, 59))	('miR-22-3p', 'Gene', '407008', (118, 127))	('knockdown', 'Var', (60, 69))	('BLCA', 'Phenotype', 'HP:0009725', (73, 77))
45416	31488130	The tumor cells were positive for CD21 and vimentin, partly positive for CD23, D2-40 and CD35.	('tumor', 'Disease', (4, 9))	('CD21', 'Gene', (34, 38))	('CD23', 'Gene', '2208', (73, 77))	('vimentin', 'cellular_component', 'GO:0045098', ('43', '51'))	('CD35', 'Gene', '1378', (89, 93))	('CD21', 'Gene', '1380', (34, 38))	('CD23', 'Gene', (73, 77))	('positive', 'Reg', (21, 29))	('CD35', 'Gene', (89, 93))	('vimentin', 'Gene', '7431', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('vimentin', 'Gene', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('vimentin', 'cellular_component', 'GO:0045099', ('43', '51'))	('D2-40', 'Var', (79, 84))
45465	31488130	Cell cycle regulatory gene such as P16 showed alteration and tumor suppressor gene P53 mutation were also found in FDCS.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('61', '77'))	('alteration', 'Reg', (46, 56))	('P16', 'Gene', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor suppressor', 'biological_process', 'GO:0051726', ('61', '77'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('P53', 'Gene', (83, 86))	('P16', 'Gene', '1029', (35, 38))	('FDCS', 'Disease', (115, 119))	('mutation', 'Var', (87, 95))	('P53', 'Gene', '7157', (83, 86))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('tumor', 'Disease', (61, 66))
45470	31488130	found that the involvement of BRAF mutations in the development of bladder UC was infrequent.	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('bladder UC', 'Disease', (67, 77))	('mutations', 'Var', (35, 44))
45546	28984210	Figure 4c shows the percentage of samples with mutations of the 32 TargetCancer genes, their function classification, and number of targeting drugs.	('Cancer', 'Disease', (73, 79))	('Cancer', 'Disease', 'MESH:D009369', (73, 79))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (47, 56))
45547	28984210	Indeed, for the 32 Target Cancer genes, there was a significant correlation between the percentages of samples with mutations and numbers of targeted drugs (Pearson's correlation: r = 0.40, P = 0.0230).	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (116, 125))	('Cancer', 'Disease', 'MESH:D009369', (26, 32))	('Cancer', 'Disease', (26, 32))
45549	28984210	Its mutations significantly occur in the brain cancer GBM (27.1%), lung cancer (13.5%), COAD/READ (5.8%), HNSC (6.2%).	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('occur', 'Reg', (28, 33))	('brain cancer', 'Disease', 'MESH:D001932', (41, 53))	('COAD', 'Disease', 'MESH:D029424', (88, 92))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('HNSC', 'Disease', (106, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('brain cancer', 'Phenotype', 'HP:0030692', (41, 53))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('READ', 'Disease', 'None', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (4, 13))	('brain cancer', 'Disease', (41, 53))	('COAD', 'Disease', (88, 92))	('lung cancer', 'Disease', (67, 78))	('READ', 'Disease', (93, 97))
45613	24533189	Serological test showed C-reactive protein 0.03 mg/dL, negative for hepatitis B surface antigen, negative for hepatitis C virus antibody, C3 114 mg/dL, C4 104 mg/dL, CH50 60 U/mL, and antinuclear antibody x40.	('antibody', 'cellular_component', 'GO:0019814', ('196', '204'))	('C4 104 mg/dL', 'Var', (152, 164))	('hepatitis', 'Disease', 'MESH:D056486', (68, 77))	('C-reactive protein', 'MPA', (24, 42))	('antibody', 'cellular_component', 'GO:0019814', ('128', '136'))	('hepatitis', 'Disease', (68, 77))	('antibody', 'molecular_function', 'GO:0003823', ('196', '204'))	('hepatitis C virus antibody', 'Phenotype', 'HP:0410371', (110, 136))	('antibody', 'cellular_component', 'GO:0042571', ('196', '204'))	('antibody', 'molecular_function', 'GO:0003823', ('128', '136'))	('antibody', 'cellular_component', 'GO:0042571', ('128', '136'))	('hepatitis C virus', 'Species', '11103', (110, 127))	('hepatitis', 'Phenotype', 'HP:0012115', (110, 119))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('hepatitis', 'Disease', 'MESH:D056486', (110, 119))	('antibody', 'cellular_component', 'GO:0019815', ('196', '204'))	('antibody', 'cellular_component', 'GO:0019815', ('128', '136'))	('C3 114 mg/dL', 'Var', (138, 150))	('CH50', 'Var', (166, 170))	('hepatitis', 'Disease', (110, 119))	('antinuclear antibody', 'Phenotype', 'HP:0003493', (184, 204))	('hepatitis', 'Phenotype', 'HP:0012115', (68, 77))
45630	24533189	They proved that antibody formation against a specific component of basement membrane, common to both kidney and tumor, gave rise to the nephropathy in this case.	('nephropathy', 'Disease', (137, 148))	('tumor', 'Disease', (113, 118))	('gave rise to', 'Reg', (120, 132))	('antibody', 'cellular_component', 'GO:0019814', ('17', '25'))	('antibody formation', 'Var', (17, 35))	('antibody', 'molecular_function', 'GO:0003823', ('17', '25'))	('formation', 'biological_process', 'GO:0009058', ('26', '35'))	('nephropathy', 'Disease', 'MESH:D007674', (137, 148))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('basement membrane', 'cellular_component', 'GO:0005604', ('68', '85'))	('antibody', 'cellular_component', 'GO:0042571', ('17', '25'))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('antibody', 'cellular_component', 'GO:0019815', ('17', '25'))	('nephropathy', 'Phenotype', 'HP:0000112', (137, 148))
45721	32039002	While there have been very few reports of such variants to determine their clinical significance in dogs, in one study, canine InvUC with fibromyxoid stroma was associated with invasion of the muscle layer, suggesting a more aggressive behavior.	('variants', 'Var', (47, 55))	('InvUC', 'Disease', 'MESH:D009361', (127, 132))	('associated', 'Reg', (161, 171))	('InvUC', 'Disease', (127, 132))	('dogs', 'Species', '9615', (100, 104))	('aggressive behavior', 'Phenotype', 'HP:0000718', (225, 244))	('aggressive behavior', 'biological_process', 'GO:0002118', ('225', '244'))	('fibromyxoid stroma', 'Disease', 'None', (138, 156))	('canine', 'Species', '9615', (120, 126))	('fibromyxoid stroma', 'Disease', (138, 156))	('invasion of the muscle layer', 'CPA', (177, 205))
45750	32039002	The luminal tumors are enriched for ER, TRIM24, FOXA1, GATA3, PPARG, and activating FGFR3 mutations (with good response to FGFR inhibitors).	('TRIM24', 'Gene', '609728', (40, 46))	('GATA3', 'Gene', (55, 60))	('PPARG', 'Gene', (62, 67))	('mutations', 'Var', (90, 99))	('luminal tumors', 'Disease', 'MESH:D009369', (4, 18))	('FOXA1', 'Gene', (48, 53))	('PPARG', 'Gene', '403606', (62, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('123', '127'))	('TRIM24', 'Gene', (40, 46))	('activating', 'PosReg', (73, 83))	('FGFR3', 'Gene', '488808', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('FGFR', 'molecular_function', 'GO:0005007', ('84', '88'))	('GATA3', 'Gene', '487134', (55, 60))	('luminal tumors', 'Disease', (4, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('FOXA1', 'Gene', '490657', (48, 53))	('FGFR3', 'Gene', (84, 89))
45766	32039002	In mice there was accumulation of the Can225-IR700 conjugate in the tumors with high tumor-to-background ratio, and tumor growth was significantly inhibited by near infrared photoimmunotherapy application.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (85, 90))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('mice', 'Species', '10090', (3, 7))	('Can225-IR700 conjugate', 'Var', (38, 60))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('accumulation', 'PosReg', (18, 30))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('inhibited', 'NegReg', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (116, 121))
45777	32039002	Mutations in several other genes implicated in the development and progression of InvUC and other cancers in humans have been identified in canine InvUC.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('InvUC', 'Disease', (82, 87))	('InvUC', 'Disease', 'MESH:D009361', (147, 152))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('InvUC', 'Disease', (147, 152))	('humans', 'Species', '9606', (109, 115))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', (98, 105))	('canine', 'Species', '9615', (140, 146))	('InvUC', 'Disease', 'MESH:D009361', (82, 87))	('identified', 'Reg', (126, 136))	('men', 'Species', '9606', (58, 61))
45782	32039002	The majority (67-85%) of canine InvUCs harbor a BRAFV595E mutation, which is homologous to the BRAFV600E mutation in humans.	('humans', 'Species', '9606', (117, 123))	('canine', 'Species', '9615', (25, 31))	('InvUC', 'Disease', 'MESH:D009361', (32, 37))	('BRAFV600E', 'Mutation', 'rs113488022', (95, 104))	('BRAFV595E', 'Var', (48, 57))	('InvUC', 'Disease', (32, 37))
45783	32039002	This mutation is considered a driver mutation of 8% of all human cancer across cancer types, and is especially common in human metastatic melanoma.	('common', 'Reg', (111, 117))	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('human', 'Species', '9606', (59, 64))	('melanoma', 'Disease', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('human', 'Species', '9606', (121, 126))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('mutation', 'Var', (5, 13))
45784	32039002	While BRAF mutations are common in certain forms of human cancer, these mutations are rare in human InvUC.	('common', 'Reg', (25, 31))	('mutations', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('InvUC', 'Disease', 'MESH:D009361', (100, 105))	('human', 'Species', '9606', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('human', 'Species', '9606', (94, 99))	('InvUC', 'Disease', (100, 105))	('cancer', 'Disease', (58, 64))	('BRAF', 'Gene', (6, 10))
45785	32039002	Other mutations within the MAPK pathway, however, occur in ~30% of human InvUC cases.	('InvUC', 'Disease', 'MESH:D009361', (73, 78))	('MAPK', 'molecular_function', 'GO:0004707', ('27', '31'))	('InvUC', 'Disease', (73, 78))	('human', 'Species', '9606', (67, 72))	('occur', 'Reg', (50, 55))	('mutations', 'Var', (6, 15))	('MAPK pathway', 'Pathway', (27, 39))
45786	32039002	It is intriguing that even though BRAF mutations are common in canine InvUC and that different molecular drivers are more common in human InvUC, the cancer in both species converges into a disease possessing the same molecular subtypes.	('cancer', 'Disease', (149, 155))	('InvUC', 'Disease', 'MESH:D009361', (138, 143))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('InvUC', 'Disease', 'MESH:D009361', (70, 75))	('mutations', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('InvUC', 'Disease', (138, 143))	('InvUC', 'Disease', (70, 75))	('human', 'Species', '9606', (132, 137))	('BRAF', 'Gene', (34, 38))	('canine', 'Species', '9615', (63, 69))
45856	32039002	Interestingly, the number of tumor-infiltrating lymphocytes (TILs) increased multifold in 73% of cases receiving celecoxib, compared to 38% of control cases (Dhawan and Knapp, unpublished data).	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('celecoxib', 'Var', (113, 122))	('increased', 'PosReg', (67, 76))	('tumor', 'Disease', (29, 34))	('celecoxib', 'Chemical', 'MESH:C105934', (113, 122))
45956	29137333	Before the background adjustment, intravesical RFS, visceral RFS, CSS, and OS after radical nephroureterectomy were significantly shorter in the CKD group than in the non-CKD group.	('CKD', 'Var', (145, 148))	('CKD', 'Phenotype', 'HP:0012622', (171, 174))	('OS', 'Chemical', '-', (75, 77))	('CKD', 'Phenotype', 'HP:0012622', (145, 148))	('RFS', 'Gene', '65211', (47, 50))	('RFS', 'Gene', '65211', (61, 64))	('CSS', 'MPA', (66, 69))	('shorter', 'NegReg', (130, 137))	('RFS', 'Gene', (61, 64))	('RFS', 'Gene', (47, 50))	('CSS', 'Chemical', '-', (66, 69))
45957	29137333	Background-adjusted IPTW analysis demonstrated that preoperative CKD was significantly associated with poor visceral RFS, CSS, and OS after radical nephroureterectomy.	('RFS', 'Gene', '65211', (117, 120))	('poor visceral', 'Disease', (103, 116))	('RFS', 'Gene', (117, 120))	('OS', 'Chemical', '-', (131, 133))	('CSS', 'Disease', (122, 125))	('CKD', 'Phenotype', 'HP:0012622', (65, 68))	('CSS', 'Chemical', '-', (122, 125))	('CKD', 'Var', (65, 68))	('IPTW', 'Chemical', '-', (20, 24))
45960	29137333	Upper tract urothelial carcinoma patients with preoperative CKD had a significantly lower survival probability than those without CKD.	('CKD', 'Phenotype', 'HP:0012622', (60, 63))	('patients', 'Species', '9606', (33, 41))	('CKD', 'Phenotype', 'HP:0012622', (130, 133))	('CKD', 'Var', (60, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('tract urothelial carcinoma', 'Disease', (6, 32))	('tract urothelial carcinoma', 'Disease', 'MESH:D012142', (6, 32))	('lower', 'NegReg', (84, 89))	('survival', 'CPA', (90, 98))
45972	29137333	The number of patients with adjuvant/salvage chemotherapy after RNU were significantly higher in the CKD group (n = 47, 19%) than those of the non-CKD group (n = 20, 11%) (P = 0.038) (Table 1).	('adjuvant/salvage chemotherapy', 'CPA', (28, 57))	('CKD', 'Phenotype', 'HP:0012622', (147, 150))	('CKD', 'Var', (101, 104))	('RNU', 'Chemical', '-', (64, 67))	('patients', 'Species', '9606', (14, 22))	('CKD', 'Phenotype', 'HP:0012622', (101, 104))	('higher', 'PosReg', (87, 93))
45975	29137333	Before the background adjustment, there were significant differences in the number of patients experiencing visceral recurrence (P < 0.001), cancer mortality (P < 0.001), and overall mortality (P < 0.001) in the CKD group compared with the non-CKD group (Table 1).	('overall mortality', 'CPA', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('visceral recurrence', 'Disease', (108, 127))	('CKD', 'Phenotype', 'HP:0012622', (212, 215))	('CKD', 'Var', (212, 215))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('CKD', 'Phenotype', 'HP:0012622', (244, 247))	('cancer', 'Disease', (141, 147))	('patients', 'Species', '9606', (86, 94))
45977	29137333	Five-year intravesical RFS, visceral RFS, CSS, and OS rates for the CKD and non-CKD groups were 60% vs. 72% (Figure 1A, P = 0.004), 59% vs. 85% (Figure 1B, P < 0.001), 70% vs. 89% (Figure 1C, P < 0.001), and 66% vs. 80% (Figure 1D, P < 0.001), respectively.	('CSS', 'Chemical', '-', (42, 45))	('OS', 'Chemical', '-', (51, 53))	('CKD', 'Phenotype', 'HP:0012622', (68, 71))	('CSS', 'CPA', (42, 45))	('RFS', 'Gene', '65211', (23, 26))	('RFS', 'Gene', '65211', (37, 40))	('CKD', 'Var', (68, 71))	('RFS', 'Gene', (23, 26))	('RFS', 'Gene', (37, 40))	('CKD', 'Phenotype', 'HP:0012622', (80, 83))
45982	29137333	Background-adjusted multivariate Cox regression analyses using IPTW methods demonstrated that preoperative CKD was significantly associated with poor visceral RFS (P = 0.003; hazard ratio [HR], 2.33, 95% confidence interval [CI], 1.34-4.04), CSS (P = 0.039; HR, 1.96; 95% CI, 1.03-3.70), and OS (P = 0.037 HR, 1.76; 95% CI, 1.04-2.99) after RNU (Table 2, lower row).	('poor', 'NegReg', (145, 149))	('CSS', 'Disease', (242, 245))	('Cox', 'Gene', (33, 36))	('OS', 'Chemical', '-', (292, 294))	('IPTW', 'Chemical', '-', (63, 67))	('CKD', 'Var', (107, 110))	('RFS', 'Gene', (159, 162))	('RNU', 'Chemical', '-', (341, 344))	('CSS', 'Chemical', '-', (242, 245))	('CKD', 'Phenotype', 'HP:0012622', (107, 110))	('Cox', 'Gene', '1351', (33, 36))	('RFS', 'Gene', '65211', (159, 162))
45994	29137333	Similarly, preoperative CKD decreased the 5-year risk of CSS from 64% to 45% (a 19% decline) in the same patient population.	('CKD', 'Var', (24, 27))	('patient', 'Species', '9606', (105, 112))	('decreased', 'NegReg', (28, 37))	('CSS', 'Disease', (57, 60))	('CKD', 'Phenotype', 'HP:0012622', (24, 27))	('CSS', 'Chemical', '-', (57, 60))
45997	29137333	Evidence from a prospective population-based cohort study suggested that the incidences of urinary tract malignancies increases in patients with CKD.	('patients', 'Species', '9606', (131, 139))	('malignancies increases', 'Disease', (105, 127))	('CKD', 'Var', (145, 148))	('urinary tract malignancies', 'Phenotype', 'HP:0010786', (91, 117))	('malignancies increases', 'Disease', 'MESH:D009369', (105, 127))	('CKD', 'Phenotype', 'HP:0012622', (145, 148))
45999	29137333	A recent meta-analysis reported a prevalence of preoperative renal insufficiency among patients with bladder cancer of 16.9% (ranging from 13.0% to 25.5%) and preoperative renal insufficiency as associated with increased disease recurrence (HR = 1.65; 95% CI, 1.11-2.19), CSS (HR = 1.59; 95% CI, 1.14-2.05), and OS (HR = 1.45; 95% CI, 1.19-1.71).	('renal insufficiency', 'Disease', 'MESH:D051437', (61, 80))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('OS', 'Chemical', '-', (312, 314))	('CSS', 'Disease', (272, 275))	('renal insufficiency', 'Phenotype', 'HP:0000083', (61, 80))	('bladder cancer', 'Disease', (101, 115))	('renal insufficiency', 'Disease', (172, 191))	('increased', 'PosReg', (211, 220))	('preoperative', 'Disease', (48, 60))	('renal insufficiency', 'Disease', 'MESH:D051437', (172, 191))	('preoperative', 'Var', (159, 171))	('renal insufficiency', 'Phenotype', 'HP:0000083', (172, 191))	('disease recurrence', 'CPA', (221, 239))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))	('patients', 'Species', '9606', (87, 95))	('renal insufficiency', 'Disease', (61, 80))	('CSS', 'Chemical', '-', (272, 275))
46004	29137333	Currently, CKD is reported to be an independent risk factor for survival in head and neck, stomach, liver, colorectal, urinary tract, gynecological and hematologic malignancies.	('colorectal', 'Disease', (107, 117))	('urinary tract', 'Disease', (119, 132))	('hematologic malignancies', 'Disease', 'MESH:D019337', (152, 176))	('CKD', 'Phenotype', 'HP:0012622', (11, 14))	('hematologic malignancies', 'Disease', (152, 176))	('stomach', 'Disease', (91, 98))	('neck', 'cellular_component', 'GO:0044326', ('85', '89'))	('liver', 'Disease', (100, 105))	('gynecological', 'Disease', (134, 147))	('CKD', 'Var', (11, 14))
46012	29137333	Long-term inflammation and oxidative stress caused by CKD and linked to organ degradation may increase carcinogenicity.	('CKD', 'Phenotype', 'HP:0012622', (54, 57))	('increase', 'PosReg', (94, 102))	('CKD', 'Var', (54, 57))	('oxidative stress', 'Phenotype', 'HP:0025464', (27, 43))	('carcinogenicity', 'CPA', (103, 118))	('inflammation', 'biological_process', 'GO:0006954', ('10', '22'))	('degradation', 'biological_process', 'GO:0009056', ('78', '89'))	('oxidative stress', 'CPA', (27, 43))	('inflammation', 'Disease', 'MESH:D007249', (10, 22))	('inflammation', 'Disease', (10, 22))
46022	29137333	In conclusion, UTUC patients with preoperative CKD had significantly lower survival than those without CKD after RNU.	('CKD', 'Phenotype', 'HP:0012622', (47, 50))	('lower', 'NegReg', (69, 74))	('survival', 'MPA', (75, 83))	('patients', 'Species', '9606', (20, 28))	('CKD', 'Var', (47, 50))	('RNU', 'Chemical', '-', (113, 116))	('CKD', 'Phenotype', 'HP:0012622', (103, 106))
46025	29137333	We stratified patients into two groups according to preoperative renal function as follows: eGFR >=60 mL/min/1.73 m2 (non-CKD group) and eGFR <60 mL/min/1.73 m2 (CKD group).	('min/1', 'Gene', '966', (149, 154))	('>=60', 'Var', (97, 101))	('eGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('CKD', 'Phenotype', 'HP:0012622', (162, 165))	('min/1', 'Gene', '966', (105, 110))	('CKD', 'Phenotype', 'HP:0012622', (122, 125))	('min/1', 'Gene', (149, 154))	('eGFR', 'molecular_function', 'GO:0005006', ('137', '141'))	('min/1', 'Gene', (105, 110))	('patients', 'Species', '9606', (14, 22))	('eGFR', 'MPA', (92, 96))
46053	28489584	Cancer is typically a genetic disease derived from genome aberrances such as somatic mutations, copy-number alterations, DNA methylations, and gene fusions.	('genetic disease', 'Disease', (22, 37))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('copy-number alterations', 'Var', (96, 119))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('gene fusions', 'Var', (143, 155))	('genetic disease', 'Disease', 'MESH:D030342', (22, 37))
46055	28489584	For example, PAM50, a widely used breast cancer classifier based on gene expression profile, can divide patients into five subtypes corresponding to different clinical outcomes.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('gene expression', 'biological_process', 'GO:0010467', ('68', '83'))	('breast cancer', 'Gene', '672', (34, 47))	('PAM50', 'Var', (13, 18))	('patients', 'Species', '9606', (104, 112))	('breast cancer', 'Gene', (34, 47))
46066	28489584	Studies on mutations, structural variations, or DNA copy number alterations have demonstrated the value of normal tissues in identifying cancer-associated genome variations accurately.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('variations', 'Var', (162, 172))	('cancer', 'Disease', (137, 143))
46098	28489584	Among tumor samples, immune scores were significantly higher in both C6-KIRC/KIRP and C8-LUAD/LUSC than those in the other clusters (C6 posthoc Maximum p value = 3.3E-06, C8 posthoc Maximum p value = 2.1E-05).	('higher', 'PosReg', (54, 60))	('immune scores', 'MPA', (21, 34))	('C8-LUAD', 'Disease', 'OMIM:613790', (86, 93))	('C8-LUAD', 'Disease', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('C6-KIRC/KIRP', 'Var', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
46103	28489584	We found that apoptosis and cell cycle regulator TP53 harbored a high number of mutations in both two subtypes (Supplementary Figure 6A).	('TP53', 'Gene', '7157', (49, 53))	('mutations', 'Var', (80, 89))	('TP53', 'Gene', (49, 53))	('apoptosis', 'Gene', (14, 23))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('28', '48'))	('apoptosis', 'biological_process', 'GO:0097194', ('14', '23'))	('apoptosis', 'biological_process', 'GO:0006915', ('14', '23'))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('28', '48'))
46126	28489584	Short hairpin RNAs (shRNA) were designed to knock down the expression levels of FAM64A and TROAP in MDA-MB-231 cells.	('FAM64A', 'Gene', (80, 86))	('FAM64A', 'Gene', '54478', (80, 86))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (100, 110))	('knock', 'Var', (44, 49))	('expression', 'MPA', (59, 69))	('TROAP', 'Gene', (91, 96))	('TROAP', 'Gene', '10024', (91, 96))
46128	28489584	Compared with the control group, the groups with knockdown of FAM64A and TROAP exhibited significantly slower proliferation (1.76- and 1.41-fold, respectively) (Figure 6).	('knockdown', 'Var', (49, 58))	('TROAP', 'Gene', (73, 78))	('slower', 'NegReg', (103, 109))	('TROAP', 'Gene', '10024', (73, 78))	('FAM64A', 'Gene', (62, 68))	('FAM64A', 'Gene', '54478', (62, 68))
46129	28489584	These results suggest that inhibiting either FAM64A or TROAP can suppress the growth of breast cancer cells.	('inhibiting', 'Var', (27, 37))	('TROAP', 'Gene', (55, 60))	('breast cancer', 'Gene', '672', (88, 101))	('TROAP', 'Gene', '10024', (55, 60))	('growth of', 'CPA', (78, 87))	('breast cancer', 'Gene', (88, 101))	('FAM64A', 'Gene', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('suppress', 'NegReg', (65, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('FAM64A', 'Gene', '54478', (45, 51))
46180	28489584	The average and standard deviation of cell numbers of the three wells for FAM64A and TROAP knockdown groups and control group were calculated during five days.	('TROAP', 'Gene', '10024', (85, 90))	('FAM64A', 'Gene', (74, 80))	('knockdown', 'Var', (91, 100))	('FAM64A', 'Gene', '54478', (74, 80))	('TROAP', 'Gene', (85, 90))
46188	27440446	In order to decipher a mechanism for the contribution of galectin-1 to the malignant behavior of urinary bladder urothelial carcinoma, two bladder cancer cell lines (T24 and J82) were established with knockdown of galectin-1 expression by shRNA.	('J82', 'CellLine', 'CVCL:0359', (174, 177))	('bladder cancer', 'Disease', 'MESH:D001749', (139, 153))	('urinary bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (97, 133))	('galectin-1', 'Gene', (214, 224))	('bladder cancer', 'Disease', (139, 153))	('knockdown', 'Var', (201, 210))	('urinary bladder urothelial carcinoma', 'Disease', (97, 133))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('galectin', 'molecular_function', 'GO:0001577', ('214', '222'))	('bladder cancer', 'Phenotype', 'HP:0009725', (139, 153))	('galectin', 'molecular_function', 'GO:0001577', ('57', '65'))
46189	27440446	Bladder cancer cells with LGALS1 gene silencing showed reduced cell proliferation, lower invasive capability, and lower clonogenicity.	('gene silencing', 'Var', (33, 47))	('cancer', 'Disease', (8, 14))	('clonogenicity', 'CPA', (120, 133))	('reduced', 'NegReg', (55, 62))	('lower', 'NegReg', (83, 88))	('cell proliferation', 'CPA', (63, 81))	('LGALS1', 'Gene', (26, 32))	('invasive capability', 'CPA', (89, 108))	('LGALS1', 'Gene', '3956', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lower', 'NegReg', (114, 119))	('gene silencing', 'biological_process', 'GO:0016458', ('33', '47'))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
46192	27440446	These results revealed that silencing the galectin-1-mediated MAPK signaling pathway presented a novel strategy for bladder cancer therapy.	('bladder cancer', 'Phenotype', 'HP:0009725', (116, 130))	('galectin-1-mediated', 'Protein', (42, 61))	('MAPK', 'Gene', '5594', (62, 66))	('bladder cancer', 'Disease', 'MESH:D001749', (116, 130))	('bladder cancer', 'Disease', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('MAPK', 'Gene', (62, 66))	('MAPK', 'molecular_function', 'GO:0004707', ('62', '66'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('62', '76'))	('galectin', 'molecular_function', 'GO:0001577', ('42', '50'))	('silencing', 'Var', (28, 37))	('signaling pathway', 'biological_process', 'GO:0007165', ('67', '84'))
46210	27440446	J82 cells with Gal-1 knockdown by siRNA DNA precursor were constructed similarly as described above.	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('knockdown', 'Var', (21, 30))	('J82', 'CellLine', 'CVCL:0359', (0, 3))	('Gal-1', 'Gene', (15, 20))
46241	27440446	Characterization of tumor cell behavior indicated that sh-Gal-1(+120) and sh-Gal-1(+380) T24 cells proliferated more slowly than sh-Sc cells (Fig.	('sh-Gal-1', 'Var', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('proliferated', 'CPA', (99, 111))	('slowly', 'NegReg', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('sh-Gal-1', 'Var', (74, 82))	('tumor', 'Disease', (20, 25))
46242	27440446	Galectin-1 knockdown also reduced the migration and invasion capabilities of sh-Gal-1(+120) J82 cells (Fig.	('sh-Gal-1', 'Var', (77, 85))	('Galectin-1', 'Gene', (0, 10))	('reduced', 'NegReg', (26, 33))	('invasion capabilities', 'CPA', (52, 73))	('Galectin-1', 'Gene', '3956', (0, 10))	('Galectin', 'molecular_function', 'GO:0001577', ('0', '8'))	('knockdown', 'Var', (11, 20))	('migration', 'CPA', (38, 47))	('J82', 'CellLine', 'CVCL:0359', (92, 95))
46244	27440446	Our previous cohort study reported that Gal-1 overexpression is significantly linked to UBUC invasion.23 In addition, Gal-1 silencing inhibited the invasive ability of T24 cells and MMP9 is closely associated with tumor metastasis.25 Thus, we hypothesized that the reduced invasive ability of sh-Gal-1(+120) T24 and sh-Gal-1(+120) J82 cells might be attributed to decreased MMP9 expression.	('tumor metastasis', 'Disease', (214, 230))	('MMP9', 'molecular_function', 'GO:0004229', ('374', '378'))	('J82', 'CellLine', 'CVCL:0359', (331, 334))	('MMP9', 'Gene', '4318', (374, 378))	('MMP9', 'Gene', (182, 186))	('decreased', 'NegReg', (364, 373))	('reduced', 'NegReg', (265, 272))	('sh-Gal-1(+120) T24', 'Var', (293, 311))	('MMP9', 'Gene', '4318', (182, 186))	('sh-Gal-1(+120', 'Var', (316, 329))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('invasive ability', 'CPA', (273, 289))	('expression', 'MPA', (379, 389))	('MMP9', 'molecular_function', 'GO:0004229', ('182', '186'))	('MMP9', 'Gene', (374, 378))	('tumor metastasis', 'Disease', 'MESH:D009362', (214, 230))
46245	27440446	In accordance with our expectation, the results of the MMP9 assay revealed that MMP9 mRNA as well as protein syntheses were suppressed and MMP9 activity was also inhibited in sh-Gal-1(+120) T24 and J82 cells (Fig.	('J82', 'CellLine', 'CVCL:0359', (198, 201))	('MMP9', 'molecular_function', 'GO:0004229', ('139', '143'))	('MMP9', 'Gene', (55, 59))	('inhibited', 'NegReg', (162, 171))	('MMP9', 'Gene', '4318', (55, 59))	('MMP9', 'Gene', (80, 84))	('MMP9', 'Gene', (139, 143))	('MMP9', 'molecular_function', 'GO:0004229', ('80', '84'))	('MMP9', 'Gene', '4318', (80, 84))	('protein syntheses', 'MPA', (101, 118))	('sh-Gal-1(+120) T24', 'Var', (175, 193))	('MMP9', 'Gene', '4318', (139, 143))	('suppressed', 'NegReg', (124, 134))	('MMP9', 'molecular_function', 'GO:0004229', ('55', '59'))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('activity', 'MPA', (144, 152))
46249	27440446	Furthermore, the expression levels of JNK and phosphorylated-JNK protein were downregulated in sh-Gal-1(+120) T24 and J82 cells (Fig.	('expression levels', 'MPA', (17, 34))	('JNK', 'molecular_function', 'GO:0004705', ('38', '41'))	('JNK', 'Gene', '5599', (38, 41))	('JNK', 'Gene', (61, 64))	('J82', 'CellLine', 'CVCL:0359', (118, 121))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('JNK', 'molecular_function', 'GO:0004705', ('61', '64'))	('sh-Gal-1', 'Var', (95, 103))	('JNK', 'Gene', '5599', (61, 64))	('JNK', 'Gene', (38, 41))	('downregulated', 'NegReg', (78, 91))
46252	27440446	In this study we showed that the c-Jun protein level was reduced in the nucleus of sh-Gal-1(+120) T24 cells while that in the cytosol was slightly increased compared to sh-Sc(+120) T24 cells (Fig.	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('increased', 'PosReg', (147, 156))	('reduced', 'NegReg', (57, 64))	('c-Jun', 'Gene', (33, 38))	('cytosol', 'cellular_component', 'GO:0005829', ('126', '133'))	('nucleus', 'cellular_component', 'GO:0005634', ('72', '79'))	('sh-Gal-1(+120) T24', 'Var', (83, 101))	('c-Jun', 'Gene', '3725', (33, 38))
46253	27440446	3a), suggesting that Gal-1 attenuation restricted the movement of activated c-Jun.	('c-Jun', 'Gene', (76, 81))	('restricted', 'NegReg', (39, 49))	('c-Jun', 'Gene', '3725', (76, 81))	('Gal-1', 'Gene', (21, 26))	('attenuation', 'Var', (27, 38))
46256	27440446	To further characterize the link of Gal-1-JNK to UBUC cell invasiveness, we observed the impacts of bFGF (JNK pathway agonist)30 on invasive/migratory capabilities of sh-Gal-1(+120) and sh-Sc(+120) T24 cells.	('JNK', 'Gene', (42, 45))	('JNK', 'Gene', '5599', (42, 45))	('bFGF', 'Gene', '2247', (100, 104))	('bFGF', 'Gene', (100, 104))	('JNK', 'molecular_function', 'GO:0004705', ('106', '109'))	('JNK', 'Gene', (106, 109))	('JNK', 'molecular_function', 'GO:0004705', ('42', '45'))	('sh-Gal-1', 'Var', (167, 175))	('JNK', 'Gene', '5599', (106, 109))	('invasive/migratory capabilities', 'CPA', (132, 163))
46257	27440446	The results in Figure 4 showed that bFGF treatment could boost the invasive/migratory abilities of sh-Sc(+120) T24 cells, but those of sh-Gal-1(+120) T24 cells were hardly affected.	('boost', 'PosReg', (57, 62))	('sh-Sc(+120) T24', 'Var', (99, 114))	('bFGF', 'Gene', '2247', (36, 40))	('invasive/migratory abilities', 'CPA', (67, 95))	('bFGF', 'Gene', (36, 40))
46259	27440446	In addition, Rac1 agonist treatment could evoke the invasive/migratory abilities of sh-Gal-1(+120) T24 cells (Fig.	('evoke', 'PosReg', (42, 47))	('Rac1', 'Gene', (13, 17))	('Rac1', 'Gene', '5879', (13, 17))	('invasive/migratory abilities', 'CPA', (52, 80))	('sh-Gal-1', 'Var', (84, 92))
46262	27440446	4(j) indicate that Gal-1 silencing deteriorated the inhibition of sh-Gal-1(+120) T24 cell migration by SP600125 treatment.	('silencing', 'Var', (25, 34))	('Gal-1', 'Gene', (19, 24))	('cell migration', 'biological_process', 'GO:0016477', ('85', '99'))	('SP600125', 'Chemical', 'MESH:C432165', (103, 111))	('inhibition', 'NegReg', (52, 62))
46274	27440446	Matrix metalloproteinase-9 is closely tied to tumor invasion and metastasis.25 In accordance with the previously documented observations, this study showed that inhibition of LGALS1 gene expression dwindled MMP9 gene expression and its enzymatic activity in T24 cells.	('gene expression', 'biological_process', 'GO:0010467', ('182', '197'))	('gene expression', 'biological_process', 'GO:0010467', ('212', '227'))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Matrix metalloproteinase-9', 'Gene', (0, 26))	('Matrix metalloproteinase-9', 'Gene', '4318', (0, 26))	('MMP9', 'Gene', (207, 211))	('inhibition', 'Var', (161, 171))	('tumor', 'Disease', (46, 51))	('MMP9', 'Gene', '4318', (207, 211))	('LGALS1', 'Gene', (175, 181))	('LGALS1', 'Gene', '3956', (175, 181))	('MMP9', 'molecular_function', 'GO:0004229', ('207', '211'))	('enzymatic activity', 'MPA', (236, 254))	('dwindled', 'NegReg', (198, 206))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
46275	27440446	Our further results revealed that reduced MMP9 gene expression, mediated by Gal-1 knockdown in T24 cells, might be attributed to the intervention of the JNK signaling pathway to activate c-Jun, which in turn impaired the movement of activated c-Jun to the nucleus to form AP1 transcription factor.	('transcription factor', 'molecular_function', 'GO:0000981', ('276', '296'))	('JNK', 'Gene', (153, 156))	('gene expression', 'biological_process', 'GO:0010467', ('47', '62'))	('JNK', 'molecular_function', 'GO:0004705', ('153', '156'))	('AP1', 'cellular_component', 'GO:0005907', ('272', '275'))	('JNK', 'Gene', '5599', (153, 156))	('reduced', 'NegReg', (34, 41))	('activate', 'PosReg', (178, 186))	('knockdown', 'Var', (82, 91))	('transcription', 'biological_process', 'GO:0006351', ('276', '289'))	('turn impaired the movement', 'Disease', 'MESH:D009069', (203, 229))	('nucleus', 'cellular_component', 'GO:0005634', ('256', '263'))	('turn impaired the movement', 'Disease', (203, 229))	('JNK signaling pathway', 'biological_process', 'GO:0031098', ('153', '174'))	('Gal-1', 'Gene', (76, 81))	('c-Jun', 'Gene', '3725', (187, 192))	('AP1', 'Gene', '3725', (272, 275))	('MMP9', 'Gene', '4318', (42, 46))	('MMP9', 'Gene', (42, 46))	('AP1', 'Gene', (272, 275))	('c-Jun', 'Gene', (187, 192))	('c-Jun', 'Gene', '3725', (243, 248))	('expression', 'MPA', (52, 62))	('MMP9', 'molecular_function', 'GO:0004229', ('42', '46'))	('c-Jun', 'Gene', (243, 248))
46277	27440446	Galectin-1 silencing causes protein kinase Cepsilon and vimentin to accumulate around the nucleus in glioblastoma cells,33 which interferes with beta-integrin trafficking and recycling to the cell membrane, and thus leads to a decreased amount of integrin receptors on the cell membrane.	('glioblastoma', 'Disease', 'MESH:D005909', (101, 113))	('Galectin-1', 'Gene', (0, 10))	('vimentin', 'cellular_component', 'GO:0045099', ('56', '64'))	('glioblastoma', 'Disease', (101, 113))	('amount of integrin receptors on the', 'MPA', (237, 272))	('Galectin', 'molecular_function', 'GO:0001577', ('0', '8'))	('cell membrane', 'cellular_component', 'GO:0005886', ('273', '286'))	('glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('accumulate', 'PosReg', (68, 78))	('beta-integrin trafficking', 'MPA', (145, 170))	('protein kinase Cepsilon', 'Enzyme', (28, 51))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))	('vimentin', 'Gene', '7431', (56, 64))	('vimentin', 'Gene', (56, 64))	('vimentin', 'cellular_component', 'GO:0045098', ('56', '64'))	('interferes', 'NegReg', (129, 139))	('silencing', 'Var', (11, 20))	('decreased', 'NegReg', (227, 236))	('nucleus', 'cellular_component', 'GO:0005634', ('90', '97'))	('recycling to the cell membrane', 'MPA', (175, 205))	('Galectin-1', 'Gene', '3956', (0, 10))	('cell membrane', 'cellular_component', 'GO:0005886', ('192', '205'))
46281	27440446	These results reveal that silencing the Gal-1-mediated MAPK signaling pathway presents a novel strategy for bladder cancer therapy.	('MAPK', 'molecular_function', 'GO:0004707', ('55', '59'))	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('bladder cancer', 'Disease', (108, 122))	('MAPK', 'Gene', '5594', (55, 59))	('MAPK signaling', 'biological_process', 'GO:0000165', ('55', '69'))	('MAPK', 'Gene', (55, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('signaling pathway', 'biological_process', 'GO:0007165', ('60', '77'))	('silencing', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
46329	22859931	Pyk2 depletion (Figure 3A) severely inhibited IGF-I-induced tumor cell migration (Figure 3B) and invasion through Matrigel  (Figure 3C).	('depletion', 'Var', (5, 14))	('inhibited', 'NegReg', (36, 45))	('IGF-I', 'Gene', (46, 51))	('Pyk2', 'Gene', '2185', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('Pyk2', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('IGF-I', 'Gene', '3479', (46, 51))	('cell migration', 'biological_process', 'GO:0016477', ('66', '80'))	('tumor', 'Disease', (60, 65))	('invasion through Matrigel', 'CPA', (97, 122))
46330	22859931	Interestingly, Pyk2 depletion slightly upregulated FAK levels (Figure 3A), although FAK was unable to compensate for Pyk2 loss.	('FAK', 'molecular_function', 'GO:0004717', ('84', '87'))	('FAK', 'Gene', (84, 87))	('FAK', 'Gene', '5747', (84, 87))	('upregulated', 'PosReg', (39, 50))	('FAK', 'molecular_function', 'GO:0004717', ('51', '54'))	('depletion', 'Var', (20, 29))	('Pyk2', 'Gene', '2185', (117, 121))	('FAK', 'Gene', '5747', (51, 54))	('Pyk2', 'Gene', (117, 121))	('FAK', 'Gene', (51, 54))	('Pyk2', 'Gene', '2185', (15, 19))	('Pyk2', 'Gene', (15, 19))
46331	22859931	In addition, Pyk2 knockdown in 5637 cells affected IGF-IR-downstream signaling and inhibited IGF-I-dependent activation of Akt and ERK1/2 and downstream effectors S6K and p90RSK (Figure 3D).	('Pyk2', 'Gene', (13, 17))	('inhibited', 'NegReg', (83, 92))	('p90RSK', 'Gene', (171, 177))	('IGF-I', 'Gene', '3479', (51, 56))	('S6K', 'Gene', '6198', (163, 166))	('activation', 'MPA', (109, 119))	('Pyk2', 'Gene', '2185', (13, 17))	('signaling', 'biological_process', 'GO:0023052', ('69', '78'))	('Akt', 'Gene', (123, 126))	('IGF-I', 'Gene', (93, 98))	('knockdown', 'Var', (18, 27))	('ERK1', 'molecular_function', 'GO:0004707', ('131', '135'))	('Akt', 'Gene', '207', (123, 126))	('IGF-I', 'Gene', '3479', (93, 98))	('S6K', 'Gene', (163, 166))	('p90RSK', 'Gene', '6195', (171, 177))	('ERK1/2', 'Gene', (131, 137))	('ERK1/2', 'Gene', '5595;5594', (131, 137))	('affected', 'Reg', (42, 50))	('IGF-IR', 'Gene', (51, 57))	('IGF-IR', 'Gene', '3480', (51, 57))	('IGF-I', 'Gene', (51, 56))
46334	22859931	In addition, Pyk2 ablation in T24 cells was associated with reduced IGF-I-dependent activation of ERK1/2 and S6K, while Akt and p90RSK activation was not affected (Figure S1D).	('p90RSK', 'Gene', '6195', (128, 134))	('ERK1/2', 'Gene', '5595;5594', (98, 104))	('Pyk2', 'Gene', '2185', (13, 17))	('ERK1', 'molecular_function', 'GO:0004707', ('98', '102'))	('S6K', 'Gene', '6198', (109, 112))	('Pyk2', 'Gene', (13, 17))	('activation', 'PosReg', (84, 94))	('p90RSK', 'Gene', (128, 134))	('IGF-I', 'Gene', '3479', (68, 73))	('Akt', 'Gene', '207', (120, 123))	('ERK1/2', 'Gene', (98, 104))	('IGF-I', 'Gene', (68, 73))	('reduced', 'NegReg', (60, 67))	('S6K', 'Gene', (109, 112))	('ablation', 'Var', (18, 26))	('Akt', 'Gene', (120, 123))
46345	22859931	These qualitative differences may be likely due to differences in the relative abundance of these proteins in 5637 and T24 cells as in fact 5637 cells express higher level of Pyk2 proteins compared to T4 (data not shown).	('5637', 'Var', (140, 144))	('higher', 'PosReg', (159, 165))	('Pyk2', 'Gene', '2185', (175, 179))	('Pyk2', 'Gene', (175, 179))
46379	22859931	As Pyk2 depletion severely inhibits IGF-I-induced signaling, it could be argued that the effects of Pyk suppression on migration are a consequence of reduced proliferation/survival.	('suppression', 'NegReg', (104, 115))	('depletion', 'Var', (8, 17))	('inhibits', 'NegReg', (27, 35))	('IGF-I', 'Gene', '3479', (36, 41))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('migration', 'CPA', (119, 128))	('Pyk', 'Gene', '5256', (3, 6))	('Pyk', 'Gene', (3, 6))	('Pyk2', 'Gene', '2185', (3, 7))	('Pyk', 'Gene', '5256', (100, 103))	('Pyk', 'Gene', (100, 103))	('IGF-I', 'Gene', (36, 41))	('Pyk2', 'Gene', (3, 7))	('reduced', 'NegReg', (150, 157))	('proliferation/survival', 'CPA', (158, 180))
46413	22859931	siRNA efficiency was detected by immunobloting using anti-FAK (#3285) and anti-Pyk2 (#3090) polyclonal antibodies (both from Cell Signaling Technology, Beverly, MA, USA).	('FAK', 'molecular_function', 'GO:0004717', ('58', '61'))	('#3285', 'Var', (63, 68))	('Pyk2', 'Gene', '2185', (79, 83))	('FAK', 'Gene', (58, 61))	('Pyk2', 'Gene', (79, 83))	('FAK', 'Gene', '5747', (58, 61))	('Signaling', 'biological_process', 'GO:0023052', ('130', '139'))	('#3090', 'Var', (85, 90))
46414	22859931	5637 cells were transiently transfected using the TransIT -Prostate Transfection Kit (Mirus BIO LLC) with the expression plasmid pShCMV.3X FLAG expressing either wild type or kinase-dead (K457A) Pyk2 mutant protein.	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('K457A', 'Var', (188, 193))	('Pyk2', 'Gene', '2185', (195, 199))	('Pyk2', 'Gene', (195, 199))	('mutant', 'Var', (200, 206))	('K457A', 'Mutation', 'p.K457A', (188, 193))	('protein', 'Protein', (207, 214))	('LLC', 'cellular_component', 'GO:0038045', ('96', '99'))
46523	19468362	Loss of heterozygosity (LOH) on Chromosome 9 is found in >50% of all bladder tumors and is more prevalent in the low-grade non-invasive papillary tumors [Table 1a, b].	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('bladder tumors', 'Phenotype', 'HP:0009725', (69, 83))	('papillary tumors', 'Phenotype', 'HP:0007482', (136, 152))	('bladder tumor', 'Phenotype', 'HP:0009725', (69, 82))	('bladder tumors', 'Disease', (69, 83))	('Loss of heterozygosity', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))	('papillary tumors', 'Disease', 'MESH:D002291', (136, 152))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('papillary tumors', 'Disease', (136, 152))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('bladder tumors', 'Disease', 'MESH:D001749', (69, 83))
46524	19468362	In addition, deletions on Chromosome 9 have been demonstrated in urothelial hyperplasia and normal appearing urothelium adjacent to tumor lesions.	('urothelial hyperplasia', 'Disease', (65, 87))	('tumor lesions', 'Disease', 'MESH:D051437', (132, 145))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('deletions', 'Var', (13, 22))	('urothelial hyperplasia', 'Disease', 'MESH:D006965', (65, 87))	('tumor lesions', 'Disease', (132, 145))	('demonstrated', 'Reg', (49, 61))
46526	19468362	Therefore, deletions on Chromosome 9 may set the stage for tumorigenesis and contribute to both pathways of urothelial carcinogenesis by predisposing urothelial cells to a cascade of genetic alterations.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('contribute', 'Reg', (77, 87))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (108, 133))	('deletions', 'Var', (11, 20))	('Chromosome', 'cellular_component', 'GO:0005694', ('24', '34'))	('set', 'Reg', (41, 44))	('urothelial carcinogenesis', 'Disease', (108, 133))	('predisposing', 'Reg', (137, 149))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
46527	19468362	A retrospective study applying FISH to tumor specimens demonstrated that polysomy of Chromosome 17 and LOH on Chromosome 9 were independent predictors of tumor recurrence.	('Chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('polysomy', 'Var', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('LOH', 'Var', (103, 106))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (154, 159))
46530	19468362	Approximately, 70% of low-grade non-muscle-invasive papillary tumors have been shown to demonstrate FGFR3 gene mutations compared with 20% of invasive tumors.	('mutations', 'Var', (111, 120))	('papillary tumors', 'Disease', (52, 68))	('invasive tumors', 'Disease', (142, 157))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('papillary tumors', 'Disease', 'MESH:D002291', (52, 68))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('invasive tumors', 'Disease', 'MESH:D009369', (142, 157))	('FGFR3', 'Gene', '2261', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('papillary tumors', 'Phenotype', 'HP:0007482', (52, 68))	('FGFR3', 'Gene', (100, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('100', '104'))
46531	19468362	The expression of activating mutant FGFR3 gene in urothelial cell carcinoma correlates with noninvasive clinical course.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('FGFR3', 'Gene', (36, 41))	('mutant', 'Var', (29, 35))	('urothelial cell carcinoma', 'Disease', 'MESH:C538614', (50, 75))	('expression', 'MPA', (4, 14))	('activating', 'PosReg', (18, 28))	('FGFR3', 'Gene', '2261', (36, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))	('urothelial cell carcinoma', 'Disease', (50, 75))
46532	19468362	A study by van Rhijn examined 260 bladder cancer specimens and demonstrated FGFR3 genetic alterations were found predominantly (60%) in low-grade non-muscle-invasive tumors and were associated with favorable outcomes.	('associated', 'Reg', (182, 192))	('muscle-invasive tumors', 'Disease', (150, 172))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('FGFR3', 'Gene', '2261', (76, 81))	('bladder cancer', 'Disease', 'MESH:D001749', (34, 48))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))	('genetic alterations', 'Var', (82, 101))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('bladder cancer', 'Disease', (34, 48))	('FGFR3', 'Gene', (76, 81))	('found', 'Reg', (107, 112))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (150, 172))
46537	19468362	Mutations in HRAS are primarily associated with non-muscle-invasive urothelial carcinoma and transgenic mouse models have demonstrated evolution of urothelial hyperplasia to low-grade non-invasive papillary tumors.	('HRAS', 'Gene', (13, 17))	('transgenic', 'Species', '10090', (93, 103))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (68, 88))	('papillary tumors', 'Disease', (197, 213))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('papillary tumors', 'Disease', 'MESH:D002291', (197, 213))	('urothelial hyperplasia', 'Disease', (148, 170))	('mouse', 'Species', '10090', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('Mutations', 'Var', (0, 9))	('urothelial carcinoma', 'Disease', (68, 88))	('papillary tumors', 'Phenotype', 'HP:0007482', (197, 213))	('associated', 'Reg', (32, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('urothelial hyperplasia', 'Disease', 'MESH:D006965', (148, 170))
46544	19468362	Mutations involved in the p53 protein dysfunction occur in two phases: initially one allele is affected, followed by loss of a second, wild-type allele.	('protein dysfunction', 'Disease', (30, 49))	('p53', 'Gene', (26, 29))	('Mutations', 'Var', (0, 9))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('protein dysfunction', 'Disease', 'MESH:D011488', (30, 49))
46545	19468362	Overexpression of p53 as determined by immunohistochemistry is routinely used to measure TP53 mutations which are infrequent in low-grade non-invasive papillary tumors, but very common (>50%) in high-grade invasive urothelial tumors and CIS tumors.	('TP53', 'Gene', '7157', (89, 93))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('TP53', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('papillary tumors', 'Phenotype', 'HP:0007482', (151, 167))	('invasive urothelial tumors and CIS tumors', 'Disease', 'MESH:D009369', (206, 247))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('papillary tumors', 'Disease', (151, 167))	('common', 'Reg', (178, 184))	('papillary tumors', 'Disease', 'MESH:D002291', (151, 167))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
46546	19468362	The product of a mutated TP53 gene has been shown to be a metabolically stable protein with a long half-life.	('TP53', 'Gene', '7157', (25, 29))	('TP53', 'Gene', (25, 29))	('mutated', 'Var', (17, 24))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))
46548	19468362	However, a meta-analysis by Malats reviewing 117 studies spanning 10 years of research concluded that the evidence is not yet sufficient to conclude whether changes in P53 act as markers of outcome in patients with bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (215, 229))	('patients', 'Species', '9606', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('bladder cancer', 'Disease', 'MESH:D001749', (215, 229))	('P53', 'Gene', (168, 171))	('changes', 'Var', (157, 164))	('bladder cancer', 'Disease', (215, 229))	('P53', 'Gene', '7157', (168, 171))
46549	19468362	Hence, it would appear that expression of p53 has molecular significance in bladder carcinogenesis and closely correlates with disease progression, but its prognostic utility is confounded by its close association with standard clinical and pathologic prognostic features.	('p53', 'Gene', (42, 45))	('bladder carcinogenesis', 'Disease', (76, 98))	('correlates', 'Reg', (111, 121))	('expression', 'Var', (28, 38))	('significance', 'Reg', (60, 72))	('bladder carcinogenesis', 'Disease', 'MESH:D063646', (76, 98))
46550	19468362	The expression of p21 protein, a cyclin-dependent kinase inhibitor and an important downstream target of p53, is downregulated in the majority of urothelial carcinomas with TP53 mutations.	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('p21', 'Gene', (18, 21))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('50', '66'))	('downregulated', 'NegReg', (113, 126))	('expression', 'MPA', (4, 14))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (146, 167))	('p21', 'Gene', '644914', (18, 21))	('urothelial carcinomas', 'Disease', (146, 167))	('protein', 'Protein', (22, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('TP53', 'Gene', '7157', (173, 177))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('TP53', 'Gene', (173, 177))	('mutations', 'Var', (178, 187))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('33', '66'))
46552	19468362	In a second study retrospectively examining radical cystectomy specimens, alteration of p21 expression was independently associated with disease progression and disease-specific survival.	('alteration', 'Var', (74, 84))	('disease-specific survival', 'CPA', (161, 186))	('associated', 'Reg', (121, 131))	('p21', 'Gene', (88, 91))	('disease progression', 'CPA', (137, 156))	('expression', 'MPA', (92, 102))	('p21', 'Gene', '644914', (88, 91))
46553	19468362	Recently, a study retrospectively reviewing non-muscle-invasive bladder tumor specimens from transurethral resections (TUR) demonstrated that altered p21 expression was independently associated with disease progression but not recurrence.	('p21', 'Gene', '644914', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('bladder tumor', 'Disease', 'MESH:D001749', (64, 77))	('altered', 'Var', (142, 149))	('bladder tumor', 'Phenotype', 'HP:0009725', (64, 77))	('disease progression', 'CPA', (199, 218))	('invasive bladder', 'Phenotype', 'HP:0100645', (55, 71))	('p21', 'Gene', (150, 153))	('associated with', 'Reg', (183, 198))	('non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (44, 71))	('bladder tumor', 'Disease', (64, 77))	('expression', 'MPA', (154, 164))
46556	19468362	High-grade and invasive urothelial tumors harbor inactivating mutations of the RB gene.	('invasive urothelial tumors', 'Disease', 'MESH:D001749', (15, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('inactivating mutations', 'Var', (49, 71))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('High-grade', 'Disease', (0, 10))	('invasive urothelial tumors', 'Disease', (15, 41))
46557	19468362	In a retrospective study using immunohistochemical analysis of high-grade and invasive bladder cancer specimens, p53, p21 and Rb status were independent predictors of time to recurrence and overall survival.	('invasive bladder', 'Phenotype', 'HP:0100645', (78, 94))	('invasive bladder cancer', 'Disease', (78, 101))	('p53', 'Var', (113, 116))	('time', 'CPA', (167, 171))	('overall survival', 'CPA', (190, 206))	('p21', 'Gene', (118, 121))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (78, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('p21', 'Gene', '644914', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
46558	19468362	Urothelial tumors with alterations in both p53 and Rb expression had increased rates of recurrence and progression and worse survival then tumors harboring defects of either gene.	('recurrence', 'CPA', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('Urothelial tumors', 'Disease', 'MESH:D001749', (0, 17))	('increased', 'PosReg', (69, 78))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('alterations', 'Var', (23, 34))	('p53', 'Gene', (43, 46))	('tumors', 'Disease', (139, 145))	('Urothelial tumors', 'Disease', (0, 17))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('progression', 'CPA', (103, 114))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
46564	19468362	Alteration of E-cadherin expression induces a defect in cell-cell adhesion and is primarily seen in high-grade muscle-invasive tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('E-cadherin', 'Gene', '999', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('Alteration', 'Var', (0, 10))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (111, 133))	('cell-cell adhesion', 'CPA', (56, 74))	('seen', 'Reg', (92, 96))	('defect', 'NegReg', (46, 52))	('muscle-invasive tumors', 'Disease', (111, 133))	('E-cadherin', 'Gene', (14, 24))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('56', '74'))
46585	19468362	Loss of Heterozygosity (LOH): In a heterozygote, the loss of one of the two alleles at one or more loci in a cell lineage or cancer cell population due to chromosome loss, deletion or mitotic crossing-over.	('chromosome', 'cellular_component', 'GO:0005694', ('155', '165'))	('chromosome', 'CPA', (155, 165))	('mitotic crossing-over', 'CPA', (184, 205))	('loss', 'NegReg', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('loss', 'NegReg', (53, 57))	('deletion', 'Var', (172, 180))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
46595	33621953	Ten lncRNAs (LOC105375787, CYTOR, URB1-AS1, C21orf91-OT1, CASC15, LOC101928433, FLJ45139, LINC00960, HOTAIR and TTTY19) with the highest prognostic values were identified to establish the prognostic model.	('CYTOR', 'Gene', '112597', (27, 32))	('HOTAIR', 'Gene', (101, 107))	('LINC00960', 'Gene', '401074', (90, 99))	('FLJ45139', 'Chemical', '-', (80, 88))	('FLJ45139', 'Var', (80, 88))	('LOC105375787', 'Gene', (13, 25))	('C21orf91-OT1', 'Gene', '246312', (44, 56))	('LINC00960', 'Gene', (90, 99))	('URB1-AS1', 'Gene', (34, 42))	('LOC101928433', 'Gene', '101928433', (66, 78))	('TTTY19', 'Gene', '252952', (112, 118))	('CYTOR', 'Gene', (27, 32))	('CASC15', 'Gene', (58, 64))	('CASC15', 'Gene', '401237', (58, 64))	('C21orf91-OT1', 'Gene', (44, 56))	('LOC105375787', 'Gene', '105375787', (13, 25))	('LOC101928433', 'Gene', (66, 78))	('URB1-AS1', 'Gene', '84996;9875;5729', (34, 42))	('HOTAIR', 'Gene', '100124700', (101, 107))	('TTTY19', 'Gene', (112, 118))
46612	33621953	Inferentially, positive coefficients implied that higher expression levels of 8 genes including LOC105375787, CYTOR, URB1-AS1, C21orf91-OT1, CASC15, LOC101928433, FLJ45139 and HOTAIR predicted shorter survival.	('HOTAIR', 'Gene', '100124700', (176, 182))	('URB1-AS1', 'Gene', (117, 125))	('LOC101928433', 'Gene', '101928433', (149, 161))	('CYTOR', 'Gene', (110, 115))	('CASC15', 'Gene', (141, 147))	('CASC15', 'Gene', '401237', (141, 147))	('C21orf91-OT1', 'Gene', (127, 139))	('HOTAIR', 'Gene', (176, 182))	('LOC105375787', 'Gene', '105375787', (96, 108))	('LOC101928433', 'Gene', (149, 161))	('URB1-AS1', 'Gene', '84996;9875;5729', (117, 125))	('shorter', 'NegReg', (193, 200))	('CYTOR', 'Gene', '112597', (110, 115))	('FLJ45139', 'Var', (163, 171))	('FLJ45139', 'Chemical', '-', (163, 171))	('higher', 'PosReg', (50, 56))	('LOC105375787', 'Gene', (96, 108))	('C21orf91-OT1', 'Gene', '246312', (127, 139))	('expression levels', 'MPA', (57, 74))
46616	33621953	High TTTY19 expression was significantly associated with longer survival in BLCA patients (log-rank test<0.05).	('longer', 'PosReg', (57, 63))	('TTTY19', 'Gene', (5, 11))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (81, 89))	('TTTY19', 'Gene', '252952', (5, 11))	('expression', 'MPA', (12, 22))
46619	33621953	To further investigate the association of this 10-lncRNA signature with BLCA prognosis, a prognostic model was constructed as follows:  i Coefficient (lncRNAi) x Expression (lncRNAi), which was Risk score= (4.4 x expression level of LOC105375787) + (1.2 x expression level of CYTOR) + (1.2 x expression level of URB1-AS1) + (3.2 x expression level of C21orf91-OT1) + (0.62 x expression level of CASC15) + (0.91 x expression level of LOC101928433) + (1.3 x expression level of FLJ45139) + (1.9 + expression level of HOTAIR) + (-0.39 x expression level of LINC00960) + (-4.1 x expression level of TTTY19).	('C21orf91-OT1', 'Gene', (351, 363))	('TTTY19', 'Gene', (595, 601))	('URB1-AS1)', 'Gene', '84996', (312, 321))	('LOC101928433', 'Gene', '101928433', (433, 445))	('FLJ45139', 'Var', (476, 484))	('FLJ45139', 'Chemical', '-', (476, 484))	('LOC105375787', 'Gene', '105375787', (233, 245))	('CASC15', 'Gene', (395, 401))	('CASC15', 'Gene', '401237', (395, 401))	('LOC101928433', 'Gene', (433, 445))	('URB1-AS1', 'Gene', (312, 320))	('HOTAIR', 'Gene', '100124700', (515, 521))	('LINC00960', 'Gene', '401074', (554, 563))	('CYTOR)', 'Gene', '112597', (276, 282))	('HOTAIR', 'Gene', (515, 521))	('TTTY19', 'Gene', '252952', (595, 601))	('LOC105375787', 'Gene', (233, 245))	('C21orf91-OT1)', 'Gene', '246312', (351, 364))	('CYTOR', 'Gene', (276, 281))	('LINC00960', 'Gene', (554, 563))
46627	33621953	Similarly, in GSE13507, shorter DSS times were observed in the high-risk subgroup (log-rank test P=0.018) (Figure 4C).	('GSE13507', 'Var', (14, 22))	('DSS', 'Chemical', '-', (32, 35))	('shorter', 'NegReg', (24, 31))	('DSS times', 'MPA', (32, 41))
46637	33621953	After stratifying the patients from GSE32894 and GSE32548 into the muscle invasion (>=T2) subgroup or non-muscle invasion (Ta or T1) subgroup, Kaplan-Meier plots showed that for patients in the same tumour invasion subgroup, those with higher risk scores had significantly shorter DSS times than those with lower risk scores (Figure 7A, 7B).	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('shorter', 'NegReg', (273, 280))	('GSE32894', 'Var', (36, 44))	('GSE32548', 'Var', (49, 57))	('DSS', 'Chemical', '-', (281, 284))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('patients', 'Species', '9606', (22, 30))	('patients', 'Species', '9606', (178, 186))	('DSS times', 'MPA', (281, 290))	('tumour', 'Disease', (199, 205))
46639	33621953	The patients in both GSE32894 and GSE32548 were classified into three groups (G1, G2 and G3) based on different tumour grades.	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', (112, 118))	('GSE32894', 'Var', (21, 29))	('patients', 'Species', '9606', (4, 12))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('GSE32548', 'Var', (34, 42))
46652	33621953	In all three independent series, the 10-lncRNA signature demonstrated a discriminatory ability for predicting DSS, with AUC values of 0.871 (95% CI=0.808-0.934) in GSE32894 (Figure 8A), 0.752 (95% CI=0.624-0.879) in GSE32548 (Figure 8B) and 0.707 (95% CI=0.597-0.816) in GSE13507 (Figure 8C).	('GSE32894', 'Var', (164, 172))	('0.707', 'Var', (241, 246))	('DSS', 'Chemical', '-', (110, 113))	('DSS', 'Disease', (110, 113))	('GSE13507', 'Var', (271, 279))	('0.752', 'Var', (186, 191))	('GSE32548', 'Var', (216, 224))
46653	33621953	In GSE32894, as shown in Figure 8A, both the 10-lncRNA risk score (AUC=0.871) and tumour stage (AUC=0.920) showed a high predictive performance with no significant difference (P=0.134).	('tumour', 'Disease', (82, 88))	('GSE32894', 'Var', (3, 11))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Disease', 'MESH:D009369', (82, 88))
46655	33621953	In GSE13507, as presented in Figure 8C, despite a smaller AUC (AUC=0.707), which was still estimated to exceed 0.70, there was no significant difference between the signature and tumour stage or histopathological grade (P=0.05 and P=0.36, respectively).	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('AUC', 'MPA', (58, 61))	('GSE13507', 'Var', (3, 11))	('tumour', 'Disease', (179, 185))	('smaller', 'NegReg', (50, 57))
46659	33621953	In addition, several genomic alterations, such as HER-2 (ERBB2), ERBB3 and FGFR3, which were included in this study, have been identified to be amenable in principle to therapeutic targeting and were reported to be associated with advanced BLCA in previous studies.	('advanced BLCA', 'Disease', (231, 244))	('FGFR3', 'Gene', (75, 80))	('ERBB2', 'Gene', '2064', (57, 62))	('ERBB3', 'Gene', '2065', (65, 70))	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('ERBB2', 'Gene', (57, 62))	('HER-2', 'Gene', '2064', (50, 55))	('ERBB3', 'Gene', (65, 70))	('alterations', 'Var', (29, 40))	('HER-2', 'Gene', (50, 55))	('FGFR3', 'Gene', '2261', (75, 80))	('associated', 'Reg', (215, 225))
46673	33621953	We found that LOC105375787, CYTOR, URB1-AS1, C21orf91-OT1, CASC15, LOC101928433, FLJ45139, and HOTAIR acted as oncogenes, while LINC00960 and TTTY19 acted as suppressors.	('TTTY19', 'Gene', '252952', (142, 148))	('FLJ45139', 'Chemical', '-', (81, 89))	('FLJ45139', 'Var', (81, 89))	('C21orf91-OT1', 'Gene', '246312', (45, 57))	('URB1-AS1', 'Gene', (35, 43))	('CYTOR', 'Gene', (28, 33))	('LOC105375787', 'Gene', (14, 26))	('LINC00960', 'Gene', '401074', (128, 137))	('HOTAIR', 'Gene', '100124700', (95, 101))	('LOC101928433', 'Gene', '101928433', (67, 79))	('TTTY19', 'Gene', (142, 148))	('URB1-AS1', 'Gene', '84996;9875;5729', (35, 43))	('C21orf91-OT1', 'Gene', (45, 57))	('HOTAIR', 'Gene', (95, 101))	('LOC101928433', 'Gene', (67, 79))	('CASC15', 'Gene', (59, 65))	('CASC15', 'Gene', '401237', (59, 65))	('CYTOR', 'Gene', '112597', (28, 33))	('LINC00960', 'Gene', (128, 137))	('oncogenes', 'CPA', (111, 120))	('LOC105375787', 'Gene', '105375787', (14, 26))
46690	33621953	reported that individuals with a higher number of altered alleles in DNA repair and the cell cycle are at an increased risk of developing bladder cancer, and these genetic effects were found to be significantly related to smoking.	('bladder cancer', 'Disease', 'MESH:D001749', (138, 152))	('bladder cancer', 'Disease', (138, 152))	('alleles', 'Var', (58, 65))	('related', 'Reg', (211, 218))	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('DNA', 'Gene', (69, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('DNA repair', 'biological_process', 'GO:0006281', ('69', '79'))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cell cycle', 'CPA', (88, 98))	('altered alleles', 'Var', (50, 65))	('cell cycle', 'biological_process', 'GO:0007049', ('88', '98'))
46701	33621953	reported that CASC15 could epigenetically silence the expression of the immunomodulatory molecule programmed cell death 4 (PDCD4) and facilitate proliferation and invasion in melanoma cells.	('expression', 'MPA', (54, 64))	('CASC15', 'Gene', (14, 20))	('CASC15', 'Gene', '401237', (14, 20))	('programmed cell death 4', 'Gene', '27250', (98, 121))	('programmed cell death 4', 'Gene', (98, 121))	('programmed cell death', 'biological_process', 'GO:0012501', ('98', '119'))	('silence', 'NegReg', (42, 49))	('PDCD4', 'Gene', (123, 128))	('epigenetically', 'Var', (27, 41))	('PDCD4', 'Gene', '27250', (123, 128))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('facilitate', 'PosReg', (134, 144))	('melanoma', 'Disease', (175, 183))	('invasion', 'CPA', (163, 171))
46704	33621953	All data series were included based on the following criteria: 1. public expression data generated for BLCA were obtained; 2. the same manufacturer platform was used (in this paper, the following Illumina human expression beadchip platforms were used: GPL6947 and GPL6102); and 3. raw nonnormalized data and matched clinical data with follow-up information were obtained.	('human', 'Species', '9606', (205, 210))	('GPL6102', 'Var', (264, 271))	('GPL6947', 'Var', (252, 259))
46705	33621953	Ultimately, GS32894, GSE32548 and GSE13507 were included in the present study after an initial quality check.	('GS32894', 'Var', (12, 19))	('GS32894', 'Chemical', '-', (12, 19))	('GSE13507', 'Var', (34, 42))	('GSE32548', 'Var', (21, 29))
46719	32354045	In the current study, two single nucleotide polymorphisms (SNPs) in the GAS5 gene, rs145204276 and rs55829688, were selected to investigate correlations between these single SNPs and susceptibility to UCC.	('rs145204276', 'Mutation', 'rs145204276', (83, 94))	('GAS5', 'Gene', '60674', (72, 76))	('rs55829688', 'Mutation', 'rs55829688', (99, 109))	('rs55829688', 'Var', (99, 109))	('rs145204276', 'Var', (83, 94))	('GAS', 'molecular_function', 'GO:0034005', ('72', '75'))	('UCC', 'Disease', (201, 204))	('GAS5', 'Gene', (72, 76))
46724	32354045	In conclusion, genetic variations in GAS5 rs145204276 may serve as a critical predictor of the clinical status of female patients with UCC.	('rs145204276', 'Mutation', 'rs145204276', (42, 53))	('GAS5', 'Gene', (37, 41))	('rs145204276', 'Var', (42, 53))	('GAS5', 'Gene', '60674', (37, 41))	('GAS', 'molecular_function', 'GO:0034005', ('37', '40'))	('UCC', 'Disease', (135, 138))	('patients', 'Species', '9606', (121, 129))
46734	32354045	Overexpression of GAS5 in hepatic stellate cells (HSCs) prevents liver fibrosis by targeting miR-222, resulting in cell cycle arrest and the inhibition of HSC activation.	('arrest', 'Disease', (126, 132))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (115, 132))	('HSC', 'cellular_component', 'GO:0035301', ('155', '158'))	('liver fibrosis', 'Phenotype', 'HP:0001395', (65, 79))	('GAS5', 'Gene', (18, 22))	('miR-222', 'Gene', '407007', (93, 100))	('HSC', 'Gene', (155, 158))	('HSC', 'Gene', '2523', (155, 158))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('115', '132'))	('inhibition', 'NegReg', (141, 151))	('arrest', 'Disease', 'MESH:D006323', (126, 132))	('HSC', 'Gene', (50, 53))	('HSC', 'Gene', '2523', (50, 53))	('GAS', 'molecular_function', 'GO:0034005', ('18', '21'))	('miR-222', 'Gene', (93, 100))	('fibrosis', 'Disease', 'MESH:D005355', (71, 79))	('fibrosis', 'Disease', (71, 79))	('GAS5', 'Gene', '60674', (18, 22))	('targeting', 'Var', (83, 92))	('prevents', 'NegReg', (56, 64))
46736	32354045	Studies of single nucleotide polymorphisms (SNPs) have investigated their role in the function of GAS5.	('GAS', 'molecular_function', 'GO:0034005', ('98', '101'))	('GAS5', 'Gene', (98, 102))	('GAS5', 'Gene', '60674', (98, 102))	('single nucleotide polymorphisms', 'Var', (11, 42))
46737	32354045	SNPs in GAS5 rs145204276 Ins/Del and Del/Del genotypes were associated with a reduced risk of atherosclerosis, because they inhibit cell proliferation and stimulate the apoptosis of endothelial cells by targeting the GAS5/miR-21/PDCD4 signaling pathway.	('signaling pathway', 'biological_process', 'GO:0007165', ('235', '252'))	('GAS5', 'Gene', (217, 221))	('targeting', 'Reg', (203, 212))	('GAS5', 'Gene', '60674', (8, 12))	('rs145204276', 'Mutation', 'rs145204276', (13, 24))	('apoptosis of endothelial cells', 'CPA', (169, 199))	('apoptosis of endothelial cells', 'biological_process', 'GO:0072577', ('169', '199'))	('inhibit', 'NegReg', (124, 131))	('PDCD4', 'Gene', (229, 234))	('GAS5', 'Gene', (8, 12))	('miR-21', 'Gene', '406991', (222, 228))	('Del/Del', 'Var', (37, 44))	('stimulate', 'PosReg', (155, 164))	('reduced', 'NegReg', (78, 85))	('GAS', 'molecular_function', 'GO:0034005', ('217', '220'))	('atherosclerosis', 'Disease', 'MESH:D050197', (94, 109))	('PDCD4', 'Gene', '27250', (229, 234))	('GAS5', 'Gene', '60674', (217, 221))	('atherosclerosis', 'Disease', (94, 109))	('GAS', 'molecular_function', 'GO:0034005', ('8', '11'))	('rs145204276 Ins/Del', 'Var', (13, 32))	('cell proliferation', 'CPA', (132, 150))	('cell proliferation', 'biological_process', 'GO:0008283', ('132', '150'))	('miR-21', 'Gene', (222, 228))	('atherosclerosis', 'Phenotype', 'HP:0002621', (94, 109))
46738	32354045	Expression of GAS5 was upregulated in patients with acute myeloid leukemia (AML) and the GAS5 rs55829688 CC genotype; the promoter activity of GAS5 was increased through interaction with TP63, which in turn led to a worse prognosis for AML.	('rs55829688', 'Mutation', 'rs55829688', (94, 104))	('GAS5', 'Gene', '60674', (89, 93))	('upregulated', 'PosReg', (23, 34))	('AML', 'Disease', (76, 79))	('AML', 'Phenotype', 'HP:0004808', (76, 79))	('patients', 'Species', '9606', (38, 46))	('GAS5', 'Gene', '60674', (14, 18))	('GAS5', 'Gene', (143, 147))	('GAS5', 'Gene', (89, 93))	('promoter activity', 'MPA', (122, 139))	('GAS', 'molecular_function', 'GO:0034005', ('143', '146'))	('acute myeloid leukemia', 'Disease', (52, 74))	('AML', 'Disease', 'MESH:D015470', (236, 239))	('TP63', 'Gene', (187, 191))	('rs55829688 CC', 'Var', (94, 107))	('increased', 'PosReg', (152, 161))	('AML', 'Phenotype', 'HP:0004808', (236, 239))	('AML', 'Disease', (236, 239))	('GAS5', 'Gene', (14, 18))	('GAS', 'molecular_function', 'GO:0034005', ('89', '92'))	('interaction', 'Interaction', (170, 181))	('TP63', 'Gene', '8626', (187, 191))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (52, 74))	('GAS', 'molecular_function', 'GO:0034005', ('14', '17'))	('leukemia', 'Phenotype', 'HP:0001909', (66, 74))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (52, 74))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (58, 74))	('GAS5', 'Gene', '60674', (143, 147))	('AML', 'Disease', 'MESH:D015470', (76, 79))
46739	32354045	In a previous study, we identified that patients with prostate cancer and the Ins/Del or Del/Del genotype of GAS5 rs145204276 were at a significantly decreased risk of pathological lymph node metastasis compared with those with the Ins/Ins genotype (odds ratio (OR)  =  0.545; p = 0.043).	('rs145204276', 'Var', (114, 125))	('GAS5', 'Gene', (109, 113))	('rs145204276', 'Mutation', 'rs145204276', (114, 125))	('prostate cancer', 'Disease', (54, 69))	('patients', 'Species', '9606', (40, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (54, 69))	('decreased risk of pathological lymph node', 'Phenotype', 'HP:0002732', (150, 191))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('GAS', 'molecular_function', 'GO:0034005', ('109', '112'))	('prostate cancer', 'Disease', 'MESH:D011471', (54, 69))	('Del/Del', 'Var', (89, 96))	('GAS5', 'Gene', '60674', (109, 113))	('pathological lymph node metastasis', 'CPA', (168, 202))	('decreased', 'NegReg', (150, 159))
46740	32354045	Another report on bladder cancer indicated that patients in Iranian populations with the TG haplotype carriers of GAS5 (rs2067079 and rs6790) have a high risk of bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (18, 32))	('rs2067079', 'Var', (120, 129))	('GAS5', 'Gene', (114, 118))	('bladder cancer', 'Disease', (18, 32))	('bladder cancer', 'Phenotype', 'HP:0009725', (162, 176))	('GAS5', 'Gene', '60674', (114, 118))	('rs2067079', 'Mutation', 'rs2067079', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('rs6790', 'Mutation', 'rs6790', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('bladder cancer', 'Phenotype', 'HP:0009725', (18, 32))	('GAS', 'molecular_function', 'GO:0034005', ('114', '117'))	('patients', 'Species', '9606', (48, 56))	('rs6790', 'Var', (134, 140))	('bladder cancer', 'Disease', 'MESH:D001749', (162, 176))	('bladder cancer', 'Disease', (162, 176))
46741	32354045	Whether GAS5 SNPs (rs145204276 and rs55829688) affect susceptibility to UCC remains unclear.	('rs55829688', 'Var', (35, 45))	('GAS5', 'Gene', (8, 12))	('rs145204276', 'Var', (19, 30))	('GAS', 'molecular_function', 'GO:0034005', ('8', '11'))	('rs145204276', 'Mutation', 'rs145204276', (19, 30))	('GAS5', 'Gene', '60674', (8, 12))	('UCC', 'Disease', (72, 75))	('rs55829688', 'Mutation', 'rs55829688', (35, 45))
46742	32354045	In this case-control study, we identified the relationship between two GAS5 polymorphisms (rs145204276 and rs55829688) and clinical characteristics in Taiwanese patients with UCC.	('rs55829688', 'Var', (107, 117))	('GAS5', 'Gene', (71, 75))	('rs145204276', 'Var', (91, 102))	('UCC', 'Disease', (175, 178))	('rs145204276', 'Mutation', 'rs145204276', (91, 102))	('patients', 'Species', '9606', (161, 169))	('GAS', 'molecular_function', 'GO:0034005', ('71', '74'))	('GAS5', 'Gene', '60674', (71, 75))	('rs55829688', 'Mutation', 'rs55829688', (107, 117))
46752	32354045	All the patients with cN3 status received NAC, and consequently were excluded from the population.	('NAC', 'Gene', '6622', (42, 45))	('cN3 status', 'Var', (22, 32))	('NAC', 'Gene', (42, 45))	('NAC', 'cellular_component', 'GO:0005854', ('42', '45'))	('patients', 'Species', '9606', (8, 16))
46767	32354045	The distributions of genotype and allele frequencies of GAS5 polymorphisms among patients with UCC and the control participants are denoted in Table 2.	('polymorphisms', 'Var', (61, 74))	('GAS5', 'Gene', '60674', (56, 60))	('patients', 'Species', '9606', (81, 89))	('GAS5', 'Gene', (56, 60))	('GAS', 'molecular_function', 'GO:0034005', ('56', '59'))	('participants', 'Species', '9606', (115, 127))	('UCC', 'Disease', (95, 98))
46768	32354045	In the recruited control group, the distribution of GAS5 genotypes revealed that the most frequent alleles were heterozygous Ins/Del for rs145204276 and homozygous T/T for rs55829688.	('GAS', 'molecular_function', 'GO:0034005', ('52', '55'))	('GAS5', 'Gene', '60674', (52, 56))	('rs145204276', 'Var', (137, 148))	('GAS5', 'Gene', (52, 56))	('rs145204276', 'Mutation', 'rs145204276', (137, 148))	('rs55829688', 'Mutation', 'rs55829688', (172, 182))	('rs55829688', 'Var', (172, 182))	('frequent', 'Reg', (90, 98))
46769	32354045	We used a logistic regression test to analyze the genotypes and found no obvious differences in the allele and genotype frequencies of rs145204276 and rs55829688 SNPs in GAS5 between the patients with UCC and the healthy controls (Table 2).	('patients', 'Species', '9606', (187, 195))	('rs145204276', 'Mutation', 'rs145204276', (135, 146))	('GAS5', 'Gene', '60674', (170, 174))	('GAS', 'molecular_function', 'GO:0034005', ('170', '173'))	('rs55829688', 'Mutation', 'rs55829688', (151, 161))	('rs55829688 SNPs', 'Var', (151, 166))	('UCC', 'Disease', (201, 204))	('GAS5', 'Gene', (170, 174))	('rs145204276', 'Var', (135, 146))
46770	32354045	To clarify the role of SNP GAS5 rs145204276 in the clinicopathologic status of patients with UCC, we calculated the distribution frequency of clinical statuses and frequency of GAS5 genotypes in 430 patients with UCC.	('GAS5', 'Gene', '60674', (27, 31))	('GAS', 'molecular_function', 'GO:0034005', ('177', '180'))	('UCC', 'Disease', (213, 216))	('GAS5', 'Gene', (177, 181))	('rs145204276', 'Mutation', 'rs145204276', (32, 43))	('GAS5', 'Gene', (27, 31))	('GAS', 'molecular_function', 'GO:0034005', ('27', '30'))	('GAS5', 'Gene', '60674', (177, 181))	('patients', 'Species', '9606', (79, 87))	('patients', 'Species', '9606', (199, 207))	('rs145204276', 'Var', (32, 43))
46772	32354045	Next, we estimated genotype distributions of rs145204276 GAS5 gene polymorphisms among 159 female patients with UCC (Table 4).	('GAS5', 'Gene', (57, 61))	('GAS', 'molecular_function', 'GO:0034005', ('57', '60'))	('patients', 'Species', '9606', (98, 106))	('rs145204276', 'Var', (45, 56))	('GAS5', 'Gene', '60674', (57, 61))	('rs145204276', 'Mutation', 'rs145204276', (45, 56))
46773	32354045	The patients with the deletion allele (Ins/Del or Del/Del genotype) for rs145204276 were at a significantly higher risk of larger tumor status relative to patients with the Ins/Ins genotype (OR  =  3.373; 95% CI 1.329-8.558; p = 0.009; OR  =  2.628; 95% CI 1.001-6.929; p = 0.048; Table 4).	('rs145204276', 'Mutation', 'rs145204276', (72, 83))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('rs145204276', 'Var', (72, 83))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (155, 163))	('tumor', 'Disease', (130, 135))
46778	32354045	Moreover, the results revealed that female patients with BLCA and low levels of GAS5 expression had significantly poorer overall survival than did those with high GAS5 expression (Figure 1D and Table 5).	('GAS5', 'Gene', (163, 167))	('GAS', 'molecular_function', 'GO:0034005', ('80', '83'))	('overall survival', 'CPA', (121, 137))	('patients', 'Species', '9606', (43, 51))	('GAS5', 'Gene', '60674', (163, 167))	('GAS5', 'Gene', '60674', (80, 84))	('low levels', 'Var', (66, 76))	('poorer', 'NegReg', (114, 120))	('GAS', 'molecular_function', 'GO:0034005', ('163', '166'))	('GAS5', 'Gene', (80, 84))
46786	32354045	Carriers of the Ins/Del or Del/Del genotype of GAS5 rs145204276 are at low risk for pathological lymph node metastasis of prostate cancer in Taiwanese populations.	('rs145204276', 'Mutation', 'rs145204276', (52, 63))	('prostate cancer', 'Phenotype', 'HP:0012125', (122, 137))	('GAS5', 'Gene', (47, 51))	('Ins/Del', 'Var', (16, 23))	('metastasis of prostate cancer', 'Disease', (108, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('GAS5', 'Gene', '60674', (47, 51))	('metastasis of prostate cancer', 'Disease', 'MESH:D011471', (108, 137))	('GAS', 'molecular_function', 'GO:0034005', ('47', '50'))	('rs145204276', 'Var', (52, 63))	('Del/Del', 'Var', (27, 34))
46787	32354045	GAS5 polymorphisms rs2067079 and rs6790 serve as predictive biomarkers for platinum-based, concurrent, chemoradiotherapy-induced severe myelosuppression and neutropenia among patients with nasopharyngeal carcinoma.	('GAS5', 'Gene', '60674', (0, 4))	('myelosuppression and neutropenia', 'Disease', 'MESH:D009503', (136, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (189, 213))	('rs2067079', 'Mutation', 'rs2067079', (19, 28))	('carcinoma', 'Disease', 'MESH:D009369', (204, 213))	('neutropenia', 'Phenotype', 'HP:0001875', (157, 168))	('GAS5', 'Gene', (0, 4))	('platinum', 'Chemical', 'MESH:D010984', (75, 83))	('patients', 'Species', '9606', (175, 183))	('carcinoma', 'Disease', (204, 213))	('rs6790', 'Var', (33, 39))	('rs6790', 'Mutation', 'rs6790', (33, 39))	('GAS', 'molecular_function', 'GO:0034005', ('0', '3'))	('rs2067079', 'Var', (19, 28))
46789	32354045	The deletion allele of rs145204276 is significantly associated with an increased risk of hepatocellular carcinoma (HCC) and is positively correlated with higher levels of GAS5 in HCC tissue.	('hepatocellular carcinoma', 'Disease', (89, 113))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (89, 113))	('rs145204276', 'Var', (23, 34))	('GAS', 'molecular_function', 'GO:0034005', ('171', '174'))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('correlated', 'Reg', (138, 148))	('GAS5', 'Gene', (171, 175))	('higher', 'PosReg', (154, 160))	('rs145204276', 'Mutation', 'rs145204276', (23, 34))	('deletion', 'Var', (4, 12))	('increased risk of hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (71, 113))	('GAS5', 'Gene', '60674', (171, 175))
46790	32354045	Individuals with the TG genotypes of GAS5 rs2067079 and rs6790 are at a significantly increased risk of bladder cancer compared with those with the wild-type genotype in Iranian populations.	('bladder cancer', 'Disease', (104, 118))	('GAS5', 'Gene', (37, 41))	('rs6790', 'Var', (56, 62))	('rs6790', 'Mutation', 'rs6790', (56, 62))	('rs2067079', 'Var', (42, 51))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('GAS5', 'Gene', '60674', (37, 41))	('GAS', 'molecular_function', 'GO:0034005', ('37', '40'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('rs2067079', 'Mutation', 'rs2067079', (42, 51))	('bladder cancer', 'Disease', 'MESH:D001749', (104, 118))
46791	32354045	This may suggest that the SNPs of GAS5 play different roles in the susceptibility to and progression of different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('GAS5', 'Gene', '60674', (34, 38))	('roles', 'Reg', (54, 59))	('GAS', 'molecular_function', 'GO:0034005', ('34', '37'))	('SNPs', 'Var', (26, 30))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('GAS5', 'Gene', (34, 38))	('cancer', 'Disease', (123, 129))
46792	32354045	Our study demonstrates that female patients with UCC and carrying the Ins/Del or Del/Del genotype of GAS5 rs145204276 have a higher risk of larger tumor status (Table 4).	('Ins/Del', 'Var', (70, 77))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('GAS', 'molecular_function', 'GO:0034005', ('101', '104'))	('rs145204276', 'Var', (106, 117))	('GAS5', 'Gene', '60674', (101, 105))	('UCC', 'Disease', (49, 52))	('rs145204276', 'Mutation', 'rs145204276', (106, 117))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Del/Del', 'Var', (81, 88))	('patients', 'Species', '9606', (35, 43))	('GAS5', 'Gene', (101, 105))
46793	32354045	At diagnosis, among 91 female patients with UCC and carrying the Ins/Del or Del/Del genotype, the percentage of patients with larger high tumor status (T1-T4) reached 90.1% (Table 4).	('Ins/Del', 'Var', (65, 72))	('tumor', 'Disease', (138, 143))	('Del/Del', 'Var', (76, 83))	('patients', 'Species', '9606', (112, 120))	('patients', 'Species', '9606', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
46794	32354045	These results suggest that female patients with BLCA have decreased overall specific survival resulting from carrying the deletion allele for rs145204276.	('rs145204276', 'Mutation', 'rs145204276', (142, 153))	('decreased', 'NegReg', (58, 67))	('deletion', 'Var', (122, 130))	('patients', 'Species', '9606', (34, 42))	('rs145204276', 'Var', (142, 153))	('specific survival', 'MPA', (76, 93))
46795	32354045	The variant rs145204276, a 5 bp indel polymorphism shown as "-/AGGCA", was located in the promoter region of GAS5.	('GAS5', 'Gene', (109, 113))	('rs145204276', 'Mutation', 'rs145204276', (12, 23))	('GAS', 'molecular_function', 'GO:0034005', ('107', '110'))	('GAS5', 'Gene', '60674', (109, 113))	('5 bp indel', 'Mutation', 'c.delins5', (27, 37))	('rs145204276', 'Var', (12, 23))
46796	32354045	Many studies have demonstrated that carriers of GAS5 rs145204276 have an increased risk of various types of cancer, including gastric cancer and HCC.	('GAS5', 'Gene', '60674', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('gastric cancer', 'Disease', (126, 140))	('rs145204276', 'Mutation', 'rs145204276', (53, 64))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('GAS5', 'Gene', (48, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('HCC', 'Disease', (145, 148))	('rs145204276', 'Var', (53, 64))	('GAS', 'molecular_function', 'GO:0034005', ('48', '51'))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
46797	32354045	Furthermore, in one study, individuals with the genotype Del/Del of GAS5 rs145204276 had a smaller size of osteosarcoma tumor than those with Ins/Ins, and those with the genotype Del/Del rs145204276 had remarkably higher expression of GAS5.	('GAS', 'molecular_function', 'GO:0034005', ('68', '71'))	('Del/Del rs145204276', 'Var', (179, 198))	('higher', 'PosReg', (214, 220))	('GAS5', 'Gene', (68, 72))	('rs145204276', 'Mutation', 'rs145204276', (73, 84))	('osteosarcoma tumor', 'Disease', 'MESH:D012516', (107, 125))	('rs145204276', 'Mutation', 'rs145204276', (187, 198))	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('osteosarcoma tumor', 'Disease', (107, 125))	('GAS5', 'Gene', '60674', (235, 239))	('GAS', 'molecular_function', 'GO:0034005', ('235', '238'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('rs145204276', 'Var', (73, 84))	('GAS5', 'Gene', '60674', (68, 72))	('expression', 'MPA', (221, 231))	('smaller', 'NegReg', (91, 98))	('GAS5', 'Gene', (235, 239))
46798	32354045	A recent study determined that the methylation frequency of the Del/Del genotype rs145204276 was significantly higher than that of either the Ins/Ins or Ins/Del genotype.	('rs145204276', 'Var', (81, 92))	('methylation', 'MPA', (35, 46))	('rs145204276', 'Mutation', 'rs145204276', (81, 92))	('higher', 'PosReg', (111, 117))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))
46800	32354045	In conclusion, polymorphic variants of GAS5 were associated with the clinicopathologic status of female patients with UCC.	('GAS5', 'Gene', (39, 43))	('associated', 'Reg', (49, 59))	('GAS5', 'Gene', '60674', (39, 43))	('polymorphic variants', 'Var', (15, 35))	('GAS', 'molecular_function', 'GO:0034005', ('39', '42'))	('UCC', 'Disease', (118, 121))	('patients', 'Species', '9606', (104, 112))
46801	32354045	The data presented here demonstrate that carriers of the deletion allele of GAS5 rs145204276 are at a higher risk of larger tumor status than carriers of the wild type Ins/Ins genotype.	('rs145204276', 'Var', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('deletion', 'Var', (57, 65))	('GAS', 'molecular_function', 'GO:0034005', ('76', '79'))	('GAS5', 'Gene', '60674', (76, 80))	('tumor', 'Disease', (124, 129))	('rs145204276', 'Mutation', 'rs145204276', (81, 92))	('GAS5', 'Gene', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
46802	32354045	Variations in GAS5 may be a reliable prognostic indicator of disease progression in female patients with UCC.	('UCC', 'Disease', (105, 108))	('GAS5', 'Gene', '60674', (14, 18))	('patients', 'Species', '9606', (91, 99))	('GAS5', 'Gene', (14, 18))	('GAS', 'molecular_function', 'GO:0034005', ('14', '17'))	('Variations', 'Var', (0, 10))
46804	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))
46814	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'))
46821	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))	('epitranscriptome', 'MPA', (4, 20))	('neoplasms', 'Disease', (229, 238))	('m6A', 'Gene', '56339', (129, 132))
46824	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))
46827	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))
46828	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))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('FTO', 'Gene', '79068', (172, 175))	('FTO', 'Gene', '79068', (51, 54))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('FTO', 'Gene', (172, 175))	('associated', 'Reg', (80, 90))	('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))
46830	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))
46833	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))
46835	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))
46838	30428628	Again, the knockdown of YTHDF3 sensitized cancer cells to chemotherapy and, additionally, oncogene c-Myc was found to drive YTHDF1 expression.	('drive', 'PosReg', (118, 123))	('YTHDF1', 'Gene', (124, 130))	('YTHDF3', 'Gene', (24, 30))	('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))
46842	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))
46843	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))
46845	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))
46849	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))
46850	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))
46851	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))	('IDH1/2', 'Gene', '3417;3418', (187, 193))	('D', 'Chemical', 'MESH:D003903', (362, 363))	('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))
46853	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))
46869	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))
46875	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))
46884	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))
46889	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))
46903	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))
46934	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))
46961	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))
46994	28761758	In addition to our personal experience at the MUV, Giuliani and colleagues from Italy have presented their experience with pivotal phase III randomised trials on tyrosine-kinase inhibitors (TKIs) first line for advanced lung cancer with activating epidermal growth factor receptor mutations.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('248', '271'))	('activating', 'PosReg', (237, 247))	('epidermal growth factor receptor', 'Gene', (248, 280))	('lung cancer', 'Disease', (220, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('mutations', 'Var', (281, 290))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('epidermal growth factor receptor', 'Gene', '1956', (248, 280))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
47054	28761758	Of note, subgroup analyses demonstrated a particular OS benefit for programmed death-ligand 1 (PD-L1) expression >1% and p16-positive patients; however, the study was not powered to detect a significant difference herein and further data need to be awaited also in terms of ESMO-MCBS assessment.	('ligand', 'molecular_function', 'GO:0005488', ('85', '91'))	('expression >1%', 'Var', (102, 116))	('>1%', 'Var', (113, 116))	('patients', 'Species', '9606', (134, 142))	('programmed death-ligand 1', 'Gene', '29126', (68, 93))	('OS', 'Chemical', '-', (53, 55))	('PD-L1', 'Gene', (95, 100))	('p16-positive', 'Gene', (121, 133))	('programmed death-ligand 1', 'Gene', (68, 93))	('ESMO-MCBS', 'Chemical', '-', (274, 283))	('PD-L1', 'Gene', '29126', (95, 100))
47104	28761758	Olaratumab/doxorubicin resulted in a significant improvement of secondary endpoint OS (+11.8 months; HR 0.46, 95% CI 0.30 to 0.71) and the corresponding MCBS-FT score of 4 reflects clearly the high clinical benefit to be expected of this combination.	('improvement', 'PosReg', (49, 60))	('OS', 'Chemical', '-', (83, 85))	('Olaratumab', 'Chemical', 'MESH:C000589393', (0, 10))	('MCBS-FT', 'Chemical', '-', (153, 160))	('doxorubicin', 'Chemical', 'MESH:D004317', (11, 22))	('secondary endpoint OS', 'MPA', (64, 85))	('Olaratumab/doxorubicin', 'Var', (0, 22))
47152	21798077	The GSTT1 null was marginally associated with increased urothelial carcinoma (UC) risk (HR, 1.91, 95% CI, 1.00-3.65), while the association was not observed for other GSTs.	('null', 'Var', (10, 14))	('urothelial carcinoma', 'Disease', (56, 76))	('GSTs', 'Gene', '373156', (167, 171))	('increased', 'PosReg', (46, 55))	('GSTT1', 'Gene', '2952', (4, 9))	('GSTs', 'Gene', (167, 171))	('GSTT1', 'Gene', (4, 9))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (56, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))
47156	21798077	Diplotype analysis showed that among subjects exposed to high levels of arsenic, the AGG/AGG variant of GSTO1 Ala140Asp, GSTO2 5'UTR (-183)A/G, and GSTO2 Asn142Asp was associated with an increased cancer risk (HRs, 4.91, 95% CI, 1.02-23.74) when compared to the all-wildtype reference, respectively.	('GSTO2', 'Gene', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('Ala140Asp', 'Mutation', 'rs4925', (110, 119))	('Asn142Asp', 'Mutation', 'rs156697', (154, 163))	('arsenic', 'Chemical', 'MESH:D001151', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('GSTO2', 'Gene', '119391', (148, 153))	('GSTO2', 'Gene', '119391', (121, 126))	('GSTO1', 'Gene', (104, 109))	('(-183)A/G', 'Mutation', 'c.(-183A>G', (133, 142))	('Ala140Asp', 'Var', (110, 119))	('GSTO1', 'Gene', '9446', (104, 109))	('GSTO2', 'Gene', (121, 126))	('variant', 'Var', (93, 100))
47164	21798077	Nutritional status, ethnicity, an early age of exposure and variations in arsenic biotransformation are all potentially responsible for differences in individual susceptibility to arsenic-induced carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (196, 210))	('responsible', 'Reg', (120, 131))	('arsenic', 'Chemical', 'MESH:D001151', (180, 187))	('carcinogenesis', 'Disease', (196, 210))	('arsenic', 'Chemical', 'MESH:D001151', (74, 81))	('variations', 'Var', (60, 70))
47170	21798077	Inefficient methylation of arsenic has been documented to be a significant modifier for arsenic-induced skin lesions and cancers, bladder cancer, peripheral arterial disease, hypertension and carotid atherosclerosis.	('carotid atherosclerosis', 'Disease', (192, 215))	('arsenic', 'Chemical', 'MESH:D001151', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('cancers', 'Disease', (121, 128))	('methylation', 'biological_process', 'GO:0032259', ('12', '23'))	('arsenic', 'Chemical', 'MESH:D001151', (88, 95))	('methylation', 'Var', (12, 23))	('atherosclerosis', 'Phenotype', 'HP:0002621', (200, 215))	('hypertension', 'Disease', 'MESH:D006973', (175, 187))	('skin lesions', 'Disease', 'MESH:D012871', (104, 116))	('arsenic-induced', 'Gene', (88, 103))	('hypertension', 'Disease', (175, 187))	('carotid atherosclerosis', 'Disease', 'MESH:D002340', (192, 215))	('peripheral arterial disease', 'Phenotype', 'HP:0004950', (146, 173))	('Inefficient methylation', 'Var', (0, 23))	('peripheral arterial disease', 'Disease', (146, 173))	('skin lesions', 'Disease', (104, 116))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('bladder cancer', 'Disease', 'MESH:D001749', (130, 144))	('bladder cancer', 'Disease', (130, 144))	('peripheral arterial disease', 'Disease', 'MESH:D058729', (146, 173))	('hypertension', 'Phenotype', 'HP:0000822', (175, 187))	('bladder cancer', 'Phenotype', 'HP:0009725', (130, 144))
47174	21798077	The relationship between the GSTOs and arsenic metabolism has been explored to test if GSTO polymorphisms can explain variation in arsenic methylation capacity as well as variation in individual susceptibility to arsenic exposure.	('polymorphisms', 'Var', (92, 105))	('GST', 'Gene', (87, 90))	('metabolism', 'biological_process', 'GO:0008152', ('47', '57'))	('GST', 'Gene', (29, 32))	('methylation', 'biological_process', 'GO:0032259', ('139', '150'))	('GST', 'Gene', '373156', (87, 90))	('arsenic methylation capacity', 'MPA', (131, 159))	('arsenic', 'Chemical', 'MESH:D001151', (131, 138))	('GST', 'Gene', '373156', (29, 32))	('arsenic', 'Chemical', 'MESH:D001151', (39, 46))	('arsenic', 'Chemical', 'MESH:D001151', (213, 220))
47176	21798077	A study of a northern Mexican population also suggested that there is an association between GSTO1 E155del and an increased percentage of inorganic arsenic, either AsIII or AsV .	('inorganic arsenic', 'MPA', (138, 155))	('GSTO1', 'Gene', (93, 98))	('AsIII', 'Chemical', '-', (164, 169))	('E155del', 'Mutation', 'p.155delE', (99, 106))	('E155del', 'Var', (99, 106))	('AsV', 'Chemical', 'MESH:C571889', (173, 176))	('inorganic arsenic', 'Chemical', '-', (138, 155))	('GSTO1', 'Gene', '9446', (93, 98))
47178	21798077	The polymorphisms in GSTOs could be a significant modifier for arsenic-induced skin lesions and urothelial carcinoma (UC).	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('GST', 'Gene', '373156', (21, 24))	('skin lesions', 'Disease', (79, 91))	('arsenic', 'Chemical', 'MESH:D001151', (63, 70))	('polymorphisms', 'Var', (4, 17))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (96, 116))	('modifier', 'Reg', (50, 58))	('urothelial carcinoma', 'Disease', (96, 116))	('skin lesions', 'Disease', 'MESH:D012871', (79, 91))	('GST', 'Gene', (21, 24))
47199	21798077	The GSTP1 I105V A/G polymorphisms were classified as homozygous A/A (major allele), heterozygous for A/G, or homozygous for G/G (minor allele).	('GSTP1', 'Gene', (4, 9))	('I105V A/G', 'Var', (10, 19))	('I105V', 'Mutation', 'rs1695', (10, 15))	('GSTP1', 'Gene', '2950', (4, 9))
47200	21798077	Real-time PCR: Genotyping for polymorphisms in GSTO1 A140D, K208E, E155del and GSTO2 5'UTR(-183) A/G and N142D was performed using real-time PCR.	('GSTO1', 'Gene', (47, 52))	('E155del', 'Mutation', 'p.155delE', (67, 74))	('GSTO1', 'Gene', '9446', (47, 52))	('E155del', 'Var', (67, 74))	('GSTO2', 'Gene', '119391', (79, 84))	('N142D', 'Var', (105, 110))	('A140D', 'Mutation', 'rs4925', (53, 58))	('N142D', 'Mutation', 'rs156697', (105, 110))	('GSTO2', 'Gene', (79, 84))	('K208E', 'Mutation', 'rs11509438', (60, 65))	('K208E', 'Var', (60, 65))	('A140D', 'Var', (53, 58))
47205	21798077	RFLP for GSTO1 and GSTO2: The GSTO1 A140D genotype was determined by PCR-RFLP.	('A140D', 'Var', (36, 41))	('GSTO2', 'Gene', (19, 24))	('GSTO1', 'Gene', '9446', (30, 35))	('A140D', 'Mutation', 'rs4925', (36, 41))	('GSTO1', 'Gene', (9, 14))	('GSTO2', 'Gene', '119391', (19, 24))	('GSTO1', 'Gene', '9446', (9, 14))	('GSTO1', 'Gene', (30, 35))
47217	21798077	Linkage disequilibrium was analyzed by calculating D' values for GSTO1 A140D, GSTO2 5'UTR(-183)A/G, and GSTO2 N142D.	('A140D', 'Var', (71, 76))	('GSTO2', 'Gene', (104, 109))	('GSTO1', 'Gene', (65, 70))	('N142D', 'Mutation', 'rs156697', (110, 115))	('GSTO2', 'Gene', '119391', (104, 109))	('GSTO2', 'Gene', (78, 83))	('GSTO1', 'Gene', '9446', (65, 70))	('A140D', 'Mutation', 'rs4925', (71, 76))	('GSTO2', 'Gene', '119391', (78, 83))	('(-183)A/G', 'Mutation', 'c.(-183A>G', (89, 98))
47227	21798077	The incidence rates of UC per 100,000 person-years was 26.4, 207.2 and 835.1 for CAE < 10.0, 10.0   CAE < 20.0 and CAE >= 20.0, respectively.	('person', 'Species', '9606', (38, 44))	('CAE', 'Chemical', '-', (81, 84))	('CAE < 10.0', 'Var', (81, 91))	('CAE', 'Chemical', '-', (100, 103))	('CAE >= 20.0', 'Var', (115, 126))	('10.0', 'Var', (93, 97))	('CAE', 'Chemical', '-', (115, 118))
47231	21798077	The incidences and age-sex-adjusted HRs for the SNPs of interest and the GSTO1 A140D-O2 A(-183)G-O2 N142D diplotype are shown in Table 3.	('N142D', 'Mutation', 'rs156697', (100, 105))	('GSTO1', 'Gene', (73, 78))	('A140D', 'Mutation', 'rs4925', (79, 84))	('GSTO1', 'Gene', '9446', (73, 78))	('N142D', 'Var', (100, 105))
47232	21798077	The GSTT1 null genotype was found to be significantly associated with an increased cancer risk (HR, 1.91, 95% CI: 1.00-3.65, p = 0.05).	('null', 'Var', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('GSTT1', 'Gene', '2952', (4, 9))	('GSTT1', 'Gene', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
47233	21798077	The GSTO diplotype AGG/AGG was potentially associated with increased cancer risk, but the association was not statistically significant.	('diplotype', 'Var', (9, 18))	('GST', 'Gene', '373156', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('AGG/AGG', 'Protein', (19, 26))	('associated', 'Reg', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('GST', 'Gene', (4, 7))	('cancer', 'Disease', (69, 75))
47234	21798077	Based on the sensitive analysis with various cutoff points of arsenic exposure level, it was consistently shown that the gene effect of GSTT1 and GSTO1 A140D was largely confined to high cumulative arsenic exposure (Additional file 1).	('arsenic', 'Chemical', 'MESH:D001151', (62, 69))	('A140D', 'Mutation', 'rs4925', (152, 157))	('GSTT1', 'Gene', '2952', (136, 141))	('GSTT1', 'Gene', (136, 141))	('GSTO1', 'Gene', (146, 151))	('A140D', 'Var', (152, 157))	('GSTO1', 'Gene', '9446', (146, 151))	('arsenic', 'Chemical', 'MESH:D001151', (198, 205))
47235	21798077	When CAE cutoff point was 20 mg/l*years, the significant association of both GSTT1 and GSTO1 A140D with UC risk could be observed.	('CAE', 'Chemical', '-', (5, 8))	('GSTT1', 'Gene', (77, 82))	('GSTO1', 'Gene', (87, 92))	('GSTT1', 'Gene', '2952', (77, 82))	('A140D', 'Var', (93, 98))	('GSTO1', 'Gene', '9446', (87, 92))	('A140D', 'Mutation', 'rs4925', (93, 98))
47238	21798077	The subjects with both a high exposure level and the homozygous variant of GSTO1 Asp140 had an increased HR of 4.79 (95% CI, 1.03-22.39, p = 0.05), with incidence rates of 3508.8 per 100,000.	('Asp140', 'Chemical', '-', (81, 87))	('GSTO1', 'Gene', '9446', (75, 80))	('variant', 'Var', (64, 71))	('GSTO1', 'Gene', (75, 80))	('Asp140', 'Var', (81, 87))
47239	21798077	Analysis of GSTO1/O2 showed that among the CAE >= 20 subjects, the diplotype AGG/AGG had a significantly increased cancer risk compared to CAA/CAA subjects with an estimated HR of 4.91 (95% CI, 1.02-23.74, p = 0.05).	('GSTO1', 'Gene', '9446', (12, 17))	('cancer', 'Disease', (115, 121))	('CAE', 'Chemical', '-', (43, 46))	('diplotype', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('GSTO1', 'Gene', (12, 17))	('AGG/AGG', 'Gene', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
47242	21798077	The subjects with GSTT1 null genotype and high arsenic exposure had a 4.1-fold higher risk of UC (HR, 4.08, 95% CI, 1.46-11.40, p < 0.01) when compared to the subjects with low exposure and the GSTT1 non-null genotype.	('arsenic', 'Chemical', 'MESH:D001151', (47, 54))	('GSTT1', 'Gene', '2952', (194, 199))	('GSTT1', 'Gene', (18, 23))	('null genotype', 'Var', (24, 37))	('GSTT1', 'Gene', '2952', (18, 23))	('GSTT1', 'Gene', (194, 199))
47254	21798077	The current result was inconsistent with the previous studies showing the GSTT1 non-null genotype was associated with an increased risk of As-induced skin lesions and UC.	('GSTT1', 'Gene', '2952', (74, 79))	('GSTT1', 'Gene', (74, 79))	('As', 'Chemical', 'MESH:D001151', (139, 141))	('skin lesions', 'Disease', (150, 162))	('skin lesions', 'Disease', 'MESH:D012871', (150, 162))	('non-null', 'Var', (80, 88))
47257	21798077	These observations reveal the possibility that the effects of GSTT1 polymorphism on susceptibility to arsenic-induced urothelial carcinoma depend on arsenic exposure level.	('effects', 'Reg', (51, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('arsenic', 'Chemical', 'MESH:D001151', (149, 156))	('urothelial carcinoma depend', 'Disease', (118, 145))	('urothelial carcinoma depend', 'Disease', 'MESH:D000437', (118, 145))	('GSTT1', 'Gene', (62, 67))	('polymorphism', 'Var', (68, 80))	('GSTT1', 'Gene', '2952', (62, 67))	('arsenic', 'Chemical', 'MESH:D001151', (102, 109))
47262	21798077	By contrast, the study in Argentina showed that the GSTT1 null was associated with lower percentage of DMA.	('DMA', 'Chemical', '-', (103, 106))	('null', 'Var', (58, 62))	('lower', 'NegReg', (83, 88))	('GSTT1', 'Gene', '2952', (52, 57))	('GSTT1', 'Gene', (52, 57))	('DMA', 'Disease', (103, 106))
47271	21798077	The evidence generally supports the modulating effect of GSTM1 and GSTT1 polymorphisms on cancers closely-related to chemical exposure, including bladder cancer.	('cancers', 'Disease', (90, 97))	('GSTT1', 'Gene', '2952', (67, 72))	('bladder cancer', 'Disease', 'MESH:D001749', (146, 160))	('bladder cancer', 'Disease', (146, 160))	('GSTT1', 'Gene', (67, 72))	('GSTM1', 'Gene', '2944', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('GSTM1', 'Gene', (57, 62))	('polymorphisms', 'Var', (73, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (146, 160))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('modulating effect', 'Reg', (36, 53))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
47278	21798077	However, among high As-exposed subjects with 75% UC cases diagnosed in this subgroup (24 among a total of 32 UC cases with known exposure levels), a significant association between GSTO polymorphism and UC was observed.	('GST', 'Gene', (181, 184))	('GST', 'Gene', '373156', (181, 184))	('polymorphism', 'Var', (186, 198))	('As', 'Chemical', 'MESH:D001151', (20, 22))
47282	21798077	For examples, GSTO2 A424G and A-183G homovariant was associated with a 1.6-fold and a 2.4-fold UC risk, respectively in one hospital-based case-control study.	('GSTO2', 'Gene', '119391', (14, 19))	('A424G', 'Var', (20, 25))	('A-183G', 'Var', (30, 36))	('A424G', 'Mutation', 'rs156697', (20, 25))	('GSTO2', 'Gene', (14, 19))	('A-183G', 'Mutation', 'rs2297235', (30, 36))
47285	21798077	However, the magnitude of the association between GSTOs polymorphisms and As-induced cancers across different exposure levels has not been well-evaluated.	('As', 'Chemical', 'MESH:D001151', (74, 76))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('GST', 'Gene', (50, 53))	('polymorphisms', 'Var', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('GST', 'Gene', '373156', (50, 53))
47287	21798077	Different GSTO polymorphisms may be of different capacity of arsenic metabolism, which may explain for variation susceptibility to arsenic.	('arsenic', 'Chemical', 'MESH:D001151', (61, 68))	('GST', 'Gene', '373156', (10, 13))	('arsenic', 'Chemical', 'MESH:D001151', (131, 138))	('metabolism', 'biological_process', 'GO:0008152', ('69', '79'))	('polymorphisms', 'Var', (15, 28))	('GST', 'Gene', (10, 13))
47288	21798077	Inefficient methylation of arsenic has been reported to be associated with arsenic-induced skin lesions, skin cancers, bladder cancers and cardiovascular diseases.	('arsenic', 'Chemical', 'MESH:D001151', (27, 34))	('skin lesions', 'Disease', 'MESH:D012871', (91, 103))	('skin cancers', 'Disease', 'MESH:D012878', (105, 117))	('methylation', 'biological_process', 'GO:0032259', ('12', '23'))	('skin lesions', 'Disease', (91, 103))	('cardiovascular diseases', 'Disease', (139, 162))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (139, 162))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('methylation', 'Var', (12, 23))	('bladder cancers', 'Phenotype', 'HP:0009725', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('bladder cancer', 'Phenotype', 'HP:0009725', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Inefficient methylation', 'Var', (0, 23))	('skin cancers', 'Phenotype', 'HP:0008069', (105, 117))	('bladder cancers', 'Disease', 'MESH:D001749', (119, 134))	('associated', 'Reg', (59, 69))	('bladder cancers', 'Disease', (119, 134))	('arsenic', 'Protein', (27, 34))	('arsenic', 'Chemical', 'MESH:D001151', (75, 82))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (139, 162))	('skin cancers', 'Disease', (105, 117))
47289	21798077	Our previous study indicated that GSTO2 N142D GG genotype was associated with a higher percentage of iAs.	('GSTO2', 'Gene', '119391', (34, 39))	('As', 'Chemical', 'MESH:D001151', (102, 104))	('iAs', 'Disease', (101, 104))	('N142D', 'Var', (40, 45))	('GSTO2', 'Gene', (34, 39))	('N142D', 'Mutation', 'rs156697', (40, 45))
47290	21798077	Two studies displayed that GSTO1 E155del was associated with markedly-changed percentage of iAs when compared to the wild homotype.	('E155del', 'Mutation', 'p.155delE', (33, 40))	('GSTO1', 'Gene', (27, 32))	('E155del', 'Var', (33, 40))	('GSTO1', 'Gene', '9446', (27, 32))	('As', 'Chemical', 'MESH:D001151', (93, 95))	('iAs', 'Disease', (92, 95))
47291	21798077	These studies suggest the effects of GSTOs polymorphisms on percentage of iAs.	('polymorphisms', 'Var', (43, 56))	('iAs', 'Disease', (74, 77))	('GST', 'Gene', (37, 40))	('effects', 'Reg', (26, 33))	('As', 'Chemical', 'MESH:D001151', (75, 77))	('GST', 'Gene', '373156', (37, 40))
47315	19428366	p53 mutations as fingerprints for aristolochic acid - an environmental carcinogen in endemic (Balkan) nephropathy The activation of protooncogenes and inactivation of tumor suppressor genes are considered to be the main molecular events in the multistep process of carcinogenesis.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('aristolochic acid', 'Chemical', 'MESH:C000228', (34, 51))	('activation', 'PosReg', (118, 128))	('nephropathy', 'Disease', (102, 113))	('nephropathy', 'Phenotype', 'HP:0000112', (102, 113))	('inactivation', 'Var', (151, 163))	('tumor suppressor', 'biological_process', 'GO:0051726', ('167', '183'))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('167', '183'))	('carcinogenesis', 'Disease', 'MESH:D063646', (265, 279))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('nephropathy', 'Disease', 'MESH:D007674', (102, 113))	('mutations', 'Var', (4, 13))	('carcinogenesis', 'Disease', (265, 279))	('tumor', 'Disease', (167, 172))
47316	19428366	Mutations of the TP53 tumor suppressor gene have been found in nearly all tumor types and are estimated to contribute to more than 50% of all cancers.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('22', '38'))	('cancers', 'Disease', (142, 149))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('found', 'Reg', (54, 59))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (74, 79))	('contribute', 'Reg', (107, 117))	('tumor', 'Disease', (22, 27))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('tumor suppressor', 'biological_process', 'GO:0051726', ('22', '38'))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
47317	19428366	Most mutations lead to the synthesis of highly stable, inactive proteins that accumulate in the nucleus of cancer cells.	('lead to', 'Reg', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mutations', 'Var', (5, 14))	('synthesis', 'MPA', (27, 36))	('synthesis', 'biological_process', 'GO:0009058', ('27', '36'))	('nucleus', 'cellular_component', 'GO:0005634', ('96', '103'))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('proteins', 'Protein', (64, 72))	('cancer', 'Disease', (107, 113))	('accumulate', 'PosReg', (78, 88))
47318	19428366	Among the 393 codons of the human p53 gene, 222 are targets of 698 different types of mutations.	('mutations', 'Var', (86, 95))	('p53', 'Gene', (34, 37))	('human', 'Species', '9606', (28, 33))
47319	19428366	Alterations of codons 175, 248, 273 and 282 correspond to 19 % of all mutations and are considered general hot spot mutations.	('rat', 'Species', '10116', (4, 7))	('Alterations', 'Var', (0, 11))	('mutations', 'Var', (70, 79))
47325	19428366	Recently, we reported the presence of AA-DNA adducts in renal cortex and A   T p53 mutations in tumor tissue of patients from Croatia and Bosnia with endemic nephropathy.	('renal cortex', 'Disease', 'MESH:D007673', (56, 68))	('mutations', 'Var', (83, 92))	('Croatia and Bosnia', 'Disease', 'None', (126, 144))	('nephropathy', 'Phenotype', 'HP:0000112', (158, 169))	('nephropathy', 'Disease', (158, 169))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('T p53', 'Gene', (77, 82))	('renal cortex', 'Disease', (56, 68))	('tumor', 'Disease', (96, 101))	('patients', 'Species', '9606', (112, 120))	('nephropathy', 'Disease', 'MESH:D007674', (158, 169))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
47328	19428366	The most common cancer-related genetic changes in humans are mutations within the p53 gene.	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('humans', 'Species', '9606', (50, 56))	('mutations', 'Var', (61, 70))	('p53', 'Gene', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
47333	19428366	First, p53 mutations are the single most frequent in human tumors and are directly involved in cancer formation (more than 20, 000 occurrences of human p53 mutations have been registered to date in the International Tumor Registry IARC p53 database (http://www-p53.iarc.fr).	('mutations', 'Var', (11, 20))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('p53', 'Gene', (152, 155))	('formation', 'biological_process', 'GO:0009058', ('102', '111'))	('involved', 'Reg', (83, 91))	('cancer', 'Disease', (95, 101))	('tumors', 'Disease', (59, 65))	('human', 'Species', '9606', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('human', 'Species', '9606', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('Tumor', 'Phenotype', 'HP:0002664', (216, 221))
47335	19428366	Third, most mutations fall into the DNA binding domain (DBD), responsible for sequence-specific DNA binding and transcriptional activity, as well as for a direct mitochondrial pro-apoptotic activity.	('DBD', 'Chemical', '-', (56, 59))	('fall', 'Phenotype', 'HP:0002527', (22, 26))	('DNA binding', 'molecular_function', 'GO:0003677', ('36', '47'))	('mutations', 'Var', (12, 21))	('binding', 'Interaction', (100, 107))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('transcriptional', 'MPA', (112, 127))	('sequence-specific DNA binding', 'molecular_function', 'GO:0043565', ('78', '107'))	('mitochondrial pro-apoptotic', 'MPA', (162, 189))
47336	19428366	Many studies have demonstrated a significant correlation between p53 mutational spectra and exposure to various types of carcinogens.	('p53', 'Gene', (65, 68))	('mutational', 'Var', (69, 79))	('rat', 'Species', '10116', (25, 28))
47337	19428366	On the other hand, G:C   T:A (G   T) transversions, the most frequent substitutions in human cancers, are likely to be caused by carcinogen-DNA adducts, and are more frequent in lung cancers of smokers compared to lung cancers of nonsmokers.	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('lung cancers', 'Phenotype', 'HP:0100526', (178, 190))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('transversions', 'Var', (37, 50))	('cancers', 'Disease', (183, 190))	('human', 'Species', '9606', (87, 92))	('G:C   T:A', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('caused', 'Reg', (119, 125))	('frequent', 'Reg', (166, 174))	('lung cancers', 'Disease', 'MESH:D008175', (214, 226))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('cancers', 'Disease', (219, 226))	('lung cancers', 'Disease', (214, 226))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('cancers', 'Disease', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('lung cancers', 'Disease', 'MESH:D008175', (178, 190))	('lung cancers', 'Phenotype', 'HP:0100526', (214, 226))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('lung cancers', 'Disease', (178, 190))
47338	19428366	Cigarette smoking has been established as a major risk factor for the incidence of lung cancer, and p53 mutational hotspots are codons 157, 158, 248, 249 and 273.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('codons 157', 'Var', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('p53', 'Gene', (100, 103))
47339	19428366	Codon 157, G   T transversions, one of the hotspots in lung, breast, and head and neck cancers, is uncommon in other types of cancer, and is associated with smoking in lung cancer patients.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('head and neck cancers', 'Phenotype', 'HP:0012288', (73, 94))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('breast', 'Disease', (61, 67))	('patients', 'Species', '9606', (180, 188))	('lung', 'Disease', (55, 59))	('G   T transversions', 'Var', (11, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('cancer', 'Disease', (126, 132))	('associated', 'Reg', (141, 151))	('head and neck cancers', 'Disease', 'MESH:D006258', (73, 94))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('neck', 'cellular_component', 'GO:0044326', ('82', '86'))	('lung cancer', 'Disease', (168, 179))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('Codon 157', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
47343	19428366	In liver tumors from populations living in endemic areas where aflatoxin B1 and hepatitis B virus are risk factors for hepatocellular carcinoma, most p53 mutations occur at the third nucleotide position (AGG to AGT) of codon 249ser.	('249ser', 'Chemical', '-', (225, 231))	('occur', 'Reg', (164, 169))	('hepatitis', 'Phenotype', 'HP:0012115', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('liver tumors', 'Disease', 'MESH:D008113', (3, 15))	('hepatitis B virus', 'Species', '10407', (80, 97))	('liver tumors', 'Phenotype', 'HP:0002896', (3, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('liver tumors', 'Disease', (3, 15))	('p53', 'Gene', (150, 153))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (119, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('ser', 'cellular_component', 'GO:0005790', ('228', '231'))	('mutations', 'Var', (154, 163))	('hepatocellular carcinoma', 'Disease', (119, 143))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (119, 143))
47344	19428366	The 249ser p53 mutant is more effective in inhibiting wild-type (wt) p53 transcriptional activity in human liver cells than other p53 mutants (143ala, 175his, 248trp and 282his).	('inhibiting', 'NegReg', (43, 53))	('p53', 'Gene', (11, 14))	('143ala', 'Var', (143, 149))	('p53', 'Gene', (69, 72))	('ser', 'cellular_component', 'GO:0005790', ('7', '10'))	('249ser', 'Var', (4, 10))	('human', 'Species', '9606', (101, 106))	('transcriptional activity', 'MPA', (73, 97))	('249ser', 'Chemical', '-', (4, 10))	('175his', 'Var', (151, 157))
47345	19428366	Another association between p53 mutational spectra and carcinogen exposure was found in skin carcinoma caused by UV irradiation - p53 mutations are located at dipyrimidine sites, generating CC   TT double-base transitions.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('rat', 'Species', '10116', (183, 186))	('dipyrimidine', 'Chemical', '-', (159, 171))	('skin carcinoma', 'Disease', (88, 102))	('skin carcinoma', 'Disease', 'MESH:D012878', (88, 102))	('mutations', 'Var', (134, 143))	('p53', 'Gene', (130, 133))
47346	19428366	Furthermore, the p53 mutational pattern in radon-associated lung cancer from uranium miners differs from the one in lung cancer caused by smoking alone.	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Disease', (116, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('miners', 'Species', '265634', (85, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))	('p53', 'Gene', (17, 20))	('mutational', 'Var', (21, 31))
47347	19428366	Moreover, liver angiosarcomas of vinyl chloride-exposed factory workers have higher frequency of p53 A:T   T:A transversions comparing to sporadic angiosarcoma.	('angiosarcomas', 'Phenotype', 'HP:0200058', (16, 29))	('liver angiosarcomas', 'Disease', 'MESH:D006394', (10, 29))	('angiosarcoma', 'Disease', (16, 28))	('p53 A:T   T:A transversions', 'Var', (97, 124))	('vinyl chloride', 'Chemical', 'MESH:D014752', (33, 47))	('angiosarcoma', 'Disease', 'MESH:D006394', (147, 159))	('angiosarcoma', 'Phenotype', 'HP:0200058', (16, 28))	('liver angiosarcomas', 'Disease', (10, 29))	('angiosarcoma', 'Disease', (147, 159))	('angiosarcoma', 'Disease', 'MESH:D006394', (16, 28))	('angiosarcoma', 'Phenotype', 'HP:0200058', (147, 159))
47359	19428366	The herbal drugs containing Aristolochia have been associated with development of a characteristic chronic interstitial nephropathy associated with proximal tubular damage and severe interstitial fibrosis starting from cortex with paucy cellular infiltratates sparing glomeruli called aristolochic acid nephropathy (AAN).	('interstitial nephropathy', 'Disease', 'MESH:D007674', (107, 131))	('Aristolochia', 'Species', '425107', (28, 40))	('nephropathy', 'Disease', (303, 314))	('nephropathy', 'Disease', 'MESH:D007674', (303, 314))	('interstitial nephropathy', 'Disease', (107, 131))	('nephropathy', 'Disease', (120, 131))	('rat', 'Species', '10116', (252, 255))	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (183, 204))	('AAN', 'Chemical', '-', (316, 319))	('nephropathy', 'Disease', 'MESH:D007674', (120, 131))	('aristolochic acid', 'Chemical', 'MESH:C000228', (285, 302))	('nephropathy', 'Phenotype', 'HP:0000112', (303, 314))	('associated', 'Reg', (132, 142))	('chronic interstitial nephropathy', 'Phenotype', 'HP:0004743', (99, 131))	('Aristolochia', 'Var', (28, 40))	('tubular damage', 'Disease', (157, 171))	('fibrosis', 'Disease', 'MESH:D005355', (196, 204))	('fibrosis', 'Disease', (196, 204))	('nephropathy', 'Phenotype', 'HP:0000112', (120, 131))	('tubular damage', 'Disease', 'MESH:D004194', (157, 171))	('associated', 'Reg', (51, 61))	('acid nephropathy', 'Phenotype', 'HP:0001947', (298, 314))	('interstitial nephropathy', 'Phenotype', 'HP:0001970', (107, 131))
47363	19428366	Thus, upper urinary tract cancers are uncommon and typically associated with particular exogenous carcinogens.. Atypia of urothelial cells throughout the renal tubules, pelvis and ureter are commonly reported in AAN.	('Atypia', 'Var', (112, 118))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('AAN', 'Chemical', '-', (212, 215))	('upper urinary tract cancers', 'Disease', 'MESH:D014571', (6, 33))	('upper urinary tract cancers', 'Disease', (6, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (12, 32))	('upper urinary tract cancer', 'Phenotype', 'HP:0010935', (6, 32))
47376	19428366	DNA binding studies confirmed that AAI and AAII bind to the adenines of mouse ras codon 61, forming adducts associated with distinct activation of H-ras by a specific A   T transversion at codon 61 (wt CAA   CTA).	('DNA binding', 'molecular_function', 'GO:0003677', ('0', '11'))	('AAI', 'Chemical', '-', (43, 46))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('mouse', 'Species', '10090', (72, 77))	('H-ras', 'Protein', (147, 152))	('activation', 'PosReg', (133, 143))	('AAI', 'Chemical', '-', (35, 38))	('adenines', 'Chemical', 'MESH:D000225', (60, 68))	('A   T transversion at', 'Var', (167, 188))
47383	19428366	Five of the 10 established cultures harbored p53 DBD mutations that produced aberrant nuclear overexpression of the mutant protein.	('p53', 'Gene', (45, 48))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('mutations', 'Var', (53, 62))	('DBD', 'Chemical', '-', (49, 52))	('nuclear overexpression', 'MPA', (86, 108))
47387	19428366	Moreover, the mutated base adenine has the same neighboring bases in codon 139 of the p53 gene as in codon 61 (CAA) of the H-ras gene, suggesting a sequence specific mechanism during mutagenesis.	('mutagenesis', 'biological_process', 'GO:0006280', ('183', '194'))	('mutated', 'Var', (14, 21))	('adenine', 'Chemical', 'MESH:D000225', (27, 34))	('p53', 'Gene', (86, 89))
47388	19428366	Another mutation (G   A) was found in codon 245 (hotspot for p53 mutations) in the p53 gene in DNA from the breast and liver tumors of the same AAN patient.	('p53', 'Gene', (83, 86))	('liver tumors', 'Phenotype', 'HP:0002896', (119, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('AAN', 'Chemical', '-', (144, 147))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('patient', 'Species', '9606', (148, 155))	('breast and liver tumors', 'Disease', 'MESH:D001943', (108, 131))	('mutations', 'Var', (65, 74))
47389	19428366	Since G   A transitions are not typical of AA, it is not likely that the p53 mutation in the breast and liver tumors was induced by AA and probably only the urothelial tumor was causally related to AA exposure.	('urothelial tumor', 'Disease', 'MESH:D001749', (157, 173))	('urothelial tumor', 'Disease', (157, 173))	('p53', 'Gene', (73, 76))	('mutation', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('liver tumors', 'Phenotype', 'HP:0002896', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('breast and liver tumors', 'Disease', 'MESH:D001943', (93, 116))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('induced', 'Reg', (121, 128))
47392	19428366	Six immortalized cultures from 18 primary cultures exposed to AAI (50 muM for 48 h) again harbored p53 mutations in the human DNA binding domain.	('mutations', 'Var', (103, 112))	('human', 'Species', '9606', (120, 125))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('AAI', 'Chemical', '-', (62, 65))	('DNA binding', 'molecular_function', 'GO:0003677', ('126', '137'))	('p53', 'Gene', (99, 102))
47398	19428366	These results link AA exposure that eventually results in kidney tumors in rats, to a significant increase in AA-induced DNA adduct formation with a characteristic mutation in kidney tissue.	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('DNA adduct formation', 'MPA', (121, 141))	('rats', 'Species', '10116', (75, 79))	('kidney tumors', 'Disease', (58, 71))	('results in', 'Reg', (47, 57))	('formation', 'biological_process', 'GO:0009058', ('132', '141'))	('mutation', 'Var', (164, 172))	('increase', 'PosReg', (98, 106))	('kidney tumors', 'Disease', 'MESH:D007674', (58, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('kidney tumors', 'Phenotype', 'HP:0009726', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
47399	19428366	Although the same treatment does not produce tumors in rat liver, it does induce DNA adducts and mutations in this tissue, albeit at lower levels than in the kidney.	('mutations', 'Var', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('DNA adducts', 'MPA', (81, 92))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('rat', 'Species', '10116', (55, 58))	('induce', 'Reg', (74, 80))
47400	19428366	Moreover, the mutation frequency in kidneys of AA-treated rats was shown to correlate with tumor incidence in the kidney.	('rats', 'Species', '10116', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('mutation', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
47419	19428366	In addition, we have reported on the p53 mutations in urothelial tumors of Croatian and Bosnian EN patients.	('mutations', 'Var', (41, 50))	('Bosnia', 'Disease', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('urothelial tumors', 'Disease', (54, 71))	('patients', 'Species', '9606', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('p53', 'Gene', (37, 40))	('urothelial tumors', 'Disease', 'MESH:D001749', (54, 71))	('Bosnia', 'Disease', 'None', (88, 94))	('EN', 'Chemical', '-', (96, 98))
47420	19428366	Of note, p53 mutations in EN patients with urothelial cancers from Croatia and Bosnia are unique and not consistent with IARC p53 database R12, November 2007.	('urothelial cancers', 'Disease', 'MESH:D014523', (43, 61))	('patients', 'Species', '9606', (29, 37))	('R12', 'Gene', '2840', (139, 142))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('urothelial cancers', 'Disease', (43, 61))	('p53', 'Gene', (9, 12))	('EN', 'Chemical', '-', (26, 28))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (13, 22))	('R12', 'Gene', (139, 142))	('Croatia and Bosnia', 'Disease', 'None', (67, 85))
47421	19428366	Namely, in other parts of the world (in the general population of patients with upper urothelial cancers) the A   T transition account for only 4% of all p53 mutations (Figure 3B).	('upper urothelial cancers', 'Disease', (80, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('upper urothelial cancers', 'Disease', 'MESH:D014523', (80, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('upper urothelial cancer', 'Phenotype', 'HP:0010935', (80, 103))	('p53', 'Gene', (154, 157))	('mutations', 'Var', (158, 167))	('patients', 'Species', '9606', (66, 74))
47422	19428366	In addition, p53 mutations in the patients whom we tested appear to cluster between amino acid residues 270 and 290 and at four sites mutations occurred twice (179-2, 274-3, 280-3, and 291-1).	('patients', 'Species', '9606', (34, 42))	('mutations', 'Var', (17, 26))	('p53', 'Gene', (13, 16))
47458	32922550	The disruption of CA4 may be associated with the perturbation of pH homeostasis in retina and correlated with retinitis pigmentosa.	('retinitis pigmentosa', 'Disease', (110, 130))	('correlated', 'Reg', (94, 104))	('pH homeostasis', 'MPA', (65, 79))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (110, 130))	('perturbation', 'MPA', (49, 61))	('homeostasis', 'biological_process', 'GO:0042592', ('68', '79'))	('retinitis', 'Phenotype', 'HP:0032118', (110, 119))	('retinitis pigmentosa', 'Disease', 'MESH:C538365', (110, 130))	('disruption', 'Var', (4, 14))	('associated', 'Reg', (29, 39))	('CA4', 'Gene', (18, 21))	('CA4', 'Gene', '762', (18, 21))
47489	32922550	Formalin-fixed, paraffin-embedded KIRC tissues and human renal tissues were stained for anti-CA4 using ab236315 (Abcam, USA) at 1/3000 dilution in Fudan University Shanghai Cancer Center (FUSCC) cohort, and then independently evaluated by two experienced pathologists.	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('Cancer', 'Disease', 'MESH:D009369', (173, 179))	('Cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Cancer', 'Disease', (173, 179))	('human', 'Species', '9606', (51, 56))	('ab236315', 'Var', (103, 111))	('paraffin', 'Chemical', 'MESH:D010232', (16, 24))	('CA4', 'Gene', (93, 96))	('CA4', 'Gene', '762', (93, 96))
47508	32922550	Remarkably, CA4 amplification was obviously related to better PFS (KIRC: hazard ratio [HR] = 0.661, p < 0.001; LGG: HR = 0.552, p = 0.002; LUAD: HR = 0.922, p = 0.020; UVM: HR = 0.454, p = 0.001) and better OS (KIRC: HR = 0.847, p < 0.001; LGG: HR = 0.552, p < 0.001; LUAD: HR = 0.918, p = 0.007; UVM: HR = 0.454, p < 0.001) in all of these four cancers.	('CA4', 'Gene', (12, 15))	('CA4', 'Gene', '762', (12, 15))	('UVM', 'Phenotype', 'HP:0007716', (297, 300))	('LUAD', 'Phenotype', 'HP:0030078', (268, 272))	('PFS', 'MPA', (62, 65))	('amplification', 'Var', (16, 29))	('cancers', 'Disease', 'MESH:D009369', (346, 353))	('cancers', 'Phenotype', 'HP:0002664', (346, 353))	('LUAD', 'Phenotype', 'HP:0030078', (139, 143))	('cancers', 'Disease', (346, 353))	('better', 'PosReg', (55, 61))	('UVM', 'Phenotype', 'HP:0007716', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))
47515	32922550	Notably, CA4 amplification obviously correlated with better PFS in KIRC, LGG and LUAD (KIRC: HR = 0.749, p = 0.003; LGG: HR = 0.585, p = 0.005; LUAD: HR = 0.927, p = 0.029) and better OS in KIRC, LGG and UVM (KIRC: HR = 0.900, p = 0.022; LGG: HR = 0.655, p = 0.029; UVM: HR = 0.689, p = 0.005).	('PFS', 'MPA', (60, 63))	('LUAD', 'Phenotype', 'HP:0030078', (81, 85))	('LUAD', 'Phenotype', 'HP:0030078', (144, 148))	('CA4', 'Gene', (9, 12))	('CA4', 'Gene', '762', (9, 12))	('UVM', 'Phenotype', 'HP:0007716', (266, 269))	('UVM', 'Phenotype', 'HP:0007716', (204, 207))	('amplification', 'Var', (13, 26))	('better', 'PosReg', (53, 59))
47539	32922550	Compared with low or no protein expression, high expression of CA2 is related to better survival outcomes, suggesting that CA2 can be a potential marker for this interstitial tumor diagnosis.	('survival', 'CPA', (88, 96))	('high', 'Var', (44, 48))	('better', 'PosReg', (81, 87))	('tumor', 'Disease', (175, 180))	('CA2', 'Gene', (123, 126))	('CA2', 'Gene', '760', (123, 126))	('CA2', 'Gene', (63, 66))	('CA2', 'Gene', '760', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
47576	29487377	We validate a progressed version of Urothelial-like A (UroA-Prog) that shows FGFR3 mutations and CDKN2A deletions, and we show that the variant Urothelial-like C is almost devoid of FGFR3 mutations.	('mutations', 'Var', (83, 92))	('FGFR3', 'Gene', (77, 82))	('CDKN2A', 'Gene', (97, 103))	('Uro', 'Chemical', '-', (55, 58))	('FGFR3', 'Gene', '2261', (182, 187))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('CDKN2A', 'Gene', '1029', (97, 103))	('Uro', 'Chemical', '-', (36, 39))	('FGFR', 'molecular_function', 'GO:0005007', ('182', '186'))	('FGFR3', 'Gene', (182, 187))	('FGFR3', 'Gene', '2261', (77, 82))	('deletions', 'Var', (104, 113))	('Uro', 'Chemical', '-', (144, 147))
47611	29487377	Supporting this conclusion is the expression of the FGFR3 gene signature composed of genes associated with FGFR3 gene mutations, known to show high expression in Uro and low expression in GU cases (Fig.	('low', 'NegReg', (170, 173))	('expression', 'MPA', (174, 184))	('FGFR3', 'Gene', '2261', (107, 112))	('Uro', 'Chemical', '-', (162, 165))	('FGFR3', 'Gene', '2261', (52, 57))	('mutations', 'Var', (118, 127))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('FGFR3', 'Gene', (107, 112))	('FGFR3', 'Gene', (52, 57))	('expression', 'MPA', (148, 158))
47623	29487377	TP53 mutations were seen in all subtypes but were particularly enriched in the GU subtype, present in 71% of the cases.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
47624	29487377	RB1 mutations were also enriched in the GU subtype, seen in 37% of the cases, but also frequent in Basal/SCC-like tumors.	('RB1', 'Gene', '5925', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (4, 13))	('RB1', 'Gene', (0, 3))	('frequent', 'Reg', (87, 95))
47625	29487377	FGFR3 mutations were predominately seen in UroA-Prog (44%) and UroB (50%) cases, but were almost depleted in the UroC subtype (4%).	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('Uro', 'Chemical', '-', (63, 66))	('UroC', 'Gene', (113, 117))	('UroB', 'Disease', (63, 67))	('FGFR3', 'Gene', (0, 5))	('UroC', 'Gene', '7349', (113, 117))	('seen', 'Reg', (35, 39))	('UroA-Prog', 'Disease', (43, 52))	('Uro', 'Chemical', '-', (43, 46))	('Uro', 'Chemical', '-', (113, 116))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
47627	29487377	Mutations in the ANKHD1 gene did not pass the MutSigCV test.	('ANKHD1', 'Gene', (17, 23))	('Mutations', 'Var', (0, 9))	('ANKHD1', 'Gene', '54882', (17, 23))
47628	29487377	We then formed groups of genes based on GO-terms for "biological processes", identified tumors with mutations in any or none of the GO-term grouped genes, and then performed Fisher's exact test for subtype associations.	('mutations', 'Var', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
47632	29487377	The UroC differed from other Urothelial-like subtypes in one important respect, the absence of FGFR3 mutations.	('UroC', 'Gene', '7349', (4, 8))	('mutations', 'Var', (101, 110))	('FGFR', 'molecular_function', 'GO:0005007', ('95', '99'))	('FGFR3', 'Gene', (95, 100))	('Uro', 'Chemical', '-', (29, 32))	('UroC', 'Gene', (4, 8))	('FGFR3', 'Gene', '2261', (95, 100))	('Uro', 'Chemical', '-', (4, 7))
47636	29487377	Notably, several of the cases with amplified PPARG showed downregulation of the gene (Supplementary Fig.	('downregulation', 'NegReg', (58, 72))	('PPARG', 'Gene', '5468', (45, 50))	('PPARG', 'Gene', (45, 50))	('amplified', 'Var', (35, 44))
47645	29487377	In addition, both Urothelial-like subtypes and Genomically Unstable cases show distinct genomic profiles; Uro-cases show frequent 9q, 9p21, and 11p losses and 11q13 amplifications whereas GU show frequent RB1 losses but almost complete absence of CDKN2A homozygous losses.	('absence', 'NegReg', (236, 243))	('Uro', 'Chemical', '-', (18, 21))	('RB1', 'Gene', (205, 208))	('CDKN2A', 'Gene', (247, 253))	('11q13 amplifications', 'Var', (159, 179))	('losses', 'NegReg', (209, 215))	('CDKN2A', 'Gene', '1029', (247, 253))	('RB1', 'Gene', '5925', (205, 208))	('Uro', 'Chemical', '-', (106, 109))
47654	29487377	Transcription factors primarily expressed in GU, Basal/SCC-like, and Sc/NE-like cases included FOXM1 and MYBL2, as well as E2F1 and E2F2 (Fig.	('E2F2', 'Gene', (132, 136))	('E2F1', 'Var', (123, 127))	('E2F2', 'Gene', '1870', (132, 136))	('FOXM1', 'Gene', (95, 100))	('Sc/NE-like', 'Disease', (69, 79))	('MYBL2', 'Gene', (105, 110))
47693	29487377	In addition, UroC shares several genomic alterations with the non-muscle invasive UroA, UroA-Prog, and UroB subtypes, such as losses of 9q, 11p, CDKN2A, and genomic amplifications of CCND1, indicating a strong genomic relationship.	('11p', 'Protein', (140, 143))	('CCND1', 'Gene', (183, 188))	('genomic amplifications', 'Var', (157, 179))	('CDKN2A', 'Gene', '1029', (145, 151))	('Uro', 'Chemical', '-', (103, 106))	('CCND1', 'Gene', '595', (183, 188))	('UroC', 'Gene', (13, 17))	('Uro', 'Chemical', '-', (88, 91))	('UroC', 'Gene', '7349', (13, 17))	('Uro', 'Chemical', '-', (82, 85))	('Uro', 'Chemical', '-', (13, 16))	('losses', 'Var', (126, 132))	('CDKN2A', 'Gene', (145, 151))
47694	29487377	However, UroC was almost devoid of FGFR3 mutations.	('UroC', 'Gene', (9, 13))	('mutations', 'Var', (41, 50))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR3', 'Gene', '2261', (35, 40))	('UroC', 'Gene', '7349', (9, 13))	('FGFR3', 'Gene', (35, 40))
47695	29487377	This suggests that UroC have developed along a route independent of any hardwiring changes of this pathway making it possible to progress towards a GU-like phenotype, underscored by the frequent 2p25 (YWHAQ), 3p25 (RAF1), and 6p22 (E2F3/CDKAL1/SOX4) genomic amplifications seen in both UroC and in GU tumors.	('UroC', 'Gene', (19, 23))	('2p25', 'Var', (195, 199))	('UroC', 'Gene', '7349', (286, 290))	('GU tumors', 'Disease', 'MESH:D009369', (298, 307))	('GU tumors', 'Disease', (298, 307))	('UroC', 'Gene', '7349', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('GU tumors', 'Phenotype', 'HP:0007379', (298, 307))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))	('UroC', 'Gene', (286, 290))
47699	29487377	GU also showed the strongest enrichment for mutations in genes implicated in genomic instability, as well as the highest frequency of TP53 mutations.	('mutations', 'Var', (139, 148))	('TP53', 'Gene', '7157', (134, 138))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', (134, 138))
47712	29487377	Nevertheless, Sc/NE-like tumors are similar to GU tumors by showing frequent gains of 2p25 (YWHAQ), 3p25 (RAF1), and 6p22 (E2F3, CDKAL1, SOX4), as well as a strong activation of the FOXM1/MYBL2/E2F1/E2F2/MuvB driver of the cell cycle.	('cell cycle', 'biological_process', 'GO:0007049', ('223', '233'))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('GU tumors', 'Disease', 'MESH:D009369', (47, 56))	('tumors', 'Disease', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('6p22', 'Var', (117, 121))	('gains', 'PosReg', (77, 82))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('E2F2', 'Gene', (199, 203))	('3p25', 'Var', (100, 104))	('E2F2', 'Gene', '1870', (199, 203))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('GU tumors', 'Disease', (47, 56))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('2p25', 'Var', (86, 90))	('activation', 'PosReg', (164, 174))	('GU tumors', 'Phenotype', 'HP:0007379', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('Sc/NE-like', 'Disease', (14, 24))	('tumors', 'Disease', (50, 56))
47716	29487377	The robust identification of Sc/NE-like UC may be of unexpected clinical relevance; patients with small-cell or neuroendocrine histological variant tumors generally have a worse prognosis but respond well to "neuroendocrine" systemic chemotherapy regimens, e.g., the etoposide and ifosfamide containing IA-EP doublet.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('neuroendocrine histological', 'Gene', (112, 139))	('patients', 'Species', '9606', (84, 92))	('etoposide', 'Chemical', 'MESH:D005047', (267, 276))	('tumors', 'Disease', (148, 154))	('variant', 'Var', (140, 147))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('ifosfamide', 'Chemical', 'MESH:D007069', (281, 291))	('small-cell', 'Disease', (98, 108))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('neuroendocrine histological variant', 'Phenotype', 'HP:0100634', (112, 147))
47740	29487377	After determining the frequently altered regions, samples were analyzed for the presence of aberrations using the following criteria; (1) for individual genes 100% should be altered for gains, and >50% for deletions, (2) for regions with size <5 Mbp, >75% should be altered for both gains and deletions, and (3) for regions with size > 5Mbp and chromosomal arms, >50% should be altered for both gains and deletions.	('deletions', 'Var', (293, 302))	('Mbp', 'Gene', '4155', (337, 340))	('Mbp', 'Gene', (337, 340))	('Mbp', 'Gene', (246, 249))	('Mbp', 'Gene', '4155', (246, 249))	('deletions', 'Var', (206, 215))	('altered', 'Reg', (174, 181))
47744	29383036	Development of a personalized therapeutic strategy for ERBB-gene-mutated cancers The application of genomic technologies to patient tumor samples identified groups of signaling pathways which acquire activating mutations.	('signaling pathways', 'Pathway', (167, 185))	('cancers', 'Disease', (73, 80))	('signaling', 'biological_process', 'GO:0023052', ('167', '176'))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('ERBB', 'Gene', '1956', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mutations', 'Var', (211, 220))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('tumor', 'Disease', (132, 137))	('patient', 'Species', '9606', (124, 131))	('activating', 'PosReg', (200, 210))	('ERBB', 'Gene', (55, 59))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
47745	29383036	Some cancers are dependent on these mutations and the aberrant proteins resulting from these mutations can be targeted by novel drugs which can eradicate the cancer.	('proteins', 'Protein', (63, 71))	('mutations', 'Var', (93, 102))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('aberrant proteins', 'Protein', (54, 71))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('cancer', 'Disease', (5, 11))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('S', 'Chemical', 'MESH:D013455', (0, 1))
47746	29383036	We used www.cbioportal.org to determine the frequency of ERBB mutations in solid tumors.	('ERBB', 'Gene', (57, 61))	('solid tumors', 'Disease', 'MESH:D009369', (75, 87))	('ERBB', 'Gene', '1956', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (62, 71))	('solid tumors', 'Disease', (75, 87))
47750	29383036	In cancers not commonly associated with HER family protein overexpression, such as ovarian, endometrial, melanoma and head and neck cancers (n = 2116), we found that ERBB family mutations are enriched, occurring at rates from 14% to 34% and commonly co-occur with PIK3CA mutations.	('co-occur', 'Reg', (250, 258))	('mutations', 'Var', (178, 187))	('mutations', 'Var', (271, 280))	('PIK3CA', 'Gene', '5290', (264, 270))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('ovarian', 'Disease', (83, 90))	('ovarian', 'Disease', 'MESH:D010051', (83, 90))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))	('neck', 'cellular_component', 'GO:0044326', ('127', '131'))	('PIK3CA', 'Gene', (264, 270))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('ERBB', 'Gene', (166, 170))	('head and neck cancers', 'Phenotype', 'HP:0012288', (118, 139))	('cancers', 'Disease', (132, 139))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('ERBB', 'Gene', '1956', (166, 170))	('head and neck cancer', 'Phenotype', 'HP:0012288', (118, 138))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancers', 'Disease', (3, 10))	('head and neck cancers', 'Disease', 'MESH:D006258', (118, 139))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
47751	29383036	Importantly, we demonstrate that ERBB family mutant cancers are sensitive to treatment with PI3K inhibitors.	('P', 'Chemical', 'MESH:D010758', (92, 93))	('mutant', 'Var', (45, 51))	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ERBB', 'Gene', (33, 37))	('PI3K', 'molecular_function', 'GO:0016303', ('92', '96'))	('ERBB', 'Gene', '1956', (33, 37))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
47753	29383036	We demonstrate that ERBB family mutations are common in cancers not associated with overexpression or amplification of HER family proteins.	('cancers', 'Disease', (56, 63))	('ERBB', 'Gene', '1956', (20, 24))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('common', 'Reg', (46, 52))	('mutations', 'Var', (32, 41))	('ERBB', 'Gene', (20, 24))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
47754	29383036	These ERBB family mutant cancers are sensitive to treatment with PI3K inhibitors, and when combined with pan-HER inhibitors have synergistic antiproliferative effects.	('ERBB', 'Gene', '1956', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('mutant', 'Var', (18, 24))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('ERBB', 'Gene', (6, 10))	('P', 'Chemical', 'MESH:D010758', (65, 66))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('antiproliferative effects', 'CPA', (141, 166))
47756	29383036	In some cases, cancers are dependent on these mutations and the resulting aberrant proteins can be targeted by novel drugs.	('proteins', 'Protein', (83, 91))	('targeted', 'Reg', (99, 107))	('mutations', 'Var', (46, 55))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('aberrant', 'Var', (74, 82))
47758	29383036	Some tumors thus contain mutations within oncogenes or tumor suppressor genes that predict responses to targeted anticancer therapies.	('tumors', 'Disease', (5, 11))	('mutations', 'Var', (25, 34))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('predict', 'Reg', (83, 90))	('cancer', 'Disease', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor suppressor', 'biological_process', 'GO:0051726', ('55', '71'))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (55, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('55', '71'))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Disease', (5, 10))	('oncogenes', 'Gene', (42, 51))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('S', 'Chemical', 'MESH:D013455', (0, 1))
47759	29383036	Examples include epidermal growth factor receptor (EGFR) mutations which are found in up to 15% of non-small cell lung cancers and are targetable by EGFR inhibitors (erlotinib and gefitinib).	('EGFR', 'Gene', (51, 55))	('mutations', 'Var', (57, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('lung cancers', 'Phenotype', 'HP:0100526', (114, 126))	('cell lung cancers', 'Disease', 'MESH:D008175', (109, 126))	('cell lung cancers', 'Disease', (109, 126))	('gefitinib', 'Chemical', 'MESH:D000077156', (180, 189))	('EGFR', 'Gene', '1956', (149, 153))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (99, 126))	('EGFR', 'Gene', '1956', (51, 55))	('erlotinib', 'Chemical', 'MESH:D000069347', (166, 175))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('17', '40'))	('epidermal growth factor receptor', 'Gene', (17, 49))	('epidermal growth factor receptor', 'Gene', '1956', (17, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('EGFR', 'Gene', (149, 153))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (103, 126))
47762	29383036	Dimerization results in activation of signal transduction pathways such as the PI3K/AKT and MAPK/ERK pathways, which are associated with oncogenesis and cancer therapy resistance.	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('79', '83'))	('ERK', 'Gene', '5594', (97, 100))	('AKT', 'Gene', (84, 87))	('ERK', 'molecular_function', 'GO:0004707', ('97', '100'))	('activation', 'PosReg', (24, 34))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('MAPK', 'molecular_function', 'GO:0004707', ('92', '96'))	('Dimerization', 'Var', (0, 12))	('ERK', 'Gene', (97, 100))	('P', 'Chemical', 'MESH:D010758', (79, 80))	('activation of signal transduction', 'biological_process', 'GO:0009967', ('24', '57'))	('oncogenesis', 'Disease', 'MESH:D063646', (137, 148))	('oncogenesis', 'biological_process', 'GO:0007048', ('137', '148'))	('AKT', 'Gene', '207', (84, 87))	('signal transduction pathways', 'Pathway', (38, 66))	('oncogenesis', 'Disease', (137, 148))	('P', 'Chemical', 'MESH:D010758', (94, 95))
47763	29383036	Recent studies found that somatic ERBB2, ERBB3 and ERBB4 mutations occur in breast, colorectal and gastric cancers, with ERBB3 mutations being associated with an aggressive phenotype.	('associated', 'Reg', (143, 153))	('gastric cancers', 'Phenotype', 'HP:0012126', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast', 'Disease', (76, 82))	('ERBB3', 'Gene', '2065', (121, 126))	('ERBB2', 'Gene', (34, 39))	('ERBB3', 'Gene', (41, 46))	('ERBB3', 'Gene', '2065', (41, 46))	('colorectal and gastric cancers', 'Disease', 'MESH:D013274', (84, 114))	('ERBB4', 'Gene', '2066', (51, 56))	('mutations', 'Var', (57, 66))	('ERBB3', 'Gene', (121, 126))	('ERBB2', 'Gene', '2064', (34, 39))	('occur', 'Reg', (67, 72))	('mutations', 'Var', (127, 136))	('ERBB4', 'Gene', (51, 56))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
47764	29383036	Modeling experiments of ERBB4 mutations have shown their ability to alter the signaling properties of the HER family members.	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('ERBB4', 'Gene', '2066', (24, 29))	('alter', 'Reg', (68, 73))	('ERBB4', 'Gene', (24, 29))	('mutations', 'Var', (30, 39))	('signaling properties of', 'MPA', (78, 101))
47765	29383036	Our study identifies that ERBB family mutations which are commonly enriched in cancers which are not HER2 amplified are targetable with PI3K inhibitors.	('cancers', 'Disease', (79, 86))	('HER2', 'Gene', (101, 105))	('P', 'Chemical', 'MESH:D010758', (136, 137))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('HER2', 'Gene', '2064', (101, 105))	('ERBB', 'Gene', (26, 30))	('PI3K', 'molecular_function', 'GO:0016303', ('136', '140'))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('mutations', 'Var', (38, 47))	('ERBB', 'Gene', '1956', (26, 30))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
47766	29383036	We also demonstrate that cancers which have both an ERBB family and PIK3CA mutation are most sensitive to the combination of the pan-HER kinase inhibitor afatinib and the PI3K inhibitor copanlisib, identifying a new therapeutic strategy for treating patients who harbor ERBB family mutations.	('ERBB', 'Gene', (270, 274))	('P', 'Chemical', 'MESH:D010758', (171, 172))	('afatinib', 'Chemical', 'MESH:D000077716', (154, 162))	('ERBB', 'Gene', '1956', (52, 56))	('PIK3CA', 'Gene', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('copanlisib', 'Chemical', 'MESH:C000589253', (186, 196))	('P', 'Chemical', 'MESH:D010758', (68, 69))	('mutation', 'Var', (75, 83))	('patients', 'Species', '9606', (250, 258))	('PIK3CA', 'Gene', '5290', (68, 74))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('137', '153'))	('ERBB', 'Gene', '1956', (270, 274))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('PI3K', 'molecular_function', 'GO:0016303', ('171', '175'))	('ERBB', 'Gene', (52, 56))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))
47767	29383036	Individual ERBB family (EGFR, ERBB2, ERBB3 and ERBB4) somatic mutations were detected in 12% of cancers identified from www.cbioportal.org.	('EGFR', 'Gene', '1956', (24, 28))	('ERBB', 'Gene', (37, 41))	('ERBB', 'Gene', (30, 34))	('ERBB', 'Gene', '1956', (37, 41))	('detected', 'Reg', (77, 85))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('ERBB3', 'Gene', '2065', (37, 42))	('ERBB4', 'Gene', '2066', (47, 52))	('cancers', 'Disease', (96, 103))	('ERBB', 'Gene', '1956', (30, 34))	('ERBB4', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ERBB', 'Gene', (11, 15))	('mutations', 'Var', (62, 71))	('ERBB', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (24, 28))	('ERBB2', 'Gene', (30, 35))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('ERBB3', 'Gene', (37, 42))	('ERBB2', 'Gene', '2064', (30, 35))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('ERBB', 'Gene', (47, 51))	('ERBB', 'Gene', '1956', (47, 51))
47768	29383036	Our analysis included 14,539 cases of cancer from 81 different datasets (Table 1), and found PIK3CA mutations occur in 13% of patient tumors, 14% have an ERBB family gene mutation, while 2% have a co-occurring PIK3CA and ERBB family gene mutation [Figure 1(a)].	('mutations', 'Var', (100, 109))	('tumors', 'Disease', (134, 140))	('PIK3CA', 'Gene', '5290', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('mutation', 'Var', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('patient', 'Species', '9606', (126, 133))	('ERBB', 'Gene', (154, 158))	('ERBB', 'Gene', '1956', (221, 225))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('PIK3CA', 'Gene', (210, 216))	('PIK3CA', 'Gene', '5290', (210, 216))	('cancer', 'Disease', (38, 44))	('PIK3CA', 'Gene', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('ERBB', 'Gene', '1956', (154, 158))	('ERBB', 'Gene', (221, 225))
47769	29383036	Mutations in the PIK3CA gene are some of the most commonly occurring targetable mutations detected in solid tumors.	('solid tumors', 'Disease', (102, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('Mutations', 'Var', (0, 9))	('solid tumors', 'Disease', 'MESH:D009369', (102, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
47771	29383036	In these studies we found somatic ERBB family mutations in 29% of cases (both alone and co-occurring with PIK3CA mutations), whilst PIK3CA mutations alone occur in 15% of cancers [Figure 1(b)].	('ERBB', 'Gene', '1956', (34, 38))	('mutations', 'Var', (46, 55))	('PIK3CA', 'Gene', (106, 112))	('PIK3CA', 'Gene', '5290', (106, 112))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('mutations', 'Var', (113, 122))	('ERBB', 'Gene', (34, 38))	('cancers', 'Disease', (171, 178))	('PIK3CA', 'Gene', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('PIK3CA', 'Gene', '5290', (132, 138))
47772	29383036	We also found that ERBB family mutations and PIK3CA mutations co-occur in 6% of these cancers.	('mutations', 'Var', (52, 61))	('mutations', 'Var', (31, 40))	('ERBB', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('PIK3CA', 'Gene', (45, 51))	('ERBB', 'Gene', '1956', (19, 23))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('PIK3CA', 'Gene', '5290', (45, 51))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
47773	29383036	Our findings demonstrate that even in cancer subtypes not commonly associated with HER family protein overexpression such as ovarian, endometrial, melanoma and head and neck cancer that ERBB family mutations are enriched and can co-occur with PIK3CA mutations.	('ovarian', 'Disease', (125, 132))	('ovarian', 'Disease', 'MESH:D010051', (125, 132))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('neck', 'cellular_component', 'GO:0044326', ('169', '173'))	('ERBB', 'Gene', (186, 190))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))	('PIK3CA', 'Gene', (243, 249))	('ERBB', 'Gene', '1956', (186, 190))	('cancer', 'Disease', (174, 180))	('mutations', 'Var', (198, 207))	('endometrial', 'Disease', (134, 145))	('cancer', 'Disease', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('neck cancer', 'Disease', 'MESH:D006258', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('neck cancer', 'Disease', (169, 180))	('head and neck cancer', 'Phenotype', 'HP:0012288', (160, 180))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('PIK3CA', 'Gene', '5290', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (38, 44))
47775	29383036	We found that somatic ERBB family mutations occur between a rate of 14.7% in head and neck squamous cell carcinoma and 27.7% in skin cutaneous melanoma.	('neck squamous cell carcinoma', 'Disease', (86, 114))	('ERBB', 'Gene', (22, 26))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (128, 151))	('neck', 'cellular_component', 'GO:0044326', ('86', '90'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (86, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (77, 114))	('ERBB', 'Gene', '1956', (22, 26))	('skin cutaneous melanoma', 'Disease', (128, 151))	('mutations', 'Var', (34, 43))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (133, 151))
47776	29383036	Analysis of ERBB family mutations reveals that over 20% of bladder urothelial carcinoma (n = 33/130), colorectal adenocarcinoma (n = 130/619), esophageal carcinoma (n = 38/185), pan-lung cancer (n = 271/1144), stomach adenocarcinoma (n = 98/289) and skin cutaneous melanomas (n = 101/366) have an ERBB family mutation which does not co-occur with a PI3KCA mutation.	('esophageal carcinoma', 'Disease', (143, 163))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (255, 273))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (255, 274))	('skin cutaneous melanomas', 'Disease', 'MESH:C562393', (250, 274))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (210, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('ERBB', 'Gene', (12, 16))	('colorectal adenocarcinoma', 'Disease', (102, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('ERBB', 'Gene', (297, 301))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (143, 163))	('ERBB', 'Gene', '1956', (12, 16))	('ERBB', 'Gene', '1956', (297, 301))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (102, 127))	('pan-lung cancer', 'Disease', 'MESH:D008175', (178, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('mutation', 'Var', (309, 317))	('pan-lung cancer', 'Disease', (178, 193))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('stomach adenocarcinoma', 'Disease', (210, 232))	('skin cutaneous melanomas', 'Disease', (250, 274))	('melanomas', 'Phenotype', 'HP:0002861', (265, 274))	('bladder urothelial carcinoma', 'Disease', (59, 87))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (143, 163))	('P', 'Chemical', 'MESH:D010758', (349, 350))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (59, 87))
47777	29383036	Analysis of the datasets for which somatic ERBB family mutations are enriched (>12%) reveals that somatic PIK3CA mutation rates vary between 1.4% in melanoma and 41.7% in uterine corpus endometrioid carcinoma (Table 3).	('mutation', 'Var', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('ERBB', 'Gene', (43, 47))	('PIK3CA', 'Gene', (106, 112))	('corpus endometrioid carcinoma', 'Disease', (179, 208))	('PIK3CA', 'Gene', '5290', (106, 112))	('corpus endometrioid carcinoma', 'Disease', 'MESH:D016889', (179, 208))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (186, 208))	('ERBB', 'Gene', '1956', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
47779	29383036	We finally found that co-occurring ERBB family and PIK3CA mutations can be identified in this subset of patient tumors at rates ranging between 1.5% in pan-lung cancer patients and 11.3% in uterine corpus endometrioid carcinomas.	('mutations', 'Var', (58, 67))	('pan-lung cancer', 'Disease', (152, 167))	('patient', 'Species', '9606', (168, 175))	('patient', 'Species', '9606', (104, 111))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (205, 228))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('PIK3CA', 'Gene', (51, 57))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (205, 227))	('ERBB', 'Gene', (35, 39))	('ERBB', 'Gene', '1956', (35, 39))	('PIK3CA', 'Gene', '5290', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('corpus endometrioid carcinomas', 'Disease', (198, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('corpus endometrioid carcinomas', 'Disease', 'MESH:D016889', (198, 228))	('patients', 'Species', '9606', (168, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (218, 228))	('pan-lung cancer', 'Disease', 'MESH:D008175', (152, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('tumors', 'Disease', (112, 118))
47780	29383036	Interestingly, in bladder urothelial carcinomas, stomach adenocarcinomas and uterine corpus endometrioid carcinomas more than 8% of patient tumors have a co-occurring PIK3CA and ERBB family mutation.	('PIK3CA', 'Gene', '5290', (167, 173))	('stomach adenocarcinomas', 'Disease', (49, 72))	('corpus endometrioid carcinomas', 'Disease', (85, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('corpus endometrioid carcinomas', 'Disease', 'MESH:D016889', (85, 115))	('stomach adenocarcinomas', 'Disease', 'MESH:D013274', (49, 72))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('ERBB', 'Gene', (178, 182))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (92, 114))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('PIK3CA', 'Gene', (167, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (92, 115))	('tumors', 'Disease', (140, 146))	('ERBB', 'Gene', '1956', (178, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('patient', 'Species', '9606', (132, 139))	('mutation', 'Var', (190, 198))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('bladder urothelial carcinomas', 'Disease', (18, 47))	('bladder urothelial carcinomas', 'Disease', 'MESH:D001749', (18, 47))
47784	29383036	In patients with bladder urothelial carcinomas PIK3CA mutations significantly co-occur with ERBB3 (p = 0.035) and EGFR (p = 0.039), whilst in cervical squamous cell carcinomas and endocervical adenocarcinomas PIK3CA mutations significantly co-occur with ERBB2 (p = 0.027).	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (151, 175))	('ERBB2', 'Gene', (254, 259))	('ERBB3', 'Gene', '2065', (92, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))	('endocervical adenocarcinomas', 'Disease', (180, 208))	('PIK3CA', 'Gene', '5290', (47, 53))	('squamous cell carcinomas', 'Disease', (151, 175))	('PIK3CA', 'Gene', (209, 215))	('mutations', 'Var', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('ERBB2', 'Gene', '2064', (254, 259))	('carcinomas', 'Phenotype', 'HP:0030731', (198, 208))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('co-occur', 'Reg', (78, 86))	('endocervical adenocarcinomas', 'Disease', 'MESH:D000230', (180, 208))	('patients', 'Species', '9606', (3, 11))	('ERBB3', 'Gene', (92, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('PIK3CA', 'Gene', (47, 53))	('bladder urothelial carcinomas', 'Disease', (17, 46))	('PIK3CA', 'Gene', '5290', (209, 215))	('EGFR', 'Gene', '1956', (114, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (151, 175))	('bladder urothelial carcinomas', 'Disease', 'MESH:D001749', (17, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))
47786	29383036	Finally, in stomach adenocarcinomas there is a significant likelihood that tumors which have a PIK3CA mutation have a co-occurring mutation in ERBB3 (p = 0.008), EGFR (p = 0.014) and ERBB2 (p = 0.037) (Table 4).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('ERBB3', 'Gene', '2065', (143, 148))	('EGFR', 'Gene', (162, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('ERBB2', 'Gene', (183, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (25, 35))	('mutation', 'Var', (131, 139))	('PIK3CA', 'Gene', '5290', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('ERBB2', 'Gene', '2064', (183, 188))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'molecular_function', 'GO:0005006', ('162', '166'))	('stomach adenocarcinomas', 'Disease', (12, 35))	('ERBB3', 'Gene', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('stomach adenocarcinomas', 'Disease', 'MESH:D013274', (12, 35))	('PIK3CA', 'Gene', (95, 101))	('mutation', 'Var', (102, 110))
47787	29383036	Despite the obvious co-occurrence of mutations in these families of genes, little work to date has been performed to understand the functional and prognostic importance of co-occurring mutations in PIK3CA and ERBB family mutations in cancer.	('ERBB', 'Gene', '1956', (209, 213))	('PIK3CA', 'Gene', '5290', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('ERBB', 'Gene', (209, 213))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('PIK3CA', 'Gene', (198, 204))	('mutations', 'Var', (185, 194))	('cancer', 'Disease', (234, 240))
47790	29383036	In-vitro analysis of the antiproliferative effects of the PI3K inhibitors copanlisib (61 cell lines), pictilisib (23 cell lines) and gedatolisib (17 cell lines) representing multiple cancer types identified that cells with a PIK3CA mutation were 6.45 fold more sensitive to copanlisib (n = 8, p = 0.046), 2.14 fold more sensitive to pictilisib (n = 4, p = 0.025) and 6.27 fold more sensitive to gedatolisib (not significant, n = 5) than those cell lines which were wild type for PIK3CA (Table 5).	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('pictilisib', 'Chemical', 'MESH:C532162', (102, 112))	('PIK3CA', 'Gene', '5290', (225, 231))	('PIK3CA', 'Gene', '5290', (479, 485))	('PI3K', 'Gene', (58, 62))	('P', 'Chemical', 'MESH:D010758', (225, 226))	('P', 'Chemical', 'MESH:D010758', (479, 480))	('gedatolisib', 'Chemical', 'MESH:C549060', (133, 144))	('gedatolisib', 'Chemical', 'MESH:C549060', (395, 406))	('cancer', 'Disease', (183, 189))	('P', 'Chemical', 'MESH:D010758', (58, 59))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('PIK3CA', 'Gene', (225, 231))	('PIK3CA', 'Gene', (479, 485))	('mutation', 'Var', (232, 240))	('copanlisib', 'Chemical', 'MESH:C000589253', (274, 284))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('pictilisib', 'Chemical', 'MESH:C532162', (333, 343))	('copanlisib', 'Gene', (74, 84))	('copanlisib', 'Chemical', 'MESH:C000589253', (74, 84))
47791	29383036	This result demonstrates the importance of PIK3CA mutations as a biomarker of response to PI3K inhibitors.	('PIK3CA', 'Gene', '5290', (43, 49))	('mutations', 'Var', (50, 59))	('P', 'Chemical', 'MESH:D010758', (90, 91))	('PI3K', 'molecular_function', 'GO:0016303', ('90', '94'))	('P', 'Chemical', 'MESH:D010758', (43, 44))	('PIK3CA', 'Gene', (43, 49))
47792	29383036	Interestingly, we also demonstrated that cell lines with only an ERBB family mutation are more sensitive to PI3K inhibition with copanlisib (p = 0.039) and gedatolisib (p = 0.002) relative to those cells which are WT for both PIK3CA and ERBB family genes (Figure 2).	('P', 'Chemical', 'MESH:D010758', (226, 227))	('ERBB', 'Gene', '1956', (65, 69))	('ERBB', 'Gene', '1956', (237, 241))	('mutation', 'Var', (77, 85))	('PIK3CA', 'Gene', (226, 232))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))	('sensitive', 'MPA', (95, 104))	('PI3K inhibition', 'Pathway', (108, 123))	('PIK3CA', 'Gene', '5290', (226, 232))	('ERBB', 'Gene', (65, 69))	('gedatolisib', 'Chemical', 'MESH:C549060', (156, 167))	('P', 'Chemical', 'MESH:D010758', (108, 109))	('copanlisib', 'Chemical', 'MESH:C000589253', (129, 139))	('ERBB', 'Gene', (237, 241))
47793	29383036	However, we also found cell lines with an ERBB family mutation (both ERBB family Mut and PIK3CA/ERBB family Mut cells) were 8.39 fold more sensitive to copanlisib (n = 22, p = 0.005), 2.86 fold more sensitive to pictilisib (n = 10, p = 3 x 10-4), and 6.33 fold more sensitive to gedatolisib (n = 5, p = 0.048) than cell lines which were ERBB family/PIK3CA WT (Table 6).	('sensitive', 'MPA', (139, 148))	('mutation', 'Var', (54, 62))	('ERBB', 'Gene', '1956', (96, 100))	('PIK3CA', 'Gene', (349, 355))	('ERBB', 'Gene', '1956', (69, 73))	('ERBB', 'Gene', '1956', (337, 341))	('ERBB', 'Gene', '1956', (42, 46))	('copanlisib', 'MPA', (152, 162))	('PIK3CA', 'Gene', (89, 95))	('gedatolisib', 'Chemical', 'MESH:C549060', (279, 290))	('pictilisib', 'Chemical', 'MESH:C532162', (212, 222))	('PIK3CA', 'Gene', '5290', (89, 95))	('copanlisib', 'Chemical', 'MESH:C000589253', (152, 162))	('PIK3CA', 'Gene', '5290', (349, 355))	('ERBB', 'Gene', (96, 100))	('ERBB', 'Gene', (69, 73))	('ERBB', 'Gene', (337, 341))	('ERBB', 'Gene', (42, 46))
47794	29383036	There were no significant differences between the copanlisib and pictilisib half-maximal inhibitory concentration IC50s in cells with only an ERBB family mutation versus either only PIK3CA-mutated cells or cell lines with both an ERBB family and a PIK3CA mutation.	('50s', 'Species', '1214577', (116, 119))	('ERBB', 'Gene', '1956', (142, 146))	('PIK3CA', 'Gene', (182, 188))	('PIK3CA', 'Gene', '5290', (248, 254))	('mutation', 'Var', (154, 162))	('pictilisib', 'Chemical', 'MESH:C532162', (65, 75))	('PIK3CA', 'Gene', '5290', (182, 188))	('ERBB', 'Gene', (230, 234))	('PIK3CA', 'Gene', (248, 254))	('copanlisib', 'Chemical', 'MESH:C000589253', (50, 60))	('ERBB', 'Gene', (142, 146))	('ERBB', 'Gene', '1956', (230, 234))
47799	29383036	SW620 and LoVo cell lines are both KRAS mutant whilst C2BBE1 cells have an Mammalian target of rapamycin (mTOR) mutation.	('BBE', 'molecular_function', 'GO:0050468', ('56', '59'))	('KRAS', 'Gene', (35, 39))	('mutation', 'Var', (112, 120))	('Mammalian target of rapamycin', 'Gene', '2475', (75, 104))	('SW620', 'CellLine', 'CVCL:0547', (0, 5))	('Mammalian target of rapamycin', 'Gene', (75, 104))	('KRAS', 'Gene', '3845', (35, 39))	('C2BBE1', 'CellLine', 'CVCL:1096', (54, 60))	('mTOR', 'Gene', (106, 110))	('mTOR', 'Gene', '2475', (106, 110))	('LoVo', 'CellLine', 'CVCL:0399', (10, 14))
47807	29383036	Treatment with the combination of afatinib and copanlisib significantly reduces the phosphorylation of AKT (S473, T308) and p70 S6K (T389) in all cell lines tested [Figure 4(c)].	('copanlisib', 'Gene', (47, 57))	('afatinib', 'Chemical', 'MESH:D000077716', (34, 42))	('AKT', 'Gene', '207', (103, 106))	('T308', 'Chemical', '-', (114, 118))	('S473', 'Var', (108, 112))	('reduces', 'NegReg', (72, 79))	('p70 S6K', 'Gene', (124, 131))	('T308', 'Var', (114, 118))	('S', 'Chemical', 'MESH:D013455', (108, 109))	('S', 'Chemical', 'MESH:D013455', (128, 129))	('AKT', 'Gene', (103, 106))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('p70 S6K', 'Gene', '6198', (124, 131))	('copanlisib', 'Chemical', 'MESH:C000589253', (47, 57))	('phosphorylation', 'MPA', (84, 99))
47808	29383036	Treatment with the combination of afatinib and copanlisib also significantly reduces MEK (S217/221) and MAPK (T202/Y204) phosphorylation in all cell lines apart from HT29 (PIK3CA Mut).	('copanlisib', 'Gene', (47, 57))	('MEK', 'Gene', '5609', (85, 88))	('afatinib', 'Chemical', 'MESH:D000077716', (34, 42))	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))	('S', 'Chemical', 'MESH:D013455', (90, 91))	('P', 'Chemical', 'MESH:D010758', (106, 107))	('HT29', 'CellLine', 'CVCL:0320', (166, 170))	('P', 'Chemical', 'MESH:D010758', (172, 173))	('phosphorylation', 'MPA', (121, 136))	('PIK3CA', 'Gene', (172, 178))	('PIK3CA', 'Gene', '5290', (172, 178))	('MAPK', 'molecular_function', 'GO:0004707', ('104', '108'))	('MAPK', 'Protein', (104, 108))	('copanlisib', 'Chemical', 'MESH:C000589253', (47, 57))	('reduces', 'NegReg', (77, 84))	('T202/Y204', 'Var', (110, 119))	('MEK', 'Gene', (85, 88))
47812	29383036	In H1975 cells (ERBB family/PIK3CA Mut) the combination of copanlisib (120 nM) and afatinib (500 nM) was significantly more likely to increase apoptosis relative to the cell lines that are WT for both mutations (p = 0.006) or ERBB family mutant (p = 0.001) or PIK3CA mutant (p = 0.04).	('PIK3CA', 'Gene', (260, 266))	('PIK3CA', 'Gene', (28, 34))	('ERBB', 'Gene', (226, 230))	('apoptosis', 'CPA', (143, 152))	('increase', 'PosReg', (134, 142))	('ERBB', 'Gene', '1956', (226, 230))	('500 nM', 'Var', (93, 99))	('combination', 'Interaction', (44, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('H1975', 'Var', (3, 8))	('H1975', 'CellLine', 'CVCL:1511', (3, 8))	('afatinib', 'Chemical', 'MESH:D000077716', (83, 91))	('PIK3CA', 'Gene', '5290', (260, 266))	('120 nM', 'Var', (71, 77))	('PIK3CA', 'Gene', '5290', (28, 34))	('copanlisib', 'Gene', (59, 69))	('copanlisib', 'Chemical', 'MESH:C000589253', (59, 69))	('ERBB', 'Gene', (16, 20))	('ERBB', 'Gene', '1956', (16, 20))
47814	29383036	The combined evidence points towards the combination of afatinib and copanlisib producing a pro-apoptotic signal in H1975 cells, which is not observed in the remaining cell lines tested.	('combination', 'Var', (41, 52))	('copanlisib', 'Chemical', 'MESH:C000589253', (69, 79))	('afatinib', 'Chemical', 'MESH:D000077716', (56, 64))	('copanlisib', 'Gene', (69, 79))	('pro-apoptotic signal', 'MPA', (92, 112))	('H1975', 'CellLine', 'CVCL:1511', (116, 121))	('producing', 'Reg', (80, 89))
47816	29383036	ERBB family mutations have been shown in our studies and by others to be enriched in classically non-ERBB-family amplified cancers.	('ERBB', 'Gene', '1956', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('ERBB', 'Gene', '1956', (101, 105))	('mutations', 'Var', (12, 21))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('ERBB', 'Gene', (0, 4))	('ERBB', 'Gene', (101, 105))
47817	29383036	However, we also found that ERBB family mutations co-occur with PIK3CA mutations in endometrial, colorectal, ovarian and stomach cancers.	('stomach cancers', 'Phenotype', 'HP:0012126', (121, 136))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('PIK3CA', 'Gene', (64, 70))	('ERBB', 'Gene', '1956', (28, 32))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('colorectal, ovarian and stomach cancers', 'Disease', 'MESH:D015179', (97, 136))	('PIK3CA', 'Gene', '5290', (64, 70))	('mutations', 'Var', (40, 49))	('mutations', 'Var', (71, 80))	('endometrial', 'Disease', (84, 95))	('ERBB', 'Gene', (28, 32))
47818	29383036	This therefore indicates that patients who have an ERBB family or PIK3CA mutation are significantly more likely to have an activated PI3K/AKT signaling pathway.	('ERBB', 'Gene', '1956', (51, 55))	('P', 'Chemical', 'MESH:D010758', (133, 134))	('AKT', 'Gene', (138, 141))	('PIK3CA', 'Gene', (66, 72))	('P', 'Chemical', 'MESH:D010758', (66, 67))	('patients', 'Species', '9606', (30, 38))	('AKT signaling', 'biological_process', 'GO:0043491', ('138', '151'))	('PI3K', 'molecular_function', 'GO:0016303', ('133', '137'))	('ERBB', 'Gene', (51, 55))	('PIK3CA', 'Gene', '5290', (66, 72))	('mutation', 'Var', (73, 81))	('signaling pathway', 'biological_process', 'GO:0007165', ('142', '159'))	('AKT', 'Gene', '207', (138, 141))
47823	29383036	In our study we wanted to test the antiproliferative impact of PI3K inhibition in a panel of cell lines that were selected based on their ERBB family and PIK3CA mutational status.	('PIK3CA', 'Gene', (154, 160))	('PI3K', 'molecular_function', 'GO:0016303', ('63', '67'))	('P', 'Chemical', 'MESH:D010758', (154, 155))	('ERBB', 'Gene', '1956', (138, 142))	('P', 'Chemical', 'MESH:D010758', (63, 64))	('antiproliferative', 'CPA', (35, 52))	('PIK3CA', 'Gene', '5290', (154, 160))	('inhibition', 'NegReg', (68, 78))	('ERBB', 'Gene', (138, 142))	('mutational', 'Var', (161, 171))
47824	29383036	The cell lines were also chosen to represent the solid tumors in which ERBB family and PIK3CA mutations are commonly found, such as colorectal, ovarian, endometrial and lung cancers.	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('colorectal', 'Disease', 'MESH:D015179', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('PIK3CA', 'Gene', '5290', (87, 93))	('lung cancers', 'Phenotype', 'HP:0100526', (169, 181))	('mutations', 'Var', (94, 103))	('endometrial and lung cancers', 'Disease', 'MESH:D016889', (153, 181))	('solid tumors', 'Disease', (49, 61))	('found', 'Reg', (117, 122))	('ovarian', 'Disease', (144, 151))	('colorectal', 'Disease', (132, 142))	('ERBB', 'Gene', (71, 75))	('ovarian', 'Disease', 'MESH:D010051', (144, 151))	('ERBB', 'Gene', '1956', (71, 75))	('PIK3CA', 'Gene', (87, 93))	('solid tumors', 'Disease', 'MESH:D009369', (49, 61))
47825	29383036	Interestingly, in vitro analysis of the antiproliferative impact of the PI3K inhibitors in multiple cell lines of differing histologies found that cells which harbored an ERBB family mutation were as sensitive to PI3K inhibition as those cell lines which are PIK3CA mutated.	('PIK3CA', 'Gene', '5290', (259, 265))	('antiproliferative', 'MPA', (40, 57))	('P', 'Chemical', 'MESH:D010758', (213, 214))	('PI3K', 'molecular_function', 'GO:0016303', ('213', '217'))	('ERBB', 'Gene', (171, 175))	('P', 'Chemical', 'MESH:D010758', (72, 73))	('PI3K', 'molecular_function', 'GO:0016303', ('72', '76'))	('PIK3CA', 'Gene', (259, 265))	('mutation', 'Var', (183, 191))	('P', 'Chemical', 'MESH:D010758', (259, 260))	('ERBB', 'Gene', '1956', (171, 175))
47826	29383036	We therefore demonstrated that PI3K inhibitors could be effective for the treatment of patients who not only harbor PIK3CA mutations but also ERBB family mutations.	('PIK3CA', 'Gene', (116, 122))	('P', 'Chemical', 'MESH:D010758', (116, 117))	('ERBB', 'Gene', '1956', (142, 146))	('PIK3CA', 'Gene', '5290', (116, 122))	('P', 'Chemical', 'MESH:D010758', (31, 32))	('PI3K', 'molecular_function', 'GO:0016303', ('31', '35'))	('ERBB', 'Gene', (142, 146))	('patients', 'Species', '9606', (87, 95))	('mutations', 'Var', (123, 132))
47828	29383036	Afatinib which has not been tested clinically in combination with PI3K inhibitors provides a rational approach for targeting cancers in which the PI3K pathway may be activated by ERBB family mutation.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('PI3K', 'molecular_function', 'GO:0016303', ('146', '150'))	('PI3K pathway', 'Pathway', (146, 158))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('PI3K', 'molecular_function', 'GO:0016303', ('66', '70'))	('ERBB', 'Gene', (179, 183))	('targeting cancers', 'Disease', (115, 132))	('P', 'Chemical', 'MESH:D010758', (66, 67))	('targeting cancers', 'Disease', 'MESH:D009369', (115, 132))	('P', 'Chemical', 'MESH:D010758', (146, 147))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('ERBB', 'Gene', '1956', (179, 183))	('mutation', 'Var', (191, 199))	('activated', 'PosReg', (166, 175))
47829	29383036	In fact when we combined afatinib and copanlisib together we found that cell lines which harbored both an ERBB family mutation and a PIK3CA mutation had the greatest antiproliferative response to the combination treatment.	('afatinib', 'Chemical', 'MESH:D000077716', (25, 33))	('copanlisib', 'Chemical', 'MESH:C000589253', (38, 48))	('PIK3CA', 'Gene', (133, 139))	('PIK3CA', 'Gene', '5290', (133, 139))	('mutation', 'Var', (140, 148))	('ERBB', 'Gene', (106, 110))	('antiproliferative response', 'CPA', (166, 192))	('mutation', 'Var', (118, 126))	('ERBB', 'Gene', '1956', (106, 110))
47830	29383036	We also demonstrated that two-thirds of cell lines that are ERBB family mutant, but were WT for PIK3CA, had synergistic inhibition of proliferation to the combination of afatinib and copanlisib.	('mutant', 'Var', (72, 78))	('ERBB', 'Gene', (60, 64))	('copanlisib', 'Chemical', 'MESH:C000589253', (183, 193))	('PIK3CA', 'Gene', (96, 102))	('inhibition', 'NegReg', (120, 130))	('afatinib', 'Chemical', 'MESH:D000077716', (170, 178))	('PIK3CA', 'Gene', '5290', (96, 102))	('ERBB', 'Gene', '1956', (60, 64))	('proliferation', 'CPA', (134, 147))
47837	29383036	This is an interesting observation as despite ERBB-family-mutant cell lines being sensitive to the combination of afatinib and copanlisib, it was only in the ERBB family/PIK3CA mutant cell lines that the combination produced a proapoptotic impact, likely indicating that the combination was cytostatic and not cytotoxic in cell lines which harbor an ERBB family mutation only.	('PIK3CA', 'Gene', '5290', (170, 176))	('proapoptotic impact', 'MPA', (227, 246))	('copanlisib', 'Chemical', 'MESH:C000589253', (127, 137))	('ERBB', 'Gene', (46, 50))	('afatinib', 'Chemical', 'MESH:D000077716', (114, 122))	('ERBB', 'Gene', '1956', (46, 50))	('ERBB', 'Gene', (158, 162))	('ERBB', 'Gene', (350, 354))	('mutant', 'Var', (177, 183))	('PIK3CA', 'Gene', (170, 176))	('ERBB', 'Gene', '1956', (350, 354))	('ERBB', 'Gene', '1956', (158, 162))
47842	29383036	However, our study clearly highlights the ability to identify and stratify patients based on the presence of ERBB family mutations, with patients whose tumors cofeature PIK3CA mutations the most likely to gain robust antitumor responses.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mutations', 'Var', (176, 185))	('mutations', 'Var', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('ERBB', 'Gene', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Disease', (152, 157))	('gain', 'PosReg', (205, 209))	('patients', 'Species', '9606', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('ERBB', 'Gene', '1956', (109, 113))	('tumors', 'Disease', (152, 158))	('PIK3CA', 'Gene', (169, 175))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('PIK3CA', 'Gene', '5290', (169, 175))
47860	29383036	Cells were then treated with the relevant drug and concentration KLE [WT/WT (group A), afat 125 nM, cop 8 nM or afat:cop 125:8 nM], H1975 [WT/Mut (group B), afat 30 nM, cop 8 nM or afat:cop 30:8 nM], C2BBE1 [Mut/WT (group C) afat 250 nM, cop 62.5 nM, afat:cop 250:62.5 nM], HT29 [Mut/Mut (group D) afat 125 nM, cop 30 nM or afat:cop 125:30 nM] or a similar concentration of DMSO/DMSO-TFA (vehicle control) in 5% FCS for 30 min.	('KLE', 'Chemical', '-', (65, 68))	('S', 'Chemical', 'MESH:D013455', (381, 382))	('S', 'Chemical', 'MESH:D013455', (376, 377))	('H1975 [', 'Var', (132, 139))	('C2BBE1 [Mut/WT', 'Var', (200, 214))	('S', 'Chemical', 'MESH:D013455', (414, 415))	('C2BBE1', 'CellLine', 'CVCL:1096', (200, 206))	('HT29', 'CellLine', 'CVCL:0320', (274, 278))	('DMSO', 'Chemical', 'MESH:D004121', (379, 383))	('cop 62.5 nM', 'Var', (238, 249))	('H1975', 'CellLine', 'CVCL:1511', (132, 137))	('DMSO', 'Chemical', 'MESH:D004121', (374, 378))	('HT29 [Mut/Mut', 'Var', (274, 287))	('BBE', 'molecular_function', 'GO:0050468', ('202', '205'))
47874	28525385	A systematic review and meta-analysis The clinical implications of histological variants in urothelial carcinoma of the bladder has been a subject of significant controversy with many unanswered questions that remain.	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (92, 127))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (92, 127))	('variants', 'Var', (80, 88))	('urothelial carcinoma of the bladder', 'Disease', (92, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
47875	28525385	To clarify whether histological variants presage poor prognosis for patients suffering from urothelial carcinoma of the bladder, we scoured through various electronic databases such as Medline, Web of Knowledge, and the Cochrane Library up to August 18, 2016.	('patients', 'Species', '9606', (68, 76))	('variants', 'Var', (32, 40))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (92, 127))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (92, 127))	('urothelial carcinoma of the bladder', 'Disease', (92, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
47883	28525385	Studies have suggested that the presence of histological variants (HVs) are associated with cancer-specific mortality in patients with urothelial carcinoma of the bladder when treated with radical cystectomy or intravesical immunotherapy, however, some do not support this conclusion.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('HVs', 'molecular_function', 'GO:0034003', ('67', '70'))	('associated with', 'Reg', (76, 91))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (135, 170))	('urothelial carcinoma of the bladder', 'Disease', (135, 170))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (135, 170))	('variants', 'Var', (57, 65))	('patients', 'Species', '9606', (121, 129))
47884	28525385	Furthermore, using cancer specific survival (CSS) or overall survival (OS) to evaluate the outcomes of histology variants produces different results.	('CSS', 'Chemical', '-', (45, 48))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('OS', 'Chemical', '-', (71, 73))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('variants', 'Var', (113, 121))
47978	26674132	Mismatch repair deficiency associated with complete remission to combination programmed cell death ligand immune therapy in a patient with sporadic urothelial carcinoma: immunotheranostic considerations Mismatch repair deficiency (MMRD) is a common pathway of malignant transformation accounting for approximately 15-20 % of human carcinogensis.	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('Mismatch repair', 'biological_process', 'GO:0006298', ('0', '15'))	('sporadic urothelial carcinoma', 'Disease', (139, 168))	('ligand', 'molecular_function', 'GO:0005488', ('99', '105'))	('patient', 'Species', '9606', (126, 133))	('sporadic urothelial carcinoma', 'Disease', 'MESH:C538614', (139, 168))	('Mismatch repair', 'biological_process', 'GO:0006298', ('203', '218'))	('programmed cell death', 'biological_process', 'GO:0012501', ('77', '98'))	('deficiency', 'Var', (16, 26))	('human', 'Species', '9606', (325, 330))
47982	26674132	A patient with sporadic, high grade urothelial carcinoma of the renal pelvis was found to have a hypermutator genotype with 73 mutations occurring amidst 62 known drivers of malignancy, and 340 VUS alterations.	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('malignancy', 'Disease', (174, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('renal pelvis', 'Phenotype', 'HP:0000125', (64, 76))	('mutations', 'Var', (127, 136))	('carcinoma of the renal pelvis', 'Phenotype', 'HP:0006762', (47, 76))	('patient', 'Species', '9606', (2, 9))	('urothelial carcinoma of the renal pelvis', 'Disease', 'MESH:C538614', (36, 76))	('urothelial carcinoma of the renal pelvis', 'Disease', (36, 76))
47983	26674132	MMR deficiency phenotype was confirmed by the absence of MSH2 and MSH6 as well as deleterious mutations in these genes.	('absence', 'NegReg', (46, 53))	('mutations', 'Var', (94, 103))	('MSH6', 'Gene', (66, 70))	('MSH2', 'Gene', '4436', (57, 61))	('MMR deficiency', 'Disease', (0, 14))	('MMR deficiency', 'Disease', 'MESH:C536143', (0, 14))	('MSH6', 'Gene', '2956', (66, 70))	('MMR', 'biological_process', 'GO:0006298', ('0', '3'))	('MSH2', 'Gene', (57, 61))
47989	26674132	Patients with epigenetic silencing or deleterious mutations involving these key enzymes have a predilection for a variety of cancers due to altered microsatellite nucleotides and replication errors causing a hypermutant phenotype with hundreds or thousands of mutations.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('altered', 'Reg', (140, 147))	('cancers', 'Disease', (125, 132))	('hypermutant phenotype', 'MPA', (208, 229))	('microsatellite', 'Protein', (148, 162))	('epigenetic silencing', 'Var', (14, 34))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Patients', 'Species', '9606', (0, 8))	('causing', 'Reg', (198, 205))	('replication errors', 'CPA', (179, 197))
47990	26674132	In contrast to chromosomal instability, microsatellite instability (MSI) caused by MMR deficiency represents a distinct pathway of carcinogenesis through mutations in genes controlling growth pathways.	('carcinogenesis', 'Disease', (131, 145))	('MMR', 'biological_process', 'GO:0006298', ('83', '86'))	('MSI', 'Disease', (68, 71))	('carcinogenesis', 'Disease', 'MESH:D063646', (131, 145))	('chromosomal instability', 'Phenotype', 'HP:0040012', (15, 38))	('microsatellite instability', 'MPA', (40, 66))	('mutations', 'Var', (154, 163))	('MMR deficiency', 'Disease', (83, 97))	('MMR deficiency', 'Disease', 'MESH:C536143', (83, 97))	('MSI', 'Disease', 'None', (68, 71))
47991	26674132	The hereditary syndromes involving mutations of mismatch repair enzymes (MLH1, MSH2, MSH6, and PMS2) were originally identified by Dr. Henry Lynch and is now divided into Lynch syndrome I consisting of colon cancer-only families, and Lynch syndrome II that includes a variety of malignancies such as genitourinary, gynecologic, and other gastrointestinal cancers.	('hereditary syndromes', 'Disease', (4, 24))	('malignancies', 'Disease', 'MESH:D009369', (279, 291))	('Lynch syndrome II', 'Disease', (234, 251))	('Lynch syndrome', 'Disease', (171, 185))	('MSH2', 'Gene', (79, 83))	('colon cancer', 'Disease', 'MESH:D015179', (202, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('malignancies', 'Disease', (279, 291))	('genitourinary', 'Disease', (300, 313))	('gynecologic', 'Disease', (315, 326))	('mismatch repair', 'biological_process', 'GO:0006298', ('48', '63'))	('MSH2', 'Gene', '4436', (79, 83))	('Lynch syndrome', 'Disease', 'MESH:D003123', (171, 185))	('MSH6', 'Gene', (85, 89))	('colon cancer', 'Disease', (202, 214))	('hereditary syndromes', 'Disease', 'MESH:D009386', (4, 24))	('MSH6', 'Gene', '2956', (85, 89))	('PMS2', 'Gene', '5395', (95, 99))	('Lynch syndrome II', 'Disease', 'MESH:D055847', (234, 251))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('MLH1', 'Gene', (73, 77))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (338, 362))	('cancers', 'Phenotype', 'HP:0002664', (355, 362))	('Lynch syndrome', 'Disease', 'MESH:D003123', (234, 248))	('colon cancer', 'Phenotype', 'HP:0003003', (202, 214))	('MLH1', 'Gene', '4292', (73, 77))	('gastrointestinal cancers', 'Disease', (338, 362))	('PMS2', 'Gene', (95, 99))	('mutations', 'Var', (35, 44))
47992	26674132	Deleterious mutations in MSH2 are specifically associated with both upper (5.6 %) and lower tract (12.3 %) urothelial cancers.	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('Deleterious mutations', 'Var', (0, 21))	('MSH2', 'Gene', (25, 29))	('MSH2', 'Gene', '4436', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('lower tract', 'Disease', (86, 97))	('urothelial cancers', 'Disease', 'MESH:D014523', (107, 125))	('associated', 'Reg', (47, 57))	('upper', 'Disease', (68, 73))	('urothelial cancers', 'Disease', (107, 125))
47996	26674132	But in advanced colorectal cancer, MSI is frequently associated with BRAF mutations and portends an unusually poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('BRAF', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('MSI', 'Disease', 'None', (35, 38))	('colorectal cancer', 'Disease', 'MESH:D015179', (16, 33))	('MSI', 'Disease', (35, 38))	('associated', 'Reg', (53, 63))	('BRAF', 'Gene', '673', (69, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))	('colorectal cancer', 'Disease', (16, 33))
48006	26674132	This patient enrolled on a phase I clinical trial testing the combination of MEDI4736 and MEDI0680.	('MEDI4736', 'Var', (77, 85))	('MEDI0680', 'Gene', (90, 98))	('patient', 'Species', '9606', (5, 12))
48013	26674132	She was deemed as having G3 pT3N0M0, AJCC Stage III cancer.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('G3 pT3N0M0', 'Var', (25, 35))	('cancer', 'Disease', (52, 58))
48019	26674132	Three deleterious mutations were identified in MSH2 (A913fs*2, E226*, E580*) and one in MSH6 (R361H) (Table 1).	('MSH2', 'Gene', (47, 51))	('MSH2', 'Gene', '4436', (47, 51))	('E226*', 'SUBSTITUTION', 'None', (63, 68))	('E226*', 'Var', (63, 68))	('E580*', 'Var', (70, 75))	('MSH6', 'Gene', (88, 92))	('R361H', 'Mutation', 'rs63750440', (94, 99))	('A913fs*2', 'Var', (53, 61))	('E580*', 'SUBSTITUTION', 'None', (70, 75))	('MSH6', 'Gene', '2956', (88, 92))	('A913fs', 'Mutation', 'p.A913fsX', (53, 59))
48028	26674132	At relapse, the molecular profiling evaluation revealed a hypermutant genotype and led to discovering the somatic knockout of MSH2 and MSH6 induced by deleterious mutations.	('mutations', 'Var', (163, 172))	('MSH2', 'Gene', (126, 130))	('MSH6', 'Gene', (135, 139))	('MSH2', 'Gene', '4436', (126, 130))	('MSH6', 'Gene', '2956', (135, 139))
48029	26674132	While this patient's cancer proved to have deleterious mutations in MSH2 and MSH6, IHC testing for MSI to identify epigenetic silencing in the absence of mutation represents an exceptional example where NGS assessments of DNA cannot substitute for protein assessment.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('MSH6', 'Gene', '2956', (77, 81))	('MSI', 'Disease', (99, 102))	('mutations', 'Var', (55, 64))	('epigenetic silencing', 'MPA', (115, 135))	('MSH2', 'Gene', '4436', (68, 72))	('protein', 'cellular_component', 'GO:0003675', ('248', '255'))	('DNA', 'cellular_component', 'GO:0005574', ('222', '225'))	('patient', 'Species', '9606', (11, 18))	('MSH6', 'Gene', (77, 81))	('MSI', 'Disease', 'None', (99, 102))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('MSH2', 'Gene', (68, 72))
48032	26674132	The clinical trial she enrolled on is actively testing the combination of MEDI4736 mAb that blocks PD-L1 and MEDI0680 mAb that blocks PD-1, a dual blockade that may be more effective than targeting either target alone.	('PD-1', 'Gene', (134, 138))	('PD-1', 'Gene', '5133', (134, 138))	('PD-L1', 'Gene', (99, 104))	('MEDI4736', 'Var', (74, 82))	('PD-L1', 'Gene', '29126', (99, 104))
48035	26674132	Other PD-L1/PD-1 agents, MPDL3280A, atezolizumab, and MK3475, pembrolizumab, have already been reported as having impressive efficacy in urothelial cancer, but so far there has been no evaluation whether those patients' cancers had MMRD.	('urothelial cancer', 'Disease', (137, 154))	('MK3475', 'Var', (54, 60))	('pembrolizumab', 'Chemical', 'MESH:C582435', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('PD-L1/PD-1', 'Gene', '29126;5133', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('MK3475', 'Chemical', 'MESH:C582435', (54, 60))	('MPDL3280A', 'Var', (25, 34))	('urothelial cancer', 'Disease', 'MESH:D014523', (137, 154))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('patients', 'Species', '9606', (210, 218))	('cancers', 'Disease', (220, 227))	('PD-L1/PD-1', 'Gene', (6, 16))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (25, 34))	('atezolizumab', 'Chemical', 'MESH:C000594389', (36, 48))
48036	26674132	Whole exome sequencing (WES) has demonstrated that mutation load has a direct bearing on a given cancer's immunogenicity and predicts the likelihood of benefit from ipilumumab.	('cancer', 'Disease', (97, 103))	('bearing', 'Reg', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutation load', 'Var', (51, 64))	('ipilumumab', 'Chemical', '-', (165, 175))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
48037	26674132	It follows that the MSI phenomenon which causes 10 to 1000 times more mutations than found in MSS cancers creates neo-antigens and increases antigenicity, thus explaining the usual inflammatory reaction of TIL, and accounting for the improved prognosis of early stage, MMRD cancers.	('antigenicity', 'MPA', (141, 153))	('MSI', 'Disease', 'None', (20, 23))	('MSS cancers', 'Disease', 'MESH:D013132', (94, 105))	('MSS cancers', 'Disease', (94, 105))	('mutations', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('MMRD cancers', 'Disease', 'MESH:D009369', (269, 281))	('cancers', 'Phenotype', 'HP:0002664', (274, 281))	('increases', 'PosReg', (131, 140))	('MSI', 'Disease', (20, 23))	('MMRD cancers', 'Disease', (269, 281))	('neo-antigens', 'MPA', (114, 126))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
48043	26674132	The susceptibility of heavy carcinogen-associated cancers, such as lung and head and neck cancers, to checkpoint immunotherapy supports the notion that the antigenicity of cancer increases with rising mutation burden from any cause.	('increases', 'PosReg', (179, 188))	('cancers', 'Disease', (90, 97))	('cancer', 'Disease', (50, 56))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancers', 'Disease', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('neck', 'cellular_component', 'GO:0044326', ('85', '89'))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutation', 'Var', (201, 209))	('neck cancers', 'Disease', (85, 97))	('neck cancers', 'Disease', 'MESH:D006258', (85, 97))	('head and neck cancer', 'Phenotype', 'HP:0012288', (76, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancer', 'Disease', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung', 'Disease', (67, 71))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('head and neck cancers', 'Phenotype', 'HP:0012288', (76, 97))	('cancer', 'Disease', (90, 96))
48134	25995755	In atypical teratoid/rhabdoid tumors, high BMP4 expression was negatively associated with patients' survival.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('BMP4', 'Gene', (43, 47))	('negatively', 'NegReg', (63, 73))	('expression', 'MPA', (48, 58))	('high', 'Var', (38, 42))	('rhabdoid tumors', 'Disease', (21, 36))	('BMP4', 'Gene', '652', (43, 47))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (21, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('patients', 'Species', '9606', (90, 98))
48137	25995755	In advanced ovarian cancer, high expression of BMP4 was associated with better progression-free and overall survival.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('BMP4', 'Gene', (47, 51))	('overall survival', 'CPA', (100, 116))	('ovarian cancer', 'Disease', (12, 26))	('better', 'PosReg', (72, 78))	('BMP4', 'Gene', '652', (47, 51))	('progression-free', 'CPA', (79, 95))	('ovarian cancer', 'Phenotype', 'HP:0100615', (12, 26))	('high expression', 'Var', (28, 43))	('ovarian cancer', 'Disease', 'MESH:D010051', (12, 26))
48148	25995755	Interestingly, in contrast to these findings, high expression of BMP2 was associated with worse prognosis in gastric cancer and glioma.	('BMP2', 'Gene', '650', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('glioma', 'Disease', (128, 134))	('gastric cancer', 'Disease', (109, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('BMP2', 'Gene', (65, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('high expression', 'Var', (46, 61))
48156	25995755	Low levels of BMP2 and BMP7 in tumor tissue were associated with shorter time to relapse, and hence can be considered as prognostic factors in UC.	('BMP2', 'Gene', '650', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('time to relapse', 'CPA', (73, 88))	('BMP7', 'Gene', '655', (23, 27))	('tumor', 'Disease', (31, 36))	('shorter', 'NegReg', (65, 72))	('BMP2', 'Gene', (14, 18))	('BMP7', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('Low', 'Var', (0, 3))
48183	20588175	Furthermore, mice deficient in NKX3.1 have been shown to develop prostatic epithelial hyperplasia and PIN, and in mice with targeted disruption of Pten or Cdkn1b (encoding p27), loss of one or both NKX3.1 alleles results in accelerated and more aggressive prostate tumorigenesis.	('mice', 'Species', '10090', (13, 17))	('prostatic epithelial hyperplasia', 'Disease', (65, 97))	('more', 'PosReg', (240, 244))	('Pten', 'Gene', (147, 151))	('Pten', 'Gene', '19211', (147, 151))	('PIN', 'CPA', (102, 105))	('develop', 'PosReg', (57, 64))	('Cdkn1b', 'Gene', (155, 161))	('tumor', 'Disease', (265, 270))	('aggressive', 'CPA', (245, 255))	('p27', 'Gene', (172, 175))	('disruption', 'Var', (133, 143))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('p27', 'Gene', '12576', (172, 175))	('mice', 'Species', '10090', (114, 118))	('loss', 'Var', (178, 182))	('Cdkn1b', 'Gene', '12576', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('prostatic epithelial hyperplasia', 'Disease', 'MESH:D011470', (65, 97))	('accelerated', 'PosReg', (224, 235))
48200	20588175	Patient ages ranged from 43 to 89 years (median = 60), the Gleason sums for the primary prostate cancers varied from 6 to 9 (mean = 7.06) and the pathologic stages ranged from T2N0Mx to T3bN1Mx.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('T2N0Mx', 'Var', (176, 182))	('T3bN1Mx', 'Var', (186, 193))	('prostate cancers', 'Phenotype', 'HP:0012125', (88, 104))	('primary prostate cancers', 'Disease', (80, 104))	('to 9', 'Species', '1214577', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))	('primary prostate cancers', 'Disease', 'MESH:D011471', (80, 104))	('Patient', 'Species', '9606', (0, 7))
48247	20588175	Another relatively recently discovered protein, P501S (also known as prostein), that is selectively expressed in prostatic epithelium, has also been reported to be effective in identifying prostatic origin in metastatic carcinomas.	('carcinomas', 'Disease', 'MESH:D002277', (220, 230))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('carcinomas', 'Phenotype', 'HP:0030731', (220, 230))	('carcinomas', 'Disease', (220, 230))	('P501S', 'Mutation', 'p.P501S', (48, 53))	('prostein', 'Gene', '85414', (69, 77))	('P501S', 'Var', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('prostein', 'Gene', (69, 77))	('prostatic origin', 'Disease', (189, 205))
48248	20588175	In addition, a earlier study employing the metastatic prostate carcinoma TMA used in this study, found 68 of the 69 metastatic prostate carcinoma cases and 15 of the 15 distant metastasis cases to be positive for p501s.	('metastatic prostate carcinoma', 'Phenotype', 'HP:0012125', (116, 145))	('prostate carcinoma', 'Disease', 'MESH:D011472', (54, 72))	('prostate carcinoma', 'Disease', 'MESH:D011472', (127, 145))	('prostate carcinoma TMA', 'Disease', (54, 76))	('metastatic prostate carcinoma', 'Phenotype', 'HP:0012125', (43, 72))	('prostate carcinoma TMA', 'Disease', 'MESH:D011472', (54, 76))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (54, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('positive', 'Reg', (200, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (127, 145))	('prostate carcinoma', 'Disease', (127, 145))	('p501s', 'Var', (213, 218))
48249	20588175	Like PSA and PSAP, however, P501s staining is exclusively cytoplasmic.	('P501s', 'Var', (28, 33))	('PSA', 'Gene', '354', (5, 8))	('PSA', 'Gene', (5, 8))	('PSA', 'Gene', '354', (13, 16))	('PSA', 'Gene', (13, 16))
48250	20588175	Thus, the potential usefulness of NKX3.1 is also highlighted by the finding that its localization is predominantly nuclear, which can add additional diagnostic confidence in cases in which there is only relatively weak staining for one or more of the cytoplasmic markers such as PSA, PSAP, or P501s.	('PSA', 'Gene', '354', (279, 282))	('PSA', 'Gene', (279, 282))	('PSA', 'Gene', (284, 287))	('localization', 'biological_process', 'GO:0051179', ('85', '97'))	('PSA', 'Gene', '354', (284, 287))	('P501s', 'Var', (293, 298))
48260	28538387	By Kaplan-Meier analysis, UCDD was found to be significantly correlated with worse IRFS, CSS, and OS (all P < .01).	('IRFS', 'Disease', (83, 87))	('UCDD', 'Var', (26, 30))	('CSS', 'Disease', (89, 92))	('CSS', 'Chemical', '-', (89, 92))	('OS', 'Chemical', '-', (98, 100))	('UCDD', 'Chemical', '-', (26, 30))
48313	28538387	On univariate and multivariate analysis, variant UTUC histology, advanced tumor stage were independent prognostic factors for IRFS, CSS, and OS (all P < .05, Tables 7-9).	('IRFS', 'Disease', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('OS', 'Chemical', '-', (141, 143))	('CSS', 'Chemical', '-', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('variant', 'Var', (41, 48))	('CSS', 'Disease', (132, 135))
48318	28538387	IHC stain in these cases was positive for CKp, P63, and Ki67.	('P63', 'Gene', (47, 50))	('Ki67', 'Var', (56, 60))	('P63', 'Gene', '8626', (47, 50))	('CKp', 'Protein', (42, 45))	('positive', 'Reg', (29, 37))
48326	28538387	On the basis of previous reports, some researchers found an association of variant histology with adverse clinicopathologic characteristics in patients with bladder cancer or the upper urinary tract.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('variant', 'Var', (75, 82))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('association', 'Reg', (60, 71))	('patients', 'Species', '9606', (143, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (157, 171))	('bladder cancer', 'Disease', (157, 171))
48364	27465361	The pattern was mainly seen in aneuploid high-grade cancers.	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('aneuploid', 'Var', (31, 40))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
48367	27465361	Severe and prolonged disturbances of the circadian timing system are believed to predispose to cancer development in different organs, not only in the mammary and prostate glands, but also in several other types of cancer, including ovarian, kidney, brain, colorectal, lung, head/neck, pancreatic cancer and hematological malignancies.	('pancreatic cancer', 'Disease', (286, 303))	('disturbances', 'Var', (21, 33))	('head/neck', 'Disease', (275, 284))	('ovarian', 'Disease', (233, 240))	('hematological malignancies', 'Disease', (308, 334))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', (95, 101))	('colorectal', 'Disease', 'MESH:D015179', (257, 267))	('predispose', 'Reg', (81, 91))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (286, 303))	('lung', 'Disease', (269, 273))	('kidney', 'Disease', (242, 248))	('cancer', 'Disease', (297, 303))	('hematological malignancies', 'Disease', 'MESH:D019337', (308, 334))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('neck', 'cellular_component', 'GO:0044326', ('280', '284'))	('hematological malignancies', 'Phenotype', 'HP:0004377', (308, 334))	('pancreatic cancer', 'Disease', 'MESH:D010190', (286, 303))	('brain', 'Disease', (250, 255))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('colorectal', 'Disease', (257, 267))
48382	27465361	Such circadian variations led us to postulate that similar to other organs, perturbation of the clockwork may be a contributory mechanism of dysregulation during the development of urothelial cancer.	('dysregulation', 'MPA', (141, 154))	('perturbation', 'Var', (76, 88))	('urothelial cancer', 'Disease', (181, 198))	('clock', 'Gene', '9575', (96, 101))	('clock', 'Gene', (96, 101))	('urothelial cancer', 'Disease', 'MESH:D014523', (181, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
48465	27465361	There was a similar expression pattern between 6N blue, the outlier, and its adjacent tumour sample (23T red).	('6N blue', 'Var', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('6N blue', 'Chemical', '-', (47, 54))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('tumour', 'Disease', (86, 92))
48478	27465361	The average expression of BMAL1 was slightly up-regulated in the aneuploid cells while CRY2 was slightly down-regulated for the aneuploid cells and up-regulated in the diploid cells.	('down-regulated', 'NegReg', (105, 119))	('up-regulated', 'PosReg', (45, 57))	('BMAL1', 'Gene', '406', (26, 31))	('BMAL1', 'Gene', (26, 31))	('CRY2', 'Gene', (87, 91))	('up-regulated', 'PosReg', (148, 160))	('expression', 'MPA', (12, 22))	('CRY2', 'Gene', '1408', (87, 91))	('aneuploid', 'Var', (65, 74))
48480	27465361	For the other cancer related genes, the total T/B averages for p16 and PTEN were found divergent in the two categories; with four fold higher expression in the diploid compared to the aneuploid stem line.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('p16', 'Gene', (63, 66))	('PTEN', 'Gene', (71, 75))	('diploid', 'Var', (160, 167))	('PTEN', 'Gene', '5728', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('expression', 'MPA', (142, 152))	('higher', 'PosReg', (135, 141))	('p16', 'Gene', '1029', (63, 66))
48481	27465361	The opposite pattern was seen for EGFR and HRAS, with an average of two fold higher expression in the aneuploid compared to the diploid cells.	('HRAS', 'Gene', (43, 47))	('EGFR', 'Gene', (34, 38))	('higher', 'PosReg', (77, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('HRAS', 'Gene', '3265', (43, 47))	('aneuploid', 'Var', (102, 111))	('expression', 'MPA', (84, 94))	('EGFR', 'Gene', '1956', (34, 38))
48484	27465361	However, the trend among the five cytokeratins revealed an increased (several T/B-fold) level of gene expression in the aneuploid as compared to the diploid cancer cells.	('diploid cancer', 'Disease', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gene expression', 'biological_process', 'GO:0010467', ('97', '112'))	('diploid cancer', 'Disease', 'MESH:C548012', (149, 163))	('aneuploid', 'Var', (120, 129))	('increased', 'PosReg', (59, 68))
48506	27465361	This extends earlier findings that malignant behaviour in urothelial cells may at least in part be due to a combined action of oncogenes, altered suppressor genes and aberrant clock gene expression.	('aberrant', 'Var', (167, 175))	('gene expression', 'biological_process', 'GO:0010467', ('182', '197'))	('clock', 'Gene', '9575', (176, 181))	('clock', 'Gene', (176, 181))	('behaviour', 'biological_process', 'GO:0007610', ('45', '54'))	('malignant behaviour', 'CPA', (35, 54))	('due to', 'Reg', (99, 105))
48507	27465361	Alternatively, mutations and/or deletions in either of them, leading to non-functional proteins could be critical steps in development of biological malignancy.	('deletions', 'Var', (32, 41))	('non-functional proteins', 'MPA', (72, 95))	('malignancy', 'Disease', 'MESH:D009369', (149, 159))	('mutations', 'Var', (15, 24))	('malignancy', 'Disease', (149, 159))
48511	27465361	In rodents, it has been reported that mutation of the CSNK1 priming site in PER2 (Ser662), leads to decreased phosphorylation of stabilizing sites in PER2 and accelerated circadian rhythms.	('Ser', 'cellular_component', 'GO:0005790', ('82', '85'))	('PER2', 'Gene', '8864', (150, 154))	('PER2', 'Gene', (76, 80))	('Ser662', 'Chemical', '-', (82, 88))	('PER2', 'Gene', '8864', (76, 80))	('decreased', 'NegReg', (100, 109))	('phosphorylation', 'MPA', (110, 125))	('mutation', 'Var', (38, 46))	('circadian rhythms', 'MPA', (171, 188))	('PER2', 'Gene', (150, 154))	('phosphorylation', 'biological_process', 'GO:0016310', ('110', '125'))	('CSNK1', 'Gene', (54, 59))	('accelerated', 'PosReg', (159, 170))
48515	27465361	PER2 has also been found to function as a tumour suppressor, with the absence of both its copies causing an increased rate of radiation-induced cancers.	('PER2', 'Gene', '8864', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('tumour', 'Disease', (42, 48))	('absence', 'Var', (70, 77))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('PER2', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
48518	27465361	The majority of all advanced human tumours have mutations in the TP53 gene, and in rodents PER2 expression is also found directly regulated by p53 binding to a response element in the PER2 promoter.	('tumours', 'Disease', (35, 42))	('human', 'Species', '9606', (29, 34))	('PER2', 'Gene', '8864', (91, 95))	('TP53', 'Gene', '7157', (65, 69))	('binding', 'Interaction', (147, 154))	('TP53', 'Gene', (65, 69))	('p53', 'Gene', '7157', (143, 146))	('PER2', 'Gene', (184, 188))	('expression', 'MPA', (96, 106))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('p53 binding', 'molecular_function', 'GO:0002039', ('143', '154'))	('PER2', 'Gene', (91, 95))	('PER2', 'Gene', '8864', (184, 188))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('tumours', 'Disease', 'MESH:D009369', (35, 42))	('p53', 'Gene', (143, 146))	('mutations', 'Var', (48, 57))
48525	27465361	However, two open questions remain: Could the observed clock gene alterations be due to a longstanding phase shift of otherwise normal oscillations and not a disruption of the clock work per se?	('clock', 'Gene', (55, 60))	('clock', 'Gene', '9575', (176, 181))	('clock', 'Gene', (176, 181))	('clock', 'Gene', '9575', (55, 60))	('alterations', 'Var', (66, 77))
48533	27465361	A correlation was found between altered mRNA and protein expression of various clock genes and common tumour markers in urothelial cancer, indicating that disturbed function in the cellular clockwork may be an important additional mechanism contributing to cancer progression and malignant behaviour.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('clock', 'Gene', (79, 84))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('altered', 'Reg', (32, 39))	('tumour', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('clock', 'Gene', (190, 195))	('disturbed', 'Var', (155, 164))	('contributing', 'Reg', (241, 253))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('urothelial cancer', 'Disease', 'MESH:D014523', (120, 137))	('cancer', 'Disease', (131, 137))	('behaviour', 'biological_process', 'GO:0007610', ('290', '299'))	('urothelial cancer', 'Disease', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('clock', 'Gene', '9575', (79, 84))	('cancer', 'Disease', (257, 263))	('clock', 'Gene', '9575', (190, 195))
48534	27465361	These alterations are most pronounced in aneuploid, high grade tumours, and are to some extent also seen in the neighbouring mucosa.	('tumours', 'Disease', (63, 70))	('aneuploid', 'Var', (41, 50))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
48677	25887442	In the BA06 30894 study, neoadjuvant CMV treatment was associated with a 16% reduction in the risk of death [HR: 0.84, CI 95%: 0.72-0.99], corresponding to an absolute improvement of 6% in the 10-year overall survival (OS) [30% to 36%; p = 0.037].	('BA06', 'Chemical', '-', (7, 11))	('OS', 'Chemical', '-', (219, 221))	('reduction', 'NegReg', (77, 86))	('men', 'Species', '9606', (46, 49))	('overall', 'MPA', (201, 208))	('CMV', 'Chemical', 'MESH:C046870', (37, 40))	('neoadjuvant', 'Var', (25, 36))	('men', 'Species', '9606', (175, 178))	('improvement', 'PosReg', (168, 179))
48682	25887442	reported that there were no significant differences in OS and disease-free survival in patients with stage pT2G3, pT3-4, or N0-1 MIBC treated with four cycles of gemcitabine and cisplatin (GC) compared to no adjuvant chemotherapy after radical cystectomy [HR 1.29, p = 0.24 for OS].	('OS', 'Chemical', '-', (278, 280))	('MIBC', 'Chemical', '-', (129, 133))	('OS', 'Chemical', '-', (55, 57))	('GC', 'Chemical', '-', (189, 191))	('pT2G3', 'Var', (107, 112))	('gemcitabine', 'Chemical', 'MESH:C056507', (162, 173))	('pT3', 'Gene', '7694', (114, 117))	('pT3', 'Gene', (114, 117))	('patients', 'Species', '9606', (87, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (178, 187))
48683	25887442	In contrast, a randomized phase III trial comparing four cycles of PGC (paclitaxel, gemcitabine, and cisplatin) with no adjuvant treatment in 142 patients with stage pT3-4 and/or pN+ found that OS was significantly improved in the PGC arm [five-years OS: 60% vs 31%, p < 0.0009].	('paclitaxel', 'Chemical', 'MESH:D017239', (72, 82))	('OS', 'Chemical', '-', (251, 253))	('PGC', 'Var', (231, 234))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('GC', 'Chemical', '-', (232, 234))	('OS', 'Chemical', '-', (194, 196))	('improved', 'PosReg', (215, 223))	('pT3', 'Gene', '7694', (166, 169))	('GC', 'Chemical', '-', (68, 70))	('pT3', 'Gene', (166, 169))	('patients', 'Species', '9606', (146, 154))	('gemcitabine', 'Chemical', 'MESH:C056507', (84, 95))	('men', 'Species', '9606', (134, 137))
48708	25887442	In a retrospective analysis, Sonpavde et al., found that PS > 0, Hb level < 10 g/dl, liver metastasis, and a shorter time period between prior and new chemotherapy treatments were independent significant prognostic factors for OS and PFS in the setting of second-line therapy for advanced urothelial carcinoma.	('urothelial carcinoma', 'Disease', (289, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('liver metastasis', 'Disease', 'MESH:D009362', (85, 101))	('liver metastasis', 'Disease', (85, 101))	('OS', 'Chemical', '-', (227, 229))	('men', 'Species', '9606', (169, 172))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (289, 309))	('PS > 0', 'Var', (57, 63))	('PFS', 'Disease', (234, 237))
48725	22273550	Known risk factors for the development of urothelial carcinoma include smoking, pelvic radiation, and a number of occupational exposures including aniline dyes, aromatic amines, nitrites, acrolein, coal, and arsenic.	('nitrites', 'Chemical', 'MESH:D009573', (178, 186))	('aniline', 'Chemical', 'MESH:C023650', (147, 154))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (42, 62))	('acrolein', 'Chemical', 'MESH:D000171', (188, 196))	('aromatic amines', 'Chemical', '-', (161, 176))	('aromatic', 'Var', (161, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('arsenic', 'Chemical', 'MESH:D001151', (208, 215))	('urothelial carcinoma', 'Disease', (42, 62))
48733	22273550	At a median follow-up of 8 years, investigators documented a 16% reduction in all-cause mortality and a 23% reduction in death or metastasis in those patients receiving neoadjuvant CMV compared to those undergoing local therapy alone.	('a 23', 'Gene', (102, 106))	('all-cause', 'MPA', (78, 87))	('a 16', 'Gene', (59, 63))	('CMV', 'Var', (181, 184))	('a 16', 'Gene', '28910', (59, 63))	('a 23', 'Gene', '28923', (102, 106))	('patients', 'Species', '9606', (150, 158))	('death', 'Disease', 'MESH:D003643', (121, 126))	('death', 'Disease', (121, 126))	('CMV', 'Chemical', '-', (181, 184))	('reduction', 'NegReg', (65, 74))	('reduction', 'NegReg', (108, 117))
48738	22273550	In addition to the SWOG and MRC/EORTC trials, pooled data from the Nordic Collaborative Group evaluated survival following neoadjuvant cisplatin/doxorubicin or cisplatin/methotrexate and confirmed a 20% improvement in risk of death, favoring the NAC cohort.	('improvement', 'PosReg', (203, 214))	('survival', 'MPA', (104, 112))	('EORTC', 'Chemical', '-', (32, 37))	('death', 'Disease', 'MESH:D003643', (226, 231))	('cisplatin/methotrexate', 'Var', (160, 182))	('a 20', 'Gene', (197, 201))	('death', 'Disease', (226, 231))	('NAC', 'cellular_component', 'GO:0005854', ('246', '249'))	('methotrexate', 'Chemical', 'MESH:D008727', (170, 182))	('cisplatin', 'Chemical', 'MESH:D002945', (160, 169))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('NAC', 'Chemical', '-', (246, 249))	('doxorubicin', 'Chemical', 'MESH:D004317', (145, 156))	('a 20', 'Gene', '28935', (197, 201))
48739	22273550	These data have been corroborated by a meta-analysis performed by the Advanced Bladder Cancer Meta Analysis Collaboration who documented a 5% absolute overall survival benefit conferred to those patients receiving cisplatin-based NAC compared to those not receiving chemotherapy.	('Advanced Bladder Cancer', 'Disease', 'MESH:D001749', (70, 93))	('NAC', 'Chemical', '-', (230, 233))	('NAC', 'cellular_component', 'GO:0005854', ('230', '233'))	('cisplatin', 'Chemical', 'MESH:D002945', (214, 223))	('patients', 'Species', '9606', (195, 203))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (79, 93))	('Advanced Bladder Cancer', 'Disease', (70, 93))	('cisplatin-based', 'Var', (214, 229))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))
48828	16901344	However, telomeric DNA is lost at each cell division as a result of the inability of DNA polymerases to replicate the 5' end of linear DNA, and erosion of these sequences beyond a critical point is thought to signal cell cycle arrest and entry into cellular senescence.	('inability', 'NegReg', (72, 81))	('arrest', 'Disease', 'MESH:D006323', (227, 233))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('216', '233'))	('cellular senescence', 'CPA', (249, 268))	('cell division', 'biological_process', 'GO:0051301', ('39', '52'))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('arrest', 'Disease', (227, 233))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (216, 233))	('signal', 'Reg', (209, 215))	('cellular senescence', 'biological_process', 'GO:0090398', ('249', '268'))	('erosion', 'Var', (144, 151))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
48829	16901344	A close association between the activation of the telomerase enzyme and cellular immortality has been established, and the presence of functional telomerase enables cells to be capable of extended proliferation or to become immortal, and in concordance with this hypothesis, telomerase activity has been detected in the great majority of malignant tumor specimens tested.	('malignant tumor', 'Disease', (338, 353))	('activation', 'PosReg', (32, 42))	('cellular immortality', 'CPA', (72, 92))	('immortal', 'CPA', (224, 232))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('presence', 'Var', (123, 131))	('extended proliferation', 'CPA', (188, 210))	('malignant tumor', 'Disease', 'MESH:D018198', (338, 353))	('telomerase activity', 'molecular_function', 'GO:0003720', ('275', '294'))
48924	31685958	To analyze mosaicism on a large scale, we surveyed haplotype-specific somatic copy number alterations (sCNAs) in 1,708 normal-appearing adjacent-to-tumor (NAT) tissue samples from 27 cancer sites and in 7,149 blood samples from The Cancer Genome Atlas.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Disease', (183, 189))	('copy', 'Var', (78, 82))	('Cancer', 'Disease', 'MESH:D009369', (232, 238))	('Cancer', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Disease', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('Cancer', 'Disease', (232, 238))
48926	31685958	These results shed light on pan-tissue mutations characteristic of field cancerization, the presence of oncogenic processes adjacent to cancer cells.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (39, 48))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
48928	31685958	Genetic profiling of tumors has revealed cancer-site-specific and pan-cancer patterns of somatic mutations.	('mutations', 'Var', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
48929	31685958	The largest studies of mosaicism in healthy tissue have surveyed existing blood genotype data and have revealed positive associations between blood mosaicism and age, and between blood mosaicism and incidence of hematological cancers.	('hematological cancers', 'Disease', 'MESH:D009369', (212, 233))	('hematological cancers', 'Disease', (212, 233))	('age', 'Gene', '5973', (162, 165))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('blood mosaicism', 'Var', (142, 157))	('age', 'Gene', (162, 165))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
48930	31685958	Surveys of the somatic mutational landscape of blood and non-blood tissues have revealed that healthy individuals harbor mutations in cancer-driver genes.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mutations', 'Var', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (134, 140))
48931	31685958	Mosaicism has been implicated in other non-cancer chronic conditions, emphasizing the need for comprehensive surveys of mosaicism across human tissues.	('human', 'Species', '9606', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('Mosaicism', 'Var', (0, 9))	('implicated', 'Reg', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
48945	31685958	The mosaicism rates of NAT tissues were different across cancer sites with BRCA, HNSC and KIRC reaching statistical significance after multiple testing correction (P < 0.05, binomial test; Supplementary Table 3).	('mosaicism', 'Var', (4, 13))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('BRCA', 'Phenotype', 'HP:0003002', (75, 79))	('BRCA', 'Gene', '672', (75, 79))	('different', 'Reg', (40, 49))	('BRCA', 'Gene', (75, 79))
48949	31685958	Alterations on 1q and 9q were the most frequent in NAT tissues, whereas 13q and 20q were the most frequent in blood.	('frequent', 'Reg', (39, 47))	('Alterations', 'Var', (0, 11))	('13q', 'Chemical', '-', (72, 75))
48952	31685958	Deletions on 13q, which were common in blood, were not observed in NAT tissues; instead, 13q sCNAs in NAT tissues were primarily gains, with no observed losses (Fig.	('13q', 'Chemical', '-', (13, 16))	('13q', 'Chemical', '-', (89, 92))	('gains', 'PosReg', (129, 134))	('13q', 'Var', (89, 92))	('Deletions', 'Var', (0, 9))
48960	31685958	HNSC had a pronounced enrichment for 9q sCNAs in NAT tissues (adjusted P = 1 x 10-7; Bonferroni correction for five cancer sites), BLCA for 9p (adjusted P = 0.01), BRCA for 1q (adjusted P = 3 x 10-5) and STAD had an enrichment for chromosome 20 gains (adjusted = 0.02) (Fig.	('BRCA', 'Gene', (164, 168))	('cancer', 'Disease', (116, 122))	('gains', 'PosReg', (245, 250))	('chromosome', 'Var', (231, 241))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('9q sCNAs', 'Var', (37, 45))	('chromosome', 'cellular_component', 'GO:0005694', ('231', '241'))	('BRCA', 'Phenotype', 'HP:0003002', (164, 168))	('BRCA', 'Gene', '672', (164, 168))
48968	31685958	In blood, we also observe the previously reported association of age with sCNAs in chromosome X (P = 1.5 x 10-5, LR).	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))	('age', 'Gene', (65, 68))	('association', 'Interaction', (50, 61))	('sCNAs in chromosome', 'Var', (74, 93))	('age', 'Gene', '5973', (65, 68))
48969	31685958	The TCGA dataset allowed us to examine these associations in NAT tissues, where the presence of sCNAs in autosomes is marginally associated with age (P = 0.10, LR, adjusting for sex and cancer site), and the presence of sCNAs in chromosome X does not show an association (P = 0.30, LR, adjusting for cancer site).	('associated', 'Reg', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('age', 'Gene', (145, 148))	('age', 'Gene', '5973', (145, 148))	('presence', 'Var', (84, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('229', '239'))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', (300, 306))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
48982	31685958	For sCNAs in chromosome X, 30% of those detected in blood were concordant (50% overlap) with tumor as compared to 54% for NAT tissues; this difference bordered on significance (P = 0.06, chi2 test).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('sCNAs in chromosome', 'Var', (4, 23))	('tumor', 'Disease', (93, 98))	('chromosome', 'cellular_component', 'GO:0005694', ('13', '23'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
48986	31685958	We did not observe an association between sCNAs in NAT tissues and mutational burden or microsatellite instability in the adjacent tumors (Supplementary Note 5).	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('microsatellite instability', 'Var', (88, 114))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))
48987	31685958	Directional allelic imbalance comparisons between overlapping sCNA calls from paired NAT and tumor tissues revealed examples of independent mutation (Fig.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('mutation', 'Var', (140, 148))	('imbalance', 'Phenotype', 'HP:0002172', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
48988	31685958	For NAT-tumor samples, these independent mutations include gains of established oncogenes (H3F3A in LUAD; CARD11, EGFR and JAK2 in HNSC; and FLT3 in STAD), as well as two independent losses of APC in the tumor and the NAT tissue from a patient with LUSC (Fig.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('FLT3', 'Gene', (141, 145))	('H3F3A', 'Gene', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('JAK', 'molecular_function', 'GO:0004713', ('123', '126'))	('CARD11', 'Gene', (106, 112))	('NAT-tumor', 'Disease', 'MESH:D009369', (4, 13))	('mutations', 'Var', (41, 50))	('FLT3', 'Gene', '2322', (141, 145))	('APC', 'cellular_component', 'GO:0005680', ('193', '196'))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('CARD11', 'Gene', '84433', (106, 112))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('gains', 'PosReg', (59, 64))	('EGFR', 'Gene', (114, 118))	('patient', 'Species', '9606', (236, 243))	('JAK2', 'Gene', '3717', (123, 127))	('losses', 'NegReg', (183, 189))	('tumor', 'Disease', (8, 13))	('APC', 'Disease', 'MESH:D011125', (193, 196))	('H3F3A', 'Gene', '3020', (91, 96))	('APC', 'Disease', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('JAK2', 'Gene', (123, 127))	('EGFR', 'Gene', '1956', (114, 118))	('tumor', 'Disease', (204, 209))	('NAT-tumor', 'Disease', (4, 13))
48989	31685958	Independent mutations targeting APC, an essential driver of colorectal cancer, have been reported in adenomas of the colon.	('APC', 'Disease', (32, 35))	('reported', 'Reg', (89, 97))	('APC', 'cellular_component', 'GO:0005680', ('32', '35'))	('mutations', 'Var', (12, 21))	('adenomas of the colon', 'Disease', (101, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('adenomas of the colon', 'Disease', 'MESH:D000236', (101, 122))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('APC', 'Disease', 'MESH:D011125', (32, 35))	('colorectal cancer', 'Disease', (60, 77))
48997	31685958	Three truncating FAT1 mutations in NAT tissues were not detected in the adjacent tumor (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('FAT1', 'Gene', '2195', (17, 21))	('mutations', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('FAT1', 'Gene', (17, 21))	('tumor', 'Disease', (81, 86))
48998	31685958	Positive selection of FAT1 mutations has been reported in epithelial tissues from healthy individuals.	('mutations', 'Var', (27, 36))	('FAT1', 'Gene', '2195', (22, 26))	('FAT1', 'Gene', (22, 26))
48999	31685958	Truncating mutations in PPM1D have been reported at a frequency of 0.7% in blood from patients with cancer (solid tumors).	('Truncating mutations', 'Var', (0, 20))	('patients', 'Species', '9606', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PPM1D', 'Gene', (24, 29))	('solid tumors', 'Disease', (108, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('reported', 'Reg', (40, 48))	('solid tumors', 'Disease', 'MESH:D009369', (108, 120))	('PPM1D', 'Gene', '8493', (24, 29))
49000	31685958	We observed that all four NAT tissues with putative HNSC driver mutations (SNVs) that were detected in the adjacent tumor have at least one sCNA (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('HNSC driver', 'Gene', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', (116, 121))
49001	31685958	These shared drivers include a missense PIK3CA SNV recurrent in cancer and truncating mutations in TP53 and CASP8.	('truncating mutations', 'Var', (75, 95))	('TP53', 'Gene', (99, 103))	('missense', 'Var', (31, 39))	('PIK3CA', 'Gene', (40, 46))	('PIK3CA', 'Gene', '5290', (40, 46))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('CASP8', 'Gene', '841', (108, 113))	('CASP8', 'Gene', (108, 113))	('TP53', 'Gene', '7157', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
49018	31685958	We observe these events less than expected, because on average only half of independent sCNAs of the same mutation type would result in mirrored allelic imbalance.	('mutation', 'Var', (106, 114))	('imbalance', 'Phenotype', 'HP:0002172', (153, 162))	('age', 'Gene', (59, 62))	('result in', 'Reg', (126, 135))	('allelic imbalance', 'MPA', (145, 162))	('age', 'Gene', '5973', (59, 62))
49019	31685958	Drivers of such parallel evolution could be extracellular and/or environmental exposures or genetic and epigenetic mutations that are shared among clones at a cancer site.	('cancer', 'Disease', (159, 165))	('extracellular', 'cellular_component', 'GO:0005576', ('44', '57'))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('epigenetic mutations', 'Var', (104, 124))
49022	31685958	Furthermore, studies of human embryonic stem cells have shown a growth advantage for cells with amplifications in chromosome 20q.	('age', 'Gene', (77, 80))	('human', 'Species', '9606', (24, 29))	('chromosome', 'cellular_component', 'GO:0005694', ('114', '124'))	('age', 'Gene', '5973', (77, 80))	('amplifications in chromosome', 'Var', (96, 124))
49024	31685958	Although, their path may be in parallel to that of the adjacent tumor as evidenced by NAT tissues with HNSC-driver mutations that are not detected in the tumor (Supplementary Fig.	('mutations', 'Var', (115, 124))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (154, 159))
49025	31685958	The potential for these clones to develop into secondary tumors may depend on their specific mutational and epigenetic profiles, as recent studies demonstrate that mutations in cancer-driver genes are common in tissues from healthy individuals, for example, a higher frequency of NOTCH1 mutations in normal esophageal tissues relative to esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('age', 'Gene', (312, 315))	('age', 'Gene', (343, 346))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('NOTCH1', 'Gene', '4851', (280, 286))	('NOTCH1', 'Gene', (280, 286))	('secondary tumors', 'Disease', (47, 63))	('secondary tumors', 'Disease', 'MESH:D060085', (47, 63))	('cancer', 'Disease', (349, 355))	('mutations', 'Var', (287, 296))	('age', 'Gene', '5973', (312, 315))	('age', 'Gene', '5973', (343, 346))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))
49026	31685958	NOTCH1 mutations have also been reported in airways that appear to be pathologically normal from patients with lung cancer, as well as premalignant lesions of the lung.	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('patients', 'Species', '9606', (97, 105))	('reported', 'Reg', (32, 40))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('mutations', 'Var', (7, 16))
49028	31685958	For HNSC, we observe that two of 11 NAT samples with 9q sCNAs have NOTCH1 mutations.	('NOTCH1', 'Gene', '4851', (67, 73))	('mutations', 'Var', (74, 83))	('NOTCH1', 'Gene', (67, 73))
49030	31685958	These results suggest that some of the somatic mutations in HNSC NAT tissues are due to clonal expansions that are common in healthy tissues and may not necessarily lead to carcinogenesis.	('carcinogenesis', 'Disease', (173, 187))	('due', 'Reg', (81, 84))	('mutations', 'Var', (47, 56))	('lead to', 'Reg', (165, 172))	('carcinogenesis', 'Disease', 'MESH:D063646', (173, 187))
49031	31685958	It is also possible that some of these somatic mutations are found to be protective against progression toward malignancy, serving as markers of cellular age or exposures.	('age', 'Gene', (154, 157))	('malignancy', 'Disease', 'MESH:D009369', (111, 121))	('mutations', 'Var', (47, 56))	('malignancy', 'Disease', (111, 121))	('age', 'Gene', '5973', (154, 157))
49039	31685958	In comparison to LRR-based methods, hapLOH integrates BAF and haplotype information, thus mitigating the effect of marker-level measurement errors and batch effects, which allowed us to produce a set of high-confidence sCNA calls.	('hapLOH', 'Var', (36, 42))	('BAF', 'Gene', '8815', (54, 57))	('BAF', 'Gene', (54, 57))
49043	31685958	We removed two NAT samples (TCGA-BJ-A28W-11A-11D-A16M-01 and TCGA-BR-6710-11A-01D-1881-01), because tumor samples from these patients had 0 and 1 somatic nucleotide variants, respectively, which is suggestive of possible tumor-NAT sample swaps (https://portal.gdc.cancer.gov/).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('A16M', 'Mutation', 'p.A16M', (49, 53))	('tumor', 'Disease', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('A-01D-1881-01', 'CellLine', 'CVCL:6244', (76, 89))	('A28W', 'SUBSTITUTION', 'None', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('A28W', 'Var', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Disease', (264, 270))	('patients', 'Species', '9606', (125, 133))
49045	31685958	It is noted in Broad GDAC Firehose annotation files that a patient with thyroid carcinoma, TCGA-EL-A3H2, with detectable mosaicism in NAT tissue (TCGA-EL-A3H2-11A-11D-A20A-01) had "received radiation in early childhood to the thyroid unrelated to treatment of any malignancy"; this sample was included.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('malignancy', 'Disease', 'MESH:D009369', (264, 274))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (72, 89))	('malignancy', 'Disease', (264, 274))	('mosaicism', 'Var', (121, 130))	('thyroid carcinoma', 'Disease', (72, 89))	('patient', 'Species', '9606', (59, 66))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (72, 89))
49058	31685958	The average number of heterozygous calls from arrays was tenfold higher than for exome sequences (22,000 heterozygotes).	('higher', 'PosReg', (65, 71))	('age', 'Gene', '5973', (8, 11))	('age', 'Gene', (8, 11))	('arrays', 'Var', (46, 52))
49083	29628290	Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers.	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('TP53', 'Gene', '7157', (89, 93))	('IDH1', 'Gene', '3417', (66, 70))	('CTNNB1', 'Gene', '1499', (49, 55))	('lower', 'NegReg', (42, 47))	('NRAS', 'Gene', (57, 61))	('mutations', 'Var', (16, 25))	('leukocyte levels', 'MPA', (105, 121))	('higher', 'PosReg', (75, 81))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('CTNNB1', 'Gene', (49, 55))	('BRAF', 'Gene', '673', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('BRAF', 'Gene', (83, 87))	('CASP8', 'Gene', '841', (98, 103))	('TP53', 'Gene', (89, 93))	('NRAS', 'Gene', '4893', (57, 61))	('IDH1', 'Gene', (66, 70))	('CASP8', 'Gene', (98, 103))
49084	29628290	Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes.	('tumor', 'Disease', (158, 163))	('transcription', 'biological_process', 'GO:0006351', ('77', '90'))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('extracellular', 'cellular_component', 'GO:0005576', ('53', '66'))	('involved', 'Reg', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('copy number', 'Var', (103, 114))	('intracellular', 'cellular_component', 'GO:0005622', ('35', '48'))
49092	29628290	Antibodies against CTLA-4, PD-1, and PD-L1 are effective in treating a variety of malignancies.	('Antibodies', 'Var', (0, 10))	('PD-L1', 'Gene', (37, 42))	('CTLA-4', 'Gene', '1493', (19, 25))	('malignancies', 'Disease', (82, 94))	('PD-1', 'Gene', (27, 31))	('PD-1', 'Gene', '5133', (27, 31))	('PD-L1', 'Gene', '29126', (37, 42))	('CTLA-4', 'Gene', (19, 25))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))
49107	29628290	The six resulting clusters "Immune Subtypes", C1-C6 (with 2416, 2591, 2397, 1157, 385 and 180 cases, respectively) were characterized by a distinct distribution of scores over the five representative signatures (Figure 1A, bottom panel), and showed distinct immune signatures based on the dominant sample characteristics of their tumor samples (Figure 1B-C).	('C1-C6', 'Var', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('tumor', 'Disease', (330, 335))	('tumor', 'Disease', 'MESH:D009369', (330, 335))
49117	29628290	IDH mutations were enriched in C5 over C4 (80% of IDH mutations, p<2x10-16, Fisher's exact test), suggesting an association of IDH-mutations with favorable immune composition.	('association', 'Interaction', (112, 123))	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (54, 63))	('IDH', 'Gene', (50, 53))	('mutations', 'Var', (4, 13))	('IDH', 'Gene', '3417', (50, 53))
49130	29628290	The spatial fraction of tumor regions with tumor infiltrating lymphocytes (TILs), estimated by analysis of digitized TCGA H&E stained slides, varied by immune subtype, with C2 the highest (p<10-16, Figure 2D).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('with', 'Var', (168, 172))	('H&E', 'Chemical', '-', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
49143	29628290	The immune infiltrate was related to measures of DNA damage, including copy number variation (CNV) burden (both in terms of number of segments and fraction of genome alterations), aneuploidy, loss of heterozygosity (LOH), homologous recombination deficiency (HRD), and intratumor heterogeneity (ITH) (Figure 4A).	('aneuploidy', 'Disease', (180, 190))	('loss of heterozygosity', 'Var', (192, 214))	('homologous recombination', 'biological_process', 'GO:0035825', ('222', '246'))	('copy number variation', 'MPA', (71, 92))	('homologous recombination deficiency', 'Disease', (222, 257))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('HRD', 'Disease', (259, 262))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('aneuploidy', 'Disease', 'MESH:D000782', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('HRD', 'Disease', 'None', (259, 262))	('men', 'Species', '9606', (137, 140))
49144	29628290	LF correlated negatively with CNV segment burden, with strongest correlation in C6 and C2, and positively with aneuploidy, LOH, HRD, and mutation load, particularly in C3.	('HRD', 'Disease', (128, 131))	('LOH', 'Var', (123, 126))	('aneuploidy', 'Disease', (111, 121))	('negatively', 'NegReg', (14, 24))	('HRD', 'Disease', 'None', (128, 131))	('men', 'Species', '9606', (37, 40))	('aneuploidy', 'Disease', 'MESH:D000782', (111, 121))	('CNV segment burden', 'MPA', (30, 48))	('mutation load', 'Var', (137, 150))
49145	29628290	Chromosome 1p (including TNFRS9 and VTCN1) amplification associated with higher LF, while its deletion did the opposite.	('VTCN1', 'Gene', '79679', (36, 41))	('amplification', 'Var', (43, 56))	('TNFRS9', 'Gene', (25, 31))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('VTCN1', 'Gene', (36, 41))	('higher', 'PosReg', (73, 79))
49147	29628290	Amplification of chr2, 20q, and 22q (including CTLA4, CD40, and ADORA2 respectively), and deletions of 5q, 9p, and chr19 (including IL13 and IL4, IFNA1 and IFNA2, and ICAM1 respectively) associated with changes in macrophage polarity (Figure S4A).	('macrophage polarity', 'CPA', (214, 233))	('IL13', 'molecular_function', 'GO:0005144', ('132', '136'))	('IFNA1', 'Gene', '3439', (146, 151))	('ADORA2', 'Gene', (64, 70))	('chr19', 'Gene', (115, 120))	('CTLA4', 'Gene', (47, 52))	('chr2', 'Gene', (17, 21))	('IL13', 'Gene', (132, 136))	('ICAM1', 'Gene', (167, 172))	('deletions', 'Var', (90, 99))	('ICAM1', 'Gene', '3383', (167, 172))	('IL4', 'molecular_function', 'GO:0005136', ('141', '144'))	('IFNA2', 'Gene', (156, 161))	('CD40', 'Gene', (54, 58))	('IFNA2', 'Gene', '3440', (156, 161))	('associated', 'Reg', (187, 197))	('changes', 'Reg', (203, 210))	('ADORA2', 'Gene', '135', (64, 70))	('IFNA1', 'Gene', (146, 151))	('CD40', 'Gene', '958', (54, 58))	('IL4', 'Gene', '3565', (141, 144))	('IL4', 'Gene', (141, 144))	('IL13', 'Gene', '3596', (132, 136))	('CTLA4', 'Gene', '1493', (47, 52))
49148	29628290	IL-13 influences macrophage polarization, implying a possible basis for our observation that IL13 deletions associated with altered M0 macrophage fractions.	('IL-13', 'Gene', '3596', (0, 5))	('macrophage polarization', 'biological_process', 'GO:0042116', ('17', '40'))	('influences', 'Reg', (6, 16))	('IL13', 'Gene', (93, 97))	('IL13', 'Gene', '3596', (93, 97))	('IL13', 'molecular_function', 'GO:0005144', ('93', '97'))	('IL-13', 'molecular_function', 'GO:0005144', ('0', '5'))	('macrophage polarization', 'CPA', (17, 40))	('IL-13', 'Gene', (0, 5))	('deletions', 'Var', (98, 107))
49151	29628290	We correlated mutations in 299 cancer driver genes with immune subtypes, and found 33 significant associations (q<0.1) (Figure 4C, Table S2).	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('associations', 'Interaction', (98, 110))	('cancer', 'Disease', (31, 37))	('mutations', 'Var', (14, 23))
49152	29628290	C1 was enriched in mutations in driver genes, such as TP53, PIK3CA, PTEN or KRAS.	('PIK3CA', 'Gene', (60, 66))	('KRAS', 'Gene', (76, 80))	('PIK3CA', 'Gene', '5290', (60, 66))	('mutations', 'Var', (19, 28))	('KRAS', 'Gene', '3845', (76, 80))	('PTEN', 'Gene', (68, 72))	('TP53', 'Gene', '7157', (54, 58))	('PTEN', 'Gene', '5728', (68, 72))	('TP53', 'Gene', (54, 58))
49154	29628290	C3 was enriched in BRAF, CDH1 and PBRM1 mutations, a finding of note since patients with PBRM1 mutations respond particularly well to IM therapy.	('BRAF', 'Gene', '673', (19, 23))	('CDH1', 'Gene', '999', (25, 29))	('BRAF', 'Gene', (19, 23))	('PBRM1', 'Gene', (89, 94))	('PBRM1', 'Gene', (34, 39))	('PBRM1', 'Gene', '55193', (89, 94))	('PBRM1', 'Gene', '55193', (34, 39))	('patients', 'Species', '9606', (75, 83))	('mutations', 'Var', (40, 49))	('mutations', 'Var', (95, 104))	('CDH1', 'Gene', (25, 29))
49155	29628290	C4 was enriched in CTNNB1, EGFR, and IDH1 mutations.	('CTNNB1', 'Gene', (19, 25))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('IDH1', 'Gene', (37, 41))	('CTNNB1', 'Gene', '1499', (19, 25))	('IDH1', 'Gene', '3417', (37, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('mutations', 'Var', (42, 51))
49157	29628290	C6 only showed an enrichment in KRAS G12 mutations.	('mutations', 'Var', (41, 50))	('men', 'Species', '9606', (24, 27))	('KRAS', 'Gene', (32, 36))	('KRAS', 'Gene', '3845', (32, 36))
49158	29628290	Mutations in 23 driver genes associated with increased LF either in specific tumor types or across them, including TP53, HLA-B, BRAF, PTEN, NF1, APC and CASP8.	('tumor type', 'Disease', (77, 87))	('CASP8', 'Gene', (153, 158))	('PTEN', 'Gene', '5728', (134, 138))	('APC', 'cellular_component', 'GO:0005680', ('145', '148'))	('HLA-B', 'Gene', '3106', (121, 126))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (115, 119))	('tumor type', 'Disease', 'MESH:D009369', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('NF1', 'Gene', '4763', (140, 143))	('NF1', 'Gene', (140, 143))	('APC', 'Disease', 'MESH:D011125', (145, 148))	('APC', 'Disease', (145, 148))	('HLA-B', 'Gene', (121, 126))	('TP53', 'Gene', '7157', (115, 119))	('BRAF', 'Gene', '673', (128, 132))	('CASP8', 'Gene', '841', (153, 158))	('PTEN', 'Gene', (134, 138))	('BRAF', 'Gene', (128, 132))
49159	29628290	Twelve other events were associated with lower LF, including the IDH1 R132H mutation, GATA3, KRAS, NRAS, CTNNB1 and NOTCH1 (Figure 4D).	('IDH1', 'Gene', '3417', (65, 69))	('GATA3', 'Gene', (86, 91))	('R132H', 'Var', (70, 75))	('KRAS', 'Gene', (93, 97))	('NOTCH1', 'Gene', '4851', (116, 122))	('NOTCH1', 'Gene', (116, 122))	('R132H', 'Mutation', 'rs121913500', (70, 75))	('GATA3', 'Gene', '2625', (86, 91))	('lower', 'NegReg', (41, 46))	('KRAS', 'Gene', '3845', (93, 97))	('CTNNB1', 'Gene', '1499', (105, 111))	('NRAS', 'Gene', (99, 103))	('NRAS', 'Gene', '4893', (99, 103))	('IDH1', 'Gene', (65, 69))	('CTNNB1', 'Gene', (105, 111))
49161	29628290	PI3K, NOTCH and RTK/RAS pathway disruptions showed variable, tumor type specific effects on immune factors, while TGF-beta pathway disruptions more consistently associated with lower LF (most prominently in C2 and C6; Figure S4C), higher eosinophils (C2), and increased macrophages.	('lower', 'NegReg', (177, 182))	('TGF-beta', 'Gene', '7040', (114, 122))	('disruptions', 'Var', (131, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('RTK/RAS pathway', 'Gene', (16, 31))	('disruptions', 'Var', (32, 43))	('increased', 'PosReg', (260, 269))	('eosinophils', 'MPA', (238, 249))	('higher', 'PosReg', (231, 237))	('TGF-beta', 'Gene', (114, 122))	('tumor type', 'Disease', (61, 71))	('eosin', 'Chemical', 'MESH:D004801', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor type', 'Disease', 'MESH:D009369', (61, 71))	('macrophages', 'CPA', (270, 281))
49163	29628290	Thus, TGF-beta pathway disruption has context-dependent effects on LF, but may promote increased macrophages, particularly M1.	('TGF-beta', 'Gene', (6, 14))	('disruption', 'Var', (23, 33))	('promote increased', 'PosReg', (79, 96))	('macrophages', 'CPA', (97, 108))	('TGF-beta', 'Gene', '7040', (6, 14))
49169	29628290	No single cis-eQTL significantly correlated with PD-L1 expression, although the SNP rs822337, approximately 1KB upstream of CD274 transcription start, correlated weakly (p=0.074;1.3x10-4 unadjusted; Figure S4G).	('CD274', 'Gene', (124, 129))	('PD-L1', 'Gene', '29126', (49, 54))	('transcription', 'biological_process', 'GO:0006351', ('130', '143'))	('CD274', 'Gene', '29126', (124, 129))	('rs822337', 'Var', (84, 92))	('PD-L1', 'Gene', (49, 54))	('rs822337', 'Mutation', 'rs822337', (84, 92))
49170	29628290	Lymphocyte fractions tended to be lower in people of Asian ancestry, particularly in UCEC and BLCA (Figure S4H).	('BLCA', 'Disease', (94, 98))	('lower', 'NegReg', (34, 39))	('Asian ancestry', 'Var', (53, 67))	('Lymphocyte fractions', 'CPA', (0, 20))	('UCEC', 'Disease', (85, 89))	('BLCA', 'Chemical', '-', (94, 98))	('people', 'Species', '9606', (43, 49))
49171	29628290	Peptides predicted to bind with MHC proteins (pMHCs) and induce antitumor adaptive immunity were identified from SNV and indel mutations.	('tumor', 'Disease', (68, 73))	('MHC proteins', 'Protein', (32, 44))	('indel mutations', 'Var', (121, 136))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('bind', 'Interaction', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('induce', 'PosReg', (57, 63))
49173	29628290	Neoantigen load also associated with higher content of CD8 T cells, M1 macrophages, and CD4 memory T cells, and lower Tregs, mast, dendritic, and memory B cells in multiple tumor types (Figure S4K).	('content', 'MPA', (44, 51))	('CD8', 'Gene', '925', (55, 58))	('memory', 'biological_process', 'GO:0007613', ('146', '152'))	('higher', 'PosReg', (37, 43))	('CD4 memory T cells', 'CPA', (88, 106))	('tumor type', 'Disease', (173, 183))	('memory', 'biological_process', 'GO:0007613', ('92', '98'))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor type', 'Disease', 'MESH:D009369', (173, 183))	('CD8', 'Gene', (55, 58))	('Neoantigen', 'Var', (0, 10))	('multiple tumor', 'Disease', 'MESH:D009369', (164, 178))	('multiple tumor', 'Disease', (164, 178))	('Tregs', 'CPA', (118, 123))	('lower', 'NegReg', (112, 117))
49181	29628290	In a regression model of all tumors, high load of each virus type associated with immune features (Figure S5C, cancer-type adjusted).	('tumors', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('immune', 'Disease', (82, 88))	('associated', 'Reg', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('high load', 'Var', (37, 46))
49200	29628290	CD40 (Figure 6C), IL10 and IDO1, inversely correlated with gene expression, suggesting epigenetic silencing.	('IL10', 'Gene', (18, 22))	('CD40', 'Gene', (0, 4))	('IDO1', 'Gene', (27, 31))	('IL10', 'molecular_function', 'GO:0005141', ('18', '22'))	('IL10', 'Gene', '3586', (18, 22))	('correlated', 'Reg', (43, 53))	('gene expression', 'MPA', (59, 74))	('epigenetic silencing', 'Var', (87, 107))	('IDO1', 'Gene', '3620', (27, 31))	('gene expression', 'biological_process', 'GO:0010467', ('59', '74'))	('IDO', 'molecular_function', 'GO:0033754', ('27', '30'))	('CD40', 'Gene', '958', (0, 4))	('IDO', 'molecular_function', 'GO:0047719', ('27', '30'))
49203	29628290	In particular, IMs SLAMF7, SELP, TNFSF4 (OX40L), IL10, and CD40 were amplified less frequently in C5 relative to all samples, while TGFB1, KIR2DL1, and KIR2DL3 deletions were enriched in C5 (Figure 6D), consistent with our observation of lower immune infiltration with TGFB1 deletion (Figure S4A).	('CD40', 'Gene', (59, 63))	('IL10', 'Gene', '3586', (49, 53))	('IL10', 'molecular_function', 'GO:0005141', ('49', '53'))	('TGFB1', 'Gene', '7040', (269, 274))	('TGFB1', 'Gene', (269, 274))	('SELP', 'Gene', '6403', (27, 31))	('CD40', 'Gene', '958', (59, 63))	('TNFSF4', 'Gene', '7292', (33, 39))	('SELP', 'Gene', (27, 31))	('TGFB1', 'Gene', '7040', (132, 137))	('deletion', 'Var', (275, 283))	('KIR2DL1', 'Gene', '3802', (139, 146))	('TGFB1', 'Gene', (132, 137))	('OX40L', 'Gene', (41, 46))	('KIR2DL3', 'Gene', (152, 159))	('TNFSF4', 'Gene', (33, 39))	('KIR2DL3', 'Gene', '3804', (152, 159))	('lower', 'NegReg', (238, 243))	('IL10', 'Gene', (49, 53))	('SLAMF7', 'Gene', '57823', (19, 25))	('KIR2DL1', 'Gene', (139, 146))	('OX40L', 'Gene', '7292', (41, 46))	('SLAMF7', 'Gene', (19, 25))
49217	29628290	Some T cell associated ligands were subtype specific, such as CD276 (C2, C6), IL1B (C6), and VEGFB (C4).	('cell associated', 'cellular_component', 'GO:0009986', ('7', '22'))	('IL1', 'molecular_function', 'GO:0005149', ('78', '81'))	('VEGFB', 'Gene', '7423', (93, 98))	('IL1B', 'Gene', (78, 82))	('VEGFB', 'Gene', (93, 98))	('IL1B', 'Gene', '3553', (78, 82))	('CD276', 'Var', (62, 67))
49222	29628290	Somatic alterations in AKAP9, HRAS, KRAS and PREX2 were inferred to modulate the activity of IMs according to both the MR- and SYGNAL-PanImmune, a significant overlap (p=1.6x10-7, Fisher's exact test).	('HRAS', 'Gene', (30, 34))	('PREX2', 'Gene', (45, 50))	('alterations', 'Var', (8, 19))	('KRAS', 'Gene', (36, 40))	('modulate', 'Reg', (68, 76))	('KRAS', 'Gene', '3845', (36, 40))	('AKAP9', 'Gene', '10142', (23, 28))	('activity', 'MPA', (81, 89))	('AKAP9', 'Gene', (23, 28))	('HRAS', 'Gene', '3265', (30, 34))	('PREX2', 'Gene', '80243', (45, 50))
49227	29628290	Conversely, causal mutations shared across tumor types may associate with different tumor-specific downstream regulators.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mutations', 'Var', (19, 28))	('tumor type', 'Disease', (43, 53))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor type', 'Disease', 'MESH:D009369', (43, 53))	('tumor', 'Disease', (43, 48))	('associate', 'Reg', (59, 68))
49232	29628290	C3 was regulated by KLF15 and miR-141-3p.	('KLF15', 'Gene', (20, 25))	('miR-141-3p', 'Var', (30, 40))	('KLF15', 'Gene', '28999', (20, 25))
49252	29628290	For example, KRAS mutations were enriched in C1 and but infrequent in C5, suggesting that mutations in driver oncogenes alter pathways that affect immune cells.	('mutations', 'Var', (90, 99))	('alter', 'Reg', (120, 125))	('pathways', 'Pathway', (126, 134))	('affect', 'Reg', (140, 146))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('mutations', 'Var', (18, 27))
49253	29628290	Driver mutations such as TP53, by inducing genomic instability, may alter the immune landscape via the generation of neoantigens.	('TP53', 'Gene', (25, 29))	('inducing', 'Reg', (34, 42))	('alter', 'Reg', (68, 73))	('genomic instability', 'MPA', (43, 62))	('immune landscape', 'MPA', (78, 94))	('TP53', 'Gene', '7157', (25, 29))	('neoantigens', 'MPA', (117, 128))	('mutations', 'Var', (7, 16))
49254	29628290	Our findings confirmed previous work showing that mutations in BRAF enhance the immune infiltrate while those in IDH1 diminish it.	('diminish', 'NegReg', (118, 126))	('immune infiltrate', 'CPA', (80, 97))	('IDH1', 'Gene', (113, 117))	('mutations', 'Var', (50, 59))	('IDH1', 'Gene', '3417', (113, 117))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (63, 67))	('enhance', 'PosReg', (68, 75))
49262	29628290	Predicted intracellular networks implied that seven immune related TFs(including interferon and STAT-family transcription factors) may play an active role in transcriptional events related to leukocyte infiltration, and that mutations in six genes (including Ras-family proteins) may influence immune infiltration.	('influence', 'Reg', (284, 293))	('mutations', 'Var', (225, 234))	('STAT', 'Disease', (96, 100))	('immune infiltration', 'CPA', (294, 313))	('intracellular', 'cellular_component', 'GO:0005622', ('10', '23'))	('STAT', 'Disease', 'None', (96, 100))	('transcription', 'biological_process', 'GO:0006351', ('108', '121'))
49330	29628290	Comparing functional annotations of these clusters, we found that overlap to be reflected in the concordant distribution of mean scores of IFN-gamma, TGF-beta, mutation load and overall leukocyte infiltrate among the overlapping clusters.	('IFN-gamma', 'Gene', '3458', (139, 148))	('IFN-gamma', 'Gene', (139, 148))	('TGF-beta', 'Gene', '7040', (150, 158))	('mutation load', 'Var', (160, 173))	('TGF-beta', 'Gene', (150, 158))
49359	29628290	All clonality calls for quantifying intratumoral heterogeneity (ITH) were also determined by ABSOLUTE, which models tumor copy number alterations and mutations as mixtures of subclonal and clonal components of varying ploidy.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutations', 'Var', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (116, 121))
49361	29628290	Scores for copy number burden, aneuploidy, loss of heterozygosity, and homologous recombination deficiency (HRD) were derived.	('aneuploidy', 'Disease', (31, 41))	('aneuploidy', 'Disease', 'MESH:D000782', (31, 41))	('homologous recombination', 'biological_process', 'GO:0035825', ('71', '95'))	('HRD', 'Disease', 'None', (108, 111))	('copy number burden', 'Var', (11, 29))	('loss of heterozygosity', 'Var', (43, 65))	('HRD', 'Disease', (108, 111))
49362	29628290	Copy number burden scores frac_altered and n_segs ("fraction altered", and "number of segments", respectively) represent the fraction of bases deviating from baseline ploidy (defined as above 0.1 or below - 0.1 in log2 relative copy number (CN) space), and the total number of segments in each sample's copy number profile, respectively.	('men', 'Species', '9606', (89, 92))	('deviating', 'NegReg', (143, 152))	('frac_altered', 'Var', (26, 38))	('men', 'Species', '9606', (280, 283))
49363	29628290	LOH_n_seg and LOH_frac_altered are the number of segments with LOH events and fraction of bases with LOH events, respectively.	('LOH_n_seg', 'Var', (0, 9))	('men', 'Species', '9606', (52, 55))	('LOH_frac_altered', 'Var', (14, 30))
49364	29628290	HRD score is a measure quantifying defects in homologous recombination that sums 3 separate metrics of genomic scarring: large (>15 Mb) non-arm-level regions with LOH, large-scale state transitions (breaks between adjacent segments of >10 Mb), and subtelomeric regions with allelic imbalance.	('imbalance', 'Phenotype', 'HP:0002172', (282, 291))	('HRD', 'Disease', 'None', (0, 3))	('scarring', 'Phenotype', 'HP:0100699', (111, 119))	('homologous recombination', 'biological_process', 'GO:0035825', ('46', '70'))	('defects', 'Var', (35, 42))	('HRD', 'Disease', (0, 3))	('LOH', 'NegReg', (163, 166))	('men', 'Species', '9606', (226, 229))
49365	29628290	Aneuploidy scores were calculated as the sum total of amplified or deleted (collectively "altered") arms.	('deleted', 'Var', (67, 74))	('Aneuploidy', 'Disease', 'MESH:D000782', (0, 10))	('Aneuploidy', 'Disease', (0, 10))
49366	29628290	To call arm alterations, sample chromosome arms were first stratified by sample tumor type, type of alteration being tested (amplification or deletion), and chromosome arm (1p, 1q, etc.).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('alterations', 'Var', (12, 23))	('tumor type', 'Disease', 'MESH:D009369', (80, 90))	('tumor type', 'Disease', (80, 90))	('deletion', 'Var', (142, 150))	('chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))	('chromosome', 'cellular_component', 'GO:0005694', ('157', '167'))
49372	29628290	Furthermore, for each gene, we similarly computed significances of differences of CIBERSORT-estimated relative immune cell subtype levels from their expected levels first in "amplified" and then in "deleted" samples in order to identify the effects of copy number amplification and deletion respectively on immune infiltrate composition while controlling for cancer disease type.	('cancer disease', 'Disease', 'MESH:D009369', (359, 373))	('deletion', 'Var', (282, 290))	('effects', 'Reg', (241, 248))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('cancer disease', 'Disease', (359, 373))	('copy number amplification', 'Var', (252, 277))
49373	29628290	Contributors: Galen Gao, Andrew Cherniack We focused our analysis on genes identified as drivers by the TCGA PanCancer Atlas Driver Mutation Working Group (the CGAT list; TCGA Research Network, "Comprehensive Discovery and Characterization of Driver Genes and Mutations in Human Cancers", unpublished data) that were identified as 1) having 10 or more mutations overall and 2) mutated in two or more tissues.	('CGAT', 'Gene', (160, 164))	('Human', 'Species', '9606', (273, 278))	('Cancer', 'Disease', 'MESH:D009369', (112, 118))	('Cancer', 'Disease', (112, 118))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (352, 361))	('Cancer', 'Phenotype', 'HP:0002664', (279, 285))	('Cancers', 'Disease', (279, 286))	('Cancer', 'Disease', (279, 285))	('Cancers', 'Disease', 'MESH:D009369', (279, 286))	('Cancers', 'Phenotype', 'HP:0002664', (279, 286))	('Cancer', 'Disease', 'MESH:D009369', (279, 285))	('CGAT', 'Gene', '6570', (160, 164))
49376	29628290	Contributor: Eduard Porta Pardo We used domainXplorer to identify driver genes and mutations that correlate with the leukocyte fraction of the tumor sample.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
49377	29628290	The algorithm uses a linear model that takes into account potential biases caused by differences in the immune responses between the tissues of origin of the tumors, the gender of the patient, the total number of missense mutations in the sample or the patient's age as covariates.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('patient', 'Species', '9606', (253, 260))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('missense mutations', 'Var', (213, 231))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('patient', 'Species', '9606', (184, 191))
49381	29628290	For each pathway, samples from each of 30 tumor types were divided into two groups of altered and intact cases based on acquisition of non-silent or frameshift mutations, heterozygous or homozygous deletions, or amplifications, in at least one member of the pathway.	('tumor type', 'Disease', (42, 52))	('amplifications', 'Var', (212, 226))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor type', 'Disease', 'MESH:D009369', (42, 52))
49391	29628290	To perform association analyses with single nucleotide polymorphisms (SNPs) at the PDL1 locus, we imputed the genotype data using the Haplotype Reference Consortium as a reference.	('PDL1', 'Gene', '29126', (83, 87))	('single nucleotide polymorphisms', 'Var', (37, 68))	('PDL1', 'Gene', (83, 87))
49400	29628290	Variation in sequencing coverage and tumor purity require careful consideration in order to mitigate the risk of impacting mutation calls and on pMHC, and prior to pMHC calling, sequencing data was subjected to rigorous harmonization efforts, performed by the PanCancer MC3 Consortium.	('Cancer', 'Disease', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('impacting', 'Reg', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('Cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mutation calls', 'Var', (123, 137))	('Cancer', 'Disease', 'MESH:D009369', (263, 269))
49427	29628290	Using output from a PanCan GISTIC2.0 run on ISAR-corrected Affymetrix genome-wide human SNP6.0 array data, deep amplifications, shallow amplifications, non-alterations, shallow deletions, and deep deletions of each immunomodulator gene were called as described in "Genomic Correlations with Immune Phenotype" above for 8461 tumors that both were immune subtyped and had ABSOLUTE purity and ploidy calls.	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('non-alterations', 'Var', (152, 167))	('human', 'Species', '9606', (82, 87))	('tumors', 'Disease', (324, 330))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('shallow deletions', 'Var', (169, 186))	('tumors', 'Disease', 'MESH:D009369', (324, 330))	('deep deletions', 'Var', (192, 206))	('shallow amplifications', 'Var', (128, 150))
49443	29628290	Mutation or copy-number events identified by the domainXplorer algorithm were tested for statistical association with the 32 cMRs identified, using the DIGGIT algorithm (above), and retained if associated with one or more of the 32 cMRs in at least one tumor-specific context.	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (253, 258))	('copy-number', 'Var', (12, 23))
49475	29625051	Transcriptional and epigenetic dysregulation of cancer cells frequently leads to oncogenic de-differentiation and acquisition of stemness features by altering core signaling pathways that regulate the phenotypes of normal stem cells.	('altering', 'Reg', (150, 158))	('core signaling pathways', 'Pathway', (159, 182))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('epigenetic dysregulation', 'Var', (20, 44))	('core', 'cellular_component', 'GO:0019013', ('159', '163'))	('acquisition', 'CPA', (114, 125))	('stemness features', 'CPA', (129, 146))	('oncogenic de-differentiation', 'CPA', (81, 109))	('leads to', 'Reg', (72, 80))	('dysregulation', 'Var', (31, 44))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))
49515	29625051	This result could arise from a high frequency of IDH1/2 mutations and resulting DNA hypermethylation.	('DNA hypermethylation', 'MPA', (80, 100))	('mutations', 'Var', (56, 65))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('IDH1/2', 'Gene', '3417;3418', (49, 55))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('80', '100'))	('IDH1/2', 'Gene', (49, 55))
49518	29625051	BRCA samples with high mRNAsi were more likely to be ER-negative, and enriched for FAT3 and TP53 mutations.	('mutations', 'Var', (97, 106))	('BRCA', 'Gene', (0, 4))	('FAT3', 'Gene', (83, 87))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('FAT3', 'Gene', '120114', (83, 87))	('BRCA', 'Gene', '672', (0, 4))
49527	29625051	High mRNAsi was associated with higher expression of miR-181c-3p, miR-22-3p, and miR-30b-3p (Figure 3B, right bottom).	('miR-22-3p', 'Gene', '407008', (66, 75))	('higher', 'PosReg', (32, 38))	('miR-30b-3p', 'Var', (81, 91))	('miR-181c-3p', 'Var', (53, 64))	('expression', 'MPA', (39, 49))	('miR-22-3p', 'Gene', (66, 75))
49528	29625051	We found a strong association between high mDNAsi, high pathologic grade and recently published molecular subtypes of glioma (Figure 3C).	('glioma', 'Disease', (118, 124))	('high', 'Var', (38, 42))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('mole', 'Phenotype', 'HP:0003764', (96, 100))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
49529	29625051	mDNAsi was low in less aggressive gliomas that are characterized by codel and G-CIMP-high features and was highest in highly aggressive GBMs characterized by IDH mutations (G-CIMP-low) and poor clinical outcome.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('IDH', 'Gene', '3417', (158, 161))	('mutations', 'Var', (162, 171))	('aggressive gliomas', 'Disease', 'MESH:D005910', (23, 41))	('less', 'Disease', (18, 22))	('G-CIMP', 'Chemical', '-', (173, 179))	('low', 'NegReg', (11, 14))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('aggressive gliomas', 'Disease', (23, 41))	('G-CIMP', 'Chemical', '-', (78, 84))	('IDH', 'Gene', (158, 161))	('highest', 'Reg', (107, 114))
49530	29625051	Also, high mDNAsi is strongly associated with more aggressive classical and mesenchymal subtypes of GBM, suggesting that it can stratify tumors with distinct clinical outcomes.	('associated', 'Reg', (30, 40))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('GBM', 'Disease', (100, 103))	('high', 'Var', (6, 10))	('mDNAsi', 'Gene', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
49531	29625051	We also found that high mDNAsi was associated with mutations in NF1 and EGFR and infrequent mutations in IDH1, TP53, CIC, and ATRX (Figure 3C, left), with higher expression of ANNEXIN-A1 protein and lower expression of ANNEXIN-A7, and with expression of the miR-200 family (Figure 3C, right bottom).	('mutations', 'Var', (51, 60))	('EGFR', 'Gene', '1956', (72, 76))	('ATRX', 'Gene', (126, 130))	('mDNAsi', 'Disease', (24, 30))	('NF1', 'Gene', (64, 67))	('IDH1', 'Gene', '3417', (105, 109))	('ATRX', 'Gene', '546', (126, 130))	('ANNEXIN-A7', 'Gene', '310', (219, 229))	('TP53', 'Gene', '7157', (111, 115))	('CIC', 'Gene', (117, 120))	('ANNEXIN-A7', 'Gene', (219, 229))	('higher', 'PosReg', (155, 161))	('ANNEXIN-A1', 'Gene', (176, 186))	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('lower', 'NegReg', (199, 204))	('EGFR', 'Gene', (72, 76))	('expression', 'MPA', (205, 215))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('ANNEXIN-A1', 'Gene', '301', (176, 186))	('IDH1', 'Gene', (105, 109))	('TP53', 'Gene', (111, 115))	('expression', 'MPA', (162, 172))	('NF1', 'Gene', '4763', (64, 67))
49534	29625051	IDH1 mutations are known to reduce cell differentiation, and high values of the mRNAsi in a subset of IDH mutant gliomas might capture this phenomenon.	('IDH', 'Gene', '3417', (102, 105))	('mutant', 'Var', (106, 112))	('IDH', 'Gene', (0, 3))	('mRNAsi', 'MPA', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('cell differentiation', 'CPA', (35, 55))	('cell differentiation', 'biological_process', 'GO:0030154', ('35', '55'))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (5, 14))	('gliomas', 'Disease', (113, 120))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('reduce', 'NegReg', (28, 34))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('IDH1', 'Gene', (0, 4))	('IDH', 'Gene', (102, 105))	('IDH1', 'Gene', '3417', (0, 4))
49537	29625051	The most salient associations of mRNAsi and mDNAsi are presented in Figure 4, while the following results of the comprehensive analyses are shown in the supplementary material: associations with mutations (Figure S3), associations with miRNA expression and protein abundance (Figure S4), associations with the tumor grading and clinical outcome (Figure S5).	('protein', 'cellular_component', 'GO:0003675', ('257', '264'))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('miRNA expression', 'MPA', (236, 252))	('tumor', 'Disease', (310, 315))	('mutations', 'Var', (195, 204))	('protein abundance', 'MPA', (257, 274))	('associations', 'Interaction', (218, 230))	('associations', 'Interaction', (288, 300))	('associations', 'Interaction', (177, 189))
49538	29625051	We found a strong association between mDNAsi and known molecular subtypes, somatic mutations in SETD2 and TP53 genes, and with tobacco smoking status in LUAD (Figures 4A and S3).	('mutations', 'Var', (83, 92))	('tobacco', 'Species', '4097', (127, 134))	('mDNAsi', 'Disease', (38, 44))	('SETD2', 'Gene', '29072', (96, 101))	('mole', 'Phenotype', 'HP:0003764', (55, 59))	('SETD2', 'Gene', (96, 101))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
49545	29625051	Analyses of HNSC samples revealed that high indices are correlated with NSD1 mutation, E-cadherin protein expression, miR-200-3p, and previously identified classical molecular subtypes (Figure 4B).	('NSD1', 'Gene', '64324', (72, 76))	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', '999', (87, 97))	('mole', 'Phenotype', 'HP:0003764', (166, 170))	('mutation', 'Var', (77, 85))	('miR-200-3p', 'Var', (118, 128))	('expression', 'MPA', (106, 116))	('NSD1', 'Gene', (72, 76))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('cadherin', 'molecular_function', 'GO:0008014', ('89', '97'))
49546	29625051	NSD1 mutation was recently linked in HNSC tumors to blockade of cellular differentiation and promotion of oncogenesis.	('cellular differentiation', 'CPA', (64, 88))	('NSD1', 'Gene', (0, 4))	('linked', 'Reg', (27, 33))	('oncogenesis', 'biological_process', 'GO:0007048', ('106', '117'))	('promotion', 'PosReg', (93, 102))	('oncogenesis', 'CPA', (106, 117))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('HNSC tumors', 'Disease', 'MESH:D009369', (37, 48))	('blockade', 'NegReg', (52, 60))	('mutation', 'Var', (5, 13))	('NSD1', 'Gene', '64324', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('HNSC tumors', 'Disease', (37, 48))
49555	29625051	Detailed analyses of ACC samples revealed an association between high mRNAsi and defined molecular subtypes, clinical stage, and mutations in PRKAR1A and TP53 genes (Figure 4D).	('TP53', 'Gene', (154, 158))	('ACC', 'Gene', (21, 24))	('PRKAR1A', 'Gene', '5573', (142, 149))	('mutations', 'Var', (129, 138))	('ACC', 'Gene', '31', (21, 24))	('mole', 'Phenotype', 'HP:0003764', (89, 93))	('PRKAR1A', 'Gene', (142, 149))	('TP53', 'Gene', '7157', (154, 158))
49562	29625051	Roughly 80% of LGG tumors carry an IDH1/2 mutation and, as demonstrated by our group and others, tconfers a genome-wide hypermethylator phenotype (G-CIMP).	('IDH1/2', 'Gene', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('LGG tumors', 'Disease', (15, 25))	('IDH1/2', 'Gene', '3417;3418', (35, 41))	('mutation', 'Var', (42, 50))	('hypermethylator', 'MPA', (120, 135))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('LGG tumors', 'Disease', 'MESH:D009369', (15, 25))	('G-CIMP', 'Chemical', '-', (147, 153))
49565	29625051	Compared to G-CIMP-high tumors, G-CIMP-low tumors are known to be more proliferative, express cell-cycle-related genes, and have various stem cell-like genomic features.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('G-CIMP-low', 'Var', (32, 42))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('G-CIMP', 'Chemical', '-', (12, 18))	('proliferative', 'CPA', (71, 84))	('G-CIMP', 'Chemical', '-', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cell-cycle', 'biological_process', 'GO:0007049', ('94', '104'))	('more', 'PosReg', (66, 70))	('cell-cycle-related', 'Gene', (94, 112))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
49620	29625051	High mRNAsi was associated with basal breast carcinomas but also Her2 and lumB subtypes that are more aggressive than the hormone-dependent lumA group.	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('associated', 'Reg', (16, 26))	('Her2', 'Gene', '2064', (65, 69))	('lumA', 'Gene', (140, 144))	('breast carcinomas', 'Disease', 'MESH:D001943', (38, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('breast carcinomas', 'Disease', (38, 55))	('High mRNAsi', 'Var', (0, 11))	('breast carcinomas', 'Phenotype', 'HP:0003002', (38, 55))	('lumB', 'Disease', (74, 78))	('Her2', 'Gene', (65, 69))	('lumA', 'Gene', '79188', (140, 144))
49621	29625051	In contrast, high mDNAsi was strongly associated with high-grade glioblastomas, poor overall and progression-free survival.	('mDNAsi', 'Gene', (18, 24))	('associated', 'Reg', (38, 48))	('poor', 'NegReg', (80, 84))	('high', 'Var', (13, 17))	('glioblastomas', 'Phenotype', 'HP:0012174', (65, 78))	('glioblastomas', 'Disease', 'MESH:D005909', (65, 78))	('glioblastomas', 'Disease', (65, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))
49623	29625051	Dedifferentiated cells can arise from different sources: from long-lived stem or progenitor cells that accumulate mutations in oncogenic pathways, or via dedifferentiation from non-stem cancer cells that convert to CSCs through deregulation of developmental and/or non-developmental pathways.	('deregulation', 'Reg', (228, 240))	('dedifferentiation', 'biological_process', 'GO:0043696', ('154', '171'))	('mutations', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('oncogenic pathways', 'Pathway', (127, 145))	('developmental and/or', 'Pathway', (244, 264))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
49629	29625051	Cancer cells in many primary solid tumors are basically epithelial regardless of their degrees of dedifferentiation, but some cells in such contexts could acquire mesenchymal characteristics, either by accumulating additional mutations or by undergoing epigenetic changes shaped by the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('accumulating', 'PosReg', (202, 214))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('solid tumors', 'Disease', 'MESH:D009369', (29, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('undergoing', 'Reg', (242, 252))	('mutations', 'Var', (226, 235))	('mesenchymal characteristics', 'CPA', (163, 190))	('acquire', 'PosReg', (155, 162))	('dedifferentiation', 'biological_process', 'GO:0043696', ('98', '115'))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('solid tumors', 'Disease', (29, 41))	('epigenetic changes', 'Var', (253, 271))
49669	29625051	Additionally, we downloaded independent, non-TCGA datasets of gliomas [ (GSE36245, GSE36278) and (GSE30339)] and BRCA samples (GSE59000) and applied our metrics to measure the stemness in the validation data.	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('GSE59000', 'Var', (127, 135))	('BRCA', 'Gene', '672', (113, 117))	('GSE30339)]', 'Var', (98, 108))	('gliomas', 'Disease', (62, 69))	('BRCA', 'Gene', (113, 117))	('GSE36278', 'Var', (83, 91))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
49673	29625051	To eliminate somatic tissue-specific probes, we removed probes that were consistently methylated (standard deviation beta value > 0.05) in non-tumor adult tissues available through TCGA.	('non-tumor', 'Disease', 'MESH:D009369', (139, 148))	('methylated', 'Var', (86, 96))	('non-tumor', 'Disease', (139, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
49725	27697976	A meta-analysis including 9 trials of 2,820 patients with non-muscle-invasive bladder cancer reported that mitomycin C was superior to BCG without maintenance in preventing recurrence, but inferior to BCG in trials with maintenance.	('non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (58, 85))	('patients', 'Species', '9606', (44, 52))	('bladder cancer', 'Phenotype', 'HP:0009725', (78, 92))	('BCG', 'Species', '33892', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('invasive bladder', 'Phenotype', 'HP:0100645', (69, 85))	('mitomycin C', 'Chemical', 'MESH:D016685', (107, 118))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (62, 92))	('muscle-invasive bladder cancer', 'Disease', (62, 92))	('mitomycin', 'Var', (107, 116))	('BCG', 'Species', '33892', (201, 204))
49772	27697976	In a meta-analysis of 11 trials involving 3,005 patients, cisplatin-based neoadjuvant chemotherapy was associated with improved 5-year OS and disease-free survival (DFS) (5% and 9% absolute improvement, respectively).	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('men', 'Species', '9606', (197, 200))	('disease-free survival', 'CPA', (142, 163))	('cisplatin-based', 'Var', (58, 73))	('improved', 'PosReg', (119, 127))	('patients', 'Species', '9606', (48, 56))
49780	27697976	An additional neoadjuvant clinical trial of ddMVAC with bevacizumab reported 5-year survival outcomes of 63% and 64% (OS and disease-specific survival, respectively; median follow-up, 49 months), with pT0N0 and less than or equal to pT1N0 downstaging rates of 38% and 53%, respectively.	('downstaging', 'NegReg', (239, 250))	('pT0N0', 'Var', (201, 206))	('bevacizumab', 'Chemical', 'MESH:D000068258', (56, 67))	('ddMVAC', 'Chemical', '-', (44, 50))
49797	27697976	The NCCN Bladder Cancer Panel strengthened the recommendations for neoadjuvant chemotherapy for patients with cT2, cT3, and cT4a bladder cancer, and for adjuvant chemotherapy for patients with pT3 or pT4 disease or positive nodes (see BL-4 and BL-5, pages 1217 and 1218).	('cT2', 'Gene', (110, 113))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (9, 23))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('NCCN Bladder Cancer', 'Disease', 'MESH:D001749', (4, 23))	('cT2', 'Gene', '30848', (110, 113))	('cT3', 'Gene', '285782', (115, 118))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('cT4a', 'Var', (124, 128))	('men', 'Species', '9606', (52, 55))	('bladder cancer', 'Disease', 'MESH:D001749', (129, 143))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('NCCN Bladder Cancer', 'Disease', (4, 23))	('bladder cancer', 'Disease', (129, 143))	('cT3', 'Gene', (115, 118))	('pT3', 'Gene', '7694', (193, 196))	('patients', 'Species', '9606', (179, 187))	('patients', 'Species', '9606', (96, 104))	('pT3', 'Gene', (193, 196))
49824	27697976	A higher progression-free survival was seen in patients with positive PD-L1 tumor cells versus patients that did not express PD-L1 (58.3% vs 16.6% at 24 weeks), although some patients who were PD-L1-negative did experience a response to treatment.	('higher', 'PosReg', (2, 8))	('PD-L1', 'Gene', '29126', (70, 75))	('positive', 'Var', (61, 69))	('PD-L1', 'Gene', (193, 198))	('patients', 'Species', '9606', (95, 103))	('PD-L1', 'Gene', '29126', (125, 130))	('PD-L1 tumor', 'Disease', 'MESH:D010300', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('patients', 'Species', '9606', (47, 55))	('PD-L1', 'Gene', '29126', (193, 198))	('men', 'Species', '9606', (242, 245))	('patients', 'Species', '9606', (175, 183))	('progression-free survival', 'CPA', (9, 34))	('PD-L1', 'Gene', (125, 130))	('PD-L1 tumor', 'Disease', (70, 81))	('PD-L1', 'Gene', (70, 75))
49860	32903763	CCND1 Amplification Contributes to Immunosuppression and Is Associated With a Poor Prognosis to Immune Checkpoint Inhibitors in Solid Tumors Cyclin D1 (CCND1) amplification relevant to malignant biological behavior exists in solid tumors.	('Tumors', 'Phenotype', 'HP:0002664', (134, 140))	('Amplification', 'Var', (6, 19))	('Contributes', 'Reg', (20, 31))	('CCND1', 'Gene', '595', (152, 157))	('Tumor', 'Phenotype', 'HP:0002664', (134, 139))	('CCND1', 'Gene', '595', (0, 5))	('CCND1', 'Gene', (152, 157))	('Immunosuppression', 'MPA', (35, 52))	('Tumors', 'Disease', (134, 140))	('CCND1', 'Gene', (0, 5))	('solid tumors', 'Disease', (225, 237))	('Cyclin D1', 'Gene', '595', (141, 150))	('Cyclin D1', 'Gene', (141, 150))	('Tumors', 'Disease', 'MESH:D009369', (134, 140))	('amplification', 'Var', (159, 172))	('solid tumors', 'Disease', 'MESH:D009369', (225, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('Cyclin', 'molecular_function', 'GO:0016538', ('141', '147'))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))
49861	32903763	The prevalence and utility of CCND1 amplification as a biomarker for the clinical response to treatment with immune checkpoint inhibitors (ICIs) are unknown.	('amplification', 'Var', (36, 49))	('CCND1', 'Gene', (30, 35))	('CCND1', 'Gene', '595', (30, 35))
49862	32903763	Our study is a preliminary investigation mainly focused on the predictive function of CCND1 amplification in the tumor microenvironment (TME) in the aspect of genome and transcriptome.	('CCND1', 'Gene', (86, 91))	('tumor', 'Disease', (113, 118))	('CCND1', 'Gene', '595', (86, 91))	('amplification', 'Var', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
49864	32903763	Comprehensive profiling was performed to determine the prevalence of CCND1 amplification and the correlation with the prognosis and the response to ICIs.	('amplification', 'Var', (75, 88))	('CCND1', 'Gene', (69, 74))	('CCND1', 'Gene', '595', (69, 74))
49865	32903763	A CCND1 amplification occurs in many cancer types and correlates with shorter overall survival and inferior outcomes with ICI therapy.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('amplification', 'Var', (8, 21))	('shorter', 'NegReg', (70, 77))	('CCND1', 'Gene', (2, 7))	('overall survival', 'MPA', (78, 94))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('CCND1', 'Gene', '595', (2, 7))
49867	32903763	The gene set enrichment analysis suggested that CCND1 amplification correlates with multiple aggressive, immunosuppressive hallmarks including epithelial-mesenchymal transition, transforming growth factor (TGF)-beta signaling, KRAS signaling, phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, p53 pathway, and hypoxia signaling in solid tumors.	('hypoxia', 'Disease', (345, 352))	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('KRAS', 'Gene', '3845', (227, 231))	('transforming growth factor (TGF)-beta', 'Gene', '7039', (178, 215))	('AKT', 'Gene', (276, 279))	('solid tumors', 'Disease', 'MESH:D009369', (366, 378))	('tumors', 'Phenotype', 'HP:0002664', (372, 378))	('p53', 'Gene', (328, 331))	('hypoxia', 'Disease', 'MESH:D000860', (345, 352))	('phosphoinositide 3-kinase', 'Gene', (243, 268))	('KRAS', 'Gene', (227, 231))	('CCND1', 'Gene', '595', (48, 53))	('correlates', 'Reg', (68, 78))	('mTOR', 'Gene', (311, 315))	('CCND1', 'Gene', (48, 53))	('mammalian target of rapamycin', 'Gene', '2475', (280, 309))	('epithelial-mesenchymal transition', 'CPA', (143, 176))	('AKT', 'Gene', '207', (276, 279))	('mTOR', 'Gene', '2475', (311, 315))	('mammalian target of rapamycin', 'Gene', (280, 309))	('amplification', 'Var', (54, 67))	('solid tumors', 'Disease', (366, 378))	('p53', 'Gene', '7157', (328, 331))	('phosphoinositide 3-kinase', 'Gene', '5295', (243, 268))
49868	32903763	These findings indicate that CCND1 amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs.	('amplification', 'Var', (35, 48))	('hinders', 'NegReg', (146, 153))	('CCND1', 'Gene', (29, 34))	('ICIs', 'CPA', (222, 226))	('malignancy hallmarks', 'Disease', (117, 137))	('malignancy hallmarks', 'Disease', 'MESH:D009369', (117, 137))	('CCND1', 'Gene', '595', (29, 34))
49875	32903763	Recently, several studies revealed that CCND1 amplification associates with a negative response to ICIs.	('negative', 'NegReg', (78, 86))	('response to ICIs', 'MPA', (87, 103))	('amplification', 'Var', (46, 59))	('CCND1', 'Gene', (40, 45))	('CCND1', 'Gene', '595', (40, 45))
49879	32903763	Although there are currently few reported cases, the clinical phenomena suggest the potential value of CCND1 amplification as a biomarker for predicting negative therapeutic effects of ICIs.	('amplification', 'Var', (109, 122))	('CCND1', 'Gene', (103, 108))	('CCND1', 'Gene', '595', (103, 108))
49880	32903763	We hypothesized that CCND1 amplification may be associated with poor clinical benefits of ICI therapy through suppressing the antitumor immunity in TME.	('amplification', 'Var', (27, 40))	('CCND1', 'Gene', '595', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('suppressing', 'NegReg', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('CCND1', 'Gene', (21, 26))	('tumor', 'Disease', (130, 135))
49881	32903763	We mainly focused on the predictive function of CCND1 amplification in the TME in the aspect of genome and transcriptome.	('CCND1', 'Gene', (48, 53))	('amplification', 'Var', (54, 67))	('CCND1', 'Gene', '595', (48, 53))
49883	32903763	Importantly, we aimed to explore whether CCND1 amplification correlates with a poor response to ICIs in solid tumors, for which the potential mechanism may be correlated with events within the TME.	('CCND1', 'Gene', '595', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('solid tumors', 'Disease', (104, 116))	('amplification', 'Var', (47, 60))	('CCND1', 'Gene', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
49887	32903763	Specifically, for the CCND1 gene, samples with chromosome 11q13.3 alterations were further reviewed for CNAs.	('CNAs', 'Disease', (104, 108))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('CCND1', 'Gene', (22, 27))	('CCND1', 'Gene', '595', (22, 27))	('alterations', 'Var', (66, 77))
49890	32903763	Survival information and RSEM-normalized gene-level data from cancers with CCND1 amplification frequency ranked first to 10th were further downloaded.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('amplification frequency', 'Var', (81, 104))	('CCND1', 'Gene', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('CCND1', 'Gene', '595', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
49892	32903763	Patients with CCND1 amplification or neutral phenotypes were further analyzed.	('amplification', 'Var', (20, 33))	('Patients', 'Species', '9606', (0, 8))	('CCND1', 'Gene', (14, 19))	('CCND1', 'Gene', '595', (14, 19))
49896	32903763	Survival information from cancers with CCND1 amplification frequency ranked first to 10th was further downloaded.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('CCND1', 'Gene', (39, 44))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('amplification frequency', 'Var', (45, 68))	('CCND1', 'Gene', '595', (39, 44))
49899	32903763	To explore the association between CCND1 amplification and the clinical outcomes of ICIs, we included CNA and clinical data from four clinical cohorts treated with ICIs.	('amplification', 'Var', (41, 54))	('CCND1', 'Gene', (35, 40))	('CCND1', 'Gene', '595', (35, 40))
49907	32903763	Based on the hallmark gene sets, Gene Set Enrichment Analysis (GSEA) software version 3.0 (Broad Institute) was used to identify the different regulated pathways between the CCND1 amplification and neutral groups in the TCGA pan-cancer cohort ( NES  > 1, NOM P-value <0.10, FDR q-value <0.25).	('GSEA', 'Chemical', '-', (63, 67))	('amplification', 'Var', (180, 193))	('CCND1', 'Gene', '595', (174, 179))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('CCND1', 'Gene', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
49913	32903763	Gene expression analysis from the TCGA database showed that CCND1 amplification was significantly related to the upregulation of mRNA expression of CCND1 across the top nine cancer types (TCGA pan-cancer: cancers with CCND1 amplification frequency ranked first to 10th; CHOL was excluded because of the limited number of samples) (Figure 1B).	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('CCND1', 'Gene', (218, 223))	('CCND1', 'Gene', (60, 65))	('CHOL', 'Disease', (270, 274))	('mRNA expression', 'MPA', (129, 144))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('amplification', 'Var', (66, 79))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', (197, 203))	('cancers', 'Disease', (205, 212))	('CCND1', 'Gene', '595', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('CCND1', 'Gene', (148, 153))	('upregulation', 'PosReg', (113, 125))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('CHOL', 'Disease', 'None', (270, 274))	('CCND1', 'Gene', '595', (218, 223))	('CCND1', 'Gene', '595', (60, 65))
49914	32903763	Next, we examined the association of CCND1 amplification with clinical outcome for pan-cancer in the TCGA and MSKCC databases.	('cancer', 'Disease', (87, 93))	('CCND1', 'Gene', (37, 42))	('amplification', 'Var', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CCND1', 'Gene', '595', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
49915	32903763	Kaplan-Meier survival analysis showed that CCND1 amplification was not associated with median OS for pan-cancer in the TCGA database.	('amplification', 'Var', (49, 62))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('CCND1', 'Gene', (43, 48))	('median OS', 'Disease', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('CCND1', 'Gene', '595', (43, 48))
49916	32903763	The median OS for the CCND1 amplification and CCND1 neutral groups was 1,838.0 and 2,133.0 days, respectively [P = 0.1305, HR 1.13 (95% CI 0.96-1.32); Figure 1C].	('CCND1', 'Gene', (46, 51))	('CCND1', 'Gene', (22, 27))	('CCND1', 'Gene', '595', (46, 51))	('CCND1', 'Gene', '595', (22, 27))	('amplification', 'Var', (28, 41))
49920	32903763	For melanoma in the MSKCC database, the median OS for the CCND1 amplification and CCND1 neutral groups was 13.5 months and not reached [P = 0.0139, HR 2.56 (95% CI 0.79-8.29); Figure S1B].	('CCND1', 'Gene', '595', (58, 63))	('amplification', 'Var', (64, 77))	('CCND1', 'Gene', (82, 87))	('CCND1', 'Gene', (58, 63))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('CCND1', 'Gene', '595', (82, 87))	('melanoma', 'Disease', (4, 12))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))
49926	32903763	Based on the impact of CCND1 amplification as a negative prognostic factor for efficacy of ICIs in melanoma, we further investigated its role in patients with a solid tumor.	('patients', 'Species', '9606', (145, 153))	('amplification', 'Var', (29, 42))	('CCND1', 'Gene', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('negative', 'NegReg', (48, 56))	('CCND1', 'Gene', '595', (23, 28))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('tumor', 'Disease', (167, 172))
49927	32903763	To validate CCND1 amplification as a clinical factor associated with poor prognosis in patients with solid tumors treated with ICIs, we performed three analyses.	('solid tumors', 'Disease', 'MESH:D009369', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('CCND1', 'Gene', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('CCND1', 'Gene', '595', (12, 17))	('solid tumors', 'Disease', (101, 113))	('amplification', 'Var', (18, 31))	('patients', 'Species', '9606', (87, 95))
49929	32903763	Fifty-two patients with CCND1 amplification were identified comprising of 14 melanomas, 11 head and neck carcinomas (HNCs), 11 bladder carcinomas, eight non-small-cell lung carcinomas, five breast carcinomas, three esophagogastric carcinomas, and one glioma (Table S3).	('melanomas', 'Disease', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('glioma', 'Disease', 'MESH:D005910', (251, 257))	('amplification', 'Var', (30, 43))	('carcinomas', 'Disease', 'MESH:D009369', (105, 115))	('lung carcinomas', 'Disease', 'MESH:D008175', (168, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Disease', (173, 183))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('carcinomas', 'Disease', (197, 207))	('lung carcinomas', 'Disease', (168, 183))	('carcinomas', 'Disease', 'MESH:D009369', (135, 145))	('CCND1', 'Gene', '595', (24, 29))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('neck carcinomas', 'Disease', 'MESH:D006258', (100, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('head and neck carcinomas', 'Phenotype', 'HP:0012288', (91, 115))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('HNCs', 'Phenotype', 'HP:0012288', (117, 121))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('carcinomas', 'Disease', 'MESH:D009369', (231, 241))	('carcinomas', 'Phenotype', 'HP:0030731', (231, 241))	('breast carcinomas', 'Disease', 'MESH:D001943', (190, 207))	('CCND1', 'Gene', (24, 29))	('breast carcinomas', 'Disease', (190, 207))	('neck carcinomas', 'Disease', (100, 115))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (127, 144))	('carcinomas', 'Disease', 'MESH:D009369', (173, 183))	('esophagogastric', 'Disease', (215, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('carcinomas', 'Disease', 'MESH:D009369', (197, 207))	('carcinomas', 'Phenotype', 'HP:0030731', (197, 207))	('neck', 'cellular_component', 'GO:0044326', ('100', '104'))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (127, 145))	('patients', 'Species', '9606', (10, 18))	('carcinomas', 'Disease', (105, 115))	('breast carcinomas', 'Phenotype', 'HP:0003002', (190, 207))	('bladder carcinomas', 'Disease', 'MESH:D001749', (127, 145))	('breast carcinoma', 'Phenotype', 'HP:0003002', (190, 206))	('small-cell lung carcinomas', 'Phenotype', 'HP:0030357', (157, 183))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('carcinomas', 'Disease', (135, 145))	('non-small-cell lung carcinomas', 'Phenotype', 'HP:0030358', (153, 183))	('carcinomas', 'Disease', (231, 241))	('glioma', 'Disease', (251, 257))	('bladder carcinomas', 'Disease', (127, 145))
49930	32903763	Across the entire cohort, CCND1 amplification was associated with a decreased OS.	('CCND1', 'Gene', (26, 31))	('decreased', 'NegReg', (68, 77))	('amplification', 'Var', (32, 45))	('CCND1', 'Gene', '595', (26, 31))
49931	32903763	The median OS for the CCND1 amplification and CCND1 neutral groups was 11.0 and 18.0 months, respectively [P = 0.0024, HR 1.63 (95% CI 1.09-2.43); Figure 2B].	('CCND1', 'Gene', (46, 51))	('CCND1', 'Gene', (22, 27))	('CCND1', 'Gene', '595', (46, 51))	('CCND1', 'Gene', '595', (22, 27))	('amplification', 'Var', (28, 41))
49932	32903763	We performed a stratified analysis with the melanoma (n = 231) and bladder carcinoma patients (n = 111) and observed a similar association between CCND1 amplification with a shorter OS.	('CCND1', 'Gene', '595', (147, 152))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('amplification', 'Var', (153, 166))	('melanoma', 'Disease', (44, 52))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (67, 84))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('patients', 'Species', '9606', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('bladder carcinoma', 'Disease', 'MESH:D001749', (67, 84))	('CCND1', 'Gene', (147, 152))	('bladder carcinoma', 'Disease', (67, 84))
49933	32903763	In melanoma (n = 231), the median OS for the CCND1 amplification and CCND1 neutral groups was 22.0 and 42.0 months [P = 0.0029, HR 2.48 (95% CI 0.99-6.23); Figure S1D].	('CCND1', 'Gene', (45, 50))	('CCND1', 'Gene', '595', (69, 74))	('CCND1', 'Gene', '595', (45, 50))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('CCND1', 'Gene', (69, 74))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('amplification', 'Var', (51, 64))
49934	32903763	In bladder carcinoma (n = 111), the median OS for the CCND1 amplification and CCND1 neutral groups was 8.0 and 16.0 months, respectively [P = 0.0244, HR 2.17 (95% CI 0.83-5.66); Figure S1E].	('bladder carcinoma', 'Phenotype', 'HP:0002862', (3, 20))	('amplification', 'Var', (60, 73))	('bladder carcinoma', 'Disease', (3, 20))	('bladder carcinoma', 'Disease', 'MESH:D001749', (3, 20))	('CCND1', 'Gene', (78, 83))	('CCND1', 'Gene', (54, 59))	('CCND1', 'Gene', '595', (78, 83))	('CCND1', 'Gene', '595', (54, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
49935	32903763	Recent studies have shown that a high level of TMB associates with improved survival in patients receiving ICIs across a wide variety of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('TMB', 'Chemical', '-', (47, 50))	('high', 'Var', (33, 37))	('survival', 'MPA', (76, 84))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('TMB', 'MPA', (47, 50))	('improved', 'PosReg', (67, 75))
49937	32903763	We compared the TMB between the CCND1 amplification group and the CCND1 neutral group in the MSKCC-IO cohort and found no difference between the two groups.	('CCND1', 'Gene', '595', (66, 71))	('TMB', 'MPA', (16, 19))	('CCND1', 'Gene', (32, 37))	('TMB', 'Chemical', '-', (16, 19))	('CCND1', 'Gene', '595', (32, 37))	('amplification', 'Var', (38, 51))	('CCND1', 'Gene', (66, 71))
49938	32903763	The median TMB for the CCND1 amplification and CCND1 neutral groups was 6.79 vs. 5.90 (P = 0.46; Figure S2).	('amplification', 'Var', (29, 42))	('TMB', 'Chemical', '-', (11, 14))	('CCND1', 'Gene', (23, 28))	('CCND1', 'Gene', (47, 52))	('CCND1', 'Gene', '595', (23, 28))	('CCND1', 'Gene', '595', (47, 52))	('TMB', 'MPA', (11, 14))
49941	32903763	Of note, according to a study by Robert M. Samstein et al., in patients treated with ICIs, there is a significant association between a high level of TMB and a better OS.	('high', 'Var', (136, 140))	('better', 'Disease', (160, 166))	('TMB', 'MPA', (150, 153))	('patients', 'Species', '9606', (63, 71))	('TMB', 'Chemical', '-', (150, 153))
49942	32903763	But in our stratified analysis, in spite of a high level of TMB, patients with CCND1 amplification have a significantly decreased median OS [10.0 vs. 41.0 months, HR 2.82 (95% CI 1.11-7.20), P = 0.0003; Figure 2D].	('decreased', 'NegReg', (120, 129))	('CCND1', 'Gene', '595', (79, 84))	('median OS', 'MPA', (130, 139))	('amplification', 'Var', (85, 98))	('patients', 'Species', '9606', (65, 73))	('CCND1', 'Gene', (79, 84))	('TMB', 'Chemical', '-', (60, 63))
49943	32903763	Finally, a multivariable analysis using Cox proportional-hazards regression demonstrated that CCND1 amplification was significantly associated with a shorter median OS [HR 1.60 (95% CI 1.16-2.21), P = 0.0040], with adjustment for TMB, cancer type, age, drug class of ICI, and the year of ICI start (Table S4).	('amplification', 'Var', (100, 113))	('TMB', 'Chemical', '-', (230, 233))	('CCND1', 'Gene', (94, 99))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('median OS [', 'MPA', (158, 169))	('CCND1', 'Gene', '595', (94, 99))	('shorter', 'NegReg', (150, 157))
49945	32903763	reported 319 patients with CCND1 amplification and 46 cases received ICIs.	('CCND1', 'Gene', (27, 32))	('amplification', 'Var', (33, 46))	('CCND1', 'Gene', '595', (27, 32))	('patients', 'Species', '9606', (13, 21))
49956	32903763	For example, the median values of B cells (-0.1870 vs. -0.1691, P < 0.001), T cells (-0.2160 vs. -0.1935, P = 0.0090), CD8+ T cells (0.0914 vs. 0.1009, P < 0.001), and DC cells (-0.1810 vs. -0.1465, P = 0.0170) were significantly attenuated in the CCND1 amplification group in breast cancer, while Th2 cells (0.05419 vs. 0.0148, P < 0.001) and MDSCs (0.0051 vs. -0.0198, P = 0.0094) appear upregulated (Figure S4).	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('-0.1870', 'Var', (43, 50))	('CCND1', 'Gene', '595', (248, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('CD8', 'Gene', (119, 122))	('attenuated', 'NegReg', (230, 240))	('breast cancer', 'Disease', (277, 290))	('CD8', 'Gene', '925', (119, 122))	('0.0051 vs. -0.0198', 'Var', (351, 369))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('0.05419', 'Var', (309, 316))	('CCND1', 'Gene', (248, 253))	('upregulated', 'PosReg', (390, 401))	('-0.2160', 'Var', (85, 92))
49957	32903763	The signature of immune cell subsets in HNSCC showed a dramatic decrease in median values of cytotoxic cells (-0.1418 vs. -0.0970, P = 0.0030), T cells (-0.2357 vs. -0.2056, P = 0.0010), CD8+ T cells (0.0730 vs. 0.0761, P = 0.1310), DC cells (-0.2267 vs. -0.1796, P < 0.001), and B cells (-0.1676 vs. -0.1373, P < 0.001), while MDSCs (0.0250 vs. -0.0058, P < 0.001) (Figure S4).	('decrease', 'NegReg', (64, 72))	('-0.1418', 'Var', (110, 117))	('B cells', 'CPA', (280, 287))	('-0.2357', 'Var', (153, 160))	('-0.1676', 'Var', (289, 296))	('DC cells', 'CPA', (233, 241))	('CD8', 'Gene', (187, 190))	('HNSCC', 'Phenotype', 'HP:0012288', (40, 45))	('CD8', 'Gene', '925', (187, 190))	('T cells', 'CPA', (144, 151))	('0.0730 vs. 0.0761', 'Var', (201, 218))
49958	32903763	To investigate signaling pathways activated for CCND1 amplification tumors, we performed GSEA comparing the CCND1 amplification group and the CCND1 neutral group in the TCGA pan-cancer cohort.	('CCND1', 'Gene', (142, 147))	('amplification', 'Var', (114, 127))	('tumors', 'Disease', (68, 74))	('CCND1', 'Gene', (108, 113))	('CCND1', 'Gene', '595', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('CCND1', 'Gene', '595', (142, 147))	('GSEA', 'Chemical', '-', (89, 93))	('CCND1', 'Gene', '595', (108, 113))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CCND1', 'Gene', (48, 53))	('signaling', 'biological_process', 'GO:0023052', ('15', '24'))
49965	32903763	Another study showed that cyclin D1 (encoded by CCND1) may play a key role in the maintenance of VEGFs, and antisense to cyclin D1 could be useful for targeting both cancer cells and blood vessels in tumors.	('cyclin D1', 'Gene', (121, 130))	('antisense', 'Var', (108, 117))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cyclin', 'molecular_function', 'GO:0016538', ('121', '127'))	('CCND1', 'Gene', '595', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cyclin', 'molecular_function', 'GO:0016538', ('26', '32'))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('cyclin D1', 'Gene', '595', (26, 35))	('tumors', 'Disease', (200, 206))	('cyclin D1', 'Gene', (26, 35))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cyclin D1', 'Gene', '595', (121, 130))	('CCND1', 'Gene', (48, 53))
49968	32903763	We found that CCND1 amplification can hinder not only the natural host immune response but also the efficacy of ICIs.	('CCND1', 'Gene', '595', (14, 19))	('immune response', 'biological_process', 'GO:0006955', ('71', '86'))	('hinder', 'NegReg', (38, 44))	('ICIs', 'CPA', (112, 116))	('amplification', 'Var', (20, 33))	('CCND1', 'Gene', (14, 19))
49969	32903763	A CCND1 amplification may potentially identify a patient population that will not benefit from ICIs irrespective of TMB status.	('TMB', 'Chemical', '-', (116, 119))	('amplification', 'Var', (8, 21))	('CCND1', 'Gene', (2, 7))	('patient', 'Species', '9606', (49, 56))	('CCND1', 'Gene', '595', (2, 7))
49971	32903763	To our knowledge, our results are the first to reveal that a CCND1 amplification may significantly correlate with tumorigenesis and attenuation of various types of effector immune cells in the TME, including cytotoxic cells, T cells, CD8+ T cells, DC cells, and B cells, and upregulation of Treg cells and MDSCs.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('upregulation', 'PosReg', (275, 287))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('amplification', 'Var', (67, 80))	('CCND1', 'Gene', (61, 66))	('Treg cells', 'CPA', (291, 301))	('CD8', 'Gene', (234, 237))	('tumor', 'Disease', (114, 119))	('CD8', 'Gene', '925', (234, 237))	('CCND1', 'Gene', '595', (61, 66))	('attenuation', 'NegReg', (132, 143))
49974	32903763	In our analysis of the TCGA pan-cancer cohort, CCND1 amplification showed a statistically significant correlation with high mRNA expression of TGFB1.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('amplification', 'Var', (53, 66))	('CCND1', 'Gene', (47, 52))	('TGFB1', 'Gene', (143, 148))	('high mRNA expression', 'MPA', (119, 139))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CCND1', 'Gene', '595', (47, 52))	('TGFB1', 'Gene', '7040', (143, 148))
49975	32903763	More importantly, further study showed significant upregulation of mRNA expression of VEGFA, another known factor inducing tumor immune escape and immunotherapy resistance, associated with the CCND1 amplification phenotype.	('upregulation', 'PosReg', (51, 63))	('tumor', 'Disease', (123, 128))	('CCND1', 'Gene', (193, 198))	('amplification phenotype', 'Var', (199, 222))	('VEGFA', 'Gene', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('VEGFA', 'Gene', '7422', (86, 91))	('CCND1', 'Gene', '595', (193, 198))	('mRNA expression', 'MPA', (67, 82))
49976	32903763	From the survival analysis in TCGA and MSKCC public databases, we found no significant correlation between CCND1 amplification with prognosis in the pan-cancer group.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('CCND1', 'Gene', '595', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('amplification', 'Var', (113, 126))	('CCND1', 'Gene', (107, 112))
49981	32903763	Meanwhile, the analysis of the transcriptome showed that the amplification of CCND1 was strongly correlated with higher expression level of mRNA.	('expression level of mRNA', 'MPA', (120, 144))	('higher', 'PosReg', (113, 119))	('CCND1', 'Gene', (78, 83))	('amplification', 'Var', (61, 74))	('CCND1', 'Gene', '595', (78, 83))
49982	32903763	Thirdly, according to our investigation, activations of a variety of oncogenes and deactivations of tumor suppressor genes were observed along with the amplification of CCND1 in different cancer types.	('amplification', 'Var', (152, 165))	('deactivations', 'MPA', (83, 96))	('activations', 'PosReg', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('CCND1', 'Gene', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('tumor', 'Disease', (100, 105))	('CCND1', 'Gene', '595', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('cancer', 'Disease', (188, 194))	('oncogenes', 'Gene', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
49984	32903763	Nevertheless, the CCND1 amplification is a potential predictive biomarker for the use of ICIs in patients with solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('CCND1', 'Gene', '595', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('amplification', 'Var', (24, 37))	('CCND1', 'Gene', (18, 23))	('solid tumors', 'Disease', (111, 123))	('patients', 'Species', '9606', (97, 105))
49985	32903763	In the melanoma pooled cohort, the median OS was shorter in the CCND1 amplification subgroup.	('melanoma', 'Disease', 'MESH:D008545', (7, 15))	('shorter', 'NegReg', (49, 56))	('median OS', 'MPA', (35, 44))	('CCND1', 'Gene', (64, 69))	('CCND1', 'Gene', '595', (64, 69))	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('melanoma', 'Disease', (7, 15))	('amplification', 'Var', (70, 83))
49986	32903763	The survival analysis in the MSKCC-IO cohort further verified the negative impact of CCND1 amplification on the efficacy of ICIs.	('ICIs', 'CPA', (124, 128))	('CCND1', 'Gene', '595', (85, 90))	('amplification', 'Var', (91, 104))	('CCND1', 'Gene', (85, 90))	('negative', 'NegReg', (66, 74))
49987	32903763	Strikingly, by comparing CCND1 amplification with TMB in patients with solid tumors from the MSKCC-IO cohort, we found that the association between CCND1 amplification and a worse clinical outcome was more distinct in TMB-high patients.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('CCND1', 'Gene', (25, 30))	('CCND1', 'Gene', (148, 153))	('solid tumors', 'Disease', (71, 83))	('patients', 'Species', '9606', (57, 65))	('CCND1', 'Gene', '595', (25, 30))	('CCND1', 'Gene', '595', (148, 153))	('patients', 'Species', '9606', (227, 235))	('amplification', 'Var', (154, 167))	('solid tumors', 'Disease', 'MESH:D009369', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TMB', 'Chemical', '-', (50, 53))	('TMB', 'Chemical', '-', (218, 221))	('TMB-high', 'Disease', (218, 226))
49988	32903763	This indicates that ICIs may not be useful, and even harmful, to patients with CCND1 amplification.	('CCND1', 'Gene', '595', (79, 84))	('amplification', 'Var', (85, 98))	('patients', 'Species', '9606', (65, 73))	('CCND1', 'Gene', (79, 84))
49989	32903763	First, various types of effector immune cell exclusion and immunosuppression in the TME were found in tumors with CCND1 amplification.	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('CCND1', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('CCND1', 'Gene', '595', (114, 119))	('amplification', 'Var', (120, 133))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
49990	32903763	Second, CCND1 amplification results in high mRNA expression of TGFB1, VEGFA, and HIF1A; these molecules have direct or indirect negative effects on components of the immune system.	('TGFB1', 'Gene', '7040', (63, 68))	('VEGFA', 'Gene', (70, 75))	('HIF1A', 'Gene', (81, 86))	('CCND1', 'Gene', (8, 13))	('HIF1A', 'Gene', '3091', (81, 86))	('TGFB1', 'Gene', (63, 68))	('mRNA expression', 'MPA', (44, 59))	('negative', 'NegReg', (128, 136))	('VEGFA', 'Gene', '7422', (70, 75))	('CCND1', 'Gene', '595', (8, 13))	('amplification', 'Var', (14, 27))
49991	32903763	Finally, some oncogene pathways are activated in CCND1 amplification tumor that may lead to acceleration of tumor growth.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('amplification', 'Var', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CCND1', 'Gene', '595', (49, 54))	('tumor', 'Disease', (69, 74))	('oncogene pathways', 'Pathway', (14, 31))	('activated', 'PosReg', (36, 45))	('tumor', 'Disease', (108, 113))	('acceleration', 'PosReg', (92, 104))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('CCND1', 'Gene', (49, 54))
49992	32903763	Recently, a study reported on five patients experiencing hyper-progression who had NGS performed on pretreatment tumor tissue, and it confirmed CNAs in MDM2/MDM4, epidermal growth factor receptor (EGFR), and several genes located on 11q13 associated with hyper-progression.	('associated', 'Reg', (239, 249))	('tumor', 'Disease', (113, 118))	('MDM4', 'Gene', (157, 161))	('MDM2', 'Gene', '4193', (152, 156))	('epidermal growth factor receptor', 'Gene', '1956', (163, 195))	('epidermal growth factor receptor', 'Gene', (163, 195))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('EGFR', 'Gene', '1956', (197, 201))	('patients', 'Species', '9606', (35, 43))	('CNAs', 'Var', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('163', '186'))	('MDM4', 'Gene', '4194', (157, 161))	('EGFR', 'Gene', (197, 201))	('EGFR', 'molecular_function', 'GO:0005006', ('197', '201'))	('MDM2', 'Gene', (152, 156))
49994	32903763	Considering the immunosuppression in the TME and overexpression of various oncogenes caused by CCND1 amplification, patients with such features should avoid ICI monotherapy.	('patients', 'Species', '9606', (116, 124))	('CCND1', 'Gene', (95, 100))	('amplification', 'Var', (101, 114))	('CCND1', 'Gene', '595', (95, 100))
49997	32903763	The small number of CCND1 amplification tumors and the rarity of the event suggest that further additional data are warranted.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('amplification', 'Var', (26, 39))	('CCND1', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('CCND1', 'Gene', '595', (20, 25))
49998	32903763	Our study is a preliminary investigation mainly focused on the predictive function of CCND1 amplification in the tumor microenvironment in the aspect of genome and transcriptome.	('CCND1', 'Gene', (86, 91))	('tumor', 'Disease', (113, 118))	('CCND1', 'Gene', '595', (86, 91))	('amplification', 'Var', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
50001	32903763	These findings indicate that CCND1 amplification may be a key point related to immunosuppression in the TME and multiple malignancy hallmark; it may be a common mechanism of resistance to ICIs.	('malignancy hallmark', 'Disease', (121, 140))	('amplification', 'Var', (35, 48))	('malignancy hallmark', 'Disease', 'MESH:D009369', (121, 140))	('CCND1', 'Gene', (29, 34))	('related', 'Reg', (68, 75))	('CCND1', 'Gene', '595', (29, 34))
50029	24318901	Moreover, cisplatin based regimens are associated with substantial toxicities including nephrotoxicity, ototoxicity, neuropathy and treatment related mortality of 1-3 %.	('neuropathy', 'Disease', 'MESH:D009422', (117, 127))	('nephrotoxicity', 'Disease', (88, 102))	('toxicities', 'Disease', (67, 77))	('toxicities', 'Disease', 'MESH:D064420', (67, 77))	('nephrotoxicity', 'Disease', 'MESH:D007674', (88, 102))	('neuropathy', 'Phenotype', 'HP:0009830', (117, 127))	('ototoxicity', 'Disease', (104, 115))	('ototoxicity', 'Disease', 'MESH:D006311', (104, 115))	('cisplatin based', 'Var', (10, 25))	('neuropathy', 'Disease', (117, 127))	('cisplatin', 'Chemical', 'MESH:D002945', (10, 19))
50044	24318901	A Phase III trial in patients with metastatic breast cancer compared nab-paclitaxel at 260 mg/m2 to conventional paclitaxel 175 mg/m2 given every 3 weeks.	('nab-paclitaxel', 'Var', (69, 83))	('paclitaxel', 'Chemical', 'MESH:D017239', (73, 83))	('paclitaxel', 'Chemical', 'MESH:D017239', (113, 123))	('patients', 'Species', '9606', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('nab', 'Chemical', '-', (69, 72))	('breast cancer', 'Disease', (46, 59))
50045	24318901	The overall response rate was significantly higher for nab-paclitaxel than for paclitaxel (33 % v 19 % respectively; P =0.001).	('paclitaxel', 'Chemical', 'MESH:D017239', (79, 89))	('response', 'MPA', (12, 20))	('nab-paclitaxel', 'Var', (55, 69))	('paclitaxel', 'Chemical', 'MESH:D017239', (59, 69))	('higher', 'PosReg', (44, 50))	('nab', 'Chemical', '-', (55, 58))
50046	24318901	Median time to progression was also significantly longer with nab-paclitaxel than with paclitaxel (23.0 v 16.9 weeks, respectively; hazard ratio [HR]=0.75; P =0.006).	('paclitaxel', 'Chemical', 'MESH:D017239', (66, 76))	('paclitaxel', 'Chemical', 'MESH:D017239', (87, 97))	('nab', 'Chemical', '-', (62, 65))	('nab-paclitaxel', 'Var', (62, 76))	('longer', 'PosReg', (50, 56))
50047	24318901	There was a trend towards greater median survival in patients treated with nab-paclitaxel (65.0 v 55.7 weeks, respectively; P =0.374).	('paclitaxel', 'Chemical', 'MESH:D017239', (79, 89))	('patients', 'Species', '9606', (53, 61))	('nab', 'Chemical', '-', (75, 78))	('median survival', 'MPA', (34, 49))	('nab-paclitaxel', 'Var', (75, 89))	('greater', 'PosReg', (26, 33))
50144	24250246	Both in vitro and in vivo studies showed that eIF5A2 could initiate tumor formation, enhance cancer cell growth, and increase cancer cell motility and metastasis by inducing epithelial-mesenchymal transition.	('increase cancer cell motility', 'Disease', (117, 146))	('enhance', 'PosReg', (85, 92))	('tumor', 'Disease', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('increase cancer cell motility', 'Disease', 'MESH:C538614', (117, 146))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('174', '207'))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('epithelial-mesenchymal transition', 'CPA', (174, 207))	('cell motility', 'biological_process', 'GO:0048870', ('133', '146'))	('inducing', 'Reg', (165, 173))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('formation', 'biological_process', 'GO:0009058', ('74', '83'))	('eIF5A2', 'Var', (46, 52))	('cancer', 'Disease', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cell growth', 'biological_process', 'GO:0016049', ('100', '111'))
50148	24250246	Amplification of 3q26.2 is one of the most frequent genetic alternations found in solid tumors.	('Amplification', 'Var', (0, 13))	('solid tumors', 'Disease', (82, 94))	('3q26.2', 'Gene', (17, 23))	('solid tumors', 'Disease', 'MESH:D009369', (82, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
50159	24250246	Our previous studies showed that over-expression of eIF5A2 could initiate tumor formation, promote cancer cell growth and enhance cell invasion/metastasis by inducing epithelial-mesenchymal transition (EMT) both in vitro and in vivo, suggesting it might have an oncogenic role in mammals.	('promote', 'PosReg', (91, 98))	('epithelial-mesenchymal transition', 'CPA', (167, 200))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('over-expression', 'Var', (33, 48))	('inducing', 'Reg', (158, 166))	('cell invasion/metastasis', 'CPA', (130, 154))	('enhance', 'PosReg', (122, 129))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('167', '200'))	('EMT', 'biological_process', 'GO:0001837', ('202', '205'))	('cancer', 'Disease', (99, 105))	('tumor', 'Disease', (74, 79))	('cell growth', 'biological_process', 'GO:0016049', ('106', '117'))	('formation', 'biological_process', 'GO:0009058', ('80', '89'))	('eIF5A2', 'Gene', (52, 58))	('initiate', 'PosReg', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
50168	24250246	The function of the C-terminal domain of eIF5A1 is shown by the finding that the mutation of Ser 149 to Pro in yeast eIF5A1 decreases general protein synthesis by 30% and increases mRNA stability.	('mRNA stability', 'MPA', (181, 195))	('general protein synthesis', 'MPA', (134, 159))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('yeast', 'Species', '4932', (111, 116))	('Ser 149 to Pro', 'Mutation', 'p.S149P', (93, 107))	('decreases', 'NegReg', (124, 133))	('mutation', 'Var', (81, 89))	('protein synthesis', 'biological_process', 'GO:0006412', ('142', '159'))	('Ser', 'cellular_component', 'GO:0005790', ('93', '96'))	('eIF5A1', 'Gene', (117, 123))	('increases', 'PosReg', (171, 180))	('Ser', 'Gene', (93, 96))
50170	24250246	find that both eIF5A isoforms are acetylated at lysine-47, and hypusination of K50 can reduce acetylation in eIF5A2.	('lysine', 'Chemical', 'MESH:D008239', (48, 54))	('eIF5A', 'Gene', (15, 20))	('eIF5A', 'Gene', '1984', (15, 20))	('eIF5A', 'Gene', (109, 114))	('acetylation', 'MPA', (94, 105))	('eIF5A', 'Gene', '1984', (109, 114))	('reduce', 'NegReg', (87, 93))	('hypusination', 'Var', (63, 75))
50172	24250246	The authors further investigated the impact of hypusination and acetylation on the subcellular localization of eIF5A2 via its expression of Flag-tagged eIF5A2 wild type and the mutants in Hela cells.	('eIF5A2', 'Gene', (152, 158))	('investigated', 'Reg', (20, 32))	('localization', 'biological_process', 'GO:0051179', ('95', '107'))	('mutants', 'Var', (177, 184))	('Hela', 'CellLine', 'CVCL:0030', (188, 192))	('eIF5A2', 'Gene', (111, 117))
50191	24250246	In agreement with these observations, our previous studies have shown that over-expression of eIF5A2 in NIH3T3 cells causes cell transformation and that EIF5A2 stably transfected LO2 cells (immortalized human liver cell line) displayed increased colony formation in soft agar and xenograph formation in nude mice.	('formation', 'biological_process', 'GO:0009058', ('290', '299'))	('LO2', 'CellLine', 'CVCL:6926', (179, 182))	('cell transformation', 'CPA', (124, 143))	('human', 'Species', '9606', (203, 208))	('formation', 'biological_process', 'GO:0009058', ('253', '262'))	('NIH3T3', 'CellLine', 'CVCL:0594', (104, 110))	('nude mice', 'Species', '10090', (303, 312))	('EIF5A2', 'Var', (153, 159))	('colony formation in soft agar', 'CPA', (246, 275))	('xenograph formation', 'CPA', (280, 299))	('increased', 'PosReg', (236, 245))	('over-expression', 'PosReg', (75, 90))	('eIF5A2', 'Gene', (94, 100))
50192	24250246	Similarly, the reduction of EIF5A2 in UACC-1598 inhibits cell growth; and the oncogenic ability of EIF5A2 can also be blocked by eIF5A2 silencing.	('UACC-1598', 'CellLine', 'CVCL:4040', (38, 47))	('inhibits', 'NegReg', (48, 56))	('oncogenic ability', 'CPA', (78, 95))	('cell growth', 'CPA', (57, 68))	('UACC-1598', 'Gene', (38, 47))	('reduction', 'NegReg', (15, 24))	('cell growth', 'biological_process', 'GO:0016049', ('57', '68'))	('EIF5A2', 'Gene', (28, 34))	('eIF5A2', 'Gene', (129, 135))	('silencing', 'Var', (136, 145))
50203	24250246	However, despite a lack of changes in Rho-GTPase activity, we also found that eIF5A2 enhances CRC cell invasion/metastasis and EMT mainly by up-regulating MTA1 expression through promoting c-myc, TIP60 and GCN5 binding with MTA1 promoter (Fig 2.).	('CRC', 'Phenotype', 'HP:0030731', (94, 97))	('binding', 'Interaction', (211, 218))	('promoting', 'PosReg', (179, 188))	('EMT', 'biological_process', 'GO:0001837', ('127', '130'))	('binding', 'molecular_function', 'GO:0005488', ('211', '218'))	('c-myc', 'Gene', (189, 194))	('expression', 'MPA', (160, 170))	('MTA1', 'Gene', (155, 159))	('GTPase activity', 'molecular_function', 'GO:0003924', ('42', '57'))	('CRC cell invasion/metastasis', 'CPA', (94, 122))	('TIP60', 'Gene', (196, 201))	('GCN5', 'Gene', (206, 210))	('TIP60', 'Gene', '81601', (196, 201))	('GCN5', 'Gene', '14534', (206, 210))	('eIF5A2', 'Var', (78, 84))	('c-myc', 'Gene', '4609', (189, 194))	('up-regulating', 'PosReg', (141, 154))	('enhances', 'PosReg', (85, 93))	('EMT', 'CPA', (127, 130))
50210	24250246	But aberrant expression of c-myc can also induce apoptosis.	('c-myc', 'Gene', '4609', (27, 32))	('induce', 'Reg', (42, 48))	('c-myc', 'Gene', (27, 32))	('aberrant expression', 'Var', (4, 23))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))	('apoptosis', 'CPA', (49, 58))
50230	24250246	eIF5A is important in protein translation since disruption of the hypusination process by the DHS inhibitor, N1-guanyl- 1,7-diaminoheptane (GC7), has been shown to inhibit the growth of endothelial cells.	('eIF5A', 'Gene', '1984', (0, 5))	('N1-guanyl- 1,7-diaminoheptane', 'Chemical', 'MESH:C100667', (109, 138))	('hypusination process', 'MPA', (66, 86))	('disruption', 'Var', (48, 58))	('inhibit', 'NegReg', (164, 171))	('growth of endothelial cells', 'CPA', (176, 203))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('eIF5A', 'Gene', (0, 5))	('GC7', 'Chemical', '-', (140, 143))	('protein translation', 'biological_process', 'GO:0006412', ('22', '41'))
50231	24250246	Moreover, mutants of eIF5A that cannot be hypusinated induce apoptosis in numerous cancer cell types including colon, cervical, skin, and lung cancer, thus inhibiting the growth of solid tumors.	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('skin', 'Disease', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('solid tumors', 'Disease', (181, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('inhibiting', 'NegReg', (156, 166))	('apoptosis', 'CPA', (61, 70))	('numerous cancer', 'Disease', 'MESH:D009369', (74, 89))	('eIF5A', 'Gene', '1984', (21, 26))	('solid tumors', 'Disease', 'MESH:D009369', (181, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('mutants', 'Var', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cervical', 'Disease', (118, 126))	('colon', 'Disease', (111, 116))	('lung cancer', 'Disease', (138, 149))	('numerous cancer', 'Disease', (74, 89))	('induce', 'Reg', (54, 60))	('eIF5A', 'Gene', (21, 26))
50235	24250246	Our previous study showed that a combined treatment of eIF5A2 siRNA and GC7, an inhibitor of DHS, on HCC cells results in the synergistic inhibition of cell migration.	('inhibition', 'NegReg', (138, 148))	('GC7', 'Chemical', '-', (72, 75))	('HCC', 'Gene', '619501', (101, 104))	('HCC', 'Phenotype', 'HP:0001402', (101, 104))	('inhibition of cell migration', 'biological_process', 'GO:0030336', ('138', '166'))	('eIF5A2', 'Var', (55, 61))	('combined', 'Interaction', (33, 41))	('cell migration', 'CPA', (152, 166))	('HCC', 'Gene', (101, 104))	('GC7', 'Gene', (72, 75))
50239	24250246	In addition, antisense DNA against EIF5A2 or EIF5A2 specific siRNA effectively inhibits tumor cell growth and reduces tumor cells' ability to migrate.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('inhibits', 'NegReg', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('reduces', 'NegReg', (110, 117))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('EIF5A2', 'Gene', (45, 51))	('cell growth', 'biological_process', 'GO:0016049', ('94', '105'))	('EIF5A2', 'Gene', (35, 41))	('antisense', 'Var', (13, 22))	('tumor', 'Disease', (88, 93))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))
50321	32266509	FGFR mutation appeared to act as an adjunct to the prognostication in only High-Grade cancer.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('mutation', 'Var', (5, 13))	('cancer', 'Disease', (86, 92))
50340	32944636	We found that the frequency of single-nucleotide variations (SNVs) in RMC is some of the lowest seen across all cancers.	('single-nucleotide variations', 'Var', (31, 59))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('RMC', 'Disease', (70, 73))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('RMC', 'Chemical', '-', (70, 73))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
50341	32944636	However, RMC is characterized by an abundance of larger structural alterations such as recurrent focal copy number alterations (often in chromosomal fragile sites), gain of chromosome 8q (where c-MYC is located), as well as deletions and inactivating translocations of the SMARCB1 gene.	('gain', 'PosReg', (165, 169))	('inactivating translocations', 'Var', (238, 265))	('chromosome', 'cellular_component', 'GO:0005694', ('173', '183'))	('RMC', 'Disease', (9, 12))	('c-MYC', 'Gene', (194, 199))	('deletions', 'Var', (224, 233))	('SMARCB1', 'Gene', '6598', (273, 280))	('SMARCB1', 'Gene', (273, 280))	('chromosomal fragile sites', 'Phenotype', 'HP:0040012', (137, 162))	('RMC', 'Chemical', '-', (9, 12))	('c-MYC', 'Gene', '4609', (194, 199))
50355	32944636	We noted that RMC does share some commonalities with urothelial carcinomas: 1) RMC profoundly upregulates the cancer-associated long non-coding RNA (lncRNA) urothelial cancer associated 1 (UCA1) to similar levels as those found in UTUC.	('RNA', 'cellular_component', 'GO:0005562', ('144', '147'))	('cancer', 'Disease', (168, 174))	('urothelial cancer associated 1', 'Gene', (157, 187))	('UCA1', 'Gene', '652995', (189, 193))	('UCA1', 'Gene', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('RMC', 'Chemical', '-', (79, 82))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (53, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('urothelial cancer associated 1', 'Gene', '652995', (157, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('upregulates', 'PosReg', (94, 105))	('cancer', 'Disease', (110, 116))	('RMC', 'Chemical', '-', (14, 17))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('RMC', 'Var', (79, 82))	('urothelial carcinomas', 'Disease', (53, 74))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
50357	32944636	2) RMC tumors often harbor NOTCH2 amplifications and concurrent deletions of NOTCH1 and NOTCH3, a distinct pattern associated with increased aggressiveness in the basal subtype of bladder urothelial carcinoma.	('NOTCH2', 'Gene', (27, 33))	('NOTCH3', 'Gene', '4854', (88, 94))	('amplifications', 'Var', (34, 48))	('RMC tumors', 'Disease', (3, 13))	('NOTCH1', 'Gene', '4851', (77, 83))	('NOTCH1', 'Gene', (77, 83))	('aggressiveness', 'Disease', 'MESH:D001523', (141, 155))	('deletions', 'Var', (64, 73))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (180, 208))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('bladder urothelial carcinoma', 'Disease', (180, 208))	('RMC tumors', 'Disease', 'MESH:D009369', (3, 13))	('NOTCH2', 'Gene', '4853', (27, 33))	('aggressiveness', 'Disease', (141, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('NOTCH3', 'Gene', (88, 94))	('aggressiveness', 'Phenotype', 'HP:0000718', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
50512	29997433	Plx and chitosan gels containing MSs showed 1.9 and 1.4 times higher bioadhesive values than their mixture with Tyrode solution.	('Tyrode', 'Chemical', '-', (112, 118))	('higher', 'PosReg', (62, 68))	('chitosan', 'Chemical', 'MESH:D048271', (8, 16))	('bioadhesive values', 'CPA', (69, 87))	('Plx', 'Chemical', 'MESH:D020442', (0, 3))	('MSs', 'Var', (33, 36))
50518	29997433	In addition, viscosity values of Chi gels were decreased with the incorporation of MSs at both 25 C and 37 C+-0.1 C, and these results showed good agreement with literature findings.	('rat', 'Species', '10116', (166, 169))	('incorporation', 'Var', (66, 79))	('viscosity values', 'MPA', (13, 29))	('men', 'Species', '9606', (152, 155))	('MSs', 'Gene', (83, 86))	('rat', 'Species', '10116', (73, 76))	('decreased', 'NegReg', (47, 56))
50559	29997433	RT4 is representative of noninvasive superficial cancer and T24 representative of invasive bladder tumor with a metastatic profile.	('invasive bladder', 'Phenotype', 'HP:0100645', (82, 98))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('invasive bladder tumor', 'Disease', 'MESH:D001749', (82, 104))	('bladder tumor', 'Phenotype', 'HP:0009725', (91, 104))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('invasive bladder tumor', 'Disease', (82, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('T24', 'Var', (60, 63))	('cancer', 'Disease', (49, 55))
50612	29671787	The results of this study showed that galectin-1 knockdown could induce 15 down-regulated proteins and two up-regulated proteins in T24 cells.	('knockdown', 'Var', (49, 58))	('up-regulated', 'PosReg', (107, 119))	('galectin', 'molecular_function', 'GO:0001577', ('38', '46'))	('proteins', 'Protein', (90, 98))	('galectin-1', 'Gene', '3956', (38, 48))	('galectin-1', 'Gene', (38, 48))	('down-regulated', 'NegReg', (75, 89))	('proteins', 'MPA', (120, 128))
50639	29671787	Furthermore, the results of cohort studies showed that dys-regulations of glutamine synthetase and fatty acid binding protein 4 in clinical samples were respectively linked to disease-specific survival and metastasis-free survival in univariate analyses.	('fatty acid binding protein 4', 'Gene', (99, 127))	('glutamine synthetase', 'Gene', '2752', (74, 94))	('clinical samples', 'Species', '191496', (131, 147))	('fatty acid binding protein 4', 'Gene', '2167', (99, 127))	('metastasis-free survival', 'CPA', (206, 230))	('glutamine synthetase', 'Gene', (74, 94))	('fatty acid binding', 'molecular_function', 'GO:0005504', ('99', '117'))	('linked', 'Reg', (166, 172))	('disease-specific survival', 'CPA', (176, 201))	('dys-regulations', 'Var', (55, 70))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
50641	29671787	In this study, we exploited proteomics to find more novel molecular pathways evoked by galectin-1 dysregulation in UBUC cells, which might be related to UBUC carcinogenesis.	('galectin-1', 'Gene', (87, 97))	('dysregulation', 'Var', (98, 111))	('galectin-1', 'Gene', '3956', (87, 97))	('evoked', 'Reg', (77, 83))	('molecular pathways', 'Pathway', (58, 76))	('UBUC carcinogenesis', 'Disease', 'MESH:D063646', (153, 172))	('UBUC carcinogenesis', 'Disease', (153, 172))	('galectin', 'molecular_function', 'GO:0001577', ('87', '95'))
50644	29671787	To prevent the gel-to-gel variation, 11 replica gel pairs were obtained to find those de-regulated proteins provoked by galectin-1 knockdown.	('knockdown', 'Var', (131, 140))	('galectin-1', 'Gene', (120, 130))	('de-regulated', 'NegReg', (86, 98))	('galectin', 'molecular_function', 'GO:0001577', ('120', '128'))	('galectin-1', 'Gene', '3956', (120, 130))	('proteins', 'MPA', (99, 107))
50652	29671787	In this study, our results showed that galectin-1 knockdown in T24 cells could lower FABP 4 protein expression.	('galectin-1', 'Gene', (39, 49))	('FABP 4', 'Gene', (85, 91))	('galectin-1', 'Gene', '3956', (39, 49))	('lower', 'NegReg', (79, 84))	('knockdown', 'Var', (50, 59))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('galectin', 'molecular_function', 'GO:0001577', ('39', '47'))	('FABP 4', 'Gene', '2167', (85, 91))
50658	29671787	The results from western immunoblotting validated the dys-regulated proteins provoked by galectin-1 knockdown in Sh-Gal-1(+120) T24 cells.	('galectin', 'molecular_function', 'GO:0001577', ('89', '97'))	('knockdown', 'Var', (100, 109))	('galectin-1', 'Gene', (89, 99))	('Gal-1', 'Gene', '3956', (116, 121))	('Gal-1', 'Gene', (116, 121))	('galectin-1', 'Gene', '3956', (89, 99))	('dys-regulated proteins', 'MPA', (54, 76))
50664	29671787	In line with our previous results and the above proteomics data, a high galectin-1 expression level was predictive of a shorter metastasis-free survival time (Figure 3d).	('expression level', 'MPA', (83, 99))	('shorter', 'NegReg', (120, 127))	('high', 'Var', (67, 71))	('galectin', 'molecular_function', 'GO:0001577', ('72', '80'))	('metastasis-free survival time', 'CPA', (128, 157))	('high galectin-1', 'Phenotype', 'HP:0032205', (67, 82))	('galectin-1', 'Gene', (72, 82))	('galectin-1', 'Gene', '3956', (72, 82))
50681	29671787	Abnormal FABP 4 functions may disrupt the lipid-mediated biological processes and result in diseases such as diabetes, obesity, and cancer.	('cancer', 'Disease', (132, 138))	('lipid-mediated biological', 'MPA', (42, 67))	('lipid', 'Chemical', 'MESH:D008055', (42, 47))	('FABP 4', 'Gene', '2167', (9, 15))	('obesity', 'Disease', 'MESH:D009765', (119, 126))	('result in', 'Reg', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('diabetes', 'Disease', 'MESH:D003920', (109, 117))	('obesity', 'Disease', (119, 126))	('diabetes', 'Disease', (109, 117))	('Abnormal', 'Var', (0, 8))	('obesity', 'Phenotype', 'HP:0001513', (119, 126))	('disrupt', 'NegReg', (30, 37))	('FABP 4', 'Gene', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
50687	29671787	Our present studies suggested that galectin-1 knockdown reduced FABP 4 expression, likely through modulating PPAR-gamma.	('expression', 'MPA', (71, 81))	('galectin-1', 'Gene', '3956', (35, 45))	('galectin', 'molecular_function', 'GO:0001577', ('35', '43'))	('FABP 4', 'Gene', (64, 70))	('knockdown', 'Var', (46, 55))	('reduced', 'NegReg', (56, 63))	('FABP 4', 'Gene', '2167', (64, 70))	('PPAR-gamma', 'Gene', (109, 119))	('galectin-1', 'Gene', (35, 45))	('modulating', 'Reg', (98, 108))	('PPAR-gamma', 'Gene', '5468', (109, 119))
50700	29671787	Our present data showed that galectin-1 knockdown reduced TOLLIP expression and galectin-1 expression was closely associated with TOLLIP expression in the findings of biopsy samples.	('galectin-1', 'Gene', (29, 39))	('galectin-1', 'Gene', '3956', (80, 90))	('galectin', 'molecular_function', 'GO:0001577', ('29', '37'))	('galectin', 'molecular_function', 'GO:0001577', ('80', '88'))	('galectin-1', 'Gene', '3956', (29, 39))	('knockdown', 'Var', (40, 49))	('TOLLIP', 'Gene', (130, 136))	('TOLLIP', 'Gene', (58, 64))	('associated', 'Reg', (114, 124))	('TOLLIP', 'Gene', '54472', (130, 136))	('reduced', 'NegReg', (50, 57))	('TOLLIP', 'Gene', '54472', (58, 64))	('galectin-1', 'Gene', (80, 90))
50709	29671787	Results in this investigation showed that galectin-1 knockdown decreased STMN 1 expression, suggesting that galectin-1 might control UBUC progression, probably through modulating STMN 1 expression.	('galectin', 'molecular_function', 'GO:0001577', ('108', '116'))	('STMN 1', 'Gene', (179, 185))	('galectin-1', 'Gene', '3956', (108, 118))	('STMN 1', 'Gene', (73, 79))	('UBUC', 'Disease', (133, 137))	('decreased', 'NegReg', (63, 72))	('modulating', 'Reg', (168, 178))	('knockdown', 'Var', (53, 62))	('galectin-1', 'Gene', (42, 52))	('STMN 1', 'Gene', '3925', (179, 185))	('expression', 'MPA', (80, 90))	('expression', 'MPA', (186, 196))	('galectin-1', 'Gene', '3956', (42, 52))	('galectin', 'molecular_function', 'GO:0001577', ('42', '50'))	('control', 'MPA', (125, 132))	('STMN 1', 'Gene', '3925', (73, 79))	('galectin-1', 'Gene', (108, 118))
50717	29671787	(2008) reported that PMF1 methylation is significantly linked to UBUC progression.	('methylation', 'Var', (26, 37))	('PMF1', 'Gene', '11243', (21, 25))	('linked', 'Reg', (55, 61))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('UBUC progression', 'Disease', (65, 81))	('PMF1', 'Gene', (21, 25))
50719	29671787	In conclusion, the results of this study implicated that multi-functional galectin-1 contributed to UBUC carcinogenesis, probably through regulating amino acid/lipid/glucose metabolism, cytoskeleton rearrangement, cellular transcription, cell invasion, and protein degradation.	('protein', 'cellular_component', 'GO:0003675', ('257', '264'))	('contributed', 'Reg', (85, 96))	('cytoskeleton', 'MPA', (186, 198))	('UBUC carcinogenesis', 'Disease', 'MESH:D063646', (100, 119))	('protein degradation', 'biological_process', 'GO:0030163', ('257', '276'))	('glucose metabolism', 'Disease', (166, 184))	('cellular transcription', 'CPA', (214, 236))	('cellular transcription', 'biological_process', 'GO:0006351', ('214', '236'))	('galectin-1', 'Gene', '3956', (74, 84))	('glucose metabolism', 'biological_process', 'GO:0006006', ('166', '184'))	('glucose metabolism', 'Disease', 'MESH:D044882', (166, 184))	('galectin-1', 'Gene', (74, 84))	('galectin', 'molecular_function', 'GO:0001577', ('74', '82'))	('cell invasion', 'CPA', (238, 251))	('regulating', 'Reg', (138, 148))	('lipid', 'Chemical', 'MESH:D008055', (160, 165))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('186', '198'))	('multi-functional', 'Var', (57, 73))	('UBUC carcinogenesis', 'Disease', (100, 119))	('protein degradation', 'CPA', (257, 276))
50753	29671787	After blocking for 1 h in 3% (w/v) bovine albumin serum (BSA) (aMResco, Solon, OH, USA) at room temperature, membranes were probed for 2 h at room temperature with primary antibodies (UBE2K (1:10,000), STMN1 (1:8000), TOLLIP (1:2000), FABP 4 (1:1000), AKR1A1(1:5000), GS (1:500) and actin (1:5000) from Merck Millipore, Darmstadt, Germany; PMF1 (1:1000), SNX9 (1:2000), TRXR1 (1:1000) from Santa Cruz Biotechnology, Dallas, TX, USA).	('AKR1A1', 'Gene', (252, 258))	('bovine', 'Species', '9913', (35, 41))	('UBE2K', 'Gene', (184, 189))	('GS', 'Gene', '2752', (268, 270))	('AKR1A1', 'Gene', '10327', (252, 258))	('STMN1', 'Gene', '3925', (202, 207))	('FABP 4', 'Gene', '2167', (235, 241))	('SNX9', 'Gene', (355, 359))	('1:2000', 'Var', (361, 367))	('FABP 4', 'Gene', (235, 241))	('STMN1', 'Gene', (202, 207))	('TOLLIP', 'Gene', (218, 224))	('SNX9', 'Gene', '51429', (355, 359))	('TOLLIP', 'Gene', '54472', (218, 224))	('PMF1', 'Gene', (340, 344))	('TRXR1', 'Gene', '7296', (370, 375))	('PMF1', 'Gene', '11243', (340, 344))	('UBE2K', 'Gene', '3093', (184, 189))	('TRXR1', 'Gene', (370, 375))
50769	29671787	The results of this study implicated that multi-functional galectin-1 contributed to UBUC carcinogenesis, probably through regulating amino acid/lipid/glucose metabolism, cytoskeleton rearrangement, cellular transcription, cell invasion, and protein degradation.	('contributed', 'Reg', (70, 81))	('cytoskeleton', 'MPA', (171, 183))	('cellular transcription', 'CPA', (199, 221))	('UBUC carcinogenesis', 'Disease', 'MESH:D063646', (85, 104))	('glucose metabolism', 'biological_process', 'GO:0006006', ('151', '169'))	('galectin', 'molecular_function', 'GO:0001577', ('59', '67'))	('galectin-1', 'Gene', '3956', (59, 69))	('lipid', 'Chemical', 'MESH:D008055', (145, 150))	('glucose metabolism', 'Disease', (151, 169))	('galectin-1', 'Gene', (59, 69))	('protein', 'cellular_component', 'GO:0003675', ('242', '249'))	('regulating', 'Reg', (123, 133))	('cell invasion', 'CPA', (223, 236))	('multi-functional', 'Var', (42, 58))	('cellular transcription', 'biological_process', 'GO:0006351', ('199', '221'))	('protein degradation', 'biological_process', 'GO:0030163', ('242', '261'))	('protein degradation', 'CPA', (242, 261))	('UBUC carcinogenesis', 'Disease', (85, 104))	('glucose metabolism', 'Disease', 'MESH:D044882', (151, 169))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('171', '183'))
50778	29670371	Moreover, knockdown of FSIP1 expression suppressed the tumor formation and growth of bladder cancer xenografts (P<0.05).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (85, 99))	('suppressed', 'NegReg', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('bladder cancer', 'Disease', 'MESH:D001749', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', (55, 60))	('FSIP1', 'Gene', (23, 28))	('bladder cancer', 'Disease', (85, 99))	('growth of', 'CPA', (75, 84))	('knockdown', 'Var', (10, 19))	('formation', 'biological_process', 'GO:0009058', ('61', '70'))
50779	29670371	At the gene level, knockdown of FSIP1 expression downregulated the activity of the PI3K/AKT signaling pathway.	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('knockdown', 'Var', (19, 28))	('AKT', 'Gene', '207', (88, 91))	('signaling pathway', 'biological_process', 'GO:0007165', ('92', '109'))	('activity', 'MPA', (67, 75))	('AKT signaling', 'biological_process', 'GO:0043491', ('88', '101'))	('FSIP1', 'Gene', (32, 37))	('downregulated', 'NegReg', (49, 62))	('AKT', 'Gene', (88, 91))
50780	29670371	This study demonstrated that knockdown of FSIP1 suppressed bladder cancer cell malignant behaviors in vitro and in vivo through the inhibition of the PI3K/AKT signaling pathway, suggesting that targeting FSIP1 could be further evaluated as a potential therapeutic strategy in bladder cancer.	('AKT', 'Gene', (155, 158))	('FSIP1', 'Gene', (42, 47))	('knockdown', 'Var', (29, 38))	('inhibition', 'NegReg', (132, 142))	('AKT signaling', 'biological_process', 'GO:0043491', ('155', '168'))	('bladder cancer', 'Disease', 'MESH:D001749', (276, 290))	('bladder cancer', 'Disease', (276, 290))	('bladder cancer', 'Phenotype', 'HP:0009725', (276, 290))	('bladder cancer', 'Phenotype', 'HP:0009725', (59, 73))	('signaling pathway', 'biological_process', 'GO:0007165', ('159', '176'))	('suppressed', 'NegReg', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('PI3K', 'molecular_function', 'GO:0016303', ('150', '154'))	('bladder cancer', 'Disease', 'MESH:D001749', (59, 73))	('AKT', 'Gene', '207', (155, 158))	('bladder cancer', 'Disease', (59, 73))
50805	29670371	The cells were then infected with Lv-FSIP1-shRNA (Group KF) or negative control lentivirus Lv-FSIP1-shNC (Group NC) at an MOI of 10 following our pre-experiment according to the manufacturer's viral infection protocol.	("manufacturer's viral infection", 'Disease', (178, 208))	('men', 'Species', '9606', (156, 159))	('viral infection', 'biological_process', 'GO:0016032', ('193', '208'))	('pre', 'molecular_function', 'GO:0003904', ('146', '149'))	("manufacturer's viral infection", 'Disease', 'MESH:D001102', (178, 208))	('Lv-FSIP1-shRNA', 'Var', (34, 48))
50834	29670371	For animal experiments, T24 cells were grown and infected with Lv-FSIP1-shRNA, Lv-FSIP1-shNC, or empty vector for 5 days and then harvested and suspended in serum-free DMEM.	('Lv-FSIP1-shRNA', 'Var', (63, 77))	('DMEM', 'Chemical', '-', (168, 172))	('men', 'Species', '9606', (17, 20))	('Lv-FSIP1-shNC', 'Var', (79, 92))
50852	29670371	The MTT assay was used to detect the effect of FSIP1 knockdown on the regulation of bladder cancer cell proliferation.	('bladder cancer', 'Phenotype', 'HP:0009725', (84, 98))	('bladder cancer', 'Disease', 'MESH:D001749', (84, 98))	('bladder cancer', 'Disease', (84, 98))	('regulation', 'biological_process', 'GO:0065007', ('70', '80'))	('knockdown', 'Var', (53, 62))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('cell proliferation', 'biological_process', 'GO:0008283', ('99', '117'))	('FSIP1', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
50853	29670371	To further confirm this finding, we assessed the effect of FSIP1 knockdown on the cell growth of bladder cancer cells using the colony formation assay.	('FSIP1', 'Gene', (59, 64))	('formation', 'biological_process', 'GO:0009058', ('135', '144'))	('bladder cancer', 'Disease', 'MESH:D001749', (97, 111))	('bladder cancer', 'Disease', (97, 111))	('cell growth', 'biological_process', 'GO:0016049', ('82', '93'))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('knockdown', 'Var', (65, 74))
50855	29670371	Compared with Group BC and Group NC, levels of Cyclin D1 and Cyclin B1 expressions, the key regulators of the cell cycle progression, were significantly reduced after knockdown of FSIP1 expression in T24 cells (Figure 2D).	('reduced', 'NegReg', (153, 160))	('FSIP1', 'Gene', (180, 185))	('Cyclin D1', 'Gene', '595', (47, 56))	('knockdown', 'Var', (167, 176))	('Cyclin D1', 'Gene', (47, 56))	('Cyclin B1', 'Gene', '891', (61, 70))	('Cyclin', 'molecular_function', 'GO:0016538', ('47', '53'))	('cell cycle', 'biological_process', 'GO:0007049', ('110', '120'))	('Cyclin', 'molecular_function', 'GO:0016538', ('61', '67'))	('Cyclin B1', 'Gene', (61, 70))
50861	29670371	Thus far, we demonstrated that knockdown of FSIP1 expression in bladder cancer T24 cells significantly reduced tumor cell viability in vitro and tumorigenesis in vivo.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (64, 78))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('reduced', 'NegReg', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (111, 116))	('bladder cancer', 'Disease', (64, 78))	('tumor', 'Disease', (145, 150))	('bladder cancer', 'Disease', 'MESH:D001749', (64, 78))	('FSIP1', 'Gene', (44, 49))	('knockdown', 'Var', (31, 40))
50863	29670371	Our data showed that although the total PI3K and AKT proteins remained intact upon knockdown of FSIP1 expression, the phosphorylated PI3K and AKT levels were downregulated in Group KF compared with Group BC and Group NC (Figure 2D).	('AKT', 'Gene', (49, 52))	('FSIP1', 'Gene', (96, 101))	('downregulated', 'NegReg', (158, 171))	('AKT', 'Gene', (142, 145))	('PI3K', 'molecular_function', 'GO:0016303', ('133', '137'))	('AKT', 'Gene', '207', (49, 52))	('PI3K', 'Protein', (40, 44))	('AKT', 'Gene', '207', (142, 145))	('knockdown', 'Var', (83, 92))	('PI3K', 'molecular_function', 'GO:0016303', ('40', '44'))
50869	29670371	Moreover, knockdown of FSIP1 expression suppressed T24 cell tumorigenesis in nude mice.	('suppressed', 'NegReg', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('nude mice', 'Species', '10090', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('FSIP1', 'Gene', (23, 28))	('tumor', 'Disease', (60, 65))	('knockdown', 'Var', (10, 19))
50870	29670371	At the gene level, knockdown of FSIP1 expression reduced the activity of the PI3K/AKT signaling pathway.	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('reduced', 'NegReg', (49, 56))	('knockdown', 'Var', (19, 28))	('signaling pathway', 'biological_process', 'GO:0007165', ('86', '103'))	('AKT signaling', 'biological_process', 'GO:0043491', ('82', '95'))	('AKT', 'Gene', '207', (82, 85))	('FSIP1', 'Gene', (32, 37))	('activity', 'MPA', (61, 69))	('AKT', 'Gene', (82, 85))
50874	29670371	In our study, we applied this technique to assess the effect of FSIP1 knockdown on the progression of bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('knockdown', 'Var', (70, 79))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('bladder cancer', 'Disease', (102, 116))	('FSIP1', 'Gene', (64, 69))
50876	29670371	Moreover, FSIP1 overexpression was found to induce cancer cell mitotic errors.	('induce', 'PosReg', (44, 50))	('FSIP1', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('overexpression', 'Var', (16, 30))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
50885	29670371	Our current study showed that knockdown of FSIP1 expression induced bladder cells to undergo apoptosis in vitro and in nude mice, suggesting that overexpression of FSIP1 in bladder cancer or other human cancers could promote cancer progression.	('FSIP1', 'Gene', (164, 169))	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('knockdown', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('FSIP1', 'Gene', (43, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('overexpression', 'Var', (146, 160))	('nude mice', 'Species', '10090', (119, 128))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('bladder cancer', 'Disease', 'MESH:D001749', (173, 187))	('bladder cancer', 'Disease', (173, 187))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (203, 209))	('human', 'Species', '9606', (197, 202))	('cancer', 'Disease', (181, 187))	('bladder cancer', 'Phenotype', 'HP:0009725', (173, 187))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('promote', 'PosReg', (217, 224))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancers', 'Disease', (203, 210))
50891	29670371	Our data suggest that the levels of PI3K and AKT phosphorylation were decreased after knockdown of FSIP1 expression.	('knockdown', 'Var', (86, 95))	('AKT', 'Gene', '207', (45, 48))	('PI3K', 'Pathway', (36, 40))	('AKT', 'Gene', (45, 48))	('decreased', 'NegReg', (70, 79))	('phosphorylation', 'biological_process', 'GO:0016310', ('49', '64'))	('PI3K', 'molecular_function', 'GO:0016303', ('36', '40'))	('FSIP1', 'Gene', (99, 104))
50894	29670371	In various types of human cancers, the dysregulated expression or activity of AKT phosphorylation was considered as an important factor in antiapoptotic mechanism.	('human', 'Species', '9606', (20, 25))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('activity', 'MPA', (66, 74))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('AKT', 'Gene', '207', (78, 81))	('expression', 'MPA', (52, 62))	('cancers', 'Disease', (26, 33))	('dysregulated', 'Var', (39, 51))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))	('AKT', 'Gene', (78, 81))
50895	29670371	In our current study, we also found that knockdown of FSIP1 expression inhibited levels of p-PI3K and p-AKT in T24 cells.	('FSIP1', 'Gene', (54, 59))	('inhibited', 'NegReg', (71, 80))	('AKT', 'Gene', (104, 107))	('p-PI3K', 'Pathway', (91, 97))	('PI3K', 'molecular_function', 'GO:0016303', ('93', '97'))	('knockdown', 'Var', (41, 50))	('AKT', 'Gene', '207', (104, 107))
50896	29670371	Subsequently, level of Bcl-2 was reduced and Bax and cleavage of caspase-3 were induced, all of which indicate that knockdown of FSIP1 expression induced tumor cell apoptosis via the inactivation of the PI3K/AKT pathway; however, further study is needed to confirm whether knockdown or specific inhibitors of PI3K/p-AKT pathway genes can abolish apoptosis in this experimental setting.	('AKT', 'Gene', (316, 319))	('apoptosis', 'biological_process', 'GO:0097194', ('165', '174'))	('apoptosis', 'biological_process', 'GO:0006915', ('165', '174'))	('knockdown', 'Var', (116, 125))	('Bcl-2', 'Gene', '596', (23, 28))	('FSIP1', 'Gene', (129, 134))	('tumor', 'Disease', (154, 159))	('Bcl-2', 'molecular_function', 'GO:0015283', ('23', '28'))	('AKT', 'Gene', '207', (208, 211))	('apoptosis', 'biological_process', 'GO:0097194', ('346', '355'))	('apoptosis', 'biological_process', 'GO:0006915', ('346', '355'))	('inactivation', 'NegReg', (183, 195))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('AKT', 'Gene', '207', (316, 319))	('PI3K', 'molecular_function', 'GO:0016303', ('309', '313'))	('PI3K', 'molecular_function', 'GO:0016303', ('203', '207'))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('Bax', 'Gene', (45, 48))	('Bax', 'Gene', '581', (45, 48))	('caspase-3', 'Gene', '836', (65, 74))	('Bcl-2', 'Gene', (23, 28))	('AKT', 'Gene', (208, 211))	('caspase-3', 'Gene', (65, 74))	('men', 'Species', '9606', (370, 373))
50899	29670371	Our current study was just a proof-of-principle to demonstrate that FSIP1 was highly expressed in bladder cancer cells and that knockdown of FSIP1 significantly decreased tumor cell proliferation and induced apoptosis in vitro.	('induced', 'Reg', (200, 207))	('apoptosis', 'CPA', (208, 217))	('FSIP1', 'Gene', (68, 73))	('cell proliferation', 'biological_process', 'GO:0008283', ('177', '195'))	('decreased', 'NegReg', (161, 170))	('knockdown', 'Var', (128, 137))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('FSIP1', 'Gene', (141, 146))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('apoptosis', 'biological_process', 'GO:0097194', ('208', '217'))	('apoptosis', 'biological_process', 'GO:0006915', ('208', '217'))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
50901	29670371	Our data suggest that knockdown of FSIP1 also inhibited activation of the PI3K/AKT pathway.	('AKT', 'Gene', (79, 82))	('FSIP1', 'Gene', (35, 40))	('knockdown', 'Var', (22, 31))	('AKT', 'Gene', '207', (79, 82))	('PI3K', 'molecular_function', 'GO:0016303', ('74', '78'))	('inhibited', 'NegReg', (46, 55))
50943	28494780	However, CK7 and CK20 positivity is more likely to be correlated with urothelial, pancreatic, ovarian and cholangiocarcinoma, and GATA 3 is correlated with breast, cutaneous and urothelial cancers.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (106, 124))	('CK20', 'Gene', '54474', (17, 21))	('GATA 3', 'Gene', '2625', (130, 136))	('positivity', 'Var', (22, 32))	('GATA 3', 'Gene', (130, 136))	('CK7', 'Gene', (9, 12))	('pancreatic', 'Disease', 'MESH:D010195', (82, 92))	('ovarian and cholangiocarcinoma', 'Disease', 'MESH:D018281', (94, 124))	('breast', 'Disease', (156, 162))	('urothelial cancers', 'Disease', (178, 196))	('CK7', 'Gene', '3855', (9, 12))	('pancreatic', 'Disease', (82, 92))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('correlated', 'Reg', (140, 150))	('urothelial', 'Disease', (70, 80))	('correlated', 'Reg', (54, 64))	('urothelial cancers', 'Disease', 'MESH:D014523', (178, 196))	('cutaneous', 'Disease', (164, 173))	('CK20', 'Gene', (17, 21))
50960	27286260	Recurrence pattern and TP53 mutation in upper urinary tract urothelial carcinoma TP53 mutation patterns are associated with prognosis of various cancers.	('cancers', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('urothelial carcinoma', 'Disease', (60, 80))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('mutation', 'Var', (28, 36))	('associated', 'Reg', (108, 118))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (60, 80))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
50965	27286260	Forty-two (25.5%) patients had TP53 mutations with only other than A:T to T:A transversion (NAT group), and 68 patients (41.2%) had wide-type TP53 (WT group).	('TP53', 'Gene', '7157', (142, 146))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (142, 146))	('TP53', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('patients', 'Species', '9606', (18, 26))	('NAT', 'Gene', (92, 95))	('NAT', 'Gene', '6046', (92, 95))	('patients', 'Species', '9606', (111, 119))
50969	27286260	As a result, A:T to T:A transversion increased contralateral UTUC recurrence risk, but other mutations in TP53 raised the hazard of bladder recurrence and metastases.	('mutations', 'Var', (93, 102))	('contralateral UTUC recurrence', 'Disease', (47, 76))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('transversion', 'Var', (24, 36))	('increased', 'PosReg', (37, 46))	('raised', 'PosReg', (111, 117))	('bladder recurrence', 'Disease', (132, 150))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))	('metastases', 'Disease', (155, 165))
50972	27286260	The spectrum of TP53 mutations can be used as prognostic molecular biomarkers for various cancers.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('TP53', 'Gene', '7157', (16, 20))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('TP53', 'Gene', (16, 20))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('mutations', 'Var', (21, 30))
50973	27286260	Abnormal p53 protein translated by the mutant gene has a longer half-life than the wild-type protein, resulting in cellular accumulation of abnormal p53.	('longer', 'PosReg', (57, 63))	('p53', 'Gene', (149, 152))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('p53', 'Gene', '7157', (149, 152))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('cellular accumulation', 'MPA', (115, 136))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('mutant', 'Var', (39, 45))	('abnormal', 'Var', (140, 148))
50974	27286260	Based on this characteristic, immunohistochemical (IHC) staining for p53 has been widely utilized as a surrogate marker for the mutant TP53 gene.	('p53', 'Gene', '7157', (69, 72))	('p53', 'Gene', (69, 72))	('TP53', 'Gene', '7157', (135, 139))	('mutant', 'Var', (128, 134))	('TP53', 'Gene', (135, 139))
50976	27286260	Recently, A > T transversions in the TP53 gene of UTUC tumors have been documented as being associated with aristolochic acid (AA) exposure.	('aristolochic acid', 'MPA', (108, 125))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('men', 'Species', '9606', (76, 79))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('aristolochic acid', 'Chemical', 'MESH:C000228', (108, 125))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('A > T transversions', 'Var', (10, 29))	('associated', 'Reg', (92, 102))
50978	27286260	In addition, TP53 gene mutation patterns were shown to be associated with different prognoses in other cancers, such as colorectal and breast cancers.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('TP53', 'Gene', (13, 17))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('associated', 'Reg', (58, 68))	('mutation', 'Var', (23, 31))	('cancers', 'Disease', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('breast cancers', 'Phenotype', 'HP:0003002', (135, 149))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('colorectal and breast cancers', 'Disease', 'MESH:D015179', (120, 149))	('TP53', 'Gene', '7157', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
50979	27286260	Together with the above evidence, TP53 mutation pattern may be correlated with disease outcomes and recurrence patterns of UTUC.	('correlated', 'Reg', (63, 73))	('mutation', 'Var', (39, 47))	('TP53', 'Gene', (34, 38))	('UTUC', 'Disease', (123, 127))	('TP53', 'Gene', '7157', (34, 38))
50980	27286260	However, studies that describe the predictive value of TP53 mutations and patterns in the prognosis of UTUCs have not been reported until now.	('mutations', 'Var', (60, 69))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (55, 59))
50983	27286260	In this cohort, 55 (33.3%), 42 (25.5%), and 68 (41.2%) patients were classified as AT group (TP53 mutation with A:T to T:A SBS), NAT group (TP53 mutation with only other than A:T to T:A SBS), and WT group (wild-type TP53), respectively.	('TP53', 'Gene', (216, 220))	('TP53', 'Gene', (140, 144))	('mutation', 'Var', (98, 106))	('SBS', 'Gene', '1540', (123, 126))	('SBS', 'Gene', (186, 189))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('patients', 'Species', '9606', (55, 63))	('SBS', 'Gene', (123, 126))	('SBS', 'Gene', '1540', (186, 189))	('TP53', 'Gene', '7157', (216, 220))	('NAT', 'Gene', '6046', (129, 132))	('TP53', 'Gene', '7157', (140, 144))	('NAT', 'Gene', (129, 132))
50989	27286260	In addition, TP53 mutation rate was higher in the patients without smoking histories (72%) than those with smoking histories (47%) (Table S1).	('TP53', 'Gene', (13, 17))	('higher', 'PosReg', (36, 42))	('patients', 'Species', '9606', (50, 58))	('mutation', 'Var', (18, 26))	('TP53', 'Gene', '7157', (13, 17))
50990	27286260	In the patients with TP53 mutations, A:T to T:A transversion was more frequently noted in non-smokers, but mutation only other than A:T to T:A transversion was more identified in smokers.	('mutations', 'Var', (26, 35))	('patients', 'Species', '9606', (7, 15))	('TP53', 'Gene', (21, 25))	('TP53', 'Gene', '7157', (21, 25))
51000	27286260	Accordingly, TP53 mutations were associated with higher percentage of p53 IHC staining in tumors.	('TP53', 'Gene', (13, 17))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Disease', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('TP53', 'Gene', '7157', (13, 17))	('mutations', 'Var', (18, 27))
51002	27286260	A significant association was identified among TP53 mutation types and p53 IHC staining (Table 2).	('mutation types', 'Var', (52, 66))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))
51003	27286260	Tumors with more than 50% of p53 IHC staining had a higher proportion (79%) of missense mutations than did those with < = 50% and negative results of IHC staining (24% and 15%, respectively; p < 0.001).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('missense mutations', 'Var', (79, 97))	('p53', 'Gene', (29, 32))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('p53', 'Gene', '7157', (29, 32))
51004	27286260	Missense mutations were most frequently identified in UTUC tumors of AT (45%) and NAT (69%) groups.	('Missense mutations', 'Var', (0, 18))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('identified', 'Reg', (40, 50))	('NAT', 'Gene', '6046', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('NAT', 'Gene', (82, 85))
51009	27286260	In univariable analysis of Cox proportional hazard model (Table 3), diabetes and TP53 mutation pattern were the only two significant prognosticators of bladder recurrence.	('bladder recurrence', 'Disease', (152, 170))	('diabetes', 'Disease', 'MESH:D003920', (68, 76))	('Cox', 'Gene', '1351', (27, 30))	('Cox', 'Gene', (27, 30))	('mutation', 'Var', (86, 94))	('TP53', 'Gene', '7157', (81, 85))	('diabetes', 'Disease', (68, 76))	('TP53', 'Gene', (81, 85))
51011	27286260	Multivariable analysis of the full model (model 1) revealed that diabetes and TP53 mutations other than A:T to T:A transversions (NAT group) were associated with more bladder recurrences.	('NAT', 'Gene', (130, 133))	('mutations', 'Var', (83, 92))	('diabetes', 'Disease', (65, 73))	('NAT', 'Gene', '6046', (130, 133))	('diabetes', 'Disease', 'MESH:D003920', (65, 73))	('bladder recurrences', 'Disease', (167, 186))	('TP53', 'Gene', (78, 82))	('TP53', 'Gene', '7157', (78, 82))	('associated', 'Reg', (146, 156))
51012	27286260	In the model filled with interested variables and clinically important prognosticators, including gender, tumor grade, stage, and lower ureteral tumors, TP53 mutations other than A:T to T:A transversions still presented as an independent variable predicting a higher risk (HR: 8.4 and 3.7, p < 0.001 and = 0.01, respectively) of bladder recurrence compared with wild-type TP53 and TP53 mutations with A:T to T:A transversions.	('ureteral tumor', 'Phenotype', 'HP:0100516', (136, 150))	('bladder recurrence', 'Disease', (329, 347))	('TP53', 'Gene', '7157', (153, 157))	('TP53', 'Gene', '7157', (381, 385))	('tumor', 'Disease', (106, 111))	('ureteral tumors', 'Phenotype', 'HP:0100516', (136, 151))	('TP53', 'Gene', '7157', (372, 376))	('ureteral tumors', 'Disease', 'MESH:D014516', (136, 151))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (145, 150))	('ureteral tumors', 'Disease', (136, 151))	('mutations', 'Var', (158, 167))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('TP53', 'Gene', (153, 157))	('TP53', 'Gene', (381, 385))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('TP53', 'Gene', (372, 376))
51013	27286260	A total of 57% of the patients with previous or synchronous bladder cancer had TP53 mutations, whereas 72% of those with bladder recurrence after nephroureterectomies had TP53 mutations.	('TP53', 'Gene', (171, 175))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('TP53', 'Gene', '7157', (79, 83))	('nephroureterectomies', 'Disease', (146, 166))	('TP53', 'Gene', (79, 83))	('nephroureterectomies', 'Disease', 'None', (146, 166))	('synchronous bladder cancer', 'Disease', 'MESH:D001749', (48, 74))	('patients', 'Species', '9606', (22, 30))	('mutations', 'Var', (84, 93))	('synchronous bladder cancer', 'Disease', (48, 74))	('TP53', 'Gene', '7157', (171, 175))
51014	27286260	In addition, mutation other than A:T to T:A transversion was more frequently noted in the UTUC patients with bladder recurrence after nephroureterectomies compared to those with previous or synchronous bladder cancer history (Table S2).	('synchronous bladder cancer', 'Disease', 'MESH:D001749', (190, 216))	('bladder recurrence', 'Disease', (109, 127))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('bladder cancer', 'Phenotype', 'HP:0009725', (202, 216))	('nephroureterectomies', 'Disease', (134, 154))	('noted', 'Reg', (77, 82))	('nephroureterectomies', 'Disease', 'None', (134, 154))	('transversion', 'Var', (44, 56))	('synchronous bladder cancer', 'Disease', (190, 216))
51021	27286260	Univariable analysis revealed herbs usage, aristolactam-DNA adducts, TP53 mutation with A:T to T:A transversions, and diabetes increased risk of metachronous contralateral UTUC recurrence.	('mutation', 'Var', (74, 82))	('TP53', 'Gene', '7157', (69, 73))	('diabetes', 'Disease', (118, 126))	('TP53', 'Gene', (69, 73))	('metachronous contralateral UTUC recurrence', 'Disease', (145, 187))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('diabetes', 'Disease', 'MESH:D003920', (118, 126))
51024	27286260	Tumor stage, grade, p53 IHC staining and TP53 mutation patterns were statistically significant prognosticators of metastases.	('TP53', 'Gene', '7157', (41, 45))	('p53', 'Gene', (20, 23))	('TP53', 'Gene', (41, 45))	('metastases', 'Disease', (114, 124))	('p53', 'Gene', '7157', (20, 23))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('mutation', 'Var', (46, 54))
51031	27286260	By stratifying UTUC patients according to TP53 mutation patterns, we observed that patients with an A:T to T:A transversion in the TP53 gene had a higher risk of contralateral upper urinary tract recurrence, and those with non- A:T to T:A transversion mutations had more bladder tumor recurrences and metastases than the other two groups.	('non- A', 'Species', '12440', (223, 229))	('TP53', 'Gene', '7157', (42, 46))	('urinary tract recurrence', 'Phenotype', 'HP:0000010', (182, 206))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('bladder tumor', 'Disease', (271, 284))	('A:T to T:A transversion', 'Var', (100, 123))	('TP53', 'Gene', (42, 46))	('patients', 'Species', '9606', (83, 91))	('metastases', 'Disease', (301, 311))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('metastases', 'Disease', 'MESH:D009362', (301, 311))	('transversion', 'Var', (111, 123))	('patients', 'Species', '9606', (20, 28))	('bladder tumor', 'Disease', 'MESH:D001749', (271, 284))	('bladder tumor', 'Phenotype', 'HP:0009725', (271, 284))
51038	27286260	Hence, DNA sequencing remains the gold standard for identifying TP53 mutations.	('mutations', 'Var', (69, 78))	('TP53', 'Gene', '7157', (64, 68))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('TP53', 'Gene', (64, 68))
51042	27286260	As that in lung cancer study, a G:T transversion at codon 157 in TP53 is frequent in smokers.	('G:T transversion at codon 157', 'Var', (32, 61))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('lung cancer', 'Disease', (11, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('frequent', 'Reg', (73, 81))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))
51044	27286260	Patients who had been exposed to herbs had a higher frequency of A:T to T:A transversions, which is the signature mutation of AA.	('Patients', 'Species', '9606', (0, 8))	('transversions', 'Var', (76, 89))	('A:T to T:A transversions', 'Var', (65, 89))
51045	27286260	Furthermore, the A:T to T:A transversion was associated with poor renal function given that AA induces renal tubular damage.	('poor renal function', 'Phenotype', 'HP:0012622', (61, 80))	('A:T to T:A transversion', 'Var', (17, 40))	('transversion', 'Var', (28, 40))	('renal tubular damage', 'Disease', 'MESH:D007674', (103, 123))	('poor renal function', 'MPA', (61, 80))	('renal tubular damage', 'Disease', (103, 123))
51046	27286260	In our cohort, TP53 mutations with an A:T to T:A transversion were more frequent in female UTUC patients than males, which may be partially due the fact that more Taiwanese women tend to take herbs containing AA than men.	('women', 'Species', '9606', (173, 178))	('men', 'Species', '9606', (217, 220))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('patients', 'Species', '9606', (96, 104))	('frequent', 'Reg', (72, 80))	('mutations', 'Var', (20, 29))	('men', 'Species', '9606', (175, 178))
51048	27286260	Based on the results combining aristolactam-DNA adducts in renal cortical tissue and A:T to T:A transversions in the TP53 gene, patients with AA-induced UTUC had more high-grade and high-stage tumors than non-AA UTUC patients.	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('tumors', 'Disease', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('non-A', 'Species', '12440', (205, 210))	('transversions', 'Var', (96, 109))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('patients', 'Species', '9606', (217, 225))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('patients', 'Species', '9606', (128, 136))
51049	27286260	This extended cohort revealed that patients with TP53 mutations had more unfavorable tumor characteristics than those without TP53 mutations.	('tumor', 'Disease', (85, 90))	('TP53', 'Gene', (126, 130))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('TP53', 'Gene', '7157', (126, 130))
51050	27286260	A:T to T:A transversion pattern was associated with the worst initial tumor presentations, such as high grade and nodal or metastatic disease, in this cohort.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('high grade', 'Disease', (99, 109))	('nodal or', 'Disease', (114, 122))	('transversion pattern', 'Var', (11, 31))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
51051	27286260	As the signature mutation of AA, A:T to T:A transversion suggests that AA is responsible for carcinogenesis in these cases of UTUC.	('transversion', 'Var', (44, 56))	('carcinogenesis', 'Disease', (93, 107))	('carcinogenesis', 'Disease', 'MESH:D063646', (93, 107))
51053	27286260	UTUCs with TP53 non- A:T to T:A transversions have more and earlier bladder recurrences than those without TP53 mutations or A:T to T:A transversions.	('transversions', 'Var', (32, 45))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('non- A', 'Species', '12440', (16, 22))	('bladder recurrences', 'CPA', (68, 87))
51056	27286260	As shown in this study, UTUC patients with an A:T to T:A transversion did not have poorer outcomes of bladder recurrences or metastases than those without TP53 mutations.	('metastases', 'Disease', (125, 135))	('patients', 'Species', '9606', (29, 37))	('TP53', 'Gene', '7157', (155, 159))	('metastases', 'Disease', 'MESH:D009362', (125, 135))	('TP53', 'Gene', (155, 159))	('A:T to T:A transversion', 'Var', (46, 69))	('transversion', 'Var', (57, 69))
51057	27286260	However, non- A:T to T:A transversion mutations in the TP53 gene did predict poorer outcomes.	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (55, 59))	('non- A', 'Species', '12440', (9, 15))	('transversion mutations', 'Var', (25, 47))
51058	27286260	Hence, the precise stratification of TP53 mutations would help predict patient outcomes.	('TP53', 'Gene', (37, 41))	('patient', 'Species', '9606', (71, 78))	('mutations', 'Var', (42, 51))	('TP53', 'Gene', '7157', (37, 41))
51059	27286260	In contrast to other tumor suppressor genes which are changed by truncating mutations, most of TP53 gene mutations are missense substitutions (75%) that are resulted from SBS clustering within DNA-binding domain of protein.	('SBS', 'Gene', '1540', (171, 174))	('DNA', 'cellular_component', 'GO:0005574', ('193', '196'))	('tumor', 'Disease', (21, 26))	('missense substitutions', 'Var', (119, 141))	('tumor suppressor', 'biological_process', 'GO:0051726', ('21', '37'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('193', '204'))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('mutations', 'Var', (105, 114))	('SBS', 'Gene', (171, 174))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('21', '37'))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
51060	27286260	Our UTUC patients with TP53 mutations other than A:T to T:A transversion had higher proportion of missense mutations (69%) than those with A > T transversion (45%) and no mutation (0%) (Table 2).	('patients', 'Species', '9606', (9, 17))	('missense mutations', 'Var', (98, 116))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
51061	27286260	Tumors with TP53 mutations were supposed to be more invasive than those without mutations.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TP53', 'Gene', '7157', (12, 16))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TP53', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
51064	27286260	In this study, TP53 mutation pattern further stratified those at risk of bladder recurrence or contralateral upper tract recurrence and facilitated decisions regarding individualized follow-up protocols.	('bladder recurrence', 'Disease', (73, 91))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('mutation', 'Var', (20, 28))
51093	27286260	Chiaretti and coworkers reported that the p53 AmpliChip was superior to traditional Sanger sequencing for detection of single base substitutions, the dominant mutation class in TP53.	('p53', 'Gene', (42, 45))	('p53', 'Gene', '7157', (42, 45))	('TP53', 'Gene', '7157', (177, 181))	('single base substitutions', 'Var', (119, 144))	('TP53', 'Gene', (177, 181))
51095	27286260	TP53 SBS mutations were identified in 97 (58.8%) patients.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (9, 18))	('SBS', 'Gene', (5, 8))	('patients', 'Species', '9606', (49, 57))	('SBS', 'Gene', '1540', (5, 8))
51098	27286260	Patients with TP53 mutations only other than A:T to T:A SBSs were categorized as NAT group.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('SBS', 'Gene', (56, 59))	('mutations', 'Var', (19, 28))	('SBS', 'Gene', '1540', (56, 59))	('Patients', 'Species', '9606', (0, 8))	('NAT', 'Gene', (81, 84))	('NAT', 'Gene', '6046', (81, 84))
51118	27286260	A:T to T:A transversions increased contralateral UTUC recurrence, while mutations other than A:T to T:A transversions raised bladder tumor recurrence.	('bladder tumor', 'Disease', 'MESH:D001749', (125, 138))	('increased', 'PosReg', (25, 34))	('raised', 'PosReg', (118, 124))	('bladder tumor', 'Phenotype', 'HP:0009725', (125, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('transversions', 'Var', (11, 24))	('bladder tumor', 'Disease', (125, 138))	('contralateral UTUC recurrence', 'MPA', (35, 64))
51195	27190532	Additionally, other urinary symptoms such as painful and frequent urination were improved after KMBC treatment.	('KMBC', 'Chemical', '-', (96, 100))	('improved', 'PosReg', (81, 89))	('pain', 'Phenotype', 'HP:0012531', (45, 49))	('frequent urination', 'Phenotype', 'HP:0100515', (57, 75))	('painful', 'Disease', (45, 52))	('urination', 'biological_process', 'GO:0060073', ('66', '75'))	('painful', 'Disease', 'MESH:D010146', (45, 52))	('treatment', 'Var', (101, 110))	('urinary symptoms', 'Disease', (20, 36))	('men', 'Species', '9606', (106, 109))
51206	27190532	Several studies on the direct effect against UBC have suggested that a homogeneous polysaccharide from Panax ginseng displayed potent antiproliferative and antimetastatic activities in human bladder T24 cells, and Rg3 ginsenoside inhibited the proliferation of EJ (human bladder transitional cell carcinoma cells) by inducing apoptosis.	('human', 'Species', '9606', (185, 190))	('human', 'Species', '9606', (265, 270))	('bladder transitional cell carcinoma', 'Phenotype', 'HP:0006740', (271, 306))	('Rg3', 'Var', (214, 217))	('antiproliferative', 'CPA', (134, 151))	('apoptosis', 'biological_process', 'GO:0097194', ('326', '335'))	('apoptosis', 'biological_process', 'GO:0006915', ('326', '335'))	('proliferation', 'CPA', (244, 257))	('rat', 'Species', '10116', (251, 254))	('bladder transitional', 'Phenotype', 'HP:0100645', (271, 291))	('carcinoma cells', 'Disease', 'MESH:C538614', (297, 312))	('ginsenoside', 'Chemical', 'MESH:D036145', (218, 229))	('inducing', 'PosReg', (317, 325))	('inhibited', 'NegReg', (230, 239))	('Panax ginseng', 'Species', '4054', (103, 116))	('rat', 'Species', '10116', (145, 148))	('apoptosis', 'CPA', (326, 335))	('antimetastatic activities', 'CPA', (156, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('carcinoma cells', 'Disease', (297, 312))	('EJ', 'CellLine', 'CVCL:7039', (261, 263))	('polysaccharide', 'Chemical', 'MESH:D011134', (83, 97))
51220	27190532	In light of this, the mechanical deformation of the acupoints on the skin by acupuncture, moxibustion, and cupping therapy in the KMBC treatments induces the release of large amounts of ATP from keratinocytes, fibroblasts, and other cell types in skin, which is beneficial for the inhibition of UBC as well as the symptoms of the lower urinary tract.	('men', 'Species', '9606', (140, 143))	('deformation', 'Var', (33, 44))	('rat', 'Species', '10116', (197, 200))	('UBC', 'Disease', (295, 298))	('release', 'MPA', (158, 165))	('mechanical deformation', 'Var', (22, 44))	('KMBC', 'Chemical', '-', (130, 134))	('ATP', 'Chemical', 'MESH:D000255', (186, 189))
51269	26928298	As the cohort sizes in this study are less than twice the number of antibodies (2*187 = 374) for 7 of the 11 tumor types (Table 2), it is not surprising that SIMPLEPARCOR has poor performance in these tumor types, hence the poorest overall performance by a margin (Fig 3B).	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('poor', 'NegReg', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('SIMPLEPARCOR', 'Var', (158, 170))	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', (109, 114))
51270	26928298	Indeed, we can observe that the tumor types where SIMPLEPARCOR achieves relatively better ranks are BRCA, OVCA, KIRC, and UCEC, the four tumor types that have cohort size greater than 374 (Fig 3A and 3B and Table 2).	('tumor', 'Disease', (137, 142))	('BRCA', 'Gene', '672', (100, 104))	('KIRC', 'Disease', (112, 116))	('OVCA', 'Disease', (106, 110))	('BRCA', 'Gene', (100, 104))	('SIMPLEPARCOR', 'Var', (50, 62))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('UCEC', 'Disease', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
51289	26928298	These tumors have also been shown to have common DNA-based drivers (mutations and somatic copy number alterations), and hence have been treated as one disease.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (6, 12))	('mutations', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
51308	26928298	Processes such as cell cycle, proliferation, RTK signaling, RAS/MAPK signaling were shared between the modules; but Module 2 antibodies were involved in a greater variety of oncogenic pathways such as AKT/mTOR, Wnt, and NFkappaB signaling.	('RTK', 'Gene', (45, 48))	('AKT', 'Gene', '207', (201, 204))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('mTOR', 'Gene', (205, 209))	('oncogenic pathways', 'Pathway', (174, 192))	('mTOR', 'Gene', '2475', (205, 209))	('NFkappaB', 'Gene', (220, 228))	('AKT', 'Gene', (201, 204))	('RTK', 'Gene', '5979', (45, 48))	('NFkappaB', 'Gene', '4790', (220, 228))	('MAPK', 'molecular_function', 'GO:0004707', ('64', '68'))	('signaling', 'biological_process', 'GO:0023052', ('229', '238'))	('Wnt', 'Pathway', (211, 214))	('antibodies', 'Var', (125, 135))	('cell cycle', 'biological_process', 'GO:0007049', ('18', '28'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('64', '78'))	('involved in', 'Reg', (141, 152))
51323	26928298	In the Fig 8B heat map, we also tracked the number of significant (consensus rank < 425) interactions that match to each gene list broken down by module or group, and averaged over tumor types (S11 Table).	('broken down', 'Phenotype', 'HP:0001061', (131, 142))	('tumor', 'Disease', (181, 186))	('interactions', 'Var', (89, 101))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
51362	23554767	The role of aberrant promoter hypermethylation of DACT1 in bladder urothelial carcinoma The purpose of this study was to determine the relationship between hypermethylation of DACT1 gene promoter and lower mRNA expression in bladder urothelial carcinoma tissue.	('DACT1', 'Gene', '51339', (176, 181))	('bladder urothelial carcinoma', 'Disease', (59, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('DACT1', 'Gene', '51339', (50, 55))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (225, 253))	('hypermethylation', 'Var', (156, 172))	('DACT1', 'Gene', (176, 181))	('bladder urothelial carcinoma', 'Disease', (225, 253))	('lower', 'NegReg', (200, 205))	('aberrant', 'Var', (12, 20))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (59, 87))	('DACT1', 'Gene', (50, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('mRNA expression', 'MPA', (206, 221))
51365	23554767	Promoter hypermethylation was found in 58.62% (17/29) urothelial carcinomas and 25% (7/29) normal tissues, respectively (P < 0.05).	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (54, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('urothelial carcinomas', 'Disease', (54, 75))	('Promoter hypermethylation', 'Var', (0, 25))
51366	23554767	DACT1 gene hypermethylation was closely related to tumor size, grade and stage (P < 0.05).	('DACT1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('related', 'Reg', (40, 47))	('hypermethylation', 'Var', (11, 27))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
51367	23554767	Our results indicate that silencing and downregulation of DACT1 mRNA may be implicated in carcinogenesis and the progression of bladder urothelial carcinoma, and may be a potential prognostic factor.	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (128, 156))	('DACT1', 'Gene', (58, 63))	('downregulation', 'NegReg', (40, 54))	('bladder urothelial carcinoma', 'Disease', (128, 156))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('silencing', 'Var', (26, 35))	('implicated', 'Reg', (76, 86))	('carcinogenesis', 'Disease', (90, 104))
51370	23554767	Although the oncogenesis of bladder cancer is unclear so far, it is generally agreed that the accumulation of multiple genetic and epigenetic alternations leading to the activation of proto-oncogenes and/or inactivation of tumor-suppressor genes contribute to the development of bladder cancer.	('contribute', 'Reg', (246, 256))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('bladder cancer', 'Phenotype', 'HP:0009725', (28, 42))	('bladder cancer', 'Disease', 'MESH:D001749', (28, 42))	('activation', 'PosReg', (170, 180))	('oncogenesis', 'biological_process', 'GO:0007048', ('13', '24'))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('223', '239'))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('bladder cancer', 'Phenotype', 'HP:0009725', (279, 293))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('223', '239'))	('inactivation', 'Var', (207, 219))	('tumor-suppressor', 'Gene', (223, 239))	('bladder cancer', 'Disease', (28, 42))	('tumor-suppressor', 'Gene', '7248', (223, 239))	('proto-oncogenes', 'Gene', (184, 199))	('bladder cancer', 'Disease', 'MESH:D001749', (279, 293))	('bladder cancer', 'Disease', (279, 293))
51371	23554767	Aberrant DNA methylation is now considered to be the most important epigenetic alteration in many cancers, including bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Aberrant', 'Var', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (117, 131))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('DNA', 'Protein', (9, 12))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('bladder cancer', 'Disease', 'MESH:D001749', (117, 131))	('bladder cancer', 'Disease', (117, 131))
51372	23554767	In general, DNA methylation is one of the best-studied epigenetic alterations in human cancers and may play important roles in carcinogenesis.	('cancers', 'Disease', (87, 94))	('roles', 'Reg', (118, 123))	('DNA methylation', 'Var', (12, 27))	('carcinogenesis', 'Disease', 'MESH:D063646', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('DNA methylation', 'biological_process', 'GO:0006306', ('12', '27'))	('carcinogenesis', 'Disease', (127, 141))	('play', 'Reg', (103, 107))	('human', 'Species', '9606', (81, 86))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('DNA', 'cellular_component', 'GO:0005574', ('12', '15'))
51374	23554767	Hypermethylation of normally unmethylated tumor suppressor genes correlates with a loss of expression in cancer cell lines and primary tumors, suggesting that hypermethylation of tumor suppressor genes could promote carcinogenesis.	('expression', 'MPA', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('hypermethylation', 'Var', (159, 175))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Disease', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('promote', 'PosReg', (208, 215))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('primary tumors', 'Disease', (127, 141))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Disease', (135, 140))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('42', '58'))	('carcinogenesis', 'Disease', (216, 230))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('179', '195'))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumor suppressor', 'biological_process', 'GO:0051726', ('42', '58'))	('primary tumors', 'Disease', 'MESH:D009369', (127, 141))	('carcinogenesis', 'Disease', 'MESH:D063646', (216, 230))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor suppressor', 'biological_process', 'GO:0051726', ('179', '195'))	('tumor', 'Disease', (179, 184))
51382	23554767	Using methylation-specific polymerase chain reaction (MSP) and reverse transcription polymerase chain reaction (RT-PCR), a clear relationship was found between hypermethylation status and the low expression of DACT1 in bladder transitional cell carcinomas.	('hypermethylation status', 'Var', (160, 183))	('low', 'NegReg', (192, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('DACT1', 'Gene', (210, 215))	('carcinomas', 'Phenotype', 'HP:0030731', (245, 255))	('expression', 'MPA', (196, 206))	('carcinomas', 'Disease', (245, 255))	('carcinomas', 'Disease', 'MESH:D002277', (245, 255))	('reverse transcription', 'biological_process', 'GO:0001171', ('63', '84'))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('bladder transitional cell carcinoma', 'Phenotype', 'HP:0006740', (219, 254))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (227, 254))	('transitional cell carcinomas', 'Phenotype', 'HP:0006740', (227, 255))	('bladder transitional', 'Phenotype', 'HP:0100645', (219, 239))	('bladder transitional cell carcinomas', 'Phenotype', 'HP:0006740', (219, 255))
51383	23554767	DACT1 was hypermethylated in almost all human bladder cancers but unmethylated in normal tissues.	('DACT1', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('bladder cancers', 'Disease', (46, 61))	('bladder cancers', 'Phenotype', 'HP:0009725', (46, 61))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (46, 60))	('hypermethylated', 'Var', (10, 25))	('bladder cancers', 'Disease', 'MESH:D001749', (46, 61))	('human', 'Species', '9606', (40, 45))
51411	23554767	The promoter of the DACT1 gene in 17 out of 29 (58.62%) cancer tissue specimens and in 7 out of 29 (25%) normal tissues was hypermethylated (P < 0.05) (Fig.	('DACT1', 'Gene', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('hypermethylated', 'Var', (124, 139))
51412	23554767	Thus, these data revealed that DACT1 hypermethylation may be a neoplastic feature of bladder cancers.	('bladder cancers', 'Disease', 'MESH:D001749', (85, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('bladder cancers', 'Disease', (85, 100))	('DACT1', 'Gene', (31, 36))	('neoplastic feature', 'Phenotype', 'HP:0002664', (63, 81))	('hypermethylation', 'Var', (37, 53))	('bladder cancers', 'Phenotype', 'HP:0009725', (85, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))
51417	23554767	DACT1 gene hypermethylation was closely associated with tumor size, grade and stage (P < 0.05), but not gender and age (Table 1), suggesting that the methylation rate of the DACT1 gene increased with the progression of bladder cancer.	('DACT1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('DACT1', 'Gene', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('hypermethylation', 'Var', (11, 27))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Disease', (56, 61))	('bladder cancer', 'Phenotype', 'HP:0009725', (219, 233))	('methylation', 'biological_process', 'GO:0032259', ('150', '161'))	('bladder cancer', 'Disease', 'MESH:D001749', (219, 233))	('increased', 'PosReg', (185, 194))	('methylation', 'MPA', (150, 161))	('bladder cancer', 'Disease', (219, 233))	('associated', 'Reg', (40, 50))
51420	23554767	Substantial evidence has demonstrated that many tumor suppressor genes are methylated.	('methylated', 'Var', (75, 85))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor suppressor', 'biological_process', 'GO:0051726', ('48', '64'))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('48', '64'))
51421	23554767	found that aberrant methylation in the DBC2 promoter may be responsible for the loss of DBC2 expression in bladder cancer and this hypermethylation event could play a crucial role in the early stage of bladder tumorigenesis.	('bladder cancer', 'Disease', 'MESH:D001749', (107, 121))	('bladder cancer', 'Disease', (107, 121))	('DBC2', 'Gene', '23221', (39, 43))	('methylation', 'MPA', (20, 31))	('play', 'Reg', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('loss', 'NegReg', (80, 84))	('tumor', 'Disease', (210, 215))	('aberrant', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (107, 121))	('expression', 'MPA', (93, 103))	('DBC2', 'Gene', '23221', (88, 92))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('bladder', 'Disease', (202, 209))	('DBC2', 'Gene', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('DBC2', 'Gene', (39, 43))
51422	23554767	demonstrated that methylated RARbeta2 and APC are significantly higher in bladder cancer (62.8%, 59.5%) than benign tumors (16.4%, 5%), and virtually undetectable in healthy volunteers (0%) (P < 0.0001).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('RARbeta2', 'Gene', (29, 37))	('bladder cancer', 'Phenotype', 'HP:0009725', (74, 88))	('APC', 'cellular_component', 'GO:0005680', ('42', '45'))	('higher', 'PosReg', (64, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (74, 88))	('benign tumors', 'Disease', 'MESH:D009369', (109, 122))	('methylated', 'Var', (18, 28))	('APC', 'Disease', 'MESH:D011125', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('bladder cancer', 'Disease', (74, 88))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('APC', 'Disease', (42, 45))	('benign tumors', 'Disease', (109, 122))
51423	23554767	Hypermethylation of tumor suppressor genes SFRP1 and SOCS-1 correlates with bladder carcinogenesis and development.	('bladder carcinogenesis', 'Disease', (76, 98))	('SFRP1', 'Gene', (43, 48))	('correlates', 'Reg', (60, 70))	('SOCS-1', 'Gene', (53, 59))	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('Hypermethylation', 'Var', (0, 16))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('SOCS-1', 'Gene', '8651', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('SFRP1', 'Gene', '6422', (43, 48))	('bladder carcinogenesis', 'Disease', 'MESH:D063646', (76, 98))	('development', 'CPA', (103, 114))	('tumor', 'Disease', (20, 25))
51424	23554767	Methylation of tumor suppressor genes plays an important role in the tumorigenesis of bladder cancer.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('bladder cancer', 'Disease', (86, 100))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor suppressor', 'biological_process', 'GO:0051726', ('15', '31'))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('tumor', 'Disease', (15, 20))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('15', '31'))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))
51425	23554767	Substantial evidence has demonstrated that tumor cells display mostly hypermethylation profiles in suppressor genes, which contributes to the suppression of their expression.	('hypermethylation profiles', 'Var', (70, 95))	('suppression', 'NegReg', (142, 153))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('expression', 'MPA', (163, 173))	('tumor', 'Disease', (43, 48))	('suppressor genes', 'Gene', (99, 115))
51426	23554767	In the present study, we first examined the hypermethylation status of DACT1 in normal and bladder cancer tissue, as well as the levels of DACT1 mRNA transcripts and protein.	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('bladder cancer', 'Disease', (91, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('hypermethylation', 'Var', (44, 60))	('DACT1', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
51427	23554767	Hypermethylation was detected in bladder carcinomas by methylation specific PCR.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('Hypermethylation', 'Var', (0, 16))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (33, 51))	('bladder carcinomas', 'Disease', (33, 51))	('bladder carcinomas', 'Disease', 'MESH:D001749', (33, 51))	('methylation', 'Var', (55, 66))	('detected', 'Reg', (21, 29))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
51428	23554767	The mono-alleles were detected in most bladder cancers.	('bladder cancer', 'Phenotype', 'HP:0009725', (39, 53))	('bladder cancers', 'Disease', 'MESH:D001749', (39, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('bladder cancers', 'Disease', (39, 54))	('mono-alleles', 'Var', (4, 16))	('bladder cancers', 'Phenotype', 'HP:0009725', (39, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
51429	23554767	The DACT1 gene was hypermethylated in 58.62% (17 out of 29) urothelial carcinomas, and only 25% (7 of 29) in healthy bladder tissue (P < 0.05).	('urothelial carcinomas', 'Disease', (60, 81))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (60, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('hypermethylated', 'Var', (19, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('DACT1', 'Gene', (4, 9))
51434	23554767	Together with the fact that methylation of the DACT1 CpG island is common in bladder cancer, these findings indicate that DACT1 hypermethylation is related to the progression of bladder transitional cell carcinomas.	('hypermethylation', 'Var', (128, 144))	('carcinomas', 'Disease', (204, 214))	('bladder transitional', 'Phenotype', 'HP:0100645', (178, 198))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('transitional cell carcinomas', 'Phenotype', 'HP:0006740', (186, 214))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (186, 213))	('common', 'Reg', (67, 73))	('related to', 'Reg', (148, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('bladder cancer', 'Disease', (77, 91))	('bladder transitional cell carcinoma', 'Phenotype', 'HP:0006740', (178, 213))	('carcinomas', 'Disease', 'MESH:D002277', (204, 214))	('bladder transitional cell carcinomas', 'Phenotype', 'HP:0006740', (178, 214))	('methylation', 'Var', (28, 39))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('DACT1', 'Gene', (122, 127))
51438	23554767	Hypermethylation and silencing of genes regulating proliferation are proposed to be critical for deregulating growth in early carcinogenesis, whereas hypomethylation and activation of other genes may be more important for metastasis.	('deregulating growth', 'MPA', (97, 116))	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('Hypermethylation', 'Var', (0, 16))	('carcinogenesis', 'Disease', (126, 140))	('silencing', 'NegReg', (21, 30))
51439	23554767	The importance of hypermethylation and inactivation of tumor suppressor genes is well-documented in various cancers, but the role of DNA hypomethylation in advanced cancers and metastasis has been less thoroughly studied and remains hypothetical.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('hypermethylation', 'Var', (18, 34))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor suppressor', 'biological_process', 'GO:0051726', ('55', '71'))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('tumor', 'Disease', (55, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('55', '71'))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('133', '152'))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('inactivation', 'Var', (39, 51))	('cancers', 'Disease', (165, 172))	('cancers', 'Disease', (108, 115))
51440	23554767	In conclusion, our study showed that hypermthylation could regulate DACT1 expression in bladder transitional cell carcinomas.	('bladder transitional cell carcinoma', 'Phenotype', 'HP:0006740', (88, 123))	('expression', 'MPA', (74, 84))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (96, 123))	('DACT1', 'Gene', (68, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('transitional cell carcinomas', 'Phenotype', 'HP:0006740', (96, 124))	('carcinomas', 'Disease', (114, 124))	('carcinomas', 'Disease', 'MESH:D002277', (114, 124))	('bladder transitional', 'Phenotype', 'HP:0100645', (88, 108))	('regulate', 'Reg', (59, 67))	('bladder transitional cell carcinomas', 'Phenotype', 'HP:0006740', (88, 124))	('hypermthylation', 'Var', (37, 52))
51472	21897549	Micropapillary variant is often associated with conventional urothelial carcinoma.	('Micropapillary variant', 'Var', (0, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (61, 81))	('urothelial carcinoma', 'Disease', (61, 81))	('associated', 'Reg', (32, 42))
51483	21897549	The high association of this variant with muscle-invasive disease.	('muscle-invasive disease', 'Disease', (42, 65))	('association', 'Interaction', (9, 20))	('variant', 'Var', (29, 36))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (42, 65))
51491	33435173	UB UC was classified into CK5/6 single-positive (SP), CK20 SP, double-positive (DP) and double-negative (DN) subgroups, and transcriptional analysis was performed.	('SP', 'Chemical', '-', (59, 61))	('DP', 'Gene', '6734', (80, 82))	('UB UC', 'Disease', (0, 5))	('UB', 'Chemical', '-', (0, 2))	('SP', 'Chemical', '-', (49, 51))	('double-positive', 'Gene', (63, 78))	('CK5/6', 'Gene', '3852', (26, 31))	('double-negative', 'Var', (88, 103))	('CK20', 'Gene', (54, 58))	('CK5/6', 'Gene', (26, 31))	('CK20', 'Gene', '54474', (54, 58))	('double-positive', 'Gene', '6734', (63, 78))
51509	33435173	In fact, various studies have reported that prognosis, neoadjuvant chemotherapy response, and driver gene mutation vary among molecular subtypes in UB UC.	('mutation', 'Var', (106, 114))	('UB UC', 'Disease', (148, 153))	('UB', 'Chemical', '-', (148, 150))
51541	33435173	Between the CK5/6 SP and DN subgroups, various GO terms related to immune response and the tumor necrosis factor (TNF) signaling pathway were identified, and various related DEGs (CD86, HLA-DMB, CD209, CCL19, TLR1, BTK, IRAK3 and TLR 6) were upregulated in the CK5/6 SP subgroup.	('CD209', 'Gene', (195, 200))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('91', '112'))	('TNF', 'Gene', (114, 117))	('necrosis', 'biological_process', 'GO:0008220', ('97', '105'))	('IRAK3', 'Gene', '11213', (220, 225))	('TLR1', 'Gene', '7096', (209, 213))	('necrosis', 'biological_process', 'GO:0070265', ('97', '105'))	('necrosis', 'biological_process', 'GO:0019835', ('97', '105'))	('CCL19', 'Gene', (202, 207))	('necrosis', 'biological_process', 'GO:0001906', ('97', '105'))	('upregulated', 'PosReg', (242, 253))	('tumor necrosis factor', 'Gene', (91, 112))	('CK5/6 SP', 'Gene', (12, 20))	('CK5/6 SP', 'Gene', '3852', (261, 269))	('BTK', 'Gene', (215, 218))	('BTK', 'Gene', '695', (215, 218))	('TNF', 'Gene', '7124', (114, 117))	('HLA-DMB', 'Gene', (186, 193))	('signaling pathway', 'biological_process', 'GO:0007165', ('119', '136'))	('IRAK3', 'Gene', (220, 225))	('CK5/6 SP', 'Gene', '3852', (12, 20))	('TLR 6', 'Gene', '10333', (230, 235))	('necrosis', 'biological_process', 'GO:0008219', ('97', '105'))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CD209', 'Gene', '30835', (195, 200))	('tumor necrosis factor', 'Gene', '7124', (91, 112))	('immune response', 'biological_process', 'GO:0006955', ('67', '82'))	('TLR1', 'Gene', (209, 213))	('CCL19', 'Gene', '6363', (202, 207))	('CD86', 'Var', (180, 184))	('TLR 6', 'Gene', (230, 235))	('CK5/6 SP', 'Gene', (261, 269))	('CCL', 'molecular_function', 'GO:0044101', ('202', '205'))	('HLA-DMB', 'Gene', '3109', (186, 193))
51568	33435173	The Kaplan-Meier analysis also showed that the high expression of CK5/6 was associated with unfavorable PFS (p = 0.005) (Figure 5).	('associated', 'Reg', (76, 86))	('high', 'Var', (47, 51))	('CK5/6', 'Gene', '3852', (66, 71))	('CK5/6', 'Gene', (66, 71))
51651	33330918	Expression quantitative trait locus (eQTL) analysis has been demonstrated to help reveal the genetic mechanism of single nucleotide polymorphisms (SNPs) in cancer etiology.	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('single nucleotide polymorphisms', 'Var', (114, 145))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))
51660	33330918	It is known that single nucleotide polymorphisms (SNPs), the most common type of germline variants, play vital roles in human diseases, including cancers.	('single nucleotide polymorphisms', 'Var', (17, 48))	('cancers', 'Disease', (146, 153))	('human', 'Species', '9606', (120, 125))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('roles', 'Reg', (111, 116))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
51662	33330918	Previous studies have found that these cancer risk-associated SNPs may be involved in the development of cancers by influencing the expression levels of nearby genes.	('influencing', 'Reg', (116, 127))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Disease', (105, 111))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('expression levels', 'MPA', (132, 149))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('SNPs', 'Var', (62, 66))	('involved', 'Reg', (74, 82))
51668	33330918	Therefore, it is noteworthy that somatic mutations would also affect gene expression extending in piRNAs.	('mutations', 'Var', (41, 50))	('affect', 'Reg', (62, 68))	('gene expression', 'biological_process', 'GO:0010467', ('69', '84'))	('piR', 'Gene', '8544', (98, 101))	('gene expression', 'MPA', (69, 84))	('piR', 'Gene', (98, 101))
51708	33330918	For example, our analysis showed that piR-hsa-1945036 expression in individuals carrying the rs8018979 genotype AA (i.e.	('expression', 'MPA', (54, 64))	('rs8018979', 'Var', (93, 102))	('piR', 'Gene', (38, 41))	('rs8018979', 'Mutation', 'rs8018979', (93, 102))	('piR', 'Gene', '8544', (38, 41))
51709	33330918	GG) is significantly lower than that in individuals carrying the rs8018979 genotype AB (i.e.	('rs8018979', 'Mutation', 'rs8018979', (65, 74))	('lower', 'NegReg', (21, 26))	('rs8018979', 'Var', (65, 74))
51721	33330918	AA) genotypes have shorter survival time than patients with rs7175451 AA (i.e.	('patients', 'Species', '9606', (46, 54))	('rs7175451', 'Mutation', 'rs7175451', (60, 69))	('survival time', 'CPA', (27, 40))	('rs7175451', 'Var', (60, 69))	('shorter', 'NegReg', (19, 26))
51725	33330918	For example, the BRCA-associated eSNP rs7175451 was in the LD region of rs7170930 (r2 = 0.855), which was a potential GWAS-identified SNP for response to cytadine analogues (cytosine arabinoside).	('BRCA-associated', 'Disease', (17, 32))	('rs7175451', 'Mutation', 'rs7175451', (38, 47))	('cytadine', 'Chemical', '-', (154, 162))	('cytosine arabinoside', 'Chemical', 'MESH:D003561', (174, 194))	('BRCA', 'Phenotype', 'HP:0003002', (17, 21))	('rs7170930', 'Var', (72, 81))	('rs7175451', 'Var', (38, 47))	('rs7170930', 'Mutation', 'rs7170930', (72, 81))
51737	33330918	For example, the rs10823260 C allele was associated with increased expression levels of piR-hsa-317 (beta = 0.030; P = 0.019) and STOX1 (beta = 0.24; P = 4.51 x 10-8) in BRCA tumor tissues.	('BRCA tumor', 'Disease', 'MESH:D009369', (170, 180))	('STOX1', 'Gene', (130, 135))	('rs10823260 C', 'Var', (17, 29))	('piR', 'Gene', '8544', (88, 91))	('BRCA', 'Phenotype', 'HP:0003002', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('STOX1', 'Gene', '219736', (130, 135))	('BRCA tumor', 'Disease', (170, 180))	('increased', 'PosReg', (57, 66))	('expression levels', 'MPA', (67, 84))	('piR', 'Gene', (88, 91))	('rs10823260', 'Mutation', 'rs10823260', (17, 27))
51739	33330918	For example, the rs10215854 A allele was associated with a decreased expression level of piR-hsa-29218 in BLCA tumor tissues; besides, piR-hsa-29218 was also reported to play a crucial role in the development of bladder cancer.	('expression level', 'MPA', (69, 85))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('decreased', 'NegReg', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('piR', 'Gene', '8544', (135, 138))	('piR', 'Gene', '8544', (89, 92))	('bladder cancer', 'Phenotype', 'HP:0009725', (212, 226))	('rs10215854 A', 'Var', (17, 29))	('BLCA tumor', 'Disease', (106, 116))	('rs10215854', 'Mutation', 'rs10215854', (17, 27))	('piR', 'Gene', (135, 138))	('bladder cancer', 'Disease', 'MESH:D001749', (212, 226))	('bladder cancer', 'Disease', (212, 226))	('BLCA tumor', 'Disease', 'MESH:D009369', (106, 116))	('piR', 'Gene', (89, 92))
51742	33330918	First, this is the first eQTL database to systematically evaluate the effects of genetic variants on piRNA expression across 33 cancer types.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('effects', 'Reg', (70, 77))	('piR', 'Gene', '8544', (101, 104))	('genetic variants', 'Var', (81, 97))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('piR', 'Gene', (101, 104))	('cancer', 'Disease', (128, 134))
51752	33330918	single-nucleotide variants [SNVs], small insertions and deletions, genomic rearrangements and structural variations) on gene expression, a systematic analysis between somatic mutations and piRNA expression needs to be further performed and incorporated into this database.	('piR', 'Gene', '8544', (189, 192))	('piR', 'Gene', (189, 192))	('gene expression', 'biological_process', 'GO:0010467', ('120', '135'))	('single-nucleotide variants', 'Var', (0, 26))
51771	30132150	Despite that ALK1 inhibitors exhibited promising results in a range of different mouse models of cancer, clinical trials with the receptor decoy dalantercept (Acceleron Pharma) failed to show substantial benefit in different cancer types.	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (97, 103))	('ALK1', 'Gene', (13, 17))	('cancer', 'Disease', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('mouse', 'Species', '10090', (81, 86))	('inhibitors', 'Var', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
51808	30132150	Except for KIRC, the remaining tumor types all showed a broad range of ACVRL1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('ACVRL1', 'Gene', (71, 77))	('tumor', 'Disease', (31, 36))	('ACVRL1', 'Gene', '94', (71, 77))	('mutations', 'Var', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
51815	30132150	In conclusion, these results suggest that the observed ACVRL1 genetic lesions in epithelial cells most likely signify passenger events and not driver mutations.	('ACVRL1', 'Gene', '94', (55, 61))	('ACVRL1', 'Gene', (55, 61))	('genetic lesions', 'Var', (62, 77))
51866	30132150	In line with these observations, amplification of ACVRL1 did not confer tumors the biological advantage typical of a putative oncogenic driver.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('biological advantage', 'CPA', (83, 103))	('amplification', 'Var', (33, 46))	('ACVRL1', 'Gene', (50, 56))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('ACVRL1', 'Gene', '94', (50, 56))
51867	30132150	Interestingly, some of the loss of function mutations observed in tumors are reported to affect the receptor kinase domain (e.g., the missense R411Q, and the truncating W406*, S462*, and E470* mutations) and have already been described in human hereditary telangiectasia (HHT)2, an autosomal dominant genetic vascular disorder caused by mutations in ACVRL1.	('R411Q', 'Mutation', 'rs121909284', (143, 148))	('telangiectasia', 'Phenotype', 'HP:0001009', (256, 270))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('genetic vascular disorder', 'Disease', (301, 326))	('human', 'Species', '9606', (239, 244))	('S462*', 'SUBSTITUTION', 'None', (176, 181))	('E470*', 'SUBSTITUTION', 'None', (187, 192))	('W406*', 'SUBSTITUTION', 'None', (169, 174))	('caused', 'Reg', (327, 333))	('truncating', 'MPA', (158, 168))	('hereditary telangiectasia', 'Disease', (245, 270))	('hereditary telangiectasia', 'Disease', 'MESH:D013684', (245, 270))	('genetic vascular disorder', 'Disease', 'MESH:D030342', (301, 326))	('receptor kinase domain', 'MPA', (100, 122))	('E470*', 'Var', (187, 192))	('vascular disorder', 'Phenotype', 'HP:0002597', (309, 326))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('ACVRL1', 'Gene', (350, 356))	('affect', 'Reg', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('HHT)2', 'Gene', '94', (272, 277))	('S462*', 'Var', (176, 181))	('tumors', 'Disease', (66, 72))	('missense R411Q', 'Var', (134, 148))	('mutations', 'Var', (44, 53))	('ACVRL1', 'Gene', '94', (350, 356))	('W406*', 'Var', (169, 174))
51872	30132150	The exact role of CLEC14A in angiogenesis is still debated, as two independent studies (based on rather different investigational endpoints) reported opposite effects when knocking out Clec14a in a mouse model of lung carcinogenesis.	('Clec14a', 'Gene', (185, 192))	('knocking out', 'Var', (172, 184))	('lung carcinogenesis', 'Disease', (213, 232))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (213, 232))	('angiogenesis', 'biological_process', 'GO:0001525', ('29', '41'))	('mouse', 'Species', '10090', (198, 203))
51914	30623081	Controls were patients diagnosed with musculoskeletal diseases (ICD-9, 410-739 and ICD-10, M00-M99; 89%) and skin diseases (ICD-9, 680-709 and ICD-10, L00-L99; 11%).	('musculoskeletal diseases', 'Disease', (38, 62))	('skin diseases', 'Disease', (109, 122))	('musculoskeletal diseases', 'Disease', 'MESH:D009140', (38, 62))	('skin diseases', 'Disease', 'MESH:D012871', (109, 122))	('patients', 'Species', '9606', (14, 22))	('ICD-9', 'Var', (124, 129))
51926	30623081	The following missing data were multiply imputed: occupational class (6943, 11%), smoking (6968, 11%), alcohol consumption (19 198, 30%), hypertension (8507, 13%), diabetes (8508, 13%), and obesity (8508, 13%).	('obesity', 'Disease', 'MESH:D009765', (190, 197))	('diabetes', 'Disease', (164, 172))	('obesity', 'Disease', (190, 197))	('obesity', 'Phenotype', 'HP:0001513', (190, 197))	('diabetes', 'Disease', 'MESH:D003920', (164, 172))	('hypertension', 'Disease', 'MESH:D006973', (138, 150))	('alcohol', 'Chemical', 'MESH:D000438', (103, 110))	('hypertension', 'Disease', (138, 150))	('8507', 'Var', (152, 156))	('hypertension', 'Phenotype', 'HP:0000822', (138, 150))
52033	29744601	Risk-scores were calculated by summing 7 risk factors (SM+, LVI+, >= pT3, preoperative CKD+, cN+ or pN+, hydronephrosis+, and tumor in ureter) that were independently associated with recurrence-free survival by multivariate analysis.	('cN+', 'Disease', (93, 96))	('SM+', 'Var', (55, 58))	('tumor in ureter', 'Phenotype', 'HP:0100516', (126, 141))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('associated', 'Reg', (167, 177))	('hydronephrosis', 'Disease', 'MESH:D006869', (105, 119))	('hydronephrosis', 'Disease', (105, 119))	('tumor', 'Disease', (126, 131))
52044	28988769	We previously reported an integrated genomic analysis of 131 MIBC samples, finding a high somatic mutation rate (median 5.5 per megabase) similar to that of non-small cell lung cancer and melanoma; statistically significant recurrent mutations in 32 genes, including several chromatin regulators; four expression subtypes; recurrent in-frame activating FGFR3-TACC3 fusions; and potential therapeutic targets in 69% of the samples.	('fusions', 'Var', (365, 372))	('FGFR', 'molecular_function', 'GO:0005007', ('353', '357'))	('in-frame', 'Reg', (333, 341))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (161, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (157, 183))	('TACC3', 'Gene', '10460', (359, 364))	('TACC3', 'Gene', (359, 364))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanoma', 'Disease', (188, 196))	('MIBC', 'Chemical', '-', (61, 65))	('non-small cell lung cancer', 'Disease', (157, 183))	('FGFR3', 'Gene', (353, 358))	('chromatin', 'cellular_component', 'GO:0000785', ('275', '284'))	('mutations', 'Var', (234, 243))	('FGFR3', 'Gene', '2261', (353, 358))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('melanoma', 'Disease', 'MESH:D008545', (188, 196))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (157, 183))
52060	28988769	A third signature, consisting of C>T transitions at CpG dinucleotides, is likely due to 5-methylcytosine deamination.	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (52, 69))	('5-methylcytosine deamination', 'MPA', (88, 116))	('C>T', 'Var', (33, 36))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (88, 104))
52062	28988769	The fifth, ERCC2, had a relatively uniform spectrum of base changes and has been associated with ERCC2 mutations.	('mutations', 'Var', (103, 112))	('ERCC2', 'Gene', (11, 16))	('ERCC2', 'Gene', '2068', (97, 102))	('ERCC2', 'Gene', (97, 102))	('base changes', 'MPA', (55, 67))	('ERCC2', 'Gene', '2068', (11, 16))	('associated', 'Reg', (81, 91))
52063	28988769	As expected, levels of APOBEC-signature mutagenesis correlated with expression of APOBEC3A and APOBEC3B (Figure S2D).	('APOBEC3B', 'Gene', (95, 103))	('APOBEC', 'cellular_component', 'GO:0030895', ('82', '88'))	('expression', 'MPA', (68, 78))	('APOBEC3B', 'Gene', '9582', (95, 103))	('mutagenesis', 'biological_process', 'GO:0006280', ('40', '51'))	('mutagenesis', 'Var', (40, 51))	('APOBEC', 'cellular_component', 'GO:0030895', ('95', '101'))	('APOBEC3A', 'Gene', (82, 90))	('APOBEC', 'cellular_component', 'GO:0030895', ('23', '29'))	('APOBEC3A', 'Gene', '200315', (82, 90))
52064	28988769	C>T at CpG and ERCC2 mutation signatures accounted for 20% and 8% of total SNVs, respectively.	('ERCC2', 'Gene', '2068', (15, 20))	('C>T', 'Var', (0, 3))	('ERCC2', 'Gene', (15, 20))	('mutation', 'Var', (21, 29))
52065	28988769	64% of all mutations, as well as 62% of APOBEC-a- and 75% of APOBEC-b-signature mutations (likelihood of signature association >= 0.7; Methods) were clonal (cancer cell fraction >= 0.9), suggesting that more than half of the APOBEC-signature mutation load was likely generated early in bladder cancer development.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('mutations', 'Var', (11, 20))	('APOBEC', 'cellular_component', 'GO:0030895', ('61', '67'))	('mutations', 'Var', (80, 89))	('APOBEC-a-', 'Gene', (40, 49))	('APOBEC-b-signature', 'Gene', (61, 79))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('APOBEC', 'cellular_component', 'GO:0030895', ('40', '46'))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (294, 300))	('bladder cancer', 'Phenotype', 'HP:0009725', (286, 300))	('cancer', 'Disease', (157, 163))	('APOBEC', 'cellular_component', 'GO:0030895', ('225', '231'))	('cell fraction', 'cellular_component', 'GO:0000267', ('164', '177'))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('bladder cancer', 'Disease', 'MESH:D001749', (286, 300))	('bladder cancer', 'Disease', (286, 300))
52066	28988769	Unsupervised clustering of APOBEC-a and -b, ERCC2, and C>T-at-CpG signatures identified four mutational signature clusters, MSig1 to MSig4 (Figure 1; Figure S2E), which were associated with overall survival (Figure 1B, p = 1.4 10-4).	('APOBEC', 'cellular_component', 'GO:0030895', ('27', '33'))	('MSig1', 'Var', (124, 129))	('associated', 'Reg', (174, 184))	('APOBEC-a', 'Gene', (27, 35))	('overall survival', 'MPA', (190, 206))	('ERCC2', 'Gene', '2068', (44, 49))	('ERCC2', 'Gene', (44, 49))
52067	28988769	Patients with MSig1 cancers (high APOBEC-signature mutagenesis and high mutation burden) showed an exceptional 75% 5-year survival probability.	('high', 'Var', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Patients', 'Species', '9606', (0, 8))	('MSig1 cancers', 'Disease', (14, 27))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('APOBEC', 'cellular_component', 'GO:0030895', ('34', '40'))	('MSig1 cancers', 'Disease', 'MESH:D009369', (14, 27))	('mutagenesis', 'biological_process', 'GO:0006280', ('51', '62'))
52069	28988769	MSig4 cluster samples were enriched in both ERCC2 signature mutations (average contribution 49% vs. 17% in all others, Figure 1A) and ERCC2 mutations (24 out of 39, p = 10-13).	('ERCC2', 'Gene', (134, 139))	('MSig4', 'Gene', (0, 5))	('ERCC2', 'Gene', '2068', (44, 49))	('ERCC2', 'Gene', '2068', (134, 139))	('mutations', 'Var', (140, 149))	('mutations', 'Var', (60, 69))	('ERCC2', 'Gene', (44, 49))
52070	28988769	ERCC2 signature mutations were highest in smokers with ERCC2 mutations (p = 6.9 x 10-11); for cases with wild type ERCC2, ERCC2 signature mutations were at higher levels in smokers than in non-smokers (Figure S2F).	('ERCC2', 'Gene', '2068', (115, 120))	('ERCC2', 'Gene', '2068', (55, 60))	('ERCC2', 'Gene', (115, 120))	('mutations', 'Var', (61, 70))	('ERCC2', 'Gene', (55, 60))	('ERCC2', 'Gene', '2068', (122, 127))	('ERCC2', 'Gene', '2068', (0, 5))	('ERCC2', 'Gene', (122, 127))	('ERCC2', 'Gene', (0, 5))
52071	28988769	MutSig 2CV identified 58 significantly mutated genes (SMGs) (q < 0.1; Tables S1 and S2.9).	('SMG', 'Gene', (54, 57))	('SMG', 'Gene', '23034', (54, 57))	('mutated', 'Var', (39, 46))	('S2.9', 'Gene', (84, 88))	('S2.9', 'Gene', '6235', (84, 88))
52075	28988769	Similar analyses showed co-occurrence of alterations in TP53 and RB1, TP53 and E2F3, and FGFR3 and CDKN2A (Table S2.11, q < 0.2).	('RB1', 'Gene', (65, 68))	('E2F3', 'Gene', (79, 83))	('E2F3', 'Gene', '1871', (79, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('CDKN2A', 'Gene', (99, 105))	('TP53', 'Gene', '7157', (70, 74))	('TP53', 'Gene', '7157', (56, 60))	('FGFR3', 'Gene', (89, 94))	('S2.1', 'Gene', (113, 117))	('CDKN2A', 'Gene', '1029', (99, 105))	('RB1', 'Gene', '5925', (65, 68))	('S2.1', 'Gene', '6227', (113, 117))	('TP53', 'Gene', (56, 60))	('TP53', 'Gene', (70, 74))	('alterations', 'Var', (41, 52))	('FGFR3', 'Gene', '2261', (89, 94))
52076	28988769	FGFR3 mutations and CDKN2A focal SCNAs co-occurred in 27 (7%) tumors (Table S1), which may be MIBCs that have progressed from non-invasive tumors.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('MIBCs', 'Chemical', '-', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('FGFR3', 'Gene', (0, 5))	('co-occurred', 'Reg', (39, 50))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('CDKN2A', 'Gene', (20, 26))	('focal SCNAs', 'Disease', (27, 38))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('CDKN2A', 'Gene', '1029', (20, 26))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
52077	28988769	3 of 4 tumors with plasmacytoid histology had nonsense CDH1 mutations, consistent with a previous report.	('nonsense', 'Var', (46, 54))	('CDH1', 'Gene', (55, 59))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('CDH1', 'Gene', '999', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('mutations', 'Var', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
52079	28988769	The four MutCN clusters were characterized by: TP53 and RB1 mutations, SOX4/E2F3 amplification, mutations in chromatin-modifying genes, and FGFR3, KDM6A, and STAG2 mutations.	('FGFR', 'molecular_function', 'GO:0005007', ('140', '144'))	('KDM6A', 'Gene', (147, 152))	('RB1', 'Gene', (56, 59))	('E2F3', 'Gene', (76, 80))	('mutations', 'Var', (96, 105))	('STAG2', 'Gene', '10735', (158, 163))	('FGFR3', 'Gene', (140, 145))	('E2F3', 'Gene', '1871', (76, 80))	('SOX4', 'Gene', (71, 75))	('TP53', 'Gene', '7157', (47, 51))	('RB1', 'Gene', '5925', (56, 59))	('STAG2', 'Gene', (158, 163))	('FGFR3', 'Gene', '2261', (140, 145))	('SOX4', 'Gene', '6659', (71, 75))	('KDM6A', 'Gene', '7403', (147, 152))	('chromatin', 'cellular_component', 'GO:0000785', ('109', '118'))	('mutations', 'Var', (164, 173))	('amplification', 'PosReg', (81, 94))	('mutations', 'Var', (60, 69))	('TP53', 'Gene', (47, 51))
52081	28988769	Polysolver-based HLA mutation detection identified 21 non-synonymous variants in 19 of 412 tumors (4.6%, Table S2.13).	('tumors', 'Disease', (91, 97))	('non-synonymous variants', 'Var', (54, 77))	('S2.1', 'Gene', (111, 115))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('HLA', 'Gene', '3119', (17, 20))	('S2.1', 'Gene', '6227', (111, 115))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('HLA', 'Gene', (17, 20))
52082	28988769	HLA mutations were more common in MSig1 cluster (p = 0.039), suggesting that they may have resulted from APOBEC-signature mutagenesis.	('HLA', 'Gene', '3119', (0, 3))	('mutagenesis', 'biological_process', 'GO:0006280', ('122', '133'))	('MSig1 cluster', 'Gene', (34, 47))	('HLA', 'Gene', (0, 3))	('APOBEC', 'cellular_component', 'GO:0030895', ('105', '111'))	('mutations', 'Var', (4, 13))
52083	28988769	HLA mutations were somewhat more common in patients with prior BCG treatment, 4 of 35 (11.4%) vs. 8 of 261 (3.1%) without prior BCG treatment (p = 0.04, Chi-square test), perhaps positively selected in response to immunological pressure.	('HLA', 'Gene', '3119', (0, 3))	('patients', 'Species', '9606', (43, 51))	('common', 'Reg', (33, 39))	('HLA', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))
52085	28988769	The most common was an intra-chromosomal FGFR3-TACC3 fusion (n = 10).	('TACC3', 'Gene', (47, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('FGFR3', 'Gene', '2261', (41, 46))	('FGFR3', 'Gene', (41, 46))	('TACC3', 'Gene', '10460', (47, 52))	('fusion', 'Var', (53, 59))
52087	28988769	PPARG was involved in 4 TSEN2-PPARG and 2 MKRN2-PPARG fusions, and PPARG expression levels were higher than in samples without such fusions (p = 6 x 10-3).	('fusions', 'Var', (54, 61))	('PPARG and 2', 'Gene', '5468', (30, 41))	('involved', 'Reg', (10, 18))	('expression levels', 'MPA', (73, 90))	('TSEN2', 'Gene', (24, 29))	('PPARG', 'Gene', (67, 72))	('MKRN2', 'Gene', (42, 47))	('MKRN2', 'Gene', '23609', (42, 47))	('PPARG', 'Gene', '5468', (67, 72))	('PPARG', 'Gene', '5468', (30, 35))	('PPARG', 'Gene', (30, 35))	('PPARG', 'Gene', (0, 5))	('PPARG', 'Gene', '5468', (0, 5))	('TSEN2', 'Gene', '80746', (24, 29))	('higher', 'PosReg', (96, 102))	('PPARG', 'Gene', '5468', (48, 53))	('PPARG', 'Gene', (48, 53))
52088	28988769	Four of the six PPARG fusions led to mRNA products for which the predicted proteins retained both PPARG's DNA-binding and ligand-binding domains, suggesting that they were functional (Figure S2I).	('DNA-binding', 'MPA', (106, 117))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('PPARG', 'Gene', '5468', (16, 21))	('fusions', 'Var', (22, 29))	('PPARG', 'Gene', (16, 21))	('PPARG', 'Gene', '5468', (98, 103))	('PPARG', 'Gene', (98, 103))	('ligand-binding domains', 'MPA', (122, 144))	('binding', 'molecular_function', 'GO:0005488', ('129', '136'))	('mRNA products', 'MPA', (37, 50))	('DNA-binding', 'molecular_function', 'GO:0003677', ('106', '117'))	('ligand', 'molecular_function', 'GO:0005488', ('122', '128'))
52090	28988769	In lines 5637 and 1A6 we identified CASC15-PPARG fusions that retained PPARG's full DNA binding domain; in UC9 we identified an NR2C2-PPARG fusion that retained 75% of PPARG's ligand-binding domain.	('ligand-binding', 'MPA', (176, 190))	('CASC15', 'Gene', (36, 42))	('fusion', 'Var', (140, 146))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('PPARG', 'Gene', '5468', (71, 76))	('binding', 'molecular_function', 'GO:0005488', ('183', '190'))	('DNA binding', 'molecular_function', 'GO:0003677', ('84', '95'))	('PPARG', 'Gene', '5468', (134, 139))	('NR2C2', 'Gene', '7182', (128, 133))	('CASC15', 'Gene', '401237', (36, 42))	('PPARG', 'Gene', '5468', (43, 48))	('PPARG', 'Gene', (43, 48))	('PPARG', 'Gene', (71, 76))	('NR2C2', 'Gene', (128, 133))	('PPARG', 'Gene', (134, 139))	('PPARG', 'Gene', '5468', (168, 173))	('ligand', 'molecular_function', 'GO:0005488', ('176', '182'))	('PPARG', 'Gene', (168, 173))
52094	28988769	Samples in cluster 4 showed frequent FGFR3 mutation (p = 6 x 10-9) and CDKN2A deletion (p = 4 x 10-13), and had no TP53 or RB1mutations.	('FGFR3', 'Gene', (37, 42))	('RB1', 'Gene', '5925', (123, 126))	('CDKN2A', 'Gene', (71, 77))	('mutation', 'Var', (43, 51))	('TP53', 'Gene', '7157', (115, 119))	('deletion', 'Var', (78, 86))	('CDKN2A', 'Gene', '1029', (71, 77))	('TP53', 'Gene', (115, 119))	('FGFR3', 'Gene', '2261', (37, 42))	('RB1', 'Gene', (123, 126))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))
52097	28988769	Analysis of hypomethylated CpG sites in this group revealed 12 genes whose hypomethylation was significantly correlated with increased expression (Figure S3F; Table S2.16).	('increased', 'PosReg', (125, 134))	('expression', 'MPA', (135, 145))	('S2.1', 'Gene', '6227', (165, 169))	('S2.1', 'Gene', (165, 169))	('hypomethylation', 'Var', (75, 90))
52098	28988769	Integrated analysis of DNA methylation and gene expression identified 158 genes that were epigenetically silenced (Table S2.17, Figure S3G).	('gene expression', 'biological_process', 'GO:0010467', ('43', '58'))	('DNA methylation', 'biological_process', 'GO:0006306', ('23', '38'))	('S2.1', 'Gene', (121, 125))	('epigenetically', 'Var', (90, 104))	('S2.1', 'Gene', '6227', (121, 125))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))
52099	28988769	Although some of the silencing events were probably background epigenetic noise, CDKN2A, FAT1, and CASP8 were mutated in some tumors and (mutually exclusively) epigenetically silenced in others (Figure S3H).	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('silencing', 'MPA', (21, 30))	('mutated', 'Var', (110, 117))	('CASP8', 'Gene', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('CASP8', 'Gene', '841', (99, 104))	('CDKN2A', 'Gene', (81, 87))	('CDKN2A', 'Gene', '1029', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('FAT1', 'Gene', '2195', (89, 93))	('FAT1', 'Gene', (89, 93))
52106	28988769	Several features suggest a dominant role of FGFR3 in 44% of the luminal-papillary tumors: enrichment with FGFR3 mutations (42/57; p < 10-9), amplification (5/5; p = 5 x 10-3), overexpression (4-fold vs. median, 49/67; p < 10-11), and FGFR3-TACC3 fusions (8/10, p = 4 x 10-3).	('mutations', 'Var', (112, 121))	('papillary tumors', 'Phenotype', 'HP:0007482', (72, 88))	('TACC3', 'Gene', '10460', (240, 245))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('TACC3', 'Gene', (240, 245))	('FGFR3', 'Gene', (234, 239))	('overexpression', 'PosReg', (176, 190))	('FGFR3', 'Gene', '2261', (234, 239))	('FGFR3', 'Gene', (44, 49))	('FGFR3', 'Gene', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('FGFR3', 'Gene', '2261', (44, 49))	('amplification', 'MPA', (141, 154))	('luminal-papillary tumors', 'Disease', (64, 88))	('FGFR3', 'Gene', '2261', (106, 111))	('luminal-papillary tumors', 'Disease', 'MESH:D002291', (64, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('FGFR', 'molecular_function', 'GO:0005007', ('234', '238'))
52117	28988769	The subtype included 37 of 45 tumors squamous features (p < 10-11), was enriched in TP53 mutations (p = 5 x 10-3), and was more common in females (33% vs. 21% in other subtypes; p = 0.024).	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumors squamous', 'Disease', 'MESH:D002294', (30, 45))	('TP53', 'Gene', '7157', (84, 88))	('tumors squamous', 'Disease', (30, 45))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutations', 'Var', (89, 98))	('TP53', 'Gene', (84, 88))
52121	28988769	Loss of TP53 and RB1 is a hallmark of small cell NE cancer, and 10 of 20 (50%) samples had mutations in both TP53 and RB1, or TP53 mutation and E2F3 amplification.	('TP53', 'Gene', (126, 130))	('RB1', 'Gene', '5925', (17, 20))	('RB1', 'Gene', (118, 121))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mutation', 'Var', (131, 139))	('TP53', 'Gene', '7157', (109, 113))	('Loss', 'NegReg', (0, 4))	('TP53', 'Gene', '7157', (8, 12))	('RB1', 'Gene', '5925', (118, 121))	('TP53', 'Gene', '7157', (126, 130))	('E2F3', 'Gene', (144, 148))	('small cell NE cancer', 'Phenotype', 'HP:0030357', (38, 58))	('cancer', 'Disease', (52, 58))	('RB1', 'Gene', (17, 20))	('E2F3', 'Gene', '1871', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (91, 100))	('TP53', 'Gene', (8, 12))	('TP53', 'Gene', (109, 113))
52124	28988769	As we had previously shown, several proteins (GATA3, EGFR, CDH1, HER2) and miRNAs (miR-200s, miR-99a, miR-100) were strongly differentially expressed among the mRNA subtypes (Figures 2, S4D,E and S5A; Table S2.21, S.22).	('HER2', 'Gene', '2064', (65, 69))	('miR-200s', 'Var', (83, 91))	('GATA3', 'Gene', (46, 51))	('CDH1', 'Gene', '999', (59, 63))	('miR-100', 'Gene', '406892', (102, 109))	('GATA3', 'Gene', '2625', (46, 51))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('miR-99a', 'Gene', '407055', (93, 100))	('EGFR', 'Gene', '1956', (53, 57))	('differentially', 'Reg', (125, 139))	('EGFR', 'Gene', (53, 57))	('miR-100', 'Gene', (102, 109))	('miR-99a', 'Gene', (93, 100))	('HER2', 'Gene', (65, 69))	('CDH1', 'Gene', (59, 63))
52125	28988769	The p53/Cell Cycle pathway was inactivated in 89% of tumors, with TP53 mutations in 48%, MDM2 amplification (copy number > 4) in 6%, and MDM2 overexpression (>2-fold above the median) in 19%.	('overexpression', 'PosReg', (142, 156))	('p53', 'Gene', '7157', (4, 7))	('MDM2', 'Gene', '4193', (137, 141))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('MDM2', 'Gene', (137, 141))	('inactivated', 'NegReg', (31, 42))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (71, 80))	('MDM2', 'Gene', '4193', (89, 93))	('p53', 'Gene', (4, 7))	('MDM2', 'Gene', (89, 93))	('amplification', 'PosReg', (94, 107))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('Cell Cycle', 'biological_process', 'GO:0007049', ('8', '18'))	('tumors', 'Disease', (53, 59))
52126	28988769	TP53 mutations were enriched in tumors with genome-doubling events (p < 10-7; Table S2.23), suggesting that loss of TP53 activity facilitates genome doubling.	('TP53', 'Gene', (116, 120))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('activity', 'MPA', (121, 129))	('loss', 'Var', (108, 112))	('mutations', 'Var', (5, 14))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('genome doubling', 'CPA', (142, 157))	('tumors', 'Disease', (32, 38))	('TP53', 'Gene', '7157', (116, 120))	('facilitates', 'PosReg', (130, 141))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
52127	28988769	RB1 mutations (17%) were mostly inactivating and associated with reduced mRNA levels.	('reduced', 'NegReg', (65, 72))	('RB1', 'Gene', '5925', (0, 3))	('mRNA levels', 'MPA', (73, 84))	('mutations', 'Var', (4, 13))	('RB1', 'Gene', (0, 3))
52128	28988769	CDKN1A mutations (11%) were predominantly inactivating.	('CDKN1A', 'Gene', (0, 6))	('CDKN1A', 'Gene', '1026', (0, 6))	('mutations', 'Var', (7, 16))
52129	28988769	CDKN2A mutations (7%) and homozygous deletions (22%) were common, as previously described.	('mutations', 'Var', (7, 16))	('CDKN2A', 'Gene', '1029', (0, 6))	('CDKN2A', 'Gene', (0, 6))
52130	28988769	Alterations in DNA repair pathways included mutations in ATM (n = 57; 14%) and ERCC2 (n = 40; 9%) and deletions in RAD51B (n = 10; 2%).	('DNA repair', 'biological_process', 'GO:0006281', ('15', '25'))	('RAD51B', 'Gene', (115, 121))	('RAD51B', 'Gene', '5890', (115, 121))	('ERCC2', 'Gene', (79, 84))	('deletions', 'Var', (102, 111))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('ATM', 'Gene', (57, 60))	('mutations', 'Var', (44, 53))	('ERCC2', 'Gene', '2068', (79, 84))	('DNA repair pathways', 'Pathway', (15, 34))	('ATM', 'Gene', '472', (57, 60))	('Alterations', 'Reg', (0, 11))	('RAD', 'biological_process', 'GO:1990116', ('115', '118'))
52131	28988769	All non-silent ERCC2 mutations were missense, and many mapped within, or within +-10 amino acids of, the conserved helicase domain, suggesting that they impair ERCC2 function and may have dominant negative effects.	('conserved helicase', 'Protein', (105, 123))	('ERCC2', 'Gene', '2068', (15, 20))	('ERCC2', 'Gene', '2068', (160, 165))	('function', 'MPA', (166, 174))	('ERCC2', 'Gene', (15, 20))	('missense', 'Var', (36, 44))	('impair', 'NegReg', (153, 159))	('ERCC2', 'Gene', (160, 165))	('mutations', 'Var', (21, 30))
52132	28988769	The FGFR3, PIK3CA, and RAS oncogenes harbored recurrent hotspot mutations.	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('FGFR3', 'Gene', (4, 9))	('PIK3CA', 'Gene', (11, 17))	('PIK3CA', 'Gene', '5290', (11, 17))	('mutations', 'Var', (64, 73))	('RAS', 'Gene', (23, 26))	('FGFR3', 'Gene', '2261', (4, 9))
52133	28988769	Most FGFR3 mutations were the known S249C or Y373C, were more frequent in lower-stage tumors (21% in T2 vs. 10% in T3,T4; p = 0.003), and were associated with better survival (p = 0.04).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutations', 'Var', (11, 20))	('S249C', 'Mutation', 'rs121913483', (36, 41))	('Y373C', 'Var', (45, 50))	('Y373C', 'Mutation', 'rs121913485', (45, 50))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('better', 'PosReg', (159, 165))	('FGFR3', 'Gene', '2261', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('5', '9'))	('FGFR3', 'Gene', (5, 10))	('S249C', 'Var', (36, 41))
52134	28988769	PIK3CA mutations (n = 100; 22%) were more common in the helical domain (E542 and E545; n = 54 total) than in the kinase domain (M1043, H1047; n = 10 total), and were likely due to APOBEC mutagenic activity.	('APOBEC', 'cellular_component', 'GO:0030895', ('180', '186'))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('E542', 'Var', (72, 76))	('E545', 'Var', (81, 85))
52136	28988769	Ten of the 39 SMGs with mutation frequency >5% were in chromatin-modifying or chromatin-regulatory genes: a histone demethylase (KDM6A), histone methyltransferases (KMT2A, KMT2C, KMT2D), histone acetylases (CREBBP, EP300, KANSL1), a member of the SWI/SNF chromatin remodeling complex (ARID1A), and Polycomb group genes (ASXL1, ASXL2).	('EP300', 'Gene', (215, 220))	('chromatin', 'cellular_component', 'GO:0000785', ('55', '64'))	('KMT2D', 'Gene', '8085', (179, 184))	('KMT2A', 'Gene', '4297', (165, 170))	('SMG', 'Gene', (14, 17))	('KANSL1', 'Gene', '284058', (222, 228))	('chromatin', 'cellular_component', 'GO:0000785', ('78', '87'))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('255', '283'))	('ASXL1', 'Gene', '171023', (320, 325))	('CREBBP', 'Gene', (207, 213))	('KANSL1', 'Gene', (222, 228))	('KDM6A', 'Gene', '7403', (129, 134))	('ASXL2', 'Gene', '55252', (327, 332))	('KMT2A', 'Gene', (165, 170))	('ARID1A', 'Gene', (285, 291))	('KMT2D', 'Gene', (179, 184))	('mutation', 'Var', (24, 32))	('EP300', 'Gene', '2033', (215, 220))	('SMG', 'Gene', '23034', (14, 17))	('ASXL1', 'Gene', (320, 325))	('CREBBP', 'Gene', '1387', (207, 213))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('255', '275'))	('ARID1A', 'Gene', '8289', (285, 291))	('ASXL2', 'Gene', (327, 332))	('KDM6A', 'Gene', (129, 134))	('KMT2C', 'Gene', '58508', (172, 177))	('KMT2C', 'Gene', (172, 177))
52137	28988769	Mutations in these genes were predominantly inactivating (50% frame-shift or nonsense mutations vs. 26% in other SMGs; p = 10-30), strongly suggesting that they are functionally relevant.	('SMG', 'Gene', (113, 116))	('SMG', 'Gene', '23034', (113, 116))	('frame-shift', 'Var', (62, 73))	('Mutations', 'Var', (0, 9))	('nonsense mutations', 'Var', (77, 95))
52138	28988769	ARID1A, CREBBP, and KDM6A were also targets of genomic deletion (4.2%, 14.2%, 4.9%, respectively, Table S1).	('KDM6A', 'Gene', (20, 25))	('ARID1A', 'Gene', '8289', (0, 6))	('CREBBP', 'Gene', '1387', (8, 14))	('KDM6A', 'Gene', '7403', (20, 25))	('ARID1A', 'Gene', (0, 6))	('deletion', 'Var', (55, 63))	('CREBBP', 'Gene', (8, 14))
52139	28988769	For example, lncRNA cluster 3 (n = 76), a better-survival subset of the luminal-papillary subtype, was depleted in TP53 mutations but enriched in FGRF3 mutations and fusions.	('fusions', 'Var', (166, 173))	('mutations', 'Var', (152, 161))	('TP53', 'Gene', '7157', (115, 119))	('depleted', 'NegReg', (103, 111))	('TP53', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))	('FGRF3', 'Gene', (146, 151))
52152	28988769	For HPV we identified genomic integration in 4 tumors, with breakpoints associated with BCL2L1, SLC2A1-AS1, DEC1, SEC16A, and CCDC68 (Tables S3.4-3.6, 3.9).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('BCL2L1', 'Gene', (88, 94))	('BCL2', 'molecular_function', 'GO:0015283', ('88', '92'))	('genomic', 'Var', (22, 29))	('SEC16A', 'Gene', (114, 120))	('BCL2L1', 'Gene', '598', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('CCDC68', 'Gene', (126, 132))	('SEC16A', 'Gene', '9919', (114, 120))	('DEC1', 'Gene', '50514', (108, 112))	('SLC2A1-AS1', 'Gene', (96, 106))	('DEC1', 'Gene', (108, 112))	('SLC2A1-AS1', 'Gene', '440584', (96, 106))	('CCDC68', 'Gene', '80323', (126, 132))
52166	28988769	The variables with largest coefficients were AJCC stages III and IV, mRNA neuronal and luminal subtypes, low mutation rate MSig 2, and miRNA subtype 4, which is a subset of basal-squamous cases, and KLF4 regulon activity, all of which were associated with worse survival.	('KLF4', 'Gene', (199, 203))	('KLF4', 'Gene', '9314', (199, 203))	('MSig 2', 'Gene', (123, 129))	('low mutation rate', 'Var', (105, 122))
52172	28988769	NMIBC occurs mainly as papillary disease with frequent FGFR3 mutations, whereas MIBC has a more diverse mutation spectrum as well as copy-number instability.	('papillary disease', 'Disease', (23, 40))	('papillary disease', 'Phenotype', 'HP:0007482', (23, 40))	('FGFR3', 'Gene', '2261', (55, 60))	('mutations', 'Var', (61, 70))	('NMIBC', 'Disease', (0, 5))	('papillary disease', 'Disease', 'MESH:D002291', (23, 40))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('FGFR3', 'Gene', (55, 60))	('MIBC', 'Chemical', '-', (80, 84))	('MIBC', 'Chemical', '-', (1, 5))
52173	28988769	We identified 34 additional SMGs and 158 genes that are subject to epigenetic silencing, both of which may offer additional potential therapeutic targets, fusion events that implicate PPARG as a key gene in bladder cancer development, and refined subtypes defined by considering both miRNA and lncRNA profiling.	('PPARG', 'Gene', '5468', (184, 189))	('bladder cancer', 'Disease', 'MESH:D001749', (207, 221))	('PPARG', 'Gene', (184, 189))	('bladder cancer', 'Disease', (207, 221))	('epigenetic silencing', 'Var', (67, 87))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('bladder cancer', 'Phenotype', 'HP:0009725', (207, 221))	('SMG', 'Gene', (28, 31))	('SMG', 'Gene', '23034', (28, 31))
52174	28988769	MIBCs show high overall mutation rates similar to those of melanoma and non-small cell lung cancers, and we confirm that these high rates are principally associated with mutation signatures for an endogenous mutagenic enzyme, APOBEC cytidine deaminase.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (76, 98))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (76, 99))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('mutation', 'Var', (170, 178))	('APOBEC', 'cellular_component', 'GO:0030895', ('226', '232'))	('cytidine deaminase', 'Gene', (233, 251))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (72, 99))	('MIBCs', 'Chemical', '-', (0, 5))	('mutation', 'Var', (24, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('melanoma', 'Disease', (59, 67))	('lung cancers', 'Phenotype', 'HP:0100526', (87, 99))	('associated', 'Reg', (154, 164))	('non-small cell lung cancers', 'Disease', (72, 99))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (72, 98))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (72, 99))	('cytidine deaminase', 'Gene', '978', (233, 251))
52175	28988769	Most bladder cancer mutations are clonal, suggesting that APOBEC's mutagenic activity occurs early in bladder cancer development.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('bladder cancer', 'Phenotype', 'HP:0009725', (5, 19))	('APOBEC', 'Gene', (58, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('bladder cancer', 'Disease', (102, 116))	('bladder cancer', 'Disease', (5, 19))	('bladder cancer', 'Disease', 'MESH:D001749', (5, 19))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('APOBEC', 'cellular_component', 'GO:0030895', ('58', '64'))	('mutations', 'Var', (20, 29))
52179	28988769	Chromatin modifier gene mutations are common in bladder cancer and also open potential therapeutic opportunities through rebalancing acetylation and deacetylation, and through other chromatin modifications.	('bladder cancer', 'Disease', (48, 62))	('Chromatin modifier gene', 'Gene', (0, 23))	('Chromatin', 'cellular_component', 'GO:0000785', ('0', '9'))	('deacetylation', 'MPA', (149, 162))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('rebalancing acetylation', 'MPA', (121, 144))	('chromatin', 'cellular_component', 'GO:0000785', ('182', '191'))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))	('mutations', 'Var', (24, 33))	('common', 'Reg', (38, 44))
52180	28988769	Recent studies have identified BRD4-EZH2 chromatin modification as an important growth pathway in bladder cancer, especially in tumors with loss of KDM6A, and shown in preclinical models that the BET inhibitor JQ1 and inhibition of EZH2 have therapeutic benefit.	('BRD4', 'Gene', '23476', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('chromatin modification', 'biological_process', 'GO:0006325', ('41', '63'))	('KDM6A', 'Gene', '7403', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('EZH2', 'Gene', '2146', (232, 236))	('EZH2', 'Gene', (232, 236))	('chromatin', 'cellular_component', 'GO:0000785', ('41', '50'))	('BET', 'Gene', '92737', (196, 199))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('loss', 'Var', (140, 144))	('KDM6A', 'Gene', (148, 153))	('EZH2', 'Gene', '2146', (36, 40))	('BRD4', 'Gene', (31, 35))	('chromatin modification', 'biological_process', 'GO:0016569', ('41', '63'))	('EZH2', 'Gene', (36, 40))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('BET', 'Gene', (196, 199))
52182	28988769	As one example the p53/Rb pathway is being targeted in a multicenter phase II trial evaluating palbociclib (PD-0332991) in patients with metastatic urothelial carcinoma who have cyclin-dependent kinase inhibitor 2A (CDKN2A) loss and retained retinoblastoma (Rb) expression (NCT02334527).	('retained retinoblastoma', 'Disease', (233, 256))	('retained retinoblastoma', 'Disease', 'MESH:D012175', (233, 256))	('p53', 'Gene', (19, 22))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (178, 214))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('195', '211'))	('Rb', 'Gene', '5925', (258, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('178', '211'))	('patients', 'Species', '9606', (123, 131))	('CDKN2A', 'Gene', (216, 222))	('loss', 'NegReg', (224, 228))	('retinoblastoma', 'Phenotype', 'HP:0009919', (242, 256))	('urothelial carcinoma', 'Disease', (148, 168))	('NCT02334527', 'Var', (274, 285))	('CDKN2A', 'Gene', '1029', (216, 222))	('PD-0332991', 'Chemical', 'MESH:C500026', (108, 118))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (178, 214))	('Rb', 'Gene', '5925', (23, 25))	('p53', 'Gene', '7157', (19, 22))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (148, 168))
52185	28988769	Nonetheless, it had high levels of TP53 and RB1 mutations, as do small cell carcinomas in other tissues.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('carcinomas', 'Disease', (76, 86))	('carcinomas', 'Disease', 'MESH:D002277', (76, 86))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (65, 86))	('RB1', 'Gene', (44, 47))	('mutations', 'Var', (48, 57))	('RB1', 'Gene', '5925', (44, 47))
52190	28988769	The luminal-papillary subtype (35%) is characterized by FGFR3 mutations, fusions with TACC3, and/or amplification; by papillary histology; by active sonic hedgehog signaling; and by low CIS scores.	('fusions', 'Var', (73, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('56', '60'))	('papillary histology', 'Phenotype', 'HP:0007482', (118, 137))	('TACC3', 'Gene', '10460', (86, 91))	('FGFR3', 'Gene', '2261', (56, 61))	('FGFR3', 'Gene', (56, 61))	('TACC3', 'Gene', (86, 91))	('luminal-papillary subtype', 'Disease', (4, 29))	('mutations', 'Var', (62, 71))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))
52192	28988769	The frequency of FGFR3 alterations in luminal papillary tumors suggests that tyrosine kinase inhibitors of FGFR3 may be an effective treatment approach, especially since early phase clinical trials show benefit of pan-FGFR inhibitor agents in FGFR3-selected advanced solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('FGFR3', 'Gene', '2261', (17, 22))	('luminal papillary tumors', 'Disease', 'MESH:D002291', (38, 62))	('tumors', 'Disease', (56, 62))	('papillary tumors', 'Phenotype', 'HP:0007482', (46, 62))	('FGFR', 'molecular_function', 'GO:0005007', ('218', '222'))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('FGFR3', 'Gene', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('FGFR3', 'Gene', '2261', (107, 112))	('FGFR3', 'Gene', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('FGFR', 'molecular_function', 'GO:0005007', ('243', '247'))	('luminal papillary tumors', 'Disease', (38, 62))	('tumors', 'Disease', (273, 279))	('FGFR3', 'Gene', '2261', (243, 248))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('FGFR3', 'Gene', (17, 22))	('alterations', 'Var', (23, 34))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('tumors', 'Disease', 'MESH:D009369', (273, 279))
52234	28988769	This step realigns reads at sites that potentially harbor small insertions or deletions in either the tumor or the matched normal, to decrease the number of false positive single nucleotide variations caused by misaligned reads.	('false', 'biological_process', 'GO:0071878', ('157', '162'))	('insertions', 'Var', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('false', 'biological_process', 'GO:0071877', ('157', '162'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('deletions', 'Var', (78, 87))
52236	28988769	Identification of somatic small insertions and deletions - In this step putative somatic events were first identified within the tumor BAM file and then filtered out using the corresponding normal data, using Indellocator  Firehose (http://www.broadinstitute.org/cancer/cga/Firehose) takes the BAM files for the tumor and patient matched normal samples and performs analyses including quality control, local realignment, mutation calling, small insertion and deletion identification, rearrangement detection, coverage calculations and others as described briefly below.	('mutation', 'Var', (421, 429))	('patient', 'Species', '9606', (322, 329))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('rearrangement', 'Var', (484, 497))	('cancer', 'Disease', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('cga', 'Gene', '1113', (270, 273))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cga', 'Gene', (270, 273))	('tumor', 'Disease', (312, 317))	('tumor', 'Disease', (129, 134))	('small insertion', 'Var', (439, 454))
52243	28988769	the six base substitutions C>A, C>G, C>T, T>A, T>C, and T>G, within the tri-nucleotide sequence context that includes the bases immediately 5' and 3' to each mutated base.	('tri-nucleotide', 'Chemical', '-', (72, 86))	('T>A', 'Var', (42, 45))	('C>A', 'Var', (27, 30))	('T>G', 'Var', (56, 59))	('T>C', 'Var', (47, 50))	('C>G', 'Var', (32, 35))	('C>T', 'Var', (37, 40))
52244	28988769	All fifty independent BayesNMF runs with a different initial condition for 409 samples converged to the solution of K* = 4, identifying four distinct mutational processes, C>T_CpG, ERCC2, APOBC-b, and APOBEC-a.	('ERCC2', 'Gene', (181, 186))	('C>T_CpG', 'Var', (172, 179))	('APOBEC-a', 'Gene', (201, 209))	('ERCC2', 'Gene', '2068', (181, 186))	('APOBEC', 'cellular_component', 'GO:0030895', ('201', '207'))	('APOBC-b', 'Gene', (188, 195))
52246	28988769	We first created a binary event matrix, Q (n by m), comprised of mutations in 53 SMGs and focal SCNAs in the 25 genes that had more than ten SMG mutations and more than ten focal SCNAs across 408 samples.	('SMG', 'Gene', '23034', (141, 144))	('SMG', 'Gene', (81, 84))	('mutations', 'Var', (145, 154))	('SMG', 'Gene', '23034', (81, 84))	('SMG', 'Gene', (141, 144))	('mutations', 'Var', (65, 74))
52251	28988769	For some analyses and figures "APOBEC_MutLoad_MinEstimate" parameter was converted into categorical values as follows:  HLA typing and detection of mutations in class I HLA genes (HLA-A/B/C) was performed using Polysolver.	('HLA', 'Gene', (169, 172))	('HLA', 'Gene', '3119', (120, 123))	('HLA-A/B/C', 'Gene', '3105;3106;3107', (180, 189))	('mutations', 'Var', (148, 157))	('HLA', 'Gene', (180, 183))	('HLA', 'Gene', '3119', (180, 183))	('HLA', 'Gene', '3119', (169, 172))	('APOBEC', 'cellular_component', 'GO:0030895', ('30', '36'))	('HLA', 'Gene', (120, 123))	('HLA-A/B/C', 'Gene', (180, 189))
52256	28988769	Putative HLA reads from the tumor and the germline sample are extracted and aligned to the inferred allele sequences, followed by mutation and insertion/deletion identification with the Mutect and Strelka tools respectively.	('HLA', 'Gene', (9, 12))	('tumor', 'Disease', (28, 33))	('mutation', 'Var', (130, 138))	('insertion/deletion', 'Var', (143, 161))	('HLA', 'Gene', '3119', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
52258	28988769	For each patient, we first enumerated a list of all possible 9 and 10-mer peptides bearing somatic mutations, or overlapping open reading frame derived from frameshifting indels or nonstop mutations.	('nonstop mutations', 'Var', (181, 198))	('patient', 'Species', '9606', (9, 16))	('frameshifting indels', 'Var', (157, 177))
52261	28988769	The comparison of number of HLA mutations or number of predicted binders between groups (e.g.	('mutations', 'Var', (32, 41))	('HLA', 'Gene', (28, 31))	('binders', 'Interaction', (65, 72))	('HLA', 'Gene', '3119', (28, 31))
52272	28988769	To minimize the influence of variable tumor purity levels on a clustering result, we dichotomized the data using a beta value of >=0.3 to define positive DNA methylation and < 0.3 to specify lack of methylation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('DNA', 'cellular_component', 'GO:0005574', ('154', '157'))	('a beta', 'Gene', '351', (113, 119))	('a beta', 'Gene', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('positive DNA methylation', 'Var', (145, 169))	('methylation', 'biological_process', 'GO:0032259', ('199', '210'))	('DNA methylation', 'biological_process', 'GO:0006306', ('154', '169'))
52279	28988769	We then performed consensus clustering with the dichotomized data on 53,862 CpG sites that showed hypomethylation in at least 10% of the tumors.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('hypomethylation', 'Var', (98, 113))
52284	28988769	CDKN2A DNA methylation status was assessed based on the probe (cg13601799) located in the p16INK4 promoter CpG island.	('p16INK4', 'Gene', '1029', (90, 97))	('cg13601799', 'Var', (63, 73))	('p16INK4', 'Gene', (90, 97))	('DNA methylation', 'biological_process', 'GO:0006306', ('7', '22'))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (0, 6))
52286	28988769	The complete list of 158 genes identified as epigenetically silenced is provided in Table S2.17.	('epigenetically silenced', 'Var', (45, 68))	('S2.1', 'Gene', '6227', (90, 94))	('S2.1', 'Gene', (90, 94))
52287	28988769	We used four types of data: 1) beta values for 5386 probes for 412 primary tumour samples and 21 adjacent normal samples, 2) RSEM gene-level expression data for 408 primary tumours and 19 adjacent normals, and 3) clinical and molecular data for 412 tumor samples, and 4) pathology review of micrograph images for the adjacent normals, which indicated that we should remove BT-A20U-11, BT-A2LB-11, GD-A2C5-11, and GD-A3OP-11.	('tumour', 'Disease', (173, 179))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('primary tumours', 'Disease', 'MESH:D009369', (165, 180))	('BT-A20U-11', 'Var', (373, 383))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumour', 'Disease', (75, 81))	('primary tumours', 'Disease', (165, 180))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Disease', (249, 254))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
52309	28988769	For known oncogenes, we considered only genetic alterations inferred to be activating; for genes with tumor suppressive roles, only alterations inferred to be inactivating were considered.	('alterations', 'Var', (48, 59))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('genetic alterations', 'Var', (40, 59))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
52367	28988769	As input covariates we used 13 of the 18 that the univariate calculations returned as significant, rejecting five because they had relatively large numbers of missing values: CLIN_Node_positive_vs_negative (47 cases missing), CLIN_Combined_Tx_Node_positive (64), CLIN_ajcc_nodes_pathologic_pn (47), CLIN_T12_vs_T34 (39), CLIN_ajcc_tumor_pathologic_pt (43).	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('CLIN_ajcc_tumor', 'Disease', (321, 336))	('CLIN_ajcc_tumor', 'Disease', 'MESH:D009369', (321, 336))	('CLIN_T12_vs_T34', 'Var', (299, 314))
52374	28988769	Multiplatform analysis informs muscle-invasive bladder cancer subtyping A framework associating distinct subtyping with therapeutic options High mutational load is driven mainly by APOBEC-mediated mutagenesis APOBEC-related mutational signature corresponds to a 75% 5-year survival	('APOBEC', 'cellular_component', 'GO:0030895', ('181', '187'))	('bladder cancer', 'Disease', 'MESH:D001749', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('APOBEC', 'cellular_component', 'GO:0030895', ('209', '215'))	('invasive bladder', 'Phenotype', 'HP:0100645', (38, 54))	('bladder cancer', 'Disease', (47, 61))	('mutagenesis', 'Var', (197, 208))	('mutagenesis', 'biological_process', 'GO:0006280', ('197', '208'))	('bladder cancer', 'Phenotype', 'HP:0009725', (47, 61))
52379	28938656	In summary, our meta-analysis suggests that the presence of CTCs in the peripheral blood is an independent predictive indicator of poor outcomes for urothelial cancer patients.	('CTCs', 'Var', (60, 64))	('presence', 'Var', (48, 56))	('urothelial cancer', 'Disease', 'MESH:D014523', (149, 166))	('patients', 'Species', '9606', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('urothelial cancer', 'Disease', (149, 166))
52390	28938656	Several studies focusing on UC have showed that CTC-positive was associated with poor prognosis, and the number of CTCs may be associated with tumor stage and therapeutic effects.	('CTC-positive', 'Var', (48, 60))	('associated', 'Reg', (127, 137))	('tumor', 'Disease', (143, 148))	('poor prognosis', 'CPA', (81, 95))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
52399	28938656	The pooled HR showed that CTC-positive was highly correlated with poorer OS and higher risk of death compared with CTC-negative: HR = 3.98 (95% CI: 2.20-7.21; P < 0.001).	('death', 'Disease', 'MESH:D003643', (95, 100))	('death', 'Disease', (95, 100))	('OS', 'Chemical', '-', (73, 75))	('CTC-positive', 'Var', (26, 38))	('poorer', 'Disease', (66, 72))
52436	26742963	reported 5-year survival rates of 74.7%, 54%, 35.3%, and 12.2% for pT2, pT3, N+and pT4, respectively.	('N+and', 'Var', (77, 82))	('pT3', 'Gene', '7694', (72, 75))	('pT4', 'Var', (83, 86))	('pT3', 'Gene', (72, 75))	('pT2', 'Var', (67, 70))
52521	26742963	In this update, which is the largest single-center study to date to the best of our knowledge, we enrolled 138 patients with pT3, pT4, or N+and M0 UTUC.	('pT4', 'Var', (130, 133))	('pT3', 'Gene', '7694', (125, 128))	('pT3', 'Gene', (125, 128))	('N+and', 'Var', (138, 143))	('patients', 'Species', '9606', (111, 119))
52531	26239046	High HMGB1 expression has been reported in many cancers, such as prostate, kidney, ovarian, and gastric cancer.	('kidney', 'Disease', (75, 81))	('cancers', 'Disease', (48, 55))	('reported', 'Reg', (31, 39))	('High', 'Var', (0, 4))	('prostate', 'Disease', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('ovarian', 'Disease', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('gastric cancer', 'Disease', (96, 110))	('HMGB1', 'Gene', (5, 10))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))
52547	26239046	The cell proliferation in the shRNA groups was significantly reduced 24 h after transfection compared with both the CON and NC groups (all P < 0.05, Supplementary Table S1).	('men', 'Species', '9606', (155, 158))	('cell proliferation', 'CPA', (4, 22))	('cell proliferation', 'biological_process', 'GO:0008283', ('4', '22'))	('transfection', 'Var', (80, 92))	('reduced', 'NegReg', (61, 68))
52549	26239046	2D1, D2 D3 and D4 demonstrate that knocking down HMGB1 expression (shRNA group) induced BUC cell arrest in the G0/G1 phase, with a proliferation index (PI) that was significantly lower than the CON and NC groups (all P < 0.05).	('BUC cell arrest', 'Disease', (88, 103))	('lower', 'NegReg', (179, 184))	('G1 phase', 'biological_process', 'GO:0051318', ('114', '122'))	('knocking down', 'Var', (35, 48))	('proliferation index', 'CPA', (131, 150))	('HMGB1', 'Gene', (49, 54))	('BUC cell arrest', 'Disease', 'MESH:D006323', (88, 103))
52550	26239046	2E1, E2, F1 and F2, the number of migrating and invading BUC cells in the shRNA group were significantly lower compared with the CON and NC groups.	('lower', 'NegReg', (105, 110))	('E2, F1 and F2', 'Gene', '26765', (5, 18))	('shRNA', 'Var', (74, 79))
52557	26239046	3B, the knockdown of HMGB1 expression by shRNA-mediated RNAi inhibited the translocation of NF-kappaB/p65 from the cytoplasm to the nucleus.	('translocation', 'MPA', (75, 88))	('inhibited', 'NegReg', (61, 70))	('NF-kappaB', 'Gene', (92, 101))	('nucleus', 'cellular_component', 'GO:0005634', ('132', '139'))	('knockdown', 'Var', (8, 17))	('HMGB1', 'Gene', (21, 26))	('cytoplasm', 'cellular_component', 'GO:0005737', ('115', '124'))	('p65', 'Gene', (102, 105))	('RNAi', 'biological_process', 'GO:0016246', ('56', '60'))	('p65', 'Gene', '5970', (102, 105))	('NF-kappaB', 'Gene', '4790', (92, 101))
52558	26239046	Furthermore, the EMSA assay suggested that the DNA-binding activity of NF-kappaB/p65 in T24 cells was decreased by HMGB1 knockdown (Fig.	('knockdown', 'Var', (121, 130))	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('p65', 'Gene', (81, 84))	('NF-kappaB', 'Gene', (71, 80))	('p65', 'Gene', '5970', (81, 84))	('DNA-binding', 'Interaction', (47, 58))	('DNA-binding', 'molecular_function', 'GO:0003677', ('47', '58'))	('HMGB1', 'Gene', (115, 120))	('NF-kappaB', 'Gene', '4790', (71, 80))	('decreased', 'NegReg', (102, 111))
52563	26239046	Using MTT and flow cytometry assays, we found that knockdown of HMGB1 suppressed the proliferation and induced the apoptosis of BUC cells.	('HMGB1', 'Gene', (64, 69))	('apoptosis', 'biological_process', 'GO:0097194', ('115', '124'))	('MTT', 'Chemical', 'MESH:C070243', (6, 9))	('apoptosis', 'biological_process', 'GO:0006915', ('115', '124'))	('suppressed', 'NegReg', (70, 80))	('apoptosis', 'CPA', (115, 124))	('induced', 'Reg', (103, 110))	('proliferation', 'CPA', (85, 98))	('knockdown', 'Var', (51, 60))
52564	26239046	have reported that anti-HMGB1 neutralizing antibody could reduce the cell viability of HCCLM3 hepatocellular cancer cells, while this effect could be reversed by rhHMGB1, which indicated that HMGB1 might play an important role in cell proliferation.	('antibody', 'cellular_component', 'GO:0019815', ('43', '51'))	('hepatocellular cancer', 'Disease', (94, 115))	('anti-HMGB1 neutralizing', 'Var', (19, 42))	('antibody', 'cellular_component', 'GO:0019814', ('43', '51'))	('HCCLM3', 'CellLine', 'CVCL:6832', (87, 93))	('cell proliferation', 'biological_process', 'GO:0008283', ('230', '248'))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (94, 115))	('neutralizing', 'Var', (30, 42))	('antibody', 'molecular_function', 'GO:0003823', ('43', '51'))	('cell viability', 'CPA', (69, 83))	('reduce', 'NegReg', (58, 64))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (94, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('antibody', 'cellular_component', 'GO:0042571', ('43', '51'))
52566	26239046	They found that the knockdown of HMGB1 expression could decrease the expression of PCNA and Cyclin D1, which controls cell cycle transit, induces cell cycle G0/G1 arrest, and inhibits cell proliferation.	('PCNA', 'Gene', '5111', (83, 87))	('Cyclin D1', 'Gene', '595', (92, 101))	('cell cycle', 'biological_process', 'GO:0007049', ('146', '156'))	('Cyclin', 'molecular_function', 'GO:0016538', ('92', '98'))	('Cyclin D1', 'Gene', (92, 101))	('induces', 'Reg', (138, 145))	('expression', 'MPA', (69, 79))	('cell proliferation', 'CPA', (184, 202))	('cell cycle', 'biological_process', 'GO:0007049', ('118', '128'))	('PCNA', 'Gene', (83, 87))	('cell proliferation', 'biological_process', 'GO:0008283', ('184', '202'))	('PCNA', 'molecular_function', 'GO:0003892', ('83', '87'))	('knockdown', 'Var', (20, 29))	('HMGB1', 'Gene', (33, 38))	('decrease', 'NegReg', (56, 64))	('cell cycle G0/G1 arrest', 'CPA', (146, 169))	('inhibits', 'NegReg', (175, 183))
52567	26239046	demonstrated that knockdown of HMGB1 by shRNA plasmids in LNCaP prostate cancer cells could induce apoptosis via a caspase-3 dependent pathway.	('knockdown', 'Var', (18, 27))	('prostate cancer', 'Disease', (64, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('apoptosis', 'CPA', (99, 108))	('caspase-3', 'Gene', '836', (115, 124))	('HMGB1', 'Gene', (31, 36))	('LNCaP', 'CellLine', 'CVCL:0395', (58, 63))	('prostate cancer', 'Disease', 'MESH:D011471', (64, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('prostate cancer', 'Phenotype', 'HP:0012125', (64, 79))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('induce', 'PosReg', (92, 98))	('caspase-3', 'Gene', (115, 124))
52582	26239046	In this study, we demonstrated that knockdown of HMGB1 expression significantly inhibited the expression levels of NF-kappaB/p65 and VEGF-C, up-regulated IkappaBalpha expression, and suppressed the nuclear translocation and DNA-binding activity of NF-kappaB/p65, which indicated that HMGB1 might regulate VEGF-C expression in the development of BUC via the NF-kappaB signalling pathway.	('p65', 'Gene', (125, 128))	('men', 'Species', '9606', (337, 340))	('NF-kappaB', 'Gene', '4790', (248, 257))	('signalling pathway', 'biological_process', 'GO:0007165', ('367', '385'))	('VEGF-C', 'Gene', (133, 139))	('p65', 'Gene', (258, 261))	('suppressed', 'NegReg', (183, 193))	('expression', 'MPA', (167, 177))	('p65', 'Gene', '5970', (125, 128))	('DNA-binding activity', 'MPA', (224, 244))	('up-regulated', 'PosReg', (141, 153))	('expression levels', 'MPA', (94, 111))	('knockdown', 'Var', (36, 45))	('NF-kappaB', 'Gene', (357, 366))	('DNA-binding', 'molecular_function', 'GO:0003677', ('224', '235'))	('p65', 'Gene', '5970', (258, 261))	('NF-kappaB', 'Gene', '4790', (357, 366))	('regulate', 'Reg', (296, 304))	('NF-kappaB', 'Gene', (115, 124))	('inhibited', 'NegReg', (80, 89))	('IkappaBalpha', 'Gene', (154, 166))	('HMGB1', 'Gene', (49, 54))	('DNA', 'cellular_component', 'GO:0005574', ('224', '227'))	('IkappaBalpha', 'Gene', '4792', (154, 166))	('NF-kappaB', 'Gene', '4790', (115, 124))	('NF-kappaB', 'Gene', (248, 257))	('nuclear translocation', 'MPA', (198, 219))
52633	33664747	Patients with high PDIA5 high-expression benefited from immunotherapies.	('PDIA5', 'Gene', '10954', (19, 24))	('immunotherapies', 'CPA', (56, 71))	('PDIA5', 'Gene', (19, 24))	('Patients', 'Species', '9606', (0, 8))	('high-expression', 'Var', (25, 40))
52656	33664747	Other research has found that PDI inhibition could impair tumorigenic T cells and enhance normal T cell function.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('inhibition', 'Var', (34, 44))	('PDI', 'Gene', (30, 33))	('PDI', 'Gene', '5034', (30, 33))	('impair', 'NegReg', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('enhance', 'PosReg', (82, 89))
52679	33664747	After antigen retrieval and blocking endogenous HRP activity, the slides were blocked with 10% normal goat serum and incubated with primary antibody (anti-PDIA5 antibody human reactivity (D225376, 1:200, Sangon Biotech, China), anti-CD68 E11 human reactivity (SC-17832, 1:400, Santa Cruz, US) at 4 C overnight.	('antibody', 'cellular_component', 'GO:0019814', ('161', '169'))	('antibody', 'cellular_component', 'GO:0019814', ('140', '148'))	('antibody', 'molecular_function', 'GO:0003823', ('161', '169'))	('PDIA5', 'Gene', '10954', (155, 160))	('PDIA5', 'Gene', (155, 160))	('antibody', 'molecular_function', 'GO:0003823', ('140', '148'))	('antibody', 'cellular_component', 'GO:0019815', ('161', '169'))	('antibody', 'cellular_component', 'GO:0042571', ('161', '169'))	('antibody', 'cellular_component', 'GO:0042571', ('140', '148'))	('anti-CD68', 'Var', (228, 237))	('human', 'Species', '9606', (170, 175))	('human', 'Species', '9606', (242, 247))	('antibody', 'cellular_component', 'GO:0019815', ('140', '148'))
52689	33664747	It is well-known that several molecular biomarkers, such as isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion status and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation are related to the malignancy of gliomas.	('IDH', 'Gene', (86, 89))	('O6-methylguanine DNA methyltransferase', 'Gene', (130, 168))	('mutation', 'Var', (91, 99))	('isocitrate dehydrogenase', 'Gene', (60, 84))	('malignancy of gliomas', 'Disease', (216, 237))	('IDH', 'Gene', '3417', (86, 89))	('MGMT', 'Gene', '4255', (170, 174))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (130, 168))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('MGMT', 'Gene', (170, 174))	('isocitrate dehydrogenase', 'Gene', '3417', (60, 84))	('methylation', 'biological_process', 'GO:0032259', ('185', '196'))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('MGMT', 'molecular_function', 'GO:0003908', ('170', '174'))	('malignancy of gliomas', 'Disease', 'MESH:D005910', (216, 237))	('gliomas', 'Phenotype', 'HP:0009733', (230, 237))	('related', 'Reg', (201, 208))
52699	33664747	Furthermore, in the IVY GBM dataset, high PDIA5 level was enriched in hyperplastic blood vessels, microvascular proliferation, and peri-necrotic zones compared with other areas (Figure 1F).	('PDIA5', 'Gene', '10954', (42, 47))	('high', 'Var', (37, 41))	('microvascular proliferation', 'CPA', (98, 125))	('hyperplastic blood vessels', 'CPA', (70, 96))	('PDIA5', 'Gene', (42, 47))	('peri-necrotic zones', 'CPA', (131, 150))
52704	33664747	These results suggest that PDIA5 is significantly increased in gliomas and high PDIA5 expression may play an important role in invasive processes of gliomas.	('gliomas', 'Disease', (149, 156))	('gliomas', 'Disease', (63, 70))	('play', 'Reg', (101, 105))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('PDIA5', 'Gene', (80, 85))	('gliomas', 'Disease', 'MESH:D005910', (149, 156))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('high', 'Var', (75, 79))	('PDIA5', 'Gene', '10954', (80, 85))	('increased', 'PosReg', (50, 59))	('expression', 'MPA', (86, 96))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('PDIA5', 'Gene', '10954', (27, 32))	('PDIA5', 'Gene', (27, 32))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
52707	33664747	These findings revealed that high PDIA5 expression predicts poor clinical outcomes in multiple cancers.	('expression', 'MPA', (40, 50))	('high', 'Var', (29, 33))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('PDIA5', 'Gene', '10954', (34, 39))	('PDIA5', 'Gene', (34, 39))
52710	33664747	Similarly, high PDIA5 expression was significantly associated with poor prognosis in the CGGA dataset (Supplementary Figure S2I).	('PDIA5', 'Gene', '10954', (16, 21))	('PDIA5', 'Gene', (16, 21))	('expression', 'MPA', (22, 32))	('high', 'Var', (11, 15))
52712	33664747	Regardless of whether IDH was mutated, 1p19q was co-deleted, and MGMT promoter was methylated, low PDIA5 expression was related to a favorable outcome (Supplementary Figures S3A-F), and the same results were obtained in the analysis of chemotherapy and radiotherapy (Supplementary Figures S3G-I).	('MGMT', 'Gene', (65, 69))	('low', 'NegReg', (95, 98))	('MGMT', 'Gene', '4255', (65, 69))	('IDH', 'Gene', (22, 25))	('IDH', 'Gene', '3417', (22, 25))	('PDIA5', 'Gene', (99, 104))	('PDIA5', 'Gene', '10954', (99, 104))	('1p19q', 'Var', (39, 44))	('expression', 'MPA', (105, 115))	('MGMT', 'molecular_function', 'GO:0003908', ('65', '69'))	('p19', 'cellular_component', 'GO:0070743', ('40', '43'))
52716	33664747	Amplification of chr7 and deletion of chr10 consistently appeared in gliomas with high PDIA5 expression.	('chr10', 'Gene', (38, 43))	('PDIA5', 'Gene', '10954', (87, 92))	('chr7', 'Gene', (17, 21))	('gliomas', 'Disease', (69, 76))	('Amplification', 'Var', (0, 13))	('appeared', 'Reg', (57, 65))	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('deletion', 'Var', (26, 34))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('PDIA5', 'Gene', (87, 92))
52717	33664747	Additionally, 1p/19q codeletion more frequently occurred in gliomas with low PDIA5 expression (Supplementary Figure S4A), and 63 and 30 significant genomic events were discovered in the high and low PDIA5 groups respectively (Supplementary Figure S4B).	('occurred', 'Reg', (48, 56))	('1p/19q codeletion', 'Var', (14, 31))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('PDIA5', 'Gene', (77, 82))	('PDIA5', 'Gene', (199, 204))	('PDIA5', 'Gene', '10954', (77, 82))	('low', 'NegReg', (73, 76))	('PDIA5', 'Gene', '10954', (199, 204))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
52718	33664747	In the high PDIA5 group, focal amplification peaks, including driver oncogenes such as PIK3C2B (1q32.1), PDGFRA (4q12), EGFR (7p11.2), and CDK4 (12q14.1) were found accompanied by focal deletion peaks for tumor suppressor genes such as CHD5 (1p36.31), CDKN2A/CDKN2B (9p21.3), and PTEN (10q23.31).	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('PDIA5', 'Gene', '10954', (12, 17))	('CDKN2A', 'Gene', '1029', (252, 258))	('CHD5', 'Gene', (236, 240))	('PIK3C2B', 'Gene', '5287', (87, 94))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('205', '221'))	('CDKN2B', 'Gene', (259, 265))	('10q23.31', 'Var', (286, 294))	('CDK4', 'Gene', (139, 143))	('PTEN', 'Gene', (280, 284))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor suppressor', 'biological_process', 'GO:0051726', ('205', '221'))	('EGFR', 'Gene', (120, 124))	('CDK4', 'Gene', '1019', (139, 143))	('CDKN2B', 'Gene', '1030', (259, 265))	('PTEN', 'Gene', '5728', (280, 284))	('PDGFRA', 'Gene', (105, 111))	('CHD5', 'Gene', '26038', (236, 240))	('EGFR', 'molecular_function', 'GO:0005006', ('120', '124'))	('deletion', 'Var', (186, 194))	('CDKN2A', 'Gene', (252, 258))	('PDIA5', 'Gene', (12, 17))	('tumor', 'Disease', (205, 210))	('EGFR', 'Gene', '1956', (120, 124))	('PIK3C2B', 'Gene', (87, 94))	('CDK', 'molecular_function', 'GO:0004693', ('139', '142'))
52720	33664747	In regards to somatic mutations, mutation in TP53 (41%), TTN (25%), PTEN (23%), and EGFR (22%) were identified in the high PDIA5 group, while IDH1 (89%), CIC (45%), and FUBP1 (22%) were detected in the low PDIA5 group (Supplementary Figure S4C).	('TP53', 'Gene', (45, 49))	('TTN', 'Gene', '7273', (57, 60))	('PTEN', 'Gene', (68, 72))	('PDIA5', 'Gene', '10954', (123, 128))	('CIC', 'Disease', (154, 157))	('FUBP1', 'Gene', (169, 174))	('TTN', 'Gene', (57, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('IDH', 'Gene', (142, 145))	('EGFR', 'Gene', '1956', (84, 88))	('PTEN', 'Gene', '5728', (68, 72))	('TP53', 'Gene', '7157', (45, 49))	('PDIA5', 'Gene', (206, 211))	('mutation', 'Var', (33, 41))	('CIC', 'Disease', 'None', (154, 157))	('FUBP1', 'Gene', '8880', (169, 174))	('IDH', 'Gene', '3417', (142, 145))	('PDIA5', 'Gene', '10954', (206, 211))	('EGFR', 'Gene', (84, 88))	('PDIA5', 'Gene', (123, 128))
52722	33664747	Moreover, in combination analysis of LGG and GBM, we observed PDIA5 expression was higher in the PDIA5 copy number gain group relative to the other two groups (Supplementary Figure S5B).	('PDIA5', 'Gene', '10954', (62, 67))	('PDIA5', 'Gene', (62, 67))	('PDIA5', 'Gene', '10954', (97, 102))	('PDIA5', 'Gene', (97, 102))	('expression', 'MPA', (68, 78))	('S5B', 'Gene', '5711', (181, 184))	('S5B', 'Gene', (181, 184))	('gain', 'PosReg', (115, 119))	('higher', 'PosReg', (83, 89))	('copy number', 'Var', (103, 114))
52744	33664747	Finally, patients with high PDIA5 and CD68, high combined expression of PDIA5 and CD68 group, and high ratio of PDIA5 to CD68 group experienced shorter OS (Supplementary Figures S8B-D).	('PDIA5', 'Gene', '10954', (28, 33))	('patients', 'Species', '9606', (9, 17))	('combined', 'Interaction', (49, 57))	('high', 'Var', (23, 27))	('shorter', 'NegReg', (144, 151))	('PDIA5', 'Gene', '10954', (72, 77))	('PDIA5', 'Gene', (112, 117))	('CD68', 'Var', (38, 42))	('PDIA5', 'Gene', '10954', (112, 117))	('CD68', 'Gene', (82, 86))	('PDIA5', 'Gene', (28, 33))	('PDIA5', 'Gene', (72, 77))
52759	33664747	Finally, the results of GO enrichment analysis (Supplementary Table S3, S4, S5) and KEGG pathway analysis (Supplementary Table S6, S7, S8) in regards to PDIA5 in neoplastic cells and macrophages is shown in Supplementary Figures S9D-F and S10D-F.	('KEGG pathway', 'Pathway', (84, 96))	('PDIA5', 'Gene', (153, 158))	('PDIA5', 'Gene', '10954', (153, 158))	('S9D-F', 'Var', (229, 234))	('S10D', 'Mutation', 'p.S10D', (239, 243))	('S10D-F', 'Var', (239, 245))
52767	33664747	Furthermore, knock-down PDIA5 presented the malignant behavior decreasing of glioma cells in immune cells exhausting.	('knock-down', 'Var', (13, 23))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('malignant behavior', 'CPA', (44, 62))	('glioma', 'Disease', (77, 83))	('decreasing', 'NegReg', (63, 73))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('PDIA5', 'Gene', '10954', (24, 29))	('PDIA5', 'Gene', (24, 29))
52779	33664747	In the anti-PD-L1 cohort (IMvigor210), we observed that patients with high PDIA5 experienced significant clinical survival benefits (Figure 8A).	('patients', 'Species', '9606', (56, 64))	('PD-L1', 'Gene', (12, 17))	('clinical survival', 'CPA', (105, 122))	('benefits', 'PosReg', (123, 131))	('PD-L1', 'Gene', '29126', (12, 17))	('PDIA5', 'Gene', '10954', (75, 80))	('PDIA5', 'Gene', (75, 80))	('high', 'Var', (70, 74))
52781	33664747	In the anti-PD-L1 cohort, the percentages of complete response (CR) and progressive disease (PD) were 19.35 and 39.44% in the high PDIA5 group, respectively, and 6.7 and 58.64% in the low PDIA5 group, respectively.	('PD-L1', 'Gene', (12, 17))	('progressive disease', 'Disease', 'MESH:D018450', (72, 91))	('PDIA5', 'Gene', (131, 136))	('progressive disease', 'Disease', (72, 91))	('PDIA5', 'Gene', '10954', (131, 136))	('PD-L1', 'Gene', '29126', (12, 17))	('high', 'Var', (126, 130))	('PDIA5', 'Gene', (188, 193))	('PDIA5', 'Gene', '10954', (188, 193))	('complete', 'Disease', (45, 53))
52782	33664747	And the proportion of high PDIA5 expression in CR group and PD group were 35.93 and 11.56%, respectively.	('high', 'Var', (22, 26))	('PDIA5', 'Gene', '10954', (27, 32))	('PDIA5', 'Gene', (27, 32))	('expression', 'MPA', (33, 43))
52786	33664747	And the proportion of high PDIA5 expression in CR group, PD group, and PR group were 100, 84.35, and 94.84%, respectively (Figure 8I).	('high', 'Var', (22, 26))	('PDIA5', 'Gene', '10954', (27, 32))	('PDIA5', 'Gene', (27, 32))	('expression', 'MPA', (33, 43))
52792	33664747	Genomic alterations in gliomas are able to predict disease classification and prognosis.	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('gliomas', 'Disease', (23, 30))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('Genomic alterations', 'Var', (0, 19))	('predict', 'Reg', (43, 50))
52795	33664747	These results suggest that high PDIA5 expression plays an important role in glioma infiltration.	('expression', 'MPA', (38, 48))	('glioma infiltration', 'Disease', 'MESH:D005910', (76, 95))	('PDIA5', 'Gene', '10954', (32, 37))	('PDIA5', 'Gene', (32, 37))	('high', 'Var', (27, 31))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('glioma infiltration', 'Disease', (76, 95))
52819	33664747	Therefore, we deduced that high expression of PDIA5 may induce macrophage associated immunity, and contribute to M2 polarization of macrophage in gliomas.	('PDIA5', 'Gene', (46, 51))	('macrophage associated immunity', 'CPA', (63, 93))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('gliomas', 'Disease', (146, 153))	('contribute', 'Reg', (99, 109))	('PDIA5', 'Gene', '10954', (46, 51))	('induce', 'PosReg', (56, 62))	('high expression', 'Var', (27, 42))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('M2 polarization', 'MPA', (113, 128))
52839	33664747	Further predictive analysis based on the existing databases showed that patients with high PDIA5 had high anti-tumor immune activity and were more likely to benefit from immunotherapies in gliomas as well as other tumor types, indicating that inhibition of combined PDIA5 and these immune checkpoints could improve the clinical management of gliomas.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('PDIA5', 'Gene', '10954', (91, 96))	('gliomas', 'Phenotype', 'HP:0009733', (342, 349))	('PDIA5', 'Gene', '10954', (266, 271))	('gliomas', 'Disease', 'MESH:D005910', (189, 196))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('high', 'Var', (86, 90))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (214, 219))	('gliomas', 'Disease', (342, 349))	('benefit', 'PosReg', (157, 164))	('high', 'PosReg', (101, 105))	('glioma', 'Phenotype', 'HP:0009733', (342, 348))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('PDIA5', 'Gene', (266, 271))	('PDIA5', 'Gene', (91, 96))	('gliomas', 'Disease', 'MESH:D005910', (342, 349))	('gliomas', 'Disease', (189, 196))	('patients', 'Species', '9606', (72, 80))
52843	33664747	Prior evidence implicated that high PD-L1 contributed to immunosuppression but enhanced the response rate to anti-PD-1 therapy in metastatic melanomas and breast cancer.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('PD-1', 'Gene', '5133', (114, 118))	('PD-L1', 'Gene', (36, 41))	('immunosuppression', 'MPA', (57, 74))	('melanomas and breast cancer', 'Disease', 'MESH:D001943', (141, 168))	('enhanced', 'PosReg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('PD-L1', 'Gene', '29126', (36, 41))	('high', 'Var', (31, 35))	('PD-1', 'Gene', (114, 118))	('response rate', 'MPA', (92, 105))
52885	29125844	Significant associations between driver gene mutations and DNA methylation alterations across many cancer types Recent evidence shows that mutations in several driver genes can cause aberrant methylation patterns, a hallmark of cancer.	('hallmark of cancer', 'Disease', (216, 234))	('DNA methylation', 'biological_process', 'GO:0006306', ('59', '74'))	('cancer', 'Disease', (228, 234))	('mutations', 'Var', (139, 148))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('hallmark of cancer', 'Disease', 'MESH:D009369', (216, 234))	('methylation', 'biological_process', 'GO:0032259', ('192', '203'))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('aberrant methylation patterns', 'MPA', (183, 212))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cause', 'Reg', (177, 182))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
52887	29125844	We found that a few mutated driver genes were associated with genome-wide patterns of aberrant hypomethylation or CpG island hypermethylation in specific cancer types.	('CpG island hypermethylation', 'Var', (114, 141))	('associated', 'Reg', (46, 56))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('aberrant hypomethylation', 'Var', (86, 110))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
52888	29125844	Moreover, using these mutation-methylation associations, we were able to distinguish between two uterine and two thyroid cancer subtypes.	('uterine', 'Disease', (97, 104))	('mutation-methylation', 'Var', (22, 42))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('thyroid cancer', 'Phenotype', 'HP:0002890', (113, 127))	('thyroid cancer', 'Disease', (113, 127))	('distinguish', 'Reg', (73, 84))	('thyroid cancer', 'Disease', 'MESH:D013964', (113, 127))
52889	29125844	The driver gene mutation-associated methylation differences between the thyroid cancer subtypes were linked to differential gene expression in JAK-STAT signaling, NADPH oxidation, and other cancer-related pathways.	('thyroid cancer', 'Phenotype', 'HP:0002890', (72, 86))	('NADPH oxidation', 'biological_process', 'GO:0070995', ('163', '178'))	('methylation differences', 'Var', (36, 59))	('signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('cancer', 'Disease', (80, 86))	('cancer', 'Disease', (190, 196))	('differences', 'Var', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('thyroid cancer', 'Disease', (72, 86))	('mutation-associated', 'Reg', (16, 35))	('JAK-STAT signaling', 'MPA', (143, 161))	('gene expression', 'biological_process', 'GO:0010467', ('124', '139'))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('JAK', 'molecular_function', 'GO:0004713', ('143', '146'))	('thyroid cancer', 'Disease', 'MESH:D013964', (72, 86))	('linked', 'Reg', (101, 107))	('NADPH', 'Chemical', 'MESH:D009249', (163, 168))
52891	29125844	Mutations that alter the function of driver genes by changing DNA nucleotides have been recognized as key players in cancer progression.	('DNA nucleotides', 'MPA', (62, 77))	('function', 'MPA', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
52892	29125844	However, recent evidence has shown that DNA methylation, which can control gene expression, is also highly dysregulated in cancer and contributes to carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('gene expression', 'MPA', (75, 90))	('methylation', 'Var', (44, 55))	('carcinogenesis', 'Disease', (149, 163))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('cancer', 'Disease', (123, 129))	('contributes to', 'Reg', (134, 148))	('carcinogenesis', 'Disease', 'MESH:D063646', (149, 163))	('gene expression', 'biological_process', 'GO:0010467', ('75', '90'))	('DNA methylation', 'biological_process', 'GO:0006306', ('40', '55'))
52893	29125844	Whether methylation alterations correspond to mutated driver genes in cancer remains unclear.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (70, 76))	('methylation', 'biological_process', 'GO:0032259', ('8', '19'))	('methylation', 'Var', (8, 19))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
52894	29125844	In this study, we analyzed 4,302 tumors from 18 cancer types and demonstrated that driver gene mutations are inherently connected with the aberrant DNA methylation landscape in cancer.	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('DNA methylation', 'biological_process', 'GO:0006306', ('148', '163'))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('mutations', 'Var', (95, 104))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Disease', (33, 39))
52895	29125844	We showed that driver gene-associated methylation patterns can classify heterogeneous tumors within a cancer type into homogeneous subtypes and have the potential to influence genes that contribute to tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('methylation patterns', 'Var', (38, 58))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('genes', 'Gene', (176, 181))	('influence', 'Reg', (166, 175))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))
52896	29125844	This finding could help us better understand the fundamental connection between driver gene mutations and DNA methylation alterations in cancer, and to further improve cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('mutations', 'Var', (92, 101))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (168, 174))	('DNA methylation', 'biological_process', 'GO:0006306', ('106', '121'))
52897	29125844	DNA methylation (DNAm) is highly dysregulated in cancers from many organs, displaying aberrant CpG island (CGI) hypermethylation and long-range blocks of hypomethylation.	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('hypermethylation', 'Var', (112, 128))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))
52904	29125844	Because tumors of the same molecular subtype often harbor both dysregulated DNAm at particular locations in the genome and mutations in driver genes, we decided to investigate the connection between somatic mutations and specific aberrant DNAm patterns.	('dysregulated', 'Var', (63, 75))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))
52906	29125844	For example, mutations in SETD2, the H3K36me3 writer, lead to ectopic H3K36me3, coinciding with DNA hypermethylation in renal cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lead', 'Reg', (54, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('SETD2', 'Gene', '29072', (26, 31))	('mutations', 'Var', (13, 22))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (120, 141))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (120, 141))	('SETD2', 'Gene', (26, 31))	('ectopic H3K36me3', 'MPA', (62, 78))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('renal cell carcinomas', 'Disease', (120, 141))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('96', '116'))
52907	29125844	For example, in glioblastoma, mutated IDH1 produces abnormal 2-hydroxyglutarate.	('IDH1', 'Gene', '3417', (38, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (16, 28))	('2-hydroxyglutarate', 'MPA', (61, 79))	('mutated', 'Var', (30, 37))	('abnormal 2-hydroxyglutarate', 'Phenotype', 'HP:0012401', (52, 79))	('IDH1', 'Gene', (38, 42))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (61, 79))	('glioblastoma', 'Disease', (16, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (16, 28))
52910	29125844	Finally, the KRAS G13D mutation upregulates another transcriptional repressor, ZNF304, to establish a CIMP-intermediate pattern in colorectal cancer.	('ZNF304', 'Gene', (79, 85))	('mutation', 'Var', (23, 31))	('upregulates', 'PosReg', (32, 43))	('G13D', 'Mutation', 'rs112445441', (18, 22))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('KRAS', 'Gene', (13, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('CIMP', 'Chemical', '-', (102, 106))	('ZNF304', 'Gene', '57343', (79, 85))	('colorectal cancer', 'Disease', (131, 148))	('KRAS', 'Gene', '3845', (13, 17))
52912	29125844	In head and neck squamous cell carcinomas (HNSCs), for instance, an atypical CIMP subtype was recently identified in association with CASP8 mutations, which are not known to have a functional link to the epigenome.	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (3, 41))	('CASP8', 'Gene', (134, 139))	('CASP8', 'Gene', '841', (134, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('HNSC', 'Phenotype', 'HP:0012288', (43, 47))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (12, 41))	('neck', 'cellular_component', 'GO:0044326', ('12', '16'))	('CIMP', 'Chemical', '-', (77, 81))	('mutations', 'Var', (140, 149))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (17, 41))	('neck squamous cell carcinomas', 'Disease', (12, 41))	('association', 'Reg', (117, 128))	('HNSCs', 'Phenotype', 'HP:0012288', (43, 48))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
52913	29125844	And in gastric cancer, PIK3CA mutations co-occur with CIMP, which is thought to be caused by Epstein-Barr virus (EBV) infection.	('gastric cancer', 'Phenotype', 'HP:0012126', (7, 21))	('PIK3CA', 'Gene', (23, 29))	('CIMP', 'Chemical', '-', (54, 58))	('Epstein-Barr virus (EBV) infection', 'Disease', 'MESH:D020031', (93, 127))	('PIK3CA', 'Gene', '5290', (23, 29))	('gastric cancer', 'Disease', (7, 21))	('mutations', 'Var', (30, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (7, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('CIMP', 'Disease', (54, 58))
52914	29125844	In this type of cancer, TP53 mutations are largely mutually exclusive with PIK3CA mutations.	('PIK3CA', 'Gene', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('PIK3CA', 'Gene', '5290', (75, 81))	('TP53', 'Gene', (24, 28))	('cancer', 'Disease', (16, 22))	('mutations', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('TP53', 'Gene', '7157', (24, 28))
52915	29125844	Thus, we would also expect TP53 mutations to be associated with non-CIMP tumors.	('TP53', 'Gene', '7157', (27, 31))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('TP53', 'Gene', (27, 31))	('associated', 'Reg', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('CIMP', 'Chemical', '-', (68, 72))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (32, 41))	('tumors', 'Disease', (73, 79))
52916	29125844	Based on these findings, we hypothesized that tumor genomic and epigenetic landscapes are stable and interdependent, and that specific driver mutations are associated with specific DNAm patterns.	('mutations', 'Var', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('associated', 'Reg', (156, 166))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
52917	29125844	Thus, in this study, we systematically evaluated mutation-methylation associations across 4,302 tumors from 18 cancer types, along with 727 normal tissue samples from The Cancer Genome Atlas (TCGA).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Cancer', 'Phenotype', 'HP:0002664', (171, 177))	('Cancer Genome Atlas', 'Disease', (171, 190))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (171, 190))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('mutation-methylation', 'Var', (49, 69))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
52918	29125844	By investigating DNAm alterations associated with mutated driver genes on both a genome-wide scale and a site-specific scale, we were able to show that (i) mutated driver genes are tightly associated with DNAm variation in cancer; (ii) some driver gene associations are present across cancer types; for example, TP53 mutations predominantly correspond to hypomethylation across cancer types; (iii) other associations are cancer type-specific; and (iv) these associations can be used to classify tumors into molecular subtypes and gain insight into functional alterations.	('cancer', 'Disease', 'MESH:D009369', (378, 384))	('tumors', 'Disease', 'MESH:D009369', (495, 501))	('cancer', 'Disease', (223, 229))	('mutations', 'Var', (317, 326))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', (421, 427))	('cancer', 'Phenotype', 'HP:0002664', (421, 427))	('cancer', 'Disease', (285, 291))	('TP53', 'Gene', (312, 316))	('tumors', 'Phenotype', 'HP:0002664', (495, 501))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (378, 384))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (421, 427))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('tumor', 'Phenotype', 'HP:0002664', (495, 500))	('hypomethylation', 'Var', (355, 370))	('tumors', 'Disease', (495, 501))	('TP53', 'Gene', '7157', (312, 316))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
52919	29125844	Together, these results establish that driver mutations and DNAm alterations are tightly coupled in tumor cells, and that this coupling may affect important regulatory networks related to oncogenesis.	('regulatory networks', 'MPA', (157, 176))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutations', 'Var', (46, 55))	('tumor', 'Disease', (100, 105))	('oncogenesis', 'biological_process', 'GO:0007048', ('188', '199'))	('affect', 'Reg', (140, 146))	('DNAm', 'MPA', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
52922	29125844	For each cancer type, a driver gene was considered to be associated with a PC if samples in which the gene was mutated (any synonymous/non-synonymous mutation reported in TCGA level 2 exome-sequencing data) were unevenly distributed toward the positive or negative extremes of that PC (q<0.05; two-sided Wilcoxon rank-sum test).	('mutated', 'Var', (111, 118))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', (9, 15))
52927	29125844	For each cancer type, the full list of driver genes associated with methylation PCs can be found in S1 Table, and the full list of MutSigCV-reported driver genes can be found in S2 Table.	('cancer', 'Disease', (9, 15))	('methylation', 'Var', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
52929	29125844	Thus, the frequent driver gene-PC associations in almost every cancer type suggest a tight connection between driver gene mutations and DNA methylation alterations in cancer.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('DNA methylation', 'biological_process', 'GO:0006306', ('136', '151'))	('cancer', 'Disease', (167, 173))	('mutations', 'Var', (122, 131))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (63, 69))
52933	29125844	In total, 14 of 18 cancer types harbored significant associations between driver gene mutations and the top five methylation PCs at CGIs, 14 of 18 at SSs, and 15 of 18 in open sea regions.	('mutations', 'Var', (86, 95))	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('SSs', 'Chemical', '-', (150, 153))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
52935	29125844	Some researchers have recently proposed that aberrant DNAm in cancer is driven by cell proliferation and developed a DNAm-based mitotic index (derived from the average methylation level across 385 CpG sites).	('methylation', 'biological_process', 'GO:0032259', ('168', '179'))	('cell proliferation', 'biological_process', 'GO:0008283', ('82', '100'))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('aberrant', 'Var', (45, 53))	('cell proliferation', 'CPA', (82, 100))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
52937	29125844	However, after removing probes correlated with the DNAm-based mitotic index (p<0.05; Pearson correlation), methylation PC-driver gene associations remained for 11 cancer types (S3 Fig), indicating that mutation-methylation associations cannot be totally explained by the DNAm-based mitotic index.	('methylation', 'biological_process', 'GO:0032259', ('211', '222'))	('methylation', 'biological_process', 'GO:0032259', ('107', '118'))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('methylation', 'Var', (107, 118))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
52939	29125844	We next asked whether driver gene-associated methylation alterations correspond to genome-wide methylation patterns characteristic of cancer: i.e., widespread CGI hypermethylation and huge hypomethylated blocks, primarily in open sea regions.	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('hypermethylation', 'Var', (163, 179))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('alterations', 'Var', (57, 68))	('methylation', 'biological_process', 'GO:0032259', ('95', '106'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
52940	29125844	A high HyperZ index indicates that aberrant hypermethylation exists in many CGIs for a given sample, whereas a high HypoZ index indicates that extensive open sea hypomethylation is present.	('open sea hypomethylation', 'Disease', 'MESH:D009041', (153, 177))	('aberrant', 'Var', (35, 43))	('open sea hypomethylation', 'Disease', (153, 177))
52942	29125844	For example, a high HyperZ index was associated with BRAF in COAD and IDH1 in glioblastoma (GBM); both genes are linked to CIMP in cancer.	('cancer', 'Disease', (131, 137))	('high', 'Var', (15, 19))	('COAD', 'Disease', (61, 65))	('glioblastoma', 'Disease', (78, 90))	('glioblastoma', 'Disease', 'MESH:D005909', (78, 90))	('BRAF', 'Gene', '673', (53, 57))	('GBM', 'Phenotype', 'HP:0012174', (92, 95))	('BRAF', 'Gene', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('IDH1', 'Gene', '3417', (70, 74))	('COAD', 'Disease', 'MESH:D029424', (61, 65))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('CIMP', 'Chemical', '-', (123, 127))	('associated', 'Reg', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('linked', 'Reg', (113, 119))	('IDH1', 'Gene', (70, 74))
52944	29125844	The associations we detected in most cancer types underscore the relationship between driver gene mutations and the genome-wide methylation alterations commonly observed in cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (37, 43))	('methylation', 'biological_process', 'GO:0032259', ('128', '139'))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
52946	29125844	Next, we investigated whether the connection between driver gene mutations and methylation alterations was methylation site-specific in each cancer type.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('methylation', 'MPA', (79, 90))	('methylation', 'biological_process', 'GO:0032259', ('107', '118'))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))	('cancer', 'Disease', (141, 147))	('mutations', 'Var', (65, 74))
52947	29125844	To do so, we calculated the associations between every driver gene and every methylation array probe for all 18 cancer types, testing whether the presence of mutations in a driver gene was associated with high or low methylation levels at a given probe site (q<0.05; Wilcoxon rank-sum test).	('methylation', 'biological_process', 'GO:0032259', ('77', '88'))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('methylation levels', 'MPA', (217, 235))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('low', 'NegReg', (213, 216))	('methylation', 'biological_process', 'GO:0032259', ('217', '228'))	('mutations', 'Var', (158, 167))
52949	29125844	An example of the chromosomal distribution of driver gene-associated methylation probes present in kidney renal clear cell carcinoma (KIRC) is shown in S4A Fig.	('methylation', 'biological_process', 'GO:0032259', ('69', '80'))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (99, 132))	('methylation', 'Var', (69, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('kidney renal clear cell carcinoma', 'Disease', (99, 132))
52950	29125844	A heat map illustrates mutations in these 14 genes in KIRC (S4B Fig), showing some co-occurrence between SETD2 mutations and PBRM1 mutations, and between BAP1 mutations and PBRM1 mutations, whereas SETD2 mutations and BAP1 mutations are almost mutually exclusive.	('PBRM1', 'Gene', (173, 178))	('mutations', 'Var', (111, 120))	('mutations', 'Var', (131, 140))	('SETD2', 'Gene', '29072', (105, 110))	('PBRM1', 'Gene', '55193', (173, 178))	('SETD2', 'Gene', (198, 203))	('BAP1', 'Gene', (154, 158))	('mutations', 'Var', (159, 168))	('SETD2', 'Gene', (105, 110))	('PBRM1', 'Gene', '55193', (125, 130))	('BAP1', 'Gene', '8314', (218, 222))	('co-occurrence', 'Interaction', (83, 96))	('mutations', 'Var', (179, 188))	('PBRM1', 'Gene', (125, 130))	('BAP1', 'Gene', (218, 222))	('BAP1', 'Gene', '8314', (154, 158))	('SETD2', 'Gene', '29072', (198, 203))
52954	29125844	By definition, positive associations indicate higher methylation levels among tumor samples in the presence of driver gene mutations, whereas negative associations indicate lower methylation levels.	('methylation', 'MPA', (179, 190))	('higher', 'PosReg', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('driver gene', 'Gene', (111, 122))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('methylation levels', 'MPA', (53, 71))	('lower', 'NegReg', (173, 178))	('tumor', 'Disease', (78, 83))	('methylation', 'biological_process', 'GO:0032259', ('179', '190'))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))	('mutations', 'Var', (123, 132))
52961	29125844	Genomic distribution analysis on RNF43-associated probes revealed that positively associated probes were enriched in gene promoters, whereas negatively associated probes were enriched in gene bodies, suggesting that they may have different functional impacts (S5 Fig).	('RNF43', 'Gene', '54894', (33, 38))	('probes', 'Var', (93, 99))	('RNF43', 'Gene', (33, 38))
52962	29125844	In short, a few driver genes were linked to genome-wide patterns of CGI hypermethylation and open sea hypomethylation in particular cancer types, whereas many more driver genes were linked to a few probe sites aberrantly methylated in cancer (S2 Table).	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('open sea hypomethylation in particular cancer', 'Disease', 'MESH:D009369', (93, 138))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('hypermethylation', 'Var', (72, 88))	('open sea hypomethylation in particular cancer', 'Disease', (93, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('linked', 'Reg', (34, 40))
52968	29125844	These genes were selected because they were associated with extensive methylation alterations (more than 1,000 probe associations per driver gene) in at least two cancer types.	('methylation', 'biological_process', 'GO:0032259', ('70', '81'))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('methylation alterations', 'Var', (70, 93))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Disease', (163, 169))
52970	29125844	This suggests a tight connection between TP53 mutations and open sea hypomethylation across multiple cancer types.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('open sea hypomethylation across multiple cancer', 'Disease', (60, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('open sea hypomethylation across multiple cancer', 'Disease', 'MESH:D009369', (60, 107))
52973	29125844	By contrast, IDH1 strongly favored positive associations in two cancer types, GBM and SKCM, consistent with reports that mutated IDH1 downregulates TET-dependent demethylation, resulting in aberrant CGI hypermethylation.	('SKCM', 'Disease', (86, 90))	('IDH1', 'Gene', (129, 133))	('GBM', 'Phenotype', 'HP:0012174', (78, 81))	('downregulates', 'NegReg', (134, 147))	('CGI hypermethylation', 'MPA', (199, 219))	('TET-dependent demethylation', 'MPA', (148, 175))	('cancer', 'Disease', (64, 70))	('mutated', 'Var', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('IDH1', 'Gene', (13, 17))	('demethylation', 'biological_process', 'GO:0070988', ('162', '175'))	('IDH1', 'Gene', '3417', (129, 133))	('IDH1', 'Gene', '3417', (13, 17))	('TET', 'Chemical', 'MESH:C010349', (148, 151))	('GBM', 'Disease', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
52983	29125844	For each cancer type, we then identified genes whose expression levels were correlated with TP53-associated probes (q<0.05; Spearman correlation) in gene promoters or bodies exhibiting aberrant methylation changes (magnitude of median difference in beta values between TP53-mutated tumors and normal samples >0.1).	('cancer', 'Disease', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('methylation', 'biological_process', 'GO:0032259', ('194', '205'))	('tumors', 'Disease', (282, 288))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('TP53', 'Gene', '7157', (269, 273))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('TP53', 'Gene', (269, 273))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('methylation changes', 'Var', (194, 213))	('expression', 'MPA', (53, 63))
52987	29125844	The enriched pathways/gene sets remained largely the same when repeating the analysis restricted to genes corresponding to TP53-negatively associated probes, whereas no enriched pathways/gene sets were found for genes corresponding to TP53-positively associated probes.	('probes', 'Var', (150, 156))	('TP53', 'Gene', '7157', (235, 239))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (235, 239))	('TP53', 'Gene', (123, 127))
52992	29125844	And in UCEC, mutations in TP53 were nearly mutually exclusive with PTEN and CTNNB1 mutations, which co-occurred in many tumor samples.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (83, 92))	('CTNNB1', 'Gene', '1499', (76, 82))	('TP53', 'Gene', '7157', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('PTEN', 'Gene', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CTNNB1', 'Gene', (76, 82))	('mutations', 'Var', (13, 22))	('PTEN', 'Gene', '5728', (67, 71))	('tumor', 'Disease', (120, 125))
52993	29125844	For both cancer types, we performed hierarchical clustering on the union of the 500 methylation probes most significantly associated with mutations in each of the top three genes (Fig 4).	('associated', 'Reg', (122, 132))	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('methylation', 'biological_process', 'GO:0032259', ('84', '95'))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('mutations', 'Var', (138, 147))
52995	29125844	SS and open sea regions); BRAF mutants displayed hypomethylation in open sea and some SS regions, whereas NRAS and HRAS mutants displayed methylation levels similar to normal samples in open sea and SS regions, with little hypermethylation.	('mutants', 'Var', (31, 38))	('BRAF', 'Gene', '673', (26, 30))	('HRAS', 'Gene', '3265', (115, 119))	('BRAF', 'Gene', (26, 30))	('methylation', 'biological_process', 'GO:0032259', ('138', '149'))	('NRAS', 'Gene', (106, 110))	('HRAS', 'Gene', (115, 119))	('hypomethylation', 'MPA', (49, 64))	('methylation levels', 'MPA', (138, 156))	('NRAS', 'Gene', '4893', (106, 110))
52999	29125844	Two methylation subtypes were also identified in UCEC, this time corresponding to TP53 vs. PTEN mutations, consistent with the serous vs. endometrioid histological subtypes of UCEC, respectively (Fig 4B).	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('UCEC', 'Disease', (49, 53))	('PTEN', 'Gene', (91, 95))	('PTEN', 'Gene', '5728', (91, 95))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('mutations', 'Var', (96, 105))
53001	29125844	Most UCEC samples with mutations in both PTEN and CTNNB1 displayed greater levels of open sea hypomethylation than samples with PTEN mutations alone, a finding which has not been previously reported.	('CTNNB1', 'Gene', (50, 56))	('PTEN', 'Gene', (128, 132))	('PTEN', 'Gene', '5728', (128, 132))	('CTNNB1', 'Gene', '1499', (50, 56))	('mutations', 'Var', (23, 32))	('greater', 'PosReg', (67, 74))	('PTEN', 'Gene', (41, 45))	('PTEN', 'Gene', '5728', (41, 45))	('open sea hypomethylation', 'Disease', 'MESH:D009041', (85, 109))	('open sea hypomethylation', 'Disease', (85, 109))
53005	29125844	We focused on CpG sites in promoter regions and gene bodies in NRAS and HRAS mutants (the NRAS-HRAS group) vs. BRAF mutants (the BRAF group).	('NRAS', 'Gene', '4893', (63, 67))	('NRAS', 'Gene', (90, 94))	('HRAS', 'Gene', (95, 99))	('BRAF', 'Gene', (129, 133))	('HRAS', 'Gene', '3265', (72, 76))	('BRAF', 'Gene', '673', (129, 133))	('NRAS', 'Gene', '4893', (90, 94))	('NRAS-HRAS group', 'Gene', '4893', (90, 105))	('HRAS', 'Gene', (72, 76))	('mutants', 'Var', (77, 84))	('NRAS-HRAS group', 'Gene', (90, 105))	('BRAF', 'Gene', '673', (111, 115))	('HRAS', 'Gene', '3265', (95, 99))	('NRAS', 'Gene', (63, 67))	('BRAF', 'Gene', (111, 115))
53016	29125844	We did not find a substantial proportion of differentially methylated genes implicated in tumor progression among the top differentially expressed genes (defined by median difference in expression between NRAS-HRAS mutants and normal samples).	('NRAS-HRAS', 'Gene', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('mutants', 'Var', (215, 222))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
53017	29125844	However, when we considered the top 17 differentially expressed, highly transcribed genes (median expression level in mutants > 10 log2 RSEM; median difference > 1 log2 RSEM; highlighted in S6 Table in bold), 6 out of 17 were implicated in tumorigenesis.	('tumor', 'Disease', (240, 245))	('mutants', 'Var', (118, 125))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('expression level', 'MPA', (98, 114))	('implicated', 'Reg', (226, 236))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
53022	29125844	This result demonstrates that methylation changes are indeed associated with differential gene expression between BRAF-mutated and NRAS- and HRAS-mutated samples in THCA.	('gene expression', 'biological_process', 'GO:0010467', ('90', '105'))	('methylation changes', 'Var', (30, 49))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('HRAS', 'Gene', '3265', (141, 145))	('THCA', 'Phenotype', 'HP:0002890', (165, 169))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('HRAS', 'Gene', (141, 145))	('NRAS-', 'Gene', '4893', (131, 136))	('differential gene expression', 'MPA', (77, 105))	('NRAS-', 'Gene', (131, 136))	('associated', 'Reg', (61, 71))
53023	29125844	In this study, we demonstrated that driver gene mutations are tightly tied to the DNAm landscape in multiple types of cancer.	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))
53024	29125844	In each cancer type, a few driver genes dominate the site-specific associations, and some potentially contribute to CGI hypermethylation and extensive hypomethylation, i.e., the hallmarks of cancer.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', (8, 14))	('contribute', 'Reg', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('extensive hypomethylation', 'MPA', (141, 166))	('hypermethylation', 'Var', (120, 136))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('CGI', 'MPA', (116, 119))
53026	29125844	Several driver genes that displayed primarily positive or negative associations with methylation probes in this study have been previously linked to CGI hypermethylation or open sea hypomethylation, respectively.	('methylation', 'Var', (85, 96))	('methylation', 'biological_process', 'GO:0032259', ('85', '96'))	('open sea hypomethylation', 'Disease', 'MESH:D009041', (173, 197))	('open sea hypomethylation', 'Disease', (173, 197))	('linked', 'Reg', (139, 145))	('CGI', 'Disease', (149, 152))	('negative', 'NegReg', (58, 66))	('associations', 'Interaction', (67, 79))
53029	29125844	In addition to these examples, we identified novel driver genes that may contribute to CGI hypermethylation, such as BAP1 in KIRC, or to open sea hypomethylation, such as CTNNB1 in LIHC.	('contribute', 'Reg', (73, 83))	('CTNNB1', 'Gene', (171, 177))	('BAP1', 'Gene', '8314', (117, 121))	('CGI', 'MPA', (87, 90))	('BAP1', 'Gene', (117, 121))	('hypermethylation', 'Var', (91, 107))	('CTNNB1', 'Gene', '1499', (171, 177))	('open sea hypomethylation', 'Disease', 'MESH:D009041', (137, 161))	('open sea hypomethylation', 'Disease', (137, 161))
53030	29125844	By illuminating the driver genes associated with widespread DNAm alterations, as well as driver genes associated with more limited DNAm alterations, our comprehensive analysis provides a detailed mutation-methylation map for many types of cancer.	('alterations', 'Var', (65, 76))	('methylation', 'biological_process', 'GO:0032259', ('205', '216'))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
53031	29125844	Several mutated driver genes displayed consistent and widespread positive or negative associations across cancers, corresponding to extensive DNAm alterations.	('negative', 'NegReg', (77, 85))	('associations', 'Interaction', (86, 98))	('mutated', 'Var', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('positive', 'PosReg', (65, 73))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
53033	29125844	For example, mutations in IDH1 and SETD2 directly affect the epigenetic landscape by inhibiting TET-dependent demethylation and disturbing DNA methyltransferase targeting, respectively.	('epigenetic landscape', 'MPA', (61, 81))	('demethylation', 'biological_process', 'GO:0070988', ('110', '123'))	('inhibiting', 'NegReg', (85, 95))	('DNA methyltransferase targeting', 'MPA', (139, 170))	('disturbing', 'Reg', (128, 138))	('IDH1', 'Gene', (26, 30))	('TET', 'Chemical', 'MESH:C010349', (96, 99))	('affect', 'Reg', (50, 56))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('SETD2', 'Gene', '29072', (35, 40))	('mutations', 'Var', (13, 22))	('IDH1', 'Gene', '3417', (26, 30))	('SETD2', 'Gene', (35, 40))	('TET-dependent demethylation', 'MPA', (96, 123))
53034	29125844	BRAF mutations, by contrast, displayed inconsistent methylation patterns between cancer types in this study.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('BRAF', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
53035	29125844	In COAD, BRAF-mutated samples mutations displayed widespread CGI hypermethylation.	('CGI hypermethylation', 'MPA', (61, 81))	('BRAF', 'Gene', (9, 13))	('COAD', 'Disease', (3, 7))	('mutations', 'Var', (30, 39))	('COAD', 'Disease', 'MESH:D029424', (3, 7))	('BRAF', 'Gene', '673', (9, 13))
53037	29125844	However, in THCA, BRAF-mutated samples (260/266 of which harbored the V600E mutation) largely displayed hypomethylation.	('THCA', 'Phenotype', 'HP:0002890', (12, 16))	('V600E', 'Var', (70, 75))	('displayed', 'Reg', (94, 103))	('BRAF', 'Gene', '673', (18, 22))	('hypomethylation', 'MPA', (104, 119))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('BRAF', 'Gene', (18, 22))
53038	29125844	Although no mechanistic explanation for this observation is yet available, it is possible that the mutation does not upregulate MAFG in THCA.	('THCA', 'Phenotype', 'HP:0002890', (136, 140))	('THCA', 'Disease', (136, 140))	('MAFG', 'Gene', (128, 132))	('mutation', 'Var', (99, 107))	('MAFG', 'Gene', '4097', (128, 132))
53040	29125844	Several mechanisms have been documented to support the consistent hypomethylation we observed in association with TP53 mutations, across cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('TP53', 'Gene', '7157', (114, 118))	('association', 'Interaction', (97, 108))	('cancer', 'Disease', (137, 143))	('TP53', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))
53041	29125844	For example, in hepatocellular carcinoma, loss-of-function mutations in TP53 allow pre-malignant cells to bypass senescence induced by global hypomethylation, which could explain the connection between TP53 mutations and hypomethylation.	('TP53', 'Gene', (202, 206))	('TP53', 'Gene', '7157', (72, 76))	('senescence', 'biological_process', 'GO:0010149', ('113', '123'))	('pre', 'molecular_function', 'GO:0003904', ('83', '86'))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (16, 40))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (16, 40))	('TP53', 'Gene', (72, 76))	('hepatocellular carcinoma', 'Disease', (16, 40))	('loss-of-function', 'NegReg', (42, 58))	('mutations', 'Var', (59, 68))	('global', 'MPA', (135, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('TP53', 'Gene', '7157', (202, 206))
53042	29125844	In this study, we found that hypomethylated sites associated with TP53 mutation are shared across cancer types and correspond to upregulated E2F-targets and genes involved in cell cycle regulation.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('hypomethylated sites', 'Var', (29, 49))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('175', '196'))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('mutation', 'Var', (71, 79))	('upregulated', 'PosReg', (129, 140))	('E2F-targets', 'MPA', (141, 152))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))
53044	29125844	Moreover, CpG methylation regulates E2F activity by preventing E2F family members from binding target promoters, supporting the correlation between TP53-associated hypomethylation at E2F targets and their upregulation.	('binding', 'molecular_function', 'GO:0005488', ('87', '94'))	('regulates', 'Reg', (26, 35))	('preventing', 'NegReg', (52, 62))	('upregulation', 'PosReg', (205, 217))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('binding', 'Interaction', (87, 94))	('E2F', 'Protein', (63, 66))	('methylation', 'Var', (14, 25))	('activity', 'MPA', (40, 48))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))
53045	29125844	Upregulated E2F activity may promote cell proliferation, consistent with the association between TP53 mutations and a high expression-based mitotic index in 9 cancer types found in this study (S3 Table).	('cancer', 'Disease', (159, 165))	('promote', 'PosReg', (29, 36))	('cell proliferation', 'biological_process', 'GO:0008283', ('37', '55'))	('TP53', 'Gene', '7157', (97, 101))	('cell proliferation', 'CPA', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('activity', 'MPA', (16, 24))	('Upregulated', 'PosReg', (0, 11))	('E2F', 'Protein', (12, 15))
53046	29125844	Therefore, the hypomethylation at E2F targets could regulate E2F activity or could simply represent the footprint of upregulated E2F activity due to TP53 loss, yielding the association between TP53 mutations and DNAm changes at E2F targets.	('TP53', 'Gene', '7157', (193, 197))	('E2F activity', 'MPA', (61, 73))	('TP53', 'Gene', '7157', (149, 153))	('mutations', 'Var', (198, 207))	('association', 'Interaction', (173, 184))	('TP53', 'Gene', (149, 153))	('TP53', 'Gene', (193, 197))	('loss', 'NegReg', (154, 158))	('regulate', 'Reg', (52, 60))
53048	29125844	Future research is needed to elucidate the role of hypomethylation in TP53-mutated tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TP53', 'Gene', '7157', (70, 74))	('hypomethylation', 'Var', (51, 66))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('TP53', 'Gene', (70, 74))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
53049	29125844	However, the DNAm landscape can be affected by mutations in epigenetic modifying enzymes such as SETD2, the H3K36me3 writer.	('H3K36me3 writer', 'Var', (108, 123))	('mutations', 'Var', (47, 56))	('affected', 'Reg', (35, 43))	('SETD2', 'Gene', '29072', (97, 102))	('DNAm landscape', 'MPA', (13, 27))	('SETD2', 'Gene', (97, 102))
53052	29125844	The TP53-associated hypomethylation at E2F targets found in this study may also be explained in this way.	('hypomethylation', 'Var', (20, 35))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', (4, 8))
53054	29125844	Conversely, changes in DNAm can cause mutations in cancer.	('DNAm', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cause', 'Reg', (32, 37))	('changes', 'Var', (12, 19))
53057	29125844	The associations observed may simply reflect the presence of specific DNAm patterns in the same tumor subtypes in which particular driver gene mutations are enriched or depleted.	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (96, 101))	('mutations', 'Var', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))
53058	29125844	In the previously mentioned example, DNA hypomethylation triggers TP53-mediated senescence, and hepatocellular carcinoma emerges when senescence is bypassed due to later TP53 loss.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('hepatocellular carcinoma', 'Disease', (96, 120))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (96, 120))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('triggers', 'Reg', (57, 65))	('TP53', 'Gene', '7157', (170, 174))	('TP53', 'Gene', (170, 174))	('DNA hypomethylation', 'Var', (37, 56))	('loss', 'NegReg', (175, 179))	('senescence', 'biological_process', 'GO:0010149', ('80', '90'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('37', '56'))	('senescence', 'biological_process', 'GO:0010149', ('134', '144'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (96, 120))
53059	29125844	In this manner, positive selection for both the gene level and the DNAm level alterations could mechanistically link two non-causal events during tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('alterations', 'Var', (78, 89))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
53060	29125844	Because mutation-methylation patterns may reflect important oncogenic characteristics, using these patterns to separate tumors into molecular subtypes could potentially aid treatment selection.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('aid', 'Reg', (169, 172))	('mutation-methylation patterns', 'Var', (8, 37))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
53062	29125844	Likewise, the two UCEC subtypes characterized by PTEN and TP53 mutations corresponded to the endometrioid-like and serous-like subtypes identified in TCGA analysis, respectively (Fig 4B).	('mutations', 'Var', (63, 72))	('PTEN', 'Gene', '5728', (49, 53))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('endometrioid-like', 'Disease', (93, 110))	('PTEN', 'Gene', (49, 53))
53063	29125844	Moreover, TCGA classification indicated that the endometrioid-like subtype could be further subdivided into a microsatellite instability subtype (with a low frequency of CTNNB1 mutations) and a low-copy-number subtype (with a high frequency of CTNNB1 mutations).	('CTNNB1', 'Gene', '1499', (244, 250))	('microsatellite instability', 'MPA', (110, 136))	('mutations', 'Var', (177, 186))	('CTNNB1', 'Gene', '1499', (170, 176))	('endometrioid-like', 'Disease', (49, 66))	('CTNNB1', 'Gene', (244, 250))	('CTNNB1', 'Gene', (170, 176))
53064	29125844	Consistent with this finding, in our study tumors with co-occurring PTEN and CTNNB1 mutations displayed more hypomethylation (corresponding to the low-copy-number subtype) than tumors with PTEN mutations alone.	('hypomethylation', 'MPA', (109, 124))	('PTEN', 'Gene', (189, 193))	('PTEN', 'Gene', '5728', (189, 193))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('CTNNB1', 'Gene', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('PTEN', 'Gene', (68, 72))	('mutations', 'Var', (84, 93))	('CTNNB1', 'Gene', '1499', (77, 83))	('PTEN', 'Gene', '5728', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (43, 49))	('tumors', 'Disease', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
53066	29125844	The mutual exclusivity of the NRAS, HRAS, and BRAF mutations in THCA tumors has been interpreted to mean that these mutations must have interchangeable effects on MAPK signaling activation, the main cancer-driving event in papillary thyroid carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('carcinomas', 'Phenotype', 'HP:0030731', (241, 251))	('mutations', 'Var', (51, 60))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (223, 250))	('HRAS', 'Gene', '3265', (36, 40))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (223, 251))	('activation', 'PosReg', (178, 188))	('HRAS', 'Gene', (36, 40))	('cancer', 'Disease', (199, 205))	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('NRAS', 'Gene', '4893', (30, 34))	('THCA', 'Disease', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Disease', (69, 75))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (233, 250))	('THCA', 'Phenotype', 'HP:0002890', (64, 68))	('papillary thyroid carcinomas', 'Disease', (223, 251))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (223, 251))	('MAPK', 'MPA', (163, 167))	('MAPK signaling', 'biological_process', 'GO:0000165', ('163', '177'))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (233, 251))	('MAPK', 'molecular_function', 'GO:0004707', ('163', '167'))	('NRAS', 'Gene', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
53067	29125844	Our analysis, however, highlights substantial differences in DNAm between BRAF-mutated vs. NRAS- and HRAS-mutated THCA tumors; moreover, the differences in DNAm appear to profoundly shape gene expression profiles, which may contribute to thyroid tumorigenesis.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('HRAS', 'Gene', '3265', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('HRAS', 'Gene', (101, 105))	('gene expression', 'biological_process', 'GO:0010467', ('188', '203'))	('thyroid tumor', 'Disease', 'MESH:D013959', (238, 251))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('shape', 'Reg', (182, 187))	('differences', 'Var', (141, 152))	('tumors', 'Disease', (119, 125))	('thyroid tumor', 'Disease', (238, 251))	('gene expression profiles', 'MPA', (188, 212))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('NRAS-', 'Gene', '4893', (91, 96))	('contribute', 'Reg', (224, 234))	('THCA', 'Phenotype', 'HP:0002890', (114, 118))	('NRAS-', 'Gene', (91, 96))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('thyroid tumor', 'Phenotype', 'HP:0100031', (238, 251))
53068	29125844	In this study, differential DNAm in six JAK and STAT family genes were found to correlate with their upregulation in BRAF-mutated tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('upregulation', 'PosReg', (101, 113))	('JAK', 'Gene', (40, 43))	('differential DNAm', 'Var', (15, 32))	('STAT family genes', 'Gene', (48, 65))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('BRAF', 'Gene', '673', (117, 121))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('JAK', 'molecular_function', 'GO:0004713', ('40', '43'))	('BRAF', 'Gene', (117, 121))
53072	29125844	Paired with the aggressiveness of BRAF vs. RAS mutation-positive thyroid tumors, our results support a connection between BRAF mutations, JAK-STAT signaling upregulation (including STAT3 activation), and THCA metastasis, suggesting the role of STAT3 and other JAK-STAT family genes in oncogenesis in THCA.	('THCA', 'Disease', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('JAK', 'molecular_function', 'GO:0004713', ('138', '141'))	('THCA', 'Phenotype', 'HP:0002890', (300, 304))	('STAT3', 'Gene', (181, 186))	('THCA', 'Phenotype', 'HP:0002890', (204, 208))	('JAK-STAT signaling', 'MPA', (138, 156))	('STAT3', 'Gene', (244, 249))	('STAT3', 'Gene', '6774', (181, 186))	('upregulation', 'PosReg', (157, 169))	('STAT3', 'Gene', '6774', (244, 249))	('thyroid tumors', 'Disease', 'MESH:D013959', (65, 79))	('mutations', 'Var', (127, 136))	('signaling', 'biological_process', 'GO:0023052', ('147', '156'))	('aggressiveness', 'Disease', (16, 30))	('aggressiveness', 'Phenotype', 'HP:0000718', (16, 30))	('JAK', 'molecular_function', 'GO:0004713', ('260', '263'))	('thyroid tumor', 'Phenotype', 'HP:0100031', (65, 78))	('aggressiveness', 'Disease', 'MESH:D001523', (16, 30))	('oncogenesis', 'biological_process', 'GO:0007048', ('285', '296'))	('BRAF', 'Gene', '673', (122, 126))	('thyroid tumors', 'Disease', (65, 79))	('BRAF', 'Gene', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))
53074	29125844	These differences in the molecular processes linked to different driver gene mutations may contribute to distinct pathways of tumorigenesis, yielding different prognoses and clinical phenotypes.	('contribute', 'Reg', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('mutations', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
53075	29125844	For example, although the majority of BRAF-mutated samples carried the V600E mutation (25 out of 34 BRAF-mutated tumors carried BRAF V600E in COAD, 167/195 in SKCM, and 260/266 in THCA), this group also included a few non-V600E mutations.	('COAD', 'Disease', 'MESH:D029424', (142, 146))	('BRAF', 'Gene', '673', (128, 132))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('V600E', 'Mutation', 'rs113488022', (222, 227))	('V600E', 'Mutation', 'rs113488022', (133, 138))	('BRAF', 'Gene', '673', (38, 42))	('COAD', 'Disease', (142, 146))	('BRAF', 'Gene', '673', (100, 104))	('V600E', 'Var', (71, 76))	('BRAF', 'Gene', (38, 42))	('V600E', 'Var', (133, 138))	('BRAF', 'Gene', (100, 104))	('THCA', 'Phenotype', 'HP:0002890', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('BRAF', 'Gene', (128, 132))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
53076	29125844	However, combinatorial effects of driver gene mutations on methylation could exist, as several driver gene mutations typically co-occur in a given tumor.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('mutations', 'Var', (107, 116))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
53077	29125844	Although MutSigCV is one of the most reliable driver gene-detection tools available, limitations associated with the detection algorithm:paired with limitations imposed by the number of tumor samples available in TCGA:may have led us to miss methylation-altering mutations that occurred in unknown driver genes.	('methylation', 'biological_process', 'GO:0032259', ('242', '253'))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('mutations', 'Var', (263, 272))	('tumor', 'Disease', (186, 191))	('methylation-altering', 'MPA', (242, 262))
53083	29125844	In addition, in the future, further analysis of methylation and expression data may identify driver gene mutation-induced methylation alterations that dysregulate genes/pathways that promote tumor growth.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('mutation-induced', 'Reg', (105, 121))	('dysregulate', 'Reg', (151, 162))	('methylation alterations', 'Var', (122, 145))	('genes/pathways', 'Pathway', (163, 177))	('alterations', 'Var', (134, 145))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('methylation', 'biological_process', 'GO:0032259', ('122', '133'))	('promote', 'PosReg', (183, 190))
53085	29125844	Demethylating agents such as 5-aza-2'-deoxycytidine, for example, have been used to reactivate epigenetically silenced tumor suppressor genes and also to decrease overexpression of oncogenes.	('overexpression', 'MPA', (163, 177))	('tumor', 'Disease', (119, 124))	('tumor suppressor', 'biological_process', 'GO:0051726', ('119', '135'))	('reactivate epigenetically silenced', 'Var', (84, 118))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (29, 51))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('119', '135'))	('decrease', 'NegReg', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('oncogenes', 'Protein', (181, 190))
53086	29125844	By contrast, the methyl donor S-adenosylmethionine has been shown to downregulate the oncogenes c-MYC and HRAS, inhibiting cancer cell growth.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('c-MYC', 'Gene', (96, 101))	('HRAS', 'Gene', (106, 110))	('S-adenosylmethionine', 'Chemical', 'MESH:D012436', (30, 50))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('downregulate', 'NegReg', (69, 81))	('c-MYC', 'Gene', '4609', (96, 101))	('HRAS', 'Gene', '3265', (106, 110))	('donor', 'Species', '9606', (24, 29))	('S-adenosylmethionine', 'Var', (30, 50))	('cell growth', 'biological_process', 'GO:0016049', ('130', '141'))	('inhibiting', 'NegReg', (112, 122))
53087	29125844	In summary, in light of the connection between driver gene mutations and DNA methylation shown here, it will be important to further study how coordinated genomic and epigenomic alterations result in the hallmarks of cancer.	('result in', 'Reg', (190, 199))	('DNA methylation', 'biological_process', 'GO:0006306', ('73', '88'))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('mutations', 'Var', (59, 68))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
53094	29125844	The following types of probes were removed from the analysis: (i) probes on the X and Y chromosomes, (ii) cross-reactive probes, (iii) probes near single nucleotide polymorphisms (SNPs), and (iv) probes with missing rates >=90% across all samples for a given cancer type.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('single nucleotide polymorphisms', 'Var', (147, 178))	('cancer', 'Disease', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('probes', 'Var', (135, 141))
53106	29125844	A driver gene was classified as either mutated (any mutations) or not mutated (no mutations) for each tumor sample.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))
53107	29125844	Finally, we performed the same association test for every driver gene and the HyperZ and HypoZ indices, to identify driver genes potentially associated with genome-wide CGI hypermethylation and open sea hypomethylation.	('hypermethylation', 'Var', (173, 189))	('open sea hypomethylation', 'Disease', 'MESH:D009041', (194, 218))	('associated', 'Reg', (141, 151))	('open sea hypomethylation', 'Disease', (194, 218))
53110	29125844	First, we visually identified two THCA molecular subtypes based on driver gene mutations and DNA methylation patterns (Fig 4A): (i) BRAF-mutated tumors (the BRAF group) and (ii) NRAS- and HRAS-mutated tumors (the NRAS-HRAS group).	('HRAS', 'Gene', (188, 192))	('NRAS-HRAS group', 'Gene', '4893', (213, 228))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('mutations', 'Var', (79, 88))	('DNA methylation', 'biological_process', 'GO:0006306', ('93', '108'))	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('NRAS-', 'Gene', (213, 218))	('NRAS-', 'Gene', '4893', (213, 218))	('BRAF', 'Gene', '673', (157, 161))	('HRAS', 'Gene', '3265', (218, 222))	('BRAF', 'Gene', (157, 161))	('HRAS', 'Gene', (218, 222))	('BRAF', 'Gene', '673', (132, 136))	('BRAF', 'Gene', (132, 136))	('THCA', 'Phenotype', 'HP:0002890', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('NRAS-', 'Gene', '4893', (178, 183))	('NRAS-', 'Gene', (178, 183))	('NRAS-HRAS group', 'Gene', (213, 228))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('HRAS', 'Gene', '3265', (188, 192))	('tumors', 'Disease', (201, 207))
53111	29125844	The search was restricted to genes whose aberrant expression levels coincided with hyper- or hypomethylated probes associated with BRAF, HRAS, and NRAS mutations (see section below).	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', (131, 135))	('mutations', 'Var', (152, 161))	('expression levels', 'MPA', (50, 67))	('NRAS', 'Gene', (147, 151))	('HRAS', 'Gene', '3265', (137, 141))	('NRAS', 'Gene', '4893', (147, 151))	('HRAS', 'Gene', (137, 141))
53112	29125844	We sought genes whose aberrant expression was correlated with aberrant methylation in the presence of BRAF, HRAS, or NRAS mutations.	('NRAS', 'Gene', (117, 121))	('HRAS', 'Gene', '3265', (108, 112))	('BRAF', 'Gene', '673', (102, 106))	('NRAS', 'Gene', '4893', (117, 121))	('HRAS', 'Gene', (108, 112))	('aberrant', 'Var', (62, 70))	('BRAF', 'Gene', (102, 106))	('methylation', 'MPA', (71, 82))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('mutations', 'Var', (122, 131))
53114	29125844	Third, we integrated the results from the first and second steps to identify aberrantly methylated probes whose methylation levels were significantly correlated with the expression levels of their corresponding genes for each group of BRAF-, HRAS-, and NRAS- mutated samples.	('BRAF', 'Gene', '673', (235, 239))	('methylation', 'biological_process', 'GO:0032259', ('112', '123'))	('methylation levels', 'MPA', (112, 130))	('BRAF', 'Gene', (235, 239))	('HRAS', 'Gene', '3265', (242, 246))	('expression levels', 'MPA', (170, 187))	('NRAS-', 'Gene', '4893', (253, 258))	('HRAS', 'Gene', (242, 246))	('correlated', 'Reg', (150, 160))	('NRAS-', 'Gene', (253, 258))	('aberrantly methylated probes', 'Var', (77, 105))
53115	29125844	For example, when we looked for genes that were upregulated in BRAF-mutated samples but exhibited no change or were downregulated in HRAS- and NRAS-mutated samples, we restricted the search to genes that were hyper- (or hypo-) methylated in BRAF-mutated samples but exhibited no change or were hypo- (or hyper-) methylated in HRAS- and NRAS-mutated samples in the third step.	('NRAS-', 'Gene', '4893', (143, 148))	('hypo-', 'Var', (220, 225))	('NRAS-', 'Gene', (143, 148))	('hyper-', 'Var', (209, 215))	('BRAF', 'Gene', (241, 245))	('BRAF', 'Gene', '673', (241, 245))	('BRAF', 'Gene', '673', (63, 67))	('HRAS', 'Gene', '3265', (133, 137))	('upregulated', 'PosReg', (48, 59))	('HRAS', 'Gene', '3265', (326, 330))	('HRAS', 'Gene', (133, 137))	('BRAF', 'Gene', (63, 67))	('HRAS', 'Gene', (326, 330))	('NRAS-', 'Gene', (336, 341))	('NRAS-', 'Gene', '4893', (336, 341))
53163	27733208	Three hundred forty-seven patients (27.5%) had blood group A, 332 had blood group B (26.4%), 101 had blood group AB (8.0%), and 480 had blood group O (38.1%).	('blood group B', 'Var', (70, 83))	('blood group A', 'Var', (47, 60))	('patients', 'Species', '9606', (26, 34))
53184	27733208	In this study, 1896 patients with pancreatic cancer and 1939 controls were genotyped, and a significant association was reported with rs505922, a single nucleotide polymorphism (SNP) that maps to the first intron of the ABO gene.	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('ABO', 'Gene', '28', (220, 223))	('ABO', 'Gene', (220, 223))	('rs505922', 'Mutation', 'rs505922', (134, 142))	('rs505922', 'Var', (134, 142))	('patients', 'Species', '9606', (20, 28))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('pancreatic cancer', 'Disease', (34, 51))
53185	27733208	The ABO SNP rs505922 is in strong linkage disequilibrium with O/non-O blood group alleles, indicating that people with non-O blood groups are at increased risk for developing pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (175, 192))	('pancreatic cancer', 'Disease', (175, 192))	('people', 'Species', '9606', (107, 113))	('ABO', 'Gene', (4, 7))	('rs505922', 'Mutation', 'rs505922', (12, 20))	('ABO', 'Gene', '28', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (175, 192))	('rs505922', 'Var', (12, 20))
53186	27733208	In addition, two recent genome-wide association studies identified variants in ABO (rs505922), 1q32.1 (rs3790844), 13q22.1 (rs9543325), and 5p15.3 (rs401681) that were associated with a modestly increased risk of pancreatic cancer.	('pancreatic cancer', 'Disease', (213, 230))	('rs505922', 'Var', (84, 92))	('pancreatic cancer', 'Disease', 'MESH:D010190', (213, 230))	('rs3790844', 'Var', (103, 112))	('rs505922', 'Mutation', 'rs505922', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('rs401681', 'Var', (148, 156))	('ABO', 'Gene', (79, 82))	('ABO', 'Gene', '28', (79, 82))	('rs401681', 'Mutation', 'rs401681', (148, 156))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (213, 230))	('rs3790844', 'Mutation', 'rs3790844', (103, 112))	('rs9543325', 'Mutation', 'rs9543325', (124, 133))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (195, 230))	('rs9543325', 'Var', (124, 133))
53194	27733208	indicated that nasopharyngeal carcinoma (NPC) patients with blood group A had significantly lower OS rate (adjusted HR = 1.49 [95% CI 1.03-2.17]) and distant metastasis-free survival rate (HR = 1.68 [95% CI 1.13-2.51]) than patients with non-A blood groups (B, AB, and O).	('NPC', 'Disease', 'MESH:D052556', (41, 44))	('blood group A', 'Var', (60, 73))	('NPC', 'Disease', (41, 44))	('patients', 'Species', '9606', (46, 54))	('distant metastasis-free survival rate', 'CPA', (150, 187))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (15, 39))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (15, 39))	('non-A', 'Species', '12440', (238, 243))	('nasopharyngeal carcinoma', 'Disease', (15, 39))	('patients', 'Species', '9606', (224, 232))	('OS', 'Chemical', '-', (98, 100))	('OS rate', 'CPA', (98, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('NPC', 'Phenotype', 'HP:0100630', (41, 44))	('lower', 'NegReg', (92, 97))	('NPC', 'cellular_component', 'GO:0005643', ('41', '44'))
53199	27733208	found that non-muscle invasive bladder urothelial carcinoma patients with blood group O had higher recurrence and progression rates than patients with blood group A (P = 0.015 and 0.031, respectively) or blood group B (P = 0.004 and 0.075, respectively).	('higher', 'PosReg', (92, 98))	('patients', 'Species', '9606', (60, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('patients', 'Species', '9606', (137, 145))	('recurrence', 'CPA', (99, 109))	('blood group O', 'Var', (74, 87))	('invasive bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (22, 59))	('invasive bladder', 'Phenotype', 'HP:0100645', (22, 38))	('progression rates', 'CPA', (114, 131))	('invasive bladder urothelial carcinoma', 'Disease', (22, 59))
53201	27733208	found that patients with blood group B/O had lower OS rate than patients with blood group A/AB (P = 0.024).	('OS', 'Chemical', '-', (51, 53))	('patients', 'Species', '9606', (64, 72))	('lower', 'NegReg', (45, 50))	('blood group B/O', 'Var', (25, 40))	('OS rate', 'MPA', (51, 58))	('patients', 'Species', '9606', (11, 19))
53205	27733208	showed that, in patients with renal cell carcinoma who underwent nephrectomy or partial nephrectomy, non-O blood groups were significantly associated with decreased OS (HR = 1.68, 95% CI 1.18-2.39, P = 0.004).	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('OS', 'Chemical', '-', (165, 167))	('patients', 'Species', '9606', (16, 24))	('renal cell carcinoma', 'Disease', (30, 50))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (30, 50))	('decreased', 'NegReg', (155, 164))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (30, 50))	('non-O blood groups', 'Var', (101, 119))
53206	27733208	showed that NSCLC patients with blood group O or B had significantly longer OS, disease-free survival, and local recurrence-free survival than NSCLC patients with blood group A or AB.	('patients', 'Species', '9606', (149, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (12, 17))	('NSCLC', 'Disease', (143, 148))	('OS', 'Chemical', '-', (76, 78))	('local recurrence-free survival', 'CPA', (107, 137))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('NSCLC', 'Disease', (12, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('longer', 'PosReg', (69, 75))	('blood', 'Var', (32, 37))	('disease-free survival', 'CPA', (80, 101))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('patients', 'Species', '9606', (18, 26))
53238	33679865	Previous studies have presented the association of certain miRNAs with lung metastasis, including miR-629-3p, miR-106b-5p, and so on.	('miR-629-3p', 'Var', (98, 108))	('miR-106b', 'Gene', (110, 118))	('miR-106b', 'Gene', '406900', (110, 118))	('association', 'Interaction', (36, 47))	('lung', 'Disease', (71, 75))
53285	33679865	Compared the TNM stage alone, the NRI values for miRNA-based prediction nomogram were 0.216 (95% CI, 0.048-0.384, value of p = 0.012), 0.307 (95% CI, 0.020-0.594, value of p = 0.036) and 0.308 (95% CI, 0.081-0.535, value of p = 0.008) in the training cohort and two validation cohorts, respectively (Table 5).	('age', 'Gene', (19, 22))	('0.308', 'Var', (187, 192))	('0.307', 'Var', (135, 140))	('age', 'Gene', '5973', (19, 22))
53361	33364434	Moreover, the patients' overall survival was notably shorter in the high SLC12A8 group.	('SLC12A8', 'Gene', '84561', (73, 80))	('overall survival', 'CPA', (24, 40))	('high', 'Var', (68, 72))	('shorter', 'NegReg', (53, 60))	('SLC12A8', 'Gene', (73, 80))	('patients', 'Species', '9606', (14, 22))
53404	33364434	The primary antibodies used in this study were as follows: SLC12A8 (ab122152, Abcam), E-cadherin (ab40772, Abcam), beta-catenin (ab227499, Abcam), vimentin (ab45939, Abcam), snail (ab82846, Abcam), and slug (ab27568, Abcam).	('slug', 'Gene', '6591', (202, 206))	('vimentin', 'cellular_component', 'GO:0045099', ('147', '155'))	('beta-catenin', 'Gene', (115, 127))	('snail', 'Gene', '6615', (174, 179))	('ab227499', 'Var', (129, 137))	('cadherin', 'molecular_function', 'GO:0008014', ('88', '96'))	('vimentin', 'cellular_component', 'GO:0045098', ('147', '155'))	('SLC12A8', 'Gene', (59, 66))	('slug', 'Gene', (202, 206))	('ab82846', 'Var', (181, 188))	('beta-catenin', 'Gene', '1499', (115, 127))	('snail', 'Gene', (174, 179))	('E-cadherin', 'Gene', (86, 96))	('E-cadherin', 'Gene', '999', (86, 96))	('SLC12A8', 'Gene', '84561', (59, 66))	('vimentin', 'Gene', '7431', (147, 155))	('ab40772', 'Var', (98, 105))	('vimentin', 'Gene', (147, 155))
53452	33364434	The outcomes of plate cloning experiment showed that compared with the control group, the proliferation rate of the T24 cells was significantly reduced after knockdown of SLC12A8 by si-SLC12A8#1 or si-SLC12A8#2 (Figure 3d-e) (p < 0.01).	('SLC12A8', 'Gene', (201, 208))	('reduced', 'NegReg', (144, 151))	('SLC12A8', 'Gene', '84561', (201, 208))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('proliferation rate of the T24 cells', 'CPA', (90, 125))	('SLC12A8', 'Gene', (171, 178))	('si', 'Chemical', 'MESH:D012825', (198, 200))	('SLC12A8', 'Gene', '84561', (171, 178))	('knockdown', 'Var', (158, 167))	('SLC12A8', 'Gene', (185, 192))	('si', 'Chemical', 'MESH:D012825', (182, 184))	('SLC12A8', 'Gene', '84561', (185, 192))
53456	33364434	Similarly, the invasive (40.73%) and migratory (51.27%) abilities of T24 cells were reduced after knockdown of SLC12A8 by si-SLC12A8#2 treatment (p < 0.01, Figure 3h).	('SLC12A8', 'Gene', '84561', (111, 118))	('SLC12A8', 'Gene', '84561', (125, 132))	('SLC12A8', 'Gene', (125, 132))	('knockdown', 'Var', (98, 107))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('reduced', 'NegReg', (84, 91))	('SLC12A8', 'Gene', (111, 118))
53457	33364434	The aforementioned results indicated that the knockdown of SLC12A8 can reduce the invasive and migratory capacities of bladder cancer cells.	('reduce', 'NegReg', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('bladder cancer', 'Phenotype', 'HP:0009725', (119, 133))	('knockdown', 'Var', (46, 55))	('bladder cancer', 'Disease', 'MESH:D001749', (119, 133))	('SLC12A8', 'Gene', (59, 66))	('bladder cancer', 'Disease', (119, 133))	('SLC12A8', 'Gene', '84561', (59, 66))	('si', 'Chemical', 'MESH:D012825', (86, 88))
53462	33364434	The western blot evidenced the aforementioned results: beta-catenin, vimentin, snail, and slug protein were decreased, and E-cadherin protein was increased when SLC12A8 was knocked down by si-SLC12A8#1 or si-SLC12A8#2 in T24 cells (Figure 4b and c), while the result was opposite when SLC12A8 was upregulated in 5,637 cells (Figure 4d).	('SLC12A8', 'Gene', '84561', (208, 215))	('vimentin', 'cellular_component', 'GO:0045099', ('69', '77'))	('knocked', 'Var', (173, 180))	('beta-catenin', 'Gene', (55, 67))	('SLC12A8', 'Gene', '84561', (285, 292))	('slug', 'Gene', '6591', (90, 94))	('increased', 'PosReg', (146, 155))	('beta-catenin', 'Gene', '1499', (55, 67))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('E-cadherin', 'Gene', (123, 133))	('E-cadherin', 'Gene', '999', (123, 133))	('si', 'Chemical', 'MESH:D012825', (205, 207))	('SLC12A8', 'Gene', (192, 199))	('snail', 'Gene', '6615', (79, 84))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('SLC12A8', 'Gene', (161, 168))	('cadherin', 'molecular_function', 'GO:0008014', ('125', '133'))	('vimentin', 'cellular_component', 'GO:0045098', ('69', '77'))	('si', 'Chemical', 'MESH:D012825', (275, 277))	('vimentin', 'Gene', '7431', (69, 77))	('slug', 'Gene', (90, 94))	('si', 'Chemical', 'MESH:D012825', (189, 191))	('SLC12A8', 'Gene', (208, 215))	('vimentin', 'Gene', (69, 77))	('decreased', 'NegReg', (108, 117))	('SLC12A8', 'Gene', '84561', (192, 199))	('SLC12A8', 'Gene', '84561', (161, 168))	('snail', 'Gene', (79, 84))	('SLC12A8', 'Gene', (285, 292))
53471	33364434	found that SLC12A8 was correlated with a shorter overall survival of breast cancer patients, probably because the variation of SLC12A8 may be involved in the transportation of chemotherapeutic drugs, leading to a worse prognosis.	('overall survival', 'MPA', (49, 65))	('shorter', 'NegReg', (41, 48))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('si', 'Chemical', 'MESH:D012825', (225, 227))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('SLC12A8', 'Gene', (127, 134))	('SLC12A8', 'Gene', (11, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('involved', 'Reg', (142, 150))	('SLC12A8', 'Gene', '84561', (127, 134))	('variation', 'Var', (114, 123))	('patients', 'Species', '9606', (83, 91))	('SLC12A8', 'Gene', '84561', (11, 18))
53542	32887577	More significantly, high Ki67 expression and low cyclinD1 expression were associated with an increased risk of recurrence in young patients, but not in older patients.	('patients', 'Species', '9606', (131, 139))	('cyclinD1', 'Gene', (49, 57))	('expression', 'MPA', (30, 40))	('expression', 'MPA', (58, 68))	('recurrence', 'Disease', (111, 121))	('cyclinD1', 'Gene', '595', (49, 57))	('low', 'NegReg', (45, 48))	('Ki67', 'Gene', (25, 29))	('high', 'Var', (20, 24))	('patients', 'Species', '9606', (158, 166))
53697	31291718	Although the number of deaths in the positive group looked small compared to the 16 deaths in the negative PD-L1 group, the proportional survival rate of PD-L1 positive was higher (60%) than the negative PD-L1 negative group (10.2%).	('PD-L1', 'Gene', (204, 209))	('PD-L1', 'Gene', '29126', (107, 112))	('PD-L1', 'Gene', '29126', (204, 209))	('PD-L1', 'Gene', (154, 159))	('proportional survival', 'CPA', (124, 145))	('PD-L1', 'Gene', '29126', (154, 159))	('PD-L1', 'Gene', (107, 112))	('positive', 'Var', (160, 168))	('higher', 'PosReg', (173, 179))
53738	28824949	A subset of these variants appear to impact pathological and clinical stage and/or response to chemotherapy.	('response to chemotherapy', 'CPA', (83, 107))	('impact', 'Reg', (37, 43))	('variants', 'Var', (18, 26))	('clinical', 'Species', '191496', (61, 69))
53739	28824949	In the majority of cases, however, variant morphology occurs in a background of conventional urothelial carcinoma (UC) and the response of variants to emerging therapies is largely unknown.	('occurs', 'Reg', (54, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (93, 113))	('variant', 'Var', (35, 42))	('urothelial carcinoma', 'Disease', (93, 113))
53741	28824949	Emerging molecular data have identified unique molecular alterations in a subset of variants, including HER2 amplification in micropapillary UC and E-cadherin deletions in plasmacytoid UC that may be useful in further defining these variants in future studies.	('E-cadherin', 'Gene', (148, 158))	('E-cadherin', 'Gene', '999', (148, 158))	('amplification', 'Var', (109, 122))	('cadherin', 'molecular_function', 'GO:0008014', ('150', '158'))	('HER2', 'Gene', (104, 108))	('deletions', 'Var', (159, 168))	('HER2', 'Gene', '2064', (104, 108))
53758	28824949	Furthermore, currently available cell lines may not be representative of bladder cancers, as comparison of the genotype of a large panel of bladder cancer cell lines to bladder cancers revealed that cell lines are more likely to have TP53 mutations and less likely to have FGFR3 mutations.	('bladder cancer', 'Disease', 'MESH:D001749', (169, 183))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('mutations', 'Var', (239, 248))	('bladder cancers', 'Phenotype', 'HP:0009725', (169, 184))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('bladder cancer', 'Phenotype', 'HP:0009725', (169, 183))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))	('mutations', 'Var', (279, 288))	('TP53', 'Gene', (234, 238))	('bladder cancers', 'Phenotype', 'HP:0009725', (73, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('bladder cancers', 'Disease', 'MESH:D001749', (169, 184))	('bladder cancers', 'Disease', (169, 184))	('FGFR3', 'Gene', (273, 278))	('bladder cancer', 'Disease', 'MESH:D001749', (140, 154))	('bladder cancer', 'Disease', (140, 154))	('bladder cancers', 'Disease', 'MESH:D001749', (73, 88))	('FGFR3', 'Gene', '2261', (273, 278))	('bladder cancers', 'Disease', (73, 88))	('TP53', 'Gene', '7157', (234, 238))	('FGFR', 'molecular_function', 'GO:0005007', ('273', '277'))	('bladder cancer', 'Phenotype', 'HP:0009725', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
53775	28824949	Surprisingly, single mutations in p53/RB1 tumor suppressor pathways also appear to lack tumorigenicity.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('tumor', 'Disease', (42, 47))	('RB1', 'Gene', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('lack', 'NegReg', (83, 87))	('tumor suppressor', 'biological_process', 'GO:0051726', ('42', '58'))	('RB1', 'Gene', '5925', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('single mutations', 'Var', (14, 30))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('42', '58'))	('tumor', 'Disease', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
53776	28824949	Urothelium-specific ablation of p53 and RB1 or PTEN does, however, lead to urothelial abnormality and tumor development.	('RB1', 'Gene', '5925', (40, 43))	('lead to', 'Reg', (67, 74))	('urothelial abnormality', 'Disease', 'MESH:D001745', (75, 97))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('men', 'Species', '9606', (115, 118))	('p53', 'Gene', (32, 35))	('RB1', 'Gene', (40, 43))	('p53', 'Gene', '7157', (32, 35))	('PTEN', 'Gene', (47, 51))	('PTEN', 'Gene', '5728', (47, 51))	('ablation', 'Var', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('urothelial abnormality', 'Disease', (75, 97))
53785	28824949	Notably, this experimental observation was born out in patients, in which those who were PPD-positive at the start of therapy had improved recurrence-free survival compared to those who were PPD-negative at the onset of therapy.	('recurrence-free survival', 'CPA', (139, 163))	('PPD-positive', 'Var', (89, 101))	('patients', 'Species', '9606', (55, 63))	('improved', 'PosReg', (130, 138))	('men', 'Species', '9606', (20, 23))
53813	28824949	The alteration of the fibroblast growth factor receptor (FRFG) and the related pathway has been long known in the pathophysiology of bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('alteration', 'Var', (4, 14))	('FRFG', 'Gene', (57, 61))	('bladder cancer', 'Disease', 'MESH:D001749', (133, 147))	('bladder cancer', 'Disease', (133, 147))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('22', '46'))
53814	28824949	FGFR3 is known to be dysregulated in some forms of bladder cancer with the identification of the FGFR3-TACC3 fusion in both in vitro models and clinical samples.	('bladder cancer', 'Disease', (51, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('TACC3', 'Gene', '10460', (103, 108))	('FGFR3', 'Gene', (0, 5))	('FGFR3', 'Gene', '2261', (97, 102))	('TACC3', 'Gene', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('97', '101'))	('clinical samples', 'Species', '191496', (144, 160))	('FGFR3', 'Gene', (97, 102))	('bladder cancer', 'Disease', 'MESH:D001749', (51, 65))	('fusion', 'Var', (109, 115))	('FGFR3', 'Gene', '2261', (0, 5))
53818	28824949	A Phase 2 study: Two-arm Multicenter, Open-Label Study to Determine the Efficacy and the Safety of Two Different Dose Regimens of a pan-FGFR Tyrosine Kinase Inhibitor JNJ-42756493 in Subjects with Metastatic or Surgically Unresectable Urothelial Cancer with FGFR Genomic Alterations (NCT02365597), is now underway to better characterize the activity of this agent.	('JNJ-42756493', 'Var', (167, 179))	('FGFR', 'molecular_function', 'GO:0005007', ('258', '262'))	('Urothelial Cancer', 'Disease', 'MESH:D014523', (235, 252))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (167, 179))	('Kinase Inhibitor', 'biological_process', 'GO:0033673', ('150', '166'))	('FGFR', 'molecular_function', 'GO:0005007', ('136', '140'))	('Urothelial Cancer', 'Disease', (235, 252))	('men', 'Species', '9606', (122, 125))	('Cancer', 'Phenotype', 'HP:0002664', (246, 252))
53830	28824949	Two ADCs have been licensed and are in current clinical use in oncology: T-DM1 in breast cancer and brentuximab vedotin in classical Hodgkin lymphoma and systemic anaplastic large cell lymphoma.	('Hodgkin lymphoma', 'Disease', (133, 149))	('breast cancer', 'Disease', (82, 95))	('lymphoma', 'Phenotype', 'HP:0002665', (141, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (133, 149))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (133, 149))	('oncology', 'Phenotype', 'HP:0002664', (63, 71))	('cell lymphoma', 'Phenotype', 'HP:0012191', (180, 193))	('lymphoma', 'Phenotype', 'HP:0002665', (185, 193))	('cell lymphoma', 'Disease', 'MESH:D016399', (180, 193))	('clinical', 'Species', '191496', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('T-DM1', 'Var', (73, 78))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cell lymphoma', 'Disease', (180, 193))
53852	28824949	Hence, while cell type of origin may influence the types of tumors that arise in some instances, genomic alterations and gene expression changes are likely to be the "master regulators" of tumor subtypes in UC.	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))	('tumor', 'Disease', (189, 194))	('influence', 'Reg', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('changes', 'Var', (137, 144))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Disease', (60, 66))
53854	28824949	Whether this phenomenon is linked to epigenetic changes or acquisition of particular mutations is unknown.	('men', 'Species', '9606', (18, 21))	('linked', 'Reg', (27, 33))	('epigenetic changes', 'Var', (37, 55))
53856	28824949	On the other hand, genes on the X chromosome that escape inactivation may exert a suppressive effect with respect to tumor formation or progression in females.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('suppressive effect', 'CPA', (82, 100))	('progression', 'CPA', (136, 147))	('tumor', 'Disease', (117, 122))	('X chromosome', 'cellular_component', 'GO:0000805', ('32', '44'))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('inactivation', 'Var', (57, 69))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))
53858	28824949	Histopathological analysis of CIS, MIUC, and papillary lesions often reveals a fair degree of intra-tumor heterogeneity, including domains with variant histology, which recent studies suggest may have an important impact on clinical behavior.	('clinical', 'Species', '191496', (224, 232))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('intra-tumor', 'Disease', (94, 105))	('papillary lesions', 'Phenotype', 'HP:0007482', (45, 62))	('papillary lesions', 'Disease', 'MESH:D007681', (45, 62))	('intra-tumor', 'Disease', 'MESH:D009369', (94, 105))	('papillary lesions', 'Disease', (45, 62))	('variant', 'Var', (144, 151))	('impact', 'Reg', (214, 220))
53861	28824949	These studies reveal that micropapillary domains tend to be associated with luminal like subtypes, while squamous histological variants tend to be associated with basal-like tumors.	('micropapillary', 'Var', (26, 40))	('tumors', 'Disease', (174, 180))	('associated', 'Reg', (147, 157))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('luminal like subtypes', 'Disease', (76, 97))	('associated', 'Reg', (60, 70))
53877	28824949	By conditionally deleting KDM6A from the mouse bladder urothelium,Dr.	('mouse', 'Species', '10090', (41, 46))	('KDM6A', 'Gene', (26, 31))	('deleting', 'Var', (17, 25))
53879	28824949	Moreover, human KDM6A is frequently mutated in human UC; and mutations of KDM6A predicted poor outcome of disease-free survival in female bladder cancer patients.	('bladder cancer', 'Disease', 'MESH:D001749', (138, 152))	('bladder cancer', 'Disease', (138, 152))	('poor', 'NegReg', (90, 94))	('human', 'Species', '9606', (10, 15))	('patients', 'Species', '9606', (153, 161))	('mutations', 'Var', (61, 70))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('KDM6A', 'Gene', (74, 79))	('human', 'Species', '9606', (47, 52))
53884	28824949	This work demonstrated that knockdown of endophilin A1 enhanced EGFR and c-MET signaling in RT4 cells, and was associated with an increase in survival, proliferation, and growth of tumor xenografts.	('tumor', 'Disease', (181, 186))	('RT4', 'CellLine', 'CVCL:0036', (92, 95))	('c-MET', 'Gene', (73, 78))	('proliferation', 'CPA', (152, 165))	('enhanced', 'PosReg', (55, 63))	('endophilin A1', 'Gene', '6456', (41, 54))	('EGFR', 'Gene', '1950', (64, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('c-MET', 'Gene', '4233', (73, 78))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('endophilin A1', 'Gene', (41, 54))	('growth', 'CPA', (171, 177))	('knockdown', 'Var', (28, 37))	('EGFR', 'Gene', (64, 68))	('increase', 'PosReg', (130, 138))	('survival', 'CPA', (142, 150))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
53885	28824949	Dr. Adam hypothesized that loss of endophilin A1 may predict increased sensitivity to EGFR- and c-MET-targeted tyrosine kinase inhibitors.	('endophilin A1', 'Gene', (35, 48))	('c-MET', 'Gene', (96, 101))	('loss', 'Var', (27, 31))	('EGFR', 'Gene', '1950', (86, 90))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('c-MET', 'Gene', '4233', (96, 101))	('EGFR', 'Gene', (86, 90))	('increased', 'PosReg', (61, 70))	('endophilin A1', 'Gene', '6456', (35, 48))
54010	31885571	It has been observed that the abnormal expression of miRNA can destroy the RNA network in cancer cells and promote the occurrence and development of tumors, especially urinary tumors.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('miRNA', 'Protein', (53, 58))	('occurrence', 'CPA', (119, 129))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('urinary tumors', 'Disease', (168, 182))	('RNA', 'cellular_component', 'GO:0005562', ('75', '78'))	('abnormal expression', 'Var', (30, 49))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('RNA', 'MPA', (75, 78))	('tumors', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('urinary tumors', 'Phenotype', 'HP:0010786', (168, 182))	('promote', 'PosReg', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('destroy', 'NegReg', (63, 70))	('tumors', 'Disease', (176, 182))	('cancer', 'Disease', (90, 96))	('urinary tumors', 'Disease', 'MESH:D001749', (168, 182))
54011	31885571	In addition, some studies have shown that miRNAs also regulate the epithelial-mesenchymal transition (EMT) process, which enhances the invasiveness of cancer and enriches the abundance of stem cells in tumor tissues.	('EMT', 'biological_process', 'GO:0001837', ('102', '105'))	('regulate', 'Reg', (54, 62))	('tumor', 'Disease', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('enhances', 'PosReg', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('67', '100'))	('miRNAs', 'Var', (42, 48))	('epithelial-mesenchymal transition', 'CPA', (67, 100))
54047	31885571	Increasing evidence showed that the abnormal expression of miRNA plays an important role in the metastasis and development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('metastasis', 'CPA', (96, 106))	('cancer', 'Disease', (126, 132))	('abnormal', 'Var', (36, 44))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('expression', 'MPA', (45, 55))	('miRNA', 'Protein', (59, 64))	('development of', 'CPA', (111, 125))
54063	31885571	In addition, it has been reported that miR-138 improved the sensitivity of tumor patients to gefitinib by silencing the G protein-coupled receptor (GPCR).	('improved', 'PosReg', (47, 55))	('miR-138', 'Var', (39, 46))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('miR-138', 'Chemical', '-', (39, 46))	('gefitinib', 'Chemical', 'MESH:D000077156', (93, 102))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('silencing', 'NegReg', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('G protein-coupled receptor', 'MPA', (120, 146))	('tumor', 'Disease', (75, 80))	('sensitivity', 'MPA', (60, 71))
54135	25843513	Recurrent TERT promoter mutations identified in a large-scale study of multiple tumor types are associated with increased TERT expression and telomerase activation Several somatic mutation hotspots were recently identified in the TERT promoter region in human cancers.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('TERT', 'Gene', (122, 126))	('activation', 'PosReg', (153, 163))	('human', 'Species', '9606', (254, 259))	('telomerase', 'MPA', (142, 152))	('cancers', 'Disease', 'MESH:D009369', (260, 267))	('TERT', 'Gene', (230, 234))	('TERT', 'Gene', (10, 14))	('TERT', 'Gene', '7015', (122, 126))	('cancers', 'Disease', (260, 267))	('tumor', 'Disease', (80, 85))	('TERT', 'Gene', '7015', (230, 234))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('increased', 'PosReg', (112, 121))	('TERT', 'Gene', '7015', (10, 14))	('mutations', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))
54136	25843513	Large scale studies of these mutations in multiple tumor types are limited, in particular in Asian populations.	('multiple tumor', 'Disease', (42, 56))	('multiple tumor', 'Disease', 'MESH:D009369', (42, 56))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))
54137	25843513	This study aimed to: analyze TERT promoter mutations in multiple tumor types in a large Chinese patient cohort, investigate novel tumor types and assess the functional significance of the mutations.	('multiple tumor', 'Disease', 'MESH:D009369', (56, 70))	('TERT', 'Gene', '7015', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('patient', 'Species', '9606', (96, 103))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (130, 135))	('TERT', 'Gene', (29, 33))	('multiple tumor', 'Disease', (56, 70))
54141	25843513	TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%), and hepatocellular carcinoma (31.4%).	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('oligodendroglioma', 'Disease', (100, 117))	('medulloblastoma', 'Disease', 'MESH:D008527', (127, 142))	('medulloblastoma', 'Phenotype', 'HP:0002885', (127, 142))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (156, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('medulloblastoma', 'Disease', (127, 142))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (156, 180))	('mutations', 'Var', (14, 23))	('urothelial carcinoma', 'Disease', (70, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('hepatocellular carcinoma', 'Disease', (156, 180))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))	('frequent', 'Reg', (36, 44))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('TERT', 'Gene', (0, 4))	('oligodendroglioma', 'Disease', 'MESH:D009837', (100, 117))	('TERT', 'Gene', '7015', (0, 4))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (70, 90))	('glioblastoma', 'Disease', (48, 60))
54142	25843513	C228T and C250T were the most common mutations.	('C228T', 'Var', (0, 5))	('C250T', 'Mutation', 'rs942160050', (10, 15))	('C228T', 'Mutation', 'rs779838241', (0, 5))	('C250T', 'Var', (10, 15))
54145	25843513	TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas.	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('adult gliomas', 'Disease', (107, 120))	('telomerase', 'Enzyme', (84, 94))	('upregulated', 'PosReg', (47, 58))	('TERT', 'Gene', (59, 63))	('TERT', 'Gene', (0, 4))	('telomerase activity', 'molecular_function', 'GO:0003720', ('84', '103'))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', '7015', (59, 63))	('activity', 'MPA', (95, 103))	('adult gliomas', 'Disease', 'MESH:D005910', (107, 120))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('mutations', 'Var', (14, 23))
54146	25843513	These mutations differentially enhanced the transcriptional activity of the TERT core promoter.	('TERT', 'Gene', '7015', (76, 80))	('enhanced', 'PosReg', (31, 39))	('core', 'cellular_component', 'GO:0019013', ('81', '85'))	('TERT', 'Gene', (76, 80))	('transcriptional activity', 'MPA', (44, 68))	('mutations', 'Var', (6, 15))
54147	25843513	TERT promoter mutations are frequent in multiple tumor types and have similar distributions in Chinese cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('multiple tumor', 'Disease', (40, 54))	('multiple tumor', 'Disease', 'MESH:D009369', (40, 54))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('mutations', 'Var', (14, 23))	('patients', 'Species', '9606', (110, 118))
54148	25843513	The functional significance of these mutations reflect the importance to telomere maintenance and hence tumorigenesis, making them potential therapeutic targets.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('telomere maintenance', 'biological_process', 'GO:0000723', ('73', '93'))	('telomere', 'cellular_component', 'GO:0000781', ('73', '81'))	('mutations', 'Var', (37, 46))	('telomere', 'cellular_component', 'GO:0005696', ('73', '81'))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
54151	25843513	Recently, two somatic mutations in the promoter region of TERT were reported in melanomas,.	('melanomas', 'Phenotype', 'HP:0002861', (80, 89))	('melanomas', 'Disease', 'MESH:D008545', (80, 89))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('TERT', 'Gene', (58, 62))	('mutations', 'Var', (22, 31))	('TERT', 'Gene', '7015', (58, 62))	('melanomas', 'Disease', (80, 89))	('reported', 'Reg', (68, 76))
54152	25843513	The two most common mutations occurred at -124 and -146 base pairs upstream of the TERT ATG start site (hereafter referred to as C228T and C250T, respectively).	('C228T', 'Mutation', 'rs779838241', (129, 134))	('TERT', 'Gene', (83, 87))	('C228T', 'Var', (129, 134))	('TERT', 'Gene', '7015', (83, 87))	('C250T', 'Mutation', 'rs942160050', (139, 144))	('C250T', 'Var', (139, 144))
54153	25843513	These mutations occurred in nearly 70% of melanoma tumors and cell lines.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('melanoma tumors', 'Disease', 'MESH:D008545', (42, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('occurred', 'Reg', (16, 24))	('melanoma tumors', 'Disease', (42, 57))	('mutations', 'Var', (6, 15))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
54154	25843513	Although the exact mechanism is unclear, each mutation independently generates a novel E-twenty-six (ETS) transcription factor binding site (GGAA/T) and has been shown to increase the transcriptional activity of the TERT promoter,.	('TERT', 'Gene', (216, 220))	('mutation', 'Var', (46, 54))	('TERT', 'Gene', '7015', (216, 220))	('transcriptional activity', 'MPA', (184, 208))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('increase', 'PosReg', (171, 179))	('ETS', 'Chemical', '-', (101, 104))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('106', '134'))
54155	25843513	Interestingly, TERT promoter mutations are not restricted to melanoma and occur frequently in several tumor types, including gliomas,, liposarcomas, urothelial carcinomas,,,,, and hepatocellular carcinomas,.	('TERT', 'Gene', '7015', (15, 19))	('gliomas', 'Disease', (125, 132))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (180, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('liposarcomas', 'Disease', (135, 147))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('mutations', 'Var', (29, 38))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (180, 205))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('carcinomas', 'Phenotype', 'HP:0030731', (195, 205))	('urothelial carcinomas', 'Disease', (149, 170))	('tumor', 'Disease', (102, 107))	('liposarcomas', 'Disease', 'MESH:D008080', (135, 147))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (149, 170))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (180, 205))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('hepatocellular carcinomas', 'Disease', (180, 205))	('occur', 'Reg', (74, 79))	('liposarcomas', 'Phenotype', 'HP:0012034', (135, 147))	('TERT', 'Gene', (15, 19))
54174	25843513	The constructs with different TERT promoter mutations were generated by using the QuikChange site-directed mutagenesis kit (Stratagene, USA).	('TERT', 'Gene', '7015', (30, 34))	('mutations', 'Var', (44, 53))	('mutagenesis', 'biological_process', 'GO:0006280', ('107', '118'))	('TERT', 'Gene', (30, 34))
54177	25843513	For the luciferase reporter assay, U87-MG cells were seeded in 24-well tissue culture plates and then transfected with wild-type or mutant TERT promoter reporter (Life Technologies, USA).	('U87-MG', 'CellLine', 'CVCL:0022', (35, 41))	('mutant', 'Var', (132, 138))	('TERT', 'Gene', '7015', (139, 143))	('TERT', 'Gene', (139, 143))
54178	25843513	We evaluated TERT promoter mutations successfully in 799 tumor specimens and identified 268 samples (33.5%) with TERT promoter mutations.	('TERT', 'Gene', (13, 17))	('TERT', 'Gene', '7015', (13, 17))	('TERT', 'Gene', '7015', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mutations', 'Var', (127, 136))	('tumor', 'Disease', (57, 62))	('TERT', 'Gene', (113, 117))
54179	25843513	Overall, the hotspot mutations C228T (64.6%) and C250T (23.9%) were the most common and were mutually exclusive.	('C228T', 'Mutation', 'rs779838241', (31, 36))	('C250T', 'Var', (49, 54))	('C228T', 'Var', (31, 36))	('C250T', 'Mutation', 'rs942160050', (49, 54))
54180	25843513	These TERT promoter mutations occurred in many tumor types, including glioblastoma, medulloblastoma, urothelial carcinoma, hepatocellular carcinoma, and gallbladder carcinoma.	('TERT', 'Gene', (6, 10))	('TERT', 'Gene', '7015', (6, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (123, 147))	('glioblastoma', 'Disease', (70, 82))	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('occurred', 'Reg', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (123, 147))	('medulloblastoma', 'Disease', 'MESH:D008527', (84, 99))	('urothelial carcinoma', 'Disease', (101, 121))	('medulloblastoma', 'Phenotype', 'HP:0002885', (84, 99))	('medulloblastoma', 'Disease', (84, 99))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (153, 174))	('hepatocellular carcinoma', 'Disease', (123, 147))	('tumor', 'Disease', (47, 52))	('mutations', 'Var', (20, 29))	('gallbladder carcinoma', 'Disease', (153, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (101, 121))
54185	25843513	All TERT promoter mutations were C228T or C250T, except for 1 case of C242T+C243T.	('C243T', 'Mutation', 'c.243C>T', (76, 81))	('C242T', 'Mutation', 'c.242C>T', (70, 75))	('C228T', 'Mutation', 'rs779838241', (33, 38))	('C250T', 'Mutation', 'rs942160050', (42, 47))	('TERT', 'Gene', (4, 8))	('C250T', 'Var', (42, 47))	('C228T', 'Var', (33, 38))	('TERT', 'Gene', '7015', (4, 8))	('C242T+C243T', 'Var', (70, 81))
54186	25843513	TERT promoter mutations were highly prevalent in adult GBM (83.9%, 47/56), oligodendroglioma (70%, 7/10), diffuse astrocytoma (20%, 8/40), anaplastic astrocytoma (33.3%, 4/12) and medulloblastoma (33.3%, 2/6).	('adult GBM', 'Disease', (49, 58))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('astrocytoma', 'Phenotype', 'HP:0009592', (114, 125))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (139, 161))	('oligodendroglioma', 'Disease', (75, 92))	('medulloblastoma', 'Disease', 'MESH:D008527', (180, 195))	('medulloblastoma', 'Phenotype', 'HP:0002885', (180, 195))	('mutations', 'Var', (14, 23))	('astrocytoma', 'Phenotype', 'HP:0009592', (150, 161))	('medulloblastoma', 'Disease', (180, 195))	('astrocytoma', 'Disease', 'MESH:D001254', (114, 125))	('astrocytoma', 'Disease', (114, 125))	('anaplastic astrocytoma', 'Disease', (139, 161))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('prevalent', 'Reg', (36, 45))	('astrocytoma', 'Disease', 'MESH:D001254', (150, 161))	('oligodendroglioma', 'Disease', 'MESH:D009837', (75, 92))	('astrocytoma', 'Disease', (150, 161))
54187	25843513	In gliomas of grades II-IV and II-III, TERT promoter mutations were associated with an older age at diagnosis (p <0.0005 and p <0.05, respectively, Table S3).	('TERT', 'Gene', (39, 43))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('TERT', 'Gene', '7015', (39, 43))	('mutations', 'Var', (53, 62))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('gliomas', 'Disease', (3, 10))
54193	25843513	The majority of these mutations were C228T (39.7%, 116/292) and C250T (14.4%, 42/292).	('C228T', 'Mutation', 'rs779838241', (37, 42))	('C250T', 'Mutation', 'rs942160050', (64, 69))	('C228T', 'Var', (37, 42))	('C250T', 'Var', (64, 69))
54194	25843513	We also identified 10 additional mutations: A161C (n=12), C242T+C243T (n=6), C158A (n=3), C228A (n=2), G149T (n=2), C250T+C242T+C243T (n=1) and G245A (n=1), T198G (n=1), C193T (n=1), C190T+C184T (n=1) (Figure S1, Tables 1, S2, and S4-B).	('C242T', 'Mutation', 'c.242C>T', (58, 63))	('C193T', 'Var', (170, 175))	('C158A', 'Var', (77, 82))	('A161C', 'Var', (44, 49))	('C242T+C243T', 'Var', (58, 69))	('G245A', 'Mutation', 'c.245G>A', (144, 149))	('G149T', 'Var', (103, 108))	('C250T', 'Mutation', 'rs942160050', (116, 121))	('C250T+C242T+C243T', 'Var', (116, 133))	('C228A', 'Mutation', 'rs1338921187', (90, 95))	('C190T+C184T', 'CellLine', 'CVCL:S258', (183, 194))	('C190T+C184T', 'Var', (183, 194))	('C243T', 'Mutation', 'c.243C>T', (128, 133))	('A161C', 'Mutation', 'c.161A>C', (44, 49))	('C243T', 'Mutation', 'c.243C>T', (64, 69))	('C193T', 'Mutation', 'c.193C>T', (170, 175))	('C158A', 'Mutation', 'c.158C>A', (77, 82))	('T198G', 'Var', (157, 162))	('G149T', 'Mutation', 'c.149G>T', (103, 108))	('G245A', 'Var', (144, 149))	('T198G', 'Mutation', 'c.198T>G', (157, 162))	('C228A', 'Var', (90, 95))	('C242T', 'Mutation', 'c.242C>T', (122, 127))
54197	25843513	In hepatocellular carcinoma samples, 31.4% (11/35) samples had TERT promoter mutations, among them 25.7% (9/35) were C228T and 5.7% were C250T (Tables 1, S2, and S4-C).	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('C228T', 'Var', (117, 122))	('C250T', 'Mutation', 'rs942160050', (137, 142))	('C250T', 'Var', (137, 142))	('TERT', 'Gene', (63, 67))	('TERT', 'Gene', '7015', (63, 67))	('C228T', 'Mutation', 'rs779838241', (117, 122))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
54200	25843513	We also identified one C228T mutation in a gallbladder carcinoma (GBC) sample (Tables 1, S2, S4-C).	('C228T', 'Mutation', 'rs779838241', (23, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('gallbladder carcinoma', 'Disease', (43, 64))	('C228T', 'Var', (23, 28))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (43, 64))
54211	25843513	To assess whether TERT promoter mutations affect TERT mRNA expression, we assessed TERT mRNA expression in 43 primary glioma tumor tissues, including 18 GBMs, 17 oligodendrogliomas, and 8 astrocytomas (Table S4-H).	('glioma tumor', 'Disease', 'MESH:D005910', (118, 130))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('glioma tumor', 'Disease', (118, 130))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('astrocytomas', 'Disease', (188, 200))	('mutations', 'Var', (32, 41))	('TERT', 'Gene', (83, 87))	('TERT', 'Gene', '7015', (83, 87))	('affect', 'Reg', (42, 48))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (162, 180))	('TERT', 'Gene', (18, 22))	('TERT', 'Gene', (49, 53))	('TERT', 'Gene', '7015', (49, 53))	('TERT', 'Gene', '7015', (18, 22))	('astrocytomas', 'Disease', 'MESH:D001254', (188, 200))	('astrocytoma', 'Phenotype', 'HP:0009592', (188, 199))	('oligodendrogliomas', 'Disease', (162, 180))
54212	25843513	As shown in Figure 2a, TERT mRNA expression levels in both C228T and C250T promoter mutant samples were significantly higher (P<0.001) than in TERT promoter wild-type samples, suggesting that TERT promoter mutations activate TERT expression.	('C228T', 'Var', (59, 64))	('higher', 'PosReg', (118, 124))	('mutations', 'Var', (206, 215))	('TERT', 'Gene', '7015', (225, 229))	('TERT', 'Gene', (143, 147))	('TERT', 'Gene', (23, 27))	('TERT', 'Gene', '7015', (23, 27))	('activate', 'PosReg', (216, 224))	('TERT', 'Gene', (192, 196))	('TERT', 'Gene', '7015', (192, 196))	('C250T', 'Mutation', 'rs942160050', (69, 74))	('C250T', 'Var', (69, 74))	('TERT', 'Gene', '7015', (143, 147))	('C228T', 'Mutation', 'rs779838241', (59, 64))	('TERT', 'Gene', (225, 229))
54213	25843513	We also investigated whether TERT promoter mutations regulate telomerase activity.	('TERT', 'Gene', '7015', (29, 33))	('regulate', 'Reg', (53, 61))	('activity', 'MPA', (73, 81))	('telomerase activity', 'molecular_function', 'GO:0003720', ('62', '81'))	('mutations', 'Var', (43, 52))	('telomerase', 'Enzyme', (62, 72))	('TERT', 'Gene', (29, 33))
54215	25843513	As shown in Figure 2c, TERT promoter mutant xenografts (both C228T and C250T) exhibited high telomerase activity as indicated by the 6 bp incremental ladder of TRAP products on gel electrophoresis.	('TERT', 'Gene', (23, 27))	('TERT', 'Gene', '7015', (23, 27))	('activity', 'MPA', (104, 112))	('telomerase', 'Enzyme', (93, 103))	('TRAP', 'Gene', '100187907', (160, 164))	('C228T', 'Mutation', 'rs779838241', (61, 66))	('TRAP', 'Gene', (160, 164))	('C228T', 'Var', (61, 66))	('C250T', 'Mutation', 'rs942160050', (71, 76))	('telomerase activity', 'molecular_function', 'GO:0003720', ('93', '112'))	('C250T', 'Var', (71, 76))
54220	25843513	However, in agreement with the phenomena observed in xenografts, the typical TRAP products were only detected in the TERT promoter mutant samples but not in the TERT wide-type samples (Figure 2d).	('TERT', 'Gene', (161, 165))	('mutant', 'Var', (131, 137))	('TERT', 'Gene', '7015', (161, 165))	('TRAP', 'Gene', '100187907', (77, 81))	('TERT', 'Gene', (117, 121))	('TERT', 'Gene', '7015', (117, 121))	('TRAP', 'Gene', (77, 81))
54221	25843513	In addition to the two most common TERT promoter mutations, C228T and C250T, several other TERT promoter mutations were also identified in this study.	('TERT', 'Gene', (91, 95))	('C250T', 'Mutation', 'rs942160050', (70, 75))	('C250T', 'Var', (70, 75))	('TERT', 'Gene', '7015', (91, 95))	('C228T', 'Mutation', 'rs779838241', (60, 65))	('C228T', 'Var', (60, 65))	('TERT', 'Gene', (35, 39))	('TERT', 'Gene', '7015', (35, 39))
54223	25843513	We aimed to assess whether these common TERT promoter mutations play a similar role in increasing TERT promoter activity.	('TERT', 'Gene', '7015', (40, 44))	('TERT', 'Gene', (98, 102))	('mutations', 'Var', (54, 63))	('TERT', 'Gene', '7015', (98, 102))	('increasing', 'PosReg', (87, 97))	('TERT', 'Gene', (40, 44))
54225	25843513	We assayed the four most frequently mutated TERT core promoters identified in our study: C228T, C250T, A161C, and C242T+C243T.	('TERT', 'Gene', (44, 48))	('C242T+C243T', 'Var', (114, 125))	('TERT', 'Gene', '7015', (44, 48))	('core', 'cellular_component', 'GO:0019013', ('49', '53'))	('C242T', 'Mutation', 'c.242C>T', (114, 119))	('A161C', 'Mutation', 'c.161A>C', (103, 108))	('C250T', 'Mutation', 'rs942160050', (96, 101))	('C250T', 'Var', (96, 101))	('C228T', 'Mutation', 'rs779838241', (89, 94))	('C243T', 'Mutation', 'c.243C>T', (120, 125))	('C228T', 'Var', (89, 94))	('A161C', 'Var', (103, 108))
54226	25843513	The transcriptional activities of all the mutated TERT core promoter constructs are significantly higher (from 2.8- to 5.3-fold) than the wild-type TERT core promoter.	('mutated', 'Var', (42, 49))	('TERT', 'Gene', '7015', (50, 54))	('transcriptional activities', 'MPA', (4, 30))	('higher', 'PosReg', (98, 104))	('TERT', 'Gene', (148, 152))	('core', 'cellular_component', 'GO:0019013', ('153', '157'))	('TERT', 'Gene', '7015', (148, 152))	('TERT', 'Gene', (50, 54))	('core', 'cellular_component', 'GO:0019013', ('55', '59'))
54227	25843513	Among the single mutants, the A161C mutant has the strongest activity, whereas the C242T+C243T tandem mutated construct shows relatively weak up-regulation (2.8-fold, Figure 2b).	('C242T+C243T', 'Var', (83, 94))	('C242T', 'Mutation', 'c.242C>T', (83, 88))	('A161C', 'Mutation', 'c.161A>C', (30, 35))	('A161C', 'Var', (30, 35))	('C243T', 'Mutation', 'c.243C>T', (89, 94))	('regulation', 'biological_process', 'GO:0065007', ('145', '155'))	('activity', 'MPA', (61, 69))
54228	25843513	Since the first discovery of the TERT promoter mutations in melanoma,, many studies have been performed to establish their role as a novel genetic mechanism in human tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('mutations', 'Var', (47, 56))	('tumor', 'Disease', (166, 171))	('melanoma', 'Disease', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('human', 'Species', '9606', (160, 165))
54229	25843513	Subsequent research has revealed high frequencies of TERT promoter mutations in glioblastoma,, bladder cancer, hepatocellular carcinoma, and other human cancers.	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('cancers', 'Disease', (153, 160))	('human', 'Species', '9606', (147, 152))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (111, 135))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('hepatocellular carcinoma', 'Disease', (111, 135))	('bladder cancer', 'Disease', 'MESH:D001749', (95, 109))	('bladder cancer', 'Disease', (95, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (111, 135))	('mutations', 'Var', (67, 76))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('glioblastoma', 'Disease', (80, 92))
54231	25843513	Here, we report for the first time TERT promoter mutations in various types of cancer in a large cohort of 799 Chinese patients.	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (79, 85))	('patients', 'Species', '9606', (119, 127))	('TERT', 'Gene', (35, 39))	('TERT', 'Gene', '7015', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
54232	25843513	We show that mutations in the promoter region of TERT occur frequently in glioblastoma (83.9%), oligodendroglioma (70%), urinary tract cancer (64.4%), hepatocellular carcinoma (31.4%), and medulloblastoma (33.3%).	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (151, 175))	('urinary tract cancer', 'Disease', 'MESH:D014571', (121, 141))	('hepatocellular carcinoma', 'Disease', (151, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('glioblastoma', 'Disease', 'MESH:D005909', (74, 86))	('medulloblastoma', 'Disease', 'MESH:D008527', (189, 204))	('oligodendroglioma', 'Disease', 'MESH:D009837', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('medulloblastoma', 'Phenotype', 'HP:0002885', (189, 204))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('medulloblastoma', 'Disease', (189, 204))	('glioblastoma', 'Disease', (74, 86))	('oligodendroglioma', 'Disease', (96, 113))	('urinary tract cancer', 'Disease', (121, 141))	('glioblastoma', 'Phenotype', 'HP:0012174', (74, 86))	('TERT', 'Gene', (49, 53))	('TERT', 'Gene', '7015', (49, 53))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (121, 141))	('mutations', 'Var', (13, 22))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (151, 175))
54234	25843513	Slightly higher frequencies of TERT promoter mutations have been reported in HCC (44.2%, 50.9%) and urothelial carcinoma (83%, 74%), although other reports reflect the opposite trend in urothelial carcinoma of the bladder (66%, 65.4%) and upper urinary tract (47.3%).	('mutations', 'Var', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('HCC', 'Gene', '619501', (77, 80))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (100, 120))	('HCC', 'Phenotype', 'HP:0001402', (77, 80))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (186, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('urothelial carcinoma of the bladder', 'Disease', (186, 221))	('TERT', 'Gene', (31, 35))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (186, 206))	('TERT', 'Gene', '7015', (31, 35))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (186, 221))	('urothelial carcinoma', 'Disease', (100, 120))	('HCC', 'Gene', (77, 80))
54235	25843513	Previously, it has been speculated that cancers bearing frequent TERT promoter mutations largely originate in tissues that are not constantly self-renewing under normal conditions.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancers', 'Disease', (40, 47))	('TERT', 'Gene', (65, 69))	('originate', 'Reg', (97, 106))	('TERT', 'Gene', '7015', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('mutations', 'Var', (79, 88))
54238	25843513	In addition to previously reported C228T, C250T, A161C, C158A, G149T, C242T+C243T, and G245A mutations, we identified five novel mutations: T198G, C193T, C190T+C184T, and C250T+C242T+C243T.	('C243T', 'Mutation', 'c.243C>T', (76, 81))	('T198G', 'Var', (140, 145))	('T198G', 'Mutation', 'c.198T>G', (140, 145))	('C190T+C184T', 'Var', (154, 165))	('C242T', 'Mutation', 'c.242C>T', (177, 182))	('C193T', 'Var', (147, 152))	('C250T', 'Mutation', 'rs942160050', (171, 176))	('G245A', 'Mutation', 'c.245G>A', (87, 92))	('C158A', 'Mutation', 'c.158C>A', (56, 61))	('C242T', 'Mutation', 'c.242C>T', (70, 75))	('C250T', 'Mutation', 'rs942160050', (42, 47))	('C228T', 'Var', (35, 40))	('C243T', 'Mutation', 'c.243C>T', (183, 188))	('G149T', 'Mutation', 'c.149G>T', (63, 68))	('C193T', 'Mutation', 'c.193C>T', (147, 152))	('A161C', 'Mutation', 'c.161A>C', (49, 54))	('C250T+C242T+C243T', 'Var', (171, 188))	('C228T', 'Mutation', 'rs779838241', (35, 40))	('C190T+C184T', 'CellLine', 'CVCL:S258', (154, 165))
54239	25843513	However, it is still interesting to note aside from C228T, C250T, and C242T+C243T, the other 8 mutations we identified were only found in bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (138, 152))	('bladder cancer', 'Disease', (138, 152))	('C243T', 'Mutation', 'c.243C>T', (76, 81))	('C228T', 'Var', (52, 57))	('C242T', 'Mutation', 'c.242C>T', (70, 75))	('C250T', 'Mutation', 'rs942160050', (59, 64))	('C250T', 'Var', (59, 64))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('C242T+C243T', 'Var', (70, 81))	('C228T', 'Mutation', 'rs779838241', (52, 57))
54241	25843513	Further study is warranted to investigate the etiology of this mutation bias in bladder cancer, which may be due to carcinogen exposure.	('bladder cancer', 'Disease', 'MESH:D001749', (80, 94))	('bladder cancer', 'Disease', (80, 94))	('mutation', 'Var', (63, 71))	('bladder cancer', 'Phenotype', 'HP:0009725', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
54248	25843513	In this study, we evaluated the functional consequences of TERT promoter mutations in gliomas.	('TERT', 'Gene', (59, 63))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('mutations', 'Var', (73, 82))	('TERT', 'Gene', '7015', (59, 63))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('gliomas', 'Disease', (86, 93))
54250	25843513	We found that TERT promoter mutations are highly correlated with telomerase activation using the TRAP assay in both xenografts and primary tumor tissues.	('telomerase', 'Enzyme', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('TRAP', 'Gene', '100187907', (97, 101))	('TRAP', 'Gene', (97, 101))	('TERT', 'Gene', (14, 18))	('tumor', 'Disease', (139, 144))	('TERT', 'Gene', '7015', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('activation', 'PosReg', (76, 86))	('mutations', 'Var', (28, 37))
54252	25843513	Among the mutations identified (Table S1), C228T, C250T, C242T+C243T, C250T+C242T+C243T, A161C, C158A and G149T generate a CCGGAA/T or GGAA/T motif, which is a possible transcription factor binding site for Ets transcription factors (Figure 1).	('C250T', 'Mutation', 'rs942160050', (70, 75))	('C243T', 'Mutation', 'c.243C>T', (82, 87))	('C242T', 'Mutation', 'c.242C>T', (57, 62))	('C242T+C243T', 'Var', (57, 68))	('C158A', 'Mutation', 'c.158C>A', (96, 101))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('169', '197'))	('C228T', 'Var', (43, 48))	('C243T', 'Mutation', 'c.243C>T', (63, 68))	('A161C', 'Var', (89, 94))	('G149T', 'Mutation', 'c.149G>T', (106, 111))	('transcription', 'biological_process', 'GO:0006351', ('169', '182'))	('C250T', 'Mutation', 'rs942160050', (50, 55))	('C158A', 'Var', (96, 101))	('C250T', 'Var', (50, 55))	('C250T+C242T+C243T', 'Var', (70, 87))	('A161C', 'Mutation', 'c.161A>C', (89, 94))	('C228T', 'Mutation', 'rs779838241', (43, 48))	('C242T', 'Mutation', 'c.242C>T', (76, 81))	('transcription', 'biological_process', 'GO:0006351', ('211', '224'))	('G149T', 'Var', (106, 111))
54253	25843513	We compared the transcriptional activity of the high frequency (n>=6) mutations using a luciferase reporter assay and found that they could all increase TERT promoter activity.	('TERT', 'Gene', '7015', (153, 157))	('TERT', 'Gene', (153, 157))	('mutations', 'Var', (70, 79))	('increase', 'PosReg', (144, 152))
54254	25843513	Our findings show similar distribution of TERT promoter mutations in tumor types from a Chinese population.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mutations', 'Var', (56, 65))	('tumor', 'Disease', (69, 74))	('TERT', 'Gene', (42, 46))	('TERT', 'Gene', '7015', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
54255	25843513	Alongside our functional assays, this work reflects the importance of these mutations to telomere maintenance and human tumorigenesis.	('mutations', 'Var', (76, 85))	('telomere', 'cellular_component', 'GO:0005696', ('89', '97'))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('telomere maintenance', 'biological_process', 'GO:0000723', ('89', '109'))	('human', 'Species', '9606', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('telomere', 'cellular_component', 'GO:0000781', ('89', '97'))	('tumor', 'Disease', (120, 125))
54256	25843513	Development of sensitive assays for detection of these mutations may aid in earlier diagnosis of several tumor types.	('aid', 'Reg', (69, 72))	('mutations', 'Var', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
54257	25843513	TERT telomerase reverse transcriptase TRAP telomeric repeat amplification protocol GIST gastrointestinal stromal tumor ETS E-twenty-six FFPE formalin-fixed, paraffin-embedded DNA deoxyribonucleic acid mRNA messenger ribonucleic acid RT-qPCR reverse-transcriptase quantitative polymerase chain reaction PCR polymerase chain reaction BGI Beijing Genomics Institute GBC gallbladder carcinoma HCC hepatocellular carcinoma GBM glioblastoma multiforme ALT alternative lengthening of telomeres MEM minimum essential media C228T mutation at chr5: 1,295,228 C>T.	('transcriptase', 'molecular_function', 'GO:0003968', ('249', '262'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (393, 417))	('C228T', 'Var', (515, 520))	('transcriptase', 'molecular_function', 'GO:0034062', ('249', '262'))	('HCC', 'Gene', (389, 392))	('minimum essential media', 'Chemical', '-', (491, 514))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (88, 118))	('ALT', 'molecular_function', 'GO:0004021', ('446', '449'))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (393, 417))	('transcriptase', 'molecular_function', 'GO:0003968', ('24', '37'))	('228 C>T', 'Mutation', 'rs779838241', (545, 552))	('transcriptase', 'molecular_function', 'GO:0034062', ('24', '37'))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (88, 118))	('TRAP', 'Gene', '100187907', (38, 42))	('DNA', 'cellular_component', 'GO:0005574', ('175', '178'))	('transcriptase', 'molecular_function', 'GO:0003899', ('249', '262'))	('C228T', 'Mutation', 'rs779838241', (515, 520))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (367, 388))	('carcinoma', 'Phenotype', 'HP:0030731', (379, 388))	('gallbladder carcinoma', 'Disease', (367, 388))	('gastrointestinal stromal tumor', 'Disease', (88, 118))	('hepatocellular carcinoma', 'Disease', (393, 417))	('glioblastoma', 'Phenotype', 'HP:0012174', (422, 434))	('HCC', 'Phenotype', 'HP:0001402', (389, 392))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('formalin', 'Chemical', 'MESH:D005557', (141, 149))	('ETS', 'Chemical', '-', (119, 122))	('transcriptase', 'molecular_function', 'GO:0003899', ('24', '37'))	('glioblastoma multiforme', 'Disease', (422, 445))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('ALT', 'Chemical', '-', (446, 449))	('carcinoma', 'Phenotype', 'HP:0030731', (408, 417))	('HCC', 'Gene', '619501', (389, 392))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (422, 445))	('TRAP', 'Gene', (38, 42))	('paraffin', 'Chemical', 'MESH:D010232', (157, 165))
54291	20181175	Interestingly, Khono and associates recently reported the first pathological complete response found at radical cystectomy for cT4N0M0 plasmacytoid urothelial carcinoma treated with neoadjuvant chemotherapy (methotrexate, vinblastine, etoposide, and cisplatin).	('urothelial carcinoma', 'Disease', (148, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('etoposide', 'Chemical', 'MESH:D005047', (235, 244))	('cT4N0M0', 'Var', (127, 134))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (148, 168))	('methotrexate', 'Chemical', 'MESH:D008727', (208, 220))	('vinblastine', 'Chemical', 'MESH:D014747', (222, 233))	('cisplatin', 'Chemical', 'MESH:D002945', (250, 259))
54302	33489471	Results showed that high sTIL indicated improved survival (CSS, p = .022; RFS, p = .015; DFS, p = .004), and was an independent predictor of better CSS (HR, 0.577; 95% CI, 0.391-0.851; p = .006), RFS (HR, 0.613; 95% CI 0.406-0.925; p = .020) and DFS (HR, 0.609; 95% CI, 0.447-0.829; p = .002).	('sTIL', 'Gene', '6491', (25, 29))	('RFS', 'Disease', (74, 77))	('RFS', 'Disease', 'MESH:D005198', (74, 77))	('RFS', 'Disease', (196, 199))	('better', 'PosReg', (141, 147))	('survival', 'CPA', (49, 57))	('CSS', 'CPA', (148, 151))	('DFS', 'CPA', (246, 249))	('sTIL', 'Gene', (25, 29))	('high', 'Var', (20, 24))	('RFS', 'Disease', 'MESH:D005198', (196, 199))	('improved', 'PosReg', (40, 48))
54304	33489471	We also found that aristolochic acid (AA) exposure was associated with increased sTIL and elevated PD-L1 expression, indicating that AA-related UTUC might be a distinct subgroup with unique tumor microenvironment characteristics.	('sTIL', 'Gene', '6491', (81, 85))	('aristolochic acid', 'Var', (19, 36))	('elevated', 'PosReg', (90, 98))	('unique tumor', 'Disease', 'MESH:C566733', (183, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('PD-L1', 'Gene', (99, 104))	('unique tumor', 'Disease', (183, 195))	('sTIL', 'Gene', (81, 85))	('increased', 'PosReg', (71, 80))	('aristolochic acid', 'Chemical', 'MESH:C000228', (19, 36))	('expression', 'MPA', (105, 115))
54309	33489471	The 5-year cancer-specific survival rate of patients has reached 73% after RNU in overall populations, whereas those of patients with advanced-stage and/or lymph node metastasis have markedly decreased (pT3, 54%; pT4, 12%; nodal involvement, 35%).	('RNU', 'Var', (75, 78))	('decreased', 'NegReg', (192, 201))	('patients', 'Species', '9606', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('RNU', 'Chemical', '-', (75, 78))	('pT3', 'Gene', '7694', (203, 206))	('pT3', 'Gene', (203, 206))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('patients', 'Species', '9606', (120, 128))	('cancer', 'Disease', (11, 17))
54375	33489471	The present study indicated that sTIL was an independent prognostic factor and high sTIL predicted improved outcomes in locally advanced UTUC.	('sTIL', 'Gene', (33, 37))	('improved', 'PosReg', (99, 107))	('sTIL', 'Gene', (84, 88))	('locally advanced UTUC', 'Disease', (120, 141))	('outcomes', 'MPA', (108, 116))	('high', 'Var', (79, 83))	('sTIL', 'Gene', '6491', (33, 37))	('sTIL', 'Gene', '6491', (84, 88))
54389	33489471	We found that high sTIL is independently correlated with improved survival and there are strong correlations between sTIL and the PD-L1/PD-1/CD8 axis, suggesting that it can be an easily acquired biomarker for prognostic stratification and might have potential role in immunotherapy response prediction.	('sTIL', 'Gene', (19, 23))	('sTIL', 'Gene', '6491', (117, 121))	('high', 'Var', (14, 18))	('CD8', 'Gene', (141, 144))	('survival', 'CPA', (66, 74))	('improved', 'PosReg', (57, 65))	('correlations', 'Interaction', (96, 108))	('CD8', 'Gene', '925', (141, 144))	('sTIL', 'Gene', '6491', (19, 23))	('sTIL', 'Gene', (117, 121))
54396	32493368	This tumor showed positivity for AFP, GLP3 and SALL4, and negativity for CK7 and EMA.	('GLP3', 'Gene', (38, 42))	('SALL4', 'Gene', '57167', (47, 52))	('AFP', 'Gene', (33, 36))	('SALL4', 'Gene', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('CK7', 'Gene', '3855', (73, 76))	('AFP', 'Gene', '174', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('positivity', 'Var', (18, 28))	('tumor', 'Disease', (5, 10))	('EMA', 'Gene', (81, 84))	('CK7', 'Gene', (73, 76))	('EMA', 'Gene', '2108', (81, 84))
54436	32493368	A majority of these neoplasms shows positivity for AFP, SALL4, and negativity for differentiated epithelial markers, such as CK7 and EMA.	('neoplasms', 'Disease', 'MESH:D009369', (20, 29))	('CK7', 'Gene', (125, 128))	('neoplasms', 'Disease', (20, 29))	('EMA', 'Gene', '2108', (133, 136))	('neoplasm', 'Phenotype', 'HP:0002664', (20, 28))	('AFP', 'Gene', '174', (51, 54))	('CK7', 'Gene', '3855', (125, 128))	('neoplasms', 'Phenotype', 'HP:0002664', (20, 29))	('SALL4', 'Gene', '57167', (56, 61))	('AFP', 'Gene', (51, 54))	('EMA', 'Gene', (133, 136))	('positivity', 'Var', (36, 46))	('SALL4', 'Gene', (56, 61))
54441	32493368	The polysomic pattern of 12p abnormality has been described previously in germ cell tumors of the central nervous system, although it is of unknown significance.	('polysomic pattern', 'Var', (4, 21))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('described', 'Reg', (50, 59))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (84, 120))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
54442	32493368	Chromosome 12 abnormalities, either as an i12p or as 12p overrepresentation, are the hallmark cytogenetic alteration of germ cell tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('12p', 'CPA', (53, 56))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('i12p', 'Chemical', '-', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('i12p', 'Var', (42, 46))
54443	32493368	These alterations are identified in the majority of gonadal germ cell tumors, with few exceptions, and in somatic type malignancies, derived from germ cell tumors.	('gonadal', 'Disease', (52, 59))	('alterations', 'Var', (6, 17))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('malignancies', 'Disease', (119, 131))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', (156, 162))	('malignancies', 'Disease', 'MESH:D009369', (119, 131))
54445	32493368	While some authors identified i12p and other alterations of chromosome 12, other authors reported cases without i12p, arguing that their results were consistent with the possible somatic origin of the YST component in these neoplasms.	('alterations', 'Var', (45, 56))	('neoplasms', 'Disease', 'MESH:D009369', (224, 233))	('neoplasms', 'Disease', (224, 233))	('neoplasm', 'Phenotype', 'HP:0002664', (224, 232))	('i12p', 'Chemical', '-', (112, 116))	('i12p', 'Chemical', '-', (30, 34))	('i12p', 'Var', (30, 34))	('neoplasms', 'Phenotype', 'HP:0002664', (224, 233))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))
54464	32493368	The diagnosis of YST differentiation in somatic neoplasms requires confirmation with immunohistochemistry results, which necessarily include positivity for AFP, GLP3 and SALL4, and negativity for epithelial markers like CK7 and EMA.	('somatic neoplasms', 'Disease', (40, 57))	('YST differentiation', 'Disease', (17, 36))	('SALL4', 'Gene', (170, 175))	('AFP', 'Gene', '174', (156, 159))	('CK7', 'Gene', '3855', (220, 223))	('neoplasm', 'Phenotype', 'HP:0002664', (48, 56))	('positivity', 'Var', (141, 151))	('negativity', 'Var', (181, 191))	('somatic neoplasms', 'Disease', 'MESH:D013001', (40, 57))	('CK7', 'Gene', (220, 223))	('EMA', 'Gene', (228, 231))	('neoplasms', 'Phenotype', 'HP:0002664', (48, 57))	('SALL4', 'Gene', '57167', (170, 175))	('AFP', 'Gene', (156, 159))	('EMA', 'Gene', '2108', (228, 231))	('GLP3', 'Gene', (161, 165))
54497	30518063	In breast and prostate cancers, the rate of the GR positivity or its overexpression was significantly lower in tumors than in the corresponding non-tumorous tissues, all of which appeared to express the GR.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('GR', 'Gene', '2908', (203, 205))	('overexpression', 'PosReg', (69, 83))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('positivity', 'Var', (51, 61))	('tumor', 'Disease', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('GR', 'Gene', '2908', (48, 50))	('lower', 'NegReg', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('prostate cancer', 'Phenotype', 'HP:0012125', (14, 29))	('breast and prostate cancers', 'Disease', 'MESH:D011471', (3, 30))	('prostate cancers', 'Phenotype', 'HP:0012125', (14, 30))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
54509	30518063	In a meta-analysis, high levels of GR expression in ER-positive breast cancers were found to be associated with significantly longer relapse-free survival.	('GR', 'Gene', '2908', (35, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('breast cancers', 'Disease', 'MESH:D001943', (64, 78))	('high levels', 'Var', (20, 31))	('breast cancers', 'Disease', (64, 78))	('longer', 'PosReg', (126, 132))	('ER', 'Gene', '2099', (52, 54))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('relapse-free survival', 'CPA', (133, 154))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancers', 'Phenotype', 'HP:0003002', (64, 78))
54510	30518063	Similar results, suggesting an association between the GR expression in the ER-positive breast cancer and significantly improved recurrence-free survival, were demonstrated in a more recent study.	('improved', 'PosReg', (120, 128))	('recurrence-free survival', 'CPA', (129, 153))	('GR', 'Gene', '2908', (55, 57))	('ER', 'Gene', '2099', (76, 78))	('expression', 'Var', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
54511	30518063	Conversely, in the ER-negative early-stage breast cancers from those who did or did not undergo adjuvant chemotherapy, high GR expression was associated with worse patient outcomes, compared to no or low GR expression.	('breast cancers', 'Disease', 'MESH:D001943', (43, 57))	('breast cancers', 'Disease', (43, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('GR', 'Gene', '2908', (204, 206))	('GR', 'Gene', '2908', (124, 126))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('high', 'Var', (119, 123))	('patient', 'Species', '9606', (164, 171))	('breast cancers', 'Phenotype', 'HP:0003002', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('ER', 'Gene', '2099', (19, 21))
54515	30518063	In patients with bladder cancer, we found that a loss of strong GR expression (i.e., 0/1+ or 0/1+/2+) was also associated with considerably higher risks for the recurrence of non-muscle-invasive tumors and progression of cancer-specific mortality of the muscle-invasive tumors.	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (254, 276))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('muscle-invasive tumors', 'Disease', (254, 276))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('bladder cancer', 'Disease', 'MESH:D001749', (17, 31))	('bladder cancer', 'Disease', (17, 31))	('cancer', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('0/1+/2+', 'Var', (93, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (17, 31))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (179, 201))	('loss', 'NegReg', (49, 53))	('cancer', 'Disease', (221, 227))	('muscle-invasive tumors', 'Disease', (179, 201))	('patients', 'Species', '9606', (3, 11))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('GR', 'Gene', '2908', (64, 66))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))
54528	30518063	In these studies, dexamethasone was also shown to reduce apoptosis, while inducing cell cycle arrest at the G1 phase (in bladder cancer lines) or S phase (in a cervical cancer line).	('bladder cancer', 'Disease', (121, 135))	('cervical cancer', 'Disease', (160, 175))	('cervical cancer', 'Disease', 'MESH:D002583', (160, 175))	('bladder cancer', 'Phenotype', 'HP:0009725', (121, 135))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('S phase', 'biological_process', 'GO:0051320', ('146', '153'))	('inducing', 'Reg', (74, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('57', '66'))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('apoptosis', 'biological_process', 'GO:0006915', ('57', '66'))	('S phase', 'CPA', (146, 153))	('dexamethasone', 'Var', (18, 31))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('83', '100'))	('cell cycle arrest at the G1 phase', 'CPA', (83, 116))	('reduce', 'NegReg', (50, 56))	('apoptosis', 'CPA', (57, 66))	('G1 phase', 'biological_process', 'GO:0051318', ('108', '116'))	('dexamethasone', 'Chemical', 'MESH:D003907', (18, 31))	('bladder cancer', 'Disease', 'MESH:D001749', (121, 135))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))
54545	30518063	In our previous study, comparing the growth of bladder cancer sublines stably expressing control-shRNA versus GR-shRNA, the GR knockdown resulted in significant induction of the migration of the TCCSUP cells, suggesting a suppressive role of the GR (i.e., GRalpha) in urothelial cancer.	('induction', 'Reg', (161, 170))	('GR', 'Gene', '2908', (110, 112))	('GR', 'Gene', '2908', (124, 126))	('bladder cancer', 'Disease', 'MESH:D001749', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('urothelial cancer', 'Disease', (268, 285))	('suppressive', 'NegReg', (222, 233))	('bladder cancer', 'Disease', (47, 61))	('GR', 'Gene', '2908', (256, 258))	('GR', 'Gene', '2908', (246, 248))	('migration', 'CPA', (178, 187))	('knockdown', 'Var', (127, 136))	('bladder cancer', 'Phenotype', 'HP:0009725', (47, 61))	('urothelial cancer', 'Disease', 'MESH:D014523', (268, 285))
54546	30518063	However, there were no significant differences in cell migration, cell invasion, and tumor growth in xenograft-bearing mice, between the UMUC3-control-shRNA versus the UMUC3-GR-shRNA sublines.	('tumor', 'Disease', (85, 90))	('mice', 'Species', '10090', (119, 123))	('cell migration', 'biological_process', 'GO:0016477', ('50', '64'))	('UMUC3-control-shRNA', 'Var', (137, 156))	('cell invasion', 'CPA', (66, 79))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cell migration', 'CPA', (50, 64))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('GR', 'Gene', '2908', (174, 176))
54550	30518063	Additional findings derived from a mutational analysis of the three prime untranslated region in the same study suggested that microRNA-144 might regulate GRbeta expression during bladder cancer cell migration.	('bladder cancer', 'Disease', 'MESH:D001749', (180, 194))	('bladder cancer', 'Disease', (180, 194))	('GR', 'Gene', '2908', (155, 157))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('microRNA-144', 'Var', (127, 139))	('bladder cancer', 'Phenotype', 'HP:0009725', (180, 194))	('expression', 'MPA', (162, 172))	('cell migration', 'biological_process', 'GO:0016477', ('195', '209'))	('regulate', 'Reg', (146, 154))
54574	30518063	In addition, ERalpha (p = 0.041; Figure 1a) or ERbeta (p = 0.034; Figure 1b) expression in non-muscle-invasive bladder tumors with moderate (2+) to strong (3+) GR expression (n = 55) was associated with a significantly lower or higher risk, respectively, of disease recurrence (Ide et al., unpublished data; immunostaining was performed previously in a set of tissue microarray).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('disease', 'Disease', (258, 265))	('bladder tumor', 'Phenotype', 'HP:0009725', (111, 124))	('ERalpha', 'Gene', (13, 20))	('bladder tumors', 'Disease', (111, 125))	('ERbeta', 'Gene', '2100', (47, 53))	('invasive bladder', 'Phenotype', 'HP:0100645', (102, 118))	('ERalpha', 'Gene', '2099', (13, 20))	('lower', 'NegReg', (219, 224))	('GR', 'Gene', '2908', (160, 162))	('bladder tumors', 'Phenotype', 'HP:0009725', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('ERbeta', 'Gene', (47, 53))	('moderate (2+', 'Var', (131, 143))	('non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (91, 118))	('bladder tumors', 'Disease', 'MESH:D001749', (111, 125))	('Ide', 'molecular_function', 'GO:0004231', ('278', '281'))
54581	30518063	In human bladder cancer cells, we demonstrated that CpdA significantly inhibited cell proliferation of the two GR-positive/AR-positive lines (i.e., TCCSUP, UMUC3) and the two GR-positive/AR-negative lines (i.e., 5637, 647V), as well as the two GR-knockdown/AR-positive sublines (i.e., TCCSUP-GR-shRNA, UMUC3-GR-shRNA).	('cell proliferation', 'CPA', (81, 99))	('GR', 'Gene', '2908', (244, 246))	('GR', 'Gene', '2908', (292, 294))	('bladder cancer', 'Disease', 'MESH:D001749', (9, 23))	('bladder cancer', 'Disease', (9, 23))	('inhibited', 'NegReg', (71, 80))	('GR', 'Gene', '2908', (111, 113))	('human', 'Species', '9606', (3, 8))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('CpdA', 'Chemical', '-', (52, 56))	('GR', 'Gene', '2908', (308, 310))	('CpdA', 'Var', (52, 56))	('bladder cancer', 'Phenotype', 'HP:0009725', (9, 23))	('GR', 'Gene', '2908', (175, 177))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
54582	30518063	Similarly, CpdA significantly inhibited the migration and invasion of the GR-positive/AR-positive or the GR-positive/AR-negative cells, as well as the growth of their xenograft tumors in mice.	('growth', 'CPA', (151, 157))	('xenograft tumors', 'Disease', (167, 183))	('inhibited', 'NegReg', (30, 39))	('mice', 'Species', '10090', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('invasion', 'CPA', (58, 66))	('GR', 'Gene', '2908', (74, 76))	('GR', 'Gene', '2908', (105, 107))	('CpdA', 'Var', (11, 15))	('CpdA', 'Chemical', '-', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('xenograft tumors', 'Disease', 'MESH:D009369', (167, 183))
54586	30518063	Co-immunoprecipitation further confirmed the induction of the interactions between the GR and NF-kappaB by not only dexamethasone but also CpdA.	('CpdA', 'Chemical', '-', (139, 143))	('GR', 'Gene', '2908', (87, 89))	('dexamethasone', 'Chemical', 'MESH:D003907', (116, 129))	('interactions', 'Interaction', (62, 74))	('CpdA', 'Var', (139, 143))	('NF-kappaB', 'Gene', '4790', (94, 103))	('NF-kappaB', 'Gene', (94, 103))
54599	30518063	Indeed, the CpdA that selectively induces transrepression has been shown to inhibit not only cell migration/invasion of bladder cancer but also the cell proliferation of even AR-negative bladder cancer lines, primarily via the GR pathway.	('GR', 'Gene', '2908', (227, 229))	('cell proliferation', 'biological_process', 'GO:0008283', ('148', '166'))	('transrepression', 'Var', (42, 57))	('CpdA', 'Chemical', '-', (12, 16))	('inhibit', 'NegReg', (76, 83))	('bladder cancer', 'Disease', 'MESH:D001749', (187, 201))	('bladder cancer', 'Disease', 'MESH:D001749', (120, 134))	('bladder cancer', 'Disease', (187, 201))	('cell migration/invasion', 'CPA', (93, 116))	('bladder cancer', 'Disease', (120, 134))	('cell proliferation', 'CPA', (148, 166))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('bladder cancer', 'Phenotype', 'HP:0009725', (187, 201))	('cell migration', 'biological_process', 'GO:0016477', ('93', '107'))	('bladder cancer', 'Phenotype', 'HP:0009725', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
54611	26292924	Currently several studies have analyzed genome-wide mutational patterns in different cancer types and identified genes harboring functional mutations implicated in cancerogenesis.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('mutations', 'Var', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
54612	26292924	Cancer is thought to be driven by gene expression pattern changes due to the accumulation of mutations or epigenetic modifications; thus, a comprehensive characterization of alterations in gene expression will not only advance our understanding of cancer biology, it will also provide a large number of new potential diagnostic and therapeutic targets for cancer.	('cancer', 'Disease', (248, 254))	('gene expression', 'biological_process', 'GO:0010467', ('34', '49'))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('advance', 'PosReg', (219, 226))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', (356, 362))	('alterations', 'Var', (174, 185))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('gene expression', 'biological_process', 'GO:0010467', ('189', '204'))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))
54632	26292924	Driver mutations are causally implicated in carcinogenesis while passenger mutations don't contribute to the development of cancer.	('Driver mutations', 'Var', (0, 16))	('cancer', 'Disease', (124, 130))	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('carcinogenesis', 'Disease', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('implicated', 'Reg', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
54634	26292924	In cancers, as a result of mutations, this regulatory process malfunctions, resulting in uncontrolled cell proliferation that leads to carcinogenesis.	('mutations', 'Var', (27, 36))	('uncontrolled', 'MPA', (89, 101))	('leads to', 'Reg', (126, 134))	('carcinogenesis', 'Disease', (135, 149))	('resulting', 'Reg', (76, 85))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cell proliferation', 'biological_process', 'GO:0008283', ('102', '120'))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('carcinogenesis', 'Disease', 'MESH:D063646', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
54636	26292924	1: (1) one or more driver mutations are within a cell cycle-associated pathway, altering its expression pattern and consequently leading to cancer; (2) one or more driver mutations lie in an organ/tissue-specific pathway or other pathways not related to cell cycle, which interacts with a cell cycle-associated pathway, alters its expression pattern, and ultimately results in cancer.	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('cell cycle', 'biological_process', 'GO:0007049', ('289', '299'))	('cell cycle', 'biological_process', 'GO:0007049', ('254', '264'))	('cancer', 'Disease', (140, 146))	('leading to', 'Reg', (129, 139))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('mutations', 'Var', (26, 35))	('results in', 'Reg', (366, 376))	('expression pattern', 'MPA', (93, 111))	('altering', 'Reg', (80, 88))	('cancer', 'Disease', (377, 383))	('alters', 'Reg', (320, 326))	('cancer', 'Disease', 'MESH:D009369', (377, 383))	('mutations', 'Var', (171, 180))	('cell cycle', 'biological_process', 'GO:0007049', ('49', '59'))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('expression pattern', 'MPA', (331, 349))
54645	26292924	Gene set CLUSTER2556 is significant in BLCA, COAD, and LUSC.	('LUSC', 'Disease', (55, 59))	('COAD', 'Disease', (45, 49))	('CLUSTER2556', 'Var', (9, 20))	('BLCA', 'Disease', (39, 43))	('COAD', 'Disease', 'MESH:D029424', (45, 49))
54649	26292924	We identified seven cross-cancer gene signatures: CLUSTER241, CLUSTER514, CLUSTER1011, CLUSTER932, CLUSTER574, CLUSTER3137, and CLUSTER184, that were altered in at least four types of human cancers.	('CLUSTER574', 'Var', (99, 109))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('CLUSTER514', 'Var', (62, 72))	('cancers', 'Disease', (190, 197))	('CLUSTER3137', 'Var', (111, 122))	('cross-cancer', 'Disease', (20, 32))	('CLUSTER1011', 'Var', (74, 85))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('cross-cancer', 'Disease', 'MESH:C537866', (20, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('human', 'Species', '9606', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('CLUSTER184', 'Var', (128, 138))	('CLUSTER932', 'Var', (87, 97))	('CLUSTER241', 'Var', (50, 60))
54662	26292924	Baculoviral IAP repeat containing 5 (BIRC5) is over-expressed in most human cancers; the microRNA targeting BIRC5 suppresses cell proliferation in triple-negative breast cancer (TNBC) cells.	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('BIRC5', 'Gene', '332', (37, 42))	('cancers', 'Disease', (76, 83))	('BIRC5', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('suppresses', 'NegReg', (114, 124))	('BIRC5', 'Gene', '332', (108, 113))	('Baculoviral IAP repeat containing 5', 'Gene', '332', (0, 35))	('BIRC5', 'Gene', (108, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('TNBC', 'Disease', 'None', (178, 182))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('microRNA targeting', 'Var', (89, 107))	('human', 'Species', '9606', (70, 75))	('cell proliferation', 'CPA', (125, 143))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Disease', (163, 176))	('TNBC', 'Disease', (178, 182))	('Baculoviral IAP repeat containing 5', 'Gene', (0, 35))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cell proliferation', 'biological_process', 'GO:0008283', ('125', '143'))
54671	26292924	Mutations in BRCA1 interacting protein C-terminal helicase 1 (BRIP1) have been associated with ovarian cancer and breast cancer.	('BRIP1', 'Gene', (62, 67))	('associated', 'Reg', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BRIP1', 'Gene', '83990', (62, 67))	('BRCA1', 'Gene', (13, 18))	('ovarian cancer', 'Disease', 'MESH:D010051', (95, 109))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))	('ovarian cancer', 'Disease', (95, 109))	('Mutations', 'Var', (0, 9))	('helicase 1', 'Gene', '56916', (50, 60))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('BRCA1', 'Gene', '672', (13, 18))	('breast cancer', 'Disease', (114, 127))	('helicase 1', 'Gene', (50, 60))
54678	26292924	The aberrant expression of cell division cycle 6 (CDC6) has been documented in multiple human cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('cell division cycle', 'biological_process', 'GO:0007049', ('27', '46'))	('CDC6', 'Gene', '990', (50, 54))	('aberrant', 'Var', (4, 12))	('CDC6', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (88, 93))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
54681	26292924	CLUSTER574 is significantly altered in six cancer types: BRCA, COAD, HNSC, LIHC, LUAD, and LUSC.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('COAD', 'Disease', 'MESH:D029424', (63, 67))	('altered', 'Reg', (28, 35))	('COAD', 'Disease', (63, 67))	('cancer', 'Disease', (43, 49))	('CLUSTER574', 'Var', (0, 10))	('HNSC', 'Disease', (69, 73))	('LIHC', 'Disease', (75, 79))	('BRCA', 'Gene', '672', (57, 61))	('LIHC', 'Disease', 'None', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('BRCA', 'Gene', (57, 61))	('LUSC', 'Disease', (91, 95))	('LUAD', 'Disease', (81, 85))
54689	26292924	CLUSTER3137 is significantly altered in five cancer types: BLCA, COAD, LIHC, LUAD, and LUSC.	('cancer', 'Disease', (45, 51))	('CLUSTER3137', 'Var', (0, 11))	('LUSC', 'Disease', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('LIHC', 'Disease', (71, 75))	('COAD', 'Disease', (65, 69))	('BLCA', 'Disease', (59, 63))	('LIHC', 'Disease', 'None', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('altered', 'Reg', (29, 36))	('LUAD', 'Disease', (77, 81))	('COAD', 'Disease', 'MESH:D029424', (65, 69))
54694	26292924	The polymorphisms of DNMT1 have been reported to increase breast cancer risk.	('DNMT1', 'Gene', '1786', (21, 26))	('increase', 'PosReg', (49, 57))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('polymorphisms', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('DNMT1', 'Gene', (21, 26))
54702	26292924	Therefore, the perturbation of CLUSTER3137 might be an epigenetic trigger of tumorigenesis.	('CLUSTER3137', 'Gene', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('perturbation', 'Var', (15, 27))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
54703	26292924	The deregulation of CLUSTER1011 may reveal the roles of components of the Fanconi anemia/BRCA pathway in human cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('deregulation', 'Var', (4, 16))	('CLUSTER1011', 'Gene', (20, 31))	('anemia', 'Phenotype', 'HP:0001903', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('BRCA', 'Gene', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Fanconi anemia', 'Disease', (74, 88))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (74, 88))	('reveal', 'Reg', (36, 42))	('human', 'Species', '9606', (105, 110))	('Fanconi anemia', 'Disease', 'MESH:D005199', (74, 88))	('BRCA', 'Gene', '672', (89, 93))
54710	26292924	21 clusters were significantly altered only in one or both of lung cancers, three of which, CLUSTER1520, CLUSTER901 and CLUSTER1057, have been implicated in lung diseases.	('lung diseases', 'Disease', 'MESH:D008171', (157, 170))	('altered', 'Reg', (31, 38))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('lung diseases', 'Disease', (157, 170))	('CLUSTER1520', 'Var', (92, 103))	('lung diseases', 'Phenotype', 'HP:0002088', (157, 170))	('lung cancers', 'Disease', (62, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('CLUSTER901', 'Var', (105, 115))	('implicated', 'Reg', (143, 153))	('lung cancers', 'Disease', 'MESH:D008175', (62, 74))	('lung cancers', 'Phenotype', 'HP:0100526', (62, 74))	('CLUSTER1057', 'Var', (120, 131))
54716	26292924	The top associated disease for CLUSTER901 is Lung Neoplasms (adjP = 0.0006).	('Neoplasms', 'Disease', 'MESH:D009369', (50, 59))	('CLUSTER901', 'Var', (31, 41))	('Neoplasms', 'Disease', (50, 59))	('Neoplasms', 'Phenotype', 'HP:0002664', (50, 59))	('Lung Neoplasms', 'Phenotype', 'HP:0100526', (45, 59))
54718	26292924	G protein-coupled receptor, class C, group 5, member A (Gprc5a) protein is detected in the lungs more than in any other tissue; Gprc5a knockout promotes lung inflammation and tumorigenesis in mice.	('inflammation', 'biological_process', 'GO:0006954', ('158', '170'))	('tumor', 'Disease', (175, 180))	('mice', 'Species', '10090', (192, 196))	('knockout', 'Var', (135, 143))	('member A', 'Gene', (46, 54))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('protein', 'cellular_component', 'GO:0003675', ('2', '9'))	('Gprc5a', 'Gene', (56, 62))	('Gprc5a', 'Gene', '232431', (56, 62))	('G protein-coupled receptor, class C, group 5', 'Gene', '23890', (0, 44))	('promotes', 'PosReg', (144, 152))	('Gprc5a', 'Gene', (128, 134))	('Gprc5a', 'Gene', '232431', (128, 134))	('lung inflammation', 'Disease', 'MESH:D011014', (153, 170))	('member A', 'Gene', '9052', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('lung inflammation', 'Disease', (153, 170))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
54721	26292924	Claudin 18 (CLDN18) deficiency is related to alveolar barrier dysfunction.	('alveolar barrier dysfunction', 'Disease', (45, 73))	('Claudin 18', 'Gene', (0, 10))	('deficiency', 'Var', (20, 30))	('alveolar barrier dysfunction', 'Disease', 'MESH:C536830', (45, 73))	('Claudin 18', 'Gene', '51208', (0, 10))	('CLDN18', 'Gene', (12, 18))	('related', 'Reg', (34, 41))	('CLDN18', 'Gene', '51208', (12, 18))
54723	26292924	The top associated diseases for CLUSTER1057 are Lung Diseases (adjP = 0.0037), Respiratory Tract Diseases (adjP = 0.0037), and Airway Obstruction (adjP = 0.0037).	('Lung Diseases', 'Disease', (48, 61))	('Airway Obstruction', 'Disease', (127, 145))	('CLUSTER1057', 'Var', (32, 43))	('Respiratory Tract Diseases', 'Disease', (79, 105))	('Airway Obstruction', 'Phenotype', 'HP:0002781', (127, 145))	('Respiratory Tract Diseases', 'Disease', 'MESH:D012140', (79, 105))	('Lung Diseases', 'Phenotype', 'HP:0002088', (48, 61))
54724	26292924	CLUSTER1057 contains many immunity-associated genes and might contribute to the immune reactions to lung cancers.	('lung cancers', 'Disease', (100, 112))	('CLUSTER1057', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancers', 'Disease', 'MESH:D008175', (100, 112))	('lung cancers', 'Phenotype', 'HP:0100526', (100, 112))	('contribute', 'Reg', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
54726	26292924	Thirteen clusters were significantly altered only in BLCA, two of which, CLUSTER2174 and CLUSTER1860, have been implicated in bladder abnormalities.	('CLUSTER2174', 'Var', (73, 84))	('bladder abnormalities', 'Disease', 'MESH:D001745', (126, 147))	('CLUSTER1860', 'Var', (89, 100))	('implicated', 'Reg', (112, 122))	('bladder abnormalities', 'Phenotype', 'HP:0000014', (126, 147))	('bladder abnormalities', 'Disease', (126, 147))	('altered', 'Reg', (37, 44))
54727	26292924	The top associated disease for CLUSTER2174 is Urogenital Abnormalities (adjP = 0.0008).	('CLUSTER2174', 'Var', (31, 42))	('Urogenital Abnormalities', 'Disease', 'MESH:D014564', (46, 70))	('Urogenital Abnormalities', 'Disease', (46, 70))	('Urogenital Abnormalities', 'Phenotype', 'HP:0000119', (46, 70))
54729	26292924	The top associated disease for CLUSTER1860 is Cystitis (adjP = 3.08e-05).	('Cystitis', 'Disease', 'MESH:D003556', (46, 54))	('CLUSTER1860', 'Var', (31, 42))	('Cystitis', 'Disease', (46, 54))
54732	26292924	CLUSTER891 is significantly altered only in BRCA.	('BRCA', 'Gene', (44, 48))	('CLUSTER891', 'Var', (0, 10))	('BRCA', 'Gene', '672', (44, 48))	('altered', 'Reg', (28, 35))
54735	26292924	p53 represses hepatoma-derived growth factor (HDGF), and loss of p53 function contributes to tumorigenesis by elevating HDGF expression.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('HDGF', 'Gene', (46, 50))	('hepatoma-derived growth factor', 'Gene', '3068', (14, 44))	('hepatoma-derived growth factor', 'Gene', (14, 44))	('elevating', 'PosReg', (110, 119))	('HDGF', 'Gene', '3068', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('HDGF', 'Gene', (120, 124))	('expression', 'MPA', (125, 135))	('HDGF', 'Gene', '3068', (46, 50))	('loss', 'Var', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
54738	26292924	CLUSTER2240 is significantly altered only in KICH.	('CLUSTER2240', 'Var', (0, 11))	('KICH', 'Disease', 'None', (45, 49))	('altered', 'Reg', (29, 36))	('KICH', 'Disease', (45, 49))
54739	26292924	The top associated disease for CLUSTER2240 is Ciliary Motility Disorders (adjP = 1.85e-05), and Ciliary dysfunction is a risk factor for both syndromic and isolated kidney cystic disease.	('CLUSTER2240', 'Var', (31, 42))	('Ciliary dysfunction', 'Disease', 'MESH:D002925', (96, 115))	('Ciliary Motility', 'biological_process', 'GO:0003341', ('46', '62'))	('syndromic and isolated kidney cystic disease', 'Disease', 'MESH:D052177', (142, 186))	('kidney cystic disease', 'Phenotype', 'HP:0000107', (165, 186))	('Ciliary Motility Disorders', 'Phenotype', 'HP:0012262', (46, 72))	('Ciliary Motility Disorders', 'Disease', (46, 72))	('Ciliary Motility Disorders', 'Disease', 'MESH:D002925', (46, 72))	('Ciliary dysfunction', 'Disease', (96, 115))
54740	26292924	Nephronophthisis 1 (NPHP1/NPH1) gene deletion is correlated with nephronophthisis.	('NPHP1', 'Gene', '4867', (20, 25))	('correlated', 'Reg', (49, 59))	('NPH1', 'Gene', (26, 30))	('Nephronophthisis', 'Disease', 'MESH:C537699', (0, 16))	('NPH1', 'Gene', '4867', (26, 30))	('deletion', 'Var', (37, 45))	('nephronophthisis', 'Disease', 'MESH:C537699', (65, 81))	('Nephronophthisis', 'Disease', (0, 16))	('nephronophthisis', 'Disease', (65, 81))	('NPHP1', 'Gene', (20, 25))	('Nephronophthisis', 'Phenotype', 'HP:0000090', (0, 16))	('nephronophthisis', 'Phenotype', 'HP:0000090', (65, 81))
54747	26292924	These partly verified our hypothesis that alterations in cell cycle-associated pathways directly contribute to the initiation and development of cancers, while some organ/tissue-specific pathways can lead to cancers possibly by altering the expression of cell-cycle associated pathways.	('cancers', 'Disease', (145, 152))	('lead to', 'Reg', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('contribute', 'Reg', (97, 107))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('alterations', 'Var', (42, 53))	('cancers', 'Disease', (208, 215))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('expression', 'MPA', (241, 251))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cell cycle-associated pathways', 'Pathway', (57, 87))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cell cycle', 'biological_process', 'GO:0007049', ('57', '67'))	('cell-cycle', 'biological_process', 'GO:0007049', ('255', '265'))	('altering', 'Reg', (228, 236))	('cell-cycle associated pathways', 'Pathway', (255, 285))
54748	26292924	Seven gene sets, CLUSTER241, CLUSTER514, CLUSTER1011, CLUSTER932, CLUSTER574, CLUSTER3137, and CLUSTER184, were differentially expressed in at least four of the seven cancer types: BLCA, BRCA, COAD, HNSC, LUAD, and LUSC.	('CLUSTER184', 'Var', (95, 105))	('CLUSTER932', 'Var', (54, 64))	('COAD', 'Disease', 'MESH:D029424', (193, 197))	('HNSC', 'Disease', (199, 203))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('CLUSTER514', 'Var', (29, 39))	('cancer', 'Disease', (167, 173))	('CLUSTER241', 'Var', (17, 27))	('LUAD', 'Disease', (205, 209))	('BLCA', 'Disease', (181, 185))	('CLUSTER574', 'Var', (66, 76))	('CLUSTER1011', 'Var', (41, 52))	('COAD', 'Disease', (193, 197))	('LUSC', 'Disease', (215, 219))	('BRCA', 'Gene', (187, 191))	('CLUSTER3137', 'Var', (78, 89))	('BRCA', 'Gene', '672', (187, 191))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
54754	26292924	To test if the same holds true for other non-TCGA data sources, we downloaded two RNA-Seq data sets, GSE40419 and GSE50760, and one microarray data set, GSE5364, from the Gene Expression Omnibus (GEO: http://www.ncbi.nlm.nih.gov/geo).	('RNA', 'cellular_component', 'GO:0005562', ('82', '85'))	('GSE50760', 'Var', (114, 122))	('GSE40419', 'Var', (101, 109))	('GSE5364', 'Chemical', '-', (153, 160))	('Gene Expression', 'biological_process', 'GO:0010467', ('171', '186'))
54755	26292924	GSE40419 includes the RNA-Seq expression values for 87 lung adenocarcinomas and 77 adjacent normal tissues, while GSE50760 contains the RNA-Seq expression values of 54 samples (18 primary colorectal cancer, 18 liver metastasis, and 18 normal colon) generated from 18 colorectal cancer patients.	('lung adenocarcinomas', 'Disease', (55, 75))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (55, 75))	('colorectal cancer', 'Disease', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('RNA', 'cellular_component', 'GO:0005562', ('22', '25'))	('GSE50760', 'Var', (114, 122))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (55, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('colorectal cancer', 'Disease', 'MESH:D015179', (267, 284))	('RNA', 'cellular_component', 'GO:0005562', ('136', '139'))	('GSE40419', 'Var', (0, 8))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (267, 284))	('patients', 'Species', '9606', (285, 293))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))	('colorectal cancer', 'Disease', (267, 284))
54757	26292924	We found that the tumor and normal samples were accurately classified, the predictive accuracy for GSE40419 and GSE50760 were 97.14% and 93.33%, respectively.	('tumor', 'Disease', (18, 23))	('GSE40419', 'Var', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('GSE50760', 'Var', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
54762	26292924	We found that CLUSTER1520 is a lung cancer-specific gene signature.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('lung cancer', 'Disease', (31, 42))	('CLUSTER1520', 'Var', (14, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
54764	26292924	Moreover, CLUSTER1520 showed a substantially reduced level of expression in the lung tumor samples as compared to lung normal samples.	('lung tumor', 'Disease', (80, 90))	('reduced', 'NegReg', (45, 52))	('lung tumor', 'Phenotype', 'HP:0100526', (80, 90))	('expression', 'MPA', (62, 72))	('CLUSTER1520', 'Var', (10, 21))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('lung tumor', 'Disease', 'MESH:D008175', (80, 90))
54767	26292924	We also validate that CLUSTER1520 is a lung cancer-specific gene signature on a non-TCGA microarray data set (GSE5364).	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('lung cancer', 'Disease', (39, 50))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('GSE5364', 'Chemical', '-', (110, 117))	('CLUSTER1520', 'Var', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
54768	26292924	GSE5364 includes 6 tumor types, and we divided those tumor samples into two classes: lung tumor samples and non-lung tumor samples (breast, colon, liver, oesophagus, thyroid).	('colon', 'Disease', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('lung tumor', 'Disease', 'MESH:D008175', (85, 95))	('lung tumor', 'Phenotype', 'HP:0100526', (112, 122))	('tumor', 'Disease', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('breast', 'Disease', (132, 138))	('GSE5364', 'Var', (0, 7))	('oesophagus', 'Disease', (154, 164))	('non-lung tumor', 'Disease', (108, 122))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('lung tumor', 'Disease', 'MESH:D008175', (112, 122))	('GSE5364', 'Chemical', '-', (0, 7))	('lung tumor', 'Disease', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('liver', 'Disease', (147, 152))	('lung tumor', 'Phenotype', 'HP:0100526', (85, 95))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('non-lung tumor', 'Disease', 'MESH:D002289', (108, 122))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
54769	26292924	The predictive accuracy of LOOCV for these two classes of tumor samples was 100%, this demonstrated that lung tumor samples and non-lung tumor samples were accurately classified based on CLUSTER1520.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('lung tumor', 'Disease', 'MESH:D008175', (132, 142))	('tumor', 'Disease', (137, 142))	('non-lung tumor', 'Disease', (128, 142))	('lung tumor', 'Disease', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('lung tumor', 'Phenotype', 'HP:0100526', (105, 115))	('lung tumor', 'Disease', 'MESH:D008175', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('lung tumor', 'Phenotype', 'HP:0100526', (132, 142))	('non-lung tumor', 'Disease', 'MESH:D002289', (128, 142))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('CLUSTER1520', 'Var', (187, 198))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
54770	26292924	These results show that CLUSTER1520 is a lung cancer-specific gene signature, and genes in this signature are potential targets for developing novel lung cancer therapies.	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('lung cancer', 'Disease', (41, 52))	('CLUSTER1520', 'Var', (24, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung cancer', 'Disease', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))
54771	26292924	In order to test if the significant gene sets we identified from TCGA data can be validated on non-TCGA data sources, we performed gene set association analysis on two non-TCGA cohorts: a lung adenocarcinoma data set (GSE40419) and a colorectal cancer data set (GSE50760), the results are shown in Supplementary Table S5.	('colorectal cancer', 'Phenotype', 'HP:0003003', (234, 251))	('GSE40419', 'Var', (218, 226))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (188, 207))	('colorectal cancer', 'Disease', (234, 251))	('colorectal cancer', 'Disease', 'MESH:D015179', (234, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('lung adenocarcinoma', 'Disease', (188, 207))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (188, 207))
54772	26292924	For GSE40419, we identified 1 significant gene set (FDR < 0.25), CLUSTER514, which is one of the seven cross-cancer gene signatures.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('GSE40419', 'Var', (4, 12))	('cross-cancer', 'Disease', (103, 115))	('cross-cancer', 'Disease', 'MESH:C537866', (103, 115))
54773	26292924	For GSE50760, we identified five significant gene sets (FDR < 0.25), two of them, CLUSTER2556 and CLUSTER514, were also identified as significant using TCGA COAD data.	('COAD', 'Disease', 'MESH:D029424', (157, 161))	('GSE50760', 'Var', (4, 12))	('COAD', 'Disease', (157, 161))
54779	26292924	These results reveal the aberrations in cancer transcriptomes and lead to a deeper understanding of the formation and development of human cancers.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('aberrations', 'Var', (25, 36))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('formation', 'biological_process', 'GO:0009058', ('104', '113'))	('cancer', 'Disease', (40, 46))	('human', 'Species', '9606', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', (139, 145))
54781	26292924	Our results reveal that four gene sets, CLUSTER241, CLUSTER514, CLUSTER1011, and CLUSTER932, are significantly altered across seven cancer types: BLCA, BRCA, COAD, HNSC, LIHC, LUAD, and LUSC (Table 2).	('HNSC', 'Disease', (164, 168))	('cancer', 'Disease', (132, 138))	('LIHC', 'Disease', (170, 174))	('CLUSTER241', 'Var', (40, 50))	('CLUSTER932', 'Var', (81, 91))	('COAD', 'Disease', (158, 162))	('LIHC', 'Disease', 'None', (170, 174))	('altered', 'Reg', (111, 118))	('CLUSTER1011', 'Var', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('LUSC', 'Disease', (186, 190))	('LUAD', 'Disease', (176, 180))	('COAD', 'Disease', 'MESH:D029424', (158, 162))	('BRCA', 'Gene', '672', (152, 156))	('BRCA', 'Gene', (152, 156))	('BLCA', 'Disease', (146, 150))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('CLUSTER514', 'Var', (52, 62))
54786	26292924	We hypothesize that some of these mutations or epimutations may disrupt a pathway responsible for cell cycle regulation that directly drives cells into uncontrolled proliferation, while others may lie within an organ-specific pathway that turn a healthy cell into a cancer cell by altering the expression of cell cycle-associated pathways.	('altering', 'Reg', (281, 289))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('expression', 'MPA', (294, 304))	('cancer', 'Disease', (266, 272))	('cell cycle', 'biological_process', 'GO:0007049', ('308', '318'))	('cell cycle-associated pathways', 'Pathway', (308, 338))	('cell cycle regulation', 'MPA', (98, 119))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('turn', 'Reg', (239, 243))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('98', '119'))	('disrupt', 'NegReg', (64, 71))	('epimutations', 'Var', (47, 59))	('mutations', 'Var', (34, 43))
54789	26292924	Some of these gene sets may be cancer-specific gene signatures, say CLUSTER1520 and CLUSTER2318, that shed light on the mechanisms underlying cancer-driving abnormalities in a specific organ, while many of them may still represent a cellular process broadly perturbed across cancer types, and the differentiation is just stronger in one cancer type than other cancer types.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', 'MESH:D009369', (337, 343))	('cellular process', 'biological_process', 'GO:0009987', ('233', '249'))	('cancer', 'Disease', 'MESH:D009369', (360, 366))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Disease', (337, 343))	('cancer', 'Disease', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('cellular process', 'cellular_component', 'GO:0042995', ('233', '249'))	('CLUSTER2318', 'Var', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('cancer', 'Disease', (360, 366))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('CLUSTER1520', 'Var', (68, 79))
54793	26292924	Some genes, for example tumor protein p53 (TP53/p53), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), and retinoblastoma 1 (RB1), are frequently mutated in a number of cancers and are key genes contributing to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('retinoblastoma', 'Phenotype', 'HP:0009919', (140, 154))	('p53', 'Gene', '7157', (48, 51))	('retinoblastoma 1 (RB1', 'Gene', '5925', (140, 161))	('PIK3CA', 'Gene', '5290', (127, 133))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('TP53', 'Gene', (43, 47))	('mutated', 'Var', (179, 186))	('p53', 'Gene', (48, 51))	('p53', 'Gene', '7157', (38, 41))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('p53', 'Gene', (38, 41))	('tumor', 'Disease', (244, 249))	('PIK3CA', 'Gene', (127, 133))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancers', 'Disease', (202, 209))	('TP53', 'Gene', '7157', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
54794	26292924	However, among 20530 genes in the BLCA, BRCA, COAD, HNSC, LIHC, LUAD, LUSC, KICH, KIRC, KIRP, PRAD, and THCA datasets, we found that TP53 was ranked at 11834, 14601, 7752, 18515, 17359, 8769, 11116, 14995, 4200, 986, 4776, and 2094, PIK3CA at 16090, 7012, 14799, 4118, 13535, 13228, 6632, 12475, 14634, 17065, 19153, and 18438, RB1 at 15691, 15157, 6836, 16116, 16543, 9168, 19208, 8333, 9565, 4233, 16756, and 11160, respectively (Supplementary Table S1).	('6836', 'Var', (349, 353))	('COAD', 'Disease', 'MESH:D029424', (46, 50))	('15691', 'Var', (335, 340))	('LIHC', 'Disease', (58, 62))	('KICH', 'Disease', 'None', (76, 80))	('9565', 'Var', (388, 392))	('9168', 'Var', (369, 373))	('PIK3CA', 'Gene', (233, 239))	('11160', 'Var', (411, 416))	('COAD', 'Disease', (46, 50))	('8333', 'Var', (382, 386))	('16543', 'Var', (362, 367))	('TP53', 'Gene', '7157', (133, 137))	('LIHC', 'Disease', 'None', (58, 62))	('KICH', 'Disease', (76, 80))	('BRCA', 'Gene', '672', (40, 44))	('16116', 'Var', (355, 360))	('RB1', 'Gene', (328, 331))	('15157', 'Var', (342, 347))	('PIK3CA', 'Gene', '5290', (233, 239))	('BRCA', 'Gene', (40, 44))	('TP53', 'Gene', (133, 137))	('RB1', 'Gene', '5925', (328, 331))
54795	26292924	One reason could be that mutations in TP53/PIK3CA/RB1 substantially change the expression of its downstream target genes rather than genes harboring them.	('mutations', 'Var', (25, 34))	('PIK3CA', 'Gene', '5290', (43, 49))	('change', 'Reg', (68, 74))	('expression', 'MPA', (79, 89))	('TP53', 'Gene', (38, 42))	('TP53', 'Gene', '7157', (38, 42))	('RB1', 'Gene', (50, 53))	('RB1', 'Gene', '5925', (50, 53))	('PIK3CA', 'Gene', (43, 49))
54901	32322508	The World Health Organization classification of urothelial cancers lists 13 different histologic variants of urothelial cancer, where non-urothelial bladder cancer and variants of urothelial carcinoma account for 25% of all bladder cancers.	('non-urothelial bladder cancer', 'Disease', (134, 163))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('urothelial cancers', 'Disease', 'MESH:D014523', (48, 66))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('bladder cancers', 'Phenotype', 'HP:0009725', (224, 239))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (180, 200))	('bladder cancer', 'Phenotype', 'HP:0009725', (224, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('urothelial carcinoma', 'Disease', (180, 200))	('variants', 'Var', (168, 176))	('bladder cancers', 'Disease', 'MESH:D001749', (224, 239))	('bladder cancer', 'Phenotype', 'HP:0009725', (149, 163))	('urothelial cancer', 'Disease', 'MESH:D014523', (48, 65))	('bladder cancers', 'Disease', (224, 239))	('urothelial cancers', 'Disease', (48, 66))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('non-urothelial bladder cancer', 'Disease', 'MESH:D001749', (134, 163))	('urothelial cancer', 'Disease', 'MESH:D014523', (109, 126))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('urothelial cancer', 'Disease', (109, 126))
54924	32322508	Historically, variant histology bladder cancer is associated with these supradiaphragmatic cutaneous metastasis and therefore, confers a worse prognosis.	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('bladder cancer', 'Disease', (32, 46))	('associated', 'Reg', (50, 60))	('supradiaphragmatic', 'Disease', (72, 90))	('variant histology', 'Var', (14, 31))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
54983	28356754	Alterations of TP53 are predictive for BUC recurrence and are markedly associated with an unfavorable prognosis after radical cystectomy.	('Alterations', 'Var', (0, 11))	('BUC recurrence', 'Disease', (39, 53))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('associated with', 'Reg', (71, 86))
54984	28356754	GO enrichment analysis for biological processes demonstrated that BUC tumors were associated with mitotic recombination, sister chromatid segregation, and mitotic sister chromatid segregation, all of which are related to cell cycle regulation.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('associated', 'Reg', (82, 92))	('BUC tumors', 'Disease', 'MESH:D009369', (66, 76))	('chromatid', 'cellular_component', 'GO:0005695', ('128', '137'))	('BUC tumors', 'Disease', (66, 76))	('mitotic sister chromatid', 'Var', (155, 179))	('sister chromatid segregation', 'CPA', (121, 149))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('chromatid', 'cellular_component', 'GO:0005694', ('128', '137'))	('sister chromatid segregation', 'biological_process', 'GO:0000819', ('121', '149'))	('mitotic sister chromatid segregation', 'biological_process', 'GO:0000070', ('155', '191'))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('221', '242'))	('chromatid', 'cellular_component', 'GO:0005695', ('170', '179'))	('mitotic recombination', 'CPA', (98, 119))	('chromatid', 'cellular_component', 'GO:0005694', ('170', '179'))	('mitotic recombination', 'biological_process', 'GO:0006312', ('98', '119'))
54995	28356754	Earlier studies have reported that the cAMP-PKA-cAMP response element-binding (CREB) signaling pathway modulates vascular endothelial growth factor (VEGF), whereas loss of the dimethylarginine dimethylaminohydrolase 1 (DDAH1) effect on the NO-cGMP-PKG pathway results in decreased angiogenesis.	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('113', '147'))	('vascular endothelial growth factor', 'Gene', (113, 147))	('modulates', 'Reg', (103, 112))	('CREB', 'Gene', (79, 83))	('VEGF', 'Gene', (149, 153))	('DDAH1', 'Gene', '23576', (219, 224))	('angiogenesis', 'CPA', (281, 293))	('PKG', 'Gene', '5592', (248, 251))	('PKA', 'cellular_component', 'GO:0005952', ('44', '47'))	('decreased', 'NegReg', (271, 280))	('angiogenesis', 'biological_process', 'GO:0001525', ('281', '293'))	('CREB', 'Gene', '1385', (79, 83))	('PKA', 'molecular_function', 'GO:0004691', ('44', '47'))	('cAMP', 'Chemical', 'MESH:D000242', (48, 52))	('PKG', 'Gene', (248, 251))	('cGMP', 'Chemical', 'MESH:D006152', (243, 247))	('loss', 'Var', (164, 168))	('PKG', 'molecular_function', 'GO:0004692', ('248', '251'))	('cAMP', 'Chemical', 'MESH:D000242', (39, 43))	('DDAH1', 'Gene', (219, 224))	('dimethylarginine dimethylaminohydrolase 1', 'Gene', (176, 217))	('signaling pathway', 'biological_process', 'GO:0007165', ('85', '102'))	('vascular endothelial growth factor', 'Gene', '7422', (113, 147))	('VEGF', 'Gene', '7422', (149, 153))	('cAMP response element-binding', 'molecular_function', 'GO:0035497', ('48', '77'))	('dimethylarginine dimethylaminohydrolase 1', 'Gene', '23576', (176, 217))
55005	28356754	Similarly, a study of colorectal cancer showed that arginine ADP-ribosyltransferase 1 promotes expression of hypoxia-inducible factor 1-alpha via the PI3K-AKT signaling pathway, whereas upregulation of VEGF and basic fibroblast growth factor promotes cancer angiogenesis.	('cancer', 'Disease', (33, 39))	('VEGF', 'Gene', '7422', (202, 206))	('signaling pathway', 'biological_process', 'GO:0007165', ('159', '176'))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('promotes', 'PosReg', (86, 94))	('VEGF', 'Gene', (202, 206))	('colorectal cancer', 'Phenotype', 'HP:0003003', (22, 39))	('AKT', 'Gene', (155, 158))	('angiogenesis', 'biological_process', 'GO:0001525', ('258', '270'))	('hypoxia-inducible factor 1-alpha', 'Gene', (109, 141))	('hypoxia-inducible factor 1-alpha', 'Gene', '3091', (109, 141))	('PI3K', 'molecular_function', 'GO:0016303', ('150', '154'))	('expression', 'MPA', (95, 105))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('AKT signaling', 'biological_process', 'GO:0043491', ('155', '168'))	('arginine', 'Var', (52, 60))	('ADP-ribosyltransferase 1', 'Gene', (61, 85))	('colorectal cancer', 'Disease', 'MESH:D015179', (22, 39))	('ADP-ribosyltransferase 1', 'Gene', '417', (61, 85))	('AKT', 'Gene', '207', (155, 158))	('cancer', 'Disease', (251, 257))	('colorectal cancer', 'Disease', (22, 39))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('217', '241'))
55008	28356754	However, inhibition of p38 MAPK decreased BUC proliferation, growth, and cell invasiveness of bladder cancer via the MAPK pathway.	('MAPK', 'molecular_function', 'GO:0004707', ('117', '121'))	('p38', 'Gene', '5594', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('MAPK', 'Gene', (27, 31))	('MAPK', 'Gene', '5595;5594;5595', (27, 31))	('decreased', 'NegReg', (32, 41))	('MAPK', 'Gene', (117, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('invasiveness of bladder cancer', 'Disease', (78, 108))	('MAPK', 'Gene', '5595;5594;5595', (117, 121))	('MAPK', 'molecular_function', 'GO:0004707', ('27', '31'))	('p38', 'Gene', (23, 26))	('invasiveness of bladder cancer', 'Disease', 'MESH:D001749', (78, 108))	('growth', 'CPA', (61, 67))	('inhibition', 'Var', (9, 19))	('BUC proliferation', 'CPA', (42, 59))
55050	20460488	Blockade of CTLA-4 has led to enhanced T cell activation in animal models and mechanistic studies have shown that anti-CTLA-4 treated animals have an increased ratio of effector to regulatory T cells, which correlates with tumor regression.	('CTLA-4', 'Gene', '1493', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('enhanced', 'PosReg', (30, 38))	('enhanced T cell', 'Phenotype', 'HP:0100828', (30, 45))	('activation', 'PosReg', (46, 56))	('Blockade', 'Var', (0, 8))	('ratio', 'MPA', (160, 165))	('CTLA-4', 'Gene', '1493', (119, 125))	('T cell activation', 'biological_process', 'GO:0042110', ('39', '56'))	('CTLA-4', 'Gene', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('enhanced T cell activation', 'Phenotype', 'HP:0005419', (30, 56))	('increased', 'PosReg', (150, 159))	('CTLA-4', 'Gene', (119, 125))	('T cell', 'CPA', (39, 45))
55059	20460488	We found that CTLA-4 blockade led to an increased frequency of CD4+ICOShi T cells in tumor tissues that could be correlated with an increased frequency of these cells in the peripheral blood.	('tumor', 'Disease', (85, 90))	('CD4', 'Gene', (63, 66))	('CTLA-4', 'Gene', (14, 20))	('ICOS', 'Gene', (67, 71))	('CD4', 'Gene', '920', (63, 66))	('ICOS', 'Gene', '29851', (67, 71))	('blockade', 'Var', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('increased', 'PosReg', (40, 49))	('CTLA-4', 'Gene', '1493', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
55062	20460488	We now report that increases in CD4+ICOShi T cells were more pronounced after treatment with 10 mg/kg/dose of antibody, with concomitant increases in CD8+ICOShi T cells, which were not observed after treatment with 3 mg/kg/dose of antibody.	('ICOS', 'Gene', (36, 40))	('CD8', 'Gene', '925', (150, 153))	('antibody', 'cellular_component', 'GO:0019814', ('110', '118'))	('increases', 'PosReg', (19, 28))	('ICOS', 'Gene', '29851', (154, 158))	('increases', 'PosReg', (137, 146))	('antibody', 'molecular_function', 'GO:0003823', ('231', '239'))	('antibody', 'cellular_component', 'GO:0042571', ('231', '239'))	('antibody', 'molecular_function', 'GO:0003823', ('110', '118'))	('ICOS', 'Gene', (154, 158))	('antibody', 'cellular_component', 'GO:0042571', ('110', '118'))	('CD8', 'Gene', (150, 153))	('antibody', 'Var', (110, 118))	('antibody', 'cellular_component', 'GO:0019815', ('231', '239'))	('CD4', 'Gene', '920', (32, 35))	('antibody', 'cellular_component', 'GO:0019815', ('110', '118'))	('ICOS', 'Gene', '29851', (36, 40))	('CD4', 'Gene', (32, 35))	('antibody', 'cellular_component', 'GO:0019814', ('231', '239'))
55112	20460488	Peripheral blood samples from patients treated with 3 mg/kg/dose of antibody also showed a 2 to 7-fold increase in CD4+ICOShi T cells.	('antibody', 'molecular_function', 'GO:0003823', ('68', '76'))	('increase', 'PosReg', (103, 111))	('ICOS', 'Gene', (119, 123))	('antibody', 'cellular_component', 'GO:0042571', ('68', '76'))	('CD4', 'Gene', (115, 118))	('antibody', 'cellular_component', 'GO:0019815', ('68', '76'))	('patients', 'Species', '9606', (30, 38))	('to 7', 'Species', '1214577', (93, 97))	('ICOS', 'Gene', '29851', (119, 123))	('antibody', 'Var', (68, 76))	('antibody', 'cellular_component', 'GO:0019814', ('68', '76'))	('CD4', 'Gene', '920', (115, 118))
55116	20460488	At 10 mg/kg/dose of antibody, CD4+ICOShi T cells were similarly increased in tumor tissues and, in addition, CD8+ICOShi T cells were detectable in tumor tissues (Figure 1A), which were not detected in tumor samples from untreated patients or patients treated with 3 mg/kg/dose of antibody.	('antibody', 'cellular_component', 'GO:0019814', ('20', '28'))	('ICOS', 'Gene', '29851', (113, 117))	('antibody', 'cellular_component', 'GO:0019814', ('280', '288'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('CD4', 'Gene', (30, 33))	('ICOS', 'Gene', '29851', (34, 38))	('patients', 'Species', '9606', (242, 250))	('tumor', 'Disease', (147, 152))	('ICOS', 'Gene', (113, 117))	('CD8', 'Gene', '925', (109, 112))	('antibody', 'molecular_function', 'GO:0003823', ('280', '288'))	('antibody', 'molecular_function', 'GO:0003823', ('20', '28'))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('ICOS', 'Gene', (34, 38))	('antibody', 'Var', (20, 28))	('tumor', 'Disease', (201, 206))	('antibody', 'cellular_component', 'GO:0042571', ('280', '288'))	('antibody', 'cellular_component', 'GO:0042571', ('20', '28'))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('antibody', 'cellular_component', 'GO:0019815', ('20', '28'))	('CD8', 'Gene', (109, 112))	('antibody', 'cellular_component', 'GO:0019815', ('280', '288'))	('patients', 'Species', '9606', (230, 238))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('increased', 'PosReg', (64, 73))	('CD4', 'Gene', '920', (30, 33))	('tumor', 'Disease', (77, 82))
55122	20460488	Similarly, at 10 mg/kg/dose of antibody we observed an increase in frequency of CD8+ICOShi T cells within the systemic circulation (Figure 3A, Lower Panel), which was not detectable after patients received treatment with 3 mg/kg/dose of antibody.	('antibody', 'cellular_component', 'GO:0019815', ('237', '245'))	('increase', 'PosReg', (55, 63))	('CD8', 'Gene', '925', (80, 83))	('antibody', 'cellular_component', 'GO:0019815', ('31', '39'))	('antibody', 'cellular_component', 'GO:0019814', ('237', '245'))	('ICOS', 'Gene', (84, 88))	('antibody', 'cellular_component', 'GO:0019814', ('31', '39'))	('antibody', 'cellular_component', 'GO:0042571', ('31', '39'))	('antibody', 'molecular_function', 'GO:0003823', ('31', '39'))	('ICOS', 'Gene', '29851', (84, 88))	('antibody', 'molecular_function', 'GO:0003823', ('237', '245'))	('patients', 'Species', '9606', (188, 196))	('antibody', 'Var', (31, 39))	('CD8', 'Gene', (80, 83))	('antibody', 'cellular_component', 'GO:0042571', ('237', '245'))
55201	20460488	The UroVysion Kit is designed and has been FDA cleared to detect aneuploidy for chromosomes 3, 7, 17, and loss of 9p21 locus in transitional cell carcinoma urine specimens.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (128, 155))	('carcinoma', 'Disease', (146, 155))	('loss of', 'Var', (106, 113))	('aneuploidy', 'Var', (65, 75))	('carcinoma', 'Disease', 'MESH:D002277', (146, 155))
55282	30719635	We found that within 30 months, the recurrence-free rate was higher in patients who underwent TUR-BT under pCLE than in the non-pCLE group with 78.2% and 60.3%, respectively.	('pCLE', 'Chemical', '-', (107, 111))	('TUR-BT', 'Var', (94, 100))	('recurrence-free rate', 'CPA', (36, 56))	('patients', 'Species', '9606', (71, 79))	('higher', 'PosReg', (61, 67))	('pCLE', 'Chemical', '-', (128, 132))
55356	30213195	Among several factors, performance status, multifocality, NLR level, pT stage, pN stage, LVI, and presence of SD were significantly associated with OS and RFS.	('OS', 'Chemical', '-', (148, 150))	('RFS', 'Disease', (155, 158))	('LVI', 'Chemical', '-', (89, 92))	('LVI', 'Disease', (89, 92))	('RFS', 'Chemical', '-', (155, 158))	('associated', 'Reg', (132, 142))	('presence', 'Var', (98, 106))	('SD', 'Chemical', '-', (110, 112))
55378	30213195	In contrast, our results reveal that the presence of SD is associated with increased risk of mortality.	('SD', 'Chemical', '-', (53, 55))	('mortality', 'Disease', (93, 102))	('presence', 'Var', (41, 49))
55393	30213195	NAC has been reported to increase the proportion of downstaging and provide a survival benefit, especially in stage III cases.	('NAC', 'Var', (0, 3))	('stage III cases', 'Disease', (110, 125))	('NAC', 'Chemical', '-', (0, 3))	('survival benefit', 'CPA', (78, 94))	('downstaging', 'MPA', (52, 63))	('NAC', 'cellular_component', 'GO:0005854', ('0', '3'))
55411	30213195	Multifocality in MIBC caused increases in the tumor burden.	('Multifocality', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('MIBC', 'Chemical', '-', (17, 21))	('tumor', 'Disease', (46, 51))	('increases', 'PosReg', (29, 38))	('MIBC', 'Gene', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
55419	30213195	Our study suggests that SD in UC of the bladder may be associated with poor oncological outcome after RC and predict lowered rates of OS and RFS.	('SD in UC', 'Var', (24, 32))	('RFS', 'Chemical', '-', (141, 144))	('lowered', 'NegReg', (117, 124))	('OS', 'Chemical', '-', (134, 136))	('SD', 'Chemical', '-', (24, 26))
55520	33191847	Further analysis documented that high expression of MMP-28 was associated with decreased overall survival in bladder cancer patients.	('MMP', 'molecular_function', 'GO:0004235', ('52', '55'))	('high', 'Var', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('decreased', 'NegReg', (79, 88))	('bladder cancer', 'Disease', 'MESH:D001749', (109, 123))	('bladder cancer', 'Disease', (109, 123))	('MMP-28', 'Gene', (52, 58))	('overall survival', 'MPA', (89, 105))	('men', 'Species', '9606', (21, 24))	('patients', 'Species', '9606', (124, 132))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))
55521	33191847	The abnormal expression of MMP-28 may be related to the initiation and development of urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (86, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('MMP', 'molecular_function', 'GO:0004235', ('27', '30'))	('MMP-28', 'Gene', (27, 33))	('related', 'Reg', (41, 48))	('men', 'Species', '9606', (78, 81))	('urothelial carcinoma', 'Disease', (86, 106))
55562	33191847	Spearman correlation coefficients of MMP-28 expression and the characteristics of bladder cancer were 0.143 for tumor size, 0.152 for the number of tumors, 0.133 for infiltration depth, 0.204 for lymph node metastasis, 0.162 for tumor histological grade, and 0.173 for distant metastasis (P < 0.05 in all cases).	('0.204', 'Var', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))	('bladder cancer', 'Disease', (82, 96))	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('MMP-28', 'Gene', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('0.173', 'Var', (259, 264))	('lymph node metastasis', 'CPA', (196, 217))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', (112, 117))	('distant metastasis', 'CPA', (269, 287))	('0.133', 'Var', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('0.152', 'Var', (124, 129))	('MMP', 'molecular_function', 'GO:0004235', ('37', '40'))	('tumor', 'Disease', (229, 234))	('tumors', 'Disease', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (148, 153))	('0.162', 'Var', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
55563	33191847	Patients with high MMP-28 expression had a significantly lower mean survival time (35.65 +- 1.47 months) than those with a low MMP28 level (56.36 +- 1.25 months, P < 0.001).	('MMP-28', 'Gene', (19, 25))	('MMP', 'molecular_function', 'GO:0004235', ('127', '130'))	('MMP', 'molecular_function', 'GO:0004235', ('19', '22'))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (57, 62))
55575	33191847	The findings of the current investigation have shown that MMP-28 is an independent predictor of prognosis, and its overexpression in tumor tissues is closely related to the poor outcome in bladder cancer patients.	('patients', 'Species', '9606', (204, 212))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('bladder cancer', 'Phenotype', 'HP:0009725', (189, 203))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('related', 'Reg', (158, 165))	('MMP-28', 'Var', (58, 64))	('tumor', 'Disease', (133, 138))	('bladder cancer', 'Disease', 'MESH:D001749', (189, 203))	('bladder cancer', 'Disease', (189, 203))	('MMP', 'molecular_function', 'GO:0004235', ('58', '61'))	('overexpression', 'PosReg', (115, 129))
55628	29685957	With respect to short-term outcomes after surgery, low preoperative serum albumin level was significantly related to a lower 90dM after surgery (random-effects model; OR = 4.24, 95% CI: 2.20-8.16, P<0.0001; I2 = 78%, P=0.0003) (Figure 3A), and a lower rate of 30dCs after surgery (random-effects model; OR = 1.93, 95% CI: 1.16-3.20, P=0.01; I2 = 97%, PP<0.00001) (Figure 3B).	('serum albumin', 'Gene', (68, 81))	('serum albumin', 'Gene', '213', (68, 81))	('lower', 'NegReg', (119, 124))	('90dM after surgery', 'MPA', (125, 143))	('low', 'Var', (51, 54))	('lower', 'NegReg', (246, 251))
55630	29685957	Next, we performed the meta-regression analysis to further explore the potential sources of heterogeneity based on five covariates, including tumor type (UTUC compared with BC), ethnicity (Asian compared with non-Asian), analysis type (univariate compared with multivariate), cut-off value (3.5 g/dl compared with others), and sample size (>600 compared with <=600).	('3.5', 'Var', (291, 294))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('BC', 'Phenotype', 'HP:0009725', (173, 175))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
55635	29685957	Our results demonstrated that low levels of preoperative serum albumin are significantly associated with worse OS, CSS, RFS, complications, and early mortality.	('low levels', 'Var', (30, 40))	('CSS', 'Disease', (115, 118))	('CSS', 'Chemical', '-', (115, 118))	('RFS', 'Disease', (120, 123))	('OS', 'Chemical', '-', (111, 113))	('worse OS', 'Disease', (105, 113))	('serum albumin', 'Gene', '213', (57, 70))	('serum albumin', 'Gene', (57, 70))	('complications', 'Disease', (125, 138))
55685	29486777	Then, we identified and compared regulatory variants associated with the three subtypes of lung cancer, as well as their target genes.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('subtypes of lung cancer', 'Disease', 'MESH:D008175', (79, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('subtypes of lung cancer', 'Disease', (79, 102))	('variants', 'Var', (44, 52))
55701	29486777	investigated how genetic variation affects gene expression levels in human lung tissues.	('gene expression', 'biological_process', 'GO:0010467', ('43', '58'))	('genetic variation', 'Var', (17, 34))	('gene expression levels', 'MPA', (43, 65))	('human', 'Species', '9606', (69, 74))	('affects', 'Reg', (35, 42))
55719	29486777	This one SNP was rs578776, on chromosome 15 in the 3' untranslated region of CHRNA3, in the chr.15q25 locus known to be associated with different histology subtypes of lung cancer.	('associated', 'Reg', (120, 130))	('rs578776', 'Var', (17, 25))	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))	('CHRNA3', 'Gene', (77, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('subtypes of lung cancer', 'Disease', 'MESH:D008175', (156, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('subtypes of lung cancer', 'Disease', (156, 179))	('CHRNA3', 'Gene', '1136', (77, 83))	('rs578776', 'Mutation', 'rs578776', (17, 25))
55721	29486777	After we removed duplicated SNPs within each subtype, we found 8295 SNPs associated with LUAD, 8734 with LUSC, and 8361 with SCLC, among which 167 SNPs overlapped between all three subtypes (Additional file 1: Figure S2B).	('LUAD', 'Disease', (89, 93))	('SNPs', 'Var', (68, 72))	('SCLC', 'Gene', (125, 129))	('SCLC', 'Gene', '7864', (125, 129))	('SCLC', 'Phenotype', 'HP:0030357', (125, 129))	('associated', 'Reg', (73, 83))	('LUSC', 'Phenotype', 'HP:0030359', (105, 109))	('LUSC', 'Disease', (105, 109))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))
55755	29486777	It is also possible that somatic mutations can act in concert with expression-altering SNPs in driving the tumor and would not have the same effect on growth advantage in the absence of the SNP.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('driving', 'CPA', (95, 102))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
55756	29486777	Additionally, a specific understanding of the regulatory roles that common genetic variants play in the development of lung cancer subtypes is an important research question because the majority of common variants that increase cancer risk are located within non-coding regions and most likely act as regulators of gene expression.	('lung cancer', 'Disease', (119, 130))	('increase cancer', 'Disease', (219, 234))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('men', 'Species', '9606', (111, 114))	('gene expression', 'biological_process', 'GO:0010467', ('315', '330'))	('increase cancer', 'Disease', 'MESH:D009369', (219, 234))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('variants', 'Var', (205, 213))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))
55759	29486777	We used marginally significant GWAS results (p < 1 x 10- 3) to search for regulatory roles for common variants associated with LUAD, LUSC, and SCLC.	('variants', 'Var', (102, 110))	('SCLC', 'Gene', '7864', (143, 147))	('LUSC', 'Disease', (133, 137))	('SCLC', 'Gene', (143, 147))	('LUSC', 'Phenotype', 'HP:0030359', (133, 137))	('LUAD', 'Disease', (127, 131))	('LUAD', 'Phenotype', 'HP:0030078', (127, 131))	('SCLC', 'Phenotype', 'HP:0030357', (143, 147))
55784	29486777	In summary, we used common genetic variants found in three lung cancer subtypes to interrogate the similarity between them at four biological levels (SNP, gene, regulatory, and pathway levels).	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('variants', 'Var', (35, 43))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
55788	29486777	eQTL Expression quantitative trait loci FANTOM Functional Annotation of the Mammalian Genome GTEx Genotype-Tissue Expression project GWAS Genome-wide association study IM-PET Integrated Methods for Predicting Enhancer Targets KEGG Kyoto Encyclopedia of Genes and Genomes LD Linkage disequilibrium LUAD Lung adenocarcinoma LUSC Lung squamous cell carcinoma NCBI National Center for Biotechnology Information NSCLC Non-small cell lung cancer PCA Principal component analysis SCLC Small cell lung cancer SNP Single-nucleotide polymorphism TCGA The Cancer Genome Atlas TDO, PJ, and ZZ contributed to the conception and design of the study.	('squamous cell carcinoma', 'Disease', (332, 355))	('Small cell lung cancer', 'Disease', (478, 500))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (417, 439))	('NSCLC', 'Phenotype', 'HP:0030358', (407, 412))	('SCLC', 'Phenotype', 'HP:0030357', (473, 477))	('cancer', 'Phenotype', 'HP:0002664', (494, 500))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (413, 439))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (545, 564))	('SCLC', 'Gene', (473, 477))	('Small cell lung cancer', 'Disease', 'MESH:D055752', (478, 500))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (332, 355))	('SCLC', 'Gene', '7864', (473, 477))	('adenocarcinoma', 'Disease', (307, 321))	('Cancer Genome Atlas', 'Disease', (545, 564))	('GTEx', 'Chemical', '-', (93, 97))	('Non-small cell lung cancer', 'Disease', (413, 439))	('SCLC', 'Phenotype', 'HP:0030357', (408, 412))	('LUSC', 'Phenotype', 'HP:0030359', (322, 326))	('carcinoma', 'Phenotype', 'HP:0030731', (346, 355))	('NSCLC', 'Disease', 'MESH:D002289', (407, 412))	('SCLC', 'Gene', (408, 412))	('adenocarcinoma', 'Disease', 'MESH:D000230', (307, 321))	('lung cancer', 'Phenotype', 'HP:0100526', (428, 439))	('TDO', 'Gene', (565, 568))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (332, 355))	('SCLC', 'Gene', '7864', (408, 412))	('Single-nucleotide polymorphism', 'Var', (505, 535))	('TDO', 'Gene', '6999', (565, 568))	('Small cell lung cancer', 'Phenotype', 'HP:0030357', (478, 500))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (413, 439))	('cancer', 'Phenotype', 'HP:0002664', (433, 439))	('Cancer', 'Phenotype', 'HP:0002664', (545, 551))	('TDO', 'molecular_function', 'GO:0004833', ('565', '568'))	('Mammalian', 'Species', '9606', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('LUAD', 'Phenotype', 'HP:0030078', (297, 301))	('NSCLC', 'Disease', (407, 412))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (302, 321))	('lung cancer', 'Phenotype', 'HP:0100526', (489, 500))
55824	25971253	The Cancer Gene Census (CGC) (version download 10-01-2014) [http://www.sanger.ac.uk/genetics/CGP/Census/] provides information about genes with somatic mutations that are associated to different types of cancer.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('mutations', 'Var', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('associated', 'Reg', (171, 181))
55848	25971253	The studies of showed that the methylation patterns of PCDH10 and PCDH8 were significantly associated with stage, grade, recurrence and tumor size.	('PCDH10', 'Gene', (55, 61))	('stage', 'CPA', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('grade', 'CPA', (114, 119))	('recurrence', 'CPA', (121, 131))	('PCDH8', 'Gene', '5100', (66, 71))	('PCDH10', 'Gene', '57575', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('methylation patterns', 'Var', (31, 51))	('PCDH8', 'Gene', (66, 71))	('associated', 'Reg', (91, 101))
55873	25971253	On the genomic level, the GRNs were investigated for genomic UC targets, where we identified genomic regions with known diagnostic and prognostic properties for urothelial cancer such as 1q23.3 (Oligo GRN), 8q24.3 (Bead GRN) and 5q31.3 (RNAseq GRN).	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('1q23.3', 'Var', (187, 193))	('urothelial cancer', 'Disease', (161, 178))	('urothelial cancer', 'Disease', 'MESH:D014523', (161, 178))
55887	33652650	We found that the expression levels of the androgen receptor and a molecule (BXDC2) were inversely correlated and that loss of BXDC2 was associated with cisplatin resistance.	('BXDC2', 'Gene', (127, 132))	('associated', 'Reg', (137, 147))	('androgen receptor', 'Gene', '367', (43, 60))	('expression levels', 'MPA', (18, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('androgen receptor', 'Gene', (43, 60))	('BXDC2', 'Gene', '55299', (77, 82))	('cisplatin resistance', 'MPA', (153, 173))	('BXDC2', 'Gene', (77, 82))	('loss', 'Var', (119, 123))	('BXDC2', 'Gene', '55299', (127, 132))
55898	33652650	Additionally, in those undergoing cisplatin-based chemotherapy, BXDC2 positivity alone (p = 0.083) or together with AR negativity (p = 0.047) was associated with favorable response.	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('positivity', 'Var', (70, 80))	('AR', 'Gene', '367', (116, 118))	('BXDC2', 'Gene', '55299', (64, 69))	('BXDC2', 'Gene', (64, 69))	('favorable response', 'CPA', (162, 180))
55924	33652650	Similarly, no significant effect of DHT and a considerable stimulatory effect of HF on BXDC2 expression were seen in 5637 and 5637-AR, respectively (Figure 1D).	('BXDC2', 'Gene', '55299', (87, 92))	('AR', 'Gene', '367', (131, 133))	('BXDC2', 'Gene', (87, 92))	('5637', 'Var', (117, 121))	('DHT', 'Chemical', 'MESH:D013196', (36, 39))	('stimulatory', 'PosReg', (59, 70))	('HF', 'Chemical', 'MESH:C014290', (81, 83))
55928	33652650	To compare the cytotoxic effects of CDDP in BXDC2-positive versus BXDC2-negative cells, we silenced BXDC2.	('BXDC2', 'Gene', '55299', (66, 71))	('BXDC2', 'Gene', '55299', (100, 105))	('BXDC2', 'Gene', (66, 71))	('BXDC2', 'Gene', (100, 105))	('CDDP', 'Chemical', '-', (36, 40))	('silenced', 'Var', (91, 99))	('BXDC2', 'Gene', '55299', (44, 49))	('BXDC2', 'Gene', (44, 49))
55989	33652650	We obtained anti-AR (N-20), anti-BXDC2 (C-1), and anti-GAPDH (6c5) antibodies, and anti-p-ATF2 (Thr71), anti-p-p44/42 MAPK (ERK) (Thr202/Tyr204), anti-PTEN (D4.3), and anti-cleaved caspase-3 (Asp175) antibodies from Santa Cruz Biotechnology and Cell Signaling Technology, respectively.	('ERK', 'Gene', (124, 127))	('Asp175', 'Chemical', '-', (192, 198))	('anti-p-p44/42', 'Var', (104, 117))	('caspase-3', 'Gene', '836', (181, 190))	('ATF2', 'Gene', (90, 94))	('BXDC2', 'Gene', '55299', (33, 38))	('ATF2', 'Gene', '1386', (90, 94))	('BXDC2', 'Gene', (33, 38))	('AR', 'Gene', '367', (17, 19))	('caspase-3', 'Gene', (181, 190))	('Thr71', 'Chemical', '-', (96, 101))	('Thr202', 'Chemical', '-', (130, 136))	('MAPK', 'molecular_function', 'GO:0004707', ('118', '122'))	('Signaling', 'biological_process', 'GO:0023052', ('250', '259'))	('ERK', 'Gene', '5594', (124, 127))	('PTEN', 'Gene', (151, 155))	('Tyr204', 'Chemical', '-', (137, 143))	('ERK', 'molecular_function', 'GO:0004707', ('124', '127'))	('PTEN', 'Gene', '5728', (151, 155))
56005	33652650	We identified BXDC2 as a key downstream effector of AR in modulating CDDP sensitivity in bladder cancer.	('BXDC2', 'Gene', (14, 19))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('AR', 'Gene', '367', (52, 54))	('modulating', 'Var', (58, 68))	('CDDP', 'Chemical', '-', (69, 73))	('BXDC2', 'Gene', '55299', (14, 19))
56020	23714499	In addition, there are already many well-established mutations and genetic alterations in urothelial carcinoma that likely contribute in an important way to tumor development.	('tumor', 'Disease', (157, 162))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (90, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('genetic alterations', 'Var', (67, 86))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('contribute', 'Reg', (123, 133))	('mutations', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('urothelial carcinoma', 'Disease', (90, 110))
56021	23714499	In addition, urothelial cancer genome-wide association studies have identified common variants associated with urothelial cancer risk and protein expression that can potentially be therapeutically targeted.	('urothelial cancer', 'Disease', 'MESH:D014523', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('urothelial cancer', 'Disease', (13, 30))	('variants', 'Var', (86, 94))	('protein expression', 'MPA', (138, 156))	('urothelial cancer', 'Disease', (111, 128))	('urothelial cancer', 'Disease', 'MESH:D014523', (13, 30))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('associated', 'Reg', (95, 105))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))
56027	23714499	The discovery of vemurafenib for melanoma tumors that harbor the B-Raf V600E mutations and the inhibition of ABL and c-Kit by imatinib for CML and GIST, respectively, have significantly changed clinical practice.	('CML', 'Disease', (139, 142))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('ABL', 'Gene', '25', (109, 112))	('c-Kit', 'Gene', (117, 122))	('B-Raf', 'Gene', (65, 70))	('V600E', 'Var', (71, 76))	('melanoma tumors', 'Disease', 'MESH:D008545', (33, 48))	('GIST', 'Disease', (147, 151))	('GIST', 'Phenotype', 'HP:0100723', (147, 151))	('changed', 'Reg', (186, 193))	('melanoma tumors', 'Disease', (33, 48))	('ABL', 'Gene', (109, 112))	('V600E', 'Mutation', 'p.V600E', (71, 76))	('CML', 'Phenotype', 'HP:0005506', (139, 142))	('GIST', 'Disease', 'MESH:D046152', (147, 151))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('B-Raf', 'Gene', '673', (65, 70))	('imatinib', 'Chemical', 'MESH:C097613', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('c-Kit', 'Gene', '3815', (117, 122))	('vemurafenib', 'Chemical', 'MESH:C551177', (17, 28))	('CML', 'Disease', 'MESH:D015464', (139, 142))
56040	23714499	Mutations were frequently (13% to 21%) identified in multiple genes involved in chromatin remodeling, including histone demethylases (UTX), histone acetyltransferases (CREBBP, EP300), a SWI/SNF-related gene (ARID1A); and less commonly in histone methyltransferases (MLL, MLL3) and others.	('MLL', 'Gene', '4297', (266, 269))	('UTX', 'Gene', '7403', (134, 137))	('CREBBP', 'Gene', '1387', (168, 174))	('chromatin', 'cellular_component', 'GO:0000785', ('80', '89'))	('MLL', 'Gene', (271, 274))	('MLL', 'Gene', '4297', (271, 274))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('80', '100'))	('EP300', 'Gene', '2033', (176, 181))	('MLL3', 'Gene', (271, 275))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (39, 49))	('CREBBP', 'Gene', (168, 174))	('EP300', 'Gene', (176, 181))	('ARID1A', 'Gene', (208, 214))	('MLL3', 'Gene', '58508', (271, 275))	('ARID1A', 'Gene', '8289', (208, 214))	('UTX', 'Gene', (134, 137))	('MLL', 'Gene', (266, 269))
56041	23714499	For all of these genes, most of the mutations identified were clearly inactivating, suggesting that it was the genes' loss of function that was important in urothelial carcinoma development.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('urothelial carcinoma', 'Disease', (157, 177))	('mutations', 'Var', (36, 45))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (157, 177))
56042	23714499	The report by Gui et al and the TCGA findings indicate that mutations in chromatin regulator genes are very common, perhaps nearly universal in urothelial carcinoma, and seen at a higher rate than perhaps any other common adult malignancy.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (144, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('malignancy', 'Disease', 'MESH:D009369', (228, 238))	('chromatin regulator genes', 'Gene', (73, 98))	('mutations', 'Var', (60, 69))	('urothelial carcinoma', 'Disease', (144, 164))	('malignancy', 'Disease', (228, 238))	('chromatin', 'cellular_component', 'GO:0000785', ('73', '82'))
56043	23714499	Hence, these alterations are very likely to contribute in an important way to urothelial carcinoma development by altering gene expression in a global manner.	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('gene expression', 'MPA', (123, 138))	('contribute', 'Reg', (44, 54))	('urothelial carcinoma', 'Disease', (78, 98))	('altering', 'Reg', (114, 122))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (78, 98))	('alterations', 'Var', (13, 24))	('gene expression', 'biological_process', 'GO:0010467', ('123', '138'))
56044	23714499	PIK3CA, TSC1, and most recently TSC2 (the latter two genes are the cause of the human tumor suppressor gene syndrome tuberous sclerosis complex [TSC]) are recognized to be mutated in a collective 20% to 30% of urothelial carcinoma (COSMIC [www.sanger.ac.uk/genetics/CGP/cosmic/] and TCGA data).	('TSC1', 'Gene', '7248', (8, 12))	('tuberous sclerosis', 'Disease', (117, 135))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('117', '143'))	('mutated', 'Var', (172, 179))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('86', '102'))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('TSC', 'Gene', (145, 148))	('human', 'Species', '9606', (80, 85))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumor suppressor', 'biological_process', 'GO:0051726', ('86', '102'))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (210, 230))	('TSC', 'Gene', '7248;7249', (145, 148))	('TSC2', 'Gene', '7249', (32, 36))	('TSC', 'Gene', (8, 11))	('urothelial carcinoma', 'Disease', (210, 230))	('TSC', 'Gene', (32, 35))	('TSC1', 'Gene', (8, 12))	('tumor', 'Disease', (86, 91))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (117, 135))	('PIK3CA', 'Gene', (0, 6))	('TSC', 'Gene', '7248;7249', (8, 11))	('TSC2', 'Gene', (32, 36))	('TSC', 'Gene', '7248;7249', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
56045	23714499	These mutations have common effects in activating mTOR, a master kinase that regulates cell growth through enhancement of protein synthesis and other effects.	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('cell growth', 'biological_process', 'GO:0016049', ('87', '98'))	('enhancement', 'PosReg', (107, 118))	('mTOR', 'Gene', (50, 54))	('mTOR', 'Gene', '2475', (50, 54))	('protein synthesis', 'MPA', (122, 139))	('protein synthesis', 'biological_process', 'GO:0006412', ('122', '139'))	('activating', 'MPA', (39, 49))	('mutations', 'Var', (6, 15))
56046	23714499	Hence, patients with urothelial carcinoma with mutations in these genes are potential candidates for therapy targeting mTOR (for TSC1, TSC2 mutations) or more directly PIK3CA for mutations in that gene.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (21, 41))	('TSC1', 'Gene', '7248', (129, 133))	('TSC1', 'Gene', (129, 133))	('PIK3CA', 'Gene', (168, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('mutations', 'Var', (47, 56))	('PIK3CA', 'Gene', '5290', (168, 174))	('TSC2', 'Gene', '7249', (135, 139))	('TSC2', 'Gene', (135, 139))	('mTOR', 'Gene', (119, 123))	('mutations', 'Var', (140, 149))	('mutations', 'Var', (179, 188))	('urothelial carcinoma', 'Disease', (21, 41))	('patients', 'Species', '9606', (7, 15))	('mTOR', 'Gene', '2475', (119, 123))
56048	23714499	Notably, PIK3CA mutations in urothelial carcinoma are primarily in the central PIK domain, not H1047R, and effectiveness of these agents for that category of mutation will require further evaluation.	('urothelial carcinoma', 'Disease', (29, 49))	('mutations', 'Var', (16, 25))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (29, 49))	('H1047R', 'Mutation', 'p.H1047R', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('PIK3CA', 'Gene', (9, 15))	('PIK3CA', 'Gene', '5290', (9, 15))
56050	23714499	This patient's cancer was found to have mutations in both TSC1 and NF2, as well as other genes.	('patient', 'Species', '9606', (5, 12))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('NF2', 'Gene', '4771', (67, 70))	('NF2', 'Gene', (67, 70))	('mutations', 'Var', (40, 49))	('TSC1', 'Gene', '7248', (58, 62))	('TSC1', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
56051	23714499	At least four other patients on this clinical trial also had TSC1 mutations and transient minor responses to everolimus.	('mutations', 'Var', (66, 75))	('responses to everolimus', 'MPA', (96, 119))	('TSC1', 'Gene', '7248', (61, 65))	('everolimus', 'Chemical', 'MESH:C107135', (109, 119))	('TSC1', 'Gene', (61, 65))	('patients', 'Species', '9606', (20, 28))
56052	23714499	Everolimus has been shown to be effective for the treatment of several tumors that develop in TSC and for PEComas:a type of sarcoma in which TSC1/TSC2 gene mutations are common.	('TSC1', 'Gene', (141, 145))	('TSC', 'Gene', '7248;7249', (141, 144))	('TSC', 'Gene', '7248;7249', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('TSC1', 'Gene', '7248', (141, 145))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('sarcoma', 'Disease', (124, 131))	('TSC2', 'Gene', '7249', (146, 150))	('PEComas', 'Disease', 'MESH:D054973', (106, 113))	('Everolimus', 'Chemical', 'MESH:C107135', (0, 10))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('TSC', 'Gene', (146, 149))	('PEComas', 'Disease', (106, 113))	('mutations', 'Var', (156, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('TSC2', 'Gene', (146, 150))	('TSC', 'Gene', '7248;7249', (146, 149))	('TSC', 'Gene', (141, 144))	('TSC', 'Gene', (94, 97))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
56054	23714499	Hence, collectively these observations suggest that the TSC1 mutation was an important factor in the complete response to everolimus by the patient with urothelial carcinoma.	('TSC1', 'Gene', (56, 60))	('urothelial carcinoma', 'Disease', (153, 173))	('everolimus', 'Chemical', 'MESH:C107135', (122, 132))	('mutation', 'Var', (61, 69))	('patient', 'Species', '9606', (140, 147))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (153, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('TSC1', 'Gene', '7248', (56, 60))
56056	23714499	We have recently used multiplex inversion probe analysis to perform a genome-wide screen for copy number alterations in urothelial cancer.	('urothelial cancer', 'Disease', (120, 137))	('urothelial cancer', 'Disease', 'MESH:D014523', (120, 137))	('copy number alterations', 'Var', (93, 116))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))
56060	23714499	Furthermore, amplification of the E2F3/SOX4 region alone was also seen more commonly in the Ta grade 3 and T2 grade 2 cancers (11 of 61) than in Ta grade 1 or 1 to 2 cancers (0 of 23, p = 0.03).	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('E2F3', 'Gene', '1871', (34, 38))	('Ta', 'Chemical', 'MESH:D013635', (145, 147))	('SOX4', 'Gene', (39, 43))	('SOX4', 'Gene', '6659', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('amplification', 'Var', (13, 26))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Ta', 'Chemical', 'MESH:D013635', (92, 94))	('E2F3', 'Gene', (34, 38))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
56063	23714499	Urothelial cancer genome-wide association studies have identified common variants associated with urothelial cancer risk.	('Urothelial cancer', 'Disease', (0, 17))	('urothelial cancer', 'Disease', (98, 115))	('associated', 'Reg', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('variants', 'Var', (73, 81))	('urothelial cancer', 'Disease', 'MESH:D014523', (98, 115))	('Urothelial cancer', 'Disease', 'MESH:D014523', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
56064	23714499	A missense variant rs2294008 in the prostate stem cell antigen (PSCA) gene showed consistent association with urothelial cancer.	('association', 'Reg', (93, 104))	('urothelial cancer', 'Disease', 'MESH:D014523', (110, 127))	('PSCA', 'Gene', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('PSCA', 'Gene', '8000', (64, 68))	('rs2294008', 'Var', (19, 28))	('urothelial cancer', 'Disease', (110, 127))	('rs2294008', 'Mutation', 'rs2294008', (19, 28))
56065	23714499	Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense single nucleotide polymorphism in PSCA, identifying rs2294008 as a new urothelial cancer susceptibility locus.	('PSCA', 'Gene', '8000', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('urothelial cancer', 'Disease', (161, 178))	('rs2294008', 'Var', (52, 61))	('PSCA', 'Gene', '8000', (124, 128))	('rs2294008', 'Var', (142, 151))	('PSCA', 'Gene', (20, 24))	('urothelial cancer', 'Disease', 'MESH:D014523', (161, 178))	('rs2294008', 'Mutation', 'rs2294008', (52, 61))	('PSCA', 'Gene', (124, 128))	('rs2294008', 'Mutation', 'rs2294008', (142, 151))
56066	23714499	We have found that the genetic variant rs2294008 is a strong predictor of PSCA protein expression in both non-muscle-invasive and muscle-invasive urothelial tumors.	('PSCA', 'Gene', (74, 78))	('predictor', 'Reg', (61, 70))	('muscle-invasive urothelial tumors', 'Disease', 'MESH:D019042', (130, 163))	('rs2294008', 'Mutation', 'rs2294008', (39, 48))	('non-muscle-invasive', 'Disease', (106, 125))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('expression', 'MPA', (87, 97))	('muscle-invasive urothelial tumors', 'Disease', (130, 163))	('PSCA', 'Gene', '8000', (74, 78))	('rs2294008', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
56070	23714499	HGF dysregulation is associated with tumor growth, metastasis, and invasion.	('metastasis', 'CPA', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('HGF', 'Gene', (0, 3))	('invasion', 'CPA', (67, 75))	('dysregulation', 'Var', (4, 17))	('associated', 'Reg', (21, 31))	('HGF', 'Gene', '3082', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))
56071	23714499	Oncogenesis, tumor angiogenesis, and metastasis are driven by dysfunctional pathway activation through MET gene amplification, overexpression, mutation, or autocrine loop formation in many tumors, including urothelial cancer.	('tumor', 'Disease', (13, 18))	('Oncogenesis', 'biological_process', 'GO:0007048', ('0', '11'))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('Oncogenesis', 'CPA', (0, 11))	('metastasis', 'CPA', (37, 47))	('MET', 'Gene', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('urothelial cancer', 'Disease', 'MESH:D014523', (207, 224))	('angiogenesis', 'biological_process', 'GO:0001525', ('19', '31'))	('mutation', 'Var', (143, 151))	('tumors', 'Disease', (189, 195))	('urothelial cancer', 'Disease', (207, 224))	('tumor', 'Disease', (189, 194))	('formation', 'biological_process', 'GO:0009058', ('171', '180'))	('activation', 'PosReg', (84, 94))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('overexpression', 'PosReg', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('dysfunctional', 'Pathway', (62, 75))
56072	23714499	MET expression has been associated with a worse prognosis in many tumors and may be associated with more aggressive urothelial tumors.	('MET expression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('aggressive urothelial tumors', 'Disease', (105, 133))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('aggressive urothelial tumors', 'Disease', 'MESH:D001523', (105, 133))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('associated', 'Reg', (84, 94))
56081	23714499	Inhibition of MET can amplify the effects of VEGFR blockade and leads to rapid, robust, and progressive regression of tumor vasculature, increased intratumoral hypoxia and apoptosis, and reduced tumor invasiveness and metastasis in vivo.	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor invasiveness', 'Disease', 'MESH:D009361', (195, 213))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('regression', 'NegReg', (104, 114))	('hypoxia', 'Disease', (160, 167))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (152, 157))	('VEGFR', 'Gene', '3791', (45, 50))	('increased', 'PosReg', (137, 146))	('apoptosis', 'biological_process', 'GO:0097194', ('172', '181'))	('apoptosis', 'CPA', (172, 181))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('apoptosis', 'biological_process', 'GO:0006915', ('172', '181'))	('VEGFR', 'Gene', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('hypoxia', 'Disease', 'MESH:D000860', (160, 167))	('MET', 'Gene', (14, 17))	('tumor invasiveness', 'Disease', (195, 213))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('reduced', 'NegReg', (187, 194))	('tumor', 'Disease', (118, 123))
56091	23714499	Furthermore, it appears clear from the existing genomic datasets that the diversity of mutations seen in urothelial carcinoma will require personalized targeted therapy:similar to lung adenocarcinoma, in which multiple different agents are used for different mutation subsets.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (180, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('urothelial carcinoma', 'Disease', (105, 125))	('lung adenocarcinoma', 'Disease', (180, 199))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (105, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('mutations', 'Var', (87, 96))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (180, 199))
56100	29312470	JQ1 alone induced cell cycle arrest, but only limited apoptosis in eight UC cell lines with strongly varying IC50 values between 0.18 and 10 muM.	('arrest', 'Disease', 'MESH:D006323', (29, 35))	('muM', 'Gene', '56925', (141, 144))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('JQ1', 'Var', (0, 3))	('muM', 'Gene', (141, 144))	('arrest', 'Disease', (29, 35))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('18', '35'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (18, 35))
56102	29312470	In UC cells, anti-apoptotic and oncogenic factors Survivin, BCL-2, BCL-XL, c-MYC, EZH2 and SKP2 were consistently downregulated by the drug combination and AKT phosphorylation was diminished.	('EZH2', 'Gene', (82, 86))	('EZH2', 'Gene', '2146', (82, 86))	('BCL-2', 'Gene', (60, 65))	('c-MYC', 'Gene', '4609', (75, 80))	('BCL-XL', 'Gene', '598', (67, 73))	('c-MYC', 'Gene', (75, 80))	('downregulated', 'NegReg', (114, 127))	('AKT', 'Gene', (156, 159))	('BCL-2', 'molecular_function', 'GO:0015283', ('60', '65'))	('phosphorylation', 'biological_process', 'GO:0016310', ('160', '175'))	('SKP2', 'Gene', (91, 95))	('SKP2', 'Gene', '6502', (91, 95))	('BCL-XL', 'Gene', (67, 73))	('diminished', 'NegReg', (180, 190))	('Survivin', 'Gene', (50, 58))	('AKT', 'Gene', '207', (156, 159))	('anti-apoptotic', 'CPA', (13, 27))	('drug combination', 'Var', (135, 151))	('BCL-2', 'Gene', '596', (60, 65))
56107	29312470	Intriguingly, among all cancer types, urothelial carcinoma appears to have the highest prevalence of mutations in chromatin regulator proteins, including various components of the trithorax-like histone-modifying and SWI/SNF1 chromatin remodeling protein complexes.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('protein', 'cellular_component', 'GO:0003675', ('247', '254'))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (101, 110))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('226', '246'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (38, 58))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('chromatin', 'cellular_component', 'GO:0000785', ('114', '123'))	('chromatin', 'cellular_component', 'GO:0000785', ('226', '235'))	('chromatin regulator proteins', 'Protein', (114, 142))	('urothelial carcinoma', 'Disease', (38, 58))
56108	29312470	It is therefore reasonable to assume that epigenetic inhibitors represent an alternative approach to chemotherapy of urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (117, 137))	('urothelial carcinoma', 'Disease', (117, 137))	('epigenetic inhibitors', 'Var', (42, 63))
56116	29312470	Inhibition of BRD4 in particular disrupts super enhancers and represses the oncogenes c-MYC and EZH2.	('disrupts', 'NegReg', (33, 41))	('super enhancers', 'MPA', (42, 57))	('represses', 'NegReg', (62, 71))	('c-MYC', 'Gene', (86, 91))	('EZH2', 'Gene', '2146', (96, 100))	('EZH2', 'Gene', (96, 100))	('BRD4', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('c-MYC', 'Gene', '4609', (86, 91))
56119	29312470	In the present study, we therefore investigated whether JQ1 exerts antineoplastic effects on a broader range of UC cell lines which cover the heterogeneity of urothelial carcinoma more comprehensively.	('JQ1', 'Var', (56, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('antineoplastic effects', 'MPA', (67, 89))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (159, 179))	('urothelial carcinoma', 'Disease', (159, 179))
56120	29312470	The combination of JQ1 with Romidepsin however displayed strong synergies in tumor cell growth suppression and apoptosis induction across all cell lines; concomitantly, histone acetylation was broadly enhanced.	('histone acetylation', 'MPA', (169, 188))	('cell growth', 'biological_process', 'GO:0016049', ('83', '94'))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('JQ1', 'Var', (19, 22))	('enhanced', 'PosReg', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('apoptosis induction', 'CPA', (111, 130))	('combination', 'Interaction', (4, 15))	('tumor', 'Disease', (77, 82))	('histone acetylation', 'biological_process', 'GO:0016573', ('169', '188'))
56135	29312470	Viability of cells after siRNA-mediated BRD4 knockdown or treatment with Q-VD-Oph was measured via total cellular ATP using CellTiter-Glo Assay (Promega, Mannheim, Germany).	('Oph', 'molecular_function', 'GO:0004063', ('78', '81'))	('BRD4', 'Gene', (40, 44))	('Q-VD-Oph', 'Chemical', 'MESH:C468548', (73, 81))	('ATP', 'Chemical', 'MESH:D000255', (114, 117))	('knockdown', 'Var', (45, 54))
56139	29312470	To assess apoptotic cell death and necrosis, cells were incubated with Annexin V-FITC (31490013, Immunotools, Friesoythe, Germany), Annexin V binding buffer, and propidium iodide at 2 mug/ml.	('propidium iodide', 'Chemical', 'MESH:D011419', (162, 178))	('necrosis', 'Disease', (35, 43))	('mug', 'molecular_function', 'GO:0043739', ('184', '187'))	('necrosis', 'biological_process', 'GO:0070265', ('35', '43'))	('necrosis', 'biological_process', 'GO:0008220', ('35', '43'))	('binding', 'molecular_function', 'GO:0005488', ('142', '149'))	('necrosis', 'biological_process', 'GO:0001906', ('35', '43'))	('necrosis', 'biological_process', 'GO:0019835', ('35', '43'))	('necrosis', 'Disease', 'MESH:D009336', (35, 43))	('Annexin V', 'Gene', '308', (132, 141))	('necrosis', 'biological_process', 'GO:0008219', ('35', '43'))	('31490013', 'Var', (87, 95))	('Annexin V', 'Gene', (71, 80))	('Annexin V', 'Gene', '308', (71, 80))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('10', '30'))	('Annexin V', 'Gene', (132, 141))
56149	29312470	Cells were transfected by X-tremeGENE 9 DNA transfection reagent (Roche, Penzberg, Germany) with p57 Double Nickase Plasmid (sc-400444-NIC-2, Santa Cruz Biotechnology, Heidelberg, Germany) encoding a GFP marker, puromycin resistance, and two different sgRNAs targeting CDKN1C exon 1 and D10A mutant Cas9 (Nickase).	('CDKN1C', 'Gene', (269, 275))	('D10A', 'Var', (287, 291))	('CDKN1C', 'Gene', '1028', (269, 275))	('Cas', 'cellular_component', 'GO:0005650', ('299', '302'))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('puromycin', 'Chemical', 'MESH:D011691', (212, 221))	('Cas9', 'Gene', (299, 303))	('D10A', 'SUBSTITUTION', 'None', (287, 291))
56176	29312470	Accordingly, active pAKT was diminished in three of four cell lines by JQ1 single treatment, but particularly strongly by combined treatment (Fig.	('combined', 'Interaction', (122, 130))	('JQ1', 'Var', (71, 74))	('AKT', 'Gene', '207', (21, 24))	('AKT', 'Gene', (21, 24))	('diminished', 'NegReg', (29, 39))
56180	29312470	These findings suggest that, in addition to increased transcription of CDKN1C, stabilization of p57 contributes to its accumulation.	('accumulation', 'MPA', (119, 131))	('transcription', 'biological_process', 'GO:0006351', ('54', '67'))	('CDKN1C', 'Gene', (71, 77))	('stabilization', 'MPA', (79, 92))	('CDKN1C', 'Gene', '1028', (71, 77))	('increased', 'PosReg', (44, 53))	('transcription', 'MPA', (54, 67))	('p57', 'Var', (96, 99))
56181	29312470	Of note, reduced activity of AKT by combined treatment is likely to diminish pro-survival signaling in UCCs by other pathways as well.	('pro-survival signaling', 'MPA', (77, 99))	('combined', 'Var', (36, 44))	('pro-survival', 'biological_process', 'GO:0043066', ('77', '89'))	('AKT', 'Gene', '207', (29, 32))	('diminish', 'NegReg', (68, 76))	('reduced', 'NegReg', (9, 16))	('UCCs', 'Disease', (103, 107))	('AKT', 'Gene', (29, 32))	('signaling', 'biological_process', 'GO:0023052', ('90', '99'))	('activity', 'MPA', (17, 25))
56186	29312470	Strikingly, H3K4 trimethylation was increased at the TSS of BCL2, CDKN1C/p57, and SKP2 genes after treatment with JQ1 alone, but decreased, mostly significantly, at the TSS of genes downregulated by the combination treatment.	('JQ1', 'Var', (114, 117))	('H3K4', 'Protein', (12, 16))	('CDKN1C', 'Gene', '1028', (66, 72))	('SKP2', 'Gene', '6502', (82, 86))	('trimethylation', 'MPA', (17, 31))	('BCL2', 'molecular_function', 'GO:0015283', ('60', '64'))	('increased', 'PosReg', (36, 45))	('BCL2', 'Gene', '596', (60, 64))	('SKP2', 'Gene', (82, 86))	('decreased', 'NegReg', (129, 138))	('BCL2', 'Gene', (60, 64))	('CDKN1C', 'Gene', (66, 72))
56187	29312470	In this study, we examined the efficacy of a combination treatment with small-molecule inhibitors of chromatin regulators in urothelial carcinoma cell lines.	('urothelial carcinoma', 'Disease', (125, 145))	('chromatin', 'cellular_component', 'GO:0000785', ('101', '110'))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (125, 145))	('small-molecule', 'Var', (72, 86))
56196	29312470	shRNA mediated knockdown in the respective cells, decreased cell viability in a time-dependent manner (72 h), and induced cell cycle arrest in G0/G1 phase.	('cell viability', 'CPA', (60, 74))	('G1 phase', 'biological_process', 'GO:0051318', ('146', '154'))	('knockdown', 'Var', (15, 24))	('decreased', 'NegReg', (50, 59))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('122', '139'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (122, 139))	('arrest', 'Disease', 'MESH:D006323', (133, 139))	('induced', 'Reg', (114, 121))	('shRNA', 'Gene', (0, 5))	('arrest', 'Disease', (133, 139))
56198	29312470	Indeed, in our study, siRNA-mediated knockdown of BRD4 in both VM-Cub1 and UM-UC-3 cells resulted in a time-dependent reduction of cell viability and long-term proliferation, but the cells responded differentially with respect to cell cycle arrest.	('BRD4', 'Gene', (50, 54))	('long-term proliferation', 'CPA', (150, 173))	('cell cycle', 'CPA', (230, 240))	('arrest', 'Disease', (241, 247))	('cell viability', 'CPA', (131, 145))	('reduction', 'NegReg', (118, 127))	('knockdown', 'Var', (37, 46))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('230', '247'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (230, 247))	('arrest', 'Disease', 'MESH:D006323', (241, 247))
56209	29312470	Similar synergistic effects on proliferation and apoptosis have been reported in pancreatic cancer, neuroblastoma, and AML cells by combination treatment using JQ1 with the pan-HDAC inhibitors SAHA (vorinostat) or panobinostat and in melanoma cells by panobinostat and BET inhibitor I-BET151.	('JQ1', 'Var', (160, 163))	('HDAC', 'Gene', '9734', (177, 181))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))	('BET', 'Gene', '92737', (285, 288))	('BET', 'Gene', '92737', (269, 272))	('panobinostat', 'Chemical', 'MESH:D000077767', (252, 264))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))	('vorinostat', 'Chemical', 'MESH:D000077337', (199, 209))	('combination', 'Interaction', (132, 143))	('proliferation', 'CPA', (31, 44))	('AML', 'Disease', 'MESH:D015470', (119, 122))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('HDAC', 'Gene', (177, 181))	('AML', 'Disease', (119, 122))	('SAHA', 'Chemical', 'MESH:D000077337', (193, 197))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('melanoma', 'Disease', (234, 242))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('I-BET151', 'Chemical', 'MESH:C568713', (283, 291))	('BET', 'Gene', (285, 288))	('neuroblastoma', 'Disease', (100, 113))	('BET', 'Gene', (269, 272))	('neuroblastoma', 'Phenotype', 'HP:0003006', (100, 113))	('panobinostat', 'Chemical', 'MESH:D000077767', (214, 226))	('apoptosis', 'CPA', (49, 58))	('neuroblastoma', 'Disease', 'MESH:D009447', (100, 113))	('pancreatic cancer', 'Disease', (81, 98))
56213	29312470	Anti-apoptotic proteins like BCL-2 may be induced by activated STAT3, and in pancreatic adenocarcinoma cells, the combination of JQ1 and SAHA diminished STAT3 phosphorylation to downregulate BCL-2.	('STAT3', 'Gene', '6774', (153, 158))	('phosphorylation', 'MPA', (159, 174))	('STAT3', 'Gene', '6774', (63, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('159', '174'))	('BCL-2', 'molecular_function', 'GO:0015283', ('29', '34'))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (77, 102))	('downregulate', 'NegReg', (178, 190))	('BCL-2', 'Gene', '596', (191, 196))	('BCL-2', 'Gene', (191, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('Anti-apoptotic', 'MPA', (0, 14))	('SAHA', 'Chemical', 'MESH:D000077337', (137, 141))	('BCL-2', 'Gene', '596', (29, 34))	('diminished', 'NegReg', (142, 152))	('BCL-2', 'Gene', (29, 34))	('pancreatic adenocarcinoma', 'Disease', (77, 102))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (77, 102))	('STAT3', 'Gene', (153, 158))	('BCL-2', 'molecular_function', 'GO:0015283', ('191', '196'))	('JQ1', 'Var', (129, 132))	('STAT3', 'Gene', (63, 68))
56220	29312470	In pancreatic cancer cells, depletion of p57 by shRNA decreased apoptotic markers induced by JQ1 and SAHA combination treatment; Cas9-mediated knockout of Cdkn1c in mice significantly diminished apoptosis of combination-treated animals.	('Cdkn1c', 'Gene', (155, 161))	('apoptosis', 'biological_process', 'GO:0097194', ('195', '204'))	('Cas', 'cellular_component', 'GO:0005650', ('129', '132'))	('pancreatic cancer', 'Disease', (3, 20))	('apoptotic markers induced', 'MPA', (64, 89))	('mice', 'Species', '10090', (165, 169))	('apoptosis', 'biological_process', 'GO:0006915', ('195', '204'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('apoptosis', 'CPA', (195, 204))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('knockout', 'Var', (143, 151))	('decreased', 'NegReg', (54, 63))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('diminished', 'NegReg', (184, 194))	('SAHA', 'Chemical', 'MESH:D000077337', (101, 105))	('Cdkn1c', 'Gene', '12577', (155, 161))
56225	29312470	Genes undergoing hyperacetylation of H3K27 within a 5 kb region around their transcriptional start site by this treatment appear to become particularly dependent on binding of BET proteins like BRD4 to their regulatory regions, including enhancers, to promote gene transcription.	('gene transcription', 'MPA', (260, 278))	('promote', 'PosReg', (252, 259))	('BET', 'Gene', '92737', (176, 179))	('BET', 'Gene', (176, 179))	('binding', 'Interaction', (165, 172))	('transcription', 'biological_process', 'GO:0006351', ('265', '278'))	('H3K27', 'Protein', (37, 42))	('hyperacetylation', 'Var', (17, 33))	('binding', 'molecular_function', 'GO:0005488', ('165', '172'))
56258	31894921	Khan et al demonstrated that patients who experienced low-grade dermatological irAEs had longer OS in IMvigor211 (P = 0.024; hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.45-0.95) and IMvigor210 (P = 0.0023; HR 0.53; 95% CI 0.35-0.80) trials.	('low-grade', 'Var', (54, 63))	('patients', 'Species', '9606', (29, 37))	('longer', 'PosReg', (89, 95))	('IMvigor211', 'Gene', (102, 112))
56259	31894921	In their analysis, polygenic risk for psoriasis was associated with an increased odds of skin irAEs (P = 0.002; OR 1.79; 95% CI 1.24-2.40), while high polygenic risks for vitiligo (P = 0.0016; HR 0.58; 95% CI 0.41-0.81) and psoriasis (P = 5.5 x 10-5; HR 0.50; 95% CI 0.36-0.70), as well as low for atopic dermatitis (P = 0.0008; HR 0.57; 95% CI 0.41-0.79) were associated with longer OS under anti-PD-L1 atezolizumab monotherapy in comparison with chemotherapy.	('atopic dermatitis', 'Disease', 'MESH:D003876', (298, 315))	('dermatitis', 'Phenotype', 'HP:0011123', (305, 315))	('atopic dermatitis', 'Disease', (298, 315))	('skin irAEs', 'Disease', (89, 99))	('vitiligo', 'Disease', (171, 179))	('psoriasis', 'Disease', 'MESH:D011565', (224, 233))	('psoriasis', 'Disease', 'MESH:D011565', (38, 47))	('psoriasis', 'Phenotype', 'HP:0003765', (224, 233))	('polygenic', 'Var', (19, 28))	('skin irAEs', 'Disease', 'MESH:D012871', (89, 99))	('psoriasis', 'Phenotype', 'HP:0003765', (38, 47))	('vitiligo', 'Phenotype', 'HP:0001045', (171, 179))	('psoriasis', 'Disease', (224, 233))	('psoriasis', 'Disease', (38, 47))	('atopic dermatitis', 'Phenotype', 'HP:0001047', (298, 315))
56297	30274701	Furthermore, APOBEC3A/3B expression and mutations in genes involved in DNA damage response were associated with TMB and response to CPB.	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('CPB', 'Chemical', '-', (132, 135))	('DNA damage response', 'biological_process', 'GO:0006974', ('71', '90'))	('associated', 'Reg', (96, 106))	('expression', 'MPA', (25, 35))	('response to CPB', 'MPA', (120, 135))	('mutations', 'Var', (40, 49))	('APOBEC', 'cellular_component', 'GO:0030895', ('13', '19'))	('TMB', 'Disease', (112, 115))	('TMB', 'Chemical', '-', (112, 115))	('APOBEC3A/3B', 'Gene', (13, 24))
56316	30274701	Inhibition of the PPAR-gamma pathway enhanced inflammatory chemokines and cytokines in mouse models.	('inflammatory chemokines', 'MPA', (46, 69))	('PPAR-gamma pathway', 'Pathway', (18, 36))	('mouse', 'Species', '10090', (87, 92))	('cytokines', 'MPA', (74, 83))	('Inhibition', 'Var', (0, 10))	('enhanced', 'PosReg', (37, 45))
56317	30274701	Recent data on erdafitinib (pan-FGFR inhibitor) in mUC patients with prespecified FGFR alterations demonstrated robust responses (ORR 70%) in patients with prior CPB.	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('CPB', 'Chemical', '-', (162, 165))	('FGFR', 'Gene', (82, 86))	('alterations', 'Var', (87, 98))	('FGFR', 'molecular_function', 'GO:0005007', ('82', '86'))	('UC', 'Disease', 'MESH:D014523', (52, 54))	('erdafitinib', 'Chemical', 'MESH:C000604580', (15, 26))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (142, 150))
56318	30274701	Whether FGFR inhibitors can resensitize luminal I tumors to immunotherapy remains to be explored.	('luminal I tumors', 'Disease', (40, 56))	('inhibitors', 'Var', (13, 23))	('FGFR', 'molecular_function', 'GO:0005007', ('8', '12'))	('luminal I tumors', 'Disease', 'MESH:D009369', (40, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('FGFR', 'Gene', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
56321	30274701	These preliminary data on PPAR-y modulators, FGFR inhibitors, and NKTR-214 show potential strategies to "ignite" immune-cold UC and restore immunosurveillance, as has been shown with BRAF inhibition in melanoma.	('NKTR', 'Gene', '4820', (66, 70))	('PPAR', 'Gene', '5465', (26, 30))	('FGFR', 'Gene', (45, 49))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('NKTR', 'Gene', (66, 70))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('immune-cold', 'MPA', (113, 124))	('PPAR', 'Gene', (26, 30))	('BRAF', 'Gene', '673', (183, 187))	('melanoma', 'Disease', (202, 210))	('restore', 'PosReg', (132, 139))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('immunosurveillance', 'MPA', (140, 158))	('BRAF', 'Gene', (183, 187))	('UC', 'Disease', 'MESH:D014523', (125, 127))	('modulators', 'Var', (33, 43))
56342	30274701	Even higher response rates were observed in patients with LAG-3 positivity on intratumoral immune cells, suggesting that expression of LAG-3 might be a resistance mechanism to anti-PD-1 therapy.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('LAG-3', 'Gene', (135, 140))	('positivity', 'Var', (64, 74))	('patients', 'Species', '9606', (44, 52))	('PD-1', 'Gene', (181, 185))	('higher', 'PosReg', (5, 11))	('tumor', 'Disease', (83, 88))	('PD-1', 'Gene', '5133', (181, 185))	('LAG-3', 'Gene', (58, 63))	('LAG-3', 'Gene', '3902', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('LAG-3', 'Gene', '3902', (135, 140))
56366	30274701	In a mouse model exhibiting the immune-excluded phenotype, treatment with anti-TGF-ss plus anti-PD-Ll lowered TGF-ss signaling in stromal cells, enhanced intratumoral T-cell trafficking and induced T-cell-mediated tumor rejection.	('induced', 'Reg', (190, 197))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('lowered', 'NegReg', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', (159, 164))	('TGF-ss signaling', 'MPA', (110, 126))	('anti-PD-Ll', 'Var', (91, 101))	('tumor', 'Disease', (214, 219))	('mouse', 'Species', '10090', (5, 10))	('enhanced', 'PosReg', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))
56367	30274701	T-cell function can also be impaired by adenosine.	('adenosine', 'Chemical', 'MESH:D000241', (40, 49))	('T-cell function', 'CPA', (0, 15))	('adenosine', 'Var', (40, 49))	('impaired', 'NegReg', (28, 36))
56382	30274701	Moreover, lactate and other metabolic products such as kynurenines and PGE2 further impair antitumor T-cell function.	('PGE2', 'Gene', (71, 75))	('lactate', 'MPA', (10, 17))	('kynurenines', 'Chemical', 'MESH:D007737', (55, 66))	('PGE2', 'Chemical', 'MESH:D015232', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('impair', 'NegReg', (84, 90))	('lactate', 'Chemical', 'MESH:D019344', (10, 17))	('kynurenines', 'Var', (55, 66))	('tumor', 'Disease', (95, 100))
56387	30274701	Epacadostat and BMS-986205, both selective blockers of IDO1, were recently tested in combination with anti-PD-1 in single-arm studies and showed efficacy in mUC.	('BMS-986205', 'Var', (16, 26))	('IDO', 'molecular_function', 'GO:0047719', ('55', '58'))	('IDO1', 'Gene', (55, 59))	('UC', 'Disease', 'MESH:D014523', (158, 160))	('PD-1', 'Gene', (107, 111))	('IDO', 'molecular_function', 'GO:0033754', ('55', '58'))	('PD-1', 'Gene', '5133', (107, 111))
56391	30274701	Other amino acids essential for T-cell and tumor cell metabolism and function are arginine and glutamine.	('arginine', 'Chemical', 'MESH:D001120', (82, 90))	('metabolism', 'biological_process', 'GO:0008152', ('54', '64'))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('glutamine', 'Chemical', 'MESH:D005973', (95, 104))	('arginine', 'Var', (82, 90))	('tumor cell metabolism', 'Disease', (43, 64))	('tumor cell metabolism', 'Disease', 'MESH:D008659', (43, 64))
56395	30274701	High LDH levels are correlated with poor prognosis and lower ORR to CPB in melanoma.	('LDH levels', 'MPA', (5, 15))	('ORR to CPB', 'MPA', (61, 71))	('High', 'Var', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('CPB', 'Chemical', '-', (68, 71))	('lower', 'NegReg', (55, 60))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))
56401	30274701	Tumors can evade CD8+ T-cell immune surveillance through genetic and epigenetic alterations in the antigen-presenting machinery.	('epigenetic alterations', 'Var', (69, 91))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('genetic', 'Var', (57, 64))	('evade', 'NegReg', (11, 16))	('CD8', 'Gene', (17, 20))	('CD8', 'Gene', '925', (17, 20))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
56402	30274701	Early studies with epigenetic modifiers resulted in re-expression of tumor-associated antigens and MHC-antigen complexes, whereas potential synergy was observed when epigenetic modifiers were combined with CPB.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('re-expression', 'MPA', (52, 65))	('epigenetic modifiers', 'Var', (19, 39))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('CPB', 'Chemical', '-', (206, 209))
56403	30274701	Likewise, point mutations and deletions in beta-2-microglobulin (B2M), a crucial building block required for MHC class I assembly, were found in almost 30% of melanoma tumors upon CPB resistance.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('melanoma tumors', 'Disease', (159, 174))	('CPB', 'Chemical', '-', (180, 183))	('beta-2-microglobulin', 'Gene', '567', (43, 63))	('deletions', 'Var', (30, 39))	('melanoma tumors', 'Disease', 'MESH:D008545', (159, 174))	('B2M', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('beta-2-microglobulin', 'Gene', (43, 63))	('B2M', 'Gene', '567', (65, 68))	('point mutations', 'Var', (10, 25))	('found', 'Reg', (136, 141))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
56405	30274701	In UC, early data suggest that HLA loss by mutations in beta2-microglobulin genes was not the underlying cause of low HLA class I presence.	('loss', 'NegReg', (35, 39))	('beta2-microglobulin', 'Gene', (56, 75))	('HLA', 'Disease', (31, 34))	('mutations', 'Var', (43, 52))	('UC', 'Disease', 'MESH:D014523', (3, 5))	('beta2-microglobulin', 'Gene', '567', (56, 75))
56413	30274701	In melanoma, mutational analysis showed that primary resistance to ipilimumab was associated with mutations in IFNg receptors 1 and 2 (IFNGR1 and IFNGR2), interferon regulatory factor 1, and JAK1 and JAK2, allowing cancer cells to escape from IFNg-mediated killing.	('IFNGR2', 'Gene', (146, 152))	('interferon regulatory factor 1', 'Gene', '3659', (155, 185))	('associated', 'Reg', (82, 92))	('JAK', 'molecular_function', 'GO:0004713', ('200', '203'))	('IFNg', 'Gene', '3458', (111, 115))	('IFNg', 'Gene', (243, 247))	('JAK', 'molecular_function', 'GO:0004713', ('191', '194'))	('JAK2', 'Gene', (200, 204))	('cancer', 'Disease', (215, 221))	('IFNg', 'Gene', '3458', (243, 247))	('IFNGR1', 'Gene', '3459', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('IFNGR1', 'Gene', (135, 141))	('JAK1', 'Gene', '3716', (191, 195))	('interferon regulatory factor 1', 'Gene', (155, 185))	('primary resistance', 'MPA', (45, 63))	('IFNg', 'Gene', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('ipilimumab', 'Chemical', 'MESH:D000074324', (67, 77))	('mutations', 'Var', (98, 107))	('JAK2', 'Gene', '3717', (200, 204))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('IFNGR2', 'Gene', '3460', (146, 152))	('JAK1', 'Gene', (191, 195))
56448	30996049	Lastly, we examined possible links between tRFs and the repeat-element content of genes, and between tRFs and sex disparities.	('tRF', 'Gene', (101, 104))	('tRF', 'Gene', (43, 46))	('tRF', 'Gene', '7200', (101, 104))	('repeat-element content', 'Var', (56, 78))	('tRF', 'Gene', '7200', (43, 46))
56463	30996049	Intuitively, had a modified base at position N of the mature tRNA stopped reverse transcription during library preparation, then tRFs from this tRNA would have appeared to possess a "pseudo-5 " terminus at position N+1.	('reverse transcription', 'biological_process', 'GO:0001171', ('74', '95'))	('tRNA', 'molecular_function', 'GO:0030533', ('144', '148'))	('stopped', 'NegReg', (66, 73))	('modified', 'Var', (19, 27))	('tRF', 'Gene', (129, 132))	('reverse transcription', 'MPA', (74, 95))	('tRF', 'Gene', '7200', (129, 132))	('tRNA', 'molecular_function', 'GO:0030533', ('61', '65'))
56465	30996049	Additionally, for 3 -tRFs, we also evaluated whether there is benefit in mapping tRFs after allowing a single nucleotide mismatch.	('single nucleotide mismatch', 'Var', (103, 129))	('tRF', 'Gene', (81, 84))	('tRF', 'Gene', '7200', (81, 84))	('tRF', 'Gene', (21, 24))	('tRF', 'Gene', '7200', (21, 24))
56466	30996049	Such a mismatch would, in principle, alleviate the potential impact on the sequenced reads of the known m1A58 modification (methylated adenine at position 58 of the mature tRNA).	('alleviate', 'NegReg', (37, 46))	('mismatch', 'Var', (7, 15))	('m1A58', 'Gene', (104, 109))	('tRNA', 'molecular_function', 'GO:0030533', ('172', '176'))	('impact', 'MPA', (61, 67))	('methylated adenine', 'Chemical', '-', (124, 142))
56474	30996049	We kept tRF-mRNA pairs with Spearman correlation <= -0.333 or >= 0.333 and an associated False Discovery Rate (FDR) <= 5%.	('>= 0.333', 'Var', (62, 70))	('<= -0.333', 'Var', (49, 58))	('tRF', 'Gene', (8, 11))	('tRF', 'Gene', '7200', (8, 11))
56502	30996049	In principle, such modifications could hinder the reverse-transcription step during sequencing leading to an artificial 5  endpoint for some tRFs, or, to misreading the nucleotide at the modified location.	('reverse-transcription', 'MPA', (50, 71))	('tRF', 'Gene', '7200', (141, 144))	('artificial 5  endpoint', 'MPA', (109, 131))	('modifications', 'Var', (19, 32))	('reverse-transcription', 'biological_process', 'GO:0001171', ('50', '71'))	('tRF', 'Gene', (141, 144))	('hinder', 'NegReg', (39, 45))
56504	30996049	Our analysis also confirmed that permitting nucleotide mismatches when mapping reads to the genome greatly hinders one's ability to distinguish among tRFs and non-tRFs (Supplemental Fig.	('tRF', 'Gene', (163, 166))	('hinders', 'NegReg', (107, 114))	('tRF', 'Gene', (150, 153))	('tRF', 'Gene', '7200', (163, 166))	('tRF', 'Gene', '7200', (150, 153))	('nucleotide mismatches', 'Var', (44, 65))
56508	30996049	Examination of the -1 positions of all 5 -tRFs from tRNAHisGTG across all TCGA samples revealed unexpectedly that His(-1U) is the most abundant modification (Fig.	('tRF', 'Gene', '7200', (42, 45))	('His(-1U', 'Var', (114, 121))	('His', 'Chemical', 'MESH:D006639', (114, 117))	('His', 'Chemical', 'MESH:D006639', (56, 59))	('tRF', 'Gene', (42, 45))	('-1U', 'Var', (118, 121))
56563	30996049	As far as positive correlations are concerned, mRNAs encoding nuclear proteins are significantly enriched in some cancer types, e.g.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mRNAs', 'Var', (47, 52))	('enriched', 'Reg', (97, 105))	('cancer', 'Disease', (114, 120))
56575	30996049	For example, the KEGG pathway "ribosome" (hsa03010) is significantly overrepresented in 21 cancer types (Supplemental Tables S7 and S8) and the corresponding mRNAs are correlated with both nuclear and MT tRFs (Fig.	('S7', 'Gene', '6264', (125, 127))	('tRF', 'Gene', (204, 207))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('overrepresented', 'PosReg', (69, 84))	('tRF', 'Gene', '7200', (204, 207))	('KEGG pathway', 'Pathway', (17, 29))	('hsa03010', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ribosome', 'cellular_component', 'GO:0005840', ('30', '38'))
56602	30996049	ALU and MIR retrotransposons are most significantly enriched or depleted across multiple cancer types.	('depleted', 'NegReg', (64, 72))	('ALU', 'Var', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('MIR', 'Gene', '220972', (8, 11))	('MIR', 'Gene', (8, 11))	('transposons', 'Species', '2387', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
56614	30996049	On the other hand, the gene set with high repeat density includes G proteins, tyrosine and serine-threonine kinases, as well as proteins with DHR1, DHR2, FERM and/or EF-hand domains.	('G proteins', 'Protein', (66, 76))	('tyrosine', 'MPA', (78, 86))	('proteins', 'Protein', (128, 136))	('DHR2', 'Var', (148, 152))	('DHR1', 'Var', (142, 146))	('serine', 'Chemical', 'MESH:D012694', (91, 97))
56615	30996049	Moreover, genes with high repeat density belong to signaling pathways, including: MAPK, ErbB, Ras, PI3K-Akt, and cGMP-PKG.	('Akt', 'Gene', (104, 107))	('PI3K', 'molecular_function', 'GO:0016303', ('99', '103'))	('ErbB', 'Gene', (88, 92))	('ErbB', 'Gene', '1956', (88, 92))	('Ras', 'Disease', (94, 97))	('PKG', 'molecular_function', 'GO:0004692', ('118', '121'))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('signaling pathways', 'Pathway', (51, 69))	('belong', 'Reg', (41, 47))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('Akt', 'Gene', '207', (104, 107))	('cGMP', 'Chemical', 'MESH:D006152', (113, 117))	('high repeat density', 'Var', (21, 40))	('MAPK', 'Gene', (82, 86))
56650	30996049	From this perspective, the identified links to tRFs could shed light on the molecular events behind their regulation and functions in different tissues and cancer types.	('regulation', 'biological_process', 'GO:0065007', ('106', '116'))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('links', 'Var', (38, 43))	('tRF', 'Gene', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tRF', 'Gene', '7200', (47, 50))
56666	30996049	In the context of cancer, repeat elements continue to emerge as important components in genomic rearrangements as well as potent regulators of gene expression, and as determinants of overall survival.	('cancer', 'Disease', (18, 24))	('repeat elements', 'Var', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('gene expression', 'biological_process', 'GO:0010467', ('143', '158'))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
56667	30996049	As repeat elements are also associated with chimeric transcripts involving protein-coding exons, it is conceivable that tRFs can interact with such junctions just like we previously reported for miRNAs.	('chimeric', 'Var', (44, 52))	('associated', 'Reg', (28, 38))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('tRF', 'Gene', (120, 123))	('interact', 'Interaction', (129, 137))	('tRF', 'Gene', '7200', (120, 123))
56677	29374051	They find that SCCB and SCLC both harbor near universal loss of function mutations in RB1 and TP53.	('SCLC', 'Gene', (24, 28))	('RB1', 'Gene', (86, 89))	('SCLC', 'Phenotype', 'HP:0030357', (24, 28))	('RB1', 'Gene', '5925', (86, 89))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('loss of function', 'NegReg', (56, 72))	('mutations', 'Var', (73, 82))	('SCLC', 'Gene', '7864', (24, 28))
56680	29374051	To further explore this hypothesis, they sequenced distinct regions from mixed histology tumor specimens that had both urothelial and small cell components and found that the small cell component uniquely harbored RB1 and TP53 mutations providing stronger evidence that RB1 and TP53 loss is required for the development of SCCB and that SCCB arises from a preexisting urothelial cancer.	('SCCB', 'Disease', (337, 341))	('TP53', 'Gene', '7157', (278, 282))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('TP53', 'Gene', (278, 282))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('RB1', 'Gene', '5925', (214, 217))	('urothelial cancer', 'Disease', (368, 385))	('loss', 'NegReg', (283, 287))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('RB1', 'Gene', (214, 217))	('RB1', 'Gene', (270, 273))	('urothelial cancer', 'Disease', 'MESH:D014523', (368, 385))	('SCCB', 'Disease', (323, 327))	('TP53', 'Gene', '7157', (222, 226))	('TP53', 'Gene', (222, 226))	('tumor', 'Disease', (89, 94))	('RB1', 'Gene', '5925', (270, 273))	('mutations', 'Var', (227, 236))
56681	29374051	Urothelial cancers have a high frequency of mutations in chromatin modifying enzymes including mutations in KDM6A and ARID1A.	('Urothelial cancers', 'Disease', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Urothelial cancers', 'Disease', 'MESH:D014523', (0, 18))	('KDM6A', 'Gene', (108, 113))	('mutations', 'Var', (44, 53))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('mutations', 'Var', (95, 104))	('ARID1A', 'Gene', '8289', (118, 124))	('KDM6A', 'Gene', '7403', (108, 113))	('ARID1A', 'Gene', (118, 124))	('chromatin', 'cellular_component', 'GO:0000785', ('57', '66'))
56682	29374051	SCCB, but not SCLC, share these mutations in the same chromatin modifying enzymes at similar frequencies to urothelial carcinoma demonstrating that SCCB is unique from SCLC and raising the likely possibility that SCCB arises from a preexisting urothelial carcinoma.	('urothelial carcinoma', 'Disease', (244, 264))	('urothelial carcinoma', 'Disease', (108, 128))	('SCLC', 'Gene', '7864', (14, 18))	('SCLC', 'Gene', (14, 18))	('SCLC', 'Gene', '7864', (168, 172))	('SCLC', 'Gene', (168, 172))	('SCLC', 'Phenotype', 'HP:0030357', (14, 18))	('SCLC', 'Phenotype', 'HP:0030357', (168, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (244, 264))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (108, 128))	('chromatin', 'cellular_component', 'GO:0000785', ('54', '63'))	('mutations', 'Var', (32, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))
56684	29374051	Like SCLC, nearly all SCCBs harbor mutations in RB1 and TP53.	('RB1', 'Gene', (48, 51))	('TP53', 'Gene', '7157', (56, 60))	('RB1', 'Gene', '5925', (48, 51))	('TP53', 'Gene', (56, 60))	('SCLC', 'Gene', '7864', (5, 9))	('SCLC', 'Phenotype', 'HP:0030357', (5, 9))	('SCLC', 'Gene', (5, 9))	('mutations', 'Var', (35, 44))
56689	29374051	Both lung and prostate cancers that acquire RB1 and TP53 mutations are no longer responsive to inhibition of their respective oncogenic driver (e.g.	('TP53', 'Gene', '7157', (52, 56))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('TP53', 'Gene', (52, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (14, 29))	('mutations', 'Var', (57, 66))	('RB1', 'Gene', (44, 47))	('prostate cancers', 'Phenotype', 'HP:0012125', (14, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('lung and prostate cancers', 'Disease', 'MESH:D011471', (5, 30))	('RB1', 'Gene', '5925', (44, 47))
56692	29374051	There are however, low frequency mutations and amplifications in ERBB2 and ERBB3, which are also present in SCCB at similar frequencies and are potentially druggable targets.	('ERBB3', 'Gene', (75, 80))	('ERBB3', 'Gene', '2065', (75, 80))	('mutations', 'Var', (33, 42))	('ERBB2', 'Gene', (65, 70))	('ERBB2', 'Gene', '2064', (65, 70))	('amplifications', 'Var', (47, 61))
56693	29374051	Chang and colleagues also described a patient with a mixed histology tumor and a hotspot mutation in PIK3CA Q546P that was found in both the urothelial and the small cell component.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('PIK3CA', 'Gene', '5290', (101, 107))	('Q546P', 'Var', (108, 113))	('tumor', 'Disease', (69, 74))	('Q546P', 'Mutation', 'rs397517201', (108, 113))	('patient', 'Species', '9606', (38, 45))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('PIK3CA', 'Gene', (101, 107))
56695	29374051	Similar to lung and prostate cancers that have transdifferentiated to a small cell neuroendocrine tumor, we hypothesize that as a consequence of inactivating RB1 and TP53 and becoming neuroendocrine, SCCB tumors downregulate expression of the activating oncogene (e.g.	('prostate cancer', 'Phenotype', 'HP:0012125', (20, 35))	('downregulate', 'NegReg', (212, 224))	('SCCB tumors', 'Disease', (200, 211))	('prostate cancers', 'Phenotype', 'HP:0012125', (20, 36))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('expression', 'MPA', (225, 235))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (83, 103))	('RB1', 'Gene', '5925', (158, 161))	('inactivating', 'Var', (145, 157))	('TP53', 'Gene', '7157', (166, 170))	('lung and prostate cancers', 'Disease', 'MESH:D011471', (11, 36))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('small cell neuroendocrine tumor', 'Disease', 'MESH:D018358', (72, 103))	('SCCB tumors', 'Disease', 'MESH:D009369', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('small cell neuroendocrine tumor', 'Disease', (72, 103))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('TP53', 'Gene', (166, 170))	('RB1', 'Gene', (158, 161))
56699	29374051	Chang and colleagues point out that roughly 10% of urothelial cancers harbor mutations in both RB1 and TP53 suggesting that RB1 and TP53 loss are not sufficient for the small cell neuroendocrine state.	('TP53', 'Gene', '7157', (103, 107))	('urothelial cancers', 'Disease', (51, 69))	('RB1', 'Gene', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('TP53', 'Gene', (103, 107))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('RB1', 'Gene', (95, 98))	('RB1', 'Gene', '5925', (124, 127))	('mutations', 'Var', (77, 86))	('loss', 'NegReg', (137, 141))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('RB1', 'Gene', '5925', (95, 98))	('urothelial cancers', 'Disease', 'MESH:D014523', (51, 69))
56702	29374051	Inactivation of SOX2 reverses these effects.	('SOX2', 'Gene', '6657', (16, 20))	('Inactivation', 'Var', (0, 12))	('SOX2', 'Gene', (16, 20))
56705	29374051	The most common driver mutations in SCCB are loss of function mutations in RB1 and TP53.	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', (83, 87))	('RB1', 'Gene', (75, 78))	('loss of function', 'NegReg', (45, 61))	('mutations', 'Var', (23, 32))	('RB1', 'Gene', '5925', (75, 78))	('SCCB', 'Gene', (36, 40))	('mutations', 'Var', (62, 71))
56711	29416205	Based on results obtained by the research it is confirmed that aristolochic acid is causative agent of endemic nephropathy (EN).	('nephropathy', 'Disease', 'MESH:D007674', (111, 122))	('aristolochic acid', 'Chemical', 'MESH:C000228', (63, 80))	('aristolochic acid', 'Var', (63, 80))	('nephropathy', 'Disease', (111, 122))	('nephropathy', 'Phenotype', 'HP:0000112', (111, 122))
56727	29416205	Aristolactam-DNA adducts were detected in renal cortex as A:T > T:A mutations in the 5'-CpApG-3' context accumulating on the nontranscribed strand of the TP53 gene in EN/UTUC cases and presents as biomarkers of AA exposure in this geographical region.	('mutations', 'Var', (68, 77))	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('TP53', 'Gene', '7157', (154, 158))	('TP53', 'Gene', (154, 158))
56768	29416205	Although, we did not found significant differences in CKD stage between patients from Croatian and Bosnian EN regions we did found more elevated blood levels of urea and creatinine in group of patients from Croatian EN region and more decreased levels of Hemoglobin in the same group when compared with patients from Bosnian EN group.	('patients', 'Species', '9606', (193, 201))	('Bosnia', 'Disease', 'None', (99, 105))	('patients', 'Species', '9606', (303, 311))	('creatinine', 'Chemical', 'MESH:D003404', (170, 180))	('Bosnia', 'Disease', (99, 105))	('Croatian', 'Var', (207, 215))	('Bosnia', 'Disease', (317, 323))	('elevated blood levels of urea and creatinine', 'Phenotype', 'HP:0003259', (136, 180))	('levels of Hemoglobin', 'MPA', (245, 265))	('elevated', 'PosReg', (136, 144))	('urea', 'Chemical', 'MESH:D014508', (161, 165))	('creatinine', 'MPA', (170, 180))	('decreased', 'NegReg', (235, 244))	('decreased levels of Hemoglobin', 'Phenotype', 'HP:0001903', (235, 265))	('Bosnia', 'Disease', 'None', (317, 323))	('blood levels of urea', 'MPA', (145, 165))	('patients', 'Species', '9606', (72, 80))
56772	23675690	Alterations of Histone H1 Phosphorylation During Bladder Carcinogenesis There is a crucial need for development of prognostic and predictive biomarkers in human bladder carcinogenesis in order to personalize preventive and therapeutic strategies and improve outcomes.	('p', 'Chemical', 'MESH:D010758', (106, 107))	('p', 'Chemical', 'MESH:D010758', (196, 197))	('Histone H1', 'Gene', '3005', (15, 25))	('Alterations', 'Var', (0, 11))	('bladder carcinogenesis', 'Disease', 'MESH:D063646', (161, 183))	('human', 'Species', '9606', (155, 160))	('p', 'Chemical', 'MESH:D010758', (115, 116))	('bladder carcinogenesis', 'Disease', (161, 183))	('p', 'Chemical', 'MESH:D010758', (208, 209))	('p', 'Chemical', 'MESH:D010758', (252, 253))	('Phosphorylation', 'biological_process', 'GO:0016310', ('26', '41'))	('p', 'Chemical', 'MESH:D010758', (228, 229))	('p', 'Chemical', 'MESH:D010758', (130, 131))	('p', 'Chemical', 'MESH:D010758', (30, 31))	('Histone H1', 'Gene', (15, 25))
56773	23675690	Epigenetic alterations, such as histone modifications, are implicated in the genetic dysregulation that is fundamental to carcinogenesis.	('Epigenetic alterations', 'Var', (0, 22))	('men', 'Species', '9606', (112, 115))	('carcinogenesis', 'Disease', 'MESH:D063646', (122, 136))	('carcinogenesis', 'Disease', (122, 136))	('p', 'Chemical', 'MESH:D010758', (1, 2))	('p', 'Chemical', 'MESH:D010758', (61, 62))	('histone modifications', 'Var', (32, 53))	('implicated', 'Reg', (59, 69))
56795	23675690	Core histone modifications are reported as having cancer biomarker potential in the bladder  as well as prostate , lung , kidney , breast  and pancreas .	('breast  and pancreas', 'Disease', 'MESH:D010190', (131, 151))	('histone', 'Protein', (5, 12))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('p', 'Chemical', 'MESH:D010758', (143, 144))	('p', 'Chemical', 'MESH:D010758', (104, 105))	('p', 'Chemical', 'MESH:D010758', (67, 68))	('lung', 'Disease', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('p', 'Chemical', 'MESH:D010758', (33, 34))	('prostate', 'Disease', (104, 112))	('modifications', 'Var', (13, 26))	('kidney', 'Disease', (122, 128))
56798	23675690	The human histone H1 variants H1.0, H1.1, H1.2, H1.3, H1.4, H1.5 and H1.X are expressed in somatic cells.	('H1.1', 'Gene', '3024', (36, 40))	('H1', 'Gene', '3009', (69, 71))	('H1.3', 'Gene', (48, 52))	('H1', 'Gene', '3009', (36, 38))	('H1', 'Gene', '3009', (60, 62))	('histone H1', 'Gene', (10, 20))	('H1.2', 'Gene', (42, 46))	('H1', 'Gene', '3009', (42, 44))	('H1.5', 'Gene', '3009', (60, 64))	('H1.2', 'Gene', '3006', (42, 46))	('H1.4', 'Gene', (54, 58))	('H1.3', 'Gene', '3007', (48, 52))	('H1', 'Gene', '3009', (48, 50))	('H1.5', 'Gene', (60, 64))	('histone H1', 'Gene', '3005', (10, 20))	('H1', 'Gene', '3009', (18, 20))	('H1.4', 'Gene', '3008', (54, 58))	('H1.1', 'Gene', (36, 40))	('variants', 'Var', (21, 29))	('human', 'Species', '9606', (4, 9))	('p', 'Chemical', 'MESH:D010758', (80, 81))	('H1', 'Gene', '3009', (54, 56))	('H1', 'Gene', '3009', (30, 32))
56799	23675690	Four additional histone H1 variants are expressed solely in germ line cells .	('variants', 'Var', (27, 35))	('histone H1', 'Gene', (16, 26))	('histone H1', 'Gene', '3005', (16, 26))	('p', 'Chemical', 'MESH:D010758', (42, 43))
56806	23675690	It has been suggested that H1 variants have different functions yet these differences are still under investigation .	('variants', 'Var', (30, 38))	('H1', 'Gene', '3009', (27, 29))	('functions', 'MPA', (54, 63))
56888	23675690	The deconvoluted mass spectra of histone H1 variant H1.5 is shown in Figure 2.	('histone H1', 'Gene', (33, 43))	('variant', 'Var', (44, 51))	('H1.5', 'Gene', '3009', (52, 56))	('histone H1', 'Gene', '3005', (33, 43))	('p', 'Chemical', 'MESH:D010758', (23, 24))	('H1.5', 'Gene', (52, 56))
56897	23675690	For histone variant H1.5, a statistically significant difference (p<0.05) was observed between the invasive human bladder cancer cell lines and both the immortalized normal human bladder epithelium (hTERT) and the non-invasive human bladder cancer cell line (RT4).	('bladder cancer', 'Disease', 'MESH:D001749', (114, 128))	('bladder cancer', 'Disease', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('bladder cancer', 'Phenotype', 'HP:0009725', (233, 247))	('bladder cancer', 'Phenotype', 'HP:0009725', (114, 128))	('p', 'Chemical', 'MESH:D010758', (188, 189))	('hTERT', 'Gene', (199, 204))	('H1.5', 'Gene', '3009', (20, 24))	('p', 'Chemical', 'MESH:D010758', (66, 67))	('H1.5', 'Gene', (20, 24))	('human', 'Species', '9606', (173, 178))	('variant', 'Var', (12, 19))	('human', 'Species', '9606', (227, 232))	('human', 'Species', '9606', (108, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (233, 247))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('significant difference', 'Reg', (42, 64))	('hTERT', 'Gene', '7015', (199, 204))	('bladder cancer', 'Disease', (233, 247))
56900	23675690	In addition, for these variants, the invasive human bladder cancer cell lines T24 and UMUC3 demonstrated statistically significant differences (p<0.05) relative to the invasive human bladder cancer cell line J82.	('bladder cancer', 'Disease', 'MESH:D001749', (183, 197))	('p', 'Chemical', 'MESH:D010758', (144, 145))	('bladder cancer', 'Disease', (183, 197))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (46, 51))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('significant differences', 'Reg', (119, 142))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('bladder cancer', 'Phenotype', 'HP:0009725', (183, 197))	('variants', 'Var', (23, 31))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('bladder cancer', 'Disease', (52, 66))	('human', 'Species', '9606', (177, 182))
56901	23675690	Furthermore, J82 demonstrated a significant difference (p<0.05) relative to the immortalized normal human bladder epithelium (hTERT) and the non-invasive human bladder cancer cell line (RT4) for the histone variant H1.4.	('hTERT', 'Gene', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('human', 'Species', '9606', (154, 159))	('bladder cancer', 'Disease', 'MESH:D001749', (160, 174))	('J82', 'Var', (13, 16))	('H1.4', 'Gene', (215, 219))	('human', 'Species', '9606', (100, 105))	('bladder cancer', 'Disease', (160, 174))	('p', 'Chemical', 'MESH:D010758', (56, 57))	('p', 'Chemical', 'MESH:D010758', (115, 116))	('H1.4', 'Gene', '3008', (215, 219))	('hTERT', 'Gene', '7015', (126, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('difference', 'Reg', (44, 54))
56902	23675690	For the histone variants H1.5, H1.2, and H1.4, there were no significant differences between the immortalized normal human bladder epithelium (hTERT) and the non-invasive human bladder cancer cell line (RT4) or between the invasive cell lines T24 and UMUC3.	('H1.4', 'Gene', '3008', (41, 45))	('hTERT', 'Gene', (143, 148))	('bladder cancer', 'Disease', (177, 191))	('H1.2', 'Gene', '3006', (31, 35))	('bladder cancer', 'Disease', 'MESH:D001749', (177, 191))	('H1.5', 'Gene', '3009', (25, 29))	('human', 'Species', '9606', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('H1.5', 'Gene', (25, 29))	('p', 'Chemical', 'MESH:D010758', (132, 133))	('hTERT', 'Gene', '7015', (143, 148))	('H1.4', 'Gene', (41, 45))	('variants', 'Var', (16, 24))	('bladder cancer', 'Phenotype', 'HP:0009725', (177, 191))	('human', 'Species', '9606', (171, 176))	('H1.2', 'Gene', (31, 35))
56910	23675690	reported that the p-T146 antibody stained HeLa cells undergoing mitosis .	('p-T146', 'Var', (18, 24))	('mitosis', 'biological_process', 'GO:0000278', ('64', '71'))	('p', 'Chemical', 'MESH:D010758', (18, 19))	('antibody', 'cellular_component', 'GO:0019815', ('25', '33'))	('antibody', 'cellular_component', 'GO:0019814', ('25', '33'))	('p-T146', 'Chemical', '-', (18, 24))	('mitosis', 'Disease', (64, 71))	('antibody', 'molecular_function', 'GO:0003823', ('25', '33'))	('mitosis', 'Disease', 'None', (64, 71))	('p', 'Chemical', 'MESH:D010758', (2, 3))	('HeLa', 'CellLine', 'CVCL:0030', (42, 46))	('antibody', 'cellular_component', 'GO:0042571', ('25', '33'))
56916	23675690	The staining in S phase is likely due to a small proportion of the cells already cycling to M. The cell cycle dependence of p-T146 can be seen by immunohistochemical staining of the formalin fixed, paraffin embedded cell block of unsynchronized UMUC3 cells (Supplementary Figure 17).	('p-T146', 'Var', (124, 130))	('men', 'Species', '9606', (264, 267))	('cyclin', 'Gene', '5111', (81, 87))	('cell cycle', 'biological_process', 'GO:0007049', ('99', '109'))	('p', 'Chemical', 'MESH:D010758', (18, 19))	('p', 'Chemical', 'MESH:D010758', (261, 262))	('p', 'Chemical', 'MESH:D010758', (52, 53))	('cyclin', 'Gene', (81, 87))	('p', 'Chemical', 'MESH:D010758', (124, 125))	('p', 'Chemical', 'MESH:D010758', (49, 50))	('p-T146', 'Chemical', '-', (124, 130))	('p', 'Chemical', 'MESH:D010758', (198, 199))	('S phase', 'biological_process', 'GO:0051320', ('16', '23'))	('paraffin', 'Chemical', 'MESH:D010232', (198, 206))	('formalin', 'Chemical', 'MESH:D005557', (182, 190))	('p', 'Chemical', 'MESH:D010758', (112, 113))	('p', 'Chemical', 'MESH:D010758', (260, 261))
56936	23675690	The LC-MS analysis clearly demonstrates distinct differences in phosphorylation of the histone H1 variants H1.5, H1.2 and H1.4 between the normal bladder epithelium, low-grade non-invasive and high-grade invasive bladder cancer cell lines, while histone variant H1.3 displayed no differences.	('invasive bladder cancer', 'Disease', 'MESH:D001749', (204, 227))	('phosphorylation', 'biological_process', 'GO:0016310', ('64', '79'))	('H1.2', 'Gene', (113, 117))	('H1.3', 'Gene', (262, 266))	('H1.2', 'Gene', '3006', (113, 117))	('p', 'Chemical', 'MESH:D010758', (64, 65))	('differences', 'Reg', (49, 60))	('H1.4', 'Gene', '3008', (122, 126))	('variants', 'Var', (98, 106))	('invasive bladder cancer', 'Disease', (204, 227))	('phosphorylation', 'MPA', (64, 79))	('p', 'Chemical', 'MESH:D010758', (155, 156))	('H1.3', 'Gene', '3007', (262, 266))	('H1.5', 'Gene', '3009', (107, 111))	('histone H1', 'Gene', (87, 97))	('p', 'Chemical', 'MESH:D010758', (68, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (213, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('H1.5', 'Gene', (107, 111))	('histone H1', 'Gene', '3005', (87, 97))	('H1.4', 'Gene', (122, 126))	('invasive bladder', 'Phenotype', 'HP:0100645', (204, 220))	('p', 'Chemical', 'MESH:D010758', (270, 271))
56938	23675690	The striking differences in H1 phosphorylation of variants H1.5, H1.2 and H1.4 between superficial (non-invasive) and invasive cell lines may be useful in bladder cancer screening, and/or predictive biomarkers of recurrence, invasiveness, progression and response to treatment.	('p', 'Chemical', 'MESH:D010758', (31, 32))	('H1 p', 'Gene', (28, 32))	('H1.4', 'Gene', '3008', (74, 78))	('variants', 'Var', (50, 58))	('H1.2', 'Gene', (65, 69))	('p', 'Chemical', 'MESH:D010758', (188, 189))	('p', 'Chemical', 'MESH:D010758', (258, 259))	('men', 'Species', '9606', (272, 275))	('H1.2', 'Gene', '3006', (65, 69))	('H1 p', 'Gene', '3009', (28, 32))	('H1.5', 'Gene', '3009', (59, 63))	('differences', 'Reg', (13, 24))	('H1.5', 'Gene', (59, 63))	('p', 'Chemical', 'MESH:D010758', (35, 36))	('bladder cancer', 'Disease', 'MESH:D001749', (155, 169))	('p', 'Chemical', 'MESH:D010758', (89, 90))	('bladder cancer', 'Disease', (155, 169))	('H1.4', 'Gene', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('bladder cancer', 'Phenotype', 'HP:0009725', (155, 169))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))	('p', 'Chemical', 'MESH:D010758', (239, 240))
56948	23675690	Evidence supports the role of epigenetic modifications in bladder cancer carcinogenesis and monitoring these epigenetic changes (i.e.	('epigenetic modifications', 'Var', (30, 54))	('bladder cancer carcinogenesis', 'Disease', 'MESH:D001749', (58, 87))	('p', 'Chemical', 'MESH:D010758', (11, 12))	('p', 'Chemical', 'MESH:D010758', (31, 32))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('p', 'Chemical', 'MESH:D010758', (110, 111))	('p', 'Chemical', 'MESH:D010758', (12, 13))	('bladder cancer carcinogenesis', 'Disease', (58, 87))
56950	23675690	demonstrated that the linker histone phosphorylation is one of the early alterations in the progression of head and neck squamous cell carcinomas .	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (121, 145))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (107, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('p', 'Chemical', 'MESH:D010758', (41, 42))	('histone phosphorylation', 'biological_process', 'GO:0016572', ('29', '52'))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (116, 145))	('p', 'Chemical', 'MESH:D010758', (37, 38))	('linker', 'Var', (22, 28))	('p', 'Chemical', 'MESH:D010758', (92, 93))	('neck', 'cellular_component', 'GO:0044326', ('116', '120'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))	('neck squamous cell carcinomas', 'Disease', (116, 145))
56966	33213447	Unexpectedly, a number of alterations in basal-like breast cancer were identified that distinguished it from other subtypes, which could bring future clinical benefits.	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('fits', 'Disease', 'MESH:D012640', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('alterations', 'Var', (26, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('fits', 'Disease', (163, 167))
56970	33213447	It postulates that carcinogenesis is determined by alterations in cancer regulatory genes, of which two crucial groups are tumor suppressors and oncogenes, both responsible for apoptosis and proliferation regulation being utmost importance in the model of cancer platform.	('alterations', 'Var', (51, 62))	('tumor', 'Disease', (123, 128))	('carcinogenesis', 'Disease', (19, 33))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('regulation', 'biological_process', 'GO:0065007', ('205', '215'))	('cancer', 'Disease', (256, 262))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('apoptosis', 'biological_process', 'GO:0097194', ('177', '186'))	('apoptosis', 'biological_process', 'GO:0006915', ('177', '186'))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Disease', (66, 72))
56977	33213447	GCCN3/4GGC, GCCN3/4GGG or CCCCAGGC while the binding of transcription factors' themselves is dictated by a proline-rich motif located in the activation domain (excluding AP-2delta, which lacks these critical residues).	('AP-2delta', 'Gene', (170, 179))	('GGC', 'Gene', (7, 10))	('transcription', 'biological_process', 'GO:0006351', ('56', '69'))	('binding', 'Interaction', (45, 52))	('GGC', 'Gene', (31, 34))	('GGC', 'Gene', '79017', (7, 10))	('GGC', 'Gene', '79017', (31, 34))	('binding', 'molecular_function', 'GO:0005488', ('45', '52'))	('AP-2delta', 'Gene', '83741', (170, 179))	('proline', 'Chemical', 'MESH:D011392', (107, 114))	('dictated by', 'Reg', (93, 104))	('AP-2', 'cellular_component', 'GO:0005908', ('170', '174'))	('GCCN3/4GGG', 'Var', (12, 22))
56980	33213447	It was suggested that in the case of mutation, the loss of TF activity of AP-2 members can lead to the impairment of proliferation, differentiation and apoptosis processes, suggesting AP-2 activity may play role in development.	('impairment', 'NegReg', (103, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('AP-2', 'Gene', '7020', (184, 188))	('proliferation', 'CPA', (117, 130))	('mutation', 'Var', (37, 45))	('activity', 'MPA', (62, 70))	('apoptosis processes', 'CPA', (152, 171))	('AP-2', 'Gene', '7020', (74, 78))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('AP-2', 'Gene', (184, 188))	('AP-2', 'cellular_component', 'GO:0005908', ('184', '188'))	('AP-2', 'cellular_component', 'GO:0005908', ('74', '78'))	('AP-2', 'Gene', (74, 78))	('loss', 'NegReg', (51, 55))
56984	33213447	The other case of chemoresistance (to 5-fluorouracil) was shown in colorectal cancer upregulating AP-2gamma while endometrial cancer example demonstrated that knockdown of this AP-2 member sensitizes cells to megestrol acetate via Estrogen receptor alpha (ERalpha) expression upregulation.	('AP-2', 'Gene', (98, 102))	('megestrol acetate', 'Chemical', 'MESH:D019290', (209, 226))	('upregulating', 'PosReg', (85, 97))	('AP-2', 'Gene', (177, 181))	('ERalpha', 'Gene', '2099', (256, 263))	('AP-2gamma', 'Gene', '7022', (98, 107))	('AP-2gamma', 'Gene', (98, 107))	('AP-2', 'cellular_component', 'GO:0005908', ('98', '102'))	('upregulation', 'PosReg', (276, 288))	('AP-2', 'Gene', '7020', (98, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('Estrogen receptor alpha', 'Gene', '2099', (231, 254))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('AP-2', 'Gene', '7020', (177, 181))	('Estrogen receptor alpha', 'Gene', (231, 254))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (38, 52))	('endometrial cancer', 'Phenotype', 'HP:0012114', (114, 132))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('sensitizes', 'Reg', (189, 199))	('knockdown', 'Var', (159, 168))	('endometrial cancer', 'Disease', (114, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('AP-2', 'cellular_component', 'GO:0005908', ('177', '181'))	('endometrial cancer', 'Disease', 'MESH:D016889', (114, 132))	('ERalpha', 'Gene', (256, 263))	('colorectal cancer', 'Disease', (67, 84))
56991	33213447	Latest data regarding contribution in cancer indicates that AP-2beta overexpression has been found to promote tumor growth in both breast and thyroid cancer and predicted poor prognosis or tumor progression, respectively.	('overexpression', 'Var', (69, 83))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('thyroid cancer', 'Phenotype', 'HP:0002890', (142, 156))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('cancer', 'Disease', (150, 156))	('AP-2beta', 'Gene', (60, 68))	('cancer', 'Disease', (38, 44))	('AP-2beta', 'Gene', '7021', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('AP-2', 'cellular_component', 'GO:0005908', ('60', '64'))	('promote', 'PosReg', (102, 109))	('breast and thyroid cancer', 'Disease', 'MESH:D001943', (131, 156))	('tumor', 'Disease', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('tumor', 'Disease', (110, 115))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
57059	33213447	Among the others, signaling pathways such as Wnt, Notch (for KIRP) or ERBB (for BRCA) were implicated in explanation which is coherent with other research.	('BRCA', 'Gene', '672', (80, 84))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('ERBB', 'Gene', '1956', (70, 74))	('BRCA', 'Gene', (80, 84))	('Notch', 'Var', (50, 55))	('ERBB', 'Gene', (70, 74))
57070	33213447	Nevertheless, the tumors could be distinguished using modules 2, 11 and 19 which included genes related to cell adhesion, regulation of cell cycle arrest and inactivation of MAPK activity.	('activity', 'MPA', (179, 187))	('arrest', 'Disease', (147, 153))	('MAPK', 'Gene', (174, 178))	('inactivation', 'Var', (158, 170))	('MAPK', 'molecular_function', 'GO:0004707', ('174', '178'))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('cell adhesion', 'biological_process', 'GO:0007155', ('107', '120'))	('inactivation of MAPK activity', 'biological_process', 'GO:0000188', ('158', '187'))	('regulation of cell cycle arrest', 'biological_process', 'GO:0071156', ('122', '153'))	('arrest', 'Disease', 'MESH:D006323', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
57080	33213447	The last mentioned might be supported by a threefold difference in the frequency of EGFR mutations between LUSC and LUAD during a previous pan-cancer analysis.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('EGFR', 'Gene', '1956', (84, 88))	('mutations', 'Var', (89, 98))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', (143, 149))	('EGFR', 'Gene', (84, 88))
57104	33194603	In multivariable Cox regression analyses, PLND compared with non-PLND was associated with OS benefit in patients with transitional cell carcinoma (hazard ratio [HR], 0.595; 95% confidence interval [95% CI], 0.557-0.634 [P < 0.001]), squamous cell carcinoma (HR, 0.646; 95% CI, 0.494-0.846 [P = 0.002]), and signet ring cell carcinoma (HR, 0.233; 95% CI, 0.107-0.504 [P < 0.001]), whereas no significant differences in OS were observed in other histological subsets.	('transitional cell carcinoma', 'Disease', (118, 145))	('squamous cell carcinoma', 'Disease', (233, 256))	('signet ring cell carcinoma', 'Disease', 'MESH:D018279', (307, 333))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (118, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('benefit', 'PosReg', (93, 100))	('patients', 'Species', '9606', (104, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('transitional cell carcinoma', 'Disease', 'MESH:D002295', (118, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (233, 256))	('signet ring cell carcinoma', 'Disease', (307, 333))	('PLND', 'Var', (42, 46))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (233, 256))
57176	33194603	In conclusion, variant histologic types were significantly associated with the presence of lymph node invasion in patients with bladder cancer.	('lymph node invasion', 'CPA', (91, 110))	('bladder cancer', 'Disease', 'MESH:D001749', (128, 142))	('bladder cancer', 'Disease', (128, 142))	('variant', 'Var', (15, 22))	('associated', 'Reg', (59, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('patients', 'Species', '9606', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
57183	31122840	Urinary TERT promoter mutations as non-invasive biomarkers for the comprehensive detection of urothelial cancer Recurrent mutations in the promoter of the telomerase reverse transcriptase (TERT) gene (C228T and C250T) detected in tumours and cells shed into urine of urothelial cancer (UC) patients are putative biomarkers for UC detection and monitoring.	('TERT', 'Gene', (8, 12))	('urothelial cancer', 'Disease', 'MESH:D014523', (94, 111))	('TERT', 'Gene', '7015', (8, 12))	('urothelial cancer', 'Disease', 'MESH:D014523', (267, 284))	('telomerase reverse transcriptase', 'Gene', '7015', (155, 187))	('TERT', 'Gene', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TERT', 'Gene', '7015', (189, 193))	('transcriptase', 'molecular_function', 'GO:0003899', ('174', '187'))	('urothelial cancer', 'Disease', (94, 111))	('urothelial cancer', 'Disease', (267, 284))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('patients', 'Species', '9606', (290, 298))	('C228T', 'Mutation', 'rs750993939', (201, 206))	('tumours', 'Disease', (230, 237))	('C250T', 'Var', (211, 216))	('tumours', 'Phenotype', 'HP:0002664', (230, 237))	('tumours', 'Disease', 'MESH:D009369', (230, 237))	('C228T', 'Var', (201, 206))	('transcriptase', 'molecular_function', 'GO:0003968', ('174', '187'))	('transcriptase', 'molecular_function', 'GO:0034062', ('174', '187'))	('C250T', 'Mutation', 'rs141046429', (211, 216))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('telomerase reverse transcriptase', 'Gene', (155, 187))
57184	31122840	We developed a single-plex assay (UroMuTERT) for the detection of low-abundance TERT promoter mutations.	('TERT', 'Gene', (39, 43))	('UroMuTERT', 'Chemical', '-', (34, 43))	('mutations', 'Var', (94, 103))	('TERT', 'Gene', '7015', (39, 43))	('TERT', 'Gene', (80, 84))	('TERT', 'Gene', '7015', (80, 84))
57186	31122840	In the French series, C228T or C250T were detected in urinary cfDNA or cellDNA in 81 cases (87 1%; 95% CI 78 6-93 2), and five controls (Specificity 94 7%; 95%CI 88 0-98 3), with 98 6% (95% CI 92 5-99 96) concordance in matched tumours.	('tumours', 'Disease', (228, 235))	('C228T', 'Var', (22, 27))	('cellDNA', 'Disease', (71, 78))	('C250T', 'Mutation', 'rs141046429', (31, 36))	('C250T', 'Var', (31, 36))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('C228T', 'Mutation', 'rs750993939', (22, 27))	('tumours', 'Phenotype', 'HP:0002664', (228, 235))	('tumours', 'Disease', 'MESH:D009369', (228, 235))
57190	31122840	The discovery in 2013 of two highly recurrent mutations (C228T and C250T) in the promoter of the Telomerase Reverse Transcriptase gene (TERT), in various human cancers and particularly in UCs where it is seen in 60-85% of cases including in early stages lesions reinvigorated the research field of UC biomarkers by providing an excellent opportunity for a simple non-invasive assay for the detection and monitoring of UCs.	('C250T', 'Var', (67, 72))	('human', 'Species', '9606', (154, 159))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('Transcriptase', 'molecular_function', 'GO:0003899', ('116', '129'))	('TERT', 'Gene', (136, 140))	('cancers', 'Disease', (160, 167))	('TERT', 'Gene', '7015', (136, 140))	('Transcriptase', 'molecular_function', 'GO:0034062', ('116', '129'))	('Telomerase Reverse Transcriptase', 'Gene', (97, 129))	('Transcriptase', 'molecular_function', 'GO:0003968', ('116', '129'))	('C228T', 'Var', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('C228T', 'Mutation', 'rs750993939', (57, 62))	('C250T', 'Mutation', 'rs141046429', (67, 72))	('Telomerase Reverse Transcriptase', 'Gene', '7015', (97, 129))
57193	31122840	The novelty of our study is evidenced by: (i) the development of a simple, clinically implementable single-plex assay (UroMuTERT) with unprecedented detection threshold for the detection of low-allelic fraction TERT promoter mutations and (ii) the systematic analysis of cell-free circulating DNA (cfDNA) in blood and urine, or DNA from urinary exfoliated cells (cellDNA) in prospectively collected fit-for-purpose samples of UC cases and controls.	('UroMuTERT', 'Chemical', '-', (119, 128))	('TERT', 'Gene', '7015', (211, 215))	('DNA', 'cellular_component', 'GO:0005574', ('328', '331'))	('mutations', 'Var', (225, 234))	('TERT', 'Gene', (124, 128))	('DNA', 'cellular_component', 'GO:0005574', ('293', '296'))	('TERT', 'Gene', (211, 215))	('TERT', 'Gene', '7015', (124, 128))
57196	31122840	We lay out a strategy integrating urinary TERT promoter mutations as a primary diagnostic tool to individuals at high-risk or under surveillance for UC recurrence, with the intent to provide urological societies with rationale how it could impact current medical standards for UC detection.	('TERT', 'Gene', '7015', (42, 46))	('mutations', 'Var', (56, 65))	('impact', 'Reg', (240, 246))	('TERT', 'Gene', (42, 46))
57201	31122840	Mutations in the promoter of the Telomerase Reverse Transcriptase gene (TERT) are frequent in various human cancers.	('Telomerase Reverse Transcriptase', 'Gene', '7015', (33, 65))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('Transcriptase', 'molecular_function', 'GO:0034062', ('52', '65'))	('frequent', 'Reg', (82, 90))	('Transcriptase', 'molecular_function', 'GO:0003968', ('52', '65'))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Mutations', 'Var', (0, 9))	('Telomerase Reverse Transcriptase', 'Gene', (33, 65))	('Transcriptase', 'molecular_function', 'GO:0003899', ('52', '65'))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('TERT', 'Gene', (72, 76))	('TERT', 'Gene', '7015', (72, 76))	('cancers', 'Disease', (108, 115))	('human', 'Species', '9606', (102, 107))
57216	31122840	A single-plex of 147 bp was designed to be smaller than the 167 bp average fragment size of cfDNA and to cover the genomic positions of the 2 most prevalent TERT promoter mutations (C228T and C250T).	('C228T', 'Var', (182, 187))	('C250T', 'Var', (192, 197))	('C250T', 'Mutation', 'rs141046429', (192, 197))	('C228T', 'Mutation', 'rs750993939', (182, 187))	('TERT', 'Gene', (157, 161))	('TERT', 'Gene', '7015', (157, 161))
57218	31122840	Genomic DNA from the mutated cell-lines HepG2 and A375 harbouring TERT C228T and C250T respectively were serially diluted into human wild-type genomic DNA of a lymphoblastoid cell-line in order to assess the accuracy and the detection threshold of the minimum mutant allelic fractions (MAFs).	('C250T', 'Var', (81, 86))	('C250T', 'Mutation', 'rs141046429', (81, 86))	('human', 'Species', '9606', (127, 132))	('C228T', 'Mutation', 'rs750993939', (71, 76))	('HepG2', 'CellLine', 'CVCL:0027', (40, 45))	('TERT', 'Gene', (66, 70))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('TERT', 'Gene', '7015', (66, 70))	('MAF', 'Gene', (286, 289))	('MAF', 'Gene', '4094', (286, 289))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))
57219	31122840	It includes C228T and C250T and other rare mutations previously reported (C181T, C176G, C228A, CC242-243TT, G245T).	('C250T', 'Var', (22, 27))	('C228A', 'Var', (88, 93))	('C176G', 'Mutation', 'c.176C>G', (81, 86))	('C181T', 'Var', (74, 79))	('C181T', 'Mutation', 'rs1475342285', (74, 79))	('C176G', 'Var', (81, 86))	('C228T', 'Var', (12, 17))	('C228T', 'Mutation', 'rs750993939', (12, 17))	('CC242-243TT', 'Var', (95, 106))	('G245T', 'Var', (108, 113))	('C250T', 'Mutation', 'rs141046429', (22, 27))	('C228A', 'Mutation', 'rs1338921187', (88, 93))	('G245T', 'Mutation', 'rs111782749', (108, 113))
57225	31122840	Technical validation showed that UroMuTERT could detect C228T and C250T mutations down to respectively 0.8% and 0.5% Mutant Allelic Fractions (MAFs) at sequencing read depth > 10,000x (appendix pp.	('MAF', 'Gene', '4094', (143, 146))	('C228T', 'Var', (56, 61))	('C228T', 'Mutation', 'rs750993939', (56, 61))	('C250T', 'Mutation', 'rs141046429', (66, 71))	('MAF', 'Gene', (143, 146))	('C250T', 'Var', (66, 71))	('UroMuTERT', 'Chemical', '-', (33, 42))
57227	31122840	The sensitivity of C228T and/or C250T was 81 8% (95% CI 72 2-89 2) for US and 83 5% (95% CI 74 3-90 5) for UP (Table 2).	('C250T', 'Mutation', 'rs141046429', (32, 37))	('C228T', 'Var', (19, 24))	('C228T', 'Mutation', 'rs750993939', (19, 24))	('C250T', 'Var', (32, 37))
57229	31122840	In both US and UP, MAFs correlated with the tumour risk-score, with significantly higher mutational load in high-risk (pTa/pT1 high grade and any stage associated with CIS) compared with low-risk NMIUC (Low-grade pTa or pT1 tumours) (appendix p 7).	('pTa', 'Gene', '171558', (213, 216))	('pTa', 'Gene', '171558', (119, 122))	('pT1', 'Gene', (220, 223))	('CIS', 'Gene', (168, 171))	('pT1', 'Gene', '58492', (123, 126))	('pT1', 'Gene', (123, 126))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('tumours', 'Disease', (224, 231))	('pTa', 'molecular_function', 'GO:0008959', ('119', '122'))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Disease', (44, 50))	('CIS', 'Gene', '1154', (168, 171))	('p 7', 'Gene', '84068', (243, 246))	('tumours', 'Phenotype', 'HP:0002664', (224, 231))	('tumours', 'Disease', 'MESH:D009369', (224, 231))	('p 7', 'Gene', (243, 246))	('pTa', 'molecular_function', 'GO:0008959', ('213', '216'))	('mutational', 'Var', (89, 99))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('tumour', 'Disease', 'MESH:D009369', (224, 230))	('tumour', 'Disease', (224, 230))	('pTa', 'Gene', (213, 216))	('pTa', 'Gene', (119, 122))	('MAF', 'Gene', (19, 22))	('higher', 'PosReg', (82, 88))	('pT1', 'Gene', '58492', (220, 223))	('MAF', 'Gene', '4094', (19, 22))
57232	31122840	We noted comparable performance in detecting UC when rare but concomitant mutations to the predominant C228T/C250T detected in ten urinary DNAs of cases (C228A, CC242-243TT and a newly discovered G238A) were considered (Table 2, and appendix p 8-11).	('CC242-243TT', 'Var', (161, 172))	('C228T', 'Var', (103, 108))	('C228A', 'Var', (154, 159))	('C250T', 'Mutation', 'rs141046429', (109, 114))	('C228A', 'Mutation', 'rs1338921187', (154, 159))	('G238A', 'Mutation', 'rs777683054', (196, 201))	('G238A', 'Var', (196, 201))	('C228T', 'SUBSTITUTION', 'None', (103, 108))
57234	31122840	We assessed the analytical sensitivity on the 83/93 available matched tumours and identified urinary TERT promoter mutation(s) in US or UP in 71 of the 72 TERT mutated tumours (analytical sensitivity of 98 6%; 95% CI 92 5-99 96).	('TERT', 'Gene', '7015', (101, 105))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumours', 'Phenotype', 'HP:0002664', (168, 175))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('tumours', 'Disease', 'MESH:D009369', (168, 175))	('TERT', 'Gene', (101, 105))	('tumours', 'Disease', (168, 175))	('TERT', 'Gene', (155, 159))	('mutation', 'Var', (115, 123))	('TERT', 'Gene', '7015', (155, 159))	('tumours', 'Disease', (70, 77))
57235	31122840	Of the 11 tumours without TERT promoter mutations, eight were also negative in urine samples, two were positive for C228T in both US and UP (MAF ranged from 1 1 to 7 0%), highlighting the superiority of the urine in 2 4% of cases to detect tumour-derived mutations that are not necessarily captured by a unique piece of tumour tissue due to clonal heterogeneity.	('C228T', 'Var', (116, 121))	('MAF', 'Gene', (141, 144))	('mutations', 'Var', (255, 264))	('tumours', 'Disease', (10, 17))	('tumour', 'Phenotype', 'HP:0002664', (320, 326))	('MAF', 'Gene', '4094', (141, 144))	('mutations', 'Var', (40, 49))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('tumour', 'Disease', 'MESH:D009369', (320, 326))	('tumours', 'Disease', 'MESH:D009369', (10, 17))	('tumour', 'Disease', (320, 326))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('tumour', 'Disease', 'MESH:D009369', (240, 246))	('tumour', 'Disease', 'MESH:D009369', (10, 16))	('tumour', 'Disease', (10, 16))	('tumour', 'Disease', (240, 246))	('TERT', 'Gene', (26, 30))	('to 7', 'Species', '1214577', (161, 165))	('TERT', 'Gene', '7015', (26, 30))	('C228T', 'Mutation', 'rs750993939', (116, 121))
57236	31122840	One case showed discordant results with a mutation C228A detected only in the tumour at 0 4%, likely reflecting a minor tumoral clone undetectable in US or UP.	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('tumour', 'Disease', (78, 84))	('tumoral', 'Disease', (120, 127))	('tumoral', 'Disease', 'MESH:D009369', (120, 127))	('C228A', 'Mutation', 'rs1338921187', (51, 56))	('C228A', 'Var', (51, 56))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
57241	31122840	The detection of concomitant C228T/C228A in plasma cfDNA, US, and UP at consistent levels (mean of 17 3%/0 4% respectively) in a control prompted us to screen WBC to determine the origin of the multiple TERT positivity.	('C228T', 'SUBSTITUTION', 'None', (29, 34))	('TERT', 'Gene', '7015', (203, 207))	('BC', 'Phenotype', 'HP:0009725', (160, 162))	('TERT', 'Gene', (203, 207))	('C228T', 'Var', (29, 34))	('C228A', 'Mutation', 'rs1338921187', (35, 40))
57242	31122840	WBC tested positive for C228T/C228A at similar levels, which is suggestive of mosaicism or clonal haematopoiesis associated with haematuria.	('C228A', 'Mutation', 'rs1338921187', (30, 35))	('haematuria', 'Disease', (129, 139))	('BC', 'Phenotype', 'HP:0009725', (1, 3))	('C228T', 'SUBSTITUTION', 'None', (24, 29))	('haematuria', 'Disease', 'MESH:D006417', (129, 139))	('C228T', 'Var', (24, 29))
57243	31122840	Two additional controls scored C250T positive (0 5% and 5 5% MAF) but negative in UP and US.	('C250T', 'Mutation', 'rs141046429', (31, 36))	('MAF', 'Gene', (61, 64))	('C250T', 'Var', (31, 36))	('MAF', 'Gene', '4094', (61, 64))
57254	31122840	In this study, we developed UroMuTERT, a simple, non-invasive and sensitive assay with detection thresholds of 0 8% and 0 5% MAFs for C228T and C250T mutations respectively.	('UroMuTERT', 'Chemical', '-', (28, 37))	('C250T', 'Mutation', 'rs141046429', (144, 149))	('C250T', 'Var', (144, 149))	('MAF', 'Gene', '4094', (125, 128))	('C228T', 'Var', (134, 139))	('C228T', 'Mutation', 'rs750993939', (134, 139))	('MAF', 'Gene', (125, 128))
57256	31122840	In addition, the ability of UroMuTERT to quantify low-level mutations down to 0 5% enabled the detection of a significant proportion of cases with MAF < 5% (26 4% in US and 13 0% in UP) and is therefore a critical parameter for accurate detection and enhanced sensitivity.	('mutations', 'Var', (60, 69))	('MAF', 'Gene', (147, 150))	('MAF', 'Gene', '4094', (147, 150))	('UroMuTERT', 'Chemical', '-', (28, 37))
57257	31122840	Analysing additional rare TERT promoter mutations did not improve UroMuTERT performance, as they were concomitant to the prevalent C228T and/or C250T.	('TERT', 'Gene', (26, 30))	('TERT', 'Gene', (71, 75))	('TERT', 'Gene', '7015', (71, 75))	('C250T', 'Mutation', 'rs141046429', (144, 149))	('C250T', 'Var', (144, 149))	('C228T', 'Var', (131, 136))	('TERT', 'Gene', '7015', (26, 30))	('C228T', 'Mutation', 'rs750993939', (131, 136))	('UroMuTERT', 'Chemical', '-', (66, 75))	('mutations', 'Var', (40, 49))
57259	31122840	Our UroMuTERT assay demonstrated comparable performance to that of recently developed UroSEEK multiple markers assay (including C228T and C250T) for the detection of primary or early UC (sensitivity of 86 7% versus 83%; Specificity of 94 7% versus 93%) and higher sensitivity for the detection of UC recurrence (87 5% versus 68%).	('UroMuTERT', 'Chemical', '-', (4, 13))	('UroSEEK', 'Chemical', '-', (86, 93))	('C250T', 'Var', (138, 143))	('C228T', 'Var', (128, 133))	('C250T', 'Mutation', 'rs141046429', (138, 143))	('C228T', 'Mutation', 'rs750993939', (128, 133))	('early UC', 'Disease', (177, 185))	('primary', 'Disease', (166, 173))
57260	31122840	Previously reported to be mutually exclusive mutations in UC, we revealed co-occurrence of urinary TERT promoters mutations in UC in 10 7% of UC cases, similarly to what has recently been reported in a minority of early-onset bladder tumours.	('bladder tumours', 'Disease', 'MESH:D001749', (226, 241))	('TERT', 'Gene', (99, 103))	('mutations', 'Var', (114, 123))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('TERT', 'Gene', '7015', (99, 103))	('tumours', 'Phenotype', 'HP:0002664', (234, 241))	('bladder tumours', 'Disease', (226, 241))
57273	31122840	We report for the first time, the rare occurrence of TERT promoter mutations in the white blood cells DNA, plasma and urine samples in three UC cases and one control, likely reflecting somatic mosaicism (clonal haematopoiesis or post-zygotic mosaicism) in the control and a probable synergetic mechanism of mosaicism with tumorigenesis in the cases.	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))	('mutations', 'Var', (67, 76))
57274	31122840	In addition, although never reported for C228T but for TERT c.-57T>G in familial melanoma, we cannot exclude that the C228T identified in one case at 35-40% MAF is of germline origin.	('familial melanoma', 'Disease', (72, 89))	('MAF', 'Gene', '4094', (157, 160))	('C228T', 'Mutation', 'rs750993939', (41, 46))	('MAF', 'Gene', (157, 160))	('C228T', 'Var', (118, 123))	('familial melanoma', 'Disease', 'OMIM:155600', (72, 89))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('c.-57T>G', 'Mutation', 'c.-57T>G', (60, 68))	('TERT', 'Gene', (55, 59))	('TERT', 'Gene', '7015', (55, 59))	('C228T', 'Mutation', 'rs750993939', (118, 123))
57275	31122840	Blood-based clonal mosaicism has been associated with age and increased risk of solid and haematological cancers and recent evidence showed that blood-based mutations could predict the risk of acute myeloid leukaemia years prior to the disease onset.	('Blood-based clonal mosaicism', 'Var', (0, 28))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (193, 216))	('associated', 'Reg', (38, 48))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('haematological cancers', 'Disease', (90, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('haematological cancers', 'Disease', 'MESH:D009369', (90, 112))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (199, 216))	('acute myeloid leukaemia', 'Disease', (193, 216))
57276	31122840	Rare mosaicism in patients with UC has been observed and may therefore add a layer of complexity in the interpretation of an urinary TERT positive test with negative subsequent cystoscopy or urography.	('TERT', 'Gene', '7015', (133, 137))	('mosaicism', 'Var', (5, 14))	('patients', 'Species', '9606', (18, 26))	('TERT', 'Gene', (133, 137))
57280	31122840	In conclusion, our study demonstrates unprecedented performance of a single-gene assay quantifying tumour-derived TERT promoter mutation load in urine for the detection of all forms of UC and lays the foundations for large-scale validation and clinical utility studies for implementation into clinical practice.	('TERT', 'Gene', '7015', (114, 118))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('mutation load', 'Var', (128, 141))	('TERT', 'Gene', (114, 118))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
57281	31122840	The role of rare TERT promoter mutations in leucocytes on UC development and its impact on the clinical use of the biomarkers should be further examined.	('TERT', 'Gene', (17, 21))	('mutations', 'Var', (31, 40))	('TERT', 'Gene', '7015', (17, 21))
57291	27127359	This study was aimed at exploring the role of the quantitative expression of micro-RNAs (miRNAs) in bladder cancer tissue in comparison with normal mucosa and healthy controls (HCs) as a molecular marker.	('bladder cancer', 'Disease', (100, 114))	('micro-RNAs', 'Var', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (100, 114))	('HCs', 'molecular_function', 'GO:0004077', ('177', '180'))	('bladder cancer', 'Disease', 'MESH:D001749', (100, 114))
57297	27127359	The fold change of miR129, miR205 and miR200a was significantly higher in the normal-looking mucosa of bladder tumor patients than the HC (P < 0.005).	('bladder tumor', 'Phenotype', 'HP:0009725', (103, 116))	('fold change', 'MPA', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('higher', 'PosReg', (64, 70))	('miR200a', 'Gene', (38, 45))	('bladder tumor', 'Disease', (103, 116))	('miR129', 'Var', (19, 25))	('bladder tumor', 'Disease', 'MESH:D001749', (103, 116))	('miR200a', 'Gene', '406983', (38, 45))	('miR205', 'Gene', '406988', (27, 33))	('patients', 'Species', '9606', (117, 125))	('miR205', 'Gene', (27, 33))
57298	27127359	Expression of miR129, miR205 and miR200a in the normal-looking mucosa of bladder cancer patients was significantly higher than the normal mucosa of a HC.	('miR205', 'Gene', '406988', (22, 28))	('miR129', 'Var', (14, 20))	('bladder cancer', 'Disease', (73, 87))	('miR200a', 'Gene', '406983', (33, 40))	('Expression', 'MPA', (0, 10))	('miR205', 'Gene', (22, 28))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('higher', 'PosReg', (115, 121))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))	('miR200a', 'Gene', (33, 40))
57325	27127359	Expression of only miR-21 and miR-129 were both correlated with grade and stage (P = 0.001 and <0.009, respectively).	('miR-129', 'Chemical', '-', (30, 37))	('miR-21', 'Gene', '406991', (19, 25))	('correlated', 'Reg', (48, 58))	('miR-129', 'Var', (30, 37))	('miR-21', 'Gene', (19, 25))
57336	27127359	The most relevant research done so far is on allelic loss on chromosome 9, which is found to be associated with well-differentiated tumors, whereas in the aggressive subtype of TCC, alterations on chromosome 17p, which is the site for the p53gene, has been reported.	('chromosome', 'cellular_component', 'GO:0005694', ('61', '71'))	('associated', 'Reg', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('allelic loss', 'Var', (45, 57))	('TCC', 'cellular_component', 'GO:0005579', ('177', '180'))	('chromosome', 'cellular_component', 'GO:0005694', ('197', '207'))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('p53', 'Gene', (239, 242))	('tumors', 'Disease', (132, 138))	('p53', 'Gene', '7157', (239, 242))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
57346	27127359	Depletion of miR-21 in breast cancer cell lines, furthermore, was shown to suppress cell growth and promote apoptosis.	('breast cancer', 'Disease', (23, 36))	('miR-21', 'Gene', (13, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('cell growth', 'biological_process', 'GO:0016049', ('84', '95'))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('cell growth', 'CPA', (84, 95))	('Depletion', 'Var', (0, 9))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('miR-21', 'Gene', '406991', (13, 19))	('suppress', 'NegReg', (75, 83))	('promote', 'PosReg', (100, 107))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('apoptosis', 'CPA', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
57361	27127359	Pending further studies and validations, we suggest that miRNA-200a, miR-205 and miR-129 might be used for predicting early metastasis in clinical practice.	('miR-205', 'Gene', '406988', (69, 76))	('miRNA-200a', 'Var', (57, 67))	('miR-129', 'Chemical', '-', (81, 88))	('miR-129', 'Var', (81, 88))	('miR-205', 'Gene', (69, 76))	('early metastasis', 'CPA', (118, 134))
57364	27127359	There was a highly significant difference in the expression of miR-129, miR-200a and miR-205 between normal-looking mucosa of a bladder cancer patient and that of a healthy person.	('bladder cancer', 'Disease', 'MESH:D001749', (128, 142))	('bladder cancer', 'Disease', (128, 142))	('miR-129', 'Chemical', '-', (63, 70))	('patient', 'Species', '9606', (143, 150))	('significant', 'Reg', (19, 30))	('miR-129', 'Var', (63, 70))	('miR-205', 'Gene', (85, 92))	('expression', 'MPA', (49, 59))	('miR-205', 'Gene', '406988', (85, 92))	('person', 'Species', '9606', (173, 179))	('miR-200a', 'Gene', (72, 80))	('miR-200a', 'Gene', '406983', (72, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
57366	27127359	Genetic changes precede phenotypic changes, which could be the reason of recurrence of tumor in different zones of bladder epithelium.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Genetic changes', 'Var', (0, 15))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
57374	27050392	The silencing of circHIPK3 but not HIPK3 mRNA significantly inhibits human cell growth.	('human', 'Species', '9606', (69, 74))	('HIPK3', 'Gene', '10114', (21, 26))	('HIPK3', 'Gene', (21, 26))	('inhibits', 'NegReg', (60, 68))	('cell growth', 'biological_process', 'GO:0016049', ('75', '86'))	('HIPK3', 'Gene', '10114', (35, 40))	('HIPK3', 'Gene', (35, 40))	('silencing', 'Var', (4, 13))	('human cell growth', 'CPA', (69, 86))
57380	27050392	Exon skipping leads to a lariat whose restricted structure promotes circularization, whereas direct back-splicing refers to the pairing of a downstream splice donor with an unspliced upstream splice acceptor, which results in the circularization of the intervening RNA.	('circularization', 'MPA', (68, 83))	('splicing', 'biological_process', 'GO:0045292', ('105', '113'))	('donor', 'Species', '9606', (159, 164))	('circularization', 'MPA', (230, 245))	('results in', 'Reg', (215, 225))	('RNA', 'cellular_component', 'GO:0005562', ('265', '268'))	('promotes', 'PosReg', (59, 67))	('Exon skipping', 'Var', (0, 13))
57388	27050392	The formation of circHIPK3 is due to the long intronic complementary repeat elements.	('formation', 'biological_process', 'GO:0009058', ('4', '13'))	('long intronic complementary repeat elements', 'Var', (41, 84))	('HIPK3', 'Gene', '10114', (21, 26))	('HIPK3', 'Gene', (21, 26))
57420	27050392	qRT-PCR analysis of nuclear and cytoplasmic circHIPK3 RNA and fluorescence in situ hybridization (FISH) against circHIPK3 demonstrated that the circular form of HIPK3 preferentially localized in the cytoplasm (Fig.	('circular', 'Var', (144, 152))	('HIPK3', 'Gene', '10114', (116, 121))	('localized', 'MPA', (182, 191))	('HIPK3', 'Gene', (116, 121))	('HIPK3', 'Gene', (161, 166))	('HIPK3', 'Gene', '10114', (161, 166))	('RNA', 'cellular_component', 'GO:0005562', ('54', '57'))	('HIPK3', 'Gene', '10114', (48, 53))	('preferentially', 'PosReg', (167, 181))	('HIPK3', 'Gene', (48, 53))	('CR', 'Chemical', '-', (5, 7))	('cytoplasm', 'cellular_component', 'GO:0005737', ('199', '208'))
57423	27050392	An analysis of the flanking introns of HIPK3 Exon2 showed highly complementary Alu repeats with 28 short interspersed elements in the intron upstream of HIPK3 Exon2 and 51 short interspersed elements downstream from Exon3 (Fig.	('HIPK3', 'Gene', '10114', (39, 44))	('HIPK3', 'Gene', (39, 44))	('Alu repeats', 'Var', (79, 90))	('HIPK3', 'Gene', '10114', (153, 158))	('HIPK3', 'Gene', (153, 158))
57431	27050392	Surprisingly, the deletion of the upstream Alu sequence did not decrease the formation of circHIPK3, rather, it slight increased the formation of this RNA (Fig.	('formation', 'MPA', (133, 142))	('formation', 'biological_process', 'GO:0009058', ('133', '142'))	('RNA', 'cellular_component', 'GO:0005562', ('151', '154'))	('formation', 'biological_process', 'GO:0009058', ('77', '86'))	('HIPK3', 'Gene', '10114', (94, 99))	('deletion', 'Var', (18, 26))	('HIPK3', 'Gene', (94, 99))	('increased', 'PosReg', (119, 128))
57432	27050392	The result showed that circHIPK3 was significantly downregulated on the deletion of the intron (Fig.	('intron', 'Gene', (88, 94))	('HIPK3', 'Gene', '10114', (27, 32))	('downregulated', 'NegReg', (51, 64))	('HIPK3', 'Gene', (27, 32))	('deletion', 'Var', (72, 80))
57440	27050392	An EdU incorporation assay also revealed that the proliferation of various human cells was impaired on the knockdown of circHIPK3 expression (Fig.	('knockdown', 'Var', (107, 116))	('impaired', 'NegReg', (91, 99))	('EdU', 'Chemical', 'MESH:C031086', (3, 6))	('HIPK3', 'Gene', '10114', (124, 129))	('human', 'Species', '9606', (75, 80))	('HIPK3', 'Gene', (124, 129))	('expression', 'Species', '29278', (130, 140))
57441	27050392	Consistent with this result from the siRNA knockdown experiments, we observed that cell proliferation was significantly suppressed on the knockdown of circHIPK3 expression in HEK-293 T cells via CRISPR/Cas9 technology (Supplementary Fig.	('knockdown', 'Var', (138, 147))	('suppressed', 'NegReg', (120, 130))	('expression', 'Species', '29278', (161, 171))	('cell proliferation', 'CPA', (83, 101))	('cell proliferation', 'biological_process', 'GO:0008283', ('83', '101'))	('HEK-293 T', 'CellLine', 'CVCL:0063', (175, 184))	('CR', 'Chemical', '-', (195, 197))	('Cas', 'cellular_component', 'GO:0005650', ('202', '205'))	('HIPK3', 'Gene', '10114', (155, 160))	('HIPK3', 'Gene', (155, 160))
57447	27050392	We hypothesized that circHIPK3-associated miRNAs may potentially inhibit the luciferase activity, presumably via the miRNA-mediated activation of deadenylation and subsequent exonucleolytic degradation.	('luciferase activity', 'molecular_function', 'GO:0050397', ('77', '96'))	('activation', 'PosReg', (132, 142))	('exonucleolytic degradation', 'MPA', (175, 201))	('deadenylation', 'MPA', (146, 159))	('miRNAs', 'Var', (42, 48))	('luciferase', 'Enzyme', (77, 87))	('luciferase activity', 'molecular_function', 'GO:0047077', ('77', '96'))	('degradation', 'biological_process', 'GO:0009056', ('190', '201'))	('activity', 'MPA', (88, 96))	('luciferase activity', 'molecular_function', 'GO:0045289', ('77', '96'))	('HIPK3', 'Gene', '10114', (25, 30))	('HIPK3', 'Gene', (25, 30))	('inhibit', 'NegReg', (65, 72))	('luciferase activity', 'molecular_function', 'GO:0047712', ('77', '96'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('77', '96'))
57448	27050392	Supporting this hypothesis, we observed that inclusion of the circHIPK3 sequence in the 3'-untranslated region (UTR; without any other cellular perturbations) causes downregulation of luciferase activity (Fig.	('luciferase activity', 'molecular_function', 'GO:0047077', ('184', '203'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('184', '203'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('184', '203'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('184', '203'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('184', '203'))	('HIPK3', 'Gene', '10114', (66, 71))	('HIPK3', 'Gene', (66, 71))	('downregulation', 'NegReg', (166, 180))	('inclusion', 'Var', (45, 54))	('activity', 'MPA', (195, 203))	('luciferase', 'Enzyme', (184, 194))
57449	27050392	Subsequently, knockdown of the endogenous circHIPK3 further decreases the luciferase activity (from the LUC+circHIPK3 plasmid).	('decreases', 'NegReg', (60, 69))	('luciferase activity', 'molecular_function', 'GO:0047077', ('74', '93'))	('HIPK3', 'Gene', '10114', (112, 117))	('HIPK3', 'Gene', (112, 117))	('luciferase activity', 'molecular_function', 'GO:0045289', ('74', '93'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('74', '93'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('74', '93'))	('luciferase', 'Enzyme', (74, 84))	('luciferase activity', 'molecular_function', 'GO:0050248', ('74', '93'))	('knockdown', 'Var', (14, 23))	('HIPK3', 'Gene', '10114', (46, 51))	('HIPK3', 'Gene', (46, 51))	('activity', 'MPA', (85, 93))
57454	27050392	Compared with the control RNA, 9 miRNAs (miR-124, miR-152, miR-193a, miR-29a, miR-29b, miR-338, miR-379, miR-584 and miR-654) out of the 424 miRNAs were able to reduce the luciferase reporter activities by at least 30% (Fig.	('miR-338', 'Gene', (87, 94))	('miR-379', 'Gene', (96, 103))	('miR-29b', 'Gene', '407024', (78, 85))	('miR-584', 'Gene', '693169', (105, 112))	('miR-584', 'Gene', (105, 112))	('miR-338', 'Gene', '442906', (87, 94))	('miR-29b', 'Gene', (78, 85))	('miR-654', 'Gene', '724024', (117, 124))	('miR-193a', 'Gene', '406968', (59, 67))	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))	('miR-193a', 'Gene', (59, 67))	('miR-152', 'Gene', (50, 57))	('miR-29a', 'Gene', '407021', (69, 76))	('miR-124', 'Var', (41, 48))	('luciferase reporter', 'Enzyme', (172, 191))	('reduce', 'NegReg', (161, 167))	('miR-29a', 'Gene', (69, 76))	('miR-654', 'Gene', (117, 124))	('miR-152', 'Gene', '406943', (50, 57))	('miR-379', 'Gene', '494328', (96, 103))
57458	27050392	We further mutated each miRNA target site from the luciferase reporter with inclusion of the circHIPK3 sequence in the 3'-UTR and circHIPK3 expressing vector, respectively.	('HIPK3', 'Gene', '10114', (134, 139))	('HIPK3', 'Gene', (134, 139))	('HIPK3', 'Gene', '10114', (97, 102))	('mutated', 'Var', (11, 18))	('HIPK3', 'Gene', (97, 102))
57459	27050392	In addition, transfecting a mutant circHIPK3 circle that lacks a given miRNA-binding site is unable to rescue luciferase activities (Supplementary Fig.	('luciferase', 'Enzyme', (110, 120))	('HIPK3', 'Gene', '10114', (39, 44))	('activities', 'MPA', (121, 131))	('HIPK3', 'Gene', (39, 44))	('mutant', 'Var', (28, 34))	('miRNA-binding', 'molecular_function', 'GO:0035198', ('71', '84'))
57463	27050392	A cell proliferation assay revealed that four of the miRNAs (miR-124, miR-193, miR-379 and miR-654) could significantly inhibit HEK-293 T cell growth, and miR-124 exerted the most striking effect (Fig.	('miR-654', 'Gene', (91, 98))	('HEK-293 T', 'CellLine', 'CVCL:0063', (128, 137))	('cell growth', 'biological_process', 'GO:0016049', ('138', '149'))	('miR-379', 'Gene', '494328', (79, 86))	('miR-124', 'Var', (61, 68))	('miR-193', 'Var', (70, 77))	('HEK-293 T cell growth', 'CPA', (128, 149))	('inhibit', 'NegReg', (120, 127))	('miR-124', 'Var', (155, 162))	('miR-379', 'Gene', (79, 86))	('cell proliferation', 'biological_process', 'GO:0008283', ('2', '20'))	('miR-654', 'Gene', '724024', (91, 98))
57464	27050392	Using a biotin-coupled miR-124 mimic, we observed a more than fivefold enrichment of circHIPK3 in the miR-124-captured fraction compared with the negative control (Fig.	('HIPK3', 'Gene', '10114', (89, 94))	('miR-124-captured', 'Var', (102, 118))	('HIPK3', 'Gene', (89, 94))	('biotin', 'Chemical', 'MESH:D001710', (8, 14))
57466	27050392	In addition, two known proliferation-promoted targets (IL6R and DLX2) of miR-124 were found to be downregulated by the knockdown of circHIPK3, and the miR-124-mediated repression of the two target genes was rescued by ectopic expression of circHIPK3 (Fig.	('downregulated', 'NegReg', (98, 111))	('IL6R', 'molecular_function', 'GO:0004915', ('55', '59'))	('expression', 'Species', '29278', (226, 236))	('HIPK3', 'Gene', '10114', (136, 141))	('HIPK3', 'Gene', (136, 141))	('HIPK3', 'Gene', (244, 249))	('miR-124', 'Gene', (73, 80))	('HIPK3', 'Gene', '10114', (244, 249))	('knockdown', 'Var', (119, 128))
57467	27050392	Moreover, the ectopic expression of circHIPK3 could attenuate the anti-proliferative effects of miR-124 (Fig.	('HIPK3', 'Gene', '10114', (40, 45))	('HIPK3', 'Gene', (40, 45))	('miR-124', 'Gene', (96, 103))	('attenuate', 'NegReg', (52, 61))	('expression', 'Species', '29278', (22, 32))	('ectopic expression', 'Var', (14, 32))	('anti-proliferative effects', 'CPA', (66, 92))
57537	27050392	Mutations of each miRNA-binding sites in circHIPK3 sequence were performed using Mut Express II Fast Mutagenesis Kit (Vazyme, NanJing, China).	('miRNA-binding', 'molecular_function', 'GO:0035198', ('18', '31'))	('Mutations', 'Var', (0, 9))	('Mutagenesis', 'biological_process', 'GO:0006280', ('101', '112'))	('HIPK3', 'Gene', (45, 50))	('HIPK3', 'Gene', '10114', (45, 50))
57538	27050392	The mutations were performed in both circHIPK3 expressing vector and luciferae reporter harbouring circHIPK3 sequence.	('HIPK3', 'Gene', '10114', (41, 46))	('HIPK3', 'Gene', '10114', (103, 108))	('HIPK3', 'Gene', (41, 46))	('HIPK3', 'Gene', (103, 108))	('mutations', 'Var', (4, 13))
57550	27050392	Huh-7, HCT-116, HeLa cells (1 x 104) were seeded in each well of 96-well plates for transfection with si-HIPK3, si-circHIPK3, si-both or negative control (NC) oligonucleotide.	('HIPK3', 'Gene', '10114', (105, 110))	('HIPK3', 'Gene', (105, 110))	('HIPK3', 'Gene', '10114', (119, 124))	('HIPK3', 'Gene', (119, 124))	('oligonucleotide', 'Chemical', 'MESH:D009841', (159, 174))	('HeLa', 'CellLine', 'CVCL:0030', (16, 20))	('Huh-7', 'Gene', (0, 5))	('Huh-7', 'Gene', '284424', (0, 5))	('HCT-116', 'CellLine', 'CVCL:0291', (7, 14))	('si-both', 'Var', (126, 133))
57588	26783756	This cell line has been used to show that both Cd+2 and As+3 can cause the malignant transformation of human urothelial cells.	('Cd+2', 'Var', (47, 51))	('human', 'Species', '9606', (103, 108))	('cause', 'Reg', (65, 70))	('As+3', 'Chemical', '-', (56, 60))	('malignant transformation of human urothelial cells', 'CPA', (75, 125))	('As+3', 'Var', (56, 60))
57589	26783756	These resulting As+3- and Cd+2-transformed cell lines were all shown to retain a morphology consistent with human urothelial cancer and to display phenotypic differences characteristic of tumor heterogeneity.	('tumor', 'Disease', (188, 193))	('urothelial cancer', 'Disease', 'MESH:D014523', (114, 131))	('Cd+', 'Chemical', 'MESH:D002104', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('Cd+2-transformed', 'Var', (26, 42))	('human', 'Species', '9606', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('urothelial cancer', 'Disease', (114, 131))	('As+3', 'Chemical', '-', (16, 20))
57596	26783756	It was also shown that acute exposure of the parental UROtsa cells to either As+3 or Cd+2 resulted in a marked reduction in SPARC expression.	('reduction', 'NegReg', (111, 120))	('As+3', 'Chemical', '-', (77, 81))	('Cd+', 'Chemical', 'MESH:D002104', (85, 88))	('Cd+2', 'Var', (85, 89))	('SPARC expression', 'MPA', (124, 140))
57639	26783756	An analysis of SPARC mRNA expression confirmed that the As+3-and Cd+2-transformed cells had significantly reduced levels of SPARC mRNA compared to the parental UROtsa cells (Fig 1A).	('levels', 'MPA', (114, 120))	('Cd+2-transformed', 'Var', (65, 81))	('As+3', 'Chemical', '-', (56, 60))	('Cd+', 'Chemical', 'MESH:D002104', (65, 68))	('SPARC mRNA', 'MPA', (124, 134))	('reduced', 'NegReg', (106, 113))
57699	26783756	These studies show that the localization of SPARC in the transfectants was very similar to that seen in the parental UROtsa cells, suggesting that cells transformed by As+3 and Cd+2 do not alter the localization of SPARC when it is stably transfected back into these cell lines.	('localization', 'biological_process', 'GO:0051179', ('199', '211'))	('Cd+2', 'Var', (177, 181))	('localization', 'MPA', (199, 211))	('localization', 'biological_process', 'GO:0051179', ('28', '40'))	('As+3', 'Chemical', '-', (168, 172))	('Cd+', 'Chemical', 'MESH:D002104', (177, 180))
57706	26783756	The results of this analysis showed that SPARC expression caused a significant decrease in chemotaxis for 3 of the 4 SPARC transfected cell lines (As#3, Cd#1, Cd#4) while the other cell line showed no significant differences between the SPARC transfected cell line and it non-transfected counterpart (As#6).	('chemotaxis', 'biological_process', 'GO:0006935', ('91', '101'))	('As', 'Chemical', 'MESH:D001151', (147, 149))	('expression', 'Var', (47, 57))	('decrease', 'NegReg', (79, 87))	('chemotaxis', 'CPA', (91, 101))	('As#6', 'Chemical', 'MESH:C043832', (301, 305))	('SPARC', 'Gene', (41, 46))	('As', 'Chemical', 'MESH:D001151', (301, 303))
57737	26783756	This finding will allow the elucidation of the molecular signature of TICs isolated from an urothelial cell line transformed by As+3 and Cd+2, two common environmental pollutants.	('Cd+2', 'Var', (137, 141))	('TIC', 'Phenotype', 'HP:0100033', (70, 73))	('Cd+', 'Chemical', 'MESH:D002104', (137, 140))	('As+3', 'Chemical', '-', (128, 132))	('TICs', 'Phenotype', 'HP:0100033', (70, 74))	('TIC', 'Disease', (70, 73))	('TIC', 'Disease', 'None', (70, 73))
57772	26783756	In conclusion, this study demonstrates that TICs can be isolated from cultures of UROtsa cells malignantly transformed by either As+3 or Cd+2.	('Cd+2', 'Var', (137, 141))	('TIC', 'Disease', (44, 47))	('TIC', 'Disease', 'None', (44, 47))	('Cd+', 'Chemical', 'MESH:D002104', (137, 140))	('As+3', 'Chemical', '-', (129, 133))	('TIC', 'Phenotype', 'HP:0100033', (44, 47))	('TICs', 'Phenotype', 'HP:0100033', (44, 48))
57803	23251807	The rate of accompanying liver cirrhosis was significantly lower in the EHPM group (31.3%) than the HCC-only group (51.3%; P = 0.0025).	('EHPM', 'Var', (72, 76))	('liver cirrhosis', 'Disease', 'MESH:D008103', (25, 40))	('lower', 'NegReg', (59, 64))	('liver cirrhosis', 'Disease', (25, 40))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (25, 40))	('HCC', 'Phenotype', 'HP:0001402', (100, 103))
57844	23251807	This may suggest a relationship between gastric cancer and HCV, especially for infection with genotype 1b.	('gastric cancer', 'Phenotype', 'HP:0012126', (40, 54))	('HCV', 'Species', '11103', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('relationship', 'Reg', (19, 31))	('gastric cancer', 'Disease', (40, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (40, 54))	('HCV', 'Disease', (59, 62))	('genotype 1b', 'Var', (94, 105))
57877	33926541	devised a 'suitability score' as a metric of the molecular similarity of CCLs to high-grade serous ovarian carcinoma based on a heuristic weighting of copy number alterations, mutation status of several genes that distinguish ovarian cancer subtypes, and hypermutation status.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('serous ovarian carcinoma', 'Disease', (92, 116))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('copy number alterations', 'Var', (151, 174))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (92, 116))	('ovarian cancer', 'Disease', 'MESH:D010051', (226, 240))	('CCLs', 'Chemical', '-', (73, 77))	('ovarian cancer', 'Disease', (226, 240))	('CCLs', 'Disease', (73, 77))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (99, 116))	('mutation', 'Var', (176, 184))	('ovarian cancer', 'Phenotype', 'HP:0100615', (226, 240))
57878	33926541	transcriptomic and copy number alterations) to quantify the similarity of cell lines to tumors.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('copy number', 'Var', (19, 30))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
57881	33926541	have developed methods to assess CCLs using molecular traits such as copy number alterations (CNA), somatic mutations, DNA methylation, and transcriptomics.	('DNA methylation', 'biological_process', 'GO:0006306', ('119', '134'))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('copy number alterations', 'Var', (69, 92))	('CCLs', 'Chemical', '-', (33, 37))	('CCLs', 'Disease', (33, 37))
57952	33926541	SK-OV-3, Vcap, and RT4 were cultured in Dulbecco's modified Eagle medium (DMEM, high glucose, 11960069, Gibco) with 1% penicillin-streptomycin-glutamine (10378016, Life Technologies); Caov-4, PC-3, NCCIT, and A2780 were cultured using RPMI-1640 medium (11875093, Gibco) while HEC-59 was in Iscove's modified Dulbecco's medium (IMDM, 12440053, Gibco).	('Vcap', 'Chemical', '-', (9, 13))	('11875093', 'Var', (253, 261))	('penicillin', 'Chemical', 'MESH:D010406', (119, 129))	('PC-3', 'Gene', '57332', (192, 196))	('PC-3', 'Gene', (192, 196))	('high glucose', 'Phenotype', 'HP:0003074', (80, 92))	('SK-OV-3', 'Chemical', '-', (0, 7))	('glucose', 'Chemical', 'MESH:D005947', (85, 92))	('streptomycin', 'Chemical', 'MESH:D013307', (130, 142))	('HEC-59', 'CellLine', 'CVCL:2930', (276, 282))
58034	33926541	We reasoned that if SK-OV-3, A2780, and PC-3 were classified most strongly as UCEC, TGCT, and BLCA, respectively, then they would express proteins that are indicative of these cancer types.	('PC-3', 'Gene', (40, 44))	('PC-3', 'Gene', '57332', (40, 44))	('proteins', 'Protein', (138, 146))	('UCEC', 'Disease', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('express', 'Reg', (130, 137))	('A2780', 'Var', (29, 34))	('BLCA', 'Phenotype', 'HP:0009725', (94, 98))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('SK-OV-3', 'Chemical', '-', (20, 27))	('TGCT', 'Disease', (84, 88))
58039	33926541	From our computational analysis and experimental validation, SK-OV-3 is most likely an endometrioid subtype of ovarian cancer.	('ovarian cancer', 'Disease', (111, 125))	('SK-OV-3', 'Var', (61, 68))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('SK-OV-3', 'Chemical', '-', (61, 68))	('ovarian cancer', 'Disease', 'MESH:D010051', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
58040	33926541	This result is also consistent with prior classification of SK-OV-3, and the fact that SK-OV-3 lacks p53 mutations, which is prevalent in high-grade serous ovarian cancer, and it harbors an endometrioid-associated mutation in ARID1A.	('SK-OV-3', 'Chemical', '-', (87, 94))	('lacks', 'NegReg', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('ARID1A', 'Gene', '8289', (226, 232))	('SK-OV-3', 'Chemical', '-', (60, 67))	('serous ovarian cancer', 'Disease', (149, 170))	('ARID1A', 'Gene', (226, 232))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (149, 170))	('mutations', 'Var', (105, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (156, 170))	('high-grade', 'Disease', (138, 148))
58042	33926541	The OV marker WT1 was also expressed in fewer A2780 cells as compared to Caov-4 (48% vs 85%), which suggests that A2780 could be a germ cell-derived ovarian tumor.	('ovarian tumor', 'Phenotype', 'HP:0100615', (149, 162))	('ovarian tumor', 'Disease', 'MESH:D010051', (149, 162))	('A2780', 'Var', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('ovarian tumor', 'Disease', (149, 162))
58043	33926541	Taken together, our results suggest that SK-OV-3 and A2780 could represent OV subtypes that are not well represented in TCGA training data, which resulted in a low OV score and higher CCN score in other categories.	('low', 'NegReg', (160, 163))	('OV score', 'MPA', (164, 172))	('higher', 'PosReg', (177, 183))	('CCN', 'Chemical', '-', (184, 187))	('CCN score', 'MPA', (184, 193))	('SK-OV-3', 'Var', (41, 48))	('SK-OV-3', 'Chemical', '-', (41, 48))	('A2780', 'Var', (53, 58))
58054	33926541	For example, HEC-1A, HEC-1B, and KLE were previously characterized as type II endometrial cancer, which includes a serous histological subtype.	('type II endometrial cancer', 'Disease', 'MESH:D016889', (70, 96))	('HEC-1A', 'Disease', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('KLE', 'Disease', (33, 36))	('HEC-1B', 'Var', (21, 27))	('endometrial cancer', 'Phenotype', 'HP:0012114', (78, 96))	('type II endometrial cancer', 'Disease', (70, 96))
58061	33926541	Similarly, LUDLU-1 and EPLC-272H, previously reported as classical and basal respectively, had maximal tumor subtype CCN scores for these subtypes (0.323 and 0.256) (Fig.	('CCN', 'Chemical', '-', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('EPLC-272H', 'Var', (23, 32))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
58084	33926541	In contrast to LGG CCLs, LGG GEMMs, generated by Nf1 mutations expressed in different neural progenitors in combination with Pten deletion, consistently were classified as LGG (Fig.	('LGG', 'Disease', (172, 175))	('Nf1', 'Gene', '4763', (49, 52))	('Nf1', 'Gene', (49, 52))	('mutations', 'Var', (53, 62))	('CCLs', 'Chemical', '-', (19, 23))	('Pten', 'Gene', '5728', (125, 129))	('Pten', 'Gene', (125, 129))
58087	33926541	GEMMs sharing genotypes across studies, such as LUAD GEMMs driven by Kras mutation and loss of p53, also received similar general and subtype classification scores (Fig.	('mutation', 'Var', (74, 82))	('loss', 'Var', (87, 91))	('LUAD', 'Phenotype', 'HP:0030078', (48, 52))	('p53', 'Gene', '7157', (95, 98))	('p53', 'Gene', (95, 98))	('Kras', 'Gene', (69, 73))	('Kras', 'Gene', '3845', (69, 73))
58101	33926541	Most of the LUAD GEMMs, which were generated using various combinations of activating Kras mutation, loss of Trp53, and loss of Smarca4L, were correctly classified (Fig.	('mutation', 'Var', (91, 99))	('Kras', 'Gene', '3845', (86, 90))	('loss', 'NegReg', (101, 105))	('Trp53', 'Gene', '7157', (109, 114))	('loss', 'Var', (120, 124))	('Smarca4L', 'Gene', (128, 136))	('LUAD', 'Phenotype', 'HP:0030078', (12, 16))	('Trp53', 'Gene', (109, 114))	('activating', 'PosReg', (75, 85))	('Kras', 'Gene', (86, 90))
58189	33926541	Microarray tumor validation data: Microarray tumor datasets used for validation are available in the GEO database: GSE36771, GSE21653, GSE20685, GSE50948, GSE23177, GSE26639, GSE12276, GSE31448, GSE32646, GSE65194, GSE42568, GSE26682, GSE17536, GSE41328, GSE33114, GSE26906, GSE39582, GSE62080, GSE20916, GSE18088, GSE17537, GSE23878, GSE60697, GSE37892, GSE30540, GSE50161, GSE4290, GSE60184, GSE36245, GSE53733, GSE32374, GSE34824, GSE41137, GSE53757, GSE46699, GSE36895, GSE2109, GSE45436, GSE9843, GSE6222, GSE19665, GSE41804, GSE10245, GSE12667, GSE37745, GSE19188, GSE40595, GSE12172, GSE20565, GSE18520, GSE10971, GSE51373, GSE14001, GSE26193, GSE55512, GSE42404, GSE16515, GSE17891, GSE15471, GSE22780, GSE32688, GSE17951, GSE32448, GSE7307, GSE32982, GSE3325, GSE26910, GSE55945, GSE7553, GSE10282, GSE19293, GSE19234, GSE35640, GSE22968, GSE34599, and GSE23376.	('GSE23376', 'Var', (862, 870))	('GSE35640', 'Var', (828, 836))	('GSE22968', 'Var', (838, 846))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('GSE10282', 'Var', (798, 806))	('tumor', 'Disease', (11, 16))	('GSE7307', 'Var', (741, 748))	('GSE32982', 'Var', (750, 758))	('GSE19234', 'Var', (818, 826))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('GSE55945', 'Var', (779, 787))	('GSE34599', 'Var', (848, 856))	('GSE7553', 'Var', (789, 796))	('GSE32448', 'Var', (731, 739))	('GSE3325', 'Var', (760, 767))	('GSE19293', 'Var', (808, 816))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('GSE26910', 'Var', (769, 777))
58192	33926541	The other tumoroid datasets are available in the GEO database: GSE84073, GSE103990, and GSE109982.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('GSE103990', 'Var', (73, 82))	('GSE84073', 'Var', (63, 71))	('GSE109982', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
58209	32810311	These include an immune-inflamed phenotype, 15 ,  16  expression of T cell signaling pathway genes such as IFNgamma, 17  microsatellite instability, 18  somatic copy-number alterations, 19  human leukocyte antigen (HLA) class I diversity, 20  T cell repertoire clonality change, 21  WNT-beta-catenin signaling, 22  TGFbeta expression, 23  and even commensal microbiota.	('IFNgamma', 'Gene', '3458', (107, 115))	('beta-catenin', 'Gene', '1499', (287, 299))	('T cell signaling pathway genes', 'Gene', (68, 98))	('TGFbeta', 'Gene', (315, 322))	('alterations', 'Var', (173, 184))	('TGFbeta', 'Gene', '7039', (315, 322))	('beta-catenin', 'Gene', (287, 299))	('human', 'Species', '9606', (190, 195))	('signaling', 'biological_process', 'GO:0023052', ('300', '309'))	('signaling pathway', 'biological_process', 'GO:0007165', ('75', '92'))	('IFNgamma', 'Gene', (107, 115))
58268	32810311	We analyzed RNA-Seq data of 28 pretreatment tumors from melanoma patients who received anti-PD-1 ICI.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('anti-PD-1', 'Var', (87, 96))	('RNA', 'cellular_component', 'GO:0005562', ('12', '15'))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (65, 73))
58274	32810311	35  Axis 6 (Treg) and axis 7 (MDSC) were high in Pt25 and Pt16, respectively, suggesting that the strategies to deplete Treg or MDSC might be recommended to these patients.	('Pt16', 'Var', (58, 62))	('Treg', 'Chemical', '-', (12, 16))	('Pt25', 'Var', (49, 53))	('patients', 'Species', '9606', (163, 171))	('Treg', 'Chemical', '-', (120, 124))
58289	32810311	For example, immunograms for hallmarks of cancer could also be compiled by adopting gene sets for the eight hallmarks: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming of energy metabolism, and evading immune destruction.	('cell death', 'biological_process', 'GO:0008219', ('193', '203'))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('activating', 'PosReg', (262, 272))	('angiogenesis', 'biological_process', 'GO:0001525', ('248', '260'))	('reprogramming', 'Reg', (298, 311))	('angiogenesis', 'CPA', (248, 260))	('evading', 'Var', (155, 162))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (29, 48))	('death', 'Disease', (198, 203))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('invasion', 'CPA', (273, 281))	('inducing', 'PosReg', (239, 247))	('replicative immortality', 'CPA', (214, 237))	('metabolism', 'biological_process', 'GO:0008152', ('322', '332'))	('sustaining', 'PosReg', (119, 129))	('death', 'Disease', 'MESH:D003643', (198, 203))	('hallmarks of cancer', 'Disease', (29, 48))	('immune destruction', 'CPA', (346, 364))	('enabling', 'PosReg', (205, 213))	('proliferative signaling', 'MPA', (130, 153))
58309	31455378	The results of our study reveal a new potential regulatory pathway in which metformin inhibits cell proliferation via AMPKalpha/Yap1/TEAD4/CCNE1/2 axis in BLCA cells, providing new insights into novel molecular therapeutic targets for BLCA.	('cell proliferation', 'CPA', (95, 113))	('BLCA', 'Phenotype', 'HP:0009725', (235, 239))	('cell proliferation', 'biological_process', 'GO:0008283', ('95', '113'))	('AMPK', 'Gene', (118, 122))	('CCNE1/2', 'Gene', '898;9134', (139, 146))	('AMPK', 'Gene', '5563', (118, 122))	('inhibits', 'NegReg', (86, 94))	('metformin', 'Var', (76, 85))	('BLCA', 'Phenotype', 'HP:0009725', (155, 159))	('CCNE1/2', 'Gene', (139, 146))	('metformin', 'Chemical', 'MESH:D008687', (76, 85))
58321	31455378	On the contrary, the knockout of AMPK accelerates the development of lymphomas in MYC oncogene transgenic mice and promotes Warburg effect through stabilization of HIF1alpha.	('lymphomas', 'Disease', (69, 78))	('AMPK', 'Gene', (33, 37))	('HIF1alpha', 'Gene', '15251', (164, 173))	('lymphomas', 'Disease', 'MESH:D008223', (69, 78))	('AMPK', 'molecular_function', 'GO:0050405', ('33', '37'))	('HIF1alpha', 'Gene', (164, 173))	('lymphomas', 'Phenotype', 'HP:0002665', (69, 78))	('accelerates', 'PosReg', (38, 49))	('transgenic mice', 'Species', '10090', (95, 110))	('AMPK', 'molecular_function', 'GO:0004691', ('33', '37'))	('AMPK', 'molecular_function', 'GO:0047322', ('33', '37'))	('knockout', 'Var', (21, 29))	('AMPK', 'Gene', '5563', (33, 37))	('men', 'Species', '9606', (61, 64))	('promotes', 'PosReg', (115, 123))	('Warburg effect', 'CPA', (124, 138))
58325	31455378	As one of the most popular drugs used for type 2 diabetes therapy, metformin, an activator of AMPK, has aroused keen interest as a potential anticancer agent and reduces cancer risk and mortality, including bladder cancer, which has been proved by many studies.	('cancer', 'Disease', (145, 151))	('AMPK', 'Gene', (94, 98))	('diabetes', 'Disease', (49, 57))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('reduces', 'NegReg', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('metformin', 'Var', (67, 76))	('AMPK', 'molecular_function', 'GO:0004691', ('94', '98'))	('bladder cancer', 'Disease', 'MESH:D001749', (207, 221))	('cancer', 'Disease', (215, 221))	('metformin', 'Chemical', 'MESH:D008687', (67, 76))	('bladder cancer', 'Disease', (207, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('bladder cancer', 'Phenotype', 'HP:0009725', (207, 221))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('diabetes', 'Disease', 'MESH:D003920', (49, 57))	('AMPK', 'molecular_function', 'GO:0047322', ('94', '98'))	('AMPK', 'Gene', '5563', (94, 98))	('mortality', 'CPA', (186, 195))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (42, 57))	('AMPK', 'molecular_function', 'GO:0050405', ('94', '98'))
58329	31455378	While, some studies showed that metformin has no considerable inhibitory effect on the recurrence rate of bladder cancer, but that it can delay tumor recurrence.	('metformin', 'Var', (32, 41))	('tumor', 'Disease', (144, 149))	('delay', 'NegReg', (138, 143))	('metformin', 'Chemical', 'MESH:D008687', (32, 41))	('bladder cancer', 'Disease', 'MESH:D001749', (106, 120))	('bladder cancer', 'Disease', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('bladder cancer', 'Phenotype', 'HP:0009725', (106, 120))
58337	31455378	Yap1 also plays an important role in the development of bladder and the deregulation of Yap1 is significantly associated with the development and metastasis of human bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (166, 180))	('bladder cancer', 'Disease', (166, 180))	('bladder', 'Disease', (56, 63))	('men', 'Species', '9606', (48, 51))	('Yap1', 'Gene', (88, 92))	('deregulation', 'Var', (72, 84))	('metastasis', 'Disease', 'MESH:D009362', (146, 156))	('metastasis', 'Disease', (146, 156))	('associated', 'Reg', (110, 120))	('bladder cancer', 'Phenotype', 'HP:0009725', (166, 180))	('men', 'Species', '9606', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('human', 'Species', '9606', (160, 165))
58341	31455378	And in the glioma cells, cytoplasmic retention was enhanced by metformin, and thus the transcriptional modulating activity of Yap was inhibited.	('transcriptional modulating activity', 'MPA', (87, 122))	('Yap', 'Gene', (126, 129))	('glioma', 'Disease', 'MESH:D005910', (11, 17))	('inhibited', 'NegReg', (134, 143))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('metformin', 'Var', (63, 72))	('enhanced', 'PosReg', (51, 59))	('metformin', 'Chemical', 'MESH:D008687', (63, 72))	('retention', 'biological_process', 'GO:0051235', ('37', '46'))	('Yap', 'Gene', '10413', (126, 129))	('cytoplasmic retention', 'CPA', (25, 46))	('glioma', 'Disease', (11, 17))
58368	31455378	Immunoprecipitates were then probed with Anti TEAD4 (abcam- Mouse) and anti Yap1 (CST, Rabbit).	('anti Yap1', 'Var', (71, 80))	('Anti TEAD4', 'Var', (41, 51))	('CST', 'Gene', (82, 85))	('Rabbit', 'Species', '9986', (87, 93))	('Mouse', 'Species', '10090', (60, 65))	('CST', 'Gene', '106478911', (82, 85))
58392	31455378	Taken together, these results proved that metformin inhibits the expressions of key proteins related to G1-S transition and induces G1 cell cycle arrest in BLCA cells without inducing apoptosis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (135, 152))	('metformin', 'Var', (42, 51))	('expressions of key proteins', 'MPA', (65, 92))	('induces', 'Reg', (124, 131))	('inhibits', 'NegReg', (52, 60))	('apoptosis', 'biological_process', 'GO:0097194', ('184', '193'))	('apoptosis', 'biological_process', 'GO:0006915', ('184', '193'))	('metformin', 'Chemical', 'MESH:D008687', (42, 51))	('G1 cell cycle arrest', 'CPA', (132, 152))	('BLCA', 'Phenotype', 'HP:0009725', (156, 160))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('135', '152'))
58405	31455378	Here, we evaluated the expression of Yap1 in the BLCA cells treated with metformin and found that metformin decreased the expressions of total Yap1 and Yap1 phosphorylation at Ser127 in a dose-dependent manner (Fig.	('Yap1', 'Gene', (152, 156))	('phosphorylation', 'biological_process', 'GO:0016310', ('157', '172'))	('expressions', 'MPA', (122, 133))	('metformin', 'Chemical', 'MESH:D008687', (98, 107))	('phosphorylation', 'MPA', (157, 172))	('Yap1', 'Gene', (143, 147))	('BLCA', 'Phenotype', 'HP:0009725', (49, 53))	('decreased', 'NegReg', (108, 117))	('Ser', 'cellular_component', 'GO:0005790', ('176', '179'))	('metformin', 'Chemical', 'MESH:D008687', (73, 82))	('Ser127', 'Chemical', '-', (176, 182))	('metformin', 'Var', (98, 107))
58414	31455378	To evaluate the role of Yap1 in suppression of cellular viability in the bladder cancer cells treated with metformin, first we used RNAi method to knockdown the expression of Yap1 (Fig.	('RNAi', 'biological_process', 'GO:0016246', ('132', '136'))	('bladder cancer', 'Disease', (73, 87))	('Yap1', 'Gene', (175, 179))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('metformin', 'Chemical', 'MESH:D008687', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('knockdown', 'Var', (147, 156))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))
58416	31455378	3b) (Mutation of all five serine to alanine at S61A, S109A, S127A, S164A, S381A) to generate a constitutively YAP mutant resistant to phosphorylation by its up-stream kinases.	('S61A', 'Mutation', 'p.S61A', (47, 51))	('S127A', 'Mutation', 'rs762471803', (60, 65))	('S381A', 'Var', (74, 79))	('S127A', 'Var', (60, 65))	('S61A', 'Var', (47, 51))	('S381A', 'Mutation', 'p.S381A', (74, 79))	('alanine', 'Chemical', 'MESH:D000409', (36, 43))	('S164A', 'Mutation', 'p.S164A', (67, 72))	('S109A', 'Var', (53, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('134', '149'))	('serine', 'Chemical', 'MESH:D012694', (26, 32))	('S109A', 'Mutation', 'p.S109A', (53, 58))	('S164A', 'Var', (67, 72))
58417	31455378	The results from the cell viability assay showed that Yap1 knockdown obviously decreases the cellular viabilities of T24 and SW780 cells and the Yap 5SA expression rescues the cell viabilities loss caused by the Yap1 knockdown (Fig.	('viabilities loss', 'Disease', 'MESH:D015431', (181, 197))	('decreases', 'NegReg', (79, 88))	('Yap', 'Gene', (212, 215))	('Yap', 'Gene', (145, 148))	('Yap', 'Gene', '10413', (54, 57))	('SW780', 'CellLine', 'CVCL:1728', (125, 130))	('knockdown', 'Var', (59, 68))	('knockdown', 'Var', (217, 226))	('Yap', 'Gene', '10413', (212, 215))	('viabilities loss', 'Disease', (181, 197))	('Yap', 'Gene', (54, 57))	('Yap', 'Gene', '10413', (145, 148))
58418	31455378	And the cell cycle analysis showed that Yap1 knockdown induces G0/G1 cell cycle arrest in T24 and SW780 cells, which can be reversed by the Yap-5SA expression (Fig.	('SW780', 'CellLine', 'CVCL:1728', (98, 103))	('Yap', 'Gene', (140, 143))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('69', '86'))	('Yap', 'Gene', '10413', (40, 43))	('cell cycle', 'biological_process', 'GO:0007049', ('8', '18'))	('Yap', 'Gene', '10413', (140, 143))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (69, 86))	('Yap', 'Gene', (40, 43))	('G0/G1 cell cycle arrest', 'CPA', (63, 86))	('knockdown', 'Var', (45, 54))
58420	31455378	3e, Yap1 knockdown could significantly decreases the CCNE1/2, CCND1 and CDK4/6 expressions at protein level, while expression of YAP-5SA restores their expressions in the T24 and Sw780 cells.	('CDK4/6', 'Gene', (72, 78))	('CDK', 'molecular_function', 'GO:0004693', ('72', '75'))	('knockdown', 'Var', (9, 18))	('CCND1', 'Gene', '595', (62, 67))	('CCNE1/2', 'Gene', '898;9134', (53, 60))	('CDK4/6', 'Gene', '1019;1021', (72, 78))	('Sw780', 'CellLine', 'CVCL:U282', (179, 184))	('expressions', 'MPA', (79, 90))	('CCNE1/2', 'Gene', (53, 60))	('Yap1', 'Gene', (4, 8))	('decreases', 'NegReg', (39, 48))	('expressions', 'MPA', (152, 163))	('CCND1', 'Gene', (62, 67))	('YAP-5SA', 'Var', (129, 136))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
58437	31455378	5b, both the knockdown of Yap1 and TEAD4 obviously inhibited the gene expressions of CCNE1/2, suggesting that Yap1 and TEAD4 could be the key regulator of CCNE1/2 expressions in the bladder cancer cells.	('CCNE1/2', 'Gene', '898;9134', (155, 162))	('bladder cancer', 'Disease', (182, 196))	('bladder cancer', 'Phenotype', 'HP:0009725', (182, 196))	('gene expressions', 'MPA', (65, 81))	('CCNE1/2', 'Gene', (155, 162))	('CCNE1/2', 'Gene', '898;9134', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('bladder cancer', 'Disease', 'MESH:D001749', (182, 196))	('inhibited', 'NegReg', (51, 60))	('knockdown', 'Var', (13, 22))	('CCNE1/2', 'Gene', (85, 92))
58441	31455378	We found that the transduction of wild-type CCNE1 and CCNE2 promoter regions can show the enhancement of luciferase activity and the mutants in the promoter regions of CCNE1 and CCNE2 could not affect the luciferase activity (Fig.	('luciferase activity', 'molecular_function', 'GO:0050248', ('105', '124'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('105', '124'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('205', '224'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('205', '224'))	('men', 'Species', '9606', (97, 100))	('luciferase activity', 'molecular_function', 'GO:0045289', ('205', '224'))	('CCNE2', 'Gene', (178, 183))	('luciferase activity', 'molecular_function', 'GO:0050397', ('205', '224'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('205', '224'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('105', '124'))	('activity', 'MPA', (116, 124))	('luciferase activity', 'molecular_function', 'GO:0045289', ('105', '124'))	('enhancement', 'PosReg', (90, 101))	('luciferase activity', 'molecular_function', 'GO:0047712', ('105', '124'))	('luciferase', 'Enzyme', (105, 115))	('CCNE1', 'Gene', (168, 173))	('transduction', 'biological_process', 'GO:0009293', ('18', '30'))	('mutants', 'Var', (133, 140))	('activity', 'MPA', (216, 224))
58482	31455378	And we found that CCNE1/2 expressions are obviously decreased in the BLCA cell challenged by metformin and Yap1 knockdown can also inhibit its expression.	('expressions', 'MPA', (26, 37))	('inhibit', 'NegReg', (131, 138))	('expression', 'MPA', (143, 153))	('decreased', 'NegReg', (52, 61))	('CCNE1/2', 'Gene', (18, 25))	('knockdown', 'Var', (112, 121))	('BLCA', 'Phenotype', 'HP:0009725', (69, 73))	('Yap1', 'Gene', (107, 111))	('metformin', 'MPA', (93, 102))	('metformin', 'Chemical', 'MESH:D008687', (93, 102))	('CCNE1/2', 'Gene', '898;9134', (18, 25))
58486	31455378	TEAD4 knock-down also results in decreased expressions of CCNE1/2 in the BLCA cells.	('expressions', 'MPA', (43, 54))	('knock-down', 'Var', (6, 16))	('CCNE1/2', 'Gene', '898;9134', (58, 65))	('BLCA', 'Phenotype', 'HP:0009725', (73, 77))	('decreased', 'NegReg', (33, 42))	('TEAD4', 'Gene', (0, 5))	('CCNE1/2', 'Gene', (58, 65))
58510	31455378	This work was supported by grants from National Natural Science Foundation of China (81572831, 81700977 and 81560362), the Science and Technology Research Project of Education Department of Liaoning Province (LK201616); and Foundation for New Teacher of China Medical University (1210516018).	('81572831', 'Var', (85, 93))	('men', 'Species', '9606', (182, 185))	('81700977', 'Var', (95, 103))	('81560362', 'Var', (108, 116))
58562	27870887	Biological interactions were observed between intravesical chemotherapy, low-level Ki-67 and EGFR negativity.	('EGFR', 'molecular_function', 'GO:0005006', ('93', '97'))	('EGFR', 'Gene', '1956', (93, 97))	('low-level', 'Var', (73, 82))	('Ki-67', 'Gene', (83, 88))	('EGFR', 'Gene', (93, 97))	('Ki-67', 'Chemical', '-', (83, 88))
58563	27870887	The multivariate analysis showed that after balancing a variety of factors, intravesical chemotherapy is a protective factor for preventing intravesical recurrence in the negative EGFR, low-level Ki-67 and preoperative positive urine cytology sub-groups but not in their corresponding sub-groups.	('Ki-67', 'Var', (196, 201))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('Ki-67', 'Chemical', '-', (196, 201))	('EGFR', 'molecular_function', 'GO:0005006', ('180', '184'))	('low-level Ki-67', 'Var', (186, 201))	('positive urine cytology', 'Phenotype', 'HP:0012614', (219, 242))	('intravesical recurrence', 'Disease', (140, 163))
58564	27870887	Additionally, the multivariate analysis revealed that preoperative positive urine cytology and Ki-67 were not but that EGFR positivity was an independent risk factor for recurrence after intravesical chemotherapy.	('EGFR', 'molecular_function', 'GO:0005006', ('119', '123'))	('Ki-67', 'Chemical', '-', (95, 100))	('positivity', 'Var', (124, 134))	('positive urine cytology', 'Phenotype', 'HP:0012614', (67, 90))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'Gene', (119, 123))
58606	27870887	Moreover, a significant synergistic biological interaction was observed between EGFR negativity and intravesical chemotherapy in preventing bladder tumor recurrence (Fig 3A, S = 2.991, AP = 0.591).	('bladder tumor', 'Disease', (140, 153))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('negativity', 'Var', (85, 95))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('EGFR', 'Gene', (80, 84))	('preventing', 'NegReg', (129, 139))	('bladder tumor', 'Disease', 'MESH:D001749', (140, 153))	('bladder tumor', 'Phenotype', 'HP:0009725', (140, 153))
58607	27870887	Additionally, after intravesical chemotherapy, the incidence rates of UTUC recurrence in the bladder decreased more in the low-level Ki-67 sub-groups than in the high-level Ki-67 sub-groups (Fig 3B, P = 0.025), and a synergistic biological interaction was observed between low-level Ki-67 labeling and without intravesical chemotherapy in leading to bladder tumor recurrence (Fig 3B, S = 3.118, AP = 0.598).	('Ki-67', 'Chemical', '-', (283, 288))	('Ki-67', 'Chemical', '-', (133, 138))	('bladder tumor', 'Disease', (350, 363))	('UTUC', 'MPA', (70, 74))	('bladder tumor', 'Phenotype', 'HP:0009725', (350, 363))	('tumor', 'Phenotype', 'HP:0002664', (358, 363))	('decreased', 'NegReg', (101, 110))	('bladder tumor', 'Disease', 'MESH:D001749', (350, 363))	('low-level', 'Var', (123, 132))	('Ki-67', 'Chemical', '-', (173, 178))
58609	27870887	Additionally, the multivariate analyses on sub-groups revealed that after balancing varieties of factors, intravesical chemotherapy was a protective factor in preventing intravesical recurrence in negative EGFR, low-level Ki-67 and preoperative positive urine cytology sub-groups but not in the corresponding sub-groups (S1 Table).	('EGFR', 'molecular_function', 'GO:0005006', ('206', '210'))	('Ki-67', 'Chemical', '-', (222, 227))	('EGFR', 'Gene', (206, 210))	('intravesical recurrence', 'Disease', (170, 193))	('positive urine cytology', 'Phenotype', 'HP:0012614', (245, 268))	('low-level', 'Var', (212, 221))	('EGFR', 'Gene', '1956', (206, 210))
58620	27870887	The multivariate analysis revealed that while preoperative positive urine cytology and Ki-67 were not, EGFR positivity was an independent risk factor for recurrence after intravesical chemotherapy (group 2).	('positive urine cytology', 'Phenotype', 'HP:0012614', (59, 82))	('EGFR', 'Gene', '1956', (103, 107))	('EGFR', 'Gene', (103, 107))	('positivity', 'Var', (108, 118))	('Ki-67', 'Chemical', '-', (87, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('recurrence', 'Disease', (154, 164))
58624	27870887	Additionally, low-level Ki-67 patients appeared to be more sensitive to intravesical chemotherapy than high-level Ki-67 patients.	('Ki-67', 'Var', (24, 29))	('Ki-67', 'Chemical', '-', (24, 29))	('sensitive', 'MPA', (59, 68))	('low-level Ki-67', 'Var', (14, 29))	('patients', 'Species', '9606', (30, 38))	('patients', 'Species', '9606', (120, 128))	('Ki-67', 'Chemical', '-', (114, 119))
58625	27870887	The bladder recurrence rate after intravesical chemotherapy decreased more in low-level Ki-67 patients than in high-level Ki-67 patients, and a synergistic biological interaction could be observed between low-level Ki-67 staining and without intravesical chemotherapy in leading to bladder recurrence.	('Ki-67', 'Chemical', '-', (88, 93))	('decreased', 'NegReg', (60, 69))	('low-level Ki-67', 'Var', (78, 93))	('patients', 'Species', '9606', (94, 102))	('Ki-67', 'Chemical', '-', (215, 220))	('Ki-67', 'Chemical', '-', (122, 127))	('bladder recurrence', 'Disease', (282, 300))	('Ki-67', 'Var', (88, 93))	('bladder recurrence', 'CPA', (4, 22))	('patients', 'Species', '9606', (128, 136))
58628	27870887	Additionally, the multivariate analyses on different sub-groups revealed that after balancing varieties of factors, intravesical chemotherapy was a protective factor for preventing intravesical recurrence in the negative EGFR, low-level Ki-67 and preoperative positive urine cytology sub-groups; however, in the positive EGFR, high-level Ki-67 and preoperative negative urine cytology sub-groups, intravesical chemotherapy did not show a protective effect, which further confirmed that patients with positive EGFR, high-level Ki-67 and preoperative negative urine cytology may be less sensitive to intravesical chemotherapy than the corresponding sub-groups.	('negative urine', 'Phenotype', 'HP:0100519', (361, 375))	('EGFR', 'Gene', '1956', (221, 225))	('Ki-67', 'Chemical', '-', (237, 242))	('positive', 'Var', (500, 508))	('EGFR', 'Gene', (321, 325))	('EGFR', 'Gene', (509, 513))	('less', 'NegReg', (580, 584))	('positive urine cytology', 'Phenotype', 'HP:0012614', (260, 283))	('Ki-67', 'Chemical', '-', (338, 343))	('negative urine', 'Phenotype', 'HP:0100519', (549, 563))	('EGFR', 'Gene', (221, 225))	('Ki-67', 'Chemical', '-', (526, 531))	('EGFR', 'Gene', '1956', (321, 325))	('EGFR', 'Gene', '1956', (509, 513))	('patients', 'Species', '9606', (486, 494))	('EGFR', 'molecular_function', 'GO:0005006', ('221', '225'))	('EGFR', 'molecular_function', 'GO:0005006', ('509', '513'))	('high-level Ki-67', 'Var', (515, 531))	('EGFR', 'molecular_function', 'GO:0005006', ('321', '325'))
58635	27870887	Aberrant EGFR signaling plays an important role in the tumorigenesis, migration, apoptosis resistance and stromal invasion of bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (126, 140))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('signaling', 'biological_process', 'GO:0023052', ('14', '23'))	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('Aberrant', 'Var', (0, 8))	('migration', 'CPA', (70, 79))	('apoptosis resistance', 'CPA', (81, 101))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('EGFR', 'Gene', '1956', (9, 13))	('stromal invasion', 'CPA', (106, 122))	('EGFR', 'Gene', (9, 13))	('bladder cancer', 'Disease', (126, 140))	('bladder cancer', 'Disease', 'MESH:D001749', (126, 140))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
58644	27870887	Regarding UTUC, a previous study and this study show that low-level Ki-67 expression was an independent predictor of bladder tumor recurrence in patients without instillation therapy.	('patients', 'Species', '9606', (145, 153))	('expression', 'MPA', (74, 84))	('low-level', 'Var', (58, 67))	('bladder tumor', 'Phenotype', 'HP:0009725', (117, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Ki-67', 'Chemical', '-', (68, 73))	('bladder tumor', 'Disease', (117, 130))	('bladder tumor', 'Disease', 'MESH:D001749', (117, 130))	('Ki-67', 'Gene', (68, 73))
58658	25984002	The diffuse strong staining of SV40 T-antigen and p53 within both the in situ and invasive carcinoma suggest that BKV may play a role in the oncogenic pathway in this clinical setting.	('SV40', 'Var', (31, 35))	('oncogenic pathway', 'Pathway', (141, 158))	('role', 'Reg', (129, 133))	('invasive carcinoma', 'Disease', 'MESH:D009361', (82, 100))	('p53', 'Gene', (50, 53))	('play', 'Reg', (122, 126))	('BKV', 'Species', '1891762', (114, 117))	('p53', 'Gene', '7157', (50, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('SV40 T-antigen', 'molecular_function', 'GO:0016887', ('31', '45'))	('SV40', 'Species', '1891767', (31, 35))	('invasive carcinoma', 'Disease', (82, 100))
58680	25984002	Diffuse strong expression of SV40 T-Ag was seen in both the invasive and in situ carcinoma (Figure 3), whereas the non-malignant urothelium and atrophic native kidney were negative.	('SV40', 'Species', '1891767', (29, 33))	('SV40', 'Var', (29, 33))	('atrophic', 'Disease', 'MESH:D020966', (144, 152))	('T-Ag', 'Gene', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('T-Ag', 'Gene', '404663', (34, 38))	('situ carcinoma', 'Disease', 'MESH:D002278', (76, 90))	('atrophic', 'Disease', (144, 152))	('situ carcinoma', 'Disease', (76, 90))	('invasive', 'Disease', (60, 68))
58686	25984002	Arylamines, analgesics, schistosomiasis infection, smoking and cyclophosphamide are known risk factors for bladder cancer by causing prolonged local irritation of the mucosa.	('bladder cancer', 'Disease', 'MESH:D001749', (107, 121))	('bladder cancer', 'Disease', (107, 121))	('schistosomiasis infection', 'Disease', 'MESH:D012552', (24, 49))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (63, 79))	('cyclophosphamide', 'Var', (63, 79))	('schistosomiasis infection', 'Disease', (24, 49))	('schistosomiasis infection', 'Phenotype', 'HP:0001981', (24, 49))	('local irritation', 'MPA', (143, 159))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('causing', 'Reg', (125, 132))	('bladder cancer', 'Phenotype', 'HP:0009725', (107, 121))	('Arylamines', 'Chemical', 'MESH:C023650', (0, 10))
58714	25984002	We have also demonstrated strong expression of SV40 and P53 not only in the invasive tumour but also within in situ urothelial carcinoma in the cystectomy specimen in our patient.	('P53', 'Gene', '7157', (56, 59))	('patient', 'Species', '9606', (171, 178))	('situ urothelial carcinoma', 'Disease', (111, 136))	('SV40', 'Species', '1891767', (47, 51))	('SV40', 'Var', (47, 51))	('men', 'Species', '9606', (160, 163))	('situ urothelial carcinoma', 'Disease', 'MESH:D002278', (111, 136))	('P53', 'Gene', (56, 59))	('invasive tumour', 'Disease', (76, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('invasive tumour', 'Disease', 'MESH:D009361', (76, 91))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
58766	30719168	Our results showed a high rate of C>T transversion and a high rate of transition/transversion (Ti/Tv) in TMIT I bladder tumors.	('TMIT I bladder tumors', 'Disease', 'MESH:D001749', (105, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('C>T transversion', 'Var', (34, 50))	('transition/transversion', 'Var', (70, 93))	('bladder tumors', 'Phenotype', 'HP:0009725', (112, 126))	('bladder tumor', 'Phenotype', 'HP:0009725', (112, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('TMIT I bladder tumors', 'Disease', (105, 126))
58767	30719168	The RB1 mutation was significantly associated with TMIT I bladder cancer and be significantly co-occurring with the TP53 mutation.	('TP53', 'Gene', (116, 120))	('RB1', 'Gene', '5925', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('associated', 'Reg', (35, 45))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('TMIT I bladder cancer', 'Disease', (51, 72))	('TMIT I bladder cancer', 'Disease', 'MESH:D001749', (51, 72))	('mutation', 'Var', (8, 16))	('TP53', 'Gene', '7157', (116, 120))	('RB1', 'Gene', (4, 7))
58768	30719168	However, FGFR3 mutation and TP53 mutation were mutually exclusive in TMIT II bladder tumors.	('mutation', 'Var', (15, 23))	('TP53', 'Gene', '7157', (28, 32))	('mutation', 'Var', (33, 41))	('TMIT II bladder', 'Phenotype', 'HP:0000011', (69, 84))	('TMIT II bladder tumors', 'Disease', (69, 91))	('TP53', 'Gene', (28, 32))	('bladder tumors', 'Phenotype', 'HP:0009725', (77, 91))	('FGFR3', 'Gene', '2261', (9, 14))	('FGFR', 'molecular_function', 'GO:0005007', ('9', '13'))	('TMIT II bladder tumors', 'Disease', 'MESH:D001749', (69, 91))	('bladder tumor', 'Phenotype', 'HP:0009725', (77, 90))	('FGFR3', 'Gene', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
58769	30719168	More importantly, different amino acid changes by FGFR3/RB1 mutations were also found between TMIT I and TMIT II bladder cancer, such as amino acid changes in "Immunoglobulin I-set domain (260-356)"and "Protein tyrosine kinase (472-748)".	('TMIT I', 'Chemical', '-', (94, 100))	('260-356', 'Var', (189, 196))	('472-748', 'Var', (228, 235))	('FGFR3', 'Gene', (50, 55))	('TMIT I', 'Disease', (94, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('RB1', 'Gene', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('TMIT I', 'Chemical', '-', (105, 111))	('TMIT II bladder cancer', 'Disease', (105, 127))	('RB1', 'Gene', '5925', (56, 59))	('TMIT II bladder cancer', 'Disease', 'MESH:D001749', (105, 127))	('TMIT II bladder', 'Phenotype', 'HP:0000011', (105, 120))	('FGFR3', 'Gene', '2261', (50, 55))	('mutations', 'Var', (60, 69))	('Protein', 'MPA', (203, 210))
58773	30719168	TMIT I (high PD-L1/high CD8A) is significantly correlated with more somatic mutation burden, and facilitates CD8+ T-cell infiltration and activates T-effector and IFN-gamma associated gene signature.	('CD8A', 'Gene', (24, 28))	('CD8', 'Gene', (109, 112))	('somatic mutation burden', 'MPA', (68, 91))	('TMIT', 'Var', (0, 4))	('CD8', 'Gene', '925', (109, 112))	('IFN-gamma', 'Gene', '3458', (163, 172))	('IFN-gamma', 'Gene', (163, 172))	('CD8', 'Gene', (24, 27))	('PD-L1', 'Gene', (13, 18))	('facilitates', 'PosReg', (97, 108))	('more', 'PosReg', (63, 67))	('CD8', 'Gene', '925', (24, 27))	('CD8A', 'Gene', '925', (24, 28))	('TMIT I', 'Chemical', '-', (0, 6))	('activates', 'PosReg', (138, 147))	('PD-L1', 'Gene', '29126', (13, 18))
58786	30719168	Mutation spectrum for each tumor was evaluated as the percentage of six possible single nucleotide changes among single nucleotide substitutions as previously reported.	('single nucleotide changes', 'Var', (81, 106))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))
58800	30719168	Bladder tumors with more somatic mutation burden (higher than the median value) were accompanied with the higher proportion of TMIT I, compared with those with fewer mutations (44.6% vs.28.9%; P < 0.01; Fig.	('Bladder tumors', 'Phenotype', 'HP:0009725', (0, 14))	('Bladder tumors', 'Disease', 'MESH:D001749', (0, 14))	('somatic mutation burden', 'Var', (25, 48))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('Bladder tumors', 'Disease', (0, 14))	('TMIT I', 'Disease', (127, 133))	('TMIT I', 'Chemical', '-', (127, 133))
58802	30719168	Our results showed a high rate of C>T transversion and a high rate of transition/transversion (Ti/Tv) in TMIT I bladder tumors (Fig.	('TMIT I bladder tumors', 'Disease', 'MESH:D001749', (105, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('C>T transversion', 'Var', (34, 50))	('transition/transversion', 'Var', (70, 93))	('bladder tumors', 'Phenotype', 'HP:0009725', (112, 126))	('bladder tumor', 'Phenotype', 'HP:0009725', (112, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('TMIT I bladder tumors', 'Disease', (105, 126))
58806	30719168	Specifically, a higher rate of FGFR3 mutation in TMIT II bladder tumors and a higher rate of RB1 mutation in TMIT I bladder tumors were found.	('mutation', 'Var', (37, 45))	('TMIT II bladder', 'Phenotype', 'HP:0000011', (49, 64))	('bladder tumors', 'Phenotype', 'HP:0009725', (57, 71))	('TMIT II bladder tumors', 'Disease', 'MESH:D001749', (49, 71))	('FGFR3', 'Gene', (31, 36))	('TMIT I bladder tumors', 'Disease', (109, 130))	('FGFR3', 'Gene', '2261', (31, 36))	('RB1', 'Gene', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('bladder tumor', 'Phenotype', 'HP:0009725', (57, 70))	('mutation', 'Var', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('bladder tumors', 'Phenotype', 'HP:0009725', (116, 130))	('RB1', 'Gene', '5925', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('TMIT II bladder tumors', 'Disease', (49, 71))	('higher', 'Reg', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('bladder tumor', 'Phenotype', 'HP:0009725', (116, 129))	('TMIT I bladder tumors', 'Disease', 'MESH:D001749', (109, 130))
58807	30719168	Interestingly, the vast majority of tumors with FGFR3 mutation were classified as TMIT II (low PD-L1/low CD8A), which was totally opposed to TMIT I (high PD-L1/high CD8A) (Fig.	('CD8A', 'Gene', (165, 169))	('mutation', 'Var', (54, 62))	('FGFR3', 'Gene', '2261', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('PD-L1', 'Gene', (154, 159))	('CD8A', 'Gene', '925', (105, 109))	('PD-L1', 'Gene', (95, 100))	('TMIT I', 'Chemical', '-', (82, 88))	('FGFR3', 'Gene', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('CD8A', 'Gene', (105, 109))	('PD-L1', 'Gene', '29126', (154, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('TMIT I', 'Chemical', '-', (141, 147))	('CD8A', 'Gene', '925', (165, 169))	('tumors', 'Disease', (36, 42))	('PD-L1', 'Gene', '29126', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
58808	30719168	Similarly, the proportion of TMIT I in FGFR3 mutated tumors was statistical significantly lower than that in FGFR3 wild-type group (13.3% vs.40.8%; P < 0.001; Fig.	('FGFR', 'molecular_function', 'GO:0005007', ('39', '43'))	('FGFR3', 'Gene', (109, 114))	('TMIT I', 'Chemical', '-', (29, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('109', '113'))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('lower', 'NegReg', (90, 95))	('FGFR3', 'Gene', (39, 44))	('FGFR3', 'Gene', '2261', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('TMIT I', 'CPA', (29, 35))	('FGFR3', 'Gene', '2261', (109, 114))	('tumors', 'Disease', (53, 59))	('mutated', 'Var', (45, 52))
58809	30719168	S3a), consistent with the distribution of FGFR3 mutations in the scatter plot.	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('FGFR3', 'Gene', (42, 47))	('mutations', 'Var', (48, 57))	('FGFR3', 'Gene', '2261', (42, 47))
58810	30719168	However, the high proportion of tumors with RB1 mutation were grouped into TMIT I (Fig.	('TMIT I', 'Disease', (75, 81))	('TMIT I', 'Chemical', '-', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('RB1', 'Gene', (44, 47))	('mutation', 'Var', (48, 56))	('tumors', 'Disease', (32, 38))	('RB1', 'Gene', '5925', (44, 47))
58811	30719168	2c), and the proportion of TMIT I in RB1 mutated tumors was statistically significantly higher than that in RB1 wild-type group (56.3% vs. 32.6%; P < 0.001; Fig.	('higher', 'PosReg', (88, 94))	('mutated', 'Var', (41, 48))	('RB1', 'Gene', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('RB1', 'Gene', '5925', (108, 111))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('RB1', 'Gene', (37, 40))	('TMIT I', 'Chemical', '-', (27, 33))	('RB1', 'Gene', '5925', (37, 40))
58812	30719168	In consideration of the actual discovery that FGFR3/RB1 mutations were significantly correlated different between TMIT I and TMIT II bladder tumors, our study next to explore whether there were different amino acid changes by FGFR3/RB1 mutations between TMIT I and TMIT II bladder cancer.	('TMIT I', 'Chemical', '-', (114, 120))	('TMIT II bladder tumors', 'Disease', (125, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('FGFR3', 'Gene', '2261', (46, 51))	('TMIT I', 'Chemical', '-', (254, 260))	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('TMIT II bladder', 'Phenotype', 'HP:0000011', (125, 140))	('FGFR3', 'Gene', (226, 231))	('FGFR', 'molecular_function', 'GO:0005007', ('226', '230'))	('TMIT II bladder tumors', 'Disease', 'MESH:D001749', (125, 147))	('TMIT I', 'Chemical', '-', (125, 131))	('TMIT II bladder cancer', 'Disease', (265, 287))	('FGFR3', 'Gene', '2261', (226, 231))	('RB1', 'Gene', (52, 55))	('TMIT II bladder cancer', 'Disease', 'MESH:D001749', (265, 287))	('RB1', 'Gene', (232, 235))	('bladder tumors', 'Phenotype', 'HP:0009725', (133, 147))	('mutations', 'Var', (236, 245))	('bladder tumor', 'Phenotype', 'HP:0009725', (133, 146))	('TMIT II bladder', 'Phenotype', 'HP:0000011', (265, 280))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('RB1', 'Gene', '5925', (52, 55))	('RB1', 'Gene', '5925', (232, 235))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('FGFR3', 'Gene', (46, 51))	('TMIT I', 'Chemical', '-', (265, 271))	('bladder cancer', 'Phenotype', 'HP:0009725', (273, 287))
58813	30719168	Our labelling points revealed that there were different amino acid changes in "Immunoglobulin I-set domain (260-356) "and "Protein tyrosine kinase (472-748)" by FGFR3 mutation between TMIT I and TMIT II bladder tumors (Fig.	('TMIT II bladder', 'Phenotype', 'HP:0000011', (195, 210))	('TMIT II bladder tumors', 'Disease', 'MESH:D001749', (195, 217))	('FGFR3', 'Gene', '2261', (161, 166))	('FGFR3', 'Gene', (161, 166))	('mutation', 'Var', (167, 175))	('TMIT I', 'Chemical', '-', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('bladder tumors', 'Phenotype', 'HP:0009725', (203, 217))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('TMIT I', 'Chemical', '-', (184, 190))	('bladder tumor', 'Phenotype', 'HP:0009725', (203, 216))	('TMIT II bladder tumors', 'Disease', (195, 217))
58814	30719168	We also found different amino acid changes in "Retinoblastoma-associated protein A domain (373-573)", "Retinoblastoma-associated protein B domain (645 - 766)" and "Rb C-terminal domain (768 - 927)" by RB1 mutation between these two subgroups (Fig.	('Retinoblastoma-associated protein', 'Gene', (103, 136))	('Retinoblastoma-associated protein', 'Gene', '5925', (47, 80))	('RB1', 'Gene', (201, 204))	('768 - 927', 'Var', (186, 195))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (103, 117))	('RB1', 'Gene', '5925', (201, 204))	('Retinoblastoma-associated protein', 'Gene', (47, 80))	('Retinoblastoma-associated protein', 'Gene', '5925', (103, 136))	('mutation', 'Var', (205, 213))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (47, 61))
58817	30719168	The results demonstrated that in TMIT I bladder tumors, RB1 mutation and TP53 mutation were found to be significantly co-occurring (P < 0.05).While in TMIT II bladder tumors, FGFR3 mutation was proved to be significantly associated with STAG2 mutation and KDM6A mutation (P < 0.05).	('TP53', 'Gene', '7157', (73, 77))	('RB1', 'Gene', (56, 59))	('FGFR', 'molecular_function', 'GO:0005007', ('175', '179'))	('TMIT I bladder tumors', 'Disease', (33, 54))	('TMIT II bladder', 'Phenotype', 'HP:0000011', (151, 166))	('KDM6A', 'Gene', (256, 261))	('STAG2', 'Gene', '10735', (237, 242))	('bladder tumors', 'Phenotype', 'HP:0009725', (159, 173))	('TMIT II bladder tumors', 'Disease', 'MESH:D001749', (151, 173))	('bladder tumors', 'Phenotype', 'HP:0009725', (40, 54))	('RB1', 'Gene', '5925', (56, 59))	('associated', 'Reg', (221, 231))	('STAG2', 'Gene', (237, 242))	('bladder tumor', 'Phenotype', 'HP:0009725', (159, 172))	('TP53', 'Gene', (73, 77))	('bladder tumor', 'Phenotype', 'HP:0009725', (40, 53))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('TMIT I bladder tumors', 'Disease', 'MESH:D001749', (33, 54))	('KDM6A', 'Gene', '7403', (256, 261))	('FGFR3', 'Gene', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('mutation', 'Var', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('FGFR3', 'Gene', '2261', (175, 180))	('TMIT II bladder tumors', 'Disease', (151, 173))
58818	30719168	More importantly, FGFR3 mutation and TP53 mutation were mutually exclusive in TMIT II bladder tumors (P < 0.05).	('bladder tumors', 'Phenotype', 'HP:0009725', (86, 100))	('FGFR3', 'Gene', '2261', (18, 23))	('bladder tumor', 'Phenotype', 'HP:0009725', (86, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('FGFR3', 'Gene', (18, 23))	('TMIT II bladder tumors', 'Disease', (78, 100))	('mutation', 'Var', (42, 50))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('mutation', 'Var', (24, 32))	('TP53', 'Gene', '7157', (37, 41))	('TMIT II bladder tumors', 'Disease', 'MESH:D001749', (78, 100))	('TP53', 'Gene', (37, 41))	('TMIT II bladder', 'Phenotype', 'HP:0000011', (78, 93))
58819	30719168	Most of the variants in cancer-causing genes are enriched at few specific loci.	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('variants', 'Var', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))
58823	30719168	We next explored the clusters of mutations in kataegis in both TMIT I and TMIT II cohorts.	('TMIT I', 'Chemical', '-', (63, 69))	('kataegis', 'Gene', (46, 54))	('TMIT I', 'Chemical', '-', (74, 80))	('mutations', 'Var', (33, 42))
58834	30719168	The proportion of PD-L1 amplification in bladder cancers was 21.1% (86/408).	('bladder cancers', 'Phenotype', 'HP:0009725', (41, 56))	('bladder cancers', 'Disease', 'MESH:D001749', (41, 56))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('bladder cancer', 'Phenotype', 'HP:0009725', (41, 55))	('amplification', 'Var', (24, 37))	('bladder cancers', 'Disease', (41, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('PD-L1', 'Gene', (18, 23))	('PD-L1', 'Gene', '29126', (18, 23))
58860	30719168	In this study, the vast majority of tumors with PD-L1 amplification were classified as TMIT I.	('TMIT I', 'Disease', (87, 93))	('PD-L1', 'Gene', '29126', (48, 53))	('TMIT I', 'Chemical', '-', (87, 93))	('amplification', 'Var', (54, 67))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('PD-L1', 'Gene', (48, 53))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
58861	30719168	More importantly, the proportion of TMIT I in the tumors with PD-L1 amplification was remarkably higher than that in the control group without PD-L1 amplification, which indicated the potential synergistic effects of TMIT I tumors on activating PD-L1 expression.	('higher', 'PosReg', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('TMIT I tumors', 'Disease', 'MESH:D009369', (217, 230))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('PD-L1', 'Gene', (245, 250))	('TMIT I tumors', 'Disease', (217, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('PD-L1', 'Gene', '29126', (245, 250))	('PD-L1', 'Gene', (143, 148))	('PD-L1', 'Gene', (62, 67))	('amplification', 'Var', (68, 81))	('PD-L1', 'Gene', '29126', (143, 148))	('PD-L1', 'Gene', '29126', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('TMIT I', 'Chemical', '-', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('TMIT I', 'Chemical', '-', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))
58865	30719168	In this study, we found the significant association between high IFN-gamma mRNA expression and TMIT I.	('IFN-gamma', 'Gene', '3458', (65, 74))	('IFN-gamma', 'Gene', (65, 74))	('high', 'Var', (60, 64))	('TMIT I', 'Disease', (95, 101))	('TMIT I', 'Chemical', '-', (95, 101))
58868	30719168	Blockade of TIGIT could prevent natural killer (NK) cell exhaustion and promote NK cell-dependent tumor immunity.	('TIGIT', 'Gene', '201633', (12, 17))	('TIGIT', 'Gene', (12, 17))	('Blockade', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('promote', 'PosReg', (72, 79))	('prevent', 'NegReg', (24, 31))	('tumor', 'Disease', (98, 103))
58872	30719168	Recently TP53 mutation has been considered to show significant clinical benefit to PD-1 inhibitors by altering a group of genes involved in cell-cycle regulating, DNA replication and damage repair.	('altering', 'Reg', (102, 110))	('cell-cycle', 'biological_process', 'GO:0007049', ('140', '150'))	('PD-1', 'Gene', (83, 87))	('DNA replication', 'biological_process', 'GO:0006260', ('163', '178'))	('PD-1', 'Gene', '5133', (83, 87))	('TP53', 'Gene', '7157', (9, 13))	('mutation', 'Var', (14, 22))	('TP53', 'Gene', (9, 13))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))
58873	30719168	In this study, we were surprised to found that RB1 mutation was significantly associated with TMIT I bladder cancer, and be significantly co-occurring with TP53 mutation, which could significantly activate T-effector and IFN-gamma signature.	('associated', 'Reg', (78, 88))	('TMIT I bladder cancer', 'Disease', 'MESH:D001749', (94, 115))	('RB1', 'Gene', '5925', (47, 50))	('IFN-gamma', 'Gene', '3458', (221, 230))	('IFN-gamma', 'Gene', (221, 230))	('RB1', 'Gene', (47, 50))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('mutation', 'Var', (51, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))	('activate', 'PosReg', (197, 205))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('TMIT I bladder cancer', 'Disease', (94, 115))
58874	30719168	However, the FGFR3 mutation was negatively correlated with TMIT I subgroup.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('mutation', 'Var', (19, 27))	('correlated', 'Reg', (43, 53))	('FGFR3', 'Gene', (13, 18))	('negatively', 'NegReg', (32, 42))	('TMIT I subgroup', 'Disease', (59, 74))	('FGFR3', 'Gene', '2261', (13, 18))	('TMIT I', 'Chemical', '-', (59, 65))
58876	30719168	More importantly, different amino acid changes by FGFR3/RB1 mutations were also found between TMIT I and TMIT II bladder cancer (Fig.2b, Fig.2d), such as amino acid changes in "Immunoglobulin I-set domain (260-356)"and "Protein tyrosine kinase (472-748)", which were consistent with our GSEA observations that TMIT I was significantly associated with anti-tumor immune-related signaling pathway, including the cytokine-mediated signaling pathway, IFN-gamma mediated signaling pathway and MHC I -dependent antigen processing and presentation, thereby affecting anti-tumor immune response in bladder tumors.	('associated', 'Reg', (335, 345))	('RB1', 'Gene', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('TMIT I', 'Chemical', '-', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (356, 361))	('bladder tumor', 'Phenotype', 'HP:0009725', (590, 603))	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('TMIT I', 'Chemical', '-', (310, 316))	('bladder tumors', 'Disease', 'MESH:D001749', (590, 604))	('tumor', 'Disease', (565, 570))	('RB1', 'Gene', '5925', (56, 59))	('tumor', 'Disease', (598, 603))	('GSEA', 'Chemical', '-', (287, 291))	('TMIT I', 'Chemical', '-', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (565, 570))	('tumor', 'Disease', 'MESH:D009369', (598, 603))	('cytokine-mediated signaling pathway', 'Pathway', (410, 445))	('TMIT II bladder cancer', 'Disease', (105, 127))	('TMIT II bladder cancer', 'Disease', 'MESH:D001749', (105, 127))	('bladder tumors', 'Disease', (590, 604))	('affecting', 'Reg', (550, 559))	('tumors', 'Phenotype', 'HP:0002664', (598, 604))	('tumor', 'Disease', (356, 361))	('MHC', 'Gene', (488, 491))	('IFN-gamma', 'Gene', '3458', (447, 456))	('IFN-gamma', 'Gene', (447, 456))	('FGFR3', 'Gene', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (565, 570))	('tumor', 'Phenotype', 'HP:0002664', (598, 603))	('tumor', 'Disease', 'MESH:D009369', (356, 361))	('TMIT II bladder', 'Phenotype', 'HP:0000011', (105, 120))	('bladder tumors', 'Phenotype', 'HP:0009725', (590, 604))	('FGFR3', 'Gene', '2261', (50, 55))	('mutations', 'Var', (60, 69))
58879	30719168	We also discovered different clusters of mutations in kataegis between TMIT I and TMIT II bladder tumors.	('mutations', 'Var', (41, 50))	('TMIT II bladder tumors', 'Disease', 'MESH:D001749', (82, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('TMIT I', 'Chemical', '-', (71, 77))	('bladder tumor', 'Phenotype', 'HP:0009725', (90, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('TMIT I', 'Chemical', '-', (82, 88))	('TMIT II bladder', 'Phenotype', 'HP:0000011', (82, 97))	('TMIT II bladder tumors', 'Disease', (82, 104))	('bladder tumors', 'Phenotype', 'HP:0009725', (90, 104))
58880	30719168	Previous studies have highlighted that kataegis was characterized by clusters of C>T or C>G mutations, which were substantially enriched at TpCpN trinucleotides and on the same DNA strand.	('C>G', 'Var', (88, 91))	('DNA', 'cellular_component', 'GO:0005574', ('177', '180'))	('kataegis', 'Disease', (39, 47))	('trinucleotides', 'Chemical', '-', (146, 160))	('C>T', 'Var', (81, 84))
58885	30719168	Secondly, we preliminarily investigated the underlining biology process of TMITs and found that BR1 mutation in TMIT I subset and FGFR3 mutation in TMIT II subset might play important roles in predicting clinical response to PD-L1/PD-1 immunotherapy.	('roles', 'Reg', (184, 189))	('PD-L1', 'Gene', (225, 230))	('TMIT I', 'Chemical', '-', (148, 154))	('FGFR', 'molecular_function', 'GO:0005007', ('130', '134'))	('TMIT', 'Chemical', '-', (148, 152))	('FGFR3', 'Gene', (130, 135))	('mutation', 'Var', (136, 144))	('TMIT I', 'Chemical', '-', (112, 118))	('BR1', 'Gene', (96, 99))	('PD-L1', 'Gene', '29126', (225, 230))	('PD-1', 'Gene', '5133', (231, 235))	('BR1', 'Gene', '6373', (96, 99))	('mutation', 'Var', (100, 108))	('TMIT', 'Chemical', '-', (75, 79))	('PD-1', 'Gene', (231, 235))	('TMIT', 'Chemical', '-', (112, 116))	('FGFR3', 'Gene', '2261', (130, 135))
58890	30719168	TCGA The Cancer Genome Atlas PD-1 programmed cell death 1 PD-L1 PD-1 ligand CTL cytotoxic T cells TMIT tumor microenvironment immune type MAF mutation annotation format CAN copy number alteration GSEA Gene Set Enrichment Analysis FDR false discovery rate NES normalized enrichment score Ti/Tv transition/transversion IFN-gamma interferon gamma TIL tumor infiltrates lymphocytes.	('PD-L1', 'Gene', '29126', (58, 63))	('IFN-gamma', 'Gene', (317, 326))	('IFN-gamma', 'Gene', '3458', (317, 326))	('PD-1', 'Gene', '5133', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('programmed cell death', 'biological_process', 'GO:0012501', ('34', '55'))	('false', 'biological_process', 'GO:0071878', ('234', '239'))	('Cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('TMIT', 'Chemical', '-', (98, 102))	('ligand', 'molecular_function', 'GO:0005488', ('69', '75'))	('PD-1', 'Gene', (64, 68))	('PD-1', 'Gene', '5133', (64, 68))	('tumor', 'Disease', (103, 108))	('Ti/Tv', 'Var', (287, 292))	('GSEA', 'Chemical', '-', (196, 200))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('false', 'biological_process', 'GO:0071877', ('234', '239'))	('interferon gamma', 'molecular_function', 'GO:0005133', ('327', '343'))	('PD-L1', 'Gene', (58, 63))	('tumor', 'Disease', (348, 353))	('PD-1', 'Gene', (29, 33))
58897	30846479	Ectopic expression of the CPT1B in high-grade BLCA cells led to reduced EMT in in vitro, and reduced cell proliferation, EMT, and metastasis in vivo.	('EMT in in vitro', 'CPA', (72, 87))	('EMT', 'biological_process', 'GO:0001837', ('121', '124'))	('CPT1B', 'Gene', (26, 31))	('EMT', 'CPA', (121, 124))	('CPT1B', 'Gene', '1375', (26, 31))	('reduced EMT', 'Phenotype', 'HP:0032198', (64, 75))	('reduced', 'NegReg', (93, 100))	('Ectopic expression', 'Var', (0, 18))	('EMT', 'biological_process', 'GO:0001837', ('72', '75'))	('cell proliferation', 'biological_process', 'GO:0008283', ('101', '119'))	('CPT', 'molecular_function', 'GO:0004142', ('26', '29'))	('reduced', 'NegReg', (64, 71))	('CPT', 'molecular_function', 'GO:0004095', ('26', '29'))	('cell proliferation', 'CPA', (101, 119))	('BLCA', 'Phenotype', 'HP:0009725', (46, 50))
58914	30846479	Ectopic expression of CPT1B in high grade BLCA cells increased FAO which in turn reduced epithelial mesenchymal transition (EMT).	('CPT', 'molecular_function', 'GO:0004095', ('22', '25'))	('CPT1B', 'Gene', (22, 27))	('CPT1B', 'Gene', '1375', (22, 27))	('FAO', 'Chemical', '-', (63, 66))	('FAO', 'MPA', (63, 66))	('Ectopic expression', 'Var', (0, 18))	('EMT', 'biological_process', 'GO:0001837', ('124', '127'))	('increased', 'PosReg', (53, 62))	('BLCA', 'Phenotype', 'HP:0009725', (42, 46))	('epithelial mesenchymal transition', 'biological_process', 'GO:0001837', ('89', '122'))	('reduced', 'NegReg', (81, 88))	('CPT', 'molecular_function', 'GO:0004142', ('22', '25'))	('epithelial mesenchymal transition', 'CPA', (89, 122))
58942	30846479	To identify genes associated with low vs high CPT1B gene expression, we used the gene expression data from five independent public cohorts: The cancer genomic atlas (TCGA), Kim (GSE13507), Sjodahl (GSE32894), Lindgren (GSE32548), and Riester (GSE31684).	('GSE32894', 'Var', (198, 206))	('CPT1B', 'Gene', '1375', (46, 51))	('GSE31684', 'Var', (243, 251))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('CPT', 'molecular_function', 'GO:0004142', ('46', '49'))	('cancer', 'Disease', (144, 150))	('GSE13507', 'Var', (178, 186))	('CPT', 'molecular_function', 'GO:0004095', ('46', '49'))	('gene expression', 'biological_process', 'GO:0010467', ('52', '67'))	('CPT1B', 'Gene', (46, 51))	('gene expression', 'biological_process', 'GO:0010467', ('81', '96'))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('GSE32548', 'Var', (219, 227))
58944	30846479	Next, we generated a rank file for each expressed gene by the log2 fold change of low CPT1B samples over high CPT1B samples.	('CPT', 'molecular_function', 'GO:0004142', ('110', '113'))	('CPT', 'molecular_function', 'GO:0004142', ('86', '89'))	('CPT', 'molecular_function', 'GO:0004095', ('110', '113'))	('CPT', 'molecular_function', 'GO:0004095', ('86', '89'))	('low', 'Var', (82, 85))	('CPT1B', 'Gene', (86, 91))	('CPT1B', 'Gene', '1375', (86, 91))	('CPT1B', 'Gene', (110, 115))	('CPT1B', 'Gene', '1375', (110, 115))
58998	30846479	For each cohort, the signature consisted of the genes that were differentially expressed by at least 1.25 fold between the patients with high and low CPT1B expression, respectively.	('low', 'NegReg', (146, 149))	('CPT', 'molecular_function', 'GO:0004142', ('150', '153'))	('CPT', 'molecular_function', 'GO:0004095', ('150', '153'))	('CPT1B', 'Gene', (150, 155))	('high', 'Var', (137, 141))	('CPT1B', 'Gene', '1375', (150, 155))	('patients', 'Species', '9606', (123, 131))	('expression', 'MPA', (156, 166))
59000	30846479	We used GSEA method to determine the enriched pathways of the CPT1B high vs. CPT1B low signatures in each cohort.	('CPT1B', 'Gene', (77, 82))	('high', 'Var', (68, 72))	('CPT', 'molecular_function', 'GO:0004142', ('77', '80'))	('CPT1B', 'Gene', '1375', (77, 82))	('GSEA', 'Chemical', '-', (8, 12))	('CPT', 'molecular_function', 'GO:0004095', ('77', '80'))	('CPT', 'molecular_function', 'GO:0004142', ('62', '65'))	('CPT1B', 'Gene', (62, 67))	('CPT1B', 'Gene', '1375', (62, 67))	('CPT', 'molecular_function', 'GO:0004095', ('62', '65'))
59007	30846479	Given that CPT1B loss and FAO disruption led to significantly increased activity in pathways associated with EMT and invasion (Figure 5), we hypothesized that CPT1B overexpression leads to a reduction in the metastatic capabilities of cancer cells.	('increased', 'PosReg', (62, 71))	('EMT', 'biological_process', 'GO:0001837', ('109', '112'))	('FAO', 'Chemical', '-', (26, 29))	('overexpression', 'PosReg', (165, 179))	('CPT1B', 'Gene', '1375', (159, 164))	('CPT', 'molecular_function', 'GO:0004095', ('11', '14'))	('disruption', 'Var', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('activity', 'MPA', (72, 80))	('CPT', 'molecular_function', 'GO:0004142', ('159', '162'))	('CPT1B', 'Gene', (11, 16))	('loss', 'NegReg', (17, 21))	('CPT1B', 'Gene', '1375', (11, 16))	('CPT1B', 'Gene', (159, 164))	('CPT', 'molecular_function', 'GO:0004142', ('11', '14'))	('cancer', 'Disease', (235, 241))	('reduction', 'NegReg', (191, 200))	('CPT', 'molecular_function', 'GO:0004095', ('159', '162'))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
59019	30846479	Alteration of metabolism is one of the hallmarkers for cancer progression.	('metabolism', 'MPA', (14, 24))	('Alteration', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('metabolism', 'biological_process', 'GO:0008152', ('14', '24'))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
59029	30846479	Each of these genes has a profound impact on the cellular metabolism, and particularly lipid metabolism highlighting the importance of fatty acids in cell proliferation and tumorigenesis.	('lipid metabolism', 'biological_process', 'GO:0006629', ('87', '103'))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('cellular metabolism', 'MPA', (49, 68))	('lipid', 'Chemical', 'MESH:D008055', (87, 92))	('fatty acids', 'Chemical', 'MESH:D005227', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('cellular metabolism', 'biological_process', 'GO:0044237', ('49', '68'))	('genes', 'Var', (14, 19))	('cell proliferation', 'biological_process', 'GO:0008283', ('150', '168'))	('impact', 'Reg', (35, 41))	('lipid metabolism', 'MPA', (87, 103))
59071	29581876	Prostatic cancer-specific survival is significantly shorter for patients with grade group 5 than patients with grade group 4 for the biopsy (hazard ratio [HR] = 2.13, 95% confidence interval [CI] = 1.37-3.30) and radical prostatectomy groups (HR = 2.38, 95% CI = 1.74-3.28).	('Prostatic cancer', 'Disease', (0, 16))	('grade group 5', 'Var', (78, 91))	('patients', 'Species', '9606', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('Prostatic cancer', 'Phenotype', 'HP:0012125', (0, 16))	('shorter', 'NegReg', (52, 59))	('patients', 'Species', '9606', (97, 105))	('Prostatic cancer', 'Disease', 'MESH:D011471', (0, 16))
59108	29581876	Chromosome 6q15 is frequently deleted in ductal adenocarcinoma cells, and deletions of MAP3K7, which is harbored in this locus, are associated with early biochemical recurrence, advanced tumor stage, and high GS.	('deletions', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('ductal adenocarcinoma', 'Disease', (41, 62))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('MAP3K7', 'Gene', '6885', (87, 93))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('tumor', 'Disease', (187, 192))	('early biochemical recurrence', 'CPA', (148, 176))	('GS', 'Disease', 'MESH:D011125', (209, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('associated with', 'Reg', (132, 147))	('ductal adenocarcinoma', 'Disease', 'MESH:D044584', (41, 62))	('MAP3K7', 'Gene', (87, 93))	('MAP3K', 'molecular_function', 'GO:0004709', ('87', '92'))
59109	29581876	MAP3K7 deletions are associated well with the TMPRSS2-ERG absence, which is more common in ductal than acinar adenocarcinomas.	('acinar adenocarcinomas', 'Disease', 'MESH:D018267', (103, 125))	('MAP3K7', 'Gene', '6885', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('associated', 'Reg', (21, 31))	('deletions', 'Var', (7, 16))	('TMPRSS2', 'Gene', '7113', (46, 53))	('ERG', 'Gene', '2078', (54, 57))	('ERG absence', 'Phenotype', 'HP:0000550', (54, 65))	('MAP3K', 'molecular_function', 'GO:0004709', ('0', '5'))	('common', 'Reg', (81, 87))	('MAP3K7', 'Gene', (0, 6))	('ERG', 'Gene', (54, 57))	('TMPRSS2', 'Gene', (46, 53))	('acinar adenocarcinomas', 'Disease', (103, 125))
59123	29581876	Inactivation of the tumor suppressors RB1 and TP53 commonly occurs in prostatic SmCCs, similar to their counterparts in the lung and other organs.	('occurs', 'Reg', (60, 66))	('RB1', 'Gene', (38, 41))	('RB1', 'Gene', '5925', (38, 41))	('TP53', 'Gene', '7157', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('TP53', 'Gene', (46, 50))	('prostatic SmCCs', 'Disease', (70, 85))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('Inactivation', 'Var', (0, 12))	('tumor', 'Disease', (20, 25))
59124	29581876	Inactivation of these genes through allelic loss or mutation, as well as lack of expression of their encoded proteins, is characteristic of prostatic SmCCs.	('prostatic SmCCs', 'Disease', (140, 155))	('lack', 'NegReg', (73, 77))	('allelic loss', 'Disease', 'MESH:C566065', (36, 48))	('allelic loss', 'Disease', (36, 48))	('mutation', 'Var', (52, 60))	('Inactivation', 'NegReg', (0, 12))	('expression', 'MPA', (81, 91))
59126	29581876	Therefore, the loss of RB1 likely represents a critical event in the development of prostatic SmCC and may serve as a diagnostic marker and potential therapeutic target.	('loss', 'Var', (15, 19))	('RB1', 'Gene', '5925', (23, 26))	('RB1', 'Gene', (23, 26))	('prostatic SmCC', 'Disease', (84, 98))
59187	29581876	The tumor stained positive for NKX3-1 (nuclear staining; Figure 2B), prostein (P501S) (granular perinuclear pattern; Figure 2C), PSA (Figure 2D), PSMA (Figure 2E), and AR (nuclear staining; Figure 2F).	('tumor', 'Disease', (4, 9))	('NKX3-1', 'Gene', '4824', (31, 37))	('P501S', 'Mutation', 'p.P501S', (79, 84))	('PSMA', 'Gene', '2346', (146, 150))	('PSA', 'Gene', '354', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('prostein', 'Gene', '85414', (69, 77))	('PSMA', 'molecular_function', 'GO:0043275', ('146', '150'))	('P501S', 'Var', (79, 84))	('NKX3-1', 'Gene', (31, 37))	('PSMA', 'Gene', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('prostein', 'Gene', (69, 77))	('PSA', 'Gene', (129, 132))	('AR', 'Gene', '367', (168, 170))
59195	29581876	The ETS-positive subset, comprising 59% of all cases, was enriched in PTEN deletions.	('PTEN', 'Gene', (70, 74))	('PTEN', 'Gene', '5728', (70, 74))	('deletions', 'Var', (75, 84))
59196	29581876	The SPOP-mutant subset, comprising 11% of all cases, harbored distinct SCNA profiles (including deletions of CHD1, 6q, and 2q), consistent with results from previous studies.	('CHD1', 'Gene', '1105', (109, 113))	('SPOP', 'Gene', (4, 8))	('deletions', 'Var', (96, 105))	('SPOP', 'Gene', '8405', (4, 8))	('CHD1', 'Gene', (109, 113))
59201	29581876	The overall mutational burden was 0.94 mutations per megabase (median, range 0.04-24 per megabase), which corresponds to 19 nonsynonymous mutations per tumor genome (median, 13-25, 25th and 75th percentiles, respectively).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('mutations', 'Var', (39, 48))
59206	29581876	Although the overall mutational burden was substantially higher in metastatic cancers, consistent with previous studies, the primary and metastatic cancers were remarkably similar in their subtype distributions, except that metastatic cancers harbored no IDH1 mutations.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('higher', 'Reg', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (235, 242))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('IDH1', 'Gene', (255, 259))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('IDH1', 'Gene', '3417', (255, 259))	('mutational', 'Var', (21, 31))
59214	29581876	As expected, the IDH1-mutant subset harbored the greatest number of epigenetically silenced genes among all prostatic cancers.	('epigenetically silenced genes', 'Var', (68, 97))	('prostatic cancers', 'Phenotype', 'HP:0012125', (108, 125))	('prostatic cancers', 'Disease', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('prostatic cancers', 'Disease', 'MESH:D011471', (108, 125))	('IDH1', 'Gene', (17, 21))	('IDH1', 'Gene', '3417', (17, 21))	('prostatic cancer', 'Phenotype', 'HP:0012125', (108, 124))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
59216	29581876	Consistent with these findings, SPOP mutations were previously implicated in androgen signaling because both AR and AR coactivators undergo deregulation in the presence of SPOP mutations.	('SPOP', 'Gene', '8405', (172, 176))	('SPOP', 'Gene', (172, 176))	('mutations', 'Var', (177, 186))	('AR', 'Gene', '367', (116, 118))	('SPOP', 'Gene', '8405', (32, 36))	('AR', 'Gene', '367', (109, 111))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('SPOP', 'Gene', (32, 36))	('deregulation', 'MPA', (140, 152))
59217	29581876	AR signaling was more frequently altered in metastatic samples, most often by amplifications or mutations of AR, which were essentially absent in localized prostatic cancers.	('prostatic cancer', 'Phenotype', 'HP:0012125', (156, 172))	('amplifications', 'Var', (78, 92))	('prostatic cancers', 'Phenotype', 'HP:0012125', (156, 173))	('AR', 'Gene', '367', (109, 111))	('localized prostatic cancers', 'Disease', (146, 173))	('altered', 'Reg', (33, 40))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('signaling', 'biological_process', 'GO:0023052', ('3', '12'))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('localized prostatic cancers', 'Disease', 'MESH:D011471', (146, 173))	('AR', 'Gene', '367', (0, 2))	('mutations', 'Var', (96, 105))
59220	29581876	Nearly 20% of all cases harbored the inactivation of DNA repair genes, including BRCA2 (3%), BRCA1 (1%), CDK12 (2%), ATM (4%), FANCD2 (7%), and RAD51C (3%).	('FANCD2', 'Gene', (127, 133))	('CDK12', 'Gene', '51755', (105, 110))	('DNA repair genes', 'Gene', (53, 69))	('ATM', 'Gene', '472', (117, 120))	('BRCA1', 'Gene', '672', (93, 98))	('RAD', 'biological_process', 'GO:1990116', ('144', '147'))	('CDK12', 'Gene', (105, 110))	('CDK', 'molecular_function', 'GO:0004693', ('105', '108'))	('BRCA2', 'Gene', (81, 86))	('BRCA1', 'Gene', (93, 98))	('DNA repair', 'biological_process', 'GO:0006281', ('53', '63'))	('RAD51C', 'Gene', (144, 150))	('RAD51C', 'Gene', '5889', (144, 150))	('BRCA2', 'Gene', '675', (81, 86))	('FANCD2', 'Gene', '2177', (127, 133))	('inactivation', 'Var', (37, 49))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('ATM', 'Gene', (117, 120))
59221	29581876	Recent evidence suggests that the incidence of germline mutations in genes mediating DNA repair processes was 11.8% in patients with metastatic prostatic cancer, which is significantly higher than in patients with localized prostatic cancer.	('DNA repair', 'biological_process', 'GO:0006281', ('85', '95'))	('localized prostatic cancer', 'Disease', (214, 240))	('prostatic cancer', 'Disease', (144, 160))	('patients', 'Species', '9606', (200, 208))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('germline mutations', 'Var', (47, 65))	('patients', 'Species', '9606', (119, 127))	('prostatic cancer', 'Disease', 'MESH:D011471', (144, 160))	('prostatic cancer', 'Phenotype', 'HP:0012125', (144, 160))	('prostatic cancer', 'Disease', 'MESH:D011471', (224, 240))	('localized prostatic cancer', 'Disease', 'MESH:D011471', (214, 240))	('prostatic cancer', 'Phenotype', 'HP:0012125', (224, 240))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
59222	29581876	In 2005, genetic rearrangements of androgen-regulated genes with members of the ETS transcription factor family were identified in more than half of prostatic cancer cases.	('prostatic cancer', 'Disease', 'MESH:D011471', (149, 165))	('prostatic cancer', 'Phenotype', 'HP:0012125', (149, 165))	('identified', 'Reg', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('androgen-regulated genes', 'Gene', (35, 59))	('genetic rearrangements', 'Var', (9, 31))	('transcription factor', 'molecular_function', 'GO:0000981', ('84', '104'))	('prostatic cancer', 'Disease', (149, 165))	('transcription', 'biological_process', 'GO:0006351', ('84', '97'))
59223	29581876	The most common rearrangement manifests as a fusion of the 5' untranslated region of the androgen-regulated TMPRSS2 gene with the coding area of ERG, accounting for 90% of ETS family fusions.	('TMPRSS2', 'Gene', '7113', (108, 115))	('ERG', 'Gene', '2078', (145, 148))	('fusion', 'Var', (45, 51))	('ERG', 'Gene', (145, 148))	('TMPRSS2', 'Gene', (108, 115))
59225	29581876	ETS rearrangements have been occasionally detected in HGPIN and appear to be an early event in prostate carcinogenesis.	('prostate carcinogenesis', 'Disease', (95, 118))	('PIN', 'Gene', (56, 59))	('rearrangements', 'Var', (4, 18))	('PIN', 'Gene', '8655', (56, 59))	('prostate carcinogenesis', 'Disease', 'MESH:D063646', (95, 118))
59226	29581876	ETS-rearranged cancers are notably enriched in genomic alterations in a number of canonical pathways, including PTEN deletions, TP53 alterations, PIK3 pathway alterations, and the specific amplification of 3p.	('alterations', 'Reg', (159, 170))	('alterations', 'Var', (133, 144))	('alterations', 'Reg', (55, 66))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('PIK3', 'Gene', (146, 150))	('PTEN', 'Gene', '5728', (112, 116))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', (15, 22))	('canonical pathways', 'Pathway', (82, 100))	('PIK3', 'Gene', '5294', (146, 150))	('PTEN', 'Gene', (112, 116))	('deletions', 'Var', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
59227	29581876	ERG overexpression accelerates prostatic carcinogenesis when combined with PTEN deletions.	('ERG', 'Gene', '2078', (0, 3))	('ERG', 'Gene', (0, 3))	('accelerates', 'PosReg', (19, 30))	('prostatic carcinogenesis', 'Disease', 'MESH:D063646', (31, 55))	('PTEN', 'Gene', (75, 79))	('deletions', 'Var', (80, 89))	('PTEN', 'Gene', '5728', (75, 79))	('prostatic carcinogenesis', 'Disease', (31, 55))
59228	29581876	PTEN deletions are associated with metastatic disease, higher GP, higher risk of progression, recurrence after therapy, and death from diseases.	('associated', 'Reg', (19, 29))	('PTEN', 'Gene', '5728', (0, 4))	('death', 'Disease', 'MESH:D003643', (124, 129))	('death', 'Disease', (124, 129))	('PTEN', 'Gene', (0, 4))	('metastatic disease', 'Disease', (35, 53))	('higher', 'PosReg', (55, 61))	('deletions', 'Var', (5, 14))
59231	29581876	Although the prognostic implications of ETS rearrangements remain unclear, recent evidence suggests that TMPRSS2-ERG fusions are associated with young patients and low-grade prostatic cancer.	('fusions', 'Var', (117, 124))	('associated', 'Reg', (129, 139))	('prostatic cancer', 'Disease', 'MESH:D011471', (174, 190))	('prostatic cancer', 'Phenotype', 'HP:0012125', (174, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('patients', 'Species', '9606', (151, 159))	('TMPRSS2', 'Gene', '7113', (105, 112))	('ERG', 'Gene', '2078', (113, 116))	('prostatic cancer', 'Disease', (174, 190))	('ERG', 'Gene', (113, 116))	('TMPRSS2', 'Gene', (105, 112))
59233	29581876	The SPOP mutation is the most common point mutation (6%-15%) in all prostatic cancers.	('mutation', 'Var', (9, 17))	('SPOP', 'Gene', (4, 8))	('prostatic cancer', 'Phenotype', 'HP:0012125', (68, 84))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('prostatic cancers', 'Phenotype', 'HP:0012125', (68, 85))	('prostatic cancers', 'Disease', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('prostatic cancers', 'Disease', 'MESH:D011471', (68, 85))	('SPOP', 'Gene', '8405', (4, 8))
59234	29581876	The SPOP gene encodes the substrate-recognition component of the Cullin3-based E3-ubiquitin ligase; missense mutations are found exclusively in the substrate-binding cleft of SPOP, indicating that this mutation alters substrate binding.	('Cullin3', 'Gene', (65, 72))	('SPOP', 'Gene', (175, 179))	('binding', 'molecular_function', 'GO:0005488', ('158', '165'))	('SPOP', 'Gene', (4, 8))	('binding', 'molecular_function', 'GO:0005488', ('228', '235'))	('Cullin3', 'Gene', '8452', (65, 72))	('substrate', 'MPA', (218, 227))	('missense mutations', 'Var', (100, 118))	('SPOP', 'Gene', '8405', (175, 179))	('SPOP', 'Gene', '8405', (4, 8))	('ubiquitin', 'molecular_function', 'GO:0031386', ('82', '91'))	('alters', 'Reg', (211, 217))
59235	29581876	SPOP mutations and ETS rearrangements are mutually exclusive.	('SPOP', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('SPOP', 'Gene', '8405', (0, 4))
59236	29581876	Because SPOP mutations can be detected in HGPINs adjacent to cancers, SPOP mutations are likely to be early events in prostatic carcinogenesis.	('prostatic carcinogenesis', 'Disease', (118, 142))	('SPOP', 'Gene', '8405', (70, 74))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('SPOP', 'Gene', (70, 74))	('PIN', 'Gene', (44, 47))	('cancers', 'Disease', (61, 68))	('SPOP', 'Gene', '8405', (8, 12))	('SPOP', 'Gene', (8, 12))	('PIN', 'Gene', '8655', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('prostatic carcinogenesis', 'Disease', 'MESH:D063646', (118, 142))	('mutations', 'Var', (13, 22))
59237	29581876	Functionally, SPOP mutation promotes oncogenesis by pereventing the degradation of oncogenic facters including ERG and AR.	('SPOP', 'Gene', (14, 18))	('oncogenesis', 'CPA', (37, 48))	('degradation of', 'MPA', (68, 82))	('mutation', 'Var', (19, 27))	('oncogenesis', 'biological_process', 'GO:0007048', ('37', '48'))	('ERG', 'Gene', '2078', (111, 114))	('promotes', 'PosReg', (28, 36))	('ERG', 'Gene', (111, 114))	('AR', 'Gene', '367', (119, 121))	('degradation', 'biological_process', 'GO:0009056', ('68', '79'))	('SPOP', 'Gene', '8405', (14, 18))
59240	29581876	A recent study demonstrated that CHD1 is a putative synthetic-essential gene in PTEN-deficient cancers, and CHD1 depletion profoundly and specifically suppresses cell proliferation in PTEN-deficient prostate cancers.	('CHD1', 'Gene', '1105', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('CHD1', 'Gene', (33, 37))	('deficient prostate', 'Phenotype', 'HP:0008687', (189, 207))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('PTEN-deficient cancers', 'Disease', 'MESH:D006223', (80, 102))	('CHD1', 'Gene', '1105', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('PTEN-deficient prostate cancers', 'Disease', (184, 215))	('prostate cancer', 'Phenotype', 'HP:0012125', (199, 214))	('CHD1', 'Gene', (108, 112))	('depletion', 'Var', (113, 122))	('prostate cancers', 'Phenotype', 'HP:0012125', (199, 215))	('PTEN-deficient cancers', 'Disease', (80, 102))	('suppresses', 'NegReg', (151, 161))	('cell proliferation', 'CPA', (162, 180))	('PTEN-deficient prostate cancers', 'Disease', 'MESH:D006223', (184, 215))	('cell proliferation', 'biological_process', 'GO:0008283', ('162', '180'))
59241	29581876	Another recent study showed that SPOP mutations activate both PIK3/MTOR and AR signaling pathways, effectively uncoupling the normal negative-feedback mechanism between these two pathways.	('MTOR', 'Gene', '2475', (67, 71))	('AR', 'Gene', '367', (76, 78))	('PIK3', 'Gene', (62, 66))	('activate', 'PosReg', (48, 56))	('MTOR', 'Gene', (67, 71))	('SPOP', 'Gene', '8405', (33, 37))	('PIK3', 'Gene', '5294', (62, 66))	('SPOP', 'Gene', (33, 37))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('mutations', 'Var', (38, 47))
59250	29581876	Another recent study suggests that AR variants are dependent on FOXA1 for sustaining a pro-proliferative gene signatures and agents targeting FOXA1 may represent novel therapeutic options for patients with castrate-resistant prostatic cancer.	('FOXA1', 'Gene', (64, 69))	('prostatic cancer', 'Disease', 'MESH:D011471', (225, 241))	('variants', 'Var', (38, 46))	('prostatic cancer', 'Phenotype', 'HP:0012125', (225, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('patients', 'Species', '9606', (192, 200))	('FOXA1', 'Gene', '3169', (64, 69))	('FOXA1', 'Gene', (142, 147))	('prostatic cancer', 'Disease', (225, 241))	('FOXA1', 'Gene', '3169', (142, 147))	('sustaining', 'PosReg', (74, 84))	('AR', 'Gene', '367', (35, 37))
59251	29581876	IDH1, which encodes a metabolic enzyme, is recurrently mutated in prostatic cancers, resulting in a methylator phenotype.	('prostatic cancers', 'Disease', (66, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('prostatic cancers', 'Phenotype', 'HP:0012125', (66, 83))	('prostatic cancers', 'Disease', 'MESH:D011471', (66, 83))	('mutated', 'Var', (55, 62))	('methylator phenotype', 'MPA', (100, 120))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('IDH1', 'Gene', (0, 4))	('prostatic cancer', 'Phenotype', 'HP:0012125', (66, 82))	('IDH1', 'Gene', '3417', (0, 4))
59252	29581876	The presence of IDH1 mutations appears to represent a rare and unique subset of early onset prostate cancers, with relatively few SCNAs and high levels of genomic hypermethylation.	('prostate cancer', 'Phenotype', 'HP:0012125', (92, 107))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('prostate cancers', 'Phenotype', 'HP:0012125', (92, 108))	('prostate cancers', 'Disease', 'MESH:D011471', (92, 108))	('prostate cancers', 'Disease', (92, 108))	('IDH1', 'Gene', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('IDH1', 'Gene', '3417', (16, 20))	('mutations', 'Var', (21, 30))
59259	29581876	ADT androgen deprivation therapy AMACR alpha-methylacyl-CoA racemase AR androgen receptor BCC basal cell carcinoma CI confidence interval GP Gleason pattern GS Gleason score HGPIN high-grade prostatic intraepithelial neoplasia HR hazard ratio IDC-P intraductal carcinoma of the prostate ISUP International Society of Urological Pathology LCNEC large cell neuroendocrine carcinoma LOH loss of heterozygosity PAP prostatic acid phosphatase PARP poly ADP ribose polymerase PIN prostatic intraepithelial neoplasia PSA prostate-specific antigen PSMA prostate-specific membrane antigen SCNA somatic copy-number alteration SqCC squamous cell carcinoma SmCC small cell carcinoma TCGA The Cancer Genome Atlas WHO World Health Organization	('intraductal carcinoma of the prostate', 'Disease', (249, 286))	('AR', 'Gene', '367', (69, 71))	('carcinoma', 'Disease', 'MESH:D002277', (261, 270))	('androgen receptor', 'Gene', (72, 89))	('PAP', 'Gene', '55', (407, 410))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (94, 114))	('prostate-specific membrane antigen', 'Gene', (545, 579))	('PSA', 'Gene', '354', (510, 513))	('AR', 'Gene', '367', (439, 441))	('androgen receptor', 'Gene', '367', (72, 89))	('prostatic intraepithelial neoplasia', 'Disease', (191, 226))	('carcinoma', 'Disease', 'MESH:D002277', (370, 379))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (484, 509))	('carcinoma', 'Phenotype', 'HP:0030731', (661, 670))	('carcinoma', 'Phenotype', 'HP:0030731', (635, 644))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (355, 379))	('carcinoma', 'Disease', (661, 670))	('prostate-specific membrane antigen', 'molecular_function', 'GO:0043275', ('545', '579'))	('carcinoma', 'Disease', (105, 114))	('prostatic acid phosphatase', 'Gene', '55', (411, 437))	('carcinoma', 'Disease', (635, 644))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (621, 644))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (621, 644))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (650, 670))	('ADT', 'Chemical', '-', (0, 3))	('neoplasia', 'Phenotype', 'HP:0002664', (217, 226))	('cell neuroendocrine carcinoma', 'Disease', (350, 379))	('phosphatase', 'molecular_function', 'GO:0016791', ('426', '437'))	('PAP', 'molecular_function', 'GO:0043751', ('407', '410'))	('AMACR', 'Gene', (33, 38))	('alteration', 'Var', (605, 615))	('prostatic intraepithelial neoplasia', 'Disease', 'MESH:D019048', (474, 509))	('prostate-specific membrane antigen', 'Gene', '2346', (545, 579))	('poly ADP ribose polymerase', 'Gene', (443, 469))	('PIN', 'Gene', (470, 473))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('squamous cell carcinoma', 'Disease', (621, 644))	('PIN', 'Gene', (176, 179))	('carcinoma', 'Disease', (261, 270))	('prostatic intraepithelial neoplasia', 'Disease', (474, 509))	('small cell carcinoma', 'Disease', (650, 670))	('PSMA', 'Gene', '2346', (540, 544))	('PARP', 'Gene', '142', (438, 442))	('carcinoma', 'Disease', 'MESH:D002277', (105, 114))	('AMACR', 'Gene', '23600', (33, 38))	('small cell carcinoma', 'Disease', 'MESH:D018288', (650, 670))	('intraductal carcinoma of the prostate', 'Disease', 'MESH:D002285', (249, 286))	('PSA', 'Gene', (510, 513))	('carcinoma', 'Disease', 'MESH:D002277', (661, 670))	('GS', 'Disease', 'MESH:D011125', (157, 159))	('alpha-methylacyl-CoA racemase', 'Gene', '23600', (39, 68))	('cell neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (350, 379))	('carcinoma', 'Disease', 'MESH:D002277', (635, 644))	('carcinoma', 'Phenotype', 'HP:0030731', (370, 379))	('PSMA', 'Gene', (540, 544))	('large cell neuroendocrine carcinoma', 'Phenotype', 'HP:0030360', (344, 379))	('neoplasia', 'Phenotype', 'HP:0002664', (500, 509))	('PARP', 'Gene', (438, 442))	('PSMA', 'molecular_function', 'GO:0043275', ('540', '544'))	('PIN', 'Gene', '8655', (470, 473))	('ADT', 'cellular_component', 'GO:0030956', ('0', '3'))	('carcinoma', 'Disease', (370, 379))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (201, 226))	('PIN', 'Gene', '8655', (176, 179))	('PAP', 'Gene', (407, 410))	('Cancer', 'Phenotype', 'HP:0002664', (680, 686))	('poly ADP ribose polymerase', 'Gene', '142', (443, 469))	('membrane', 'cellular_component', 'GO:0016020', ('563', '571'))	('alpha-methylacyl-CoA racemase', 'Gene', (39, 68))	('prostatic intraepithelial neoplasia', 'Disease', 'MESH:D019048', (191, 226))	('prostatic acid phosphatase', 'Gene', (411, 437))
59275	29331675	True cancer driver genes are those whose perturbation pushes a cell towards a malignant phenotype.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('pushes', 'PosReg', (54, 60))	('cancer', 'Disease', (5, 11))	('perturbation', 'Var', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
59276	29331675	Within this study, we define cancer driver genes as genes that fulfill all of the following criteria: (1) genes that are genetically and/or epigenetically deregulated in cancer, (2) genes whose genetic and epigenetic aberrations have a direct impact on their own functional gene expression levels, and (3) genes that are predicted to play regulatory roles high in the causal hierarchy of the origin of tumors.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (402, 408))	('cancer', 'Disease', (170, 176))	('gene expression', 'biological_process', 'GO:0010467', ('274', '289'))	('tumors', 'Disease', (402, 408))	('tumors', 'Disease', 'MESH:D009369', (402, 408))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('impact', 'Reg', (243, 249))	('functional gene expression levels', 'MPA', (263, 296))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('epigenetic aberrations', 'Var', (206, 228))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (402, 407))
59277	29331675	These include, for example, transcription factors, cell cycle genes or epigenetic modifying enzymes, whose altered state in cancer results in deregulation of downstream target genes; as well as upstream signaling molecules.	('cancer', 'Disease', (124, 130))	('deregulation', 'MPA', (142, 154))	('transcription', 'biological_process', 'GO:0006351', ('28', '41'))	('signaling', 'biological_process', 'GO:0023052', ('203', '212'))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cell cycle', 'biological_process', 'GO:0007049', ('51', '61'))	('epigenetic modifying enzymes', 'Var', (71, 99))	('cell cycle genes', 'Gene', (51, 67))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
59283	29331675	Integration of epigenomics data is essential to comprehensive analysis of cancer genomic analysis, as DNA methylation is a major mechanism of transcriptional deregulation in virtually all cancers.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('methylation', 'Var', (106, 117))	('cancers', 'Disease', (188, 195))	('cancer', 'Disease', (74, 80))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('DNA methylation', 'biological_process', 'GO:0006306', ('102', '117'))	('cancer', 'Disease', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
59284	29331675	For example, cancer driver genes such as BRCA1 and MLH1, which are often altered by mutation in cancer, are also frequently deregulated by DNA methylation in other patients, with similar downstream consequences.	('deregulated', 'PosReg', (124, 135))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('BRCA1', 'Gene', '672', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('DNA methylation', 'Var', (139, 154))	('BRCA1', 'Gene', (41, 46))	('MLH1', 'Gene', '4292', (51, 55))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('MLH1', 'Gene', (51, 55))	('DNA methylation', 'biological_process', 'GO:0006306', ('139', '154'))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('patients', 'Species', '9606', (164, 172))	('BRCA', 'Phenotype', 'HP:0003002', (41, 45))	('cancer', 'Disease', (96, 102))	('mutation', 'Var', (84, 92))
59301	29331675	To establish a list of cancer driver genes, we thus investigate the linear effects of copy number and DNA methylation on gene expression through a linear regression model performed on each gene independently: We used the R2 statistic to evaluate whether copy number has a significant positive effect (beta2 > 0) and DNA methylation a significant negative effect (beta1 < 0) on gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('377', '392'))	('negative', 'NegReg', (346, 354))	('positive', 'PosReg', (284, 292))	('beta2', 'Gene', (301, 306))	('DNA', 'cellular_component', 'GO:0005574', ('316', '319'))	('DNA methylation', 'biological_process', 'GO:0006306', ('316', '331'))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('DNA methylation', 'biological_process', 'GO:0006306', ('102', '117'))	('copy number', 'Var', (254, 265))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))	('beta2', 'Gene', '10383', (301, 306))
59321	29331675	Four perturbation experiments measuring experimental targets of GPX2 knockdown in the A549 cell line were available in LINCS, including three shRNA experiments and a consensus signature derived from these three experiments.	('GPX2', 'Gene', '2877', (64, 68))	('A549', 'CellLine', 'CVCL:0023', (86, 90))	('knockdown', 'Var', (69, 78))	('GPX2', 'Gene', (64, 68))
59322	29331675	In one of these four experiments, a positive differential expression z-score for GPX2 was measured, and we therefore removed this experiment from the analysis since successful GPX2 knockdown is expected to result in a negative z-score.	('GPX2', 'Gene', '2877', (176, 180))	('expression', 'MPA', (58, 68))	('GPX2', 'Gene', (176, 180))	('GPX2', 'Gene', '2877', (81, 85))	('z-score', 'MPA', (227, 234))	('GPX2', 'Gene', (81, 85))	('knockdown', 'Var', (181, 190))
59331	29331675	AMARETTO modules capture the major oncogenic pathways whereas randomly permuted modules do not result in significant gene sets in all cancer sites (Fig.	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('oncogenic pathways', 'Pathway', (35, 53))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('AMARETTO', 'Var', (0, 8))
59341	29331675	Interestingly, for all cancers, a higher proportion of selected drivers are DNA methylation driven compared to DNA copy number driven genes (Supplementary Fig.	('DNA methylation', 'biological_process', 'GO:0006306', ('76', '91'))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('cancers', 'Disease', (23, 30))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('methylation', 'Var', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
59343	29331675	We found that adding methylation driver genes led to an averaged R-squared increase of between 6% for LUSC up to 16% for BRCA when predicting cognate gene expression (Fig.	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('BRCA', 'Phenotype', 'HP:0003002', (121, 125))	('gene expression', 'biological_process', 'GO:0010467', ('150', '165'))	('BRCA', 'Gene', '672', (121, 125))	('methylation', 'Var', (21, 32))	('BRCA', 'Gene', (121, 125))	('LUSC', 'Phenotype', 'HP:0030359', (102, 106))	('increase', 'PosReg', (75, 83))
59366	29331675	We observed that the target genes of these modules that are activated by induced GPX2 expression are significantly repressed upon knockdown of GPX2 in the A549 cell line.	('knockdown', 'Var', (130, 139))	('GPX2', 'Gene', '2877', (143, 147))	('activated', 'PosReg', (60, 69))	('A549', 'CellLine', 'CVCL:0023', (155, 159))	('GPX2', 'Gene', '2877', (81, 85))	('GPX2', 'Gene', (81, 85))	('GPX2', 'Gene', (143, 147))	('expression', 'Var', (86, 96))
59386	29331675	To investigate this further, we tested the correlation of OAS2, as a marker of the IFN-responsive/M1 TAM signature, with both ligands for the immune checkpoint receptor PD-1: CD274, the gene encoding PD-L1, and PDCD1LG2, encoding PD-L2.	('tested', 'Reg', (32, 38))	('TAM', 'Chemical', '-', (101, 104))	('CD274', 'Var', (175, 180))	('IFN', 'Gene', '3439', (83, 86))	('PDCD1LG2', 'Gene', '80380', (211, 219))	('PD-L2', 'Gene', (230, 235))	('PD-L2', 'Gene', '80380', (230, 235))	('PD-1', 'Gene', (169, 173))	('PD-1', 'Gene', '5133', (169, 173))	('PDCD1LG2', 'Gene', (211, 219))	('IFN', 'Gene', (83, 86))
59389	29331675	AMARETTO first identifies cancer drivers, by considering genes with either DNA copy number or DNA methylation aberrations that have an effect on gene expression.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('effect', 'Reg', (135, 141))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('gene expression', 'biological_process', 'GO:0010467', ('145', '160'))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('methylation aberrations', 'Var', (98, 121))	('gene expression', 'MPA', (145, 160))	('DNA methylation', 'biological_process', 'GO:0006306', ('94', '109'))
59412	29331675	Given that OAS2 is a viral dsRNA sensor, and all of the IFN response subnetwork regulators were abnormally methylated, it is plausible that expression of this subnetwork reflects response to reactivation of HERVs, a frequent event in, and potential cause of, many cancers.	('IFN', 'Gene', (56, 59))	('abnormally', 'Var', (96, 106))	('cancers', 'Disease', 'MESH:D009369', (264, 271))	('cancers', 'Disease', (264, 271))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('HERVs', 'Species', '206037', (207, 212))	('IFN', 'Gene', '3439', (56, 59))	('HERVs', 'Protein', (207, 212))
59572	19949672	According to the report of Sarosdy et al., patients with false-positive FISH had a significantly higher recurrence rate than those with a true-negative result.	('higher', 'PosReg', (97, 103))	('patients', 'Species', '9606', (43, 51))	('false', 'biological_process', 'GO:0071878', ('57', '62'))	('recurrence', 'CPA', (104, 114))	('false', 'biological_process', 'GO:0071877', ('57', '62'))	('false-positive', 'Var', (57, 71))
59585	32590974	Upper tract urothelial carcinoma (UTUC) with pure non-urothelial histology is an exception but variants are present in ~25% of cases, including squamous cell carcinoma and adenocarcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (144, 167))	('adenocarcinoma', 'Disease', (172, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('pure', 'molecular_function', 'GO:0034023', ('45', '49'))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('Upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (0, 32))	('Upper tract urothelial carcinoma', 'Disease', (0, 32))	('adenocarcinoma', 'Disease', 'MESH:D000230', (172, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('variants', 'Var', (95, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('squamous cell carcinoma', 'Disease', (144, 167))
59673	28434403	In phase II clinical trial, a total of 255 patients with mRCC were treated with HD-IL2 (600,000 or 720,000 IU/kg) every 8 hourly up to 14 consecutive doses for 5 days.	('IL2', 'Gene', (83, 86))	('HD', 'Disease', 'MESH:D006816', (80, 82))	('patients', 'Species', '9606', (43, 51))	('IL2', 'molecular_function', 'GO:0005134', ('83', '86'))	('IL2', 'Gene', '3558', (83, 86))	('RCC', 'Disease', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('600,000', 'Var', (88, 95))
59726	28434403	ORR as assessed by PD-L1 expression was higher for IC1/2/3 positive tumors 18% compared to IC0 (negative tumors) of 9%.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('PD-L1', 'Gene', (19, 24))	('tumors', 'Disease', (68, 74))	('higher', 'PosReg', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('positive', 'Var', (59, 67))	('PD-L1', 'Gene', '29126', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('IC1/2/3', 'Gene', (51, 58))	('IC1/2/3', 'Gene', '105259599;1781', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
59767	28434403	Unlike lung cancer, smoking was not associated with a higher mutational load and did not predict response to atezolizumab.	('lung cancer', 'Disease', (7, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (7, 18))	('mutational', 'Var', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('lung cancer', 'Disease', 'MESH:D008175', (7, 18))	('atezolizumab', 'Chemical', 'MESH:C000594389', (109, 121))
59808	28434403	The HR for death with sipuleucel-T vs. placebo was 0.78 (95% CI, 0.61-0.98; p = 0.03) with a 22% relative reduction in the risk of death.	('sipuleucel-T', 'Var', (22, 34))	('reduction', 'NegReg', (106, 115))	('sipuleucel', 'Chemical', '-', (22, 32))
59809	28434403	Sipuleucel-T therapy was commonly associated with chills, fever, fatigue, back pain, and headache.	('pain', 'Phenotype', 'HP:0012531', (79, 83))	('associated', 'Reg', (34, 44))	('chills', 'Disease', (50, 56))	('fatigue', 'Disease', (65, 72))	('headache', 'Disease', (89, 97))	('back pain', 'Disease', (74, 83))	('chills', 'Phenotype', 'HP:0025143', (50, 56))	('fatigue', 'Phenotype', 'HP:0012378', (65, 72))	('headache', 'Phenotype', 'HP:0002315', (89, 97))	('fever', 'Disease', 'MESH:D005334', (58, 63))	('Sipuleucel-T', 'Var', (0, 12))	('fever', 'Disease', (58, 63))	('headache', 'Disease', 'MESH:D006261', (89, 97))	('back pain', 'Phenotype', 'HP:0003418', (74, 83))	('fever', 'Phenotype', 'HP:0001945', (58, 63))	('back pain', 'Disease', 'MESH:D001416', (74, 83))	('fatigue', 'Disease', 'MESH:D005221', (65, 72))
59811	28434403	Cerebrovascular events were seen in 8 of 338 patients (2.4%) in the sipuleucel-T group and 3 of 168 patients (1.8%) in the placebo group.	('sipuleucel', 'Chemical', '-', (68, 78))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (45, 53))	('sipuleucel-T', 'Var', (68, 80))	('Cerebrovascular events', 'Phenotype', 'HP:0001297', (0, 22))	('Cerebrovascular', 'Disease', (0, 15))
59814	28434403	They observed elevated IgG levels against multiple secondary antigens, including PSA, after treatment sipuleucel-T, which correlated with sipuleucel-T efficacy.	('IgG levels against multiple secondary antigens', 'MPA', (23, 69))	('men', 'Species', '9606', (97, 100))	('sipuleucel', 'Chemical', '-', (102, 112))	('elevated IgG', 'Phenotype', 'HP:0003237', (14, 26))	('PSA', 'Gene', (81, 84))	('sipuleucel-T', 'Var', (102, 114))	('PSA', 'Gene', '354', (81, 84))	('elevated', 'PosReg', (14, 22))	('sipuleucel', 'Chemical', '-', (138, 148))
59841	28434403	Ipilimumab was commonly associated with diarrhea, pruritus, and rash.	('diarrhea', 'Disease', 'MESH:D003967', (40, 48))	('pruritus', 'Disease', (50, 58))	('pruritus', 'Disease', 'MESH:D011537', (50, 58))	('associated', 'Reg', (24, 34))	('rash', 'Disease', (64, 68))	('Ipilimumab', 'Var', (0, 10))	('rash', 'Phenotype', 'HP:0000988', (64, 68))	('pruritus', 'Phenotype', 'HP:0000989', (50, 58))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (0, 10))	('diarrhea', 'Phenotype', 'HP:0002014', (40, 48))	('diarrhea', 'Disease', (40, 48))	('rash', 'Disease', 'MESH:D005076', (64, 68))
59871	28434403	Overall survival in patients with low-PD-L1 expression was also improved with a hazard ratio ((HR = 0.43, p = 0.04) compared to patients with high-PD-L1 expression.	('PD-L1', 'Gene', '29126', (147, 152))	('expression', 'Var', (44, 54))	('PD-L1', 'Gene', (38, 43))	('PD-L1', 'Gene', (147, 152))	('patients', 'Species', '9606', (20, 28))	('Overall survival', 'MPA', (0, 16))	('patients', 'Species', '9606', (128, 136))	('improved', 'PosReg', (64, 72))	('PD-L1', 'Gene', '29126', (38, 43))
59887	28434403	There are a number of issues, which remain unaddressed to validate PD-L1 positivity as a predictive marker.	('positivity', 'Var', (73, 83))	('PD-L1', 'Gene', (67, 72))	('PD-L1', 'Gene', '29126', (67, 72))
59891	28434403	Tumors with a high mutational load like bladder cancer, melanoma, and lung cancer demonstrate a very high response rate to checkpoint inhibitors.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('response', 'MPA', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutational load', 'Var', (19, 34))
59893	28434403	Neoantigens: Tumor-specific mutant antigens or neoantigens are specific protein epitopes present on tumor cells, which form an important target for checkpoint inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutant', 'Var', (28, 34))	('tumor', 'Disease', (100, 105))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('Tumor', 'Phenotype', 'HP:0002664', (13, 18))
59894	28434403	With recent innovation in molecular biology and genetics, it is possible to identify the immune response to neoantigens that derived from tumor-specific mutations.	('tumor', 'Disease', (138, 143))	('mutations', 'Var', (153, 162))	('immune response', 'biological_process', 'GO:0006955', ('89', '104'))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
59897	28434403	Activation of the WNT/beta-catenin pathway by either mutations or increased expression occurs in a number of malignancies.	('beta-catenin', 'Gene', '1499', (22, 34))	('increased', 'PosReg', (66, 75))	('malignancies', 'Disease', (109, 121))	('mutations', 'Var', (53, 62))	('Activation', 'PosReg', (0, 10))	('expression', 'MPA', (76, 86))	('beta-catenin', 'Gene', (22, 34))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))
59911	27165743	For example, an elevated mutation rate of EGFR in female patients with non-small cell lung cancer may contribute to enhanced response rates among female patients; and H3K27me3 demethylase UTX has been identified as a sex-specific tumor suppressor in T-cell acute lymphoblastic leukemia.	('tumor suppressor', 'biological_process', 'GO:0051726', ('230', '246'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (75, 97))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (71, 97))	('leukemia', 'Phenotype', 'HP:0001909', (277, 285))	('mutation', 'Var', (25, 33))	('EGFR', 'Gene', (42, 46))	('tumor', 'Disease', (230, 235))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (257, 285))	('non-small cell lung cancer', 'Disease', (71, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (250, 285))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('H3K27me3 demethylase', 'Var', (167, 187))	('enhanced', 'PosReg', (116, 124))	('EGFR', 'Gene', '1956', (42, 46))	('patients', 'Species', '9606', (153, 161))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (263, 285))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('230', '246'))	('patients', 'Species', '9606', (57, 65))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (250, 285))	('T-cell acute lymphoblastic leukemia', 'Disease', (250, 285))	('response rates', 'CPA', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (71, 97))
59917	27165743	We focused on 13 major TCGA cancer types with sufficient sample sizes (>=30 for both male and female patients) for at least 5 out of 6 molecular data types (somatic mutations, somatic copy-number alternations [SCNAs], mRNA expression, DNA methylation, miRNA expression and protein expression, Table 1).	('DNA', 'cellular_component', 'GO:0005574', ('235', '238'))	('DNA methylation', 'biological_process', 'GO:0006306', ('235', '250'))	('patients', 'Species', '9606', (101, 109))	('DNA methylation', 'MPA', (235, 250))	('miRNA expression', 'MPA', (252, 268))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('copy-number alternations', 'Var', (184, 208))	('mRNA expression', 'MPA', (218, 233))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('protein expression', 'MPA', (273, 291))	('cancer', 'Disease', (28, 34))	('protein', 'cellular_component', 'GO:0003675', ('273', '280'))
59936	27165743	Clinically, inactivating mutations in this gene may predict sensitivity to mTOR inhibitors, SRC inhibitors and the metabolism drug phenformin in lung cancer.	('metabolism drug phenformin', 'MPA', (115, 141))	('predict', 'Reg', (52, 59))	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('SRC', 'Gene', '6714', (92, 95))	('SRC', 'Gene', (92, 95))	('phenformin', 'Chemical', 'MESH:D010629', (131, 141))	('inactivating mutations', 'Var', (12, 34))	('lung cancer', 'Disease', (145, 156))	('metabolism', 'biological_process', 'GO:0008152', ('115', '125'))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
59938	27165743	The mutations in this gene were highly biased toward female patients (8.4% vs. 19.6%, p < 3.7x10-4, FDR = 0.029).	('mutations', 'Var', (4, 13))	('patients', 'Species', '9606', (60, 68))	('biased', 'Reg', (39, 45))
59939	27165743	EGFR, a major therapeutic target in LUAD, showed a higher mutation frequency in female patients but did not reach the FDR cutoff (9.8% vs 15.8%, p < 0.042, FDR = 0.28), which is consistent with previous reports.	('EGFR', 'Gene', (0, 4))	('mutation', 'Var', (58, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('patients', 'Species', '9606', (87, 95))	('EGFR', 'Gene', '1956', (0, 4))
59942	27165743	Figure 3 provides an overview of the statistical significance of sex-biased focal amplifications and deletions in these three cancer types, showing a total of 21 significant peaks (FDR <= 0.1).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('focal amplifications', 'Var', (76, 96))	('deletions', 'Var', (101, 110))
59944	27165743	In LUSC, a SCNA (17q11.2) harboring NF1 is more frequently deleted in females, and the inactivation of this gene has been associated with sensitivity to mTOR inhibitors and resistance to MEK inhibitors.	('NF1', 'Gene', (36, 39))	('NF1', 'Gene', '4763', (36, 39))	('mTOR', 'Gene', (153, 157))	('associated with', 'Reg', (122, 137))	('mTOR', 'Gene', '2475', (153, 157))	('inactivation', 'Var', (87, 99))	('MEK', 'Gene', (187, 190))	('MEK', 'Gene', '5609', (187, 190))
59945	27165743	In KIRP, the 4q34.3 deletion containing FBXW7 occurs more frequently in females, and the deletion of this gene may affect the sensitivity to rapamycin treatment and antitubulin chemotherapeutics.	('sensitivity to rapamycin treatment', 'MPA', (126, 160))	('antitubulin chemotherapeutics', 'MPA', (165, 194))	('affect', 'Reg', (115, 121))	('FBXW7', 'Gene', (40, 45))	('men', 'Species', '9606', (156, 159))	('deletion', 'Var', (89, 97))	('rapamycin', 'Chemical', 'MESH:D020123', (141, 150))	('FBXW7', 'Gene', '55294', (40, 45))
59946	27165743	In KIRC, the amplicon 3q26 containing PI3KCA occurs more frequently in females, and PI3KCA activation has been reported to predict the sensitivity to PI3K/AKT/mTOR inhibitors; and the deletions of 1p36.23 (harboring MTOR) and 10q23.31 (harboring PTEN) are more prevalent in male patients.	('AKT', 'Gene', (155, 158))	('1p36.23', 'Gene', (197, 204))	('mTOR', 'Gene', (159, 163))	('mTOR', 'Gene', '2475', (159, 163))	('PTEN', 'Gene', (246, 250))	('10q23.31', 'Gene', (226, 234))	('PTEN', 'Gene', '5728', (246, 250))	('AKT', 'Gene', '207', (155, 158))	('patients', 'Species', '9606', (279, 287))	('MTOR', 'Gene', (216, 220))	('sensitivity', 'MPA', (135, 146))	('deletions', 'Var', (184, 193))	('PI3K', 'molecular_function', 'GO:0016303', ('150', '154'))	('PI3KCA', 'Var', (38, 44))	('MTOR', 'Gene', '2475', (216, 220))
59949	27165743	The deletion involving PDCD1 (PD-1) shows a similar bias; this gene represents an immune checkpoint and has been a major focus in the development of immunotherapy.	('PD-1', 'Disease', (30, 34))	('men', 'Species', '9606', (141, 144))	('PD-1', 'Disease', 'MESH:D010300', (30, 34))	('deletion', 'Var', (4, 12))	('PDCD1', 'Gene', '5133', (23, 28))	('PDCD1', 'Gene', (23, 28))
59953	27165743	One of the most commonly identified genes is XIST, a major effector of chromosome X inactivation; and its role in cancer has been extensively studied.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('genes', 'Var', (36, 41))	('XIST', 'Gene', '7503', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('chromosome', 'cellular_component', 'GO:0005694', ('71', '81'))	('XIST', 'Gene', (45, 49))	('cancer', 'Disease', (114, 120))
59966	27165743	Thus, targeted inhibition of SRC signaling has been suggested as an effective therapeutic strategy and has been under intensive clinical investigation in several cancers, including renal cell cancer.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('SRC', 'Gene', '6714', (29, 32))	('cancers', 'Disease', (162, 169))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('SRC', 'Gene', (29, 32))	('targeted inhibition', 'Var', (6, 25))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('renal cell cancer', 'Phenotype', 'HP:0005584', (181, 198))	('signaling', 'biological_process', 'GO:0023052', ('33', '42'))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('renal cell cancer', 'Disease', (181, 198))	('renal cell cancer', 'Disease', 'MESH:C538614', (181, 198))
60023	25987535	In SWOG 8710, 317 patients with stage T2N0M0 to T4aN0M0 bladder cancer were randomized to receive MVAC (methotrexate 30 mg/m2 days 1, 15, 22, vinblastine 3 mg/m2 days 2, 15, 22, doxorubicin 30 mg/m2 day 2 and cisplatin 70 mg/m2 day 2) for three cycles every 28 days followed by cystectomy compared to cystectomy alone.	('methotrexate', 'Chemical', 'MESH:D008727', (104, 116))	('vinblastine', 'Chemical', 'MESH:D014747', (142, 153))	('MVAC', 'Chemical', 'MESH:C044361', (98, 102))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('doxorubicin', 'Chemical', 'MESH:D004317', (178, 189))	('patients', 'Species', '9606', (18, 26))	('T4aN0M0', 'Var', (48, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (209, 218))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('bladder cancer', 'Disease', (56, 70))
60034	25987535	In two separate studies patients with cT2-cT4a N0-N1 MIBC were treated with three (Plimack) or four cycles (Choueiri) of neoadjuvant aMVAC.	('MIBC', 'Chemical', '-', (53, 57))	('MIBC', 'Disease', (53, 57))	('aMVAC', 'Chemical', '-', (133, 138))	('patients', 'Species', '9606', (24, 32))	('cT2-cT4a N0-N1', 'Var', (38, 52))
60040	25987535	In a trial by the, National Cancer Research Institute Bladder Cancer Clinical Studies Group, patients with T2 -T4a N0/x UCB were randomized to CMV (methotrexate 30 mg/m2 days 1 and 8, vinblastine 4 mg/m2 day 1 and 9, cisplatin 100 mg/m2 day 2 with folinic acid) every 21 days for 3 cycles prior to cystectomy or radiotherapy.	('Bladder Cancer', 'Phenotype', 'HP:0009725', (54, 68))	('Cancer', 'Disease', (62, 68))	('vinblastine', 'Chemical', 'MESH:D014747', (184, 195))	('folinic acid', 'Chemical', 'MESH:D002955', (248, 260))	('methotrexate', 'Chemical', 'MESH:D008727', (148, 160))	('Cancer', 'Disease', 'MESH:D009369', (28, 34))	('Cancer', 'Disease', (28, 34))	('Cancer', 'Disease', 'MESH:D009369', (62, 68))	('Cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('T2 -T4a', 'Var', (107, 114))	('patients', 'Species', '9606', (93, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (217, 226))
60049	25987535	Patients with residual p>T2 tumors or positive lymph nodes had significantly worse survival outcomes compared to those with complete pathologic response.	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('Patients', 'Species', '9606', (0, 8))	('worse', 'NegReg', (77, 82))	('p>T2', 'Var', (23, 27))	('survival', 'MPA', (83, 91))
60052	25987535	Of those 120 patients, 77 received neoadjuvant chemotherapy, the majority of which was platinum based, and had "high risk" features, (cT3b on exam under anesthesia, cT4a, LVI on TURBT, cN+ on imaging, hydronephrosis).	('cT4a', 'Var', (165, 169))	('platinum', 'Chemical', 'MESH:D010984', (87, 95))	('hydronephrosis', 'Phenotype', 'HP:0000126', (201, 215))	('patients', 'Species', '9606', (13, 21))	('cN+', 'Var', (185, 188))	('cT3b', 'Var', (134, 138))	('LV', 'Chemical', 'MESH:D002955', (171, 173))	('hydronephrosis', 'Disease', (201, 215))	('LVI', 'Disease', (171, 174))	('hydronephrosis', 'Disease', 'MESH:D006869', (201, 215))
60070	25987535	In a single institution cohort of 81 patients who underwent cystectomy without neoadjuvant chemotherapy, somatic mutations in one or more of six DNA repair genes (ATM, ERCC2, FANCD2, PALB2, BRCA1 and 2) were associated with improvement in recurrence free survival.	('PALB2', 'Gene', (183, 188))	('PALB2', 'Gene', '79728', (183, 188))	('DNA', 'cellular_component', 'GO:0005574', ('145', '148'))	('ERCC2', 'Gene', (168, 173))	('patients', 'Species', '9606', (37, 45))	('ATM', 'Gene', '472', (163, 166))	('BRCA1 and 2', 'Gene', '672;675', (190, 201))	('recurrence free survival', 'CPA', (239, 263))	('FANCD2', 'Gene', '2177', (175, 181))	('mutations', 'Var', (113, 122))	('FANCD2', 'Gene', (175, 181))	('DNA repair', 'biological_process', 'GO:0006281', ('145', '155'))	('ATM', 'Gene', (163, 166))	('ERCC2', 'Gene', '2068', (168, 173))	('improvement', 'PosReg', (224, 235))
60072	25987535	In their prospective aMVAC cohort, Plimack demonstrated by DNA sequencing of pretreatment tissue, 13/13 patients who achieved pCR had variants in >= 1of ATM, RB1 or FANCC genes, with roles in maintenance of chromatin structure and DNA repair.	('variants', 'Var', (134, 142))	('ATM', 'Gene', (153, 156))	('aMVAC', 'Chemical', '-', (21, 26))	('RB1', 'Gene', '5925', (158, 161))	('DNA', 'cellular_component', 'GO:0005574', ('231', '234'))	('FANCC', 'Gene', '2176', (165, 170))	('FANCC', 'Gene', (165, 170))	('ATM', 'Gene', '472', (153, 156))	('chromatin', 'cellular_component', 'GO:0000785', ('207', '216'))	('RB1', 'Gene', (158, 161))	('DNA repair', 'biological_process', 'GO:0006281', ('231', '241'))	('patients', 'Species', '9606', (104, 112))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
60088	25987535	A randomized study of adjuvant cellular immunotherapy with DN 2402 vs. surveilliance in patients with high risk her 2 positive urothelial carcinoma has completed accrual (NCT01353222).	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (127, 147))	('patients', 'Species', '9606', (88, 96))	('urothelial carcinoma', 'Disease', (127, 147))	('DN 2402', 'Var', (59, 66))
60273	19132098	This same study also found a lower rate of recurrence among patients treated with MMC or BCG compared to those treated with thiotepa or oral 5-fluorouracil.	('MMC', 'Chemical', 'MESH:D016685', (82, 85))	('patients', 'Species', '9606', (60, 68))	('thiotepa', 'Chemical', 'MESH:D013852', (124, 132))	('MMC', 'Var', (82, 85))	('BCG', 'Var', (89, 92))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (141, 155))
60295	32638267	Moreover, we found that hypo-DNA methylation, DNA amplification, and TP53 mutation were contributing to the high expression levels of pyrimidine metabolic rate-limiting enzymes in lung cancer cells.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('mutation', 'Var', (74, 82))	('pyrimidine', 'Chemical', 'MESH:C030986', (134, 144))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('TP53', 'Gene', '7157', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('TP53', 'Gene', (69, 73))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('DNA amplification', 'biological_process', 'GO:0006277', ('46', '63'))	('DNA methylation', 'biological_process', 'GO:0006306', ('29', '44'))	('expression levels', 'MPA', (113, 130))	('lung cancer', 'Disease', (180, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('high', 'PosReg', (108, 112))
60313	32638267	Also, inhibition of pyrimidine synthesis sensitizes triple-negative breast cancer cells to chemotherapy.	('synthesis', 'biological_process', 'GO:0009058', ('31', '40'))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('pyrimidine', 'Chemical', 'MESH:C030986', (20, 30))	('breast cancer', 'Disease', (68, 81))	('pyrimidine synthesis', 'MPA', (20, 40))	('inhibition', 'Var', (6, 16))	('sensitizes', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
60320	32638267	The gene expression series matrix of normal and cancerous lung tissues was downloaded from the GEO website (www.ncbi.nlm.nih.gov/geo) and included GSE7670, GSE10072, GSE18842, GSE19188, GSE27262, GSE30219, GSE31210, GSE31908, GSE33532, and GSE75324 datasets.	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))	('GSE10072', 'Var', (156, 164))	('GSE19188', 'Var', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancerous', 'Disease', 'MESH:D009369', (48, 57))	('GSE31908', 'Var', (216, 224))	('GSE7670', 'Var', (147, 154))	('GSE27262', 'Var', (186, 194))	('GSE18842', 'Var', (166, 174))	('GSE7670', 'Chemical', '-', (147, 154))	('cancerous', 'Disease', (48, 57))
60338	32638267	Among all the enriched metabolic signaling pathways, the pyrimidine metabolism signaling pathway was significantly enriched in seven out of ten datasets, including GSE10072, GSE18842, GSE19188, GSE27262, GSE30219, GSE31210, and GSE75324 datasets, representing the most frequently enriched metabolic signaling pathway (Fig.	('pyrimidine', 'Chemical', 'MESH:C030986', (57, 67))	('GSE30219', 'Var', (204, 212))	('pyrimidine metabolism', 'biological_process', 'GO:0006206', ('57', '78'))	('GSE31210', 'Var', (214, 222))	('GSE75324', 'Var', (228, 236))	('signaling pathway', 'biological_process', 'GO:0007165', ('79', '96'))	('GSE19188', 'Var', (184, 192))	('pyrimidine metabolism', 'biological_process', 'GO:0006220', ('57', '78'))	('signaling pathway', 'biological_process', 'GO:0007165', ('299', '316'))	('GSE18842', 'Var', (174, 182))	('signaling', 'biological_process', 'GO:0023052', ('33', '42'))	('GSE10072', 'Var', (164, 172))	('pyrimidine metabolism', 'biological_process', 'GO:0006213', ('57', '78'))	('GSE27262', 'Var', (194, 202))	('enriched', 'Reg', (115, 123))	('pyrimidine metabolism signaling pathway', 'Pathway', (57, 96))
60339	32638267	Only in GSE7670, GSE31908, and GSE33532 three datasets, the pyrimidine metabolism signaling pathway was not significantly correlated with the transcriptional profiling of lung cancer (Fig.	('pyrimidine metabolism', 'biological_process', 'GO:0006213', ('60', '81'))	('signaling pathway', 'biological_process', 'GO:0007165', ('82', '99'))	('pyrimidine', 'Chemical', 'MESH:C030986', (60, 70))	('pyrimidine metabolism', 'biological_process', 'GO:0006206', ('60', '81'))	('lung cancer', 'Disease', (171, 182))	('GSE31908', 'Var', (17, 25))	('GSE7670', 'Chemical', '-', (8, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('GSE33532', 'Var', (31, 39))	('pyrimidine metabolism', 'biological_process', 'GO:0006220', ('60', '81'))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))	('GSE7670', 'Var', (8, 15))
60345	32638267	The expression levels of those pyrimidine metabolic rate-limiting enzymes in lung normal and tumor tissues were investigated in GSE7670, GSE10072, GSE18842, GSE19188, GSE27262, GSE31908, GSE33532, and GSE75324 datasets.	('GSE7670', 'Var', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('GSE10072', 'Var', (137, 145))	('GSE7670', 'Chemical', '-', (128, 135))	('tumor', 'Disease', (93, 98))	('pyrimidine', 'Chemical', 'MESH:C030986', (31, 41))	('GSE19188', 'Var', (157, 165))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
60378	32638267	Also, TK1 amplification occurred in 2.2% lung cancer patients (Fig.	('TK1', 'Gene', (6, 9))	('patients', 'Species', '9606', (53, 61))	('lung cancer', 'Disease', (41, 52))	('TK1', 'Gene', '7083', (6, 9))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('amplification', 'Var', (10, 23))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))
60383	32638267	We found that pyrimidine metabolic rate-limiting enzymes CAD, CTPS, DTYMK, RRM1, RRM2, TYMS, UCK2, and TK1 were all highly expressed in TP53 mutant lung cancer patients (Fig.	('UCK2', 'Gene', '7371', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('TYMS', 'Gene', '7298', (87, 91))	('DTYMK', 'Gene', '1841', (68, 73))	('pyrimidine', 'Chemical', 'MESH:C030986', (14, 24))	('TP53', 'Gene', '7157', (136, 140))	('RRM1', 'Gene', '6240', (75, 79))	('CTPS', 'Gene', (62, 66))	('highly expressed', 'PosReg', (116, 132))	('RRM2', 'Gene', (81, 85))	('DTYMK', 'Gene', (68, 73))	('TK1', 'Gene', (103, 106))	('TK1', 'Gene', '7083', (103, 106))	('CAD', 'Chemical', 'MESH:C075764', (57, 60))	('lung cancer', 'Disease', (148, 159))	('mutant', 'Var', (141, 147))	('TYMS', 'Gene', (87, 91))	('UCK2', 'Gene', (93, 97))	('TP53', 'Gene', (136, 140))	('RRM1', 'Gene', (75, 79))	('patients', 'Species', '9606', (160, 168))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('CTPS', 'Gene', '1503', (62, 66))	('RRM2', 'Gene', '6241', (81, 85))
60385	32638267	The expression levels of pyrimidine metabolic rate-limiting enzymes CAD, CTPS, DTYMK, RRM1, RRM2, TYMS, UCK2, and TK1 were particularly higher in TP53 mutant lung cancer patients (Fig.	('lung cancer', 'Disease', (158, 169))	('UCK2', 'Gene', (104, 108))	('TYMS', 'Gene', (98, 102))	('TP53', 'Gene', (146, 150))	('RRM1', 'Gene', (86, 90))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('RRM2', 'Gene', '6241', (92, 96))	('CTPS', 'Gene', '1503', (73, 77))	('DTYMK', 'Gene', '1841', (79, 84))	('UCK2', 'Gene', '7371', (104, 108))	('expression levels', 'MPA', (4, 21))	('patients', 'Species', '9606', (170, 178))	('mutant', 'Var', (151, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('DTYMK', 'Gene', (79, 84))	('pyrimidine', 'Chemical', 'MESH:C030986', (25, 35))	('RRM2', 'Gene', (92, 96))	('CTPS', 'Gene', (73, 77))	('TP53', 'Gene', '7157', (146, 150))	('higher', 'PosReg', (136, 142))	('RRM1', 'Gene', '6240', (86, 90))	('TYMS', 'Gene', '7298', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('TK1', 'Gene', (114, 117))	('TK1', 'Gene', '7083', (114, 117))	('CAD', 'Chemical', 'MESH:C075764', (68, 71))
60387	32638267	Overall, our results suggested that hypo-DNA methylation, DNA amplification, and TP53 mutation were combined contributing to the high expression levels of pyrimidine metabolic rate-limiting enzymes in lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('DNA methylation', 'biological_process', 'GO:0006306', ('41', '56'))	('high', 'PosReg', (129, 133))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('DNA amplification', 'biological_process', 'GO:0006277', ('58', '75'))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('expression levels', 'MPA', (134, 151))	('pyrimidine', 'Chemical', 'MESH:C030986', (155, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('mutation', 'Var', (86, 94))	('lung cancer', 'Disease', (201, 212))	('contributing', 'Reg', (109, 121))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
60453	27338857	These strategies have reshaped how we view the cancer genome and have shown that individual tumors harbor their own unique genetic makeup containing mutations, copy number changes, epigenetic modifications, and aberrant expression of hundreds to thousands of genes; therefore highlighting that multidimensional genomic data contributes to understanding cancer.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (149, 158))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('copy number changes', 'Var', (160, 179))	('epigenetic modifications', 'Var', (181, 205))	('cancer', 'Disease', 'MESH:D009369', (353, 359))	('cancer', 'Disease', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cancer', 'Disease', (353, 359))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('aberrant', 'Var', (211, 219))	('tumors', 'Disease', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))
60454	27338857	Genomics has been successfully applied to oncology in many different contexts including the identification of cancer subgroups such as the intrinsic subtypes in breast cancer, the development of breast cancer prognostic tools such as Oncotype DX and MammaPrint to predict the risk of cancer recurrence, and the identification of KRAS mutations as predictors of poor drug response in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('lung cancer', 'Disease', 'MESH:D008175', (383, 394))	('cancer', 'Disease', (168, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (383, 394))	('KRAS', 'Gene', '3845', (329, 333))	('mutations', 'Var', (334, 343))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('oncology', 'Phenotype', 'HP:0002664', (42, 50))	('KRAS', 'Gene', (329, 333))	('cancer', 'Disease', (388, 394))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('cancer', 'Disease', (110, 116))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('breast cancer', 'Disease', (195, 208))	('cancer', 'Disease', (284, 290))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', (383, 394))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Disease', (161, 174))	('cancer', 'Disease', 'MESH:D009369', (388, 394))	('cancer', 'Disease', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
60455	27338857	Although approximately 140 driver mutations have been discovered in human cancer, most of these mutations converge on roughly 12 pathways that regulate three vital cellular processes: cell growth, cell survival, and genome maintenance.	('human', 'Species', '9606', (68, 73))	('cell growth', 'biological_process', 'GO:0016049', ('184', '195'))	('cell growth', 'CPA', (184, 195))	('converge', 'Reg', (106, 114))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cell survival', 'CPA', (197, 210))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('mutations', 'Var', (96, 105))
60457	27338857	The RAS pathway is one of the most frequently dysregulated pathways in cancer, with approximately 30% of all patient tumors expressing activating RAS gene mutations.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('patient', 'Species', '9606', (109, 116))	('mutations', 'Var', (155, 164))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (71, 77))	('RAS', 'Gene', (146, 149))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('activating', 'PosReg', (135, 145))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('RAS pathway', 'Pathway', (4, 15))
60459	27338857	Cancers with RAS gene mutations are associated with drug resistance, poor prognosis, shorter survival, and enhanced metastasis.	('shorter', 'NegReg', (85, 92))	('drug resistance', 'biological_process', 'GO:0042493', ('52', '67'))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('enhanced', 'PosReg', (107, 115))	('drug resistance', 'CPA', (52, 67))	('drug resistance', 'Phenotype', 'HP:0020174', (52, 67))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (22, 31))	('metastasis', 'CPA', (116, 126))	('drug resistance', 'biological_process', 'GO:0009315', ('52', '67'))	('RAS', 'Gene', (13, 16))
60461	27338857	Also, as omic-level measurement captures RAS activity in both RAS-mutant and RAS-wild type tumors, these approaches may enable identification of novel RAS pathway inhibitors not specific to mutant RAS.	('RAS-mutant', 'Var', (62, 72))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('type tumors', 'Disease', (86, 97))	('type tumors', 'Disease', 'MESH:D009369', (86, 97))	('RAS pathway', 'Pathway', (151, 162))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
60463	27338857	While extracellular growth signals normally activate the RAS pathway, in cancer, activating mutations in RAS pathway genes lead to sustained pathway signaling, resulting in the aberrant activation of downstream oncogenic processes such as cellular proliferation, cell survival, metabolic changes, and metastasis.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('signaling', 'biological_process', 'GO:0023052', ('149', '158'))	('RAS pathway', 'Pathway', (57, 68))	('activation', 'PosReg', (186, 196))	('extracellular', 'cellular_component', 'GO:0005576', ('6', '19'))	('sustained pathway signaling', 'MPA', (131, 158))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (92, 101))	('metabolic changes', 'CPA', (278, 295))	('metastasis', 'CPA', (301, 311))	('cellular proliferation', 'CPA', (239, 261))	('RAS pathway', 'Gene', (105, 116))	('cell survival', 'CPA', (263, 276))	('activating', 'PosReg', (81, 91))
60469	27338857	Here, we highlight the spectrum of RAS pathway aberrations from the TCGA's findings in several cancer types including lung adenocarcinoma, colorectal carcinoma, and head and neck squamous cell carcinoma (HNSCC).	('neck squamous cell carcinoma', 'Disease', (174, 202))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (174, 202))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('colorectal carcinoma', 'Disease', (139, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('lung adenocarcinoma', 'Disease', (118, 137))	('cancer', 'Disease', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (118, 137))	('neck', 'cellular_component', 'GO:0044326', ('174', '178'))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (139, 159))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (165, 202))	('RAS pathway', 'Pathway', (35, 46))	('aberrations', 'Var', (47, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))
60470	27338857	Upon profiling colorectal carcinoma, the TCGA found that 55% of non-hypermutated colorectal carcinomas, a molecular subtype accounting for 84% of the studied samples, demonstrated KRAS, NRAS, or BRAF alterations; mutations in these genes were found to be significantly mutually exclusive.	('KRAS', 'Gene', (180, 184))	('alterations', 'Var', (200, 211))	('NRAS', 'Gene', (186, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('colorectal carcinoma', 'Disease', (15, 35))	('NRAS', 'Gene', '4893', (186, 190))	('colorectal carcinomas', 'Disease', (81, 102))	('KRAS', 'Gene', '3845', (180, 184))	('BRAF', 'Gene', (195, 199))	('BRAF', 'Gene', '673', (195, 199))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (81, 102))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (15, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (81, 101))
60471	27338857	Interestingly, the TCGA also found a co-occurrence of RAS pathway and PI3K pathway mutations in one-third of colorectal tumors, indicating the need to target both pathways to effectively inhibit tumor growth in cancers of this type.	('mutations', 'Var', (83, 92))	('PI3K pathway', 'Pathway', (70, 82))	('tumor', 'Disease', (195, 200))	('inhibit', 'NegReg', (187, 194))	('cancers', 'Disease', 'MESH:D009369', (211, 218))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancers', 'Disease', (211, 218))	('RAS pathway', 'Pathway', (54, 65))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('colorectal tumors', 'Disease', 'MESH:D015179', (109, 126))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('colorectal tumors', 'Disease', (109, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))	('tumor', 'Disease', (120, 125))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))
60472	27338857	Furthermore, genomic analysis of lung adenocarcinoma revealed that 62% of these cancers bear a canonical oncogenic driver mutation in the RAS/RAF/MEK pathway.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('RAF', 'Gene', '22882', (142, 145))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (33, 52))	('mutation', 'Var', (122, 130))	('cancers', 'Disease', (80, 87))	('RAF', 'Gene', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('lung adenocarcinoma', 'Disease', (33, 52))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (33, 52))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
60473	27338857	Upon expanding this analysis to include focal amplifications of upstream receptor tyrosine kinases (RTKs), as well as loss of function mutations in tumor suppressor genes in the RAS pathway, such as NF1, the number of lung adenocarcinomas with driver mutations in the RAS pathway increased to 76%.	('mutations', 'Var', (251, 260))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (218, 237))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('148', '164'))	('increased', 'PosReg', (280, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('tumor', 'Disease', (148, 153))	('mutations', 'Var', (135, 144))	('lung adenocarcinomas', 'Disease', (218, 238))	('carcinomas', 'Phenotype', 'HP:0030731', (228, 238))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (218, 238))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (218, 238))	('NF1', 'Gene', (199, 202))	('tumor suppressor', 'biological_process', 'GO:0051726', ('148', '164'))	('RAS pathway', 'Pathway', (268, 279))	('NF1', 'Gene', '4763', (199, 202))
60476	27338857	Subsequent investigation of HNSCC demonstrated that in this cancer type, 5% of HPV-negative cancers contain an HRAS mutation.	('cancer', 'Disease', (92, 98))	('HRAS', 'Gene', '3265', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutation', 'Var', (116, 124))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('contain', 'Reg', (100, 107))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('HRAS', 'Gene', (111, 115))	('cancer', 'Disease', (60, 66))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
60477	27338857	It is important to note, however, that the study also found mutation or amplification in EGFR (15% of HPV-negative samples), FGFR1 (10%), ERBB2 (5%), IGF1R (4%), and several other RTKs (3% or less), thus contributing to a wider spectrum of RAS pathway aberrations than HRAS mutation alone.	('FGFR1', 'Gene', '2260', (125, 130))	('mutation', 'Var', (60, 68))	('contributing to', 'Reg', (204, 219))	('amplification', 'Var', (72, 85))	('EGFR', 'Gene', (89, 93))	('HRAS', 'Gene', '3265', (269, 273))	('FGFR', 'molecular_function', 'GO:0005007', ('125', '129'))	('IGF1R', 'Gene', (150, 155))	('ERBB2', 'Gene', '2064', (138, 143))	('IGF1R', 'Gene', '3480', (150, 155))	('HRAS', 'Gene', (269, 273))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('RAS pathway', 'Pathway', (240, 251))	('ERBB2', 'Gene', (138, 143))	('FGFR1', 'Gene', (125, 130))	('EGFR', 'Gene', '1956', (89, 93))
60478	27338857	Therefore, by implementing whole-genome sequencing, the TCGA research network confirmed the high prevalence of somatic mutations and amplifications contributing to RAS pathway activation in RAS-driven cancers.	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancers', 'Disease', (201, 208))	('amplifications', 'Var', (133, 147))	('RAS pathway', 'Pathway', (164, 175))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('activation', 'PosReg', (176, 186))
60479	27338857	Using the TCGA colorectal cancer dataset, they showed that mutations in the RAS pathway occur late in tumorigenesis--mutations in APC or FBXW7 and either TP53 or PIK3CA generally occur before members of the RAS pathway are mutated in colorectal cancers.	('PIK3CA', 'Gene', '5290', (162, 168))	('APC', 'cellular_component', 'GO:0005680', ('130', '133'))	('FBXW7', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (234, 251))	('colorectal cancers', 'Disease', (234, 252))	('colorectal cancer', 'Disease', 'MESH:D015179', (15, 32))	('colorectal cancer', 'Disease', (15, 32))	('PIK3CA', 'Gene', (162, 168))	('mutations', 'Var', (117, 126))	('FBXW7', 'Gene', '55294', (137, 142))	('TP53', 'Gene', (154, 158))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('colorectal cancer', 'Disease', 'MESH:D015179', (234, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('tumor', 'Disease', (102, 107))	('colorectal cancers', 'Disease', 'MESH:D015179', (234, 252))	('APC', 'Disease', 'MESH:D011125', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('APC', 'Disease', (130, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (15, 32))	('RAS pathway', 'Pathway', (76, 87))	('TP53', 'Gene', '7157', (154, 158))
60480	27338857	Additionally, Want and colleagues integrated the TCGA breast cancer data consisting of somatic mutations, copy number variations, transcriptomics, and DNA methylomics, into "risk pathways" by mapping alterations in genes at each tested omic level to pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) to determine pathways altered in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (346, 359))	('breast cancer', 'Disease', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (346, 359))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))	('alterations', 'Var', (200, 211))	('breast cancer', 'Disease', (346, 359))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
60488	27338857	in generating a pathway-based gene expression signature by overexpressing mutant HRAS in human primary epithelial cells.	('human', 'Species', '9606', (89, 94))	('overexpressing', 'PosReg', (59, 73))	('HRAS', 'Gene', (81, 85))	('HRAS', 'Gene', '3265', (81, 85))	('mutant', 'Var', (74, 80))	('gene expression', 'biological_process', 'GO:0010467', ('30', '45'))
60489	27338857	This signature accurately predicted RAS pathway activation in mice and human tumors with RAS mutations, such as in human non-small cell lung carcinoma.	('tumors', 'Disease', (77, 83))	('RAS pathway', 'Pathway', (36, 47))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (121, 150))	('human', 'Species', '9606', (71, 76))	('mutations', 'Var', (93, 102))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (131, 150))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('mice', 'Species', '10090', (62, 66))	('human', 'Species', '9606', (115, 120))	('cell lung carcinoma', 'Disease', (131, 150))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('activation', 'PosReg', (48, 58))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (125, 150))	('RAS', 'Gene', (89, 92))
60493	27338857	To further explore pathway activation in relation to mutational status, we measured pathway activity and mutational status for key RAS pathway components EGFR, KRAS, and RAF across 8 different cancers in TCGA which express varying levels of KRAS, EGFR, or BRAF mutations.	('RAF', 'Gene', (257, 260))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('EGFR', 'molecular_function', 'GO:0005006', ('247', '251'))	('cancers', 'Disease', (193, 200))	('BRAF', 'Gene', '673', (256, 260))	('BRAF', 'Gene', (256, 260))	('RAF', 'Gene', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('EGFR', 'Gene', (247, 251))	('EGFR', 'Gene', (154, 158))	('KRAS', 'Gene', '3845', (241, 245))	('KRAS', 'Gene', '3845', (160, 164))	('mutations', 'Var', (261, 270))	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('KRAS', 'Gene', (241, 245))	('KRAS', 'Gene', (160, 164))	('EGFR', 'Gene', '1956', (247, 251))	('RAF', 'Gene', '22882', (257, 260))	('EGFR', 'Gene', '1956', (154, 158))	('EGFR', 'molecular_function', 'GO:0005006', ('154', '158'))	('RAF', 'Gene', '22882', (170, 173))
60496	27338857	To illustrate the ability of gene expression signatures to accurately predict pathway activation in patient tumors, we highlight situations in which gene mutations complement pathway activation.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patient', 'Species', '9606', (100, 107))	('gene expression', 'biological_process', 'GO:0010467', ('29', '44'))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (154, 163))
60497	27338857	For example, 81% of all rectum adenocarcinoma patients harboring KRAS mutations also have high KRAS activation scores (Figure 2B).	('KRAS', 'Gene', '3845', (95, 99))	('rectum adenocarcinoma', 'Disease', (24, 45))	('mutations', 'Var', (70, 79))	('patients', 'Species', '9606', (46, 54))	('KRAS', 'Gene', '3845', (65, 69))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (24, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('KRAS', 'Gene', (95, 99))	('KRAS', 'Gene', (65, 69))
60500	27338857	For example, in bladder urothelial carcinoma (Figure 2G), only 3 patients had EGFR mutations, and no mutations were found in KRAS or RAF, but pathway activation was found in 42%, 22%, and 38% of cases for EGFR, KRAS, and RAF pathways, respectively, thus highlighting that the absence of mutations does not always mean the pathway is inactivated.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('KRAS', 'Gene', (125, 129))	('KRAS', 'Gene', (211, 215))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'molecular_function', 'GO:0005006', ('205', '209'))	('bladder urothelial carcinoma', 'Disease', (16, 44))	('EGFR', 'Gene', '1956', (78, 82))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (16, 44))	('RAF', 'Gene', '22882', (221, 224))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('RAF', 'Gene', '22882', (133, 136))	('EGFR', 'Gene', (205, 209))	('RAF', 'Gene', (221, 224))	('patients', 'Species', '9606', (65, 73))	('EGFR', 'Gene', (78, 82))	('RAF', 'Gene', (133, 136))	('mutations', 'Var', (83, 92))	('KRAS', 'Gene', '3845', (125, 129))	('KRAS', 'Gene', '3845', (211, 215))
60504	27338857	While FTIs efficiently inhibited farnesylation in HRAS mutant cancers, they failed to show efficacy in KRAS and NRAS mutant cancers as these isoforms can undergo alternative methods of membrane association.	('KRAS', 'Gene', (103, 107))	('KRAS', 'Gene', '3845', (103, 107))	('inhibited', 'NegReg', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutant', 'Var', (55, 61))	('farnesylation', 'MPA', (33, 46))	('NRAS', 'Gene', (112, 116))	('HRAS', 'Gene', '3265', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('HRAS', 'Gene', (50, 54))	('NRAS', 'Gene', '4893', (112, 116))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('cancers', 'Disease', (124, 131))	('membrane', 'cellular_component', 'GO:0016020', ('185', '193'))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
60507	27338857	However, recent studies have identified compounds capable of either binding to mutant RAS proteins directly or interfering with RAS's ability to bind to the guanine nucleotide exchange factor Son of Sevenless (SOS).	('ability', 'MPA', (134, 141))	('binding', 'Interaction', (68, 75))	('bind', 'Interaction', (145, 149))	('RAS', 'Gene', (86, 89))	('mutant', 'Var', (79, 85))	('SOS', 'Disease', 'MESH:D006504', (210, 213))	('proteins', 'Protein', (90, 98))	('interfering', 'NegReg', (111, 122))	('binding', 'molecular_function', 'GO:0005488', ('68', '75'))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (157, 175))	('SOS', 'Disease', (210, 213))	('guanine nucleotide exchange factor', 'MPA', (157, 191))
60508	27338857	The discovery of RAS effector proteins and recurrent oncogenic mutations in downstream RAS pathway components (BRAF, MEK, ERK, and PI3K pathway members), led to the development of several inhibitors including sorafenib, vemurafenib, and dabrafenib for RAF-mutated cancers, and trametinib and cobimetinib for MEK-mutated cancers.	('trametinib', 'Chemical', 'MESH:C560077', (277, 287))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('ERK', 'Gene', '5594', (122, 125))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('RAF', 'Gene', '22882', (112, 115))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (111, 115))	('mutations', 'Var', (63, 72))	('cancers', 'Disease', (264, 271))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('ERK', 'molecular_function', 'GO:0004707', ('122', '125'))	('RAF', 'Gene', '22882', (252, 255))	('dabrafenib', 'Chemical', 'MESH:C561627', (237, 247))	('sorafenib', 'Chemical', 'MESH:D000077157', (209, 218))	('ERK', 'Gene', (122, 125))	('RAF', 'Gene', (112, 115))	('cancers', 'Disease', 'MESH:D009369', (320, 327))	('RAF', 'Gene', (252, 255))	('cobimetinib', 'Chemical', 'MESH:C574276', (292, 303))	('cancers', 'Disease', 'MESH:D009369', (264, 271))	('vemurafenib', 'Chemical', 'MESH:D000077484', (220, 231))	('PI3K', 'molecular_function', 'GO:0016303', ('131', '135'))	('cancers', 'Phenotype', 'HP:0002664', (320, 327))	('cancers', 'Disease', (320, 327))
60511	27338857	Measuring the mutational status of RAS pathway genes has provided clinical benefits such as guiding the use of targeted therapies, and selecting appropriate patient populations for clinical trials in particular cancers.	('patient', 'Species', '9606', (157, 164))	('mutational', 'Var', (14, 24))	('RAS pathway genes', 'Gene', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('particular cancers', 'Disease', (200, 218))	('particular cancers', 'Disease', 'MESH:D009369', (200, 218))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))
60512	27338857	For example, KRAS mutations are indicative of resistance to anti-EGFR therapies, and BRAF V600E mutations are indicative of response to RAF inhibitors.	('RAF', 'Gene', '22882', (86, 89))	('RAF', 'Gene', '22882', (136, 139))	('V600E', 'Mutation', 'rs113488022', (90, 95))	('RAF', 'Gene', (86, 89))	('KRAS', 'Gene', '3845', (13, 17))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('KRAS', 'Gene', (13, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))	('RAF', 'Gene', (136, 139))	('mutations', 'Var', (18, 27))
60514	27338857	Cancers carrying mutations in the RAS pathway are not always dependent on RAS signaling, and the absence of RAS gene mutations does not always correlate with RAS inactivity as additional components of the network may be activated.	('mutations', 'Var', (117, 126))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('Cancers', 'Disease', (0, 7))	('RAS', 'Gene', (108, 111))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('mutations', 'Var', (17, 26))
60515	27338857	For example, absence of negative-feedback regulators, such as Sprouty (SPRY) and Sprouty-related (SPRED), and RAS GAPs such as NF1, can also activate the RAS pathway in various cancers.	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('RAS pathway', 'Pathway', (154, 165))	('absence', 'Var', (13, 20))	('NF1', 'Gene', (127, 130))	('activate', 'PosReg', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('NF1', 'Gene', '4763', (127, 130))	('negative-feedback', 'MPA', (24, 41))
60526	27338857	This signature consisted of a combination of mutational signatures from patients with KRAS, BRAF, and PIK3CA mutations and characterized response to the EGFR inhibitor cetuximab.	('BRAF', 'Gene', '673', (92, 96))	('PIK3CA', 'Gene', (102, 108))	('KRAS', 'Gene', (86, 90))	('BRAF', 'Gene', (92, 96))	('KRAS', 'Gene', '3845', (86, 90))	('patients', 'Species', '9606', (72, 80))	('EGFR', 'Gene', '1956', (153, 157))	('PIK3CA', 'Gene', '5290', (102, 108))	('mutations', 'Var', (109, 118))	('EGFR', 'molecular_function', 'GO:0005006', ('153', '157'))	('EGFR', 'Gene', (153, 157))	('cetuximab', 'Chemical', 'MESH:D000068818', (168, 177))
60539	27338857	For example, BRAF inhibitors work well in melanomas harboring mutations in the BRAF gene, but have no therapeutic effect in colorectal cancer patients harboring the identical BRAF mutations, due to PI3K/AKT activation common in colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('BRAF', 'Gene', (175, 179))	('BRAF', 'Gene', '673', (175, 179))	('BRAF', 'Gene', '673', (79, 83))	('colorectal cancer', 'Phenotype', 'HP:0003003', (228, 245))	('PI3K', 'molecular_function', 'GO:0016303', ('198', '202'))	('BRAF', 'Gene', (79, 83))	('melanomas', 'Disease', 'MESH:D008545', (42, 51))	('colorectal cancers', 'Disease', (228, 246))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('BRAF', 'Gene', '673', (13, 17))	('melanomas', 'Disease', (42, 51))	('BRAF', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (62, 71))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('AKT', 'Gene', (203, 206))	('mutations', 'Var', (180, 189))	('activation', 'PosReg', (207, 217))	('colorectal cancer', 'Disease', 'MESH:D015179', (228, 245))	('colorectal cancer', 'Disease', (124, 141))	('colorectal cancers', 'Disease', 'MESH:D015179', (228, 246))	('melanomas', 'Phenotype', 'HP:0002861', (42, 51))	('patients', 'Species', '9606', (142, 150))	('AKT', 'Gene', '207', (203, 206))
60549	27338857	HMECs were probed with the following primary antibodies: EGFR (#4267), pEGFR ((#2234), KRAS (sc-30), pMEK ((#9154), p-cRAF ((#9427), GAPDH ((#5174), and beta-tubulin ((#2146).	('cRAF', 'molecular_function', 'GO:0004709', ('118', '122'))	('EGFR', 'Gene', '1956', (72, 76))	('RAF', 'Gene', '22882', (119, 122))	('#4267', 'Var', (63, 68))	('(#9154', 'Var', (107, 113))	('GAPDH', 'Gene', '2597', (133, 138))	('EGFR', 'Gene', (57, 61))	('(#9427', 'Var', (124, 130))	('RAF', 'Gene', (119, 122))	('(#2234', 'Var', (78, 84))	('KRAS', 'Gene', '3845', (87, 91))	('(#5174', 'Var', (140, 146))	('beta-tubulin', 'Protein', (153, 165))	('EGFR', 'Gene', (72, 76))	('GAPDH', 'Gene', (133, 138))	('(#2146', 'Var', (167, 173))	('KRAS', 'Gene', (87, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('EGFR', 'Gene', '1956', (57, 61))
60552	27338857	This data is available on Gene Expression Omnibus (GEO) accession numbers: GSE73628 for RAF1, GSE76877 for KRAS (G12V), and GSE59765 for EGFR.	('EGFR', 'Gene', (137, 141))	('KRAS', 'Gene', (107, 111))	('RAF1', 'Gene', (88, 92))	('RAF1', 'Gene', '5894', (88, 92))	('G12V', 'Mutation', 'rs121913529', (113, 117))	('Gene Expression', 'biological_process', 'GO:0010467', ('26', '41'))	('KRAS', 'Gene', '3845', (107, 111))	('EGFR', 'Gene', '1956', (137, 141))	('GSE59765', 'Var', (124, 132))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))	('GSE73628', 'Var', (75, 83))	('GSE76877', 'Var', (94, 102))
60554	27338857	Any mutations found in KRAS, EGFR, or BRAF were included on heatmaps.	('BRAF', 'Gene', '673', (38, 42))	('KRAS', 'Gene', (23, 27))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('BRAF', 'Gene', (38, 42))	('mutations', 'Var', (4, 13))	('KRAS', 'Gene', '3845', (23, 27))	('EGFR', 'molecular_function', 'GO:0005006', ('29', '33'))
60575	29108369	Aristolochic acid is especially reported to induce upper urinary tract urothelial carcinoma (UTUC).	('induce', 'PosReg', (44, 50))	('upper urinary tract urothelial carcinoma', 'Disease', 'MESH:D014552', (51, 91))	('upper urinary tract urothelial carcinoma', 'Disease', (51, 91))	('Aristolochic acid', 'Chemical', 'MESH:C000228', (0, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('Aristolochic acid', 'Var', (0, 17))
60665	33072575	Transcriptome profiling studies revealed that Erk signaling was involved in the tumor progression mediated by DUSP9 silencing, which is confirmed by cell experiments and clinical tissue sample staining analysis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('involved', 'Reg', (64, 72))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Erk', 'molecular_function', 'GO:0004707', ('46', '49'))	('Erk', 'Gene', (46, 49))	('DUSP9', 'Gene', (110, 115))	('tumor', 'Disease', (80, 85))	('Erk', 'Gene', '5594', (46, 49))	('silencing', 'Var', (116, 125))
60713	33072575	The results showed that DUSP9 was hypermethylated in a variety of cancers, such as colon adenocarcinoma (COAD), bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma, etc.	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (284, 309))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('hypermethylated', 'Var', (34, 49))	('bladder urothelial carcinoma', 'Disease', (112, 140))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (83, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('lung adenocarcinoma', 'Disease', (256, 275))	('breast invasive carcinoma', 'Disease', (149, 174))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (112, 140))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('pancreatic adenocarcinoma', 'Disease', (284, 309))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (149, 174))	('COAD', 'Disease', 'MESH:D029424', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('BRCA', 'Gene', '672', (176, 180))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (256, 275))	('DUSP9', 'Gene', (24, 29))	('colon adenocarcinoma', 'Disease', (83, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (256, 275))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('COAD', 'Disease', (105, 109))	('BRCA', 'Gene', (176, 180))	('cancers', 'Disease', (66, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (284, 309))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (183, 247))
60716	33072575	The results showed that with the increase of 5-aza-dC concentration, the methylation level of DUSP9 decreased (Figure 2E), while the protein expression level increased gradually (Figure 2F).	('methylation level', 'MPA', (73, 90))	('5-aza-dC', 'Var', (45, 53))	('methylation', 'biological_process', 'GO:0032259', ('73', '84'))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (45, 53))	('increase', 'PosReg', (33, 41))	('decreased', 'NegReg', (100, 109))	('protein expression level', 'MPA', (133, 157))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('DUSP9', 'Protein', (94, 99))	('increased', 'PosReg', (158, 167))
60719	33072575	On the contrary, micro-1246 inhibition can elevate the expression of DUSP9 in both mRNA and protein levels (Figures 3D,E).	('elevate', 'PosReg', (43, 50))	('DUSP9', 'Gene', (69, 74))	('micro-1246', 'Var', (17, 27))	('expression', 'MPA', (55, 65))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('micro-1246', 'Chemical', '-', (17, 27))	('inhibition', 'NegReg', (28, 38))
60721	33072575	In addition, miR-1246 mimics attenuated the ability of DUSP9 to inhibit the proliferation of CRC cells, whereas miR-1246 inhibition decreased the proliferation by DUSP9 knockdown in CRC cells (Figure 3G).	('miR-1246', 'Gene', '100302142', (112, 120))	('miR-1246', 'Gene', '100302142', (13, 21))	('knockdown', 'Var', (169, 178))	('proliferation', 'CPA', (146, 159))	('miR-1246', 'Gene', (112, 120))	('CRC', 'Phenotype', 'HP:0003003', (93, 96))	('miR-1246', 'Gene', (13, 21))	('proliferation', 'CPA', (76, 89))	('inhibit', 'NegReg', (64, 71))	('attenuated', 'NegReg', (29, 39))	('DUSP9', 'Gene', (163, 168))	('inhibition decreased', 'NegReg', (121, 141))	('CRC', 'Phenotype', 'HP:0003003', (182, 185))
60724	33072575	To further investigate the direct relationship between miR-1246 and DUSP9, we conducted dual luciferase reporters containing the 3'UTR of DUSP9 and the mutant type 3'UTR of DUSP9 (Figure 3I).	('miR-1246', 'Gene', '100302142', (55, 63))	('mutant', 'Var', (152, 158))	('miR-1246', 'Gene', (55, 63))	('DUSP9', 'Gene', (138, 143))
60726	33072575	The number of 5-ethynyl-2'-deoxyuridine (EdU) incorporation was significantly increased in SW480 cells with DUSP9 knockdown but was markedly decreased in LoVo cells with DUSP9 overexpression compared with controls (Figure 4A).	('SW480', 'CellLine', 'CVCL:0546', (91, 96))	("5-ethynyl-2'-deoxyuridine", 'Chemical', 'MESH:C031086', (14, 39))	('knockdown', 'Var', (114, 123))	('DUSP9', 'Gene', (108, 113))	('decreased', 'NegReg', (141, 150))	('EdU', 'Chemical', 'MESH:C031086', (41, 44))	('increased', 'PosReg', (78, 87))	('LoVo', 'CellLine', 'CVCL:0399', (154, 158))	("5-ethynyl-2'-deoxyuridine", 'MPA', (14, 39))
60727	33072575	The scratch wound healing assays showed that knockdown of DUSP9 significantly promoted the migratory ability of SW480 cells.	('SW480', 'CellLine', 'CVCL:0546', (112, 117))	('DUSP9', 'Gene', (58, 63))	('migratory ability of SW480 cells', 'CPA', (91, 123))	('wound healing', 'biological_process', 'GO:0042060', ('12', '25'))	('promoted', 'PosReg', (78, 86))	('knockdown', 'Var', (45, 54))
60730	33072575	However, knockdown of DUSP9 in SW480 cells acted the opposite way (Figure 4C).	('SW480', 'CellLine', 'CVCL:0546', (31, 36))	('knockdown', 'Var', (9, 18))	('DUSP9', 'Gene', (22, 27))
60733	33072575	The results showed that mesenchymal markers (N-cadherin and vimentin) were significantly increased and epithelial markers (E-cadherin and zonula occludens-1) were remarkably decreased when DUSP9 was knocked down in SW480 cells.	('epithelial markers', 'MPA', (103, 121))	('SW480', 'CellLine', 'CVCL:0546', (215, 220))	('decreased', 'NegReg', (174, 183))	('DUSP9', 'Gene', (189, 194))	('mesenchymal markers', 'CPA', (24, 43))	('zonula occludens', 'cellular_component', 'GO:0005923', ('138', '154'))	('N-cadherin', 'Gene', (45, 55))	('vimentin', 'cellular_component', 'GO:0045099', ('60', '68'))	('knocked down', 'Var', (199, 211))	('E-cadherin', 'Gene', (123, 133))	('E-cadherin', 'Gene', '999', (123, 133))	('vimentin', 'Gene', '7431', (60, 68))	('cadherin', 'molecular_function', 'GO:0008014', ('47', '55'))	('vimentin', 'cellular_component', 'GO:0045098', ('60', '68'))	('cadherin', 'molecular_function', 'GO:0008014', ('125', '133'))	('vimentin', 'Gene', (60, 68))	('increased', 'PosReg', (89, 98))	('N-cadherin', 'Gene', '1000', (45, 55))
60735	33072575	In order to further verify the tumorigenicity of DUSP9 in vivo, we constructed a tumor model of nude mice using SW480 and LoVo CRC cell lines with stable overexpression or knockdown of DUSP9.	('DUSP9', 'Gene', (185, 190))	('SW480', 'CellLine', 'CVCL:0546', (112, 117))	('CRC', 'Phenotype', 'HP:0003003', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('overexpression', 'PosReg', (154, 168))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('LoVo CRC', 'CellLine', 'CVCL:0399', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('nude mice', 'Species', '10090', (96, 105))	('knockdown', 'Var', (172, 181))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', (81, 86))
60738	33072575	Tumors derived from SW480 cells with stable DUSP9 knockdown showed an increased growth rate and less net weight at the fourth week when compared with control mice (Figure 5A).	('net weight at the fourth week', 'CPA', (101, 130))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SW480', 'CellLine', 'CVCL:0546', (20, 25))	('increased', 'PosReg', (70, 79))	('mice', 'Species', '10090', (158, 162))	('knockdown', 'Var', (50, 59))	('growth rate', 'CPA', (80, 91))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('less', 'NegReg', (96, 100))	('DUSP9', 'Gene', (44, 49))
60740	33072575	Moreover, when compared with controls, the xenografts developed from SW480 cells with DUSP9 stable knockdown exhibited a significant increase of positive PCNA staining.	('PCNA', 'molecular_function', 'GO:0003892', ('154', '158'))	('DUSP9', 'Gene', (86, 91))	('PCNA', 'Gene', (154, 158))	('SW480', 'CellLine', 'CVCL:0546', (69, 74))	('knockdown', 'Var', (99, 108))	('PCNA', 'Gene', '5111', (154, 158))	('increase', 'PosReg', (133, 141))
60743	33072575	To determine the biological function of DUSP9 in CRC, we performed RNA-seq in SW480 cells upon DUSP9 knockdown followed by a differential expression analysis to determine which genes are significantly deregulated.	('RNA', 'cellular_component', 'GO:0005562', ('67', '70'))	('CRC', 'Phenotype', 'HP:0003003', (49, 52))	('knockdown', 'Var', (101, 110))	('DUSP9', 'Gene', (95, 100))	('SW480', 'CellLine', 'CVCL:0546', (78, 83))
60745	33072575	In order to explore the role of DURP9 in tumor progression, we performed KEGG pathway analysis of these DEGs between two groups, and the results showed that many tumor growth and metastasis-related pathways, such as Erk, JNK, Wnt, Akt/mTOR, and ErbB signaling pathways, were significantly enriched in the DUSP9 knockdown group.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('Wnt', 'Pathway', (226, 229))	('Akt', 'Gene', '207', (231, 234))	('JNK', 'molecular_function', 'GO:0004705', ('221', '224'))	('ErbB', 'Gene', '1956', (245, 249))	('tumor', 'Disease', (162, 167))	('mTOR', 'Gene', '2475', (235, 239))	('DEGs', 'Gene', '8560', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('Erk', 'Gene', (216, 219))	('Erk', 'Gene', '5594', (216, 219))	('ErbB signaling', 'biological_process', 'GO:0038127', ('245', '259'))	('JNK', 'Gene', (221, 224))	('JNK', 'Gene', '5599', (221, 224))	('DUSP9', 'Gene', (305, 310))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('ErbB', 'Gene', (245, 249))	('tumor', 'Disease', (41, 46))	('Erk', 'molecular_function', 'GO:0004707', ('216', '219'))	('knockdown', 'Var', (311, 320))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('enriched', 'Reg', (289, 297))	('DEGs', 'Gene', (104, 108))	('mTOR', 'Gene', (235, 239))	('Akt', 'Gene', (231, 234))
60746	33072575	This suggests that DUSP9 knockdown can activate tumor growth and metastasis-related pathways (Figure 6B).	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('DUSP9', 'Gene', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('knockdown', 'Var', (25, 34))	('activate', 'PosReg', (39, 47))
60748	33072575	As shown in the heatmap, cell proliferation-related markers (bcl2 and PCNA) were significantly increased and cell apoptosis-related markers (such as Bax) were remarkably decreased in shDUSP9 SW480 cells than in control cells, indicating that DUSP9 knockdown significantly promotes the progression of CRC.	('PCNA', 'Gene', '5111', (70, 74))	('CRC', 'Disease', (300, 303))	('shDUSP9', 'Gene', (183, 190))	('cell proliferation', 'biological_process', 'GO:0008283', ('25', '43'))	('CRC', 'Phenotype', 'HP:0003003', (300, 303))	('cell proliferation-related', 'CPA', (25, 51))	('bcl2', 'Gene', '596', (61, 65))	('bcl2', 'Gene', (61, 65))	('DUSP9', 'Gene', (242, 247))	('Bax', 'Gene', (149, 152))	('knockdown', 'Var', (248, 257))	('Bax', 'Gene', '581', (149, 152))	('promotes', 'PosReg', (272, 280))	('PCNA', 'Gene', (70, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('114', '123'))	('apoptosis', 'biological_process', 'GO:0006915', ('114', '123'))	('cell apoptosis-related', 'CPA', (109, 131))	('decreased', 'NegReg', (170, 179))	('bcl2', 'molecular_function', 'GO:0015283', ('61', '65'))	('PCNA', 'molecular_function', 'GO:0003892', ('70', '74'))	('increased', 'PosReg', (95, 104))	('SW480', 'CellLine', 'CVCL:0546', (191, 196))
60751	33072575	To test this possibility, we treated SW480 cells or LoVo cells with the specific Erk signaling inhibitor PD98059 or Erk signaling activator Curcumin.	('Erk', 'molecular_function', 'GO:0004707', ('81', '84'))	('Curcumin', 'Chemical', 'MESH:D003474', (140, 148))	('PD98059', 'Chemical', 'MESH:C093973', (105, 112))	('Erk', 'Gene', '5594', (116, 119))	('SW480', 'CellLine', 'CVCL:0546', (37, 42))	('Erk', 'Gene', '5594', (81, 84))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('Erk', 'molecular_function', 'GO:0004707', ('116', '119'))	('Erk', 'Gene', (81, 84))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('Erk', 'Gene', (116, 119))	('PD98059', 'Var', (105, 112))	('LoVo', 'CellLine', 'CVCL:0399', (52, 56))
60752	33072575	As shown in Figures 7A,B, PD98059 treatment significantly decreased the growth of SW480 cells induced by DUSP9 knockdown, whereas Curcumin treatment significantly increased the growth of LoVo cells suppressed by DUSP9 overexpression.	('SW480', 'CellLine', 'CVCL:0546', (82, 87))	('knockdown', 'Var', (111, 120))	('PD98059', 'Chemical', 'MESH:C093973', (26, 33))	('increased', 'PosReg', (163, 172))	('LoVo', 'CellLine', 'CVCL:0399', (187, 191))	('decreased', 'NegReg', (58, 67))	('growth', 'MPA', (72, 78))	('DUSP9', 'Gene', (105, 110))	('Curcumin', 'Chemical', 'MESH:D003474', (130, 138))
60754	33072575	The results of MTS cell viability assay also showed that PD98059 treatment significantly decreased the growth of SW480 cells induced by DUSP9 knockdown, whereas Curcumin treatment significantly increased the growth of LoVo cells suppressed by DUSP9 overexpression, indicating that Erk activation is involved in the DUSP9 silencing-mediated tumor growth of CRC (Figure 7D).	('CRC', 'Phenotype', 'HP:0003003', (356, 359))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('Erk', 'Gene', (281, 284))	('DUSP9', 'Gene', (315, 320))	('decreased', 'NegReg', (89, 98))	('Erk', 'Gene', '5594', (281, 284))	('LoVo', 'CellLine', 'CVCL:0399', (218, 222))	('increased', 'PosReg', (194, 203))	('Erk', 'molecular_function', 'GO:0004707', ('281', '284'))	('silencing-mediated', 'NegReg', (321, 339))	('growth', 'MPA', (208, 214))	('PD98059', 'Chemical', 'MESH:C093973', (57, 64))	('growth', 'MPA', (103, 109))	('DUSP9', 'Gene', (136, 141))	('knockdown', 'Var', (142, 151))	('tumor', 'Disease', (340, 345))	('PD98059', 'Var', (57, 64))	('SW480', 'CellLine', 'CVCL:0546', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (340, 345))	('Curcumin', 'Chemical', 'MESH:D003474', (161, 169))
60755	33072575	As expected, western blot analysis showed that the protein expression of p-Erk and two major cell apoptosis-related molecules Bax and caspase3 was decreased in SW480 cells with DUSP9 knockdown, while overexpression of DUSP9 in LoVo cells had the opposite effect (Figure 7E), confirming the role of DUSP9 in promoting cell apoptosis progression in CRC cells by inhibiting the Erk pathway.	('Erk', 'Gene', (375, 378))	('SW480', 'CellLine', 'CVCL:0546', (160, 165))	('apoptosis', 'biological_process', 'GO:0097194', ('322', '331'))	('promoting', 'PosReg', (307, 316))	('apoptosis', 'biological_process', 'GO:0006915', ('322', '331'))	('decreased', 'NegReg', (147, 156))	('Erk', 'Gene', '5594', (375, 378))	('CRC', 'Phenotype', 'HP:0003003', (347, 350))	('caspase3', 'Gene', '836', (134, 142))	('LoVo', 'CellLine', 'CVCL:0399', (227, 231))	('inhibiting', 'NegReg', (360, 370))	('protein expression', 'MPA', (51, 69))	('Erk', 'molecular_function', 'GO:0004707', ('75', '78'))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))	('Erk', 'molecular_function', 'GO:0004707', ('375', '378'))	('Bax', 'Gene', (126, 129))	('DUSP9', 'Gene', (177, 182))	('cell apoptosis progression', 'CPA', (317, 343))	('Bax', 'Gene', '581', (126, 129))	('knockdown', 'Var', (183, 192))	('Erk', 'Gene', (75, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('caspase3', 'Gene', (134, 142))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('Erk', 'Gene', '5594', (75, 78))
60764	33072575	In gastric cancer, low expression level of DUSP9 has been found to be linked with the increased JNK activity and decreased apoptosis, suggesting that DUSP9 may inhibit the proliferation of gastric cancer cells through JNK signaling pathway.	('increased', 'PosReg', (86, 95))	('JNK', 'Gene', '5599', (96, 99))	('inhibit', 'NegReg', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('JNK', 'molecular_function', 'GO:0004705', ('218', '221'))	('gastric cancer', 'Disease', (189, 203))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('expression level', 'MPA', (23, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (189, 203))	('DUSP9', 'Gene', (43, 48))	('activity', 'MPA', (100, 108))	('JNK', 'molecular_function', 'GO:0004705', ('96', '99'))	('JNK signaling pathway', 'biological_process', 'GO:0031098', ('218', '239'))	('proliferation', 'CPA', (172, 185))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))	('apoptosis', 'CPA', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Phenotype', 'HP:0012126', (189, 203))	('JNK', 'Gene', (218, 221))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('JNK', 'Gene', '5599', (218, 221))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('JNK', 'Gene', (96, 99))	('DUSP9', 'Var', (150, 155))
60765	33072575	In CRC, DUSP9 is known to inactivate many members of the mitogen-activated protein (MAP) kinase superfamily (such as SAPK, MAPK, and p38) by dephosphorylating both the phosphotyrosine and phosphoserine/threonine residues.	('phosphoserine', 'Chemical', 'MESH:D010768', (188, 201))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('threonine', 'Chemical', 'MESH:D013912', (202, 211))	('p38', 'Gene', '1432', (133, 136))	('SAPK', 'molecular_function', 'GO:0004707', ('117', '121'))	('MAPK', 'molecular_function', 'GO:0004707', ('123', '127'))	('inactivate', 'NegReg', (26, 36))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('p38', 'Gene', (133, 136))	('dephosphorylating', 'MPA', (141, 158))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (168, 183))	('DUSP9', 'Var', (8, 13))	('MAP', 'molecular_function', 'GO:0004239', ('84', '87'))
60769	33072575	In this study, we found that Erk signaling activation was involved in the tumor progression mediated by DUSP9 silencing.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('silencing', 'Var', (110, 119))	('activation', 'PosReg', (43, 53))	('DUSP9', 'Gene', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Erk', 'molecular_function', 'GO:0004707', ('29', '32'))	('signaling', 'biological_process', 'GO:0023052', ('33', '42'))	('Erk', 'Gene', (29, 32))	('tumor', 'Disease', (74, 79))	('Erk', 'Gene', '5594', (29, 32))
60779	33072575	Methylation of CpG island in the promoter region of tumor suppressor genes can promote the initiation of many cancers, including CRC.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancers', 'Disease', (110, 117))	('tumor', 'Disease', (52, 57))	('Methylation', 'Var', (0, 11))	('CRC', 'Disease', (129, 132))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('52', '68'))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('promote', 'PosReg', (79, 86))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('52', '68'))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('CRC', 'Phenotype', 'HP:0003003', (129, 132))
60780	33072575	Moreover, the de novo methylation of genes seems to be a common event in most malignancies.	('malignancies', 'Disease', (78, 90))	('malignancies', 'Disease', 'MESH:D009369', (78, 90))	('methylation', 'biological_process', 'GO:0032259', ('22', '33'))	('methylation', 'Var', (22, 33))
60781	33072575	In many types of cancer, hypermethylation of CpG island in the promoter of tumor suppressor genes is an important event.	('hypermethylation', 'Var', (25, 41))	('hypermethylation of CpG island', 'biological_process', 'GO:0044027', ('25', '55'))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('tumor suppressor', 'biological_process', 'GO:0051726', ('75', '91'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Disease', (17, 23))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('75', '91'))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('CpG', 'Protein', (45, 48))	('tumor', 'Disease', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
60783	33072575	Furthermore, BSE analysis revealed the hypermethylation status of CpG island in the promoter of DUSP9, which further led to a significant decrease of DUSP9 expression levels in human CRC.	('CpG', 'Gene', (66, 69))	('DUSP9', 'Gene', (96, 101))	('CRC', 'Phenotype', 'HP:0003003', (183, 186))	('expression levels', 'MPA', (156, 173))	('decrease', 'NegReg', (138, 146))	('human', 'Species', '9606', (177, 182))	('DUSP9', 'Gene', (150, 155))	('hypermethylation status', 'Var', (39, 62))
60809	27209351	The autoimmune response is elicited by the ectopic expression of neural antigens in neoplastic tissues, which eventually attack the nervous system of PNS patients.	('autoimmune response', 'Phenotype', 'HP:0002960', (4, 23))	('ectopic expression', 'Var', (43, 61))	('attack', 'Reg', (121, 127))	('patients', 'Species', '9606', (154, 162))
60868	27209351	Matsumoto L. reported that CIS of the testis triggered severe hypokinesis as a paraneoplastic manifestation and detection of anti-Ma2 antibodies.	('hypokinesis', 'Disease', 'MESH:D018754', (62, 73))	('Ma2', 'Gene', (130, 133))	('CIS', 'Phenotype', 'HP:0030075', (27, 30))	('CIS', 'Var', (27, 30))	('Ma2', 'Gene', '10687', (130, 133))	('hypokinesis', 'Disease', (62, 73))
60875	27209351	Table 3 shows that the bladder cancer antibodies inducing PNS are anti-Ri, anti-Hu, anti-Yo and anti-VGKC.	('bladder cancer', 'Disease', 'MESH:D001749', (23, 37))	('bladder cancer', 'Disease', (23, 37))	('anti-Yo', 'Var', (84, 91))	('Yo', 'Chemical', '-', (89, 91))	('anti-VGKC', 'Var', (96, 105))	('anti-Ri', 'Var', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('bladder cancer', 'Phenotype', 'HP:0009725', (23, 37))	('anti-Hu', 'Var', (75, 82))
60876	27209351	SCC and CYFRA21-1 are squamous cell carcinoma markers and not paraneoplastic antibodies.	('SCC', 'Disease', (0, 3))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (22, 45))	('CYFRA21-1', 'Var', (8, 17))	('squamous cell carcinoma', 'Disease', (22, 45))
60918	25191845	Lymphovascular invasion was more common in patients of histological variants in upper urinary tract (p = 0.007), whereas the prevalence of it was not different among patients with UC of the bladder according to the histological variation.	('patients', 'Species', '9606', (43, 51))	('histological variants', 'Var', (55, 76))	('common', 'Reg', (33, 39))	('Lymphovascular invasion', 'CPA', (0, 23))	('patients', 'Species', '9606', (166, 174))
60920	25191845	Among 84 patients who died of upper urinary tract UC, 14 (16.7%) had variant form.	('variant', 'Var', (69, 76))	('patients', 'Species', '9606', (9, 17))	('upper urinary tract UC', 'Disease', (30, 52))
60928	25191845	In upper urinary tract, Kaplan-Meier curve showed that the presence of histological variant was associated with worse CSS (p<0.001) (Figure 1B).	('variant', 'Var', (84, 91))	('CSS', 'Chemical', '-', (118, 121))	('CSS', 'Disease', (118, 121))
60931	25191845	The presence of histological variant was associated with significantly worse OS when the tumors were located in upper urinary tract (p<0.001) (Figure 2B).	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('variant', 'Var', (29, 36))	('OS', 'Chemical', '-', (77, 79))	('worse', 'NegReg', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
60943	25191845	reported that CSS or OS of patients with squamous differentiation were worse than those with squamous cell carcinoma of the bladder at a median follow-up of 44 months.	('squamous cell carcinoma of the bladder', 'Disease', (93, 131))	('CSS', 'Chemical', '-', (14, 17))	('OS', 'Chemical', '-', (21, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('squamous differentiation', 'Var', (41, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('patients', 'Species', '9606', (27, 35))	('CSS', 'Disease', (14, 17))	('squamous cell carcinoma of the bladder', 'Disease', 'MESH:D002294', (93, 131))
60947	25191845	reported that histological variants were associated with significantly higher risk of recurrence and worse cancer-specific mortality in univariate analysis.	('higher', 'PosReg', (71, 77))	('variants', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('worse', 'NegReg', (101, 106))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('recurrence', 'CPA', (86, 96))	('cancer', 'Disease', (107, 113))
60951	25191845	reported that patients with variant histology tended to have more disease recurrence and cancer-specific mortality than those with pure upper urinary tract UC.	('disease recurrence', 'CPA', (66, 84))	('pure', 'molecular_function', 'GO:0034023', ('131', '135'))	('more', 'PosReg', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('variant histology', 'Var', (28, 45))	('patients', 'Species', '9606', (14, 22))
60954	25191845	In our result, although Kaplan-Meier curve showed worse survival outcomes of histological variants in upper urinary tract UC compared to pure UC, the tumor location was not associated with either OS or CSS in Cox regression analysis.	('Cox', 'Gene', '1351', (209, 212))	('Cox', 'Gene', (209, 212))	('upper urinary tract UC', 'Disease', (102, 124))	('pure', 'molecular_function', 'GO:0034023', ('137', '141'))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('variants', 'Var', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('CSS', 'Chemical', '-', (202, 205))	('OS', 'Chemical', '-', (196, 198))
61006	15685232	In case of haematological toxicity on day 8 (ANC<1.5 x 109 l-1, PLT<100 x 109 l-1), the gemcitabine treatment of day 8 was delayed for 1 week.	('gemcitabine', 'Chemical', 'MESH:C056507', (88, 99))	('toxicity', 'Disease', 'MESH:D064420', (26, 34))	('toxicity', 'Disease', (26, 34))	('men', 'Species', '9606', (105, 108))	('PLT', 'Var', (64, 67))
61092	33195415	However, the characterization of aberrant ACE2 expression in malignant tumors has not been elucidated.	('malignant tumors', 'Disease', (61, 77))	('malignant tumors', 'Disease', 'MESH:D009369', (61, 77))	('ACE2', 'Gene', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('aberrant', 'Var', (33, 41))	('ACE2', 'Gene', '59272', (42, 46))
61105	33195415	GSEA analysis which was carried out to determine the effect of ACE2 on tumors indicated that several cancer-associated pathways and immune-related pathways were hyperactivated in the high ACE2 expression group of most tumors.	('hyperactivated', 'PosReg', (161, 175))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('expression', 'MPA', (193, 203))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('GSEA', 'Chemical', '-', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('ACE2', 'Gene', '59272', (63, 67))	('tumors', 'Disease', (218, 224))	('cancer', 'Disease', (101, 107))	('ACE2', 'Gene', '59272', (188, 192))	('ACE2', 'Gene', (63, 67))	('immune-related pathways', 'Pathway', (132, 155))	('ACE2', 'Gene', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('high', 'Var', (183, 187))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
61140	33195415	Neoantigen is a neonatal antigen that is encoded by a mutant gene of a tumor cell.	('mutant', 'Var', (54, 60))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
61142	33195415	Neoantigen vaccines can be developed using the immune activity of tumor neoantigens, according to a specific mutation in the tumor cells, then administered to patients to achieve the required therapeutic effect.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('patients', 'Species', '9606', (159, 167))	('mutation', 'Var', (109, 117))
61145	33195415	The Tumor Mutational Burden (TMB) is usually measured by the number of somatic mutations that occur within an average of 1 Mb in the coding region (exon region) of the tumor cell genome (non-synonymous mutations).	('Tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('TMB', 'Chemical', '-', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('mutations', 'Var', (79, 88))
61149	33195415	Microsatellite Instability (MSI) refers to any change in the length of a microsatellite due to the insertion or deletion of a repeating unit in a tumor compared to normal tissue.	('change', 'Reg', (47, 53))	('S', 'Gene', '43740568', (29, 30))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('length', 'MPA', (61, 67))	('insertion', 'Var', (99, 108))	('deletion', 'Var', (112, 120))	('tumor', 'Disease', (146, 151))	('Microsatellite Instability', 'Disease', (0, 26))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
61155	33195415	We visualized the tumor with the most ACE2 mutations using an R data package, maftools.	('tumor', 'Disease', (18, 23))	('ACE2', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('ACE2', 'Gene', '59272', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
61156	33195415	Therefore, TCGA expression profiling was used to evaluate the relationship between ACE2 and five MMRs genes: MLH1, MSH2, MSH6, PMS2, and EPCAM mutations.	('PMS2', 'Gene', (127, 131))	('MLH1', 'Gene', '4292', (109, 113))	('MLH1', 'Gene', (109, 113))	('MSH6', 'Gene', (121, 125))	('PMS2', 'Gene', '5395', (127, 131))	('ACE2', 'Gene', (83, 87))	('MMRs genes', 'Gene', (97, 107))	('EPCAM', 'Gene', (137, 142))	('MSH6', 'Gene', '2956', (121, 125))	('MSH2', 'Gene', (115, 119))	('ACE2', 'Gene', '59272', (83, 87))	('MSH2', 'Gene', '4436', (115, 119))	('EPCAM', 'Gene', '4072', (137, 142))	('mutations', 'Var', (143, 152))
61215	33195415	A schematic diagram of the tumor with the highest number of mutations is shown in Figure 12.	('tumor', 'Disease', (27, 32))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))
61216	33195415	Notably, ACE2 mutations were only observed in BLCA, BRCA, COAD, HNSC, LAML, LGG, LUAD, LUSC, OV, SKCM, STAD, and UCEC.	('S', 'Gene', '43740568', (66, 67))	('S', 'Gene', '43740568', (97, 98))	('S', 'Gene', '43740568', (103, 104))	('ACE2', 'Gene', '59272', (9, 13))	('BRCA', 'Gene', (52, 56))	('BRCA', 'Gene', '672', (52, 56))	('COAD', 'Disease', (58, 62))	('S', 'Gene', '43740568', (89, 90))	('COAD', 'Disease', 'MESH:D029424', (58, 62))	('mutations', 'Var', (14, 23))	('ACE2', 'Gene', (9, 13))
61217	33195415	These findings indicate that ACE2 mutations seldom occur in most tumors.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('ACE2', 'Gene', '59272', (29, 33))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (34, 43))	('ACE2', 'Gene', (29, 33))
61222	33195415	DNA hypermethylation in the promoter region of a tumor suppressor gene leads to gene silencing, which in turn leads to dysregulation of multiple signaling pathways associated with human malignancy.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('multiple signaling pathways', 'Pathway', (136, 163))	('gene', 'MPA', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('gene silencing', 'biological_process', 'GO:0016458', ('80', '94'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('malignancy', 'Disease', 'MESH:D009369', (186, 196))	('leads to', 'Reg', (110, 118))	('human', 'Species', '9606', (180, 185))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('49', '65'))	('tumor', 'Disease', (49, 54))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('0', '20'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('49', '65'))	('malignancy', 'Disease', (186, 196))	('dysregulation', 'MPA', (119, 132))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))	('hypermethylation', 'Var', (4, 20))
61262	33195415	It has been demonstrated that overexpressed ACE2 may inhibit cell growth and vascular endothelial growth factor production in lung cancer, breast cancer, colon cancer, and pancreatic cancer.	('ACE2', 'Gene', '59272', (44, 48))	('colon cancer', 'Phenotype', 'HP:0003003', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ACE2', 'Gene', (44, 48))	('inhibit', 'NegReg', (53, 60))	('vascular endothelial growth factor', 'Gene', '7422', (77, 111))	('pancreatic cancer', 'Disease', 'MESH:D010190', (172, 189))	('lung cancer', 'Disease', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colon cancer', 'Disease', 'MESH:D015179', (154, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('vascular endothelial growth factor production', 'biological_process', 'GO:0010573', ('77', '122'))	('vascular endothelial growth factor', 'Gene', (77, 111))	('cell growth', 'biological_process', 'GO:0016049', ('61', '72'))	('pancreatic cancer', 'Disease', (172, 189))	('cell growth', 'CPA', (61, 72))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('breast cancer', 'Disease', (139, 152))	('overexpressed', 'Var', (30, 43))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('colon cancer', 'Disease', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('77', '111'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (172, 189))
61263	33195415	On the other hand, overexpressed ACE2 may promote the migration and invasion of human renal carcinoma cells.	('ACE2', 'Gene', '59272', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('renal carcinoma', 'Disease', 'MESH:C538614', (86, 101))	('migration', 'CPA', (54, 63))	('promote', 'PosReg', (42, 49))	('overexpressed', 'Var', (19, 32))	('human', 'Species', '9606', (80, 85))	('renal carcinoma', 'Disease', (86, 101))	('ACE2', 'Gene', (33, 37))	('renal carcinoma', 'Phenotype', 'HP:0005584', (86, 101))
61272	33195415	ACE2 expression also has a significantly positive correlation with the infiltrating levels of dendritic cells, macrophages M0, mast cells resting, and neutrophils in multiple cancers.	('ACE2', 'Gene', (0, 4))	('multiple cancers', 'Disease', (166, 182))	('expression', 'Var', (5, 15))	('infiltrating levels of dendritic cells', 'MPA', (71, 109))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('ACE2', 'Gene', '59272', (0, 4))	('multiple cancers', 'Disease', 'MESH:D009369', (166, 182))	('positive correlation', 'Reg', (41, 61))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
61276	33195415	We found that increased ACE2 expression correlates with immune infiltration levels in most tumors and that higher ACE2 expression was related to immune neoantigen, TMB, and microsatellite instability.	('increased', 'PosReg', (14, 23))	('tumors', 'Disease', (91, 97))	('expression', 'MPA', (119, 129))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('TMB', 'Chemical', '-', (164, 167))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('ACE2', 'Gene', '59272', (114, 118))	('related', 'Reg', (134, 141))	('ACE2', 'Gene', (24, 28))	('microsatellite', 'Var', (173, 187))	('higher', 'PosReg', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('ACE2', 'Gene', '59272', (24, 28))	('expression', 'MPA', (29, 39))	('ACE2', 'Gene', (114, 118))	('immune infiltration levels', 'MPA', (56, 82))
61291	32233022	An alteration in genes that play a key role in cell cycle regulation can contribute to high-grade tumours and may alter the sensitivity to drugs in BC.	('contribute', 'Reg', (73, 83))	('BC', 'Phenotype', 'HP:0009725', (148, 150))	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('sensitivity to drugs', 'MPA', (124, 144))	('alteration', 'Var', (3, 13))	('tumours', 'Disease', 'MESH:D009369', (98, 105))	('tumours', 'Disease', (98, 105))	('genes', 'Gene', (17, 22))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('47', '68'))	('alter', 'Reg', (114, 119))
61322	32233022	Among the network, miR-124 could target OSBPL10 and EPHA2, while EPHA2 was simultaneously regulated by miR-124, miR-141, miR-200a, miR-26a, miR-26b, miR-302b, miR-506, miR-520d and miR-95(Figure 8A).	('EPHA2', 'Gene', '1969', (65, 70))	('miR-200a', 'Gene', '406983', (121, 129))	('miR-124', 'Var', (103, 110))	('miR-520d', 'Gene', '574482', (168, 176))	('miR-506', 'Gene', '574511', (159, 166))	('regulated', 'Reg', (90, 99))	('miR-95', 'Gene', (181, 187))	('miR-520d', 'Gene', (168, 176))	('EPHA2', 'Gene', (52, 57))	('miR-141', 'Gene', '406933', (112, 119))	('miR-95', 'Gene', '407052', (181, 187))	('miR-141', 'Gene', (112, 119))	('EPHA2', 'Gene', (65, 70))	('miR-200a', 'Gene', (121, 129))	('OSBPL10', 'Gene', '114884', (40, 47))	('miR-26b', 'Gene', '407017', (140, 147))	('miR-26a', 'Gene', (131, 138))	('miR-506', 'Gene', (159, 166))	('miR-302b', 'Gene', (149, 157))	('miR-124', 'Gene', (19, 26))	('EPHA2', 'Gene', '1969', (52, 57))	('miR-26a', 'Gene', '407015', (131, 138))	('miR-26b', 'Gene', (140, 147))	('OSBPL10', 'Gene', (40, 47))	('miR-302b', 'Gene', '442894', (149, 157))
61329	32233022	Molecular interaction in ceRNA network could promote co-ordination of BP, and if the balance is compromised, it can lead to cancer.	('Molecular interaction', 'Var', (0, 21))	('cancer', 'Disease', (124, 130))	('co-ordination', 'MPA', (53, 66))	('lead to', 'Reg', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('promote', 'PosReg', (45, 52))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
61346	32233022	And this modulation of EphA2 also had distinct effects on cell proliferation and migration in GC.	('cell proliferation', 'CPA', (58, 76))	('modulation', 'Var', (9, 19))	('EphA2', 'Gene', (23, 28))	('migration', 'CPA', (81, 90))	('EphA2', 'Gene', '1969', (23, 28))	('effects', 'Reg', (47, 54))	('cell proliferation', 'biological_process', 'GO:0008283', ('58', '76'))
61365	27057873	In univariate analysis, CKD, female gender, age, hypertension, hematuria, repeated urinary tract infection, bladder cancer, and ESRD were all associated with UTUC.	('hematuria', 'Disease', (63, 72))	('urinary tract infection', 'Disease', (83, 106))	('UTUC', 'Disease', (158, 162))	('hypertension', 'Disease', 'MESH:D006973', (49, 61))	('associated', 'Reg', (142, 152))	('hematuria', 'Disease', 'MESH:D006417', (63, 72))	('hypertension', 'Disease', (49, 61))	('hematuria', 'Phenotype', 'HP:0000790', (63, 72))	('ESRD', 'Disease', (128, 132))	('CKD', 'Phenotype', 'HP:0012622', (24, 27))	('hypertension', 'Phenotype', 'HP:0000822', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ESRD', 'Phenotype', 'HP:0003774', (128, 132))	('ESRD', 'Disease', 'MESH:D007676', (128, 132))	('repeated', 'Disease', (74, 82))	('CKD', 'Var', (24, 27))	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('bladder cancer', 'Disease', (108, 122))	('repeated urinary tract infection', 'Phenotype', 'HP:0000010', (74, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('urinary tract infection', 'Disease', 'MESH:D014552', (83, 106))
61388	27057873	Patients were excluded if dialysis (defined as being registered in CID for dialysis) or kidney transplantation (ICD-9-CM code v42.0) or UTUC (ICD-9-CM code 1891, 1892 and being registered in CID) were recorded before their index date.	('CID', 'Disease', (191, 194))	('CID', 'Disease', (67, 70))	('CID', 'Disease', 'None', (67, 70))	('CID', 'Disease', 'None', (191, 194))	('Patients', 'Species', '9606', (0, 8))	('ICD-9-CM', 'Var', (142, 150))
61406	27057873	Comorbidities, including diabetes mellitus, hypertension, hematuria, repeated UTI, and bladder cancer, were more prevalent in the CKD group than in the control group (all P values < 0.001).	('diabetes mellitus', 'Disease', (25, 42))	('hematuria', 'Phenotype', 'HP:0000790', (58, 67))	('hypertension', 'Disease', (44, 56))	('diabetes mellitus', 'Disease', 'MESH:D003920', (25, 42))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('hypertension', 'Phenotype', 'HP:0000822', (44, 56))	('hematuria', 'Disease', (58, 67))	('CKD', 'Phenotype', 'HP:0012622', (130, 133))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (25, 42))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('CKD', 'Var', (130, 133))	('hematuria', 'Disease', 'MESH:D006417', (58, 67))	('prevalent', 'Reg', (113, 122))	('bladder cancer', 'Disease', 'MESH:D001749', (87, 101))	('bladder cancer', 'Disease', (87, 101))	('hypertension', 'Disease', 'MESH:D006973', (44, 56))	('repeated UTI', 'Disease', (69, 81))
61412	27057873	Using univariate analysis, we found that CKD, female gender, age, hypertension, hematuria, repeated UTI, bladder cancer, and ESRD were all associated with UTUC.	('ESRD', 'Disease', 'MESH:D007676', (125, 129))	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('UTUC', 'Disease', (155, 159))	('hematuria', 'Phenotype', 'HP:0000790', (80, 89))	('repeated UTI', 'Disease', (91, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (105, 119))	('bladder cancer', 'Disease', (105, 119))	('hematuria', 'Disease', (80, 89))	('hypertension', 'Disease', 'MESH:D006973', (66, 78))	('ESRD', 'Disease', (125, 129))	('CKD', 'Phenotype', 'HP:0012622', (41, 44))	('associated', 'Reg', (139, 149))	('hypertension', 'Disease', (66, 78))	('CKD', 'Var', (41, 44))	('hypertension', 'Phenotype', 'HP:0000822', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('hematuria', 'Disease', 'MESH:D006417', (80, 89))	('ESRD', 'Phenotype', 'HP:0003774', (125, 129))
61421	27057873	During the mean follow-up period of 9.1 years, we confirmed that CKD patients had an elevated risk of UTUC compared with non-CKD patients.	('patients', 'Species', '9606', (129, 137))	('CKD', 'Var', (65, 68))	('CKD', 'Phenotype', 'HP:0012622', (65, 68))	('patients', 'Species', '9606', (69, 77))	('UTUC', 'Disease', (102, 106))	('CKD', 'Phenotype', 'HP:0012622', (125, 128))
61430	27057873	A population-based study also revealed that the use of aristolochic acid-containing Chinese herbal products is associated with a dose-dependent increased risk of urinary tract cancer.	('aristolochic acid-containing', 'Var', (55, 83))	('urinary tract cancer', 'Disease', (162, 182))	('increased risk of urinary tract', 'Phenotype', 'HP:0000010', (144, 175))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('aristolochic acid', 'Chemical', 'MESH:C000228', (55, 72))	('urinary tract cancer', 'Disease', 'MESH:D014571', (162, 182))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (162, 182))
61431	27057873	CKD is associated with an increased risk of bladder cancer recurrence in patients with UTUC who have been treated by nephroureterectomy.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (44, 58))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (44, 69))	('CKD', 'Phenotype', 'HP:0012622', (0, 3))	('bladder cancer', 'Disease', 'MESH:D001749', (44, 58))	('bladder cancer', 'Disease', (44, 58))	('patients', 'Species', '9606', (73, 81))	('CKD', 'Var', (0, 3))
61437	27057873	Though the risk for UTUC in CKD patients was only 0.22% in this present study, it was 3 times higher than that in non-CKD patients.	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (122, 130))	('CKD', 'Phenotype', 'HP:0012622', (28, 31))	('CKD', 'Phenotype', 'HP:0012622', (118, 121))	('CKD', 'Var', (28, 31))	('UTUC', 'Disease', (20, 24))
61443	27057873	We also observed significantly higher rates of diabetes mellitus and hypertension in the CKD group.	('diabetes mellitus', 'Disease', 'MESH:D003920', (47, 64))	('CKD', 'Phenotype', 'HP:0012622', (89, 92))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (47, 64))	('CKD', 'Var', (89, 92))	('hypertension', 'Disease', 'MESH:D006973', (69, 81))	('diabetes mellitus', 'Disease', (47, 64))	('higher', 'PosReg', (31, 37))	('hypertension', 'Disease', (69, 81))	('hypertension', 'Phenotype', 'HP:0000822', (69, 81))
61444	27057873	In developed countries, CKD is generally associated with old age, diabetes mellitus, and hypertension.	('CKD', 'Var', (24, 27))	('hypertension', 'Disease', 'MESH:D006973', (89, 101))	('diabetes mellitus', 'Disease', (66, 83))	('associated', 'Reg', (41, 51))	('diabetes mellitus', 'Disease', 'MESH:D003920', (66, 83))	('CKD', 'Phenotype', 'HP:0012622', (24, 27))	('hypertension', 'Disease', (89, 101))	('hypertension', 'Phenotype', 'HP:0000822', (89, 101))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (66, 83))
61445	27057873	The increased prevalence of microvascular diseases, including neurological and renal disorders, is associated with arsenic ingestion.	('arsenic', 'Gene', (115, 122))	('microvascular diseases', 'Disease', (28, 50))	('arsenic', 'Chemical', 'MESH:D001151', (115, 122))	('ingestion', 'Var', (123, 132))	('neurological and renal disorders', 'Disease', 'MESH:D007674', (62, 94))	('microvascular diseases', 'Disease', 'MESH:D017566', (28, 50))
61452	27057873	We demonstrated that CKD patients have an elevated risk for UTUC compared with non-CKD patients.	('CKD', 'Phenotype', 'HP:0012622', (21, 24))	('UTUC', 'Disease', (60, 64))	('patients', 'Species', '9606', (25, 33))	('CKD', 'Phenotype', 'HP:0012622', (83, 86))	('CKD', 'Var', (21, 24))	('patients', 'Species', '9606', (87, 95))
61465	27022277	Adjusted for age in binary logistic regression analysis, the presence of MetS predicts the risk of higher T stage (odds ratio =4.029, P<0.001) and grade (odds ratio =3.870, P<0.001) of bladder cancer.	('higher T stage', 'CPA', (99, 113))	('bladder cancer', 'Phenotype', 'HP:0009725', (185, 199))	('MetS', 'Gene', (73, 77))	('bladder cancer', 'Disease', 'MESH:D001749', (185, 199))	('bladder cancer', 'Disease', (185, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('presence', 'Var', (61, 69))
61466	27022277	The patients with MetS in the People's Republic of China were found to have statistically significant higher T stage and grade of bladder cancer.	('People', 'Species', '9606', (30, 36))	('T stage', 'CPA', (109, 116))	('higher', 'PosReg', (102, 108))	('bladder cancer', 'Disease', (130, 144))	('bladder cancer', 'Disease', 'MESH:D001749', (130, 144))	('MetS', 'Var', (18, 22))	('grade', 'CPA', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('patients', 'Species', '9606', (4, 12))	('bladder cancer', 'Phenotype', 'HP:0009725', (130, 144))
61477	27022277	Also, some researches showed that MetS promotes tumorigenesis by a number of inflammatory molecules including interleukin-6 and tumor necrosis factor-alpha.	('tumor', 'Disease', (128, 133))	('promotes', 'PosReg', (39, 47))	('interleukin-6 and tumor necrosis factor-alpha', 'Gene', '3569;7124', (110, 155))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('MetS', 'Var', (34, 38))	('necrosis', 'biological_process', 'GO:0008219', ('134', '142'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('128', '149'))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('necrosis', 'biological_process', 'GO:0070265', ('134', '142'))	('necrosis', 'biological_process', 'GO:0019835', ('134', '142'))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('necrosis', 'biological_process', 'GO:0008220', ('134', '142'))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('necrosis', 'biological_process', 'GO:0001906', ('134', '142'))
61502	27022277	In age-adjusted binary logistic regression analysis, the presence of MetS predicts the risk of higher T stage (odds ratio =4.029, P<0.001) and grade (odds ratio =3.870, P<0.001) of bladder cancer.	('higher T stage', 'CPA', (95, 109))	('bladder cancer', 'Phenotype', 'HP:0009725', (181, 195))	('MetS', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('bladder cancer', 'Disease', 'MESH:D001749', (181, 195))	('presence', 'Var', (57, 65))	('bladder cancer', 'Disease', (181, 195))
61522	27022277	Excessive fat is also associated with systemic inflammatory response, which may play an important role in cancer.	('Excessive fat', 'Phenotype', 'HP:0001513', (0, 13))	('inflammatory response', 'biological_process', 'GO:0006954', ('47', '68'))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('systemic inflammatory response', 'Disease', (38, 68))	('cancer', 'Disease', (106, 112))	('Excessive fat', 'Var', (0, 13))	('associated', 'Reg', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
61543	27022277	Patients with MetS were found to have statistically significant higher T stage and grade of bladder cancer, while the parameters of MetS, BMI, DM, and high blood pressure, cannot individually predict higher T stage and grade of bladder cancer.	('T stage', 'CPA', (71, 78))	('high blood pressure', 'Phenotype', 'HP:0000822', (151, 170))	('bladder cancer', 'Disease', 'MESH:D001749', (228, 242))	('higher', 'PosReg', (64, 70))	('bladder cancer', 'Disease', (92, 106))	('bladder cancer', 'Disease', (228, 242))	('grade', 'CPA', (83, 88))	('MetS', 'Var', (14, 18))	('bladder cancer', 'Disease', 'MESH:D001749', (92, 106))	('DM', 'Disease', 'MESH:D009223', (143, 145))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (228, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('bladder cancer', 'Phenotype', 'HP:0009725', (92, 106))
61612	26392819	Superficial low grade and invasive high grade bladder cancer show very distinct characteristics in regard to molecular alterations (like FGFR3 or TP53 mutations) and clinical behavior and might represent different etiologic entities.	('clinical', 'Species', '191496', (166, 174))	('FGFR', 'molecular_function', 'GO:0005007', ('137', '141'))	('FGFR3', 'Gene', (137, 142))	('Superficial low grade', 'Disease', (0, 21))	('TP53', 'Gene', (146, 150))	('bladder cancer', 'Disease', (46, 60))	('bladder cancer', 'Disease', 'MESH:D001749', (46, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (151, 160))
61622	26392819	With our methods we cannot rule out that HPV plays a role at very early cancer stages, for example with a "hit and run mechanism" as discussed by Iwasaka et al.. For instance HPV could inactivate the p53 tumor suppressor gene years before tumors occur and may be undetectable at the later stages.	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('HPV', 'Species', '10566', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('HPV', 'Var', (175, 178))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('inactivate', 'NegReg', (185, 195))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', (239, 244))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('HPV', 'Species', '10566', (175, 178))	('cancer', 'Disease', (72, 78))
61632	26392819	Detection of genomic DNA, particularly in low copy numbers, shows no causal cancer relationship.	('low copy numbers', 'Var', (42, 58))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
61642	33087120	PanDM takes summary statistics from separate analyses as input and performs methylation site clustering, differential methylation detection, and pan-cancer pattern discovery.	('cancer', 'Disease', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('methylation', 'biological_process', 'GO:0032259', ('118', '129'))	('methylation', 'Var', (76, 87))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('PanDM', 'Chemical', '-', (0, 5))
61655	33087120	Aberrant DNA methylation has been confirmed as one of the hallmarks of cancer and has been proposed as a biomarker for cancer prognosis, diagnosis, treatment response, and therapeutic targets.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('DNA', 'Protein', (9, 12))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
61677	33087120	Next, they focused on DM CpG sites that are consistently hypermethylated or hypomethylated in at least 8 out of 15 cancer types, as well as those CpG sites that show DM in only a single cancer type.	('DM', 'Disease', 'MESH:D009223', (22, 24))	('cancer', 'Disease', (115, 121))	('hypomethylated', 'Var', (76, 90))	('hypermethylated', 'Var', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('DM', 'Disease', 'MESH:D009223', (166, 168))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
61720	33087120	ag=k indicates that CpG site g belongs to pattern k. For DM pattern k, the probability of DM in cancer type c is equal to qkc.	('pattern k', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('DM', 'Disease', 'MESH:D009223', (90, 92))	('cancer', 'Disease', (96, 102))	('DM', 'Disease', 'MESH:D009223', (57, 59))
61791	33087120	Dysregulated secretin receptors have been linked to aberrant methylation in breast cancer tissues.	('secretin', 'molecular_function', 'GO:0046659', ('13', '21'))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('aberrant methylation', 'MPA', (52, 72))	('secretin', 'molecular_function', 'GO:0008565', ('13', '21'))	('secretin receptors', 'Protein', (13, 31))	('breast cancer', 'Disease', (76, 89))	('Dysregulated', 'Var', (0, 12))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('linked', 'Reg', (42, 48))
61830	33087120	Moreover, the current approach enables PanDM to be applied to pan-cancer analyses of other types of functional genomic assays such as gene expression, SNP data, and copy number variation detection as long as p-values for each individual cancer type are provided.	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('PanDM', 'Chemical', '-', (39, 44))	('copy number', 'Var', (165, 176))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('gene expression', 'biological_process', 'GO:0010467', ('134', '149'))	('cancer', 'Disease', (237, 243))	('cancer', 'Disease', (66, 72))
61909	32339189	PD-L1 expression was also categorized as high or low based on CPS >= 10 and ICTCArea >= 5% (IC >= 5%) cutoffs.	('TC', 'Chemical', '-', (78, 80))	('CPS >', 'Var', (62, 67))	('expression', 'MPA', (6, 16))	('PD-L1', 'Gene', (0, 5))	('low', 'NegReg', (49, 52))	('PD-L1', 'Gene', '29126', (0, 5))	('CPS', 'Chemical', '-', (62, 65))
61922	32339189	The largest separation in the OS curves occurred for the combined TC/IC algorithm at cutoffs of >= 25%/>= 25% and >= 50%/>= 25%.	('TC', 'Chemical', '-', (66, 68))	('TC/IC', 'Gene', (66, 71))	('>= 50%/>= 25%', 'Var', (114, 127))
61923	32339189	IC PD-L1 expression was associated with better median OS compared with TC PD-L1 expression at any cutoff (Fig 5).	('TC', 'Chemical', '-', (71, 73))	('expression', 'Var', (9, 19))	('PD-L1', 'Gene', '29126', (3, 8))	('PD-L1', 'Gene', (74, 79))	('median OS', 'MPA', (47, 56))	('PD-L1', 'Gene', '29126', (74, 79))	('PD-L1', 'Gene', (3, 8))	('better', 'PosReg', (40, 46))
61924	32339189	Consistent with Kaplan-Meier OS data, the difference in median OS between PD-L1-high and-low expressing patients appeared to be optimal for ICs and TC/IC at cutoffs of >= 25% and >= 50% (IC), and >= 25%/>= 25% and >= 50%/>= 25% (TC/IC) (Fig 5).	('TC/IC', 'Disease', (148, 153))	('PD-L1', 'Gene', (74, 79))	('>= 25%/>= 25%', 'Var', (196, 209))	('PD-L1', 'Gene', '29126', (74, 79))	('ICs', 'Disease', (140, 143))	('TC', 'Chemical', '-', (148, 150))	('>= 50%/>= 25', 'Var', (214, 226))	('patients', 'Species', '9606', (104, 112))	('>= 50', 'Var', (179, 184))	('>= 25%', 'Var', (168, 174))	('TC', 'Chemical', '-', (229, 231))
61925	32339189	Concordance index (c-index), revealed that for the TCs, >= 25% had the highest c-index (0.514), and for IC, >= 25% and >= 50% were highest (0.698 and 0.711, respectively) (S2 Table).	('>= 25%', 'Var', (56, 62))	('TCs', 'Chemical', '-', (51, 54))	('c-index', 'MPA', (79, 86))
61934	32339189	The highest negative predictive values (NPV), were seen with IC >= 1% (95%), TC >= 1%/IC >= 1% (100%), and TC >= 25%/IC >= 25% (94%).	('TC >= 25%/IC >=', 'Var', (107, 122))	('TC', 'Chemical', '-', (77, 79))	('negative predictive', 'NegReg', (12, 31))	('TC >= 1%/IC', 'Var', (77, 88))	('TC', 'Chemical', '-', (107, 109))	('IC >= 1%', 'Var', (61, 69))
61938	32339189	In contrast, TC PD-L1 expression was only significantly associated with best tumor size percentage decrease (P = 0.02) in multivariate analysis, although a similar directionality of benefit was seen as for IC PD-L1 in other outcome measurements.	('expression', 'Var', (22, 32))	('PD-L1', 'Gene', (16, 21))	('TC', 'Chemical', '-', (13, 15))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('decrease', 'NegReg', (99, 107))	('PD-L1', 'Gene', (209, 214))	('PD-L1', 'Gene', '29126', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('PD-L1', 'Gene', '29126', (209, 214))
61944	32339189	As for other cutoffs, OS was longer for samples from PD-L1-high patients compared with PD-L1-low patients categorized using both the CPS >= 10 and especially the IC >= 5% cutoffs (Fig 3; S2 Fig).	('CPS >= 10', 'Var', (133, 142))	('PD-L1', 'Gene', (53, 58))	('PD-L1', 'Gene', '29126', (87, 92))	('patients', 'Species', '9606', (64, 72))	('IC >= 5%', 'Var', (162, 170))	('PD-L1', 'Gene', '29126', (53, 58))	('PD-L1', 'Gene', (87, 92))	('CPS', 'Chemical', '-', (133, 136))	('patients', 'Species', '9606', (97, 105))
61945	32339189	For the CPS >= 10 cutoff, ORR was 25% for patients categorized as PD-L1-high compared with 13% for patients with PD-L1-low expression.	('PD-L1', 'Gene', '29126', (66, 71))	('CPS', 'Chemical', '-', (8, 11))	('PD-L1', 'Gene', (113, 118))	('patients', 'Species', '9606', (99, 107))	('PD-L1', 'Gene', '29126', (113, 118))	('patients', 'Species', '9606', (42, 50))	('PD-L1', 'Gene', (66, 71))	('CPS >= 10', 'Var', (8, 17))
61962	32339189	The nature of the CPS >= 10 algorithm means it is more sensitive to low levels of TC PD-L1 expression than IC expression.	('CPS', 'Var', (18, 21))	('CPS', 'Chemical', '-', (18, 21))	('TC', 'Chemical', '-', (82, 84))	('PD-L1', 'Gene', (85, 90))	('PD-L1', 'Gene', '29126', (85, 90))
61975	32339189	In contrast, Bellmunt et al 2015 showed that PD-L1 expression on IC but not TC was associated with better survival in patients with metastatic UC treated with platinum chemotherapy.	('better', 'PosReg', (99, 105))	('PD-L1', 'Gene', '29126', (45, 50))	('patients', 'Species', '9606', (118, 126))	('TC', 'Chemical', '-', (76, 78))	('metastatic UC', 'Disease', (132, 145))	('survival', 'MPA', (106, 114))	('expression', 'Var', (51, 61))	('PD-L1', 'Gene', (45, 50))	('platinum', 'Chemical', 'MESH:D010984', (159, 167))
61976	32339189	Based on the literature, both TC and IC PD-L1 expression may have effects on survival in UC implying that caution is needed with respect to the use of PD-L1 expression to predict outcomes to treatment.	('expression', 'Var', (46, 56))	('PD-L1', 'Gene', '29126', (151, 156))	('TC', 'Chemical', '-', (30, 32))	('PD-L1', 'Gene', (151, 156))	('PD-L1', 'Gene', (40, 45))	('PD-L1', 'Gene', '29126', (40, 45))	('survival', 'MPA', (77, 85))	('effects', 'Reg', (66, 73))
61993	32339189	Confirm that "CPS 10" and "IC2/3" on the Figures refer to CPS >10 and IC> 5%, respectively.	('CPS', 'Chemical', '-', (14, 17))	('CPS >10', 'Var', (58, 65))	('IC2/3', 'Gene', '1781', (27, 32))	('IC2/3', 'Gene', (27, 32))	('CPS', 'Chemical', '-', (58, 61))
62047	29719336	Mean PCNA LI was maximum in high-grade tumors (85.4% +- 6.3%) and minimum in PUNLMP (58% +- 5.4%, P < 0.001).	('high-grade', 'Var', (28, 38))	('PCNA', 'Gene', (5, 9))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('PCNA', 'Gene', '5111', (5, 9))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('PCNA', 'molecular_function', 'GO:0003892', ('5', '9'))	('tumors', 'Disease', (39, 45))
62064	29719336	carried out a subjective quantitative assessment on bladder urothelial carcinomas using C-erB2 and CD44 in addition to PCNA.	('bladder urothelial carcinomas', 'Disease', 'MESH:D001749', (52, 81))	('PCNA', 'Gene', (119, 123))	('CD44', 'Gene', '960', (99, 103))	('C-erB2', 'Var', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('CD44', 'Gene', (99, 103))	('PCNA', 'Gene', '5111', (119, 123))	('bladder urothelial carcinomas', 'Disease', (52, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('PCNA', 'molecular_function', 'GO:0003892', ('119', '123'))
62126	32392774	BCG therapy elicits an inflammatory reaction involving different immune cell subsets that kill cancer cells by direct cytotoxicity or by the secretion of toxic compounds, like the tumor necrosis factor-inducing ligand.	('tumor necrosis', 'Disease', 'MESH:D009336', (180, 194))	('secretion', 'biological_process', 'GO:0046903', ('141', '150'))	('tumor necrosis', 'Disease', (180, 194))	('necrosis', 'biological_process', 'GO:0008220', ('186', '194'))	('therapy', 'Var', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Disease', (95, 101))	('secretion', 'MPA', (141, 150))	('necrosis', 'biological_process', 'GO:0070265', ('186', '194'))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ligand', 'molecular_function', 'GO:0005488', ('211', '217'))	('BC', 'Phenotype', 'HP:0009725', (0, 2))	('cytotoxicity', 'Disease', (118, 130))	('necrosis', 'biological_process', 'GO:0019835', ('186', '194'))	('necrosis', 'biological_process', 'GO:0001906', ('186', '194'))	('cytotoxicity', 'Disease', 'MESH:D064420', (118, 130))	('elicits', 'Reg', (12, 19))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('180', '201'))	('BCG', 'Species', '33892', (0, 3))	('necrosis', 'biological_process', 'GO:0008219', ('186', '194'))
62144	32392774	Generally, in tumors, mutated or incorrectly expressed proteins are processed via the immunoproteasome into peptides that are usually loaded onto MHC (major histocompatibility complex) class I molecules, which further not always are able to elicit CD8+ T cell response.	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('151', '183'))	('proteins', 'Protein', (55, 63))	('elicit', 'Reg', (241, 247))	('tumors', 'Disease', (14, 20))	('incorrectly expressed', 'Var', (33, 54))	('mutated', 'Var', (22, 29))	('CD8', 'Gene', (248, 251))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('CD8', 'Gene', '925', (248, 251))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
62149	32392774	Overall, bladder cancer is a genetically heterogenous disease, with a high rate of somatic mutations, including genes involved in cell-cycle regulation, chromatin regulation, and signaling pathways.	('bladder cancer', 'Disease', 'MESH:D001749', (9, 23))	('bladder cancer', 'Disease', (9, 23))	('signaling', 'biological_process', 'GO:0023052', ('179', '188'))	('cell-cycle regulation', 'biological_process', 'GO:0051726', ('130', '151'))	('mutations', 'Var', (91, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (9, 23))	('chromatin', 'cellular_component', 'GO:0000785', ('153', '162'))	('regulation', 'biological_process', 'GO:0065007', ('163', '173'))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
62151	32392774	Among most frequent mutations, one can enumerate aneuploidy, chromosomal instability, and fractional allelic losses.	('aneuploidy', 'Disease', (49, 59))	('chromosomal instability', 'CPA', (61, 84))	('aneuploidy', 'Disease', 'MESH:D000782', (49, 59))	('chromosomal instability', 'Phenotype', 'HP:0040012', (61, 84))	('mutations', 'Var', (20, 29))
62152	32392774	Thus, those differences in the molecular features of BC, together with personal characteristic of patients, may seriously influence the efficacy of the use of the immune checkpoint inhibitors.	('influence', 'Reg', (122, 131))	('differences', 'Var', (12, 23))	('BC', 'Phenotype', 'HP:0009725', (53, 55))	('patients', 'Species', '9606', (98, 106))
62155	32392774	This promotes self-tolerance by preventing the immune system from indiscriminately attacking the cells of the body, but it can also stop the immune system from attacking cancer cells that express PD-L1.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('self-tolerance', 'CPA', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('PD-L1', 'Var', (196, 201))	('promotes', 'PosReg', (5, 13))
62167	32392774	Lately, research was conducted on the use of durvalumab in patients with BC and it was concluded that the activity of this particular drug is high in PD-L1 positive and negative patients, but higher responses were noted in patients with high PD-L1 expression.	('patients', 'Species', '9606', (223, 231))	('BC', 'Phenotype', 'HP:0009725', (73, 75))	('PD-L1', 'Gene', (242, 247))	('patients', 'Species', '9606', (178, 186))	('PD-L1', 'Gene', (150, 155))	('positive', 'Var', (156, 164))	('patients', 'Species', '9606', (59, 67))	('activity', 'MPA', (106, 114))	('durvalumab', 'Chemical', 'MESH:C000613593', (45, 55))	('high', 'PosReg', (142, 146))
62168	32392774	An interesting study was held to find out whether the use of circulating tumor DNA (ctDNA) may influence the effect of durvalumab and the results show that changes in somatic mutations in ctDNA are correlated with this anti-PD-L1 form of therapy and may be a good predictor of a successful immunotherapy.	('changes', 'Var', (156, 163))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('influence', 'Reg', (95, 104))	('correlated', 'Reg', (198, 208))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('durvalumab', 'Chemical', 'MESH:C000613593', (119, 129))	('tumor', 'Disease', (73, 78))	('mutations', 'Var', (175, 184))	('ctDNA', 'Gene', (188, 193))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
62174	32392774	However, a difference in drug effects was observed in patients with PD-L1 overexpression compared to patients in the low-expression subgroup.	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (54, 62))	('difference', 'Reg', (11, 21))	('PD-L1', 'Gene', (68, 73))	('drug effects', 'MPA', (25, 37))	('overexpression', 'Var', (74, 88))
62192	32392774	The inhibition of CTLA-4 may increase the regulation of the immune response to BC.	('immune response', 'biological_process', 'GO:0006955', ('60', '75'))	('CTLA-4', 'Gene', (18, 24))	('increase', 'PosReg', (29, 37))	('inhibition', 'Var', (4, 14))	('regulation', 'biological_process', 'GO:0065007', ('42', '52'))	('regulation', 'MPA', (42, 52))	('CTLA-4', 'Gene', '1493', (18, 24))	('BC', 'Phenotype', 'HP:0009725', (79, 81))
62255	32392774	It is worth remembering that genetic instability of bladder cancer together with individual features of the patient are the keys in proper and efficient treatment.	('genetic instability', 'Var', (29, 48))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('patient', 'Species', '9606', (108, 115))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('bladder cancer', 'Disease', (52, 66))	('men', 'Species', '9606', (158, 161))
62290	32392774	Up to 90% of cancers have been associated with epigenetic modifications.	('epigenetic modifications', 'Var', (47, 71))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('associated', 'Reg', (31, 41))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Disease', (13, 20))
62315	31657881	The results showed that BLCA patients with high EMT risk scores were strongly associated with shorter disease-free survival and overall survival than BLCA patients with low risk scores.	('disease-free survival', 'CPA', (102, 123))	('patients', 'Species', '9606', (29, 37))	('high', 'Var', (43, 47))	('overall survival', 'CPA', (128, 144))	('BLCA', 'Phenotype', 'HP:0009725', (150, 154))	('shorter', 'NegReg', (94, 101))	('EMT', 'biological_process', 'GO:0001837', ('48', '51'))	('BLCA', 'Phenotype', 'HP:0009725', (24, 28))	('BLCA', 'Disease', (24, 28))	('high EMT', 'Phenotype', 'HP:0008151', (43, 51))	('patients', 'Species', '9606', (155, 163))
62357	31657881	In contrast, MIBC seems to originate from flat dysplasia and carcinoma in situ (CIS) and is genetically unstable and shows a high risk of progression and metastasis.22 Our study also showed that MIBC patients have a significantly lower overall survival and disease-free survival rate compared with NMIBC patients.	('CIS', 'Phenotype', 'HP:0030075', (80, 83))	('MIBC', 'Var', (195, 199))	('carcinoma', 'Disease', 'MESH:D009369', (61, 70))	('lower', 'NegReg', (230, 235))	('patients', 'Species', '9606', (200, 208))	('patients', 'Species', '9606', (304, 312))	('disease-free survival rate', 'CPA', (257, 283))	('MIBC', 'Chemical', '-', (13, 17))	('MIBC', 'Chemical', '-', (195, 199))	('NMIBC', 'Chemical', '-', (298, 303))	('MIBC', 'Chemical', '-', (299, 303))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('flat dysplasia', 'Disease', (42, 56))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (61, 78))	('overall survival', 'CPA', (236, 252))	('carcinoma', 'Disease', (61, 70))	('flat dysplasia', 'Disease', 'MESH:D005413', (42, 56))
62360	31657881	Moreover, the presence of CIS greatly increases the risk of disease progression to MIBC.25 Due to this complicated process, the main obstacle of BLCA therapy is choosing the most suitable treatment for the right patient at the right time.	('disease', 'MPA', (60, 67))	('presence', 'Var', (14, 22))	('CIS', 'Phenotype', 'HP:0030075', (26, 29))	('patient', 'Species', '9606', (212, 219))	('men', 'Species', '9606', (193, 196))	('MIBC', 'Chemical', '-', (83, 87))	('BLCA', 'Phenotype', 'HP:0009725', (145, 149))	('MIBC.25', 'Gene', (83, 90))
62517	31123852	Eligible for inclusion were RNU-treated patients with pT2-pT4 N0M0 or pTany N1-N3M0 UTUC and a performance status of 0-1.	('UTUC', 'Disease', 'MESH:D012141', (84, 88))	('pTa', 'Disease', (70, 73))	('pTa', 'Disease', 'None', (70, 73))	('patients', 'Species', '9606', (40, 48))	('pT2-pT4 N0M0', 'Var', (54, 66))	('UTUC', 'Disease', (84, 88))	('RNU', 'Disease', (28, 31))	('RNU', 'Disease', 'None', (28, 31))
62539	29572294	Systematic characterization of pan-cancer mutation clusters Cancer genome sequencing has shown that driver genes can often be distinguished not only by the elevated mutation frequency but also by specific nucleotide positions that accumulate changes at a high rate.	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('mutation', 'Var', (42, 50))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
62542	29572294	We find that such mutations (i) are more prominent in proteins that can exist in the on and off state, (ii) reflect the identity of a tumor of origin, and (iii) often localize within interfaces which mediate interactions with other proteins or ligands.	('localize', 'Reg', (167, 175))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('proteins', 'Protein', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('interactions', 'Interaction', (208, 220))	('tumor', 'Disease', (134, 139))	('mutations', 'Var', (18, 27))
62543	29572294	Following, we further examine structural data for human protein complexes and identify a number of additional protein interfaces that accumulate cancer mutations at a high rate.	('cancer', 'Disease', (145, 151))	('mutations', 'Var', (152, 161))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('human', 'Species', '9606', (50, 55))
62544	29572294	Jointly, these analyses suggest that disruption and dysregulation of protein interactions can be instrumental in switching functions of cancer proteins and activating downstream changes.	('switching', 'Reg', (113, 122))	('functions', 'MPA', (123, 132))	('disruption', 'Var', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('protein interactions', 'Protein', (69, 89))	('cancer', 'Disease', (136, 142))	('dysregulation', 'Var', (52, 65))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
62547	29572294	Analysis of different cancer genomics datasets has further underscored a high degree of heterogeneity in the mutation frequency and spectrum among different cancer types (Garraway & Lander, 2013; Lawrence et al, 2013) and uncovered a long tail of low-frequency driver mutations (Garraway & Lander, 2013).	('driver', 'Var', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('long tail', 'Phenotype', 'HP:0002831', (234, 243))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
62550	29572294	Large-scale cancer genome initiatives, specifically The Cancer Genome Atlas (TCGA, https://cancergenome.nih.gov/) and International Cancer Genome Consortium (International Cancer Genome et al, 2010; ICGC, http://icgc.org/), have increased statistical power in the analyses of cancer mutations and have driven the development of innovative approaches for the study of patient data (Dees et al, 2012; Hofree et al, 2013; Kandoth et al, 2013; Lawrence et al, 2013, 2014; Chen et al, 2014; Sanchez-Garcia et al, 2014).	('Sanchez-Garcia', 'Disease', (486, 500))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('patient', 'Species', '9606', (367, 374))	('Cancer', 'Disease', (172, 178))	('Cancer', 'Disease', (132, 138))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (56, 75))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('statistical', 'MPA', (239, 250))	('Sanchez-Garcia', 'Disease', 'MESH:C536767', (486, 500))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Disease', 'MESH:D009369', (172, 178))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Cancer Genome Atlas', 'Disease', (56, 75))	('Cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (276, 282))	('mutations', 'Var', (283, 292))	('Cancer', 'Disease', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Disease', (12, 18))	('cancer', 'Disease', (91, 97))	('increased', 'PosReg', (229, 238))	('Cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Cancer', 'Disease', 'MESH:D009369', (56, 62))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))
62553	29572294	Many of the individual cancer mutations are not well studied in terms of how they influence the properties of proteins (Cancer Genome Atlas Research et al, 2013).	('influence', 'Reg', (82, 91))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('properties of proteins', 'MPA', (96, 118))	('Cancer Genome Atlas', 'Disease', (120, 139))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (120, 139))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
62555	29572294	In this study, we applied the tool to 40 cancer types with the TCGA or ICGC sequencing data and identified 180 hotspot mutation residues in 160 genes that had a likely functional impact.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('mutation residues', 'Var', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (41, 47))
62556	29572294	These mutations alone had the power to cluster tumors based on the cell type of origin, and many of the hotspots were found within proteins, for example, enzymes, that are known to exist in the active and inactive states.	('cluster tumors', 'Disease', 'MESH:D003027', (39, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cluster tumors', 'Disease', (39, 53))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (6, 15))
62560	29572294	We mapped protein interfaces in these and based on the presence of mutation clusters within the mapped interfaces, we were able to identify 87 proteins in which cancer mutations were likely to affect protein interactions.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('mutation', 'Var', (67, 75))	('affect', 'Reg', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('protein', 'Protein', (200, 207))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('cancer', 'Disease', (161, 167))	('mutations', 'Var', (168, 177))
62563	29572294	Overall, characterization of the recurrent functional mutations suggests that a disruption and dysregulation of protein interactions could be an important molecular mechanism for switching functions of cancer proteins.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('interactions', 'Interaction', (120, 132))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('dysregulation', 'MPA', (95, 108))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('cancer', 'Disease', (202, 208))	('protein', 'Protein', (112, 119))
62564	29572294	Collectively, the data encompassed 40 different cancer types from 22 tissues, with the sequencing information from ~10,000 tumor samples, including ~1,300,000 mutations within coding sequences (see Materials and Methods).	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mutations', 'Var', (159, 168))	('000 tumor', 'Disease', 'MESH:D009369', (119, 128))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('000 tumor', 'Disease', (119, 128))
62566	29572294	The tool identifies and characterizes individual hotspot protein residues that accumulate mutations at a significantly higher rate than their surrounding protein sequence (Figs 1 and EV1).	('mutations', 'Var', (90, 99))	('EV1', 'Gene', (183, 186))	('EV1', 'Gene', '11322', (183, 186))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))
62569	29572294	Simulations of randomly re-assigned mutations within titin, that is, a gene with the highest overall mutation burden, did not report any hotspot residues (1,000 repetitions).	('titin', 'Gene', (53, 58))	('titin', 'Gene', '7273', (53, 58))	('mutations', 'Var', (36, 45))
62570	29572294	Using the approach introduced here, we applied the DominoEffect tool to the pan-cancer data and identified both known instances of hotspot driver mutations as well as residues that were as yet not annotated as such.	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (146, 155))	('cancer', 'Disease', (80, 86))
62571	29572294	In total, we identified 180 hotspots within 160 genes (Dataset EV1) for which the reported mutations were categorized as deleterious by the PolyPhen-2.	('mutations', 'Var', (91, 100))	('EV1', 'Gene', '11322', (63, 66))	('EV1', 'Gene', (63, 66))
62574	29572294	Of note, on average, 88% of tumor allele changes assigned as hotspot mutations were reported as heterozygotic in the TCGA dataset.	('mutations', 'Var', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))
62577	29572294	Independently of the hotspot analysis, we additionally searched for cancer mutation clusters in known and modeled protein interaction interfaces (Fig 1).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutation', 'Var', (75, 83))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))
62578	29572294	Strikingly, 36% (3,679/10,118) of the analyzed cancer genomes had at least one of the 180 hotspot residues mutated (Fig 2A).	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (47, 53))	('mutated', 'Var', (107, 114))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
62579	29572294	For a comparison, the same size randomly selected gene set that contained any of the protein positions with five or more pan-cancer mutations was on average mutated in 14% of the patients (P < 6 x 10-12, distance from the observed distribution of 1,000 random values).	('mutations', 'Var', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Disease', (125, 131))	('mutated', 'Var', (157, 164))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
62580	29572294	The major contributors to the highly prevalent mutations were the well-studied oncogenes KRAS, BRAF, IDH1, PIK3CA, NRAS, SF3B1, CTNNB1, and PTEN: More than one-quarter (i.e., 27%) of all patients had a hotspot mutation in at least one of these genes.	('NRAS', 'Gene', (115, 119))	('PIK3CA', 'Gene', (107, 113))	('SF3B1', 'Gene', (121, 126))	('PTEN', 'Gene', (140, 144))	('patients', 'Species', '9606', (187, 195))	('CTNNB1', 'Gene', '1499', (128, 134))	('BRAF', 'Gene', '673', (95, 99))	('mutations', 'Var', (47, 56))	('BRAF', 'Gene', (95, 99))	('KRAS', 'Gene', '3845', (89, 93))	('IDH1', 'Gene', (101, 105))	('PTEN', 'Gene', '5728', (140, 144))	('SF3B1', 'Gene', '23451', (121, 126))	('NRAS', 'Gene', '4893', (115, 119))	('PIK3CA', 'Gene', '5290', (107, 113))	('KRAS', 'Gene', (89, 93))	('CTNNB1', 'Gene', (128, 134))	('IDH1', 'Gene', '3417', (101, 105))	('hotspot', 'PosReg', (202, 209))
62585	29572294	The obtained extensive set of known and candidate cancer-associated genes with hotspot mutations provides an opportunity to define gene and protein characteristics associated with such residues.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutations', 'Var', (87, 96))
62587	29572294	Among the most prominent examples of cancer drivers with hotspot residues are kinases and Ras proteins where the hotspot mutations frequently act by switching the proteins to a constantly active state.	('residues', 'Var', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('mutations', 'Var', (121, 130))	('cancer', 'Disease', (37, 43))	('proteins', 'MPA', (163, 171))	('Ras', 'Protein', (90, 93))	('switching', 'Reg', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
62591	29572294	Moreover, the fraction of enzymes was even two times higher among the here-identified genes with hotspot residues than among the genes in the Cancer Gene Census that were involved in translocations (P < 0.0003).	('higher', 'PosReg', (53, 59))	('residues', 'Var', (105, 113))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('enzymes', 'MPA', (26, 33))	('Cancer', 'Disease', (142, 148))	('fraction', 'MPA', (14, 22))	('Cancer', 'Disease', 'MESH:D009369', (142, 148))
62600	29572294	Overall, this shows that many of the genes with hotspot residues relate to cancer-associated processes and that jointly more than a third of them encode proteins that are known to exist in an active and inactive state.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('encode', 'Reg', (146, 152))	('residues', 'Var', (56, 64))	('cancer', 'Disease', (75, 81))	('proteins', 'Protein', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('relate', 'Reg', (65, 71))
62602	29572294	We found that domains which were targets of hotspot mutations in two or more proteins were often associated with enzymatic activities, or with binding to proteins, nucleic acids, or lipids (Fig 2E and Dataset EV1).	('mutations', 'Var', (52, 61))	('proteins', 'Protein', (154, 162))	('binding', 'Interaction', (143, 150))	('lipids', 'Chemical', 'MESH:D008055', (182, 188))	('enzymatic activities', 'MPA', (113, 133))	('EV1', 'Gene', '11322', (209, 212))	('domains', 'MPA', (14, 21))	('binding', 'molecular_function', 'GO:0005488', ('143', '150'))	('EV1', 'Gene', (209, 212))	('associated', 'Reg', (97, 107))
62606	29572294	A hotspot residue within this protein mapped to the KH domain that has a role in nucleic acid recognition and is also a target of a hotspot mutation in the known cancer driver FUBP1.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('FUBP1', 'Gene', '8880', (176, 181))	('mutation', 'Var', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('FUBP1', 'Gene', (176, 181))	('nucleic acid', 'cellular_component', 'GO:0005561', ('81', '93'))	('role', 'Reg', (73, 77))
62608	29572294	As a following step, we analyzed the PDB structures of proteins with the identified hotspot mutations (Berman et al, 2000; www.rcsb.org).	('PDB', 'Gene', (37, 40))	('PDB', 'Gene', '5131', (37, 40))	('mutations', 'Var', (92, 101))
62609	29572294	When structural data were available, we aligned the segments with hotspot mutations onto the corresponding PDB sequences (see Materials and Methods).	('mutations', 'Var', (74, 83))	('PDB', 'Gene', '5131', (107, 110))	('PDB', 'Gene', (107, 110))
62614	29572294	The observed hotspot mutations in CARM1 and METTL4 could thus have an effect on the interactions between the CARM1 proteins that together form a complex, or on the METTL4 binding to its interactor protein METTL3.	('binding', 'molecular_function', 'GO:0005488', ('171', '178'))	('effect', 'Reg', (70, 76))	('METTL4', 'Gene', (44, 50))	('interactions', 'Interaction', (84, 96))	('METTL4', 'Gene', '64863', (44, 50))	('CARM1', 'Gene', (109, 114))	('METTL3', 'Gene', (205, 211))	('binding', 'Interaction', (171, 178))	('CARM1', 'Gene', '10498', (34, 39))	('proteins', 'Protein', (115, 123))	('METTL3', 'Gene', '56339', (205, 211))	('CARM1', 'Gene', (34, 39))	('complex', 'Interaction', (145, 152))	('have', 'Reg', (62, 66))	('mutations', 'Var', (21, 30))	('METTL4', 'Gene', (164, 170))	('METTL4', 'Gene', '64863', (164, 170))	('CARM1', 'Gene', '10498', (109, 114))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))
62616	29572294	Finally, hotspot residues in the PBX2 and MAX proteins mapped to their conserved DNA interfaces, suggesting abolished or altered transcriptional regulation.	('PBX2', 'Gene', (33, 37))	('transcriptional regulation', 'MPA', (129, 155))	('altered', 'Reg', (121, 128))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('regulation', 'biological_process', 'GO:0065007', ('145', '155'))	('residues', 'Var', (17, 25))	('PBX2', 'Gene', '5089', (33, 37))
62617	29572294	In the case of the PTEN (Papa et al, 2014), FBXW7 (Welcker & Clurman, 2008) and SMAD4 (Miyaki & Kuroki, 2003) genes, as well as several other tumor suppressors (de Vries et al, 2002; Hanel et al, 2013), a frequent mechanism of inactivation is through point mutations that reoccur at the defined residues and act dominantly on the molecular level.	('FBXW7', 'Gene', '55294', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('mechanism', 'NegReg', (214, 223))	('FBXW7', 'Gene', (44, 49))	('tumor', 'Disease', (142, 147))	('PTEN', 'Gene', (19, 23))	('SMAD4', 'Gene', '4089', (80, 85))	('PTEN', 'Gene', '5728', (19, 23))	('is through', 'Var', (240, 250))	('Papa', 'Gene', '5069', (25, 29))	('and', 'Gene', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('Papa', 'Gene', (25, 29))	('SMAD4', 'Gene', (80, 85))
62618	29572294	In the cancer genomics studies, mutational clustering is often used as a signature that is associated with oncogenes (Davoli et al, 2013; Vogelstein et al, 2013).	('mutational', 'Var', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
62620	29572294	In order to categorize hotspot mutations that could function by inactivating tumor suppressors, we analyzed which of the here-identified genes were categorized as tumor suppressors in the Cancer Gene Census, or were predicted to be suppressors based on mutation signatures in an independent study (Davoli et al, 2013).	('mutations', 'Var', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('inactivating', 'NegReg', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Cancer', 'Disease', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('Cancer', 'Phenotype', 'HP:0002664', (188, 194))	('Cancer', 'Disease', 'MESH:D009369', (188, 194))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
62621	29572294	In addition, to further expand the set of tumor suppressor candidates, we assessed the frequency of deleterious mutations within the here-defined set of hotspot genes using the mutation data from the above-described TCGA and ICGC datasets.	('tumor', 'Disease', (42, 47))	('tumor suppressor', 'biological_process', 'GO:0051726', ('42', '58'))	('mutations', 'Var', (112, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('42', '58'))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
62622	29572294	Using a conservative threshold that required an overrepresentation of deleterious over neutral changes within a protein, we found that 15 genes with a hotspot mutation also exhibited mutation patterns typical of tumor suppressors (Dataset EV5).	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('mutation', 'Var', (159, 167))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (212, 217))
62627	29572294	Furthermore, to gain additional insights into the distribution of functional effects of hotspot mutations, we classified genes in which hotspot residues were mutated in 10 or more tumor samples into the following three categories: (i) instances where mutations occurred within a tumor suppressor and were likely inactivating, (ii) instances where mutations affected protein binding properties and were likely activating, and (iii) all other instances (Fig 3B and Dataset EV6).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor suppressor', 'biological_process', 'GO:0051726', ('279', '295'))	('mutations', 'Var', (251, 260))	('activating', 'MPA', (409, 419))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('protein', 'cellular_component', 'GO:0003675', ('366', '373'))	('protein binding', 'molecular_function', 'GO:0005515', ('366', '381'))	('inactivating', 'NegReg', (312, 324))	('tumor', 'Disease', (279, 284))	('affected', 'Reg', (357, 365))	('tumor', 'Disease', (180, 185))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('279', '295'))	('protein', 'Protein', (366, 373))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('mutations', 'Var', (96, 105))	('mutations', 'Var', (347, 356))
62628	29572294	These more frequently mutated instances encompassed in total 53 genes and included the experimentally characterized hotspots within the PTEN, FBXW7, SMAD4, EP300, and CREBBP tumor suppressors.	('tumor', 'Disease', (174, 179))	('EP300', 'Gene', (156, 161))	('EP300', 'Gene', '2033', (156, 161))	('SMAD4', 'Gene', (149, 154))	('CREBBP', 'Gene', (167, 173))	('encompassed', 'Reg', (40, 51))	('mutated', 'Var', (22, 29))	('FBXW7', 'Gene', '55294', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('SMAD4', 'Gene', '4089', (149, 154))	('FBXW7', 'Gene', (142, 147))	('CREBBP', 'Gene', '1387', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('PTEN', 'Gene', (136, 140))	('PTEN', 'Gene', '5728', (136, 140))
62629	29572294	In the set of proteins with more frequently mutated and better-characterized hotspots, 32% (i.e.,17 of 53) were tumor suppressor, 51% (i.e., 27 of 53) represented instances where hotspot mutations were likely to affect protein binding properties, and 17% (i.e., 9 of 53) were proteins in which the impacts of hotspot mutations could not be readily classified.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('112', '128'))	('protein binding', 'molecular_function', 'GO:0005515', ('219', '234'))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('mutated', 'Var', (44, 51))	('mutations', 'Var', (187, 196))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('affect', 'Reg', (212, 218))	('tumor suppressor', 'biological_process', 'GO:0051726', ('112', '128'))	('protein', 'cellular_component', 'GO:0003675', ('219', '226'))	('protein', 'Protein', (219, 226))
62632	29572294	Using a complementary approach, we compared the presence of iPfam domains (Wang et al, 2012; Finn et al, 2014), that is, Pfam domains that can mediate protein-protein interactions, in the protein sets that we established above: (i) proteins that contain hotspot mutations, (ii) other proteins encoded by the Cancer Gene Census (described above), and (iii) all other human proteins.	('Finn', 'Species', '1754191', (93, 97))	('Cancer', 'Disease', (308, 314))	('Cancer', 'Phenotype', 'HP:0002664', (308, 314))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('Cancer', 'Disease', 'MESH:D009369', (308, 314))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('mutations', 'Var', (262, 271))	('human', 'Species', '9606', (366, 371))
62638	29572294	Individually, 20 (i.e., 19%) of these 106 proteins had interaction neighborhoods strongly enriched in the known cancer drivers (adjusted P < 0.05, Dataset EV7), and these clusters often included other proteins with hotspot mutations (Dataset EV7).	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('interaction', 'Interaction', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (223, 232))	('included', 'Reg', (186, 194))
62641	29572294	Additionally, 27 interaction pairs in which one partner was a candidate with a hotspot mutation and the other partner was a Cancer Gene Census protein were also supported with a PDB structure or a homology-based structural model that indicated a stable interaction between the proteins (see Materials and Methods).	('Cancer', 'Disease', 'MESH:D009369', (124, 130))	('PDB', 'Gene', '5131', (178, 181))	('Cancer', 'Disease', (124, 130))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('mutation', 'Var', (87, 95))	('Cancer', 'Phenotype', 'HP:0002664', (124, 130))	('interaction', 'Interaction', (253, 264))	('PDB', 'Gene', (178, 181))
62643	29572294	The hotspot mutation in this gene was originally reported in the TCGA study of bladder cancer (Cancer Genome Atlas Research, 2014a), but its impact has as yet not been characterized.	('Cancer', 'Phenotype', 'HP:0002664', (95, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (79, 93))	('Cancer Genome Atlas', 'Disease', (95, 114))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (95, 114))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (79, 93))	('mutation', 'Var', (12, 20))	('bladder cancer', 'Disease', (79, 93))
62644	29572294	The observation that a number of the candidates with hotspot mutations were physically associated with each other or with known cancer drivers suggests their possible connections to interaction networks relevant in disease development.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('interaction', 'Interaction', (182, 193))	('connections', 'Interaction', (167, 178))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('associated', 'Interaction', (87, 97))	('cancer', 'Disease', (128, 134))
62647	29572294	We found that 35 out of 180 hotspot residues were largely associated with one tumor type, that is, more than 75% of the mutations on these 35 positions were reported in a single tumor type (Dataset EV8).	('tumor', 'Disease', (178, 183))	('associated', 'Reg', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('mutations', 'Var', (120, 129))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
62650	29572294	For instance, for 89 hotspot positions, a single tumor type never contributed to 50% or more of the mutations (Dataset EV8).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('mutations', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))
62651	29572294	Next, we performed a hierarchical clustering of the analyzed tumor types, based on the percentage of patients that had a mutation in each of the identified hotspots.	('patients', 'Species', '9606', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mutation', 'Var', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
62652	29572294	Patterns of hotspot mutations could also point to the shared and cell-type-specific pathways in cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('point', 'Reg', (41, 46))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (20, 29))
62659	29572294	Blood tumors were largely defined by the scarcity of point mutations, and skin cutaneous melanoma and thyroid cancer were clustered together based on a high frequency of the BRAF hotspot mutation.	('thyroid cancer', 'Disease', 'MESH:D013964', (102, 116))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('skin cutaneous melanoma', 'Disease', (74, 97))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('BRAF', 'Gene', '673', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('BRAF', 'Gene', (174, 178))	('thyroid cancer', 'Disease', (102, 116))	('thyroid cancer', 'Phenotype', 'HP:0002890', (102, 116))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (74, 97))	('mutation', 'Var', (187, 195))	('Blood tumors', 'Phenotype', 'HP:0004377', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
62661	29572294	Overall, this analysis showed a strong power of hotspot mutations to reflect the identity of a tumor of origin.	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
62663	29572294	Proteins in which the mutation clusters were identified with the most significant P-values were cancer drivers for which it was previously shown that mutations in their interfaces can lead to disease development by disrupting interactions with regulatory proteins (PIK3CA and PPP2R1A) or by preventing GTP hydrolysis (KRAS, HRAS, and GNAS); Dataset EV9, 87 proteins in total.	('mutation', 'Var', (22, 30))	('GNAS', 'Gene', '2778', (334, 338))	('interactions', 'Interaction', (226, 238))	('HRAS', 'Gene', '3265', (324, 328))	('preventing', 'NegReg', (291, 301))	('HRAS', 'Gene', (324, 328))	('cancer', 'Disease', (96, 102))	('disrupting', 'NegReg', (215, 225))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('PIK3CA', 'Gene', (265, 271))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('302', '316'))	('PPP2R1A', 'Gene', '5518', (276, 283))	('mutations', 'Var', (150, 159))	('KRAS', 'Gene', '3845', (318, 322))	('disease', 'Disease', (192, 199))	('KRAS', 'Gene', (318, 322))	('GTP', 'Chemical', 'MESH:D006160', (302, 305))	('PPP2R1A', 'Gene', (276, 283))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('lead to', 'Reg', (184, 191))	('GTP hydrolysis', 'MPA', (302, 316))	('GNAS', 'Gene', (334, 338))	('PIK3CA', 'Gene', '5290', (265, 271))
62669	29572294	Of interest, both CUL1 and CUL4B had a mutation cluster at one of the interface contacts with the regulator protein CAND1 (Fig 6C).	('CUL4B', 'Gene', '8450', (27, 32))	('mutation', 'Var', (39, 47))	('CUL1', 'Gene', (18, 22))	('CAND1', 'Gene', (116, 121))	('CAND1', 'Gene', '55832', (116, 121))	('CUL1', 'Gene', '8454', (18, 22))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('CUL4B', 'Gene', (27, 32))
62670	29572294	In addition, we used annotations of protein complexes from the ConsensusPathDB (Kamburov et al, 2013) and found a number of protein complexes relevant in cancer that would be affected through these mutations (Dataset EV10).	('EV1', 'Gene', (217, 220))	('EV1', 'Gene', '11322', (217, 220))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('affected', 'Reg', (175, 183))	('protein', 'Protein', (124, 131))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('mutations', 'Var', (198, 207))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))
62672	29572294	Of relevance, mutations in the GNB1 protein interface were recently shown to promote cellular growth and transformation, as well as kinase inhibitor resistance (Yoda et al, 2015).	('GNB1', 'Gene', '2782', (31, 35))	('promote', 'PosReg', (77, 84))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('cellular growth', 'CPA', (85, 100))	('cellular growth', 'biological_process', 'GO:0016049', ('85', '100'))	('GNB1', 'Gene', (31, 35))	('transformation', 'CPA', (105, 119))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('132', '148'))	('protein', 'Protein', (36, 43))	('kinase inhibitor resistance', 'MPA', (132, 159))	('mutations', 'Var', (14, 23))
62675	29572294	In addition to finding mutation clusters within protein-protein interfaces, the analysis identified a mutation cluster at the interface of the PAX5 transcription factor with DNA, as well as a number of contacts with small ligands, most commonly ATP and GTP.	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('PAX5', 'Gene', '5079', (143, 147))	('mutation', 'Var', (102, 110))	('PAX5', 'Gene', (143, 147))	('transcription factor', 'molecular_function', 'GO:0000981', ('148', '168'))	('DNA', 'cellular_component', 'GO:0005574', ('174', '177'))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('GTP', 'Chemical', 'MESH:D006160', (253, 256))	('ATP', 'Chemical', 'MESH:D000255', (245, 248))	('transcription', 'biological_process', 'GO:0006351', ('148', '161'))
62676	29572294	PAX5 is a known tumor suppressor with a highly conserved DNA-binding motif (Garvie et al, 2001) that is often involved in leukemia development, however, most frequently through translocations.	('leukemia', 'Disease', (122, 130))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('leukemia', 'Disease', 'MESH:D007938', (122, 130))	('tumor suppressor', 'biological_process', 'GO:0051726', ('16', '32'))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('PAX5', 'Gene', (0, 4))	('translocations', 'Var', (177, 191))	('PAX5', 'Gene', '5079', (0, 4))	('involved', 'Reg', (110, 118))	('tumor', 'Disease', (16, 21))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('16', '32'))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('57', '68'))
62677	29572294	Overall, mutation clusters in structural interfaces were able to highlight additional cancer-relevant proteins and protein regions, which can mediate a switch in protein activity and function.	('mutation', 'Var', (9, 17))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('activity', 'MPA', (170, 178))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
62680	29572294	Here, based on the sequencing data for more than 10,000 cancer genomes, we composed a set of most common hotspot mutations with a likely functional effect and characterized these using available structural and interaction data, as well as protein sequence features and residue annotations.	('000 cancer', 'Disease', 'MESH:D009369', (52, 62))	('000 cancer', 'Disease', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (113, 122))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))
62684	29572294	Mechanistically, these mutations tend to disrupt the original protein function, exemplified by the disrupted substrate binding in CREBBP and EP300, or to prevent the activation of a tumor suppressor, exemplified by mutations within the SMAD4 interface or CHEK2 activation loop (Dataset EV5).	('CREBBP', 'Gene', (130, 136))	('disrupted', 'NegReg', (99, 108))	('EP300', 'Gene', (141, 146))	('activation', 'MPA', (166, 176))	('substrate', 'MPA', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('protein', 'Protein', (62, 69))	('SMAD4', 'Gene', (236, 241))	('mutations', 'Var', (215, 224))	('mutations', 'Var', (23, 32))	('CREBBP', 'Gene', '1387', (130, 136))	('prevent', 'NegReg', (154, 161))	('disrupt', 'NegReg', (41, 48))	('CHEK2', 'Gene', (255, 260))	('SMAD4', 'Gene', '4089', (236, 241))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('182', '198'))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('CHEK2', 'Gene', '11200', (255, 260))	('original', 'MPA', (53, 61))	('tumor', 'Disease', (182, 187))	('tumor suppressor', 'biological_process', 'GO:0051726', ('182', '198'))	('EP300', 'Gene', '2033', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
62685	29572294	Alternatively, these mutations can interfere with the oncogene regulation, exemplified by the PIK3R1 interface to PIK3CA.	('PIK3CA', 'Gene', '5290', (114, 120))	('regulation', 'biological_process', 'GO:0065007', ('63', '73'))	('oncogene regulation', 'MPA', (54, 73))	('interfere', 'Reg', (35, 44))	('PIK3R1', 'Gene', '5295', (94, 100))	('PIK3R1', 'Gene', (94, 100))	('PIK3CA', 'Gene', (114, 120))	('mutations', 'Var', (21, 30))
62688	29572294	As more cancer genomes get sequenced, we expect that the list of genes with hotspot mutations will expand.	('mutations', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
62692	29572294	Cancer classification based on molecular data, which include point mutations, copy number variations, and mRNA and protein expression, has proven to be able to recapitulate pathological subtypes and suggest finer subclasses within tumor types (Hoadley et al, 2014).	('point mutations', 'Var', (61, 76))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('copy number variations', 'Var', (78, 100))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', (231, 236))	('mRNA', 'MPA', (106, 110))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))
62693	29572294	Remarkably, here we observed that clustering of tumor types based on a small number of functional hotspot mutations was able to largely mimic the behavior of much more complex molecular datasets.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('mutations', 'Var', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
62698	29572294	Of relevance, many (i.e., 45) of the proteins with hotspot mutations are classified as druggable (Dataset EV12).	('EV1', 'Gene', (106, 109))	('EV1', 'Gene', '11322', (106, 109))	('mutations', 'Var', (59, 68))
62702	29572294	In this way, we detect a number of additional interaction interfaces that are significantly affected by cancer mutations.	('mutations', 'Var', (111, 120))	('affected', 'Reg', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('interaction', 'Interaction', (46, 57))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
62706	29572294	Eventually, a larger catalog of cancer-associated mutations further characterized in vitro and in model organisms would be invaluable for understanding different routes of disease emergence and for identifying therapeutic opportunities.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
62709	29572294	In this study, we used the package on the Pan-cancer data, but with more permissive thresholds, it can also be used for finding hotspot mutations relevant for individual tumor types.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('cancer', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
62718	29572294	Jointly, the analyzed TCGA and ICGC mutation datasets covered 40 different tumor types which spanned 23 tissues of origin.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('TCGA', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ICGC', 'Gene', (31, 35))	('tumor', 'Disease', (75, 80))	('mutation', 'Var', (36, 44))
62720	29572294	A major source of false positives in the set of the identified hotspot mutations is due to common variants that, incorrectly, were not detected in the paired healthy tissue from the same patient.	('false', 'biological_process', 'GO:0071877', ('18', '23'))	('mutations', 'Var', (71, 80))	('false', 'biological_process', 'GO:0071878', ('18', '23'))	('patient', 'Species', '9606', (187, 194))	('variants', 'Var', (98, 106))
62723	29572294	Based on this catalogue, we classified the genes with the identified hotspot mutations as known or candidate cancer driver genes.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))
62724	29572294	Next, through the Ensembl BioMart service (Kinsella et al, 2011), we retrieved predictions for all human genes that are homologous to those with hotspot mutations, and assessed which of these were in the cancer Gene Census or had a hotspot mutation themselves.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('mutations', 'Var', (153, 162))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('human', 'Species', '9606', (99, 104))
62725	29572294	We composed two other sets of genes to which we compared those with hotspot mutations: (i) all other genes in the Cancer Gene Census, that is, excluding those with hotspots and paralogs of genes with hotspot mutations (based on the Ensembl homology assignments) and (ii) all other protein coding genes in the UniProtKB reference set of human proteins (release 2016_06, July 2016), that is, excluding all Cancer Gene Census genes or genes with hotspot mutations.	('Cancer', 'Phenotype', 'HP:0002664', (404, 410))	('Cancer', 'Disease', (404, 410))	('mutations', 'Var', (76, 85))	('Cancer', 'Disease', 'MESH:D009369', (404, 410))	('mutations', 'Var', (208, 217))	('protein', 'cellular_component', 'GO:0003675', ('281', '288'))	('Cancer', 'Disease', (114, 120))	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Cancer', 'Disease', 'MESH:D009369', (114, 120))	('human', 'Species', '9606', (336, 341))
62730	29572294	For all proteins with hotspot mutations, for which X-ray structural data were available, we obtained a representative PDB structure.	('mutations', 'Var', (30, 39))	('PDB', 'Gene', (118, 121))	('PDB', 'Gene', '5131', (118, 121))
62737	29572294	Genes with a high number of the reported deleterious changes (at least 25) and large contribution of these changes to the overall mutation load (the ratio of deleterious over synonymous changes was higher than 0.7) were considered as tumor suppressor candidates.	('changes', 'Var', (53, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('234', '250'))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor suppressor', 'biological_process', 'GO:0051726', ('234', '250'))
62738	29572294	To address whether a mechanism of action for any of the mutations was interference with the activation of tumor suppressors through phosphorylation, we obtained positions of phosphosites in these proteins using the PhosphoSitePlus resource (Hornbeck et al, 2012).	('mutations', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('phosphorylation', 'biological_process', 'GO:0016310', ('132', '147'))	('tumor', 'Disease', (106, 111))
62739	29572294	To compare a fraction of domains that mediate protein interactions among the previously composed sets of genes (genes with hotspot mutations, other genes in the Cancer Gene Census and background human proteins), we obtained domain annotations from the iPfam 1.0 (June 2013) and used chi-squared test in R. Further, we used a Functional Annotation service from the ConsensusPathDB-human database compendium (Kamburov et al, 2013).	('human', 'Species', '9606', (195, 200))	('mutations', 'Var', (131, 140))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('Cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Cancer', 'Disease', (161, 167))	('Cancer', 'Disease', 'MESH:D009369', (161, 167))	('human', 'Species', '9606', (380, 385))
62746	29572294	For each of the identified hotspot mutations, we looked at the individual tumor types and calculated a fraction of patients which had this residue mutated.	('patients', 'Species', '9606', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (35, 44))
62747	29572294	We next drew a heatmap plot where the clustering of tissue types was defined with the pvclust results and where, for the clarity, we reduced the number of the visualized hotspots by including only those mutated in one-third or more of the patients in at least one tumor type.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('mutated', 'Var', (203, 210))	('tumor', 'Disease', (264, 269))	('patients', 'Species', '9606', (239, 247))	('tumor', 'Disease', 'MESH:D009369', (264, 269))
62753	29572294	It was initially developed to identify phosphosites that had a mutation pattern which significantly differed from the gene background mutation rate, while accounting for the differences in mutation rates between structured and disordered protein regions.	('disordered protein', 'Disease', (227, 245))	('disordered protein', 'Disease', 'MESH:D001796', (227, 245))	('protein', 'cellular_component', 'GO:0003675', ('238', '245'))	('mutation', 'Var', (63, 71))
62754	29572294	For the required mutation data, we provided the amino acid changes reported in the above-described TCGA and ICGC datasets, and we specified intrinsically disordered protein regions by using the IUPred tool (Dosztanyi et al, 2005; version 1.0) with the settings for short disorder and a residue disorder prediction threshold of 0.5.	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('short disorder', 'Disease', 'MESH:C537327', (265, 279))	('disordered protein', 'Disease', 'MESH:D001796', (154, 172))	('mutation', 'Var', (17, 25))	('short disorder', 'Disease', (265, 279))	('disordered protein', 'Disease', (154, 172))
62757	29572294	Using as thresholds CNV values > 1 and mRNA z-scores > 2, we looked at the percentages of patients in each tumor type that had the "hotspot genes" amplified and/or overexpressed.	('amplified', 'Var', (147, 156))	('overexpressed', 'PosReg', (164, 177))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('patients', 'Species', '9606', (90, 98))
62780	27495099	Other studies showed that with a cut-off of 20%, a high KI was associated with advanced pathological stage, higher tumor grade, lymphovascular invasion, metastasis, disease recurrence, and stage-adjusted disease-specific mortality in patients with bladder urothelial carcinoma who underwent radical cystectomy.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (248, 276))	('lymphovascular invasion', 'CPA', (128, 151))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('bladder urothelial carcinoma', 'Disease', (248, 276))	('advanced pathological stage', 'CPA', (79, 106))	('high KI', 'Var', (51, 58))	('associated', 'Reg', (63, 73))	('metastasis', 'CPA', (153, 163))	('tumor', 'Disease', (115, 120))	('disease recurrence', 'CPA', (165, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('patients', 'Species', '9606', (234, 242))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
62819	27495099	The intraclass correlation coefficients for a single KI measurement and for the average of 2 KI measurements were 0.987 (95% CI, 0.972-0.994, P < 0.001) and 0.993 (95% CI, 0.986-0.997, P < 0.001) in the whole mount tissue preparations, 0.995 (95% CI, 0.989-0.997, P < 0.001) and 0.997 (95% CI, 0.994-0.999, P < 0.001) in the 1 mm TMA samples, and 0.991 (95% CI, 0.982-0.996, P < 0.001) and 0.996 (95% CI, 0.991-0.998, P < 0.001) in the 0.6 mm TMA samples, respectively.	('men', 'Species', '9606', (63, 66))	('men', 'Species', '9606', (103, 106))	('TMA', 'Chemical', '-', (443, 446))	('0.991', 'Var', (347, 352))	('0.997', 'Var', (279, 284))	('TMA', 'Chemical', '-', (330, 333))
62820	27495099	The intraclass correlation coefficients for a single AI measurement and for the average of 2 AI measurements were 0.989 (95% CI, 0.978-0.995, P < 0.001) and 0.995 (95% CI, 0.989-0.997, P < 0.001) in the whole mount tissue preparations, 0.992 (95% CI, 0.984-0.996, P < 0.001) and 0.996 (95% CI, 0.992-0.998, P < 0.001) in the 1 mm TMA samples, and 0.994 (95% CI, 0.989-0.997, P < 0.001) and 0.997 (95% CI, 0.994-0.999, P < 0.001) in the 0.6 mm TMA samples, respectively.	('men', 'Species', '9606', (63, 66))	('0.996', 'Var', (279, 284))	('men', 'Species', '9606', (103, 106))	('TMA', 'Chemical', '-', (443, 446))	('0.994', 'Var', (347, 352))	('TMA', 'Chemical', '-', (330, 333))	('0.997', 'Var', (390, 395))
62846	27495099	The likely cause of this phenomenon is that smaller samples are influenced by heterogeneous biomarker expression; therefore, much greater numbers of cores from sites containing adequate tumor cells would likely be required to obtain concordant results for WMTPs, 0.6 mm TMAs, and 1 mm TMAs.	('WMTPs', 'Var', (256, 261))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('men', 'Species', '9606', (30, 33))	('TMAs', 'Chemical', '-', (285, 289))	('tumor', 'Disease', (186, 191))	('TMAs', 'Chemical', '-', (270, 274))	('0.6 mm', 'Var', (263, 269))
62854	26992457	Dynamic changes of driver genes' mutations across clinical stages in nine cancer types The driver genes play critical roles for tumorigenesis, and the number of identified driver genes reached plateau.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('roles', 'Reg', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('mutations', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Disease', (74, 80))	('tumor', 'Disease', (128, 133))	('changes', 'Reg', (8, 15))
62856	26992457	We investigated 138 driver genes' mutation changes across clinical stages using 3,477 cases in nine cancer types from the Cancer Genome Atlas (TCGA) and constructed their temporal order relationships.	('Cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutation', 'Var', (34, 42))	('Cancer Genome Atlas', 'Disease', (122, 141))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (122, 141))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
62859	26992457	Across the clinical stages, we categorized three patterns for the behaviors of driver genes' mutation changes in the nine cancer types: recurrently mutated in all the stages and triggering other mutations; certain mutations lost meanwhile other mutations emerged; mutations dominated across entire stages, while other mutations gradually appeared or disappeared.	('mutations', 'MPA', (245, 254))	('cancer', 'Disease', (122, 128))	('lost', 'NegReg', (224, 228))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('mutation', 'Var', (93, 101))
62860	26992457	We observed different codon changes dominated in different stages and revealed mutations recurrently occurring on the hotspot regions of the coding sequence may be the core factor for driver genes' tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('core', 'cellular_component', 'GO:0019013', ('168', '172'))	('mutations', 'Var', (79, 88))
62864	26992457	In contrast, a "passenger" mutation which is often found during cell division has no functional contribution on cancer growth 2.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cell division', 'biological_process', 'GO:0051301', ('62', '75'))	('mutation', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
62866	26992457	One estimation in the lung and colorectal cancers showed that only three driver gene mutations were required for a normal human cell to progress to an advanced cancer 9.	('human', 'Species', '9606', (122, 127))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (160, 166))	('colorectal cancers', 'Disease', 'MESH:D015179', (31, 49))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('mutations', 'Var', (85, 94))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colorectal cancers', 'Disease', (31, 49))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))
62869	26992457	The observation that older patients have more mutations and prediction in certain tumors showing the number of mutations correlated with the age of patients indicate the mutations occurred in cancers were matter of timing 1, 10.	('patients', 'Species', '9606', (148, 156))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (46, 55))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('patients', 'Species', '9606', (27, 35))	('cancers', 'Disease', (192, 199))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
62870	26992457	One best studied example is the temporal order of APC, KRAS, PIK3CA, and TP53 mutations at the transitions between each tumor stage in colorectal cancer 11, 12.	('KRAS', 'Gene', (55, 59))	('PIK3CA', 'Gene', (61, 67))	('TP53', 'Gene', '7157', (73, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('APC', 'cellular_component', 'GO:0005680', ('50', '53'))	('APC', 'Disease', (50, 53))	('PIK3CA', 'Gene', '5290', (61, 67))	('KRAS', 'Gene', '3845', (55, 59))	('TP53', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('colorectal cancer', 'Disease', (135, 152))	('APC', 'Disease', 'MESH:D011125', (50, 53))	('tumor', 'Disease', (120, 125))
62872	26992457	Targeting the key driver mutations according to the tumor stage may make it efficient to inhibit the tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (25, 34))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('inhibit', 'NegReg', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
62873	26992457	However, it is unclear whether the driver gene mutations in other cancer type showed any patterns during the tumorigenesis stages.	('tumor', 'Disease', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutations', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
62875	26992457	Here, we used total 3,477 cases' of exome-seq data across nine cancer types from TCGA to analyze the 138 public-reported driver genes' mutation changes in different stages.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutation changes', 'Var', (135, 151))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
62880	26992457	In general, a total of 18,306 mutated genes harboring 404,863 subtle mutations from the Catalogue of Somatic Mutations in Cancer (COSMIC) database were assessed as driver genes and checked whether they were likely to be oncogenes or tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('mutations', 'Var', (69, 78))	('Cancer', 'Disease', (122, 128))	('tumor', 'Disease', (233, 238))	('Cancer', 'Disease', 'MESH:D009369', (122, 128))	('Cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor suppressor', 'biological_process', 'GO:0051726', ('233', '249'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('233', '249'))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
62881	26992457	If >20% of the recorded mutations in the gene were inactivating, the gene was categorized as a tumor suppressor gene.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mutations', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('inactivating', 'NegReg', (51, 63))	('tumor', 'Disease', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))
62891	26992457	In each cancer type, we merged all the driver genes' mutation into one matrix of genes versus tumor samples with 0/1 entries indicating the absence/presence status of a mutation in a gene for each sample.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Disease', (8, 14))	('mutation', 'Var', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
62894	26992457	We observed that the number of nonsynonymous mutations had no correlation with the clinical stages in all cancer types (Fig.	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('nonsynonymous mutations', 'Var', (31, 54))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
62898	26992457	Given the driver mutations' important roles for cancer progression, we selected those 138 public reported driver genes for study.	('cancer', 'Disease', (48, 54))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))
62899	26992457	The same driver gene mutated in one cancer type may also mutate in other cancer type and also serve as the driver role in that cancer 6, 7, 8.	('mutate', 'Var', (57, 63))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('mutated', 'Var', (21, 28))
62903	26992457	Among these recurrently mutated driver genes, the mutations on TP53 widely mutated.	('mutations', 'Var', (50, 59))	('mutated', 'Reg', (75, 82))	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (63, 67))
62909	26992457	We named this pattern "dominant" meaning there were mutations predominantly occurring among patients across all stages and triggering other mutations.	('mutations', 'Var', (52, 61))	('patients', 'Species', '9606', (92, 100))	('occurring', 'Reg', (76, 85))
62913	26992457	In BRCA, another interesting pattern was observed that mutations on PIK3CA dominated while other mutations greatly changed (Fig.	('PIK3CA', 'Gene', (68, 74))	('BRCA', 'Gene', '672', (3, 7))	('BRCA', 'Gene', (3, 7))	('mutations', 'Var', (55, 64))	('PIK3CA', 'Gene', '5290', (68, 74))
62915	26992457	It has spread to distant organs or to lymph nodes far from the breast (M1), TP53 mutated mostly in patients (patient proportion: 46.7%), even surpassing PIK3CA (patient proportion: 33.3%).	('PIK3CA', 'Gene', '5290', (153, 159))	('patient', 'Species', '9606', (99, 106))	('patient', 'Species', '9606', (109, 116))	('patient', 'Species', '9606', (161, 168))	('TP53', 'Gene', '7157', (76, 80))	('patients', 'Species', '9606', (99, 107))	('mutated', 'Var', (81, 88))	('TP53', 'Gene', (76, 80))	('PIK3CA', 'Gene', (153, 159))
62925	26992457	It has not spread to nearby lymph nodes (N0) or distant sites (M0), mutations on EP300, MLL2, and MLL3 were predominant, while after Stage III these genes faded away (patient proportion: 0), but other genes such as FBXW7, PIK3CA, ERBB2, and ATRX gradually appeared and played one leading role.	('EP300', 'Gene', (81, 86))	('FBXW7', 'Gene', (215, 220))	('PIK3CA', 'Gene', (222, 228))	('EP300', 'Gene', '2033', (81, 86))	('PIK3CA', 'Gene', '5290', (222, 228))	('MLL2', 'Gene', '9757', (88, 92))	('ERBB2', 'Gene', (230, 235))	('MLL3', 'Gene', (98, 102))	('ERBB2', 'Gene', '2064', (230, 235))	('patient', 'Species', '9606', (167, 174))	('MLL2', 'Gene', (88, 92))	('ATRX', 'Gene', (241, 245))	('MLL3', 'Gene', '58508', (98, 102))	('mutations', 'Var', (68, 77))	('FBXW7', 'Gene', '55294', (215, 220))	('ATRX', 'Gene', '546', (241, 245))
62934	26992457	We calculated the number of patients harboring each amino acids changes of TP53 in each stage subgroup and checked the changes across stages.	('patients', 'Species', '9606', (28, 36))	('TP53', 'Gene', '7157', (75, 79))	('amino acids changes', 'Var', (52, 71))	('TP53', 'Gene', (75, 79))
62936	26992457	Some codon changes highly occurred in all stages, such as in BLCA the R248Q mutation.	('R248Q', 'Mutation', 'rs11540652', (70, 75))	('R248Q', 'Var', (70, 75))	('occurred', 'Reg', (26, 34))	('BLCA', 'Disease', (61, 65))
62937	26992457	While in some cancer types like BRCA, R175H mutated mostly among patients in Stage IIA ([T2 N0 M0]: tumor more than 2 cm but not more than 5 cm in greatest dimension [T2], no regional lymph node metastasis [N0], no distant metastasis [M0]), and Stage IIB ([T3, N0, M0]: tumor is larger than 5 cm across but does not grow into the chest wall or skin and has not spread to lymph nodes (T3, N0).	('cancer', 'Disease', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutated', 'Var', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('BRCA', 'Gene', '672', (32, 36))	('R175H', 'Mutation', 'p.R175H', (38, 43))	('R175H mutated', 'Var', (38, 51))	('patients', 'Species', '9606', (65, 73))	('BRCA', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (270, 275))
62938	26992457	The cancer has not spread to distant sites (M0), but R248W took one leading role in Stage IIIC ([any T, N3, M0]: tumor is any size and has spread to 10 or more axillary lymph nodes (N3), the cancer has not spread to distant sites (M0).	('tumor', 'Disease', (113, 118))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('R248W', 'Mutation', 'rs121912651', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('R248W', 'Var', (53, 58))	('cancer', 'Disease', (4, 10))
62939	26992457	Similarly, in LUAD, R280T and E286* in Stage IB ([T2a, N0, M0]: the main tumor is larger than 3 cm across but not larger than 5 cm, has not spread to lymph nodes or distant sites), and D281Y in Stage IIB ([T3, N0, M0]: the main tumor is larger than 7 cm across, and has not spread to lymph nodes or distant sites (Fig.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('R280T', 'Var', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('R280T', 'Mutation', 'rs121912660', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('D281Y', 'Var', (185, 190))	('tumor', 'Disease', (73, 78))	('D281Y', 'Mutation', 'rs764146326', (185, 190))	('tumor', 'Disease', (228, 233))	('E286*', 'Var', (30, 35))	('E286*', 'SUBSTITUTION', 'None', (30, 35))
62941	26992457	All the seven cancer types harbored mutations on these hotspots (Fig.	('cancer', 'Disease', (14, 20))	('harbored', 'Reg', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
62944	26992457	We noticed earlier that in LUAD, TP53 mostly mutated among patients while did not contribute much for cancer development (Fig.	('LUAD', 'Disease', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('TP53', 'Gene', '7157', (33, 37))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('patients', 'Species', '9606', (59, 67))	('TP53', 'Gene', (33, 37))	('mutated', 'Var', (45, 52))
62945	26992457	S6), only three codon changes mostly occurred among patients: R280T, E286*, and D281Y, still these were not the hotspots.	('D281Y', 'Mutation', 'rs764146326', (80, 85))	('E286*', 'Var', (69, 74))	('E286*', 'SUBSTITUTION', 'None', (69, 74))	('R280T', 'Var', (62, 67))	('occurred', 'Reg', (37, 45))	('R280T', 'Mutation', 'rs121912660', (62, 67))	('D281Y', 'Var', (80, 85))	('patients', 'Species', '9606', (52, 60))
62946	26992457	This indicated that the mutations occurred at the hotspots might drive the cancer toward one more aggressive stage.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('drive', 'Reg', (65, 70))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (24, 33))
62947	26992457	In other five cancer types, mutations in these hotspots all occurred mostly among the patients in the corresponding stages.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('occurred', 'Reg', (60, 68))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('mutations', 'Var', (28, 37))	('patients', 'Species', '9606', (86, 94))
62949	26992457	Mutations occurred on other regions may also be recurrent, but they did not contribute much for cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
62951	26992457	Three hotspots were also identified 21, 22: H1047R in the kinase domain, E542K and E545K in the helical domain.	('E542K', 'Var', (73, 78))	('E545K', 'Mutation', 'rs104886003', (83, 88))	('H1047R', 'Var', (44, 50))	('E542K', 'Mutation', 'rs121913273', (73, 78))	('E545K', 'Var', (83, 88))	('H1047R', 'Mutation', 'rs121913279', (44, 50))
62952	26992457	Interestingly, we observed H1047R obviously occurred in Stage IIA ([T2a, N0, M0]: the cancer has not spread into the tissues next to the cervix (called the parametria).	('H1047R', 'Mutation', 'rs121913279', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('occurred', 'Reg', (44, 52))	('H1047R', 'Var', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
62954	26992457	It has not spread to nearby lymph nodes (N0) or distant sites (M0), followed by E545K mutation in BRCA (Fig.	('BRCA', 'Gene', (98, 102))	('E545K', 'Var', (80, 85))	('BRCA', 'Gene', '672', (98, 102))	('E545K', 'Mutation', 'rs104886003', (80, 85))
62963	26992457	In this study, we demonstrated three dynamic patterns for 138 driver genes' mutation behaviors across different clinical stages in the nine cancer types.	('driver genes', 'Gene', (62, 74))	('mutation', 'Var', (76, 84))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
62964	26992457	Additionally, our results of the codon changes of TP53 and PIK3CA revealed different leaderships for codon changes in different stages and indicated that recurrent mutations on hotspot regions of the driver genes coding sequence may be the core factor for tumorigenesis.	('core', 'cellular_component', 'GO:0019013', ('240', '244'))	('TP53', 'Gene', '7157', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('PIK3CA', 'Gene', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('TP53', 'Gene', (50, 54))	('mutations', 'Var', (164, 173))	('tumor', 'Disease', (256, 261))	('PIK3CA', 'Gene', '5290', (59, 65))
62965	26992457	These findings expanded our understanding of the mutations of driver genes and especially their dynamic roles during the progression of cancer that would greatly improve therapeutic strategies for cancer.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('mutations', 'Var', (49, 58))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
62966	26992457	Cancer results from genetic alterations and the mutational landscape is complex.	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('results from', 'Reg', (7, 19))	('genetic alterations', 'Var', (20, 39))
62976	26992457	Previous cancer studies investigated recurrent mutations in cancer and associated them with the function to promote cancer progression 27.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (47, 56))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('promote', 'PosReg', (108, 115))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
62977	26992457	Take the cervical cancer for example, the somatic mutations in PIK3CA, PTEN, TP53, KRAS, EP300, FBXW7, NFE2L2, and so on, were recurrently occurred and have been implicated in the pathogenesis of cervical carcinomas 27.	('implicated', 'Reg', (162, 172))	('KRAS', 'Gene', '3845', (83, 87))	('occurred', 'Reg', (139, 147))	('PTEN', 'Gene', '5728', (71, 75))	('FBXW7', 'Gene', (96, 101))	('cervical carcinomas', 'Disease', (196, 215))	('TP53', 'Gene', (77, 81))	('cancer', 'Disease', (18, 24))	('KRAS', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('pathogenesis', 'biological_process', 'GO:0009405', ('180', '192'))	('PIK3CA', 'Gene', '5290', (63, 69))	('EP300', 'Gene', '2033', (89, 94))	('FBXW7', 'Gene', '55294', (96, 101))	('NFE2L2', 'Gene', '4780', (103, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (205, 215))	('TP53', 'Gene', '7157', (77, 81))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cervical carcinomas', 'Disease', 'MESH:D002575', (196, 215))	('EP300', 'Gene', (89, 94))	('mutations', 'Var', (50, 59))	('PTEN', 'Gene', (71, 75))	('PIK3CA', 'Gene', (63, 69))	('NFE2L2', 'Gene', (103, 109))
62978	26992457	Our data agreed with these important potential driver genes, but we put weight on the EP300, MLL2, and MLL3 for their predominant carcinogenesis roles before Stage III; but in the late Stage IV we mostly focused on the mutations on other genes such as FBXW7, PIK3CA, ERBB2, and ATRX.	('ERBB2', 'Gene', '2064', (267, 272))	('PIK3CA', 'Gene', '5290', (259, 265))	('MLL2', 'Gene', (93, 97))	('MLL3', 'Gene', '58508', (103, 107))	('FBXW7', 'Gene', (252, 257))	('ERBB2', 'Gene', (267, 272))	('ATRX', 'Gene', '546', (278, 282))	('ATRX', 'Gene', (278, 282))	('EP300', 'Gene', '2033', (86, 91))	('EP300', 'Gene', (86, 91))	('PIK3CA', 'Gene', (259, 265))	('MLL3', 'Gene', (103, 107))	('mutations', 'Var', (219, 228))	('MLL2', 'Gene', '9757', (93, 97))	('FBXW7', 'Gene', '55294', (252, 257))
62980	26992457	Interestingly, when we carefully checked the tumor suppressor and oncogene function for the "dominant" or "wave" genes in each cancer type, it is obvious that the tumor suppressor genes mainly mutated in each cancer type.	('tumor suppressor', 'biological_process', 'GO:0051726', ('159', '175'))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor suppressor', 'biological_process', 'GO:0051726', ('45', '61'))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('45', '61'))	('tumor', 'Disease', (45, 50))	('mutated', 'Var', (193, 200))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('159', '175'))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (209, 215))	('tumor', 'Disease', (163, 168))	('cancer', 'Disease', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
62982	26992457	But TP53, one tumor suppressor gene, were most frequently mutated across all stages in this cancer type.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('14', '30'))	('tumor', 'Disease', (14, 19))	('cancer', 'Disease', (92, 98))	('TP53', 'Gene', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutated', 'Var', (58, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('14', '30'))	('TP53', 'Gene', '7157', (4, 8))
62988	26992457	In general, the observation in these nine cancer types indicated the mutation of the tumor suppressor genes appeared more like tumorigenic, and the mutation of the oncogenes seems requiring the combination of the tumor suppressor genes.	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor suppressor', 'biological_process', 'GO:0051726', ('213', '229'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('85', '101'))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('213', '229'))	('tumor', 'Disease', (127, 132))	('mutation', 'Var', (69, 77))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('85', '101'))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('cancer', 'Disease', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
63106	30781730	noted an 85% 5-year CSS in pT0N0 patients which was statistically improved from those with residual disease (31%, p = 0.092).	('patients', 'Species', '9606', (33, 41))	('CSS', 'Chemical', '-', (20, 23))	('pT0', 'Chemical', 'MESH:D010984', (27, 30))	('improved', 'PosReg', (66, 74))	('CSS', 'MPA', (20, 23))	('pT0N0', 'Var', (27, 32))
63120	30781730	The five-year survival rate of pT0 patients was 85%, with a significantly higher median OS compared to those who had residual disease at RC (13.6 years vs. 3.4 years).	('higher', 'PosReg', (74, 80))	('pT0', 'Chemical', 'MESH:D010984', (31, 34))	('patients', 'Species', '9606', (35, 43))	('OS', 'Chemical', '-', (88, 90))	('pT0', 'Var', (31, 34))
63123	30781730	After a median follow-up of eight years, it was noted that there was a 16% reduction in the risk of death and 23% reduction in risk of metastases in patients who received NAC.	('NAC', 'Chemical', '-', (171, 174))	('patients', 'Species', '9606', (149, 157))	('metastases', 'Disease', (135, 145))	('reduction', 'NegReg', (114, 123))	('NAC', 'cellular_component', 'GO:0005854', ('171', '174'))	('metastases', 'Disease', 'MESH:D009362', (135, 145))	('death', 'Disease', 'MESH:D003643', (100, 105))	('reduction', 'NegReg', (75, 84))	('death', 'Disease', (100, 105))	('NAC', 'Var', (171, 174))
63124	30781730	A meta-analysis of these trials demonstrated a 5% improvement in the 5 year survival rate with the addition of NAC compared to surgery alone although it was associated with substantial toxicity.	('NAC', 'cellular_component', 'GO:0005854', ('111', '114'))	('addition', 'Var', (99, 107))	('toxicity', 'Disease', 'MESH:D064420', (185, 193))	('toxicity', 'Disease', (185, 193))	('improvement', 'PosReg', (50, 61))	('NAC', 'Chemical', '-', (111, 114))	('NAC', 'Gene', (111, 114))
63129	30781730	comparing ddMVAC to GC, there was a higher likelihood of downstaging and complete response with patients who received ddMVAC (pT0N0 41.3% vs. 24.5%) with a nonsignificant trend towards improved OS (HR 0.44, p = 0.16).	('pT0', 'Chemical', 'MESH:D010984', (126, 129))	('ddMVAC', 'Var', (118, 124))	('ddMVAC', 'Chemical', '-', (118, 124))	('complete response', 'CPA', (73, 90))	('downstaging', 'CPA', (57, 68))	('OS', 'Chemical', '-', (194, 196))	('patients', 'Species', '9606', (96, 104))	('ddMVAC', 'Chemical', '-', (10, 16))	('GC', 'Chemical', '-', (20, 22))
63149	30781730	In a meta-analysis of patients with micropapillary variant, NAC did result in pathological downstaging in a significant number of patients ranging from 11% to 55%, but this did not translate to better recurrence free survival outcomes.	('micropapillary variant', 'Var', (36, 58))	('patients', 'Species', '9606', (22, 30))	('patients', 'Species', '9606', (130, 138))	('NAC', 'cellular_component', 'GO:0005854', ('60', '63'))	('downstaging', 'NegReg', (91, 102))	('NAC', 'Disease', (60, 63))	('NAC', 'Chemical', '-', (60, 63))
63154	30781730	In a comparison of primary and secondary MIBC patients treated with NAC to those treated with RC alone, NAC increased the chance of pathologic downstaging in primary MIBC with improved RFS but worsened RFS in those with secondary MIBC.	('worsened', 'NegReg', (193, 201))	('NAC', 'Chemical', '-', (68, 71))	('patients', 'Species', '9606', (46, 54))	('NAC', 'cellular_component', 'GO:0005854', ('68', '71'))	('RFS', 'MPA', (185, 188))	('NAC', 'Var', (104, 107))	('MIBC', 'Chemical', '-', (230, 234))	('MIBC', 'Chemical', '-', (41, 45))	('improved', 'PosReg', (176, 184))	('primary MIBC', 'Disease', (158, 170))	('NAC', 'Chemical', '-', (104, 107))	('NAC', 'cellular_component', 'GO:0005854', ('104', '107'))	('MIBC', 'Chemical', '-', (166, 170))	('downstaging', 'NegReg', (143, 154))	('RFS', 'MPA', (202, 205))
63178	30781730	The pathologic T stage was significantly lower in patients receiving NAC compared to those without NAC (37.5% vs. 59.6%).	('patients', 'Species', '9606', (50, 58))	('NAC', 'Var', (69, 72))	('NAC', 'Chemical', '-', (69, 72))	('lower', 'NegReg', (41, 46))	('NAC', 'cellular_component', 'GO:0005854', ('99', '102'))	('NAC', 'cellular_component', 'GO:0005854', ('69', '72'))	('NAC', 'Chemical', '-', (99, 102))
63182	30781730	In fact, delaying RC for NAC in those patients has been shown to worsen their survival outcomes.	('NAC', 'Chemical', '-', (25, 28))	('NAC', 'Gene', (25, 28))	('survival outcomes', 'CPA', (78, 95))	('delaying', 'Var', (9, 17))	('NAC', 'cellular_component', 'GO:0005854', ('25', '28'))	('patients', 'Species', '9606', (38, 46))	('worsen', 'NegReg', (65, 71))
63191	30781730	Germline changes in NER and HR pathways could affect the response to cisplatin-based chemotherapy.	('response to cisplatin-based chemotherapy', 'MPA', (57, 97))	('changes', 'Var', (9, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('NER', 'biological_process', 'GO:0006289', ('20', '23'))	('affect', 'Reg', (46, 52))	('response to cisplatin', 'biological_process', 'GO:0072718', ('57', '78'))	('HR pathways', 'Pathway', (28, 39))
63192	30781730	determined that alterations in one or more of three DNA repair genes, ATM, RB1, and FANCC not only predicted pathologic response but also better overall survival.	('FANCC', 'Gene', '2176', (84, 89))	('FANCC', 'Gene', (84, 89))	('DNA repair', 'biological_process', 'GO:0006281', ('52', '62'))	('alterations', 'Var', (16, 27))	('overall survival', 'CPA', (145, 161))	('RB1', 'Gene', (75, 78))	('ATM', 'Gene', '472', (70, 73))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('better', 'PosReg', (138, 144))	('pathologic response', 'CPA', (109, 128))	('RB1', 'Gene', '5925', (75, 78))	('ATM', 'Gene', (70, 73))	('predicted', 'Reg', (99, 108))
63195	30781730	These alterations were also predictive of improved PFS and OS.	('alterations', 'Var', (6, 17))	('PFS', 'CPA', (51, 54))	('OS', 'Chemical', '-', (59, 61))	('improved', 'PosReg', (42, 50))
63197	30781730	Somatic ERCC2 mutations have been identified in 12% of urothelial carcinomas in the TCGA.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('ERCC2', 'Gene', '2068', (8, 13))	('urothelial carcinomas', 'Disease', (55, 76))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (55, 76))	('ERCC2', 'Gene', (8, 13))	('identified', 'Reg', (34, 44))	('mutations', 'Var', (14, 23))
63200	30781730	In vitro analysis of the ERCC2 mutations suggests that they result in loss of normal NER capacity.	('ERCC2', 'Gene', '2068', (25, 30))	('mutations', 'Var', (31, 40))	('loss', 'NegReg', (70, 74))	('ERCC2', 'Gene', (25, 30))	('NER', 'biological_process', 'GO:0006289', ('85', '88'))
63201	30781730	These findings were confirmed in an independent validation cohort where 8/20 responders (40%) compared to 2/28 nonresponders (7%) had an ERCC2 mutation.	('ERCC2', 'Gene', '2068', (137, 142))	('mutation', 'Var', (143, 151))	('ERCC2', 'Gene', (137, 142))
63203	30781730	demonstrated that ERCC2 missense mutations were more prevalent in primary MIBC (11% primary vs. 1.8% secondary, p = 0.044), which may account for the difference in pathologic downstaging between these two populations.	('MIBC', 'Chemical', '-', (74, 78))	('missense mutations', 'Var', (24, 42))	('ERCC2', 'Gene', (18, 23))	('primary MIBC', 'Disease', (66, 78))	('prevalent', 'Reg', (53, 62))	('ERCC2', 'Gene', '2068', (18, 23))
63206	30781730	Median OS was 168 months in those with low/intermediate BRCA1 levels compared to 34 months in those with high levels of expression and BRCA1 levels were found to be an independent prognostic factor for OS on multivariate analysis.	('OS', 'Chemical', '-', (202, 204))	('OS', 'Chemical', '-', (7, 9))	('BRCA1', 'Gene', '672', (56, 61))	('BRCA1', 'Gene', '672', (135, 140))	('low/intermediate', 'Var', (39, 55))	('BRCA1', 'Gene', (56, 61))	('BRCA1', 'Gene', (135, 140))
63207	30781730	In addition, low/intermediate BRCA1 levels were associated with a higher pathologic response to NAC compared to high levels (66% vs. 22%, p = 0.01).	('BRCA1', 'Gene', (30, 35))	('pathologic response to NAC', 'MPA', (73, 99))	('NAC', 'cellular_component', 'GO:0005854', ('96', '99'))	('NAC', 'Chemical', '-', (96, 99))	('low/intermediate', 'Var', (13, 29))	('higher', 'PosReg', (66, 72))	('BRCA1', 'Gene', '672', (30, 35))
63224	30781730	In a larger cohort of 432 patients after RC, ERCC1 positivity (71.3%) was associated with reduced disease recurrence than ERCC1-negative tumors (DFS 62% vs. 49%).	('ERCC1', 'Gene', (122, 127))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('reduced', 'NegReg', (90, 97))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('positivity', 'Var', (51, 61))	('ERCC1', 'Gene', '2067', (45, 50))	('ERCC1', 'Gene', (45, 50))	('patients', 'Species', '9606', (26, 34))	('ERCC1', 'Gene', '2067', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('disease recurrence', 'CPA', (98, 116))
63227	30781730	In MIBC, downregulation of members of antiapoptotic pathways, such as survivin, Bcl-xL, Rho-GDP dissociation inhibitor, tissue transglutaminase 2, and GADD45 are noted in long-term survivors; si-RNA-mediated knockdown of Bcl-xl and survivin sensitized UCB cell lines to both mitomycin and cisplatin.	('UCB', 'Phenotype', 'HP:0006740', (252, 255))	('GADD45', 'Gene', '1647', (151, 157))	('Bcl-xl', 'Gene', (221, 227))	('sensitized', 'Reg', (241, 251))	('knockdown', 'Var', (208, 217))	('tissue transglutaminase', 'molecular_function', 'GO:0003810', ('120', '143'))	('cisplatin', 'MPA', (289, 298))	('cisplatin', 'Chemical', 'MESH:D002945', (289, 298))	('UCB', 'Chemical', '-', (252, 255))	('MIBC', 'Chemical', '-', (3, 7))	('Bcl-xL', 'Gene', '598', (80, 86))	('RNA', 'cellular_component', 'GO:0005562', ('195', '198'))	('GADD45', 'Gene', (151, 157))	('Bcl-xl', 'Gene', '598', (221, 227))	('Bcl-xL', 'Gene', (80, 86))	('mitomycin', 'MPA', (275, 284))	('si-RNA-mediated', 'Var', (192, 207))	('mitomycin', 'Chemical', 'MESH:D016685', (275, 284))
63228	30781730	Retrospective studies have suggested that alterations in the tumor suppressor gene p53 are an independent prognostic factor for survival in patients treated with NAC, although pathologic response to NAC was not significant.	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('alterations', 'Var', (42, 53))	('NAC', 'Chemical', '-', (199, 202))	('NAC', 'cellular_component', 'GO:0005854', ('162', '165'))	('NAC', 'cellular_component', 'GO:0005854', ('199', '202'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('NAC', 'Chemical', '-', (162, 165))	('tumor suppressor', 'biological_process', 'GO:0051726', ('61', '77'))	('patients', 'Species', '9606', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('61', '77'))	('tumor', 'Disease', (61, 66))
63246	30781730	In an analysis of 178 cancer-associated genes in prechemotherapy TUR specimens by Groenendijk et al., ERBB2 had the highest enrichment for mutations in complete responders compared to nonresponders.	('ERBB2', 'Gene', '2064', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('mutations', 'Var', (139, 148))	('ERBB2', 'Gene', (102, 107))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
63247	30781730	In their discovery and validation cohort combined, ERBB2 missense mutations were seen in 9/38 (24%) complete responders as compared to 0/33 (0%) of nonresponders (p = 0.003).	('missense mutations', 'Var', (57, 75))	('ERBB2', 'Gene', (51, 56))	('ERBB2', 'Gene', '2064', (51, 56))
63256	30781730	In addition, after two years, 65% of those with high MDR1 expression had progressed compared to only 25% of patients with low MDR1 expression.	('MDR1', 'Gene', (53, 57))	('MDR', 'molecular_function', 'GO:0004745', ('126', '129'))	('MDR1', 'Gene', (126, 130))	('MDR1', 'Gene', '5243', (53, 57))	('MDR1', 'Gene', '5243', (126, 130))	('MDR', 'molecular_function', 'GO:0004745', ('53', '56'))	('patients', 'Species', '9606', (108, 116))	('high', 'Var', (48, 52))	('progressed', 'PosReg', (73, 83))
63258	30781730	MDR1 expression was a stronger determinant of patient outcomes in the MVEC arm compared to the CM arm.	('patient', 'Species', '9606', (46, 53))	('MDR', 'molecular_function', 'GO:0004745', ('0', '3'))	('MVEC', 'Var', (70, 74))	('MDR1', 'Gene', (0, 4))	('MDR1', 'Gene', '5243', (0, 4))	('MVEC', 'Chemical', '-', (70, 74))
63269	30781730	Luminal tumors exhibited strong peroxisome proliferator-activated receptor (PPAR) pathway and estrogen receptor (ER) activation as well as activating FGFR3 mutations.	('peroxisome proliferator-activated receptor', 'Gene', '5465', (32, 74))	('peroxisome', 'cellular_component', 'GO:0005777', ('32', '42'))	('Luminal tumors', 'Disease', (0, 14))	('PPAR', 'Gene', (76, 80))	('mutations', 'Var', (156, 165))	('FGFR3', 'Gene', (150, 155))	('peroxisome proliferator-activated receptor', 'Gene', (32, 74))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('estrogen', 'Protein', (94, 102))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('Luminal tumors', 'Disease', 'MESH:D009369', (0, 14))	('activating', 'PosReg', (139, 149))	('PPAR', 'Gene', '5465', (76, 80))	('activation', 'PosReg', (117, 127))	('FGFR', 'molecular_function', 'GO:0005007', ('150', '154'))	('FGFR3', 'Gene', '2261', (150, 155))
63283	30781730	These tumors arise primarily from basal tumors but show significantly increased rates of RB1, EP300, and NCOR1 mutations as well as increased percentage of EGFR mutations and decreased FGFR3 mutations.	('RB1', 'Gene', '5925', (89, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('156', '160'))	('increased', 'PosReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('EP300', 'Gene', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('decreased', 'NegReg', (175, 184))	('tumors', 'Disease', (40, 46))	('mutations', 'Var', (111, 120))	('EGFR', 'Gene', '1956', (156, 160))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (191, 200))	('NCOR1', 'Gene', (105, 110))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('NCOR1', 'Gene', '9611', (105, 110))	('FGFR3', 'Gene', (185, 190))	('tumors', 'Disease', (6, 12))	('RB1', 'Gene', (89, 92))	('basal tumors', 'Phenotype', 'HP:0002671', (34, 46))	('FGFR3', 'Gene', '2261', (185, 190))	('FGFR', 'molecular_function', 'GO:0005007', ('185', '189'))	('basal tumors', 'Disease', (34, 46))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('EGFR', 'Gene', (156, 160))	('EP300', 'Gene', '2033', (94, 99))	('mutations', 'Var', (161, 170))	('basal tumors', 'Disease', 'MESH:D002280', (34, 46))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
63344	25408727	12 patients with divergent differentiation (urothelial and squamous carcinoma) received the indication for adjuvant treatment accordingly to the TNM-G staging: pT1 - 1 case, pT2 - 2 cases, pT3 - 4 cases, pT4 - 5 cases, N0 - 2 cases, N1 - 2 cases, N2 - 5 cases, N3 - 1 case, Nx - 2 cases, G2 - 2 cases, G3 - 11 cases.	('TNM', 'Gene', (145, 148))	('TNM', 'Gene', '10178', (145, 148))	('pT1', 'Gene', '58492', (160, 163))	('pT3', 'Gene', '7694', (189, 192))	('pT2 - 2', 'Var', (174, 181))	('pT3', 'Gene', (189, 192))	('patients', 'Species', '9606', (3, 11))	('urothelial and squamous carcinoma', 'Disease', 'MESH:D002294', (44, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('pT4 - 5 cases', 'Var', (204, 217))	('pT1', 'Gene', (160, 163))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (59, 77))	('N0 - 2', 'Var', (219, 225))
63403	33478005	Cell-cycle dysregulation causing unrestrained cell proliferation has been correlated with UBUC development.	('unrestrained cell proliferation', 'CPA', (33, 64))	('Cell-cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('Cell-cycle', 'CPA', (0, 10))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))	('UBUC', 'Chemical', '-', (90, 94))	('Cell-cycle dysregulation', 'Phenotype', 'HP:0011018', (0, 24))	('dysregulation', 'Var', (11, 24))	('rat', 'Species', '10116', (58, 61))	('UBUC', 'Disease', (90, 94))
63423	33478005	As shown in Figure 1B, after treatment with ABT-751 for 24 h, cell percentages in sub-G1 (p < 0.001) and G2/M (p < 0.001) phases were increased, however, cell percentages in G1 (p < 0.001) and S (p < 0.001) phases were decreased, suggesting that ABT-751 induced apoptosis, G2/M cell cycle arrest and suppressed DNA synthesis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (278, 295))	('ABT-751', 'Var', (246, 253))	('arrest', 'Disease', 'MESH:D006323', (289, 295))	('ABT-751', 'Chemical', 'MESH:C490492', (246, 253))	('DNA synthesis', 'MPA', (311, 324))	('decreased', 'NegReg', (219, 228))	('ABT-751', 'Chemical', 'MESH:C490492', (44, 51))	('DNA', 'cellular_component', 'GO:0005574', ('311', '314'))	('apoptosis', 'biological_process', 'GO:0097194', ('262', '271'))	('arrest', 'Disease', (289, 295))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('278', '295'))	('suppressed', 'NegReg', (300, 310))	('apoptosis', 'biological_process', 'GO:0006915', ('262', '271'))	('induced', 'Reg', (254, 261))	('apoptosis', 'CPA', (262, 271))	('DNA synthesis', 'biological_process', 'GO:0071897', ('311', '324'))	('increased', 'PosReg', (134, 143))
63443	33478005	However, 4 muM of MG132 treatment is more effective to upregulate endogenous CDKN1B protein level (Supplementary Materials Figure S5).	('MG132', 'Chemical', 'MESH:C072553', (18, 23))	('endogenous', 'MPA', (66, 76))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('MG132', 'Var', (18, 23))	('CDKN1B', 'Gene', '1027', (77, 83))	('protein level', 'MPA', (84, 97))	('CDKN1B', 'Gene', (77, 83))	('upregulate', 'PosReg', (55, 65))
63451	33478005	Furthermore, treatment with a PI3K/AKT inhibitor, LY294002 in BFTC905 and J82 cells notably downregulated pAKT1(S473), pCHUK(T23), NFKBIA, pNFKBIA(S32/S36), RELA, SKP2, pSKP2(S72) while it upregulated CDKN1A and CDKN1B protein levels, similar to those that were treated with ABT-751 (Figure 4H).	('CDKN1B', 'Gene', (212, 218))	('CHUK', 'Gene', (120, 124))	('RELA', 'Gene', (157, 161))	('NFKBIA', 'Gene', (131, 137))	('RELA', 'Gene', '5970', (157, 161))	('NFKBIA', 'Gene', '4792', (131, 137))	('CHUK', 'Gene', '1147', (120, 124))	('LY294002', 'Var', (50, 58))	('upregulated', 'PosReg', (189, 200))	('CDKN1A', 'Gene', (201, 207))	('CDKN1A', 'Gene', '1026', (201, 207))	('SKP2', 'Gene', (170, 174))	('SKP2', 'Gene', (163, 167))	('AKT1', 'Gene', '207', (107, 111))	('CDKN1B', 'Gene', '1027', (212, 218))	('SKP2', 'Gene', '6502', (170, 174))	('SKP2', 'Gene', '6502', (163, 167))	('LY294002', 'Chemical', 'MESH:C085911', (50, 58))	('AKT1', 'Gene', (107, 111))	('protein', 'cellular_component', 'GO:0003675', ('219', '226'))	('downregulated', 'NegReg', (92, 105))	('PI3K', 'molecular_function', 'GO:0016303', ('30', '34'))	('ABT-751', 'Chemical', 'MESH:C490492', (275, 282))	('NFKBIA', 'Gene', (140, 146))	('NFKBIA', 'Gene', '4792', (140, 146))
63452	33478005	Moreover, treatment with LY294002 downregulated SKP2 mRNA levels compared to the control, which is comparable to the effect of ABT-751 in BFTC905 cells (Figure 4I).	('LY294002', 'Var', (25, 33))	('SKP2', 'Gene', (48, 52))	('downregulated', 'NegReg', (34, 47))	('LY294002', 'Chemical', 'MESH:C085911', (25, 33))	('ABT-751', 'Chemical', 'MESH:C490492', (127, 134))	('SKP2', 'Gene', '6502', (48, 52))
63458	33478005	The treatment of ABT-751 in SKP2 transfectants for 24 h notably downregulated pSKP2(S72), pSKP2(S64) whereas it upregulated CDKN1A and CDKN1B protein levels (Figure 5A) and downregulated SKP2-induced cell proliferation (p < 0.001, Figure 5B).	('CDKN1A', 'Gene', '1026', (124, 130))	('CDKN1B', 'Gene', '1027', (135, 141))	('SKP2', 'Gene', (187, 191))	('ABT-751', 'Gene', (17, 24))	('SKP2', 'Gene', '6502', (187, 191))	('downregulated', 'NegReg', (64, 77))	('SKP2', 'Gene', (28, 32))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('protein levels', 'MPA', (142, 156))	('ABT-751', 'Chemical', 'MESH:C490492', (17, 24))	('SKP2', 'Gene', '6502', (28, 32))	('rat', 'Species', '10116', (212, 215))	('SKP2', 'Gene', (91, 95))	('cell proliferation', 'biological_process', 'GO:0008283', ('200', '218'))	('SKP2', 'Gene', '6502', (91, 95))	('CDKN1B', 'Gene', (135, 141))	('transfectants', 'Var', (33, 46))	('downregulated', 'NegReg', (173, 186))	('SKP2', 'Gene', (79, 83))	('upregulated', 'PosReg', (112, 123))	('SKP2', 'Gene', '6502', (79, 83))	('CDKN1A', 'Gene', (124, 130))
63472	33478005	Cell cycle dysregulation by downregulation or mutation in a series of CKIs including CDKN1A is a transition event where low-grade non-invasive papillary tumors progress to high-grade invasive UBUCs.	('papillary tumors', 'Phenotype', 'HP:0007482', (143, 159))	('CDKN1A', 'Gene', (85, 91))	('Cell cycle dysregulation', 'CPA', (0, 24))	('CDKN1A', 'Gene', '1026', (85, 91))	('Cell cycle dysregulation', 'Phenotype', 'HP:0011018', (0, 24))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('high-grade invasive UBUCs', 'Disease', (172, 197))	('downregulation', 'NegReg', (28, 42))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('CKI', 'Gene', '1119', (70, 73))	('papillary tumors', 'Disease', 'MESH:D002291', (143, 159))	('CKI', 'Gene', (70, 73))	('UBUC', 'Chemical', '-', (192, 196))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('papillary tumors', 'Disease', (143, 159))	('mutation', 'Var', (46, 54))	('progress', 'PosReg', (160, 168))
63476	33478005	This complex is next translocated to the nucleus to transactivate target genes involving in cell growth including SKP2.	('cell growth', 'biological_process', 'GO:0016049', ('92', '103'))	('transactivate', 'Var', (52, 65))	('nucleus', 'cellular_component', 'GO:0005634', ('41', '48'))	('SKP2', 'Gene', (114, 118))	('SKP2', 'Gene', '6502', (114, 118))
63480	33478005	In the AKT-CHUK-NFKBIA-NFKB pathway, the protein expression pattern treated by ABT-751 was quite similar to that of treatment with a PI3K-AKT inhibitor, LY294002, suggesting that ABT-751 may be also a PI3K-AKT inhibitor.	('LY294002', 'Chemical', 'MESH:C085911', (153, 161))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('NFKBIA-NFKB', 'Gene', (16, 27))	('CHUK', 'Gene', '1147', (11, 15))	('CHUK', 'Gene', (11, 15))	('NFKBIA-NFKB', 'Gene', '4792', (16, 27))	('ABT-751', 'Chemical', 'MESH:C490492', (179, 186))	('PI3K', 'molecular_function', 'GO:0016303', ('201', '205'))	('PI3K', 'molecular_function', 'GO:0016303', ('133', '137'))	('CHUK', 'molecular_function', 'GO:0008384', ('11', '15'))	('ABT-751', 'Chemical', 'MESH:C490492', (79, 86))	('ABT-751', 'Var', (79, 86))
63482	33478005	Recent biochemical experiments disclosed that SKP2 can be phosphorylated by AKT1 and CDK2 or MTOR at residues S72 and S64.	('MTOR', 'Gene', (93, 97))	('S64', 'Var', (118, 121))	('MTOR', 'Gene', '2475', (93, 97))	('SKP2', 'Gene', (46, 50))	('CDK2', 'Gene', '1017', (85, 89))	('CDK', 'molecular_function', 'GO:0004693', ('85', '88'))	('AKT1', 'Gene', '207', (76, 80))	('AKT1', 'Gene', (76, 80))	('SKP2', 'Gene', '6502', (46, 50))	('CDK2', 'Gene', (85, 89))
63494	33478005	Loss of CDH1 function is believed to confer tumorigenicity by increasing proliferation, invasion, and/or metastasis.	('invasion', 'CPA', (88, 96))	('proliferation', 'CPA', (73, 86))	('rat', 'Species', '10116', (80, 83))	('metastasis', 'Disease', 'MESH:D009362', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('CDH1', 'Gene', (8, 12))	('increasing', 'PosReg', (62, 72))	('metastasis', 'Disease', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('CDH1', 'Gene', '999', (8, 12))	('Loss', 'Var', (0, 4))	('tumor', 'Disease', (44, 49))
63502	33478005	We further identified that intrinsic and extrinsic apoptosis were rapidly induced after ABT-751 treatments in two distinct UBUC-derived cells, accompanied with alteration on the expression levels of specific markers.	('extrinsic apoptosis', 'biological_process', 'GO:0097191', ('41', '60'))	('expression levels', 'MPA', (178, 195))	('ABT-751', 'Gene', (88, 95))	('alteration', 'Reg', (160, 170))	('ABT-751', 'Chemical', 'MESH:C490492', (88, 95))	('UBUC', 'Chemical', '-', (123, 127))	('rat', 'Species', '10116', (164, 167))	('treatments', 'Var', (96, 106))	('induced', 'PosReg', (74, 81))
63509	33478005	However, difference in overall survival (p = 0.034, log-rank; median 3.3 vs. 8.1 months) favored ABT-751 in the squamous NSCLC subgroup.	('ABT-751', 'Var', (97, 104))	('ABT-751', 'Chemical', 'MESH:C490492', (97, 104))	('squamous NSCLC', 'Disease', (112, 126))	('squamous NSCLC', 'Disease', 'MESH:D002294', (112, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
63516	33478005	ABT-751 inhibited SKP2 protein level was ubiquitin-proteasome-irrelevant, however, it suppressed SKP2 at both transcriptional and post-translational levels through the AKT-CHUK-NFKBIA-NFKB (RELA) axis and acted like a PI3K-AKT inhibitor.	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('proteasome', 'cellular_component', 'GO:0000502', ('51', '61'))	('post', 'Gene', (130, 134))	('NFKBIA-NFKB', 'Gene', (177, 188))	('ubiquitin', 'molecular_function', 'GO:0031386', ('41', '50'))	('PI3K', 'molecular_function', 'GO:0016303', ('218', '222'))	('ABT-751', 'Var', (0, 7))	('suppressed', 'NegReg', (86, 96))	('SKP2', 'Gene', (18, 22))	('SKP2', 'Gene', (97, 101))	('CHUK', 'Gene', (172, 176))	('SKP2', 'Gene', '6502', (18, 22))	('SKP2', 'Gene', '6502', (97, 101))	('ABT-751', 'Chemical', 'MESH:C490492', (0, 7))	('CHUK', 'Gene', '1147', (172, 176))	('post', 'Gene', '159371', (130, 134))	('inhibited', 'NegReg', (8, 17))	('NFKBIA-NFKB', 'Gene', '4792', (177, 188))	('proteasome', 'molecular_function', 'GO:0004299', ('51', '61'))	('RELA', 'Gene', (190, 194))	('RELA', 'Gene', '5970', (190, 194))	('CHUK', 'molecular_function', 'GO:0008384', ('172', '176'))
63519	33478005	Both cell lines were maintained in a humidified incubator with 5% CO2 at 37  C. The BFTC905 and J82 cell lines were characterized to embrace a wild type and multiple mutations of the tumor protein p53 (TP53) gene, respectively.	('TP53', 'Gene', (202, 206))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('mutations', 'Var', (166, 175))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('CO2', 'Chemical', 'MESH:D002245', (66, 69))	('p53', 'Gene', (197, 200))	('p53', 'Gene', '7157', (197, 200))	('tumor', 'Disease', (183, 188))	('TP53', 'Gene', '7157', (202, 206))
63532	33478005	The incubation periods were 7 days after treatment with DMSO (control) or ABT-751 (BFTC905, 0.6 muM and J82, 0.7 muM).	('BFTC905', 'Var', (83, 90))	('ABT-751', 'Gene', (74, 81))	('ABT-751', 'Chemical', 'MESH:C490492', (74, 81))	('J82', 'Var', (104, 107))	('DMSO', 'Chemical', 'MESH:D004121', (56, 60))
63545	33478005	Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was applied to quantify the mRNA expression levels of several genes using predesigned TaqMan  reagents from ThermoFisher (SKP2: Hs01021864_m1 (59 bp); TP53: Hs01034249_m1 (108 bp); CDKN1A: Hs00355782_m1 (66 bp); CDKN1B: Hs01597588_m1 (151 bp); RB1: Hs01078066_m1 (72 bp); E2F1: Hs00153451_m1 (84 bp); TFDP1: Hs00955488_g1 (102 bp); glyceraldehyde-3-phosphate dehydrogenase (GAPDH): Hs02758991_g1 (93 bp); CD44 molecule, Indian blood group (CD44): Hs01075861_m1 (70 bp); cadherin 1 (CDH1): Hs01023895_m1 (80 bp); vimentin (VIM): Hs00185584_m1 (73 bp); MTOR: Hs00234508_m1 (103 bp)) along with LightCycler  96 System (Roche, Basel, Switzerland) and DeltaDeltaCT calculation.	('CD44', 'Gene', (510, 514))	('TFDP1', 'Gene', '7027', (371, 376))	('VIM', 'Gene', (592, 595))	('CDKN1B', 'Gene', (282, 288))	('CDKN1A', 'Gene', '1026', (251, 257))	('E2F1', 'Gene', (342, 346))	('MTOR', 'Gene', (621, 625))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (402, 442))	('MTOR', 'Gene', '2475', (621, 625))	('CDH1', 'Gene', '999', (552, 556))	('vimentin', 'cellular_component', 'GO:0045098', ('582', '590'))	('TP53', 'Gene', '7157', (221, 225))	('vimentin', 'Gene', '7431', (582, 590))	('E2F1', 'Gene', '1869', (342, 346))	('cadherin', 'molecular_function', 'GO:0008014', ('540', '548'))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (402, 442))	('vimentin', 'Gene', (582, 590))	('GAPDH', 'Gene', '2597', (444, 449))	('CDH1', 'Gene', (552, 556))	('SKP2', 'Gene', (192, 196))	('cadherin 1', 'Gene', '999', (540, 550))	('CDKN1B', 'Gene', '1027', (282, 288))	('Hs00185584_m1', 'Var', (598, 611))	('DeltaCT', 'Mutation', 'c.delCT', (722, 729))	('TFDP1', 'Gene', (371, 376))	('SKP2', 'Gene', '6502', (192, 196))	('RB1', 'Gene', (314, 317))	('GAPDH', 'Gene', (444, 449))	('CD44', 'Gene', '960', (475, 479))	('RB1', 'Gene', '5925', (314, 317))	('CD44', 'Gene', (475, 479))	('vimentin', 'cellular_component', 'GO:0045099', ('582', '590'))	('Hs01023895_m1', 'Var', (559, 572))	('reverse transcription', 'biological_process', 'GO:0001171', ('13', '34'))	('CDKN1A', 'Gene', (251, 257))	('TP53', 'Gene', (221, 225))	('cadherin 1', 'Gene', (540, 550))	('VIM', 'Gene', '7431', (592, 595))	('CD44', 'Gene', '960', (510, 514))	('Hs00234508_m1', 'Var', (627, 640))
63547	33478005	The relative expression folds of target transcripts were given by 2-DeltaDeltaCT, where DeltaDeltaCT = DeltaCT(treatment) - DeltaCT(control).	('DeltaCT', 'Mutation', 'c.delCT', (73, 80))	('DeltaCT', 'Mutation', 'c.delCT', (93, 100))	('DeltaCT', 'Mutation', 'c.delCT', (103, 110))	('DeltaDeltaCT', 'Var', (88, 100))	('DeltaCT', 'Var', (103, 110))	('DeltaCT', 'Mutation', 'c.delCT', (124, 131))
63556	33478005	Two plasmids, pCMV10-3xFlag-SKP2(WT) (#81115) and pHRIG-AKT1 (#53583, constitutive expression of the active AKT1 gene), were obtained from addgene (Watertown, MA, USA).	('SKP2', 'Gene', (28, 32))	('AKT1', 'Gene', '207', (108, 112))	('#53583', 'Var', (62, 68))	('AKT1', 'Gene', '207', (56, 60))	('AKT1', 'Gene', (108, 112))	('SKP2', 'Gene', '6502', (28, 32))	('AKT1', 'Gene', (56, 60))
63568	29180607	While these events appeared to arise early in all affected tumors and likely reflect an evolutionary branch point that may have driven small cell lineage differentiation, they were unlikely the founding transforming event, as they were often preceded by diverse and less common driver mutations, many of which are common in bladder urothelial cancers but not small cell lung tumors.	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('small cell lineage differentiation', 'CPA', (135, 169))	('mutations', 'Var', (285, 294))	('small cell lung tumors', 'Phenotype', 'HP:0030357', (359, 381))	('bladder urothelial cancers', 'Disease', (324, 350))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('cancers', 'Phenotype', 'HP:0002664', (343, 350))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('lung tumors', 'Phenotype', 'HP:0100526', (370, 381))	('lung tumors', 'Disease', (370, 381))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumors', 'Disease', (375, 381))	('tumors', 'Disease', 'MESH:D009369', (375, 381))	('bladder urothelial cancers', 'Disease', 'MESH:D001749', (324, 350))	('tumors', 'Phenotype', 'HP:0002664', (375, 381))	('lung tumors', 'Disease', 'MESH:D008175', (370, 381))
63570	29180607	While arising at different chronological points in the evolution of the disease, GD was often preceded by biallelic mutations in TP53 with retention of two intact copies.	('preceded', 'Reg', (94, 102))	('TP53', 'Gene', '7157', (129, 133))	('biallelic mutations', 'Var', (106, 125))	('retention', 'biological_process', 'GO:0051235', ('139', '148'))	('TP53', 'Gene', (129, 133))
63597	29180607	Mutations and CNAs in either 281 or 341 genes were also profiled (in 17 and 41 additional patients respectively) using a solution-phase hybridization-based exon capture and deep sequencing assay as previously described (Supplementary Tables 1-2).	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (90, 98))	('men', 'Species', '9606', (226, 229))	('341', 'Gene', (36, 39))
63601	29180607	These transcriptome data were utilized for fusion detection, mutation cross-validation, and exploring RB1 dysfunction in presumed RB1-wildtype tumors.	('RB1 dysfunction', 'Disease', 'MESH:D012175', (102, 117))	('RB1', 'Gene', '5925', (102, 105))	('RB1', 'Gene', '5925', (130, 133))	('RB1 dysfunction', 'Disease', (102, 117))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('mutation', 'Var', (61, 69))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('RB1', 'Gene', (130, 133))	('RB1', 'Gene', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
63618	29180607	The purity and integer copy number results from FACETS analysis, along with coverage levels and allele frequencies, were used to estimate the fraction of cancer cells harboring each mutation (cancer cell fraction, CCF) in all evaluable specimens (n=77).	('men', 'Species', '9606', (241, 244))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cell fraction', 'cellular_component', 'GO:0000267', ('199', '212'))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('mutation', 'Var', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
63619	29180607	The timing of emergence of GD relative to somatic mutations was estimated by applying a Gaussian mixture model to the allele fractions of somatic mutations in genomic regions of balanced tetraploidy in 10 tumors for which a sufficient number of such mutations were present (>=20).	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('mutations', 'Var', (146, 155))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('mutations', 'Var', (250, 259))	('tumors', 'Disease', (205, 211))
63620	29180607	The number of copies of each mutation per cancer cell, and therefore timing relative to GD, was estimated when there was sufficient separation between component allele fraction distributions per sample.	('mutation', 'Var', (29, 37))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))
63623	29180607	As the estimated tumor purity was similar, for all mutations shared between the two cell populations in regions that lacked CNAs, we determined the mode of the distribution of the ratio of allele frequencies between the small cell and other histologic population.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (17, 22))
63627	29180607	Whole-exome and/or genome sequencing of the tumor and matched normal specimens from 17 patients revealed a high somatic mutational burden (median of 10.7 mutations per million bases (Mb) sequenced) that was significantly greater than other genitourinary cancers (Fig.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('genitourinary cancers', 'Disease', 'MESH:D014565', (240, 261))	('mutational', 'Var', (120, 130))	('men', 'Species', '9606', (74, 77))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (87, 95))	('genitourinary cancers', 'Disease', (240, 261))	('tumor', 'Disease', (44, 49))
63629	29180607	Indeed, 95% of these patients harbored evidence of an APOBEC-mediated mutational process that accounted for a median of 60 +- 23.7% of all somatic mutations in each patient (Fig.	('mutations', 'Var', (147, 156))	('patient', 'Species', '9606', (21, 28))	('APOBEC-mediated', 'Gene', (54, 69))	('patient', 'Species', '9606', (165, 172))	('patients', 'Species', '9606', (21, 29))	('APOBEC', 'cellular_component', 'GO:0030895', ('54', '60'))
63630	29180607	This APOBEC-driven mutational signature (predominantly C>G or C>T mutations at the TCW trinucleotide context) was observed to a lesser degree in bladder urothelial carcinoma (UC), but was largely absent from small cell lung cancers, despite a shared risk factor of past smoking history in all three cancer types (Fig.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (145, 173))	('C>T mutations', 'Var', (62, 75))	('APOBEC', 'cellular_component', 'GO:0030895', ('5', '11'))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('lung cancers', 'Phenotype', 'HP:0100526', (219, 231))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('cancer', 'Disease', (224, 230))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (208, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('APOBEC-driven', 'Gene', (5, 18))	('C>G', 'Var', (55, 58))	('small cell lung cancers', 'Disease', 'MESH:D055752', (208, 231))	('small cell lung cancers', 'Disease', (208, 231))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (208, 231))	('trinucleotide', 'Chemical', '-', (87, 100))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('cancer', 'Disease', (299, 305))	('lung cancer', 'Phenotype', 'HP:0100526', (219, 230))	('bladder urothelial carcinoma', 'Disease', (145, 173))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))
63631	29180607	Endogenous mutational processes other than APOBEC were present in a subset of samples including two patients with a mutational signature associated with polymerase eta/activation-induced cytidine deaminase (AID) defects.	('APOBEC', 'cellular_component', 'GO:0030895', ('43', '49'))	('AID', 'Gene', (207, 210))	('AID', 'Gene', '57379', (207, 210))	('patients', 'Species', '9606', (100, 108))	('defects', 'Var', (212, 219))
63635	29180607	Mutations in these genes co-occurred in 80% of all tumors, a pattern that is consistent with small cell lung cancers and underscores the importance of G1- to S-phase cell-cycle dysregulation in small cell cancers independent of their organ of origin.	('small cell cancers', 'Disease', 'MESH:D055752', (194, 212))	('small cell cancers', 'Disease', (194, 212))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('small cell lung cancers', 'Disease', 'MESH:D055752', (93, 116))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (93, 116))	('small cell lung cancers', 'Disease', (93, 116))	('S-phase', 'biological_process', 'GO:0051320', ('158', '165'))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('Mutations', 'Var', (0, 9))	('cell-cycle', 'biological_process', 'GO:0007049', ('166', '176'))	('lung cancers', 'Phenotype', 'HP:0100526', (104, 116))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('small cell cancer', 'Phenotype', 'HP:0030357', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (93, 115))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('co-occurred', 'Reg', (25, 36))	('tumors', 'Disease', (51, 57))
63637	29180607	We confirmed with immunohistochemistry in two additional RB1-wildtype patients that these tumors did not express the retinoblastoma protein (RB) (Supplementary Figure 1), suggesting the presence of occult lesions or epigenetic silencing as the basis for RB1 inactivation in such cases.	('retinoblastoma', 'Disease', 'MESH:D012175', (117, 131))	('retinoblastoma', 'Disease', (117, 131))	('RB1', 'Gene', (254, 257))	('RB1', 'Gene', '5925', (57, 60))	('patients', 'Species', '9606', (70, 78))	('epigenetic silencing', 'Var', (216, 236))	('occult lesions', 'Disease', (198, 212))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('RB1', 'Gene', '5925', (254, 257))	('men', 'Species', '9606', (152, 155))	('occult lesions', 'Disease', 'MESH:D005596', (198, 212))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('retinoblastoma', 'Phenotype', 'HP:0009919', (117, 131))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('RB1', 'Gene', (57, 60))
63638	29180607	SCCBs also had a much higher rate of biallelic mutation in these genes compared to urothelial tumors (Supplementary Figure 2).	('biallelic mutation', 'Var', (37, 55))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('men', 'Species', '9606', (108, 111))	('urothelial tumors', 'Disease', 'MESH:D001749', (83, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('SCCBs', 'Disease', (0, 5))	('urothelial tumors', 'Disease', (83, 100))
63639	29180607	However, 12% of histologically confirmed urothelial bladder cancers also harbored co-occurring alterations in TP53 and RB1 suggesting that mutations in one or both of these genes are necessary but not sufficient for the development of the small cell phenotype.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('men', 'Species', '9606', (227, 230))	('bladder cancers', 'Phenotype', 'HP:0009725', (52, 67))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('alterations', 'Var', (95, 106))	('urothelial bladder cancers', 'Disease', (41, 67))	('RB1', 'Gene', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('RB1', 'Gene', '5925', (119, 122))	('urothelial bladder cancers', 'Disease', 'MESH:D001749', (41, 67))
63640	29180607	Targeted sequencing of 341 key cancer-associated genes at high depth of coverage in 46 additional SCCB confirmed these coincident mutations and further revealed that 95% of SCCB harbor TERT promoter mutations that are also present less frequently in 70% of urothelial tumors (prospective cohort, see Methods; p-value < 1.6x10-4 Fisher exact test), but that are absent from other small cell cancer types including small cell lung cancers.	('urothelial tumors', 'Disease', 'MESH:D001749', (257, 274))	('cancer', 'Disease', (429, 435))	('cancer', 'Phenotype', 'HP:0002664', (429, 435))	('lung cancer', 'Phenotype', 'HP:0100526', (424, 435))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('lung cancers', 'Phenotype', 'HP:0100526', (424, 436))	('cancer', 'Disease', (390, 396))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('cancers', 'Phenotype', 'HP:0002664', (429, 436))	('cancer', 'Phenotype', 'HP:0002664', (390, 396))	('cancer', 'Disease', (31, 37))	('SCCB', 'Gene', (173, 177))	('small cell cancer', 'Phenotype', 'HP:0030357', (379, 396))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (413, 435))	('cancer', 'Disease', 'MESH:D009369', (429, 435))	('TERT', 'Gene', (185, 189))	('TERT', 'Gene', '7015', (185, 189))	('small cell lung cancers', 'Disease', 'MESH:D055752', (413, 436))	('urothelial tumors', 'Disease', (257, 274))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (413, 436))	('small cell lung cancers', 'Disease', (413, 436))	('cancer', 'Disease', 'MESH:D009369', (390, 396))	('mutations', 'Var', (130, 139))	('cancer', 'Disease', 'MESH:D009369', (31, 37))
63641	29180607	Combining the unbiased and targeted sequencing cohorts, we found that recurrent mutations in diverse epigenetic modifiers (KDM6A, ARID1A, CREBBP, EP300, KMT2A/C/D) were present in most SCCB patients (74%, n=45 of 61), a mutational frequency of these genes similar to that observed in UC.	('ARID1A', 'Gene', '8289', (130, 136))	('ARID1A', 'Gene', (130, 136))	('KMT2A', 'Gene', (153, 158))	('KDM6A', 'Gene', (123, 128))	('mutations', 'Var', (80, 89))	('patients', 'Species', '9606', (190, 198))	('CREBBP', 'Gene', '1387', (138, 144))	('KMT2A', 'Gene', '4297', (153, 158))	('EP300', 'Gene', (146, 151))	('EP300', 'Gene', '2033', (146, 151))	('KDM6A', 'Gene', '7403', (123, 128))	('SCCB', 'Disease', (185, 189))	('CREBBP', 'Gene', (138, 144))
63642	29180607	Mutations in these chromatin modifying genes were, however, uncommon in small cell lung cancers (p-value < 10-6, Fisher exact test; Fig.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (72, 94))	('small cell lung cancers', 'Disease', (72, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('Mutations', 'Var', (0, 9))	('chromatin', 'cellular_component', 'GO:0000785', ('19', '28'))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('small cell lung cancers', 'Disease', 'MESH:D055752', (72, 95))	('lung cancers', 'Phenotype', 'HP:0100526', (83, 95))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (72, 95))
63646	29180607	Focal homozygous and heterozygous deletions of the RB1 and TP53 loci were the most frequent CNAs, contributing to biallelic alterations.	('RB1', 'Gene', (51, 54))	('TP53', 'Gene', '7157', (59, 63))	('TP53', 'Gene', (59, 63))	('biallelic alterations', 'MPA', (114, 135))	('deletions', 'Var', (34, 43))	('RB1', 'Gene', '5925', (51, 54))	('contributing', 'Reg', (98, 110))
63647	29180607	Focal CDKN2A deletions and CCND1 amplifications, while common in UC, were absent from SCCB (p-values = 0.02 and 0.0005, Fisher exact test).	('CCND1', 'Gene', '595', (27, 32))	('deletions', 'Var', (13, 22))	('CDKN2A', 'Gene', (6, 12))	('CCND1', 'Gene', (27, 32))	('CDKN2A', 'Gene', '1029', (6, 12))
63650	29180607	Moreover, the presence of E2F3 amplifications in RB1-null tumors indicates that the former may confer an additional growth advantage or that these effectors have organ-, rather than cell-type-specific non-redundant roles, despite their shared regulation of the G1 to S-phase transition of the cell cycle.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('S-phase', 'biological_process', 'GO:0051320', ('267', '274'))	('RB1', 'Gene', (49, 52))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('RB1', 'Gene', '5925', (49, 52))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('regulation', 'biological_process', 'GO:0065007', ('243', '253'))	('amplifications', 'Var', (31, 45))	('growth advantage', 'CPA', (116, 132))	('E2F3', 'Gene', '1871', (26, 30))	('E2F3', 'Gene', (26, 30))	('cell cycle', 'biological_process', 'GO:0007049', ('293', '303'))
63653	29180607	Indeed, 5p genomic gains targeted the wildtype allele of TERT in four tumors, indicating that there is a selective pressure for 5p gains beyond elevating expression of mutant TERT, perhaps targeting another oncogene on the chromosome arm.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mutant', 'Var', (168, 174))	('TERT', 'Gene', (57, 61))	('TERT', 'Gene', (175, 179))	('TERT', 'Gene', '7015', (57, 61))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('TERT', 'Gene', '7015', (175, 179))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('223', '233'))	('elevating', 'PosReg', (144, 153))	('expression', 'MPA', (154, 164))
63657	29180607	Whereas GD has been associated with TP53 mutations in other tumor types, GD was more common in SCCBs with missense rather than loss-of-function TP53 mutations (nonsense, frameshift, splice site, and homozygous deletions; p-value < 10-4, Fisher exact test; Fig.	('mutations', 'Var', (41, 50))	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (144, 148))	('missense', 'Var', (106, 114))	('mutations', 'Var', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('TP53', 'Gene', '7157', (36, 40))	('frameshift', 'Var', (170, 180))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('TP53', 'Gene', (36, 40))	('tumor', 'Disease', (60, 65))	('SCCBs', 'Disease', (95, 100))
63658	29180607	Moreover, there appeared to be selection for biallelic alteration of TP53 missense-mutant GD-positive tumors.	('GD-positive tumors', 'Disease', (90, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('missense-mutant', 'Var', (74, 89))	('GD-positive tumors', 'Disease', 'MESH:D005776', (90, 108))	('biallelic alteration', 'Var', (45, 65))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
63659	29180607	Among tumors with TP53 biallelic mutation, a single mutation followed by copy-neutral loss-of-heterozygosity (CN-LOH) predominated (Fig.	('TP53', 'Gene', '7157', (18, 22))	('biallelic mutation', 'Var', (23, 41))	('loss-of-heterozygosity', 'NegReg', (86, 108))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('TP53', 'Gene', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
63661	29180607	Notably, in GD-positive tumors from three patients in which the two independent TP53 mutations could be phased, we confirmed they were present in trans (Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('GD-positive tumors', 'Disease', (12, 30))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('mutations', 'Var', (85, 94))	('GD-positive tumors', 'Disease', 'MESH:D005776', (12, 30))	('patients', 'Species', '9606', (42, 50))
63663	29180607	In 10 tumors harboring sufficient somatic mutations (>=20) in regions of balanced tetraploidy for the timing analysis, we found that GD arose at various points in molecular time relative to other somatic mutations (Fig.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('mutations', 'Var', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
63667	29180607	In other patients, the APOBEC-associated mutational process produced most somatic mutations early, but ebbed as the tumor evolved after GD.	('patients', 'Species', '9606', (9, 17))	('APOBEC-associated', 'Gene', (23, 40))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('APOBEC', 'cellular_component', 'GO:0030895', ('23', '29'))	('tumor', 'Disease', (116, 121))	('mutational', 'Var', (41, 51))
63668	29180607	Integrating these chronological analyses in a representative SCCB (patient 61), we found that the cardinal TP53, RB1, and TERT promoter mutations all arose very early in molecular time.	('TERT', 'Gene', (122, 126))	('TERT', 'Gene', '7015', (122, 126))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('RB1', 'Gene', (113, 116))	('mutations', 'Var', (136, 145))	('RB1', 'Gene', '5925', (113, 116))	('patient', 'Species', '9606', (67, 74))
63669	29180607	RB1 and PTEN biallelic inactivation evolved from truncating mutations after which heterozygous losses targeted the wildtype allele occurred.	('RB1', 'Gene', '5925', (0, 3))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('biallelic', 'Var', (13, 22))	('truncating mutations', 'Var', (49, 69))	('RB1', 'Gene', (0, 3))
63670	29180607	Conversely, a TP53 E285K missense mutation was followed by CN-LOH resulting in two copies of the mutant allele after which GD arose, increasing the mutant allele burden of all four of these genes (Fig.	('E285K', 'Mutation', 'rs112431538', (19, 24))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('increasing', 'PosReg', (133, 143))	('mutant allele burden', 'MPA', (148, 168))	('E285K missense mutation', 'Var', (19, 42))
63674	29180607	By comparing the mutations common among, or specific to, multiple histologically distinct regions of mixed-histology tumors presumably originating from a single common ancestor, we can draw inferences on the timing of their emergence and their phylogenetic origins.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('mutations', 'Var', (17, 26))
63676	29180607	In one patient, a single CREBBP L1458* nonsense mutation was clonal in both the small cell and urothelial cell populations (Fig.	('CREBBP', 'Gene', '1387', (25, 31))	('patient', 'Species', '9606', (7, 14))	('L1458*', 'SUBSTITUTION', 'None', (32, 38))	('CREBBP', 'Gene', (25, 31))	('L1458*', 'Var', (32, 38))
63678	29180607	Conversely, several mutations including KDM6A E1102K were present exclusively in the urothelial component, a finding that is consistent with the increased frequency of KDM6A mutations in UC overall compared to SCCB (Fig.	('KDM6A', 'Gene', (168, 173))	('KDM6A', 'Gene', '7403', (40, 45))	('KDM6A', 'Gene', '7403', (168, 173))	('KDM6A', 'Gene', (40, 45))	('E1102K', 'Var', (46, 52))	('E1102K', 'Mutation', 'rs1453322733', (46, 52))
63679	29180607	In the other patient, both a TERT promoter mutation (-145/C>T) and a PIK3CA Q546P hotspot mutation, along with several others, were clonal in both the small cell and urothelial (papillary) tumor components arising prior to the cellular differentiation program that defined the two histologies (Supplementary Figure 6).	('TERT', 'Gene', '7015', (29, 33))	('tumor', 'Disease', (189, 194))	('-145/C>T', 'Mutation', 'c.-145C>T', (53, 61))	('patient', 'Species', '9606', (13, 20))	('men', 'Species', '9606', (300, 303))	('-145/C>T', 'Var', (53, 61))	('Q546P', 'Mutation', 'rs397517201', (76, 81))	('PIK3CA', 'Gene', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('PIK3CA', 'Gene', '5290', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('TERT', 'Gene', (29, 33))
63680	29180607	On the other hand, the small cell component again exclusively possessed RB1 and TP53 mutations, whereas the papillary population possessed a clonal activating ERBB2 L755S mutation.	('L755S', 'Mutation', 'rs121913470', (165, 170))	('RB1', 'Gene', (72, 75))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('mutations', 'Var', (85, 94))	('RB1', 'Gene', '5925', (72, 75))	('ERBB2', 'Gene', (159, 164))	('ERBB2', 'Gene', '2064', (159, 164))	('L755S', 'Var', (165, 170))
63681	29180607	These results reaffirm the nearly obligate emergence of RB1 and TP53 mutations in SCCB, but also indicate that these two cardinal events are not the founder mutations necessary for initial transformation and clonal outgrowth of a histologically distinct bladder tumor cell population (Fig.	('mutations', 'Var', (69, 78))	('SCCB', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('RB1', 'Gene', (56, 59))	('bladder tumor', 'Disease', (254, 267))	('RB1', 'Gene', '5925', (56, 59))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('bladder tumor', 'Phenotype', 'HP:0009725', (254, 267))	('bladder tumor', 'Disease', 'MESH:D001749', (254, 267))
63683	29180607	In total, 13% of patients (8 of 61) harbored mutations in PIK3CA (Supplementary Figure 7A).	('mutations', 'Var', (45, 54))	('men', 'Species', '9606', (72, 75))	('PIK3CA', 'Gene', (58, 64))	('PIK3CA', 'Gene', '5290', (58, 64))	('patients', 'Species', '9606', (17, 25))	('harbored', 'Reg', (36, 44))
63684	29180607	Unlike in UC, SCCBs lack ERBB2 amplifications, but 14 patients harbored likely activating ERBB2 mutations including hotspot mutations in both the extracellular (S310) and kinase domains (L755) (Supplementary Figure 7B).	('extracellular', 'cellular_component', 'GO:0005576', ('146', '159'))	('mutations', 'Var', (124, 133))	('activating', 'PosReg', (79, 89))	('patients', 'Species', '9606', (54, 62))	('S310', 'Var', (161, 165))	('men', 'Species', '9606', (200, 203))	('ERBB2', 'Gene', '2064', (25, 30))	('ERBB2', 'Gene', '2064', (90, 95))	('ERBB2', 'Gene', (25, 30))	('ERBB2', 'Gene', (90, 95))	('mutations', 'Var', (96, 105))
63685	29180607	Among other RTKs, ERBB3 mutations affected 15% of patients.	('ERBB3', 'Gene', '2065', (18, 23))	('patients', 'Species', '9606', (50, 58))	('affected', 'Reg', (34, 42))	('ERBB3', 'Gene', (18, 23))	('mutations', 'Var', (24, 33))
63686	29180607	FGFR3 hotspot mutations (S249C) were much less common in SCCB than in UC, likely owing to their mutual exclusivity with RB1 loss, reaffirming the highly RB1-dependent G1/S checkpoint dysfunction in these tumors.	('loss', 'NegReg', (124, 128))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', '2261', (0, 5))	('RB1', 'Gene', '5925', (120, 123))	('SCCB', 'Disease', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('S249C', 'Var', (25, 30))	('FGFR3', 'Gene', (0, 5))	('S249C', 'Mutation', 'rs121913483', (25, 30))	('RB1', 'Gene', (153, 156))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('less', 'NegReg', (42, 46))	('RB1', 'Gene', '5925', (153, 156))	('RB1', 'Gene', (120, 123))	('G1/S checkpoint', 'biological_process', 'GO:0000075', ('167', '182'))	('mutations (S249C', 'Var', (14, 30))
63687	29180607	Beyond mutations in ERCC2, which correlate with sensitivity to platinum-based therapy in muscle-invasive bladder cancers, there were also mutations in other effectors of DNA repair signaling (Supplementary Figure 7C).	('ERCC2', 'Gene', (20, 25))	('DNA repair', 'biological_process', 'GO:0006281', ('170', '180'))	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('muscle-invasive bladder cancers', 'Disease', (89, 120))	('invasive bladder', 'Phenotype', 'HP:0100645', (96, 112))	('signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('ERCC2', 'Gene', '2068', (20, 25))	('bladder cancers', 'Phenotype', 'HP:0009725', (105, 120))	('muscle-invasive bladder cancers', 'Disease', 'MESH:D001749', (89, 120))	('men', 'Species', '9606', (198, 201))	('mutations', 'Var', (138, 147))	('platinum', 'Chemical', 'MESH:D010984', (63, 71))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))	('mutations', 'Var', (7, 16))
63691	29180607	We also identified bladder-specific mutations in the TERT promoter and in chromatin modifying genes, among others.	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('chromatin modifying genes', 'Gene', (74, 99))	('chromatin', 'cellular_component', 'GO:0000785', ('74', '83'))	('mutations', 'Var', (36, 45))
63692	29180607	A substantial subset of TP53 mutations were biallelic missense rather than loss-of-function, a setting in which GD arose preferentially suggesting that GD is more strongly associated with TP53 neomorphism rather than conventional loss of function in SCCB.	('loss-of-function', 'NegReg', (75, 91))	('TP53', 'Gene', (24, 28))	('neomorphism', 'Var', (193, 204))	('mutations', 'Var', (29, 38))	('associated', 'Reg', (172, 182))	('biallelic missense', 'Var', (44, 62))	('TP53', 'Gene', '7157', (188, 192))	('TP53', 'Gene', (188, 192))	('TP53', 'Gene', '7157', (24, 28))
63693	29180607	Also, while evolutionarily diverse, we demonstrated that there are truncal mutations in tumors with mixed histology, but histology-specific lesions in RB1 and TP53 determine the small cell phenotype and appear to arise early in molecular time, likely shortly after the founding driver.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('RB1', 'Gene', '5925', (151, 154))	('lesions', 'Var', (140, 147))	('TP53', 'Gene', '7157', (159, 163))	('TP53', 'Gene', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('RB1', 'Gene', (151, 154))
63695	29180607	Of course, a small percentage of UC also harbor alterations in RB1 and TP53, which can be detected in even non-invasive precursor lesions (unpublished data).	('alterations', 'Var', (48, 59))	('RB1', 'Gene', '5925', (63, 66))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('RB1', 'Gene', (63, 66))
63697	29180607	Therefore, future studies should explore whether epigenomic or transcriptional events interact with the loss of RB1 and TP53 to confer the small cell phenotype.	('RB1', 'Gene', '5925', (112, 115))	('loss', 'Var', (104, 108))	('confer', 'Reg', (128, 134))	('small cell phenotype', 'Disease', (139, 159))	('RB1', 'Gene', (112, 115))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
63699	29180607	Overall, aside from RB1 and TP53 alterations, genomic alterations present in SCCB more closely resemble UC than small cell lung cancers, indicating that most alterations contribute to oncogenesis in an organ-specific manner rather than cell type-specific manner.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('TP53', 'Gene', '7157', (28, 32))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (112, 135))	('contribute', 'Reg', (170, 180))	('small cell lung cancers', 'Disease', (112, 135))	('RB1', 'Gene', '5925', (20, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('TP53', 'Gene', (28, 32))	('lung cancers', 'Phenotype', 'HP:0100526', (123, 135))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (112, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('oncogenesis', 'biological_process', 'GO:0007048', ('184', '195'))	('alterations', 'Var', (158, 169))	('oncogenesis', 'CPA', (184, 195))	('RB1', 'Gene', (20, 23))	('small cell lung cancers', 'Disease', 'MESH:D055752', (112, 135))
63719	26343003	Overexpression of the vascular endothelial growth factor receptor (VEGFR) is associated with significantly worse outcomes following neoadjuvant chemotherapy.	('vascular endothelial growth factor receptor', 'Gene', (22, 65))	('VEGFR', 'Gene', (67, 72))	('vascular endothelial growth factor receptor', 'Gene', '3791', (22, 65))	('Overexpression', 'Var', (0, 14))	('VEGFR', 'Gene', '3791', (67, 72))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('22', '56'))
63739	26343003	The new GEP data from this study were uploaded to Gene Expression Omnibus with accession numbers GSE69795 (DDMVAC + bevacizumab cohort) and GSE70691 (MVAC confirmation cohort).	('GSE70691', 'Var', (140, 148))	('Gene Expression', 'biological_process', 'GO:0010467', ('50', '65'))	('MVAC', 'Chemical', '-', (109, 113))	('DDMVAC', 'Chemical', '-', (107, 113))	('GEP', 'Gene', (8, 11))	('bevacizumab', 'Chemical', 'MESH:D000068258', (116, 127))	('MVAC', 'Chemical', '-', (150, 154))
63837	23394492	Most patients with locally advanced UC are treated without regard to the underlying histology, although it has been reported that tumors with variant histology are associated with a higher risk of progression than conventional high grade UC.	('tumors', 'Disease', (130, 136))	('progression', 'MPA', (197, 208))	('variant', 'Var', (142, 149))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('patients', 'Species', '9606', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
63838	23394492	As for PUC we could show in the largest series described to date, that on the one hand this subtype of UC accumulates prognostic unfavourable molecular features, like such as the loss of CK20, a high proliferation index and p53 accumulation, and as well as on the other hand exhibits characteristic molecular features, like such as a complete loss of membranous E-cadherin expression.	('E-cadherin', 'Gene', (362, 372))	('p53', 'Gene', (224, 227))	('p53', 'Gene', '7157', (224, 227))	('E-cadherin', 'Gene', '999', (362, 372))	('expression', 'MPA', (373, 383))	('CK20', 'Gene', (187, 191))	('CK20', 'Gene', '54474', (187, 191))	('high proliferation index', 'CPA', (195, 219))	('loss', 'NegReg', (343, 347))	('loss', 'Var', (179, 183))	('cadherin', 'molecular_function', 'GO:0008014', ('364', '372'))	('accumulation', 'PosReg', (228, 240))
63876	32939323	Lung cancer patients with positive Siglec-15 expression showed significantly short survival rates in progression-free survival concomitant with reduced infiltration of CD20 + B, and dendritic cells by immunohistochemistry.	('short', 'NegReg', (77, 82))	('reduced', 'NegReg', (144, 151))	('patients', 'Species', '9606', (12, 20))	('positive', 'Var', (26, 34))	('Siglec-15', 'Gene', (35, 44))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('CD20', 'Gene', '54474', (168, 172))	('CD20', 'Gene', (168, 172))	('Lung cancer', 'Disease', (0, 11))	('progression-free survival', 'CPA', (101, 126))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('expression', 'Var', (45, 55))	('infiltration', 'MPA', (152, 164))	('Siglec-15', 'Gene', '284266', (35, 44))
63907	32939323	We investigated the copy number alterations (CNA) and mutations of Siglec-15 in different cancers.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (54, 63))	('copy number alterations', 'Var', (20, 43))	('Siglec-15', 'Gene', '284266', (67, 76))	('Siglec-15', 'Gene', (67, 76))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
63942	32939323	Genetic and epigenetic changes play a critical role in regulating cancer development and immune tolerance.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Genetic', 'Var', (0, 7))	('immune tolerance', 'CPA', (89, 105))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('epigenetic changes', 'Var', (12, 30))	('cancer', 'Disease', (66, 72))
63944	32939323	We found that patients with high Siglec-15 expression were accompanied by gene alterations in OV, HNSC, sarcoma (SARC), UCEC, BLCA, BRCA, SKCM, and lymphoid neoplasm diffuse large B-cell lymphoma (DLBC) (Figure 2a, Supplementary Figure S2a).	('neoplasm', 'Phenotype', 'HP:0002664', (157, 165))	('alterations', 'Reg', (79, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (180, 195))	('patients', 'Species', '9606', (14, 22))	('HNSC', 'Disease', (98, 102))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (180, 195))	('OV', 'Phenotype', 'HP:0012887', (94, 96))	('lymphoid neoplasm', 'Disease', (148, 165))	('SARC', 'Phenotype', 'HP:0100242', (113, 117))	('B-cell lymphoma', 'Disease', (180, 195))	('Siglec-15', 'Gene', (33, 42))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('high', 'Var', (28, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (187, 195))	('lymphoid neoplasm', 'Disease', 'MESH:D008223', (148, 165))	('sarcoma', 'Disease', (104, 111))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('lymphoid neoplasm', 'Phenotype', 'HP:0002665', (148, 165))	('Siglec-15', 'Gene', '284266', (33, 42))	('expression', 'MPA', (43, 53))
63945	32939323	The trends in Siglec-15 genetic alteration were consistent with its mRNA levels in these cancers.	('Siglec-15', 'Gene', (14, 23))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('genetic alteration', 'Var', (24, 42))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('Siglec-15', 'Gene', '284266', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
63964	32939323	High Siglec-15 expression predicted worse outcomes in LUAD, BRCA-basal, BRCA-Her2+ ,and STAD (Figure 3d).	('High', 'Var', (0, 4))	('BRCA', 'Phenotype', 'HP:0003002', (72, 76))	('Her2', 'Gene', (77, 81))	('Siglec-15', 'Gene', '284266', (5, 14))	('Her2', 'Gene', '2064', (77, 81))	('expression', 'MPA', (15, 25))	('Siglec-15', 'Gene', (5, 14))	('LUAD', 'Phenotype', 'HP:0030078', (54, 58))	('BRCA', 'Phenotype', 'HP:0003002', (60, 64))	('STAD', 'Disease', (88, 92))	('LUAD', 'Disease', (54, 58))	('BRCA-basal', 'Disease', (60, 70))
63965	32939323	Furthermore, high Siglec-15 expression was associated with poor OS and FP in LUAD; poor OS in BRCA-basal; poor RFS in BRCA-Her2+; poor OS and PPS in STAD-intestinal; and poor OS in STAD-mixed.	('Siglec-15', 'Gene', (18, 27))	('high', 'Var', (13, 17))	('BRCA', 'Phenotype', 'HP:0003002', (94, 98))	('Her2', 'Gene', (123, 127))	('expression', 'MPA', (28, 38))	('BRCA', 'Phenotype', 'HP:0003002', (118, 122))	('Her2', 'Gene', '2064', (123, 127))	('LUAD', 'Phenotype', 'HP:0030078', (77, 81))	('PPS', 'Chemical', '-', (142, 145))	('Siglec-15', 'Gene', '284266', (18, 27))
63982	32939323	Siglec-15 was positively associated with naive B cells, neutrophils, and activated mast cells and negatively associated with follicular helper T cells in metastatic SKCM in GSE8401 compared to the associations in primary SKCM.	('positively', 'PosReg', (14, 24))	('follicular helper T cells', 'CPA', (125, 150))	('associated', 'Interaction', (109, 119))	('associated', 'Interaction', (25, 35))	('negatively', 'NegReg', (98, 108))	('Siglec-15', 'Gene', '284266', (0, 9))	('GSE8401', 'Var', (173, 180))	('Siglec-15', 'Gene', (0, 9))	('metastatic SKCM', 'Disease', (154, 169))
63984	32939323	These results suggest opposite correlation patterns in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) in GSE26886; however, the results were not significant.	('adenocarcinoma', 'Disease', (112, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('adenocarcinoma', 'Disease', 'MESH:D000230', (112, 126))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (55, 89))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (101, 126))	('esophageal squamous cell carcinoma', 'Disease', (55, 89))	('EAC', 'Phenotype', 'HP:0011459', (128, 131))	('GSE26886', 'Var', (136, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
64004	32939323	And PI3 K was significantly positively associated with Siglec-15 expression (Pearson r = 0.54, p = .01).	('Siglec-15', 'Gene', '284266', (55, 64))	('Siglec-15', 'Gene', (55, 64))	('PI3 K', 'Var', (4, 9))	('expression', 'MPA', (65, 75))	('PI3 K', 'molecular_function', 'GO:0016303', ('4', '9'))
64037	32939323	For example, mutant PD-L1 with structural variations leads to aberrant PD-L1 expression and immunosuppression.	('mutant', 'Var', (13, 19))	('expression', 'MPA', (77, 87))	('PD-L1', 'Gene', (71, 76))	('PD-L1', 'Gene', (20, 25))	('PD-L1', 'Gene', '29126', (71, 76))	('leads to', 'Reg', (53, 61))	('PD-L1', 'Gene', '29126', (20, 25))
64038	32939323	JAK2/PD-L1/PD-L2 (9p24.1) amplifications can also bring about constitutive overexpression of PD-L1 and a significant response to checkpoint inhibitors.	('PD-L1', 'Gene', '29126', (93, 98))	('overexpression', 'PosReg', (75, 89))	('PD-L1', 'Gene', (5, 10))	('JAK2', 'Gene', '3717', (0, 4))	('response to checkpoint inhibitors', 'MPA', (117, 150))	('PD-L1', 'Gene', '29126', (5, 10))	('JAK2', 'Gene', (0, 4))	('bring about', 'Reg', (50, 61))	('JAK', 'molecular_function', 'GO:0004713', ('0', '3'))	('PD-L1', 'Gene', (93, 98))	('PD-L2', 'Gene', (11, 16))	('PD-L2', 'Gene', '80380', (11, 16))	('amplifications', 'Var', (26, 40))
64040	32939323	Preliminary analysis suggested that Siglec-15 expression was genetically and epigenetically regulated through CNA and promoter methylation.	('promoter methylation', 'Var', (118, 138))	('Siglec-15', 'Gene', (36, 45))	('Siglec-15', 'Gene', '284266', (36, 45))	('expression', 'MPA', (46, 56))	('methylation', 'biological_process', 'GO:0032259', ('127', '138'))
64057	32939323	There is an increasing trend for CXCR3 and MMP9 in patients with overexpressed Siglec-15, which may recruit Treg.	('overexpressed', 'Var', (65, 78))	('Siglec-15', 'Gene', (79, 88))	('CXCR3', 'Gene', '2833', (33, 38))	('patients', 'Species', '9606', (51, 59))	('MMP9', 'Gene', (43, 47))	('CXCR3', 'Gene', (33, 38))	('MMP9', 'molecular_function', 'GO:0004229', ('43', '47'))	('MMP9', 'Gene', '4318', (43, 47))	('Siglec-15', 'Gene', '284266', (79, 88))
64099	30121007	During oncogenic transformation, alternations in cellular metabolism have been shown to be involved in cancer cell proliferation.	('involved', 'Reg', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('alternations', 'Var', (33, 45))	('cellular metabolism', 'MPA', (49, 68))	('cell proliferation', 'biological_process', 'GO:0008283', ('110', '128'))	('cellular metabolism', 'biological_process', 'GO:0044237', ('49', '68'))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
64133	30121007	Wild-type or mutant 3'-untranslated regions (UTRs) of PAICS were cloned into the pMIR-REPORT miRNA Expression Reporter Vector (Life Technologies).	('mutant', 'Var', (13, 19))	('miR', 'Gene', (93, 96))	('miR', 'Gene', '220972', (93, 96))
64134	30121007	VM-CUB1 cells were co-transfected with pre-miR-128-3p (#PM11746) or controls (#AM17110) and wild-type or mutant 3'-UTR-luc, as well as pRL-TK vector as an internal control for luciferase activity.	('luciferase activity', 'molecular_function', 'GO:0047077', ('176', '195'))	('pre', 'molecular_function', 'GO:0003904', ('39', '42'))	('miR', 'Gene', '220972', (43, 46))	('luciferase activity', 'molecular_function', 'GO:0045289', ('176', '195'))	('miR', 'Gene', (43, 46))	('#PM11746', 'Var', (55, 63))	('luciferase activity', 'molecular_function', 'GO:0047712', ('176', '195'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('176', '195'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('176', '195'))	('mutant', 'Var', (105, 111))
64146	30121007	MiR-128 is known to have tumor suppressor function by targeting several oncogenes including ZEB1 and RPS6KB1 in prostate cancer, VEGF-C in BLCA, CYP2C9 in hepatocellular carcinoma, and p70S6K1 in glioma.	('CYP2C9', 'Gene', (145, 151))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (155, 179))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('25', '41'))	('glioma', 'Disease', 'MESH:D005910', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor suppressor', 'biological_process', 'GO:0051726', ('25', '41'))	('p70S6K1', 'Var', (185, 192))	('BLCA', 'Phenotype', 'HP:0009725', (139, 143))	('MiR', 'Gene', '220972', (0, 3))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (155, 179))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('RPS6KB1', 'Gene', '6198', (101, 108))	('ZEB1', 'Gene', (92, 96))	('prostate cancer', 'Disease', 'MESH:D011471', (112, 127))	('MiR', 'Gene', (0, 3))	('BLCA', 'Disease', (139, 143))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('hepatocellular carcinoma', 'Disease', (155, 179))	('CYP2C9', 'Gene', '1559', (145, 151))	('tumor', 'Disease', (25, 30))	('prostate cancer', 'Disease', (112, 127))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('VEGF-C', 'Gene', (129, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('RPS6KB1', 'Gene', (101, 108))	('ZEB1', 'Gene', '6935', (92, 96))	('VEGF-C', 'Gene', '7424', (129, 135))	('glioma', 'Disease', (196, 202))
64152	30121007	This reduction in luciferase activity is curtailed when miR-128 target site is mutated (Figure 4H).	('luciferase activity', 'molecular_function', 'GO:0045289', ('18', '37'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('18', '37'))	('reduction', 'NegReg', (5, 14))	('mutated', 'Var', (79, 86))	('luciferase activity', 'molecular_function', 'GO:0050397', ('18', '37'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('18', '37'))	('activity', 'MPA', (29, 37))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))	('luciferase', 'Enzyme', (18, 28))	('luciferase activity', 'molecular_function', 'GO:0047077', ('18', '37'))	('curtailed', 'NegReg', (41, 50))
64159	30121007	Additionally, we also observed decreased levels of SLUG and VIM transcript upon PAICS knockdown (Figure 5A).	('knockdown', 'Var', (86, 95))	('SLUG', 'Gene', '6591', (51, 55))	('decreased', 'NegReg', (31, 40))	('VIM', 'Gene', (60, 63))	('SLUG', 'Gene', (51, 55))	('levels', 'MPA', (41, 47))	('VIM', 'Gene', '7431', (60, 63))
64160	30121007	Among these, PAICS depletion increased E-cadherin expression in both VM-CUB1 and RT112 cells (Figure 5B).	('depletion', 'Var', (19, 28))	('E-cadherin', 'Gene', (39, 49))	('E-cadherin', 'Gene', '999', (39, 49))	('cadherin', 'molecular_function', 'GO:0008014', ('41', '49'))	('RT112', 'CellLine', 'CVCL:1670', (81, 86))	('increased', 'PosReg', (29, 38))	('expression', 'MPA', (50, 60))
64161	30121007	Concurrently, the E-cadherin protein levels were elevated in situ in RT112 cells upon PAICS knockdown (Figure 5C).	('knockdown', 'Var', (92, 101))	('cadherin', 'molecular_function', 'GO:0008014', ('20', '28'))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('elevated', 'PosReg', (49, 57))	('RT112', 'CellLine', 'CVCL:1670', (69, 74))	('E-cadherin', 'Gene', (18, 28))	('E-cadherin', 'Gene', '999', (18, 28))
64162	30121007	To investigate the role of PAICS in tumorigenesis, we generated VM-CUB1and 5637 cells stably expressing PAICS or nontargeting shRNA through the lentivirus expression system.	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('PAICS', 'Var', (104, 109))
64173	30121007	In addition, we found that PAICS knockdown resulted in the induction of E-cadherin, a mesenchymal to epithelial transition marker, as well as the suppression of EMT markers SNAI1, SLUG, and vimentin.	('SLUG', 'Gene', (180, 184))	('cadherin', 'molecular_function', 'GO:0008014', ('74', '82'))	('SNAI1', 'Gene', (173, 178))	('induction', 'PosReg', (59, 68))	('vimentin', 'Gene', '7431', (190, 198))	('suppression', 'NegReg', (146, 157))	('knockdown', 'Var', (33, 42))	('vimentin', 'cellular_component', 'GO:0045099', ('190', '198'))	('EMT markers', 'CPA', (161, 172))	('mesenchymal to epithelial transition', 'biological_process', 'GO:0060231', ('86', '122'))	('PAICS', 'Gene', (27, 32))	('vimentin', 'cellular_component', 'GO:0045098', ('190', '198'))	('EMT', 'biological_process', 'GO:0001837', ('161', '164'))	('vimentin', 'Gene', (190, 198))	('SLUG', 'Gene', '6591', (180, 184))	('E-cadherin', 'Gene', (72, 82))	('E-cadherin', 'Gene', '999', (72, 82))	('SNAI1', 'Gene', '6615', (173, 178))
64175	30121007	We found that PAICS knockdown considerably inhibited tumor formation and subsequent tumor growth.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('inhibited', 'NegReg', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (84, 89))	('PAICS', 'Gene', (14, 19))	('tumor', 'Disease', (53, 58))	('knockdown', 'Var', (20, 29))
64237	32178979	In univariate Cox regression, solitary CNS lesions and SRS were significantly associated with increased RS, and poor performance status with decreased RS but in multivariate analysis they were no longer significant, table 1-B.	('solitary CNS lesions', 'Var', (30, 50))	('SRS', 'Disease', (55, 58))	('increased', 'PosReg', (94, 103))	('SRS', 'Disease', 'MESH:C536678', (55, 58))
64248	32178979	In univariate and multivariate analysis, presence of prior extra-CNS metastasis and radical surgery for the primary tumor were significantly associated with increased TTCM, but no significant associations were identified between age at UC diagnosis, gender, chemotherapy receipt prior to CNS metastasis, or year of publication (used as an approximation of year of diagnosis) and TTCM, table 2.	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('extra-CNS metastasis', 'CPA', (59, 79))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('increased', 'PosReg', (157, 166))	('TTCM', 'Disease', (167, 171))	('presence', 'Var', (41, 49))
64263	32178979	It has also been speculated that distinct molecular profiles may be responsible for this CNS predisposition, such as mutations in PI3K/Akt/mTOR pathway in the case of brain metastases from melanoma, but this hypothesis has not been formally tested in UC.	('Akt', 'Gene', '207', (135, 138))	('mutations', 'Var', (117, 126))	('PI3K', 'molecular_function', 'GO:0016303', ('130', '134'))	('mTOR', 'Gene', (139, 143))	('Akt', 'Gene', (135, 138))	('mTOR', 'Gene', '2475', (139, 143))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('brain metastases', 'Disease', (167, 183))	('brain metastases', 'Disease', 'MESH:D009362', (167, 183))
64307	30832569	MLP's optimal architectures were 1L_64U for the scenarios of TCGA (stage classification) and NSCLC (adenocarcinoma vs squamous); 1L_128U for the scenarios of TCGA (cancer vs normal), NSCLC (stage classification), and CKD (stage classification).	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('adenocarcinoma', 'Disease', 'MESH:D000230', (100, 114))	('NSCLC', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('NSCLC', 'Disease', (183, 188))	('CKD', 'Phenotype', 'HP:0012622', (217, 220))	('cancer', 'Disease', (164, 170))	('adenocarcinoma', 'Disease', (100, 114))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('1L_128U', 'Var', (129, 136))
64308	30832569	CNN's best performing architectures were 3L1_64U for all scenarios except for NSCLC (stage classification), which favored 1L_128U.	('1L_128U', 'Var', (122, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('CNN', 'Chemical', '-', (0, 3))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('3L1_64U', 'Var', (41, 48))
64325	30832569	Particularly, at imbalance ratios 4 and 7, the average Kappa of CNN dropped to near zero.	('imbalance', 'Phenotype', 'HP:0002172', (17, 26))	('CNN', 'Chemical', '-', (64, 67))	('dropped', 'NegReg', (68, 75))	('imbalance ratios', 'Var', (17, 33))	('Kappa', 'MPA', (55, 60))
64358	30832569	These five datasets were accessed via IDs GSE10245, GSE11969, GSE19804, GSE41271, and GSE42127, which involved 58, 144, 59, 265, and 174 human subjects, respectively.	('GSE42127', 'Var', (86, 94))	('human', 'Species', '9606', (137, 142))	('GSE11969', 'Var', (52, 60))	('GSE19804', 'Var', (62, 70))	('GSE41271', 'Var', (72, 80))	('GSE10245', 'Var', (42, 50))
64362	30832569	The 703 subjects include 587 CKD patients with five stages (CKD1 = 120, CKD2 = 104, CKD3 = 110, CKD4 = 119, CKD5 = 134) and 116 age-matched normal healthy controls.	('CKD', 'Phenotype', 'HP:0012622', (29, 32))	('CKD', 'Phenotype', 'HP:0012622', (60, 63))	('patients', 'Species', '9606', (33, 41))	('CKD1', 'Var', (60, 64))	('CKD', 'Phenotype', 'HP:0012622', (96, 99))	('CKD2 =', 'Var', (72, 78))	('CKD', 'Phenotype', 'HP:0012622', (72, 75))	('CKD3 =', 'Var', (84, 90))	('CKD', 'Phenotype', 'HP:0012622', (84, 87))
64426	28195647	We confirmed this finding by analysis of CDKN2A (p16) protein expression, which was also low in both Uro and GU-Uro cases, but high in GU-GU cases (Figure 1B, C), consistent with CDKN2A deletions/mutations being frequent in progressed Uro cases 5 and with GU showing frequent overexpression of p16 8.	('CDKN2A', 'Gene', '1029', (179, 185))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('p16', 'Gene', (294, 297))	('deletions/mutations', 'Var', (186, 205))	('p16', 'Gene', (49, 52))	('Uro', 'Chemical', '-', (101, 104))	('Uro', 'Chemical', '-', (235, 238))	('CDKN2A', 'Gene', (41, 47))	('Uro', 'Chemical', '-', (112, 115))	('p16', 'Gene', '1029', (294, 297))	('CDKN2A', 'Gene', (179, 185))	('p16', 'Gene', '1029', (49, 52))	('CDKN2A', 'Gene', '1029', (41, 47))	('progressed Uro', 'Disease', (224, 238))
64491	28195647	This group differs from early-stage UroA by being invariably high-grade, by having lost urothelial-like stratification, and by showing frequent CDKN2A genomic losses 14.	('genomic losses 14', 'Var', (151, 168))	('Uro', 'Chemical', '-', (36, 39))	('lost', 'NegReg', (83, 87))	('CDKN2A', 'Gene', (144, 150))	('urothelial-like stratification', 'CPA', (88, 118))	('CDKN2A', 'Gene', '1029', (144, 150))
64576	22367511	Furthermore, everolimus has been evaluated in second-line setting based on the observation that there is over-expression of activated mammalian target of rapamycin (mTOR) pathway markers including phosphor-S6 and phosphor-4E bP1 in invasive transitional cell carcinoma specimens.	('invasive transitional cell carcinoma', 'Phenotype', 'HP:0006740', (232, 268))	('mammalian target of rapamycin', 'Gene', '2475', (134, 163))	('carcinoma', 'Disease', 'MESH:D002277', (259, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('mTOR', 'Gene', (165, 169))	('mammalian target of rapamycin', 'Gene', (134, 163))	('carcinoma', 'Disease', (259, 268))	('everolimus', 'Chemical', 'MESH:D000068338', (13, 23))	('over-expression', 'PosReg', (105, 120))	('mTOR', 'Gene', '2475', (165, 169))	('phosphor-S6', 'Var', (197, 208))	('bP1', 'Gene', (225, 228))	('bP1', 'Gene', '474256', (225, 228))
64580	22367511	Furthermore, EGFR was shown to be overexpressed in bladder tumor, and the degree of EGFR expression also has been shown to be associated with poorer prognosis and advanced stage and grade, which provided rationale for targeting the EGFR pathway in the treatment of urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (265, 285))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('EGFR', 'Gene', '1956', (13, 17))	('overexpressed', 'PosReg', (34, 47))	('associated', 'Reg', (126, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('bladder tumor', 'Phenotype', 'HP:0009725', (51, 64))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (232, 236))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('EGFR', 'molecular_function', 'GO:0005006', ('232', '236'))	('poorer prognosis', 'CPA', (142, 158))	('grade', 'CPA', (182, 187))	('expression', 'Var', (89, 99))	('bladder tumor', 'Disease', (51, 64))	('EGFR', 'Gene', (13, 17))	('urothelial carcinoma', 'Disease', (265, 285))	('bladder tumor', 'Disease', 'MESH:D001749', (51, 64))	('advanced stage', 'CPA', (163, 177))	('EGFR', 'Gene', '1956', (232, 236))	('EGFR', 'Gene', (84, 88))
64602	22367511	In preclinical studies, BCG induced tumor regression in mice models before transplantation of tumor cells as compared to mice that did not receive BCG, an observation that led to the first ever use of nonspecific immunotherapy: use of BCG in non-muscle-invasive bladder cancer.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('invasive bladder', 'Phenotype', 'HP:0100645', (253, 269))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (246, 276))	('muscle-invasive bladder cancer', 'Disease', (246, 276))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('bladder cancer', 'Phenotype', 'HP:0009725', (262, 276))	('BCG', 'Var', (24, 27))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('BCG', 'Species', '33892', (235, 238))	('mice', 'Species', '10090', (56, 60))	('mice', 'Species', '10090', (121, 125))	('BCG', 'Species', '33892', (147, 150))	('non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (242, 269))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('BCG', 'Species', '33892', (24, 27))	('tumor', 'Disease', (36, 41))
64616	22367511	These additional signals for optimal T cell priming involve agonist coreceptors, such as CD28, 4-1BB, and OX40, and inhibitory coreceptors, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4).	('CTLA-4', 'Gene', (182, 188))	('4-1BB', 'Gene', (95, 100))	('OX40', 'Gene', (106, 110))	('CD28', 'Var', (89, 93))	('cytotoxic T-lymphocyte antigen-4', 'Gene', (148, 180))	('CT', 'Phenotype', 'HP:0010788', (182, 184))	('CTLA-4', 'Gene', '1493', (182, 188))	('4-1BB', 'Gene', '3604', (95, 100))	('lymphocyte antigen', 'molecular_function', 'GO:0005557', ('160', '178'))	('OX40', 'Gene', '7293', (106, 110))	('cytotoxic T-lymphocyte antigen-4', 'Gene', '1493', (148, 180))
64625	22367511	Several studies have shown conflicting results: some suggest that p53 mutation is correlated with poor prognosis and resistance to MVAC chemotherapy, where other studies suggest poor prognosis but increased sensitivity to MVAC or similar combination regimen.	('MVAC', 'Chemical', 'MESH:C044361', (222, 226))	('p53', 'Gene', '7157', (66, 69))	('mutation', 'Var', (70, 78))	('MVAC', 'Chemical', 'MESH:C044361', (131, 135))	('p53', 'Gene', (66, 69))
64631	22367511	Lastly, studies have evaluated different molecular markers such as p53 mutation status and drug resistance-associated proteins as potential predictive and/or prognostic biomarkers, mostly with conflicting results.	('mutation', 'Var', (71, 79))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('drug resistance', 'biological_process', 'GO:0009315', ('91', '106'))	('drug resistance', 'Phenotype', 'HP:0020174', (91, 106))	('drug resistance', 'biological_process', 'GO:0042493', ('91', '106'))
64651	33894748	Treatment with ICIs such as anti-programmed cell death protein 1(PD-1), anti-programmed death-ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can significantly increase OS and result in durable remission for many advanced cancers, including melanoma, non-small cell lung cancer, renal cancer and urothelial cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (298, 309))	('renal cancer', 'Disease', 'MESH:D007680', (311, 323))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (283, 309))	('PD-L1', 'Gene', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('PD-L1', 'Gene', '29126', (104, 109))	('urothelial cancer', 'Disease', 'MESH:D014523', (328, 345))	('PD-1', 'Gene', (65, 69))	('melanoma', 'Disease', 'MESH:D008545', (273, 281))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('PD-1', 'Gene', '5133', (65, 69))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (287, 309))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('cancers', 'Disease', (254, 261))	('urothelial cancer', 'Disease', (328, 345))	('programmed cell death protein 1', 'Gene', (33, 64))	('lung cancer', 'Disease', (298, 309))	('result in', 'Reg', (208, 217))	('lung cancer', 'Disease', 'MESH:D008175', (298, 309))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (121, 164))	('increase', 'PosReg', (192, 200))	('programmed cell death', 'biological_process', 'GO:0012501', ('33', '54'))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('renal cancer', 'Disease', (311, 323))	('CTLA-4', 'Gene', '1493', (166, 172))	('ligand', 'molecular_function', 'GO:0005488', ('94', '100'))	('renal cancer', 'Phenotype', 'HP:0009726', (311, 323))	('melanoma', 'Phenotype', 'HP:0002861', (273, 281))	('melanoma', 'Disease', (273, 281))	('CTLA-4', 'Gene', (166, 172))	('programmed cell death protein 1', 'Gene', '5133', (33, 64))	('anti-programmed', 'Var', (72, 87))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (121, 164))	('cancers', 'Disease', 'MESH:D009369', (254, 261))
64689	33894748	Among them, NTRK3 had the biggest hazard ratio (HR) value, indicating that the high expression of NTRK3 may be a risk factor.	('NTRK3', 'Gene', '4916', (12, 17))	('NTRK3', 'Gene', '4916', (98, 103))	('NTRK3', 'Gene', (12, 17))	('high expression', 'Var', (79, 94))	('NTRK3', 'Gene', (98, 103))
64712	33894748	8, NTRK3 staining was higher in tumor samples than in normal tissue, which was consistent with the result of survival analysis, indicating that high expression of NTRK3 is a risk factor in bladder cancer.	('high expression', 'Var', (144, 159))	('NTRK3', 'Gene', (3, 8))	('NTRK3', 'Gene', '4916', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('bladder cancer', 'Phenotype', 'HP:0009725', (189, 203))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('NTRK3', 'Gene', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('bladder cancer', 'Disease', 'MESH:D001749', (189, 203))	('bladder cancer', 'Disease', (189, 203))	('NTRK3', 'Gene', '4916', (3, 8))	('tumor', 'Disease', (32, 37))	('risk factor', 'Reg', (174, 185))
64724	33894748	Moreover, meaningful GSEA results were all enriched in the low TMB group and most were immune-related, indicating that low TMB might enhance the tumor heterogeneity in BLCA.	('enhance', 'PosReg', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('low', 'Var', (119, 122))	('TMB', 'Chemical', '-', (63, 66))	('BLCA', 'Phenotype', 'HP:0009725', (168, 172))	('tumor', 'Disease', (145, 150))	('TMB', 'Gene', (123, 126))	('BLCA', 'Disease', (168, 172))	('GSEA', 'Chemical', '-', (21, 25))	('TMB', 'Chemical', '-', (123, 126))
64728	33894748	In terms of immune cell infiltration, the high proportion of CD4+ T cells, CD8+ T cells and Tfhs may be an important factor leading to better OS in the high TMB group.	('CD4', 'Gene', '920', (61, 64))	('Tfh', 'Chemical', '-', (92, 95))	('TMB', 'Chemical', '-', (157, 160))	('CD8', 'Gene', '925', (75, 78))	('CD8', 'Gene', (75, 78))	('high', 'Var', (152, 156))	('CD4', 'Gene', (61, 64))
64739	33894748	In recent years, many studies have reported that TRK pathway aberrations such as single nucleotide variation, gene fusion and gene overexpression are involved in the pathogenesis of many cancers, among which NTRK3 gene fusion is the most fully verified carcinogenic event.	('carcinogenic', 'Disease', 'MESH:D063646', (253, 265))	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('carcinogenic', 'Disease', (253, 265))	('involved', 'Reg', (150, 158))	('cancers', 'Disease', (187, 194))	('NTRK3', 'Gene', '4916', (208, 213))	('TRK', 'Gene', (209, 212))	('TRK', 'Gene', '4914', (209, 212))	('gene fusion', 'Var', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('TRK', 'Gene', (49, 52))	('single nucleotide variation', 'Var', (81, 108))	('TRK', 'Gene', '4914', (49, 52))	('pathogenesis', 'biological_process', 'GO:0009405', ('166', '178'))	('NTRK3', 'Gene', (208, 213))	('overexpression', 'PosReg', (131, 145))	('gene fusion', 'Var', (214, 225))
64759	33894748	found that A2A receptor (A2AR) regulated CD8+ T cells in TME and the application of its inhibitors could enhance the effect of immunotherapy in melanoma and bladder cancer cells.	('melanoma and bladder cancer', 'Disease', 'MESH:D001749', (144, 171))	('A2AR', 'Gene', '135', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('A2AR', 'Gene', (25, 29))	('A2A receptor', 'Gene', (11, 23))	('CD8', 'Gene', (41, 44))	('CD8', 'Gene', '925', (41, 44))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('A2A receptor', 'Gene', '135', (11, 23))	('enhance', 'PosReg', (105, 112))	('inhibitors', 'Var', (88, 98))
64776	33537076	Bladder cancer with high Siglec15 expression was not sensitive to cancer immunotherapy, but exhibited a higher incidence of hyperprogression.	('Siglec15', 'Gene', (25, 33))	('expression', 'MPA', (34, 44))	('cancer', 'Disease', (8, 14))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('hyperprogression', 'CPA', (124, 140))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Siglec15', 'Gene', '284266', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('high', 'Var', (20, 24))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
64794	33537076	demonstrated that Siglec15 promoted tumor growth by inhibiting the proliferation of CD8+ T cells, and Siglec15 inhibitors could relieve this immunosuppression.	('Siglec15', 'Gene', '284266', (102, 110))	('CD8', 'Gene', '925', (84, 87))	('Siglec15', 'Gene', (18, 26))	('inhibiting', 'NegReg', (52, 62))	('promoted', 'PosReg', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('Siglec15', 'Gene', '284266', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('inhibitors', 'Var', (111, 121))	('CD8', 'Gene', (84, 87))	('tumor', 'Disease', (36, 41))	('Siglec15', 'Gene', (102, 110))
64807	33537076	Gene Expression Omnibus (GEO): Eight BLCA GEO cohorts with detailed survival data were downloaded, namely GSE13507, GSE31684, GSE48075, GSE48277, GSE69795, GSE70691, GSE32894, and GSE5287.	('GSE48075', 'Var', (126, 134))	('BLCA', 'Phenotype', 'HP:0009725', (37, 41))	('GSE32894', 'Var', (166, 174))	('GSE69795', 'Var', (146, 154))	('Gene Expression', 'biological_process', 'GO:0010467', ('0', '15'))	('GSE31684', 'Var', (116, 124))	('GSE5287', 'Var', (180, 187))	('GSE5287', 'Chemical', '-', (180, 187))	('GSE48277', 'Var', (136, 144))	('GSE13507', 'Var', (106, 114))	('GSE70691', 'Var', (156, 164))
64808	33537076	Three immunotherapy-related cohorts, GSE78220 (melanoma), GSE135222 (NSCLC), and GSE91061 (melanoma), were also downloaded.	('NSCLC', 'Disease', (69, 74))	('GSE135222', 'Var', (58, 67))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))
64818	33537076	The amplification and high mRNA expression of MDM2, MDM4, DNMT3A, CCND1, FGF19, FGF4, and FGF3 are positively correlated with hyperprogression.	('MDM4', 'Gene', '4194', (52, 56))	('hyperprogression', 'Disease', (126, 142))	('FGF4', 'Gene', '2249', (80, 84))	('correlated', 'Reg', (110, 120))	('FGF3', 'Gene', '2248', (90, 94))	('CCND1', 'Gene', '595', (66, 71))	('MDM4', 'Gene', (52, 56))	('FGF19', 'Gene', '9965', (73, 78))	('amplification', 'Var', (4, 17))	('DNMT3A', 'Gene', (58, 64))	('mRNA expression', 'MPA', (27, 42))	('FGF4', 'Gene', (80, 84))	('FGF19', 'Gene', (73, 78))	('DNMT3A', 'Gene', '1788', (58, 64))	('FGF3', 'Gene', (90, 94))	('MDM2', 'Gene', '4193', (46, 50))	('MDM2', 'Gene', (46, 50))	('CCND1', 'Gene', (66, 71))
64819	33537076	In addition, the deletion and low mRNA expression of CDKN2A and CDKN2B are also positively correlated with hyperprogression.	('CDKN2A', 'Gene', (53, 59))	('low', 'NegReg', (30, 33))	('mRNA expression', 'MPA', (34, 49))	('CDKN2A', 'Gene', '1029', (53, 59))	('correlated', 'Reg', (91, 101))	('CDKN2B', 'Gene', (64, 70))	('deletion', 'Var', (17, 25))	('hyperprogression', 'Disease', (107, 123))	('CDKN2B', 'Gene', '1030', (64, 70))
64843	33537076	Subsequently, it was noted that the mutation statuses of several critical genes, including RB1, ATM, ERBB2, ERCC2, and FANCC, were predictors of the response to neoadjuvant chemotherapy in BLCA.	('ATM', 'Gene', '472', (96, 99))	('ERCC2', 'Gene', '2068', (108, 113))	('predictors', 'Reg', (131, 141))	('FANCC', 'Gene', '2176', (119, 124))	('FANCC', 'Gene', (119, 124))	('ERCC2', 'Gene', (108, 113))	('RB1', 'Gene', (91, 94))	('BLCA', 'Phenotype', 'HP:0009725', (189, 193))	('ATM', 'Gene', (96, 99))	('ERBB2', 'Gene', '2064', (101, 106))	('RB1', 'Gene', '5925', (91, 94))	('ERBB2', 'Gene', (101, 106))	('mutation statuses', 'Var', (36, 53))
64851	33537076	Moreover, the predictive accuracy of Siglec15 was validated in four external validation cohorts, including two general BLCA cohorts (GSE31684, GSE48277), one immunotherapy-related cohort (IMvigor210), and one neoadjuvant chemotherapy-related cohort (GSE70691).	('Siglec15', 'Gene', '284266', (37, 45))	('BLCA', 'Phenotype', 'HP:0009725', (119, 123))	('GSE31684', 'Var', (133, 141))	('GSE48277', 'Var', (143, 151))	('Siglec15', 'Gene', (37, 45))
64875	33537076	Notably, copy number deletion and methylation of the Siglec15 reduced the expression of Siglec15 mRNA (Figure S6B-C).	('expression', 'MPA', (74, 84))	('Siglec15', 'Gene', '284266', (53, 61))	('Siglec15', 'Gene', '284266', (88, 96))	('mRNA', 'MPA', (97, 101))	('methylation', 'Var', (34, 45))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('Siglec15', 'Gene', (88, 96))	('Siglec15', 'Gene', (53, 61))	('reduced', 'NegReg', (62, 69))	('copy number deletion', 'Var', (9, 29))
64876	33537076	These results indicate that epigenetic modifications of the Siglec15 gene may be an alternative therapeutic method of intervention for anti-Siglec15 inhibitors.	('Siglec15', 'Gene', '284266', (60, 68))	('Siglec15', 'Gene', (140, 148))	('Siglec15', 'Gene', '284266', (140, 148))	('epigenetic modifications', 'Var', (28, 52))	('Siglec15', 'Gene', (60, 68))
64890	33537076	In addition, Siglec15 was negatively correlated with the marker genes of macrophages (Figure S14B-E).	('Siglec15', 'Gene', '284266', (13, 21))	('S14B', 'SUBSTITUTION', 'None', (93, 97))	('negatively', 'NegReg', (26, 36))	('S14B', 'Var', (93, 97))	('correlated', 'Interaction', (37, 47))	('Siglec15', 'Gene', (13, 21))
64902	33537076	Finally, we found that the Siglec15 expression was negatively correlated with the PD-L1 expression (Figure 4E, Figure S14J).	('PD-L1', 'Gene', (82, 87))	('negatively', 'NegReg', (51, 61))	('Siglec15', 'Gene', '284266', (27, 35))	('S14J', 'Var', (118, 122))	('S14J', 'SUBSTITUTION', 'None', (118, 122))	('PD-L1', 'Gene', '29126', (82, 87))	('expression', 'MPA', (36, 46))	('Siglec15', 'Gene', (27, 35))
64904	33537076	Siglec15 was negatively correlated with a majority of immunomodulators, effector genes of TIICs, and immune checkpoints in GSE32894, GSE31684, and IMvigor210 cohorts (Figure S15A-C, Figure S16A-C, Figure S17A-C).	('Siglec15', 'Gene', (0, 8))	('S17A', 'Mutation', 'p.S17A', (204, 208))	('Siglec15', 'Gene', '284266', (0, 8))	('S15A', 'Var', (174, 178))	('S15A', 'SUBSTITUTION', 'None', (174, 178))	('negatively', 'NegReg', (13, 23))	('S16A', 'Mutation', 'p.S16A', (189, 193))
64911	33537076	Results of the subgroup analyses indicated that high Siglec15 was negatively correlated with these immune signatures and predicted a lower response to immunotherapy in all subgroups (Figure S18-S21).	('negatively', 'NegReg', (66, 76))	('S21', 'Gene', '6227', (194, 197))	('S18', 'Gene', (190, 193))	('Siglec15', 'Gene', (53, 61))	('response to immunotherapy', 'CPA', (139, 164))	('S21', 'Gene', (194, 197))	('S18', 'Gene', '6222', (190, 193))	('high', 'Var', (48, 52))	('lower', 'NegReg', (133, 138))	('Siglec15', 'Gene', '284266', (53, 61))
64934	33537076	Consequently, inhibiting these pathways promoted the formation of an inflamed TME, thereby reactivating cancer immunity.	('promoted', 'PosReg', (40, 48))	('reactivating', 'PosReg', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('inhibiting', 'Var', (14, 24))	('formation', 'biological_process', 'GO:0009058', ('53', '62'))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
64938	33537076	Therefore, targeted therapy blocking these pathways can be used in combination with anti-Siglec15 therapy for the treatment of BLCA with high Siglec15 expression.	('Siglec15', 'Gene', (89, 97))	('Siglec15', 'Gene', (142, 150))	('BLCA', 'Phenotype', 'HP:0009725', (127, 131))	('Siglec15', 'Gene', '284266', (89, 97))	('high', 'Var', (137, 141))	('BLCA', 'Disease', (127, 131))	('Siglec15', 'Gene', '284266', (142, 150))
64940	33537076	We found that anti-angiogenic therapy may be suitable for BLCA with high Siglec15 expression (Figure 5G, Table S10).	('expression', 'MPA', (82, 92))	('Siglec15', 'Gene', (73, 81))	('high', 'Var', (68, 72))	('BLCA', 'Phenotype', 'HP:0009725', (58, 62))	('Siglec15', 'Gene', '284266', (73, 81))	('S10', 'Gene', (111, 114))	('S10', 'Gene', '6204', (111, 114))
64961	33537076	Overall, 524 DERs were found to affect prognosis based on univariate Cox analysis (Table S18).	('affect', 'Reg', (32, 38))	('S18', 'Gene', (89, 92))	('DERs', 'Var', (13, 17))	('prognosis', 'MPA', (39, 48))	('S18', 'Gene', '6222', (89, 92))
64963	33537076	As shown in Figure 7D, patients with low IRS had significantly longer overall survival time than those with high IRS.	('patients', 'Species', '9606', (23, 31))	('low IRS', 'Var', (37, 44))	('overall survival', 'MPA', (70, 86))	('longer', 'PosReg', (63, 69))
64968	33537076	The expression of several immune checkpoints, such as PD-L1, CTLA-4, and LAG-3, was significantly higher in the high IRS group (Figure S29C).	('LAG-3', 'Gene', (73, 78))	('LAG-3', 'Gene', '3902', (73, 78))	('CTLA-4', 'Gene', '1493', (61, 67))	('S29C', 'Mutation', 'p.S29C', (135, 139))	('PD-L1', 'Gene', (54, 59))	('expression', 'MPA', (4, 14))	('higher', 'PosReg', (98, 104))	('high IRS', 'Var', (112, 120))	('PD-L1', 'Gene', '29126', (54, 59))	('CTLA-4', 'Gene', (61, 67))
64970	33537076	Lastly, the enrichment scores of most immunotherapy positively related signatures were significantly higher in the high IRS group (Figure S29G).	('enrichment scores', 'MPA', (12, 29))	('high IRS', 'Var', (115, 123))	('S29G', 'Mutation', 'rs753987047', (138, 142))	('higher', 'PosReg', (101, 107))
64972	33537076	In GSE78220 (melanoma), TIDE behaved better in predicting the ICB response than IRS (C-index: 0.76 Vs. 0.69) (Figure S30A) Meanwhile, high TIDE or IRS predicted poor prognosis (Figure S30B-C).	('S30B', 'Var', (184, 188))	('S30A', 'Mutation', 'p.S30A', (117, 121))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Disease', (13, 21))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('high TIDE', 'MPA', (134, 143))	('ICB', 'Chemical', '-', (62, 65))	('GSE78220', 'Var', (3, 11))	('S30B', 'SUBSTITUTION', 'None', (184, 188))
64974	33537076	In GSE91061 (melanoma), there was no difference in the predictive accuracy in predicting ICB response between the two algorithms (Figure S31A).	('S31A', 'Var', (137, 141))	('S31A', 'SUBSTITUTION', 'None', (137, 141))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Disease', (13, 21))	('ICB', 'Chemical', '-', (89, 92))	('GSE91061', 'Var', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))
64977	33537076	In PMID29301960 (KIRC), IRS behaved better in predicting ICB response than TIDE (C-index: 0.75 vs. 0.56) (Figure S32A).	('PMID29301960', 'Var', (3, 15))	('S32A', 'Mutation', 'rs1250629456', (113, 117))	('ICB response', 'MPA', (57, 69))	('ICB', 'Chemical', '-', (57, 60))
64988	33537076	Findings from preclinical research and phase I clinical trials of Siglec15 inhibitors indicated that Siglec15 may be a broad-spectrum therapeutic target.	('inhibitors', 'Var', (75, 85))	('Siglec15', 'Gene', (66, 74))	('Siglec15', 'Gene', (101, 109))	('Siglec15', 'Gene', '284266', (66, 74))	('Siglec15', 'Gene', '284266', (101, 109))
65002	33537076	In our study, the expression of inhibitory immune checkpoints was significantly downregulated in the high Siglec15 group, which might be attributed to the downregulation of pre-existing TIICs.	('Siglec15', 'Gene', (106, 114))	('inhibitory immune', 'MPA', (32, 49))	('Siglec15', 'Gene', '284266', (106, 114))	('pre', 'molecular_function', 'GO:0003904', ('173', '176'))	('expression', 'MPA', (18, 28))	('downregulated', 'NegReg', (80, 93))	('high', 'Var', (101, 105))
65015	33537076	Likewise, a prior treatment option for BLCA with high Siglec15 expression was to transform a non-inflamed TME into an inflamed TME and consequently trigger an anti-cancer immune response.	('Siglec15', 'Gene', '284266', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('BLCA', 'Phenotype', 'HP:0009725', (39, 43))	('transform', 'Reg', (81, 90))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('high', 'Var', (49, 53))	('Siglec15', 'Gene', (54, 62))	('immune response', 'biological_process', 'GO:0006955', ('171', '186'))	('trigger', 'Reg', (148, 155))
65021	33537076	Interestingly, we found that CSF1R and CSF1 were downregulated in samples with high Siglec15 expression.	('CSF1', 'Gene', '1435', (29, 33))	('CSF1R', 'Gene', (29, 34))	('CSF1', 'Gene', (29, 33))	('CSF1', 'Gene', '1435', (39, 43))	('CSF1', 'molecular_function', 'GO:0005011', ('29', '33'))	('CSF1', 'Gene', (39, 43))	('high', 'Var', (79, 83))	('Siglec15', 'Gene', (84, 92))	('expression', 'MPA', (93, 103))	('downregulated', 'NegReg', (49, 62))	('CSF1', 'molecular_function', 'GO:0005011', ('39', '43'))	('CSF1R', 'Gene', '1436', (29, 34))	('Siglec15', 'Gene', '284266', (84, 92))
65125	32832698	Interestingly, and somewhat similar to the estimates by Sloan et al for localized bladder cancer, stage 0 patients in our study treated with LOC generated the greatest lifetime burden ($188,140) as well as continuation costs ($1,208 per month), compared to LOC recipients of higher disease stage.	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('localized bladder cancer', 'Disease', 'MESH:D001749', (72, 96))	('localized bladder cancer', 'Disease', (72, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('patients', 'Species', '9606', (106, 114))	('LOC', 'Var', (141, 144))
65130	32832698	At the same time, however, stage III LOC recipients had lower lifetime costs than the average stage III patients, mainly attributable to lower costs during the continuation phase.	('LOC', 'Var', (37, 40))	('lifetime costs', 'MPA', (62, 76))	('lower', 'NegReg', (137, 142))	('lower', 'NegReg', (56, 61))	('patients', 'Species', '9606', (104, 112))
65145	31762799	Establishing the prediction models for recurrence and progression of T1G3 bladder urothelial carcinoma We aim to determine clinical recurrence and progression risk factors of T1G3 bladder cancer (BCa), and to establish recurrence and progression prediction models.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('bladder cancer', 'Disease', 'MESH:D001749', (180, 194))	('bladder cancer', 'Disease', (180, 194))	('BCa', 'Phenotype', 'HP:0009725', (196, 199))	('BCa', 'Disease', (196, 199))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('T1G3', 'Var', (175, 179))	('BCa', 'Disease', 'MESH:D001749', (196, 199))	('bladder cancer', 'Phenotype', 'HP:0009725', (180, 194))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (74, 102))	('bladder urothelial carcinoma', 'Disease', (74, 102))
65166	31762799	In the current study, a retrospective analysis of 106 patients with T1G3 bladder cancer in our hospital was performed, to determine the recurrence risk factors of these patients, including large size of tumor, multifocal tumors, recrudescent tumor, Non-BCG perfusion therapy, as well as progression risk factors, including large size of tumor, multifocal tumors, recrudescent tumor and concomitant CIS.	('tumor', 'Disease', (203, 208))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Disease', (376, 381))	('tumor', 'Disease', (337, 342))	('BCG', 'Species', '33892', (253, 256))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumors', 'Phenotype', 'HP:0002664', (355, 361))	('multifocal tumors', 'Disease', 'None', (210, 227))	('tumor', 'Disease', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('multifocal tumors', 'Disease', 'None', (344, 361))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (376, 381))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('bladder cancer', 'Disease', (73, 87))	('multifocal tumors', 'Disease', (210, 227))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('multifocal tumors', 'Disease', (344, 361))	('CIS', 'Phenotype', 'HP:0030075', (398, 401))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('tumor', 'Disease', 'MESH:D009369', (355, 360))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('recrudescent tumor', 'Disease', (229, 247))	('tumor', 'Disease', (221, 226))	('recrudescent tumor', 'Disease', (363, 381))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('recrudescent tumor', 'Disease', 'MESH:D012008', (229, 247))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('recrudescent tumor', 'Disease', 'MESH:D012008', (363, 381))	('patients', 'Species', '9606', (169, 177))	('tumor', 'Disease', (355, 360))	('T1G3', 'Var', (68, 72))
65169	31762799	The development cohort included 106 patients with T1G3 bladder cancer at the Department of Urology, Zhongnan Hospital of Wuhan University from January 2012 to December 2016.	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('bladder cancer', 'Disease', (55, 69))	('patients', 'Species', '9606', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('men', 'Species', '9606', (83, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('T1G3', 'Var', (50, 54))	('men', 'Species', '9606', (11, 14))
65172	31762799	Several studies have compared the two classification methods, indicating that that WHO1973 grade cannot be replaced by the WHO2004 classification in NMIBC guidelines.	('WHO1973', 'CellLine', 'CVCL:E046', (83, 90))	('MIBC', 'Disease', 'MESH:D001749', (150, 154))	('MIBC', 'Disease', (150, 154))	('WHO1973', 'Var', (83, 90))
65186	31762799	Cox univariate and multivariate analyses were performed to determine the independent recurrence and progression risk factors of T1G3 bladder urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('T1G3', 'Var', (128, 132))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (133, 161))	('bladder urothelial carcinoma', 'Disease', (133, 161))
65195	31762799	Table 3 listed the clinicopathological factors of T1G3 bladder cancer recurrence.	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('bladder cancer', 'Disease', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('T1G3', 'Var', (50, 54))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (55, 80))
65197	31762799	Chi-square test results showed that T1G3 BCa recurrence was associated with gender (p=0.035), multifocal (p=0.018), past medical history (p=0.024) and perfusion therapy (p=0.028).	('BCa', 'Phenotype', 'HP:0009725', (41, 44))	('T1G3', 'Var', (36, 40))	('BCa', 'Disease', 'MESH:D001749', (41, 44))	('BCa', 'Disease', (41, 44))
65199	31762799	Whereas no significant association was seen between T1G3 bladder cancer recurrence and several factors in our study, including smoking history, tumor location, concomitant CIS and operative method.	('tumor', 'Disease', (144, 149))	('bladder cancer', 'Disease', 'MESH:D001749', (57, 71))	('bladder cancer', 'Disease', (57, 71))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (57, 82))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('T1G3', 'Var', (52, 56))	('CIS', 'Phenotype', 'HP:0030075', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))
65201	31762799	It showed that T1G3 BCa progression was associated with tumor size (p=0.026), multifocal (p=0.017), past medical history (p=0.045) and concomitant CIS (p=0.044).	('BCa', 'Disease', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('progression', 'PosReg', (24, 35))	('BCa', 'Disease', 'MESH:D001749', (20, 23))	('CIS', 'Phenotype', 'HP:0030075', (147, 150))	('T1G3', 'Var', (15, 19))	('CIS', 'Disease', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('BCa', 'Phenotype', 'HP:0009725', (20, 23))
65207	31762799	In the Kaplan-Meier survival analyses, compared to those T1G3 BCa patients with little size of tumor (<3 cm), unifocal tumor, initial tumor and BCG perfusion therapy, patients with large size of tumor (>=3 cm; HR=1.822; 95%CI: 1.413 - 2.350; p<0.0001), multifocal tumors (HR=2.038; 95%CI: 1.555 - 2.671; p<0.0001), recrudescent tumor (HR=1.801; 95%CI: 1.218 - 2.663; p=0.0004) and Non-BCG perfusion therapy (HR=2.423; 95%CI: 1.660 - 3.538; p<0.0001) had adverse recurrence survival.	('tumor', 'Disease', (195, 200))	('Non-BCG perfusion therapy', 'Var', (381, 406))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', (328, 333))	('BCa', 'Phenotype', 'HP:0009725', (62, 65))	('tumor', 'Disease', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('BCG', 'Species', '33892', (385, 388))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('multifocal tumors', 'Disease', 'None', (253, 270))	('recrudescent tumor', 'Disease', (315, 333))	('multifocal tumors', 'Disease', (253, 270))	('recrudescent tumor', 'Disease', 'MESH:D012008', (315, 333))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', (134, 139))	('patients', 'Species', '9606', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', (119, 124))	('BCa', 'Disease', (62, 65))	('BCa', 'Disease', 'MESH:D001749', (62, 65))	('patients', 'Species', '9606', (167, 175))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('BCG', 'Species', '33892', (144, 147))
65209	31762799	It indicated that large size of tumor, multifocal tumors, recrudescent tumor, Non-BCG perfusion therapy and concomitant CIS led to adverse prognostic impact for T1G3 BCa patients, which was consistent with cox multivariate analyses.	('recrudescent tumor', 'Disease', 'MESH:D012008', (58, 76))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('T1G3', 'Var', (161, 165))	('BCa', 'Phenotype', 'HP:0009725', (166, 169))	('tumor', 'Disease', (50, 55))	('multifocal tumors', 'Disease', 'None', (39, 56))	('patients', 'Species', '9606', (170, 178))	('cox', 'Gene', '1351', (206, 209))	('BCG', 'Species', '33892', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('CIS', 'Phenotype', 'HP:0030075', (120, 123))	('multifocal tumors', 'Disease', (39, 56))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('cox', 'Gene', (206, 209))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('recrudescent tumor', 'Disease', (58, 76))	('BCa', 'Disease', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('BCa', 'Disease', 'MESH:D001749', (166, 169))
65219	31762799	Among these patients, T1G3 tumors have a higher propensity to recur and progress to MIBC, and its death rates as high as 34%.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('T1G3', 'Var', (22, 26))	('patients', 'Species', '9606', (12, 20))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('MIBC', 'Disease', (84, 88))	('progress', 'PosReg', (72, 80))	('MIBC', 'Disease', 'MESH:D001749', (84, 88))
65220	31762799	T1G3 tumor have been repeatedly reported as important risk factors for NMIBC recurrence and progression in a number of publications, on account of the poor prognosis and the high recurrence rate of T1G3 BCa patients, the optimal treatment choice for these patients remains controversial.	('patients', 'Species', '9606', (207, 215))	('BCa', 'Phenotype', 'HP:0009725', (203, 206))	('BCa', 'Disease', (203, 206))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('MIBC', 'Disease', (72, 76))	('patients', 'Species', '9606', (256, 264))	('BCa', 'Disease', 'MESH:D001749', (203, 206))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('MIBC', 'Disease', 'MESH:D001749', (72, 76))	('tumor', 'Disease', (5, 10))	('T1G3', 'Var', (198, 202))	('men', 'Species', '9606', (234, 237))
65221	31762799	It has been reported that the 5-year progression-free survival rate of T1G3 BCa patients treated with TURBT and intravesical BCG/chemotherapy was in the range of 60-80%, while the T1G3 BCa patients with immediate radical cystectomy were reported with a 65-85% 5-year progression-free survival rate, indicating that there was no much difference in prognosis between the two treatment approaches.	('BCa', 'Phenotype', 'HP:0009725', (185, 188))	('men', 'Species', '9606', (378, 381))	('BCa', 'Disease', (185, 188))	('patients', 'Species', '9606', (80, 88))	('BCG', 'Species', '33892', (125, 128))	('BCa', 'Phenotype', 'HP:0009725', (76, 79))	('BCa', 'Disease', (76, 79))	('BCa', 'Disease', 'MESH:D001749', (185, 188))	('BCa', 'Disease', 'MESH:D001749', (76, 79))	('patients', 'Species', '9606', (189, 197))	('T1G3', 'Var', (71, 75))
65242	31762799	Besides the gender and smoking history, the correlation analysis between recurrence and clinicopathological factors of T1G3 bladder urothelial carcinoma indicated T1G3 BCa recurrence was associated with old age (p=0.047), tumor size (p=0.031), multifocal (p=0.018), past medical history (p=0.024) and perfusion therapy (p=0.028).	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('bladder urothelial carcinoma', 'Disease', (124, 152))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('BCa', 'Disease', 'MESH:D001749', (168, 171))	('T1G3', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('T1G3', 'Var', (163, 167))	('BCa', 'Phenotype', 'HP:0009725', (168, 171))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (124, 152))	('BCa', 'Disease', (168, 171))
65244	31762799	In addition, the correlation analysis between progression and clinicopathological factors of T1G3 bladder urothelial carcinoma showed that T1G3 BCa progression was associated with tumor size (p=0.026), multifocal (p=0.017), past medical history (p=0.045) and concomitant CIS (p=0.044).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('BCa', 'Phenotype', 'HP:0009725', (144, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('BCa', 'Disease', (144, 147))	('associated', 'Reg', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('T1G3', 'Var', (139, 143))	('tumor', 'Disease', (180, 185))	('BCa', 'Disease', 'MESH:D001749', (144, 147))	('CIS', 'Phenotype', 'HP:0030075', (271, 274))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (98, 126))	('CIS', 'Disease', (271, 274))	('bladder urothelial carcinoma', 'Disease', (98, 126))	('T1G3', 'Gene', (93, 97))
65247	31762799	has developed a clinical decision-making tool (nomogram) to predict the progression to muscle-invasive disease in patients with pT1G3 bladder cancer.	('muscle-invasive disease', 'Disease', (87, 110))	('bladder cancer', 'Disease', 'MESH:D001749', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('muscle-invasive disease', 'Disease', 'MESH:D019042', (87, 110))	('bladder cancer', 'Disease', (134, 148))	('patients', 'Species', '9606', (114, 122))	('pT1G3', 'Var', (128, 133))	('bladder cancer', 'Phenotype', 'HP:0009725', (134, 148))
65255	31762799	Based on 106 patients with T1G3 BCa in our hospital, this study evaluated several recrudescent and progresses risk factors of T1G3 bladder urothelial carcinoma, indicating that large size of tumor, multifocal tumors, recrudescent tumor were the independent risk factors for T1G3 BCa recurrence, meanwhile BCG perfusion therapy was a protective factor for recurrence.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (131, 159))	('patients', 'Species', '9606', (13, 21))	('BCa', 'Phenotype', 'HP:0009725', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (209, 214))	('BCG', 'Species', '33892', (305, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('BCa', 'Phenotype', 'HP:0009725', (279, 282))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('multifocal tumors', 'Disease', 'None', (198, 215))	('tumor', 'Disease', (230, 235))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('BCa', 'Disease', (279, 282))	('BCa', 'Disease', 'MESH:D001749', (279, 282))	('BCa', 'Disease', (32, 35))	('multifocal tumors', 'Disease', (198, 215))	('tumor', 'Disease', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('BCa', 'Disease', 'MESH:D001749', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('recrudescent tumor', 'Disease', (217, 235))	('T1G3', 'Var', (126, 130))	('T1G3', 'Gene', (274, 278))	('bladder urothelial carcinoma', 'Disease', (131, 159))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('recrudescent tumor', 'Disease', 'MESH:D012008', (217, 235))
65301	31632067	It is generally understood the gene variation plays a vitally significant role in the emergence and development of carcinoma, associated with prognosis and cancer-specific survival as well.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinoma', 'Disease', (115, 124))	('gene variation', 'Var', (31, 45))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('carcinoma', 'Disease', 'MESH:D002277', (115, 124))
65303	31632067	Nowadays, gene expression profiling for cancer has gained increasing attention owing to its ability to figure out a detailed and complete map to discover the molecular cancer subtypes at the transcriptome level, or based on the genetic and epigenetic alteration.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('gene expression', 'biological_process', 'GO:0010467', ('10', '25'))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', (168, 174))	('epigenetic alteration', 'Var', (240, 261))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
65306	31632067	A group fixes their concentration on the relationship between copy number variation and lymph node metastasis, consequently detect copy number gain at chr3p25 and chr11p11, approximately a set of 22 genes, which related to Ln+ and survival in bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('copy number gain', 'Var', (131, 147))	('bladder cancer', 'Phenotype', 'HP:0009725', (243, 257))	('chr11p11', 'Gene', (163, 171))	('related', 'Reg', (212, 219))	('chr3p25', 'Gene', (151, 158))	('bladder cancer', 'Disease', (243, 257))	('bladder cancer', 'Disease', 'MESH:D001749', (243, 257))	('Ln', 'Chemical', 'MESH:C401404', (223, 225))	('Ln+', 'Disease', (223, 226))
65343	31632067	Proteolytic processing of VEGF-C has proved to increase its receptor affinity and biological activity.	('receptor affinity', 'Interaction', (60, 77))	('VEGF-C', 'Gene', '7424', (26, 32))	('VEGF-C', 'Gene', (26, 32))	('increase', 'PosReg', (47, 55))	('biological activity', 'MPA', (82, 101))	('Proteolytic processing', 'Var', (0, 22))
65363	31632067	Cross-talks between Shh and TGF-beta may participate in the development and progression of bladder cancer as the consequence of manifesting EMT and bladder cancer stemness.	('Cross-talks', 'Var', (0, 11))	('bladder cancer stemness', 'Disease', 'MESH:D001749', (148, 171))	('bladder cancer', 'Disease', 'MESH:D001749', (148, 162))	('TGF-beta', 'Gene', (28, 36))	('Shh', 'Gene', '6469', (20, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (148, 162))	('bladder cancer', 'Disease', (91, 105))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('bladder cancer stemness', 'Disease', (148, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('EMT', 'biological_process', 'GO:0001837', ('140', '143'))	('Shh', 'Gene', (20, 23))	('participate', 'Reg', (41, 52))	('TGF-beta', 'Gene', '7040', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
65386	31632067	As a consequence, inhibition of VEGF-C/VEGF-D/VEGFR-3 recognizes a potential way to restrain tumor progression.	('VEGF-C', 'Gene', '7424', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('VEGF-D', 'Gene', (39, 45))	('tumor', 'Disease', (93, 98))	('VEGF-D', 'Gene', '2277', (39, 45))	('VEGF-C', 'Gene', (32, 38))	('restrain', 'NegReg', (84, 92))	('VEGFR-3', 'Gene', '2324', (46, 53))	('inhibition', 'Var', (18, 28))	('VEGFR-3', 'Gene', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
65392	31632067	Other potentially useful reagents, including neutralizing mAbs to NRP2 and COX enzymes, are also in undergoing investigation, with showing potential therapeutic targets.	('mAbs', 'Var', (58, 62))	('NRP2', 'Gene', (66, 70))	('NRP', 'biological_process', 'GO:0085015', ('66', '69'))	('NRP2', 'Gene', '8828', (66, 70))	('neutralizing mAbs', 'Var', (45, 62))	('COX enzymes', 'Enzyme', (75, 86))
65401	31632067	To more specific, direct LEC-T cell interactions and antigen presentation to dendritic cells can induce the dysfunctional CD8+ T cell activation or the CD4+ T cell apoptosis, or lymphatic endothelial cells produce several biological factors(e.g., IDO, MHCs, and NO) that indirectly aid in the maintenance of regulatory T cell populations and impairment of DCs maturation and T cell activation.	('interactions', 'Var', (36, 48))	('LEC', 'Gene', (25, 28))	('LEC', 'Gene', '6360', (25, 28))	('T cell apoptosis', 'biological_process', 'GO:0070231', ('157', '173'))	('IDO', 'molecular_function', 'GO:0033754', ('247', '250'))	('T cell activation', 'CPA', (375, 392))	('T cell activation', 'biological_process', 'GO:0042110', ('127', '144'))	('antigen presentation', 'biological_process', 'GO:0019882', ('53', '73'))	('DCs maturation', 'CPA', (356, 370))	('T cell activation', 'biological_process', 'GO:0042110', ('375', '392'))	('IDO', 'molecular_function', 'GO:0047719', ('247', '250'))	('N', 'Chemical', 'MESH:D009584', (262, 263))	('regulatory T cell populations', 'CPA', (308, 337))	('aid', 'PosReg', (282, 285))
65407	31632067	It is thus urgent to decipher precisely the roles for LVs in tumor cell dissemination and anti-tumor T cell immunity; Furthermore, novel imaging methods and whole-genome functional screens with LECs are needed to monitor the efficiency of anti-lymphangiogenesis drugs accurately, and to provide precise treatment for those patients who can get more benefits from these treatments; Additionally, anti-lymphangiogenic therapy may enhance interstitial fluid pressure and hamper drug delivery to cancerous cells.	('tumor T', 'Disease', 'MESH:D009369', (95, 102))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('244', '261'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('enhance', 'PosReg', (428, 435))	('patients', 'Species', '9606', (323, 331))	('interstitial fluid pressure', 'MPA', (436, 463))	('cancerous', 'Disease', 'MESH:D009369', (492, 501))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor T', 'Disease', (95, 102))	('hamper', 'NegReg', (468, 474))	('cancer', 'Phenotype', 'HP:0002664', (492, 498))	('LEC', 'Gene', '6360', (194, 197))	('cancerous', 'Disease', (492, 501))	('tumor', 'Disease', (95, 100))	('anti-lymphangiogenic therapy', 'Var', (395, 423))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('LEC', 'Gene', (194, 197))	('tumor', 'Disease', (61, 66))
65413	31632067	Currently, the VEGF-C/VEGF-D-VEGFR-3 pathway is correlated with the tumor-derived lymphatic vessels and metastasis in UBC, blocking such signaling pathway suppresses tumor lymphangiogenesis.	('blocking', 'Var', (123, 131))	('VEGFR-3', 'Gene', (29, 36))	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('VEGF-C', 'Gene', '7424', (15, 21))	('VEGF-D', 'Gene', '2277', (22, 28))	('tumor', 'Disease', (166, 171))	('VEGF-D', 'Gene', (22, 28))	('UBC', 'Disease', 'MESH:D001749', (118, 121))	('signaling pathway', 'biological_process', 'GO:0007165', ('137', '154'))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('VEGFR-3', 'Gene', '2324', (29, 36))	('VEGF-C', 'Gene', (15, 21))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('172', '189'))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('suppresses', 'NegReg', (155, 165))	('UBC', 'Disease', (118, 121))
65502	28134806	irAEs were more common in the pembrolizumab arm including thyroid abnormalities (9.4% vs. 1.6%), pneumonitis (4.1% vs. 0.4%), and colitis (2.3% vs. 0.4%).	('pembrolizumab', 'Chemical', 'MESH:C582435', (30, 43))	('pneumonitis', 'Disease', (97, 108))	('colitis', 'Phenotype', 'HP:0002583', (130, 137))	('AEs', 'Chemical', 'MESH:C045560', (2, 5))	('colitis', 'Disease', 'MESH:D003092', (130, 137))	('thyroid abnormalities', 'Phenotype', 'HP:0000820', (58, 79))	('pneumonitis', 'Disease', 'MESH:D011014', (97, 108))	('pembrolizumab', 'Var', (30, 43))	('thyroid abnormalities', 'Disease', 'MESH:D013959', (58, 79))	('colitis', 'Disease', (130, 137))	('thyroid abnormalities', 'Disease', (58, 79))
65533	28134806	Median PFS was two months (1.87 months in patients with <1% PD-L1 expression (n = 143) and 3.55 months in patients with PD-L1 expression of >1% (n = 122)).	('expression', 'Var', (66, 76))	('patients', 'Species', '9606', (42, 50))	('patients', 'Species', '9606', (106, 114))	('PD-L1', 'Gene', (60, 65))
65535	28134806	In a further biomarker analysis, ORR was 28.4% in patients expressing PD-L1 >=5% and 15.8% in patients expressing PD-L1 <5%.	('PD-L1 >=5%', 'Var', (70, 80))	('>=5%', 'Var', (76, 80))	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (94, 102))
65587	28134806	Others were split into a two-armed phase II dose expansion study of only chemo-refractory subjects receiving either 0.06 mg/kg ALT-801 and GC or 0.06 mg/kg ALT-801 and G depending on renal function (group 2).	('0.06 mg/kg', 'Var', (116, 126))	('ALT', 'Gene', '76282', (156, 159))	('ALT', 'molecular_function', 'GO:0004021', ('156', '159'))	('GC', 'Chemical', '-', (139, 141))	('ALT', 'Gene', (127, 130))	('0.06 mg/kg', 'Var', (145, 155))	('ALT', 'Gene', '76282', (127, 130))	('ALT', 'molecular_function', 'GO:0004021', ('127', '130'))	('ALT', 'Gene', (156, 159))
65592	28134806	Interleukin-15 (IL-15) is a key factor for the development, proliferation, and activation of effector natural killer (NK) cells and CD8+ memory T cells, and ALT-803 is a novel IL-15 mutant (N72D) with enhanced IL-15 biological activity.	('IL-15', 'Gene', '3600', (176, 181))	('memory', 'biological_process', 'GO:0007613', ('137', '143'))	('IL-15', 'molecular_function', 'GO:0016170', ('16', '21'))	('ALT', 'Gene', (157, 160))	('IL-15', 'Gene', '3600', (16, 21))	('ALT', 'molecular_function', 'GO:0004021', ('157', '160'))	('IL-15', 'molecular_function', 'GO:0016170', ('176', '181'))	('IL-15', 'Gene', (176, 181))	('enhanced', 'PosReg', (201, 209))	('IL-15', 'Gene', (210, 215))	('ALT', 'Gene', '76282', (157, 160))	('Interleukin-15', 'Gene', (0, 14))	('N72D', 'Mutation', 'p.N72D', (190, 194))	('N72D', 'Var', (190, 194))	('Interleukin-15', 'Gene', '3600', (0, 14))	('IL-15', 'molecular_function', 'GO:0016170', ('210', '215'))	('IL-15', 'Gene', (16, 21))	('IL-15', 'Gene', '3600', (210, 215))
65609	28134806	While PD-L1 expression seems to correlate to greater treatment response, the current approval of atezolizumab does not require PD-L1 testing.	('treatment response', 'CPA', (53, 71))	('expression', 'Var', (12, 22))	('greater', 'PosReg', (45, 52))	('PD-L1', 'Gene', (6, 11))	('atezolizumab', 'Chemical', 'MESH:C000594389', (97, 109))
65637	24518776	In contrast, NAC was aligned to the inclusion criteria in the SWOG study (pre-surgical treatment with chemotherapy for patients with clinical tumor-node- metastasis (TNM) stage T2N0M0 to T4aN0M0).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('pre', 'molecular_function', 'GO:0003904', ('74', '77'))	('tumor', 'Disease', (142, 147))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('NAC', 'cellular_component', 'GO:0005854', ('13', '16'))	('NAC', 'Chemical', '-', (13, 16))	('T4aN0M0', 'Var', (187, 194))
65726	33845814	In mice, CD276 binds to the triggering receptor expressed on myeloid cells like transcript 2 (TLT-2) protein to modulate T-cell responses.	('CD276', 'Var', (9, 14))	('mice', 'Species', '10090', (3, 7))	('modulate', 'Reg', (112, 120))	('TLT-2', 'Gene', (94, 99))	('T-cell responses', 'CPA', (121, 137))	('TLT-2', 'Gene', '328833', (94, 99))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))
65728	33845814	In another study, CD276 prevented activation of anti-tumor responses by blocking CD4+Th1- activation.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('blocking', 'NegReg', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('CD4', 'Gene', (81, 84))	('CD276', 'Var', (18, 23))	('tumor', 'Disease', (53, 58))	('CD4', 'Gene', '920', (81, 84))
65729	33845814	There is experimental evidence promising success of anti-CD276 tumor therapies, and several clinical studies are underway or already completed (see https://clinicaltrials.gov).	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('anti-CD276', 'Var', (52, 62))
65772	33845814	Total protein expression is often regulated on the transcript level and tumor grade-depended elevation of CD276 transcripts and CD276 total protein were found in BC.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('BC', 'Phenotype', 'HP:0009725', (162, 164))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('Total', 'MPA', (0, 5))	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('CD276', 'Var', (128, 133))	('tumor', 'Disease', (72, 77))	('CD276', 'Gene', (106, 111))	('elevation', 'PosReg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('transcripts', 'MPA', (112, 123))
65820	33451055	Since EGFR-driven signaling is related to unregulated cell growth and division through several molecular pathways, EGFR gene mutations and amplifications have been considered targetable alterations in a variety of cancers.	('mutations', 'Var', (125, 134))	('EGFR', 'molecular_function', 'GO:0005006', ('6', '10'))	('EGFR', 'Gene', (6, 10))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancers', 'Disease', (214, 221))	('EGFR', 'Gene', '1956', (115, 119))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('EGFR', 'molecular_function', 'GO:0005006', ('115', '119'))	('EGFR', 'Gene', (115, 119))	('cell growth', 'biological_process', 'GO:0016049', ('54', '65'))	('EGFR', 'Gene', '1956', (6, 10))
65821	33451055	Recent studies have reported that nearly 14% of urothelial tumors have some amplification or overexpression of EGFR, these aberrations being associated with more aggressive forms of the disease and a tendency to developing CT resistance.	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('EGFR', 'Gene', '1956', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('urothelial tumors', 'Disease', 'MESH:D001749', (48, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('EGFR', 'Gene', (111, 115))	('associated', 'Reg', (141, 151))	('CT resistance', 'MPA', (223, 236))	('urothelial tumors', 'Disease', (48, 65))	('overexpression', 'PosReg', (93, 107))	('amplification', 'Var', (76, 89))
65832	33451055	Although anti-HER2 targeted therapy has been mainly developed in breast and gastric cancer, recent comprehensive molecular profiling has demonstrated an incidence of ErbB family mutations, amplifications and over-expression in up to 20-30% of BC patients, with particularly high rates of HER2 alterations in micropapillary bladder tumors.	('ErbB', 'Gene', '1956', (166, 170))	('patients', 'Species', '9606', (246, 254))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('over-expression', 'Var', (208, 223))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('amplifications', 'Var', (189, 203))	('HER2', 'Gene', (288, 292))	('micropapillary bladder tumors', 'Disease', 'MESH:D001749', (308, 337))	('HER2', 'Gene', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (331, 337))	('gastric cancer', 'Disease', (76, 90))	('HER2', 'Gene', '2064', (14, 18))	('ErbB', 'Gene', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder tumors', 'Phenotype', 'HP:0009725', (323, 337))	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('micropapillary bladder tumors', 'Disease', (308, 337))	('HER2', 'Gene', '2064', (288, 292))	('BC', 'Phenotype', 'HP:0009725', (243, 245))	('mutations', 'Var', (178, 187))
65834	33451055	Although HER2 has been undoubtedly proved a prognostic and predictive biomarker in human cancer, its clinical extrapolation is conditioned by the variability of reported HER2 alterations depending on the disease stage, the tested populations and both inter-tumor and intra-tumor heterogeneity.	('HER2', 'Gene', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (257, 262))	('HER2', 'Gene', '2064', (170, 174))	('HER2', 'Gene', (9, 13))	('intra-tumor', 'Disease', 'MESH:D009369', (267, 278))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('HER2', 'Gene', '2064', (9, 13))	('human', 'Species', '9606', (83, 88))	('cancer', 'Disease', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('intra-tumor', 'Disease', (267, 278))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('alterations', 'Var', (175, 186))
65846	33451055	The median period to progression/discontinuation was 6.6 months in cases with HER2 or ERBB3 mutations compared with 1.4 months in wild type cases.	('ERBB3', 'Gene', '2065', (86, 91))	('HER2', 'Gene', (78, 82))	('mutations', 'Var', (92, 101))	('ERBB3', 'Gene', (86, 91))	('HER2', 'Gene', '2064', (78, 82))
65847	33451055	These findings supported afatinib as a potential therapy in selected patients with HER2/ERBB3 alterations.	('afatinib', 'Chemical', 'MESH:D000077716', (25, 33))	('ERBB3', 'Gene', (88, 93))	('alterations', 'Var', (94, 105))	('patients', 'Species', '9606', (69, 77))	('HER2', 'Gene', (83, 87))	('ERBB3', 'Gene', '2065', (88, 93))	('HER2', 'Gene', '2064', (83, 87))
65848	33451055	A phase II is currently evaluating afatinib in mUC patients who have progressed to CT and harbor EGFR alterations (HER2/ERBB3 mutations, HER2 amplification, EGFR amplification).	('EGFR', 'Gene', (157, 161))	('alterations', 'Var', (102, 113))	('ERBB3', 'Gene', (120, 125))	('HER2', 'Gene', (115, 119))	('EGFR', 'Gene', '1956', (97, 101))	('HER2', 'Gene', '2064', (115, 119))	('afatinib', 'Chemical', 'MESH:D000077716', (35, 43))	('HER2', 'Gene', (137, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('157', '161'))	('EGFR', 'Gene', (97, 101))	('HER2', 'Gene', '2064', (137, 141))	('patients', 'Species', '9606', (51, 59))	('mutations', 'Var', (126, 135))	('EGFR', 'Gene', '1956', (157, 161))	('ERBB3', 'Gene', '2065', (120, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))
65879	33451055	Specifically, amplifications of FGFR1 gene have been found in 9-10% of urothelial BC, followed by FGFR3 (3-5%) and FGFR2 (0.8%), and activating mutations of FGFR3 gene have been described in 38-66% of non-invasive BC and 15-20% of invasive BC.	('FGFR3', 'Gene', (157, 162))	('FGFR2', 'Gene', (115, 120))	('BC', 'Phenotype', 'HP:0009725', (82, 84))	('urothelial BC', 'Disease', (71, 84))	('FGFR3', 'Gene', '2261', (157, 162))	('BC', 'Phenotype', 'HP:0009725', (240, 242))	('FGFR1', 'Gene', (32, 37))	('BC', 'Phenotype', 'HP:0009725', (214, 216))	('FGFR2', 'Gene', '2263', (115, 120))	('non-invasive BC', 'Disease', (201, 216))	('activating', 'PosReg', (133, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('FGFR3', 'Gene', (98, 103))	('amplifications', 'Var', (14, 28))	('FGFR3', 'Gene', '2261', (98, 103))	('invasive BC', 'Disease', (231, 242))	('FGFR', 'molecular_function', 'GO:0005007', ('157', '161'))	('FGFR', 'molecular_function', 'GO:0005007', ('115', '119'))	('FGFR1', 'Gene', '2260', (32, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('98', '102'))
65880	33451055	Amplification of FGFR represents around 66% of FGFR alterations, with FGFR1 being the most frequently amplified subtype.	('FGFR', 'Gene', (47, 51))	('FGFR', 'Gene', (17, 21))	('Amplification', 'Var', (0, 13))	('alterations', 'Var', (52, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('70', '74'))	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('FGFR1', 'Gene', (70, 75))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('FGFR1', 'Gene', '2260', (70, 75))
65881	33451055	FGFR1 amplification seems to be much more represented in early than advanced-stage tumors, suggesting a possible role of FGFR1 amplification during the initial phase of oncogenesis, which may be clinically relevant for therapeutic purposes.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'molecular_function', 'GO:0005007', ('121', '125'))	('tumors', 'Disease', (83, 89))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('FGFR1', 'Gene', (121, 126))	('amplification', 'Var', (6, 19))	('oncogenesis', 'biological_process', 'GO:0007048', ('169', '180'))	('amplification', 'Var', (127, 140))	('FGFR1', 'Gene', '2260', (121, 126))
65883	33451055	Despite these genetic alterations having set the stage for the development of targeted therapies, the modest response rates observed in clinical trials, and the accumulating evidence related to other TKIs, suggest that primary or acquired resistance is an unavoidable concern related to the current FGFR inhibitors.	('genetic alterations', 'Var', (14, 33))	('FGFR', 'molecular_function', 'GO:0005007', ('299', '303'))	('men', 'Species', '9606', (70, 73))	('acquired', 'CPA', (230, 238))	('FGFR', 'Gene', (299, 303))	('alterations', 'Var', (22, 33))
65885	33451055	Gatekeeper mutations, including FGFR1V561M, FGFR2V564F/I, FGFR3V555M and FGFR4V550E/L, can either occur de novo or during treatment with targeted therapies, leading to amino acid substitutions for the valine residue located in the drug-binding pocket of the tyrosine-kinase domain that may alter the mode of drug-FGFR interactions.	('Gatekeeper', 'Species', '111938', (0, 10))	('alter', 'Reg', (290, 295))	('FGFR2', 'Gene', (44, 49))	('FGFR1', 'Gene', (32, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('drug-binding', 'molecular_function', 'GO:0008144', ('231', '243'))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('FGFR4', 'Gene', '2264', (73, 78))	('FGFR2', 'Gene', '2263', (44, 49))	('substitutions', 'Var', (179, 192))	('amino acid substitutions', 'Var', (168, 192))	('men', 'Species', '9606', (127, 130))	('interactions', 'Interaction', (318, 330))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('tyrosine', 'Chemical', 'MESH:D014443', (258, 266))	('FGFR', 'molecular_function', 'GO:0005007', ('313', '317'))	('FGFR', 'molecular_function', 'GO:0005007', ('73', '77'))	('FGFR4', 'Gene', (73, 78))	('FGFR3', 'Gene', (58, 63))	('FGFR3', 'Gene', '2261', (58, 63))	('valine', 'Chemical', 'MESH:D014633', (201, 207))	('FGFR1', 'Gene', '2260', (32, 37))
65887	33451055	Further research is necessary to adequately monitor and identify the emergence of resistant tumor subclones with an activation of parallel pathways or secondary FGFR mutations, enabling the detection of treatment resistance and the stratification of patients to receive appropriate targeted therapies.	('mutations', 'Var', (166, 175))	('FGFR', 'Gene', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('patients', 'Species', '9606', (250, 258))	('FGFR', 'molecular_function', 'GO:0005007', ('161', '165'))	('men', 'Species', '9606', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
65888	33451055	Erdafitinib is a novel pan-FGFR kinase inhibitor recently approved by the FDA for patients with locally advanced cancer or mUC with susceptible FGFR3 or FGFR2 genetic alterations who have progressed during or following platinum-based CT. Approval was based on data from the primary analysis of the BLC2001 study.	('Erdafitinib', 'Chemical', 'MESH:C000604580', (0, 11))	('genetic alterations', 'Var', (159, 178))	('FGFR3', 'Gene', '2261', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('153', '157'))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('FGFR2', 'Gene', (153, 158))	('FGFR2', 'Gene', '2263', (153, 158))	('cancer', 'Disease', (113, 119))	('FGFR3', 'Gene', (144, 149))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('32', '48'))	('platinum', 'Chemical', 'MESH:D010984', (219, 227))
65895	33451055	The aim of the combination of an FGFR inhibitor and an anti-PD-1/PD-L1, such as NORSE study, FORT-2 or FIGHT-205, is to prove that targeting FGFR makes it possible to turn an immunologically cold tumor into a hot tumor.	('tumor', 'Disease', (213, 218))	('PD-L1', 'Gene', '29126', (65, 70))	('tumor', 'Disease', (196, 201))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('cold tumor', 'Disease', 'MESH:D000067390', (191, 201))	('FGFR', 'Gene', (141, 145))	('PD-L1', 'Gene', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('FGFR', 'molecular_function', 'GO:0005007', ('141', '145'))	('cold tumor', 'Disease', (191, 201))	('targeting', 'Var', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
65896	33451055	Therefore, a phase Ib/II clinical trial (NORSE study) evaluated erdafitinib in combination with cetrelimab, a PD-1 inhibitor, in 15 patients with mUC and FGFR2/3 alterations after progression to at least one line of treatment.	('erdafitinib', 'Chemical', 'MESH:C000604580', (64, 75))	('FGFR2/3', 'Gene', '2263;2261', (154, 161))	('alterations', 'Var', (162, 173))	('mUC', 'Gene', (146, 149))	('men', 'Species', '9606', (221, 224))	('FGFR', 'molecular_function', 'GO:0005007', ('154', '158'))	('FGFR2/3', 'Gene', (154, 161))	('cetrelimab', 'Chemical', '-', (96, 106))	('patients', 'Species', '9606', (132, 140))
65900	33451055	However, in high risk, BCG refractory NMIBC with FGFR gene alterations, erdafitinib is being compared with intravesical CT (NCT 04172675).	('alterations', 'Var', (59, 70))	('MIBC', 'Chemical', '-', (39, 43))	('FGFR', 'Gene', (49, 53))	('erdafitinib', 'Chemical', 'MESH:C000604580', (72, 83))	('BC', 'Phenotype', 'HP:0009725', (23, 25))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('BC', 'Phenotype', 'HP:0009725', (41, 43))
65903	33451055	Thirty-three mUC patients with activating FGFR3 mutations or fusions received BGJ398 125 mg on a once-a-day, 3 weeks on/1 week off regimen.	('BGJ398', 'Gene', (78, 84))	('FGFR3', 'Gene', '2261', (42, 47))	('men', 'Species', '9606', (135, 138))	('activating', 'PosReg', (31, 41))	('FGFR3', 'Gene', (42, 47))	('patients', 'Species', '9606', (17, 25))	('BGJ398', 'Chemical', 'MESH:C568950', (78, 84))	('mutations', 'Var', (48, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))
65912	33451055	In the exploratory analysis directed at patients with FGFR3 DNA mutations or fusions, ORR was 52.4% for rogaratinib:higher compared to CT's 26.7%.	('DNA', 'PosReg', (60, 63))	('FGFR3', 'Gene', (54, 59))	('patients', 'Species', '9606', (40, 48))	('fusions', 'Var', (77, 84))	('mutations', 'Var', (64, 73))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('FGFR', 'molecular_function', 'GO:0005007', ('54', '58'))	('FGFR3', 'Gene', '2261', (54, 59))
65918	33451055	Sixty-four patients with some FGFR3 mutation or fusion were assigned to cohort A, and 36 patients with other FGF/FGFR genetic mutations were assigned to cohort B and received pemigatinib.	('FGFR3', 'Gene', '2261', (30, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('113', '117'))	('FGFR3', 'Gene', (30, 35))	('fusion', 'Var', (48, 54))	('pemigatinib', 'Chemical', '-', (175, 186))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (11, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('mutation', 'Var', (36, 44))
65930	33451055	FIDES-02 is a clinical trial that is evaluating the safety and antitumor activity of single-agent derazantinib or in combination with atezolizumab in patients with mUC and FGFR aberrations (NCT04045613).	('atezolizumab', 'Chemical', 'MESH:C000594389', (134, 146))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('derazantinib', 'Chemical', 'MESH:C000621805', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('patients', 'Species', '9606', (150, 158))	('aberrations (NCT04045613', 'Var', (177, 201))	('tumor', 'Disease', (67, 72))	('FGFR', 'molecular_function', 'GO:0005007', ('172', '176'))	('NCT04045613', 'Var', (190, 201))
65932	33451055	Thus, in patients with FGFR, homologous repair gene or mTOR alterations, the study failed to significantly improve the ORR of 27.6% with durvalumab alone compared to AZD4547+durvalumab (ORR = 28.6%), olaparib+durvalumab (ORR = 35.7%) or vistusertib+durvalumab (ORR = 24.1%).	('patients', 'Species', '9606', (9, 17))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('mTOR', 'Gene', (55, 59))	('ORR', 'MPA', (119, 122))	('FGFR', 'Gene', (23, 27))	('mTOR', 'Gene', '2475', (55, 59))	('durvalumab', 'Chemical', 'MESH:C000613593', (249, 259))	('durvalumab', 'Chemical', 'MESH:C000613593', (209, 219))	('durvalumab', 'Chemical', 'MESH:C000613593', (174, 184))	('AZD4547', 'Chemical', 'MESH:C572463', (166, 173))	('vistusertib', 'Chemical', 'MESH:C585537', (237, 248))	('durvalumab', 'Chemical', 'MESH:C000613593', (137, 147))	('alterations', 'Var', (60, 71))	('olaparib', 'Chemical', 'MESH:C531550', (200, 208))
65935	33451055	PI3K stimulation leads to the recruitment of signaling proteins such as Akt/PKB, and the production of second messengers that regulate several processes involved in cell cycle modulation.	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PI3K', 'Var', (0, 4))	('Akt/PKB', 'Gene', (72, 79))	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('cell cycle modulation', 'biological_process', 'GO:0051726', ('165', '186'))	('regulate', 'Reg', (126, 134))	('Akt/PKB', 'Gene', '207', (72, 79))	('men', 'Species', '9606', (37, 40))	('recruitment', 'MPA', (30, 41))	('production of second messengers', 'MPA', (89, 120))
65939	33451055	Besides, several targets of Akt are involved in protein synthesis, glycogen metabolism and cell cycle regulation, especially regarding a positive modulation of G1/S progression through the inactivation of GSK3 (Figure 3).	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('Akt', 'Gene', (28, 31))	('GSK3', 'Gene', (205, 209))	('glycogen', 'Chemical', 'MESH:D006003', (67, 75))	('inactivation', 'Var', (189, 201))	('glycogen metabolism', 'biological_process', 'GO:0005977', ('67', '86'))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('91', '112'))	('protein synthesis', 'biological_process', 'GO:0006412', ('48', '65'))	('GSK', 'molecular_function', 'GO:0050321', ('205', '208'))	('Akt', 'Gene', '207', (28, 31))	('G1/S', 'Disease', (160, 164))
65941	33451055	In fact, since the loss of PTEN leads to permanent PI3K/Akt activation, its mutations in germ-cell lines result in a higher risk of different malignancies, including urothelial cancers.	('Akt', 'Gene', '207', (56, 59))	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('mutations', 'Var', (76, 85))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('Akt', 'Gene', (56, 59))	('malignancies', 'Disease', 'MESH:D009369', (142, 154))	('activation', 'PosReg', (60, 70))	('loss', 'Var', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('PTEN', 'Gene', (27, 31))	('malignancies', 'Disease', (142, 154))	('PTEN', 'Gene', '5728', (27, 31))	('urothelial cancers', 'Disease', 'MESH:D014523', (166, 184))	('urothelial cancers', 'Disease', (166, 184))
65953	33451055	Mutations in PI3KCA are present in 21-25% of patients and loss of PTEN expression can be found in 39-94% of cases.	('PI3KCA', 'Gene', (13, 19))	('expression', 'MPA', (71, 81))	('loss', 'NegReg', (58, 62))	('PTEN', 'Gene', (66, 70))	('PTEN', 'Gene', '5728', (66, 70))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (45, 53))
65954	33451055	A small proportion of the patients have tumors with less common aberrations, such as inhibiting mutations in PTEN (3-4%) and activating mutations in AKT1 (2-3%).	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('inhibiting', 'NegReg', (85, 95))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('PTEN', 'Gene', (109, 113))	('patients', 'Species', '9606', (26, 34))	('activating', 'PosReg', (125, 135))	('PTEN', 'Gene', '5728', (109, 113))	('AKT1', 'Gene', '207', (149, 153))	('AKT1', 'Gene', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('mutations', 'Var', (96, 105))	('tumors', 'Disease', (40, 46))
65963	33451055	conducted a trial with everolimus, and one patient with an inactivating TSC-1 mutation had significant shrinkage and a durable response.	('mutation', 'Var', (78, 86))	('TSC-1', 'Gene', (72, 77))	('patient', 'Species', '9606', (43, 50))	('shrinkage', 'NegReg', (103, 112))	('everolimus', 'Chemical', 'MESH:D000068338', (23, 33))	('TSC-1', 'Gene', '7248', (72, 77))
65966	33451055	One partial response and two stable diseases were reported in patients who did not have any PI3K/AKT/mTOR mutations.	('AKT', 'Gene', '207', (97, 100))	('mTOR', 'Gene', (101, 105))	('mTOR', 'Gene', '2475', (101, 105))	('AKT', 'Gene', (97, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('92', '96'))	('mutations', 'Var', (106, 115))	('patients', 'Species', '9606', (62, 70))
65969	33451055	Six patients displayed stable disease (one of which presented with a TSC1 mutation), and there was one partial response in a patient with a TSC1 mutation.	('mutation', 'Var', (74, 82))	('stable disease', 'Disease', (23, 37))	('patient', 'Species', '9606', (4, 11))	('TSC1', 'Gene', '7248', (140, 144))	('TSC1', 'Gene', '7248', (69, 73))	('patient', 'Species', '9606', (125, 132))	('patients', 'Species', '9606', (4, 12))	('TSC1', 'Gene', (140, 144))	('TSC1', 'Gene', (69, 73))
65974	33451055	Oncogenic mutations affecting the RAS pathway and receptor crosstalk with other growth factors can stimulate VEGF expression.	('stimulate', 'PosReg', (99, 108))	('RAS pathway', 'Pathway', (34, 45))	('VEGF', 'Gene', (109, 113))	('mutations', 'Var', (10, 19))	('crosstalk', 'Var', (59, 68))	('VEGF', 'Gene', '7422', (109, 113))
65976	33451055	Overexpression of HIF-1 and VEGF has been demonstrated in urothelial tumors samples, and has been associated with a worse prognosis and higher rates of disease progression, recurrence and metastatic dissemination.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('VEGF', 'Gene', (28, 32))	('HIF-1', 'Gene', (18, 23))	('HIF-1', 'Gene', '3091', (18, 23))	('disease progression', 'CPA', (152, 171))	('higher', 'PosReg', (136, 142))	('urothelial tumors', 'Disease', 'MESH:D001749', (58, 75))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('VEGF', 'Gene', '7422', (28, 32))	('Overexpression', 'Var', (0, 14))	('metastatic dissemination', 'CPA', (188, 212))	('associated', 'Reg', (98, 108))	('urothelial tumors', 'Disease', (58, 75))	('recurrence', 'CPA', (173, 183))
66009	33451055	Although translocation is the most frequent alteration of the ALK gene, and it has been mainly studied in non-small cell lung cancer, other genetic anomalies have also been described as pro-oncogenic events in different kinds of tumors.	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (106, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (110, 132))	('genetic anomalies', 'Disease', (140, 157))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('ALK', 'Gene', (62, 65))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('translocation', 'Var', (9, 22))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('genetic anomalies', 'Disease', 'MESH:D030342', (140, 157))	('ALK', 'Gene', '238', (62, 65))	('tumors', 'Disease', (229, 235))
66010	33451055	Preclinical studies have shown that malignant cells with ALK aberrations nearly completely depend on ALK intracellular signaling mechanisms for survival, explaining why their proliferation can be stopped by the inhibitory activity of specific targeted drugs.	('depend', 'Reg', (91, 97))	('ALK', 'Gene', (101, 104))	('ALK', 'Gene', (57, 60))	('ALK', 'Gene', '238', (101, 104))	('intracellular', 'cellular_component', 'GO:0005622', ('105', '118'))	('aberrations', 'Var', (61, 72))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))	('ALK', 'Gene', '238', (57, 60))
66012	33451055	found that ALK gene alterations, defined as minor copy number alterations (CNA) in the proximity of ALK locus detected by array comparative genomic hybridization (aCGH) were only present in 3 out of 96 (3.1%) tissue samples from patients with advanced urothelial cancer.	('alterations', 'Var', (20, 31))	('patients', 'Species', '9606', (229, 237))	('urothelial cancer', 'Disease', 'MESH:D014523', (252, 269))	('ALK', 'Gene', (100, 103))	('ALK', 'Gene', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('urothelial cancer', 'Disease', (252, 269))	('ALK', 'Gene', '238', (100, 103))	('ALK', 'Gene', '238', (11, 14))
66013	33451055	This may suggest a very low prevalence of ALK-activating mutations in advanced BC, entailing that a significant therapeutic benefit from ALK inhibitors in BC might be restricted to a select group of patients.	('ALK', 'Gene', '238', (42, 45))	('ALK', 'Gene', (137, 140))	('ALK', 'Gene', (42, 45))	('mutations', 'Var', (57, 66))	('patients', 'Species', '9606', (199, 207))	('ALK', 'Gene', '238', (137, 140))	('BC', 'Phenotype', 'HP:0009725', (79, 81))	('BC', 'Phenotype', 'HP:0009725', (155, 157))
66015	33451055	Additionally, a phase IIa study is currently evaluating trastuzumab/pertuzumab, erlotinib, vemurafenib/cobimenitib, vismodegib, alectinib (ALK) and atezolizumab in patients with advanced solid tumors and mutations or gene expression abnormalities predictive of response to one of these agents.	('erlotinib', 'Chemical', 'MESH:D000069347', (80, 89))	('solid tumors', 'Disease', 'MESH:D009369', (187, 199))	('ALK', 'Gene', (139, 142))	('gene expression', 'biological_process', 'GO:0010467', ('217', '232'))	('mutations', 'Var', (204, 213))	('vismodegib', 'Chemical', 'MESH:C538724', (116, 126))	('alectinib', 'Chemical', 'MESH:C582670', (128, 137))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('atezolizumab', 'Chemical', 'MESH:C000594389', (148, 160))	('ALK', 'Gene', '238', (139, 142))	('solid tumors', 'Disease', (187, 199))	('cobimenitib', 'Chemical', '-', (103, 114))	('trastuzumab', 'Chemical', 'MESH:D000068878', (56, 67))	('pertuzumab', 'Chemical', 'MESH:C485206', (68, 78))	('patients', 'Species', '9606', (164, 172))	('vemurafenib', 'Chemical', 'MESH:D000077484', (91, 102))
66033	33451055	Several studies have shown that some FGFR molecular alterations lead to the constitutive activation of SRC, which at the same time is regulated by EGFR-dependent mechanisms, SRC being a possible resistance pathway to FGFR.	('SRC', 'Gene', (103, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('217', '221'))	('EGFR', 'Gene', (147, 151))	('alterations', 'Var', (52, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('147', '151'))	('lead to', 'Reg', (64, 71))	('SRC', 'Gene', '6714', (174, 177))	('SRC', 'Gene', (174, 177))	('activation', 'PosReg', (89, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('EGFR', 'Gene', '1956', (147, 151))	('FGFR', 'Gene', (37, 41))	('SRC', 'Gene', '6714', (103, 106))
66049	33451055	In a study where immunohistochemistry was performed on 65 BC cancer specimens prior to radical cystectomy, Axl immunopositivity was associated with unsuspected lymph-node metastases and reduced disease-specific survival.	('cys', 'Chemical', 'MESH:D003545', (95, 98))	('men', 'Species', '9606', (73, 76))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('metastases', 'Disease', 'MESH:D009362', (171, 181))	('immunopositivity', 'Var', (111, 127))	('cancer', 'Disease', (61, 67))	('reduced', 'NegReg', (186, 193))	('Axl', 'Gene', '558', (107, 110))	('metastases', 'Disease', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('BC', 'Phenotype', 'HP:0009725', (58, 60))	('Axl', 'Gene', (107, 110))	('disease-specific survival', 'CPA', (194, 219))
66057	33451055	The main advance in recent years has been the irruption of the ICI, particularly PD1/PDL-1 inhibitors, in different contexts of the first- and second-line treatment and maintenance strategy, resulting in a small percentage of patients remaining alive for long periods of time.	('PDL-1', 'Gene', '29126', (85, 90))	('irruption', 'Var', (46, 55))	('PDL-1', 'Gene', (85, 90))	('patients', 'Species', '9606', (226, 234))	('men', 'Species', '9606', (160, 163))
66065	33451055	This diagnostic test is able to identify two-point mutations in exon 7 (p.R248C (c.742C>T); p.S249C (c.746C>G)), two-point mutations in exon 10 (p.G370C (c.1108G>T) and p.Y373C (c.1118A>G)) and two fusions (FGFR3:TACC3v1 and FGFR3:TACC3v3) in the FGFR3 gene.	('FGFR3', 'Gene', (207, 212))	('FGFR3', 'Gene', '2261', (247, 252))	('p.G370C', 'SUBSTITUTION', 'None', (145, 152))	('c.742C>T', 'SUBSTITUTION', 'None', (81, 89))	('FGFR3', 'Gene', '2261', (207, 212))	('FGFR', 'molecular_function', 'GO:0005007', ('207', '211'))	('c.746C>G', 'SUBSTITUTION', 'None', (101, 109))	('FGFR', 'molecular_function', 'GO:0005007', ('247', '251'))	('c.742C>T', 'Var', (81, 89))	('p.R248C', 'SUBSTITUTION', 'None', (72, 79))	('TACC3', 'Gene', '10460', (231, 236))	('c.1108G>T', 'Var', (154, 163))	('TACC3', 'Gene', (231, 236))	('FGFR3', 'Gene', (225, 230))	('c.1118A>G', 'SUBSTITUTION', 'None', (178, 187))	('c.1118A>G', 'Var', (178, 187))	('p.S249C', 'SUBSTITUTION', 'None', (92, 99))	('FGFR3', 'Gene', '2261', (225, 230))	('TACC3', 'Gene', '10460', (213, 218))	('p.G370C', 'Var', (145, 152))	('c.746C>G', 'Var', (101, 109))	('c.1108G>T', 'SUBSTITUTION', 'None', (154, 163))	('TACC3', 'Gene', (213, 218))	('p.Y373C', 'SUBSTITUTION', 'None', (169, 176))	('p.S249C', 'Var', (92, 99))	('FGFR3', 'Gene', (247, 252))	('p.Y373C', 'Var', (169, 176))	('p.R248C', 'Var', (72, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('225', '229'))
66070	33451055	Due to the common oncogenic mechanism and mutations found, it is believed that luminal papillary subtype may response to FGFR targeted therapy, whilst stroma and basal subtypes are supposed to be responsive to EGFR targeted therapies.	('FGFR', 'molecular_function', 'GO:0005007', ('121', '125'))	('luminal', 'Chemical', 'MESH:D010634', (79, 86))	('EGFR', 'Gene', (210, 214))	('FGFR', 'Gene', (121, 125))	('response', 'Reg', (109, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('210', '214'))	('targeted therapy', 'Var', (126, 142))	('EGFR', 'Gene', '1956', (210, 214))
66073	33451055	A high rate of HER2 alterations was reported in BC, and the availability of anti-HER2 targeted therapies, and their efficacy in other solid tumors harboring alterations in HER2, encouraged the development of those drugs for BC.	('alterations', 'Var', (20, 31))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('solid tumors', 'Disease', (134, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('HER2', 'Gene', (15, 19))	('BC', 'Phenotype', 'HP:0009725', (224, 226))	('HER2', 'Gene', (81, 85))	('HER2', 'Gene', '2064', (15, 19))	('men', 'Species', '9606', (200, 203))	('HER2', 'Gene', '2064', (81, 85))	('solid tumors', 'Disease', 'MESH:D009369', (134, 146))	('HER2', 'Gene', (172, 176))	('alterations', 'Var', (157, 168))	('BC', 'Phenotype', 'HP:0009725', (48, 50))	('HER2', 'Gene', '2064', (172, 176))
66074	33451055	Nowadays novel therapies are being tested in this setting of metastatic patients, such as DS8201a in combination with nivolumab (NCT03523572), RC48-ADC for HER2-overexpressing patients (NCT03809013), RC48-ADC for HER2-negative patients (NCT04073602) and PRS-343 (bispecific antibody to HER2/41BB) (NCT03330561).	('PRS', 'Chemical', 'MESH:D011221', (254, 257))	('HER2', 'Gene', (156, 160))	('NCT04073602', 'Var', (237, 248))	('NCT03330561', 'Var', (298, 309))	('NCT03809013', 'Var', (186, 197))	('antibody', 'cellular_component', 'GO:0019814', ('274', '282'))	('HER2', 'Gene', '2064', (286, 290))	('antibody', 'molecular_function', 'GO:0003823', ('274', '282'))	('HER2', 'Gene', '2064', (213, 217))	('patients', 'Species', '9606', (227, 235))	('nivolumab', 'Chemical', 'MESH:D000077594', (118, 127))	('antibody', 'cellular_component', 'GO:0042571', ('274', '282'))	('HER2', 'Gene', '2064', (156, 160))	('HER2', 'Gene', (286, 290))	('patients', 'Species', '9606', (176, 184))	('antibody', 'cellular_component', 'GO:0019815', ('274', '282'))	('NCT03523572', 'Var', (129, 140))	('HER2', 'Gene', (213, 217))	('patients', 'Species', '9606', (72, 80))
66124	31243065	However, MFA, the matrix decomposition method used in MOGSA, is sensitive to outliers, because it minimizes sum squared error between original matrix and its low-rank approximation.	('GSA', 'Gene', (56, 59))	('minimizes', 'NegReg', (98, 107))	('MFA', 'Chemical', '-', (9, 12))	('GSA', 'Gene', '2778', (56, 59))	('sum squared error', 'MPA', (108, 125))	('MFA', 'Var', (9, 12))
66183	31243065	The significant (BH corrected p < 0.01) GSSs of this term are 0.097, -0.086 and -0.053 in NFF, iPSC and H9 cells respectively.	('H9', 'CellLine', 'CVCL:1240', (104, 106))	('0.097', 'Var', (62, 67))	('GSS', 'Gene', '2937', (40, 43))	('GSS', 'Gene', (40, 43))	('BH', 'Chemical', '-', (17, 19))
66291	27642214	Since it resembled a poorly differentiated urothelial carcinoma, immunohistochemistry was performed with markers positive for urothelial carcinoma, such as uroplakin II, GATA3, p63, p40, and 34betaE12.	('p63', 'Gene', '8626', (177, 180))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (43, 63))	('p40', 'cellular_component', 'GO:0043514', ('182', '185'))	('GATA3', 'Gene', (170, 175))	('p40', 'Gene', (182, 185))	('34betaE12', 'Var', (191, 200))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (126, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('urothelial carcinoma', 'Disease', (43, 63))	('uroplakin II', 'Gene', '7379', (156, 168))	('GATA3', 'Gene', '2625', (170, 175))	('p40', 'Gene', '8626', (182, 185))	('p63', 'Gene', (177, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('p40', 'cellular_component', 'GO:0070743', ('182', '185'))	('uroplakin II', 'Gene', (156, 168))	('urothelial carcinoma', 'Disease', (126, 146))
66369	33668859	Mutations of TP53 were solely observed in high-grade (HG) tumors, whereas mutations in KDM6A and KMT2D were commonly detected in UTUCs of both low and high grade.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TP53', 'Gene', (13, 17))	('tumors', 'Disease', (58, 64))	('KDM6A', 'Gene', (87, 92))	('KMT2D', 'Gene', '8085', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('Mutations', 'Var', (0, 9))	('high-grade', 'Disease', (42, 52))	('observed', 'Reg', (30, 38))	('KDM6A', 'Gene', '7403', (87, 92))	('TP53', 'Gene', '7157', (13, 17))	('KMT2D', 'Gene', (97, 102))
66370	33668859	Mutations in TP53, FGFR3, CREBBP, KMT2C and STAG2 were significantly associated with histological grade.	('TP53', 'Gene', (13, 17))	('CREBBP', 'Gene', (26, 32))	('associated', 'Reg', (69, 79))	('FGFR3', 'Gene', '2261', (19, 24))	('Mutations', 'Var', (0, 9))	('STAG2', 'Gene', (44, 49))	('CREBBP', 'Gene', '1387', (26, 32))	('KMT2C', 'Gene', '58508', (34, 39))	('KMT2C', 'Gene', (34, 39))	('TP53', 'Gene', '7157', (13, 17))	('STAG2', 'Gene', '10735', (44, 49))	('FGFR3', 'Gene', (19, 24))
66371	33668859	Tumors presenting mutations of FGFR3, CREBBP and STAG2 were more frequently LG, whereas those with TP53 mutations were more frequently HG.	('TP53', 'Gene', (99, 103))	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('STAG2', 'Gene', (49, 54))	('FGFR3', 'Gene', '2261', (31, 36))	('STAG2', 'Gene', '10735', (49, 54))	('CREBBP', 'Gene', (38, 44))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TP53', 'Gene', '7157', (99, 103))	('FGFR3', 'Gene', (31, 36))	('CREBBP', 'Gene', '1387', (38, 44))	('mutations', 'Var', (18, 27))
66372	33668859	Tumors with FGFR3 mutations were usually pTa/pT1/pT2, whereas those with TP53, CCND1, ERBB2, ERBB3 and KRAS alterations were more frequently pT3/pT4.	('TP53', 'Gene', '7157', (73, 77))	('pT1', 'Gene', (45, 48))	('pT3', 'Gene', '7694', (141, 144))	('ERBB3', 'Gene', '2065', (93, 98))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CCND1', 'Gene', '595', (79, 84))	('Tumors', 'Disease', (0, 6))	('pTa', 'molecular_function', 'GO:0008959', ('41', '44'))	('CCND1', 'Gene', (79, 84))	('ERBB2', 'Gene', (86, 91))	('FGFR3', 'Gene', (12, 17))	('KRAS', 'Gene', '3845', (103, 107))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))	('TP53', 'Gene', (73, 77))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('ERBB3', 'Gene', (93, 98))	('ERBB2', 'Gene', '2064', (86, 91))	('pT3', 'Gene', (141, 144))	('FGFR3', 'Gene', '2261', (12, 17))	('KRAS', 'Gene', (103, 107))	('pT1', 'Gene', '58492', (45, 48))	('mutations', 'Var', (18, 27))
66373	33668859	These results are similar to those reported by Nassar et al: FGFR3 alterations were seen in 80% of LG-UTUC and TP53 mutations only in HG cancers.	('LG-UTUC', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('FGFR3', 'Gene', (61, 66))	('TP53', 'Gene', '7157', (111, 115))	('FGFR', 'molecular_function', 'GO:0005007', ('61', '65'))	('alterations', 'Var', (67, 78))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('TP53', 'Gene', (111, 115))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('mutations', 'Var', (116, 125))	('cancers', 'Disease', (137, 144))	('FGFR3', 'Gene', '2261', (61, 66))
66374	33668859	demonstrated a similar FGFR3 mutations frequency in BC (48/100, 46%) and UTUC (71/147, 48%).	('FGFR3', 'Gene', (23, 28))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('mutations', 'Var', (29, 38))	('FGFR3', 'Gene', '2261', (23, 28))
66375	33668859	FGFR3 was more frequently mutated in ureter specimens than in renal pelvis ones (59% vs. 39%).	('men', 'Species', '9606', (49, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('renal pelvis ones', 'Disease', (62, 79))	('renal pelvis ones', 'Disease', 'MESH:D007680', (62, 79))	('FGFR3', 'Gene', (0, 5))	('renal pelvis', 'Phenotype', 'HP:0000125', (62, 74))	('mutated', 'Var', (26, 33))	('FGFR3', 'Gene', '2261', (0, 5))
66376	33668859	These alterations were associated with low-stage tumors and a less aggressive disease course in UTUC.	('alterations', 'Var', (6, 17))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('aggressive disease', 'Disease', (67, 85))	('low-stage tumors', 'Disease', 'MESH:D009800', (39, 55))	('low-stage tumors', 'Disease', (39, 55))	('associated', 'Reg', (23, 33))	('aggressive disease', 'Disease', 'MESH:D001523', (67, 85))
66377	33668859	Moreover, patients with pT2-pT4 UTUCs with FGFR3 mutations had a better survival.	('mutations', 'Var', (49, 58))	('FGFR3', 'Gene', (43, 48))	('better', 'PosReg', (65, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('FGFR3', 'Gene', '2261', (43, 48))	('survival', 'CPA', (72, 80))	('patients', 'Species', '9606', (10, 18))
66378	33668859	An evaluation of the correlation between genetic alterations and anatomical UTUC origin was performed by Necchi et al.. FGFR3 and HRAS mutations were more common in renal pelvis tumors, while the frequencies of KRAS and NRAS mutations were similar across anatomical sites (pelvis/ureter).	('HRAS', 'Gene', (130, 134))	('renal pelvis tumors', 'Disease', (165, 184))	('NRAS', 'Gene', '4893', (220, 224))	('common', 'Reg', (155, 161))	('FGFR3', 'Gene', (120, 125))	('renal pelvis', 'Phenotype', 'HP:0000125', (165, 177))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('mutations', 'Var', (135, 144))	('KRAS', 'Gene', (211, 215))	('KRAS', 'Gene', '3845', (211, 215))	('HRAS', 'Gene', '3265', (130, 134))	('renal pelvis tumors', 'Disease', 'MESH:D007680', (165, 184))	('FGFR', 'molecular_function', 'GO:0005007', ('120', '124'))	('NRAS', 'Gene', (220, 224))	('pelvis/ureter', 'Disease', (273, 286))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('FGFR3', 'Gene', '2261', (120, 125))	('pelvis/ureter', 'Disease', 'MESH:D014516', (273, 286))
66380	33668859	At the analysis of the mutational profiles of UTUC, FGFR3 was found to be the most commonly mutated gene, in 74% of all tumors; the FGFR3 mutation rate rose to 92% in LG UTUC.	('FGFR3', 'Gene', (132, 137))	('tumors', 'Disease', (120, 126))	('LG UTUC', 'Disease', (167, 174))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('FGFR', 'molecular_function', 'GO:0005007', ('132', '136'))	('FGFR3', 'Gene', '2261', (52, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('rose', 'PosReg', (152, 156))	('mutation', 'Var', (138, 146))	('FGFR3', 'Gene', (52, 57))	('FGFR3', 'Gene', '2261', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
66382	33668859	When the mutational characteristics of low- and high-grade tumors were compared, a higher incidence of mutations in the p53 signaling and greater genomic instability in HG tumors were shown to occur.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mutations', 'Var', (103, 112))	('tumors', 'Disease', (172, 178))	('p53', 'Gene', '7157', (120, 123))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('signaling', 'biological_process', 'GO:0023052', ('124', '133'))	('genomic instability', 'CPA', (146, 165))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('p53', 'Gene', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
66383	33668859	Mutations of p53 have been identified in approximately 50% of all human cancers; expression of altered p53 has been detected in 30-60% of UTUC.	('identified', 'Reg', (27, 37))	('UTUC', 'Disease', (138, 142))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('detected', 'Reg', (116, 124))	('p53', 'Gene', (13, 16))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('p53', 'Gene', '7157', (13, 16))
66388	33668859	Conversely, the incidence of alterations in TP53 and MDM2 was considerably higher in patients with >= pT2 disease.	('MDM2', 'Gene', '4193', (53, 57))	('MDM2', 'Gene', (53, 57))	('higher', 'Reg', (75, 81))	('alterations', 'Var', (29, 40))	('patients', 'Species', '9606', (85, 93))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))
66389	33668859	The link between genes mutations and bladder recurrence was evaluated, and alterations in FGFR3, KDM6A and CCND1 were found to be significantly associated with a higher risk of developing a subsequent bladder tumor, whereas TP53 alterations were associated with a lower risk.	('bladder tumor', 'Disease', 'MESH:D001749', (201, 214))	('bladder tumor', 'Phenotype', 'HP:0009725', (201, 214))	('associated', 'Reg', (144, 154))	('TP53', 'Gene', (224, 228))	('CCND1', 'Gene', '595', (107, 112))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))	('KDM6A', 'Gene', (97, 102))	('FGFR3', 'Gene', '2261', (90, 95))	('alterations', 'Var', (75, 86))	('bladder tumor', 'Disease', (201, 214))	('FGFR3', 'Gene', (90, 95))	('KDM6A', 'Gene', '7403', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('CCND1', 'Gene', (107, 112))	('TP53', 'Gene', '7157', (224, 228))
66390	33668859	evaluated an association between genomic alterations in UTUC and adverse pathological and clinical outcomes in 83 patients with clinically localized disease treated with RNU.	('RNU', 'Chemical', '-', (170, 173))	('genomic alterations', 'Var', (33, 52))	('patients', 'Species', '9606', (114, 122))	('localized disease', 'Disease', (139, 156))	('UTUC', 'Gene', (56, 60))	('localized disease', 'Disease', 'MESH:D012594', (139, 156))
66391	33668859	They found that mutations of TP53/MDM2 are linked to worse clinicopathological outcomes, whereas FGFR3 alterations are associated with favorable outcomes.	('FGFR3', 'Gene', '2261', (97, 102))	('MDM2', 'Gene', '4193', (34, 38))	('mutations', 'Var', (16, 25))	('FGFR', 'molecular_function', 'GO:0005007', ('97', '101'))	('MDM2', 'Gene', (34, 38))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('FGFR3', 'Gene', (97, 102))
66392	33668859	Mutations in TP53, TP53/MDM2 alteration and CCND1 alteration significantly increased the risk of death from disease, whereas FGFR3 mutation significantly decreased this risk.	('decreased', 'NegReg', (154, 163))	('death from', 'MPA', (97, 107))	('TP53', 'Gene', (13, 17))	('alteration', 'Var', (50, 60))	('TP53', 'Gene', '7157', (13, 17))	('FGFR3', 'Gene', '2261', (125, 130))	('FGFR', 'molecular_function', 'GO:0005007', ('125', '129'))	('MDM2', 'Gene', '4193', (24, 28))	('MDM2', 'Gene', (24, 28))	('CCND1', 'Gene', (44, 49))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('FGFR3', 'Gene', (125, 130))	('increased', 'PosReg', (75, 84))	('CCND1', 'Gene', '595', (44, 49))
41798	33668859	Alteration of TP53 was found in 25% of cases.	('Alteration', 'Var', (0, 10))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))
66400	33668859	To summarize, the most frequently detected alterations include FGFR3, chromatin remodeling genes (e.g., KMT2D and KDM6A), TP53/MDM2 and other tumor suppressors/oncogenes such as CDKN2A or RAS.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('FGFR3', 'Gene', '2261', (63, 68))	('CDKN2A', 'Gene', (178, 184))	('KDM6A', 'Gene', (114, 119))	('KMT2D', 'Gene', (104, 109))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('70', '90'))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('alterations', 'Var', (43, 54))	('CDKN2A', 'Gene', '1029', (178, 184))	('TP53', 'Gene', (122, 126))	('tumor', 'Disease', (142, 147))	('MDM2', 'Gene', (127, 131))	('KDM6A', 'Gene', '7403', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('KMT2D', 'Gene', '8085', (104, 109))	('chromatin', 'cellular_component', 'GO:0000785', ('70', '79'))	('MDM2', 'Gene', '4193', (127, 131))	('FGFR3', 'Gene', (63, 68))	('RAS', 'Disease', (188, 191))	('TP53', 'Gene', '7157', (122, 126))
66401	33668859	The frequency of FGFR3 alterations and TP53/MDM2 status is different across articles.	('MDM2', 'Gene', '4193', (44, 48))	('FGFR3', 'Gene', '2261', (17, 22))	('MDM2', 'Gene', (44, 48))	('FGFR3', 'Gene', (17, 22))	('alterations', 'Var', (23, 34))	('TP53', 'Gene', '7157', (39, 43))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('TP53', 'Gene', (39, 43))
66404	33668859	Lynch syndrome (LS) (i.e., hereditary non-polyposis colorectal cancer (HNPCC)) is an autosomal dominant multi-organ cancer syndrome resulting from germline mutations of mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2).	('MLH1', 'Gene', (198, 202))	('MLH1', 'Gene', '4292', (198, 202))	('autosomal dominant multi-organ cancer syndrome', 'Disease', (85, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('resulting from', 'Reg', (132, 146))	('PMS2', 'Gene', (218, 222))	('MSH2', 'Gene', (204, 208))	('MSH6', 'Gene', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('MMR', 'Gene', (186, 189))	('hereditary non-polyposis colorectal cancer', 'Disease', 'MESH:D003123', (27, 69))	('MSH6', 'Gene', '2956', (210, 214))	('HNPCC', 'Disease', 'None', (71, 76))	('HNPCC', 'Disease', (71, 76))	('Lynch syndrome', 'Disease', (0, 14))	('germline mutations', 'Var', (147, 165))	('hereditary non-polyposis colorectal cancer', 'Disease', (27, 69))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('MMR', 'biological_process', 'GO:0006298', ('186', '189'))	('MSH2', 'Gene', '4436', (204, 208))	('mismatch repair', 'biological_process', 'GO:0006298', ('169', '184'))	('autosomal dominant multi-organ cancer syndrome', 'Disease', 'MESH:D009369', (85, 131))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('PMS2', 'Gene', '5395', (218, 222))
66409	33668859	LS-UTUCs shown a significantly higher number of mutations per tumor, as expected in a microsatellite instability-associated malignancy.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('microsatellite', 'Var', (86, 100))	('tumor', 'Disease', (62, 67))	('malignancy', 'Disease', 'MESH:D009369', (124, 134))	('malignancy', 'Disease', (124, 134))	('mutations', 'Var', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
66413	33668859	Both groups showed almost equal amounts of FGFR3 mutations, however LS-UTUC presented FGFR3 mutations that were mainly R248C, making it a possible biomarker for LS-UTUC patients.	('R248C', 'Mutation', 'rs121913482', (119, 124))	('patients', 'Species', '9606', (169, 177))	('FGFR3', 'Gene', (43, 48))	('FGFR3', 'Gene', '2261', (86, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('FGFR3', 'Gene', '2261', (43, 48))	('LS-UTUC', 'Disease', (68, 75))	('FGFR3', 'Gene', (86, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('86', '90'))	('R248C', 'Var', (119, 124))
66419	33668859	DNA adducts exhibit mutagenic properties generating predominantly A:T to T:A transversions; moreover, endemic nephropathy-related UTUC showed an AA-specific mutational signature in the tumor suppressor gene TP53, dominated by A:T to T:A transversions, which is different from the mutational load of sporadic UTUC.	('tumor', 'Disease', (185, 190))	('tumor suppressor', 'biological_process', 'GO:0051726', ('185', '201'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('TP53', 'Gene', '7157', (207, 211))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('185', '201'))	('nephropathy', 'Phenotype', 'HP:0000112', (110, 121))	('nephropathy', 'Disease', (110, 121))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('TP53', 'Gene', (207, 211))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('nephropathy', 'Disease', 'MESH:D007674', (110, 121))	('mutational', 'Var', (157, 167))
66420	33668859	In particular, cancer promoting genes such as TP53, NRAS and HRAS were found to be frequently mutated in patients with nephropathy-related UTUC and next generation sequencing studies revealing that up to 83 cancer driver genes harbored signature mutations in these cohorts.	('NRAS', 'Gene', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('HRAS', 'Gene', (61, 65))	('nephropathy', 'Disease', (119, 130))	('patients', 'Species', '9606', (105, 113))	('nephropathy', 'Phenotype', 'HP:0000112', (119, 130))	('NRAS', 'Gene', '4893', (52, 56))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('TP53', 'Gene', '7157', (46, 50))	('nephropathy', 'Disease', 'MESH:D007674', (119, 130))	('mutations', 'Var', (246, 255))	('TP53', 'Gene', (46, 50))	('HRAS', 'Gene', '3265', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
66421	33668859	Of note, mutations were also highly prevalent in genes encoding chromatin re-modeling (such as MLL2 (62%), CREBBP (38%), KDM6A (15%) and members of the SWI/SNF family of proteins (SMARCA4: 15%; ARID1A, ARID1B and ARID2: 12%), histone modification, transcriptional regulation, DNA damage response and DNA repair.	('mutations', 'Var', (9, 18))	('KDM6A', 'Gene', (121, 126))	('ARID1A', 'Gene', '8289', (194, 200))	('DNA repair', 'biological_process', 'GO:0006281', ('300', '310'))	('histone modification', 'biological_process', 'GO:0016570', ('226', '246'))	('SMARCA4', 'Gene', '6597', (180, 187))	('MLL2', 'Gene', '8085', (95, 99))	('CREBBP', 'Gene', '1387', (107, 113))	('regulation', 'biological_process', 'GO:0065007', ('264', '274'))	('DNA damage response', 'biological_process', 'GO:0006974', ('276', '295'))	('ARID2', 'Gene', '196528', (213, 218))	('MLL2', 'Gene', (95, 99))	('DNA', 'cellular_component', 'GO:0005574', ('276', '279'))	('chromatin', 'cellular_component', 'GO:0000785', ('64', '73'))	('SMARCA4', 'Gene', (180, 187))	('KDM6A', 'Gene', '7403', (121, 126))	('ARID2', 'Gene', (213, 218))	('ARID1B', 'Gene', (202, 208))	('histone', 'MPA', (226, 233))	('DNA', 'cellular_component', 'GO:0005574', ('300', '303'))	('ARID1B', 'Gene', '57492', (202, 208))	('prevalent', 'Reg', (36, 45))	('CREBBP', 'Gene', (107, 113))	('ARID1A', 'Gene', (194, 200))
66423	33668859	Differently from sporadic UTUC, FGFR3 mutations are rare in AA-induced tumors.	('FGFR3', 'Gene', (32, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('FGFR3', 'Gene', '2261', (32, 37))	('tumors', 'Disease', (71, 77))	('mutations', 'Var', (38, 47))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
66424	33668859	It is reported that approximately 74% of UTUC cases in the United States showed FGFR3 mutations as compared to only 3% of nephropathic diseases.	('mutations', 'Var', (86, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('nephropathic diseases', 'Disease', (122, 143))	('FGFR3', 'Gene', '2261', (80, 85))	('nephropathic diseases', 'Disease', 'MESH:D003554', (122, 143))	('FGFR3', 'Gene', (80, 85))
66431	33668859	In this setting, since checkpoint inhibitors have stronger antineoplastic effects on tumors with high mutational burden, they are considered as promising therapeutic options for AA-induced urothelial carcinomas.	('antineoplastic effects', 'MPA', (59, 81))	('checkpoint', 'Gene', (23, 33))	('stronger', 'PosReg', (50, 58))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (189, 210))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('carcinomas', 'Phenotype', 'HP:0030731', (200, 210))	('urothelial carcinomas', 'Disease', (189, 210))	('mutational', 'Var', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
66436	33668859	A higher number of FGFR3-TACC3 fusions was detected in the UTUC group, whereas no RB1 mutations were found.	('RB1', 'Gene', '5925', (82, 85))	('TACC3', 'Gene', '10460', (25, 30))	('TACC3', 'Gene', (25, 30))	('FGFR3', 'Gene', '2261', (19, 24))	('RB1', 'Gene', (82, 85))	('fusions', 'Var', (31, 38))	('FGFR3', 'Gene', (19, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))
66437	33668859	The authors proposed a pattern in which low-grade tumors with FGFR3 and HRAS mutations may be more prone to progress to high-grade invasive disease when they occur in the upper tract than in the bladder.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('invasive disease', 'Disease', 'MESH:D009361', (131, 147))	('FGFR3', 'Gene', '2261', (62, 67))	('HRAS', 'Gene', '3265', (72, 76))	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('high-grade', 'MPA', (120, 130))	('invasive disease', 'Disease', (131, 147))	('HRAS', 'Gene', (72, 76))	('progress', 'PosReg', (108, 116))	('mutations', 'Var', (77, 86))	('FGFR3', 'Gene', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
66445	33668859	found that the mutational landscape of low-grade UTUC was similar to that of LG non-muscle invasive BC with a prevalence of KDM6A, STAG2 and FGFR3 alterations.	('STAG2', 'Gene', (131, 136))	('FGFR3', 'Gene', '2261', (141, 146))	('non-muscle invasive BC', 'Disease', (80, 102))	('STAG2', 'Gene', '10735', (131, 136))	('KDM6A', 'Gene', (124, 129))	('FGFR3', 'Gene', (141, 146))	('FGFR', 'molecular_function', 'GO:0005007', ('141', '145'))	('KDM6A', 'Gene', '7403', (124, 129))	('alterations', 'Var', (147, 158))
66447	33668859	TERT, TP53 and CDKN2A were the most frequently mutated genes, but TERT and TP53 were less common in UTUC.	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('CDKN2A', 'Gene', (15, 21))	('CDKN2A', 'Gene', '1029', (15, 21))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', (66, 70))	('TERT', 'Gene', '7015', (66, 70))	('mutated', 'Var', (47, 54))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
66463	33668859	In this disease, ERBB2 mutations and HER2 overexpression are more common than in pure urothelial cancer.	('common', 'Reg', (66, 72))	('HER2', 'Gene', (37, 41))	('ERBB2', 'Gene', '2064', (17, 22))	('HER2', 'Gene', '2064', (37, 41))	('mutations', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ERBB2', 'Gene', (17, 22))	('urothelial cancer', 'Disease', (86, 103))	('overexpression', 'PosReg', (42, 56))	('urothelial cancer', 'Disease', 'MESH:D014523', (86, 103))
66478	33668859	Usually, in this type of cancer, co-alterations in TP53 and RB1 resulting in loss of function of both genes were detected.	('loss of function', 'NegReg', (77, 93))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('TP53', 'Gene', (51, 55))	('RB1', 'Gene', (60, 63))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('RB1', 'Gene', '5925', (60, 63))	('cancer', 'Disease', (25, 31))	('co-alterations', 'Var', (33, 47))	('TP53', 'Gene', '7157', (51, 55))
66486	33668859	Postoperative predictors of worse prognosis include high tumor stage and grade, lymph node involvement, lymphovascular invasion, positive surgical margins, extensive tumor necrosis, sessile growth pattern architecture and concomitant carcinoma in situ.	('necrosis', 'biological_process', 'GO:0008220', ('172', '180'))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('carcinoma', 'Disease', 'MESH:D009369', (234, 243))	('men', 'Species', '9606', (98, 101))	('necrosis', 'biological_process', 'GO:0070265', ('172', '180'))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (234, 251))	('necrosis', 'biological_process', 'GO:0019835', ('172', '180'))	('lymph node involvement', 'CPA', (80, 102))	('necrosis', 'biological_process', 'GO:0001906', ('172', '180'))	('growth pattern', 'biological_process', 'GO:0007150', ('190', '204'))	('tumor', 'Disease', (57, 62))	('sessile growth pattern architecture', 'Disease', 'MESH:D006130', (182, 217))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (166, 171))	('lymphovascular invasion', 'Disease', (104, 127))	('lymphovascular invasion', 'Disease', 'MESH:D009361', (104, 127))	('growth pattern', 'biological_process', 'GO:0040007', ('190', '204'))	('high', 'Var', (52, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('sessile growth pattern architecture', 'Disease', (182, 217))	('necrosis', 'biological_process', 'GO:0008219', ('172', '180'))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('carcinoma', 'Disease', (234, 243))	('tumor necrosis', 'Disease', 'MESH:D009336', (166, 180))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor necrosis', 'Disease', (166, 180))
66496	33668859	reported that FGFR3 mutations correlated with low-stage tumors and better survival in patients with UTUC.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('low-stage tumors', 'Disease', 'MESH:D009800', (46, 62))	('low-stage tumors', 'Disease', (46, 62))	('FGFR3', 'Gene', '2261', (14, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('FGFR3', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))	('better', 'PosReg', (67, 73))	('patients', 'Species', '9606', (86, 94))
66504	33668859	However, STAG2 loss was significantly associated with worse clinical outcome in UTUC with high Ki-67 proliferation indexes, but not in UTUC with low Ki-67 expression.	('STAG2', 'Gene', (9, 14))	('STAG2', 'Gene', '10735', (9, 14))	('loss', 'NegReg', (15, 19))	('high', 'Var', (90, 94))	('Ki-67', 'Gene', (95, 100))
66512	33668859	A molecular profiling approach to UTUC could be useful in the preoperative setting, as proposed by Bagrodia et al.. For example, patients with altered TP53/MDM2 may be considered for adjuvant chemotherapy or enrollment in clinical trials.	('altered', 'Var', (143, 150))	('MDM2', 'Gene', (156, 160))	('TP53', 'Gene', (151, 155))	('patients', 'Species', '9606', (129, 137))	('men', 'Species', '9606', (214, 217))	('TP53', 'Gene', '7157', (151, 155))	('MDM2', 'Gene', '4193', (156, 160))
66538	33198698	In addition, positive VUC is an adverse predictor of RFS and CSS, which might be due to the association between positive VUC and high tumor grade.	('VUC', 'Chemical', '-', (121, 124))	('RFS', 'Disease', 'MESH:D005198', (53, 56))	('VUC', 'Chemical', '-', (22, 25))	('RFS', 'Disease', (53, 56))	('tumor', 'Disease', (134, 139))	('CSS', 'Disease', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('CSS', 'Chemical', '-', (61, 64))	('positive VUC', 'Var', (13, 25))
66545	33198698	Several studies suggested that preoperative positive VUC increased the risk of bladder recurrence after RNU; however, the results remain controversial.	('RNU', 'Chemical', '-', (104, 107))	('increased the risk of bladder recurrence', 'Phenotype', 'HP:0012786', (57, 97))	('bladder recurrence', 'Disease', (79, 97))	('VUC', 'Chemical', '-', (53, 56))	('positive VUC', 'Var', (44, 56))
66580	33198698	Five-year intravesical recurrence-free survival (RFS), RFS, CSS, and overall survival (OS) rates for the positive and negative VUC groups were 79% vs. 89% (P = 0.064; Fig.	('overall survival', 'CPA', (69, 85))	('RFS', 'Disease', (49, 52))	('RFS', 'Disease', (55, 58))	('CSS', 'Chemical', '-', (60, 63))	('VUC', 'Gene', (127, 130))	('RFS', 'Disease', 'MESH:D005198', (49, 52))	('VUC', 'Chemical', '-', (127, 130))	('RFS', 'Disease', 'MESH:D005198', (55, 58))	('positive', 'Var', (105, 113))
66591	33198698	We confirmed that VUC before RNU was an independent prognostic factor for disease recurrence and cancer-specific mortality, but not overall mortality.	('disease recurrence', 'CPA', (74, 92))	('VUC before RNU', 'Var', (18, 32))	('VUC', 'Chemical', '-', (18, 21))	('cancer', 'Disease', (97, 103))	('mortality', 'Disease', 'MESH:D003643', (140, 149))	('mortality', 'Disease', 'MESH:D003643', (113, 122))	('RNU', 'Chemical', '-', (29, 32))	('mortality', 'Disease', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mortality', 'Disease', (140, 149))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
66592	33198698	In agreement with several previous studies, we found that preoperative VUC was an independent predictor of bladder recurrence in UTUC patients (HR = 2.21, 95% CI 1.06-4.64; P = 0.035).	('patients', 'Species', '9606', (134, 142))	('bladder recurrence', 'Disease', (107, 125))	('VUC', 'Var', (71, 74))	('VUC', 'Chemical', '-', (71, 74))
66613	33198698	Moreover, other studies showed that positive preoperative VUC is associated with disease recurrence and cancer-specific mortality after transurethral resection of bladder tumors.	('bladder tumors', 'Phenotype', 'HP:0009725', (163, 177))	('mortality', 'Disease', 'MESH:D003643', (120, 129))	('bladder tumors', 'Disease', 'MESH:D001749', (163, 177))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('bladder tumors', 'Disease', (163, 177))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('associated with', 'Reg', (65, 80))	('mortality', 'Disease', (120, 129))	('VUC', 'Gene', (58, 61))	('VUC', 'Chemical', '-', (58, 61))	('positive', 'Var', (36, 44))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('disease recurrence', 'CPA', (81, 99))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
66615	33198698	found that preoperative VUC increased cancer-specific mortality in UTUC patients, but 116 patients (22%) synchronously suffered bladder cancer, which made it difficult to identify the source of malignant cells in urine.	('VUC', 'Var', (24, 27))	('bladder cancer', 'Disease', 'MESH:D001749', (128, 142))	('bladder cancer', 'Disease', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('mortality', 'Disease', (54, 63))	('VUC', 'Chemical', '-', (24, 27))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('suffered', 'Reg', (119, 127))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('mortality', 'Disease', 'MESH:D003643', (54, 63))	('patients', 'Species', '9606', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('patients', 'Species', '9606', (72, 80))
66616	33198698	After excluding patients experiencing bladder cancer before and/or during RNU, the present study proved that preoperative VUC independently not only increased the risk of cancer-specific mortality (HR = 1.87, 95% CI 1.10-3.18; P = 0.020) but also the risk of disease recurrence (HR = 1.80, 95% CI 1.08-2.99; P = 0.023).	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('increased', 'PosReg', (149, 158))	('patients', 'Species', '9606', (16, 24))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('mortality', 'Disease', (187, 196))	('RNU', 'Chemical', '-', (74, 77))	('cancer', 'Disease', (171, 177))	('bladder cancer', 'Phenotype', 'HP:0009725', (38, 52))	('disease', 'Disease', (259, 266))	('bladder cancer', 'Disease', 'MESH:D001749', (38, 52))	('bladder cancer', 'Disease', (38, 52))	('VUC', 'Var', (122, 125))	('VUC', 'Chemical', '-', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('mortality', 'Disease', 'MESH:D003643', (187, 196))
66638	30570744	Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a single-arm, open-label phase 2 study.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('CREB binding protein', 'Gene', (323, 343))	('urothelial carcinoma', 'Disease', (79, 99))	('EP300', 'Gene', '2033', (386, 391))	('protein', 'cellular_component', 'GO:0003675', ('372', '379'))	('CREBBP', 'Gene', '1387', (345, 351))	('urothelial carcinoma', 'Disease', (253, 273))	('mocetinostat', 'Chemical', 'MESH:C523184', (178, 190))	('EP300', 'Gene', (386, 391))	('CREB binding protein', 'Gene', '1387', (323, 343))	('E1A binding protein p300', 'Gene', (360, 384))	('Mocetinostat', 'Chemical', 'MESH:C523184', (0, 12))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (79, 99))	('E1A binding protein p300', 'Gene', '2033', (360, 384))	('patients', 'Species', '9606', (17, 25))	('CREB binding', 'molecular_function', 'GO:0008140', ('323', '335'))	('deletions', 'Var', (310, 319))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (253, 273))	('patients', 'Species', '9606', (239, 247))	('protein', 'cellular_component', 'GO:0003675', ('336', '343'))	('binding', 'molecular_function', 'GO:0005488', ('364', '371'))	('inactivating mutations', 'Var', (284, 306))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('CREBBP', 'Gene', (345, 351))
66650	30570744	After the genomic-based selection of patients with urothelial cancer with inactivating mutations/deletions in the histone acetyltransferase genes CREBBP and/or EP300, single-agent mocetinostat appears to be associated with significant toxicities that limit drug exposure.	('CREBBP', 'Gene', (146, 152))	('toxicities', 'Disease', 'MESH:D064420', (235, 245))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('patients', 'Species', '9606', (37, 45))	('CREBBP', 'Gene', '1387', (146, 152))	('mocetinostat', 'Chemical', 'MESH:C523184', (180, 192))	('toxicities', 'Disease', (235, 245))	('single-agent', 'Var', (167, 179))	('mocetinostat', 'Gene', (180, 192))	('urothelial cancer', 'Disease', (51, 68))	('limit drug exposure', 'Phenotype', 'HP:0020173', (251, 270))	('inactivating mutations/deletions', 'Var', (74, 106))	('EP300', 'Gene', (160, 165))	('EP300', 'Gene', '2033', (160, 165))	('urothelial cancer', 'Disease', 'MESH:D014523', (51, 68))
66653	30570744	Dysregulated histone acetylation is implicated in the pathogenesis of several cancers, including urothelial carcinoma.	('urothelial carcinoma', 'Disease', (97, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('histone acetylation', 'biological_process', 'GO:0016573', ('13', '32'))	('implicated', 'Reg', (36, 46))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('histone', 'Protein', (13, 20))	('pathogenesis', 'biological_process', 'GO:0009405', ('54', '66'))	('cancers', 'Disease', (78, 85))	('Dysregulated', 'Var', (0, 12))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (97, 117))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
66655	30570744	Thus, we hypothesized that treating patients with urothelial carcinoma harboring inactivating mutations in CREBBP and EP300 with selective HDAC inhibitors may restore the expression of tumor suppressor genes, resulting in antitumor responses.	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (50, 70))	('EP300', 'Gene', (118, 123))	('tumor', 'Disease', (185, 190))	('patients', 'Species', '9606', (36, 44))	('CREBBP', 'Gene', '1387', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('inactivating mutations', 'Var', (81, 103))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('185', '201'))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('expression', 'MPA', (171, 181))	('tumor suppressor', 'biological_process', 'GO:0051726', ('185', '201'))	('urothelial carcinoma', 'Disease', (50, 70))	('CREBBP', 'Gene', (107, 113))	('restore', 'PosReg', (159, 166))	('EP300', 'Gene', '2033', (118, 123))	('tumor', 'Disease', (226, 231))
66656	30570744	This phase 2 study investigated single-agent mocetinostat in patients with locally advanced or metastatic urothelial carcinoma who previously were treated with platinum-based chemotherapy and inactivating tumor mutations or deletions in CREBBP and/or EP300.	('mocetinostat', 'Chemical', 'MESH:C523184', (45, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('EP300', 'Gene', '2033', (251, 256))	('patients', 'Species', '9606', (61, 69))	('mutations', 'Var', (211, 220))	('EP300', 'Gene', (251, 256))	('deletions', 'Var', (224, 233))	('platinum', 'Chemical', 'MESH:D010984', (160, 168))	('metastatic urothelial carcinoma', 'Disease', 'MESH:C538445', (95, 126))	('CREBBP', 'Gene', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('inactivating', 'Var', (192, 204))	('tumor', 'Disease', (205, 210))	('locally advanced', 'Disease', (75, 91))	('metastatic urothelial carcinoma', 'Disease', (95, 126))	('CREBBP', 'Gene', '1387', (237, 243))
66658	30570744	Eligible patients had adequate bone marrow, hepatic, and renal function and an inactivating mutation or deletion (homozygous or hemizygous) in CREBBP and/or EP300 (see Supporting Materials).	('CREBBP', 'Gene', '1387', (143, 149))	('patients', 'Species', '9606', (9, 17))	('EP300', 'Gene', (157, 162))	('EP300', 'Gene', '2033', (157, 162))	('inactivating mutation', 'Var', (79, 100))	('CREBBP', 'Gene', (143, 149))	('hepatic', 'MPA', (44, 51))	('deletion', 'Var', (104, 112))
66674	30570744	Frequently altered genes included TP53, AT-rich interaction domain 1A [ARID1A], MLL2 (KMT2D), KDM6A, MLL3 (KMT2C), retinoblastoma protein (RB1), and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) (Fig.	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('149', '182'))	('MLL3', 'Gene', '58508', (101, 105))	('2A/B', 'SUBSTITUTION', 'None', (183, 187))	('MLL2', 'Gene', '8085', (80, 84))	('2A/B', 'Var', (183, 187))	('KMT2D', 'Gene', '8085', (86, 91))	('ARID1A]', 'Gene', '8289', (71, 78))	('KDM6A', 'Gene', '7403', (94, 99))	('MLL2', 'Gene', (80, 84))	('retinoblastoma', 'Gene', '5925', (115, 129))	('retinoblastoma', 'Phenotype', 'HP:0009919', (115, 129))	('MLL3', 'Gene', (101, 105))	('KMT2D', 'Gene', (86, 91))	('TP53', 'Gene', (34, 38))	('CDKN2A/B', 'Gene', (189, 197))	('KDM6A', 'Gene', (94, 99))	('RB1', 'Gene', (139, 142))	('2A/B', 'Var', (193, 197))	('RB1', 'Gene', '5925', (139, 142))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('166', '182'))	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('retinoblastoma', 'Gene', (115, 129))	('ARID1A]', 'Gene', (71, 78))	('2A/B', 'SUBSTITUTION', 'None', (193, 197))	('CDKN2A/B', 'Gene', '1029;1030', (189, 197))	('KMT2C', 'Gene', '58508', (107, 112))	('KMT2C', 'Gene', (107, 112))	('TP53', 'Gene', '7157', (34, 38))
66675	30570744	Thirty-three patients (21%) had >=1 of the 40 qualifying tumor mutations in CREBBP or EP300 identified: 27 CREBBP mutations were identified among 23 patients (15%), 13 EP300 mutations were identified among 12 patients (8%), and mutations in both genes were identified in 2 patients (1%).	('mutations', 'Var', (63, 72))	('patients', 'Species', '9606', (149, 157))	('patients', 'Species', '9606', (273, 281))	('CREBBP', 'Gene', '1387', (76, 82))	('mutations', 'Var', (114, 123))	('EP300', 'Gene', (168, 173))	('EP300', 'Gene', '2033', (168, 173))	('CREBBP', 'Gene', '1387', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('EP300', 'Gene', '2033', (86, 91))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('EP300', 'Gene', (86, 91))	('tumor', 'Disease', (57, 62))	('CREBBP', 'Gene', (107, 113))	('patients', 'Species', '9606', (209, 217))	('CREBBP', 'Gene', (76, 82))
66676	30570744	Qualifying CREBBP alterations were most commonly nonsense (5% [8 patients]), frameshift (5% [7 patients]), or missense (3% [5 patients]) mutations.	('CREBBP', 'Gene', '1387', (11, 17))	('patients', 'Species', '9606', (95, 103))	('missense', 'Var', (110, 118))	('frameshift', 'Var', (77, 87))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (126, 134))	('CREBBP', 'Gene', (11, 17))	('nonsense', 'Var', (49, 57))
66677	30570744	EP300 mutations were most commonly missense mutations (3% [5 patients]).	('EP300', 'Gene', '2033', (0, 5))	('patients', 'Species', '9606', (61, 69))	('missense', 'Var', (35, 43))	('EP300', 'Gene', (0, 5))
66681	30570744	Twenty-two qualifying mutations were identified in these 17 patients: 14 CREBBP mutations in 12 patients and 8 EP300 mutations in 7 patients, and 2 patients had qualifying mutations of both CREBBP and EP300 (see Supporting Table S3).	('CREBBP', 'Gene', (73, 79))	('CREBBP', 'Gene', (190, 196))	('patients', 'Species', '9606', (148, 156))	('mutations', 'Var', (80, 89))	('patients', 'Species', '9606', (60, 68))	('CREBBP', 'Gene', '1387', (190, 196))	('CREBBP', 'Gene', '1387', (73, 79))	('EP300', 'Gene', (111, 116))	('EP300', 'Gene', '2033', (111, 116))	('patients', 'Species', '9606', (96, 104))	('EP300', 'Gene', '2033', (201, 206))	('EP300', 'Gene', (201, 206))	('patients', 'Species', '9606', (132, 140))
66687	30570744	His primary tumor contained 2 qualifying EP300 missense mutations (G1347E and P925T) and other mutations (truncating mutations in ARID1A, MLL2 [KMT2D], and CHEK2; a missense mutation in ATM; and amplification of TERC and PRKCI).	('ATM', 'Gene', (186, 189))	('ARID1A', 'Gene', (130, 136))	('TERC', 'Gene', '7012', (212, 216))	('KMT2D', 'Gene', (144, 149))	('tumor', 'Disease', (12, 17))	('CHEK2', 'Gene', (156, 161))	('ARID1A', 'Gene', '8289', (130, 136))	('PRKCI', 'Gene', '5584', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('TERC', 'Gene', (212, 216))	('CHEK2', 'Gene', '11200', (156, 161))	('G1347E', 'Mutation', 'rs372872379', (67, 73))	('ATM', 'Gene', '472', (186, 189))	('MLL2', 'Gene', '8085', (138, 142))	('KMT2D', 'Gene', '8085', (144, 149))	('EP300', 'Gene', '2033', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('PRKCI', 'Gene', (221, 226))	('G1347E', 'Var', (67, 73))	('MLL2', 'Gene', (138, 142))	('P925T', 'Mutation', 'rs148884710', (78, 83))	('P925T', 'Var', (78, 83))	('EP300', 'Gene', (41, 46))
66715	30570744	It is interesting to note that the patient with a confirmed PR harbored 2 EP300 mutations in trans, P925T, and G1347E, suggesting that biallelic loss of function in this pathway could be therapeutically significant; however, this patient had lymph node-only metastasis, which is a favorable prognostic factor.	('EP300', 'Gene', '2033', (74, 79))	('patient', 'Species', '9606', (35, 42))	('patient', 'Species', '9606', (230, 237))	('G1347E', 'Var', (111, 117))	('G1347E', 'Mutation', 'rs372872379', (111, 117))	('P925T', 'Mutation', 'rs148884710', (100, 105))	('lymph node-only metastasis', 'CPA', (242, 268))	('P925T', 'Var', (100, 105))	('loss of function', 'NegReg', (145, 161))	('EP300', 'Gene', (74, 79))
66717	30570744	Furthermore, we hypothesized a mechanism of action of mocetinostat to reactivate the transcription of tumor suppressor genes, but a relatively high frequency of inactivating alterations in the tumor suppressor genes TP53, CDKN2A/B, and RB1 may have limited the potential of epigenetic modulation by mocetinostat to induce tumor response.	('RB1', 'Gene', (236, 239))	('tumor', 'Disease', 'MESH:D009369', (322, 327))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('102', '118'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('193', '209'))	('mocetinostat', 'Chemical', 'MESH:C523184', (54, 66))	('transcription', 'biological_process', 'GO:0006351', ('85', '98'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('mocetinostat', 'Chemical', 'MESH:C523184', (299, 311))	('tumor suppressor', 'biological_process', 'GO:0051726', ('102', '118'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('193', '209'))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('RB1', 'Gene', '5925', (236, 239))	('tumor', 'Disease', (193, 198))	('CDKN2A/B', 'Gene', (222, 230))	('TP53', 'Gene', (216, 220))	('transcription', 'MPA', (85, 98))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('inactivating alterations', 'Var', (161, 185))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('CDKN2A/B', 'Gene', '1029;1030', (222, 230))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('TP53', 'Gene', '7157', (216, 220))	('tumor', 'Disease', (322, 327))
66766	33139244	The coefficient of variation (CV) of TMB derived from panel sequencing decreases in a manner that is inversely proportional with both the square root of the panel size and the square root of the TMB level; for example, halving the CV requires a four-fold increase in panel size.	('TMB', 'Chemical', '-', (195, 198))	('decreases', 'NegReg', (71, 80))	('halving', 'Var', (219, 226))	('TMB', 'Chemical', '-', (37, 40))
66770	33139244	Both MSK-IMPACT and FoundationOne CDx  panels detect somatic coding mutations (non-synonymous) per megabase of tumor genome examined, inclusive of frameshift, point mutations, and small insertions and deletions (indels) (see Supplementary Data).	('CDx', 'Chemical', '-', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('MSK', 'Gene', '150094', (5, 8))	('MSK', 'Gene', (5, 8))	('point mutations', 'Var', (159, 174))	('insertions', 'Var', (186, 196))	('deletions', 'Var', (201, 210))	('frameshift', 'Var', (147, 157))	('FoundationOne', 'Chemical', '-', (20, 33))
66771	33139244	While synonymous mutations are detected by these panels (not reported by MSK-IMPACT), they are not involved in neoantigen production although their inclusion may reduce sampling noise and improve the approximation of TMB across the whole genome if tumor-normal pairs are sequenced.	('reduce', 'NegReg', (162, 168))	('tumor', 'Disease', (248, 253))	('improve', 'PosReg', (188, 195))	('MSK', 'Gene', '150094', (73, 76))	('MSK', 'Gene', (73, 76))	('TMB', 'Chemical', '-', (217, 220))	('approximation', 'MPA', (200, 213))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('sampling noise', 'MPA', (169, 183))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('inclusion', 'Var', (148, 157))	('TMB', 'MPA', (217, 220))
66774	33139244	Genetic changes in cancer include non-synonymous (including missense, nonsense, frameshift and splice-site mutations) and synonymous mutations, insertion or deletion mutations (indels), and gene copy number alterations (CNAs).	('nonsense', 'Var', (70, 78))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('frameshift', 'Var', (80, 90))	('cancer', 'Disease', (19, 25))	('insertion or deletion mutations', 'Var', (144, 175))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('non-synonymous', 'Var', (34, 48))	('missense', 'Var', (60, 68))	('gene copy number alterations', 'Var', (190, 218))
66787	33139244	Bioinformatics pipelines usually include negative filtering for cancer hotspot mutations further mitigating the influence of the panel composition.	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
66793	33139244	In these cancers, TMB distribution is shaped by the occurrence of hypermutation in MMR deficient and/or POLE/POLD1 mutated tumors and permits relatively clean dichotomization.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('MMR', 'Gene', (83, 86))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('MMR', 'biological_process', 'GO:0006298', ('83', '86'))	('TMB', 'Chemical', '-', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('deficient', 'NegReg', (87, 96))	('POLD1', 'Gene', (109, 114))	('POLD1', 'Gene', '5424', (109, 114))	('hypermutation', 'Var', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
66802	33139244	Mutational processes that can cause a very high TMB and hypermutation include: POLE/POLD1 mutation, mismatch repair deficiency, UV light, tobacco smoking, AID/APOBEC activation and the three clock-like mutational processes (SBS1, SBS5) (Fig.	('AID', 'Gene', '57379', (155, 158))	('AID', 'Gene', (155, 158))	('POLD1', 'Gene', '5424', (84, 89))	('TMB', 'Chemical', '-', (48, 51))	('POLD1', 'Gene', (84, 89))	('tobacco', 'Species', '4097', (138, 145))	('APOBEC', 'cellular_component', 'GO:0030895', ('159', '165'))	('mismatch repair', 'MPA', (100, 115))	('mutation', 'Var', (90, 98))	('mismatch repair', 'biological_process', 'GO:0006298', ('100', '115'))
66811	33139244	The first evidence to support this hypothesis came from studies of melanoma and NSCLC treated with anti-CTLA-4 and anti-PD-1 antibodies, respectively, whereby a higher nonsynonymous mutation burden was associated with improved objective response rate (ORR) and progression-free survival (PFS).	('CTLA-4', 'Gene', (104, 110))	('nonsynonymous mutation burden', 'Var', (168, 197))	('progression-free survival', 'CPA', (261, 286))	('objective response rate', 'CPA', (227, 250))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('NSCLC', 'Disease', (80, 85))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('higher', 'PosReg', (161, 167))	('CTLA-4', 'Gene', '1493', (104, 110))	('improved', 'PosReg', (218, 226))
66823	33139244	The ORR and PFS were superior in patients with TMB-high vs. low tumors (ORR: 30.3% vs 6.8%; PFS at 12 months: 26.4% vs 14.1%).	('TMB', 'Chemical', '-', (47, 50))	('low tumors', 'Disease', (60, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('patients', 'Species', '9606', (33, 41))	('TMB-high', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('low tumors', 'Disease', 'MESH:D009800', (60, 70))
66824	33139244	Among the TMB-high group, 85/99 (85.9%) tumors were microsatellite stable (MSS) indicating that MSI-H status did not account for the predictive utility of TMB-high.	('TMB', 'Chemical', '-', (10, 13))	('microsatellite', 'Var', (52, 66))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('TMB', 'Chemical', '-', (155, 158))	('MSI', 'Gene', (96, 99))	('tumors', 'Disease', (40, 46))	('MSI', 'Gene', '5928', (96, 99))
66843	33139244	Importantly, TMB differed significantly among melanomas harboring mutations in BRAF, NRAS, NF1 or triple wild-type (WT) tumors with median TMB values of 12.0, 17.6, 62.7, and 2.2 mut/Mb, respectively (p< 0.001).	('mutations', 'Var', (66, 75))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('NF1', 'Gene', (91, 94))	('melanomas', 'Disease', 'MESH:D008545', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('differed', 'Reg', (17, 25))	('NF1', 'Gene', '4763', (91, 94))	('NRAS', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (79, 83))	('melanomas', 'Disease', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('NRAS', 'Gene', '4893', (85, 89))	('BRAF', 'Gene', (79, 83))	('TMB', 'Chemical', '-', (139, 142))	('TMB', 'Chemical', '-', (13, 16))
66844	33139244	Melanomas with NF1 mutations are associated with chronic UV damage and thus, have a high TMB.	('chronic UV damage', 'Disease', (49, 66))	('NF1', 'Gene', (15, 18))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('NF1', 'Gene', '4763', (15, 18))	('Melanomas', 'Disease', (0, 9))	('chronic UV damage', 'Disease', 'MESH:C563466', (49, 66))	('mutations', 'Var', (19, 28))	('TMB', 'MPA', (89, 92))	('associated', 'Reg', (33, 43))	('TMB', 'Chemical', '-', (89, 92))
66848	33139244	Certain genomic alterations such as mutations in NF1 or BRCA2 were more common in responders to ICI treatment compared to triple WT tumors.	('WT tumors', 'Disease', (129, 138))	('common', 'Reg', (72, 78))	('BRCA2', 'Gene', '675', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mutations', 'Var', (36, 45))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('WT tumors', 'Disease', 'MESH:C536751', (129, 138))	('NF1', 'Gene', (49, 52))	('BRCA2', 'Gene', (56, 61))	('NF1', 'Gene', '4763', (49, 52))
66855	33139244	Of note, smoking status is inversely related to prevalence of targetable oncogenic driver mutations in EGFR, ALK and ROS1 genes in lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('EGFR', 'Gene', '1956', (103, 107))	('lung adenocarcinoma', 'Disease', (131, 150))	('mutations', 'Var', (90, 99))	('ALK', 'Gene', (109, 112))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (131, 150))	('EGFR', 'Gene', (103, 107))	('ALK', 'Gene', '238', (109, 112))	('ROS1', 'Gene', (117, 121))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('ROS1', 'Gene', '6098', (117, 121))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (131, 150))
66856	33139244	Among lung cancers [squamous carcinoma and small cell lung cancers (SCLC)] associated with cigarette smoking, mutations in BRAF, KRAS, PTEN and PIK3CA are most common.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('PIK3CA', 'Gene', '5290', (144, 150))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (43, 65))	('SCLC', 'Disease', (68, 72))	('PTEN', 'Gene', '5728', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (20, 38))	('KRAS', 'Gene', '3845', (129, 133))	('squamous carcinoma', 'Disease', 'MESH:D002294', (20, 38))	('KRAS', 'Gene', (129, 133))	('lung cancers', 'Disease', 'MESH:D008175', (54, 66))	('mutations', 'Var', (110, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('PIK3CA', 'Gene', (144, 150))	('small cell lung cancers', 'Disease', 'MESH:D055752', (43, 66))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (43, 66))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('small cell lung cancers', 'Disease', (43, 66))	('SCLC', 'Disease', 'MESH:D018288', (68, 72))	('lung cancers', 'Disease', 'MESH:D008175', (6, 18))	('lung cancers', 'Disease', (6, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('squamous carcinoma', 'Disease', (20, 38))	('lung cancers', 'Phenotype', 'HP:0100526', (54, 66))	('PTEN', 'Gene', (135, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (6, 17))	('common', 'Reg', (160, 166))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('lung cancers', 'Phenotype', 'HP:0100526', (6, 18))
66858	33139244	Variability of TMB has been identified among molecular subgroups of lung cancer.	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('Variability', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TMB', 'Gene', (15, 18))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('TMB', 'Chemical', '-', (15, 18))
66870	33139244	In the CheckMate 568 study, TMB >=10 mut/Mb was a cutpoint for ORR and was validated as a predictive biomarker when prospectively applied to CheckMate 227 where it showed improved PFS for nivolumab and ipilimumab compared to standard chemotherapy.	('TMB >=10 mut/Mb', 'Var', (28, 43))	('ipilimumab', 'Chemical', 'MESH:D000074324', (202, 212))	('TMB', 'Chemical', '-', (28, 31))	('nivolumab', 'Chemical', 'MESH:D000077594', (188, 197))	('PFS', 'MPA', (180, 183))	('improved', 'PosReg', (171, 179))
66873	33139244	Among 17 patients from a pan-cancer cohort treated with a combination of anti-PD-1 and anti-CTLA4 antibodies, TMB levels were not associated with treatment efficacy.	('patients', 'Species', '9606', (9, 17))	('CTLA4', 'Gene', (92, 97))	('cancer', 'Disease', (29, 35))	('anti-PD-1', 'Var', (73, 82))	('TMB', 'Chemical', '-', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('CTLA4', 'Gene', '1493', (92, 97))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
66883	33139244	Mutation in the apolipoprotein B editing enzyme (APOBEC) was common in all stages and locations of urothelial carcinoma, was strongly associated with TMB, and was more frequent in muscle invasive (MIBC) and high grade non muscle invasive bladder cancers (NMIBC).	('apolipoprotein B', 'Gene', '338', (16, 32))	('common', 'Reg', (61, 67))	('associated', 'Reg', (134, 144))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('apolipoprotein', 'molecular_function', 'GO:0005319', ('16', '30'))	('bladder cancers', 'Phenotype', 'HP:0009725', (238, 253))	('TMB', 'Disease', (150, 153))	('muscle invasive bladder cancers', 'Disease', 'MESH:D001749', (222, 253))	('APOBEC', 'Gene', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('frequent', 'Reg', (168, 176))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (99, 119))	('apolipoprotein B', 'Gene', (16, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('urothelial carcinoma', 'Disease', (99, 119))	('APOBEC', 'cellular_component', 'GO:0030895', ('49', '55'))	('TMB', 'Chemical', '-', (150, 153))	('invasive bladder', 'Phenotype', 'HP:0100645', (229, 245))	('apolipoprotein', 'molecular_function', 'GO:0005320', ('16', '30'))	('Mutation', 'Var', (0, 8))	('muscle invasive bladder cancers', 'Disease', (222, 253))	('muscle invasive', 'Disease', (180, 195))
66887	33139244	In a phase II single-arm trial I of atezolizumab monotherapy in this same study population, median TMB (measured in 150 patients by a 315-gene panel) was significantly increased in responders vs. non-responders (12.4 mut/Mb vs. 6.4 mut/Mb, p<0.0001) [Table 2].	('increased', 'PosReg', (168, 177))	('mut/Mb', 'Var', (217, 223))	('patients', 'Species', '9606', (120, 128))	('TMB', 'MPA', (99, 102))	('atezolizumab', 'Chemical', 'MESH:C000594389', (36, 48))	('TMB', 'Chemical', '-', (99, 102))
66901	33139244	Cancers with the highest known TMB levels are ultramutated and are caused by mutations in polymerase epsilon (POLE) that impair DNA proofreading.	('POLE', 'Gene', (110, 114))	('Cancers', 'Disease', (0, 7))	('TMB', 'Chemical', '-', (31, 34))	('caused by', 'Reg', (67, 76))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('impair', 'NegReg', (121, 127))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('mutations', 'Var', (77, 86))	('DNA proofreading', 'MPA', (128, 144))
66902	33139244	Such tumors are nearly exclusively microsatellite stable (MSS), have TMB values ranging from 122 mut/Mb to 303 mut/Mb, and comprise approximately 1-2% of all MSS CRCs.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('microsatellite', 'Var', (35, 49))	('TMB', 'Chemical', '-', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
66911	33139244	Among 17 patients with MSS advanced hepatocellular carcinoma treated with an anti-PD-1 antibody, one patient (TMB 15 mut/Mb) had a sustained complete response to nivolumab lasting >2 years.	('patients', 'Species', '9606', (9, 17))	('antibody', 'cellular_component', 'GO:0019814', ('87', '95'))	('antibody', 'cellular_component', 'GO:0019815', ('87', '95'))	('TMB', 'Chemical', '-', (110, 113))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (36, 60))	('antibody', 'molecular_function', 'GO:0003823', ('87', '95'))	('hepatocellular carcinoma', 'Disease', (36, 60))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (36, 60))	('patient', 'Species', '9606', (9, 16))	('patient', 'Species', '9606', (101, 108))	('nivolumab', 'Chemical', 'MESH:D000077594', (162, 171))	('antibody', 'cellular_component', 'GO:0042571', ('87', '95'))	('anti-PD-1', 'Var', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
66917	33139244	While these differences in TMB were statistically significant, they are within the error range of large gene panels.	('differences', 'Var', (12, 23))	('TMB', 'Gene', (27, 30))	('TMB', 'Chemical', '-', (27, 30))
66919	33139244	In a single center cohort of patients with metastatic TNBC (N=62) treated with an anti-PD-1/PD-L1 antibody, patients whose tumors had high TMB (>=10 mut/Mb) had a 2-fold increase in likelihood of response compared to those with lower TMB (Table 2).	('met', 'Gene', (43, 46))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('antibody', 'molecular_function', 'GO:0003823', ('98', '106'))	('patients', 'Species', '9606', (108, 116))	('antibody', 'cellular_component', 'GO:0042571', ('98', '106'))	('patients', 'Species', '9606', (29, 37))	('TMB', 'Chemical', '-', (234, 237))	('high', 'Var', (134, 138))	('TMB', 'Chemical', '-', (139, 142))	('antibody', 'cellular_component', 'GO:0019815', ('98', '106'))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('PD-L1', 'Gene', (92, 97))	('increase', 'PosReg', (170, 178))	('response', 'MPA', (196, 204))	('PD-L1', 'Gene', '29126', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (123, 129))	('antibody', 'cellular_component', 'GO:0019814', ('98', '106'))	('met', 'Gene', '79811', (43, 46))
66937	33139244	MSI-H tumors show hypermutation including frameshift mutations that generate numerous neopeptides.	('frameshift mutations', 'Var', (42, 62))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('MSI-H tumors', 'Disease', (0, 12))	('generate', 'Reg', (68, 76))	('MSI-H tumors', 'Disease', 'MESH:D009369', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('neopeptides', 'MPA', (86, 97))
66939	33139244	WES revealed a mean of 1,782 somatic mutations per MSI-H tumors as compared with 73 in MSS tumors (P=0.007), suggesting that a markedly increased number of mutation-associated neoantigens is responsible for enhanced anti-PD-1 response.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('MSI-H tumors', 'Disease', 'MESH:D009369', (51, 63))	('MSI-H tumors', 'Disease', (51, 63))	('mutation-associated', 'Reg', (156, 175))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('MSS tumors', 'Disease', 'MESH:D013132', (87, 97))	('enhanced', 'PosReg', (207, 215))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('increased', 'PosReg', (136, 145))	('MSS tumors', 'Disease', (87, 97))	('anti-PD-1 response', 'MPA', (216, 234))
66951	33139244	These data suggest that high TMB in MSI-H/dMMR tumors is associated with increased and durable responses to ICIs, and that TMB may further identify responders to ICIs within MSI-H cancers.	('increased', 'PosReg', (73, 82))	('responses to ICIs', 'MPA', (95, 112))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('ICIs within MSI-H cancers', 'Disease', 'MESH:D009369', (162, 187))	('MSI-H/dMMR tumors', 'Disease', (36, 53))	('MSI-H/dMMR tumors', 'Disease', 'MESH:D009369', (36, 53))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('TMB', 'MPA', (29, 32))	('ICIs within MSI-H cancers', 'Disease', (162, 187))	('high', 'Var', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('TMB', 'Chemical', '-', (29, 32))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('TMB', 'Chemical', '-', (123, 126))
66960	33139244	These data suggest that mechanisms beside DNA repair defects, such as DNA replication mutations (POLD1 and POLE) or TP53 mutations, may underlie their increased TMB.	('TMB', 'Chemical', '-', (161, 164))	('TP53', 'Gene', (116, 120))	('POLD1', 'Gene', (97, 102))	('POLD1', 'Gene', '5424', (97, 102))	('mutations', 'Var', (121, 130))	('DNA replication', 'biological_process', 'GO:0006260', ('70', '85'))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('TP53', 'Gene', '7157', (116, 120))	('DNA repair', 'biological_process', 'GO:0006281', ('42', '52'))	('TMB', 'Disease', (161, 164))
66964	33139244	Alterations in DNA Damage Response and Repair (DDR) genes are associated with genomic instability and increased somatic tumor mutational burden, which may enhance immunogenicity through increased tumor-specific neoantigen load.	('increased', 'PosReg', (102, 111))	('tumor', 'Disease', (196, 201))	('associated', 'Reg', (62, 72))	('Alterations', 'Var', (0, 11))	('increased', 'PosReg', (186, 195))	('enhance', 'PosReg', (155, 162))	('DNA Damage Response', 'biological_process', 'GO:0006974', ('15', '34'))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('DDR) genes', 'Gene', (47, 57))	('immunogenicity', 'MPA', (163, 177))	('genomic instability', 'CPA', (78, 97))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', (120, 125))
66966	33139244	Recent evidence revealed deleterious somatic DDR mutations in approximately 50% of patients with NSCLC or urothelial carcinomas.	('urothelial carcinomas', 'Disease', (106, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('mutations', 'Var', (49, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('NSCLC', 'Disease', (97, 102))	('DDR', 'Gene', (45, 48))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (106, 127))	('patients', 'Species', '9606', (83, 91))
66967	33139244	Patients with DDR mutations had significantly increased tumor TMB levels and longer PFS and OS independent of covariates.	('TMB', 'Chemical', '-', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('increased', 'PosReg', (46, 55))	('tumor', 'Disease', (56, 61))	('Patients', 'Species', '9606', (0, 8))	('DDR', 'Gene', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('mutations', 'Var', (18, 27))
66968	33139244	The prevalence of DDR alterations was 17% among 17,486 GI carcinomas, of which ARID1A (9.2%) and ATM (4.7%) were most common followed by BRCA2 (2.3%), BRCA1 (1.1%) and CHEK2 (1.0%).	('GI carcinomas', 'Disease', 'MESH:D004067', (55, 68))	('BRCA2', 'Gene', '675', (137, 142))	('CHEK2', 'Gene', '11200', (168, 173))	('GI carcinomas', 'Disease', (55, 68))	('BRCA1', 'Gene', '672', (151, 156))	('CHEK2', 'Gene', (168, 173))	('common', 'Reg', (118, 124))	('ARID1A', 'Gene', '8289', (79, 85))	('BRCA1', 'Gene', (151, 156))	('alterations', 'Var', (22, 33))	('ARID1A', 'Gene', (79, 85))	('DDR', 'Gene', (18, 21))	('BRCA2', 'Gene', (137, 142))	('GI carcinomas', 'Phenotype', 'HP:0002672', (55, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
66971	33139244	An important caveat is that tumors with high TMB and/or MSI-H are more likely to harbor DDR mutations which suggest the potential for confounding.	('DDR', 'Gene', (88, 91))	('MSI', 'Gene', (56, 59))	('tumors', 'Disease', (28, 34))	('MSI', 'Gene', '5928', (56, 59))	('harbor', 'Reg', (81, 87))	('TMB', 'Chemical', '-', (45, 48))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
66978	33139244	Other strategies include screening for actionable mutations or biomarkers, refining immunotherapy response prediction (such as negative predictors of response and variants predisposing to toxic effects), align panel-based TMB values to a WES-based TMB reference to ensure consistency across assays, standardize bioinformatic algorithms used for mutation calling and filtering, use variant allele frequency (VAF) as proxy for clonality to further refine TMB quantification and allow calibration of results from different studies.	('TMB', 'Chemical', '-', (222, 225))	('mutations', 'Var', (50, 59))	('TMB', 'Chemical', '-', (453, 456))	('TMB', 'Chemical', '-', (248, 251))	('variants', 'Var', (163, 171))
66982	33139244	Data in CRC and melanoma suggest that frameshift indels generate a higher number of immunogenic neoantigens than do non-synonymous single-nucleotide variant (SNV) mutations which awaits confirmation.	('frameshift indels', 'Var', (38, 55))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('immunogenic neoantigens', 'MPA', (84, 107))	('melanoma', 'Disease', (16, 24))
66983	33139244	Furthermore, the proportion of indels in conjunction with TMB values can identify different tumor types and genetic subgroups, including MSI-H cases (Table 3).	('TMB', 'Chemical', '-', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('MSI', 'Gene', (137, 140))	('MSI', 'Gene', '5928', (137, 140))	('tumor', 'Disease', (92, 97))	('indels', 'Var', (31, 37))
66988	33139244	Furthermore, high TMB in MSI-H tumors can be identified and was associated with increased and durable responses to ICIs, suggesting that stratification of MSI-H tumor using TMB may distinguish responders vs nonresponders to ICIs.	('MSI-H tumor', 'Disease', (155, 166))	('TMB', 'MPA', (18, 21))	('MSI-H tumor', 'Disease', 'MESH:D009369', (25, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('MSI-H tumor', 'Disease', 'MESH:D009369', (155, 166))	('MSI-H tumors', 'Disease', (25, 37))	('high', 'Var', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('TMB', 'Chemical', '-', (18, 21))	('TMB', 'Chemical', '-', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('MSI-H tumors', 'Disease', 'MESH:D009369', (25, 37))
66997	33139244	The number of mutations detected in cfDNA was positively correlated with ICIs efficacy and OS across various cancer types (n=69).	('correlated', 'Reg', (57, 67))	('ICIs efficacy', 'Disease', (73, 86))	('cfDNA', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (14, 23))	('OS across various cancer', 'Disease', 'MESH:C567932', (91, 115))	('OS across various cancer', 'Disease', (91, 115))
67017	30463956	Additionally, we defined germline variants associated with the abundance of immune cells that infiltrated the tumor.	('variants', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('associated', 'Reg', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
67022	30463956	Herein, we systematically determined the association of common germline genetic variants with gene expression and immune cell infiltration of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('gene expression', 'biological_process', 'GO:0010467', ('94', '109'))	('association', 'Interaction', (41, 52))	('tumor', 'Disease', (146, 151))	('variants', 'Var', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
67028	30463956	To thrive, tumor cells acquire characteristics of sustained proliferation, genome instability, and mutation.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('genome instability', 'CPA', (75, 93))	('mutation', 'Var', (99, 107))	('sustained proliferation', 'CPA', (50, 73))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
67036	30463956	To formally test whether similar underlying genetic variants are determinants of gene expression in cancer, we applied a similar approach, establishing the set of common hereditable factors that are associated with cancer-immune phenotypes.	('associated', 'Reg', (199, 209))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('variants', 'Var', (52, 60))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('gene expression', 'biological_process', 'GO:0010467', ('81', '96'))
67055	30463956	Interestingly, several cancer types, including THCA, prostate adenocarcinoma (PRAD), brain lower grade glioma, and acute myeloid leukemia, had a higher number of eGenes than other cancer types when sample size differences were adjusted (SI Appendix, Fig.	('THCA', 'Phenotype', 'HP:0002890', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('SI Appendix', 'Disease', 'MESH:D001063', (237, 248))	('glioma', 'Disease', (103, 109))	('cancer', 'Disease', (180, 186))	('acute myeloid leukemia', 'Disease', (115, 137))	('SI Appendix', 'Disease', (237, 248))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('cancer', 'Disease', (23, 29))	('prostate adenocarcinoma', 'Disease', (53, 76))	('eGenes', 'Var', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('leukemia', 'Phenotype', 'HP:0001909', (129, 137))	('THCA', 'Disease', (47, 51))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (115, 137))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (53, 76))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (115, 137))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (121, 137))
67070	30463956	We asked if copy number alteration, a common anomaly in cancer, could be one of the unexplained confounding factors.	('anomaly', 'Disease', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('copy number alteration', 'Var', (12, 34))	('anomaly', 'Disease', 'MESH:D000014', (45, 52))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
67071	30463956	Indeed, we found in many cancer types that select PEER factors correlated with copy number (SI Appendix, Fig.	('correlated', 'Reg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('SI Appendix', 'Disease', 'MESH:D001063', (92, 103))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('copy number', 'Var', (79, 90))	('SI Appendix', 'Disease', (92, 103))
67076	30463956	The impact of copy number on SETD4 expression is illustrated by the boxplot showing a positive correlation between SETD4 copy number and SETD4 mRNA expression levels (Fig.	('SETD4', 'Gene', '54093', (115, 120))	('SETD4', 'Gene', (115, 120))	('SETD4', 'Gene', '54093', (29, 34))	('SETD4', 'Gene', (29, 34))	('mRNA expression levels', 'MPA', (143, 165))	('copy number', 'Var', (121, 132))	('SETD4', 'Gene', '54093', (137, 142))	('SETD4', 'Gene', (137, 142))
67085	30463956	We focused on eQTL-eGene pairs for which associated genetic variants most strongly contribute to heterogeneity in tumor gene expression.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('heterogeneity', 'MPA', (97, 110))	('variants', 'Var', (60, 68))	('gene expression', 'biological_process', 'GO:0010467', ('120', '135'))	('contribute', 'Reg', (83, 93))
67089	30463956	For the top eQTL, rs2927608, the effect sizes (beta) on ERAP2 gene expression ranged from 1.02 in lung squamous cell carcinoma (LUSC) to 0.98 in skin cutaneous melanoma (SKCM) (Fig.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (98, 126))	('gene expression', 'biological_process', 'GO:0010467', ('62', '77'))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('lung squamous cell carcinoma', 'Disease', (98, 126))	('rs2927608', 'Mutation', 'rs2927608', (18, 27))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (145, 168))	('ERAP2', 'Gene', (56, 61))	('skin cutaneous melanoma', 'Disease', (145, 168))	('rs2927608', 'Var', (18, 27))	('ERAP2', 'Gene', '64167', (56, 61))	('expression', 'MPA', (67, 77))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))
67090	30463956	For example, in BLCA, the genotype of rs2927608 was associated with expression levels of ERAP2 (beta = 1.19, P = 6.69 x 10-36) (Fig.	('rs2927608', 'Mutation', 'rs2927608', (38, 47))	('ERAP2', 'Gene', (89, 94))	('ERAP2', 'Gene', '64167', (89, 94))	('rs2927608', 'Var', (38, 47))	('expression levels', 'MPA', (68, 85))
67092	30463956	Interestingly, the haplotype associated with low ERAP2 expression, tagged by the rs2927608-G allele, contains an SNP that has been previously reported to alter a splice donor site, and thus to result in intronic read-through and the introduction of a stop codon, which, in turn, leads to nonsense-mediated decay (NMD) of the ERAP2 mRNA (haplotype B in SI Appendix, Fig.	('SI Appendix', 'Disease', 'MESH:D001063', (352, 363))	('leads to', 'Reg', (279, 287))	('alter', 'Reg', (154, 159))	('intronic read-through', 'MPA', (203, 224))	('SI Appendix', 'Disease', (352, 363))	('rs2927608-G', 'Var', (81, 92))	('SNP', 'Var', (113, 116))	('rs2927608', 'Mutation', 'rs2927608', (81, 90))	('donor', 'Species', '9606', (169, 174))	('ERAP2', 'Gene', (49, 54))	('ERAP2', 'Gene', (325, 330))	('nonsense-mediated decay', 'MPA', (288, 311))	('result in', 'Reg', (193, 202))	('expression', 'MPA', (55, 65))	('low', 'NegReg', (45, 48))	('ERAP2', 'Gene', '64167', (49, 54))	('stop', 'MPA', (251, 255))	('mRNA', 'MPA', (331, 335))	('ERAP2', 'Gene', '64167', (325, 330))	('splice donor site', 'MPA', (162, 179))
67094	30463956	The most significant eQTL for ICOSLG, rs7278940, mapped to a haplotype with a known GWAS hit for celiac disease.	('rs7278940', 'Mutation', 'rs7278940', (38, 47))	('celiac disease', 'Phenotype', 'HP:0002608', (97, 111))	('ICOSLG', 'Disease', (30, 36))	('rs7278940', 'Var', (38, 47))	('celiac disease', 'Disease', (97, 111))
67095	30463956	The rs7278940 eQTL showed an effect size on ICOSLG gene expression that ranged from 0.85 in stomach adenocarcinoma (STAD) to 1.2 in LUSC (SI Appendix, Fig.	('SI Appendix', 'Disease', 'MESH:D001063', (138, 149))	('ICOSLG gene', 'Gene', (44, 55))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (92, 114))	('gene expression', 'biological_process', 'GO:0010467', ('51', '66'))	('SI Appendix', 'Disease', (138, 149))	('stomach adenocarcinoma', 'Disease', (92, 114))	('rs7278940', 'Var', (4, 13))	('expression', 'MPA', (56, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('rs7278940', 'Mutation', 'rs7278940', (4, 13))
67102	30463956	Additionally, activating ICOS has been shown to enhance tumor immunity in mice, and agonist antibodies are being developed for cancer immunotherapy in humans.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('activating', 'Var', (14, 24))	('ICOS', 'Protein', (25, 29))	('enhance', 'PosReg', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('mice', 'Species', '10090', (74, 78))	('humans', 'Species', '9606', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
67107	30463956	Consistent with mouse studies, patients with low ERAP2 expression had better overall survival relative to those with higher ERAP2 expression (P = 0.03) (Fig.	('ERAP2', 'Gene', '64167', (124, 129))	('ERAP2', 'Gene', (49, 54))	('better', 'PosReg', (70, 76))	('overall survival', 'MPA', (77, 93))	('ERAP2', 'Gene', (124, 129))	('ERAP2', 'Gene', '64167', (49, 54))	('patients', 'Species', '9606', (31, 39))	('mouse', 'Species', '10090', (16, 21))	('low', 'Var', (45, 48))
67112	30463956	These data suggest that ERAP2 is an independent prognostic predictor of survival in patients with luminal subtype bladder cancer receiving anti-PD-L1 therapy, and, in fact, low ERAP2 expression can be used along with the IFN-gamma response to establish a further improved prognostic biomarker signature.	('low', 'Var', (173, 176))	('ERAP2', 'Gene', '64167', (177, 182))	('patients', 'Species', '9606', (84, 92))	('ERAP2', 'Gene', (24, 29))	('luminal subtype bladder cancer', 'Disease', (98, 128))	('IFN-gamma', 'Gene', (221, 230))	('IFN-gamma', 'Gene', '3458', (221, 230))	('ERAP2', 'Gene', '64167', (24, 29))	('luminal subtype bladder cancer', 'Disease', 'MESH:D001749', (98, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('bladder cancer', 'Phenotype', 'HP:0009725', (114, 128))	('ERAP2', 'Gene', (177, 182))
67130	30463956	For example, the gsQTL rs35051459 was associated with the NKT cell gene signature in HNSC (beta = 0.44, P = 1.79 x 10-10) (Fig.	('gsQTL', 'Gene', (17, 22))	('associated', 'Reg', (38, 48))	('NKT cell gene signature', 'Gene', (58, 81))	('rs35051459', 'Var', (23, 33))	('rs35051459', 'Mutation', 'rs35051459', (23, 33))	('HNSC', 'Disease', (85, 89))
67133	30463956	Interestingly, expression of SEMA4D has been shown to influence the infiltration and distribution of leukocytes in the tumor microenvironment, and the inhibition of SEMA4D promoted immune infiltration into the tumor.	('SEMA4D', 'Gene', '10507', (165, 171))	('tumor', 'Disease', (119, 124))	('expression', 'Var', (15, 25))	('SEMA4D', 'Gene', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('infiltration', 'MPA', (68, 80))	('SEMA4D', 'Gene', '10507', (29, 35))	('tumor', 'Disease', (210, 215))	('SEMA4D', 'Gene', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('promoted', 'PosReg', (172, 180))	('inhibition', 'Var', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('distribution', 'MPA', (85, 97))	('influence', 'Reg', (54, 63))
67134	30463956	In agreement, the rs35051459 genotype associated with lower SEMA4D expression was associated with a higher NKT cell gene signature (Fig.	('SEMA4D', 'Gene', (60, 66))	('rs35051459', 'Mutation', 'rs35051459', (18, 28))	('rs35051459', 'Var', (18, 28))	('higher', 'PosReg', (100, 106))	('expression', 'MPA', (67, 77))	('NKT', 'MPA', (107, 110))	('SEMA4D', 'Gene', '10507', (60, 66))	('lower', 'NegReg', (54, 59))
67135	30463956	As a second example in STAD, the association between the gsQTL rs9308067 and the monocyte gene signature (beta = -0.95, P = 6.25 x 10-9) was partially mediated through the MARCH1 gene (Fig.	('MARCH1', 'Gene', (172, 178))	('MARCH1', 'Gene', '55016', (172, 178))	('rs9308067', 'Mutation', 'rs9308067', (63, 72))	('rs9308067', 'Var', (63, 72))	('gsQTL', 'Gene', (57, 62))	('monocyte gene signature', 'MPA', (81, 104))	('association', 'Interaction', (33, 44))
67137	30463956	For example, the gsQTL rs12063638 was associated with the cDC gene signature in STAD (beta = 0.44, P = 1.79 x 10-10) (Dataset S1).	('gsQTL', 'Gene', (17, 22))	('associated', 'Reg', (38, 48))	('rs12063638', 'Var', (23, 33))	('rs12063638', 'Mutation', 'rs12063638', (23, 33))	('STAD', 'Disease', (80, 84))	('cDC gene signature', 'Gene', (58, 76))
67138	30463956	Although rs12063638 has not been shown to be an eQTL, it is located downstream of the gene that encodes for glycoprotein podoplanin (PDPN) (Fig.	('rs12063638', 'Var', (9, 19))	('rs12063638', 'Mutation', 'rs12063638', (9, 19))	('podoplanin', 'Gene', '10630', (121, 131))	('podoplanin', 'Gene', (121, 131))	('PDPN', 'Gene', '10630', (133, 137))	('PDPN', 'Gene', (133, 137))
67139	30463956	We also highlight the gsQTL rs73016119, which was associated with the plasma cell gene signature in PAAD (beta = 1.39, P = 3.39 x 10-9).	('associated', 'Reg', (50, 60))	('PAAD', 'Phenotype', 'HP:0006725', (100, 104))	('rs73016119', 'Var', (28, 38))	('rs73016119', 'Mutation', 'rs73016119', (28, 38))
67140	30463956	Notably, rs73016119 is in LD with rs561722 (R2 = 0.74), which has been shown through GWASs to be associated with ulcerative colitis (Fig.	('rs73016119', 'Mutation', 'rs73016119', (9, 19))	('ulcerative colitis', 'Disease', (113, 131))	('rs561722', 'Var', (34, 42))	('rs561722', 'Mutation', 'rs561722', (34, 42))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (113, 131))	('colitis', 'Phenotype', 'HP:0002583', (124, 131))	('associated', 'Reg', (97, 107))	('rs73016119', 'Var', (9, 19))	('ulcerative colitis', 'Disease', 'MESH:D003093', (113, 131))
67142	30463956	Together, the presence of gsQTLs for immune gene signatures suggests that germline genetic variants may influence the abundance, infiltration, and composition of immune cells in tumors.	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('composition', 'CPA', (147, 158))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('infiltration', 'CPA', (129, 141))	('abundance', 'MPA', (118, 127))	('variants', 'Var', (91, 99))	('influence', 'Reg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
67147	30463956	This allowed us to assign with confidence the impact of germline variants on the heterogeneous genes in patient tumors.	('germline variants', 'Var', (56, 73))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patient', 'Species', '9606', (104, 111))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('heterogeneous genes', 'MPA', (81, 100))
67154	30463956	As discussed, haplotype B is known to generate an RNA transcript that is susceptible to NMD, providing a likely explanation for the low level of ERAP2 expression that is associated with the rs2927608-G allele.	('rs2927608-G', 'Var', (190, 201))	('expression', 'MPA', (151, 161))	('rs2927608', 'Mutation', 'rs2927608', (190, 199))	('ERAP2', 'Gene', (145, 150))	('RNA', 'cellular_component', 'GO:0005562', ('50', '53'))	('ERAP2', 'Gene', '64167', (145, 150))
67155	30463956	The other major ERAP2 haplotype, tagged by the rs2927608-A allele, contains multiple risk alleles for autoimmune and inflammatory diseases, as identified in prior GWASs (SI Appendix, Fig.	('ERAP2', 'Gene', '64167', (16, 21))	('SI Appendix', 'Disease', 'MESH:D001063', (170, 181))	('SI Appendix', 'Disease', (170, 181))	('rs2927608', 'Mutation', 'rs2927608', (47, 56))	('rs2927608-A', 'Var', (47, 58))	('ERAP2', 'Gene', (16, 21))
67160	30463956	While seemingly paradoxical, ERAAP deficiency does not necessarily reduce the number of epitopes presented; instead, it alters the peptide repertoire, which may confer enhanced T cell responses in some individuals or mouse models.	('mouse', 'Species', '10090', (217, 222))	('alters', 'Reg', (120, 126))	('peptide repertoire', 'MPA', (131, 149))	('ERAAP', 'Gene', (29, 34))	('enhanced', 'PosReg', (168, 176))	('deficiency', 'Var', (35, 45))	('T cell responses', 'CPA', (177, 193))
67165	30463956	Further studies will be necessary to evaluate whether the prognostic effect of low ERAP2 expression can be generalized to other cancer types or other clinical trial datasets.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('expression', 'MPA', (89, 99))	('ERAP2', 'Gene', (83, 88))	('ERAP2', 'Gene', '64167', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('low', 'Var', (79, 82))	('cancer', 'Disease', (128, 134))
67167	30463956	Studies of autoimmune diseases, including ankylosing spondylitis and birdshot chorioretinitis, have already demonstrated strong interactions between ERAP2 polymorphisms and HLA haplotypes.	('chorioretinitis', 'Disease', (78, 93))	('autoimmune diseases', 'Disease', 'MESH:D001327', (11, 30))	('chorioretinitis', 'Disease', 'MESH:C566236', (78, 93))	('autoimmune diseases', 'Disease', (11, 30))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (11, 30))	('ankylosing spondylitis', 'Disease', 'MESH:D013167', (42, 64))	('interactions', 'Interaction', (128, 140))	('chorioretinitis', 'Phenotype', 'HP:0012424', (78, 93))	('ERAP2', 'Gene', (149, 154))	('ERAP2', 'Gene', '64167', (149, 154))	('polymorphisms', 'Var', (155, 168))	('ankylosing spondylitis', 'Disease', (42, 64))
67168	30463956	While we did not observe stratification in our sample of patients with bladder cancer receiving anti-PD-L1, the strong underlying role for germline genetics may be an important consideration for active clinical development programs that are attempting to extend preclinical observations from mice.	('anti-PD-L1', 'Var', (96, 106))	('bladder cancer', 'Disease', 'MESH:D001749', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (57, 65))	('bladder cancer', 'Disease', (71, 85))	('mice', 'Species', '10090', (292, 296))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))
67255	28095848	reported that the 5-year OS and CSS rates were lower in the LNU group than in the ONU group in patients with locally advanced UTUC.	('lower', 'NegReg', (47, 52))	('OS', 'Chemical', '-', (25, 27))	('patients', 'Species', '9606', (95, 103))	('CSS', 'Chemical', '-', (32, 35))	('LNU', 'Var', (60, 63))	('LNU', 'Chemical', '-', (60, 63))	('ONU', 'Chemical', '-', (82, 85))
67256	28095848	Furthermore, on multivariable analysis, LNU was found to be an independent predictor of poorer OS and CSS than ONU.	('CSS', 'CPA', (102, 105))	('ONU', 'Chemical', '-', (111, 114))	('LNU', 'Var', (40, 43))	('poorer OS', 'CPA', (88, 97))	('LNU', 'Chemical', '-', (40, 43))	('OS', 'Chemical', '-', (95, 97))	('CSS', 'Chemical', '-', (102, 105))
67300	26008846	Urobasal A (UroA) tumors show papillary growth, good prognosis and frequent mutation and expression of FGFR3.	('FGFR', 'molecular_function', 'GO:0005007', ('103', '107'))	('expression', 'MPA', (89, 99))	('FGFR3', 'Gene', '2261', (103, 108))	('papillary growth', 'Phenotype', 'HP:0007482', (30, 46))	('UroA', 'Chemical', '-', (12, 16))	('FGFR3', 'Gene', (103, 108))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('mutation', 'Var', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
67302	26008846	Genomically Unstable (GU) tumors are undifferentiated, highly proliferative and characterized by frequent E2F3/SOX4 amplifications, RB1 deletions, TP53 mutations and ERBB2 expression.	('SOX4', 'Gene', (111, 115))	('TP53', 'Gene', (147, 151))	('mutations', 'Var', (152, 161))	('SOX4', 'Gene', '6659', (111, 115))	('deletions', 'Var', (136, 145))	('RB1', 'Gene', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('ERBB2', 'Gene', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('ERBB2', 'Gene', '2064', (166, 171))	('E2F3', 'Gene', '1871', (106, 110))	('TP53', 'Gene', '7157', (147, 151))	('RB1', 'Gene', '5925', (132, 135))	('E2F3', 'Gene', (106, 110))	('tumors', 'Disease', (26, 32))	('Genomically Unstable', 'Disease', (0, 20))
67304	26008846	We identify loss of PPARG and ADIRF, a novel regulator of fatty acid metabolism, as well as upregulation of STAT3 expression, as putative mediators of the SCCL phenotype.	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('58', '79'))	('STAT3 expression', 'MPA', (108, 124))	('ADIRF', 'Gene', '10974', (30, 35))	('upregulation', 'PosReg', (92, 104))	('loss', 'Var', (12, 16))	('PPARG', 'Gene', (20, 25))	('ADIRF', 'Gene', (30, 35))	('fatty acid', 'Chemical', 'MESH:D005227', (58, 68))
67322	26008846	PPARG and RXRA cooperate as heterodimers and induce differentiation though the transcription factors ELF3, FOXA1 and members of the GATA transcription factor family (Additional file 2: Figure S1).	('transcription', 'biological_process', 'GO:0006351', ('79', '92'))	('GATA', 'Gene', '55278', (132, 136))	('ELF3', 'Gene', (101, 105))	('ELF3', 'Gene', '1999', (101, 105))	('induce', 'PosReg', (45, 51))	('FOXA1', 'Gene', (107, 112))	('differentiation', 'CPA', (52, 67))	('transcription', 'biological_process', 'GO:0006351', ('137', '150'))	('PPARG', 'Var', (0, 5))	('transcription factor', 'molecular_function', 'GO:0000981', ('137', '157'))	('GATA', 'Gene', (132, 136))
67389	26008846	Methylation of TBX2 and TBX3 has been found to be associated with urothelial tumor progression, however their full role in urothelial carcinoma is not yet clear.	('urothelial tumor', 'Disease', 'MESH:D001749', (66, 82))	('Methylation', 'Var', (0, 11))	('TBX3', 'Gene', '6926', (24, 28))	('urothelial carcinoma', 'Disease', (123, 143))	('TBX2', 'Gene', '6909', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TBX3', 'Gene', (24, 28))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('urothelial tumor', 'Disease', (66, 82))	('TBX2', 'Gene', (15, 19))	('associated', 'Reg', (50, 60))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (123, 143))
67489	25015855	In contrast, there was no significant difference in GR expression between pN0 tumors and those with lymph node involvement.	('GR', 'Gene', '2908', (52, 54))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('men', 'Species', '9606', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('pN0', 'Var', (74, 77))
67503	25015855	In the NMI subgroup, low GR (0/1+) was found to correlate with tumor recurrence (hazard ratio [HR] = 0.444; 95% confidence interval [CI] = 0.210-0.939; P = .034), but not with tumor progression (HR = 0.704; 95% CI = 0.184-2.703; P = .610).	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('GR', 'Gene', '2908', (25, 27))	('tumor', 'Disease', (176, 181))	('low', 'Var', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
67525	25015855	Accordingly, low-dose GC treatment that does not induce immunosuppression has the potential to be a chemopreventive and therapeutic approach in patients with bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (158, 172))	('patients', 'Species', '9606', (144, 152))	('bladder cancer', 'Disease', 'MESH:D001749', (158, 172))	('bladder cancer', 'Disease', (158, 172))	('men', 'Species', '9606', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('low-dose', 'Var', (13, 21))
67554	19096525	Overall, patients undergoing parenchymal-sparing surgery had a lower actuarial 5-year disease-free survival rate than those treated with initial aggressive surgical resection (23% versus 45%, P < .0009).	('patients', 'Species', '9606', (9, 17))	('parenchymal-sparing surgery', 'Var', (29, 56))	('lower', 'NegReg', (63, 68))	('disease-free survival', 'CPA', (86, 107))
67596	19096525	Metastatic disease developed in 3 out of 15 hand-assisted cases and in 2 patients of the standard group.	('Metastatic disease', 'Disease', 'MESH:C538445', (0, 18))	('patients', 'Species', '9606', (73, 81))	('Metastatic disease', 'Disease', (0, 18))	('hand-assisted', 'Var', (44, 57))
67683	19096525	Lymph node dissection was associated with an increased cancer-specific survival in patients with no evidence of lymph-vascular invasion.	('increased', 'PosReg', (45, 54))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('patients', 'Species', '9606', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Lymph node dissection', 'Var', (0, 21))	('cancer', 'Disease', (55, 61))
67711	19096525	Fifteen patients with papillary disease of the urinary tract in 16 renal units were treated (TaG1 in 2, TaG2 in 6, TaG3 in 2, T1G3 in 2, and Tx in 4).	('TaG1', 'Gene', '6900', (93, 97))	('patients', 'Species', '9606', (8, 16))	('papillary disease', 'Phenotype', 'HP:0007482', (22, 39))	('T1G3', 'Var', (126, 130))	('TaG2', 'Var', (104, 108))	('TaG1', 'Gene', (93, 97))	('TaG3', 'Var', (115, 119))	('papillary disease', 'Disease', 'MESH:D002291', (22, 39))	('papillary disease', 'Disease', (22, 39))
67784	33397425	For instance, circ_Foxo3 was found to block cell cycle progression by binding to the cell cycle proteins cyclin-dependent kinase 2 (CDK2) and cyclin-dependent kinase inhibitor 1 (p21).	('block', 'NegReg', (38, 43))	('binding', 'molecular_function', 'GO:0005488', ('70', '77'))	('cyclin', 'molecular_function', 'GO:0016538', ('105', '111'))	('cyclin-dependent kinase inhibitor 1', 'Gene', '1026', (142, 177))	('p21', 'Gene', '1026', (179, 182))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('142', '175'))	('cell cycle', 'biological_process', 'GO:0007049', ('85', '95'))	('CDK', 'molecular_function', 'GO:0004693', ('132', '135'))	('cyclin-dependent kinase 2', 'Gene', '1017', (105, 130))	('cell cycle progression', 'CPA', (44, 66))	('cell cycle', 'biological_process', 'GO:0007049', ('44', '54'))	('cyclin-dependent kinase 2', 'Gene', (105, 130))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('159', '175'))	('cyclin-dependent kinase inhibitor 1', 'Gene', (142, 177))	('circ_Foxo3', 'Var', (14, 24))	('CDK2', 'Gene', '1017', (132, 136))	('p21', 'Gene', (179, 182))	('binding', 'Interaction', (70, 77))	('CDK2', 'Gene', (132, 136))
67790	33397425	In addition, circFXBW7 can be translated into a novel 21-kDa protein to suppress the tumorigenesis of glioma.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('suppress', 'NegReg', (72, 80))	('circFXBW7', 'Var', (13, 22))	('tumorigenesis', 'CPA', (85, 98))	('glioma', 'Disease', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
67806	33397425	also suggested that circ_0058063 facilitates BCa cell proliferation and invasion via the circ_0058063/miR-486-3p/FOXP4 axis.	('FOXP4', 'Gene', (113, 118))	('BCa cell proliferation', 'CPA', (45, 67))	('miR', 'Gene', '220972', (102, 105))	('circ_0058063', 'Var', (20, 32))	('miR', 'Gene', (102, 105))	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('FOXP4', 'Gene', '116113', (113, 118))	('invasion', 'CPA', (72, 80))	('facilitates', 'PosReg', (33, 44))	('BCa', 'Phenotype', 'HP:0009725', (45, 48))
67807	33397425	Circ_0071662 has been identified to suppress BCa cell proliferation and invasion by upregulating the tumour suppressor genes HPGD and NF2.	('BCa cell proliferation', 'CPA', (45, 67))	('tumour', 'Disease', (101, 107))	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('suppress', 'NegReg', (36, 44))	('HPGD', 'Gene', (125, 129))	('NF2', 'Gene', '4771', (134, 137))	('HPGD', 'Gene', '3248', (125, 129))	('Circ_0071662', 'Var', (0, 12))	('upregulating', 'PosReg', (84, 96))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('invasion', 'CPA', (72, 80))	('NF2', 'Gene', (134, 137))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('BCa', 'Phenotype', 'HP:0009725', (45, 48))
67809	33397425	proposed that circ_PDSS1 may promote proliferation, invasion and migration by inhibiting the tumour suppressor miR-16.	('promote', 'PosReg', (29, 36))	('migration', 'CPA', (65, 74))	('tumour', 'Disease', (93, 99))	('circ_PDSS1', 'Var', (14, 24))	('inhibiting', 'NegReg', (78, 88))	('miR-16', 'Gene', (111, 117))	('miR-16', 'Gene', '51573', (111, 117))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('proliferation', 'CPA', (37, 50))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('invasion', 'CPA', (52, 60))
67818	33397425	Additionally, dysregulation of cell cycle regulators contributes to limitless tumour cell growth and proliferation.	('cell cycle', 'biological_process', 'GO:0007049', ('31', '41'))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('dysregulation', 'Var', (14, 27))	('tumour', 'Disease', (78, 84))	('cell growth', 'biological_process', 'GO:0016049', ('85', '96'))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
67822	33397425	As reported by Zheng et al., circ_NR3C1 can induce G0/G1 arrest by suppressing cyclin D1 expression and subsequently inhibits cell cycle progression in BCa.	('cyclin D1', 'Gene', (79, 88))	('cyclin', 'molecular_function', 'GO:0016538', ('79', '85'))	('circ_NR3C1', 'Var', (29, 39))	('expression', 'MPA', (89, 99))	('inhibits', 'NegReg', (117, 125))	('BCa', 'CPA', (152, 155))	('arrest', 'Disease', 'MESH:D006323', (57, 63))	('BCa', 'Phenotype', 'HP:0009725', (152, 155))	('arrest', 'Disease', (57, 63))	('cell cycle progression', 'CPA', (126, 148))	('cyclin D1', 'Gene', '595', (79, 88))	('suppressing', 'NegReg', (67, 78))	('cell cycle', 'biological_process', 'GO:0007049', ('126', '136'))
67828	33397425	also discovered that circ_0058063 enhances BCa cell proliferation and migration abilities via the circ_0058063/miR-145-5p/CDK6 pathway in BCa.	('miR-145', 'Gene', (111, 118))	('circ_0058063', 'Var', (21, 33))	('miR-145', 'Gene', '406937', (111, 118))	('BCa', 'Phenotype', 'HP:0009725', (138, 141))	('CDK6', 'Gene', (122, 126))	('CDK6', 'Gene', '1021', (122, 126))	('enhances', 'PosReg', (34, 42))	('BCa cell proliferation', 'CPA', (43, 65))	('BCa', 'Phenotype', 'HP:0009725', (43, 46))	('CDK', 'molecular_function', 'GO:0004693', ('122', '125'))	('cell proliferation', 'biological_process', 'GO:0008283', ('47', '65'))	('migration abilities', 'CPA', (70, 89))
67835	33397425	Proapoptotic effects of circ_Foxo3 have also been observed in breast carcinoma biopsies and in cancer cell lines.	('breast carcinoma', 'Phenotype', 'HP:0003002', (62, 78))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('circ_Foxo3', 'Var', (24, 34))	('breast carcinoma', 'Disease', (62, 78))	('Proapoptotic effects', 'MPA', (0, 20))	('breast carcinoma', 'Disease', 'MESH:D001943', (62, 78))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
67836	33397425	found by KEGG analysis that hsa_circ_0018069 may mediate the Foxo signalling pathway to exert anticancer effects (Fig.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('mediate', 'Reg', (49, 56))	('signalling pathway', 'biological_process', 'GO:0007165', ('66', '84'))	('cancer', 'Disease', (98, 104))	('Foxo signalling pathway', 'Pathway', (61, 84))	('hsa_circ_0018069', 'Var', (28, 44))
67839	33397425	According to Li et al., circ_BCRC4 enhances apoptosis through miR-101/EZH2 signalling.	('circ_BCRC4', 'Var', (24, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('signalling', 'biological_process', 'GO:0023052', ('75', '85'))	('apoptosis', 'CPA', (44, 53))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('EZH2', 'Gene', '2146', (70, 74))	('EZH2', 'Gene', (70, 74))	('enhances', 'PosReg', (35, 43))
67842	33397425	reported that circ_0001361, which is derived from two exons of the FNDC3B gene, increases MMP9 expression to promote BCa cell invasion and metastasis.	('BCa cell invasion', 'CPA', (117, 134))	('BCa', 'Phenotype', 'HP:0009725', (117, 120))	('promote', 'PosReg', (109, 116))	('MMP9', 'Gene', (90, 94))	('MMP9', 'molecular_function', 'GO:0004229', ('90', '94'))	('metastasis', 'CPA', (139, 149))	('MMP9', 'Gene', '4318', (90, 94))	('increases', 'PosReg', (80, 89))	('FNDC3B', 'Gene', '64778', (67, 73))	('FNDC3B', 'Gene', (67, 73))	('circ_0001361', 'Var', (14, 26))	('expression', 'MPA', (95, 105))
67845	33397425	indicated that circ_5912 suppresses the invasion and migration of BCa cells via the TGF-beta2-induced EMT signalling pathway.	('EMT', 'biological_process', 'GO:0001837', ('102', '105'))	('circ_5912', 'Var', (15, 24))	('BCa', 'Phenotype', 'HP:0009725', (66, 69))	('TGF-beta2', 'Gene', '7042', (84, 93))	('TGF-beta2', 'Gene', (84, 93))	('circ_5912', 'Chemical', '-', (15, 24))	('signalling pathway', 'biological_process', 'GO:0007165', ('106', '124'))	('suppresses', 'NegReg', (25, 35))
67846	33397425	further revealed that circ_FUT8 suppresses the invasion and migration of BCa cells by regulating Slug and EMT.	('BCa', 'Phenotype', 'HP:0009725', (73, 76))	('suppresses', 'NegReg', (32, 42))	('EMT', 'biological_process', 'GO:0001837', ('106', '109'))	('circ_FUT8', 'Var', (22, 31))	('Slug', 'Gene', '6591', (97, 101))	('regulating', 'Reg', (86, 96))	('Slug', 'Gene', (97, 101))
67850	33397425	illustrated that circ_0058063 promotes BCa cell proliferation and invasion by upregulating FOXP4 expression.	('circ_0058063', 'Var', (17, 29))	('promotes', 'PosReg', (30, 38))	('cell proliferation', 'biological_process', 'GO:0008283', ('43', '61'))	('FOXP4', 'Gene', '116113', (91, 96))	('BCa cell proliferation', 'CPA', (39, 61))	('BCa', 'Phenotype', 'HP:0009725', (39, 42))	('invasion', 'CPA', (66, 74))	('FOXP4', 'Gene', (91, 96))	('expression', 'MPA', (97, 107))	('upregulating', 'PosReg', (78, 90))
67856	33397425	Circ_103809 has been identified to be highly expressed in bladder CSCs and to promote the self-renewal, migration and invasion of BCa by sponging miR-511.	('miR-511', 'Gene', '574445', (146, 153))	('bladder CSCs', 'Disease', (58, 70))	('promote', 'PosReg', (78, 85))	('migration', 'CPA', (104, 113))	('bladder CSCs', 'Disease', 'MESH:D001745', (58, 70))	('miR-511', 'Gene', (146, 153))	('Circ_103809', 'Var', (0, 11))	('self-renewal', 'CPA', (90, 102))	('invasion', 'CPA', (118, 126))	('BCa', 'Phenotype', 'HP:0009725', (130, 133))
67860	33397425	proposed that circ_DOCK1 increases the proliferation and migration potential of BCa cells via the circDOCK1/hsa-miR-132-3p/Sox5 signalling pathway.	('Sox5', 'Gene', '6660', (123, 127))	('migration potential', 'CPA', (57, 76))	('Sox5', 'Gene', (123, 127))	('hsa-miR-132-3p', 'Gene', '100302255', (108, 122))	('increases', 'PosReg', (25, 34))	('BCa', 'Phenotype', 'HP:0009725', (80, 83))	('proliferation', 'CPA', (39, 52))	('signalling pathway', 'biological_process', 'GO:0007165', ('128', '146'))	('circ_DOCK1', 'Var', (14, 24))	('hsa-miR-132-3p', 'Gene', (108, 122))
67864	33397425	illustrated that hsa_circ_0017247 enhances BCa cell metastasis by activating the Wnt/beta-catenin signalling pathway.	('beta-catenin', 'Gene', '1499', (85, 97))	('beta-catenin', 'Gene', (85, 97))	('activating', 'Reg', (66, 76))	('signalling pathway', 'biological_process', 'GO:0007165', ('98', '116'))	('enhances', 'PosReg', (34, 42))	('BCa', 'Phenotype', 'HP:0009725', (43, 46))	('hsa_circ_0017247', 'Var', (17, 33))	('BCa cell metastasis', 'CPA', (43, 62))
67867	33397425	According to Wu et al., circ_0023642 suppresses BCa cell invasion and metastasis by modulating the circ_0023642/miR-490-5p/EGFR signalling pathway.	('EGFR', 'Gene', (123, 127))	('suppresses', 'NegReg', (37, 47))	('BCa', 'Phenotype', 'HP:0009725', (48, 51))	('miR', 'Gene', '220972', (112, 115))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('miR', 'Gene', (112, 115))	('circ_0023642', 'Var', (24, 36))	('modulating', 'Reg', (84, 94))	('signalling pathway', 'biological_process', 'GO:0007165', ('128', '146'))	('EGFR', 'Gene', '1956', (123, 127))
67869	33397425	found that circ_MTO1 inhibits BCa cell EMT and metastasis by sponging miR-221.	('miR-221', 'Gene', (70, 77))	('inhibits', 'NegReg', (21, 29))	('circ_MTO1', 'Gene', (11, 20))	('EMT', 'biological_process', 'GO:0001837', ('39', '42'))	('miR-221', 'Gene', '407006', (70, 77))	('BCa', 'Phenotype', 'HP:0009725', (30, 33))	('sponging', 'Var', (61, 69))
67877	33397425	Circ_0001429 has been reported to induce angiogenesis to promote BCa cell growth and metastasis by increasing VEGFA expression.	('BCa', 'Phenotype', 'HP:0009725', (65, 68))	('expression', 'MPA', (116, 126))	('induce', 'PosReg', (34, 40))	('promote', 'PosReg', (57, 64))	('increasing', 'PosReg', (99, 109))	('Circ_0001429', 'Var', (0, 12))	('VEGFA', 'Gene', (110, 115))	('BCa cell growth', 'CPA', (65, 80))	('angiogenesis', 'CPA', (41, 53))	('angiogenesis', 'biological_process', 'GO:0001525', ('41', '53'))	('metastasis', 'CPA', (85, 95))	('VEGFA', 'Gene', '7422', (110, 115))	('cell growth', 'biological_process', 'GO:0016049', ('69', '80'))
67880	33397425	In addition, circ_403658, which is induced by HIF-1alpha, increases the expression of VEGFR and EGFR.	('circ_403658', 'Var', (13, 24))	('increases', 'PosReg', (58, 67))	('EGFR', 'Gene', '1956', (96, 100))	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', (96, 100))	('EGFR', 'Gene', (87, 91))	('VEGFR', 'Gene', '3791', (86, 91))	('HIF-1alpha', 'Gene', (46, 56))	('expression', 'MPA', (72, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('VEGFR', 'Gene', (86, 91))	('HIF-1alpha', 'Gene', '3091', (46, 56))
67918	33397425	In contrast, circ_0071662 is downregulated in BCa tissues and cell lines, and its expression levels are significantly associated with LNM and DM.	('LNM', 'Disease', (134, 137))	('BCa', 'Phenotype', 'HP:0009725', (46, 49))	('associated', 'Reg', (118, 128))	('DM', 'Disease', 'MESH:D009223', (142, 144))	('expression levels', 'MPA', (82, 99))	('downregulated', 'NegReg', (29, 42))	('circ_0071662', 'Var', (13, 25))
67920	33397425	According to Su and colleagues, circ_5912 is significantly downregulated in BCa tissues compared with normal control tissues, and its levels are correlated with BCa grade, stage, and metastasis.	('BCa', 'Disease', (161, 164))	('correlated', 'Reg', (145, 155))	('circ_5912', 'Var', (32, 41))	('metastasis', 'CPA', (183, 193))	('downregulated', 'NegReg', (59, 72))	('BCa', 'Phenotype', 'HP:0009725', (76, 79))	('BCa', 'Disease', (76, 79))	('circ_5912', 'Chemical', '-', (32, 41))	('levels', 'MPA', (134, 140))	('BCa', 'Phenotype', 'HP:0009725', (161, 164))
67924	33397425	Circ_FAM114A2 has been identified to be downregulated in both BUC tissue specimens and cell lines, and high circ_FAM114A2 expression levels are negatively associated with pathological TNM stage and grade.	('FAM114A2', 'Gene', (113, 121))	('FAM114A2', 'Gene', '10827', (5, 13))	('TNM', 'Gene', (184, 187))	('expression levels', 'MPA', (122, 139))	('downregulated', 'NegReg', (40, 53))	('FAM114A2', 'Gene', '10827', (113, 121))	('high', 'Var', (103, 107))	('TNM', 'Gene', '10178', (184, 187))	('FAM114A2', 'Gene', (5, 13))	('grade', 'CPA', (198, 203))	('negatively', 'NegReg', (144, 154))
67928	33397425	Circ_0023642 and circ_FNTA are estrogen receptor- and androgen receptor-mediated circRNAs, respectively.	('FNTA', 'Gene', (22, 26))	('FNTA', 'Gene', '2339', (22, 26))	('estrogen receptor', 'Gene', (31, 48))	('androgen receptor', 'Gene', (54, 71))	('Circ_0023642', 'Var', (0, 12))	('estrogen receptor', 'Gene', '2099', (31, 48))	('androgen receptor', 'Gene', '367', (54, 71))
67933	33397425	Kaplan-Meier survival analysis indicated that higher expression of circ_0137439, circ_CASC15, and circPRMT5 was associated with poorer DFS.	('circPRMT5', 'Gene', (98, 107))	('CASC15', 'Gene', '401237', (86, 92))	('higher', 'PosReg', (46, 52))	('poorer', 'NegReg', (128, 134))	('circ_0137439', 'Var', (67, 79))	('expression', 'MPA', (53, 63))	('CASC15', 'Gene', (86, 92))	('DFS', 'MPA', (135, 138))
67935	33397425	In addition, patients with high circ_CDYL and circ_HIPK3 expression were reported to have a reduced risk of progression.	('circ_HIPK3 expression', 'Var', (46, 67))	('patients', 'Species', '9606', (13, 21))	('CDYL', 'Gene', '9425', (37, 41))	('reduced', 'NegReg', (92, 99))	('CDYL', 'Gene', (37, 41))
67949	32978523	In addition, the siRNA knockdown of EGFR impaired SCaBER viability suggesting a putative "Achilles heel" of Sq-BLCA.	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('knockdown', 'Var', (23, 32))	('SCaBER viability', 'CPA', (50, 66))	('EGFR', 'Gene', '1956', (36, 40))	('impaired', 'NegReg', (41, 49))	('EGFR', 'Gene', (36, 40))
67960	32978523	In carcinogenesis, aberrant TK activity, triggered by overexpression, point mutations, in-frame deletions and autocrine ligand-receptor simulation drives growth and progression of various tumor types including breast and head and neck cancer.	('tumor', 'Disease', (188, 193))	('activity', 'MPA', (31, 39))	('in-frame deletions', 'Var', (87, 105))	('ligand', 'molecular_function', 'GO:0005488', ('120', '126'))	('breast', 'Disease', (210, 216))	('neck', 'cellular_component', 'GO:0044326', ('230', '234'))	('point mutations', 'Var', (70, 85))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('head and neck cancer', 'Phenotype', 'HP:0012288', (221, 241))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('aberrant', 'Var', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('neck cancer', 'Disease', 'MESH:D006258', (230, 241))	('neck cancer', 'Disease', (230, 241))
67961	32978523	Since trastuzumab, an anti-ERBB2 antibody for the treatment of breast cancer, was approved in 1998, various selective inhibitors (antibodies or small molecules) of ERBB TK have been shown to be effective in different tumor entities either overexpressing EGFR (e.g., head and neck squamous cell carcinoma (HNSCC)) or exhibiting activating EGFR mutations (e.g., non-small cell lung cancer (NSCLC)).	('NSCLC', 'Disease', 'MESH:D002289', (388, 393))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (266, 303))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('SCC', 'Gene', (307, 310))	('breast cancer', 'Disease', (63, 76))	('ERBB', 'Gene', (27, 31))	('overexpressing', 'PosReg', (239, 253))	('ERBB', 'Gene', (164, 168))	('ERBB2', 'Gene', '2064', (27, 32))	('mutations', 'Var', (343, 352))	('non-small cell lung cancer', 'Disease', (360, 386))	('lung cancer', 'Phenotype', 'HP:0100526', (375, 386))	('antibody', 'molecular_function', 'GO:0003823', ('33', '41'))	('activating', 'PosReg', (327, 337))	('NSCLC', 'Disease', (388, 393))	('ERBB', 'Gene', '1956', (27, 31))	('ERBB', 'Gene', '1956', (164, 168))	('antibody', 'cellular_component', 'GO:0042571', ('33', '41'))	('tumor', 'Disease', (217, 222))	('EGFR', 'Gene', '1956', (338, 342))	('trastuzumab', 'Chemical', 'MESH:D000068878', (6, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (380, 386))	('EGFR', 'molecular_function', 'GO:0005006', ('254', '258'))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (360, 386))	('EGFR', 'Gene', (254, 258))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('neck squamous cell carcinoma', 'Disease', (275, 303))	('EGFR', 'molecular_function', 'GO:0005006', ('338', '342'))	('antibody', 'cellular_component', 'GO:0019815', ('33', '41'))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (275, 303))	('SCC', 'Phenotype', 'HP:0002860', (307, 310))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (364, 386))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (280, 303))	('neck', 'cellular_component', 'GO:0044326', ('275', '279'))	('EGFR', 'Gene', (338, 342))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (360, 386))	('antibody', 'cellular_component', 'GO:0019814', ('33', '41'))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('SCC', 'Gene', '6317', (307, 310))	('ERBB2', 'Gene', (27, 32))	('EGFR', 'Gene', '1956', (254, 258))
67963	32978523	Importantly, unselected clinical studies assessing EGFR inhibitors in patients with MIBC failed to demonstrate superior treatment efficacy of combined chemotherapy compared to standard chemotherapy alone.	('patients', 'Species', '9606', (70, 78))	('MIBC', 'Chemical', '-', (84, 88))	('EGFR', 'Gene', (51, 55))	('MIBC', 'Disease', (84, 88))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('inhibitors', 'Var', (56, 66))	('EGFR', 'Gene', '1956', (51, 55))
67980	32978523	In parallel, genetic EGFR alterations were studied, i.e., EGFR amplification, EGFR activating mutations, and activating RAS mutations (HRAS, KRAS, NRAS) which would convey resistance to EGFR inhibitor treatment.	('KRAS', 'Gene', (141, 145))	('EGFR', 'molecular_function', 'GO:0005006', ('186', '190'))	('EGFR', 'Gene', (186, 190))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (58, 62))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('NRAS', 'Gene', '4893', (147, 151))	('mutations', 'Var', (94, 103))	('EGFR', 'Gene', '1956', (186, 190))	('EGFR', 'Gene', (78, 82))	('EGFR', 'Gene', '1956', (58, 62))	('EGFR', 'Gene', (21, 25))	('mutations', 'Var', (124, 133))	('KRAS', 'Gene', '3845', (141, 145))	('HRAS', 'Gene', '3265', (135, 139))	('HRAS', 'Gene', (135, 139))	('NRAS', 'Gene', (147, 151))	('EGFR', 'molecular_function', 'GO:0005006', ('21', '25'))
67981	32978523	No activating mutations in the EGFR gene (0/71) and only a single activating RAS mutation (1/69; HRAS p.Q61L) was identified (Fig.	('EGFR', 'Gene', '1956', (31, 35))	('HRAS', 'Gene', '3265', (97, 101))	('EGFR', 'Gene', (31, 35))	('HRAS', 'Gene', (97, 101))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('p.Q61L', 'Var', (102, 108))	('p.Q61L', 'Mutation', 'rs121913233', (102, 108))
67983	32978523	EGFR cluster amplifications overlapped with strong EGFR protein expression (7/9) (Supplementary Table 3).	('EGFR', 'Gene', (0, 4))	('amplifications', 'Var', (13, 27))	('EGFR', 'Gene', (51, 55))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', '1956', (51, 55))
68007	32978523	Compared to the DMSO control, erlotinib treatment caused a slight upregulation of ERBB2 (fold change (FC): 2.1) and ERBB3 (FC: 1.9) mRNA expression, however, re-expression was shown for ERBB4 mRNA in SCaBER (FC: 20.7) (Fig.	('mRNA expression', 'MPA', (132, 147))	('ERBB3', 'Gene', (116, 121))	('upregulation', 'PosReg', (66, 78))	('ERBB3', 'Gene', '2065', (116, 121))	('erlotinib', 'Var', (30, 39))	('ERBB2', 'Gene', '2064', (82, 87))	('DMSO', 'Chemical', 'MESH:D004121', (16, 20))	('ERBB2', 'Gene', (82, 87))	('ERBB4', 'Gene', '2066', (186, 191))	('erlotinib', 'Chemical', 'MESH:D000069347', (30, 39))	('ERBB4', 'Gene', (186, 191))
68016	32978523	The knockdown of EGFR by siRNA led to impaired cell viability 48 h after siRNA transfection in SCaBER cells (Fig.	('EGFR', 'molecular_function', 'GO:0005006', ('17', '21'))	('EGFR', 'Gene', '1956', (17, 21))	('cell viability', 'CPA', (47, 61))	('knockdown', 'Var', (4, 13))	('impaired', 'NegReg', (38, 46))	('EGFR', 'Gene', (17, 21))
68017	32978523	Basal apoptosis was not affected by EGFR knockdown (data not shown).	('apoptosis', 'biological_process', 'GO:0006915', ('6', '15'))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('EGFR', 'Gene', '1956', (36, 40))	('EGFR', 'Gene', (36, 40))	('knockdown', 'Var', (41, 50))	('apoptosis', 'biological_process', 'GO:0097194', ('6', '15'))
68054	32978523	Aberrant activation of ERBB signaling pathways has emerged as an effective therapeutic target in the field of precision medicine.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('ERBB', 'Gene', (23, 27))	('ERBB', 'Gene', '1956', (23, 27))	('activation of ERBB signaling', 'biological_process', 'GO:1901186', ('9', '37'))
68056	32978523	In the present study, we provide a rationale for combining EGFR inhibitors with standard chemotherapy as treatment strategy for pure and mixed squamous bladder cancers, characterized by a strong dependency on wild-type EGFR signaling.	('EGFR', 'Gene', '1956', (219, 223))	('squamous bladder cancers', 'Disease', 'MESH:D001749', (143, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('EGFR', 'Gene', (59, 63))	('squamous bladder cancers', 'Disease', (143, 167))	('EGFR', 'Gene', (219, 223))	('pure', 'Disease', (128, 132))	('pure', 'molecular_function', 'GO:0034023', ('128', '132'))	('EGFR', 'molecular_function', 'GO:0005006', ('219', '223'))	('inhibitors', 'Var', (64, 74))	('bladder cancers', 'Phenotype', 'HP:0009725', (152, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('bladder cancer', 'Phenotype', 'HP:0009725', (152, 166))	('signaling', 'biological_process', 'GO:0023052', ('224', '233'))	('EGFR', 'Gene', '1956', (59, 63))
68066	32978523	Hence, squamous-differentiated bladder cancer appears to be oncogenically addicted to EGFR activity and consequently sensitive to both EGFR inhibition and knockdown without any short-term escape mechanisms, thereby suggesting a putative "Achilles heel".	('knockdown', 'Var', (155, 164))	('EGFR', 'Gene', '1956', (86, 90))	('squamous-differentiated bladder cancer', 'Disease', 'MESH:D001749', (7, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('135', '139'))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('EGFR', 'Gene', '1956', (135, 139))	('bladder cancer', 'Phenotype', 'HP:0009725', (31, 45))	('squamous-differentiated bladder cancer', 'Disease', (7, 45))	('EGFR', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('EGFR', 'Gene', (135, 139))
68069	32978523	A single activating mutation in ERBB2 (R678Q) may contribute to reduced sensitivity against TKIs by heterodimerization with EGFR.	('ERBB2', 'Gene', (32, 37))	('ERBB2', 'Gene', '2064', (32, 37))	('R678Q', 'Var', (39, 44))	('EGFR', 'Gene', '1956', (124, 128))	('sensitivity against TKIs', 'MPA', (72, 96))	('EGFR', 'Gene', (124, 128))	('R678Q', 'Mutation', 'rs1057519862', (39, 44))	('activating', 'PosReg', (9, 19))	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('reduced', 'NegReg', (64, 71))	('heterodimerization', 'MPA', (100, 118))
68077	32978523	By combining EGFR inhibitors and cytotoxic chemotherapeutics, we further revealed strong synergistic effects in SCaBER cells.	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('inhibitors', 'Var', (18, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))
68082	32978523	It has been shown that the application of gefitinib and cisplatin displayed a dose-dependent antagonism in EGFR wild-type and EGFR mutant NSCLC cell lines, revealing an interference of cisplatin cell entry at a concentration range of gefitinib between 0.001-0.3 microM.	('gefitinib', 'Chemical', 'MESH:D000077156', (234, 243))	('EGFR', 'molecular_function', 'GO:0005006', ('107', '111'))	('cisplatin cell entry', 'MPA', (185, 205))	('NSCLC', 'Disease', (138, 143))	('EGFR', 'Gene', (126, 130))	('interference', 'Reg', (169, 181))	('mutant', 'Var', (131, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('gefitinib', 'Chemical', 'MESH:D000077156', (42, 51))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('EGFR', 'Gene', '1956', (107, 111))	('EGFR', 'Gene', (107, 111))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))	('EGFR', 'Gene', '1956', (126, 130))
68086	32978523	Considering the order of treatment, mechanisms impairing the efficacies of EGFR inhibitors and cisplatin have been reported in both directions.	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('EGFR', 'Gene', '1956', (75, 79))	('impairing', 'NegReg', (47, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('EGFR', 'Gene', (75, 79))	('inhibitors', 'Var', (80, 90))
68128	30338346	IGF1R positivity was defined as Her2-score >= 1+.	('Her2', 'Gene', (32, 36))	('positivity', 'Var', (6, 16))	('Her2', 'Gene', '2064', (32, 36))	('IGF1R', 'Gene', (0, 5))	('IGF1R', 'Gene', '3480', (0, 5))
68162	30338346	Cases with IGF1R H-score higher than the median were considered to show high IGF1R expression.	('IGF1R', 'Gene', '3480', (11, 16))	('IGF1R', 'Gene', (77, 82))	('high IGF1R', 'Phenotype', 'HP:0030269', (72, 82))	('IGF1R', 'Gene', '3480', (77, 82))	('IGF1R', 'Gene', (11, 16))	('expression', 'MPA', (83, 93))	('H-score', 'Var', (17, 24))
68186	30338346	Figure 2 shows the survival curves for tumor recurrence, tumor progression, overall mortality, and cancer-specific mortality considering IGF1R positivity.	('positivity', 'Var', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancer', 'Disease', (99, 105))	('IGF1R', 'Gene', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (57, 62))	('IGF1R', 'Gene', '3480', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
68194	30338346	IGF1R positivity was not associated with any outcome.	('positivity', 'Var', (6, 16))	('IGF1R', 'Gene', '3480', (0, 5))	('IGF1R', 'Gene', (0, 5))
68201	30338346	To date, clinical trials using monoclonal anti-IGF1R antibodies have spanned a diverse group of cancers including hematologic malignancies, sarcomas, and brain tumors.	('hematologic malignancies', 'Disease', 'MESH:D019337', (114, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('brain tumors', 'Disease', (154, 166))	('sarcomas', 'Disease', (140, 148))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('IGF1R', 'Gene', (47, 52))	('hematologic malignancies', 'Disease', (114, 138))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('brain tumors', 'Disease', 'MESH:D001932', (154, 166))	('brain tumors', 'Phenotype', 'HP:0030692', (154, 166))	('IGF1R', 'Gene', '3480', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('monoclonal', 'Var', (31, 41))	('sarcomas', 'Disease', 'MESH:D012509', (140, 148))	('cancers', 'Disease', (96, 103))
68225	30338346	Evaluations of IGF1R expression in variants of urothelial carcinoma could be of additional value.	('IGF1R', 'Gene', (15, 20))	('variants', 'Var', (35, 43))	('IGF1R', 'Gene', '3480', (15, 20))	('urothelial carcinoma', 'Disease', (47, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (47, 67))
68231	31322264	Epidemiological studies indicate that arsenic is one of the main risk factors for the development of bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('arsenic', 'Chemical', 'MESH:D001151', (38, 45))	('bladder cancer', 'Disease', (101, 115))	('arsenic', 'Var', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))
68238	31322264	The data indicated that WIF1 gene expression was decreased by sodium arsenite, whereas this was not noted for CBS, MALAT1 and ADORA1.	('sodium arsenite', 'Var', (62, 77))	('expression', 'MPA', (34, 44))	('sodium arsenite', 'Chemical', 'MESH:C017947', (62, 77))	('WIF1 gene', 'Gene', (24, 33))	('decreased', 'NegReg', (49, 58))	('gene expression', 'biological_process', 'GO:0010467', ('29', '44'))
68254	31322264	In male F344 rats, dimethylarsinic acid induced urothelial carcinoma at a dosage higher than 50 ppm following 104 weeks of treatment.	('rats', 'Species', '10116', (13, 17))	('induced', 'Reg', (40, 47))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (48, 68))	('dimethylarsinic acid', 'Var', (19, 39))	('dimethylarsinic acid', 'Chemical', 'MESH:D002101', (19, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('urothelial carcinoma', 'Disease', (48, 68))
68255	31322264	An additional study reported that dimethylarsinic acid induced urothelial carcinogenesis in rats but not in mice.	('rats', 'Species', '10116', (92, 96))	('dimethylarsinic acid', 'Var', (34, 54))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (63, 88))	('mice', 'Species', '10090', (108, 112))	('urothelial carcinogenesis', 'Disease', (63, 88))	('dimethylarsinic acid', 'Chemical', 'MESH:D002101', (34, 54))
68264	31322264	For example, E-cadherin expression was revealed to be enhanced and integrin beta3 expression decreased by sodium arsenite (iAsIII), monomethylarsonous acid (MMAIII), and dimethylarsinous acid (DMAIII) treatment in SV-HUC-1 immortalized human uroepithelial cells.	('human', 'Species', '9606', (236, 241))	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('monomethylarsonous acid', 'Chemical', 'MESH:C406082', (132, 155))	('expression', 'MPA', (82, 92))	('expression', 'MPA', (24, 34))	('MMAIII', 'Chemical', 'MESH:C406082', (157, 163))	('sodium arsenite', 'Chemical', 'MESH:C017947', (106, 121))	('decreased', 'NegReg', (93, 102))	('dimethylarsinous acid', 'Var', (170, 191))	('integrin beta3', 'Gene', '3690', (67, 81))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('integrin beta3', 'Gene', (67, 81))	('dimethylarsinous acid', 'Chemical', 'MESH:C472511', (170, 191))	('SV-HUC-1', 'CellLine', 'CVCL:3798', (214, 222))	('enhanced', 'PosReg', (54, 62))	('DMAIII', 'Chemical', '-', (193, 199))
68331	31322264	1B and C) revealed that arsenic induced 83.3% (10/12) hyperplasia and 8.3% (1/12) dysplasia in mouse urothelium, which represented the precancerous characteristics of the urothelium.	('cancer', 'Disease', (138, 144))	('hyperplasia', 'Disease', 'MESH:D006965', (54, 65))	('arsenic', 'Chemical', 'MESH:D001151', (24, 31))	('dysplasia', 'Disease', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('hyperplasia', 'Disease', (54, 65))	('arsenic', 'Var', (24, 31))	('dysplasia', 'Disease', 'MESH:D004476', (82, 91))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('mouse', 'Species', '10090', (95, 100))
68339	31322264	Furthermore, arsenic caused additional extensive hydropic degeneration of hepatocytes, characterized by diffuse vacuolated swelling of the hepatocytic cytoplasm and narrowed sinusoidal capillary spaces (Fig.	('hydropic', 'MPA', (49, 57))	('swelling of the hepatocytic', 'Disease', (123, 150))	('narrowed', 'NegReg', (165, 173))	('arsenic', 'Var', (13, 20))	('degeneration of hepatocytes', 'Phenotype', 'HP:0001404', (58, 85))	('cytoplasm', 'cellular_component', 'GO:0005737', ('151', '160'))	('rat', 'Species', '10116', (64, 67))	('swelling of the hepatocytic', 'Disease', 'MESH:D004487', (123, 150))	('arsenic', 'Chemical', 'MESH:D001151', (13, 20))
68348	31322264	Hypermethylation of WIF1 DNA has also been reported in bladder cancer, chondrosarcoma, and non-small cell lung cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('bladder cancer', 'Disease', (55, 69))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (91, 117))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (71, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('Hypermethylation', 'Var', (0, 16))	('non-small cell lung cancer', 'Disease', (91, 117))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (95, 117))	('WIF1 DNA', 'Gene', (20, 28))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('chondrosarcoma', 'Disease', (71, 85))	('chondrosarcoma', 'Disease', 'MESH:D002813', (71, 85))	('reported', 'Reg', (43, 51))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (91, 117))
68378	31322264	5C), indicating that WIF1 gene expression was inhibited in urothelial carcinoma cells, possibly as a result of DNA CpG methylation.	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('methylation', 'Var', (119, 130))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (59, 79))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('WIF1 gene', 'Gene', (21, 30))	('gene expression', 'biological_process', 'GO:0010467', ('26', '41'))	('expression', 'MPA', (31, 41))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))	('inhibited', 'NegReg', (46, 55))	('urothelial carcinoma', 'Disease', (59, 79))
68400	31322264	In addition to bladder cancer, WIF1 DNA hypermethylation has been identified as a potential biomarker for the diagnosis of lung cancer and chondrosarcoma.	('bladder cancer', 'Disease', 'MESH:D001749', (15, 29))	('bladder cancer', 'Disease', (15, 29))	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('chondrosarcoma', 'Disease', 'MESH:D002813', (139, 153))	('WIF1 DNA', 'Gene', (31, 39))	('chondrosarcoma', 'Disease', (139, 153))	('hypermethylation', 'Var', (40, 56))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('bladder cancer', 'Phenotype', 'HP:0009725', (15, 29))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('36', '56'))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
68406	31322264	In the present study, arsenic increased Cbs mRNA expression without altering its DNA methylation levels (Fig.	('arsenic', 'Var', (22, 29))	('Cbs', 'Gene', '12411', (40, 43))	('DNA methylation', 'biological_process', 'GO:0006306', ('81', '96'))	('Cbs', 'Gene', (40, 43))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('increased', 'PosReg', (30, 39))	('arsenic', 'Chemical', 'MESH:D001151', (22, 29))
68417	31322264	Our previous study demonstrated that N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) caused a decrease in glutathione S-transferase Mu1 (Gstm1) levels by downregulating the expression of the corresponding gene.	('downregulating', 'NegReg', (151, 165))	('glutathione S-transferase Mu1', 'Gene', (103, 132))	('BBN', 'Chemical', 'MESH:D002085', (77, 80))	('Gstm1', 'Gene', (134, 139))	('rat', 'Species', '10116', (26, 29))	('Gstm1', 'Gene', '14862', (134, 139))	('N-butyl-N-(4-hydroxybutyl) nitrosamine', 'Chemical', 'MESH:D002085', (37, 75))	('glutathione S-transferase Mu1', 'Gene', '14862', (103, 132))	('N-butyl-N-', 'Var', (37, 47))	('decrease', 'NegReg', (91, 99))	('expression', 'MPA', (170, 180))
68434	29973584	Large-scale tumor sequencing has revolutionized the identification of somatic driver alterations but has had limited impact on the identification of cancer predisposition genes (CPGs).	('cancer', 'Disease', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('alterations', 'Var', (85, 96))	('tumor', 'Disease', (12, 17))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
68436	29973584	Applied to ~10,000 tumor exomes the approach identifies known and putative CPGs - including the chromatin modifier NSD1 - that contribute to cancer through a combination of rare germline variants and somatic loss-of-heterozygosity (LOH).	('000 tumor', 'Disease', 'MESH:D009369', (15, 24))	('germline variants', 'Var', (178, 195))	('NSD1', 'Gene', '64324', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('loss-of-heterozygosity', 'NegReg', (208, 230))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('000 tumor', 'Disease', (15, 24))	('contribute', 'Reg', (127, 137))	('NSD1', 'Gene', (115, 119))	('chromatin', 'cellular_component', 'GO:0000785', ('96', '105'))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
68438	29973584	Inherited germline variants and somatic mutations contribute to cancer.	('contribute', 'Reg', (50, 60))	('germline variants', 'Var', (10, 27))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
68439	29973584	Here, the authors present the statistical method ALFRED that tests the two-hit hypothesis of tumorigenesis and apply it to ~10,000 tumor exomes to identify rare germline variants that affect putative cancer predisposition genes, contributing substantially to cancer risk.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', (93, 98))	('variants', 'Var', (170, 178))	('tumor', 'Disease', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('000 tumor', 'Disease', 'MESH:D009369', (127, 136))	('contributing', 'Reg', (229, 241))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('000 tumor', 'Disease', (127, 136))	('cancer', 'Disease', (200, 206))	('cancer', 'Disease', (259, 265))
68441	29973584	However, it was Alfred Knudson's 'two-hit' hypothesis that initiated the identification of cancer predisposition genes (CPGs) in which deleterious germline variants have been associated with increased risks of cancer.	('associated', 'Reg', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('variants', 'Var', (156, 164))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (210, 216))
68442	29973584	Through a statistical analysis of retinoblastoma cases, Knudson proposed that 'two hits' to the DNA were necessary to cause cancer and that in children with the inherited form of the disease the first hit is inherited variation in one allele of the gene with the 'second hit' being a somatically acquired inactivation of the second allele.	('retinoblastoma', 'Gene', '5925', (34, 48))	('retinoblastoma', 'Gene', (34, 48))	('cancer', 'Disease', (124, 130))	('retinoblastoma', 'Phenotype', 'HP:0009919', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('children', 'Species', '9606', (143, 151))	('variation', 'Var', (218, 227))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
68443	29973584	This model was confirmed by the identification of biallelic inactivation of the RB1 gene in retinoblastoma and indeed most known high-penetrance inherited cancer predisposition variants are loss-of-function mutations in recessively acting tumor suppressor (TS) genes.	('tumor suppressor', 'biological_process', 'GO:0051726', ('239', '255'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('239', '255'))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('TS', 'Gene', '7248', (257, 259))	('RB1', 'Gene', (80, 83))	('retinoblastoma', 'Gene', (92, 106))	('tumor suppressor', 'Gene', (239, 255))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('retinoblastoma', 'Phenotype', 'HP:0009919', (92, 106))	('biallelic inactivation', 'Var', (50, 72))	('variants', 'Var', (177, 185))	('tumor suppressor', 'Gene', '7248', (239, 255))	('RB1', 'Gene', '5925', (80, 83))	('loss-of-function', 'NegReg', (190, 206))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('retinoblastoma', 'Gene', '5925', (92, 106))
68444	29973584	Tumor sequencing has led to the systematic identification of somatically acquired cancer driver alterations.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('alterations', 'Var', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
68445	29973584	As for other genetic diseases, an important reason for this is the low statistical power to detect associations between rare genetic variants and disease risk in genome-wide analyses, even in large population studies.	('variants', 'Var', (133, 141))	('genetic diseases', 'Disease', 'MESH:D030342', (13, 29))	('genetic diseases', 'Disease', (13, 29))
68449	29973584	To predict loss of heterozygosity (LOH) in each tumor from exome sequencing data, ALFRED uses all germline variants in coding and noncoding regions within each gene with sufficient sequencing coverage (expanding the analyzed region to 100 kb for genes shorter than this size) and then tests for allelic imbalance (AI), a change in variant allele frequencies (VAFs) in the tumor compared to in the matched non-tumor sample from each patient, Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (372, 377))	('tumor', 'Disease', (409, 414))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('patient', 'Species', '9606', (432, 439))	('variants', 'Var', (107, 115))	('tumor', 'Disease', (372, 377))	('tests', 'Reg', (285, 290))	('tumor', 'Disease', 'MESH:D009369', (409, 414))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (409, 414))	('change', 'Reg', (321, 327))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('imbalance', 'Phenotype', 'HP:0002172', (303, 312))
68450	29973584	ALFRED classifies germline variants (identified from non-tumor DNA; mainly from blood) as potentially damaging if they have a minor allele frequency (MAF) <0.1% in the Exome Aggregation Consortium (ExAC) database and result in a premature stop codon, frameshift, splice site inactivation, or missense change predicted as deleterious by the MetaLR consensus algorithm.	('splice site', 'MPA', (263, 274))	('premature stop codon', 'MPA', (229, 249))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('missense change', 'Var', (292, 307))	('tumor', 'Disease', (57, 62))	('frameshift', 'MPA', (251, 261))
68452	29973584	The first test is for an excess of RDGVs in a gene in tumor samples with putative LOH of the gene, compared to the frequency of RDGVs in the samples without LOH in that gene.	('LOH', 'Var', (82, 85))	('RDGVs', 'Var', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
68460	29973584	At a false discovery rate (FDR) = 0.2, 13 genes were individually enriched for RDGVs in tumors with AI and exhibited AI in favor of the variant allele (henceforth referred to as 'ALFRED genes') (Supplementary Data 3).	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('false', 'biological_process', 'GO:0071878', ('5', '10'))	('variant', 'Var', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('false', 'biological_process', 'GO:0071877', ('5', '10'))
68467	29973584	Five genes were enriched for rare PTVs in tumors with AI and exhibited AI in favor of the variant alleles, of which three genes (BRCA1/2 and ATM) overlap with our initial ALFRED design (RDGVs based model), while TNFSF13B (excess of rare PTVs in AI samples over samples without AI samples = 0.37%, PTV-ALFRED P = 1.85 x 10-3) and ACACB (excess = 0.41%, PTV-ALFRED P = 3.02 x 10-3) are newly detected (Supplementary Fig.	('PTV', 'cellular_component', 'GO:1990257', ('352', '355'))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('ACACB', 'Gene', '32', (329, 334))	('PTV', 'cellular_component', 'GO:1990257', ('297', '300'))	('TNFSF13B', 'Gene', '10673', (212, 220))	('BRCA', 'Phenotype', 'HP:0003002', (129, 133))	('ACACB', 'Gene', (329, 334))	('BRCA1/2 and ATM', 'Gene', '472;672;675', (129, 144))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('TNFSF13B', 'Gene', (212, 220))	('variant', 'Var', (90, 97))
68471	29973584	We next tested whether cancer genes identified by recurrent somatic alterations but not previously reported to harbor inherited risk variants also showed evidence of carrying recessive RDGVs that predispose to cancer via a two-hit mechanism.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('variants', 'Var', (133, 141))	('cancer', 'Disease', (210, 216))
68472	29973584	Somatic cancer genes known to act via gain-of-function alterations (oncogenes; OGs) showed no significant enrichment for RDGVs in samples with AI (Fig.	('cancer', 'Disease', (8, 14))	('alterations', 'Var', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('gain-of-function', 'PosReg', (38, 54))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
68485	29973584	2d and Supplementary Data 5) also had an enrichment of RDGVs in a matched cancer type compared to in controls (P < 0.05, Fig.	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('RDGVs', 'Var', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
68491	29973584	If RDGVs in a gene contribute similar risk to many cancer types then they would not show enrichment in this test.	('RDGVs', 'Var', (3, 8))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))
68493	29973584	We performed two analyses: the first using all samples and the second restricted to tumor samples with AI in the gene of interest.	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('AI in', 'Var', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))
68496	29973584	For example, RDGVs in BRCA1 and BRCA2 were, as expected, significantly enriched in OV and BRCA compared to in all the other cancer samples (BRCA1, excess of RDGVs in BRCA compared to non-breast cancer = 2.1%, 95% CI: 1.1-3.1%, excess in OV = 6.7%, 5.1-8.2%; BRCA2, excess in BRCA = 1.3%, 0.49-2.1%; excess in OV = 3.9%, 2.7-5.1%).	('BRCA2', 'Gene', '675', (258, 263))	('BRCA1', 'Gene', (140, 145))	('BRCA', 'Gene', (166, 170))	('non-breast cancer', 'Disease', 'MESH:D001943', (183, 200))	('OV', 'Phenotype', 'HP:0025318', (237, 239))	('BRCA', 'Gene', '672', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('BRCA', 'Gene', '672', (140, 144))	('OV', 'Phenotype', 'HP:0025318', (309, 311))	('BRCA', 'Gene', '672', (258, 262))	('BRCA', 'Gene', (275, 279))	('BRCA', 'Phenotype', 'HP:0003002', (90, 94))	('BRCA2', 'Gene', (32, 37))	('BRCA', 'Phenotype', 'HP:0003002', (32, 36))	('non-breast cancer', 'Disease', (183, 200))	('RDGVs', 'Var', (157, 162))	('BRCA', 'Gene', (22, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('BRCA', 'Phenotype', 'HP:0003002', (166, 170))	('BRCA', 'Gene', (140, 144))	('BRCA', 'Gene', (258, 262))	('BRCA', 'Gene', '672', (90, 94))	('BRCA', 'Gene', '672', (32, 36))	('BRCA2', 'Gene', '675', (32, 37))	('BRCA2', 'Gene', (258, 263))	('RDGVs', 'Var', (13, 18))	('OV', 'Phenotype', 'HP:0025318', (83, 85))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BRCA', 'Gene', '672', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('BRCA1', 'Gene', '672', (22, 27))	('BRCA', 'Gene', (90, 94))	('BRCA', 'Gene', (32, 36))	('BRCA', 'Phenotype', 'HP:0003002', (22, 26))	('BRCA', 'Phenotype', 'HP:0003002', (140, 144))	('BRCA1', 'Gene', '672', (140, 145))	('BRCA1', 'Gene', (22, 27))	('BRCA', 'Gene', '672', (275, 279))
68499	29973584	Next, we estimated the total contribution of RDGVs in the ALFRED genes to cancer risk by quantifying the excess frequency of ALFRED gene RDGVs in cancer patients over that in the general population.	('RDGVs', 'Var', (137, 142))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('ALFRED', 'Gene', (58, 64))	('patients', 'Species', '9606', (153, 161))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
68503	29973584	Strikingly, 21.7% of OV patients carried RDGVs in ALFRED genes, which is an excess of 14.6% over controls (95% CI: 11.6-17.1%).	('OV', 'Phenotype', 'HP:0025318', (21, 23))	('ALFRED genes', 'Gene', (50, 62))	('RDGVs', 'Var', (41, 46))	('patients', 'Species', '9606', (24, 32))
68504	29973584	Other cancer types with a substantial contribution of RDGVs in ALFRED genes include BRCA (7.0% by excess of cases versus controls, adjusted to random expectation; 95% CI: 4.7-9.1%) and UCEC (3.8% excess, 95% CI: 1.1-6.2%).	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('BRCA', 'Gene', (84, 88))	('BRCA', 'Phenotype', 'HP:0003002', (84, 88))	('BRCA', 'Gene', '672', (84, 88))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('RDGVs', 'Var', (54, 59))	('UCEC', 'Disease', (185, 189))	('cancer', 'Disease', (6, 12))	('ALFRED genes', 'Gene', (63, 75))
68507	29973584	The excess of RDGVs in these three CPGs in cases versus controls suggests that RDGVs in these three genes are implicated in a median of 1.2% of cancer cases across the 17 cancer types (range: 0.24-11.4%).	('RDGVs', 'Var', (79, 84))	('implicated in', 'Reg', (110, 123))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (171, 177))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
68509	29973584	In OV, for example, the excess of cancer cases that carry RDGVs in any ALFRED gene after excluding known CPGs is 4.0% (95% CI: 1.6-5.0%).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('ALFRED gene', 'Gene', (71, 82))	('RDGVs', 'Var', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('OV', 'Phenotype', 'HP:0025318', (3, 5))
68514	29973584	To estimate the total proportion of cancer cases attributable to rare germline risk variants for each cancer type, we combined the ALFRED genes with the previously reported CPGs (for any cancer type).	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (187, 193))	('cancer', 'Disease', (36, 42))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('variants', 'Var', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
68515	29973584	In total, RDGVs in these 56 genes explain a median of 5.4% of cancer cases across the 17 cancer types (excess frequency of cases with a RDGV over frequency of controls, adjusted to a random expectation; range 2.3-15.2%).	('RDGVs', 'Var', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
68516	29973584	For instance, a total of 15.2% (95% CI: 12.1-17.7%) of OV and 9.3% of BRCA cases (95% CI: 6.2-12.4%) can be explained by RDGVs in the 56 genes (Supplementary Fig.	('OV', 'Phenotype', 'HP:0025318', (55, 57))	('BRCA', 'Phenotype', 'HP:0003002', (70, 74))	('RDGVs', 'Var', (121, 126))	('BRCA', 'Gene', '672', (70, 74))	('BRCA', 'Gene', (70, 74))
68520	29973584	Our results suggest that multiple somatic cancer drivers and putative new genes also harbor germline genetic variants that predispose to cancer in the general population.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('variants', 'Var', (109, 117))	('predispose', 'Reg', (123, 133))
68521	29973584	For example, the histone H3 lysine 36 methyltransferase NSD1 was the second most significantly enriched gene in our case-control analysis with an excess of RDGVs in cases compared with controls = 0.72% (P < 1.14 x 10-3, 95% CI: 0.27-1.2%).	('NSD1', 'Gene', (56, 60))	('RDGVs', 'Var', (156, 161))	('NSD1', 'Gene', '64324', (56, 60))	('lysine', 'Chemical', 'MESH:D008239', (28, 34))
68522	29973584	This suggests that RDGVs in NSD1 are causally implicated in ~0.72% of cancers, a similar magnitude of effect as we observe for the well-known cancer predisposition genes BRCA1 (0.64%) and ATM (0.68%).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('implicated', 'Reg', (46, 56))	('NSD1', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('BRCA', 'Phenotype', 'HP:0003002', (170, 174))	('BRCA1', 'Gene', '672', (170, 175))	('ATM', 'Gene', (188, 191))	('RDGVs', 'Var', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('BRCA1', 'Gene', (170, 175))	('cancers', 'Disease', (70, 77))	('ATM', 'Gene', '472', (188, 191))	('cancer', 'Disease', (70, 76))	('NSD1', 'Gene', '64324', (28, 32))	('cancer', 'Disease', (142, 148))
68524	29973584	Here we have presented evidence that NSD1 also carries germline cancer predisposition variants.	('NSD1', 'Gene', '64324', (37, 41))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('variants', 'Var', (86, 94))	('NSD1', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
68526	29973584	However, the variants in NSD1 enriched in cancer patients are distinct from the variants that cause Sotos syndrome (Supplementary Fig.	('variants', 'Var', (13, 21))	('NSD1', 'Gene', (25, 29))	('Sotos syndrome', 'Disease', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('NSD1', 'Gene', '64324', (25, 29))	('Sotos syndrome', 'Disease', 'MESH:D058495', (100, 114))	('patients', 'Species', '9606', (49, 57))
68528	29973584	Considered as a set, RDGVs in the ALFRED genes can explain a substantial proportion of the cancer cases analyzed by the TCGA project: a median of 2.3% across the 17 individual cancer types with sufficient sample sizes.	('RDGVs', 'Var', (21, 26))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ALFRED genes', 'Gene', (34, 46))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
68529	29973584	However, in several cancers the contribution is substantially higher, with 14.6% of OV, 7.0% of BRCA, and 3.8% of UCEC cases attributable to RDGVs in these genes.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('BRCA', 'Phenotype', 'HP:0003002', (96, 100))	('BRCA', 'Gene', '672', (96, 100))	('UCEC', 'Disease', (114, 118))	('BRCA', 'Gene', (96, 100))	('RDGVs', 'Var', (141, 146))	('OV', 'Phenotype', 'HP:0025318', (84, 86))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
68530	29973584	Including additional known CPGs further increases the estimate of the proportion of cases attributable to RDGVs: a median of 5.4% across the 17 individual cancer types, with 15.2% of OV, 9.3% of BRCA, and 6.0% of UCEC cases attributable to RDGVs in ALFRED genes, respectively.	('OV', 'Phenotype', 'HP:0025318', (183, 185))	('RDGVs', 'Var', (240, 245))	('BRCA', 'Phenotype', 'HP:0003002', (195, 199))	('BRCA', 'Gene', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ALFRED genes', 'Gene', (249, 261))	('esp', 'Gene', '148713', (264, 267))	('UCEC', 'Disease', (213, 217))	('esp', 'Gene', (264, 267))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('BRCA', 'Gene', '672', (195, 199))
68543	29973584	(http://exac.broadinstitute.org/), the TCGA cancer samples had a median 4574 nonsynonymous, stop gain and stop loss, splice SNVs and coding indels in the filtered regions, as annotated by the Annovar tool version 2014-11-12 (ref.	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('splice SNVs', 'Var', (117, 128))	('nonsynonymous', 'MPA', (77, 90))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('TCGA', 'Gene', (39, 43))	('coding indels', 'Var', (133, 146))
68546	29973584	We called the germline variants (single-nucleotide and short indels) on the normal and the tumor samples independently using Illumina IVC.	('tumor', 'Disease', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('single-nucleotide', 'Var', (33, 50))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
68547	29973584	Of the data Annovar reports, we used (i) the consequences of the mutations: synonymous, missense, truncating, splice site, frameshift indel, and in-frame indel, using the RefSeq gene annotations; (ii) the estimated effect of missense mutations via the MetaLR predictor, which combines nine deleteriousness scores including PolyPhen-2, SIFT and others.	('missense mutations', 'Var', (225, 243))	('SIFT', 'Disease', (335, 339))	('SIFT', 'Disease', 'None', (335, 339))
68548	29973584	This filtering was performed on the full ExAC, which includes germline variants of TCGA samples in addition to other non-cancer cohorts.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('germline variants', 'Var', (62, 79))	('non-cancer', 'Disease', (117, 127))	('non-cancer', 'Disease', 'MESH:D009369', (117, 127))	('TCGA', 'Gene', (83, 87))
68550	29973584	Before performing a statistical test to call LOH, we applied an effect size threshold, requiring that the tumor VAF of a germline variant must be either higher than 0.7 or lower than 0.3.	('variant', 'Var', (130, 137))	('lower', 'NegReg', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
68552	29973584	Each variant in a gene (and possibly surrounding regions) that meets the effect size threshold was further tested individually using a two-tailed Fisher's test that compares the read counts supporting the variant and the reference alleles in the tumor, versus the read counts supporting the variant and the reference alleles in the normal (noncancerous) tissue.	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('variant', 'Var', (205, 212))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('cancer', 'Disease', (343, 349))	('cancer', 'Disease', 'MESH:D009369', (343, 349))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (246, 251))
68555	29973584	Additionally, we removed the RDGVs that were recurrent at the same position in more than 1% of our samples (TCGA or control samples), thereby excluding four variants (17-46608203-A-G, 20-5548206-TC-T, 21-34924148-A-G and X-2833605-C-T).	('20-5548206-TC-T', 'Var', (184, 199))	('X-2833605-C-T', 'Var', (221, 234))	('20-5548206-TC-T', 'CellLine', 'CVCL:2300', (184, 199))	('excluding', 'NegReg', (142, 151))	('17-46608203-A-G', 'Var', (167, 182))	('21-34924148-A-G', 'Var', (201, 216))
68556	29973584	We first tested for an excess of RDGVs in samples with putative LOH compared to in samples without putative LOH of all possible genes (N = 14,143), collapsing together all SNVs/indels in each gene in each sample and using the exomes of all 30 cancer types (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Disease', (243, 249))	('SNVs/indels', 'Var', (172, 183))
68557	29973584	Finally, 2983 genes were defined as ALFRED tested genes, which carried at least five RDGVs (of which at least one with >=10% increased VAF of RDGVs in tumor compared to matched normal sample; 6692 genes were excluded that were carrying less than five RDGVs and, additionally, 329 genes were excluded if they carried no RDGV with >=10% increased VAF), with an above-average (10.0%) frequency of putative LOH in the gene in the pan-cancer data (8809 genes were excluded that were lower than 10.0% frequency of putative LOH; 4672 genes were carrying less than five RDGVs and lower putative LOH frequencies than average frequency of putative LOH; Supplementary Fig, 6a).	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (430, 436))	('tumor', 'Disease', (151, 156))	('4672 genes', 'Var', (522, 532))	('cancer', 'Disease', 'MESH:D009369', (430, 436))	('cancer', 'Disease', (430, 436))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
68563	29973584	Genes with dominant gain-of-function variants would not be significant in ALFRED analysis (e.g., no excess of RDGVs in AI samples compared to no-AI samples), but would be significant in the case-control analysis, meaning the variants are enriched in cancer patients in comparison to the general population.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (250, 256))	('gain-of-function', 'PosReg', (20, 36))	('patients', 'Species', '9606', (257, 265))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('variants', 'Var', (37, 45))
68593	29973584	To empirically estimate the effects of the 10% cutoff, we examined the samples containing rare truncating (nonsense or frameshift indel) variants of six genes that were previously associated with inherited ovarian carcinoma(BRCA1, BRCA2, MSH6, PALB2, RAD51, and TP53) in the TCGA ovarian cancer data (N = 51 in our data set); these were the putative true positive LOH events.	('BRCA2', 'Gene', (231, 236))	('MSH6', 'Gene', (238, 242))	('PALB2', 'Gene', (244, 249))	('MSH6', 'Gene', '2956', (238, 242))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('variants', 'Var', (137, 145))	('BRCA', 'Phenotype', 'HP:0003002', (224, 228))	('TP53', 'Gene', '7157', (262, 266))	('ovarian cancer', 'Disease', 'MESH:D010051', (280, 294))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('BRCA', 'Phenotype', 'HP:0003002', (231, 235))	('BRCA2', 'Gene', '675', (231, 236))	('PALB2', 'Gene', '79728', (244, 249))	('inherited ovarian carcinoma', 'Disease', (196, 223))	('BRCA1', 'Gene', '672', (224, 229))	('ovarian cancer', 'Disease', (280, 294))	('BRCA1', 'Gene', (224, 229))	('inherited ovarian carcinoma', 'Disease', 'MESH:D010051', (196, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (280, 294))	('RAD51', 'Gene', (251, 256))	('RAD51', 'Gene', '5888', (251, 256))	('TP53', 'Gene', (262, 266))	('RAD', 'biological_process', 'GO:1990116', ('251', '254'))	('associated with', 'Reg', (180, 195))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (206, 223))
68636	25126590	nitrosamine and acetaldehyde), activation of dietary phytochemicals, metabolism of hormones, xenobiotics, and modification of tumor promoting bile acids.	('acetaldehyde', 'MPA', (16, 28))	('metabolism', 'MPA', (69, 79))	('nitrosamine', 'Chemical', 'MESH:D009602', (0, 11))	('metabolism', 'biological_process', 'GO:0008152', ('69', '79'))	('acetaldehyde', 'Chemical', 'MESH:D000079', (16, 28))	('bile acids', 'Chemical', 'MESH:D001647', (142, 152))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('modification', 'Var', (110, 122))	('activation', 'PosReg', (31, 41))	('tumor', 'Disease', (126, 131))
68659	25126590	Variations in microbiota may be a new risk factor for a variety of cancers.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Variations', 'Var', (0, 10))
68717	32547059	Response to Anti-HER2-Based Treatment in a Patient with Bladder Adenocarcinoma Harboring HER2 Amplification and S310F Mutation Discovered by Next-Generation Sequencing: A Case Report HER2 overexpression has been identified in approximately 14% of bladder adenocarcinomas.	('Adenocarcinoma', 'Disease', (64, 78))	('HER2', 'Gene', '2064', (183, 187))	('S310F', 'Var', (112, 117))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('S310F', 'Mutation', 'rs1057519816', (112, 117))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (247, 269))	('HER2', 'Gene', (17, 21))	('overexpression', 'PosReg', (188, 202))	('bladder adenocarcinomas', 'Disease', (247, 270))	('bladder adenocarcinomas', 'Disease', 'MESH:D001749', (247, 270))	('HER2', 'Gene', (89, 93))	('HER2', 'Gene', '2064', (17, 21))	('Patient', 'Species', '9606', (43, 50))	('Bladder Adenocarcinoma', 'Phenotype', 'HP:0002862', (56, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('HER2', 'Gene', '2064', (89, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('HER2', 'Gene', (183, 187))
68718	32547059	However, until now, there has been no approved standard targeted therapy for bladder adenocarcinoma patients harboring HER2 genetic alteration.	('bladder adenocarcinoma', 'Disease', (77, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('bladder adenocarcinoma', 'Disease', 'MESH:D001749', (77, 99))	('HER2', 'Gene', (119, 123))	('HER2', 'Gene', '2064', (119, 123))	('patients', 'Species', '9606', (100, 108))	('genetic alteration', 'Var', (124, 142))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (77, 99))
68722	32547059	HER2 amplification, approximately 7 times, was discovered together with the S310F mutation (mutant abundance 90%).	('S310F', 'Var', (76, 81))	('HER2', 'Gene', (0, 4))	('S310F', 'Mutation', 'rs1057519816', (76, 81))	('HER2', 'Gene', '2064', (0, 4))
68725	32547059	NGS was performed on a rebiopsy, and the result showed no amplification of HER2, and the S310F mutant abundance was reduced to 27.9%.	('HER2', 'Gene', '2064', (75, 79))	('S310F', 'Var', (89, 94))	('HER2', 'Gene', (75, 79))	('S310F', 'Mutation', 'rs1057519816', (89, 94))
68726	32547059	This is the first case report describing a bladder adenocarcinoma patient harboring HER2 amplification who responded to trastuzumab.	('bladder adenocarcinoma', 'Disease', (43, 65))	('trastuzumab', 'Chemical', 'MESH:D000068878', (120, 131))	('HER2', 'Gene', (84, 88))	('bladder adenocarcinoma', 'Disease', 'MESH:D001749', (43, 65))	('responded to trastuzumab', 'MPA', (107, 131))	('HER2', 'Gene', '2064', (84, 88))	('patient', 'Species', '9606', (66, 73))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (43, 65))	('amplification', 'Var', (89, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
68728	32547059	The genetic change after treatment also implied possible mechanisms of resistance to trastuzumab-based therapy, which requires more investigation.	('genetic change', 'Var', (4, 18))	('trastuzumab', 'Chemical', 'MESH:D000068878', (85, 96))	('implied', 'Reg', (40, 47))
68737	32547059	HER2 amplification could act as a major driver mutation and has been confirmed as an important treatment target in breast and gastric cancers.	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('amplification', 'Var', (5, 18))	('gastric cancers', 'Disease', 'MESH:D013274', (126, 141))	('breast', 'Disease', (115, 121))	('gastric cancers', 'Disease', (126, 141))	('gastric cancers', 'Phenotype', 'HP:0012126', (126, 141))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
68738	32547059	Recent studies have found that the rate of HER2 amplification in bladder cancer follows only that in breast and gastric cancers.	('bladder cancer', 'Disease', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('gastric cancers', 'Disease', (112, 127))	('gastric cancers', 'Disease', 'MESH:D013274', (112, 127))	('HER2', 'Gene', (43, 47))	('gastric cancers', 'Phenotype', 'HP:0012126', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('HER2', 'Gene', '2064', (43, 47))	('bladder cancer', 'Phenotype', 'HP:0009725', (65, 79))	('bladder cancer', 'Disease', 'MESH:D001749', (65, 79))	('breast', 'Disease', (101, 107))	('amplification', 'Var', (48, 61))
68747	32547059	Here, we present a patient with metastatic bladder adenocarcinoma harboring HER2 amplification who achieved a partial response (PR) after late-line treatment with trastuzumab and albumin-bound paclitaxel under the guidance of NGS.	('bladder adenocarcinoma', 'Disease', (43, 65))	('HER2', 'Gene', (76, 80))	('patient', 'Species', '9606', (19, 26))	('HER2', 'Gene', '2064', (76, 80))	('bladder adenocarcinoma', 'Disease', 'MESH:D001749', (43, 65))	('albumin', 'Gene', (179, 186))	('albumin', 'Gene', '213', (179, 186))	('trastuzumab', 'Chemical', 'MESH:D000068878', (163, 174))	('amplification', 'Var', (81, 94))	('paclitaxel', 'Chemical', 'MESH:D017239', (193, 203))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (43, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
68749	32547059	The pathological diagnosis was bladder adenocarcinoma (Figure 1A), with immunohistochemistry (IHC) showing CK7 (+), CK20 (+), CDX2 (+), GATA-3 (+-), LI-cad (+), PSA (-), P63 (-), P53 (+), HER2 (3+), and the Ki-67 proliferation index was 80% (Figure 1C).	('P63', 'Gene', '8626', (170, 173))	('P63', 'Gene', (170, 173))	('CK7', 'Gene', '3855', (107, 110))	('HER2', 'Gene', '2064', (188, 192))	('P53', 'Gene', (179, 182))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (31, 53))	('bladder adenocarcinoma', 'Disease', (31, 53))	('GATA-3', 'Gene', '2625', (136, 142))	('CDX2', 'Gene', '1045', (126, 130))	('LI-cad', 'Var', (149, 155))	('CK20', 'Gene', (116, 120))	('bladder adenocarcinoma', 'Disease', 'MESH:D001749', (31, 53))	('HER2', 'Gene', (188, 192))	('CDX2', 'Gene', (126, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('P53', 'Gene', '7157', (179, 182))	('GATA-3', 'Gene', (136, 142))	('CK20', 'Gene', '54474', (116, 120))	('CK7', 'Gene', (107, 110))
68757	32547059	To determine potential treatment opportunities, NGS of the primary bladder tumor was conducted on March 23, 2016, and the results showed that the HER2 gene was amplified approximately 7 times, with an S310F mutant abundance of 90% (Table 1).	('HER2', 'Gene', '2064', (146, 150))	('S310F mutant', 'Var', (201, 213))	('bladder tumor', 'Disease', 'MESH:D001749', (67, 80))	('S310F', 'Mutation', 'rs1057519816', (201, 206))	('bladder tumor', 'Phenotype', 'HP:0009725', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('bladder tumor', 'Disease', (67, 80))	('HER2', 'Gene', (146, 150))
68768	32547059	The results showed no amplification of HER2, and the S310F mutant abundance was reduced to 27.9% (Table 1).	('S310F', 'Mutation', 'rs1057519816', (53, 58))	('HER2', 'Gene', '2064', (39, 43))	('S310F', 'Var', (53, 58))	('HER2', 'Gene', (39, 43))
68771	32547059	The patient was found to harbor HER2 amplification and the S310F mutation by NGS of the primary bladder tumor.	('HER2', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('bladder tumor', 'Phenotype', 'HP:0009725', (96, 109))	('HER2', 'Gene', '2064', (32, 36))	('S310F', 'Var', (59, 64))	('patient', 'Species', '9606', (4, 11))	('bladder tumor', 'Disease', (96, 109))	('S310F', 'Mutation', 'rs1057519816', (59, 64))	('bladder tumor', 'Disease', 'MESH:D001749', (96, 109))
68773	32547059	The patient responded very well to trastuzumab-based treatment, with a PFS period of 6 months, suggesting that trastuzumab-based therapy may be a potential treatment option for bladder adenocarcinoma patients harboring HER2 amplification.	('patients', 'Species', '9606', (200, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('bladder adenocarcinoma', 'Disease', 'MESH:D001749', (177, 199))	('patient', 'Species', '9606', (4, 11))	('trastuzumab', 'Chemical', 'MESH:D000068878', (35, 46))	('trastuzumab', 'Chemical', 'MESH:D000068878', (111, 122))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (177, 199))	('HER2', 'Gene', (219, 223))	('amplification', 'Var', (224, 237))	('bladder adenocarcinoma', 'Disease', (177, 199))	('patient', 'Species', '9606', (200, 207))	('HER2', 'Gene', '2064', (219, 223))
68774	32547059	After tumor progression, NGS was conducted again and showed no HER2 amplification, and the S310F mutant abundance was reduced to 27.9%.	('S310F', 'Var', (91, 96))	('S310F', 'Mutation', 'rs1057519816', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('HER2', 'Gene', (63, 67))	('HER2', 'Gene', '2064', (63, 67))	('tumor', 'Disease', (6, 11))
68777	32547059	HER2 amplification leading to protein overexpression has been reported in 0-25% of bladder cancer patients heterogeneously.	('amplification', 'Var', (5, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('patients', 'Species', '9606', (98, 106))	('overexpression', 'PosReg', (38, 52))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('HER2', 'Gene', (0, 4))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('HER2', 'Gene', '2064', (0, 4))	('protein', 'Protein', (30, 37))	('bladder cancer', 'Disease', (83, 97))
68782	32547059	NGS, as a new genetic alteration detection approach, cannot only uncover various types of mutations but also comprehensively analyze the genetic changes of malignancy, which may help identify new therapeutic targets.	('malignancy', 'Disease', 'MESH:D009369', (156, 166))	('mutations', 'Var', (90, 99))	('malignancy', 'Disease', (156, 166))
68784	32547059	This trial involves patients with HER2 amplification or mutation who were treated with anti-HER2 therapies, but the final results are still pending.	('amplification', 'Var', (39, 52))	('HER2', 'Gene', '2064', (92, 96))	('HER2', 'Gene', (92, 96))	('patients', 'Species', '9606', (20, 28))	('HER2', 'Gene', (34, 38))	('mutation', 'Var', (56, 64))	('HER2', 'Gene', '2064', (34, 38))
68793	32547059	In another phase II trial, afatinib demonstrated significant activity in patients with platinum-refractory urothelial carcinoma with HER2 or ERBB3 alterations.	('platinum', 'Chemical', 'MESH:D010984', (87, 95))	('afatinib', 'Chemical', 'MESH:D000077716', (27, 35))	('HER2', 'Gene', (133, 137))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (107, 127))	('ERBB3', 'Gene', '2065', (141, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('HER2', 'Gene', '2064', (133, 137))	('ERBB3', 'Gene', (141, 146))	('activity', 'MPA', (61, 69))	('patients', 'Species', '9606', (73, 81))	('urothelial carcinoma', 'Disease', (107, 127))	('alterations', 'Var', (147, 158))
68802	32547059	NGS of the primary tumor showed that HER2 was amplified approximately 7 times, with an S310F mutant abundance of 90%.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('HER2', 'Gene', (37, 41))	('HER2', 'Gene', '2064', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('S310F', 'Var', (87, 92))	('tumor', 'Disease', (19, 24))	('S310F', 'Mutation', 'rs1057519816', (87, 92))
68803	32547059	Both HER2 amplification and S310F mutations are believed to be associated with the effectiveness of anti-HER2 treatment.	('HER2', 'Gene', (105, 109))	('HER2', 'Gene', (5, 9))	('HER2', 'Gene', '2064', (105, 109))	('associated', 'Reg', (63, 73))	('HER2', 'Gene', '2064', (5, 9))	('S310F', 'Var', (28, 33))	('S310F', 'Mutation', 'rs1057519816', (28, 33))
68810	32547059	After tumor progression, the second NGS analysis showed no HER2 amplification, and the abundance of the S310F mutation was reduced to 27.9%.	('amplification', 'MPA', (64, 77))	('S310F', 'Mutation', 'rs1057519816', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('HER2', 'Gene', (59, 63))	('S310F', 'Var', (104, 109))	('HER2', 'Gene', '2064', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
68812	32547059	The genetic change in the HER2 pathway implied the value of anti-HER2 treatment.	('HER2', 'Gene', '2064', (65, 69))	('HER2', 'Gene', (65, 69))	('HER2', 'Gene', (26, 30))	('HER2', 'Gene', '2064', (26, 30))	('genetic change', 'Var', (4, 18))
68815	32547059	In the present case, gene correlation analysis suggested that the TP53 mutation was the central node of mutant genes in the two NGS analyses (Figure 2A and B).	('mutation', 'Var', (71, 79))	('TP53', 'Gene', (66, 70))	('TP53', 'Gene', '7157', (66, 70))
68817	32547059	However, the relationship between other mutant genes and HER2 decreased after treatment (Figure 2B).	('decreased', 'NegReg', (62, 71))	('HER2', 'Gene', (57, 61))	('HER2', 'Gene', '2064', (57, 61))	('mutant', 'Var', (40, 46))	('relationship', 'Interaction', (13, 25))
68822	32547059	Although this patient's primary tumor specimen had a genetic alteration in HER2, the initial treatment was a conventional treatment plan following the guidelines.	('genetic alteration', 'Var', (53, 71))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('HER2', 'Gene', (75, 79))	('patient', 'Species', '9606', (14, 21))	('HER2', 'Gene', '2064', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
68828	32547059	Based on this finding, trastuzumab-based therapy might be considered an optimal treatment for bladder adenocarcinoma patients harboring HER2 amplification.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('amplification', 'Var', (141, 154))	('trastuzumab', 'Chemical', 'MESH:D000068878', (23, 34))	('bladder adenocarcinoma', 'Disease', 'MESH:D001749', (94, 116))	('HER2', 'Gene', (136, 140))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (94, 116))	('bladder adenocarcinoma', 'Disease', (94, 116))	('HER2', 'Gene', '2064', (136, 140))	('patients', 'Species', '9606', (117, 125))
68838	30856170	Moreover, we show that CA20 upregulation is positively associated with genomic instability, alteration of specific chromosomal arms and C>T mutations, and we propose novel molecular players associated with CA in cancer.	('alteration', 'Var', (92, 102))	('CA20', 'Gene', (23, 27))	('C>T mutations', 'Var', (136, 149))	('CA20', 'Chemical', '-', (23, 27))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('genomic', 'MPA', (71, 78))	('upregulation', 'PosReg', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
68839	30856170	Finally, high CA20 is associated with poor prognosis and, by integrating drug sensitivity with drug perturbation profiles in cell lines, we identify candidate compounds for selectively targeting cancer cells exhibiting transcriptomic evidence for CA.	('drug sensitivity', 'Phenotype', 'HP:0020174', (73, 89))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('CA20', 'Gene', (14, 18))	('CA20', 'Chemical', '-', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('high', 'Var', (9, 13))
68847	30856170	Supernumerary centrosomes generate multipolar mitosis and consequent genome instability, they can accelerate and promote tumourigenesis in vivo and promote cellular invasion and metastatic behaviour.	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('mitosis', 'biological_process', 'GO:0000278', ('46', '53'))	('promote', 'PosReg', (113, 120))	('metastatic behaviour', 'CPA', (178, 198))	('multipolar mitosis', 'Disease', 'None', (35, 53))	('cellular invasion', 'CPA', (156, 173))	('behaviour', 'biological_process', 'GO:0007610', ('189', '198'))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('multipolar mitosis', 'Disease', (35, 53))	('tumour', 'Disease', (121, 127))	('promote', 'PosReg', (148, 155))	('accelerate', 'PosReg', (98, 108))	('genome instability', 'CPA', (69, 87))	('Supernumerary', 'Var', (0, 13))
68855	30856170	Finally, we show that high CA20 is associated with poor clinical outcome in different cancer types, having identified candidate compounds for selectively targeting cancer cells exhibiting transcriptomic evidence for this hallmark of cancer.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('high', 'Var', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CA20', 'Gene', (27, 31))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('CA20', 'Chemical', '-', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
68873	30856170	The difference between ductal and lobular subtypes is consistent in non-triple negative breast tumours (p-value < 0.0001, Wilcoxon rank-sum test; S2d Fig), as well as in samples from tumour stages II and III (p-value < 0.0001 and < 0.01, respectively, Wilcoxon rank-sum test; S2e Fig).	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('breast tumours', 'Disease', 'MESH:D001943', (88, 102))	('tumour', 'Disease', (183, 189))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('tumour', 'Disease', (95, 101))	('breast tumour', 'Phenotype', 'HP:0100013', (88, 101))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('non-triple negative', 'Var', (68, 87))	('breast tumours', 'Disease', (88, 102))
68882	30856170	CA20 varies across integrative clusters (p-value < 0.0001, Fligner-Killeen test) and is particularly enriched in cluster 10 (FDR < 0.0001, Wilcoxon rank-sum test, for comparisons with each of all the other clusters; S2h Fig), characterized by high proportion of basal-like tumours, high genomic instability, high rate of TP53 mutations, chromosome arm 5q deletions and very poor prognosis in the short term.	('chromosome', 'cellular_component', 'GO:0005694', ('337', '347'))	('genomic instability', 'MPA', (287, 306))	('basal-like tumours', 'Disease', (262, 280))	('basal-like tumours', 'Phenotype', 'HP:0002671', (262, 280))	('tumours', 'Phenotype', 'HP:0002664', (273, 280))	('mutations', 'Var', (326, 335))	('tumour', 'Phenotype', 'HP:0002664', (273, 279))	('TP53', 'Gene', '7157', (321, 325))	('basal-like tumours', 'Disease', 'MESH:D002280', (262, 280))	('CA20', 'Chemical', '-', (0, 4))	('chromosome', 'Var', (337, 347))	('TP53', 'Gene', (321, 325))
68887	30856170	CA and consequent multipolar mitoses have been associated with aneuploidy, genomic instability and tumourigenesis for more than a century.	('aneuploidy', 'Disease', (63, 73))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('genomic instability', 'CPA', (75, 94))	('aneuploidy', 'Disease', 'MESH:D000782', (63, 73))	('associated', 'Reg', (47, 57))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('multipolar mitoses', 'Var', (18, 36))
68890	30856170	Given the known association between loss of p53 and CA and the recent observation that p53 null cells tend to have an enrichment of chromosome losses over gains, we tested the hypothesis that the observed association between CA20 and chromosomal deletions could be linked to TP53 mutations.	('TP53', 'Gene', '7157', (275, 279))	('gains', 'PosReg', (155, 160))	('TP53', 'Gene', (275, 279))	('CA20', 'Chemical', '-', (225, 229))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('loss', 'NegReg', (36, 40))	('mutations', 'Var', (280, 289))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('losses', 'NegReg', (143, 149))	('CA20', 'Var', (225, 229))	('chromosome', 'cellular_component', 'GO:0005694', ('132', '142'))
68891	30856170	However, the increase in the proportion of deletions per sample from low to high CA20 samples is consistent within both TP53 wild-type and mutated samples (p-value < 0.0001 and < 0.05, respectively, Wilcoxon rank-sum test; S4d and S4e Fig), showing it is independent of TP53 mutations (two-way ANOVA p-value for interaction = 0.6; S4d Fig).	('deletions', 'Var', (43, 52))	('TP53', 'Gene', '7157', (270, 274))	('CA20', 'Chemical', '-', (81, 85))	('TP53', 'Gene', (270, 274))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
68892	30856170	Investigating the hypothesis that CA20-associated aneuploidy levels could vary between chromosomes, we identified 20 chromosome arms whose deletion (10 arms) or amplification (10 arms) was enriched in tumour samples with higher CA20 (linear regression, FDR < 0.05; Fig 3c and S2 and S5 Tables).	('CA20', 'Gene', (228, 232))	('tumour', 'Disease', (201, 207))	('aneuploidy', 'Disease', 'MESH:D000782', (50, 60))	('deletion', 'Var', (139, 147))	('amplification', 'MPA', (161, 174))	('chromosome', 'cellular_component', 'GO:0005694', ('117', '127'))	('CA20', 'Chemical', '-', (228, 232))	('aneuploidy', 'Disease', (50, 60))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('CA20', 'Chemical', '-', (34, 38))	('tumour', 'Disease', 'MESH:D009369', (201, 207))	('higher', 'PosReg', (221, 227))
68893	30856170	Interestingly, 5q deletion was previously associated with CA20-high basal-like breast tumours and METABRIC integrative cluster 10 (Fig 2c and 2g and S2h Fig).	('CA20-high', 'Disease', (58, 67))	('5q deletion', 'Var', (15, 26))	('breast tumour', 'Phenotype', 'HP:0100013', (79, 92))	('associated', 'Reg', (42, 52))	('breast tumours', 'Disease', (79, 93))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('breast tumours', 'Disease', 'MESH:D001943', (79, 93))	('CA20', 'Chemical', '-', (58, 62))
68894	30856170	The association between CA20 and 5q deletion remains when removing the breast cancer cohort (linear regression p-value < 2.2e-16; S5 Fig and S2 Table).	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('CA20', 'Var', (24, 28))	('CA20', 'Chemical', '-', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
68898	30856170	In addition to tumour aneuploidy, CA20 is positively correlated with mutation burden, number of somatic Copy Number Alterations (CNA) and number of clones per tumour (Spearman's correlation coefficient, r = 0.48, 0.47 and 0.43, respectively, p-value < 2.2e-16 for all; Fig 3d-3f).	('tumour', 'Disease', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour aneuploidy', 'Disease', 'MESH:D000782', (15, 32))	('tumour', 'Disease', (15, 21))	('mutation', 'Var', (69, 77))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('CA20', 'Chemical', '-', (34, 38))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumour aneuploidy', 'Disease', (15, 32))
68899	30856170	We found that the correlation with mutation burden holds for different types of mutations (silent, missense, splice site and nonsense), as well as for mutations shown to be pathogenic (data from ClinVar https://www.ncbi.nlm.nih.gov/clinvar/) in all diseases and particularly in cancer (S8 Fig).	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('nonsense', 'Var', (125, 133))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('mis', 'Gene', '268', (99, 102))	('cancer', 'Disease', (278, 284))	('mis', 'Gene', (99, 102))
68901	30856170	We identified independent positive associations between CA20 and all genomic instability features, with stronger association for CNAs (linear regression p-values = 1.3e-5, 7.2e-4, 5.3e-10 and 6.4e-3 for aneuploidy, mutation burden, CNA and number for clones, respectively; Fig 3g and S2 Table).	('positive', 'PosReg', (26, 34))	('CA20', 'Chemical', '-', (56, 60))	('aneuploidy', 'Disease', 'MESH:D000782', (203, 213))	('stronger', 'PosReg', (104, 112))	('CA20', 'Gene', (56, 60))	('mutation burden', 'Var', (215, 230))	('CNAs', 'Disease', (129, 133))	('genomic instability', 'MPA', (69, 88))	('aneuploidy', 'Disease', (203, 213))
68902	30856170	These associations remain significant when proliferation rate is used as an additional covariate in the regression (p-values = 2.3e-5, 7e-4, 2.4e-9 and 0.03 for aneuploidy, mutation burden, CNA and number for clones, respectively; S2 Table).	('CNA', 'CPA', (190, 193))	('mutation burden', 'Var', (173, 188))	('aneuploidy', 'Disease', (161, 171))	('aneuploidy', 'Disease', 'MESH:D000782', (161, 171))
68903	30856170	We performed similar analyses per TCGA cohort and identified a group of cancer types where CA20 is mostly associated with CNA and aneuploidy (prostate adenocarcinoma, glioblastoma multiforme, bladder urothelial carcinoma, and brain low-grade glioma; Fig 3g and S9 Fig; S2 Table).	('bladder urothelial carcinoma', 'Disease', (192, 220))	('CA20', 'Var', (91, 95))	('associated', 'Reg', (106, 116))	('glioblastoma multiforme', 'Disease', (167, 190))	('CNA', 'Disease', (122, 125))	('glioma', 'Disease', (242, 248))	('CA20', 'Chemical', '-', (91, 95))	('aneuploidy', 'Disease', (130, 140))	('glioma', 'Disease', 'MESH:D005910', (242, 248))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (192, 220))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (167, 190))	('cancer', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('prostate adenocarcinoma', 'Disease', (142, 165))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('aneuploidy', 'Disease', 'MESH:D000782', (130, 140))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (142, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('glioblastoma', 'Phenotype', 'HP:0012174', (167, 179))
68905	30856170	Point mutations are one of the most common types of mutational events that impact the stability of a cancer genome.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('impact', 'Reg', (75, 81))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Point mutations', 'Var', (0, 15))
68906	30856170	We examined the pan-cancer association between CA20 and somatic mutations in 14,589 genes and found 752 whose mutations are associated with CA20 (FDR < 0.05; Fig 4a and S2 and S7 Tables).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (110, 119))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('associated', 'Reg', (124, 134))	('CA20', 'Chemical', '-', (47, 51))	('CA20', 'Chemical', '-', (140, 144))	('cancer', 'Disease', (20, 26))	('CA20', 'Disease', (140, 144))
68911	30856170	Given its tumour suppressor role in cancer and the fact that its mutations mostly induce loss of function, this result suggests loss of E-cadherin is associated with lower CA in human tumours, which is contrary to what have been reported in epithelial cancer cells.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cadherin', 'molecular_function', 'GO:0008014', ('138', '146'))	('human', 'Species', '9606', (178, 183))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumours', 'Disease', (184, 191))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('epithelial cancer', 'Phenotype', 'HP:0031492', (241, 258))	('tumour', 'Disease', (184, 190))	('tumours', 'Phenotype', 'HP:0002664', (184, 191))	('loss of function', 'NegReg', (89, 105))	('loss', 'NegReg', (128, 132))	('tumours', 'Disease', 'MESH:D009369', (184, 191))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', (252, 258))	('E-cadherin', 'Gene', (136, 146))	('E-cadherin', 'Gene', '999', (136, 146))	('lower', 'NegReg', (166, 171))	('tumour', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumour', 'Disease', (10, 16))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('mutations', 'Var', (65, 74))
68912	30856170	GSEA on genes whose mutations are associated with CA20 found that they are enriched in cancer-associated pathways and Wnt/beta-catenin signalling (S10c-S10f Fig).	('cancer', 'Disease', (87, 93))	('GSEA', 'Chemical', '-', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('CA20', 'Chemical', '-', (50, 54))	('beta-catenin', 'Gene', '1499', (122, 134))	('enriched', 'Reg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('signalling', 'biological_process', 'GO:0023052', ('135', '145'))	('beta-catenin', 'Gene', (122, 134))	('CA20', 'Gene', (50, 54))	('mutations', 'Var', (20, 29))
68914	30856170	Within the tested 33 genes with at least 10 mutated samples, we found three (TP53, PIK3CA and EGFR) whose driver mutations are associated with CA20 (FDR < 0.05; S10b Fig and S2 and S8 Tables), TP53 being again the strongest association.	('CA20', 'Disease', (143, 147))	('EGFR', 'molecular_function', 'GO:0005006', ('94', '98'))	('associated', 'Reg', (127, 137))	('EGFR', 'Gene', '1956', (94, 98))	('TP53', 'Gene', '7157', (193, 197))	('CA20', 'Chemical', '-', (143, 147))	('EGFR', 'Gene', (94, 98))	('mutations', 'Var', (113, 122))	('TP53', 'Gene', (193, 197))	('PIK3CA', 'Gene', (83, 89))	('PIK3CA', 'Gene', '5290', (83, 89))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
68917	30856170	We therefore retrieved the contribution of the 30 published mutational signatures for each TCGA tumour sample from mSignatureDB and uncovered three of them positively associated with CA20: signature 3, associated with BRCA1/2 mutations; signature 13, attributed to APOBEC activity; and signature 4, characteristic of smoking's mutational pattern (FDR < 0.05; S11 Fig).	('BRCA1/2', 'Gene', '672;675', (218, 225))	('positively', 'PosReg', (156, 166))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('BRCA1/2', 'Gene', (218, 225))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('BRCA', 'Phenotype', 'HP:0003002', (218, 222))	('mutations', 'Var', (226, 235))	('associated', 'Reg', (167, 177))	('CA20', 'Chemical', '-', (183, 187))	('APOBEC', 'cellular_component', 'GO:0030895', ('265', '271'))	('tumour', 'Disease', (96, 102))
68919	30856170	Signature 1, linked with ageing and characterised by C>T substitutions (S12a Fig), and its "reverse" (T>C substitution bias) Signature 12, found mainly in liver cancer (S12b Fig), are respectively positively and negatively associated (FDR < 0.05) with CA20 (Fig 4c), independently of other types of genomic instability and even when proliferation rate is added as a variable (FDR = 0.051 for both signatures).	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('liver cancer', 'Phenotype', 'HP:0002896', (155, 167))	('ageing', 'biological_process', 'GO:0007568', ('25', '31'))	('associated', 'Reg', (223, 233))	('liver cancer', 'Disease', 'MESH:D006528', (155, 167))	('CA20', 'Chemical', '-', (252, 256))	('C>T substitutions', 'Var', (53, 70))	('liver cancer', 'Disease', (155, 167))	('CA20', 'Disease', (252, 256))	('negatively', 'NegReg', (212, 222))
68920	30856170	To evaluate the putative causality of CA20-associated mutations (Fig 4a), we interrogated the Connectivity Map (CMap) database of signatures about the impact of each of the 3,799 gene knock-downs on the CA20 gene set in human cancer cell lines.	('human', 'Species', '9606', (220, 225))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('CA20', 'Chemical', '-', (38, 42))	('CA20', 'Chemical', '-', (203, 207))	('knock-downs', 'Var', (184, 195))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
68922	30856170	We thereby identified 6 genes with a putative causal effect on CA20 scores ( connectivity score  > 80; Fig 4d): P2RY12, RB1, ITSN1 and MYCBP2 are putative inhibitors of CA (their knock-down up-regulate CA20 genes), whereas ABCC5 and COPA are putative promoters of CA (their knock-down down-regulate CA20 genes).	('ITSN1', 'Gene', (125, 130))	('P2RY12', 'Gene', '64805', (112, 118))	('RB1', 'Gene', '5925', (120, 123))	('knock-down', 'Var', (179, 189))	('CA20 genes', 'Gene', (299, 309))	('COPA', 'Gene', (233, 237))	('ABCC5', 'Gene', '10057', (223, 228))	('P2RY12', 'Gene', (112, 118))	('CA20', 'Chemical', '-', (63, 67))	('ABCC5', 'Gene', (223, 228))	('knock-down', 'Var', (274, 284))	('MYCBP2', 'Gene', (135, 141))	('CA20 genes', 'Gene', (202, 212))	('up-regulate', 'PosReg', (190, 201))	('CA20', 'Chemical', '-', (299, 303))	('ITSN1', 'Gene', '6453', (125, 130))	('MYCBP2', 'Gene', '23077', (135, 141))	('COPA', 'Gene', '1314', (233, 237))	('CA20', 'Chemical', '-', (202, 206))	('RB1', 'Gene', (120, 123))
68924	30856170	Genes from a manually curated list of centriole duplication factors (93 genes, including only 10 from the CA20 signature; S10 Table) are enriched in negative CMap knock-down scores (GSEA p-value < 0.001; Fig 4e), suggesting they are indeed needed for cells to express CA-associated genes.	('centriole', 'cellular_component', 'GO:0005814', ('38', '47'))	('CA20', 'Chemical', '-', (106, 110))	('knock-down', 'Var', (163, 173))	('negative', 'NegReg', (149, 157))	('CMap', 'Gene', (158, 162))	('centriole duplication', 'biological_process', 'GO:0007099', ('38', '59'))	('GSEA', 'Chemical', '-', (182, 186))
68927	30856170	We therefore tested CA20's association with overall patient's survival across 31 TCGA cancer types with more than 40 samples each, finding high CA20 significantly associated with worse prognosis in 8 different cancer types (FDR < 0.05, log-rank test; Fig 5a and S11 Table).	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CA20', 'Gene', (144, 148))	('associated', 'Reg', (163, 173))	('CA20', 'Chemical', '-', (20, 24))	('patient', 'Species', '9606', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('CA20', 'Chemical', '-', (144, 148))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (210, 216))	('high', 'Var', (139, 143))	('cancer', 'Disease', (86, 92))
68934	30856170	CA20 is associated with lower stromal (Spearman's correlation coefficient, r = -0.52, p-value < 2.2e-16; Fig 5d) and immune (Spearman's correlation coefficient, r = -0.34, p-value < 2.2e-16; S13c Fig) cell infiltration in TCGA.	('stromal', 'CPA', (30, 37))	('CA20', 'Var', (0, 4))	('CA20', 'Chemical', '-', (0, 4))	('lower', 'NegReg', (24, 29))
68936	30856170	We have also performed similar analyses for each of the 5 TCGA cohorts with information for all covariates and found that CA20 is significantly associated (FDR < 0.05) with lower stromal infiltration in head and neck and lung cancers (Fig 5e), with lower immune infiltration in glioblastoma, and with higher immune infiltration in head and neck cancer (S13e Fig), all independently of genomic instability (S2 Table).	('neck', 'cellular_component', 'GO:0044326', ('340', '344'))	('immune infiltration', 'MPA', (255, 274))	('CA20', 'Var', (122, 126))	('CA20', 'Chemical', '-', (122, 126))	('head and neck cancer', 'Phenotype', 'HP:0012288', (331, 351))	('lower', 'NegReg', (249, 254))	('neck cancer', 'Disease', 'MESH:D006258', (340, 351))	('neck cancer', 'Disease', (340, 351))	('stromal infiltration', 'CPA', (179, 199))	('lung cancers', 'Disease', 'MESH:D008175', (221, 233))	('immune infiltration', 'MPA', (308, 327))	('infiltration in head and neck', 'Phenotype', 'HP:0012288', (187, 216))	('lung cancers', 'Disease', (221, 233))	('glioblastoma', 'Disease', 'MESH:D005909', (278, 290))	('infiltration in head and neck', 'Phenotype', 'HP:0012288', (315, 344))	('lung cancers', 'Phenotype', 'HP:0100526', (221, 233))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('neck', 'cellular_component', 'GO:0044326', ('212', '216'))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('glioblastoma', 'Disease', (278, 290))	('lower', 'NegReg', (173, 178))	('glioblastoma', 'Phenotype', 'HP:0012174', (278, 290))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
68940	30856170	higher CA20 was associated with lower drug AUC and, therefore, higher drug activity.	('drug activity', 'MPA', (70, 83))	('drug AUC', 'MPA', (38, 46))	('CA20', 'Var', (7, 11))	('CA20', 'Chemical', '-', (7, 11))	('higher', 'PosReg', (63, 69))	('lower', 'NegReg', (32, 37))
68944	30856170	Interestingly, BI-2536 has been in clinical trials for several solid and liquid tumours (https://clinicaltrials.gov/ct2/results?cond=&term=bi+2536&cntry=&state=&city=&dist) and is an inhibitor of polo-like kinase 1 (PLK1), whose inhibition has already been associated with CA suppression.	('BI-2536', 'Chemical', 'MESH:C518477', (15, 22))	('tumours', 'Disease', 'MESH:D009369', (80, 87))	('PLK1', 'Gene', '5347', (216, 220))	('&term=bi+2536', 'Var', (133, 146))	('tumours', 'Disease', (80, 87))	('polo-like kinase 1', 'Gene', '5347', (196, 214))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('polo-like kinase 1', 'Gene', (196, 214))	('PLK1', 'Gene', (216, 220))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('has already', 'Disease', (240, 251))
68956	30856170	Despite the lack of a full direct experimental validation of CA20 as a surrogate of CA levels, our observations are very consistent with known CA's features, namely CA20's upregulation in cancer and in basal-like breast tumours, and its association with the knock-down of centriole duplication factors, genomic instability, loss of p53 and pRB, hypoxia and worse patient's prognosis.	('hypoxia', 'Disease', (345, 352))	('tumour', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('pRB', 'Gene', '5925', (340, 343))	('hypoxia', 'Disease', 'MESH:D000860', (345, 352))	('centriole duplication', 'biological_process', 'GO:0007099', ('272', '293'))	('knock-down', 'Var', (258, 268))	('pRB', 'Gene', (340, 343))	('breast tumours', 'Disease', (213, 227))	('loss', 'Var', (324, 328))	('p53', 'Gene', '7157', (332, 335))	('patient', 'Species', '9606', (363, 370))	('CA20', 'Gene', (165, 169))	('centriole', 'cellular_component', 'GO:0005814', ('272', '281'))	('CA20', 'Chemical', '-', (165, 169))	('cancer', 'Disease', (188, 194))	('p53', 'Gene', (332, 335))	('centriole duplication factors', 'Protein', (272, 301))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('upregulation', 'PosReg', (172, 184))	('breast tumour', 'Phenotype', 'HP:0100013', (213, 226))	('genomic instability', 'CPA', (303, 322))	('tumours', 'Phenotype', 'HP:0002664', (220, 227))	('CA20', 'Chemical', '-', (61, 65))	('breast tumours', 'Disease', 'MESH:D001943', (213, 227))
68965	30856170	Our data show that centrosome amplification is associated with breast cancer clinical features and endorses the potential of using a gene-expression-based signature for patient stratification.	('gene-expression', 'biological_process', 'GO:0010467', ('133', '148'))	('centrosome', 'cellular_component', 'GO:0005813', ('19', '29'))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('patient', 'Species', '9606', (169, 176))	('centrosome amplification', 'Var', (19, 43))	('associated', 'Reg', (47, 57))
68967	30856170	In particular, CA20 is more strongly associated with chromosomal deletions than amplifications, independently of TP53 mutations.	('CA20', 'Var', (15, 19))	('CA20', 'Chemical', '-', (15, 19))	('TP53', 'Gene', '7157', (113, 117))	('associated', 'Reg', (37, 47))	('TP53', 'Gene', (113, 117))	('chromosomal', 'Disease', (53, 64))
68968	30856170	In fact, through a more detailed analysis, we found an association with alterations in specific chromosomal arms, that may be due to the localisation of genes encoding for regulators of CA20 genes therein and/or to those arms' higher susceptibility to the genomic instability triggered by centrosome abnormalities.	('CA20', 'Chemical', '-', (186, 190))	('alterations', 'Var', (72, 83))	('centrosome abnormalities', 'Disease', (289, 313))	('localisation', 'biological_process', 'GO:0051179', ('137', '149'))	('centrosome', 'cellular_component', 'GO:0005813', ('289', '299'))	('centrosome abnormalities', 'Disease', 'MESH:D000014', (289, 313))	('genomic instability', 'CPA', (256, 275))	('association', 'Reg', (55, 66))
68969	30856170	The latter is supported by recent work showing that human chromosome mis-segregation is not random and can be biased by inherent properties of individual chromosomes, and also by our observation that normal samples whose matched tumours lost 5q or 16p have higher CA20 predictive of those deletions (S6 Fig).	('mis', 'Gene', '268', (69, 72))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))	('tumours', 'Disease', 'MESH:D009369', (229, 236))	('mis', 'Gene', (69, 72))	('tumours', 'Disease', (229, 236))	('human', 'Species', '9606', (52, 57))	('tumours', 'Phenotype', 'HP:0002664', (229, 236))	('lost', 'NegReg', (237, 241))	('higher', 'PosReg', (257, 263))	('CA20', 'Chemical', '-', (264, 268))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))	('deletions', 'Var', (289, 298))	('CA20', 'MPA', (264, 268))
68971	30856170	Genes whose mutations are associated with CA20 are enriched in cancer driver genes, and particularly in Wnt/beta-catenin signalling.	('beta-catenin', 'Gene', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (12, 21))	('beta-catenin', 'Gene', '1499', (108, 120))	('signalling', 'biological_process', 'GO:0023052', ('121', '131'))	('CA20', 'Gene', (42, 46))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('CA20', 'Chemical', '-', (42, 46))	('associated', 'Reg', (26, 36))	('cancer', 'Disease', (63, 69))
68972	30856170	Wnt/beta-catenin signalling components interact with the centrosome and a previous study has demonstrated that mutant beta-catenin induces centrosome aberrations in normal epithelial cells and is required for CA in cancer cells.	('centrosome aberrations', 'MPA', (139, 161))	('centrosome', 'cellular_component', 'GO:0005813', ('57', '67'))	('beta-catenin', 'Gene', '1499', (4, 16))	('cancer', 'Disease', (215, 221))	('mutant', 'Var', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('centrosome', 'cellular_component', 'GO:0005813', ('139', '149'))	('beta-catenin', 'Gene', (118, 130))	('signalling', 'biological_process', 'GO:0023052', ('17', '27'))	('beta-catenin', 'Gene', '1499', (118, 130))	('induces', 'Reg', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('beta-catenin', 'Gene', (4, 16))
68973	30856170	Our results extend this previous association to human cancer samples, suggesting mutations in beta-catenin might contribute to the observed CA in cancer.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('contribute', 'Reg', (113, 123))	('human', 'Species', '9606', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('beta-catenin', 'Gene', (94, 106))	('cancer', 'Disease', (54, 60))	('beta-catenin', 'Gene', '1499', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('mutations', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
68974	30856170	Finally, we show the usefulness of a novel approach whereby we integrated information on genes whose somatic mutations are associated with CA20 in TCGA tumour samples with the impact of their knock-downs on the CA20 expression in human cancer cell lines, aiming at unveiling candidate molecular players in CA in cancer.	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('CA20 in TCGA', 'Mutation', 'rs1232261739', (139, 151))	('associated', 'Reg', (123, 133))	('CA20', 'Chemical', '-', (139, 143))	('tumour', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('CA20', 'Chemical', '-', (211, 215))	('cancer', 'Disease', (236, 242))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('cancer', 'Disease', (312, 318))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('mutations', 'Var', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('CA20', 'Gene', (139, 143))	('human', 'Species', '9606', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))
68975	30856170	Concordantly with previous work on CA, we observed that high CA20 is associated with poor patient's survival in several cancer types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('poor', 'NegReg', (85, 89))	('CA20', 'Chemical', '-', (61, 65))	('patient', 'Species', '9606', (90, 97))	('high CA20', 'Var', (56, 65))
68978	30856170	When looking at the tumour cellular composition, we found that tumours with high CA20 have lower stromal and immune cell infiltration, although the latter is not independent of tumour genomic instability and proliferation rate.	('lower', 'NegReg', (91, 96))	('tumours', 'Disease', (63, 70))	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('tumour', 'Disease', (177, 183))	('tumour genomic instability', 'Disease', 'MESH:D042822', (177, 203))	('CA20', 'Gene', (81, 85))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))	('tumour genomic instability', 'Disease', (177, 203))	('tumour', 'Disease', (20, 26))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('CA20', 'Chemical', '-', (81, 85))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('high', 'Var', (76, 80))	('tumours', 'Disease', 'MESH:D009369', (63, 70))	('tumour', 'Disease', (63, 69))
68997	30856170	The four missing genes are three (LOC149464, LOC56901 and TIMM23) for which expression levels were not available and NDRG1, excluded for being part of the CA20 gene signature.	('NDRG1', 'Gene', (117, 122))	('CA20', 'Chemical', '-', (155, 159))	('mis', 'Gene', '268', (9, 12))	('TIMM23', 'Gene', (58, 64))	('NDRG1', 'Gene', '10397', (117, 122))	('TIMM23', 'Gene', '100287932', (58, 64))	('LOC56901', 'Var', (45, 53))	('mis', 'Gene', (9, 12))	('LOC149464', 'Var', (34, 43))
69006	30856170	According to their immunoprofile, breast tumour samples were classified as luminal A (ER+, PR+, HER2- and Ki67-), luminal B (ER+, PR+, HER2 overexpressing or Ki67+), HER2 (ER-, PR-, HER2 overexpressing) or basal-like carcinomas (ER-, PR-, HER2-, basal marker+).	('carcinomas', 'Disease', 'MESH:D002277', (217, 227))	('basal-like carcinomas', 'Phenotype', 'HP:0002671', (206, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('breast tumour', 'Disease', 'MESH:D001943', (34, 47))	('Ki67+', 'Var', (158, 163))	('HER2', 'Gene', '2064', (239, 243))	('breast tumour', 'Disease', (34, 47))	('breast tumour', 'Phenotype', 'HP:0100013', (34, 47))	('HER2', 'Gene', '2064', (135, 139))	('HER2', 'Gene', '2064', (166, 170))	('HER2', 'Gene', (96, 100))	('HER2', 'Gene', '2064', (182, 186))	('carcinomas', 'Disease', (217, 227))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('HER2', 'Gene', (239, 243))	('PR', 'Gene', '5241', (130, 132))	('PR', 'Gene', '5241', (91, 93))	('PR', 'Gene', '5241', (234, 236))	('HER2', 'Gene', (135, 139))	('HER2', 'Gene', (166, 170))	('PR', 'Gene', '5241', (177, 179))	('HER2', 'Gene', '2064', (96, 100))	('HER2', 'Gene', (182, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (217, 227))
69031	28548944	Furthermore, high expression of A2bR was associated with poor prognosis of patients with BUC.	('high', 'Var', (13, 17))	('A2bR', 'Gene', '11541', (32, 36))	('patients', 'Species', '9606', (75, 83))	('A2bR', 'Gene', (32, 36))
69043	28548944	Adenosine acts its biological functions via four subtypes of adenosine receptors (ARs), A1, A2a, A2b, and A3.	('adenosine receptors', 'Protein', (61, 80))	('Adenosine', 'Chemical', 'MESH:D000241', (0, 9))	('A2a', 'Var', (92, 95))	('adenosine', 'Chemical', 'MESH:D000241', (61, 70))	('A2b', 'Var', (97, 100))
69060	28548944	To explore the impact of A2bR on BUC cells proliferation, short hairpin RNAs (shRNA 1, shRNA 2 and shRNA 3) were used to knock down A2bR expression in EJ and T24 cells.	('A2bR', 'Gene', '11541', (25, 29))	('knock down', 'Var', (121, 131))	('A2bR', 'Gene', (25, 29))	('A2bR', 'Gene', '11541', (132, 136))	('A2bR', 'Gene', (132, 136))	('EJ', 'CellLine', 'CVCL:7039', (151, 153))
69063	28548944	Similarly, colony formation capacity was reduced following A2bR knockdown (Figure 3B; P < 0.05).	('reduced', 'NegReg', (41, 48))	('A2bR', 'Gene', '11541', (59, 63))	('A2bR', 'Gene', (59, 63))	('formation', 'biological_process', 'GO:0009058', ('18', '27'))	('knockdown', 'Var', (64, 73))	('colony formation capacity', 'CPA', (11, 36))
69067	28548944	To further explore the mechanism underlying the inhibitory effect of A2bR knockdown on cell growth, we analyzed the protein expression of cyclin family and P21.	('cyclin', 'molecular_function', 'GO:0016538', ('138', '144'))	('cyclin', 'Gene', (138, 144))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('cell growth', 'biological_process', 'GO:0016049', ('87', '98'))	('A2bR', 'Gene', '11541', (69, 73))	('A2bR', 'Gene', (69, 73))	('P21', 'Gene', (156, 159))	('knockdown', 'Var', (74, 83))	('cyclin', 'Gene', '5111', (138, 144))	('P21', 'Gene', '644914', (156, 159))
69071	28548944	The results of wound healing assay showed that BUC cells with A2bR knockdown migrated into the scratching area more slowly than control cells (Figure 4A, P < 0.001).	('A2bR', 'Gene', (62, 66))	('slowly', 'NegReg', (116, 122))	('knockdown', 'Var', (67, 76))	('A2bR', 'Gene', '11541', (62, 66))	('wound healing', 'biological_process', 'GO:0042060', ('15', '28'))
69078	28548944	Together, these results indicated that A2bR knockdown inhibited the migration and invasion of BUC cells by decreasing MMP-2 and MMP-9.	('inhibited', 'NegReg', (54, 63))	('MMP-2', 'Gene', '4313', (118, 123))	('MMP-9', 'Gene', '4318', (128, 133))	('decreasing', 'NegReg', (107, 117))	('MMP-9', 'Gene', (128, 133))	('MMP-2', 'molecular_function', 'GO:0004228', ('118', '123'))	('A2bR', 'Gene', '11541', (39, 43))	('knockdown', 'Var', (44, 53))	('A2bR', 'Gene', (39, 43))	('MMP-2', 'Gene', (118, 123))	('MMP-9', 'molecular_function', 'GO:0004229', ('128', '133'))
69079	28548944	As described above, we discovered that A2bR knockdown could restrain the growth rate of BUC cells in vitro.	('A2bR', 'Gene', '11541', (39, 43))	('restrain', 'NegReg', (60, 68))	('A2bR', 'Gene', (39, 43))	('knockdown', 'Var', (44, 53))	('growth rate of BUC cells in vitro', 'CPA', (73, 106))
69082	28548944	We found the average tumor volume decreased in the group inoculated with A2bR knockdown cells (184.4+-51.3 and 171.8+-51.6, shRNA1 and shRNA2, respectively), compared with the control groups (362.8+-49.5 and 336.8+-51.4, ctrl and NC, respectively) (Figure 6C).	('A2bR', 'Gene', (73, 77))	('tumor', 'Disease', (21, 26))	('decreased', 'NegReg', (34, 43))	('knockdown', 'Var', (78, 87))	('A2bR', 'Gene', '11541', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
69084	28548944	These data showed that A2bR knockdown could decrease the ability of BUC cells to form tumor in nude mice.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('decrease', 'NegReg', (44, 52))	('tumor', 'Disease', (86, 91))	('nude mice', 'Species', '10090', (95, 104))	('knockdown', 'Var', (28, 37))	('A2bR', 'Gene', '11541', (23, 27))	('A2bR', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
69087	28548944	These results suggested that A2bR knockdown inhibited malignancy of BUC cells, at least partly, through the MAPK pathway.	('inhibited', 'NegReg', (44, 53))	('MAPK', 'Gene', (108, 112))	('MAPK', 'Gene', '5595;5594;5595', (108, 112))	('A2bR', 'Gene', '11541', (29, 33))	('A2bR', 'Gene', (29, 33))	('knockdown', 'Var', (34, 43))	('malignancy', 'Disease', 'MESH:D009369', (54, 64))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('malignancy', 'Disease', (54, 64))
69092	28548944	In addition, high A2bR expression in triple negative breast cancer was significantly associated with poor prognosis.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('A2bR', 'Gene', '11541', (18, 22))	('A2bR', 'Gene', (18, 22))	('high', 'Var', (13, 17))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))	('expression', 'MPA', (23, 33))
69093	28548944	Using the Oncomine database (https://www.oncomine.org), similar results were also observed in other human malignancies, such as colorectal, renal and prostate cancers, in which patients with high expression of A2bR always had a worse overall survival.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('prostate cancers', 'Phenotype', 'HP:0012125', (150, 166))	('A2bR', 'Gene', '11541', (210, 214))	('A2bR', 'Gene', (210, 214))	('patients', 'Species', '9606', (177, 185))	('colorectal, renal and prostate cancers', 'Disease', 'MESH:D015179', (128, 166))	('human', 'Species', '9606', (100, 105))	('malignancies', 'Disease', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('oncomine', 'Chemical', '-', (41, 49))	('Oncomine', 'Chemical', '-', (10, 18))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('prostate cancer', 'Phenotype', 'HP:0012125', (150, 165))	('high expression', 'Var', (191, 206))
69100	28548944	Using the A2bR antagonist, MRS1754 or PBS603 or ATL801, the growth of cancer cells was inhibited in vitro and in vivo.	('A2bR', 'Gene', (10, 14))	('A2bR', 'Gene', '11541', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('MRS1754', 'Var', (27, 34))	('PBS603', 'Chemical', '-', (38, 44))	('inhibited', 'NegReg', (87, 96))	('PBS603', 'Var', (38, 44))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
69104	28548944	Further functional studies indicated that the suppression of A2bR expression by transfection with shRNA in both EJ and T24 cells led to reducing cell growth in vitro and inhibiting tumorigenicity in vivo.	('cell growth', 'CPA', (145, 156))	('tumor', 'Disease', (181, 186))	('reducing', 'NegReg', (136, 144))	('EJ', 'CellLine', 'CVCL:7039', (112, 114))	('A2bR', 'Gene', '11541', (61, 65))	('cell growth', 'biological_process', 'GO:0016049', ('145', '156'))	('A2bR', 'Gene', (61, 65))	('suppression', 'NegReg', (46, 57))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('shRNA', 'Gene', (98, 103))	('transfection', 'Var', (80, 92))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('inhibiting', 'NegReg', (170, 180))
69105	28548944	Notably, A2bR knockdown arrested human BUC cell lines at the G0/G1 phase, but was not associated with cell apoptosis (Supplementary Figure S1).	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('arrest', 'Disease', (24, 30))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('human BUC cell lines at the G0/G1 phase', 'CPA', (33, 72))	('A2bR', 'Gene', '11541', (9, 13))	('A2bR', 'Gene', (9, 13))	('human', 'Species', '9606', (33, 38))	('arrest', 'Disease', 'MESH:D006323', (24, 30))	('knockdown', 'Var', (14, 23))	('G1 phase', 'biological_process', 'GO:0051318', ('64', '72'))
69106	28548944	Moreover, to further explore the mechanism underlying the inhibitory effect of A2bR knockdown on cell cycle, the protein levels of cyclin family and P21 were examined.	('cyclin', 'Gene', (131, 137))	('P21', 'Gene', (149, 152))	('A2bR', 'Gene', '11541', (79, 83))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('A2bR', 'Gene', (79, 83))	('cyclin', 'molecular_function', 'GO:0016538', ('131', '137'))	('knockdown', 'Var', (84, 93))	('cell cycle', 'biological_process', 'GO:0007049', ('97', '107'))	('cyclin', 'Gene', '5111', (131, 137))	('P21', 'Gene', '644914', (149, 152))
69107	28548944	Our results showed that suppression of A2bR could upregulate P21 but downregulate cyclin B1, D and E1.	('P21', 'Gene', '644914', (61, 64))	('upregulate', 'PosReg', (50, 60))	('P21', 'Gene', (61, 64))	('cyclin B1', 'Gene', '891', (82, 91))	('cyclin B1', 'Gene', (82, 91))	('downregulate', 'NegReg', (69, 81))	('A2bR', 'Gene', (39, 43))	('A2bR', 'Gene', '11541', (39, 43))	('suppression', 'Var', (24, 35))	('cyclin', 'molecular_function', 'GO:0016538', ('82', '88'))
69110	28548944	Interestingly, the experimental and spontaneous metastasis could be decreased by A2bR antagonist or knockdown of A2bR in mouse models of melanoma and triple-negative breast cancer.	('decreased', 'NegReg', (68, 77))	('knockdown', 'Var', (100, 109))	('mouse', 'Species', '10090', (121, 126))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('A2bR', 'Gene', '11541', (113, 117))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('A2bR', 'Gene', (113, 117))	('breast cancer', 'Disease', (166, 179))	('melanoma', 'Disease', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('A2bR', 'Gene', '11541', (81, 85))	('A2bR', 'Gene', (81, 85))
69121	28548944	Our results showed that knocking down the expression of A2bR reduced the phosphorylation level of P38, JNK and ERK.	('phosphorylation', 'biological_process', 'GO:0016310', ('73', '88'))	('P38', 'Gene', (98, 101))	('knocking down', 'Var', (24, 37))	('ERK', 'Gene', '5594', (111, 114))	('JNK', 'molecular_function', 'GO:0004705', ('103', '106'))	('A2bR', 'Gene', '11541', (56, 60))	('JNK', 'Gene', '5599', (103, 106))	('A2bR', 'Gene', (56, 60))	('ERK', 'Gene', (111, 114))	('phosphorylation level', 'MPA', (73, 94))	('P38', 'Gene', '5594', (98, 101))	('ERK', 'molecular_function', 'GO:0004707', ('111', '114'))	('reduced', 'NegReg', (61, 68))	('JNK', 'Gene', (103, 106))
69145	28548944	The following antibodies against P38 (#8690), p-P38 (#4515), ERK (#4695), p-ERK (#4370), JNK (9252), p-JNK (#4668), MMP-2 (#13132), MMP-9 (#13667) and beta-actin (#12620) were purchased from Cell Signaling technology.	('#12620', 'Var', (163, 169))	('#4695', 'Var', (66, 71))	('JNK', 'molecular_function', 'GO:0004705', ('89', '92'))	('MMP-2', 'Gene', '4313', (116, 121))	('Signaling', 'biological_process', 'GO:0023052', ('196', '205'))	('#4515', 'Var', (53, 58))	('ERK', 'Gene', (61, 64))	('JNK', 'Gene', (103, 106))	('MMP-9', 'molecular_function', 'GO:0004229', ('132', '137'))	('ERK', 'Gene', (76, 79))	('JNK', 'Gene', '5599', (103, 106))	('MMP-9', 'Gene', '4318', (132, 137))	('P38', 'Gene', '5594', (33, 36))	('#4370', 'Var', (81, 86))	('MMP-9', 'Gene', (132, 137))	('beta-actin', 'Gene', '728378', (151, 161))	('MMP-2', 'molecular_function', 'GO:0004228', ('116', '121'))	('#8690', 'Var', (38, 43))	('MMP-2', 'Gene', (116, 121))	('JNK', 'molecular_function', 'GO:0004705', ('103', '106'))	('#4668', 'Var', (108, 113))	('P38', 'Gene', '5594', (48, 51))	('ERK', 'molecular_function', 'GO:0004707', ('61', '64'))	('P38', 'Gene', (33, 36))	('ERK', 'molecular_function', 'GO:0004707', ('76', '79'))	('#13132', 'Var', (123, 129))	('P38', 'Gene', (48, 51))	('ERK', 'Gene', '5594', (61, 64))	('JNK', 'Gene', (89, 92))	('JNK', 'Gene', '5599', (89, 92))	('beta-actin', 'Gene', (151, 161))	('#13667', 'Var', (139, 145))	('ERK', 'Gene', '5594', (76, 79))
69146	28548944	Antibodies against P21 (60214-1-Ig), cyclin D (60186-1-Ig), cyclin E1 (11554-1-AP), cyclin B1 (55004-1-AP) were obtained from Proteinch.	('cyclin', 'molecular_function', 'GO:0016538', ('37', '43'))	('55004-1-AP', 'Var', (95, 105))	('cyclin', 'molecular_function', 'GO:0016538', ('60', '66'))	('cyclin', 'molecular_function', 'GO:0016538', ('84', '90'))	('cyclin', 'Gene', '5111', (60, 66))	('cyclin', 'Gene', (84, 90))	('cyclin', 'Gene', (37, 43))	('cyclin E1', 'Gene', '898', (60, 69))	('11554-1-AP', 'Var', (71, 81))	('cyclin', 'Gene', (60, 66))	('P21', 'Gene', (19, 22))	('cyclin B1', 'Gene', '891', (84, 93))	('cyclin B1', 'Gene', (84, 93))	('cyclin E1', 'Gene', (60, 69))	('60186-1-Ig', 'Var', (47, 57))	('cyclin', 'Gene', '5111', (84, 90))	('cyclin', 'Gene', '5111', (37, 43))	('P21', 'Gene', '644914', (19, 22))
69163	28418868	GRIK2 gene knockdown by siRNAs decreased the sphere-forming ability and invasion ability, whereas GRIK2 overexpression increased the sphere-forming ability, invasion ability and tumorigenicity, indicating that GRIK2 has a role in the maintenance of CSCs/CICs.	('invasion ability', 'CPA', (157, 173))	('tumor', 'Disease', (178, 183))	('CIC', 'Gene', (254, 257))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('decreased', 'NegReg', (31, 40))	('siRNAs', 'Gene', (24, 30))	('GRIK2', 'Gene', (98, 103))	('sphere-forming ability', 'CPA', (133, 155))	('sphere-forming ability', 'CPA', (45, 67))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('invasion ability', 'CPA', (72, 88))	('GRIK2', 'Gene', (0, 5))	('CIC', 'Gene', '23152', (254, 257))	('knockdown', 'Var', (11, 20))	('increased', 'PosReg', (119, 128))
69172	28418868	Deregulation of this class of enzymes is implicated in multiple cancers.	('Deregulation', 'Var', (0, 12))	('multiple cancers', 'Disease', 'MESH:D009369', (55, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('implicated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('multiple cancers', 'Disease', (55, 71))
69175	28418868	GRIK2 is expressed in some normal organs including stomach, and a recent study revealed that GRIK2 transcription was repressed by hypermethylation of promoter region in gastric cancers, suggesting that GRIK2 might be a novel tumor suppressor gene in gastric cancers.	('gastric cancers', 'Disease', 'MESH:D013274', (250, 265))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('gastric cancers', 'Disease', (250, 265))	('gastric cancers', 'Phenotype', 'HP:0012126', (250, 265))	('transcription', 'biological_process', 'GO:0006351', ('99', '112'))	('tumor', 'Disease', (225, 230))	('gastric cancer', 'Phenotype', 'HP:0012126', (250, 264))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('gastric cancers', 'Disease', (169, 184))	('gastric cancers', 'Phenotype', 'HP:0012126', (169, 184))	('gastric cancers', 'Disease', 'MESH:D013274', (169, 184))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('GRIK2', 'Gene', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('transcription', 'MPA', (99, 112))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('225', '241'))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('hypermethylation', 'Var', (130, 146))	('tumor suppressor', 'biological_process', 'GO:0051726', ('225', '241'))
69176	28418868	Recently, polymorohism of GRIK2 TT (rs1335022) was associated with high risk of oral cancer in tobacco habitues, indicating that GRIK2 might be related to carcinogenesis.	('rs1335022', 'Var', (36, 45))	('tobacco', 'Species', '4097', (95, 102))	('polymorohism', 'Var', (10, 22))	('oral cancer', 'Disease', 'MESH:D009062', (80, 91))	('associated', 'Reg', (51, 61))	('carcinogenesis', 'Disease', 'MESH:D063646', (155, 169))	('rs1335022', 'Mutation', 'rs1335022', (36, 45))	('GRIK2', 'Gene', (26, 31))	('oral cancer', 'Disease', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('carcinogenesis', 'Disease', (155, 169))
69191	28418868	ALDH1high cells initiated the formation of tumors in all of the 6 mice, whereas ALDH1low cells initiated the formation of tumors in only 3 of the 6 mice.	('ALDH1high', 'Var', (0, 9))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('ALDH', 'molecular_function', 'GO:0004030', ('80', '84'))	('formation', 'biological_process', 'GO:0009058', ('109', '118'))	('ALDH', 'molecular_function', 'GO:0004030', ('0', '4'))	('formation', 'biological_process', 'GO:0009058', ('30', '39'))	('mice', 'Species', '10090', (66, 70))	('mice', 'Species', '10090', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
69192	28418868	Tumors derived from ALDH1high cells were significantly larger than those derived from ALDH1low cells (P < 0.05) (Figure 1E).	('larger', 'PosReg', (55, 61))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ALDH1high cells', 'Var', (20, 35))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('ALDH', 'molecular_function', 'GO:0004030', ('20', '24'))	('ALDH', 'molecular_function', 'GO:0004030', ('86', '90'))
69196	28418868	We thus analyzed the sensitivity to chemotherapy of ALDH1high cells and found that ALDH1high cells were more resistant to cisplatin than were ALDH1low cells (Figure 2B).	('ALDH1high', 'Var', (83, 92))	('resistant to cisplatin', 'MPA', (109, 131))	('ALDH', 'molecular_function', 'GO:0004030', ('52', '56'))	('ALDH', 'molecular_function', 'GO:0004030', ('142', '146'))	('ALDH', 'molecular_function', 'GO:0004030', ('83', '87'))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))
69202	28418868	A limiting dilution assay revealed that estimated CSCs/CICs frequency was significantly decreased by GRIK2 knockdown by siRNAs (Table 1).	('knockdown', 'Var', (107, 116))	('CIC', 'Gene', (55, 58))	('GRIK2', 'Gene', (101, 106))	('CIC', 'Gene', '23152', (55, 58))	('decreased', 'NegReg', (88, 97))
69208	28418868	Tumors derived from T24/GRIK2 cells were significantly larger than those derived from T24/Mock cells (P < 0.05) (Figure 4E).	('larger', 'PosReg', (55, 61))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('T24/GRIK2', 'Var', (20, 29))
69209	28418868	We previously described ALDH1 expression is associated with poor prognosis in patients with upper urinary tract UC, and ALDH1 is a well accepted marker for CSCs/CICs.	('associated', 'Reg', (44, 54))	('upper urinary tract UC', 'Disease', (92, 114))	('expression', 'Var', (30, 40))	('patients', 'Species', '9606', (78, 86))	('CIC', 'Gene', '23152', (161, 164))	('ALDH', 'molecular_function', 'GO:0004030', ('120', '124'))	('ALDH1', 'Gene', (24, 29))	('CIC', 'Gene', (161, 164))	('ALDH', 'molecular_function', 'GO:0004030', ('24', '28'))
69226	28418868	To our knowledge, this is the first report showing that ALDH1high cells can also be isolated from UM-UC3 urothelial carcinoma cells by the ALDEFLUOR assay and that ALDH1high cells have stem cell characteristics.	('ALDH', 'molecular_function', 'GO:0004030', ('56', '60'))	('ALDH1high', 'Var', (164, 173))	('urothelial carcinoma', 'Disease', (105, 125))	('ALDH1high', 'Gene', (56, 65))	('ALDH', 'molecular_function', 'GO:0004030', ('164', '168'))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('ALDEFLUOR', 'Chemical', '-', (139, 148))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (105, 125))	('stem cell characteristics', 'CPA', (185, 210))
69240	28418868	GRIK2 was expressed in normal gastric tissue; however, its expression was repressed in gastric cancer tissues by GRIK2 promoter region methylation.	('methylation', 'Var', (135, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('GRIK2', 'Gene', (113, 118))	('gastric cancer', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))	('methylation', 'biological_process', 'GO:0032259', ('135', '146'))
69243	28418868	Recently, polymorohism of GRIK2 TT (rs1335022) was associated with oral cancer.	('rs1335022', 'Var', (36, 45))	('GRIK2 TT', 'Gene', (26, 34))	('polymorohism', 'Var', (10, 22))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('associated', 'Reg', (51, 61))	('rs1335022', 'Mutation', 'rs1335022', (36, 45))	('oral cancer', 'Disease', 'MESH:D009062', (67, 78))	('oral cancer', 'Disease', (67, 78))
69252	28418868	In summary, we found that a UC cell line with high ALDH1 activity had CSC/CIC properties.	('high', 'Var', (46, 50))	('ALDH1', 'Gene', (51, 56))	('ALDH', 'molecular_function', 'GO:0004030', ('51', '55'))	('CIC', 'Gene', '23152', (74, 77))	('CIC', 'Gene', (74, 77))	('activity', 'MPA', (57, 65))
69280	28418868	A dye swap experiment was also done to label ALDH1high and ALDH1low cells with Cy3 and Cy5, respectively.	('ALDH', 'molecular_function', 'GO:0004030', ('59', '63'))	('Cy3', 'Var', (79, 82))	('ALDH', 'molecular_function', 'GO:0004030', ('45', '49'))	('Cy5', 'Var', (87, 90))	('Cy3', 'Chemical', '-', (79, 82))	('Cy5', 'Chemical', 'MESH:C085321', (87, 90))
69325	26448011	According to Figure 4, 7 studies reported RFS in renal cancer, upper tract urothelial carcinoma, and bladder cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('renal cancer', 'Disease', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('renal cancer', 'Phenotype', 'HP:0009726', (49, 61))	('bladder cancer', 'Disease', (101, 115))	('upper tract urothelial carcinoma', 'Disease', (63, 95))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (63, 95))	('renal cancer', 'Disease', 'MESH:D007680', (49, 61))	('RFS', 'Var', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))
69330	26448011	In Figure 6, only 3 studies showed MFS in renal cancer and upper tract urothelial carcinoma, and the pooled results also favored patients with a low NLR (pooled HR: 1.60, 95% CI: 1.29-1.98 in renal cell carcinoma; pooled HR: 2.47, 95% CI: 1.16-5.29 in upper tract urothelial carcinoma).	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('patients', 'Species', '9606', (129, 137))	('renal cancer', 'Disease', (42, 54))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (252, 284))	('MFS', 'Var', (35, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (59, 91))	('renal cancer', 'Disease', 'MESH:D007680', (42, 54))	('renal cancer', 'Phenotype', 'HP:0009726', (42, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('upper tract urothelial carcinoma', 'Disease', (59, 91))	('renal cell carcinoma', 'Disease', (192, 212))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (192, 212))	('upper tract urothelial carcinoma', 'Disease', (252, 284))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (192, 212))
69545	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))
69546	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))
69556	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))
69557	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))
69560	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))
69561	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.	('Brg1', 'Gene', '20586', (0, 4))	('mice', 'Species', '10090', (82, 86))	('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))
69564	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))
69570	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))
69584	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))	('negative', 'NegReg', (151, 159))	('mutations', 'Var', (101, 110))	('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))
69585	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))
69586	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))
69588	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))
69592	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.	('uveal melanoma', 'Phenotype', 'HP:0007716', (161, 175))	('uveal melanoma', 'Disease', (161, 175))	('liposarcoma', 'Disease', 'MESH:D008080', (145, 156))	('High', 'Var', (0, 4))	('SMARCA4', 'Gene', (19, 26))	('lung adenocarcinoma', 'Disease', (124, 143))	('liposarcoma', 'Phenotype', 'HP:0012034', (145, 156))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (97, 122))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (124, 143))	('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))	('liposarcoma', 'Disease', (145, 156))	('SMARCA4', 'Gene', '6597', (19, 26))
69593	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))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('SMARCA2', 'Gene', (32, 39))	('SMARCA2', 'Gene', '6595', (32, 39))	('liposarcoma', 'Disease', (128, 139))
69594	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))
69602	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))	('SKCM', 'Disease', (115, 119))	('high expression', 'Var', (39, 54))	('SMARCA4', 'Gene', '6597', (58, 65))	('KIRC', 'Disease', (124, 128))	('LIHC', 'Disease', (103, 107))
69603	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))
69604	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))
69607	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))
69608	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))
69610	29391527	Similarly, in KIRC tumors, high expression of SMARCA4 is associated with increased undifferentiated histological grade (Fig.	('increased', 'PosReg', (73, 82))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (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))
69612	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))
69636	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.	('ELK1', 'Gene', (103, 107))	('tumor', 'Disease', (185, 190))	('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))
69644	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))
69678	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))
69679	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))
69680	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))
69687	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))
69688	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))
69702	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'))
69708	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))	('activation', 'PosReg', (30, 40))	('SMARCA4-deficient human adrenal adenocarcinoma', 'Disease', (84, 130))	('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))
69711	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))
69756	27983635	Moreover, T-UCR 8+ silencing increased miR-596 expression, which in turn reduced total T-UCR 283+, showing that the perturbation of one element in this network changes the expression of other interactors.	('changes', 'Reg', (160, 167))	('T-UCR 283+', 'MPA', (87, 97))	('interactors', 'Interaction', (192, 203))	('reduced', 'NegReg', (73, 80))	('silencing', 'Var', (19, 28))	('T-UCR', 'Var', (10, 15))	('increased', 'PosReg', (29, 38))	('expression', 'MPA', (172, 182))	('miR-596', 'Gene', '693181', (39, 46))	('miR-596', 'Gene', (39, 46))	('expression', 'MPA', (47, 57))
69767	27983635	Consequently, aberrant T-UCR expression profiles can be used to differentiate cancer behaviors.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer behaviors', 'Disease', (78, 94))	('cancer behaviors', 'Disease', 'MESH:D009369', (78, 94))	('aberrant', 'Var', (14, 22))
69768	27983635	Regulation of T-UCR expression has been found to occur via two main mechanisms: by interactions with miRNAs or by hypermethylation of CpG island promoters.	('hypermethylation of CpG island', 'biological_process', 'GO:0044027', ('114', '144'))	('hypermethylation', 'Var', (114, 130))	('interactions', 'Interaction', (83, 95))	('T-UCR', 'Gene', (14, 19))	('miR', 'Gene', '220972', (101, 104))	('miR', 'Gene', (101, 104))
69781	27983635	Cells were grown in a humidified incubator in a 5% carbon dioxide atmosphere at 37  C. For the transient silencing of T-UCR 8+, J82 cells were transfected with small interference RNAs (siRNAs) using HiPerFect transfection reagent (Qiagen, Hilden, Germany), according to the manufacturer's instructions.	('carbon dioxide', 'Chemical', 'MESH:D002245', (51, 65))	('J82', 'CellLine', 'CVCL:0359', (128, 131))	('silencing', 'NegReg', (105, 114))	('small', 'Var', (160, 165))
69796	27983635	Total RNA (300 mug) extracted from J82 cell line was incubated in an appropriate buffer with 100 pmol of 5'-biotinylated oligonucleotides T-UCR 8+, T-UCR 201+, T-UCR 128+ and one oligonucleotide scramble in miR-596 binding site overnight at 4  C with rotation.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('T-UCR 8+', 'Var', (138, 146))	('mug', 'molecular_function', 'GO:0043739', ('15', '18'))	('oligonucleotide', 'Chemical', 'MESH:D009841', (121, 136))	('oligonucleotide', 'Chemical', 'MESH:D009841', (179, 194))	('binding', 'molecular_function', 'GO:0005488', ('215', '222'))	('J82', 'CellLine', 'CVCL:0359', (35, 38))	('miR-596', 'Gene', '693181', (207, 214))	('T-UCR 201+', 'Var', (148, 158))	('biotinylated oligonucleotides', 'Chemical', '-', (108, 137))	('miR-596', 'Gene', (207, 214))	('T-UCR 128+', 'Var', (160, 170))
69807	27983635	In addition, T-UCR 8+ was previously found to contain miR-596-binding elements and to function as a competitive sponge for miR-596 binding.	('miR-596', 'Gene', '693181', (123, 130))	('miR-596', 'Gene', (123, 130))	('T-UCR', 'Var', (13, 18))	('binding', 'Interaction', (131, 138))	('miR-596', 'Gene', '693181', (54, 61))	('binding', 'molecular_function', 'GO:0005488', ('131', '138'))	('miR-596', 'Gene', (54, 61))	('binding', 'molecular_function', 'GO:0005488', ('62', '69'))
69809	27983635	As shown in Figure 1C,D, the silencing of T-UCR 8+ in J82 cells increased miR-596 expression by about fourfold (p < 0.001), completely abrogated T-UCR 283+ transcription (Figure 1D), and upregulated T-UCR 201+ expression by an almost fourfold change compared to control (p < 0.01) (Figure 1D).	('J82', 'CellLine', 'CVCL:0359', (54, 57))	('T-UCR 8+', 'Gene', (42, 50))	('expression', 'MPA', (82, 92))	('silencing', 'Var', (29, 38))	('transcription', 'biological_process', 'GO:0006351', ('156', '169'))	('abrogated', 'NegReg', (135, 144))	('miR-596', 'Gene', '693181', (74, 81))	('increased', 'PosReg', (64, 73))	('T-UCR 201+ expression', 'MPA', (199, 220))	('T-UCR 283+ transcription', 'MPA', (145, 169))	('upregulated', 'PosReg', (187, 198))	('miR-596', 'Gene', (74, 81))
69810	27983635	We then knocked down miR-596 (Figure 1E) by using an antagomiR that decreased the endogenous expression of miR-596 by about 10-fold (p < 0.001), resulting in increased expression of both T-UCR 201+ and T-UCR 283+ mRNAs by twofold (p < 0.001) compared to the control Figure 1D.	('T-UCR 283+ mRNAs', 'Var', (202, 218))	('decreased', 'NegReg', (68, 77))	('miR-596', 'Gene', '693181', (21, 28))	('miR-596', 'Gene', (21, 28))	('expression', 'MPA', (168, 178))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('miR-596', 'Gene', '693181', (107, 114))	('miR', 'Gene', '220972', (59, 62))	('miR-596', 'Gene', (107, 114))	('miR', 'Gene', (59, 62))	('T-UCR 201+', 'Var', (187, 197))	('endogenous expression', 'MPA', (82, 103))	('knocked down', 'Var', (8, 20))	('miR', 'Gene', '220972', (107, 110))	('miR', 'Gene', (107, 110))	('increased', 'PosReg', (158, 167))
69811	27983635	These data suggest that T-UCR 283+ may be a target of miR-596 while T-UCR 201+ could function as a sponge in combination with T-UCR 8+ in order to repress miR-596 intracellular expression.	('intracellular', 'cellular_component', 'GO:0005622', ('163', '176'))	('T-UCR 201+', 'Var', (68, 78))	('repress', 'NegReg', (147, 154))	('miR-596', 'Gene', '693181', (155, 162))	('miR-596', 'Gene', (155, 162))	('miR-596', 'Gene', '693181', (54, 61))	('miR-596', 'Gene', (54, 61))
69813	27983635	T-UCR 8+-PNA was used as positive control while T-UCR 128+-PNA was used as negative control since T-UCR 128+ has no predicted binding site for any miRNAs.	('T-UCR', 'Var', (98, 103))	('binding', 'Interaction', (126, 133))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', (147, 150))	('binding', 'molecular_function', 'GO:0005488', ('126', '133'))
69817	27983635	The program predicted one possible YY1 binding site in both T-UCR 8+ and T-UCR 201+ sequences, as shown in Figure 2B,C.	('YY1', 'Gene', (35, 38))	('binding', 'molecular_function', 'GO:0005488', ('39', '46'))	('YY1', 'Gene', '7528', (35, 38))	('T-UCR 8+', 'Var', (60, 68))	('T-UCR 201+', 'Var', (73, 83))	('binding', 'Interaction', (39, 46))
69818	27983635	A significant enrichment of T-UCR 8+ was observed with YY1 antibody (sixfold higher) compared to input (Figure 3A).	('antibody', 'cellular_component', 'GO:0019815', ('59', '67'))	('antibody', 'cellular_component', 'GO:0019814', ('59', '67'))	('T-UCR', 'Var', (28, 33))	('YY1', 'Gene', '7528', (55, 58))	('antibody', 'molecular_function', 'GO:0003823', ('59', '67'))	('antibody', 'cellular_component', 'GO:0042571', ('59', '67'))	('YY1', 'Gene', (55, 58))
69824	27983635	Here, we have computationally identified a network of nine T-UCRs (T-UCR 8+, 195+, 201+, 283+, 305+, 388+, 390+, 393+ and 457+), both up- and downregulated in BlCa tissues that share binding sites for miR-596.	('binding', 'molecular_function', 'GO:0005488', ('183', '190'))	('up-', 'PosReg', (134, 137))	('283+', 'Var', (89, 93))	('201+', 'Var', (83, 87))	('downregulated', 'NegReg', (142, 155))	('miR-596', 'Gene', '693181', (201, 208))	('miR-596', 'Gene', (201, 208))
69826	27983635	A large deletion involving miR-596 was found in urothelial carcinomas, supporting the hypothesis of its key role in carcinogenesis.	('miR-596', 'Gene', '693181', (27, 34))	('carcinogenesis', 'Disease', 'MESH:D063646', (116, 130))	('miR-596', 'Gene', (27, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('found', 'Reg', (39, 44))	('carcinogenesis', 'Disease', (116, 130))	('urothelial carcinomas', 'Disease', (48, 69))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (48, 69))	('deletion', 'Var', (8, 16))
69827	27983635	In vitro RNA fishing experiments validated the direct biding between miR-596, T-UCR 8+ and T-UCR 201+, thus reinforcing a possible regulatory role of T-UCRs on miRNAs.	('miR', 'Gene', (160, 163))	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('biding', 'Interaction', (54, 60))	('miR-596', 'Gene', '693181', (69, 76))	('miR-596', 'Gene', (69, 76))	('T-UCR 8+', 'Var', (78, 86))	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (69, 72))	('miR', 'Gene', '220972', (160, 163))	('T-UCR 201+', 'Var', (91, 101))
69830	27983635	Specifically, when intracellular miR-596 levels were modulated using a specific antagomiR, in our cell system, we observed an increased expression of T-UCR 201+, showing that the perturbation of one element in this network changes the expression levels of other interactors.	('T-UCR 201+', 'Var', (150, 160))	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (33, 36))	('expression', 'MPA', (136, 146))	('miR-596', 'Gene', '693181', (33, 40))	('intracellular', 'cellular_component', 'GO:0005622', ('19', '32'))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))	('expression levels', 'MPA', (235, 252))	('changes', 'Reg', (223, 230))	('miR-596', 'Gene', (33, 40))	('increased', 'PosReg', (126, 135))
69831	27983635	Moreover, in absence of T-UCR 8+, miR-596 is available to bind other T-UCRs, such as T-UCR 283+, and may regulate its expression.	('regulate', 'Reg', (105, 113))	('bind', 'Interaction', (58, 62))	('miR-596', 'Gene', '693181', (34, 41))	('miR-596', 'Gene', (34, 41))	('T-UCR', 'Var', (85, 90))	('expression', 'MPA', (118, 128))
69838	27983635	In agreement, dose-dependent shYY1 plasmids affect the available amount of miR-596, opening up the possibility of new and as yet unexplored regulatory mechanisms orchestrated by polycomb YY1.	('rat', 'Species', '10116', (169, 172))	('YY1', 'Gene', (187, 190))	('available amount of', 'MPA', (55, 74))	('YY1', 'Gene', '7528', (31, 34))	('miR-596', 'Gene', '693181', (75, 82))	('YY1', 'Gene', (31, 34))	('YY1', 'Gene', '7528', (187, 190))	('affect', 'Reg', (44, 50))	('miR-596', 'Gene', (75, 82))	('plasmids', 'Var', (35, 43))
69846	22991510	None of six clinical trials yielded convincing results for blockading ErbB receptor signaling in urothelial carcinoma.	('ErbB', 'Gene', (70, 74))	('urothelial carcinoma', 'Disease', (97, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('blockading', 'Var', (59, 69))	('ErbB', 'Gene', '1956', (70, 74))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (97, 117))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))
69859	22991510	In practice, therapy that targets EGFR gene mutations in primary tumors has extended the theme of targeted cancer therapies.	('EGFR', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (44, 53))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('primary tumors', 'Disease', 'MESH:D009369', (57, 71))	('primary tumors', 'Disease', (57, 71))	('EGFR', 'Gene', '1956', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
69867	22991510	Original articles published between January 1985 and May 2011 showing prognostic significance of expression or amplification of ErbB receptor members in patients with bladder cancer were systematically reviewed.	('amplification', 'Var', (111, 124))	('patients', 'Species', '9606', (153, 161))	('bladder cancer', 'Phenotype', 'HP:0009725', (167, 181))	('bladder cancer', 'Disease', 'MESH:D001749', (167, 181))	('bladder cancer', 'Disease', (167, 181))	('ErbB', 'Gene', '1956', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('ErbB', 'Gene', (128, 132))
69870	22991510	Our database was designed to ensure the breadth of relevant data obtained, based on study design, patient outcomes, tumor characteristics, statistical analyses, biological samples, analytical methods (namely, immunohistochemistry [IHC], fluorescence in situ hybridization [FISH], and real-time polymerase chain reaction [RT-PCR]), and the incidence of overexpression or gene amplification of ErbB receptor family members.	('ErbB', 'Gene', '1956', (392, 396))	('overexpression', 'PosReg', (352, 366))	('patient', 'Species', '9606', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('gene amplification', 'Var', (370, 388))	('ErbB', 'Gene', (392, 396))
69919	22991510	The conventional paradigm is that aberrant activation of ErbB receptors is generated by the overexpression or mutations of the receptor, and by the autocrine production of ligands.	('mutations', 'Var', (110, 119))	('overexpression', 'PosReg', (92, 106))	('activation', 'PosReg', (43, 53))	('ErbB', 'Gene', '1956', (57, 61))	('ErbB', 'Gene', (57, 61))
69927	22991510	Several studies have reported that overexpressed or mutant EGFR family members drive the development of human cancers, including lung, breast, melanoma, prostate, and urinary bladder cancer.	('prostate', 'Disease', (153, 161))	('EGFR', 'Gene', (59, 63))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('bladder cancer', 'Phenotype', 'HP:0009725', (175, 189))	('drive', 'Reg', (79, 84))	('urinary bladder cancer', 'Disease', (167, 189))	('human', 'Species', '9606', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('EGFR', 'Gene', '1956', (59, 63))	('cancers', 'Disease', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (167, 189))	('mutant', 'Var', (52, 58))	('breast', 'Disease', (135, 141))	('lung', 'Disease', (129, 133))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
69928	22991510	Alternatively, other aberrations, such as mutant forms of RAF or PI3K, manipulate the downstream signaling in cancer through negative feedback loops.	('RAF', 'Gene', '22882', (58, 61))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('mutant', 'Var', (42, 48))	('manipulate', 'Reg', (71, 81))	('downstream signaling', 'MPA', (86, 106))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('PI3K', 'Var', (65, 69))	('negative feedback loops', 'MPA', (125, 148))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('signaling', 'biological_process', 'GO:0023052', ('97', '106'))	('RAF', 'Gene', (58, 61))
69931	22991510	A number of studies have reported the association of EGFR and ErbB2 overexpression with advanced stages of bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (107, 121))	('bladder cancer', 'Disease', (107, 121))	('ErbB2', 'Gene', '2064', (62, 67))	('association', 'Interaction', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (107, 121))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('ErbB2', 'Gene', (62, 67))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('overexpression', 'Var', (68, 82))
70027	19917108	Another possible mechanism is that the increased IHC CD10 expression with increasing grade and stage may indicate accumulation of mutated, nonfunctional CD10 rather than its normal counterpart.	('expression', 'MPA', (58, 68))	('CD10', 'Gene', '4311', (153, 157))	('CD10', 'Gene', (153, 157))	('accumulation', 'PosReg', (114, 126))	('increased', 'PosReg', (39, 48))	('CD10', 'Gene', '4311', (53, 57))	('CD10', 'Gene', (53, 57))	('mutated', 'Var', (130, 137))	('CD10', 'molecular_function', 'GO:0004245', ('53', '57'))	('CD10', 'molecular_function', 'GO:0004245', ('153', '157'))
70028	19917108	On the other hand, it was recently found that CD10 expression was associated with higher apoptotic index in diffuse large B cell lymphoma.	('lymphoma', 'Disease', (129, 137))	('apoptotic index', 'CPA', (89, 104))	('lymphoma', 'Disease', 'MESH:D008223', (129, 137))	('lymphoma', 'Phenotype', 'HP:0002665', (129, 137))	('CD10', 'Gene', (46, 50))	('higher', 'PosReg', (82, 88))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (122, 137))	('large B cell', 'Phenotype', 'HP:0005404', (116, 128))	('CD10', 'Gene', '4311', (46, 50))	('CD10', 'molecular_function', 'GO:0004245', ('46', '50'))	('expression', 'Var', (51, 61))
70031	19917108	Moreover, CD10 expression may take part in preventing unwanted inflammatory reaction initiated by activated cells undergoing apoptosis, and it may protect these cells from potential attacks by the immune system.	('expression', 'Var', (15, 25))	('CD10', 'Gene', '4311', (10, 14))	('CD10', 'molecular_function', 'GO:0004245', ('10', '14'))	('apoptosis', 'biological_process', 'GO:0097194', ('125', '134'))	('apoptosis', 'biological_process', 'GO:0006915', ('125', '134'))	('preventing', 'NegReg', (43, 53))	('unwanted inflammatory reaction', 'MPA', (54, 84))	('CD10', 'Gene', (10, 14))
70033	19917108	Indeed, the results of several studies in human tumors other than urothelial carcinoma have also revealed that changes in CD10 activity produce different influences in different tumor types.	('urothelial carcinoma', 'Disease', (66, 86))	('changes', 'Var', (111, 118))	('human', 'Species', '9606', (42, 47))	('tumors', 'Disease', (48, 54))	('CD10', 'molecular_function', 'GO:0004245', ('122', '126'))	('CD10', 'Gene', '4311', (122, 126))	('activity', 'MPA', (127, 135))	('tumor', 'Disease', (178, 183))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (66, 86))	('CD10', 'Gene', (122, 126))	('tumor', 'Disease', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('influences', 'Reg', (154, 164))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
70061	11875692	Long-term results of the Phase III Intergroup Study showed that the treatment with M-VAC provided a significant survival advantage over cisplatin alone (Saxman et al, 1997).	('survival advantage', 'CPA', (112, 130))	('M-VAC', 'Var', (83, 88))	('M-VAC', 'Chemical', '-', (83, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))
70170	31915791	Operative time, blood loss and hospital stay were significantly lower in the LNU group than in the ONU group (p=0.0001, p=0.0001, p=0.0018).	('hospital stay', 'CPA', (31, 44))	('blood loss', 'Disease', 'MESH:D006473', (16, 26))	('LNU', 'Chemical', '-', (77, 80))	('lower', 'NegReg', (64, 69))	('Operative time', 'CPA', (0, 14))	('LNU', 'Var', (77, 80))	('ONU', 'Chemical', '-', (99, 102))	('blood loss', 'Disease', (16, 26))
70227	31915791	The operative time calculated as the time of making incision to closure of wound in both groups was significantly lower in the LNU group than in the ONU group (p=0.0001 (Table 2).	('LNU', 'Var', (127, 130))	('LNU', 'Chemical', '-', (127, 130))	('lower', 'NegReg', (114, 119))	('ONU', 'Chemical', '-', (149, 152))
70229	31915791	Three patients (2 in ONU and one LNU) in which ureteral stump recurrence occurred due to non-excision of bladder cuff underwent distal ureterectomy and bladder cuff excision.	('ureter', 'Disease', (47, 53))	('LNU', 'Chemical', '-', (33, 36))	('ureter', 'Disease', 'MESH:D014516', (135, 141))	('ONU', 'Chemical', '-', (21, 24))	('patients', 'Species', '9606', (6, 14))	('non-excision', 'Var', (89, 101))	('ureter', 'Disease', 'MESH:D014516', (47, 53))	('ureter', 'Disease', (135, 141))
70240	31915791	Similarly, Kaplan-Meier estimates for bladder cancer recurrence was significantly associated with H/O bladder cancer (log-rank p=0.027), multifocality of tumor (log-rank p=0.001) and preoperative URS with biopsy (log-rank p=0.004), as shown in Figures 2A-2C.	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('tumor', 'Disease', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (38, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('bladder cancer', 'Disease', (102, 116))	('associated', 'Interaction', (82, 92))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('bladder cancer', 'Disease', 'MESH:D001749', (38, 52))	('bladder cancer', 'Disease', (38, 52))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (38, 63))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('multifocality', 'Var', (137, 150))
70242	31915791	Several patient series have published the technical feasibility and lower postoperative morbidity of LNU with less blood loss, short hospital stay, and even short operative time compared with ONU, regardless of the technique used in LNU for lower ureter management.	('ureter', 'Disease', 'MESH:D014516', (247, 253))	('blood loss', 'Disease', 'MESH:D006473', (115, 125))	('LNU', 'Chemical', '-', (101, 104))	('LNU', 'Var', (101, 104))	('blood loss', 'Disease', (115, 125))	('ureter', 'Disease', (247, 253))	('ONU', 'Chemical', '-', (192, 195))	('LNU', 'Chemical', '-', (233, 236))	('patient', 'Species', '9606', (8, 15))
70243	31915791	In our study, we observed a significant decrease in blood loss, shorter hospital stays, and decrease in operative time in patients with LNU as compared to those in the ONU group.	('decrease', 'NegReg', (92, 100))	('operative', 'MPA', (104, 113))	('ONU', 'Chemical', '-', (168, 171))	('patients', 'Species', '9606', (122, 130))	('LNU', 'Chemical', '-', (136, 139))	('LNU', 'Var', (136, 139))	('decrease in blood loss', 'Disease', (40, 62))	('decrease in blood loss', 'Disease', 'MESH:D016063', (40, 62))	('shorter', 'NegReg', (64, 71))
70250	31915791	Peyronnet et al found that outcomes of patients treated with LNU had significantly poorer outcomes in high-grade and stage tumors than with ONU, whereas there was no difference in oncological outcome in low-stage and low-grade disease.	('had', 'Gene', (65, 68))	('tumors', 'Disease', (123, 129))	('high-grade', 'CPA', (102, 112))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('patients', 'Species', '9606', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('LNU', 'Chemical', '-', (61, 64))	('poorer', 'NegReg', (83, 89))	('ONU', 'Chemical', '-', (140, 143))	('LNU', 'Var', (61, 64))	('had', 'Gene', '23498', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
70253	31915791	Moreover, in univariate and multivariate Cox regression analyses in pT3/T4 patients, LRNU was an independent predictor of worse OS (HR: 2.59; 95% CI: 1.44-4.65; p=0.001) and CSS (HR: 2.50; 95% CI: 1.32-4.71; p=0.005) rates than ORNU.	('LRNU', 'Var', (85, 89))	('RNU', 'Chemical', '-', (229, 232))	('patients', 'Species', '9606', (75, 83))	('RNU', 'Chemical', '-', (86, 89))	('CSS', 'CPA', (174, 177))
70263	31915791	Few studies, have reported that LNU was significantly associated with the bladder cancer recurrence rate as compared to ONU (HR: 1.62; 95% CI: 1.18-2.22).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (74, 88))	('LNU', 'Chemical', '-', (32, 35))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (74, 99))	('LNU', 'Var', (32, 35))	('bladder cancer', 'Disease', 'MESH:D001749', (74, 88))	('bladder cancer', 'Disease', (74, 88))	('ONU', 'Chemical', '-', (120, 123))	('associated', 'Reg', (54, 64))
70443	28655867	We diagnosed 107 patients with low-grade UC using a UroVysion kit to detect chromosomes 3, 7, 17, and P16 in the urine.	('low-grade UC', 'Disease', (31, 43))	('P16', 'Gene', (102, 105))	('P16', 'Gene', '1029', (102, 105))	('patients', 'Species', '9606', (17, 25))	('chromosomes', 'Var', (76, 87))
70453	28655867	However, both WHO1973 G2 and WHO 2004 low-grade UC cannot fully reflect the classification of tumor recurrence and progression.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('WHO1973', 'CellLine', 'CVCL:E046', (14, 21))	('tumor', 'Disease', (94, 99))	('WHO1973 G2', 'Var', (14, 24))
70456	28655867	Chromosomes 7 and/or 17 positive are considered to be a high-risk group, and chromosomes 3 and/or p16 positive are a low-risk group generated in intermediate-risk urothelial carcinoma.	('p16', 'Gene', (98, 101))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (163, 183))	('p16', 'Gene', '1029', (98, 101))	('Chromosomes 7', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('urothelial carcinoma', 'Disease', (163, 183))
70477	28655867	Twenty-three cases had progression: 8 were both CSP7/CSP17-positive and CSP3/GLPp16-positive, 4 were only CSP3/GLPp16-positive, 10 were only CSP7/CSP17-positive, and 1 was FISH-negative).	('p16', 'Gene', '1029', (114, 117))	('CSP7/CSP17-positive', 'Var', (48, 67))	('p16', 'Gene', '1029', (80, 83))	('p16', 'Gene', (114, 117))	('p16', 'Gene', (80, 83))
70479	28655867	Nevertheless, CSP3/GLPp16 positivity was not associated with any risk factors in low-grade UC (P>0.05).	('low-grade UC', 'Disease', (81, 93))	('p16', 'Gene', '1029', (22, 25))	('p16', 'Gene', (22, 25))	('positivity', 'Var', (26, 36))
70484	28655867	In multivariate Cox regression analyses, we showed that CSP7/CSP17 positivity on FISH test in low-grade UC significantly affected overall survival (HR=2.306, 95%CI: 1.009-5.268, P=0.048), disease-free survival (HR=2.890, 95%CI: 1.654-5.051, P<0.001), and cancer-specific survival (HR=3.210, 95%CI: 1.184-8.703, P=0.022).	('disease-free survival', 'CPA', (188, 209))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('CSP7/CSP17', 'Gene', (56, 66))	('Cox', 'Gene', '1351', (16, 19))	('affected', 'Reg', (121, 129))	('positivity', 'Var', (67, 77))	('cancer', 'Disease', (255, 261))	('Cox', 'Gene', (16, 19))	('overall survival', 'CPA', (130, 146))
70500	28655867	This study confirmed that FISH detection of mutations in chromosomes 3, 7, 17, and 9p21 in urine samples can facilitate risk stratification of low-grade UC patients.	('9p21', 'Gene', (83, 87))	('patients', 'Species', '9606', (156, 164))	('low-grade UC', 'Disease', (143, 155))	('mutations', 'Var', (44, 53))
70505	23145155	HERV-E-Mediated Modulation of PLA2G4A Transcription in Urothelial Carcinoma Human endogenous retroviruses (HERV) and related elements account for more than 8% of the human genome and significantly contribute to the human transcriptome by long terminal repeat (LTR) promoter activity.	('PLA2G4A', 'Gene', (30, 37))	('Urothelial Carcinoma', 'Disease', (55, 75))	('human', 'Species', '9606', (166, 171))	('Urothelial Carcinoma', 'Disease', 'MESH:D014526', (55, 75))	('PLA2G4A', 'Gene', '5321', (30, 37))	('Carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('Modulation', 'Var', (16, 26))	('Human endogenous retroviruses', 'Species', '206037', (76, 105))	('human', 'Species', '9606', (215, 220))
70508	23145155	We established a characteristic HERV signature consisting of six ubiquitously active HERV subgroups (E4-1, HERV-Rb, ERV9, HERV-K-T47D, NMWV3, HERV-KC4).	('HERV-K', 'Species', '45617', (122, 128))	('HERV-K-T47D', 'Var', (122, 133))	('HERV-K', 'Species', '45617', (142, 148))	('E4-1', 'Var', (101, 105))
70535	23145155	However, hypomethylation of TEs in human urothelial carcinomas suggests a possible activation of retroelements including HERVs.	('retroelements', 'CPA', (97, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('HERVs', 'Species', '206037', (121, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('urothelial carcinomas', 'Disease', (41, 62))	('human', 'Species', '9606', (35, 40))	('TEs', 'Gene', (28, 31))	('HERVs', 'Disease', (121, 126))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (41, 62))	('hypomethylation', 'Var', (9, 24))	('activation', 'PosReg', (83, 93))
70588	23145155	and signal cut-off calculation (data not shown) revealed a distinct urothelium-specific HERV core signature consisting of six active HERV subgroups (HERV-E4-1, HERV-Rb, ERV9, HERV-K-T47D, NMWV3, HERV-KC4) that are transcribed in at least 11 of 13 non-malignant tissue samples (Table 2).	('HERV-K-T47D', 'Var', (175, 186))	('HERV-E4-1', 'Var', (149, 158))	('ERV9', 'Var', (169, 173))	('HERV-K', 'Species', '45617', (175, 181))	('HERV-K', 'Species', '45617', (195, 201))	('core', 'cellular_component', 'GO:0019013', ('93', '97'))
70651	23145155	Deregulation of HERV expression has been associated with many cancers (reviewed in).	('associated', 'Reg', (41, 51))	('HERV', 'Protein', (16, 20))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
70674	23145155	Therefore, a significant bias to antisense orientation of HERVs in introns is observed indicating a strong negative selection pressure.	('HERVs', 'Gene', (58, 63))	('antisense orientation', 'Var', (33, 54))	('HERVs', 'Species', '206037', (58, 63))
70712	31123404	These include tumor mutation burden (TMB) or tumor mutation load, neoantigen burden, DNA mismatch repair deficiency, and high microsatellite instability.	('TMB', 'Chemical', '-', (37, 40))	('neoantigen burden', 'MPA', (66, 83))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('high microsatellite instability', 'MPA', (121, 152))	('mismatch repair', 'biological_process', 'GO:0006298', ('89', '104'))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('deficiency', 'Var', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
70739	31123404	Here, we followed the F1CDx approach to calculate the TMB for our panel, defining the cutoff values as TMB-high (>=20 mutations/Mb), TMB-medium (<20 mutations/Mb >=10 mutations/Mb) and TMB-low (<10 mutations/Mb).	('TMB', 'Chemical', '-', (133, 136))	('mutations/Mb', 'Var', (118, 130))	('TMB', 'Chemical', '-', (185, 188))	('TMB', 'Chemical', '-', (103, 106))	('TMB', 'Chemical', '-', (54, 57))	('F1CDx', 'Chemical', '-', (22, 27))	('<20 mutations/Mb', 'Var', (145, 161))
70742	31123404	We calculated the proportion of patient samples from 15 different cancers with mutations in each gene.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('patient', 'Species', '9606', (32, 39))	('mutations', 'Var', (79, 88))
70762	31123404	Some well-established cancer-associated genes, such as PI3KCA and TP53, were frequently mutated in most cancer types.	('PI3', 'Gene', (55, 58))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (22, 28))	('PI3', 'Gene', '5266', (55, 58))	('mutated', 'Var', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
70769	31123404	TP53, EGFR, PIC3CA and KRAS were often mutated in TMB-low samples in LUAD.	('TP53', 'Gene', '7157', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('6', '10'))	('TP53', 'Gene', (0, 4))	('EGFR', 'Gene', (6, 10))	('KRAS', 'Gene', '3845', (23, 27))	('PIC3CA', 'Gene', (12, 18))	('KRAS', 'Gene', (23, 27))	('mutated', 'Var', (39, 46))	('PIC', 'cellular_component', 'GO:0019035', ('12', '15'))	('PIC', 'cellular_component', 'GO:0097550', ('12', '15'))	('TMB', 'Chemical', '-', (50, 53))	('EGFR', 'Gene', '1956', (6, 10))
70774	31123404	MUC16 (coding length, 43524 bp) encodes a transmembrane glycoprotein with a molecular weight of 2000 kDa, meaning that it also has a high risk of mutation TMB is defined as the number of somatic coding mutations per million bases.	('MUC16', 'Gene', '94025', (0, 5))	('TMB', 'Chemical', '-', (155, 158))	('transmembrane', 'cellular_component', 'GO:0044214', ('42', '55'))	('transmembrane', 'cellular_component', 'GO:0016021', ('42', '55'))	('MUC16', 'Gene', (0, 5))	('mutation', 'Var', (146, 154))
70777	31123404	However, the relationship of those hotspot mutations with TMB are still not well-understood.	('TMB', 'Chemical', '-', (58, 61))	('TMB', 'Disease', (58, 61))	('mutations', 'Var', (43, 52))
70779	31123404	Firstly, we defined hotspot mutations as highly frequent mutations found in at least ten samples in the complete set of cancer WES data (Figure S2).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (28, 37))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
70780	31123404	Next, we focused on those hotspot mutations which occurred in at least three samples in one cancer type.	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutations', 'Var', (34, 43))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))
70781	31123404	Finally, a total of 150 unique mutations were investigated for their association to TMB level (327 cancer type-specific mutations).	('mutations', 'Var', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('TMB level', 'Disease', (84, 93))	('cancer', 'Disease', (99, 105))	('association', 'Interaction', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TMB', 'Chemical', '-', (84, 87))
70782	31123404	For these mutations, we calculated the P-value using a Mann-Whitney U-test and the fold-change by the median TMB value in mutation-positive samples (samples containing the mutation) and mutation-negative samples (samples without the mutation), as listed in Figure S3.	('mutation', 'Var', (172, 180))	('mutation-positive', 'Reg', (122, 139))	('TMB', 'Chemical', '-', (109, 112))	('mutations', 'Var', (10, 19))
70783	31123404	Figure 3A shows that most of these hotspot mutations were associated with high TMB (101/327) and only a small number of mutations were associated with low TMB (5/327).	('mutations', 'Var', (43, 52))	('high TMB', 'Disease', (74, 82))	('TMB', 'Chemical', '-', (155, 158))	('TMB', 'Chemical', '-', (79, 82))
70784	31123404	We found that some hotspot mutations occurred in only one cancer type.	('cancer', 'Disease', (58, 64))	('mutations', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))
70785	31123404	For example, the mutations P.S71L in OR2A5, P.G362E in CNTNAP2, P.F17F in BCL2L12 and P.T554I in SLC27A5 only occurred in SKCM and were associated with high TMB, with an adjusted-log10 (P-value)>1.3 and log2 (fold-change)>1.	('associated', 'Reg', (136, 146))	('CNTNAP2', 'Gene', (55, 62))	('BCL2L12', 'Gene', (74, 81))	('TMB', 'Chemical', '-', (157, 160))	('BCL2L12', 'Gene', '83596', (74, 81))	('F17F', 'Mutation', 'rs267605591', (66, 70))	('SLC27A5', 'Gene', '10998', (97, 104))	('T554I', 'Mutation', 'rs868246582', (88, 93))	('S71L', 'Mutation', 'rs149614119', (29, 33))	('P.G362E', 'Var', (44, 51))	('SLC27A5', 'Gene', (97, 104))	('OR2A5', 'Gene', (37, 42))	('OR2A5', 'Gene', '393046', (37, 42))	('CNTNAP2', 'Gene', '26047', (55, 62))	('P.F17F', 'Var', (64, 70))	('G362E', 'Mutation', 'p.G362E', (46, 51))	('BCL2', 'molecular_function', 'GO:0015283', ('74', '78'))	('high TMB', 'Disease', (152, 160))	('P.S71L', 'Var', (27, 33))	('P.T554I', 'Var', (86, 93))
70786	31123404	However, other hotspot mutations occurred in at least two cancer types.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('occurred', 'Reg', (33, 41))	('mutations', 'Var', (23, 32))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
70787	31123404	For example, the mutation KRAS:P.G12V appeared in BRCA, COAD, LUAD, OV, PAAD, STAD and UCEC, but only in OV was this mutation was positively related to low TMB, with a -log10 (P-value) of 2.29 and log2 (fold-change) of -2.26.	('COAD', 'Disease', 'MESH:D029424', (56, 60))	('P.G12V', 'Var', (31, 37))	('low TMB', 'MPA', (152, 159))	('G12V', 'Mutation', 'rs121913529', (33, 37))	('COAD', 'Disease', (56, 60))	('BRCA', 'Gene', '672', (50, 54))	('TMB', 'Chemical', '-', (156, 159))	('KRAS', 'Gene', (26, 30))	('BRCA', 'Gene', (50, 54))	('KRAS', 'Gene', '3845', (26, 30))
70788	31123404	As shown in Figure 3A-B, only in LUAD were the mutations P.E746_A750del and P.L858R in EGFR significantly associated with low TMB (adjusted P-value <0.00006 and log2 (fold-change) of 4.28).	('TMB', 'Chemical', '-', (126, 129))	('L858R', 'Mutation', 'rs121434568', (78, 83))	('EGFR', 'Gene', '1956', (87, 91))	('A750del', 'Mutation', 'c.750delA', (64, 71))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('EGFR', 'Gene', (87, 91))	('low', 'NegReg', (122, 125))	('TMB', 'MPA', (126, 129))	('P.E746_A750del', 'Var', (57, 71))	('P.L858R', 'Var', (76, 83))
70789	31123404	In other words, samples with these two hotspot mutations were usually TMB-low in LUAD and would be targetable by first-generation tyrosine kinase inhibitors.	('LUAD', 'Disease', (81, 85))	('mutations', 'Var', (47, 56))	('TMB', 'Chemical', '-', (70, 73))
70790	31123404	Most colorectal patients with the BRAF P.V600E mutation were TMB-high, with a P-value of 8.21E-19 (fold-change: 31.9 vs 3.4).	('TMB', 'Chemical', '-', (61, 64))	('colorectal', 'Disease', 'MESH:D015179', (5, 15))	('patients', 'Species', '9606', (16, 24))	('colorectal', 'Disease', (5, 15))	('BRAF', 'Gene', '673', (34, 38))	('P.V600E', 'Var', (39, 46))	('BRAF', 'Gene', (34, 38))	('V600E', 'Mutation', 'rs113488022', (41, 46))
70791	31123404	However, the BRAF V600E mutation was associated with TMB-low in LUAD patients with P-value 0.015 (fold change: 1.9 vs 5.9).	('V600E', 'Var', (18, 23))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('patients', 'Species', '9606', (69, 77))	('TMB', 'Chemical', '-', (53, 56))	('TMB-low', 'Disease', (53, 60))
70792	31123404	In summary, our results indicated that some hotspot mutations were strongly associated with TMB level, either low or high.	('associated', 'Reg', (76, 86))	('TMB', 'Chemical', '-', (92, 95))	('mutations', 'Var', (52, 61))	('TMB level', 'Disease', (92, 101))
70796	31123404	TMB estimated from simulated F1CDx and MSK-IMPACT panels showed a high correlation to TMB estimated from WES, with R2 correlation values of 0.95 and 0.94, respectively, for total mutations (Figure 4A and B).	('TMB', 'Chemical', '-', (86, 89))	('TMB', 'Chemical', '-', (0, 3))	('MSK', 'Gene', '150094', (39, 42))	('F1CDx', 'Chemical', '-', (29, 34))	('MSK', 'Gene', (39, 42))	('mutations', 'Var', (179, 188))
70808	31123404	Besides, we found that randomly selected gene sets had little difference between F1CDx, MSK-IMPACT and F1CDX+MSK in almost all cancer types.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('F1CDX+MSK', 'Gene', '150094', (103, 112))	('F1CDx', 'Var', (81, 86))	('MSK', 'Gene', '150094', (88, 91))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('MSK', 'Gene', (88, 91))	('MSK', 'Gene', '150094', (109, 112))	('MSK', 'Gene', (109, 112))	('cancer', 'Disease', (127, 133))	('F1CDX+MSK', 'Gene', (103, 112))	('F1CDx', 'Chemical', '-', (81, 86))
70868	30745855	To determine whether one or both receptors were responsible for the pro-apoptotic effect of TRAIL in T24 cells, we used small-interfering (si)RNAs to block innate DR4/DR5 translation (si1201 and si955 targeting DR4 and DR5 mRNA, respectively) according to their knockdown efficiency determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays (Figure 4B).	('DR5', 'Gene', (219, 222))	('TRAIL', 'Gene', (92, 97))	('DR4', 'Gene', '8797', (211, 214))	('DR4', 'Gene', (163, 166))	('DR4', 'Gene', (211, 214))	('DR5', 'Gene', '8795', (219, 222))	('block', 'NegReg', (150, 155))	('si955', 'Var', (195, 200))	('reverse transcription', 'biological_process', 'GO:0001171', ('310', '331'))	('DR5', 'Gene', (167, 170))	('TRAIL', 'Gene', '8743', (92, 97))	('si1201', 'Var', (184, 190))	('DR4', 'Gene', '8797', (163, 166))	('translation', 'biological_process', 'GO:0006412', ('171', '182'))	('DR5', 'Gene', '8795', (167, 170))
70871	30745855	Flow cytometry confirmed those from MTS assays showing that blocking DR5 translation was more effective at reducing the apoptosis rate as compared with blocking DR4 translation (apoptosis rates: 14.41 +- 0.21% in DR4-knockdown cells and 8.07+-0.22% in DR5-knockdown cells) (Figure 4D).	('DR5', 'Gene', (69, 72))	('DR5', 'Gene', '8795', (69, 72))	('translation', 'biological_process', 'GO:0006412', ('73', '84'))	('translation', 'biological_process', 'GO:0006412', ('165', '176'))	('DR5', 'Gene', (252, 255))	('DR4', 'Gene', '8797', (213, 216))	('DR5', 'Gene', '8795', (252, 255))	('reducing', 'NegReg', (107, 115))	('apoptosis rate', 'CPA', (120, 134))	('DR4', 'Gene', (161, 164))	('DR4', 'Gene', (213, 216))	('DR4', 'Gene', '8797', (161, 164))	('apoptosis', 'biological_process', 'GO:0097194', ('120', '129'))	('apoptosis', 'biological_process', 'GO:0097194', ('178', '187'))	('apoptosis', 'biological_process', 'GO:0006915', ('120', '129'))	('apoptosis', 'biological_process', 'GO:0006915', ('178', '187'))	('blocking', 'Var', (60, 68))
70872	30745855	Because combined treatment enhanced DR4 and DR5 protein levels in T24 cells (Figure 4A), we performed GSEA of the TCGA profiles of 414 bladder patients, which indicated that both high TNFRSF10A and TNFRSF10B expression were positively correlated with the p53-signaling pathway (Figure 5A).	('TNFRSF10A', 'Gene', '8797', (184, 193))	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('DR4', 'Gene', '8797', (36, 39))	('TNFRSF10A', 'Gene', (184, 193))	('DR4', 'Gene', (36, 39))	('TNFRSF10B', 'Gene', '8795', (198, 207))	('p53-signaling pathway', 'biological_process', 'GO:0030330', ('255', '276'))	('enhanced', 'PosReg', (27, 35))	('high', 'Var', (179, 183))	('DR5', 'Gene', (44, 47))	('patients', 'Species', '9606', (143, 151))	('correlated', 'Reg', (235, 245))	('p53', 'Gene', '7157', (255, 258))	('TNFRSF10B', 'Gene', (198, 207))	('GSEA', 'Chemical', '-', (102, 106))	('DR5', 'Gene', '8795', (44, 47))	('p53', 'Gene', (255, 258))
70874	30745855	Following qRT-PCR and immunoblot confirmation of p53-knockdown efficiency (Figure 5B), immunoblot results revealed that Andro enhanced p53 levels while p53 knockdown attenuated Andro-induced upregulation of DR4 and DR5 levels in T24 cells (Figure 5C).	('DR4', 'Gene', '8797', (207, 210))	('knockdown', 'Var', (156, 165))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('enhanced', 'PosReg', (126, 134))	('upregulation', 'PosReg', (191, 203))	('DR4', 'Gene', (207, 210))	('p53', 'Gene', (152, 155))	('DR5', 'Gene', (215, 218))	('p53', 'Gene', '7157', (152, 155))	('p53', 'Gene', (135, 138))	('Andro', 'Chemical', 'MESH:C030419', (177, 182))	('p53', 'Gene', '7157', (135, 138))	('DR5', 'Gene', '8795', (215, 218))	('attenuated', 'NegReg', (166, 176))	('Andro', 'Chemical', 'MESH:C030419', (120, 125))
70876	30745855	Knocking down of p53 expression also contributed to attenuated synergistic effect of Andro for which decreased cell apoptosis rate in TRAIL-treated T24 cells (control shRNA, 23.88+-0.77% vs. p53 shRNA, 13.99+-0.88%) (Figure S1).	('synergistic effect', 'MPA', (63, 81))	('TRAIL', 'Gene', (134, 139))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('Knocking down', 'Var', (0, 13))	('attenuated', 'NegReg', (52, 62))	('p53', 'Gene', (17, 20))	('decreased', 'NegReg', (101, 110))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('p53', 'Gene', (191, 194))	('p53', 'Gene', '7157', (191, 194))	('Andro', 'Chemical', 'MESH:C030419', (85, 90))	('TRAIL', 'Gene', '8743', (134, 139))	('cell apoptosis rate', 'CPA', (111, 130))	('p53', 'Gene', '7157', (17, 20))
70893	30745855	In the present study, clinical database analysis and GSEA revealed that mRNA expression of death receptors of TRAIL is positively associated with apoptosis signaling pathway in BLCA patients (Figure 1A and B).	('BLCA', 'Disease', (177, 181))	('TRAIL', 'Gene', '8743', (110, 115))	('signaling pathway', 'biological_process', 'GO:0007165', ('156', '173'))	('BLCA', 'Chemical', '-', (177, 181))	('patients', 'Species', '9606', (182, 190))	('GSEA', 'Chemical', '-', (53, 57))	('apoptosis signaling pathway', 'Pathway', (146, 173))	('TRAIL', 'Gene', (110, 115))	('apoptosis signaling', 'biological_process', 'GO:0006915', ('146', '165'))	('mRNA', 'Var', (72, 76))	('associated', 'Reg', (130, 140))
70907	30745855	Crucially, we noticed that silencing DR5 in BLCA cells is more effective in restoring the resistance for Andro/TRAIL treatment than silencing DR4, indicating that DR5 expression level is the major determinant for the sensitization by Andro in BLCA cells.	('DR4', 'Gene', (142, 145))	('silencing', 'Var', (27, 36))	('DR5', 'Gene', (163, 166))	('DR5', 'Gene', '8795', (163, 166))	('restoring', 'PosReg', (76, 85))	('TRAIL', 'Gene', '8743', (111, 116))	('Andro', 'Chemical', 'MESH:C030419', (105, 110))	('DR5', 'Gene', (37, 40))	('TRAIL', 'Gene', (111, 116))	('sensitization', 'biological_process', 'GO:0046960', ('217', '230'))	('BLCA', 'Chemical', '-', (44, 48))	('DR4', 'Gene', '8797', (142, 145))	('BLCA', 'Chemical', '-', (243, 247))	('Andro', 'Chemical', 'MESH:C030419', (234, 239))	('DR5', 'Gene', '8795', (37, 40))
70931	30745855	Z-VAD-FMK (HY-16658), Necrostatin-1 (HY-15760), and PDTC (HY-18738) were purchased from MedChemExpress (Monmouth Junction, NJ, USA).	('HY-16658', 'Var', (11, 19))	('PDTC', 'Chemical', 'MESH:C020972', (52, 56))	('HY-15760', 'Var', (37, 45))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (0, 9))
70953	30745855	Andro andrographolide IC50 50% inhibitory concentration MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium TRAIL tumor necrosis factor-related apoptosis-inducing ligand BLCA bladder urothelial carcinoma TCGA The Cancer Genome Atlas MMP matrix metalloproteinase DMSO dimethyl sulfoxide FITC fluorescein isothiocyanate GSEA Gene set enrichment analysis Nec-1 necrostatin-1 SD standard deviation shRNA short-hairpin RNA TNFRSF10A/B tumor necrosis factor receptor superfamily member 10A/B Bcl-2 B cell lymphoma 2 cIAP2 cellular inhibitor of apoptosis 2 qRT-PCR quantitative reverse transcription polymerase chain reaction RelA NF-kappaB p65 subunit XIAP X-linked inhibitor of apoptosis.	('necrosis', 'Disease', (478, 486))	('bladder urothelial carcinoma', 'Disease', (217, 245))	('X-linked inhibitor of apoptosis', 'Gene', (693, 724))	('cIAP2', 'Gene', (552, 557))	('TNFRSF10A', 'Gene', '8797', (460, 469))	('Cancer Genome Atlas', 'Disease', (255, 274))	('tumor', 'Disease', (472, 477))	('necrosis', 'biological_process', 'GO:0001906', ('162', '170'))	('XIAP', 'Gene', (688, 692))	('tumor', 'Disease', (156, 161))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (309, 327))	('TNFRSF10A', 'Gene', (460, 469))	('X-linked inhibitor of apoptosis', 'Gene', '331', (693, 724))	('necrosis', 'biological_process', 'GO:0008220', ('478', '486'))	('GSEA', 'Chemical', '-', (360, 364))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (217, 245))	('reverse transcription', 'biological_process', 'GO:0001171', ('613', '634'))	('3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium', 'Chemical', '-', (60, 149))	('tumor', 'Disease', 'MESH:D009369', (472, 477))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (534, 549))	('ligand', 'molecular_function', 'GO:0005488', ('205', '211'))	('fluorescein isothiocyanate', 'Chemical', 'MESH:D016650', (333, 359))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cIAP2', 'Gene', '330', (552, 557))	('lymphoma', 'Phenotype', 'HP:0002665', (541, 549))	('B cell lymphoma 2', 'Gene', '596', (534, 551))	('FITC', 'Chemical', '-', (328, 332))	('necrosis', 'biological_process', 'GO:0008219', ('162', '170'))	('Cancer', 'Phenotype', 'HP:0002664', (255, 261))	('Bcl-2', 'molecular_function', 'GO:0015283', ('528', '533'))	('apoptosis', 'biological_process', 'GO:0006915', ('580', '589'))	('necrosis', 'biological_process', 'GO:0070265', ('478', '486'))	('apoptosis', 'biological_process', 'GO:0097194', ('580', '589'))	('Andro', 'Chemical', 'MESH:C030419', (0, 5))	('necrosis', 'biological_process', 'GO:0019835', ('478', '486'))	('Bcl-2', 'Gene', (528, 533))	('TRAIL', 'Gene', '8743', (150, 155))	('10A/B', 'SUBSTITUTION', 'None', (466, 471))	('BLCA', 'Chemical', '-', (212, 216))	('necrosis', 'biological_process', 'GO:0001906', ('478', '486'))	('apoptosis', 'biological_process', 'GO:0097194', ('715', '724'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('156', '177'))	('RelA', 'Gene', (661, 665))	('tumor', 'Phenotype', 'HP:0002664', (472, 477))	('apoptosis', 'biological_process', 'GO:0006915', ('715', '724'))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('10A/B', 'Var', (522, 527))	('B cell lymphoma 2', 'Gene', (534, 551))	('XIAP', 'Gene', '331', (688, 692))	('necrosis', 'Disease', 'MESH:D009336', (162, 170))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('472', '493'))	('cellular inhibitor of apoptosis 2', 'Gene', '330', (558, 591))	('apoptosis', 'biological_process', 'GO:0097194', ('186', '195'))	('necrosis', 'biological_process', 'GO:0008220', ('162', '170'))	('Bcl-2', 'Gene', '596', (528, 533))	('apoptosis', 'biological_process', 'GO:0006915', ('186', '195'))	('10A/B', 'Var', (466, 471))	('DMSO', 'Chemical', 'MESH:D004121', (304, 308))	('TRAIL', 'Gene', (150, 155))	('10A/B', 'SUBSTITUTION', 'None', (522, 527))	('NF-kappaB p65', 'Gene', (666, 679))	('NF-kappaB p65', 'Gene', '5970', (666, 679))	('MMP', 'molecular_function', 'GO:0004235', ('275', '278'))	('necrosis', 'Disease', (162, 170))	('RelA', 'Gene', '5970', (661, 665))	('necrosis', 'biological_process', 'GO:0070265', ('162', '170'))	('necrosis', 'biological_process', 'GO:0019835', ('162', '170'))	('necrosis', 'Disease', 'MESH:D009336', (478, 486))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (255, 274))	('necrosis', 'biological_process', 'GO:0008219', ('478', '486'))	('cellular inhibitor of apoptosis 2', 'Gene', (558, 591))	('andrographolide', 'Chemical', 'MESH:C030419', (6, 21))	('RNA', 'cellular_component', 'GO:0005562', ('456', '459'))
70957	30546953	These datasets were comprised of urothelial carcinoma patients receiving anti-PD-L1 (n = 25), melanoma patients receiving anti-PD-1 (n = 28), and melanoma patients receiving anti-CTLA-4 (n = 42).	('CTLA-4', 'Gene', (179, 185))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('PD-1', 'Gene', (127, 131))	('anti-PD-L1', 'Var', (73, 83))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('PD-1', 'Gene', '5133', (127, 131))	('patients', 'Species', '9606', (54, 62))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Disease', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('urothelial carcinoma', 'Disease', (33, 53))	('CTLA-4', 'Gene', '1493', (179, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (103, 111))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (33, 53))
70965	30546953	Blocking these proteins has led to increased immune activity in the tumor microenvironments of responsive patients, resulting in long-term remission and clinical benefit.	('tumor', 'Disease', (68, 73))	('increased', 'PosReg', (35, 44))	('Blocking', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('immune activity', 'MPA', (45, 60))	('proteins', 'Protein', (15, 23))	('patients', 'Species', '9606', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
70974	30546953	In this study, we applied an expression-based, immune signature-driven framework to identify correlates of response to the immune checkpoint inhibitors anti-PD-L1, anti-PD-1, and anti-CTLA-4.	('CTLA-4', 'Gene', (184, 190))	('anti-PD-L1', 'Var', (152, 162))	('PD-1', 'Gene', (169, 173))	('CTLA-4', 'Gene', '1493', (184, 190))	('PD-1', 'Gene', '5133', (169, 173))
70977	30546953	We began our study by applying this method to a discovery dataset that included gene expression and treatment response information for 21 pre-treatment urothelial tumor biopsies from patients receiving anti-PD-L1 therapy.	('anti-PD-L1', 'Var', (202, 212))	('pre', 'molecular_function', 'GO:0003904', ('138', '141'))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('gene expression', 'biological_process', 'GO:0010467', ('80', '95'))	('urothelial tumor', 'Disease', 'MESH:D001749', (152, 168))	('urothelial tumor', 'Disease', (152, 168))	('patients', 'Species', '9606', (183, 191))
70979	30546953	These improved response rates also translated to post-treatment survival, where patients with MBL scores in the top quartile had significantly longer progression-free survival (median 398 days) compared to patients with scores in the bottom quartile (median 64 days, P = 0.02; Figure 1B).	('progression-free survival', 'CPA', (150, 175))	('scores', 'Var', (98, 104))	('patients', 'Species', '9606', (80, 88))	('longer', 'PosReg', (143, 149))	('patients', 'Species', '9606', (206, 214))	('MBL', 'Gene', (94, 97))	('MBL', 'Gene', '4153', (94, 97))
70984	30546953	Furthermore, patients with MBL scores in the top quartile had a median overall survival time of 548 days compared to 186 days for patients with MBL scores in the bottom quartile, a difference that trended toward significance (P = 0.06; Figure 1D).	('patients', 'Species', '9606', (13, 21))	('scores', 'Var', (31, 37))	('MBL', 'Gene', (27, 30))	('patients', 'Species', '9606', (130, 138))	('MBL', 'Gene', '4153', (27, 30))	('MBL', 'Gene', '4153', (144, 147))	('MBL', 'Gene', (144, 147))
70992	30546953	To increase the power of these analyses, we then pooled the datasets into two cohorts, one combining the anti-PD-1 and anti-PD-L1 datasets and one combining the datasets for all three immune checkpoint inhibitors (Supplementary Table S1).	('PD-1', 'Gene', (110, 114))	('PD-1', 'Gene', '5133', (110, 114))	('anti-PD-L1', 'Var', (119, 129))
70994	30546953	This result was also reflected in the two-class survival analyses, where patients with MBL scores in the top quartile of each dataset exhibited significantly prolonged survival time in the combined anti-PD-1/anti-PD-L1 cohort (meta-P = 3e-3) and the combined checkpoint inhibitor cohort (meta-P = 6e-5; Figure 3B).	('prolonged', 'PosReg', (158, 167))	('scores', 'Var', (91, 97))	('PD-1', 'Gene', (203, 207))	('patients', 'Species', '9606', (73, 81))	('PD-1', 'Gene', '5133', (203, 207))	('survival time', 'CPA', (168, 181))	('MBL', 'Gene', (87, 90))	('MBL', 'Gene', '4153', (87, 90))
71008	30546953	These results notably differed from the original anti-PD-1 study, which reported that somatic mutation burden was associated with improved survival following treatment.	('PD-1', 'Gene', '5133', (54, 58))	('somatic mutation burden', 'Var', (86, 109))	('survival', 'CPA', (139, 147))	('PD-1', 'Gene', (54, 58))	('improved', 'PosReg', (130, 138))
71012	30546953	In a univariate setting, the IPRES signature was associated with both patient response to anti-PD-1 in a logistic regression model (P = 3e-3; Supplementary Table S2) and poor patient survival in a Cox proportional hazards model (P = 0.04, HR = 3.46; Supplementary Table S2).	('poor', 'NegReg', (170, 174))	('patient survival', 'CPA', (175, 191))	('PD-1', 'Gene', '5133', (95, 99))	('PD-1', 'Gene', (95, 99))	('patient', 'Species', '9606', (175, 182))	('patient', 'Species', '9606', (70, 77))	('patient response', 'MPA', (70, 86))	('IPRES signature', 'Var', (29, 44))
71023	30546953	Performing this procedure in each dataset gave us AUCs of 0.74, 0.68, and 0.72 for the anti-PD-L1, anti-PD-1 and anti-CTLA-4 datasets, respectively (Supplementary Table S2).	('anti-PD-L1', 'Var', (87, 97))	('CTLA-4', 'Gene', (118, 124))	('PD-1', 'Gene', (104, 108))	('PD-1', 'Gene', '5133', (104, 108))	('CTLA-4', 'Gene', '1493', (118, 124))
71026	30546953	In all three datasets, the AUCs from the simulated datasets remained high (AUC = 0.70, 0.66, and 0.71 for anti-PD-L1, anti-PD-1, and anti-CTLA-4, respectively), with the lower-bound of the 95% confidence interval never crossing the 0.5 random classification threshold in any case (Supplementary Table S2).	('PD-1', 'Gene', (123, 127))	('PD-1', 'Gene', '5133', (123, 127))	('CTLA-4', 'Gene', (138, 144))	('AUCs', 'MPA', (27, 31))	('CTLA-4', 'Gene', '1493', (138, 144))	('anti-PD-L1', 'Var', (106, 116))
71044	30546953	In contrast, the anti-PD-1 genes were most associated with antigen presentation (GO:0002475, GO:0019883), T cell activity (GO:0001916) and B cell activity (GO:0050855), while the anti-CTLA-4 genes were most associated with T-helper cell function (GO:0002295, GO:0042088) and B cell activity (GO:0002923, GO:0045579) (Supplementary Table S5).	('PD-1', 'Gene', (22, 26))	('PD-1', 'Gene', '5133', (22, 26))	('GO:0002475', 'Var', (81, 91))	('B cell activity', 'CPA', (275, 290))	('associated', 'Reg', (207, 217))	('CTLA-4', 'Gene', '1493', (184, 190))	('GO:0002923', 'Var', (292, 302))	('GO:0045579', 'Var', (304, 314))	('CTLA-4', 'Gene', (184, 190))	('B cell activity', 'CPA', (139, 154))	('GO:0050855', 'Var', (156, 166))	('GO:0019883', 'Var', (93, 103))	('T-helper cell function', 'CPA', (223, 245))	('associated', 'Reg', (43, 53))	('GO:0002295', 'Var', (247, 257))	('GO:0001916', 'Var', (123, 133))	('antigen presentation', 'biological_process', 'GO:0019882', ('59', '79'))	('GO:0042088', 'Var', (259, 269))	('antigen presentation', 'MPA', (59, 79))
71142	29416608	In the subgroup of tumor grade, our data indicated that patients who suffered from high grade tumor accompanied by SD had a higher recurrence rate (78.5% vs. 67.2%, P = 0.041, group 1 vs. group 2; Table 3) and progression rate (30.8% vs. 17.4%, P = 0.034, group 1 vs. group 2; Table 4), supporting the idea that patients with high-risk non-muscle-invasive tumors and variant histology should be offered early cystectomy, especially for patients harboring SD.	('tumors', 'Disease', (356, 362))	('tumors', 'Disease', 'MESH:D009369', (356, 362))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('patients', 'Species', '9606', (56, 64))	('tumors', 'Phenotype', 'HP:0002664', (356, 362))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('patients', 'Species', '9606', (312, 320))	('SD', 'Disease', 'MESH:D029461', (115, 117))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (356, 361))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('variant', 'Var', (367, 374))	('SD', 'Disease', 'MESH:D029461', (455, 457))	('tumor', 'Disease', (19, 24))	('patients', 'Species', '9606', (436, 444))	('tumor', 'Phenotype', 'HP:0002664', (356, 361))	('tumor', 'Disease', (356, 361))
71227	29118536	Another mesenchymal bladder neoplasm was extraskeletal myxoid chondrosarcoma in a 1 year old male who also had EWSR1 gene mutation.	('bladder neoplasm', 'Phenotype', 'HP:0009725', (20, 36))	('mutation', 'Var', (122, 130))	('EWSR1', 'Gene', (111, 116))	('neoplasm', 'Phenotype', 'HP:0002664', (28, 36))	('bladder neoplasm', 'Disease', 'MESH:D001749', (20, 36))	('myxoid chondrosarcoma', 'Disease', (55, 76))	('EWSR1', 'Gene', '2130', (111, 116))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (62, 76))	('bladder neoplasm', 'Disease', (20, 36))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (55, 76))
71265	27733243	Nivolumab has shown improved OS in melanoma, non-small-cell lung cancer, renal cell carcinoma, and head and neck cancer, and studies have shown promising clinical activity in multiple additional malignancies including Hodgkin's lymphoma and microsatellite-unstable colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (265, 282))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (73, 93))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (49, 71))	('colorectal cancer', 'Disease', (265, 282))	('head and neck cancer', 'Phenotype', 'HP:0012288', (99, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('neck', 'cellular_component', 'GO:0044326', ('108', '112'))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (218, 236))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (45, 71))	('renal cell carcinoma', 'Disease', (73, 93))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (218, 236))	('lung cancer', 'Disease', (60, 71))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (73, 93))	('OS', 'Chemical', 'MESH:D009992', (29, 31))	('colorectal cancer', 'Phenotype', 'HP:0003003', (265, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('head and neck cancer', 'Disease', 'MESH:D006258', (99, 119))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('microsatellite-unstable', 'Var', (241, 264))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))	('improved', 'PosReg', (20, 28))	("Hodgkin's lymphoma", 'Disease', (218, 236))	('malignancies', 'Disease', 'MESH:D009369', (195, 207))	('Nivolumab', 'Chemical', 'MESH:D000077594', (0, 9))	('lymphoma', 'Phenotype', 'HP:0002665', (228, 236))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('malignancies', 'Disease', (195, 207))
71322	27733243	An objective response was achieved in six (24 0%; 95% CI 9 4-45 1) of 25 patients with PD-L1 expression >=1% (complete response in four patients [16 0%] and partial response in two [8 0%] patients), and in 11 (26 2%; 95% CI 13 9-42 0) of 42 patients with PD-L1 expression <1% (complete response in one patient [2 4%] and partial response in ten [23 8%] patients).	('patient', 'Species', '9606', (136, 143))	('patient', 'Species', '9606', (188, 195))	('patient', 'Species', '9606', (353, 360))	('patients', 'Species', '9606', (353, 361))	('patient', 'Species', '9606', (302, 309))	('patient', 'Species', '9606', (241, 248))	('patients', 'Species', '9606', (188, 196))	('patient', 'Species', '9606', (73, 80))	('patients', 'Species', '9606', (136, 144))	('PD-L1', 'Gene', (87, 92))	('patients', 'Species', '9606', (73, 81))	('patients', 'Species', '9606', (241, 249))	('>=1%', 'Var', (104, 108))
71324	27733243	Median OS was 16 2 months (95% CI 7 6-not estimable) in patients with PD-L1 expression >=1% and 9 9 months (7 0-not estimable) in patients with PD-L1 expression <1% (appendix, p8).	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (130, 138))	('PD-L1', 'Gene', (70, 75))	('OS', 'Chemical', 'MESH:D009992', (7, 9))	('>=1%', 'Var', (87, 91))
71325	27733243	Median PFS was 5 5 months (95% CI 1 4-11 2) in patients with PD-L1 expression >=1% and 2 8 months (1 4-6 5) in patients with PD-L1 expression <1% (appendix, p9).	('>=1%', 'Var', (78, 82))	('PD-L1', 'Gene', (61, 66))	('patients', 'Species', '9606', (47, 55))	('patients', 'Species', '9606', (111, 119))
71352	27733243	PD-L1 expression on tumour cells, as defined by the Dako immunohistochemical assay, did not correlate with objective responses; patients whose tumours were defined as having >=1% of tumour cells expressing PD-L1 had an ORR similar to that in patients whose tumours had <1% of tumour cells expressing PD-L1.	('tumour', 'Disease', (276, 282))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('tumour', 'Disease', (20, 26))	('tumours', 'Phenotype', 'HP:0002664', (257, 264))	('tumours', 'Disease', 'MESH:D009369', (257, 264))	('patients', 'Species', '9606', (242, 250))	('tumour', 'Phenotype', 'HP:0002664', (257, 263))	('tumour', 'Disease', 'MESH:D009369', (257, 263))	('tumour', 'Disease', (257, 263))	('tumours', 'Disease', (143, 150))	('PD-L1', 'Var', (206, 211))	('tumours', 'Phenotype', 'HP:0002664', (143, 150))	('tumours', 'Disease', 'MESH:D009369', (143, 150))	('patients', 'Species', '9606', (128, 136))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('tumour', 'Disease', (143, 149))	('tumour', 'Disease', (182, 188))	('tumour', 'Phenotype', 'HP:0002664', (276, 282))	('tumour', 'Disease', 'MESH:D009369', (276, 282))	('tumours', 'Disease', (257, 264))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
71353	27733243	Patients whose tumours had >=1% of tumour cells expressing PD-L1 had a median OS of 16 2 months, while those whose tumours had <1% of tumour cells expressing PD-L1 had a median OS of 9 9 months.	('tumours', 'Disease', (115, 122))	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Disease', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('OS', 'Chemical', 'MESH:D009992', (177, 179))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('tumour', 'Disease', (115, 121))	('tumours', 'Disease', 'MESH:D009369', (115, 122))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('Patients', 'Species', '9606', (0, 8))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('tumour', 'Disease', (35, 41))	('tumours', 'Disease', (15, 22))	('PD-L1', 'Var', (59, 64))	('OS', 'Chemical', 'MESH:D009992', (78, 80))	('had >=1', 'CellLine', '10090', (23, 30))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))	('tumours', 'Disease', 'MESH:D009369', (15, 22))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('tumour', 'Disease', (134, 140))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
71375	28552987	Although mutation load and PD-L1 immune cell (IC) staining have been associated with response, they lack sufficient sensitivity and specificity for clinical use.	('associated with', 'Reg', (69, 84))	('response', 'Disease', (85, 93))	('mutation load', 'Var', (9, 22))	('PD-L1', 'Gene', (27, 32))	('PD-L1', 'Gene', '29126', (27, 32))
71376	28552987	Thus, there is a need to evaluate the peripheral blood immune environment and to conduct detailed analyses of mutation load, predicted neoantigens, and immune cellular infiltration in tumors to enhance our understanding of the biologic underpinnings of response and resistance.	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('tumors', 'Disease', (184, 190))	('mutation', 'Var', (110, 118))
71377	28552987	The goals of this study were to (1) evaluate the association of mutation load and predicted neoantigen load with therapeutic benefit and (2) determine whether intratumoral and peripheral blood T cell receptor (TCR) clonality inform clinical outcomes in urothelial carcinoma treated with atezolizumab.	('tumor', 'Disease', (164, 169))	('atezolizumab', 'Chemical', 'MESH:C000594389', (287, 299))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (253, 273))	('neoantigen load', 'MPA', (92, 107))	('TCR', 'Gene', '6962', (210, 213))	('TCR', 'cellular_component', 'GO:0042101', ('210', '213'))	('urothelial carcinoma', 'Disease', (253, 273))	('association', 'Interaction', (49, 60))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('T cell receptor', 'Gene', (193, 208))	('T cell receptor', 'Gene', '6962', (193, 208))	('TCR', 'biological_process', 'GO:0006283', ('210', '213'))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('TCR', 'Gene', (210, 213))	('mutation load', 'Var', (64, 77))
71378	28552987	We hypothesized that an elevated mutation load in combination with T cell clonal dominance among intratumoral lymphocytes prior to treatment or among peripheral T cells after treatment would be associated with effective tumor control upon treatment with anti-PD-L1 therapy.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('PD-L1', 'Gene', (259, 264))	('mutation', 'Var', (33, 41))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('PD-L1', 'Gene', '29126', (259, 264))	('associated', 'Reg', (194, 204))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
71385	28552987	Missense mutation load, predicted neoantigen load, and expressed neoantigen load did not demonstrate significant association with DCB (n = 25, Mann-Whitney p = 0.22, n = 25, Mann-Whitney p = 0.55, and n = 25, Mann-Whitney p = 0.29, respectively).	('DCB', 'Chemical', '-', (130, 133))	('neoantigen load', 'MPA', (34, 49))	('Missense mutation load', 'Var', (0, 22))	('DCB', 'Disease', (130, 133))
71400	28552987	Similar to predictive factor analyses in melanoma, colon cancer, and non-small cell lung cancer studies with other checkpoint blockade agents, Rosenberg and colleagues reported a statistically significant association between mutation load and response to atezolizumab in urothelial cancer patients.	('significant association', 'Reg', (193, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('non-small cell lung cancer', 'Disease', (69, 95))	('atezolizumab', 'Chemical', 'MESH:C000594389', (255, 267))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('colon cancer', 'Disease', 'MESH:D015179', (51, 63))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (69, 95))	('urothelial cancer', 'Disease', 'MESH:D014523', (271, 288))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('patients', 'Species', '9606', (289, 297))	('colon cancer', 'Disease', (51, 63))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (73, 95))	('urothelial cancer', 'Disease', (271, 288))	('mutation load', 'Var', (225, 238))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (69, 95))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('response', 'MPA', (243, 251))	('colon cancer', 'Phenotype', 'HP:0003003', (51, 63))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))
71402	28552987	Similar to findings from prior studies, the association between this predicted mutation load and outcomes in patients with urothelial cancer was not dichotomous; there were tumors from patients with elevated mutation load that did not respond to therapy, and vice versa.	('patients', 'Species', '9606', (109, 117))	('urothelial cancer', 'Disease', (123, 140))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Disease', (173, 179))	('urothelial cancer', 'Disease', 'MESH:D014523', (123, 140))	('patients', 'Species', '9606', (185, 193))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('mutation load', 'Var', (208, 221))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
71404	28552987	A statistical model suggested that both PD-L1 staining and mutation load impacted the likelihood of response.	('mutation', 'Var', (59, 67))	('impacted', 'Reg', (73, 81))	('PD-L1', 'Gene', (40, 45))	('PD-L1', 'Gene', '29126', (40, 45))
71429	28552987	ImmunoSEQ then amplifies and sequences the molecules with rearranged TCRbeta chains.	('TCRbeta', 'Gene', '6962', (69, 76))	('rearranged', 'Var', (58, 68))	('TCRbeta', 'Gene', (69, 76))
71475	28552987	We found that low pretreatment peripheral TCR clonality was associated with improved PFS (split by median clonality, n = 29, log-rank p = 0.048), overall survival (OS, split by median clonality, n = 29, log-rank p = 0.011), and OS greater than 12 months (DCB-OS, n = 29, Mann-Whitney p = 0.0061; Fig 1C, 1D and 1E), although not with DCB (Fig 1F, n = 29, Mann-Whitney p = 0.25).	('TCR', 'Gene', (42, 45))	('overall survival', 'CPA', (146, 162))	('PFS', 'CPA', (85, 88))	('OS', 'Chemical', '-', (259, 261))	('DCB', 'Chemical', '-', (334, 337))	('TCR', 'biological_process', 'GO:0006283', ('42', '45'))	('TCR', 'Gene', '6962', (42, 45))	('improved', 'PosReg', (76, 84))	('OS', 'Chemical', '-', (228, 230))	('TCR', 'cellular_component', 'GO:0042101', ('42', '45'))	('DCB-OS', 'Chemical', '-', (255, 261))	('low', 'Var', (14, 17))	('OS', 'Chemical', '-', (164, 166))	('DCB', 'Chemical', '-', (255, 258))
71483	28552987	There was no significant association between median missense mutation load and DCB (median mutations per megabase 3.24 [range 0.038-11.46] in patients with DCB compared to 0.45 [range 0.019-9.90] in those without DCB, n = 25, Mann-Whitney p = 0.22, Fig 2B).	('DCB', 'Disease', (79, 82))	('DCB', 'Chemical', '-', (79, 82))	('DCB', 'Chemical', '-', (156, 159))	('missense mutation load', 'Var', (52, 74))	('DCB', 'Var', (156, 159))	('patients', 'Species', '9606', (142, 150))	('DCB', 'Chemical', '-', (213, 216))
71484	28552987	There was also no significant association between missense mutation load and DCB-OS (n = 25, Mann-Whitney p = 0.37, S2A Fig).	('DCB-OS', 'Chemical', '-', (77, 83))	('missense mutation load', 'Var', (50, 72))	('DCB-OS', 'Disease', (77, 83))
71486	28552987	When filtering to expressed mutations, we found a median of 0.79 (range 0.00-3.36) expressed mutations per megabase for patients with DCB and a median of 0.16 (range 0.00-3.34) expressed mutations per megabase for patients without DCB (n = 25, Mann-Whitney p = 0.26, S2B Fig).	('DCB', 'Chemical', '-', (134, 137))	('mutations', 'Var', (93, 102))	('patients', 'Species', '9606', (214, 222))	('patients', 'Species', '9606', (120, 128))	('DCB', 'Chemical', '-', (231, 234))	('DCB', 'Disease', (134, 137))
71489	28552987	One hypothesis for explaining the association between mutation load and outcome to treatment with checkpoint blockade is the generation of neoantigens, altered peptides presented by the major histocompatibility complex that are capable of eliciting an antitumor T cell response and are more common with increased mutation load.	('mutation', 'Var', (54, 62))	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('186', '218'))	('mutation load', 'Var', (313, 326))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('eliciting', 'Reg', (239, 248))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Disease', (256, 261))
71494	28552987	Given that the mutation load and outcomes were weakly associated in the complete IMvigor210 dataset and not statistically significantly associated in this cohort, we embarked upon an exploration of additional factors, including tumor microenvironmental and systemic measures, which may modify the importance of this variable or independently affect outcomes.	('mutation', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('affect', 'Reg', (342, 348))	('tumor', 'Disease', (228, 233))	('modify', 'Reg', (286, 292))
71496	28552987	In terms of the estimate of these effects, patients who survived longer than 3 months exhibited a stronger association between the number of somatic mutations per megabase and a lower risk of subsequent mortality (n = 11, HR = 0.80, 95% CI [0.60, 1.00]) as compared to those who survived less than or equal to 3 months (n = 25, HR = 1.02, 95% CI [0.79, 1.22], Fig 3B).	('lower', 'NegReg', (178, 183))	('patients', 'Species', '9606', (43, 51))	('mutations', 'Var', (149, 158))
71503	28552987	There were no significant differences in these patients with respect to Bacillus Calmette-Guerin (BCG) exposure (n = 29, Fisher's Exact p = 0.20), missense SNV load (n = 25, Mann-Whitney p = 0.26), and pretreatment peripheral TCR clonality (n = 29, Mann-Whitney p = 0.12).	('TCR', 'cellular_component', 'GO:0042101', ('226', '229'))	('Bacillus Calmette-Guerin', 'Species', '33892', (72, 96))	('TCR', 'Gene', '6962', (226, 229))	('TCR', 'biological_process', 'GO:0006283', ('226', '229'))	('patients', 'Species', '9606', (47, 55))	('BCG', 'Species', '33892', (98, 101))	('TCR', 'Gene', (226, 229))	('missense SNV', 'Var', (147, 159))
71508	28552987	When we performed GSEA using the Hallmark Geneset, we did not observe any differentially expressed gene sets between tumors from patients with DCB versus no DCB.	('DCB', 'Var', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('GSEA', 'Chemical', '-', (18, 22))	('patients', 'Species', '9606', (129, 137))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('DCB', 'Chemical', '-', (157, 160))	('DCB', 'Chemical', '-', (143, 146))
71515	28552987	Interestingly, of the 4 IC2 tumors among HAVCR2-high patients (HAVCR2 expression greater than the median), 2 had missense SNV loads at or below the median (2 and 57); the other 2 had 180 and 412 SNVs.	('HAVCR2', 'Gene', '84868', (63, 69))	('patients', 'Species', '9606', (53, 61))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('HAVCR2', 'Gene', '84868', (41, 47))	('IC2 tumors', 'Disease', (24, 34))	('HAVCR2', 'Gene', (41, 47))	('missense', 'Var', (113, 121))	('IC2 tumors', 'Disease', 'MESH:D009369', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('HAVCR2', 'Gene', (63, 69))
71517	28552987	Unanswered questions that arise from the many studies of biomarker correlates of checkpoint blockade response are whether measures such as mutation load, PD-L1 staining, and others reflect the same "tumor state" or if each confers an independent effect on outcome?	('tumor', 'Disease', (199, 204))	('PD-L1', 'Gene', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('PD-L1', 'Gene', '29126', (154, 159))	('mutation load', 'Var', (139, 152))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
71519	28552987	Among patients with tumors showing little-to-no expression of PD-L1 (IC0 rated), each unit increase in missense SNV count per megabase was associated with a negligible change in hazard (n = 4, HR = 1.43, 95% CI [0.75, 2.98]).	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('PD-L1', 'Gene', '29126', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('increase', 'PosReg', (91, 99))	('missense', 'Var', (103, 111))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('PD-L1', 'Gene', (62, 67))
71520	28552987	Among patients with tumors expressing PD-L1 at moderate or high levels (IC1 or IC2 staining), missense SNV count per megabase was associated with lower risk for disease progression or mortality (among IC1: n = 11, HR = 0.75, 95% CI [0.47, 1.14]; among IC2: n = 10, HR = 0.73, 95% CI [0.48, 1.06]).	('mortality', 'CPA', (184, 193))	('IC1', 'Gene', (72, 75))	('IC2', 'Gene', '1781', (79, 82))	('lower', 'NegReg', (146, 151))	('patients', 'Species', '9606', (6, 14))	('IC2', 'Gene', (79, 82))	('IC2', 'Gene', (252, 255))	('IC2', 'Gene', '1781', (252, 255))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('IC1', 'Gene', '105259599', (72, 75))	('PD-L1', 'Gene', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('missense SNV count', 'Var', (94, 112))	('disease progression', 'CPA', (161, 180))	('PD-L1', 'Gene', '29126', (38, 43))	('IC1', 'Gene', (201, 204))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('IC1', 'Gene', '105259599', (201, 204))
71521	28552987	Although our limited sample size precludes making an assertion that mutation load is associated with survival in any particular subgroup (e.g., when looking among IC1 and IC2 tumors alone), our data do support the presence of an interaction among these variables (p = 0.046 for interaction; S5A Fig).	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('IC1', 'Gene', (163, 166))	('associated with', 'Reg', (85, 100))	('IC2 tumors', 'Disease', (171, 181))	('mutation load', 'Var', (68, 81))	('IC1', 'Gene', '105259599', (163, 166))	('IC2 tumors', 'Disease', 'MESH:D009369', (171, 181))	('interaction', 'Interaction', (229, 240))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
71524	28552987	Among patients without liver metastasis, somatic mutation load was associated with a lower risk for disease progression or mortality (n = 16, HR = 0.73, 95% CI [0.50, 1.02], S5B Fig) than patients with liver metastasis (n = 9, HR = 0.96, 95% CI [0.66, 1.37], S5B Fig).	('disease progression', 'CPA', (100, 119))	('liver metastasis', 'Disease', 'MESH:D009362', (202, 218))	('liver metastasis', 'Disease', (202, 218))	('lower', 'NegReg', (85, 90))	('somatic mutation load', 'Var', (41, 62))	('patients', 'Species', '9606', (188, 196))	('patients', 'Species', '9606', (6, 14))	('mortality', 'CPA', (123, 132))	('liver metastasis', 'Disease', 'MESH:D009362', (23, 39))	('liver metastasis', 'Disease', (23, 39))
71525	28552987	To our surprise, although both PD-L1 staining and mutation load were each associated with response in the original study, these variables did not correlate with each other (Fig 4A).	('PD-L1', 'Gene', '29126', (31, 36))	('PD-L1', 'Gene', (31, 36))	('associated', 'Reg', (74, 84))	('mutation load', 'Var', (50, 63))
71542	28552987	Although the overall study found significant associations between mutation load as measured by the Foundation Medicine targeted sequencing panel and radiographic response, there was no statistically significant association between mutation load and DCB or survival in the patient subset studied here, despite the similarity of our study population to the parent study.	('DCB', 'Chemical', '-', (249, 252))	('mutation', 'Var', (66, 74))	('patient', 'Species', '9606', (272, 279))	('DCB', 'Disease', (249, 252))
71543	28552987	To illustrate the fickle nature of defining mutation load, counting only the mutations excluded by BQSR, as opposed to only those remaining after BQSR, showed a significant association with DCB.	('mutations', 'Var', (77, 86))	('DCB', 'Disease', (190, 193))	('DCB', 'Chemical', '-', (190, 193))
71544	28552987	The weak association of mutation load with DCB and the lack of such standardization render this biomarker unfit for application to individual patients at present.	('mutation load', 'Var', (24, 37))	('DCB', 'Disease', (43, 46))	('DCB', 'Chemical', '-', (43, 46))	('patients', 'Species', '9606', (142, 150))	('association', 'Interaction', (9, 20))
71546	28552987	We found that even in this small dataset, TCR clonality below the median in the peripheral blood prior to treatment, expansion of tumor-associated TCR in the periphery 3 weeks after initiating treatment, and higher TIL proportion are all associated with clinical benefit.	('TCR', 'biological_process', 'GO:0006283', ('147', '150'))	('TCR', 'Gene', (42, 45))	('expansion', 'Var', (117, 126))	('TCR', 'Gene', '6962', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('TCR', 'Gene', '6962', (42, 45))	('TCR', 'cellular_component', 'GO:0042101', ('42', '45'))	('TCR', 'cellular_component', 'GO:0042101', ('147', '150'))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('TCR', 'Gene', (147, 150))	('tumor', 'Disease', (130, 135))	('TCR', 'biological_process', 'GO:0006283', ('42', '45'))
71550	28552987	We hypothesize that low TCR clonality in the peripheral blood prior to treatment increases the likelihood that a patient harbors 1 or several clones capable of tumor recognition, whether of neoantigens or tumor-associated antigens.	('patient', 'Species', '9606', (113, 120))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('TCR', 'Gene', '6962', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (205, 210))	('low', 'Var', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('TCR', 'cellular_component', 'GO:0042101', ('24', '27'))	('tumor', 'Disease', (160, 165))	('TCR', 'biological_process', 'GO:0006283', ('24', '27'))	('TCR', 'Gene', (24, 27))
71553	28552987	For example, while mutation load seemed to be associated with outcome more significantly in PD-L1 IC1 and IC2 tumors, high PD-L1 IC staining in the setting of high peripheral TCR clonality was associated with a substantial hazard for poor outcome.	('high', 'Var', (118, 122))	('IC2 tumors', 'Disease', 'MESH:D009369', (106, 116))	('mutation load', 'Var', (19, 32))	('TCR', 'Gene', '6962', (175, 178))	('PD-L1', 'Gene', (92, 97))	('TCR', 'cellular_component', 'GO:0042101', ('175', '178'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('PD-L1', 'Gene', (123, 128))	('IC2 tumors', 'Disease', (106, 116))	('IC1', 'Gene', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('PD-L1', 'Gene', '29126', (92, 97))	('TCR', 'biological_process', 'GO:0006283', ('175', '178'))	('associated', 'Reg', (46, 56))	('TCR', 'Gene', (175, 178))	('PD-L1', 'Gene', '29126', (123, 128))	('associated', 'Reg', (193, 203))	('IC1', 'Gene', '105259599', (98, 101))
71558	28552987	AUC area under the curve BCG Bacillus Calmette-Guerin BQSR Base Quality Score Recalibration DCB durable clinical benefit DCB-OS overall survival greater than 12 months DDR DNA damage response FDR false discovery rate FFPE formalin-fixed paraffin embedded GSEA Gene Set Enrichment Analysis HR hazard ratio IC immune cell OS overall survival PBMC peripheral blood mononuclear cell PD-L1 programmed death-ligand 1 PFS progression-free survival RNA-seq RNA sequencing TCR T cell receptor TCR-seq T cell receptor sequencing TIL tumor-infiltrating T lymphocytes VAF variant allele frequency WES whole exome sequencing	('tumor', 'Disease', 'MESH:D009369', (523, 528))	('programmed death-ligand 1', 'Gene', '29126', (385, 410))	('OS', 'Chemical', '-', (320, 322))	('VAF', 'Chemical', '-', (556, 559))	('paraffin', 'Chemical', 'MESH:D010232', (237, 245))	('false', 'biological_process', 'GO:0071877', ('196', '201'))	('ligand', 'molecular_function', 'GO:0005488', ('402', '408'))	('TCR', 'Gene', '6962', (484, 487))	('GSEA', 'Chemical', '-', (255, 259))	('TCR', 'cellular_component', 'GO:0042101', ('464', '467'))	('RNA', 'cellular_component', 'GO:0005562', ('441', '444'))	('tumor', 'Phenotype', 'HP:0002664', (523, 528))	('TCR', 'biological_process', 'GO:0006283', ('464', '467'))	('DCB', 'Chemical', '-', (121, 124))	('DNA damage response', 'biological_process', 'GO:0006974', ('172', '191'))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('TCR', 'Gene', (484, 487))	('false', 'biological_process', 'GO:0071878', ('196', '201'))	('PD-L1', 'Gene', (379, 384))	('formalin', 'Chemical', 'MESH:D005557', (222, 230))	('OS', 'Chemical', '-', (125, 127))	('TCR', 'Gene', '6962', (464, 467))	('PD-L1', 'Gene', '29126', (379, 384))	('RNA', 'cellular_component', 'GO:0005562', ('449', '452'))	('BCG', 'Species', '33892', (25, 28))	('variant', 'Var', (560, 567))	('TCR', 'cellular_component', 'GO:0042101', ('484', '487'))	('programmed death-ligand 1', 'Gene', (385, 410))	('TCR', 'biological_process', 'GO:0006283', ('484', '487'))	('T cell receptor', 'Gene', '6962', (492, 507))	('T cell receptor', 'Gene', (468, 483))	('tumor', 'Disease', (523, 528))	('T cell receptor', 'Gene', '6962', (468, 483))	('Bacillus Calmette-Guerin', 'Species', '33892', (29, 53))	('T cell receptor', 'Gene', (492, 507))	('DCB-OS', 'Chemical', '-', (121, 127))	('DCB', 'Chemical', '-', (92, 95))	('TCR', 'Gene', (464, 467))
71559	27926531	An annotated list of bivalent chromatin regions in human ES cells: a new tool for cancer epigenetic research CpG islands (CGI) marked by bivalent chromatin in stem cells are believed to be more prone to aberrant DNA methylation in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('DNA', 'cellular_component', 'GO:0005574', ('212', '215'))	('prone', 'Reg', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('chromatin', 'cellular_component', 'GO:0000785', ('146', '155'))	('cancer', 'Disease', (82, 88))	('tumor', 'Disease', (231, 236))	('human', 'Species', '9606', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('DNA methylation', 'biological_process', 'GO:0006306', ('212', '227'))	('DNA methylation', 'Var', (212, 227))	('chromatin', 'cellular_component', 'GO:0000785', ('30', '39'))
71562	27926531	As proof-of-concept, we assessed the DNA methylation pattern of eight types of tumors and confirmed that aberrant cancer-associated DNA hypermethylation preferentially targets CGI characterized by bivalent chromatin in hESCs.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('132', '152'))	('cancer', 'Disease', (114, 120))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('preferentially', 'PosReg', (153, 167))	('DNA methylation', 'biological_process', 'GO:0006306', ('37', '52'))	('DNA', 'Gene', (132, 135))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('chromatin', 'cellular_component', 'GO:0000785', ('206', '215'))	('aberrant', 'Var', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('CGI', 'Protein', (176, 179))
71564	27926531	Consistently, in addition to genetic lesions, epigenetic alterations are important actors in various human pathologies, including carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (130, 144))	('genetic lesions', 'Disease', (29, 44))	('epigenetic alterations', 'Var', (46, 68))	('carcinogenesis', 'Disease', (130, 144))	('human', 'Species', '9606', (101, 106))	('genetic lesions', 'Disease', 'MESH:D020022', (29, 44))
71565	27926531	Specifically, aberrant DNA hypermethylation at gene promoter-associated CpG Islands (CGI/promoter) is a well characterized feature of cancer cells.	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('23', '43'))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('aberrant DNA hypermethylation', 'Var', (14, 43))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))
71568	27926531	Strikingly, CIMP-positive tumors exhibit specific molecular features, clinical prognosis and outcome compared with CIMP-negative tumors, thus underlying the potential of these signatures as cancer biomarkers.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (129, 135))	('CIMP', 'Chemical', '-', (115, 119))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('CIMP-positive', 'Var', (12, 25))	('CIMP', 'Chemical', '-', (12, 16))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
71571	27926531	Altogether, these observations led to the hypothesis that besides mediating the stable silencing of tumor suppressor genes, the main consequence of CGI hypermethylation is to aberrantly maintain cancer cells in a "plastic" stem-cell like state (poor differentiation capacity and unlimited self-renewal) that contributes to cancer initiation and progression.	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('maintain', 'Reg', (186, 194))	('contributes', 'Reg', (308, 319))	('cancer initiation', 'Disease', (323, 340))	('cancer', 'Disease', (323, 329))	('tumor', 'Disease', (100, 105))	('cancer', 'Disease', (195, 201))	('hypermethylation', 'Var', (152, 168))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('cancer initiation', 'Disease', 'MESH:D009369', (323, 340))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('CGI', 'Gene', (148, 151))	('silencing', 'NegReg', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
71573	27926531	Also, recent integrative genome-wide analyses revealed that aberrant CGI hypermethylation affects primarily genes that are already repressed in the matched normal tissue, indicating that most of the aberrantly methylated genes are not involved in carcinogenesis.	('hypermethylation', 'Var', (73, 89))	('carcinogenesis', 'Disease', 'MESH:D063646', (247, 261))	('carcinogenesis', 'Disease', (247, 261))	('CGI', 'Gene', (69, 72))	('affects', 'Reg', (90, 97))	('aberrant', 'Var', (60, 68))
71574	27926531	To account for these observations, Sproul and Meehan proposed an alternative hypothesis in which the stable repression brought by aberrant DNA hypermethylation at CGIs/promoters restricts the epigenetic plasticity of cancer cells and their ability to adapt following environmental changes, such as during metastasis formation or treatment, thus acting as a protective mechanism against cancer progression.	('epigenetic plasticity', 'MPA', (192, 213))	('cancer', 'Disease', 'MESH:D009369', (386, 392))	('aberrant', 'Var', (130, 138))	('restricts', 'NegReg', (178, 187))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('139', '159'))	('cancer', 'Disease', (386, 392))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('adapt', 'MPA', (251, 256))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('formation', 'biological_process', 'GO:0009058', ('316', '325'))	('DNA', 'Gene', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
71584	27926531	For each hESC line, peaks were called in the H3K4me3 and H3K27me3 datasets using Macs1.4.2.	('Macs', 'Gene', (81, 85))	('H3K27me3', 'Var', (57, 65))	('Macs', 'Gene', '54453', (81, 85))	('H3K4me3', 'Var', (45, 52))
71585	27926531	We next isolated regions enriched for both histone marks and defined as bivalent domains all regions where H3K4me3 and H3K27me3 peaks overlapped for at least 1Kbp (Figure 1B).	('Kbp', 'Gene', '26128', (159, 162))	('Kbp', 'Gene', (159, 162))	('H3K27me3', 'Var', (119, 127))	('H3K4me3', 'Var', (107, 114))
71588	27926531	By using the same criteria (i.e., more than 1Kbp in size and common to the five hESC lines), we also established a list of HC H3K4me3-only (n = 11 966) and H3K27me3-only (n = 16 361) regions (Supplementary Figure S1).	('Kbp', 'Gene', '26128', (45, 48))	('Kbp', 'Gene', (45, 48))	('H3K27me3-only', 'Var', (156, 169))
71592	27926531	It has been proposed that CGI/promoters prone to be hypermethylated in cancer cells are depleted in retroelements at the transcriptional start site (TSS).	('hypermethylated', 'Var', (52, 67))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
71595	27926531	Conversely, H3K4me2, H2AZ or H3K9ac marked also bivalent regions (Figure 2B, Supplementary Figure S2D).	('H2AZ', 'Gene', '3015', (21, 25))	('H2AZ', 'Gene', (21, 25))	('H3K4me2', 'Var', (12, 19))	('H3K9ac', 'Var', (29, 35))
71596	27926531	However, while H3K4me2 and H2AZ signals intensity was comparable at H3K4me3-only and bivalent promoters, H3K9ac signal was stronger at H3K4me3-only promoters.	('H2AZ', 'Gene', '3015', (27, 31))	('H2AZ', 'Gene', (27, 31))	('H3K9ac', 'Var', (105, 111))	('stronger', 'PosReg', (123, 131))
71597	27926531	Besides histone modifications, the analysis of ChIP-seq data for 59 transcription factors in the hES1 cell line stressed that differently from H3K4me3-only promoters, transcription factor occupancy was low at H3K27me3-only promoters in hESCs (Supplementary Figure S4, Supplementary Table S6).	('transcription', 'biological_process', 'GO:0006351', ('68', '81'))	('hES1', 'Gene', (97, 101))	('transcription factor occupancy', 'MPA', (167, 197))	('hES1', 'Gene', '8209', (97, 101))	('H3K27me3-only', 'Var', (209, 222))	('transcription', 'biological_process', 'GO:0006351', ('167', '180'))	('low', 'NegReg', (202, 205))	('transcription factor', 'molecular_function', 'GO:0000981', ('167', '187'))
71598	27926531	As expected, components of the PRC2 complex that mediates H3K27me3 deposition were enriched at bivalent promoters (EZH2: 92.8% of bivalent vs 17.2% of H3K4me3-only promoters: Chi-squared test p < 2.2e-16; SUZ12: 59.4% of bivalent vs 12.5% of H3K4me3-only promoters: Chi-squared test p < 2.2e-16).	('EZH2', 'Gene', (115, 119))	('H3K27me3', 'Var', (58, 66))	('PRC2 complex', 'cellular_component', 'GO:0035098', ('31', '43'))	('EZH2', 'Gene', '2146', (115, 119))
71605	27926531	The HM450K array covers 482421 CpG sites and allows interrogating 98.9% of HC bivalent regions (mean coverage, MC: 10.9 probes per region), 88.1% of H3K4me3-only regions (MC: 8.7 probes/region) and 55.7% of H3K27me3-only regions (MC: 2.4 probes/regions).	('H3K27me3-only', 'Var', (207, 220))	('H3K4me3-only', 'Protein', (149, 161))	('MC', 'Chemical', 'MESH:D008748', (171, 173))	('MC', 'Chemical', 'MESH:D008748', (230, 232))	('MC', 'Chemical', 'MESH:D008748', (111, 113))
71606	27926531	Coverage is higher with the EPIC arrays that allow interrogating 863904 CpG sites, with 99.5% of HC bivalent regions (MC: 12.4 probes/region), 93.3% of H3K4me3-only regions (MC: 10.3 probes /regions) and 73.5% of H3K27me3-only (MC: 3.1 probes/region) (Supplementary Table S7).	('MC', 'Chemical', 'MESH:D008748', (174, 176))	('MC', 'Chemical', 'MESH:D008748', (118, 120))	('H3K27me3-only', 'Var', (213, 226))	('MC', 'Chemical', 'MESH:D008748', (228, 230))	('H3K4me3-only', 'Var', (152, 164))
71609	27926531	Compared with normal tissues, in tumor samples we detected DNA methylation changes at CGIs predominantly in bivalent (black) and none-regions (gray), with an overall gain of methylation (increased median value).	('DNA methylation', 'biological_process', 'GO:0006306', ('59', '74'))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('gain', 'PosReg', (166, 170))	('tumor', 'Disease', (33, 38))	('methylation', 'Var', (63, 74))	('methylation', 'biological_process', 'GO:0032259', ('174', '185'))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('methylation', 'MPA', (174, 185))
71612	27926531	We then observed that hypermethylated probes (delta beta value > 0.25 tumor vs control, FDR < 0.05) were greatly enriched at bivalent regions, irrespectively of the tumor CIMP status.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('hypermethylated', 'Var', (22, 37))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('CIMP', 'Chemical', '-', (171, 175))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (165, 170))
71616	27926531	Finally and although less prominent than hypermethylation, we also observed hypomethylated probes at CGIs in tumors (delta beta value < 0.25 tumor vs control, FDR <0.05), mainly in none-regions.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('hypomethylated', 'Var', (76, 90))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('tumor', 'Disease', (109, 114))
71617	27926531	We next determined the genomic features associated with hypermethylated probes in the eight tumor types (Figure 6D).	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('hypermethylated probes', 'Var', (56, 78))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
71618	27926531	The distribution of hypermethylated probes was similar in CIMP-positive and CIMP-negative tumors and they were mainly located in promoter regions.	('CIMP', 'Chemical', '-', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('hypermethylated', 'Var', (20, 35))	('CIMP', 'Chemical', '-', (58, 62))
71620	27926531	Overall, gene expression was significantly lower in normal tissues for genes with methylated CGI/promoter in the corresponding tumor, regardless of the CIMP status, compared with gene with unaltered DNA methylation patterns (Figure 6E, Supplementary Figure S7).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('methylated', 'Var', (82, 92))	('gene expression', 'biological_process', 'GO:0010467', ('9', '24'))	('CIMP', 'Chemical', '-', (152, 156))	('tumor', 'Disease', (127, 132))	('DNA methylation', 'biological_process', 'GO:0006306', ('199', '214'))	('DNA', 'cellular_component', 'GO:0005574', ('199', '202'))	('CGI/promoter', 'Gene', (93, 105))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('gene expression', 'MPA', (9, 24))	('lower', 'NegReg', (43, 48))
71624	27926531	This suggests that hypermethylation of homeobox gene promoters could constitute a pan-cancer signature.	('homeobox gene', 'Gene', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('hypermethylation', 'Var', (19, 35))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
71628	27926531	This include, as previously documented, the histone variant H2AZ and some acetylated histone forms, indicating that, similarly to H3K4me3, a subset of active histone modifications can co-exist with the repressive H3K27me3 mark in a poised configuration.	('H2AZ', 'Gene', '3015', (60, 64))	('modifications', 'Var', (166, 179))	('H2AZ', 'Gene', (60, 64))
71629	27926531	Intriguingly, our analysis also revealed that H3K23me2, a recently identified new heterochromatin mark in C. elegans, highly marks bivalent regions and, to a lesser extent, H3K4me3-only regions.	('heterochromatin', 'cellular_component', 'GO:0000792', ('82', '97'))	('C. elegans', 'Species', '6239', (106, 116))	('bivalent regions', 'MPA', (131, 147))	('H3K23me2', 'Var', (46, 54))
71630	27926531	Specifically, bivalent promoters associated with high PolII and TAF1 occupancy in hESCs (cluster 1 in this study) are more prone to be expressed upon development.	('PolII', 'MPA', (54, 59))	('occupancy', 'Var', (69, 78))	('TAF1', 'Gene', '6872', (64, 68))	('prone', 'PosReg', (123, 128))	('TAF1', 'Gene', (64, 68))
71632	27926531	In a proof-of-concept study, conducted using data from eight solid tumor types, we confirmed that aberrant cancer-associated DNA hypermethylation targets mainly CGIs that carry a bivalent signature in hESCs.	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('125', '145'))	('aberrant', 'Var', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))	('CGIs', 'Protein', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Disease', (67, 72))	('hypermethylation', 'Var', (129, 145))	('cancer', 'Disease', (107, 113))
71633	27926531	Consistently, we show that promoter hypermethylation of HOX genes, which are a paradigm of bivalent region-associated genes, could constitute a pan-cancer signature.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('HOX genes', 'Gene', (56, 65))	('promoter hypermethylation', 'Var', (27, 52))
71635	27926531	We observed that these two categories of genes are expressed in most tested tissues and, therefore, their aberrant methylation is more likely to have a functional impact that could contribute to the tumorigenic process.	('tumor', 'Disease', (199, 204))	('contribute', 'Reg', (181, 191))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('aberrant methylation', 'Var', (106, 126))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('methylation', 'biological_process', 'GO:0032259', ('115', '126'))
71636	27926531	This is supported, in part, by our finding that bivalent CGI/promoters are the main target of aberrant hypermethylation in both CIMP-positive and CIMP-negative tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('aberrant hypermethylation', 'Var', (94, 119))	('hypermethylation', 'Var', (103, 119))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('CIMP', 'Chemical', '-', (128, 132))	('CIMP', 'Chemical', '-', (146, 150))
71638	27926531	This hypothesis is sustained by the observation that mutations in isocitrate deshydrogenase (IDH) that affect histone demethylation are sufficient to establish a CIMP-positive status in glioma, the main brain tumor type.	('glioma', 'Disease', (186, 192))	('IDH', 'Gene', (93, 96))	('histone demethylation', 'biological_process', 'GO:0016577', ('110', '131'))	('mutations', 'Var', (53, 62))	('brain tumor', 'Disease', (203, 214))	('histone demethylation', 'MPA', (110, 131))	('glioma', 'Disease', 'MESH:D005910', (186, 192))	('IDH', 'Gene', '3417', (93, 96))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('brain tumor', 'Disease', 'MESH:D001932', (203, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('brain tumor', 'Phenotype', 'HP:0030692', (203, 214))	('CIMP', 'Chemical', '-', (162, 166))	('affect', 'Reg', (103, 109))
71639	27926531	Similarly, alterations in factors that control only a small subset of bivalent CGIs could lead to a CIMP-negative status.	('alterations', 'Var', (11, 22))	('CIMP', 'Chemical', '-', (100, 104))	('lead', 'Reg', (90, 94))	('CIMP-negative', 'MPA', (100, 113))
71641	27926531	In addition to cancer research, it can be used in a variety of DNA methylation-based customized analyses, for instance the age-associated epigenetic drift.	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('epigenetic drift', 'Var', (138, 154))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('DNA methylation', 'biological_process', 'GO:0006306', ('63', '78'))
71644	27926531	HC bivalent regions were defined as regions where H3K4me3 and H3K27me3 peaks overlapped for at least 1Kbp and in all five hESC lines.	('Kbp', 'Gene', '26128', (102, 105))	('H3K4me3', 'Var', (50, 57))	('Kbp', 'Gene', (102, 105))	('H3K27me3', 'Var', (62, 70))
71655	27926531	Relevant partitioning was obtained for four transcription factors: EZH2 (GSM1003524), TAF1 (GSM803450), PolII (GSM803366) and TCF12 (GSM803427).	('TAF1', 'Gene', (86, 90))	('TAF1', 'Gene', '6872', (86, 90))	('GSM803450', 'Var', (92, 101))	('GSM803427', 'Var', (133, 142))	('GSM1003524', 'Var', (73, 83))	('TCF12', 'Gene', (126, 131))	('transcription', 'biological_process', 'GO:0006351', ('44', '57'))	('EZH2', 'Gene', '2146', (67, 71))	('TCF12', 'Gene', '6938', (126, 131))	('EZH2', 'Gene', (67, 71))	('GSM803366', 'Var', (111, 120))
71661	27926531	HM450K probes were considered differentially methylated when FDR < 0.05 and when the beta value difference between tumor and matched normal sample was higher than 0.25.	('HM450K', 'Var', (0, 6))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))
71670	32629423	Inhibition of system XC-, which is a membrane Na+-dependent cysteine-glutamate exchange transporter, and GPX4 can disrupt the oxidation-reduction balance and cause overwhelming lipid peroxidation that ultimately results in cell death.	('death', 'Disease', (228, 233))	('GPX4', 'Gene', '2879', (105, 109))	('death', 'Disease', 'MESH:D003643', (228, 233))	('lipid peroxidation', 'MPA', (177, 195))	('oxidation-reduction balance', 'MPA', (126, 153))	('cell death', 'biological_process', 'GO:0008219', ('223', '233'))	('cause', 'Reg', (158, 163))	('disrupt', 'NegReg', (114, 121))	('oxidation-reduction', 'biological_process', 'GO:0055114', ('126', '145'))	('Inhibition', 'Var', (0, 10))	('results in', 'Reg', (212, 222))	('membrane', 'cellular_component', 'GO:0016020', ('37', '45'))	('lipid', 'Chemical', 'MESH:D008055', (177, 182))	('GPX4', 'Gene', (105, 109))
71675	32629423	Ductal pancreatic cancer cells with a mutant KRAS gene are more susceptible to ferroptosis than wild-type cells.	('mutant', 'Var', (38, 44))	('KRAS', 'Gene', '3845', (45, 49))	('Ductal pancreatic cancer', 'Disease', (0, 24))	('ferroptosis', 'biological_process', 'GO:0097707', ('79', '90'))	('susceptible', 'Reg', (64, 75))	('ferroptosis', 'MPA', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (7, 24))	('Ductal pancreatic cancer', 'Disease', 'MESH:D010190', (0, 24))	('KRAS', 'Gene', (45, 49))
71677	32629423	In addition, changes in the gene expression of tumor cells also affect ferroptosis, and a number of genes have been confirmed to regulate ferroptosis.	('gene expression', 'biological_process', 'GO:0010467', ('28', '43'))	('changes', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('ferroptosis', 'CPA', (71, 82))	('ferroptosis', 'biological_process', 'GO:0097707', ('138', '149'))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('affect', 'Reg', (64, 70))	('tumor', 'Disease', (47, 52))	('ferroptosis', 'biological_process', 'GO:0097707', ('71', '82'))
71688	32629423	The analysis of nonsynonymous mutations in 20 cancer types showed that the mutation frequencies for FRGs were generally low in almost all cancers and relatively high in UCEC (Figure S1A).	('FRGs', 'Gene', (100, 104))	('cancer', 'Disease', (138, 144))	('UCEC', 'Disease', (169, 173))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('mutation', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('low', 'NegReg', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('high', 'Reg', (161, 165))	('cancers', 'Disease', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
71689	32629423	Furthermore, NFE2L2, which encodes NRF2 and plays a master regulator role in antioxidant responses and has been shown to cause resistance to ferroptosis, showed relatively high mutation frequencies in multiple cancers including BLCA, CESC, ESCA, HNSC, LUSC, and UCEC (Figure S1A).	('LUSC', 'Disease', (252, 256))	('mutation', 'Var', (177, 185))	('NFE2L2', 'Gene', '4780', (13, 19))	('NRF2', 'Gene', '4780', (35, 39))	('multiple cancers', 'Disease', (201, 217))	('BLCA', 'Disease', (228, 232))	('ESCA', 'Disease', (240, 244))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('NFE2L2', 'Gene', (13, 19))	('NRF2', 'Gene', (35, 39))	('ferroptosis', 'biological_process', 'GO:0097707', ('141', '152'))	('multiple cancers', 'Disease', 'MESH:D009369', (201, 217))	('HNSC', 'Disease', (246, 250))	('resistance', 'MPA', (127, 137))	('UCEC', 'Disease', (262, 266))	('CESC', 'Disease', (234, 238))
71691	32629423	For example, TTC35, HSPB1, TFRC, and RPL8 were more prone to copy number gain than copy number loss in almost all tumors, but SCL7A11 and ALOX15 showed the opposite profile.	('RPL8', 'Gene', '6132', (37, 41))	('copy number', 'Var', (61, 72))	('RPL8', 'Gene', (37, 41))	('gain', 'PosReg', (73, 77))	('TFRC', 'Gene', (27, 31))	('HSPB1', 'Gene', '3315', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('HSPB1', 'Gene', (20, 25))	('TFRC', 'Gene', '7037', (27, 31))	('tumors', 'Disease', (114, 120))	('ALOX15', 'Gene', (138, 144))	('TTC35', 'Gene', (13, 18))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('TTC35', 'Gene', '9694', (13, 18))	('ALOX15', 'Gene', '246', (138, 144))
71707	32629423	This result indicates that the aberrance of copy number for FRGs is common in most cancers and can influence gene expression.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('gene expression', 'biological_process', 'GO:0010467', ('109', '124'))	('gene expression', 'MPA', (109, 124))	('copy number', 'Var', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('influence', 'Reg', (99, 108))	('aberrance', 'Var', (31, 40))	('FRGs', 'Gene', (60, 64))	('common', 'Reg', (68, 74))
71708	32629423	In addition to SCNA, the methylation of promoter can regulate gene expression and aberrant DNA methylation of the promoter is associated with tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('regulate', 'Reg', (53, 61))	('gene expression', 'biological_process', 'GO:0010467', ('62', '77'))	('DNA methylation', 'biological_process', 'GO:0006306', ('91', '106'))	('associated with', 'Reg', (126, 141))	('tumor', 'Disease', (142, 147))	('gene expression', 'MPA', (62, 77))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('aberrant', 'Var', (82, 90))
71719	32629423	This suggests that miRNAs play a regulatory role in FRGs expression, and the aberrant expression of miRNAs in tumors could impact ferroptosis.	('impact', 'NegReg', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('ferroptosis', 'biological_process', 'GO:0097707', ('130', '141'))	('ferroptosis', 'CPA', (130, 141))	('miRNAs', 'Gene', (100, 106))	('aberrant expression', 'Var', (77, 96))
71746	32629423	Strikingly, somatic mutations, namely, NFE2L2, BRAF, and TP53, were positively associated with FPI in pancancer associations, but a mutation in TP53 was negatively correlated with ferroptosis in LUSC.	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (144, 148))	('associated', 'Reg', (79, 89))	('NFE2L2', 'Gene', (39, 45))	('BRAF', 'Gene', (47, 51))	('cancer', 'Disease', (105, 111))	('BRAF', 'Gene', '673', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ferroptosis', 'biological_process', 'GO:0097707', ('180', '191'))	('TP53', 'Gene', '7157', (57, 61))	('NFE2L2', 'Gene', '4780', (39, 45))	('TP53', 'Gene', (57, 61))	('mutation', 'Var', (132, 140))	('FPI', 'Disease', (95, 98))
71747	32629423	This observation was verified by the comparison of FPI between the TP53 mutant and wild-type groups (Figure S3B), consistent with previous findings that showed that TP53 played a dual role in regulating ferroptosis.	('TP53', 'Gene', (165, 169))	('mutant', 'Var', (72, 78))	('ferroptosis', 'Disease', (203, 214))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('TP53', 'Gene', '7157', (165, 169))	('ferroptosis', 'biological_process', 'GO:0097707', ('203', '214'))
71748	32629423	The influences of KRAS mutations on FPI were also investigated, and the results showed that the relationship between KRAS mutation and FPI was significantly negative in gastric tumors (Figure S3C) but slightly positive in hepatocellular carcinoma (Figures S3A and S3C).	('KRAS', 'Gene', (117, 121))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('KRAS', 'Gene', (18, 22))	('negative', 'NegReg', (157, 165))	('positive', 'Reg', (210, 218))	('mutation', 'Var', (122, 130))	('KRAS', 'Gene', '3845', (18, 22))	('KRAS', 'Gene', '3845', (117, 121))	('gastric tumors', 'Phenotype', 'HP:0006753', (169, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (222, 246))	('gastric tumors', 'Disease', (169, 183))	('gastric tumors', 'Disease', 'MESH:D013274', (169, 183))	('hepatocellular carcinoma', 'Disease', (222, 246))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (222, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
71750	32629423	Furthermore, differential expression of FRGs between wild-type and tumors with mutant TP53 (Figure S3D) and KRAS (Figure S3E) was found to be ubiquitous in most cancers.	('KRAS', 'Gene', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('TP53', 'Gene', '7157', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('mutant', 'Var', (79, 85))	('KRAS', 'Gene', '3845', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('TP53', 'Gene', (86, 90))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('cancers', 'Disease', (161, 168))	('tumors', 'Disease', (67, 73))
71754	32629423	For example, terpenoid backbone biosynthesis and steroid biosynthesis were enriched in the low-FPI group in 19 and 16 cancers, respectively (Figure 3A).	('terpenoid backbone biosynthesis', 'MPA', (13, 44))	('cancers', 'Disease', (118, 125))	('low-FPI', 'Var', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('steroid biosynthesis', 'MPA', (49, 69))	('steroid biosynthesis', 'biological_process', 'GO:0006694', ('49', '69'))	('steroid', 'Chemical', 'MESH:D013256', (49, 56))	('biosynthesis', 'biological_process', 'GO:0009058', ('32', '44'))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('terpenoid', 'Chemical', 'MESH:D013729', (13, 22))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
71766	32629423	Based on the clinical data from TCGA, survival analysis was performed and the results were consistent since it was found that the lower FPI predicted a better survival in five cancers including GBM, KIRC, KIRP, LIHC, and LUAD (Figure 4).	('cancers', 'Disease', (176, 183))	('survival', 'MPA', (159, 167))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('lower', 'Var', (130, 135))	('LIHC', 'Disease', (211, 215))	('KIRP', 'Disease', (205, 209))	('LUAD', 'Disease', (221, 225))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('GBM', 'Disease', (194, 197))	('KIRC', 'Disease', (199, 203))	('better', 'PosReg', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))
71778	32629423	However, high expression of CARS and MT1G showed consistently better survival among cancers including KICH, UCEC, PAAD, and HNSC (Figure S3I).	('MT1G', 'Gene', (37, 41))	('high expression', 'Var', (9, 24))	('MT1', 'molecular_function', 'GO:0043791', ('37', '40'))	('CARS', 'Gene', (28, 32))	('MT1', 'molecular_function', 'GO:0047152', ('37', '40'))	('PAAD', 'Disease', (114, 118))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('MT1G', 'Gene', '4495', (37, 41))	('better', 'PosReg', (62, 68))	('HNSC', 'Disease', (124, 128))	('cancers', 'Disease', (84, 91))	('KICH', 'Disease', 'None', (102, 106))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('MT1', 'molecular_function', 'GO:0043834', ('37', '40'))	('CARS', 'Gene', '833', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('KICH', 'Disease', (102, 106))	('UCEC', 'Disease', (108, 112))
71845	28638271	The gene encoding TOP2A is the target for numerous anticancer agents; mutations in this gene have been related with the development of drug resistance.	('TOP2A', 'Gene', '7153', (18, 23))	('mutations', 'Var', (70, 79))	('drug resistance', 'MPA', (135, 150))	('TOP2A', 'Gene', (18, 23))	('drug resistance', 'biological_process', 'GO:0009315', ('135', '150'))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('drug resistance', 'biological_process', 'GO:0042493', ('135', '150'))	('drug resistance', 'Phenotype', 'HP:0020174', (135, 150))	('related', 'Reg', (103, 110))
71847	28638271	Deregulation of MCM2 function has been suggested to contribute to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Deregulation', 'Var', (0, 12))	('tumor', 'Disease', (66, 71))	('MCM2', 'Gene', '4171', (16, 20))	('MCM2', 'Gene', (16, 20))	('contribute', 'Reg', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
71901	27256983	Incidentally, the remedies for CKD containing aristolochic acid (AA) are carcinogenic.	('aristolochic acid', 'Chemical', 'MESH:C000228', (46, 63))	('aristolochic acid', 'Var', (46, 63))	('CKD', 'Phenotype', 'HP:0012622', (31, 34))	('carcinogenic', 'Disease', 'MESH:D063646', (73, 85))	('carcinogenic', 'Disease', (73, 85))
71920	27256983	These research findings imply that CKD or ESRD as risk factors might promote the development of urothelial carcinomas especially in the upper urinary tract.	('CKD', 'Var', (35, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('urothelial carcinomas', 'Disease', (96, 117))	('ESRD', 'Disease', (42, 46))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (96, 117))	('CKD', 'Phenotype', 'HP:0012622', (35, 38))	('men', 'Species', '9606', (88, 91))	('promote', 'PosReg', (69, 76))	('ESRD', 'Phenotype', 'HP:0003774', (42, 46))	('ESRD', 'Disease', 'MESH:D007676', (42, 46))
71959	27256983	Nephrotoxic and carcinogenic agents mainly include aristolochic acids (AA) of the Chinese herb owing to such a popularity of Chinese herbs consumption, inducing nephrotubular lesions and malignant neoplastic alteration in the urothelial cells of the entire urinary tract.	('aristolochic acids', 'Chemical', 'MESH:D034341', (51, 69))	('Nephrotoxic and carcinogenic', 'Disease', 'MESH:D007674', (0, 28))	('aristolochic acids', 'Var', (51, 69))	('malignant neoplastic alteration', 'CPA', (187, 218))	('nephrotubular lesions', 'Disease', (161, 182))	('inducing', 'Reg', (152, 160))	('neoplastic alteration', 'Phenotype', 'HP:0002664', (197, 218))	('nephrotubular lesions', 'Disease', 'MESH:D051437', (161, 182))
71963	27256983	It was shown that high-stage and high-grade tumors had more copy number variants.	('tumors', 'Disease', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('copy number variants', 'Var', (60, 80))	('high-stage', 'CPA', (18, 28))
71964	27256983	Although the effect of uremia on an increased risk of UUC remains unknown, it is observed that a high prevalence of UUC is found among patients using carcinogenic remedies, such as those containing aristolochic acid (AA).	('UUC', 'Chemical', '-', (54, 57))	('patients', 'Species', '9606', (135, 143))	('carcinogenic', 'Disease', 'MESH:D063646', (150, 162))	('UUC', 'Chemical', '-', (116, 119))	('carcinogenic', 'Disease', (150, 162))	('uremia', 'Disease', 'MESH:D014511', (23, 29))	('uremia', 'Disease', (23, 29))	('aristolochic acid', 'Var', (198, 215))	('UUC', 'Disease', (116, 119))	('aristolochic acid', 'Chemical', 'MESH:C000228', (198, 215))
71973	27256983	Furthermore, AA exposure is capable of inducing mutations in the tumor suppressor gene, TP53, in UUC through A - T transversions on the non-transcribed strand.	('inducing', 'Reg', (39, 47))	('tumor', 'Disease', (65, 70))	('tumor suppressor', 'biological_process', 'GO:0051726', ('65', '81'))	('TP53', 'Gene', '7157', (88, 92))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('65', '81'))	('UUC', 'Chemical', '-', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('TP53', 'Gene', (88, 92))	('mutations', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
71977	27256983	In addition, high-arsenic artesian well water is also a contributing risk factor in the development of UUC in Taiwan.	('UUC', 'Disease', (103, 106))	('arsenic', 'Chemical', 'MESH:D001151', (18, 25))	('water', 'Chemical', 'MESH:D014867', (40, 45))	('men', 'Species', '9606', (95, 98))	('high-arsenic', 'Var', (13, 25))	('UUC', 'Chemical', '-', (103, 106))
71985	27256983	The severity of CKD is closely associated with higher aggressiveness of urothelial cancer.	('CKD', 'Var', (16, 19))	('aggressiveness', 'Phenotype', 'HP:0000718', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('aggressiveness of urothelial cancer', 'Disease', 'MESH:D014523', (54, 89))	('aggressiveness of urothelial cancer', 'Disease', (54, 89))	('CKD', 'Phenotype', 'HP:0012622', (16, 19))
72006	27256983	Several aberrations include 1q22-25.3, 8q, 19p13.2, 20q among amplified chromosomal regions, and 2q21.2-24.3, 9p21.2-24.3, 10q, 11, 13p, 13q14.11, 18p among deleted chromosomal regions in female ESRD patients, while only one aberration 8p12-22 was found in males.	('1q22-25.3', 'Var', (28, 37))	('patients', 'Species', '9606', (200, 208))	('ESRD', 'Disease', (195, 199))	('9p21.2-24.3', 'Var', (110, 121))	('ESRD', 'Phenotype', 'HP:0003774', (195, 199))	('ESRD', 'Disease', 'MESH:D007676', (195, 199))	('2q21.2-24.3', 'Var', (97, 108))
72109	23082147	The 5-year recurrence-free survival rates of papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade papillary urothelial carcinoma(LGPUC) and high-grade papillary urothelial carcinoma (HGPUC) were 69.8%, 67.1% and 42.0% respectively and the 5-year progression-free survival rates were 100%, 90.9% and 54.8% respectively.	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (175, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('neoplasm', 'Phenotype', 'HP:0002664', (66, 74))	('papillary urothelial carcinoma', 'Disease', (122, 152))	('papillary urothelial carcinoma', 'Disease', 'MESH:D002291', (122, 152))	('papillary urothelial carcinoma', 'Disease', 'MESH:D002291', (175, 205))	('papillary urothelial neoplasm', 'Disease', 'MESH:D002291', (45, 74))	('low-grade', 'Var', (112, 121))	('papillary urothelial neoplasm', 'Disease', (45, 74))	('papillary urothelial carcinoma', 'Disease', (175, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (122, 152))
72152	23082147	reported that 112 patients with PUNLMP and up to 35 yr of follow-up (median, 12.8years) were at 26.8% risk of local recurrence and 3.6% risk of stage progression.	('local recurrence', 'CPA', (110, 126))	('PUNLMP', 'Var', (32, 38))	('patients', 'Species', '9606', (18, 26))
72156	23082147	Furthermore, certain molecular markers have been evaluated such as point mutations in the FGFR3 gene, which were detected in 85% of PUNLMP tumors and in 88% of low-grade carcinomas, and in our data, Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))	('FGFR3', 'Gene', '2261', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('tumors', 'Disease', (139, 145))	('carcinomas', 'Disease', (170, 180))	('detected', 'Reg', (113, 121))	('carcinomas', 'Disease', 'MESH:D002277', (170, 180))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('FGFR3', 'Gene', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('point mutations', 'Var', (67, 82))
72232	33612111	Some studies have found that T cell depletion is one of the main phenotypes of genetic changes in patients with UTUC.	('patients', 'Species', '9606', (98, 106))	('T cell', 'MPA', (29, 35))	('changes', 'Var', (87, 94))	('UTUC', 'Disease', (112, 116))
72234	33612111	One clinical trial has shown that the FGFR inhibitor erdafitinib has offered significant benefit in the treatment of advanced urothelial cancer patients with FGFR changes, with a remission rate of approximately 40% (complete remission rate 3%, partial remission rate 37%).	('changes', 'Var', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('urothelial cancer', 'Disease', (126, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('158', '162'))	('FGFR', 'Gene', (158, 162))	('patients', 'Species', '9606', (144, 152))	('urothelial cancer', 'Disease', 'MESH:D014523', (126, 143))	('erdafitinib', 'Chemical', 'MESH:C000604580', (53, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))
72255	29937935	Knockdown of CDKN2B-AS gene inactivated Wnt signaling pathway, and Wnt signaling pathway mediated the effects on Gemcitabine sensitivity induced by CDKN2B-AS knockdown in T24/Gem cells.	('Wnt signaling pathway', 'Pathway', (40, 61))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('40', '61'))	('Gemcitabine sensitivity', 'MPA', (113, 136))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('67', '88'))	('inactivated', 'NegReg', (28, 39))	('CDKN2B-AS', 'Gene', (13, 22))	('CDKN2B-AS', 'Gene', '100048912', (13, 22))	('knockdown', 'Var', (158, 167))	('Gemcitabine', 'Chemical', 'MESH:C056507', (113, 124))	('CDKN2B-AS', 'Gene', (148, 157))	('CDKN2B-AS', 'Gene', '100048912', (148, 157))	('Wnt signaling pathway', 'Pathway', (67, 88))
72294	29937935	The TOP Flash and FOP FLASH luciferase reporter vectors which contain wild-type or mutant TCF binding sites were purchased from Biovector NTCC Ltd (Beijing, China).	('TCF', 'Gene', (90, 93))	('TCF', 'Gene', '3172', (90, 93))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('mutant', 'Var', (83, 89))
72305	29937935	And, knockdown of CDKN2B-AS decreased the IC50 of Gemcitabine from 5.85+-0.33 mug/mL to 2.16+-0.15 mug/mL in T24/Gem cells (Fig.2D, P<0.05), which certified that CDKN2B-AS knockdown sensitized T24/Gem cells to Gemcitabine.	('sensitized', 'Reg', (182, 192))	('decreased', 'NegReg', (28, 37))	('Gemcitabine', 'Chemical', 'MESH:C056507', (210, 221))	('knockdown', 'Var', (5, 14))	('mug', 'molecular_function', 'GO:0043739', ('99', '102'))	('mug', 'molecular_function', 'GO:0043739', ('78', '81'))	('CDKN2B-AS', 'Gene', '100048912', (18, 27))	('Gemcitabine', 'Chemical', 'MESH:C056507', (50, 61))	('CDKN2B-AS', 'Gene', (18, 27))	('IC50 of Gemcitabine', 'MPA', (42, 61))	('CDKN2B-AS', 'Gene', (162, 171))	('CDKN2B-AS', 'Gene', '100048912', (162, 171))
72306	29937935	Moreover, under treating with Gemcitabine (0.5 mug/mL), knockdown of CDKN2B-AS depressed cell viability of T24/Gem cells (Fig.2E, P<0.05), and promoted apoptosis of T24/Gem cells (Fig.2F, P<0.05).	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('mug', 'molecular_function', 'GO:0043739', ('47', '50'))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('promoted', 'PosReg', (143, 151))	('depressed', 'Disease', (79, 88))	('CDKN2B-AS', 'Gene', (69, 78))	('CDKN2B-AS', 'Gene', '100048912', (69, 78))	('depressed', 'Disease', 'MESH:D000275', (79, 88))	('knockdown', 'Var', (56, 65))	('apoptosis', 'CPA', (152, 161))	('Gemcitabine', 'Chemical', 'MESH:C056507', (30, 41))	('cell viability', 'CPA', (89, 103))
72308	29937935	Luciferase assay discovered knockdown of CDKN2B-AS restrained significantly the relative TOP/FOP luciferase ratio in T24/Gem cells (Fig.3A, P<0.05).	('CDKN2B-AS', 'Gene', (41, 50))	('CDKN2B-AS', 'Gene', '100048912', (41, 50))	('TOP/FOP luciferase ratio', 'MPA', (89, 113))	('knockdown', 'Var', (28, 37))
72310	29937935	Those founding proved CDKN2B-AS knockdown inactivated Wnt signaling pathway.	('CDKN2B-AS', 'Gene', (22, 31))	('CDKN2B-AS', 'Gene', '100048912', (22, 31))	('knockdown', 'Var', (32, 41))	('inactivated', 'NegReg', (42, 53))	('Wnt signaling pathway', 'Pathway', (54, 75))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('54', '75'))
72311	29937935	Plasmid pUC-CTNNB1 was transfected into T24/Gem cells to activate Wnt signaling pathway which restrained by knockdown of CDKN2B-AS.	('knockdown', 'Var', (108, 117))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('66', '87'))	('CTNNB1', 'Gene', '1499', (12, 18))	('Wnt signaling pathway', 'Pathway', (66, 87))	('CDKN2B-AS', 'Gene', (121, 130))	('CDKN2B-AS', 'Gene', '100048912', (121, 130))	('activate', 'PosReg', (57, 65))	('CTNNB1', 'Gene', (12, 18))
72315	29937935	To sum up, activating of Wnt signaling pathway restored mostly the effecting of CDKN2B-AS knockdown on Gemcitabine sensitivity in T24/Gem cells.	('CDKN2B-AS', 'Gene', (80, 89))	('CDKN2B-AS', 'Gene', '100048912', (80, 89))	('effecting', 'MPA', (67, 76))	('knockdown', 'Var', (90, 99))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('25', '46'))	('activating', 'MPA', (11, 21))	('Gemcitabine', 'Chemical', 'MESH:C056507', (103, 114))	('Gemcitabine sensitivity', 'MPA', (103, 126))
72332	29937935	Accumulating evidence showed that abnormal expression of lncRNAs were associated with activating of Wnt signaling pathway, following modulated the chemotherapeutic resistance of cancers.	('abnormal', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('100', '121'))	('activating', 'MPA', (86, 96))	('modulated', 'Reg', (133, 142))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('lncRNAs', 'Protein', (57, 64))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('Wnt signaling pathway', 'Pathway', (100, 121))	('expression', 'MPA', (43, 53))
72334	29937935	Our previous study revealed that knockdown of Taurine Up-Regulated 1 (TUG1) restrained the resistance of BUC to Doxorubicin through Wnt signaling pathway.	('TUG1', 'Gene', '55000', (70, 74))	('resistance of BUC to Doxorubicin', 'MPA', (91, 123))	('restrained', 'NegReg', (76, 86))	('knockdown', 'Var', (33, 42))	('TUG1', 'Gene', (70, 74))	('Taurine Up-Regulated 1', 'Gene', (46, 68))	('Doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('Taurine Up-Regulated 1', 'Gene', '55000', (46, 68))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('132', '153'))
72339	29937935	Then, Flash luciferase assay and western blotting confirmed CDKN2B-AS knockdown inactivated Wnt signaling pathway.	('knockdown', 'Var', (70, 79))	('CDKN2B-AS', 'Gene', (60, 69))	('CDKN2B-AS', 'Gene', '100048912', (60, 69))	('inactivated', 'NegReg', (80, 91))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('92', '113'))	('Wnt signaling pathway', 'Pathway', (92, 113))
72340	29937935	Accordingly, we speculate that knockdown of CDKN2B-AS can advance Gemcitabine sensitivity of BUC through Wnt signaling pathway.	('Gemcitabine', 'Chemical', 'MESH:C056507', (66, 77))	('Gemcitabine sensitivity', 'MPA', (66, 89))	('CDKN2B-AS', 'Gene', (44, 53))	('advance', 'PosReg', (58, 65))	('CDKN2B-AS', 'Gene', '100048912', (44, 53))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('105', '126'))	('BUC through Wnt signaling pathway', 'Pathway', (93, 126))	('knockdown', 'Var', (31, 40))
72341	29937935	Follow up experiments verified this hypothesis, Wnt signaling pathway mainly mediated the effects on Gemcitabine sensitivity induced by CDKN2B-AS knockdown in 24/Gem cells.	('knockdown', 'Var', (146, 155))	('CDKN2B-AS', 'Gene', (136, 145))	('CDKN2B-AS', 'Gene', '100048912', (136, 145))	('Gemcitabine', 'Chemical', 'MESH:C056507', (101, 112))	('Wnt signaling pathway', 'Pathway', (48, 69))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('48', '69'))	('Gemcitabine sensitivity', 'MPA', (101, 124))
72399	28255490	Others observed GATA3 expression in 88% of UC variants including micropapillary, plasmacytoid, nested, clear cell, and microcystic tumors.	('micropapillary', 'Disease', (65, 79))	('microcystic tumors', 'Disease', (119, 137))	('plasmacytoid', 'Disease', (81, 93))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('nested', 'Disease', (95, 101))	('GATA3', 'Gene', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('clear cell', 'Disease', (103, 113))	('variants', 'Var', (46, 54))	('microcystic tumors', 'Disease', 'MESH:D000236', (119, 137))	('GATA3', 'Gene', '2625', (16, 21))	('observed', 'Reg', (7, 15))
72470	26114883	Among the tumor types, PD-L1 was associated with worse 3 year-OS of esophageal cancer, gastric cancer, hepatocellular carcinoma, and urothelial cancer, and 5 year-OS of esophageal cancer, gastric cancer and colorectal cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (188, 202))	('colorectal cancer', 'Disease', 'MESH:D015179', (207, 224))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 127))	('OS of esophageal cancer', 'Disease', (62, 85))	('OS of esophageal cancer', 'Disease', 'MESH:C567932', (62, 85))	('colorectal cancer', 'Disease', (207, 224))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PD-L1', 'Var', (23, 28))	('tumor', 'Disease', (10, 15))	('hepatocellular carcinoma', 'Disease', (103, 127))	('gastric cancer', 'Disease', (188, 202))	('OS of esophageal cancer', 'Disease', (163, 186))	('OS of esophageal cancer', 'Disease', 'MESH:C567932', (163, 186))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (207, 224))	('gastric cancer', 'Disease', 'MESH:D013274', (188, 202))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('urothelial cancer', 'Disease', 'MESH:D014523', (133, 150))	('gastric cancer', 'Disease', (87, 101))	('urothelial cancer', 'Disease', (133, 150))
72471	26114883	These results suggest that expression of PD-L1 is associated with worse survival in solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('worse', 'NegReg', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('expression', 'Var', (27, 37))	('associated', 'Reg', (50, 60))	('PD-L1', 'Gene', (41, 46))	('solid tumors', 'Disease', (84, 96))
72476	26114883	The abnormal expression of these ligands has been linked with prognosis and treatment response of multiple malignancies.	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('multiple malignancies', 'Disease', 'MESH:D009369', (98, 119))	('linked', 'Reg', (50, 56))	('multiple malignancies', 'Disease', (98, 119))
72481	26114883	Another two studies showed that across multiple cancer types, responses were observed in patients with tumors expressing high levels of PD-L1, especially when PD-L1 expressed on tumor-infiltrating immune cells.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (178, 183))	('multiple cancer', 'Disease', (39, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('tumors', 'Disease', (103, 109))	('PD-L1', 'Var', (136, 141))	('multiple cancer', 'Disease', 'MESH:D009369', (39, 54))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('patients', 'Species', '9606', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
72508	26114883	A decade ago some studies reported that blockade of PD-L1 could improve antitumor immunity.	('blockade', 'Var', (40, 48))	('improve', 'PosReg', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('PD-L1', 'Gene', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
72514	26114883	Among the tumor types evaluated, esophageal cancer was the tumor type most linked with worse 3-year and 5-year outcome for patients with high levels of PD-L1.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Disease', (10, 15))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('esophageal cancer', 'Disease', (33, 50))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('PD-L1', 'Gene', (152, 157))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('high levels', 'Var', (137, 148))
72518	26114883	A recent study reported that epithelial-originated cancer patients with positive expression of PD-L1 on tumor tissues were associated with significantly poorer OS when compared to those with negative expression of PD-L1.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PD-L1', 'Gene', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('poorer', 'NegReg', (153, 159))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Disease', (51, 57))	('positive expression', 'Var', (72, 91))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
72529	21864408	Deletion of the Pten tumor suppressor gene in murine urothelial cells in vivo results in upregulation of cyclin-dependent kinase inhibitor p21.	('tumor', 'Disease', (21, 26))	('tumor suppressor', 'biological_process', 'GO:0051726', ('21', '37'))	('murine', 'Species', '10090', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('Pten', 'Gene', (16, 20))	('cyclin-dependent kinase inhibitor p21', 'MPA', (105, 142))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('21', '37'))	('upregulation', 'PosReg', (89, 101))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('105', '138'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('122', '138'))	('Deletion', 'Var', (0, 8))
72530	21864408	We have previously shown in mice that p21 expression blocks an increase in urothelial cell proliferation due to Pten deletion.	('increase', 'PosReg', (63, 71))	('urothelial cell proliferation', 'CPA', (75, 104))	('expression', 'Species', '29278', (42, 52))	('Pten', 'Gene', (112, 116))	('mice', 'Species', '10090', (28, 32))	('rat', 'Species', '10116', (98, 101))	('urothelial cell proliferation', 'biological_process', 'GO:0050674', ('75', '104'))	('deletion', 'Var', (117, 125))
72532	21864408	Mice with conditional deletion of Pten in bladder urothelium were also examined for evidence of PI3-kinase pathway signaling events that affect p21 expression.	('p21 expression', 'MPA', (144, 158))	('deletion', 'Var', (22, 30))	('expression', 'Species', '29278', (148, 158))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('Mice', 'Species', '10090', (0, 4))	('Pten', 'Gene', (34, 38))	('affect', 'Reg', (137, 143))
72537	21864408	We found that a combined treatment of LY294002 and SB-216763 improved the cytotoxic effect against UMUC-3 and UMUC-14 carcinoma cells over LY294002 alone, suggesting potential therapeutic uses for GSK-3beta inhibitors.	('improved', 'PosReg', (61, 69))	('GSK', 'molecular_function', 'GO:0050321', ('197', '200'))	('LY294002', 'Var', (38, 46))	('carcinoma', 'Disease', 'MESH:D002277', (118, 127))	('LY294002', 'Chemical', 'MESH:C085911', (139, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinoma', 'Disease', (118, 127))	('SB-216763', 'Gene', (51, 60))	('SB-216763', 'Chemical', 'MESH:C417521', (51, 60))	('LY294002', 'Chemical', 'MESH:C085911', (38, 46))	('cytotoxic effect', 'CPA', (74, 90))
72538	21864408	Immunohistochemical staining in bladders from wild-type and Pten-deleted mice indicated that GSK-3beta inhibitory phosphorylation increases when Pten is deleted.	('Pten', 'Gene', (145, 149))	('GSK', 'molecular_function', 'GO:0050321', ('93', '96'))	('mice', 'Species', '10090', (73, 77))	('GSK-3beta', 'Protein', (93, 102))	('deleted', 'Var', (153, 160))	('phosphorylation', 'biological_process', 'GO:0016310', ('114', '129'))	('increases', 'PosReg', (130, 139))
72539	21864408	PI3-kinase and AKT cause an upregulation of p21 by suppressing GSK-3beta activity and activating mTOR in both cultured human urothelial carcinoma cells and mouse urothelial cells in vivo.	('mTOR', 'Gene', '2475', (97, 101))	('AKT', 'Pathway', (15, 18))	('activity', 'MPA', (73, 81))	('urothelial carcinoma', 'Disease', (125, 145))	('mTOR', 'Gene', (97, 101))	('GSK-3beta', 'Enzyme', (63, 72))	('GSK', 'molecular_function', 'GO:0050321', ('63', '66'))	('activating', 'PosReg', (86, 96))	('PI3-kinase', 'Var', (0, 10))	('mouse', 'Species', '10090', (156, 161))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (125, 145))	('suppressing', 'NegReg', (51, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('upregulation', 'PosReg', (28, 40))	('human', 'Species', '9606', (119, 124))
72541	21864408	Studies in the last few years have shown that PTEN mutation is also associated with bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (84, 98))	('bladder cancer', 'Disease', 'MESH:D001749', (84, 98))	('associated', 'Reg', (68, 78))	('bladder cancer', 'Disease', (84, 98))	('PTEN', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
72547	21864408	PIP3 in the plasma membrane generated by PI3-kinase leads to the recruitment and activation of the AKT serine/threonine kinase.	('AKT serine/threonine kinase', 'Pathway', (99, 126))	('recruitment', 'MPA', (65, 76))	('rat', 'Species', '10116', (32, 35))	('serine', 'Chemical', 'MESH:D012694', (103, 109))	('activation', 'PosReg', (81, 91))	('plasma membrane', 'cellular_component', 'GO:0005886', ('12', '27'))	('PI3-kinase', 'Var', (41, 51))	('PIP3', 'Chemical', '-', (0, 4))
72551	21864408	In a previous study, we generated mice in which Pten was conditionally deleted in bladder urothelium in order to study the effects on tumorigenesis and PI3-kinase signaling.	('mice', 'Species', '10090', (34, 38))	('signaling', 'biological_process', 'GO:0023052', ('163', '172'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('deleted', 'Var', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Pten', 'Gene', (48, 52))	('rat', 'Species', '10116', (28, 31))	('tumor', 'Disease', (134, 139))
72552	21864408	This increase in p21 levels is important because it suppresses bladder urothelial proliferation elicited by the Pten deletion, and may contribute to reduced tumorigenesis in the bladder.	('tumor', 'Disease', (157, 162))	('p21 levels', 'MPA', (17, 27))	('bladder urothelial', 'Disease', 'MESH:D001745', (63, 81))	('Pten', 'Gene', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('bladder urothelial', 'Disease', (63, 81))	('reduced', 'NegReg', (149, 156))	('rat', 'Species', '10116', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('suppresses', 'NegReg', (52, 62))	('deletion', 'Var', (117, 125))
72553	21864408	The p21 protein inhibits cell proliferation by functioning as a cyclin-dependent kinase inhibitor, and p21 exhibits tumor suppressor functions as shown by the finding that p21-/- 129Sv/C57Bl6 mice develop spontaneous tumors at 16 months of age.	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('cell proliferation', 'biological_process', 'GO:0008283', ('25', '43'))	('protein', 'Protein', (8, 15))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('116', '132'))	('inhibits', 'NegReg', (16, 24))	('tumor', 'Disease', (217, 222))	('p21', 'Gene', (103, 106))	('cell proliferation', 'CPA', (25, 43))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('64', '97'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('116', '132'))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('develop', 'PosReg', (197, 204))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('mice', 'Species', '10090', (192, 196))	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('rat', 'Species', '10116', (37, 40))	('p21', 'Gene', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('129Sv', 'Species', '10090', (179, 184))	('p21-/- 129Sv/C57Bl6', 'Var', (172, 191))	('tumors', 'Disease', (217, 223))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('81', '97'))	('tumor', 'Disease', (116, 121))
72557	21864408	In many cell types, PI3-kinase/AKT signaling leads to increased cell proliferation, so the fact that it induces p21 and inhibits cell proliferation in bladder urothelial cells is surprising.	('inhibits', 'NegReg', (120, 128))	('PI3-kinase/AKT', 'Var', (20, 34))	('bladder urothelial', 'Disease', (151, 169))	('rat', 'Species', '10116', (76, 79))	('cell proliferation', 'CPA', (64, 82))	('bladder urothelial', 'Disease', 'MESH:D001745', (151, 169))	('p21', 'MPA', (112, 115))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('cell proliferation', 'biological_process', 'GO:0008283', ('129', '147'))	('increased', 'PosReg', (54, 63))	('induces', 'Reg', (104, 111))	('rat', 'Species', '10116', (141, 144))	('AKT signaling', 'biological_process', 'GO:0043491', ('31', '44'))
72593	21864408	In our previous studies, we found that deletion of Pten in murine bladder epithelium leads to an increase in p21 expression, and that the p21 mediates a significant decrease in cell proliferation.	('increase', 'PosReg', (97, 105))	('p21 expression', 'MPA', (109, 123))	('cell proliferation', 'biological_process', 'GO:0008283', ('177', '195'))	('deletion', 'Var', (39, 47))	('decrease', 'NegReg', (165, 173))	('expression', 'Species', '29278', (113, 123))	('Pten', 'Gene', (51, 55))	('murine', 'Species', '10090', (59, 65))	('rat', 'Species', '10116', (189, 192))	('cell proliferation', 'CPA', (177, 195))
72602	21864408	As seen in Figure 1C, EGF treatment actually significantly decreased the number of viable cells, and knock down of p21 prevented this effect of EGF (ANOVA; p = .002), showing that the induction of p21 in response to EGF results in reduced cell proliferation.	('EGF', 'molecular_function', 'GO:0005154', ('216', '219'))	('cell proliferation', 'CPA', (239, 257))	('decreased', 'NegReg', (59, 68))	('EGF', 'molecular_function', 'GO:0005154', ('22', '25'))	('EGF', 'molecular_function', 'GO:0005154', ('144', '147'))	('cell proliferation', 'biological_process', 'GO:0008283', ('239', '257'))	('knock down', 'Var', (101, 111))	('reduced', 'NegReg', (231, 238))	('rat', 'Species', '10116', (251, 254))
72611	21864408	Since the PI3-kinase/AKT signaling pathway is known to inhibit GSK-3beta activity, and GSK-3beta has been reported to cause the degradation of other proteins such as beta catenin and SMAD1, we decided to investigate its involvement in p21 regulation in bladder cells.	('beta catenin', 'Gene', (166, 178))	('PI3-kinase/AKT signaling pathway', 'Pathway', (10, 42))	('GSK-3beta', 'Var', (87, 96))	('GSK-3beta', 'Gene', (63, 72))	('degradation', 'MPA', (128, 139))	('activity', 'MPA', (73, 81))	('AKT signaling', 'biological_process', 'GO:0043491', ('21', '34'))	('regulation', 'biological_process', 'GO:0065007', ('239', '249'))	('inhibit', 'NegReg', (55, 62))	('proteins', 'Protein', (149, 157))	('GSK', 'molecular_function', 'GO:0050321', ('63', '66'))	('degradation', 'biological_process', 'GO:0009056', ('128', '139'))	('SMAD1', 'Gene', '4086', (183, 188))	('signaling pathway', 'biological_process', 'GO:0007165', ('25', '42'))	('beta catenin', 'Gene', '1499', (166, 178))	('GSK', 'molecular_function', 'GO:0050321', ('87', '90'))	('SMAD1', 'Gene', (183, 188))	('cause', 'Reg', (118, 123))
72618	21864408	Levels of p21 were initially low after serum starvation, but increased in response to SB216763 treatment (Figure 5A), indicating that GSK-3 activity negatively regulates p21 expression.	('GSK-3', 'Gene', (134, 139))	('expression', 'Species', '29278', (174, 184))	('SB216763', 'Chemical', 'MESH:C417521', (86, 94))	('expression', 'MPA', (174, 184))	('negatively', 'NegReg', (149, 159))	('GSK-3', 'Gene', '56637', (134, 139))	('ser', 'Chemical', 'MESH:D012694', (39, 42))	('p21', 'Gene', (170, 173))	('increased', 'PosReg', (61, 70))	('GSK', 'molecular_function', 'GO:0050321', ('134', '137'))	('regulates', 'Reg', (160, 169))	('SB216763', 'Var', (86, 94))
72619	21864408	UMUC-3 cells contain a mutated p53, so the p21 induction in response to SB216763 is not p53-dependent in these cells.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('SB216763', 'Chemical', 'MESH:C417521', (72, 80))	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (88, 91))	('mutated', 'Var', (23, 30))	('p21', 'Gene', (43, 46))
72626	21864408	The ability of the GSK-3 inhibitor SB216763 to induce p21 led us to speculate that SB216763 should inhibit urothelial carcinoma cell proliferation.	('SB216763', 'Var', (83, 91))	('GSK-3', 'Gene', '56637', (19, 24))	('GSK', 'molecular_function', 'GO:0050321', ('19', '22'))	('rat', 'Species', '10116', (140, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('inhibit', 'NegReg', (99, 106))	('p21', 'Disease', (54, 57))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (107, 127))	('GSK-3', 'Gene', (19, 24))	('SB216763', 'Chemical', 'MESH:C417521', (35, 43))	('SB216763', 'Chemical', 'MESH:C417521', (83, 91))	('cell proliferation', 'biological_process', 'GO:0008283', ('128', '146'))	('urothelial carcinoma', 'Disease', (107, 127))
72627	21864408	We further hypothesized that the combination of SB216763 with a PI3-kinase inhibitor such as LY294002 should more effectively inhibit cell proliferation and/or induce cytotoxicity than LY294002 alone.	('cell proliferation', 'CPA', (134, 152))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('68', '84'))	('rat', 'Species', '10116', (146, 149))	('LY294002', 'Var', (93, 101))	('cytotoxicity', 'Disease', (167, 179))	('cytotoxicity', 'Disease', 'MESH:D064420', (167, 179))	('LY294002', 'Chemical', 'MESH:C085911', (185, 193))	('inhibit', 'NegReg', (126, 133))	('SB216763', 'Chemical', 'MESH:C417521', (48, 56))	('induce', 'PosReg', (160, 166))	('SB216763', 'Var', (48, 56))	('cell proliferation', 'biological_process', 'GO:0008283', ('134', '152'))	('LY294002', 'Chemical', 'MESH:C085911', (93, 101))
72628	21864408	In order to test these hypotheses, we treated UMUC-3 and UMUC-14 cells with various concentrations of SB216763 in the presence or absence of LY294002.	('rat', 'Species', '10116', (91, 94))	('SB216763', 'Chemical', 'MESH:C417521', (102, 110))	('SB216763', 'Gene', (102, 110))	('LY294002', 'Var', (141, 149))	('LY294002', 'Chemical', 'MESH:C085911', (141, 149))
72631	21864408	After 72 hours, the UMUC-3 cells did not show significant decreases in viability due to treatment with LY294002 alone or SB216763 alone, even at the highest concentrations used in this assay, although there was a trend toward decreased viability for both drugs.	('LY294002', 'Var', (103, 111))	('rat', 'Species', '10116', (164, 167))	('LY294002', 'Chemical', 'MESH:C085911', (103, 111))	('SB216763', 'Var', (121, 129))	('SB216763', 'Chemical', 'MESH:C417521', (121, 129))
72632	21864408	A combination of the two drugs was most effective for cell cytotoxicity; 2 muM LY294002 plus SB216763 at any tested concentration caused significant decreases in UMUC-3 cell viability compared to 2 muM LY294002 alone (Oneway ANOVA; p < .0001).	('cytotoxicity', 'Disease', 'MESH:D064420', (59, 71))	('LY294002', 'Var', (79, 87))	('rat', 'Species', '10116', (123, 126))	('LY294002', 'Chemical', 'MESH:C085911', (202, 210))	('decreases', 'NegReg', (149, 158))	('cytotoxicity', 'Disease', (59, 71))	('LY294002', 'Chemical', 'MESH:C085911', (79, 87))	('UMUC-3 cell viability', 'CPA', (162, 183))	('SB216763', 'Var', (93, 101))	('SB216763', 'Chemical', 'MESH:C417521', (93, 101))
72633	21864408	While treatment of the UMUC-14 cells with 2 muM LY294002 alone had no significant effect on cell viability compared to untreated cells, there was a dose-dependent cytotoxicity response to SB216763 alone (Oneway ANOVA; p < .0001), and there was a significant decrease in cell viability at 10 muM SB216763 (Tukey-Kramer HSD; p = .0004) and at 40 muM SB216763 (Tukey-Kramer HSD; p < .0001) compared to the untreated control cells.	('SB216763', 'Var', (348, 356))	('cytotoxicity', 'Disease', 'MESH:D064420', (163, 175))	('HSD', 'Gene', (371, 374))	('HSD', 'Gene', '9469', (371, 374))	('SB216763', 'Chemical', 'MESH:C417521', (348, 356))	('LY294002', 'Var', (48, 56))	('SB216763', 'Chemical', 'MESH:C417521', (188, 196))	('HSD', 'Gene', '9469', (318, 321))	('SB216763', 'Chemical', 'MESH:C417521', (295, 303))	('decrease', 'NegReg', (258, 266))	('SB216763', 'Var', (188, 196))	('cytotoxicity', 'Disease', (163, 175))	('cell viability', 'CPA', (270, 284))	('LY294002', 'Chemical', 'MESH:C085911', (48, 56))	('HSD', 'Gene', (318, 321))
72634	21864408	A combination of the two drugs was once again more effective for cytotoxicity; when 2 muM LY294002 was added to the UMUC-14 cells together with 10 muM SB216763, there was a significant further decrease in cell viability compared to LY294002 alone (Oneway ANOVA; p < .0001; Tukey-Kramer HSD; p = .0007).	('cytotoxicity', 'Disease', 'MESH:D064420', (65, 77))	('LY294002', 'Chemical', 'MESH:C085911', (232, 240))	('HSD', 'Gene', '9469', (286, 289))	('LY294002', 'Var', (90, 98))	('SB216763', 'Chemical', 'MESH:C417521', (151, 159))	('HSD', 'Gene', (286, 289))	('cell viability', 'CPA', (205, 219))	('cytotoxicity', 'Disease', (65, 77))	('decrease', 'NegReg', (193, 201))	('LY294002', 'Chemical', 'MESH:C085911', (90, 98))
72635	21864408	In addition, there was significantly more cytotoxicity at 40 muM SB216763 when comparing cells in the presence of LY294002 compared to the cells that received no LY294004 (Student's t-test; p = .02).	('cytotoxicity', 'Disease', 'MESH:D064420', (42, 54))	('LY294004', 'Chemical', '-', (162, 170))	('LY294002', 'Var', (114, 122))	('more', 'PosReg', (37, 41))	('cytotoxicity', 'Disease', (42, 54))	('SB216763', 'Chemical', 'MESH:C417521', (65, 73))	('LY294002', 'Chemical', 'MESH:C085911', (114, 122))	('SB216763', 'Var', (65, 73))
72636	21864408	This suggests that increased inhibition of cell viability can be attained with a combination of the LY294002 PI3-kinase inhibitor and the SB216763 GSK-3 inhibitor.	('GSK-3', 'Gene', (147, 152))	('LY294002', 'Var', (100, 108))	('inhibition', 'NegReg', (29, 39))	('GSK-3', 'Gene', '56637', (147, 152))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('113', '129'))	('LY294002', 'Chemical', 'MESH:C085911', (100, 108))	('SB216763', 'Chemical', 'MESH:C417521', (138, 146))	('cell viability', 'CPA', (43, 57))	('GSK', 'molecular_function', 'GO:0050321', ('147', '150'))
72640	21864408	Given the evidence that GSK-3beta inhibition causes elevated p21 levels in PI3-kinase stimulated human urothelial cells, we examined if GSK-3beta is also inhibited in mice that are conditionally deficient for Pten (Fabpl-Cre;Ptenloxp/loxp)in bladder urothelium.	('GSK', 'molecular_function', 'GO:0050321', ('24', '27'))	('inhibition', 'Var', (34, 44))	('loxp', 'Chemical', '-', (234, 238))	('human', 'Species', '9606', (97, 102))	('inhibited', 'NegReg', (154, 163))	('Ptenloxp', 'Chemical', '-', (225, 233))	('GSK', 'molecular_function', 'GO:0050321', ('136', '139'))	('p21 levels', 'MPA', (61, 71))	('mice', 'Species', '10090', (167, 171))	('loxp', 'Chemical', '-', (229, 233))	('elevated', 'PosReg', (52, 60))
72642	21864408	Immunohistochemical staining of Pten deficient mouse bladders and their wild-type littermates showed not only higher levels of p21 positive cells in the bladder, but also greatly increased cytoplasmic staining of phospho-GSK3alpha and beta at serines 9 and 21 (Figure 7).	('deficient', 'Var', (37, 46))	('Pten', 'Gene', (32, 36))	('cytoplasmic staining', 'MPA', (189, 209))	('GSK3alpha', 'Gene', '606496', (221, 230))	('beta', 'Protein', (235, 239))	('serines', 'Chemical', 'MESH:D012694', (243, 250))	('GSK', 'molecular_function', 'GO:0050321', ('221', '224'))	('p21', 'Var', (127, 130))	('higher', 'PosReg', (110, 116))	('increased', 'PosReg', (179, 188))	('GSK3alpha', 'Gene', (221, 230))	('mouse', 'Species', '10090', (47, 52))	('levels', 'MPA', (117, 123))
72644	21864408	Deletion of Pten causes increased tumorigenesis in a mouse model of bladder cancer, and there is a great deal of evidence of decreased PTEN expression in human bladder carcinomas.	('bladder cancer', 'Phenotype', 'HP:0009725', (68, 82))	('human', 'Species', '9606', (154, 159))	('expression', 'Species', '29278', (140, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('Pten', 'Gene', (12, 16))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('mouse', 'Species', '10090', (53, 58))	('Deletion', 'Var', (0, 8))	('PTEN', 'Protein', (135, 139))	('decreased', 'NegReg', (125, 134))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (160, 178))	('bladder carcinomas', 'Disease', 'MESH:D001749', (160, 178))	('increased', 'PosReg', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('expression', 'MPA', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('bladder carcinomas', 'Disease', (160, 178))	('bladder cancer', 'Disease', 'MESH:D001749', (68, 82))	('bladder cancer', 'Disease', (68, 82))
72648	21864408	Our studies in the mouse and multiple studies by others in human and rat bladder cancer cell lines have shown that induction of p21 inhibits cell proliferation.	('human', 'Species', '9606', (59, 64))	('bladder cancer', 'Disease', (73, 87))	('rat', 'Species', '10116', (153, 156))	('p21', 'Gene', (128, 131))	('cell proliferation', 'biological_process', 'GO:0008283', ('141', '159'))	('inhibits', 'NegReg', (132, 140))	('induction', 'Var', (115, 124))	('cell proliferation', 'CPA', (141, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('mouse', 'Species', '10090', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('rat', 'Species', '10116', (69, 72))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))
72649	21864408	Therefore, when bladder cells acquire mutations that cause overactive PI3-kinase/AKT signaling, the ensuing p21 expression provides a protective response by suppressing proliferation, and it may delay tumorigenesis.	('overactive', 'PosReg', (59, 69))	('rat', 'Species', '10116', (176, 179))	('delay', 'NegReg', (195, 200))	('p21', 'Gene', (108, 111))	('PI3-kinase/AKT signaling', 'Pathway', (70, 94))	('suppressing', 'NegReg', (157, 168))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('AKT signaling', 'biological_process', 'GO:0043491', ('81', '94'))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('proliferation', 'CPA', (169, 182))	('expression', 'Species', '29278', (112, 122))	('tumor', 'Disease', (201, 206))	('mutations', 'Var', (38, 47))
72653	21864408	It was our observation that in the Pten deficient animals, the p21 levels remained elevated for over a year.	('Pten', 'Gene', (35, 39))	('p21 levels', 'MPA', (63, 73))	('deficient', 'Var', (40, 49))	('ser', 'Chemical', 'MESH:D012694', (13, 16))	('elevated', 'PosReg', (83, 91))
72655	21864408	Our finding that the UMUC-14 cells were initially more susceptible to LY294002 cytotoxicity than the UMUC-3 cells was surprising, since UMUC-14 cells show low levels of AKT activation (8).	('cytotoxicity', 'Disease', 'MESH:D064420', (79, 91))	('LY294002', 'Chemical', 'MESH:C085911', (70, 78))	('cytotoxicity', 'Disease', (79, 91))	('LY294002', 'Var', (70, 78))	('AKT', 'Pathway', (169, 172))
72663	21864408	Although GSK-3beta is generally considered to negatively regulate cell growth, GSK-3beta inhibitors have been found to reduce colon and ovarian tumor cell growth; these drugs may be appropriate in bladder cancer because of their effects on p21.	('cell growth', 'biological_process', 'GO:0016049', ('66', '77'))	('GSK-3beta', 'Gene', (79, 88))	('colon', 'Disease', (126, 131))	('ovarian tumor', 'Disease', (136, 149))	('bladder cancer', 'Disease', (197, 211))	('bladder cancer', 'Disease', 'MESH:D001749', (197, 211))	('reduce', 'NegReg', (119, 125))	('GSK', 'molecular_function', 'GO:0050321', ('9', '12'))	('inhibitors', 'Var', (89, 99))	('GSK', 'molecular_function', 'GO:0050321', ('79', '82'))	('ovarian tumor', 'Phenotype', 'HP:0100615', (136, 149))	('cell growth', 'biological_process', 'GO:0016049', ('150', '161'))	('colon', 'Disease', 'MESH:D015179', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('ovarian tumor', 'Disease', 'MESH:D010051', (136, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('bladder cancer', 'Phenotype', 'HP:0009725', (197, 211))
72667	21864408	We have found evidence that inhibition of GSK-3beta either through activation of the PI3-kinase/AKT signaling pathway or through the use of pharmacological inhibitors of GSK-3beta leads to an increase in p21 levels, while an overexpression of GSK-3beta in cells with reduced PI3-kinase/AKT signaling leads to a decrease in p21.	('GSK-3beta', 'Gene', (42, 51))	('AKT signaling', 'biological_process', 'GO:0043491', ('96', '109'))	('signaling pathway', 'biological_process', 'GO:0007165', ('100', '117'))	('activation', 'PosReg', (67, 77))	('inhibition of GSK', 'biological_process', 'GO:1902948', ('28', '45'))	('AKT signaling', 'biological_process', 'GO:0043491', ('286', '299'))	('GSK', 'molecular_function', 'GO:0050321', ('243', '246'))	('inhibition', 'Var', (28, 38))	('p21 levels', 'MPA', (204, 214))	('PI3-kinase/AKT signaling pathway', 'Pathway', (85, 117))	('increase', 'PosReg', (192, 200))	('expression', 'Species', '29278', (229, 239))	('GSK', 'molecular_function', 'GO:0050321', ('170', '173'))	('GSK', 'molecular_function', 'GO:0050321', ('42', '45'))
72710	32182655	According to a recent report, urothelial cancer patients with FGFR3 mutations had lower immune cell infiltration and lower TGFbeta signals than patients without FGFR3 mutations.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('urothelial cancer', 'Disease', (30, 47))	('FGFR3', 'Gene', '2261', (62, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('immune cell infiltration', 'CPA', (88, 112))	('FGFR3', 'Gene', (161, 166))	('FGFR', 'molecular_function', 'GO:0005007', ('161', '165'))	('TGFbeta', 'Gene', (123, 130))	('lower', 'NegReg', (117, 122))	('urothelial cancer', 'Disease', 'MESH:D014523', (30, 47))	('patients', 'Species', '9606', (144, 152))	('FGFR3', 'Gene', (62, 67))	('mutations', 'Var', (68, 77))	('patients', 'Species', '9606', (48, 56))	('TGFbeta', 'Gene', '7039', (123, 130))	('lower immune cell', 'Phenotype', 'HP:0002721', (82, 99))	('FGFR3', 'Gene', '2261', (161, 166))	('lower', 'NegReg', (82, 87))
72711	32182655	We identified that FGFR3 mutations were enriched in class 1 (Figure S2).	('FGFR3', 'Gene', '2261', (19, 24))	('mutations', 'Var', (25, 34))	('FGFR3', 'Gene', (19, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))
72744	32182655	Interestingly, among these individuals, patients with inactivation of the TGFbeta and YAP/TAZ pathways and activation of the cell cycle and DDR were more responsive to ICI therapy than patients without these traits.	('inactivation', 'Var', (54, 66))	('cell cycle', 'biological_process', 'GO:0007049', ('125', '135'))	('YAP', 'Gene', (86, 89))	('TGFbeta', 'Gene', (74, 81))	('cell cycle', 'CPA', (125, 135))	('patients', 'Species', '9606', (40, 48))	('DDR', 'Gene', (140, 143))	('YAP', 'Gene', '10413', (86, 89))	('TAZ', 'Gene', '6901', (90, 93))	('patients', 'Species', '9606', (185, 193))	('TAZ', 'Gene', (90, 93))	('TGFbeta', 'Gene', '7039', (74, 81))	('responsive to ICI therapy', 'MPA', (154, 179))	('activation', 'PosReg', (107, 117))
72750	32182655	In recently updated data from TCGA, these patients showed enrichment of FGFR3 mutations.	('FGFR3', 'Gene', '2261', (72, 77))	('mutations', 'Var', (78, 87))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('FGFR3', 'Gene', (72, 77))	('patients', 'Species', '9606', (42, 50))
72751	32182655	Bladder cancer patients with FGFR3 mutations have been associated with lower immune cell infiltration and lower TGFbeta signals than patients without FGFR3 mutations.	('patients', 'Species', '9606', (15, 23))	('immune', 'MPA', (77, 83))	('Bladder cancer', 'Disease', (0, 14))	('TGFbeta', 'Gene', (112, 119))	('FGFR3', 'Gene', (150, 155))	('patients', 'Species', '9606', (133, 141))	('FGFR', 'molecular_function', 'GO:0005007', ('29', '33'))	('TGFbeta', 'Gene', '7039', (112, 119))	('FGFR3', 'Gene', '2261', (150, 155))	('FGFR3', 'Gene', (29, 34))	('lower', 'NegReg', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('FGFR3', 'Gene', '2261', (29, 34))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('lower immune cell', 'Phenotype', 'HP:0002721', (71, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('150', '154'))	('lower', 'NegReg', (71, 76))	('Bladder cancer', 'Disease', 'MESH:D001749', (0, 14))	('mutations', 'Var', (35, 44))
72752	32182655	Patients with FGFR mutations or fusions may be less likely to have a response to immunotherapy than those without such alterations.	('fusions', 'Var', (32, 39))	('less', 'NegReg', (47, 51))	('mutations', 'Var', (19, 28))	('FGFR', 'Gene', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('response', 'CPA', (69, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))
72753	32182655	The pan-FGFR inhibitor erdafitinib had a measurable benefit in patients with advanced urothelial carcinoma with FGFR alteration.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (86, 106))	('benefit', 'PosReg', (52, 59))	('FGFR', 'molecular_function', 'GO:0005007', ('112', '116'))	('FGFR', 'molecular_function', 'GO:0005007', ('8', '12'))	('alteration', 'Var', (117, 127))	('patients', 'Species', '9606', (63, 71))	('urothelial carcinoma', 'Disease', (86, 106))	('erdafitinib', 'Chemical', 'MESH:C000604580', (23, 34))
72762	32182655	DDR gene alterations are independently associated with the response to PD-1/PD-L1 inhibitors in patients with advanced urothelial cancer.	('associated with', 'Reg', (39, 54))	('PD-1', 'Gene', '5133', (71, 75))	('urothelial cancer', 'Disease', (119, 136))	('PD-L1', 'Gene', (76, 81))	('PD-L1', 'Gene', '29126', (76, 81))	('alterations', 'Var', (9, 20))	('urothelial cancer', 'Disease', 'MESH:D014523', (119, 136))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('response', 'MPA', (59, 67))	('PD-1', 'Gene', (71, 75))	('DDR gene', 'Gene', (0, 8))
72763	32182655	Future studies using next-generation sequencing technologies will continue to uncover associations between mutation- or expression-based changes in tumor DNA repair pathway function and response to immunotherapy.	('DNA', 'cellular_component', 'GO:0005574', ('154', '157'))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('DNA repair', 'biological_process', 'GO:0006281', ('154', '164'))	('tumor', 'Disease', (148, 153))	('changes', 'Reg', (137, 144))	('mutation-', 'Var', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('function', 'MPA', (173, 181))
72789	31803629	Urine biopsy utilizing next-generation sequencing (NGS) can prove useful at all stages of urologic malignancy care, where urine can be collected to aid in clinical decision making through the identification of commonly known mutations, and potentially reduce or avoid all forms of invasive procedures.	('aid', 'Gene', (148, 151))	('aid', 'Gene', '57379', (148, 151))	('mutations', 'Var', (225, 234))
72793	31803629	for the detection of mutations, translocations or copy number alterations, and the expression of specific markers of cancer at the mRNA/small RNA level.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('translocations', 'Var', (32, 46))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('RNA', 'cellular_component', 'GO:0005562', ('142', '145'))	('copy number alterations', 'Var', (50, 73))	('cancer', 'Disease', (117, 123))	('mutations', 'Var', (21, 30))
72796	31803629	Blood is the source of CTCs or circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), and exosomes, released by tumor tissues, which can be potentially used to detect mutations present in the tumors.	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', (119, 124))	('tumors', 'Disease', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('mutations', 'Var', (174, 183))	('tumor', 'Disease', (43, 48))	('RNA', 'cellular_component', 'GO:0005562', ('80', '83'))
72804	31803629	Several studies have shown that urine supernatant is superior to urine pellet for detection of genetic aberrations in urothelial cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('urothelial cancer', 'Disease', 'MESH:D014523', (118, 135))	('patients', 'Species', '9606', (136, 144))	('genetic aberrations', 'Var', (95, 114))	('urothelial cancer', 'Disease', (118, 135))
72806	31803629	Nevertheless, urine pellet has also been successfully used to detect mutations in the upper and lower tract urothelial carcinomas that matched with the mutation profile obtained from tumor tissues of respective patients.	('mutations', 'Var', (69, 78))	('patients', 'Species', '9606', (211, 219))	('tract urothelial carcinomas', 'Disease', 'MESH:D001661', (102, 129))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('tract urothelial carcinomas', 'Disease', (102, 129))
72809	31803629	Tagged amplicon deep sequencing (TAm-Seq)-based NGS utilizes efficient library preparation and statistical analysis to detect mutations across a gene panel with a detection limit of 0.02% and specificity of 99.99%.	('TAm', 'Chemical', 'MESH:C113538', (33, 36))	('detect', 'Reg', (119, 125))	('mutations', 'Var', (126, 135))
72811	31803629	Droplet digital PCR is based on a water-in-oil emulsion where the tumor or normal DNA is distributed into millions of droplets followed by amplification using TaqMan fluorescence probes which are specific to either the mutant or normal sequences.	('mutant', 'Var', (219, 225))	('Droplet digital', 'Disease', 'MESH:D058066', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('Droplet digital', 'Disease', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
72814	31803629	Somatic hotspot mutations within the promoter region of TERT are one of the most frequently occurring mutations in different cancers including bladder cancer, of which the most common variants are C>T transition at either of two positions: chr5:12952228 and chr5:1295250, 146 and 124 base-pairs upstream, respectively, of start codon.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('bladder cancer', 'Phenotype', 'HP:0009725', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('C>T transition', 'Var', (197, 211))	('chr5:12952228', 'Var', (240, 253))	('bladder cancer', 'Disease', 'MESH:D001749', (143, 157))	('TERT', 'Gene', (56, 60))	('chr5:1295250', 'Var', (258, 270))	('bladder cancer', 'Disease', (143, 157))	('TERT', 'Gene', '7015', (56, 60))
72815	31803629	The high frequency of TERT promoter mutation has been shown to be prevalent in both muscle-invasive and non-muscle invasive bladder cancer and can be easily detected in urine.	('TERT', 'Gene', (22, 26))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (115, 138))	('muscle-invasive', 'Disease', (84, 99))	('invasive bladder cancer', 'Disease', (115, 138))	('TERT', 'Gene', '7015', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (124, 138))	('invasive bladder', 'Phenotype', 'HP:0100645', (115, 131))	('prevalent', 'Reg', (66, 75))	('mutation', 'Var', (36, 44))
72816	31803629	analyzed uDNA from 76 patients with non-invasive urothelial carcinoma and showed that mutation in the TERT promoter region could be used as a biomarker for early detection of disease in patients being worked up for bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (215, 229))	('TERT', 'Gene', (102, 106))	('non-invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (36, 69))	('TERT', 'Gene', '7015', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('bladder cancer', 'Disease', 'MESH:D001749', (215, 229))	('patients', 'Species', '9606', (22, 30))	('non-invasive urothelial carcinoma', 'Disease', (36, 69))	('bladder cancer', 'Disease', (215, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('mutation in', 'Var', (86, 97))	('patients', 'Species', '9606', (186, 194))
72818	31803629	In another study, TERT promoter mutation was significantly associated with 6-month recurrence of pT1 bladder cancer presence of TERT mutation increased the risk of recurrence 5-fold, and TERT promoter hotspots could be used to non-invasively follow up non-muscle invasive bladder cancer patients after surgery.	('bladder cancer', 'Phenotype', 'HP:0009725', (272, 286))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('TERT', 'Gene', (187, 191))	('TERT', 'Gene', '7015', (187, 191))	('invasive bladder', 'Phenotype', 'HP:0100645', (263, 279))	('pT1', 'Gene', '58492', (97, 100))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (263, 286))	('pT1', 'Gene', (97, 100))	('TERT', 'Gene', (18, 22))	('presence', 'Var', (116, 124))	('TERT', 'Gene', (128, 132))	('TERT', 'Gene', '7015', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('TERT', 'Gene', '7015', (18, 22))	('invasive bladder cancer', 'Disease', (263, 286))	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('bladder cancer', 'Disease', (101, 115))	('patients', 'Species', '9606', (287, 295))	('associated', 'Reg', (59, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))	('bladder cancer', 'Disease', 'MESH:D001749', (272, 286))
72820	31803629	Similarly, FGFR3 is mutated in two-thirds of non-muscle invasive bladder cancers [at one of 5 hotspots, with S249C being by far the most common ], and the detection of FGFR3 mutation in urine biopsy was associated with 4-fold higher risk of recurrence.	('FGFR3', 'Gene', '2261', (168, 173))	('FGFR3', 'Gene', '2261', (11, 16))	('bladder cancers', 'Phenotype', 'HP:0009725', (65, 80))	('mutation', 'Var', (174, 182))	('FGFR3', 'Gene', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('bladder cancer', 'Phenotype', 'HP:0009725', (65, 79))	('FGFR3', 'Gene', (11, 16))	('invasive bladder cancers', 'Disease', (56, 80))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (56, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('168', '172'))	('S249C', 'Chemical', 'MESH:C504332', (109, 114))	('invasive bladder', 'Phenotype', 'HP:0100645', (56, 72))	('FGFR', 'molecular_function', 'GO:0005007', ('11', '15'))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('mutated', 'Var', (20, 27))	('S249C', 'Var', (109, 114))
72822	31803629	Reliance on FGFR3 mutations is ideal for low grade disease, as these variants are common for these cancers.	('FGFR3', 'Gene', (12, 17))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))	('cancers', 'Disease', (99, 106))	('FGFR3', 'Gene', '2261', (12, 17))	('common', 'Reg', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('mutations', 'Var', (18, 27))
72824	31803629	showed that the presence of mutations detected by either targeted hotspot panel or copy number alteration detected with shallow whole genome sequencing in uDNA during second neoadjuvant chemotherapy (NAC) cycle was associated with recurrence of bladder cancer with 83% sensitivity and 100% specificity, while the persons without mutation had low recurrence rate with 100% positive predictive value and 85.7% negative predictive value.	('copy number alteration', 'Var', (83, 105))	('bladder cancer', 'Disease', 'MESH:D001749', (245, 259))	('recurrence of bladder cancer', 'Phenotype', 'HP:0012786', (231, 259))	('bladder cancer', 'Disease', (245, 259))	('NAC', 'cellular_component', 'GO:0005854', ('200', '203'))	('persons', 'Species', '9606', (313, 320))	('bladder cancer', 'Phenotype', 'HP:0009725', (245, 259))	('associated with', 'Reg', (215, 230))	('mutations', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
72828	31803629	UroVysion  uses exfoliated urothelial cells from urine and analyzes chromosome aneuploidy along with loss of locus 9p21 for the detection of recurrent bladder cancer.	('bladder cancer', 'Disease', (151, 165))	('p21', 'Gene', (116, 119))	('p21', 'Gene', '644914', (116, 119))	('recurrent bladder', 'Phenotype', 'HP:0012786', (141, 158))	('loss', 'Var', (101, 105))	('aneuploidy', 'Disease', 'MESH:D000782', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('bladder cancer', 'Phenotype', 'HP:0009725', (151, 165))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('bladder cancer', 'Disease', 'MESH:D001749', (151, 165))	('aneuploidy', 'Disease', (79, 89))
72831	31803629	The role of non-coding RNAs in bladder cancer has recently emerged in the diagnosis and prognosis of bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('non-coding RNAs', 'Var', (12, 27))	('bladder cancer', 'Phenotype', 'HP:0009725', (31, 45))	('bladder cancer', 'Disease', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))	('bladder cancer', 'Disease', 'MESH:D001749', (31, 45))	('bladder cancer', 'Disease', (31, 45))
72841	31803629	measured DNA methylation in urine biopsy samples and used multivariable analysis of clinical risk factors in hematuria patients to achieve 93% sensitivity and 86% specificity for bladder cancer, thus potentially reducing the need for diagnostic cystoscopy by 77%.	('bladder cancer', 'Phenotype', 'HP:0009725', (179, 193))	('reducing', 'NegReg', (212, 220))	('methylation', 'Var', (13, 24))	('patients', 'Species', '9606', (119, 127))	('hematuria', 'Disease', 'MESH:D006417', (109, 118))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('bladder cancer', 'Disease', 'MESH:D001749', (179, 193))	('bladder cancer', 'Disease', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('DNA', 'Gene', (9, 12))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('hematuria', 'Phenotype', 'HP:0000790', (109, 118))	('hematuria', 'Disease', (109, 118))
72846	31803629	UroSEEK , a massively parallel sequencing-based assay developed by Springer et al., which detects mutations in FGFR3, TP53, CDKN2A, ERBB2, HRAS, KRAS, PIK3CA, MET, VHL, and MLL, promoter region of TERT, and detection of aneuploidy.	('CDKN2A', 'Gene', (124, 130))	('FGFR3', 'Gene', '2261', (111, 116))	('TP53', 'Gene', (118, 122))	('MET', 'Gene', (159, 162))	('TERT', 'Gene', (197, 201))	('CDKN2A', 'Gene', '1029', (124, 130))	('VHL', 'Disease', 'MESH:D006623', (164, 167))	('TERT', 'Gene', '7015', (197, 201))	('HRAS', 'Gene', '3265', (139, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('KRAS', 'Gene', '3845', (145, 149))	('PIK3CA', 'Gene', '5290', (151, 157))	('HRAS', 'Gene', (139, 143))	('MLL', 'Gene', (173, 176))	('MLL', 'Gene', '4297', (173, 176))	('MET', 'Chemical', 'MESH:C098756', (159, 162))	('KRAS', 'Gene', (145, 149))	('aneuploidy', 'Disease', 'MESH:D000782', (220, 230))	('TP53', 'Gene', '7157', (118, 122))	('ERBB2', 'Gene', (132, 137))	('VHL', 'Disease', (164, 167))	('PIK3CA', 'Gene', (151, 157))	('mutations', 'Var', (98, 107))	('FGFR3', 'Gene', (111, 116))	('ERBB2', 'Gene', '2064', (132, 137))	('aneuploidy', 'Disease', (220, 230))
72854	31803629	used urine CAPP-Seq technique to detect mutations in uDNA for the surveillance of bladder cancer after intravesical treatment, being able to detect recurrent cases in overall 91% of patients that included all patients with positive cytology and more than 80% of the patients that cytology missed.	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('patients', 'Species', '9606', (266, 274))	('uDNA', 'Gene', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (209, 217))	('bladder cancer', 'Disease', (82, 96))	('patients', 'Species', '9606', (182, 190))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))
72855	31803629	analyzed DNA from urine cell pellets using Safe-SeqS technique in the aforementioned study to show that the presence of TERT promoter mutation in uDNA can be directly correlated with recurrence.	('presence', 'Var', (108, 116))	('TERT', 'Gene', (120, 124))	('TERT', 'Gene', '7015', (120, 124))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('correlated', 'Reg', (167, 177))
72856	31803629	As previously mentioned, the detection of FGFR3, RAS, and/or PIK3CA mutations can also predict recurrence with excellent accuracy.	('PIK3CA', 'Gene', (61, 67))	('PIK3CA', 'Gene', '5290', (61, 67))	('FGFR3', 'Gene', '2261', (42, 47))	('RAS', 'Gene', (49, 52))	('FGFR3', 'Gene', (42, 47))	('mutations', 'Var', (68, 77))	('recurrence', 'Disease', (95, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))
72871	31803629	For instance, ctDNA can be used to identify EGFR mutations for treatment assignment to EGFR inhibitors, and similarly can be used to identify the emergence of resistance to these drugs.	('EGFR', 'Gene', '1956', (87, 91))	('mutations', 'Var', (49, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('EGFR', 'Gene', (87, 91))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))
72874	31803629	One might envision the use of afatinib in patients with localized cancers whose tumors contain mutations in ERBB2 or ERBB3, which are common in muscle-invasive bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('localized cancers whose tumors', 'Disease', (56, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('afatinib', 'Chemical', 'MESH:C522924', (30, 38))	('ERBB3', 'Gene', '2065', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('invasive bladder', 'Phenotype', 'HP:0100645', (151, 167))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (144, 174))	('muscle-invasive bladder cancer', 'Disease', (144, 174))	('ERBB3', 'Gene', (117, 122))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('mutations', 'Var', (95, 104))	('localized cancers whose tumors', 'Disease', 'MESH:D009369', (56, 86))	('ERBB2', 'Gene', '2064', (108, 113))	('patients', 'Species', '9606', (42, 50))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('ERBB2', 'Gene', (108, 113))
72876	31803629	Given the preponderance of FGFR3 alterations in bladder cancer, FGFR3 inhibitors in biomarker-selected patients using a urine biopsy might be a highly desirable path forward.	('bladder cancer', 'Disease', (48, 62))	('FGFR3', 'Gene', '2261', (27, 32))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('FGFR3', 'Gene', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('FGFR3', 'Gene', (27, 32))	('alterations', 'Var', (33, 44))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))	('patients', 'Species', '9606', (103, 111))	('FGFR3', 'Gene', '2261', (64, 69))
72877	31803629	Additionally, alterations in DNA repair genes are associated with the increased response of bladder cancer patients to NAC and chemoradiation.	('DNA repair genes', 'Gene', (29, 45))	('alterations', 'Var', (14, 25))	('DNA repair', 'biological_process', 'GO:0006281', ('29', '39'))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('NAC', 'cellular_component', 'GO:0005854', ('119', '122'))	('increased', 'PosReg', (70, 79))	('bladder cancer', 'Disease', 'MESH:D001749', (92, 106))	('bladder cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (92, 106))	('associated', 'Reg', (50, 60))	('patients', 'Species', '9606', (107, 115))
72890	30854414	Here, we report the first evaluation on expression of B7x in spontaneous canine invasive bladder cancer, a novel model system for the study of invasive human urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (158, 178))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('canine', 'Species', '9615', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('B7x', 'Var', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('human', 'Species', '9606', (152, 157))	('urothelial carcinoma', 'Disease', (158, 178))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (80, 103))	('invasive bladder', 'Phenotype', 'HP:0100645', (80, 96))	('invasive bladder cancer', 'Disease', (80, 103))
72895	30854414	In human BLCA, B7x expression was significantly associated with worse overall survival (p = 0.02).	('human', 'Species', '9606', (3, 8))	('worse', 'NegReg', (64, 69))	('overall survival', 'MPA', (70, 86))	('B7x expression', 'Var', (15, 29))
72896	30854414	Our results suggest that B7x is over expressed in canine bladder cancer.	('over expressed', 'PosReg', (32, 46))	('canine', 'Species', '9615', (50, 56))	('bladder cancer', 'Disease', 'MESH:D001749', (57, 71))	('bladder cancer', 'Disease', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('B7x', 'Var', (25, 28))	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))
72897	30854414	Thus canine model can be vital in advancing the translational research on B7x, a new potential therapeutic target in human bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('human', 'Species', '9606', (117, 122))	('canine', 'Species', '9615', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('B7x', 'Var', (74, 77))	('bladder cancer', 'Disease', 'MESH:D001749', (123, 137))	('bladder cancer', 'Disease', (123, 137))
72904	30854414	B7x is associated with increased TNM stage, pathological grade and poorer outcomes with urothelial carcinoma.	('TNM stage', 'CPA', (33, 42))	('urothelial carcinoma', 'Disease', (88, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('increased', 'PosReg', (23, 32))	('B7x', 'Var', (0, 3))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (88, 108))
72916	30854414	In this study, using immunohistochemistry and RNA-seq we report over expression of B7x in tissues from canine bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (110, 124))	('over expression', 'PosReg', (64, 79))	('B7x', 'Var', (83, 86))	('canine', 'Species', '9615', (103, 109))	('bladder cancer', 'Disease', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('bladder cancer', 'Phenotype', 'HP:0009725', (110, 124))	('RNA', 'cellular_component', 'GO:0005562', ('46', '49'))
72924	30854414	BoxWhisker plot was used to visualize the difference in enrichment of B7x in normal and tumor samples.	('tumor', 'Disease', (88, 93))	('B7x', 'Var', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
72934	30854414	The BoxWhisker plot demonstrates the enrichment of B7x in canine invasive bladder cancer samples as compared to normal urothelial samples (Fig.	('canine', 'Species', '9615', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (74, 88))	('invasive bladder', 'Phenotype', 'HP:0100645', (65, 81))	('invasive bladder cancer', 'Disease', (65, 88))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (65, 88))	('B7x', 'Var', (51, 54))
72937	30854414	At diagnosis, 13% of dogs with low B7x expression had metastases (1 case with N0M1, 3 cases with N1M1 stage disease).	('metastases', 'Disease', (54, 64))	('dogs', 'Species', '9615', (21, 25))	('low B7x expression', 'Var', (31, 49))	('metastases', 'Disease', 'MESH:D009362', (54, 64))
72958	30854414	B7x blockade has yielded promising results in mouse colon and breast cancer models.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('mouse', 'Species', '10090', (46, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('colon', 'Disease', (52, 57))	('B7x', 'Var', (0, 3))	('colon', 'Disease', 'MESH:D015179', (52, 57))
72959	30854414	In a humanized mouse model of ovarian cancer, tumor growth was delayed when animals were treated with anti-B7x single chain fragments variable (scFv).	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('anti-B7x single chain fragments', 'Var', (102, 133))	('ovarian cancer', 'Disease', 'MESH:D010051', (30, 44))	('ovarian cancer', 'Disease', (30, 44))	('tumor', 'Disease', (46, 51))	('delayed', 'NegReg', (63, 70))	('mouse', 'Species', '10090', (15, 20))	('human', 'Species', '9606', (5, 10))	('ovarian cancer', 'Phenotype', 'HP:0100615', (30, 44))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
72960	30854414	Similarly, anti-B7x CAR T-cell therapy significantly reduced tumor burden in a human ovarian tumor xenograft model.	('human', 'Species', '9606', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ovarian tumor', 'Disease', (85, 98))	('CAR', 'cellular_component', 'GO:0005826', ('20', '23'))	('tumor', 'Disease', (93, 98))	('ovarian tumor', 'Phenotype', 'HP:0100615', (85, 98))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('reduced', 'NegReg', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('ovarian tumor', 'Disease', 'MESH:D010051', (85, 98))	('anti-B7x', 'Var', (11, 19))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
72961	30854414	Combining gemcitabine with B7x deficiency in B7x knockout host also showed better response than when treated with gemcitabine alone.	('response', 'MPA', (82, 90))	('gemcitabine', 'Chemical', 'MESH:C056507', (114, 125))	('gemcitabine', 'Chemical', 'MESH:C056507', (10, 21))	('B7x deficiency', 'Var', (27, 41))
72962	30854414	Additionally, in murine pulmonary metastasis model, inducing expression of B7x resulted in increased tumor progression and led to immune suppression in the tumor microenvironment.	('pulmonary metastasis', 'Disease', (24, 44))	('B7x', 'Var', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (24, 44))	('immune suppression', 'CPA', (130, 148))	('murine', 'Species', '10090', (17, 23))	('increased', 'PosReg', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
72963	30854414	We report over expression of the immune checkpoint B7x in canine bladder cancer.	('bladder cancer', 'Disease', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('bladder cancer', 'Phenotype', 'HP:0009725', (65, 79))	('over expression', 'PosReg', (10, 25))	('B7x', 'Var', (51, 54))	('canine', 'Species', '9615', (58, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (65, 79))
72964	30854414	Using TCGA and GTEx, we examined B7x expression in 599 human bladder urothelial carcinoma (BLCA) and showed that B7x expression was significantly associated with worse overall survival in human BLCA.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('overall', 'MPA', (168, 175))	('human', 'Species', '9606', (188, 193))	('human', 'Species', '9606', (55, 60))	('B7x', 'Var', (113, 116))	('worse', 'NegReg', (162, 167))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (61, 89))	('bladder urothelial carcinoma', 'Disease', (61, 89))
73013	30417049	Notably, patients who received MMC on IO had a significantly reduced risk of BTR in the first year postoperatively (adjusted HR = 0.113, 95% CI = 0.028-0.63, p = 0.01).	('patients', 'Species', '9606', (9, 17))	('MMC', 'Var', (31, 34))	('BTR', 'Disease', (77, 80))	('MMC', 'Chemical', 'MESH:D016685', (31, 34))	('reduced', 'NegReg', (61, 68))	('IO', 'Chemical', '-', (38, 40))
73021	30417049	This theory has been supported by evaluation of tumor DNA showing similar mutations in BTR specimens compared to the original UTUC primary lesion and based upon location of BTR.	('tumor', 'Disease', (48, 53))	('BTR', 'Gene', (87, 90))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
73099	28928837	Furthermore, by plotting the KM survival curve, we found that the survival time of patients expressing high hsa-mir-7705 and hsa-mir-192 levels were significantly shorter than those of patients expressing low levels.	('hsa-mir-192', 'Gene', '406967', (125, 136))	('hsa-mir-192', 'Gene', (125, 136))	('hsa-mir-7705', 'Gene', (108, 120))	('shorter', 'NegReg', (163, 170))	('survival time', 'CPA', (66, 79))	('patients', 'Species', '9606', (185, 193))	('high', 'Var', (103, 107))	('patients', 'Species', '9606', (83, 91))	('hsa-mir-7705', 'Gene', '102466854', (108, 120))
73107	25184754	Unambiguous Detection of Multiple TP53 Gene Mutations in AAN-Associated Urothelial Cancer in Belgium Using Laser Capture Microdissection In the Balkan and Taiwan, the relationship between exposure to aristolochic acid and risk of urothelial neoplasms was inferred from the A>T genetic hallmark in TP53 gene from malignant cells.	('urothelial neoplasms', 'Disease', (230, 250))	('TP53', 'Gene', (34, 38))	('AAN-Associated Urothelial Cancer', 'Disease', (57, 89))	('urothelial neoplasms', 'Disease', 'MESH:D014523', (230, 250))	('AAN-Associated Urothelial Cancer', 'Disease', 'MESH:D014523', (57, 89))	('Mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (297, 301))	('aristolochic acid', 'Chemical', 'MESH:C000228', (200, 217))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('neoplasms', 'Phenotype', 'HP:0002664', (241, 250))	('TP53', 'Gene', (297, 301))	('TP53', 'Gene', '7157', (34, 38))
73112	25184754	After DNA extraction, mutations in the TP53 hot spot region (exons 5-8) were identified using nested-PCR and sequencing.	('TP53', 'Gene', '7157', (39, 43))	('DNA', 'cellular_component', 'GO:0005574', ('6', '9'))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', (39, 43))
73116	25184754	While current results are in line with A>T prevalence previously reported in Balkan and Taiwan studies, they also demonstrate that multiple mutations in the TP53 hot spot region and a high frequency of G>T transversion appear as a complementary signature reflecting the toxicity of a cumulative dose of aristolochic acid ingested over a short period of time.	('TP53', 'Gene', (157, 161))	('G>T transversion', 'Var', (202, 218))	('aristolochic acid', 'Chemical', 'MESH:C000228', (303, 320))	('mutations', 'Var', (140, 149))	('toxicity', 'Disease', (270, 278))	('toxicity', 'Disease', 'MESH:D064420', (270, 278))	('TP53', 'Gene', '7157', (157, 161))
73117	25184754	The Aristolochic Acid Nephropathy (AAN) was first reported in the early 1990's in Belgian patients having undertaken a weight-loss regimen contaminated with aristolochic acid (AA).	('aristolochic acid', 'Chemical', 'MESH:C000228', (157, 174))	('Nephropathy', 'Disease', (22, 33))	('weight-loss', 'Phenotype', 'HP:0001824', (119, 130))	('Aristolochic Acid', 'Chemical', 'MESH:C000228', (4, 21))	('Nephropathy', 'Phenotype', 'HP:0000112', (22, 33))	('aristolochic', 'Var', (157, 169))	('patients', 'Species', '9606', (90, 98))	('Acid Nephropathy', 'Phenotype', 'HP:0001947', (17, 33))	('Nephropathy', 'Disease', 'MESH:D007674', (22, 33))
73120	25184754	While the mechanism of AA nephrotoxicity remains to be thoroughly explored, the carcinogenic activity is currently attributed to genotoxicity of AL (aristolactam)-DNA adducts characterized by a high frequency of A>T transversion in the TP53 tumour suppressor gene of AA-associated tumors.	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))	('toxicity', 'Disease', (32, 40))	('TP53', 'Gene', (236, 240))	('toxicity', 'Disease', 'MESH:D064420', (133, 141))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('nephrotoxicity', 'Disease', (26, 40))	('tumour', 'Disease', 'MESH:D009369', (241, 247))	('AL', 'Chemical', '-', (145, 147))	('tumour', 'Disease', (241, 247))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('toxicity', 'Disease', (133, 141))	('nephrotoxicity', 'Disease', 'MESH:D007674', (26, 40))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('TP53', 'Gene', '7157', (236, 240))	('A>T transversion', 'Var', (212, 228))	('carcinogenic', 'Disease', (80, 92))	('tumors', 'Disease', (281, 287))	('carcinogenic', 'Disease', 'MESH:D063646', (80, 92))	('aristolactam', 'Chemical', '-', (149, 161))	('toxicity', 'Disease', 'MESH:D064420', (32, 40))
73139	25184754	The diagnosis of AAN was based on the following criteria: AA intake through a weight-loss regimen phytochemically demonstrated as contaminated (patients 1, 2, 3 and 5), a typical renal histology of interstitial fibrosis (all five patients), identification of AL-DNA adducts in kidney tissue (patients 1, 3 and 4) and development of upper urinary tract malignancy (all five patients).	('interstitial fibrosis', 'Disease', 'MESH:D005355', (198, 219))	('weight-loss', 'Phenotype', 'HP:0001824', (78, 89))	('interstitial fibrosis', 'Disease', (198, 219))	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (198, 219))	('upper urinary tract malignancy', 'Disease', (332, 362))	('upper urinary tract malignancy', 'Disease', 'MESH:D014552', (332, 362))	('patients', 'Species', '9606', (230, 238))	('patients', 'Species', '9606', (144, 152))	('AL-DNA', 'Var', (259, 265))	('patients', 'Species', '9606', (373, 381))	('DNA', 'cellular_component', 'GO:0005574', ('262', '265'))	('patients', 'Species', '9606', (292, 300))	('AL', 'Chemical', '-', (259, 261))	('urinary tract malignancy', 'Phenotype', 'HP:0010786', (338, 362))
73165	25184754	Exons 5 to 8, corresponding to the p53 DNA binding domain, a so-called "hot spot" for TP53 gene mutations, were amplified by nested-PCR.	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('DNA binding', 'molecular_function', 'GO:0003677', ('39', '50'))	('TP53', 'Gene', '7157', (86, 90))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('TP53', 'Gene', (86, 90))	('mutations', 'Var', (96, 105))
73171	25184754	(a) To assess the ability of the current microdissection procedure to identify DNA mutations, four colo-rectal adenocarcinomas previously investigated for KRas mutation by routine clinical testing on FFPE (Formalin-fixed paraffin-embedded) tissue specimens were selected.	('colo', 'Species', '307630', (99, 103))	('mutations', 'Var', (83, 92))	('Formalin', 'Chemical', 'MESH:D005557', (206, 214))	('paraffin', 'Chemical', 'MESH:D010232', (221, 229))	('adenocarcinomas', 'Disease', 'MESH:D000230', (111, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('adenocarcinomas', 'Disease', (111, 126))	('KRas', 'Gene', '3845', (155, 159))	('KRas', 'Gene', (155, 159))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
73175	25184754	While the constitutional mutation had already been identified by FASAY (functional analysis of separated alleles in yeast) of the TP53 mRNA extracted from peripheral mononuclear cells of the patient, the tumour specimen was studied to further confirm the ability of the current microdissection procedure to identify correctly this TP53 mutation in frozen sections of the tumour.	('tumour', 'Disease', (204, 210))	('tumour', 'Phenotype', 'HP:0002664', (371, 377))	('TP53', 'Gene', '7157', (331, 335))	('patient', 'Species', '9606', (191, 198))	('mutation', 'Var', (336, 344))	('tumour', 'Disease', 'MESH:D009369', (371, 377))	('yeast', 'Species', '4932', (116, 121))	('TP53', 'Gene', (331, 335))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('tumour', 'Disease', (371, 377))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('tumour', 'Disease', 'MESH:D009369', (204, 210))
73182	25184754	For the limit of detection study, DNA was extracted from two Head and Neck Squamous Cell Carcinoma cell lines (SC173 and SC263, kindly provided by A.C. Begg, Netherlands Cancer Institute, The Netherlands) carrying different TP53 mutations and from a wild-type TP53 HNSCC cell line (HN30, kindly provided by M. Flinterman, Department of Oral Medicine and Pathology, King's College London, The Rain Institute, UK).	('TP53', 'Gene', (260, 264))	('Cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (61, 98))	('Carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('TP53', 'Gene', (224, 228))	('mutations', 'Var', (229, 238))	('Neck Squamous Cell Carcinoma', 'Disease', (70, 98))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (70, 98))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('TP53', 'Gene', '7157', (260, 264))	('TP53', 'Gene', '7157', (224, 228))
73185	25184754	SC263 presents a compound heterozygous alteration involving a nonsense mutation R306X in exon 8 (CGA>TGA) and a 32-bp deletion in exon 7 (del 704-735) (CTMA laboratory data).	('R306X', 'Var', (80, 85))	('R306X', 'Mutation', 'p.R306X', (80, 85))	('CGA', 'Gene', (97, 100))	('del 704-735', 'Var', (138, 149))	('CGA', 'Gene', '1113', (97, 100))	('del 704-735', 'Mutation', 'c.704_735del', (138, 149))	('TGA', 'Gene', '6899', (101, 104))	('TGA', 'Gene', (101, 104))
73186	25184754	DNA from both TP53 mutated cells was serially diluted and spiked in the wild-type cell DNA to have 50 to 1.25% mutant to wild-type DNA ratios.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('mutant', 'Var', (111, 117))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))
73187	25184754	A Poisson regression model was built to compare the prevalence and type (A>T and G>T) of TP53 mutations in p53 binding site between current (n = 5) and previous [BEN (n = 11 and n = 97) and Taiwanese (n = 151)] clinical series, and to compare the results of this analysis with those from patients with urothelial malignancies (bladder, ureter, upper urinary tract and renal pelvis) (n = 1111) as reported in the TP53 IARC database.	('TP53', 'Gene', '7157', (412, 416))	('TP53', 'Gene', '7157', (89, 93))	('urothelial malignancies', 'Disease', 'MESH:D009369', (302, 325))	('TP53', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('p53', 'Gene', (107, 110))	('TP53', 'Gene', (412, 416))	('patients', 'Species', '9606', (288, 296))	('p53', 'Gene', '7157', (107, 110))	('renal pelvis', 'Phenotype', 'HP:0000125', (368, 380))	('ureter', 'Disease', (336, 342))	('p53 binding', 'molecular_function', 'GO:0002039', ('107', '118'))	('renal pelvis', 'Disease', 'MESH:D010386', (368, 380))	('urothelial malignancies', 'Disease', (302, 325))	('renal pelvis', 'Disease', (368, 380))
73189	25184754	Regarding the identification of KRas mutations on snap-frozen adenocarcinomas, results were strictly identical to those previously obtained on FFPE samples (i.e., identification of G12S and G12D mutations in the KRas mutated tissues and wild-type status in the other two tumours).	('G12D', 'Var', (190, 194))	('KRas', 'Gene', (32, 36))	('adenocarcinomas', 'Disease', 'MESH:D000230', (62, 77))	('KRas', 'Gene', '3845', (32, 36))	('tumour', 'Phenotype', 'HP:0002664', (271, 277))	('G12D', 'Mutation', 'rs121913529', (190, 194))	('G12S', 'Var', (181, 185))	('snap', 'molecular_function', 'GO:0005483', ('50', '54'))	('KRas', 'Gene', (212, 216))	('adenocarcinomas', 'Disease', (62, 77))	('KRas', 'Gene', '3845', (212, 216))	('G12S', 'Mutation', 'rs121913530', (181, 185))	('tumours', 'Phenotype', 'HP:0002664', (271, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('tumours', 'Disease', 'MESH:D009369', (271, 278))	('tumours', 'Disease', (271, 278))
73190	25184754	Regarding identification of a constitutional g.13380 G>A, p.R248Q mutation identified by FASAY assay in peripheral blood cells of a patient with Li-Fraumeni syndrome, this mutation was also found in malignant cells from the granulosa cell tumor using DNA extraction, microdissection, nested-PCR and sequencing procedures as used in the present study.	('p.R248Q', 'Mutation', 'rs11540652', (58, 65))	('granulosa cell tumor', 'Disease', 'MESH:D006106', (224, 244))	('g.13380 G>A', 'Mutation', 'g.13380G>A', (45, 56))	('granulosa cell tumor', 'Disease', (224, 244))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (145, 165))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('Li-Fraumeni syndrome', 'Disease', (145, 165))	('p.R248Q', 'Var', (58, 65))	('DNA', 'cellular_component', 'GO:0005574', ('251', '254'))	('patient', 'Species', '9606', (132, 139))	('g.13380 G>A', 'Var', (45, 56))
73193	25184754	The only exception was the ureter sample from a type 2 diabetic patient with a G>A transition (g.12455, p.R156H) in exon 5 of the TP53 gene after microdissection under high laser power.	('patient', 'Species', '9606', (64, 71))	('p.R156H', 'Var', (104, 111))	('diabetic', 'Disease', 'MESH:D003920', (55, 63))	('diabetic', 'Disease', (55, 63))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('p.R156H', 'Mutation', 'rs371524413', (104, 111))	('g.12455', 'Var', (95, 102))
73195	25184754	The limit of detection for Sanger sequencing was identified at 6.25% of mutant to wild-type DNA ratio with both TP53 mutated cell lines, irrespective of the mutation or deletion assessed.	('mutant', 'Var', (72, 78))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('TP53', 'Gene', '7157', (112, 116))	('TP53', 'Gene', (112, 116))
73199	25184754	Including two previously reported results, a total of 16 totally different exonic (n = 13) or intronic (n = 3) mutations of the TP53 gene were found in malignant urothelial tissues from the Belgian AAN cohort (Table 1).	('TP53', 'Gene', '7157', (128, 132))	('mutations', 'Var', (111, 120))	('TP53', 'Gene', (128, 132))	('found', 'Reg', (143, 148))
73204	25184754	The Poisson regression model showed a highly significant (p<0.001) relative increase of the TP53 mutation prevalence in p53 hotspot codons from the current clinical series, compared with IARC database results (Table 3).	('increase', 'PosReg', (76, 84))	('p53', 'Gene', '7157', (120, 123))	('TP53', 'Gene', (92, 96))	('TP53', 'Gene', '7157', (92, 96))	('mutation', 'Var', (97, 105))	('p53', 'Gene', (120, 123))
73205	25184754	Regarding the number of A>T transversion per patient, a significant relative increase was found in the current, both BEN, and the Taiwanese clinical series, compared with IARC database results (Table 4).	('transversion', 'Var', (28, 40))	('patient', 'Species', '9606', (45, 52))	('increase', 'PosReg', (77, 85))
73206	25184754	This is the first report of the mutational spectrum of TP53 tumor suppressor gene in a series of Belgian patients (n = 5) with documented AAN and subsequent development of TCC in the upper urinary tract together with bladder involvement in one of them.	('patients', 'Species', '9606', (105, 113))	('TCC in the upper urinary tract', 'Phenotype', 'HP:0010935', (172, 202))	('TP53', 'Gene', '7157', (55, 59))	('bladder involvement', 'Disease', (217, 236))	('TP53', 'Gene', (55, 59))	('bladder involvement', 'Disease', 'MESH:D001745', (217, 236))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('TCC', 'cellular_component', 'GO:0005579', ('172', '175'))	('mutational', 'Var', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('TCC', 'Phenotype', 'HP:0006740', (172, 175))	('tumor', 'Disease', (60, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))	('TCC', 'Disease', (172, 175))
73210	25184754	To prove that TP53 mutations did not result from technological artifacts when using frozen section, a special attention was paid to thorough validation procedures.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))
73212	25184754	It enabled indeed a correct identification of known KRas oncogenic mutations in adenocarcinomas.	('KRas', 'Gene', (52, 56))	('adenocarcinomas', 'Disease', 'MESH:D000230', (80, 95))	('mutations', 'Var', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('KRas', 'Gene', '3845', (52, 56))	('adenocarcinomas', 'Disease', (80, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))
73213	25184754	It also enabled a correct identification of a previously characterized TP53 constitutional mutation associated with a Li-Fraumeni syndrome.	('mutation', 'Var', (91, 99))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (118, 138))	('associated', 'Reg', (100, 110))	('Li-Fraumeni syndrome', 'Disease', (118, 138))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))
73216	25184754	The sole mutation found was a single G>A transition (g.12455, p.R156H) in the tissue specimen from a type 2 diabetic patient without any history of neoplasia.	('neoplasia', 'Disease', (148, 157))	('p.R156H', 'Var', (62, 69))	('neoplasia', 'Disease', 'MESH:D009369', (148, 157))	('neoplasia', 'Phenotype', 'HP:0002664', (148, 157))	('patient', 'Species', '9606', (117, 124))	('diabetic', 'Disease', 'MESH:D003920', (108, 116))	('p.R156H', 'Mutation', 'rs371524413', (62, 69))	('g.12455', 'Var', (53, 60))	('diabetic', 'Disease', (108, 116))
73218	25184754	As assessed by serial dilutions of TP53 mutated DNA, the detection limit of the current genotyping procedure was 6.25% of mutant to wild-type ratio.	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('mutant', 'Var', (122, 128))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))
73219	25184754	Of interest, all patients from the current series were women and each of them presented at least one TP53 mutation in their malignant urothelial tissues whereas a more balanced male/female ratio was found (53%/47%) in previous studies.	('women', 'Species', '9606', (55, 60))	('TP53', 'Gene', '7157', (101, 105))	('mutation', 'Var', (106, 114))	('TP53', 'Gene', (101, 105))	('patients', 'Species', '9606', (17, 25))
73220	25184754	In previous studies, the reported prevalence of patients with TP53 hotspot mutation varied from 100% (11/11 BEN patients) to 37% (36/97 BEN tumors) or 47% (71/151) Taiwanese AA-patients.	('TP53', 'Gene', '7157', (62, 66))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('patients', 'Species', '9606', (177, 185))	('mutation', 'Var', (75, 83))	('TP53', 'Gene', (62, 66))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('patients', 'Species', '9606', (48, 56))
73221	25184754	Considering that only a single patient was reported with a quintuple mutation in the IARC database, the current observation that 40% (2/5) of the patients harbored multiple TP53 mutations, each with six distinct mutations (five exonic and one intronic mutations, among which one splice site mutation in patient 5) was a striking and very unusual finding.	('harbored', 'Reg', (155, 163))	('patient', 'Species', '9606', (31, 38))	('patient', 'Species', '9606', (303, 310))	('TP53', 'Gene', '7157', (173, 177))	('TP53', 'Gene', (173, 177))	('patient', 'Species', '9606', (146, 153))	('mutations', 'Var', (178, 187))	('patients', 'Species', '9606', (146, 154))
73222	25184754	It is also interesting to note that this quintuple mutation was also found in the BEN series which is one of the hitherto largest reported human series of AA related TP53 mutations.	('mutations', 'Var', (171, 180))	('TP53', 'Gene', '7157', (166, 170))	('TP53', 'Gene', (166, 170))	('human', 'Species', '9606', (139, 144))
73223	25184754	Compared to data from non AA-related urothelial cancers in the IARC database (n = 1111) and from the Taiwanese series (n = 151), the current series showed the highest relative increased prevalence of mutation and G>T transversion in the TP53 hotspot region.	('urothelial cancers', 'Disease', 'MESH:D014523', (37, 55))	('TP53', 'Gene', '7157', (237, 241))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('urothelial cancers', 'Disease', (37, 55))	('TP53', 'Gene', (237, 241))	('G>T transversion', 'Var', (213, 229))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('mutation', 'Var', (200, 208))
73224	25184754	Our finding confirms that the number and profile of TP53 mutations per patient is highly unusual, probably reflecting a sudden highly toxic exposure.	('mutations', 'Var', (57, 66))	('patient', 'Species', '9606', (71, 78))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))
73226	25184754	They were dominated by transversions with A>T and G>T accounting each for 18.7% (3/16) of all TP53 mutations.	('TP53', 'Gene', '7157', (94, 98))	('A>T', 'Var', (42, 45))	('TP53', 'Gene', (94, 98))	('G>T', 'Var', (50, 53))	('mutations', 'Var', (99, 108))
73228	25184754	In all these studies, the population was exposed to AA for many years, with figures as high as 66% (33/50) to 72% (13/18) and 55% (46/84) of all TP53 mutations, respectively.	('TP53', 'Gene', (145, 149))	('mutations', 'Var', (150, 159))	('TP53', 'Gene', '7157', (145, 149))
73229	25184754	In the current series, one tumour with multiple TP53 mutations harbored two A>T transversions, a feature also commonly reported in the BEN and Taiwanese series.	('TP53', 'Gene', '7157', (48, 52))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('tumour', 'Disease', (27, 33))
73230	25184754	Animal studies further confirmed the high frequency of A>T transversions in AA-induced tumours, for instance in the forestomach epidermoid neoplastic cells from AA-exposed rats at codon 61 of the Ha-ras proto-oncogene, as well as in human p53 knock-in (Hupki) mouse embryonic fibroblasts exposed to AAI (Aristolochic Acid I).	('forestomach epidermoid neoplastic', 'Disease', 'MESH:D013274', (116, 149))	('tumours', 'Disease', (87, 94))	('human', 'Species', '9606', (233, 238))	('A>T transversions', 'Var', (55, 72))	('rats', 'Species', '10116', (172, 176))	('transversions', 'Var', (59, 72))	('Aristolochic Acid', 'Chemical', 'MESH:C000228', (304, 321))	('p53', 'Gene', (239, 242))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('AAI', 'Chemical', 'MESH:C000228', (299, 302))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('forestomach epidermoid neoplastic', 'Disease', (116, 149))	('p53', 'Gene', '7157', (239, 242))	('mouse', 'Species', '10090', (260, 265))	('tumours', 'Disease', 'MESH:D009369', (87, 94))
73233	25184754	The prevalence of G>T transversion is usually associated with tobacco exposure as evidenced in the Hupki mouse embryonic fibroblasts exposed to the prominent tobacco-derived carcinogen benzo[a]pyrene, as well as in smoking-related human lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('transversion', 'Var', (22, 34))	('benzo[a]pyrene', 'Chemical', 'MESH:D001564', (185, 199))	('lung cancers', 'Disease', (237, 249))	('tobacco', 'Species', '4097', (158, 165))	('G>T transversion', 'Var', (18, 34))	('tobacco', 'Species', '4097', (62, 69))	('lung cancers', 'Disease', 'MESH:D008175', (237, 249))	('human', 'Species', '9606', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('lung cancers', 'Phenotype', 'HP:0100526', (237, 249))	('mouse', 'Species', '10090', (105, 110))
73235	25184754	In line with these observations, the prevalence of G>T transversion in AA-associated human urothelial cancers in Taiwan is low (12%) and found in none of both BEN series.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('urothelial cancers', 'Disease', 'MESH:D014523', (91, 109))	('G>T transversion', 'Var', (51, 67))	('urothelial cancers', 'Disease', (91, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('AA-associated', 'Disease', (71, 84))	('human', 'Species', '9606', (85, 90))
73236	25184754	In the current series comprising only female patients, the statistically significant higher frequency of non-smoking associated G>T transversions compared with IARC database and other AAN clinical series, and the unusual occurrence of two G>T transversions in the same sample were therefore extremely unusual findings.	('patients', 'Species', '9606', (45, 53))	('G>T transversions', 'Var', (128, 145))	('non-smoking', 'Disease', (105, 116))	('higher', 'PosReg', (85, 91))
73238	25184754	Consequently, this unusually high G>T frequency in the TP53 hot spot region has to be considered at the light of major differences between previous studies and the current work.	('TP53', 'Gene', (55, 59))	('G>T', 'Var', (34, 37))	('TP53', 'Gene', '7157', (55, 59))
73247	25184754	In that respect, it is interesting to note that the spectrum of TP53 genetic alterations in Taiwan and BEN patients whom tumors were assessed using identical TP53 genotyping, was notably similar.	('TP53', 'Gene', '7157', (158, 162))	('genetic alterations', 'Var', (69, 88))	('TP53', 'Gene', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('patients', 'Species', '9606', (107, 115))
73248	25184754	In conclusion, our documentation of expected A > T transversions attributable to AA exposure in the TP53 gene of the Belgian AAN associated TCC is the first demonstration of a clear causal relationship between AA exposure and the development of urothelial malignancy in this cohort.	('TP53', 'Gene', '7157', (100, 104))	('TP53', 'Gene', (100, 104))	('TCC', 'cellular_component', 'GO:0005579', ('140', '143'))	('urothelial malignancy', 'Disease', (245, 266))	('TCC', 'Phenotype', 'HP:0006740', (140, 143))	('urothelial malignancy', 'Disease', 'MESH:D009369', (245, 266))	('transversions', 'Var', (51, 64))	('A > T transversions', 'Var', (45, 64))
73249	25184754	Interestingly, and although assessed on small series of female patients, there are two striking highly significant observations characterizing the current series: the addition of poly- or multiclonal TP53 alterations to the otherwise well-known AA mutational fingerprint and the unusually high prevalence of G>T transversion in the p53 binding site, two new features appearing as a complementary signature possibly reflecting the toxicity of a cumulative dose of AA over a short period of time.	('toxicity', 'Disease', 'MESH:D064420', (430, 438))	('toxicity', 'Disease', (430, 438))	('alterations', 'Var', (205, 216))	('TP53', 'Gene', '7157', (200, 204))	('TP53', 'Gene', (200, 204))	('patients', 'Species', '9606', (63, 71))	('G>T transversion', 'Var', (308, 324))	('p53', 'Gene', (332, 335))	('p53 binding', 'molecular_function', 'GO:0002039', ('332', '343'))	('p53', 'Gene', '7157', (332, 335))
73266	33241650	The number of mutations can vary across tumor type, and many mutagenic processes can drive high TMB, including but not limited to DNA replication infidelity, mismatch repair deficiency, environmental mutagens such as tobacco smoke and ultraviolet light, contaminated food pathogens, and aging.	('deficiency', 'Disease', 'MESH:D007153', (174, 184))	('DNA replication', 'biological_process', 'GO:0006260', ('130', '145'))	('TMB', 'Chemical', '-', (96, 99))	('drive', 'Reg', (85, 90))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('mismatch', 'Var', (158, 166))	('tobacco', 'Species', '4097', (217, 224))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('high TMB', 'Disease', (91, 99))	('men', 'Species', '9606', (193, 196))	('aging', 'biological_process', 'GO:0007568', ('287', '292'))	('deficiency', 'Disease', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('mismatch repair', 'biological_process', 'GO:0006298', ('158', '173'))	('mutations', 'Var', (14, 23))
73267	33241650	9  Nonsynonymous mutations increase the number of tumor-specific neoantigens recognized by the immune system, thus, TMB is a proxy estimate of the neoantigen load of a tumor.	('tumor', 'Disease', (168, 173))	('TMB', 'Chemical', '-', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('Nonsynonymous mutations', 'Var', (3, 26))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('increase', 'PosReg', (27, 35))	('tumor', 'Disease', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
73276	33241650	Seven studies evaluating the efficacy and safety of atezolizumab monotherapy were included in this analysis, as described in Table S1: (a) OAK (ClinicalTrials.gov ID NCT02008227):a phase III, open-label, randomized study of atezolizumab vs docetaxel in platinum-treated NSCLC, (b) POPLAR (NCT01903993):a phase II, open-label, randomized study of atezolizumab vs docetaxel in platinum-treated NSCLC; (c) BIRCH (NCT02031458) and (d) FIR (NCT01846416):both phase II, open-label, single-arm studies of atezolizumab in PD-L1-selected locally advanced or metastatic NSCLC; (e) IMvigor211 (NCT02302807):a phase III, open-label, randomized study of atezolizumab vs chemotherapy in platinum-treated locally advanced or metastatic urothelial carcinoma; (f) IMvigor210:a phase II, open-label, single-arm study of atezolizumab in previously untreated (NCT02951767) or platinum-treated (NCT02108652) metastatic urothelial carcinoma; and (g) PCD4989g:a first-in-human, phase I, open-label, dose-escalation study (NCT01375842) of atezolizumab as a single agent in locally advanced or metastatic solid tumors or hematologic malignancies.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (721, 741))	('NSCLC', 'Disease', 'MESH:D002289', (270, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (732, 741))	('hematologic malignancies', 'Disease', (1096, 1120))	('solid tumors', 'Disease', 'MESH:D009369', (1080, 1092))	('tumor', 'Phenotype', 'HP:0002664', (1086, 1091))	('urothelial carcinoma', 'Disease', (898, 918))	('PC', 'Chemical', 'MESH:C053518', (928, 930))	('atezolizumab', 'Chemical', 'MESH:C000594389', (224, 236))	('atezolizumab', 'Chemical', 'MESH:C000594389', (802, 814))	('tumors', 'Phenotype', 'HP:0002664', (1086, 1092))	('urothelial carcinoma', 'Disease', (721, 741))	('NSCLC', 'Disease', (270, 275))	('hematologic malignancies', 'Disease', 'MESH:D019337', (1096, 1120))	('PCD', 'biological_process', 'GO:0012501', ('928', '931'))	('atezolizumab', 'Chemical', 'MESH:C000594389', (1015, 1027))	('NSCLC', 'Phenotype', 'HP:0030358', (270, 275))	('NSCLC', 'Disease', 'MESH:D002289', (392, 397))	('NSCLC', 'Disease', 'MESH:D002289', (560, 565))	('NSCLC', 'Disease', (392, 397))	('NSCLC', 'Disease', (560, 565))	('atezolizumab', 'Chemical', 'MESH:C000594389', (498, 510))	('NCT02951767', 'Var', (840, 851))	('solid tumors', 'Disease', (1080, 1092))	('NSCLC', 'Phenotype', 'HP:0030358', (392, 397))	('NSCLC', 'Phenotype', 'HP:0030358', (560, 565))	('atezolizumab', 'Chemical', 'MESH:C000594389', (641, 653))	('human', 'Species', '9606', (948, 953))	('atezolizumab', 'Chemical', 'MESH:C000594389', (346, 358))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (898, 918))	('carcinoma', 'Phenotype', 'HP:0030731', (909, 918))	('atezolizumab', 'Chemical', 'MESH:C000594389', (52, 64))
73284	33241650	27 ,  28 ,  29  Briefly, the assay detects substitutions, insertion, deletion alterations, and copy number alterations in 324 genes using DNA from formalin-fixed paraffin-embedded solid tumor specimens.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('deletion alterations', 'Var', (69, 89))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('paraffin', 'Chemical', 'MESH:D010232', (162, 170))	('tumor', 'Disease', (186, 191))	('insertion', 'Var', (58, 67))	('formalin', 'Chemical', 'MESH:D005557', (147, 155))	('men', 'Species', '9606', (197, 200))	('substitutions', 'Var', (43, 56))	('copy number alterations', 'Var', (95, 118))
73320	33241650	The median C-reactive protein levels were approximately 20% lower in tTMB-low patients than tTMB-high patients, while the neutrophil-to-lymphocyte ratio and albumin and lactate dehydrogenase levels were balanced between both groups.	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (78, 86))	('tTMB', 'Chemical', '-', (92, 96))	('albumin and lactate dehydrogenase', 'Gene', '213', (157, 190))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('tTMB-low', 'Var', (69, 77))	('tTMB', 'Chemical', '-', (69, 73))	('C-reactive protein', 'Gene', '1401', (11, 29))	('C-reactive protein', 'Gene', (11, 29))	('lower', 'NegReg', (60, 65))
73321	33241650	The median tTMB was approximately three-fold lower in patients with low tTMB vs high-tTMB.	('tTMB', 'Chemical', '-', (72, 76))	('tTMB', 'Chemical', '-', (11, 15))	('patients', 'Species', '9606', (54, 62))	('tTMB', 'MPA', (11, 15))	('lower', 'NegReg', (45, 50))	('low', 'Var', (68, 71))	('tTMB', 'Chemical', '-', (85, 89))
73345	33241650	More pronounced tumor shrinkage over time was seen in patients with high tTMB.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('tTMB', 'Chemical', '-', (73, 77))	('high tTMB', 'Var', (68, 77))
73346	33241650	At 18 weeks (126 days), the mean reduction in SLD from baseline was -26.8% in patients with high TMB compared with -12.5% in patients with low TMB.	('TMB', 'Chemical', '-', (143, 146))	('reduction', 'NegReg', (33, 42))	('SLD', 'MPA', (46, 49))	('TMB', 'Chemical', '-', (97, 100))	('patients', 'Species', '9606', (78, 86))	('high TMB', 'Var', (92, 100))	('patients', 'Species', '9606', (125, 133))
73358	33241650	In patients with high tTMB, objective responses occurred across four tumor types: urothelial carcinoma (UC; bladder cancer), endometrial, melanoma, or NSCLC; the nonresponsive tumor types comprised only 9 patients.	('patients', 'Species', '9606', (205, 213))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('tTMB', 'Chemical', '-', (22, 26))	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('NSCLC', 'Disease', (151, 156))	('tumor', 'Disease', (176, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('patients', 'Species', '9606', (3, 11))	('endometrial', 'Disease', 'MESH:D014591', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (82, 102))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('bladder cancer', 'Disease', (108, 122))	('melanoma', 'Disease', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (69, 74))	('endometrial', 'Disease', (125, 136))	('high', 'Var', (17, 21))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('urothelial carcinoma', 'Disease', (82, 102))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
73360	33241650	For the 2 responsive tumor types represented in both tTMB subgroups, response rates were higher in tTMB-high patients than tTMB-low patients: 23 of 83 patients (28%) with high-tTMB NSCLC and 23 of 70 patients (33%) with high-tTMB UC had an objective response to atezolizumab, compared with 41 of 259 (16%) and 52 of 330 (16%) patients with low-tTMB tumors, respectively.	('NSCLC', 'Disease', 'MESH:D002289', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (349, 355))	('high-tTMB', 'Var', (171, 180))	('tumor', 'Disease', (21, 26))	('patients', 'Species', '9606', (109, 117))	('tTMB', 'Chemical', '-', (53, 57))	('tTMB', 'Chemical', '-', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('NSCLC', 'Disease', (181, 186))	('patients', 'Species', '9606', (132, 140))	('tTMB', 'Chemical', '-', (225, 229))	('NSCLC', 'Phenotype', 'HP:0030358', (181, 186))	('tTMB', 'Chemical', '-', (99, 103))	('atezolizumab', 'Chemical', 'MESH:C000594389', (262, 274))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tTMB', 'Chemical', '-', (176, 180))	('tTMB', 'Chemical', '-', (344, 348))	('response', 'MPA', (69, 77))	('tumor', 'Disease', (349, 354))	('patients', 'Species', '9606', (200, 208))	('low-tTMB tumors', 'Disease', 'MESH:D009800', (340, 355))	('patients', 'Species', '9606', (326, 334))	('patients', 'Species', '9606', (151, 159))	('higher', 'PosReg', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('low-tTMB tumors', 'Disease', (340, 355))
73367	33241650	We observed that high tTMB is a potential positive predictive marker associated with increased clinical benefit following treatment with atezolizumab in diverse cancers:a finding similar to that in meta-analyses of other PD-L1/PD-1 agents.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('atezolizumab', 'Chemical', 'MESH:C000594389', (137, 149))	('clinical benefit', 'MPA', (95, 111))	('high', 'Var', (17, 21))	('tTMB', 'Chemical', '-', (22, 26))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('increased', 'PosReg', (85, 94))	('cancers', 'Disease', (161, 168))	('tTMB', 'MPA', (22, 26))	('men', 'Species', '9606', (127, 130))
73370	33241650	46  Additionally, baseline C-reactive protein (a factor known to be associated with immune-related AEs) was 24% higher at the median in patients with high-tTMB than in patients with low-tTMB.	('high-tTMB', 'Var', (150, 159))	('higher', 'PosReg', (112, 118))	('tTMB', 'Chemical', '-', (186, 190))	('patients', 'Species', '9606', (136, 144))	('patients', 'Species', '9606', (168, 176))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('C-reactive protein', 'Gene', (27, 45))	('C-reactive protein', 'Gene', '1401', (27, 45))	('tTMB', 'Chemical', '-', (155, 159))
73378	33241650	A comparable safety profile was seen in patients with high tTMB and in the entire tTMB-evaluable population with grade 3/4 AEs; there were some numerical differences indicating a slightly higher incidence of all-grade AESIs in the high-tTMB population, but these rates were comparable to those in patients treated with other anti-PD-L1/PD-1 agents.	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (297, 305))	('AESIs', 'Disease', (218, 223))	('tTMB', 'Chemical', '-', (236, 240))	('higher', 'PosReg', (188, 194))	('tTMB', 'Chemical', '-', (82, 86))	('tTMB', 'Chemical', '-', (59, 63))	('high-tTMB', 'Var', (231, 240))
73424	32333246	On the cell membrane, AKT is recruited via its PH domain ascribing to the accumulation of PI(3,4,5)P3 and PI(3,4)P2 (less extent), and plays a catalytic role by activating two regulatory sites, including a threonine phosphorylated by PDK1 at Thr308(AKT1), Thr309(AKT2), Thr305(AKT3) and a serine phosphorylated by the mammalian Target of Rapamycin (mTOR) Complex mTORC2 at Ser473(AKT1), Ser474(AKT2), Ser472(AKT3) respectively as well as specifically.	('Ser474', 'Var', (387, 393))	('AKT2', 'Gene', '208', (394, 398))	('activating', 'PosReg', (161, 171))	('AKT', 'Gene', '207', (249, 252))	('AKT', 'Gene', (22, 25))	('AKT3', 'Gene', (277, 281))	('AKT2', 'Gene', (394, 398))	('AKT', 'Gene', (394, 397))	('AKT', 'Gene', (277, 280))	('mTORC2', 'cellular_component', 'GO:0031932', ('363', '369'))	('mTOR) Complex', 'cellular_component', 'GO:0038201', ('349', '362'))	('AKT1', 'Gene', (380, 384))	('AKT', 'Gene', '207', (263, 266))	('AKT', 'Gene', '207', (380, 383))	('PDK1', 'Gene', (234, 238))	('AKT1', 'Gene', '207', (249, 253))	('AKT2', 'Gene', '208', (263, 267))	('serine', 'Chemical', 'MESH:D012694', (289, 295))	('AKT', 'Gene', (408, 411))	('cell membrane', 'cellular_component', 'GO:0005886', ('7', '20'))	('AKT3', 'Gene', '10000', (408, 412))	('AKT1', 'Gene', '207', (380, 384))	('AKT', 'Gene', '207', (22, 25))	('mTORC2', 'Gene', (363, 369))	('AKT2', 'Gene', (263, 267))	('AKT', 'Gene', '207', (277, 280))	('AKT', 'Gene', '207', (394, 397))	('Ser473', 'Var', (373, 379))	('Ser', 'cellular_component', 'GO:0005790', ('401', '404'))	('AKT', 'Gene', (249, 252))	('AKT1', 'Gene', (249, 253))	('AKT3', 'Gene', (408, 412))	('Ser', 'cellular_component', 'GO:0005790', ('373', '376'))	('Ser472', 'Var', (401, 407))	('Ser', 'cellular_component', 'GO:0005790', ('387', '390'))	('PDK1', 'Gene', '5163', (234, 238))	('AKT', 'Gene', '207', (408, 411))	('mammalian Target of Rapamycin', 'Gene', '2475', (318, 347))	('PDK1', 'molecular_function', 'GO:0004740', ('234', '238'))	('AKT', 'Gene', (263, 266))	('AKT', 'Gene', (380, 383))	('AKT3', 'Gene', '10000', (277, 281))	('mammalian Target of Rapamycin', 'Gene', (318, 347))
73428	32333246	As a lipid phosphatase, PTEN directly suppresses the activation of PI3K/AKT pathway via converting the PIP3 generated by PI3K back to PIP2.	('AKT', 'Gene', '207', (72, 75))	('PTEN', 'Gene', '5728', (24, 28))	('PI3K', 'molecular_function', 'GO:0016303', ('67', '71'))	('phosphatase', 'molecular_function', 'GO:0016791', ('11', '22'))	('AKT', 'Gene', (72, 75))	('PI3K', 'Var', (121, 125))	('PI3K', 'molecular_function', 'GO:0016303', ('121', '125'))	('suppresses', 'NegReg', (38, 48))	('PIP3 generated', 'MPA', (103, 117))	('PIP3', 'Chemical', '-', (103, 107))	('PTEN', 'Gene', (24, 28))
73431	32333246	Indeed, the abnormality of PTEN have been validated in diverse cancers, even directly related with carcinogenesis in some cancers.	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('PTEN', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('carcinogenesis', 'Disease', (99, 113))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('abnormality', 'Var', (12, 23))	('cancers', 'Disease', (122, 129))	('PTEN', 'Gene', '5728', (27, 31))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
73432	32333246	Following the emerging alterations of PI3K/AKT pathway genes have been widely reported in cancers recently, the inhibitors of PI3K/AKT pathway have brought a new era for targeted therapy of cancer.	('PI3K', 'molecular_function', 'GO:0016303', ('126', '130'))	('cancer', 'Disease', (190, 196))	('cancers', 'Disease', (90, 97))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('AKT', 'Gene', '207', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('inhibitors', 'Var', (112, 122))	('AKT', 'Gene', '207', (43, 46))	('AKT', 'Gene', (131, 134))	('PI3K', 'molecular_function', 'GO:0016303', ('38', '42'))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('AKT', 'Gene', (43, 46))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
73443	32333246	Considering that the incidence and mortality of the brain and central nervous system tumors is 1.6% and 2.5% respectively in the worldwide (https://gco.iarc.fr/, Table 1), particularly the most common primary malignant tumor, glioblastoma multiforme (GBM), contributes to the poor prognosis partly for its tolerance of radiation therapy, hyper-activation of PI3K/AKT pathway in GBM caused by the mutations of PIK3CA or PIK3R1 (18.3%) and other PI3K family genes (6.8%) has urged researchers to seek novel targeted treatments to control the disease.	('GBM', 'Disease', (378, 381))	('PI3K', 'molecular_function', 'GO:0016303', ('358', '362'))	('men', 'Species', '9606', (519, 522))	('PIK3R1', 'Gene', (419, 425))	('AKT', 'Gene', (363, 366))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('central nervous system tumors', 'Disease', (62, 91))	('mutations', 'Var', (396, 405))	('PIK3CA', 'Gene', (409, 415))	('glioblastoma', 'Phenotype', 'HP:0012174', (226, 238))	('PI3K', 'molecular_function', 'GO:0016303', ('444', '448'))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('malignant tumor', 'Disease', (209, 224))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('mortality', 'Disease', (35, 44))	('PIK3R1', 'Gene', '5295', (419, 425))	('AKT', 'Gene', '207', (363, 366))	('glioblastoma multiforme', 'Disease', (226, 249))	('central nervous system tumors', 'Disease', 'MESH:D016543', (62, 91))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (226, 249))	('malignant tumor', 'Disease', 'MESH:D009369', (209, 224))	('hyper-activation', 'PosReg', (338, 354))	('mortality', 'Disease', 'MESH:D003643', (35, 44))
73444	32333246	Moreover, knockdown of PIK3CA or PIK3R1 significantly inhibits cell viability, migration and invasion in GBM cells via hypo-activation of AKT and FAK.	('FAK', 'Gene', (146, 149))	('invasion in GBM cells', 'CPA', (93, 114))	('PIK3CA', 'Gene', (23, 29))	('AKT', 'Gene', (138, 141))	('FAK', 'molecular_function', 'GO:0004717', ('146', '149'))	('cell viability', 'CPA', (63, 77))	('inhibits', 'NegReg', (54, 62))	('PIK3R1', 'Gene', '5295', (33, 39))	('PIK3R1', 'Gene', (33, 39))	('FAK', 'Gene', '5747', (146, 149))	('knockdown', 'Var', (10, 19))	('AKT', 'Gene', '207', (138, 141))
73446	32333246	PIK3CB knockdown suppresses cell proliferation and induces caspase-dependent apoptosis in GBM in vitro and vivo instead of suppressing GBM cell migration.	('cell proliferation', 'biological_process', 'GO:0008283', ('28', '46'))	('GBM cell migration', 'CPA', (135, 153))	('suppressing', 'NegReg', (123, 134))	('cell proliferation', 'CPA', (28, 46))	('PIK3CB', 'Gene', (0, 6))	('induces', 'Reg', (51, 58))	('caspase-dependent apoptosis', 'MPA', (59, 86))	('suppresses', 'NegReg', (17, 27))	('PIK3CB', 'Gene', '5291', (0, 6))	('cell migration', 'biological_process', 'GO:0016477', ('139', '153'))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('knockdown', 'Var', (7, 16))
73447	32333246	As a matter of fact that more than 50 PI3K inhibitors have been designed and produced for cancer treatment, but only a minority of them such as BKM120, XL147, XL765 and GDC-0084 have successfully entered into clinical trials for GBM treatment (https://clinicaltrials.gov, Table 2).	('men', 'Species', '9606', (238, 241))	('BKM120', 'Chemical', 'MESH:C571178', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('PI3K', 'molecular_function', 'GO:0016303', ('38', '42'))	('men', 'Species', '9606', (102, 105))	('GBM', 'Disease', (229, 232))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('BKM120', 'Var', (144, 150))	('XL765', 'Var', (159, 164))
73448	32333246	Some p110alpha isoform-selective inhibitors, such as A66 or PIK-75, could effectively suppress the GBM cell growth, survival and migration in vitro, while inhibition of p110beta by TGX-221 only arrests cell migration, and inhibition of p110delta by IC87114 or CAL-101 moderately blocks cell proliferation and migration.	('p110beta', 'Gene', '5291', (169, 177))	('IC87114', 'Chemical', 'MESH:C477872', (249, 256))	('suppress', 'NegReg', (86, 94))	('cell migration', 'CPA', (202, 216))	('p110alpha', 'Gene', '5290', (5, 14))	('cell proliferation', 'biological_process', 'GO:0008283', ('286', '304'))	('CAL-101', 'Chemical', 'MESH:C552946', (260, 267))	('p110beta', 'Gene', (169, 177))	('migration', 'CPA', (129, 138))	('PIK-75', 'Gene', (60, 66))	('GBM cell growth', 'CPA', (99, 114))	('cell proliferation', 'CPA', (286, 304))	('p110alpha', 'Gene', (5, 14))	('blocks', 'NegReg', (279, 285))	('cell growth', 'biological_process', 'GO:0016049', ('103', '114'))	('cell migration', 'biological_process', 'GO:0016477', ('202', '216'))	('TGX-221', 'Gene', (181, 188))	('p110delta', 'Var', (236, 245))
73449	32333246	However, PI3K inhibitors including A66 and BEZ235 are observed to increase the expression of cancer stem cell (CSC) genes (SOX2, OCT4 and MSI1) in GBM CSC models, which exhibit therapy resistance.	('BEZ235', 'Var', (43, 49))	('cancer', 'Disease', (93, 99))	('MSI1', 'Gene', (138, 142))	('increase', 'PosReg', (66, 74))	('A66', 'Var', (35, 38))	('expression', 'MPA', (79, 89))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('OC', 'Phenotype', 'HP:0100615', (129, 131))	('SOX2', 'Gene', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('OCT4', 'Gene', '5460', (129, 133))	('PI3K', 'molecular_function', 'GO:0016303', ('9', '13'))	('OCT4', 'Gene', (129, 133))	('MSI1', 'Gene', '4440', (138, 142))	('SOX2', 'Gene', '6657', (123, 127))	('PI3K', 'Var', (9, 13))	('BEZ235', 'Chemical', 'MESH:C531198', (43, 49))
73452	32333246	Notably, building on that 22% genetic alterations of PTEN was detected in GBM (https://www.cbioportal.org, Table 1), especially deep deletion, which caused the loss of function of PTEN tumor suppressor, PTEN was deeply involved in the pathological effects of PI3K/AKT pathway in GBM.	('PTEN', 'Gene', (203, 207))	('PTEN', 'Gene', '5728', (203, 207))	('AKT', 'Gene', (264, 267))	('tumor suppressor', 'biological_process', 'GO:0051726', ('185', '201'))	('deep deletion', 'Var', (128, 141))	('PTEN', 'Gene', (180, 184))	('involved', 'Reg', (219, 227))	('PTEN tumor', 'Disease', 'MESH:D006223', (180, 190))	('PTEN tumor', 'Disease', (180, 190))	('PTEN', 'Gene', '5728', (180, 184))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('185', '201'))	('PI3K', 'molecular_function', 'GO:0016303', ('259', '263'))	('PTEN', 'Gene', (53, 57))	('PTEN', 'Gene', '5728', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('AKT', 'Gene', '207', (264, 267))	('loss of function', 'NegReg', (160, 176))
73453	32333246	Meanwhile, genetic loss of PTEN is associated with each subtype of GBM.	('PTEN', 'Gene', '5728', (27, 31))	('associated', 'Reg', (35, 45))	('GBM', 'Disease', (67, 70))	('PTEN', 'Gene', (27, 31))	('genetic loss', 'Var', (11, 23))
73459	32333246	The loss of FBW7 function increases SOX9 protein levels, increasing the malignancy of cancer and resistance to cisplatin.	('increasing', 'PosReg', (57, 67))	('FBW7', 'Gene', '55294', (12, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('FBW7', 'Gene', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('SOX9', 'Gene', (36, 40))	('resistance', 'CPA', (97, 107))	('malignancy of cancer', 'Disease', 'MESH:D009369', (72, 92))	('increases', 'PosReg', (26, 35))	('SOX9', 'Gene', '6662', (36, 40))	('malignancy of cancer', 'Disease', (72, 92))	('loss', 'Var', (4, 8))
73460	32333246	As a major oncoprotein inhibitor, once FBW7 is deleted or mutated, it can cause tumors to occur directly.	('FBW7', 'Gene', '55294', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('FBW7', 'Gene', (39, 43))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('mutated', 'Var', (58, 65))	('deleted', 'Var', (47, 54))	('cause', 'Reg', (74, 79))
73461	32333246	Moreover, experiments show that combination of PI3K inhibitor, mTOR inhibitor and cisplatin can achieve better therapeutic effect, and how well LY3023414 works in recurrent MBM is being tested in an ongoing clinical trial (NCT03213678, Table 2).	('PI3K', 'Gene', (47, 51))	('MBM', 'Disease', (173, 176))	('therapeutic effect', 'MPA', (111, 129))	('men', 'Species', '9606', (16, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('LY3023414', 'Chemical', 'MESH:C000621566', (144, 153))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('LY3023414', 'Var', (144, 153))
73465	32333246	Obviously, the overall genetic alterations of PI3K/AKT pathway in TC are inconspicuous (Table 1), but genetic mutations in PI3K/AKT pathway are common in PDTC and ATC, specifically more common in ATC than in PDTC.	('ATC', 'Disease', (196, 199))	('PDTC', 'Chemical', '-', (154, 158))	('TC', 'Phenotype', 'HP:0002890', (164, 166))	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('common', 'Reg', (186, 192))	('TC', 'Phenotype', 'HP:0002890', (66, 68))	('AKT', 'Gene', (51, 54))	('TC', 'Phenotype', 'HP:0002890', (210, 212))	('AKT', 'Gene', (128, 131))	('genetic mutations', 'Var', (102, 119))	('PI3K', 'molecular_function', 'GO:0016303', ('123', '127'))	('PDTC', 'Chemical', '-', (208, 212))	('TC', 'Phenotype', 'HP:0002890', (156, 158))	('PDTC', 'Disease', (154, 158))	('common', 'Reg', (144, 150))	('AKT', 'Gene', '207', (128, 131))	('TC', 'Phenotype', 'HP:0002890', (197, 199))	('AKT', 'Gene', '207', (51, 54))
73466	32333246	Besides PIK3CA (18% vs. 2%) and PTEN (15% vs. 4%), mutations of PIK3C2G (6% vs. 1%), PIK3CG (6% vs. 1%), PIK3C3 (0 vs. 1%), PIK3R1 (0 vs. 1%), PIK3R2 (3% vs. 0), AKT3 (0 vs. 1%) are also observed in ATC and PDTC respectively.	('PIK3C2G', 'Gene', (64, 71))	('mutations', 'Var', (51, 60))	('PDTC', 'Chemical', '-', (207, 211))	('PIK3C2G', 'Gene', '5288', (64, 71))	('PIK3R1', 'Gene', (124, 130))	('PIK3R2', 'Gene', (143, 149))	('AKT3', 'Gene', '10000', (162, 166))	('PIK3C3', 'Gene', '5289', (105, 111))	('PIK3C3', 'Gene', (105, 111))	('PIK3R2', 'Gene', '5296', (143, 149))	('PDTC', 'Disease', (207, 211))	('AKT3', 'Gene', (162, 166))	('PTEN', 'Gene', (32, 36))	('PIK3R1', 'Gene', '5295', (124, 130))	('PIK3CG', 'Gene', (85, 91))	('ATC', 'Disease', (199, 202))	('PIK3CG', 'Gene', '5294', (85, 91))	('TC', 'Phenotype', 'HP:0002890', (209, 211))	('PTEN', 'Gene', '5728', (32, 36))	('TC', 'Phenotype', 'HP:0002890', (200, 202))
73468	32333246	Actually, exclusive activating mutations of BRAF (60% vs. 33% and 38%) in PTC are more frequently observed than in PDTC and ATC, while mice experiments show that co-mutation of BRAF and PIK3CA can promote the development of lethal ATC, but neither BRAF nor PIK3CA mutations alone can.	('men', 'Species', '9606', (216, 219))	('development of lethal ATC', 'CPA', (209, 234))	('mutations', 'Var', (31, 40))	('activating', 'PosReg', (20, 30))	('BRAF', 'Gene', (177, 181))	('TC', 'Phenotype', 'HP:0002890', (117, 119))	('BRAF', 'Gene', (44, 48))	('co-mutation', 'Var', (162, 173))	('men', 'Species', '9606', (146, 149))	('TC', 'Phenotype', 'HP:0002890', (125, 127))	('PTC', 'Disease', (74, 77))	('PIK3CA', 'Gene', (186, 192))	('PDTC', 'Chemical', '-', (115, 119))	('mice', 'Species', '10090', (135, 139))	('TC', 'Phenotype', 'HP:0002890', (232, 234))	('TC', 'Phenotype', 'HP:0002890', (75, 77))	('promote', 'PosReg', (197, 204))
73469	32333246	In addition, mutations in BRAF and PIK3CA can activate the MAPK pathway and the PI3K/AKT pathway respectively and lead to the occurrence of ATC, whereas dual blocking PI3K and MAPK pathways can effectively inhibit ATC.	('MAPK pathway', 'Pathway', (59, 71))	('AKT', 'Gene', '207', (85, 88))	('BRAF', 'Gene', (26, 30))	('TC', 'Phenotype', 'HP:0002890', (141, 143))	('MAPK', 'molecular_function', 'GO:0004707', ('59', '63'))	('PI3K', 'molecular_function', 'GO:0016303', ('80', '84'))	('PIK3CA', 'Gene', (35, 41))	('activate', 'PosReg', (46, 54))	('AKT', 'Gene', (85, 88))	('PI3K', 'molecular_function', 'GO:0016303', ('167', '171'))	('mutations', 'Var', (13, 22))	('MAPK', 'molecular_function', 'GO:0004707', ('176', '180'))	('lead to', 'Reg', (114, 121))	('TC', 'Phenotype', 'HP:0002890', (215, 217))	('ATC', 'Disease', (140, 143))
73476	32333246	Apart from those widely recognized alterations, such as EGFR and KRAS gene mutations, MET amplification, EML4-ALK rearrangements in NSCLC, somatic mutations and amplification in PIK3CA are described in 3-10% vs. 35% of SCC and 0-2.7% vs. 7% of ADC respectively.	('mutations', 'Var', (147, 156))	('EGFR', 'Gene', '1956', (56, 60))	('SCC', 'Disease', (219, 222))	('CC', 'Phenotype', 'HP:0002664', (220, 222))	('PIK3CA', 'Gene', (178, 184))	('KRAS', 'Gene', '3845', (65, 69))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('amplification', 'Var', (161, 174))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('EML4', 'Gene', (105, 109))	('KRAS', 'Gene', (65, 69))	('EML4', 'Gene', '27436', (105, 109))	('ADC', 'Disease', (244, 247))	('NSCLC', 'Disease', (132, 137))	('EGFR', 'Gene', (56, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (132, 137))	('ALK', 'Gene', '238', (110, 113))	('SCC', 'Phenotype', 'HP:0002860', (219, 222))	('LC', 'Phenotype', 'HP:0100526', (135, 137))	('rearrangements', 'Var', (114, 128))	('ALK', 'Gene', (110, 113))	('men', 'Species', '9606', (123, 126))	('SCLC', 'Phenotype', 'HP:0030357', (133, 137))
73483	32333246	Whether combining daily BKM120 with cisplatin and etoposide was safe and effective in extensive stage SCLC patients had been attempted in a completed clinical trial (NCT02194049, Table 3).	('SCLC', 'Phenotype', 'HP:0030357', (102, 106))	('BKM120', 'Chemical', 'MESH:C571178', (24, 30))	('LC', 'Phenotype', 'HP:0100526', (104, 106))	('etoposide', 'Chemical', 'MESH:D005047', (50, 59))	('SCLC', 'Gene', '7864', (102, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('SCLC', 'Gene', (102, 106))	('BKM120', 'Var', (24, 30))	('patients', 'Species', '9606', (107, 115))
73485	32333246	As expected, NPC has a relatively lower mutational burdens with PIK3CA mutations of 1.8% (Table 1), however, there are still numerous of researches involved in PI3K/AKT pathway in NPC.	('AKT', 'Gene', (165, 168))	('PIK3CA', 'Gene', (64, 70))	('NPC', 'Phenotype', 'HP:0100630', (180, 183))	('NPC', 'cellular_component', 'GO:0005643', ('180', '183'))	('PI3K', 'molecular_function', 'GO:0016303', ('160', '164'))	('NPC', 'Gene', (180, 183))	('NPC', 'cellular_component', 'GO:0005643', ('13', '16'))	('NPC', 'Gene', '4864', (180, 183))	('NPC', 'Phenotype', 'HP:0100630', (13, 16))	('mutations', 'Var', (71, 80))	('NPC', 'Gene', (13, 16))	('AKT', 'Gene', '207', (165, 168))	('PC', 'Phenotype', 'HP:0002894', (181, 183))	('PC', 'Phenotype', 'HP:0002894', (14, 16))	('NPC', 'Gene', '4864', (13, 16))
73489	32333246	A series of studies show the mutational events of PI3K pathway (30.5%) in 151 head and neck squamous cell carcinomas (HNSCCs) containing 29 laryngeal squamous cell carcinomas (LSCCs), particularly PIK3CA mutations of 12.6%.	('PIK3CA', 'Gene', (197, 203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('HNSCC', 'Disease', 'MESH:D000077195', (118, 123))	('squamous cell carcinomas', 'Disease', (150, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('CC', 'Phenotype', 'HP:0002664', (178, 180))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (92, 116))	('neck', 'cellular_component', 'GO:0044326', ('87', '91'))	('CC', 'Phenotype', 'HP:0002664', (121, 123))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (92, 116))	('mutations', 'Var', (204, 213))	('HNSCC', 'Disease', (118, 123))	('PI3K', 'molecular_function', 'GO:0016303', ('50', '54'))	('PI3K pathway', 'Pathway', (50, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))	('neck squamous cell carcinomas', 'Disease', (87, 116))	('mutational', 'Var', (29, 39))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (150, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('SCC', 'Phenotype', 'HP:0002860', (177, 180))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (150, 174))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (87, 116))
73493	32333246	Even more, the safety and efficacy of AKT inhibitor MK2206 in NPC patients had been evaluated in a completed clinical trial (Table 3).	('AKT', 'Gene', (38, 41))	('MK2206', 'Chemical', 'MESH:C548887', (52, 58))	('NPC', 'Phenotype', 'HP:0100630', (62, 65))	('NPC', 'cellular_component', 'GO:0005643', ('62', '65'))	('MK2206', 'Var', (52, 58))	('AKT', 'Gene', '207', (38, 41))	('NPC', 'Gene', (62, 65))	('PC', 'Phenotype', 'HP:0002894', (63, 65))	('patients', 'Species', '9606', (66, 74))	('NPC', 'Gene', '4864', (62, 65))
73496	32333246	In general, the genetic alterations of PIK3CA (24%), and PTEN (7%) are observed in ESCA (Table 1), especially the somatic mutations of PIK3CA (7.2% vs 12.5%), PIK3C2A (0.7% vs. 0), PIK3CG (2.9% vs. 4.2%) and PIK3C2G (0 vs. 37.5%) are observed respectively in 139 paired ESCC cases and 24 cell lines.	('PIK3C2G', 'Gene', (208, 215))	('PIK3CG', 'Gene', (181, 187))	('ESCC', 'Disease', (270, 274))	('PIK3C2G', 'Gene', '5288', (208, 215))	('SCC', 'Phenotype', 'HP:0002860', (271, 274))	('PIK3CG', 'Gene', '5294', (181, 187))	('CC', 'Phenotype', 'HP:0002664', (272, 274))	('ESCA', 'Disease', (83, 87))	('PTEN', 'Gene', (57, 61))	('PIK3CA', 'Gene', (135, 141))	('PTEN', 'Gene', '5728', (57, 61))	('mutations', 'Var', (122, 131))	('PIK3C2A', 'Gene', '5286', (159, 166))	('PIK3C2A', 'Gene', (159, 166))
73497	32333246	Even more, PIK3CA mutations are frequent in ESCC associated with chagasic megaesophagus and are associated with a worse patient outcome.	('ESCC', 'Disease', (44, 48))	('associated', 'Reg', (96, 106))	('associated', 'Reg', (49, 59))	('patient', 'Species', '9606', (120, 127))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('PIK3CA', 'Gene', (11, 17))	('chagasic megaesophagus', 'Disease', (65, 87))	('CC', 'Phenotype', 'HP:0002664', (46, 48))	('mutations', 'Var', (18, 27))
73502	32333246	But one research reveals that PI3K/AKT pathway genetic mutations are found in 69 (16%) of the 431 GC patients including PIK3CA (13.2%) and PTEN (4.0%), as well as PIK3CA amplifications are found in 206 (47.8%) of the patients.	('patients', 'Species', '9606', (101, 109))	('PIK3CA', 'Gene', (120, 126))	('AKT', 'Gene', (35, 38))	('mutations', 'Var', (55, 64))	('PTEN', 'Gene', (139, 143))	('PTEN', 'Gene', '5728', (139, 143))	('PI3K', 'molecular_function', 'GO:0016303', ('30', '34'))	('AKT', 'Gene', '207', (35, 38))	('patients', 'Species', '9606', (217, 225))	('found', 'Reg', (69, 74))
73503	32333246	Another research shows that advanced GC patient have more frequency of PIK3CA mutations in codon 545 than in codon 1047.	('patient', 'Species', '9606', (40, 47))	('advanced GC', 'Disease', (28, 39))	('PIK3CA', 'Gene', (71, 77))	('mutations', 'Var', (78, 87))
73506	32333246	Table 2) and AKT inhibitors (MK2206, GSK2110183 and GDC-0068.	('MK2206', 'Var', (29, 35))	('GDC-0068', 'Chemical', 'MESH:C583616', (52, 60))	('GSK2110183', 'Chemical', 'MESH:C000595148', (37, 47))	('AKT', 'Gene', '207', (13, 16))	('MK2206', 'Chemical', 'MESH:C548887', (29, 35))	('GSK', 'molecular_function', 'GO:0050321', ('37', '40'))	('AKT', 'Gene', (13, 16))
73510	32333246	Contrary to predictions, PIK3CA mutations do not predict aggressive clinicopathological characteristics in CRC, whereas they are closely associated with KRAS mutations, as well as PIK3CA exon 9 and 20 mutations show different tendencies with respect to BRAF mutation and MSI status.	('CRC', 'Disease', (107, 110))	('associated', 'Reg', (137, 147))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('KRAS', 'Gene', (153, 157))	('PIK3CA', 'Gene', (25, 31))	('mutations', 'Var', (32, 41))	('PIK3CA', 'Gene', (180, 186))	('KRAS', 'Gene', '3845', (153, 157))
73512	32333246	CXCL12, NLRC3, Wnt/beta-catenin target genes including BAMBI, BOP1, CKS2 and NFIL3, as well as miRNA-135b, Linc00659 and CRNDE are associated with the proliferation, invasion or metastasis of CRC cells via PI3K/AKT signaling.	('CXCL12', 'Gene', (0, 6))	('NFIL3', 'Gene', '4783', (77, 82))	('CKS2', 'Gene', '1164', (68, 72))	('CKS2', 'Gene', (68, 72))	('CRNDE', 'Gene', '643911', (121, 126))	('CRNDE', 'Gene', (121, 126))	('NLRC3', 'Gene', (8, 13))	('BAMBI', 'Gene', (55, 60))	('proliferation', 'CPA', (151, 164))	('NLRC3', 'Gene', '197358', (8, 13))	('AKT', 'Gene', (211, 214))	('BAMBI', 'Gene', '25805', (55, 60))	('BOP1', 'Gene', (62, 66))	('CRC', 'Phenotype', 'HP:0003003', (192, 195))	('AKT signaling', 'biological_process', 'GO:0043491', ('211', '224'))	('PI3K', 'molecular_function', 'GO:0016303', ('206', '210'))	('metastasis', 'CPA', (178, 188))	('Linc00659', 'Gene', (107, 116))	('Linc00659', 'Gene', '100652730', (107, 116))	('invasion', 'CPA', (166, 174))	('NFIL3', 'Gene', (77, 82))	('BOP1', 'Gene', '23246', (62, 66))	('AKT', 'Gene', '207', (211, 214))	('CXCL12', 'Gene', '6387', (0, 6))	('miRNA-135b', 'Var', (95, 105))	('beta-catenin', 'Gene', (19, 31))	('associated with', 'Reg', (131, 146))	('beta-catenin', 'Gene', '1499', (19, 31))
73514	32333246	As the most common mesenchymal tumor of the digestive system, gastrointestinal stromal tumors (GISTs) mainly harbor mutually exclusive KIT or PDGFRA mutations, which lead to constitutive activation of the encoded receptor tyrosine kinase (RTK) and activation of downstream pathways including PI3K/AKT pathway.	('receptor tyrosine kinase', 'Gene', (213, 237))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('activation', 'PosReg', (187, 197))	('PDGFRA', 'Gene', '5156', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('PDGFRA', 'Gene', (142, 148))	('GISTs', 'Phenotype', 'HP:0100723', (95, 100))	('KIT', 'Gene', '3815', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (62, 93))	('AKT', 'Gene', (297, 300))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (62, 93))	('RTK', 'Gene', (239, 242))	('PI3K', 'molecular_function', 'GO:0016303', ('292', '296'))	('activation', 'PosReg', (248, 258))	('RTK', 'Gene', '5979', (239, 242))	('mutations', 'Var', (149, 158))	('KIT', 'molecular_function', 'GO:0005020', ('135', '138'))	('mesenchymal tumor', 'Disease', 'MESH:C535700', (19, 36))	('gastrointestinal stromal tumors', 'Disease', (62, 93))	('receptor tyrosine kinase', 'Gene', '5979', (213, 237))	('AKT', 'Gene', '207', (297, 300))	('KIT', 'Gene', (135, 138))	('mesenchymal tumor', 'Disease', (19, 36))
73515	32333246	Genetic alterations of PIK3CA and PTEN are observed more frequency in malignant GISTs than in less malignant GISTs in 65 GIST samples with 14/65 overall genetic alterations of PI3K/AKT pathway.	('Genetic alterations', 'Var', (0, 19))	('PIK3CA', 'Gene', (23, 29))	('AKT', 'Gene', (181, 184))	('genetic alterations', 'Var', (153, 172))	('PI3K', 'molecular_function', 'GO:0016303', ('176', '180'))	('GISTs', 'Phenotype', 'HP:0100723', (109, 114))	('AKT', 'Gene', '207', (181, 184))	('GISTs', 'Phenotype', 'HP:0100723', (80, 85))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))	('malignant', 'Disease', (70, 79))
73516	32333246	It is noted that FASN overexpression often occurs in high-risk and metastatic GISTs, whereas combination therapy with imatinib and C75 targeting FASN has been demonstrated in vitro and vivo to down-regulate the phosphorylation levels of the KIT and PI3K/AKT/mTOR pathway.	('imatinib', 'Chemical', 'MESH:D000068877', (118, 126))	('KIT', 'molecular_function', 'GO:0005020', ('241', '244'))	('FASN', 'Gene', (17, 21))	('phosphorylation levels', 'MPA', (211, 233))	('AKT', 'Gene', (254, 257))	('overexpression', 'PosReg', (22, 36))	('FASN', 'Gene', '2194', (17, 21))	('AKT', 'Gene', '207', (254, 257))	('phosphorylation', 'biological_process', 'GO:0016310', ('211', '226'))	('C75', 'Var', (131, 134))	('KIT', 'Gene', '3815', (241, 244))	('PI3K', 'molecular_function', 'GO:0016303', ('249', '253'))	('FASN', 'Gene', (145, 149))	('FASN', 'Gene', '2194', (145, 149))	('down-regulate', 'NegReg', (193, 206))	('GISTs', 'Phenotype', 'HP:0100723', (78, 83))	('KIT', 'Gene', (241, 244))
73518	32333246	Combination of imatinib mesylate (IM) and MK2206 provide obviously greater efficacy than treatment with IM or MK2206 alone in vitro and vivo preclinical study of GIST.	('MK2206', 'Chemical', 'MESH:C548887', (42, 48))	('men', 'Species', '9606', (94, 97))	('efficacy', 'MPA', (75, 83))	('MK2206', 'Chemical', 'MESH:C548887', (110, 116))	('MK2206', 'Var', (42, 48))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (15, 32))	('greater', 'PosReg', (67, 74))
73519	32333246	Furthermore, clinical trials of combination of Imatinib and BKM120 (NCT01468688) or BYL719 (NCT01735968, Table 2) were tested in GIST patients.	('BKM120', 'Gene', (60, 66))	('Imatinib', 'Chemical', 'MESH:D000068877', (47, 55))	('BKM120', 'Chemical', 'MESH:C571178', (60, 66))	('NCT01468688', 'Var', (68, 79))	('patients', 'Species', '9606', (134, 142))
73523	32333246	A small amount of clinical trials of PI3K inhibitors (SF1126, GSK2636771) and AKT inhibitors (MK2206) in HCC patients may give them an opportunity for relief (Tables 2 and 3).	('HCC', 'Disease', (105, 108))	('GSK', 'molecular_function', 'GO:0050321', ('62', '65'))	('patients', 'Species', '9606', (109, 117))	('CC', 'Phenotype', 'HP:0002664', (106, 108))	('HCC', 'Phenotype', 'HP:0001402', (105, 108))	('SF1126', 'Var', (54, 60))	('SF1126', 'Chemical', 'MESH:C526549', (54, 60))	('AKT', 'Gene', '207', (78, 81))	('MK2206', 'Chemical', 'MESH:C548887', (94, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('37', '41'))	('AKT', 'Gene', (78, 81))	('GSK2636771', 'Chemical', 'MESH:C000627739', (62, 72))	('PI3K', 'Protein', (37, 41))
73524	32333246	Regarding gallbladder cancer (GBC) is the most common malignancy of the biliary tract, the general genetic abnormalities of PIK3CA (10%) and PTEN (2.3%) are found (Table 1), especially the PIK3CA E545K mutation rate (6.15%).	('genetic abnormalities', 'Disease', 'MESH:D030342', (99, 120))	('PTEN', 'Gene', (141, 145))	('PTEN', 'Gene', '5728', (141, 145))	('genetic abnormalities', 'Disease', (99, 120))	('PIK3CA', 'Gene', (189, 195))	('E545K', 'Mutation', 'rs104886003', (196, 201))	('E545K', 'Var', (196, 201))	('PIK3CA', 'Gene', (124, 130))	('BC', 'Phenotype', 'HP:0003002', (31, 33))	('bladder cancer', 'Phenotype', 'HP:0009725', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('malignancy', 'Disease', 'MESH:D009369', (54, 64))	('gallbladder cancer', 'Disease', (10, 28))	('gallbladder cancer', 'Disease', 'MESH:D005706', (10, 28))	('malignancy', 'Disease', (54, 64))
73525	32333246	Due to ErbB2 and ErbB3 mutations at a frequency of 7-8% in GBC, ErbB2/ErbB3 mutation inducing PD-L1 overexpression can mediate immune escape of tumor cells via PI3K/AKT pathway in vitro.	('mediate', 'Reg', (119, 126))	('BC', 'Phenotype', 'HP:0003002', (60, 62))	('ErbB3', 'Gene', '2065', (17, 22))	('ErbB3', 'Gene', (70, 75))	('PI3K', 'molecular_function', 'GO:0016303', ('160', '164'))	('mutation', 'Var', (76, 84))	('overexpression', 'PosReg', (100, 114))	('AKT', 'Gene', (165, 168))	('mutations', 'Var', (23, 32))	('ErbB3', 'Gene', '2065', (70, 75))	('ErbB2', 'Gene', '2064', (64, 69))	('ErbB2', 'Gene', '2064', (7, 12))	('tumor', 'Disease', (144, 149))	('PD-L1', 'Gene', (94, 99))	('PD-L1', 'Gene', '29126', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('AKT', 'Gene', '207', (165, 168))	('ErbB3', 'Gene', (17, 22))	('ErbB2', 'Gene', (64, 69))	('ErbB2', 'Gene', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
73527	32333246	Currently, only MK2206 was tested in clinical trials (NCT01859182 and NCT01425879) in GBC patients.	('GBC', 'Disease', (86, 89))	('NCT01859182', 'Var', (54, 65))	('NCT01425879', 'Var', (70, 81))	('MK2206', 'Chemical', 'MESH:C548887', (16, 22))	('BC', 'Phenotype', 'HP:0003002', (87, 89))	('patients', 'Species', '9606', (90, 98))
73532	32333246	Significantly, the mutations of PIK3CG in PDAC are also revealed.	('PIK3CG', 'Gene', (32, 38))	('PIK3CG', 'Gene', '5294', (32, 38))	('PDAC', 'Chemical', '-', (42, 46))	('mutations', 'Var', (19, 28))
73533	32333246	EG-VEGF, TMEM158, miR-107, as well as LncRNA ABHD11-AS1, SNHG1 and AB209630 are involved in proliferation, apoptosis, metastasis or carcinogenesis of PDAC cells through PI3K/AKT pathway.	('TMEM158', 'Gene', '25907', (9, 16))	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('PDAC', 'Chemical', '-', (150, 154))	('AS1', 'Gene', '5729', (52, 55))	('AB209630', 'Var', (67, 75))	('EG-VEGF', 'Gene', (0, 7))	('ABHD11', 'Gene', '83451', (45, 51))	('SNHG1', 'Gene', (57, 62))	('carcinogenesis', 'Disease', (132, 146))	('ABHD11', 'Gene', (45, 51))	('metastasis', 'CPA', (118, 128))	('AKT', 'Gene', '207', (174, 177))	('proliferation', 'CPA', (92, 105))	('apoptosis', 'CPA', (107, 116))	('involved', 'Reg', (80, 88))	('carcinogenesis', 'Disease', 'MESH:D063646', (132, 146))	('AS1', 'Gene', (52, 55))	('miR-107', 'Gene', (18, 25))	('SNHG1', 'Gene', '23642', (57, 62))	('EG-VEGF', 'Gene', '84432', (0, 7))	('TMEM158', 'Gene', (9, 16))	('PI3K', 'molecular_function', 'GO:0016303', ('169', '173'))	('miR-107', 'Gene', '406901', (18, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('AKT', 'Gene', (174, 177))
73534	32333246	Plenty of clinical trials of PI3K inhibitors (BKM120, BYL719, GSK2636771, PKI-587, BEZ235 and LY3023414.	('BKM120', 'Chemical', 'MESH:C571178', (46, 52))	('LY3023414', 'Chemical', 'MESH:C000621566', (94, 103))	('PI3K', 'molecular_function', 'GO:0016303', ('29', '33'))	('GSK', 'molecular_function', 'GO:0050321', ('62', '65'))	('LY3023414', 'Var', (94, 103))	('BEZ235', 'Chemical', 'MESH:C531198', (83, 89))	('BKM120', 'Var', (46, 52))	('GSK2636771', 'Chemical', 'MESH:C000627739', (62, 72))
73538	32333246	Compared to the recognized genetically diverse of Her2 and TOP2A of BCs, the overall genetic alterations of PI3K/AKT pathway are not uncommon, especially PIK3CA (37%) and PTEN (8%, Table 1).	('Her2', 'Gene', (50, 54))	('TOP2A', 'Gene', (59, 64))	('PIK3CA', 'Var', (154, 160))	('BC', 'Phenotype', 'HP:0003002', (68, 70))	('AKT', 'Gene', '207', (113, 116))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))	('Her2', 'Gene', '2064', (50, 54))	('PTEN', 'Gene', (171, 175))	('AKT', 'Gene', (113, 116))	('PTEN', 'Gene', '5728', (171, 175))	('TOP2A', 'Gene', '7153', (59, 64))
73539	32333246	Remarkably, hotspot mutations in PIK3CA are frequent in ER+BCs, which account for up to 80% of BCs, and Her2 mutations hyperactivate the HER3/PI3K/AKT/mTOR axis, leading to anti-ER resistance in ER+BCs.	('BC', 'Phenotype', 'HP:0003002', (95, 97))	('BC', 'Phenotype', 'HP:0003002', (198, 200))	('PI3K', 'molecular_function', 'GO:0016303', ('142', '146'))	('Her2', 'Gene', '2064', (104, 108))	('ER+BCs', 'Disease', (56, 62))	('BC', 'Phenotype', 'HP:0003002', (59, 61))	('AKT', 'Gene', '207', (147, 150))	('HER3', 'Gene', (137, 141))	('PIK3CA', 'Gene', (33, 39))	('mutations', 'Var', (109, 118))	('hyperactivate', 'PosReg', (119, 132))	('HER3', 'Gene', '2065', (137, 141))	('Her2', 'Gene', (104, 108))	('leading to', 'Reg', (162, 172))	('anti-ER resistance', 'MPA', (173, 191))	('mutations', 'Var', (20, 29))	('AKT', 'Gene', (147, 150))
73540	32333246	Hence, dual blockade of the Her2 and ER pathways is necessary for the treatment of ER+/Her2 mutant BCs.	('Her2', 'Gene', '2064', (28, 32))	('Her2', 'Gene', '2064', (87, 91))	('BC', 'Phenotype', 'HP:0003002', (99, 101))	('men', 'Species', '9606', (75, 78))	('mutant', 'Var', (92, 98))	('Her2', 'Gene', (28, 32))	('Her2', 'Gene', (87, 91))
73541	32333246	Moreover, PIK3CA and MAP3K1 alterations reveal Luminal A status in ER+ metastatic BCs and the patients are likely to clinically benefit from BKM120.	('patients', 'Species', '9606', (94, 102))	('BC', 'Phenotype', 'HP:0003002', (82, 84))	('alterations', 'Var', (28, 39))	('Luminal', 'Chemical', 'MESH:D010634', (47, 54))	('MAP3K', 'molecular_function', 'GO:0004709', ('21', '26'))	('PIK3CA', 'Gene', (10, 16))	('MAP3K1', 'Gene', (21, 27))	('BKM120', 'Chemical', 'MESH:C571178', (141, 147))	('MAP3K1', 'Gene', '4214', (21, 27))	('ER+ metastatic BCs', 'Disease', (67, 85))	('Luminal A status', 'MPA', (47, 63))	('reveal', 'Reg', (40, 46))
73542	32333246	On the other hand, top to 70% of patients with breast cancer brain metastases (BCBM) show the activated PI3K pathway, and GDC-0084 induces apoptosis of PIK3CA-mutant BCBM cells by suppressing activation of AKT and p70 S6 kinase.	('AKT', 'Gene', (206, 209))	('breast cancer brain metastases', 'Disease', 'MESH:D001943', (47, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('p70', 'Gene', (214, 217))	('BCBM', 'Chemical', '-', (79, 83))	('suppressing', 'NegReg', (180, 191))	('BCBM', 'Chemical', '-', (166, 170))	('apoptosis', 'biological_process', 'GO:0097194', ('139', '148'))	('apoptosis', 'biological_process', 'GO:0006915', ('139', '148'))	('breast cancer brain metastases', 'Disease', (47, 77))	('AKT', 'Gene', '207', (206, 209))	('PIK3CA-mutant', 'Gene', (152, 165))	('apoptosis', 'CPA', (139, 148))	('GDC-0084', 'Var', (122, 130))	('BC', 'Phenotype', 'HP:0003002', (79, 81))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('p70', 'Gene', '84959', (214, 217))	('PI3K pathway', 'Pathway', (104, 116))	('BC', 'Phenotype', 'HP:0003002', (166, 168))	('patients', 'Species', '9606', (33, 41))	('PI3K', 'molecular_function', 'GO:0016303', ('104', '108'))	('induces', 'PosReg', (131, 138))
73547	32333246	Ovarian serous cystadenocarcinoma (OSC), the leading common subtype of epithelial ovarian cancers (EOC) accounting for 90% of OC, harbors overall genetic alterations of PIK3CA (29%), PIK3R1 (5%), PIK3R2 (9%), AKT1 (5%), AKT2 (8%) and PTEN (7%, Table 1) besides the mutant p53 in high-grade OSC (HGOSC), germline BRCA1 and BRCA2 mutations.	('p53', 'Gene', '7157', (272, 275))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutant', 'Var', (265, 271))	('Ovarian serous cystadenocarcinoma', 'Disease', (0, 33))	('OSC', 'molecular_function', 'GO:0000250', ('35', '38'))	('BRCA1', 'Gene', '672', (312, 317))	('PIK3R1', 'Gene', '5295', (183, 189))	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (8, 33))	('OC', 'Phenotype', 'HP:0100615', (100, 102))	('PTEN', 'Gene', (234, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('BRCA1', 'Gene', (312, 317))	('p53', 'Gene', (272, 275))	('high-grade OSC', 'Disease', (279, 293))	('OS', 'Phenotype', 'HP:0002669', (297, 299))	('ovarian cancers', 'Phenotype', 'HP:0100615', (82, 97))	('OS', 'Phenotype', 'HP:0002669', (290, 292))	('OSC', 'molecular_function', 'GO:0000250', ('290', '293'))	('OS', 'Phenotype', 'HP:0002669', (35, 37))	('PTEN', 'Gene', '5728', (234, 238))	('AKT1', 'Gene', '207', (209, 213))	('PIK3R2', 'Gene', (196, 202))	('epithelial ovarian cancers', 'Disease', (71, 97))	('BRCA2', 'Gene', (322, 327))	('PIK3R1', 'Gene', (183, 189))	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('AKT2', 'Gene', '208', (220, 224))	('PIK3R2', 'Gene', '5296', (196, 202))	('AKT1', 'Gene', (209, 213))	('OC', 'Phenotype', 'HP:0100615', (126, 128))	('epithelial ovarian cancers', 'Disease', 'MESH:D000077216', (71, 97))	('mutations', 'Var', (328, 337))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('BRCA2', 'Gene', '675', (322, 327))	('AKT2', 'Gene', (220, 224))	('Ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (0, 33))
73548	32333246	Furthermore, another subtype of EOC, ovarian clear cell carcinomas (OCCCs), shows more frequently mutations of PIK3CA (33%) and PTEN (5%) in overall 97 OCCC cases, especially mutations of PIK3CA (46%) in the 28 cases of affinity purified OCCCs and OCCC cell lines, than the mutation of PIK3CA and PTEN (both < 5%) in HGOSC.	('PIK3CA', 'Gene', (188, 194))	('CC', 'Phenotype', 'HP:0002664', (69, 71))	('mutations', 'Var', (175, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('ovarian clear cell carcinomas', 'Disease', (37, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('OC', 'Phenotype', 'HP:0100615', (68, 70))	('PTEN', 'Gene', (297, 301))	('CC', 'Phenotype', 'HP:0002664', (153, 155))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (37, 66))	('OC', 'Phenotype', 'HP:0100615', (33, 35))	('CC', 'Phenotype', 'HP:0002664', (249, 251))	('PTEN', 'Gene', (128, 132))	('PIK3CA', 'Gene', (111, 117))	('OS', 'Phenotype', 'HP:0002669', (319, 321))	('PTEN', 'Gene', '5728', (297, 301))	('OC', 'Phenotype', 'HP:0100615', (248, 250))	('OC', 'Phenotype', 'HP:0100615', (238, 240))	('OC', 'Phenotype', 'HP:0100615', (152, 154))	('CC', 'Phenotype', 'HP:0002664', (239, 241))	('PTEN', 'Gene', '5728', (128, 132))	('mutations', 'Var', (98, 107))
73549	32333246	Huge amounts of studies have shown YAP, PKG II, SIK2, SERPIND1, miR-15b, -21, -150, -222-3p, -337-3p, -497, -503 and -936, as well as LncRNA MALAT1 and JPX modulate proliferation, apoptosis, invasion, migration, angiogenesis, progression, glucose metabolism or drug resistance of OC cells by PI3K/AKT pathway.	('SIK2', 'Gene', (48, 52))	('SIK2', 'Gene', '23235', (48, 52))	('modulate', 'Reg', (156, 164))	('SERPIND1', 'Gene', (54, 62))	('proliferation', 'CPA', (165, 178))	('apoptosis', 'CPA', (180, 189))	('glucose metabolism', 'biological_process', 'GO:0006006', ('239', '257'))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('drug resistance', 'CPA', (261, 276))	('glucose metabolism', 'Disease', (239, 257))	('MALAT1', 'Gene', (141, 147))	('AKT', 'Gene', (297, 300))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('PI3K', 'molecular_function', 'GO:0016303', ('292', '296'))	('PKG II', 'molecular_function', 'GO:0004692', ('40', '46'))	('invasion', 'CPA', (191, 199))	('MALAT1', 'Gene', '378938', (141, 147))	('OC', 'Phenotype', 'HP:0100615', (280, 282))	('YAP', 'Gene', (35, 38))	('migration', 'CPA', (201, 210))	('JPX', 'Gene', '554203', (152, 155))	('angiogenesis', 'CPA', (212, 224))	('drug resistance', 'biological_process', 'GO:0009315', ('261', '276'))	('angiogenesis', 'biological_process', 'GO:0001525', ('212', '224'))	('glucose metabolism', 'Disease', 'MESH:D044882', (239, 257))	('drug resistance', 'biological_process', 'GO:0042493', ('261', '276'))	('JPX', 'Gene', (152, 155))	('AKT', 'Gene', '207', (297, 300))	('SERPIND1', 'Gene', '3053', (54, 62))	('drug resistance', 'Phenotype', 'HP:0020174', (261, 276))	('progression', 'CPA', (226, 237))	('miR-15b', 'Var', (64, 71))	('YAP', 'Gene', '10413', (35, 38))
73552	32333246	Furthermore, aberrant p53/KRASV12/c-Myc or p53/KRASV12/PI3K/AKT signaling is the minimum requirement for fallopian tube secretory epithelial cells (FTSECs) carcinogenesis, and increased copy number of PIK3CA has been observed in six fallopian tube carcinomas (FTCs).	('copy number', 'Var', (186, 197))	('c-Myc', 'Gene', (34, 39))	('fallopian tube carcinomas', 'Disease', 'MESH:D005185', (233, 258))	('EC', 'Phenotype', 'HP:0012114', (151, 153))	('FTCs', 'Phenotype', 'HP:0030394', (260, 264))	('SE', 'Disease', 'None', (150, 152))	('p53', 'Gene', (43, 46))	('c-Myc', 'Gene', '4609', (34, 39))	('men', 'Species', '9606', (96, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (248, 258))	('carcinogenesis', 'Disease', (156, 170))	('TC', 'Phenotype', 'HP:0002890', (261, 263))	('fallopian tube carcinomas', 'Disease', (233, 258))	('p53', 'Gene', '7157', (22, 25))	('PIK3CA', 'Gene', (201, 207))	('AKT', 'Gene', (60, 63))	('KRAS', 'Gene', '3845', (26, 30))	('aberrant', 'Var', (13, 21))	('TCs', 'Chemical', 'MESH:D013667', (261, 264))	('carcinogenesis', 'Disease', 'MESH:D063646', (156, 170))	('fallopian tube carcinomas', 'Phenotype', 'HP:0030394', (233, 258))	('fallopian tube carcinoma', 'Phenotype', 'HP:0030394', (233, 257))	('increased', 'PosReg', (176, 185))	('p53', 'Gene', (22, 25))	('PI3K', 'molecular_function', 'GO:0016303', ('55', '59'))	('KRAS', 'Gene', (26, 30))	('KRAS', 'Gene', '3845', (47, 51))	('AKT signaling', 'biological_process', 'GO:0043491', ('60', '73'))	('AKT', 'Gene', '207', (60, 63))	('EC', 'Gene', '1913', (151, 153))	('KRAS', 'Gene', (47, 51))	('p53', 'Gene', '7157', (43, 46))	('observed', 'Reg', (217, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
73555	32333246	A litany of genetic alterations induced by HPVs in CC activate four major upstream pathways (GFR, Notch receptor, RAS isoforms and p110alpha) to stimulate host cell survival, proliferation and carcinogenesis through the PI3K/AKT/mTOR pathway.	('GFR', 'Gene', (93, 96))	('p110alpha', 'Gene', (131, 140))	('p110alpha', 'Gene', '5290', (131, 140))	('host cell survival', 'CPA', (155, 173))	('AKT', 'Gene', '207', (225, 228))	('carcinogenesis', 'Disease', (193, 207))	('genetic alterations', 'Var', (12, 31))	('CC', 'Phenotype', 'HP:0002664', (51, 53))	('AKT', 'Gene', (225, 228))	('host cell', 'cellular_component', 'GO:0043657', ('155', '164'))	('stimulate', 'PosReg', (145, 154))	('carcinogenesis', 'Disease', 'MESH:D063646', (193, 207))	('HPV', 'Species', '10566', (43, 46))	('PI3K', 'molecular_function', 'GO:0016303', ('220', '224'))	('proliferation', 'CPA', (175, 188))
73556	32333246	Considerable overall genetic alterations of PI3K/AKT pathway in CC have emerged with PIK3CA (39%) and PTEN (13%, Table 1).	('AKT', 'Gene', (49, 52))	('CC', 'Phenotype', 'HP:0002664', (64, 66))	('PTEN', 'Gene', (102, 106))	('AKT', 'Gene', '207', (49, 52))	('genetic alterations', 'Var', (21, 40))	('PTEN', 'Gene', '5728', (102, 106))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))
73557	32333246	In particular, the mutations of PIK3CA E542K and E545K promote glycolysis and proliferation of CC in vitro and vivo.	('CC', 'Phenotype', 'HP:0002664', (95, 97))	('E542K', 'Var', (39, 44))	('E545K', 'Mutation', 'rs104886003', (49, 54))	('E545K', 'Var', (49, 54))	('proliferation', 'CPA', (78, 91))	('E542K', 'Mutation', 'rs121913273', (39, 44))	('promote', 'PosReg', (55, 62))	('glycolysis', 'MPA', (63, 73))	('glycolysis', 'biological_process', 'GO:0006096', ('63', '73'))	('PIK3CA', 'Gene', (32, 38))
73559	32333246	Currently, only preclinical trials of PI3K inhibitor LY294002 has revealed it significantly radiosensitized CC cell lines in vitro and vivo, and the terminated clinical trials of AKT inhibitor GSK2141795 (NCT01958112, Table 3) has tried to display a novel treatment approach to patients of CC.	('AKT', 'Gene', (179, 182))	('men', 'Species', '9606', (261, 264))	('CC', 'Phenotype', 'HP:0002664', (290, 292))	('GSK', 'molecular_function', 'GO:0050321', ('193', '196'))	('LY294002', 'Chemical', 'MESH:C085911', (53, 61))	('radiosensitized', 'NegReg', (92, 107))	('PI3K', 'molecular_function', 'GO:0016303', ('38', '42'))	('LY294002', 'Var', (53, 61))	('CC', 'Phenotype', 'HP:0002664', (108, 110))	('AKT', 'Gene', '207', (179, 182))	('patients', 'Species', '9606', (278, 286))	('GSK2141795', 'Chemical', 'MESH:C000595149', (193, 203))
73561	32333246	Particularly, the endometrioid type of EC (EEC) progressing from intraepithelial endometrial neoplasia in a large proportion of cases belongs to ER-related cancer, and is directly associated with inactivation of PTEN.	('EC', 'Phenotype', 'HP:0012114', (44, 46))	('endometrioid type', 'Disease', (18, 35))	('inactivation', 'Var', (196, 208))	('EC', 'Gene', '1913', (44, 46))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('neoplasia', 'Phenotype', 'HP:0002664', (93, 102))	('EEC', 'Gene', (43, 46))	('associated', 'Reg', (180, 190))	('PTEN', 'Gene', '5728', (212, 216))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('EEC', 'Gene', '1913', (43, 46))	('PTEN', 'Gene', (212, 216))	('EC', 'Phenotype', 'HP:0012114', (39, 41))	('EC', 'Gene', '1913', (39, 41))	('endometrial neoplasia', 'Disease', 'MESH:D014591', (81, 102))	('endometrial neoplasia', 'Disease', (81, 102))
73563	32333246	What's more, it's revealed that the majority of the G3 EEC samples have exhibited PIK3CA mutations (39%) and PTEN mutations (67%).	('EEC', 'Gene', '1913', (55, 58))	('PIK3CA', 'Gene', (82, 88))	('mutations', 'Var', (114, 123))	('PTEN', 'Gene', (109, 113))	('EC', 'Phenotype', 'HP:0012114', (56, 58))	('PTEN', 'Gene', '5728', (109, 113))	('mutations', 'Var', (89, 98))	('EEC', 'Gene', (55, 58))
73564	32333246	Moreover, JQ1, NEDD4, PDCD4, miR-101, -494-3p, Lnc RNA LINP1 and MEG3 have shown their aptitudes for controlling tumorigenesis, proliferation, apoptosis, invasion, progression of EC cells via PI3K/AKT pathway.	('PDCD4', 'Gene', '27250', (22, 27))	('AKT', 'Gene', (197, 200))	('proliferation', 'CPA', (128, 141))	('miR-101', 'Var', (29, 36))	('apoptosis', 'CPA', (143, 152))	('LINP1', 'Gene', '108570035', (55, 60))	('RNA', 'cellular_component', 'GO:0005562', ('51', '54'))	('MEG3', 'Gene', '55384', (65, 69))	('EC', 'Gene', '1913', (179, 181))	('invasion', 'CPA', (154, 162))	('NEDD4', 'Gene', (15, 20))	('PI3K', 'molecular_function', 'GO:0016303', ('192', '196'))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('tumor', 'Disease', (113, 118))	('progression', 'CPA', (164, 175))	('AKT', 'Gene', '207', (197, 200))	('EC', 'Phenotype', 'HP:0012114', (179, 181))	('controlling', 'PosReg', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('LINP1', 'Gene', (55, 60))	('PDCD4', 'Gene', (22, 27))	('NEDD4', 'Gene', '4734', (15, 20))	('MEG3', 'Gene', (65, 69))
73567	32333246	Seeing that loss of function of PTEN, resulting in dysregulated activation of the PI3K signaling network, is recognized as one of the most common driving events in PCa development, the overall genetic alterations of PI3K/AKT pathway in PCa have demonstrated with PIK3CA (6%), and visible PTEN (18%, Table 1).	('PI3K', 'molecular_function', 'GO:0016303', ('216', '220'))	('PI3K signaling network', 'Pathway', (82, 104))	('dysregulated', 'MPA', (51, 63))	('genetic alterations', 'Var', (193, 212))	('AKT', 'Gene', (221, 224))	('PI3K signaling', 'biological_process', 'GO:0014065', ('82', '96'))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('PTEN', 'Gene', (288, 292))	('men', 'Species', '9606', (175, 178))	('AKT', 'Gene', '207', (221, 224))	('PTEN', 'Gene', (32, 36))	('PC', 'Phenotype', 'HP:0002894', (236, 238))	('PC', 'Phenotype', 'HP:0002894', (164, 166))	('PTEN', 'Gene', '5728', (288, 292))	('activation', 'PosReg', (64, 74))	('PCa', 'Phenotype', 'HP:0012125', (236, 239))	('PTEN', 'Gene', '5728', (32, 36))	('PCa', 'Phenotype', 'HP:0012125', (164, 167))	('loss of function', 'NegReg', (12, 28))
73578	32333246	Indeed, PIK3CA mutations are considered as an early genetic alteration associated with FGFR3 mutations in superficial papillary NMIBC and the activation of the PI3K/AKT pathway is identified to induce urothelial carcinoma of the renal pelvis.	('AKT', 'Gene', (165, 168))	('mutations', 'Var', (93, 102))	('activation', 'PosReg', (142, 152))	('FGFR3', 'Gene', '2261', (87, 92))	('renal pelvis', 'Phenotype', 'HP:0000125', (229, 241))	('mutations', 'Var', (15, 24))	('induce', 'Reg', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('FGFR3', 'Gene', (87, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('AKT', 'Gene', '207', (165, 168))	('BC', 'Phenotype', 'HP:0003002', (131, 133))	('urothelial carcinoma of the renal pelvis', 'Disease', 'MESH:C538614', (201, 241))	('PI3K', 'molecular_function', 'GO:0016303', ('160', '164'))	('urothelial carcinoma of the renal pelvis', 'Disease', (201, 241))	('PIK3CA', 'Gene', (8, 14))
73592	32333246	Furthermore, differences related to EBV status or histological subtypes are observed for PI3K signaling in pediatric HL patients by using hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA), where MCCHL and EBV+ cases were less frequently affected by mutations in ITPKB and GNA13 genes.	('EBV', 'Species', '10376', (244, 247))	('ITPKB', 'Gene', (301, 306))	('PI3K', 'molecular_function', 'GO:0016303', ('89', '93'))	('CC', 'Phenotype', 'HP:0002664', (235, 237))	('HL', 'CellLine', 'CVCL:2492', (117, 119))	('HL', 'Phenotype', 'HP:0012189', (117, 119))	('GNA13', 'Gene', '10672', (311, 316))	('EBV', 'Species', '10376', (36, 39))	('ITPKB', 'Gene', '3707', (301, 306))	('HL', 'Phenotype', 'HP:0012189', (237, 239))	('CHL', 'Disease', (236, 239))	('HL', 'CellLine', 'CVCL:2492', (237, 239))	('CHL', 'Disease', 'MESH:D006689', (236, 239))	('patients', 'Species', '9606', (120, 128))	('GNA13', 'Gene', (311, 316))	('mutations', 'Var', (288, 297))	('PI3K signaling', 'biological_process', 'GO:0014065', ('89', '103'))	('DNA', 'cellular_component', 'GO:0005574', ('214', '217'))
73600	32333246	Despite the recognized fact that overwhelming majority of FL cases have the characteristic (14;18) translocation involving the IgH/bcl-2 genes, while B-cells "arrested" in germinal centers of FL acquire dozens of additional genetic aberrations that influence key pathways controlling their physiological development including B Cell Receptor (BCR) signaling, PI3K/AKT pathway, and so on.	('translocation', 'Var', (99, 112))	('AKT', 'Gene', (364, 367))	('BC', 'Phenotype', 'HP:0003002', (343, 345))	('IgH', 'Gene', '3492', (127, 130))	('IgH', 'Gene', (127, 130))	('signaling', 'biological_process', 'GO:0023052', ('346', '355'))	('bcl-2', 'molecular_function', 'GO:0015283', ('131', '136'))	('PI3K', 'molecular_function', 'GO:0016303', ('357', '361'))	('bcl-2', 'Gene', (131, 136))	('bcl-2', 'Gene', '596', (131, 136))	('men', 'Species', '9606', (311, 314))	('AKT', 'Gene', '207', (364, 367))	('influence', 'Reg', (249, 258))
73601	32333246	Especially, the facts that deletion of PIK3CD results in decreased number of marginal zone (MZ) B cells and pleural/peritoneal cavities in mice, as well as the evidences that PIK3CD-depleted B cells also fail to proliferate in vitro in response to BCR or CD40 signals and have impaired both humoral T-cell-dependent and T-cell-independent responses suggest that p110delta plays a critical role in B cell homeostasis and function.	('T-cell-independent responses', 'CPA', (320, 348))	('B cell homeostasis', 'biological_process', 'GO:0001782', ('397', '415'))	('PIK3CD', 'Gene', (39, 45))	('impaired both humoral T', 'Disease', (277, 300))	('impaired both humoral T', 'Disease', 'MESH:C562390', (277, 300))	('deletion', 'Var', (27, 35))	('mice', 'Species', '10090', (139, 143))	('BC', 'Phenotype', 'HP:0003002', (248, 250))	('CD40', 'Gene', '21939', (255, 259))	('decreased', 'NegReg', (57, 66))	('CD40', 'Gene', (255, 259))
73602	32333246	Consequently, following with the world's first selective PI3Kdelta inhibitor CAL-101 was approved by the FDA for the treatment of FL, CLL and SLL in 2014 [NCT01282424, NCT02136511], the PI3K/AKT inhibitors have shown remarkable activity in an increasing subset of patients with NHL (Tables 2, 3).	('HL', 'CellLine', 'CVCL:2492', (279, 281))	('SLL', 'Gene', (142, 145))	('AKT', 'Gene', '207', (191, 194))	('NCT02136511]', 'Var', (168, 180))	('CAL-101', 'Chemical', 'MESH:C552946', (77, 84))	('HL', 'Phenotype', 'HP:0012189', (279, 281))	('NHL', 'Disease', (278, 281))	('AKT', 'Gene', (191, 194))	('patients', 'Species', '9606', (264, 272))	('SLL', 'Gene', '347734', (142, 145))	('activity', 'MPA', (228, 236))	('PI3Kdelta', 'Gene', (57, 66))	('PI3K', 'molecular_function', 'GO:0016303', ('186', '190'))	('men', 'Species', '9606', (122, 125))	('PI3Kdelta', 'Gene', '5293', (57, 66))
73605	32333246	One study shows that deregulation of the PI3K/AKT pathway by the inactivation of PTEN are found in 55% of GCB-DLBCL cases, but only in 14% of non-GCB-DLBCL and worsens prognosis in 248 primary DLBCL patients.	('AKT', 'Gene', '207', (46, 49))	('BC', 'Phenotype', 'HP:0003002', (112, 114))	('PI3K', 'molecular_function', 'GO:0016303', ('41', '45'))	('deregulation', 'PosReg', (21, 33))	('inactivation', 'Var', (65, 77))	('BC', 'Phenotype', 'HP:0003002', (195, 197))	('AKT', 'Gene', (46, 49))	('PTEN', 'Gene', (81, 85))	('GCB-DLBCL', 'Disease', (106, 115))	('patients', 'Species', '9606', (199, 207))	('PTEN', 'Gene', '5728', (81, 85))	('BC', 'Phenotype', 'HP:0003002', (152, 154))
73608	32333246	Preclinical trial of BAY80-6946 in DLBCL cells and the clinical trials of BAY80-6946, INCB050465, CUDC-907 and MK2206 in patients with DLBCL have improved our ability to manage patients with this disorder (Table 2).	('BAY80-6946', 'Chemical', 'MESH:C000589253', (74, 84))	('INCB050465', 'Var', (86, 96))	('patients', 'Species', '9606', (177, 185))	('MK2206', 'Chemical', 'MESH:C548887', (111, 117))	('BC', 'Phenotype', 'HP:0003002', (137, 139))	('BAY80-6946', 'Var', (74, 84))	('improved', 'PosReg', (146, 154))	('BAY80-6946', 'Chemical', 'MESH:C000589253', (21, 31))	('BAY80-6946', 'Var', (21, 31))	('CUDC-907', 'Chemical', 'MESH:C576940', (98, 106))	('MK2206', 'Var', (111, 117))	('DLBCL', 'Disease', (135, 140))	('patients', 'Species', '9606', (121, 129))	('BC', 'Phenotype', 'HP:0003002', (37, 39))
73609	32333246	T/NK-NHL is a heterogeneous group of malignancies often associated with poor clinical outcomes, and each malignancy within this group is characterized by unique clinicopathologic features, while T cell receptor/NF/kB (TCR/NF/kB) signaling highly enriched and dysregulation of JAK/STAT pathway, specifically aberrant STAT3 activation, are the common feature among these lymphomas.	('STAT', 'Gene', '6774', (280, 284))	('lymphoma', 'Phenotype', 'HP:0002665', (369, 377))	('STAT', 'Gene', (280, 284))	('associated', 'Reg', (56, 66))	('dysregulation', 'Var', (259, 272))	('JAK', 'molecular_function', 'GO:0004713', ('276', '279'))	('STAT3', 'Gene', (316, 321))	('lymphomas', 'Disease', 'MESH:D008223', (369, 378))	('lymphomas', 'Phenotype', 'HP:0002665', (369, 378))	('HL', 'CellLine', 'CVCL:2492', (6, 8))	('STAT3', 'Gene', '6774', (316, 321))	('TCR', 'cellular_component', 'GO:0042101', ('218', '221'))	('aberrant', 'Var', (307, 315))	('signaling', 'biological_process', 'GO:0023052', ('229', '238'))	('malignancy', 'Disease', 'MESH:D009369', (105, 115))	('TC', 'Phenotype', 'HP:0002890', (218, 220))	('STAT', 'Gene', '6774', (316, 320))	('malignancies', 'Disease', 'MESH:D009369', (37, 49))	('TCR', 'biological_process', 'GO:0006283', ('218', '221'))	('STAT', 'Gene', (316, 320))	('HL', 'Phenotype', 'HP:0012189', (6, 8))	('malignancies', 'Disease', (37, 49))	('activation', 'PosReg', (322, 332))	('lymphomas', 'Disease', (369, 378))	('malignancy', 'Disease', (105, 115))
73610	32333246	A study with 426 adult T cell leukemia/lymphoma (ATL) cases associated with human T cell leukemia virus type-1 (HTLV-1) infection shows that PI3KCD mutation is also observed in 9 of 370 (2.4%) cases besides the highly enriched for TCR/NF/kB signaling, T cell trafficking and other T cell-related pathways.	('KC', 'Phenotype', 'HP:0009726', (144, 146))	('lymphoma', 'Phenotype', 'HP:0002665', (39, 47))	('human T cell leukemia virus type-1 (HTLV-1) infection', 'Disease', 'MESH:D015490', (76, 129))	('leukemia', 'Phenotype', 'HP:0001909', (30, 38))	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('TCR', 'cellular_component', 'GO:0042101', ('231', '234'))	('adult T cell leukemia/lymphoma', 'Disease', 'MESH:D015459', (17, 47))	('TCR', 'biological_process', 'GO:0006283', ('231', '234'))	('signaling', 'biological_process', 'GO:0023052', ('241', '250'))	('mutation', 'Var', (148, 156))	('PI3KCD mutation', 'Var', (141, 156))	('TCR/NF/kB signaling', 'Pathway', (231, 250))	('TC', 'Phenotype', 'HP:0002890', (231, 233))	('adult T cell leukemia/lymphoma', 'Disease', (17, 47))
73614	32333246	Despite that hotspot mutations of PIK3CA (E542K, E545K and H1047R) and AKT1 genes (E17K) are absent in MM, the R310C mutation of PIK3CA gene is identified in some cases of MM, as well as ROR2 drives the interaction of MM cells with TME through AKT activation.	('R310C', 'Var', (111, 116))	('E545K', 'Var', (49, 54))	('ROR2', 'Gene', '4920', (187, 191))	('ROR2', 'Gene', (187, 191))	('AKT1', 'Gene', (71, 75))	('R310C', 'Mutation', 'rs780572147', (111, 116))	('PIK3CA', 'Gene', (34, 40))	('AKT', 'Gene', '207', (71, 74))	('AKT', 'Gene', (244, 247))	('H1047R', 'Var', (59, 65))	('activation', 'PosReg', (248, 258))	('PIK3CA', 'Gene', (129, 135))	('interaction', 'Interaction', (203, 214))	('H1047R', 'Mutation', 'rs121913279', (59, 65))	('E542K', 'Mutation', 'rs121913273', (42, 47))	('E542K', 'Var', (42, 47))	('AKT', 'Gene', '207', (244, 247))	('E17K', 'Mutation', 'rs121434592', (83, 87))	('E545K', 'Mutation', 'rs104886003', (49, 54))	('AKT', 'Gene', (71, 74))	('AKT1', 'Gene', '207', (71, 75))
73615	32333246	Furthermore, only the blockade of PIK3CA is sufficient to induce cell death in a sizeable subgroup of MM samples, and PIK3CA inhibitor BYL-719 in combination treatments with other compounds establishes anti-myeloma agents resulted in strongly enhanced MM cell death.	('myeloma', 'Disease', (207, 214))	('enhanced', 'PosReg', (243, 251))	('death', 'Disease', 'MESH:D003643', (260, 265))	('blockade', 'Var', (22, 30))	('PIK3CA', 'Gene', (34, 40))	('MM cell death', 'Disease', (252, 265))	('men', 'Species', '9606', (163, 166))	('MM cell death', 'Disease', 'MESH:D003643', (252, 265))	('death', 'Disease', (260, 265))	('cell death', 'biological_process', 'GO:0008219', ('65', '75'))	('myeloma', 'Disease', 'MESH:D009101', (207, 214))	('death', 'Disease', 'MESH:D003643', (70, 75))	('death', 'Disease', (70, 75))	('PIK3CA', 'Gene', (118, 124))	('BYL-719', 'Chemical', 'MESH:C585539', (135, 142))	('cell death', 'biological_process', 'GO:0008219', ('255', '265'))
73616	32333246	Therefore, some preclinical studies have examined PI3K/AKT pathway inhibitors in MM, such as TAS-117, PI-103 and BEZ235.	('PI-103', 'Var', (102, 108))	('AKT', 'Gene', (55, 58))	('BEZ235', 'Chemical', 'MESH:C531198', (113, 119))	('PI-103', 'Chemical', 'MESH:C522973', (102, 108))	('PI3K', 'molecular_function', 'GO:0016303', ('50', '54'))	('AKT', 'Gene', '207', (55, 58))	('TAS', 'Chemical', 'MESH:D013635', (93, 96))
73617	32333246	Fortunately, some of the clinical trials of PI3K/AKT inhibitors have demonstrated encouraging clinical activity in relapsed and relapsed/refractory (R/R) MM (NCT01002248; NCT01476137; NCT00881946) (Tables 2 and 3).	('AKT', 'Gene', '207', (49, 52))	('NCT01002248', 'Var', (158, 169))	('AKT', 'Gene', (49, 52))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))
73624	32333246	Since CAL-101 has been approved for marketing in patients with CLL/SLL, the clinical trials of PI3K/AKT inhibitors such as: BAY80-6946, KM120, YY-20394, BEZ235, PKI-587, IPI-145, CAL-101, TGR-1202, MK2206 and GSK2141795 try to seek new therapeutic approach in relapse or refractory patients with CLL or newly diagnosed AML and acute lymphocytic leukemia (ALL, Tables 2 and 3).	('KM120', 'Var', (136, 141))	('AML', 'Disease', 'MESH:D015470', (319, 322))	('AML', 'Disease', (319, 322))	('CAL-101', 'Chemical', 'MESH:C552946', (179, 186))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (327, 353))	('AML', 'Phenotype', 'HP:0004808', (319, 322))	('AKT', 'Gene', (100, 103))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (327, 353))	('IPI-145', 'Chemical', 'MESH:C586691', (170, 177))	('patients', 'Species', '9606', (282, 290))	('PI3K', 'molecular_function', 'GO:0016303', ('95', '99'))	('GSK2141795', 'Chemical', 'MESH:C000595149', (209, 219))	('leukemia', 'Phenotype', 'HP:0001909', (345, 353))	('MK2206', 'Chemical', 'MESH:C548887', (198, 204))	('patients', 'Species', '9606', (49, 57))	('BAY80-6946', 'Chemical', 'MESH:C000589253', (124, 134))	('AKT', 'Gene', '207', (100, 103))	('SLL', 'Gene', '347734', (67, 70))	('CLL', 'Disease', (296, 299))	('SLL', 'Gene', (67, 70))	('acute lymphocytic leukemia', 'Disease', (327, 353))	('CAL-101', 'Chemical', 'MESH:C552946', (6, 13))	('GSK', 'molecular_function', 'GO:0050321', ('209', '212'))	('BEZ235', 'Chemical', 'MESH:C531198', (153, 159))
73628	32333246	Besides the alterations of TP53, RB1, ATRX and DLG2 in OS, total genetic alterations in the PI3K/AKT/mTOR pathway are observed in 14 of 59 (24%) OS patients, and PIK3CA and mTOR are vital for the proliferation and survival of OS cells (Table 1).	('TP53', 'Gene', '7157', (27, 31))	('AKT', 'Gene', '207', (97, 100))	('alterations', 'Reg', (73, 84))	('TP53', 'Gene', (27, 31))	('patients', 'Species', '9606', (148, 156))	('OS', 'Phenotype', 'HP:0002669', (55, 57))	('OS', 'Phenotype', 'HP:0002669', (145, 147))	('alterations', 'Var', (12, 23))	('DLG2', 'Gene', '1740', (47, 51))	('ATRX', 'Gene', (38, 42))	('AKT', 'Gene', (97, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('92', '96'))	('RB1', 'Gene', (33, 36))	('OS', 'Phenotype', 'HP:0002669', (226, 228))	('ATRX', 'Gene', '546', (38, 42))	('DLG2', 'Gene', (47, 51))	('RB1', 'Gene', '5925', (33, 36))
73629	32333246	Furthermore, dual PI3K/mTOR inhibitors are effective at inducing apoptosis in primary OS cell cultures in vitro in both human and mouse OS, while specific PI3K or mTOR inhibitors are not effective, which is consistent with the preclinical study's result that BEZ235 inhibits proliferation and tumor development of OS cells in vivo.	('human', 'Species', '9606', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('men', 'Species', '9606', (306, 309))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('OS', 'Phenotype', 'HP:0002669', (136, 138))	('PI3K', 'molecular_function', 'GO:0016303', ('155', '159'))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('inducing', 'Reg', (56, 64))	('tumor', 'Disease', (293, 298))	('apoptosis', 'CPA', (65, 74))	('PI3K', 'molecular_function', 'GO:0016303', ('18', '22'))	('BEZ235', 'Chemical', 'MESH:C531198', (259, 265))	('inhibits', 'NegReg', (266, 274))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('OS', 'Phenotype', 'HP:0002669', (86, 88))	('PI3K/mTOR', 'Var', (18, 27))	('mouse', 'Species', '10090', (130, 135))	('OS', 'Phenotype', 'HP:0002669', (314, 316))
73633	32333246	In addition, hnRNPM motifs are significantly enriched under the inhibition of the PI3K/AKT/mTOR pathway by BEZ235 in EWS cells.	('EWS', 'Phenotype', 'HP:0012254', (117, 120))	('EWS', 'Gene', '2130', (117, 120))	('EWS', 'Gene', (117, 120))	('AKT', 'Gene', (87, 90))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('BEZ235', 'Var', (107, 113))	('inhibition', 'NegReg', (64, 74))	('BEZ235', 'Chemical', 'MESH:C531198', (107, 113))	('hnRNPM', 'Gene', (13, 19))	('hnRNPM', 'Gene', '4670', (13, 19))	('AKT', 'Gene', '207', (87, 90))
73635	32333246	Currently, pediatric patients of OS or EWS may be beneficial from the ongoing clinical trials of BAY80-6946 (NCT03458728) and LY3023414 (NCT03213678, Table 2).	('BAY80-6946', 'Chemical', 'MESH:C000589253', (97, 107))	('OS', 'Phenotype', 'HP:0002669', (33, 35))	('NCT03458728', 'Var', (109, 120))	('patients', 'Species', '9606', (21, 29))	('EWS', 'Gene', '2130', (39, 42))	('EWS', 'Gene', (39, 42))	('EWS', 'Phenotype', 'HP:0012254', (39, 42))	('LY3023414', 'Chemical', 'MESH:C000621566', (126, 135))	('BAY80-6946 (NCT03458728', 'Var', (97, 120))	('LY3023414', 'Var', (126, 135))
73638	32333246	Even though solar ultraviolet exposure is the main environmental risk factor for cutaneous melanoma development, there are still genetic susceptibility factors, such as germline mutations in p16 or CDK4, and genesis of melanoma, such as the main genetic drivers BRAF, NF1 and NRAS mutations.	('men', 'Species', '9606', (107, 110))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('CDK4', 'Gene', '1019', (198, 202))	('NRAS', 'Gene', '4893', (276, 280))	('BRAF', 'Gene', (262, 266))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('NF1', 'Gene', '4763', (268, 271))	('p16', 'Gene', (191, 194))	('NF1', 'Gene', (268, 271))	('NRAS', 'Gene', (276, 280))	('CDK', 'molecular_function', 'GO:0004693', ('198', '201'))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('p16', 'Gene', '1029', (191, 194))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('melanoma', 'Disease', (219, 227))	('CDK4', 'Gene', (198, 202))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (81, 99))	('mutations', 'Var', (281, 290))	('cutaneous melanoma', 'Disease', (81, 99))	('mutations', 'Var', (178, 187))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (81, 99))	('men', 'Species', '9606', (58, 61))
73639	32333246	Since BRAFV600E-mutated melanomagenesis is often accompanied by silencing of PTEN, the increasing genetic alterations in PI3K/AKT pathway have been observed in melanoma including: PIK3CA (5%) and PTEN (12%, Table 1).	('BRAFV600E', 'Mutation', 'rs113488022', (6, 15))	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('AKT', 'Gene', (126, 129))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('PTEN', 'Gene', (77, 81))	('PTEN', 'Gene', '5728', (77, 81))	('PTEN', 'Gene', (196, 200))	('silencing', 'NegReg', (64, 73))	('AKT', 'Gene', '207', (126, 129))	('PTEN', 'Gene', '5728', (196, 200))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))	('PI3K', 'molecular_function', 'GO:0016303', ('121', '125'))	('BRAFV600E-mutated', 'Var', (6, 23))
73640	32333246	Notably, dysfunction mutations of NF1 induce BRAF inhibitor resistance by activating RAS and its downstreams including both MAPK and PI3K/AKT/mTOR pathways in cutaneous melanoma.	('activating', 'PosReg', (74, 84))	('MAPK', 'Pathway', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('AKT', 'Gene', (138, 141))	('dysfunction mutations', 'Var', (9, 30))	('cutaneous melanoma', 'Disease', (159, 177))	('RAS', 'Pathway', (85, 88))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (159, 177))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (159, 177))	('MAPK', 'molecular_function', 'GO:0004707', ('124', '128'))	('BRAF inhibitor resistance', 'MPA', (45, 70))	('PI3K', 'molecular_function', 'GO:0016303', ('133', '137'))	('NF1', 'Gene', (34, 37))	('NF1', 'Gene', '4763', (34, 37))	('AKT', 'Gene', '207', (138, 141))
73641	32333246	Even more, the onset of MEK1/2 inhibitor resistance in BRAF-mutated melanoma can be forestalled by PI3K blockade.	('MEK1', 'molecular_function', 'GO:0004708', ('24', '28'))	('PI3K', 'molecular_function', 'GO:0016303', ('99', '103'))	('MEK', 'Gene', (24, 27))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('MEK', 'Gene', '5609', (24, 27))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('BRAF-mutated', 'Var', (55, 67))
73643	32333246	And now, a limited number of clinical trials of PI3K/AKT pathway inhibitors (BKM120, PX-866, GSK2636771, GSK2141795 and MK2206) try to find new ways other than current classic RAF/MEK/MAPK pathway inhibitors to treat the patients with metastatic or advanced melanomas (Tables 2 and 3).	('patients', 'Species', '9606', (221, 229))	('melanomas', 'Disease', 'MESH:D008545', (258, 267))	('melanomas', 'Disease', (258, 267))	('PI3K', 'molecular_function', 'GO:0016303', ('48', '52'))	('MEK', 'Gene', '5609', (180, 183))	('RAF', 'Gene', (176, 179))	('PX-866', 'Chemical', 'MESH:C496788', (85, 91))	('MEK', 'Gene', (180, 183))	('AKT', 'Gene', (53, 56))	('melanomas', 'Phenotype', 'HP:0002861', (258, 267))	('GSK', 'molecular_function', 'GO:0050321', ('93', '96'))	('MK2206', 'Chemical', 'MESH:C548887', (120, 126))	('BKM120', 'Chemical', 'MESH:C571178', (77, 83))	('GSK2636771', 'Chemical', 'MESH:C000627739', (93, 103))	('GSK', 'molecular_function', 'GO:0050321', ('105', '108'))	('RAF', 'Gene', '673;109880', (176, 179))	('melanoma', 'Phenotype', 'HP:0002861', (258, 266))	('GSK2141795', 'Chemical', 'MESH:C000595149', (105, 115))	('MK2206', 'Var', (120, 126))	('metastatic', 'Disease', (235, 245))	('AKT', 'Gene', '207', (53, 56))	('GSK2141795', 'Var', (105, 115))	('MAPK', 'molecular_function', 'GO:0004707', ('184', '188'))
73644	32333246	In general, ATC, NSCLC, EC, GC, CRC, BC, OC, CC, EC and BLCA exhibit higher frequencies of PIK3CA mutations than other tumors, while PTEN mutations are predominantly found in GBM, EC and PCa (Fig.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('NSCLC', 'Disease', (17, 22))	('EC', 'Phenotype', 'HP:0012114', (24, 26))	('CC', 'Phenotype', 'HP:0002664', (45, 47))	('PCa', 'Disease', (187, 190))	('EC', 'Phenotype', 'HP:0012114', (180, 182))	('PTEN', 'Gene', '5728', (133, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('LC', 'Phenotype', 'HP:0100526', (20, 22))	('PIK3CA', 'Gene', (91, 97))	('tumors', 'Disease', (119, 125))	('GBM', 'Disease', (175, 178))	('SCLC', 'Phenotype', 'HP:0030357', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('CRC', 'Disease', (32, 35))	('TC', 'Phenotype', 'HP:0002890', (13, 15))	('EC', 'Gene', '1913', (49, 51))	('LC', 'Phenotype', 'HP:0100526', (57, 59))	('CRC', 'Phenotype', 'HP:0003003', (32, 35))	('OC', 'Phenotype', 'HP:0100615', (41, 43))	('BLCA', 'Phenotype', 'HP:0009725', (56, 60))	('BC', 'Phenotype', 'HP:0003002', (37, 39))	('PC', 'Phenotype', 'HP:0002894', (187, 189))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('EC', 'Gene', '1913', (24, 26))	('mutations', 'Var', (98, 107))	('PTEN', 'Gene', (133, 137))	('EC', 'Phenotype', 'HP:0012114', (49, 51))	('EC', 'Gene', '1913', (180, 182))	('PCa', 'Phenotype', 'HP:0012125', (187, 190))
73645	32333246	No matter what kind of the genetic alteration happens in PI3K/AKT pathway, or the factor influences cellular behaviors via PI3K/AKT pathway, it leads to the hyper-activation of PI3K/AKT pathway.	('AKT', 'Gene', (62, 65))	('influences', 'Reg', (89, 99))	('AKT', 'Gene', (128, 131))	('cellular behaviors', 'CPA', (100, 118))	('AKT', 'Gene', '207', (182, 185))	('PI3K', 'molecular_function', 'GO:0016303', ('123', '127'))	('genetic alteration', 'Var', (27, 45))	('AKT', 'Gene', '207', (62, 65))	('PI3K', 'molecular_function', 'GO:0016303', ('177', '181'))	('alteration', 'Var', (35, 45))	('PI3K', 'molecular_function', 'GO:0016303', ('57', '61'))	('AKT', 'Gene', '207', (128, 131))	('hyper-activation', 'PosReg', (157, 173))	('AKT', 'Gene', (182, 185))
73651	32333246	Obviously, CAL-101 not only causes a rapid and sustained reduction in lymphadenopathy, but also regulates the immune environment in CLL.	('immune environment', 'MPA', (110, 128))	('lymphadenopathy', 'Disease', (70, 85))	('men', 'Species', '9606', (124, 127))	('reduction', 'NegReg', (57, 66))	('CAL-101', 'Var', (11, 18))	('lymphadenopathy', 'Disease', 'MESH:D008206', (70, 85))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (70, 85))	('regulates', 'Reg', (96, 105))	('CAL-101', 'Chemical', 'MESH:C552946', (11, 18))
73654	32333246	There are some other embarrassments findings that small molecule PI3K/AKT pathway inhibitors could promote the (re)phosphorylation of AKT2 which is linked to the redistribution and adaptive reprogramming of mitochondria, contributing to drug resistance and metastasis in GBM cells.	('drug resistance', 'biological_process', 'GO:0009315', ('237', '252'))	('inhibitors', 'Var', (82, 92))	('drug resistance', 'biological_process', 'GO:0042493', ('237', '252'))	('AKT', 'Gene', (134, 137))	('drug resistance', 'CPA', (237, 252))	('AKT', 'Gene', (70, 73))	('phosphorylation', 'biological_process', 'GO:0016310', ('115', '130'))	('mitochondria', 'cellular_component', 'GO:0005739', ('207', '219'))	('small molecule', 'Var', (50, 64))	('contributing', 'Reg', (221, 233))	('AKT', 'Gene', '207', (134, 137))	('men', 'Species', '9606', (30, 33))	('AKT2', 'Gene', '208', (134, 138))	('metastasis', 'CPA', (257, 267))	('AKT', 'Gene', '207', (70, 73))	('drug resistance', 'Phenotype', 'HP:0020174', (237, 252))	('promote', 'PosReg', (99, 106))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('AKT2', 'Gene', (134, 138))
73721	32010623	PD-L1 inhibitors increase the infiltration level of CD8+ T cells, which is an effective anti-tumor immune response.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('PD-L1', 'Gene', (0, 5))	('inhibitors', 'Var', (6, 16))	('immune response', 'biological_process', 'GO:0006955', ('99', '114'))	('increase', 'PosReg', (17, 25))	('CD8', 'Gene', (52, 55))	('CD8', 'Gene', '925', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
73735	32010623	Activated T cells, effector T (Teff) cells, including CD8+ T, CD4+ Th1, CD4+ Th2, and Th17, activated DCs, and activated M1 macrophages all use aerobic glycolysis, while the immunosuppressive cell subsets, such as regulatory T (Treg) cells, myeloid-derived suppressor cells, DC resting, and naive T cells use fatty acid oxidation to supply energy.	('Th1', 'Gene', '51497', (67, 70))	('CD8', 'Gene', '925', (54, 57))	('Th1', 'Gene', (86, 89))	('fatty acid oxidation', 'MPA', (309, 329))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('309', '329'))	('CD4+ Th2', 'Var', (72, 80))	('aerobic glycolysis', 'MPA', (144, 162))	('Th1', 'Gene', (67, 70))	('glycolysis', 'biological_process', 'GO:0006096', ('152', '162'))	('Th1', 'Gene', '51497', (86, 89))	('fatty acid', 'Chemical', 'MESH:D005227', (309, 319))	('CD8', 'Gene', (54, 57))
73745	32010623	found that PI3K inhibitor /AKT inhibitor could significantly increase the infiltration of CD8+T cells in tumor tissues and significantly prolong survival time.	('CD8', 'Gene', '925', (90, 93))	('PI3K inhibitor /AKT', 'Gene', (11, 30))	('PI3K inhibitor /AKT', 'Gene', '207', (11, 30))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('inhibitor', 'Var', (31, 40))	('CD8', 'Gene', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('PI3K', 'molecular_function', 'GO:0016303', ('11', '15'))	('survival time', 'CPA', (145, 158))	('increase', 'PosReg', (61, 69))	('tumor', 'Disease', (105, 110))	('prolong', 'PosReg', (137, 144))
73766	30991713	Systematic Multiomics Analysis of Alterations in C1QBP mRNA Expression and Relevance for Clinical Outcomes in Cancers C1QBP (Complement Component 1 Q Subcomponent-Binding Protein), a multicompartmental protein, participates in various cellular processes, including mRNA splicing, ribosome biogenesis, protein synthesis in mitochondria, apoptosis, transcriptional regulation, and infection processes of viruses.	('mitochondria', 'cellular_component', 'GO:0005739', ('322', '334'))	('men', 'Species', '9606', (131, 134))	('Cancers', 'Disease', (110, 117))	('C1QBP', 'Gene', (118, 123))	('Cancers', 'Phenotype', 'HP:0002664', (110, 117))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('mRNA splicing', 'biological_process', 'GO:0000373', ('265', '278'))	('C1QBP', 'Gene', '708', (49, 54))	('mRNA splicing', 'biological_process', 'GO:0000372', ('265', '278'))	('apoptosis', 'biological_process', 'GO:0097194', ('336', '345'))	('protein synthesis', 'biological_process', 'GO:0006412', ('301', '318'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('265', '278'))	('apoptosis', 'biological_process', 'GO:0006915', ('336', '345'))	('Alterations', 'Var', (34, 45))	('regulation', 'biological_process', 'GO:0065007', ('363', '373'))	('C1QBP', 'Gene', '708', (118, 123))	('Complement Component 1 Q Subcomponent-Binding Protein', 'Gene', '708', (125, 178))	('mRNA splicing', 'biological_process', 'GO:0006371', ('265', '278'))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ribosome biogenesis', 'biological_process', 'GO:0042254', ('280', '299'))	('Cancers', 'Disease', 'MESH:D009369', (110, 117))	('mRNA splicing', 'biological_process', 'GO:0000394', ('265', '278'))	('C1QBP', 'Gene', (49, 54))	('protein', 'cellular_component', 'GO:0003675', ('301', '308'))	('participates in', 'Reg', (211, 226))	('mRNA splicing', 'biological_process', 'GO:0000374', ('265', '278'))	('ribosome', 'cellular_component', 'GO:0005840', ('280', '288'))	('men', 'Species', '9606', (195, 198))
73770	30991713	Mutations and copy number alterations in C1QBP were also analyzed using cBioPortal, and subsequently, the relationship between C1QBP expression and survival probability of cancer patients was explored using the PrognoScan database and the R2: Kaplan Meier Scanner.	('C1QBP', 'Gene', (127, 132))	('C1QBP', 'Gene', '708', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('C1QBP', 'Gene', (41, 46))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Disease', (172, 178))	('C1QBP', 'Gene', '708', (127, 132))
73788	30991713	Moreover, ectopic expression of C1QBP enhances metastasis in melanoma cells.	('C1QBP', 'Gene', '708', (32, 37))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('C1QBP', 'Gene', (32, 37))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('ectopic expression', 'Var', (10, 28))	('enhances', 'PosReg', (38, 46))
73802	30991713	Expression of C1QBP was examined by each alteration status (deep deletion, shallow deletion, diploid, gain, and amplification) and plotted.	('C1QBP', 'Gene', '708', (14, 19))	('C1QBP', 'Gene', (14, 19))	('deep deletion', 'Var', (60, 73))	('shallow deletion', 'Var', (75, 91))
73834	30991713	C1QBP expression was positively associated with the copy number alteration status, significantly (ANOVA, p < 0.0001) (Figure 2e).	('copy number alteration status', 'Var', (52, 81))	('associated', 'Interaction', (32, 42))	('expression', 'MPA', (6, 16))	('C1QBP', 'Gene', '708', (0, 5))	('C1QBP', 'Gene', (0, 5))
73845	30991713	The proportion of genetic alterations (predominantly upregulation) in the C1QBP gene in LUAD (TCGA PanCanAtlas dataset) and LUSC (TCGA Provisional dataset) was around 4% (Figure 3d).	('genetic alterations', 'Var', (18, 37))	('LUSC', 'Phenotype', 'HP:0030359', (124, 128))	('C1QBP', 'Gene', '708', (74, 79))	('C1QBP', 'Gene', (74, 79))	('upregulation', 'PosReg', (53, 65))	('LUAD', 'Phenotype', 'HP:0030078', (88, 92))
73846	30991713	C1QBP mRNA expression showed a significant positive correlation with the copy number alteration status in LUSC (analysis based on TCGA Provisional dataset) (Figure 3e).	('positive', 'PosReg', (43, 51))	('copy number alteration', 'Var', (73, 95))	('mRNA expression', 'MPA', (6, 21))	('C1QBP', 'Gene', '708', (0, 5))	('LUSC', 'Phenotype', 'HP:0030359', (106, 110))	('C1QBP', 'Gene', (0, 5))
73847	30991713	The patient group with a high expression level of C1QBP mRNA showed significantly poor overall survival compared to the low expression group, as revealed by the analysis of the jacob-00182-HLM dataset, accessed from thePrognoScan database (Figure 3f, Supplementary Table S4).	('men', 'Species', '9606', (257, 260))	('overall survival', 'CPA', (87, 103))	('high expression level', 'Var', (25, 46))	('patient', 'Species', '9606', (4, 11))	('C1QBP', 'Gene', '708', (50, 55))	('poor', 'NegReg', (82, 86))	('C1QBP', 'Gene', (50, 55))
73848	30991713	Therefore, these results suggest that C1QBP expression, owing to copy number alterations, is upregulated in lung cancer tissues, and is positively correlated with patient poor survival.	('C1QBP', 'Gene', (38, 43))	('expression', 'MPA', (44, 54))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('copy number alterations', 'Var', (65, 88))	('lung cancer', 'Disease', (108, 119))	('patient', 'Species', '9606', (163, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('upregulated', 'PosReg', (93, 104))	('C1QBP', 'Gene', '708', (38, 43))	('correlated', 'Reg', (147, 157))
73854	30991713	Alterations in the C1QBP gene (TCGA PanCanAtlas dataset) were found in COAD, mucinous adenocarcinoma of the colon and rectum (MACR), rectal adenocarcinoma (RAD), and colorectal adenocarcinoma (CA) (Figure 4c).	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (133, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('Alterations', 'Var', (0, 11))	('COAD', 'Disease', 'MESH:D029424', (71, 75))	('RAD', 'Disease', 'MESH:C535729', (156, 159))	('colorectal adenocarcinoma', 'Disease', (166, 191))	('adenocarcinoma of the colon', 'Phenotype', 'HP:0040276', (86, 113))	('C1QBP', 'Gene', (19, 24))	('RAD', 'Disease', (156, 159))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (170, 191))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (166, 191))	('COAD', 'Disease', (71, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('rectal adenocarcinoma', 'Disease', (133, 154))	('mucinous adenocarcinoma of the colon', 'Disease', (77, 113))	('mucinous adenocarcinoma of the colon', 'Disease', 'MESH:D002288', (77, 113))	('C1QBP', 'Gene', '708', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('RAD', 'biological_process', 'GO:1990116', ('156', '159'))
73856	30991713	There was a significant difference in C1QBP expression level between shallow deletions and diploid in the copy number alteration status in COAD, according to TCGA PanCanAtlas data-based analysis (Figure 4d).	('C1QBP', 'Gene', (38, 43))	('COAD', 'Disease', 'MESH:D029424', (139, 143))	('shallow deletions', 'Var', (69, 86))	('COAD', 'Disease', (139, 143))	('C1QBP', 'Gene', '708', (38, 43))
73858	30991713	These results suggest that colon cancers have significant C1QBP gene alterations related to augmented C1QBP expression, which are negatively correlated with overall survival in colon cancer patients.	('alterations', 'Var', (69, 80))	('colon cancers', 'Phenotype', 'HP:0003003', (27, 40))	('patients', 'Species', '9606', (190, 198))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('colon cancer', 'Disease', 'MESH:D015179', (27, 39))	('C1QBP', 'Gene', (102, 107))	('colon cancer', 'Phenotype', 'HP:0003003', (177, 189))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('colon cancers', 'Disease', 'MESH:D015179', (27, 40))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('men', 'Species', '9606', (95, 98))	('C1QBP', 'Gene', '708', (102, 107))	('colon cancers', 'Disease', (27, 40))	('C1QBP', 'Gene', (58, 63))	('colon cancer', 'Disease', 'MESH:D015179', (177, 189))	('augmented', 'PosReg', (92, 101))	('colon cancer', 'Phenotype', 'HP:0003003', (27, 39))	('colon cancer', 'Disease', (177, 189))	('expression', 'MPA', (108, 118))	('C1QBP', 'Gene', '708', (58, 63))
73864	30991713	The expression level of C1QBP mRNA was positively correlated with copy number alteration status from diploid and amplification (Figure 5e).	('expression level', 'MPA', (4, 20))	('C1QBP', 'Gene', (24, 29))	('copy number alteration', 'Var', (66, 88))	('correlated', 'Reg', (50, 60))	('C1QBP', 'Gene', '708', (24, 29))
73874	30991713	Lymphoma patients' group with a high expression level of C1QBP mRNA showed significantly poor overall survival compared to the low expression group (Figure 6f).	('patients', 'Species', '9606', (9, 17))	('overall survival', 'CPA', (94, 110))	('C1QBP', 'Gene', '708', (57, 62))	('C1QBP', 'Gene', (57, 62))	('poor', 'NegReg', (89, 93))	('high expression level', 'Var', (32, 53))	('Lymphoma', 'Disease', 'MESH:D008223', (0, 8))	('Lymphoma', 'Phenotype', 'HP:0002665', (0, 8))	('Lymphoma', 'Disease', (0, 8))
73892	30991713	Level of C1QBP expression was positively correlated with copy number alterations and negatively correlated with patient survival in breast, lung, colon, and bladder cancers as well as lymphoma.	('C1QBP', 'Gene', '708', (9, 14))	('bladder cancers', 'Disease', 'MESH:D001749', (157, 172))	('colon', 'Disease', (146, 151))	('bladder cancers', 'Disease', (157, 172))	('copy number alterations', 'Var', (57, 80))	('patient', 'Species', '9606', (112, 119))	('lymphoma', 'Phenotype', 'HP:0002665', (184, 192))	('breast', 'Disease', (132, 138))	('correlated', 'Reg', (41, 51))	('correlated', 'Reg', (96, 106))	('C1QBP', 'Gene', (9, 14))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('lymphoma', 'Disease', (184, 192))	('lymphoma', 'Disease', 'MESH:D008223', (184, 192))	('bladder cancers', 'Phenotype', 'HP:0009725', (157, 172))	('lung', 'Disease', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('negatively', 'NegReg', (85, 95))
73919	30032159	The effects of Rab11 perturbations on cell growth rate and invasion were analyzed by CCK8, cell cycle assay, and matrix gel invasion assay.	('matrix gel invasion', 'CPA', (113, 132))	('cell growth', 'biological_process', 'GO:0016049', ('38', '49'))	('Rab11', 'Gene', '8766', (15, 20))	('cell cycle', 'biological_process', 'GO:0007049', ('91', '101'))	('perturbations', 'Var', (21, 34))	('cell growth rate', 'CPA', (38, 54))	('Rab11', 'Gene', (15, 20))
73923	30032159	We found a significant correlation between high Rab11 expression and depth of tumor invasion (P=0.004).	('expression', 'MPA', (54, 64))	('Rab11', 'Gene', '8766', (48, 53))	('high', 'Var', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('Rab11', 'Gene', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
73924	30032159	Rab11 overexpression was observed to promote the growth rate and invasiveness of cancer cells through upregulation of MMP9, cyclin E, and cyclin D1 levels.	('cyclin', 'molecular_function', 'GO:0016538', ('138', '144'))	('cyclin', 'Gene', (138, 144))	('overexpression', 'Var', (6, 20))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('growth rate', 'CPA', (49, 60))	('MMP9', 'Gene', (118, 122))	('upregulation', 'PosReg', (102, 114))	('MMP9', 'Gene', '4318', (118, 122))	('cyclin', 'molecular_function', 'GO:0016538', ('124', '130'))	('cyclin', 'Gene', '5111', (124, 130))	('Rab11', 'Gene', '8766', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cyclin', 'Gene', '5111', (138, 144))	('cyclin D1', 'Gene', (138, 147))	('cyclin', 'Gene', (124, 130))	('Rab11', 'Gene', (0, 5))	('promote', 'PosReg', (37, 44))	('MMP9', 'molecular_function', 'GO:0004229', ('118', '122'))	('cyclin D1', 'Gene', '595', (138, 147))
73927	30032159	Our research proved that high Rab11 expression enhances cellular multiplication and invasiveness of bladder cancer, possibly by regulating the NF-kappaB signaling pathway.	('Rab11', 'Gene', (30, 35))	('NF-kappaB', 'Gene', '4790', (143, 152))	('invasiveness of bladder cancer', 'Disease', 'MESH:D001749', (84, 114))	('expression', 'Var', (36, 46))	('enhances', 'PosReg', (47, 55))	('high', 'Var', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (100, 114))	('NF-kappaB', 'Gene', (143, 152))	('invasiveness of bladder cancer', 'Disease', (84, 114))	('regulating', 'Reg', (128, 138))	('Rab11', 'Gene', '8766', (30, 35))	('cellular multiplication', 'CPA', (56, 79))	('signaling pathway', 'biological_process', 'GO:0007165', ('153', '170'))
73941	30032159	High expression of Rab11 is associated with multiple biological processes of malignant tumors, such as tumor formation, tumor progression, and poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('High', 'Var', (0, 4))	('malignant tumors', 'Disease', (77, 93))	('associated', 'Reg', (28, 38))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (87, 92))	('malignant tumors', 'Disease', 'MESH:D018198', (77, 93))	('Rab11', 'Gene', '8766', (19, 24))	('Rab11', 'Gene', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('formation', 'biological_process', 'GO:0009058', ('109', '118'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (120, 125))
73982	30032159	BIU-87 cells showed increased S phase population upon ectopic expression of Rab11.	('increased', 'PosReg', (20, 29))	('BIU-87', 'CellLine', 'CVCL:6881', (0, 6))	('Rab11', 'Gene', '8766', (76, 81))	('S phase population', 'CPA', (30, 48))	('ectopic expression', 'Var', (54, 72))	('Rab11', 'Gene', (76, 81))	('S phase', 'biological_process', 'GO:0051320', ('30', '37'))
73984	30032159	In addition, we found that Rab11 depletion decreased the protein and mRNA levels of cyclin E and cyclin D1 in T24 cells.	('Rab11', 'Gene', '8766', (27, 32))	('depletion', 'Var', (33, 42))	('cyclin D1', 'Gene', (97, 106))	('cyclin', 'Gene', (97, 103))	('cyclin', 'molecular_function', 'GO:0016538', ('84', '90'))	('cyclin', 'Gene', (84, 90))	('cyclin', 'molecular_function', 'GO:0016538', ('97', '103'))	('protein', 'MPA', (57, 64))	('Rab11', 'Gene', (27, 32))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('cyclin', 'Gene', '5111', (97, 103))	('decreased', 'NegReg', (43, 52))	('cyclin', 'Gene', '5111', (84, 90))	('cyclin D1', 'Gene', '595', (97, 106))
73991	30032159	As shown in Figure 4B, Rab11 knockdown also decreased MMP9 expression in the T24 cell line but BIU-87 cells with elevated Rab11 showed upregulated MMP9.	('MMP9', 'molecular_function', 'GO:0004229', ('54', '58'))	('MMP9', 'Gene', (147, 151))	('Rab11', 'Gene', (23, 28))	('BIU-87', 'CellLine', 'CVCL:6881', (95, 101))	('Rab11', 'Gene', (122, 127))	('knockdown', 'Var', (29, 38))	('elevated', 'PosReg', (113, 121))	('Rab11', 'Gene', '8766', (23, 28))	('MMP9', 'Gene', '4318', (54, 58))	('MMP9', 'Gene', (54, 58))	('MMP9', 'Gene', '4318', (147, 151))	('Rab11', 'Gene', '8766', (122, 127))	('MMP9', 'molecular_function', 'GO:0004229', ('147', '151'))	('decreased', 'NegReg', (44, 53))	('upregulated', 'PosReg', (135, 146))
73992	30032159	Luciferase reporter assay revealed that Rab11 overexpression enhanced functionality of NF-kappaB promoter but Rab11 knockdown decreased NF-kappaB promoter function.	('decreased', 'NegReg', (126, 135))	('Rab11', 'Gene', (40, 45))	('enhanced', 'PosReg', (61, 69))	('NF-kappaB', 'Gene', '4790', (136, 145))	('NF-kappaB', 'Gene', (136, 145))	('Rab11', 'Gene', '8766', (110, 115))	('knockdown', 'Var', (116, 125))	('NF-kappaB', 'Gene', '4790', (87, 96))	('Rab11', 'Gene', (110, 115))	('Rab11', 'Gene', '8766', (40, 45))	('NF-kappaB', 'Gene', (87, 96))	('functionality', 'MPA', (70, 83))
73993	30032159	Moreover, immunoblotting showed that Rab11 transfection increased p-IkappaB expression but the reverse was found for Rab11 depletion (Figure 5A).	('Rab11', 'Gene', '8766', (117, 122))	('transfection', 'Var', (43, 55))	('increased', 'PosReg', (56, 65))	('p-IkappaB', 'Protein', (66, 75))	('Rab11', 'Gene', (117, 122))	('expression', 'MPA', (76, 86))	('Rab11', 'Gene', '8766', (37, 42))	('Rab11', 'Gene', (37, 42))
74016	30032159	We retrospectively analyzed the correlation between high Rab11 expression and clinicopathological attributes in 159 BLCA patients.	('Rab11', 'Gene', (57, 62))	('BLCA', 'Disease', (116, 120))	('high', 'Var', (52, 56))	('Rab11', 'Gene', '8766', (57, 62))	('patients', 'Species', '9606', (121, 129))
74019	30032159	Then, we silenced Rab11 in the T24 cells (high endogenous Rab11) and transfected Rab11 plasmid to overexpress Rab11 in BIU-87 cells.	('Rab11', 'Gene', '8766', (18, 23))	('BIU-87', 'CellLine', 'CVCL:6881', (119, 125))	('Rab11', 'Gene', '8766', (58, 63))	('Rab11', 'Gene', (81, 86))	('overexpress', 'PosReg', (98, 109))	('Rab11', 'Gene', (58, 63))	('Rab11', 'Gene', '8766', (110, 115))	('Rab11', 'Gene', (18, 23))	('silenced', 'Var', (9, 17))	('Rab11', 'Gene', (110, 115))	('Rab11', 'Gene', '8766', (81, 86))
74020	30032159	CCK-8 assay proved proliferation to be significantly inhibited after Rab11 was knocked down and strongly increased upon Rab11 overexpression, which is consistent with previous studies.	('Rab11', 'Gene', '8766', (69, 74))	('inhibited', 'NegReg', (53, 62))	('Rab11', 'Gene', (120, 125))	('overexpression', 'PosReg', (126, 140))	('knocked down', 'Var', (79, 91))	('Rab11', 'Gene', (69, 74))	('proliferation', 'CPA', (19, 32))	('increased', 'PosReg', (105, 114))	('Rab11', 'Gene', '8766', (120, 125))
74022	30032159	The result indicated that Rab11 knockdown inhibited G1 to S phase transition, thereby inhibiting cell cycle progression, while Rab11 overexpression promoted cell cycle progression.	('Rab11', 'Gene', (26, 31))	('Rab11', 'Gene', '8766', (127, 132))	('cell cycle', 'biological_process', 'GO:0007049', ('157', '167'))	('S phase', 'biological_process', 'GO:0051320', ('58', '65'))	('cell cycle progression', 'CPA', (97, 119))	('knockdown', 'Var', (32, 41))	('cell cycle', 'biological_process', 'GO:0007049', ('97', '107'))	('inhibiting', 'NegReg', (86, 96))	('Rab11', 'Gene', (127, 132))	('inhibited', 'NegReg', (42, 51))	('G1 to S phase transition', 'CPA', (52, 76))	('Rab11', 'Gene', '8766', (26, 31))	('cell cycle progression', 'CPA', (157, 179))	('promoted', 'PosReg', (148, 156))
74028	30032159	Thus, our study showed that Rab11 modulates MMP9 to regulate the invasion ability of bladder cancer cells.	('bladder cancer', 'Phenotype', 'HP:0009725', (85, 99))	('modulates', 'Var', (34, 43))	('invasion ability of', 'CPA', (65, 84))	('Rab11', 'Gene', '8766', (28, 33))	('Rab11', 'Gene', (28, 33))	('bladder cancer', 'Disease', 'MESH:D001749', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('MMP9', 'molecular_function', 'GO:0004229', ('44', '48'))	('MMP9', 'Gene', (44, 48))	('bladder cancer', 'Disease', (85, 99))	('MMP9', 'Gene', '4318', (44, 48))	('regulate', 'Reg', (52, 60))
74064	33962639	Blockade of PD-L1 under hypoxia enhances myeloid-derived suppressor cells (MDSCs) regulated T cell activation and down-regulates the expression levels of IL-6 and IL-10.	('enhances', 'PosReg', (32, 40))	('PD-L1', 'Gene', (12, 17))	('IL-10', 'Gene', (163, 168))	('IL-6', 'Gene', '3569', (154, 158))	('T cell activation', 'biological_process', 'GO:0042110', ('92', '109'))	('Blockade', 'Var', (0, 8))	('IL-6', 'molecular_function', 'GO:0005138', ('154', '158'))	('hypoxia', 'Disease', 'MESH:D000860', (24, 31))	('IL-10', 'molecular_function', 'GO:0005141', ('163', '168'))	('IL-6', 'Gene', (154, 158))	('expression levels', 'MPA', (133, 150))	('IL-10', 'Gene', '3586', (163, 168))	('down-regulates', 'NegReg', (114, 128))	('hypoxia', 'Disease', (24, 31))	('myeloid-derived suppressor cells', 'CPA', (41, 73))	('T cell', 'CPA', (92, 98))
74141	33962639	High expression of solute carrier family 2 facilitated glucose transporter member 3 (SLC2A3) is closely associated with poor prognosis of papillary thyroid cancer and colorectal cancer.	('colorectal cancer', 'Disease', (167, 184))	('High', 'Var', (0, 4))	('SLC2A3', 'Gene', '6515', (85, 91))	('SLC2A3', 'Gene', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('thyroid cancer', 'Phenotype', 'HP:0002890', (148, 162))	('carrier', 'molecular_function', 'GO:0005215', ('26', '33'))	('associated', 'Reg', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('papillary thyroid cancer', 'Disease', (138, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (167, 184))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (138, 162))	('solute carrier family 2 facilitated glucose transporter member 3', 'Gene', '6515', (19, 83))	('colorectal cancer', 'Phenotype', 'HP:0003003', (167, 184))
74162	33962639	Immune checkpoints are potential targets for cancer therapy, and inhibitors that block key molecules have shown an impressive efficacy against cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('inhibitors', 'Var', (65, 75))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', (45, 51))
74326	30825026	Note that the negative value of the Spearman correlation coefficient is due to the fact that higher scores on the fatigue and pain domains from EORTC-QLQ C30 indicate a worse health state while higher values on the single-items GP1 (fatigue) and GP4 (pain) indicate better health state.	('fatigue', 'Disease', 'MESH:D005221', (114, 121))	('EORTC-QLQ C30', 'Var', (144, 157))	('GP1', 'Gene', (228, 231))	('GP4', 'Gene', '948', (246, 249))	('GP4', 'Gene', (246, 249))	('higher scores', 'PosReg', (93, 106))	('pain', 'Disease', (251, 255))	('fatigue', 'Disease', (233, 240))	('higher', 'PosReg', (194, 200))	('pain', 'Disease', (126, 130))	('fatigue', 'Phenotype', 'HP:0012378', (233, 240))	('fatigue', 'Disease', (114, 121))	('fatigue', 'Phenotype', 'HP:0012378', (114, 121))	('pain', 'Phenotype', 'HP:0012531', (251, 255))	('pain', 'Phenotype', 'HP:0012531', (126, 130))	('GP1', 'Gene', '9567', (228, 231))	('fatigue', 'Disease', 'MESH:D005221', (233, 240))	('pain', 'Disease', 'MESH:D010146', (251, 255))	('pain', 'Disease', 'MESH:D010146', (126, 130))
74358	30447837	Whole exome sequencing data analysis revealed that the main mutation signature within these tumors was derived from APOBEC mutagenesis, attributed to a family of enzymes known to contribute to cancer mutagenesis and the development of hypermutation phenotypes.	('APOBEC', 'Gene', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mutagenesis', 'biological_process', 'GO:0006280', ('123', '134'))	('APOBEC', 'cellular_component', 'GO:0030895', ('116', '122'))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('mutagenesis', 'biological_process', 'GO:0006280', ('200', '211'))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('mutagenesis', 'Var', (123, 134))	('tumors', 'Disease', (92, 98))
74359	30447837	The APOBEC family of enzymes catalyzes typical base changes within a trinucleotide context and two APOBEC-mediated mutation signatures are associated with 66% of the single nucleotide variants (SNVs) within muscle-invasive bladder cancer (MIBC).	('MIBC', 'Disease', 'MESH:D001749', (239, 243))	('invasive bladder', 'Phenotype', 'HP:0100645', (214, 230))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (207, 237))	('muscle-invasive bladder cancer', 'Disease', (207, 237))	('single nucleotide variants', 'Var', (166, 192))	('bladder cancer', 'Phenotype', 'HP:0009725', (223, 237))	('MIBC', 'Disease', (239, 243))	('APOBEC', 'cellular_component', 'GO:0030895', ('99', '105'))	('associated', 'Reg', (139, 149))	('APOBEC', 'cellular_component', 'GO:0030895', ('4', '10'))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
74360	30447837	It was shown that the presence of APOBEC3-associated mutation signature is associated with better prognosis and improved 5-year overall survival in patients with MIBC in the updated TCGA cohort.	('better', 'PosReg', (91, 97))	('patients', 'Species', '9606', (148, 156))	('MIBC', 'Disease', (162, 166))	('APOBEC3-associated', 'Gene', (34, 52))	('MIBC', 'Disease', 'MESH:D001749', (162, 166))	('APOBEC', 'cellular_component', 'GO:0030895', ('34', '40'))	('presence', 'Var', (22, 30))	('improved', 'PosReg', (112, 120))
74361	30447837	A second mutational signature associated with ERCC2 mutations is thought to cause approximately 20% of all SNVs.	('mutations', 'Var', (52, 61))	('ERCC2', 'Gene', '2068', (46, 51))	('ERCC2', 'Gene', (46, 51))	('cause', 'Reg', (76, 81))	('SNVs', 'Disease', (107, 111))
74363	30447837	Mutations in ERCC2, as well as other genes involved in DNA damage response and repair, were shown to be associated with improved response to cisplatin based chemotherapy as well as immune checkpoint blockade and radiation therapy for advanced bladder cancer.	('improved', 'PosReg', (120, 128))	('ERCC2', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('bladder cancer', 'Phenotype', 'HP:0009725', (243, 257))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('DNA damage response', 'biological_process', 'GO:0006974', ('55', '74'))	('response', 'MPA', (129, 137))	('response to cisplatin', 'biological_process', 'GO:0072718', ('129', '150'))	('Mutations', 'Var', (0, 9))	('bladder cancer', 'Disease', (243, 257))	('bladder cancer', 'Disease', 'MESH:D001749', (243, 257))	('ERCC2', 'Gene', '2068', (13, 18))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))
74367	30447837	Examples include mutations in TP53 (48%), the most commonly altered gene, which were mutually exclusive with MDM2 amplifications (7%), both events resulting in dysregulation of the cell cycle.	('MDM2', 'Gene', (109, 113))	('TP53', 'Gene', (30, 34))	('resulting in', 'Reg', (147, 159))	('dysregulation', 'MPA', (160, 173))	('dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (160, 191))	('cell cycle', 'biological_process', 'GO:0007049', ('181', '191'))	('TP53', 'Gene', '7157', (30, 34))	('mutations', 'Var', (17, 26))	('MDM2', 'Gene', '4193', (109, 113))
74368	30447837	RB1 inactivating alterations were identified in 18% of tumors while CDKN2A deletions were observed in 24% of specimens.	('deletions', 'Var', (75, 84))	('RB1', 'Gene', '5925', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CDKN2A', 'Gene', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (55, 61))	('CDKN2A', 'Gene', '1029', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('inactivating alterations', 'Var', (4, 28))	('RB1', 'Gene', (0, 3))
74369	30447837	Oncogenic alterations within genes involved in cell signaling were noted, including hotspot activating FGFR3 and PIK3CA point mutations as well as FGFR3 fusions.	('fusions', 'Var', (153, 160))	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('FGFR3', 'Gene', '2261', (147, 152))	('FGFR3', 'Gene', '2261', (103, 108))	('PIK3CA', 'Gene', (113, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('103', '107'))	('point mutations', 'Var', (120, 135))	('PIK3CA', 'Gene', '5290', (113, 119))	('FGFR3', 'Gene', (147, 152))	('FGFR3', 'Gene', (103, 108))	('FGFR', 'molecular_function', 'GO:0005007', ('147', '151'))	('activating', 'PosReg', (92, 102))
74370	30447837	While bladder tumors can be grouped based upon significantly mutated genes, and this can also have therapeutic utility through the identification of potentially targetable alterations, several groups, including TCGA, have also identified RNA expression-based molecular subtypes of bladder cancer that may have both prognostic relevance and prediction for response to a variety of therapies.	('bladder tumors', 'Disease', (6, 20))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('bladder cancer', 'Disease', 'MESH:D001749', (281, 295))	('bladder cancer', 'Disease', (281, 295))	('RNA', 'cellular_component', 'GO:0005562', ('238', '241'))	('bladder tumors', 'Disease', 'MESH:D001749', (6, 20))	('mutated', 'Var', (61, 68))	('bladder tumors', 'Phenotype', 'HP:0009725', (6, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('bladder cancer', 'Phenotype', 'HP:0009725', (281, 295))	('bladder tumor', 'Phenotype', 'HP:0009725', (6, 19))
74374	30447837	FGFR3 mutations were enriched within MS1 tumors (55% vs 7% in MS2, p<0.05) and TP53 mutations were more common in MS2 tumors.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('tumors', 'Disease', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('MS1 tumors', 'Disease', (37, 47))	('TP53', 'Gene', '7157', (79, 83))	('MS2', 'Gene', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('MS2', 'Gene', '100271694', (62, 65))	('tumors', 'Disease', (118, 124))	('mutations', 'Var', (6, 15))	('MS1 tumors', 'Disease', 'MESH:D009103', (37, 47))	('mutations', 'Var', (84, 93))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('common', 'Reg', (104, 110))	('TP53', 'Gene', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('FGFR3', 'Gene', (0, 5))	('MS2', 'Gene', (114, 117))	('MS2', 'Gene', '100271694', (114, 117))	('FGFR3', 'Gene', '2261', (0, 5))
74375	30447837	Sjodahl et al subsequently expanded this analysis by performing gene expression profiling and immunohistochemical expression on a larger cohort of tumors and identified 5 discrete molecular subtypes: urobasal A characterized by KRT5 and FGFR3 overexpression and a favorable prognosis; genomically unstable, harboring TP53 mutations and ERBB2 overexpression and enriched with muscle-invasive high grade tumors; a squamous cell carcinoma-like subtype typified by squamous cell differentiation, overexpression of basal keratins, and a poor prognosis; urobasal B tumors which shared features of the other 3 subtypes; infiltrated tumors with infiltration of immunologic cells and extracellular matrix gene expression.	('ERBB2', 'Gene', '2064', (336, 341))	('tumors', 'Disease', 'MESH:D009369', (559, 565))	('KRT5', 'Gene', '3852', (228, 232))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('FGFR3', 'Gene', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (625, 630))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (412, 435))	('tumors', 'Phenotype', 'HP:0002664', (402, 408))	('FGFR3', 'Gene', '2261', (237, 242))	('TP53', 'Gene', '7157', (317, 321))	('gene expression', 'biological_process', 'GO:0010467', ('696', '711'))	('tumors', 'Phenotype', 'HP:0002664', (625, 631))	('tumor', 'Phenotype', 'HP:0002664', (402, 407))	('tumors', 'Phenotype', 'HP:0002664', (559, 565))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (412, 435))	('KRT5', 'Gene', (228, 232))	('cell differentiation', 'biological_process', 'GO:0030154', ('470', '490'))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('gene expression', 'biological_process', 'GO:0010467', ('64', '79'))	('tumors', 'Disease', (402, 408))	('mutations', 'Var', (322, 331))	('overexpression', 'PosReg', (342, 356))	('tumors', 'Disease', (625, 631))	('tumor', 'Phenotype', 'HP:0002664', (559, 564))	('carcinoma', 'Phenotype', 'HP:0030731', (426, 435))	('tumors', 'Disease', (559, 565))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('squamous cell carcinoma', 'Disease', (412, 435))	('tumors', 'Disease', (147, 153))	('ERBB2', 'Gene', (336, 341))	('tumors', 'Disease', 'MESH:D009369', (625, 631))	('tumors', 'Disease', 'MESH:D009369', (402, 408))	('TP53', 'Gene', (317, 321))	('FGFR', 'molecular_function', 'GO:0005007', ('237', '241'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('675', '695'))
74380	30447837	The luminal-papillary cluster was enriched in tumors with papillary morphology and lower stage and was enriched with FGFR3 overexpression associated with FGFR3 mutations, amplification, and FGFR3-TACC3 fusions.	('TACC3', 'Gene', '10460', (196, 201))	('mutations', 'Var', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('TACC3', 'Gene', (196, 201))	('FGFR3', 'Gene', '2261', (190, 195))	('FGFR3', 'Gene', (117, 122))	('amplification', 'Var', (171, 184))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('190', '194'))	('FGFR3', 'Gene', '2261', (117, 122))	('overexpression', 'PosReg', (123, 137))	('FGFR', 'molecular_function', 'GO:0005007', ('117', '121'))	('fusions', 'Var', (202, 209))	('tumors', 'Disease', (46, 52))	('papillary morphology', 'Phenotype', 'HP:0007482', (58, 78))	('FGFR3', 'Gene', (154, 159))	('FGFR3', 'Gene', '2261', (154, 159))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('154', '158'))	('papillary morphology', 'CPA', (58, 78))	('associated', 'Reg', (138, 148))	('FGFR3', 'Gene', (190, 195))
74386	30447837	It was also enriched in TP53 mutations, was more common in females and showed a strong immune gene signature expression as well as lymphocytic infiltrates.	('TP53', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('TP53', 'Gene', '7157', (24, 28))
74389	30447837	In only a subset of these 20 tumors were there mutations in both TP53 and RB1, which is the hallmark alteration in small cell/neuroendocrine carcinoma.	('neuroendocrine carcinoma', 'Disease', (126, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (126, 150))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mutations', 'Var', (47, 56))	('RB1', 'Gene', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (126, 150))	('RB1', 'Gene', '5925', (74, 77))
74397	30447837	At the molecular level, it has been recently shown that the presence of CDH1 truncating mutations (or less frequently CDH1 promoter hypermethylation) is the defining feature of plasmacytoid variant of bladder cancer.	('CDH1', 'Gene', (72, 76))	('truncating mutations', 'Var', (77, 97))	('presence', 'Var', (60, 68))	('variant of bladder cancer', 'Disease', (190, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('CDH1', 'Gene', (118, 122))	('CDH1', 'Gene', '999', (72, 76))	('CDH1', 'Gene', '999', (118, 122))	('bladder cancer', 'Phenotype', 'HP:0009725', (201, 215))	('variant of bladder cancer', 'Disease', 'MESH:D001749', (190, 215))
74398	30447837	Using whole exome and targeted sequencing, truncating somatic alterations in the CDH1 gene were identified in 84% of plasmacytoid carcinomas and were specific to this histologic variant (Figure 2A).	('CDH1', 'Gene', '999', (81, 85))	('truncating somatic alterations', 'Var', (43, 73))	('identified', 'Reg', (96, 106))	('plasmacytoid carcinoma', 'Disease', (117, 139))	('plasmacytoid carcinoma', 'Disease', 'MESH:D008258', (117, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('CDH1', 'Gene', (81, 85))	('carcinomas', 'Disease', (130, 140))	('carcinomas', 'Disease', 'MESH:D002277', (130, 140))
74400	30447837	Aside from CDH1 mutation, the genomic landscape of plasmacytoid carcinoma was similar to that of urothelial carcinoma, NOS with frequent mutations in chromatin modifying genes, cell cycle regulators and PI3 kinase pathway alterations, suggesting that plasmacytoid and classic urothelial carcinoma likely evolve from a shared cell of origin.	('urothelial carcinoma', 'Disease', (97, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('mutation', 'Var', (16, 24))	('CDH1', 'Gene', (11, 15))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (97, 117))	('urothelial carcinoma', 'Disease', (276, 296))	('cell cycle', 'biological_process', 'GO:0007049', ('177', '187'))	('chromatin', 'cellular_component', 'GO:0000785', ('150', '159'))	('plasmacytoid carcinoma', 'Disease', (51, 73))	('plasmacytoid', 'Disease', (251, 263))	('mutations', 'Var', (137, 146))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (276, 296))	('CDH1', 'Gene', '999', (11, 15))	('PI3', 'Gene', '5266', (203, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('plasmacytoid carcinoma', 'Disease', 'MESH:D008258', (51, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('PI3', 'Gene', (203, 206))
74402	30447837	Both histologic regions shared mutations in CDKN1A (A45fs) and PIK3C2G (S48R), implying that these were early truncal alterations occurring within a common precursor cell.	('A45fs', 'Var', (52, 57))	('CDKN1A', 'Gene', (44, 50))	('PIK3C2G', 'Gene', (63, 70))	('CDKN1A', 'Gene', '1026', (44, 50))	('A45fs', 'Mutation', 'p.A45fsX', (52, 57))	('PIK3C2G', 'Gene', '5288', (63, 70))	('S48R', 'Mutation', 'p.S48R', (72, 76))	('S48R', 'Var', (72, 76))
74403	30447837	A CDH1 Y68fs mutation, along with mutations in other genes was, however, unique to the plasmacytoid component.	('CDH1', 'Gene', '999', (2, 6))	('Y68fs', 'Mutation', 'rs786202151', (7, 12))	('CDH1', 'Gene', (2, 6))	('Y68fs', 'Var', (7, 12))
74405	30447837	By performing Clustered Regularly Interspersed Palindromic Repeat (CRISPR)/Cas9-mediated knockout of CDH1 in two CDH1 wild-type urothelial carcinoma cell lines (RT4 and MGHU4), loss of E-cadherin expression resulted in increased invasion and migratory capability of MGHU4 and RT4 cells.	('urothelial carcinoma', 'Disease', (128, 148))	('Cas', 'cellular_component', 'GO:0005650', ('75', '78'))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (128, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('expression', 'MPA', (196, 206))	('CDH1', 'Gene', (101, 105))	('loss', 'NegReg', (177, 181))	('E-cadherin', 'Gene', (185, 195))	('E-cadherin', 'Gene', '999', (185, 195))	('CDH1', 'Gene', '999', (101, 105))	('cadherin', 'molecular_function', 'GO:0008014', ('187', '195'))	('knockout', 'Var', (89, 97))	('CDH1', 'Gene', (113, 117))	('CDH1', 'Gene', '999', (113, 117))	('increased', 'PosReg', (219, 228))
74407	30447837	This work and that of others reporting common E-cadherin loss by immunohistochemistry in the majority of plasmacytoid carcinomas, indicate that E-cadherin loss, typically as a result of CDH1 mutation and less commonly as a result of CDH1 promoter methylation, is the defining molecular event of the distinct local invasion and spread patterns observed in patients with plasmacytoid carcinoma.	('E-cadherin', 'Gene', (46, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (382, 391))	('E-cadherin', 'Gene', '999', (46, 56))	('carcinomas', 'Disease', (118, 128))	('plasmacytoid carcinoma', 'Disease', (105, 127))	('cadherin', 'molecular_function', 'GO:0008014', ('48', '56'))	('loss', 'NegReg', (155, 159))	('patients', 'Species', '9606', (355, 363))	('plasmacytoid carcinoma', 'Disease', 'MESH:D008258', (105, 127))	('methylation', 'biological_process', 'GO:0032259', ('247', '258'))	('CDH1', 'Gene', '999', (186, 190))	('mutation', 'Var', (191, 199))	('CDH1', 'Gene', '999', (233, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('CDH1', 'Gene', (186, 190))	('cadherin', 'molecular_function', 'GO:0008014', ('146', '154'))	('carcinomas', 'Disease', 'MESH:D002277', (118, 128))	('E-cadherin', 'Gene', (144, 154))	('E-cadherin', 'Gene', '999', (144, 154))	('CDH1', 'Gene', (233, 237))	('plasmacytoid carcinoma', 'Disease', (369, 391))	('plasmacytoid carcinoma', 'Disease', 'MESH:D008258', (369, 391))
74408	30447837	Notably, in contrast to the germline CDH1 mutations typically seen in patients with diffuse hereditary gastric cancers and a subset of lobular breast cancer, no germline CDH1 mutations were identified in plasmacytoid urothelial carcinoma.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('breast cancer', 'Disease', (143, 156))	('mutations', 'Var', (175, 184))	('CDH1', 'Gene', '999', (37, 41))	('patients', 'Species', '9606', (70, 78))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (135, 156))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CDH1', 'Gene', (37, 41))	('CDH1', 'Gene', '999', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('CDH1', 'Gene', (170, 174))	('gastric cancers', 'Phenotype', 'HP:0012126', (103, 118))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (217, 237))	('diffuse hereditary gastric cancers', 'Disease', 'MESH:D013274', (84, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('diffuse hereditary gastric cancers', 'Disease', (84, 118))	('urothelial carcinoma', 'Disease', (217, 237))	('mutations', 'Var', (42, 51))
74409	30447837	These results indicate that somatic loss-of-function mutations in CDH1, with consequent E-cadherin loss, leads to enhanced cellular migration and invasive properties in plasmacytoid carcinoma, characterized by marked cell discohesion and single cell infiltration.	('cadherin', 'molecular_function', 'GO:0008014', ('90', '98'))	('invasive properties', 'CPA', (146, 165))	('E-cadherin', 'Gene', (88, 98))	('E-cadherin', 'Gene', '999', (88, 98))	('CDH1', 'Gene', (66, 70))	('CDH1', 'Gene', '999', (66, 70))	('mutations', 'Var', (53, 62))	('enhanced', 'PosReg', (114, 122))	('loss', 'NegReg', (99, 103))	('plasmacytoid carcinoma', 'Disease', (169, 191))	('loss-of-function', 'NegReg', (36, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('plasmacytoid carcinoma', 'Disease', 'MESH:D008258', (169, 191))	('cellular migration', 'CPA', (123, 141))
74416	30447837	It has been recently reported that mutations in known hotspots in ERBB2 are common in micropapillary carcinoma of the bladder but it is likely that the frequency of such mutations is not higher in this variant histology than it is in classic urothelial carcinoma.	('common', 'Reg', (76, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('urothelial carcinoma', 'Disease', (242, 262))	('carcinoma of the bladder', 'Disease', 'MESH:D001749', (101, 125))	('carcinoma of the bladder', 'Disease', (101, 125))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (242, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('ERBB2', 'Gene', '2064', (66, 71))	('ERBB2', 'Gene', (66, 71))	('mutations', 'Var', (35, 44))
74420	30447837	A near universal finding was the presence of co-alterations in TP53 and RB1 resulting in loss of function of both genes.	('loss of function', 'NegReg', (89, 105))	('RB1', 'Gene', (72, 75))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('co-alterations', 'Var', (45, 59))	('RB1', 'Gene', '5925', (72, 75))
74421	30447837	In one study, TP53 and RB1 alterations were detected in 90% and 87% of cases, respectively, and 80% of tumors displayed co-alterations of both genes (Figure 5).	('TP53', 'Gene', '7157', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('TP53', 'Gene', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('RB1', 'Gene', (23, 26))	('RB1', 'Gene', '5925', (23, 26))	('alterations', 'Var', (27, 38))
74422	30447837	Further, in some tumors without RB1 loss of function mutations, there was loss RB expression by immunohistochemistry, suggesting an alternative mechanism, such as epigenetic silencing, that contributed to RB loss.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('expression', 'MPA', (82, 92))	('tumors', 'Disease', (17, 23))	('RB1', 'Gene', (32, 35))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('loss', 'NegReg', (74, 78))	('mutations', 'Var', (53, 62))	('RB loss', 'Disease', (205, 212))	('RB1', 'Gene', '5925', (32, 35))	('loss of function', 'NegReg', (36, 52))	('RB loss', 'Disease', 'MESH:D012175', (205, 212))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
74424	30447837	Notable exceptions include the near absence of KDM6A truncating mutations, CDKN2A deletion and CCND1 amplifications in the bladder small cell carcinoma cohort, compared to urothelial, carcinoma where such alterations are common.	('carcinoma', 'Disease', 'MESH:D002277', (184, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('KDM6A', 'Gene', '7403', (47, 52))	('truncating', 'MPA', (53, 63))	('CDKN2A', 'Gene', (75, 81))	('bladder small', 'Phenotype', 'HP:0005343', (123, 136))	('carcinoma', 'Disease', (142, 151))	('deletion', 'Var', (82, 90))	('CDKN2A', 'Gene', '1029', (75, 81))	('bladder small cell carcinoma cohort', 'Disease', 'MESH:D018288', (123, 158))	('bladder small cell carcinoma cohort', 'Disease', (123, 158))	('carcinoma', 'Disease', (184, 193))	('CCND1', 'Gene', (95, 100))	('KDM6A', 'Gene', (47, 52))	('carcinoma', 'Disease', 'MESH:D002277', (142, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (131, 151))	('CCND1', 'Gene', '595', (95, 100))
74425	30447837	E2F3 amplification was found in both small cell and urothelial bladder tumors, while this event was rare in small cell lung cancer.	('urothelial bladder tumors', 'Disease', (52, 77))	('E2F3', 'Gene', '1871', (0, 4))	('bladder tumor', 'Phenotype', 'HP:0009725', (63, 76))	('small cell lung cancer', 'Disease', 'MESH:D055752', (108, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('amplification', 'Var', (5, 18))	('found', 'Reg', (23, 28))	('urothelial bladder tumors', 'Disease', 'MESH:D001749', (52, 77))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (108, 130))	('small cell', 'Disease', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('small cell lung cancer', 'Disease', (108, 130))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('E2F3', 'Gene', (0, 4))	('bladder tumors', 'Phenotype', 'HP:0009725', (63, 77))
74426	30447837	A high level of chromosomal instability was observed in bladder small cell carcinoma, including whole genome duplication in 72% of tumors that correlated with the presence of TP53 missense mutations, particularly those associated with biallelic silencing.	('biallelic', 'Var', (235, 244))	('TP53', 'Gene', (175, 179))	('bladder small cell carcinoma', 'Disease', 'MESH:D018288', (56, 84))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (64, 84))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('high level of chromosomal instability', 'Phenotype', 'HP:0040012', (2, 39))	('presence', 'Var', (163, 171))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('bladder small', 'Phenotype', 'HP:0005343', (56, 69))	('missense mutations', 'Var', (180, 198))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('TP53', 'Gene', '7157', (175, 179))	('bladder small cell carcinoma', 'Disease', (56, 84))
74429	30447837	It still remains unexplained; however, how small cell carcinoma develops and what molecular mechanisms underlie its development from its urothelial precursor beyond the combined RB1/TP53 alterations which are co-mutated in a subset of classic urothelial carcinoma that clearly does not display small cell/neuroendocrine differentiation.	('small cell carcinoma', 'Phenotype', 'HP:0030357', (43, 63))	('TP53', 'Gene', '7157', (182, 186))	('TP53', 'Gene', (182, 186))	('RB1', 'Gene', '5925', (178, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('alterations', 'Var', (187, 198))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (243, 263))	('urothelial carcinoma', 'Disease', (243, 263))	('small cell carcinoma', 'Disease', (43, 63))	('small cell carcinoma', 'Disease', 'MESH:D018288', (43, 63))	('RB1', 'Gene', (178, 181))
74431	30447837	Bladder cancer is genomically heterogeneous and is associated with high mutation burden Mutational signature strongly associated with APOBEC activity Different mutational signatures may be associated with different clinical outcomes Urothelial carcinoma can be grouped into distinct molecular subtypes based on expression profiles Many classification systems exist for this molecular subtyping, with significant overlap among them Some of the molecular subtypes may have predictive or prognostic significance The stability of these subtypes within the same tumor and disease states is under investigation Rare and aggressive variant of bladder cancer Discohesive and infiltrating growth Loss of E-cadherin expression due to truncating CDH1 mutations or promoter hypermethylation is pathognomonic Genomic background otherwise similar to urothelial carcinoma No association with CDH1 germline mutations Rare and aggressive variant of bladder cancer Characterized by small tight clusters of high grade tumor cells lacking true fibrovascular cores and present within lacunar spaces Strong association with ERBB2 gene amplification and HER2 overexpression Rare and aggressive variant of bladder cancer Similar to small cell carcinoma in other organs Strong association with TP53/RB1 co-alterations Genetic background similar to bladder cancer and strongly associated with APOBEC signature Aside from TP53/RB1 co-alterations, genetic background is different from lung small cell carcinoma Bladder cancer is morphologically and genomically heterogeneous Urothelial carcinoma has high mutation burden associated with variable mutational signatures and variable clinical outcomes Many molecular subtypes of urothelial carcinoma are present based on expression profiles Some variants of urothelial carcinoma can be characterized by specific genetic aberrations Most variant histologies harbor similar genetic alterations to those seen in classic urothelial carcinoma	('HER2', 'Gene', (1131, 1135))	('Bladder cancer', 'Disease', 'MESH:D001749', (1483, 1497))	('small cell carcinoma', 'Disease', (1208, 1228))	('Urothelial carcinoma', 'Disease', 'MESH:D014523', (1547, 1567))	('CDH1', 'Gene', '999', (877, 881))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (1777, 1797))	('lung small', 'Phenotype', 'HP:0002089', (1457, 1467))	('E-cadherin', 'Gene', (695, 705))	('TP53', 'Gene', '7157', (1269, 1273))	('urothelial carcinoma', 'Disease', (1777, 1797))	('ERBB2', 'Gene', (1102, 1107))	('Urothelial carcinoma', 'Disease', 'MESH:D014523', (233, 253))	('cancer', 'Phenotype', 'HP:0002664', (644, 650))	('bladder cancer', 'Phenotype', 'HP:0009725', (636, 650))	('tumor', 'Disease', 'MESH:D009369', (557, 562))	('carcinoma Bladder', 'Phenotype', 'HP:0002862', (1473, 1490))	('variant of bladder cancer', 'Disease', (921, 946))	('variant', 'Var', (1856, 1863))	('variant of bladder cancer', 'Disease', 'MESH:D001749', (625, 650))	('HER2', 'Gene', '2064', (1131, 1135))	('carcinoma', 'Phenotype', 'HP:0030731', (1473, 1482))	('lung small cell carcinoma', 'Phenotype', 'HP:0030357', (1457, 1482))	('bladder cancer', 'Disease', 'MESH:D001749', (1323, 1337))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (1462, 1482))	('variant of bladder cancer', 'Disease', 'MESH:D001749', (1171, 1196))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (1936, 1956))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (1698, 1718))	('urothelial carcinoma', 'Disease', (1936, 1956))	('tumor', 'Phenotype', 'HP:0002664', (999, 1004))	('APOBEC', 'cellular_component', 'GO:0030895', ('1367', '1373'))	('E-cadherin', 'Gene', '999', (695, 705))	('urothelial carcinoma', 'Disease', (1698, 1718))	('bladder cancer', 'Phenotype', 'HP:0009725', (1182, 1196))	('tumor', 'Disease', (557, 562))	('cancer', 'Phenotype', 'HP:0002664', (1190, 1196))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (836, 856))	('carcinoma', 'Phenotype', 'HP:0030731', (1219, 1228))	('cancer', 'Phenotype', 'HP:0002664', (1331, 1337))	('growth Loss', 'Phenotype', 'HP:0001510', (680, 691))	('bladder cancer', 'Disease', (1323, 1337))	('RB1', 'Gene', (1400, 1403))	('Urothelial carcinoma', 'Disease', (1547, 1567))	('urothelial carcinoma', 'Disease', (836, 856))	('bladder cancer', 'Phenotype', 'HP:0009725', (932, 946))	('cancer', 'Phenotype', 'HP:0002664', (940, 946))	('Urothelial carcinoma', 'Disease', (233, 253))	('Bladder cancer', 'Disease', (0, 14))	('CDH1', 'Gene', '999', (735, 739))	('variant of bladder cancer', 'Disease', (1171, 1196))	('RB1', 'Gene', '5925', (1400, 1403))	('TP53', 'Gene', (1395, 1399))	('bladder cancer', 'Disease', 'MESH:D001749', (1182, 1196))	('small cell carcinoma', 'Disease', 'MESH:D018288', (1462, 1482))	('CDH1', 'Gene', (735, 739))	('Bladder cancer', 'Disease', (1483, 1497))	('bladder cancer', 'Disease', 'MESH:D001749', (636, 650))	('RB1', 'Gene', (1274, 1277))	('lung small cell carcinoma', 'Disease', (1457, 1482))	('TP53', 'Gene', '7157', (1395, 1399))	('ERBB2', 'Gene', '2064', (1102, 1107))	('tumor', 'Disease', (999, 1004))	('variant of bladder cancer', 'Disease', (625, 650))	('RB1', 'Gene', '5925', (1274, 1277))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (1208, 1228))	('tumor', 'Disease', 'MESH:D009369', (999, 1004))	('lung small cell carcinoma', 'Disease', 'MESH:D055752', (1457, 1482))	('small cell carcinoma', 'Disease', 'MESH:D018288', (1208, 1228))	('APOBEC', 'cellular_component', 'GO:0030895', ('134', '140'))	('CDH1', 'Gene', (877, 881))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('variant of bladder cancer', 'Disease', 'MESH:D001749', (921, 946))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('genetic aberrations', 'Disease', (1831, 1850))	('carcinoma', 'Phenotype', 'HP:0030731', (847, 856))	('cadherin', 'molecular_function', 'GO:0008014', ('697', '705'))	('genetic aberrations', 'Disease', 'MESH:D030342', (1831, 1850))	('Bladder cancer', 'Phenotype', 'HP:0009725', (1483, 1497))	('carcinoma', 'Phenotype', 'HP:0030731', (1558, 1567))	('tumor', 'Phenotype', 'HP:0002664', (557, 562))	('bladder cancer', 'Disease', 'MESH:D001749', (932, 946))	('Bladder cancer', 'Disease', 'MESH:D001749', (0, 14))	('bladder cancer', 'Phenotype', 'HP:0009725', (1323, 1337))	('TP53', 'Gene', (1269, 1273))
74492	29396848	For the knockdown of COX2, COX-2 Silencer Select siRNA (Thermo Fisher Scientific) was used.	('knockdown', 'Var', (8, 17))	('COX2', 'Gene', (21, 25))	('COX-2', 'Gene', '4513', (27, 32))	('COX2', 'Gene', '5743', (21, 25))	('COX-2', 'Gene', (27, 32))
74516	29396848	As determined by the MTT assay, cell survival was significantly greater in spheroid 12M As-cells compared with spheroid 12M UE-cells, whereas re-differentiated cells were more sensitive to chemotherapy than spheroid cells (Fig 1E, left panel).	('As', 'Chemical', 'MESH:D001151', (88, 90))	('spheroid 12M As-cells', 'Var', (75, 96))	('MTT', 'Chemical', 'MESH:C070243', (21, 24))	('As', 'Chemical', 'MESH:D001151', (0, 2))	('cell survival', 'CPA', (32, 45))	('greater', 'PosReg', (64, 71))
74521	29396848	Interestingly, SOX2 knockdown lead to the downregulation of OCT4, NANOG, CD133 and CD24 (Fig.	('NANOG', 'Gene', (66, 71))	('CD24', 'Gene', (83, 87))	('CD133', 'Gene', (73, 78))	('NANOG', 'Gene', '79923', (66, 71))	('CD133', 'Gene', '8842', (73, 78))	('OCT4', 'Gene', '5460', (60, 64))	('downregulation', 'NegReg', (42, 56))	('SOX2', 'Gene', (15, 19))	('OCT4', 'Gene', (60, 64))	('CD24', 'Gene', '100133941', (83, 87))	('knockdown', 'Var', (20, 29))
74522	29396848	In addition, SOX2 knockdown significantly attenuated an anti-apoptotic ability against CDDP treatment in spheroid cells (Fig.	('knockdown', 'Var', (18, 27))	('attenuated', 'NegReg', (42, 52))	('CDDP', 'Chemical', 'MESH:D002945', (87, 91))	('anti-apoptotic ability', 'CPA', (56, 78))	('SOX2', 'Gene', (13, 17))
74538	29396848	As expected, the genetic knockdown of COX2 resulted in reduced expression of SOX2 and its related molecules, such as OCT4 and NANOG (Fig.	('OCT4', 'Gene', '5460', (117, 121))	('NANOG', 'Gene', '79923', (126, 131))	('NANOG', 'Gene', (126, 131))	('reduced', 'NegReg', (55, 62))	('OCT4', 'Gene', (117, 121))	('As', 'Chemical', 'MESH:D001151', (0, 2))	('expression', 'MPA', (63, 73))	('COX2', 'Gene', (38, 42))	('SOX2', 'Gene', (77, 81))	('COX2', 'Gene', '5743', (38, 42))	('knockdown', 'Var', (25, 34))
74540	29396848	In contrast, SOX2 knockdown attenuated PGE2-accelerated stemness properties (Fig.	('knockdown', 'Var', (18, 27))	('attenuated', 'NegReg', (28, 38))	('SOX2', 'Gene', (13, 17))	('PGE2-accelerated', 'Gene', (39, 55))	('PGE2', 'Chemical', 'MESH:D015232', (39, 43))
74609	29396848	Apoptosis is a well-recognized cell death mechanism due to cytotoxic therapies; however, apoptotic cells release COX2/PGE2 that stimulates the proliferation of surviving CSCs and ultimately accelerates tumor cell repopulation and treatment failure.	('COX2', 'Gene', (113, 117))	('accelerates', 'PosReg', (190, 201))	('apoptotic', 'Var', (89, 98))	('tumor', 'Disease', (202, 207))	('COX2', 'Gene', '5743', (113, 117))	('treatment failure', 'CPA', (230, 247))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('cell death', 'biological_process', 'GO:0008219', ('31', '41'))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('stimulates', 'PosReg', (128, 138))	('proliferation', 'CPA', (143, 156))	('PGE2', 'Chemical', 'MESH:D015232', (118, 122))
74614	29396848	Although it needs to be validated in other pre-clinical models, our findings suggest that an EGFR inhibitor combined with a COX2 inhibitor may be an effective therapeutic strategy for basal-type UCB.	('basal-type UCB', 'Disease', (184, 198))	('EGFR', 'molecular_function', 'GO:0005006', ('93', '97'))	('EGFR', 'Gene', '1956', (93, 97))	('UCB', 'Chemical', '-', (195, 198))	('EGFR', 'Gene', (93, 97))	('pre', 'molecular_function', 'GO:0003904', ('43', '46'))	('COX2', 'Gene', (124, 128))	('COX2', 'Gene', '5743', (124, 128))	('inhibitor', 'Var', (98, 107))
74629	29396848	Indeed, chronic cigarette smoke-exposed human bronchial epithelial cells are unable to form tumors in mice; however, these cells can form in vivo tumor following the introduction of a single KRAS mutation known to be involved in lung cancer initiation.	('mice', 'Species', '10090', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('form', 'Reg', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('lung cancer initiation', 'Disease', (229, 251))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('human', 'Species', '9606', (40, 45))	('KRAS', 'Gene', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (229, 240))	('lung cancer initiation', 'Disease', 'MESH:D008175', (229, 251))	('mutation', 'Var', (196, 204))	('KRAS', 'Gene', '16653', (191, 195))	('tumor', 'Disease', (92, 97))
74645	29210993	Aberrant N-Glycosylation Profile of Serum Immunoglobulins is a Diagnostic Biomarker of Urothelial Carcinomas The aim of this study to determine whether the aberrant N-glycosylated serum immunoglobulins (Igs) can be applied as a diagnostic marker of urothelial carcinoma (UC).	('urothelial carcinoma', 'Disease', 'MESH:D014526', (249, 269))	('urothelial carcinoma', 'Disease', (249, 269))	('Urothelial Carcinomas', 'Disease', 'MESH:D014526', (87, 108))	('N', 'Chemical', 'MESH:D009584', (165, 166))	('Urothelial Carcinomas', 'Disease', (87, 108))	('Carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('aberrant', 'Var', (156, 164))	('N', 'Chemical', 'MESH:D009584', (9, 10))	('Glycosylation', 'biological_process', 'GO:0070085', ('11', '24'))
74652	29210993	The dNGscore based on aberrant N-glycosylation signatures of Igs were found to be promising diagnostic biomarkers of UCs.	('aberrant', 'Var', (22, 30))	('N-glycosylation', 'MPA', (31, 46))	('UCs', 'Disease', (117, 120))	('N', 'Chemical', 'MESH:D009584', (5, 6))	('glycosylation', 'biological_process', 'GO:0070085', ('33', '46'))	('N', 'Chemical', 'MESH:D009584', (31, 32))
74666	29210993	Although differences in Ig glycosylation are mainly described in immune system-related diseases, there are several papers describing aberrant glycosylation of IgG in cancer such as prostate cancer, gastric cancer and colorectal cancer.	('gastric cancer', 'Disease', (198, 212))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('IgG', 'Protein', (159, 162))	('colorectal cancer', 'Disease', (217, 234))	('cancer', 'Disease', (190, 196))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (133, 155))	('gastric cancer', 'Disease', 'MESH:D013274', (198, 212))	('glycosylation', 'MPA', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Disease', (206, 212))	('aberrant', 'Var', (133, 141))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('colorectal cancer', 'Phenotype', 'HP:0003003', (217, 234))	('glycosylation', 'biological_process', 'GO:0070085', ('142', '155'))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('gastric cancer', 'Phenotype', 'HP:0012126', (198, 212))	('glycosylation', 'biological_process', 'GO:0070085', ('27', '40'))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('colorectal cancer', 'Disease', 'MESH:D015179', (217, 234))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('prostate cancer', 'Disease', 'MESH:D011471', (181, 196))	('prostate cancer', 'Phenotype', 'HP:0012125', (181, 196))	('prostate cancer', 'Disease', (181, 196))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
74668	29210993	Thus, in the present study, we performed N-glycomics of serum Igs fractions between healthy volunteers (HVs), prostate cancer (PC) and UCs patients to identify the UC-specific aberrant N-glycosylated Igs.	('PC', 'Phenotype', 'HP:0012125', (127, 129))	('patients', 'Species', '9606', (139, 147))	('prostate cancer', 'Disease', 'MESH:D011471', (110, 125))	('HVs', 'molecular_function', 'GO:0034003', ('104', '107'))	('N', 'Chemical', 'MESH:D009584', (185, 186))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('aberrant', 'Var', (176, 184))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('prostate cancer', 'Disease', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
74675	29210993	The asialo biantennary type N-glycans (m/z 1606 and 2074) on Igs were significantly downregulated in the UC group compared with the levels in the HV and PC groups (p = 0.0001).	('downregulated', 'NegReg', (84, 97))	('N-glycans', 'Chemical', '-', (28, 37))	('asialo biantennary type N-glycans', 'Protein', (4, 37))	('m/z 1606', 'Var', (39, 47))	('PC', 'Phenotype', 'HP:0012125', (153, 155))
74678	29210993	Especially the asialo bisecting GlcNAc with core fucosylated N-glycan (m/z 2118) on Igs was significantly upregulated in UC group (p = 0.0001) but not detectable in HV and PC groups.	('N-glycan', 'Chemical', '-', (61, 69))	('upregulated', 'PosReg', (106, 117))	('m/z 2118', 'Var', (71, 79))	('PC', 'Phenotype', 'HP:0012125', (172, 174))	('core', 'cellular_component', 'GO:0019013', ('44', '48'))	('GlcNAc', 'Chemical', 'MESH:D000117', (32, 38))
74685	29210993	At the cut-off dNGScore (-0.0955 points) for prediction of UCs, the negative predictive value (NPV) was 96.1%, which was much higher than the NPV of urine cytology (75.8%) and hematuria (89.5%).	('N', 'Chemical', 'MESH:D009584', (16, 17))	('hematuria', 'Phenotype', 'HP:0000790', (176, 185))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('-0.0955', 'Var', (25, 32))	('hematuria', 'Disease', (176, 185))	('N', 'Chemical', 'MESH:D009584', (142, 143))	('hematuria', 'Disease', 'MESH:D006417', (176, 185))	('UCs', 'Disease', (59, 62))
74689	29210993	Although these reports showed that the levels of highly branched sialylated N-glycans (m/z 2890, 3560, 3865) were increased in the sera of patients with bladder cancer, they did not identify carrier proteins of aberrant N-glycosylation.	('bladder cancer', 'Disease', 'MESH:D001749', (153, 167))	('bladder cancer', 'Disease', (153, 167))	('m/z 2890', 'Var', (87, 95))	('highly branched sialylated N-glycans', 'MPA', (49, 85))	('3560', 'Var', (97, 101))	('patients', 'Species', '9606', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('sera', 'molecular_function', 'GO:0004617', ('131', '135'))	('N-glycans', 'Chemical', '-', (76, 85))	('levels', 'MPA', (39, 45))	('increased', 'PosReg', (114, 123))	('N', 'Chemical', 'MESH:D009584', (220, 221))	('bladder cancer', 'Phenotype', 'HP:0009725', (153, 167))	('carrier', 'molecular_function', 'GO:0005215', ('191', '198'))	('N', 'Chemical', 'MESH:D009584', (76, 77))	('glycosylation', 'biological_process', 'GO:0070085', ('222', '235'))
74692	29210993	We showed that, in total, five types of N-glycans, including bisecting GlcNAc-, biantennary-type N-glycans with or without core fucose in serum Igs fractions, were associated with UC detection (Figure 1).	('bisecting', 'Var', (61, 70))	('N-glycans', 'Chemical', '-', (40, 49))	('associated', 'Reg', (164, 174))	('core', 'cellular_component', 'GO:0019013', ('123', '127'))	('N-glycans', 'Chemical', '-', (97, 106))	('GlcNAc', 'Chemical', 'MESH:D000117', (71, 77))	('biantennary-type', 'Var', (80, 96))	('fucose', 'Chemical', 'MESH:D005643', (128, 134))	('UC detection', 'Disease', (180, 192))
74694	29210993	In this study, we found asialo biantennary- (m/z 1606 and 1769) and monosialyl biantennary-typed N-glycan (m/z 2074) and monosialyl bisecting GlcNAc-typed N-glycans (m/z 2423) were significantly decreased in UC patients and upregulated only asialo bisecting GlcNAc typed N-glycan (m/z 2118) on Igs in UC patients.	('m/z 2074', 'Var', (107, 115))	('patients', 'Species', '9606', (211, 219))	('patients', 'Species', '9606', (304, 312))	('N-glycan', 'Chemical', '-', (271, 279))	('GlcNAc', 'Chemical', 'MESH:D000117', (258, 264))	('m/z 2118', 'Var', (281, 289))	('N-glycans', 'Chemical', '-', (155, 164))	('GlcNAc', 'Chemical', 'MESH:D000117', (142, 148))	('m/z 2423', 'Var', (166, 174))	('upregulated', 'PosReg', (224, 235))	('N-glycan', 'Chemical', '-', (155, 163))	('N-glycan', 'Chemical', '-', (97, 105))	('m/z 1606', 'Var', (45, 53))	('decreased', 'NegReg', (195, 204))
74697	29210993	Thus, accumulation of asialo bisecting GlcNAc typed N-glycan (m/z 2118) was more of a UTUC-specific phenomenon than that of UCB.	('accumulation', 'PosReg', (6, 18))	('men', 'Species', '9606', (105, 108))	('m/z 2118', 'Var', (62, 70))	('GlcNAc', 'Chemical', 'MESH:D000117', (39, 45))	('N-glycan', 'Chemical', '-', (52, 60))	('asialo bisecting GlcNAc typed N-glycan', 'Protein', (22, 60))
74700	29210993	On the other hand, in PC case, upregulation of monosialyl biantennary-typed N-glycan (m/z 2074) and down-regulation of monosialyl bisecting GlcNAc-typed N-glycans (m/z 2423) is observed.	('PC', 'Phenotype', 'HP:0012125', (22, 24))	('N-glycan', 'Chemical', '-', (153, 161))	('m/z 2074', 'Var', (86, 94))	('m/z 2423', 'Var', (164, 172))	('upregulation', 'PosReg', (31, 43))	('regulation', 'biological_process', 'GO:0065007', ('105', '115'))	('N-glycans', 'Chemical', '-', (153, 162))	('monosialyl bisecting GlcNAc-typed', 'MPA', (119, 152))	('N-glycan', 'Chemical', '-', (76, 84))	('down-regulation', 'NegReg', (100, 115))	('GlcNAc', 'Chemical', 'MESH:D000117', (140, 146))	('monosialyl', 'Protein', (47, 57))
74701	29210993	This suggests that monosialyl biantennary-typed N-glycan (m/z 2074) on Igs is significantly accumulated in PC patients and might be the candidate aberrant glycosylation of prostate cancer detection.	('glycosylation of prostate cancer', 'Disease', 'MESH:D011471', (155, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('prostate cancer', 'Phenotype', 'HP:0012125', (172, 187))	('monosialyl', 'Var', (19, 29))	('N-glycan', 'Chemical', '-', (48, 56))	('PC', 'Phenotype', 'HP:0012125', (107, 109))	('accumulated', 'PosReg', (92, 103))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (146, 168))	('glycosylation of prostate cancer', 'Disease', (155, 187))	('glycosylation', 'biological_process', 'GO:0070085', ('155', '168'))	('patients', 'Species', '9606', (110, 118))
74703	29210993	Thus, asialo bisecting type N-glycosylated Igs can be applied as a promising UC-specific diagnostic biomarker.	('asialo', 'Var', (6, 12))	('N', 'Chemical', 'MESH:D009584', (28, 29))	('Igs', 'Protein', (43, 46))
74704	29210993	To the best of our knowledge, this is the first report to demonstrate the clinical significance of aberrant N-glycosylated Igs as diagnostic biomarkers of UCs.	('UCs', 'Disease', (155, 158))	('Igs', 'Protein', (123, 126))	('aberrant', 'Var', (99, 107))	('N', 'Chemical', 'MESH:D009584', (108, 109))
74707	29210993	Overproduction of aberrantly glycosylated IgA1 has a key role in the development of IgA nephropathy.	('aberrantly glycosylated', 'Var', (18, 41))	('IgA1', 'Gene', '3493', (42, 46))	('men', 'Species', '9606', (76, 79))	('nephropathy', 'Disease', 'MESH:D007674', (88, 99))	('nephropathy', 'Phenotype', 'HP:0000112', (88, 99))	('nephropathy', 'Disease', (88, 99))	('IgA1', 'Gene', (42, 46))	('IgA nephropathy', 'Phenotype', 'HP:0000794', (84, 99))
74710	29210993	From these observations, aberrant glycosylated Igs appear to change their glycans because of disease-associated immunoreactions.	('change', 'Reg', (61, 67))	('glycans', 'Chemical', 'MESH:D011134', (74, 81))	('aberrant glycosylated', 'Var', (25, 46))	('glycans', 'MPA', (74, 81))
74712	29210993	In the present study, the dNGScore, combination of 5 N-glycans including biantennary and bisecting GlcNAc, clearly discriminate UC from healthy controls and prostate cancer patients with 92.8% sensitivity and 97.2% specificity.	('N', 'Chemical', 'MESH:D009584', (53, 54))	('biantennary', 'Var', (73, 84))	('prostate cancer', 'Disease', 'MESH:D011471', (157, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('patients', 'Species', '9606', (173, 181))	('bisecting', 'Var', (89, 98))	('N', 'Chemical', 'MESH:D009584', (102, 103))	('discriminate', 'Reg', (115, 127))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('prostate cancer', 'Disease', (157, 172))	('N-glycans', 'Chemical', '-', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('GlcNAc', 'Chemical', 'MESH:D000117', (99, 105))
74718	29210993	Despite these limitations, the strength of the present study was that it is the largest to assess the implications of aberrant N-glycosyleted Igs for UCs detection.	('N', 'Chemical', 'MESH:D009584', (127, 128))	('aberrant', 'Var', (118, 126))	('UCs', 'Disease', (150, 153))
74740	29210993	In conclusion, aberrant N-glycosylation profiles of Igs determined by N-glycomics may be useful as diagnostic biomarkers for identifying UC patients.	('N', 'Chemical', 'MESH:D009584', (24, 25))	('patients', 'Species', '9606', (140, 148))	('aberrant', 'Var', (15, 23))	('glycosylation', 'biological_process', 'GO:0070085', ('26', '39'))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('N-glycosylation profiles', 'MPA', (24, 48))
74752	26943042	In vitro experiments evaluating the effects of uc.8+ silencing, showed significantly decreased capacities for cancer cell invasion, migration, and proliferation.	('cancer', 'Disease', (110, 116))	('decreased', 'NegReg', (85, 94))	('rat', 'Species', '10116', (135, 138))	('rat', 'Species', '10116', (154, 157))	('men', 'Species', '9606', (15, 18))	('migration', 'CPA', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('uc.8+ silencing', 'Var', (47, 62))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('proliferation', 'CPA', (147, 160))
74753	26943042	From this, we proposed and validated a model of interaction in which uc.8+ shuttles from the nucleus to the cytoplasm of BlCa cells, interacts with microRNA (miR)-596, and cooperates in the promotion and development of BlCa.	('BlCa', 'Phenotype', 'HP:0009725', (121, 125))	('promotion', 'CPA', (190, 199))	('rat', 'Species', '10116', (177, 180))	('microRNA (miR)-596', 'Gene', '693181', (148, 166))	('interacts', 'Interaction', (133, 142))	('nucleus', 'cellular_component', 'GO:0005634', ('93', '100'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('108', '117'))	('BlCa', 'Disease', (219, 223))	('men', 'Species', '9606', (211, 214))	('development', 'CPA', (204, 215))	('microRNA (miR)-596', 'Gene', (148, 166))	('cooperates', 'Reg', (172, 182))	('uc.8+', 'Var', (69, 74))	('BlCa', 'Phenotype', 'HP:0009725', (219, 223))
74760	26943042	Researchers have described a role for ultraconserved RNAs (uc).73+A and uc.338+ as oncogenes in colorectal cancer samples, whereas other groups identified uc.388+ as an oncogene in hepatocellular carcinoma tissues.	('hepatocellular carcinoma', 'Disease', (181, 205))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (181, 205))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('uc.338+', 'Var', (72, 79))	('colorectal cancer', 'Disease', (96, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (181, 205))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
74761	26943042	Recently, researchers found uc.283+ to be highly specific for pluripotent stem cells and highly expressed in cases of glioma, one of the most untreatable cancers.	('expressed', 'Reg', (96, 105))	('glioma', 'Disease', (118, 124))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('uc.283+', 'Var', (28, 35))	('cancers', 'Disease', (154, 161))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
74766	26943042	We proposed and validated a model in which uc.8+ acts as an efficient decoy for miR-596 and plays an important regulatory role in BlCa tumorigenesis.	('BlCa', 'Disease', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('miR-596', 'Gene', '693181', (80, 87))	('uc.8+', 'Var', (43, 48))	('miR-596', 'Gene', (80, 87))	('BlCa', 'Phenotype', 'HP:0009725', (130, 134))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
74773	26943042	Particularly, expression of uc.8+, uc.78+, uc.249+, uc.282+, and uc.339+ was markedly higher in PBlCa than in NBE but was markedly lower in BlCa than in PBlCa tissues (Supplementary Figure S1A).	('BlCa', 'Phenotype', 'HP:0009725', (140, 144))	('PBlCa', 'Disease', (96, 101))	('uc.78+', 'Var', (35, 41))	('uc.339+', 'Var', (65, 72))	('BlCa', 'Phenotype', 'HP:0009725', (97, 101))	('expression', 'MPA', (14, 24))	('uc.249+', 'Var', (43, 50))	('higher', 'PosReg', (86, 92))	('lower', 'NegReg', (131, 136))	('uc.282+', 'Var', (52, 59))	('men', 'Species', '9606', (174, 177))	('BlCa', 'Phenotype', 'HP:0009725', (154, 158))	('uc.8+', 'Var', (28, 33))
74775	26943042	uc.8+ was the most upregulated ultraconserved element in PBlCa tissue samples (Figure 1D) when compared with corresponding BlCa tissue samples (3_BlCa and 3_PBlCa) obtained from 18 patients (clinical characteristics are shown in Table 1, dataset 3).	('upregulated', 'PosReg', (19, 30))	('men', 'Species', '9606', (49, 52))	('BlCa', 'Phenotype', 'HP:0009725', (146, 150))	('PBlCa', 'Disease', (57, 62))	('patients', 'Species', '9606', (181, 189))	('BlCa', 'Phenotype', 'HP:0009725', (123, 127))	('uc.8+', 'Var', (0, 5))	('BlCa', 'Phenotype', 'HP:0009725', (158, 162))	('BlCa', 'Phenotype', 'HP:0009725', (58, 62))
74776	26943042	To validate the results obtained by microarray analysis, we assayed the expression of four ultraconserved RNAs (uc.8+, uc.195+, uc.339+, and uc.217+A), by quantitative real-time polymerase chain reaction (qRT-PCR) in a subset of 22 patients and 10 normal controls randomly selected from dataset 4 (clinical characteristics are shown in Table 1).	('uc.195+', 'Var', (119, 126))	('patients', 'Species', '9606', (232, 240))	('uc.339+', 'Var', (128, 135))	('uc.8+', 'Var', (112, 117))	('uc.217+A', 'Var', (141, 149))
74780	26943042	uc.285+ is an example of T-UCR that maps to multiple transcripts of CCAR1 gene (Figure S2B).	('CCAR1', 'Gene', '55749', (68, 73))	('CCAR1', 'Gene', (68, 73))	('uc.285+', 'Var', (0, 7))
74783	26943042	We detected uc.8+ expression in most of the samples (15/18): in seven out of nine high-grade tumors and in eight out of nine low-grade tumors.	('uc.8+ expression', 'Var', (12, 28))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumors', 'Disease', (93, 99))	('detected', 'Reg', (3, 11))
74793	26943042	We next evaluated the uc.8+/CASZ1 expression ratio in BlCa cell line J82, which had higher expression of uc.8+ than BlCa cell line RT112 (Supplementary Figure S4).	('expression', 'MPA', (91, 101))	('RT112', 'CellLine', 'CVCL:1670', (131, 136))	('men', 'Species', '9606', (144, 147))	('higher', 'PosReg', (84, 90))	('J82', 'CellLine', 'CVCL:0359', (69, 72))	('uc.8+', 'Var', (105, 110))	('CASZ1', 'Gene', (28, 33))	('BlCa', 'Phenotype', 'HP:0009725', (54, 58))	('BlCa', 'Phenotype', 'HP:0009725', (116, 120))	('CASZ1', 'Gene', '54897', (28, 33))	('rat', 'Species', '10116', (45, 48))
74795	26943042	The oligonucleotides used to silence the expression of uc.8+ had no effect on the expression of the host gene CASZ1 (Figure 3C).	('uc.8+', 'Var', (55, 60))	('CASZ1', 'Gene', '54897', (110, 115))	('expression', 'MPA', (82, 92))	('oligonucleotides', 'Chemical', 'MESH:D009841', (4, 20))	('CASZ1', 'Gene', (110, 115))
74798	26943042	In humans, we observed that uc.8+ is located within intron 1 of CASZ1 near six other T-UCRs: uc.2+ and uc.3+ are located within intron 4, uc.4+ is located within intron 3, uc.5+ and uc.6+ are located within intron 2, and uc.7+ is located within intron 1 of the main transcript identified as CASZ1 (Figure 4A and 4B).	('CASZ1', 'Gene', (291, 296))	('CASZ1', 'Gene', (64, 69))	('CASZ1', 'Gene', '54897', (291, 296))	('humans', 'Species', '9606', (3, 9))	('CASZ1', 'Gene', '54897', (64, 69))	('uc.4+', 'Var', (138, 143))
74810	26943042	We performed an in vitro wound-healing assay to measure cell migration, 36 h after silencing uc.8+ (Figure 6C).	('uc.8+', 'Gene', (93, 98))	('rat', 'Species', '10116', (64, 67))	('cell migration', 'biological_process', 'GO:0016477', ('56', '70'))	('wound-healing', 'biological_process', 'GO:0042060', ('25', '38'))	('silencing', 'Var', (83, 92))
74811	26943042	Imaging of cell migration revealed that uc.8+ silencing impaired the motility of J82 cells in vitro by about 40% when compared with control siRNA-transfected cells (Figure 6D).	('motility', 'CPA', (69, 77))	('cell migration', 'biological_process', 'GO:0016477', ('11', '25'))	('uc.8+ silencing', 'Var', (40, 55))	('rat', 'Species', '10116', (19, 22))	('J82', 'CellLine', 'CVCL:0359', (81, 84))	('impaired', 'NegReg', (56, 64))
74812	26943042	Taken together, these results suggest that uc.8+ silencing suppressed the ability of BlCa cells to proliferate, migrate, and invade in vitro.	('rat', 'Species', '10116', (115, 118))	('BlCa', 'Phenotype', 'HP:0009725', (85, 89))	('invade', 'CPA', (125, 131))	('suppressed', 'NegReg', (59, 69))	('uc.8+', 'Var', (43, 48))	('rat', 'Species', '10116', (106, 109))	('migrate', 'CPA', (112, 119))
74813	26943042	By using highly stringent conditions to predict miR binding sites, we identified only two miR-binding sites:for miR-596 (Supplementary Figure S7A) and miR-381-3p (Supplementary Figure S7B):on the uc.8+ sequence.	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('men', 'Species', '9606', (169, 172))	('men', 'Species', '9606', (127, 130))	('miR-381-3p', 'Var', (151, 161))	('miR-596', 'Gene', '693181', (112, 119))	('miR-596', 'Gene', (112, 119))
74820	26943042	However, the secondary structure of uc.8+ suggests that it is more likely to form an RNA duplex with miR-596.	('RNA', 'cellular_component', 'GO:0005562', ('85', '88'))	('uc.8+', 'Var', (36, 41))	('miR-596', 'Gene', '693181', (101, 108))	('miR-596', 'Gene', (101, 108))
74834	26943042	Furthermore, uc.8+ knockdown resulted in a concomitant increase in miR-596 expression by about four fold in J82 cells (P<0.001; Figure 7C), supporting a biological correlation between the two molecules.	('increase', 'PosReg', (55, 63))	('uc.8+ knockdown', 'Var', (13, 28))	('J82', 'CellLine', 'CVCL:0359', (108, 111))	('miR-596', 'Gene', '693181', (67, 74))	('miR-596', 'Gene', (67, 74))	('expression', 'MPA', (75, 85))
74841	26943042	Expression of miR-596 was significantly increased, by 77% (P<0.001), in PNA-596-transfected J82 cells compared with the control (Figure 7D), confirming the binding of miR-596 to uc.8+.	('PNA-596-transfected', 'Gene', (72, 91))	('PNA-596-transfected', 'Var', (72, 91))	('miR-596', 'Gene', (167, 174))	('miR-596', 'Gene', '693181', (14, 21))	('miR-596', 'Gene', (14, 21))	('Expression', 'MPA', (0, 10))	('increased', 'PosReg', (40, 49))	('binding', 'molecular_function', 'GO:0005488', ('156', '163'))	('binding', 'Interaction', (156, 163))	('miR-596', 'Gene', '693181', (167, 174))	('J82', 'CellLine', 'CVCL:0359', (92, 95))
74844	26943042	The polyarginine sequence at a final concentration of 4 muM has been demonstrated to efficiently carry PNAs into the cytoplasm of many cells.	('rat', 'Species', '10116', (76, 79))	('PNAs', 'Protein', (103, 107))	('muM', 'Gene', '56925', (56, 59))	('rat', 'Species', '10116', (44, 47))	('cytoplasm', 'cellular_component', 'GO:0005737', ('117', '126'))	('carry', 'Reg', (97, 102))	('polyarginine', 'Chemical', 'MESH:C015462', (4, 16))	('muM', 'Gene', (56, 59))	('polyarginine', 'Var', (4, 16))
74850	26943042	We observed an inverse correlation between the expression of miR-596 and that of its putative target MMP9 in BlCa tissues (Figure 8B), suggesting that uc.8+ acts as a decoy for miR-596, preventing the binding to the miR targets.	('miR-596', 'Gene', (61, 68))	('MMP9', 'molecular_function', 'GO:0004229', ('101', '105'))	('preventing', 'NegReg', (186, 196))	('miR-596', 'Gene', '693181', (61, 68))	('binding', 'molecular_function', 'GO:0005488', ('201', '208'))	('MMP9', 'Gene', (101, 105))	('BlCa', 'Phenotype', 'HP:0009725', (109, 113))	('MMP9', 'Gene', '4318', (101, 105))	('miR-596', 'Gene', '693181', (177, 184))	('binding', 'Interaction', (201, 208))	('miR-596', 'Gene', (177, 184))	('uc.8+', 'Var', (151, 156))
74851	26943042	To confirm these observations, we evaluated the effect of uc.8+ silencing on MMP9 expression and observed a decrease in MMP9 expression of about 50% compared with the control (P<0.01) (Figure 8C).	('MMP9', 'molecular_function', 'GO:0004229', ('120', '124'))	('expression', 'MPA', (82, 92))	('expression', 'MPA', (125, 135))	('MMP9', 'molecular_function', 'GO:0004229', ('77', '81'))	('uc.8+ silencing', 'Var', (58, 73))	('MMP9', 'Gene', '4318', (77, 81))	('decrease', 'NegReg', (108, 116))	('MMP9', 'Gene', (77, 81))	('MMP9', 'Gene', '4318', (120, 124))	('MMP9', 'Gene', (120, 124))
74852	26943042	These results suggest that miR-596 has a tumor-suppressive effect in BlCa and that uc.8+ promotes BlCa.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('miR-596', 'Gene', '693181', (27, 34))	('BlCa', 'Disease', (98, 102))	('miR-596', 'Gene', (27, 34))	('tumor', 'Disease', (41, 46))	('promotes', 'PosReg', (89, 97))	('BlCa', 'Disease', (69, 73))	('BlCa', 'Phenotype', 'HP:0009725', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('uc.8+', 'Var', (83, 88))	('BlCa', 'Phenotype', 'HP:0009725', (69, 73))
74854	26943042	We found that the expression of uc.8+ was highly upregulated in BlCa tissues and cell lines and that the silencing of uc.8+ expression in BlCa cells, markedly reduced cell proliferation, migration, and invasion.	('rat', 'Species', '10116', (179, 182))	('BlCa', 'Phenotype', 'HP:0009725', (138, 142))	('reduced', 'NegReg', (159, 166))	('rat', 'Species', '10116', (190, 193))	('cell proliferation', 'biological_process', 'GO:0008283', ('167', '185'))	('migration', 'CPA', (187, 196))	('uc.8+', 'Gene', (118, 123))	('upregulated', 'PosReg', (49, 60))	('invasion', 'CPA', (202, 210))	('BlCa', 'Phenotype', 'HP:0009725', (64, 68))	('silencing', 'Var', (105, 114))	('uc.8+', 'Gene', (32, 37))	('cell proliferation', 'CPA', (167, 185))
74855	26943042	These findings suggest that, in normal cells, uc.8+ has a function unrelated to tumorigenesis but that its increased expression after cell transformation, promotes tumor cell growth, migration, and invasion.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('invasion', 'CPA', (198, 206))	('tumor', 'Disease', (164, 169))	('uc.8+', 'Var', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('rat', 'Species', '10116', (186, 189))	('increased', 'PosReg', (107, 116))	('migration', 'CPA', (183, 192))	('expression', 'MPA', (117, 127))	('tumor', 'Disease', (80, 85))	('promotes', 'PosReg', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cell growth', 'biological_process', 'GO:0016049', ('170', '181'))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
74861	26943042	Furthermore, our in situ hybridization findings in BlCa tissues indicated that positive spots for uc.8+ occurred mainly in the nucleus in both NBE and high-grade BlCa, whereas in low-grade BlCa, the spot signals were mainly delocalized in the cytoplasm, where uc.8+ can interact with other cytoplasmic molecules in the early stages of cancer.	('BlCa', 'Phenotype', 'HP:0009725', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('nucleus', 'cellular_component', 'GO:0005634', ('127', '134'))	('BlCa', 'Phenotype', 'HP:0009725', (162, 166))	('cytoplasm', 'cellular_component', 'GO:0005737', ('243', '252'))	('cancer', 'Disease', (335, 341))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('uc.8+', 'Var', (98, 103))	('BlCa', 'Phenotype', 'HP:0009725', (51, 55))
74869	26943042	We found that uc.8+ acts as a decoy for miR-596, inducing the upregulation of its targets, including MMP9, which supports previous findings that miR-596 is a tumor suppressor involved in regulating MMP9.	('tumor', 'Disease', (158, 163))	('inducing', 'PosReg', (49, 57))	('MMP9', 'molecular_function', 'GO:0004229', ('101', '105'))	('miR-596', 'Gene', '693181', (145, 152))	('tumor suppressor', 'biological_process', 'GO:0051726', ('158', '174'))	('MMP9', 'molecular_function', 'GO:0004229', ('198', '202'))	('MMP9', 'Gene', (101, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('158', '174'))	('miR-596', 'Gene', (145, 152))	('MMP9', 'Gene', '4318', (101, 105))	('miR-596', 'Gene', '693181', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('MMP9', 'Gene', (198, 202))	('miR-596', 'Gene', (40, 47))	('MMP9', 'Gene', '4318', (198, 202))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('uc.8+', 'Var', (14, 19))	('upregulation', 'PosReg', (62, 74))
74871	26943042	Additionally, we show that the expression of miR-596 is reduced by uc.8+, which acts like a sponge; this finding is consistent with a previous report.	('miR-596', 'Gene', '693181', (45, 52))	('miR-596', 'Gene', (45, 52))	('reduced', 'NegReg', (56, 63))	('uc.8+', 'Var', (67, 72))	('expression', 'MPA', (31, 41))
74872	26943042	Clustered T-UCRs localized in the intronic region of CASZ1 are differentially expressed in cancer cells and are members of the BlCa signature: uc.3+, uc.4+, and uc.5+ expression is downregulated and uc.8+ expression is upregulated in BlCa tissue.	('downregulated', 'NegReg', (181, 194))	('BlCa', 'Disease', (234, 238))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('upregulated', 'PosReg', (219, 230))	('uc.8+ expression', 'MPA', (199, 215))	('uc.3+', 'Var', (143, 148))	('CASZ1', 'Gene', '54897', (53, 58))	('uc.4+', 'Var', (150, 155))	('uc.5+', 'Var', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('BlCa', 'Phenotype', 'HP:0009725', (127, 131))	('BlCa', 'Phenotype', 'HP:0009725', (234, 238))	('CASZ1', 'Gene', (53, 58))
74873	26943042	In a mouse model, some of the scanned conserved regions in this locus, including uc.2+, uc.5+, and uc.8+, activate flanking genes and have been associated with gene regulation.	('regulation', 'biological_process', 'GO:0065007', ('165', '175'))	('activate', 'PosReg', (106, 114))	('associated', 'Reg', (144, 154))	('uc.2+', 'Var', (81, 86))	('flanking genes', 'MPA', (115, 129))	('uc.8+', 'Var', (99, 104))	('uc.5+', 'Var', (88, 93))	('mouse', 'Species', '10090', (5, 10))
74918	26943042	The concentration of siRNA oligonucleotideswas estimated spectrophotometrically at 90 C using the following additive molar extinction coefficients: epsilon260 (L cm-1 mol-1) T=8800, A=15400, C=7200, G=11500, and U=9900 for the natural nucleobases.	('A=15400', 'Var', (182, 189))	('C=7200', 'Var', (191, 197))	('oligonucleotides', 'Chemical', 'MESH:D009841', (27, 43))	('rat', 'Species', '10116', (11, 14))	('U=9900', 'Var', (212, 218))	('T=8800', 'Var', (174, 180))	('G=11500', 'Var', (199, 206))
74965	26943042	J82 cells (150,000 cells per well) were seeded in 6-well plates and were incubated for approximately 1 h at 37 C. After incubation, cells were transfected with PNA-596 and PNA TO-PNA1-R8 using HiPerFect Transfection Reagent, at a final concentration of 200 nM for PNA-596 and 4 muM for TO-PNA1-R8.	('PNA TO-PNA1-R8', 'Var', (172, 186))	('J82', 'CellLine', 'CVCL:0359', (0, 3))	('muM', 'Gene', '56925', (278, 281))	('rat', 'Species', '10116', (243, 246))	('muM', 'Gene', (278, 281))	('PNA-596', 'Var', (160, 167))
74971	22190004	The role of c-FLIP splice variants in urothelial tumours Deregulation of apoptosis is common in cancer and is often caused by overexpression of anti-apoptotic proteins in tumour cells.	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('tumour', 'Disease', 'MESH:D009369', (171, 177))	('tumour', 'Disease', (171, 177))	('c-FLIP', 'Gene', '8837', (12, 18))	('cancer', 'Disease', (96, 102))	('urothelial tumours', 'Disease', (38, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('urothelial tumours', 'Disease', 'MESH:D014523', (38, 56))	('c-FLIP', 'Gene', (12, 18))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('apoptosis', 'CPA', (73, 82))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('Deregulation', 'Var', (57, 69))	('tumour', 'Disease', (49, 55))	('overexpression', 'PosReg', (126, 140))
74973	22190004	Here, we addressed the question whether deregulated c-FLIP expression in urothelial carcinoma impinges on the ability of death ligands to induce apoptosis.	('deregulated', 'Var', (40, 51))	('urothelial carcinoma', 'Disease', (73, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (73, 93))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('c-FLIP', 'Gene', '8837', (52, 58))	('c-FLIP', 'Gene', (52, 58))	('impinges', 'Reg', (94, 102))
74981	22190004	Deregulation of apoptosis disturbs the balance between the proliferation and death of cells, with too much proliferation leading to tumour formation and cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('rat', 'Species', '10116', (114, 117))	('tumour', 'Disease', (132, 138))	('cancer', 'Disease', (153, 159))	('Deregulation', 'Var', (0, 12))	('apoptosis', 'CPA', (16, 25))	('rat', 'Species', '10116', (66, 69))	('formation', 'biological_process', 'GO:0009058', ('139', '148'))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('apoptosis', 'biological_process', 'GO:0006915', ('16', '25'))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('apoptosis', 'biological_process', 'GO:0097194', ('16', '25'))	('disturbs', 'Reg', (26, 34))	('leading to', 'Reg', (121, 131))
74986	22190004	Interestingly, a functional single nucleotide polymorphism (SNP) regulates whether c-FLIPS or FLIPR is produced in humans.	('humans', 'Species', '9606', (115, 121))	('single nucleotide polymorphism', 'Var', (28, 58))	('regulates', 'Reg', (65, 74))	('c-FLIPS', 'Gene', (83, 90))	('c-FLIPS', 'Gene', '8837', (83, 90))
74989	22190004	The initiator caspases 8 and 10 become activated upon dimerisation and proteolytic cleavage at the DISC, initiating a signalling cascade resulting in apoptosis.	('DISC', 'cellular_component', 'GO:0031264', ('99', '103'))	('resulting in', 'Reg', (137, 149))	('activated', 'PosReg', (39, 48))	('dimerisation', 'Var', (54, 66))	('apoptosis', 'CPA', (150, 159))	('apoptosis', 'biological_process', 'GO:0097194', ('150', '159'))	('caspases', 'Gene', (14, 22))	('apoptosis', 'biological_process', 'GO:0006915', ('150', '159'))	('caspases', 'Gene', '841', (14, 22))	('signalling cascade', 'biological_process', 'GO:0007165', ('118', '136'))	('initiating', 'Reg', (105, 115))
75021	22190004	Of note, a few tissue samples did not express c-FLIPS at all, most likely due to the presence of a functional SNP (rs10190751 A/G) in the c-FLIP gene, which determines whether c-FLIPR or FLIPS is produced.	('c-FLIP', 'Gene', '8837', (176, 182))	('c-FLIP', 'Gene', (176, 182))	('c-FLIPS', 'Gene', (46, 53))	('c-FLIP', 'Gene', '8837', (138, 144))	('c-FLIP', 'Gene', (138, 144))	('c-FLIPS', 'Gene', '8837', (46, 53))	('c-FLIPR', 'Gene', (176, 183))	('rs10190751', 'Mutation', 'rs10190751', (115, 125))	('c-FLIP', 'Gene', '8837', (46, 52))	('c-FLIP', 'Gene', (46, 52))	('c-FLIPR', 'Gene', '8837', (176, 183))	('rs10190751 A/G', 'Var', (115, 129))
75039	22190004	As it is known that all three c-FLIP splice variants can inhibit death receptor-mediated apoptosis, we investigated whether overexpression of any c-FLIP isoform could protect VMCub1 and SD cells against apoptosis.	('death receptor-mediated', 'Pathway', (65, 88))	('c-FLIP', 'Gene', '8837', (146, 152))	('c-FLIP', 'Gene', (146, 152))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('death receptor-mediated apoptosis', 'biological_process', 'GO:0008625', ('65', '98'))	('death receptor-mediated apoptosis', 'biological_process', 'GO:0097191', ('65', '98'))	('inhibit', 'NegReg', (57, 64))	('c-FLIP', 'Gene', '8837', (30, 36))	('c-FLIP', 'Gene', (30, 36))	('variants', 'Var', (44, 52))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))
75041	22190004	The generated constructs were first transiently transfected into 293T cells to verify that the respective c-FLIP variants and in addition GFP were expressed at the protein level (Figure 3b).	('rat', 'Species', '10116', (8, 11))	('293T', 'CellLine', 'CVCL:0063', (65, 69))	('c-FLIP', 'Gene', (106, 112))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('c-FLIP', 'Gene', '8837', (106, 112))	('variants', 'Var', (113, 121))
75043	22190004	Indeed, both VMCub1 (Figures 3c and d) and SD cells (Figures 3e and f) were protected by overexpression of any c-FLIP variant against CD95L-mediated apoptosis.	('variant', 'Var', (118, 125))	('c-FLIP', 'Gene', (111, 117))	('CD95L', 'Gene', '356', (134, 139))	('CD95L', 'Gene', (134, 139))	('overexpression', 'PosReg', (89, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('149', '158'))	('apoptosis', 'biological_process', 'GO:0006915', ('149', '158'))	('c-FLIP', 'Gene', '8837', (111, 117))
75048	22190004	Still, we observed more efficient shRNA knockdowns in the urothelial cell lines VMCub1 and SD than in the human T-cell line CEM.	('CEM', 'CellLine', 'CVCL:0207', (124, 127))	('knockdowns', 'Var', (40, 50))	('shRNA', 'Gene', (34, 39))	('human', 'Species', '9606', (106, 111))
75052	22190004	Moreover, SD cells with knockdown of c-FLIPL alone were highly susceptible towards CD95L-induced apoptosis, whereas SD cells with knockdown of c-FLIPS alone remained resistant (Figure 4b).	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('CD95L', 'Gene', '356', (83, 88))	('c-FLIPL', 'Gene', '8837', (37, 44))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('c-FLIPS', 'Gene', (143, 150))	('c-FLIPS', 'Gene', '8837', (143, 150))	('c-FLIPL', 'Gene', (37, 44))	('CD95L', 'Gene', (83, 88))	('knockdown', 'Var', (24, 33))	('susceptible', 'Reg', (63, 74))
75054	22190004	The effects of c-FLIPL or c-FLIPS knockdown on DNA fragmentation was paralleled by effects on caspase processing.	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('c-FLIPL', 'Gene', '8837', (15, 22))	('men', 'Species', '9606', (55, 58))	('c-FLIPS', 'Gene', (26, 33))	('effects', 'Reg', (83, 90))	('DNA', 'MPA', (47, 50))	('c-FLIPS', 'Gene', '8837', (26, 33))	('c-FLIPL', 'Gene', (15, 22))	('DNA fragmentation', 'biological_process', 'GO:0006309', ('47', '64'))	('knockdown', 'Var', (34, 43))
75059	22190004	We also investigated the effect of isoform-specific c-FLIP knockdown on TRAIL-induced apoptosis in VMCub1 and SD cells.	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('TRAIL', 'Gene', '8743', (72, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('investigated', 'Reg', (8, 20))	('TRAIL', 'Gene', (72, 77))	('knockdown', 'Var', (59, 68))	('c-FLIP', 'Gene', '8837', (52, 58))	('c-FLIP', 'Gene', (52, 58))
75081	22190004	In the SD model system, isoform-specific knockdown of c-FLIPL was sufficient to sensitise cells for apoptosis induction by death ligands.	('c-FLIPL', 'Gene', '8837', (54, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('c-FLIPL', 'Gene', (54, 61))	('sensitise', 'Reg', (80, 89))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('knockdown', 'Var', (41, 50))	('apoptosis', 'CPA', (100, 109))
75085	22190004	Our observation that c-FLIPL is downregulated in urothelial carcinoma appears counterintuitive at first as one would expect that high expression of an anti-apoptotic molecule is generally beneficial for tumour cell survival.	('downregulated', 'NegReg', (32, 45))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('urothelial carcinoma', 'Disease', (49, 69))	('high expression', 'Var', (129, 144))	('c-FLIPL', 'Gene', '8837', (21, 28))	('tumour', 'Disease', 'MESH:D009369', (203, 209))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (49, 69))	('tumour', 'Disease', (203, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('c-FLIPL', 'Gene', (21, 28))	('beneficial', 'PosReg', (188, 198))
75091	22190004	Even more complicated, c-FLIPL acquires proapoptotic function in the presence of high c-FLIPS expression.	('c-FLIPL', 'Gene', '8837', (23, 30))	('high', 'Var', (81, 85))	('c-FLIPL', 'Gene', (23, 30))	('proapoptotic function', 'MPA', (40, 61))	('expression', 'MPA', (94, 104))	('c-FLIPS', 'Gene', (86, 93))	('c-FLIPS', 'Gene', '8837', (86, 93))
75139	22190004	c-FLIP cellular FLICE inhibitory protein c-FLIPL c-FLIPlong c-FLIPR c-FLIPRaji c-FLIPS c-FLIPshort CHX cycloheximide DED death effector domain DISC death-inducing signalling complex FADD Fas-associated death domain NUC normal urothelial cells shRNA short hairpin RNA SNP single nucleotide polymorphism TNF tumour necrosis factor TNF-R1 tumour necrosis factor receptor 1 TRAIL TNF-related apoptosis-inducing ligand The authors declare no conflict of interest.	('TNF-R1', 'Gene', (329, 335))	('necrosis', 'biological_process', 'GO:0019835', ('313', '321'))	('c-FLIP', 'Gene', (49, 55))	('tumour necrosis factor', 'Gene', (336, 358))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('TRAIL', 'Gene', (370, 375))	('TNF', 'Gene', (376, 379))	('tumour', 'Phenotype', 'HP:0002664', (306, 312))	('necrosis', 'biological_process', 'GO:0001906', ('313', '321'))	('c-FLIPL', 'Gene', '8837', (41, 48))	('c-FLIPlong', 'Gene', '8837', (49, 59))	('c-FLIP', 'Gene', '8837', (60, 66))	('c-FLIPRaji', 'Gene', '8837', (68, 78))	('necrosis', 'biological_process', 'GO:0008219', ('343', '351'))	('c-FLIP', 'Gene', '8837', (68, 74))	('c-FLIP', 'Gene', (0, 6))	('c-FLIPL', 'Gene', (41, 48))	('c-FLIP', 'Gene', (79, 85))	('cycloheximide', 'Chemical', 'MESH:D003513', (103, 116))	('TNF', 'Gene', '7124', (329, 332))	('tumour necrosis factor', 'Gene', '7124', (306, 328))	('c-FLIPS', 'Gene', '8837', (79, 86))	('signalling', 'biological_process', 'GO:0023052', ('163', '173'))	('c-FLIP', 'Gene', (87, 93))	('FADD', 'Gene', (182, 186))	('FLICE', 'Gene', '841', (16, 21))	('RNA', 'cellular_component', 'GO:0005562', ('263', '266'))	('single nucleotide polymorphism', 'Var', (271, 301))	('tumour necrosis factor', 'Gene', '7124', (336, 358))	('necrosis', 'biological_process', 'GO:0070265', ('313', '321'))	('TNF', 'Gene', '7124', (376, 379))	('TNF-R1', 'Gene', '7132', (329, 335))	('apoptosis', 'biological_process', 'GO:0006915', ('388', '397'))	('c-FLIPshort', 'Gene', '8837', (87, 98))	('apoptosis', 'biological_process', 'GO:0097194', ('388', '397'))	('necrosis', 'biological_process', 'GO:0008220', ('343', '351'))	('c-FLIP', 'Gene', '8837', (41, 47))	('necrosis', 'biological_process', 'GO:0008219', ('313', '321'))	('c-FLIP', 'Gene', '8837', (49, 55))	('c-FLIPR', 'Gene', '8837', (60, 67))	('DED', 'Gene', '26574', (117, 120))	('FLICE', 'Gene', (16, 21))	('tumour', 'Phenotype', 'HP:0002664', (336, 342))	('c-FLIPR', 'Gene', '8837', (68, 75))	('TNF', 'Gene', (302, 305))	('necrosis', 'biological_process', 'GO:0070265', ('343', '351'))	('c-FLIPR', 'Gene', (60, 67))	('c-FLIPlong', 'Gene', (49, 59))	('c-FLIP', 'Gene', (60, 66))	('necrosis', 'biological_process', 'GO:0019835', ('343', '351'))	('c-FLIPR', 'Gene', (68, 75))	('ligand', 'molecular_function', 'GO:0005488', ('407', '413'))	('c-FLIP', 'Gene', (68, 74))	('TRAIL', 'Gene', '8743', (370, 375))	('c-FLIP', 'Gene', '8837', (0, 6))	('c-FLIP', 'Gene', '8837', (79, 85))	('necrosis', 'biological_process', 'GO:0001906', ('343', '351'))	('necrosis', 'biological_process', 'GO:0008220', ('313', '321'))	('c-FLIP', 'Gene', '8837', (87, 93))	('FADD', 'Gene', '8772', (182, 186))	('DISC', 'cellular_component', 'GO:0031264', ('143', '147'))	('TNF', 'Gene', '7124', (302, 305))	('c-FLIPshort', 'Gene', (87, 98))	('tumour necrosis factor', 'Gene', (306, 328))	('c-FLIPRaji', 'Gene', (68, 78))	('TNF', 'Gene', (329, 332))	('c-FLIPS', 'Gene', (79, 86))	('DED', 'Gene', (117, 120))	('death-inducing signalling complex', 'cellular_component', 'GO:0031264', ('148', '181'))	('c-FLIP', 'Gene', (41, 47))
75140	17579624	Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation The purpose of this study was to investigate the accumulation of genetic alterations during metachronous and/or synchronous development of multifocal low-grade superficial urothelial tumours in the same patient, by using array-based comparative genomic hybridisation (array-CGH) and FGFR mutation analysis.	('urothelial cancers', 'Disease', 'MESH:D014523', (43, 61))	('mutation analysis', 'Var', (399, 416))	('tumour', 'Phenotype', 'HP:0002664', (294, 300))	('urothelial tumours', 'Disease', 'MESH:D014523', (283, 301))	('tumours', 'Phenotype', 'HP:0002664', (294, 301))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('urothelial cancers', 'Disease', (43, 61))	('FGFR', 'Gene', (394, 398))	('urothelial tumours', 'Disease', (283, 301))	('FGFR', 'molecular_function', 'GO:0005007', ('394', '398'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('patient', 'Species', '9606', (314, 321))
75146	17579624	In some cases, FGFR mutation seemed to occur later during multifocal tumour development.	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('mutation', 'Var', (20, 28))	('multifocal tumour', 'Disease', (58, 75))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('multifocal tumour', 'Disease', 'None', (58, 75))	('FGFR', 'Gene', (15, 19))
75147	17579624	Taken together, these findings suggest that low-grade superficial urothelial tumours accumulate minor genetic alterations during multifocal development, although these tumours are genetically stable.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('urothelial tumours', 'Disease', (66, 84))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumours', 'Phenotype', 'HP:0002664', (168, 175))	('tumours', 'Disease', (77, 84))	('urothelial tumours', 'Disease', 'MESH:D014523', (66, 84))	('tumours', 'Disease', 'MESH:D009369', (168, 175))	('tumours', 'Disease', (168, 175))	('genetic alterations', 'Var', (102, 121))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
75148	17579624	It is now commonly accepted that solid primary cancers, including urothelial tumours and cancer of the colon, breast, and lung, arise due to a multistep process involving the accumulation of genetic alterations (Hittelman, 2001; Almadori et al, 2004).	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('cancer of the colon', 'Disease', 'MESH:D015179', (89, 108))	('cancer of the colon', 'Disease', (89, 108))	('urothelial tumours', 'Disease', (66, 84))	('cancer of the colon', 'Phenotype', 'HP:0100273', (89, 108))	('breast', 'Disease', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('genetic alterations', 'Var', (191, 210))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('urothelial tumours', 'Disease', 'MESH:D014523', (66, 84))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
75157	17579624	An understanding of the mechanism leading to accumulation of genetic alterations during multifocal tumour development may provide new prospects for both the early detection and prevention of the recurrence of urothelial cancer.	('multifocal tumour', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('urothelial cancer', 'Disease', (209, 226))	('multifocal tumour', 'Disease', 'None', (88, 105))	('genetic alterations', 'Var', (61, 80))	('urothelial cancer', 'Disease', 'MESH:D014523', (209, 226))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('recurrence of urothelial cancer', 'Phenotype', 'HP:0000010', (195, 226))
75162	17579624	Over 70% of the low-grade superficial cancers have FGFR3 mutations versus only 10-20% of invasive cancers, strongly suggesting that activation of FGFR3 is one of the key genetic events underlying the development of low-grade superficial urothelial cancer (Wu, 2005).	('invasive cancers', 'Disease', 'MESH:D009362', (89, 105))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('urothelial cancer', 'Disease', (237, 254))	('invasive cancers', 'Disease', (89, 105))	('mutations', 'Var', (57, 66))	('cancers', 'Disease', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('FGFR3', 'Gene', (146, 151))	('FGFR', 'molecular_function', 'GO:0005007', ('146', '150'))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('FGFR3', 'Gene', '2261', (146, 151))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('FGFR3', 'Gene', (51, 56))	('cancers', 'Disease', (38, 45))	('FGFR3', 'Gene', '2261', (51, 56))	('urothelial cancer', 'Disease', 'MESH:D014523', (237, 254))
75163	17579624	Recent array-based comparative genomic hybridisation (array-CGH) and SNP array analyses have shown that DNA copy number changes are more frequent in invasive cancer than in low-grade superficial tumours (Primdahl et al, 2002; Blaveri et al, 2005).	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('frequent', 'Reg', (137, 145))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('DNA', 'Gene', (104, 107))	('invasive cancer', 'Disease', 'MESH:D009362', (149, 164))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('invasive cancer', 'Disease', (149, 164))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('tumours', 'Disease', (195, 202))	('copy number changes', 'Var', (108, 127))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
75187	17579624	Mutations of FGFR3 were identified by direct sequencing of tumour DNA.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('tumour', 'Disease', (59, 65))	('FGFR3', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('FGFR3', 'Gene', '2261', (13, 18))
75191	17579624	Copy number alterations were found in a large fraction of most tumours.	('tumours', 'Disease', (63, 70))	('found', 'Reg', (29, 34))	('Copy number alterations', 'Var', (0, 23))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
75198	17579624	Mutations of FGFR3 are strongly associated with a low tumour grade and stage, with up to 60-70% of low-grade pTa tumours showing these mutations (Billerey et al, 2001; van Rhijn et al, 2001; Jebar et al, 2005).	('pTa tumours', 'Disease', (109, 120))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('pTa', 'molecular_function', 'GO:0008959', ('109', '112'))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('low tumour', 'Disease', 'MESH:D009800', (50, 60))	('mutations', 'Var', (135, 144))	('FGFR3', 'Gene', (13, 18))	('pTa tumours', 'Disease', 'MESH:D009369', (109, 120))	('Mutations', 'Var', (0, 9))	('low tumour', 'Disease', (50, 60))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('FGFR3', 'Gene', '2261', (13, 18))
75199	17579624	Therefore, in addition to chromosomal alterations, FGFR3 mutations are used as a clonal marker.	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('FGFR3', 'Gene', (51, 56))	('mutations', 'Var', (57, 66))	('FGFR3', 'Gene', '2261', (51, 56))
75200	17579624	A total of 23 FGFR3 mutations were found in the 24 tumours (Table 1).	('FGFR3', 'Gene', '2261', (14, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('FGFR3', 'Gene', (14, 19))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('mutations', 'Var', (20, 29))	('tumours', 'Disease', (51, 58))	('found', 'Reg', (35, 40))
75201	17579624	In three patients (Patients 2, 16, and 31), all of their tumours had the S249C mutation.	('patients', 'Species', '9606', (9, 17))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('Patients', 'Species', '9606', (19, 27))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumours', 'Disease', (57, 64))	('S249C', 'Var', (73, 78))	('S249C', 'Mutation', 'rs121913483', (73, 78))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))
75202	17579624	In Patient 21, all tumours had the Y375C mutation.	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('Y375C', 'Var', (35, 40))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('Y375C', 'Mutation', 'rs121913485', (35, 40))	('Patient', 'Species', '9606', (3, 10))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
75204	17579624	In Patient 1, however, tumours 2-4 had the Y375C mutation, while tumour 1 was WT FGFR3.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('Y375C', 'Var', (43, 48))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('FGFR3', 'Gene', (81, 86))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('tumours', 'Disease', 'MESH:D009369', (23, 30))	('Y375C', 'Mutation', 'rs121913485', (43, 48))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumour', 'Disease', (23, 29))	('tumours', 'Disease', (23, 30))	('Patient', 'Species', '9606', (3, 10))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('FGFR3', 'Gene', '2261', (81, 86))	('tumour', 'Disease', (65, 71))
75205	17579624	This suggests that FGFR mutation may occur later during multifocal tumour development in some cases.	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))	('mutation', 'Var', (24, 32))	('multifocal tumour', 'Disease', (56, 73))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('FGFR', 'Gene', (19, 23))	('multifocal tumour', 'Disease', 'None', (56, 73))
75206	17579624	Based on the results obtained with respect to array-CGH and FGFR3 mutations, possible schematic pathways of the genetic alterations that occur during the development of multifocal low-grade superficial urothelial tumours are presented in Figure 3.	('mutations', 'Var', (66, 75))	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('urothelial tumours', 'Disease', (202, 220))	('FGFR3', 'Gene', (60, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('tumours', 'Phenotype', 'HP:0002664', (213, 220))	('urothelial tumours', 'Disease', 'MESH:D014523', (202, 220))	('FGFR3', 'Gene', '2261', (60, 65))
75217	17579624	A tumour with additional genetic alterations may develop earlier than a tumour without such alterations, even though both lesions are derived from the same precursor cell.	('tumour', 'Disease', 'MESH:D009369', (2, 8))	('tumour', 'Disease', (2, 8))	('develop', 'CPA', (49, 56))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (2, 8))	('tumour', 'Disease', (72, 78))	('genetic alterations', 'Var', (25, 44))
75229	17579624	When Koed et al (2005) studied at least two tumours of different stages from the same patient, they found that allelic imbalances were more common in later stage (T2-4) tumours than in earlier stage (Ta-1) tumours.	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('imbalances', 'Phenotype', 'HP:0002172', (119, 129))	('allelic imbalances', 'Var', (111, 129))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('tumours', 'Disease', (169, 176))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('tumours', 'Disease', (44, 51))	('Ta-1) tumours', 'Disease', 'MESH:D009369', (200, 213))	('patient', 'Species', '9606', (86, 93))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('tumours', 'Disease', 'MESH:D009369', (206, 213))	('common', 'Reg', (140, 146))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumours', 'Phenotype', 'HP:0002664', (169, 176))	('tumours', 'Disease', (206, 213))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('tumours', 'Disease', 'MESH:D009369', (169, 176))
75231	17579624	This was consistent with the findings of Blaveri et al (2005), who showed that low grade pTa tumours had a much lower FGA (median: 8%) than pT1 tumours (27%) or those with muscle invasion (18%).	('FGA', 'Gene', (118, 121))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('pT1', 'Gene', (140, 143))	('tumours', 'Disease', (93, 100))	('pTa tumours', 'Disease', (89, 100))	('low grade', 'Var', (79, 88))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('FGA', 'Gene', '2243', (118, 121))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('pT1', 'Gene', '58492', (140, 143))	('pTa tumours', 'Disease', 'MESH:D009369', (89, 100))	('tumours', 'Disease', 'MESH:D009369', (144, 151))	('pTa', 'molecular_function', 'GO:0008959', ('89', '92'))	('tumours', 'Disease', (144, 151))	('tumours', 'Disease', 'MESH:D009369', (93, 100))	('lower', 'NegReg', (112, 117))
75234	17579624	Furthermore, the majority of the additional genetic alterations does not affect the biological behaviour of these tumours and might not confer any survival advantage on the tumour cells.	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('tumour', 'Disease', (114, 120))	('tumour', 'Disease', (173, 179))	('tumours', 'Disease', (114, 121))	('behaviour', 'biological_process', 'GO:0007610', ('95', '104'))	('genetic alterations', 'Var', (44, 63))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('biological behaviour', 'CPA', (84, 104))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('tumour', 'Disease', 'MESH:D009369', (173, 179))
75235	17579624	Our data are consistent with the view that deletions involving chromosome 9 and mutations of FGFR3 occur early in the development of low-grade papillary urothelial tumours (Knowles, 2006).	('deletions', 'Var', (43, 52))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('papillary urothelial tumours', 'Disease', 'MESH:D000077273', (143, 171))	('mutations', 'Var', (80, 89))	('FGFR3', 'Gene', '2261', (93, 98))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('FGFR3', 'Gene', (93, 98))	('papillary urothelial tumours', 'Disease', (143, 171))
75347	33498666	Compounding this, cancer-derived 2D cell lines typically exhibit genetic drift after multiple passages.	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('genetic', 'Var', (65, 72))	('exhibit', 'Reg', (57, 64))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
75402	33498666	(2016) showed that knocking out HOTAIR in UBC cell lines resulted in reduced cell migration and invasion, demonstrating a potential therapeutic use in UBC.	('HOTAIR', 'Gene', (32, 38))	('reduced', 'NegReg', (69, 76))	('rat', 'Species', '10116', (85, 88))	('knocking out', 'Var', (19, 31))	('rat', 'Species', '10116', (113, 116))	('HOTAIR', 'Gene', '100124700', (32, 38))	('invasion', 'CPA', (96, 104))	('cell migration', 'biological_process', 'GO:0016477', ('77', '91'))	('cell migration', 'CPA', (77, 91))
75404	33498666	Indeed, using deep sequencing, exosomal DNA was found to have somatic mutations that are commonly found in UBC cells and provide insights into the genetic abnormalities of UBC tumors.	('mutations', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('genetic abnormalities of UBC tumors', 'Disease', 'MESH:D030342', (147, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('exosomal DNA', 'Gene', (31, 43))	('genetic abnormalities of UBC tumors', 'Disease', (147, 182))
75574	31420300	TAGLN was highly expressed in BLCA and correlated with advanced prognostic features.	('BLCA', 'Disease', 'MESH:D001749', (30, 34))	('correlated', 'Reg', (39, 49))	('BLCA', 'Phenotype', 'HP:0009725', (30, 34))	('TAGLN', 'Var', (0, 5))	('BLCA', 'Disease', (30, 34))
75575	31420300	TAGLN promoted cell colony formation and cell migration and invasion both in vitro and in vivo by inducing invadopodia formation and epithelial-mesenchymal transition, during which a significant correlation between TAGLN and Slug was observed.	('epithelial-mesenchymal transition', 'CPA', (133, 166))	('invasion', 'CPA', (60, 68))	('cell migration', 'CPA', (41, 55))	('TAGLN', 'Var', (0, 5))	('formation', 'biological_process', 'GO:0009058', ('27', '36'))	('cell migration', 'biological_process', 'GO:0016477', ('41', '55'))	('promoted', 'PosReg', (6, 14))	('inducing', 'Reg', (98, 106))	('invadopodia formation', 'CPA', (107, 128))	('Slug', 'Gene', '6591', (225, 229))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('133', '166'))	('formation', 'biological_process', 'GO:0009058', ('119', '128'))	('cell colony formation', 'CPA', (15, 36))	('Slug', 'Gene', (225, 229))
75584	31420300	According to our results, TAGLN was highly expressed in bladder cancer and correlated with advanced prognostic features, including stage, grade and overall survival.	('TAGLN', 'Var', (26, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('correlated', 'Reg', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('bladder cancer', 'Disease', (56, 70))
75609	31420300	Consistent with the functional prediction performed for TAGLN, TAGLN promotes migration and invasion of BLCA cells both in vitro and in vivo.	('BLCA', 'Disease', 'MESH:D001749', (104, 108))	('promotes', 'PosReg', (69, 77))	('TAGLN', 'Var', (63, 68))	('BLCA', 'Phenotype', 'HP:0009725', (104, 108))	('migration', 'CPA', (78, 87))	('BLCA', 'Disease', (104, 108))
75621	31420300	The samples were subsequently incubated in the presence of anti-TAGLN or anti-Slug primary antibody at 4  C overnight and were then processed using the Power-VisionTM two-step histostaining reagent and a 3,3-diaminobenzidine tetrahydrochloride substrate kit (ZSGB-Bio, China) according to the manufacturer's protocol.	('Slug', 'Gene', (78, 82))	('3,3-diaminobenzidine tetrahydrochloride', 'Chemical', 'MESH:D015100', (204, 243))	('antibody', 'cellular_component', 'GO:0042571', ('91', '99'))	('anti-TAGLN', 'Var', (59, 69))	('China', 'Species', '998089', (269, 274))	('antibody', 'cellular_component', 'GO:0019815', ('91', '99'))	('antibody', 'cellular_component', 'GO:0019814', ('91', '99'))	('antibody', 'molecular_function', 'GO:0003823', ('91', '99'))	('Slug', 'Gene', '6591', (78, 82))
75660	31420300	Furthermore, both univariate and multivariate analyses showed that patients with BLCA that expressed high levels of TAGLN had a shorter overall survival (OS) than patients with cancers that expressed low levels of TAGLN in all three cohorts (Fig.	('patients', 'Species', '9606', (163, 171))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('patients', 'Species', '9606', (67, 75))	('BLCA', 'Disease', 'MESH:D001749', (81, 85))	('BLCA', 'Phenotype', 'HP:0009725', (81, 85))	('TAGLN', 'Var', (116, 121))	('cancers', 'Disease', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('shorter', 'NegReg', (128, 135))	('BLCA', 'Disease', (81, 85))	('high levels', 'Var', (101, 112))	('overall survival', 'MPA', (136, 152))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
75661	31420300	Crucially, we also found that high TAGLN level was significantly correlated with poor metastasis-free survival (MFS) of BLCA patients in PKU-BLCA cohort (Fig.	('BLCA', 'Disease', 'MESH:D001749', (120, 124))	('BLCA', 'Phenotype', 'HP:0009725', (120, 124))	('metastasis-free survival', 'CPA', (86, 110))	('BLCA', 'Disease', (120, 124))	('poor', 'NegReg', (81, 85))	('high', 'Var', (30, 34))	('TAGLN level', 'MPA', (35, 46))	('BLCA', 'Disease', 'MESH:D001749', (141, 145))	('BLCA', 'Phenotype', 'HP:0009725', (141, 145))	('BLCA', 'Disease', (141, 145))	('patients', 'Species', '9606', (125, 133))
75666	31420300	All enrichment analyses indicated that TAGLN is involved in actin cytoskeleton regulation, cell adhesion, cell motility and EMT in BLCA.	('BLCA', 'Disease', (131, 135))	('TAGLN', 'Var', (39, 44))	('cell motility', 'CPA', (106, 119))	('cell adhesion', 'biological_process', 'GO:0007155', ('91', '104'))	('actin cytoskeleton regulation', 'MPA', (60, 89))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('60', '78'))	('EMT', 'biological_process', 'GO:0001837', ('124', '127'))	('involved', 'Reg', (48, 56))	('regulation', 'biological_process', 'GO:0065007', ('79', '89'))	('BLCA', 'Disease', 'MESH:D001749', (131, 135))	('BLCA', 'Phenotype', 'HP:0009725', (131, 135))	('cell adhesion', 'CPA', (91, 104))	('cell motility', 'biological_process', 'GO:0048870', ('106', '119'))
75673	31420300	BLCA cell lines were then established that stably overexpressed either TAGLN or an shRNA that targeted TAGLN (Fig.	('TAGLN', 'Var', (103, 108))	('BLCA', 'Disease', 'MESH:D001749', (0, 4))	('BLCA', 'Phenotype', 'HP:0009725', (0, 4))	('BLCA', 'Disease', (0, 4))
75675	31420300	A significant reduction in tumour metastasis in the TAGLN-silenced group compared with the control group was observed (Fig.	('TAGLN-silenced', 'Var', (52, 66))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumour metastasis', 'Disease', (27, 44))	('reduction', 'NegReg', (14, 23))	('tumour metastasis', 'Disease', 'MESH:D009362', (27, 44))
75676	31420300	Overall, these results indicated that TAGLN promotes the invasiveness of BLCA cells both in vitro and in vivo, which is consistent with the earlier functional prediction.	('promotes', 'PosReg', (44, 52))	('invasiveness', 'Disease', (57, 69))	('BLCA', 'Disease', 'MESH:D001749', (73, 77))	('TAGLN', 'Var', (38, 43))	('invasiveness', 'Disease', 'MESH:D009361', (57, 69))	('BLCA', 'Phenotype', 'HP:0009725', (73, 77))	('BLCA', 'Disease', (73, 77))
75681	31420300	Also, we found that the cell lines with greater expression of TAGLN also showed higher expression of cortactin (Supplementary Fig.	('cortactin', 'Gene', (101, 110))	('cortactin', 'Gene', '2017', (101, 110))	('expression', 'MPA', (87, 97))	('TAGLN', 'Var', (62, 67))	('higher', 'PosReg', (80, 86))
75682	31420300	Reactivation of EMT in cancer cells enhances the metastatic phenotype.	('enhances', 'PosReg', (36, 44))	('EMT', 'biological_process', 'GO:0001837', ('16', '19'))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('EMT', 'Gene', (16, 19))	('Reactivation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('metastatic phenotype', 'CPA', (49, 69))
75683	31420300	As suggested by the functional prediction as well as the positive effect of TAGLN on cancer metastasis, there was a potential reliable connection between TAGLN and EMT.	('cancer metastasis', 'Disease', 'MESH:D009362', (85, 102))	('TAGLN', 'Var', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('EMT', 'CPA', (164, 167))	('EMT', 'biological_process', 'GO:0001837', ('164', '167'))	('connection', 'Interaction', (135, 145))	('cancer metastasis', 'Disease', (85, 102))
75684	31420300	The expression of the mesenchymal markers/transcription factors N-cadherin, beta-catenin and Slug were significantly decreased in TAGLN-silenced cells and increased in TAGLN-transduced cells, while the expression of the epithelial marker E-cadherin was downregulated in TAGLN-overexpressed cells (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('66', '74'))	('E-cadherin', 'Gene', (238, 248))	('N-cadherin', 'Gene', (64, 74))	('E-cadherin', 'Gene', '999', (238, 248))	('cadherin', 'molecular_function', 'GO:0008014', ('240', '248'))	('increased', 'PosReg', (155, 164))	('beta-catenin', 'Gene', (76, 88))	('decreased', 'NegReg', (117, 126))	('expression', 'MPA', (4, 14))	('expression', 'MPA', (202, 212))	('Slug', 'Gene', '6591', (93, 97))	('N-cadherin', 'Gene', '1000', (64, 74))	('transcription', 'biological_process', 'GO:0006351', ('42', '55'))	('TAGLN-silenced', 'Var', (130, 144))	('Slug', 'Gene', (93, 97))	('beta-catenin', 'Gene', '1499', (76, 88))	('downregulated', 'NegReg', (253, 266))
75693	31420300	Our results also showed that the expression of TGFB2 and TAGLN was closely associated in basal subtype BLCA cells, which were more aggressive and resulted in reduced survival compared with luminal cancers (Fig.	('TGFB2', 'Gene', (47, 52))	('survival', 'MPA', (166, 174))	('TGFB2', 'Gene', '7042', (47, 52))	('luminal cancers', 'Disease', 'MESH:D009369', (189, 204))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('TAGLN', 'Var', (57, 62))	('BLCA', 'Disease', 'MESH:D001749', (103, 107))	('BLCA', 'Phenotype', 'HP:0009725', (103, 107))	('luminal cancers', 'Disease', (189, 204))	('BLCA', 'Disease', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('associated', 'Reg', (75, 85))	('reduced', 'NegReg', (158, 165))
75707	31420300	The results demonstrated that TAGLN contributes to poor prognosis in BLCA.	('BLCA', 'Disease', 'MESH:D001749', (69, 73))	('BLCA', 'Phenotype', 'HP:0009725', (69, 73))	('TAGLN', 'Var', (30, 35))	('BLCA', 'Disease', (69, 73))
75710	31420300	Additionally, TGF-beta-mediated migration was shown to be abolished by the inhibition of TAGLN.	('TGF-beta', 'Gene', (14, 22))	('inhibition', 'Var', (75, 85))	('abolished', 'NegReg', (58, 67))	('TAGLN', 'Gene', (89, 94))	('TGF-beta', 'Gene', '7040', (14, 22))
75717	31420300	Ambiguous results, such as those that have been found for TAGLN, have also been found for other cancers that affect SMC-rich tissues, including oesophageal cancer and colorectal cancer.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('colorectal cancer', 'Disease', (167, 184))	('oesophageal cancer', 'Disease', 'MESH:D009369', (144, 162))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('oesophageal cancer', 'Disease', (144, 162))	('TAGLN', 'Var', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (167, 184))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('colorectal cancer', 'Phenotype', 'HP:0003003', (167, 184))	('cancers', 'Disease', (96, 103))	('SMC', 'cellular_component', 'GO:0016029', ('116', '119'))
75718	31420300	As a benefit of the meta-analyses, the combined effects of each prognostic feature were determined in all three cohorts, which all demonstrated the unfavourable effects of TAGLN on BLCA.	('BLCA', 'Phenotype', 'HP:0009725', (181, 185))	('BLCA', 'Disease', 'MESH:D001749', (181, 185))	('BLCA', 'Disease', (181, 185))	('TAGLN', 'Var', (172, 177))
75720	31420300	Additionally, aberrant expression of TAGLN has also been shown to be involved in other cancers; for example, unfavourable prognostic effects have been noted for colorectal cancer.	('cancers', 'Disease', (87, 94))	('colorectal cancer', 'Disease', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('involved', 'Reg', (69, 77))	('TAGLN', 'Gene', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))	('aberrant expression', 'Var', (14, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
75727	31420300	As indicated by the enrichment analyses, TAGLN may be involved in actin regulation and cell motility in BLCA.	('cell motility', 'biological_process', 'GO:0048870', ('87', '100'))	('BLCA', 'Disease', 'MESH:D001749', (104, 108))	('BLCA', 'Phenotype', 'HP:0009725', (104, 108))	('actin', 'MPA', (66, 71))	('cell motility', 'CPA', (87, 100))	('TAGLN', 'Var', (41, 46))	('BLCA', 'Disease', (104, 108))	('regulation', 'biological_process', 'GO:0065007', ('72', '82'))	('involved', 'Reg', (54, 62))
75729	31420300	Interestingly, TAGLN promotes the clonogenicity of BLCA cells rather than cell proliferation, which indicates the potential role of TAGLN in metastatic colonization.	('TAGLN', 'Var', (15, 20))	('BLCA', 'Disease', 'MESH:D001749', (51, 55))	('promotes', 'PosReg', (21, 29))	('BLCA', 'Phenotype', 'HP:0009725', (51, 55))	('BLCA', 'Disease', (51, 55))	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))
75758	31420300	Since the progression-dependent correlation between TGF-beta and TAGLN was highlighted in bladder cancer, TGF-beta inhibitors could serve as potential drugs.	('TGF-beta', 'Gene', (106, 114))	('bladder cancer', 'Disease', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('TGF-beta', 'Gene', (52, 60))	('TAGLN', 'Var', (65, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('TGF-beta', 'Gene', '7040', (106, 114))	('TGF-beta', 'Gene', '7040', (52, 60))
75761	31420300	Recently, Zhong et.al reported that salvianolic acid A enhances vasoconstriction by targeting the transgelin-actin complex.	('vasoconstriction', 'MPA', (64, 80))	('transgelin', 'Gene', '6876', (98, 108))	('salvianolic acid A', 'Chemical', 'MESH:C066201', (36, 54))	('vasoconstriction', 'biological_process', 'GO:0042310', ('64', '80'))	('salvianolic acid', 'Var', (36, 52))	('enhances', 'PosReg', (55, 63))	('transgelin', 'Gene', (98, 108))
75776	31119885	In multivariable analysis, PORT was independently associated with improved OS: hazard ratio 0.87 (95% CI, 0.78-0.97); P = 0.008.	('PORT', 'Var', (27, 31))	('improved', 'PosReg', (66, 74))	('OS', 'Chemical', '-', (75, 77))
75818	31119885	In multivariable analysis, PORT was independently associated with an improved OS (HR: 0.87 [95% CI, 0.78-0.97]; P = 0.008) (Table 3).	('PORT', 'Var', (27, 31))	('improved', 'PosReg', (69, 77))	('OS', 'Chemical', '-', (78, 80))
75820	31119885	Our sensitivity analysis showed that if there was an unmeasured confounder with a deleterious effect on OS with a HR of 1.25 and was 9% more common in the no PORT cohort, adjusting for it would not change the overall findings that PORT is associated with significantly improved OS (updated HR 0.90, 95% CI 0.80-0.99).	('improved', 'PosReg', (269, 277))	('OS', 'Chemical', '-', (278, 280))	('PORT', 'Var', (231, 235))	('OS', 'Chemical', '-', (104, 106))
75860	31119885	Based on this retrospective analysis, PORT appears to be associated with improved OS and these findings lend support to the use of PORT.	('OS', 'Chemical', '-', (82, 84))	('PORT', 'Var', (38, 42))	('improved', 'PosReg', (73, 81))
75933	32455829	At the same time, some investigators reported that bladder cancer expressing high PD-L1 showed a poor prognosis, but others suggested high PD-L1 level predicted the good prognosis.	('bladder cancer', 'Disease', (51, 65))	('PD-L1', 'Gene', (82, 87))	('high', 'Var', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('bladder cancer', 'Disease', 'MESH:D001749', (51, 65))
75965	32455829	Unlike all groups described above, 29.7 +- 1.2% of tumor area of high-grade double-negative p-53 mutant subtype of recurrent NMIBC was occupied by CD8+-expressing cells; more than twice lower T-suppressor population (12.3 +- 0.9%; p = 0.001 intergroup comparison) infiltrated relapsed double-negative p53-expressing bladder carcinoma with low malignant potential.	('bladder carcinoma', 'Phenotype', 'HP:0002862', (316, 333))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('CD8', 'Gene', (147, 150))	('p-53', 'Gene', '7157', (92, 96))	('tumor', 'Disease', (51, 56))	('p53', 'Gene', (301, 304))	('mutant', 'Var', (97, 103))	('bladder carcinoma', 'Disease', 'MESH:D001749', (316, 333))	('CD8', 'Gene', '925', (147, 150))	('bladder carcinoma', 'Disease', (316, 333))	('p53', 'Gene', '7157', (301, 304))	('p-53', 'Gene', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
75972	32455829	Immune cells of luminal and more malignant types of basal and double-negative p53 mutant tumors were highly PD-L1-expressive.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('luminal', 'Chemical', 'MESH:D010634', (16, 23))	('p53', 'Gene', (78, 81))	('p53', 'Gene', '7157', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mutant', 'Var', (82, 88))
75975	32455829	In the group of patients who had not utilized frontline treatment after TUR, the Kaplan-Meier plot showed that relapse time was lower for those with high-grade luminal NMIBC.	('high-grade luminal', 'Var', (149, 167))	('luminal', 'Var', (160, 167))	('patients', 'Species', '9606', (16, 24))	('relapse time', 'CPA', (111, 123))	('luminal', 'Chemical', 'MESH:D010634', (160, 167))	('lower', 'NegReg', (128, 133))
75980	32455829	In the case of high-grade basal NMIBC, relapse-free survival was lower in comparison with low-grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('high-grade', 'Var', (15, 25))	('relapse-free survival', 'CPA', (39, 60))	('lower', 'NegReg', (65, 70))	('tumors', 'Disease', (100, 106))	('basal NMIBC', 'Disease', (26, 37))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))
75981	32455829	Survival time to double-negative p53 mutant NMIBC recurrence was not associated with the tumor grade.	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mutant', 'Var', (37, 43))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
75984	32455829	For double-negative p53-expressing NMIBC, relapse time was the same for patients with high- and low-grade bladder malignancies.	('double-negative', 'Var', (4, 19))	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('bladder malignancies', 'Disease', 'MESH:D001749', (106, 126))	('bladder malignancies', 'Disease', (106, 126))	('bladder malignancies', 'Phenotype', 'HP:0009725', (106, 126))	('patients', 'Species', '9606', (72, 80))
75993	32455829	Taking into consideration molecular and malignant diversity of primary and relapsed bladder cancer, the idea of our study was to analyze how PD-L1 expression associates with relapse-free survival of patients with recurrent GATA3 (+), KRT5/6 (+) and double-negative NMIBC regarding tumor grade and previous surgical and chemo-/immunotherapy settings.	('bladder cancer', 'Phenotype', 'HP:0009725', (84, 98))	('PD-L1', 'Gene', (141, 146))	('KRT', 'Gene', (234, 237))	('relapse-free', 'Disease', (174, 186))	('bladder cancer', 'Disease', (84, 98))	('bladder cancer', 'Disease', 'MESH:D001749', (84, 98))	('GATA3', 'Gene', '2625', (223, 228))	('associates with', 'Reg', (158, 173))	('relapsed bladder cancer', 'Phenotype', 'HP:0012786', (75, 98))	('tumor', 'Disease', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('KRT', 'Gene', '643865', (234, 237))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('patients', 'Species', '9606', (199, 207))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('double-negative', 'Var', (249, 264))	('GATA3', 'Gene', (223, 228))
75999	32455829	It is utterly important to determine a nature of PD-L1 positivity for each molecular and malignant kind of relapsed urothelial carcinoma, because targeting of PD-1/PD-L1 pathway on the membrane of neoplastic cells and on CD8+ T-suppressor cells possesses powerful potency for effective disease control.	('CD8', 'Gene', '925', (221, 224))	('PD-1/PD-L1', 'Gene', (159, 169))	('urothelial carcinoma', 'Disease', (116, 136))	('targeting', 'Var', (146, 155))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (116, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('membrane', 'cellular_component', 'GO:0016020', ('185', '193'))	('CD8', 'Gene', (221, 224))
76002	32455829	The researchers underlined that prevalence of immune cell PD-L1 positivity was characterized for non-invasive T1 urothelial cancer, whereas in muscular invasive bladder tumors, the authors detected a high number of positively stained neoplastic cells.	('positivity', 'Var', (64, 74))	('bladder tumors', 'Phenotype', 'HP:0009725', (161, 175))	('urothelial cancer', 'Disease', 'MESH:D014523', (113, 130))	('muscular invasive bladder tumors', 'Disease', 'MESH:D001749', (143, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('bladder tumor', 'Phenotype', 'HP:0009725', (161, 174))	('invasive bladder', 'Phenotype', 'HP:0100645', (152, 168))	('muscular invasive bladder tumors', 'Disease', (143, 175))	('urothelial cancer', 'Disease', (113, 130))
76063	32429941	cancer-related differentially expressed genes or structural variations, as well as predicting the clinical outcomes, such as the risk stratification for the patients in cancers.	('cancer', 'Disease', (169, 175))	('differentially expressed genes', 'Gene', (15, 45))	('structural variations', 'Var', (49, 70))	('cancers', 'Disease', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (0, 6))	('patients', 'Species', '9606', (157, 165))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
76092	32429941	In terms of details, for the easily predicted cancer types, the performance of SWT-CNN was better than that of SVM.	('better', 'PosReg', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('SWT-CNN', 'Var', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
76095	32429941	When predicting the tumor stages of KIRC, the mean AUC achieved by SWT-CNN (mean AUC = 0.74) was 0.19 higher than that achieved by SVM (mean AUC = 0.55).	('higher', 'PosReg', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('AUC', 'MPA', (51, 54))	('SWT-CNN', 'Var', (67, 74))	('tumor', 'Disease', (20, 25))
76154	32429941	The gene fusion of SLC34A2 and ROS1 played an important role in the progression of non-small cell lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (83, 109))	('gene fusion', 'Var', (4, 15))	('SLC34A2', 'Gene', '10568', (19, 26))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (83, 109))	('ROS1', 'Gene', (31, 35))	('SLC34A2', 'Gene', (19, 26))	('ROS1', 'Gene', '6098', (31, 35))	('non-small cell lung cancer', 'Disease', (83, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (87, 109))
76218	31262032	The phenomenon that TFP alleviated cisplatin resistance to T24/R was accompanied with concurrent suppression of Bcl-xL.	('Bcl-xL', 'Gene', (112, 118))	('TFP', 'cellular_component', 'GO:0044096', ('20', '23'))	('TFP', 'Var', (20, 23))	('TFP', 'Chemical', 'MESH:D014268', (20, 23))	('cisplatin resistance', 'MPA', (35, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('suppression', 'NegReg', (97, 108))	('Bcl-xL', 'Gene', '598', (112, 118))	('alleviated', 'NegReg', (24, 34))
76240	31262032	As illustrated in Figure 1A,B, cisplatin effectively induced cytotoxicity and apoptosis in T24 cells at 24 h after treatment.	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('apoptosis', 'CPA', (78, 87))	('cytotoxicity', 'Disease', (61, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('cytotoxicity', 'Disease', 'MESH:D064420', (61, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('cisplatin', 'Var', (31, 40))
76244	31262032	As presented in Figure 2A, TFP effectively inhibited cell viability in a dose-dependent manner at 24 and 48 h. In addition, treatment with TFP (25 muM) for 24 h significantly induced apoptosis in cisplatin-resistant T24/R cells.	('TFP', 'Var', (139, 142))	('TFP', 'cellular_component', 'GO:0044096', ('27', '30'))	('cisplatin', 'Chemical', 'MESH:D002945', (196, 205))	('TFP', 'Chemical', 'MESH:D014268', (27, 30))	('muM', 'Gene', (147, 150))	('apoptosis', 'biological_process', 'GO:0097194', ('183', '192'))	('induced', 'Reg', (175, 182))	('TFP', 'cellular_component', 'GO:0044096', ('139', '142'))	('TFP', 'Chemical', 'MESH:D014268', (139, 142))	('apoptosis', 'CPA', (183, 192))	('apoptosis', 'biological_process', 'GO:0006915', ('183', '192'))	('muM', 'Gene', '56925', (147, 150))
76246	31262032	Meanwhile, the anti-apoptotic molecule Bcl-xL decreased after TFP treatment.	('Bcl-xL', 'Gene', (39, 45))	('TFP', 'Chemical', 'MESH:D014268', (62, 65))	('TFP', 'cellular_component', 'GO:0044096', ('62', '65'))	('treatment', 'Var', (66, 75))	('decreased', 'NegReg', (46, 55))	('Bcl-xL', 'Gene', '598', (39, 45))
76247	31262032	A previous study reported that TFP caused cell cycle arrest at the G0/G1 phase.	('G1 phase', 'biological_process', 'GO:0051318', ('70', '78'))	('TFP', 'cellular_component', 'GO:0044096', ('31', '34'))	('TFP', 'Var', (31, 34))	('TFP', 'Chemical', 'MESH:D014268', (31, 34))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('42', '59'))	('cell cycle arrest at the G0/G1 phase', 'CPA', (42, 78))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (42, 59))
76255	31262032	However, TFP alleviated drug resistance of T24/R to cisplatin and enhanced the apoptotic and cytotoxic effects of cisplatin on T24/R cells (Figure 4A-C).	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('drug resistance', 'biological_process', 'GO:0042493', ('24', '39'))	('drug', 'CPA', (24, 28))	('drug resistance', 'Phenotype', 'HP:0020174', (24, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('enhanced', 'PosReg', (66, 74))	('TFP', 'Chemical', 'MESH:D014268', (9, 12))	('TFP', 'cellular_component', 'GO:0044096', ('9', '12'))	('alleviated', 'NegReg', (13, 23))	('TFP', 'Var', (9, 12))	('drug resistance', 'biological_process', 'GO:0009315', ('24', '39'))
76259	31262032	The expression of Bcl-xL was more abundant in T24/R cells when compared to that in the parental T24 cells (Figure 4D).	('abundant', 'PosReg', (34, 42))	('T24/R', 'Var', (46, 51))	('Bcl-xL', 'Gene', '598', (18, 24))	('expression', 'MPA', (4, 14))	('Bcl-xL', 'Gene', (18, 24))
76263	31262032	TFP alleviated cisplatin resistance in T24/R cells and resensitized T24/R cells to cisplatin and was accompanied with the suppression of Bcl-xL.	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('TFP', 'Var', (0, 3))	('TFP', 'Chemical', 'MESH:D014268', (0, 3))	('Bcl-xL', 'Gene', (137, 143))	('TFP', 'cellular_component', 'GO:0044096', ('0', '3'))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))	('alleviated', 'NegReg', (4, 14))	('cisplatin resistance', 'MPA', (15, 35))	('Bcl-xL', 'Gene', '598', (137, 143))	('suppression', 'NegReg', (122, 133))
76265	31262032	After treating T24/R cells with 10 nM Bcl-xL siRNA or non-targeting scramble siRNA as a control, we observed Bcl-xL knockdown decreased Bcl-xL levels and restored the cisplatin-induced DNA damage (phospho-histone H2A.X activation) and cytotoxicity (Figure 4F).	('decreased', 'NegReg', (126, 135))	('cytotoxicity', 'Disease', (235, 247))	('Bcl-xL', 'Gene', (109, 115))	('restored', 'PosReg', (154, 162))	('DNA', 'cellular_component', 'GO:0005574', ('185', '188'))	('Bcl-xL', 'Gene', (136, 142))	('Bcl-xL', 'Gene', '598', (38, 44))	('Bcl-xL', 'Gene', (38, 44))	('cisplatin-induced DNA damage', 'MPA', (167, 195))	('knockdown', 'Var', (116, 125))	('cytotoxicity', 'Disease', 'MESH:D064420', (235, 247))	('activation', 'PosReg', (219, 229))	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('Bcl-xL', 'Gene', '598', (136, 142))	('Bcl-xL', 'Gene', '598', (109, 115))
76318	31262032	This work was supported by grants from National Taiwan University Hospital (108-4104, 108-M4137, and 107-S3784), the Taiwan Ministry and Science and Technology (107-2321-B-008-001 and 107-2314-B-002-268-MY2) and New Taipei City Hospital (108).	('268-MY2', 'CellLine', 'CVCL:3034', (199, 206))	('107-S3784', 'Var', (101, 110))	('107-2314-B-002-268-MY2', 'Var', (184, 206))	('108-4104', 'Var', (76, 84))	('107-2321-B-008-001', 'Var', (161, 179))
76341	30550540	The histology of subcutaneous tumor transplants produced by all the above Cd2+-and As3+-transformed UROtsa cells displayed histologic features of human urothelial carcinoma, each with variable focal areas of prominent squamous differentiation.	('urothelial carcinoma', 'Disease', (152, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('As3+-transformed', 'Var', (83, 99))	('Cd2+-and', 'Var', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('human', 'Species', '9606', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (152, 172))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (17, 35))	('tumor', 'Disease', (30, 35))
76373	30550540	These 25 genes were used to determine if the tumor transplants generated from the UROtsa cells transformed by Cd2+ and As3+ had gene expression patterns that associated with the basal or luminal subtypes of MIBC.	('As3+', 'Var', (119, 123))	('MIBC', 'Chemical', '-', (207, 211))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('MIBC', 'Disease', (207, 211))	('associated', 'Reg', (158, 168))	('gene expression', 'biological_process', 'GO:0010467', ('128', '143'))	('tumor', 'Disease', (45, 50))	('Cd2+', 'Var', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('basal', 'Disease', (178, 183))
76380	30550540	The tumor samples from the As3+ and Cd2+-transformed cell lines were shown to be at the same levels of the MIBCs in the PC2 axis.	('tumor', 'Disease', (4, 9))	('PC2', 'Gene', '3872', (120, 123))	('Cd2+-transformed', 'Var', (36, 52))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('MIBCs', 'Chemical', '-', (107, 112))	('PC2', 'Gene', (120, 123))
76382	30550540	The tumor transplants generated by the As3+ and Cd2+-transformed UROtsa cells all clustered with the basal subtype of MIBC.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('Cd2+-transformed', 'Var', (48, 64))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('MIBC', 'Chemical', '-', (118, 122))
76384	30550540	One subtype consists of only tumors generated from the Cd2+ and As3+- transformed UROtsa cells.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Cd2+', 'Var', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))
76419	30550540	The staining of KRT7 was similar in both the well-differentiated and less differentiated areas of tumor for the tumors generated from Cd2+- transformed UROtsa cells.	('tumor', 'Disease', (112, 117))	('KRT7', 'Gene', '3855', (16, 20))	('KRT7', 'Gene', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))	('Cd2+- transformed', 'Var', (134, 151))
76431	30550540	The results of this analysis for 9 basal markers, KRT17 and p63 demonstrated that five markers were altered in the urospheres isolated from the Cd2+-transformed cell lines (Fig 7A).	('altered', 'Reg', (100, 107))	('p63', 'Gene', '8626', (60, 63))	('KRT17', 'Gene', '3872', (50, 55))	('Cd2+-transformed', 'Var', (144, 160))	('KRT17', 'Gene', (50, 55))	('p63', 'Gene', (60, 63))
76459	30550540	Thus, tumors derived from As3+ and Cd2+-transformed UROtsa cells have an expression pattern consistent with that found for the basal subtype of MIBCs.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('expression', 'MPA', (73, 83))	('Cd2+-transformed', 'Var', (35, 51))	('MIBCs', 'Chemical', '-', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('As3+', 'Var', (26, 30))
76467	30550540	The tumors produces by the As3+ and Cd2+-transformed UROtsa cells showed the most similarity to the SCCL tumors with some shared characteristics with uroB tumors.	('tumors', 'Disease', (105, 111))	('uroB tumors', 'Disease', (150, 161))	('Cd2+-transformed', 'Var', (36, 52))	('SCCL tumors', 'Disease', (100, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('uroB tumors', 'Disease', 'MESH:D009369', (150, 161))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('As3+', 'Var', (27, 31))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('SCCL tumors', 'Disease', 'MESH:D018288', (100, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
76484	30550540	There was increased expression of KRT1, KRT6C, KRT14 and KRT16 in the urospheres compared to the transformed cell lines and these keratin genes were also elevated in the MIBCs.	('KRT1', 'Gene', (57, 61))	('KRT1', 'Gene', (47, 51))	('expression', 'MPA', (20, 30))	('KRT16', 'Gene', (57, 62))	('MIBCs', 'Chemical', '-', (170, 175))	('MIBCs', 'Var', (170, 175))	('KRT1', 'Gene', '3848', (47, 51))	('KRT14', 'Gene', '3861', (47, 52))	('KRT1', 'Gene', '3848', (57, 61))	('KRT1', 'Gene', (34, 38))	('keratin genes', 'Gene', (130, 143))	('KRT6C', 'Gene', '286887', (40, 45))	('KRT1', 'Gene', '3848', (34, 38))	('KRT14', 'Gene', (47, 52))	('elevated', 'PosReg', (154, 162))	('KRT16', 'Gene', '3868', (57, 62))	('KRT6C', 'Gene', (40, 45))	('increased', 'PosReg', (10, 19))
76531	29180460	As shown in Table 1, pembrolizumab was associated with a 3-month improvement in median overall survival.	('pembrolizumab', 'Var', (21, 34))	('pembrolizumab', 'Chemical', 'MESH:C582435', (21, 34))	('improvement', 'PosReg', (65, 76))	('overall survival', 'MPA', (87, 103))
76542	29180460	As summarized in Table 2, these assays vary considerably in the type of cells used to determine PD-L1 expression (on tumor cells, tumor-infiltrating immune cells, or both) and have different cutoff points to distinguish patients with high PD-L1 expression from those with low PD-L1 expression.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('PD-L1', 'Gene', '29126', (96, 101))	('PD-L1', 'Gene', '29126', (276, 281))	('PD-L1', 'Gene', (239, 244))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('high', 'Var', (234, 238))	('patients', 'Species', '9606', (220, 228))	('PD-L1', 'Gene', '29126', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('expression', 'MPA', (245, 255))	('PD-L1', 'Gene', (96, 101))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('PD-L1', 'Gene', (276, 281))
76543	29180460	With each of the listed products, the response rate is greater in patients with high PD-L1 expression in tumor specimens (Table 2).	('PD-L1', 'Gene', (85, 90))	('greater', 'PosReg', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('response', 'MPA', (38, 46))	('PD-L1', 'Gene', '29126', (85, 90))	('tumor', 'Disease', (105, 110))	('high', 'Var', (80, 84))	('patients', 'Species', '9606', (66, 74))
76544	29180460	However, the differences in response rate between patients with high and low PD-L1 expression in tumor specimens are not sufficient to support use of any of the assays as a companion diagnostic device, but are appropriate to inform the risk-benefit decision.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('high', 'Var', (64, 68))	('patients', 'Species', '9606', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('PD-L1', 'Gene', (77, 82))	('tumor', 'Disease', (97, 102))	('PD-L1', 'Gene', '29126', (77, 82))	('low', 'NegReg', (73, 76))
76545	29180460	With all of these drugs, there were patients with low PD-L1 expression who had durable responses, indicating that these PD-L1 assays cannot be considered essential or used as companion diagnostics to select patients who may most benefit from the products.	('expression', 'MPA', (60, 70))	('patients', 'Species', '9606', (207, 215))	('patients', 'Species', '9606', (36, 44))	('low', 'Var', (50, 53))	('PD-L1', 'Gene', (54, 59))	('PD-L1', 'Gene', (120, 125))	('PD-L1', 'Gene', '29126', (120, 125))	('PD-L1', 'Gene', '29126', (54, 59))
76671	26513724	The presence of BPV-2 and BPV-13 E5 RNA was confirmed by sequencing of amplicons according to BPV-2 sequence M20219.1 and to BPV-13 sequence JQ798171.1 (Figs 1 and 2).	('JQ798171.1', 'Var', (141, 151))	('RNA', 'cellular_component', 'GO:0005562', ('36', '39'))	('BPV-2', 'Species', '10560', (94, 99))	('BPV-2', 'Gene', (94, 99))	('BPV-2', 'Species', '10560', (16, 21))	('M20219.1', 'Var', (109, 117))
76707	26513724	Our suggestion appears to be corroborated by recent reports showing that expression of mincle contributes to the control of Mycobacterium bovis BCG infection.	('Mycobacterium', 'Disease', (124, 137))	('expression', 'Var', (73, 83))	('mincle', 'Gene', (87, 93))	('bovis BCG infection', 'Disease', 'MESH:C565907', (138, 157))	('contributes', 'Reg', (94, 105))	('bovis BCG infection', 'Disease', (138, 157))	('control', 'MPA', (113, 120))
76724	25089155	Various risk factors are associated with development of bladder carcinomas including cigarette smoking, arylamines, aniline dyes, auramines, phenacetin, and cyclophosphomide.	('cyclophosphomide', 'Chemical', '-', (157, 173))	('arylamines', 'Var', (104, 114))	('cyclophosphomide', 'Disease', (157, 173))	('men', 'Species', '9606', (48, 51))	('phenacetin', 'Chemical', 'MESH:D010615', (141, 151))	('bladder carcinomas', 'Disease', (56, 74))	('aniline', 'Chemical', 'MESH:C023650', (116, 123))	('auramines', 'MPA', (130, 139))	('auramines', 'Chemical', 'MESH:D001576', (130, 139))	('arylamines', 'Chemical', 'MESH:C023650', (104, 114))	('bladder carcinomas', 'Disease', 'MESH:D001749', (56, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('phenacetin', 'Disease', (141, 151))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (56, 74))
76733	25089155	Being a cell proliferation regulating and pro-apoptotic gene, mutation in p53 can nullify its normal functions and increased expression of the mutant protein is regarded as a predictor of poor prognosis of urothelial tumors .	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('mutant', 'Var', (143, 149))	('increased', 'PosReg', (115, 124))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('p53', 'Gene', (74, 77))	('expression', 'MPA', (125, 135))	('urothelial tumors', 'Disease', 'MESH:D001749', (206, 223))	('mutation', 'Var', (62, 70))	('p53', 'Gene', '7157', (74, 77))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('protein', 'Protein', (150, 157))	('nullify', 'NegReg', (82, 89))	('cell proliferation', 'biological_process', 'GO:0008283', ('8', '26'))	('urothelial tumors', 'Disease', (206, 223))
76779	25089155	Wild-type p53 protein has a short half-life; however, the protein encoded by mutated p53 remains active for a long period.	('p53', 'Gene', '7157', (10, 13))	('mutated', 'Var', (77, 84))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('active', 'MPA', (97, 103))	('p53', 'Gene', (85, 88))	('p53', 'Gene', '7157', (85, 88))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('p53', 'Gene', (10, 13))
76780	25089155	Therefore, mutation of p53 gene results in p53 accumulation in cells nuclei.	('p53', 'Gene', '7157', (23, 26))	('p53', 'Gene', (23, 26))	('p53', 'Gene', (43, 46))	('mutation', 'Var', (11, 19))	('p53', 'Gene', '7157', (43, 46))	('accumulation', 'PosReg', (47, 59))
76781	25089155	This accumulation is detectable with immunohistochemical methods and correlates with p53 gene mutation, thus, detection of p53 protein in the nuclei of cells by immunohistochemical methods.	('p53', 'Gene', (85, 88))	('p53', 'Gene', (123, 126))	('p53', 'Gene', '7157', (85, 88))	('p53', 'Gene', '7157', (123, 126))	('mutation', 'Var', (94, 102))
76801	25089155	They found cytokeratin 20 positivity was associated with increasing tumor grade and stage.	('tumor', 'Disease', (68, 73))	('cytokeratin 20', 'Gene', '54474', (11, 25))	('stage', 'CPA', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cytokeratin 20', 'Gene', (11, 25))	('positivity', 'Var', (26, 36))
76830	33392066	Dysregulation of the immune microenvironment promoted the malignant progression from NMIBC to MIBC.	('Dysregulation', 'Var', (0, 13))	('MIBC', 'Disease', (94, 98))	('NMIBC', 'Disease', (85, 90))	('NMIBC', 'Chemical', '-', (85, 90))	('malignant progression', 'CPA', (58, 79))	('promoted', 'PosReg', (45, 53))	('men', 'Species', '9606', (40, 43))	('Dysregulation of the immune microenvironment', 'Phenotype', 'HP:0002958', (0, 44))	('MIBC', 'Chemical', '-', (94, 98))	('MIBC', 'Chemical', '-', (86, 90))
76845	33392066	Several studies have reported that the dysfunction of tumor-infiltrating immune cells (TIICs) and immune-related genes is associated with tumor stage, tumor grade and patients' prognoses in BLCA, indicating that immune dysregulation may be relevant to malignant progression in this disease.	('associated', 'Reg', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('immune dysregulation', 'Phenotype', 'HP:0002958', (212, 232))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (151, 156))	('patients', 'Species', '9606', (167, 175))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('BLCA', 'Phenotype', 'HP:0009725', (190, 194))	('dysfunction', 'Var', (39, 50))	('BLCA', 'Disease', (190, 194))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
76885	33392066	Except for GSE31684, patients with high risk had worse OS than those with low risk in GSE32894, GSE13507 and GSE48277 ( Figures 4A-D ).	('patients', 'Species', '9606', (21, 29))	('GSE32894', 'Var', (86, 94))	('GSE13507', 'Var', (96, 104))
76921	33392066	The presence of EMT-like features was associated with the upregulation of immune-suppressive signals/targets in human cancers, but the directionality of this association and mechanistic determinants are not well understood.	('cancers', 'Disease', (118, 125))	('EMT-like features', 'CPA', (16, 33))	('immune-suppressive', 'MPA', (74, 92))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('EMT', 'biological_process', 'GO:0001837', ('16', '19'))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('human', 'Species', '9606', (112, 117))	('presence', 'Var', (4, 12))	('upregulation', 'PosReg', (58, 70))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
76932	33392066	Publicly available datasets were analyzed in this study, these can be found in The Cancer Genome Atlas ; the NCBI Gene Expression Omnibus (GSE32894, GSE13507, GSE48277, and GSE31684).	('GSE32894', 'Var', (139, 147))	('Gene Expression', 'biological_process', 'GO:0010467', ('114', '129'))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Disease', (83, 89))	('GSE48277', 'Var', (159, 167))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))
76944	32299393	Loss-of-function assays revealed that knockdown of FTO significantly promotes proliferation and migration of 5637 and T24 cells.	('migration', 'CPA', (96, 105))	('FTO', 'Gene', '79068', (51, 54))	('promotes', 'PosReg', (69, 77))	('proliferation', 'CPA', (78, 91))	('FTO', 'Gene', (51, 54))	('knockdown', 'Var', (38, 47))	('si', 'Chemical', 'MESH:D012825', (55, 57))
76955	32299393	RNA methylation of gene expression modulation is an aspect of physiological development, and its dysregulation is involved in carcinogenesis.	('RNA methylation', 'biological_process', 'GO:0001510', ('0', '15'))	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('carcinogenesis', 'Disease', (126, 140))	('dysregulation', 'Var', (97, 110))	('si', 'Chemical', 'MESH:D012825', (137, 139))	('involved', 'Reg', (114, 122))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('gene expression', 'biological_process', 'GO:0010467', ('19', '34'))
76957	32299393	Epigenetic modifications could affect gene expression without altering the DNA structure, which offer us additional therapeutic options.	('affect', 'Reg', (31, 37))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('gene expression', 'MPA', (38, 53))	('Epigenetic modifications', 'Var', (0, 24))	('gene expression', 'biological_process', 'GO:0010467', ('38', '53'))	('si', 'Chemical', 'MESH:D012825', (49, 51))
77006	32299393	Overall, these data suggest that knockdown of FTO could promote the proliferation and migration of 5637 and T24 cells.	('proliferation', 'CPA', (68, 81))	('FTO', 'Gene', (46, 49))	('migration', 'CPA', (86, 95))	('knockdown', 'Var', (33, 42))	('FTO', 'Gene', '79068', (46, 49))	('promote', 'PosReg', (56, 63))
77022	32299393	For example, alterations in some genes (BCL2) could contribute to resistance to cisplatin in patients with muscle-invasive bladder cancer.	('si', 'Chemical', 'MESH:D012825', (118, 120))	('resistance to cisplatin', 'MPA', (66, 89))	('BCL2', 'molecular_function', 'GO:0015283', ('40', '44'))	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('BC', 'Phenotype', 'HP:0009725', (40, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('muscle-invasive bladder cancer', 'Disease', (107, 137))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('contribute', 'Reg', (52, 62))	('BCL2', 'Gene', '596', (40, 44))	('invasive bladder', 'Phenotype', 'HP:0100645', (114, 130))	('alterations', 'Var', (13, 24))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (107, 137))	('BCL2', 'Gene', (40, 44))	('patients', 'Species', '9606', (93, 101))
77023	32299393	In the present study, we find that knockdown of FTO significantly promotes proliferation and migration of 5637 and T24 cells.	('knockdown', 'Var', (35, 44))	('FTO', 'Gene', '79068', (48, 51))	('migration', 'CPA', (93, 102))	('promotes', 'PosReg', (66, 74))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('proliferation', 'CPA', (75, 88))	('FTO', 'Gene', (48, 51))
77029	32299393	Recent studies show that obesity-linked FTO mutations do not affect the FTO protein though they are the most common genetic contributor to obesity.	('FTO', 'Gene', (72, 75))	('obesity-linked FTO', 'Disease', 'MESH:D009765', (25, 43))	('obesity', 'Phenotype', 'HP:0001513', (25, 32))	('obesity', 'Disease', 'MESH:D009765', (139, 146))	('FTO', 'Gene', (40, 43))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('obesity', 'Disease', (139, 146))	('obesity', 'Phenotype', 'HP:0001513', (139, 146))	('obesity', 'Disease', 'MESH:D009765', (25, 32))	('mutations', 'Var', (44, 53))	('obesity-linked FTO', 'Disease', (25, 43))	('FTO', 'Gene', '79068', (40, 43))	('FTO', 'Gene', '79068', (72, 75))	('obesity', 'Disease', (25, 32))
77030	32299393	Human obesity is linked to mutations within the FTO gene, which controls the expression of neighboring genes.	('mutations', 'Var', (27, 36))	('Human', 'Species', '9606', (0, 5))	('obesity', 'Phenotype', 'HP:0001513', (6, 13))	('FTO', 'Gene', '79068', (48, 51))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('obesity', 'Disease', 'MESH:D009765', (6, 13))	('obesity', 'Disease', (6, 13))	('FTO', 'Gene', (48, 51))	('linked', 'Reg', (17, 23))
77038	32299393	Yang's study also demonstrated that knockdown of FTO sensitized melanoma cells to interferon gamma and anti-PD-1 treatments depending on adaptive immunity.	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('FTO', 'Gene', '79068', (49, 52))	('melanoma', 'Disease', (64, 72))	('interferon gamma', 'molecular_function', 'GO:0005133', ('82', '98'))	('interferon gamma', 'Gene', '3458', (82, 98))	('knockdown', 'Var', (36, 45))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('PD-1', 'Gene', (108, 112))	('sensitized', 'Reg', (53, 63))	('FTO', 'Gene', (49, 52))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('PD-1', 'Gene', '9825', (108, 112))	('interferon gamma', 'Gene', (82, 98))
77084	27220888	Importantly, progranulin depletion sensitized urothelial cancer cells to cisplatin treatment, further proving a pro-survival function of progranulin.	('urothelial cancer', 'Disease', 'MESH:D014523', (46, 63))	('progranulin', 'Protein', (13, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('sensitized', 'Reg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('depletion', 'Var', (25, 34))	('urothelial cancer', 'Disease', (46, 63))	('pro-survival', 'biological_process', 'GO:0043066', ('112', '124'))
77088	27220888	The levels of progranulin secretion in media conditioned by UMUC- 3 (Figure 1A) or T24T (Figure 2A) transfected with the shPGRN plasmid were significantly (95%) reduced in both cell lines compared to parental (P) or scrambled-(Scr)-transfected cells.	('reduced', 'NegReg', (161, 168))	('levels', 'MPA', (4, 10))	('transfected', 'Var', (100, 111))	('GRN', 'Gene', (124, 127))	('secretion', 'biological_process', 'GO:0046903', ('26', '35'))	('GRN', 'Gene', '2896', (124, 127))
77089	27220888	Progranulin depletion caused a robust inhibition (***P < 0.001) of the ability of UMUC- 3 (Figure 1B) and T24T (Figure 2B) cells to migrate.	('Progranulin', 'Gene', (0, 11))	('Progranulin', 'Gene', '2896', (0, 11))	('inhibition', 'NegReg', (38, 48))	('depletion', 'Var', (12, 21))
77092	27220888	Next, given the pro-motility activity of progranulin, we tested whether progranulin depletion would also affect the ability of urothelial cancer cells to invade through a 3D extracellular matrix.	('invade', 'CPA', (154, 160))	('tested', 'Reg', (57, 63))	('depletion', 'Var', (84, 93))	('progranulin', 'Protein', (72, 83))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('174', '194'))	('urothelial cancer', 'Disease', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('affect', 'Reg', (105, 111))	('urothelial cancer', 'Disease', 'MESH:D014523', (127, 144))
77097	27220888	To extend the above in vitro finding into an in vivo setting, we generated tumor xenograft models and determined whether targeting progranulin could suppress the ability of UMUC-3 cells to form tumors.	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('suppress', 'NegReg', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumor', 'Disease', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('progranulin', 'Protein', (131, 142))	('targeting', 'Var', (121, 130))	('tumors', 'Disease', (194, 200))	('tumor', 'Disease', (75, 80))
77103	27220888	To further expand the above findings regarding the role of progranulin in bladder tumor formation in vivo, we generated orthotopic bladder cancer xenografts by injecting UMUC-3/shScr and UMUC-3/shPGRN into the bladder of immunocompromised mice under ultrasound guidance.	('formation', 'biological_process', 'GO:0009058', ('88', '97'))	('bladder cancer', 'Disease', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('bladder tumor', 'Disease', 'MESH:D001749', (74, 87))	('bladder tumor', 'Phenotype', 'HP:0009725', (74, 87))	('GRN', 'Gene', (197, 200))	('bladder cancer', 'Phenotype', 'HP:0009725', (131, 145))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('UMUC-3/shScr', 'Var', (170, 182))	('mice', 'Species', '10090', (239, 243))	('bladder cancer', 'Disease', 'MESH:D001749', (131, 145))	('GRN', 'Gene', '2896', (197, 200))	('bladder tumor', 'Disease', (74, 87))
77106	27220888	Ki67 was significantly reduced in UMUC-3/shPGRN xenografts (10% positive nuclei) compared to UMUC-3/shScr tissue control (47% positive nuclei) (Figure 7C) suggesting that progranulin depletion inhibits tumor proliferation in vivo.	('depletion', 'Var', (183, 192))	('GRN', 'Gene', '2896', (44, 47))	('tumor', 'Disease', (202, 207))	('inhibits', 'NegReg', (193, 201))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('reduced', 'NegReg', (23, 30))	('GRN', 'Gene', (44, 47))	('progranulin', 'Protein', (171, 182))
77122	27220888	These results further strengthen the hypothesis that progranulin is a leading pro-survival factor in bladder cancer and suggest that targeting progranulin together with cisplatin could enhance therapeutic efficacy of cisplatin-based therapy in invasive bladder tumors.	('invasive bladder tumors', 'Disease', (244, 267))	('pro-survival', 'biological_process', 'GO:0043066', ('78', '90'))	('cisplatin', 'Chemical', 'MESH:D002945', (217, 226))	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('invasive bladder tumors', 'Disease', 'MESH:D001749', (244, 267))	('targeting', 'Var', (133, 142))	('bladder tumors', 'Phenotype', 'HP:0009725', (253, 267))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('enhance', 'PosReg', (185, 192))	('invasive bladder', 'Phenotype', 'HP:0100645', (244, 260))	('bladder cancer', 'Disease', (101, 115))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('bladder tumor', 'Phenotype', 'HP:0009725', (253, 266))	('cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))	('progranulin', 'Protein', (143, 154))
77139	27220888	b) Progranulin targeting significantly diminished the ability of urothelial cancer cells to grow in anchorage-independency.	('diminished', 'NegReg', (39, 49))	('Progranulin', 'Gene', '2896', (3, 14))	('urothelial cancer', 'Disease', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Progranulin', 'Gene', (3, 14))	('urothelial cancer', 'Disease', 'MESH:D014523', (65, 82))	('targeting', 'Var', (15, 24))
77141	27220888	d) Progranulin depletion sensitizes UMUC-3 cells to cisplatin treatment.	('depletion', 'Var', (15, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('Progranulin', 'Gene', '2896', (3, 14))	('Progranulin', 'Gene', (3, 14))	('sensitizes', 'Reg', (25, 35))
77146	27220888	Reduced progranulin levels are associated with frontotemporal dementia similarly to haploinsufficiency associated with progranulin gene mutations and targeted manipulation of the sortilin/progranulin axis rescues progranulin haploinsufficiency.	('progranulin levels', 'MPA', (8, 26))	('sortilin', 'Gene', (179, 187))	('Reduced', 'NegReg', (0, 7))	('haploinsufficiency', 'Disease', (84, 102))	('associated', 'Reg', (31, 41))	('haploinsufficiency', 'Disease', (225, 243))	('dementia', 'Phenotype', 'HP:0000726', (62, 70))	('mutations', 'Var', (136, 145))	('dementia', 'Disease', (62, 70))	('sortilin', 'Gene', '6272', (179, 187))	('frontotemporal dementia', 'Phenotype', 'HP:0002145', (47, 70))	('haploinsufficiency', 'Disease', 'MESH:D058495', (84, 102))	('dementia', 'Disease', 'MESH:D003704', (62, 70))	('haploinsufficiency', 'Disease', 'MESH:D058495', (225, 243))
77152	27220888	In addition, in the presence of CpG-ONDs progranulin proteolytic fragments are soluble cofactors for Toll-like receptor 9 (TLR9) and regulate innate immunity.	('CpG-ONDs', 'Var', (32, 40))	('regulate', 'Reg', (133, 141))	('innate immunity', 'biological_process', 'GO:0045087', ('142', '157'))	('innate immunity', 'CPA', (142, 157))	('soluble', 'cellular_component', 'GO:0005625', ('79', '86'))	('TLR9', 'Gene', (123, 127))	('Toll-like receptor 9', 'Gene', '54106', (101, 121))	('Toll-like receptor 9', 'Gene', (101, 121))	('TLR9', 'Gene', '54106', (123, 127))
77306	26604797	This study provides further evidence that the presence of LVI in TURBT specimens is significantly associated with an increased risk of disease recurrence and a shorter RFS time in patients with newly diagnosed T1 urothelial carcinoma of the bladder.	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (213, 248))	('urothelial carcinoma of the bladder', 'Disease', (213, 248))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (213, 248))	('presence', 'Var', (46, 54))	('disease', 'Disease', (135, 142))	('RFS time', 'MPA', (168, 176))	('men', 'Species', '9606', (76, 79))	('LVI', 'Chemical', '-', (58, 61))	('LVI', 'Disease', (58, 61))	('shorter', 'NegReg', (160, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('patients', 'Species', '9606', (180, 188))
77338	25367311	The epithelial cells expressed CK7 and CK34betaE12, and the lymphocytes CD3 and CD20 (Figure 4).	('CK34betaE12', 'Var', (39, 50))	('CK7', 'Gene', '3855', (31, 34))	('CD20', 'Gene', '54474', (80, 84))	('CD20', 'Gene', (80, 84))	('CK7', 'Gene', (31, 34))
77401	33925044	Metastatic urothelial carcinomas often harbor APOBEC3B-mediated mutations in which tCw to T or G substitution occurs.	('APOBEC', 'cellular_component', 'GO:0030895', ('46', '52'))	('APOBEC3B', 'Gene', '9582', (46, 54))	('Metastatic urothelial carcinomas', 'Disease', (0, 32))	('Metastatic urothelial carcinomas', 'Disease', 'MESH:C538445', (0, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('mutations', 'Var', (64, 73))	('APOBEC3B', 'Gene', (46, 54))	('tCw', 'Chemical', '-', (83, 86))
77407	33925044	The median overall survival was longer in patients with high APOBEC3B expression (15 months) than in those with low expression (p = 0.045).	('longer', 'PosReg', (32, 38))	('overall survival', 'MPA', (11, 27))	('APOBEC', 'cellular_component', 'GO:0030895', ('61', '67'))	('APOBEC3B', 'Gene', (61, 69))	('APOBEC3B', 'Gene', '9582', (61, 69))	('patients', 'Species', '9606', (42, 50))	('high', 'Var', (56, 60))
77416	33925044	The risk factors for bladder cancer are exposure to chemicals, such as those in tobacco, chronic irritation, and abnormalities in genes related to cell cycle regulation.	('irritation', 'Disease', (97, 107))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('147', '168'))	('bladder cancer', 'Phenotype', 'HP:0009725', (21, 35))	('irritation', 'Disease', 'MESH:D001523', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('bladder cancer', 'Disease', 'MESH:D001749', (21, 35))	('abnormalities', 'Var', (113, 126))	('bladder cancer', 'Disease', (21, 35))	('tobacco', 'Species', '4097', (80, 87))
77417	33925044	In terms of gene abnormalities, an analysis of the frequency of somatic mutations using 3083 tumor-normal paired specimens from 27 types of cancer revealed that bladder cancer has a mean non-synonymous mutation rate of 8.2 mutations/megabyte (MB) and a median rate of 5.8 mutations/MB.	('cancer', 'Disease', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('bladder cancer', 'Phenotype', 'HP:0009725', (161, 175))	('tumor', 'Disease', (93, 98))	('gene abnormalities', 'Disease', (12, 30))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('bladder cancer', 'Disease', 'MESH:D001749', (161, 175))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutations/megabyte', 'Var', (223, 241))	('gene abnormalities', 'Disease', 'MESH:D006623', (12, 30))	('bladder cancer', 'Disease', (161, 175))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
77419	33925044	An analysis of the mutation spectrum showed that the major mutation pattern differs for each cancer type, such as TpC > mutation for bladder cancer, C > T for malignant melanoma, C > A for lung cancer, and CpG > T for gastrointestinal track cancer.	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('gastrointestinal track cancer', 'Phenotype', 'HP:0007378', (218, 247))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('C > T', 'Var', (149, 154))	('CpG > T', 'Var', (206, 213))	('malignant melanoma', 'Phenotype', 'HP:0002861', (159, 177))	('malignant melanoma', 'Disease', 'MESH:D008545', (159, 177))	('lung cancer', 'Disease', (189, 200))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('bladder cancer', 'Disease', 'MESH:D001749', (133, 147))	('bladder cancer', 'Disease', (133, 147))	('gastrointestinal track cancer', 'Disease', 'MESH:D004067', (218, 247))	('C > A', 'Var', (179, 184))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))	('cancer', 'Disease', (93, 99))	('gastrointestinal track cancer', 'Disease', (218, 247))	('cancer', 'Disease', (194, 200))	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('TpC > mutation', 'Var', (114, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('malignant melanoma', 'Disease', (159, 177))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (241, 247))
77421	33925044	Of these, signatures 2 and 13 overlap with the aforementioned TpC > mutation pattern, which is a well-known form of apolipoprotein B mRNA editing enzyme (APOBEC)-mediated mutation in which the C in the tCw triplet motif is changed to a T or G. APOBEC enzymes are a family of evolutionarily conserved cytidine deaminases and are endogenous mutagens that induce somatic driver and passenger gene mutations in human cancers through cytidine deaminase.	('apolipoprotein', 'molecular_function', 'GO:0005320', ('116', '130'))	('cancers', 'Disease', (413, 420))	('mRNA editing', 'biological_process', 'GO:0016556', ('133', '145'))	('cancers', 'Disease', 'MESH:D009369', (413, 420))	('APOBEC', 'cellular_component', 'GO:0030895', ('154', '160'))	('APOBEC', 'cellular_component', 'GO:0030895', ('244', '250'))	('apolipoprotein', 'molecular_function', 'GO:0005319', ('116', '130'))	('cytidine', 'Chemical', 'MESH:D003562', (429, 437))	('apolipoprotein B', 'Gene', '338', (116, 132))	('cancer', 'Phenotype', 'HP:0002664', (413, 419))	('cytidine', 'Chemical', 'MESH:D003562', (300, 308))	('cancers', 'Phenotype', 'HP:0002664', (413, 420))	('tCw', 'Chemical', '-', (202, 205))	('mutations', 'Var', (394, 403))	('human', 'Species', '9606', (407, 412))	('apolipoprotein B', 'Gene', (116, 132))
77423	33925044	The mutational pattern C > A is known to be related to smoking and is often observed in lung cancer, whereas the tCw > T or G mutational pattern is mainly observed in bladder cancer.	('lung cancer', 'Disease', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('bladder cancer', 'Phenotype', 'HP:0009725', (167, 181))	('bladder cancer', 'Disease', 'MESH:D001749', (167, 181))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('C > A', 'Var', (23, 28))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('bladder cancer', 'Disease', (167, 181))	('tCw', 'Chemical', '-', (113, 116))	('observed', 'Reg', (76, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
77424	33925044	This suggests that, in addition to smoking, APOBEC-mediated mutations are a major contributor to bladder cancer development.	('APOBEC', 'cellular_component', 'GO:0030895', ('44', '50'))	('bladder cancer', 'Disease', 'MESH:D001749', (97, 111))	('bladder cancer', 'Disease', (97, 111))	('APOBEC-mediated', 'Gene', (44, 59))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('mutations', 'Var', (60, 69))
77427	33925044	We hypothesized that these results may be associated with the infiltration of T lymphocytes into tumors as a result of an APOBEC-mediated high mutation burden.	('high mutation burden', 'Var', (138, 158))	('APOBEC', 'cellular_component', 'GO:0030895', ('122', '128'))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('APOBEC-mediated', 'Gene', (122, 137))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
77437	33925044	The median OS was longer in patients with high APOBEC3B expression at 15 months than in those with low expression at nine months (p = 0.045 by log-rank test; Figure 1a).	('APOBEC3B', 'Gene', (47, 55))	('APOBEC3B', 'Gene', '9582', (47, 55))	('expression', 'MPA', (56, 66))	('high', 'Var', (42, 46))	('patients', 'Species', '9606', (28, 36))	('APOBEC', 'cellular_component', 'GO:0030895', ('47', '53'))
77438	33925044	Similarly, the median progression-free survival (PFS) was longer in patients with high APOBEC3B expression at seven months than in those with low expression at four months (p = 0.018 by log-rank test; Figure 1b).	('high', 'Var', (82, 86))	('expression', 'MPA', (96, 106))	('longer', 'PosReg', (58, 64))	('patients', 'Species', '9606', (68, 76))	('APOBEC3B', 'Gene', (87, 95))	('APOBEC', 'cellular_component', 'GO:0030895', ('87', '93'))	('APOBEC3B', 'Gene', '9582', (87, 95))	('progression-free survival', 'CPA', (22, 47))
77441	33925044	As APOBEC3B is an endogenous carcinogenic mutagen by APOBEC-mediated cytidine deamination, we hypothesized that APOBEC mutation would result in the production of a tumor neoantigen and increased infiltration of T lymphocytes into intra- or peri-tumor tissues.	('carcinogenic', 'Disease', (29, 41))	('tumor', 'Disease', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('APOBEC3B', 'Gene', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('carcinogenic', 'Disease', 'MESH:D063646', (29, 41))	('APOBEC', 'Gene', (112, 118))	('APOBEC', 'cellular_component', 'GO:0030895', ('3', '9'))	('cytidine deamination', 'biological_process', 'GO:0009972', ('69', '89'))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('increased', 'PosReg', (185, 194))	('APOBEC', 'cellular_component', 'GO:0030895', ('53', '59'))	('mutation', 'Var', (119, 127))	('APOBEC', 'cellular_component', 'GO:0030895', ('112', '118'))	('cytidine', 'Chemical', 'MESH:D003562', (69, 77))	('APOBEC3B', 'Gene', '9582', (3, 11))	('tumor', 'Disease', (245, 250))	('production', 'MPA', (148, 158))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('result in', 'Reg', (134, 143))	('infiltration', 'CPA', (195, 207))
77449	33925044	Therefore, considering the association of APOBEC3B expression with TILs, we expected that high APOBEC3B expression might be associated with a better cytotoxic effect for metastatic urothelial carcinoma.	('APOBEC3B', 'Gene', (95, 103))	('APOBEC', 'cellular_component', 'GO:0030895', ('42', '48'))	('APOBEC3B', 'Gene', '9582', (95, 103))	('expression', 'MPA', (104, 114))	('APOBEC3B', 'Gene', (42, 50))	('urothelial carcinoma', 'Disease', (181, 201))	('better', 'PosReg', (142, 148))	('cytotoxic effect', 'CPA', (149, 165))	('APOBEC3B', 'Gene', '9582', (42, 50))	('high', 'Var', (90, 94))	('APOBEC', 'cellular_component', 'GO:0030895', ('95', '101'))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (181, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
77452	33925044	In a previous comparative study of 14 cancer types, APOBEC-mediated mutations in bladder cancer were observed at a higher rate than those in other cancers.	('cancers', 'Disease', (147, 154))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('APOBEC', 'cellular_component', 'GO:0030895', ('52', '58'))	('bladder cancer', 'Phenotype', 'HP:0009725', (81, 95))	('mutations', 'Var', (68, 77))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('bladder cancer', 'Disease', 'MESH:D001749', (81, 95))	('bladder cancer', 'Disease', (81, 95))	('cancer', 'Disease', (89, 95))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (38, 44))	('cancer', 'Disease', (147, 153))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('APOBEC-mediated', 'Gene', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
77453	33925044	APOBEC-mediated mutation has been reported to correlate with APOBEC mRNA expression, and APOBEC1, APOBEC3A, APOBEC3B, APOBEC3F, and APOBEC3G, among the APOBEC family members, have been statistically confirmed to correlate with mRNA expression.	('APOBEC3G', 'Gene', (132, 140))	('APOBEC1', 'Gene', '339', (89, 96))	('APOBEC3F', 'Gene', '200316', (118, 126))	('APOBEC3B', 'Gene', '9582', (108, 116))	('APOBEC', 'cellular_component', 'GO:0030895', ('152', '158'))	('APOBEC3A', 'Gene', (98, 106))	('APOBEC', 'cellular_component', 'GO:0030895', ('118', '124'))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('APOBEC', 'cellular_component', 'GO:0030895', ('98', '104'))	('APOBEC3A', 'Gene', '200315', (98, 106))	('APOBEC', 'cellular_component', 'GO:0030895', ('89', '95'))	('APOBEC3G', 'Gene', '60489', (132, 140))	('APOBEC-mediated', 'Gene', (0, 15))	('APOBEC3B', 'Gene', (108, 116))	('mutation', 'Var', (16, 24))	('APOBEC', 'Gene', (61, 67))	('APOBEC', 'cellular_component', 'GO:0030895', ('61', '67'))	('APOBEC', 'cellular_component', 'GO:0030895', ('108', '114'))	('APOBEC1', 'Gene', (89, 96))	('APOBEC', 'cellular_component', 'GO:0030895', ('132', '138'))	('mRNA expression', 'MPA', (227, 242))	('APOBEC3F', 'Gene', (118, 126))
77461	33925044	Subsequently, APOBEC mutation of the tCw motif was identified, and it was found to be highly specific in single-stranded DNA and responsible for somatic mutations that may induce carcinogenesis and cancer evolution in various types of human solid cancers.	('mutations', 'Var', (153, 162))	('carcinogenesis', 'Disease', (179, 193))	('cancer', 'Disease', (247, 253))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancers', 'Disease', (247, 254))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Disease', (198, 204))	('carcinogenesis', 'Disease', 'MESH:D063646', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('responsible', 'Reg', (129, 140))	('single-stranded DNA', 'MPA', (105, 124))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('human', 'Species', '9606', (235, 240))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('induce', 'Reg', (172, 178))	('APOBEC', 'cellular_component', 'GO:0030895', ('14', '20'))	('mutation', 'Var', (21, 29))	('tCw', 'Chemical', '-', (37, 40))
77462	33925044	Gene mutations in bladder cancer resulting in a high expression of APOBEC are frequently observed in genes related to DNA damage response, chromatin modification, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), and tumor protein p53 (TP53).	('PIK3CA', 'Gene', (236, 242))	('TP53', 'Gene', (268, 272))	('tumor', 'Disease', (249, 254))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('DNA damage response', 'biological_process', 'GO:0006974', ('118', '137'))	('p53', 'Gene', '7157', (263, 266))	('bladder cancer', 'Disease', 'MESH:D001749', (18, 32))	('chromatin modification', 'biological_process', 'GO:0006325', ('139', '161'))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('bladder cancer', 'Disease', (18, 32))	('p53', 'Gene', (263, 266))	('bladder cancer', 'Phenotype', 'HP:0009725', (18, 32))	('APOBEC', 'cellular_component', 'GO:0030895', ('67', '73'))	('chromatin modification', 'MPA', (139, 161))	('TP53', 'Gene', '7157', (268, 272))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('PIK3CA', 'Gene', '5290', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('mutations', 'Var', (5, 14))	('expression', 'MPA', (53, 63))	('DNA damage', 'MPA', (118, 128))	('chromatin modification', 'biological_process', 'GO:0016569', ('139', '161'))	('protein', 'cellular_component', 'GO:0003675', ('255', '262'))	('chromatin', 'cellular_component', 'GO:0000785', ('139', '148'))
77463	33925044	In contrast, specimens with a low expression of APOBEC are reported to have mutations in KRAS and fibroblast growth factor receptor 3 (FGFR3).	('mutations', 'Var', (76, 85))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('98', '122'))	('FGFR3', 'Gene', (135, 140))	('APOBEC', 'Gene', (48, 54))	('fibroblast growth factor receptor 3', 'Gene', '2261', (98, 133))	('FGFR3', 'Gene', '2261', (135, 140))	('fibroblast growth factor receptor 3', 'Gene', (98, 133))	('APOBEC', 'cellular_component', 'GO:0030895', ('48', '54'))	('KRAS', 'Gene', (89, 93))	('FGFR', 'molecular_function', 'GO:0005007', ('135', '139'))	('KRAS', 'Gene', '3845', (89, 93))
77464	33925044	These distinct mutational characteristics suggest that the tumor biology of bladder cancer may be different between those with high and low expression of APOBEC3B and that the APOBEC3B activity may be associated with DNA damage response.	('activity', 'MPA', (185, 193))	('DNA damage response', 'biological_process', 'GO:0006974', ('217', '236'))	('APOBEC', 'cellular_component', 'GO:0030895', ('176', '182'))	('tumor', 'Disease', (59, 64))	('high', 'Var', (127, 131))	('APOBEC3B', 'Gene', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('APOBEC3B', 'Gene', (176, 184))	('APOBEC', 'cellular_component', 'GO:0030895', ('154', '160'))	('DNA', 'cellular_component', 'GO:0005574', ('217', '220'))	('low', 'NegReg', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('APOBEC3B', 'Gene', '9582', (154, 162))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('APOBEC3B', 'Gene', '9582', (176, 184))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))	('bladder cancer', 'Disease', (76, 90))	('expression', 'MPA', (140, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('associated', 'Reg', (201, 211))
77467	33925044	In addition, in APOBEC3A-expressing cells, inhibition of ataxia telangiectasia and Rad3-related protein (ATR), a protein involved in DNA damage response, results in an increase in apurinic/apyrimidinic (abasic) sites and the accumulation of single-stranded DNA, which drive cells into a replication catastrophe, including massive DNA breakage and cell death.	('increase', 'PosReg', (168, 176))	('APOBEC3A', 'Gene', '200315', (16, 24))	('inhibition', 'Var', (43, 53))	('massive DNA breakage', 'Phenotype', 'HP:0040012', (322, 342))	('Rad', 'biological_process', 'GO:1990116', ('83', '86'))	('accumulation', 'PosReg', (225, 237))	('cell death', 'biological_process', 'GO:0008219', ('347', '357'))	('ATR', 'Gene', '545', (105, 108))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('ataxia telangiectasia and Rad3-related protein', 'Gene', '545', (57, 103))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('telangiectasia', 'Phenotype', 'HP:0001009', (64, 78))	('DNA damage response', 'biological_process', 'GO:0006974', ('133', '152'))	('ataxia', 'Phenotype', 'HP:0001251', (57, 63))	('APOBEC', 'cellular_component', 'GO:0030895', ('16', '22'))	('DNA', 'cellular_component', 'GO:0005574', ('257', '260'))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('ATR', 'Gene', (105, 108))	('DNA breakage', 'CPA', (330, 342))	('DNA', 'cellular_component', 'GO:0005574', ('330', '333'))	('single-stranded', 'Var', (241, 256))	('APOBEC3A', 'Gene', (16, 24))
77476	33925044	These previous study results suggest that, in metastatic bladder cancer, the differences in survival curves depending on APOBEC3B expression may be associated with APOBEC-mediated mutations and TILs.	('mutations', 'Var', (180, 189))	('APOBEC', 'cellular_component', 'GO:0030895', ('121', '127'))	('bladder cancer', 'Disease', 'MESH:D001749', (57, 71))	('bladder cancer', 'Disease', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('associated', 'Reg', (148, 158))	('APOBEC3B', 'Gene', (121, 129))	('APOBEC', 'cellular_component', 'GO:0030895', ('164', '170'))	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))	('APOBEC3B', 'Gene', '9582', (121, 129))
77482	33925044	Second, there is considerable evidence from previous studies regarding correlations between total non-synonymous mutation of cancer-associated genes and mRNA expression of APOBEC3B.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('non-synonymous mutation', 'Var', (98, 121))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('correlations', 'Interaction', (71, 83))	('APOBEC3B', 'Gene', (172, 180))	('APOBEC', 'cellular_component', 'GO:0030895', ('172', '178'))	('cancer', 'Disease', (125, 131))	('APOBEC3B', 'Gene', '9582', (172, 180))	('mRNA expression', 'MPA', (153, 168))
77489	33925044	Perhaps, this is related to immune surveillance and is a factor leading to a better prognosis of patients with high APOBEC expression in bladder cancer undergoing cytotoxic chemotherapy than patients with low APOBEC expression.	('APOBEC', 'Gene', (116, 122))	('patients', 'Species', '9606', (191, 199))	('bladder cancer', 'Phenotype', 'HP:0009725', (137, 151))	('APOBEC', 'cellular_component', 'GO:0030895', ('209', '215'))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (137, 151))	('APOBEC', 'cellular_component', 'GO:0030895', ('116', '122'))	('bladder cancer', 'Disease', (137, 151))	('high', 'Var', (111, 115))	('patients', 'Species', '9606', (97, 105))
77493	33925044	In bladder cancer, anti-PD1 or PD-L1 monoclonal antibodies are among the therapeutic choices for treating patients with metastatic urothelial carcinoma.	('anti-PD1', 'Var', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('urothelial carcinoma', 'Disease', (131, 151))	('PD-L1', 'Gene', '29126', (31, 36))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (131, 151))	('patients', 'Species', '9606', (106, 114))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('PD-L1', 'Gene', (31, 36))
77496	33925044	Another study suggested that APOBEC-induced mutagenesis affects immune evasion of cancer cells through HLA mutations in urothelial carcinoma.	('HLA', 'Gene', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('mutations', 'Var', (107, 116))	('immune evasion', 'biological_process', 'GO:0051842', ('64', '78'))	('mutagenesis', 'biological_process', 'GO:0006280', ('44', '55'))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('APOBEC', 'cellular_component', 'GO:0030895', ('29', '35'))	('APOBEC-induced', 'Gene', (29, 43))	('urothelial carcinoma', 'Disease', (120, 140))	('mutagenesis', 'Var', (44, 55))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (120, 140))	('affects', 'Reg', (56, 63))	('immune evasion', 'biological_process', 'GO:0042783', ('64', '78'))
77497	33925044	Contrary to a good response expected due to increased tumor mutation burden, these results support the possibility of resistance to ICIs in metastatic urothelial carcinoma by harboring APOBEC3B-mediated mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('APOBEC', 'cellular_component', 'GO:0030895', ('185', '191'))	('APOBEC3B', 'Gene', '9582', (185, 193))	('APOBEC3B', 'Gene', (185, 193))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('urothelial carcinoma', 'Disease', (151, 171))	('tumor', 'Disease', (54, 59))	('mutations', 'Var', (203, 212))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (151, 171))
77498	33925044	Therefore, besides cytotoxic chemotherapy, further studies are needed to evaluate the influence of APOBEC3B mutation on ICIs in urothelial carcinoma.	('urothelial carcinoma', 'Disease', (128, 148))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (128, 148))	('APOBEC3B', 'Gene', (99, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('APOBEC3B', 'Gene', '9582', (99, 107))	('APOBEC', 'cellular_component', 'GO:0030895', ('99', '105'))	('mutation', 'Var', (108, 116))
77549	29217288	Factors predictive of shorter survival include abnormal albumin and low haemoglobin concentrations, reduced performance status, and presence of liver metastasis.	('liver metastasis', 'Disease', 'MESH:D009362', (144, 160))	('liver metastasis', 'Disease', (144, 160))	('reduced', 'NegReg', (100, 107))	('performance', 'MPA', (108, 119))	('low', 'NegReg', (68, 71))	('albumin', 'Gene', (56, 63))	('albumin', 'Gene', '213', (56, 63))	('abnormal', 'Var', (47, 55))	('low haemoglobin concentrations', 'Phenotype', 'HP:0020062', (68, 98))	('low haemoglobin', 'Phenotype', 'HP:0001903', (68, 83))	('shorter', 'NegReg', (22, 29))	('abnormal albumin', 'Phenotype', 'HP:0012116', (47, 63))
77555	29217288	Anti-PD-L1 and anti-PD-1 antibodies have been associated with antitumour responses in patients with metastatic urothelial carcinoma, showing the therapeutic potential of these agents.	('urothelial carcinoma', 'Disease', (111, 131))	('Anti-PD-L1', 'Var', (0, 10))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (111, 131))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('antibodies', 'Var', (25, 35))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('anti-PD-1', 'Gene', (15, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('tumour', 'Disease', (66, 72))	('patients', 'Species', '9606', (86, 94))
77559	29217288	In patients with metastatic urothelial carcinoma treated with systemic chemotherapy, tumour PD-L1 positivity did not correlate with overall survival, but PD-L1 on tumour-infiltrating mononuclear cells was associated with longer overall survival.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (28, 48))	('tumour PD-L1', 'Disease', (85, 97))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour PD-L1', 'Disease', 'MESH:D010300', (85, 97))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('tumour', 'Disease', (85, 91))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('overall survival', 'MPA', (228, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('PD-L1', 'Var', (154, 159))	('patients', 'Species', '9606', (3, 11))	('longer', 'PosReg', (221, 227))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('urothelial carcinoma', 'Disease', (28, 48))	('tumour', 'Disease', (163, 169))
77584	29217288	Permanent discontinuation of treatment was specified for any grade 3 or worse adverse events (exceptions included single laboratory values out of normal range that were unrelated to trial treatment according to the investigator, that did not have clinical correlates, and that resolved within 7 days with adequate medical intervention; transient [<=6 h] flu-like symptoms or fever controlled with medical management; fatigue, local infusion-related reaction, headache, nausea, or emesis that resolved to grade <=1 within 24 h; tumour flare, defined as local pain, irritation, or rash localised at sites of known or suspected malignant tissue); any grade 3 or worse drug-related amylase or lipase abnormality that was not associated with symptoms or clinical manifestations of pancreatitis that did not require dose delay, or recurring grade 2 treatment-related adverse events.	('flu-like symptoms or fever', 'Phenotype', 'HP:0002373', (354, 380))	('fever', 'Phenotype', 'HP:0001945', (375, 380))	('headache', 'Disease', 'MESH:D006261', (459, 467))	('pancreatitis', 'Phenotype', 'HP:0001733', (776, 788))	('pain', 'Disease', (558, 562))	('abnormality', 'Var', (696, 707))	('tumour', 'Phenotype', 'HP:0002664', (527, 533))	('nausea', 'Phenotype', 'HP:0002018', (469, 475))	('tumour', 'Disease', 'MESH:D009369', (527, 533))	('pain', 'Phenotype', 'HP:0012531', (558, 562))	('tumour', 'Disease', (527, 533))	('rash', 'Phenotype', 'HP:0000988', (579, 583))	('fatigue', 'Disease', (417, 424))	('pancreatitis', 'Disease', 'MESH:D010195', (776, 788))	('irritation', 'Disease', (564, 574))	('fatigue', 'Phenotype', 'HP:0012378', (417, 424))	('rash localised', 'Phenotype', 'HP:0011355', (579, 593))	('headache', 'Phenotype', 'HP:0002315', (459, 467))	('emesis', 'Phenotype', 'HP:0002013', (480, 486))	('nausea', 'Disease', (469, 475))	('emesis', 'Disease', 'MESH:D014839', (480, 486))	('pancreatitis', 'Disease', (776, 788))	('emesis', 'Disease', (480, 486))	('rash', 'Disease', (579, 583))	('pain', 'Disease', 'MESH:D010146', (558, 562))	('headache', 'Disease', (459, 467))	('fever', 'Disease', 'MESH:D005334', (375, 380))	('fever', 'Disease', (375, 380))	('irritation', 'Disease', 'MESH:D001523', (564, 574))	('nausea', 'Disease', 'MESH:D009325', (469, 475))	('rash', 'Disease', 'MESH:D005076', (579, 583))	('fatigue', 'Disease', 'MESH:D005221', (417, 424))
77587	29217288	Resulting mutations were analysed with NetMHCPan to predict peptide binding to major histocompatibility complex molecules of known sequences.	('peptide binding', 'molecular_function', 'GO:0042277', ('60', '75'))	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('79', '111'))	('peptide', 'MPA', (60, 67))	('NetMHCPan', 'Chemical', '-', (39, 48))	('mutations', 'Var', (10, 19))
77622	29217288	B ased o n 2 9 s amples evaluable for mutational load, an exploratory post-hoc analysis of association between increased mutational load and improved antitumour response did not reach statistical significance ( p=0 076, W ilcoxon r ank s um test; figure 3B).	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('mutational load', 'Var', (121, 136))	('tumour', 'Disease', (154, 160))	('improved', 'PosReg', (141, 149))
77625	29217288	Figure 4A shows progression-free survival in patients with PD-L1-positive and PD-L1-negative tumours according to independent review.	('PD-L1-negative tumours', 'Disease', (78, 100))	('PD-L1-negative tumours', 'Disease', 'MESH:D010300', (78, 100))	('patients', 'Species', '9606', (45, 53))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('PD-L1-positive', 'Var', (59, 73))
77656	29217288	The association between PD-L1 status and anti-PD-L1 or anti-PD-1 treatment activity in urothelial carcinoma is still uncertain.	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (87, 107))	('anti-PD-L1', 'Var', (41, 51))	('urothelial carcinoma', 'Disease', (87, 107))
77662	29217288	An association between increased mutational load and improved outcome has been reported in similar analyses with other anti-PD-L1 or anti-PD-1 inhibitors; however, our similar analysis in a small subset of patients did not reach statistical significance.	('improved', 'PosReg', (53, 61))	('patients', 'Species', '9606', (206, 214))	('mutational load', 'Var', (33, 48))
77663	29217288	Assessment of antitumour activity related to mutational load and PD-L1 expression as a combined measure could provide further insights into the possible predictive role of these biomarkers; however, this analysis could not be done because of the small number of evaluable samples available.	('mutational load', 'Var', (45, 60))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('PD-L1', 'Gene', (65, 70))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('tumour', 'Disease', (18, 24))
77678	29217288	Between 2016 and 2017, several phase 1 and 2 trials of anti-programmed death ligand 1 (PD-L1) and anti-programmed death-1 (PD-1) monoclonal antibodies reported encouraging antitumour activity and safety for treatment of advanced or metastatic urothelial carcinoma.	('programmed death ligand 1', 'Gene', (60, 85))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('anti-programmed', 'Var', (98, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('death-1 (PD-1) monoclonal', 'Disease', 'MESH:D010300', (114, 139))	('urothelial carcinoma', 'Disease', (243, 263))	('programmed death ligand 1', 'Gene', '574058', (60, 85))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (243, 263))	('tumour', 'Disease', (176, 182))	('ligand', 'molecular_function', 'GO:0005488', ('77', '83'))
77762	30634925	Although many explorations have revealed that high TMB may yield many neoantigens to incite antitumor immune response, a systematic exploration of the correlation between TMB and immune signatures in different cancer types is lacking.	('neoantigens', 'MPA', (70, 81))	('high', 'Var', (46, 50))	('incite', 'PosReg', (85, 91))	('TMB', 'Chemical', '-', (171, 174))	('TMB', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('TMB', 'Chemical', '-', (51, 54))	('tumor', 'Disease', (96, 101))	('immune response', 'biological_process', 'GO:0006955', ('102', '117'))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Disease', (210, 216))
77766	30634925	Importantly, high TMB was associated with elevated expression of PD-L1 in diverse prevailing cancers.	('PD-L1', 'Gene', '29126', (65, 70))	('cancers', 'Disease', (93, 100))	('high', 'Var', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('TMB', 'Chemical', '-', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PD-L1', 'Gene', (65, 70))	('expression', 'MPA', (51, 61))	('elevated', 'PosReg', (42, 50))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
77768	30634925	High TMB may inhibit immune cell infiltrations while promote CTAs expression and inflammatory response in cancer.	('CTAs expression', 'CPA', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('High TMB', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('immune cell infiltrations', 'CPA', (21, 46))	('inflammatory response', 'biological_process', 'GO:0006954', ('81', '102'))	('cancer', 'Disease', (106, 112))	('inhibit', 'NegReg', (13, 20))	('inflammatory response', 'CPA', (81, 102))	('TMB', 'Chemical', '-', (5, 8))	('promote', 'PosReg', (53, 60))
77770	30634925	Our data implicate that higher-TMB patients could gain a more favorable prognosis in diverse cancer types if treated with immunotherapy, otherwise would have a poorer prognosis compared to lower-TMB patients.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('TMB', 'Chemical', '-', (195, 198))	('TMB', 'Chemical', '-', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('gain', 'PosReg', (50, 54))	('patients', 'Species', '9606', (199, 207))	('patients', 'Species', '9606', (35, 43))	('higher-TMB', 'Var', (24, 34))
77774	30634925	Some well-recognized molecular determinants include PD-L1 expression on tumor, DNA mismatch-repair deficiency, neoantigen load, and tumor-infiltrating lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('deficiency', 'Var', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('PD-L1', 'Gene', '29126', (52, 57))	('mismatch-repair', 'biological_process', 'GO:0006298', ('83', '98'))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (132, 137))	('PD-L1', 'Gene', (52, 57))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
77777	30634925	These studies demonstrated that higher nonsynonymous mutation burden in tumors is inclined to form more neoantigens that make tumors to have higher immunogenicity, and thus result to improved clinical response to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('improved', 'PosReg', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('make tumors', 'Disease', (121, 132))	('higher', 'PosReg', (141, 147))	('clinical response', 'CPA', (192, 209))	('nonsynonymous mutation burden', 'Var', (39, 68))	('make tumors', 'Disease', 'MESH:C537705', (121, 132))	('immunogenicity', 'MPA', (148, 162))
77790	30634925	These results suggest that the relatedness between TMB and Treg cells infiltration degree depends on cancer types, whereas the lower-TMB subtype is likely to have stronger Treg cells infiltration than the higher-TMB subtype in diverse cancers.	('TMB', 'Chemical', '-', (133, 136))	('TMB', 'Chemical', '-', (212, 215))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', (235, 241))	('TMB', 'Chemical', '-', (51, 54))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('cancers', 'Disease', (235, 242))	('Treg cells infiltration', 'CPA', (172, 195))	('lower-TMB', 'Var', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('stronger', 'PosReg', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
77810	30634925	Again, this suggests that high TMB tends to inhibit immune cell infiltration in cancer.	('high', 'Var', (26, 30))	('inhibit', 'NegReg', (44, 51))	('TMB', 'Chemical', '-', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('immune cell infiltration', 'CPA', (52, 76))	('cancer', 'Disease', (80, 86))
77818	30634925	These results indicated that although the association between TMB and TILs infiltration was cancer type dependent, high TMB tended to inhibit TILs infiltration in various cancer types.	('high', 'Var', (115, 119))	('TILs infiltration', 'MPA', (142, 159))	('TMB', 'Chemical', '-', (120, 123))	('TMB', 'Chemical', '-', (62, 65))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('inhibit', 'NegReg', (134, 141))	('association', 'Interaction', (42, 53))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('TMB', 'Gene', (120, 123))
77829	30634925	These results suggest that high TMB is associated with elevated expression of many CTAs in cancer.	('expression', 'MPA', (64, 74))	('CTAs', 'Disease', (83, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('high', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('TMB', 'Chemical', '-', (32, 35))	('elevated', 'PosReg', (55, 63))
77842	30634925	It suggests that high TMB may lead to depressed cytokine activity in diverse cancers.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('depressed cytokine activity', 'Phenotype', 'HP:0031407', (38, 65))	('cancers', 'Disease', (77, 84))	('high', 'Var', (17, 21))	('TMB', 'Chemical', '-', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cytokine', 'Gene', '943', (48, 56))	('cytokine', 'Gene', (48, 56))	('cytokine activity', 'molecular_function', 'GO:0005125', ('48', '65'))	('depressed', 'NegReg', (38, 47))
77861	30634925	However, the Treg cells, immune cell infiltrate, TILs, and CCR signatures were inclined to be upregulated in the lower-TMB subtype of various cancer types, suggesting that high TMB may inhibit immune cell infiltration in the TIM.	('TMB', 'Chemical', '-', (119, 122))	('lower-TMB', 'Disease', (113, 122))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('high TMB', 'Var', (172, 180))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('immune cell infiltration in the TIM', 'CPA', (193, 228))	('TMB', 'Chemical', '-', (177, 180))	('CCR', 'molecular_function', 'GO:0043880', ('59', '62'))	('upregulated', 'PosReg', (94, 105))	('inhibit', 'NegReg', (185, 192))	('cancer', 'Disease', (142, 148))
77862	30634925	In contrast, the CTA and pro-inflammatory signatures tended to be upregulated in the higher-TMB subtype of various cancer types, suggesting that high TMB may promote CTA expression and tumor inflammatory response.	('tumor', 'Disease', (185, 190))	('inflammatory response', 'biological_process', 'GO:0006954', ('191', '212'))	('cancer', 'Disease', (115, 121))	('CTA', 'MPA', (17, 20))	('high', 'Var', (145, 149))	('promote', 'PosReg', (158, 165))	('upregulated', 'PosReg', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('CTA', 'Protein', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('TMB', 'Chemical', '-', (150, 153))	('TMB', 'Chemical', '-', (92, 95))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('expression', 'MPA', (170, 180))
77865	30634925	In fact, when we compared survival prognosis between the lower-TMB subtype and the higher-TMB subtype of cancers, we found that the lower-TMB subtype had better OS and/or DFS prognosis than the higher-TMB subtype in three of the four cancer types including HNSC, ACC, and LIHC (Fig.	('HNSC', 'Disease', (257, 261))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', (105, 111))	('cancers', 'Disease', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('LIHC', 'Disease', (272, 276))	('OS', 'Chemical', '-', (161, 163))	('better', 'PosReg', (154, 160))	('TMB', 'Chemical', '-', (90, 93))	('TMB', 'Chemical', '-', (138, 141))	('TMB', 'Chemical', '-', (201, 204))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('lower-TMB', 'Var', (132, 141))	('DFS', 'MPA', (171, 174))	('ACC', 'Gene', '31', (263, 266))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('ACC', 'Gene', (263, 266))	('TMB', 'Chemical', '-', (63, 66))	('cancer', 'Disease', (234, 240))
77867	30634925	Interestingly, we found that high TMB was associated with elevated pro-inflammatory immune activity while depressed immune cell infiltration in diverse cancers.	('high', 'Var', (29, 33))	('pro-inflammatory immune activity', 'MPA', (67, 99))	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('TMB', 'Chemical', '-', (34, 37))	('depressed immune cell', 'Phenotype', 'HP:0002721', (106, 127))	('elevated', 'PosReg', (58, 66))	('immune cell infiltration', 'CPA', (116, 140))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('depressed', 'NegReg', (106, 115))	('TMB', 'Gene', (34, 37))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
77868	30634925	These findings appear to be contradictory and disagree with the established notion that high TMB may yield numerous neoantigens that incite anti-tumor immune response.	('high', 'Var', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('incite', 'PosReg', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('TMB', 'Chemical', '-', (93, 96))	('tumor', 'Disease', (145, 150))	('immune response', 'biological_process', 'GO:0006955', ('151', '166'))	('neoantigens', 'MPA', (116, 127))
77869	30634925	The possible explanations are that high TMB is often associated with genome instability that may inhibit anti-tumor immune response, and that the increased pro-inflammatory immune activity could be attributed to the higher percent of tumor necrosis component elicited by gene mutations in the higher-TMB cancer.	('pro-inflammatory immune activity', 'MPA', (156, 188))	('inhibit', 'NegReg', (97, 104))	('tumor', 'Disease', (234, 239))	('necrosis', 'biological_process', 'GO:0008219', ('240', '248'))	('cancer', 'Disease', (304, 310))	('TMB', 'Chemical', '-', (300, 303))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('gene mutations', 'Var', (271, 285))	('increased', 'PosReg', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('necrosis', 'biological_process', 'GO:0008220', ('240', '248'))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('immune response', 'biological_process', 'GO:0006955', ('116', '131'))	('tumor necrosis', 'Disease', 'MESH:D009336', (234, 248))	('necrosis', 'biological_process', 'GO:0070265', ('240', '248'))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('necrosis', 'biological_process', 'GO:0019835', ('240', '248'))	('tumor necrosis', 'Disease', (234, 248))	('necrosis', 'biological_process', 'GO:0001906', ('240', '248'))	('high', 'Disease', (35, 39))	('TMB', 'Chemical', '-', (40, 43))	('tumor', 'Disease', (110, 115))	('higher', 'PosReg', (216, 222))	('higher-TMB', 'Disease', (293, 303))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
77890	30634925	High TMB was associated with elevated expression of PD-L1 in diverse prevailing cancers.	('elevated', 'PosReg', (29, 37))	('High', 'Var', (0, 4))	('PD-L1', 'Gene', '29126', (52, 57))	('expression', 'MPA', (38, 48))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('TMB', 'Chemical', '-', (5, 8))	('PD-L1', 'Gene', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
77893	30634925	Consistent with a method we proposed previously, the TMB score of a tumor sample was calculated as follows:  total number of truncating mutations * 2.0 + total number of non-truncating mutations * 1.0  Nonsense, frame-shift deletion or insertion, and splice-site mutations were included in the truncating mutation category, and missense, in-frame deletion or insertion, and nonstop mutations were included in the non-truncating mutation category.	('tumor', 'Disease', (68, 73))	('missense', 'Var', (328, 336))	('frame-shift deletion', 'Var', (212, 232))	('insertion', 'Var', (236, 245))	('splice-site mutations', 'Var', (251, 272))	('Nonsense', 'Var', (202, 210))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('in-frame deletion', 'Var', (338, 355))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('TMB', 'Chemical', '-', (53, 56))
77896	30634925	The Kaplan-Meier method was used to compare survival (OS and DFS) between two classes of cancer patients (higher-TMB versus lower-TMB, and gene-set higher-expression-level (upper half) versus gene-set lower-expression-level (bottom half)).	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('OS', 'Chemical', '-', (54, 56))	('gene-set', 'Var', (139, 147))	('cancer', 'Disease', (89, 95))	('higher-expression-level', 'PosReg', (148, 171))	('patients', 'Species', '9606', (96, 104))	('TMB', 'Chemical', '-', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('TMB', 'Chemical', '-', (130, 133))
77936	26793516	The Cancer Diagnostic (PCDx) Report revealed an EGFR c.2367C>T mutation which was considered as silent and not actionable (the finding is however 2 bases away from an actionable finding).	('EGFR', 'Gene', '1956', (48, 52))	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('c.2367C>T', 'Var', (53, 62))	('EGFR', 'Gene', (48, 52))	('c.2367C>T', 'Mutation', 'c.2367C>T', (53, 62))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
78018	20860834	In the following research the frequency of local recurrences in patients with pT4 was 4.8%, while the frequency of distant metastases was equal to 9.6%.	('pT4', 'Var', (78, 81))	('patients', 'Species', '9606', (64, 72))	('metastases', 'Disease', (123, 133))	('to 9', 'Species', '1214577', (144, 148))	('metastases', 'Disease', 'MESH:D009362', (123, 133))
78112	29748589	With recent approvals for immune checkpoint inhibitors (ICI) such as cytotoxic T lymphocyte associated antigen 4 inhibitors and programmed cell death protein 1 inhibitors in caners harboring programmed death ligand 1 (PD-L1) overexpression, microsatellite instability and high mutation load, many questions regarding the biomarker for the optimal use of ICI that block these pathways are raising.	('cytotoxic T lymphocyte associated antigen 4 inhibitors and programmed cell death protein 1', 'Gene', '5133', (69, 159))	('programmed death ligand 1', 'Gene', (191, 216))	('microsatellite instability', 'Var', (241, 267))	('PD-L1', 'Gene', (218, 223))	('overexpression', 'PosReg', (225, 239))	('programmed death ligand 1', 'Gene', '29126', (191, 216))	('programmed cell death', 'biological_process', 'GO:0012501', ('128', '149'))	('ligand', 'molecular_function', 'GO:0005488', ('208', '214'))	('PD-L1', 'Gene', '29126', (218, 223))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('high mutation load', 'Var', (272, 290))
78115	29748589	also focused on TILs in the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy and demonstrated that MEK inhibition upregulated PD-L1 expression in TNBC cells with lower TILs, suggesting the possible combination use of MEK inhibitor and ICI.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('breast cancers', 'Disease', 'MESH:D001943', (64, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('breast cancers', 'Disease', (64, 78))	('inhibition', 'Var', (136, 146))	('PD-L1', 'Gene', '29126', (159, 164))	('expression', 'MPA', (165, 175))	('upregulated', 'PosReg', (147, 158))	('MEK', 'Gene', (132, 135))	('MEK', 'Gene', '5609', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('TNBC', 'Disease', 'None', (179, 183))	('MEK', 'Gene', (250, 253))	('TNBC', 'Disease', (179, 183))	('MEK', 'Gene', '5609', (250, 253))	('PD-L1', 'Gene', (159, 164))	('breast cancers', 'Phenotype', 'HP:0003002', (64, 78))
78144	29147208	This would suggest that ZA could induce an objective tumor response in metastatic tumors in bone that harbor oncogenic Ras, as the oncogenic Ras in these tumors would require similar post-translational modifications.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('ZA', 'Chemical', 'MESH:D000077211', (24, 26))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('oncogenic Ras', 'Var', (109, 122))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (154, 159))
78151	29147208	Based on the described case report, we propose that in the same way that ZA interferes with isoprenylation of osteoclasts, leading to inhibition of osteoclast activity, interference with oncogenic Ras could induce a response in bony metastases containing oncogenic Ras.	('bony metastases', 'Disease', 'MESH:D009362', (228, 243))	('interference', 'Var', (169, 181))	('isoprenylation', 'MPA', (92, 106))	('osteoclast activity', 'CPA', (148, 167))	('ZA', 'Chemical', 'MESH:D000077211', (73, 75))	('inhibition', 'NegReg', (134, 144))	('induce', 'Reg', (207, 213))	('bony metastases', 'Disease', (228, 243))
78159	29147208	Because Ras is a potential downstream target of zoledronic acid, the presence of a K-Ras mutation in the tumor cells may offer a possible explanation for the patient's robust response.	('patient', 'Species', '9606', (158, 165))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (48, 63))	('mutation', 'Var', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('K-Ras', 'Gene', '3845', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('K-Ras', 'Gene', (83, 88))	('tumor', 'Disease', (105, 110))
78160	29147208	Several independent studies have found the incidence of K-Ras mutation in bladder cancer to be a rare event.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (74, 88))	('bladder cancer', 'Disease', 'MESH:D001749', (74, 88))	('mutation', 'Var', (62, 70))	('K-Ras', 'Gene', '3845', (56, 61))	('bladder cancer', 'Disease', (74, 88))	('K-Ras', 'Gene', (56, 61))
78161	29147208	We propose the possibility that patients with urothelial and other solid tumors metastatic to bone harboring an oncogenic Ras protein may be candidates for ZA, not only to reduce skeletal related events (SREs) but also to potentially produce an objective response.	('solid tumors', 'Disease', (67, 79))	('patients', 'Species', '9606', (32, 40))	('oncogenic', 'Var', (112, 121))	('skeletal related events', 'CPA', (179, 202))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('solid tumors', 'Disease', 'MESH:D009369', (67, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('reduce', 'NegReg', (172, 178))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('ZA', 'Chemical', 'MESH:D000077211', (156, 158))
78164	29147208	ZA may be a 'targeted' therapy in the circumstance of bony metastases harboring an oncogenic Ras mutation.	('bony metastases', 'Disease', (54, 69))	('ZA', 'Chemical', 'MESH:D000077211', (0, 2))	('bony metastases', 'Disease', 'MESH:D009362', (54, 69))	('Ras', 'Gene', (93, 96))	('mutation', 'Var', (97, 105))
78167	29147208	A study that prospectively tests patients' bony metastatic tumors for Ras mutations and then assesses treatment outcomes after ZA therapy could help to determine if tumors harboring oncogenic Ras are especially sensitive to zoledronic acid treatment.	('patients', 'Species', '9606', (33, 41))	('ZA', 'Chemical', 'MESH:D000077211', (127, 129))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('mutations', 'Var', (74, 83))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (224, 239))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
78171	25994132	Its overexpression induces an aggressive phenotype in many cancers and aberrant expression of homeotic HOX transcription factors, especially HOXD10, that regulate differentiation and tissue homeostasis.	('tissue homeostasis', 'biological_process', 'GO:0001894', ('183', '201'))	('HOXD10', 'Gene', (141, 147))	('HOXD10', 'Gene', '3236', (141, 147))	('aggressive phenotype', 'CPA', (30, 50))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('transcription', 'biological_process', 'GO:0006351', ('107', '120'))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('expression', 'MPA', (80, 90))	('overexpression', 'PosReg', (4, 18))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))	('induces', 'Reg', (19, 26))	('aberrant', 'Var', (71, 79))
78187	25994132	These findings call for the delineation of the mechanisms regulating normal and aberrant differentiation in the urothelium in order to improve prognostic classification and to develop new strategies for targeting the tumor-initiating cell populations as a driving force of progression, metastasis and recurrence.	('aberrant', 'Var', (80, 88))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))
78200	25994132	Subsequent to modulation of HOTAIR expression by knockdown or ectopic overexpression, we did not observe the same effects on HOTAIR target genes among the posterior HOXD genes as previously reported for other cancer types.	('knockdown', 'Var', (49, 58))	('HOTAIR', 'Gene', '100124700', (28, 34))	('HOTAIR', 'Gene', '100124700', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('HOXD', 'Gene', '3230', (165, 169))	('cancer', 'Disease', (209, 215))	('HOXD', 'Gene', (165, 169))	('HOTAIR', 'Gene', (28, 34))	('modulation', 'Reg', (14, 24))	('HOTAIR', 'Gene', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
78248	25994132	Of these, 2835 genes were common to both cell lines, but only 784 of these were downregulated, indicating that also transcription activating chromatin modifications may be mediated by HOTAIR.	('modifications', 'Var', (151, 164))	('transcription', 'MPA', (116, 129))	('HOTAIR', 'Gene', '100124700', (184, 190))	('transcription', 'biological_process', 'GO:0006351', ('116', '129'))	('HOTAIR', 'Gene', (184, 190))	('chromatin', 'cellular_component', 'GO:0000785', ('141', '150'))
78251	25994132	Downregulated genes in VM-CUB1_HOTAIR cells encoded cytokeratins (KRT5, 6A/B, 13, 14, 19, 80), E-Cadherin and negative cell cycle regulators.	('6A/B', 'Var', (72, 76))	('HOTAIR', 'Gene', '100124700', (31, 37))	('E-Cadherin', 'Gene', (95, 105))	('cell cycle', 'biological_process', 'GO:0007049', ('119', '129'))	('6A/B', 'SUBSTITUTION', 'None', (72, 76))	('E-Cadherin', 'Gene', '999', (95, 105))	('Downregulated', 'NegReg', (0, 13))	('KRT5', 'Gene', (66, 70))	('HOTAIR', 'Gene', (31, 37))	('Cadherin', 'molecular_function', 'GO:0008014', ('97', '105'))
78298	25994132	Moreover, by using the same siRNA-technique as previous authors we achieved the same degree of HOTAIR knockdown, but no induction of HOXD10 expression in UC cell lines.	('HOXD10', 'Gene', '3236', (133, 139))	('HOTAIR', 'Gene', (95, 101))	('knockdown', 'Var', (102, 111))	('HOXD10', 'Gene', (133, 139))	('HOTAIR', 'Gene', '100124700', (95, 101))
78301	25994132	Considering the data from ectopic overexpression and the report of a lack of HOXD10 induction after HOTAIR knockdown in ovarian cancer cells, our finding strongly argues that HOTAIR target genes are tissue-specific.	('knockdown', 'Var', (107, 116))	('HOXD10', 'Gene', (77, 83))	('lack', 'NegReg', (69, 73))	('HOTAIR', 'Gene', '100124700', (100, 106))	('ovarian cancer', 'Disease', 'MESH:D010051', (120, 134))	('ovarian cancer', 'Disease', (120, 134))	('HOTAIR', 'Gene', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('HOTAIR', 'Gene', '100124700', (175, 181))	('HOXD10', 'Gene', '3236', (77, 83))	('HOTAIR', 'Gene', (100, 106))	('ovarian cancer', 'Phenotype', 'HP:0100615', (120, 134))
78309	25994132	Similarly, modulation of HOTAIR expression by ectopic expression or depletion resulted in changes in migration and invasion capacity in esophageal cancer, lung cancer cells and one bladder cancer cell line (T-24).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('ectopic expression', 'Var', (46, 64))	('invasion capacity', 'CPA', (115, 132))	('depletion', 'MPA', (68, 77))	('HOTAIR', 'Gene', '100124700', (25, 31))	('modulation', 'Var', (11, 21))	('migration', 'CPA', (101, 110))	('bladder cancer', 'Disease', 'MESH:D001749', (181, 195))	('lung cancer', 'Disease', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('HOTAIR', 'Gene', (25, 31))	('bladder cancer', 'Disease', (181, 195))	('esophageal cancer', 'Disease', 'MESH:D004938', (136, 153))	('bladder cancer', 'Phenotype', 'HP:0009725', (181, 195))	('changes', 'Reg', (90, 97))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))	('esophageal cancer', 'Disease', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))
78317	25994132	Due to mutational inactivation of both pRB1 and p53, 5637 cells are unable to undergo regular senescence, but a partial senescence induction accompanied by SASP could account for the observed slower proliferation of HOTAIR-overexpressing 5637 cells.	('pRB1', 'Gene', '5542', (39, 43))	('p53', 'Gene', (48, 51))	('slower proliferation', 'CPA', (192, 212))	('HOTAIR', 'Gene', '100124700', (216, 222))	('p53', 'Gene', '7157', (48, 51))	('SASP', 'Gene', (156, 160))	('SASP', 'Gene', '7295', (156, 160))	('senescence', 'biological_process', 'GO:0010149', ('120', '130'))	('partial senescence induction', 'MPA', (112, 140))	('mutational inactivation', 'Var', (7, 30))	('pRB1', 'Gene', (39, 43))	('senescence', 'biological_process', 'GO:0010149', ('94', '104'))	('HOTAIR', 'Gene', (216, 222))
78322	25994132	In addition, DeltaNp63, a likely regulator of stemness in genitourinary epithelia, was differentially expressed indicating that aberrant HOTAIR expression may be involved in the establishment of aberrant differentiation states in bladder cancer.	('DeltaNp63', 'Gene', (13, 22))	('bladder cancer', 'Phenotype', 'HP:0009725', (230, 244))	('stemness in genitourinary epithelia', 'Disease', (46, 81))	('bladder cancer', 'Disease', 'MESH:D001749', (230, 244))	('aberrant', 'Var', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('HOTAIR', 'Gene', (137, 143))	('bladder cancer', 'Disease', (230, 244))	('involved', 'Reg', (162, 170))	('HOTAIR', 'Gene', '100124700', (137, 143))	('stemness in genitourinary epithelia', 'Disease', 'MESH:D014564', (46, 81))
78324	25994132	on HOTAIR transfected MDA-MB-231 cells revealed only four HOX genes (HOXA4, C8, D10, D13) with increased PRC2 occupancy, although none appeared to gain the repressive H3K27me chromatin mark.	('HOXA4', 'Gene', '3201', (69, 74))	('H3K27me', 'Var', (167, 174))	('gain', 'PosReg', (147, 151))	('HOXA4', 'Gene', (69, 74))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (22, 32))	('H3', 'Chemical', 'MESH:C012616', (167, 169))	('HOTAIR', 'Gene', (3, 9))	('chromatin', 'cellular_component', 'GO:0000785', ('175', '184'))	('HOTAIR', 'Gene', '100124700', (3, 9))
78373	25994132	The antibodies used for immunoprecipitation were H3K4me3 (#39915, Active Motif), H3K27me3 (#39535, Active Motif) and H3K9me3 (ab-8898, abcam).	('H3K4me3', 'Protein', (49, 56))	('#39915', 'Var', (58, 64))	('H3', 'Chemical', 'MESH:C012616', (81, 83))	('H3K9me3', 'Var', (117, 124))	('#39535', 'Var', (91, 97))	('H3', 'Chemical', 'MESH:C012616', (117, 119))	('H3', 'Chemical', 'MESH:C012616', (49, 51))
78435	32321559	Hartmann and co-authors examined 132 urothelial carcinomas of the upper urinary tract exhibiting some degree of inverted growth, and found that 35 (26.5%) were microsatellite unstable by polymerase chain reaction analysis.	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('urothelial carcinomas', 'Disease', (37, 58))	('urothelial carcinomas of the upper urinary', 'Phenotype', 'HP:0010935', (37, 79))	('microsatellite', 'Var', (160, 174))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (37, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
78449	31957155	Silencing SPAG5 reversed the increase of apoptosis and decrease of autophagy in high glucose-treated HPCs.	('apoptosis', 'biological_process', 'GO:0097194', ('41', '50'))	('apoptosis', 'biological_process', 'GO:0006915', ('41', '50'))	('autophagy', 'biological_process', 'GO:0006914', ('67', '76'))	('decrease', 'NegReg', (55, 63))	('high glucose', 'Phenotype', 'HP:0003074', (80, 92))	('SPAG5', 'Gene', (10, 15))	('glucose', 'Chemical', 'MESH:D005947', (85, 92))	('autophagy', 'CPA', (67, 76))	('Silencing', 'Var', (0, 9))	('SPAG5', 'Gene', '10615', (10, 15))	('autophagy', 'biological_process', 'GO:0016236', ('67', '76'))
78470	31957155	Following the transfer of membrane onto PVDF, protein samples were probed with the primary antibodies including anti-SPAG5 (ab200671; Abcam), anti-c-Caspase 3 (ab2302; Abcam), anti-t-Caspase 3 (ab13847; Abcam), anti-c-Caspase 9 (ab2324; Abcam), anti-t-Caspase 9 (ab32539; Abcam), anti-Bax (ab32503; Abcam), anti-Bcl-2 (ab32124; Abcam), anti-LC-3I/II (ABC929, Millipore, St. Charles, MI, USA), anti-p62 (ab56416), anti-Beclin1 (ab210498), anti-p-AKT (thr30; ab105731), anti-p-AKT (ser473; ab81283), anti-t-AKT (ab179463), anti-p-mTOR (ser2448; ab109268), anti-t-mTOR (ab2732), anti-YY1 (ab109228), anti-USP14 (ab192618), anti-p-USP14 (S432; sc-393872, Santa Cruz Biotechnology) and anti-GAPDH.	('Caspase 3', 'Gene', (183, 192))	('AKT', 'Gene', (475, 478))	('mTOR', 'Gene', '2475', (561, 565))	('YY1', 'Gene', '7528', (581, 584))	('Caspase 9', 'Gene', (252, 261))	('LC-3', 'Gene', (341, 345))	('mTOR', 'Gene', '2475', (528, 532))	('GAPDH', 'Gene', (686, 691))	('USP', 'molecular_function', 'GO:0051748', ('627', '630'))	('Caspase 3', 'Gene', (149, 158))	('ab109228', 'Var', (586, 594))	('ab2732', 'Var', (567, 573))	('AKT', 'Gene', (505, 508))	('YY1', 'Gene', (581, 584))	('LC-3', 'Gene', '84557', (341, 345))	('AKT', 'Gene', '207', (445, 448))	('Bcl-2', 'Gene', (312, 317))	('Beclin1', 'Gene', '8678', (418, 425))	('SPAG5', 'Gene', (117, 122))	('Caspase 9', 'Gene', (218, 227))	('ser', 'cellular_component', 'GO:0005790', ('534', '537'))	('AKT', 'Gene', '207', (475, 478))	('Bax', 'Gene', (285, 288))	('USP14', 'Gene', (602, 607))	('ser', 'cellular_component', 'GO:0005790', ('480', '483'))	('ser2448; ab109268', 'Var', (534, 551))	('Bcl-2', 'molecular_function', 'GO:0015283', ('312', '317'))	('Caspase 3', 'Gene', '836', (183, 192))	('Bax', 'Gene', '581', (285, 288))	('USP14', 'Gene', (627, 632))	('Bcl-2', 'Gene', '596', (312, 317))	('AKT', 'Gene', '207', (505, 508))	('ser473', 'Chemical', '-', (480, 486))	('USP14', 'Gene', '9097', (602, 607))	('SPAG5', 'Gene', '10615', (117, 122))	('p62', 'Gene', '8878', (398, 401))	('USP14', 'Gene', '9097', (627, 632))	('Beclin1', 'Gene', (418, 425))	('Caspase 9', 'Gene', '842', (252, 261))	('p62', 'Gene', (398, 401))	('Caspase 3', 'Gene', '836', (149, 158))	('ser2448', 'Chemical', '-', (534, 541))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('mTOR', 'Gene', (561, 565))	('membrane', 'cellular_component', 'GO:0016020', ('26', '34'))	('AKT', 'Gene', (445, 448))	('mTOR', 'Gene', (528, 532))	('USP', 'molecular_function', 'GO:0051748', ('602', '605'))	('GAPDH', 'Gene', '2597', (686, 691))	('Caspase 9', 'Gene', '842', (218, 227))
78473	31957155	Cells were treated with the following primary antibodies against anti-podocin (P0372; Sigma-Aldrich Co), SPAG5, USP14 and LC-3 (ProteinTech Group) at 4 C overnight, with secondary antibodies at 37C for 1 hour.	('podocin', 'Gene', '7827', (70, 77))	('LC-3', 'Gene', (122, 126))	('SPAG5', 'Gene', (105, 110))	('USP14', 'Gene', '9097', (112, 117))	('USP', 'molecular_function', 'GO:0051748', ('112', '115'))	('SPAG5', 'Gene', '10615', (105, 110))	('LC-3', 'Gene', '84557', (122, 126))	('P0372;', 'Var', (79, 85))	('USP14', 'Gene', (112, 117))	('podocin', 'Gene', (70, 77))
78487	31957155	SPAG5-AS1 or YY1 fragments containing wild-type (Wt) or mutant (Mut) miR-769-5p binding sites were inserted into pmirGLO reporter vector (Promega) and named as SPAG5-AS1 WT/Mut or YY1 WT/Mut, followed by the co-transfection of miR-769-5p mimic or NC mimic into cells, respectively.	('miR-769-5p', 'Gene', (69, 79))	('YY1', 'Gene', '7528', (13, 16))	('mutant', 'Var', (56, 62))	('YY1', 'Gene', (13, 16))	('binding', 'molecular_function', 'GO:0005488', ('80', '87'))	('YY1', 'Gene', '7528', (180, 183))	('YY1', 'Gene', (180, 183))
78502	31957155	To test the influence of SPAG5, we confirmed the knockdown of SPAG5 at mRNA and protein levels by two sh-RNAs in HG-treated HPCs (Figure 1C).	('SPAG5', 'Gene', '10615', (62, 67))	('knockdown', 'Var', (49, 58))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('HG', 'Phenotype', 'HP:0003074', (113, 115))	('SPAG5', 'Gene', (25, 30))	('SPAG5', 'Gene', (62, 67))	('SPAG5', 'Gene', '10615', (25, 30))
78503	31957155	Later, we observed that compared to NG and MA treatments, HG induced apoptosis of HPCs, and knocking down of SPAG5 attenuated apoptosis in HG-treated HPCs (Figure 1D).	('HG', 'Phenotype', 'HP:0003074', (139, 141))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('SPAG5', 'Gene', (109, 114))	('attenuated', 'NegReg', (115, 125))	('SPAG5', 'Gene', '10615', (109, 114))	('HG', 'Phenotype', 'HP:0003074', (58, 60))	('knocking down', 'Var', (92, 105))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))
78504	31957155	HG treatment in HPCs induced the levels of cleaved caspase 3, cleaved caspase 9 and Bax, whereas reduced the level of Bcl-2, and silencing SPAG5 in HG-treated HPCs reversed such phenomenon (Figure 1E).	('SPAG5', 'Gene', (139, 144))	('HG', 'Phenotype', 'HP:0003074', (148, 150))	('Bax', 'Gene', (84, 87))	('levels', 'MPA', (33, 39))	('SPAG5', 'Gene', '10615', (139, 144))	('Bcl-2', 'Gene', (118, 123))	('silencing', 'Var', (129, 138))	('reduced', 'NegReg', (97, 104))	('cleaved caspase 3', 'MPA', (43, 60))	('caspase 9', 'Gene', (70, 79))	('Bcl-2', 'Gene', '596', (118, 123))	('Bcl-2', 'molecular_function', 'GO:0015283', ('118', '123'))	('HG', 'Phenotype', 'HP:0003074', (0, 2))	('Bax', 'Gene', '581', (84, 87))	('caspase 9', 'Gene', '842', (70, 79))
78505	31957155	The fluorescence intensities of LC-3 and podocin in HPCs were reduced by HG treatment, and were restored by the depletion of SPAG5 (Figure 1F).	('podocin', 'Gene', (41, 48))	('SPAG5', 'Gene', '10615', (125, 130))	('LC-3', 'Gene', '84557', (32, 36))	('restored', 'PosReg', (96, 104))	('depletion', 'Var', (112, 121))	('HG', 'Phenotype', 'HP:0003074', (73, 75))	('fluorescence intensities', 'MPA', (4, 28))	('SPAG5', 'Gene', (125, 130))	('LC-3', 'Gene', (32, 36))	('reduced', 'NegReg', (62, 69))	('podocin', 'Gene', '7827', (41, 48))
78507	31957155	Consequently, HG treatment decreased the red and yellow puncta compared to control, and such effect was contracted by silencing SPAG5 in HPCs (Figure S1A), suggesting that SPAG5 knockdown restored autophagic flux that was inhibited by HG in HPCs.	('SPAG5', 'Gene', (128, 133))	('decreased', 'NegReg', (27, 36))	('autophagic flux', 'CPA', (197, 212))	('SPAG5', 'Gene', '10615', (128, 133))	('HG', 'Phenotype', 'HP:0003074', (235, 237))	('HG', 'Phenotype', 'HP:0003074', (14, 16))	('silencing', 'Var', (118, 127))	('SPAG5', 'Gene', (172, 177))	('knockdown', 'Var', (178, 187))	('SPAG5', 'Gene', '10615', (172, 177))	('restored', 'PosReg', (188, 196))
78508	31957155	Besides, we confirmed that SPAG5 knockdown reversed the decrease of LC-3II/LC-3I and Beclin1 levels and the increase of p62 levels in HG-treated HPCs (Figure 1G).	('p62', 'Gene', '8878', (120, 123))	('increase', 'PosReg', (108, 116))	('LC-3', 'Gene', (68, 72))	('p62', 'Gene', (120, 123))	('LC-3', 'Gene', (75, 79))	('knockdown', 'Var', (33, 42))	('HG', 'Phenotype', 'HP:0003074', (134, 136))	('LC-3', 'Gene', '84557', (68, 72))	('Beclin1', 'Gene', '8678', (85, 92))	('LC-3', 'Gene', '84557', (75, 79))	('SPAG5', 'Gene', (27, 32))	('decrease', 'NegReg', (56, 64))	('SPAG5', 'Gene', '10615', (27, 32))	('Beclin1', 'Gene', (85, 92))
78510	31957155	Altogether, these results suggested that SPAG5 silence attenuated apoptosis, induced autophagy and suppressed AKT/mTOR pathway in high glucose-treated HPCs.	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('autophagy', 'biological_process', 'GO:0016236', ('85', '94'))	('SPAG5', 'Gene', '10615', (41, 46))	('suppressed', 'NegReg', (99, 109))	('attenuated', 'NegReg', (55, 65))	('AKT', 'Gene', (110, 113))	('autophagy', 'biological_process', 'GO:0006914', ('85', '94'))	('mTOR', 'Gene', '2475', (114, 118))	('silence', 'Var', (47, 54))	('glucose', 'Chemical', 'MESH:D005947', (135, 142))	('high glucose', 'Phenotype', 'HP:0003074', (130, 142))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))	('mTOR', 'Gene', (114, 118))	('SPAG5', 'Gene', (41, 46))	('apoptosis', 'CPA', (66, 75))	('induced', 'PosReg', (77, 84))	('autophagy', 'CPA', (85, 94))	('AKT', 'Gene', '207', (110, 113))
78515	31957155	The mRNA level of SPAG5 induced by HG in HPCs was impaired by the knockdown of SPAG5-AS1 (Figure 2G).	('SPAG5', 'Gene', '10615', (18, 23))	('HG', 'Phenotype', 'HP:0003074', (35, 37))	('impaired', 'NegReg', (50, 58))	('SPAG5', 'Gene', (79, 84))	('SPAG5', 'Gene', (18, 23))	('SPAG5', 'Gene', '10615', (79, 84))	('knockdown', 'Var', (66, 75))
78516	31957155	Western blot analysis depicted that levels of SPAG5 and phosphorylated AKT (thr308 and ser473) and mTOR (ser2448) were induced by HG, and impaired by SPAG5-AS1 knockdown in HPCs (Figure 2H), indicating that SPAG5-AS1 positively regulated SPAG5/AKT/mTOR axis in HG-treated HPCs.	('SPAG5', 'Gene', (46, 51))	('induced', 'PosReg', (119, 126))	('mTOR', 'Gene', (99, 103))	('impaired', 'NegReg', (138, 146))	('HG', 'Phenotype', 'HP:0003074', (261, 263))	('SPAG5', 'Gene', (238, 243))	('ser', 'cellular_component', 'GO:0005790', ('105', '108'))	('SPAG5', 'Gene', (207, 212))	('mTOR', 'Gene', (248, 252))	('AKT', 'Gene', '207', (71, 74))	('SPAG5', 'Gene', (150, 155))	('AKT', 'Gene', (244, 247))	('ser473', 'Chemical', '-', (87, 93))	('ser', 'cellular_component', 'GO:0005790', ('87', '90'))	('mTOR', 'Gene', '2475', (99, 103))	('mTOR', 'Gene', '2475', (248, 252))	('SPAG5', 'Gene', '10615', (46, 51))	('thr308', 'Chemical', '-', (76, 82))	('knockdown', 'Var', (160, 169))	('SPAG5', 'Gene', '10615', (238, 243))	('SPAG5', 'Gene', '10615', (207, 212))	('HG', 'Phenotype', 'HP:0003074', (130, 132))	('SPAG5', 'Gene', '10615', (150, 155))	('AKT', 'Gene', '207', (244, 247))	('ser2448', 'Chemical', '-', (105, 112))	('AKT', 'Gene', (71, 74))	('ser473', 'Var', (87, 93))
78518	31957155	Luciferase activity of SPAG5 promoter reporter was attenuated by the knockdown of SPAG5-AS1 silence in HG-treated HPCs (Figure 2I).	('SPAG5', 'Gene', (23, 28))	('activity', 'MPA', (11, 19))	('SPAG5', 'Gene', (82, 87))	('Luciferase activity', 'molecular_function', 'GO:0050397', ('0', '19'))	('attenuated', 'NegReg', (51, 61))	('SPAG5', 'Gene', '10615', (82, 87))	('SPAG5', 'Gene', '10615', (23, 28))	('Luciferase activity', 'molecular_function', 'GO:0047712', ('0', '19'))	('Luciferase activity', 'molecular_function', 'GO:0047077', ('0', '19'))	('Luciferase activity', 'molecular_function', 'GO:0050248', ('0', '19'))	('HG', 'Phenotype', 'HP:0003074', (103, 105))	('Luciferase', 'Enzyme', (0, 10))	('knockdown', 'Var', (69, 78))	('Luciferase activity', 'molecular_function', 'GO:0045289', ('0', '19'))
78521	31957155	Results showed that silence of SPAG5-AS1 facilitated the degradation of SPAG5 protein in HG-treated HPCs (Figure 2K).	('silence', 'Var', (20, 27))	('degradation', 'MPA', (57, 68))	('HG', 'Phenotype', 'HP:0003074', (89, 91))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('SPAG5', 'Gene', (72, 77))	('SPAG5', 'Gene', (31, 36))	('facilitated', 'PosReg', (41, 52))	('degradation', 'biological_process', 'GO:0009056', ('57', '68'))	('SPAG5', 'Gene', '10615', (72, 77))	('SPAG5', 'Gene', '10615', (31, 36))
78523	31957155	Silence of SPAG5-AS1 impaired the high expression of cleaved caspase 3, cleaved caspase 9 and Bax and reversed the low expression of Bcl-2 in HG-treated HPCs (Figure 3B).	('Bcl-2', 'molecular_function', 'GO:0015283', ('133', '138'))	('cleaved', 'MPA', (53, 60))	('SPAG5-AS1', 'Gene', (11, 20))	('HG', 'Phenotype', 'HP:0003074', (142, 144))	('Bax', 'Gene', '581', (94, 97))	('Bcl-2', 'Gene', (133, 138))	('high expression', 'MPA', (34, 49))	('Bcl-2', 'Gene', '596', (133, 138))	('cleaved', 'MPA', (72, 79))	('impaired', 'NegReg', (21, 29))	('caspase 9', 'Gene', (80, 89))	('caspase 3', 'Protein', (61, 70))	('Silence', 'Var', (0, 7))	('Bax', 'Gene', (94, 97))	('caspase 9', 'Gene', '842', (80, 89))
78525	31957155	The GFP-mRFP-LC3 assay exhibited that silencing SPAG5-AS1 restored the autophagic flux that was blocked by HG in HPCs (Figure S1B).	('LC3', 'Gene', (13, 16))	('autophagic flux', 'CPA', (71, 86))	('SPAG5-AS1', 'Gene', (48, 57))	('LC3', 'Gene', '84557', (13, 16))	('restored', 'PosReg', (58, 66))	('HG', 'Phenotype', 'HP:0003074', (107, 109))	('silencing', 'Var', (38, 47))
78526	31957155	The decrease of LC-3II/LC-3I and Beclin 1 levels and increase of p62 level under HG treatment were reversed by SPAG5-AS1 knockdown in HPCs (Figure 3D).	('knockdown', 'Var', (121, 130))	('LC-3', 'Gene', (23, 27))	('SPAG5-AS1', 'Gene', (111, 120))	('LC-3', 'Gene', (16, 20))	('p62', 'Gene', '8878', (65, 68))	('p62', 'Gene', (65, 68))	('LC-3', 'Gene', '84557', (23, 27))	('decrease', 'NegReg', (4, 12))	('increase', 'PosReg', (53, 61))	('LC-3', 'Gene', '84557', (16, 20))	('Beclin 1', 'Gene', (33, 41))	('HG', 'Phenotype', 'HP:0003074', (81, 83))	('Beclin 1', 'Gene', '8678', (33, 41))
78538	31957155	Luciferase reporter analysis elucidated that in HG-treated HPCs, the silence of YY1 reduced the luciferase activity of SPAG5-AS1/SPAG5 promoter, and mutation of site 1 or site 3, instead of site 2, could partly restore the luciferase activity (Figure 4G).	('silence', 'Var', (69, 76))	('SPAG5', 'Gene', '10615', (129, 134))	('luciferase', 'Enzyme', (96, 106))	('luciferase activity', 'molecular_function', 'GO:0047077', ('96', '115'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('223', '242'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('96', '115'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('96', '115'))	('SPAG5', 'Gene', (119, 124))	('restore', 'PosReg', (211, 218))	('YY1', 'Gene', '7528', (80, 83))	('YY1', 'Gene', (80, 83))	('luciferase activity', 'molecular_function', 'GO:0047077', ('223', '242'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('96', '115'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('96', '115'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('223', '242'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('223', '242'))	('SPAG5', 'Gene', '10615', (119, 124))	('activity', 'MPA', (234, 242))	('SPAG5', 'Gene', (129, 134))	('activity', 'MPA', (107, 115))	('reduced', 'NegReg', (84, 91))	('luciferase activity', 'molecular_function', 'GO:0050397', ('223', '242'))	('HG', 'Phenotype', 'HP:0003074', (48, 50))	('luciferase', 'Enzyme', (223, 233))	('mutation', 'Var', (149, 157))
78540	31957155	Later, we confirmed that knockdown of YY1 reduced the levels of YY1 mRNA, SPAG5-AS1 and SPAG5 mRNA (Figure 4H).	('YY1', 'Gene', '7528', (64, 67))	('reduced', 'NegReg', (42, 49))	('SPAG5', 'Gene', (88, 93))	('SPAG5', 'Gene', '10615', (74, 79))	('YY1', 'Gene', '7528', (38, 41))	('YY1', 'Gene', (64, 67))	('SPAG5', 'Gene', '10615', (88, 93))	('levels', 'MPA', (54, 60))	('YY1', 'Gene', (38, 41))	('knockdown', 'Var', (25, 34))	('SPAG5', 'Gene', (74, 79))
78541	31957155	Also, protein levels of YY1, SPAG5, p-AKT (thr308 and ser473) and p-mTOR (ser2448) were reduced by YY1 knockdown in HG-treated HPCs, with total AKT and mTOR levels unchanged (Figure 4I).	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('AKT', 'Gene', (144, 147))	('mTOR', 'Gene', '2475', (68, 72))	('ser', 'cellular_component', 'GO:0005790', ('74', '77'))	('AKT', 'Gene', (38, 41))	('mTOR', 'Gene', (152, 156))	('YY1', 'Gene', '7528', (24, 27))	('HG', 'Phenotype', 'HP:0003074', (116, 118))	('YY1', 'Gene', (24, 27))	('protein levels', 'MPA', (6, 20))	('reduced', 'NegReg', (88, 95))	('AKT', 'Gene', '207', (144, 147))	('ser473', 'Chemical', '-', (54, 60))	('SPAG5', 'Gene', (29, 34))	('mTOR', 'Gene', '2475', (152, 156))	('thr308', 'Chemical', '-', (43, 49))	('AKT', 'Gene', '207', (38, 41))	('ser473', 'MPA', (54, 60))	('knockdown', 'Var', (103, 112))	('YY1', 'Gene', '7528', (99, 102))	('ser2448', 'Chemical', '-', (74, 81))	('SPAG5', 'Gene', '10615', (29, 34))	('ser', 'cellular_component', 'GO:0005790', ('54', '57'))	('YY1', 'Gene', (99, 102))	('mTOR', 'Gene', (68, 72))
78546	31957155	Also, we validated that YY1 mRNA and protein levels were induced by HG in HPCs and silencing SPAG5-AS1 impaired YY1 mRNA and protein levels (Figure 5B).	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('YY1', 'Gene', '7528', (112, 115))	('SPAG5-AS1', 'Gene', (93, 102))	('induced', 'Reg', (57, 64))	('YY1', 'Gene', '7528', (24, 27))	('YY1', 'Gene', (112, 115))	('HG', 'Phenotype', 'HP:0003074', (68, 70))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('YY1', 'Gene', (24, 27))	('impaired', 'NegReg', (103, 111))	('silencing', 'Var', (83, 92))
78551	31957155	RIP analysis confirmed that miR-769-5p was co-immunoprecipitated with SPAG5-AS1 and YY1 by Ago2 antibody (Figure 5G).	('YY1', 'Gene', (84, 87))	('antibody', 'cellular_component', 'GO:0019815', ('96', '104'))	('antibody', 'cellular_component', 'GO:0019814', ('96', '104'))	('Ago2', 'Gene', '27161', (91, 95))	('antibody', 'molecular_function', 'GO:0003823', ('96', '104'))	('miR-769-5p', 'Var', (28, 38))	('YY1', 'Gene', '7528', (84, 87))	('Ago2', 'Gene', (91, 95))	('antibody', 'cellular_component', 'GO:0042571', ('96', '104'))
78552	31957155	The predicted miR-769-5p sites on SPAG5-AS1 and YY1 were substituted with complementary sequences to generate SPAG5-AS1 Mut and YY1 Mut reporters (Figure 5H).	('YY1', 'Gene', '7528', (128, 131))	('YY1', 'Gene', '7528', (48, 51))	('SPAG5-AS1', 'Var', (110, 119))	('YY1', 'Gene', (128, 131))	('YY1', 'Gene', (48, 51))
78553	31957155	Luciferase reporter assay confirmed that miR-769-5p overexpression abrogated luciferase activity of SPAG5-AS1 WT and YY1 WT in HG-treated HPCs (Figure 5H).	('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'))	('YY1', 'Gene', '7528', (117, 120))	('activity', 'MPA', (88, 96))	('abrogated', 'NegReg', (67, 76))	('miR-769-5p', 'Var', (41, 51))	('HG', 'Phenotype', 'HP:0003074', (127, 129))	('luciferase activity', 'molecular_function', 'GO:0045289', ('77', '96'))	('YY1', 'Gene', (117, 120))	('SPAG5-AS1', 'Var', (100, 109))
78555	31957155	It was probable that miR-769-5p mimic reduced SPAG5-AS1 level because miR-769-5p reduced YY1 expression so that weakened the YY1-mediated transactivation of SPAG5-AS1.	('YY1', 'Gene', (125, 128))	('YY1', 'Gene', '7528', (89, 92))	('reduced', 'NegReg', (38, 45))	('weakened', 'NegReg', (112, 120))	('transactivation', 'biological_process', 'GO:2000144', ('138', '153'))	('YY1', 'Gene', (89, 92))	('SPAG5-AS1 level', 'MPA', (46, 61))	('expression', 'MPA', (93, 103))	('YY1', 'Gene', '7528', (125, 128))	('reduced', 'NegReg', (81, 88))	('miR-769-5p', 'Var', (70, 80))
78557	31957155	Western blot confirmed that inhibiting miR-769-5p impaired the repressive effect of SPAG5-AS1 silence on the levels of YY1, SPAG5, p-AKT (thr308 and ser473) and p-mTOR (ser2448) in HG-treated HPCs, with total AKT and mTOR unchanged (Figure 5K, Figure S2C).	('repressive effect', 'MPA', (63, 80))	('SPAG5', 'Gene', '10615', (124, 129))	('ser', 'cellular_component', 'GO:0005790', ('169', '172'))	('ser', 'cellular_component', 'GO:0005790', ('149', '152'))	('miR-769-5p', 'Var', (39, 49))	('mTOR', 'Gene', (163, 167))	('AKT', 'Gene', (133, 136))	('ser2448', 'Var', (169, 176))	('mTOR', 'Gene', (217, 221))	('YY1', 'Gene', '7528', (119, 122))	('mTOR', 'Gene', '2475', (163, 167))	('impaired', 'NegReg', (50, 58))	('YY1', 'Gene', (119, 122))	('ser473', 'Chemical', '-', (149, 155))	('HG', 'Phenotype', 'HP:0003074', (181, 183))	('AKT', 'Gene', (209, 212))	('SPAG5', 'Gene', (84, 89))	('mTOR', 'Gene', '2475', (217, 221))	('AKT', 'Gene', '207', (133, 136))	('ser2448', 'Chemical', '-', (169, 176))	('SPAG5', 'Gene', (124, 129))	('SPAG5', 'Gene', '10615', (84, 89))	('thr308', 'Chemical', '-', (138, 144))	('AKT', 'Gene', '207', (209, 212))	('ser473', 'Var', (149, 155))	('inhibiting miR-769-5p', 'Var', (28, 49))
78562	31957155	Western blot assay confirmed the enrichment of USP14 in the pulldown of SPAG5-AS1 biotin group instead of SPAG5-AS1 no-biotin group in HG-treated HPCs (Figure 6A).	('HG', 'Phenotype', 'HP:0003074', (135, 137))	('biotin', 'Chemical', 'MESH:D001710', (119, 125))	('biotin', 'Chemical', 'MESH:D001710', (82, 88))	('AS1 biotin', 'Chemical', '-', (78, 88))	('USP14', 'Gene', '9097', (47, 52))	('USP14', 'Gene', (47, 52))	('SPAG5-AS1', 'Var', (72, 81))	('USP', 'molecular_function', 'GO:0051748', ('47', '50'))
78564	31957155	RNA immunoprecipitation analysis confirmed that SPAG5-AS1 was abundant in USP14-binding complexes (Figure 6B).	('USP14', 'Gene', '9097', (74, 79))	('binding', 'molecular_function', 'GO:0005488', ('80', '87'))	('USP14', 'Gene', (74, 79))	('USP', 'molecular_function', 'GO:0051748', ('74', '77'))	('SPAG5-AS1', 'Var', (48, 57))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
78566	31957155	Co-IP assay demonstrated that in HG-treated HPCs, SPAG5 was enriched in the precipitated products of anti-USP14, and silencing SPAG5-AS1 reduced such enrichment, with the input level of SPAG5 reduced and input level of USP14 unchanged (Figure 6D), indicating that SPAG5-AS1 mediated the binding of USP14 to SPAG5.	('SPAG5', 'Gene', '10615', (186, 191))	('SPAG5', 'Gene', '10615', (307, 312))	('SPAG5', 'Gene', (50, 55))	('USP14', 'Gene', '9097', (219, 224))	('USP14', 'Gene', (298, 303))	('USP14', 'Gene', (106, 111))	('SPAG5', 'Gene', '10615', (264, 269))	('reduced', 'NegReg', (137, 144))	('silencing', 'Var', (117, 126))	('USP14', 'Gene', '9097', (106, 111))	('SPAG5', 'Gene', '10615', (50, 55))	('USP', 'molecular_function', 'GO:0051748', ('219', '222'))	('SPAG5', 'Gene', (127, 132))	('USP14', 'Gene', '9097', (298, 303))	('binding', 'molecular_function', 'GO:0005488', ('287', '294'))	('USP', 'molecular_function', 'GO:0051748', ('106', '109'))	('USP', 'molecular_function', 'GO:0051748', ('298', '301'))	('SPAG5', 'Gene', (186, 191))	('SPAG5', 'Gene', '10615', (127, 132))	('SPAG5', 'Gene', (307, 312))	('binding', 'Interaction', (287, 294))	('HG', 'Phenotype', 'HP:0003074', (33, 35))	('enrichment', 'MPA', (150, 160))	('SPAG5', 'Gene', (264, 269))	('USP14', 'Gene', (219, 224))
78567	31957155	Pull-down assay illustrated that SPAG5 and USP14 were both enriched in the pulldown of SPAG5-AS1 biotin group rather than no-biotin group, and the silence of USP14 reduced such enrichment, with input levels of USP14 and SPAG5 decreased (Figure 6E), indicating that USP14 was required for the interaction between SPAG5-AS1 and SPAG5.	('SPAG5', 'Gene', (33, 38))	('SPAG5', 'Gene', (326, 331))	('SPAG5', 'Gene', '10615', (312, 317))	('USP14', 'Gene', (43, 48))	('SPAG5', 'Gene', (87, 92))	('silence', 'Var', (147, 154))	('USP14', 'Gene', (210, 215))	('USP14', 'Gene', (265, 270))	('USP14', 'Gene', '9097', (43, 48))	('SPAG5', 'Gene', '10615', (33, 38))	('SPAG5', 'Gene', '10615', (326, 331))	('biotin', 'Chemical', 'MESH:D001710', (97, 103))	('USP14', 'Gene', '9097', (265, 270))	('enrichment', 'MPA', (177, 187))	('USP14', 'Gene', '9097', (210, 215))	('AS1 biotin', 'Chemical', '-', (93, 103))	('SPAG5', 'Gene', '10615', (87, 92))	('USP', 'molecular_function', 'GO:0051748', ('158', '161'))	('biotin', 'Chemical', 'MESH:D001710', (125, 131))	('SPAG5', 'Gene', (220, 225))	('reduced', 'NegReg', (164, 171))	('USP14', 'Gene', (158, 163))	('SPAG5', 'Gene', (312, 317))	('USP', 'molecular_function', 'GO:0051748', ('43', '46'))	('USP14', 'Gene', '9097', (158, 163))	('USP', 'molecular_function', 'GO:0051748', ('265', '268'))	('USP', 'molecular_function', 'GO:0051748', ('210', '213'))	('SPAG5', 'Gene', '10615', (220, 225))
78569	31957155	As expected, the silence of SPAG5-AS1 reduced the level of p-USP14 (S432) without changing its total protein level in HG-treated HPCs (Figure 6F).	('silence', 'Var', (17, 24))	('USP', 'molecular_function', 'GO:0051748', ('61', '64'))	('HG', 'Phenotype', 'HP:0003074', (118, 120))	('level', 'MPA', (50, 55))	('reduced', 'NegReg', (38, 45))	('USP14', 'Gene', '9097', (61, 66))	('USP14', 'Gene', (61, 66))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('SPAG5-AS1', 'Gene', (28, 37))
78570	31957155	We also confirmed that knockdown of USP14 failed to impact SPAG5-AS1 level in HG-treated HPCs (Figure 6G).	('USP', 'molecular_function', 'GO:0051748', ('36', '39'))	('SPAG5-AS1 level', 'MPA', (59, 74))	('knockdown', 'Var', (23, 32))	('USP14', 'Gene', '9097', (36, 41))	('HG', 'Phenotype', 'HP:0003074', (78, 80))	('impact', 'Reg', (52, 58))	('USP14', 'Gene', (36, 41))
78571	31957155	Then, we validated that the silence of SPAG5-AS1 increased the ubiquitination of SPAG5 protein in HG-treated HPCs (Figure 6H).	('SPAG5', 'Gene', (39, 44))	('silence', 'Var', (28, 35))	('SPAG5', 'Gene', (81, 86))	('increased', 'PosReg', (49, 58))	('SPAG5', 'Gene', '10615', (39, 44))	('ubiquitination', 'MPA', (63, 77))	('SPAG5', 'Gene', '10615', (81, 86))	('HG', 'Phenotype', 'HP:0003074', (98, 100))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
78572	31957155	Overexpression of USP14 counteracted the facilitative effect of SPAG5-AS1 knockdown on SPAG5 protein degradation in HG-treated HPCs (Figure 6I, Figure S2D).	('SPAG5', 'Gene', '10615', (87, 92))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('USP', 'molecular_function', 'GO:0051748', ('18', '21'))	('knockdown', 'Var', (74, 83))	('SPAG5', 'Gene', (64, 69))	('HG', 'Phenotype', 'HP:0003074', (116, 118))	('protein degradation', 'biological_process', 'GO:0030163', ('93', '112'))	('USP14', 'Gene', '9097', (18, 23))	('SPAG5', 'Gene', (87, 92))	('SPAG5', 'Gene', '10615', (64, 69))	('USP14', 'Gene', (18, 23))
78574	31957155	Overexpression of USP14 restored the levels of SPAG5, p-AKT (thr308 and ser473) and p-mTOR (ser2448) that were reduced by SPAG5-AS1 silence in HG-treated HPCs, with total AKT and mTOR unchanged (Figure 6J, Figure S2E).	('mTOR', 'Gene', '2475', (86, 90))	('ser473', 'Chemical', '-', (72, 78))	('AKT', 'Gene', (56, 59))	('HG', 'Phenotype', 'HP:0003074', (143, 145))	('ser', 'cellular_component', 'GO:0005790', ('72', '75'))	('SPAG5', 'Gene', '10615', (122, 127))	('mTOR', 'Gene', '2475', (179, 183))	('USP14', 'Gene', (18, 23))	('SPAG5', 'Gene', (47, 52))	('thr308', 'Chemical', '-', (61, 67))	('USP14', 'Gene', '9097', (18, 23))	('AKT', 'Gene', (171, 174))	('AKT', 'Gene', '207', (56, 59))	('ser2448', 'Chemical', '-', (92, 99))	('USP', 'molecular_function', 'GO:0051748', ('18', '21'))	('reduced', 'NegReg', (111, 118))	('SPAG5', 'Gene', '10615', (47, 52))	('ser473', 'Var', (72, 78))	('SPAG5', 'Gene', (122, 127))	('mTOR', 'Gene', (86, 90))	('AKT', 'Gene', '207', (171, 174))	('mTOR', 'Gene', (179, 183))	('ser', 'cellular_component', 'GO:0005790', ('92', '95'))
78580	31957155	Also, Western blot analysis confirmed that overexpression of SPAG5 restored p-AKT (thr308 and ser473) and p-mTOR (ser2448) that were reduced by SPAG5-AS1 knockdown, whereas MHY1485 only restored p-mTOR (ser2448) in HG-treated HPCs (Figure 7B, Figure S3B).	('mTOR', 'Gene', '2475', (108, 112))	('MHY1485', 'Chemical', 'MESH:C577756', (173, 180))	('HG', 'Phenotype', 'HP:0003074', (215, 217))	('SPAG5', 'Gene', (144, 149))	('ser', 'cellular_component', 'GO:0005790', ('94', '97'))	('ser', 'cellular_component', 'GO:0005790', ('203', '206'))	('mTOR', 'Gene', '2475', (197, 201))	('AKT', 'Gene', (78, 81))	('ser', 'cellular_component', 'GO:0005790', ('114', '117'))	('knockdown', 'Var', (154, 163))	('ser473', 'Chemical', '-', (94, 100))	('SPAG5', 'Gene', '10615', (144, 149))	('SPAG5', 'Gene', (61, 66))	('AKT', 'Gene', '207', (78, 81))	('ser2448', 'Chemical', '-', (203, 210))	('ser2448', 'Chemical', '-', (114, 121))	('thr308', 'Chemical', '-', (83, 89))	('mTOR', 'Gene', (108, 112))	('mTOR', 'Gene', (197, 201))	('SPAG5', 'Gene', '10615', (61, 66))
78583	31957155	LC-3 fluorescence intensity and podocin expression were induced by SPAG5-AS1 silence and impaired by the co-transfection of pcDNA3.1/SPAG5 or treatment of MHY1485 (Figure 7E, Figure S3E).	('SPAG5', 'Gene', (133, 138))	('expression', 'MPA', (40, 50))	('fluorescence intensity', 'MPA', (5, 27))	('SPAG5', 'Gene', (67, 72))	('MHY1485', 'Chemical', 'MESH:C577756', (155, 162))	('podocin', 'Gene', '7827', (32, 39))	('SPAG5', 'Gene', '10615', (67, 72))	('podocin', 'Gene', (32, 39))	('LC-3', 'Gene', (0, 4))	('induced', 'PosReg', (56, 63))	('SPAG5', 'Gene', '10615', (133, 138))	('silence', 'Var', (77, 84))	('DN', 'Disease', 'MESH:D003928', (126, 128))	('impaired', 'NegReg', (89, 97))	('LC-3', 'Gene', '84557', (0, 4))
78585	31957155	The increase of LC-3II/LC-3I and Beclin1 and decrease of p62 caused by SPAG5-AS1 silence were reversed by pcDNA3.1/SPAG5 or activation of mTOR (Figure 7F, Figure S3G).	('SPAG5', 'Gene', '10615', (115, 120))	('p62', 'Gene', (57, 60))	('LC-3', 'Gene', (23, 27))	('mTOR', 'Gene', (138, 142))	('mTOR', 'Gene', '2475', (138, 142))	('LC-3', 'Gene', (16, 20))	('SPAG5', 'Gene', (71, 76))	('Beclin1', 'Gene', '8678', (33, 40))	('SPAG5', 'Gene', '10615', (71, 76))	('LC-3', 'Gene', '84557', (23, 27))	('LC-3', 'Gene', '84557', (16, 20))	('decrease', 'NegReg', (45, 53))	('SPAG5', 'Gene', (115, 120))	('Beclin1', 'Gene', (33, 40))	('increase', 'PosReg', (4, 12))	('silence', 'Var', (81, 88))	('p62', 'Gene', '8878', (57, 60))	('DN', 'Disease', 'MESH:D003928', (108, 110))
78590	31957155	Herein, we firstly revealed that SPAG5 was upregulated in HPCs under HG treatment and silence of SPAG5 reversed the HG-caused apoptosis induction and autophagy inhibition in HPCs, indicating that targeting SPAG5 could alleviate HG-induced podocyte damage.	('SPAG5', 'Gene', (33, 38))	('autophagy inhibition', 'CPA', (150, 170))	('HG', 'Phenotype', 'HP:0003074', (228, 230))	('SPAG5', 'Gene', '10615', (97, 102))	('upregulated', 'PosReg', (43, 54))	('silence', 'Var', (86, 93))	('HG', 'Phenotype', 'HP:0003074', (69, 71))	('apoptosis induction', 'CPA', (126, 145))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('SPAG5', 'Gene', '10615', (33, 38))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('HG', 'Phenotype', 'HP:0003074', (116, 118))	('SPAG5', 'Gene', (206, 211))	('autophagy', 'biological_process', 'GO:0016236', ('150', '159'))	('SPAG5', 'Gene', (97, 102))	('SPAG5', 'Gene', '10615', (206, 211))	('autophagy', 'biological_process', 'GO:0006914', ('150', '159'))
78601	31957155	Former studies showed that miR-769-5p participated in prolonged concussion symptoms and acted a predictor of lung cancer patient survival.34, 35 However, this was the first time for miR-769-5p to be related to HG-induced podocyte injury.	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('patient', 'Species', '9606', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('HG-induced podocyte injury', 'Disease', (210, 236))	('related', 'Reg', (199, 206))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('HG', 'Phenotype', 'HP:0003074', (210, 212))	('miR-769-5p', 'Var', (182, 192))
78602	31957155	We suggested that miR-769-5p regulated SPAG5-AS1 through YY1-mediated transcription.	('miR-769-5p', 'Var', (18, 28))	('YY1', 'Gene', '7528', (57, 60))	('regulated', 'Reg', (29, 38))	('SPAG5-AS1', 'Gene', (39, 48))	('YY1', 'Gene', (57, 60))	('transcription', 'biological_process', 'GO:0006351', ('70', '83'))
78605	31957155	Also, we validated that SPAG5-AS1 could induce p-USP14 (ser432).	('USP14', 'Gene', (49, 54))	('ser432', 'Chemical', '-', (56, 62))	('SPAG5-AS1', 'Var', (24, 33))	('ser', 'cellular_component', 'GO:0005790', ('56', '59'))	('induce', 'Reg', (40, 46))	('USP14', 'Gene', '9097', (49, 54))	('USP', 'molecular_function', 'GO:0051748', ('49', '52'))
78608	31957155	Finally, rescue assay suggested that SPAG5-AS1 knockdown attenuated HG-induced podocyte injury through SPAG5/AKT/mTOR axis.	('SPAG5', 'Gene', (37, 42))	('podocyte injury', 'CPA', (79, 94))	('AKT', 'Gene', '207', (109, 112))	('SPAG5', 'Gene', '10615', (37, 42))	('mTOR', 'Gene', (113, 117))	('knockdown', 'Var', (47, 56))	('mTOR', 'Gene', '2475', (113, 117))	('HG', 'Phenotype', 'HP:0003074', (68, 70))	('HG-induced', 'Disease', (68, 78))	('SPAG5', 'Gene', (103, 108))	('attenuated', 'NegReg', (57, 67))	('AKT', 'Gene', (109, 112))	('SPAG5', 'Gene', '10615', (103, 108))
78610	31957155	Functionally, silencing SPAG5 attenuated apoptosis and induced autophagy in HG-treated HPCs.	('apoptosis', 'biological_process', 'GO:0097194', ('41', '50'))	('silencing', 'Var', (14, 23))	('apoptosis', 'biological_process', 'GO:0006915', ('41', '50'))	('autophagy', 'CPA', (63, 72))	('autophagy', 'biological_process', 'GO:0016236', ('63', '72'))	('autophagy', 'biological_process', 'GO:0006914', ('63', '72'))	('SPAG5', 'Gene', (24, 29))	('apoptosis', 'CPA', (41, 50))	('induced', 'Reg', (55, 62))	('SPAG5', 'Gene', '10615', (24, 29))	('attenuated', 'NegReg', (30, 40))	('HG', 'Phenotype', 'HP:0003074', (76, 78))
78639	24587796	CK7, CK20, p63, Ki-67, and CK903, variable P53.	('p63', 'Gene', (11, 14))	('P53', 'Gene', (43, 46))	('CK903', 'Var', (27, 32))	('P53', 'Gene', '7157', (43, 46))	('p63', 'Gene', '8626', (11, 14))	('CK20', 'Gene', (5, 9))	('CK20', 'Gene', '54474', (5, 9))	('CK7', 'Gene', (0, 3))	('Ki-67', 'Var', (16, 21))	('CK7', 'Gene', '3855', (0, 3))
78649	24587796	They had stained formalin-fixed, paraffin-embedded archival tissues from 12 cases of nested variant of urothelial carcinoma with monoclonal antibodies to p21, p27, p53, EGF-R, and bcl-2, as well as the proliferation marker MIB-1.	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('EGF', 'molecular_function', 'GO:0005154', ('169', '172'))	('p53', 'Var', (164, 167))	('EGF-R', 'Gene', (169, 174))	('bcl-2', 'molecular_function', 'GO:0015283', ('180', '185'))	('MIB-1', 'Gene', (223, 228))	('formalin', 'Chemical', 'MESH:D005557', (17, 25))	('bcl-2', 'Gene', (180, 185))	('MIB-1', 'Gene', '57534', (223, 228))	('p27', 'Var', (159, 162))	('paraffin', 'Chemical', 'MESH:D010232', (33, 41))	('p21', 'Gene', (154, 157))	('p21', 'Gene', '644914', (154, 157))	('EGF-R', 'Gene', '1956', (169, 174))
78658	24587796	The neoplastic cells were positive for pancytokeratin and OC125 (cytoplasmic) while being negative for chromogranin, synaptophysin, CD56, CK7, CK20, CDX2, TTF1, ER, PR, p53, and BRST2.	('OC125', 'Gene', (58, 63))	('positive', 'Reg', (26, 34))	('CDX2', 'Gene', (149, 153))	('synaptophysin', 'Gene', '6855', (117, 130))	('CDX2', 'Gene', '1045', (149, 153))	('CK20', 'Var', (143, 147))	('CD56', 'Gene', '4684', (132, 136))	('TTF1', 'Gene', (155, 159))	('CD56', 'Gene', (132, 136))	('synaptophysin', 'Gene', (117, 130))	('TTF1', 'Gene', '7270', (155, 159))	('pancytokeratin', 'Protein', (39, 53))
78682	24587796	One case was characterized by positive cytokeratins, EMA, p53, Ki-67 (labeling = 15%), CD10, CEA, and MUC1.	('CD10', 'Gene', '4311', (87, 91))	('CD10', 'Gene', (87, 91))	('CEA', 'Gene', (93, 96))	('Ki-67', 'Gene', (63, 68))	('CEA', 'Gene', '5670', (93, 96))	('MUC1', 'Gene', (102, 106))	('MUC1', 'Gene', '4582', (102, 106))	('CD10', 'molecular_function', 'GO:0004245', ('87', '91'))	('p53', 'Var', (58, 61))	('cytokeratins', 'Protein', (39, 51))
78699	24587796	The immunohistochemical staining characteristics of the tumour include immunoreactivity for high-molecular cytokeratin 903 and cytokeratin 7 and negativity for prostate specific antigen, prostate acid phosphatase, S100, and chromogranin.	('S100', 'Gene', (214, 218))	('prostate specific antigen', 'Gene', (160, 185))	('S100', 'Gene', '6271', (214, 218))	('prostate', 'Protein', (187, 195))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('phosphatase', 'molecular_function', 'GO:0016791', ('201', '212'))	('prostate specific antigen', 'Gene', '354', (160, 185))	('chromogranin', 'Protein', (224, 236))	('negativity', 'Var', (145, 155))
78707	24587796	Clinicopathologic information from their 16 cases combined with the 8 cases of nested variant of transitional cell carcinoma that were reported before the publication of their paper confirms that nested variant of transitional cell carcinoma is a persistent and aggressive neoplasm that is notable for its innocuous appearance in histologic preparations.	('transitional cell carcinoma', 'Disease', (214, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('nested variant', 'Var', (196, 210))	('aggressive neoplasm', 'Disease', 'MESH:D001523', (262, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('aggressive neoplasm', 'Disease', (262, 281))	('neoplasm', 'Phenotype', 'HP:0002664', (273, 281))
78722	24587796	Death rate from nested variant of urothelial carcinoma can be up to 25% of cases and persistent or progressive disease has been reported in up to 60% of cases which had led some authors to conclude that nested variant of urothelial carcinoma has a clinical course which is similar to that of high-grade urothelial carcinomas.	('Death', 'Disease', 'MESH:D003643', (0, 5))	('nested variant', 'Var', (203, 217))	('Death', 'Disease', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (314, 323))	('carcinomas', 'Phenotype', 'HP:0030731', (314, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
78792	21692050	In agreement with our previous findings, we found that addition of NMP22 improves the accuracy of the base model that includes age and gender to predict bladder cancer recurrence and progression by a statistically and clinically significant margin.	('addition', 'Var', (55, 63))	('bladder cancer', 'Disease', (153, 167))	('bladder cancer', 'Disease', 'MESH:D001749', (153, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('men', 'Species', '9606', (8, 11))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (153, 178))	('NMP22', 'Gene', (67, 72))	('NMP22', 'Gene', '4926', (67, 72))	('accuracy', 'MPA', (86, 94))	('bladder cancer', 'Phenotype', 'HP:0009725', (153, 167))	('improves', 'PosReg', (73, 81))
78805	32102337	Although several epigenetic-based biomarkers have been proposed, their ability to discriminate BlCa from common benign conditions of the urinary tract, especially inflammatory diseases, has not been adequately explored.	('BlCa', 'Disease', (95, 99))	('epigenetic-based', 'Var', (17, 33))	('benign conditions of the urinary tract', 'Phenotype', 'HP:0006778', (112, 150))	('BlCa', 'Disease', 'MESH:D001749', (95, 99))	('BlCa', 'Phenotype', 'HP:0009725', (95, 99))
78825	32102337	In 2010, a three-gene panel comprised GDF15, TMEFF2 and VIM methylation identified BlCa with 94% sensitivity and 100% specificity in urine samples from 51 BlCa patients.	('patients', 'Species', '9606', (160, 168))	('BlCa', 'Disease', 'MESH:D001749', (155, 159))	('identified', 'Reg', (72, 82))	('BlCa', 'Phenotype', 'HP:0009725', (155, 159))	('VIM', 'Gene', (56, 59))	('methylation', 'Var', (60, 71))	('BlCa', 'Disease', (83, 87))	('BlCa', 'Phenotype', 'HP:0009725', (83, 87))	('GDF15', 'Gene', (38, 43))	('BlCa', 'Disease', (155, 159))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('VIM', 'Gene', '7431', (56, 59))	('GDF15', 'Gene', '9518', (38, 43))	('BlCa', 'Disease', 'MESH:D001749', (83, 87))	('TMEFF2', 'Gene', (45, 51))	('TMEFF2', 'Gene', '23671', (45, 51))
78883	32102337	Despite the fact that several studies suggest various genomic mutations and/or proteins' expression deregulation as biomarkers for BlCa detection and prognostication, the search for novel epigenetic biomarkers, mostly DNA methylation-based, for BlCa detection has been attempted by several research teams, probably due to the stability of the markers and the possibility of high-throughput tests.	('proteins', 'Protein', (79, 87))	('DNA methylation', 'biological_process', 'GO:0006306', ('218', '233'))	('expression', 'MPA', (89, 99))	('BlCa', 'Disease', 'MESH:D001749', (245, 249))	('BlCa', 'Disease', 'MESH:D001749', (131, 135))	('DNA', 'cellular_component', 'GO:0005574', ('218', '221'))	('BlCa', 'Phenotype', 'HP:0009725', (245, 249))	('BlCa', 'Phenotype', 'HP:0009725', (131, 135))	('deregulation', 'NegReg', (100, 112))	('BlCa', 'Disease', (131, 135))	('BlCa', 'Disease', (245, 249))	('mutations', 'Var', (62, 71))
78896	32102337	VIM de-novo expression or overexpression has been reported in various epithelial cancers, including those of prostate, breast and lung, associating with increased tumour growth and invasion.	('breast', 'Disease', (119, 125))	('prostate', 'Disease', (109, 117))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('overexpression', 'PosReg', (26, 40))	('increased', 'PosReg', (153, 162))	('VIM', 'Gene', '7431', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('tumour growth', 'Disease', (163, 176))	('epithelial cancers', 'Disease', 'MESH:D000077216', (70, 88))	('invasion', 'CPA', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('VIM', 'Gene', (0, 3))	('epithelial cancers', 'Disease', (70, 88))	('tumour growth', 'Disease', 'MESH:D006130', (163, 176))	('lung', 'Disease', (130, 134))	('de-novo expression', 'Var', (4, 22))
78899	32102337	Moreover, microRNAs have been extensively implicated in urological malignancies.	('implicated', 'Reg', (42, 52))	('malignancies', 'Disease', 'MESH:D009369', (67, 79))	('microRNAs', 'Var', (10, 19))	('malignancies', 'Disease', (67, 79))
78918	31897084	Negative p16 accompanied by a positive Ki-67 rate at 5% or more could be considered as an additional marker for further clinical follow-up.	('p16', 'Gene', '1029', (9, 12))	('p16', 'Gene', (9, 12))	('Ki-67', 'CPA', (39, 44))	('Ki-67', 'Chemical', '-', (39, 44))	('Negative', 'Var', (0, 8))
78955	31897084	The normal controls [Figure 3] were completely negative for both markers, whereas 27/84 (32.1%) samples were positive for either p16 (n = 5) or Ki-67 (n = 22) [Figures 4 and 5].	('p16', 'Gene', (129, 132))	('Ki-67', 'Var', (144, 149))	('Ki-67', 'Chemical', '-', (144, 149))	('p16', 'Gene', '1029', (129, 132))	('positive', 'Reg', (109, 117))
78974	31897084	In equivocal cases, positivity for p16 may be suspicious of recurrence.	('p16', 'Gene', '1029', (35, 38))	('positivity', 'Var', (20, 30))	('p16', 'Gene', (35, 38))
78975	31897084	The anonymous samples in our material showed positivity of p16 in 43.8%, which is on the same level as the primary diagnosed carcinomas.	('p16', 'Gene', '1029', (59, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Disease', 'MESH:D009369', (125, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('positivity', 'Var', (45, 55))	('carcinomas', 'Disease', (125, 135))	('p16', 'Gene', (59, 62))
78977	31897084	None of the benign samples were positive for p16, indicating that p16 positivity, regardless of the number of positive cells, would be a strong indication that the cells might be malignant and that cystoscopy should be done for further investigation.	('p16', 'Gene', '1029', (45, 48))	('positivity', 'Var', (70, 80))	('p16', 'Gene', (66, 69))	('p16', 'Gene', (45, 48))	('p16', 'Gene', '1029', (66, 69))
78985	31897084	Overexpression is associated with higher tumor grades and stages, disease progression, and decreased survival.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('higher', 'PosReg', (34, 40))	('Overexpression', 'Var', (0, 14))	('survival', 'CPA', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('stages', 'CPA', (58, 64))	('disease progression', 'CPA', (66, 85))	('decreased', 'NegReg', (91, 100))
78986	31897084	The optimal cutoff for detection of all types of UC, taken as a whole, was calculated at 5% for p53 and 3% for Ki-67.	('Ki-67', 'Chemical', '-', (111, 116))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('Ki-67', 'Var', (111, 116))
78988	31897084	They conclude that testing for p53 and/or Ki-67 increases the specificity without reducing the sensitivity.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('increases', 'PosReg', (48, 57))	('specificity', 'MPA', (62, 73))	('Ki-67', 'Var', (42, 47))	('Ki-67', 'Chemical', '-', (42, 47))
79006	31897084	Positivity of p16 alone is a strong indication of malignancy or risk of recurrence and thus an indication for follow-up and eventually cystoscopy.	('p16', 'Gene', '1029', (14, 17))	('p16', 'Gene', (14, 17))	('Positivity', 'Var', (0, 10))	('malignancy', 'Disease', 'MESH:D009369', (50, 60))	('malignancy', 'Disease', (50, 60))
79017	31624709	Mutations/epigenetic alterations in the key molecules of Wnt/beta-catenin canonical pathway have been linked with tumorigenesis, development of drug resistance and enhanced survival.	('Wnt/beta-catenin canonical pathway', 'Pathway', (57, 91))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Mutations/epigenetic alterations', 'Var', (0, 32))	('drug resistance', 'biological_process', 'GO:0009315', ('144', '159'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('enhanced', 'PosReg', (164, 172))	('drug resistance', 'biological_process', 'GO:0042493', ('144', '159'))	('tumor', 'Disease', (114, 119))	('rat', 'Species', '10116', (25, 28))	('linked', 'Reg', (102, 108))	('survival', 'CPA', (173, 181))	('drug resistance', 'Phenotype', 'HP:0020174', (144, 159))
79023	31624709	Mutations/epigenetic alterations in the regulatory components of Wnt/beta-catenin signaling lead to acquisition of urothelial cancer stem cell phenotype, chemoresistance and enhanced survival.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('enhanced', 'PosReg', (174, 182))	('acquisition of urothelial cancer', 'Disease', 'MESH:D014523', (100, 132))	('Mutations/epigenetic alterations', 'Var', (0, 32))	('signaling', 'biological_process', 'GO:0023052', ('82', '91'))	('chemoresistance', 'CPA', (154, 169))	('acquisition of urothelial cancer', 'Disease', (100, 132))	('survival', 'CPA', (183, 191))	('rat', 'Species', '10116', (25, 28))
79032	31624709	Recent experimental studies validate the involvement of oncogenic mutations in telomerase reverse transcriptase, fibroblast growth factor (FGF) receptor, Harvey rat sarcoma viral oncogene, and phosphoinositide 3'-kinase (PI3K); activation of mitogen-activated protein kinases; and increased expression of cyclin D1 in the development of papillary cancer.	('mutations', 'Var', (66, 75))	('transcriptase', 'molecular_function', 'GO:0003899', ('98', '111'))	('sarcoma', 'Disease', 'MESH:D012509', (165, 172))	('sarcoma', 'Disease', (165, 172))	('protein', 'cellular_component', 'GO:0003675', ('260', '267'))	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('113', '137'))	('increased', 'PosReg', (281, 290))	('cyclin D1', 'Protein', (305, 314))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('mitogen-activated protein kinases', 'Pathway', (242, 275))	('transcriptase', 'molecular_function', 'GO:0003968', ('98', '111'))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('transcriptase', 'molecular_function', 'GO:0034062', ('98', '111'))	('papillary cancer', 'Disease', 'MESH:D009369', (337, 353))	('PI3K', 'molecular_function', 'GO:0016303', ('221', '225'))	('expression', 'MPA', (291, 301))	("phosphoinositide 3'-kinase", 'Gene', '85243', (193, 219))	('papillary cancer', 'Disease', (337, 353))	('activation', 'PosReg', (228, 238))	('cyclin', 'molecular_function', 'GO:0016538', ('305', '311'))	("phosphoinositide 3'-kinase", 'Gene', (193, 219))	('rat', 'Species', '10116', (161, 164))
79034	31624709	Gene expression, whole genome array-comparative genomic hybridization and mutation analyses validate frequent alterations in loss of tumor protein 53 function; increased instability of chromosomes; inactivation of phosphatase tensin homolog; severe disturbances in cell cycle regulators; loss in functions of retinoblastoma and cyclin dependent kinase inhibitor 2A (CDKN2A)/p16INK4A; and the effect of altered DNA methylation on the expression of cell cycle regulators, in muscle invasive disease.	('retinoblastoma', 'Disease', (309, 323))	('loss', 'NegReg', (125, 129))	('disturbances', 'NegReg', (249, 261))	('cell cycle', 'CPA', (265, 275))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cyclin dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('328', '361'))	('N', 'Chemical', 'MESH:D009584', (378, 379))	('phosphatase tensin homolog', 'Gene', (214, 240))	('increased instability of chromosomes', 'Phenotype', 'HP:0040012', (160, 196))	('muscle invasive disease', 'Disease', 'MESH:D019042', (473, 496))	('N', 'Chemical', 'MESH:D009584', (369, 370))	('functions', 'MPA', (296, 305))	('CDKN2A', 'Gene', (366, 372))	('loss', 'NegReg', (288, 292))	('phosphatase', 'molecular_function', 'GO:0016791', ('214', '225'))	('p16INK4A', 'Gene', (374, 382))	('tumor protein 53', 'Gene', (133, 149))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('345', '361'))	('p16INK4A', 'Gene', '1029', (374, 382))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('retinoblastoma', 'Disease', 'MESH:D012175', (309, 323))	('function', 'MPA', (150, 158))	('tumor protein 53', 'Gene', '7157', (133, 149))	('cyclin dependent kinase inhibitor 2A', 'Gene', (328, 364))	('increased', 'PosReg', (160, 169))	('instability', 'MPA', (170, 181))	('CDKN2A', 'Gene', '1029', (366, 372))	('muscle invasive disease', 'Disease', (473, 496))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('alterations', 'Var', (110, 121))	('rat', 'Species', '10116', (114, 117))	('cell cycle', 'biological_process', 'GO:0007049', ('447', '457'))	('N', 'Chemical', 'MESH:D009584', (411, 412))	('retinoblastoma', 'Phenotype', 'HP:0009919', (309, 323))	('cell cycle', 'biological_process', 'GO:0007049', ('265', '275'))	('rat', 'Species', '10116', (41, 44))	('DNA methylation', 'biological_process', 'GO:0006306', ('410', '425'))	('cyclin dependent kinase inhibitor 2A', 'Gene', '1029', (328, 364))	('DNA', 'cellular_component', 'GO:0005574', ('410', '413'))	('inactivation', 'Var', (198, 210))
79035	31624709	Castillo-Martin et al report the presence of mutations in PI3K, tumor suppressor genes, deleted in bladder cancer, tuberous sclerosis 1, CDKN2A and patched in both papillary and invasive tumors.	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('tumor', 'Disease', (187, 192))	('PI3K', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('invasive tumors', 'Disease', 'MESH:D009361', (178, 193))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('CDKN2A', 'Gene', (137, 143))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('64', '80'))	('invasive tumors', 'Disease', (178, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('tumor suppressor', 'biological_process', 'GO:0051726', ('64', '80'))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('CDKN2A', 'Gene', '1029', (137, 143))	('mutations', 'Var', (45, 54))	('tumor', 'Disease', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('bladder cancer', 'Disease', (99, 113))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tuberous sclerosis 1', 'Gene', (115, 135))	('tuberous sclerosis 1', 'Gene', '7248', (115, 135))
79046	31624709	Understanding the mechanisms of Wnt signaling dysregulation in the development and progression of UCB could help to develop pathway inhibitors and augment current therapies by targeting UCSCs and bulk tumor progenies.	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('UCB', 'Disease', (98, 101))	('UCB', 'Phenotype', 'HP:0006740', (98, 101))	('UCB', 'Disease', 'MESH:D001749', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('signaling', 'biological_process', 'GO:0023052', ('36', '45'))	('dysregulation', 'Var', (46, 59))	('tumor', 'Disease', (201, 206))
79053	31624709	Epigenetic changes, genomic instability, altered tumor microenvironment, and mutations in proto-oncogenes/tumor suppressor genes lead to aberrant molecular pathways in either adult stem cells or differentiated tumor progenies and thus transform them into a subset of unique UCSCs.	('aberrant', 'Var', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('transform', 'Reg', (235, 244))	('lead to', 'Reg', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', (49, 54))	('genomic', 'MPA', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', (106, 111))	('tumor suppressor', 'biological_process', 'GO:0051726', ('106', '122'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('106', '122'))	('Epigenetic changes', 'Var', (0, 18))	('molecular pathways', 'Pathway', (146, 164))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
79066	31624709	In Wnt "OFF" state, casein kinase 1 phosphorylation at Ser45 primes beta-catenin for subsequent phosphorylation by glycogen synthase kinase-3beta (GSK-3beta) on Thr41, Ser37 and Ser33.	('Ser', 'Chemical', 'MESH:C530429', (168, 171))	('phosphorylation', 'MPA', (96, 111))	('Ser37', 'Var', (168, 173))	('phosphorylation', 'biological_process', 'GO:0016310', ('94', '109'))	('GSK-3beta', 'Gene', '2932', (147, 156))	('Ser', 'Chemical', 'MESH:C530429', (55, 58))	('Ser', 'cellular_component', 'GO:0005790', ('176', '179'))	('glycogen synthase kinase-3beta', 'Gene', (115, 145))	('GSK-3beta', 'Gene', (147, 156))	('Ser', 'cellular_component', 'GO:0005790', ('53', '56'))	('Thr', 'Chemical', 'MESH:C055175', (161, 164))	('Ser', 'cellular_component', 'GO:0005790', ('166', '169'))	('phosphorylation', 'MPA', (36, 51))	('Ser45', 'Gene', (55, 60))	('Ser', 'Chemical', 'MESH:C530429', (178, 181))	('GSK', 'molecular_function', 'GO:0050321', ('145', '148'))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('Ser33', 'Var', (178, 183))	('glycogen synthase kinase-3beta', 'Gene', '2932', (115, 145))
79067	31624709	Phosphorylation at N-terminal serine and threonine residues creates a binding site for the ubiquitin ligase, SCFb-TrCP and targets beta-catenin for proteasomal degradation and consequently maintains beta-catenin in cytoplasm at a low level.	('cytoplasm', 'cellular_component', 'GO:0005737', ('215', '224'))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('binding', 'Interaction', (70, 77))	('serine', 'Chemical', 'MESH:C047902', (30, 36))	('beta-catenin', 'MPA', (199, 211))	('Phosphorylation', 'Var', (0, 15))	('SCFb-TrCP', 'Gene', (109, 118))	('binding', 'molecular_function', 'GO:0005488', ('70', '77'))	('proteasomal degradation', 'MPA', (148, 171))	('ubiquitin', 'molecular_function', 'GO:0031386', ('91', '100'))	('degradation', 'biological_process', 'GO:0009056', ('160', '171'))	('beta-catenin', 'MPA', (131, 143))	('threonine', 'Chemical', 'MESH:C061951', (41, 50))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))
79068	31624709	In Wnt "ON" state, binding of receptors to Wnt activates the downstream signaling cascade; initiates the disassembly of the destruction complex consisting of DVL/AXIN/APC (adenomatous polyposis coli)/GSK-3beta/CK1; facilitates the release of the stabilized beta-catenin to cytoplasm and its translocation to nucleus.	('translocation', 'MPA', (291, 304))	('APC', 'Disease', 'MESH:D011125', (167, 170))	('APC', 'Disease', (167, 170))	('activates', 'PosReg', (47, 56))	('cytoplasm', 'cellular_component', 'GO:0005737', ('271', '280'))	('signaling cascade', 'biological_process', 'GO:0007165', ('70', '87'))	('GSK-3beta', 'Gene', '2932', (200, 209))	('AXIN', 'Gene', (162, 166))	('binding', 'molecular_function', 'GO:0005488', ('17', '24'))	('binding', 'Var', (19, 26))	('DVL', 'Gene', '1855', (158, 161))	('beta-catenin', 'Protein', (257, 269))	('N', 'Chemical', 'MESH:D009584', (9, 10))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (172, 198))	('adenomatous polyposis coli', 'Disease', (172, 198))	('downstream signaling cascade', 'Pathway', (61, 89))	('GSK-3beta', 'Gene', (200, 209))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (172, 198))	('DVL', 'Gene', (158, 161))	('facilitates', 'PosReg', (215, 226))	('APC', 'cellular_component', 'GO:0005680', ('165', '168'))	('GSK', 'molecular_function', 'GO:0050321', ('198', '201'))	('release', 'MPA', (231, 238))	('CK1', 'Species', '2498238', (210, 213))	('AXIN', 'Gene', '8312', (162, 166))	('N', 'Chemical', 'MESH:D009584', (165, 166))	('stabilized', 'MPA', (246, 256))	('nucleus', 'cellular_component', 'GO:0005634', ('306', '313'))
79083	31624709	IP3 triggers release of intracellular Ca2+in the endoplasmic reticulum and activates downstream targets, including calcineurin, calmodulin-dependent protein kinase II (CamKII), and protein kinase C (PKC).	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('49', '70'))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('calcineurin', 'MPA', (115, 126))	('calmodulin-dependent protein kinase II', 'Gene', '818', (128, 166))	('CamKII', 'Gene', '818', (168, 174))	('CamKII', 'cellular_component', 'GO:0005954', ('168', '174'))	('PKC', 'molecular_function', 'GO:0004697', ('199', '202'))	('Ca2+', 'Chemical', 'MESH:D002118', (38, 42))	('intracellular', 'cellular_component', 'GO:0005622', ('24', '37'))	('CamKII', 'Gene', (168, 174))	('calcineurin', 'molecular_function', 'GO:0004722', ('115', '126'))	('activates', 'PosReg', (75, 84))	('calcineurin', 'molecular_function', 'GO:0004723', ('115', '126'))	('calmodulin-dependent protein kinase II', 'Gene', (128, 166))	('CamKII', 'molecular_function', 'GO:0004683', ('168', '174'))	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))	('IP3', 'Var', (0, 3))
79088	31624709	Nevertheless, their aberrant activation results in the development of many human tumors and others diseases.	('tumors', 'Disease', (81, 87))	('activation', 'PosReg', (29, 39))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('aberrant', 'Var', (20, 28))	('results in', 'Reg', (40, 50))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('human', 'Species', '9606', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
79090	31624709	Overexpression of WNT ligands, impaired cytosolic beta-catenin degradation, modulated activities of the TCF/LEF transcription factors and epigenetic repression of WNT antagonists contribute to the pathogenesis of malignant neoplasms of the hematopoietic system.	('modulated', 'Var', (76, 85))	('pathogenesis', 'biological_process', 'GO:0009405', ('197', '209'))	('activities', 'MPA', (86, 96))	('malignant neoplasms of the hematopoietic system', 'Disease', (213, 260))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('TCF', 'Gene', (104, 107))	('TCF', 'Gene', '3172', (104, 107))	('contribute', 'Reg', (179, 189))	('N', 'Chemical', 'MESH:D009584', (164, 165))	('degradation', 'biological_process', 'GO:0009056', ('63', '74'))	('cytosolic beta-catenin degradation', 'MPA', (40, 74))	('malignant neoplasms of the hematopoietic system', 'Disease', 'MESH:D019337', (213, 260))	('epigenetic repression', 'Var', (138, 159))	('neoplasms', 'Phenotype', 'HP:0002664', (223, 232))	('impaired', 'NegReg', (31, 39))	('transcription', 'biological_process', 'GO:0006351', ('112', '125'))
79091	31624709	Aberrant Wnt/beta-catenin signaling due to mutations in APC and beta-catenin genes is reported in colorectal cancer.	('beta-catenin genes', 'Gene', (64, 82))	('colorectal cancer', 'Disease', (98, 115))	('Wnt/beta-catenin signaling', 'MPA', (9, 35))	('APC', 'cellular_component', 'GO:0005680', ('56', '59'))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('mutations', 'Var', (43, 52))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('APC', 'Disease', 'MESH:D011125', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('APC', 'Disease', (56, 59))
79093	31624709	Deregulation of canonical Wnt signaling and its functions in promoting DNA damage repair and inhibiting apoptosis has been examined to be associated with radioresistance of multiple cancers.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('DNA damage repair', 'MPA', (71, 88))	('N', 'Chemical', 'MESH:D009584', (72, 73))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('Deregulation', 'Var', (0, 12))	('multiple cancers', 'Disease', (173, 189))	('apoptosis', 'CPA', (104, 113))	('signaling', 'biological_process', 'GO:0023052', ('30', '39'))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('associated', 'Reg', (138, 148))	('multiple cancers', 'Disease', 'MESH:D009369', (173, 189))	('canonical Wnt signaling', 'Pathway', (16, 39))	('promoting', 'PosReg', (61, 70))	('inhibiting', 'NegReg', (93, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('104', '113'))	('apoptosis', 'biological_process', 'GO:0006915', ('104', '113'))
79094	31624709	Genomic mutations and epigenetic changes are being examined to regulate the cancer stem cell phenotype by controlling the expression levels of Wnt/beta-catenin components.	('epigenetic changes', 'Var', (22, 40))	('controlling', 'Reg', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('regulate', 'Reg', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('expression levels', 'MPA', (122, 139))
79095	31624709	Single nucleotide polymorphisms in about forty genes that participate in Wnt/beta-catenin stem cell pathway are genotyped and the genomic variants have been reported to be associated with the etiology of the bladder cancer.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('bladder cancer', 'Disease', 'MESH:D001749', (208, 222))	('bladder cancer', 'Disease', (208, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('associated', 'Reg', (172, 182))	('variants', 'Var', (138, 146))	('bladder cancer', 'Phenotype', 'HP:0009725', (208, 222))
79096	31624709	Aberrant Wnt signaling due to mutations in beta-catenin in CSCs results in induced tumorigenic proliferation.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('signaling', 'biological_process', 'GO:0023052', ('13', '22'))	('beta-catenin', 'Protein', (43, 55))	('rat', 'Species', '10116', (102, 105))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
79097	31624709	Missense/ inactivating mutations in APC tumor suppressor (in 13% of tumors) and frameshift deletions (in 3% of tumors) in regions adjacent to beta-catenin binding sites result in beta-catenin accumulation, dysregulation of Wnt/beta-catenin in cancer cells or UCSCs, induce neoplastic proliferation and increase invasion potential.	('induce', 'PosReg', (266, 272))	('APC tumor', 'Disease', (36, 45))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('increase', 'PosReg', (302, 310))	('neoplastic proliferation', 'Phenotype', 'HP:0002664', (273, 297))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('beta-catenin accumulation', 'MPA', (179, 204))	('beta-catenin binding', 'molecular_function', 'GO:0008013', ('142', '162'))	('tumors', 'Disease', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('frameshift deletions', 'Var', (80, 100))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('APC tumor', 'Disease', 'MESH:D011125', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('Missense/ inactivating mutations', 'Var', (0, 32))	('APC', 'cellular_component', 'GO:0005680', ('36', '39'))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('result in', 'Reg', (169, 178))	('rat', 'Species', '10116', (291, 294))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('invasion potential', 'CPA', (311, 329))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('tumors', 'Disease', (68, 74))	('cancer', 'Disease', (243, 249))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('dysregulation', 'Var', (206, 219))	('Wnt/beta-catenin', 'Protein', (223, 239))	('neoplastic proliferation', 'CPA', (273, 297))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))
79101	31624709	Epigenetic silencing of these antagonists due to DNA promoter methylation is well known mechanism in urothelial carcinogenesis.	('methylation', 'biological_process', 'GO:0032259', ('62', '73'))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (101, 126))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('Epigenetic silencing', 'Var', (0, 20))	('urothelial carcinogenesis', 'Disease', (101, 126))
79106	31624709	Mounting evidences suggest that lower levels of E-cadherin (epithelial marker protein) due to promoter hypermethylation may induce inappropriate responsiveness to Wnt factors.	('responsiveness to Wnt factors', 'Interaction', (145, 174))	('promoter hypermethylation', 'Var', (94, 119))	('cadherin', 'molecular_function', 'GO:0008014', ('50', '58'))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('E-cadherin', 'Gene', (48, 58))	('E-cadherin', 'Gene', '999', (48, 58))	('levels', 'MPA', (38, 44))	('lower', 'NegReg', (32, 37))
79108	31624709	Recent studies report the association of specific genotype of E-cadherin with susceptibility to UCB and a worse clinical prognosis.	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('susceptibility', 'Reg', (78, 92))	('genotype', 'Var', (50, 58))	('cadherin', 'molecular_function', 'GO:0008014', ('64', '72'))	('UCB', 'Phenotype', 'HP:0006740', (96, 99))	('E-cadherin', 'Gene', (62, 72))	('UCB', 'Disease', 'MESH:D001749', (96, 99))	('UCB', 'Disease', (96, 99))	('association', 'Interaction', (26, 37))	('E-cadherin', 'Gene', '999', (62, 72))
79118	31624709	Given the important roles and pleiotropic effects of canonical Wnt signaling in cell self-renewal/maintenance of stemness, plasticity regulation (differentiation/dedifferentiation) and tissue homeostasis, loss of Wnt/beta-catenin pathway has been examined to be associated with the inhibition of stemness of UCSCs.	('stemness', 'Disease', 'MESH:D020295', (113, 121))	('stemness', 'Disease', (113, 121))	('tissue homeostasis', 'biological_process', 'GO:0001894', ('185', '203'))	('loss', 'Var', (205, 209))	('regulation', 'biological_process', 'GO:0065007', ('134', '144'))	('dedifferentiation', 'biological_process', 'GO:0043696', ('162', '179'))	('stemness', 'Disease', 'MESH:D020295', (296, 304))	('stemness', 'Disease', (296, 304))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))
79119	31624709	Expression studies examine that dysregulated Wnt/beta-catenin support dedifferentiation, EMT and hypoxia which might be responsible for the transformation of early bladder cancer cells into cancer stem cells.	('hypoxia', 'Disease', (97, 104))	('cancer', 'Disease', (190, 196))	('hypoxia', 'Disease', 'MESH:D000860', (97, 104))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('bladder cancer', 'Phenotype', 'HP:0009725', (164, 178))	('dedifferentiation', 'biological_process', 'GO:0043696', ('70', '87'))	('dysregulated', 'Var', (32, 44))	('Wnt/beta-catenin', 'Protein', (45, 61))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('bladder cancer', 'Disease', 'MESH:D001749', (164, 178))	('bladder cancer', 'Disease', (164, 178))	('cancer', 'Disease', (172, 178))	('dedifferentiation', 'CPA', (70, 87))	('EMT', 'CPA', (89, 92))	('EMT', 'biological_process', 'GO:0001837', ('89', '92'))
79137	31624709	Experiments on miR-940 mimics/miR-940 inhibitor small interference RNA mediated knockdown of inositol polyphosphate-4-phosphatase type 1 A or GSK-3beta resulted in regulation of malignant behavior of bladder cancer cells.	('bladder cancer', 'Disease', 'MESH:D001749', (200, 214))	('bladder cancer', 'Disease', (200, 214))	('miR-940', 'Gene', (30, 37))	('miR-940', 'Gene', (15, 22))	('regulation', 'biological_process', 'GO:0065007', ('164', '174'))	('malignant behavior of', 'CPA', (178, 199))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('bladder cancer', 'Phenotype', 'HP:0009725', (200, 214))	('GSK', 'molecular_function', 'GO:0050321', ('142', '145'))	('inositol polyphosphate', 'Chemical', 'MESH:D011122', (93, 115))	('miR-940', 'Gene', '100126328', (30, 37))	('miR-940', 'Gene', '100126328', (15, 22))	('RNA', 'cellular_component', 'GO:0005562', ('67', '70'))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('regulation', 'Reg', (164, 174))	('GSK-3beta', 'Gene', '2932', (142, 151))	('knockdown', 'Var', (80, 89))	('GSK-3beta', 'Gene', (142, 151))	('phosphatase', 'molecular_function', 'GO:0016791', ('118', '129'))
79145	31624709	Short hairpin RNA mediated knockdown of Med19 was examined to remarkably reduce the expression of Wnt2, active beta-catenin, cyclin D1 and MMP9, and increase the levels of GSK-3beta and E-cadherin.	('GSK-3beta', 'Gene', '2932', (172, 181))	('MMP9', 'molecular_function', 'GO:0004229', ('139', '143'))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('cyclin D1', 'Protein', (125, 134))	('Wnt2', 'Gene', (98, 102))	('active beta-catenin', 'Protein', (104, 123))	('E-cadherin', 'Gene', (186, 196))	('E-cadherin', 'Gene', '999', (186, 196))	('GSK-3beta', 'Gene', (172, 181))	('increase', 'PosReg', (149, 157))	('Med19', 'Gene', '219541', (40, 45))	('Wnt2', 'Gene', '7472', (98, 102))	('knockdown', 'Var', (27, 36))	('GSK', 'molecular_function', 'GO:0050321', ('172', '175'))	('MMP9', 'Gene', (139, 143))	('Med19', 'Gene', (40, 45))	('MMP9', 'Gene', '4318', (139, 143))	('cadherin', 'molecular_function', 'GO:0008014', ('188', '196'))	('expression', 'MPA', (84, 94))	('N', 'Chemical', 'MESH:D009584', (15, 16))	('levels', 'MPA', (162, 168))	('cyclin', 'molecular_function', 'GO:0016538', ('125', '131'))	('reduce', 'NegReg', (73, 79))
79151	31624709	CYD 6-17 with an IC50 at nM range, exhibits potent inhibitory effect on chemoresistant bladder cancer cells, thus offers rational therapeutic regimen to MIBC.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('MIBC', 'Disease', (153, 157))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('chemoresistant', 'CPA', (72, 86))	('inhibitory effect', 'NegReg', (51, 68))	('bladder cancer', 'Disease', 'MESH:D001749', (87, 101))	('bladder cancer', 'Disease', (87, 101))	('MIBC', 'Disease', 'MESH:D001749', (153, 157))	('CYD', 'Var', (0, 3))	('rat', 'Species', '10116', (121, 124))
79183	28427201	Aberrant activation of Wnt signaling pathways have been involved in a large variety of diseases.	('activation', 'PosReg', (9, 19))	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('Wnt', 'Gene', '7474', (23, 26))	('Wnt', 'Gene', (23, 26))	('Aberrant', 'Var', (0, 8))	('involved', 'Reg', (56, 64))
79196	28427201	Additionally, we found that CTHRC1 is highly expressed in the tumors with high Ror2 expression.	('CTHRC1', 'Gene', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('high', 'Var', (74, 78))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('Ror2', 'Gene', '4920', (79, 83))	('Ror2', 'Gene', (79, 83))	('CTHRC1', 'Gene', '115908', (28, 34))
79279	26975779	In risk groups based on 0-3 presence of adverse prognostic factors (PS >=1, haemoglobin <=10 g/dl and liver metastasis), median OS: 13.2, 9.9, 3.6, and 2.4 months (P < .0001), respectively; 3.3 months (1.9-5.6) in PS >= 2 subgroup.	('PS', 'Chemical', '-', (214, 216))	('haemoglobin', 'Var', (76, 87))	('liver metastasis', 'Disease', (102, 118))	('OS', 'Chemical', '-', (128, 130))	('PS', 'Chemical', '-', (68, 70))	('liver metastasis', 'Disease', 'MESH:D009362', (102, 118))
79409	26464434	Genome-wide CpG island methylation and intergenic demethylation propensities vary among different tumor sites The epigenetic landscape of cancer includes both focal hypermethylation and broader hypomethylation in a genome-wide manner.	('focal hypermethylation', 'Var', (159, 181))	('cancer', 'Disease', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('demethylation', 'biological_process', 'GO:0070988', ('50', '63'))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('tumor', 'Disease', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
79410	26464434	By means of a comprehensive genomic analysis on 6637 tissues of 21 tumor types, we here show that the degrees of overall methylation in CpG island (CGI) and demethylation in intergenic regions, defined as 'backbone', largely vary among different tumors.	('methylation', 'biological_process', 'GO:0032259', ('121', '132'))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('methylation', 'MPA', (121, 132))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('demethylation', 'Var', (157, 170))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('demethylation', 'biological_process', 'GO:0070988', ('157', '170'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (67, 72))	('vary', 'Reg', (225, 229))	('tumor', 'Disease', (246, 251))	('tumors', 'Disease', (246, 252))
79412	26464434	We found connections between CGI methylation and hypermutability, microsatellite instability, IDH1 mutation, 19p gain and polycomb features, and backbone demethylation with chromosomal instability, NSD1 and TP53 mutations, 5q and 19p loss and long repressive domains.	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('IDH1', 'Gene', (94, 98))	('microsatellite instability', 'MPA', (66, 92))	('TP53', 'Gene', '7157', (207, 211))	('NSD1', 'Gene', '64324', (198, 202))	('backbone', 'MPA', (145, 153))	('IDH1', 'Gene', '3417', (94, 98))	('demethylation', 'biological_process', 'GO:0070988', ('154', '167'))	('mutation', 'Var', (99, 107))	('TP53', 'Gene', (207, 211))	('gain', 'PosReg', (113, 117))	('mutations', 'Var', (212, 221))	('NSD1', 'Gene', (198, 202))	('chromosomal instability', 'Phenotype', 'HP:0040012', (173, 196))	('loss', 'NegReg', (234, 238))
79413	26464434	These broad epigenetic patterns add a new dimension to our understanding of tumor biology and its clinical implications.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('epigenetic patterns', 'Var', (12, 31))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
79414	26464434	Epigenetic alterations have pivotal roles in development and cancer biology.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
79415	26464434	A canonical observation in many cancers is the de novo methylation of CpG islands (CGIs) in the promoters of tumor-related genes, which is significantly associated with clinical behavior in many tumors.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Disease', (195, 200))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('cancers', 'Disease', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('associated', 'Reg', (153, 163))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('methylation', 'Var', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (109, 114))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
79422	26464434	TF-binding sites behaved differently according to TF contents; the binding sites of embryonic stem cell (ESC)-related TFs including polycomb proteins and CTBP2 were frequently de novo methylated while the binding sites of other differentiation-associated TFs were rather demethylated or unchanged.	('binding', 'molecular_function', 'GO:0005488', ('67', '74'))	('binding', 'molecular_function', 'GO:0005488', ('205', '212'))	('CTBP2', 'Gene', '1488', (154, 159))	('polycomb proteins', 'Protein', (132, 149))	('TF-binding', 'molecular_function', 'GO:0008134', ('0', '10'))	('methylated', 'Var', (184, 194))	('binding', 'Interaction', (67, 74))	('CTBP2', 'Gene', (154, 159))
79442	26464434	Likewise, we selected 49 277 CpGs in backbone, as defined above, and averaged their methylation levels for each tumor.	('CpGs', 'Var', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('methylation', 'biological_process', 'GO:0032259', ('84', '95'))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('methylation levels', 'MPA', (84, 102))
79447	26464434	Nonetheless, most tumors showed both CGI methylation and backbone demethylation with variable degrees (HC-LB; Figure 1F; Supplementary Figure S2).	('backbone demethylation', 'MPA', (57, 79))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('demethylation', 'biological_process', 'GO:0070988', ('66', '79'))	('methylation', 'Var', (41, 52))	('HC-LB; Figure 1F; Supplementary Figure S2', 'Disease', 'MESH:D017034', (103, 144))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('HC-LB; Figure 1F; Supplementary Figure S2', 'Disease', (103, 144))	('CGI', 'MPA', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
79449	26464434	And in most tumors, DNA methylation correlated with mRNA expression, miRNA expression, copy number and pathway clusters suggesting an underlying biological background.	('copy number', 'Var', (87, 98))	('DNA methylation', 'biological_process', 'GO:0006306', ('20', '35'))	('DNA', 'Gene', (20, 23))	('pathway clusters', 'Pathway', (103, 119))	('methylation', 'Var', (24, 35))	('correlated', 'Reg', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('miRNA expression', 'MPA', (69, 85))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))	('mRNA expression', 'MPA', (52, 67))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
79453	26464434	In THCA, histories of lymphocytic thyroiditis significantly correlated with high CGI methylation (P = 6.3 x 10-4).	('CGI', 'Protein', (81, 84))	('methylation', 'biological_process', 'GO:0032259', ('85', '96'))	('thyroiditis', 'Phenotype', 'HP:0100646', (34, 45))	('THCA', 'Phenotype', 'HP:0002890', (3, 7))	('lymphocytic thyroiditis', 'Disease', (22, 45))	('lymphocytic thyroiditis', 'Phenotype', 'HP:0000872', (22, 45))	('lymphocytic thyroiditis', 'Disease', 'MESH:D013967', (22, 45))	('high', 'Var', (76, 80))
79455	26464434	In COADREAD, CGI methylation was highest in cecum tumors and became modest when moving towards the rectum (P = 1.3 x 10-16; Supplementary Figure S25A).	('highest', 'Reg', (33, 40))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('S25A', 'SUBSTITUTION', 'None', (145, 149))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('S25A', 'Var', (145, 149))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
79456	26464434	In HNSC, CGI methylation was highest in the oral cavity and lower in the caudal direction in the oropharangeal tract (P = 8.9 x 10-5; Supplementary Figure S25B).	('methylation', 'MPA', (13, 24))	('S25B', 'SUBSTITUTION', 'None', (155, 159))	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('highest', 'Reg', (29, 36))	('S25B', 'Var', (155, 159))	('CGI', 'MPA', (9, 12))	('HNSC', 'Phenotype', 'HP:0012288', (3, 7))	('lower', 'NegReg', (60, 65))
79460	26464434	Type 2 KIRP, an eosinophilic tumor with worse prognosis, was associated with both CGI methylation and backbone demethylation (P = 4.4 x 10-5 and 1.9 x 10-3, respectively).	('backbone demethylation', 'MPA', (102, 124))	('Type 2 KIRP', 'Disease', (0, 11))	('eosinophilic tumor', 'Disease', (16, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('methylation', 'biological_process', 'GO:0032259', ('86', '97'))	('methylation', 'Var', (86, 97))	('demethylation', 'biological_process', 'GO:0070988', ('111', '124'))	('eosinophilic tumor', 'Disease', 'MESH:D004802', (16, 34))	('CGI', 'MPA', (82, 85))
79462	26464434	In PRAD, Gleason scores tended to be high both in CGI-methylated and backbone-demethylated tumors (P = 6.1 x 10-3 and 3.9 x 10-4, respectively).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('CGI-methylated', 'Var', (50, 64))	('high', 'PosReg', (37, 41))	('PRAD', 'Disease', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Gleason', 'MPA', (9, 16))	('backbone-demethylated', 'Var', (69, 90))
79463	26464434	An association of CGI methylation with high mitosis was observed in ACC (P = 4.5 x 10-4).	('association', 'Interaction', (3, 14))	('high mitosis', 'Disease', (39, 51))	('ACC', 'Phenotype', 'HP:0006744', (68, 71))	('methylation', 'biological_process', 'GO:0032259', ('22', '33'))	('high mitosis', 'Disease', 'MESH:D008228', (39, 51))	('ACC', 'Disease', (68, 71))	('mitosis', 'biological_process', 'GO:0000278', ('44', '51'))	('CGI', 'Protein', (18, 21))	('methylation', 'Var', (22, 33))
79466	26464434	MSI-H tumors were very significantly associated with CGI methylation in COADREAD, STAD and UCEC (P = 3.2 x 10-12, 2.4 x 10-7 and 2.0 x 10-22, respectively) (Figure 2B).	('methylation', 'Var', (57, 68))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('CGI', 'Protein', (53, 56))	('associated', 'Reg', (37, 47))	('MSI-H tumors', 'Disease', 'MESH:D009369', (0, 12))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('MSI-H tumors', 'Disease', (0, 12))
79467	26464434	In COADREAD, CGI methylation was associated with negative expression of MSH6 and PMS2 proteins (P = 9.3 x 10-3).	('MSH6', 'Gene', (72, 76))	('expression', 'MPA', (58, 68))	('proteins', 'Protein', (86, 94))	('PMS2', 'Gene', '5395', (81, 85))	('methylation', 'Var', (17, 28))	('negative', 'NegReg', (49, 57))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('MSH6', 'Gene', '2956', (72, 76))	('PMS2', 'Gene', (81, 85))
79468	26464434	In BRCA, CGI methylation was significantly associated with positive expression of estrogen and HER2/neu receptors (P = 1.5 x 10-5 and 8.3 x 10-8, respectively) and thus with luminal B subtype (P = 1.3 x 10-9).	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('BRCA', 'Gene', (3, 7))	('expression', 'MPA', (68, 78))	('CGI methylation', 'Var', (9, 24))	('methylation', 'Var', (13, 24))	('BRCA', 'Gene', '672', (3, 7))	('positive', 'PosReg', (59, 67))	('estrogen', 'Protein', (82, 90))	('HER2/neu receptors', 'Protein', (95, 113))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))
79469	26464434	The number of gene mutations correlated positively with CGI methylation in THCA, KIRC, LAML, LGG, GBM, PRAD, STAD, BRCA, ACC and UCEC (Figure 2A and B).	('ACC', 'Phenotype', 'HP:0006744', (121, 124))	('CGI methylation', 'MPA', (56, 71))	('THCA', 'Phenotype', 'HP:0002890', (75, 79))	('BRCA', 'Phenotype', 'HP:0003002', (115, 119))	('BRCA', 'Gene', '672', (115, 119))	('mutations', 'Var', (19, 28))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('BRCA', 'Gene', (115, 119))
79470	26464434	In line with the previous knowledge, IDH1 mutation was associated with high CGI methylation in LGG (P = 2.1 x 10-20), GBM, PRAD and CESC, and IDH2 was so in LAML.	('IDH2', 'Gene', '3418', (142, 146))	('IDH1', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', '3417', (37, 41))	('methylation', 'biological_process', 'GO:0032259', ('80', '91'))	('CGI methylation', 'MPA', (76, 91))	('IDH2', 'Gene', (142, 146))
79471	26464434	Mutations in CIC, NOTCH1 and FUBP1 were very significantly associated with high CGI methylation in LGG (P = 5.7 x 10-11, 5.2 x 10-7 and 9.9 x 10-5, respectively), mutation in PIK3CA was so in STAD (P = 7.4 x 10-9), and mutations in PTEN and PIK3R1 were so in UCEC (P = 5.9 x 10-7 and 1.6 x 10-4, respectively).	('NOTCH1', 'Gene', (18, 24))	('PIK3CA', 'Gene', (175, 181))	('UCEC', 'Disease', (259, 263))	('PIK3R1', 'Gene', '5295', (241, 247))	('PIK3R1', 'Gene', (241, 247))	('PIK3CA', 'Gene', '5290', (175, 181))	('methylation', 'biological_process', 'GO:0032259', ('84', '95'))	('associated', 'Reg', (59, 69))	('high CGI methylation', 'MPA', (75, 95))	('Mutations', 'Var', (0, 9))	('FUBP1', 'Gene', '8880', (29, 34))	('PTEN', 'Gene', '5728', (232, 236))	('PTEN', 'Gene', (232, 236))	('mutations', 'Var', (219, 228))	('CIC', 'Gene', (13, 16))	('mutation', 'Var', (163, 171))	('FUBP1', 'Gene', (29, 34))	('NOTCH1', 'Gene', '4851', (18, 24))
79472	26464434	NRAS mutation was frequent in THCA with higher CGI methylation and BRAF was so in THCA with lower backbone methylation (P = 5.9 x 10-3 and 9.9 x 10-7, respectively) but this may be confounded by the difference in methylation according to histological type, as described above, and high frequency of NRAS mutation in follicular and BRAF mutation in papillary types.	('THCA', 'Phenotype', 'HP:0002890', (82, 86))	('BRAF', 'Gene', (331, 335))	('BRAF', 'Gene', '673', (67, 71))	('NRAS', 'Gene', '4893', (299, 303))	('higher', 'PosReg', (40, 46))	('BRAF', 'Gene', '673', (331, 335))	('backbone methylation', 'MPA', (98, 118))	('methylation', 'biological_process', 'GO:0032259', ('213', '224'))	('THCA', 'Phenotype', 'HP:0002890', (30, 34))	('BRAF', 'Gene', (67, 71))	('methylation', 'biological_process', 'GO:0032259', ('107', '118'))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('CGI methylation', 'MPA', (47, 62))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))	('mutation', 'Var', (5, 13))	('NRAS', 'Gene', (299, 303))
79473	26464434	TP53 mutation was associated with backbone demethylation in STAD and PRAD (P = 5.1 x 10-5 and 4.9 x 10-3, respectively) (Figure 2C), and NSD1 mutation was so in HNSC (P = 3.2 x 10-9) (Supplementary Figure S17B).	('TP53', 'Gene', '7157', (0, 4))	('NSD1', 'Gene', (137, 141))	('backbone demethylation', 'MPA', (34, 56))	('TP53', 'Gene', (0, 4))	('S17B', 'Var', (205, 209))	('S17B', 'SUBSTITUTION', 'None', (205, 209))	('NSD1', 'Gene', '64324', (137, 141))	('HNSC', 'Phenotype', 'HP:0012288', (161, 165))	('demethylation', 'biological_process', 'GO:0070988', ('43', '56'))	('mutation', 'Var', (5, 13))
79478	26464434	The most remarkable P value peak was in chromosome 5q showing recurrent correlations between deletion and backbone demethylation in many tumors (Figure 3A and B).	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('backbone demethylation', 'MPA', (106, 128))	('tumors', 'Disease', (137, 143))	('correlations', 'Reg', (72, 84))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('demethylation', 'biological_process', 'GO:0070988', ('115', '128'))	('chromosome', 'cellular_component', 'GO:0005694', ('40', '50'))	('deletion', 'Var', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
79479	26464434	Candidate genes in this region include CHD1, LMNB1, KDM3B, HDAC3 and NSD1, and among them, NSD1 was of particular interest in that mutation in this gene also showed the most significant association with backbone demethylation in HNSC and other tumors (Figure 3C).	('NSD1', 'Gene', (69, 73))	('backbone demethylation', 'MPA', (203, 225))	('mutation', 'Var', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('HDAC3', 'Gene', (59, 64))	('CHD1', 'Gene', '1105', (39, 43))	('LMNB1', 'Gene', '4001', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('NSD1', 'Gene', '64324', (69, 73))	('NSD1', 'Gene', (91, 95))	('CHD1', 'Gene', (39, 43))	('HNSC', 'Disease', (229, 233))	('tumors', 'Disease', (244, 250))	('KDM3B', 'Gene', '51780', (52, 57))	('LMNB1', 'Gene', (45, 50))	('HDAC3', 'Gene', '8841', (59, 64))	('HNSC', 'Phenotype', 'HP:0012288', (229, 233))	('association', 'Reg', (186, 197))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('NSD1', 'Gene', '64324', (91, 95))	('demethylation', 'biological_process', 'GO:0070988', ('212', '225'))	('KDM3B', 'Gene', (52, 57))
79480	26464434	Bi-allelic aberration of NSD1 either by mutation or copy loss showed more demethylation (Figure 3D).	('mutation', 'Var', (40, 48))	('NSD1', 'Gene', (25, 29))	('demethylation', 'MPA', (74, 87))	('copy loss', 'Var', (52, 61))	('demethylation', 'biological_process', 'GO:0070988', ('74', '87'))	('NSD1', 'Gene', '64324', (25, 29))
79483	26464434	Among the pathways recurrently associated in several tumors, the bone morphogenic protein (BMP) receptor pathway was significantly suppressed among backbone-demethylated tumors in LGG, PRAD and LIHC and CGI-methylated tumors in LUAD.	('backbone-demethylated', 'Var', (148, 169))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('BMP', 'Gene', '649', (91, 94))	('LIHC', 'Disease', (194, 198))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('CGI-methylated', 'Var', (203, 217))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('LIHC', 'Disease', 'None', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PRAD', 'Disease', (185, 189))	('BMP', 'Gene', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('LGG', 'Disease', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('suppressed', 'NegReg', (131, 141))	('LUAD', 'Phenotype', 'HP:0030078', (228, 232))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
79490	26464434	In all tumor types, differentially methylated CpGs were highly enriched in binding sites of polycomb-related SUZ12, EZH2 and CTBP2, and the enrichment rate strongly correlated with the degree of CGI methylation (Supplementary Figure S30).	('EZH2', 'Gene', (116, 120))	('EZH2', 'Gene', '2146', (116, 120))	('tumor', 'Disease', (7, 12))	('differentially', 'Var', (20, 34))	('correlated', 'Reg', (165, 175))	('binding', 'molecular_function', 'GO:0005488', ('75', '82'))	('CTBP2', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('methylation', 'biological_process', 'GO:0032259', ('199', '210'))	('CGI methylation', 'MPA', (195, 210))	('CTBP2', 'Gene', '1488', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('binding sites', 'Interaction', (75, 88))	('SUZ12', 'Gene', '23512', (109, 114))	('SUZ12', 'Gene', (109, 114))
79491	26464434	Demethylated CpGs were often enriched in IKZF1, BATF and ZNF217 binding sites but the enrichment rate usually did not correlate with the degree of backbone demethylation, suggesting a minor role of transcription factors in the genome-wide demethylation (Supplementary Figure S31).	('BATF', 'Gene', (48, 52))	('binding', 'molecular_function', 'GO:0005488', ('64', '71'))	('BATF', 'Gene', '10538', (48, 52))	('demethylation', 'biological_process', 'GO:0070988', ('239', '252'))	('IKZF1', 'Gene', '10320', (41, 46))	('demethylation', 'biological_process', 'GO:0070988', ('156', '169'))	('ZNF217', 'Gene', (57, 63))	('transcription', 'biological_process', 'GO:0006351', ('198', '211'))	('ZNF217', 'Gene', '7764', (57, 63))	('IKZF1', 'Gene', (41, 46))	('Demethylated', 'Var', (0, 12))
79495	26464434	Intriguingly, CGI-methylated tumors showed better primary responses in STAD and LUAD (P = 7.5 x 10-3 and 1.8 x 10-2, respectively).	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('LUAD', 'Disease', (80, 84))	('primary responses', 'CPA', (50, 67))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('better', 'PosReg', (43, 49))	('STAD', 'Disease', (71, 75))	('CGI-methylated', 'Var', (14, 28))
79502	26464434	As supporting evidence, we could observe correlation of HC-tumors with many CIMP-associated features such as MSI-H and IDH1 mutation.	('HC-tumors', 'Disease', (56, 65))	('CIMP', 'Chemical', '-', (76, 80))	('MSI-H', 'Disease', (109, 114))	('correlation', 'Interaction', (41, 52))	('IDH1', 'Gene', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('MSI-H', 'Disease', 'MESH:D000848', (109, 114))	('mutation', 'Var', (124, 132))	('HC-tumors', 'Disease', 'MESH:D009369', (56, 65))	('IDH1', 'Gene', '3417', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
79507	26464434	Polycomb site methylation has now been accepted as a hallmark of cancers, and so the enrichment of polycomb proteins, SUZ12 and EZH2, should be an innate quality.	('hallmark of cancers', 'Disease', (53, 72))	('hallmark of cancers', 'Disease', 'MESH:D009369', (53, 72))	('Polycomb', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('EZH2', 'Gene', (128, 132))	('SUZ12', 'Gene', '23512', (118, 123))	('EZH2', 'Gene', '2146', (128, 132))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('SUZ12', 'Gene', (118, 123))
79509	26464434	Global demethylation in repetitive elements has been suggested in many cancers and yet a systematical analysis is lacking.	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Disease', (71, 78))	('demethylation', 'biological_process', 'GO:0070988', ('7', '20'))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Global demethylation', 'Var', (0, 20))
79510	26464434	Associations of demethylation with histological grade and stage have been suggested in several tumors, and we could find such an association in an expanded set of tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('Associations', 'Interaction', (0, 12))	('demethylation', 'Var', (16, 29))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('demethylation', 'biological_process', 'GO:0070988', ('16', '29'))
79512	26464434	Although it has been experimentally shown that demethylation is linked to mitotic dysfunction and genomic rearrangement and anticipated to cause chromosome instability, it remained uninvestigated in clinical series.	('demethylation', 'biological_process', 'GO:0070988', ('47', '60'))	('mitotic dysfunction', 'Disease', (74, 93))	('chromosome instability', 'MPA', (145, 167))	('demethylation', 'Var', (47, 60))	('mitotic dysfunction', 'Disease', 'MESH:C536987', (74, 93))	('linked', 'Reg', (64, 70))	('chromosome instability', 'Phenotype', 'HP:0040012', (145, 167))	('genomic rearrangement', 'CPA', (98, 119))	('cause', 'Reg', (139, 144))	('chromosome', 'cellular_component', 'GO:0005694', ('145', '155'))
79516	26464434	NSD1 is a SET domain histone methyltransferase that primarily dimethylates histone H3K36, implicated in Sotos and Weaver overgrowth syndromes.	('NSD1', 'Gene', (0, 4))	('dimethylates', 'Var', (62, 74))	('overgrowth', 'Phenotype', 'HP:0001548', (121, 131))	('Weaver overgrowth syndromes', 'Disease', 'MESH:C536687', (114, 141))	('histone H3K36', 'Protein', (75, 88))	('Weaver overgrowth syndromes', 'Disease', (114, 141))	('NSD1', 'Gene', '64324', (0, 4))
79521	26464434	TP53 was also among the most significant genes, and this can be understood on the basis that TP53 mutations can directly cause DNA demethylation.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('DNA demethylation', 'biological_process', 'GO:0080111', ('127', '144'))	('mutations', 'Var', (98, 107))	('cause', 'Reg', (121, 126))	('DNA demethylation', 'MPA', (127, 144))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))
79522	26464434	Moreover, TP53 plays critical roles DNA repair and maintaining genomic stability and its mutation may exhibit communal pathways with DNA demethylation leading to chromosome instability.	('chromosome instability', 'MPA', (162, 184))	('TP53', 'Gene', (10, 14))	('mutation', 'Var', (89, 97))	('DNA repair', 'biological_process', 'GO:0006281', ('36', '46'))	('DNA demethylation', 'biological_process', 'GO:0080111', ('133', '150'))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('TP53', 'Gene', '7157', (10, 14))	('genomic', 'MPA', (63, 70))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('chromosome instability', 'Phenotype', 'HP:0040012', (162, 184))	('chromosome', 'cellular_component', 'GO:0005694', ('162', '172'))	('leading to', 'Reg', (151, 161))	('exhibit', 'Reg', (102, 109))
79523	26464434	It is often hypothesized that demethylation in cancer cells can activate proto-oncogenes and thus contribute to tumorigenesis.	('demethylation', 'biological_process', 'GO:0070988', ('30', '43'))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('proto-oncogenes', 'Gene', (73, 88))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('contribute to', 'Reg', (98, 111))	('cancer', 'Disease', (47, 53))	('demethylation', 'Var', (30, 43))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (112, 117))	('activate', 'PosReg', (64, 72))
79524	26464434	As more supporting evidence, we found that many pathways such as BMP receptor, LPA receptor, Ephrin B, PLK1, Aurora A and B, FoxM1, neurotrophic factor and p75NTR pathways tended to be suppressed rather than activated in demethylated tumors.	('Ephrin B', 'Gene', (93, 101))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('LPA', 'Protein', (79, 82))	('neurotrophic factor', 'Gene', '4908', (132, 151))	('Ephrin', 'molecular_function', 'GO:0046875', ('93', '99'))	('demethylated', 'Var', (221, 233))	('BMP', 'Gene', '649', (65, 68))	('Aurora A and B', 'Gene', '6790;9212', (109, 123))	('PLK1', 'Gene', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('activated', 'PosReg', (208, 217))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('neurotrophic factor', 'Gene', (132, 151))	('p75NTR', 'Gene', (156, 162))	('FoxM1', 'Gene', '2305', (125, 130))	('LPA', 'Chemical', 'MESH:C032881', (79, 82))	('BMP', 'Gene', (65, 68))	('PLK1', 'Gene', '5347', (103, 107))	('suppressed', 'NegReg', (185, 195))	('Ephrin', 'molecular_function', 'GO:0005106', ('93', '99'))	('tumors', 'Disease', (234, 240))	('p75NTR', 'Gene', '4804', (156, 162))	('FoxM1', 'Gene', (125, 130))
79526	26464434	We observed that low BMP, especially BMP-7, activity is associated with backbone demethylation and such demethylated tumors show aggressive features like high Gleason score and prostate specific antigen level (Supplementary Figure S10B).	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('S10B', 'Var', (231, 235))	('BMP', 'Gene', '649', (37, 40))	('associated', 'Reg', (56, 66))	('prostate specific antigen', 'Gene', (177, 202))	('demethylated', 'Var', (104, 116))	('demethylation', 'biological_process', 'GO:0070988', ('81', '94'))	('prostate specific antigen', 'Gene', '354', (177, 202))	('BMP', 'Gene', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BMP-7', 'Gene', '655', (37, 42))	('tumors', 'Disease', (117, 123))	('low', 'Var', (17, 20))	('BMP', 'Gene', (37, 40))	('BMP-7', 'Gene', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('activity', 'MPA', (44, 52))	('backbone demethylation', 'MPA', (72, 94))	('S10B', 'SUBSTITUTION', 'None', (231, 235))	('BMP', 'Gene', '649', (21, 24))
79528	26464434	We also noticed that the demethylated tumors also tended to have worse outcome although the significance varied according to the cutoffs for average backbone methylation (data not shown).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('methylation', 'biological_process', 'GO:0032259', ('158', '169'))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('demethylated', 'Var', (25, 37))	('tumors', 'Disease', 'MESH:D009369', (38, 44))
79530	26464434	We observed low BMP activity in demethylated LGGs which showed higher histological grade and worse treatment response and survival (Supplementary Figure S9B).	('histological', 'CPA', (70, 82))	('BMP', 'Gene', '649', (16, 19))	('survival', 'CPA', (122, 130))	('treatment response', 'CPA', (99, 117))	('BMP', 'Gene', (16, 19))	('demethylated', 'Var', (32, 44))	('higher', 'PosReg', (63, 69))	('low', 'NegReg', (12, 15))
79537	26464434	We observed that Ephrin pathways are epigenetically suppressed in a set of tumors preferentially by backbone demethylation.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('Ephrin', 'molecular_function', 'GO:0005106', ('17', '23'))	('Ephrin', 'molecular_function', 'GO:0046875', ('17', '23'))	('demethylation', 'biological_process', 'GO:0070988', ('109', '122'))	('suppressed', 'NegReg', (52, 62))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Ephrin pathways', 'Pathway', (17, 32))	('tumors', 'Disease', (75, 81))	('backbone demethylation', 'Var', (100, 122))
79539	26464434	We found that PLK1 and Aurora pathways are often suppressed and sometimes activated in backbone-demethylated or CGI-methylated tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('CGI-methylated', 'Var', (112, 126))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('activated', 'PosReg', (74, 83))	('Aurora pathways', 'Pathway', (23, 38))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('suppressed', 'NegReg', (49, 59))	('backbone-demethylated', 'Var', (87, 108))	('PLK1', 'Gene', (14, 18))	('PLK1', 'Gene', '5347', (14, 18))
79541	26464434	Either loss or gain of FoxM function can alter cell fate and promote tumorigenesis, and we observed epigenetic suppression of FoxM1 pathway in a set of tumors.	('cell fate', 'CPA', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('loss', 'NegReg', (7, 11))	('FoxM', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', (69, 74))	('FoxM1', 'Gene', '2305', (126, 131))	('promote', 'PosReg', (61, 68))	('FoxM1', 'Gene', (126, 131))	('tumor', 'Disease', (152, 157))	('alter', 'Reg', (41, 46))	('gain', 'PosReg', (15, 19))	('epigenetic suppression', 'Var', (100, 122))	('tumors', 'Disease', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
79551	26464434	The slightly-high tumors showed poor survival compared to slightly-low tumors.	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('slightly-high', 'Var', (4, 17))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
79556	26464434	Collectively, we present a pan-cancer model connecting CGI methylation with hypermutability, MSI-H, IDH1 mutation, 19p gain and polycomb proteins and backbone demethylation with chromosomal instability, NSD1 and TP53 mutations, 5q and 19p loss and long repressive domains (Figure 5).	('MSI-H', 'Disease', 'MESH:D000848', (93, 98))	('mutation', 'Var', (105, 113))	('NSD1', 'Gene', '64324', (203, 207))	('IDH1', 'Gene', '3417', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('chromosomal instability', 'Phenotype', 'HP:0040012', (178, 201))	('NSD1', 'Gene', (203, 207))	('MSI-H', 'Disease', (93, 98))	('loss', 'NegReg', (239, 243))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('demethylation', 'biological_process', 'GO:0070988', ('159', '172'))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('IDH1', 'Gene', (100, 104))	('cancer', 'Disease', (31, 37))	('mutations', 'Var', (217, 226))	('TP53', 'Gene', '7157', (212, 216))	('gain', 'PosReg', (119, 123))	('TP53', 'Gene', (212, 216))
79558	26464434	Since many pathways are suppressed in methylated and demethylated tumors, thoughtful usage of new targeted drugs inhibiting such pathways is warranted.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('methylated', 'Var', (38, 48))	('tumors', 'Disease', (66, 72))	('suppressed', 'NegReg', (24, 34))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('pathways', 'Pathway', (11, 19))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('demethylated', 'Var', (53, 65))
79685	33977078	Papillary Renal Cell Carcinoma in Lynch/Muir-Torre Syndrome with Germline Pathogenic Variant in MSH6 and Molecular Analysis: Report of a Case and Review of the Literature Lynch syndrome (LS) is an autosomal dominant inherited disorder due to pathogenic variations in the mismatch repair genes, which predisposes to malignancies, most commonly colon and endometrial carcinoma.	('Lynch syndrome', 'Disease', (171, 185))	('Variant', 'Var', (85, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (365, 374))	('endometrial carcinoma', 'Disease', (353, 374))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (10, 30))	('Carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('Papillary Renal Cell Carcinoma', 'Disease', (0, 30))	('Lynch syndrome', 'Disease', 'MESH:D003123', (171, 185))	('autosomal dominant inherited disorder', 'Disease', 'MESH:D030342', (197, 234))	('colon', 'Disease', (343, 348))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (353, 374))	('Papillary Renal Cell Carcinoma', 'Phenotype', 'HP:0006766', (0, 30))	('autosomal dominant inherited disorder', 'Disease', (197, 234))	('MSH6', 'Gene', (96, 100))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (353, 374))	('variations', 'Var', (253, 263))	('malignancies', 'Disease', 'MESH:D009369', (315, 327))	('mismatch repair', 'biological_process', 'GO:0006298', ('271', '286'))	('mismatch repair genes', 'Gene', (271, 292))	('malignancies', 'Disease', (315, 327))	('MSH6', 'Gene', '2956', (96, 100))	('Papillary Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (0, 30))
79690	33977078	The LS was diagnosed when he presented with multiple sebaceous adenomas and genetic testing showed a pathogenic variant in MSH6 mismatch repair gene.	('MSH6', 'Gene', '2956', (123, 127))	('pathogenic', 'Reg', (101, 111))	('sebaceous adenoma', 'Phenotype', 'HP:0009720', (53, 70))	('sebaceous adenomas', 'Phenotype', 'HP:0009720', (53, 71))	('variant', 'Var', (112, 119))	('MSH6', 'Gene', (123, 127))	('adenomas', 'Disease', 'MESH:D000236', (63, 71))	('mismatch repair', 'biological_process', 'GO:0006298', ('128', '143'))	('adenomas', 'Disease', (63, 71))
79698	33977078	These tumors showed MLH1 mutation most commonly, unlike the urothelial malignancies in LS which involve MSH2.	('urothelial malignancies', 'Disease', (60, 83))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('mutation', 'Var', (25, 33))	('tumors', 'Disease', (6, 12))	('MSH2', 'Gene', (104, 108))	('MLH1', 'Gene', (20, 24))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('MSH2', 'Gene', '4436', (104, 108))	('urothelial malignancies', 'Disease', 'MESH:D009369', (60, 83))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
79699	33977078	Among the 4 cases of RCC with MSH6 mutation, three were in females, indicating some gender differences.	('MSH6', 'Gene', '2956', (30, 34))	('mutation', 'Var', (35, 43))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('RCC', 'Disease', (21, 24))	('MSH6', 'Gene', (30, 34))
79701	33977078	It is associated with germline pathogenic variants in the DNA mismatch repair (MMR) genes including MLH1 (mutL homolog 1), MSH2/MSH6 (mutS homolog 2 or 6), and PMS2 (PMS1 homologue 2).	('MSH2', 'Gene', (123, 127))	('PMS1 homologue 2', 'Gene', (166, 182))	('DNA', 'Gene', (58, 61))	('MSH2', 'Gene', '4436', (123, 127))	('associated', 'Reg', (6, 16))	('MSH6', 'Gene', (128, 132))	('variants', 'Var', (42, 50))	('mismatch repair', 'biological_process', 'GO:0006298', ('62', '77'))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('mutL homolog 1', 'Gene', '4292', (106, 120))	('MMR', 'biological_process', 'GO:0006298', ('79', '82'))	('MSH6', 'Gene', '2956', (128, 132))	('PMS2', 'Gene', (160, 164))	('mutL homolog 1', 'Gene', (106, 120))	('PMS2', 'Gene', '5395', (160, 164))	('MLH1', 'Gene', (100, 104))	('PMS1 homologue 2', 'Gene', '5395;5378', (166, 182))	('MMR', 'Gene', (79, 82))
79702	33977078	Rarely, it can also be caused by a deletion in the EPCAM (epithelial cell adhesion molecule) gene, which leads to epigenetic silencing of MSH2.	('epigenetic silencing', 'MPA', (114, 134))	('cell adhesion', 'biological_process', 'GO:0007155', ('69', '82'))	('EPCAM', 'Gene', '4072', (51, 56))	('epithelial cell adhesion molecule', 'Gene', (58, 91))	('caused by', 'Reg', (23, 32))	('epithelial cell adhesion molecule', 'Gene', '4072', (58, 91))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('69', '91'))	('MSH2', 'Gene', (138, 142))	('MSH2', 'Gene', '4436', (138, 142))	('EPCAM', 'Gene', (51, 56))	('deletion', 'Var', (35, 43))
79705	33977078	The routine screening for genetic colorectal adenocarcinoma by immunohistochemistry (IHC) and/or Microsatellite instability (MSI) testing has led to better detection and an increased understanding of LS.	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('Microsatellite', 'Var', (97, 111))	('colorectal adenocarcinoma', 'Disease', (34, 59))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (34, 59))
79707	33977078	Most commonly, the germline defect involves pathogenic variants in MLH1 or MSH2 genes.	('MLH1', 'Gene', (67, 71))	('variants', 'Var', (55, 63))	('MSH2', 'Gene', (75, 79))	('MSH2', 'Gene', '4436', (75, 79))	('pathogenic', 'Reg', (44, 54))	('germline defect', 'Disease', (19, 34))
79709	33977078	Although LS and MTS share a defect in one of the 4 MMR genes, a few studies have shown that the frequency of the MMR defect in patients with MTS mostly involves MSH2.	('defect', 'Var', (117, 123))	('MSH2', 'Gene', (161, 165))	('MSH2', 'Gene', '4436', (161, 165))	('patients', 'Species', '9606', (127, 135))	('MMR', 'biological_process', 'GO:0006298', ('113', '116'))	('MMR', 'biological_process', 'GO:0006298', ('51', '54'))
79711	33977078	Recent studies have shown increased frequency of pathogenic variants in MSH2 in urological malignancies.	('malignancies', 'Disease', (91, 103))	('MSH2', 'Gene', (72, 76))	('MSH2', 'Gene', '4436', (72, 76))	('malignancies', 'Disease', 'MESH:D009369', (91, 103))	('variants', 'Var', (60, 68))
79714	33977078	Here, we encountered a case of papillary RCC (PRCC) in a LS/MTS patient with germline MSH6 pathogenic variant.	('patient', 'Species', '9606', (64, 71))	('MSH6', 'Gene', (86, 90))	('papillary RCC', 'Disease', 'MESH:C538614', (31, 44))	('PRCC', 'Gene', '5546', (46, 50))	('papillary RCC', 'Disease', (31, 44))	('variant', 'Var', (102, 109))	('MSH6', 'Gene', '2956', (86, 90))	('PRCC', 'Gene', (46, 50))
79719	33977078	Genetic testing showed a pathogenic variant in MSH6 Exon 9 (c.3980_3983, dupATCA (p.L1330Vfs'12)).	('p.L1330V', 'SUBSTITUTION', 'None', (82, 90))	('dupATCA', 'Disease', (73, 80))	('p.L1330V', 'Var', (82, 90))	('MSH6', 'Gene', '2956', (47, 51))	('c.3980_3983', 'Var', (60, 71))	('MSH6', 'Gene', (47, 51))	('c.3980_3983, dupATCA', 'Mutation', 'rs267608121', (60, 80))	('pathogenic', 'Reg', (25, 35))
79720	33977078	In addition a heterozygous novel variant of uncertain significance (c.8419A>G(p.T2807A) in the APC gene was also detected.	('c.8419A>G', 'Mutation', 'rs147287751', (68, 77))	('APC', 'Disease', (95, 98))	('APC', 'cellular_component', 'GO:0005680', ('95', '98'))	('p.T2807A', 'Mutation', 'rs894164638', (78, 86))	('c.8419A>G', 'Var', (68, 77))	('APC', 'Disease', 'MESH:D011125', (95, 98))
79721	33977078	Since he did not have the typical presentation of polyposis and lack of certainty regarding pathogenicity of the APC variant as well as presence of pathogenic variant in the MSH6 gene, a diagnosis of LS was made.	('APC', 'Disease', 'MESH:D011125', (113, 116))	('APC', 'cellular_component', 'GO:0005680', ('113', '116'))	('MSH6', 'Gene', '2956', (174, 178))	('APC', 'Disease', (113, 116))	('variant', 'Var', (117, 124))	('variant', 'Var', (159, 166))	('MSH6', 'Gene', (174, 178))
79723	33977078	The subsequent subtotal colectomy showed a T3N0 mucin-producing adenocarcinoma in the cecum.	('adenocarcinoma', 'Disease', (64, 78))	('T3N0', 'Var', (43, 47))	('mucin', 'Gene', (48, 53))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('mucin', 'Gene', '100508689', (48, 53))
79747	33977078	The genomic abnormalities included ARID1A S90fs*11, MSH6 L1330fs*12, SETD2 N1725fs*3, and STAG2 E143fs*3.	('S90fs', 'Mutation', 'p.S90fsX', (42, 47))	('S90fs*11', 'Var', (42, 50))	('E143fs', 'Mutation', 'p.E143fsX', (96, 102))	('MSH6', 'Gene', (52, 56))	('STAG2', 'Gene', (90, 95))	('STAG2', 'Gene', '10735', (90, 95))	('SETD2', 'Gene', '29072', (69, 74))	('MSH6', 'Gene', '2956', (52, 56))	('ARID1A', 'Gene', '8289', (35, 41))	('ARID1A', 'Gene', (35, 41))	('SETD2', 'Gene', (69, 74))	('N1725fs*3', 'Var', (75, 84))	('L1330fs*12', 'Var', (57, 67))	('E143fs*3', 'Var', (96, 104))
79748	33977078	In addition, variants of unknown significance (VUS) were detected in the tumor.	('variants', 'Var', (13, 21))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))
79751	33977078	There has been an increasing understanding of LS attributed to pathogenic variants in one of the four mismatch repair (MMR) genes, namely, MLH1, MSH2, MSH6, and PMS2.	('PMS2', 'Gene', (161, 165))	('MLH1', 'Gene', (139, 143))	('MSH6', 'Gene', '2956', (151, 155))	('PMS2', 'Gene', '5395', (161, 165))	('MMR', 'Gene', (119, 122))	('mismatch repair', 'biological_process', 'GO:0006298', ('102', '117'))	('variants', 'Var', (74, 82))	('MMR', 'biological_process', 'GO:0006298', ('119', '122'))	('MSH2', 'Gene', (145, 149))	('MSH6', 'Gene', (151, 155))	('MSH2', 'Gene', '4436', (145, 149))
79753	33977078	These include three dinucleotide repeats (D2S123, D5S346, and D17S250) and two mononucleotide repeats (BAT25, BAT26).	('dinucleotide', 'Chemical', 'MESH:D015226', (20, 32))	('D5S346', 'Var', (50, 56))	('mononucleotide', 'Chemical', '-', (79, 93))	('D17S250', 'Var', (62, 69))	('D2S123', 'Var', (42, 48))
79768	33977078	Unlike the upper tract urothelial carcinoma, which are more commonly associated with MSH2 variants, RCC was associated with MLH1 variants, which was seen in 16 cases (57.1%).	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('MSH2', 'Gene', (85, 89))	('MSH2', 'Gene', '4436', (85, 89))	('urothelial carcinoma', 'Disease', (23, 43))	('associated', 'Reg', (69, 79))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('variants', 'Var', (90, 98))	('associated', 'Reg', (108, 118))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (23, 43))	('MLH1', 'Gene', (124, 128))	('RCC', 'Disease', (100, 103))	('variants', 'Var', (129, 137))
79769	33977078	Variants in MSH2 were seen in 7 cases (25%) and in MSH6 in 4 cases (14.8%).	('MSH2', 'Gene', '4436', (12, 16))	('Variants', 'Var', (0, 8))	('MSH6', 'Gene', '2956', (51, 55))	('seen', 'Reg', (22, 26))	('MSH2', 'Gene', (12, 16))	('MSH6', 'Gene', (51, 55))
79770	33977078	Interestingly, three out of four patients with the MSH6 variants were females.	('variants', 'Var', (56, 64))	('patients', 'Species', '9606', (33, 41))	('MSH6', 'Gene', (51, 55))	('MSH6', 'Gene', '2956', (51, 55))
79773	33977078	Abnormalities in the MSH6 gene were first discovered in studies involving hereditary nonpolyposis colorectal cancers, from 5 Japanese families who did not fulfill the Amsterdam criteria and had no pathogenic variants in MLH1 and MSH2 but had a family history of endometrial and ovarian cancers.	('MSH2', 'Gene', '4436', (229, 233))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancers', 'Phenotype', 'HP:0100615', (278, 293))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('MSH6', 'Gene', '2956', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('MLH1', 'Gene', (220, 224))	('variants', 'Var', (208, 216))	('hereditary nonpolyposis colorectal cancers', 'Disease', (74, 116))	('MSH6', 'Gene', (21, 25))	('hereditary nonpolyposis colorectal cancers', 'Disease', 'MESH:D003123', (74, 116))	('endometrial and ovarian cancers', 'Disease', 'MESH:D004714', (262, 293))	('MSH2', 'Gene', (229, 233))	('cancers', 'Phenotype', 'HP:0002664', (286, 293))
79776	33977078	When a pathogenic variant in the MSH6 gene is suspected, a panel of five mononucleotides (NR21, BAT25, BAT26, NR24, and NR22) is recommended to assess the MSI status.	('MSH6', 'Gene', (33, 37))	('men', 'Species', '9606', (134, 137))	('mononucleotides', 'Chemical', '-', (73, 88))	('pathogenic', 'Reg', (7, 17))	('MSH6', 'Gene', '2956', (33, 37))	('variant', 'Var', (18, 25))
79777	33977078	There have been relatively few publications of isolated MSH6 variants.	('MSH6', 'Gene', (56, 60))	('MSH6', 'Gene', '2956', (56, 60))	('variants', 'Var', (61, 69))
79778	33977078	A large study of 113 families with MSH6 variant carriers from multiple countries has shown some differences in presentations and in malignancies associated with MSH6.	('variant', 'Var', (40, 47))	('MSH6', 'Gene', '2956', (161, 165))	('MSH6', 'Gene', (35, 39))	('malignancies', 'Disease', 'MESH:D009369', (132, 144))	('presentations', 'MPA', (111, 124))	('MSH6', 'Gene', '2956', (35, 39))	('MSH6', 'Gene', (161, 165))	('malignancies', 'Disease', (132, 144))
79780	33977078	These studies suggest long-term screening requirement for patients with the MSH6 pathogenic variant.	('men', 'Species', '9606', (49, 52))	('MSH6', 'Gene', (76, 80))	('variant', 'Var', (92, 99))	('MSH6', 'Gene', '2956', (76, 80))	('patients', 'Species', '9606', (58, 66))
79781	33977078	Endometrial carcinoma is the most common presentation among women with pathogenic variants in this gene, and the women have a sixfold increased incidence of other cancers associated with LS including ovary, stomach, kidney, ureter, or brain.	('variants', 'Var', (82, 90))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('brain', 'Disease', (235, 240))	('Endometrial carcinoma', 'Disease', 'MESH:D016889', (0, 21))	('women', 'Species', '9606', (60, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('stomach', 'Disease', (207, 214))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('kidney', 'Disease', (216, 222))	('ureter', 'Disease', (224, 230))	('women', 'Species', '9606', (113, 118))	('Endometrial carcinoma', 'Phenotype', 'HP:0012114', (0, 21))	('ovary', 'Disease', (200, 205))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('Endometrial carcinoma', 'Disease', (0, 21))
79783	33977078	The reported studies also show occurrence of other malignancies such as lymphoma, leukemia, Langerhan's cell histiocytosis, and testicular germ cell tumors with MSH6 variants.	("Langerhan's cell histiocytosis", 'Disease', (92, 122))	('leukemia', 'Disease', (82, 90))	('lymphoma', 'Phenotype', 'HP:0002665', (72, 80))	('malignancies', 'Disease', 'MESH:D009369', (51, 63))	('lymphoma', 'Disease', 'MESH:D008223', (72, 80))	('MSH6', 'Gene', '2956', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('lymphoma', 'Disease', (72, 80))	('variants', 'Var', (166, 174))	('malignancies', 'Disease', (51, 63))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('histiocytosis', 'Phenotype', 'HP:0100727', (109, 122))	('germ cell tumors', 'Phenotype', 'HP:0100728', (139, 155))	('MSH6', 'Gene', (161, 165))	('leukemia', 'Phenotype', 'HP:0001909', (82, 90))	('leukemia', 'Disease', 'MESH:D007938', (82, 90))
79784	33977078	These studies suggest a different set of malignancies must be considered in the screening of patients with MSH6 pathogenic variant.	('malignancies', 'Disease', 'MESH:D009369', (41, 53))	('MSH6', 'Gene', (107, 111))	('variant', 'Var', (123, 130))	('malignancies', 'Disease', (41, 53))	('MSH6', 'Gene', '2956', (107, 111))	('patients', 'Species', '9606', (93, 101))
79785	33977078	There were six cases of kidney tumors in the study of pure MSH6 variants by Baglietto et al., but the type of tumor, whether urothelial carcinoma or RCC, was not specified.	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('kidney tumors', 'Disease', (24, 37))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('not specified', 'Species', '32644', (158, 171))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (125, 145))	('pure', 'molecular_function', 'GO:0034023', ('54', '58'))	('variants', 'Var', (64, 72))	('MSH6', 'Gene', (59, 63))	('urothelial carcinoma', 'Disease', (125, 145))	('MSH6', 'Gene', '2956', (59, 63))	('kidney tumors', 'Disease', 'MESH:D007680', (24, 37))	('RCC', 'Disease', (149, 152))	('tumor', 'Disease', (31, 36))	('kidney tumors', 'Phenotype', 'HP:0009726', (24, 37))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('RCC', 'Disease', 'MESH:C538614', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
79788	33977078	Similarly, in our review, there were four RCCs associated with MSH6 variants including the current case.	('variants', 'Var', (68, 76))	('MSH6', 'Gene', (63, 67))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('MSH6', 'Gene', '2956', (63, 67))	('RCC', 'Disease', (42, 45))
79790	33977078	This current report is the only case of PRCC in a male with MTS and a pathogenic variant in MSH6.	('PRCC', 'Gene', '5546', (40, 44))	('variant', 'Var', (81, 88))	('MSH6', 'Gene', (92, 96))	('PRCC', 'Gene', (40, 44))	('MSH6', 'Gene', '2956', (92, 96))
79793	33977078	However, the loss of expression of the MSH6 protein by IHC and the MSH6 variant in this papillary tumor as confirmed by the tumor NGS analysis, confirms this to be definitively associated with MSH6.	('tumor', 'Disease', (124, 129))	('MSH6', 'Gene', (39, 43))	('tumor', 'Disease', (98, 103))	('variant', 'Var', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('MSH6', 'Gene', '2956', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('papillary tumor', 'Disease', 'MESH:D002291', (88, 103))	('papillary tumor', 'Disease', (88, 103))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('MSH6', 'Gene', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('MSH6', 'Gene', '2956', (193, 197))	('MSH6', 'Gene', (67, 71))	('protein', 'Protein', (44, 51))	('MSH6', 'Gene', '2956', (67, 71))	('expression', 'MPA', (21, 31))	('loss', 'NegReg', (13, 17))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))
79796	33977078	In one case with LS due to the MSH2 variant, loss of the MSH2 expression and MSI were present in the colon, ureter, and cervical adenocarcinoma, but the PRCC of the kidney was microsatellite stable and did not show any loss of the MMR proteins.	('adenocarcinoma', 'Disease', (129, 143))	('variant', 'Var', (36, 43))	('MSH2', 'Gene', '4436', (31, 35))	('MSH2', 'Gene', '4436', (57, 61))	('expression', 'MPA', (62, 72))	('adenocarcinoma', 'Disease', 'MESH:D000230', (129, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('PRCC', 'Gene', '5546', (153, 157))	('MSH2', 'Gene', (31, 35))	('MSI', 'MPA', (77, 80))	('loss', 'NegReg', (45, 49))	('MMR', 'biological_process', 'GO:0006298', ('231', '234'))	('PRCC', 'Gene', (153, 157))	('MSH2', 'Gene', (57, 61))
79801	33977078	Our case is the first report of PRCC associated with pathogenic variants in MSH6 in LS/MTS.	('MSH6', 'Gene', (76, 80))	('PRCC', 'Gene', '5546', (32, 36))	('MSH6', 'Gene', '2956', (76, 80))	('associated', 'Reg', (37, 47))	('PRCC', 'Gene', (32, 36))	('variants', 'Var', (64, 72))
79802	33977078	The MSH6 abnormality (L1330fs*12) was also seen in the papillary carcinoma.	('L1330fs*12', 'Var', (22, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('papillary carcinoma', 'Disease', (55, 74))	('MSH6', 'Gene', '2956', (4, 8))	('papillary carcinoma', 'Disease', 'MESH:D002291', (55, 74))	('seen', 'Reg', (43, 47))	('MSH6', 'Gene', (4, 8))
79803	33977078	Other abnormalities included ARID1A S90fs*11, SETD2 N1725fs*3, and STAG2 E143fs*3.	('SETD2', 'Gene', (46, 51))	('S90fs*11', 'Var', (36, 44))	('N1725fs*3', 'Var', (52, 61))	('E143fs', 'Mutation', 'p.E143fsX', (73, 79))	('E143fs*3', 'Var', (73, 81))	('SETD2', 'Gene', '29072', (46, 51))	('S90fs', 'Mutation', 'p.S90fsX', (36, 41))	('ARID1A', 'Gene', '8289', (29, 35))	('STAG2', 'Gene', (67, 72))	('STAG2', 'Gene', '10735', (67, 72))	('ARID1A', 'Gene', (29, 35))
79817	33977078	The MiT family translocation carcinomas include tumors with gene fusions involving the TFE3 or TFEB locus.	('TFE3', 'Gene', '7030', (87, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('carcinomas', 'Disease', 'MESH:D009369', (29, 39))	('TFEB', 'Gene', '7942', (95, 99))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('TFEB', 'Gene', (95, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('carcinomas', 'Disease', (29, 39))	('gene fusions', 'Var', (60, 72))	('TFE3', 'Gene', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
79828	33977078	The next-generation sequencing of 10 of these tumors performed by the same group showed KRAS missense variants in eight tumors.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('KRAS', 'Gene', (88, 92))	('KRAS', 'Gene', '3845', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', (46, 52))	('missense variants', 'Var', (93, 110))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
79830	33977078	One case of GATA3-positive papillary renal neoplasm with reverse polarity with KRAS and PIK3CA mutation is also described by Lee et al..	('PIK3CA', 'Gene', '5290', (88, 94))	('KRAS', 'Gene', '3845', (79, 83))	('GATA3', 'Gene', (12, 17))	('papillary renal neoplasm', 'Disease', (27, 51))	('papillary renal neoplasm', 'Phenotype', 'HP:0006766', (27, 51))	('renal neoplasm', 'Phenotype', 'HP:0009726', (37, 51))	('papillary renal neoplasm', 'Disease', 'MESH:D007681', (27, 51))	('GATA3', 'Gene', '2625', (12, 17))	('PIK3CA', 'Gene', (88, 94))	('neoplasm', 'Phenotype', 'HP:0002664', (43, 51))	('KRAS', 'Gene', (79, 83))	('mutation', 'Var', (95, 103))
79831	33977078	Similarly, KRAS mutations were also observed by Kim and Tong et al.	('KRAS', 'Gene', (11, 15))	('KRAS', 'Gene', '3845', (11, 15))	('mutations', 'Var', (16, 25))
79832	33977078	who have described KRAS mutations in papillary renal neoplasm with reverse polarity, but GATA3 immunohistochemical stain was not performed in these two studies.	('GATA3', 'Gene', '2625', (89, 94))	('papillary renal neoplasm', 'Phenotype', 'HP:0006766', (37, 61))	('papillary renal neoplasm', 'Disease', 'MESH:D007681', (37, 61))	('KRAS', 'Gene', (19, 23))	('renal neoplasm', 'Phenotype', 'HP:0009726', (47, 61))	('KRAS', 'Gene', '3845', (19, 23))	('GATA3', 'Gene', (89, 94))	('neoplasm', 'Phenotype', 'HP:0002664', (53, 61))	('mutations', 'Var', (24, 33))	('papillary renal neoplasm', 'Disease', (37, 61))
79835	33977078	These studies indicate that the KRAS mutation is seen in oncocytic papillary neoplasms.	('seen', 'Reg', (49, 53))	('mutation', 'Var', (37, 45))	('neoplasms', 'Phenotype', 'HP:0002664', (77, 86))	('KRAS', 'Gene', (32, 36))	('oncocytic papillary neoplasms', 'Disease', (57, 86))	('oncocytic papillary neoplasms', 'Disease', 'MESH:C535584', (57, 86))	('KRAS', 'Gene', '3845', (32, 36))	('neoplasm', 'Phenotype', 'HP:0002664', (77, 85))
79838	33977078	Interestingly, a KRAS variant was detected in this tumor as in papillary tumors with reverse polarity.	('papillary tumors', 'Disease', (63, 79))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('variant', 'Var', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('papillary tumors', 'Disease', 'MESH:D002291', (63, 79))	('tumor', 'Disease', (51, 56))	('papillary tumors', 'Phenotype', 'HP:0007482', (63, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', (73, 78))	('KRAS', 'Gene', (17, 21))	('KRAS', 'Gene', '3845', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
79842	33977078	The presence of KRAS mutation in this tumor suggests that this mutation may not be restricted to the papillary renal neoplasm with reverse polarity and this entity should be better defined with the study of large number of cases.	('renal neoplasm', 'Phenotype', 'HP:0009726', (111, 125))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('papillary renal neoplasm', 'Disease', 'MESH:D007681', (101, 125))	('neoplasm', 'Phenotype', 'HP:0002664', (117, 125))	('mutation', 'Var', (21, 29))	('KRAS', 'Gene', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('papillary renal neoplasm', 'Disease', (101, 125))	('KRAS', 'Gene', '3845', (16, 20))	('papillary renal neoplasm', 'Phenotype', 'HP:0006766', (101, 125))
79854	33977078	We describe the first case of PRCC in a patient with Lynch/MTS with the MSH6 pathogenic variant.	('patient', 'Species', '9606', (40, 47))	('MSH6', 'Gene', (72, 76))	('PRCC', 'Gene', (30, 34))	('variant', 'Var', (88, 95))	('MSH6', 'Gene', '2956', (72, 76))	('PRCC', 'Gene', '5546', (30, 34))
79856	33977078	There was also KRAS mutation, but the tumor was microsatellite stable.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('KRAS', 'Gene', (15, 19))	('mutation', 'Var', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('KRAS', 'Gene', '3845', (15, 19))
79864	33565732	COSMIC, cBioPortal, and CCLE were used to examine FZD2 mutations in human cancers.	('human', 'Species', '9606', (68, 73))	('mutations', 'Var', (55, 64))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('CCLE', 'Chemical', '-', (24, 28))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('FZD2', 'Gene', '2535', (50, 54))	('FZD2', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
79894	33565732	The catalog of somatic mutations in cancer (COSMIC) database (https://cancer.sanger.ac.uk/cosmic/) collects millions of coding mutations, noncoding mutations, genome rearrangements, fusion genes, copy number abnormalities, and gene expression variations in the human genome [12].	('fusion genes', 'Var', (182, 194))	('number abnormalities', 'Disease', 'MESH:D007674', (201, 221))	('variations', 'Var', (243, 253))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (36, 42))	('human', 'Species', '9606', (261, 266))	('number abnormalities', 'Disease', (201, 221))	('gene expression', 'biological_process', 'GO:0010467', ('227', '242'))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
79895	33565732	In this study, COSMIC was used to examine FZD2 mutations in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('FZD2', 'Gene', '2535', (42, 46))	('FZD2', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('human', 'Species', '9606', (60, 65))
79898	33565732	The Cancer Cell Line Encyclopedia (CCLE) project dataset is a compilation of gene expression data from human cancer cell lines and was used to analyze FZD2 mutations in various cancer cell lines [14].	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('FZD2', 'Gene', '2535', (151, 155))	('FZD2', 'Gene', (151, 155))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('mutations', 'Var', (156, 165))	('human', 'Species', '9606', (103, 108))	('cancer', 'Disease', (109, 115))	('CCLE', 'Chemical', '-', (35, 39))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('gene expression', 'biological_process', 'GO:0010467', ('77', '92'))
79899	33565732	Tumor mutation burden (TMB) is defined as the total number of somatic gene coding errors, base substitutions, insertions, or deletions detected per million bases.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TMB', 'Chemical', '-', (23, 26))	('insertions', 'Var', (110, 120))	('deletions', 'Var', (125, 134))	('Tumor mutation burden', 'Disease', (0, 21))	('base substitutions', 'Var', (90, 108))
79923	33565732	According to the median expression of FZD2 across the different cancer types, patients were divided into either a high or low expression group; when analyzed, it was found that the survival difference between the high and low expression groups was significant and that patients with high FZD2 expression had earlier recurrence after tumor resection (Fig.	('earlier', 'PosReg', (308, 315))	('tumor', 'Disease', (333, 338))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('high', 'Var', (283, 287))	('FZD2', 'Gene', (38, 42))	('FZD2', 'Gene', '2535', (38, 42))	('cancer', 'Disease', (64, 70))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('FZD2', 'Gene', (288, 292))	('expression', 'MPA', (293, 303))	('FZD2', 'Gene', '2535', (288, 292))	('recurrence', 'CPA', (316, 326))	('patients', 'Species', '9606', (269, 277))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
79924	33565732	COSMIC provides information about FZD2 mutations in different cancers, including missense mutations, nonsense mutations, and synonymous mutations (Figs 3A and Fig.	('missense mutations', 'Var', (81, 99))	('FZD2', 'Gene', (34, 38))	('FZD2', 'Gene', '2535', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (39, 48))	('nonsense mutations', 'Var', (101, 119))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('synonymous mutations', 'Var', (125, 145))	('cancers', 'Disease', (62, 69))
79927	33565732	C>T and G>A mutations were found to be the most common in the FZD2 coding chain, while A>T and T>A mutations were rare.	('G>A mutations', 'Var', (8, 21))	('C>T', 'Var', (0, 3))	('FZD2', 'Gene', '2535', (62, 66))	('FZD2', 'Gene', (62, 66))	('common', 'Reg', (48, 54))
79930	33565732	Among these, the mutation rate was higher in esophagogastric adenocarcinoma and endometrial carcinoma (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mutation', 'Var', (17, 25))	('esophagogastric adenocarcinoma', 'Phenotype', 'HP:0011459', (45, 75))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('adenocarcinoma and endometrial carcinoma', 'Disease', 'MESH:D016889', (61, 101))	('higher', 'Reg', (35, 41))
79931	33565732	Missense mutations and silent mutations were also found in cancer cell lines (Fig.	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Missense mutations', 'Var', (0, 18))
79966	33565732	In addition, the latest research has found that FZD2 is more highly expressed in hepatocellular carcinoma tissues than in adjacent tissues, and the recurrence-free survival rate of patients with high FZD2 expression is significantly lower than that of patients with low expression.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('recurrence-free survival rate', 'CPA', (148, 177))	('patients', 'Species', '9606', (252, 260))	('FZD2', 'Gene', '2535', (48, 52))	('FZD2', 'Gene', (48, 52))	('lower', 'NegReg', (233, 238))	('highly', 'PosReg', (61, 67))	('FZD2', 'Gene', '2535', (200, 204))	('high', 'Var', (195, 199))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (81, 105))	('patients', 'Species', '9606', (181, 189))	('hepatocellular carcinoma', 'Disease', (81, 105))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (81, 105))	('FZD2', 'Gene', (200, 204))	('expression', 'MPA', (205, 215))
79967	33565732	Furthermore, FZD2 expression is significantly correlated with the mesenchymal phenotype in HCC cell lines, and knocking out FZD2 can inhibit the migration and invasiveness of liver cancer cells [23].	('liver cancer', 'Phenotype', 'HP:0002896', (175, 187))	('FZD2', 'Gene', '2535', (13, 17))	('FZD2', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('knocking out', 'Var', (111, 123))	('invasiveness of liver cancer', 'Disease', (159, 187))	('migration', 'CPA', (145, 154))	('FZD2', 'Gene', '2535', (124, 128))	('FZD2', 'Gene', (124, 128))	('inhibit', 'NegReg', (133, 140))	('invasiveness of liver cancer', 'Disease', 'MESH:D006528', (159, 187))
79975	33565732	Knockout of FZD7 or use of Wnt/beta-catenin inhibitors has been shown to reduce the stemness and chemoresistance of GC cells [33].	('chemoresistance', 'CPA', (97, 112))	('beta-catenin', 'Gene', (31, 43))	('GC', 'Phenotype', 'HP:0012126', (116, 118))	('beta-catenin', 'Gene', '1499', (31, 43))	('Knockout', 'Var', (0, 8))	('FZD7', 'Gene', '8324', (12, 16))	('FZD7', 'Gene', (12, 16))	('reduce', 'NegReg', (73, 79))
79976	33565732	FZD8 is highly expressed in human lung cancer tissue samples and cell lines, and knockout of FZD8 can increase the sensitivity of lung cancer cells to paclitaxel [34].	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('FZD8', 'Gene', '8325', (93, 97))	('paclitaxel', 'Chemical', 'MESH:D017239', (151, 161))	('FZD8', 'Gene', (93, 97))	('lung cancer', 'Disease', (34, 45))	('human', 'Species', '9606', (28, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('knockout', 'Var', (81, 89))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('increase', 'PosReg', (102, 110))	('sensitivity', 'MPA', (115, 126))	('FZD8', 'Gene', '8325', (0, 4))	('lung cancer', 'Disease', (130, 141))	('FZD8', 'Gene', (0, 4))
79992	33565732	Those with high TMB expression have been shown to benefit more from immune checkpoint inhibitor therapy [44].	('TMB', 'Chemical', '-', (16, 19))	('TMB', 'Protein', (16, 19))	('benefit', 'PosReg', (50, 57))	('high', 'Var', (11, 15))
79993	33565732	TMB reflects the total number of replacement and insertion/deletion mutations per megabase in the exon coding region of the evaluated gene in the tumor cell genome.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('TMB', 'Chemical', '-', (0, 3))	('tumor', 'Disease', (146, 151))	('insertion/deletion mutations', 'Var', (49, 77))	('replacement', 'Var', (33, 44))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
79994	33565732	Driving gene mutations can lead to tumors, and a large number of somatic mutations can produce new antigens, which can activate T cells and cause immune responses [45].	('T cells', 'CPA', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cause', 'Reg', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('immune responses', 'CPA', (146, 162))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('lead to', 'Reg', (27, 34))	('mutations', 'Var', (13, 22))	('activate', 'PosReg', (119, 127))	('mutations', 'Var', (73, 82))	('produce', 'Reg', (87, 94))
79997	33565732	Studies have shown that frameshift mutations of AXIN2 and TCF7L2 are common in GC with high MSI, and these mutations may promote the development of GC through the control of Wnt signaling [46].	('mutations', 'Var', (107, 116))	('AXIN2', 'Gene', (48, 53))	('development', 'CPA', (133, 144))	('AXIN2', 'Gene', '8313', (48, 53))	('GC', 'Phenotype', 'HP:0012126', (79, 81))	('signaling', 'biological_process', 'GO:0023052', ('178', '187'))	('TCF7L2', 'Gene', (58, 64))	('GC', 'Phenotype', 'HP:0012126', (148, 150))	('TCF7L2', 'Gene', '6934', (58, 64))	('promote', 'PosReg', (121, 128))	('frameshift mutations', 'Var', (24, 44))
79999	33565732	It was also found that FZD2 was mutated in breast, endometrial, large intestine, liver, lung, skin, and stomach cancer.	('endometrial', 'Disease', (51, 62))	('skin', 'Disease', (94, 98))	('stomach cancer', 'Disease', 'MESH:D013274', (104, 118))	('stomach cancer', 'Phenotype', 'HP:0012126', (104, 118))	('liver', 'Disease', (81, 86))	('FZD2', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('large intestine', 'Disease', (64, 79))	('mutated', 'Var', (32, 39))	('stomach cancer', 'Disease', (104, 118))	('breast', 'Disease', (43, 49))	('FZD2', 'Gene', '2535', (23, 27))	('lung', 'Disease', (88, 92))
80009	27250763	Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines Targeting of class I histone deacetylases (HDACs) exerts antineoplastic actions in various cancer types by modulation of transcription, upregulation of tumor suppressors, induction of cell cycle arrest, replication stress and promotion of apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('367', '376'))	('apoptosis', 'biological_process', 'GO:0006915', ('367', '376'))	('Targeting', 'Var', (128, 137))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (312, 329))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('antineoplastic actions', 'CPA', (185, 207))	('Urothelial Carcinoma Cell', 'Disease', (96, 121))	('transcription', 'CPA', (249, 262))	('4SC', 'Chemical', '-', (85, 88))	('Carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('tumor', 'Disease', (280, 285))	('upregulation', 'PosReg', (264, 276))	('Urothelial Carcinoma Cell', 'Disease', 'MESH:C538614', (96, 121))	('apoptosis', 'CPA', (367, 376))	('HDAC', 'Gene', '9734', (70, 74))	('modulation', 'Reg', (235, 245))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('transcription', 'biological_process', 'GO:0006351', ('249', '262'))	('cancer', 'Disease', (219, 225))	('cell cycle arrest', 'CPA', (312, 329))	('HDAC', 'Gene', '9734', (171, 175))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('HDAC', 'Gene', (70, 74))	('promotion', 'PosReg', (354, 363))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('replication stress', 'CPA', (331, 349))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('312', '329'))	('HDAC', 'Gene', (171, 175))
80019	27250763	Specific pharmacological inhibition of class I HDACs by 4SC-202 impairs UC cell viability, inducing cell cycle disturbances and cell death.	('4SC-202', 'Chemical', 'MESH:C000614036', (56, 63))	('cell cycle', 'biological_process', 'GO:0007049', ('100', '110'))	('impairs', 'NegReg', (64, 71))	('cell cycle disturbances', 'CPA', (100, 123))	('inducing', 'PosReg', (91, 99))	('HDAC', 'Gene', (47, 51))	('cell cycle disturbances', 'Phenotype', 'HP:0011018', (100, 123))	('4SC-202', 'Gene', (56, 63))	('inhibition', 'Var', (25, 35))	('HDAC', 'Gene', '9734', (47, 51))	('cell death', 'CPA', (128, 138))	('cell death', 'biological_process', 'GO:0008219', ('128', '138'))
80052	27250763	For distinguishing modes of cell death, cells were treated additionally with Necrox-2 (20 muM, sc-391057, Santa Cruz, Dallas, USA) or Q-VD-OPh (30 muM, SML0063, Sigma Aldrich); Etoposide was used to induce apoptosis (25 muM, S1225, Selleck Chemicals) and H2O2 to induce necrosis (30 muM, 107210, Merck, Darmstadt, Germany) as previously described.	('muM', 'Gene', (283, 286))	('necrosis', 'Disease', 'MESH:D009336', (270, 278))	('muM', 'Gene', '56925', (90, 93))	('muM', 'Gene', (147, 150))	('Necrox-2', 'Chemical', '-', (77, 85))	('cell death', 'biological_process', 'GO:0008219', ('28', '38'))	('muM', 'Gene', (90, 93))	('necrosis', 'Disease', (270, 278))	('necrosis', 'biological_process', 'GO:0070265', ('270', '278'))	('Etoposide', 'Chemical', 'MESH:D005047', (177, 186))	('necrosis', 'biological_process', 'GO:0019835', ('270', '278'))	('S1225', 'Var', (225, 230))	('necrosis', 'biological_process', 'GO:0001906', ('270', '278'))	('OPh', 'molecular_function', 'GO:0004063', ('139', '142'))	('Q-VD-OPh', 'Chemical', 'MESH:C468548', (134, 142))	('H2O2', 'Chemical', 'MESH:D006861', (255, 259))	('necrosis', 'biological_process', 'GO:0008219', ('270', '278'))	('apoptosis', 'biological_process', 'GO:0097194', ('206', '215'))	('apoptosis', 'biological_process', 'GO:0006915', ('206', '215'))	('muM', 'Gene', '56925', (220, 223))	('muM', 'Gene', (220, 223))	('muM', 'Gene', '56925', (283, 286))	('necrosis', 'biological_process', 'GO:0008220', ('270', '278'))	('muM', 'Gene', '56925', (147, 150))
80053	27250763	As a positive control for histone acetylation analysis, VM-CUB1 cells were also treated with romidepsin (3 nM, S3020, Selleck Chemicals).	('S3020', 'Var', (111, 116))	('3 nM', 'Var', (105, 109))	('romidepsin', 'Chemical', 'MESH:C087123', (93, 103))	('histone acetylation', 'biological_process', 'GO:0016573', ('26', '45'))
80085	27250763	Treatment with 4SC-202 resulted in a dose-dependent, significantly reduced proliferation rate of all UCCs, independent of their HDAC expression profile described elsewhere, with only slight variations in IC50 values (range: 0.15 - 0.51 muM).	('HDAC', 'Gene', (128, 132))	('HDAC', 'Gene', '9734', (128, 132))	('4SC-202', 'Chemical', 'MESH:C000614036', (15, 22))	('reduced', 'NegReg', (67, 74))	('muM', 'Gene', '56925', (236, 239))	('proliferation rate', 'CPA', (75, 93))	('muM', 'Gene', (236, 239))	('4SC-202', 'Var', (15, 22))
80096	27250763	The mRNA levels of class I HDACs were not consistently deregulated by 4SC-202 (Fig.	('HDAC', 'Gene', '9734', (27, 31))	('mRNA levels', 'MPA', (4, 15))	('4SC-202', 'Var', (70, 77))	('4SC-202', 'Chemical', 'MESH:C000614036', (70, 77))	('HDAC', 'Gene', (27, 31))
80104	27250763	The non-urothelial non-malignant HEK-293 cells showed more pronounced morphological changes in cell attachment and shape, indicating apoptotic features following treatment with 4SC-202 than with romidepsin, givinostat or SAHA (Fig.	('romidepsin', 'Chemical', 'MESH:C087123', (195, 205))	('4SC-202', 'Chemical', 'MESH:C000614036', (177, 184))	('cell attachment', 'CPA', (95, 110))	('HEK-293', 'CellLine', 'CVCL:0045', (33, 40))	('morphological changes', 'CPA', (70, 91))	('4SC-202', 'Var', (177, 184))	('apoptotic features', 'CPA', (133, 151))	('givinostat', 'Chemical', 'MESH:C575255', (207, 217))	('SAHA', 'Chemical', 'MESH:D000077337', (221, 225))
80105	27250763	Clonogenicity was impaired by treatment with either 4SC-202 or SAHA in VM-CUB1 and UM-UC-3 cells (Fig.	('4SC-202', 'Chemical', 'MESH:C000614036', (52, 59))	('UM-UC-3', 'CellLine', 'CVCL:1783', (83, 90))	('Clonogenicity', 'CPA', (0, 13))	('4SC-202', 'Var', (52, 59))	('SAHA', 'Chemical', 'MESH:D000077337', (63, 67))	('impaired', 'NegReg', (18, 26))
80111	27250763	Further, we investigated to which extent apoptosis and necrosis contributed to cell death upon treatment with 4SC-202, as compared to SAHA (Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('41', '50'))	('necrosis', 'biological_process', 'GO:0008219', ('55', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('41', '50'))	('4SC-202', 'Chemical', 'MESH:C000614036', (110, 117))	('necrosis', 'biological_process', 'GO:0019835', ('55', '63'))	('necrosis', 'Disease', (55, 63))	('necrosis', 'biological_process', 'GO:0008220', ('55', '63'))	('necrosis', 'biological_process', 'GO:0001906', ('55', '63'))	('necrosis', 'Disease', 'MESH:D009336', (55, 63))	('SAHA', 'Chemical', 'MESH:D000077337', (134, 138))	('cell death', 'biological_process', 'GO:0008219', ('79', '89'))	('4SC-202', 'Var', (110, 117))	('necrosis', 'biological_process', 'GO:0070265', ('55', '63'))
80112	27250763	For the evaluation of an apoptotic response, caspase-3/7 activity was measured after 24 and 48 h treatments with 4SC-202 or SAHA in UCCs and control cells (Fig.	('caspase-3', 'Gene', '836', (45, 54))	('4SC-202', 'Var', (113, 120))	('4SC-202', 'Chemical', 'MESH:C000614036', (113, 120))	('activity', 'MPA', (57, 65))	('SAHA', 'Chemical', 'MESH:D000077337', (124, 128))	('caspase-3', 'Gene', (45, 54))
80115	27250763	More efficient induction of apoptosis by 4SC-202 as compared to SAHA was also evidenced by enhanced cleaved PARP detected by western blotting (Fig.	('induction of apoptosis', 'biological_process', 'GO:0006915', ('15', '37'))	('SAHA', 'Chemical', 'MESH:D000077337', (64, 68))	('PARP', 'Gene', '1302', (108, 112))	('4SC-202', 'Var', (41, 48))	('apoptosis', 'CPA', (28, 37))	('PARP', 'Gene', (108, 112))	('4SC-202', 'Chemical', 'MESH:C000614036', (41, 48))	('enhanced', 'PosReg', (91, 99))
80128	27250763	The changes in the cell cycle profiles elicited by 4SC-202 were not reflected in according changes in the expression of cyclins in VM-CUB1 and UM-UC-3 cells (Fig.	('UM-UC-3', 'CellLine', 'CVCL:1783', (143, 150))	('cell cycle profiles', 'CPA', (19, 38))	('4SC-202', 'Var', (51, 58))	('cell cycle', 'biological_process', 'GO:0007049', ('19', '29'))	('4SC-202', 'Chemical', 'MESH:C000614036', (51, 58))
80129	27250763	Notably, induction of p21CIP1, a classical marker of cell cycle arrest induction by HDAC inhibitors, was less prominent with 4SC-202 compared to SAHA in VM-CUB1 and UM-UC-3 cells after 24 h treatment.	('SAHA', 'Chemical', 'MESH:D000077337', (145, 149))	('4SC-202', 'Chemical', 'MESH:C000614036', (125, 132))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (53, 70))	('p21CIP1', 'Gene', '1026', (22, 29))	('less', 'NegReg', (105, 109))	('UM-UC-3', 'CellLine', 'CVCL:1783', (165, 172))	('HDAC', 'Gene', (84, 88))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('53', '70'))	('HDAC', 'Gene', '9734', (84, 88))	('4SC-202', 'Var', (125, 132))	('p21CIP1', 'Gene', (22, 29))
80133	27250763	Next, we analyzed exemplarily in VM-CUB1 cells whether 4SC-202 (24 h) induces gammaH2A.X (phosphorylated histone H2A.X on Ser139), to determine to which extent double-strand breaks (DSBs) contribute to the cell cycle disturbances.	('gammaH2A', 'Chemical', '-', (78, 86))	('cell cycle disturbances', 'Phenotype', 'HP:0011018', (206, 229))	('cell cycle', 'CPA', (206, 216))	('Ser', 'cellular_component', 'GO:0005790', ('122', '125'))	('cell cycle', 'biological_process', 'GO:0007049', ('206', '216'))	('Ser139', 'Chemical', '-', (122, 128))	('4SC-202', 'Var', (55, 62))	('4SC-202', 'Chemical', 'MESH:C000614036', (55, 62))
80134	27250763	As gammaH2A.X can also be induced by other forms of DNA damage, we additionally performed double-staining for 53-BP1, which colocalizes with gammaH2A.X in DSB foci.	('DSB', 'Disease', (155, 158))	('gammaH2A', 'Chemical', '-', (3, 11))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('gammaH2A.X', 'Var', (141, 151))	('53-BP1', 'Gene', (110, 116))	('gammaH2A', 'Chemical', '-', (141, 149))	('53-BP1', 'Gene', '7158', (110, 116))
80149	27250763	4SC-202 significantly impaired proliferation of UCCs at submicromolar levels and was more efficacious in abrogating clonogenic growth than the pan-HDAC inhibitor SAHA.	('SAHA', 'Chemical', 'MESH:D000077337', (162, 166))	('4SC-202', 'Var', (0, 7))	('abrogating', 'NegReg', (105, 115))	('proliferation', 'CPA', (31, 44))	('UCCs', 'CPA', (48, 52))	('clonogenic growth', 'CPA', (116, 133))	('impaired', 'NegReg', (22, 30))	('HDAC', 'Gene', (147, 151))	('4SC-202', 'Chemical', 'MESH:C000614036', (0, 7))	('HDAC', 'Gene', '9734', (147, 151))
80155	27250763	First, 4SC-202 is a benzamide type HDACi exhibiting a slower on-kinetic as compared to the bicyclic peptide romidepsin.	('romidepsin', 'Chemical', 'MESH:C087123', (108, 118))	('HDAC', 'Gene', (35, 39))	('4SC-202', 'Var', (7, 14))	('benzamide', 'Chemical', 'MESH:C037689', (20, 29))	('HDAC', 'Gene', '9734', (35, 39))	('4SC-202', 'Chemical', 'MESH:C000614036', (7, 14))
80161	27250763	Importantly, inhibition of proliferation and clonogenic growth upon treatment with 4SC-202 was likewise observed in non-cancerous cell lines at comparable concentrations.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('proliferation', 'CPA', (27, 40))	('clonogenic growth', 'CPA', (45, 62))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('4SC-202', 'Var', (83, 90))	('inhibition', 'NegReg', (13, 23))	('4SC-202', 'Chemical', 'MESH:C000614036', (83, 90))
80162	27250763	In comparison to romidepsin and givinostat, 4SC-202 had stronger effects especially on HEK-293 cells, whereas the immortalized urothelial HBLAK cells were less affected and inhibition of growth was rather due to senescence than cell death.	('4SC-202', 'Var', (44, 51))	('HEK-293', 'CellLine', 'CVCL:0045', (87, 94))	('senescence', 'biological_process', 'GO:0010149', ('212', '222'))	('effects', 'MPA', (65, 72))	('4SC-202', 'Chemical', 'MESH:C000614036', (44, 51))	('cell death', 'biological_process', 'GO:0008219', ('228', '238'))	('inhibition of growth', 'biological_process', 'GO:0045926', ('173', '193'))	('romidepsin', 'Chemical', 'MESH:C087123', (17, 27))	('givinostat', 'Chemical', 'MESH:C575255', (32, 42))
80167	27250763	In contrast, HEK-293 cells were notably more sensitive to 4SC-202 than to romidepsin and givinostat.	('4SC-202', 'Var', (58, 65))	('givinostat', 'Chemical', 'MESH:C575255', (89, 99))	('HEK-293', 'CellLine', 'CVCL:0045', (13, 20))	('romidepsin', 'Chemical', 'MESH:C087123', (74, 84))	('4SC-202', 'Chemical', 'MESH:C000614036', (58, 65))	('sensitive', 'MPA', (45, 54))
80169	27250763	In particular, 4SC-202 may unfold its antineoplastic activity in UC by impacting on LSD1 and Wnt and Hedgehog signaling (data presented at MMC Cancer Stem Cell Symposium 2014 & Keystone Symposium "Stem Cells and Cancer" 2014, data available online at https://4SC.de).	('impacting', 'Reg', (71, 80))	('4SC', 'Chemical', '-', (259, 262))	('Cancer', 'Disease', (212, 218))	('Cancer', 'Disease', (143, 149))	('4SC', 'Chemical', '-', (15, 18))	('LSD1', 'Gene', (84, 88))	('Cancer', 'Disease', 'MESH:D009369', (212, 218))	('4SC-202', 'Chemical', 'MESH:C000614036', (15, 22))	('Cancer', 'Disease', 'MESH:D009369', (143, 149))	('Cancer', 'Phenotype', 'HP:0002664', (212, 218))	('LSD1', 'Gene', '23028', (84, 88))	('Cancer', 'Phenotype', 'HP:0002664', (143, 149))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))	('4SC-202', 'Var', (15, 22))
80170	27250763	Albeit not caused by canonical mechanisms, dysregulation of WNT and Hedgehog signaling has also been observed in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('dysregulation', 'Var', (43, 56))	('observed', 'Reg', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (113, 127))	('bladder cancer', 'Disease', (113, 127))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))
80172	27250763	Inhibition of LSD1 alone also has limited effects on UC cell lines (Hoffmann et al., to be published elsewhere).	('LSD1', 'Gene', (14, 18))	('UC cell lines', 'CPA', (53, 66))	('Inhibition', 'Var', (0, 10))	('LSD1', 'Gene', '23028', (14, 18))
80173	27250763	However, LSD1 inhibition appeared to enhance and especially to accelerate the action of the HDAC1/2 inhibitor romidepsin.	('romidepsin', 'Chemical', 'MESH:C087123', (110, 120))	('action of the', 'MPA', (78, 91))	('HDAC1/2', 'Gene', '3065;3066', (92, 99))	('LSD1', 'Gene', (9, 13))	('accelerate', 'PosReg', (63, 73))	('LSD1', 'Gene', '23028', (9, 13))	('inhibition', 'Var', (14, 24))	('enhance', 'PosReg', (37, 44))	('HDAC1/2', 'Gene', (92, 99))
80175	27250763	Interestingly, a synergism between LSD1 and HDAC inhibition has been demonstrated for glioblastoma, where combined inhibition of LSD1 and HDACs synergistically induce apoptotic cell death in glioblastoma cells, but not in benign control cells.	('HDAC', 'Gene', (138, 142))	('glioblastoma', 'Disease', 'MESH:D005909', (86, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (191, 203))	('HDAC', 'Gene', '9734', (138, 142))	('apoptotic cell death', 'CPA', (167, 187))	('LSD1', 'Gene', (35, 39))	('LSD1', 'Gene', (129, 133))	('LSD1', 'Gene', '23028', (35, 39))	('HDAC', 'Gene', (44, 48))	('glioblastoma', 'Disease', (86, 98))	('inhibition', 'Var', (115, 125))	('induce', 'Reg', (160, 166))	('HDAC', 'Gene', '9734', (44, 48))	('LSD1', 'Gene', '23028', (129, 133))	('glioblastoma', 'Disease', (191, 203))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('167', '187'))	('glioblastoma', 'Disease', 'MESH:D005909', (191, 203))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))
80178	27250763	For example, necrosis was observed in melanoma cells with mutant B-RAF upon co-treatment with a B-RAF-inhibitor and either panobinostat or SAHA.	('mutant', 'Var', (58, 64))	('SAHA', 'Chemical', 'MESH:D000077337', (139, 143))	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('necrosis', 'biological_process', 'GO:0008219', ('13', '21'))	('necrosis', 'biological_process', 'GO:0070265', ('13', '21'))	('panobinostat', 'Disease', 'None', (123, 135))	('necrosis', 'Disease', 'MESH:D009336', (13, 21))	('B-RAF', 'Gene', '673', (65, 70))	('necrosis', 'biological_process', 'GO:0019835', ('13', '21'))	('necrosis', 'biological_process', 'GO:0001906', ('13', '21'))	('panobinostat', 'Disease', (123, 135))	('B-RAF', 'Gene', '673', (96, 101))	('necrosis', 'biological_process', 'GO:0008220', ('13', '21'))	('B-RAF', 'Gene', (65, 70))	('necrosis', 'Disease', (13, 21))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('B-RAF', 'Gene', (96, 101))	('melanoma', 'Disease', (38, 46))
80179	27250763	In UC cells treated with 4SC-202, we observed a mixture of apoptotic and necrotic cell death.	('necrotic cell death', 'Disease', 'MESH:D003643', (73, 92))	('4SC-202', 'Var', (25, 32))	('necrotic cell death', 'biological_process', 'GO:0070265', ('73', '92'))	('necrotic cell death', 'Disease', (73, 92))	('4SC-202', 'Chemical', 'MESH:C000614036', (25, 32))
80180	27250763	Rather, especially after 24 h and with higher concentrations of 4SC-202, the UCCs accumulated in the G2/M phase.	('4SC-202', 'Var', (64, 71))	('M phase', 'biological_process', 'GO:0000279', ('104', '111'))	('accumulated', 'PosReg', (82, 93))	('4SC-202', 'Chemical', 'MESH:C000614036', (64, 71))
80186	27250763	In keeping with our observations, very recently, 4SC-202 was reported to induce G2/M arrest and apoptosis in colorectal cancer cells.	('colorectal cancer', 'Disease', (109, 126))	('M arrest', 'Disease', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('4SC-202', 'Var', (49, 56))	('M arrest', 'Disease', 'MESH:D006323', (83, 91))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('apoptosis', 'CPA', (96, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('induce', 'PosReg', (73, 79))	('4SC-202', 'Chemical', 'MESH:C000614036', (49, 56))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
80189	27250763	Treatment with 4SC-202 disturbs mitosis in the first cell cycle leading to accumulation of cells in the G2/M phase, followed by irregular cell division, resulting in cells with apparent subG1 and S-phase content that undergo secondary necrosis or apoptosis.	('necrosis', 'biological_process', 'GO:0070265', ('235', '243'))	('S-phase', 'biological_process', 'GO:0051320', ('196', '203'))	('necrosis', 'biological_process', 'GO:0019835', ('235', '243'))	('mitosis', 'biological_process', 'GO:0000278', ('32', '39'))	('necrosis', 'biological_process', 'GO:0001906', ('235', '243'))	('accumulation', 'PosReg', (75, 87))	('disturbs mitosis', 'Disease', 'MESH:D010468', (23, 39))	('apoptosis', 'biological_process', 'GO:0097194', ('247', '256'))	('apoptosis', 'biological_process', 'GO:0006915', ('247', '256'))	('disturbs mitosis', 'Disease', (23, 39))	('necrosis', 'Disease', 'MESH:D009336', (235, 243))	('necrosis', 'biological_process', 'GO:0008219', ('235', '243'))	('4SC-202', 'Chemical', 'MESH:C000614036', (15, 22))	('secondary necrosis', 'Phenotype', 'HP:0010885', (225, 243))	('M phase', 'biological_process', 'GO:0000279', ('107', '114'))	('necrosis', 'Disease', (235, 243))	('undergo', 'Reg', (217, 224))	('necrosis', 'biological_process', 'GO:0008220', ('235', '243'))	('apoptosis', 'CPA', (247, 256))	('cell division', 'biological_process', 'GO:0051301', ('138', '151'))	('subG1', 'MPA', (186, 191))	('cell cycle', 'biological_process', 'GO:0007049', ('53', '63'))	('4SC-202', 'Var', (15, 22))
80318	22088332	Positive soft tissue margins were associated with worse cancer specific survival (HR 6.92, 95% CI 2.98-16.10, p <= 0.0005) and overall survival (HR 3.68, 95% CI 1.84-7.35, p <= 0.0005) in patients with pure squamous cell carcinoma.	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (207, 230))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('patients', 'Species', '9606', (188, 196))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (207, 230))	('pure', 'molecular_function', 'GO:0034023', ('202', '206'))	('squamous cell carcinoma', 'Disease', (207, 230))	('Positive', 'Var', (0, 8))	('cancer', 'Disease', (56, 62))	('worse', 'NegReg', (50, 55))	('overall survival', 'CPA', (127, 143))
80361	22088332	Compared to patients with conventional urothelial carcinoma, overall and disease specific survival were significantly worse for those with SCC (log rank OS p < 0.001, CSS p < 0.001) and SqD (log rank OS p < 0.001, CSS p < 0.001).	('SCC', 'Gene', '6317', (139, 142))	('patients', 'Species', '9606', (12, 20))	('OS', 'Chemical', 'MESH:D009992', (200, 202))	('OS', 'Chemical', 'MESH:D009992', (153, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('CSS', 'Gene', '55907', (167, 170))	('CSS', 'Gene', '55907', (214, 217))	('urothelial carcinoma', 'Disease', (39, 59))	('CSS', 'Gene', (214, 217))	('SCC', 'Gene', (139, 142))	('SqD', 'Var', (186, 189))	('worse', 'NegReg', (118, 123))	('CSS', 'Gene', (167, 170))	('disease specific survival', 'CPA', (73, 98))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (39, 59))
80405	32396860	Specific findings included an increased FBXW7 mutations in patients of African origin, decreased VHL and PBRM1 mutations in renal cancer patients of African origin, and decreased immune activity in bladder cancer patients of East Asian origin.	('VHL', 'Gene', '7428', (97, 100))	('PBRM1', 'Gene', '55193', (105, 110))	('renal cancer', 'Disease', (124, 136))	('renal cancer', 'Phenotype', 'HP:0009726', (124, 136))	('patients', 'Species', '9606', (213, 221))	('decreased', 'NegReg', (169, 178))	('increased', 'PosReg', (30, 39))	('mutations', 'Var', (111, 120))	('PBRM1', 'Gene', (105, 110))	('bladder cancer', 'Disease', 'MESH:D001749', (198, 212))	('mutations', 'Var', (46, 55))	('decreased', 'NegReg', (87, 96))	('FBXW7', 'Gene', (40, 45))	('bladder cancer', 'Disease', (198, 212))	('renal cancer', 'Disease', 'MESH:D007680', (124, 136))	('patients', 'Species', '9606', (59, 67))	('immune', 'MPA', (179, 185))	('bladder cancer', 'Phenotype', 'HP:0009725', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('patients', 'Species', '9606', (137, 145))	('FBXW7', 'Gene', '55294', (40, 45))	('VHL', 'Gene', (97, 100))	('decreased immune activity', 'Phenotype', 'HP:0002721', (169, 194))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
80411	32396860	The Cancer Genome Atlas (TCGA) is the largest and most comprehensive multi-omics oncology cohort, rendering possible the simultaneous assessment of ancestry associations in mRNA and miRNA expression and DNA methylation and mutation across 33 cancer types.	('associations', 'Reg', (157, 169))	('DNA', 'cellular_component', 'GO:0005574', ('203', '206'))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('oncology', 'Phenotype', 'HP:0002664', (81, 89))	('DNA methylation', 'biological_process', 'GO:0006306', ('203', '218'))	('mutation', 'Var', (223, 231))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
80427	32396860	Two of these in the AFR-EUR comparison have been described: enriched mutations of TP53 in AFR samples and of PIK3CA in EUR samples.	('mutations', 'Var', (69, 78))	('TP53', 'Gene', (82, 86))	('PIK3CA', 'Gene', (109, 115))	('AFR', 'molecular_function', 'GO:0016656', ('90', '93'))	('PIK3CA', 'Gene', '5290', (109, 115))	('AFR', 'molecular_function', 'GO:0033712', ('20', '23'))	('AFR', 'molecular_function', 'GO:0033712', ('90', '93'))	('TP53', 'Gene', '7157', (82, 86))	('AFR', 'molecular_function', 'GO:0016656', ('20', '23'))
80428	32396860	We also observed enriched CCND1 amplification in EAS samples and FBXW7 mutation in AFR samples.	('AFR', 'molecular_function', 'GO:0033712', ('83', '86'))	('amplification', 'MPA', (32, 45))	('CCND1', 'Gene', '595', (26, 31))	('FBXW7', 'Gene', '55294', (65, 70))	('mutation', 'Var', (71, 79))	('CCND1', 'Gene', (26, 31))	('FBXW7', 'Gene', (65, 70))	('AFR', 'molecular_function', 'GO:0016656', ('83', '86'))	('EAS', 'Disease', (49, 52))	('EAS', 'Chemical', 'MESH:D004976', (49, 52))
80431	32396860	Three additional datasets supported the association between FBXW7 mutations and AFR ancestry.	('mutations', 'Var', (66, 75))	('FBXW7', 'Gene', (60, 65))	('AFR', 'molecular_function', 'GO:0016656', ('80', '83'))	('AFR ancestry', 'Disease', (80, 92))	('AFR', 'molecular_function', 'GO:0033712', ('80', '83'))	('FBXW7', 'Gene', '55294', (60, 65))
80432	32396860	First, international Cancer Genome Consortium Pan-Cancer Analysis of Whole Genomes (ICGC PCAWG) data (excluding TCGA samples) and MSK-IMPACT data, which primarily included EUR samples (PCAWG also included many EAS samples) exhibited few FBXW7 mutations (20/1225=1.6% in PCAWG and 360/10336=3.5% in MSK-IMPACT) relative to the 6.7% mutation rate we had observed in AFR samples.	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Disease', (50, 56))	('Pan-Cancer', 'Disease', (46, 56))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('AFR', 'molecular_function', 'GO:0016656', ('364', '367'))	('FBXW7', 'Gene', '55294', (237, 242))	('Cancer', 'Disease', (21, 27))	('Pan-Cancer', 'Disease', 'MESH:D009369', (46, 56))	('AFR', 'molecular_function', 'GO:0033712', ('364', '367'))	('Cancer', 'Disease', 'MESH:D009369', (21, 27))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('FBXW7', 'Gene', (237, 242))	('360/10336=3.5', 'Var', (280, 293))	('EAS', 'Chemical', 'MESH:D004976', (210, 213))
80434	32396860	However, an independent Foundation Medicine (FMI) cohort of 60,454 tumors from 12 cancer types (Table S2) also exhibited more frequent FBXW7 mutations in AFR relative to EUR samples (Fisher's exact p=0.01), and specifically in HNSC (16/134 AFR and 117/2268 EUR samples, p=0.007) and UCEC (116/730 AFR and 520/4333 EUR samples, p=0.005).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('AFR', 'molecular_function', 'GO:0016656', ('297', '300'))	('mutations', 'Var', (141, 150))	('AFR', 'molecular_function', 'GO:0016656', ('240', '243'))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('AFR', 'molecular_function', 'GO:0033712', ('154', '157'))	('AFR', 'molecular_function', 'GO:0033712', ('240', '243'))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('FBXW7', 'Gene', '55294', (135, 140))	('AFR', 'molecular_function', 'GO:0033712', ('297', '300'))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('AFR', 'molecular_function', 'GO:0016656', ('154', '157'))	('tumors', 'Disease', (67, 73))	('FBXW7', 'Gene', (135, 140))
80435	32396860	Within cancer types, we observed four genes with differential mutation rates, with two in a single cancer type: kidney clear-cell carcinomas (KIRC), in which AFR samples lacked VHL and PBRM1 mutations (OR 0.37 and 0.25, respectively; FDR q=0.06 and 0.04).	('AFR', 'molecular_function', 'GO:0033712', ('158', '161'))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('VHL', 'Gene', (177, 180))	('PBRM1', 'Gene', (185, 190))	('kidney clear-cell carcinomas', 'Disease', (112, 140))	('VHL', 'Gene', '7428', (177, 180))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('mutations', 'Var', (191, 200))	('cancer', 'Disease', (99, 105))	('PBRM1', 'Gene', '55193', (185, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('AFR', 'molecular_function', 'GO:0016656', ('158', '161'))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('lacked', 'NegReg', (170, 176))	('kidney clear-cell carcinomas', 'Disease', 'MESH:C538614', (112, 140))
80436	32396860	EAS bladder and esophageal cancers were enriched in HRAS (OR=6.6; q=0.03), and NFE2L2 (OR=11.6, q=0.07) mutations, respectively (Figure 2B, Table S2).	('EAS bladder and esophageal cancers', 'Disease', 'MESH:D001749', (0, 34))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutations', 'Var', (104, 113))	('HRAS', 'Gene', '3265', (52, 56))	('HRAS', 'Gene', (52, 56))	('NFE2L2', 'Gene', '4780', (79, 85))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('NFE2L2', 'Gene', (79, 85))
80437	32396860	The finding that only pan-cancer analyses identified differential mutation rates in FBXW7 indicates that these differences spanned more than one cancer type.	('cancer', 'Disease', (145, 151))	('FBXW7', 'Gene', (84, 89))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('FBXW7', 'Gene', '55294', (84, 89))	('mutation', 'Var', (66, 74))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
80439	32396860	We validated the associations between VHL, PBRM1, HRAS and NFE2L2 mutations and ancestry in external cohorts.	('mutations', 'Var', (66, 75))	('PBRM1', 'Gene', (43, 48))	('PBRM1', 'Gene', '55193', (43, 48))	('NFE2L2', 'Gene', '4780', (59, 65))	('HRAS', 'Gene', '3265', (50, 54))	('HRAS', 'Gene', (50, 54))	('NFE2L2', 'Gene', (59, 65))	('VHL', 'Gene', (38, 41))	('VHL', 'Gene', '7428', (38, 41))
80440	32396860	We observed fewer VHL and PBRM1 mutations among AFR KIRC samples in the FMI cohort (OR=0.20 and 0.44 respectively; p<0.01 in each case; Table S2).	('VHL', 'Gene', '7428', (18, 21))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('AFR', 'molecular_function', 'GO:0016656', ('48', '51'))	('fewer', 'NegReg', (12, 17))	('mutations', 'Var', (32, 41))	('VHL', 'Gene', (18, 21))	('AFR', 'molecular_function', 'GO:0033712', ('48', '51'))
80441	32396860	An independent study also found significantly more VHL mutations in EUR (101/125) than AFR KIRC samples (4/10; p=0.008).	('VHL', 'Gene', '7428', (51, 54))	('AFR', 'molecular_function', 'GO:0016656', ('87', '90'))	('mutations', 'Var', (55, 64))	('AFR', 'molecular_function', 'GO:0033712', ('87', '90'))	('VHL', 'Gene', (51, 54))
80442	32396860	In this cohort, fewer PBRM1 mutations were also detected in AFR (4/10) than EUR (62/125) samples, but the association was not significant, possibly due to the small number of AFR samples.	('PBRM1', 'Gene', '55193', (22, 27))	('AFR', 'molecular_function', 'GO:0033712', ('60', '63'))	('AFR', 'molecular_function', 'GO:0033712', ('175', '178'))	('fewer', 'NegReg', (16, 21))	('AFR', 'molecular_function', 'GO:0016656', ('60', '63'))	('AFR', 'molecular_function', 'GO:0016656', ('175', '178'))	('mutations', 'Var', (28, 37))	('AFR', 'Disease', (60, 63))	('PBRM1', 'Gene', (22, 27))
80443	32396860	We observed enrichment of HRAS mutations in EAS (5/89) relative to EUR (64/2482) bladder cancers in the FMI cohort and in two additional datasets ( and), where 22/448 EUR and 7/69 EAS samples carried those mutations.	('mutations', 'Var', (31, 40))	('EAS', 'Chemical', 'MESH:D004976', (180, 183))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('bladder cancer', 'Phenotype', 'HP:0009725', (81, 95))	('bladder cancers', 'Disease', (81, 96))	('EAS', 'Chemical', 'MESH:D004976', (44, 47))	('EAS', 'Disease', (44, 47))	('HRAS', 'Gene', '3265', (26, 30))	('bladder cancers', 'Phenotype', 'HP:0009725', (81, 96))	('carried', 'Reg', (192, 199))	('bladder cancers', 'Disease', 'MESH:D001749', (81, 96))	('HRAS', 'Gene', (26, 30))
80444	32396860	For NFE2L2 in ESCA, a study from East Asia reported 7/94 samples with mutations-a similar rate to the 5/117 EUR samples with the mutation in TCGA.	('NFE2L2', 'Gene', '4780', (4, 10))	('TCGA', 'Gene', (141, 145))	('NFE2L2', 'Gene', (4, 10))	('mutations-a', 'Var', (70, 81))
80445	32396860	Although prior studies suggested that NFE2L2 mutations are enriched in EAS esophageal squamous cell carcinoma, we conclude that we could not validate NFE2L2.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('mutations', 'Var', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('NFE2L2', 'Gene', (150, 156))	('NFE2L2', 'Gene', '4780', (38, 44))	('NFE2L2', 'Gene', (38, 44))	('EAS esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 109))	('enriched', 'Reg', (59, 67))	('NFE2L2', 'Gene', '4780', (150, 156))	('EAS esophageal squamous cell carcinoma', 'Disease', (71, 109))
80446	32396860	We also validated the VHL and PBRM associations in KIRC patients with admixed AFR and EUR ancestry.	('patients', 'Species', '9606', (56, 64))	('VHL', 'Gene', (22, 25))	('associations', 'Var', (35, 47))	('VHL', 'Gene', '7428', (22, 25))	('AFR', 'molecular_function', 'GO:0033712', ('78', '81'))	('PBRM', 'Gene', (30, 34))	('AFR', 'molecular_function', 'GO:0016656', ('78', '81'))
80458	32396860	First, 3p loss, encompassing both VHL and PBRM1, was more frequent in EUR than AFR KIRC samples (q=0.02; Figure 2E).	('PBRM1', 'Gene', (42, 47))	('AFR', 'molecular_function', 'GO:0033712', ('79', '82'))	('VHL', 'Gene', (34, 37))	('PBRM1', 'Gene', '55193', (42, 47))	('VHL', 'Gene', '7428', (34, 37))	('3p loss', 'Var', (7, 14))	('AFR', 'molecular_function', 'GO:0016656', ('79', '82'))
80459	32396860	This, along with our prior finding that VHL and PBRM1 mutations are enriched in EUR KIRC samples, indicates that these genes are biallelically inactivated more often in EUR KIRC samples.	('VHL', 'Gene', (40, 43))	('mutations', 'Var', (54, 63))	('PBRM1', 'Gene', (48, 53))	('VHL', 'Gene', '7428', (40, 43))	('PBRM1', 'Gene', '55193', (48, 53))
80460	32396860	Prior work noted the disparity in VHL mutations, but not loss of chromosome 3p, between TCGA AFR and EUR KIRC samples.	('AFR', 'molecular_function', 'GO:0016656', ('93', '96'))	('VHL', 'Gene', '7428', (34, 37))	('AFR', 'molecular_function', 'GO:0033712', ('93', '96'))	('VHL', 'Gene', (34, 37))	('mutations', 'Var', (38, 47))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))
80468	32396860	Across the six cancer types we analyzed, an average of 3,116 sites exhibited ancestry-associations (range 474-12,176), eight times the number in the pan-cancer analysis.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('ancestry-associations', 'Var', (77, 98))
80469	32396860	However, when we performed the same analysis on the 65 "rs" probes on the array that interrogate SNP variants and would therefore often differ between ancestries, we detected significant differences for 63 probes in the pan-cancer analysis, and only 43 probes on average in cancer-specific analyses, consistent with the greater power in pan-cancer analyses (Figure S3F).	('differences', 'Reg', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', (274, 280))	('variants', 'Var', (101, 109))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('cancer', 'Disease', (341, 347))	('cancer', 'Disease', (224, 230))
80471	32396860	For instance, when we did not distinguish BLCA luminal and basal subtypes, we detected considerably more ancestry-differential sites (36,926 rather than 16,716), highlighting the need to account for cancer subtype.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('sites', 'Var', (127, 132))	('BLCA', 'Phenotype', 'HP:0009725', (42, 46))	('cancer', 'Disease', (199, 205))
80472	32396860	Among the 374 pan-cancer ancestry-differential CpG sites, 204 exhibited multimodal distributions in methylation signal (p<0.05, Hartigan's unimodality test; four exemplary cases are shown in Figure S3H), likely representing biallelic lack of methylation, monoallelic methylation, and biallelic methylation.	('methylation', 'biological_process', 'GO:0032259', ('242', '253'))	('lack', 'NegReg', (234, 238))	('methylation', 'biological_process', 'GO:0032259', ('100', '111'))	('exhibited', 'Reg', (62, 71))	('methylation signal', 'MPA', (100, 118))	('methylation', 'biological_process', 'GO:0032259', ('294', '305'))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('methylation', 'biological_process', 'GO:0032259', ('267', '278'))	('monoallelic methylation', 'Var', (255, 278))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('methylation', 'Var', (242, 253))
80474	32396860	For example, all four FAAP20 sites were more frequently methylated in AFR samples while all four HOOK2 sites were less frequently methylated in those samples.	('more', 'PosReg', (40, 44))	('FAAP20', 'Gene', (22, 28))	('HOOK2', 'Gene', (97, 102))	('AFR', 'molecular_function', 'GO:0016656', ('70', '73'))	('methylated', 'Var', (56, 66))	('FAAP20', 'Gene', '199990', (22, 28))	('AFR', 'Disease', (70, 73))	('HOOK2', 'Gene', '29911', (97, 102))	('AFR', 'molecular_function', 'GO:0033712', ('70', '73'))
80480	32396860	These findings indicate that many ancestry-associated methylation differences reflect regional chromatin states, and that ancestry-associated methylation effects in cancers often reflect similar patterns in normal tissue.	('chromatin', 'cellular_component', 'GO:0000785', ('95', '104'))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('differences', 'Var', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('methylation', 'biological_process', 'GO:0032259', ('142', '153'))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('methylation', 'MPA', (54, 65))	('cancers', 'Disease', (165, 172))	('reflect', 'Reg', (78, 85))
80488	32396860	For example, four AFR-associated genes (CRYBB2, NOTCH2NL, LOC90784, PPIL3) and eight EAS-associated genes (POM121L10P, TSPAN10, THOC3, XKR9, LOC162632, SIRPB2, MGC23270, DDX11L2, TGOLN2) were significant in at least 33% of the cancer types (Figures 4A-B and 4E-F).	('XKR9', 'Gene', '389668', (135, 139))	('DDX11L2', 'Gene', '84771', (170, 177))	('MGC23270', 'Gene', (160, 168))	('THOC3', 'Gene', '84321', (128, 133))	('SIRPB2', 'Gene', (152, 158))	('EAS', 'Chemical', 'MESH:D004976', (85, 88))	('THOC3', 'Gene', (128, 133))	('AFR', 'molecular_function', 'GO:0016656', ('18', '21'))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('LOC162632', 'Var', (141, 150))	('TGOLN2', 'Gene', (179, 185))	('TSPAN10', 'Gene', '83882', (119, 126))	('POM121L10P', 'Gene', (107, 117))	('POM121L10P', 'Gene', '646074', (107, 117))	('AFR', 'molecular_function', 'GO:0033712', ('18', '21'))	('DDX11L2', 'Gene', (170, 177))	('SIRPB2', 'Gene', '284759', (152, 158))	('cancer', 'Disease', (227, 233))	('TSPAN10', 'Gene', (119, 126))	('PPIL3', 'Gene', (68, 73))	('LOC90784', 'Var', (58, 66))	('CRYBB2', 'Gene', (40, 46))	('NOTCH2NL', 'Gene', '388677', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('XKR9', 'Gene', (135, 139))	('CRYBB2', 'Gene', '1415', (40, 46))	('PPIL3', 'Gene', '53938', (68, 73))	('TGOLN2', 'Gene', '10618', (179, 185))	('NOTCH2NL', 'Gene', (48, 56))
80497	32396860	As a result, when not controlling for subtype, over 2,000 genes appeared to be associated with AFR ancestry in BRCA (Table S4) and 1,427 genes appeared to be associated with EAS ancestry in esophageal cancers.	('AFR', 'molecular_function', 'GO:0033712', ('95', '98'))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('associated', 'Reg', (79, 89))	('associated', 'Reg', (158, 168))	('AFR', 'Var', (95, 98))	('EAS', 'Chemical', 'MESH:D004976', (174, 177))	('AFR', 'molecular_function', 'GO:0016656', ('95', '98'))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('esophageal cancers', 'Disease', (190, 208))	('BRCA', 'Disease', (111, 115))	('esophageal cancers', 'Disease', 'MESH:D004938', (190, 208))
80510	32396860	However, none of the 117 significant miR-ancestry associations that reached our effect size threshold corresponded to an mRNA that was similarly differentially expressed between the same ancestries in the same cancer type.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('miR-ancestry', 'Gene', (37, 49))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('associations', 'Var', (50, 62))	('cancer', 'Disease', (210, 216))
80518	32396860	Much of the ancestry-associated differences in expression linked to cis- or trans-eQTLs can be explained by differences in genotype frequencies underlying these loci (Figures 6C, S7C).	('cis-', 'Var', (68, 72))	('S7C', 'Mutation', 'p.S7C', (179, 182))	('trans-eQTLs', 'Var', (76, 87))	('expression', 'MPA', (47, 57))
80521	32396860	In aggregate, both the 191 loci with pan-cancer ancestry-associated differences in mRNA expression (excluding genes that spanned ancestry blocks and therefore had ambiguous results) and the 176 loci with pan-cancer ancestry-associated differences in methylation were modestly enriched for one ancestry-most often AFR-relative to what would be expected by chance (Wilcoxon p<0.001 in both cases; Figures S7D-E).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (208, 214))	('differences', 'Reg', (68, 79))	('AFR', 'molecular_function', 'GO:0016656', ('313', '316'))	('methylation', 'biological_process', 'GO:0032259', ('250', '261'))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('methylation', 'MPA', (250, 261))	('mRNA expression', 'MPA', (83, 98))	('cancer', 'Disease', (41, 47))	('differences', 'Var', (235, 246))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('AFR', 'molecular_function', 'GO:0033712', ('313', '316'))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
80542	32396860	This ability to control for subtypes, for example, allowed us to focus on FBXW7 mutations as associated with ancestry, where prior analyses had instead identified TP53 and PIK3CA mutations that we found to disappear with subtype controls.	('ancestry', 'Disease', (109, 117))	('mutations', 'Var', (80, 89))	('TP53', 'Gene', '7157', (163, 167))	('PIK3CA', 'Gene', (172, 178))	('associated', 'Reg', (93, 103))	('PIK3CA', 'Gene', '5290', (172, 178))	('TP53', 'Gene', (163, 167))	('FBXW7', 'Gene', '55294', (74, 79))	('FBXW7', 'Gene', (74, 79))
80543	32396860	A particularly robust finding was enrichment of VHL and PBRM1 mutations and chromosome 3p loss, on which these genes reside, in EUR over AFR KIRC samples.	('VHL', 'Gene', '7428', (48, 51))	('loss', 'NegReg', (90, 94))	('AFR', 'molecular_function', 'GO:0033712', ('137', '140'))	('chromosome', 'cellular_component', 'GO:0005694', ('76', '86'))	('PBRM1', 'Gene', (56, 61))	('VHL', 'Gene', (48, 51))	('AFR', 'molecular_function', 'GO:0016656', ('137', '140'))	('chromosome', 'Gene', (76, 86))	('PBRM1', 'Gene', '55193', (56, 61))	('mutations', 'Var', (62, 71))
80545	32396860	Many of the VHL wild-type cases not only differ transcriptomically from VHL mutants, but have very disparate expression profiles themselves.	('VHL', 'Gene', (12, 15))	('VHL', 'Gene', '7428', (72, 75))	('VHL', 'Gene', '7428', (12, 15))	('mutants', 'Var', (76, 83))	('VHL', 'Gene', (72, 75))
80587	32396860	For the pan-cancer analyses, we counted somatic SNVs, indels and focal CNAs for all significantly mutated genes in all cancer types.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('indels', 'Var', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
80600	32396860	From the pan-cancer analysis, cancer subtypes known for global methylation alterations such as TGCT with hypomethylation and IDH mutant with hypermethylation are seen with a higher number of corresponding cancer-type and subtype differential probes, validating our model fitting (Figure S3H).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('methylation', 'MPA', (63, 74))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('hypermethylation', 'Var', (141, 157))	('IDH', 'Gene', (125, 128))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('IDH', 'Gene', '3417', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('TGCT', 'Gene', (95, 99))	('hypomethylation', 'Var', (105, 120))	('mutant', 'Var', (129, 135))
80631	32396860	This large analysis identified ancestry correlates in cancer Ancestry-associated artifacts and confounders were identified Ancestry effects are profoundly tissue-specific Rates of FBXW7, VHL, and PBRM1 mutations and immune activity vary by ancestry	('VHL', 'Gene', (187, 190))	('VHL', 'Gene', '7428', (187, 190))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('FBXW7', 'Gene', '55294', (180, 185))	('PBRM1', 'Gene', (196, 201))	('cancer', 'Disease', (54, 60))	('PBRM1', 'Gene', '55193', (196, 201))	('FBXW7', 'Gene', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (202, 211))
80637	31639157	Whilst other studies of PIAS1 suggest an important biological role in cancer, this study shows that PIAS1 has no influence on reducing the cytotoxic effects of Cisplatin or cell recovery after DNA damage induced by irradiation.	('Cisplatin', 'Chemical', 'MESH:D002945', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('DNA', 'cellular_component', 'GO:0005574', ('193', '196'))	('reducing', 'NegReg', (126, 134))	('cell recovery', 'CPA', (173, 186))	('PIAS1', 'Var', (100, 105))	('cytotoxic', 'CPA', (139, 148))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
80661	31639157	Cells were seeded onto glass coverslips and allowed to attach for 24 h. Depending on the assay, they were grown for 2 d without treatment (for localization studies) or transfected with siRNA against PIAS1 or control siRNA (for siRNA efficiency studies and p21 expression experiments).	('PIAS1', 'Var', (199, 204))	('transfected', 'Reg', (168, 179))	('localization', 'biological_process', 'GO:0051179', ('143', '155'))	('p21', 'Gene', (256, 259))	('p21', 'Gene', '644914', (256, 259))
80668	31639157	4 h before mesurment, one-tenth volume of the 10-fold working stock was added to each well and incubated for 4 h. Fluorescence (560EX nm/590EM nm) and absorbance (570 nm) was measured using a SPARK 10M Microplate reader (TECAN, Mannedorf, Switzerland).	('560EX nm/590EM', 'Var', (128, 142))	('TECAN', 'Chemical', 'None', (221, 226))	('Fluorescence', 'MPA', (114, 126))	('absorbance', 'MPA', (151, 161))
80677	31639157	In contrast to the findings in PCa, knock down or overexpression of PIAS1 did not influence the viability of urothelial cancer cell lines (Fig 3A and 3B).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('urothelial cancer', 'Disease', 'MESH:D014523', (109, 126))	('PCa', 'Disease', (31, 34))	('PCa', 'Disease', 'MESH:D011471', (31, 34))	('PIAS1', 'Gene', (68, 73))	('knock down', 'Var', (36, 46))	('PCa', 'Phenotype', 'HP:0012125', (31, 34))	('urothelial cancer', 'Disease', (109, 126))
80679	31639157	1,2-intrastrand cross-links of purine bases which result in apoptotic cell death.	('result in', 'Reg', (50, 59))	('cross-links', 'Var', (16, 27))	('apoptotic cell death', 'CPA', (60, 80))	('purine', 'Protein', (31, 37))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('60', '80'))	('purine', 'Chemical', 'MESH:D011687', (31, 37))
80680	31639157	To explore if PIAS1 expression influences the effects of Cisplatin on cell viability, RT112 and T24 cell lines with overexpression or siRNA knock down of PIAS1 were treated with Cisplatin.	('Cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('influences', 'Reg', (31, 41))	('overexpression', 'PosReg', (116, 130))	('PIAS1', 'Gene', (154, 159))	('Cisplatin', 'Chemical', 'MESH:D002945', (178, 187))	('knock down', 'Var', (140, 150))
80682	31639157	However, cell viability assays showed no change in the dose response experiments in cisplatin-treated RT112 and T24 cell lines after PIAS1 knock down (Fig 5B) or overexpression (Fig 5C) compared to controls.	('PIAS1', 'Gene', (133, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('overexpression', 'PosReg', (162, 176))	('knock down', 'Var', (139, 149))
80686	31639157	Especially TGF-beta signalling seem to be highly regulated by SUMOylation in UC.	('signalling', 'biological_process', 'GO:0023052', ('20', '30'))	('TGF-beta', 'Gene', '7040', (11, 19))	('TGF-beta', 'Gene', (11, 19))	('UC', 'Disease', 'MESH:D014523', (77, 79))	('SUMOylation', 'biological_process', 'GO:0016925', ('62', '73'))	('SUMOylation', 'Var', (62, 73))
80687	31639157	Tan and collegues revealed that SUMOylation of SnoN by the SUMO E3 ligase inhibits TGF-beta induced epithelial-mesenchymal transition (EMT) and invasion.	('SnoN', 'Gene', (47, 51))	('TGF-beta', 'Gene', (83, 91))	('SUMOylation', 'biological_process', 'GO:0016925', ('32', '43'))	('EMT', 'biological_process', 'GO:0001837', ('135', '138'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('100', '133'))	('SUMOylation', 'Var', (32, 43))	('SnoN', 'Gene', '6498', (47, 51))	('inhibits', 'NegReg', (74, 82))	('TGF-beta', 'Gene', '7040', (83, 91))
80701	31639157	Whilst not completely clarified, data in PCa models show that upregulation of p21 by PIAS1 knock down leads to cell cycle arrest.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (111, 128))	('p21', 'Gene', '644914', (78, 81))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('111', '128'))	('PCa', 'Disease', (41, 44))	('PCa', 'Disease', 'MESH:D011471', (41, 44))	('PIAS1', 'Gene', (85, 90))	('PCa', 'Phenotype', 'HP:0012125', (41, 44))	('cell cycle arrest', 'CPA', (111, 128))	('knock down', 'Var', (91, 101))	('p21', 'Gene', (78, 81))	('upregulation', 'PosReg', (62, 74))
80704	31639157	In contrast to these findings, knock down of PIAS1 in the tested UC cell lines showed no effect on viability or clonogenic potential.	('PIAS1', 'Gene', (45, 50))	('knock down', 'Var', (31, 41))	('clonogenic potential', 'CPA', (112, 132))	('UC', 'Disease', 'MESH:D014523', (65, 67))
80710	31639157	However, knock down and overexpression of PIAS1 did not influence the sensitivity to cisplatin in UC and therefore seems not to be involved in resistance to the drug.	('knock down', 'Var', (9, 19))	('UC', 'Disease', 'MESH:D014523', (98, 100))	('sensitivity', 'MPA', (70, 81))	('PIAS1', 'Gene', (42, 47))	('overexpression', 'PosReg', (24, 38))	('involved', 'Reg', (131, 139))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
80714	31639157	These mutations may alter the normal response to DNA damage as induced here by cisplatin and irradiation and therefore not crosstalk with PIAS1.	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('alter', 'Reg', (20, 25))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('mutations', 'Var', (6, 15))	('response to DNA damage', 'MPA', (37, 59))
80737	29358573	The striking improvement in knowledge of immunology has led to the identification of immune checkpoint molecules (such as CTLA-4 and PD-1), whose blockade enhances antitumor immunity in many types of cancers (Fig.	('PD-1', 'Gene', '5133', (133, 137))	('tumor', 'Disease', (168, 173))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('CTLA-4', 'Gene', '1493', (122, 128))	('CTLA-4', 'Gene', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('blockade', 'Var', (146, 154))	('enhances', 'PosReg', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('PD-1', 'Gene', (133, 137))
80747	29358573	As with other types of cancer, genomic and epigenomic alterations in urothelial cells are the driver forces in UBC pathogenesis.	('UBC', 'Disease', (111, 114))	('pathogenesis', 'biological_process', 'GO:0009405', ('115', '127'))	('UBC', 'Chemical', '-', (111, 114))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('genomic', 'Var', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('epigenomic alterations', 'Var', (43, 65))
80751	29358573	The mean somatic mutation rate is of 7.7 per megabase listed after melanoma and NSCLC, more than 30% of bladder cancer patients have nonsynonymous mutations above 192 mutations as the threshold in melanoma and NSCLC.	('bladder cancer', 'Disease', (104, 118))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (197, 205))	('NSCLC', 'Disease', (210, 215))	('melanoma', 'Disease', (67, 75))	('NSCLC', 'Disease', (80, 85))	('patients', 'Species', '9606', (119, 127))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('NSCLC', 'Disease', 'MESH:D002289', (210, 215))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('nonsynonymous mutations', 'Var', (133, 156))	('bladder cancer', 'Disease', 'MESH:D001749', (104, 118))
80752	29358573	On average, there are 204 segmental alterations in genomic copy number, 302 nonsynonymous gene mutations, and 22 genomic rearrangements in each sample, and the UBC-specific known genes CDKN1A (P21), EGCC2 (XPD), RXRA, ELF3 (E74 like ETS transcription factor 3), KLF5 (transcription factor), FOXQ1 (forkhead box protein Q1), RHOB (Rho-related GTP-binding protein RhoB), PAIP1 (polyadenlate-binding protein-interacting protein 1), and BTG (B-cell translocation gene) are significantly mutated at >3% frequency.	('XPD', 'Gene', (206, 209))	('transcription', 'biological_process', 'GO:0006351', ('268', '281'))	('RhoB', 'Gene', '388', (362, 366))	('RhoB', 'Gene', (362, 366))	('forkhead box protein Q1', 'Gene', '94234', (298, 321))	('mutated', 'Var', (483, 490))	('ELF3', 'Gene', (218, 222))	('transcription factor', 'molecular_function', 'GO:0000981', ('237', '257'))	('P21', 'Gene', '1026', (193, 196))	('protein', 'cellular_component', 'GO:0003675', ('354', '361'))	('transcription', 'biological_process', 'GO:0006351', ('237', '250'))	('P21', 'Gene', (193, 196))	('UBC', 'Chemical', '-', (160, 163))	('FOXQ1', 'Gene', (291, 296))	('CDKN1A', 'Gene', (185, 191))	('binding', 'molecular_function', 'GO:0005488', ('389', '396'))	('forkhead box protein Q1', 'Gene', (298, 321))	('CDKN1A', 'Gene', '1026', (185, 191))	('protein', 'cellular_component', 'GO:0003675', ('311', '318'))	('FOXQ1', 'Gene', '94234', (291, 296))	('RXRA', 'Gene', '6256', (212, 216))	('XPD', 'Gene', '2068', (206, 209))	('KLF5', 'Gene', '688', (262, 266))	('GTP-binding', 'molecular_function', 'GO:0005525', ('342', '353'))	('BTG', 'Gene', (433, 436))	('transcription factor', 'molecular_function', 'GO:0000981', ('268', '288'))	('PAIP1', 'Gene', '10605', (369, 374))	('KLF5', 'Gene', (262, 266))	('RXRA', 'Gene', (212, 216))	('PAIP1', 'Gene', (369, 374))	('ELF3', 'Gene', '1999', (218, 222))	('protein', 'cellular_component', 'GO:0003675', ('397', '404'))	('RHOB', 'Gene', '388', (324, 328))	('protein', 'cellular_component', 'GO:0003675', ('417', '424'))	('EGCC2', 'Gene', (199, 204))	('RHOB', 'Gene', (324, 328))
80754	29358573	The Cancer Genome Atlas (TCGA) study of UBC found that genes regulating chromatin remodeling are more frequently mutated in UBC than in other types of cancer.	('UBC', 'Chemical', '-', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('UBC', 'Chemical', '-', (40, 43))	('chromatin', 'cellular_component', 'GO:0000785', ('72', '81'))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (151, 157))	('mutated', 'Var', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('Cancer Genome Atlas', 'Disease', (4, 23))	('UBC', 'Disease', (124, 127))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('72', '92'))
80756	29358573	These genomic alterations not only change the hallmarks of cancer fundamental cellular pathways such as the p53/RB cell cycle pathway, the RTK/PI3K/mTOR proliferative pathway, and the histone modification chromatin regulatory network, which become potential druggable targets for UBC, but they also produce many non-self, or "foreign" proteins, which could be recognized by activated effector T cells and potentiate cancer cells responding to immune checkpoint inhibitors.	('alterations', 'Var', (14, 25))	('mTOR', 'Gene', '2475', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (416, 422))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('UBC', 'Chemical', '-', (280, 283))	('potentiate', 'PosReg', (405, 415))	('PI3K', 'molecular_function', 'GO:0016303', ('143', '147'))	('cancer', 'Disease', 'MESH:D009369', (416, 422))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('produce', 'Reg', (299, 306))	('p53', 'Gene', '7157', (108, 111))	('change', 'Reg', (35, 41))	('histone modification', 'biological_process', 'GO:0016570', ('184', '204'))	('mTOR', 'Gene', (148, 152))	('p53', 'Gene', (108, 111))	('cell cycle', 'biological_process', 'GO:0007049', ('115', '125'))	('chromatin', 'cellular_component', 'GO:0000785', ('205', '214'))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', (416, 422))
80768	29358573	Tumors from BCG failure present few effector cells and more suppressive immune cells, for an example, CD4+ subpopulation and GATA3+ T cells (a master regulator of T helper 2-cell differentiation) are scarce in a tumor; expression of FOXP3+ (forkhead box P3, also known as scurfin) and CD25+ Tregs as well as CD68+ and CD163+ (markers of M2 macrophage) tumor-associated macrophages are high in TME.	('CD68+', 'CPA', (308, 313))	('CD25+ Tregs', 'CPA', (285, 296))	('suppressive immune cells', 'Phenotype', 'HP:0002721', (60, 84))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('BCG', 'Species', '33892', (12, 15))	('CD163+', 'CPA', (318, 324))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (352, 357))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('T helper 2-cell differentiation', 'biological_process', 'GO:0045064', ('163', '194'))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('FOXP3+', 'Var', (233, 239))	('CD4', 'Gene', (102, 105))	('tumor', 'Disease', (212, 217))	('CD4', 'Gene', '920', (102, 105))
80808	29358573	High somatic mutational load is associated with long-term clinical benefit of CTLA-4 blockage treatment in advanced melanoma, and somatic neoepitope load correlates with responsiveness to CTLA-4 blockade.	('CTLA-4', 'Gene', '1493', (78, 84))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('CTLA-4', 'Gene', '1493', (188, 194))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('CTLA-4', 'Gene', (78, 84))	('CTLA-4', 'Gene', (188, 194))	('blockage', 'Var', (85, 93))
80810	29358573	The median mutation load was significantly increased in atezolizumab-responders (12.4 mutations/Mb/patient) compared to non-responders (6.4 mutations/Mb/patient).	('patient', 'Species', '9606', (99, 106))	('atezolizumab', 'Chemical', 'MESH:C000594389', (56, 68))	('increased', 'PosReg', (43, 52))	('patient', 'Species', '9606', (153, 160))	('mutation', 'Var', (11, 19))
80813	29358573	Whether mutational burden in bladder cancer could be used as an independent predictive parameter for checkpoint inhibitor therapy remains to be validated with large cohort.	('bladder cancer', 'Disease', 'MESH:D001749', (29, 43))	('bladder cancer', 'Disease', (29, 43))	('mutational', 'Var', (8, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
80814	29358573	Mutational epitopes were positively related to CTL infiltration and amount of memory T cells within a tumor.	('related', 'Reg', (36, 43))	('Mutational', 'Var', (0, 10))	('memory T cells', 'Disease', (78, 92))	('memory', 'biological_process', 'GO:0007613', ('78', '84'))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('CTL infiltration', 'CPA', (47, 63))	('memory T cells', 'Disease', 'MESH:D008569', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
80830	29358573	Moreover, important somatic gene mutations in DNA repair, in homologous recombination (BRCA1 mutation), and in replication processes have been identified by their correlation with the responsiveness to anti-PD-1.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('DNA repair', 'biological_process', 'GO:0006281', ('46', '56'))	('BRCA1', 'Gene', '672', (87, 92))	('mutations', 'Var', (33, 42))	('homologous recombination', 'biological_process', 'GO:0035825', ('61', '85'))	('BRCA1', 'Gene', (87, 92))	('PD-1', 'Gene', (207, 211))	('PD-1', 'Gene', '5133', (207, 211))	('mutation', 'Var', (93, 101))
80834	29358573	Modulating inhibitory pathways on immune cells has been a recent major breakthrough in cancer treatment.	('Modulating', 'Var', (0, 10))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('inhibitory pathways', 'Pathway', (11, 30))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
80841	29358573	On the other hand, cancer cells can escape immune surveillance and, under selective pressure, HLA gene mutations, particularly at TCR-binding domains, and other mutations in antigen-presentation-machinery genes have been detected at high level in tumors that are rich in tumor-infiltrating lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Disease', (247, 253))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (103, 112))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Disease', (247, 252))	('HLA gene', 'Gene', (94, 102))	('tumor', 'Disease', (271, 276))	('TCR', 'cellular_component', 'GO:0042101', ('130', '133'))	('antigen-presentation', 'biological_process', 'GO:0019882', ('174', '194'))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('TCR', 'biological_process', 'GO:0006283', ('130', '133'))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('detected', 'Reg', (221, 229))	('TCR-binding', 'molecular_function', 'GO:0042608', ('130', '141'))
80847	24953177	Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis.	('PIM', 'Gene', (30, 33))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('patient', 'Species', '9606', (52, 59))	('Overexpression', 'Var', (0, 14))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('PIM', 'Gene', '5292', (30, 33))	('tumors', 'Disease', (60, 66))
80852	24953177	TP-3654 displays favorable human ether-a-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability.	('cytochrome P450', 'Enzyme', (64, 79))	('cytochrome P450', 'molecular_function', 'GO:0019825', ('64', '79'))	('human', 'Species', '9606', (27, 32))	('TP-', 'Chemical', 'MESH:C011314', (0, 3))	('PIM', 'Gene', '5292', (135, 138))	('SGI', 'Gene', '6406', (150, 153))	('human ether-a-go-go-related gene', 'Enzyme', (27, 59))	('TP-3654', 'Var', (0, 7))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('64', '79'))	('PIM', 'Gene', (135, 138))	('SGI', 'Gene', (150, 153))
80862	24953177	Overexpression of PIM kinases is often associated with poor prognosis in each of these cancers.	('cancers', 'Disease', (87, 94))	('PIM', 'Gene', '5292', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('PIM', 'Gene', (18, 21))	('Overexpression', 'Var', (0, 14))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
80867	24953177	Inhibition of PIM kinases has also been shown to decrease eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) and cyclin D1 protein levels, suggesting a role for PIM kinases in translation and cell cycle regulation.	('4EBP1', 'Gene', '1978', (121, 126))	('4E binding protein 1', 'Gene', '1978', (99, 119))	('cyclin D1', 'Gene', '595', (132, 141))	('cyclin', 'molecular_function', 'GO:0016538', ('132', '138'))	('PIM', 'Gene', '5292', (14, 17))	('PIM', 'Gene', '5292', (180, 183))	('translation', 'biological_process', 'GO:0006412', ('195', '206'))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('4E binding protein 1', 'Gene', (99, 119))	('4EBP1', 'Gene', (121, 126))	('binding', 'molecular_function', 'GO:0005488', ('102', '109'))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('211', '232'))	('decrease', 'NegReg', (49, 57))	('translation initiation', 'biological_process', 'GO:0006413', ('69', '91'))	('Inhibition', 'Var', (0, 10))	('eukaryotic translation', 'MPA', (58, 80))	('cyclin D1', 'Gene', (132, 141))	('PIM', 'Gene', (14, 17))	('PIM', 'Gene', (180, 183))
80869	24953177	PIM-1 phosphorylates serine 10 of histone H3 on the nucleosome of c-myc-binding sites, and this colocalization contributes to increased transcriptional activation of c-myc.	('activation', 'PosReg', (152, 162))	('PIM-1', 'Gene', (0, 5))	('serine', 'Var', (21, 27))	('serine', 'Chemical', 'MESH:D012694', (21, 27))	('c-myc', 'Gene', '4609', (166, 171))	('c-myc', 'Gene', '4609', (66, 71))	('nucleosome', 'cellular_component', 'GO:0000786', ('52', '62'))	('c-myc', 'Gene', (166, 171))	('c-myc', 'Gene', (66, 71))	('binding', 'molecular_function', 'GO:0005488', ('72', '79'))	('transcriptional', 'MPA', (136, 151))	('increased', 'PosReg', (126, 135))
80871	24953177	An ex vivo analysis of human prostate tumors showed that coexpression of PIM-1 and c-MYC is associated with higher Gleason scores.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('prostate tumors', 'Disease', (29, 44))	('c-MYC', 'Gene', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('coexpression', 'Var', (57, 69))	('prostate tumors', 'Disease', 'MESH:D011471', (29, 44))	('Gleason', 'MPA', (115, 122))	('c-MYC', 'Gene', '4609', (83, 88))	('human', 'Species', '9606', (23, 28))	('PIM-1', 'Gene', (73, 78))	('higher', 'PosReg', (108, 114))
80876	24953177	Studies have demonstrated that SGI-1776 exhibited potent antitumor activity in preclinical models of fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutant AML.	('FLT3', 'Gene', '2322', (129, 133))	('SGI', 'Gene', (31, 34))	('AML', 'Disease', (176, 179))	('fms', 'molecular_function', 'GO:0005011', ('101', '104'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('fms-like tyrosine kinase 3', 'Gene', '2322', (101, 127))	('FLT3', 'Gene', (129, 133))	('SGI', 'Gene', '6406', (31, 34))	('mutant', 'Var', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('-internal tandem duplication', 'Var', (134, 162))	('fms-like tyrosine kinase 3', 'Gene', (101, 127))	('AML', 'Disease', 'MESH:D015470', (176, 179))	('tumor', 'Disease', (61, 66))
80878	24953177	In contrast, models without the FLT3-internal tandem duplication (ITD) mutation were sensitive to SGI-1776, suggesting that PIM-specific activity may be responsible for the observed antiproliferative effects.	('FLT3', 'Gene', '2322', (32, 36))	('SGI', 'Gene', (98, 101))	('mutation', 'Var', (71, 79))	('FLT3', 'Gene', (32, 36))	('PIM', 'Gene', '5292', (124, 127))	('SGI', 'Gene', '6406', (98, 101))	('PIM', 'Gene', (124, 127))
80887	24953177	On the basis of the structure of this lead compound, we conducted systematic modifications around this scaffold to improve in vitro potency against the PIM kinases, as well as other critical physicochemical properties.	('PIM', 'Gene', (152, 155))	('PIM', 'Gene', '5292', (152, 155))	('modifications', 'Var', (77, 90))	('improve', 'PosReg', (115, 122))
80888	24953177	TP-3654 retains potent pan-PIM inhibition but with minimal to no hERG and cytochrome P450 inhibition as observed with SGI-1776.	('hERG', 'Gene', '2078', (65, 69))	('hERG', 'Gene', (65, 69))	('PIM', 'Gene', '5292', (27, 30))	('SGI', 'Gene', '6406', (118, 121))	('inhibition', 'MPA', (31, 41))	('PIM', 'Gene', (27, 30))	('TP-', 'Chemical', 'MESH:C011314', (0, 3))	('SGI', 'Gene', (118, 121))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('74', '89'))	('TP-3654', 'Var', (0, 7))	('cytochrome P450', 'molecular_function', 'GO:0019825', ('74', '89'))
80901	24953177	CHO cells stably expressing hERG potassium channels from Aviva Biosciences (San Diego, CA) were tested with TP-3654 at six concentrations, three-fold dilution starting at 30 muM with a final DMSO concentration of 0.15%, and compared to vehicle (negative) control and Amitriptyline (WuXi AppTec, Shanghai, China) (positive) controls.	('hERG', 'Gene', (28, 32))	('DMSO', 'Chemical', 'MESH:D004121', (191, 195))	('muM', 'Gene', (174, 177))	('CHO', 'CellLine', 'CVCL:0213', (0, 3))	('Amitriptyline', 'Chemical', 'MESH:D000639', (267, 280))	('TP-', 'Chemical', 'MESH:C011314', (108, 111))	('CHO', 'molecular_function', 'GO:0043848', ('0', '3'))	('TP-3654', 'Var', (108, 115))	('muM', 'Gene', '56925', (174, 177))	('hERG', 'Gene', '2078', (28, 32))
80938	24953177	TP-3654 was tested against a panel of 340 kinases at 1 muM and inhibited 38 kinases by >50% (Appendix A).	('muM', 'Gene', '56925', (55, 58))	('TP-', 'Chemical', 'MESH:C011314', (0, 3))	('muM', 'Gene', (55, 58))	('inhibited', 'NegReg', (63, 72))	('TP-3654', 'Var', (0, 7))
80939	24953177	TP-3654 displays at least 10-fold or greater selectivity for PIM-1 compared to any other kinase tested.	('selectivity', 'MPA', (45, 56))	('PIM-1', 'Gene', (61, 66))	('TP-3654', 'Var', (0, 7))	('TP-', 'Chemical', 'MESH:C011314', (0, 3))
80940	24953177	One notable kinase family inhibited by TP-3654 was PI3K (gamma, delta, and alpha), whereas selectivity against FLT3 was reduced by nearly 100-fold relative to SGI-1776 (Table 1).	('TP-', 'Chemical', 'MESH:C011314', (39, 42))	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('inhibited', 'NegReg', (26, 35))	('FLT3', 'Gene', (111, 115))	('TP-3654', 'Var', (39, 46))	('SGI', 'Gene', (159, 162))	('PI3K (gamma, delta, and alpha', 'Gene', '5294', (51, 80))	('FLT3', 'Gene', '2322', (111, 115))	('SGI', 'Gene', '6406', (159, 162))
80942	24953177	Overexpression of the catalytically inactive mutant PIM-1 (K67M) did not increase phosphorylation of BAD compared to BAD transfection alone (Figure 2A) and was used as a negative control to subtract BAD phosphorylation by cellular kinases other than PIM-1.	('phosphorylation', 'MPA', (82, 97))	('K67M', 'Var', (59, 63))	('PIM-1', 'Gene', (52, 57))	('K67M', 'Mutation', 'p.K67M', (59, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))	('phosphorylation', 'biological_process', 'GO:0016310', ('203', '218'))
80944	24953177	In addition, TP-3654 treatment reduced levels of phospho-BAD in vitro using the bladder cancer cell line UM-UC-3 (Figure 2B).	('bladder cancer', 'Disease', 'MESH:D001749', (80, 94))	('bladder cancer', 'Disease', (80, 94))	('reduced', 'NegReg', (31, 38))	('TP-', 'Chemical', 'MESH:C011314', (13, 16))	('bladder cancer', 'Phenotype', 'HP:0009725', (80, 94))	('TP-3654', 'Var', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('levels of phospho-BAD', 'MPA', (39, 60))
80946	24953177	We found no appreciable difference in levels of phospho-4EBP1 in TP-3654-treated cells (Figure 2B), providing further evidence that PIM inhibition was the primary mechanism for the phospho-BAD decrease observed in TP-3654-treated cells and not activity of the compound inhibiting AKT, another known kinase that can phosphorylate BAD.	('PIM', 'Gene', (132, 135))	('phospho-BAD', 'MPA', (181, 192))	('4EBP1', 'Gene', (56, 61))	('AKT', 'Gene', '207', (280, 283))	('TP-', 'Chemical', 'MESH:C011314', (65, 68))	('inhibition', 'NegReg', (136, 146))	('PIM', 'Gene', '5292', (132, 135))	('AKT', 'Gene', (280, 283))	('TP-3654-treated', 'Var', (214, 229))	('decrease', 'NegReg', (193, 201))	('4EBP1', 'Gene', '1978', (56, 61))	('TP-', 'Chemical', 'MESH:C011314', (214, 217))
80950	24953177	PIM-1 overexpression in 22RV1 cells significantly enhanced subcutaneous tumor growth compared to the parental cell line when grown as mouse xenografts (22RV1 + vehicle vs 22RV1/PIM-1 + vehicle), and the growth was significantly reduced by administration of TP-3654 (22RV1/PIM-1 + vehicle vs 22RV1/PIM-1 + TP-3654) (Figure 2C).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PIM-1', 'Gene', (0, 5))	('TP-', 'Chemical', 'MESH:C011314', (257, 260))	('tumor', 'Disease', (72, 77))	('overexpression', 'Var', (6, 20))	('reduced', 'NegReg', (228, 235))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (59, 77))	('enhanced', 'PosReg', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('TP-', 'Chemical', 'MESH:C011314', (305, 308))	('mouse', 'Species', '10090', (134, 139))
80954	24953177	Translational models with more clinical relevance were explored for PIM dependency using shRNA knockdown.	('knockdown', 'Var', (95, 104))	('shRNA', 'Gene', (89, 94))	('PIM', 'Gene', (68, 71))	('PIM', 'Gene', '5292', (68, 71))
80956	24953177	Furthermore, PIM-1 protein was reduced using PIM-1 shRNA compared to nontarget shRNA, and colony growth in soft agar was markedly reduced with PIM-1 knockdown (Figure 3A), comparable to a previous report in the literature.	('agar', 'Chemical', 'MESH:D000362', (112, 116))	('reduced', 'NegReg', (31, 38))	('knockdown', 'Var', (149, 158))	('PIM-1', 'Gene', (13, 18))	('PIM-1', 'Gene', (143, 148))	('reduced', 'NegReg', (130, 137))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))	('colony growth in soft agar', 'CPA', (90, 116))	('protein', 'Protein', (19, 26))	('PIM-1 shRNA', 'Var', (45, 56))
80957	24953177	Additionally, TP-3654 reduced colony growth of T24 and UM-UC3 cells (Figure 3, B and C, respectively), confirming the PIM-1-dependent growth for both cell lines.	('UM-UC3', 'CellLine', 'CVCL:1783', (55, 61))	('TP-', 'Chemical', 'MESH:C011314', (14, 17))	('reduced', 'NegReg', (22, 29))	('colony growth', 'CPA', (30, 43))	('TP-3654', 'Var', (14, 21))
80960	24953177	Low-grade noninvasive tumors demonstrated the highest percentage of cases expressing PIM-1 (43%) and PIM-3 (52%), whereas invasive high-grade lesions demonstrated the lowest percentage of PIM-1 (12%) and PIM-3 (13%) staining.	('PIM-3', 'Gene', (204, 209))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('invasive tumors', 'Disease', 'MESH:D009369', (13, 28))	('PIM-1', 'Var', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('PIM-3', 'Gene', '415116', (204, 209))	('invasive tumors', 'Disease', (13, 28))	('PIM-3', 'Gene', (101, 106))	('PIM-3', 'Gene', '415116', (101, 106))
80961	24953177	We next tested whether TP-3654 could inhibit the growth of established mouse xenograft tumors using the UM-UC-3 and PC-3 solid tumor cell lines that were tested in vitro.	('tested', 'Reg', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('TP-', 'Chemical', 'MESH:C011314', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('TP-3654', 'Var', (23, 30))	('inhibit', 'NegReg', (37, 44))	('growth', 'CPA', (49, 55))	('PC-3', 'CellLine', 'CVCL:0035', (116, 120))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('solid tumor', 'Disease', (121, 132))	('solid tumor', 'Disease', 'MESH:D009369', (121, 132))	('tumors', 'Disease', (87, 93))	('mouse', 'Species', '10090', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
80963	24953177	Previous studies showed that SGI-1776 exhibited favorable pharmacokinetic properties , so we determined if TP-3654 retained or possibly improved on the pharmacokinetic parameters of SGI-1776.	('TP-3654', 'Var', (107, 114))	('SGI', 'Gene', (182, 185))	('improved', 'PosReg', (136, 144))	('SGI', 'Gene', '6406', (29, 32))	('SGI', 'Gene', '6406', (182, 185))	('TP-', 'Chemical', 'MESH:C011314', (107, 110))	('SGI', 'Gene', (29, 32))
80968	24953177	To date, numerous inhibitors of PIM kinases that exhibit growth suppressive activity in tumor cell line models in vitro and in vivo have been generated.	('PIM', 'Gene', '5292', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('growth suppressive activity', 'CPA', (57, 84))	('PIM', 'Gene', (32, 35))	('tumor', 'Disease', (88, 93))	('inhibitors', 'Var', (18, 28))
80969	24953177	Previous PIM kinase inhibitors demonstrated antitumor activity in xenograft models of FLT3-ITD mutant AML and renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (110, 130))	('tumor', 'Disease', (48, 53))	('PIM', 'Gene', '5292', (9, 12))	('FLT3', 'Gene', (86, 90))	('AML', 'Disease', 'MESH:D015470', (102, 105))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (110, 130))	('AML', 'Disease', (102, 105))	('mutant', 'Var', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('FLT3', 'Gene', '2322', (86, 90))	('renal cell carcinoma', 'Disease', (110, 130))	('PIM', 'Gene', (9, 12))
80976	24953177	Furthermore, it was shown that shRNA knockdown of PIM-1 in bladder carcinoma cell lines reduced the growth of the cells in vitro, indicating a prominent role for PIM-1 in bladder carcinoma.	('bladder carcinoma', 'Disease', (171, 188))	('bladder carcinoma', 'Disease', 'MESH:D001749', (171, 188))	('PIM-1', 'Gene', (50, 55))	('bladder carcinoma', 'Disease', 'MESH:D001749', (59, 76))	('bladder carcinoma', 'Disease', (59, 76))	('knockdown', 'Var', (37, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (171, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('reduced', 'NegReg', (88, 95))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (59, 76))	('growth of the cells in vitro', 'CPA', (100, 128))
80981	24953177	Superficial, noninvasive urothelial carcinomas are frequently characterized by the mutation of growth factor signaling molecules, whereas the high-grade, more aggressive tumors contain significant loss of tumor suppressor genes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('205', '221'))	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (16, 46))	('signaling', 'biological_process', 'GO:0023052', ('109', '118'))	('growth factor signaling molecules', 'Gene', (95, 128))	('Superficial', 'Disease', (0, 11))	('invasive urothelial carcinomas', 'Disease', (16, 46))	('aggressive tumors', 'Disease', (159, 176))	('loss of tumor', 'Disease', 'MESH:D009369', (197, 210))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mutation', 'Var', (83, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('characterized', 'Reg', (62, 75))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('loss of tumor', 'Disease', (197, 210))	('tumor suppressor', 'biological_process', 'GO:0051726', ('205', '221'))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))	('aggressive tumors', 'Disease', 'MESH:D001523', (159, 176))
81028	21716882	Immunohistochemical studies have shown that plasmacytoid urothelial carcinoma cells to be positive for CK-7, CK-20, CK, AE1/AE3, EMA and CD-138, but negative for LCA, S 100, HMB 45, kappa, lambda and CD 79-alpha, as was seen in our case also.	('CD 79-alpha', 'Gene', (200, 211))	('AE1', 'Gene', (120, 123))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (57, 77))	('CD', 'Chemical', 'MESH:D002104', (200, 202))	('AE1', 'Gene', '6521', (120, 123))	('CD 79-alpha', 'Gene', '973', (200, 211))	('urothelial carcinoma', 'Disease', (57, 77))	('AE3', 'Gene', (124, 127))	('CK-20', 'Gene', '54474', (109, 114))	('CK-20', 'Gene', (109, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('CD', 'Chemical', 'MESH:D002104', (137, 139))	('CK-7', 'Gene', '3855', (103, 107))	('CD-138', 'Var', (137, 143))	('AE3', 'Gene', '6508', (124, 127))	('CK-7', 'Gene', (103, 107))
81081	31810243	Eight downregulated lncRNAs:lnc-ACSBG2-1:1; lnc-ANKRD54-1:1; lnc-BOD1-1:7, -1:8, and -1:9; and lnc-MUC22-1:1, -1:7, and -1:8:demonstrated correlation between lower patient survival rate with lower expression of lncRNA, indicating a potential tumor-suppressing role for these lncRNAs.	('lncRNA', 'Protein', (211, 217))	('lnc-ACSBG2-1:1', 'Var', (28, 42))	('lower', 'NegReg', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('patient survival rate', 'CPA', (164, 185))	('patient', 'Species', '9606', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('BOD1', 'Gene', (65, 69))	('BOD1', 'Gene', '91272', (65, 69))	('tumor', 'Disease', (242, 247))	('lower', 'NegReg', (191, 196))	('expression', 'MPA', (197, 207))
81085	31810243	We obtained the external lncRNA panel from Seitz et al., and derived the mRNA expression panel by locating 40 genes most implicated in bladder cancer through a literature search.	('bladder cancer', 'Disease', 'MESH:D001749', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('bladder cancer', 'Disease', (135, 149))	('bladder cancer', 'Phenotype', 'HP:0009725', (135, 149))	('locating', 'Var', (98, 106))
81087	31810243	We discovered that most of the core 20 lncRNAs exhibited correlations with histologic grade, primary therapy outcome success, and cancer status, indicating that survival-associated, dysregulated lncRNAs are associated with cancer cell phenotype and ease of elimination.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', (130, 136))	('core', 'cellular_component', 'GO:0019013', ('31', '35'))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lncRNAs', 'Gene', (195, 202))	('cancer', 'Disease', (223, 229))	('dysregulated', 'Var', (182, 194))
81091	31810243	For upregulated lncRNAs, higher expression of lnc-CGRRF1-3:1; lnc-EIF2AK4-1:1, -1:4, and -1:5; lnc-GCH1-2:1, -2:2, and -2:3; lnc-IYD-2:1; lnc-TMEM206-6:1; and lnc-ULBP3-2:1 were associated with both lack of primary therapy outcome success and higher tumor grade, indicating the potential oncogenic roles of these lncRNAs in MIBC.	('ULBP3', 'Gene', '79465', (163, 168))	('EIF2AK4', 'Gene', (66, 73))	('higher', 'PosReg', (25, 31))	('MIBC', 'Disease', (324, 328))	('EIF2', 'cellular_component', 'GO:0005850', ('66', '70'))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('upregulated', 'PosReg', (4, 15))	('lnc-GCH1-2:1', 'Var', (95, 107))	('EIF2AK4', 'Gene', '440275', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('MIBC', 'Disease', 'MESH:D001749', (324, 328))	('lnc-TMEM206-6:1', 'Var', (138, 153))	('expression', 'MPA', (32, 42))	('ULBP3', 'Gene', (163, 168))	('tumor', 'Disease', (250, 255))	('CGRRF1', 'Gene', (50, 56))	('CGRRF1', 'Gene', '10668', (50, 56))
81096	31810243	For downregulated lncRNAs, lnc-ACSBG2-1:1 and lnc-BOD1-1:7, -1:8, and -1:9 exhibit similar landscapes of pathway enrichment, where their low expression correlates with a high expression of genes in immune- and cancer-associated pathways, as represented by a negative enrichment score (Figure 3).	('expression', 'MPA', (175, 185))	('BOD1', 'Gene', (50, 54))	('downregulated', 'NegReg', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('lnc-ACSBG2-1:1', 'Var', (27, 41))	('expression', 'MPA', (141, 151))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('men', 'Species', '9606', (119, 122))	('men', 'Species', '9606', (273, 276))	('cancer', 'Disease', (210, 216))	('BOD1', 'Gene', '91272', (50, 54))
81098	31810243	Multiple pathways related to fibroblast growth factor receptor (FGFR) signaling, G-protein-coupled receptors, and extracellular communication are implicated with lnc-ACSBG2-1:1, while pathways related to the extracellular matrix, G-protein-coupled receptors, and oncogenic transcription factors are implicated with lnc-BOD1-1:7, -1:8, and -1:9 (Figure 3).	('transcription', 'biological_process', 'GO:0006351', ('273', '286'))	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('extracellular', 'cellular_component', 'GO:0005576', ('114', '127'))	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('implicated', 'Reg', (146, 156))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('29', '53'))	('lnc-ACSBG2-1:1', 'Var', (162, 176))	('BOD1', 'Gene', '91272', (319, 323))	('protein', 'cellular_component', 'GO:0003675', ('232', '239'))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('BOD1', 'Gene', (319, 323))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('208', '228'))
81100	31810243	For lnc-ANKRD54-1:1, which is also downregulated in MIBC, cancer- or immune-associated pathways are not enriched in the same direction.	('MIBC', 'Disease', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('MIBC', 'Disease', 'MESH:D001749', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('downregulated', 'NegReg', (35, 48))	('cancer', 'Disease', (58, 64))	('lnc-ANKRD54-1:1', 'Var', (4, 19))
81103	31810243	On the other hand, for upregulated lncRNAs, lnc-CGRRF1-3:1 and lnc-GCH1-2:1, -2:2, and -2:3 share nearly identical correlations with pathways, and we found that high lncRNA expression for these four lncRNAs leads to increased immune activity, but decreased apoptosis (Figure 4).	('decreased', 'NegReg', (247, 256))	('CGRRF1', 'Gene', (48, 54))	('CGRRF1', 'Gene', '10668', (48, 54))	('apoptosis', 'biological_process', 'GO:0097194', ('257', '266'))	('high', 'Var', (161, 165))	('apoptosis', 'biological_process', 'GO:0006915', ('257', '266'))	('apoptosis', 'CPA', (257, 266))	('lncRNA expression', 'MPA', (166, 183))	('immune activity', 'CPA', (226, 241))	('increased', 'PosReg', (216, 225))
81110	31810243	This exhaustive process aims to identify genomic alterations that are functionally responsible for the range of lncRNA expression values in the patient samples, as opposed to associations with the general potential driving processes of bladder cancer that we performed using GSEA.	('alterations', 'Var', (49, 60))	('bladder cancer', 'Disease', 'MESH:D001749', (236, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('patient', 'Species', '9606', (144, 151))	('bladder cancer', 'Disease', (236, 250))	('lncRNA expression values', 'MPA', (112, 136))	('bladder cancer', 'Phenotype', 'HP:0009725', (236, 250))
81113	31810243	We analyzed the potential for miRNAs significantly dysregulated in MIBC to bind to the key lncRNAs using the LncBase tool in DIANA tools, which outputs an interaction score between a given lncRNA and miRNA pair.	('dysregulated', 'Var', (51, 63))	('interaction', 'Interaction', (155, 166))	('MIBC', 'Disease', (67, 71))	('bind', 'Interaction', (75, 79))	('MIBC', 'Disease', 'MESH:D001749', (67, 71))
81115	31810243	Long non-coding RNAs are known to play important roles in cancer pathogenesis pathways, including promoting cancer initiation and maintaining cancer development, illustrating their great potential as diagnostic biomarkers or therapeutic targets for cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer initiation', 'Disease', (108, 125))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('men', 'Species', '9606', (156, 159))	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Disease', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('promoting', 'PosReg', (98, 107))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('Long non-coding RNAs', 'Var', (0, 20))	('pathogenesis', 'biological_process', 'GO:0009405', ('65', '77'))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancer initiation', 'Disease', 'MESH:D009369', (108, 125))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', (142, 148))
81123	31810243	When performing GSEA for canonical pathways using the C2 gene set, we found that some lncRNAs, including lnc-BOD1-1:7, -1:8, and -1:9, as well as lnc-GCH1-2:1, -2:2, and -2:3 were associated with many immune- and cancer-associated pathways.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('BOD1', 'Gene', (109, 113))	('BOD1', 'Gene', '91272', (109, 113))	('lnc-GCH1-2:1', 'Var', (146, 158))	('associated', 'Reg', (180, 190))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))
81148	31810243	For example, if the signature contained genes upregulated after manipulation of a cancer-related gene, only plots where upregulation of the signature genes correlates with the dysregulation of an lncRNA were retained.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('manipulation', 'Var', (64, 76))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('upregulation', 'PosReg', (120, 132))	('dysregulation', 'MPA', (176, 189))	('upregulated', 'PosReg', (46, 57))
81152	31810243	In this study, we identified a panel of 20 significantly dysregulated lncRNAs that may be the most clinically important for MIBC in a 400-patient database.	('MIBC', 'Disease', (124, 128))	('MIBC', 'Disease', 'MESH:D001749', (124, 128))	('patient', 'Species', '9606', (138, 145))	('dysregulated', 'Var', (57, 69))
81159	31244661	AA-derived DNA adducts are recognized as specific biomarkers of AA exposure, and a mutational signature predominantly characterized by A T transversions has been detected in AA-induced UTUC tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('T transversions', 'Var', (137, 152))	('tumor', 'Disease', (190, 195))
81163	31244661	Aristolochic acids (AAs) are identified as a group of toxins that can cause end-stage renal failure associated with urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (116, 136))	('end-stage renal failure', 'Phenotype', 'HP:0003774', (76, 99))	('renal failure', 'Phenotype', 'HP:0000083', (86, 99))	('AAs', 'Chemical', 'MESH:D034341', (20, 23))	('Aristolochic', 'Var', (0, 12))	('urothelial carcinoma', 'Disease', (116, 136))	('cause', 'Reg', (70, 75))	('Aristolochic acids', 'Chemical', 'MESH:D034341', (0, 18))	('end-stage renal failure', 'Disease', (76, 99))	('end-stage renal failure', 'Disease', 'MESH:D007676', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
81207	31244661	AA-derived DNA adducts and TP53 mutations were also found in the ureteric tissues (Cosyns et al.,; Lord et al.,), which indicated the carcinogenic potential of AAs on the urothelium.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('carcinogenic', 'Disease', 'MESH:D063646', (134, 146))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('carcinogenic', 'Disease', (134, 146))	('mutations', 'Var', (32, 41))	('AAs', 'Chemical', 'MESH:D034341', (160, 163))
81211	31244661	In 2002 and 2012, the World Health Organization International Agency for Research on Cancer (IARC) classified AAs as group I carcinogen according to the available strong evidence that AA-specific DNA adducts and TP53 mutations were found in humans exposed to materials obtained from plant species containing AAs (IARC,).	('AAs', 'Chemical', 'MESH:D034341', (308, 311))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('AAs', 'Chemical', 'MESH:D034341', (110, 113))	('DNA', 'cellular_component', 'GO:0005574', ('196', '199'))	('humans', 'Species', '9606', (241, 247))	('mutations', 'Var', (217, 226))	('TP53', 'Gene', '7157', (212, 216))	('TP53', 'Gene', (212, 216))
81218	31244661	In addition, AA-derived DNA adducts and TP53 mutations are clinically meaningful to explore the involvement of AAs in UTUC (Chen et al.,; Chen et al.,; Aydin et al.,; Yang et al.,; Sun et al.,).	('mutations', 'Var', (45, 54))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('AAs', 'Chemical', 'MESH:D034341', (111, 114))
81227	31244661	Furthermore, aristolochic acid I (AAI)-induced gastrotoxicity characterized by fore-stomach damage presents prior to renal injury (Pu et al.,).	('renal injury', 'Disease', 'MESH:D007674', (117, 129))	('aristolochic acid I', 'Chemical', 'MESH:C000228', (13, 32))	('AAI', 'Chemical', 'MESH:C000228', (34, 37))	('aristolochic', 'Var', (13, 25))	('gastrotoxicity', 'Disease', 'None', (47, 61))	('renal injury', 'Disease', (117, 129))	('gastrotoxicity', 'Disease', (47, 61))
81228	31244661	In addition, AAI could induce apoptotic cell death in the ovaries and testis of mice and cause severe reduction of organ size and weight (Kwak et al.,; Kwak and Lee,).	('apoptotic cell death', 'biological_process', 'GO:0006915', ('30', '50'))	('ovaries', 'Disease', (58, 65))	('apoptotic cell death', 'CPA', (30, 50))	('AAI', 'Chemical', 'MESH:C000228', (13, 16))	('AAI', 'Var', (13, 16))	('reduction', 'NegReg', (102, 111))	('mice', 'Species', '10090', (80, 84))	('ovaries', 'Disease', 'MESH:D010051', (58, 65))
81232	31244661	The TP53 mutations and formation of AA-derived DNA adducts are considered as biomarkers for the assessment of AA exposure (Slade et al.,; Stiborova et al.,).	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('TP53', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('formation', 'biological_process', 'GO:0009058', ('23', '32'))	('TP53', 'Gene', '7157', (4, 8))
81240	31244661	These adducts can lead to A T transversions and elicit renal disease and cancers (Stiborova et al.,; Stiborova et al.,).	('cancers', 'Disease', (73, 80))	('renal disease', 'Phenotype', 'HP:0000112', (55, 68))	('T transversions', 'MPA', (28, 43))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('adducts', 'Var', (6, 13))	('elicit', 'Reg', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('lead to', 'Reg', (18, 25))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('renal disease', 'Disease', (55, 68))	('renal disease', 'Disease', 'MESH:D007674', (55, 68))
81246	31244661	It is assumed that the genes of enzymes existing in variant forms or showing polymorphisms may be one of the factors affecting the individual's susceptibility to AAs (Stiborova et al.,).	('variant', 'Var', (52, 59))	('AAs', 'Disease', (162, 165))	('AAs', 'Chemical', 'MESH:D034341', (162, 165))
81266	31244661	In reductive reactions, NQO1 is more effective in activating of AAI than AAII (Martinek et al.,), and the extent of AAI-DNA adducts is much higher than that of AAII-DNA adducts in most in vitro enzymatic systems (Schmeiser et al.,).	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))	('AAI', 'Chemical', 'MESH:C000228', (160, 163))	('AAI', 'Chemical', 'MESH:C000228', (64, 67))	('AAI', 'Chemical', 'MESH:C000228', (116, 119))	('adducts', 'Var', (124, 131))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('NQO1', 'Gene', (24, 28))	('NQO1', 'molecular_function', 'GO:0003955', ('24', '28'))	('NQO1', 'Gene', '1728', (24, 28))	('AAI', 'Chemical', 'MESH:C000228', (73, 76))	('activating', 'MPA', (50, 60))
81276	31244661	Animal study has suggested that AAs increase the proportion of myeloid CD11bhighF4/80mid and decrease their counterpart.	('myeloid', 'MPA', (63, 70))	('decrease', 'NegReg', (93, 101))	('CD11bhighF4/80mid', 'Var', (71, 88))	('AAs', 'Chemical', 'MESH:D034341', (32, 35))	('counterpart', 'MPA', (108, 119))
81285	31244661	Interestingly, some other studies have described that AAI inhibits Akt and/or ERK1/2 phosphorylation, impedes relevant apoptosis, and causes severe injury resulting in the development of ovarian and testis in mice (Kwak et al.,; Kwak and Lee,; Yu et al.,).	('ERK1', 'molecular_function', 'GO:0004707', ('78', '82'))	('mice', 'Species', '10090', (209, 213))	('AAI', 'Var', (54, 57))	('causes', 'Reg', (134, 140))	('AAI', 'Chemical', 'MESH:C000228', (54, 57))	('ERK1/2', 'Pathway', (78, 84))	('inhibits', 'NegReg', (58, 66))	('impedes', 'NegReg', (102, 109))	('apoptosis', 'biological_process', 'GO:0097194', ('119', '128'))	('apoptosis', 'CPA', (119, 128))	('development', 'CPA', (172, 183))	('Akt', 'Pathway', (67, 70))	('apoptosis', 'biological_process', 'GO:0006915', ('119', '128'))	('ovarian and testis', 'Disease', 'MESH:D013736', (187, 205))	('injury', 'Disease', (148, 154))	('injury', 'Disease', 'MESH:D058186', (148, 154))	('phosphorylation', 'biological_process', 'GO:0016310', ('85', '100'))
81291	31244661	A characteristically mutational signature of A T transversions observed in the tumor tissues also implies the exposure of AAs.	('tumor', 'Disease', (79, 84))	('implies', 'Reg', (98, 105))	('AAs', 'Chemical', 'MESH:D034341', (122, 125))	('T transversions', 'Var', (47, 62))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
81298	31244661	This work was supported by grants from the National Science and Technology Major Project (2015ZX09501004-003-001 and 2018ZX09101002-003), Beijing Science and Technology Projects (Z151100000115012 and Z161100004916025), and China Academy of Chinese Medical Sciences Foundation (ZZ10-025 and ZZ12-001).	('Z151100000115012', 'Disease', (179, 195))	('2015ZX09501004-003-001', 'Disease', (90, 112))	('Z151100000115012', 'Disease', 'None', (179, 195))	('Z161100004916025', 'Var', (200, 216))	('2015ZX09501004-003-001', 'Disease', 'MESH:D015431', (90, 112))
81315	26723185	It should be noted that carboplatin also can potentially cause renal impairment, despite dose reduction based upon area under the curve (AUC).	('cause', 'Reg', (57, 62))	('renal impairment', 'Phenotype', 'HP:0000083', (63, 79))	('carboplatin', 'Chemical', 'MESH:D016190', (24, 35))	('carboplatin', 'Var', (24, 35))	('renal impairment', 'Disease', (63, 79))	('renal impairment', 'Disease', 'MESH:D007674', (63, 79))
81390	26723185	In 2 of 3 patients who initially had clinically node-positive disease, sequencing from GTA to cisplatin-based therapy was associated with down-staging to ypN0.	('GTA', 'Chemical', '-', (87, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('sequencing', 'Var', (71, 81))	('patients', 'Species', '9606', (10, 18))	('down-staging', 'NegReg', (138, 150))
81505	28410909	Elderly patients receiving NAC had similar pathologic complete response, downstaging, and overall survival compared with younger patients, despite more GCarbo usage.	('NAC', 'Var', (27, 30))	('NAC', 'Chemical', '-', (27, 30))	('GCarbo', 'Chemical', '-', (152, 158))	('age', 'Gene', (161, 164))	('patients', 'Species', '9606', (129, 137))	('downstaging', 'CPA', (73, 84))	('NAC', 'cellular_component', 'GO:0005854', ('27', '30'))	('age', 'Gene', '5973', (161, 164))	('patients', 'Species', '9606', (8, 16))
81516	30665945	Finally, these cells seem to rely heavily on PARP1/2 for DNA repair, and treatment with the PARP1/2 inhibitor olaparib leads to synthetic lethality, suggesting that cancer cells with low KMT2C expression are attractive targets for therapies with PARP1/2 inhibitors.	('KMT2C', 'Gene', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('synthetic lethality', 'MPA', (128, 147))	('DNA repair', 'biological_process', 'GO:0006281', ('57', '67'))	('olaparib', 'Chemical', 'MESH:C531550', (110, 118))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('low', 'Var', (183, 186))
81517	30665945	It is well established that epigenetic dysregulation is an integral component of cancer etiology and progression 1.	('epigenetic dysregulation', 'Var', (28, 52))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('component of cancer', 'Disease', 'MESH:D009369', (68, 87))	('component of cancer', 'Disease', (68, 87))
81520	30665945	Although originally identified as oncogenic fusions in leukemia 6, recent genome-wide mutation studies have revealed frequent, presumably loss-of-function, mutations in various members of the MLL family, including MLL2/KMT2B, MLL3/KMT2C, and MLL4/KMT2D in a variety of malignancies, particularly solid tumors 7, 8, 9, 10, 11.	('MLL', 'Gene', '4297', (192, 195))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('MLL', 'Gene', (192, 195))	('leukemia', 'Phenotype', 'HP:0001909', (55, 63))	('loss-of-function', 'NegReg', (138, 154))	('KMT2D', 'Gene', (247, 252))	('MLL3', 'Gene', '58508', (226, 230))	('MLL2', 'Gene', '8085', (214, 218))	('MLL2', 'Gene', (214, 218))	('malignancies', 'Disease', 'MESH:D009369', (269, 281))	('leukemia', 'Disease', 'MESH:D007938', (55, 63))	('leukemia', 'Disease', (55, 63))	('malignancies', 'Disease', (269, 281))	('MLL4', 'Gene', '8085', (242, 246))	('MLL4', 'Gene', (242, 246))	('MLL', 'Gene', (214, 217))	('MLL', 'Gene', '4297', (214, 217))	('mutations', 'Var', (156, 165))	('MLL3', 'Gene', (226, 230))	('KMT2B', 'Gene', '9757', (219, 224))	('solid tumors', 'Disease', (296, 308))	('MLL', 'Gene', '4297', (242, 245))	('KMT2D', 'Gene', '8085', (247, 252))	('MLL', 'Gene', (242, 245))	('MLL', 'Gene', (226, 229))	('MLL', 'Gene', '4297', (226, 229))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('KMT2B', 'Gene', (219, 224))	('solid tumors', 'Disease', 'MESH:D009369', (296, 308))
81527	30665945	Recent genome-wide studies on superficial and muscle-invasive urothelial carcinoma have indicated that epigenetic regulators, including KMT2C, are commonly mutated in both types 11, 20.	('epigenetic regulators', 'MPA', (103, 124))	('muscle-invasive urothelial carcinoma', 'Disease', (46, 82))	('KMT2C', 'Gene', (136, 141))	('mutated', 'Var', (156, 163))	('muscle-invasive urothelial carcinoma', 'Disease', 'MESH:D009217', (46, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
81530	30665945	Mutational data from published studies show that the majority of KMT2C mutations cluster within the plant homeodomain (PHD) fingers 1-3 located in the N-terminus of the protein (Catalogue of Somatic Mutations in Cancer:COSMIC).	('fingers 1-3', 'Phenotype', 'HP:0010706', (124, 135))	('PHD', 'molecular_function', 'GO:0050175', ('119', '122'))	('Cancer', 'Disease', (212, 218))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('Cancer', 'Disease', 'MESH:D009369', (212, 218))	('Cancer', 'Phenotype', 'HP:0002664', (212, 218))	('mutations', 'Var', (71, 80))	('KMT2C', 'Gene', (65, 70))
81534	30665945	We identified mutations primarily within PHD fingers 1-3 (Fig 1A), which showed no statistical preference with respect to grade and stage (mutations were found in 12/43 high grade vs. 4/29 low grade, and 9/32 invasive vs. 7/40 superficial tumors).	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('mutations', 'Var', (139, 148))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('found', 'Reg', (154, 159))	('PHD', 'molecular_function', 'GO:0050175', ('41', '44'))	('PHD fingers 1-3', 'Phenotype', 'HP:0010706', (41, 56))	('fingers 1-3', 'Phenotype', 'HP:0010706', (45, 56))	('high grade', 'CPA', (169, 179))
81535	30665945	Interestingly, a recent study on non-invasive bladder cancer also identified a high frequency (15%) of KMT2C likely loss-of-function mutations in non-invasive bladder cancer 20, indicating that KMT2C inactivation might occur early in carcinogenesis.	('invasive bladder', 'Phenotype', 'HP:0100645', (150, 166))	('loss-of-function', 'NegReg', (116, 132))	('bladder cancer', 'Disease', 'MESH:D001749', (159, 173))	('bladder cancer', 'Disease', (159, 173))	('invasive bladder', 'Phenotype', 'HP:0100645', (37, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (46, 60))	('bladder cancer', 'Disease', (46, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (159, 173))	('carcinogenesis', 'Disease', 'MESH:D063646', (234, 248))	('mutations', 'Var', (133, 142))	('bladder cancer', 'Phenotype', 'HP:0009725', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('carcinogenesis', 'Disease', (234, 248))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('KMT2C', 'Gene', (103, 108))
81536	30665945	In our mutation detection study, both frameshift and missense mutations were identified, the vast majority of which are predicted to be damaging (Fig 1A and Table EV1).	('EV1', 'Gene', (163, 166))	('frameshift', 'Var', (38, 48))	('missense mutations', 'Var', (53, 71))	('EV1', 'Gene', '11322', (163, 166))
81537	30665945	Recently identified missense mutations within the PHD fingers 1-3 have been shown to disrupt the interaction between KMT2C and BAP1 leading to reduced recruitment of KMT2C to gene enhancers 1.	('recruitment', 'MPA', (151, 162))	('BAP1', 'Gene', (127, 131))	('PHD', 'molecular_function', 'GO:0050175', ('50', '53'))	('PHD fingers 1-3', 'Phenotype', 'HP:0010706', (50, 65))	('missense mutations', 'Var', (20, 38))	('fingers 1-3', 'Phenotype', 'HP:0010706', (54, 65))	('interaction', 'Interaction', (97, 108))	('disrupt', 'NegReg', (85, 92))	('BAP1', 'Gene', '8314', (127, 131))	('KMT2C', 'Gene', (117, 122))	('reduced', 'NegReg', (143, 150))
81544	30665945	This is in agreement with the fact that KMT2C truncating mutations account for only 0.6% in these cancer types (2/397, 2/512, 0/41, 3/200, and 2/254 cases, respectively; not shown).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('KMT2C', 'Gene', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('truncating mutations', 'Var', (46, 66))
81545	30665945	Our meta-analysis of publicly available DNA methylation data 7 obtained from the MethHC database 29 indicates that two Illumina methylation detection probes (cg17322443 and cg19258062) located within a CpG island (chr7:152435133-152437025, assembly GRCh38/hg38, ENCODE) spanning the KMT2C proximal promoter are subject to DNA methylation in bladder tumor samples, while remaining methylation-free in normal tissue (Fig EV1A and B), confirming a previously published report 30.	('EV1', 'Gene', (419, 422))	('cg19258062', 'Var', (173, 183))	('EV1', 'Gene', '11322', (419, 422))	('DNA methylation', 'biological_process', 'GO:0006306', ('322', '337'))	('bladder tumor', 'Phenotype', 'HP:0009725', (341, 354))	('DNA', 'cellular_component', 'GO:0005574', ('322', '325'))	('methylation', 'biological_process', 'GO:0032259', ('128', '139'))	('bladder tumor', 'Disease', (341, 354))	('chr7:152435133-152437025', 'STRUCTURAL_ABNORMALITY', 'None', (214, 238))	('bladder tumor', 'Disease', 'MESH:D001749', (341, 354))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('DNA methylation', 'biological_process', 'GO:0006306', ('40', '55'))	('methylation', 'biological_process', 'GO:0032259', ('380', '391'))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('hg38', 'Gene', (256, 260))	('hg38', 'Gene', '8549', (256, 260))	('cg17322443', 'Var', (158, 168))
81546	30665945	More importantly, the same CpG island within the KMT2C proximal promoter is also hypermethylated in tumor samples from COAD, NSCLC, and HNSCC (Fig EV1C).	('KMT2C', 'Gene', (49, 54))	('COAD', 'Disease', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('NSCLC', 'Disease', (125, 130))	('tumor', 'Disease', (100, 105))	('hypermethylated', 'Var', (81, 96))	('COAD', 'Disease', 'MESH:D029424', (119, 123))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('EV1', 'Gene', '11322', (147, 150))	('HNSCC', 'Phenotype', 'HP:0012288', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('EV1', 'Gene', (147, 150))
81547	30665945	Collectively, these data indicate that both mutational inactivation and transcriptional downregulation via promoter methylation of KMT2C might contribute to reduced activity facilitating tumor development in several epithelial cancers.	('activity', 'MPA', (165, 173))	('downregulation', 'NegReg', (88, 102))	('transcriptional', 'MPA', (72, 87))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('promoter', 'MPA', (107, 115))	('mutational inactivation', 'Var', (44, 67))	('epithelial cancers', 'Disease', 'MESH:D000077216', (216, 234))	('epithelial cancers', 'Disease', (216, 234))	('tumor', 'Disease', (187, 192))	('methylation', 'biological_process', 'GO:0032259', ('116', '127'))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('KMT2C', 'Gene', (131, 136))	('reduced', 'NegReg', (157, 164))
81548	30665945	To investigate its role in urothelial carcinoma cells, we used two independent shRNAs (KD1/KD2) to knock down KMT2C levels in human BC cell lines (Fig 2A).	('KMT2C', 'Gene', (110, 115))	('human', 'Species', '9606', (126, 131))	('BC', 'Phenotype', 'HP:0009725', (132, 134))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (27, 47))	('knock down', 'Var', (99, 109))	('urothelial carcinoma', 'Disease', (27, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))
81551	30665945	GO analysis on genes of this group that are also downregulated upon KMT2C silencing (1.5-fold or higher reduction) revealed an enrichment in processes such as focal adhesion and integrin-mediated adhesion as well as ErbB and Wnt signaling pathways (Fig 2F).	('reduction', 'NegReg', (104, 113))	('Wnt', 'Gene', (225, 228))	('Wnt', 'Gene', '80326;7481', (225, 228))	('ErbB', 'Gene', (216, 220))	('focal adhesion', 'CPA', (159, 173))	('integrin-mediated adhesion', 'CPA', (178, 204))	('silencing', 'Var', (74, 83))	('KMT2C', 'Gene', (68, 73))	('ErbB', 'Gene', '1956', (216, 220))	('signaling', 'biological_process', 'GO:0023052', ('229', '238'))	('downregulated', 'NegReg', (49, 62))	('focal adhesion', 'cellular_component', 'GO:0005925', ('159', '173'))
81552	30665945	More specifically, we identified genes that encode proteins which are critical for cell adherence to the epithelial basement membrane: ITGB1, ITGB6, RHOB, a putative tumor suppressor also commonly mutated in BC 7, 20, MMP7; (Fig 2G); the extracellular matrix organization LOXL2, LOXL4 and TIMP4, an epigenetically silenced putative tumor suppressor in bladder carcinoma 33, and epithelial development and differentiation (SMAD6, SOX2, EREG, WNT11, BMP2).	('BC', 'Phenotype', 'HP:0009725', (208, 210))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('LOXL2', 'Gene', (272, 277))	('epithelia', 'Disease', (105, 114))	('mutated', 'Var', (197, 204))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (352, 369))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('bladder carcinoma', 'Disease', 'MESH:D001749', (352, 369))	('ITGB6', 'Gene', '3694', (142, 147))	('SMAD6', 'Gene', '4091', (422, 427))	('ITGB6', 'Gene', (142, 147))	('BMP2', 'Gene', (448, 452))	('ITGB1', 'Gene', (135, 140))	('epithelia', 'Disease', 'None', (378, 387))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('166', '182'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('238', '258'))	('bladder carcinoma', 'Disease', (352, 369))	('SOX2', 'Gene', (429, 433))	('WNT11', 'Gene', (441, 446))	('TIMP4', 'Gene', (289, 294))	('SOX2', 'Gene', '6657', (429, 433))	('TIMP4', 'Gene', '7079', (289, 294))	('MMP7', 'Gene', '4316', (218, 222))	('WNT11', 'Gene', '7481', (441, 446))	('tumor', 'Disease', (166, 171))	('basement membrane', 'cellular_component', 'GO:0005604', ('116', '133'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('166', '182'))	('LOXL2', 'Gene', '4017', (272, 277))	('epithelia', 'Disease', (378, 387))	('LOXL4', 'Gene', (279, 284))	('EREG', 'Gene', '2069', (435, 439))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('332', '348'))	('tumor', 'Disease', (332, 337))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('ITGB1', 'Gene', '3688', (135, 140))	('extracellular matrix organization', 'biological_process', 'GO:0030198', ('238', '271'))	('EREG', 'Gene', (435, 439))	('epithelia', 'Disease', 'None', (105, 114))	('LOXL4', 'Gene', '84171', (279, 284))	('tumor suppressor', 'biological_process', 'GO:0051726', ('332', '348'))	('RHOB', 'Gene', '388', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('RHOB', 'Gene', (149, 153))	('SMAD6', 'Gene', (422, 427))	('carcinoma', 'Phenotype', 'HP:0030731', (360, 369))	('BMP2', 'Gene', '650', (448, 452))	('MMP7', 'molecular_function', 'GO:0004235', ('218', '222'))	('MMP7', 'Gene', (218, 222))
81554	30665945	An analysis of transcription factor binding motifs in KMT2C peaks, located at enhancers that are characterized by significant H3K27ac loss upon KMT2C silencing, identified JUNB, TEAD, RUNX1, and MAFA as the most enriched transcription factors (Fig 2H).	('RUNX1', 'Gene', (184, 189))	('RUNX1', 'Gene', '861', (184, 189))	('KMT2C', 'Gene', (54, 59))	('MAFA', 'Gene', '389692', (195, 199))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('15', '43'))	('transcription', 'biological_process', 'GO:0006351', ('15', '28'))	('H3K27ac', 'Protein', (126, 133))	('silencing', 'Var', (150, 159))	('JUNB', 'Gene', '3726', (172, 176))	('MAFA', 'Gene', (195, 199))	('KMT2C', 'Gene', (144, 149))	('JUNB', 'Gene', (172, 176))	('transcription', 'biological_process', 'GO:0006351', ('221', '234'))	('loss', 'NegReg', (134, 138))
81555	30665945	This finding indicates that besides enhancer regulation, KMT2C is also involved in promoter activation in cancer cells.	('KMT2C', 'Var', (57, 62))	('involved', 'Reg', (71, 79))	('promoter', 'MPA', (83, 91))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('regulation', 'biological_process', 'GO:0065007', ('45', '55'))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
81557	30665945	More specifically, KMT2C silencing was associated with decreased expression of key components of DDR (ATM, ATR) and the HR DNA repair pathway (BRCA1, BRCA2, RAD50, RAD51; Fig 3E).	('silencing', 'Var', (25, 34))	('RAD', 'biological_process', 'GO:1990116', ('157', '160'))	('KMT2C', 'Gene', (19, 24))	('ATR', 'Gene', '545', (107, 110))	('DDR', 'Gene', (97, 100))	('ATM', 'Gene', '472', (102, 105))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('HR DNA repair pathway', 'Pathway', (120, 141))	('expression', 'MPA', (65, 75))	('BRCA2', 'Gene', (150, 155))	('RAD50', 'Gene', (157, 162))	('RAD', 'biological_process', 'GO:1990116', ('164', '167'))	('ATM', 'Gene', (102, 105))	('decreased', 'NegReg', (55, 64))	('ATR', 'Gene', (107, 110))	('RAD50', 'Gene', '10111', (157, 162))	('BRCA2', 'Gene', '675', (150, 155))	('BRCA1', 'Gene', '672', (143, 148))	('RAD51', 'Gene', (164, 169))	('RAD51', 'Gene', '5888', (164, 169))	('BRCA1', 'Gene', (143, 148))	('DNA repair', 'biological_process', 'GO:0006281', ('123', '133'))
81562	30665945	This observation prompted us to knock down KMT2C expression in a wide panel of BC, COAD, HNSCC, and NSCLC cell lines which according to publicly available data showed variable KMT2C expression levels (Fig 4B).	('knock', 'Var', (32, 37))	('NSCLC', 'Disease', (100, 105))	('COAD', 'Disease', (83, 87))	('KMT2C', 'Gene', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('COAD', 'Disease', 'MESH:D029424', (83, 87))	('HNSCC', 'Phenotype', 'HP:0012288', (89, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('BC', 'Phenotype', 'HP:0009725', (79, 81))
81566	30665945	Deficiencies in DNA repair due to germline or somatic mutations is a common event in cancer 39, while reduced expression of DNA repair components due to epigenetic control, primarily DNA methylation, is also observed 40, 41.	('Deficiencies', 'Var', (0, 12))	('DNA', 'cellular_component', 'GO:0005574', ('183', '186'))	('DNA repair', 'biological_process', 'GO:0006281', ('124', '134'))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('germline', 'Var', (34, 42))	('cancer', 'Disease', (85, 91))	('DNA repair', 'biological_process', 'GO:0006281', ('16', '26'))	('expression', 'MPA', (110, 120))	('DNA methylation', 'biological_process', 'GO:0006306', ('183', '198'))	('reduced', 'NegReg', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('DNA repair', 'MPA', (16, 26))
81568	30665945	Cisplatin is known to cause DSBs which, in cells beyond the G1 phase, are repaired by the HR machinery.	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('Cisplatin', 'Var', (0, 9))	('G1 phase', 'biological_process', 'GO:0051318', ('60', '68'))	('DSBs', 'Disease', (28, 32))	('DSBs', 'Chemical', '-', (28, 32))
81574	30665945	These functional data indicate that loss of KMT2C leads to HR deficiency due to downregulation of multiple HR components, as well as compromisation of DNA replication under genotoxic stress.	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))	('HR deficiency', 'Disease', (59, 72))	('DNA', 'MPA', (151, 154))	('loss', 'Var', (36, 40))	('KMT2C', 'Gene', (44, 49))	('DNA replication', 'biological_process', 'GO:0006260', ('151', '166'))	('HR deficiency', 'Disease', 'MESH:D001919', (59, 72))	('downregulation', 'NegReg', (80, 94))	('compromisation', 'NegReg', (133, 147))
81580	30665945	To this direction, we compared the activity of NHEJ pathway between KMT2C/KD1 and Scr control cells by counting chromosomal fusion events in a dicentric assay.	('NHEJ', 'biological_process', 'GO:0006303', ('47', '51'))	('NHEJ pathway', 'Pathway', (47, 59))	('KMT2C/KD1', 'Var', (68, 77))	('EJ', 'CellLine', 'CVCL:7039', (49, 51))
81581	30665945	Repair of DSBs induced by ionizing radiation (IR) in this assay generated chromosomal fusions with equal frequency between KMT2C/KD1 and Scr control cells (Figs 7B and EV3B), implying that both employ non-HR mechanisms for DNA repair equally.	('KMT2C/KD1', 'Var', (123, 132))	('chromosomal fusions', 'CPA', (74, 93))	('DNA', 'cellular_component', 'GO:0005574', ('223', '226'))	('DSBs', 'Disease', (10, 14))	('DNA repair', 'biological_process', 'GO:0006281', ('223', '233'))	('DSBs', 'Chemical', '-', (10, 14))
81585	30665945	PARP1/2 inhibition in BRCA-deficient cells is known to lead to accumulation of chromosome fragments and radial structures, a phenotype associated with c-NHEJ 52, 58, 59.	('accumulation', 'PosReg', (63, 75))	('c-NHEJ', 'biological_process', 'GO:0097680', ('151', '157'))	('chromosome', 'cellular_component', 'GO:0005694', ('79', '89'))	('chromosome fragments', 'CPA', (79, 99))	('BRCA', 'Gene', '672', (22, 26))	('inhibition', 'Var', (8, 18))	('PARP1/2', 'Gene', (0, 7))	('EJ', 'CellLine', 'CVCL:7039', (155, 157))	('BRCA', 'Gene', (22, 26))
81587	30665945	Comparable results were obtained when the c-NHEJ and alt-EJ pathways were genetically inhibited through shRNA knockdown of ligase IV and ligase III, respectively (Fig EV4A and B).	('ligase', 'Enzyme', (137, 143))	('knockdown', 'Var', (110, 119))	('alt-EJ pathways', 'Pathway', (53, 68))	('ligase', 'Enzyme', (123, 129))	('EJ', 'CellLine', 'CVCL:7039', (46, 48))	('EJ', 'CellLine', 'CVCL:7039', (57, 59))	('c-NHEJ', 'biological_process', 'GO:0097680', ('42', '48'))	('alt', 'molecular_function', 'GO:0004021', ('53', '56'))	('inhibited', 'NegReg', (86, 95))	('c-NHEJ', 'Pathway', (42, 48))
81590	30665945	In fact, recently published results from a Phase II clinical trial indicated that patients with castration-resistant prostate cancer that carry mutations in DNA repair genes, such as BRCA1/2, ATM, Fanconi anemia components, and CHEK2, show positive response to olaparib, indicating a dependence on PARP1/2 for survival upon DNA damage 61.	('response', 'MPA', (249, 257))	('ATM', 'Gene', (192, 195))	('CHEK2', 'Gene', '11200', (228, 233))	('mutations', 'Var', (144, 153))	('BRCA1/2', 'Gene', (183, 190))	('Fanconi anemia', 'Disease', (197, 211))	('olaparib', 'Chemical', 'MESH:C531550', (261, 269))	('positive', 'PosReg', (240, 248))	('anemia', 'Phenotype', 'HP:0001903', (205, 211))	('Fanconi anemia', 'Disease', 'MESH:D005199', (197, 211))	('DNA repair', 'biological_process', 'GO:0006281', ('157', '167'))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('patients', 'Species', '9606', (82, 90))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('BRCA1/2', 'Gene', '672;675', (183, 190))	('ATM', 'Gene', '472', (192, 195))	('prostate cancer', 'Disease', (117, 132))	('DNA', 'cellular_component', 'GO:0005574', ('324', '327'))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (197, 211))	('CHEK2', 'Gene', (228, 233))
81602	30665945	Bladder cancer presents some of the highest reported mutation rates in KMT2C and KMT2D, and to a lesser extent in KMT2B 7, 11, 63.	('KMT2C', 'Var', (71, 76))	('KMT2B', 'Gene', (114, 119))	('Bladder cancer', 'Disease', (0, 14))	('KMT2D', 'Gene', (81, 86))	('KMT2D', 'Gene', '8085', (81, 86))	('Bladder cancer', 'Disease', 'MESH:D001749', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('KMT2B', 'Gene', '9757', (114, 119))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))
81603	30665945	Recent reports, however, indicate that loss of the catalytic activity of KMT2C and KMT2D has a less severe effect on transcription regulation than the respective complete gene knockout 16, 17, implying that these proteins may have additional roles in transcriptional regulation beyond H3K4 monomethylation.	('KMT2D', 'Gene', '8085', (83, 88))	('regulation', 'biological_process', 'GO:0065007', ('131', '141'))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('regulation', 'biological_process', 'GO:0065007', ('267', '277'))	('loss', 'NegReg', (39, 43))	('KMT2C', 'Var', (73, 78))	('KMT2D', 'Gene', (83, 88))	('catalytic activity', 'MPA', (51, 69))	('catalytic activity', 'molecular_function', 'GO:0003824', ('51', '69'))	('transcription regulation', 'MPA', (117, 141))
81605	30665945	Therefore, somatic mutations, even those truncating the protein from its catalytic activity, might not be the only MLL-related genetic events associated with cancer.	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('mutations', 'Var', (19, 28))	('cancer', 'Disease', (158, 164))	('MLL', 'Gene', (115, 118))	('MLL', 'Gene', '4297', (115, 118))	('catalytic activity', 'molecular_function', 'GO:0003824', ('73', '91'))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
81607	30665945	We thus speculate that loss-of-function mutations in combination with progressively reduced gene expression due to promoter methylation limit KMT2C activity in cancer cells.	('loss-of-function', 'NegReg', (23, 39))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('methylation', 'biological_process', 'GO:0032259', ('124', '135'))	('cancer', 'Disease', (160, 166))	('gene expression', 'MPA', (92, 107))	('promoter methylation', 'Var', (115, 135))	('activity', 'MPA', (148, 156))	('gene expression', 'biological_process', 'GO:0010467', ('92', '107'))	('reduced', 'NegReg', (84, 91))	('mutations', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
81609	30665945	In support of this model, KMT2C mutations were recently identified as late events in subclones of lung adenocarcinomas during tumor evolution 66 and in metastatic breast cancer subclones 67.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('KMT2C', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('lung adenocarcinomas', 'Disease', (98, 118))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('mutations', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (98, 118))	('breast cancer', 'Disease', (163, 176))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (98, 118))	('tumor', 'Disease', (126, 131))
81612	30665945	Recent studies, however, have shown that alterations in the enhancer epigenetic landscape also correlate with tumorigenesis 71, 72, 73.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('enhancer', 'PosReg', (60, 68))	('alterations', 'Var', (41, 52))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
81615	30665945	This may imply that KMT2C and KMT2D proteins exert coordinated and synergistic functions in enhancer elements and their loss during carcinogenesis deregulates cell adhesion and signaling with profound effects to tumor progression and invasion.	('signaling', 'biological_process', 'GO:0023052', ('177', '186'))	('carcinogenesis', 'Disease', (132, 146))	('KMT2D', 'Gene', '8085', (30, 35))	('cell adhesion', 'biological_process', 'GO:0007155', ('159', '172'))	('invasion', 'CPA', (234, 242))	('cell adhesion', 'CPA', (159, 172))	('effects', 'Reg', (201, 208))	('KMT2D', 'Gene', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('deregulates', 'NegReg', (147, 158))	('carcinogenesis', 'Disease', 'MESH:D063646', (132, 146))	('loss', 'Var', (120, 124))	('tumor', 'Disease', (212, 217))
81617	30665945	Our own meta-analysis of the publicly available TCGA RNA-seq and mutation data failed to substantiate any consistent correlation between TP53 mutation status and KMT2C expression levels or mutation status (Appendix Fig S5A and B).	('expression levels', 'MPA', (168, 185))	('RNA', 'cellular_component', 'GO:0005562', ('53', '56'))	('S5A and B', 'Gene', '5710;5711', (219, 228))	('mutation', 'Var', (142, 150))	('TP53', 'Gene', (137, 141))
81621	30665945	HR deficiency as a result of epigenetic regulation of BRCA1/2 expression levels has also been described (reviewed by Konstantinopoulos et al 76).	('epigenetic', 'Var', (29, 39))	('regulation', 'biological_process', 'GO:0065007', ('40', '50'))	('HR deficiency', 'Disease', (0, 13))	('expression levels', 'MPA', (62, 79))	('BRCA1/2', 'Gene', (54, 61))	('HR deficiency', 'Disease', 'MESH:D001919', (0, 13))	('BRCA1/2', 'Gene', '672;675', (54, 61))
81641	30665945	Scramble, anti-DNA ligase III (TRCN0000048502), and anti-ligase IV (TRCN0000009847) short hairpin RNA-producing DNA sequences (Sigma-Aldrich) were cloned in PLKO.1-blast plasmid (Addgene: #26655).	('TRCN0000048502', 'Var', (31, 45))	('RNA', 'cellular_component', 'GO:0005562', ('98', '101'))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('DNA ligase III', 'Gene', (15, 29))	('DNA ligase III', 'Gene', '3980', (15, 29))	('TRCN0000009847', 'Var', (68, 82))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))
81694	27347176	E-cadherin and N-cadherin double-negative expression was identified in various pathological grades of infiltrative bladder cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('bladder cancers', 'Disease', (115, 130))	('cadherin', 'molecular_function', 'GO:0008014', ('17', '25'))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('bladder cancers', 'Disease', 'MESH:D001749', (115, 130))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('bladder cancers', 'Phenotype', 'HP:0009725', (115, 130))	('N-cadherin', 'Gene', (15, 25))	('E-cadherin', 'Gene', (0, 10))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('double-negative', 'Var', (26, 41))	('N-cadherin', 'Gene', '1000', (15, 25))	('E-cadherin', 'Gene', '999', (0, 10))
81780	27347176	Several studies have revealed that the loss of E-cadherin function may induce EMT and increase tumor invasion and metastasis.	('cadherin', 'molecular_function', 'GO:0008014', ('49', '57'))	('E-cadherin', 'Gene', (47, 57))	('increase tumor', 'Disease', 'MESH:D009369', (86, 100))	('E-cadherin', 'Gene', '999', (47, 57))	('loss', 'Var', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('induce', 'PosReg', (71, 77))	('EMT', 'CPA', (78, 81))	('increase tumor', 'Disease', (86, 100))	('EMT', 'biological_process', 'GO:0001837', ('78', '81'))
81793	27347176	In addition, the present study detected E-cadherin and N-cadherin double-negative expression in low-, mid- and high-level infiltrative bladder urothelial carcinoma using immunofluorescence assays.	('double-negative', 'Var', (66, 81))	('infiltrative bladder urothelial carcinoma', 'Phenotype', 'HP:0006740', (122, 163))	('expression', 'MPA', (82, 92))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (135, 163))	('E-cadherin', 'Gene', (40, 50))	('E-cadherin', 'Gene', '999', (40, 50))	('cadherin', 'molecular_function', 'GO:0008014', ('42', '50'))	('N-cadherin', 'Gene', (55, 65))	('bladder urothelial carcinoma', 'Disease', (135, 163))	('cadherin', 'molecular_function', 'GO:0008014', ('57', '65'))	('N-cadherin', 'Gene', '1000', (55, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))
81794	27347176	These results suggest that E-cadherin and N-cadherin double-negative expression exists in bladder urothelial carcinoma.	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (90, 118))	('bladder urothelial carcinoma', 'Disease', (90, 118))	('N-cadherin', 'Gene', (42, 52))	('double-negative', 'Var', (53, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('N-cadherin', 'Gene', '1000', (42, 52))	('cadherin', 'molecular_function', 'GO:0008014', ('29', '37'))	('E-cadherin', 'Gene', (27, 37))	('E-cadherin', 'Gene', '999', (27, 37))
81802	27347176	The present results suggest that the biological characteristics of bladder cancer cells with E-cadherin and N-cadherin double-negative expression were significantly stronger compared with bladder cancer cells of E-cadherin positive and N-cadherin negative expression.	('N-cadherin', 'Gene', '1000', (236, 246))	('N-cadherin', 'Gene', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('E-cadherin', 'Gene', (212, 222))	('E-cadherin', 'Gene', '999', (212, 222))	('biological characteristics', 'CPA', (37, 63))	('N-cadherin', 'Gene', '1000', (108, 118))	('E-cadherin', 'Gene', (93, 103))	('E-cadherin', 'Gene', '999', (93, 103))	('cadherin', 'molecular_function', 'GO:0008014', ('95', '103'))	('cadherin', 'molecular_function', 'GO:0008014', ('238', '246'))	('stronger', 'PosReg', (165, 173))	('cadherin', 'molecular_function', 'GO:0008014', ('214', '222'))	('bladder cancer', 'Disease', 'MESH:D001749', (188, 202))	('bladder cancer', 'Disease', (188, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('bladder cancer', 'Phenotype', 'HP:0009725', (188, 202))	('double-negative expression', 'Var', (119, 145))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('cadherin', 'molecular_function', 'GO:0008014', ('110', '118'))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('N-cadherin', 'Gene', (236, 246))
81855	27256178	The PSA (1:50, ER-PR8, Dako) was negative in the neoplastic cells, while high molecular weight keratin (1:50, 34BetaE12, Dako) and thrombomodulin (1:25, 141C01, Thermo Scientific) were intensely positive (Figure-2B).	('PSA', 'Gene', '354', (4, 7))	('PSA', 'Gene', (4, 7))	('1:25', 'Var', (147, 151))	('1:50', 'Var', (104, 108))	('thrombomodulin', 'Gene', (131, 145))	('thrombomodulin', 'Gene', '7056', (131, 145))	('BetaE12', 'CellLine', 'CVCL:R799', (112, 119))
81872	27256178	Other antibodies useful in the interpretation of urothelial carcinoma include CK7+, CK20+, PSA-, PAP-, and CD57-.	('PAP', 'molecular_function', 'GO:0043751', ('97', '100'))	('CD57', 'Gene', (107, 111))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (49, 69))	('CK7+', 'Var', (78, 82))	('CK20', 'Gene', (84, 88))	('CK20', 'Gene', '54474', (84, 88))	('PSA', 'Gene', '354', (91, 94))	('PAP-', 'Disease', (97, 101))	('PSA', 'Gene', (91, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('urothelial carcinoma', 'Disease', (49, 69))	('CD57', 'Gene', '27087', (107, 111))
81874	27256178	Additionally, they consider that high-molecular weight cytokeratin and P63 are more sensitive for the diagnosis of urothelial carcinoma compared with thrombomodulin and S100P.	('S100P', 'SUBSTITUTION', 'None', (169, 174))	('urothelial carcinoma', 'Disease', (115, 135))	('P63', 'Gene', (71, 74))	('S100P', 'Var', (169, 174))	('P63', 'Gene', '8626', (71, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('thrombomodulin', 'Gene', (150, 164))	('high-molecular weight', 'Protein', (33, 54))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (115, 135))	('thrombomodulin', 'Gene', '7056', (150, 164))
81875	27256178	Amin et al., and the members of the ISUP Immunohistochemistry in Diagnostic Urologic Pathology Group have found that on the basis of the differential diagnostic consideration, positivity for GATA3, CK20, p63, and either high-molecular weight cytokeratin or cytokeratin 5/6 are quite useful to support urothelial differentiation in the appropriate clinicopathologic context.	('p63', 'Gene', '8626', (204, 207))	('urothelial differentiation', 'CPA', (301, 327))	('GATA3', 'Gene', (191, 196))	('support', 'Reg', (293, 300))	('positivity', 'Var', (176, 186))	('cytokeratin 5/6', 'Gene', '3852', (257, 272))	('CK20', 'Gene', (198, 202))	('cytokeratin 5/6', 'Gene', (257, 272))	('p63', 'Gene', (204, 207))	('CK20', 'Gene', '54474', (198, 202))	('GATA3', 'Gene', '2625', (191, 196))
81908	23891158	This included absolute neutrophil count >= 1500/mm3, platelets >= 100,000/mm3, white blood cell count >= 3000 cells/mm3, measured creatinine clearance >= 60 mL/min/1.73 m2, total bilirubin equal to or less than normal institutional limits, prothrombin time (PTT)/international normalized ratio/activated PTT <= 1.2 times the upper limit of normal, and aspartate aminotransferase (serum glutamic oxaloacetic transaminase) or alanine aminotransferase (serum glutamic pyruvic transaminase) <= 2.5 times the institutional upper limit of normal.	('creatinine clearance', 'MPA', (130, 150))	('serum glutamic oxaloacetic transaminase', 'Phenotype', 'HP:0031956', (380, 419))	('serum glutamic oxaloacetic transaminase) or alanine aminotransferase', 'Gene', '2875', (380, 448))	('min/1', 'Gene', '966', (160, 165))	('>= 3000', 'Var', (102, 109))	('aspartate', 'MPA', (352, 361))	('min/1', 'Gene', (160, 165))	('>= 1500/mm3', 'Var', (40, 51))
81957	23891158	Three polymorphisms in IL-8 and 5 polymorphisms in HIF-1alpha and VEGF-A showed an association with progression-free survival and response rate, respectively.	('IL-8', 'Gene', '3576', (23, 27))	('progression-free survival', 'CPA', (100, 125))	('HIF-1alpha', 'Gene', (51, 61))	('VEGF-A', 'Gene', '7422', (66, 72))	('IL-8', 'Gene', (23, 27))	('polymorphisms', 'Var', (34, 47))	('polymorphisms', 'Var', (6, 19))	('VEGF-A', 'Gene', (66, 72))	('response rate', 'CPA', (130, 143))	('IL-8', 'molecular_function', 'GO:0005153', ('23', '27'))	('HIF-1alpha', 'Gene', '3091', (51, 61))	('association', 'Reg', (83, 94))
81958	23891158	Germline variants in angiogenesis-related genes, if validated prospectively, may predict the response to anti-angiogenics in patients with cancer, including those with urothelial carcinoma.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('patients', 'Species', '9606', (125, 133))	('angiogenesis', 'biological_process', 'GO:0001525', ('21', '33'))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (168, 188))	('Germline', 'Var', (0, 8))	('angiogenesis-related genes', 'Gene', (21, 47))	('predict', 'Reg', (81, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('response', 'MPA', (93, 101))	('urothelial carcinoma', 'Disease', (168, 188))	('cancer', 'Disease', (139, 145))
81975	33430801	Among them, miR-486-5p, a tumor suppressor miRNA, was negatively correlated with the TNM classification of clinical BC samples in The Cancer Genome Atlas (TCGA) database.	('si', 'Chemical', 'MESH:D012825', (93, 95))	('miR-486-5p', 'Var', (12, 22))	('Cancer', 'Disease', (134, 140))	('TNM', 'Gene', (85, 88))	('Cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('BC', 'Phenotype', 'HP:0009725', (116, 118))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor suppressor', 'biological_process', 'GO:0051726', ('26', '42'))	('negatively', 'NegReg', (54, 64))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('26', '42'))	('miR-486-5p', 'Chemical', '-', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('TNM', 'Gene', '10178', (85, 88))
81976	33430801	Transfection of miRNA-486-5p significantly inhibited cancer cell proliferation, migration, and invasion, and also improved the cells' resistance to cisplatin.	('si', 'Chemical', 'MESH:D012825', (29, 31))	('invasion', 'CPA', (95, 103))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('cancer', 'Disease', (53, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('inhibited', 'NegReg', (43, 52))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('migration', 'CPA', (80, 89))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('improved', 'PosReg', (114, 122))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('resistance to cisplatin', 'MPA', (134, 157))	('miRNA-486-5p', 'Var', (16, 28))	('miRNA-486-5p', 'Chemical', '-', (16, 28))
81978	33430801	EHHADH was directly regulated by miRNA-486-5p as determined by a dual-luciferase reporter assay.	('miRNA-486-5p', 'Chemical', '-', (33, 45))	('miRNA-486-5p', 'Var', (33, 45))	('EHHADH', 'Gene', (0, 6))	('EHHADH', 'Gene', '1962', (0, 6))
81987	33430801	Crosslinks and damage to DNA result, and apoptosis is induced.	('apoptosis', 'biological_process', 'GO:0097194', ('41', '50'))	('apoptosis', 'biological_process', 'GO:0006915', ('41', '50'))	('Crosslinks', 'Var', (0, 10))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('apoptosis', 'CPA', (41, 50))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))
81997	33430801	determined that miRNA-181b was downregulated in cisplatin-resistant lung cancer lines, and that miRNA-181b modulated cisplatin resistance by targeting the anti-apoptotic gene BCL2.	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('lung cancer', 'Disease', (68, 79))	('BCL2', 'Gene', (175, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('BCL2', 'molecular_function', 'GO:0015283', ('175', '179'))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('miRNA-181b', 'Gene', (16, 26))	('si', 'Chemical', 'MESH:D012825', (129, 131))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('miRNA-181b', 'Var', (96, 106))	('cisplatin resistance', 'MPA', (117, 137))	('targeting', 'Reg', (141, 150))	('downregulated', 'NegReg', (31, 44))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('BC', 'Phenotype', 'HP:0009725', (175, 177))	('modulated', 'Reg', (107, 116))	('BCL2', 'Gene', '596', (175, 179))
82030	33430801	HSS105529 and HSS105531) and negative-control si-RNA (D-001810-10) were used in loss-of-function experiments.	('HSS105529', 'Var', (0, 9))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('loss-of-function', 'NegReg', (80, 96))	('HSS105531', 'Var', (14, 23))	('RNA', 'cellular_component', 'GO:0005562', ('49', '52'))
82035	33430801	Candidate target genes were significantly downregulated after transfection with miRNA-486-5p compared with control microRNA (fold-change < - 1.0) in CDDP-R-BOY and CDDP-R-T24.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('CDDP-R-BOY', 'Chemical', '-', (149, 159))	('downregulated', 'NegReg', (42, 55))	('miRNA-486-5p', 'Var', (80, 92))	('miRNA-486-5p', 'Chemical', '-', (80, 92))	('CDDP-R-T24', 'Chemical', '-', (164, 174))
82039	33430801	To identify possible target genes of miRNA-486-5p, we extracted genes that were reduced by transfection of miR486-5p in mRNA sequence analysis with genes that may be targeted by miRNA-486-5p based on TargetScan database Release 7.1 (http://www.targetscan.org).	('miRNA-486-5p', 'Chemical', '-', (37, 49))	('miRNA-486-5p', 'Chemical', '-', (178, 190))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('reduced', 'NegReg', (80, 87))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('miR486-5p', 'Var', (107, 116))
82047	33430801	13412-1-AP; Proteintech Group, Inc., Chicago, IL, USA), anti-cleaved PARP antibodies (1:750, #5625; Cell Signaling Technology), PARP antibodies (1:750, #9532; Cell Signaling Technology) and anti-beta-actin antibodies (1:5000; cat.	('Signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('PARP', 'Gene', '1302', (69, 73))	('PARP', 'Gene', '1302', (128, 132))	('cat', 'molecular_function', 'GO:0004096', ('226', '229'))	('beta-actin', 'Gene', '728378', (195, 205))	('Signaling', 'biological_process', 'GO:0023052', ('164', '173'))	('beta-actin', 'Gene', (195, 205))	('PARP', 'Gene', (69, 73))	('PARP', 'Gene', (128, 132))	('anti-cleaved', 'Var', (56, 68))
82074	33430801	Ultimately, 5 microRNAs (miRNA-486-5p, miRNA-624-3p, miRNA-424-5p, miRNA-545-5p and miR-628-3p) were identified as candidates (Fig.	('miRNA-486-5p', 'Var', (25, 37))	('miRNA-486-5p', 'Chemical', '-', (25, 37))	('miR-628-3p', 'Var', (84, 94))	('miRNA-424', 'Gene', '494336', (53, 62))	('miRNA-545-5p', 'Var', (67, 79))	('miRNA-424', 'Gene', (53, 62))	('miRNA-624-3p', 'Var', (39, 51))
82075	33430801	Among the bladder urothelial carcinoma (BLCA) cohort in TCGA, miRNA-486-5p and miRNA-545-5p showed significant difference between pathological category T1/2 vs T3/4.	('miRNA-545-5p', 'Var', (79, 91))	('bladder urothelial carcinoma', 'Disease', (10, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('miRNA-486-5p', 'Var', (62, 74))	('miRNA-486-5p', 'Chemical', '-', (62, 74))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (10, 38))
82076	33430801	On the other hand, Kaplan-Meier analysis showed that overall survival (OS) exhibited no significant difference between the high expression group and the low expression group in miRNA-486-5p and miRNA-545-5p (Fig.	('miRNA-486-5p', 'Var', (177, 189))	('miRNA-486-5p', 'Chemical', '-', (177, 189))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('si', 'Chemical', 'MESH:D012825', (134, 136))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('miRNA-545-5p', 'Var', (194, 206))
82077	33430801	Because miRNA-545-5p transfection did not suppress cell proliferation in CDDP-R BC cells (data not shown) and there was no correlations between miRNA-545-5p and the target gene (Supplementary Figure 2c), we focused on miRNA-486-5p as a strong candidate tumor suppressor that could overcome cisplatin resistance in this study.	('BC', 'Phenotype', 'HP:0009725', (80, 82))	('miRNA-486-5p', 'Chemical', '-', (218, 230))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('253', '269'))	('cell proliferation', 'biological_process', 'GO:0008283', ('51', '69'))	('si', 'Chemical', 'MESH:D012825', (302, 304))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (253, 258))	('tumor suppressor', 'biological_process', 'GO:0051726', ('253', '269'))	('cisplatin', 'Chemical', 'MESH:D002945', (290, 299))	('CDDP-R', 'Chemical', '-', (73, 79))	('miRNA-486-5p', 'Var', (218, 230))
82078	33430801	First, we used qRT-PCR to confirm that expression of miRNA-486-5p was downregulated in CDDP-R BC cells compared with parental cells (Fig.	('BC', 'Phenotype', 'HP:0009725', (94, 96))	('CDDP-R', 'Chemical', '-', (87, 93))	('downregulated', 'NegReg', (70, 83))	('expression', 'MPA', (39, 49))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('miRNA-486-5p', 'Var', (53, 65))	('miRNA-486-5p', 'Chemical', '-', (53, 65))
82079	33430801	We also performed gain-of-function studies of parental cell lines (BOY and T24) and CDDP-R cell lines (CDDP-R-BOY and CDDP-R-T24) transfected with miRNA-486-5p (Supplementary Figure 3a) to investigate the functional roles of miRNA-486-5p.	('CDDP-R-BOY', 'Chemical', '-', (103, 113))	('CDDP-R', 'Chemical', '-', (84, 90))	('miRNA-486-5p', 'Var', (147, 159))	('miRNA-486-5p', 'Chemical', '-', (147, 159))	('CDDP-R-T24', 'Chemical', '-', (118, 128))	('CDDP-R', 'Chemical', '-', (118, 124))	('CDDP-R', 'Chemical', '-', (103, 109))	('transfected', 'Var', (130, 141))	('gain-of-function', 'PosReg', (18, 34))	('BOY', 'Species', '9606', (110, 113))	('BOY', 'Species', '9606', (67, 70))	('miRNA-486-5p', 'Chemical', '-', (225, 237))
82080	33430801	Cell proliferation of both parental and CDDP-R BC cells transfected with miRNA-486-5p was significantly inhibited in the XTT assay in comparison with mock or microRNA-control transfected cells (Fig.	('si', 'Chemical', 'MESH:D012825', (90, 92))	('CDDP-R', 'Chemical', '-', (40, 46))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('XTT assay', 'CPA', (121, 130))	('miRNA-486-5p', 'Var', (73, 85))	('miRNA-486-5p', 'Chemical', '-', (73, 85))	('BC', 'Phenotype', 'HP:0009725', (47, 49))	('inhibited', 'NegReg', (104, 113))	('Cell proliferation', 'CPA', (0, 18))
82081	33430801	Moreover, cell migration activity in wound healing assays and cell invasion in Matrigel invasion assays showed significant inhibition in the miRNA-486-5p transfectants compared to their counterparts (Fig.	('miRNA-486-5p transfectants', 'Var', (141, 167))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('cell invasion in Matrigel invasion assays', 'CPA', (62, 103))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('cell migration', 'biological_process', 'GO:0016477', ('10', '24'))	('cell migration activity in wound healing assays', 'CPA', (10, 57))	('wound healing', 'biological_process', 'GO:0042060', ('37', '50'))	('inhibition', 'NegReg', (123, 133))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('miRNA-486-5p', 'Chemical', '-', (141, 153))
82083	33430801	The expression level of cleaved PARP increased in miRNA-486-5p transfectants (Fig.	('expression level', 'MPA', (4, 20))	('miRNA-486-5p transfectants', 'Var', (50, 76))	('increased', 'PosReg', (37, 46))	('PARP', 'Gene', '1302', (32, 36))	('PARP', 'Gene', (32, 36))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('miRNA-486-5p', 'Chemical', '-', (50, 62))
82084	33430801	Thus, miRNA-486-5p induced apoptosis in both parental and CDDP-R BC cells and provided anti-tumor effects.	('si', 'Chemical', 'MESH:D012825', (33, 35))	('apoptosis', 'biological_process', 'GO:0006915', ('27', '36'))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('miRNA-486-5p', 'Var', (6, 18))	('miRNA-486-5p', 'Chemical', '-', (6, 18))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('CDDP-R', 'Chemical', '-', (58, 64))	('apoptosis', 'CPA', (27, 36))	('tumor', 'Disease', (92, 97))	('apoptosis', 'biological_process', 'GO:0097194', ('27', '36'))	('BC', 'Phenotype', 'HP:0009725', (65, 67))
82086	33430801	However, by simultaneous miRNA-486-5p transfection, cell proliferation decreased to the level observed in parental BOY (Fig.	('BOY', 'Species', '9606', (115, 118))	('miRNA-486-5p transfection', 'Var', (25, 50))	('si', 'Chemical', 'MESH:D012825', (12, 14))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('cell proliferation', 'CPA', (52, 70))	('miRNA-486-5p', 'Chemical', '-', (25, 37))	('decreased', 'NegReg', (71, 80))
82088	33430801	Next, we examined cell proliferation following cisplatin treatment and miRNA-486-5p transfection.	('miRNA-486-5p', 'Chemical', '-', (71, 83))	('cell proliferation', 'biological_process', 'GO:0008283', ('18', '36'))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('examined', 'Reg', (9, 17))	('miRNA-486-5p', 'Var', (71, 83))
82090	33430801	The combination of miRNA-486-5p transfection and cisplatin administration clearly had additive effects and significantly suppressed cell proliferation (Fig.	('miRNA-486-5p', 'Chemical', '-', (19, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('suppressed', 'NegReg', (121, 131))	('miRNA-486-5p transfection', 'Var', (19, 44))	('cell proliferation', 'CPA', (132, 150))	('cell proliferation', 'biological_process', 'GO:0008283', ('132', '150'))	('si', 'Chemical', 'MESH:D012825', (107, 109))
82092	33430801	The combination of miRNA-486-5p transfection and cisplatin induced more apoptotic cells in flow cytometric analyses (Fig.	('apoptotic cells', 'CPA', (72, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('miRNA-486-5p transfection', 'Var', (19, 44))	('miRNA-486-5p', 'Chemical', '-', (19, 31))
82094	33430801	These results suggested that miRNA-486-5p functioned as a tumor suppressor in CDDP-R cells and increased their sensitivity to cisplatin.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('miRNA-486-5p', 'Chemical', '-', (29, 41))	('si', 'Chemical', 'MESH:D012825', (114, 116))	('CDDP-R', 'Chemical', '-', (78, 84))	('sensitivity to cisplatin', 'MPA', (111, 135))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('increased', 'PosReg', (95, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))	('miRNA-486-5p', 'Var', (29, 41))
82095	33430801	Next, we sought further insights into the molecular mechanisms regulated by tumor suppressive miRNA-486-5p.	('miRNA-486-5p', 'Chemical', '-', (94, 106))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('miRNA-486-5p', 'Var', (94, 106))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
82104	33430801	The luminescence intensity was significantly reduced by co-transfection with miRNA-486-5p and the vector carrying the WT 3'-UTR, whereas it was not reduced by transfection with the deletion vector from which the binding site had been removed (Fig.	('UTR', 'Gene', (124, 127))	('reduced', 'NegReg', (45, 52))	('luminescence intensity', 'MPA', (4, 26))	('miRNA-486-5p', 'Var', (77, 89))	('binding', 'molecular_function', 'GO:0005488', ('212', '219'))	('miRNA-486-5p', 'Chemical', '-', (77, 89))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('UTR', 'Gene', '2837', (124, 127))	('si', 'Chemical', 'MESH:D012825', (220, 222))	('si', 'Chemical', 'MESH:D012825', (31, 33))
82105	33430801	These data suggested that miRNA-486-5p was directly bound to each specific position in the 3'-UTR of EHHADH mRNA.	('EHHADH', 'Gene', '1962', (101, 107))	('EHHADH', 'Gene', (101, 107))	('miRNA-486-5p', 'Var', (26, 38))	('miRNA-486-5p', 'Chemical', '-', (26, 38))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('UTR', 'Gene', '2837', (94, 97))	('UTR', 'Gene', (94, 97))
82119	33430801	Moreover, Matrigel invasion assays and wound healing assays showed that cell invasion and migration activities were significantly inhibited in these si-EHHADH transfectants compared to their counterparts (Fig.	('si', 'Chemical', 'MESH:D012825', (149, 151))	('EHHADH', 'Gene', '1962', (152, 158))	('wound healing', 'biological_process', 'GO:0042060', ('39', '52'))	('EHHADH', 'Gene', (152, 158))	('inhibited', 'NegReg', (130, 139))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('Matrigel invasion assays', 'CPA', (10, 34))	('migration activities', 'CPA', (90, 110))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('cell invasion', 'CPA', (72, 85))	('transfectants', 'Var', (159, 172))
82120	33430801	The apoptotic cell numbers were significantly greater in si-EHHADH transfectants than in their counterparts.	('si', 'Chemical', 'MESH:D012825', (32, 34))	('EHHADH', 'Gene', '1962', (60, 66))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('EHHADH', 'Gene', (60, 66))	('apoptotic cell numbers', 'CPA', (4, 26))	('greater', 'PosReg', (46, 53))	('transfectants', 'Var', (67, 80))
82121	33430801	Western blots showed that cleaved PARP expression was markedly increased in si-EHHADH transfectants.	('si', 'Chemical', 'MESH:D012825', (76, 78))	('increased', 'PosReg', (63, 72))	('PARP', 'Gene', '1302', (34, 38))	('PARP', 'Gene', (34, 38))	('cleaved', 'MPA', (26, 33))	('EHHADH', 'Gene', '1962', (79, 85))	('transfectants', 'Var', (86, 99))	('EHHADH', 'Gene', (79, 85))	('si', 'Chemical', 'MESH:D012825', (45, 47))
82122	33430801	We also investigated whether knockdown of EHHADH improved the sensitivity to cisplatin in CDDP-R-BC cells.	('sensitivity to cisplatin', 'MPA', (62, 86))	('improved', 'PosReg', (49, 57))	('knockdown', 'Var', (29, 38))	('BC', 'Phenotype', 'HP:0009725', (97, 99))	('EHHADH', 'Gene', (42, 48))	('EHHADH', 'Gene', '1962', (42, 48))	('CDDP-R', 'Chemical', '-', (90, 96))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('si', 'Chemical', 'MESH:D012825', (65, 67))
82134	33430801	In cancer cells, abnormal expression of microRNAs can disturb normally operating RNA networks and disrupt physiologic processes.	('microRNAs', 'Protein', (40, 49))	('RNA networks', 'CPA', (81, 93))	('disturb', 'Reg', (54, 61))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('physiologic processes', 'CPA', (106, 127))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('disrupt', 'Reg', (98, 105))	('cancer', 'Disease', (3, 9))	('normally operating', 'MPA', (62, 80))	('abnormal', 'Var', (17, 25))	('RNA', 'cellular_component', 'GO:0005562', ('81', '84'))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
82140	33430801	Herein, we focused on miRNA-486-5p, a transcript that was downregulated in CDDP-R BC cell lines (CDDP-R-BOY, CDDP-R-T24) compared with parental BC cell lines (BOY, T24).	('CDDP-R', 'Chemical', '-', (97, 103))	('miRNA-486-5p', 'Var', (22, 34))	('miRNA-486-5p', 'Chemical', '-', (22, 34))	('CDDP-R', 'Chemical', '-', (75, 81))	('CDDP-R', 'Chemical', '-', (109, 115))	('CDDP-R-BOY', 'Chemical', '-', (97, 107))	('downregulated', 'NegReg', (58, 71))	('CDDP-R', 'Disease', (75, 81))	('CDDP-R-T24', 'Chemical', '-', (109, 119))	('BC', 'Phenotype', 'HP:0009725', (82, 84))	('BC', 'Phenotype', 'HP:0009725', (144, 146))	('BOY', 'Species', '9606', (159, 162))	('BOY', 'Species', '9606', (104, 107))
82141	33430801	The molecular mechanism by which miRNA-486-5p is downregulated in BC remains unclear.	('BC', 'Phenotype', 'HP:0009725', (66, 68))	('miRNA-486-5p', 'Var', (33, 45))	('miRNA-486-5p', 'Chemical', '-', (33, 45))	('downregulated', 'NegReg', (49, 62))
82142	33430801	However, miRNA-486-5p is located on chromosome 8p11, and loss of material from chromosome arm 8p was a frequent cytogenetic alteration in uroepithelial carcinoma.	('uroepithelial carcinoma', 'Disease', (138, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('uroepithelial carcinoma', 'Disease', 'MESH:D009369', (138, 161))	('miRNA-486-5p', 'Var', (9, 21))	('loss', 'Var', (57, 61))	('miRNA-486-5p', 'Chemical', '-', (9, 21))	('chromosome', 'cellular_component', 'GO:0005694', ('36', '46'))	('chromosome', 'cellular_component', 'GO:0005694', ('79', '89'))
82143	33430801	It was reported that miRNA-486-5p was a tumor suppressor miRNA in many cancer types such as non-small cell lung, breast, colon and hepatocellular carcinoma.	('breast', 'Disease', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('miRNA-486-5p', 'Var', (21, 33))	('cancer', 'Disease', (71, 77))	('miRNA-486-5p', 'Chemical', '-', (21, 33))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (131, 155))	('colon and hepatocellular carcinoma', 'Disease', 'MESH:D003110', (121, 155))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))
82144	33430801	As a tumor suppressor gene, miRNA-486-5p overexpression inhibited cell proliferation, migration and invasion, and induced apoptosis in BC and CDDP-R BC cell lines.	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('cell proliferation', 'CPA', (66, 84))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('5', '21'))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('BC', 'Phenotype', 'HP:0009725', (135, 137))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor suppressor', 'biological_process', 'GO:0051726', ('5', '21'))	('miRNA-486-5p', 'Chemical', '-', (28, 40))	('CDDP-R', 'Chemical', '-', (142, 148))	('BC', 'Phenotype', 'HP:0009725', (149, 151))	('apoptosis', 'CPA', (122, 131))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('miRNA-486-5p overexpression', 'Var', (28, 55))	('inhibited', 'NegReg', (56, 65))	('tumor', 'Disease', (5, 10))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('induced', 'Reg', (114, 121))
82145	33430801	Also, miRNA-486-5p was reportedly involved in sensitivity to cisplatin in non-small cell lung cancer.	('lung cancer', 'Disease', (89, 100))	('involved', 'Reg', (34, 42))	('miRNA-486-5p', 'Var', (6, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('miRNA-486-5p', 'Chemical', '-', (6, 18))	('sensitivity to cisplatin', 'MPA', (46, 70))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (78, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (74, 100))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('si', 'Chemical', 'MESH:D012825', (49, 51))
82146	33430801	reported that miRNA-486-5p inhibits EMT by targeting TWF1 and improves sensitivity to cisplatin.	('TWF1', 'Gene', '5756', (53, 57))	('inhibits', 'NegReg', (27, 35))	('targeting', 'Reg', (43, 52))	('TWF1', 'Gene', (53, 57))	('EMT', 'CPA', (36, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('miRNA-486-5p', 'Var', (14, 26))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('miRNA-486-5p', 'Chemical', '-', (14, 26))	('EMT', 'biological_process', 'GO:0001837', ('36', '39'))	('sensitivity to cisplatin', 'MPA', (71, 95))	('improves', 'PosReg', (62, 70))
82147	33430801	Similarly, we revealed that miRNA-486-5p overcomes cisplatin resistance and the additive effect on cell growth suppression.	('si', 'Chemical', 'MESH:D012825', (118, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('cell growth', 'biological_process', 'GO:0016049', ('99', '110'))	('cisplatin resistance', 'MPA', (51, 71))	('cell growth suppression', 'CPA', (99, 122))	('miRNA-486-5p', 'Var', (28, 40))	('miRNA-486-5p', 'Chemical', '-', (28, 40))	('overcomes', 'NegReg', (41, 50))	('si', 'Chemical', 'MESH:D012825', (63, 65))
82148	33430801	showed that miRNA-486-5p had anti-tumor effects and improved CDDP sensitivity through induction of apoptosis in muscle-invasive BC.	('BC', 'Phenotype', 'HP:0009725', (128, 130))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('86', '108'))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('improved', 'PosReg', (52, 60))	('apoptosis', 'CPA', (99, 108))	('miRNA-486-5p', 'Var', (12, 24))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('muscle-invasive BC', 'Disease', (112, 130))	('CDDP sensitivity', 'MPA', (61, 77))	('CDDP', 'Chemical', '-', (61, 65))	('miRNA-486-5p', 'Chemical', '-', (12, 24))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('si', 'Chemical', 'MESH:D012825', (69, 71))
82149	33430801	Therefore, Our finding adds a new perspective to their reports, we demonstrated that EHHADH was a directly targeted by miR-486-5p.	('miR-486-5p', 'Chemical', '-', (119, 129))	('EHHADH', 'Gene', '1962', (85, 91))	('EHHADH', 'Gene', (85, 91))	('miR-486-5p', 'Var', (119, 129))
82150	33430801	According to TargetScan database Release 7.1, it is possible that among the 28 microRNAs that are downregulated in cisplatin-resistant BC cell lines (CDDP-R-BOY, CDDP-R-T24), 5 microRNAs (miR-486-5p, miR-6768-5p, miR-548ar-3p, miR-6816-3p, miR-4731-3p) regulate the expression of EHHADH.	('expression', 'MPA', (266, 276))	('regulate', 'Reg', (253, 261))	('EHHADH', 'Gene', '1962', (280, 286))	('EHHADH', 'Gene', (280, 286))	('miR-6768', 'Gene', '102465460', (200, 208))	('miR-548ar-3p', 'Var', (213, 225))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('si', 'Chemical', 'MESH:D012825', (272, 274))	('CDDP-R-T24', 'Chemical', '-', (162, 172))	('BC', 'Phenotype', 'HP:0009725', (135, 137))	('miR-6816-3p', 'Var', (227, 238))	('CDDP-R-BOY', 'Chemical', '-', (150, 160))	('miR-486-5p', 'Var', (188, 198))	('miR-4731-3p', 'Var', (240, 251))	('si', 'Chemical', 'MESH:D012825', (127, 129))	('miR-6768', 'Gene', (200, 208))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('miR-486-5p', 'Chemical', '-', (188, 198))
82153	33430801	In this study, we confirmed that the level of EHHADH protein was elevated in CDDP-R BC cell lines compared with parental cell lines, and that loss of EHHADH gene function significantly inhibited cancer cell proliferation, migration and invasion and increased the cells' sensitivity to cisplatin.	('EHHADH', 'Gene', '1962', (46, 52))	('invasion', 'CPA', (236, 244))	('loss', 'Var', (142, 146))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('migration', 'CPA', (222, 231))	('sensitivity to cisplatin', 'MPA', (270, 294))	('si', 'Chemical', 'MESH:D012825', (240, 242))	('EHHADH', 'Gene', (150, 156))	('inhibited', 'NegReg', (185, 194))	('increased', 'PosReg', (249, 258))	('cell proliferation', 'biological_process', 'GO:0008283', ('202', '220'))	('elevated', 'PosReg', (65, 73))	('EHHADH', 'Gene', (46, 52))	('CDDP-R', 'Chemical', '-', (77, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (285, 294))	('BC', 'Phenotype', 'HP:0009725', (84, 86))	('cancer', 'Disease', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('EHHADH', 'Gene', '1962', (150, 156))	('si', 'Chemical', 'MESH:D012825', (273, 275))	('si', 'Chemical', 'MESH:D012825', (171, 173))	('level', 'MPA', (37, 42))
82166	33430801	In another example, TP53 mutant patients are often cisplatin-resistant in ovarian cancer.	('mutant', 'Var', (25, 31))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TP53', 'Gene', (20, 24))	('ovarian cancer', 'Phenotype', 'HP:0100615', (74, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('ovarian cancer', 'Disease', 'MESH:D010051', (74, 88))	('cisplatin-resistant', 'MPA', (51, 70))	('ovarian cancer', 'Disease', (74, 88))	('TP53', 'Gene', '7157', (20, 24))	('si', 'Chemical', 'MESH:D012825', (63, 65))
82174	33430801	We identified EHHADH as a novel target of miRNA-486-5p in cisplatin-resistant BCs.	('si', 'Chemical', 'MESH:D012825', (70, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('cisplatin-resistant BCs', 'Disease', (58, 81))	('BC', 'Phenotype', 'HP:0009725', (78, 80))	('miRNA-486-5p', 'Var', (42, 54))	('miRNA-486-5p', 'Chemical', '-', (42, 54))	('EHHADH', 'Gene', '1962', (14, 20))	('EHHADH', 'Gene', (14, 20))
82183	32111026	Disparity between Inter-Patient Molecular Heterogeneity and Repertoires of Target Drugs Used for Different Types of Cancer in Clinical Oncology Inter-patient molecular heterogeneity is the major declared driver of an expanding variety of anticancer drugs and personalizing their prescriptions.	('Cancer', 'Disease', (116, 122))	('Patient', 'Species', '9606', (24, 31))	('patient', 'Species', '9606', (150, 157))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('Cancer', 'Disease', 'MESH:D009369', (116, 122))	('Cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Oncology', 'Phenotype', 'HP:0002664', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('Inter-patient', 'Var', (144, 157))
82209	32111026	The effectiveness of Epidermal Growth Factor Receptor (EGFR)-specific tyrosine kinase inhibitors in NSCLC is associated with mutations in EGFR gene, that is, deletions of the 19-21st exons and amplifications of EGFR gene positively correlate with the clinical benefit of treatment.	('Epidermal Growth Factor Receptor', 'Gene', '1956', (21, 53))	('mutations', 'Var', (125, 134))	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('EGFR', 'Gene', '1956', (138, 142))	('NSCLC', 'Disease', (100, 105))	('Epidermal Growth Factor Receptor', 'Gene', (21, 53))	('EGFR', 'Gene', (55, 59))	('deletions', 'Var', (158, 167))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('EGFR', 'Gene', (138, 142))	('effectiveness', 'MPA', (4, 17))	('EGFR', 'Gene', '1956', (211, 215))	('EGFR', 'molecular_function', 'GO:0005006', ('211', '215'))	('EGFR', 'molecular_function', 'GO:0005006', ('138', '142'))	('EGFR', 'Gene', (211, 215))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('Epidermal Growth Factor', 'molecular_function', 'GO:0005154', ('21', '44'))
82211	32111026	Tyrosine kinase inhibitor Larotrectinib is recommended for solid tumors with fusions of NTRK genes.	('fusions', 'Var', (77, 84))	('Larotrectinib', 'Chemical', 'MESH:C000609083', (26, 39))	('NTRK', 'Gene', (88, 92))	('solid tumors', 'Disease', (59, 71))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('9', '25'))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('NTRK', 'Gene', '4915;4916', (88, 92))	('solid tumors', 'Disease', 'MESH:D009369', (59, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
82212	32111026	In turn, inhibitors of isocitrate dehydrogenase-1 (IDH1) protein are used for the treatment of patients with relapsed or refractory acute myeloid leukemia with a diagnostic mutation in IDH1 gene.	('IDH1', 'Gene', '3417', (51, 55))	('IDH1', 'Gene', '3417', (185, 189))	('patients', 'Species', '9606', (95, 103))	('myeloid leukemia', 'Disease', (138, 154))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('isocitrate dehydrogenase-1', 'Gene', '3417', (23, 49))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (138, 154))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('myeloid leukemia', 'Disease', 'MESH:D007951', (138, 154))	('isocitrate dehydrogenase-1', 'Gene', (23, 49))	('IDH1', 'Gene', (51, 55))	('IDH1', 'Gene', (185, 189))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (132, 154))	('mutation', 'Var', (173, 181))
82218	32111026	Exceptions are made only for a narrow spectrum of specific genetic damages, such as diagnostic mutations discussed above or epigenetic changes like methylation of MGMT gene promoter in brain tumors.	('brain tumor', 'Phenotype', 'HP:0030692', (185, 196))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('MGMT', 'Gene', (163, 167))	('MGMT', 'Gene', '4255', (163, 167))	('methylation', 'biological_process', 'GO:0032259', ('148', '159'))	('brain tumors', 'Disease', 'MESH:D001932', (185, 197))	('brain tumors', 'Phenotype', 'HP:0030692', (185, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('mutations', 'Var', (95, 104))	('MGMT', 'molecular_function', 'GO:0003908', ('163', '167'))	('methylation', 'Var', (148, 159))	('brain tumors', 'Disease', (185, 197))
82307	32111026	Thus, thyroid carcinomas bearing BRAF mutations are less sensitive to BRAF inhibitors than melanomas and develop primary or acquired resistance due to additional mutations and activation of alternative signaling pathways that reinforce ERK signaling.	('BRAF', 'Gene', '673', (33, 37))	('sensitive', 'MPA', (57, 66))	('BRAF', 'Gene', (33, 37))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (6, 24))	('thyroid carcinomas', 'Disease', (6, 24))	('melanomas', 'Disease', 'MESH:D008545', (91, 100))	('ERK', 'molecular_function', 'GO:0004707', ('236', '239'))	('melanomas', 'Disease', (91, 100))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (6, 24))	('BRAF', 'Gene', '673', (70, 74))	('mutations', 'Var', (38, 47))	('signaling', 'biological_process', 'GO:0023052', ('202', '211'))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('BRAF', 'Gene', (70, 74))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('signaling', 'biological_process', 'GO:0023052', ('240', '249'))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('develop', 'Reg', (105, 112))	('mutations', 'Var', (162, 171))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('less', 'NegReg', (52, 56))
82308	32111026	Recently NRG Oncology/Gynecologic Oncology Group study showed association of FGFR2 mutations with poor outcomes in endometrial cancer.	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('FGFR2', 'Gene', '2263', (77, 82))	('association', 'Interaction', (62, 73))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('endometrial cancer', 'Disease', (115, 133))	('Oncology', 'Phenotype', 'HP:0002664', (13, 21))	('endometrial cancer', 'Phenotype', 'HP:0012114', (115, 133))	('Oncology', 'Phenotype', 'HP:0002664', (34, 42))	('endometrial cancer', 'Disease', 'MESH:D016889', (115, 133))	('FGFR2', 'Gene', (77, 82))
82311	32111026	Temozolomide showed a modest activity in colorectal cancers with MGMT promoter methylation and the corresponding clinical trial did not meet its primary end point.	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('MGMT', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('promoter methylation', 'Var', (70, 90))	('MGMT', 'Gene', '4255', (65, 69))	('colorectal cancers', 'Disease', 'MESH:D015179', (41, 59))	('activity', 'MPA', (29, 37))	('colorectal cancers', 'Disease', (41, 59))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))	('MGMT', 'molecular_function', 'GO:0003908', ('65', '69'))	('Temozolomide', 'Chemical', 'MESH:D000077204', (0, 12))
82312	32111026	Tracing FGFR3 mutation is currently used for following bladder cancer recurrence but no related therapeutic options became available.	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('bladder cancer', 'Disease', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('FGFR3', 'Gene', '2261', (8, 13))	('mutation', 'Var', (14, 22))	('FGFR', 'molecular_function', 'GO:0005007', ('8', '12'))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (55, 80))	('FGFR3', 'Gene', (8, 13))
82313	32111026	Finally, the role of mutated NTRK3 as target gene for treatment of non-small cell lung cancer is exploited by clinical trials, whereas targeting FGFR2 and EGFR in stomach cancer is considered promising for improving current strategies.	('non-small cell lung cancer', 'Disease', (67, 93))	('EGFR', 'Gene', (155, 159))	('stomach cancer', 'Disease', (163, 177))	('mutated', 'Var', (21, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('FGFR2', 'Gene', (145, 150))	('NTRK3', 'Gene', '4916', (29, 34))	('NTRK3', 'Gene', (29, 34))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (67, 93))	('EGFR', 'molecular_function', 'GO:0005006', ('155', '159'))	('EGFR', 'Gene', '1956', (155, 159))	('stomach cancer', 'Disease', 'MESH:D013274', (163, 177))	('stomach cancer', 'Phenotype', 'HP:0012126', (163, 177))	('FGFR2', 'Gene', '2263', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (71, 93))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (67, 93))	('FGFR', 'molecular_function', 'GO:0005007', ('145', '149'))
82333	32111026	Gene mutation data were extracted from the COSMIC database v76 containing validated mutations for TCGA tumor samples.	('mutations', 'Var', (84, 93))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
82428	28506596	observed that despite modest sensitivity and specificity for RCC (74% and 80%, respectively), imaging with FDG influenced the therapeutic strategy for a high proportion of patients (43%), and FDG-positive cases resulted in significantly lower five-year overall survival rates compared to FDG-negative cases (69% vs. 19%, respectively).	('FDG', 'Chemical', '-', (107, 110))	('lower', 'NegReg', (237, 242))	('FDG', 'Chemical', '-', (288, 291))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('FDG', 'Chemical', '-', (192, 195))	('RCC', 'Disease', (61, 64))	('patients', 'Species', '9606', (172, 180))	('FDG-positive', 'Var', (192, 204))	('influenced', 'Reg', (111, 121))
82451	28506596	Many ongoing imaging studies are embedded in clinical trials of antiangiogenic agents, chemotherapy, and immunotherapy with checkpoint inhibition (NCT02788201, NCT01688999 and NCT02496208), with the goal of improving tumor burden and treatment response assessment in metastatic urothelial carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('NCT01688999', 'Var', (160, 171))	('improving', 'PosReg', (207, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('NCT02496208', 'Var', (176, 187))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (278, 298))	('men', 'Species', '9606', (259, 262))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('men', 'Species', '9606', (239, 242))	('urothelial carcinoma', 'Disease', (278, 298))	('NCT02788201', 'Var', (147, 158))
82464	28506596	On the other hand, DCE-MRI has been found to be superior to traditional unenhanced T1- and T2-weighted anatomic imaging owing to its ability to distinguish urothelial carcinoma from normal bladder wall.	('urothelial carcinoma', 'Disease', (156, 176))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (156, 176))	('DCE', 'Chemical', 'MESH:C024565', (19, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('DCE-MRI', 'Var', (19, 26))
82466	28506596	One study revealed 84% accuracy for DCE-MRI in tumor staging compared to 67% accuracy for unenhanced T1- and T2-weighted imaging.	('DCE', 'Chemical', 'MESH:C024565', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('DCE-MRI', 'Var', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
82484	28506596	More lesions were detected with FDG-PET/CT than with CT or MRI, which substantially affected clinical management.	('men', 'Species', '9606', (108, 111))	('FDG', 'Chemical', '-', (32, 35))	('FDG-PET/CT', 'Var', (32, 42))	('affected', 'Reg', (84, 92))
82490	28506596	However, another study asserted that FDG-PET/CT added only a small benefit in detecting lymph node metastasis outside the pelvis compared to CT, with 69% sensitivity and 95% specificity for FDG-PET/CT compared to 41% sensitivity and 98% specificity for CT, which was not considered enough of an advantage to justify the use of FDG PET/CT.	('FDG', 'Chemical', '-', (327, 330))	('FDG', 'Chemical', '-', (190, 193))	('lymph node metastasis outside the pelvis', 'CPA', (88, 128))	('FDG', 'Chemical', '-', (37, 40))	('FDG-PET/CT', 'Var', (190, 200))
82504	28506596	Based on preliminary studies, hybrid PET/MRI appears to provide superior sensitivity and specificity for tumor detection and characterization.	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('hybrid', 'Var', (30, 36))
82508	28506596	For some tumors, the clear benefits of PET/MRI are its one-stop ease of use, comprehensive tumor staging, and potentially improved lymph node staging in the abdomen and pelvis.	('PET/MRI', 'Var', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('lymph', 'MPA', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Disease', (9, 15))	('tumor', 'Disease', (91, 96))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('men', 'Species', '9606', (161, 164))	('improved', 'PosReg', (122, 130))
82516	28506596	Although it is not fully established in clinical routine, mpMRI targeted biopsy can potentially enable sampling of the worst portion of primary prostate adenocarcinoma lesions and aid accurate treatment management.	('treatment management', 'CPA', (193, 213))	('aid', 'Reg', (180, 183))	('primary prostate adenocarcinoma lesions', 'Disease', (136, 175))	('primary prostate adenocarcinoma lesions', 'Disease', 'MESH:D011469', (136, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('men', 'Species', '9606', (209, 212))	('men', 'Species', '9606', (198, 201))	('mpMRI', 'Var', (58, 63))
82567	29263839	Identification of potentially oncogenic alterations from tumor-only samples reveals Fanconi anemia pathway mutations in bladder carcinomas Cancer is caused by germline and somatic mutations, which can share biological features such as amino acid change.	('Fanconi anemia', 'Phenotype', 'HP:0001994', (84, 98))	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))	('bladder carcinomas', 'Disease', 'MESH:D001749', (120, 138))	('mutations', 'Var', (107, 116))	('Fanconi anemia', 'Disease', (84, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('caused', 'Reg', (149, 155))	('Fanconi anemia', 'Disease', 'MESH:D005199', (84, 98))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (120, 138))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (120, 137))	('anemia', 'Phenotype', 'HP:0001903', (92, 98))	('tumor', 'Disease', (57, 62))	('bladder carcinomas', 'Disease', (120, 138))
82568	29263839	We present a framework that uses machine learning to learn features of recurrent somatic mutations to (1) predict somatic variants from tumor-only samples and (2) identify somatic-like germline variants for integrated analysis of tumor-normal DNA.	('tumor', 'Disease', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('mutations', 'Var', (89, 98))	('DNA', 'cellular_component', 'GO:0005574', ('243', '246'))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', (136, 141))
82569	29263839	Using data from 1769 patients from seven cancer types (bladder, glioblastoma, low-grade glioma, lung, melanoma, stomach, and pediatric glioma), we show that "somatic-like" germline variants are enriched for autosomal-dominant cancer-predisposition genes (p < 4.35 x 10-15), including TP53.	('patients', 'Species', '9606', (21, 29))	('cancer', 'Disease', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('glioma', 'Disease', (88, 94))	('pediatric glioma', 'Disease', 'MESH:D005910', (125, 141))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('pediatric glioma', 'Disease', (125, 141))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('TP53', 'Gene', '7157', (284, 288))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('autosomal-dominant cancer', 'Disease', (207, 232))	('glioma', 'Disease', (135, 141))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('autosomal-dominant cancer', 'Disease', 'MESH:D009369', (207, 232))	('glioblastoma', 'Disease', (64, 76))	('variants', 'Var', (181, 189))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('cancer', 'Disease', (226, 232))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('TP53', 'Gene', (284, 288))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
82570	29263839	Our framework identifies germline and somatic nonsense variants in BRCA2 and other Fanconi anemia genes in 11% (11/100) of bladder cancer cases, suggesting a potential genetic predisposition in these patients.	('Fanconi anemia', 'Disease', 'MESH:D005199', (83, 97))	('patients', 'Species', '9606', (200, 208))	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('nonsense variants', 'Var', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('BRCA2', 'Gene', (67, 72))	('bladder cancer', 'Disease', 'MESH:D001749', (123, 137))	('Fanconi anemia', 'Disease', (83, 97))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (83, 97))	('bladder cancer', 'Disease', (123, 137))	('anemia', 'Phenotype', 'HP:0001903', (91, 97))
82571	29263839	The bladder carcinoma patients with Fanconi anemia nonsense variants display a BRCA-deficiency somatic mutation signature, suggesting treatment targeted to DNA repair.	('bladder carcinoma', 'Disease', 'MESH:D001749', (4, 21))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (36, 50))	('nonsense variants', 'Var', (51, 68))	('bladder carcinoma', 'Disease', (4, 21))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (4, 21))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('Fanconi anemia', 'Disease', (36, 50))	('patients', 'Species', '9606', (22, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('BRCA-deficiency', 'Disease', (79, 94))	('DNA repair', 'biological_process', 'GO:0006281', ('156', '166'))	('BRCA-deficiency', 'Disease', 'OMIM:604370', (79, 94))	('Fanconi anemia', 'Disease', 'MESH:D005199', (36, 50))	('anemia', 'Phenotype', 'HP:0001903', (44, 50))
82572	29263839	Bladder cancer cells often harbor DNA mutations that occur after tumor development, including some mutations that affect DNA repair.	('DNA repair', 'biological_process', 'GO:0006281', ('121', '131'))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('tumor', 'Disease', (65, 70))	('Bladder cancer', 'Disease', (0, 14))	('DNA', 'Gene', (34, 37))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('Bladder cancer', 'Disease', 'MESH:D001749', (0, 14))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mutations', 'Var', (38, 47))	('harbor', 'Reg', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
82573	29263839	Raul Rabadan, Jiguang Wang, and colleagues from Columbia University in New York, USA, developed an analytic framework for identifying genetic variants, both inherited and newly arisen, that contribute to tumor development.	('contribute', 'Reg', (190, 200))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('variants', 'Var', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))
82574	29263839	The machine-learning tool:known as Tumor-Only Boosting Identification, or TOBI:learns what's a cancer-associated mutation from a small training set of tumor samples and matched healthy controls.	('mutation', 'Var', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('TOBI', 'Chemical', '-', (74, 78))	('tumor', 'Disease', (151, 156))	('cancer', 'Disease', (95, 101))	('Tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
82576	29263839	They found that TOBI pinpointed many inherited and non-inherited mutations known to contribute to cancer growth.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('TOBI', 'Chemical', '-', (16, 20))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('mutations', 'Var', (65, 74))
82577	29263839	In bladder cancer samples, the tool also revealed a previously unknown role for inherited mutations in BRCA2 and other DNA repair genes in the so-called Fanconi anemia pathway.	('DNA repair', 'biological_process', 'GO:0006281', ('119', '129'))	('anemia', 'Phenotype', 'HP:0001903', (161, 167))	('mutations', 'Var', (90, 99))	('Fanconi anemia', 'Disease', (153, 167))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('Fanconi anemia', 'Disease', 'MESH:D005199', (153, 167))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('so-called Fanconi anemia', 'Phenotype', 'HP:0001994', (143, 167))	('BRCA2', 'Gene', (103, 108))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (153, 167))
82578	29263839	Cancer often results from specific DNA alterations, and identification of cancer-causing mutations underlies genome-based precision cancer treatment.	('cancer', 'Disease', (132, 138))	('results from', 'Reg', (13, 25))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', (74, 80))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('alterations', 'Var', (39, 50))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
82582	29263839	Common attempts to identify somatic variants from tumor-only WES data involve removing dbSNP mutations common in the general population and focusing on genes in the Catalogue Of Somatic Mutations In Cancer (COSMIC).	('dbSNP', 'Gene', (87, 92))	('mutations', 'Var', (93, 102))	('Cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
82584	29263839	Certain strategies rely on a single patient's sequence alignment information, either predicting somatic deletions based on read-pair alignments and read depth or predicting somatic single nucleotide variants (SNV) using base quality, variant allele frequency (VAF), and sequencing error.	('deletions', 'Var', (104, 113))	('single nucleotide variants', 'Var', (181, 207))	('patient', 'Species', '9606', (36, 43))
82588	29263839	The tumor-normal cases would form a test set for identifying true somatic mutations, and the biological features of these confirmed somatic variants would be used to classify variants from the remaining tumor-only samples.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('variants', 'Var', (140, 148))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
82592	29263839	A machine learning framework built upon biological features of somatic variants would have high power to identify germline variants with somatic features that might influence tumor development.	('tumor', 'Disease', (175, 180))	('influence', 'Reg', (165, 174))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('variants', 'Var', (123, 131))
82594	29263839	Our Tumor-Only Boosting Identification framework (TOBI) learns from a small training set of tumor-normal pairs to generate a classification model that identifies variants with somatic characteristics from tumor-only samples.	('TOBI', 'Chemical', '-', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('variants', 'Var', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', (92, 97))	('Tumor', 'Phenotype', 'HP:0002664', (4, 9))
82597	29263839	Using 1769 patients across seven tumor types, we developed TOBI, evaluated TOBI's ability to identify somatic variants, and identified somatic-like germline variants (SLG variants), including variants with known or possible oncogenic potential.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('TOBI', 'Chemical', '-', (75, 79))	('variants', 'Var', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('SLG', 'Gene', '89858', (167, 170))	('TOBI', 'Chemical', '-', (59, 63))	('tumor', 'Disease', (33, 38))	('patients', 'Species', '9606', (11, 19))	('SLG', 'Gene', (167, 170))
82601	29263839	Ten biological features were used for gradient boosting (full features in Supplementary Text); features include database-derived features from COSMIC, cohort-associated features such as "Variants per Gene", and individual sequence features such as tumor VAF.	('Variants', 'Var', (187, 195))	('tumor', 'Disease', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
82618	29263839	", representing the number of cases in COSMIC with a specific variant; this may reflect both the lower mutation burden in pediatric glioma and the prevalence of hotspot mutations in H3F3A.	('H3F3A', 'Gene', '3020', (182, 187))	('mutations', 'Var', (169, 178))	('mutation burden', 'MPA', (103, 118))	('pediatric glioma', 'Disease', (122, 138))	('H3F3A', 'Gene', (182, 187))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('pediatric glioma', 'Disease', 'MESH:D005910', (122, 138))
82619	29263839	We compared TOBI's somatic classifications to published somatic calls from tumor-normal analysis of test set cases, Across all variants, TOBI had a sensitivity of 86.6%; for nonsynonymous variants, TOBI had a sensitivity of 87.2%.	('variants', 'Var', (127, 135))	('TOBI', 'Chemical', '-', (198, 202))	('TOBI', 'Chemical', '-', (12, 16))	('TOBI', 'Chemical', '-', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
82620	29263839	TOBI also has high sensitivity for variants with tumor VAF as low as 5% (Supplementary figure 5b,c).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('variants', 'Var', (35, 43))	('tumor', 'Disease', (49, 54))	('TOBI', 'Chemical', '-', (0, 4))
82623	29263839	While TOBI identifies variants with somatic characteristics, an important challenge in precision medicine involves finding genes that promote tumor development ("driver genes").	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('promote', 'PosReg', (134, 141))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('TOBI', 'Chemical', '-', (6, 10))	('variants', 'Var', (22, 30))
82625	29263839	In six cancers, TOBI has a higher true positive rate of nonsynonymous variants in driver genes compared to all genes (Fig.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('TOBI', 'Chemical', '-', (16, 20))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('cancers', 'Disease', (7, 14))	('nonsynonymous variants', 'Var', (56, 78))
82629	29263839	All predicted BRAF and IDH1 variants occurred at known somatic hotspots (BRAF V600E, IDH1 R132H).	('BRAF', 'Gene', '673', (73, 77))	('variants', 'Var', (28, 36))	('R132H', 'Var', (90, 95))	('IDH1', 'Gene', (23, 27))	('V600E', 'Mutation', 'rs113488022', (78, 83))	('occurred', 'Reg', (37, 45))	('BRAF', 'Gene', '673', (14, 18))	('R132H', 'Mutation', 'rs121913500', (90, 95))	('IDH1', 'Gene', '3417', (23, 27))	('IDH1', 'Gene', (85, 89))	('V600E', 'Var', (78, 83))	('BRAF', 'Gene', (14, 18))	('BRAF', 'Gene', (73, 77))	('IDH1', 'Gene', '3417', (85, 89))
82638	29263839	TOBI's false positive (FP) variants could include germline variants that share features with true somatic variants, making them "somatic-like" germline (SLG) variants.	('false', 'biological_process', 'GO:0071878', ('7', '12'))	('variants', 'Var', (27, 35))	('SLG', 'Gene', '89858', (153, 156))	('SLG', 'Gene', (153, 156))	('false', 'biological_process', 'GO:0071877', ('7', '12'))	('TOBI', 'Chemical', '-', (0, 4))
82639	29263839	SLG variants could be benign or oncogenic.	('SLG', 'Gene', (0, 3))	('variants', 'Var', (4, 12))	('SLG', 'Gene', '89858', (0, 3))
82640	29263839	Alternatively, FP variants might be tumor-specific variants that were not previously published due to variability in somatic variant analysis.	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('variants', 'Var', (18, 26))
82642	29263839	Since FP variants may include SLG variants, we also calculated the FPR from applying the Ped.Glioma classification model to a set of 100 non-tumor exomes from individuals without cancer sequenced by the 1000 Genomes Project.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('SLG', 'Gene', '89858', (30, 33))	('Glioma', 'Disease', 'MESH:D005910', (93, 99))	('tumor', 'Disease', (141, 146))	('SLG', 'Gene', (30, 33))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('variants', 'Var', (9, 17))	('cancer', 'Disease', (179, 185))	('Glioma', 'Phenotype', 'HP:0009733', (93, 99))	('Glioma', 'Disease', (93, 99))
82645	29263839	To identify SLG variants, we analyzed germline VAF from 1327 test cases in six cancers excluding GBM.	('cancers', 'Disease', (79, 86))	('SLG', 'Gene', '89858', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('SLG', 'Gene', (12, 15))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('variants', 'Var', (16, 24))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
82647	29263839	To be classified as an SLG variant, a FP variant needed a germline VAF of at least 30% to decrease the probability that the germline variant represented tumor contamination or artifacts.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('SLG', 'Gene', '89858', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('SLG', 'Gene', (23, 26))	('variant', 'Var', (41, 48))
82648	29263839	Since certain germline variants highly increase predisposition to cancer, we analyzed SLG variants for enrichment in 60 genes associated with autosomal dominant cancer-predisposition syndromes, or "AD genes" (listed in Supplementary Table 9), and found significant enrichment of AD genes in nonsynonymous SLG variants (p < 1.53 x 10-10; Fig.	('cancer', 'Disease', (161, 167))	('SLG', 'Gene', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('SLG', 'Gene', '89858', (305, 308))	('variants', 'Var', (309, 317))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('increase', 'PosReg', (39, 47))	('variants', 'Var', (90, 98))	('SLG', 'Gene', (305, 308))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('SLG', 'Gene', '89858', (86, 89))	('variants', 'Var', (23, 31))	('cancer', 'Disease', (66, 72))
82649	29263839	SLG nonsynonymous variants in TP53 occurred in seven cases (Fig.	('TP53', 'Gene', (30, 34))	('nonsynonymous variants', 'Var', (4, 26))	('SLG', 'Gene', '89858', (0, 3))	('TP53', 'Gene', '7157', (30, 34))	('SLG', 'Gene', (0, 3))	('occurred', 'Reg', (35, 43))
82650	29263839	Certain inactivating mutations in tumor suppressors are heterozygous germline variants, but show loss of heterozygosity in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (127, 132))	('inactivating mutations', 'Var', (8, 30))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
82651	29263839	Five of TP53 SLG variants exhibit evidence of loss of heterozygosity, with germline VAFs below 45% and tumor VAFs above 70%.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('variants', 'Var', (17, 25))	('tumor', 'Disease', (103, 108))	('SLG', 'Gene', '89858', (13, 16))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('heterozygosity', 'MPA', (54, 68))	('SLG', 'Gene', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
82652	29263839	Focusing on nonsynonymous FP variants in AD genes, we found 15 cases with TP53 mutations and at least seven cases with mutations in CDH1, RB1, RET or TSC2 (Fig.	('TSC2', 'Gene', (150, 154))	('RB1', 'Gene', (138, 141))	('CDH1', 'Gene', (132, 136))	('RET', 'Gene', (143, 146))	('RB1', 'Gene', '5925', (138, 141))	('CDH1', 'Gene', '999', (132, 136))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))	('RET', 'Gene', '5979', (143, 146))	('mutations', 'Var', (79, 88))	('TSC2', 'Gene', '7249', (150, 154))
82653	29263839	In three Ped.Glioma cases, TOBI predicted somatic TP53 variants with tumor VAF greater than 65% and germline VAF of 0% (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('variants', 'Var', (55, 63))	('tumor', 'Disease', (69, 74))	('Glioma', 'Disease', 'MESH:D005910', (13, 19))	('Glioma', 'Phenotype', 'HP:0009733', (13, 19))	('Glioma', 'Disease', (13, 19))	('TP53', 'Gene', '7157', (50, 54))	('TOBI', 'Chemical', '-', (27, 31))	('TP53', 'Gene', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
82654	29263839	3c; variants G105V, R175H, and R273C).	('R273C', 'Var', (31, 36))	('G105V', 'Mutation', 'rs587781504', (13, 18))	('R273C', 'Mutation', 'rs121913343', (31, 36))	('R175H', 'Mutation', 'rs28934578', (20, 25))	('G105V', 'Var', (13, 18))	('R175H', 'Var', (20, 25))
82656	29263839	Certain germline variants in cancer-associated genes correlate with earlier age of diagnosis, so we analyzed whether presence of nonsynonymous SLG variants in 565 cancer-associated genes (list in Supplementary Table 9) associated with earlier age of diagnosis in any cancer type.	('cancer', 'Disease', (29, 35))	('variants', 'Var', (147, 155))	('associated with', 'Reg', (219, 234))	('cancer', 'Disease', (267, 273))	('variants', 'Var', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('SLG', 'Gene', '89858', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('SLG', 'Gene', (143, 146))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
82657	29263839	Supplementary table 10 provides the number of cases with SLG variants in these cancer-associated genes for each cancer type.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('SLG', 'Gene', '89858', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('SLG', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', (79, 85))	('variants', 'Var', (61, 69))
82658	29263839	In LGG, patients with cancer-associated SLG variants had significantly earlier age at diagnosis (median 37 years vs. 41 years, p = 0.0013; Fig.	('LGG', 'Disease', (3, 6))	('SLG', 'Gene', '89858', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('SLG', 'Gene', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('variants', 'Var', (44, 52))	('patients', 'Species', '9606', (8, 16))
82659	29263839	The most LGG cases had SLG variants in TP53 (n = 4), followed by IDH1 (three cases: V71I [COSM96923], one case: R82K [COSM4169909]) and RET (Y791F [COSM1159820], I852M [COSM4573611], R982H [COSM1264016], T1038A [COSM4650197]).	('Y791F', 'Mutation', 'rs77724903', (141, 146))	('LGG', 'Disease', (9, 12))	('SLG', 'Gene', (23, 26))	('T1038A', 'Mutation', 'rs201740483', (204, 210))	('Y791F [COSM1159820]', 'Var', (141, 160))	('RET', 'Gene', '5979', (136, 139))	('R982H', 'Mutation', 'rs368550200', (183, 188))	('IDH1', 'Gene', '3417', (65, 69))	('SLG', 'Gene', '89858', (23, 26))	('V71I', 'Mutation', 'rs73070954', (84, 88))	('I852M [COSM4573611]', 'Var', (162, 181))	('TP53', 'Gene', '7157', (39, 43))	('RET', 'Gene', (136, 139))	('COSM1159820', 'Chemical', '-', (148, 159))	('T1038A [COSM4650197]', 'Var', (204, 224))	('COSM1264016', 'Chemical', '-', (190, 201))	('R82K', 'Mutation', 'rs775186249', (112, 116))	('I852M', 'Mutation', 'rs377767426', (162, 167))	('R982H [COSM1264016]', 'Var', (183, 202))	('IDH1', 'Gene', (65, 69))	('TP53', 'Gene', (39, 43))
82660	29263839	Many genes with SLG variants in LGG have also shown recurrent somatic mutations in prior analysis (e.g., TP53, IDH1, EGFR, and NF2; Fig.	('NF2', 'Gene', (127, 130))	('SLG', 'Gene', '89858', (16, 19))	('variants', 'Var', (20, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('117', '121'))	('LGG', 'Gene', (32, 35))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('IDH1', 'Gene', '3417', (111, 115))	('NF2', 'Gene', '4771', (127, 130))	('SLG', 'Gene', (16, 19))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('IDH1', 'Gene', (111, 115))
82661	29263839	Truncating germline alterations in cancer predisposition genes have been reported in 4-19% of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('reported', 'Reg', (73, 81))	('Truncating germline alterations', 'Var', (0, 31))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
82662	29263839	Accordingly, we examined the exome-wide SLG nonsense variants in each cancer type.	('SLG', 'Gene', '89858', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SLG', 'Gene', (40, 43))	('nonsense variants', 'Var', (44, 61))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
82663	29263839	Bladder carcinoma cases showed significant enrichment of SLG nonsense variants in the FA pathway based on pathway assessment with g:Profiler (49 genes with SLG variants, 54 genes in FA pathway, 3 overlapping genes; p-value of 0.029 after multiple testing correction; Supplementary Fig.	('FA', 'Phenotype', 'HP:0001994', (182, 184))	('SLG', 'Gene', '89858', (156, 159))	('FA pathway', 'Pathway', (86, 96))	('carcinoma', 'Disease', 'MESH:D002277', (8, 17))	('SLG', 'Gene', (156, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('SLG', 'Gene', '89858', (57, 60))	('Bladder carcinoma', 'Phenotype', 'HP:0002862', (0, 17))	('FA', 'Phenotype', 'HP:0001994', (86, 88))	('carcinoma', 'Disease', (8, 17))	('SLG', 'Gene', (57, 60))	('variants', 'Var', (160, 168))
82665	29263839	In bladder cancer, TOBI predicted these variants in 11% (11/100) of patients.	('TOBI', 'Chemical', '-', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('patients', 'Species', '9606', (68, 76))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('variants', 'Var', (40, 48))
82666	29263839	Less than 2.5% of patients in any other cancer type had predicted nonsense FA variants.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('nonsense FA', 'Var', (66, 77))	('cancer', 'Disease', (40, 46))	('patients', 'Species', '9606', (18, 26))	('FA', 'Phenotype', 'HP:0001994', (75, 77))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
82667	29263839	True somatic nonsense variants occurred in 6% of BLCA cases, affecting genes BRCA2, FANCM, FANCE, REV3L, and SLX4.	('SLX4', 'Gene', (109, 113))	('affecting', 'Reg', (61, 70))	('REV3L', 'Gene', '5980', (98, 103))	('FANCM', 'Gene', '57697', (84, 89))	('FA', 'Phenotype', 'HP:0001994', (91, 93))	('BRCA2', 'Gene', (77, 82))	('FANCE', 'Gene', (91, 96))	('SLX4', 'Gene', '84464', (109, 113))	('FA', 'Phenotype', 'HP:0001994', (84, 86))	('FANCE', 'Gene', '2178', (91, 96))	('FANCM', 'Gene', (84, 89))	('REV3L', 'Gene', (98, 103))	('nonsense variants', 'Var', (13, 30))	('variants', 'Var', (22, 30))
82669	29263839	Several of these germline variants showed potential loss of heterozygosity based on increased VAF in tumor DNA compared to germline DNA (Fig.	('VAF', 'Protein', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('increased', 'PosReg', (84, 93))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('variants', 'Var', (26, 34))
82670	29263839	5b: FANCM R1931*, BRCA2 Y3308*).	('Y3308*', 'SUBSTITUTION', 'None', (24, 30))	('R1931*', 'Var', (10, 16))	('FA', 'Phenotype', 'HP:0001994', (4, 6))	('Y3308*', 'Var', (24, 30))	('R1931*', 'SUBSTITUTION', 'None', (10, 16))	('FANCM', 'Gene', '57697', (4, 9))	('FANCM', 'Gene', (4, 9))
82671	29263839	Of note, BRCA2 variant Y3308* has been associated with hereditary colorectal and breast cancer.	('Y3308*', 'SUBSTITUTION', 'None', (23, 29))	('BRCA2', 'Gene', (9, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('Y3308*', 'Var', (23, 29))	('hereditary colorectal and breast cancer', 'Disease', 'MESH:D015179', (55, 94))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
82672	29263839	Mice ES cells with BRCA2 Y3308* mutations showed hypersensitivity to ionizing radiation and crosslinking agents, as well as decreased homologous recombination efficiency.	('hypersensitivity', 'Disease', 'MESH:D004342', (49, 65))	('hypersensitivity', 'biological_process', 'GO:0002524', ('49', '65'))	('BRCA2', 'Gene', (19, 24))	('hypersensitivity', 'Disease', (49, 65))	('homologous recombination', 'biological_process', 'GO:0035825', ('134', '158'))	('Y3308*', 'SUBSTITUTION', 'None', (25, 31))	('decreased', 'NegReg', (124, 133))	('Mice', 'Species', '10090', (0, 4))	('homologous recombination efficiency', 'CPA', (134, 169))	('Y3308*', 'Var', (25, 31))
82673	29263839	Additionally, FANCM R1931* was associated with increased breast cancer risk and deficient DNA repair.	('R1931*', 'Var', (20, 26))	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('FANCM', 'Gene', (14, 19))	('R1931*', 'SUBSTITUTION', 'None', (20, 26))	('FA', 'Phenotype', 'HP:0001994', (14, 16))	('increased', 'PosReg', (47, 56))	('DNA repair', 'biological_process', 'GO:0006281', ('90', '100'))	('deficient', 'NegReg', (80, 89))	('FANCM', 'Gene', '57697', (14, 19))	('DNA repair', 'CPA', (90, 100))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
82676	29263839	Enrichment of this somatic mutation signature in bladder cancer cases with nonsense FA variants suggests that these FA nonsense variants, whether somatic or germline, affect the bladder cancer somatic mutation landscape.	('bladder cancer', 'Disease', (49, 63))	('bladder cancer', 'Phenotype', 'HP:0009725', (178, 192))	('somatic mutation landscape', 'MPA', (193, 219))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('variants', 'Var', (87, 95))	('bladder cancer', 'Phenotype', 'HP:0009725', (49, 63))	('variants', 'Var', (128, 136))	('affect', 'Reg', (167, 173))	('FA', 'Phenotype', 'HP:0001994', (84, 86))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('bladder cancer', 'Disease', 'MESH:D001749', (178, 192))	('bladder cancer', 'Disease', (178, 192))	('bladder cancer', 'Disease', 'MESH:D001749', (49, 63))	('FA', 'Phenotype', 'HP:0001994', (116, 118))
82677	29263839	In this report, we present TOBI, a new unifying framework that uses the gradient boosting machine learning algorithm to identify somatic variants from tumor-only data or identify somatic-like germline variants in patients with tumor-normal DNA available.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('variants', 'Var', (137, 145))	('tumor', 'Disease', (227, 232))	('tumor', 'Disease', (151, 156))	('TOBI', 'Chemical', '-', (27, 31))	('patients', 'Species', '9606', (213, 221))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('DNA', 'cellular_component', 'GO:0005574', ('240', '243'))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
82679	29263839	In tumor-only analysis, TOBI successfully identified 87% of nonsynonymous somatic variants.	('tumor', 'Disease', (3, 8))	('TOBI', 'Chemical', '-', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('nonsynonymous somatic', 'Var', (60, 81))
82680	29263839	Higher true positive rates in driver genes suggest that TOBI enriches for cancer-causing variants.	('TOBI', 'Chemical', '-', (56, 60))	('variants', 'Var', (89, 97))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
82682	29263839	A TOBI modification trained on FFPE artifacts could potentially remove more FFPE sequencing artifacts, although this modification would need testing.	('remove', 'NegReg', (64, 70))	('modification', 'Var', (7, 19))	('TOBI', 'Chemical', '-', (2, 6))	('FFPE sequencing artifacts', 'MPA', (76, 101))
82686	29263839	Second, TOBI uses the powerful gradient boosting algorithm to classify variants, allowing TOBI to learn features important to specific tumor types (Fig.	('variants', 'Var', (71, 79))	('TOBI', 'Chemical', '-', (90, 94))	('TOBI', 'Chemical', '-', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
82688	29263839	These SLG variants include oncogenic germline variants validated by outside groups, such as the TP53 R248Q alteration confirmed as germline by tumor-normal analysis of a pediatric glioma case.	('tumor', 'Disease', (143, 148))	('variants', 'Var', (10, 18))	('R248Q alteration', 'Var', (101, 117))	('TP53', 'Gene', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('pediatric glioma', 'Disease', 'MESH:D005910', (170, 186))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('SLG', 'Gene', '89858', (6, 9))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('R248Q', 'Mutation', 'rs11540652', (101, 106))	('pediatric glioma', 'Disease', (170, 186))	('SLG', 'Gene', (6, 9))	('TP53', 'Gene', '7157', (96, 100))
82689	29263839	SLG variants in cancer genes also associated with earlier age of diagnosis in patients with low-grade glioma (Fig.	('associated', 'Reg', (34, 44))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('variants', 'Var', (4, 12))	('cancer', 'Disease', (16, 22))	('patients', 'Species', '9606', (78, 86))	('SLG', 'Gene', '89858', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('glioma', 'Disease', (102, 108))	('SLG', 'Gene', (0, 3))
82690	29263839	4a), suggesting that TOBI's SLG variants are enriched for cancer-associated variants.	('SLG', 'Gene', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('TOBI', 'Chemical', '-', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('variants', 'Var', (32, 40))	('SLG', 'Gene', '89858', (28, 31))	('cancer', 'Disease', (58, 64))
82691	29263839	Analysis of bladder carcinoma cases using TOBI revealed largely unreported germline inactivating mutations in the FA pathway, suggesting a potential genetic predisposition in 5% of patients.	('TOBI', 'Chemical', '-', (42, 46))	('germline', 'Var', (75, 83))	('FA pathway', 'Pathway', (114, 124))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (12, 29))	('patients', 'Species', '9606', (181, 189))	('FA', 'Phenotype', 'HP:0001994', (114, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('bladder carcinoma', 'Disease', (12, 29))	('bladder carcinoma', 'Disease', 'MESH:D001749', (12, 29))
82692	29263839	Outside analysis of a 14-patient bladder tumor cohort found a germline nonsense variant in BRCA2, but did not assess FA mutations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('FA', 'Phenotype', 'HP:0001994', (117, 119))	('bladder tumor', 'Disease', 'MESH:D001749', (33, 46))	('BRCA2', 'Gene', (91, 96))	('bladder tumor', 'Phenotype', 'HP:0009725', (33, 46))	('patient', 'Species', '9606', (25, 32))	('bladder tumor', 'Disease', (33, 46))	('germline nonsense', 'Var', (62, 79))
82693	29263839	Germline BRCA2 nonsense mutations in bladder carcinoma may reflect the pan-cancer susceptibility attributed to germline BRCA2 mutations in analysis of other adult cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('BRCA2', 'Gene', (9, 14))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('nonsense mutations', 'Var', (15, 33))	('cancer', 'Disease', (75, 81))	('adult cancers', 'Disease', (157, 170))	('adult cancers', 'Disease', 'MESH:C535836', (157, 170))	('BRCA2', 'Gene', (120, 125))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (37, 54))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('bladder carcinoma', 'Disease', (37, 54))	('bladder carcinoma', 'Disease', 'MESH:D001749', (37, 54))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))
82694	29263839	Future assessment of a larger BLCA cohort may reveal associations between germline FA mutations and clinical outcomes, similar to how an expanded cohort of prostate cancer patients revealed significantly more deleterious germline mutations in DNA repair genes in patients with metastatic vs. localized prostate cancer.	('prostate cancer', 'Disease', (156, 171))	('DNA repair genes', 'Gene', (243, 259))	('FA', 'Phenotype', 'HP:0001994', (83, 85))	('DNA repair', 'biological_process', 'GO:0006281', ('243', '253'))	('localized prostate cancer', 'Disease', 'MESH:D011471', (292, 317))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('germline mutations', 'Var', (221, 239))	('metastatic', 'Disease', (277, 287))	('prostate cancer', 'Disease', 'MESH:D011471', (302, 317))	('prostate cancer', 'Phenotype', 'HP:0012125', (302, 317))	('patients', 'Species', '9606', (172, 180))	('mutations', 'Var', (86, 95))	('localized prostate cancer', 'Disease', (292, 317))	('DNA', 'cellular_component', 'GO:0005574', ('243', '246'))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('patients', 'Species', '9606', (263, 271))	('prostate cancer', 'Disease', 'MESH:D011471', (156, 171))	('associations', 'Interaction', (53, 65))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))
82695	29263839	Our integrated somatic and germline analysis identified nonsense FA pathway mutations in 11% of BLCA cases, suggesting a role for aberrant interstrand crosslink repair in bladder tumor development.	('nonsense', 'Var', (56, 64))	('mutations', 'Var', (76, 85))	('bladder tumor', 'Disease', (171, 184))	('FA', 'Phenotype', 'HP:0001994', (65, 67))	('bladder tumor', 'Disease', 'MESH:D001749', (171, 184))	('BLCA', 'Disease', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('bladder tumor', 'Phenotype', 'HP:0009725', (171, 184))
82696	29263839	Enrichment for a BRCA-deficiency somatic signature in these patients indicates similarity between FA mutant bladder cancers and BRCA-mutant breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancers', 'Disease', 'MESH:D001943', (140, 154))	('breast cancers', 'Disease', (140, 154))	('BRCA-deficiency', 'Disease', 'OMIM:604370', (17, 32))	('BRCA-deficiency', 'Disease', (17, 32))	('bladder cancers', 'Disease', 'MESH:D001749', (108, 123))	('bladder cancers', 'Disease', (108, 123))	('breast cancers', 'Phenotype', 'HP:0003002', (140, 154))	('FA', 'Phenotype', 'HP:0001994', (98, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('patients', 'Species', '9606', (60, 68))	('BRCA', 'Gene', '672', (17, 21))	('BRCA', 'Gene', '672', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('BRCA', 'Gene', (17, 21))	('bladder cancers', 'Phenotype', 'HP:0009725', (108, 123))	('BRCA', 'Gene', (128, 132))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('mutant', 'Var', (101, 107))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))
82699	29263839	Additionally, recent research found that the presence of tumor DNA alterations in FANCC (a member of the FA pathway), ATM, and RB1 predicted beneficial response to cisplatin neoadjuvant chemotherapy.	('ATM', 'Gene', (118, 121))	('FANCC', 'Gene', '2176', (82, 87))	('FA', 'Phenotype', 'HP:0001994', (105, 107))	('RB1', 'Gene', '5925', (127, 130))	('response to cisplatin', 'biological_process', 'GO:0072718', ('152', '173'))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('beneficial', 'PosReg', (141, 151))	('FANCC', 'Gene', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('ATM', 'Gene', '472', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('RB1', 'Gene', (127, 130))	('tumor', 'Disease', (57, 62))	('FA', 'Phenotype', 'HP:0001994', (82, 84))	('response to cisplatin neoadjuvant chemotherapy', 'MPA', (152, 198))	('presence', 'Var', (45, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))
82700	29263839	Future research could determine whether FA nonsense mutations also predict beneficial response to Cisplatin, particularly given the beneficial response to cisplatin in patients with BRCA1 mutant breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (195, 209))	('BRCA1', 'Gene', '672', (182, 187))	('breast cancers', 'Disease', 'MESH:D001943', (195, 209))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('breast cancers', 'Disease', (195, 209))	('Cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('response to Cisplatin', 'biological_process', 'GO:0072718', ('86', '107'))	('beneficial', 'PosReg', (132, 142))	('BRCA1', 'Gene', (182, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('beneficial', 'PosReg', (75, 85))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('patients', 'Species', '9606', (168, 176))	('FA', 'Phenotype', 'HP:0001994', (40, 42))	('response to cisplatin', 'biological_process', 'GO:0072718', ('143', '164'))	('mutant', 'Var', (188, 194))
82707	29263839	Fourth, for germline variant analysis, TOBI's designation of SLG variants denotes "somatic-like" status, but does not differentiate oncogenic and benign germline variants.	('TOBI', 'Chemical', '-', (39, 43))	('variants', 'Var', (65, 73))	('SLG', 'Gene', (61, 64))	('SLG', 'Gene', '89858', (61, 64))
82708	29263839	Finally, fully understanding the role of FA variants in bladder cancer requires experimental validation.	('FA', 'Phenotype', 'HP:0001994', (41, 43))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('bladder cancer', 'Disease', (56, 70))	('variants', 'Var', (44, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
82709	29263839	In sum, we propose a framework that analyzes either tumor-only samples or samples with matched tumor-normal DNA for variants with somatic features.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('variants', 'Var', (116, 124))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (95, 100))
82713	29263839	Applying the TOBI framework to seven cancer types illustrated that TOBI recovers known oncogenic variants of somatic and germline origin, and suggests a previously unreported role for inactivating mutations in the FA pathway in bladder cancer.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('TOBI', 'Chemical', '-', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (37, 43))	('TOBI', 'Chemical', '-', (13, 17))	('bladder cancer', 'Disease', (228, 242))	('cancer', 'Disease', (236, 242))	('bladder cancer', 'Disease', 'MESH:D001749', (228, 242))	('bladder cancer', 'Phenotype', 'HP:0009725', (228, 242))	('inactivating mutations', 'Var', (184, 206))	('FA', 'Phenotype', 'HP:0001994', (214, 216))	('FA pathway', 'Pathway', (214, 224))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))
82715	29263839	For the remaining five TCGA cancers (BLCA, LGG, LUAD, SKCM, STAD), we downloaded Protected Mutation vcf files with somatic and germline variants for entry into the TOBI.vcf pathway indicated in Fig.	('cancers', 'Disease', (28, 35))	('variants', 'Var', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('LUAD', 'Phenotype', 'HP:0030078', (48, 52))	('LUAD', 'Disease', (48, 52))	('SKCM', 'Disease', (54, 58))	('TOBI', 'Chemical', '-', (164, 168))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('LGG', 'Disease', (43, 46))	('cancers', 'Disease', 'MESH:D009369', (28, 35))
82718	29263839	Bam files were available for datasets EGAD00001000807 (St. Jude Children's Research Hospital:Washington University Pediatric Cancer Genome Project Steering Committee) and EGAD00001000706 (ICR DIPG Data Access Committee).	('EGAD00001000706', 'Var', (171, 186))	('Children', 'Species', '9606', (64, 72))	('EGAD00001000807', 'Var', (38, 53))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))
82720	29263839	For 1000 Genomes Project samples, phase 3 bam files were downloaded from the public FTP site for the first 99 "mapped" samples listed in ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/alignment_indices/20130502.exome.alignment.index, as well as sample NA11994, which was previously reported to have a germline variant in TP53 (R273H).	('R273H', 'Var', (321, 326))	('R273H', 'Mutation', 'rs28934576', (321, 326))	('TP53', 'Gene', '7157', (315, 319))	('TP53', 'Gene', (315, 319))
82728	29263839	For each cancer, TOBI generates an optimum classification model by running a systematic grid search through gradient boosting's three parameters: number of trees (100, 150, 200), interaction depth (3-7 splits), and shrinkage (constant at 0.1).	('cancer', 'Disease', (9, 15))	('100', 'Var', (163, 166))	('TOBI', 'Chemical', '-', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
82738	29263839	For enrichment of gene sets in FP variants, the Poisson cumulative distribution was calculated for each gene set, with g total genes and n FP variants in those genes from a cancer dataset with N variants found in G genes, as the probability of a value greater than  with  using the R ppois function: ppois(n-1, g*N/G, lower.tail = FALSE).	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('variants', 'Var', (34, 42))	('cancer', 'Disease', (173, 179))	('variants', 'Var', (142, 150))	('FA', 'Phenotype', 'HP:0001994', (331, 333))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))
82741	29263839	We compared the distribution of diagnosis age for cases with or without SLG variants using the Wilcoxon-Mann-Whitney test in R, wilcox.test.	('SLG', 'Gene', (72, 75))	('variants', 'Var', (76, 84))	('SLG', 'Gene', '89858', (72, 75))
82742	29263839	g:Profiler analysis of BLCA nonsense SLG variants was run using defaults (Significant only; Hierarchical sorting; Numeric IDs treated as: WIKIGENE_ACC; Significance threshold: g:SCS threshold; Statistical domain size: Only annotated genes.)	('SLG', 'Gene', (37, 40))	('variants', 'Var', (41, 49))	('SLG', 'Gene', '89858', (37, 40))	('SCS', 'molecular_function', 'GO:0004776', ('178', '181'))
82752	25556547	Expression of tumor suppressive microRNA-34a is associated with a reduced risk of bladder cancer recurrence Bladder cancer is the 4th most common cancer among men in the U.S. and more than half of patients experience recurrences within 5 years after initial diagnosis.	('reduced', 'NegReg', (66, 73))	('cancer', 'Disease', (146, 152))	('Bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('patients', 'Species', '9606', (197, 205))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Expression', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('recurrence Bladder cancer', 'Phenotype', 'HP:0012786', (97, 122))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))	('bladder cancer', 'Disease', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('men', 'Species', '9606', (159, 162))	('microRNA-34a', 'Gene', '407040', (32, 44))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('Bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('cancer', 'Disease', (116, 122))	('Bladder cancer', 'Disease', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('microRNA-34a', 'Gene', (32, 44))	('tumor', 'Disease', (14, 19))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (82, 107))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Disease', (90, 96))
82784	25556547	For all cases with registry T values of T2b (tumor invading greater than one-half of the muscle wall) or higher, the registry T values were used; otherwise histologic grade and tumor stage was assigned by the study pathologist.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('T2b', 'Var', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
82822	25556547	We then compared the lists of differentially expressed mRNAs observed with miR-34a dysregulation against the in silico sequence-predicted miR-34a 'target genes' from a combination of sources (MicroT, Microcosm, Pictar, Segal, TargetScan).	('miR-34a', 'Gene', (138, 145))	('miR-34a', 'Gene', '407040', (75, 82))	('miR-34a', 'Gene', (75, 82))	('dysregulation', 'Var', (83, 96))	('miR-34a', 'Gene', '407040', (138, 145))
82849	25556547	Specifically, we assessed whether modulation of miR-34a expression in a controlled experimental setting could modify the behavior of cells in tumorigenic assays using cultured bladder epithelial cell lines.	('miR-34a', 'Gene', '407040', (48, 55))	('modify', 'Reg', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('miR-34a', 'Gene', (48, 55))	('men', 'Species', '9606', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('modulation', 'Var', (34, 44))
82869	25556547	In other cell types, the downregulation of miR-34a was not correlated with deletion of the chromosomal region encoding miR-34a (1p36), nor with P53 mutation.	('deletion', 'Var', (75, 83))	('miR-34a', 'Gene', '407040', (43, 50))	('P53', 'Gene', (144, 147))	('miR-34a', 'Gene', '407040', (119, 126))	('miR-34a', 'Gene', (119, 126))	('chromosomal region', 'cellular_component', 'GO:0098687', ('91', '109'))	('downregulation', 'NegReg', (25, 39))	('miR-34a', 'Gene', (43, 50))	('P53', 'Gene', '7157', (144, 147))
82873	25556547	MiR-34a is silenced by methylation of CpGs in the promoter in several types of cancer and methylation was observed in two of six bladder cell lines (33%).	('silenced', 'NegReg', (11, 19))	('methylation', 'Var', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('MiR-34a', 'Gene', (0, 7))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('methylation', 'biological_process', 'GO:0032259', ('90', '101'))	('MiR-34a', 'Gene', '407040', (0, 7))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('CpGs', 'Protein', (38, 42))
82874	25556547	Likewise, five out of the seven (71%) muscle invasive urothelial cell tumor tissue samples tested in a previous study had methylated miR-34a CpGs.	('methylated', 'Var', (122, 132))	('invasive urothelial cell tumor', 'Disease', 'MESH:D001749', (45, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('invasive urothelial cell tumor', 'Disease', (45, 75))	('miR-34a', 'Gene', '407040', (133, 140))	('muscle invasive urothelial cell tumor', 'Phenotype', 'HP:0006740', (38, 75))	('miR-34a', 'Gene', (133, 140))
82878	25556547	Anti-miR-34a treatment of normal urothelial cells to simulate loss of miR-34 revealed a variety of downstream differences in mRNA expression (Supplementary Figure 1).	('loss', 'Var', (62, 66))	('miR-34', 'Gene', '407040', (70, 76))	('men', 'Species', '9606', (18, 21))	('miR-34a', 'Gene', '407040', (5, 12))	('men', 'Species', '9606', (148, 151))	('miR-34', 'Gene', (5, 11))	('miR-34a', 'Gene', (5, 12))	('differences', 'Reg', (110, 121))	('mRNA expression', 'MPA', (125, 140))	('miR-34', 'Gene', '407040', (5, 11))	('miR-34', 'Gene', (70, 76))
82880	25556547	We reaffirmed this opposing relationship in bladder tissue with the observation that tumors showing loss of miR-34a also show 4-fold higher expression of S100P compared to normal tissue.	('loss', 'Var', (100, 104))	('expression', 'MPA', (140, 150))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('miR-34a', 'Gene', (108, 115))	('higher', 'PosReg', (133, 139))	('S100P', 'Gene', '6286', (154, 159))	('S100P', 'Gene', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('miR-34a', 'Gene', '407040', (108, 115))	('tumors', 'Disease', (85, 91))
82882	25556547	S100P positivity was also previously associated with 7-fold shorter breast cancer survival, poor clinical outcomes for gastric cancer patients, and is a marker of aggressive, hormone-resistant and metastatic prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('positivity', 'Var', (6, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('patients', 'Species', '9606', (134, 142))	('gastric cancer', 'Disease', (119, 133))	('breast cancer', 'Disease', (68, 81))	('prostate cancer', 'Disease', 'MESH:D011471', (208, 223))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('prostate cancer', 'Phenotype', 'HP:0012125', (208, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('S100P', 'Gene', '6286', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('shorter', 'NegReg', (60, 67))	('prostate cancer', 'Disease', (208, 223))	('S100P', 'Gene', (0, 5))
82949	30112447	Study Title: A Phase 2, Open-Label, Single-Agent, Multicenter Study to Evaluate the Efficacy and Safety of INCB054828 in Subjects with Metastatic or Surgically Unresectable Urothelial Carcinoma Harboring FGF/FGFR Alterations Protocol Number: NCT02872714 Sponsor: Incyte Rationale: This is an open-label monotherapy study of INCB054828, a selective FGFR 1, 2, and 3 inhibitor, in subjects with metastatic or surgically unresectable urothelial carcinoma harboring FGF/FGFR alterations.	('alterations', 'Var', (471, 482))	('Urothelial Carcinoma Harboring FGF', 'Disease', (173, 207))	('urothelial carcinoma', 'Disease', (431, 451))	('carcinoma', 'Phenotype', 'HP:0030731', (442, 451))	('FGFR 1', 'Gene', '2260', (348, 354))	('FGFR', 'molecular_function', 'GO:0005007', ('208', '212'))	('FGFR', 'molecular_function', 'GO:0005007', ('466', '470'))	('FGF/FGFR', 'Gene', (462, 470))	('FGFR', 'molecular_function', 'GO:0005007', ('348', '352'))	('INCB054828', 'Gene', (324, 334))	('Urothelial Carcinoma Harboring FGF', 'Disease', 'MESH:C537062', (173, 207))	('Carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('FGFR 1', 'Gene', (348, 354))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (431, 451))
82950	30112447	Study Design: Subjects must have a known FGF/FGFR alteration and have either: (a) failed at least 1 previous treatment for their metastatic or surgically unresectable urothelial carcinoma (ie, chemotherapy, immunotherapy), or (b) have not received chemotherapy for metastatic or surgically unresectable urothelial carcinoma due to poor ECOG performance or have insufficient renal function (ie, creatinine clearance < 60 mL/min or local guidelines).	('urothelial carcinoma', 'Disease', (303, 323))	('creatinine', 'Chemical', 'MESH:D003404', (394, 404))	('insufficient renal function', 'Disease', 'MESH:D051437', (361, 388))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (167, 187))	('alteration', 'Var', (50, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (314, 323))	('creatinine clearance', 'MPA', (394, 414))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (303, 323))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('urothelial carcinoma', 'Disease', (167, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('insufficient renal function', 'Disease', (361, 388))
82951	30112447	Primary endpoints: Objective response rate in subjects with FGFR3 mutations or fusions based on central genomics laboratory results (Cohort A).	('mutations', 'Var', (66, 75))	('FGFR3', 'Gene', (60, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('FGFR3', 'Gene', '2261', (60, 65))	('fusions', 'Var', (79, 86))
82952	30112447	Secondary Endpoints: Objective response rate in all subjects with FGFR3 mutations or fusions and all other FGF/FGFR alterations (Cohorts A and B combined).	('mutations', 'Var', (72, 81))	('FGFR3', 'Gene', '2261', (66, 71))	('fusions', 'Var', (85, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('FGFR3', 'Gene', (66, 71))
82953	30112447	Enrollment: Approximately 140 patients Study Title: A Phase 2, Two-arm Multicenter, Open-Label Study to Determine the Efficacy and the Safety of Two Different Dose Regimens of a pan-FGFR Tyrosine Kinase Inhibitor JNJ-42756493 in Subjects with Metastatic or Surgically Unresectable Urothelial Cancer with FGFR Genomic Alterations Protocol Number: NCT02365597 Sponsor: Janssen Research & Development, LLC Rationale: JNJ-42756493 (Erdafitinib) is a selective and potent orally administered pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor with activity in patients with solid tumors with alterations in the FGFR pathway including urothelial carcinoma, indicating the potential to be a new therapeutic option for these patients.	('kinase inhibitor', 'biological_process', 'GO:0033673', ('541', '557'))	('Kinase Inhibitor', 'biological_process', 'GO:0033673', ('196', '212'))	('FGFR', 'molecular_function', 'GO:0005007', ('526', '530'))	('solid tumors', 'Disease', 'MESH:D009369', (589, 601))	('patients', 'Species', '9606', (737, 745))	('FGFR', 'molecular_function', 'GO:0005007', ('304', '308'))	('tumor', 'Phenotype', 'HP:0002664', (595, 600))	('the FGFR', 'Pathway', (622, 630))	('carcinoma', 'Phenotype', 'HP:0030731', (660, 669))	('patients', 'Species', '9606', (30, 38))	('FGFR', 'molecular_function', 'GO:0005007', ('182', '186'))	('Urothelial Cancer', 'Disease', 'MESH:D014523', (281, 298))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (428, 439))	('urothelial carcinoma', 'Disease', (649, 669))	('Urothelial Cancer', 'Disease', (281, 298))	('patients', 'Species', '9606', (575, 583))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('491', '515'))	('LLC', 'cellular_component', 'GO:0038045', ('399', '402'))	('Cancer', 'Phenotype', 'HP:0002664', (292, 298))	('with', 'Var', (602, 606))	('solid tumors', 'Disease', (589, 601))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (649, 669))	('FGFR', 'molecular_function', 'GO:0005007', ('626', '630'))	('tumors', 'Phenotype', 'HP:0002664', (595, 601))	('with', 'MPA', (558, 562))
82955	30112447	Results: The Phase 2 study BLC2001 presented at the 2018 ASCO Genitourinary Cancers Symposium showed an overall response rate of 42 percent in 59 patients with relapsed/refractory metastatic urothelial cancer whose tumors harbored actionable FGFR mutations (ASCO-GU abstract #411, ASCO abstract #4503) A Breakthrough Therapy Designation in March 2018 was granted by the US FDA based on data from this multicenter, open-label Phase 2 clinical trial evaluating the efficacy and safety of erdafitinib in the treatment of adult patients with locally advanced or metastatic urothelial cancer, whose tumors have certain fibroblast growth factor receptor (FGFR) genetic alterations.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumors', 'Phenotype', 'HP:0002664', (594, 600))	('FGFR', 'molecular_function', 'GO:0005007', ('242', '246'))	('ASCO Genitourinary', 'Phenotype', 'HP:0000119', (57, 75))	('Genitourinary Cancers', 'Disease', (62, 83))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('urothelial cancer', 'Disease', 'MESH:D014523', (569, 586))	('mutations', 'Var', (247, 256))	('cancer', 'Phenotype', 'HP:0002664', (580, 586))	('tumors', 'Disease', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (594, 599))	('urothelial cancer', 'Disease', (569, 586))	('tumors', 'Disease', (594, 600))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('614', '638'))	('FGFR', 'Gene', (649, 653))	('locally advanced', 'Disease', (538, 554))	('patients', 'Species', '9606', (146, 154))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('FGFR', 'molecular_function', 'GO:0005007', ('649', '653'))	('tumors', 'Disease', 'MESH:D009369', (594, 600))	('Genitourinary Cancers', 'Disease', 'MESH:D014565', (62, 83))	('genetic alterations', 'Var', (655, 674))	('Cancers', 'Phenotype', 'HP:0002664', (76, 83))	('FGFR', 'Gene', (242, 246))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('urothelial cancer', 'Disease', 'MESH:D014523', (191, 208))	('patients', 'Species', '9606', (524, 532))	('erdafitinib', 'Chemical', 'MESH:C000604580', (486, 497))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('urothelial cancer', 'Disease', (191, 208))
82959	30112447	Cohort 1: Erdafitinib vs Vinflunine or Docetaxel Cohort 2: Erdafitinib vs. Pembrolizumab Primary Endpoint: Overall Survival (OS) Secondary Endpoints: Time Frame: Approximately up to 3 years ; Progression-free Survival (PFS), Overall Response Rate (ORR), Patient-Reported Health Status, Patient-Global Impression of Severity (PGIS) Score, the Visual Analog Scale (VAS) of the EQ-5D-5L, Utility Scale of the EQ-5D-5L, Duration of Response (DOR), Safety, Oral Clearance (CL/F) of Erdafitinib, AUC of Erdafitinib Enrollment: 631 Study Title: Study of Rogaratinib (BAY1163877) vs Chemotherapy in Patients With FGFR (Fibroblast Growth Factor Receptor)-Positive Locally Advanced or Metastatic Urothelial Carcinoma (FORT-1) Protocol Number: NCT03410693 Sponsor: Bayer Rationale: To compare rogaratinib (BAY1163877) with chemotherapy (docetaxel, paclitaxel or vinflunine) in terms of prolonging the Overall survival (OS) of patients with FGFR positive urothelial carcinoma.	('Fibroblast Growth Factor', 'molecular_function', 'GO:0005104', ('611', '635'))	('BAY1163877', 'Chemical', '-', (560, 570))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (477, 488))	('Patients', 'Species', '9606', (591, 599))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (10, 21))	('Patient', 'Species', '9606', (286, 293))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (75, 88))	('FGFR positive', 'Gene', (929, 942))	('Carcinoma', 'Phenotype', 'HP:0030731', (697, 706))	('carcinoma', 'Phenotype', 'HP:0030731', (954, 963))	('paclitaxel', 'Chemical', 'MESH:D017239', (837, 847))	('CL', 'Disease', 'None', (468, 470))	('urothelial carcinoma', 'Disease', (943, 963))	('vinflunine', 'Chemical', 'MESH:C111217', (851, 861))	('docetaxel', 'Chemical', 'MESH:D000077143', (826, 835))	('Overall survival', 'MPA', (890, 906))	('FGFR', 'molecular_function', 'GO:0005007', ('605', '609'))	('prolonging', 'PosReg', (875, 885))	('FGFR', 'molecular_function', 'GO:0005007', ('929', '933'))	('patients', 'Species', '9606', (915, 923))	('Metastatic Urothelial Carcinoma', 'Disease', 'MESH:C538445', (675, 706))	('Patient', 'Species', '9606', (591, 598))	('BAY1163877', 'Chemical', '-', (795, 805))	('Rogaratinib', 'Chemical', '-', (547, 558))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (497, 508))	('BAY1163877', 'Var', (795, 805))	('Vinflunine', 'Chemical', 'MESH:C111217', (25, 35))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (943, 963))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (59, 70))	('Metastatic Urothelial Carcinoma', 'Disease', (675, 706))	('rogaratinib', 'Chemical', '-', (782, 793))	('Docetaxel', 'Chemical', 'MESH:D000077143', (39, 48))	('Patient', 'Species', '9606', (254, 261))
82964	30112447	Primary Endpoint: Overall Survival Secondary Endpoints: Time Frame: Up to 45 months; Progression-free survival (PFS), Objective response rate (ORR,) Disease-control rate (DCR), Duration of response (DOR), safety and tolerability Enrollment: 400 participants Comments: The FGFR inhibitor trials are all being conducted in patients with FGFR alterations and locally advanced UC and the preliminary data presented at ASCO in at least one inhibitor is very encouraging.	('participants', 'Species', '9606', (245, 257))	('alterations', 'Var', (340, 351))	('patients', 'Species', '9606', (321, 329))	('FGFR', 'Gene', (335, 339))	('FGFR', 'molecular_function', 'GO:0005007', ('272', '276'))	('FGFR', 'molecular_function', 'GO:0005007', ('335', '339'))
82978	27567210	Finally, targeted therapy against alterations present in rare patients (less than 2%) across diseases has the potential to drastically alter patterns of care and choices of therapeutic options.	('alter', 'Reg', (135, 140))	('patients', 'Species', '9606', (62, 70))	('targeted therapy', 'Var', (9, 25))
82995	27567210	First, this can refer to classic targeted therapy, in which a specific gene product serves as both the biomarker and the target of therapeutic action:HER2 overexpression in breast cancer, or BRAF mutations in melanoma, are classic examples.	('BRAF', 'Gene', (191, 195))	('HER2', 'Gene', '2064', (150, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('HER2', 'Gene', (150, 154))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('overexpression', 'PosReg', (155, 169))	('melanoma', 'Disease', (209, 217))	('BRAF', 'Gene', '673', (191, 195))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('mutations', 'Var', (196, 205))	('breast cancer', 'Disease', (173, 186))
83001	27567210	Application of these technologies, including systematic studies as part of the International Cancer Genome Consortium and The Cancer Genome Atlas projects, has led to a massive expansion of the catalog of known alterations in urologic oncology, the starting point for defining biomarkers with real relevance for clinical care.	('oncology', 'Phenotype', 'HP:0002664', (235, 243))	('Cancer', 'Disease', (126, 132))	('Cancer', 'Disease', 'MESH:D009369', (126, 132))	('Cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Cancer Genome Atlas', 'Disease', (126, 145))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))	('alterations', 'Var', (211, 222))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (126, 145))	('Cancer', 'Disease', (93, 99))	('urologic oncology', 'Disease', (226, 243))	('Cancer', 'Disease', 'MESH:D009369', (93, 99))
83003	27567210	The oldest form of targeted therapy in urology (and perhaps in all of oncology) came with the recognition that ablation of androgens via surgical castration resulted in regression of advanced prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (192, 207))	('advanced prostate cancer', 'Disease', (183, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('oncology', 'Phenotype', 'HP:0002664', (70, 78))	('ablation', 'Var', (111, 119))	('advanced prostate cancer', 'Disease', 'MESH:D011471', (183, 207))
83008	27567210	Deregulation of the androgen signaling axis is common in prostate cancer, and alterations in the AR gene itself become highly prevalent in CRPC.	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('prostate cancer', 'Disease', (57, 72))	('CRPC', 'Disease', (139, 143))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (57, 72))	('AR gene', 'Gene', (97, 104))	('alterations', 'Var', (78, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (57, 72))	('androgen signaling axis', 'Pathway', (20, 43))	('prevalent', 'Reg', (126, 135))
83010	27567210	Several studies suggest that AR amplification and mutation are more common in patients progressing on these therapies compared with responders, and there are suggestions that amplification of AR can predict response to both enzalutamide and abiraterone.	('response', 'MPA', (207, 215))	('enzalutamide', 'Chemical', 'MESH:C540278', (224, 236))	('abiraterone', 'Chemical', 'MESH:C089740', (241, 252))	('patients', 'Species', '9606', (78, 86))	('amplification', 'Var', (175, 188))	('mutation', 'Var', (50, 58))	('predict', 'Reg', (199, 206))
83017	27567210	Clear cell RCC (ccRCC), the most common and among the most aggressive histological variant, is highly associated with inactivation of the tumor suppressor VHL.	('RCC', 'Disease', (18, 21))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('VHL', 'Gene', '7428', (155, 158))	('associated', 'Reg', (102, 112))	('tumor', 'Disease', (138, 143))	('tumor suppressor', 'biological_process', 'GO:0051726', ('138', '154'))	('VHL', 'Gene', (155, 158))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('138', '154'))	('inactivation', 'Var', (118, 130))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
83018	27567210	The VHL gene undergoes inactivation via point mutations, genomic deletions, and gene methylation in ccRCC.	('gene methylation', 'Var', (80, 96))	('point mutations', 'Var', (40, 55))	('methylation', 'biological_process', 'GO:0032259', ('85', '96'))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('inactivation', 'MPA', (23, 35))	('RCC', 'Disease', (102, 105))	('VHL', 'Gene', (4, 7))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('VHL', 'Gene', '7428', (4, 7))
83020	27567210	Inactivation of VHL in RCC leads to increased HIFalpha expression, and increased activation of targets genes such as VEGF and PDGF.	('VEGF', 'Gene', (117, 121))	('VHL', 'Gene', (16, 19))	('PDGF', 'molecular_function', 'GO:0005161', ('126', '130'))	('VHL', 'Gene', '7428', (16, 19))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('VEGF', 'Gene', '7422', (117, 121))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('increased', 'PosReg', (36, 45))	('RCC', 'Disease', (23, 26))	('increased activation', 'PosReg', (71, 91))	('HIFalpha expression', 'MPA', (46, 65))	('Inactivation', 'Var', (0, 12))
83021	27567210	Because of the universality of VHL inactivation and activation of the HIF/vascular endothelial growth factor (VEGF) pathways in RCC, interference with downstream effects of HIF (in particular VEGF and PDGF signaling) emerged as a major focus of drug development and clinical research over the past decade.	('VHL', 'Gene', '7428', (31, 34))	('HIF/vascular endothelial growth factor', 'Gene', '7422', (70, 108))	('VEGF', 'Gene', '7422', (192, 196))	('RCC', 'Disease', (128, 131))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('men', 'Species', '9606', (257, 260))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('signaling', 'biological_process', 'GO:0023052', ('206', '215'))	('inactivation', 'Var', (35, 47))	('VEGF', 'Gene', '7422', (110, 114))	('PDGF', 'molecular_function', 'GO:0005161', ('201', '205'))	('HIF/vascular endothelial growth factor', 'Gene', (70, 108))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('74', '108'))	('VEGF', 'Gene', (192, 196))	('VHL', 'Gene', (31, 34))	('VEGF', 'Gene', (110, 114))	('activation', 'PosReg', (52, 62))
83029	27567210	Like VHL inactivation and upregulation of hypoxia transcriptional programs, activation of the mTOR/PI3K pathway is common in RCC.	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('PI3K', 'molecular_function', 'GO:0016303', ('99', '103'))	('RCC', 'Disease', (125, 128))	('mTOR', 'Gene', (94, 98))	('VHL', 'Gene', (5, 8))	('mTOR', 'Gene', '2475', (94, 98))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('VHL', 'Gene', '7428', (5, 8))	('upregulation', 'PosReg', (26, 38))	('hypoxia', 'Disease', (42, 49))	('inactivation', 'Var', (9, 21))	('hypoxia', 'Disease', 'MESH:D000860', (42, 49))	('activation', 'PosReg', (76, 86))
83030	27567210	Genomic alterations in this pathway are relatively uncommon when estimated from a single tumor sample, with mutations in genes such as MTOR, TSC1, PIK3CA, and PTEN occurring in less than 10% of RCC patients.	('TSC1', 'Gene', (141, 145))	('mutations', 'Var', (108, 117))	('PTEN', 'Gene', (159, 163))	('MTOR', 'Gene', (135, 139))	('patients', 'Species', '9606', (198, 206))	('PTEN', 'Gene', '5728', (159, 163))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('PIK3CA', 'Gene', (147, 153))	('RCC', 'Disease', (194, 197))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('MTOR', 'Gene', '2475', (135, 139))	('PIK3CA', 'Gene', '5290', (147, 153))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('TSC1', 'Gene', '7248', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
83032	27567210	It is increasingly clear that somatic mutations in the mTOR pathway display clear evidence of intratumor heterogeneity, commonly occurring in some tumor subclones but not others.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', (147, 152))	('mTOR', 'Gene', (55, 59))	('occurring', 'Reg', (129, 138))	('mTOR', 'Gene', '2475', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mutations', 'Var', (38, 47))
83035	27567210	Inhibitors of mTOR signaling are currently used as standard options for poor risk RCC patients.	('mTOR', 'Gene', '2475', (14, 18))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('Inhibitors', 'Var', (0, 10))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('mTOR', 'Gene', (14, 18))	('patients', 'Species', '9606', (86, 94))
83054	27567210	Similarly, Plimack et al showed that lesions in DNA repair genes ATM, RB1, and FANCC predicted pathologic response to neoadjuvant cisplatin.	('ATM', 'Gene', '472', (65, 68))	('lesions', 'Var', (37, 44))	('RB1', 'Gene', (70, 73))	('pathologic response to neoadjuvant cisplatin', 'MPA', (95, 139))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('FANCC', 'Gene', '2176', (79, 84))	('FANCC', 'Gene', (79, 84))	('RB1', 'Gene', '5925', (70, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('DNA repair', 'biological_process', 'GO:0006281', ('48', '58'))	('ATM', 'Gene', (65, 68))	('predicted', 'Reg', (85, 94))
83056	27567210	Utilizing targeted sequencing of urothelial carcinoma (muscle invasive and metastatic tumors) from patients treated with platinum-based chemotherapy regimens, Groenendijk and colleagues reported that ERBB2 mutations were associated with improved response to neoadjuvant chemotherapy.	('platinum', 'Chemical', 'MESH:D010984', (121, 129))	('mutations', 'Var', (206, 215))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('response', 'CPA', (246, 254))	('improved', 'PosReg', (237, 245))	('urothelial carcinoma', 'Disease', (33, 53))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('men', 'Species', '9606', (153, 156))	('patients', 'Species', '9606', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('ERBB2', 'Gene', '2064', (200, 205))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (33, 53))	('ERBB2', 'Gene', (200, 205))
83063	27567210	A phase 2 trial of the polyadenosine diphosphate ribose polymerase inihibitor olaparib in metastatic CRPC showed patient responses specifically associated with defects in DNA repair pathways, with further trials ongoing.	('olaparib', 'Chemical', 'MESH:C531550', (78, 86))	('patient', 'Species', '9606', (113, 120))	('defects', 'Var', (160, 167))	('metastatic CRPC', 'Disease', (90, 105))	('DNA', 'cellular_component', 'GO:0005574', ('171', '174'))	('DNA repair pathways', 'Pathway', (171, 190))	('DNA repair', 'biological_process', 'GO:0006281', ('171', '181'))
83065	27567210	Furthermore, emerging data also suggest that CRPC patients have a surprising prevalence of germline defects in DNA repair genes (eg, BRCA carriers), expanding the potential impact.	('defects', 'Var', (100, 107))	('patients', 'Species', '9606', (50, 58))	('BRCA', 'Gene', '672;675', (133, 137))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('DNA repair', 'biological_process', 'GO:0006281', ('111', '121'))	('CRPC', 'Disease', (45, 49))	('DNA repair genes', 'Gene', (111, 127))	('BRCA', 'Gene', (133, 137))
83075	27567210	In urothelial carcinoma, genome sequencing revealed that a patient with an exceptional response to everolimus harbored mutations in the mTOR and NF genes.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (3, 23))	('patient', 'Species', '9606', (59, 66))	('urothelial carcinoma', 'Disease', (3, 23))	('everolimus', 'Chemical', 'MESH:D000068338', (99, 109))	('harbored', 'Reg', (110, 118))	('mTOR', 'Gene', (136, 140))	('mTOR', 'Gene', '2475', (136, 140))	('mutations', 'Var', (119, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
83076	27567210	These alterations were subsequently shown to impact the response of cancer cells to everolimus, nominating these alterations as potential biomarkers of response to mTOR inhibition.	('alterations', 'Var', (6, 17))	('response', 'MPA', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('everolimus', 'Chemical', 'MESH:D000068338', (84, 94))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('impact', 'Reg', (45, 51))	('cancer', 'Disease', (68, 74))	('mTOR', 'Gene', (164, 168))	('mTOR', 'Gene', '2475', (164, 168))
83079	27567210	Many distinct, legitimately targetable alterations, with currently available therapeutics of proven efficacy, exist in urologic malignancies.	('urologic malignancies', 'Disease', 'MESH:D014570', (119, 140))	('alterations', 'Var', (39, 50))	('urologic malignancies', 'Disease', (119, 140))
83083	27567210	It should also be borne in mind that large-scale alterations in whole or parts of chromosomes that are currently refractory to contemporary targeted therapy strategies, can also drive tumor progression.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('alterations', 'Var', (49, 60))	('drive', 'Reg', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))
83084	27567210	For instance, in papillary renal cancer driver gene mutations are often subclonal alterations, in contrast to large-scale chromosomal alterations that were found to be clonal in nature.	('mutations', 'Var', (52, 61))	('papillary renal cancer', 'Disease', (17, 39))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (17, 39))	('renal cancer', 'Phenotype', 'HP:0009726', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('papillary renal cancer', 'Disease', 'MESH:D007681', (17, 39))
83086	27567210	Amplifications, activating mutations, and gene fusions in the kinase BRAF (a common driver in melanoma and other cancers) occur in roughly 1-5% of prostate cancers:these may be targetable with currently available inhibitors.	('mutations', 'Var', (27, 36))	('prostate cancer', 'Phenotype', 'HP:0012125', (147, 162))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('prostate cancers', 'Phenotype', 'HP:0012125', (147, 163))	('prostate cancers', 'Disease', (147, 163))	('activating', 'PosReg', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('BRAF', 'Gene', '673', (69, 73))	('BRAF', 'Gene', (69, 73))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('prostate cancers', 'Disease', 'MESH:D011471', (147, 163))	('cancers', 'Disease', (156, 163))	('gene fusions', 'Var', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
83087	27567210	Amplifications and mutations in ERRB2, encoding the growth factor receptor tyrosine kinase HER2/neu, are present in about 10% of muscle invasive bladder cancers :these cancers may be susceptible to trastuzumab (Herceptin).	('cancers', 'Disease', (153, 160))	('bladder cancers', 'Phenotype', 'HP:0009725', (145, 160))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('cancers', 'Disease', (168, 175))	('muscle invasive bladder cancers', 'Disease', 'MESH:D001749', (129, 160))	('trastuzumab', 'Chemical', 'MESH:D000068878', (198, 209))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('HER2/neu', 'Gene', (91, 99))	('Herceptin', 'Chemical', 'MESH:D000068878', (211, 220))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('invasive bladder', 'Phenotype', 'HP:0100645', (136, 152))	('ERRB2', 'Gene', (32, 37))	('muscle invasive bladder cancers', 'Disease', (129, 160))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('HER2/neu', 'Gene', '2064', (91, 99))	('mutations', 'Var', (19, 28))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
83088	27567210	Mutations in the epigenetic modifying enzyme IDH1, one of the most common mutations in gliomas, occur in about 1% of prostate cancers.	('IDH1', 'Gene', '3417', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('prostate cancers', 'Disease', 'MESH:D011471', (117, 133))	('occur', 'Reg', (96, 101))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('Mutations', 'Var', (0, 9))	('prostate cancers', 'Phenotype', 'HP:0012125', (117, 133))	('IDH1', 'Gene', (45, 49))	('prostate cancers', 'Disease', (117, 133))	('gliomas', 'Disease', (87, 94))
83089	27567210	IDH1 mutation also represents an attractive target for therapy, with promising preclinical data.	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
83102	27366083	Furthermore, MST in ERCC1 and BRCA1 double-positive patients was shorter than ERCC1 and BRCA1 double-negative patients (P<0.05).	('BRCA1', 'Gene', (88, 93))	('ERCC1', 'Gene', (20, 25))	('BRCA1', 'Gene', (30, 35))	('ERCC1', 'Gene', '2067', (20, 25))	('shorter', 'NegReg', (65, 72))	('BRCA1', 'Gene', '672', (88, 93))	('BRCA1', 'Gene', '672', (30, 35))	('double-positive', 'Var', (36, 51))	('ERCC1', 'Gene', '2067', (78, 83))	('ERCC1', 'Gene', (78, 83))	('patients', 'Species', '9606', (110, 118))	('patients', 'Species', '9606', (52, 60))	('MST', 'MPA', (13, 16))
83144	27366083	The MSTs for those groups with ERCC1 and BRCA1 dual-negative or -positive were 26.6 (95% CI: 19.97-33.24) or 16.6 months (95% CI: 7.98-25.22), respectively.	('dual-negative', 'Var', (47, 60))	('BRCA1', 'Gene', '672', (41, 46))	('ERCC1', 'Gene', '2067', (31, 36))	('BRCA1', 'Gene', (41, 46))	('ERCC1', 'Gene', (31, 36))
83150	27366083	The abnormal expression of these DNA repair-related genes in tumor cells is considered as one of the mechanisms for the development of chemotherapy drug resistance.	('DNA repair', 'biological_process', 'GO:0006281', ('33', '43'))	('abnormal', 'Var', (4, 12))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('DNA repair-related genes', 'Gene', (33, 57))	('drug resistance', 'Phenotype', 'HP:0020174', (148, 163))	('drug resistance', 'biological_process', 'GO:0009315', ('148', '163'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('drug resistance', 'biological_process', 'GO:0042493', ('148', '163'))	('tumor', 'Disease', (61, 66))
83156	27366083	Previously, in a cohort of 57 cases of advanced bladder cancer, the patients with low expression levels of ERCC1 were found to have an obviously longer MST (25.4 months) than those with high expression levels of ERCC1 (15.4 months).	('bladder cancer', 'Disease', (48, 62))	('ERCC1', 'Gene', '2067', (212, 217))	('ERCC1', 'Gene', (212, 217))	('ERCC1', 'Gene', '2067', (107, 112))	('ERCC1', 'Gene', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('patients', 'Species', '9606', (68, 76))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))	('MST', 'MPA', (152, 155))	('low expression levels', 'Var', (82, 103))	('longer', 'PosReg', (145, 151))
83161	27366083	The mutation rate of BRCA1 is ~35%-40% in familial breast and ovarian cancer.	('BRCA1', 'Gene', '672', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('BRCA1', 'Gene', (21, 26))	('mutation', 'Var', (4, 12))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('familial breast and ovarian cancer', 'Disease', 'MESH:D061325', (42, 76))
83166	27366083	Among many factors analyzed for prognosis, only the low expression of BRCA1 and lymph node metastasis were independent prognostic factors.	('BRCA1', 'Gene', (70, 75))	('BRCA1', 'Gene', '672', (70, 75))	('low', 'Var', (52, 55))
83232	19371909	Pathological findings for the other 6 patients showed pT2-T4, grade 3 TCC.	('TCC', 'cellular_component', 'GO:0005579', ('70', '73'))	('TCC', 'Gene', '94081', (70, 73))	('patients', 'Species', '9606', (38, 46))	('TCC', 'Gene', (70, 73))	('pT2-T4', 'Var', (54, 60))
83268	19371909	Single-institution studies have demonstrated that patients with cT0 status after chemotherapy who forego cystectomy have a survival rate similar to those undergoing immediate cystectomy.	('cT0 status', 'Var', (64, 74))	('survival', 'MPA', (123, 131))	('patients', 'Species', '9606', (50, 58))	('cT0', 'Chemical', '-', (64, 67))
83278	31412252	show that p63 and SOX2 cooperate to induce enhanced GLUT1 expression, driving a critical reliance on glucose, in squamous cell carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('enhanced', 'PosReg', (43, 51))	('p63', 'Var', (10, 13))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (113, 137))	('expression', 'MPA', (58, 68))	('glucose', 'Chemical', 'MESH:D005947', (101, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('GLUT1', 'Protein', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (113, 137))	('squamous cell carcinomas', 'Disease', (113, 137))
83279	31412252	Systemic glucose restriction by ketogenic diet or SGLT2 inhibition attenuates squamous tumor progression by disrupting redox homeostasis and insulin/AKT pathways in vivo.	('squamous tumor', 'Disease', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('glucose', 'Chemical', 'MESH:D005947', (9, 16))	('redox homeostasis', 'MPA', (119, 136))	('homeostasis', 'biological_process', 'GO:0042592', ('125', '136'))	('insulin', 'molecular_function', 'GO:0016088', ('141', '148'))	('attenuates', 'NegReg', (67, 77))	('squamous tumor', 'Phenotype', 'HP:0002860', (78, 92))	('inhibition', 'Var', (56, 66))	('disrupting', 'NegReg', (108, 118))	('insulin', 'Gene', (141, 148))	('squamous tumor', 'Disease', 'MESH:D002294', (78, 92))	('insulin', 'Gene', '3630', (141, 148))	('SGLT2', 'Gene', (50, 55))
83284	31412252	Despite the unique microenvironmental cues of the tissues where SCCs arise, the majority of SCCs share common oncogenic abnormalities, such as the amplification of chromosome 3q, which contains important transcriptional regulators p63 and SOX2.	('SCC', 'Gene', '6317', (92, 95))	('SCC', 'Gene', '6317', (64, 67))	('oncogenic abnormalities', 'Disease', 'MESH:C537751', (110, 133))	('SCC', 'Gene', (92, 95))	('chromosome', 'cellular_component', 'GO:0005694', ('164', '174'))	('amplification', 'Var', (147, 160))	('oncogenic abnormalities', 'Disease', (110, 133))	('SCC', 'Gene', (64, 67))
83285	31412252	p63, part of the p53 protein family, is a master transcription factor of stem cell pluripotency and remains crucial in basal epithelial development, differentiation, and prevention of senescence.	('transcription factor', 'molecular_function', 'GO:0000981', ('49', '69'))	('p53', 'Gene', (17, 20))	('transcription', 'biological_process', 'GO:0006351', ('49', '62'))	('senescence', 'biological_process', 'GO:0010149', ('184', '194'))	('p63', 'Var', (0, 3))	('p53', 'Gene', '7157', (17, 20))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
83286	31412252	Recent studies have established the oncogenicity of amplified DeltaNp63, an isoform that lacks the N-terminal transactivation (TA) domains as a result of an alternative transcriptional start site, in squamous cancer development and progression.	('amplified', 'Var', (52, 61))	('DeltaNp63', 'Gene', (62, 71))	('squamous cancer', 'Disease', (200, 215))	('squamous cancer', 'Disease', 'MESH:D018307', (200, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('transactivation', 'biological_process', 'GO:2000144', ('110', '125'))	('squamous cancer', 'Phenotype', 'HP:0002860', (200, 215))
83289	31412252	Ectopic SOX2 expression in autochthonous mouse models of lung cancer resulted in squamous lineage restriction.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('SOX2', 'Protein', (8, 12))	('mouse', 'Species', '10090', (41, 46))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('Ectopic', 'Var', (0, 7))	('squamous lineage restriction', 'CPA', (81, 109))	('resulted in', 'Reg', (69, 80))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
83292	31412252	Here, we seek to further uncover the precise mechanism through which p63 and SOX2 cooperatively exert a SCC-specific oncogenic phenotype.	('SCC', 'Gene', (104, 107))	('exert', 'Reg', (96, 101))	('SOX2', 'Gene', (77, 81))	('SCC', 'Gene', '6317', (104, 107))	('p63', 'Var', (69, 72))
83301	31412252	Moreover, glucose restriction by ketogenic diet, inhibition of renal glucose reabsorption with US Food and Drug Administration (FDA)-approved SGLT2 inhibitor canagliflozin, and genetic ablation of the SLC2A1 gene effectively and specifically suppressed the tumor growth of SCC xenografts as well as autochthonous transgenic mouse models.	('SCC', 'Gene', '6317', (273, 276))	('glucose', 'Chemical', 'MESH:D005947', (10, 17))	('glucose', 'Chemical', 'MESH:D005947', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (257, 262))	('glucose reabsorption', 'biological_process', 'GO:0035623', ('69', '89'))	('renal glucose reabsorption', 'Disease', 'MESH:D007674', (63, 89))	('canagliflozin', 'Chemical', 'MESH:D000068896', (158, 171))	('mouse', 'Species', '10090', (324, 329))	('SLC2A1', 'Gene', (201, 207))	('SCC', 'Gene', (273, 276))	('suppressed', 'NegReg', (242, 252))	('inhibition', 'NegReg', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('renal glucose reabsorption', 'Disease', (63, 89))	('genetic ablation', 'Var', (177, 193))
83319	31412252	Previous studies and our TCGA copy number variation (CNV) analysis have shown that transcription factor p63 is highly expressed in major SCCs mainly through genomic amplification of chromosome 3q26 and functions as a squamous lineage-specific oncogene (Figure S3A).	('transcription factor', 'molecular_function', 'GO:0000981', ('83', '103'))	('transcription', 'biological_process', 'GO:0006351', ('83', '96'))	('SCC', 'Gene', '6317', (137, 140))	('chromosome', 'cellular_component', 'GO:0005694', ('182', '192'))	('genomic', 'Var', (157, 164))	('transcription factor p63', 'Gene', (83, 107))	('SCC', 'Gene', (137, 140))
83325	31412252	As DeltaNp63 is generally the predominant isoform expressed in squamous cancer cells, we validated that DeltaNp63 is indeed predominantly expressed in a panel of SCC cell lines (Figure S4A), whereas TAp63 was undetectable by immunoblot assays.	('squamous cancer', 'Disease', (63, 78))	('squamous cancer', 'Disease', 'MESH:D018307', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('SCC', 'Gene', (162, 165))	('squamous cancer', 'Phenotype', 'HP:0002860', (63, 78))	('SCC', 'Gene', '6317', (162, 165))	('DeltaNp63', 'Var', (104, 113))
83326	31412252	DeltaNp63-specific knockdown consistently suppressed GLUT1 mRNA and protein expression in SCC cell lines (Figure 2D), whereas TAp63 knockdown showed no effect on GLUT1 expression or glucose uptake (Figures S4B and S4C).	('GLUT1', 'Protein', (53, 58))	('knockdown', 'Var', (19, 28))	('SCC', 'Gene', (90, 93))	('suppressed', 'NegReg', (42, 52))	('glucose uptake', 'biological_process', 'GO:0046323', ('182', '196'))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('S4C', 'Mutation', 'p.S4C', (214, 217))	('SCC', 'Gene', '6317', (90, 93))	('glucose', 'Chemical', 'MESH:D005947', (182, 189))	('DeltaNp63-specific', 'Gene', (0, 18))
83327	31412252	Conversely, we ectopically introduced DeltaNp63 or TAp63 and observed that only ectopically expressed DeltaNp63 further increased GLUT1 mRNA, protein levels, and glucose uptake in SCC cell lines (Figures 2E, 2F, S4D, and S4E).	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('glucose', 'Chemical', 'MESH:D005947', (162, 169))	('protein levels', 'MPA', (142, 156))	('glucose uptake', 'CPA', (162, 176))	('SCC', 'Gene', (180, 183))	('DeltaNp63', 'Var', (102, 111))	('GLUT1 mRNA', 'MPA', (130, 140))	('SCC', 'Gene', '6317', (180, 183))	('increased', 'PosReg', (120, 129))	('S4E', 'Mutation', 'p.S4E', (221, 224))	('glucose uptake', 'biological_process', 'GO:0046323', ('162', '176'))	('S4D', 'Mutation', 'p.S4D', (212, 215))
83328	31412252	These results indicate that DeltaNp63 but not TAp63 isoforms transcriptionally activate GLUT1 expression in SCCs.	('GLUT1', 'Gene', (88, 93))	('SCC', 'Gene', (108, 111))	('activate', 'PosReg', (79, 87))	('SCC', 'Gene', '6317', (108, 111))	('expression', 'MPA', (94, 104))	('DeltaNp63', 'Var', (28, 37))
83334	31412252	These data suggest that p63/GLUT1-mediated increased glucose influx fuels anabolic pathways to generate NADPH and GSH in SCC.	('glucose influx', 'MPA', (53, 67))	('GSH', 'Chemical', '-', (114, 117))	('glucose', 'Chemical', 'MESH:D005947', (53, 60))	('SCC', 'Gene', (121, 124))	('increased glucose', 'Phenotype', 'HP:0003074', (43, 60))	('GSH', 'MPA', (114, 117))	('NADPH', 'Chemical', 'MESH:D009249', (104, 109))	('increased', 'PosReg', (43, 52))	('SCC', 'Gene', '6317', (121, 124))	('anabolic', 'MPA', (74, 82))	('NADPH', 'MPA', (104, 109))	('p63/GLUT1-mediated', 'Var', (24, 42))
83338	31412252	p63 knockdown markedly suppressed glucose influx into R5-P, serine, and lactate in SCC cells (Figures 3C, S5C, S6B, and S6C).	('lactate', 'MPA', (72, 79))	('suppressed', 'NegReg', (23, 33))	('serine', 'Chemical', 'MESH:D012694', (60, 66))	('R5-P', 'Chemical', 'MESH:C031626', (54, 58))	('p63', 'Gene', (0, 3))	('S5C', 'Mutation', 'rs780680200', (106, 109))	('SCC', 'Gene', (83, 86))	('glucose influx into R5-P', 'MPA', (34, 58))	('SCC', 'Gene', '6317', (83, 86))	('lactate', 'Chemical', 'MESH:D019344', (72, 79))	('S6C', 'Mutation', 'p.S6C', (120, 123))	('knockdown', 'Var', (4, 13))	('glucose', 'Chemical', 'MESH:D005947', (34, 41))
83339	31412252	Accordingly, reduced glucose influx into anabolic pathways by p63 or GLUT1 knockdown resulted in increases in cellular ROS measured by a universal oxidative indicator, 2'-7'-dichlorodihydrofluorescein (H2DCFDA) (Figure 3F), a small molecule probe for superoxide radicals, dihydroethidium (DHE) (Figure 3G), and a lipid peroxidation sensor, C11-BODIPY (Figure S6D).	('C11-BODIPY', 'Gene', (340, 350))	('p63', 'Gene', (62, 65))	('C11-BODIPY', 'Gene', '1109', (340, 350))	('increases', 'PosReg', (97, 106))	('dihydroethidium', 'Chemical', 'MESH:C067883', (272, 287))	('glucose influx into anabolic', 'MPA', (21, 49))	('GLUT1', 'Gene', (69, 74))	('knockdown', 'Var', (75, 84))	("2'-7'-dichlorodihydrofluorescein", 'Chemical', 'MESH:C065013', (168, 200))	('lipid', 'Chemical', 'MESH:D008055', (313, 318))	('glucose', 'Chemical', 'MESH:D005947', (21, 28))	('DHE', 'Chemical', 'MESH:C067883', (289, 292))	('H2DCFDA', 'Chemical', 'MESH:C110400', (202, 209))	('reduced', 'NegReg', (13, 20))	('superoxide', 'Chemical', 'MESH:D013481', (251, 261))	('ROS', 'Chemical', 'MESH:D017382', (119, 122))	('cellular ROS', 'MPA', (110, 122))
83340	31412252	Importantly, increased ROS upon p63 or GLUT1 knockdown is associated with significant reduction in intracellular NADPH/NADP+ and GSH/GSSG ratios (Figures 3H, 3I, and S6E), in vitro cell proliferation (Figures 3J and S6F), and transformation capacity (Figure 3K).	('reduction', 'NegReg', (86, 95))	('NADPH', 'Chemical', 'MESH:D009249', (113, 118))	('intracellular', 'cellular_component', 'GO:0005622', ('99', '112'))	('NADP+', 'Chemical', 'MESH:D009249', (119, 124))	('ROS', 'MPA', (23, 26))	('GSH/GSSG ratios', 'MPA', (129, 144))	('increased', 'PosReg', (13, 22))	('transformation capacity', 'CPA', (226, 249))	('cell proliferation', 'biological_process', 'GO:0008283', ('181', '199'))	('p63', 'Gene', (32, 35))	('S6E', 'Mutation', 'p.S6E', (166, 169))	('GSH', 'Chemical', '-', (129, 132))	('ROS', 'Chemical', 'MESH:D017382', (23, 26))	('GLUT1', 'Gene', (39, 44))	('knockdown', 'Var', (45, 54))	('GSSG', 'Chemical', 'MESH:D019803', (133, 137))
83342	31412252	It should be noted that p63 shRNA-induced cell death and GLUT1 attenuation were rescued by ectopic introduction of shRNA-resistant DeltaNp63 but not TAp63, validating the predominant role the DeltaNp63 isoform plays in modulating SCC GLUT1 expression and maintaining viability (Figure S6I).	('GLUT1', 'Gene', (57, 62))	('SCC', 'Gene', (230, 233))	('modulating', 'Reg', (219, 229))	('DeltaNp63', 'Var', (131, 140))	('death', 'Disease', 'MESH:D003643', (47, 52))	('death', 'Disease', (47, 52))	('SCC', 'Gene', '6317', (230, 233))	('cell death', 'biological_process', 'GO:0008219', ('42', '52'))	('expression', 'MPA', (240, 250))	('attenuation', 'NegReg', (63, 74))	('p63', 'Var', (24, 27))
83344	31412252	In vivo tumor growth of lung SCC HCC2814 was also significantly impaired by doxycycline-inducible DeltaNp63 knockdown (Figures 3N, S6K, and S6L).	('knockdown', 'Var', (108, 117))	('doxycycline', 'Chemical', 'MESH:D004318', (76, 87))	('SCC', 'Gene', '6317', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('impaired', 'NegReg', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('S6L', 'Mutation', 'p.S6L', (140, 143))	('tumor', 'Disease', (8, 13))	('HCC2814', 'CellLine', 'CVCL:V586', (33, 40))	('DeltaNp63', 'Gene', (98, 107))	('S6K', 'Mutation', 'p.S6K', (131, 134))	('SCC', 'Gene', (29, 32))
83346	31412252	GLUT1 is expressed only in a small population of cells that retain p63 expression in Tet-shDeltaNp63 tumors, further supporting the dependency of GLUT1 expression on DeltaNp63 (Figure S6M).	('p63', 'Var', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('Tet', 'Chemical', 'MESH:C010349', (85, 88))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
83348	31412252	Collectively, these results suggest that p63 essentially contributes to cellular proliferation and survival of SCC by transcriptionally activating GLUT1, thus promoting subsequent glucose influx into NADPH and GSH-generating anabolic pathways to sustain anti-oxidative capacity in SCC.	('GSH', 'Chemical', '-', (210, 213))	('cellular proliferation', 'CPA', (72, 94))	('anti-oxidative capacity', 'MPA', (254, 277))	('activating', 'PosReg', (136, 146))	('glucose', 'Chemical', 'MESH:D005947', (180, 187))	('SCC', 'Gene', '6317', (281, 284))	('promoting', 'PosReg', (159, 168))	('GLUT1', 'Gene', (147, 152))	('SCC', 'Gene', (111, 114))	('GSH-generating', 'MPA', (210, 224))	('NADPH', 'Chemical', 'MESH:D009249', (200, 205))	('p63', 'Var', (41, 44))	('SCC', 'Gene', '6317', (111, 114))	('SCC', 'Gene', (281, 284))	('glucose influx', 'MPA', (180, 194))
83350	31412252	Ectopic overexpression of GLUT1 in p63-deficient SCC cells markedly restored cellular proliferation and viability upon p63 knockdown in lung (HCC2814) and skin (A431) SCC cell lines (Figures 4A, 4B, S7A, and S7B).	('A431', 'CellLine', 'CVCL:0037', (161, 165))	('GLUT1', 'Gene', (26, 31))	('S7A', 'Mutation', 'p.S7A', (199, 202))	('SCC', 'Gene', (49, 52))	('SCC', 'Gene', '6317', (167, 170))	('HCC2814', 'CellLine', 'CVCL:V586', (142, 149))	('cellular proliferation', 'CPA', (77, 99))	('SCC', 'Gene', '6317', (49, 52))	('viability', 'CPA', (104, 113))	('knockdown', 'Var', (123, 132))	('SCC', 'Gene', (167, 170))	('restored', 'PosReg', (68, 76))
83351	31412252	GLUT1 reconstitution increased glucose uptake, implicating GLUT1 as primarily responsible for glucose influx (Figure 4C), and reduced oxidative stress (Figure 4D) by restoring NADPH and GSH production (Figures 4E and 4F) in p63-deficient SCC cells.	('glucose', 'Chemical', 'MESH:D005947', (94, 101))	('NADPH', 'MPA', (176, 181))	('increased', 'PosReg', (21, 30))	('restoring', 'PosReg', (166, 175))	('GSH production', 'MPA', (186, 200))	('oxidative stress', 'Phenotype', 'HP:0025464', (134, 150))	('NADPH', 'Chemical', 'MESH:D009249', (176, 181))	('glucose uptake', 'biological_process', 'GO:0046323', ('31', '45'))	('SCC', 'Gene', (238, 241))	('oxidative stress', 'MPA', (134, 150))	('GSH', 'Chemical', '-', (186, 189))	('glucose', 'Chemical', 'MESH:D005947', (31, 38))	('SCC', 'Gene', '6317', (238, 241))	('glucose influx', 'MPA', (94, 108))	('glucose uptake', 'MPA', (31, 45))	('increased glucose', 'Phenotype', 'HP:0003074', (21, 38))	('reduced', 'NegReg', (126, 133))	('reconstitution', 'Var', (6, 20))
83355	31412252	Indeed, SOX2 knockdown attenuates GLUT1 mRNA and protein expression (Figures 5A, 5B, S8B, and S8C) as well as cellular glucose uptake and lactate production in SCC cell lines (Figures 5C and S8D).	('lactate production', 'MPA', (138, 156))	('GLUT1 mRNA', 'Protein', (34, 44))	('SOX2', 'Gene', (8, 12))	('SCC', 'Gene', (160, 163))	('glucose', 'Chemical', 'MESH:D005947', (119, 126))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('lactate', 'Chemical', 'MESH:D019344', (138, 145))	('attenuates', 'NegReg', (23, 33))	('knockdown', 'Var', (13, 22))	('glucose uptake', 'biological_process', 'GO:0046323', ('119', '133'))	('SCC', 'Gene', '6317', (160, 163))	('cellular glucose uptake', 'MPA', (110, 133))
83356	31412252	Analogous to p63 inhibition, SOX2 knockdown significantly attenuated NADPH/NADP+ and GSH/GSSG ratios (Figures 5H, 5I, S8G, and S8H), which is associated with an increase in ROS (Figures 5J, S8I, and S8J) and marked decreases in in vitro proliferation (Figures 5K and S8K) and cellular transformation capacity (Figure 5L).	('S8K', 'Mutation', 'p.S8K', (267, 270))	('attenuated', 'NegReg', (58, 68))	('S8H', 'Mutation', 'p.S8H', (127, 130))	('ROS', 'MPA', (173, 176))	('GSSG', 'Chemical', 'MESH:D019803', (89, 93))	('NADPH', 'Chemical', 'MESH:D009249', (69, 74))	('S8I', 'Mutation', 'p.S8I', (190, 193))	('SOX2', 'Gene', (29, 33))	('cellular transformation capacity', 'CPA', (276, 308))	('GSH', 'Chemical', '-', (85, 88))	('increase', 'PosReg', (161, 169))	('NADPH/NADP+', 'MPA', (69, 80))	('knockdown', 'Var', (34, 43))	('ROS', 'Chemical', 'MESH:D017382', (173, 176))	('S8G', 'Mutation', 'p.S8G', (118, 121))	('NADP+', 'Chemical', 'MESH:D009249', (75, 80))	('decreases', 'NegReg', (215, 224))
83364	31412252	Corroborating the in vitro results, glucose restriction by ketogenic diet induced oxidative stress in lung SCC xenograft tumors as indicated by a significant increase in p-H2AX and 4-HNE staining (Figures 6C).	('p-H2AX', 'MPA', (170, 176))	('oxidative stress', 'Phenotype', 'HP:0025464', (82, 98))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('glucose restriction', 'Var', (36, 55))	('lung SCC xenograft tumors', 'Disease', 'MESH:D008175', (102, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('4-HNE staining', 'MPA', (181, 195))	('lung SCC xenograft tumors', 'Disease', (102, 127))	('glucose', 'Chemical', 'MESH:D005947', (36, 43))	('4-HNE', 'Chemical', 'MESH:C027576', (181, 186))	('oxidative stress', 'MPA', (82, 98))	('increase', 'PosReg', (158, 166))
83365	31412252	We also observed increased oxidative stress in SCC tumors treated with glycolytic inhibitor, 2-deoxyglucose (2-DG), or GLUT1 inhibitor, WZB117, as well as shRNA-mediated GLUT1 knockdown, which is associated with significant tumor growth inhibition as we previously reported (Figure S10A-S10C).	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('SCC tumors', 'Disease', 'MESH:D009369', (47, 57))	('SCC tumors', 'Disease', (47, 57))	('oxidative stress', 'MPA', (27, 43))	('WZB117', 'Chemical', 'MESH:C576807', (136, 142))	('tumor', 'Disease', (51, 56))	('knockdown', 'Var', (176, 185))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('S10C', 'Mutation', 'p.S10C', (287, 291))	('tumor', 'Disease', (224, 229))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (17, 43))	('oxidative stress', 'Phenotype', 'HP:0025464', (27, 43))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('S10A', 'SUBSTITUTION', 'None', (282, 286))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('increased', 'PosReg', (17, 26))	('2-DG', 'Chemical', 'MESH:D003847', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('S10A', 'Var', (282, 286))	('2-deoxyglucose', 'Chemical', 'MESH:D003847', (93, 107))
83368	31412252	Our recent study and other groups have demonstrated that SCCs exhibit highly activated PI3K/AKT signaling due to the frequent amplification of chromosome 3q26 that contains PIK3CA, a catalytic subunit of the PI3K complex.	('PIK3CA', 'Gene', '5290', (173, 179))	('SCC', 'Gene', '6317', (57, 60))	('PI3K', 'molecular_function', 'GO:0016303', ('208', '212'))	('activated', 'PosReg', (77, 86))	('AKT signaling', 'biological_process', 'GO:0043491', ('92', '105'))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('PI3K/AKT signaling', 'Pathway', (87, 105))	('amplification', 'Var', (126, 139))	('PI3K', 'molecular_function', 'GO:0016303', ('87', '91'))	('SCC', 'Gene', (57, 60))	('PIK3CA', 'Gene', (173, 179))	('PI3K complex', 'cellular_component', 'GO:0005942', ('208', '220'))
83374	31412252	Combination of ketogenic diet with cisplatin (5 mg/kg/week) was evidently more effective than a single treatment of either ketogenic diet or cisplatin alone without any noticeable adverse effects (Figures 6E, S11A, and S11D).	('S11A', 'Var', (209, 213))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('S11A', 'SUBSTITUTION', 'None', (209, 213))	('S11D', 'Var', (219, 223))	('S11D', 'SUBSTITUTION', 'None', (219, 223))
83375	31412252	Accordingly, we detected a marked reduction of proliferation with an increase in apoptosis and intratumoral oxidative stress (Figure S11B).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('S11B', 'SUBSTITUTION', 'None', (133, 137))	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('tumor', 'Disease', (100, 105))	('apoptosis', 'CPA', (81, 90))	('oxidative stress', 'Phenotype', 'HP:0025464', (108, 124))	('reduction', 'NegReg', (34, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('proliferation', 'CPA', (47, 60))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('S11B', 'Var', (133, 137))
83376	31412252	Notably, cisplatin treatment neither affected blood glucose levels nor attenuated PI3K/AKT pathway signaling, thus arguing for the ketogenic-diet-dependent insulin and PI3K/AKT attenuation in SCC tumors (Figures S11B and S11C).	('S11B', 'Var', (212, 216))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('insulin', 'Gene', (156, 163))	('S11B', 'SUBSTITUTION', 'None', (212, 216))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('signaling', 'biological_process', 'GO:0023052', ('99', '108'))	('PI3K/AKT pathway signaling', 'Pathway', (82, 108))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('attenuated', 'NegReg', (71, 81))	('S11C', 'SUBSTITUTION', 'None', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('attenuation', 'NegReg', (177, 188))	('SCC tumors', 'Disease', (192, 202))	('insulin', 'Gene', '3630', (156, 163))	('blood glucose', 'Chemical', 'MESH:D001786', (46, 59))	('S11C', 'Var', (221, 225))	('PI3K', 'molecular_function', 'GO:0016303', ('168', '172'))	('insulin', 'molecular_function', 'GO:0016088', ('156', '163'))	('SCC tumors', 'Disease', 'MESH:D009369', (192, 202))
83379	31412252	Indeed, KLLuc mice fed with a ketogenic diet exhibited dramatically less SCC tumor development (Figures 7A and 7B), whereas total tumor burden or overall survival was not affected (Figures 7C, 7D, and S12A), indicating that a ketogenic diet pointedly inhibited the development of KLLuc SCC tumors but not ADC tumors.	('tumors', 'Disease', 'MESH:D009369', (290, 296))	('mice', 'Species', '10090', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (309, 315))	('inhibited', 'NegReg', (251, 260))	('KLLuc SCC tumors', 'Disease', 'MESH:D009369', (280, 296))	('tumor', 'Disease', (130, 135))	('S12A', 'SUBSTITUTION', 'None', (201, 205))	('tumor', 'Disease', (290, 295))	('S12A', 'Var', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('SCC tumor', 'Disease', 'MESH:D009369', (286, 295))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumors', 'Disease', (309, 315))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('KLLuc SCC tumors', 'Disease', (280, 296))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('tumor', 'Disease', (309, 314))	('tumors', 'Disease', 'MESH:D009369', (309, 315))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumors', 'Disease', (290, 296))	('less', 'NegReg', (68, 72))	('SCC tumor', 'Disease', (73, 82))	('development', 'CPA', (265, 276))	('tumor', 'Disease', (77, 82))	('SCC tumor', 'Disease', 'MESH:D009369', (73, 82))
83380	31412252	Substantiating the xenograft tumor results, ketogenic diet effectively reduced blood glucose and insulin levels in KLLuc mice (Figures 7E and 7F), which consequently increased oxidative stress and suppressed PI3K/AKT signaling in SCC tumors (Figure 7G), whereas in ADC tumors, oxidative stress or PI3K/AKT signaling was not affected by a ketogenic diet (Figure S12B).	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('SCC tumors', 'Disease', (230, 240))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('PI3K', 'molecular_function', 'GO:0016303', ('208', '212'))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('AKT signaling', 'biological_process', 'GO:0043491', ('213', '226'))	('S12B', 'SUBSTITUTION', 'None', (361, 365))	('SCC tumors', 'Disease', 'MESH:D009369', (230, 240))	('insulin', 'Gene', '3630', (97, 104))	('oxidative stress', 'Phenotype', 'HP:0025464', (277, 293))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Disease', (269, 275))	('reduced', 'NegReg', (71, 78))	('insulin', 'molecular_function', 'GO:0016088', ('97', '104'))	('PI3K', 'molecular_function', 'GO:0016303', ('297', '301'))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('oxidative stress', 'MPA', (176, 192))	('suppressed', 'NegReg', (197, 207))	('S12B', 'Var', (361, 365))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('AKT signaling', 'biological_process', 'GO:0043491', ('302', '315'))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (166, 192))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('mice', 'Species', '10090', (121, 125))	('blood glucose', 'Chemical', 'MESH:D001786', (79, 92))	('reduced blood glucose', 'Phenotype', 'HP:0001943', (71, 92))	('insulin', 'Gene', (97, 104))	('increased', 'PosReg', (166, 175))	('tumor', 'Disease', (269, 274))	('tumors', 'Disease', (234, 240))	('PI3K/AKT signaling', 'MPA', (208, 226))	('tumor', 'Disease', (29, 34))	('oxidative stress', 'Phenotype', 'HP:0025464', (176, 192))
83383	31412252	Yet, total tumor burden or overall survival was not affected (Figures 7C, 7D, and S12A).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('S12A', 'SUBSTITUTION', 'None', (82, 86))	('tumor', 'Disease', (11, 16))	('S12A', 'Var', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
83385	31412252	However, direct SGLT2 inhibition of tumors may not be the cause of cell death in SCC as SGLT2 is not expressed in SCC cell lines (Figures S13A), human SCC tumors (Figure S13B), and KLLuc tumors (Figures S13C-S13E).	('S13C', 'Mutation', 'p.S13C', (203, 207))	('SCC tumors', 'Disease', (151, 161))	('KLLuc tumors', 'Disease', 'MESH:D009369', (181, 193))	('human', 'Species', '9606', (145, 150))	('death', 'Disease', (72, 77))	('SCC', 'Gene', '6317', (114, 117))	('S13B', 'SUBSTITUTION', 'None', (170, 174))	('SCC tumors', 'Disease', 'MESH:D009369', (151, 161))	('SCC', 'Gene', '6317', (81, 84))	('SCC', 'Gene', (114, 117))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('cell death', 'biological_process', 'GO:0008219', ('67', '77'))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('SCC', 'Gene', (81, 84))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('KLLuc tumors', 'Disease', (181, 193))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('SCC', 'Gene', '6317', (151, 154))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('death', 'Disease', 'MESH:D003643', (72, 77))	('tumors', 'Disease', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (187, 193))	('S13A', 'Var', (138, 142))	('tumors', 'Disease', (36, 42))	('SCC', 'Gene', (151, 154))	('S13E', 'Mutation', 'p.S13E', (208, 212))	('S13A', 'SUBSTITUTION', 'None', (138, 142))	('S13B', 'Var', (170, 174))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (36, 42))
83390	31412252	To further validate the necessity of glucose in SCC survival and tumor growth, we genetically ablated Slc2a1 in KLLuc mice (LSL-KrasG12DLkb1flox/floxGlut1flox/flox, KL GLUT1-knockout [KO]).	('Slc2a1', 'Gene', (102, 108))	('tumor', 'Disease', (65, 70))	('Glut1', 'Gene', (149, 154))	('SCC', 'Gene', (48, 51))	('Lkb1', 'Gene', (136, 140))	('Slc2a1', 'Gene', '20525', (102, 108))	('ablated', 'Var', (94, 101))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('SCC', 'Gene', '6317', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mice', 'Species', '10090', (118, 122))	('Lkb1', 'Gene', '20869', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Glut1', 'Gene', '20525', (149, 154))
83391	31412252	Slc2a1 deletion dramatically decreased SCC tumors (Figures 7H and 7I), yet total tumor burden was not affected (Figure 7J), again indicating that GLUT1 plays pivotal roles in SCC tumorigenesis but remains dispensable for ADC tumors.	('SCC tumor', 'Disease', (175, 184))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('SCC tumor', 'Disease', 'MESH:D009369', (175, 184))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('Slc2a1', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('SCC tumor', 'Disease', 'MESH:D009369', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('deletion', 'Var', (7, 15))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('decreased SCC tumors', 'Disease', 'None', (29, 49))	('decreased SCC tumors', 'Disease', (29, 49))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Slc2a1', 'Gene', '20525', (0, 6))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Disease', (225, 231))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
83406	31412252	Accordingly, inhibition of DeltaNp63 or SOX2 expression deprived cellular NADPH and GSH pools and impaired cellular proliferation and viability of SCC (Figure 3).	('SCC', 'Gene', (147, 150))	('deprived', 'NegReg', (56, 64))	('DeltaNp63', 'Gene', (27, 36))	('viability', 'CPA', (134, 143))	('SOX2', 'Gene', (40, 44))	('inhibition', 'Var', (13, 23))	('GSH pools', 'MPA', (84, 93))	('SCC', 'Gene', '6317', (147, 150))	('GSH', 'Chemical', '-', (84, 87))	('impaired', 'NegReg', (98, 106))	('cellular NADPH', 'MPA', (65, 79))	('NADPH', 'Chemical', 'MESH:D009249', (74, 79))	('cellular proliferation', 'CPA', (107, 129))
83415	31412252	Our results, however, cannot completely exclude the possibility that a ketogenic diet or SGLT2 inhibitors may affect SCC metabolism and tumor growth independent of glucose- and/or insulin-mediated effects.	('insulin', 'Gene', (180, 187))	('SGLT2', 'Gene', (89, 94))	('inhibitors', 'Var', (95, 105))	('affect', 'Reg', (110, 116))	('SCC', 'Gene', (117, 120))	('insulin', 'Gene', '3630', (180, 187))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('insulin', 'molecular_function', 'GO:0016088', ('180', '187'))	('metabolism', 'biological_process', 'GO:0008152', ('121', '131'))	('SCC', 'Gene', '6317', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('glucose', 'Chemical', 'MESH:D005947', (164, 171))	('tumor', 'Disease', (136, 141))
83421	31412252	Importantly, SCC is among cancer types exhibiting highly activated PI3K/AKT signaling due to amplified PIK3CA by genomic amplification of chromosome 3q26 that also contains p63 and SOX2.	('PI3K', 'molecular_function', 'GO:0016303', ('67', '71'))	('SCC', 'Gene', '6317', (13, 16))	('amplified', 'Var', (93, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('138', '148'))	('cancer', 'Disease', (26, 32))	('activated', 'PosReg', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('AKT signaling', 'biological_process', 'GO:0043491', ('72', '85'))	('PIK3CA', 'Gene', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('PIK3CA', 'Gene', '5290', (103, 109))	('SCC', 'Gene', (13, 16))	('PI3K/AKT signaling', 'Pathway', (67, 85))
83422	31412252	Indeed, our data demonstrate a significant reduction of AKT signaling in ketogenic-diet-fed or CAG-treated SCC tumors but not in A549 ADC or KL ADC tumors, which have considerably less PI3K/AKT activity (Figures 6C, 7G, and S12B).	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('SCC tumors', 'Disease', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('reduction', 'NegReg', (43, 52))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('AKT signaling', 'MPA', (56, 69))	('S12B', 'SUBSTITUTION', 'None', (224, 228))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('PI3K/AKT', 'Pathway', (185, 193))	('SCC tumors', 'Disease', 'MESH:D009369', (107, 117))	('PI3K', 'molecular_function', 'GO:0016303', ('185', '189'))	('tumors', 'Disease', (148, 154))	('S12B', 'Var', (224, 228))	('less', 'NegReg', (180, 184))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('activity', 'MPA', (194, 202))	('AKT signaling', 'biological_process', 'GO:0043491', ('56', '69'))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('A549', 'CellLine', 'CVCL:0023', (129, 133))	('CAG', 'Chemical', 'MESH:D000068896', (95, 98))
83423	31412252	Intriguingly, recent evidence has shown that ketogenic diet and SGLT2 inhibition enhanced the efficacy of PI3K inhibitors by blocking glucose-insulin feedback that is caused by compensatory insulin elevation in response to systemic PI3K inhibition.	('insulin', 'molecular_function', 'GO:0016088', ('190', '197'))	('insulin', 'Gene', (190, 197))	('efficacy', 'MPA', (94, 102))	('SGLT2', 'Gene', (64, 69))	('enhanced', 'PosReg', (81, 89))	('insulin', 'Gene', '3630', (190, 197))	('blocking', 'NegReg', (125, 133))	('PI3K', 'Gene', (106, 110))	('PI3K', 'molecular_function', 'GO:0016303', ('232', '236'))	('glucose', 'Chemical', 'MESH:D005947', (134, 141))	('inhibition', 'Var', (70, 80))	('PI3K', 'molecular_function', 'GO:0016303', ('106', '110'))	('insulin', 'Gene', (142, 149))	('insulin', 'molecular_function', 'GO:0016088', ('142', '149'))	('insulin elevation', 'Phenotype', 'HP:0000842', (190, 207))	('insulin', 'Gene', '3630', (142, 149))
83425	31412252	Our earlier study and others have demonstrated that PI3K/AKT signaling enhances glucose uptake and retention by promoting GLUT1 expression and translocation to the plasma membrane as well as increasing HK2 activity.	('PI3K/AKT', 'Var', (52, 60))	('promoting', 'PosReg', (112, 121))	('increasing', 'PosReg', (191, 201))	('PI3K', 'molecular_function', 'GO:0016303', ('52', '56'))	('glucose', 'Chemical', 'MESH:D005947', (80, 87))	('retention', 'CPA', (99, 108))	('HK2', 'Enzyme', (202, 205))	('GLUT1', 'Protein', (122, 127))	('retention', 'biological_process', 'GO:0051235', ('99', '108'))	('enhances', 'PosReg', (71, 79))	('glucose uptake', 'CPA', (80, 94))	('plasma membrane', 'cellular_component', 'GO:0005886', ('164', '179'))	('HK2', 'molecular_function', 'GO:0008256', ('202', '205'))	('glucose uptake', 'biological_process', 'GO:0046323', ('80', '94'))	('expression', 'MPA', (128, 138))	('translocation to the plasma membrane', 'MPA', (143, 179))	('AKT signaling', 'biological_process', 'GO:0043491', ('57', '70'))	('activity', 'MPA', (206, 214))
83426	31412252	Therefore, inhibition of insulin/PI3K/AKT signaling in ketogenic-diet-fed or CAG-treated mice may reduce GLUT1 transmembrane localization and HK2 activity in SCC tumors that further restricts glucose uptake and utilization.	('localization', 'biological_process', 'GO:0051179', ('125', '137'))	('HK2', 'molecular_function', 'GO:0008256', ('142', '145'))	('HK2', 'Enzyme', (142, 145))	('inhibition', 'Var', (11, 21))	('insulin', 'Gene', '3630', (25, 32))	('CAG', 'Chemical', 'MESH:D000068896', (77, 80))	('SCC tumors', 'Disease', 'MESH:D009369', (158, 168))	('restricts', 'NegReg', (182, 191))	('GLUT1 transmembrane localization', 'MPA', (105, 137))	('AKT signaling', 'biological_process', 'GO:0043491', ('38', '51'))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('insulin', 'molecular_function', 'GO:0016088', ('25', '32'))	('insulin', 'Gene', (25, 32))	('glucose', 'Chemical', 'MESH:D005947', (192, 199))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('transmembrane', 'cellular_component', 'GO:0016021', ('111', '124'))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))	('activity', 'MPA', (146, 154))	('glucose', 'MPA', (192, 199))	('mice', 'Species', '10090', (89, 93))	('reduce', 'NegReg', (98, 104))	('glucose uptake', 'biological_process', 'GO:0046323', ('192', '206'))	('transmembrane', 'cellular_component', 'GO:0044214', ('111', '124'))	('SCC tumors', 'Disease', (158, 168))
83436	31412252	Lung (LC806, LC2085a, LC2081), head and neck (OR802), esophageal (ES2081), cervical (CR2089), and skin (SK2081) tumor tissue microarrays were purchased from US Biomax (Derwood, MD, USA), and patient clinical information is available on the website (https://biomax.us).	('LC806', 'Var', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('SK2081', 'CellLine', 'CVCL:K843', (104, 110))	('neck', 'cellular_component', 'GO:0044326', ('40', '44'))	('tumor', 'Disease', (112, 117))	('patient', 'Species', '9606', (191, 198))
83441	31412252	We adopted RBG >= 120 mg/dL to be an indication of disorders in glucose metabolism because RBG >= 120 mg/dL have been shown to have 92% specificity for detection of any glucose intolerance.	('glucose metabolism', 'Disease', 'MESH:D044882', (64, 82))	('glucose', 'Chemical', 'MESH:D005947', (169, 176))	('glucose metabolism', 'Disease', (64, 82))	('RBG', 'Chemical', '-', (91, 94))	('glucose', 'Chemical', 'MESH:D005947', (64, 71))	('glucose intolerance', 'Phenotype', 'HP:0001952', (169, 188))	('RBG >= 120 mg/dL', 'Var', (91, 107))	('glucose metabolism', 'biological_process', 'GO:0006006', ('64', '82'))	('glucose', 'MPA', (169, 176))	('RBG', 'Chemical', '-', (11, 14))
83452	31412252	Esophageal SCC lines KYSE70, KYSE30, KYSE510 and esophageal ADC lines OE33, FLO-1 were provided by Drs.	('KYSE510', 'Var', (37, 44))	('Drs', 'Gene', (99, 102))	('SCC', 'Gene', (11, 14))	('SCC', 'Gene', '6317', (11, 14))	('KYSE70', 'Var', (21, 27))	('Drs', 'Gene', '8406', (99, 102))	('KYSE30', 'Var', (29, 35))
83467	31412252	Ketogenic diet was started when xenograft tumors were approximately 100 mm3 or 5 weeks after intratracheal inhalation of adenovirus-Cre in KLLuc mice and continued until the mice were euthanized for tissue collection.	('xenograft tumors', 'Disease', (32, 48))	('mice', 'Species', '10090', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('xenograft tumors', 'Disease', 'MESH:D009369', (32, 48))	('mice', 'Species', '10090', (145, 149))	('adenovirus-Cre', 'Var', (121, 135))
83515	31412252	For lentivirus production, HEK293T cells were transfected with viral packaging plasmids psPAX2 (Addgene #12260) and pMD2.G (Addgene #12259), and pLKO.1 shRNA using Lipofectamine 3000 (Invitrogen).	('Addgene #12259', 'Var', (124, 138))	('Addgene #12260', 'Var', (96, 110))	('lentivirus', 'MPA', (4, 14))	('HEK293T', 'CellLine', 'CVCL:0063', (27, 34))	('Lipofectamine', 'Chemical', 'MESH:C086724', (164, 177))
83529	31412252	The following primary antibodies were used: p63 (1:200; Biocare Medical; CM163A), p63 (1:100; R&D Systems AF-1916), GLUT1 (1:250; Alpha Diagnostic GT11-A), SGLT2 (1:1000; Abcam ab85626), TTF1 (1:1,000; Dako M3575), Ki67 (1:500; Cell Signaling Technology #12202), Cleaved Caspase-3 (1:200; Cell Signaling Technology #9664), Ser473-p-AKT (1:500; Cell signaling Technology #4058), Ser235/236-p-S6 (1:200; Cell Signaling Technology #4858) and Thr37/46-p-4EBP1 (1:200; Cell Signaling Technology #2855), Ser139-p-Histone H2A.X (1:1,000; Cell Signaling Technology #9718), 4-Hydroxynonenal (1:500; Abcam ab46545), CK5 (1:200; Abcam ab52635).	('Ki67', 'Gene', (215, 219))	('p-S6', 'Gene', (389, 393))	('Signaling', 'biological_process', 'GO:0023052', ('407', '416'))	('TTF1', 'Gene', (187, 191))	('CK5', 'Gene', (606, 609))	('Signaling', 'biological_process', 'GO:0023052', ('294', '303'))	('Ki67', 'Gene', '17345', (215, 219))	('Signaling', 'biological_process', 'GO:0023052', ('233', '242'))	('4-Hydroxynonenal', 'Var', (565, 581))	('Signaling', 'biological_process', 'GO:0023052', ('536', '545'))	('Ser', 'cellular_component', 'GO:0005790', ('498', '501'))	('CK5', 'Gene', '3852', (606, 609))	('Signaling', 'biological_process', 'GO:0023052', ('469', '478'))	('signaling', 'biological_process', 'GO:0023052', ('349', '358'))	('Ser', 'cellular_component', 'GO:0005790', ('323', '326'))	('Ser', 'cellular_component', 'GO:0005790', ('378', '381'))	('TTF1', 'Gene', '7270', (187, 191))	('Ser473-p-AKT', 'Mutation', 'p.S473AKT', (323, 335))	('p-S6', 'Gene', '338413', (389, 393))
83539	30102398	FACER: comprehensive molecular and functional characterization of epigenetic chromatin regulators Epigenetic alterations, a well-recognized cancer hallmark, are driven by chromatin regulators (CRs).	('chromatin', 'cellular_component', 'GO:0000785', ('171', '180'))	('CRs', 'Chemical', '-', (193, 196))	('chromatin', 'cellular_component', 'GO:0000785', ('77', '86'))	('cancer hallmark', 'Disease', (140, 155))	('cancer hallmark', 'Disease', 'MESH:D009369', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Epigenetic alterations', 'Var', (98, 120))
83540	30102398	However, little is known about the extent of CR deregulation in cancer, and less is known about their common and specialized roles across various cancers.	('cancers', 'Disease', (146, 153))	('cancer', 'Disease', (146, 152))	('CR', 'Chemical', '-', (45, 47))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('deregulation', 'Var', (48, 60))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
83551	30102398	DNA methylators and histone modifiers can code and decode various modifications on cytosine and histone residues and are usually further divided into readers, writers, and erasers.	('modifications', 'Var', (66, 79))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cytosine', 'MPA', (83, 91))	('cytosine', 'Chemical', 'MESH:D003596', (83, 91))	('histone', 'Protein', (96, 103))
83554	30102398	Chromatin remodelers are a special type of CRs that can disrupt the contact between nucleosomes and DNA, shuffle nucleosomes around, replace them or remove them from the chromatin, and cause abnormal epigenetic modifications.	('contact', 'Interaction', (68, 75))	('epigenetic modifications', 'MPA', (200, 224))	('Chromatin', 'cellular_component', 'GO:0000785', ('0', '9'))	('cause', 'Reg', (185, 190))	('replace', 'Reg', (133, 140))	('disrupt', 'NegReg', (56, 63))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('CRs', 'Chemical', '-', (43, 46))	('shuffle', 'Var', (105, 112))	('remove', 'NegReg', (149, 155))	('chromatin', 'cellular_component', 'GO:0000785', ('170', '179'))
83555	30102398	The alteration of epigenetic marks is a prevalent feature in cancer.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('alteration', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('epigenetic marks', 'Var', (18, 34))
83557	30102398	For example, it is widely accepted that mutations can perturb CR functions.	('CR functions', 'CPA', (62, 74))	('mutations', 'Var', (40, 49))	('perturb', 'NegReg', (54, 61))	('CR', 'Chemical', '-', (62, 64))
83558	30102398	have found that genetic alteration of DNMT3A (a DNA methylation transferase) can induce genome-wide alterations of DNA methylation and gene expression.	('genetic alteration', 'Var', (16, 34))	('gene expression', 'MPA', (135, 150))	('alterations', 'Reg', (100, 111))	('DNA methylation', 'biological_process', 'GO:0006306', ('115', '130'))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('gene expression', 'biological_process', 'GO:0010467', ('135', '150'))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('DNMT3A', 'Gene', (38, 44))	('DNMT3A', 'Gene', '1788', (38, 44))	('DNA methylation', 'biological_process', 'GO:0006306', ('48', '63'))	('DNA methylation', 'MPA', (115, 130))
83559	30102398	Moreover, patients with DNMT3A mutations have poor prognosis compared with those without such mutations.	('DNMT3A', 'Gene', (24, 30))	('mutations', 'Var', (31, 40))	('DNMT3A', 'Gene', '1788', (24, 30))	('patients', 'Species', '9606', (10, 18))
83562	30102398	They found that dysregulation of these CRs results in structural abnormalities in chromatins and epigenetic alterations of numerous cancer-associated genes, which finally lead to increased tumor volume, extracapsular extension, and metastases in prostate cancer patients.	('numerous cancer', 'Disease', 'MESH:D009369', (123, 138))	('structural abnormalities', 'Disease', (54, 78))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('increased', 'PosReg', (179, 188))	('structural abnormalities', 'Disease', 'MESH:C566527', (54, 78))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('metastases in prostate cancer', 'Disease', 'MESH:D009362', (232, 261))	('chromatins', 'Protein', (82, 92))	('metastases in prostate cancer', 'Disease', (232, 261))	('prostate cancer', 'Phenotype', 'HP:0012125', (246, 261))	('numerous cancer', 'Disease', (123, 138))	('epigenetic alterations', 'Var', (97, 119))	('extracapsular extension', 'CPA', (203, 226))	('dysregulation', 'Var', (16, 29))	('tumor', 'Disease', (189, 194))	('CRs', 'Chemical', '-', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('patients', 'Species', '9606', (262, 270))
83593	30102398	To evaluate the global regulatory effect of a given CR on the DNA hypermethylation (or hypomethylation) in a specific cancer type, we computed the significance of Pearson correlation (P value) between CR expression and aberrant hypermethylation (or hypomethylation) of tumor samples.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('CR', 'Chemical', '-', (52, 54))	('cancer', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('aberrant', 'Var', (219, 227))	('tumor', 'Disease', (269, 274))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('CR', 'Chemical', '-', (201, 203))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('62', '82'))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
83669	30102398	Mutation frequency and centrality in PPIN were found to be the top two recurrent features (Figure 2I), which were involved in 25 and 29 cancer types, respectively.	('Mutation frequency', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('PPIN', 'Gene', (37, 41))	('cancer', 'Disease', (136, 142))	('involved', 'Reg', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
83680	30102398	Moreover, we found that DNA methylation readers and histone modification writers were the most common functional CRs across all 33 cancer types (Figure 3A).	('cancer', 'Disease', (131, 137))	('histone modification', 'biological_process', 'GO:0016570', ('52', '72'))	('DNA methylation readers', 'Var', (24, 47))	('histone modification writers', 'Var', (52, 80))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('DNA methylation', 'biological_process', 'GO:0006306', ('24', '39'))	('CRs', 'Chemical', '-', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
83683	30102398	Moreover, histone modification readers and writers as well as chromatin remodelers played important roles across cancer types compared with DNA methylation erasers and histone modification erasers (Figure 3B, bottom).	('chromatin', 'cellular_component', 'GO:0000785', ('62', '71'))	('histone modification', 'biological_process', 'GO:0016570', ('10', '30'))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('histone', 'Var', (10, 17))	('cancer', 'Disease', (113, 119))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('DNA methylation', 'biological_process', 'GO:0006306', ('140', '155'))	('played', 'Reg', (83, 89))	('histone modification', 'biological_process', 'GO:0016570', ('168', '188'))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
83689	30102398	Functional enrichment analysis showed that DNA methylators, histone modifiers and chromatin remodelers were all enriched in at least one cancer hallmark, especially in the hallmark 'genome instability and mutation', highlighting the extent of genome alternations in cancer (Supplementary Figure S8 and Supplementary Table S5).	("mutation'", 'Var', (205, 214))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('Supplementary Figure S8', 'Disease', (274, 297))	('cancer', 'Disease', (266, 272))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer hallmark', 'Disease', (137, 152))	('chromatin', 'cellular_component', 'GO:0000785', ('82', '91'))	('cancer', 'Disease', (137, 143))	('cancer hallmark', 'Disease', 'MESH:D009369', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('Supplementary Figure S8', 'Disease', 'MESH:D017034', (274, 297))
83691	30102398	Functional histone modifiers in almost all cancer types were enriched in the functions 'evading apoptosis', 'genome instability and mutation', 'insensitivity to antigrowth signals', and 'self-sufficiency in growth signals'.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	("'evading", 'Disease', (87, 95))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))	('sufficiency in growth', 'Phenotype', 'HP:0001510', (192, 213))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	("mutation'", 'Var', (132, 141))
83703	30102398	For example, we found that PHF19, a writer for H3K36me3 as a component of polycomb repressive complex 2 (PRC2), was prioritized as a breast invasive carcinoma (BRCA) related CR in our analyses.	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('H3K36me3', 'Var', (47, 55))	('PHF19', 'Gene', '26147', (27, 32))	('BRCA', 'Phenotype', 'HP:0003002', (160, 164))	('PHF19', 'Gene', (27, 32))	('BRCA', 'Gene', '672', (160, 164))	('BRCA', 'Gene', (160, 164))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (133, 158))	('CR', 'Chemical', '-', (174, 176))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (133, 158))	('breast invasive carcinoma', 'Disease', (133, 158))
83706	30102398	Moreover, the genome-wide H3K36me3 marks showed an obvious increase in cancer.	('H3K36me3 marks', 'Var', (26, 40))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('increase', 'PosReg', (59, 67))
83721	30102398	Among these CRs, 14 were up-regulated in cancer, and 1 was down-regulated (Supplementary Figure S11A).	('up-regulated', 'PosReg', (25, 37))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('CRs', 'Chemical', '-', (12, 15))	('S11A', 'Var', (96, 100))	('down-regulated', 'NegReg', (59, 73))	('S11A', 'SUBSTITUTION', 'None', (96, 100))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
83722	30102398	Interestingly, 11 of these 15 CRs showed consistent deregulation across cancer types compared with the corresponding adjacent normal samples (Supplementary Figure S11B).	('deregulation', 'MPA', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('CRs', 'Chemical', '-', (30, 33))	('S11B', 'Var', (163, 167))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('S11B', 'SUBSTITUTION', 'None', (163, 167))	('cancer', 'Disease', (72, 78))
83729	30102398	For cancer-specific CRs, we found that these CRs included 36% of the DNA methylation erasers and 35% of the histone modification erasers.	('CRs', 'Chemical', '-', (45, 48))	('CRs', 'Chemical', '-', (20, 23))	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('histone modification', 'biological_process', 'GO:0016570', ('108', '128'))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('DNA methylation', 'biological_process', 'GO:0006306', ('69', '84'))	('histone modification', 'MPA', (108, 128))	('methylation', 'Var', (73, 84))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('DNA', 'MPA', (69, 72))	('cancer', 'Disease', (4, 10))
83737	30102398	KMT2C showed a higher mutation frequency in KIRP patients, whereas the aberrant regulation of miRNAs and its regulation of DNA methylation over open sea regions were additional features in KICH patients.	('mutation', 'Var', (22, 30))	('KICH', 'Disease', (189, 193))	('patients', 'Species', '9606', (194, 202))	('regulation', 'biological_process', 'GO:0065007', ('80', '90'))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('DNA methylation', 'MPA', (123, 138))	('KMT2C', 'Gene', '58508', (0, 5))	('KMT2C', 'Gene', (0, 5))	('KICH', 'Disease', 'None', (189, 193))	('patients', 'Species', '9606', (49, 57))	('regulation of DNA methylation', 'biological_process', 'GO:0044030', ('109', '138'))
83743	30102398	We found that common CRs in cancer had higher values for all seven features compared with specific CRs, especially in four functional features (all P < 0.05, Wilcoxon rank-sum test), including mutation frequency, differential expression, degree in PPIN, and regulation of genome hypermethylation (Figure 5C, top, and Supplementary Table S8).	('higher', 'PosReg', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('regulation', 'biological_process', 'GO:0065007', ('258', '268'))	('mutation frequency', 'Var', (193, 211))	('CRs', 'Chemical', '-', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('CRs', 'Chemical', '-', (21, 24))	('PPIN', 'Protein', (248, 252))	('cancer', 'Disease', (28, 34))	('differential expression', 'MPA', (213, 236))
83769	30102398	Patients in subtype 1 of ACC showed the highest mutation frequency of TP53 and CGI methylation, while patients in subtype 3 showed high mutation of KDM6B and the lowest open sea methylation.	('TP53', 'Gene', '7157', (70, 74))	('patients', 'Species', '9606', (102, 110))	('KDM6B', 'Gene', '23135', (148, 153))	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', (70, 74))	('mutation', 'Var', (48, 56))	('ACC', 'Phenotype', 'HP:0006744', (25, 28))	('KDM6B', 'Gene', (148, 153))	('methylation', 'biological_process', 'GO:0032259', ('83', '94'))	('methylation', 'Var', (83, 94))	('methylation', 'biological_process', 'GO:0032259', ('178', '189'))	('CGI', 'Protein', (79, 82))
83794	30102398	Analysis of the functional features revealed recurrent multi-omics effects of functional CRs across 33 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('effects', 'Reg', (67, 74))	('CRs', 'Chemical', '-', (89, 92))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('functional', 'Var', (78, 88))
83799	30102398	By comparison between common, specific and mixed CRs as well as DNA methylators, histone modifiers and chromatin remodelers, we found that DNA methylation readers as well as histone modification readers and writers were with more common CRs, suggesting that these three categories of CRs tend to be aberrant across cancer types.	('chromatin', 'cellular_component', 'GO:0000785', ('103', '112'))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('methylation', 'Var', (143, 154))	('histone modification', 'biological_process', 'GO:0016570', ('174', '194'))	('DNA', 'Var', (139, 142))	('cancer', 'Disease', (315, 321))	('CRs', 'Chemical', '-', (284, 287))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('DNA methylation', 'biological_process', 'GO:0006306', ('139', '154'))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('CRs', 'Chemical', '-', (237, 240))	('CRs', 'Chemical', '-', (49, 52))
83800	30102398	We also found that DNA methylation erasers and histone modification erasers tend to be dysregulated in specific cancer type.	('DNA', 'MPA', (19, 22))	('histone modification', 'MPA', (47, 67))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('methylation', 'Var', (23, 34))	('histone modification', 'biological_process', 'GO:0016570', ('47', '67'))	('DNA methylation', 'biological_process', 'GO:0006306', ('19', '34'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
83806	30102398	Moreover, we found that DNA methylators and histone modifiers can induce the development of cancer by regulation of DNA methylation and histone modifications, such as DNMT1, DNMT3A and PHF19.	('regulation of DNA methylation', 'biological_process', 'GO:0044030', ('102', '131'))	('PHF19', 'Gene', '26147', (185, 190))	('histone', 'Protein', (136, 143))	('cancer', 'Disease', (92, 98))	('PHF19', 'Gene', (185, 190))	('development of', 'CPA', (77, 91))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('DNMT3A', 'Gene', (174, 180))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('DNMT3A', 'Gene', '1788', (174, 180))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('DNMT1', 'Gene', (167, 172))	('DNA', 'MPA', (116, 119))	('induce', 'PosReg', (66, 72))	('DNMT1', 'Gene', '1786', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('modifications', 'Var', (144, 157))
83830	29618619	Further analysis of the whole exomes of 109 melanoma patients demonstrated that the homozygous deletion of interferon (P = 0.0029, OR = 11.8) and defensin (P = 0.06, OR = 2.79) genes are significantly associated with resistance to anti-CTLA-4 (Cytotoxic T-Lymphocyte Associated protein 4) immunotherapy.	('interferon', 'Gene', (107, 117))	('CTLA-4', 'Gene', '1493', (236, 242))	('deletion', 'Var', (95, 103))	('patients', 'Species', '9606', (53, 61))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('protein', 'cellular_component', 'GO:0003675', ('278', '285'))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('CTLA-4', 'Gene', (236, 242))	('Cytotoxic T-Lymphocyte Associated protein 4', 'Gene', '1493', (244, 287))	('interferon', 'Gene', '3439', (107, 117))	('associated with', 'Reg', (201, 216))	('Cytotoxic T-Lymphocyte Associated protein 4', 'Gene', (244, 287))	('defensin', 'Gene', (146, 154))	('resistance to', 'CPA', (217, 230))
83833	29618619	Previous studies estimate that 25% of the cancer genome is affected by arm-level SCNAs and 10% by focal SCNAs with 2% overlap.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('affected', 'Reg', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('SCNAs', 'Var', (81, 86))	('cancer', 'Disease', (42, 48))
83836	29618619	Another study exploring the copy number profiles of 3131 tumor genomes across 26 cancer types identified 158 recurrent focal SCNAs including 76 amplification affecting 1566 genes and 82 deletions affecting 2001 genes.	('amplification affecting', 'Var', (144, 167))	('focal SCNAs', 'Disease', (119, 130))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Disease', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (57, 62))	('deletions', 'Var', (186, 195))
83842	29618619	Survival analyses of different tumor types indicated that patients with homozygous deletion of interferon or defensin genes exhibit much worse overall or disease-free survival.	('worse', 'NegReg', (137, 142))	('interferon', 'Gene', '3439', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('disease-free survival', 'CPA', (154, 175))	('tumor', 'Disease', (31, 36))	('overall', 'CPA', (143, 150))	('homozygous deletion', 'Var', (72, 91))	('interferon', 'Gene', (95, 105))	('patients', 'Species', '9606', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('defensin genes', 'Gene', (109, 123))
83843	29618619	RNA-seq gene expression analyses between patients with and without IFN/DEF deletion in 19 cancer types indicate that homozygous deletions of IFN and DEF activate oncogenic and cell cycle pathways but repress immune response pathways.	('gene expression', 'biological_process', 'GO:0010467', ('8', '23'))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('immune response', 'biological_process', 'GO:0006955', ('208', '223'))	('IFN', 'Gene', '3439', (141, 144))	('repress immune response', 'Phenotype', 'HP:0002721', (200, 223))	('patients', 'Species', '9606', (41, 49))	('DEF', 'Gene', (149, 152))	('immune response pathways', 'Pathway', (208, 232))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('IFN', 'Gene', '3439', (67, 70))	('activate', 'PosReg', (153, 161))	('repress', 'NegReg', (200, 207))	('cell cycle', 'biological_process', 'GO:0007049', ('176', '186'))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('IFN', 'Gene', (141, 144))	('deletions', 'Var', (128, 137))	('IFN', 'Gene', (67, 70))
83845	29618619	Since a large body of evidence suggest that interferons and defensins play major roles in tumor immunity by recognizing tumor cells and serve as a bridge to spontaneous adaptive T cell response, our findings suggest a common molecular mechanism mediated by the deletion of interferon and defensin genes, through which tumor cells escape immune detection and destruction.	('defensin genes', 'Gene', (288, 302))	('interferon', 'Gene', '3439', (273, 283))	('interferon', 'Gene', '3439', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('interferon', 'Gene', (44, 54))	('interferon', 'Gene', (273, 283))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('deletion', 'Var', (261, 269))	('tumor', 'Disease', (318, 323))	('tumor', 'Disease', (120, 125))
83858	29618619	beta = 0.2), the minimum number of required events (K) is calculated as: where Zalpha/2 = 1.96, Zbeta = 0.84, pi1 and pi2 are the proportions to be allocated into two groups and were determined by the HDI/HDD frequencies in each cancer type.	('pi1', 'Var', (110, 113))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('Zalpha/2 = 1.96', 'Var', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('pi2', 'Var', (118, 121))	('HDD', 'Disease', (205, 208))	('pi2', 'Species', '1214577', (118, 121))	('HDD', 'Disease', 'None', (205, 208))
83890	29618619	Since both interferons and defensins are involved in innate immune response and play important roles in recognizing tumor cells and inducing an anti-tumor immune response, the widespread, homozygous deletion of these genes suggests a common molecular mechanism through which tumor cells escape immune destruction.	('interferon', 'Gene', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('interferon', 'Gene', '3439', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (149, 154))	('deletion', 'Var', (199, 207))	('immune response', 'biological_process', 'GO:0006955', ('155', '170'))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Disease', (116, 121))	('innate immune response', 'biological_process', 'GO:0045087', ('53', '75'))
83915	29618619	We asked the question whether homozygous deletions of interferon genes are passive hitchhiking events due to the nearby CDKN2A deletion, or they play an active role in tumorigenesis and affect the patient survival.	('play', 'Reg', (145, 149))	('affect', 'Reg', (186, 192))	('interferon', 'Gene', '3439', (54, 64))	('tumor', 'Disease', (168, 173))	('CDKN2A', 'Gene', (120, 126))	('deletion', 'Var', (127, 135))	('interferon', 'Gene', (54, 64))	('CDKN2A', 'Gene', '1029', (120, 126))	('patient survival', 'CPA', (197, 213))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('patient', 'Species', '9606', (197, 204))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
83917	29618619	We performed the survival analyses on three patient groups: (I) patients only have CDKN2A deletion (CDKN2A-/IFN+); (II) patients have CDKN2A deletion and additional IFN gene deletions (CDKN2A-/IFN-); and (III) patients have neither CDKN2A nor IFN gene deletions (CDKN2A+/IFN+).	('deletion', 'Var', (90, 98))	('IFN', 'Gene', '3439', (271, 274))	('IFN', 'Gene', (243, 246))	('CDKN2A nor IFN', 'Gene', '1029;3439', (232, 246))	('CDKN2A', 'Gene', (83, 89))	('CDKN2A', 'Gene', '1029', (100, 106))	('CDKN2A', 'Gene', (263, 269))	('IFN', 'Gene', (193, 196))	('patient', 'Species', '9606', (64, 71))	('CDKN2A', 'Gene', (232, 238))	('patient', 'Species', '9606', (120, 127))	('CDKN2A-/IFN+);', 'Gene', '1029;3439', (100, 114))	('IFN', 'Gene', (271, 274))	('patients', 'Species', '9606', (210, 218))	('CDKN2A', 'Gene', (185, 191))	('deletion', 'Var', (141, 149))	('CDKN2A', 'Gene', '1029', (83, 89))	('CDKN2A', 'Gene', '1029', (263, 269))	('CDKN2A', 'Gene', (134, 140))	('IFN', 'Gene', '3439', (165, 168))	('CDKN2A', 'Gene', '1029', (232, 238))	('IFN', 'Gene', '3439', (108, 111))	('CDKN2A-/IFN-', 'Gene', (185, 197))	('CDKN2A nor IFN', 'Gene', (232, 246))	('CDKN2A+/IFN+', 'Gene', '3439', (263, 275))	('IFN', 'Gene', '3439', (243, 246))	('CDKN2A', 'Gene', '1029', (185, 191))	('CDKN2A-/IFN+)', 'Gene', (100, 113))	('patient', 'Species', '9606', (44, 51))	('CDKN2A-/IFN-)', 'Gene', '1029;3439', (185, 198))	('patients', 'Species', '9606', (64, 72))	('CDKN2A+/IFN+', 'Gene', (263, 275))	('CDKN2A', 'Gene', '1029', (134, 140))	('IFN', 'Gene', (165, 168))	('patients', 'Species', '9606', (120, 128))	('CDKN2A', 'Gene', (100, 106))	('patient', 'Species', '9606', (210, 217))	('IFN', 'Gene', '3439', (193, 196))	('IFN', 'Gene', (108, 111))
83924	29618619	It could be also due to other confounding factors such as PTEN and RB1 deletions, which tend to be mutually exclusive with HDIs and HDDs (Supplementary Figure 7).	('deletions', 'Var', (71, 80))	('PTEN', 'Gene', '5728', (58, 62))	('RB1', 'Gene', (67, 70))	('RB1', 'Gene', '5925', (67, 70))	('HDIs and HDDs', 'Disease', 'None', (123, 136))	('PTEN', 'Gene', (58, 62))
83925	29618619	To identify gene expression signatures associated with the deletion of IFN and DEF genes, we performed gene expression analysis on each of the 19 cancer types (or 17 cancer types when COAD and READ are combined as colorectal cancer, LUSC and LUAD are combined as lung cancer) having high frequencies of HDI and HDD.	('cancer', 'Disease', (146, 152))	('lung cancer', 'Disease', (263, 274))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', (225, 231))	('COAD', 'Disease', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('IFN', 'Gene', '3439', (71, 74))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('HDD', 'Disease', 'None', (311, 314))	('colorectal cancer', 'Disease', 'MESH:D015179', (214, 231))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('gene expression', 'biological_process', 'GO:0010467', ('12', '27'))	('colorectal cancer', 'Disease', (214, 231))	('HDD', 'Disease', (311, 314))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('IFN', 'Gene', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('gene expression', 'biological_process', 'GO:0010467', ('103', '118'))	('deletion', 'Var', (59, 67))	('cancer', 'Disease', (268, 274))	('COAD', 'Disease', 'MESH:D029424', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('colorectal cancer', 'Phenotype', 'HP:0003003', (214, 231))
83939	29618619	In a recent report, copy loss of type I interferon genes are found in 6 out of 12 melanoma patients that resist to anti-CTLA-4 treatment, but in none of the 4 responders (P = 0.23, two-tailed Fisher exact test).	('copy loss', 'Var', (20, 29))	('patients', 'Species', '9606', (91, 99))	('interferon', 'Gene', '3439', (40, 50))	('CTLA-4', 'Gene', '1493', (120, 126))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('interferon', 'Gene', (40, 50))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('CTLA-4', 'Gene', (120, 126))
83944	29618619	As a comparison, deletions of two tumor suppressor genes CDKN2A (P = 0.63) and PTEN (P = 0.55) are not associated with responders or non-responders (Fig.	('tumor', 'Disease', (34, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('CDKN2A', 'Gene', (57, 63))	('deletions', 'Var', (17, 26))	('CDKN2A', 'Gene', '1029', (57, 63))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('PTEN', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PTEN', 'Gene', '5728', (79, 83))
83945	29618619	Taken together, our meta-analyses of two independent melanoma cohorts suggest the deletion of interferon and defensin genes is significantly associated anti-CTLA-4 treatment resistance, and might be a potential prognostic biomarker to predict resistance to other immunotherapies.	('CTLA-4', 'Gene', (157, 163))	('interferon', 'Gene', (94, 104))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('CTLA-4', 'Gene', '1493', (157, 163))	('deletion', 'Var', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('associated', 'Reg', (141, 151))	('interferon', 'Gene', '3439', (94, 104))
83947	29618619	In this study, we analyzed the copy number profiles of 10,759 primary cancer tissues and found the homozygous deletions of type I interferon and defensin genes are pervasive in 19 TCGA cancer types, and the alteration frequency is much higher than those of well-known tumor suppressors PTEN and RB1 in the same cancer type (Supplementary Figure 7).	('interferon', 'Gene', '3439', (130, 140))	('PTEN', 'Gene', '5728', (286, 290))	('cancer', 'Disease', (311, 317))	('defensin', 'Gene', (145, 153))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('RB1', 'Gene', '5925', (295, 298))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('PTEN', 'Gene', (286, 290))	('tumor', 'Disease', (268, 273))	('interferon', 'Gene', (130, 140))	('RB1', 'Gene', (295, 298))	('deletions', 'Var', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
83948	29618619	More importantly, homozygous deletions of interferon and defensin genes associate with worse overall or disease-free survival, and the resistance to anti-CTLA4 treatment in melanoma patients.	('CTLA4', 'Gene', (154, 159))	('defensin', 'Gene', (57, 65))	('worse', 'NegReg', (87, 92))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('interferon', 'Gene', '3439', (42, 52))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('disease-free survival', 'CPA', (104, 125))	('resistance', 'CPA', (135, 145))	('patients', 'Species', '9606', (182, 190))	('overall', 'CPA', (93, 100))	('interferon', 'Gene', (42, 52))	('CTLA4', 'Gene', '1493', (154, 159))	('homozygous deletions', 'Var', (18, 38))
83949	29618619	Defects in the type I interferon signaling pathway have been proposed as a potential mechanism of cancer escape (insensitivity) to immunotherapy in mice and prostate cancer cell line.	('prostate cancer', 'Disease', 'MESH:D011471', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('interferon', 'Gene', '3439', (22, 32))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('type I interferon signaling pathway', 'biological_process', 'GO:0060337', ('15', '50'))	('Defects', 'Var', (0, 7))	('interferon', 'Gene', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('mice', 'Species', '10090', (148, 152))	('cancer', 'Disease', (98, 104))	('prostate cancer', 'Disease', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
83954	29618619	By analyzing the genomes of 10,759 cancer patients across 31 cancer types, we found interferon and defensin genes are homozygously deleted with high frequencies in 19 cancer types, and the surviving time of patients with these deletions are significantly reduced.	('reduced', 'NegReg', (255, 262))	('patients', 'Species', '9606', (207, 215))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('interferon', 'Gene', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('surviving time', 'CPA', (189, 203))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('interferon', 'Gene', '3439', (84, 94))	('deletions', 'Var', (227, 236))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('patients', 'Species', '9606', (42, 50))	('defensin genes', 'Gene', (99, 113))	('cancer', 'Disease', (35, 41))
83961	28977858	In addition, Celigo Cell Counting indicated that cell viability was significantly lower in hMex-3A-siRNA-transfected cells group (2196/well) than in negative control group (6777/well) (P < 0.05), but T24 cells did not show statistical significance between hMex-3A-siRNA-transfected cells group (5799/well) and negative control group (7899/well) (P >0.05).	('2196/well', 'Var', (130, 139))	('cell viability', 'CPA', (49, 63))	('hMex-3A', 'Gene', (91, 98))	('hMex-3A', 'Gene', '92312', (91, 98))	('hMex-3A', 'Gene', (256, 263))	('hMex-3A', 'Gene', '92312', (256, 263))	('lower', 'NegReg', (82, 87))
83974	28977858	In TCGA database, the difference in Mex-3A expression between cancerous tissue and para-cancerous tissue was reflected by FC (ratio of expression level in cancerous tissue to expression level in para-cancerous tissue) and P-value (statistical analysis model which is used to determine whether a statistic is consistent with null hypothesis) (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancerous', 'Disease', 'MESH:D009369', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('para-cancerous', 'Disease', (195, 209))	('cancerous', 'Disease', 'MESH:D009369', (88, 97))	('cancerous', 'Disease', (155, 164))	('para-cancerous', 'Disease', (83, 97))	('para-cancerous', 'Disease', 'MESH:D009369', (195, 209))	('para-cancerous', 'Disease', 'MESH:D009369', (83, 97))	('cancerous', 'Disease', (200, 209))	('Mex-3A', 'Gene', '92312', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancerous', 'Disease', 'MESH:D009369', (62, 71))	('cancerous', 'Disease', (88, 97))	('P-value', 'Var', (222, 229))	('difference', 'Reg', (22, 32))	('Mex-3A', 'Gene', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancerous', 'Disease', 'MESH:D009369', (155, 164))	('expression', 'MPA', (43, 53))	('cancerous', 'Disease', (62, 71))
83981	28977858	The relative mRNA levels (hMex-3A/GAPDH) in shCtrl and shMex3A groups were 1.001+-0.053 and 0.260+-0.049 in 5637 cells, and were 1.001+-0.047 and 0.319+-0.038 in T24 cells, respectively (Figure 3) (all P <0.05).	('hMex', 'Gene', '151112', (26, 30))	('Mex3A', 'Gene', '92312', (57, 62))	('hMex-3A/GAPDH', 'Gene', '2597;92312', (26, 39))	('hMex', 'Gene', (26, 30))	('hMex', 'Gene', '151112', (56, 60))	('hMex-3A/GAPDH', 'Gene', (26, 39))	('mRNA levels', 'MPA', (13, 24))	('Mex3A', 'Gene', (57, 62))	('hMex', 'Gene', (56, 60))	('0.260+-0.049', 'Var', (92, 104))
83985	28977858	Celigo Cell Counting indicated that 5637 cell growth was slower in hMex-3A-siRNA-transfected group (2196/well) than in negative control group (6777/well) (P < 0.05) in 5 days later.	('slower', 'NegReg', (57, 63))	('hMex-3A', 'Gene', (67, 74))	('hMex-3A', 'Gene', '92312', (67, 74))	('5637 cell growth', 'CPA', (36, 52))	('2196/well', 'Var', (100, 109))	('cell growth', 'biological_process', 'GO:0016049', ('41', '52'))
83987	28977858	Cell growth was slower in hMex-3A-siRNA-transfected group (5799/well) than in negative control group (7899/well) in T24 cells 5 days later.	('5799/well', 'Var', (59, 68))	('Cell growth', 'biological_process', 'GO:0016049', ('0', '11'))	('hMex-3A', 'Gene', (26, 33))	('hMex-3A', 'Gene', '92312', (26, 33))	('Cell growth', 'CPA', (0, 11))	('slower', 'NegReg', (16, 22))
83998	28977858	Recently, it has been reported that knockdown of Mex3A by siRNAs inhibits cell proliferation and migration in human gastric cancer cells.	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))	('inhibits', 'NegReg', (65, 73))	('gastric cancer', 'Disease', (116, 130))	('Mex3A', 'Gene', (49, 54))	('knockdown', 'Var', (36, 45))	('siRNAs', 'Gene', (58, 64))	('human', 'Species', '9606', (110, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Mex3A', 'Gene', '92312', (49, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (116, 130))
84002	28977858	Silencing of Mex3C leads to DNA replication stress, structural chromosome abnormalities, and chromosome mis-segregation.	('chromosome abnormalities', 'Disease', (63, 87))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (63, 87))	('Silencing', 'Var', (0, 9))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('DNA replication', 'biological_process', 'GO:0006260', ('28', '43'))	('Mex3C', 'Gene', (13, 18))	('DNA', 'MPA', (28, 31))	('leads to', 'Reg', (19, 27))	('chromosome mis-segregation', 'CPA', (93, 119))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (63, 87))
84005	28977858	Mex3C mutant mice also display a postnatal growth retardation phenotype; possibly due to a role for Mex3C in enhancing insulin-like growth factor 1 (IGF1) mRNA translation in developing bone, given that IGF1 is a primary mediator of growth hormone effects.	('mice', 'Species', '10090', (13, 17))	('mutant', 'Var', (6, 12))	('translation', 'biological_process', 'GO:0006412', ('160', '171'))	('enhancing', 'PosReg', (109, 118))	('postnatal growth retardation', 'Disease', (33, 61))	('growth retardation', 'Phenotype', 'HP:0001510', (43, 61))	('postnatal growth retardation', 'Phenotype', 'HP:0008897', (33, 61))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('119', '145'))	('Mex3C', 'Gene', (0, 5))	('mRNA translation', 'MPA', (155, 171))	('postnatal growth retardation', 'Disease', 'MESH:D006130', (33, 61))	('IGF1', 'Gene', (149, 153))	('growth hormone', 'molecular_function', 'GO:0005131', ('233', '247'))	('Mex3C', 'Gene', (100, 105))
84006	28977858	Finally, polymorphic variations in human Mex3C may produce the susceptibility to essential hypertension.	('produce', 'Reg', (51, 58))	('hypertension', 'Disease', (91, 103))	('hypertension', 'Phenotype', 'HP:0000822', (91, 103))	('human', 'Species', '9606', (35, 40))	('susceptibility', 'Reg', (63, 77))	('hypertension', 'Disease', 'MESH:D006973', (91, 103))	('polymorphic variations', 'Var', (9, 31))	('Mex3C', 'Gene', (41, 46))
84031	28977858	In summary, silencing of hMex-3A resulted in a more obvious decrease in proliferation ability of 5637 than T24 bladder cancer cells, suggesting that a reduction in the hMex-3A expression level may lead to a more marked suppression of 5637 than T24 bladder cancer cell growth.	('expression level', 'MPA', (176, 192))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('cell growth', 'biological_process', 'GO:0016049', ('263', '274'))	('bladder cancer', 'Disease', 'MESH:D001749', (111, 125))	('5637', 'MPA', (234, 238))	('decrease', 'NegReg', (60, 68))	('bladder cancer', 'Disease', (111, 125))	('bladder cancer', 'Disease', (248, 262))	('bladder cancer', 'Disease', 'MESH:D001749', (248, 262))	('bladder cancer', 'Phenotype', 'HP:0009725', (111, 125))	('bladder cancer', 'Phenotype', 'HP:0009725', (248, 262))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('suppression', 'NegReg', (219, 230))	('proliferation ability', 'CPA', (72, 93))	('silencing', 'Var', (12, 21))	('hMex-3A', 'Gene', (168, 175))	('hMex-3A', 'Gene', (25, 32))	('hMex-3A', 'Gene', '92312', (25, 32))	('reduction', 'NegReg', (151, 160))	('hMex-3A', 'Gene', '92312', (168, 175))
84087	33202946	Consistent with the critical roles of ADME genes in metabolizing and clearing anticancer drugs and cancer-modulating compounds, numerous genetic polymorphisms (e.g., single nucleotide polymorphism, SNP) of ADME genes are known to be associated with carcinogenesis and drug response.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('carcinogenesis', 'Disease', (249, 263))	('associated', 'Reg', (233, 243))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('ADME', 'Gene', (206, 210))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('single nucleotide polymorphism', 'Var', (166, 196))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('carcinogenesis', 'Disease', 'MESH:D063646', (249, 263))
84103	33202946	Of the 298 ADME genes, 157 genes (52%) were expressed in all 21 cancers and only 12 genes (4%) (CYP11B1, CYP11B2, DHRS7C, GPX5, GPX6, GSTA3, GSTA5, LOC731356, PLGLB1, SLCO6A1, SULT1C1, UGT2B17) were not expressed in any of the 21 cancer types analysed (Table S1).	('CYP11B2', 'Gene', (105, 112))	('GPX6', 'Gene', (128, 132))	('LOC731356', 'Var', (148, 157))	('DHRS7C', 'Gene', '201140', (114, 120))	('PLGLB1', 'Gene', '5343', (159, 165))	('UGT2B17', 'Gene', '7367', (185, 192))	('GSTA3', 'Gene', '2940', (134, 139))	('GSTA5', 'Gene', (141, 146))	('SULT1C1', 'Gene', '6819', (176, 183))	('cancer', 'Disease', (64, 70))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('GSTA3', 'Gene', (134, 139))	('cancers', 'Disease', (64, 71))	('cancer', 'Disease', (230, 236))	('SLCO6A1', 'Gene', '133482', (167, 174))	('PLGLB1', 'Gene', (159, 165))	('SLCO6A1', 'Gene', (167, 174))	('GSTA5', 'Gene', '221357', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('SULT1C1', 'Gene', (176, 183))	('CYP11B2', 'Gene', '1585', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('GPX5', 'Gene', (122, 126))	('UGT2B17', 'Gene', (185, 192))	('CYP11B1', 'Gene', '1584', (96, 103))	('DHRS7C', 'Gene', (114, 120))	('GPX5', 'Gene', '2880', (122, 126))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('GPX6', 'Gene', '257202', (128, 132))	('CYP11B1', 'Gene', (96, 103))
84118	33202946	A recent study reported frequent somatic DPYD mutations in SKCM and its upregulation in metastatic tumour.	('DPYD', 'Gene', '1806', (41, 45))	('upregulation', 'PosReg', (72, 84))	('mutations', 'Var', (46, 55))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('SKCM', 'Gene', (59, 63))	('DPYD', 'Gene', (41, 45))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
84120	33202946	Among the CYP genes, four (2C19, 2C8, 2C9, 3A5) showed significant associations with increased OS rates in liver cancer (LIHC); three showed correlation with reduced (2D6, E1) or increased (3A4) OS rates in kidney cancer (KIRC); CYP2D6 was also associated with increased OS rates in breast cancer (BRCA) (Figure 1).	('CYP', 'Gene', (229, 232))	('CYP2D6', 'Gene', (229, 235))	('liver cancer', 'Disease', 'MESH:D006528', (107, 119))	('kidney cancer', 'Disease', 'MESH:D007680', (207, 220))	('BRCA', 'Gene', '672', (298, 302))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (283, 296))	('liver cancer', 'Phenotype', 'HP:0002896', (107, 119))	('kidney cancer', 'Phenotype', 'HP:0009726', (207, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('kidney cancer', 'Disease', (207, 220))	('CYP', 'Gene', '9360', (10, 13))	('liver cancer', 'Disease', (107, 119))	('reduced', 'NegReg', (158, 165))	('breast cancer', 'Disease', 'MESH:D001943', (283, 296))	('BRCA', 'Gene', (298, 302))	('breast cancer', 'Disease', (283, 296))	('CYP', 'Gene', (10, 13))	('CYP', 'Gene', '9360', (229, 232))	('2C19', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('CYP2D6', 'Gene', '1565', (229, 235))
84133	33202946	Among the three ABC transporters, high ABCB1 expression was associated with increased OS rates consistently across four different cancer types (HNSC, PAAD, SARC, SKCM) (Figure 4A); high ABCG2 expression was also correlated with increased OS rates in KIRC (Figure 4A), consistent with a recent report.	('ABC', 'Gene', (16, 19))	('ABCG2', 'Gene', (186, 191))	('increased', 'PosReg', (228, 237))	('ABCG2', 'Gene', '9429', (186, 191))	('OS rates', 'MPA', (86, 94))	('ABC', 'Gene', '10058', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('increased', 'PosReg', (76, 85))	('expression', 'MPA', (192, 202))	('high', 'Var', (181, 185))	('ABC', 'Gene', (39, 42))	('ABCB1', 'Gene', (39, 44))	('ABCB1', 'Gene', '5243', (39, 44))	('ABC', 'Gene', '10058', (186, 189))	('cancer', 'Disease', (130, 136))	('ABC', 'Gene', (186, 189))	('high', 'Var', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('ABC', 'Gene', '10058', (16, 19))
84134	33202946	By contrast, high ABCC2 levels showed associations with decreased OS rates in SKCM (Figure 4A).	('high', 'Var', (13, 17))	('SKCM', 'Disease', (78, 82))	('decreased', 'NegReg', (56, 65))	('ABCC2', 'Gene', (18, 23))	('ABCC2', 'Gene', '1244', (18, 23))
84140	33202946	The finding that high SLC15A2 expression associated with favourable OS in the TCGA-LUAD dataset (Figure 4B), was corroborated by the KM-LUAD analysis.	('SLC15A2', 'Gene', '6565', (22, 29))	('expression', 'MPA', (30, 40))	('high', 'Var', (17, 21))	('SLC15A2', 'Gene', (22, 29))	('KM-LUAD', 'Chemical', '-', (133, 140))
84141	33202946	Specifically, analysis of the KM-LUAD cohort using expression data from both of the SLC15A2 probe sets: 205316_at (Figure 5A) and 205317_s_at (Figure 5B), showed a similar association with OS.	('SLC15A2', 'Gene', '6565', (84, 91))	('205317_s_at', 'Var', (130, 141))	('SLC15A2', 'Gene', (84, 91))	('KM-LUAD', 'Chemical', '-', (30, 37))	('205316_at', 'Var', (104, 113))
84143	33202946	High UGT1A1 expression was associated with favourable OS rates in TCGA LUSC (Figure 3).	('UGT1A1', 'Gene', '54658', (5, 11))	('UGT1A1', 'Gene', (5, 11))	('TCGA LUSC', 'Disease', (66, 75))	('High', 'Var', (0, 4))
84146	33202946	Of the six UGT1A1 probe sets, four (215125_s_at, 207126_x_at, 206094_x_at, 204532_x_at) target exon 5, one (208596_s_at) targets exons 3-5, and the sixth (221304_at) targets UGT1A8 exon 1.	('UGT1A8', 'Gene', '54576', (174, 180))	('UGT1A8', 'Gene', (174, 180))	('221304_at', 'Var', (155, 164))	('215125_s_at', 'Var', (36, 47))	('UGT1A1', 'Gene', '54658', (11, 17))	('UGT1A1', 'Gene', (11, 17))	('208596_s_at', 'Var', (108, 119))	('206094_x_at, 204532_x_at', 'Var', (62, 86))
84150	33202946	The exception was GSTM1, where higher expression was associated with favourable OS in KM-BRCA when analysed using data from both GSTM1 probe sets (215333_x_at, 204550_x_at) (Figure S4).	('GSTM1', 'Gene', '2944', (129, 134))	('BRCA', 'Gene', (89, 93))	('expression', 'MPA', (38, 48))	('GSTM1', 'Gene', (129, 134))	('GSTM1', 'Gene', '2944', (18, 23))	('215333_x_at', 'Var', (147, 158))	('GSTM1', 'Gene', (18, 23))	('BRCA', 'Gene', '672', (89, 93))
84151	33202946	Moreover, our finding that high CYP2D6 levels associated with favourable OS in the TCGA-BRCA dataset (Figure 1), was not corroborated by the KM-BRCA analysis when all three CYP2D6 probe sets were analysed (207498_s_at, 215809_at, 217468_at) (Table S3).	('CYP2D6', 'Gene', (173, 179))	('CYP2D6', 'Gene', (32, 38))	('BRCA', 'Gene', (144, 148))	('207498_s_at', 'Var', (206, 217))	('CYP2D6', 'Gene', '1565', (32, 38))	('BRCA', 'Gene', '672', (144, 148))	('CYP2D6', 'Gene', '1565', (173, 179))	('BRCA', 'Gene', '672', (88, 92))	('associated', 'Reg', (46, 56))	('BRCA', 'Gene', (88, 92))
84180	33202946	In BLCA, we showed an association of high UGT2B15 expression with favourable OS, consistent with a recent report.	('UGT2B15', 'Gene', (42, 49))	('high', 'Var', (37, 41))	('UGT2B15', 'Gene', '7366', (42, 49))	('favourable OS', 'Disease', (66, 79))	('expression', 'MPA', (50, 60))
84189	33202946	In LIHC, we showed the association of high CYP3A5 expression with favourable OS (Figure 1), which is consistent with the reported tumour suppressive activity of this enzyme.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('CYP3A5', 'Gene', (43, 49))	('tumour', 'Disease', (130, 136))	('high', 'Var', (38, 42))	('CYP3A5', 'Gene', '1577', (43, 49))	('favourable OS', 'Disease', (66, 79))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('expression', 'MPA', (50, 60))
84207	33202946	We showed here that high ABCC2 expression was associated with unfavourable OS in melanoma (SKCM) (Figure 4A).	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('ABCC2', 'Gene', (25, 30))	('high', 'Var', (20, 24))	('melanoma', 'Disease', (81, 89))	('expression', 'MPA', (31, 41))	('ABCC2', 'Gene', '1244', (25, 30))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('associated', 'Reg', (46, 56))
84217	33202946	High ABCB1 expression was also associated with favourable OS in neuroblastoma.	('ABCB1', 'Gene', (5, 10))	('neuroblastoma', 'Disease', 'MESH:D009447', (64, 77))	('ABCB1', 'Gene', '5243', (5, 10))	('High', 'Var', (0, 4))	('favourable OS', 'Disease', (47, 60))	('expression', 'MPA', (11, 21))	('neuroblastoma', 'Disease', (64, 77))	('associated', 'Reg', (31, 41))	('neuroblastoma', 'Phenotype', 'HP:0003006', (64, 77))
84226	33202946	Most clinical trials of inhibitors targeting ABCB1 resulted in no benefit in survival.	('inhibitors', 'Var', (24, 34))	('ABCB1', 'Gene', '5243', (45, 50))	('ABCB1', 'Gene', (45, 50))
84265	33202946	Conflicting results were seen for some genes such as DPYD in KM-LUAD, where all three DPYD probe sets showed a Bonferroni-corrected p-value of < 0.05; however, one probe set (1554534_at) was associated with unfavourable OS but the two other probe sets (1554536_at, 204646_at) showed association with favourable OS (Table S3).	('1554536_at', 'Var', (253, 263))	('DPYD', 'Gene', (86, 90))	('DPYD', 'Gene', '1806', (86, 90))	('unfavourable', 'Disease', (207, 219))	('DPYD', 'Gene', (53, 57))	('associated', 'Reg', (191, 201))	('KM-LUAD', 'Chemical', '-', (61, 68))	('DPYD', 'Gene', '1806', (53, 57))	('1554534_at', 'Var', (175, 185))	('favourable OS', 'Disease', (300, 313))
84278	32368300	Results: Analysis results showed that high CIT expression was associated with tumor size (p=0.0001), tumor grade (p<0.0001), smoking status (p=0.0143), TNM stage (p=0.0024), pathological tumor stage (p<0.0001) and aggressive phenotypes of bladder cancer.	('CIT', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('associated', 'Reg', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('high', 'Var', (38, 42))	('bladder cancer', 'Disease', 'MESH:D001749', (239, 253))	('bladder cancer', 'Disease', (239, 253))	('bladder cancer', 'Phenotype', 'HP:0009725', (239, 253))	('expression', 'MPA', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('TNM', 'Gene', '10178', (152, 155))	('tumor', 'Disease', (78, 83))	('TNM', 'Gene', (152, 155))	('CIT', 'Gene', '11113', (43, 46))	('CIT', 'biological_process', 'GO:0106106', ('43', '46'))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
84284	32368300	Loss of CIT causes failure of cytokinesis and therefore triggers apoptosis in the male germ cells and a specific population of neuroblasts.	('triggers', 'Reg', (56, 64))	('CIT', 'biological_process', 'GO:0106106', ('8', '11'))	('failure', 'CPA', (19, 26))	('cytokinesis', 'biological_process', 'GO:0000910', ('30', '41'))	('CIT', 'Gene', '11113', (8, 11))	('apoptosis', 'CPA', (65, 74))	('cytokinesis', 'CPA', (30, 41))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('Loss', 'Var', (0, 4))	('CIT', 'Gene', (8, 11))
84330	32368300	Five datasets including GSE13507, GSE31684, E-MTAB-1803, E-MTAB-4321 and TCGA-BLCA, were selected to research on the associations of CIT expression with clinical outcome of patients with bladder cancer.	('MTAB', 'molecular_function', 'GO:0047152', ('46', '50'))	('CIT', 'Gene', '11113', (133, 136))	('bladder cancer', 'Disease', 'MESH:D001749', (187, 201))	('patients', 'Species', '9606', (173, 181))	('associations', 'Interaction', (117, 129))	('CIT', 'Gene', (133, 136))	('bladder cancer', 'Disease', (187, 201))	('E-MTAB-4321', 'Var', (57, 68))	('CIT', 'biological_process', 'GO:0106106', ('133', '136'))	('GSE31684', 'Var', (34, 42))	('bladder cancer', 'Phenotype', 'HP:0009725', (187, 201))	('MTAB', 'molecular_function', 'GO:0047152', ('59', '63'))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
84331	32368300	Analysis results showed that high CIT expression was associated with tumor size (p=0.0001), tumor grade (p<0.0001) and smoking status (p=0.0143), TNM stage (p=0.0024) and pathological tumor stage (p<0.0001) (Figure 1C).	('high', 'Var', (29, 33))	('TNM', 'Gene', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('CIT', 'biological_process', 'GO:0106106', ('34', '37'))	('expression', 'MPA', (38, 48))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('CIT', 'Gene', '11113', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (184, 189))	('CIT', 'Gene', (34, 37))	('TNM', 'Gene', '10178', (146, 149))	('associated', 'Reg', (53, 63))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
84336	32368300	As shown in Figure 1G, significantly increased CIT level was observed in T24 (Grade III) compared with RT4 (Grade I).	('CIT', 'Gene', '11113', (47, 50))	('CIT', 'Gene', (47, 50))	('CIT', 'biological_process', 'GO:0106106', ('47', '50'))	('T24', 'Var', (73, 76))	('increased', 'PosReg', (37, 46))
84359	32368300	Mutation or loss of CIT had been proved to lead to defective neurogenesis in both mice humans.	('mice', 'Species', '10090', (82, 86))	('humans', 'Species', '9606', (87, 93))	('loss of CIT', 'Disease', (12, 23))	('CIT', 'biological_process', 'GO:0106106', ('20', '23'))	('loss of CIT', 'Disease', 'MESH:D014786', (12, 23))	('Mutation', 'Var', (0, 8))	('defective', 'NegReg', (51, 60))	('neurogenesis', 'biological_process', 'GO:0022008', ('61', '73'))
84362	32368300	In addition, several studies had revealed that CIT depletion led to failure of cytokinesis and dramatically inhibited cell proliferation of liver, breast, cervical and colorectal cancer cell lines.	('breast', 'Disease', (147, 153))	('CIT', 'Gene', '11113', (47, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cytokinesis', 'CPA', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('CIT', 'Gene', (47, 50))	('cytokinesis', 'biological_process', 'GO:0000910', ('79', '90'))	('colorectal cancer', 'Disease', (168, 185))	('cervical', 'Disease', (155, 163))	('CIT', 'biological_process', 'GO:0106106', ('47', '50'))	('failure', 'NegReg', (68, 75))	('cell proliferation', 'biological_process', 'GO:0008283', ('118', '136'))	('cell proliferation', 'CPA', (118, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('depletion', 'Var', (51, 60))	('inhibited', 'NegReg', (108, 117))
84434	31362898	At 6 months, survival was highest for PD-L1 positive patients treated with immunotherapy and lowest for PD-L1 negative patients treated with immunotherapy, relative to patients treated with chemotherapy (Figure 2).	('highest', 'Reg', (26, 33))	('patients', 'Species', '9606', (53, 61))	('PD-L1', 'Gene', '29126', (104, 109))	('patients', 'Species', '9606', (119, 127))	('PD-L1', 'Gene', '29126', (38, 43))	('survival', 'MPA', (13, 21))	('PD-L1', 'Gene', (38, 43))	('patients', 'Species', '9606', (168, 176))	('lowest', 'NegReg', (93, 99))	('positive', 'Var', (44, 52))	('PD-L1', 'Gene', (104, 109))
84608	25512821	The anatomopathological study of the specimen revealed transitional cell carcinoma pT2G3N0M0.	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (55, 82))	('carcinoma', 'Disease', (73, 82))	('pT2G3N0M0', 'Var', (83, 92))	('carcinoma', 'Disease', 'MESH:D002277', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
84647	33204364	Moreover, patients with pathological T1G3 NMIBC or contaminated with carcinoma in situ (CIS) are more likely to develop into MIBC or exhibit lymph node metastasis.	('develop', 'Reg', (112, 119))	('MIBC', 'Disease', (125, 129))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (69, 86))	('lymph node metastasis', 'CPA', (141, 162))	('MIBC', 'Chemical', '-', (43, 47))	('CIS', 'Phenotype', 'HP:0030075', (88, 91))	('carcinoma', 'Disease', (69, 78))	('carcinoma', 'Disease', 'MESH:D009369', (69, 78))	('T1G3 NMIBC', 'Var', (37, 47))	('MIBC', 'Chemical', '-', (125, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('patients', 'Species', '9606', (10, 18))
84675	33204364	The EMT-LN signature and significant tumour frequent mutations were selected as candidate features for univariable and multivariable logistic regression analysis.	('tumour', 'Disease', (37, 43))	('mutations', 'Var', (53, 62))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('EMT', 'biological_process', 'GO:0001837', ('4', '7'))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
84677	33204364	As expected, Kaplan-Meier survival curves demonstrated that patients with LN+ exhibited poorer overall survival (OS) than LN- patients (p < 0.001, HR = 2.23, 95%CI = [1.6-3.12], Figure 1(a)), and a similar tendency could also be found in the recurrence-free survival (RFS) estimation where LN+ patients presented a higher recurrence rate (p < 0.001, HR = 2.59, 95%CI = [1.55-4.33], Figure 1(b)).	('LN+', 'Var', (74, 77))	('patients', 'Species', '9606', (294, 302))	('patients', 'Species', '9606', (60, 68))	('overall survival', 'MPA', (95, 111))	('recurrence', 'MPA', (322, 332))	('poorer', 'NegReg', (88, 94))	('patients', 'Species', '9606', (126, 134))
84682	33204364	Moreover, we found that TP53, FGFR3, and C3orf70 within the SMGs were remarkably highly mutated in LN+ tumours when compared with LN- tumours through Fisher exact tests (Figures 2(f) and 2(g); Supplementary Table S5).	('tumours', 'Phenotype', 'HP:0002664', (134, 141))	('TP53', 'Gene', (24, 28))	('LN- tumours', 'Disease', (130, 141))	('FGFR3', 'Gene', (30, 35))	('TP53', 'Gene', '7157', (24, 28))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('LN+ tumours', 'Disease', (99, 110))	('LN+ tumours', 'Disease', 'MESH:D009369', (99, 110))	('LN- tumours', 'Disease', 'MESH:D009369', (130, 141))	('mutated', 'Var', (88, 95))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('C3orf70', 'Gene', '285382', (41, 48))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))	('FGFR3', 'Gene', '2261', (30, 35))	('C3orf70', 'Gene', (41, 48))
84683	33204364	Therefore, mutation of TP53, FGFR3, and C3orf70 was selected for further analysis.	('FGFR3', 'Gene', (29, 34))	('C3orf70', 'Gene', '285382', (40, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('29', '33'))	('C3orf70', 'Gene', (40, 47))	('FGFR3', 'Gene', '2261', (29, 34))	('TP53', 'Gene', '7157', (23, 27))	('mutation', 'Var', (11, 19))	('TP53', 'Gene', (23, 27))
84688	33204364	Furthermore, Kaplan-Meier survival curves revealed that the EMT-LN signature was associated with OS (p = 0.129) and CSS (p = 0.004) in the GSE13507 cohort (Figures 4(d) and 4(e)), as well as OS (p = 0.073) and RFS (p = 0.099) in the GSE3684 cohort (Figures 4(f) and 4(g)).	('GSE3684', 'Chemical', '-', (233, 240))	('GSE13507', 'Var', (139, 147))	('EMT-LN', 'Gene', (60, 66))	('CSS', 'Disease', (116, 119))	('EMT', 'biological_process', 'GO:0001837', ('60', '63'))	('associated', 'Reg', (81, 91))
84689	33204364	As the pathological stage and detailed TNM classification should mostly be detected by biopsy postoperatively not preoperatively, we just enrolled the EMT-LN signature and mutation of TP53, FGFR3, and C3orf70 as the candidate features to establish the preoperative nomogram.	('C3orf70', 'Gene', '285382', (201, 208))	('EMT', 'biological_process', 'GO:0001837', ('151', '154'))	('TNM', 'Gene', (39, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('190', '194'))	('FGFR3', 'Gene', '2261', (190, 195))	('C3orf70', 'Gene', (201, 208))	('mutation', 'Var', (172, 180))	('TP53', 'Gene', (184, 188))	('TP53', 'Gene', '7157', (184, 188))	('FGFR3', 'Gene', (190, 195))	('TNM', 'Gene', '10178', (39, 42))
84690	33204364	We found that only the EMT-LN signature and C3orf70 mutation have statistical significance in the full model with p < 0.05 in the logistic regression (Supplementary Table S7).	('EMT', 'biological_process', 'GO:0001837', ('23', '26'))	('C3orf70', 'Gene', (44, 51))	('C3orf70', 'Gene', '285382', (44, 51))	('mutation', 'Var', (52, 60))
84694	33204364	A considerable amount of research demonstrated that BLCA patients with LN metastasis exhibited a poorer prognosis compared with patients without lymphatic spread.	('patients', 'Species', '9606', (57, 65))	('LN metastasis', 'Var', (71, 84))	('BLCA', 'Phenotype', 'HP:0009725', (52, 56))	('patients', 'Species', '9606', (128, 136))	('BLCA', 'Disease', (52, 56))
84698	33204364	But some study demonstrated that preoperative utility of NAC in BLCA patients with occult LN metastases would induce a poor prognosis compared with patients treated with AC, which indicated the complexity of BLCA treatment and the extreme essence to know the LN metastasis status when applying distinct regimens.	('patients', 'Species', '9606', (148, 156))	('NAC', 'Chemical', '-', (57, 60))	('metastases', 'Disease', (93, 103))	('BLCA', 'Phenotype', 'HP:0009725', (64, 68))	('patients', 'Species', '9606', (69, 77))	('NAC', 'cellular_component', 'GO:0005854', ('57', '60'))	('metastases', 'Disease', 'MESH:D009362', (93, 103))	('NAC', 'Var', (57, 60))	('BLCA', 'Phenotype', 'HP:0009725', (208, 212))
84704	33204364	With the genetic and epigenetic alteration, neoplastic cells induced oncogenic EMT to favour clonal outgrowth and localized tumours development.	('favour', 'PosReg', (86, 92))	('localized tumours', 'Disease', 'MESH:D009364', (114, 131))	('EMT', 'biological_process', 'GO:0001837', ('79', '82'))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('clonal outgrowth', 'CPA', (93, 109))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('oncogenic EMT', 'CPA', (69, 82))	('localized tumours', 'Disease', (114, 131))	('epigenetic alteration', 'Var', (21, 42))	('genetic', 'Var', (9, 16))
84713	33204364	The landscape of somatic mutation was evaluated across LN+ and LN- tumours that mutation of TP53, FGFR3, and C3ort70 was differentially mutated between LN+ and LN- tumours.	('LN- tumours', 'Disease', 'MESH:D009369', (63, 74))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('FGFR3', 'Gene', (98, 103))	('LN- tumours', 'Disease', 'MESH:D009369', (160, 171))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('LN- tumours', 'Disease', (160, 171))	('mutation', 'Var', (80, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('98', '102'))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('FGFR3', 'Gene', '2261', (98, 103))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('LN- tumours', 'Disease', (63, 74))	('C3ort70', 'Gene', (109, 116))
84719	33204364	In summary, we establish an EMT-LN nomogram integrating an EMT-LN signature and C3orf70 mutation, which act as an easy-to-use tool to facilitate preoperative prediction of LN metastasis in BLCA individuals.	('EMT', 'biological_process', 'GO:0001837', ('59', '62'))	('mutation', 'Var', (88, 96))	('C3orf70', 'Gene', '285382', (80, 87))	('C3orf70', 'Gene', (80, 87))	('EMT', 'biological_process', 'GO:0001837', ('28', '31'))	('BLCA', 'Phenotype', 'HP:0009725', (189, 193))
84769	32433532	The autoimmune lymphoproliferative disorder caused by Ctla4 loss depends on the activity of CD28 because mutation of an LCK-binding carboxy-terminal proline motif in the intracellular tail of CD28 abrogates disease in mouse models.	('mutation', 'Var', (105, 113))	('Ctla4', 'Gene', (54, 59))	('LCK', 'Gene', (120, 123))	('binding', 'molecular_function', 'GO:0005488', ('124', '131'))	('LCK', 'Gene', '3932', (120, 123))	('autoimmune lymphoproliferative disorder', 'Disease', 'MESH:D056735', (4, 43))	('CD28', 'Gene', (192, 196))	('abrogates', 'NegReg', (197, 206))	('disease', 'Disease', (207, 214))	('loss', 'NegReg', (60, 64))	('intracellular', 'cellular_component', 'GO:0005622', ('170', '183'))	('proline', 'Chemical', 'MESH:D011392', (149, 156))	('lymphoproliferative disorder', 'Phenotype', 'HP:0005523', (15, 43))	('mouse', 'Species', '10090', (218, 223))	('autoimmune lymphoproliferative disorder', 'Disease', (4, 43))	('Ctla4', 'Gene', '12477', (54, 59))
84778	32433532	James Allison and colleagues first tested this idea and demonstrated that neutralizing anti-CTLA4 antibodies enhanced antitumoural immunity in mice against transplanted and established colon carcinoma and fibrosarcoma.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (205, 217))	('antibodies', 'Var', (98, 108))	('fibrosarcoma', 'Disease', 'MESH:D005354', (205, 217))	('anti-CTLA4', 'Gene', (87, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('enhanced', 'PosReg', (109, 117))	('tumour', 'Disease', (122, 128))	('colon carcinoma', 'Disease', (185, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('neutralizing anti-CTLA4 antibodies', 'Var', (74, 108))	('fibrosarcoma', 'Disease', (205, 217))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('colon carcinoma', 'Disease', 'MESH:D003110', (185, 200))	('mice', 'Species', '10090', (143, 147))
84779	32433532	In addition, during rechallenge, animals treated with anti-CTLA4 were able to rapidly eliminate tumour cells through immune mechanisms, providing evidence that blocking of CTLA4 induces long-lasting immunological memory.	('memory', 'biological_process', 'GO:0007613', ('213', '219'))	('induces', 'Reg', (178, 185))	('CTLA4', 'Gene', (172, 177))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('anti-CTLA4', 'Var', (54, 64))	('blocking', 'Var', (160, 168))	('tumour', 'Disease', (96, 102))
84791	32433532	Inhibition of CTLA4 enhances T cell clonal responses to tumour-associated neoantigens and a high neoantigen burden portends a favourable response to anti-CTLA4 therapy.	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('CTLA4', 'Gene', (14, 19))	('enhances', 'PosReg', (20, 28))	('Inhibition', 'Var', (0, 10))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Disease', (56, 62))
84798	32433532	The predominant role of the PD1 axis in the negative regulation of T cell activation became clear in 1999 when loss of the mouse PD1 orthologue, Pdcd1, was found to cause autoimmunity in vivo.	('mouse', 'Species', '10090', (123, 128))	('loss', 'Var', (111, 115))	('autoimmunity', 'Phenotype', 'HP:0002960', (171, 183))	('Pdcd1', 'Gene', '18566', (145, 150))	('autoimmunity', 'Disease', (171, 183))	('Pdcd1', 'Gene', (145, 150))	('negative regulation of T cell activation', 'biological_process', 'GO:0050868', ('44', '84'))	('autoimmunity', 'Disease', 'MESH:D001327', (171, 183))
84800	32433532	Ageing of these animals led to mild T cell-mediated lupus-like glomerulonephritis and arthritis that was exacerbated by concurrent lpr mutations in the Fas gene.	('lupus-like glomerulonephritis', 'Disease', 'MESH:D008181', (52, 81))	('glomerulonephritis', 'Phenotype', 'HP:0000099', (63, 81))	('Fas', 'Gene', (152, 155))	('arthritis', 'Disease', 'MESH:D001168', (86, 95))	('mutations', 'Var', (135, 144))	('arthritis', 'Phenotype', 'HP:0001369', (86, 95))	('exacerbated', 'PosReg', (105, 116))	('Ageing', 'biological_process', 'GO:0007568', ('0', '6'))	('lpr', 'Gene', (131, 134))	('lupus-like glomerulonephritis', 'Disease', (52, 81))	('arthritis', 'Disease', (86, 95))
84810	32433532	Second, blockade of PD1 suppressed the growth of transplanted myeloma cells in syngeneic animals.	('PD1', 'Gene', (20, 23))	('myeloma', 'Disease', 'MESH:D009101', (62, 69))	('suppressed', 'NegReg', (24, 34))	('myeloma', 'Disease', (62, 69))	('blockade', 'Var', (8, 16))
84813	32433532	Rescuing CD8+ T cell cytotoxicity by PD1 blockade depends on the expression of CD28 as PD1-mediated immunomodulation is lost in the context of CTLA4Ig, B7 blockade or CD28 conditional-knockout mice.	('CD8', 'Gene', '925', (9, 12))	('cytotoxicity', 'Disease', (21, 33))	('blockade', 'Var', (41, 49))	('mice', 'Species', '10090', (193, 197))	('PD1', 'Gene', (37, 40))	('CD28', 'Gene', (79, 83))	('cytotoxicity', 'Disease', 'MESH:D064420', (21, 33))	('CD8', 'Gene', (9, 12))
84815	32433532	PD1 inhibition not only augments antitumoural immunity but also limits haematogenous seeding of B16 melanoma and CT26 colon carcinoma metastases in mouse models.	('PD1', 'Gene', (0, 3))	('colon carcinoma metastases', 'Disease', 'MESH:D009362', (118, 144))	('CT26', 'CellLine', 'CVCL:7254', (113, 117))	('colon carcinoma metastases', 'Disease', (118, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('tumour', 'Disease', (37, 43))	('mouse', 'Species', '10090', (148, 153))	('inhibition', 'Var', (4, 14))	('augments', 'NegReg', (24, 32))	('limits', 'NegReg', (64, 70))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
84816	32433532	Thus, PD1/PDL1 blockade can both enhance tumour cytolysis and limit metastasis.	('PD1/PDL1', 'Gene', (6, 14))	('blockade', 'Var', (15, 23))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('cytolysis', 'biological_process', 'GO:0019835', ('48', '57'))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('limit', 'NegReg', (62, 67))	('metastasis', 'CPA', (68, 78))	('tumour', 'Disease', (41, 47))	('enhance', 'PosReg', (33, 40))
84824	32433532	Additional successful clinical trials expanded the use of pembrolizumab to head and neck squamous cell carcinoma, Hodgkin lymphoma, urothelial carcinoma, gastric/gastro-oesophageal junction cancer and tissue-agnostic carcinoma with a high degree of microsatellite instability.	('carcinoma', 'Disease', (217, 226))	('gastric/gastro-oesophageal junction cancer', 'Disease', 'MESH:D013274', (154, 196))	('microsatellite', 'Var', (249, 263))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('carcinoma', 'Disease', (103, 112))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (132, 152))	('carcinoma', 'Disease', 'MESH:D009369', (217, 226))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('urothelial carcinoma', 'Disease', (132, 152))	('carcinoma', 'Disease', (143, 152))	('neck', 'cellular_component', 'GO:0044326', ('84', '88'))	('Hodgkin lymphoma', 'Disease', (114, 130))	('carcinoma', 'Disease', 'MESH:D009369', (103, 112))	('neck squamous cell carcinoma', 'Disease', (84, 112))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (84, 112))	('gastric/gastro-oesophageal junction cancer', 'Disease', (154, 196))	('carcinoma', 'Disease', 'MESH:D009369', (143, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (114, 130))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (114, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('pembrolizumab', 'Chemical', 'MESH:C582435', (58, 71))
84825	32433532	Following approval in tissue-agnostic cancers with microsatellite instability, pembrolizumab became the first drug to be approved based on a molecular biomarker rather than by cancer site.	('microsatellite instability', 'Var', (51, 77))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('pembrolizumab', 'Chemical', 'MESH:C582435', (79, 92))	('cancers', 'Disease', (38, 45))
84837	32433532	Therefore, similar to PD1, blockade of PDL1 has been effective in difficult-to-treat forms of cancer.	('PDL1', 'Gene', (39, 43))	('blockade', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
84839	32433532	Human loss-of-function mutations in CTLA4 and its interacting regulatory protein, LRBA, also mirror the immune-related side effects observed with anti-CTLA4 therapy.	('CTLA4', 'Gene', (36, 41))	('Human', 'Species', '9606', (0, 5))	('loss-of-function', 'NegReg', (6, 22))	('mutations', 'Var', (23, 32))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))
84841	32433532	More severe events requiring intervention are observed in 30% and 15% of patients treated with CTLA4 and PD1 axis inhibitors, respectively.	('PD1 axis', 'Gene', (105, 113))	('CTLA4', 'Gene', (95, 100))	('patients', 'Species', '9606', (73, 81))	('inhibitors', 'Var', (114, 124))
84845	32433532	Toxicities affecting the gastrointestinal tract and brain are more common with anti-CTLA4 therapy, whereas patients treated with PD1 axis-targeted therapies are at higher risk of hypothyroidism, hepatoxicity and pneumonitis.	('patients', 'Species', '9606', (107, 115))	('Toxicities', 'Disease', (0, 10))	('Toxicities', 'Disease', 'MESH:D064420', (0, 10))	('hypothyroidism', 'Disease', 'MESH:D007037', (179, 193))	('hypothyroidism', 'Phenotype', 'HP:0000821', (179, 193))	('hepatoxicity and pneumonitis', 'Disease', 'MESH:D011014', (195, 223))	('anti-CTLA4', 'Gene', (79, 89))	('anti-CTLA4', 'Var', (79, 89))	('hypothyroidism', 'Disease', (179, 193))
84847	32433532	For example, hyperprogression of disease has been observed in a minority of patients with various tumour types treated with PD1 inhibitors.	('hyperprogression of disease', 'Disease', 'MESH:D003141', (13, 40))	('patients', 'Species', '9606', (76, 84))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('PD1', 'Gene', (124, 127))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (98, 104))	('hyperprogression of disease', 'Disease', (13, 40))	('inhibitors', 'Var', (128, 138))
84850	32433532	In addition, these criteria aim to distinguish progression from pseudoprogression, a phenomenon in which patients treated with CTLA4 or PD1 inhibitors experience a period of progression followed by rapid tumour clearance.	('tumour', 'Disease', (204, 210))	('patients', 'Species', '9606', (105, 113))	('inhibitors', 'Var', (140, 150))	('pseudoprogression', 'Disease', (64, 81))	('CTLA4', 'Gene', (127, 132))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('tumour', 'Disease', 'MESH:D009369', (204, 210))	('PD1', 'Gene', (136, 139))
84858	32433532	For example, compared with systemic delivery, transdermal patch delivery of anti-PD1 antibodies was better tolerated and unleashed a more robust antitumoural response in a mouse model of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('antibodies', 'Var', (85, 95))	('mouse', 'Species', '10090', (172, 177))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('anti-PD1', 'Gene', (76, 84))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Disease', (149, 155))
84877	32433532	In addition, knockdown of the gene encoding cytokine-inducible SH2-containing protein (Cish), a negative regulator of TCR signalling, was shown to boost the antitumoural response of ATC therapy in mouse models.	('Cish', 'Gene', '12700', (87, 91))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('TCR', 'cellular_component', 'GO:0042101', ('118', '121'))	('cytokine-inducible SH2-containing protein', 'Gene', (44, 85))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('signalling', 'biological_process', 'GO:0023052', ('122', '132'))	('tumour', 'Disease', (161, 167))	('Cish', 'Gene', (87, 91))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('mouse', 'Species', '10090', (197, 202))	('TCR', 'biological_process', 'GO:0006283', ('118', '121'))	('knockdown', 'Var', (13, 22))	('cytokine-inducible SH2-containing protein', 'Gene', '12700', (44, 85))	('boost', 'PosReg', (147, 152))
84888	32433532	Subsequent generations of CAR T cells have been engineered to include domains from CD28, CD40 ligand and other positive regulators of T cell activation to potentiate activation and cytotoxicity in vivo.	('cytotoxicity', 'Disease', 'MESH:D064420', (181, 193))	('CD40', 'Gene', (89, 93))	('ligand', 'molecular_function', 'GO:0005488', ('94', '100'))	('T cell activation', 'biological_process', 'GO:0042110', ('134', '151'))	('activation', 'CPA', (166, 176))	('CAR', 'cellular_component', 'GO:0005826', ('26', '29'))	('cytotoxicity', 'Disease', (181, 193))	('CD28', 'Gene', (83, 87))	('potentiate', 'PosReg', (155, 165))	('CD40', 'Gene', '958', (89, 93))	('domains', 'Var', (70, 77))
84907	32433532	The efficacy of CAR T cells may also be strengthened through co-expression of a chimeric cytokine receptor (4alphabeta) that stimulates proliferation in response to IL-4, a cytokine that is usually abundant in the tumour microenvironment.	('co-expression', 'Var', (61, 74))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('efficacy', 'CPA', (4, 12))	('tumour', 'Disease', (214, 220))	('CAR', 'cellular_component', 'GO:0005826', ('16', '19'))	('IL-4', 'Gene', (165, 169))	('IL-4', 'molecular_function', 'GO:0005136', ('165', '169'))	('IL-4', 'Gene', '3565', (165, 169))	('tumour', 'Disease', 'MESH:D009369', (214, 220))	('strengthened', 'PosReg', (40, 52))	('response to IL-4', 'biological_process', 'GO:0070670', ('153', '169'))	('stimulates', 'PosReg', (125, 135))	('proliferation', 'CPA', (136, 149))
84916	32433532	Other side effects of CD19-specific CAR T cell therapy include lymphopenia and hypogammaglobulinaemia, which can be effectively managed with intravenous immunoglobulin therapy, similar to the treatment that patients with primary B cell immunodeficiencies receive.	('patients', 'Species', '9606', (207, 215))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('153', '167'))	('lymphopenia', 'Phenotype', 'HP:0001888', (63, 74))	('immunodeficiencies', 'Disease', (236, 254))	('immunodeficiencies', 'Phenotype', 'HP:0002721', (236, 254))	('CAR', 'cellular_component', 'GO:0005826', ('36', '39'))	('CD19-specific', 'Var', (22, 35))	('lymphopenia and hypogammaglobulinaemia', 'Disease', 'MESH:D008231', (63, 101))	('immunodeficiencies', 'Disease', 'MESH:D007153', (236, 254))
84920	32433532	Moreover, a clinical study of low-affinity CD19-specific CAR T cells demonstrated reduced toxicity and enhanced efficacy.	('CD19-specific CAR T', 'Protein', (43, 62))	('toxicity', 'Disease', 'MESH:D064420', (90, 98))	('reduced', 'NegReg', (82, 89))	('toxicity', 'Disease', (90, 98))	('enhanced', 'PosReg', (103, 111))	('CAR', 'cellular_component', 'GO:0005826', ('57', '60'))	('low-affinity', 'Var', (30, 42))	('efficacy', 'CPA', (112, 120))
84940	32433532	However, although a higher mutational burden in the tumour has been shown to correlate with greater immunogenicity and survival after checkpoint blockade, only a small percentage of neoantigens spontaneously generate immune responses in patients with cancer.	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('immune responses', 'MPA', (217, 233))	('immunogenicity', 'MPA', (100, 114))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('tumour', 'Disease', (52, 58))	('cancer', 'Disease', (251, 257))	('greater', 'PosReg', (92, 99))	('mutational', 'Var', (27, 37))	('patients', 'Species', '9606', (237, 245))
84951	32433532	However, the current methods, consisting of validating mRNA expression of the mutation in tumour cells and using software/databases to predict peptide-MHC binding, have been surprisingly effective in clinical trials to date.	('mutation', 'Var', (78, 86))	('binding', 'Interaction', (155, 162))	('binding', 'molecular_function', 'GO:0005488', ('155', '162'))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour', 'Disease', (90, 96))	('MHC', 'Gene', (151, 154))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('MHC', 'Gene', '3107', (151, 154))
84956	32433532	Overall, the comprehensive identification of somatic mutations, and the evaluation of peptides derived from these mutations to elicit immune responses, has renewed interest in vaccination strategies for cancer treatment.	('mutations', 'Var', (114, 123))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
84959	32433532	The molecular diversity of genetic changes that transform cells in human cancers creates a plethora of diseases involving specific tissue types and cancer mechanisms.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', (73, 79))	('cancers', 'Disease', (73, 80))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('plethora', 'Phenotype', 'HP:0001050', (91, 99))	('genetic changes', 'Var', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('changes', 'Var', (35, 42))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
84964	32433532	Crosstalk between the CTLA4 and PD1 pathways, mediated by CD80 and PDL1 dimerization, provides additional insight into the mechanism behind the success of dual therapy.	('PDL1', 'Protein', (67, 71))	('CD80', 'Gene', (58, 62))	('CD80', 'Gene', '941', (58, 62))	('PD1 pathways', 'Pathway', (32, 44))	('dimerization', 'Var', (72, 84))
84977	32433532	In addition, TIM3 expression correlates with poor prognosis in non-small-cell lung cancer and follicular lymphoma, suggesting a role in cancer progression.	('lymphoma', 'Disease', 'MESH:D008223', (105, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('lymphoma', 'Phenotype', 'HP:0002665', (105, 113))	('non-small-cell lung cancer', 'Disease', (63, 89))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (63, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('TIM3', 'Gene', (13, 17))	('cancer', 'Disease', (136, 142))	('lymphoma', 'Disease', (105, 113))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('expression', 'Var', (18, 28))	('cancer', 'Disease', (83, 89))
84989	32433532	ICOS upregulation following treatment with currently approved anti-CTLA4 and anti-PD1 therapies may represent a biomarker of active antitumoural responses because it associates with favourable outcomes.	('anti-CTLA4', 'Var', (62, 72))	('anti-PD1', 'Gene', (77, 85))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Disease', (136, 142))	('upregulation', 'PosReg', (5, 17))	('ICOS', 'Gene', (0, 4))	('ICOS', 'Gene', '29851', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
84991	32433532	Data suggest that targeting TNFRSF4 amplifies anti-PD1 therapy because TNFRSF4 agonism can upregulate PDL1 expression.	('upregulate', 'PosReg', (91, 101))	('PDL1', 'Gene', (102, 106))	('TNFRSF4', 'Gene', '7293', (71, 78))	('expression', 'MPA', (107, 117))	('TNFRSF4', 'Gene', (28, 35))	('agonism', 'Var', (79, 86))	('TNFRSF4', 'Gene', '7293', (28, 35))	('TNFRSF4', 'Gene', (71, 78))
84992	32433532	In addition to synergism with checkpoint blockade, TNFRSF4 upregulation within CAR T cells by transfection represents a way to augment tumour cytotoxicity.	('CAR', 'cellular_component', 'GO:0005826', ('79', '82'))	('augment', 'PosReg', (127, 134))	('tumour cytotoxicity', 'Disease', 'MESH:D064420', (135, 154))	('tumour cytotoxicity', 'Disease', (135, 154))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('TNFRSF4', 'Gene', (51, 58))	('upregulation', 'PosReg', (59, 71))	('transfection', 'Var', (94, 106))	('TNFRSF4', 'Gene', '7293', (51, 58))
84994	32433532	Therefore, agonism of positive T cell co-stimulatory signals, in concert with the existing checkpoint inhibitors or CAR T cells, represents a novel therapeutic avenue to boost antitumoural immunity.	('boost', 'PosReg', (170, 175))	('CAR', 'cellular_component', 'GO:0005826', ('116', '119'))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('agonism', 'Var', (11, 18))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('tumour', 'Disease', (180, 186))
85002	32433532	CTLA4Ig Soluble recombinant human cytotoxic T lymphocyte antigen 4 (CTLA4) fused to the immunoglobulin Fc domain that competes with endogenous CD28 for its ligands.	('cytotoxic T lymphocyte antigen 4', 'Gene', (34, 66))	('human', 'Species', '9606', (28, 33))	('CTLA4', 'Gene', (68, 73))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('88', '102'))	('fused', 'Var', (75, 80))	('cytotoxic T lymphocyte antigen 4', 'Gene', '1493', (34, 66))	('Soluble', 'cellular_component', 'GO:0005625', ('8', '15'))	('lymphocyte antigen', 'molecular_function', 'GO:0005557', ('46', '64'))
85015	32132102	Our growing knowledge on oncological driver mutations has supported the development of targeted drugs that interfere with pathways underscoring cancer biology.	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('mutations', 'Var', (44, 53))	('interfere', 'NegReg', (107, 116))
85022	32132102	This review article will detail how precision oncology has taken many forms in urothelial cancer, ranging from molecularly matched treatments targeting driver mutations, to novel molecular biomarkers of treatment responsiveness, to fresh approaches targeting cancer-specific proteins.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (159, 168))	('urothelial cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('oncology', 'Phenotype', 'HP:0002664', (46, 54))	('urothelial cancer', 'Disease', 'MESH:D014523', (79, 96))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (259, 265))
85028	32132102	Of note, this landscape of mutations has stemmed from analyses performed on primary tumours, in non-metastatic settings.	('mutations', 'Var', (27, 36))	('tumours', 'Disease', 'MESH:D009369', (84, 91))	('tumours', 'Disease', (84, 91))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))
85032	32132102	FGFR mutations are highly oncogenic in animal models, and are detected in a wide range of human cancers including urothelial cancer.	('detected', 'Reg', (62, 70))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('urothelial cancer', 'Disease', 'MESH:D014523', (114, 131))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('FGFR', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (5, 14))	('human', 'Species', '9606', (90, 95))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('urothelial cancer', 'Disease', (114, 131))	('cancers', 'Disease', (96, 103))
85034	32132102	The robust results generated from this study provide an excellent overview of the spectrum of FGFR alterations detected in human cancers, with the most common abnormality being gene amplifications (66%), followed by gene mutations (26%) and gene rearrangements (8%).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('gene amplifications', 'Var', (177, 196))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('human', 'Species', '9606', (123, 128))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('alterations', 'Var', (99, 110))	('FGFR', 'molecular_function', 'GO:0005007', ('94', '98'))	('FGFR', 'Gene', (94, 98))
85039	32132102	Interestingly, three activating FGFR3 mutations (S249C, S248C and Y373C) were even observed to transform cells in vitro.	('FGFR3', 'Gene', (32, 37))	('Y373C', 'Var', (66, 71))	('cells in vitro', 'CPA', (105, 119))	('S248C', 'Mutation', 'p.S248C', (56, 61))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('activating', 'PosReg', (21, 31))	('transform', 'Reg', (95, 104))	('Y373C', 'Mutation', 'rs121913485', (66, 71))	('S248C', 'Var', (56, 61))	('S249C', 'Var', (49, 54))	('S249C', 'Mutation', 'rs121913483', (49, 54))	('FGFR3', 'Gene', '2261', (32, 37))
85045	32132102	Aberrant FGFR signalling in urothelial cancer has been the focus of intense investigation that has led to the development of an array of novel agents.	('Aberrant', 'Var', (0, 8))	('urothelial cancer', 'Disease', (28, 45))	('FGFR', 'molecular_function', 'GO:0005007', ('9', '13'))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('signalling', 'biological_process', 'GO:0023052', ('14', '24'))	('urothelial cancer', 'Disease', 'MESH:D014523', (28, 45))	('FGFR', 'Protein', (9, 13))
85053	32132102	The THOR study (NCT03390504), a phase III randomised, registration study of erdafitinib compared with vinflunine or docetaxel or pembrolizumab in patients with advanced urothelial cancer and selected FGFR gene aberrations, is currently open to recruitment.	('aberrations', 'Var', (210, 221))	('FGFR', 'molecular_function', 'GO:0005007', ('200', '204'))	('FGFR gene', 'Gene', (200, 209))	('urothelial cancer', 'Disease', 'MESH:D014523', (169, 186))	('erdafitinib', 'Chemical', 'MESH:C000604580', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('vinflunine', 'Chemical', 'MESH:C111217', (102, 112))	('pembrolizumab', 'Chemical', 'MESH:C582435', (129, 142))	('urothelial cancer', 'Disease', (169, 186))	('docetaxel', 'Chemical', 'MESH:D000077143', (116, 125))	('patients', 'Species', '9606', (146, 154))
85065	32132102	The high prevalence of FGFR aberrations in urothelial cancer has prompted investigation into coaberrant genes that could be additionally harnessed as therapeutic targets.	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('FGFR', 'Gene', (23, 27))	('urothelial cancer', 'Disease', (43, 60))	('aberrations', 'Var', (28, 39))	('urothelial cancer', 'Disease', 'MESH:D014523', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
85066	32132102	The signalling pathway defined by PI3K, AKT and mammalian target of rapamycin (mTOR) governs many fundamental hallmarks of cancer and promotes a microenvironment conducive to tumour growth.	('tumour growth', 'Disease', (175, 188))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('PI3K', 'Var', (34, 38))	('tumour growth', 'Disease', 'MESH:D006130', (175, 188))	('promotes', 'PosReg', (134, 142))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('signalling pathway', 'biological_process', 'GO:0007165', ('4', '22'))	('PI3K', 'molecular_function', 'GO:0016303', ('34', '38'))	('cancer', 'Disease', (123, 129))	('mammalian target of rapamycin', 'Gene', '2475', (48, 77))	('mammalian target of rapamycin', 'Gene', (48, 77))	('microenvironment', 'MPA', (145, 161))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))
85067	32132102	PIK3CA mutations are found frequently in colorectal (13%-28%), endometrial (24%-46%) and breast cancers (20%-32%).	('endometrial', 'Disease', (63, 74))	('breast cancers', 'Disease', 'MESH:D001943', (89, 103))	('breast cancers', 'Disease', (89, 103))	('breast cancers', 'Phenotype', 'HP:0003002', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('found', 'Reg', (21, 26))	('colorectal', 'Disease', (41, 51))	('mutations', 'Var', (7, 16))
85068	32132102	In urothelial cancer, PIK3CA mutations have been identified in 20%-27% of cases.	('PIK3CA', 'Gene', '5290', (22, 28))	('identified', 'Reg', (49, 59))	('mutations', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('urothelial cancer', 'Disease', (3, 20))	('urothelial cancer', 'Disease', 'MESH:D014523', (3, 20))	('PIK3CA', 'Gene', (22, 28))
85073	32132102	Three patients who were progression-free at 8 weeks did not harbour PI3K/AKT/mTOR activating mutations.	('PI3K', 'molecular_function', 'GO:0016303', ('68', '72'))	('patients', 'Species', '9606', (6, 14))	('mutations', 'Var', (93, 102))	('PI3K/AKT/mTOR', 'Var', (68, 81))
85078	32132102	Results from two patients with identified PIK3CA mutations were more encouraging, with one patient demonstrating a 16-month PR and the other displaying SD for 3.7 months.	('mutations', 'Var', (49, 58))	('PIK3CA', 'Gene', (42, 48))	('patient', 'Species', '9606', (17, 24))	('patients', 'Species', '9606', (17, 25))	('PIK3CA', 'Gene', '5290', (42, 48))	('patient', 'Species', '9606', (91, 98))	('SD', 'Chemical', '-', (152, 154))
85079	32132102	On the basis of this, an expansion cohort is recruiting patients with tumours enriched for activating PI3K/AKT/mTOR mutations (NCT01551030).	('patients', 'Species', '9606', (56, 64))	('PI3K', 'molecular_function', 'GO:0016303', ('102', '106'))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('mutations (NCT01551030', 'Var', (116, 138))	('NCT01551030', 'Var', (127, 138))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('PI3K/AKT/mTOR', 'Pathway', (102, 115))	('activating', 'PosReg', (91, 101))	('tumours', 'Disease', (70, 77))
85083	32132102	While mutations involving the ErbB family occur relatively frequently in urothelial cancer, successful treatment options in this space are still lacking.	('urothelial cancer', 'Disease', (73, 90))	('ErbB', 'Gene', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ErbB', 'Gene', '1956', (30, 34))	('mutations', 'Var', (6, 15))	('urothelial cancer', 'Disease', 'MESH:D014523', (73, 90))
85088	32132102	In preliminary results from a phase II trial of 23 patients involving afatinib, an oral tyrosine kinase inhibitor of the ErbB receptor family, encouraging activity was noted in those with HER2 and/or ERBB3 alterations, where five out of six patients achieved the primary endpoint of 3-month PFS, compared with none in the 15 patients without alterations (p<0.001).	('alterations', 'Var', (206, 217))	('ErbB', 'Gene', (121, 125))	('activity', 'MPA', (155, 163))	('patients', 'Species', '9606', (325, 333))	('PFS', 'MPA', (291, 294))	('HER2', 'Gene', (188, 192))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('97', '113'))	('afatinib', 'Chemical', 'MESH:D000077716', (70, 78))	('HER2', 'Gene', '2064', (188, 192))	('ERBB3', 'Gene', '2065', (200, 205))	('ERBB3', 'Gene', (200, 205))	('patients', 'Species', '9606', (51, 59))	('patients', 'Species', '9606', (241, 249))	('ErbB', 'Gene', '1956', (121, 125))
85089	32132102	Those with HER2/ERBB3 alterations demonstrated a median time of progression/discontinuation of 6.6 months, superior to 1.4 months in patients without alterations (p<0.001).	('patients', 'Species', '9606', (133, 141))	('alterations', 'Var', (22, 33))	('ERBB3', 'Gene', '2065', (16, 21))	('HER2', 'Gene', (11, 15))	('ERBB3', 'Gene', (16, 21))	('HER2', 'Gene', '2064', (11, 15))
85094	32132102	Although some success has been demonstrated with the use of HDAC inhibitors in the treatment of T-cell lymphoma, a recent phase II trial (NCT02236195) involving the use of mocetinostat, an oral HDAC inhibitor, in patients with advanced urothelial cancer harbouring inactivating alterations of acetyltransferase genes, unfortunately failed to show activity in the second-line setting post platinum-based chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('mocetinostat', 'Chemical', 'MESH:C523184', (172, 184))	('lymphoma', 'Phenotype', 'HP:0002665', (103, 111))	('urothelial cancer', 'Disease', 'MESH:D014523', (236, 253))	('HDAC', 'Gene', (60, 64))	('HDAC', 'Gene', (194, 198))	('HDAC', 'Gene', '9734', (60, 64))	('HDAC', 'Gene', '9734', (194, 198))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (96, 111))	('patients', 'Species', '9606', (213, 221))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (96, 111))	('platinum', 'Chemical', 'MESH:D010984', (388, 396))	('T-cell lymphoma', 'Disease', (96, 111))	('cell lymphoma', 'Phenotype', 'HP:0012191', (98, 111))	('inactivating alterations', 'Var', (265, 289))	('acetyltransferase genes', 'Gene', (293, 316))	('urothelial cancer', 'Disease', (236, 253))
85097	32132102	The identification of loss-of-function mutations in CHK1/2, RAD51, BRCA1/2, ATM, ATR, MDC1 and FANCF in urothelial tumour specimens provides good rationale for exploring the use of poly ADP ribose polymerase (PARP) inhibitors for advanced urothelial cancer.	('ATM', 'Gene', (76, 79))	('CHK1/2', 'Gene', (52, 58))	('FANCF', 'Gene', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('urothelial tumour', 'Disease', 'MESH:D014523', (104, 121))	('urothelial tumour', 'Disease', (104, 121))	('BRCA1/2', 'Gene', '672;675', (67, 74))	('ATR', 'Gene', '545', (81, 84))	('mutations', 'Var', (39, 48))	('PARP', 'Gene', '142', (209, 213))	('poly ADP ribose polymerase', 'Gene', (181, 207))	('MDC1', 'Gene', (86, 90))	('PARP', 'Gene', (209, 213))	('urothelial cancer', 'Disease', 'MESH:D014523', (239, 256))	('RAD', 'biological_process', 'GO:1990116', ('60', '63'))	('ATM', 'Gene', '472', (76, 79))	('loss-of-function', 'NegReg', (22, 38))	('FANCF', 'Gene', '2188', (95, 100))	('urothelial cancer', 'Disease', (239, 256))	('MDC1', 'Gene', '9656', (86, 90))	('ATR', 'Gene', (81, 84))	('BRCA1/2', 'Gene', (67, 74))	('poly ADP ribose polymerase', 'Gene', '142', (181, 207))	('CHK1/2', 'Gene', '1111;11200', (52, 58))	('RAD51', 'Gene', (60, 65))	('RAD51', 'Gene', '5888', (60, 65))
85098	32132102	Two phase II trials employing olaparib monotherapy in patients with metastatic urothelial cancer harbouring somatic DNA damage repair response (DDR) alterations are currently open to recruitment (NCT03448718, NCT03375307), while the ATLAS trial (NCT03397394) is aimed at evaluating the efficacy and safety of rucaparib monotherapy in unselected patients with metastatic urothelial cancer treated with 1-2 prior lines of systemic therapy.	('alterations', 'Var', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('olaparib', 'Chemical', 'MESH:C531550', (30, 38))	('urothelial cancer', 'Disease', (370, 387))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('NCT03448718', 'Var', (196, 207))	('urothelial cancer', 'Disease', (79, 96))	('patients', 'Species', '9606', (54, 62))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('urothelial cancer', 'Disease', 'MESH:D014523', (370, 387))	('rucaparib', 'Chemical', 'MESH:C531549', (309, 318))	('urothelial cancer', 'Disease', 'MESH:D014523', (79, 96))	('patients', 'Species', '9606', (345, 353))
85099	32132102	Lesions in DNA DDR genes have also been recognised to potentially predict response to platinum-based chemotherapy.	('predict', 'Reg', (66, 73))	('DNA DDR genes', 'Gene', (11, 24))	('platinum', 'Chemical', 'MESH:D010984', (86, 94))	('response', 'CPA', (74, 82))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('response to platinum', 'biological_process', 'GO:0070541', ('74', '94'))	('Lesions', 'Var', (0, 7))
85101	32132102	In this trial, those with FGFR1/2/3 mutations or fusion are randomised to receive FGFR inhibitor AZD4547 monotherapy or AZD4547 in combination with durvalumab, while the patient cohort identified to have ATM, BRCA1/2 or other homologous recombination repair gene defects are assigned PARP inhibitor olaparib and durvalumab.	('PARP', 'Gene', (284, 288))	('FGFR1/2/3', 'Gene', (26, 35))	('AZD4547', 'Chemical', 'MESH:C572463', (97, 104))	('BRCA1/2', 'Gene', '672;675', (209, 216))	('AZD4547', 'Var', (120, 127))	('durvalumab', 'Chemical', 'MESH:C000613593', (148, 158))	('AZD4547', 'Chemical', 'MESH:C572463', (120, 127))	('ATM', 'Gene', '472', (204, 207))	('homologous recombination', 'biological_process', 'GO:0035825', ('226', '250'))	('olaparib', 'Chemical', 'MESH:C531550', (299, 307))	('durvalumab', 'Chemical', 'MESH:C000613593', (312, 322))	('FGFR', 'molecular_function', 'GO:0005007', ('82', '86'))	('FGFR1/2/3', 'Gene', '2260;2263;2261', (26, 35))	('ATM', 'Gene', (204, 207))	('AZD4547', 'Var', (97, 104))	('mutations', 'Var', (36, 45))	('PARP', 'Gene', '142', (284, 288))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('BRCA1/2', 'Gene', (209, 216))	('FGFR inhibitor', 'Gene', (82, 96))	('patient', 'Species', '9606', (170, 177))
85104	32132102	In addition, two other trials are examining the use of PARP inhibitors combined with durvalumab in unselected patient cohorts, in the advanced (NCT03459846) and neoadjuvant setting (NCT03534492), respectively.	('PARP', 'Gene', '142', (55, 59))	('NCT03534492', 'Var', (182, 193))	('NCT03459846', 'Var', (144, 155))	('durvalumab', 'Chemical', 'MESH:C000613593', (85, 95))	('PARP', 'Gene', (55, 59))	('patient', 'Species', '9606', (110, 117))
85107	32132102	While molecularly matched treatments aimed at targeting driver mutations continue to be investigated as described above, a large component of precision oncology involves using predictive biomarkers to ensure the right treatment is given to the right patient at the right time; in this section, we review some of the biomarker work that will help us achieve this in urothelial cancer.	('mutations', 'Var', (63, 72))	('urothelial cancer', 'Disease', 'MESH:D014523', (365, 382))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('urothelial cancer', 'Disease', (365, 382))	('patient', 'Species', '9606', (250, 257))	('oncology', 'Phenotype', 'HP:0002664', (152, 160))
85118	32132102	This study also showed that luminal-papillary urothelial cancers are associated with potentially actionable mutations in genes such as FGFR, PIK3 and ERBB2, and also appear to have a better prognosis.	('ERBB2', 'Gene', '2064', (150, 155))	('mutations', 'Var', (108, 117))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('ERBB2', 'Gene', (150, 155))	('PIK3', 'Gene', (141, 145))	('luminal-papillary urothelial cancers', 'Disease', (28, 64))	('luminal-papillary urothelial cancers', 'Disease', 'MESH:D000077273', (28, 64))	('PIK3', 'Gene', '5294', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('FGFR', 'Gene', (135, 139))	('FGFR', 'molecular_function', 'GO:0005007', ('135', '139'))
85122	32132102	Two studies have demonstrated selected mutations in the DNA repair pathways that also confer platinum sensitivity.	('platinum', 'Chemical', 'MESH:D010984', (93, 101))	('DNA repair', 'biological_process', 'GO:0006281', ('56', '66'))	('confer', 'Reg', (86, 92))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('platinum sensitivity', 'CPA', (93, 113))	('mutations', 'Var', (39, 48))	('DNA repair pathways', 'Pathway', (56, 75))
85124	32132102	This study demonstrated that the presence of mutations in ERCC2 (important in the nucleotide excision repair pathway) was associated with cisplatin sensitivity, confirmed in an independent clinical validation study (40% of chemotherapy responders vs 7% of non-responders had ERCC2 alterations, OR 8.3).	('associated', 'Reg', (122, 132))	('mutations', 'Var', (45, 54))	('ERCC2', 'Gene', (58, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('ERCC2', 'Gene', (275, 280))	('cisplatin sensitivity', 'MPA', (138, 159))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('82', '108'))	('ERCC2', 'Gene', '2068', (58, 63))	('alterations', 'Reg', (281, 292))	('ERCC2', 'Gene', '2068', (275, 280))
85125	32132102	In a series of in vitro experiments, they were able to provide a molecular explanation for this and demonstrated that ERCC2 mutated tumours failed to rescue ultraviolet-induced DNA damage, suggesting that DNA damage caused by cisplatin in ERCC2 mutated urothelial cancers were more likely to result in apoptosis.	('tumours', 'Disease', 'MESH:D009369', (132, 139))	('mutated', 'Var', (245, 252))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('ERCC2', 'Gene', (239, 244))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('urothelial cancers', 'Disease', 'MESH:D014523', (253, 271))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('ERCC2', 'Gene', '2068', (239, 244))	('result', 'Reg', (292, 298))	('DNA', 'MPA', (205, 208))	('ERCC2', 'Gene', (118, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (226, 235))	('DNA', 'cellular_component', 'GO:0005574', ('205', '208'))	('apoptosis', 'biological_process', 'GO:0097194', ('302', '311'))	('apoptosis', 'biological_process', 'GO:0006915', ('302', '311'))	('tumours', 'Disease', (132, 139))	('ERCC2', 'Gene', '2068', (118, 123))	('urothelial cancers', 'Disease', (253, 271))	('DNA', 'cellular_component', 'GO:0005574', ('177', '180'))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))	('apoptosis', 'CPA', (302, 311))
85126	32132102	In another important body of work led by Plimack et al, alterations in a further trio of DNA repair genes, ATM, RB1 and FANCC, also emerged as predictors for pathological response, PFS and OS.	('pathological response', 'CPA', (158, 179))	('RB1', 'Gene', '5925', (112, 115))	('FANCC', 'Gene', '2176', (120, 125))	('alterations', 'Var', (56, 67))	('ATM', 'Gene', '472', (107, 110))	('FANCC', 'Gene', (120, 125))	('DNA repair', 'biological_process', 'GO:0006281', ('89', '99'))	('RB1', 'Gene', (112, 115))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('ATM', 'Gene', (107, 110))	('predictors', 'Reg', (143, 153))
85128	32132102	In the validation cohort, the frequencies of genetic alterations in ATM, RB1 and FANCC were 64% in chemotherapy responders and 15% in non-responders.	('FANCC', 'Gene', '2176', (81, 86))	('chemotherapy', 'Disease', (99, 111))	('FANCC', 'Gene', (81, 86))	('RB1', 'Gene', (73, 76))	('ATM', 'Gene', (68, 71))	('RB1', 'Gene', '5925', (73, 76))	('ATM', 'Gene', '472', (68, 71))	('genetic alterations', 'Var', (45, 64))
85129	32132102	There were statistically significant associations between ATM/RB1/FANCC alterations with PFS (p=0.0085) and OS (p=0.007) in the discovery group, and a similar trend for benefit (p=0.1018 and p=0.0545 for PFS and OS, accordingly) in the validation group.	('FANCC', 'Gene', '2176', (66, 71))	('alterations', 'Var', (72, 83))	('RB1', 'Gene', '5925', (62, 65))	('benefit', 'PosReg', (169, 176))	('ATM', 'Gene', (58, 61))	('PFS', 'Disease', (89, 92))	('FANCC', 'Gene', (66, 71))	('RB1', 'Gene', (62, 65))	('ATM', 'Gene', '472', (58, 61))
85130	32132102	While patients with ERCC2/ATM/RB1/FANCC gene alterations are likely to fall within the basal molecular subtype, it is inherently much easier to test for these individual gene mutations in individual patients than to conduct gene expression studies to determine which subtype they belong to.	('ERCC2', 'Gene', (20, 25))	('alterations', 'Var', (45, 56))	('fall', 'Phenotype', 'HP:0002527', (71, 75))	('ATM', 'Gene', (26, 29))	('FANCC', 'Gene', '2176', (34, 39))	('gene expression', 'biological_process', 'GO:0010467', ('224', '239'))	('RB1', 'Gene', (30, 33))	('ERCC2', 'Gene', '2068', (20, 25))	('patients', 'Species', '9606', (6, 14))	('FANCC', 'Gene', (34, 39))	('patients', 'Species', '9606', (199, 207))	('ATM', 'Gene', '472', (26, 29))	('RB1', 'Gene', '5925', (30, 33))
85132	32132102	This concept is being explored in three ongoing studies, two trials with neoadjuvant cisplatin-based chemotherapy alone, (the Risk Enabled Therapy After Initiating Neoadjuvant Chemotherapy for Bladder Cancer (RETAIN) trial (NCT02710734) and NCT03609216) and one trial with neoadjuvant cisplatin-based chemotherapy plus the PD-1 inhibitor, nivolumab (NCT03558087).	('Bladder Cancer', 'Disease', 'MESH:D001749', (193, 207))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (193, 207))	('Cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (285, 294))	('nivolumab', 'Chemical', 'MESH:D000077594', (339, 348))	('PD-1', 'Gene', (323, 327))	('PD-1', 'Gene', '5133', (323, 327))	('Bladder Cancer', 'Disease', (193, 207))	('NCT02710734', 'Var', (224, 235))
85134	32132102	In the other chemotherapy-based trial (NCT03609216), patients with alterations in the DDR pathway with good clinical response (<cT1) to neoadjuvant dose-dense gemcitabine and cisplatin are offered the choice of bladder sparing surgery, while patients with>=cT1 disease post neoadjuvant chemotherapy who do not harbour DDR mutations are offered radical cystectomy or chemoradiation.	('cT1', 'Gene', (257, 260))	('cT1', 'Gene', (128, 131))	('patients', 'Species', '9606', (53, 61))	('alterations', 'Var', (67, 78))	('gemcitabine', 'Chemical', 'MESH:C056507', (159, 170))	('DDR', 'Gene', (86, 89))	('cT1', 'Gene', '1489', (257, 260))	('cT1', 'Gene', '1489', (128, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('bladder sparing', 'Disease', (211, 226))	('patients', 'Species', '9606', (242, 250))
85141	32132102	While reduced amounts of other DNA repair proteins such as ERCC1 have been observed to be linked with improved outcomes through impaired nucleotide excision repair mechanisms in the context of platinum cytotoxic therapy, low concentrations of MRE11 protein have somewhat unexpectedly been found to correlate with worse outcomes following radiotherapy-based treatment.	('MRE11', 'Gene', (243, 248))	('ERCC1', 'Gene', (59, 64))	('low', 'Var', (221, 224))	('protein', 'cellular_component', 'GO:0003675', ('249', '256'))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('137', '163'))	('platinum', 'Chemical', 'MESH:D010984', (193, 201))	('ERCC1', 'Gene', '2067', (59, 64))	('impaired', 'NegReg', (128, 136))	('nucleotide excision repair mechanisms', 'MPA', (137, 174))	('protein', 'Protein', (249, 256))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('MRE11', 'Gene', '4361', (243, 248))	('improved', 'PosReg', (102, 110))	('DNA repair', 'biological_process', 'GO:0006281', ('31', '41'))
85143	32132102	Additionally, there were significantly better survival outcomes among patients with high MRE11 expression who had undergone radiotherapy compared with those with high MRE11 expression who had cystectomy (3-year CSS 69.9% vs 53.8%, p=0.021).	('patients', 'Species', '9606', (70, 78))	('CSS', 'Chemical', '-', (211, 214))	('expression', 'Var', (95, 105))	('MRE11', 'Gene', '4361', (89, 94))	('MRE11', 'Gene', '4361', (167, 172))	('MRE11', 'Gene', (167, 172))	('survival', 'CPA', (46, 54))	('better', 'PosReg', (39, 45))	('MRE11', 'Gene', (89, 94))
85145	32132102	Patients in the radiotherapy group were noted to have significant associations between high MRE11 expression and long disease-specific survival (p=0.005); however, once again, there was no predictive value of MRE11 seen in those who underwent cystectomy.	('associations', 'Interaction', (66, 78))	('expression', 'MPA', (98, 108))	('MRE11', 'Gene', '4361', (92, 97))	('Patients', 'Species', '9606', (0, 8))	('high', 'Var', (87, 91))	('MRE11', 'Gene', (92, 97))	('MRE11', 'Gene', '4361', (209, 214))	('MRE11', 'Gene', (209, 214))
85153	32132102	In this study, mutational load was found to be an independent predictive marker of response, separate from associations between molecular subtype and PD-L1 immune score.	('mutational load', 'Var', (15, 30))	('PD-L1', 'Gene', '29126', (150, 155))	('response', 'Disease', (83, 91))	('PD-L1', 'Gene', (150, 155))
85157	32132102	Moreover, a predictive model incorporating TCGA gene expression subtypes, mutational load and PD-L1 appeared to perform better (on a biomarker integration tree, strength of association of IC score alone was p=0.0159, gene expression subtype alone was p=0.0102, while the combination of three biomarkers was p=2.14x10-4), highlighting the complex genomic, molecular and immunological factors that govern efficacy for checkpoint inhibitors.	('gene expression', 'biological_process', 'GO:0010467', ('48', '63'))	('PD-L1', 'Gene', (94, 99))	('gene expression', 'biological_process', 'GO:0010467', ('217', '232'))	('PD-L1', 'Gene', '29126', (94, 99))	('TCGA', 'Gene', (43, 47))	('mutational load', 'Var', (74, 89))
85176	32132102	Overexpression of Trop-2 in many cancers, including breast cancer has been linked with a poor prognosis.	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancers', 'Disease', (33, 40))	('Trop-2', 'Gene', '4070', (18, 24))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('Overexpression', 'Var', (0, 14))	('Trop-2', 'Gene', (18, 24))
85187	32132102	Widespread uptake of driver-mutation analysis, followed by the application of mechanistically designed drugs, such as erlotinib and crizotinib for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, respectively, has revolutionised outcomes for many.	('ALK', 'Gene', (229, 232))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (201, 220))	('EGFR', 'molecular_function', 'GO:0005006', ('181', '185'))	('anaplastic lymphoma kinase', 'Gene', (201, 227))	('epidermal growth factor receptor', 'Gene', (147, 179))	('EGFR', 'Gene', (181, 185))	('crizotinib', 'Chemical', 'MESH:D000077547', (132, 142))	('erlotinib', 'Chemical', 'MESH:D000069347', (118, 127))	('uptake', 'biological_process', 'GO:0098739', ('11', '17'))	('lymphoma', 'Phenotype', 'HP:0002665', (212, 220))	('ALK', 'Gene', '238', (229, 232))	('mutations', 'Var', (187, 196))	('epidermal growth factor receptor', 'Gene', '1956', (147, 179))	('anaplastic lymphoma kinase', 'Gene', '238', (201, 227))	('EGFR', 'Gene', '1956', (181, 185))	('uptake', 'biological_process', 'GO:0098657', ('11', '17'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('147', '170'))
85191	31914088	Genetic variant of MAML2 in the NOTCH signaling pathway and the risk of bladder cancer Supplemental Digital Content is available in the text The NOTCH signaling pathway plays a crucial role in cell phenotype and transformation.	('NOTCH', 'Gene', (145, 150))	('NOTCH', 'Gene', '4851;4853', (145, 150))	('NOTCH', 'Gene', (32, 37))	('NOTCH', 'Gene', '4851;4853', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('NOTCH signaling pathway', 'biological_process', 'GO:0007219', ('145', '168'))	('NOTCH signaling pathway', 'biological_process', 'GO:0007219', ('32', '55'))	('Genetic variant', 'Var', (0, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('MAML2', 'Gene', '84441', (19, 24))	('MAML2', 'Gene', (19, 24))	('bladder cancer', 'Disease', 'MESH:D001749', (72, 86))	('bladder cancer', 'Disease', (72, 86))
85192	31914088	Single nucleotide polymorphisms (SNPs) may regulate gene expression to trigger bladder cancer susceptibility.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('regulate', 'Reg', (43, 51))	('bladder cancer', 'Phenotype', 'HP:0009725', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('trigger', 'PosReg', (71, 78))	('bladder cancer', 'Disease', 'MESH:D001749', (79, 93))	('bladder cancer', 'Disease', (79, 93))	('gene expression', 'MPA', (52, 67))	('gene expression', 'biological_process', 'GO:0010467', ('52', '67'))
85193	31914088	Here, we aimed to explore the relationships between genetic variants in the NOTCH pathway and bladder cancer progression.	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('NOTCH', 'Gene', (76, 81))	('bladder cancer', 'Disease', (94, 108))	('NOTCH', 'Gene', '4851;4853', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('genetic variants', 'Var', (52, 68))
85194	31914088	We screened SNPs located in NOTCH pathway genes using the 1000 Genomes Project dataset (CHB).	('SNPs located', 'Var', (12, 24))	('NOTCH', 'Gene', '4851;4853', (28, 33))	('NOTCH', 'Gene', (28, 33))
85197	31914088	The rs7944701 in the intron of mastermind-like 2 (MAML2) had the strongest signal and was related to bladder cancer risk (OR = 1.329, 95% CI = 1.115-1.583, P = .001).	('MAML2', 'Gene', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('mastermind-like 2', 'Gene', '84441', (31, 48))	('bladder cancer', 'Disease', (101, 115))	('mastermind-like 2', 'Gene', (31, 48))	('rs7944701', 'Var', (4, 13))	('related', 'Reg', (90, 97))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))	('rs7944701', 'Mutation', 'rs7944701', (4, 13))	('MAML2', 'Gene', '84441', (50, 55))
85198	31914088	eQTL analysis showed that rs7944701 with a C allele was negatively associated with mastermind-like 2 (MAML2) expression (TT versus TC/CC).	('mastermind-like 2', 'Gene', '84441', (83, 100))	('expression', 'MPA', (109, 119))	('negatively', 'NegReg', (56, 66))	('MAML2', 'Gene', '84441', (102, 107))	('mastermind-like 2', 'Gene', (83, 100))	('rs7944701', 'Var', (26, 35))	('rs7944701', 'Mutation', 'rs7944701', (26, 35))	('MAML2', 'Gene', (102, 107))
85200	31914088	Additionally, bladder cancer patients with high MAML2 expression had a significantly poorer prognosis (HR = 1.53, 95% CI = 1.29-1.82, P = .010).	('poorer', 'NegReg', (85, 91))	('patients', 'Species', '9606', (29, 37))	('MAML2', 'Gene', '84441', (48, 53))	('MAML2', 'Gene', (48, 53))	('high', 'Var', (43, 47))	('bladder cancer', 'Phenotype', 'HP:0009725', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('bladder cancer', 'Disease', 'MESH:D001749', (14, 28))	('bladder cancer', 'Disease', (14, 28))
85201	31914088	The rs7944701 in MAML2 was strongly associated with bladder cancer susceptibility in a Chinese population.	('MAML2', 'Gene', (17, 22))	('MAML2', 'Gene', '84441', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('rs7944701', 'Var', (4, 13))	('associated', 'Reg', (36, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('bladder cancer', 'Disease', (52, 66))	('rs7944701', 'Mutation', 'rs7944701', (4, 13))
85207	31914088	As a previous study reported, risk factors for bladder cancer are complex and include acquired carcinogen exposure (such as tobacco smoking and occupational factors) and genetic variants.	('bladder cancer', 'Disease', 'MESH:D001749', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('bladder cancer', 'Disease', (47, 61))	('tobacco', 'Species', '4097', (124, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (47, 61))	('genetic variants', 'Var', (170, 186))
85213	31914088	The NOTCH pathway itself seems to have a tumor suppressive function and inactivation promotes bladder cancer progression.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('NOTCH', 'Gene', '4851;4853', (4, 9))	('bladder cancer', 'Disease', (94, 108))	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', (41, 46))	('promotes', 'PosReg', (85, 93))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('inactivation', 'Var', (72, 84))	('NOTCH', 'Gene', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
85214	31914088	Disorder of the NOTCH pathway promotes cancer stem cell phenotype and epithelial-mesenchymal transition, thus increasing chemoresistance.	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('70', '103'))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('promotes', 'PosReg', (30, 38))	('NOTCH', 'Gene', (16, 21))	('NOTCH', 'Gene', '4851;4853', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('epithelial-mesenchymal transition', 'CPA', (70, 103))	('Disorder', 'Var', (0, 8))	('chemoresistance', 'CPA', (121, 136))	('increasing', 'PosReg', (110, 120))
85218	31914088	Multiple studies demonstrate that many functional SNPs are related to the risks of bladder cancer and regulate genetic functions in pathways.	('SNPs', 'Var', (50, 54))	('regulate', 'Reg', (102, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('genetic functions', 'MPA', (111, 128))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('bladder cancer', 'Disease', (83, 97))
85220	31914088	The aim of this study was to explore the underlying function and relationship of SNPs located in the NOTCH signaling pathway in bladder cancer.	('NOTCH', 'Gene', '4851;4853', (101, 106))	('bladder cancer', 'Disease', 'MESH:D001749', (128, 142))	('NOTCH', 'Gene', (101, 106))	('bladder cancer', 'Disease', (128, 142))	('SNPs', 'Var', (81, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('NOTCH signaling pathway', 'biological_process', 'GO:0007219', ('101', '124'))
85235	31914088	Gene Expression Omnibus (GEO) was used to download extra datasets and to verify the target gene expression in bladder cancer, and we chose GSE42089, GSE38265 and GSE37815, which had particular clinical and phenotype information in this phase.	('bladder cancer', 'Disease', 'MESH:D001749', (110, 124))	('bladder cancer', 'Disease', (110, 124))	('GSE42089', 'Var', (139, 147))	('GSE38265', 'Var', (149, 157))	('Gene Expression', 'biological_process', 'GO:0010467', ('0', '15'))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('gene expression', 'biological_process', 'GO:0010467', ('91', '106'))	('bladder cancer', 'Phenotype', 'HP:0009725', (110, 124))	('GSE37815', 'Var', (162, 170))
85238	31914088	After a logistic regression analysis adjusted for age, sex and smoking status, only rs7944701 and rs3760961 had P values below .05 (Table 2).	('rs3760961', 'Mutation', 'rs3760961', (98, 107))	('rs3760961', 'Var', (98, 107))	('rs7944701', 'Mutation', 'rs7944701', (84, 93))	('rs7944701', 'Var', (84, 93))
85239	31914088	In the additional study, we chose the rs7944701 T > C SNP located in MAML2 with the lowest P value (OR = 1.329, 95% CI = 1.115-1.583, P = .001).	('MAML2', 'Gene', '84441', (69, 74))	('MAML2', 'Gene', (69, 74))	('rs7944701 T > C', 'Var', (38, 53))	('rs7944701', 'Mutation', 'rs7944701', (38, 47))
85240	31914088	To explore the association between rs7944701 and MAML2 further, we analyzed the rs7944701 allelic discrimination and MAML2 expression in 37 bladder-adjacent normal tissues.	('rs7944701', 'Var', (80, 89))	('rs7944701', 'Mutation', 'rs7944701', (35, 44))	('MAML2', 'Gene', (117, 122))	('rs7944701', 'Mutation', 'rs7944701', (80, 89))	('MAML2', 'Gene', '84441', (117, 122))	('MAML2', 'Gene', '84441', (49, 54))	('MAML2', 'Gene', (49, 54))
85241	31914088	When rs7944701 carried the C allele, MAML2was significantly differentially expressed (P = .034) (Fig.	('MAML2', 'Gene', '84441', (37, 42))	('rs7944701', 'Var', (5, 14))	('rs7944701', 'Mutation', 'rs7944701', (5, 14))	('MAML2', 'Gene', (37, 42))
85242	31914088	Therefore, rs7944701 is an eQTL for MAML2, and allelic changes would influence MAML2 expression even though it is an intronic variant.	('MAML2', 'Gene', (36, 41))	('expression', 'MPA', (85, 95))	('rs7944701', 'Var', (11, 20))	('rs7944701', 'Mutation', 'rs7944701', (11, 20))	('MAML2', 'Gene', (79, 84))	('MAML2', 'Gene', '84441', (79, 84))	('influence', 'Reg', (69, 78))	('MAML2', 'Gene', '84441', (36, 41))
85249	31914088	As shown in Figure 2C, MAML2 expression was higher in non-tumor tissues than in tumor tissues in GSE37815, GSE38265, and GSE42089 (P = .0127, P = 7.8 x 10-3and P = 1.7 x 10-3, respectively).	('GSE42089', 'Var', (121, 129))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('higher', 'PosReg', (44, 50))	('GSE38265', 'Var', (107, 115))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('GSE37815', 'Var', (97, 105))	('MAML2', 'Gene', (23, 28))	('expression', 'MPA', (29, 39))	('MAML2', 'Gene', '84441', (23, 28))
85250	31914088	Subsequently, after dividing the BLCA cohort into two groups, high and low MAML2 expression, according to the median expression.	('low', 'NegReg', (71, 74))	('BLCA', 'Disease', (33, 37))	('MAML2', 'Gene', '84441', (75, 80))	('MAML2', 'Gene', (75, 80))	('BLCA', 'Disease', 'MESH:D001749', (33, 37))	('expression', 'MPA', (81, 91))	('high', 'Var', (62, 66))
85251	31914088	The high MAML2 expression was correlated with lower overall survival (hazard ratio (HR) = 1.53, 95% CI = 1.29-1.82, P = .010; Fig.	('overall survival', 'MPA', (52, 68))	('lower', 'NegReg', (46, 51))	('expression', 'MPA', (15, 25))	('high', 'Var', (4, 8))	('MAML2', 'Gene', (9, 14))	('MAML2', 'Gene', '84441', (9, 14))
85254	31914088	They unraveled that mutations in FGFR3 and RAS enriched in the NOTCH signaling pathway were associated with bladder cancer risk.	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('bladder cancer', 'Disease', (108, 122))	('NOTCH signaling pathway', 'biological_process', 'GO:0007219', ('63', '86'))	('FGFR3', 'Gene', (33, 38))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('FGFR3', 'Gene', '2261', (33, 38))	('NOTCH', 'Gene', '4851;4853', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('NOTCH', 'Gene', (63, 68))	('associated', 'Reg', (92, 102))	('mutations', 'Var', (20, 29))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))
85255	31914088	Notably, mutations in the pathway could promote tumorigenesis by phosphorylating ERK1/2.	('promote', 'PosReg', (40, 47))	('tumor', 'Disease', (48, 53))	('phosphorylating', 'MPA', (65, 80))	('mutations', 'Var', (9, 18))	('ERK1/2', 'Gene', '5595;5594', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('ERK1/2', 'Gene', (81, 87))	('ERK1', 'molecular_function', 'GO:0004707', ('81', '85'))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
85260	31914088	Thus, inhibition of Notch2 is a rational novel treatment strategy for invasive bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (79, 93))	('Notch2', 'Gene', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('inhibition', 'Var', (6, 16))	('invasive bladder', 'Phenotype', 'HP:0100645', (70, 86))	('invasive bladder cancer', 'Disease', (70, 93))	('Notch2', 'Gene', '4853', (20, 26))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (70, 93))
85265	31914088	In the following genotyping and statistical analysis, we found that 2 genetic variants, rs7944701 and rs3760961, had remarkable significance in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (144, 158))	('rs7944701', 'Var', (88, 97))	('significance', 'Reg', (128, 140))	('rs3760961', 'Var', (102, 111))	('rs7944701', 'Mutation', 'rs7944701', (88, 97))	('rs3760961', 'Mutation', 'rs3760961', (102, 111))	('bladder cancer', 'Disease', 'MESH:D001749', (144, 158))	('bladder cancer', 'Disease', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
85268	31914088	The SNP rs7944701 is located in MAML2, which is a member of the mastermind-like family of nuclear protein coding genes, defined as transcriptional coactivators of NOTCH receptors.	('NOTCH', 'Gene', '4851;4853', (163, 168))	('NOTCH', 'Gene', (163, 168))	('rs7944701', 'Var', (8, 17))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('rs7944701', 'Mutation', 'rs7944701', (8, 17))	('MAML2', 'Gene', (32, 37))	('MAML2', 'Gene', '84441', (32, 37))
85282	31914088	Additionally, we found that the strongest signal was represented by an intronic SNP called rs7944701, which was related to the susceptibility of bladder cancer in the Chinese population.	('susceptibility', 'Reg', (127, 141))	('related', 'Reg', (112, 119))	('rs7944701', 'Var', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('rs7944701', 'Mutation', 'rs7944701', (91, 100))	('bladder cancer', 'Disease', 'MESH:D001749', (145, 159))	('bladder cancer', 'Disease', (145, 159))
85283	31914088	Several studies have discovered many SNPs located in noncoding regions that are associated with cancer risks and progression.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('SNPs located', 'Var', (37, 49))	('associated', 'Reg', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
85284	31914088	Jiang et al demonstrated that MYC enhancer with rs6983267-G allele could be activated and enhanced colorectal cancer cell proliferation.	('colorectal cancer', 'Disease', (99, 116))	('MYC enhancer', 'Disease', 'MESH:C564835', (30, 42))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('MYC enhancer', 'Disease', (30, 42))	('rs6983267', 'Mutation', 'rs6983267', (48, 57))	('enhanced', 'PosReg', (90, 98))	('rs6983267-G', 'Var', (48, 59))	('cell proliferation', 'biological_process', 'GO:0008283', ('117', '135'))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))
85285	31914088	Recent case reported by Tian et al also revealed that the intronic SNP, rs7959129, could facilitate a promoter-enhancer interaction and synergistically increase colorectal cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('increase colorectal cancer', 'Disease', (152, 178))	('rs7959129', 'Mutation', 'rs7959129', (72, 81))	('increase colorectal cancer', 'Disease', 'MESH:D015179', (152, 178))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('promoter-enhancer interaction', 'MPA', (102, 131))	('rs7959129', 'Var', (72, 81))	('facilitate', 'PosReg', (89, 99))
85286	31914088	Pattison et al showed that the intronic SNP rs8102137 was a strong genetic variant correlating with bladder cancer risk.	('bladder cancer', 'Disease', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (100, 114))	('rs8102137', 'Var', (44, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (100, 114))	('rs8102137', 'Mutation', 'rs8102137', (44, 53))
85287	31914088	In their further research, they found that another intronic SNP, rs200996365, was in high LD with rs8102137 and was located within the KLF5 region, which is a transcriptional activator of CCNE1.	('rs200996365', 'Var', (65, 76))	('rs200996365', 'Mutation', 'rs200996365', (65, 76))	('CCNE1', 'Gene', '898', (188, 193))	('CCNE1', 'Gene', (188, 193))	('rs8102137', 'Var', (98, 107))	('KLF5', 'Gene', (135, 139))	('rs8102137', 'Mutation', 'rs8102137', (98, 107))	('KLF5', 'Gene', '688', (135, 139))
85288	31914088	These findings indicated that the high-risk intronic variant indirectly enhanced cell proliferation and the incidence of bladder cancer.	('cell proliferation', 'CPA', (81, 99))	('bladder cancer', 'Disease', (121, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('intronic variant', 'Var', (44, 60))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('bladder cancer', 'Phenotype', 'HP:0009725', (121, 135))	('enhanced', 'PosReg', (72, 80))	('bladder cancer', 'Disease', 'MESH:D001749', (121, 135))
85289	31914088	Thus, we speculated that the intronic rs7944701 would affect its host gene MAML2 expression or function and would sequentially influence the regulation of the NOTCH pathway involved in bladder cancer.	('NOTCH', 'Gene', (159, 164))	('NOTCH', 'Gene', '4851;4853', (159, 164))	('regulation', 'MPA', (141, 151))	('regulation', 'biological_process', 'GO:0065007', ('141', '151'))	('bladder cancer', 'Phenotype', 'HP:0009725', (185, 199))	('function', 'MPA', (95, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (185, 199))	('bladder cancer', 'Disease', (185, 199))	('affect', 'Reg', (54, 60))	('influence', 'Reg', (127, 136))	('rs7944701', 'Mutation', 'rs7944701', (38, 47))	('rs7944701', 'Var', (38, 47))	('MAML2', 'Gene', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('expression', 'MPA', (81, 91))	('MAML2', 'Gene', '84441', (75, 80))
85292	31914088	The results illuminated that the rs7944701 C allele was negatively associated with MAML2 expression.	('expression', 'MPA', (89, 99))	('negatively', 'NegReg', (56, 66))	('MAML2', 'Gene', '84441', (83, 88))	('MAML2', 'Gene', (83, 88))	('rs7944701', 'Mutation', 'rs7944701', (33, 42))	('rs7944701 C', 'Var', (33, 44))
85294	31914088	For the first time, we revealed that rs7944701 was an eQTL for MAML2 and enhanced the susceptibility to bladder cancer.	('bladder cancer', 'Disease', (104, 118))	('MAML2', 'Gene', (63, 68))	('susceptibility', 'MPA', (86, 100))	('MAML2', 'Gene', '84441', (63, 68))	('rs7944701', 'Var', (37, 46))	('enhanced', 'PosReg', (73, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('rs7944701', 'Mutation', 'rs7944701', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (104, 118))
85295	31914088	We also provided evidence that the TC/CC variant decreased the expression of MAML2.	('expression', 'MPA', (63, 73))	('decreased', 'NegReg', (49, 58))	('TC/CC', 'Gene', (35, 40))	('variant', 'Var', (41, 48))	('MAML2', 'Gene', '84441', (77, 82))	('MAML2', 'Gene', (77, 82))
85298	31914088	In our research, in addition to rs7944701, there was another SNP with a strong signal, rs3760961, which has significant value in bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('bladder cancer', 'Disease', 'MESH:D001749', (129, 143))	('rs7944701', 'Mutation', 'rs7944701', (32, 41))	('rs7944701', 'Var', (32, 41))	('bladder cancer', 'Disease', (129, 143))	('rs3760961', 'Var', (87, 96))	('rs3760961', 'Mutation', 'rs3760961', (87, 96))
85311	31616507	In addition, a high expression of TMSB10 was associated with shorter overall survival (OS) of patients (P<0.05; log-rank test).	('high', 'Var', (15, 19))	('overall survival', 'MPA', (69, 85))	('shorter', 'NegReg', (61, 68))	('patients', 'Species', '9606', (94, 102))	('TMSB10', 'Gene', (34, 40))
85315	31616507	The targeting of TMSB10 can reduce the migration and invasion of BCa cells.	('BCa', 'Phenotype', 'HP:0009725', (65, 68))	('BCa', 'Disease', (65, 68))	('TMSB10', 'Gene', (17, 23))	('BCa', 'Disease', 'MESH:D001749', (65, 68))	('targeting', 'Var', (4, 13))	('reduce', 'NegReg', (28, 34))	('rat', 'Species', '10116', (42, 45))
85327	31616507	The present study reported for the first time, to the best of our knowledge, that TMSB10 is frequently overexpressed in BCa and that it exhibits clinical significance in BCa, as a high expression of TMSB10 was associated with significantly poorer OS.	('BCa', 'Disease', (120, 123))	('BCa', 'Phenotype', 'HP:0009725', (120, 123))	('BCa', 'Disease', 'MESH:D001749', (120, 123))	('poorer', 'NegReg', (240, 246))	('TMSB10', 'Gene', (82, 88))	('overexpressed', 'PosReg', (103, 116))	('TMSB10', 'Var', (199, 205))	('BCa', 'Phenotype', 'HP:0009725', (170, 173))	('BCa', 'Disease', (170, 173))	('BCa', 'Disease', 'MESH:D001749', (170, 173))	('high expression', 'Var', (180, 195))
85347	31616507	The cycle program was terminated with a final extension step at 72 C for 5 min, and the products were stored at 4 C. The primers were designed using Primer Express software v. 2.0 (Applied Biosystems; Thermo Fisher Scientific, Inc.) with the following sequences: TMSB10, forward 5'-TGGCAGACAAACCAGACATGG-3' and reverse 5'-CGAAGAGGACGGGGGTAGG-3'; and ACTB, forward 5'-CGTGGACATCCGCAAAGA-3' and reverse 5'-GAAGGTGG-ACAGCGAGGC-3'.	('TMSB10', 'Var', (263, 269))	('ACTB', 'Gene', (350, 354))	('ACTB', 'Gene', '60', (350, 354))
85378	31616507	Wound healing and migration assays were performed, and it was shown that the knockdown of TMSB10 reduced the number of invasive cells and significantly suppressed mobility compared with the corresponding parameters noted in the vector control cells (Fig.	('suppressed', 'NegReg', (152, 162))	('knockdown', 'Var', (77, 86))	('reduced', 'NegReg', (97, 104))	('Wound healing', 'biological_process', 'GO:0042060', ('0', '13'))	('TMSB10', 'Gene', (90, 96))	('rat', 'Species', '10116', (21, 24))	('mobility', 'CPA', (163, 171))	('number of invasive cells', 'CPA', (109, 133))
85384	31616507	Kaplan-Meier survival analysis indicated that patients with high protein expression levels of TMSB10 exhibited lower OS compared with patients with low protein expression levels of TMSB10 (P<0.05, Fig.	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (134, 142))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('high protein expression levels', 'Var', (60, 90))	('lower', 'NegReg', (111, 116))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('TMSB10', 'Gene', (94, 100))
85399	31616507	In addition, knocking down the expression of TMSB10 caused a marked reduction in the migration and invasion of BCa cell lines.	('BCa', 'Phenotype', 'HP:0009725', (111, 114))	('BCa', 'Disease', (111, 114))	('rat', 'Species', '10116', (88, 91))	('TMSB10', 'Gene', (45, 51))	('expression', 'MPA', (31, 41))	('reduction', 'NegReg', (68, 77))	('BCa', 'Disease', 'MESH:D001749', (111, 114))	('knocking', 'Var', (13, 21))
85411	31616507	The in vitro analyses demonstrated that the migration and invasion of cancer cells were significantly reduced by silencing TMSB10.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('TMSB10', 'Gene', (123, 129))	('rat', 'Species', '10116', (29, 32))	('rat', 'Species', '10116', (47, 50))	('silencing', 'Var', (113, 122))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('reduced', 'NegReg', (102, 109))
85422	31205522	TCGA (The Cancer Genome Atlas, https://cancergenome.nih.gov/) data was reviewed to analyze the expression of PTPRZ1 gene and PTPRZ1 gene mutations.	('cancer', 'Disease', (39, 45))	('PTPRZ1', 'Gene', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('mutations', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Cancer', 'Phenotype', 'HP:0002664', (10, 16))	('PTPRZ1', 'Gene', (109, 115))
85426	31205522	The rates of PTPRZ1 gene mutations were different across tumors, and uterine corpus endometrial carcinoma (UCEC) (16.79%) has the highest rate of PTPRZ1 gene mutation, followed by lung adenocarcinoma (LUAD) (12.87%) and skin cutaneous melanoma (SKCM) (12.15%) (Figure 2).	('lung adenocarcinoma', 'Disease', (180, 199))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (84, 105))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('corpus endometrial carcinoma', 'Disease', (77, 105))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (77, 105))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (180, 199))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (180, 199))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (220, 243))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('skin cutaneous melanoma', 'Disease', (220, 243))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('rat', 'Species', '10116', (4, 7))	('rat', 'Species', '10116', (138, 141))	('LUAD', 'Phenotype', 'HP:0030078', (201, 205))	('PTPRZ1', 'Gene', (146, 152))	('mutation', 'Var', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (57, 63))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (225, 243))
85427	31205522	Fusion genes combine parts of two or more original genes, generating from chromosomal rearrangement or abnormal transcription.	('rat', 'Species', '10116', (62, 65))	('abnormal transcription', 'Var', (103, 125))	('chromosomal rearrangement', 'Var', (74, 99))	('transcription', 'biological_process', 'GO:0006351', ('112', '125'))
85430	31205522	PTPRZ1-MET induces gliomas through elevated expression levels of MET mRNA, preserve fundamental properties of wild-type MET, and enhance phosphorylation.	('MET mRNA', 'MPA', (65, 73))	('phosphorylation', 'MPA', (137, 152))	('fundamental properties', 'MPA', (84, 106))	('induces', 'Reg', (11, 18))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('gliomas', 'Disease', (19, 26))	('PTPRZ1-MET', 'Var', (0, 10))	('elevated', 'PosReg', (35, 43))	('phosphorylation', 'biological_process', 'GO:0016310', ('137', '152'))	('expression levels', 'MPA', (44, 61))	('enhance', 'PosReg', (129, 136))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
85433	31205522	Several splice variants of PTPRZ1 have been discovered, including PTPRZ1-A (9.4 kb), a full-length transmembrane receptor form; PTPRZ1-B (6.4 kb), a short transmembrane receptor form with a deletion in the extracellular region; the other two are soluble secreted forms that lack both a transmembrane region and tyrosine phosphatase activity (phosphacan, short (4 kb) and long (8.4 kb; also known as phosphacan, PTPRZ-S)).	('phosphacan', 'Gene', '5803', (342, 352))	('phosphatase activity', 'molecular_function', 'GO:0016791', ('320', '340'))	('transmembrane', 'cellular_component', 'GO:0044214', ('99', '112'))	('PTPRZ', 'Gene', (27, 32))	('PTPRZ', 'Gene', (66, 71))	('PTPRZ', 'Gene', '5803', (128, 133))	('deletion', 'Var', (190, 198))	('PTPRZ', 'Gene', '5803', (411, 416))	('PTPRZ', 'Gene', (128, 133))	('phosphacan', 'Gene', '5803', (399, 409))	('PTPRZ', 'Gene', (411, 416))	('phosphacan', 'Gene', (399, 409))	('transmembrane', 'cellular_component', 'GO:0016021', ('155', '168'))	('phosphacan', 'Gene', (342, 352))	('transmembrane', 'cellular_component', 'GO:0016021', ('286', '299'))	('transmembrane', 'cellular_component', 'GO:0016021', ('99', '112'))	('transmembrane', 'cellular_component', 'GO:0044214', ('155', '168'))	('soluble', 'cellular_component', 'GO:0005625', ('246', '253'))	('tyrosine', 'Chemical', 'MESH:D014443', (311, 319))	('PTPRZ', 'Gene', '5803', (27, 32))	('lack', 'NegReg', (274, 278))	('transmembrane', 'cellular_component', 'GO:0044214', ('286', '299'))	('PTPRZ', 'Gene', '5803', (66, 71))	('extracellular region', 'cellular_component', 'GO:0005576', ('206', '226'))
85440	31205522	PTPRZ1-PTN interaction results in accumulation of tyrosine phosphorylation of multiple downstream proteins including SRC kinase, calmodulin, anaplastic lymphoma kinase (ALK), GIT1/Cat1, beta-catenin, beta-adducin, Fyn, GIT1/Cat-1, and P190RhoGAP, which in turn have been related to activation of multiple pro-tumorigenic signaling cascades.	('Cat', 'molecular_function', 'GO:0004096', ('180', '183'))	('beta-adducin', 'Gene', (200, 212))	('lymphoma', 'Phenotype', 'HP:0002665', (152, 160))	('Fyn', 'Gene', '2534', (214, 217))	('GIT1', 'Gene', (175, 179))	('GIT1', 'Gene', '850462', (219, 223))	('Cat-1', 'Species', '717647', (224, 229))	('ALK', 'Gene', '238', (169, 172))	('accumulation', 'PosReg', (34, 46))	('P190RhoGAP', 'Gene', '2909', (235, 245))	('phosphorylation', 'biological_process', 'GO:0016310', ('59', '74'))	('tyrosine phosphorylation', 'MPA', (50, 74))	('ALK', 'Gene', (169, 172))	('SRC', 'Gene', '6714', (117, 120))	('calmodulin', 'MPA', (129, 139))	('beta-adducin', 'Gene', '119', (200, 212))	('tumor', 'Disease', (309, 314))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (141, 160))	('tyrosine', 'Chemical', 'MESH:D014443', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (141, 160))	('SRC', 'Gene', (117, 120))	('interaction', 'Var', (11, 22))	('GIT1', 'Gene', '850462', (175, 179))	('Cat1', 'Species', '717647', (180, 184))	('Fyn', 'Gene', (214, 217))	('Cat', 'molecular_function', 'GO:0004096', ('224', '227'))	('GIT1', 'Gene', (219, 223))	('PTPRZ1-PTN', 'Gene', (0, 10))	('signaling', 'biological_process', 'GO:0023052', ('321', '330'))	('beta-catenin', 'Gene', (186, 198))	('P190RhoGAP', 'Gene', (235, 245))	('beta-catenin', 'Gene', '1499', (186, 198))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('anaplastic lymphoma', 'Disease', (141, 160))
85446	31205522	PTN has been shown to activate both the mitogen- activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K)-Akt signaling axes, and inhibitors of Erk1/2 or PI3K inhibit DNA synthesis stimulated by PTN.	('Erk1/2', 'Gene', '5595;5594', (164, 170))	('phosphatidylinositol 3-kinase', 'Gene', '5295', (89, 118))	('PI3K', 'molecular_function', 'GO:0016303', ('174', '178'))	('DNA synthesis', 'MPA', (187, 200))	('DNA', 'cellular_component', 'GO:0005574', ('187', '190'))	('Erk1', 'molecular_function', 'GO:0004707', ('164', '168'))	('Erk1/2', 'Gene', (164, 170))	('inhibitors', 'Var', (150, 160))	('Akt', 'Gene', '207', (126, 129))	('MAPK', 'molecular_function', 'GO:0004707', ('75', '79'))	('PI3K', 'molecular_function', 'GO:0016303', ('120', '124'))	('Akt signaling', 'biological_process', 'GO:0043491', ('126', '139'))	('activate', 'PosReg', (22, 30))	('phosphatidylinositol 3-kinase', 'Gene', (89, 118))	('inhibit', 'NegReg', (179, 186))	('Akt', 'Gene', (126, 129))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('187', '200'))
85462	31205522	found PTPRZ1 inhibition also potentiated GSK3beta-regulated beta-catenin translocation and two pools of beta-catenin, which are regulated by PTPRZ1 and GSK3beta are partially but incompletely overlapping, with GSK3beta appearing to regulate beta-catenin availability beyond that influenced by PTPRZ1.	('PTPRZ1', 'Gene', (6, 12))	('GSK3beta', 'Gene', '2932', (210, 218))	('GSK3beta', 'Gene', '2932', (41, 49))	('GSK3beta', 'Gene', (152, 160))	('beta-catenin', 'Gene', (104, 116))	('beta-catenin', 'Gene', (241, 253))	('beta-catenin', 'Gene', '1499', (104, 116))	('inhibition', 'Var', (13, 23))	('potentiated', 'PosReg', (29, 40))	('GSK', 'molecular_function', 'GO:0050321', ('41', '44'))	('GSK3beta', 'Gene', '2932', (152, 160))	('GSK', 'molecular_function', 'GO:0050321', ('152', '155'))	('beta-catenin', 'Gene', '1499', (241, 253))	('beta-catenin', 'Gene', (60, 72))	('beta-catenin', 'Gene', '1499', (60, 72))	('GSK3beta', 'Gene', (41, 49))	('GSK', 'molecular_function', 'GO:0050321', ('210', '213'))	('GSK3beta', 'Gene', (210, 218))
85479	31205522	PTPRZ1 seems to be important for maximum tumor growth in situations of contact independence or in complex cellular environments, and blocking the PTPRZ1-PTN signaling potently suppressed glioblastoma growth and prolonged animal survival.	('glioblastoma growth', 'Disease', 'MESH:D005909', (187, 206))	('glioblastoma', 'Phenotype', 'HP:0012174', (187, 199))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('blocking', 'Var', (133, 141))	('tumor', 'Disease', (41, 46))	('glioblastoma growth', 'Disease', (187, 206))	('suppressed', 'NegReg', (176, 186))	('animal survival', 'CPA', (221, 236))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('prolonged', 'PosReg', (211, 220))	('signaling', 'biological_process', 'GO:0023052', ('157', '166'))
85486	31205522	PTPRZ1 gene knockdown increased the ability of human prostate cancer cells to migrate and invade in vitro and to metastasize in vivo .	('PTPRZ1', 'Gene', (0, 6))	('prostate cancer', 'Disease', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('rat', 'Species', '10116', (81, 84))	('knockdown', 'Var', (12, 21))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('increased', 'PosReg', (22, 31))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('metastasize', 'CPA', (113, 124))	('human', 'Species', '9606', (47, 52))
85487	31205522	PTPRZ1 gene knockdown interrupts hydrogen peroxide-induced cell migration and PTPRZ1 gene knockdown in human umbilical vein endothelial cells (HUVEC) inhibited PTN-induced migration and tube formation on matrigel.	('tube formation on matrigel', 'CPA', (186, 212))	('PTPRZ1', 'Gene', (0, 6))	('interrupts', 'NegReg', (22, 32))	('rat', 'Species', '10116', (67, 70))	('tube formation', 'biological_process', 'GO:0035148', ('186', '200'))	('hydrogen peroxide-induced', 'MPA', (33, 58))	('knockdown', 'Var', (90, 99))	('human', 'Species', '9606', (103, 108))	('inhibited', 'NegReg', (150, 159))	('cell migration', 'CPA', (59, 73))	('PTPRZ1', 'Gene', (78, 84))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (33, 50))	('rat', 'Species', '10116', (175, 178))	('cell migration', 'biological_process', 'GO:0016477', ('59', '73'))
85492	31205522	In prostate cancer, the loss of PTPRZ1 gene expression initiated EMT and increased the ability of the cells to migrate and invade.	('loss', 'Var', (24, 28))	('increased', 'PosReg', (73, 82))	('EMT', 'CPA', (65, 68))	('rat', 'Species', '10116', (114, 117))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('gene expression', 'biological_process', 'GO:0010467', ('39', '54'))	('PTPRZ1', 'Gene', (32, 38))	('EMT', 'biological_process', 'GO:0001837', ('65', '68'))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('initiated', 'PosReg', (55, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
85494	31205522	Tumor-associated macrophages (TAMs) secrete abundant PTN to stimulate glioma stem cells (GSCs) through PTPRZ1 thus promoting GBM malignant growth, and disrupting PTPRZ1 abrogated GSC maintenance and tumorigenic potential.	('PTPRZ1', 'Gene', (103, 109))	('tumor', 'Disease', (199, 204))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('glioma', 'Disease', (70, 76))	('promoting', 'PosReg', (115, 124))	('disrupting', 'Var', (151, 161))	('stimulate', 'PosReg', (60, 69))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('abrogated', 'NegReg', (169, 178))	('PTPRZ1', 'Gene', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('GBM malignant growth', 'CPA', (125, 145))	('GSC', 'cellular_component', 'GO:0032593', ('179', '182'))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('GSC maintenance', 'CPA', (179, 194))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
85495	31205522	Knocking down PTPRZ1 gene altered the expression levels of SOX2, OLIG2, and POU3F2 and decreased the sphere- forming abilities in glioblastoma cells.	('expression levels', 'MPA', (38, 55))	('decreased', 'NegReg', (87, 96))	('PTPRZ1', 'Gene', (14, 20))	('glioblastoma', 'Disease', (130, 142))	('glioblastoma', 'Disease', 'MESH:D005909', (130, 142))	('POU3F2', 'Gene', '5454', (76, 82))	('POU3F2', 'Gene', (76, 82))	('OLIG2', 'Gene', (65, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (130, 142))	('SOX2', 'Gene', '6657', (59, 63))	('altered', 'Reg', (26, 33))	('OLIG2', 'Gene', '10215', (65, 70))	('SOX2', 'Gene', (59, 63))	('Knocking', 'Var', (0, 8))
85496	31205522	Another study found the knockdown of PTPRZ1 gene led to reduction of OCT4 and SOX2 transcripts by approximately 40%.	('OCT4', 'Gene', (69, 73))	('PTPRZ1', 'Gene', (37, 43))	('SOX2', 'Gene', '6657', (78, 82))	('reduction', 'NegReg', (56, 65))	('SOX2', 'Gene', (78, 82))	('knockdown', 'Var', (24, 33))	('OCT4', 'Gene', '5460', (69, 73))
85497	31205522	OCT4 knockdown also resulted in 90% decrease of PTPRZ1 gene transcripts, consistent with the marked decrease of PTPRZ1 in differentiating embryonic stem cells.	('PTPRZ1 gene', 'Gene', (48, 59))	('knockdown', 'Var', (5, 14))	('transcripts', 'MPA', (60, 71))	('OCT4', 'Gene', '5460', (0, 4))	('OCT4', 'Gene', (0, 4))	('decrease', 'NegReg', (36, 44))
85504	31205522	Ectopic menin expression significantly repressed PTN transcription, and indirectly inhibited PTPRZ1 expression through repressing PTN expression, and further inhibits FAK and ERK1/2 phosphorylation.	('inhibited', 'NegReg', (83, 92))	('repressed', 'NegReg', (39, 48))	('Ectopic', 'Var', (0, 7))	('ERK1/2', 'Gene', (175, 181))	('ERK1/2', 'Gene', '5595;5594', (175, 181))	('expression', 'Var', (14, 24))	('inhibits', 'NegReg', (158, 166))	('PTN transcription', 'MPA', (49, 66))	('transcription', 'biological_process', 'GO:0006351', ('53', '66'))	('ERK1', 'molecular_function', 'GO:0004707', ('175', '179'))	('menin', 'Gene', '4221', (8, 13))	('PTPRZ1', 'Gene', (93, 99))	('menin', 'Gene', (8, 13))	('FAK', 'Gene', (167, 170))	('repressing', 'NegReg', (119, 129))	('PTN expression', 'MPA', (130, 144))	('FAK', 'molecular_function', 'GO:0004717', ('167', '170'))	('FAK', 'Gene', '5747', (167, 170))	('expression', 'MPA', (100, 110))	('phosphorylation', 'biological_process', 'GO:0016310', ('182', '197'))
85507	31205522	identified several other substrates: Git1, p190, PIST, MAGI-3, Veli-3, Synj2bp, Syntrophin acidic1, Syntrophin basic1, MUPP1, Cardiac troponin T, hDKFZp434G232, KIAA0167, SPOP by a genetic method named the ''yeast substrate-trapping system''.	('Synj2bp', 'Var', (71, 78))	('MAGI-3', 'Gene', (55, 61))	('PIST', 'Gene', '57120', (49, 53))	('p190', 'Var', (43, 47))	('rat', 'Species', '10116', (30, 33))	('PIST', 'Gene', (49, 53))	('MAGI-3', 'Gene', '260425', (55, 61))	('rat', 'Species', '10116', (219, 222))	('Cardiac troponin', 'MPA', (126, 142))	('yeast', 'Species', '4932', (208, 213))
85510	31205522	High PTPRZ1 gene expression might be associated with better OS in BRCA, CESC, LUAD, PAAD, and SKCM, and low PTPRZ1 expression might be associated with better OS in BLCA, COAD, GBM, LGG, LIHC.	('LIHC', 'Disease', (186, 190))	('associated', 'Reg', (135, 145))	('low', 'NegReg', (104, 107))	('BRCA', 'Phenotype', 'HP:0003002', (66, 70))	('High', 'Var', (0, 4))	('LIHC', 'Disease', 'None', (186, 190))	('expression', 'MPA', (17, 27))	('GBM', 'Disease', (176, 179))	('BLCA', 'Disease', (164, 168))	('better OS', 'Disease', (151, 160))	('associated', 'Reg', (37, 47))	('LUAD', 'Phenotype', 'HP:0030078', (78, 82))	('gene expression', 'biological_process', 'GO:0010467', ('12', '27'))	('CESC', 'Disease', (72, 76))	('COAD', 'Disease', 'MESH:D029424', (170, 174))	('LGG', 'Disease', (181, 184))	('PTPRZ1', 'Gene', (108, 114))	('BRCA', 'Gene', '672', (66, 70))	('PTPRZ1', 'Gene', (5, 11))	('LUAD', 'Disease', (78, 82))	('PAAD', 'Phenotype', 'HP:0006725', (84, 88))	('BRCA', 'Gene', (66, 70))	('expression', 'MPA', (115, 125))	('COAD', 'Disease', (170, 174))
85512	31205522	In human breast cancer, high expression of PTPRZ1 may be an independent risk indicator for triple- negative breast cancer (TNBC) recurrence and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('TNBC', 'Disease', 'None', (123, 127))	('PTPRZ1', 'Gene', (43, 49))	('high expression', 'Var', (24, 39))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Disease', (9, 22))	('TNBC', 'Disease', (123, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
85513	31205522	PTPRZ1 has a significant impact on survival of patients with oral squamous cell carcinoma, and patients with positive PTPRZ1 was associated with 8 times lower risk of death within 5 years than those with negative PTPRZ1.	('positive', 'Var', (109, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('death', 'Disease', 'MESH:D003643', (167, 172))	('patients', 'Species', '9606', (95, 103))	('death', 'Disease', (167, 172))	('PTPRZ1', 'Gene', (118, 124))	('oral squamous cell carcinoma', 'Disease', (61, 89))	('patients', 'Species', '9606', (47, 55))	('impact', 'Reg', (25, 31))	('lower', 'NegReg', (153, 158))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
85516	31205522	identified NAZ2329, a cell-permeable small molecule that allosterically inhibits PTPRZ1, which reduced the expression of SOX2 and abrogated the sphere-forming abilities in glioblastoma cells.	('SOX2', 'Gene', (121, 125))	('SOX2', 'Gene', '6657', (121, 125))	('NAZ2329', 'Chemical', '-', (11, 18))	('expression', 'MPA', (107, 117))	('glioblastoma', 'Disease', 'MESH:D005909', (172, 184))	('inhibits', 'NegReg', (72, 80))	('abrogated', 'NegReg', (130, 139))	('PTPRZ1', 'Gene', (81, 87))	('glioblastoma', 'Disease', (172, 184))	('reduced', 'NegReg', (95, 102))	('NAZ2329', 'Var', (11, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))
85520	31205522	showed the intracellular delivery of SCB4380, the first potent inhibitor for PTPRZ1, by liposome carriers inhibited PTPRZ1 activity in glioblastoma cells, and thereby suppressed cell migration and proliferation in vitro and tumor growth in a rat allograft model.	('suppressed', 'NegReg', (167, 177))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('cell migration', 'biological_process', 'GO:0016477', ('178', '192'))	('cell migration', 'CPA', (178, 192))	('inhibited', 'NegReg', (106, 115))	('PTPRZ1', 'Gene', (77, 83))	('PTPRZ1', 'Gene', (116, 122))	('rat', 'Species', '10116', (242, 245))	('rat', 'Species', '10116', (204, 207))	('tumor', 'Disease', (224, 229))	('activity', 'MPA', (123, 131))	('glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('SCB4380', 'Var', (37, 44))	('rat', 'Species', '10116', (186, 189))	('SCB4380', 'Chemical', '-', (37, 44))	('intracellular', 'cellular_component', 'GO:0005622', ('11', '24'))	('glioblastoma', 'Disease', (135, 147))
85524	31205522	Given the strong up-regulation of PTPRZ1, antagonization of PTPRZ1 expression and/or signaling may be a promising strategy to inhibit the tumor growth.	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('regulation', 'biological_process', 'GO:0065007', ('20', '30'))	('tumor', 'Disease', (138, 143))	('antagonization', 'Var', (42, 56))	('inhibit', 'NegReg', (126, 133))	('rat', 'Species', '10116', (116, 119))	('PTPRZ1', 'Gene', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('PTPRZ1', 'Gene', (34, 40))	('up-regulation', 'PosReg', (17, 30))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
85530	31205522	PTPRZ1 gene mutation accounts for a high proportion of cancer patients, especially in UCEC, the proportion could be up to 16.79%.	('PTPRZ1', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('mutation', 'Var', (12, 20))	('patients', 'Species', '9606', (62, 70))	('cancer', 'Disease', (55, 61))	('UCEC', 'Disease', (86, 90))
85531	31205522	Such a high proportion of cancer patients have PTPRZ1 mutations, so whether PTPRZ1 mutations could predict therapy efficacy or not deserved further research.	('patients', 'Species', '9606', (33, 41))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('mutations', 'Var', (54, 63))	('PTPRZ1', 'Gene', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
85534	31205522	In the future, the value of PTPRZ1 gene mutation in cancer therapy deserved to be researched and drugs that target patients with PTPRZ1 mutations were studied in literature.	('PTPRZ1', 'Gene', (28, 34))	('mutation', 'Var', (40, 48))	('patients', 'Species', '9606', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('rat', 'Species', '10116', (166, 169))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
85535	31205522	Tumors from patients harboring PTPRZ1-MET-fused glioblastoma are resistant to temozolomide therapy and have significantly compromised overall survival rates.	('temozolomide', 'Chemical', 'MESH:D000077204', (78, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('patients', 'Species', '9606', (12, 20))	('PTPRZ1-MET-fused', 'Var', (31, 47))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('compromised', 'NegReg', (122, 133))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('overall', 'MPA', (134, 141))	('rat', 'Species', '10116', (151, 154))	('glioblastoma', 'Disease', (48, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))	('resistant to temozolomide therapy', 'MPA', (65, 98))
85545	31205522	Our previous study showed high expression of PTPRZ1 may be an independent risk indicator for triple negative breast cancer recurrence and metastasis.	('PTPRZ1', 'Gene', (45, 51))	('metastasis', 'CPA', (138, 148))	('high expression', 'Var', (26, 41))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
85546	31205522	PTPRZ1 has a significant impact on survival in patients with oral squamous cell carcinoma, and patients with positive PTPRZ1 was associated with 8 times lower risk of death within 5 years than those with negative PTPRZ1.	('positive', 'Var', (109, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('death', 'Disease', 'MESH:D003643', (167, 172))	('patients', 'Species', '9606', (95, 103))	('death', 'Disease', (167, 172))	('PTPRZ1', 'Gene', (118, 124))	('oral squamous cell carcinoma', 'Disease', (61, 89))	('patients', 'Species', '9606', (47, 55))	('impact', 'Reg', (25, 31))	('lower', 'NegReg', (153, 158))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
85549	31205522	Future studies should screen drugs for patients with PTPRZ1 gene mutations, PTPRZ1 fusion genes, and PTPRZ1 protein positivity.	('PTPRZ1', 'Gene', (76, 82))	('patients', 'Species', '9606', (39, 47))	('PTPRZ1', 'Gene', (53, 59))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('mutations', 'Var', (65, 74))
85550	31205522	Second, pharmacological inhibition or activation of PTPRZ1 is a promising strategy for the treatment of several tumors.	('activation', 'Var', (38, 48))	('rat', 'Species', '10116', (76, 79))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('PTPRZ1', 'Gene', (52, 58))
85568	30352907	The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3,KDM6A,CCND1 and TP53.	('bladder recurrence', 'Disease', (12, 30))	('KDM6A', 'Gene', (95, 100))	('CCND1', 'Gene', (101, 106))	('mutations', 'Var', (76, 85))	('UC', 'Disease', 'MESH:D014523', (39, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('TP53', 'Gene', '7157', (111, 115))	('KDM6A', 'Gene', '7403', (95, 100))	('FGFR3', 'Gene', (89, 94))	('CCND1', 'Gene', '595', (101, 106))	('TP53', 'Gene', (111, 115))	('associated', 'Reg', (60, 70))	('FGFR3', 'Gene', '2261', (89, 94))
85592	30352907	To test tumors for clonal relatedness, we used somatic mutation data, including silent mutations.	('silent mutations', 'Var', (80, 96))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))
85600	30352907	Conversely, the frequency of alterations in TP53 and MDM2 was significantly increased in patients with higher stage disease (11% versus 31% and 4% versus 17%, respectively; P<0.001).	('MDM2', 'Gene', '4193', (53, 57))	('increased', 'PosReg', (76, 85))	('MDM2', 'Gene', (53, 57))	('alterations', 'Var', (29, 40))	('higher stage disease', 'Disease', (103, 123))	('TP53', 'Gene', '7157', (44, 48))	('patients', 'Species', '9606', (89, 97))	('TP53', 'Gene', (44, 48))
85601	30352907	The frequency of alterations in only 2 other genes was significantly greater in patients with lower-stage UTUC tumors: STAG2, a component of the cohesin complex that plays a role in meiosis and mitosis (24% vs. 6%, P<0.001), and FBXW7, a component of the SCF complex involved in regulating protein degradation of several oncogenes including cyclin E and c-Myc (12% vs. 0%, P<0.001).	('patients', 'Species', '9606', (80, 88))	('c-Myc', 'Gene', '4609', (354, 359))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cohesin complex', 'cellular_component', 'GO:0008278', ('145', '160'))	('tumors', 'Disease', (111, 117))	('mitosis', 'biological_process', 'GO:0000278', ('194', '201'))	('STAG2', 'Gene', '10735', (119, 124))	('FBXW7', 'Gene', (229, 234))	('meiosis and mitosis', 'Disease', 'MESH:C536875', (182, 201))	('SCF complex', 'cellular_component', 'GO:0019005', ('255', '266'))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('cyclin', 'molecular_function', 'GO:0016538', ('341', '347'))	('STAG2', 'Gene', (119, 124))	('alterations', 'Var', (17, 28))	('UC', 'Disease', 'MESH:D014523', (108, 110))	('SCF', 'molecular_function', 'GO:0005173', ('255', '258'))	('FBXW7', 'Gene', '55294', (229, 234))	('protein degradation', 'biological_process', 'GO:0030163', ('290', '309'))	('protein', 'cellular_component', 'GO:0003675', ('290', '297'))	('c-Myc', 'Gene', (354, 359))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('meiosis', 'biological_process', 'GO:0051321', ('182', '189'))
85613	30352907	Patients with Lynch syndrome have germline mutations in mismatch repair (MMR)-associated genes, which results in an increased risk for the development of tumors with microsatellite instability (MSI) and hypermutation.	('Lynch syndrome', 'Disease', (14, 28))	('microsatellite instability', 'MPA', (166, 192))	('tumors', 'Disease', (154, 160))	('MMR)-associated genes', 'Gene', (73, 94))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('Lynch syndrome', 'Disease', 'MESH:D003123', (14, 28))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('MMR', 'biological_process', 'GO:0006298', ('73', '76'))	('germline mutations', 'Var', (34, 52))	('Patients', 'Species', '9606', (0, 8))	('hypermutation', 'Var', (203, 216))	('mismatch repair', 'biological_process', 'GO:0006298', ('56', '71'))
85618	30352907	As expected, the number of mutations/Mb was significantly higher in tumors with MSIsensor scores >=10 (median: 49.3) as compared to tumors with MSIsensor scores between 3-10 (median: 13.0; P=0.002) or MSIsensor scores <3 (median: 6; P<0.001).	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('higher', 'PosReg', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Disease', (132, 138))	('mutations/Mb', 'Var', (27, 39))	('MSIsensor scores >=10', 'Var', (80, 101))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
85626	30352907	To further characterize those tumors with evidence of hypermutation but indeterminate or low MSIsensor scores, we performed mutational signature decomposition analysis on all tumor samples with 10 or more single nucleotide somatic mutations.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Disease', (175, 180))	('single nucleotide somatic', 'Var', (205, 230))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', (30, 35))
85628	30352907	In the broader cohort of UTUC samples with 10 or more mutations without an MMR germline mutation, we identified evidence of a predominant AID/APOBEC signature in 20/30, a smoking signature in 2/30 and a POLE signature in 1/30.	('AID', 'Gene', '57379', (138, 141))	('AID', 'Gene', (138, 141))	('mutations', 'Var', (54, 63))	('APOBEC', 'cellular_component', 'GO:0030895', ('142', '148'))	('UC', 'Disease', 'MESH:D014523', (27, 29))	('smoking', 'MPA', (171, 178))	('MMR', 'biological_process', 'GO:0006298', ('75', '78'))
85634	30352907	After adjusting for clinical factors associated with bladder recurrence, including sex, history of prior bladder cancer, location, grade, and tumor stage, alterations in FGFR3 (HR=3.00, 95% CI: 1.58-5.68; P=0.001), KDM6A (HR=2.27, 95% CI: 1.29-4.02; P=0.005), and CCND1 (HR=3.10, 95% CI: 1.17-8.21; P=0.023) were significantly associated with a higher risk of developing a subsequent bladder tumor, whereas TP53 alterations were associated with a lower risk (HR=0.32, 95% CI: 0.13-0.80; P=0.014) (Supplement Table S5).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('KDM6A', 'Gene', '7403', (215, 220))	('alterations', 'Var', (155, 166))	('CCND1', 'Gene', '595', (264, 269))	('bladder cancer', 'Disease', 'MESH:D001749', (105, 119))	('bladder cancer', 'Disease', (105, 119))	('tumor', 'Disease', (392, 397))	('TP53', 'Gene', '7157', (407, 411))	('associated', 'Reg', (327, 337))	('bladder tumor', 'Phenotype', 'HP:0009725', (384, 397))	('CCND1', 'Gene', (264, 269))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('170', '174'))	('tumor', 'Disease', 'MESH:D009369', (392, 397))	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('FGFR3', 'Gene', (170, 175))	('KDM6A', 'Gene', (215, 220))	('bladder tumor', 'Disease', (384, 397))	('tumor', 'Phenotype', 'HP:0002664', (392, 397))	('tumor', 'Disease', (142, 147))	('FGFR3', 'Gene', '2261', (170, 175))	('bladder tumor', 'Disease', 'MESH:D001749', (384, 397))	('TP53', 'Gene', (407, 411))	('alterations', 'Var', (412, 423))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
85640	30352907	In the 13 patients with a prior history of UCB, 75% of the mutations were found to be similar in both the UTUC and subsequent bladder tumors (Supplementary Figure S1).	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('UC', 'Disease', 'MESH:D014523', (43, 45))	('UCB', 'Phenotype', 'HP:0006740', (43, 46))	('bladder tumors', 'Disease', 'MESH:D001749', (126, 140))	('bladder tumors', 'Phenotype', 'HP:0009725', (126, 140))	('bladder tumors', 'Disease', (126, 140))	('mutations', 'Var', (59, 68))	('patients', 'Species', '9606', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('bladder tumor', 'Phenotype', 'HP:0009725', (126, 139))	('UC', 'Disease', 'MESH:D014523', (108, 110))
85642	30352907	For the 7 bladder tumors collected before radical nephroureterectomy with tissue available for sequencing, 69% of mutations were shared between the initial UCB and subsequent UTUC, with all the tumor pairs again being of shared clonal origin (P<0.005).	('bladder tumors', 'Disease', (10, 24))	('UC', 'Disease', 'MESH:D014523', (156, 158))	('tumor', 'Disease', (18, 23))	('mutations', 'Var', (114, 123))	('UC', 'Disease', 'MESH:D014523', (177, 179))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('bladder tumors', 'Phenotype', 'HP:0009725', (10, 24))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', (194, 199))	('bladder tumors', 'Disease', 'MESH:D001749', (10, 24))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('bladder tumor', 'Phenotype', 'HP:0009725', (10, 23))	('UCB', 'Phenotype', 'HP:0006740', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
85646	30352907	Consistent with prior studies, FGFR3 alterations were more common in low-grade tumors.	('common', 'Reg', (59, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('FGFR3', 'Gene', '2261', (31, 36))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('alterations', 'Var', (37, 48))	('FGFR3', 'Gene', (31, 36))	('low-grade', 'Disease', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
85647	30352907	FGFR3 mutations in urothelial cancer typically arise in one of several hotspot locations and have been shown to be oncogenic and thus represent potential therapeutic targets.	('urothelial cancer', 'Disease', (19, 36))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('arise', 'Reg', (47, 52))	('urothelial cancer', 'Disease', 'MESH:D014523', (19, 36))	('FGFR3', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('FGFR3', 'Gene', '2261', (0, 5))
85648	30352907	Notably, 31% of high-grade UTUC had FGFR3 alterations, a frequency significantly higher than that observed in high-grade UCB (21%).	('UC', 'Disease', 'MESH:D014523', (29, 31))	('FGFR3', 'Gene', (36, 41))	('alterations', 'Var', (42, 53))	('UCB', 'Phenotype', 'HP:0006740', (121, 124))	('FGFR3', 'Gene', '2261', (36, 41))	('UC', 'Disease', 'MESH:D014523', (121, 123))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
85649	30352907	As FGFR3 and TP53 tend to be mutually exclusive, our results lend further support to the model that high-grade tumors often arise de novo, in the absence of a prior low-grade lesion, whereas some low-grade tumors with FGFR3 alterations, more frequently in the upper tract than in the bladder, progress over time to high-grade disease.	('TP53', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumors', 'Disease', (111, 117))	('FGFR', 'molecular_function', 'GO:0005007', ('3', '7'))	('FGFR', 'molecular_function', 'GO:0005007', ('218', '222'))	('high-grade disease', 'Disease', (315, 333))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (206, 212))	('TP53', 'Gene', '7157', (13, 17))	('FGFR3', 'Gene', (218, 223))	('alterations', 'Var', (224, 235))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('FGFR3', 'Gene', (3, 8))	('FGFR3', 'Gene', '2261', (218, 223))	('FGFR3', 'Gene', '2261', (3, 8))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('progress', 'PosReg', (293, 301))
85653	30352907	Recently, a whole exome sequencing analysis of 27 UTUC samples confirmed that there was a significantly higher frequency of mutations in the p53 and related pathways in high-grade tumors, leading to genomic instability, copy number alterations and disruption of cell-cycle and apoptotic pathways which was corroborated by protein analysis.	('p53', 'Gene', (141, 144))	('mutations', 'Var', (124, 133))	('disruption', 'Reg', (248, 258))	('p53', 'Gene', '7157', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cell-cycle', 'biological_process', 'GO:0007049', ('262', '272'))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('genomic instability', 'MPA', (199, 218))	('protein', 'cellular_component', 'GO:0003675', ('322', '329'))	('tumors', 'Disease', (180, 186))	('copy number alterations', 'MPA', (220, 243))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('UC', 'Disease', 'MESH:D014523', (52, 54))
85657	30352907	Overall, over half of the urothelial tumors in the current study as well as the TCGA had potentially actionable genomic alterations, including ERBB2 amplifications and mutations and FGFR3 hotspot mutations.	('urothelial tumors', 'Disease', 'MESH:D001749', (26, 43))	('FGFR3', 'Gene', '2261', (182, 187))	('ERBB2', 'Gene', (143, 148))	('ERBB2', 'Gene', '2064', (143, 148))	('mutations', 'Var', (196, 205))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('amplifications', 'Var', (149, 163))	('urothelial tumors', 'Disease', (26, 43))	('FGFR3', 'Gene', (182, 187))	('FGFR', 'molecular_function', 'GO:0005007', ('182', '186'))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (168, 177))
85663	30352907	Furthermore, given the strong association between mutational burden and immunotherapy response, UTUC patients with microsatellite instability in the setting of MMR deficiency may represent a subpopulation of patients with a greater likelihood of benefiting from both local and systemic immunotherapies.	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (208, 216))	('MMR', 'biological_process', 'GO:0006298', ('160', '163'))	('MMR', 'Gene', (160, 163))	('microsatellite instability', 'Var', (115, 141))	('UC', 'Disease', 'MESH:D014523', (98, 100))	('deficiency', 'Var', (164, 174))
85665	30352907	Here, we identified a strong association in multivariable analysis between the risk of recurrence and alterations in FGFR3,KDM6A, CCND1 and TP53.	('FGFR3', 'Gene', '2261', (117, 122))	('TP53', 'Gene', (140, 144))	('KDM6A', 'Gene', (123, 128))	('KDM6A', 'Gene', '7403', (123, 128))	('FGFR3', 'Gene', (117, 122))	('CCND1', 'Gene', (130, 135))	('FGFR', 'molecular_function', 'GO:0005007', ('117', '121'))	('alterations', 'Var', (102, 113))	('CCND1', 'Gene', '595', (130, 135))	('TP53', 'Gene', '7157', (140, 144))
85683	30352907	Targeted NGS was a robust methodology for identifying UTUC patients whose tumors were microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR), the vast majority of which arose in patients with a pathogenic germline mutation in a Lynch syndrome associated gene.	('arose in', 'Reg', (187, 195))	('mismatch repair', 'biological_process', 'GO:0006298', ('126', '141'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('patients', 'Species', '9606', (196, 204))	('Lynch syndrome', 'Disease', (246, 260))	('microsatellite', 'MPA', (86, 100))	('UC', 'Disease', 'MESH:D014523', (56, 58))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('patients', 'Species', '9606', (59, 67))	('Lynch syndrome', 'Disease', 'MESH:D003123', (246, 260))	('germline mutation', 'Var', (223, 240))	('pathogenic', 'Reg', (212, 222))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
85686	28974240	Association of a novel point mutation in MSH2 gene with familial multiple primary cancers Multiple primary cancers (MPC) have been identified as two or more cancers without any subordinate relationship that occur either simultaneously or metachronously in the same or different organs of an individual.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancers', 'Disease', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Multiple primary cancers', 'Disease', 'MESH:D009369', (90, 114))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('MSH2', 'Gene', (41, 45))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('MSH2', 'Gene', '4436', (41, 45))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('point mutation', 'Var', (23, 37))	('Association', 'Interaction', (0, 11))	('Multiple primary cancers', 'Disease', (90, 114))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
85688	28974240	Lynch syndrome patients who suffer more than two cancers can also be considered as MPC; patients of this kind provide unique resources to learn how genetic mutation causes MPC in different tissues.	('patients', 'Species', '9606', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('patients', 'Species', '9606', (88, 96))	('causes', 'Reg', (165, 171))	('Lynch syndrome', 'Disease', (0, 14))	('MPC', 'Disease', (172, 175))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('cancers', 'Disease', (49, 56))	('genetic mutation', 'Var', (148, 164))
85692	28974240	We revealed a novel pathologic mutation on the MSH2 gene (G504 splicing) that associates with Lynch syndrome.	('MSH2', 'Gene', (47, 51))	('G504 splicing', 'Var', (58, 71))	('Lynch syndrome', 'Disease', (94, 108))	('Lynch syndrome', 'Disease', 'MESH:D003123', (94, 108))	('associates', 'Reg', (78, 88))	('splicing', 'biological_process', 'GO:0045292', ('63', '71'))
85694	28974240	Integrative analysis showed that truncating mutations of DNA mismatch repair (MMR) genes were significantly enriched in the patient.	('truncating mutations', 'Var', (33, 53))	('MMR', 'biological_process', 'GO:0006298', ('78', '81'))	('MMR) genes', 'Gene', (78, 88))	('patient', 'Species', '9606', (124, 131))	('mismatch repair', 'biological_process', 'GO:0006298', ('61', '76'))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))
85710	28974240	We discovered a novel MSH2 mutation (G504 splicing) associating with Lynch syndrome, which segregated with disease phenotypes in a four-generational pedigree and resulted in the inactivation of MSH2 protein.	('MSH2', 'Gene', (194, 198))	('MSH2', 'Gene', (22, 26))	('associating', 'Reg', (52, 63))	('protein', 'Protein', (199, 206))	('Lynch syndrome', 'Disease', (69, 83))	('splicing', 'biological_process', 'GO:0045292', ('42', '50'))	('Lynch syndrome', 'Disease', 'MESH:D003123', (69, 83))	('G504 splicing', 'Var', (37, 50))	('inactivation', 'NegReg', (178, 190))	('protein', 'cellular_component', 'GO:0003675', ('199', '206'))
85712	28974240	We further demonstrated that Lynch syndrome-related cancers harbored mutations in the driver genes of sporadic cancers, and that these genes might play significant roles in the carcinogenesis of Lynch syndrome.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('mutations', 'Var', (69, 78))	('Lynch syndrome', 'Disease', 'MESH:D003123', (195, 209))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (52, 59))	('cancers', 'Disease', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Lynch syndrome', 'Disease', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('sporadic cancers', 'Disease', (102, 118))	('sporadic cancers', 'Disease', 'MESH:D009369', (102, 118))	('Lynch syndrome', 'Disease', 'MESH:D003123', (29, 43))	('carcinogenesis of Lynch syndrome', 'Disease', (177, 209))	('roles', 'Reg', (164, 169))	('play', 'Reg', (147, 151))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('carcinogenesis of Lynch syndrome', 'Disease', 'MESH:D063646', (177, 209))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
85738	28974240	TCGA cancer samples were classified into three groups based on the results of the microsatellite instability (MSI) test: MSI high (MSI-H), MSI low (MSI-L), and microsatellite stable (MSS).	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('MSI-H', 'Disease', 'MESH:D000848', (131, 136))	('MSI low', 'Var', (139, 146))	('cancer', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('MSI-H', 'Disease', (131, 136))
85758	28974240	Then, we focused on HNPCC-associated DNA MMR genes and found that only one rare non-silent variant, rs267607964 (chr2: 47693796: G > T), affects the G504 splicing site of MSH2 (Fig.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('MSH2', 'Gene', (171, 175))	('MMR', 'biological_process', 'GO:0006298', ('41', '44'))	('affects', 'Reg', (137, 144))	('rs267607964', 'Var', (100, 111))	('splicing', 'biological_process', 'GO:0045292', ('154', '162'))	('rs267607964', 'Mutation', 'rs267607964', (100, 111))	('HNPCC', 'Disease', 'None', (20, 25))	('HNPCC', 'Disease', (20, 25))	('G504 splicing site', 'MPA', (149, 167))
85759	28974240	Although this site was recorded in the dbSNP database, no previous studies have reported the association of this variant with HNPCC.	('HNPCC', 'Disease', (126, 131))	('variant', 'Var', (113, 120))	('association', 'Interaction', (93, 104))	('HNPCC', 'Disease', 'None', (126, 131))
85760	28974240	To obtain more information relating to the function of rs267607964, we further searched databases and the literature and found that its adjacent site rs267607962 (chr2: 47693795: A>G) was reported to be a pathogenic variant of Lynch syndrome in the ClinVar database, which suggested that rs267607964 might also associate with Lynch syndrome.	('Lynch syndrome', 'Disease', (227, 241))	('Lynch syndrome', 'Disease', 'MESH:D003123', (227, 241))	('pathogenic', 'Reg', (205, 215))	('rs267607962', 'Var', (150, 161))	('rs267607964', 'Mutation', 'rs267607964', (288, 299))	('rs267607964', 'Mutation', 'rs267607964', (55, 66))	('Lynch syndrome', 'Disease', (326, 340))	('associate', 'Reg', (311, 320))	('rs267607962', 'Mutation', 'rs267607962', (150, 161))	('rs267607964', 'Var', (288, 299))	('Lynch syndrome', 'Disease', 'MESH:D003123', (326, 340))
85762	28974240	2b, the four healthy controls (III1, III5, IV5, and IV7) had G/G genotype, while all cancer patients (III2, III4, and III6) had G/T genotype.	('G/T', 'Var', (128, 131))	('G/G genotype', 'Var', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('patients', 'Species', '9606', (92, 100))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
85763	28974240	Finally, we examined the effect of MSH2 variation (rs267607964) on protein expression.	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('rs267607964', 'Var', (51, 62))	('rs267607964', 'Mutation', 'rs267607964', (51, 62))	('MSH2', 'Gene', (35, 39))	('examined', 'Reg', (12, 20))
85766	28974240	Of note, IV3, a 39-year-old woman who developed ovarian cancer at age 30, exhibited G/T variant of MSH2 and decreased MSH2 expression, suggesting that she had a higher risk of suffering additional Lynch syndrome-related cancers in the future.	('MSH2', 'Gene', (99, 103))	('expression', 'MPA', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('Lynch syndrome', 'Disease', (197, 211))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('ovarian cancer', 'Disease', 'MESH:D010051', (48, 62))	('decreased', 'NegReg', (108, 117))	('G/T variant', 'Var', (84, 95))	('Lynch syndrome', 'Disease', 'MESH:D003123', (197, 211))	('woman', 'Species', '9606', (28, 33))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('cancers', 'Disease', (220, 227))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('ovarian cancer', 'Disease', (48, 62))	('MSH2', 'Gene', (118, 122))
85769	28974240	A hyper-mutated genome is the typical feature of microsatellite instable cancers.	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('hyper-mutated', 'Var', (2, 15))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))
85771	28974240	There were six classes of base substitutions (C>A or G>T, C>G or G>C, C>T or G>A, T>A or A>T, T>C or A>G, and T>G or A>C), which composed 96 possible trinucleotide contexts when considering the adjacent bases.	('trinucleotide', 'Chemical', '-', (150, 163))	('T>C', 'Var', (94, 97))	('G>A', 'Var', (77, 80))	('C>G', 'Var', (58, 61))	('G>T', 'Var', (53, 56))	('C>T', 'Var', (70, 73))	('T>G or A>C', 'Var', (110, 120))	('T>A', 'Var', (82, 85))	('G>C', 'Var', (65, 68))	('C>A', 'Var', (46, 49))
85774	28974240	The mutation pattern of the Lynch syndrome proband was mostly similar to signature 6, which was associated with defective DNA MMR, and it was also found in microsatellite unstable cancers.	('MMR', 'biological_process', 'GO:0006298', ('126', '129'))	('Lynch syndrome', 'Disease', 'MESH:D003123', (28, 42))	('microsatellite unstable cancers', 'Disease', 'MESH:D053842', (156, 187))	('microsatellite unstable cancers', 'Disease', (156, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('associated', 'Reg', (96, 106))	('mutation', 'Var', (4, 12))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))	('found', 'Reg', (147, 152))	('Lynch syndrome', 'Disease', (28, 42))
85781	28974240	Such overlap was significantly lower than the similarity (30~80%) between paired primary metastasis cancers, which might indicate that cancers from different tissue origins have independent mutation landscape after initiation by MSH2 inactivation.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('inactivation', 'Var', (234, 246))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('metastasis cancers', 'Disease', 'MESH:D009362', (89, 107))	('metastasis cancers', 'Disease', (89, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lower', 'NegReg', (31, 36))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('MSH2', 'Gene', (229, 233))	('cancers', 'Disease', (100, 107))
85785	28974240	NOTCH1, THBS1, and RIN1 were mutated in both RPC and SIC.	('THBS1', 'Gene', (8, 13))	('SIC', 'Disease', (53, 56))	('THBS1', 'Gene', '7057', (8, 13))	('RIN1', 'Gene', '9610', (19, 23))	('RPC', 'Phenotype', 'HP:0006762', (45, 48))	('SIC', 'Disease', 'None', (53, 56))	('SIC', 'Phenotype', 'HP:0100833', (53, 56))	('mutated', 'Var', (29, 36))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('RPC', 'Disease', (45, 48))	('RIN1', 'Gene', (19, 23))
85791	28974240	MSI cancers had a higher proportion of mutation than MSS cancers did.	('MSI cancers', 'Disease', 'MESH:D009369', (0, 11))	('mutation', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('MSS cancers', 'Disease', 'MESH:D013132', (53, 64))	('MSS cancers', 'Disease', (53, 64))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('MSI cancers', 'Disease', (0, 11))
85793	28974240	We observed that cancers from the patient with Lynch syndrome harbored mutations in the driver genes of similar TCGA cancers (Additional file 1: Table S4).	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('mutations', 'Var', (71, 80))	('cancers', 'Disease', (17, 24))	('Lynch syndrome', 'Disease', (47, 61))	('patient', 'Species', '9606', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('Lynch syndrome', 'Disease', 'MESH:D003123', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cancers', 'Disease', (117, 124))
85794	28974240	RPC had missense mutations in two BLCA driver genes: ARID1A (MAF = 0.26), ATM (MAF = 0.30), and MTOR (MAF = 0.18).	('MTOR', 'Gene', '2475', (96, 100))	('RPC', 'Phenotype', 'HP:0006762', (0, 3))	('BLCA driver genes', 'Gene', (34, 51))	('ATM', 'Gene', (74, 77))	('ARID1A', 'Gene', '8289', (53, 59))	('ATM', 'Gene', '472', (74, 77))	('MTOR', 'Gene', (96, 100))	('missense mutations', 'Var', (8, 26))	('ARID1A', 'Gene', (53, 59))
85795	28974240	SIC had missense mutations in two driver genes of COAD: APC (MAF = 0.32) and PIK3CA (MAF = 0.41).	('PIK3CA', 'Gene', (77, 83))	('COAD', 'Disease', 'MESH:D029424', (50, 54))	('APC', 'cellular_component', 'GO:0005680', ('56', '59'))	('PIK3CA', 'Gene', '5290', (77, 83))	('SIC', 'Disease', (0, 3))	('SIC', 'Disease', 'None', (0, 3))	('COAD', 'Disease', (50, 54))	('APC', 'Disease', 'MESH:D011125', (56, 59))	('APC', 'Disease', (56, 59))	('SIC', 'Phenotype', 'HP:0100833', (0, 3))	('missense mutations', 'Var', (8, 26))
85798	28974240	Therefore, we inferred that mutations in these driver genes might be early and necessary events in the carcinogenesis of Lynch syndrome.	('mutations', 'Var', (28, 37))	('carcinogenesis of Lynch syndrome', 'Disease', 'MESH:D063646', (103, 135))	('carcinogenesis of Lynch syndrome', 'Disease', (103, 135))
85799	28974240	We comprehensively investigated the genomic landscape of the proband from a Chinese family with Lynch syndrome and found a new pathologic germline mutation on MSH2 and revealed important somatic mutations that may drive carcinogenesis.	('Lynch syndrome', 'Disease', 'MESH:D003123', (96, 110))	('mutation', 'Var', (147, 155))	('pathologic', 'Reg', (127, 137))	('carcinogenesis', 'Disease', (220, 234))	('carcinogenesis', 'Disease', 'MESH:D063646', (220, 234))	('MSH2', 'Gene', (159, 163))	('drive', 'Reg', (214, 219))	('Lynch syndrome', 'Disease', (96, 110))
85801	28974240	Sometimes, somatic mutation or methylation may serve as a "second hit" at the wild-type allele or other MMR genes, which is consistent with Knudson's double-hit model of carcinogenesis.	('carcinogenesis', 'Disease', (170, 184))	('somatic mutation', 'Var', (11, 27))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('methylation', 'Var', (31, 42))	('carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))	('MMR genes', 'Gene', (104, 113))
85802	28974240	Double-hit mutations might cause a more severe cancer in phenotype.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('cause', 'Reg', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Double-hit mutations', 'Var', (0, 20))
85803	28974240	Third, the cell accumulates huge somatic mutations, with mutations in  driver genes (oncogene or tumor suppressor gene) playing important roles in carcinogenesis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('97', '113'))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('carcinogenesis', 'Disease', 'MESH:D063646', (147, 161))	('tumor', 'Disease', (97, 102))	('mutations', 'Var', (57, 66))	('carcinogenesis', 'Disease', (147, 161))	('tumor suppressor', 'biological_process', 'GO:0051726', ('97', '113'))
85804	28974240	Somatic mutations of potential driver genes such as ARID1A, ATM, and MTOR promoted cancer growth, and many mutations were generated due to MMR deficiency.	('MMR deficiency', 'Disease', (139, 153))	('promoted', 'PosReg', (74, 82))	('MMR deficiency', 'Disease', 'MESH:C536143', (139, 153))	('MTOR', 'Gene', '2475', (69, 73))	('MMR', 'biological_process', 'GO:0006298', ('139', '142'))	('ATM', 'Gene', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('ARID1A', 'Gene', '8289', (52, 58))	('mutations', 'Var', (8, 17))	('ARID1A', 'Gene', (52, 58))	('ATM', 'Gene', '472', (60, 63))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('MTOR', 'Gene', (69, 73))
85807	28974240	Apart from inherited cancer syndromes, MSH2 mutations and loss of function were also observed in some sporadic cancers.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('MSH2', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('sporadic cancers', 'Disease', (102, 118))	('sporadic cancers', 'Disease', 'MESH:D009369', (102, 118))	('loss of function', 'NegReg', (58, 74))	('observed', 'Reg', (85, 93))	('mutations', 'Var', (44, 53))	('inherited cancer syndromes', 'Disease', 'MESH:D009386', (11, 37))	('inherited cancer syndromes', 'Disease', (11, 37))
85809	28974240	However, the MSH2 mutation in sporadic cancers occurred only in a somatic tissue and more likely occurred after the initial driver mutations.	('MSH2', 'Gene', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('sporadic cancers', 'Disease', 'MESH:D009369', (30, 46))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('sporadic cancers', 'Disease', (30, 46))	('mutation', 'Var', (18, 26))
85810	28974240	Taking sporadic colon cancer as an example, APC is the most common initial gene mutated in inherited and sporadic colon cancer; patients had MLH1 and MSH2 mutations later and their cancers were microsatellite instable, while other patients did not have mutations in MMR genes and their cancers were MSS.	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('colon cancer', 'Disease', 'MESH:D015179', (114, 126))	('MLH1', 'Gene', (141, 145))	('APC', 'cellular_component', 'GO:0005680', ('44', '47'))	('colon cancer', 'Phenotype', 'HP:0003003', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('MSH2', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('MMR', 'biological_process', 'GO:0006298', ('266', '269'))	('MLH1', 'Gene', '4292', (141, 145))	('cancers', 'Phenotype', 'HP:0002664', (286, 293))	('colon cancer', 'Disease', 'MESH:D015179', (16, 28))	('APC', 'Disease', 'MESH:D011125', (44, 47))	('cancers', 'Disease', (286, 293))	('APC', 'Disease', (44, 47))	('colon cancer', 'Disease', (114, 126))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancers', 'Disease', (181, 188))	('patients', 'Species', '9606', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('mutations', 'Var', (155, 164))	('patients', 'Species', '9606', (231, 239))	('colon cancer', 'Disease', (16, 28))	('colon cancer', 'Phenotype', 'HP:0003003', (114, 126))	('cancers', 'Disease', 'MESH:D009369', (286, 293))
85815	28974240	MSH2 germline variants were the genetic cause of inherited cancer syndrome, while somatic mutations might be merely passenger genes relative to the other driver genes in most cases.	('cause', 'Reg', (40, 45))	('MSH2', 'Gene', (0, 4))	('variants', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('inherited cancer syndrome', 'Disease', 'MESH:D009386', (49, 74))	('inherited cancer syndrome', 'Disease', (49, 74))
85816	28974240	Therefore, truncating mutations of MSH2 were more likely to cause inherited cancer syndrome.	('inherited cancer syndrome', 'Disease', (66, 91))	('cause', 'Reg', (60, 65))	('truncating mutations', 'Var', (11, 31))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('MSH2', 'Gene', (35, 39))	('inherited cancer syndrome', 'Disease', 'MESH:D009386', (66, 91))
85818	28974240	After that, we preformed genome-wide sequencing on the cancer tissues of the patient, and we revealed a novel pathologic mutation on MSH2 associating with Lynch syndrome.	('MSH2', 'Gene', (133, 137))	('associating', 'Reg', (138, 149))	('Lynch syndrome', 'Disease', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Lynch syndrome', 'Disease', 'MESH:D003123', (155, 169))	('mutation', 'Var', (121, 129))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('patient', 'Species', '9606', (77, 84))	('cancer', 'Disease', (55, 61))
85819	28974240	Moreover, integrative analysis demonstrated that truncating mutations of MMR genes were significantly enriched in the patient.	('truncating mutations', 'Var', (49, 69))	('patient', 'Species', '9606', (118, 125))	('MMR', 'biological_process', 'GO:0006298', ('73', '76'))	('MMR genes', 'Gene', (73, 82))
85824	28974240	This promoted us to investigate whether MSH2 mutation alone was strong enough to induce the occurrence of Lynch syndrome-related cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('mutation', 'Var', (45, 53))	('Lynch syndrome', 'Disease', (106, 120))	('induce', 'Reg', (81, 87))	('Lynch syndrome', 'Disease', 'MESH:D003123', (106, 120))	('MSH2', 'Gene', (40, 44))
85832	28974240	Bioinformatics analysis suggested that a typical tumor has two to eight "drive gene" mutations, which manifest selective growth advantage, while others are passenger mutations.	('growth advantage', 'CPA', (121, 137))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('mutations', 'Var', (85, 94))
85838	28974240	We showed that mutations within the entire length of the coding sequence of MSH2 were positively correlated with Lynch syndrome, which suggested that the mutation of MSH in our study is a novel pathogenic factor.	('correlated', 'Reg', (97, 107))	('mutations', 'Var', (15, 24))	('mutation', 'Var', (154, 162))	('MSH', 'Gene', (76, 79))	('MSH', 'Gene', (166, 169))	('MSH', 'Gene', '4488', (76, 79))	('MSH', 'Gene', '4488', (166, 169))	('Lynch syndrome', 'Disease', (113, 127))	('Lynch syndrome', 'Disease', 'MESH:D003123', (113, 127))
85840	28974240	We found that truncating mutations were more likely to be causal in hereditary Lynch syndrome than missense mutations.	('hereditary Lynch syndrome', 'Disease', (68, 93))	('truncating mutations', 'Var', (14, 34))	('hereditary Lynch syndrome', 'Disease', 'MESH:D003123', (68, 93))	('causal', 'Reg', (58, 64))
85847	28974240	These results suggested that double hits of DNA MMR genes might be a common event in the development of other malignancies in Lynch syndrome patients.	('Lynch syndrome', 'Disease', 'MESH:D003123', (126, 140))	('double hits', 'Var', (29, 40))	('malignancies', 'Disease', 'MESH:D009369', (110, 122))	('event', 'Reg', (76, 81))	('DNA MMR', 'Gene', (44, 51))	('malignancies', 'Disease', (110, 122))	('Lynch syndrome', 'Disease', (126, 140))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('patients', 'Species', '9606', (141, 149))	('MMR', 'biological_process', 'GO:0006298', ('48', '51'))
85848	28974240	Even more interesting is that some SMGs of sporadic tumors also had high-frequency mutations in Lynch syndrome-related cancers.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (83, 92))	('sporadic tumors', 'Disease', 'MESH:D009369', (43, 58))	('Lynch syndrome', 'Disease', 'MESH:D003123', (96, 110))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('sporadic tumors', 'Disease', (43, 58))	('cancers', 'Disease', (119, 126))	('SMG', 'Gene', (35, 38))	('SMG', 'Gene', '23034', (35, 38))	('Lynch syndrome', 'Disease', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
85849	28974240	Higher alternative allele frequency indicates that SMG mutations were not a random event, and they might occur earlier than other passenger mutations.	('SMG', 'Gene', '23034', (51, 54))	('SMG', 'Gene', (51, 54))	('mutations', 'Var', (55, 64))
85851	28974240	Based on these data, we proposed a mutation progress model of MPC in Lynch syndrome, which include germline mutations of MMR genes, double hits of MMR system, mutations in tissue-specific driver genes, and rapid accumulation of additional passenger mutations.	('Lynch syndrome', 'Disease', (69, 83))	('mutations', 'Var', (108, 117))	('mutations', 'Var', (159, 168))	('Lynch syndrome', 'Disease', 'MESH:D003123', (69, 83))	('MMR', 'biological_process', 'GO:0006298', ('121', '124'))	('MMR genes', 'Gene', (121, 130))	('MMR', 'biological_process', 'GO:0006298', ('147', '150'))
85886	24704988	Patients with uretheral stricture, bladder stones, a previous history of baldder surgery, any psychiatric diseases, uncontrolled urinary tract infections, small bladder capacity (volume <100 mL), uncontrolled urinary tuberculosis, coagulopathy (such as hemophilia), and cardiovascular disease were excluded, and patients who could not tolerate the cystoscopy or CT scan or MRI were also excluded.	('urinary tract infections', 'Disease', (129, 153))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (270, 292))	('hemophilia', 'Disease', (253, 263))	('psychiatric diseases', 'Disease', 'MESH:D001523', (94, 114))	('urinary tract infections', 'Phenotype', 'HP:0000010', (129, 153))	('cardiovascular disease', 'Disease', 'MESH:D002318', (270, 292))	('hemophilia', 'Disease', 'MESH:D006467', (253, 263))	('small', 'Var', (155, 160))	('Patients', 'Species', '9606', (0, 8))	('uretheral stricture', 'Disease', (14, 33))	('cardiovascular disease', 'Disease', (270, 292))	('psychiatric diseases', 'Disease', (94, 114))	('tuberculosis', 'Disease', 'MESH:D014376', (217, 229))	('coagulopathy', 'Phenotype', 'HP:0003256', (231, 243))	('patients', 'Species', '9606', (312, 320))	('tuberculosis', 'Disease', (217, 229))	('urinary tract infections', 'Disease', 'MESH:D014552', (129, 153))	('small bladder', 'Phenotype', 'HP:0005343', (155, 168))	('bladder stones', 'Disease', (35, 49))	('bladder stones', 'Phenotype', 'HP:0010474', (35, 49))	('coagulopathy', 'Disease', 'MESH:D001778', (231, 243))	('coagulopathy', 'Disease', (231, 243))	('psychiatric diseases', 'Phenotype', 'HP:0000708', (94, 114))	('bladder stones', 'Disease', 'MESH:D001744', (35, 49))
86019	32349330	These results are in line with the tumorcidial function of CD8+ T in immune cells, which can be mitigated by the immune escape mechanism.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('CD8+ T', 'Var', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('CD8', 'Species', '1151253', (59, 62))
86030	32349330	However, PD-L1 expression of ICs was higher in pT2-pT4 than in pTa-pT1 (p = 0.001).	('pT1', 'Gene', '58492', (67, 70))	('higher', 'PosReg', (37, 43))	('PD-L1', 'Gene', '29126', (9, 14))	('expression', 'MPA', (15, 25))	('pTa', 'molecular_function', 'GO:0008959', ('63', '66'))	('ICs', 'Gene', (29, 32))	('pT1', 'Gene', (67, 70))	('pT2-pT4', 'Var', (47, 54))	('PD-L1', 'Gene', (9, 14))
86041	32349330	In pT2-pT4 cases (n = 69), we found that expression of HER2 or IDO in TCs was associated with a shorter DFS in both univariate Cox regression analysis (p = 0.028 and p = 0.048, respectively) (Table 3) and Kaplan-Meier survival curves (p = 0.022 and p = 0.040, respectively) (Figure 3).	('TCs', 'Chemical', '-', (70, 73))	('shorter', 'NegReg', (96, 103))	('IDO', 'molecular_function', 'GO:0033754', ('63', '66'))	('DFS', 'MPA', (104, 107))	('expression', 'Var', (41, 51))	('HER2', 'Gene', (55, 59))	('IDO', 'Gene', (63, 66))	('IDO', 'molecular_function', 'GO:0047719', ('63', '66'))	('HER2', 'Gene', '2064', (55, 59))
86043	32349330	The PD-L1 expression in TCs or ICs showed no correlation with survival outcome (Table 3 and Figure 3), even though the PD-L1 expression of ICs was higher in pT2-pT4 than in pTa-pT1 (p = 0.001).	('pT1', 'Gene', '58492', (177, 180))	('PD-L1', 'Gene', (119, 124))	('TCs', 'Chemical', '-', (24, 27))	('expression', 'MPA', (125, 135))	('PD-L1', 'Gene', (4, 9))	('pT1', 'Gene', (177, 180))	('higher', 'PosReg', (147, 153))	('pTa', 'molecular_function', 'GO:0008959', ('173', '176'))	('PD-L1', 'Gene', '29126', (119, 124))	('pT2-pT4', 'Var', (157, 164))	('PD-L1', 'Gene', '29126', (4, 9))
86048	32349330	We demonstrated that PD-L1 expression in ICs was significantly higher in pT2-pT4 than in pTa-pT1.	('pT2-pT4', 'Var', (73, 80))	('expression', 'MPA', (27, 37))	('pT1', 'Gene', (93, 96))	('PD-L1', 'Gene', (21, 26))	('pTa', 'molecular_function', 'GO:0008959', ('89', '92'))	('higher', 'PosReg', (63, 69))	('pT1', 'Gene', '58492', (93, 96))	('PD-L1', 'Gene', '29126', (21, 26))
86059	32349330	In the final escape phase, the expression of IDO in cancer cells inhibits the host immune protection.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('inhibits', 'NegReg', (65, 73))	('IDO', 'molecular_function', 'GO:0033754', ('45', '48'))	('host immune protection', 'CPA', (78, 100))	('IDO', 'molecular_function', 'GO:0047719', ('45', '48'))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('IDO', 'Gene', (45, 48))	('expression', 'Var', (31, 41))
86066	32349330	One study of high-grade UCB (pT2-pT4) ranked the HER2 gene amplification as the third most significant in terms of associated genetic mutations.	('HER2', 'Gene', (49, 53))	('UCB', 'Phenotype', 'HP:0006740', (24, 27))	('amplification', 'Var', (59, 72))	('HER2', 'Gene', '2064', (49, 53))
86077	32349330	HER2 expression has recently been found to suppress antiviral defenses and antitumor immunity as a result of HER2 signaling through its intracellular domain, which interferes with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and prevents cancer cell death.	('intracellular', 'cellular_component', 'GO:0005622', ('136', '149'))	('suppress', 'NegReg', (43, 51))	('HER2', 'Gene', '2064', (0, 4))	('signaling', 'MPA', (114, 123))	('cell death', 'biological_process', 'GO:0008219', ('276', '286'))	('interferes', 'NegReg', (164, 174))	('expression', 'Var', (5, 15))	('prevents', 'NegReg', (260, 268))	('HER2', 'Gene', '2064', (109, 113))	('cancer', 'Disease', (269, 275))	('tumor', 'Disease', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('antiviral defenses', 'CPA', (52, 70))	('cyclic', 'MPA', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (269, 275))	('HER2', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('HER2', 'Gene', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
86087	32349330	Recently, phase II and preliminary phase III studies have shown that the application of a PD-L1 inhibitor in metastatic platinum-refractory NSCLC and urothelial cancer resulted in a significant improvement in the response rate and median overall survival.	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('urothelial cancer', 'Disease', (150, 167))	('overall survival', 'CPA', (238, 254))	('inhibitor', 'Var', (96, 105))	('PD-L1', 'Gene', '29126', (90, 95))	('urothelial cancer', 'Disease', 'MESH:D014523', (150, 167))	('improvement', 'PosReg', (194, 205))	('response', 'MPA', (213, 221))	('platinum', 'Chemical', 'MESH:D010984', (120, 128))	('NSCLC', 'Disease', (140, 145))	('PD-L1', 'Gene', (90, 95))
86129	30254145	Genomic characterization of six virus-associated cancers identifies changes in the tumor immune microenvironment and altered genetic programs Viruses affect approximately 20% of all human cancers and induce expression of immunogenic viral oncoproteins that make these tumors potent targets for immune checkpoint inhibitors.	('Viruses', 'Var', (142, 149))	('tumor', 'Disease', (83, 88))	('induce', 'Reg', (200, 206))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancers', 'Disease', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('expression', 'MPA', (207, 217))	('oncoproteins', 'Protein', (239, 251))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('human', 'Species', '9606', (182, 187))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('changes', 'Reg', (68, 75))	('cancers', 'Disease', (188, 195))	('tumors', 'Disease', (268, 274))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Disease', (268, 273))	('tumors', 'Disease', 'MESH:D009369', (268, 274))	('affect', 'Reg', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
86131	30254145	Across cancers, the cellular composition of the microenvironment varied by viral status, with virus-positive tumors often exhibiting increased infiltration of cytolytic cell types compared to their virus-negative counterparts.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('infiltration', 'MPA', (143, 155))	('virus-positive', 'Var', (94, 108))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('cancers', 'Disease', (7, 14))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('increased', 'PosReg', (133, 142))	('tumors', 'Disease', (109, 115))
86138	30254145	Tumor mutation burden has been identified as one such biomarker, with tumors exhibiting high mutation loads more likely to express immunogenic neoantigens that are recognized as non-self by the adaptive immune system.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mutation loads', 'Var', (93, 107))	('express immunogenic neoantigens', 'MPA', (123, 154))
86139	30254145	This association has been supported across tumor types, with high-mutation tumors yielding higher response rates than those tumors with lower mutation rates and also within tumor types, with responsive patients exhibiting significantly higher mutation burdens.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('high-mutation', 'Var', (61, 74))	('tumor', 'Disease', (124, 129))	('response', 'MPA', (98, 106))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('patients', 'Species', '9606', (202, 210))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('higher', 'PosReg', (91, 97))	('tumors', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('tumor', 'Disease', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (124, 130))
86166	30254145	Additional gene expression data and the associated virus infection and survival information were obtained from the gene expression omnibus (GEO) under accession numbers GSE40774, GSE6791, GSE55550, GSE39366, GSE65858, GSE49288, GSE62232, GSE44001, as well as from PRECOG (https://precog.stanford.edu/precog_data.php; Supplementary Table S2).	('GSE55550', 'Var', (188, 196))	('virus infection', 'Disease', 'MESH:D014412', (51, 66))	('gene expression', 'biological_process', 'GO:0010467', ('115', '130'))	('gene expression', 'biological_process', 'GO:0010467', ('11', '26'))	('GSE39366', 'Var', (198, 206))	('GSE40774', 'Var', (169, 177))	('virus infection', 'Disease', (51, 66))
86198	30254145	In most contexts, we found that mutation load was not associated with virus infection.	('virus infection', 'Disease', (70, 85))	('mutation', 'Var', (32, 40))	('virus infection', 'Disease', 'MESH:D014412', (70, 85))
86217	30254145	However, in STES, samples infected with EBV exhibited significantly lower levels of TCR diversity, indicating an antigen-driven T cell response (P = 1e-3).	('TCR', 'Gene', '6962', (84, 87))	('lower', 'NegReg', (68, 73))	('TCR', 'Gene', (84, 87))	('TCR', 'cellular_component', 'GO:0042101', ('84', '87'))	('EBV', 'Var', (40, 43))	('P = 1e-3', 'Gene', (145, 153))	('TCR', 'biological_process', 'GO:0006283', ('84', '87'))	('P = 1e-3', 'Gene', '1423;8273', (145, 153))
86221	30254145	These results indicated that the presence of EBV proteins may elicit a clonal T cell response in different tumor types.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('presence', 'Var', (33, 41))	('elicit', 'Reg', (62, 68))	('EBV proteins', 'Protein', (45, 57))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
86254	30254145	In HNSC, we found that signature-high patients exhibited significantly prolonged survival times (Figure 5A; P = 3e-3) and significantly higher ESTIMATE immune scores (Figure 5B; P = 4e-3) compared to the signature-low group.	('higher', 'PosReg', (136, 142))	('ESTIMATE immune scores', 'CPA', (143, 165))	('P = 3e-3', 'Gene', '8273', (108, 116))	('patients', 'Species', '9606', (38, 46))	('HNSC', 'Phenotype', 'HP:0012288', (3, 7))	('prolonged', 'PosReg', (71, 80))	('survival times', 'CPA', (81, 95))	('signature-high', 'Var', (23, 37))	('P = 3e-3', 'Gene', (108, 116))
86270	30254145	Several studies have characterized the immunogenic nature of these viral proteins, and our results indicate that the presence of these antigens in the tumor microenvironment can elicit a strong immune response.	('immune response', 'CPA', (194, 209))	('presence', 'Var', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('elicit', 'Reg', (178, 184))	('tumor', 'Disease', (151, 156))	('immune response', 'biological_process', 'GO:0006955', ('194', '209'))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
86290	30254145	Survival analyses using these signatures supported this finding, with virus-high HNSC patients exhibiting a prolonged prognosis and high levels of immune infiltration while virus-high BLCA patients exhibiting shorter survival and higher cell proliferation rates, despite also having a higher immune infiltration level.	('HNSC', 'Phenotype', 'HP:0012288', (81, 85))	('immune infiltration level', 'MPA', (292, 317))	('cell proliferation', 'biological_process', 'GO:0008283', ('237', '255'))	('BLCA', 'Disease', 'MESH:D001749', (184, 188))	('patients', 'Species', '9606', (189, 197))	('virus-high', 'Var', (70, 80))	('BLCA', 'Disease', (184, 188))	('patients', 'Species', '9606', (86, 94))
86304	28516157	Pooled analyses of studies reported survival data revealed an improved overall survival for patients treated with metastasectomy compared with non-surgical treatment of metastatic lesions (HR 0.63; 95% CI, 0.49-0.81).	('improved', 'PosReg', (62, 70))	('metastasectomy', 'Var', (114, 128))	('overall survival', 'MPA', (71, 87))	('patients', 'Species', '9606', (92, 100))
86337	28516157	Two studies reported that solitary metastases were independently associated with better prognosis with 5-year OS ranging from 83.3% (HR not reported) to 85.7% (HR not reported, p = 0.009).	('metastases', 'Disease', (35, 45))	('metastases', 'Disease', 'MESH:D009362', (35, 45))	('OS', 'Chemical', '-', (110, 112))	('solitary', 'Var', (26, 34))
86338	28516157	Another study showed a much longer PFS (68 months vs. 7 months, p < 0.001) in the group with solitary metastasis when compared to those patients with multiple metastatic pulmonary lesions.	('pulmonary lesions', 'Disease', 'MESH:D008171', (170, 187))	('pulmonary lesions', 'Disease', (170, 187))	('PFS', 'MPA', (35, 38))	('solitary metastasis', 'Var', (93, 112))	('patients', 'Species', '9606', (136, 144))
86339	28516157	Furthermore, one study also showed that solitary metastases <3 cm (HR 4.72, p = 0.006) were associated with improved outcomes compared with patients with larger metastases.	('solitary', 'Var', (40, 48))	('metastases', 'Disease', 'MESH:D009362', (49, 59))	('improved', 'PosReg', (108, 116))	('outcomes', 'MPA', (117, 125))	('patients', 'Species', '9606', (140, 148))	('metastases', 'Disease', 'MESH:D009362', (161, 171))	('metastases', 'Disease', (161, 171))	('metastases', 'Disease', (49, 59))
86424	22325372	The immunohistochemical staining reveals CK7(+), CK20(+), CA125(+) and EMA(+), while PR(-), ER(-), CD10(-) and HMB(-).	('CK7', 'Gene', '3855', (41, 44))	('CD10', 'molecular_function', 'GO:0004245', ('99', '103'))	('CK20', 'Gene', '54474', (49, 53))	('CK20', 'Gene', (49, 53))	('CK7', 'Gene', (41, 44))	('CA125(+', 'Var', (58, 65))	('CD10', 'Gene', (99, 103))	('CD10', 'Gene', '4311', (99, 103))
86484	32117762	PARP Inhibitors in Prostate and Urothelial Cancers Poly(ADP-ribose) polymerase (PARP) inhibitors targeting DNA repair gene mutations have shown significant clinical benefit in patients with ovarian and breast cancers.	('DNA repair', 'Gene', (107, 117))	('Poly(ADP-ribose) polymerase', 'Gene', (51, 78))	('DNA repair', 'biological_process', 'GO:0006281', ('107', '117'))	('breast cancers', 'Disease', 'MESH:D001943', (202, 216))	('breast cancers', 'Disease', (202, 216))	('ovarian', 'Disease', 'MESH:D010049', (190, 197))	('breast cancers', 'Phenotype', 'HP:0003002', (202, 216))	('Prostate and Urothelial Cancers', 'Disease', 'MESH:D011471', (19, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('PARP', 'Gene', '142', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('patients', 'Species', '9606', (176, 184))	('benefit', 'PosReg', (165, 172))	('Poly(ADP-ribose) polymerase', 'Gene', '142', (51, 78))	('PARP', 'Gene', (0, 4))	('PARP', 'Gene', '142', (80, 84))	('Cancers', 'Phenotype', 'HP:0002664', (43, 50))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('ovarian', 'Disease', (190, 197))	('PARP', 'Gene', (80, 84))	('mutations', 'Var', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
86485	32117762	In metastatic prostate cancers, the prevalence of DNA repair gene mutations is up to 20%, and early phase studies have shown clinical activity of PARP inhibitors.	('mutations', 'Var', (66, 75))	('DNA repair gene', 'Gene', (50, 65))	('PARP', 'Gene', '142', (146, 150))	('prostate cancers', 'Disease', 'MESH:D011471', (14, 30))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('DNA repair', 'biological_process', 'GO:0006281', ('50', '60'))	('prostate cancer', 'Phenotype', 'HP:0012125', (14, 29))	('PARP', 'Gene', (146, 150))	('prostate cancers', 'Phenotype', 'HP:0012125', (14, 30))	('prostate cancers', 'Disease', (14, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
86491	32117762	Multiple PARP inhibitors for the treatment of ovarian and breast cancers that harbor pathogenic BRCA mutations have been developed.	('men', 'Species', '9606', (38, 41))	('BRCA', 'Gene', '672', (96, 100))	('mutations', 'Var', (101, 110))	('breast cancers', 'Phenotype', 'HP:0003002', (58, 72))	('breast cancers', 'Disease', 'MESH:D001943', (58, 72))	('BRCA', 'Gene', (96, 100))	('breast cancers', 'Disease', (58, 72))	('PARP', 'Gene', '142', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('ovarian', 'Disease', 'MESH:D010049', (46, 53))	('ovarian', 'Disease', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('PARP', 'Gene', (9, 13))
86498	32117762	Thus, this makes the loss of a gene essential for HRR to result in synthetic lethality from PARP inhibition, in which two pathway defects that alone are non-toxic but when combined become lethal.	('loss', 'Var', (21, 25))	('PARP', 'Gene', (92, 96))	('inhibition', 'NegReg', (97, 107))	('result in', 'Reg', (57, 66))	('PARP', 'Gene', '142', (92, 96))	('HRR', 'biological_process', 'GO:0000724', ('50', '53'))	('synthetic lethality', 'MPA', (67, 86))
86500	32117762	The prevalence of mutations in the DNA repair genes involved in HRR in men with prostate cancer irrespective of age or family history is around 11-23%, with most common mutations noted in BRCA2.	('BRCA2', 'Gene', '675', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('prostate cancer', 'Disease', 'MESH:D011471', (80, 95))	('DNA repair', 'biological_process', 'GO:0006281', ('35', '45'))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('men', 'Species', '9606', (71, 74))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('HRR', 'biological_process', 'GO:0000724', ('64', '67'))	('BRCA2', 'Gene', (188, 193))	('prostate cancer', 'Disease', (80, 95))	('mutations', 'Var', (18, 27))
86502	32117762	These mutations are more prevalent in metastatic cancer than localized disease.	('prevalent', 'Reg', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))	('mutations', 'Var', (6, 15))
86503	32117762	Additionally, these mutations have been noted in high frequency with intraductal adenocarcinoma histology, lower PSA levels at diagnosis, and tumors with lymphovascular invasion.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('lymphovascular invasion', 'Disease', (154, 177))	('lymphovascular invasion', 'Disease', 'MESH:D009361', (154, 177))	('lower PSA levels', 'MPA', (107, 123))	('tumors', 'Disease', (142, 148))	('intraductal adenocarcinoma', 'Disease', (69, 95))	('noted', 'Reg', (40, 45))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('intraductal adenocarcinoma', 'Disease', 'MESH:D002285', (69, 95))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('mutations', 'Var', (20, 29))
86510	32117762	Interestingly, 100% of the patients (7/7) with BRCA2 mutation had a response.	('patients', 'Species', '9606', (27, 35))	('BRCA2', 'Gene', '675', (47, 52))	('mutation', 'Var', (53, 61))	('BRCA2', 'Gene', (47, 52))
86513	32117762	It is important to note that a predominant number of patients (94%, n = 31) who did not harbor these deleterious mutations had no response to olaparib.	('response', 'MPA', (130, 138))	('mutations', 'Var', (113, 122))	('olaparib', 'Chemical', 'MESH:C531550', (142, 150))	('patients', 'Species', '9606', (53, 61))
86515	32117762	In this landmark trial, patients with metastatic CRPC who received prior novel hormonal therapy and harbored alterations in HRR genes were randomized in a 2:1 fashion to receive either olaparib (300 mg BID) or physician's choice of novel anti-androgen agents such as enzalutamide or abiraterone.	('BID', 'Gene', (202, 205))	('metastatic CRPC', 'Disease', (38, 53))	('olaparib', 'Chemical', 'MESH:C531550', (185, 193))	('HRR', 'biological_process', 'GO:0000724', ('124', '127'))	('alterations', 'Var', (109, 120))	('BID', 'Gene', '637', (202, 205))	('HRR genes', 'Gene', (124, 133))	('patients', 'Species', '9606', (24, 32))	('enzalutamide', 'Chemical', 'MESH:C540278', (267, 279))	('abiraterone', 'Chemical', 'MESH:C089740', (283, 294))
86516	32117762	Patients were enrolled in cohort A (n = 245) if the tumors harbored BRCA1, BRCA2, or ATM mutations and cohort B (n = 142) with other DNA repair gene alterations.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('DNA repair', 'biological_process', 'GO:0006281', ('133', '143'))	('BRCA1', 'Gene', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('ATM', 'Gene', (85, 88))	('tumors', 'Disease', (52, 58))	('BRCA2', 'Gene', (75, 80))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (89, 98))	('ATM', 'Gene', '472', (85, 88))	('BRCA2', 'Gene', '675', (75, 80))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('BRCA1', 'Gene', '672', (68, 73))
86527	32117762	evaluated the efficacy of olaparib and abiraterone irrespective of HRR mutations in patients with metastatic CRPC.	('HRR', 'Gene', (67, 70))	('abiraterone', 'Chemical', 'MESH:C089740', (39, 50))	('olaparib', 'Chemical', 'MESH:C531550', (26, 34))	('patients', 'Species', '9606', (84, 92))	('mutations', 'Var', (71, 80))	('HRR', 'biological_process', 'GO:0000724', ('67', '70'))	('metastatic CRPC', 'Disease', (98, 113))
86542	32117762	Additional studies evaluating the safety and antitumor activity of olaparib in combination with radioligands such as radium 223 (COMRADE, NCT03317392) and 177Lu-PSMA (NCT03874884), cediranib (VEGFR inhibitor, NCT02893917) and AZD6738 (ATR inhibitor, NCT03787680) are ongoing (Table 2).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('ATR', 'Gene', '545', (235, 238))	('ATR', 'Gene', (235, 238))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('VEGFR', 'Gene', '3791', (192, 197))	('PSMA', 'Gene', (161, 165))	('tumor', 'Disease', (49, 54))	('PSMA', 'Gene', '2346', (161, 165))	('VEGFR', 'Gene', (192, 197))	('olaparib', 'Chemical', 'MESH:C531550', (67, 75))	('cediranib', 'Chemical', 'MESH:C500926', (181, 190))	('NCT03874884', 'Var', (167, 178))	('AZD6738', 'Chemical', 'MESH:C000611951', (226, 233))	('PSMA', 'molecular_function', 'GO:0043275', ('161', '165'))
86548	32117762	An objective response (defined as complete or partial response) of 47.5% (19/40) and a PSA response (>=50% decrease) rate of 53.6% (37/69) was seen in patients with BRCA 1/2 mutations.	('mutations', 'Var', (174, 183))	('BRCA 1/2', 'Gene', (165, 173))	('patients', 'Species', '9606', (151, 159))	('BRCA 1/2', 'Gene', '672;675', (165, 173))
86551	32117762	A randomized phase III clinical trial (TRITON3, NCT02975934) is currently comparing the efficacy of rucaparib to either novel hormonal therapy or docetaxel chemotherapy in meteastatic CRPC with HRR deficiency.	('meteastatic CRPC', 'Disease', (172, 188))	('docetaxel', 'Chemical', 'MESH:D000077143', (146, 155))	('HRR', 'Gene', (194, 197))	('HRR', 'biological_process', 'GO:0000724', ('194', '197'))	('deficiency', 'Var', (198, 208))	('rucaparib', 'Chemical', 'MESH:C531549', (100, 109))	('TRITON3', 'Chemical', '-', (39, 46))
86552	32117762	Another pilot study of 30 patients (TRIUMP, NCT03413995) is evaluating the role of upfront rucaparib as an alternative to androgen deprivation therapy in patients with metastatic castration sensitive prostate cancer who have germline HRR mutations.	('mutations', 'Var', (238, 247))	('sensitive prostate cancer', 'Disease', (190, 215))	('rucaparib', 'Chemical', 'MESH:C531549', (91, 100))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (26, 34))	('prostate cancer', 'Phenotype', 'HP:0012125', (200, 215))	('HRR', 'Gene', (234, 237))	('HRR', 'biological_process', 'GO:0000724', ('234', '237'))	('sensitive prostate cancer', 'Disease', 'MESH:D011471', (190, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
86558	32117762	This study is evaluating the safety and efficacy of niraparib 300 mg once daily in patients with metastatic CRPC who have HRR gene mutations and were previously treated with taxane-based chemotherapy and at least one androgen receptor antagonist.	('HRR gene', 'Gene', (122, 130))	('mutations', 'Var', (131, 140))	('HRR', 'biological_process', 'GO:0000724', ('122', '125'))	('androgen receptor', 'Gene', '367', (217, 234))	('metastatic CRPC', 'Disease', (97, 112))	('patients', 'Species', '9606', (83, 91))	('taxane', 'Chemical', 'MESH:C080625', (174, 180))	('niraparib', 'Chemical', 'MESH:C545685', (52, 61))	('androgen receptor', 'Gene', (217, 234))
86559	32117762	To date, of the 81 patients with biallelic HRR gene alterations, 46 have BRCA 1/2 and the rest have other HRR mutations (biallelic mutations in ATM, FANCA, PALB2, CHEK2, BRIP1, or HDAC2).	('ATM', 'Gene', '472', (144, 147))	('BRIP1', 'Gene', (170, 175))	('BRCA 1/2', 'Gene', '672;675', (73, 81))	('HRR', 'biological_process', 'GO:0000724', ('106', '109'))	('CHEK2', 'Gene', (163, 168))	('HDAC2', 'Gene', (180, 185))	('HDAC2', 'Gene', '3066', (180, 185))	('alterations', 'Var', (52, 63))	('CHEK2', 'Gene', '11200', (163, 168))	('ATM', 'Gene', (144, 147))	('HRR gene', 'Gene', (43, 51))	('FANCA', 'Gene', '2175', (149, 154))	('HRR', 'biological_process', 'GO:0000724', ('43', '46'))	('patients', 'Species', '9606', (19, 27))	('PALB2', 'Gene', (156, 161))	('BRIP1', 'Gene', '83990', (170, 175))	('BRCA 1/2', 'Gene', (73, 81))	('PALB2', 'Gene', '79728', (156, 161))	('FANCA', 'Gene', (149, 154))
86568	32117762	On exploratory biomarker analysis, response rates and radiologic PFS were better in both arms in patients with HRR gene mutations when compared to HRR wild type.	('better', 'PosReg', (74, 80))	('HRR gene', 'Gene', (111, 119))	('response rates', 'CPA', (35, 49))	('HRR', 'biological_process', 'GO:0000724', ('147', '150'))	('HRR', 'biological_process', 'GO:0000724', ('111', '114'))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (97, 105))
86575	32117762	One such mechanism is acquired BRCA2 reversion mutations, where previously BRCA-2-deficient tumor cells are able to achieve BRCA2 proficiency due to constant selection pressure of PARP inhibition.	('BRCA2', 'Gene', (31, 36))	('BRCA-2-deficient tumor', 'Disease', (75, 97))	('BRCA2', 'Gene', (124, 129))	('PARP', 'Gene', '142', (180, 184))	('mutations', 'Var', (47, 56))	('BRCA2', 'Gene', '675', (31, 36))	('BRCA-2-deficient tumor', 'Disease', 'OMIM:612555', (75, 97))	('BRCA2', 'Gene', '675', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('PARP', 'Gene', (180, 184))
86578	32117762	In a retrospective study of 23 patients with BRCA 1/2 and ATM mutations, none of the 6 patients with ATM mutations responded to olaparib.	('ATM', 'Gene', (101, 104))	('ATM', 'Gene', '472', (58, 61))	('BRCA 1/2', 'Gene', '672;675', (45, 53))	('olaparib', 'Chemical', 'MESH:C531550', (128, 136))	('ATM', 'Gene', '472', (101, 104))	('ATM', 'Gene', (58, 61))	('patients', 'Species', '9606', (31, 39))	('BRCA 1/2', 'Gene', (45, 53))	('patients', 'Species', '9606', (87, 95))	('mutations', 'Var', (62, 71))
86585	32117762	Additionally, for a subset of patients with fibroblast growth factor receptor (FGFR2/3) alterations, erdafitinib was also granted accelerated approval.	('FGFR2', 'Gene', (79, 84))	('FGFR2', 'Gene', '2263', (79, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('alterations', 'Var', (88, 99))	('patients', 'Species', '9606', (30, 38))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('44', '68'))	('erdafitinib', 'Chemical', 'MESH:C000604580', (101, 112))
86588	32117762	Additionally, the presence of DDR and repair gene mutations was associated with improved response to platinum-based chemotherapy in metastatic urothelial cancer.	('urothelial cancer', 'Disease', (143, 160))	('response to platinum', 'biological_process', 'GO:0070541', ('89', '109'))	('platinum', 'Chemical', 'MESH:D010984', (101, 109))	('mutations', 'Var', (50, 59))	('response to platinum-based chemotherapy', 'MPA', (89, 128))	('improved', 'PosReg', (80, 88))	('urothelial cancer', 'Disease', 'MESH:D014523', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
86591	32117762	This study enrolled patients with both HRR deficient and proficient tumors.	('deficient', 'Var', (43, 52))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('HRR', 'biological_process', 'GO:0000724', ('39', '42'))	('HRR', 'Gene', (39, 42))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
86592	32117762	Additional studies evaluating the efficacy of PARP inhibitors in a cohort of urothelial cancers that is selected for HRR deficiency are ongoing (Table 3).	('cohort of urothelial cancers', 'Disease', (67, 95))	('cohort of urothelial cancers', 'Disease', 'MESH:D014523', (67, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('PARP', 'Gene', '142', (46, 50))	('HRR', 'biological_process', 'GO:0000724', ('117', '120'))	('deficiency', 'Var', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PARP', 'Gene', (46, 50))
86593	32117762	In addition to enhancing sensitization to platinum chemotherapy, the presence of DNA repair gene aberrations is also associated with an increase in tumor mutation load and infiltration of lymphocytes in the tumor microenvironment.	('sensitization', 'MPA', (25, 38))	('presence', 'Var', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('DNA repair', 'biological_process', 'GO:0006281', ('81', '91'))	('DNA repair gene', 'Gene', (81, 96))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('aberrations', 'Var', (97, 108))	('sensitization', 'biological_process', 'GO:0046960', ('25', '38'))	('men', 'Species', '9606', (225, 228))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('increase', 'PosReg', (136, 144))	('tumor', 'Disease', (207, 212))	('enhancing', 'PosReg', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('platinum', 'Chemical', 'MESH:D010984', (42, 50))
86595	32117762	In a retrospective review of patients with urothelial cancer harboring known and unknown deleterious HRR gene mutations, monotherapy with PD1/PDL1 inhibitors showed higher response rates.	('patients', 'Species', '9606', (29, 37))	('urothelial cancer', 'Disease', (43, 60))	('mutations', 'Var', (110, 119))	('PD1', 'Gene', '5133', (138, 141))	('PD1', 'Gene', (138, 141))	('PDL1', 'Gene', '29126', (142, 146))	('urothelial cancer', 'Disease', 'MESH:D014523', (43, 60))	('higher', 'PosReg', (165, 171))	('HRR gene', 'Gene', (101, 109))	('HRR', 'biological_process', 'GO:0000724', ('101', '104'))	('PDL1', 'Gene', (142, 146))	('response', 'MPA', (172, 180))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
86604	32117762	Precise biomarkers that can accurately predict response to these agents is pivotal for the success of these agents as differential responses are noted in BRCA vs. non-BRCA mutations.	('mutations', 'Var', (172, 181))	('BRCA', 'Gene', '672', (154, 158))	('BRCA', 'Gene', (154, 158))	('BRCA', 'Gene', '672', (167, 171))	('BRCA', 'Gene', (167, 171))
86614	31578148	Using specific antibodies against PGK1 S203 and PDHK1 T338 phosphorylation, we performed immunohistochemistry with tissue microarray assay in additional 818 cancer cases with 619 paired normal tissues from five cancer types.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('PGK', 'molecular_function', 'GO:0004618', ('34', '37'))	('PDHK1', 'Gene', '5163', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (211, 217))	('S203', 'Var', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('phosphorylation', 'biological_process', 'GO:0016310', ('59', '74'))	('PDHK', 'molecular_function', 'GO:0004740', ('48', '52'))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('PGK1', 'Gene', (34, 38))	('PDHK1', 'Gene', (48, 53))	('PGK1', 'Gene', '5230', (34, 38))
86615	31578148	The PGK1 mRNA level was significantly elevated with hypomethylation in promotor regions and associated with advanced TNM stage in 15 and four cancer types, respectively.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('TNM', 'Gene', '10178', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('PGK', 'molecular_function', 'GO:0004618', ('4', '7'))	('mRNA level', 'MPA', (9, 19))	('N', 'Chemical', 'MESH:D009584', (11, 12))	('N', 'Chemical', 'MESH:D009584', (118, 119))	('hypomethylation', 'Var', (52, 67))	('elevated', 'PosReg', (38, 46))	('PGK1', 'Gene', '5230', (4, 8))	('associated', 'Reg', (92, 102))	('PGK1', 'Gene', (4, 8))	('TNM', 'Gene', (117, 120))	('cancer', 'Disease', (142, 148))
86617	31578148	Positively correlated PGK1 S203 and PDHK1 T338 phosphorylation levels were significantly associated with short overall survival (OS) in cancers of the breast, liver, lung, stomach, and esophagus and with advanced TNM stage in breast and esophageal cancers.	('short', 'NegReg', (105, 110))	('associated', 'Reg', (89, 99))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('PDHK', 'molecular_function', 'GO:0004740', ('36', '40'))	('PDHK1', 'Gene', (36, 41))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('cancers of the breast', 'Phenotype', 'HP:0100013', (136, 157))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('lung', 'Disease', (166, 170))	('cancers of the breast', 'Disease', (136, 157))	('S203', 'Var', (27, 31))	('PDHK1', 'Gene', '5163', (36, 41))	('cancers of the breast', 'Disease', 'MESH:D001943', (136, 157))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('PGK1', 'Gene', '5230', (22, 26))	('breast and esophageal cancers', 'Disease', 'MESH:D001943', (226, 255))	('TNM', 'Gene', '10178', (213, 216))	('PGK', 'molecular_function', 'GO:0004618', ('22', '25'))	('phosphorylation levels', 'MPA', (47, 69))	('TNM', 'Gene', (213, 216))	('PGK1', 'Gene', (22, 26))	('T338', 'Var', (42, 46))	('liver', 'Disease', (159, 164))	('esophagus', 'Disease', (185, 194))	('stomach', 'Disease', (172, 179))
86618	31578148	PGK1 pS203 and PDHK1 pT338 were also independent predictors of short OS in liver, lung, and stomach cancer.	('lung', 'Disease', (82, 86))	('pS203', 'Var', (5, 10))	('liver', 'Disease', (75, 80))	('short OS', 'Disease', (63, 71))	('stomach cancer', 'Disease', 'MESH:D013274', (92, 106))	('PDHK1', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PDHK', 'molecular_function', 'GO:0004740', ('15', '19'))	('PDHK1', 'Gene', '5163', (15, 20))	('stomach cancer', 'Phenotype', 'HP:0012126', (92, 106))	('PGK', 'molecular_function', 'GO:0004618', ('0', '3'))	('stomach cancer', 'Disease', (92, 106))	('PGK1', 'Gene', (0, 4))	('PGK1', 'Gene', '5230', (0, 4))
86628	31578148	In response to receptor tyrosine kinase activation, the expression of K-Ras G12V and B-Raf V600E, hypoxia, pyruvate metabolism in mitochondria is suppressed.	('G12V', 'Mutation', 'p.G12V', (76, 80))	('hypoxia', 'Disease', (98, 105))	('hypoxia', 'Disease', 'MESH:D000860', (98, 105))	('B-Raf V600E', 'Var', (85, 96))	('V600E', 'Mutation', 'p.V600E', (91, 96))	('pyruvate metabolism', 'biological_process', 'GO:0006090', ('107', '126'))	('mitochondria', 'cellular_component', 'GO:0005739', ('130', '142'))	('activation', 'PosReg', (40, 50))	('pyruvate', 'Chemical', 'MESH:D011773', (107, 115))	('pyruvate metabolism in mitochondria', 'MPA', (107, 142))	('V600E', 'Var', (91, 96))	('K-Ras G12V', 'Var', (70, 80))	('tyrosine', 'Chemical', 'None', (24, 32))	('suppressed', 'NegReg', (146, 156))
86632	31578148	In addition, PGK1 S203 and PDHK1 T338 phosphorylation levels were found to be positively correlated with each other, and both were correlated with PDH S293 inactivating phosphorylation levels and poor prognosis in patients with glioblastoma (GBM).	('correlated', 'Interaction', (89, 99))	('correlated', 'Reg', (131, 141))	('glioblastoma', 'Disease', 'MESH:D005909', (228, 240))	('PDHK1', 'Gene', '5163', (27, 32))	('patients', 'Species', '9606', (214, 222))	('PDH', 'Gene', '54704', (27, 30))	('PDH', 'Gene', '54704', (147, 150))	('PDH', 'molecular_function', 'GO:0004246', ('147', '150'))	('GBM', 'Phenotype', 'HP:0012174', (242, 245))	('PDHK1', 'Gene', (27, 32))	('glioblastoma', 'Disease', (228, 240))	('glioblastoma', 'Phenotype', 'HP:0012174', (228, 240))	('PDH', 'molecular_function', 'GO:0033718', ('147', '150'))	('PGK', 'molecular_function', 'GO:0004618', ('13', '16'))	('PGK1', 'Gene', '5230', (13, 17))	('inactivating', 'NegReg', (156, 168))	('PDH', 'molecular_function', 'GO:0004739', ('147', '150'))	('PDH', 'Gene', (27, 30))	('PDH', 'Gene', (147, 150))	('phosphorylation', 'biological_process', 'GO:0016310', ('169', '184'))	('PGK1', 'Gene', (13, 17))	('S203', 'Var', (18, 22))	('PDHK', 'molecular_function', 'GO:0004740', ('27', '31'))	('GBM', 'Disease', (242, 245))	('phosphorylation levels', 'MPA', (38, 60))	('GBM', 'Disease', 'MESH:D005909', (242, 245))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))
86635	31578148	We also analyzed the clinical relevance of PGK1 S203 and PDHK1 T338 phosphorylation levels by conducting immunohistochemical experiments in an additional 818 independent cancer cases (including 619 with paired normal tissues).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('PGK', 'molecular_function', 'GO:0004618', ('43', '46'))	('cancer', 'Disease', (170, 176))	('PGK1', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('PDHK1', 'Gene', (57, 62))	('PGK1', 'Gene', '5230', (43, 47))	('PDHK', 'molecular_function', 'GO:0004740', ('57', '61'))	('phosphorylation', 'biological_process', 'GO:0016310', ('68', '83'))	('PDHK1', 'Gene', '5163', (57, 62))	('clinical', 'Species', '191496', (21, 29))	('S203', 'Var', (48, 52))
86646	31578148	Rabbit polyclonal antibodies recognizing phospho-PGK1 S203 and phospho-PDHK1 T338 were obtained from Signalway Antibody (College Park, MD, USA).	('PGK1', 'Gene', '5230', (49, 53))	('PDHK', 'molecular_function', 'GO:0004740', ('71', '75'))	('S203', 'Var', (54, 58))	('PDHK1', 'Gene', (71, 76))	('PDHK1', 'Gene', '5163', (71, 76))	('PGK', 'molecular_function', 'GO:0004618', ('49', '52'))	('PGK1', 'Gene', (49, 53))	('Rabbit', 'Species', '9986', (0, 6))
86674	31578148	DNA methylation regulates gene expression and is implicated in tumor progression and therapeutic response.	('tumor', 'Disease', (63, 68))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('regulates', 'Reg', (16, 25))	('gene expression', 'MPA', (26, 41))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('methylation', 'Var', (4, 15))	('gene expression', 'biological_process', 'GO:0010467', ('26', '41'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('implicated', 'Reg', (49, 59))
86682	31578148	3b; Additional file 1: Table S4), suggesting promoter hypomethylation as a mechanism promoting PGK1 expression.	('PGK', 'molecular_function', 'GO:0004618', ('95', '98'))	('promoter hypomethylation', 'Var', (45, 69))	('expression', 'MPA', (100, 110))	('PGK1', 'Gene', (95, 99))	('PGK1', 'Gene', '5230', (95, 99))	('promoting', 'PosReg', (85, 94))
86684	31578148	We next analyzed the association between PGK1 promoter hypomethylation and the survival of patients with STAD, BLCA, ESCA, LIHC, and BRCA, and found that only in BRCA, hypomethylation of cg13203541 was associated with short OS (HR = 0.551, 95% CI 0.361-0.841, P = 0.005; Additional file 1: Table S5; Fig.	('BRCA', 'Phenotype', 'HP:0003002', (162, 166))	('BRCA', 'Disease', (133, 137))	('ESCA', 'Phenotype', 'HP:0011459', (117, 121))	('BLCA', 'Disease', 'MESH:D001749', (111, 115))	('LIHC', 'Disease', 'MESH:D006528', (123, 127))	('BRCA', 'Disease', 'MESH:D001943', (133, 137))	('PGK1', 'Gene', (41, 45))	('STAD', 'Disease', (105, 109))	('cg13203541', 'Var', (187, 197))	('patients', 'Species', '9606', (91, 99))	('BRCA', 'Disease', (162, 166))	('short OS', 'Disease', (218, 226))	('PGK', 'molecular_function', 'GO:0004618', ('41', '44'))	('BRCA', 'Disease', 'MESH:D001943', (162, 166))	('hypomethylation', 'Var', (168, 183))	('ESCA', 'Disease', (117, 121))	('BRCA', 'Phenotype', 'HP:0003002', (133, 137))	('STAD', 'Disease', 'MESH:D013274', (105, 109))	('ESCA', 'Disease', 'MESH:D004938', (117, 121))	('associated', 'Reg', (202, 212))	('LIHC', 'Disease', (123, 127))	('BLCA', 'Disease', (111, 115))	('PGK1', 'Gene', '5230', (41, 45))
86685	31578148	A multivariate Cox regression model showed that cg13203541 methylation was an independent predictor of prolonged OS in BRCA (HR = 0.599, 95% CI 0.382-0.939, P = 0.026; Additional file 1: Table S5).	('BRCA', 'Disease', (119, 123))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('BRCA', 'Phenotype', 'HP:0003002', (119, 123))	('BRCA', 'Disease', 'MESH:D001943', (119, 123))	('cg13203541 methylation', 'Var', (48, 70))
86693	31578148	Kaplan-Meier analysis showed that higher levels of both PGK1 pS203 and PDHK1 pT338 were associated with shorter OS in patients with these five cancer types (all P < 0.05) (Fig.	('shorter OS', 'Disease', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('PDHK', 'molecular_function', 'GO:0004740', ('71', '75'))	('PGK1', 'Gene', '5230', (56, 60))	('PGK1', 'Gene', (56, 60))	('higher', 'PosReg', (34, 40))	('pS203', 'Var', (61, 66))	('PDHK1', 'Gene', (71, 76))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('PDHK1', 'Gene', '5163', (71, 76))	('PGK', 'molecular_function', 'GO:0004618', ('56', '59'))	('patients', 'Species', '9606', (118, 126))
86694	31578148	An independent variable t test showed that both PGK1 pS203 and PDHK1 pT338 were associated with advanced TNM stage in patients with BRCA and ESCA (all P < 0.05) (Table 1).	('PGK1', 'Gene', (48, 52))	('TNM', 'Gene', (105, 108))	('PDHK', 'molecular_function', 'GO:0004740', ('63', '67'))	('PGK1', 'Gene', '5230', (48, 52))	('BRCA', 'Disease', 'MESH:D001943', (132, 136))	('pS203', 'Var', (53, 58))	('PDHK1', 'Gene', '5163', (63, 68))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('patients', 'Species', '9606', (118, 126))	('ESCA', 'Phenotype', 'HP:0011459', (141, 145))	('associated', 'Reg', (80, 90))	('ESCA', 'Disease', (141, 145))	('TNM', 'Gene', '10178', (105, 108))	('PGK', 'molecular_function', 'GO:0004618', ('48', '51'))	('PDHK1', 'Gene', (63, 68))	('BRCA', 'Disease', (132, 136))	('ESCA', 'Disease', 'MESH:D004938', (141, 145))
86697	31578148	Additional analyses of a cohort of 818 cases revealed that the phosphorylation levels of PGK1 S203 and PDHK1 T338 were independent prognostic biomarkers for LIHC, LUAD, and STAD.	('phosphorylation', 'biological_process', 'GO:0016310', ('63', '78'))	('PDHK1', 'Gene', (103, 108))	('PDHK', 'molecular_function', 'GO:0004740', ('103', '107'))	('T338', 'Var', (109, 113))	('PGK1', 'Gene', (89, 93))	('PDHK1', 'Gene', '5163', (103, 108))	('LUAD', 'Phenotype', 'HP:0030078', (163, 167))	('PGK', 'molecular_function', 'GO:0004618', ('89', '92'))	('LIHC', 'Disease', (157, 161))	('LUAD', 'Disease', (163, 167))	('STAD', 'Disease', 'MESH:D013274', (173, 177))	('LUAD', 'Disease', 'MESH:C538231', (163, 167))	('phosphorylation levels', 'MPA', (63, 85))	('STAD', 'Disease', (173, 177))	('LIHC', 'Disease', 'MESH:D006528', (157, 161))	('PGK1', 'Gene', '5230', (89, 93))	('S203', 'Var', (94, 98))
86698	31578148	All these findings suggest that PGK1 gene modification and PGK1-mitochondrial function were significantly associated with clinical behaviors of cancer patients.	('clinical behaviors', 'Disease', (122, 140))	('associated', 'Reg', (106, 116))	('PGK1', 'Gene', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('PGK1', 'Gene', '5230', (32, 36))	('patients', 'Species', '9606', (151, 159))	('PGK', 'molecular_function', 'GO:0004618', ('59', '62'))	('gene modification', 'Var', (37, 54))	('cancer', 'Disease', (144, 150))	('PGK1', 'Gene', (59, 63))	('clinical', 'Species', '191496', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PGK', 'molecular_function', 'GO:0004618', ('32', '35'))	('PGK1', 'Gene', '5230', (59, 63))
86708	31578148	Therefore, in the present study, we analyzed the DNA methylation data for 14 cancer types from TCGA datasets and identified hypomethylation of the PGK1 promoter (cg13203541) as an independent prognostic biomarker in BRCA patients (Additional file 1: Table S5).	('patients', 'Species', '9606', (221, 229))	('DNA methylation', 'biological_process', 'GO:0006306', ('49', '64'))	('PGK', 'molecular_function', 'GO:0004618', ('147', '150'))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('hypomethylation', 'Var', (124, 139))	('BRCA', 'Disease', (216, 220))	('cg13203541', 'Var', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('PGK1', 'Gene', (147, 151))	('BRCA', 'Phenotype', 'HP:0003002', (216, 220))	('BRCA', 'Disease', 'MESH:D001943', (216, 220))	('PGK1', 'Gene', '5230', (147, 151))
86709	31578148	We also detected mitochondrial PGK1-dependent PDHK1 T338 phosphorylation in additional cases of five cancer types and demonstrated that mitochondrial function of PGK1 significantly affected the clinical behaviors of patients with these cancers.	('PGK1', 'Gene', (162, 166))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancers', 'Disease', 'MESH:D009369', (236, 243))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('mitochondrial function', 'MPA', (136, 158))	('PDHK1', 'Gene', '5163', (46, 51))	('affected', 'Reg', (181, 189))	('PDHK', 'molecular_function', 'GO:0004740', ('46', '50'))	('PGK1', 'Gene', '5230', (31, 35))	('PDHK1', 'Gene', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('PGK', 'molecular_function', 'GO:0004618', ('31', '34'))	('cancers', 'Disease', (236, 243))	('cancer', 'Disease', (236, 242))	('patients', 'Species', '9606', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('PGK', 'molecular_function', 'GO:0004618', ('162', '165'))	('T338', 'Var', (52, 56))	('PGK1', 'Gene', (31, 35))	('PGK1', 'Gene', '5230', (162, 166))	('cancer', 'Disease', (101, 107))	('clinical behaviors', 'CPA', (194, 212))	('clinical', 'Species', '191496', (194, 202))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('phosphorylation', 'MPA', (57, 72))
86711	31578148	One important example is isocitrate dehydrogenase 1 (IDH1) mutation, which has important clinical significance and was found in GBM and myeloid malignancies, such as acute myelocytic leukaemia (AML) and myelodysplastic syndromes (MDS).	('AML', 'Disease', 'MESH:D015470', (194, 197))	('myeloid malignancies', 'Disease', (136, 156))	('acute myelocytic leukaemia', 'Disease', 'MESH:D015470', (166, 192))	('isocitrate', 'Chemical', 'MESH:D007523', (25, 35))	('AML', 'Disease', (194, 197))	('mutation', 'Var', (59, 67))	('AML', 'Phenotype', 'HP:0004808', (194, 197))	('acute myelocytic leukaemia', 'Phenotype', 'HP:0004808', (166, 192))	('MDS', 'Phenotype', 'HP:0002863', (230, 233))	('clinical', 'Species', '191496', (89, 97))	('GBM', 'Disease', (128, 131))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (203, 228))	('myeloid malignancies', 'Disease', 'OMIM:601308', (136, 156))	('GBM', 'Disease', 'MESH:D005909', (128, 131))	('myelodysplastic syndromes', 'Disease', (203, 228))	('MDS', 'Disease', 'MESH:D009190', (230, 233))	('IDH1', 'Gene', (53, 57))	('found', 'Reg', (119, 124))	('acute myelocytic leukaemia', 'Disease', (166, 192))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (203, 228))	('MDS', 'Disease', (230, 233))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('IDH1', 'Gene', '3417', (53, 57))	('myelocytic leukaemia', 'Phenotype', 'HP:0012324', (172, 192))
86712	31578148	A clinical study suggested that IDH1 mutation was an independent, favorable prognostic marker in grade 2-4 glioma.	('mutation', 'Var', (37, 45))	('IDH1', 'Gene', (32, 36))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('IDH1', 'Gene', '3417', (32, 36))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('clinical', 'Species', '191496', (2, 10))	('glioma', 'Disease', (107, 113))
86725	31578148	This study was funded by The National Key R&D Program of China (2017YFC1308702, 2017YFC1311000, 2018YFC1312100), the Beijing Municipal Science & Technology Commission (Z181100006218032, Z181100001918002), the CAMS Initiative for Innovative Medicine (2017-I2M-1-005, 2017-I2M-2-003, 2019-I2M-2-002), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2017PT32001, 2017PT32017).	('Z181100006218032', 'Chemical', 'MESH:C017788', (168, 184))	('Technology Commission', 'Var', (145, 166))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('N', 'Chemical', 'MESH:D009584', (299, 300))	('Innovative', 'Var', (229, 239))
86735	31620413	Tumor had mutations in the BRAF and KRAS genes.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('KRAS', 'Gene', (36, 40))	('BRAF', 'Gene', '673', (27, 31))	('KRAS', 'Gene', '3845', (36, 40))	('BRAF', 'Gene', (27, 31))	('mutations', 'Var', (10, 19))
86751	31620413	The Next Generation Sequencing (NGS) was performed on Gene Reader platform (QIAGEN) for regions and variants of clinical interest of the genes: KRAS, NRAS, KIT, BRAF, PDGFRA, ALK, EGFR, ERBB2, PIK3CA, ERBB3, ESR1, and RAF1.	('PIK3CA', 'Gene', '5290', (193, 199))	('KIT', 'Gene', (156, 159))	('NRAS', 'Gene', '4893', (150, 154))	('ERBB3', 'Gene', (201, 206))	('RAF1', 'Gene', '5894', (218, 222))	('EGFR', 'Gene', '1956', (180, 184))	('PIK3CA', 'Gene', (193, 199))	('KIT', 'Gene', '3815', (156, 159))	('RAF1', 'Gene', (218, 222))	('KRAS', 'Gene', '3845', (144, 148))	('ESR1', 'Gene', '2099', (208, 212))	('NRAS', 'Gene', (150, 154))	('PDGFRA', 'Gene', '5156', (167, 173))	('PDGFRA', 'Gene', (167, 173))	('ERBB3', 'Gene', '2065', (201, 206))	('KRAS', 'Gene', (144, 148))	('ESR1', 'Gene', (208, 212))	('ERBB2', 'Gene', (186, 191))	('ALK', 'Gene', '238', (175, 178))	('variants', 'Var', (100, 108))	('ALK', 'Gene', (175, 178))	('KIT', 'molecular_function', 'GO:0005020', ('156', '159'))	('EGFR', 'Gene', (180, 184))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('EGFR', 'molecular_function', 'GO:0005006', ('180', '184'))	('ERBB2', 'Gene', '2064', (186, 191))
86760	31620413	The specimen was positive for p53 mutation on immunohistochemistry.	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('mutation', 'Var', (34, 42))	('positive', 'Reg', (17, 25))
86762	31620413	The tumor genetic profile presented a pathogenic variant in the BRAF gene (c.1894C> T p.P632S), a probably pathogenic variant KRAS (c.97G> A p.D33N), and nine variants of uncertain significance in the ALK, EGFR, ERBB2, ERBB3, KIT, and PIK3CA (Table 1).	('tumor', 'Disease', (4, 9))	('BRAF', 'Gene', '673', (64, 68))	('BRAF', 'Gene', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('c.97G', 'Var', (132, 137))	('KIT', 'Gene', (226, 229))	('PIK3CA', 'Gene', (235, 241))	('p.D33N', 'SUBSTITUTION', 'None', (141, 147))	('ERBB3', 'Gene', '2065', (219, 224))	('ERBB2', 'Gene', (212, 217))	('ALK', 'Gene', '238', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('ALK', 'Gene', (201, 204))	('EGFR', 'Gene', (206, 210))	('p.P632S', 'Var', (86, 93))	('ERBB2', 'Gene', '2064', (212, 217))	('KIT', 'Gene', '3815', (226, 229))	('p.D33N', 'Var', (141, 147))	('KRAS', 'Gene', '3845', (126, 130))	('EGFR', 'molecular_function', 'GO:0005006', ('206', '210'))	('PIK3CA', 'Gene', '5290', (235, 241))	('ERBB3', 'Gene', (219, 224))	('KIT', 'molecular_function', 'GO:0005020', ('226', '229'))	('pathogenic', 'Reg', (38, 48))	('p.P632S', 'SUBSTITUTION', 'None', (86, 93))	('EGFR', 'Gene', '1956', (206, 210))	('KRAS', 'Gene', (126, 130))
86790	31620413	In adults, the most common molecular alterations in bladder UC includes fibroblast growth factor receptor 3 (FGFR3) and PI3K, which are associated with non-muscle-invasive papillary tumors; and mutations of tumor suppressor genes including p53, RB, and PTEN associated with invasive disease.	('associated', 'Reg', (136, 146))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('72', '96'))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('p53', 'Gene', '7157', (240, 243))	('fibroblast growth factor receptor 3', 'Gene', (72, 107))	('tumor suppressor', 'biological_process', 'GO:0051726', ('207', '223'))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('PTEN', 'Gene', '5728', (253, 257))	('invasive disease', 'Disease', (274, 290))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('p53', 'Gene', (240, 243))	('FGFR3', 'Gene', (109, 114))	('FGFR', 'molecular_function', 'GO:0005007', ('109', '113'))	('FGFR3', 'Gene', '2261', (109, 114))	('fibroblast growth factor receptor 3', 'Gene', '2261', (72, 107))	('PI3K', 'Var', (120, 124))	('associated', 'Reg', (258, 268))	('PI3K', 'molecular_function', 'GO:0016303', ('120', '124'))	('invasive disease', 'Disease', 'MESH:D009361', (274, 290))	('UC', 'Disease', 'MESH:D014523', (60, 62))	('papillary tumors', 'Phenotype', 'HP:0007482', (172, 188))	('tumor', 'Disease', (207, 212))	('papillary tumors', 'Disease', 'MESH:D002291', (172, 188))	('papillary tumors', 'Disease', (172, 188))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('mutations', 'Var', (194, 203))	('PTEN', 'Gene', (253, 257))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('207', '223'))
86791	31620413	showed in a series of three pediatric TCC that there was no mutation in p53 and all three tumors had a H-RAS mutation, suggesting the existence of a different molecular pathway of bladder cancer tumorigenesis among pediatric population.	('tumor', 'Disease', (195, 200))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('TCC', 'Gene', (38, 41))	('tumor', 'Disease', (90, 95))	('p53', 'Gene', '7157', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('TCC', 'Gene', '94081', (38, 41))	('bladder cancer', 'Disease', 'MESH:D001749', (180, 194))	('bladder cancer', 'Disease', (180, 194))	('p53', 'Gene', (72, 75))	('bladder cancer', 'Phenotype', 'HP:0009725', (180, 194))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('TCC', 'cellular_component', 'GO:0005579', ('38', '41'))	('H-RAS', 'Gene', (103, 108))	('mutation', 'Var', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('H-RAS', 'Gene', '3265', (103, 108))
86793	31620413	KRAS mutation are rare in urothelial carcinoma, but seems to be frequent in urachal carcinoma and has already been described in inverted urothelial papilloma, urothelial papilloma, and advanced stage high-grade urothelial carcinoma in adult population.	('papilloma', 'Phenotype', 'HP:0012740', (148, 157))	('urachal carcinoma', 'Disease', (76, 93))	('urachal carcinoma', 'Disease', 'MESH:C536475', (76, 93))	('frequent', 'Reg', (64, 72))	('urachal carcinoma', 'Phenotype', 'HP:0012618', (76, 93))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (211, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('papilloma', 'Phenotype', 'HP:0012740', (170, 179))	('KRAS', 'Gene', '3845', (0, 4))	('urothelial carcinoma', 'Disease', (211, 231))	('urothelial papilloma', 'Disease', (137, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (26, 46))	('urothelial papilloma', 'Disease', (159, 179))	('urothelial papilloma', 'Disease', 'MESH:D010212', (137, 157))	('KRAS', 'Gene', (0, 4))	('urothelial papilloma', 'Disease', 'MESH:D010212', (159, 179))	('urothelial carcinoma', 'Disease', (26, 46))	('mutation', 'Var', (5, 13))
86794	31620413	Also, in our analysis, patient's tumor presented a likely pathogenic variant in the BRAF gene.	('variant', 'Var', (69, 76))	('BRAF', 'Gene', '673', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('BRAF', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('pathogenic', 'Reg', (58, 68))	('patient', 'Species', '9606', (23, 30))
86795	31620413	Recently, activating mutations in the BRAF gene, an important activator of MAP pathway, have been described in several tumor types including melanoma, colorectal, and papillary thyroid cancer.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('tumor', 'Disease', (119, 124))	('melanoma', 'Disease', (141, 149))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('papillary thyroid cancer', 'Disease', (167, 191))	('thyroid cancer', 'Phenotype', 'HP:0002890', (177, 191))	('BRAF', 'Gene', '673', (38, 42))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (167, 191))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('BRAF', 'Gene', (38, 42))	('papillary thyroid cancer', 'Disease', 'MESH:C536915', (167, 191))	('MAP', 'molecular_function', 'GO:0004239', ('75', '78'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('activating mutations', 'Var', (10, 30))	('colorectal', 'Disease', (151, 161))
86796	31620413	One study found BRAF mutation in 18% of urachal carcinoma, which frequency seems to be similar to that of in colorectal adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (109, 135))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('mutation', 'Var', (21, 29))	('urachal carcinoma', 'Disease', (40, 57))	('colorectal adenocarcinomas', 'Disease', (109, 135))	('urachal carcinoma', 'Disease', 'MESH:C536475', (40, 57))	('urachal carcinoma', 'Phenotype', 'HP:0012618', (40, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
86797	31620413	studied the BRAF gene mutation in 30 patients with UC and found only in 2 patients this mutation.	('mutation', 'Var', (22, 30))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (74, 82))	('UC', 'Disease', 'MESH:D014523', (51, 53))
86821	30046394	Conversely, disrupting integrin-ligand interactions can induce apoptosis via integrin-mediated death (IMD), which is mediated by recruiting and activating caspase-8.	('integrin-ligand', 'molecular_function', 'GO:0005178', ('23', '38'))	('caspase-8', 'Gene', (155, 164))	('activating', 'PosReg', (144, 154))	('integrin-mediated death', 'Disease', (77, 100))	('induce', 'PosReg', (56, 62))	('integrin-ligand', 'Protein', (23, 38))	('caspase-8', 'Gene', '841', (155, 164))	('apoptosis', 'CPA', (63, 72))	('disrupting', 'Var', (12, 22))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))	('interactions', 'Interaction', (39, 51))
86898	30046394	The overexpression of alphav integrins (alphavbeta3, alphavbeta5, alphavbeta6) serves as key prognostic, and therapeutic targets in stomach cancers.	('stomach cancers', 'Disease', 'MESH:D013274', (132, 147))	('stomach cancers', 'Disease', (132, 147))	('stomach cancers', 'Phenotype', 'HP:0012126', (132, 147))	('stomach cancer', 'Phenotype', 'HP:0012126', (132, 146))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('alphavbeta6', 'Var', (66, 77))	('overexpression', 'PosReg', (4, 18))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('alphav integrins', 'Protein', (22, 38))
86902	30046394	Inhibition of individual subunits is expected to disrupt cellular signaling and acts to halt tumor metastatic processes, angiogenesis and growth.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('disrupt', 'NegReg', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('growth', 'CPA', (138, 144))	('tumor', 'Disease', (93, 98))	('cellular signaling', 'MPA', (57, 75))	('Inhibition', 'Var', (0, 10))	('angiogenesis', 'biological_process', 'GO:0001525', ('121', '133'))	('halt', 'NegReg', (88, 92))	('angiogenesis', 'CPA', (121, 133))
86914	30046394	Using this relaxed criteria, three plausible targets emerge for BLCA: alpha3beta1, alphavb6, and alpha6b4 (Figure 8A).	('beta1', 'Gene', '10678', (76, 81))	('alpha6b4', 'Var', (97, 105))	('beta1', 'Gene', (76, 81))	('BLCA', 'Chemical', '-', (64, 68))
86932	30046394	Results for each cancer type included, for each of the 27 integrin subunit genes, a log 2 value of expression difference between cancer and normal, a p-value, and a false discovery rate (FDR) adjusted according to the Benjamini-Hochberg method (Supplementary Table 2).	('expression', 'MPA', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('p-value', 'Var', (150, 157))	('false', 'biological_process', 'GO:0071877', ('165', '170'))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', (17, 23))	('false', 'biological_process', 'GO:0071878', ('165', '170'))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
86958	24957100	Chromosomal anomalies, genetic polymorphisms, genetic and epigenetic alterations have been reported to be included in the tumorigenesis and progression of bladder cancer.	('bladder cancer', 'Disease', (155, 169))	('genetic polymorphisms', 'Var', (23, 44))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('bladder cancer', 'Phenotype', 'HP:0009725', (155, 169))	('bladder cancer', 'Disease', 'MESH:D001749', (155, 169))	('included', 'Reg', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('epigenetic alterations', 'Var', (58, 80))	('tumor', 'Disease', (122, 127))	('genetic', 'Var', (46, 53))
86960	24957100	Currently, many protein-coding genes and specific genomic regions are the most popular used molecular markers of bladder cancer, such as members of the RAS family, differentially methylated DNA locus.	('differentially methylated', 'Var', (164, 189))	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('protein', 'cellular_component', 'GO:0003675', ('16', '23'))	('bladder cancer', 'Disease', 'MESH:D001749', (113, 127))	('bladder cancer', 'Disease', (113, 127))	('DNA', 'cellular_component', 'GO:0005574', ('190', '193'))
86989	24957100	The expression level of miR-99a in HU609 and HCV29 was significantly higher than that in the three bladder cancer cell lines (T24, HT1376, and J82) and was non-significantly but observably higher than the levels in the other two bladder cancer cell lines (TCCSUP and RT4) (Figure 1A).	('expression level', 'MPA', (4, 20))	('bladder cancer', 'Phenotype', 'HP:0009725', (229, 243))	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('J82', 'CellLine', 'CVCL:0359', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (229, 243))	('bladder cancer', 'Disease', (229, 243))	('miR-99a', 'Gene', '407055', (24, 31))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('HCV29', 'Var', (45, 50))	('HU609', 'Var', (35, 40))	('bladder cancer', 'Disease', (99, 113))	('higher', 'PosReg', (189, 195))	('miR-99a', 'Gene', (24, 31))	('HT1376', 'CellLine', 'CVCL:1292', (131, 137))	('higher', 'PosReg', (69, 75))	('HU609', 'CellLine', 'CVCL:8240', (35, 40))
86999	24957100	Correlation analysis showed that low-level expression of miR-99a in bladder cancer was significantly associated with a more extensive muscle invasion (p < 0.05, stage Ta, 1 vs. stage T2, 3, 4) (Figure 2A) and a more aggressive tumor phenotype (p < 0.05, grade 1, 2 vs. grade 3) (Figure 2B).	('bladder cancer', 'Phenotype', 'HP:0009725', (68, 82))	('aggressive tumor', 'Disease', 'MESH:D001523', (216, 232))	('miR-99a', 'Gene', (57, 64))	('aggressive tumor', 'Disease', (216, 232))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('low-level', 'Var', (33, 42))	('bladder cancer', 'Disease', 'MESH:D001749', (68, 82))	('bladder cancer', 'Disease', (68, 82))	('associated', 'Reg', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('miR-99a', 'Gene', '407055', (57, 64))
87006	24957100	The suppression of miR-99a on cell proliferation of HT1376 cells was a little stronger than that on J82 cells.	('suppression', 'NegReg', (4, 15))	('miR-99a', 'Gene', (19, 26))	('cell proliferation', 'CPA', (30, 48))	('J82', 'CellLine', 'CVCL:0359', (100, 103))	('HT1376', 'CellLine', 'CVCL:1292', (52, 58))	('miR-99a', 'Gene', '407055', (19, 26))	('HT1376', 'Var', (52, 58))	('cell proliferation', 'biological_process', 'GO:0008283', ('30', '48'))
87022	24957100	Because miRNAs are small, easy to deliver, stable against degradation and easy to be detected, these aberrant expression miRNAs in bladder cancer are attractive as potential biomarkers and new targets for bladder cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('bladder cancer', 'Disease', (131, 145))	('bladder cancer', 'Disease', 'MESH:D001749', (205, 219))	('bladder cancer', 'Disease', (205, 219))	('bladder cancer', 'Phenotype', 'HP:0009725', (205, 219))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('bladder cancer', 'Phenotype', 'HP:0009725', (131, 145))	('degradation', 'biological_process', 'GO:0009056', ('58', '69'))	('aberrant expression', 'Var', (101, 120))	('bladder cancer', 'Disease', 'MESH:D001749', (131, 145))
87279	32321466	This observation may indicate unidentified disease-predisposing genetic variants in this phenotypically defined subset of hereditary colorectal cancer and calls for awareness during genetic counselling and follow-up.	('hereditary colorectal cancer', 'Disease', 'MESH:D015179', (122, 150))	('variants', 'Var', (72, 80))	('hereditary colorectal cancer', 'Disease', (122, 150))	('colorectal cancer', 'Phenotype', 'HP:0003003', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
87283	32321466	a mismatch-repair stable phenotype and/or retained MMR protein expression, are referred to as familial colorectal cancer type X (FCCTX).	('familial colorectal cancer', 'Disease', 'MESH:D015179', (94, 120))	('MMR protein', 'Protein', (51, 62))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('familial colorectal cancer', 'Disease', (94, 120))	('mismatch-repair', 'biological_process', 'GO:0006298', ('2', '17'))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mismatch-repair', 'Var', (2, 17))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('FCCTX', 'Chemical', '-', (129, 134))	('MMR', 'biological_process', 'GO:0006298', ('51', '54'))
87286	32321466	heterozygous MUTYH, CHEK2, BRCA2, POLE, POLD1, SEMA4A, BMPR1A, RPS20 or OGG1 or modifying single nucleotide polymorphisms in SEMA4A, EXO1, TGFBR1, or NUDT1.	('CHEK2', 'Gene', (20, 25))	('POLD1', 'Gene', '5424', (40, 45))	('RPS20', 'Gene', '6224', (63, 68))	('CHEK2', 'Gene', '11200', (20, 25))	('BRCA2', 'Gene', '675', (27, 32))	('modifying single nucleotide polymorphisms', 'Var', (80, 121))	('BMPR1A', 'Gene', (55, 61))	('RPS20', 'Gene', (63, 68))	('NUDT1', 'Gene', (150, 155))	('TGFBR1', 'Gene', (139, 145))	('TGFBR1', 'Gene', '7046', (139, 145))	('SEMA4A', 'Gene', (47, 53))	('MUTYH', 'Gene', (13, 18))	('POLD1', 'Gene', (40, 45))	('SEMA4A', 'Gene', '64218', (47, 53))	('SEMA4A', 'Gene', (125, 131))	('NUDT1', 'Gene', '4521', (150, 155))	('OGG1', 'Gene', (72, 76))	('EXO1', 'Gene', (133, 137))	('OGG1', 'Gene', '4968', (72, 76))	('MUTYH', 'Gene', '4595', (13, 18))	('SEMA4A', 'Gene', '64218', (125, 131))	('EXO1', 'Gene', '9156', (133, 137))	('BRCA2', 'Gene', (27, 32))	('BMPR1A', 'Gene', '657', (55, 61))
87293	32321466	Families have been included based on a suspicious family history of colorectal cancer, fulfilment of the Amsterdam I or II criteria, or identification of disease-predisposing variants in genes linked to hereditary colorectal cancer.	('variants', 'Var', (175, 183))	('colorectal cancer', 'Disease', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('hereditary colorectal cancer', 'Disease', 'MESH:D015179', (203, 231))	('colorectal cancer', 'Disease', 'MESH:D015179', (214, 231))	('colorectal cancer', 'Disease', 'MESH:D015179', (68, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (214, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('hereditary colorectal cancer', 'Disease', (203, 231))
87299	32321466	A maximum of one tumour with MLH1/PMS2 protein loss in the family was accepted if this was in conjunction with a BRAF mutation and/or MLH1 promotor hypermethylation (N = 4) or normal MMR expression was found in >=1 tumour from a family member (N = 16).	('PMS2', 'Gene', '5395', (34, 38))	('MLH1', 'Gene', (134, 138))	('MLH1', 'Gene', (29, 33))	('MLH1', 'Gene', '4292', (134, 138))	('protein', 'Protein', (39, 46))	('MLH1', 'Gene', '4292', (29, 33))	('PMS2', 'Gene', (34, 38))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('mutation', 'Var', (118, 126))	('tumour', 'Disease', (17, 23))	('tumour', 'Phenotype', 'HP:0002664', (215, 221))	('BRAF', 'Gene', '673', (113, 117))	('tumour', 'Disease', 'MESH:D009369', (215, 221))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('BRAF', 'Gene', (113, 117))	('tumour', 'Disease', (215, 221))	('MMR', 'biological_process', 'GO:0006298', ('183', '186'))	('loss', 'NegReg', (47, 51))
87301	32321466	Variants of unknown significance were included only when normal MMR protein expression was verified in a tumour from the same patient (N = 2).	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('MMR', 'biological_process', 'GO:0006298', ('64', '67'))	('Variants', 'Var', (0, 8))	('tumour', 'Disease', (105, 111))	('patient', 'Species', '9606', (126, 133))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
87331	32321466	As we did not have genetic data on variants in the BRCA1/BRCA2 genes predisposing for hereditary breast and ovarian cancer or the CDH1 gene predisposing for hereditary diffuse gastric cancer, we excluded these families from the FCCTX cohort.	('CDH1', 'Gene', '999', (130, 134))	('hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (86, 122))	('variants', 'Var', (35, 43))	('BRCA1', 'Gene', '672', (51, 56))	('BRCA2', 'Gene', (57, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('BRCA1', 'Gene', (51, 56))	('hereditary diffuse gastric cancer', 'Disease', (157, 190))	('BRCA2', 'Gene', '675', (57, 62))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (157, 190))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('CDH1', 'Gene', (130, 134))	('FCCTX', 'Chemical', '-', (228, 233))
87351	32321466	Alternatively, a subset of FCCTX could harbour mutations in genes linked to urothelial cancer development, e.g.	('FCCTX', 'Chemical', '-', (27, 32))	('FCCTX', 'Gene', (27, 32))	('harbour', 'Reg', (39, 46))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('urothelial cancer', 'Disease', (76, 93))	('urothelial cancer', 'Disease', 'MESH:D014523', (76, 93))
87356	32321466	About 10-20% of gastric cancer is caused by heredity with confirmed causes in 1-3%, predominantly linked to the hereditary diffuse gastric cancer caused by pathogenic variants in the CDH1 gene.	('caused by', 'Reg', (146, 155))	('gastric cancer', 'Disease', 'MESH:D013274', (131, 145))	('variants', 'Var', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('gastric cancer', 'Disease', (16, 30))	('CDH1', 'Gene', (183, 187))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('gastric cancer', 'Disease', 'MESH:D013274', (16, 30))	('CDH1', 'Gene', '999', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (112, 145))	('hereditary diffuse gastric cancer', 'Disease', (112, 145))	('gastric cancer', 'Phenotype', 'HP:0012126', (16, 30))	('linked', 'Reg', (98, 104))
87361	32321466	The increased risks of breast cancer with IRRs 1.5-1.7 in the age group 30-69 years and pancreatic cancer with an IRR of 2.2 after age 70 support the suggestion of disease-predisposing variants in BRCA2, causing the observed malignancies in a small subset of FCCTX families.	('breast cancer', 'Disease', (23, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('variants', 'Var', (185, 193))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (88, 105))	('BRCA2', 'Gene', (197, 202))	('BRCA2', 'Gene', '675', (197, 202))	('malignancies', 'Disease', 'MESH:D009369', (225, 237))	('pancreatic cancer', 'Disease', (88, 105))	('FCCTX', 'Chemical', '-', (259, 264))	('pancreatic cancer', 'Disease', 'MESH:D010190', (88, 105))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('malignancies', 'Disease', (225, 237))
87370	32321466	Autosomal dominant inheritance of pathogenic BAP1 gene variants have been observed in 47% of uveal melanomas, while pathogenic EIF1AX variants have been found in 14-20% of the cases.	('uveal melanomas', 'Disease', 'MESH:C536494', (93, 108))	('BAP1', 'Gene', (45, 49))	('variants', 'Var', (55, 63))	('pathogenic', 'Reg', (34, 44))	('EIF1AX', 'Gene', (127, 133))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('uveal melanomas', 'Disease', (93, 108))	('uveal melanomas', 'Phenotype', 'HP:0007716', (93, 108))	('EIF1AX', 'Gene', '1964', (127, 133))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))	('BAP1', 'Gene', '8314', (45, 49))
87371	32321466	BAP1-associated uveal melanomas are diagnosed in the age of 30-59 years and are associated with cutaneous melanomas and renal cell carcinomas, while EIF1AX gene variants are associated with thyroid and ovarian cancer.	('uveal melanomas', 'Disease', (16, 31))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (96, 115))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('thyroid and ovarian cancer', 'Disease', 'MESH:D013966', (190, 216))	('associated', 'Reg', (80, 90))	('EIF1AX', 'Gene', (149, 155))	('variants', 'Var', (161, 169))	('associated', 'Reg', (174, 184))	('BAP1', 'Gene', (0, 4))	('cutaneous melanomas and renal cell carcinomas', 'Disease', 'MESH:C538614', (96, 141))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('EIF1AX', 'Gene', '1964', (149, 155))	('ovarian cancer', 'Phenotype', 'HP:0100615', (202, 216))	('uveal melanomas', 'Disease', 'MESH:C536494', (16, 31))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('uveal melanomas', 'Phenotype', 'HP:0007716', (16, 31))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (120, 141))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('BAP1', 'Gene', '8314', (0, 4))
87374	32321466	Urothelial cancer and skin cancer showed significantly lower risk levels in FCCTX compared to Lynch syndrome with IRRs of 0.06-0.31 and 0.11-0.24, respectively (Table 4).	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Lynch syndrome', 'Disease', (94, 108))	('FCCTX', 'Var', (76, 81))	('skin cancer', 'Disease', 'MESH:D012878', (22, 33))	('Lynch syndrome', 'Disease', 'MESH:D003123', (94, 108))	('FCCTX', 'Chemical', '-', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('lower', 'NegReg', (55, 60))	('skin cancer', 'Phenotype', 'HP:0008069', (22, 33))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', (11, 17))	('skin cancer', 'Disease', (22, 33))
87383	32321466	The demonstration of increased risks for breast cancer and pancreatic cancer could suggest that genetic variants in BRCA2 may explain some FCCTX families.	('pancreatic cancer', 'Disease', 'MESH:D010190', (59, 76))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('pancreatic cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('FCCTX', 'Disease', (139, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('genetic variants', 'Var', (96, 112))	('BRCA2', 'Gene', (116, 121))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (59, 76))	('FCCTX', 'Chemical', '-', (139, 144))	('BRCA2', 'Gene', '675', (116, 121))
87391	32321466	This work was funded by start-up funds from the Swedish Cancer Research Fund to M. Nilbert (2014/442), while salary to C. Therkildsen and M. Rasmussen was supported by the Danish Cancer Research Fund (R90-A6150 and R204-A12599, respectively).	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Cancer', 'Disease', (56, 62))	('Cancer', 'Disease', (179, 185))	('Cancer', 'Phenotype', 'HP:0002664', (179, 185))	('Cancer', 'Disease', 'MESH:D009369', (56, 62))	('Cancer', 'Disease', 'MESH:D009369', (179, 185))	('R204-A12599', 'Var', (215, 226))
87426	32069881	Researchers have developed successful models in four different types of mouse hosts: nude mice, scid mice, NOD (non-obese diabetic) scid mice, and mouse strains bearing targeted immunocompromising mutations in Il2rg.	('Il2', 'molecular_function', 'GO:0005134', ('210', '213'))	('NOD', 'Disease', (107, 110))	('Il2rg', 'Gene', (210, 215))	('mouse', 'Species', '10090', (147, 152))	('mouse', 'Species', '10090', (72, 77))	('non-obese diabetic', 'Disease', (112, 130))	('mutations', 'Var', (197, 206))	('non-obese diabetic', 'Disease', 'MESH:D009765', (112, 130))	('mice', 'Species', '10090', (101, 105))	('nude mice', 'Species', '10090', (85, 94))	('mice', 'Species', '10090', (90, 94))	('NOD', 'Disease', 'MESH:D009765', (107, 110))	('mice', 'Species', '10090', (137, 141))
87435	32069881	Finally, targeted mutations in Il2rg led to the development of NSG (NOD.Cg-Prkdcscid/l2rgtm1Wjl), NOG (NODShi.Cg-Prkdcscid/l2rgtm1Sug), and NRG (NOD.Cg-Rag1tm1Mom/l2rgtm1Wjl) strains with targeted deficiencies in B cells, T cells, and NK cells.	('Il2rg', 'Gene', (31, 36))	('NOD', 'Disease', (145, 148))	('Il2', 'molecular_function', 'GO:0005134', ('31', '34'))	('NOD', 'Disease', (103, 106))	('Mom', 'cellular_component', 'GO:0036407', ('159', '162'))	('NOD', 'Disease', 'MESH:D009765', (68, 71))	('NOD', 'Disease', (68, 71))	('NOD', 'Disease', 'MESH:D009765', (145, 148))	('NOD', 'Disease', 'MESH:D009765', (103, 106))	('mutations', 'Var', (18, 27))
87438	32069881	Development of spontaneous thymic lymphomas has been reported in up to 15% of C.B17 scid mice and 67% of NOD-scid mice, while the incidence of spontaneous lymphoma is much lower in Il2rg-deficient mouse models (NSG/NOG/NRG), with reported rates of 0.7% in NSG and NOG mice.	('NOD', 'Disease', 'MESH:D009765', (105, 108))	('lymphomas', 'Phenotype', 'HP:0002665', (34, 43))	('lymphoma', 'Disease', (34, 42))	('lymphoma', 'Disease', (155, 163))	('NOD', 'Disease', (105, 108))	('thymic lymphomas', 'Disease', (27, 43))	('mice', 'Species', '10090', (89, 93))	('mice', 'Species', '10090', (268, 272))	('lymphoma', 'Disease', 'MESH:D008223', (34, 42))	('lymphoma', 'Disease', 'MESH:D008223', (155, 163))	('C.B17 scid', 'Var', (78, 88))	('lymphoma', 'Phenotype', 'HP:0002665', (34, 42))	('mouse', 'Species', '10090', (197, 202))	('mice', 'Species', '10090', (114, 118))	('lymphoma', 'Phenotype', 'HP:0002665', (155, 163))	('thymic lymphomas', 'Disease', 'MESH:D013953', (27, 43))	('Il2', 'molecular_function', 'GO:0005134', ('181', '184'))
87515	32069881	Retaining parental mutational profiles is particularly important with the development of therapies targeting patient tumors that harbor specific driver mutations.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('patient', 'Species', '9606', (109, 116))	('mutations', 'Var', (152, 161))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))
87519	32069881	For example, luminal cancers that tend to be enriched in activating mutations in FGFR3 may better respond to FGFR3 inhibiting agents.	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('better', 'PosReg', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('luminal cancers', 'Disease', (13, 28))	('FGFR3', 'Gene', (81, 86))	('FGFR3', 'Gene', (109, 114))	('FGFR3', 'Gene', '2261', (81, 86))	('FGFR', 'molecular_function', 'GO:0005007', ('109', '113'))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('respond', 'MPA', (98, 105))	('mutations', 'Var', (68, 77))	('FGFR3', 'Gene', '2261', (109, 114))	('activating', 'PosReg', (57, 67))	('luminal cancers', 'Disease', 'MESH:D009369', (13, 28))
87545	32069881	Erdafitinib, a tyrosine kinase inhibitor of fibroblast growth factor receptor (FGFR), was recently approved as the first targeted systemic therapy for metastatic urothelial cancer in patients with known FGFR2/3 mutations.	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (0, 11))	('FGFR2', 'Gene', '2263', (203, 208))	('urothelial cancer', 'Disease', 'MESH:D014523', (162, 179))	('mutations', 'Var', (211, 220))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('44', '68'))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('urothelial cancer', 'Disease', (162, 179))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('24', '40'))	('FGFR', 'molecular_function', 'GO:0005007', ('203', '207'))	('patients', 'Species', '9606', (183, 191))	('FGFR2', 'Gene', (203, 208))
87610	31891128	High variability in driver mutations and heterogeneity within tumors bring challenges for the development of targeted therapies.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))
87625	31891128	The results indicated that patients with high PD-L1 mRNA expression gained an improved survival, which might be related to a higher immune competence.	('PD-L1', 'Gene', (46, 51))	('gained', 'PosReg', (68, 74))	('high', 'Var', (41, 45))	('survival', 'CPA', (87, 95))	('patients', 'Species', '9606', (27, 35))	('higher', 'PosReg', (125, 131))	('improved', 'PosReg', (78, 86))
87629	31891128	However, positive PD-L1 status in tumor-infiltrating mononuclear cells was significantly associated with longer survival in patients with metastases.	('longer', 'PosReg', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('metastases', 'Disease', (138, 148))	('tumor', 'Disease', (34, 39))	('PD-L1', 'Gene', (18, 23))	('metastases', 'Disease', 'MESH:D009362', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('positive', 'Var', (9, 17))	('patients', 'Species', '9606', (124, 132))
87673	31891128	In this study, tumor mutation load was examined before the treatment in 150 patients by sequencing 315 cancer-related genes.	('patients', 'Species', '9606', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('sequencing', 'Var', (88, 98))	('tumor', 'Disease', (15, 20))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
87678	31891128	Mouse model study indicated that co-inhibition of TGF-beta and PD-L1 converted tumor from an excluded to an inflamed phenotype for immune therapy.	('converted', 'Reg', (69, 78))	('tumor', 'Disease', (79, 84))	('co-inhibition', 'Var', (33, 46))	('TGF-beta', 'Gene', (50, 58))	('PD-L1', 'Gene', (63, 68))	('Mouse', 'Species', '10090', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
87683	30976566	Histological variants in non-muscle invasive bladder cancer Several studies evaluated the role of histological variants on oncological outcomes after radical cystectomy (RC) and they were found significantly associated with worse recurrence and survival.	('variants', 'Var', (13, 21))	('invasive bladder cancer', 'Disease', (36, 59))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (36, 59))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (25, 52))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('variants', 'Var', (111, 119))	('associated', 'Reg', (208, 218))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('-muscle invasive bladder cancer', 'Phenotype', 'HP:0006740', (28, 59))	('invasive bladder', 'Phenotype', 'HP:0100645', (36, 52))
87692	30976566	During the last ten years, the presence of histological variants in BCa became increasingly important and several studies were performed especially on patients treated with radical cystectomy (RC), to assess its role in muscle-invasive BCa: all of them found histological variants related to worse survival outcomes.	('variants', 'Var', (272, 280))	('patients', 'Species', '9606', (151, 159))	('BCa', 'Phenotype', 'HP:0009725', (236, 239))	('BCa', 'Gene', (68, 71))	('BCa', 'Phenotype', 'HP:0009725', (68, 71))
87695	30976566	The prognostic importance of variant histology in BCa was underlined by the World Health Organization (WHO), which included the category of "invasive urothelial carcinoma with divergent differentiation", defined as urothelial cancer with presence of other morphologies, in the 2016 classifications.	('urothelial cancer', 'Disease', 'MESH:D014523', (215, 232))	('variant', 'Var', (29, 36))	('urothelial carcinoma', 'Disease', (150, 170))	('BCa', 'Phenotype', 'HP:0009725', (50, 53))	('urothelial cancer', 'Disease', (215, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (150, 170))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
87707	30976566	who reported a lack of agreement for uncommon variants between TUR and RC in the entire population (P<0.001).	('TUR', 'Gene', (63, 66))	('variants', 'Var', (46, 54))	('men', 'Species', '9606', (28, 31))
87710	30976566	In general, BCa with variant histology is considered as an aggressive disease and early RC should be proposed in majority of cases of non-muscle invasive BCa.	('aggressive disease', 'Disease', (59, 77))	('non-muscle invasive BCa', 'Disease', (134, 157))	('BCa', 'Phenotype', 'HP:0009725', (12, 15))	('BCa', 'Disease', (12, 15))	('variant', 'Var', (21, 28))	('BCa', 'Phenotype', 'HP:0009725', (154, 157))	('aggressive disease', 'Disease', 'MESH:D001523', (59, 77))
87714	30976566	Similar result were found for patients with glandular differentiation and after adjusting for stage and percentage of the variant were found to have similar survival outcomes compared to patients with pure urothelial carcinoma.	('patients', 'Species', '9606', (187, 195))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (206, 226))	('patients', 'Species', '9606', (30, 38))	('glandular', 'Disease', (44, 53))	('variant', 'Var', (122, 129))	('urothelial carcinoma', 'Disease', (206, 226))	('pure', 'molecular_function', 'GO:0034023', ('201', '205'))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
87723	30976566	When analyses was focused on non-muscle invasive BCa they reported worse survival outcomes for patients treated with BCG compared to those treated immediate RC.	('survival', 'MPA', (73, 81))	('BCa', 'Phenotype', 'HP:0009725', (49, 52))	('patients', 'Species', '9606', (95, 103))	('BCG', 'Var', (117, 120))	('worse', 'NegReg', (67, 72))	('BCG', 'Species', '33892', (117, 120))
87729	30976566	In the majority of case of variant histology and in particular in case of sarcomatoid, plasmacitoid, micropapillary and neuroendocrine non-muscle invasive tumors, immediate RC should be suggested.	('sarcomatoid', 'Disease', 'MESH:C538614', (74, 85))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('micropapillary', 'Disease', (101, 115))	('neuroendocrine non-muscle invasive tumors', 'Disease', 'MESH:D018358', (120, 161))	('plasmacitoid', 'Disease', (87, 99))	('sarcomatoid', 'Disease', (74, 85))	('neuroendocrine non-muscle invasive tumors', 'Disease', (120, 161))	('variant', 'Var', (27, 34))
87731	30237864	Prevalence of MDM2 amplification and coalterations in 523 advanced cancer patients in the MD Anderson phase 1 clinic TP53 is the most commonly mutated gene in cancer and codes for the best studied tumor suppressor, p53.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('TP53', 'Gene', (117, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('197', '213'))	('p53', 'Gene', '7157', (215, 218))	('MDM2', 'Gene', '4193', (14, 18))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor suppressor', 'biological_process', 'GO:0051726', ('197', '213'))	('amplification', 'Var', (19, 32))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('p53', 'Gene', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('TP53', 'Gene', '7157', (117, 121))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('MDM2', 'Gene', (14, 18))	('tumor', 'Disease', (197, 202))
87733	30237864	In this retrospective study, we assessed the occurrence of MDM2 amplification among patients with various types of cancers and its association with clinical factors, other genetic aberrations, and response to targeted therapy in a phase I clinical trial setting.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('patients', 'Species', '9606', (84, 92))	('cancers', 'Disease', (115, 122))	('amplification', 'Var', (64, 77))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('MDM2', 'Gene', (59, 63))
87735	30237864	Patients whose tumors expressed MDM2 amplification were compared to those with tumors of the same histologic types without MDM2 amplification.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('amplification', 'Var', (37, 50))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('MDM2', 'Gene', (32, 36))	('tumors', 'Disease', (15, 21))
87736	30237864	We tested tumors from 523 patients, of which 23 (4.4%) had MDM2 amplification.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('amplification', 'Var', (64, 77))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tested', 'Reg', (3, 9))	('MDM2', 'Gene', (59, 63))	('patients', 'Species', '9606', (26, 34))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))
87737	30237864	The highest prevalence of MDM2 amplification was in sarcoma (57%), breast cancer (13%) and bladder cancer (9%).	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('sarcoma', 'Disease', (52, 59))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('MDM2', 'Gene', (26, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('amplification', 'Var', (31, 44))	('bladder cancer', 'Disease', (91, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', (67, 80))
87739	30237864	The most common molecular aberrations co-occurring with MDM2 amplification was CDK4 amplification (70%).	('CDK', 'molecular_function', 'GO:0004693', ('79', '82'))	('amplification', 'Var', (61, 74))	('CDK4', 'Gene', (79, 83))	('MDM2', 'Gene', (56, 60))	('CDK4', 'Gene', '1019', (79, 83))
87740	30237864	TP53 mutation was also detected in 7 patients (30%).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (37, 45))	('detected', 'Reg', (23, 31))	('mutation', 'Var', (5, 13))
87741	30237864	MDM2 amplification was most commonly associated with liposarcoma.	('liposarcoma', 'Disease', (53, 64))	('liposarcoma', 'Disease', 'MESH:D008080', (53, 64))	('amplification', 'Var', (5, 18))	('liposarcoma', 'Phenotype', 'HP:0012034', (53, 64))	('MDM2', 'Gene', (0, 4))	('associated', 'Reg', (37, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
87742	30237864	Concomitant alterations in additional genes such as CDK4 amplification and TP53 mutations, along with variable responses to targeted therapies including MDM2 inhibitors, suggest that further combinational studies are needed to target this population.	('CDK4', 'Gene', (52, 56))	('mutations', 'Var', (80, 89))	('alterations', 'Reg', (12, 23))	('amplification', 'Var', (57, 70))	('CDK', 'molecular_function', 'GO:0004693', ('52', '55'))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))	('CDK4', 'Gene', '1019', (52, 56))
87758	30237864	With the emergence of MDM2 inhibitors, an understanding of this particular patient population would provide a better rationale for the use of these inhibitors and help establish criteria for selection of patients most likely to benefit from them.	('patients', 'Species', '9606', (204, 212))	('MDM2', 'Gene', (22, 26))	('inhibitors', 'Var', (27, 37))	('patient', 'Species', '9606', (75, 82))	('patient', 'Species', '9606', (204, 211))
87760	30237864	We identified 523 patients who had undergone FoundationOne testing for MDM2 amplification and whose results were available for analysis.	('MDM2', 'Gene', (71, 75))	('patients', 'Species', '9606', (18, 26))	('amplification', 'Var', (76, 89))
87764	30237864	The highest prevalence of MDM2 amplification by histologic type was found in sarcoma patients (13 of 33 = 39% vs 10 of 114 non-sarcoma patients = 9%; p < 0.0001); the second highest was found in patients with metastatic breast cancer (3 of 56 = 5.3% vs 20 of 91 = 22%; p = 0.0071).	('patients', 'Species', '9606', (135, 143))	('breast cancer', 'Disease', 'MESH:D001943', (220, 233))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('MDM2', 'Gene', (26, 30))	('breast cancer', 'Disease', (220, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (220, 233))	('patients', 'Species', '9606', (85, 93))	('sarcoma', 'Disease', (77, 84))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('patients', 'Species', '9606', (195, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('sarcoma', 'Disease', (127, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('amplification', 'Var', (31, 44))
87765	30237864	Of the 13 sarcoma cases with MDM2 amplification, liposarcoma was the most common histologic subtype (9 patients).	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('MDM2', 'Gene', (29, 33))	('liposarcoma', 'Phenotype', 'HP:0012034', (49, 60))	('sarcoma', 'Disease', (10, 17))	('amplification', 'Var', (34, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('sarcoma', 'Disease', (53, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('liposarcoma', 'Disease', (49, 60))	('common', 'Reg', (74, 80))	('patients', 'Species', '9606', (103, 111))	('sarcoma', 'Disease', 'MESH:D012509', (10, 17))	('liposarcoma', 'Disease', 'MESH:D008080', (49, 60))
87769	30237864	Among the 23 patients with MDM2 amplification, 11 had an RMH score of 0 with a median overall survival (OS) was 24 months, which was significantly longer than the median OS of 6 months among the 12 patients who had an RMH score > 0 (hazard ratio [HR], 3.6; confidence interval [CI], 1.1, 11.5; p = 0.031).	('OS', 'Chemical', '-', (104, 106))	('patients', 'Species', '9606', (198, 206))	('patients', 'Species', '9606', (13, 21))	('amplification', 'Var', (32, 45))	('longer', 'PosReg', (147, 153))	('OS', 'Chemical', '-', (170, 172))	('MDM2', 'Gene', (27, 31))	('RMH', 'Chemical', '-', (218, 221))	('RMH', 'Chemical', '-', (57, 60))
87771	30237864	Sixteen of the 23 patients with MDM2 amplification were noted to have co-occurrence of CDK4 amplification, five had CDKN2A/B loss, and five had MYC amplification.	('CDK', 'molecular_function', 'GO:0004693', ('87', '90'))	('MYC', 'Gene', (144, 147))	('amplification', 'Var', (37, 50))	('CDKN2A/B', 'Gene', '1029;1030', (116, 124))	('amplification', 'Var', (92, 105))	('MYC', 'Gene', '4609', (144, 147))	('patients', 'Species', '9606', (18, 26))	('CDKN2A/B', 'Gene', (116, 124))	('CDK4', 'Gene', '1019', (87, 91))	('CDK4', 'Gene', (87, 91))	('MDM2', 'Gene', (32, 36))
87772	30237864	Other aberrations that co-occurred with MDM2 amplification in this analysis include mutations in TP53 (7 patients), PIK3CA mutation (1), and CCND1 amplification (1).	('PIK3CA', 'Gene', (116, 122))	('MDM2', 'Gene', (40, 44))	('patients', 'Species', '9606', (105, 113))	('mutation', 'Var', (123, 131))	('TP53', 'Gene', '7157', (97, 101))	('amplification', 'Var', (45, 58))	('PIK3CA', 'Gene', '5290', (116, 122))	('CCND1', 'Gene', '595', (141, 146))	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (84, 93))	('CCND1', 'Gene', (141, 146))
87773	30237864	Among the aberrations co-observed, CDK4 amplification was most commonly noted in patients with soft tissue liposarcoma (9 of 16 patients), and CDKN2A/B loss was seen in one patient each with breast cancer not otherwise specified (NOS), adenocarcinoma of the lung, soft tissue liposarcoma, squamous cell carcinoma of unknown primary, and bladder urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('patient', 'Species', '9606', (81, 88))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (337, 365))	('soft tissue liposarcoma', 'Disease', (264, 287))	('adenocarcinoma of the lung', 'Disease', (236, 262))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (289, 312))	('liposarcoma', 'Phenotype', 'HP:0012034', (276, 287))	('soft tissue liposarcoma', 'Disease', (95, 118))	('patient', 'Species', '9606', (128, 135))	('soft tissue liposarcoma', 'Disease', 'MESH:D012983', (264, 287))	('breast cancer', 'Disease', (191, 204))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('CDKN2A/B', 'Gene', (143, 151))	('soft tissue liposarcoma', 'Disease', 'MESH:D012983', (95, 118))	('squamous cell carcinoma', 'Disease', (289, 312))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('OS', 'Chemical', '-', (231, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (356, 365))	('patient', 'Species', '9606', (173, 180))	('CDK4', 'Gene', (35, 39))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (236, 262))	('loss', 'NegReg', (152, 156))	('liposarcoma', 'Phenotype', 'HP:0012034', (107, 118))	('CDKN2A/B', 'Gene', '1029;1030', (143, 151))	('patients', 'Species', '9606', (128, 136))	('CDK4', 'Gene', '1019', (35, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (289, 312))	('patients', 'Species', '9606', (81, 89))	('bladder urothelial carcinoma', 'Disease', (337, 365))	('CDK', 'molecular_function', 'GO:0004693', ('35', '38'))	('amplification', 'Var', (40, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (280, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
87775	30237864	TP53 mutation was seen in one patient each with kidney urothelial carcinoma, Ewing sarcoma, soft tissue liposarcoma, invasive ductal carcinoma of the breast, breast carcinoma NOS, hepatocellular carcinoma, and salivary adenocarcinoma NOS.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('Ewing sarcoma', 'Disease', (77, 90))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (180, 204))	('salivary adenocarcinoma NOS', 'Disease', 'MESH:D000230', (210, 237))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (133, 156))	('TP53', 'Gene', '7157', (0, 4))	('invasive ductal carcinoma of the breast, breast carcinoma NOS, hepatocellular carcinoma', 'Disease', 'MESH:D018270', (117, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (126, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('kidney urothelial carcinoma', 'Disease', 'MESH:D007674', (48, 75))	('patient', 'Species', '9606', (30, 37))	('kidney urothelial carcinoma', 'Phenotype', 'HP:0030409', (48, 75))	('kidney urothelial carcinoma', 'Disease', (48, 75))	('seen', 'Reg', (18, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (77, 90))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (77, 90))	('soft tissue liposarcoma', 'Disease', (92, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('salivary adenocarcinoma NOS', 'Disease', (210, 237))	('liposarcoma', 'Phenotype', 'HP:0012034', (104, 115))	('TP53', 'Gene', (0, 4))	('soft tissue liposarcoma', 'Disease', 'MESH:D012983', (92, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('breast carcinoma', 'Phenotype', 'HP:0003002', (158, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('mutation', 'Var', (5, 13))
87777	30237864	For the 23 patients with MDM2 amplification, we determined the copy numbers (CNs), as determined via next-generation sequencing by FoundationOne: total, 6-150 CNs; mean, 30.39; and median, 16.	('patients', 'Species', '9606', (11, 19))	('MDM2', 'Gene', (25, 29))	('amplification', 'Var', (30, 43))
87782	30237864	Two of the three tumors had TP53 mutation, and all three had MYC amplification.	('TP53', 'Gene', '7157', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mutation', 'Var', (33, 41))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (17, 23))	('TP53', 'Gene', (28, 32))	('MYC', 'Gene', '4609', (61, 64))	('MYC', 'Gene', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
87783	30237864	As shown in Figure 1, the median OS in patients with MDM2 amplification was 13.6 months versus 10.6 months in patients without amplification (p = 0.12).	('patients', 'Species', '9606', (39, 47))	('MDM2', 'Gene', (53, 57))	('OS', 'Chemical', '-', (33, 35))	('amplification', 'Var', (58, 71))	('patients', 'Species', '9606', (110, 118))
87785	30237864	The median overall age was 56 years (range = 15-81 years); the median age of patients with MDM2 amplification was 58 years (range = 23-77 years); and the median age of patients without MDM2 amplification was 55 years (range = 15-81 years).	('amplification', 'Var', (96, 109))	('patients', 'Species', '9606', (77, 85))	('MDM2', 'Gene', (91, 95))	('patients', 'Species', '9606', (168, 176))
87788	30237864	Six of the 23 patients with MDM2 amplification were enrolled in a trial involving an MDM2 inhibitor.	('amplification', 'Var', (33, 46))	('patients', 'Species', '9606', (14, 22))	('MDM2', 'Gene', (28, 32))
87792	30237864	TP53 mutation was noted in one of these six patients (this patient had enrolled prior to the availability of FoundationOne results).	('TP53', 'Gene', '7157', (0, 4))	('patient', 'Species', '9606', (44, 51))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (44, 52))	('patient', 'Species', '9606', (59, 66))	('mutation', 'Var', (5, 13))
87793	30237864	None of the 23 patients with MDM2 amplification was treated with prior immunotherapy.	('amplification', 'Var', (34, 47))	('patients', 'Species', '9606', (15, 23))	('MDM2', 'Gene', (29, 33))
87794	30237864	To our knowledge, this study is the largest analysis of MDM2 amplification in solid tumors reported in the current literature.	('solid tumors', 'Disease', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('amplification', 'Var', (61, 74))	('solid tumors', 'Disease', 'MESH:D009369', (78, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('MDM2', 'Gene', (56, 60))
87796	30237864	MDM2 amplification was most frequent in patients with liposarcoma, followed by patients with metastatic breast cancer.	('liposarcoma', 'Disease', (54, 65))	('amplification', 'Var', (5, 18))	('patients', 'Species', '9606', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('liposarcoma', 'Phenotype', 'HP:0012034', (54, 65))	('liposarcoma', 'Disease', 'MESH:D008080', (54, 65))	('breast cancer', 'Disease', (104, 117))	('MDM2', 'Gene', (0, 4))	('frequent', 'Reg', (28, 36))	('patients', 'Species', '9606', (79, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
87797	30237864	Other aberrations that most frequently co-occurred with MDM2 amplification were CDK4 amplification, CDKN2A/B loss, and MYC amplification.	('CDK4', 'Gene', (80, 84))	('CDKN2A/B', 'Gene', (100, 108))	('CDK4', 'Gene', '1019', (80, 84))	('loss', 'NegReg', (109, 113))	('CDK', 'molecular_function', 'GO:0004693', ('80', '83'))	('MYC', 'Gene', '4609', (119, 122))	('amplification', 'Var', (61, 74))	('amplification', 'Var', (85, 98))	('CDKN2A/B', 'Gene', '1029;1030', (100, 108))	('MYC', 'Gene', (119, 122))	('MDM2', 'Gene', (56, 60))
87798	30237864	Concomitant alterations of MDM2 and CDK4 are known and have been described in liposarcoma.	('described', 'Reg', (65, 74))	('liposarcoma', 'Disease', (78, 89))	('alterations', 'Var', (12, 23))	('CDK4', 'Gene', (36, 40))	('CDK4', 'Gene', '1019', (36, 40))	('CDK', 'molecular_function', 'GO:0004693', ('36', '39'))	('MDM2', 'Gene', (27, 31))	('liposarcoma', 'Phenotype', 'HP:0012034', (78, 89))	('liposarcoma', 'Disease', 'MESH:D008080', (78, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
87799	30237864	Previous studies have suggested that the presence of neochromosomes in cancer and sarcoma in particular, could explain the mechanism of MDM2 amplification in these tumors.	('neochromosomes', 'Var', (53, 67))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Disease', (164, 170))	('cancer', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('MDM2', 'Gene', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('sarcoma', 'Disease', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
87800	30237864	Neochromosomes, which are extra chromosomal structures that harbor oncogenes at high copy numbers, could incorporate Chr12q fragments including MDM2, and drive tumorigenesis.	('drive', 'PosReg', (154, 159))	('incorporate', 'Reg', (105, 116))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('MDM2', 'Gene', (144, 148))	('tumor', 'Disease', (160, 165))	('Chr12q fragments', 'Var', (117, 133))
87806	30237864	Grunewald et al reported co-expression of CDK4 amplification with MDM2 amplification in one patient with salivary duct carcinoma.	('CDK4', 'Gene', '1019', (42, 46))	('patient', 'Species', '9606', (92, 99))	('CDK', 'molecular_function', 'GO:0004693', ('42', '45'))	('salivary duct carcinoma', 'Disease', 'MESH:D012465', (105, 128))	('amplification', 'Var', (71, 84))	('amplification', 'Var', (47, 60))	('salivary duct carcinoma', 'Disease', (105, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('MDM2', 'Gene', (66, 70))	('CDK4', 'Gene', (42, 46))
87809	30237864	The significance of our study lies in the larger number of patients tested for MDM2 amplification in our analysis compared to what has been previously reported.	('amplification', 'Var', (84, 97))	('patients', 'Species', '9606', (59, 67))	('MDM2', 'Gene', (79, 83))
87814	30237864	Three of the 23 (13%) patients with MDM2 amplification had a diagnosis of metastatic breast cancer.	('MDM2', 'Gene', (36, 40))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('patients', 'Species', '9606', (22, 30))	('amplification', 'Var', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
87815	30237864	Despite the high percentage in this very limited series, two of these three patients harbored mutant TP53 and therefore were not eligible for enrollment in trials involving an MDM2 inhibitor.	('patients', 'Species', '9606', (76, 84))	('harbored', 'Reg', (85, 93))	('TP53', 'Gene', '7157', (101, 105))	('mutant', 'Var', (94, 100))	('TP53', 'Gene', (101, 105))
87816	30237864	Most MDM2 inhibitors under development target the MDM2-p53 complex, including Nutlin-3, RITA, MI-219, AMG232, and SAR405838.	('MI-219', 'Disease', (94, 100))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('RITA', 'Gene', '84934', (88, 92))	('MI-219', 'Disease', 'MESH:D009203', (94, 100))	('SAR405838', 'Var', (114, 123))	('RITA', 'Gene', (88, 92))
87817	30237864	These inhibitors have little or no effect on cancers with mutant TP53.	('mutant', 'Var', (58, 64))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))
87822	30237864	The frequency of mutant TP53 in breast cancer has been reported to be 30% to 73%, but it fluctuates widely between subclasses of breast cancer.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Disease', (32, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('TP53', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('mutant', 'Var', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('TP53', 'Gene', '7157', (24, 28))
87823	30237864	As a result, MDM2 inhibitors have no significant anticancer activity in such tumors.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('MDM2', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('inhibitors', 'Var', (18, 28))
87825	30237864	One very interesting finding in our analysis was the presence of mutant TP53 in seven patients.	('TP53', 'Gene', '7157', (72, 76))	('mutant', 'Var', (65, 71))	('TP53', 'Gene', (72, 76))	('presence', 'Reg', (53, 61))	('patients', 'Species', '9606', (86, 94))
87827	30237864	Nonetheless, the co-existence of mutant TP53 with MDM2 amplification is surprising, as they have been thought to be alternative mechanisms for inactivating the suppressing cell growth pathway and thus mutually exclusive.	('cell growth', 'biological_process', 'GO:0016049', ('172', '183'))	('suppressing cell growth pathway', 'Pathway', (160, 191))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('inactivating', 'NegReg', (143, 155))	('mutant', 'Var', (33, 39))
87828	30237864	A recent study by Sanchez-Vega et al reports the mutual exclusivity of TP53 mutations and MDM2 amplification in tumors profiled by The Cancer Genome Atlas (TCGA).	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (135, 154))	('mutations', 'Var', (76, 85))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('TP53', 'Gene', '7157', (71, 75))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('TP53', 'Gene', (71, 75))	('MDM2', 'Gene', (90, 94))	('Cancer Genome Atlas', 'Disease', (135, 154))
87830	30237864	Tumors with mutant TP53 are canonically thought to not respond to MDM2 inhibition.	('mutant', 'Var', (12, 18))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Disease', (0, 6))	('TP53', 'Gene', '7157', (19, 23))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TP53', 'Gene', (19, 23))
87831	30237864	Our analysis clearly shows that this is not a mutually exclusive phenomenon and that subsets of patients with MDM2 amplification also have a co-existing mutant TP53.	('amplification', 'Var', (115, 128))	('TP53', 'Gene', '7157', (160, 164))	('mutant', 'Var', (153, 159))	('TP53', 'Gene', (160, 164))	('patients', 'Species', '9606', (96, 104))	('MDM2', 'Gene', (110, 114))
87834	30237864	However, only one case had both TP53 mutation and high levels of MDM2 mRNA.	('MDM2 mRNA', 'MPA', (65, 74))	('TP53', 'Gene', '7157', (32, 36))	('TP53', 'Gene', (32, 36))	('mutation', 'Var', (37, 45))
87838	30237864	However, overexpression of MDM2 and p53 proteins in the nuclei of tumor cells is not correlated with MDM2 gene amplification or TP53 mutation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutation', 'Var', (133, 141))	('tumor', 'Disease', (66, 71))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('MDM2', 'Gene', (101, 105))
87839	30237864	Co-occurrence of MDM2 amplification and TP53 mutation was also noted in two patients by Grunewald et al as well.	('patients', 'Species', '9606', (76, 84))	('MDM2', 'Gene', (17, 21))	('amplification', 'Var', (22, 35))	('TP53', 'Gene', '7157', (40, 44))	('mutation', 'Var', (45, 53))	('TP53', 'Gene', (40, 44))
87840	30237864	Drummond et al reported that TP53 mutant, MDM2 amplified cell lines that were resistant to MDM2 inhibitors retain sensitivity to ionizing radiation and suggested that such patients may have alternative treatment options like radiation therapy.	('TP53', 'Gene', '7157', (29, 33))	('sensitivity to ionizing radiation', 'MPA', (114, 147))	('TP53', 'Gene', (29, 33))	('patients', 'Species', '9606', (172, 180))	('sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (114, 147))	('mutant', 'Var', (34, 40))
87841	30237864	Saiki et al demonstrated that MDM2 amplification and TP53 mutation are not mutually exclusive in tumor cell lines, possibly because of a misidentified TP53 mutation or heterozygous TP53 mutation or because cell lines harbor viral gene sequences known to inactivate p53.	('p53', 'Gene', (265, 268))	('p53', 'Gene', '7157', (265, 268))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('TP53', 'Gene', (181, 185))	('TP53', 'Gene', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', '7157', (151, 155))	('TP53', 'Gene', '7157', (181, 185))	('mutation', 'Var', (186, 194))	('TP53', 'Gene', (53, 57))	('mutation', 'Var', (156, 164))
87843	30237864	On the basis of this observation and our results which also showed that MDM2 amplification and TP53 mutations are not mutually exclusive in advanced cancers, alteration in one gene should not preclude testing for the other.	('mutations', 'Var', (100, 109))	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('cancers', 'Disease', 'MESH:D009369', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('MDM2', 'Gene', (72, 76))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
87845	30237864	The reported incidence of MDM2 amplification in various series conducted in single tumor types (0% to 6.3%) is consistent with our findings.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('MDM2', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('amplification', 'Var', (31, 44))
87846	30237864	Grunewald et al, in a series of 51 patients with salivary duct carcinomas, reported MDM2 amplification in three patients (5.8%), as well as synchronous CDK4 and MDM2 amplification in one patient with a co-expression rate of 33.3%.	('MDM2', 'Gene', (84, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('CDK4', 'Gene', '1019', (152, 156))	('CDK4', 'Gene', (152, 156))	('patient', 'Species', '9606', (112, 119))	('MDM2', 'Gene', (161, 165))	('patient', 'Species', '9606', (35, 42))	('patients', 'Species', '9606', (112, 120))	('salivary duct carcinomas', 'Phenotype', 'HP:0100684', (49, 73))	('CDK', 'molecular_function', 'GO:0004693', ('152', '155'))	('salivary duct carcinomas', 'Disease', (49, 73))	('salivary duct carcinomas', 'Disease', 'MESH:D012465', (49, 73))	('amplification', 'Var', (89, 102))	('patient', 'Species', '9606', (187, 194))	('patients', 'Species', '9606', (35, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
87848	30237864	Michalk et al reported a 6.3% incidence of MDM2 amplification in esophageal carcinomas (adenocarcinoma and squamous cell carcinoma), and Schoolmeester et al found an incidence of 5% (2 of 43 cases) in endometrial stromal tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (65, 86))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('carcinoma', 'Disease', (121, 130))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (107, 130))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('carcinoma', 'Disease', 'MESH:D002277', (76, 85))	('MDM2', 'Gene', (43, 47))	('squamous cell carcinoma', 'Disease', (107, 130))	('tumors', 'Disease', (221, 227))	('carcinoma', 'Disease', 'MESH:D002277', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('carcinoma', 'Disease', (93, 102))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('amplification', 'Var', (48, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('carcinoma', 'Disease', (76, 85))	('carcinoma', 'Disease', 'MESH:D002277', (93, 102))
87850	30237864	Zhu et al reported the first documented cases of MDM2 amplification in laryngeal and hypopharyngeal liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (100, 111))	('liposarcoma', 'Disease', 'MESH:D008080', (100, 111))	('amplification', 'Var', (54, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('laryngeal', 'Disease', (71, 80))	('liposarcoma', 'Disease', (100, 111))	('MDM2', 'Gene', (49, 53))
87852	30237864	None of the 23 patients with MDM2 amplification in our analysis was treated with prior immunotherapy as of the cut-off date.	('amplification', 'Var', (34, 47))	('patients', 'Species', '9606', (15, 23))	('MDM2', 'Gene', (29, 33))
87853	30237864	Our analysis constitutes, to our knowledge, one of the largest series of solid tumors tested for MDM2 amplification at a single center.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('solid tumors', 'Disease', (73, 85))	('amplification', 'Var', (102, 115))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('MDM2', 'Gene', (97, 101))	('solid tumors', 'Disease', 'MESH:D009369', (73, 85))
87856	30237864	Regardless of these limitations, we found that MDM2 amplification in solid tumors was associated with liposarcoma, metastatic breast cancer, CDK4 amplification, TP53 mutation, CDKN2A/B loss, and MYC amplification.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('MYC', 'Gene', (195, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('CDKN2A/B', 'Gene', (176, 184))	('solid tumors', 'Disease', (69, 81))	('liposarcoma', 'Phenotype', 'HP:0012034', (102, 113))	('amplification', 'Var', (52, 65))	('CDK', 'molecular_function', 'GO:0004693', ('141', '144'))	('amplification', 'Var', (146, 159))	('CDK4', 'Gene', '1019', (141, 145))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Disease', (126, 139))	('associated', 'Reg', (86, 96))	('MYC', 'Gene', '4609', (195, 198))	('liposarcoma', 'Disease', 'MESH:D008080', (102, 113))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('solid tumors', 'Disease', 'MESH:D009369', (69, 81))	('TP53', 'Gene', (161, 165))	('CDKN2A/B', 'Gene', '1029;1030', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutation', 'Var', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('MDM2', 'Gene', (47, 51))	('liposarcoma', 'Disease', (102, 113))	('TP53', 'Gene', '7157', (161, 165))	('CDK4', 'Gene', (141, 145))
87882	28426276	This work identified the global DNA methylation dysregulation patterns across 14 cancer types showing a higher impact for the non-CpG island areas.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('cancer', 'Disease', (81, 87))	('dysregulation', 'Var', (48, 61))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('DNA methylation', 'biological_process', 'GO:0006306', ('32', '47'))
87885	28426276	Typically, cancers include hundreds of somatic alterations to DNA, overcoming programs that control replication and apoptosis to allow survival and growth.	('cancers', 'Disease', (11, 18))	('DNA', 'Gene', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('alterations', 'Var', (47, 58))	('cancers', 'Disease', 'MESH:D009369', (11, 18))
87889	28426276	Recently, pan-cancer analyses have reported functional mutations, immunogenomic signature, and copy number alterations.	('cancer', 'Disease', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('copy number alterations', 'Var', (95, 118))
87895	28426276	Diverse methylomes within tumor type have been associated with tumor characteristics and patient prognosis.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('patient', 'Species', '9606', (89, 96))	('methylomes', 'Var', (8, 18))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('associated', 'Reg', (47, 57))
87921	28426276	Extending our assessment to summary measures of genetic somatic alterations, overall copy number alterations:represented by the fraction of the genome altered (FGA):median was 17.4%, though this had a wide IQR (4.75 to 34.3%).	('copy number alterations', 'Var', (85, 108))	('FGA', 'Gene', (160, 163))	('FGA', 'Gene', '2243', (160, 163))
87927	28426276	In contrast, the summary measures of genetic somatic alterations FGA and MCB, also presented in the figure, showed a different order and magnitude across cancer types.	('MCB', 'Gene', (73, 76))	('cancer', 'Disease', (154, 160))	('alterations', 'Var', (53, 64))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('FGA', 'Gene', '2243', (65, 68))	('FGA', 'Gene', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('MCB', 'Chemical', '-', (73, 76))
87931	28426276	Next, we visualized the gcMDI for all samples using unsupervised clustering and for each cancer type set four classes: high dysregulation, high-intermediate dysregulation, low-intermediate dysregulation, and low dysregulation (Fig.	('high dysregulation', 'Var', (119, 137))	('low-intermediate dysregulation', 'Var', (172, 202))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('low', 'Disease', (208, 211))	('cancer', 'Disease', (89, 95))	('high-intermediate dysregulation', 'Var', (139, 170))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
87960	28426276	Several CpG sites were related to long noncoding RNA or antisense genes (OTX2-AS1, LINC00466, TFAP2A-AS1, LHX5-AS1, LOC100507443, LIN28B-AS1, PAUPAR, DKFZp686K1684), transcription and regulatory factors (TFAP2B, USP44), and genes encoding tumor suppressor proteins (TRIM15, CASZ1).	('LINC00466', 'Gene', '199899', (83, 92))	('AS1', 'Gene', (111, 114))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('239', '255'))	('USP44', 'Gene', (212, 217))	('TRIM15', 'Gene', (266, 272))	('PAUPAR', 'Gene', '103157000', (142, 148))	('LINC00466', 'Gene', (83, 92))	('AS1', 'Gene', (78, 81))	('AS1', 'Gene', '5729', (137, 140))	('tumor suppressor', 'biological_process', 'GO:0051726', ('239', '255'))	('LOC100507443', 'Gene', (116, 128))	('CASZ1', 'Gene', (274, 279))	('AS1', 'Gene', (101, 104))	('LHX5-AS1', 'Gene', '104355219;64211;5729', (106, 114))	('CASZ1', 'Gene', '54897', (274, 279))	('tumor', 'Disease', (239, 244))	('TRIM15', 'Gene', '89870', (266, 272))	('USP44', 'Gene', '84101', (212, 217))	('TFAP2A-AS1', 'Gene', '100130275;7020;5729', (94, 104))	('AS1', 'Gene', '5729', (111, 114))	('LIN28B', 'Gene', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('TFAP2A-AS1', 'Gene', (94, 104))	('antisense', 'Gene', (56, 65))	('TFAP2B', 'Gene', '7021', (204, 210))	('AS1', 'Gene', '5729', (78, 81))	('AS1', 'Gene', (137, 140))	('LHX5-AS1', 'Gene', (106, 114))	('LOC100507443', 'Gene', '100507443', (116, 128))	('OTX2-AS1', 'Gene', (73, 81))	('RNA', 'cellular_component', 'GO:0005562', ('49', '52'))	('TFAP2B', 'Gene', (204, 210))	('transcription', 'biological_process', 'GO:0006351', ('166', '179'))	('AS1', 'Gene', '5729', (101, 104))	('PAUPAR', 'Gene', (142, 148))	('OTX2-AS1', 'Gene', '100309464;5015;5729', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('USP', 'molecular_function', 'GO:0051748', ('212', '215'))	('LIN28B', 'Gene', '389421', (130, 136))	('DKFZp686K1684', 'Var', (150, 163))
87961	28426276	In addition, several commonly altered CpG sites were located in enhancer elements (cg10903903, cg17754510, cg22797031, cg13539545, cg08443563) and a few were spatially near to the histone related cluster of chromosome 6 (cg10903903-HIST1H2BL, and cg01518607-PRSS16).	('cg17754510', 'Var', (95, 105))	('cg22797031', 'Var', (107, 117))	('cg10903903', 'Var', (83, 93))	('PRSS16', 'Gene', (258, 264))	('enhancer', 'PosReg', (64, 72))	('HIST1H2BL', 'Gene', '8340', (232, 241))	('HIST1H2BL', 'Gene', (232, 241))	('PRSS16', 'Gene', '10279', (258, 264))	('chromosome', 'cellular_component', 'GO:0005694', ('207', '217'))	('cg08443563', 'Var', (131, 141))	('cg13539545', 'Var', (119, 129))
87965	28426276	Globally, the amount of dysregulation was lower in CpG island regions compared with other genomic regions, such as CpG island shores and shelves, and those in less CpG dense regions across tumor types.	('tumor', 'Disease', (189, 194))	('lower', 'NegReg', (42, 47))	('dysregulation', 'MPA', (24, 37))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('CpG', 'Var', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
87967	28426276	This finding was further supported when analyzing the specific loci dysregulation, in which these cancer types cluster together; three of the four showed a pattern of loci dysregulation associated to specific metabolic genes, proto-oncogenes and oncogenes.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('dysregulation', 'Var', (172, 185))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
87969	28426276	In contrast, age was consistently associated with MDI in breast cancer and hepatocellular carcinoma globally and across the different genomic contexts.	('breast cancer', 'Disease', (57, 70))	('associated', 'Reg', (34, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('hepatocellular carcinoma globally', 'Disease', (75, 108))	('hepatocellular carcinoma globally', 'Disease', 'MESH:D006528', (75, 108))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (75, 99))	('MDI', 'Var', (50, 53))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
87978	28426276	Specific reported mutations associated with differential methylation (CIMP phenotypes) differ by cancer subtype, which precludes an integrative analysis of specific mutation signatures for all the samples.	('mutations', 'Var', (18, 27))	('CIMP', 'Chemical', '-', (70, 74))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('differential methylation', 'MPA', (44, 68))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
87987	28426276	This work contributes to the understanding of the impact of epigenetic alterations from a pan-cancer perspective.	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('epigenetic alterations', 'Var', (60, 82))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
87996	28426276	Although copy number alterations do not bias DNA methylation signals, biologically they are drivers of other cancer alterations which may alter DNA methylation levels, and were therefore included in our models.	('DNA methylation levels', 'MPA', (144, 166))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('alter', 'Reg', (138, 143))	('DNA methylation', 'biological_process', 'GO:0006306', ('45', '60'))	('copy number alterations', 'Var', (9, 32))	('DNA methylation', 'biological_process', 'GO:0006306', ('144', '159'))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))
87997	28426276	Information on the fraction of the genome with copy number alterations (FGA) and mutation count burden (MCB) were retrieved from cBioportal.	('FGA', 'Gene', (72, 75))	('MCB', 'Chemical', '-', (104, 107))	('FGA', 'Gene', '2243', (72, 75))	('copy number alterations', 'Var', (47, 70))
87998	28426276	FGA was measured using Affymetrix SNP arrays and corresponds to the fraction of the genome affected by copy number alterations, which is equivalent to the number of bases in segments with mean log2 greater than 0.2 or smaller than -0.2 divided by the number of bases in all segments profiled by the array.	('FGA', 'Gene', '2243', (0, 3))	('alterations', 'Var', (115, 126))	('copy number alterations', 'Var', (103, 126))	('affected by', 'Reg', (91, 102))	('FGA', 'Gene', (0, 3))
88031	28955911	Knock-down of S100A14 in BFTC905 also leads to an increase in the number of the cells in the S phase and higher mobility, suggesting that SOX2 suppresses cell growth and mobility through promoting the expression of S100A14.	('BFTC905', 'Gene', (25, 32))	('BFTC905', 'Chemical', '-', (25, 32))	('cell growth', 'biological_process', 'GO:0016049', ('154', '165'))	('S100A14', 'Gene', '57402', (14, 21))	('higher mobility', 'CPA', (105, 120))	('S100A14', 'Gene', (215, 222))	('Knock-down', 'Var', (0, 10))	('S phase', 'biological_process', 'GO:0051320', ('93', '100'))	('increase', 'PosReg', (50, 58))	('S100A14', 'Gene', (14, 21))	('suppresses', 'NegReg', (143, 153))	('promoting', 'PosReg', (187, 196))	('S100A14', 'Gene', '57402', (215, 222))	('expression', 'MPA', (201, 211))
88055	28955911	BFTC905/shLuc and BFTC905/shSOX2 were subsequently transfected with pTagRFP-N (Evrogen, Moscow, Russia) and pEGFP-C1 (Takara, Kyoto, Japan), respectively.	('pTagRFP-N', 'Gene', (68, 77))	('BFTC905', 'Chemical', '-', (0, 7))	('pEGFP-C1', 'Var', (108, 116))	('BFTC905', 'Chemical', '-', (18, 25))	('pTagRFP-N', 'Chemical', '-', (68, 77))	('BFTC905/shSOX2', 'Var', (18, 32))
88060	28955911	These fragments correspond to the S100A14 mRNA sequence at nt 471-589, 566-622, 643-784, 758-866, 842-930, and 907-1018.	('S100A14', 'Gene', '57402', (34, 41))	('S100A14', 'Gene', (34, 41))	('643-784', 'Var', (80, 87))
88070	28955911	The primary antibodies used for immunoblotting were anti-SOX2 (Abcam, Cambridge, UK), anti-S100A14 (Proteintech, Chicago, IL, USA) and anti-alpha-tubulin (Thermo Fisher) antibodies.	('S100A14', 'Gene', '57402', (91, 98))	('anti-alpha-tubulin', 'Protein', (135, 153))	('S100A14', 'Gene', (91, 98))	('anti-SOX2', 'Var', (52, 61))
88078	28955911	Sequencing was performed on an Illumina Miseq sequencer and provided 10,268,595 and 11,419,579 paired-end 150-base reads for BFTC905/shLuc and BFTC905/shSOX2, respectively.	('BFTC905', 'Chemical', '-', (125, 132))	('BFTC905', 'Chemical', '-', (143, 150))	('BFTC905/shSOX2', 'Var', (143, 157))	('BFTC905/shLuc', 'Var', (125, 138))
88106	28955911	Cleavage of the S100A14 mRNA by RNase H produces the ORF and 3'-UTR fragments, and the ORF and 3'-UTR fragments was detected by RT-PCR (Fig.	('Cleavage', 'Var', (0, 8))	('S100A14', 'Gene', '57402', (16, 23))	('ORF', 'MPA', (53, 56))	('S100A14', 'Gene', (16, 23))	("3'-UTR fragments", 'MPA', (61, 77))
88115	28955911	Among these probes, the probes 687-718 and 709-740 showed retarded mobility.	('retarded mobility', 'Disease', 'MESH:D014086', (58, 75))	('709-740', 'Var', (43, 50))	('retarded mobility', 'Disease', (58, 75))
88116	28955911	Furthermore, ectopic expression of SOX2 increases the retardation of probe 684-710, but not probe 710-740 (Fig.	('increases the retardation', 'Disease', (40, 65))	('SOX2', 'Gene', (35, 39))	('increases the retardation', 'Disease', 'MESH:D008607', (40, 65))	('ectopic expression', 'Var', (13, 31))	('probe 684-710', 'Var', (69, 82))
88123	28955911	Compared to the control BFTC905/shLuc, BFTC905/shSOX2 displayed a slightly faster growth rate (Fig.	('growth rate', 'CPA', (82, 93))	('BFTC905', 'Chemical', '-', (24, 31))	('faster', 'PosReg', (75, 81))	('BFTC905', 'Chemical', '-', (39, 46))	('BFTC905/shSOX2', 'Var', (39, 53))
88124	28955911	Cell cycle analysis showed that the percentage of BFTC905/shSOX2 cells in S and G1 phases was slightly increased and decreased, respectively (Fig.	('BFTC905/shSOX2', 'Var', (50, 64))	('decreased', 'NegReg', (117, 126))	('BFTC905', 'Chemical', '-', (50, 57))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('G1 phases', 'CPA', (80, 89))
88132	28955911	Together, our data indicate that expression of SOX2 slows the growth of BFTC905.	('slows', 'NegReg', (52, 57))	('expression', 'Var', (33, 43))	('BFTC905', 'Gene', (72, 79))	('BFTC905', 'Chemical', '-', (72, 79))	('growth', 'MPA', (62, 68))
88134	28955911	In the wound healing assay, the BFTC905/shSOX2 cells narrowed the gap more rapidly than the control BFTC905/shLuc cells (Fig.	('gap', 'MPA', (66, 69))	('BFTC905/shSOX2', 'Var', (32, 46))	('wound healing', 'biological_process', 'GO:0042060', ('7', '20'))	('BFTC905', 'Chemical', '-', (100, 107))	('BFTC905', 'Chemical', '-', (32, 39))	('narrowed', 'NegReg', (53, 61))
88136	28955911	In contrast, expression of SOX2 decreased the mobility of S100A14 (Fig.	('S100A14', 'Gene', (58, 65))	('expression', 'Var', (13, 23))	('mobility', 'MPA', (46, 54))	('decreased', 'NegReg', (32, 41))	('S100A14', 'Gene', '57402', (58, 65))
88137	28955911	We also examined the effect of SOX2 suppression by seeding mixed BFTC905/shLuc-TagRFP and BFTC905/shSOX2-EGFP cells in the upper chamber of the transwell apparatus.	('RFP', 'Gene', '5987', (82, 85))	('BFTC905', 'Chemical', '-', (65, 72))	('BFTC905/shSOX2-EGFP', 'Var', (90, 109))	('BFTC905', 'Chemical', '-', (90, 97))	('RFP', 'Gene', (82, 85))
88155	28955911	It has been shown that stem cell markers, such as SOX2, are activated more frequently in poorly differentiated tumors and are generally correlated with a poor prognosis, suggesting that a reversal to a stem cell property facilitates the growth and invasiveness of tumours.	('invasiveness of tumours', 'Disease', 'MESH:D009361', (248, 271))	('invasiveness of tumours', 'Disease', (248, 271))	('poorly differentiated', 'Disease', (89, 110))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('SOX2', 'Gene', (50, 54))	('reversal', 'Var', (188, 196))	('facilitates', 'PosReg', (221, 232))	('activated', 'PosReg', (60, 69))	('tumours', 'Phenotype', 'HP:0002664', (264, 271))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))
88157	28955911	However, SOX2 expression is required to maintain normal gastric epithelial stem cells, and the loss of SOX2 leads to a complete conversion from gastric to intestinal epithelial characteristics.. Epigenetic silencing of SOX2 was frequently observed in intestinal-type gastric cancer, and poor prognosis was associated with the down-regulation of SOX2.	('SOX2', 'Gene', (219, 223))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('gastric cancer', 'Phenotype', 'HP:0012126', (267, 281))	('observed', 'Reg', (239, 247))	('intestinal-type gastric cancer', 'Disease', (251, 281))	('Epigenetic silencing', 'Var', (195, 215))	('regulation', 'biological_process', 'GO:0065007', ('331', '341'))	('intestinal-type gastric cancer', 'Disease', 'MESH:D013274', (251, 281))
88158	28955911	Expression of SOX2 have been confirmed in urothelial carcinoma, and expression of SOX2 in non-muscle-invasive bladder cancer was correlated with tumor size and poorer survival.	('bladder cancer', 'Disease', 'MESH:D001749', (110, 124))	('bladder cancer', 'Disease', (110, 124))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (42, 62))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'Var', (68, 78))	('tumor', 'Disease', (145, 150))	('correlated', 'Reg', (129, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (110, 124))	('invasive bladder', 'Phenotype', 'HP:0100645', (101, 117))	('confirmed', 'Reg', (29, 38))	('SOX2', 'Gene', (82, 86))	('urothelial carcinoma', 'Disease', (42, 62))
88166	28955911	On the other hand, TSGH8301, an urothelial carcinoma cell line from a poor-differentiated stage-II patient, displays weaker attachment to the culture surface nor adheres to the neighboring cells.	('TSGH8301', 'Var', (19, 27))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (32, 52))	('patient', 'Species', '9606', (99, 106))	('urothelial carcinoma', 'Disease', (32, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('attachment', 'CPA', (124, 134))	('weaker', 'NegReg', (117, 123))	('adheres', 'CPA', (162, 169))
88167	28955911	In addition to the urothelial carcinoma, loss of SOX2 may also play a role in oncogenesis of other epithelial tissues in which SOX2 is required for normal function and maintenance.	('SOX2', 'Gene', (49, 53))	('loss', 'Var', (41, 45))	('oncogenesis', 'CPA', (78, 89))	('urothelial carcinoma', 'Disease', (19, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('oncogenesis', 'biological_process', 'GO:0007048', ('78', '89'))	('play', 'Reg', (63, 67))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (19, 39))
88175	25124389	A final histopathology examination of a cystoprostatectomy specimen revealed a pT3b, G3 urothelial carcinoma of clear cell type (>90% clear cells) and a prostatic adenocarcinoma of Gleason grade 3+3 (score=6).	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('urothelial carcinoma', 'Disease', (88, 108))	('pT3b', 'Var', (79, 83))	('prostatic adenocarcinoma', 'Disease', 'MESH:D011471', (153, 177))	('prostatic adenocarcinoma', 'Disease', (153, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('men', 'Species', '9606', (64, 67))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (88, 108))
88223	25124389	The overall apparent pattern of PAS/PAS-D reactivity correlated with tumor grade; in general, low-grade superficial urothelial cell carcinomas tended to have stronger diffuse staining, whereas poorly differentiated tumors tended to have negative or focal positivity.	('PAS', 'cellular_component', 'GO:0000407', ('32', '35'))	('urothelial cell carcinomas', 'Disease', (116, 142))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumors', 'Disease', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('PAS', 'Chemical', '-', (32, 35))	('PAS', 'cellular_component', 'GO:0000407', ('36', '39'))	('urothelial cell carcinomas', 'Disease', 'MESH:C538614', (116, 142))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('stronger', 'PosReg', (158, 166))	('tumor', 'Disease', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('diffuse staining', 'MPA', (167, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('PAS', 'Chemical', '-', (36, 39))	('low-grade', 'Var', (94, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('D', 'Chemical', 'MESH:D003903', (40, 41))
88267	32435155	Association of human XPA rs1800975 polymorphism and cancer susceptibility: an integrative analysis of 71 case-control studies The objective of the present study is to comprehensively evaluate the impact of the rs1800975 A/G polymorphism within the human xeroderma pigmentosum group A (XPA) gene on susceptibility to overall cancer by performing an integrative analysis of the current evidence.	('cancer', 'Disease', (324, 330))	('rs1800975', 'Mutation', 'rs1800975', (210, 219))	('XPA', 'Gene', '7507', (285, 288))	('human', 'Species', '9606', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('XPA', 'Gene', (285, 288))	('rs1800975', 'Mutation', 'rs1800975', (25, 34))	('human', 'Species', '9606', (248, 253))	('rs1800975 A/G', 'Var', (210, 223))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (254, 275))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('XPA', 'Gene', (21, 24))	('cancer', 'Disease', 'MESH:D009369', (324, 330))	('XPA', 'Gene', '7507', (21, 24))	('xeroderma pigmentosum', 'Disease', (254, 275))
88272	32435155	However, our eQTL/sQTL data did not support the strong links of rs1800975 with the gene expression or splicing changes of XPA in the skin tissue.	('gene expression', 'biological_process', 'GO:0010467', ('83', '98'))	('rs1800975', 'Var', (64, 73))	('rs1800975', 'Mutation', 'rs1800975', (64, 73))	('splicing', 'biological_process', 'GO:0045292', ('102', '110'))	('XPA', 'Gene', (122, 125))	('XPA', 'Gene', '7507', (122, 125))
88273	32435155	In addition, even though we observed a decreased risk of lung cancer under the homozygotic, heterozygotic and dominant models (P < 0.05, OR < 1) and an enhanced risk of colorectal cancer under the allelic, homozygotic, heterozygotic, dominant (P < 0.05, OR > 1), our data from FPRP analysis and another pooling analysis with only the population-based controls in the Caucasian population did not support the strong links between the XPA rs1800975 A/G polymorphism and the risk of lung or colorectal cancer.	('XPA', 'Gene', '7507', (433, 436))	('colorectal cancer', 'Phenotype', 'HP:0003003', (488, 505))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('XPA', 'Gene', (433, 436))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('colorectal cancer', 'Disease', 'MESH:D015179', (169, 186))	('colorectal cancer', 'Disease', (488, 505))	('rs1800975 A/G', 'Var', (437, 450))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (499, 505))	('rs1800975', 'Mutation', 'rs1800975', (437, 446))	('colorectal cancer', 'Phenotype', 'HP:0003003', (169, 186))	('colorectal cancer', 'Disease', (169, 186))	('lung', 'Disease', (480, 484))	('decreased', 'NegReg', (39, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (488, 505))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
88274	32435155	Our findings provide evidence of the close relationship between the XPA rs1800975 A/G polymorphism and susceptibility to skin cancer in the Caucasian population.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('rs1800975', 'Mutation', 'rs1800975', (72, 81))	('skin cancer', 'Phenotype', 'HP:0008069', (121, 132))	('susceptibility', 'Reg', (103, 117))	('rs1800975 A/G', 'Var', (72, 85))	('skin cancer', 'Disease', (121, 132))	('XPA', 'Gene', '7507', (68, 71))	('skin cancer', 'Disease', 'MESH:D012878', (121, 132))	('XPA', 'Gene', (68, 71))
88275	32435155	The potential effect of XPA rs1800975 on the risk of developing lung or colorectal cancer still merits the enrollment of larger well-scaled studies.	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('rs1800975', 'Mutation', 'rs1800975', (28, 37))	('XPA', 'Gene', (24, 27))	('XPA', 'Gene', '7507', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('lung', 'Disease', (64, 68))	('colorectal cancer', 'Disease', (72, 89))	('rs1800975', 'Var', (28, 37))
88278	32435155	The human XPA rs1800975 T/C polymorphism is a common single nucleotide polymorphism (SNP) in the 5'-untranslated region of the XPA gene.	('rs1800975', 'Mutation', 'rs1800975', (14, 23))	('XPA', 'Gene', (10, 13))	('human', 'Species', '9606', (4, 9))	('rs1800975 T/C polymorphism', 'Var', (14, 40))	('XPA', 'Gene', '7507', (127, 130))	('XPA', 'Gene', (127, 130))	('XPA', 'Gene', '7507', (10, 13))
88279	32435155	In the present study, we are interested in comprehensively exploring the possible effect of the XPA rs1800975 genetic variant on the susceptibility to different cancer diseases, such as skin cancer, lung cancer, breast cancer, esophageal cancer, gastric cancer, colorectal cancer or endometrial cancer.	('XPA', 'Gene', (96, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('gastric cancer', 'Disease', (246, 260))	('esophageal cancer', 'Disease', 'MESH:D004938', (227, 244))	('lung cancer', 'Disease', (199, 210))	('cancer diseases', 'Disease', 'MESH:D009369', (161, 176))	('endometrial cancer', 'Phenotype', 'HP:0012114', (283, 301))	('skin cancer', 'Disease', (186, 197))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))	('colorectal cancer', 'Disease', 'MESH:D015179', (262, 279))	('esophageal cancer', 'Disease', (227, 244))	('breast cancer', 'Disease', (212, 225))	('rs1800975', 'Mutation', 'rs1800975', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('gastric cancer', 'Disease', 'MESH:D013274', (246, 260))	('endometrial cancer', 'Disease', (283, 301))	('colorectal cancer', 'Disease', (262, 279))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('skin cancer', 'Phenotype', 'HP:0008069', (186, 197))	('endometrial cancer', 'Disease', 'MESH:D016889', (283, 301))	('lung cancer', 'Disease', 'MESH:D008175', (199, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (199, 210))	('gastric cancer', 'Phenotype', 'HP:0012126', (246, 260))	('rs1800975', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('skin cancer', 'Disease', 'MESH:D012878', (186, 197))	('colorectal cancer', 'Phenotype', 'HP:0003003', (262, 279))	('cancer diseases', 'Disease', (161, 176))	('XPA', 'Gene', '7507', (96, 99))
88280	32435155	There are different reports with distinct conclusions regarding the genetic relationship between the XPA rs1800975 polymorphism and cancer susceptibility in varied populations.	('cancer', 'Disease', (132, 138))	('XPA', 'Gene', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('XPA', 'Gene', '7507', (101, 104))	('rs1800975', 'Var', (105, 114))	('rs1800975', 'Mutation', 'rs1800975', (105, 114))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
88281	32435155	For example, the XPA rs1800975 polymorphism was reported to be related to the risk of lung cancer in Norwegian, Germany or Korean populations but not in patients from Belgium or the USA.	('rs1800975', 'Var', (21, 30))	('patients', 'Species', '9606', (153, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('XPA', 'Gene', '7507', (17, 20))	('related', 'Reg', (63, 70))	('rs1800975', 'Mutation', 'rs1800975', (21, 30))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('XPA', 'Gene', (17, 20))
88282	32435155	To the best of our knowledge, to date, only two meta-analyses regarding the association between the XPA rs1800975 polymorphism and susceptibility to overall cancer diseases have been previously reported in 2012.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('XPA', 'Gene', (100, 103))	('polymorphism', 'Var', (114, 126))	('rs1800975', 'Mutation', 'rs1800975', (104, 113))	('cancer diseases', 'Disease', 'MESH:D009369', (157, 172))	('cancer diseases', 'Disease', (157, 172))	('XPA', 'Gene', '7507', (100, 103))
88285	32435155	The inclusion criteria were as follows: genotypic frequency data for the XPA rs1800975 polymorphism in both cases and controls.	('XPA', 'Gene', '7507', (73, 76))	('rs1800975', 'Mutation', 'rs1800975', (77, 86))	('rs1800975', 'Var', (77, 86))	('XPA', 'Gene', (73, 76))
88287	32435155	If the FPRP value < 0.2 under the prior probability level of 0.1, a worthy outcome between XPA rs1800975 and cancer risk was considered.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('XPA', 'Gene', (91, 94))	('XPA', 'Gene', '7507', (91, 94))	('rs1800975', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('rs1800975', 'Mutation', 'rs1800975', (95, 104))
88294	32435155	Based on the dataset of GTEx, we also analyzed the "Significant Single-Tissue" eQTL (expression quantitative trait loci) and sQTL (splicing quantitative trait loci) in all tissues, for the XPA gene and the rs1800975 SNP.	('GTEx', 'Chemical', '-', (24, 28))	('XPA', 'Gene', (189, 192))	('rs1800975', 'Mutation', 'rs1800975', (206, 215))	('sQTL', 'Gene', (125, 129))	('rs1800975 SNP', 'Var', (206, 219))	('XPA', 'Gene', '7507', (189, 192))
88296	32435155	We failed to obtain evidence regarding the relationship between the XPA rs1800975 polymorphism and the overall risk of cancer in the overall population.	('rs1800975', 'Var', (72, 81))	('rs1800975', 'Mutation', 'rs1800975', (72, 81))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('XPA', 'Gene', '7507', (68, 71))	('XPA', 'Gene', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
88302	32435155	Moreover, we observed an enhanced risk of colorectal cancer under allelic (Table 4, P = 0.021, OR = 1.20), homozygotic (P = 0.007, OR = 1.68), heterozygotic (Table 5, P = 0.041, OR = 1.46), and dominant (P = 0.016, OR = 1.54) conditions, implying the potential effect of the AG genotype of XPA rs1800975 on the risk of colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('colorectal cancer', 'Disease', (319, 336))	('colorectal cancer', 'Disease', (42, 59))	('XPA', 'Gene', (290, 293))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('XPA', 'Gene', '7507', (290, 293))	('rs1800975', 'Mutation', 'rs1800975', (294, 303))	('colorectal cancer', 'Disease', 'MESH:D015179', (319, 336))	('rs1800975', 'Var', (294, 303))	('colorectal cancer', 'Disease', 'MESH:D015179', (42, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (319, 336))
88304	32435155	These data suggested that XPA rs1800975 may be associated with a high susceptibility to skin cancer, especially skin BCC.	('skin cancer', 'Disease', (88, 99))	('skin cancer', 'Disease', 'MESH:D012878', (88, 99))	('skin BCC', 'Disease', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('XPA', 'Gene', '7507', (26, 29))	('XPA', 'Gene', (26, 29))	('rs1800975', 'Var', (30, 39))	('rs1800975', 'Mutation', 'rs1800975', (30, 39))	('associated', 'Reg', (47, 57))	('skin cancer', 'Phenotype', 'HP:0008069', (88, 99))
88305	32435155	There were no significant differences between cases and controls in the majority of comparisons (Tables 2, 3, 4, P > 0.05), indicating that XPA rs1800975 does not seem to contribute to the risk of specific cancer types, such as breast cancer, esophageal cancer, gastric cancer, reproductive system cancer, endometrial cancer, or head and neck cancer.	('cancer', 'Disease', (318, 324))	('cancer', 'Disease', (343, 349))	('cancer', 'Disease', (254, 260))	('esophageal cancer', 'Disease', (243, 260))	('gastric cancer', 'Disease', 'MESH:D013274', (262, 276))	('rs1800975', 'Var', (144, 153))	('head and neck cancer', 'Phenotype', 'HP:0012288', (329, 349))	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('endometrial cancer', 'Phenotype', 'HP:0012114', (306, 324))	('breast cancer', 'Disease', 'MESH:D001943', (228, 241))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('cancer', 'Disease', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('breast cancer', 'Disease', (228, 241))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('gastric cancer', 'Phenotype', 'HP:0012126', (262, 276))	('endometrial cancer', 'Disease', (306, 324))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('head and neck cancer', 'Disease', 'MESH:D006258', (329, 349))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (343, 349))	('endometrial cancer', 'Disease', 'MESH:D016889', (306, 324))	('XPA', 'Gene', '7507', (140, 143))	('rs1800975', 'Mutation', 'rs1800975', (144, 153))	('XPA', 'Gene', (140, 143))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('neck', 'cellular_component', 'GO:0044326', ('338', '342'))	('cancer', 'Disease', (298, 304))	('gastric cancer', 'Disease', (262, 276))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('esophageal cancer', 'Disease', 'MESH:D004938', (243, 260))
88312	32435155	Collectively, this evidence did not support the strong association between lung cancer risk and XPA rs1800975.	('lung cancer', 'Disease', (75, 86))	('XPA', 'Gene', (96, 99))	('rs1800975', 'Var', (100, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('rs1800975', 'Mutation', 'rs1800975', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('XPA', 'Gene', '7507', (96, 99))
88315	32435155	We cannot obtain a relatively scientific conclusion regarding the potential links of XPA rs1800975 and colorectal cancer risk.	('links', 'Interaction', (76, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('colorectal cancer', 'Disease', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('XPA', 'Gene', (85, 88))	('rs1800975', 'Var', (89, 98))	('XPA', 'Gene', '7507', (85, 88))	('rs1800975', 'Mutation', 'rs1800975', (89, 98))
88319	32435155	4 shows that the cumulative Z-curve of the dominant model can cross both the lines of the TSA monitoring boundary and the required information size, suggesting a credible conclusion regarding the association between XPA rs1800975 and skin susceptibility.	('rs1800975', 'Mutation', 'rs1800975', (220, 229))	('XPA', 'Gene', (216, 219))	('association', 'Interaction', (196, 207))	('rs1800975', 'Var', (220, 229))	('TSA', 'Chemical', '-', (90, 93))	('skin susceptibility', 'Disease', (234, 253))	('TSA', 'molecular_function', 'GO:0033984', ('90', '93'))	('XPA', 'Gene', '7507', (216, 219))
88320	32435155	Finally, based on GTEx datasets, we analyzed the expression profile of the XPA gene in different tissues, and the correlation between the gene expression and rs1800975 SNP of XPA.	('GTEx', 'Chemical', '-', (18, 22))	('XPA', 'Gene', (75, 78))	('rs1800975 SNP', 'Var', (158, 171))	('XPA', 'Gene', '7507', (75, 78))	('gene expression', 'biological_process', 'GO:0010467', ('138', '153'))	('XPA', 'Gene', '7507', (175, 178))	('XPA', 'Gene', (175, 178))	('rs1800975', 'Mutation', 'rs1800975', (158, 167))
88322	32435155	6), we observed the potential association between XPA gene expression and rs1800975 SNP, in the tissues of artery aorta (P-value = 1.8e-9), artery tibial (P-value = 1.55e-6), esophagus muscularis (P-value = 3.59e-9), muscle skeletal (P-value = 6.39e-12), but not the skin tissue of ["not sun exposed (suprapubic)", P-value = 7.87e-1) or ["sun exposed (lower leg)", P-value = 5.16e-1).	('rs1800975 SNP', 'Var', (74, 87))	('lower leg', 'Phenotype', 'HP:0006385', (352, 361))	('XPA', 'Gene', (50, 53))	('rs1800975', 'Mutation', 'rs1800975', (74, 83))	('XPA', 'Gene', '7507', (50, 53))
88323	32435155	Cross-tissue meta-analysis further showed a potential overall correlation between gene expression and rs1800975 SNP of XPA (Fig.	('correlation', 'Interaction', (62, 73))	('rs1800975 SNP', 'Var', (102, 115))	('gene expression', 'biological_process', 'GO:0010467', ('82', '97'))	('XPA', 'Gene', (119, 122))	('rs1800975', 'Mutation', 'rs1800975', (102, 111))	('XPA', 'Gene', '7507', (119, 122))
88324	32435155	In addition, our sQTL data further showed a potential association between rs1800975 SNP and the splicing changes of XPA gene in the thyroid tissue (Fig.	('rs1800975 SNP', 'Var', (74, 87))	('splicing', 'MPA', (96, 104))	('rs1800975', 'Mutation', 'rs1800975', (74, 83))	('splicing', 'biological_process', 'GO:0045292', ('96', '104'))	('XPA', 'Gene', (116, 119))	('XPA', 'Gene', '7507', (116, 119))
88325	32435155	Although we observed a group of publications regarding the influence of XPA rs1800975 on the risk of certain specific cancers, such as lung cancer, head and neck cancer, breast cancer, and digestive system cancer, the evaluation strategies, study number and statistical power differed.	('cancer', 'Disease', (177, 183))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancer', 'Disease', (162, 168))	('head and neck cancer', 'Phenotype', 'HP:0012288', (148, 168))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lung cancer', 'Disease', (135, 146))	('rs1800975', 'Mutation', 'rs1800975', (76, 85))	('XPA', 'Gene', (72, 75))	('XPA', 'Gene', '7507', (72, 75))	('cancer', 'Disease', (206, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('head and neck cancer', 'Disease', 'MESH:D006258', (148, 168))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (118, 124))	('cancers', 'Disease', (118, 125))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', (140, 146))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('breast cancer', 'Disease', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('rs1800975', 'Var', (76, 85))	('neck', 'cellular_component', 'GO:0044326', ('157', '161'))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
88326	32435155	We were interested in comprehensively exploring the impact of XPA rs1800975 on overall cancer susceptibility by pooling all currently available evidence.	('XPA', 'Gene', (62, 65))	('cancer', 'Disease', (87, 93))	('rs1800975', 'Var', (66, 75))	('rs1800975', 'Mutation', 'rs1800975', (66, 75))	('XPA', 'Gene', '7507', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
88327	32435155	To date, there are only two reported meta-analyses from 2012 describing the association between XPA rs1800975 and susceptibility to overall cancer diseases.	('XPA', 'Gene', (96, 99))	('rs1800975', 'Var', (100, 109))	('rs1800975', 'Mutation', 'rs1800975', (100, 109))	('cancer diseases', 'Disease', (140, 155))	('cancer diseases', 'Disease', 'MESH:D009369', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('XPA', 'Gene', '7507', (96, 99))
88329	32435155	Based on six genetic models (allelic, carrier, homozygotic, heterozygotic, dominant and recessive), a series of overall meta-analyses and subgroup analyses using the factors of race, control source and genotyping method, were used to scientifically assess the association between XPA rs1800975 polymorphism and the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('cancer', 'Disease', (323, 329))	('carrier', 'molecular_function', 'GO:0005215', ('38', '45'))	('rs1800975', 'Mutation', 'rs1800975', (284, 293))	('XPA', 'Gene', '7507', (280, 283))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('XPA', 'Gene', (280, 283))	('polymorphism', 'Var', (294, 306))	('rs1800975 polymorphism', 'Var', (284, 306))
88332	32435155	included a total of thirty-six case-control or case-cohort studies from twenty-eight publications to conduct a meta-analysis for the genetic effect of XPA rs1800975 on the susceptibility to overall cancer.	('XPA', 'Gene', (151, 154))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('rs1800975', 'Mutation', 'rs1800975', (155, 164))	('rs1800975', 'Var', (155, 164))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('XPA', 'Gene', '7507', (151, 154))
88336	32435155	The sample size contributes to the inconsistency with the data of Ding et al.. Additionally, we detected a decreased lung cancer risk in cases under the GG vs. AA, AG vs. AA, AG + GG vs. AA models but an increased risk of colorectal cancer under the allelic, homozygotic, heterozygotic, dominant models, indicating the possible effect of the AG genotype of XPA rs1800975 on the susceptibility to colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('lung cancer', 'Disease', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('XPA', 'Gene', (357, 360))	('XPA', 'Gene', '7507', (357, 360))	('colorectal cancer', 'Disease', 'MESH:D015179', (396, 413))	('rs1800975', 'Mutation', 'rs1800975', (361, 370))	('colorectal cancer', 'Disease', 'MESH:D015179', (222, 239))	('decreased lung', 'Phenotype', 'HP:0002089', (107, 121))	('colorectal cancer', 'Disease', (396, 413))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('colorectal cancer', 'Disease', (222, 239))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('Ding', 'Gene', '6045', (66, 70))	('Ding', 'Gene', (66, 70))	('rs1800975', 'Var', (361, 370))	('colorectal cancer', 'Phenotype', 'HP:0003003', (396, 413))	('decreased', 'NegReg', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (222, 239))
88337	32435155	Nevertheless, our data from FPRP analysis and another pooling analysis with only the population-based controls in the Caucasian population did not strongly support the protective role of the G allele within the XPA rs1800975 polymorphism in the risk of lung or colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('XPA', 'Gene', '7507', (211, 214))	('colorectal cancer', 'Phenotype', 'HP:0003003', (261, 278))	('XPA', 'Gene', (211, 214))	('rs1800975', 'Var', (215, 224))	('rs1800975', 'Mutation', 'rs1800975', (215, 224))	('colorectal cancer', 'Disease', (261, 278))	('lung', 'Disease', (253, 257))	('colorectal cancer', 'Disease', 'MESH:D015179', (261, 278))
88338	32435155	Our data from the pooling analysis, FPRP analysis and TSA demonstrated a significant difference between skin cancer cases and negative controls under six genetic models, suggesting the contribution of the G allele within XPA rs1800975 to an enhanced susceptibility to skin cancer.	('TSA', 'Chemical', '-', (54, 57))	('rs1800975', 'Var', (225, 234))	('rs1800975', 'Mutation', 'rs1800975', (225, 234))	('XPA', 'Gene', (221, 224))	('skin cancer', 'Phenotype', 'HP:0008069', (268, 279))	('enhanced', 'PosReg', (241, 249))	('XPA', 'Gene', '7507', (221, 224))	('skin cancer', 'Phenotype', 'HP:0008069', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('TSA', 'molecular_function', 'GO:0033984', ('54', '57'))	('skin cancer', 'Disease', (268, 279))	('skin cancer', 'Disease', (104, 115))	('skin cancer', 'Disease', 'MESH:D012878', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('skin cancer', 'Disease', 'MESH:D012878', (268, 279))
88339	32435155	Our eQTL and sQTL analysis data of GTEx showed that the XPA rs1800975 might not be associated with the gene expression or splicing changes of XPA in the skin tissue, suggesting the existence of other molecular mechanisms.	('XPA', 'Gene', (142, 145))	('XPA', 'Gene', '7507', (142, 145))	('XPA', 'Gene', '7507', (56, 59))	('GTEx', 'Chemical', '-', (35, 39))	('XPA', 'Gene', (56, 59))	('rs1800975', 'Mutation', 'rs1800975', (60, 69))	('gene expression', 'biological_process', 'GO:0010467', ('103', '118'))	('rs1800975', 'Var', (60, 69))	('splicing', 'biological_process', 'GO:0045292', ('122', '130'))
88344	32435155	Thus, it is meaningful to explore the potential genetic influence of all XPA genetic variants or the combined variants of XPA and other relevant genes (such as xeroderma pigmentosum group D, XPD) in the pathogenesis of the above tumors, arterial or muscular system-related diseases.	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('XPA', 'Gene', (73, 76))	('variants', 'Var', (85, 93))	('XPA', 'Gene', '7507', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('xeroderma pigmentosum', 'Disease', (160, 181))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (160, 181))	('XPD', 'Gene', (191, 194))	('tumors', 'Disease', (229, 235))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('pathogenesis', 'biological_process', 'GO:0009405', ('203', '215'))	('arterial or muscular system-related diseases', 'Disease', (237, 281))	('XPD', 'Gene', '2068', (191, 194))	('XPA', 'Gene', (122, 125))	('XPA', 'Gene', '7507', (122, 125))
88345	32435155	To summarize, our comprehensive integrative analysis data demonstrated statistical evidence on the association between the XPA rs1800975 A/G polymorphism and susceptibility to skin cancer, especially skin BCC, in the Caucasian population.	('skin cancer', 'Disease', 'MESH:D012878', (176, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('rs1800975 A/G', 'Var', (127, 140))	('susceptibility', 'Reg', (158, 172))	('skin BCC', 'Disease', (200, 208))	('skin cancer', 'Phenotype', 'HP:0008069', (176, 187))	('XPA', 'Gene', '7507', (123, 126))	('XPA', 'Gene', (123, 126))	('skin cancer', 'Disease', (176, 187))	('association', 'Interaction', (99, 110))	('rs1800975', 'Mutation', 'rs1800975', (127, 136))
88346	32435155	The enrollment of more case-control studies following the HWE principle in diverse ethnicities will help researchers to further verify the potential genetic role of the XPA rs1800975 polymorphism in the risk of lung or colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (219, 236))	('XPA', 'Gene', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('XPA', 'Gene', '7507', (169, 172))	('polymorphism', 'Var', (183, 195))	('rs1800975', 'Mutation', 'rs1800975', (173, 182))	('colorectal cancer', 'Disease', (219, 236))	('lung', 'Disease', (211, 215))	('colorectal cancer', 'Disease', 'MESH:D015179', (219, 236))
88351	32188412	Tissue microarrays of 45 UC/SCC and 63 SCC samples were immunohistochemically stained with four anti-PD-L1 antibodies (28-8, 22C3, SP142 and SP263).	('SCC', 'Disease', 'MESH:D002294', (28, 31))	('SP263', 'Chemical', '-', (141, 146))	('SCC', 'Disease', (39, 42))	('SP142', 'Chemical', '-', (131, 136))	('SP263', 'Var', (141, 146))	('PD-L1', 'Gene', '29126', (101, 106))	('SP142', 'Var', (131, 136))	('SCC', 'Phenotype', 'HP:0002860', (28, 31))	('28-8', 'Var', (119, 123))	('SCC', 'Disease', (28, 31))	('SCC', 'Phenotype', 'HP:0002860', (39, 42))	('SCC', 'Disease', 'MESH:D002294', (39, 42))	('PD-L1', 'Gene', (101, 106))
88383	32188412	FFPE slides were stained for protein expression of programmed death-ligand 1 (PD-L1) with four different antibodies [28-8 (Agilent/DAKO, California, USA), 22C3 (DAKO), SP263 (Ventana, Tucson, Arizona, USA), SP142 (Ventana)].	('SP263', 'Var', (168, 173))	('programmed death-ligand 1', 'Gene', (51, 76))	('programmed death-ligand 1', 'Gene', '29126', (51, 76))	('ligand', 'molecular_function', 'GO:0005488', ('68', '74'))	('PD-L1', 'Gene', (78, 83))	('SP142', 'Chemical', '-', (207, 212))	('22C3', 'Var', (155, 159))	('SP142', 'Var', (207, 212))	('PD-L1', 'Gene', '29126', (78, 83))	('SP263', 'Chemical', '-', (168, 173))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))
88384	32188412	Automated pre-treatment was performed at pH 6 for 28-8 / 22C3, and pH 9 for SP142 / SP263.	('SP142', 'Chemical', '-', (76, 81))	('SP142 / SP263', 'Var', (76, 89))	('SP263', 'Chemical', '-', (84, 89))	('pre', 'molecular_function', 'GO:0003904', ('10', '13'))	('28-8 / 22C3', 'Var', (50, 61))
88392	32188412	Tumour cells showed PD-L1 expression (TPS >=1) in 39.5% (28-8; 17/43), 11.3% (22C3; 5/44), 51.2% (SP263; 22/43) and 0% (SP142, 0/45) (Fig.	('TPS >=1', 'Gene', '7177', (38, 45))	('TPS >=1', 'Gene', (38, 45))	('PD-L1', 'Gene', (20, 25))	('SP263', 'Chemical', '-', (98, 103))	('SP142', 'Chemical', '-', (120, 125))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('PD-L1', 'Gene', '29126', (20, 25))	('SP263;', 'Var', (98, 104))
88393	32188412	In pure SCC we observed IC-scores >=1 in 39.7% (28-8; 25/63), 31.1% (22C3; 19/61), 61.9% (SP263; 39/63) and 4.8% (SP142; 3/63) (Fig.	('SP263;', 'Var', (90, 96))	('SP142', 'Chemical', '-', (114, 119))	('SCC', 'Disease', 'MESH:D002294', (8, 11))	('SP263', 'Chemical', '-', (90, 95))	('pure', 'molecular_function', 'GO:0034023', ('3', '7'))	('SCC', 'Phenotype', 'HP:0002860', (8, 11))	('SCC', 'Disease', (8, 11))	('SP142;', 'Var', (114, 120))
88416	32188412	In fact, PD-L1 expression was shown for 28-8 in 30%, for 22C3 in 30% for SP263 in 25% and for SP142 in 7% of IC before nivolumab treatment.	('SP142', 'Chemical', '-', (94, 99))	('SP263', 'Chemical', '-', (73, 78))	('PD-L1', 'Gene', '29126', (9, 14))	('SP142', 'Var', (94, 99))	('SP263', 'Var', (73, 78))	('nivolumab', 'Chemical', 'MESH:D000077594', (119, 128))	('PD-L1', 'Gene', (9, 14))
88432	32188412	These findings, based on four different antibodies (DAKO 28-8, DAKO 22C3, Ventana SP263 and Ventana SP142), confirmed the data of the recent publications and are comparable with studies of urothelial cancer.	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('urothelial cancer', 'Disease', (189, 206))	('SP263', 'Chemical', '-', (82, 87))	('urothelial cancer', 'Disease', 'MESH:D014523', (189, 206))	('Ventana SP142', 'Var', (92, 105))	('SP142', 'Chemical', '-', (100, 105))
88439	32188412	The Blueprint PD-L1 Immunohistochemistry (IHC) Assay Comparison Project also studied the performance of the four PD-L1 IHC assays (22C3, 28-8, SP142, and SP263) in NSCLC, and found -very similar to our results- an analytical comparability of 22C3, 28-8, and SP263 whereas the SP142 assay showed lowest levels of correlation.	('NSCLC', 'Disease', (164, 169))	('SP263', 'Var', (258, 263))	('PD-L1', 'Gene', '29126', (14, 19))	('SP142', 'Chemical', '-', (276, 281))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('PD-L1', 'Gene', (113, 118))	('SP263', 'Chemical', '-', (154, 159))	('PD-L1', 'Gene', (14, 19))	('PD-L1', 'Gene', '29126', (113, 118))	('SP142', 'Chemical', '-', (143, 148))	('SP263', 'Chemical', '-', (258, 263))
88444	32188412	In clinical trials, for instance, the objective response rate (ORR) of urothelial cancer patients with nivolumab treatment did not significantly differ between PD-L1 positive (> 1%) and PD-L1 negative tumors (< 1%) (Checkmate-032 study).	('PD-L1', 'Gene', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('urothelial cancer', 'Disease', (71, 88))	('PD-L1', 'Gene', (160, 165))	('PD-L1', 'Gene', '29126', (186, 191))	('urothelial cancer', 'Disease', 'MESH:D014523', (71, 88))	('PD-L1', 'Gene', '29126', (160, 165))	('nivolumab', 'Chemical', 'MESH:D000077594', (103, 112))	('patients', 'Species', '9606', (89, 97))	('positive', 'Var', (166, 174))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))
88521	30170590	However, endoscopic management may carry risks of under-staging, under-grading, or increased risk of recurrence, where SU may not be feasible in multifocal disease or in the case of long segment of tumor involvement.	('under-grading', 'Var', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('men', 'Species', '9606', (211, 214))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('multifocal disease', 'Disease', 'None', (145, 163))	('men', 'Species', '9606', (190, 193))	('men', 'Species', '9606', (26, 29))	('multifocal disease', 'Disease', (145, 163))	('tumor', 'Disease', (198, 203))	('SU', 'Chemical', '-', (119, 121))
88589	30170590	However, resecting a kidney will cause excessive loss of renal function, which increases the risks of death and cardiovascular events.	('excessive loss of renal function', 'Disease', 'MESH:D051437', (39, 71))	('death', 'Disease', 'MESH:D003643', (102, 107))	('death', 'Disease', (102, 107))	('cardiovascular events', 'Phenotype', 'HP:0001626', (112, 133))	('excessive loss of renal function', 'Disease', (39, 71))	('loss of renal function', 'Phenotype', 'HP:0012622', (49, 71))	('resecting', 'Var', (9, 18))
88704	29540752	Finally, our results suggest that the functionally altering mutations in "double-agent" genes and oncogenes are the main driving force in cancer development, because non-silent mutations are biasedly distributed toward these two gene sets across all 12 major cancer types.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('cancer', 'Disease', (138, 144))	('altering', 'Reg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('mutations', 'Var', (60, 69))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Disease', (259, 265))
88717	29540752	For a gene with both oncogenic and tumor-suppressor potentials, it is possible that one single mutation event would unleash its oncogenic power and abolish its tumor-suppressor function.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('oncogenic power', 'CPA', (128, 143))	('tumor-suppressor', 'Gene', (160, 176))	('tumor-suppressor', 'Gene', '7248', (160, 176))	('abolish', 'NegReg', (148, 155))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('160', '176'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor-suppressor', 'Gene', '7248', (35, 51))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('160', '176'))	('tumor-suppressor', 'Gene', (35, 51))	('mutation', 'Var', (95, 103))
88718	29540752	Theoretically, one such mutation event would be enough to trigger the carcinogenic cascade in normal cells.	('carcinogenic', 'Disease', (70, 82))	('carcinogenic', 'Disease', 'MESH:D063646', (70, 82))	('mutation', 'Var', (24, 32))	('trigger', 'Reg', (58, 65))
88734	29540752	The data include 3281 cancer cases from 12 major cancer types with a total of 617,354 somatic mutations in 20,947 genes.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('mutations', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (49, 55))
88792	29540752	Both the non-silent mutation distributions and mutation rates in four gene sets propose that different types of cancers underwent different mutation processes and potential cancerous mutations are more prone to happen in POTSFs and/or ONCs.	('mutations', 'Var', (183, 192))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancerous', 'Disease', (173, 182))	('ONCs', 'Disease', (235, 239))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancers', 'Disease', (112, 119))	('POTSFs', 'Disease', (221, 227))	('cancerous', 'Disease', 'MESH:D009369', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
88793	29540752	We also examined the distribution of potential gain-of-function mutations and potential loss-of-function mutations in POTSFs, ONCs, TSGs, NCRGs, and their non-silent and silent mutation rate across 12 cancer types in this study (Figure S4, S5, S6 and S7).	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('gain-of-function', 'PosReg', (47, 63))	('cancer', 'Disease', (201, 207))	('TSG', 'Gene', (132, 135))	('ONCs', 'Gene', (126, 130))	('mutations', 'Var', (105, 114))	('TSG', 'Gene', '57045', (132, 135))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('POTSFs', 'Gene', (118, 124))	('loss-of-function', 'NegReg', (88, 104))	('NCRGs', 'Gene', (138, 143))
88806	29540752	In our expression analyses, we notice one phenomenon that the expression level of POTSFs is more akin to TSGs in both 12 cancer types and 6 human organs.	('human', 'Species', '9606', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('TSG', 'Gene', (105, 108))	('POTSFs', 'Var', (82, 88))	('TSG', 'Gene', '57045', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
88812	29540752	It proposes that POTSFs, ONCs, and TSGs are more likely to form a biological module through PPI, while NCRGs are less likely.	('TSG', 'Gene', '57045', (35, 38))	('PPI', 'biological_process', 'GO:0060134', ('92', '95'))	('TSG', 'Gene', (35, 38))	('PPI', 'Var', (92, 95))
88819	29540752	Cancer is a disease driven by accumulated somatic mutations which lead to abnormal cell proliferation.	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (74, 101))	('mutations', 'Var', (50, 59))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cell proliferation', 'biological_process', 'GO:0008283', ('83', '101'))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
88832	29540752	Since the number of mutations is positively correlated with age, the younger a cancer patient is, the less mutations his or her cancer has.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('less', 'NegReg', (102, 106))	('patient', 'Species', '9606', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('mutations', 'Var', (20, 29))	('cancer', 'Disease', (128, 134))
88833	29540752	POTSFs are oncogene and tumor-suppressor gene incorporated into one, and a single mutation event in these genes could theoretically promote its oncogenic function and inhibit its tumor-suppressor function at the same time.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('mutation', 'Var', (82, 90))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('179', '195'))	('tumor-suppressor', 'Gene', '7248', (179, 195))	('oncogenic function', 'CPA', (144, 162))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('179', '195'))	('inhibit', 'NegReg', (167, 174))	('tumor-suppressor', 'Gene', '7248', (24, 40))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor-suppressor', 'Gene', (179, 195))	('promote', 'PosReg', (132, 139))	('tumor-suppressor', 'Gene', (24, 40))
88834	29540752	Thus, a very few mutations in POTSFs could be sufficient to trigger the cellular cascade of cancerous transformation in vivo.	('POTSFs', 'Gene', (30, 36))	('trigger', 'Reg', (60, 67))	('cellular', 'CPA', (72, 80))	('cancerous', 'Disease', (92, 101))	('cancerous', 'Disease', 'MESH:D009369', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutations', 'Var', (17, 26))
88835	29540752	Our analyses of the non-silent mutation patterns for POTSFs, ONCs, TSGs, and NCRGs show that POTSFs and ONCs accumulate more mutations than TSGs and NCRGs in all 12 cancer types examined in this study.	('mutations', 'Var', (125, 134))	('TSG', 'Gene', (67, 70))	('TSG', 'Gene', '57045', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('TSG', 'Gene', '57045', (67, 70))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('TSG', 'Gene', (140, 143))
88836	29540752	This pattern is also observed in the distribution of potential gain-of-function mutations and potential loss-of-function mutations across 12 cancer types (Figure S4 and S5).	('mutations', 'Var', (121, 130))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('loss-of-function', 'NegReg', (104, 120))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('gain-of-function', 'PosReg', (63, 79))	('cancer', 'Disease', (141, 147))
88837	29540752	One thing we want to mention is that in this study non-silent mutations far outnumber silent mutations by the ratio of 3 to 1 (472,060 vs. 145,294), which propose that these 12 cancers are mainly driven by functionally altering mutations in POTSFs and ONCs.	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('ONCs', 'Gene', (252, 256))	('cancers', 'Disease', (177, 184))	('mutations', 'Var', (228, 237))	('POTSFs', 'Gene', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('non-silent', 'Var', (51, 61))
88844	29540752	The question is how gain-of-function mutation events could down-regulate the expression of TSGs in cancer cells.	('expression', 'MPA', (77, 87))	('mutation', 'Var', (37, 45))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('down-regulate', 'NegReg', (59, 72))	('cancer', 'Disease', (99, 105))	('TSG', 'Gene', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('gain-of-function', 'PosReg', (20, 36))	('TSG', 'Gene', '57045', (91, 94))
88845	29540752	One possible scenario is that the gain-of-function mutations in POTSFs promote their oncogenic functions and then the mutated POTSFs negatively regulate TSG expression during cancer development.	('promote', 'PosReg', (71, 78))	('mutations', 'Var', (51, 60))	('POTSFs', 'Gene', (64, 70))	('expression', 'MPA', (157, 167))	('TSG', 'Gene', (153, 156))	('cancer', 'Disease', (175, 181))	('mutated', 'Var', (118, 125))	('gain-of-function', 'PosReg', (34, 50))	('regulate', 'Reg', (144, 152))	('oncogenic functions', 'CPA', (85, 104))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('TSG', 'Gene', '57045', (153, 156))	('negatively', 'NegReg', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
88850	29540752	TP53 plays an essential role in controlling cell cycle and its mutations have been proved to be associated with many cancer types.	('mutations', 'Var', (63, 72))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cell cycle', 'biological_process', 'GO:0007049', ('44', '54'))	('associated', 'Reg', (96, 106))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
88860	28966917	Molecular targeting through tyrosine kinase inhibition of the vascular endothelial growth factor (VEGF) has emerged as a frontline therapy in kidney cancer with more durable responses.	('kidney cancer', 'Disease', 'MESH:D007680', (142, 155))	('VEGF', 'Gene', '7422', (98, 102))	('kidney cancer', 'Phenotype', 'HP:0009726', (142, 155))	('vascular endothelial growth factor', 'Gene', (62, 96))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('62', '96'))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('kidney cancer', 'Disease', (142, 155))	('vascular endothelial growth factor', 'Gene', '7422', (62, 96))	('VEGF', 'Gene', (98, 102))	('tyrosine kinase inhibition', 'Var', (28, 54))
88881	28966917	Metastatic disease is often treated with nephrectomy as previous studies analyzing interferon alpha-2b (INF) therapy showed an overall survival (OS) increase of approximately 6 months with resection + IFN versus IFN alone.	('resection +', 'Var', (189, 200))	('increase', 'PosReg', (149, 157))	('INF', 'Gene', '2694', (104, 107))	('INF', 'Gene', (104, 107))	('interferon alpha-2b', 'Gene', '3440', (83, 102))	('Metastatic disease', 'Disease', 'MESH:C538445', (0, 18))	('interferon alpha-2b', 'Gene', (83, 102))	('Metastatic disease', 'Disease', (0, 18))
88897	28966917	Other methods of immune surveillance, the development of chimeric T-cell receptors and cancer vaccines, have helped shape this distinct class of cancer treatments known as 'immunotherapies', which have begun to alter the approach to the way various malignancies are treated.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', (87, 93))	('malignancies', 'Disease', (249, 261))	('men', 'Species', '9606', (49, 52))	('chimeric', 'Var', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('men', 'Species', '9606', (157, 160))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('malignancies', 'Disease', 'MESH:D009369', (249, 261))
88925	28966917	Currently there is no FDA approved indication for the use of GVAX, although further clinical studies involving combination immunotherapy with this vaccine are currently underway for other types of solid malignancies (NCT02243371, NCT02451982).	('solid malignancies', 'Disease', 'MESH:D009369', (197, 215))	('NCT02243371', 'Var', (217, 228))	('NCT02451982', 'Var', (230, 241))	('solid malignancies', 'Disease', (197, 215))	('GVAX', 'Chemical', '-', (61, 65))
88927	28966917	Many solid tumor cells express PD-L1 and PD-L2, which would otherwise bind to PD-1 on T-cells, activating apoptotic pathways leading to T-cell directed death.	('apoptotic pathways', 'Pathway', (106, 124))	('PD-1', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('PD-1', 'Gene', '5133', (78, 82))	('PD-L2', 'Gene', '574057', (41, 46))	('tumor', 'Disease', (11, 16))	('T-cell directed death', 'CPA', (136, 157))	('PD-L2', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('activating', 'PosReg', (95, 105))	('PD-L1', 'Var', (31, 36))
88931	28966917	A particular area of interest has been invested in the use of these agents for treatment of patients with androgen receptor (AR) splicing variants that do not respond to other pharmacologic agents, such as abiraterone and enzalutamide.	('AR', 'Gene', '367', (125, 127))	('androgen receptor', 'Gene', (106, 123))	('androgen receptor', 'Gene', '367', (106, 123))	('splicing', 'biological_process', 'GO:0045292', ('129', '137'))	('patients', 'Species', '9606', (92, 100))	('abiraterone', 'Chemical', 'MESH:C089740', (206, 217))	('men', 'Species', '9606', (84, 87))	('enzalutamide', 'Chemical', 'MESH:C540278', (222, 234))	('splicing variants', 'Var', (129, 146))
88953	28966917	The primary endpoint of objective response rate (ORR) was seen in 26% of the IC2/3 group, 18% in the IC1/2/3 groups, and 15% overall over a one year period.	('IC2/3', 'Var', (77, 82))	('objective', 'Disease', (24, 33))	('IC1/2/3', 'Gene', (101, 108))	('IC1/2/3', 'Gene', '105259599;1781', (101, 108))
89070	28758043	After undergoing total nephroureterectomy, pathological diagnosis was confirmed as urothelial carcinoma, pT3, G2>G1, ly0, v1, N0, and M0 Stage III.	('pT3', 'Gene', (105, 108))	('M0 Stage', 'Var', (134, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('ly0', 'Var', (117, 120))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (83, 103))	('G2>G1', 'Var', (110, 115))	('pT3', 'Gene', '7694', (105, 108))	('urothelial carcinoma', 'Disease', (83, 103))
89152	27091477	However, mutations within the kinase domain and truncations of the EGFR are rarely seen in bladder cancer, and they have emerged as attractive therapeutic targets.	('truncations', 'Var', (48, 59))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('mutations', 'Var', (9, 18))	('bladder cancer', 'Disease', (91, 105))	('EGFR', 'molecular_function', 'GO:0005006', ('67', '71'))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
89167	27091477	They also found that urothelial carcinoma had more frequent mutations in chromatin regulatory genes.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (21, 41))	('chromatin', 'cellular_component', 'GO:0000785', ('73', '82'))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('urothelial carcinoma', 'Disease', (21, 41))	('mutations', 'Var', (60, 69))	('chromatin regulatory genes', 'Gene', (73, 99))
89177	26025446	Presence of variant differentiation in urothelial carcinoma at cystectomy was significantly associated with inferior survival both in univariate analysis (P = 0.005) and multivariate analysis (HR4.48, 95 % CI:1.03-19.53).	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('urothelial carcinoma', 'Disease', (39, 59))	('inferior', 'NegReg', (108, 116))	('variant differentiation', 'Var', (12, 35))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (39, 59))
89178	26025446	Patients with variant differentiation on cystectomy specimens have inferior survival.	('survival', 'MPA', (76, 84))	('variant differentiation', 'Var', (14, 37))	('inferior', 'NegReg', (67, 75))	('Patients', 'Species', '9606', (0, 8))
89182	26025446	The recognition of histological variants in UCB is of significance to both pathologists and clinicians because (a) some variants may affect prognostic consequences, (b) some may need different modalities compared with those used in conventional UCB, and (c) knowledge of the histological variants may be crucial to avoid diagnostic misinterpretations.	('UCB', 'Phenotype', 'HP:0006740', (44, 47))	('variants', 'Var', (120, 128))	('UCB', 'Chemical', '-', (44, 47))	('UCB', 'Phenotype', 'HP:0006740', (245, 248))	('prognostic consequences', 'MPA', (140, 163))	('variants', 'Var', (32, 40))	('affect', 'Reg', (133, 139))	('UCB', 'Chemical', '-', (245, 248))
89186	26025446	However, the diagnosis of UCB variants may be challenging.	('UCB', 'Gene', (26, 29))	('UCB', 'Chemical', '-', (26, 29))	('UCB', 'Phenotype', 'HP:0006740', (26, 29))	('variants', 'Var', (30, 38))
89200	26025446	Sensitivity was calculated as the proportion of RC specimens with a particular variant that also had the variant in the biopsy or last TURBT (LTURBT) specimen.	('LTURBT', 'Chemical', '-', (142, 148))	('variant', 'Var', (105, 112))	('variant', 'Var', (79, 86))
89208	26025446	Forty-five patients (31 %) exhibited variant(s) only on biopsy or TURBT(s), including 4 cases for biopsy, and 41 cases for TURBT(s).	('exhibited', 'Reg', (27, 36))	('variant', 'Var', (37, 44))	('patients', 'Species', '9606', (11, 19))
89213	26025446	Of those, 95 UCB patients were identified with variant differentiation on RC specimens.	('variant differentiation', 'Var', (47, 70))	('UCB', 'Phenotype', 'HP:0006740', (13, 16))	('UCB', 'Chemical', '-', (13, 16))	('UCB', 'Disease', (13, 16))	('patients', 'Species', '9606', (17, 25))
89214	26025446	Similarly, multivariate analyses after being adjusted for the effects of pathologic stage demonstrated that presence of variant differentiation in urothelial carcinoma at cystectomy was independently associated with cancer-specific mortality (HR4.48, 95 % CI:1.03-19.53).	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (147, 167))	('associated with', 'Reg', (200, 215))	('urothelial carcinoma', 'Disease', (147, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('variant differentiation', 'Var', (120, 143))
89216	26025446	Presence of variant differentiation in urothelial carcinoma at cystectomy portends inferior survival.	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('urothelial carcinoma', 'Disease', (39, 59))	('inferior', 'NegReg', (83, 91))	('survival', 'MPA', (92, 100))	('variant differentiation', 'Var', (12, 35))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (39, 59))
89226	26025446	Although some studies have contributed to raising the awareness of these entities and improved diagnosis, the diagnosis of UCB variants may still be challenging for (a) the limitation of biopsy samples and transurethral resectates available to the pathologist, (b) the artifact caused by tangential sectioning, cautery and mechanical injury, and (c) even more importantly the difficulty of discriminating over selected mimics.	('variants', 'Var', (127, 135))	('UCB', 'Chemical', '-', (123, 126))	('UCB', 'Phenotype', 'HP:0006740', (123, 126))	('mechanical injury', 'Disease', (323, 340))	('UCB', 'Gene', (123, 126))	('mechanical injury', 'Disease', 'MESH:D006930', (323, 340))
89239	26025446	Of the 139 patients with available follow-up information, 95 UCB patients were identified with variant differentiation on RC specimens.	('UCB', 'Phenotype', 'HP:0006740', (61, 64))	('UCB', 'Chemical', '-', (61, 64))	('UCB', 'Disease', (61, 64))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (11, 19))	('variant differentiation', 'Var', (95, 118))
89240	26025446	Patients with variant differentiation on RC specimen have inferior survival both in univariate analysis (P = 0.005) and multivariate analysis (HR4.48, 95 % CI:1.03-19.53).	('inferior', 'NegReg', (58, 66))	('variant differentiation', 'Var', (14, 37))	('survival', 'MPA', (67, 75))	('Patients', 'Species', '9606', (0, 8))
89246	26025446	Patients with variant differentiation on RC specimen have inferior survival.	('inferior', 'NegReg', (58, 66))	('variant differentiation', 'Var', (14, 37))	('Patients', 'Species', '9606', (0, 8))
89290	33663617	For example, CHD1L is a well-known activator of ARHGEF9, TCTP, SPOCK1 and NTKL and can also lead to deregulation of p53, TCTP and Nur77.	('NTKL', 'Gene', (74, 78))	('NTKL', 'Gene', '57410', (74, 78))	('TCTP', 'Gene', (57, 61))	('ARHGEF9', 'Gene', (48, 55))	('Nur77', 'Gene', (130, 135))	('SPOCK1', 'Gene', '6695', (63, 69))	('ARHGEF9', 'Gene', '23229', (48, 55))	('TCTP', 'Gene', '7178', (121, 125))	('lead to', 'Reg', (92, 99))	('TCTP', 'Gene', '7178', (57, 61))	('Nur77', 'Gene', '3164', (130, 135))	('SPOCK1', 'Gene', (63, 69))	('TCTP', 'Gene', (121, 125))	('p53', 'Protein', (116, 119))	('deregulation', 'MPA', (100, 112))	('CHD1L', 'Var', (13, 18))
89312	33663617	The HELICc is not an autonomous folding unit, but is an essential part of the helicases that utilize the energy from nucleoside triphosphate hydrolysis to provide fuel for their translocation along DNA and unwinding double-stranded DNA in the process.	('nucleoside triphosphate', 'Chemical', '-', (117, 140))	('unwinding', 'Var', (206, 215))	('DNA', 'cellular_component', 'GO:0005574', ('198', '201'))	('DNA', 'cellular_component', 'GO:0005574', ('232', '235'))	('translocation along DNA', 'MPA', (178, 201))
89314	33663617	SelS is a disordered protein which has a seleno sulfide bond (between Cys-174 and Sec-188) and a redox potential (- 234 mV).	('redox', 'MPA', (97, 102))	('Cys', 'Chemical', 'MESH:D003545', (70, 73))	('Sec-188', 'Var', (82, 89))	('SelS', 'Gene', (0, 4))	('seleno sulfide', 'Chemical', '-', (41, 55))	('seleno sulfide bond', 'MPA', (41, 60))	('SelS', 'Gene', '55829', (0, 4))	('Cys-174', 'Var', (70, 77))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
89323	33663617	PAR is produced by PAR polymerase (PARP), and single-stranded DNA breaks (SSB) and gaps can activate PARP.	('PAR', 'Chemical', 'MESH:D011064', (35, 38))	('PARP', 'Gene', '142', (101, 105))	('PARP', 'Gene', '142', (35, 39))	('PAR', 'Chemical', 'MESH:D011064', (101, 104))	('single-stranded DNA breaks', 'Var', (46, 72))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('gaps', 'Var', (83, 87))	('PAR', 'Chemical', 'MESH:D011064', (19, 22))	('PARP', 'Gene', (101, 105))	('PAR', 'Chemical', 'MESH:D011064', (0, 3))	('PARP', 'Gene', (35, 39))	('activate', 'PosReg', (92, 100))
89328	33663617	The co-operation between CHD1L and PARP is also related to the nucleotide excision repair of UV-induced DNA damage.	('PARP', 'Gene', '142', (35, 39))	('co-operation', 'Var', (4, 16))	('CHD1L', 'Gene', (25, 30))	('nucleotide excision repair of', 'MPA', (63, 92))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('63', '89'))	('PARP', 'Gene', (35, 39))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('related', 'Reg', (48, 55))
89331	33663617	Loss of ALC1 confers methyl-methanesulfonate, PARP inhibitors and formyl-dU sensitivity, which is synthetic lethal with homologous recombination deficiency (HRD).	('HRD', 'Disease', 'None', (157, 160))	('formyl-dU sensitivity', 'MPA', (66, 87))	('homologous recombination', 'biological_process', 'GO:0035825', ('120', '144'))	('ALC1', 'Gene', (8, 12))	('formyl-dU', 'Chemical', '-', (66, 75))	('PARP', 'Gene', '142', (46, 50))	('deficiency', 'Disease', (145, 155))	('methyl-methanesulfonate', 'Chemical', 'MESH:D008741', (21, 44))	('deficiency', 'Disease', 'MESH:D007153', (145, 155))	('HRD', 'Disease', (157, 160))	('methyl-methanesulfonate', 'MPA', (21, 44))	('PARP', 'Gene', (46, 50))	('ALC1', 'Gene', '9557', (8, 12))	('Loss', 'Var', (0, 4))
89334	33663617	Inhibiting the production of CHD1L can arrest embryo at the pre-blastocyst stage in mice embryonic stem (ES) cells by microinjecting antisense morpholinone.	('embryo at the pre-blastocyst stage', 'CPA', (46, 80))	('Inhibiting', 'Var', (0, 10))	('arrest', 'Disease', 'MESH:D006323', (39, 45))	('pre', 'molecular_function', 'GO:0003904', ('60', '63'))	('morpholinone', 'Chemical', '-', (143, 155))	('arrest', 'Disease', (39, 45))	('CHD1L', 'Gene', (29, 34))	('mice', 'Species', '10090', (84, 88))
89340	33663617	Three different heterozygous missense variants of CHD1L (variant Gly700Arg, variant Ile765Met and variant Ile827Val) were revealed by sequencing the entire coding region of the CHD1L gene in 61 CAKUT patients and exons 18, 19 and 21 in 24 CAKUT patients.	('CHD1L', 'Gene', (50, 55))	('patients', 'Species', '9606', (200, 208))	('patients', 'Species', '9606', (245, 253))	('Ile765Met', 'Mutation', 'rs148289715', (84, 93))	('Ile827Val', 'Var', (106, 115))	('Ile765Met', 'Var', (84, 93))	('Gly700Arg', 'SUBSTITUTION', 'None', (65, 74))	('Gly700Arg', 'Var', (65, 74))	('Ile827Val', 'Mutation', 'rs148434783', (106, 115))	('CHD1L', 'Gene', (177, 182))
89341	33663617	The interaction between all three CHD1L variants and PARP1 decreased compared with the wild-type CHD1L.	('interaction', 'Interaction', (4, 15))	('decreased', 'NegReg', (59, 68))	('CHD1L', 'Gene', (34, 39))	('PARP1', 'Gene', '142', (53, 58))	('PARP1', 'Gene', (53, 58))	('variants', 'Var', (40, 48))
89345	33663617	CHD1L can promote G1/S transition and DNA synthesis by upregulating cyclins, CDK2, 4 and downregulating P27, Rb and p53 in transgenic mouse models.	('CDK2', 'Gene', (77, 81))	('G1/S transition', 'CPA', (18, 33))	('P27', 'Gene', '12576', (104, 107))	('cyclins', 'Protein', (68, 75))	('DNA synthesis', 'biological_process', 'GO:0071897', ('38', '51'))	('upregulating', 'PosReg', (55, 67))	('P27', 'Gene', (104, 107))	('Rb', 'Gene', '19645', (109, 111))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('DNA synthesis', 'MPA', (38, 51))	('promote', 'PosReg', (10, 17))	('p53', 'Protein', (116, 119))	('CDK2', 'Gene', '12566', (77, 81))	('CHD1L', 'Var', (0, 5))	('downregulating', 'NegReg', (89, 103))	('CDK', 'molecular_function', 'GO:0004693', ('77', '80'))	('mouse', 'Species', '10090', (134, 139))
89349	33663617	CHD1L could induce G1/S transition by the dysregulation of p53-cyclinE-CDK2 pathway in glioma.	('glioma', 'Disease', (87, 93))	('CDK2', 'Gene', '12566', (71, 75))	('dysregulation', 'Var', (42, 55))	('G1/S transition', 'CPA', (19, 34))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('CDK', 'molecular_function', 'GO:0004693', ('71', '74'))	('induce', 'PosReg', (12, 18))	('CDK2', 'Gene', (71, 75))
89351	33663617	The dysregulation of p53-cyclin D1-CDK2 pathway might be related to CHD1L-induced G1/S transition, while CHD1L might drive EMT and MET and cause metastasis of cholangiocarcinoma cells.	('dysregulation', 'Var', (4, 17))	('cyclin D1', 'Gene', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('MET', 'Gene', '79811', (131, 134))	('CDK2', 'Gene', (35, 39))	('cyclin D1', 'Gene', '595', (25, 34))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (159, 177))	('EMT', 'CPA', (123, 126))	('cholangiocarcinoma', 'Disease', (159, 177))	('drive', 'PosReg', (117, 122))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (159, 177))	('cause', 'Reg', (139, 144))	('metastasis', 'CPA', (145, 155))	('cyclin', 'molecular_function', 'GO:0016538', ('25', '31'))	('EMT', 'biological_process', 'GO:0001837', ('123', '126'))	('CDK2', 'Gene', '12566', (35, 39))	('CDK', 'molecular_function', 'GO:0004693', ('35', '38'))	('CHD1L', 'Var', (105, 110))	('MET', 'Gene', (131, 134))
89354	33663617	Taken together, inappropriate expression of CHD1L target genes and deregulation of CHD1L system may link CHD1L to tumorigenesis by several mechanisms (Fig.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('CHD1L', 'Gene', (83, 88))	('tumor', 'Disease', (114, 119))	('link', 'Reg', (100, 104))	('deregulation', 'Var', (67, 79))	('CHD1L', 'Gene', (105, 110))
89380	33663617	ABCB1 knockdown coupled with CHD1L ectopic expression enhanced the effect of cisplatin on apoptosis of NSCLC cells.	('effect', 'MPA', (67, 73))	('NSCLC', 'Disease', (103, 108))	('ABCB1', 'Gene', (0, 5))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('knockdown', 'Var', (6, 15))	('apoptosis', 'CPA', (90, 99))	('enhanced', 'PosReg', (54, 62))
89385	33663617	However, elevated beta-catenin expression exhibited in the CHD1L-KD group in glioma.	('elevated', 'PosReg', (9, 17))	('beta-catenin', 'Gene', (18, 30))	('beta-catenin', 'Gene', '1499', (18, 30))	('CHD1L-KD', 'Var', (59, 67))	('glioma', 'Disease', (77, 83))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
89389	33663617	p53 protein can upregulate p21 expression, and the latter acts as a Cdk2 inhibitor, inactivating cyclinE-CDk2 complex to control the S phase entry.	('control', 'Reg', (121, 128))	('p21', 'Gene', (27, 30))	('protein', 'Protein', (4, 11))	('inactivating', 'NegReg', (84, 96))	('p21', 'Gene', '644914', (27, 30))	('upregulate', 'PosReg', (16, 26))	('Cdk2', 'Gene', '1017', (68, 72))	('CDk', 'molecular_function', 'GO:0004693', ('105', '108'))	('Cdk', 'molecular_function', 'GO:0004693', ('68', '71'))	('p53', 'Var', (0, 3))	('Cdk2', 'Gene', (68, 72))	('S phase entry', 'MPA', (133, 146))	('CDk2', 'Gene', (105, 109))	('S phase', 'biological_process', 'GO:0051320', ('133', '140'))	('CDk2', 'Gene', '1017', (105, 109))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
89395	33663617	Macro domain of CHD1L acts to interact with Nur77, while the CHD1L mutants lacking residues 600-897 cannot interact with Nur77 and prevents Nur77-mediated apoptosis of hepatocellular carcinoma.	('CHD1L', 'Gene', (61, 66))	('Nur77', 'Gene', '3164', (121, 126))	('Nur77', 'Gene', (44, 49))	('Nur77', 'Gene', (140, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('apoptosis', 'biological_process', 'GO:0006915', ('155', '164'))	('Nur77', 'Gene', '3164', (44, 49))	('mutants', 'Var', (67, 74))	('Nur77', 'Gene', '3164', (140, 145))	('apoptosis', 'biological_process', 'GO:0097194', ('155', '164'))	('Nur77', 'Gene', (121, 126))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (168, 192))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (168, 192))	('interact', 'Interaction', (30, 38))	('hepatocellular carcinoma', 'Disease', (168, 192))	('prevents', 'NegReg', (131, 139))
89404	33663617	Lysine methylation at a specific site on the histone H3 tails is associated with transcriptional regulation.	('regulation', 'biological_process', 'GO:0065007', ('97', '107'))	('transcriptional regulation', 'MPA', (81, 107))	('Lysine methylation', 'Var', (0, 18))	('associated', 'Reg', (65, 75))	('histone', 'Protein', (45, 52))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('methylation', 'biological_process', 'GO:0032259', ('7', '18'))
89413	33663617	Full length CHD1 is required in embryonic stem cell differentiation, and loss of the serine-rich region (SRR) renders CHD1 unable to support normal differentiation of ESCs into the three germ layers.	('unable', 'NegReg', (123, 129))	('CHD1', 'Gene', '1105', (12, 16))	('CHD1', 'Gene', '1105', (118, 122))	('loss', 'Var', (73, 77))	('stem cell differentiation', 'biological_process', 'GO:0048863', ('42', '67'))	('CHD1', 'Gene', (118, 122))	('serine', 'Chemical', 'MESH:D012694', (85, 91))	('CHD1', 'Gene', (12, 16))
89414	33663617	Endothelial-specific deletion of CHD1 leads to loss of definitive hematopoietic progenitors, anemia, and lethality by embryonic day (E)15.5.	('anemia', 'Disease', (93, 99))	('CHD1', 'Gene', '1105', (33, 37))	('anemia', 'Disease', 'MESH:D000740', (93, 99))	('deletion', 'Var', (21, 29))	('loss', 'NegReg', (47, 51))	('anemia', 'Phenotype', 'HP:0001903', (93, 99))	('lethality', 'CPA', (105, 114))	('CHD1', 'Gene', (33, 37))
89415	33663617	CHD1 is the 5q21 tumor suppressor gene, and inactivation of CHD1 abolishes recruitment of androgen receptor (AR) to result in downregulation of AR-responsive genes (eg.	('CHD1', 'Gene', (60, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('CHD1', 'Gene', '1105', (60, 64))	('tumor', 'Disease', (17, 22))	('downregulation', 'NegReg', (126, 140))	('androgen receptor', 'Gene', (90, 107))	('CHD1', 'Gene', (0, 4))	('recruitment', 'MPA', (75, 86))	('AR', 'Gene', '367', (109, 111))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('CHD1', 'Gene', '1105', (0, 4))	('AR', 'Gene', '367', (144, 146))	('androgen receptor', 'Gene', '367', (90, 107))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('abolishes', 'NegReg', (65, 74))	('inactivation', 'Var', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
89417	33663617	Recurrent deletion of CHD1 is a driver of prostate cancer cell invasiveness.	('CHD1', 'Gene', (22, 26))	('prostate cancer', 'Phenotype', 'HP:0012125', (42, 57))	('CHD1', 'Gene', '1105', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('prostate cancer', 'Disease', (42, 57))	('deletion', 'Var', (10, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (42, 57))
89419	33663617	a novel CHD1-RUNX1 fusion collaborated with FLT3-ITD mutation in the development of acute myeloid leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (98, 106))	('acute myeloid leukemia', 'Disease', (84, 106))	('fusion', 'Var', (19, 25))	('CHD1', 'Gene', '1105', (8, 12))	('RUNX1', 'Gene', '861', (13, 18))	('FLT3', 'Gene', '2322', (44, 48))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (84, 106))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (90, 106))	('FLT3', 'Gene', (44, 48))	('RUNX1', 'Gene', (13, 18))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (84, 106))	('CHD1', 'Gene', (8, 12))
89430	33663617	The abnormal expression of CHD1L may be prognostic factor of ACC, HNSC, KICH, KIRC, KIRP, LIHC, LUAD, MESO, SARC and THCA (Fig.	('KICH', 'Disease', 'None', (72, 76))	('ACC', 'Gene', (61, 64))	('LIHC', 'Disease', (90, 94))	('LUAD', 'Disease', (96, 100))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('HNSC', 'Disease', (66, 70))	('THCA', 'Chemical', '-', (117, 121))	('CHD1L', 'Gene', (27, 32))	('ACC', 'Gene', '31', (61, 64))	('AR', 'Gene', '367', (109, 111))	('MESO', 'Disease', (102, 106))	('KICH', 'Disease', (72, 76))	('THCA', 'Disease', (117, 121))
89441	33663617	reveal CHD1L manipulation impacts the single-strand DNA break repair response and potentiates PARPi-induced cancer killing through PARP2 trapping.	('single-strand DNA break repair response', 'MPA', (38, 77))	('impacts', 'Reg', (26, 33))	('PARP', 'Gene', '142', (94, 98))	('PARP', 'Gene', '142', (131, 135))	('CHD1L', 'Gene', (7, 12))	('manipulation', 'Var', (13, 25))	('cancer', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('PARP2', 'Gene', '10038', (131, 136))	('potentiates', 'PosReg', (82, 93))	('PARP', 'Gene', (94, 98))	('PARP', 'Gene', (131, 135))	('PARP2', 'Gene', (131, 136))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
89470	32420368	found that IGF1 in plasma of patients with urothelial carcinoma of bladder was higher than that of normal controls, and IGF1 expression was associated with an increased risk, but studies by Crystal Lin et al.	('expression', 'Var', (125, 135))	('higher', 'PosReg', (79, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('IGF1', 'MPA', (11, 15))	('IGF1', 'Gene', (120, 124))	('urothelial carcinoma of bladder', 'Disease', 'MESH:D001749', (43, 74))	('urothelial carcinoma of bladder', 'Disease', (43, 74))	('urothelial carcinoma of bladder', 'Phenotype', 'HP:0006740', (43, 74))
89497	30275370	Variations in genes, such as MSTN, VDR, and ACE, determine the variability in skeletal muscle phenotype and the prevalence of sarcopenia in an elderly population.	('MSTN', 'Gene', (29, 33))	('ACE', 'Gene', (44, 47))	('ACE', 'Gene', '1636', (44, 47))	('VDR', 'Gene', '7421', (35, 38))	('sarcopenia', 'Disease', 'MESH:D055948', (126, 136))	('determine', 'Reg', (49, 58))	('skeletal muscle phenotype', 'CPA', (78, 103))	('Variations', 'Var', (0, 10))	('MSTN', 'Gene', '2660', (29, 33))	('sarcopenia', 'Disease', (126, 136))	('VDR', 'Gene', (35, 38))
89521	30275370	In a previous study of ATGL- or HSL-deficient animal models, the absence of ATGL and, to lesser degree, HSL reduces fatty acid mobilization and adipose tissue loss, leading to maintained skeletal muscle mass, suggesting that excessive depletion of adipose tissue may be involved in the progression of skeletal muscle atrophy.	('skeletal muscle atrophy', 'biological_process', 'GO:0014732', ('301', '324'))	('HSL', 'Gene', '3991', (32, 35))	('ATGL', 'Gene', '57104', (76, 80))	('adipose', 'Gene', (144, 151))	('HSL', 'Gene', '3991', (104, 107))	('skeletal', 'Disease', (301, 309))	('muscle atrophy', 'Disease', (310, 324))	('excessive depletion of adipose tissue', 'Phenotype', 'HP:0008887', (225, 262))	('HSL-deficient', 'Disease', 'MESH:D007153', (32, 45))	('absence', 'Var', (65, 72))	('ATGL', 'Gene', (23, 27))	('HSL', 'molecular_function', 'GO:0033878', ('104', '107'))	('fatty acid mobilization', 'MPA', (116, 139))	('HSL-deficient', 'Disease', (32, 45))	('excessive', 'Chemical', '-', (225, 234))	('HSL', 'molecular_function', 'GO:0033878', ('32', '35'))	('skeletal muscle atrophy', 'Phenotype', 'HP:0003202', (301, 324))	('adipose', 'Gene', '230796', (248, 255))	('ATGL', 'Gene', '57104', (23, 27))	('muscle atrophy', 'Disease', 'MESH:D009133', (310, 324))	('ATGL', 'Gene', (76, 80))	('adipose', 'Gene', '230796', (144, 151))	('adipose tissue loss', 'Phenotype', 'HP:0008887', (144, 163))	('loss', 'NegReg', (159, 163))	('reduces', 'NegReg', (108, 115))	('HSL', 'Gene', (104, 107))	('adipose', 'Gene', (248, 255))	('fatty acid', 'Chemical', 'MESH:D005227', (116, 126))	('HSL', 'Gene', (32, 35))	('skeletal muscle mass', 'CPA', (187, 207))
89535	30275370	Interestingly, they also showed that increased oxidative stress caused by excessive fatty acid oxidation could impair muscle growth.	('excessive', 'Chemical', '-', (74, 83))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('84', '104'))	('fatty acid', 'Chemical', 'MESH:D005227', (84, 94))	('excessive', 'Var', (74, 83))	('impair', 'NegReg', (111, 117))	('oxidative stress', 'MPA', (47, 63))	('fatty acid oxidation', 'MPA', (84, 104))	('increased', 'PosReg', (37, 46))	('muscle growth', 'CPA', (118, 131))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (37, 63))
89537	30275370	Inhibiting the process of fatty acid oxidation could be efficacious in preventing cancer cachexia and sarcopenia.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Inhibiting', 'Var', (0, 10))	('cachexia', 'Phenotype', 'HP:0004326', (89, 97))	('cancer cachexia and sarcopenia', 'Disease', 'MESH:D002100', (82, 112))	('preventing', 'NegReg', (71, 81))	('fatty acid', 'Chemical', 'MESH:D005227', (26, 36))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('26', '46'))
89608	30275370	n-3 Fatty acids, including eicosapentaenoic acid and docosahexaenoic acid, can recover a cancer-induced hyper-catabolic state and improve sarcopenia and cachexia by its anti-inflammatory effects, involving the attenuation of NF-kB signaling, deceleration of the ubiquitin proteasome pathway, and antagonization of superoxide dismutase.	('superoxide dismutase', 'Enzyme', (314, 334))	('ubiquitin proteasome pathway', 'Pathway', (262, 290))	('proteasome', 'molecular_function', 'GO:0004299', ('272', '282'))	('cancer', 'Disease', (89, 95))	('cachexia', 'Phenotype', 'HP:0004326', (153, 161))	('NF-kB signaling', 'Pathway', (225, 240))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('sarcopenia and cachexia', 'Disease', 'MESH:D002100', (138, 161))	('hyper-catabolic', 'Disease', (104, 119))	('n-3 Fatty acids', 'Chemical', 'MESH:D015525', (0, 15))	('proteasome', 'cellular_component', 'GO:0000502', ('272', '282'))	('proteasome pathway', 'biological_process', 'GO:0043161', ('272', '290'))	('signaling', 'biological_process', 'GO:0023052', ('231', '240'))	('attenuation', 'NegReg', (210, 221))	('antagonization', 'Var', (296, 310))	('improve', 'PosReg', (130, 137))	('docosahexaenoic acid', 'Chemical', 'MESH:D004281', (53, 73))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('eicosapentaenoic acid', 'Chemical', 'MESH:D015118', (27, 48))	('hyper-catabolic', 'Disease', 'MESH:D053307', (104, 119))	('recover', 'PosReg', (79, 86))	('ubiquitin', 'molecular_function', 'GO:0031386', ('262', '271'))	('anti-inflammatory', 'MPA', (169, 186))	('deceleration', 'NegReg', (242, 254))	('rat', 'Species', '10116', (248, 251))
89612	30275370	Moreover, n-3 fatty acids have some effects on improving protein anabolism by activating the PI3K/Akt/mTOR pathway.	('activating', 'Reg', (78, 88))	('improving', 'PosReg', (47, 56))	('protein anabolism', 'MPA', (57, 74))	('Akt', 'Gene', '207', (98, 101))	('PI3K', 'molecular_function', 'GO:0016303', ('93', '97'))	('n-3 fatty acids', 'Chemical', 'MESH:D015525', (10, 25))	('mTOR', 'Gene', (102, 106))	('Akt', 'Gene', (98, 101))	('mTOR', 'Gene', '2475', (102, 106))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('protein anabolism', 'biological_process', 'GO:0006412', ('57', '74'))	('n-3', 'Var', (10, 13))
89613	30275370	Recently, a randomized controlled study revealed that eicosapentaenoic acid improved postoperative survival in patients undergoing metastasectomy for liver metastases from colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (172, 189))	('colorectal cancer', 'Phenotype', 'HP:0003003', (172, 189))	('metastases', 'Disease', (156, 166))	('eicosapentaenoic', 'Var', (54, 70))	('improved', 'PosReg', (76, 84))	('postoperative survival', 'CPA', (85, 107))	('colorectal cancer', 'Disease', (172, 189))	('rat', 'Species', '10116', (92, 95))	('patients', 'Species', '9606', (111, 119))	('metastases', 'Disease', 'MESH:D009362', (156, 166))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('eicosapentaenoic acid', 'Chemical', 'MESH:D015118', (54, 75))
89616	30275370	In mice models with cancer cachexia, blockage of the ActR2B pathway suppressed skeletal muscle wasting by abolishing activated ubiquitin-proteasome system and inducing atrophy-specific ubiquitin ligases in skeletal muscles, in which tumor growth and fat loss were not inhibited.	('proteasome', 'cellular_component', 'GO:0000502', ('137', '147'))	('inducing', 'Reg', (159, 167))	('cancer cachexia', 'Disease', (20, 35))	('ubiquitin', 'molecular_function', 'GO:0031386', ('127', '136'))	('cancer cachexia', 'Disease', 'MESH:D002100', (20, 35))	('tumor', 'Disease', (233, 238))	('abolishing', 'NegReg', (106, 116))	('blockage', 'Var', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('ActR2B', 'Gene', (53, 59))	('activated ubiquitin-proteasome system', 'MPA', (117, 154))	('muscle wasting', 'Phenotype', 'HP:0003202', (88, 102))	('mice', 'Species', '10090', (3, 7))	('skeletal muscle wasting', 'CPA', (79, 102))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('proteasome', 'molecular_function', 'GO:0004299', ('137', '147'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('185', '194'))	('suppressed', 'NegReg', (68, 78))	('cachexia', 'Phenotype', 'HP:0004326', (27, 35))	('atrophy', 'Disease', 'MESH:D001284', (168, 175))	('atrophy', 'Disease', (168, 175))
89617	30275370	Therefore, ActR2B antagonism has therapeutic potential for treating cancer cachexia and sarcopenia.	('cachexia', 'Phenotype', 'HP:0004326', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ActR2B', 'Gene', (11, 17))	('antagonism', 'Var', (18, 28))	('treating cancer cachexia and sarcopenia', 'Disease', 'MESH:D002100', (59, 98))
89621	30275370	Metformin increases food intake and prolongs survival in cachectic tumor-bearing rat models.	('increases', 'PosReg', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('prolongs', 'PosReg', (36, 44))	('rat', 'Species', '10116', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Metformin', 'Var', (0, 9))	('survival', 'CPA', (45, 53))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('tumor', 'Disease', (67, 72))	('food intake', 'CPA', (20, 31))
89624	30275370	Therefore, inhibitors for ATGL or HSL can be candidates for medications for cancer cachexia and sarcopenia.	('HSL', 'Gene', (34, 37))	('HSL', 'molecular_function', 'GO:0033878', ('34', '37'))	('cachexia', 'Phenotype', 'HP:0004326', (83, 91))	('ATGL', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('inhibitors', 'Var', (11, 21))	('ATGL', 'Gene', '57104', (26, 30))	('HSL', 'Gene', '3991', (34, 37))	('cancer cachexia and sarcopenia', 'Disease', 'MESH:D002100', (76, 106))
89630	30275370	Testosterone improves sarcopenia, especially in combination with protein supplementations.	('Testosterone', 'Var', (0, 12))	('sarcopenia', 'Disease', 'MESH:D055948', (22, 32))	('improves', 'PosReg', (13, 21))	('Testosterone', 'Chemical', 'MESH:D013739', (0, 12))	('sarcopenia', 'Disease', (22, 32))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))
89636	30275370	Exercise was shown to induce the secretion of interleukin-6 from muscles and elicit anti-tumor immunity in combination with epinephrine by redistributing natural killer cells to tumor microenvironments.	('elicit', 'Reg', (77, 83))	('tumor', 'Disease', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('secretion', 'biological_process', 'GO:0046903', ('33', '42'))	('Exercise', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('interleukin-6', 'Gene', '3569', (46, 59))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('interleukin-6', 'Gene', (46, 59))	('epinephrine', 'Chemical', 'MESH:D004837', (124, 135))	('secretion', 'MPA', (33, 42))	('tumor', 'Disease', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
89637	30275370	Because exercise enhances anti-tumor immunity, exercise might have a favorable effect on the efficacy of immune-oncology drugs for cancer.	('cancer', 'Disease', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('oncology', 'Phenotype', 'HP:0002664', (112, 120))	('exercise', 'Var', (8, 16))	('tumor', 'Disease', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('enhances', 'PosReg', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
89638	30275370	Moreover, exercise was shown to inhibit tumor growth by activating the Hippo tumor suppressor pathway via beta-adrenergic signaling.	('exercise', 'Var', (10, 18))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('77', '93'))	('inhibit', 'NegReg', (32, 39))	('activating', 'PosReg', (56, 66))	('beta-adrenergic signaling', 'MPA', (106, 131))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', (77, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('77', '93'))
89668	32640634	Other than patients with FGFR alteration, the molecular mechanisms of different subtypes of bladder cancer are still unknown.	('alteration', 'Var', (30, 40))	('bladder cancer', 'Disease', 'MESH:D001749', (92, 106))	('bladder cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('bladder cancer', 'Phenotype', 'HP:0009725', (92, 106))	('patients', 'Species', '9606', (11, 19))
89686	32640634	The alteration or abnormalities of TCR signaling leads to the defect of the immune response to tumor.	('abnormalities', 'Var', (18, 31))	('immune response', 'biological_process', 'GO:0006955', ('76', '91'))	('defect', 'NegReg', (62, 68))	('TCR', 'biological_process', 'GO:0006283', ('35', '38'))	('alteration', 'Var', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('signaling', 'biological_process', 'GO:0023052', ('39', '48'))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('TCR', 'Protein', (35, 38))	('TCR', 'cellular_component', 'GO:0042101', ('35', '38'))	('tumor', 'Disease', (95, 100))
89691	32640634	Alterations of cell mitosis, which is one of the cell cycle processes, would lead to abnormalities of carcinogenesis.	('lead to', 'Reg', (77, 84))	('abnormalities of carcinogenesis', 'Disease', (85, 116))	('Alterations', 'Var', (0, 11))	('cell mitosis', 'CPA', (15, 27))	('mitosis', 'biological_process', 'GO:0000278', ('20', '27'))	('cell cycle', 'biological_process', 'GO:0007049', ('49', '59'))	('abnormalities of carcinogenesis', 'Disease', 'MESH:D063646', (85, 116))
89695	32640634	Inactivation of the TRAIL-related pathways might have an impact on the tumor onset and progression.	('impact', 'Reg', (57, 63))	('TRAIL', 'Gene', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('progression', 'CPA', (87, 98))	('Inactivation', 'Var', (0, 12))	('TRAIL', 'Gene', '8743', (20, 25))
89713	32640634	With a high expression level of these genes, patients had a poor prognosis (Figure 8).	('patients', 'Species', '9606', (45, 53))	('high', 'Var', (7, 11))	('expression level', 'MPA', (12, 28))
89720	32640634	The methylation of LAMA3 and LAMC2 were associated with poor prognosis in patients with muscle invasive bladder cancer (MIBC).	('invasive bladder', 'Phenotype', 'HP:0100645', (95, 111))	('LAMA3', 'Gene', (19, 24))	('MIBC', 'Chemical', '-', (120, 124))	('patients', 'Species', '9606', (74, 82))	('LAMA3', 'Gene', '3909', (19, 24))	('LAMC2', 'Gene', (29, 34))	('methylation', 'Var', (4, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (88, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('associated', 'Reg', (40, 50))	('muscle invasive bladder cancer', 'Disease', (88, 118))
89721	32640634	Besides, the frequency of LAMC2 methylation was related to MIBC recurrence.	('methylation', 'Var', (32, 43))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('MIBC', 'Chemical', '-', (59, 63))	('MIBC recurrence', 'Disease', (59, 74))	('LAMC2', 'Gene', (26, 31))	('related', 'Reg', (48, 55))
89751	32640634	Moreover, we also found that patients with a high expression level of HIPK2 had a higher mortality risk.	('patients', 'Species', '9606', (29, 37))	('high expression level', 'Var', (45, 66))	('mortality', 'Disease', 'MESH:D003643', (89, 98))	('mortality', 'Disease', (89, 98))	('HIPK2', 'Gene', '28996', (70, 75))	('HIPK2', 'Gene', (70, 75))
89856	27936466	High expression of DPP4 in UBUC significantly associated with higher tumor pT stage (p < 0.001), presence of nodal metastasis (p = 0.033), vascular invasion (p < 0.001) and perineural invasion (p = 0.021).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('High', 'Var', (0, 4))	('tumor', 'Disease', (69, 74))	('perineural invasion', 'CPA', (173, 192))	('vascular invasion', 'CPA', (139, 156))	('nodal metastasis', 'CPA', (109, 125))	('higher', 'PosReg', (62, 68))	('DPP4', 'Gene', '1803', (19, 23))	('associated', 'Reg', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('UBUC', 'Chemical', '-', (27, 31))	('DPP4', 'Gene', (19, 23))
89862	27936466	Overexpression of DPP4 in UTUC correlated with higher tumor pT stage (p < 0.001), presence of nodal metastasis (p < 0.001), high histological grade (p = 0.019), vascular invasion (p < 0.001) and frequent mitosis (p = 0.003) (Supplementary Table S5).	('DPP4', 'Gene', '1803', (18, 22))	('mitosis', 'Disease', (204, 211))	('higher', 'PosReg', (47, 53))	('mitosis', 'Disease', 'None', (204, 211))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mitosis', 'biological_process', 'GO:0000278', ('204', '211'))	('nodal metastasis', 'CPA', (94, 110))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Overexpression', 'Var', (0, 14))	('DPP4', 'Gene', (18, 22))	('vascular invasion', 'CPA', (161, 178))	('tumor', 'Disease', (54, 59))	('high histological grade', 'CPA', (124, 147))
89863	27936466	Univariate analysis shows that high DPP4 expression is associated with dismal DSS (p < 0.0001) and MeFS (p < 0.0001) outcome in UTUC patients, along with multifocality, primary tumor (pT) stage, nodal metastasis, histological grade, vascular invasion, and perineural invasion (Figure 3, Table 2).	('DPP4', 'Gene', (36, 40))	('MeFS', 'Disease', (99, 103))	('dismal DSS', 'Disease', (71, 81))	('expression', 'MPA', (41, 51))	('patients', 'Species', '9606', (133, 141))	('associated', 'Reg', (55, 65))	('DPP4', 'Gene', '1803', (36, 40))	('primary tumor', 'Disease', (169, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('high', 'Var', (31, 35))	('primary tumor', 'Disease', 'MESH:D009369', (169, 182))	('DSS', 'Chemical', '-', (78, 81))
89870	27936466	The results show that DPP4 knockdown led to a decreased cell growth by resulting G0/G1 arrest (Figure 4C, Supplementary Figure S3).	('knockdown', 'Var', (27, 36))	('cell growth', 'biological_process', 'GO:0016049', ('56', '67'))	('DPP4', 'Gene', (22, 26))	('cell growth', 'CPA', (56, 67))	('G0/G1 arrest', 'CPA', (81, 93))	('decreased', 'NegReg', (46, 55))	('DPP4', 'Gene', '1803', (22, 26))
89871	27936466	To clarify if DPP4 promote migration and invasion in UC cell, the DPP4 knockdown UC cells are subjected to migration and invasion assays which demonstrated both the migratory and invasion abilities of the UCs was significantly suppressed after DPP4 knockdown.	('DPP4', 'Gene', '1803', (14, 18))	('DPP4', 'Gene', '1803', (66, 70))	('invasion abilities of', 'CPA', (179, 200))	('knockdown', 'Var', (249, 258))	('DPP4', 'Gene', '1803', (244, 248))	('suppressed', 'NegReg', (227, 237))	('DPP4', 'Gene', (244, 248))	('DPP4', 'Gene', (14, 18))	('DPP4', 'Gene', (66, 70))
89875	27936466	For J82 cells, the percentage of apoptotic cells increased from 3.97 +- 0.32% to 23.13 +- 0.55% after transfected with shDPP4 (P < 0.05).	('transfected', 'Var', (102, 113))	('DPP4', 'Gene', '1803', (121, 125))	('DPP4', 'Gene', (121, 125))
89876	27936466	The RTCC-1 cells showed similar observation, which apoptotic cells increased from 0.74 +- 0.19% to 8.86 +- 0.42% after transfected with shDPP4 (P < 0.05).	('DPP4', 'Gene', '1803', (138, 142))	('transfected', 'Var', (119, 130))	('apoptotic cells', 'CPA', (51, 66))	('DPP4', 'Gene', (138, 142))
89887	27936466	Overexpression of FAP is associated with poor outcome in some neoplasm (pancreatic, hepatocellular, and colonic malignancies) but not others (breast cancer).	('colonic malignancies', 'Phenotype', 'HP:0100273', (104, 124))	('pancreatic', 'Disease', (72, 82))	('neoplasm', 'Disease', (62, 70))	('FAP', 'Gene', '2191', (18, 21))	('neoplasm', 'Disease', 'MESH:D009369', (62, 70))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('neoplasm', 'Phenotype', 'HP:0002664', (62, 70))	('colonic malignancies', 'Disease', (104, 124))	('colonic malignancies', 'Disease', 'MESH:D009369', (104, 124))	('breast cancer', 'Disease', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('Overexpression', 'Var', (0, 14))	('hepatocellular', 'Disease', (84, 98))	('FAP', 'Gene', (18, 21))	('pancreatic', 'Disease', 'MESH:D010195', (72, 82))
89888	27936466	It is likely that FAP expression affected the tumor biological behavior through remodeling of the cancer cell microenvironment and regulation of the infiltration of inflammatory cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('affected', 'Reg', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('expression', 'Var', (22, 32))	('FAP', 'Gene', '2191', (18, 21))	('tumor', 'Disease', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('FAP', 'Gene', (18, 21))	('regulation', 'biological_process', 'GO:0065007', ('131', '141'))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
89893	27936466	Our results show that DPP4 knockdown cells have lower proliferative activity and enter G0/G1 phase more readily.	('knockdown', 'Var', (27, 36))	('DPP4', 'Gene', (22, 26))	('proliferative activity', 'CPA', (54, 76))	('lower', 'NegReg', (48, 53))	('G0/G1 phase', 'CPA', (87, 98))	('enter', 'Reg', (81, 86))	('G1 phase', 'biological_process', 'GO:0051318', ('90', '98'))	('DPP4', 'Gene', '1803', (22, 26))
89905	27936466	In our study, patients with UC that express a high level of DPP4 are more likely to develop an advanced disease and have aggressive tumors.	('DPP4', 'Gene', (60, 64))	('aggressive tumors', 'Disease', (121, 138))	('advanced disease', 'Disease', 'MESH:D020178', (95, 111))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('high level', 'Var', (46, 56))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('develop', 'PosReg', (84, 91))	('DPP4', 'Gene', '1803', (60, 64))	('patients', 'Species', '9606', (14, 22))	('aggressive tumors', 'Disease', 'MESH:D001523', (121, 138))	('advanced disease', 'Disease', (95, 111))
89917	27936466	In our study, DPP4 knockdown UC cells have lower migration and invasion ability.	('DPP4', 'Gene', '1803', (14, 18))	('knockdown', 'Var', (19, 28))	('migration', 'CPA', (49, 58))	('invasion ability', 'CPA', (63, 79))	('DPP4', 'Gene', (14, 18))	('lower', 'NegReg', (43, 48))
89942	27936466	Recently, a study shows that the inhibition of DPP4 will increase CD4+ and CD8+ T lymphocytes and delayed tumor growth.	('inhibition', 'Var', (33, 43))	('delayed', 'NegReg', (98, 105))	('CD4', 'Gene', (66, 69))	('CD8', 'Gene', '925', (75, 78))	('DPP4', 'Gene', (47, 51))	('CD4', 'Gene', '920', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('increase', 'PosReg', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('DPP4', 'Gene', '1803', (47, 51))	('CD8', 'Gene', (75, 78))	('tumor', 'Disease', (106, 111))
89943	27936466	They concluded that presence of DPP4 would repress CXCR3-mediated anti-tumor immunity and thus limited the infiltration of T lymphocytes.	('CXCR3', 'Gene', '2833', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('DPP4', 'Gene', (32, 36))	('DPP4', 'Gene', '1803', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('CXCR3', 'Gene', (51, 56))	('tumor', 'Disease', (71, 76))	('limited', 'NegReg', (95, 102))	('repress', 'NegReg', (43, 50))	('infiltration of T lymphocytes', 'CPA', (107, 136))	('presence', 'Var', (20, 28))
89958	27936466	For patients with pT3 or pT4 stage UBUC, with or without nodal involvement, surgeries were followed by cisplatin-based adjuvant chemotherapy.	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('UBUC', 'Chemical', '-', (35, 39))	('pT3', 'Gene', '7694', (18, 21))	('pT3', 'Gene', (18, 21))	('patients', 'Species', '9606', (4, 12))	('pT4 stage', 'Var', (25, 34))
89994	33491650	Different mutational processes induce different types of DNA mutations, providing 'mutational signatures' that have led to key insights into cancer etiology.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('DNA', 'Disease', (57, 60))	('mutations', 'Var', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('cancer', 'Disease', (141, 147))
89997	33491650	Cancer is the end result of a process of accumulation of genetic and epigenetic alterations.	('epigenetic alterations', 'Var', (69, 91))	('genetic', 'Var', (57, 64))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
89999	33491650	Carcinogens such as tobacco smoking, aflatoxin, and aristolochic acid are also known to induce characteristic mutations at specific motifs.	('mutations', 'Var', (110, 119))	('induce', 'Reg', (88, 94))	('aristolochic acid', 'Var', (52, 69))	('aristolochic acid', 'Chemical', 'MESH:C000228', (52, 69))	('tobacco', 'Species', '4097', (20, 27))	('aflatoxin', 'Chemical', 'MESH:D000348', (37, 46))
90024	33491650	It has long been known that certain types of mutations, such as C>T transitions resulting from cytosine deamination, accumulate with age.	('accumulate', 'PosReg', (117, 127))	('resulting', 'Reg', (80, 89))	('C>T transitions', 'Var', (64, 79))	('cytosine', 'Chemical', 'MESH:D003596', (95, 103))
90028	33491650	Not surprisingly, we found C>T transitions to be present in large fractions in many cancer types.	('C>T', 'Var', (27, 30))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (84, 90))
90029	33491650	However, others, such as C>A transversions in stomach and prostate adenocarcinomas, and adrenocortical carcinomas, T>C transitions in liver hepatocellular carcinomas, C>G transversions in colorectal adenocarcinomas, head and neck squamous cell carcinomas, prostate adenocarcinomas, renal clear cell carcinomas, testicular germ cell tumors, and uterine corpus carcinoma, and any mutations of the T pyrimidine in prostate and kidney cancers, and testicular tumors, had not been previously described as major age-associated mutations (Figure 4a, and Figure 4:figure supplements 1-30).	('prostate adenocarcinomas', 'Disease', (256, 280))	('cancers', 'Phenotype', 'HP:0002664', (431, 438))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (188, 214))	('neck', 'cellular_component', 'GO:0044326', ('225', '229'))	('corpus carcinoma', 'Disease', 'MESH:D009369', (352, 368))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (88, 113))	('kidney cancer', 'Phenotype', 'HP:0009726', (424, 437))	('corpus carcinoma', 'Disease', (352, 368))	('adrenocortical carcinomas', 'Disease', (88, 113))	('kidney cancers', 'Phenotype', 'HP:0009726', (424, 438))	('cancer', 'Phenotype', 'HP:0002664', (431, 437))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('tumors', 'Disease', 'MESH:D009369', (455, 461))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))	('tumors', 'Phenotype', 'HP:0002664', (332, 338))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('testicular tumors', 'Disease', 'MESH:D013736', (444, 461))	('neck squamous cell carcinomas', 'Disease', (225, 254))	('testicular tumors', 'Phenotype', 'HP:0010788', (444, 461))	('renal clear cell carcinomas', 'Disease', 'MESH:C538614', (282, 309))	('testicular', 'Disease', (311, 321))	('prostate adenocarcinomas', 'Disease', 'MESH:D011471', (58, 82))	('colorectal adenocarcinomas', 'Disease', (188, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (88, 113))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (225, 254))	('tumors', 'Disease', (332, 338))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('tumor', 'Phenotype', 'HP:0002664', (455, 460))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('prostate adenocarcinomas', 'Disease', 'MESH:D011471', (256, 280))	('tumors', 'Phenotype', 'HP:0002664', (455, 461))	('liver hepatocellular carcinomas', 'Disease', 'MESH:D006528', (134, 165))	('germ cell tumors', 'Phenotype', 'HP:0100728', (322, 338))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('prostate adenocarcinomas', 'Disease', (58, 82))	('tumors', 'Disease', 'MESH:D009369', (332, 338))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('C>G transversions', 'Var', (167, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (244, 254))	('prostate and kidney cancers', 'Disease', 'MESH:D011471', (411, 438))	('stomach', 'Disease', (46, 53))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (230, 254))	('liver hepatocellular carcinomas', 'Disease', (134, 165))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (140, 165))	('testicular tumors', 'Disease', (444, 461))	('renal clear cell carcinomas', 'Disease', (282, 309))	('tumors', 'Disease', (455, 461))
90031	33491650	We were thus able to obtain tissue-specific SuperSigs for mismatch repair deficiency, mutations in DNA polymerase delta or epsilon genes, mutations in the breast cancer susceptibility genes BRCA1 or BRCA2, methylation of the MGMT and IDH1 genes, and APOBEC (Figure 4b, Figure 4:figure supplements 31-67, Supplementary file 2, and Materials and methods).	('epsilon genes', 'Gene', (123, 136))	('methylation', 'Var', (206, 217))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('methylation', 'biological_process', 'GO:0032259', ('206', '217'))	('BRCA2', 'Gene', (199, 204))	('APOBEC', 'cellular_component', 'GO:0030895', ('250', '256'))	('MGMT', 'Gene', (225, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('mutations', 'Var', (86, 95))	('BRCA2', 'Gene', '675', (199, 204))	('BRCA1', 'Gene', '672', (190, 195))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('DNA polymerase delta', 'Gene', (99, 119))	('breast cancer', 'Disease', (155, 168))	('IDH1', 'Gene', (234, 238))	('BRCA1', 'Gene', (190, 195))	('mutations', 'Var', (138, 147))	('deficiency', 'Var', (74, 84))	('mismatch', 'Gene', (58, 66))	('MGMT', 'molecular_function', 'GO:0003908', ('225', '229'))	('DNA polymerase delta', 'Gene', '5424', (99, 119))	('MGMT', 'Gene', '4255', (225, 229))	('mismatch repair', 'biological_process', 'GO:0006298', ('58', '73'))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('APOBEC', 'Gene', (250, 256))	('IDH1', 'Gene', '3417', (234, 238))
90033	33491650	And the SuperSigs associated with BRCA gene mutations were considerably different between breast and ovarian cancers (Figure 4:figure supplements 36-37).	('BRCA', 'Gene', '672', (34, 38))	('ovarian cancers', 'Phenotype', 'HP:0100615', (101, 116))	('BRCA', 'Gene', (34, 38))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (90, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('mutations', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))
90040	33491650	For example, obesity could lead to cancer by inducing mutations or by stimulating the growth of neoplastic cells that have already acquired mutations.	('obesity', 'Phenotype', 'HP:0001513', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('obesity', 'Disease', 'MESH:D009765', (13, 20))	('inducing', 'Reg', (45, 53))	('mutations', 'Var', (54, 63))	('obesity', 'Disease', (13, 20))	('stimulating', 'PosReg', (70, 81))	('growth of neoplastic cells', 'CPA', (86, 112))	('lead to', 'Reg', (27, 34))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
90041	33491650	If the former explanation were valid, there might be a mutational signature associated with obesity, but no such signature has been previously identified.	('mutational', 'Var', (55, 65))	('obesity', 'Disease', 'MESH:D009765', (92, 99))	('obesity', 'Disease', (92, 99))	('associated', 'Reg', (76, 86))	('obesity', 'Phenotype', 'HP:0001513', (92, 99))
90046	33491650	The finding of a negative difference in the rate of T[C>G]T mutations in obese patients with uterine cancer (Figure 6) suggests an explanation for the observation that often the total number of somatic mutations found in cancers of obese patients is not significantly different from that of non-obese patients, when controlling for age.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('obese', 'Disease', (232, 237))	('patients', 'Species', '9606', (301, 309))	('obese', 'Disease', (295, 300))	('non-obese', 'Disease', (291, 300))	('obese', 'Disease', 'MESH:D009765', (232, 237))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('obese', 'Disease', (73, 78))	('obese', 'Disease', 'MESH:D009765', (295, 300))	('non-obese', 'Disease', 'MESH:D009765', (291, 300))	('obese', 'Disease', 'MESH:D009765', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('cancers', 'Disease', (221, 228))	('cancer', 'Disease', (221, 227))	('T[C>G]T mutations', 'Var', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('patients', 'Species', '9606', (238, 246))	('uterine cancer', 'Phenotype', 'HP:0010784', (93, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (79, 87))
90048	33491650	The proportion varied widely across tissues, for example it is 2% on average in endometrial cancers (UCEC) of patients with POLe mutations to 87% in pancreatic cancer (PAAD) patients who smoke.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (149, 166))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('mutations', 'Var', (129, 138))	('patients', 'Species', '9606', (174, 182))	('pancreatic cancer', 'Disease', 'MESH:D010190', (149, 166))	('endometrial cancers', 'Disease', 'MESH:D016889', (80, 99))	('endometrial cancer', 'Phenotype', 'HP:0012114', (80, 98))	('pancreatic cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('endometrial cancers', 'Disease', (80, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('patients', 'Species', '9606', (110, 118))
90056	33491650	For example, inherited mutations in the fundamental genes involved in DNA repair or recombination, such as BRCA2, might be expected to result in predispositions to cancers of all types, but they only increase cancer risk in a limited subset of tissues.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('result in predispositions', 'Reg', (135, 160))	('DNA repair', 'biological_process', 'GO:0006281', ('70', '80'))	('BRCA2', 'Gene', '675', (107, 112))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('mutations', 'Var', (23, 32))	('cancers', 'Disease', (164, 171))	('cancer', 'Disease', (209, 215))	('cancer', 'Disease', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('increase', 'Reg', (200, 208))	('BRCA2', 'Gene', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
90074	33491650	The discovery of SuperSigs for obesity in the four tissues analyzed - with two of them relatively robust in cross-validation - suggests that, at least in those tissues, part of the risk from obesity may be attributable to mutagenesis.	('mutagenesis', 'biological_process', 'GO:0006280', ('222', '233'))	('obesity', 'Disease', (191, 198))	('obesity', 'Phenotype', 'HP:0001513', (31, 38))	('obesity', 'Disease', 'MESH:D009765', (31, 38))	('obesity', 'Phenotype', 'HP:0001513', (191, 198))	('mutagenesis', 'Var', (222, 233))	('obesity', 'Disease', (31, 38))	('obesity', 'Disease', 'MESH:D009765', (191, 198))
90083	33491650	We removed samples with microsatellite instability (MSI) or with a mutation in POLE/POLE2/POLE3/POLE4 or POLD1/POLD2/POLD3/POLD4 genes - except for when the signature for the specific effects of those mutations was the objective of the analysis - because of the known large increase in the number of mutations they induce.	('POLD2', 'Gene', '5425', (111, 116))	('POLD4', 'Gene', '57804', (123, 128))	('POLE4', 'Gene', (96, 101))	('POLE4', 'Gene', '56655', (96, 101))	('mutation', 'Var', (67, 75))	('POLE2', 'Gene', (84, 89))	('POLD3', 'Gene', (117, 122))	('POLD2', 'Gene', (111, 116))	('POLD1', 'Gene', (105, 110))	('POLD1', 'Gene', '5424', (105, 110))	('POLD3', 'Gene', '10714', (117, 122))	('POLE3', 'Gene', (90, 95))	('POLE3', 'Gene', '54107', (90, 95))	('POLE2', 'Gene', '5427', (84, 89))	('POLD4', 'Gene', (123, 128))	('microsatellite instability', 'MPA', (24, 50))
90087	33491650	In addition to six single base substitutions: C>A, C>G, C>T, T>A, T>C, and T>G, named according to the pyrimidine of the mutated Watson-Crick base pair, there are 48 dinucleotides, in which the substitution is paired with a specific base as a prefix or as a suffix but not both (e.g.	('T>C', 'Var', (66, 69))	('C>T', 'Var', (56, 59))	('T>A', 'Var', (61, 64))	('dinucleotide', 'Chemical', 'MESH:D015226', (166, 178))	('C>G', 'Var', (51, 54))	('T>G', 'Var', (75, 78))	('C>A', 'Var', (46, 49))
90089	33491650	The simple substitution C>T spawns dinucleotide children, such as A[C>T], and trinucleotide grandchildren like A[C>T]G. Frequent, exposure-driven A[C>T] substitutions would increase the observed rates of both the C>T parent and the trinucleotide children, making it difficult to assign ownership to the correct generation.	('children', 'Species', '9606', (48, 56))	('dinucleotide', 'Chemical', 'MESH:D015226', (35, 47))	('children', 'Species', '9606', (97, 105))	('C>T', 'Var', (24, 27))	('children', 'Species', '9606', (246, 254))	('spawns', 'Chemical', '-', (28, 34))	('substitutions', 'Var', (153, 166))	('increase', 'PosReg', (173, 181))	('trinucleotide', 'Chemical', '-', (78, 91))	('A[C>T] substitutions', 'Var', (146, 166))	('trinucleotide', 'Chemical', '-', (232, 245))
90093	33491650	Moving down a generation, [C>T]A, as the child of the C>T substitution, and the grandchild of the total number of mutations (Total Mutations), would be tested twice to see if it significantly exceeded its expected number based on the total number of mutations as well as the number of C>T.	('child', 'Species', '9606', (41, 46))	('child', 'Species', '9606', (85, 90))	('substitution', 'Var', (58, 70))	('C>T substitution', 'Var', (54, 70))
90096	33491650	And, for each sample, its mutation count will be updated by removing the mutations of the second-phase candidate feature children.	('removing', 'NegReg', (60, 68))	('children', 'Species', '9606', (121, 129))	('mutations', 'Var', (73, 82))
90103	33491650	In step two, we randomly break down the obtained proportion of each of the six main mutation types into the 16 fundamental trinucleotide mutations (16 for C>A, 16 for C>T, and so on).	('break down', 'Phenotype', 'HP:0001061', (25, 35))	('C>A', 'Var', (155, 158))	('C>T', 'Var', (167, 170))	('trinucleotide', 'Chemical', '-', (123, 136))
90115	33491650	Pretend we had no annotation for the presence of defects in the gene POL-epsilon among patients with endometrial cancer in the UCEC-TCGA dataset and that we did not know the POL-epsilon signature.	('endometrial cancer', 'Disease', (101, 119))	('endometrial cancer', 'Phenotype', 'HP:0012114', (101, 119))	('POL-epsilon', 'Gene', (69, 80))	('endometrial cancer', 'Disease', 'MESH:D016889', (101, 119))	('patients', 'Species', '9606', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('defects', 'Var', (49, 56))
90121	33491650	A repository for the R package containing the SuperSigs algorithm can be found at https://github.com/TomasettiLab/superSigs (; copy archived at swh:1:rev:7d6aac85a1b3930cb93e0810039db4d65a242cca).	('TomasettiLab', 'Disease', 'None', (101, 113))	('rev:7d6aac85a1b3930cb93e0810039db4d65a242cca', 'Var', (150, 194))	('TomasettiLab', 'Disease', (101, 113))
90125	33491650	A repository for the R package containing the SuperSigs algorithm is found at https://github.com/TomasettiLab/superSigs (copy archived at https://archive.softwareheritage.org/swh:1:rev:7d6aac85a1b3930cb93e0810039db4d65a242cca/).	('TomasettiLab', 'Disease', (97, 109))	('rev:7d6aac85a1b3930cb93e0810039db4d65a242cca/', 'Var', (181, 226))	('TomasettiLab', 'Disease', 'None', (97, 109))
90144	33491650	Summary: In this manuscript, the authors describe a new approach to identify patterns of genetic alterations in tumors that reflect biological processes that affect DNA.	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))	('tumors', 'Disease', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('genetic alterations', 'Var', (89, 108))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
90154	33491650	For example, breast cancers are well characterized into different subtypes, especially with respect to underlying factors such as BRCA1/2 mutation status (germline) that associate with the different subtypes (e.g.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('breast cancers', 'Phenotype', 'HP:0003002', (13, 27))	('breast cancers', 'Disease', 'MESH:D001943', (13, 27))	('associate', 'Reg', (170, 179))	('breast cancers', 'Disease', (13, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('BRCA1/2', 'Gene', (130, 137))	('mutation', 'Var', (138, 146))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('BRCA1/2', 'Gene', '672;675', (130, 137))
90155	33491650	However, as a general method, SuperSigs provides a new and well-tested method for deriving mutational signatures from cancer genomic data that likely will have a significant impact on the field of cancer research and, ultimately in areas of cancer prevention as well as revealing new cancer etiologies.	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('impact', 'Reg', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mutational', 'Var', (91, 101))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
90175	33491650	Our current approach is indeed offering higher flexibility as the fundamental unit of analysis is not forced to be the trinucleotide, but it is found to be of length 1, 2 or 3 nucleotides depending on our statistically guided approach of feature engineering/selection (as depicted for example in Figure 4 of the main text, with signatures containing nucleotides, binucleotides and trinucleotides as features, which is different from Alexandrov's).	('trinucleotide', 'Chemical', '-', (119, 132))	('trinucleotides', 'Var', (381, 395))	('trinucleotide', 'Chemical', '-', (381, 394))	('binucleotides', 'Var', (363, 376))	('trinucleotides', 'Chemical', '-', (381, 395))
90195	27197067	Inhibition of PD-1/PD-L1 interactions in bladder cancer has shown an objective response rate (ORR) of 52% in patients with tumor-infiltrating immune cells showing PD-L1 expression.	('tumor', 'Disease', (123, 128))	('patients', 'Species', '9606', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('interactions', 'Interaction', (25, 37))	('PD-1', 'Gene', (14, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (41, 55))	('PD-1', 'Gene', '5133', (14, 18))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('bladder cancer', 'Disease', 'MESH:D001749', (41, 55))	('bladder cancer', 'Disease', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
90202	27197067	Stabilization of beta-catenin leads to ATF3-dependent transcriptional repression of CCL4, which ablates recruitment of Batf3-lineage dendritic cells into the tumor microenvironment.	('Batf3', 'Gene', '55509', (119, 124))	('tumor', 'Disease', (158, 163))	('recruitment', 'MPA', (104, 115))	('transcriptional repression', 'MPA', (54, 80))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('CCL4', 'Gene', (84, 88))	('Stabilization', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('Batf3', 'Gene', (119, 124))	('ablates', 'NegReg', (96, 103))	('CCL', 'molecular_function', 'GO:0044101', ('84', '87'))
90207	27197067	Exome somatic mutation data were downloaded from TCGA portal (11/16/2014) for 238 tumor-normal-sample pairs with variants from "BI Automated Mutation Calling".	('variants', 'Var', (113, 121))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
90255	27197067	Fourteen separate FGFR3 mutations were detected in 11 of the non-T cell-inflamed samples, with no mutations detected in the T-cell-inflamed samples.	('FGFR3', 'Gene', '2261', (18, 23))	('FGFR3', 'Gene', (18, 23))	('detected', 'Reg', (39, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('mutations', 'Var', (24, 33))	('non-T cell-inflamed', 'Disease', (61, 80))
90256	27197067	Nine unique mutations were identified (Table 1) and two were recurrent (G370C in 3 samples and Y373C in 4 samples).	('Y373C', 'Var', (95, 100))	('G370C', 'Var', (72, 77))	('G370C', 'Mutation', 'rs199740841', (72, 77))	('Y373C', 'Mutation', 'rs121913485', (95, 100))
90257	27197067	The two most common FGFR3 mutations, Y373C and G370C, have been reported previously in bladder cancer and lead to activation of the receptor through increased ligand-independent dimerization and phosphorylation.	('activation', 'PosReg', (114, 124))	('FGFR3', 'Gene', '2261', (20, 25))	('ligand-independent dimerization', 'MPA', (159, 190))	('G370C', 'Mutation', 'rs199740841', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('increased', 'PosReg', (149, 158))	('receptor', 'Protein', (132, 140))	('FGFR3', 'Gene', (20, 25))	('Y373C', 'Var', (37, 42))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('phosphorylation', 'biological_process', 'GO:0016310', ('195', '210'))	('phosphorylation', 'MPA', (195, 210))	('ligand', 'molecular_function', 'GO:0005488', ('159', '165'))	('bladder cancer', 'Disease', 'MESH:D001749', (87, 101))	('bladder cancer', 'Disease', (87, 101))	('Y373C', 'Mutation', 'rs121913485', (37, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('20', '24'))	('G370C', 'Var', (47, 52))
90258	27197067	Additionally, recurrent in-frame activating FGFR3-TACC3 fusions were found exclusively in non-T cell-inflamed tumors (3 samples).	('TACC3', 'Gene', (50, 55))	('fusions', 'Var', (56, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('FGFR3', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('activating', 'PosReg', (33, 43))	('FGFR3', 'Gene', '2261', (44, 49))	('TACC3', 'Gene', '10460', (50, 55))
90263	27197067	PPARGC1A mutations included A728D, C726Y, K663*, R657Q, R485W, and R408T.	('R408T', 'Mutation', 'p.R408T', (67, 72))	('PPARGC1A', 'Gene', '10891', (0, 8))	('K663*', 'Var', (42, 47))	('K663*', 'SUBSTITUTION', 'None', (42, 47))	('A728D', 'Var', (28, 33))	('A728D', 'Mutation', 'p.A728D', (28, 33))	('C726Y', 'Var', (35, 40))	('R408T', 'Var', (67, 72))	('C726Y', 'Mutation', 'p.C726Y', (35, 40))	('R485W', 'Mutation', 'p.R485W', (56, 61))	('R657Q', 'Var', (49, 54))	('PPARGC1A', 'Gene', (0, 8))	('R657Q', 'Mutation', 'rs1462773399', (49, 54))	('R485W', 'Var', (56, 61))
90264	27197067	PPARGC1B mutations included P607L, V703I, E787K, and S994L.	('S994L', 'Var', (53, 58))	('E787K', 'Var', (42, 47))	('S994L', 'Mutation', 'p.S994L', (53, 58))	('V703I', 'Var', (35, 40))	('P607L', 'Var', (28, 33))	('V703I', 'Mutation', 'rs115650813', (35, 40))	('P607L', 'Mutation', 'p.P607L', (28, 33))	('PPARGC1B', 'Gene', '133522', (0, 8))	('PPARGC1B', 'Gene', (0, 8))	('E787K', 'Mutation', 'p.E787K', (42, 47))
90265	27197067	These mutations were evaluated by a prediction algorithm, Sorting Tolerant From Intolerant (SIFT), and seventy-percent were predicted to affect protein function.	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('protein function', 'MPA', (144, 160))	('SIFT', 'Disease', (92, 96))	('affect', 'Reg', (137, 143))	('mutations', 'Var', (6, 15))	('SIFT', 'Disease', 'None', (92, 96))
90270	27197067	PPAR-gamma pathway activation and FGFR3 mutations are associated with the "luminal" intrinsic bladder subtype, and we found both were also linked with the non-T cell-inflamed phenotype.	('FGFR3', 'Gene', '2261', (34, 39))	('PPAR-gamma', 'Gene', (0, 10))	('linked', 'Reg', (139, 145))	('PPAR-gamma', 'Gene', '5468', (0, 10))	('activation', 'PosReg', (19, 29))	('FGFR3', 'Gene', (34, 39))	('mutations', 'Var', (40, 49))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('associated', 'Reg', (54, 64))
90285	24874835	In this study, we found that gene-specific mutation and copy number alteration frequencies were similar between young and old SCCOT patients in two independent cohorts.	('SCC', 'Gene', '6317', (126, 129))	('copy number alteration', 'Var', (56, 78))	('SCCOT', 'Phenotype', 'HP:0030413', (126, 131))	('patients', 'Species', '9606', (132, 140))	('SCC', 'Gene', (126, 129))
90286	24874835	TCGA data also demonstrate that the genomic effects of smoking are tumor-site specific, and we find that smoking has only a minor impact on the types of mutations observed in SCCOT.	('SCC', 'Gene', (175, 178))	('SCCOT', 'Phenotype', 'HP:0030413', (175, 180))	('mutations', 'Var', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('SCC', 'Gene', '6317', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
90306	24874835	A median of 29 and 83 mutations were identified in the YT and OT tumors, respectively.	('YT', 'Chemical', '-', (55, 57))	('OT tumors', 'Disease', 'MESH:D009369', (62, 71))	('OT tumors', 'Disease', (62, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
90307	24874835	This finding was validated in The Cancer Genome Atlas (TCGA) cohort, in which the median number of mutations increased from 63 in YT to 112 in OT.	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('YT', 'Chemical', '-', (130, 132))	('Cancer Genome Atlas', 'Disease', (34, 53))	('mutations', 'Var', (99, 108))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (34, 53))	('increased', 'PosReg', (109, 118))
90311	24874835	The TP53 mutation frequency was also elevated in the TCGA YT patients (Table 1, Fig 1).	('mutation', 'Var', (9, 17))	('TCGA', 'Disease', (53, 57))	('TP53', 'Gene', (4, 8))	('elevated', 'PosReg', (37, 45))	('patients', 'Species', '9606', (61, 69))	('YT', 'Chemical', '-', (58, 60))	('TP53', 'Gene', '7157', (4, 8))
90314	24874835	The trend of increased TP53 mutations in YT is provocative since the YT lack exposure to cigarette smoke, which has been associated with TP53 mutations.	('YT', 'Chemical', '-', (41, 43))	('YT', 'Chemical', '-', (69, 71))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('TP53', 'Gene', (137, 141))
90318	24874835	These differences were not statistically significant, although the YT had a smaller mean segment length for copy number gains (p=0.00817) (Table 2) in the MDA cohort.	('YT', 'Chemical', '-', (67, 69))	('gains', 'PosReg', (120, 125))	('men', 'Species', '9606', (92, 95))	('smaller', 'NegReg', (76, 83))	('copy number', 'Var', (108, 119))
90324	24874835	Since smoking is known to leave its mark on the genome by causing certain types of mutations, we compared mutation types in the YT and OT patients.	('YT', 'Chemical', '-', (128, 130))	('mutations', 'Var', (83, 92))	('causing', 'Reg', (58, 65))	('patients', 'Species', '9606', (138, 146))
90328	24874835	HPV+ tumors show an increase in C>T mutations (p<0.0001) and decreases in C>A, A>T (both p<0.0001) and A>G (p=0.0074) mutations when compared with HPV- HNSC tumors.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('HPV+ tumors', 'Disease', (0, 11))	('HPV+ tumors', 'Disease', 'MESH:D030361', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('HPV- HNSC tumors', 'Disease', (147, 163))	('A>G', 'Var', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('decreases', 'NegReg', (61, 70))	('HPV- HNSC tumors', 'Disease', 'MESH:D030361', (147, 163))
90329	24874835	Laryngeal tumors show a decrease in C>T mutations (p<0.0001) and increases in C>A and A>T mutations (both p<0.0001) when compared with non-laryngeal tumors (Fig 2A).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('non-laryngeal tumors', 'Disease', 'MESH:D007827', (135, 155))	('increases', 'PosReg', (65, 74))	('Laryngeal tumors', 'Phenotype', 'HP:0012118', (0, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('decrease', 'NegReg', (24, 32))	('A>T mutations', 'Var', (86, 99))	('non-laryngeal tumors', 'Disease', (135, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('Laryngeal tumors', 'Disease', 'MESH:D007822', (0, 16))	('Laryngeal tumors', 'Disease', (0, 16))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (139, 155))
90335	24874835	In LUAD tumors C>A mutations increased 23.7 percentage points in smokers when compared to non-smokers, and C>T mutation decreased 18.7 percentage points (Fig 2B, C).	('decreased', 'NegReg', (120, 129))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('LUAD tumors C', 'Disease', 'MESH:D019698', (3, 16))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('LUAD tumors C', 'Disease', (3, 16))	('C>T mutation', 'Var', (107, 119))
90337	24874835	BLCA show a much higher frequency of C>T and C>G mutations and a lower frequency of C>A when compared with LUAD (Fig 2B).	('LUAD', 'Phenotype', 'HP:0030078', (107, 111))	('BLCA', 'Chemical', '-', (0, 4))	('C>G mutations', 'Var', (45, 58))	('C>T', 'Var', (37, 40))
90353	24874835	FAT1 is inactivated in a large proportion of oral cavity tumors, either by mutation or copy number deletion.	('mutation', 'Var', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('FAT1', 'Gene', '2195', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('oral cavity tumors', 'Phenotype', 'HP:0100649', (45, 63))	('tumors', 'Disease', (57, 63))	('copy number deletion', 'Var', (87, 107))	('FAT1', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
90355	24874835	The lower frequency of FAT1 mutations in YT could suggest that its inactivation is not necessary for tumor formation or that it is somehow related to smoking status.	('YT', 'Chemical', '-', (41, 43))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('FAT1', 'Gene', '2195', (23, 27))	('FAT1', 'Gene', (23, 27))	('formation', 'biological_process', 'GO:0009058', ('107', '116'))	('mutations', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
90356	24874835	Since TP53 mutations are more frequent in YT patients this result is not likely to be an artifact.	('mutations', 'Var', (11, 20))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('frequent', 'Reg', (30, 38))	('patients', 'Species', '9606', (45, 53))	('YT', 'Chemical', '-', (42, 44))
90357	24874835	TP53 mutations are likely to be impactful on the tumor progression in YT, but a causative factor leading to increased TP53 mutations in YT is still unknown.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('YT', 'Chemical', '-', (70, 72))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('mutations', 'Var', (5, 14))	('YT', 'Chemical', '-', (136, 138))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('impactful', 'Reg', (32, 41))
90371	24874835	Since C>T is the most common mutation in many tumor types other factors must also contribute to their frequency.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('C>T', 'Var', (6, 9))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
90372	24874835	Analysis of the TCGA HNSC data for an alcohol mutation signature resulted in a less dramatic version of the smoking signature with decreases in C>T and increases in C>A in heavy drinkers (data not shown).	('C>A', 'MPA', (165, 168))	('increases', 'PosReg', (152, 161))	('decreases', 'NegReg', (131, 140))	('C>T', 'MPA', (144, 147))	('alcohol', 'Chemical', 'MESH:D000438', (38, 45))	('mutation', 'Var', (46, 54))
90401	24874835	Similarly a factor that disrupts the oral microbiome in YT could promote carcinogenesis in a way similar to the mechanism in OT.	('carcinogenesis', 'Disease', (73, 87))	('carcinogenesis', 'Disease', 'MESH:D063646', (73, 87))	('promote', 'PosReg', (65, 72))	('factor', 'Var', (12, 18))	('YT', 'Chemical', '-', (56, 58))
90403	24874835	SCCOT squamous cell carcinoma of the oral tongue HNSCC head and neck squamous cell carcinoma YT young tongue OT old tongue MDA MD Anderson Cancer Center HNSC TCGA HNSCC project CNA copy number alterations LUAD lung adenocarcinoma BLCA bladder urothelial carcinoma Genomic alterations do not explain the increasing incidence of oral tongue cancer in young patients, and smoking does not dramatically alter the genome of tongue cancer at any age.	('SCC', 'Gene', (165, 168))	('HNSCC', 'Phenotype', 'HP:0012288', (163, 168))	('SCC', 'Gene', '6317', (51, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('neck squamous cell carcinoma', 'Disease', (64, 92))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (127, 145))	('lung adenocarcinoma', 'Disease', (210, 229))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (64, 92))	('BLCA', 'Chemical', '-', (230, 234))	('patients', 'Species', '9606', (355, 363))	('carcinoma of the oral', 'Phenotype', 'HP:0100649', (20, 41))	('YT', 'Chemical', '-', (93, 95))	('SCC', 'Gene', (51, 54))	('tongue OT old tongue', 'Phenotype', 'HP:0010808', (102, 122))	('squamous cell carcinoma of the oral tongue', 'Disease', 'MESH:D002294', (6, 48))	('alterations', 'Var', (193, 204))	('tongue cancer', 'Disease', (419, 432))	('LUAD', 'Phenotype', 'HP:0030078', (205, 209))	('oral tongue cancer', 'Disease', (327, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('squamous cell carcinoma of the oral tongue', 'Phenotype', 'HP:0030413', (6, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (6, 29))	('tongue cancer', 'Disease', 'MESH:D014062', (332, 345))	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (210, 229))	('tongue cancer', 'Disease', 'MESH:D014062', (419, 432))	('SCC', 'Gene', '6317', (0, 3))	('bladder urothelial carcinoma', 'Disease', (235, 263))	('squamous cell carcinoma of the oral tongue', 'Disease', (6, 48))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (210, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (55, 92))	('MD Anderson Cancer', 'Disease', (127, 145))	('SCC', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (426, 432))	('oral tongue cancer', 'Disease', 'MESH:D014062', (327, 345))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (235, 263))	('SCC', 'Gene', '6317', (165, 168))	('SCCOT', 'Phenotype', 'HP:0030413', (0, 5))	('neck', 'cellular_component', 'GO:0044326', ('64', '68'))	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))
90410	24624923	Although all three markers could not predict progression in univariate analyses, high HDAC-1 expression was associated with a trend toward poorer prognosis.	('HDAC-1', 'Gene', '3065', (86, 92))	('HDAC-1', 'Gene', (86, 92))	('expression', 'MPA', (93, 103))	('high', 'Var', (81, 85))
90411	24624923	Patients with high-grade tumours and high expression levels of HDAC-1 were more likely to progress compared to all other patients (p < 0.05).	('HDAC-1', 'Gene', (63, 69))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('high expression levels', 'Var', (37, 59))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('Patients', 'Species', '9606', (0, 8))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('progress', 'CPA', (90, 98))	('HDAC-1', 'Gene', '3065', (63, 69))	('tumours', 'Disease', (25, 32))	('patients', 'Species', '9606', (121, 129))
90413	24624923	High grade tumours in combination with high expression of HDAC-1 showed a worse prognosis than the other tumours.	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('HDAC-1', 'Gene', (58, 64))	('high expression', 'Var', (39, 54))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumours', 'Disease', (105, 112))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('HDAC-1', 'Gene', '3065', (58, 64))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('tumours', 'Disease', (11, 18))
90451	24624923	Strong staining of HDAC-1 and HDAC-2 was associated with higher grading (both WHO 1973 and 2004), additionally tumours with high expression levels of HDAC-2 presented more often with adjacent carcinoma in situ compared to tumours with weak HDAC-2 staining.	('HDAC-2', 'Gene', (150, 156))	('carcinoma in situ', 'Disease', (192, 209))	('grading', 'MPA', (64, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('HDAC-2', 'Gene', '3066', (30, 36))	('HDAC-2', 'Gene', (30, 36))	('HDAC-1', 'Gene', '3065', (19, 25))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (192, 209))	('high expression levels', 'Var', (124, 146))	('tumours', 'Disease', (111, 118))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('carcinoma in situ', 'Disease', 'MESH:D002278', (192, 209))	('tumours', 'Disease', (222, 229))	('HDAC-1', 'Gene', (19, 25))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('tumour', 'Phenotype', 'HP:0002664', (222, 228))	('tumours', 'Disease', 'MESH:D009369', (111, 118))	('tumours', 'Phenotype', 'HP:0002664', (222, 229))	('HDAC-2', 'Gene', (240, 246))	('HDAC-2', 'Gene', '3066', (240, 246))	('tumours', 'Disease', 'MESH:D009369', (222, 229))	('HDAC-2', 'Gene', '3066', (150, 156))
90459	24624923	The combination of high-grade tumours and high expression levels of HDAC-1 was a predictor of PFS (hazard ratio [HR], 1.640; 95% confidence interval [95% CI], 1.021-2.636; p = 0.044).	('HDAC-1', 'Gene', (68, 74))	('PFS', 'Disease', (94, 97))	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('tumours', 'Disease', (30, 37))	('HDAC-1', 'Gene', '3065', (68, 74))	('high', 'Var', (42, 46))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
90464	24624923	In addition, patients with high expression levels of Ki-67 have a significantly shorter PFS (Figure 6).	('PFS', 'MPA', (88, 91))	('patients', 'Species', '9606', (13, 21))	('high expression levels', 'Var', (27, 49))	('shorter', 'NegReg', (80, 87))	('Ki-67', 'Gene', (53, 58))
90468	24624923	Additionally, high expression levels of HDAC-1 showed a tendency towards a shorter PFS.	('HDAC-1', 'Gene', '3065', (40, 46))	('high', 'Var', (14, 18))	('PFS', 'MPA', (83, 86))	('expression levels', 'MPA', (19, 36))	('shorter', 'NegReg', (75, 82))	('HDAC-1', 'Gene', (40, 46))
90486	24624923	Other study groups previously reported the association of class I HDACs with more aggressive tumours and even shortened patient survival in prostate and gastric cancer.	('association', 'Interaction', (43, 54))	('gastric cancer', 'Disease', (153, 167))	('HDAC', 'Gene', (66, 70))	('patient survival', 'CPA', (120, 136))	('aggressive tumours', 'Disease', 'MESH:D001523', (82, 100))	('aggressive tumours', 'Disease', (82, 100))	('HDAC', 'Gene', '9734', (66, 70))	('more', 'PosReg', (77, 81))	('gastric cancer', 'Disease', 'MESH:D013274', (153, 167))	('patient', 'Species', '9606', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('gastric cancer', 'Phenotype', 'HP:0012126', (153, 167))	('prostate', 'Disease', (140, 148))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('shortened', 'NegReg', (110, 119))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('class', 'Var', (58, 63))
90509	31558111	The functions of urothelial carcinoma of the bladder cells with transfected pcDNA3.1-LGALS4 were identified through MTT assay, plate clone formation assay, flow cytometry, and cell migration experiments.	('urothelial carcinoma of the bladder cells', 'Phenotype', 'HP:0006740', (17, 58))	('cell migration', 'biological_process', 'GO:0016477', ('176', '190'))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (17, 52))	('LGALS4', 'Gene', '3960', (85, 91))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (17, 52))	('urothelial carcinoma of the bladder', 'Disease', (17, 52))	('LGALS4', 'Gene', (85, 91))	('formation', 'biological_process', 'GO:0009058', ('139', '148'))	('men', 'Species', '9606', (197, 200))	('urothelial carcinoma of the bladder cell', 'Phenotype', 'HP:0006740', (17, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('MTT', 'Chemical', 'MESH:C022616', (116, 119))	('transfected', 'Var', (64, 75))
90561	31558111	The membrane was then incubated with rabbit anti-GAL4 (1:1000, ab229347) at 4 C overnight, washed by Tris-buffered saline with Tween 20 (TBS, 1 mL/L Tween-20), then incubated with horseradish peroxidase-labeled anti-rabbit IgG (1:2500, ab205718) at room temperature for 2 hours.	('TBS', 'Disease', 'MESH:C536974', (137, 140))	('horseradish', 'Species', '3704', (180, 191))	('Tween', 'Chemical', 'MESH:D011136', (127, 132))	('rabbit', 'Species', '9986', (37, 43))	('1:1000', 'Var', (55, 61))	('Tween-20', 'Chemical', 'MESH:D011136', (149, 157))	('Tween', 'Chemical', 'MESH:D011136', (149, 154))	('IgG (1', 'cellular_component', 'GO:0071735', ('223', '229'))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))	('TBS', 'Disease', (137, 140))	('rabbit', 'Species', '9986', (216, 222))
90584	31558111	Meanwhile, colony formation of UCB cells with LGALS4 overexpression was also distinctively restrained (Figure 4G-H).	('formation', 'biological_process', 'GO:0009058', ('18', '27'))	('LGALS4', 'Gene', (46, 52))	('UCB', 'Phenotype', 'HP:0006740', (31, 34))	('restrained', 'NegReg', (91, 101))	('overexpression', 'Var', (53, 67))	('LGALS4', 'Gene', '3960', (46, 52))	('colony formation of UCB cells', 'CPA', (11, 40))
90595	31558111	To investigate the etiological agent of bladder cancer, Deng et al analyzed the differential coexpression networks and found that the DEGs in bladder cancer mainly involved in cellular physiological process and cellular metabolism.	('DEG', 'Chemical', 'MESH:C042934', (134, 137))	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('bladder cancer', 'Disease', 'MESH:D001749', (142, 156))	('bladder cancer', 'Disease', (142, 156))	('cellular physiological process', 'biological_process', 'GO:0009987', ('176', '206'))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cellular metabolism', 'biological_process', 'GO:0044237', ('211', '230'))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('involved', 'Reg', (164, 172))	('DEGs', 'Var', (134, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (142, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
90602	31558111	Therefore, we analyzed the survival situations of UCB patients and found that those with high expression of LGALS4 exhibited higher probabilities of OS and DFS in both 5-year and overall situations.	('LGALS4', 'Gene', (108, 114))	('UCB', 'Phenotype', 'HP:0006740', (50, 53))	('high expression', 'Var', (89, 104))	('patients', 'Species', '9606', (54, 62))	('higher', 'PosReg', (125, 131))	('LGALS4', 'Gene', '3960', (108, 114))	('DFS', 'Disease', (156, 159))
90613	31558111	In colorectal cancer, LGALS4 was significantly downregulated and the abrogation of LGALS4 expression could promote the tumorigenesis of colorectal cancer.	('LGALS4', 'Gene', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('LGALS4', 'Gene', '3960', (83, 89))	('expression', 'MPA', (90, 100))	('colorectal cancer', 'Disease', (3, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (136, 153))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('abrogation', 'Var', (69, 79))	('colorectal cancer', 'Disease', (136, 153))	('downregulated', 'NegReg', (47, 60))	('LGALS4', 'Gene', (22, 28))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('promote', 'PosReg', (107, 114))	('LGALS4', 'Gene', '3960', (22, 28))	('colorectal cancer', 'Phenotype', 'HP:0003003', (136, 153))	('tumor', 'Disease', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
90616	31558111	High LGALS4 expression could reduce the migration and metastasis of pancreatic cancer.	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('LGALS4', 'Gene', (5, 11))	('metastasis of pancreatic cancer', 'Disease', (54, 85))	('reduce', 'NegReg', (29, 35))	('metastasis of pancreatic cancer', 'Disease', 'MESH:D010190', (54, 85))	('LGALS4', 'Gene', '3960', (5, 11))
90648	30464501	Several clinical trials using inhibitors blocking these pathways for the treatment of malignancies, such as melanoma, non-small-cell lung cancer (NSCLC), head and neck cancer, renal cell cancer, urothelial cancer, and lymphoma, have shown great promise in prolonging survival.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('renal cell cancer', 'Disease', 'MESH:C538614', (176, 193))	('lymphoma', 'Phenotype', 'HP:0002665', (218, 226))	('renal cell cancer', 'Disease', (176, 193))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('renal cell cancer', 'Phenotype', 'HP:0005584', (176, 193))	('urothelial cancer', 'Disease', 'MESH:D014523', (195, 212))	('head and neck cancer', 'Phenotype', 'HP:0012288', (154, 174))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (118, 144))	('neck', 'cellular_component', 'GO:0044326', ('163', '167'))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('neck cancer', 'Disease', 'MESH:D006258', (163, 174))	('neck cancer', 'Disease', (163, 174))	('urothelial cancer', 'Disease', (195, 212))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))	('lymphoma', 'Disease', (218, 226))	('lymphoma', 'Disease', 'MESH:D008223', (218, 226))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('NSCLC', 'Disease', (146, 151))	('inhibitors', 'Var', (30, 40))	('malignancies', 'Disease', 'MESH:D009369', (86, 98))	('prolonging', 'PosReg', (256, 266))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (118, 144))	('non-small-cell lung cancer', 'Disease', (118, 144))	('malignancies', 'Disease', (86, 98))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (122, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
90658	30464501	A previous meta-analysis determined that there was an OS advantage of PD-1/PD-L1 inhibitors for patients with EGFR wild-type NSCLC, and no OS advantage was observed for those with EGFR-mutant tumors.	('EGFR', 'Gene', '1956', (110, 114))	('inhibitors', 'Var', (81, 91))	('tumors', 'Disease', (192, 198))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('advantage', 'PosReg', (57, 66))	('NSCLC', 'Disease', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (110, 114))	('OS', 'Chemical', '-', (54, 56))	('patients', 'Species', '9606', (96, 104))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('OS', 'Chemical', '-', (139, 141))	('EGFR', 'Gene', (180, 184))	('PD-1', 'Gene', (70, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('180', '184'))	('PD-1', 'Gene', '5133', (70, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
90665	30464501	We also extracted hazard ratio (HR) and 95% CI for OS (defined as the time from randomization to death) of the intention-to-treat population and the following predefined subgroups: age (<65 vs >=65 years), sex (female vs male), performance status (PS=0 vs >=1), line of therapy (one line vs >=2 line), smoking status (never smokers vs ever smokers), tumor histology (squamous NSCLC vs non-squamous NSCLC vs melanoma), treatment type (PD-1 inhibitor vs PD-L1 inhibitor), and PD-L1 expression (<1% vs >=1% vs <5% vs >=5% vs <10% vs >=10% vs >=50%).	('OS', 'Chemical', '-', (51, 53))	('<1%', 'Var', (492, 495))	('squamous NSCLC', 'Disease', 'MESH:D002294', (389, 403))	('melanoma', 'Phenotype', 'HP:0002861', (407, 415))	('melanoma', 'Disease', (407, 415))	('squamous NSCLC', 'Disease', (367, 381))	('tumor', 'Disease', 'MESH:D009369', (350, 355))	('squamous NSCLC', 'Disease', 'MESH:D002294', (367, 381))	('melanoma', 'Disease', 'MESH:D008545', (407, 415))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('PD-L1', 'Gene', (474, 479))	('PD-1', 'Gene', (434, 438))	('squamous NSCLC', 'Disease', (389, 403))	('tumor', 'Disease', (350, 355))	('PD-1', 'Gene', '5133', (434, 438))
90686	30464501	The result of test for subgroup differences showed that the PD-L1>=1% population had better OS than the PD-L1<1% population (P=0.02, I2=80.7%; Figure 3A).	('better', 'PosReg', (85, 91))	('PD-L1>=1%', 'Var', (60, 69))	('OS', 'Chemical', '-', (92, 94))
90697	30464501	The result of test for subgroup differences showed that the PD-L1>=10% population had better OS than the PD-L1<10% population (P=0.0004, I2=92.1%; Figure 3C).	('better', 'PosReg', (86, 92))	('OS', 'Chemical', '-', (93, 95))	('PD-L1>=10%', 'Var', (60, 70))
90732	30464501	In addition, PD-L1-positive patients could achieve OS benefits from PD-1/PD-L1 inhibitors regardless of PD-L1 expression level, and a possible dose- effect relationship between the expression of PD-L1 and the OS benefit from PD-1/PD-L1 inhibitors was observed.	('PD-1', 'Gene', '5133', (68, 72))	('PD-L1-positive', 'Gene', (13, 27))	('OS', 'Chemical', '-', (51, 53))	('benefits', 'PosReg', (54, 62))	('inhibitors', 'Var', (79, 89))	('PD-L1', 'Gene', (195, 200))	('OS', 'Chemical', '-', (209, 211))	('PD-1', 'Gene', (225, 229))	('patients', 'Species', '9606', (28, 36))	('PD-1', 'Gene', '5133', (225, 229))	('PD-1', 'Gene', (68, 72))
90751	30464501	The tumor genomic landscape is obviously distinct in never smokers compared to smokers, with an average mutation frequency more than tenfold higher in smokers than in never smokers.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('mutation', 'Var', (104, 112))	('higher', 'PosReg', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
90755	30464501	The frequency of C>A transversions was defined as a smoking genetic signature that is highly correlated with both elevated mutation burden and clinical benefit with PD-1/PD-L1 inhibitors.	('PD-1', 'Gene', (165, 169))	('PD-1', 'Gene', '5133', (165, 169))	('C>A transversions', 'Var', (17, 34))
90767	30464501	Our meta-analysis found that PD-1/PD-L1 inhibitors significantly improved the OS for patients with melanoma, NSCLC, urothelial carcinoma, head and neck carcinoma, and renal cell carcinoma.	('PD-1', 'Gene', '5133', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (116, 136))	('improved', 'PosReg', (65, 73))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (167, 187))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('inhibitors', 'Var', (40, 50))	('neck', 'cellular_component', 'GO:0044326', ('147', '151'))	('patients', 'Species', '9606', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('NSCLC', 'Disease', (109, 114))	('neck carcinoma', 'Disease', (147, 161))	('neck carcinoma', 'Disease', 'MESH:D006258', (147, 161))	('urothelial carcinoma', 'Disease', (116, 136))	('renal cell carcinoma', 'Disease', (167, 187))	('OS', 'Chemical', '-', (78, 80))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (167, 187))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (138, 161))	('PD-1', 'Gene', (29, 33))
90785	30214299	Defects in the structures or function of PC could result in a variety of disorders which are called ciliopathies.	('result in', 'Reg', (50, 59))	('PC', 'Chemical', '-', (41, 43))	('ciliopathies', 'Disease', (100, 112))	('Defects', 'Var', (0, 7))
90786	30214299	Recent studies have shown that dysfunction of PC has strong correlations with cancers by influencing the cell cycle or modulating cilia-related signaling transduction.	('influencing', 'Reg', (89, 100))	('modulating', 'Reg', (119, 129))	('transduction', 'biological_process', 'GO:0009293', ('154', '166'))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('dysfunction', 'Var', (31, 42))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cilia-related signaling transduction', 'MPA', (130, 166))	('PC', 'Chemical', '-', (46, 48))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cell cycle', 'biological_process', 'GO:0007049', ('105', '115'))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cell cycle', 'CPA', (105, 115))
90789	30214299	A wide range of complementary studies suggested that changes in ciliary genes or proteins were associated with cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('changes', 'Var', (53, 60))	('cancers', 'Disease', (111, 118))	('ciliary genes', 'Gene', (64, 77))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('proteins', 'Protein', (81, 89))	('associated', 'Reg', (95, 105))
90799	30214299	Two sample data (GSM1268193 and GSM1268195) with poor heterogeneity were deleted to eliminate the interference of the tumor universality characteristics after normalization and principal component analysis plots.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('GSM1268193', 'Var', (17, 27))	('tumor', 'Disease', (118, 123))	('GSM1268195', 'Var', (32, 42))
90812	30214299	Two BLCA sample data (GSM1268193 and GSM1268195) with poor heterogeneity were deleted to eliminate the interference of the tumor universality characteristics.	('GSM1268193', 'Var', (22, 32))	('tumor', 'Disease', (123, 128))	('GSM1268195', 'Var', (37, 47))	('BLCA', 'Phenotype', 'HP:0009725', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
90816	30214299	The top pathway enriched by KEGG was Hedgehog signaling pathway, which was responsible for many aspects of vertebrate embryonic development and was disrupted in a spectrum of human tumors.	('human', 'Species', '9606', (175, 180))	('KEGG', 'Var', (28, 32))	('tumors', 'Disease', (181, 187))	('Hedgehog signaling pathway', 'Pathway', (37, 63))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('Hedgehog signaling pathway', 'biological_process', 'GO:0007224', ('37', '63'))
90833	30214299	Exome sequencing from Harlander et al revealed that mouse and human clear cell renal cell carcinomas exhibited recurrent mutations in genes associated with the primary cilium, which strongly suggested the correlation between abnormality of ciliary genes and tumor.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('abnormality of ciliary', 'Phenotype', 'HP:0012776', (225, 247))	('primary cilium', 'cellular_component', 'GO:0005929', ('160', '174'))	('mutations', 'Var', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (68, 100))	('tumor', 'Disease', (258, 263))	('human', 'Species', '9606', (62, 67))	('clear cell renal cell carcinomas', 'Disease', (68, 100))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (68, 100))	('mouse', 'Species', '10090', (52, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('primary cilium', 'cellular_component', 'GO:0097731', ('160', '174'))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (79, 100))	('tumor', 'Disease', 'MESH:D009369', (258, 263))
90835	30214299	GO analysis indicated that DEGs exhibited properties and function of PC, which was implicated in previous study that FD1 depletion at centriolar satellites promoted cilia formation in breast cancer MCF7 cells that normally did not form cilia.	('PC', 'Chemical', '-', (69, 71))	('formation', 'biological_process', 'GO:0009058', ('171', '180'))	('FD1', 'Gene', (117, 120))	('MCF7', 'CellLine', 'CVCL:0031', (198, 202))	('cilia formation', 'CPA', (165, 180))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Disease', (184, 197))	('depletion', 'Var', (121, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('promoted', 'PosReg', (156, 164))
90836	30214299	The results were also reported in Xu et al's study that inhibition of the Hedgehog signaling pathway suppresses cell proliferation by regulating the Gli2/miR-124/AURKA axis in human glioma cells.	('cell proliferation', 'CPA', (112, 130))	('Hedgehog signaling pathway', 'Pathway', (74, 100))	('AURKA', 'Gene', '6790', (162, 167))	('suppresses', 'NegReg', (101, 111))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('regulating', 'Reg', (134, 144))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('Hedgehog signaling pathway', 'biological_process', 'GO:0007224', ('74', '100'))	('AURKA', 'Gene', (162, 167))	('human', 'Species', '9606', (176, 181))	('Gli2', 'Gene', '2736', (149, 153))	('inhibition', 'Var', (56, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('112', '130'))	('glioma', 'Disease', (182, 188))	('Gli2', 'Gene', (149, 153))
90837	30214299	These results were consistent with the fact that dysfunction of PC participated in cancer pathogenesis and progression by regulating cell cycle and cell proliferation.	('participated', 'Reg', (67, 79))	('cell proliferation', 'biological_process', 'GO:0008283', ('148', '166'))	('cell cycle', 'biological_process', 'GO:0007049', ('133', '143'))	('regulating', 'Reg', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('dysfunction', 'Var', (49, 60))	('PC', 'Chemical', '-', (64, 66))	('cell proliferation', 'CPA', (148, 166))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('pathogenesis', 'biological_process', 'GO:0009405', ('90', '102'))	('cell cycle', 'CPA', (133, 143))	('cancer', 'Disease', (83, 89))
90851	30214299	These researches indicate that ciliary protein abnormality facilitates carcinogenesis by regulating the dysfunction of PC.	('abnormality', 'Var', (47, 58))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('ciliary protein', 'Protein', (31, 46))	('carcinogenesis', 'CPA', (71, 85))	('dysfunction', 'MPA', (104, 115))	('facilitates', 'PosReg', (59, 70))	('PC', 'Chemical', '-', (119, 121))
90859	30214299	The confirmation of DEGs and the prediction of their candidate TFs helped to understand the potential mechanisms of PC in BLCA and provided novel diagnosis and therapeutic targets for BLCA.	('BLCA', 'Phenotype', 'HP:0009725', (122, 126))	('BLCA', 'Disease', (122, 126))	('PC', 'Chemical', '-', (116, 118))	('BLCA', 'Phenotype', 'HP:0009725', (184, 188))	('DEGs', 'Var', (20, 24))
90863	29617661	Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns and amplified MDM2 showing a mutually exclusive pattern with BRAF mutations.	('FBXW7', 'Gene', (88, 93))	('MDM2', 'Gene', '4193', (143, 147))	('MDM2', 'Gene', (143, 147))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('mutated', 'Var', (80, 87))	('cancer', 'Disease', (99, 105))	('FBXW7', 'Gene', '55294', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
90866	29617661	These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERT amplification, and APC/PTEN deletion.	('upregulation', 'PosReg', (51, 63))	('APC', 'Disease', (162, 165))	('DNA repair', 'biological_process', 'GO:0006281', ('82', '92'))	('MYC/TERT', 'Gene', (134, 142))	('PTEN', 'Gene', (166, 170))	('APC', 'cellular_component', 'GO:0005680', ('162', '165'))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('PTEN', 'Gene', '5728', (166, 170))	('cell-cycle', 'biological_process', 'GO:0007049', ('67', '77'))	('TERT', 'CellLine', 'CVCL:C452', (138, 142))	('TP53', 'Protein', (128, 132))	('cell-cycle', 'Pathway', (67, 77))	('APC', 'Disease', 'MESH:D011125', (162, 165))	('DNA repair pathways', 'Pathway', (82, 101))	('mutated', 'Var', (120, 127))
90874	29617661	First, both basic and translational studies have shown extensive evidence connecting the malfunction of the ubiquitin pathway with tumor initiation and progression.	('tumor initiation', 'Disease', 'MESH:D009369', (131, 147))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('ubiquitin pathway', 'Pathway', (108, 125))	('ubiquitin', 'molecular_function', 'GO:0031386', ('108', '117'))	('tumor initiation', 'Disease', (131, 147))	('malfunction', 'Var', (89, 100))
90882	29617661	Overall, across 8,811 non-hypermutated cancer samples, the mutation frequency was low for both UBQ and DUB genes, with an average mutation number per patient of 4.5 and 0.5, respectively.	('patient', 'Species', '9606', (150, 157))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('UBQ', 'Gene', (95, 98))	('low', 'NegReg', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutation', 'Var', (59, 67))
90884	29617661	First, we used a ratiometric method for nominating cancer driver genes based on the enrichment of hotspot or loss-of-function (LoF) mutations among all mutations observed in a gene (Figure 1A).	('loss-of-function', 'NegReg', (109, 125))	('mutations', 'Var', (152, 161))	('mutations', 'Var', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
90885	29617661	In this pan-cancer analysis, we identified 19 UBQ/DUB genes with >30% hotspot mutations and 29 genes with >30% LoF mutations (FBXW7 was identified by both criteria).	('UBQ/DUB genes', 'Gene', (46, 59))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('LoF', 'NegReg', (111, 114))	('FBXW7', 'Gene', '55294', (126, 131))	('cancer', 'Disease', (12, 18))	('FBXW7', 'Gene', (126, 131))	('mutations', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
90890	29617661	Among 15 driver genes identified by both methods, SPOP, KEAP1, and CHD4 were enriched with hotspot mutations, while BAP1, CDH1, CUL3, EP300, KDM5C, MAP3K1, NSD1, RNF43, TLE1, VHL, and LZTR1 contained excessive LoF mutations.	('BAP1', 'Gene', (116, 120))	('VHL', 'Disease', (175, 178))	('VHL', 'Disease', 'MESH:D006623', (175, 178))	('TLE1', 'Gene', (169, 173))	('LZTR1', 'Gene', (184, 189))	('CHD4', 'Gene', (67, 71))	('NSD1', 'Gene', (156, 160))	('MAP3K', 'molecular_function', 'GO:0004709', ('148', '153'))	('mutations', 'Var', (99, 108))	('MAP3K1', 'Gene', (148, 154))	('SPOP', 'Gene', (50, 54))	('KDM5C', 'Gene', (141, 146))	('RNF43', 'Gene', (162, 167))	('CDH1', 'Gene', (122, 126))	('LoF', 'NegReg', (210, 213))
90891	29617661	Of particular interest, FBXW7 showed enrichment of both hotspot and LoF mutations (Figure 1A).	('mutations', 'Var', (72, 81))	('FBXW7', 'Gene', (24, 29))	('LoF', 'NegReg', (68, 71))	('FBXW7', 'Gene', '55294', (24, 29))
90894	29617661	To gain more insight into its mutational profile, we examined the mutation distributions of FBXW7 in different cancer types and found three distinct patterns (Figure 2A): (1) hotspot mutations were enriched in two uterine cancer types, uterine corpus endometrial carcinoma (UCEC), and uterine carcinosarcoma (UCS); (2) LoF mutations were enriched in skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), rectum adenocarcinoma (READ), and esophageal carcinoma (ESCA); and (3) the proportions of both hotspot and LoF mutations were high in head and neck squamous cell carcinoma (HNSC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), bladder urothelial carcinoma (BLCA), and colon adenocarcinoma (COAD).	('lung adenocarcinoma', 'Disease', (450, 469))	('skin cutaneous melanoma', 'Disease', (350, 373))	('mutations', 'Var', (589, 598))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('COAD', 'Disease', (794, 798))	('endometrial carcinoma', 'Disease', (251, 272))	('stomach adenocarcinoma', 'Disease', (382, 404))	('carcinosarcoma', 'Disease', 'MESH:D002296', (293, 307))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (413, 441))	('READ', 'Disease', (501, 505))	('bladder urothelial carcinoma', 'Disease', (731, 759))	('carcinoma', 'Phenotype', 'HP:0030731', (460, 469))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (450, 469))	('melanoma', 'Phenotype', 'HP:0002861', (365, 373))	('rectum adenocarcinoma', 'Disease', (478, 499))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (355, 373))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (626, 649))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (731, 759))	('uterine cancer', 'Phenotype', 'HP:0010784', (214, 228))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (418, 441))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (413, 441))	('lung squamous cell carcinoma', 'Disease', (413, 441))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (772, 792))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (512, 532))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (450, 469))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (285, 307))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (395, 404))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (251, 272))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (382, 404))	('FBXW7', 'Gene', (92, 97))	('mutations', 'Var', (323, 332))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (251, 272))	('READ', 'Disease', 'None', (501, 505))	('esophageal carcinoma', 'Disease', (512, 532))	('cancer type', 'Disease', (111, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (490, 499))	('COAD', 'Disease', 'MESH:D029424', (794, 798))	('cervical squamous cell carcinoma', 'Disease', (658, 690))	('endocervical adenocarcinoma', 'Disease', (695, 722))	('cancer type', 'Disease', (222, 233))	('cancer type', 'Disease', 'MESH:D009369', (111, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (432, 441))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (478, 499))	('cancer type', 'Disease', 'MESH:D009369', (222, 233))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (512, 532))	('colon adenocarcinoma', 'Disease', (772, 792))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (350, 373))	('neck', 'cellular_component', 'GO:0044326', ('621', '625'))	('FBXW7', 'Gene', '55294', (92, 97))	('carcinosarcoma', 'Disease', (293, 307))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (667, 690))
90895	29617661	Consistent with previous studies, FBXW7 contains three notable missense mutation hotspots (R465, R479, and R505) in the second, third, and fourth WD40 domains that recognize the consensus phospho-motif located in its substrate (Figure 2B).	('FBXW7', 'Gene', '55294', (34, 39))	('R479', 'Var', (97, 101))	('FBXW7', 'Gene', (34, 39))	('R505', 'Var', (107, 111))	('R465', 'Var', (91, 95))
90896	29617661	Figure 2C shows the FBXW7 mutation distributions for the hotspot mutation-enriched cancer types and the LoF mutation-enriched cancer types.	('LoF', 'NegReg', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('FBXW7', 'Gene', '55294', (20, 25))	('mutation', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer type', 'Disease', (126, 137))	('FBXW7', 'Gene', (20, 25))	('cancer type', 'Disease', (83, 94))	('cancer type', 'Disease', 'MESH:D009369', (126, 137))	('cancer type', 'Disease', 'MESH:D009369', (83, 94))
90897	29617661	The three missense hotspots accounted for 49% (38 of 77) of the FBXW7 mutations observed in UCEC and UCS.	('FBXW7', 'Gene', '55294', (64, 69))	('mutations', 'Var', (70, 79))	('UCEC', 'Disease', (92, 96))	('FBXW7', 'Gene', (64, 69))	('observed in', 'Reg', (80, 91))	('UCS', 'Disease', (101, 104))
90898	29617661	The contrasting mutation patterns of FBXW7 mutations may reflect tissue-specific roles of FBXW7 substrates or different FBXW7-mediated oncogenic mechanisms in different tumor contexts.	('FBXW7', 'Gene', (37, 42))	('FBXW7', 'Gene', '55294', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('FBXW7', 'Gene', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('FBXW7', 'Gene', '55294', (90, 95))	('mutations', 'Var', (43, 52))	('tumor', 'Disease', (169, 174))	('FBXW7', 'Gene', '55294', (37, 42))	('FBXW7', 'Gene', (90, 95))
90899	29617661	We further assessed the occurrence of FBXW7 mutations with those in clinically actionable cancer genes and revealed that mutations in FBXW7 and PIK3CA showed mutual exclusivity in three cancer types: CESC, BLCA, and LUSC (Figure 2D), suggesting that mutations in these two genes confer similar functional consequences.	('cancer type', 'Disease', 'MESH:D009369', (186, 197))	('mutations', 'Var', (121, 130))	('CESC', 'Disease', (200, 204))	('PIK3CA', 'Gene', (144, 150))	('FBXW7', 'Gene', (134, 139))	('FBXW7', 'Gene', '55294', (38, 43))	('LUSC', 'Disease', (216, 220))	('PIK3CA', 'Gene', '5290', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('FBXW7', 'Gene', (38, 43))	('FBXW7', 'Gene', '55294', (134, 139))	('cancer type', 'Disease', (186, 197))	('BLCA', 'Disease', (206, 210))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
90900	29617661	Patients with FBXW7 or phosphatidylinositol 3-kinase (PI3K) pathway mutations (mutations found in PIK3CA, PTEN, and STK11) had higher PI3K pathway expression activity than patients without such mutations (Figure 2E).	('STK11', 'Gene', (116, 121))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (23, 52))	('PIK3CA', 'Gene', '5290', (98, 104))	('PI3K', 'molecular_function', 'GO:0016303', ('54', '58'))	('higher', 'PosReg', (127, 133))	('PI3K pathway', 'Pathway', (134, 146))	('PI3K', 'molecular_function', 'GO:0016303', ('134', '138'))	('mutations', 'Var', (79, 88))	('phosphatidylinositol 3-kinase', 'Gene', (23, 52))	('STK11', 'Gene', '6794', (116, 121))	('Patients', 'Species', '9606', (0, 8))	('PTEN', 'Gene', (106, 110))	('FBXW7', 'Gene', (14, 19))	('patients', 'Species', '9606', (172, 180))	('activity', 'MPA', (158, 166))	('PIK3CA', 'Gene', (98, 104))	('PTEN', 'Gene', '5728', (106, 110))	('FBXW7', 'Gene', '55294', (14, 19))	('STK11', 'molecular_function', 'GO:0033868', ('116', '121'))	('mutations', 'Var', (68, 77))
90901	29617661	To infer somatic copy-number alteration (SCNA) drivers, we used GISTIC2 to identify significant focal deletion and amplification peaks in each of 33 cancer types.	('cancer type', 'Disease', 'MESH:D009369', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('deletion', 'Var', (102, 110))	('cancer type', 'Disease', (149, 160))	('amplification', 'MPA', (115, 128))
90902	29617661	UBQ and DUB genes showed similar overall SCNA profiles in terms of the amplification and deletion gene fractions across cancer types (Figures S3A and S3B).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer type', 'Disease', (120, 131))	('cancer type', 'Disease', 'MESH:D009369', (120, 131))	('deletion', 'Var', (89, 97))	('UBQ', 'Gene', (0, 3))
90904	29617661	Four cancer types (kidney renal clear cell carcinoma [KIRC], SKCM, cholangiocarcinoma [CHOL], and pancreatic adenocarcinoma [PAAD]) showed significant deletion peak enrichments, while no cancer types showed significant amplification peak enrichment (p < 0.01) (Figure 3A).	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (98, 123))	('pancreatic adenocarcinoma', 'Disease', (98, 123))	('cancer type', 'Disease', 'MESH:D009369', (187, 198))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('cancer type', 'Disease', 'MESH:D009369', (5, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('deletion', 'Var', (151, 159))	('kidney renal clear cell carcinoma', 'Disease', (19, 52))	('cholangiocarcinoma', 'Disease', (67, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (98, 123))	('SKCM', 'Disease', (61, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (19, 52))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('cancer type', 'Disease', (187, 198))	('cancer type', 'Disease', (5, 16))
90908	29617661	Among UBQ and DUB genes, we found a mutually exclusive pattern of MDM2 and SKP2 amplifications in LUAD (Figure S3E), suggesting convergence of their functions on the same downstream effectors.	('amplifications', 'Var', (80, 94))	('MDM2', 'Gene', '4193', (66, 70))	('MDM2', 'Gene', (66, 70))	('UBQ', 'Gene', (6, 9))	('SKP2', 'Gene', (75, 79))	('LUAD', 'Disease', (98, 102))
90910	29617661	For clinically actionable genes, we found that MDM2 amplifications were mutually exclusive to BRAF and ATM mutations in SKCM and BLCA, respectively (Figures 3C and S3F).	('MDM2', 'Gene', '4193', (47, 51))	('mutations', 'Var', (107, 116))	('SKCM', 'Gene', (120, 124))	('MDM2', 'Gene', (47, 51))
90911	29617661	BRAF kinase domain mutations, such as V600E, result in a constitutively activated form of the protein in around 50% of SKCM patients (45.1% in this study), which then leads to stimulated mitogen-activated protein kinase (MAPK) signaling and induces tumor cell proliferation.	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('V600E', 'Var', (38, 43))	('induces', 'PosReg', (241, 248))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('patients', 'Species', '9606', (124, 132))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('221', '236'))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('MAPK', 'molecular_function', 'GO:0004707', ('221', '225'))	('SKCM', 'Disease', (119, 123))	('tumor', 'Disease', (249, 254))	('mitogen-activated', 'MPA', (187, 204))	('V600E', 'Mutation', 'rs113488022', (38, 43))	('constitutively', 'MPA', (57, 71))	('stimulated', 'PosReg', (176, 186))	('cell proliferation', 'biological_process', 'GO:0008283', ('255', '273'))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
90913	29617661	We observed MDM2 amplification in 4.1% of the SKCM samples in this study, in which p53 protein levels were significantly lower than in samples with BRAF mutations alone or with neither BRAF mutations nor MDM2 amplifications.	('MDM2', 'Gene', '4193', (12, 16))	('MDM2', 'Gene', '4193', (204, 208))	('MDM2', 'Gene', (12, 16))	('MDM2', 'Gene', (204, 208))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('SKCM', 'Disease', (46, 50))	('lower', 'NegReg', (121, 126))	('amplification', 'Var', (17, 30))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
90915	29617661	Furthermore, the mutually exclusive pattern of MDM2 amplification and BRAF mutation suggests that a reduced p53 pathway or induced MAPK signaling can serve as an impetus for aberrant tumor cell proliferation (Figure 3E).	('MDM2', 'Gene', '4193', (47, 51))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('MDM2', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('reduced', 'NegReg', (100, 107))	('mutation', 'Var', (75, 83))	('cell proliferation', 'biological_process', 'GO:0008283', ('189', '207'))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('MAPK signaling', 'biological_process', 'GO:0000165', ('131', '145'))	('tumor', 'Disease', (183, 188))	('MAPK', 'molecular_function', 'GO:0004707', ('131', '135'))	('amplification', 'Var', (52, 65))	('MAPK signaling', 'MPA', (131, 145))	('BRAF', 'Gene', (70, 74))
90917	29617661	Studies have shown increased apoptosis and inhibition of melanoma growth by combining a BRAF inhibitor and p53 reactivation.	('apoptosis', 'CPA', (29, 38))	('combining', 'Interaction', (76, 85))	('reactivation', 'Var', (111, 123))	('inhibition', 'NegReg', (43, 53))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('BRAF inhibitor', 'Protein', (88, 102))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('increased', 'PosReg', (19, 28))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))
90923	29617661	First, in 6 of the 7 cancer types, upregulated genes showed a significantly higher proportion of copy-number amplifications than did neutral genes (chi-square test, q < 0.01) (Figure 4C, top), highlighting the significant role of somatic copy-number gain in increasing UBQ/DUB gene expression in tumor samples.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('cancer type', 'Disease', (21, 32))	('gene expression', 'biological_process', 'GO:0010467', ('277', '292'))	('tumor', 'Disease', (296, 301))	('expression', 'MPA', (282, 292))	('increasing', 'PosReg', (258, 268))	('copy-number', 'Var', (238, 249))	('upregulated', 'PosReg', (35, 46))	('UBQ/DUB', 'Gene', (269, 276))	('copy-number', 'Var', (97, 108))	('cancer type', 'Disease', 'MESH:D009369', (21, 32))	('gain', 'PosReg', (250, 254))	('tumor', 'Disease', 'MESH:D009369', (296, 301))
90943	29617661	Then we examined SCNA drivers by focusing on known oncogenes and tumor suppressors residing in amplification or deletion peaks (identified by GISTIC2) in each cancer type.	('tumor', 'Disease', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('deletion', 'Var', (112, 120))	('amplification', 'Var', (95, 108))	('cancer type', 'Disease', (159, 170))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cancer type', 'Disease', 'MESH:D009369', (159, 170))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
90944	29617661	We found that COCA2 was associated with the amplifications of MYC and TERT and the deletions of PTEN and APC in multiple cancer types (q < 0.001) (Figure 6D).	('PTEN', 'Gene', '5728', (96, 100))	('amplifications', 'Var', (44, 58))	('APC', 'Disease', (105, 108))	('associated', 'Reg', (24, 34))	('MYC', 'Protein', (62, 65))	('multiple cancer', 'Disease', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('COCA', 'Species', '289672', (14, 18))	('cancer type', 'Disease', (121, 132))	('deletions', 'Var', (83, 92))	('multiple cancer', 'Disease', 'MESH:D009369', (112, 127))	('APC', 'cellular_component', 'GO:0005680', ('105', '108'))	('TERT', 'CellLine', 'CVCL:C452', (70, 74))	('TERT', 'Gene', (70, 74))	('cancer type', 'Disease', 'MESH:D009369', (121, 132))	('COCA2', 'Disease', (14, 19))	('APC', 'Disease', 'MESH:D011125', (105, 108))	('PTEN', 'Gene', (96, 100))
90946	29617661	Deletion or low expression of the tumor suppressor PTEN has been shown to drive cell-cycle progression, proliferation, and cell survival.	('cell survival', 'CPA', (123, 136))	('drive', 'PosReg', (74, 79))	('tumor', 'Disease', (34, 39))	('PTEN', 'Gene', '5728', (51, 55))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('proliferation', 'CPA', (104, 117))	('Deletion', 'Var', (0, 8))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('cell-cycle', 'biological_process', 'GO:0007049', ('80', '90'))	('expression', 'MPA', (16, 26))	('cell-cycle progression', 'CPA', (80, 102))	('PTEN', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('low', 'NegReg', (12, 15))
90949	29617661	Therefore, we put forward a model in which mutated TP53 and amplified MYC are closely associated with primarily an upregulation of key ubiquitin-related enzymes, leading to an uncontrolled cell cycle, elevated DNA damage response, and ultimately poor survival for COCA2 patients (Figure 7).	('elevated', 'PosReg', (201, 209))	('cell cycle', 'biological_process', 'GO:0007049', ('189', '199'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('135', '144'))	('DNA', 'cellular_component', 'GO:0005574', ('210', '213'))	('upregulation', 'PosReg', (115, 127))	('TP53', 'Gene', (51, 55))	('patients', 'Species', '9606', (270, 278))	('DNA damage response', 'MPA', (210, 229))	('uncontrolled', 'MPA', (176, 188))	('COCA', 'Species', '289672', (264, 268))	('MYC', 'Protein', (70, 73))	('DNA damage response', 'biological_process', 'GO:0006974', ('210', '229'))	('amplified', 'Gene', (60, 69))	('mutated', 'Var', (43, 50))
90951	29617661	For example, substrates of FBXW7 are oncoproteins, such as cyclin E, c-Myc, and Notch, while substrates of SKP2 are tumor suppressors, such as p21, p27, and p57.	('SKP2', 'Gene', (107, 111))	('cyclin E', 'Protein', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('FBXW7', 'Gene', '55294', (27, 32))	('p27', 'Var', (148, 151))	('Notch', 'MPA', (80, 85))	('FBXW7', 'Gene', (27, 32))	('p21', 'Var', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('p57', 'Var', (157, 160))	('cyclin', 'molecular_function', 'GO:0016538', ('59', '65'))	('tumor', 'Disease', (116, 121))	('c-Myc', 'MPA', (69, 74))
90954	29617661	For example, BAP1 and VHL are frequently mutated in mesothelioma (MESO) and KIRC, respectively, whereas FBXW7 is enriched with hotspot mutations in UCEC and UCS but enriched with LoF mutations in ESCA, LUAD, LUSC, READ, SKCM, and STAD.	('BAP1', 'Gene', (13, 17))	('ESCA', 'Disease', (196, 200))	('mutations', 'Var', (183, 192))	('READ', 'Disease', (214, 218))	('mutated', 'Reg', (41, 48))	('mutations', 'Var', (135, 144))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))	('mesothelioma', 'Disease', (52, 64))	('FBXW7', 'Gene', '55294', (104, 109))	('VHL', 'Disease', (22, 25))	('LoF', 'NegReg', (179, 182))	('VHL', 'Disease', 'MESH:D006623', (22, 25))	('READ', 'Disease', 'None', (214, 218))	('FBXW7', 'Gene', (104, 109))
90955	29617661	Second, we show that compared to matched normal tissues, genes in the ubiquitin pathway tend to be overexpressed in a range of cancer types, and collectively, 71% of the upregulated genes are contributed by one of three mechanisms: somatic copy-number gain, reduced methylation-mediated gene silencing, and reduced miRNA-mediated gene regulation in tumors.	('cancer type', 'Disease', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', (349, 355))	('tumors', 'Disease', 'MESH:D009369', (349, 355))	('tumors', 'Phenotype', 'HP:0002664', (349, 355))	('reduced', 'NegReg', (258, 265))	('copy-number', 'Var', (240, 251))	('miRNA-mediated', 'MPA', (315, 329))	('regulation', 'biological_process', 'GO:0065007', ('335', '345'))	('reduced', 'NegReg', (307, 314))	('methylation-mediated gene', 'MPA', (266, 291))	('cancer type', 'Disease', 'MESH:D009369', (127, 138))	('gene silencing', 'biological_process', 'GO:0016458', ('287', '301'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('70', '79'))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('methylation', 'biological_process', 'GO:0032259', ('266', '277'))	('gain', 'PosReg', (252, 256))	('upregulated', 'PosReg', (170, 181))
90957	29617661	These tumor samples are associated with differential UBQ/DUB expression underlying the perturbation of many fundamental signaling pathways, notably cell-cycle progression and DNA damage repair, likely resulting from key molecular drivers such as TP53, MYC, TERT, PTEN, and APC.	('TERT', 'Disease', (257, 261))	('TERT', 'CellLine', 'CVCL:C452', (257, 261))	('TP53', 'Var', (246, 250))	('APC', 'cellular_component', 'GO:0005680', ('273', '276'))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('cell-cycle progression', 'CPA', (148, 170))	('MYC', 'Disease', (252, 255))	('DNA damage repair', 'MPA', (175, 192))	('perturbation', 'NegReg', (87, 99))	('DNA', 'cellular_component', 'GO:0005574', ('175', '178'))	('fundamental signaling pathways', 'Pathway', (108, 138))	('PTEN', 'Gene', (263, 267))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('UBQ/DUB', 'Gene', (53, 60))	('tumor', 'Disease', (6, 11))	('cell-cycle', 'biological_process', 'GO:0007049', ('148', '158'))	('APC', 'Disease', 'MESH:D011125', (273, 276))	('APC', 'Disease', (273, 276))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('PTEN', 'Gene', '5728', (263, 267))
90960	29617661	This could be largely due to the lack of systemic characterization of significant driver mutations, SCNA patterns, and dysregulated expression profiles in the ubiquitin pathway across cancer types through an integrated genomic analysis that would provide clinically relevant drug candidates to the pharmaceutical industry.	('cancer type', 'Disease', 'MESH:D009369', (184, 195))	('ubiquitin pathway', 'Pathway', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('ubiquitin', 'molecular_function', 'GO:0031386', ('159', '168'))	('mutations', 'Var', (89, 98))	('dysregulated', 'Var', (119, 131))	('expression', 'MPA', (132, 142))	('cancer type', 'Disease', (184, 195))
90962	29617661	Moreover, the deubiquitinase USP7 has been shown to deubiquitinate several key cancer proteins, and P5091, a highly specific inhibitor of USP7, induced apoptosis in multiple myeloma cells.	('multiple myeloma', 'Disease', (165, 181))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('14', '28'))	('multiple myeloma', 'Disease', 'MESH:D009101', (165, 181))	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('induced', 'PosReg', (144, 151))	('USP7', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (79, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('multiple myeloma', 'Phenotype', 'HP:0006775', (165, 181))	('USP', 'molecular_function', 'GO:0051748', ('138', '141'))	('USP', 'molecular_function', 'GO:0051748', ('29', '32'))	('apoptosis', 'CPA', (152, 161))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('deubiquitinate', 'MPA', (52, 66))	('P5091', 'Var', (100, 105))
90970	29617661	Across the pan-cancer cohort, hotspot mutations were defined as missense or in-frame mutations at the same protein amino acid in > 2 patient samples.	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('patient', 'Species', '9606', (133, 140))	('in-frame', 'Reg', (76, 84))	('missense', 'Var', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
90971	29617661	Mutual exclusivity for FBXW7 mutations and mutations in clinically actionable genes (annotated as in OncoKB, http://oncokb.org) was performed with the R package "cometExactTest."	('mutations', 'Var', (29, 38))	('FBXW7', 'Gene', (23, 28))	('FBXW7', 'Gene', '55294', (23, 28))
90972	29617661	To study the effects of FBXW7 mutations, PI3K pathway expression was calculated from protein levels of the PI3K/Akt pathway components as measured by RPPA with the following formula where E means expression:   We obtained SCNA data of 9,125 patient samples from Genomic Data Commons and applied GISTIC2.	('PI3K', 'molecular_function', 'GO:0016303', ('41', '45'))	('FBXW7', 'Gene', '55294', (24, 29))	('PI3K', 'molecular_function', 'GO:0016303', ('107', '111'))	('patient', 'Species', '9606', (241, 248))	('FBXW7', 'Gene', (24, 29))	('mutations', 'Var', (30, 39))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
91068	33190043	Integration of whole-exome and anchored PCR-based next generation sequencing significantly increases detection of actionable alterations in precision oncology NGS-based clinical studies have reported detection of clinically relevant alterations in ~30% of patients.	('oncology', 'Phenotype', 'HP:0002664', (150, 158))	('alterations', 'Var', (125, 136))	('patients', 'Species', '9606', (256, 264))	('detection', 'MPA', (101, 110))	('increases', 'PosReg', (91, 100))
91070	33190043	With this integrated approach, we demonstrate a significant increase in detection of targetable genomic alterations in cancer patients.	('genomic alterations', 'Var', (96, 115))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('increase', 'PosReg', (60, 68))	('detection', 'MPA', (72, 81))	('cancer', 'Disease', (119, 125))	('patients', 'Species', '9606', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
91071	33190043	Frequency of clinically relevant mutations in solid tumors by targeted and whole-exome sequencing is ~30%.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('solid tumors', 'Disease', 'MESH:D009369', (46, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (33, 42))	('solid tumors', 'Disease', (46, 58))
91075	33190043	AMP-based NGS detected 48 fusions in 31 samples (55.4%); 31.25% (15/48) were classified as targetable based on published literature.	('fusions', 'Var', (26, 33))	('AMP', 'Chemical', '-', (0, 3))	('detected', 'Reg', (14, 22))
91085	33190043	Gene fusions have been recognized as oncogenic drivers, in addition to their role as diagnostic markers in certain tumor types.	('Gene fusions', 'Var', (0, 12))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))
91089	33190043	Our clinical whole-exome sequencing (WES) assay (EXaCT-1), a test approved by the Department of Health at New York State (NYS-DOH ID#43032), detects somatic mutations, indels and copy number alterations (CNA), as well as tumor mutational burden (TMB) and microsatellite instability (MSI) but not gene fusions.	('microsatellite instability', 'MPA', (255, 281))	('copy number alterations', 'Var', (179, 202))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('mutations', 'Var', (157, 166))	('indels', 'Var', (168, 174))	('TMB', 'Chemical', '-', (246, 249))	('detects', 'Reg', (141, 148))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
91091	33190043	With the goal of increasing the detection rate of actionable alterations, we expanded the genomic characterization of tumors from patients enrolled in our WES-based precision medicine study, using the anchored multiplex PCR (AMP)-based NGS assay (Archer(R) FusionPlex(R) Solid Tumor Kit) for fusion detection.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Kit', 'Gene', (283, 286))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('alterations', 'Var', (61, 72))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('Tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumors', 'Disease', (118, 124))	('Kit', 'Gene', '3815', (283, 286))	('AMP', 'Chemical', '-', (225, 228))
91106	33190043	It is an Anchored Multiplex PCR (AMP )-based technique, which detects fusions associated with the genes in the panel, without prior knowledge of fusion partners or breakpoints.	('detects', 'Reg', (62, 69))	('fusions', 'Var', (70, 77))	('AMP', 'Chemical', '-', (33, 36))
91120	33190043	We defined copy number gain when genomic alteration leads to increased copies in tumor relative to the control sample (log2 copy number ratio between 0.5 and 1.0), copy number loss when genomic alteration leads to decreased copies in tumor relative to the control sample (log2 copy number ratio between -0.5 and -1.0), amplification as high copy number gain (log2 copy number ratio >= 1.0) and deletion when extensive copy number loss, which corresponds to homozygous deletions (log2 copy number ratio <= -1.0).	('tumor', 'Disease', (234, 239))	('loss', 'NegReg', (176, 180))	('alteration', 'Var', (194, 204))	('copy number', 'Var', (418, 429))	('copy', 'Var', (164, 168))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('alteration', 'Var', (41, 51))	('copies', 'MPA', (224, 230))	('increased', 'PosReg', (61, 70))	('deletion', 'Var', (394, 402))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('decreased', 'NegReg', (214, 223))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', (81, 86))	('copies', 'MPA', (71, 77))
91124	33190043	Fusion assays (performed at the Molecular Cytogenetics core facility at Memorial Sloan Kettering Cancer Center): FGFR3 fusions were designed using either RP5-1091E12 or RP11-339F13 (red).	('FGFR3', 'Gene', '2261', (113, 118))	('Cancer', 'Disease', 'MESH:D009369', (97, 103))	('FGFR', 'molecular_function', 'GO:0005007', ('113', '117'))	('RP5-1091E12', 'Var', (154, 165))	('FGFR3', 'Gene', (113, 118))	('RP11', 'Gene', (169, 173))	('core', 'cellular_component', 'GO:0019013', ('55', '59'))	('RP11', 'Gene', '26121', (169, 173))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Cancer', 'Disease', (97, 103))
91125	33190043	FGFR3 fusion partners included GNAS (green RP5-907D15 or RP4-543J19) and ANKRD30BL (green RP11-1L22).	('ANKRD30BL', 'Gene', (73, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('RP11', 'Gene', (90, 94))	('GNAS', 'Gene', '2778', (31, 35))	('FGFR3', 'Gene', (0, 5))	('RP11', 'Gene', '26121', (90, 94))	('ANKRD30BL', 'Gene', '554226', (73, 82))	('RP4-543J19', 'Var', (57, 67))	('GNAS', 'Gene', (31, 35))	('green RP5-907D15', 'Var', (37, 53))	('FGFR3', 'Gene', '2261', (0, 5))
91132	33190043	By WES, 29/56 tumor samples (51.8%) had alterations, which were classified as targetable (Tier1, see Methods).	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('alterations', 'Var', (40, 51))
91133	33190043	Of these, 13/29 patient samples harbored somatic mutations in either BRCA2, PIK3CA, NOTCH2, FGFR4, IDH1, ERBB4 and MET genes, or copy number alterations in EGFR or ERBB2 genes.	('ERBB4', 'Gene', (105, 110))	('EGFR', 'molecular_function', 'GO:0005006', ('156', '160'))	('PIK3CA', 'Gene', (76, 82))	('NOTCH2', 'Gene', (84, 90))	('IDH1', 'Gene', '3417', (99, 103))	('patient', 'Species', '9606', (16, 23))	('copy number alterations', 'Var', (129, 152))	('mutations', 'Var', (49, 58))	('EGFR', 'Gene', '1956', (156, 160))	('MET', 'Gene', '79811', (115, 118))	('BRCA2', 'Gene', (69, 74))	('FGFR4', 'Gene', '2264', (92, 97))	('ERBB2', 'Gene', (164, 169))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('PIK3CA', 'Gene', '5290', (76, 82))	('NOTCH2', 'Gene', '4853', (84, 90))	('BRCA2', 'Gene', '675', (69, 74))	('ERBB2', 'Gene', '2064', (164, 169))	('EGFR', 'Gene', (156, 160))	('FGFR4', 'Gene', (92, 97))	('IDH1', 'Gene', (99, 103))	('ERBB4', 'Gene', '2066', (105, 110))	('MET', 'Gene', (115, 118))
91134	33190043	Twelve had copy number loss in CDKN2A and CDKN2B genes, 7 tumors had high tumor mutational burden and 1 out of 7 samples with TMB-high showed MSI (Supplementary Table 1).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('TMB', 'Chemical', '-', (126, 129))	('copy number loss', 'Var', (11, 27))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Disease', (74, 79))	('CDKN2B', 'Gene', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('CDKN2B', 'Gene', '1030', (42, 48))	('CDKN2A', 'Gene', (31, 37))	('CDKN2A', 'Gene', '1029', (31, 37))
91136	33190043	The remaining 2 patients had fusions in NTRK3, NTRK1 and EGFR genes.	('fusions', 'Var', (29, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('patients', 'Species', '9606', (16, 24))	('NTRK1', 'Gene', '4914', (47, 52))	('NTRK3', 'Gene', '4916', (40, 45))	('EGFR', 'Gene', '1956', (57, 61))	('NTRK1', 'Gene', (47, 52))	('EGFR', 'Gene', (57, 61))	('NTRK3', 'Gene', (40, 45))
91138	33190043	Interestingly, 4 of these 29 patient samples (13.8%) whose tumors had actionable alterations by WES, also demonstrated targetable fusions on AMP-based NGS, e.g.	('patient', 'Species', '9606', (29, 36))	('fusions', 'Var', (130, 137))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('AMP', 'Chemical', '-', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
91139	33190043	WCM1230, a case of colon cancer with TPM3-NTRK1 fusion, MSI-High (MSISensor Score 9.14), and TMB-High (Supplementary Table 1).	('NTRK1', 'Gene', (42, 47))	('colon cancer', 'Phenotype', 'HP:0003003', (19, 31))	('colon cancer', 'Disease', 'MESH:D015179', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('TPM3', 'Gene', (37, 41))	('fusion', 'Var', (48, 54))	('TMB-High', 'Disease', 'MESH:D052456', (93, 101))	('colon cancer', 'Disease', (19, 31))	('NTRK1', 'Gene', '4914', (42, 47))	('TPM3', 'Gene', '7170', (37, 41))	('TMB-High', 'Disease', (93, 101))
91140	33190043	Among tumors with no targets detected by WES, 7/29 (24.1%) harbored targetable fusions, detected by AMP-based NGS.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('AMP', 'Chemical', '-', (100, 103))	('fusions', 'Var', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
91142	33190043	A TPM3-NTRK1 fusion detected in a case of colon cancer showed the highest read count of 2254 and skewed the aforementioned results.	('NTRK1', 'Gene', (7, 12))	('read count', 'MPA', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('fusion', 'Var', (13, 19))	('TPM3', 'Gene', (2, 6))	('colon cancer', 'Phenotype', 'HP:0003003', (42, 54))	('colon cancer', 'Disease', 'MESH:D015179', (42, 54))	('NTRK1', 'Gene', '4914', (7, 12))	('TPM3', 'Gene', '7170', (2, 6))	('colon cancer', 'Disease', (42, 54))
91146	33190043	Expression of ETV1 gene in 2 ETV1 fusion-positive tumors was significantly higher when compared with 17 ETV1-fusion negative tumors (Fig.	('ETV1', 'Gene', '2115', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Expression', 'MPA', (0, 10))	('higher', 'PosReg', (75, 81))	('ETV1', 'Gene', (14, 18))	('ETV1', 'Gene', (104, 108))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('fusion-positive', 'Var', (34, 49))	('ETV1', 'Gene', '2115', (14, 18))	('ETV1', 'Gene', '2115', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('ETV1', 'Gene', (29, 33))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
91147	33190043	Of the detected three ETV4-ETV1 fusions, two of them in WCM331 and WCM1004 were out-of-frame, and one in WCM1401 was in-frame (Supplementary Table 7).	('fusions', 'Var', (32, 39))	('ETV1', 'Gene', (27, 31))	('ETV4', 'Gene', '2118', (22, 26))	('ETV1', 'Gene', '2115', (27, 31))	('ETV4', 'Gene', (22, 26))
91149	33190043	Of the 15 cases with targetable fusions, 4 cases harbored FGFR fusions (3 bladder and 1 prostate) and 2 had RET fusions (thyroid carcinoma, and carcinoma of unknown primary).	('carcinoma', 'Disease', 'MESH:D009369', (129, 138))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (121, 138))	('carcinoma', 'Disease', (144, 153))	('thyroid carcinoma', 'Disease', (121, 138))	('RET', 'Gene', '5979', (108, 111))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('FGFR', 'Gene', (58, 62))	('carcinoma', 'Disease', 'MESH:D009369', (144, 153))	('RET', 'Gene', (108, 111))	('carcinoma', 'Disease', (129, 138))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (121, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('fusions', 'Var', (63, 70))
91153	33190043	A break-apart FISH assay for FGFR3 was also used to confirm gene rearrangement in two samples with FGFR3 fusions detected by AMP-based NGS: WCM882 (prostate adenocarcinoma) that harbors a novel FGFR3-MSI2 fusion partner (Fig.	('AMP', 'Chemical', '-', (125, 128))	('FGFR3', 'Gene', (29, 34))	('FGFR3', 'Gene', '2261', (99, 104))	('MSI2', 'Gene', (200, 204))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('FGFR3', 'Gene', (99, 104))	('prostate adenocarcinoma', 'Disease', (148, 171))	('fusions', 'Var', (105, 112))	('FGFR', 'molecular_function', 'GO:0005007', ('29', '33'))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (148, 171))	('FGFR3', 'Gene', '2261', (194, 199))	('MSI2', 'Gene', '124540', (200, 204))	('FGFR3', 'Gene', '2261', (29, 34))	('FGFR', 'molecular_function', 'GO:0005007', ('194', '198'))	('FGFR3', 'Gene', (194, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
91156	33190043	Although we tried to validate a novel GNAS-EGFR fusion detected in WCM1364 (neuroendocrine tumor of pancreas), a fused signal of probes recognizing GNAS and EGFR was not observed (Supplementary Figure 3B).	('EGFR', 'Gene', '1956', (157, 161))	('EGFR', 'Gene', (43, 47))	('neuroendocrine tumor', 'Disease', (76, 96))	('GNAS', 'Gene', (38, 42))	('tumor of pancreas', 'Phenotype', 'HP:0002894', (91, 108))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (76, 96))	('GNAS', 'Gene', (148, 152))	('WCM1364', 'Gene', (67, 74))	('GNAS', 'Gene', '2778', (38, 42))	('GNAS', 'Gene', '2778', (148, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('fuse', 'Gene', '2522', (113, 117))	('fuse', 'Gene', (113, 117))	('fusion', 'Var', (48, 54))	('EGFR', 'molecular_function', 'GO:0005006', ('157', '161'))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (76, 96))	('EGFR', 'Gene', '1956', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('EGFR', 'Gene', (157, 161))
91158	33190043	Overall, RNA-seq had lower supporting reads (mean 12, median 4) when compared to AMP-based NGS (mean 97, median 10).	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('AMP', 'Chemical', '-', (81, 84))	('lower', 'NegReg', (21, 26))	('RNA-seq', 'Var', (9, 16))	('supporting reads', 'MPA', (27, 43))
91194	33190043	Archer demonstrated that ETV4 fused with ETV1 as the 5' partner in all ETV4-ETV1 fusions detected in our cohort, while ETV4 is reportedly the 3' partner when that fuses with TMPRSS2 in prostate cancers that harbor such fusion event.	('prostate cancers', 'Disease', 'MESH:D011471', (185, 201))	('TMPRSS2', 'Gene', (174, 181))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('ETV1', 'Gene', (76, 80))	('ETV4', 'Gene', '2118', (25, 29))	('ETV4', 'Gene', (71, 75))	('ETV1', 'Gene', (41, 45))	('ETV4', 'Gene', '2118', (119, 123))	('prostate cancers', 'Phenotype', 'HP:0012125', (185, 201))	('fuse', 'Gene', '2522', (30, 34))	('fuse', 'Gene', (30, 34))	('prostate cancers', 'Disease', (185, 201))	('ETV1', 'Gene', '2115', (76, 80))	('fuse', 'Gene', '2522', (163, 167))	('fuse', 'Gene', (163, 167))	('ETV4', 'Gene', '2118', (71, 75))	('fusions', 'Var', (81, 88))	('ETV1', 'Gene', '2115', (41, 45))	('ETV4', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('TMPRSS2', 'Gene', '7113', (174, 181))	('ETV4', 'Gene', (119, 123))
91195	33190043	While TMPRSS2 fusions with ETS transcriptional factors, including ERG, ETV1 and ETV4 gene, are well-studied oncogenic alterations defining a distinct subsets of prostate cancers, biological consequences of ETV4-ETV1 fusion events are unclear.	('ETV1', 'Gene', (71, 75))	('ERG', 'Gene', '2078', (66, 69))	('ETV1', 'Gene', '2115', (71, 75))	('prostate cancers', 'Disease', 'MESH:D011471', (161, 177))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('ETV4', 'Gene', (206, 210))	('TMPRSS2', 'Gene', '7113', (6, 13))	('ERG', 'Gene', (66, 69))	('TMPRSS2', 'Gene', (6, 13))	('prostate cancers', 'Phenotype', 'HP:0012125', (161, 177))	('ETV4', 'Gene', '2118', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ETV1', 'Gene', (211, 215))	('prostate cancers', 'Disease', (161, 177))	('ETV4', 'Gene', (80, 84))	('fusions', 'Var', (14, 21))	('ETV4', 'Gene', '2118', (80, 84))	('ETV1', 'Gene', '2115', (211, 215))
91197	33190043	In the FGFR3-TACC3 in-frame fusion detected in 2 bladder cancer samples, the coiled-coil domain of TACC3 causes constitutive phosphorylation of key activating FGFR3 tyrosine residues without the need for ligand binding, leading to tyrosine kinase domain dimerization, auto-phosphorylation and increased and altered levels of FGFR3 activation, fusion protein phosphorylation, downstream signaling, cellular transformation, proliferation, and viability.	('proliferation', 'CPA', (422, 435))	('TACC3', 'Gene', (13, 18))	('auto-phosphorylation', 'MPA', (268, 288))	('activation', 'PosReg', (331, 341))	('FGFR3', 'Gene', (325, 330))	('FGFR3', 'Gene', '2261', (159, 164))	('increased', 'PosReg', (293, 302))	('FGFR3', 'Gene', (7, 12))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('protein phosphorylation', 'biological_process', 'GO:0006468', ('350', '373'))	('bladder cancer', 'Disease', 'MESH:D001749', (49, 63))	('FGFR3', 'Gene', '2261', (325, 330))	('TACC3', 'Gene', '10460', (99, 104))	('tyrosine', 'Chemical', 'MESH:D014443', (165, 173))	('bladder cancer', 'Disease', (49, 63))	('FGFR3', 'Gene', '2261', (7, 12))	('TACC3', 'Gene', (99, 104))	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('binding', 'molecular_function', 'GO:0005488', ('211', '218'))	('bladder cancer', 'Phenotype', 'HP:0009725', (49, 63))	('levels', 'MPA', (315, 321))	('downstream signaling', 'MPA', (375, 395))	('signaling', 'biological_process', 'GO:0023052', ('386', '395'))	('coiled-coil domain', 'Var', (77, 95))	('ligand', 'molecular_function', 'GO:0005488', ('204', '210'))	('altered', 'Reg', (307, 314))	('phosphorylation', 'biological_process', 'GO:0016310', ('273', '288'))	('protein', 'cellular_component', 'GO:0003675', ('350', '357'))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('FGFR', 'molecular_function', 'GO:0005007', ('7', '11'))	('viability', 'CPA', (441, 450))	('cellular transformation', 'CPA', (397, 420))	('tyrosine', 'Chemical', 'MESH:D014443', (231, 239))	('FGFR', 'molecular_function', 'GO:0005007', ('325', '329'))	('FGFR3', 'Gene', (159, 164))	('fusion protein phosphorylation', 'MPA', (343, 373))	('tyrosine kinase domain dimerization', 'MPA', (231, 266))	('TACC3', 'Gene', '10460', (13, 18))
91198	33190043	On the other hand, ABCA13-FGFR2 and FGFR3-MSI2 fusions were predicted to be out-of-frame, and their functional consequences are unknown.	('FGFR3', 'Gene', (36, 41))	('MSI2', 'Gene', '124540', (42, 46))	('ABCA13', 'Gene', '154664', (19, 25))	('fusions', 'Var', (47, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('FGFR2', 'Gene', (26, 31))	('FGFR3', 'Gene', '2261', (36, 41))	('MSI2', 'Gene', (42, 46))	('ABCA13', 'Gene', (19, 25))	('FGFR2', 'Gene', '2263', (26, 31))	('out-of-frame', 'NegReg', (76, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
91199	33190043	Although these FGFR2 and FGFR3 fusions with novel gene partners could still be explored as potential biomarkers, further investigation would be required.	('FGFR3', 'Gene', '2261', (25, 30))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('FGFR2', 'Gene', '2263', (15, 20))	('FGFR2', 'Gene', (15, 20))	('FGFR3', 'Gene', (25, 30))	('fusions', 'Var', (31, 38))
91207	33190043	Another patient with localized medullary carcinoma of the colon (pathologic stage pT2 pN1b) that harbors TPM3-NTRK1 fusion (case WCM1230) underwent surgery only and has not required additional/targeted therapy.	('fusion', 'Var', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinoma of the colon', 'Disease', (41, 63))	('TPM3', 'Gene', (105, 109))	('NTRK1', 'Gene', (110, 115))	('patient', 'Species', '9606', (8, 15))	('TPM3', 'Gene', '7170', (105, 109))	('NTRK1', 'Gene', '4914', (110, 115))	('carcinoma of the colon', 'Disease', 'MESH:D003110', (41, 63))
91211	33190043	One such example is tumors that show bi-allelic inactivation of genes, specifically CDK12 mutant tumors have been strongly linked to structural variants.	('tumors', 'Disease', (20, 26))	('CDK12', 'Gene', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CDK', 'molecular_function', 'GO:0004693', ('84', '87'))	('mutant', 'Var', (90, 96))	('bi-allelic inactivation', 'Var', (37, 60))	('CDK12', 'Gene', '51755', (84, 89))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('structural variants', 'Var', (133, 152))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('linked', 'Reg', (123, 129))
91218	30866868	First, we knocked down ERH in BUC T24 and 5637 cells by shRNA and then used wound healing cell scratch migration assays, transwell cell migration assays, transwell cell invasion chamber experiments and nude mouse tail vein transfer assays to determine the migration and invasion ability after ERH was knocked down.	('cell migration', 'biological_process', 'GO:0016477', ('131', '145'))	('mouse', 'Species', '10090', (207, 212))	('wound healing', 'biological_process', 'GO:0042060', ('76', '89'))	('migration', 'CPA', (256, 265))	('invasion ability', 'CPA', (270, 286))	('knocked', 'Var', (10, 17))	('ERH', 'Gene', (23, 26))
91233	30866868	Primary antibodies against Snail2 (# 9585), N-cadherin (# 13116), vimentin (# 3932) and E-cadherin (# 14472) were purchased from Cell Signaling Technology, and antibodies against fibronectin (ab6328) and Twist (ab49254) were purchased from Abcam.	('fibronectin', 'Gene', '2335', (179, 190))	('vimentin', 'cellular_component', 'GO:0045098', ('66', '74'))	('N-cadherin', 'Gene', (44, 54))	('# 3932', 'Var', (76, 82))	('Signaling', 'biological_process', 'GO:0023052', ('134', '143'))	('vimentin', 'Gene', '7431', (66, 74))	('vimentin', 'Gene', (66, 74))	('N-cadherin', 'Gene', '1000', (44, 54))	('Twist', 'Gene', '7291', (204, 209))	('# 13116', 'Var', (56, 63))	('Snail2', 'Gene', (27, 33))	('Snail2', 'Gene', '6591', (27, 33))	('E-cadherin', 'Gene', (88, 98))	('E-cadherin', 'Gene', '999', (88, 98))	('vimentin', 'cellular_component', 'GO:0045099', ('66', '74'))	('# 9585', 'Var', (35, 41))	('cadherin', 'molecular_function', 'GO:0008014', ('46', '54'))	('cadherin', 'molecular_function', 'GO:0008014', ('90', '98'))	('fibronectin', 'Gene', (179, 190))	('Twist', 'Gene', (204, 209))
91236	30866868	D-Luciferin (40902ES01) was purchased from Shanghai Qianchen Biotechnology Co., Ltd. Trypsin (T0458-50G) and PBS (1710584) were purchased from Bioengineering (Shanghai) Co., Ltd. D-Hanks was prepared by Shanghai Genechem Technology Co., Ltd. Sigma provided the Giemsa staining solution (32884) and sodium pentobarbital (P3761).	('D-Luciferin', 'Chemical', 'MESH:C532924', (0, 11))	('32884', 'Var', (287, 292))	('P3761', 'Var', (320, 325))	('ES01', 'CellLine', 'CVCL:D092', (18, 22))	('sodium pentobarbital', 'Chemical', 'MESH:D010424', (298, 318))
91239	30866868	A BCA protein assay kit (P0010S) and RIPA lysate (strong) (P0013B) were purchased from Pik Wan Company.	('P0010S', 'Var', (25, 31))	('P0010S', 'Mutation', 'p.P0010S', (25, 31))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('P0013B', 'Var', (59, 65))
91240	30866868	RIPA lysate (WB-0071) and NP-40 lysate (P0013F) were purchased from Shanghai Dingguo Biotechnology Co. Prestained protein markers (00161543) and an ECL-PLUS/Kit (M3121/1859022) were provided by Thermo.	('P0013F', 'Mutation', 'p.P0013F', (40, 46))	('00161543', 'Var', (131, 139))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('M3121/1859022', 'Var', (162, 175))
91241	30866868	A lentiviral-based shRNA strategy was used to knockdown ERH in human bladder cancer T24 cells.	('bladder cancer', 'Disease', 'MESH:D001749', (69, 83))	('bladder cancer', 'Disease', (69, 83))	('human', 'Species', '9606', (63, 68))	('knockdown', 'Var', (46, 55))	('ERH', 'Gene', (56, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
91259	30866868	4, E-cadherin expression was significantly increased in BUC 5637 and T24 cells after ERH knockdown, while the expression of fibronectin, Twist, vimentin and Snail2 was significantly decreased.	('Twist', 'Gene', '7291', (137, 142))	('vimentin', 'cellular_component', 'GO:0045098', ('144', '152'))	('Snail2', 'Gene', (157, 163))	('Snail2', 'Gene', '6591', (157, 163))	('cadherin', 'molecular_function', 'GO:0008014', ('5', '13'))	('E-cadherin', 'Gene', (3, 13))	('increased', 'PosReg', (43, 52))	('E-cadherin', 'Gene', '999', (3, 13))	('vimentin', 'Gene', '7431', (144, 152))	('vimentin', 'Gene', (144, 152))	('ERH', 'Gene', (85, 88))	('vimentin', 'cellular_component', 'GO:0045099', ('144', '152'))	('decreased', 'NegReg', (182, 191))	('fibronectin', 'Gene', (124, 135))	('Twist', 'Gene', (137, 142))	('expression', 'MPA', (110, 120))	('knockdown', 'Var', (89, 98))	('expression', 'MPA', (14, 24))	('fibronectin', 'Gene', '2335', (124, 135))
91262	30866868	Lung metastases were detected in 10/10 mice in the ERH NC-luciferase group and in 3/10 mice in the ERH KD-luciferase group (Fig.	('mice', 'Species', '10090', (87, 91))	('ERH NC-luciferase', 'Var', (51, 68))	('metastases', 'Disease', (5, 15))	('metastases', 'Disease', 'MESH:D009362', (5, 15))	('detected', 'Reg', (21, 29))	('mice', 'Species', '10090', (39, 43))
91263	30866868	The number of lung metastases in the ERH NC-luciferase group was 17.3 +- 1.59, and the number of lung metastases in the ERH KD-luciferase group was 0.30 +- 0.15 (T = 10.68, p < 0.01).	('lung metastases', 'Disease', (14, 29))	('lung metastases', 'Disease', 'MESH:D009362', (14, 29))	('lung metastases', 'Disease', (97, 112))	('lung metastases', 'Disease', 'MESH:D009362', (97, 112))	('ERH', 'Var', (37, 40))
91269	30866868	MYC gene expression in the ERH KD group was 0.345 and 0.568 times that of the ERH NC group in 5637 and T24 cells, respectively.	('MYC', 'Gene', (0, 3))	('ERH KD', 'Var', (27, 33))	('expression', 'MPA', (9, 19))	('MYC', 'Gene', '4609', (0, 3))	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))
91270	30866868	These differences were statistically significant and indicated that MYC gene expression was significantly decreased in the ERH KD group (Fig.	('decreased', 'NegReg', (106, 115))	('ERH KD', 'Var', (123, 129))	('MYC', 'Gene', '4609', (68, 71))	('gene expression', 'biological_process', 'GO:0010467', ('72', '87'))	('MYC', 'Gene', (68, 71))
91272	30866868	6d), it can be seen that MYC protein expression was significantly lower in the ERH KD group than in the NC group in 5637 and T24 cells.	('MYC', 'Gene', (25, 28))	('lower', 'NegReg', (66, 71))	('MYC', 'Gene', '4609', (25, 28))	('ERH KD', 'Var', (79, 85))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))
91273	30866868	The 5637 and T24 BUC cell lines were used to determine whether the MYC downregulation induced by ERH knockdown contributed to the inhibition of migration and invasion.	('downregulation', 'NegReg', (71, 85))	('MYC', 'Gene', '4609', (67, 70))	('MYC', 'Gene', (67, 70))	('inhibition', 'NegReg', (130, 140))	('ERH', 'Gene', (97, 100))	('knockdown', 'Var', (101, 110))
91276	30866868	The overexpression of MYC partially inhibited the dampening effect of ERH knockdown on BUC 5637 and T24 cell migration and invasion.	('MYC', 'Gene', '4609', (22, 25))	('inhibited', 'NegReg', (36, 45))	('dampening', 'NegReg', (50, 59))	('knockdown', 'Var', (74, 83))	('ERH', 'Gene', (70, 73))	('cell migration', 'biological_process', 'GO:0016477', ('104', '118'))	('MYC', 'Gene', (22, 25))
91287	30866868	In addition, ERH expression is inversely associated with the survival of colorectal cancer patients whose tumors harbor KRAS mutations.	('mutations', 'Var', (125, 134))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('patients', 'Species', '9606', (91, 99))	('associated', 'Reg', (41, 51))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('KRAS', 'Gene', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('KRAS', 'Gene', '3845', (120, 124))	('ERH', 'Gene', (13, 16))
91293	30866868	After ERH was knocked down, human BUC 5637 and T24 cell migration and invasion decreased significantly.	('decreased', 'NegReg', (79, 88))	('ERH', 'Gene', (6, 9))	('human', 'Species', '9606', (28, 33))	('cell migration', 'biological_process', 'GO:0016477', ('51', '65'))	('knocked down', 'Var', (14, 26))	('invasion', 'CPA', (70, 78))
91294	30866868	A nude mouse tail vein transfer assay showed that ERH knockdown could inhibit the metastasis of BUC T24 cells.	('knockdown', 'Var', (54, 63))	('mouse', 'Species', '10090', (7, 12))	('metastasis of BUC T24 cells', 'CPA', (82, 109))	('inhibit', 'NegReg', (70, 77))	('ERH', 'Gene', (50, 53))
91303	30866868	The expression of E-cadherin in BUC 5637 cells and T24 cells after ERH knockdown was significantly increased, while the expression of fibronectin, Twist, vimentin and Snail2 was significantly decreased.	('expression', 'MPA', (4, 14))	('vimentin', 'Gene', '7431', (154, 162))	('fibronectin', 'Gene', (134, 145))	('vimentin', 'Gene', (154, 162))	('decreased', 'NegReg', (192, 201))	('expression', 'MPA', (120, 130))	('Twist', 'Gene', (147, 152))	('increased', 'PosReg', (99, 108))	('vimentin', 'cellular_component', 'GO:0045098', ('154', '162'))	('fibronectin', 'Gene', '2335', (134, 145))	('Snail2', 'Gene', (167, 173))	('Snail2', 'Gene', '6591', (167, 173))	('ERH', 'Gene', (67, 70))	('E-cadherin', 'Gene', (18, 28))	('E-cadherin', 'Gene', '999', (18, 28))	('Twist', 'Gene', '7291', (147, 152))	('knockdown', 'Var', (71, 80))	('cadherin', 'molecular_function', 'GO:0008014', ('20', '28'))	('vimentin', 'cellular_component', 'GO:0045099', ('154', '162'))
91304	30866868	The present study indicated that the expression of E-cadherin was related to ERH knockdown in 5637 and T24 cells; these results agree with other studies showing that the loss of E-cadherin expression has been associated with migration and invasion in numerous types of epithelium-derived cancer cells.	('associated with', 'Reg', (209, 224))	('cadherin', 'molecular_function', 'GO:0008014', ('53', '61'))	('invasion', 'CPA', (239, 247))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('migration', 'CPA', (225, 234))	('cadherin', 'molecular_function', 'GO:0008014', ('180', '188'))	('cancer', 'Disease', (288, 294))	('loss', 'Var', (170, 174))	('E-cadherin', 'Gene', (178, 188))	('E-cadherin', 'Gene', '999', (178, 188))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('E-cadherin', 'Gene', (51, 61))	('E-cadherin', 'Gene', '999', (51, 61))
91306	30866868	The results of the present study also showed that the expression of Snail and Twist was related to ERH knockdown, which indicated that ERH participates in the EMT process.	('Twist', 'Gene', (78, 83))	('EMT', 'biological_process', 'GO:0001837', ('159', '162'))	('related', 'Reg', (88, 95))	('Snail', 'Gene', '6615', (68, 73))	('Snail', 'Gene', (68, 73))	('Twist', 'Gene', '7291', (78, 83))	('knockdown', 'Var', (103, 112))	('ERH', 'Gene', (99, 102))
91314	30866868	We found that ERH knockdown does inhibit migration and invasion through MYC in BUC T24 cells through functional recovery experiments.	('knockdown', 'Var', (18, 27))	('migration', 'CPA', (41, 50))	('inhibit', 'NegReg', (33, 40))	('MYC', 'Gene', (72, 75))	('ERH', 'Gene', (14, 17))	('MYC', 'Gene', '4609', (72, 75))	('invasion through', 'CPA', (55, 71))
91318	30866868	We found that ERH knockdown does inhibit migration and invasion through MYC in BUC T24 cells.	('knockdown', 'Var', (18, 27))	('migration', 'CPA', (41, 50))	('inhibit', 'NegReg', (33, 40))	('MYC', 'Gene', (72, 75))	('ERH', 'Gene', (14, 17))	('MYC', 'Gene', '4609', (72, 75))
91329	29343911	With the exception of AC, the most common variant bladder cancer histologies are all independently associated with worse DSS relative to UCC in patients undergoing radical cystectomy.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (50, 64))	('DSS', 'Chemical', '-', (121, 124))	('DSS', 'Disease', (121, 124))	('bladder cancer', 'Disease', (50, 64))	('patients', 'Species', '9606', (144, 152))	('variant', 'Var', (42, 49))	('bladder cancer', 'Phenotype', 'HP:0009725', (50, 64))
91338	29343911	Histology ICD-O-3 codes were used to identify the most commonly observed bladder cancer histology cell types: UCC (8120, 8130), squamous cell carcinoma (SCC) (8070, 8076), adenocarcinoma (AC) (8140, 8144, 8255, 8260, 8263, 8310, 8323, 8480, 8481, 8570, 8574, 8575), sarcoma (8801-8802, 8810, 8890, 8896, 8880), small cell carcinoma (8041, 8446), signet ring carcinoma (8490), and spindle cell carcinoma (8030, 8031, 8122).	('8140', 'Var', (193, 197))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (311, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('8041, 8446', 'Var', (333, 343))	('ring carcinoma', 'Disease', (353, 367))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))	('spindle cell carcinoma', 'Disease', 'MESH:D002277', (380, 402))	('bladder cancer', 'Disease', (73, 87))	('sarcoma', 'Disease', 'MESH:D012509', (266, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (358, 367))	('8570', 'Var', (247, 251))	('adenocarcinoma', 'Disease', (172, 186))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 151))	('ring carcinoma', 'Disease', 'MESH:D012303', (353, 367))	('sarcoma', 'Disease', (266, 273))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('small cell carcinoma', 'Disease', (311, 331))	('8030', 'Var', (404, 408))	('8801-8802', 'Var', (275, 284))	('spindle cell carcinoma', 'Disease', (380, 402))	('small cell carcinoma', 'Disease', 'MESH:D018288', (311, 331))	('SCC', 'Gene', '6317', (153, 156))	('squamous cell carcinoma', 'Disease', (128, 151))	('8490', 'Var', (369, 373))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	('SCC', 'Gene', (153, 156))	('adenocarcinoma', 'Disease', 'MESH:D000230', (172, 186))	('spindle', 'cellular_component', 'GO:0005819', ('380', '387'))	('carcinoma', 'Phenotype', 'HP:0030731', (393, 402))	('UCC', 'Disease', (110, 113))
91354	29343911	Compared to urothelial carcinoma, there was an increased risk of disease-specific death associated with all variants except AC (HR 1.01, 95% CI: 0.82-1.23, P = 0.92) and small cell (HR 1.40, 95% CI: 1.00-1.97, P = 0.49).	('death', 'Disease', 'MESH:D003643', (82, 87))	('urothelial carcinoma', 'Disease', (12, 32))	('death', 'Disease', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('variants', 'Var', (108, 116))	('small cell', 'Disease', (170, 180))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (12, 32))	('disease-specific', 'Disease', (65, 81))
91360	29343911	Similar to patients with pure UCC, patients with variant histology bladder cancer tended to be males although the patient population with SCC was nearly equal in terms of gender composition.	('SCC', 'Gene', (138, 141))	('pure', 'molecular_function', 'GO:0034023', ('25', '29'))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('patient', 'Species', '9606', (35, 42))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('SCC', 'Gene', '6317', (138, 141))	('patient', 'Species', '9606', (11, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('patient', 'Species', '9606', (114, 121))	('patients', 'Species', '9606', (11, 19))	('variant', 'Var', (49, 56))	('patients', 'Species', '9606', (35, 43))
91410	28359308	We use such a similarity transformation, here referred to as Higher-Order Correlations to Uncover Subtypes (HOCUS), and show that HOCUS enhances the detection of biologically-relevant clusters of patients for several Cancer Genome Atlas (TCGA) cohorts.	('HOCUS', 'Chemical', '-', (108, 113))	('HOCUS', 'Var', (130, 135))	('Cancer Genome Atlas', 'Disease', (217, 236))	('HOCUS', 'Chemical', '-', (130, 135))	('enhances', 'PosReg', (136, 144))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (217, 236))	('patients', 'Species', '9606', (196, 204))	('Cancer', 'Phenotype', 'HP:0002664', (217, 223))
91438	28359308	For instance, BCR-ABL fusions are characteristic of chronic myeloid leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (68, 76))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (60, 76))	('fusions', 'Var', (22, 29))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (52, 76))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (52, 76))	('BCR-ABL', 'Gene', '25', (14, 21))	('chronic myeloid leukemia', 'Disease', (52, 76))	('BCR-ABL', 'Gene', (14, 21))
91446	28359308	Patients in the best surviving cluster, cluster 1, had low EGFR and TTN mutation occurrence compared to that of patients in other clusters; TTN mutations are predominantly in cluster 3 and EGFR mutations distributed between clusters 2 and 3.	('TTN', 'Gene', (68, 71))	('EGFR', 'Gene', '1956', (189, 193))	('TTN', 'Gene', (140, 143))	('EGFR', 'Gene', (59, 63))	('EGFR', 'Gene', (189, 193))	('TTN', 'Gene', '7273', (68, 71))	('patients', 'Species', '9606', (112, 120))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('TTN', 'Gene', '7273', (140, 143))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'molecular_function', 'GO:0005006', ('189', '193'))	('mutations', 'Var', (144, 153))	('EGFR', 'Gene', '1956', (59, 63))
91447	28359308	All 14 of the IDH1 mutated tumors were in cluster 1, as were most (11 of 16) of the ATRX mutants.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('ATRX', 'Gene', '546', (84, 88))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('mutated', 'Var', (19, 26))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('mutants', 'Var', (89, 96))	('IDH1', 'Gene', (14, 18))	('ATRX', 'Gene', (84, 88))	('IDH1', 'Gene', '3417', (14, 18))
91449	28359308	Thus, the HOCUS clustering using mutations seems to have been able to tease out a low grade diffuse subtype, defined by IDH1 mutation status seen in younger individuals, characterized by the absence of a 1p/19q codeletion and a lack of TERT expression and an overall better prognosis.	('TERT', 'Gene', (236, 240))	('tease out', 'Phenotype', 'HP:0001061', (70, 79))	('TERT', 'Gene', '7015', (236, 240))	('low grade diffuse', 'Disease', (82, 99))	('IDH1', 'Gene', (120, 124))	('HOCUS', 'Chemical', '-', (10, 15))	('IDH1', 'Gene', '3417', (120, 124))	('absence', 'NegReg', (191, 198))	('mutation', 'Var', (125, 133))
91450	28359308	Furthermore, all 65 samples in cluster 1 have a TP53 mutation (Additional file 3: Figure S3), whereas there are none in cluster 2 and only 14 (of 105 samples) in cluster 3.	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))	('mutation', 'Var', (53, 61))
91453	28359308	In addition to TP53 mutations, several genes that are characteristic of passenger mutations were also predominant in the highly mutated cluster including TTN, MUC16, and RYR2.	('MUC16', 'Gene', (159, 164))	('RYR2', 'Gene', (170, 174))	('TTN', 'Gene', '7273', (154, 157))	('MUC16', 'Gene', '94025', (159, 164))	('RYR2', 'Gene', '6262', (170, 174))	('TP53', 'Gene', (15, 19))	('TP53', 'Gene', '7157', (15, 19))	('RYR', 'cellular_component', 'GO:1990425', ('170', '173'))	('mutations', 'Var', (20, 29))	('TTN', 'Gene', (154, 157))
91470	28359308	Interestingly, the highly mutated BLCA cluster has the best survival prognosis.	('BLCA cluster', 'Gene', (34, 46))	('highly mutated', 'Var', (19, 33))	('BLCA', 'Chemical', '-', (34, 38))
91473	28359308	In both cases, a higher rate of TP53 mutations was found (80% compared to the background rate of 50%), and a slightly higher rate of smokers was in the category.	('mutations', 'Var', (37, 46))	('TP53', 'Gene', '7157', (32, 36))	('TP53', 'Gene', (32, 36))
91476	28359308	We applied HOCUS to the TCGA Pancancer-12 mutations data.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('HOCUS', 'Chemical', '-', (11, 16))	('mutations', 'Var', (42, 51))
91480	28359308	Not surprisingly, the main difference in most of the clusters is whether they contain samples with either a TP53 or PIK3CA mutation.	('PIK3CA', 'Gene', (116, 122))	('mutation', 'Var', (123, 131))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('PIK3CA', 'Gene', '5290', (116, 122))
91486	28359308	On the other hand, when applied to a diverse collection of tumor types that span multiple tissues, the HOCUS-based mutation clusters identify major divisions that are not primarily tissue based.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('HOCUS', 'Chemical', '-', (103, 108))	('mutation', 'Var', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('HOCUS-based', 'Gene', (103, 114))
91516	28359308	We find that higher order metrics yield better clusters for BLCA and GBM patients based on mutations, as well as GBM patients based on their tumor images.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('BLCA', 'Disease', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('patients', 'Species', '9606', (73, 81))	('mutations', 'Var', (91, 100))	('patients', 'Species', '9606', (117, 125))	('BLCA', 'Chemical', '-', (60, 64))
91517	28359308	In the case of BLCA cancer, the second-order metrics revealed groupings of the patients where tumors with higher mutation rates are separated from the other tumors and these patients have an overall better survival outcome.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutation', 'Var', (113, 121))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('better', 'PosReg', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('patients', 'Species', '9606', (174, 182))	('BLCA', 'Chemical', '-', (15, 19))	('tumors', 'Disease', (94, 100))	('cancer', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('patients', 'Species', '9606', (79, 87))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
91518	28359308	Most notably, the solutions for BLCA and OV separate tumors with higher mutation rates from the others and those patients with higher mutated tumors have a better survival outlook relative to the other patients.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('patients', 'Species', '9606', (113, 121))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('OV', 'Phenotype', 'HP:0100615', (41, 43))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('patients', 'Species', '9606', (202, 210))	('BLCA', 'Chemical', '-', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('mutation', 'Var', (72, 80))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', (53, 59))	('BLCA', 'Disease', (32, 36))
91519	28359308	This result may reflect that highly mutated tumors are more sensitive to DNA damaging agents (e.g.	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Disease', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('sensitive', 'MPA', (60, 69))	('highly mutated', 'Var', (29, 43))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('more', 'PosReg', (55, 59))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))
91521	28359308	Alternatively, a higher mutation rate could increase the number of neo-antigens present on tumor cell surfaces, helping a patient's innate immune system to identify and eliminate tumor cells that lack immunosuppressive protection such as through the expression of PD-L1 and/or CTLA4.	('PD-L1', 'Gene', '29126', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('CTLA4', 'Gene', (277, 282))	('patient', 'Species', '9606', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('increase', 'PosReg', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('PD-L1', 'Gene', (264, 269))	('mutation', 'Var', (24, 32))	('CTLA4', 'Gene', '1493', (277, 282))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (179, 184))
91522	28359308	Alternatively, tumors with higher mutation rates could reflect a different subtype with an intrinsically distinct progression pattern.	('tumors', 'Disease', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutation', 'Var', (34, 42))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
91546	20385105	Here, we report that expression of the CCAAT/enhancer binding protein delta (CEBPD, C/EBPdelta, NF-IL6beta) is induced by cisplatin in the human bladder urothelial carcinoma NTUB1 cell line and is specifically elevated in a cisplatin resistant subline.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (145, 173))	('elevated', 'PosReg', (210, 218))	('induced', 'PosReg', (111, 118))	('IL6', 'molecular_function', 'GO:0005138', ('99', '102'))	('CCAAT/enhancer binding protein delta', 'Gene', (39, 75))	('CCAAT/enhancer binding protein delta', 'Gene', '1052', (39, 75))	('NF-IL6beta', 'Gene', (96, 106))	('NF-IL6beta', 'Gene', '1052', (96, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('CEBPD', 'Gene', (77, 82))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('C/EBPdelta', 'Gene', '1052', (84, 94))	('bladder urothelial carcinoma', 'Disease', (145, 173))	('cisplatin', 'Var', (122, 131))	('expression', 'MPA', (21, 31))	('C/EBPdelta', 'Gene', (84, 94))	('human', 'Species', '9606', (139, 144))	('enhancer binding', 'molecular_function', 'GO:0035326', ('45', '61'))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (224, 233))
91581	20385105	The deletion of the carboxy-terminal amino acids 197-296 of CEBPD (DeltaDBD) was constructed by PCR amplification by 5'-primer CAAGCTAGCATGAGCGCCGCGCTCTTC and 3'-primer AAGGATCCAATCTGCCGGTACTCGGGGC, and cloned into shuttle vector 5-Flag-SK+.	('shuttle vector', 'Species', '45197', (215, 229))	('CEBPD', 'Gene', (60, 65))	('deletion', 'Var', (4, 12))
91582	20385105	The shRNA target sequence for SOD1 (NM_000454) is TCCCTTGGATGTAGTCTGAGG and cloned in pLKO.1-puro vector (clone ID: TRCN0000009869; obtained from the National RNAi Core Facility, at the Institute of Molecular Biology/Genomic Research Center, Academia Sinica in Taiwan).	('NM_000454', 'Var', (36, 45))	('RNAi', 'biological_process', 'GO:0016246', ('159', '163'))	('SOD1', 'molecular_function', 'GO:0004784', ('30', '34'))	('Academia Sinica', 'Disease', 'None', (242, 257))	('Academia Sinica', 'Disease', (242, 257))
91618	20385105	Over-expression of CEBPD increased the IC50 to 3.31 muM as compared to 2.14 muM for vector transfected cells and 1.75 muM for parental cells.	('increased', 'PosReg', (25, 34))	('muM', 'Gene', '56925', (52, 55))	('muM', 'Gene', '56925', (76, 79))	('muM', 'Gene', '56925', (118, 121))	('muM', 'Gene', (52, 55))	('muM', 'Gene', (76, 79))	('Over-expression', 'Var', (0, 15))	('CEBPD', 'Gene', (19, 24))	('IC50', 'MPA', (39, 43))	('muM', 'Gene', (118, 121))
91621	20385105	Vector control clone (N-V), WT CEBPD (N-D#1) and the deletion of amino acids 197-269 CEBPD variant (N-DeltaDBD) expressing clones were used for subsequent experiments.	('N-DeltaDBD', 'Chemical', '-', (100, 110))	('CEBPD', 'Gene', (85, 90))	('men', 'Species', '9606', (161, 164))	('deletion of amino acids 197-269', 'Var', (53, 84))
91628	20385105	Flow cytometry showed that 24 h of exposure to 10 muM cisplatin led to an increase of cells in S-phase in all three cell lines, indicative of S-phase arrest (Fig.	('cisplatin', 'Var', (54, 63))	('cells in S-phase', 'CPA', (86, 102))	('increase', 'PosReg', (74, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('S-phase', 'biological_process', 'GO:0051320', ('142', '149'))	('muM', 'Gene', '56925', (50, 53))	('S-phase', 'biological_process', 'GO:0051320', ('95', '102'))	('muM', 'Gene', (50, 53))	('S-phase arrest', 'Disease', (142, 156))	('S-phase arrest', 'Disease', 'MESH:D006323', (142, 156))
91630	20385105	This effect was completely abolished in CEBPD expressing N-D#1 (5.89 +- 1.01%) cells (P < 0.05), which instead exhibited S-phase arrest.	('N-D#1', 'Var', (57, 62))	('S-phase', 'biological_process', 'GO:0051320', ('121', '128'))	('abolished', 'NegReg', (27, 36))	('S-phase arrest', 'Disease', 'MESH:D006323', (121, 135))	('S-phase arrest', 'Disease', (121, 135))
91631	20385105	These results suggest that over-expression of intact CEBPD but not of a DNA-binding mutant of CEBPD enhance cisplatin resistance by lowering the effective dose of the drug.	('over-expression', 'PosReg', (27, 42))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('72', '83'))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('enhance', 'PosReg', (100, 107))	('mutant', 'Var', (84, 90))	('CEBPD', 'Gene', (94, 99))	('cisplatin resistance', 'MPA', (108, 128))	('effective dose of the drug', 'MPA', (145, 171))	('lowering', 'NegReg', (132, 140))
91633	20385105	As expected and confirmed with others, the cellular ROS levels were increased in dose- and time-dependent manner by cisplatin in NTUB1 cells (data not shown).	('cisplatin', 'Var', (116, 125))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('increased', 'PosReg', (68, 77))	('cellular ROS levels', 'MPA', (43, 62))
91639	20385105	Since complete deletion of the DBD also removes the nuclear localization signal, we also tested an R198A point mutation (N-R198A), which does not interfere with nuclear localization but destroys the DNA binding activity.	('removes', 'NegReg', (40, 47))	('R198A', 'Mutation', 'p.R198A', (99, 104))	('DNA binding', 'Interaction', (199, 210))	('deletion', 'Var', (15, 23))	('R198A', 'Var', (99, 104))	('R198A', 'Mutation', 'p.R198A', (123, 128))	('destroys', 'NegReg', (186, 194))	('DNA', 'cellular_component', 'GO:0005574', ('199', '202'))	('DNA binding', 'molecular_function', 'GO:0003677', ('199', '210'))	('nuclear localization signal', 'MPA', (52, 79))	('localization', 'biological_process', 'GO:0051179', ('60', '72'))	('localization', 'biological_process', 'GO:0051179', ('169', '181'))
91645	20385105	Interestingly, Cu/Zn-superoxide dismutase (SOD1) was highly expressed in N-D#1 but not in N-DeltaDBD and N-V control cells, while another antioxidant enzyme, peroxiredoxin (PRX), was equally expressed in all three cell lines (Fig.	('Cu/Zn-superoxide dismutase', 'Gene', (15, 41))	('N-DeltaDBD', 'Chemical', '-', (90, 100))	('SOD1', 'molecular_function', 'GO:0004784', ('43', '47'))	('Cu/Zn-superoxide dismutase', 'Gene', '6647', (15, 41))	('N-D#1', 'Var', (73, 78))
91648	20385105	Consistent with these data, we found SOD1 expressed in the NTUB1/P14 cisplatin resistant subline and RNAi-mediated knockdown of endogenous CEBPD expression significantly reduced SOD1 levels in these cells (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('P14', 'Gene', '10923', (65, 68))	('RNAi', 'biological_process', 'GO:0016246', ('101', '105'))	('SOD1 levels', 'MPA', (178, 189))	('SOD1', 'molecular_function', 'GO:0004784', ('37', '41'))	('reduced', 'NegReg', (170, 177))	('SOD1', 'molecular_function', 'GO:0004784', ('178', '182'))	('P14', 'Gene', (65, 68))	('CEBPD', 'Gene', (139, 144))	('knockdown', 'Var', (115, 124))
91651	20385105	Thus, our results suggest that expression of wild-type CEBPD reduces the level of ROS through SOD1 induction, which then results in reduced cisplatin cytotoxicity.	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (140, 149))	('cytotoxicity', 'Disease', (150, 162))	('SOD1', 'Gene', (94, 98))	('reduced', 'NegReg', (132, 139))	('SOD1', 'molecular_function', 'GO:0004784', ('94', '98'))	('CEBPD', 'Gene', (55, 60))	('level', 'MPA', (73, 78))	('reduces', 'NegReg', (61, 68))	('ROS', 'MPA', (82, 85))	('cytotoxicity', 'Disease', 'MESH:D064420', (150, 162))	('expression', 'Var', (31, 41))
91654	20385105	4B, the SOD1 promoter activity was induced by full-length wild-type CEBPD in a dose-dependent manner, while the R198A mutation significantly impaired transactivation activity (Fig.	('impaired', 'NegReg', (141, 149))	('R198A', 'Var', (112, 117))	('SOD1', 'molecular_function', 'GO:0004784', ('8', '12'))	('SOD1', 'Gene', (8, 12))	('R198A', 'Mutation', 'p.R198A', (112, 117))	('transactivation activity', 'MPA', (150, 174))	('transactivation', 'biological_process', 'GO:2000144', ('150', '165'))
91660	20385105	The intracellular ROS levels were significantly elevated in both cisplatin and TETA treated cells and further induced by combined treatment suggesting that blockage of SOD1 activity potentiates cisplatin-induced ROS production in NTUB1 cells (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('SOD1', 'Gene', (168, 172))	('intracellular', 'cellular_component', 'GO:0005622', ('4', '17'))	('cisplatin-induced ROS production', 'MPA', (194, 226))	('blockage', 'Var', (156, 164))	('ROS', 'Chemical', 'MESH:D017382', (212, 215))	('SOD1', 'molecular_function', 'GO:0004784', ('168', '172'))	('men', 'Species', '9606', (135, 138))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (194, 203))	('potentiates', 'PosReg', (182, 193))
91681	20385105	In the present study, we have obtained compelling evidence that CEBPD reduces ROS levels and concomitantly cisplatin cytotoxicity.	('ROS', 'Chemical', 'MESH:D017382', (78, 81))	('cytotoxicity', 'Disease', 'MESH:D064420', (117, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('reduces', 'NegReg', (70, 77))	('CEBPD', 'Var', (64, 69))	('cytotoxicity', 'Disease', (117, 129))	('ROS levels', 'MPA', (78, 88))
91682	20385105	Use of CEBPD mutants established that CEBPD-mediated gene expression is critical for its contribution to cisplatin resistance in NTUB1 cells, and subsequent analyses identified SOD1 as one relevant target gene.	('gene expression', 'biological_process', 'GO:0010467', ('53', '68'))	('SOD1', 'molecular_function', 'GO:0004784', ('177', '181'))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('mutants', 'Var', (13, 20))	('cisplatin resistance', 'MPA', (105, 125))
91749	31453109	Immunohistochemistry demonstrated positivity for CK7, GATA3 (Fig.	('positivity', 'Var', (34, 44))	('CK7', 'Gene', '3855', (49, 52))	('GATA3', 'Gene', (54, 59))	('CK7', 'Gene', (49, 52))	('GATA3', 'Gene', '2625', (54, 59))
91798	27564266	In addition, tumor SPARC is subject to epigenetic silencing through promoter methylation in many cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('tumor', 'Disease', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('methylation', 'biological_process', 'GO:0032259', ('77', '88'))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('promoter methylation', 'Var', (68, 88))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('epigenetic silencing', 'Var', (39, 59))
91813	27564266	Numerous genetic and epigenetic alterations were implicated in tumorigenesis and progression of bladder cancer.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('bladder cancer', 'Phenotype', 'HP:0009725', (96, 110))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('epigenetic alterations', 'Var', (21, 43))	('bladder cancer', 'Disease', 'MESH:D001749', (96, 110))	('bladder cancer', 'Disease', (96, 110))	('genetic', 'Var', (9, 16))	('implicated', 'Reg', (49, 59))
91814	27564266	The Cancer Genome Atlas (TCGA) data revealed statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signaling pathways.	('regulation', 'biological_process', 'GO:0065007', ('174', '184'))	('cell-cycle regulation', 'biological_process', 'GO:0051726', ('141', '162'))	('signaling', 'biological_process', 'GO:0023052', ('197', '206'))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('mutations', 'Var', (81, 90))	('Cancer Genome Atlas', 'Disease', (4, 23))	('chromatin', 'cellular_component', 'GO:0000785', ('164', '173'))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))
91819	27564266	SPARC is dispensable for bladder development and function as evidenced by the normal development and function of mice with germline deletion of SPARC.	('SPARC', 'Gene', (144, 149))	('deletion', 'Var', (132, 140))	('mice', 'Species', '10090', (113, 117))
91838	27564266	Of interest is that in human bladder cancer, cyclin D1 (CCND1) is amplified in 20%, whereas inactivating mutations, hemizygous and homozygous deletions of the tumor suppressor CDKN1A gene that encodes p21CIP/WAF1 have been recently reported with higher frequencies of deletion in muscle invasive (MI) disease.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('WAF1', 'Gene', '1026', (208, 212))	('CDKN1A', 'Gene', (176, 182))	('CDKN1A', 'Gene', '1026', (176, 182))	('WAF1', 'Gene', (208, 212))	('CCND1', 'Gene', '595', (56, 61))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('159', '175'))	('human', 'Species', '9606', (23, 28))	('CCND1', 'Gene', (56, 61))	('tumor suppressor', 'biological_process', 'GO:0051726', ('159', '175'))	('bladder cancer', 'Disease', 'MESH:D001749', (29, 43))	('bladder cancer', 'Disease', (29, 43))	('tumor', 'Disease', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('bladder cancer', 'Phenotype', 'HP:0009725', (29, 43))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('cyclin D1', 'Gene', (45, 54))	('inactivating mutations', 'Var', (92, 114))	('cyclin D1', 'Gene', '595', (45, 54))	('cyclin', 'molecular_function', 'GO:0016538', ('45', '51'))
91850	27564266	In lieu of these reports we can speculate that SPARC, through its anti-oxidant and anti-inflammatory effects may exert a protective role against carcinogen- and ROS-induced genome instability and mutations.	('mutations', 'Var', (196, 205))	('ROS', 'Chemical', 'MESH:D017382', (161, 164))	('genome instability', 'CPA', (173, 191))
91874	27564266	Pairwise examination of matching lungs and bladder tissues with pre-neoplastic and neoplastic lesions revealed progressive increase in the levels of pro-inflammatory mediators with significantly higher levels in SP-/- compared with SP+/+ lungs as a function of disease progression.	('SP-/-', 'Var', (212, 217))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (83, 101))	('higher', 'PosReg', (195, 201))	('SP', 'Chemical', 'MESH:C000604007', (232, 234))	('pre', 'molecular_function', 'GO:0003904', ('64', '67'))	('levels of pro-inflammatory mediators', 'MPA', (139, 175))	('increase', 'PosReg', (123, 131))	('SP', 'Chemical', 'MESH:C000604007', (212, 214))
91875	27564266	In addition, macrophage infiltration was significantly higher in SP-/- compared with the SP+/+ lung metastases.	('metastases', 'Disease', (100, 110))	('SP', 'Chemical', 'MESH:C000604007', (65, 67))	('metastases', 'Disease', 'MESH:D009362', (100, 110))	('SP-/-', 'Var', (65, 70))	('macrophage infiltration', 'CPA', (13, 36))	('SP', 'Chemical', 'MESH:C000604007', (89, 91))	('higher', 'PosReg', (55, 61))
91878	27564266	Using a syngeneic model of spontaneous metastasis in which SPARC-proficient MB49 cells were injected SC in SP-/- and SP+/+ mice, host-SPARC not only inhibited the in vivo growth, invasiveness, angiogenesis and inflammation of primary tumors, but it also inhibited spontaneous lung metastasis through inhibition of the pre-conditioning of the inflammatory pre-metastatic and metastatic lung niche (Figure 5).	('angiogenesis', 'CPA', (193, 205))	('SP', 'Chemical', 'MESH:C000604007', (134, 136))	('SP', 'Chemical', 'MESH:C000604007', (117, 119))	('inhibition', 'NegReg', (300, 310))	('mice', 'Species', '10090', (123, 127))	('pre', 'molecular_function', 'GO:0003904', ('355', '358'))	('lung metastasis', 'Disease', 'MESH:D009362', (276, 291))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('lung metastasis', 'Disease', (276, 291))	('SP', 'Chemical', 'MESH:C000604007', (107, 109))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('inhibited', 'NegReg', (254, 263))	('inflammation of primary tumors', 'Disease', (210, 240))	('growth', 'CPA', (171, 177))	('MB49', 'CellLine', 'CVCL:7076', (76, 80))	('angiogenesis', 'biological_process', 'GO:0001525', ('193', '205'))	('pre', 'molecular_function', 'GO:0003904', ('318', '321'))	('SP', 'Chemical', 'MESH:C000604007', (59, 61))	('host-SPARC', 'Var', (129, 139))	('inflammation', 'biological_process', 'GO:0006954', ('210', '222'))	('inflammation of primary tumors', 'Disease', 'MESH:D007249', (210, 240))	('inhibited', 'NegReg', (149, 158))	('invasiveness', 'CPA', (179, 191))
91904	25864709	Additionally, we identified altered lncRNAs that may be up- or down-regulated due to an amplification or deletion, respectively, and associated lncRNA expression with the mutational status of commonly mutated genes in cancer which could suggest an acquired functional role in tumors.	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('deletion', 'Var', (105, 113))	('amplification', 'Var', (88, 101))	('cancer', 'Disease', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('tumors', 'Disease', 'MESH:D009369', (276, 282))	('lncRNA expression', 'MPA', (144, 161))	('down-regulated', 'NegReg', (63, 77))	('up-', 'PosReg', (56, 59))	('mutational', 'Var', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (276, 282))	('associated', 'Reg', (133, 143))
91949	25864709	As copy number variation plays an important role in cancer, we next investigated how amplifications and deletions might affect the expression level of lncRNAs.	('amplifications', 'Var', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('expression level', 'MPA', (131, 147))	('affect', 'Reg', (120, 126))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('deletions', 'Var', (104, 113))
91957	25864709	For example, onco-lncRNA-1, which is upregulated in 5 cancer types, has a significant association with TP53 mutation status in BRCA, LUAD, and UCEC (Fig.	('TP53', 'Gene', '7157', (103, 107))	('BRCA', 'Gene', '672', (127, 131))	('mutation status', 'Var', (108, 123))	('TP53', 'Gene', (103, 107))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('UCEC', 'Disease', (143, 147))	('onco-lncRNA-1', 'Disease', (13, 26))	('BRCA', 'Phenotype', 'HP:0003002', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('LUAD', 'Phenotype', 'HP:0030078', (133, 137))	('LUAD', 'Disease', (133, 137))	('BRCA', 'Gene', (127, 131))
91959	25864709	Similarly, MEG3 (onco-lncRNA-83) expression was associated with TP53 mutational status and may be regulated via a TP53 binding site within the MEG3 promoter (Table S10).	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('mutational status', 'Var', (69, 86))	('associated', 'Reg', (48, 58))	('TP53', 'Gene', (114, 118))	('MEG3', 'Gene', '55384', (11, 15))	('TP53', 'Gene', '7157', (114, 118))	('MEG3', 'Gene', (143, 147))	('TP53', 'Gene', '7157', (64, 68))	('expression', 'MPA', (33, 43))	('TP53', 'Gene', (64, 68))	('MEG3', 'Gene', '55384', (143, 147))	('MEG3', 'Gene', (11, 15))
91967	25864709	As the CRNDE promoter resides in the same CpG island as that of the adjacent IRX5 gene, methylation of the promoter region results in coordinated expression.	('IRX5', 'Gene', (77, 81))	('coordinated expression', 'MPA', (134, 156))	('methylation', 'Var', (88, 99))	('results in', 'Reg', (123, 133))	('IRX5', 'Gene', '10265', (77, 81))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('CRNDE', 'Gene', '643911', (7, 12))	('CRNDE', 'Gene', (7, 12))
91979	25864709	Greater than 50% knockdown of CCAT1 in NCI-H322M and NCI-H522 cells using 2 different small interfering RNAs (siRNAs) resulted in decreased cell growth of ~20% and ~40%, respectively, as measured by cell counting for 6 d (Fig.	('NCI-H522', 'CellLine', 'CVCL:1567', (53, 61))	('cell growth', 'biological_process', 'GO:0016049', ('140', '151'))	('cell growth', 'CPA', (140, 151))	('CCAT1', 'Gene', '100507056', (30, 35))	('NCI-H322M', 'CellLine', 'CVCL:1557', (39, 48))	('knockdown', 'Var', (17, 26))	('CCAT1', 'Gene', (30, 35))	('decreased', 'NegReg', (130, 139))
91993	25864709	Greater than 50% knockdown of onco-lncRNA-3 in NCI-H322M lung cells with 2 different siRNAs resulted in approximately 15% (p = 0.04) or 12% (p = 0.02), respectively, of EdU incorporation compared to 18% incorporation in scrambled control (Fig.	('rat', 'Species', '10116', (180, 183))	('EdU incorporation', 'MPA', (169, 186))	('onco-lncRNA-3', 'Gene', (30, 43))	('NCI-H322M', 'CellLine', 'CVCL:1557', (47, 56))	('knockdown', 'Var', (17, 26))	('rat', 'Species', '10116', (210, 213))	('onco-lncRNA-3', 'Gene', '100128338', (30, 43))
92009	25864709	Despite the lower sequence read coverage in a few of the cancer types, we are still able to detect a subset of altered lncRNAs, suggesting they are more highly expressed and markedly altered.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('lncRNAs', 'Protein', (119, 126))	('altered', 'Reg', (183, 190))	('altered', 'Var', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
92025	25864709	This is exemplified by the expression of MEG3 (onco-lncRNA-83), which has a TP53 binding site within its promoter, being associated with TP53 mutational status.	('MEG3', 'Gene', '55384', (41, 45))	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('mutational status', 'Var', (142, 159))	('associated', 'Reg', (121, 131))	('TP53', 'Gene', '7157', (76, 80))	('MEG3', 'Gene', (41, 45))	('TP53', 'Gene', (76, 80))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', (137, 141))
92027	25864709	Similarly we also observed an NRF2 motif upstream of onco-lncRNA-3, which was found to have elevated expression in KEAP1 mutant patients in LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (140, 144))	('NRF2', 'Gene', (30, 34))	('mutant', 'Var', (121, 127))	('KEAP1', 'Gene', '9817', (115, 120))	('elevated', 'PosReg', (92, 100))	('onco-lncRNA-3', 'Gene', (53, 66))	('onco-lncRNA-3', 'Gene', '100128338', (53, 66))	('KEAP1', 'Gene', (115, 120))	('NRF2', 'Gene', '4780', (30, 34))	('expression', 'MPA', (101, 111))	('patients', 'Species', '9606', (128, 136))
92030	25864709	Recent work has shown that KEAP1 mutant cells protect NRF2 from ubiquitination and degradation, constitutively activating the expression of NRF2 target genes.	('ubiquitination', 'MPA', (64, 78))	('KEAP1', 'Gene', '9817', (27, 32))	('degradation', 'MPA', (83, 94))	('expression', 'MPA', (126, 136))	('NRF2', 'Gene', '4780', (54, 58))	('activating', 'PosReg', (111, 121))	('KEAP1', 'Gene', (27, 32))	('degradation', 'biological_process', 'GO:0009056', ('83', '94'))	('mutant', 'Var', (33, 39))	('NRF2', 'Gene', (54, 58))	('NRF2', 'Gene', '4780', (140, 144))	('NRF2', 'Gene', (140, 144))
92031	25864709	Therefore, it is plausible that there is some interplay between KEAP1 mutant patients and elevated onco-lncRNA-3 expression via NRF2.	('KEAP1', 'Gene', '9817', (64, 69))	('expression', 'MPA', (113, 123))	('elevated', 'PosReg', (90, 98))	('KEAP1', 'Gene', (64, 69))	('NRF2', 'Gene', (128, 132))	('mutant', 'Var', (70, 76))	('patients', 'Species', '9606', (77, 85))	('onco-lncRNA-3', 'Gene', '100128338', (99, 112))	('onco-lncRNA-3', 'Gene', (99, 112))	('NRF2', 'Gene', '4780', (128, 132))
92045	25864709	For instance, antisense lncRNAs typically regulate protein-coding genes in close proximity whereas cytoplasmic competing endogenous RNAs (ceRNAs) will compete with cancer genes harboring similar microRNA binding sites to modulate expression.	('microRNA binding', 'molecular_function', 'GO:0035198', ('195', '211'))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('expression', 'MPA', (230, 240))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('protein-coding', 'Protein', (51, 65))	('antisense', 'Var', (14, 23))	('regulate', 'Reg', (42, 50))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
92066	25864709	The remaining transcripts were TMM normalized, then edgeR version 3.0.8 was used to test for differential expression between the tumor and normal pairs using a matched pair design with cutoffs of FDR <= 10-5 and absolute fold change >=2.	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('FDR <=', 'Var', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (129, 134))
92079	25864709	2) and mutated in > 5% of tumors with RNA-Seq data.	('RNA', 'cellular_component', 'GO:0005562', ('38', '41'))	('tumors', 'Disease', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mutated', 'Var', (7, 14))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
92098	25864709	The following siRNA sequences were used for knockdown of CCAT1: CCAT1 siRNA 1 (5'-UGUGGUAGGAAAGAGAAAUGAAUGG-3'), CCAT1 siRNA 2 (5'-GACCACUGCUUUAAAGCCUUUGCAU-3') or a control (a scrambled-matched %GC oligonucleotide synthesized by Invitrogen).	('GC', 'Chemical', 'MESH:C057580', (146, 148))	('GC', 'Chemical', 'MESH:C057580', (138, 140))	('GC', 'Chemical', 'MESH:C057580', (152, 154))	('oligonucleotide', 'Chemical', 'MESH:D009841', (199, 214))	('CCAT1', 'Gene', '100507056', (57, 62))	('CCAT1', 'Gene', '100507056', (64, 69))	('knockdown', 'Var', (44, 53))	('GC', 'Chemical', 'MESH:C057580', (196, 198))	('CCAT1', 'Gene', (57, 62))	('CCAT1', 'Gene', (113, 118))	('CCAT1', 'Gene', '100507056', (113, 118))	('CCAT1', 'Gene', (64, 69))
92177	33492438	In fact, the activity of AR-42 was superior to that of vorinostat in Burkitt lymphoma mouse models.	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (69, 85))	('mouse', 'Species', '10090', (86, 91))	('vorinostat', 'Chemical', 'MESH:D000077337', (55, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (77, 85))	('activity', 'MPA', (13, 21))	('Burkitt lymphoma', 'Disease', (69, 85))	('AR-42', 'Chemical', 'MESH:C524513', (25, 30))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (69, 85))	('AR-42', 'Var', (25, 30))
92287	33492438	The NF2 gene encodes the tumor suppressor protein merlin and loss of merlin in NF2 results in proliferation of Schwann and leptomeningeal cells, in part through activation of the PI3K/AKT pathway.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('25', '41'))	('NF2', 'Gene', '4771', (79, 82))	('merlin', 'Gene', (69, 75))	('loss of', 'Var', (61, 68))	('tumor suppressor', 'biological_process', 'GO:0051726', ('25', '41'))	('NF2', 'Gene', (79, 82))	('AKT', 'Gene', '207', (184, 187))	('proliferation', 'CPA', (94, 107))	('activation', 'PosReg', (161, 171))	('merlin', 'Gene', (50, 56))	('merlin', 'Gene', '4771', (69, 75))	('tumor', 'Disease', (25, 30))	('PI3K', 'molecular_function', 'GO:0016303', ('179', '183'))	('NF2', 'Gene', '4771', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('NF2', 'Gene', (4, 7))	('merlin', 'Gene', '4771', (50, 56))	('AKT', 'Gene', (184, 187))
92288	33492438	AR-42 dephosphorylates and deactivates AKT.	('AR-42', 'Chemical', 'MESH:C524513', (0, 5))	('AR-42', 'Var', (0, 5))	('AKT', 'Gene', '207', (39, 42))	('deactivates', 'NegReg', (27, 38))	('AKT', 'Gene', (39, 42))	('dephosphorylates', 'MPA', (6, 22))
92289	33492438	In preclinical studies in vitro, AR-42 decreased AKT phosphorylation and suppressed proliferation of schwannoma and meningioma cell lines by cell cycle arrest at G2 and apoptosis.	('apoptosis', 'CPA', (169, 178))	('apoptosis', 'biological_process', 'GO:0097194', ('169', '178'))	('AKT', 'Gene', (49, 52))	('schwannoma', 'Phenotype', 'HP:0100008', (101, 111))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (141, 158))	('AR-42', 'Var', (33, 38))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('141', '158'))	('schwannoma and meningioma', 'Disease', 'MESH:D009442', (101, 126))	('arrest', 'Disease', (152, 158))	('apoptosis', 'biological_process', 'GO:0006915', ('169', '178'))	('arrest', 'Disease', 'MESH:D006323', (152, 158))	('meningioma', 'Phenotype', 'HP:0002858', (116, 126))	('proliferation', 'CPA', (84, 97))	('suppressed', 'NegReg', (73, 83))	('AKT', 'Gene', '207', (49, 52))	('decreased', 'NegReg', (39, 48))	('AR-42', 'Chemical', 'MESH:C524513', (33, 38))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))
92297	33492438	Specifically AR-42 has shown preclinical activity when combined with decitabine for AML, doxorubicin for osteosarcoma, 5-FU for breast cancer, cisplatin for urothelial carcinoma, and pazopanib for melanoma cells resistant to trametinib plus dabrafenib.	('doxorubicin', 'Chemical', 'MESH:D004317', (89, 100))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (157, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('melanoma', 'Disease', (197, 205))	('AR-42', 'Chemical', 'MESH:C524513', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('urothelial carcinoma', 'Disease', (157, 177))	('osteosarcoma', 'Disease', (105, 117))	('osteosarcoma', 'Disease', 'MESH:D012516', (105, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('5-FU', 'Chemical', 'MESH:D005472', (119, 123))	('decitabine', 'Chemical', 'MESH:D000077209', (69, 79))	('AR-42', 'Var', (13, 18))	('pazopanib', 'Chemical', 'MESH:C516667', (183, 192))	('trametinib', 'Chemical', 'MESH:C560077', (225, 235))	('AML', 'Disease', 'MESH:D015470', (84, 87))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('AML', 'Phenotype', 'HP:0004808', (84, 87))	('AML', 'Disease', (84, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (105, 117))	('dabrafenib', 'Chemical', 'MESH:C561627', (241, 251))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))
92298	33492438	A recent preclinical study also demonstrated potential for AR-42 to overcome anabolic resistance in cancer-associated cachexia.	('cachexia', 'Disease', (118, 126))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('AR-42', 'Chemical', 'MESH:C524513', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cachexia', 'Phenotype', 'HP:0004326', (118, 126))	('anabolic resistance', 'MPA', (77, 96))	('AR-42', 'Var', (59, 64))	('cancer', 'Disease', (100, 106))	('overcome', 'PosReg', (68, 76))	('cachexia', 'Disease', 'MESH:D002100', (118, 126))
92303	33492438	Unfortunately, despite encouraging preclinical studies, in a phase II study that enrolled patients with urothelial carcinoma with mutations or deletions in CREB binding protein (CREBBP) and/or E1A binding protein p300 (EP300), mocetinostat failed to show efficacy.	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('EP300', 'Gene', '2033', (219, 224))	('CREBBP', 'Gene', (178, 184))	('CREB binding protein', 'Gene', (156, 176))	('EP300', 'Gene', (219, 224))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('E1A binding protein p300', 'Gene', (193, 217))	('CREBBP', 'Gene', '1387', (178, 184))	('E1A binding protein p300', 'Gene', '2033', (193, 217))	('CREB binding protein', 'Gene', '1387', (156, 176))	('mocetinostat', 'Chemical', 'MESH:C523184', (227, 239))	('CREB binding', 'molecular_function', 'GO:0008140', ('156', '168'))	('patients', 'Species', '9606', (90, 98))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (104, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('deletions', 'Var', (143, 152))	('mutations', 'Var', (130, 139))	('binding', 'molecular_function', 'GO:0005488', ('197', '204'))	('urothelial carcinoma', 'Disease', (104, 124))
92304	33492438	However, for example, mutations in BRCA1-associated protein (BAP1), which predispose to mesotheliomas, uveal melanomas, cutaneous melanoma, and renal cell carcinoma, dysregulate HDAC proteins and sensitize cells to HDAC inhibitors.	('HDAC', 'Gene', '9734', (178, 182))	('dysregulate HDAC proteins', 'Disease', (166, 191))	('HDAC', 'Gene', '9734', (215, 219))	('uveal melanomas', 'Disease', (103, 118))	('uveal melanomas', 'Phenotype', 'HP:0007716', (103, 118))	('mesotheliomas', 'Disease', (88, 101))	('HDAC', 'Gene', (178, 182))	('BRCA1-associated protein', 'Gene', '8315', (35, 59))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (144, 164))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('HDAC', 'Gene', (215, 219))	('mesotheliomas', 'Disease', 'MESH:D008654', (88, 101))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('BAP1', 'Gene', '8314', (61, 65))	('BRCA1-associated protein', 'Gene', (35, 59))	('mutations', 'Var', (22, 31))	('renal cell carcinoma', 'Disease', (144, 164))	('dysregulate HDAC proteins', 'Disease', 'MESH:D021081', (166, 191))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (144, 164))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('BAP1', 'Gene', (61, 65))	('uveal melanomas', 'Disease', 'MESH:C536494', (103, 118))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('sensitize', 'Reg', (196, 205))	('cutaneous melanoma', 'Disease', (120, 138))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (120, 138))
92305	33492438	Targeting solid tumors with BAP1 mutations may reveal a subset of patients that respond to AR-42.	('AR-42', 'Chemical', 'MESH:C524513', (91, 96))	('BAP1', 'Gene', '8314', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('BAP1', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (33, 42))	('solid tumors', 'Disease', (10, 22))	('solid tumors', 'Disease', 'MESH:D009369', (10, 22))	('patients', 'Species', '9606', (66, 74))
92325	33494738	Transurethral resection of bladder tumor followed by intravesical administration with Bacillus Calmette-Guerin or chemotherapy agents such as mitomycin, valrubicin, or gemcitabine is usually associated with a high incidence of local and systemic side effects, such as cystitis-like irritative voiding symptoms, hematuria, skin rash, arthralgia, fever, and influenza-like symptoms, which result in treatment discontinuation in 4-7% of patients.	('arthralgia', 'Disease', (333, 343))	('hematuria', 'Disease', (311, 320))	('skin rash', 'Disease', 'MESH:D005076', (322, 331))	('associated', 'Reg', (191, 201))	('-like irritative', 'Phenotype', 'HP:0000737', (276, 292))	('mitomycin', 'Chemical', 'MESH:D016685', (142, 151))	('bladder tumor', 'Phenotype', 'HP:0009725', (27, 40))	('cystitis-like irritative', 'Disease', 'MESH:D003556', (268, 292))	('patients', 'Species', '9606', (434, 442))	('gemcitabine', 'Chemical', 'MESH:C056507', (168, 179))	('Transurethral', 'Var', (0, 13))	('hematuria', 'Disease', 'MESH:D006417', (311, 320))	('skin rash', 'Phenotype', 'HP:0000988', (322, 331))	('influenza-like symptoms', 'Disease', (356, 379))	('hematuria', 'Phenotype', 'HP:0000790', (311, 320))	('Bacillus Calmette-Guerin', 'Species', '33892', (86, 110))	('fever', 'Disease', 'MESH:D005334', (345, 350))	('fever', 'Disease', (345, 350))	('cystitis-like irritative', 'Disease', (268, 292))	('bladder tumor', 'Disease', (27, 40))	('fever', 'Phenotype', 'HP:0001945', (345, 350))	('bladder tumor', 'Disease', 'MESH:D001749', (27, 40))	('arthralgia', 'Phenotype', 'HP:0002829', (333, 343))	('valrubicin', 'Chemical', 'MESH:C016163', (153, 163))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('arthralgia', 'Disease', 'MESH:D018771', (333, 343))	('skin rash', 'Disease', (322, 331))	('mitomycin', 'Var', (142, 151))
92361	33494738	After identifying the ingredients that met the criteria of predicted OB >= 30% and DL >= 0.18, seven active ingredients were finally retrieved: diosgenin (MOL000546), medioresinol (MOL002058), solanocapsine (MOL007356), quercetin (MOL000098), cholesterol (MOL000953), beta-carotene (MOL002773), and sitosterol (MOL000359) (as shown in Table 1).	('MOL000098', 'Var', (231, 240))	('MOL007356', 'Var', (208, 217))	('MOL002058', 'Var', (181, 190))	('cholesterol', 'Chemical', 'MESH:D002784', (243, 254))	('medioresinol', 'Chemical', 'MESH:C576388', (167, 179))	('MOL002773', 'Var', (283, 292))	('solanocapsine', 'Chemical', '-', (193, 206))	('quercetin', 'Chemical', 'MESH:D011794', (220, 229))	('sitosterol', 'Chemical', 'MESH:C025473', (299, 309))	('MOL000359', 'Var', (311, 320))	('OB', 'Disease', 'MESH:D009765', (69, 71))	('diosgenin', 'Chemical', 'MESH:D004144', (144, 153))	('MOL000953', 'Var', (256, 265))	('beta-carotene', 'Chemical', 'MESH:D019207', (268, 281))	('MOL000546', 'Var', (155, 164))
92372	33494738	In summary, these genes were enriched in multiple pathways known to contribute to the tumorigenesis and progression of BC, such as the HIF-1 signaling pathway (hsa04066), bladder cancer pathway (hsa05219), apoptosis pathway (hsa04210), tumor necrosis factor (TNF) signaling pathway (hsa04668), p53 signaling pathway (hsa04115), mitogen-activated protein kinase (MAPK) signaling pathway (hsa04010), and PI3K/Akt signaling pathway (hsa04151).	('PI3K', 'molecular_function', 'GO:0016303', ('402', '406'))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('signaling pathway', 'biological_process', 'GO:0007165', ('411', '428'))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor necrosis', 'Disease', 'MESH:D009336', (236, 250))	('hsa04151', 'Var', (430, 438))	('signaling pathway', 'biological_process', 'GO:0007165', ('141', '158'))	('p53', 'Gene', '7157', (294, 297))	('signaling pathway', 'biological_process', 'GO:0007165', ('264', '281'))	('TNF', 'Gene', '7124', (259, 262))	('hsa04010', 'Var', (387, 395))	('HIF-1', 'Gene', '3091', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor necrosis', 'Disease', (236, 250))	('necrosis', 'biological_process', 'GO:0008220', ('242', '250'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('236', '257'))	('HIF-1', 'Gene', (135, 140))	('contribute', 'Reg', (68, 78))	('Akt signaling', 'biological_process', 'GO:0043491', ('407', '420'))	('BC', 'Phenotype', 'HP:0009725', (119, 121))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('protein', 'cellular_component', 'GO:0003675', ('346', '353'))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('362', '377'))	('p53', 'Gene', (294, 297))	('necrosis', 'biological_process', 'GO:0070265', ('242', '250'))	('signaling pathway', 'biological_process', 'GO:0007165', ('368', '385'))	('necrosis', 'biological_process', 'GO:0019835', ('242', '250'))	('necrosis', 'biological_process', 'GO:0001906', ('242', '250'))	('MAPK', 'molecular_function', 'GO:0004707', ('362', '366'))	('bladder cancer', 'Disease', 'MESH:D001749', (171, 185))	('bladder cancer', 'Disease', (171, 185))	('p53 signaling pathway', 'biological_process', 'GO:0030330', ('294', '315'))	('Akt', 'Gene', (407, 410))	('tumor', 'Disease', (236, 241))	('apoptosis', 'biological_process', 'GO:0097194', ('206', '215'))	('apoptosis', 'biological_process', 'GO:0006915', ('206', '215'))	('Akt', 'Gene', '207', (407, 410))	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('tumor', 'Disease', (86, 91))	('hsa04115', 'Var', (317, 325))	('TNF', 'Gene', (259, 262))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('apoptosis pathway', 'Pathway', (206, 223))	('necrosis', 'biological_process', 'GO:0008219', ('242', '250'))
92375	33494738	S. nigrum may exert anti-tumor effects in BC patients mainly by regulating the BC pathway (hsa05219), MAPK signaling pathway (hsa04010), HIF-1 signaling pathway (hsa04066), TNF signaling pathway (hsa04668), apoptosis signaling pathway (hsa04210), PI3K-Akt signaling pathway (hsa04151), p53 signaling pathway (hsa04115), and NF-kappa B signaling pathway (hsa04064).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('hsa04066', 'Var', (162, 170))	('regulating', 'Reg', (64, 74))	('Akt', 'Gene', (252, 255))	('MAPK', 'molecular_function', 'GO:0004707', ('102', '106'))	('signaling pathway', 'biological_process', 'GO:0007165', ('217', '234'))	('S. nigrum', 'Species', '4112', (0, 9))	('NF-kappa B', 'Gene', (324, 334))	('signaling pathway', 'biological_process', 'GO:0007165', ('256', '273'))	('patients', 'Species', '9606', (45, 53))	('apoptosis signaling pathway', 'Pathway', (207, 234))	('hsa04668', 'Var', (196, 204))	('HIF-1', 'Gene', '3091', (137, 142))	('signaling pathway', 'biological_process', 'GO:0007165', ('143', '160'))	('hsa05219', 'Var', (91, 99))	('Akt', 'Gene', '207', (252, 255))	('HIF-1', 'Gene', (137, 142))	('apoptosis signaling', 'biological_process', 'GO:0006915', ('207', '226'))	('p53', 'Gene', '7157', (286, 289))	('signaling pathway', 'biological_process', 'GO:0007165', ('107', '124'))	('signaling pathway', 'biological_process', 'GO:0007165', ('335', '352'))	('p53 signaling pathway', 'biological_process', 'GO:0030330', ('286', '307'))	('BC', 'Phenotype', 'HP:0009725', (79, 81))	('hsa04064', 'Var', (354, 362))	('tumor', 'Disease', (25, 30))	('p53', 'Gene', (286, 289))	('TNF', 'Gene', (173, 176))	('hsa04210', 'Var', (236, 244))	('Akt signaling', 'biological_process', 'GO:0043491', ('252', '265'))	('hsa04151', 'Var', (275, 283))	('signaling pathway', 'biological_process', 'GO:0007165', ('177', '194'))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('NF-kappa B', 'Gene', '4790', (324, 334))	('MAPK signaling', 'biological_process', 'GO:0000165', ('102', '116'))	('BC pathway', 'Pathway', (79, 89))	('PI3K', 'molecular_function', 'GO:0016303', ('247', '251'))	('hsa04115', 'Var', (309, 317))	('MAPK signaling pathway', 'Pathway', (102, 124))	('TNF', 'Gene', '7124', (173, 176))	('hsa04010', 'Var', (126, 134))	('BC', 'Phenotype', 'HP:0009725', (42, 44))
92395	33494738	Notably, unlike the other active ingredients, cholesterol in high content promotes inflammatory environments via the production of different cytokines, such as CXCL9 and CXCL10, but it also characterizes tumors, including breast, prostate, ovarian, lymphoma, colorectal cancer, and renal cell carcinoma, with poor prognosis.	('lymphoma', 'Phenotype', 'HP:0002665', (249, 257))	('prostate', 'Disease', (230, 238))	('colorectal cancer', 'Phenotype', 'HP:0003003', (259, 276))	('cholesterol', 'Var', (46, 57))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('renal cell carcinoma', 'Disease', (282, 302))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (282, 302))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumors', 'Disease', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('promotes', 'PosReg', (74, 82))	('ovarian, lymphoma', 'Disease', 'MESH:D010049', (240, 257))	('cholesterol', 'Chemical', 'MESH:D002784', (46, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (259, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('inflammatory environments', 'MPA', (83, 108))	('colorectal cancer', 'Disease', (259, 276))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (282, 302))	('breast', 'Disease', (222, 228))
92405	33494738	Numerous studies have demonstrated that the aberrant expression of IL-6 and its receptor correlates with malignant phenotypes of multiple tumors, as well as the diagnosis, prognosis, and treatment of cancer.	('multiple tumors', 'Disease', (129, 144))	('IL-6', 'molecular_function', 'GO:0005138', ('67', '71'))	('correlates', 'Reg', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('IL-6', 'Gene', (67, 71))	('IL-6', 'Gene', '3569', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('multiple tumors', 'Disease', 'MESH:D009369', (129, 144))	('cancer', 'Disease', (200, 206))	('aberrant expression', 'Var', (44, 63))
92417	33494738	In addition to relaying the oncogenic signals from the upstream PI3K/AKT pathway in various cancers, mTOR may play a direct role in human tumorigenesis if mutated, including in BC, which further support the view of mTOR as one of the major therapeutic target against cancer.	('BC', 'Phenotype', 'HP:0009725', (177, 179))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('tumor', 'Disease', (138, 143))	('mTOR', 'Gene', '2475', (101, 105))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('mutated', 'Var', (155, 162))	('AKT', 'Gene', (69, 72))	('mTOR', 'Gene', (215, 219))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('PI3K', 'molecular_function', 'GO:0016303', ('64', '68'))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', (92, 98))	('mTOR', 'Gene', '2475', (215, 219))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('AKT', 'Gene', '207', (69, 72))	('mTOR', 'Gene', (101, 105))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', (92, 99))	('human', 'Species', '9606', (132, 137))
92423	33494738	In addition, S. nigrum could attenuate the malignant phenotype and tumor growth through the MAPK/mTOR signaling pathway in hepatocellular carcinoma and the p38 signaling pathway in prostate cancer cells.	('signaling pathway', 'biological_process', 'GO:0007165', ('102', '119'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (123, 147))	('tumor', 'Disease', (67, 72))	('attenuate', 'NegReg', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('mTOR', 'Gene', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (123, 147))	('p38 signaling pathway', 'Pathway', (156, 177))	('MAPK', 'molecular_function', 'GO:0004707', ('92', '96'))	('malignant phenotype', 'CPA', (43, 62))	('mTOR', 'Gene', '2475', (97, 101))	('signaling pathway', 'biological_process', 'GO:0007165', ('160', '177'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('S. nigrum', 'Species', '4112', (13, 22))	('hepatocellular carcinoma', 'Disease', (123, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('prostate cancer', 'Disease', 'MESH:D011471', (181, 196))	('prostate cancer', 'Phenotype', 'HP:0012125', (181, 196))	('S. nigrum', 'Var', (13, 22))	('prostate cancer', 'Disease', (181, 196))
92427	33494738	Moreover, S. nigrum decreased blood serum TNF-alpha levels, which is consistent with the triggering of apoptosis in tumor cells.	('TNF', 'Gene', (42, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('decreased', 'NegReg', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('S. nigrum', 'Var', (10, 19))	('TNF', 'Gene', '7124', (42, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('S. nigrum', 'Species', '4112', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
92428	33494738	Angiogenesis also plays a major role in different stages of tumor progression; therefore, some related pathways, such as the VEGF signaling pathway (hsa04370, degree = 6) and the HIF-1 signaling pathway (hsa04066, degree = 11), have been identified as the target pathways for treating BC.	('VEGF signaling pathway', 'Pathway', (125, 147))	('VEGF signaling', 'biological_process', 'GO:0038084', ('125', '139'))	('BC', 'Phenotype', 'HP:0009725', (285, 287))	('Angiogenesis', 'biological_process', 'GO:0001525', ('0', '12'))	('hsa04066', 'Var', (204, 212))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('signaling pathway', 'biological_process', 'GO:0007165', ('130', '147'))	('HIF-1', 'Gene', '3091', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('signaling pathway', 'biological_process', 'GO:0007165', ('185', '202'))	('hsa04370', 'Var', (149, 157))	('tumor', 'Disease', (60, 65))	('HIF-1', 'Gene', (179, 184))
92453	31820796	What's more, genome sequencing studies revealed that the genetic variations of NB tumor are markedly lower than that found in many other adult solid tumors, indicating the importance of post-translational modification in the occurrence and development of NB.	('genetic variations', 'Var', (57, 75))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('NB', 'Phenotype', 'HP:0003006', (255, 257))	('NB tumor', 'Disease', 'MESH:D009369', (79, 87))	('lower', 'NegReg', (101, 106))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('NB', 'Phenotype', 'HP:0003006', (79, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('post-translational modification', 'biological_process', 'GO:0043687', ('186', '217'))	('NB tumor', 'Disease', (79, 87))
92457	31820796	In recent years, accumulating studies have found that TRIM proteins regulate a wide variety of biological processes and their dysregulation are associated with various diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('regulate', 'Reg', (68, 76))	('associated', 'Reg', (144, 154))	('dysregulation', 'Var', (126, 139))	('TRIM proteins', 'Protein', (54, 67))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))
92462	31820796	For instance, TRIM16 has been shown to increase histone acetylation and reactivate the transcription of retinoic acid receptor beta2 (RARbeta2) in retinoid-resistant breast and lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('retinoid-resistant breast and lung cancer', 'Disease', 'MESH:D001943', (147, 188))	('RARbeta', 'Gene', (134, 141))	('RARbeta', 'Gene', '5914', (134, 141))	('retinoic acid receptor beta', 'Gene', '5915', (104, 131))	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))	('transcription', 'MPA', (87, 100))	('retinoic acid receptor beta', 'Gene', (104, 131))	('reactivate', 'MPA', (72, 82))	('histone acetylation', 'biological_process', 'GO:0016573', ('48', '67'))	('increase', 'PosReg', (39, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('TRIM16', 'Var', (14, 20))	('histone acetylation', 'MPA', (48, 67))
92481	31820796	In addition, it has been reported that PHOX2B germline mutations, which account for 6% hereditary NBs, are involved in the initiation of NB tumorigenesis.	('NB tumor', 'Disease', 'MESH:D009369', (137, 145))	('NB', 'Phenotype', 'HP:0003006', (137, 139))	('NB', 'Phenotype', 'HP:0003006', (98, 100))	('NB tumor', 'Disease', (137, 145))	('involved', 'Reg', (107, 115))	('NBs', 'Disease', (98, 101))	('PHOX2B', 'Gene', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('NBs', 'Disease', 'None', (98, 101))	('germline', 'Var', (46, 54))	('PHOX2B', 'Gene', '8929', (39, 45))
92484	31820796	For example, the expression of TRIM16 is significantly down-regulated in HCC and knockdown of TRIM16 enhances HCC cell migration and invasion via the promotion of EMT process.	('HCC', 'Gene', '619501', (73, 76))	('HCC', 'Phenotype', 'HP:0001402', (73, 76))	('HCC', 'Phenotype', 'HP:0001402', (110, 113))	('TRIM16', 'Gene', (94, 100))	('invasion', 'CPA', (133, 141))	('expression', 'MPA', (17, 27))	('cell migration', 'biological_process', 'GO:0016477', ('114', '128'))	('knockdown', 'Var', (81, 90))	('HCC', 'Gene', (110, 113))	('down-regulated', 'NegReg', (55, 69))	('HCC', 'Gene', (73, 76))	('EMT process', 'CPA', (163, 174))	('promotion', 'PosReg', (150, 159))	('TRIM16', 'Gene', (31, 37))	('HCC', 'Gene', '619501', (110, 113))	('EMT', 'biological_process', 'GO:0001837', ('163', '166'))	('enhances', 'PosReg', (101, 109))
92489	31820796	First, TRIM16 can enhance the transcription of retinoic acid receptor beta (RARbeta), and overexpression of TRIM16 significantly reduces the proliferation of RA-sensitive NB cells as well as RA-resistant lung and breast cancer cells.	('RARbeta', 'Gene', '5914', (76, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('RA', 'Chemical', 'MESH:D011883', (191, 193))	('TRIM16', 'Var', (108, 114))	('transcription', 'biological_process', 'GO:0006351', ('30', '43'))	('RA', 'Chemical', 'MESH:D011883', (158, 160))	('reduces', 'NegReg', (129, 136))	('NB', 'Phenotype', 'HP:0003006', (171, 173))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('breast cancer', 'Disease', (213, 226))	('proliferation', 'CPA', (141, 154))	('RA-sensitive NB', 'Disease', (158, 173))	('transcription', 'MPA', (30, 43))	('RA', 'Chemical', 'MESH:D011883', (76, 78))	('retinoic acid receptor beta', 'Gene', '5915', (47, 74))	('retinoic acid receptor beta', 'Gene', (47, 74))	('RARbeta', 'Gene', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('TRIM16', 'Var', (7, 13))	('enhance', 'PosReg', (18, 25))
92491	31820796	Further investigation showed that TRIM16 can reactivate the transcription of RARbeta2 by increasing histone H3 acetylation, with the de-acetylation of histone H3 considered to be the most common mechanism of RARbeta2 transcriptional repression in retinoid-resistant cancer cells.	('acetylation', 'MPA', (111, 122))	('RARbeta', 'Gene', (77, 84))	('RARbeta', 'Gene', '5914', (77, 84))	('histone H3 acetylation', 'biological_process', 'GO:0043966', ('100', '122'))	('TRIM16', 'Var', (34, 40))	('RARbeta', 'Gene', (208, 215))	('histone', 'MPA', (100, 107))	('RARbeta', 'Gene', '5914', (208, 215))	('transcription', 'biological_process', 'GO:0006351', ('60', '73'))	('increasing', 'PosReg', (89, 99))	('retinoid-resistant cancer', 'Disease', (247, 272))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('transcription', 'MPA', (60, 73))	('retinoid-resistant cancer', 'Disease', 'MESH:D009369', (247, 272))
92492	31820796	These studies suggest that TRIM16 may modulate the transcriptional activity of RA-related receptors that required for NB cell differentiation and could be a novel therapeutic target for retinoid-resistant NB cancer.	('retinoid-resistant NB cancer', 'Disease', 'MESH:D009369', (186, 214))	('RA', 'Chemical', 'MESH:D011883', (79, 81))	('transcriptional activity', 'MPA', (51, 75))	('RA-related receptors', 'Protein', (79, 99))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('TRIM16', 'Var', (27, 33))	('cell differentiation', 'biological_process', 'GO:0030154', ('121', '141'))	('retinoid-resistant NB cancer', 'Disease', (186, 214))	('NB', 'Phenotype', 'HP:0003006', (118, 120))	('NB', 'Phenotype', 'HP:0003006', (205, 207))	('modulate', 'Reg', (38, 46))
92493	31820796	Second, TRIM16 can affect the migration and differentiation of NB cell through down-regulating vimentin and nuclear E2F1 protein (required for cell replication).	('down-regulating', 'NegReg', (79, 94))	('vimentin', 'cellular_component', 'GO:0045099', ('95', '103'))	('vimentin', 'cellular_component', 'GO:0045098', ('95', '103'))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('affect', 'Reg', (19, 25))	('vimentin', 'Gene', '386601', (95, 103))	('vimentin', 'Gene', (95, 103))	('E2F1', 'Gene', '100036852', (116, 120))	('NB', 'Phenotype', 'HP:0003006', (63, 65))	('E2F1', 'Gene', (116, 120))	('migration', 'CPA', (30, 39))	('differentiation', 'CPA', (44, 59))	('TRIM16', 'Var', (8, 14))
92495	31820796	Third, TRIM16 can promote the apoptosis of BE(2)-C NB cells by directly interacting with caspase-2 and modulating its activity.	('activity', 'MPA', (118, 126))	('apoptosis', 'CPA', (30, 39))	('apoptosis', 'biological_process', 'GO:0006915', ('30', '39'))	('modulating', 'Reg', (103, 113))	('TRIM16', 'Var', (7, 13))	('NB', 'Phenotype', 'HP:0003006', (51, 53))	('caspase-2', 'Gene', '835', (89, 98))	('interacting', 'Interaction', (72, 83))	('BE', 'Chemical', 'MESH:D001608', (43, 45))	('promote', 'PosReg', (18, 25))	('caspase-2', 'Gene', (89, 98))	('apoptosis', 'biological_process', 'GO:0097194', ('30', '39'))
92499	31820796	Unlike majority of TRIM proteins, such as TRIM5alpha, TRIM6, TRIM20 and TRIM21, which have been demonstrated to promote autophagy, TRIM17 is notable because it can inhibit autophagy.	('TRIM5alpha', 'Gene', (42, 52))	('autophagy', 'biological_process', 'GO:0016236', ('172', '181'))	('autophagy', 'biological_process', 'GO:0006914', ('120', '129'))	('autophagy', 'CPA', (172, 181))	('TRIM6', 'Gene', '117854', (54, 59))	('TRIM5alpha', 'Gene', '85363', (42, 52))	('autophagy', 'biological_process', 'GO:0006914', ('172', '181'))	('TRIM21', 'Gene', '6737', (72, 78))	('TRIM6', 'Gene', (54, 59))	('inhibit', 'NegReg', (164, 171))	('TRIM17', 'Var', (131, 137))	('TRIM21', 'Gene', (72, 78))	('TRIM20', 'Gene', (61, 67))	('TRIM20', 'Gene', '4210', (61, 67))	('autophagy', 'biological_process', 'GO:0016236', ('120', '129'))
92501	31820796	TRIM17 has also been reported to stabilize BCL2A1, another anti-apoptotic Bcl-2 family protein that contributes to chemo-resistance in a subset of tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('stabilize', 'NegReg', (33, 42))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('TRIM17', 'Var', (0, 6))	('Bcl-2', 'Gene', '12043', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('Bcl-2', 'Gene', (74, 79))	('BCL2', 'molecular_function', 'GO:0015283', ('43', '47'))	('contributes', 'Reg', (100, 111))	('Bcl-2', 'molecular_function', 'GO:0015283', ('74', '79'))	('BCL2A1', 'Gene', (43, 49))	('BCL2A1', 'Gene', '597', (43, 49))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
92506	31820796	Mechanistically, TRIM32 is an E3 ubiquitin-ligase for some tumor suppressors, such as p53 and Abi2 (Abl-interactor 2) and can regulate their degradation.	('degradation', 'MPA', (141, 152))	('tumor', 'Disease', (59, 64))	('p53', 'Gene', '7157', (86, 89))	('regulate', 'Reg', (126, 134))	('Abi2', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('TRIM32', 'Var', (17, 23))	('Abi2', 'Gene', '10152', (94, 98))	('Abl-interactor 2', 'Gene', '10152', (100, 116))	('degradation', 'biological_process', 'GO:0009056', ('141', '152'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('33', '42'))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('Abl-interactor 2', 'Gene', (100, 116))	('p53', 'Gene', (86, 89))
92507	31820796	In addition, TRIM32 can promote the proliferation and invasion of gastric cancer cell lines by activating beta-catenin signaling pathway.	('beta-catenin', 'Gene', '1499', (106, 118))	('invasion', 'CPA', (54, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('TRIM32', 'Var', (13, 19))	('signaling pathway', 'biological_process', 'GO:0007165', ('119', '136'))	('promote', 'PosReg', (24, 31))	('proliferation', 'CPA', (36, 49))	('activating', 'Reg', (95, 105))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('beta-catenin', 'Gene', (106, 118))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
92509	31820796	Previously, several studies have shown the importance of TRIM32 in neuronal differentiation by several different mechanism as follows: First, TRIM32 can ubiquitylate and result in the proteasomal degradation of c-Myc, one of the key stem cell transcription factors (SCTFs) crucial for neuronal stem cell (NSC) renewal and maintaining an undifferentiated phenotype.	('result in', 'Reg', (170, 179))	('NSC', 'Disease', (305, 308))	('TRIM32', 'Var', (57, 63))	('transcription', 'biological_process', 'GO:0006351', ('243', '256'))	('proteasomal degradation', 'MPA', (184, 207))	('ubiquitylate', 'MPA', (153, 165))	('c-Myc', 'Gene', '4609', (211, 216))	('degradation', 'biological_process', 'GO:0009056', ('196', '207'))	('NSC', 'Disease', 'OMIM:617394', (305, 308))	('c-Myc', 'Gene', (211, 216))	('TRIM32', 'Var', (142, 148))
92510	31820796	Second, TRIM32 can interact with RARalpha and enhance its transcriptional activity, bringing about enhancement of neural differentiation.	('TRIM32', 'Var', (8, 14))	('transcriptional activity', 'MPA', (58, 82))	('neural differentiation', 'CPA', (114, 136))	('RARalpha', 'Gene', '5914', (33, 41))	('enhancement', 'PosReg', (99, 110))	('interact', 'Interaction', (19, 27))	('enhance', 'PosReg', (46, 53))	('RARalpha', 'Gene', (33, 41))
92512	31820796	Indeed, TRIM32 concentrates in one of the daughter cells during mitosis, where it interacts with MYCN and facilitates its proteasomal degradation, thus inducing asymmetric cell division (ACD) of human NB cells, resulting in one cell with neural progenitor cell activity and the other with potential for differentiation.	('TRIM32', 'Var', (8, 14))	('human', 'Species', '9606', (195, 200))	('facilitates', 'PosReg', (106, 117))	('ACD', 'Phenotype', 'HP:0100555', (187, 190))	('NB', 'Phenotype', 'HP:0003006', (201, 203))	('mitosis', 'biological_process', 'GO:0000278', ('64', '71'))	('interacts', 'Interaction', (82, 91))	('asymmetric cell division', 'biological_process', 'GO:0008356', ('161', '185'))	('asymmetric cell division', 'CPA', (161, 185))	('MYCN', 'Gene', (97, 101))	('inducing', 'Reg', (152, 160))	('MYCN', 'Gene', '4613', (97, 101))	('degradation', 'biological_process', 'GO:0009056', ('134', '145'))	('proteasomal degradation', 'MPA', (122, 145))	('asymmetric cell division', 'Phenotype', 'HP:0100555', (161, 185))
92521	31820796	Furthermore, there is an observed trend for better survival in NB patients with high TRIM36 expression indicated by bioinformatic analysis of public available Kocak datasets, which were obtained from the R2 Genomics Analysis and Visualization Platform (http://r2.amc.nl) (Figure 2).	('TRIM36', 'Gene', '55521', (85, 91))	('better', 'PosReg', (44, 50))	('expression', 'MPA', (92, 102))	('NB', 'Phenotype', 'HP:0003006', (63, 65))	('TRIM36', 'Gene', (85, 91))	('high', 'Var', (80, 84))	('patients', 'Species', '9606', (66, 74))
92524	31820796	TRIM59, also known as mouse ring finger protein 1 (MRF1), belongs to the C-XI TRIM subfamily with a RING finger, one B-box domain, a coiled-coil domain and a C-terminal trans-membrane region.	('TRIM59', 'Var', (0, 6))	('membrane region', 'cellular_component', 'GO:0098589', ('175', '190'))	('MRF1', 'Gene', '66949', (51, 55))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('MRF1', 'Gene', (51, 55))	('ring finger protein 1', 'Gene', (28, 49))	('coiled-coil', 'MPA', (133, 144))	('mouse', 'Species', '10090', (22, 27))	('ring finger protein 1', 'Gene', '19763', (28, 49))
92527	31820796	For instance, TRIM59 is highly expressed and acts as an early signal transducer of Ras signaling pathway in prostate cancer (CaP) mouse models, whereas the silencing of TRIM59 results in inhibition of cell growth and S-phase arrest in CaP cells.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('inhibition', 'NegReg', (187, 197))	('silencing', 'Var', (156, 165))	('cell growth', 'CPA', (201, 212))	('prostate cancer', 'Disease', 'MESH:D011471', (108, 123))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('187', '212'))	('signaling pathway', 'biological_process', 'GO:0007165', ('87', '104'))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('arrest', 'Disease', 'MESH:D006323', (225, 231))	('TRIM59', 'Gene', (169, 175))	('arrest', 'Disease', (225, 231))	('S-phase', 'biological_process', 'GO:0051320', ('217', '224'))	('Ras signaling pathway', 'Pathway', (83, 104))	('mouse', 'Species', '10090', (130, 135))	('prostate cancer', 'Disease', (108, 123))
92529	31820796	A study in glioblastoma (GBM) cells suggests that TRIM59 promotes GBM tumorigenesis through interaction with nuclear STAT3 and maintains its transcriptional activation by preventing its dephosphorylation.	('transcriptional activation', 'MPA', (141, 167))	('nuclear', 'Protein', (109, 116))	('dephosphorylation', 'MPA', (186, 203))	('preventing', 'NegReg', (171, 181))	('GBM', 'Gene', (66, 69))	('STAT3', 'Gene', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TRIM59', 'Var', (50, 56))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('STAT3', 'Gene', '6774', (117, 122))	('glioblastoma', 'Disease', 'MESH:D005909', (11, 23))	('interaction', 'Interaction', (92, 103))	('GBM', 'Phenotype', 'HP:0012174', (25, 28))	('dephosphorylation', 'biological_process', 'GO:0016311', ('186', '203'))	('glioblastoma', 'Disease', (11, 23))	('glioblastoma', 'Phenotype', 'HP:0012174', (11, 23))	('promotes', 'PosReg', (57, 65))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
92530	31820796	Intriguingly, TRIM59 can induce the expression of ANXA2, a protein that has been reported to enhance multidrug resistance in NB from work in my laboratory.	('TRIM59', 'Var', (14, 20))	('drug resistance', 'Phenotype', 'HP:0020174', (106, 121))	('multidrug resistance', 'MPA', (101, 121))	('NB', 'Phenotype', 'HP:0003006', (125, 127))	('enhance', 'PosReg', (93, 100))	('ANXA2', 'Gene', '302', (50, 55))	('ANXA2', 'Gene', (50, 55))	('expression', 'MPA', (36, 46))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
92531	31820796	More interestingly, TRIM59 knockdown inhibits cell proliferation by downregulating the Wnt/beta-catenin signaling pathway in human NB cells.	('TRIM59', 'Gene', (20, 26))	('knockdown', 'Var', (27, 36))	('beta-catenin', 'Gene', (91, 103))	('human', 'Species', '9606', (125, 130))	('NB', 'Phenotype', 'HP:0003006', (131, 133))	('beta-catenin', 'Gene', '1499', (91, 103))	('signaling pathway', 'biological_process', 'GO:0007165', ('104', '121'))	('inhibits', 'NegReg', (37, 45))	('cell proliferation', 'CPA', (46, 64))	('downregulating', 'NegReg', (68, 82))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
92603	31692890	However, the mechanism or mechanisms by which aromatic amine-like chemicals promote carcinogenesis, cause recurrence and progression, and reduce survival remain unclear.	('carcinogenesis', 'Disease', (84, 98))	('promote', 'PosReg', (76, 83))	('aromatic', 'Var', (46, 54))	('aromatic amine', 'Chemical', 'MESH:C470200', (46, 60))	('progression', 'CPA', (121, 132))	('recurrence', 'CPA', (106, 116))	('cause', 'Reg', (100, 105))	('survival', 'CPA', (145, 153))	('carcinogenesis', 'Disease', 'MESH:D063646', (84, 98))	('reduce', 'NegReg', (138, 144))
92611	31692890	In contrast with the results of a previous study, the present study revealed that high ALP levels were associated with favorable CSS outcomes, which might be related to the relatively small subgroup of patients with elevated ALP levels (only 3.8% of patients had ALP levels of >129 IU/L).	('ALP', 'Gene', (87, 90))	('ALP', 'Gene', (225, 228))	('high', 'Var', (82, 86))	('ALP', 'Gene', (263, 266))	('CSS', 'Disease', (129, 132))	('patients', 'Species', '9606', (250, 258))	('ALP', 'Gene', '250', (87, 90))	('ALP', 'Gene', '250', (225, 228))	('patients', 'Species', '9606', (202, 210))	('high ALP', 'Phenotype', 'HP:0003155', (82, 90))	('ALP', 'Gene', '250', (263, 266))	('elevated ALP', 'Phenotype', 'HP:0003155', (216, 228))
92612	31692890	In this context, ALP is a well-known enzyme, and high levels are associated with poor outcomes and cancer cell proliferation in various non-liver cancers.	('cancers', 'Disease', (146, 153))	('cancer', 'Disease', (146, 152))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('high levels', 'Var', (49, 60))	('liver cancers', 'Phenotype', 'HP:0002896', (140, 153))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cell proliferation', 'biological_process', 'GO:0008283', ('106', '124'))	('cancer', 'Disease', (99, 105))	('associated', 'Reg', (65, 75))	('ALP', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('ALP', 'Gene', '250', (17, 20))
92614	31692890	Among the 123 patients without a history of bladder cancer, pTis significantly predicted CSS (HR, 32.071; p=0.0168; Table 4), and similar results were reported in a previous study.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('predicted', 'Reg', (79, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (44, 58))	('pTis', 'Var', (60, 64))	('CSS', 'Disease', (89, 92))	('bladder cancer', 'Disease', (44, 58))	('bladder cancer', 'Disease', 'MESH:D001749', (44, 58))	('patients', 'Species', '9606', (14, 22))
92622	29552320	We conducted this study to identify which patients could benefit more from the treatment of programmed death-1 (PD-1)/programmed death-ligand1 (PD-L1) inhibitors.	('PD-L1', 'Gene', '29126', (144, 149))	('PD-1', 'Gene', (112, 116))	('PD-1', 'Gene', '5133', (112, 116))	('programmed death-1', 'Gene', (92, 110))	('programmed death-ligand1', 'Gene', (118, 142))	('programmed death-1', 'Gene', '5133', (92, 110))	('programmed death-ligand1', 'Gene', '29126', (118, 142))	('ligand', 'molecular_function', 'GO:0005488', ('135', '141'))	('inhibitors', 'Var', (151, 161))	('PD-L1', 'Gene', (144, 149))	('patients', 'Species', '9606', (42, 50))
92654	29552320	In total, 50of 213 (23.47%) patients with PD-L1 >= 5% level achieved objective responses, as compared with 66 objective responses out of 481 (13.72%) patients with PD-L1 < 5% level; therefore patients with higher-ratio of PD-L1-positive cells responded better to PD-1/PD-L1 antibodies (P = 3.78, OR = 0.41,95%CI:0.28-0.65; Figure 2B).	('PD-1', 'Gene', '5133', (263, 267))	('PD-L1', 'Gene', '29126', (164, 169))	('better', 'PosReg', (253, 259))	('PD-L1', 'Gene', '29126', (42, 47))	('PD-L1', 'Gene', '29126', (268, 273))	('PD-L1', 'Gene', (222, 227))	('>= 5% level', 'Var', (48, 59))	('patients', 'Species', '9606', (192, 200))	('responded', 'MPA', (243, 252))	('patients', 'Species', '9606', (150, 158))	('PD-L1', 'Gene', '29126', (222, 227))	('PD-L1', 'Gene', (164, 169))	('PD-L1', 'Gene', (42, 47))	('PD-L1', 'Gene', (268, 273))	('patients', 'Species', '9606', (28, 36))	('PD-1', 'Gene', (263, 267))
92669	29552320	This is likely that PD-1 antibodies are more sensitive to lower ratio of PD-L1-possitive cells, becausePD-1 antibodies block the interaction between PD-1 with PD-L1 and PD-L2, while PD-L1 antibodies only block the interaction between PD-1 with PD-L1.	('block', 'NegReg', (119, 124))	('PD-1', 'Gene', (234, 238))	('PD-1', 'Gene', (20, 24))	('PD-1', 'Gene', '5133', (234, 238))	('PD-1', 'Gene', '5133', (20, 24))	('PD-L1', 'Gene', (159, 164))	('PD-L1', 'Gene', (73, 78))	('PD-L1', 'Gene', '29126', (159, 164))	('PD-L2', 'Gene', '80380', (169, 174))	('PD-L1', 'Gene', '29126', (73, 78))	('PD-L1', 'Gene', (244, 249))	('PD-L1', 'Gene', (182, 187))	('PD-L1', 'Gene', '29126', (244, 249))	('PD-L1', 'Gene', '29126', (182, 187))	('PD-L2', 'Gene', (169, 174))	('PD-1', 'Gene', (103, 107))	('PD-1', 'Gene', '5133', (103, 107))	('interaction', 'Interaction', (129, 140))	('antibodies', 'Var', (108, 118))	('PD-1', 'Gene', (149, 153))	('PD-1', 'Gene', '5133', (149, 153))
92695	27873079	In non-small cell lung cancer (NSCLC), for example, targetable driver mutations such as EGFR, ALK, or ROS1 have been discovered.	('mutations', 'Var', (70, 79))	('ALK', 'Gene', '238', (94, 97))	('ROS1', 'Gene', (102, 106))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('NSCLC', 'Disease', (31, 36))	('ROS1', 'Gene', '6098', (102, 106))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('ALK', 'Gene', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('non-small cell lung cancer', 'Disease', (3, 29))	('EGFR', 'Gene', (88, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (31, 36))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))
92701	27873079	With the ability to partially reverse cancer immunosuppression, checkpoint inhibitors, in particular anti-CTLA-4 and anti-PD-1/PD-L1, have now been approved across histologies.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('PD-1', 'Gene', (122, 126))	('PD-1', 'Gene', '5133', (122, 126))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('anti-CTLA-4', 'Var', (101, 112))
92728	27873079	It was found that in those with at least 50% of tumor cells expressing PD-L1, progression free survival (PFS) was longer than in those who received docetaxel.	('progression free survival', 'CPA', (78, 103))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('docetaxel', 'Chemical', 'MESH:D000077143', (148, 157))	('PD-L1', 'Var', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('longer', 'PosReg', (114, 120))
92738	27873079	Further research into the disparate results in terms of tumor cell expression of PD-L1 by SP142 with atezolizumab versus SP263 with durvalumab is warranted.	('durvalumab', 'Chemical', 'MESH:C000613593', (132, 142))	('SP263', 'Chemical', '-', (121, 126))	('SP142', 'Chemical', '-', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('SP142', 'Var', (90, 95))	('PD-L1', 'Gene', (81, 86))	('tumor', 'Disease', (56, 61))	('atezolizumab', 'Chemical', 'MESH:C000594389', (101, 113))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
92745	27873079	The accumulation of cancer genomic errors results in microsatellite fragments that can be detected by current assays.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('microsatellite fragments', 'Var', (53, 77))	('cancer genomic errors', 'Disease', (20, 41))	('results in', 'Reg', (42, 52))	('cancer genomic errors', 'Disease', 'MESH:D009369', (20, 41))
92746	27873079	MSI can result in the development of various cancers, such as colorectal cancer and endometrial cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('result in', 'Reg', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('endometrial cancer', 'Disease', (84, 102))	('endometrial cancer', 'Phenotype', 'HP:0012114', (84, 102))	('colorectal cancer', 'Disease', (62, 79))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('MSI', 'Var', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('endometrial cancer', 'Disease', 'MESH:D016889', (84, 102))	('cancers', 'Disease', (45, 52))
92748	27873079	Patients with higher tumor mutational burden (TMB) and neoantigen load have improved response rates to immune checkpoint blockade.	('response rates', 'MPA', (85, 99))	('tumor', 'Disease', (21, 26))	('neoantigen load', 'Var', (55, 70))	('improved', 'PosReg', (76, 84))	('TMB', 'Chemical', '-', (46, 49))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
92756	27873079	De novo POLepsilon/POLdelta mutations can also occur and predispose to high TMB and therefore the development of colorectal cancer.	('colorectal cancer', 'Disease', (113, 130))	('POLepsilon/POLdelta', 'Gene', (8, 27))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('TMB', 'Chemical', '-', (76, 79))	('high TMB', 'Disease', (71, 79))	('predispose', 'Reg', (57, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('mutations', 'Var', (28, 37))
92757	27873079	It was found that, mutations in the POLepsilon proofreading domain of DNA polymerase in endometrial tumors leads to high TMB, neoepitope generation, and PD-1 expression in tumor infiltrating cells.	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('DNA polymerase', 'Gene', (70, 84))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('endometrial tumors', 'Disease', 'MESH:D016889', (88, 106))	('PD-1', 'Gene', (153, 157))	('PD-1', 'Gene', '5133', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('high TMB', 'MPA', (116, 124))	('expression', 'MPA', (158, 168))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('mutations in', 'Var', (19, 31))	('endometrial tumors', 'Disease', (88, 106))	('TMB', 'Chemical', '-', (121, 124))	('neoepitope generation', 'MPA', (126, 147))	('leads to', 'Reg', (107, 115))
92762	27873079	In all-comers, those tumors with high total exomic mutational burden, especially nonsynonymous mutations, and those who expressed a molecular smoking signature demonstrated increased PFS.	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Disease', (21, 27))	('increased', 'PosReg', (173, 182))	('PFS', 'Var', (183, 186))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
92765	27873079	This demonstrates that mutational burden and neoantigen load at the DNA level, as well as the manner of TIL activation and expansion, are all relevant in predicting anti-tumor response.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('mutational', 'Var', (23, 33))
92767	27873079	This was demonstrated by an increased concordance of PD-L1 copy number gains versus PD-L1 protein expression in the primary tumor and associate lymph node metastases (86 8% concordance versus 64 4% concordance, respectively).	('PD-L1', 'Gene', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('tumor', 'Disease', (124, 129))	('gains', 'PosReg', (71, 76))	('copy number', 'Var', (59, 70))	('metastases', 'Disease', (155, 165))
92768	27873079	Moreover, the study demonstrated a significant difference in overall survival between PD-L1 positive and negative patients (7 2 years versus 14 0 years, respectively).	('patients', 'Species', '9606', (114, 122))	('PD-L1', 'Gene', (86, 91))	('positive', 'Var', (92, 100))
92791	27873079	In high CD8+, HPV+ tumors, there was an increase in pro-inflammatory chemokines and also a higher expression of PD1 mRNA compared to HPV-negative tumors.	('tumors', 'Disease', (146, 152))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('PD1 mRNA', 'Protein', (112, 120))	('higher', 'PosReg', (91, 97))	('HPV+', 'Var', (14, 18))	('increase', 'PosReg', (40, 48))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('CD8', 'Gene', (8, 11))	('pro-inflammatory chemokines', 'MPA', (52, 79))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('CD8', 'Gene', '925', (8, 11))	('expression', 'MPA', (98, 108))
92821	27873079	Additionally, positive PD-L1 expression on TILs was associated with significantly longer survival in patients who developed metastatic disease (23 versus 12 months, P=0 02, N=89).	('patients', 'Species', '9606', (101, 109))	('PD-L1', 'Gene', (23, 28))	('longer', 'PosReg', (82, 88))	('positive', 'Var', (14, 22))	('survival', 'MPA', (89, 97))	('metastatic disease', 'CPA', (124, 142))
92827	27873079	Despite this data in mice, a clinical trial combining nivolumab with erlotinib in EGFR-mutant patients demonstrated modest overall response in the advanced NSCLC setting (ORR 19% and PFS at 24 weeks was 51%).	('EGFR-mutant', 'Gene', (82, 93))	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('patients', 'Species', '9606', (94, 102))	('mice', 'Species', '10090', (21, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('EGFR-mutant', 'Var', (82, 93))	('NSCLC', 'Disease', (156, 161))	('nivolumab', 'Chemical', 'MESH:D000077594', (54, 63))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('erlotinib', 'Chemical', 'MESH:D000069347', (69, 78))
92834	27873079	When comparing biomarker high PD-L2 expression with biomarker low PD-L2 expression, the OS HR was 0 28 in the melanoma cohort.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma cohort', 'Disease', (110, 125))	('PD-L2', 'Gene', (30, 35))	('PD-L2', 'Gene', '80380', (30, 35))	('high', 'Var', (25, 29))	('OS HR', 'Disease', 'MESH:C567932', (88, 93))	('OS HR', 'Disease', (88, 93))	('PD-L2', 'Gene', (66, 71))	('PD-L2', 'Gene', '80380', (66, 71))	('melanoma cohort', 'Disease', 'MESH:D008545', (110, 125))
92849	27873079	With blockade of PD-1, inhibition of host immune T cell activation is abrogated.	('PD-1', 'Gene', (17, 21))	('abrogated', 'NegReg', (70, 79))	('PD-1', 'Gene', '5133', (17, 21))	('blockade', 'Var', (5, 13))	('host immune T cell activation', 'CPA', (37, 66))	('T cell activation', 'biological_process', 'GO:0042110', ('49', '66'))
92900	27376118	Rationale: In a recently reported Phase I trial with update at ASCO 2015 Annual Meeting, Powles et al reported 26% overall response rate with MPDL3280A (atezolizumab) in patients with metastatic urothelial cancer.	('patients', 'Species', '9606', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('urothelial cancer', 'Disease', (195, 212))	('MPDL3280A', 'Var', (142, 151))	('urothelial cancer', 'Disease', 'MESH:D014523', (195, 212))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (142, 151))	('atezolizumab', 'Chemical', 'MESH:C000594389', (153, 165))
92908	27376118	The primary study hypotheses are that pembrolizumab will prolong OS and PFS.	('pembrolizumab', 'Var', (38, 51))	('PFS', 'CPA', (72, 75))	('pembrolizumab', 'Chemical', 'MESH:C582435', (38, 51))	('prolong', 'PosReg', (57, 64))
92926	27280069	Based on current evidence, LNU could provide equivalent prognostic effects for upper tract urothelial carcinoma, and had better oncological control of ExRFS and CSS compared to ONU.	('upper tract urothelial carcinoma', 'Disease', (79, 111))	('CSS', 'Chemical', '-', (161, 164))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (79, 111))	('LNU', 'Chemical', '-', (27, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('LNU', 'Var', (27, 30))	('ONU', 'Chemical', '-', (177, 180))
92951	27280069	The pooled results indicated that LNU could improve the cancer specific survival (HR 0.79, 95% CI [0.68-0.91]; P = 0.186, I2 = 28.1%; Fig.	('improve', 'PosReg', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('LNU', 'Chemical', '-', (34, 37))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('LNU', 'Var', (34, 37))
92960	27280069	With a median follow-up of 45 months of 1,261 UTUC patients who underwent ONU (n = 926) or LNU (n = 335), showed that the laparoscopic approach was associated with a higher risk of intravesical recurrence compared with open surgery (HR = 1.5, 95% CI [1.17-1.93]).	('LNU', 'Chemical', '-', (91, 94))	('intravesical recurrence', 'Disease', (181, 204))	('ONU', 'Chemical', '-', (74, 77))	('patients', 'Species', '9606', (51, 59))	('laparoscopic', 'Var', (122, 134))
92965	27280069	Our results showed that ONU was an independent risk for ExRFS.	('ONU', 'Chemical', '-', (24, 27))	('ONU', 'Var', (24, 27))	('ExRFS', 'Disease', (56, 61))
92980	27280069	We thought the conclusion that LNU could improve the CSS should be interpreted cautiously, although this conclusion was consistent with the previous opinion of Ni et al.	('CSS', 'MPA', (53, 56))	('improve', 'PosReg', (41, 48))	('CSS', 'Chemical', '-', (53, 56))	('LNU', 'Chemical', '-', (31, 34))	('LNU', 'Var', (31, 34))
92993	26705213	Multivariate analysis showed improved survival in patients treated with cyclophosphamide (hazard ratio (HR) = 0.42; 95% CI: 0.20-0.89; P = 0.025) and a worse survival in those treated with platinum-based regimens (HR: 4.37; 95% CI = 1.95-9.77; P < 0.01).	('patients', 'Species', '9606', (50, 58))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (72, 88))	('cyclophosphamide', 'Var', (72, 88))	('improved', 'PosReg', (29, 37))	('platinum', 'Chemical', 'MESH:D010984', (189, 197))	('survival', 'MPA', (38, 46))
92994	26705213	We observed a significantly longer overall survival in patients receiving single-agent cyclophosphamide, with few grade 3 to 4 toxicities.	('cyclophosphamide', 'Chemical', 'MESH:D003520', (87, 103))	('toxicities', 'Disease', 'MESH:D064420', (127, 137))	('longer', 'PosReg', (28, 34))	('cyclophosphamide', 'Var', (87, 103))	('patients', 'Species', '9606', (55, 63))	('overall survival', 'MPA', (35, 51))	('toxicities', 'Disease', (127, 137))
93047	26705213	The better survival associated with cyclophosphamide was also confirmed at multivariate analysis (HR = 0.42; 95% CI: 0.20-0.89; P = 0.025) (Table 6A).	('survival', 'MPA', (11, 19))	('better', 'PosReg', (4, 10))	('cyclophosphamide', 'Var', (36, 52))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (36, 52))
93060	26705213	Similarly, the use of pegylated liposomal doxorubicin as a third-line chemotherapy was associated with a median progression free survival and overall survival of 4.1 and 6.3 months in 23 patients with advanced urothelial carcinoma, whereas median time to progression and overall survival were 2 and 7.3 months, respectively, in 13 patients treated with third-line gemcitabine.	('patients', 'Species', '9606', (187, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('gemcitabine', 'Chemical', 'MESH:C056507', (364, 375))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (210, 230))	('doxorubicin', 'Chemical', 'MESH:D004317', (42, 53))	('urothelial carcinoma', 'Disease', (210, 230))	('pegylated liposomal', 'Var', (22, 41))	('patients', 'Species', '9606', (331, 339))
93071	26705213	Multivariate analysis of the use of cyclophosphamide versus other agents showed a substantial reduction of the risk of death, with an HR of 0.42; 95% CI: 0.20 to 0.89, after controlling for established prognostic factors.	('reduction', 'NegReg', (94, 103))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (36, 52))	('cyclophosphamide', 'Var', (36, 52))
93097	33183321	Non coding RNAs as the critical factors in chemo resistance of bladder tumor cells Bladder cancer (BCa) is the ninth frequent and 13th leading cause of cancer related deaths in the world which is mainly observed among men.	('bladder tumor', 'Phenotype', 'HP:0009725', (63, 76))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('bladder tumor', 'Disease', (63, 76))	('Bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('deaths', 'Disease', 'MESH:D003643', (167, 173))	('deaths', 'Disease', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('men', 'Species', '9606', (218, 221))	('BCa', 'Phenotype', 'HP:0009725', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('bladder tumor', 'Disease', 'MESH:D001749', (63, 76))	('Non coding RNAs', 'Var', (0, 15))
93123	33183321	Therefore, SIRT1 inhibition results in tumor cells death through p53 modulation and activation.	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('activation', 'PosReg', (84, 94))	('modulation', 'Var', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('SIRT1', 'Gene', '23411', (11, 16))	('SIRT1', 'Gene', (11, 16))	('tumor', 'Disease', (39, 44))	('inhibition', 'NegReg', (17, 27))
93135	33183321	As UCA1 shRNA markedly reduced the expression level of LRP, MRP1, and GST, and significantly overexpressed TOPO-II, it is hypothesized that knockdown of UCA1 decreases chemo resistance.	('decreases', 'NegReg', (158, 167))	('expression level', 'MPA', (35, 51))	('MRP1', 'Gene', (60, 64))	('UCA1', 'Gene', '652995', (153, 157))	('UCA1', 'Gene', (153, 157))	('chemo resistance', 'CPA', (168, 184))	('overexpressed', 'PosReg', (93, 106))	('MRP1', 'Gene', '4363', (60, 64))	('LRP', 'Gene', (55, 58))	('reduced', 'NegReg', (23, 30))	('knockdown', 'Var', (140, 149))	('LRP', 'Gene', '9961', (55, 58))	('UCA1', 'Gene', '652995', (3, 7))	('UCA1', 'Gene', (3, 7))
93171	33183321	It has been reported that the UCA1 activates miR-196a-5p via CREB which results in gemcitabine/cisplatin resistance.	('CREB', 'Gene', (61, 65))	('gemcitabine/cisplatin resistance', 'MPA', (83, 115))	('CREB', 'Gene', '1385', (61, 65))	('gemcitabine', 'Chemical', 'MESH:C056507', (83, 94))	('UCA1', 'Gene', '652995', (30, 34))	('UCA1', 'Gene', (30, 34))	('miR-196a-5p', 'Var', (45, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('results in', 'Reg', (72, 82))
93177	33183321	It has been reported that the TUG1 knockdown decreased Dox resistance through restraining the activity of Wnt/beta-catenin pathway; whereas, TUG1 up regulation was significantly associated with Dox resistance and poor prognosis.	('knockdown', 'Var', (35, 44))	('up regulation', 'PosReg', (146, 159))	('TUG1', 'Gene', (30, 34))	('beta-catenin', 'Gene', (110, 122))	('TUG1', 'Gene', '55000', (141, 145))	('beta-catenin', 'Gene', '1499', (110, 122))	('decreased', 'NegReg', (45, 54))	('restraining', 'NegReg', (78, 89))	('TUG1', 'Gene', (141, 145))	('activity', 'MPA', (94, 102))	('Dox', 'Chemical', 'MESH:D004317', (194, 197))	('Dox resistance', 'MPA', (55, 69))	('Dox resistance', 'Disease', (194, 208))	('TUG1', 'Gene', '55000', (30, 34))	('regulation', 'biological_process', 'GO:0065007', ('149', '159'))	('Dox', 'Chemical', 'MESH:D004317', (55, 58))
93197	33183321	Overexpression of HS3ST3B1 was significantly correlated with shorter survival rates in BCa patients.	('shorter', 'NegReg', (61, 68))	('HS3ST3B1', 'Gene', (18, 26))	('HS3ST3B1', 'Gene', '9953', (18, 26))	('patients', 'Species', '9606', (91, 99))	('BCa', 'Phenotype', 'HP:0009725', (87, 90))	('survival rates', 'CPA', (69, 83))	('BCa', 'Disease', (87, 90))	('Overexpression', 'Var', (0, 14))
93198	33183321	Furthermore, ectopic HS3ST3B1 expression enhanced tumor growth, invasiveness, and cisplatin resistance.	('cisplatin resistance', 'CPA', (82, 102))	('ectopic', 'Var', (13, 20))	('enhanced', 'PosReg', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('HS3ST3B1', 'Gene', '9953', (21, 29))	('invasiveness', 'CPA', (64, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('HS3ST3B1', 'Gene', (21, 29))
93204	33183321	The knockdown of NEAT1 suppressed the proliferation and migration of BCa cells and induced apoptosis following cisplatin treatment.	('men', 'Species', '9606', (126, 129))	('BCa', 'Phenotype', 'HP:0009725', (69, 72))	('proliferation', 'CPA', (38, 51))	('suppressed', 'NegReg', (23, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('NEAT1', 'Gene', '283131', (17, 22))	('apoptosis', 'CPA', (91, 100))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('NEAT1', 'Gene', (17, 22))	('knockdown', 'Var', (4, 13))	('induced', 'Reg', (83, 90))
93213	33183321	The carriers of rs11671784 A allele had significantly poorer outcomes after chemotherapy compared with rs11671784 GG homozygote patients.	('poorer', 'NegReg', (54, 60))	('rs11671784', 'Mutation', 'rs11671784', (16, 26))	('outcomes', 'CPA', (61, 69))	('rs11671784', 'Mutation', 'rs11671784', (103, 113))	('patients', 'Species', '9606', (128, 136))	('rs11671784 A', 'Var', (16, 28))
93217	33183321	There was a correlation between rs11671784 G/A variation and reduced miR-27a expression which results in increased RUNX-1 expression drug resistance.	('expression', 'MPA', (77, 87))	('RUNX-1', 'Gene', '861', (115, 121))	('RUNX-1', 'Gene', (115, 121))	('rs11671784', 'Mutation', 'rs11671784', (32, 42))	('miR-27a', 'Gene', '407018', (69, 76))	('rs11671784 G/A', 'Var', (32, 46))	('drug resistance', 'Phenotype', 'HP:0020174', (133, 148))	('increased', 'PosReg', (105, 114))	('drug resistance', 'biological_process', 'GO:0009315', ('133', '148'))	('drug resistance', 'biological_process', 'GO:0042493', ('133', '148'))	('reduced', 'NegReg', (61, 68))	('miR-27a', 'Gene', (69, 76))
93225	33183321	It has been observed that the miR-27a deregulation induced cisplatin resistance in BCa cells via up regulating SLC7A11, followed by increased cystine import and higher intracellular glutathione levels.	('up regulating', 'PosReg', (97, 110))	('intracellular', 'cellular_component', 'GO:0005622', ('168', '181'))	('SLC7A11', 'Gene', '23657', (111, 118))	('miR-27a', 'Gene', '407018', (30, 37))	('increased cystine', 'Phenotype', 'HP:0500151', (132, 149))	('deregulation', 'Var', (38, 50))	('miR-27a', 'Gene', (30, 37))	('glutathione', 'Chemical', 'MESH:D005978', (182, 193))	('cystine', 'Chemical', 'MESH:D003553', (142, 149))	('BCa', 'Phenotype', 'HP:0009725', (83, 86))	('cisplatin resistance', 'MPA', (59, 79))	('increased', 'PosReg', (132, 141))	('higher', 'PosReg', (161, 167))	('induced', 'Reg', (51, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('SLC7A11', 'Gene', (111, 118))	('cystine import', 'MPA', (142, 156))
93233	33183321	Dysregulated miR-34a has been associated with resistance to chemotherapeutic drugs.	('associated', 'Reg', (30, 40))	('miR-34a', 'Gene', (13, 20))	('Dysregulated', 'Var', (0, 12))	('miR-34a', 'Gene', '407040', (13, 20))
93235	33183321	Ectopic expression of miR-34a caused apoptosis, cell cycle arrest, and drug response alteration through SIRT-1, CDK6, E2F3, and BCL-2 targeting.	('SIRT-1', 'Gene', (104, 110))	('CDK6', 'Gene', '1021', (112, 116))	('miR-34a', 'Gene', '407040', (22, 29))	('E2F3', 'Gene', '1871', (118, 122))	('alteration', 'Reg', (85, 95))	('CDK', 'molecular_function', 'GO:0004693', ('112', '115'))	('SIRT-1', 'Gene', '23411', (104, 110))	('drug response', 'CPA', (71, 84))	('apoptosis', 'CPA', (37, 46))	('CDK6', 'Gene', (112, 116))	('Ectopic expression', 'Var', (0, 18))	('BCL-2', 'Gene', '596', (128, 133))	('BCL-2', 'Gene', (128, 133))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (48, 65))	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('arrest', 'Disease', (59, 65))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('48', '65'))	('E2F3', 'Gene', (118, 122))	('miR-34a', 'Gene', (22, 29))	('BCL-2', 'molecular_function', 'GO:0015283', ('128', '133'))	('arrest', 'Disease', 'MESH:D006323', (59, 65))
93242	33183321	GOLPH3 deregulation is associated with poor prognosis in BCa.	('GOLPH3', 'Gene', (0, 6))	('deregulation', 'Var', (7, 19))	('GOLPH3', 'Gene', '64083', (0, 6))	('BCa', 'Phenotype', 'HP:0009725', (57, 60))	('BCa', 'Disease', (57, 60))
93248	33183321	Aberrant p53/Rb signaling pathway is correlated with increased tumor invasiveness and growth in muscle invasive BCa.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor invasiveness', 'Disease', (63, 81))	('Aberrant', 'Var', (0, 8))	('growth', 'CPA', (86, 92))	('tumor invasiveness', 'Disease', 'MESH:D009361', (63, 81))	('Rb', 'Chemical', 'MESH:D012413', (13, 15))	('muscle invasive BCa', 'Disease', 'MESH:D009362', (96, 115))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('signaling pathway', 'biological_process', 'GO:0007165', ('16', '33'))	('increased', 'PosReg', (53, 62))	('muscle invasive BCa', 'Disease', (96, 115))	('BCa', 'Phenotype', 'HP:0009725', (112, 115))
93259	33183321	It has been reported that the miR-34b-3p attenuated chemo resistance in BCa through suppressing CCND2 and P2RY1.	('attenuated', 'NegReg', (41, 51))	('suppressing', 'NegReg', (84, 95))	('CCND2', 'Gene', '894', (96, 101))	('miR-34b-3p', 'Chemical', '-', (30, 40))	('miR-34b-3p', 'Var', (30, 40))	('BCa', 'Phenotype', 'HP:0009725', (72, 75))	('chemo resistance', 'MPA', (52, 68))	('P2RY1', 'Gene', '5028', (106, 111))	('CCND2', 'Gene', (96, 101))	('P2RY1', 'Gene', (106, 111))
93265	33183321	MiR-101-3p is considered as a tumor suppressor and is down regulated in different malignancies such as BCa, colorectal cancer, and breast cancer.	('malignancies', 'Disease', (82, 94))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('down regulated', 'NegReg', (54, 68))	('BCa', 'Phenotype', 'HP:0009725', (103, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('MiR-101-3p', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('breast cancer', 'Disease', (131, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('MiR-101-3p', 'Chemical', '-', (0, 10))	('BCa', 'Disease', (103, 106))	('colorectal cancer', 'Disease', (108, 125))	('tumor', 'Disease', (30, 35))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))
93266	33183321	EZH2 as a target of miR-101-3p is a member of the Polycomb-group family involved in transcriptional repression.	('miR-101-3p', 'Var', (20, 30))	('EZH2', 'Gene', (0, 4))	('miR-101-3p', 'Chemical', '-', (20, 30))	('EZH2', 'Gene', '2146', (0, 4))
93269	33183321	MiR-101-3p overexpression also suppressed the MRP1 expression level.	('MiR-101-3p', 'Chemical', '-', (0, 10))	('MRP1', 'Gene', '4363', (46, 50))	('MiR-101-3p', 'Var', (0, 10))	('suppressed', 'NegReg', (31, 41))	('MRP1', 'Gene', (46, 50))
93270	33183321	Therefore, miR-101-3p decreased cisplatin-resistance in bladder urothelial carcinoma through repressing EZH2 and MRP1.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (56, 84))	('miR-101-3p', 'Var', (11, 21))	('repressing', 'PosReg', (93, 103))	('EZH2', 'Gene', '2146', (104, 108))	('bladder urothelial carcinoma', 'Disease', (56, 84))	('cisplatin-resistance', 'MPA', (32, 52))	('EZH2', 'Gene', (104, 108))	('miR-101-3p', 'Chemical', '-', (11, 21))	('MRP1', 'Gene', '4363', (113, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('MRP1', 'Gene', (113, 117))	('decreased', 'NegReg', (22, 31))
93278	33183321	Substantial epigenetic changes along with genetic variations are the origin of all cancerous features.	('origin', 'Reg', (69, 75))	('cancerous', 'Disease', 'MESH:D009369', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('epigenetic changes', 'Var', (12, 30))	('cancerous', 'Disease', (83, 92))
93279	33183321	These epigenetic changes and defects have a more significant impact on tumor cells phenotype and gene expression than genetic changes.	('gene expression', 'biological_process', 'GO:0010467', ('97', '112'))	('impact', 'Reg', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('epigenetic changes', 'Var', (6, 24))	('defects', 'Var', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('gene expression', 'MPA', (97, 112))
93280	33183321	Detection of aberrant DNA methylation at promoter sequence of oncogene and tumor suppressor genes is an efficient method of early diagnosis.	('DNA methylation', 'biological_process', 'GO:0006306', ('22', '37'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('75', '91'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('aberrant DNA methylation', 'Var', (13, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('75', '91'))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('oncogene', 'Gene', (62, 70))	('tumor', 'Disease', (75, 80))
93281	33183321	MiR-193a-3p impedes tumor proliferation and decreases drug resistance through down regulation of various genes such as CCND1, ERBB4, and PTEN.	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('3p', 'Chemical', '-', (9, 11))	('drug resistance', 'biological_process', 'GO:0009315', ('54', '69'))	('drug resistance', 'biological_process', 'GO:0042493', ('54', '69'))	('impedes', 'NegReg', (12, 19))	('ERBB4', 'Gene', '2066', (126, 131))	('regulation', 'biological_process', 'GO:0065007', ('83', '93'))	('ERBB4', 'Gene', (126, 131))	('MiR-193a-3p', 'Var', (0, 11))	('PTEN', 'Gene', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('decreases', 'NegReg', (44, 53))	('CCND1', 'Gene', '595', (119, 124))	('CCND1', 'Gene', (119, 124))	('PTEN', 'Gene', '5728', (137, 141))	('drug resistance', 'MPA', (54, 69))	('down regulation', 'NegReg', (78, 93))	('drug resistance', 'Phenotype', 'HP:0020174', (54, 69))	('tumor', 'Disease', (20, 25))
93283	33183321	It has been revealed that the miR-193a-3p mediated HOXC9 down regulation which resulted in poorer sensitivity of BCa to chemotherapeutic drugs.	('HOXC9', 'Gene', '3225', (51, 56))	('regulation', 'biological_process', 'GO:0065007', ('62', '72'))	('sensitivity', 'MPA', (98, 109))	('miR-193a-3p', 'Var', (30, 41))	('down regulation', 'NegReg', (57, 72))	('3p', 'Chemical', '-', (39, 41))	('BCa', 'Phenotype', 'HP:0009725', (113, 116))	('poorer', 'NegReg', (91, 97))	('HOXC9', 'Gene', (51, 56))
93284	33183321	Oxidative stress and DNA damage response were also influenced by epigenetic suppression of HOXC9 through miR-193a-3p.	('miR-193a-3p', 'Var', (105, 116))	('HOXC9', 'Gene', '3225', (91, 96))	('DNA damage response', 'biological_process', 'GO:0006974', ('21', '40'))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('HOXC9', 'Gene', (91, 96))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('3p', 'Chemical', '-', (114, 116))	('DNA damage response', 'MPA', (21, 40))	('Oxidative stress', 'MPA', (0, 16))	('epigenetic suppression', 'Var', (65, 87))	('influenced', 'Reg', (51, 61))
93287	33183321	It has been reported that the PSEN1 was directly targeted by miR-193a-3p and executed its impact on the multi-chemo resistance.	('targeted', 'Reg', (49, 57))	('miR-193a-3p', 'Var', (61, 72))	('multi-chemo resistance', 'MPA', (104, 126))	('3p', 'Chemical', '-', (70, 72))	('PSEN1', 'Gene', (30, 35))	('PSEN1', 'Gene', '5663', (30, 35))	('impact', 'Reg', (90, 96))
93293	33183321	It was observed that CEBPD and cisplatin increased the expression levels of miR-193b-3p.	('miR-193b-3p', 'Var', (76, 87))	('increased', 'PosReg', (41, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('CEBPD', 'Gene', (21, 26))	('CEBPD', 'Gene', '1052', (21, 26))	('expression levels', 'MPA', (55, 72))	('3p', 'Chemical', '-', (85, 87))
93294	33183321	Moreover, miR-193b-3p had regulatory effect on ETS1 and CCND1.	('ETS1', 'Gene', '2113', (47, 51))	('ETS1', 'Gene', (47, 51))	('regulatory', 'MPA', (26, 36))	('CCND1', 'Gene', '595', (56, 61))	('3p', 'Chemical', '-', (19, 21))	('CCND1', 'Gene', (56, 61))	('miR-193b-3p', 'Var', (10, 21))
93295	33183321	MiR-193b-3p was also important for CDDP-triggered cell cycle arrest, cell cytotoxicity, and inhibition of cellular migration.	('arrest', 'Disease', (61, 67))	('cytotoxicity', 'Disease', (74, 86))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('CDDP', 'Chemical', '-', (35, 39))	('inhibition', 'NegReg', (92, 102))	('MiR-193b-3p', 'Chemical', '-', (0, 11))	('cytotoxicity', 'Disease', 'MESH:D064420', (74, 86))	('arrest', 'Disease', 'MESH:D006323', (61, 67))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('50', '67'))	('MiR-193b-3p', 'Var', (0, 11))	('cellular migration', 'CPA', (106, 124))
93298	33183321	The oncogenic function of miR-193a-3p is due to its suppressive effects on various genes such as KRAS and c-KIT.	('c-KIT', 'Gene', (106, 111))	('suppressive', 'NegReg', (52, 63))	('KRAS', 'Gene', (97, 101))	('miR-193a-3p', 'Var', (26, 37))	('3p', 'Chemical', '-', (35, 37))	('c-KIT', 'Gene', '3815', (106, 111))	('KRAS', 'Gene', '3845', (97, 101))	('KIT', 'molecular_function', 'GO:0005020', ('108', '111'))	('oncogenic function', 'MPA', (4, 22))
93300	33183321	It has been indicated that the miR-193a-3p induced multi-drug resistance in BCa cells through down regulating LOXL4, and thus initiating oxidative stress pathway.	('initiating', 'Reg', (126, 136))	('oxidative stress', 'Phenotype', 'HP:0025464', (137, 153))	('drug resistance', 'biological_process', 'GO:0042493', ('57', '72'))	('multi-drug resistance', 'MPA', (51, 72))	('induced', 'Reg', (43, 50))	('BCa', 'Phenotype', 'HP:0009725', (76, 79))	('LOXL4', 'Gene', '84171', (110, 115))	('miR-193a-3p', 'Var', (31, 42))	('down regulating', 'NegReg', (94, 109))	('drug resistance', 'Phenotype', 'HP:0020174', (57, 72))	('LOXL4', 'Gene', (110, 115))	('drug resistance', 'biological_process', 'GO:0009315', ('57', '72'))	('oxidative stress pathway', 'Pathway', (137, 161))	('3p', 'Chemical', '-', (40, 42))
93301	33183321	Hypermethylation of the promoter and enhancer regions are associated with epigenetically silenced status of ncRNAs and protein-coding genes.	('associated', 'Reg', (58, 68))	('ncRNA', 'Gene', '220202', (108, 113))	('Hypermethylation', 'Var', (0, 16))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('ncRNA', 'Gene', (108, 113))
93306	33183321	It has been reported that the HIC2, SRSF2, and PLAU achieve their role in relaying miR-193a-3p's effect on chemo resistance in BCa through regulation of Myc/Max, NF-jB, DNA damage response, and NOTCH pathway.	('HIC2', 'Gene', (30, 34))	('PLAU', 'Gene', (47, 51))	('DNA damage response', 'Pathway', (169, 188))	('NF-jB', 'Disease', (162, 167))	('miR-193a-3p', 'Var', (83, 94))	('DNA', 'cellular_component', 'GO:0005574', ('169', '172'))	('BCa', 'Phenotype', 'HP:0009725', (127, 130))	('NF-jB', 'Disease', 'MESH:C537392', (162, 167))	('SRSF2', 'Gene', '6427', (36, 41))	('HIC2', 'Gene', '23119', (30, 34))	('Myc', 'Gene', '4609', (153, 156))	('SRSF2', 'Gene', (36, 41))	('DNA damage response', 'biological_process', 'GO:0006974', ('169', '188'))	('chemo resistance', 'MPA', (107, 123))	('NOTCH pathway', 'Pathway', (194, 207))	('3p', 'Chemical', '-', (92, 94))	('PLAU', 'Gene', '5328', (47, 51))	('regulation', 'biological_process', 'GO:0065007', ('139', '149'))	('Myc', 'Gene', (153, 156))
93311	33183321	It has been reported that there was a correlation between epigenetic silencing of miR-200b and cisplatin resistance in BCa.	('cisplatin resistance', 'MPA', (95, 115))	('correlation', 'Interaction', (38, 49))	('miR-200b', 'Gene', '406984', (82, 90))	('epigenetic silencing', 'Var', (58, 78))	('miR-200b', 'Gene', (82, 90))	('BCa', 'Phenotype', 'HP:0009725', (119, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))
93334	33183321	Aberrant expression of miR-222 enhances tumor cell proliferation and metastasis by inhibiting the PPP2R2A, TIMP3, and p27.	('miR-222', 'Gene', '407007', (23, 30))	('Aberrant expression', 'Var', (0, 19))	('metastasis', 'CPA', (69, 79))	('TIMP3', 'Gene', (107, 112))	('PPP2R2A', 'Gene', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('PPP2R2A', 'Gene', '5520', (98, 105))	('miR-222', 'Gene', (23, 30))	('enhances', 'PosReg', (31, 39))	('inhibiting', 'NegReg', (83, 93))	('p27', 'Gene', '3429', (118, 121))	('p27', 'Gene', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('TIMP3', 'Gene', '7078', (107, 112))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
93348	28388586	EGFR amplifications were observed in 14% and ERBB2 amplifications in 23% of the reference cohort.	('amplifications', 'Var', (5, 19))	('EGFR', 'Gene', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('ERBB2', 'Gene', '2064', (45, 50))	('ERBB2', 'Gene', (45, 50))	('EGFR', 'Gene', '1956', (0, 4))
93352	28388586	Even though a good correlation between gene amplification and ERBB2 gene expression was observed in the Urothelial-like and Genomically Unstable subtypes less than half of the Basal/SCC-like cases with ERBB2 amplification showed concomitant ERBB2 mRNA and protein expression.	('Uro', 'Chemical', '-', (104, 107))	('amplification', 'Var', (208, 221))	('Basal/SCC-like', 'Disease', (176, 190))	('ERBB2', 'Gene', '2064', (202, 207))	('ERBB2', 'Gene', '2064', (241, 246))	('ERBB2', 'Gene', (62, 67))	('protein', 'cellular_component', 'GO:0003675', ('256', '263'))	('ERBB2', 'Gene', (202, 207))	('ERBB2', 'Gene', (241, 246))	('ERBB2', 'Gene', '2064', (62, 67))	('gene expression', 'biological_process', 'GO:0010467', ('68', '83'))
93371	28388586	We show that ERBB2 amplifications and expression, as well as clinically "HER2 positive" cases, may be of two fundamentally different molecular subtypes, of Uro or the GU subtypes, and that EGFR expression is associated with the SCC-like subtype.	('HER2', 'Gene', '2064', (73, 77))	('EGFR', 'Gene', '1956', (189, 193))	('HER2', 'Gene', (73, 77))	('GU', 'Chemical', '-', (167, 169))	('EGFR', 'Gene', (189, 193))	('ERBB2', 'Gene', '2064', (13, 18))	('Uro', 'Chemical', '-', (156, 159))	('ERBB2', 'Gene', (13, 18))	('associated', 'Reg', (208, 218))	('amplifications', 'Var', (19, 33))	('SCC-like subtype', 'Disease', (228, 244))
93377	28388586	The copy number array data indicated EGFR (7p11) gains in 30 tumors (12%), and focal genomic amplifications in another 4 cases (1.6%) (Figure 1B, Figure 2A and 2B).	('gains', 'PosReg', (49, 54))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('EGFR', 'Gene', '1956', (37, 41))	('focal genomic amplifications', 'Var', (79, 107))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('EGFR', 'Gene', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
93380	28388586	ERBB2 (17q12) showed copy number gains in 45 (18%) and focal genomic amplifications in 12 samples (5%) (Figure 1B, Figure 3A and 3B).	('ERBB2', 'Gene', '2064', (0, 5))	('gains', 'PosReg', (33, 38))	('genomic amplifications', 'Var', (61, 83))	('ERBB2', 'Gene', (0, 5))	('copy number', 'Var', (21, 32))
93384	28388586	ERBB3 (12q13) copy number alterations were scarce, and not significantly associated with mRNA or protein expression (Figure 1A and 1B, Supplementary Figure 1).	('ERBB3', 'Gene', '2065', (0, 5))	('ERBB3', 'Gene', (0, 5))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('copy number alterations', 'Var', (14, 37))	('associated', 'Reg', (73, 83))	('mRNA or protein expression', 'MPA', (89, 115))
93392	28388586	Among the tumors with IHC 2+ scores, 38% (22/58) were considered amplified by in-situ hybridization, whereas 82% (27/33) of the cases with IHC 3+ scores were considered amplified.	('IHC 2+ scores', 'Var', (22, 35))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))
93419	28388586	Hotspot mutation analysis of S310F/Y in ERBB2 and V104L/M and M91I in ERBB3 revealed low mutation frequencies and no subtype associations (Figure 4C).	('S310F', 'Var', (29, 34))	('ERBB2', 'Gene', '2064', (40, 45))	('low', 'NegReg', (85, 88))	('ERBB2', 'Gene', (40, 45))	('V104L', 'SUBSTITUTION', 'None', (50, 55))	('ERBB3', 'Gene', '2065', (70, 75))	('V104L', 'Var', (50, 55))	('S310F', 'SUBSTITUTION', 'None', (29, 34))	('ERBB3', 'Gene', (70, 75))	('mutation', 'MPA', (89, 97))	('M91I', 'Mutation', 'p.M91I', (62, 66))	('M91I', 'Var', (62, 66))
93429	28388586	To clarify the molecular context in which ERBB2 and EGFR gene amplifications and overexpression occur we performed an in-depth study of EGFR, ERBB2, and ERBB3 alterations in relation to existing urothelial carcinoma molecular subtypes.	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))	('urothelial carcinoma molecular subtypes', 'Disease', (195, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('EGFR', 'molecular_function', 'GO:0005006', ('136', '140'))	('alterations', 'Var', (159, 170))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('ERBB2', 'Gene', '2064', (42, 47))	('ERBB2', 'Gene', (42, 47))	('ERBB2', 'Gene', '2064', (142, 147))	('ERBB3', 'Gene', (153, 158))	('ERBB3', 'Gene', '2065', (153, 158))	('ERBB2', 'Gene', (142, 147))	('EGFR', 'Gene', '1956', (136, 140))	('urothelial carcinoma molecular subtypes', 'Disease', 'MESH:C535673', (195, 234))	('EGFR', 'Gene', (136, 140))
93436	28388586	Uro tumors differ from GU tumors by exhibiting high frequencies of FGFR3 and PIK3CA mutations and in muscle invasive urothelial carcinoma FGFR3 mutations are heavily skewed towards the Uro subtype.	('PIK3CA', 'Gene', (77, 83))	('GU tumors', 'Disease', 'MESH:D009369', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('FGFR', 'molecular_function', 'GO:0005007', ('138', '142'))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('FGFR3', 'Gene', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Uro', 'Chemical', '-', (185, 188))	('Uro tumor', 'Phenotype', 'HP:0100516', (0, 9))	('FGFR3', 'Gene', '2261', (138, 143))	('FGFR3', 'Gene', (67, 72))	('PIK3CA', 'Gene', '5290', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('mutations', 'Var', (84, 93))	('muscle invasive urothelial carcinoma', 'Disease', 'MESH:D009217', (101, 137))	('FGFR3', 'Gene', '2261', (67, 72))	('GU tumor', 'Phenotype', 'HP:0007379', (23, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('Uro', 'Chemical', '-', (0, 3))	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('GU tumors', 'Disease', (23, 32))	('tumors', 'Disease', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('GU tumors', 'Phenotype', 'HP:0007379', (23, 32))	('muscle invasive urothelial carcinoma', 'Disease', (101, 137))	('tumors', 'Disease', (26, 32))
93437	28388586	Furthermore, bi-allelic loss of the CDKN2A locus and overexpression of CCND1 are frequent events in the Uro subtype, indicating a dependency on mitogenic MAPK/PI3-K signaling for cell proliferation.	('CDKN2A', 'Gene', (36, 42))	('Uro', 'Chemical', '-', (104, 107))	('overexpression', 'PosReg', (53, 67))	('CCND1', 'Gene', (71, 76))	('CDKN2A', 'Gene', '1029', (36, 42))	('loss', 'NegReg', (24, 28))	('Uro', 'Disease', (104, 107))	('PI3', 'Gene', '5266', (159, 162))	('bi-allelic', 'Var', (13, 23))	('PI3-K signaling', 'biological_process', 'GO:0014065', ('159', '174'))	('cell proliferation', 'biological_process', 'GO:0008283', ('179', '197'))	('PI3-K', 'molecular_function', 'GO:0016303', ('159', '164'))	('CCND1', 'Gene', '595', (71, 76))	('PI3', 'Gene', (159, 162))	('MAPK', 'molecular_function', 'GO:0004707', ('154', '158'))
93438	28388586	In contrast, genomic events associated with the GU subtype, i.e., RB1 loss, TP53 mutation, and E2F3 gene amplification, allow for a more uncontrolled proliferation.	('loss', 'NegReg', (70, 74))	('TP53', 'Gene', '7157', (76, 80))	('RB1', 'Gene', '5925', (66, 69))	('mutation', 'Var', (81, 89))	('E2F3', 'Gene', '1871', (95, 99))	('TP53', 'Gene', (76, 80))	('GU', 'Chemical', '-', (48, 50))	('E2F3', 'Gene', (95, 99))	('RB1', 'Gene', (66, 69))
93443	28388586	We also noted that less than half of the ERRB2 amplifications found in tumors of the Basal/SCC-like subtype led to increased mRNA and protein levels, indicating that genomic amplification of 17q12 in Basal/SCC-like, as detected by HER2 ISH analyses, does not have the same consequence as in Uro and GU tumors.	('GU tumors', 'Phenotype', 'HP:0007379', (299, 308))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('HER2', 'Gene', '2064', (231, 235))	('tumors', 'Disease', (302, 308))	('GU tumors', 'Disease', 'MESH:D009369', (299, 308))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Uro', 'Chemical', '-', (291, 294))	('tumors', 'Disease', (71, 77))	('amplifications', 'Var', (47, 61))	('increased', 'PosReg', (115, 124))	('tumors', 'Disease', 'MESH:D009369', (302, 308))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('ERRB2', 'Gene', (41, 46))	('HER2', 'Gene', (231, 235))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('GU tumor', 'Phenotype', 'HP:0007379', (299, 307))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('GU tumors', 'Disease', (299, 308))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
93456	28388586	The reference cohort consists of 292 cases established from previously published data (GSE32894 and GSE32549) and includes all tumor stages (123 Ta, 88 T1, 79 >=T2, and 2 Tx) and grades (54 G1, 96 G2, 141 G3, and 1 Gx, WHO1999).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('GS', 'Disease', 'MESH:D011125', (87, 89))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('123 Ta', 'Var', (141, 147))	('GS', 'Disease', 'MESH:D011125', (100, 102))
93478	28388586	TMA Tissue Microarray IHC Immunohistochemistry TCS Tumor Cell Score ISH In-Situ Hybridization CEN17 Chromosome 17 centromere	('CEN17 Chromosome', 'Var', (94, 110))	('TCS', 'Chemical', '-', (47, 50))	('TMA', 'Disease', (0, 3))	('Tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Chromosome', 'cellular_component', 'GO:0005694', ('100', '110'))	('centromere', 'cellular_component', 'GO:0005698', ('114', '124'))	('TMA', 'Disease', 'MESH:D000783', (0, 3))	('centromere', 'cellular_component', 'GO:0000775', ('114', '124'))	('CEN17', 'Chemical', '-', (94, 99))
93514	23351020	The IGF-IR plays an essential role in cell growth in vitro and in vivo Mice homozygous for a targeted disruption of the insulin-like growth factor 1 receptor (IGF-IR) gene exhibit severe growth retardation, being only 45 % the size of wild-type littermates, and die shortly after birth due to respiratory failure.	('growth retardation', 'Disease', (187, 205))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('120', '146'))	('severe growth retardation', 'Phenotype', 'HP:0008850', (180, 205))	('insulin-like growth factor 1 receptor', 'Gene', (120, 157))	('insulin-like growth factor 1 receptor', 'Gene', '16001', (120, 157))	('respiratory failure', 'Disease', (293, 312))	('disruption', 'Var', (102, 112))	('respiratory failure', 'Disease', 'MESH:D012131', (293, 312))	('Mice', 'Species', '10090', (71, 75))	('growth retardation', 'Phenotype', 'HP:0001510', (187, 205))	('cell growth', 'biological_process', 'GO:0016049', ('38', '49'))	('respiratory failure', 'Phenotype', 'HP:0002878', (293, 312))	('IGF-IR', 'Gene', (159, 165))	('growth retardation', 'Disease', 'MESH:D006130', (187, 205))
93527	23351020	For example, IGF-II promotes slower kinetics of Akt-mediated phosphorylation of IRS-1 at Ser307, which is necessary for IRS-1 degradation when compared to insulin.	('insulin', 'molecular_function', 'GO:0016088', ('155', '162'))	('Akt', 'Gene', (48, 51))	('degradation', 'biological_process', 'GO:0009056', ('126', '137'))	('IGF-II', 'Gene', '16002', (13, 19))	('IRS-1', 'Gene', (80, 85))	('Ser307', 'Var', (89, 95))	('IRS-1', 'Gene', '16367', (80, 85))	('IRS-1', 'Gene', '16367', (120, 125))	('Ser', 'cellular_component', 'GO:0005790', ('89', '92'))	('Ser307', 'Chemical', '-', (89, 95))	('kinetics', 'MPA', (36, 44))	('Akt', 'Gene', '11651', (48, 51))	('IRS-1', 'Gene', (120, 125))	('slower', 'NegReg', (29, 35))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))	('IGF-II', 'Gene', (13, 19))
93536	23351020	The IGF-IR is overexpressed in diabetic kidneys from Dcn-/- compared to Dcn+/+ mice but IGF-IR upregulation could not compensate for decorin deficiency resulting in reduced fibrillin-1 levels.	('diabetic kidneys', 'Disease', (31, 47))	('fibrillin-1', 'Gene', '14118', (173, 184))	('mice', 'Species', '10090', (79, 83))	('diabetic kidneys', 'Disease', 'MESH:D003928', (31, 47))	('fibrillin', 'cellular_component', 'GO:0001527', ('173', '182'))	('Dcn-/-', 'Var', (53, 59))	('fibrillin-1', 'Gene', (173, 184))	('fibrillin', 'molecular_function', 'GO:0001511', ('173', '182'))	('reduced', 'NegReg', (165, 172))
93539	23351020	Seemingly diametric to the situation seen in the above two examples, loss of decorin in diabetic mice promotes an increase in IGF-IR levels and apoptosis with aberrant deposition of extracellular matrix.	('diabetic', 'Disease', (88, 96))	('increase', 'PosReg', (114, 122))	('decorin', 'Protein', (77, 84))	('apoptosis', 'biological_process', 'GO:0006915', ('144', '153'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('182', '202'))	('loss', 'Var', (69, 73))	('apoptosis', 'CPA', (144, 153))	('mice', 'Species', '10090', (97, 101))	('IGF-IR levels', 'MPA', (126, 139))	('diabetic', 'Disease', 'MESH:D003920', (88, 96))	('apoptosis', 'biological_process', 'GO:0097194', ('144', '153'))
93540	23351020	Intriguingly, restoration of decorin abrogates, via IGF-IR, high glucose induced apoptosis and evokes a protective response against diabetic nephropathy.	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('decorin', 'Protein', (29, 36))	('apoptosis', 'CPA', (81, 90))	('high glucose', 'Var', (60, 72))	('evokes', 'PosReg', (95, 101))	('rat', 'Species', '10116', (19, 22))	('abrogates', 'NegReg', (37, 46))	('nephropathy', 'Phenotype', 'HP:0000112', (141, 152))	('diabetic nephropathy', 'Disease', (132, 152))	('protective response against', 'CPA', (104, 131))	('diabetic nephropathy', 'Disease', 'MESH:D003928', (132, 152))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('high glucose', 'Phenotype', 'HP:0003074', (60, 72))	('glucose', 'Chemical', 'MESH:D005947', (65, 72))
93557	23351020	In the context of potential decorin based therapeutics to temper IGF-IR signaling in neoplasia, this effect will be of considerable importance as downregulation of IGF-IR promotes increased IR-A homodimer formation and thus cancer cells with enhanced IGF-II/IR-A signaling capacities.	('IGF-II', 'Gene', (251, 257))	('increased', 'PosReg', (180, 189))	('IR-A', 'Gene', (190, 194))	('downregulation', 'Var', (146, 160))	('cancer', 'Disease', (224, 230))	('IR-A', 'Gene', '16337', (258, 262))	('formation', 'biological_process', 'GO:0009058', ('205', '214'))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('neoplasia', 'Disease', 'MESH:D009369', (85, 94))	('IGF-IR', 'Gene', (164, 170))	('neoplasia', 'Disease', (85, 94))	('IR-A', 'Gene', (258, 262))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('enhanced', 'PosReg', (242, 250))	('signaling', 'biological_process', 'GO:0023052', ('263', '272'))	('IR-A', 'Gene', '16337', (190, 194))	('IGF-II', 'Gene', '16002', (251, 257))	('neoplasia', 'Phenotype', 'HP:0002664', (85, 94))
93589	23351020	For example, in Ewing's sarcomas a key resistance mechanism to inhibitors of the IGF-IR is mediated by enhanced homodimerization of the IR-A and concurrent with increased IGF-II production.	('IGF-II', 'Gene', '16002', (171, 177))	('homodimerization', 'MPA', (112, 128))	('IGF-IR', 'Gene', (81, 87))	('IR-A', 'Gene', (136, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	("Ewing's sarcomas", 'Disease', (16, 32))	('increased IGF-', 'Phenotype', 'HP:0030269', (161, 175))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (16, 32))	('IR-A', 'Gene', '16337', (136, 140))	('enhanced', 'PosReg', (103, 111))	('inhibitors', 'Var', (63, 73))	('increased', 'PosReg', (161, 170))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (16, 32))	('IGF-II', 'Gene', (171, 177))
93597	23351020	This implication would extend far beyond the mitigation of IGF-IR in neoplasia, but also serves as a much broader inhibitory activity insofar as to prevent liberation of heparan sulfate-bound growth factors.	('neoplasia', 'Phenotype', 'HP:0002664', (69, 78))	('rat', 'Species', '10116', (160, 163))	('IGF-IR', 'Var', (59, 65))	('neoplasia', 'Disease', 'MESH:D009369', (69, 78))	('liberation', 'MPA', (156, 166))	('prevent', 'NegReg', (148, 155))	('neoplasia', 'Disease', (69, 78))	('heparan sulfate', 'Chemical', 'MESH:D006497', (170, 185))	('heparan sulfate-bound growth factors', 'MPA', (170, 206))
93608	22792244	Contribution of the -160C/A Polymorphism in the E-cadherin Promoter to Cancer Risk: A Meta-Analysis of 47 Case-Control Studies The -160C/A polymorphism (rs16260) of E-cadherin, a tumor repressor gene, has been shown to be a tumor susceptibility allele for various types of cancers.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('Cancer', 'Disease', 'MESH:D009369', (71, 77))	('-160C/A', 'Mutation', 'rs16260', (20, 27))	('cancers', 'Phenotype', 'HP:0002664', (273, 280))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cancers', 'Disease', (273, 280))	('E-cadherin', 'Gene', (165, 175))	('-160C/A', 'Mutation', 'rs16260', (131, 138))	('E-cadherin', 'Gene', '999', (165, 175))	('rs16260', 'Mutation', 'rs16260', (153, 160))	('-160C/A', 'SUBSTITUTION', 'None', (20, 27))	('cadherin', 'molecular_function', 'GO:0008014', ('50', '58'))	('-160C/A', 'SUBSTITUTION', 'None', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', (224, 229))	('cancers', 'Disease', 'MESH:D009369', (273, 280))	('E-cadherin', 'Gene', (48, 58))	('E-cadherin', 'Gene', '999', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('Cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('cadherin', 'molecular_function', 'GO:0008014', ('167', '175'))	('-160C/A', 'Var', (20, 27))	('-160C/A', 'Var', (131, 138))	('tumor', 'Disease', (179, 184))
93621	22792244	The -160C/A polymorphism in the promoter region of the E-cadherin gene has been reported to have a direct effect on its transcriptional regulation and therefore may influence susceptibility to cancers.	('E-cadherin', 'Gene', (55, 65))	('The -160C/A', 'Var', (0, 11))	('E-cadherin', 'Gene', '999', (55, 65))	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('cancers', 'Disease', (193, 200))	('transcriptional regulation', 'MPA', (120, 146))	('influence', 'Reg', (165, 174))	('regulation', 'biological_process', 'GO:0065007', ('136', '146'))	('-160C/A', 'Mutation', 'rs16260', (4, 11))	('cadherin', 'molecular_function', 'GO:0008014', ('57', '65'))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('effect', 'Reg', (106, 112))	('susceptibility', 'MPA', (175, 189))
93624	22792244	To resolve the controversial question raised by this evidence and provide more statistical power for detecting the significance of -160C/A to cancer risk, we performed a meta-analysis on the 160C/A polymorphism of E-cadherin and cancer risk with 47 case-control studies including 18,194 cases and 20,207 controls as of March 2012.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('160C/A', 'Var', (191, 197))	('E-cadherin', 'Gene', (214, 224))	('E-cadherin', 'Gene', '999', (214, 224))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cadherin', 'molecular_function', 'GO:0008014', ('216', '224'))	('-160C/A', 'Mutation', 'rs16260', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('160C/A', 'Mutation', 'c.160C>A', (132, 138))	('160C/A', 'Mutation', 'c.160C>A', (191, 197))	('cancer', 'Disease', (142, 148))
93627	22792244	We conducted a systematic literature search using the databases MEDLINE (US National Library of Medicine, Bethesda, Maryland) and PubMed (National Center for Biotechnology, National Library of Medicine) as of March 2012 with the keywords "polymorphism of the E-cadherin gene," "rs16260," and "-160C/A," in combination with "cancer," "tumor," "neoplasm" or "carcinoma."	('E-cadherin', 'Gene', (259, 269))	('cancer', 'Disease', (324, 330))	('and "-160C/A', 'Var', (288, 300))	('rs16260', 'Mutation', 'rs16260', (278, 285))	('neoplasm" or "carcinoma', 'Disease', (343, 366))	('tumor', 'Disease', 'MESH:D009369', (334, 339))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('E-cadherin', 'Gene', '999', (259, 269))	('neoplasm" or "carcinoma', 'Disease', 'MESH:D009369', (343, 366))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('tumor', 'Disease', (334, 339))	('rs16260', 'Var', (278, 285))	('-160C/A', 'Mutation', 'rs16260', (293, 300))	('carcinoma', 'Phenotype', 'HP:0030731', (357, 366))	('neoplasm', 'Phenotype', 'HP:0002664', (343, 351))	('cancer', 'Disease', 'MESH:D009369', (324, 330))
93628	22792244	Published meta-analyses on the association of polymorphisms of E-cadherin with cancer risk were included in the assessment of evidence.	('E-cadherin', 'Gene', '999', (63, 73))	('polymorphisms', 'Var', (46, 59))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('association', 'Interaction', (31, 42))	('cadherin', 'molecular_function', 'GO:0008014', ('65', '73'))	('E-cadherin', 'Gene', (63, 73))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
93629	22792244	The following information was independently extracted from each study by two investigators: 1) publication date, first author, year of publication, and country of origin; 2) polymorphism of the E-cadherin gene and cancer types; 3) characteristics of cases and controls and genotyping method; and 4) number of cases and controls with heterozygous and homozygous genotypes.	('cancer', 'Disease', (214, 220))	('E-cadherin', 'Gene', '999', (194, 204))	('cadherin', 'molecular_function', 'GO:0008014', ('196', '204'))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('E-cadherin', 'Gene', (194, 204))	('polymorphism', 'Var', (174, 186))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
93645	22792244	The heterogeneity could be attributed to one dataset from Grunhage et al., in which the association was investigated between the -160C/A polymorphism and familial colorectal cancer.	('-160C/A', 'Mutation', 'rs16260', (129, 136))	('the -160C/A', 'Var', (125, 136))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('familial colorectal cancer', 'Disease', 'MESH:D015179', (154, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('familial colorectal cancer', 'Disease', (154, 180))
93658	22792244	Overall, the meta-analysis showed that the -160A carriers had a significantly increased risk of developing urothelial cancer (OR = 1.70, 95% CI = 1.11-2.61), and significant heterogeneity was found among the five studies (Q = 20.37, P = 0.0004, I2 = 80%).	('urothelial cancer', 'Disease', (107, 124))	('urothelial cancer', 'Disease', 'MESH:D014523', (107, 124))	('the -160A', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))
93664	22792244	The meta-analysis performed in this paper indicated that the -160AA homozygote predisposed its carriers to urothelial cancer.	('predisposed', 'Reg', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('urothelial cancer', 'Disease', (107, 124))	('urothelial cancer', 'Disease', 'MESH:D014523', (107, 124))	('the -160AA', 'Var', (57, 67))
93669	22792244	Bias and greater heterogeneity arose because of the further inclusion of new evidence, which suggests the requirement for more studies concerning the -160C/A polymorphism and cancer risk, especially those with rigorous selection of case and control samples and the reporting of more studies with a large sample size and negative results.	('the -160C/A', 'Var', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('-160C/A', 'Mutation', 'rs16260', (150, 157))
93676	22792244	If the relationship between the -160C/A polymorphism of E-cadherin and benign prostatic hyperplasia and other urothelial diseases could not be excluded, the selection of patients with these diseases as controls may not be suitable.	('patients', 'Species', '9606', (170, 178))	('the -160C/A', 'Var', (28, 39))	('benign prostatic hyperplasia', 'Disease', 'MESH:D011470', (71, 99))	('cadherin', 'molecular_function', 'GO:0008014', ('58', '66'))	('benign prostatic hyperplasia', 'Disease', (71, 99))	('urothelial diseases', 'Disease', 'MESH:D014522', (110, 129))	('urothelial diseases', 'Disease', (110, 129))	('-160C/A', 'Mutation', 'rs16260', (32, 39))	('benign prostatic hyperplasia', 'Phenotype', 'HP:0008711', (71, 99))	('E-cadherin', 'Gene', (56, 66))	('E-cadherin', 'Gene', '999', (56, 66))
93681	22792244	More studies are needed to properly address the bias of the existing data concerning -160A carriers and prostate cancer, especially studies with a large sample size and negative results.	('prostate cancer', 'Disease', 'MESH:D011471', (104, 119))	('-160A carriers', 'Var', (85, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (104, 119))	('prostate cancer', 'Disease', (104, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
93683	22792244	The excluded dataset investigated the association between the -160C/A polymorphism and familial colorectal cancer, which is a specific type of cancer accounting for approximately 20% of colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('familial colorectal cancer', 'Disease', (87, 113))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('colorectal cancer', 'Disease', 'MESH:D015179', (186, 203))	('-160C/A', 'Mutation', 'rs16260', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (186, 203))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('familial colorectal cancer', 'Disease', 'MESH:D015179', (87, 113))	('the -160C/A', 'Var', (58, 69))	('cancer', 'Disease', (107, 113))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))	('colorectal cancer', 'Disease', (186, 203))
26979	21464941	Many factors, such as chromosomal anomalies, genetic polymorphisms, genetic and epigenetic alterations, contribute to tumorigenesis and progression of urothelial carcinoma of the bladder.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('progression', 'CPA', (136, 147))	('epigenetic alterations', 'Var', (80, 102))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (151, 186))	('urothelial carcinoma of the bladder', 'Disease', (151, 186))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (151, 186))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('chromosomal anomalies', 'Disease', 'MESH:D002869', (22, 43))	('tumor', 'Disease', (118, 123))	('chromosomal anomalies', 'Disease', (22, 43))	('contribute', 'Reg', (104, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
24699	21464941	Aberrantly expressed miRNAs have been shown to be associated with many types of cancers.	('Aberrantly expressed', 'Var', (0, 20))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('miRNAs', 'Protein', (21, 27))	('associated', 'Reg', (50, 60))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
93748	21464941	It has been reported that select samples of histologically normal urothelium from bladder cancer patients have genetic alterations.	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('genetic alterations', 'Var', (111, 130))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))	('bladder cancer', 'Disease', (82, 96))	('patients', 'Species', '9606', (97, 105))
93773	32761678	The diagnostic capabilities for bladder cancer were 0.847 (miR-130a-3p), 0.762 (miR-130b-3p), and 0.892 (miR-301a-3p).	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('bladder cancer', 'Disease', (32, 46))	('miR-130b', 'Gene', '406920', (80, 88))	('miR-130b', 'Gene', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('miR-130a-3p', 'Var', (59, 70))
93788	32761678	11 ,  12 ,  13  Members of the miR-130 family (miR-130a-3p, miR-130b-3p, miR-301a-3p, and miR-301b-3p) share common seed sequences, and they perform similar biological functions.	('miR-301b', 'Gene', (90, 98))	('miR-130b', 'Gene', '406920', (60, 68))	('miR-130a-3p', 'Var', (47, 58))	('miR-301a-3p', 'Var', (73, 84))	('miR-130b', 'Gene', (60, 68))	('miR-301b', 'Gene', '100126318', (90, 98))
93793	32761678	First, we analyzed the differential expression of the miR-130 family (miR-130a-3p, miR-130b-3p, miR-301a-3p, and miR-301b-3p) in BC and adjacent tissues through The Cancer Genome Atlas (TCGA) database.	('miR-301b', 'Gene', '100126318', (113, 121))	('miR-130b', 'Gene', (83, 91))	('miR-130a-3p', 'Gene', (70, 81))	('Cancer', 'Disease', (165, 171))	('miR-301b', 'Gene', (113, 121))	('BC', 'Phenotype', 'HP:0009725', (129, 131))	('Cancer', 'Disease', 'MESH:D009369', (165, 171))	('Cancer', 'Phenotype', 'HP:0002664', (165, 171))	('miR-301a-3p', 'Var', (96, 107))	('miR-130b', 'Gene', '406920', (83, 91))
93815	32761678	As shown in Figure 2, three members (miR-130a-3p, miR-130b-3p, and miR-301a-3p) of the miR-130 family were highly upregulated in BC tissue, and the results were statistically significant.	('miR-301a-3p', 'Var', (67, 78))	('miR-130b', 'Gene', '406920', (50, 58))	('miR-130a-3p', 'Var', (37, 48))	('BC', 'Phenotype', 'HP:0009725', (129, 131))	('miR-130b', 'Gene', (50, 58))	('miR-130', 'Gene', (87, 94))	('upregulated', 'PosReg', (114, 125))
93818	32761678	The expression of miR-130a-3p (Figure 3A), miR-130b-3p (Figure 3C), and miR-301a-3p (Figure 3E) in the serum of patients with BC was significantly higher than that in normal human serum.	('human', 'Species', '9606', (174, 179))	('expression', 'MPA', (4, 14))	('patients', 'Species', '9606', (112, 120))	('miR-130b', 'Gene', '406920', (43, 51))	('BC', 'Phenotype', 'HP:0009725', (126, 128))	('miR-301a-3p', 'Var', (72, 83))	('miR-130b', 'Gene', (43, 51))	('higher', 'PosReg', (147, 153))	('miR-130a-3p', 'Var', (18, 29))
93820	32761678	The AUCs were 0.847 (Figure 3B), 0.762 (Figure 3D), 0.892 (Figure 3F), and 0.707 (Figure 3H) for miR-130a-3p, miR-130b-3p, miR-301a-3p, and miR-301b-3p, respectively.	('0.707', 'Var', (75, 80))	('miR-130b', 'Gene', '406920', (110, 118))	('miR-130a-3p', 'Var', (97, 108))	('miR-301a-3p', 'Var', (123, 134))	('miR-130b', 'Gene', (110, 118))	('miR-301b', 'Gene', '100126318', (140, 148))	('miR-301b', 'Gene', (140, 148))
93822	32761678	Therefore, we combined the expression data of three miR-130 family members (miR-130a-3p, miR-130b-3p, and miR-301a-3p), building a diagnostic panel by the stepwise logistic regression model.	('miR-130b', 'Gene', '406920', (89, 97))	('miR-130', 'Gene', (52, 59))	('miR-301a-3p', 'Var', (106, 117))	('miR-130b', 'Gene', (89, 97))
93824	32761678	The signal intensity of miR-130a-3p (2.725 fold change, Figure 5A), miR-130b-3p (2.134 fold change, Figure 5B), and miR-301a-3p (2.363 fold change, Figure 5C) in the serum of BC patients was significantly higher than that in the control group.	('higher', 'PosReg', (205, 211))	('miR-301a-3p', 'Var', (116, 127))	('patients', 'Species', '9606', (178, 186))	('signal intensity', 'MPA', (4, 20))	('miR-130b', 'Gene', '406920', (68, 76))	('BC', 'Phenotype', 'HP:0009725', (175, 177))	('miR-130b', 'Gene', (68, 76))	('miR-130a-3p', 'Var', (24, 35))
93829	32761678	As shown in Figure 6A and 6C, the expression levels of miR-130a-3p and miR-301a-3p were significantly correlated with tumor stage.	('expression', 'MPA', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('correlated', 'Reg', (102, 112))	('miR-301a-3p', 'Var', (71, 82))	('miR-130a-3p', 'Var', (55, 66))
93834	32761678	Notably, the expression level of miR-301a-3p (Figure 6G) was significantly different between the two groups of patients.	('different', 'Reg', (75, 84))	('expression level', 'MPA', (13, 29))	('miR-301a-3p', 'Var', (33, 44))	('patients', 'Species', '9606', (111, 119))
93842	32761678	33  Different studies have shown that miR-130a-3p is involved in different tumor pathogenesis, including esophageal adenocarcinoma, 19  hepatocellular carcinoma, 34  gastric cancer, 35  and ovarian carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('gastric cancer', 'Disease', (166, 180))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (136, 160))	('miR-130a-3p', 'Var', (38, 49))	('tumor', 'Disease', (75, 80))	('hepatocellular carcinoma', 'Disease', (136, 160))	('adenocarcinoma', 'Disease', (116, 130))	('gastric cancer', 'Disease', 'MESH:D013274', (166, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (190, 207))	('adenocarcinoma', 'Disease', 'MESH:D000230', (116, 130))	('ovarian carcinoma', 'Disease', (190, 207))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (105, 130))	('gastric cancer', 'Phenotype', 'HP:0012126', (166, 180))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (136, 160))	('involved', 'Reg', (53, 61))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (190, 207))	('pathogenesis', 'biological_process', 'GO:0009405', ('81', '93'))
93844	32761678	18  Research on miR-301a-3p and miR-301b-3p has focused on pancreatic, 38  colorectal, 39  hepatocellular, 16  and lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('colorectal', 'Disease', 'MESH:D015179', (75, 85))	('pancreatic', 'Disease', (59, 69))	('miR-301b', 'Gene', (32, 40))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('colorectal', 'Disease', (75, 85))	('hepatocellular', 'Disease', (91, 105))	('miR-301b', 'Gene', '100126318', (32, 40))	('lung cancer', 'Disease', (115, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('miR-301a-3p', 'Var', (16, 27))
93852	32761678	It was found that the miR-130 family was expressed more in the serum of high-grade BC patients, and the expression levels of miR-130a-3p and miR-301a-3p were significantly correlated with tumor stage.	('tumor', 'Disease', (188, 193))	('BC', 'Phenotype', 'HP:0009725', (83, 85))	('miR-130a-3p', 'Var', (125, 136))	('more', 'PosReg', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('miR-301a-3p', 'Var', (141, 152))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('expression', 'MPA', (104, 114))	('high-grade', 'Disease', (72, 82))	('correlated', 'Reg', (172, 182))	('patients', 'Species', '9606', (86, 94))
93857	32761678	We evaluated their ability to diagnose BC, with miR-130a-3p, miR-130b-3p, and miR-301a-3p being the most prominent.	('miR-130a-3p', 'Var', (48, 59))	('miR-301a-3p', 'Var', (78, 89))	('BC', 'Phenotype', 'HP:0009725', (39, 41))	('miR-130b', 'Gene', '406920', (61, 69))	('miR-130b', 'Gene', (61, 69))
93867	31869744	Three families of monoclonal antibodies targeting checkpoint inhibitors are already approved and being used to treat cancer:anti-CTLA4 (targeting the coinhibitory protein CTLA4 on T cells), anti-PD1 (targeting the coinhibitory protein PD-1 on T cells), and anti-PD-1L (targeting the coinhibitory protein PD-1L on cancer cells).	('CTLA4', 'Gene', '397286', (129, 134))	('PD-1', 'Gene', '100037293', (235, 239))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('PD-1', 'Gene', (304, 308))	('anti-PD1', 'Var', (190, 198))	('protein', 'cellular_component', 'GO:0003675', ('227', '234'))	('PD-1', 'Gene', '100037293', (304, 308))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('CTLA4', 'Gene', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('PD-1', 'Gene', (262, 266))	('CTLA4', 'Gene', (129, 134))	('PD-1', 'Gene', '100037293', (262, 266))	('CTLA4', 'Gene', '397286', (171, 176))	('protein', 'cellular_component', 'GO:0003675', ('296', '303'))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (313, 319))	('PD-1', 'Gene', (235, 239))
93870	31869744	Recently, both anti-PD1 and anti-PD-1L antibodies were shown to have activity in metastatic urothelial carcinoma of the bladder, with response rates ranging between 16 and 25%, depending on the trial and the agent.	('anti-PD1', 'Var', (15, 23))	('activity', 'MPA', (69, 77))	('PD-1', 'Gene', '100037293', (33, 37))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (92, 127))	('urothelial carcinoma of the bladder', 'Disease', (92, 127))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (92, 127))	('PD-1', 'Gene', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
93911	31869744	Aberrant function of BACH2 has been already implicated in several cancer types, such as lymphomas.	('BACH2', 'Gene', '60468', (21, 26))	('lymphoma', 'Phenotype', 'HP:0002665', (88, 96))	('BACH2', 'Gene', (21, 26))	('implicated', 'Reg', (44, 54))	('lymphomas', 'Disease', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('lymphomas', 'Disease', 'MESH:D008223', (88, 97))	('Aberrant function', 'Var', (0, 17))	('lymphomas', 'Phenotype', 'HP:0002665', (88, 97))	('cancer', 'Disease', (66, 72))
93924	31869744	Addressing the particular tumor characteristics, changing cancer immune set points and modulating the delicate interactions between tumor cells and immune cells are currently all major strategies aimed at enhancing the patient's ability to combat the disease (reviewed, for example, in Ref.	('modulating', 'Var', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('patient', 'Species', '9606', (219, 226))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('interactions', 'Interaction', (111, 123))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Disease', (132, 137))	('cancer', 'Disease', (58, 64))	('tumor', 'Disease', (26, 31))	('enhancing', 'PosReg', (205, 214))
93926	29211306	Telomerase Reverse Transcriptase Promoter Alterations Across Cancer Types as Detected by Next-Generation Sequencing: A Clinical and Molecular Analysis of 423 Patients Telomerase reverse transcriptase (TERT) promoter mutations that may affect telomerase activity have recently been described in human malignancies.	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('human', 'Species', '9606', (294, 299))	('transcriptase', 'molecular_function', 'GO:0034062', ('186', '199'))	('Transcriptase', 'molecular_function', 'GO:0003899', ('19', '32'))	('telomerase', 'Enzyme', (242, 252))	('Transcriptase', 'molecular_function', 'GO:0034062', ('19', '32'))	('activity', 'MPA', (253, 261))	('malignancies', 'Disease', 'MESH:D009369', (300, 312))	('telomerase activity', 'molecular_function', 'GO:0003720', ('242', '261'))	('Transcriptase', 'molecular_function', 'GO:0003968', ('19', '32'))	('affect', 'Reg', (235, 241))	('TERT', 'Gene', (201, 205))	('malignancies', 'Disease', (300, 312))	('mutations', 'Var', (216, 225))	('transcriptase', 'molecular_function', 'GO:0003968', ('186', '199'))	('transcriptase', 'molecular_function', 'GO:0003899', ('186', '199'))	('TERT', 'Gene', '7015', (201, 205))
93929	29211306	Of the 423 patients, 61 (14.4%) had TERT promoter mutations, and this placed TERT promoter alterations among the most prevalent aberrations after tumor protein 53 (TP53; 39%) and KRAS and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) alterations (15% each) in this population.	('KRAS', 'Gene', '3845', (179, 183))	('CDKN2A/B', 'Gene', '1029;1030', (228, 236))	('alterations', 'Var', (91, 102))	('KRAS', 'Gene', (179, 183))	('TERT', 'Gene', (36, 40))	('TP53', 'Gene', (164, 168))	('TERT', 'Gene', '7015', (36, 40))	('2A/B', 'Var', (232, 236))	('TERT', 'Gene', (77, 81))	('2A/B', 'SUBSTITUTION', 'None', (232, 236))	('TERT', 'Gene', '7015', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('2A/B', 'SUBSTITUTION', 'None', (222, 226))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('205', '221'))	('2A/B', 'Var', (222, 226))	('patients', 'Species', '9606', (11, 19))	('CDKN2A/B', 'Gene', (228, 236))	('TP53', 'Gene', '7157', (164, 168))	('tumor protein 53', 'Gene', (146, 162))	('mutations', 'Var', (50, 59))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('tumor protein 53', 'Gene', '7157', (146, 162))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('188', '221'))
93932	29211306	Patients harboring TERT promoter alterations or TP53 or CDKN2A/B alterations and those with 4 or more alterations demonstrated shorter survival (hazard ratio for normal TERT promoters vs aberrant ones, 0.44; P=.017).	('shorter', 'NegReg', (127, 134))	('TERT', 'Gene', (19, 23))	('alterations', 'Var', (65, 76))	('TERT', 'Gene', '7015', (169, 173))	('TERT', 'Gene', '7015', (19, 23))	('TP53', 'Gene', '7157', (48, 52))	('survival', 'MPA', (135, 143))	('TP53', 'Gene', (48, 52))	('CDKN2A/B', 'Gene', (56, 64))	('Patients', 'Species', '9606', (0, 8))	('TERT', 'Gene', (169, 173))	('CDKN2A/B', 'Gene', '1029;1030', (56, 64))
93933	29211306	Overall, TERT promoter alterations were among the most prevalent aberrations in this population, with very high rates in brain cancers (48% of patients) and melanomas (56% of patients).	('melanomas', 'Disease', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('prevalent', 'Reg', (55, 64))	('brain cancers', 'Disease', 'MESH:D001932', (121, 134))	('brain cancers', 'Disease', (121, 134))	('melanomas', 'Phenotype', 'HP:0002861', (157, 166))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (175, 183))	('melanomas', 'Disease', 'MESH:D008545', (157, 166))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('alterations', 'Var', (23, 34))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('brain cancer', 'Phenotype', 'HP:0030692', (121, 133))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (9, 13))
93934	29211306	Therapeutic options for targeting tumors with TERT promoter mutations are currently limited, although a variety of novel approaches are under development.	('TERT', 'Gene', '7015', (46, 50))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('men', 'Species', '9606', (149, 152))	('TERT', 'Gene', (46, 50))	('mutations', 'Var', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
93935	29211306	Research studies investigating oncogenic mechanisms have highlighted the strategies that cancer cells can develop to survive by manipulating pathways conferring a selective growth advantage to the tumor.	('growth advantage', 'CPA', (173, 189))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('manipulating', 'Var', (128, 140))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
93940	29211306	Reactivation or re-expression of telomerase is believed to be a widespread feature of human cancers, although its genetic basis remains poorly understood.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('re-expression', 'PosReg', (16, 29))	('Reactivation', 'Var', (0, 12))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('telomerase', 'Protein', (33, 43))
93941	29211306	Although it appears that somatic mutations in the coding region of TERT are rather infrequent in cancer, somatic mutations in the TERT promoter region have been described in several specific types of human cancers (eg, glioblastoma, bladder cancer, thyroid cancer, and skin cancer), and they lead to increased telomerase expression.	('thyroid cancer', 'Disease', (249, 263))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('bladder cancer', 'Phenotype', 'HP:0009725', (233, 247))	('increased', 'PosReg', (300, 309))	('mutations', 'Var', (113, 122))	('human', 'Species', '9606', (200, 205))	('glioblastoma', 'Disease', 'MESH:D005909', (219, 231))	('skin cancer', 'Disease', 'MESH:D012878', (269, 280))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('glioblastoma', 'Disease', (219, 231))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('thyroid cancer', 'Disease', 'MESH:D013964', (249, 263))	('cancers', 'Disease', (206, 213))	('cancer', 'Disease', (206, 212))	('described', 'Reg', (161, 170))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))	('telomerase', 'Enzyme', (310, 320))	('TERT', 'Gene', (67, 71))	('TERT', 'Gene', '7015', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('TERT', 'Gene', (130, 134))	('TERT', 'Gene', '7015', (130, 134))	('thyroid cancer', 'Phenotype', 'HP:0002890', (249, 263))	('skin cancer', 'Disease', (269, 280))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Disease', (274, 280))	('skin cancer', 'Phenotype', 'HP:0008069', (269, 280))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('bladder cancer', 'Disease', 'MESH:D001749', (233, 247))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', (257, 263))	('bladder cancer', 'Disease', (233, 247))	('expression', 'MPA', (321, 331))
93942	29211306	Mutations within the promoter region of TERT that confer enhanced TERT promoter activity have been reported in 2 major hotspots, which are located at -124 and -146 base pairs upstream of the transcriptional start site (also designated C228T and C250T, respectively).	('TERT', 'Gene', '7015', (40, 44))	('C228T', 'Mutation', 'c.228C>T', (235, 240))	('C228T', 'Var', (235, 240))	('TERT', 'Gene', (66, 70))	('TERT', 'Gene', '7015', (66, 70))	('C250T', 'Var', (245, 250))	('enhanced', 'PosReg', (57, 65))	('C250T', 'Mutation', 'c.250C>T', (245, 250))	('TERT', 'Gene', (40, 44))
93943	29211306	Interestingly, mutations in the TERT promoter region, as opposed to the coding region, allow the creation of additional binding sites for transcription factors and may represent a novel mechanism of oncogenic activation in cancer.	('TERT', 'Gene', '7015', (32, 36))	('binding', 'molecular_function', 'GO:0005488', ('120', '127'))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('binding', 'Interaction', (120, 127))	('mutations', 'Var', (15, 24))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('transcription', 'biological_process', 'GO:0006351', ('138', '151'))	('cancer', 'Disease', (223, 229))	('transcription', 'Protein', (138, 151))	('TERT', 'Gene', (32, 36))
93944	29211306	Our study objectives were to investigate the frequency of TERT promoter mutations in our population of patients with diverse cancer types and to delineate correlations with other clinical parameters.	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('TERT', 'Gene', (58, 62))	('patients', 'Species', '9606', (103, 111))	('TERT', 'Gene', '7015', (58, 62))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
93946	29211306	Next-generation sequencing was performed with Foundatio-nOne (Foundation Medicine, Cambridge, Massachusetts), which is a Clinical Laboratory Improvement Amendments-approved clinical-grade next-generation sequencing test that interrogates 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer to a typical median depth of coverage greater than 500 x (the full list is available at http://www.foundationone.com/learn.php#2).	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (321, 327))	('men', 'Species', '9606', (148, 151))	('cancer', 'Disease', (321, 327))	('men', 'Species', '9606', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('rearranged', 'Var', (296, 306))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('men', 'Species', '9606', (158, 161))
93947	29211306	This test can detect base substitutions, insertions and deletions, copy number alterations, and rearrangements from a routine tissue sample (including core or fine-needle biopsies).	('rearrangements', 'Var', (96, 110))	('detect', 'Reg', (14, 20))	('insertions', 'Var', (41, 51))	('core', 'cellular_component', 'GO:0019013', ('151', '155'))	('men', 'Species', '9606', (105, 108))	('deletions', 'Var', (56, 65))	('copy number alterations', 'Var', (67, 90))	('base substitutions', 'Var', (21, 39))
93949	29211306	Multiple logistic regressions (multivariate analysis) were fit to analyze the association between TERT promoter mutations and other patient characteristics.	('mutations', 'Var', (112, 121))	('patient', 'Species', '9606', (132, 139))	('TERT', 'Gene', (98, 102))	('TERT', 'Gene', '7015', (98, 102))
93958	29211306	In the overall population, 61 patients (14.4%) had a TERT promoter mutation, and this placed TERT promoter alterations among the most prevalent aberrations after tumor protein 53 alterations (TP53; 39%) and KRAS and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) alterations (15% each) in our population including diverse cancer types (Fig.	('2A/B', 'SUBSTITUTION', 'None', (250, 254))	('2A/B', 'Var', (250, 254))	('TERT', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (93, 97))	('CDKN2A/B', 'Gene', (256, 264))	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('alterations', 'Var', (107, 118))	('cancer', 'Disease', (325, 331))	('KRAS', 'Gene', '3845', (207, 211))	('patients', 'Species', '9606', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('216', '249'))	('TP53', 'Gene', (192, 196))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('KRAS', 'Gene', (207, 211))	('CDKN2A/B', 'Gene', '1029;1030', (256, 264))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('233', '249'))	('tumor protein 53', 'Gene', (162, 178))	('2A/B', 'SUBSTITUTION', 'None', (260, 264))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('2A/B', 'Var', (260, 264))	('tumor protein 53', 'Gene', '7157', (162, 178))	('TP53', 'Gene', '7157', (192, 196))
93959	29211306	Forty-three of 61 patients (70.5%) carried TERT promoter -124 C>T alterations, 14 patients (23%) carried 146 C>T alterations, and 4 patients (6.6%) carried 124-125 CC>TT or 138-139 CC>TT alterations (2 patients each).	('138-139 CC>TT', 'Var', (173, 186))	('146 C>T', 'Mutation', 'rs1060503013', (105, 112))	('TERT', 'Gene', (43, 47))	('TERT', 'Gene', '7015', (43, 47))	('patients', 'Species', '9606', (82, 90))	('patients', 'Species', '9606', (202, 210))	('124-125 CC>TT', 'Var', (156, 169))	('-124 C>T', 'Mutation', 'rs1242535815', (57, 65))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (132, 140))
93961	29211306	On the other hand, TERT promoter alterations were significantly less commonly observed in gastrointestinal, hematologic, breast, and lung cancers.	('TERT', 'Gene', (19, 23))	('TERT', 'Gene', '7015', (19, 23))	('lung cancers', 'Disease', 'MESH:D008175', (133, 145))	('breast', 'Disease', (121, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('lung cancers', 'Phenotype', 'HP:0100526', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('observed', 'Reg', (78, 86))	('alterations', 'Var', (33, 44))	('hematologic', 'Disease', (108, 119))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('lung cancers', 'Disease', (133, 145))	('gastrointestinal', 'Disease', (90, 106))
93962	29211306	Interestingly, TERT promoter alterations were significantly associated with an increased median number of alterations (5 vs 3; P <.0001; Table 1).	('TERT', 'Gene', '7015', (15, 19))	('TERT', 'Gene', (15, 19))	('alterations', 'Var', (29, 40))
93963	29211306	To consider potential confounders, we consecutively performed a multivariate analysis, which confirmed that TERT promoter alterations correlated with men (P =.031), brain cancers (P =.001), skin cancer/melanoma (P =.001), and a higher number of aberrations (P =.0001; Table 2).	('skin cancer', 'Disease', (190, 201))	('men', 'Species', '9606', (150, 153))	('skin cancer', 'Disease', 'MESH:D012878', (190, 201))	('brain cancer', 'Phenotype', 'HP:0030692', (165, 177))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('correlated', 'Reg', (134, 144))	('skin cancer', 'Phenotype', 'HP:0008069', (190, 201))	('men', 'Disease', (150, 153))	('TERT', 'Gene', (108, 112))	('melanoma', 'Disease', (202, 210))	('TERT', 'Gene', '7015', (108, 112))	('alterations', 'Var', (122, 133))	('brain cancers', 'Disease', 'MESH:D001932', (165, 178))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('brain cancers', 'Disease', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
93964	29211306	Indeed, TERT promoter alterations were the most frequent alterations detected in patients with brain cancers (48% of whom harbored these alterations), and they were followed by TP53 alterations (34%) and phosphatase and tensin homolog (PTEN) abnormalities (30%; Fig.	('TERT', 'Gene', (8, 12))	('TERT', 'Gene', '7015', (8, 12))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('TP53', 'Gene', (177, 181))	('brain cancer', 'Phenotype', 'HP:0030692', (95, 107))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('204', '234'))	('patients', 'Species', '9606', (81, 89))	('PTEN', 'Gene', (236, 240))	('alterations', 'Var', (22, 33))	('abnormalities', 'Var', (242, 255))	('PTEN', 'Gene', '5728', (236, 240))	('TP53', 'Gene', '7157', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('brain cancers', 'Disease', 'MESH:D001932', (95, 108))	('alterations', 'Var', (137, 148))	('brain cancers', 'Disease', (95, 108))	('phosphatase', 'molecular_function', 'GO:0016791', ('204', '215'))
93965	29211306	Similarly, 56% of patients with a skin/melanoma malignancy carried a TERT promoter mutation, and this made the gene the most frequently altered, with TP53 (38%) and CDKN2A/B alterations being in the second and third positions, respectively (Fig.	('skin/melanoma', 'Disease', (34, 47))	('TP53', 'Gene', (150, 154))	('CDKN2A/B', 'Gene', (165, 173))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma malignancy', 'Disease', (39, 58))	('CDKN2A/B', 'Gene', '1029;1030', (165, 173))	('skin/melanoma', 'Disease', 'MESH:D008545', (34, 47))	('mutation', 'Var', (83, 91))	('TERT', 'Gene', (69, 73))	('patients', 'Species', '9606', (18, 26))	('TERT', 'Gene', '7015', (69, 73))	('altered', 'Reg', (136, 143))	('TP53', 'Gene', '7157', (150, 154))	('melanoma malignancy', 'Disease', 'MESH:D008545', (39, 58))
93968	29211306	We next investigated the possible associations of TERT promoter alterations with other alterations, and we found that TERT promoter alterations were significantly associated with CDKN2A/B, PTEN, neurofibromin 1 (NF1), and BRAF alterations in a univariate analysis (all P values <=.004; Table 3).	('PTEN', 'Gene', (189, 193))	('TERT', 'Gene', '7015', (118, 122))	('PTEN', 'Gene', '5728', (189, 193))	('TERT', 'Gene', '7015', (50, 54))	('CDKN2A/B', 'Gene', (179, 187))	('neurofibromin 1', 'Gene', '4763', (195, 210))	('alterations', 'Var', (132, 143))	('BRAF', 'Gene', '673', (222, 226))	('neurofibromin 1', 'Gene', (195, 210))	('BRAF', 'Gene', (222, 226))	('associated', 'Reg', (163, 173))	('NF1', 'Gene', (212, 215))	('CDKN2A/B', 'Gene', '1029;1030', (179, 187))	('TERT', 'Gene', (50, 54))	('NF1', 'Gene', '4763', (212, 215))	('alterations', 'Var', (227, 238))	('TERT', 'Gene', (118, 122))
93969	29211306	Once adjustments were made for potential confounding variables in a multivariate analysis including brain and skin/melanoma primary tumor sites, only CDKN2A/B (P =.001) and BRAF alterations (P =.0003) remained independently associated with TERT promoter alterations.	('CDKN2A/B', 'Gene', (150, 158))	('BRAF', 'Gene', '673', (173, 177))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('skin/melanoma primary tumor', 'Disease', (110, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('BRAF', 'Gene', (173, 177))	('TERT', 'Gene', (240, 244))	('associated', 'Reg', (224, 234))	('TERT', 'Gene', '7015', (240, 244))	('skin/melanoma primary tumor', 'Disease', 'MESH:D012878', (110, 137))	('CDKN2A/B', 'Gene', '1029;1030', (150, 158))	('alterations', 'Var', (178, 189))	('men', 'Species', '9606', (11, 14))
93970	29211306	When we focused only on patients with brain tumors (n =44), TERT promoter alterations were associated with epidermal growth factor receptor (EGFR) alterations (33% vs 4.3%; P =.019), CDKN2A/B alterations (43% vs 4.3%; P =.003), and PTEN alterations (48% vs 13%; P =.020).	('EGFR', 'molecular_function', 'GO:0005006', ('141', '145'))	('CDKN2A/B', 'Gene', (183, 191))	('alterations', 'Var', (147, 158))	('TERT', 'Gene', (60, 64))	('EGFR', 'Gene', '1956', (141, 145))	('TERT', 'Gene', '7015', (60, 64))	('alterations', 'Var', (74, 85))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('CDKN2A/B', 'Gene', '1029;1030', (183, 191))	('epidermal growth factor receptor', 'Gene', (107, 139))	('brain tumors', 'Disease', 'MESH:D001932', (38, 50))	('brain tumors', 'Phenotype', 'HP:0030692', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('PTEN', 'Gene', (232, 236))	('epidermal growth factor receptor', 'Gene', '1956', (107, 139))	('associated', 'Reg', (91, 101))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('107', '130'))	('EGFR', 'Gene', (141, 145))	('PTEN', 'Gene', '5728', (232, 236))	('patients', 'Species', '9606', (24, 32))	('alterations', 'Reg', (237, 248))	('brain tumors', 'Disease', (38, 50))
93971	29211306	Although it was not statistically significant, the co-occurrence of TERT promoter alterations was less frequent in patients with TP53 alterations (19% vs 34%; P =.060).	('patients', 'Species', '9606', (115, 123))	('TERT', 'Gene', (68, 72))	('TERT', 'Gene', '7015', (68, 72))	('TP53', 'Gene', '7157', (129, 133))	('alterations', 'Var', (134, 145))	('TP53', 'Gene', (129, 133))
93972	29211306	In patients with skin/melanoma tumors (n =34), we could detect an association between TERT promoter alterations and BRAF alterations (37% vs 7%) in the multivariate model including the alterations with P <.1 in the univariate analysis.	('alterations', 'Var', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('BRAF', 'Gene', '673', (116, 120))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('BRAF', 'Gene', (116, 120))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('skin/melanoma tumors', 'Disease', (17, 37))	('patients', 'Species', '9606', (3, 11))	('TERT', 'Gene', (86, 90))	('skin/melanoma tumors', 'Disease', 'MESH:D008545', (17, 37))	('TERT', 'Gene', '7015', (86, 90))	('alterations', 'Var', (100, 111))
93973	29211306	A log-rank test (univariate) highlighted significantly shorter overall survival for patients harboring TERT promoter alterations in the overall population (P =.01) as well as TP53 or CDKN2A/B alterations.	('alterations', 'Var', (117, 128))	('overall survival', 'MPA', (63, 79))	('CDKN2A/B', 'Gene', '1029;1030', (183, 191))	('TP53', 'Gene', (175, 179))	('patients', 'Species', '9606', (84, 92))	('CDKN2A/B', 'Gene', (183, 191))	('shorter', 'NegReg', (55, 62))	('TERT', 'Gene', (103, 107))	('TERT', 'Gene', '7015', (103, 107))	('alterations', 'Var', (192, 203))	('TP53', 'Gene', '7157', (175, 179))
93974	29211306	In addition, patients with 4 or more alterations (4 alterations being the median in the overall population) also demonstrated significantly shorter overall survival.	('patients', 'Species', '9606', (13, 21))	('shorter', 'NegReg', (140, 147))	('alterations', 'Var', (37, 48))	('overall survival', 'MPA', (148, 164))
93976	29211306	Interestingly, subanalyses of the 3 tumor types with the highest prevalence of TERT alterations demonstrated consistently shorter survival (or a trend toward shorter survival) for patients with altered TERT promoters in brain tumors (n =44; P =.037), head and neck cancers (n =28; P =.2), or melanoma/skin tumors (n =34; P =.15).	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Disease', (306, 311))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('survival', 'MPA', (130, 138))	('neck', 'cellular_component', 'GO:0044326', ('260', '264'))	('neck cancers', 'Disease', (260, 272))	('patients', 'Species', '9606', (180, 188))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('melanoma/skin tumors', 'Disease', (292, 312))	('neck cancers', 'Disease', 'MESH:D006258', (260, 272))	('skin tumors', 'Phenotype', 'HP:0008069', (301, 312))	('TERT', 'Gene', (202, 206))	('TERT', 'Gene', '7015', (202, 206))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('melanoma', 'Phenotype', 'HP:0002861', (292, 300))	('shorter', 'NegReg', (122, 129))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('brain tumors', 'Disease', 'MESH:D001932', (220, 232))	('brain tumors', 'Phenotype', 'HP:0030692', (220, 232))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('altered', 'Var', (194, 201))	('melanoma/skin tumors', 'Disease', 'MESH:D008545', (292, 312))	('TERT', 'Gene', (79, 83))	('TERT', 'Gene', '7015', (79, 83))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('head and neck cancers', 'Phenotype', 'HP:0012288', (251, 272))	('brain tumors', 'Disease', (220, 232))	('tumor', 'Disease', (226, 231))
93978	29211306	Recently, TERT promoter mutations have been reported in human malignancies; they create de novo ETS1-binding motifs upregulating TERT messenger RNA and telomerase activity in malignant cells.	('upregulating', 'PosReg', (116, 128))	('telomerase activity', 'MPA', (152, 171))	('TERT', 'Gene', '7015', (129, 133))	('TERT', 'Gene', (10, 14))	('telomerase activity', 'molecular_function', 'GO:0003720', ('152', '171'))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('human', 'Species', '9606', (56, 61))	('RNA', 'cellular_component', 'GO:0005562', ('144', '147'))	('TERT', 'Gene', '7015', (10, 14))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('mutations', 'Var', (24, 33))	('malignancies', 'Disease', (62, 74))	('TERT', 'Gene', (129, 133))
93979	29211306	In our study population, 61 patients (14.4%) had a TERT promoter mutation, and this placed TERT promoter alterations among the most prevalent aberrations after TP53 (39%).	('TERT', 'Gene', (91, 95))	('TERT', 'Gene', (51, 55))	('TP53', 'Gene', '7157', (160, 164))	('TERT', 'Gene', '7015', (91, 95))	('alterations', 'Var', (105, 116))	('TERT', 'Gene', '7015', (51, 55))	('TP53', 'Gene', (160, 164))	('patients', 'Species', '9606', (28, 36))
93980	29211306	In the multivariate analysis, TERT promoter alterations were more frequent in men (21.5% of men and 8.3% of women had an alteration; P =.031) and were associated with brain tumors (48% of patients; P =.001) and skin cancer/melanoma (56% of patients; P =.001; Table 2).	('patients', 'Species', '9606', (188, 196))	('alterations', 'Var', (44, 55))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('skin cancer', 'Phenotype', 'HP:0008069', (211, 222))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('melanoma', 'Disease', (223, 231))	('TERT', 'Gene', (30, 34))	('brain tumors', 'Phenotype', 'HP:0030692', (167, 179))	('associated', 'Reg', (151, 161))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('brain tumors', 'Disease', 'MESH:D001932', (167, 179))	('TERT', 'Gene', '7015', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('skin cancer', 'Disease', 'MESH:D012878', (211, 222))	('men', 'Species', '9606', (110, 113))	('brain tumors', 'Disease', (167, 179))	('patients', 'Species', '9606', (240, 248))	('men', 'Species', '9606', (78, 81))	('women', 'Species', '9606', (108, 113))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('men', 'Species', '9606', (92, 95))	('skin cancer', 'Disease', (211, 222))
93984	29211306	The latter is consistent with other studies in which there has been an association between TERT promoter alterations and increased age.	('alterations', 'Var', (105, 116))	('TERT', 'Gene', (91, 95))	('TERT', 'Gene', '7015', (91, 95))
93985	29211306	In univariate analyses, survival was significantly shorter for patients harboring TERT promoter alterations in the overall population (P =.017) and also for patients with brain tumors (P =.037; Fig.	('alterations', 'Var', (96, 107))	('TERT', 'Gene', (82, 86))	('shorter', 'NegReg', (51, 58))	('brain tumors', 'Disease', 'MESH:D001932', (171, 183))	('brain tumors', 'Phenotype', 'HP:0030692', (171, 183))	('TERT', 'Gene', '7015', (82, 86))	('patients', 'Species', '9606', (157, 165))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('brain tumors', 'Disease', (171, 183))	('patients', 'Species', '9606', (63, 71))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('survival', 'MPA', (24, 32))
93987	29211306	Similarly, Zehir et al described poorer survival with several tumor types for patients harboring TERT promoter alterations (cutaneous melanoma, papillary thyroid cancer, and bladder urothelial carcinoma); however, it was statistically significant in the univariate analysis only for bladder urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('bladder urothelial carcinoma', 'Disease', (174, 202))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('papillary thyroid cancer', 'Disease', (144, 168))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (174, 202))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('poorer', 'NegReg', (33, 39))	('cutaneous melanoma', 'Disease', (124, 142))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (124, 142))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (124, 142))	('TERT', 'Gene', (97, 101))	('bladder urothelial carcinoma', 'Disease', (283, 311))	('thyroid cancer', 'Phenotype', 'HP:0002890', (154, 168))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (144, 168))	('TERT', 'Gene', '7015', (97, 101))	('tumor', 'Disease', (62, 67))	('alterations', 'Var', (111, 122))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (283, 311))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (144, 168))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
93988	29211306	In addition, the presence of TERT promoter mutations was previously associated with decreased overall survival in several other studies examining thyroid cancer, urogenital cancer, melanoma, laryngeal tumors, and glioblastomas.	('urogenital cancer', 'Disease', (162, 179))	('laryngeal tumors', 'Disease', (191, 207))	('glioblastoma', 'Phenotype', 'HP:0012174', (213, 225))	('glioblastomas', 'Disease', (213, 226))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (191, 207))	('TERT', 'Gene', (29, 33))	('TERT', 'Gene', '7015', (29, 33))	('thyroid cancer', 'Disease', (146, 160))	('glioblastomas', 'Disease', 'MESH:D005909', (213, 226))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('melanoma', 'Disease', (181, 189))	('overall survival', 'MPA', (94, 110))	('thyroid cancer', 'Disease', 'MESH:D013964', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('decreased', 'NegReg', (84, 93))	('urogenital cancer', 'Disease', 'MESH:D014565', (162, 179))	('glioblastomas', 'Phenotype', 'HP:0012174', (213, 226))	('thyroid cancer', 'Phenotype', 'HP:0002890', (146, 160))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('presence', 'Var', (17, 25))	('laryngeal tumors', 'Disease', 'MESH:D007822', (191, 207))	('melanoma', 'Disease', 'MESH:D008545', (181, 189))
93989	29211306	Finally, TERT promoter mutations were associated with alterations in CDKN2A, and the latter anomalies have also been associated with a poor prognosis.	('CDKN2A', 'Gene', '1029', (69, 75))	('associated', 'Reg', (38, 48))	('alterations', 'Var', (54, 65))	('CDKN2A', 'Gene', (69, 75))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (9, 13))
93990	29211306	TERT promoter alterations were significantly associated with an increased median number of alterations (5 vs 3; P <.0001) in our population.	('alterations', 'Var', (14, 25))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', (0, 4))
93992	29211306	In our study, 48% of the patients with brain tumors had the TERT promoter mutation, and patients with these alterations had shorter survival (Fig.	('mutation', 'Var', (74, 82))	('brain tumors', 'Phenotype', 'HP:0030692', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('TERT', 'Gene', '7015', (60, 64))	('brain tumors', 'Disease', 'MESH:D001932', (39, 51))	('survival', 'MPA', (132, 140))	('patients', 'Species', '9606', (88, 96))	('shorter', 'NegReg', (124, 131))	('brain tumors', 'Disease', (39, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('patients', 'Species', '9606', (25, 33))	('TERT', 'Gene', (60, 64))
93993	29211306	TERT promoter mutations have been reported in 55% to 84% of glioblastomas and have been associated with increased TERT expression.	('TERT', 'Gene', '7015', (114, 118))	('glioblastomas', 'Disease', 'MESH:D005909', (60, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('glioblastomas', 'Disease', (60, 73))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', (114, 118))	('mutations', 'Var', (14, 23))	('glioblastomas', 'Phenotype', 'HP:0012174', (60, 73))
93994	29211306	The prevalence of TERT promoter mutations is lower in pediatric patients with glioblastomas (approximately 11%).	('glioblastomas', 'Disease', 'MESH:D005909', (78, 91))	('patients', 'Species', '9606', (64, 72))	('glioblastomas', 'Disease', (78, 91))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('mutations', 'Var', (32, 41))	('TERT', 'Gene', (18, 22))	('glioblastomas', 'Phenotype', 'HP:0012174', (78, 91))	('TERT', 'Gene', '7015', (18, 22))
93997	29211306	In addition, TERT promoter mutations were associated with shorter overall survival for patients with primary glioblastomas in another study (11 vs 20 months [P =.002] and 12 vs 20 months [P =.04] for C228T and C250T, respectively).	('overall survival', 'MPA', (66, 82))	('shorter', 'NegReg', (58, 65))	('C228T', 'Mutation', 'c.228C>T', (200, 205))	('glioblastomas', 'Phenotype', 'HP:0012174', (109, 122))	('TERT', 'Gene', (13, 17))	('TERT', 'Gene', '7015', (13, 17))	('glioblastomas', 'Disease', 'MESH:D005909', (109, 122))	('C228T', 'Var', (200, 205))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('C250T', 'Var', (210, 215))	('glioblastomas', 'Disease', (109, 122))	('C250T', 'Mutation', 'c.250C>T', (210, 215))	('patients', 'Species', '9606', (87, 95))
94000	29211306	The -146 C>T mutation is the previously reported most frequently detected somatic base change in the TERT promoter.	('TERT', 'Gene', '7015', (101, 105))	('The -146 C>T', 'Var', (0, 12))	('-146 C>T', 'Mutation', 'c.-146C>T', (4, 12))	('TERT', 'Gene', (101, 105))
94001	29211306	In our skin cancer/melanoma population (as in our overall cancer population), -124 C>T was the most frequent somatic base change, with 8 of 19 TERT promoter-altered skin/melanoma tumors (42%) harboring this specific base change, whereas only 6 patients (31.6%) had a -146 C>T base change.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('skin cancer', 'Disease', 'MESH:D012878', (7, 18))	('patients', 'Species', '9606', (244, 252))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('-146 C>T', 'Mutation', 'c.-146C>T', (267, 275))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('-124 C>T', 'Var', (78, 86))	('skin cancer', 'Disease', (7, 18))	('skin/melanoma tumors', 'Disease', (165, 185))	('TERT', 'Gene', (143, 147))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('cancer', 'Disease', (12, 18))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('skin cancer', 'Phenotype', 'HP:0008069', (7, 18))	('melanoma', 'Disease', (19, 27))	('TERT', 'Gene', '7015', (143, 147))	('-124 C>T', 'Mutation', 'rs1242535815', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Disease', (58, 64))	('skin/melanoma tumors', 'Disease', 'MESH:D008545', (165, 185))
94002	29211306	TERT promoter alterations are associated with poorer survival for patients with cutaneous melanomas.	('alterations', 'Var', (14, 25))	('melanomas', 'Phenotype', 'HP:0002861', (90, 99))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (80, 99))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (80, 99))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (80, 98))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('cutaneous melanomas', 'Disease', (80, 99))	('poorer', 'NegReg', (46, 52))	('patients', 'Species', '9606', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
94003	29211306	In patients with skin/melanoma tumors (n =34), there was an association between TERT promoter alterations and BRAF alterations (37% vs 7%).	('TERT', 'Gene', '7015', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('alterations', 'Var', (94, 105))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('alterations', 'Var', (115, 126))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('skin/melanoma tumors', 'Disease', (17, 37))	('patients', 'Species', '9606', (3, 11))	('BRAF', 'Gene', '673', (110, 114))	('TERT', 'Gene', (80, 84))	('BRAF', 'Gene', (110, 114))	('skin/melanoma tumors', 'Disease', 'MESH:D008545', (17, 37))
94005	29211306	Macerola et al showed the association between TERT promoter and BRAF mutations to be an independent poor prognostic factor.	('mutations', 'Var', (69, 78))	('TERT', 'Gene', '7015', (46, 50))	('BRAF', 'Gene', '673', (64, 68))	('BRAF', 'Gene', (64, 68))	('TERT', 'Gene', (46, 50))	('association', 'Interaction', (26, 37))
94006	29211306	Vinagre et al also demonstrated that TERT messenger RNA levels are higher when TERT promoter and BRAF mutations coexist in melanomas.	('higher', 'PosReg', (67, 73))	('TERT', 'Gene', (37, 41))	('TERT', 'Gene', '7015', (37, 41))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('melanomas', 'Disease', (123, 132))	('TERT', 'Gene', (79, 83))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('mutations', 'Var', (102, 111))	('TERT', 'Gene', '7015', (79, 83))	('melanomas', 'Disease', 'MESH:D008545', (123, 132))	('BRAF', 'Gene', '673', (97, 101))	('BRAF', 'Gene', (97, 101))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))
94007	29211306	There is some evidence that BRAF mutations coexisting with TERT promoter mutations are associated with aggressive behavior in papillary thyroid cancers.	('aggressive behavior', 'Phenotype', 'HP:0000718', (103, 122))	('BRAF', 'Gene', '673', (28, 32))	('aggressive behavior', 'biological_process', 'GO:0002118', ('103', '122'))	('TERT', 'Gene', (59, 63))	('mutations', 'Var', (33, 42))	('TERT', 'Gene', '7015', (59, 63))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (126, 150))	('associated with', 'Reg', (87, 102))	('thyroid cancer', 'Phenotype', 'HP:0002890', (136, 150))	('BRAF', 'Gene', (28, 32))	('aggressive behavior in papillary thyroid cancers', 'Disease', (103, 151))	('papillary thyroid cancers', 'Phenotype', 'HP:0002895', (126, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('aggressive behavior in papillary thyroid cancers', 'Disease', 'MESH:D000077273', (103, 151))
94012	29211306	Tumor types with high levels of TERT promoter alterations almost always originate in tissues with relatively low rates of self-renewal (eg, melanomas and gliomas).	('TERT', 'Gene', '7015', (32, 36))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('melanomas', 'Disease', (140, 149))	('alterations', 'Var', (46, 57))	('originate', 'Reg', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('gliomas', 'Disease', (154, 161))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('gliomas', 'Phenotype', 'HP:0009733', (154, 161))	('gliomas', 'Disease', 'MESH:D005910', (154, 161))	('melanomas', 'Disease', 'MESH:D008545', (140, 149))	('TERT', 'Gene', (32, 36))
94013	29211306	It is speculated that TERT promoter mutations in these cancers maintain telomerase at levels that may lead to immortalization or at least prolong shortening of telomere length and senescence.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('TERT', 'Gene', (22, 26))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('telomere', 'cellular_component', 'GO:0000781', ('160', '168'))	('TERT', 'Gene', '7015', (22, 26))	('immortalization', 'CPA', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (36, 45))	('telomere', 'cellular_component', 'GO:0005696', ('160', '168'))	('shortening', 'NegReg', (146, 156))	('senescence', 'biological_process', 'GO:0010149', ('180', '190'))	('shortening of telomere', 'Phenotype', 'HP:0031413', (146, 168))	('telomere length', 'CPA', (160, 175))	('senescence', 'CPA', (180, 190))	('cancers', 'Disease', (55, 62))	('telomerase', 'Enzyme', (72, 82))
94014	29211306	This may explain the observed lack of TERT promoter mutations in gastrointestinal cancers (that continually self-renew) other than hepatocellular cancer.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (131, 152))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('TERT', 'Gene', (38, 42))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (65, 89))	('TERT', 'Gene', '7015', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('gastrointestinal cancers', 'Disease', (65, 89))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (131, 152))	('hepatocellular cancer', 'Disease', (131, 152))
94018	29211306	Therapeutic options for targeting tumors with TERT promoter mutations are currently limited, although a variety of treatment approaches to affecting TERT are under development, including immunotherapies that use TERT as a tumor-associated antigen.	('TERT', 'Gene', '7015', (149, 153))	('TERT', 'Gene', '7015', (46, 50))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Disease', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('TERT', 'Gene', (212, 216))	('TERT', 'Gene', '7015', (212, 216))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('TERT', 'Gene', (46, 50))	('mutations', 'Var', (60, 69))	('men', 'Species', '9606', (171, 174))	('TERT', 'Gene', (149, 153))	('men', 'Species', '9606', (120, 123))
94020	29211306	Further work is needed to ascertain the responses to BRAF inhibitors in the presence of coexisting TERT promoter mutations.	('BRAF', 'Gene', '673', (53, 57))	('TERT', 'Gene', (99, 103))	('BRAF', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (99, 103))	('mutations', 'Var', (113, 122))
94021	29211306	TERT promoter mutations lead to increased telomerase activity, which can be targeted with inhibitors.	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('increased', 'PosReg', (32, 41))	('telomerase activity', 'molecular_function', 'GO:0003720', ('42', '61'))	('telomerase', 'Enzyme', (42, 52))	('mutations', 'Var', (14, 23))
94024	29211306	In conclusion, abnormalities in the TERT promoter are frequent across diverse cancers, with 14.4% of our patients harboring these aberrations; this makes aberrations in the TERT promoter among the most prevalent aberrations after TP53 (39% of patients) and KRAS and CDKN2A/B alterations (15% each) in our population.	('KRAS', 'Gene', '3845', (257, 261))	('TERT', 'Gene', (173, 177))	('patients', 'Species', '9606', (105, 113))	('TERT', 'Gene', '7015', (173, 177))	('TERT', 'Gene', '7015', (36, 40))	('CDKN2A/B', 'Gene', '1029;1030', (266, 274))	('TP53', 'Gene', (230, 234))	('patients', 'Species', '9606', (243, 251))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('KRAS', 'Gene', (257, 261))	('cancers', 'Disease', (78, 85))	('CDKN2A/B', 'Gene', (266, 274))	('aberrations', 'Var', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('TERT', 'Gene', (36, 40))	('prevalent', 'Reg', (202, 211))	('TP53', 'Gene', '7157', (230, 234))
94025	29211306	TERT promoter alterations were more frequent in men and were associated with brain, skin/melanoma, and head and neck tumors.	('alterations', 'Var', (14, 25))	('skin/melanoma', 'Disease', 'MESH:D008545', (84, 97))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('men', 'Species', '9606', (48, 51))	('neck', 'cellular_component', 'GO:0044326', ('112', '116'))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('brain', 'Disease', (77, 82))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('neck tumors', 'Disease', 'MESH:D006258', (112, 123))	('associated', 'Reg', (61, 71))	('skin/melanoma', 'Disease', (84, 97))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('head and neck tumors', 'Phenotype', 'HP:0012288', (103, 123))	('neck tumors', 'Disease', (112, 123))
94026	29211306	Conversely, TERT promoter alterations were significantly less commonly observed in gastrointestinal, hematologic, breast, and lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('TERT', 'Gene', '7015', (12, 16))	('observed', 'Reg', (71, 79))	('lung cancers', 'Disease', 'MESH:D008175', (126, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('alterations', 'Var', (26, 37))	('breast', 'Disease', (114, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('hematologic', 'Disease', (101, 112))	('lung cancers', 'Phenotype', 'HP:0100526', (126, 138))	('gastrointestinal', 'Disease', (83, 99))	('lung cancers', 'Disease', (126, 138))	('TERT', 'Gene', (12, 16))
94030	25167871	Accordingly, downregulation or overactivity variously contributes to cancer development.	('contributes', 'Reg', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('downregulation', 'NegReg', (13, 27))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('overactivity', 'Var', (31, 43))
94041	25167871	As an important corollary, inhibition of canonical Notch signalling is unlikely to be efficacious and might be counter-productive in the treatment of urothelial carcinoma.	('urothelial carcinoma', 'Disease', (150, 170))	('inhibition', 'Var', (27, 37))	('Notch', 'Gene', (51, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('Notch', 'Gene', '4851;4853;4854;4855', (51, 56))	('signalling', 'biological_process', 'GO:0023052', ('57', '67'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (150, 170))
94051	25167871	In many tissues, Notch signalling contributes to the maintenance of stem cells or precursor cells and pathway hyperactivation caused by point mutations or translocations involving NOTCH genes is oncogenic by blocking cell differentiation, protecting against apoptosis and stimulating proliferation.	('translocations', 'Var', (155, 169))	('cell differentiation', 'CPA', (217, 237))	('apoptosis', 'biological_process', 'GO:0097194', ('258', '267'))	('NOTCH', 'Gene', (180, 185))	('apoptosis', 'biological_process', 'GO:0006915', ('258', '267'))	('point mutations', 'Var', (136, 151))	('hyperactivation', 'PosReg', (110, 125))	('Notch', 'Gene', (17, 22))	('pathway', 'Pathway', (102, 109))	('blocking', 'NegReg', (208, 216))	('protecting', 'Reg', (239, 249))	('NOTCH', 'Gene', '4851;4853;4854;4855', (180, 185))	('Notch', 'Gene', '4851;4853;4854;4855', (17, 22))	('proliferation', 'CPA', (284, 297))	('cell differentiation', 'biological_process', 'GO:0030154', ('217', '237'))	('apoptosis', 'CPA', (258, 267))	('signalling', 'biological_process', 'GO:0023052', ('23', '33'))	('stimulating', 'PosReg', (272, 283))
94053	25167871	Accordingly, pathway inactivation, frequently caused by NOTCH1 mutations, is observed in squamous carcinomas of several organs.	('inactivation', 'NegReg', (21, 33))	('mutations', 'Var', (63, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('pathway', 'Pathway', (13, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('squamous carcinomas', 'Disease', (89, 108))	('NOTCH1', 'Gene', (56, 62))	('squamous carcinomas', 'Disease', 'MESH:D002294', (89, 108))	('NOTCH1', 'Gene', '4851', (56, 62))
94063	25167871	Tumour stages and grading according to the UICC classification were as follows: pT3 G3 in 11 cases, pT4 G3 in 6 cases, pT2 G2 in 6 cases, pT2 G3 in 3 cases and one case each of pT3 G2, pT1 G2, pTa G3 and pTa G2 tumours.	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('pTa', 'molecular_function', 'GO:0008959', ('193', '196'))	('pTa', 'molecular_function', 'GO:0008959', ('204', '207'))	('pTa G2 tumours', 'Disease', (204, 218))	('tumours', 'Phenotype', 'HP:0002664', (211, 218))	('pTa G2 tumours', 'Disease', 'MESH:C563949', (204, 218))	('pT4 G3', 'Var', (100, 106))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('pT3', 'Disease', (80, 83))	('pT2 G3', 'Var', (138, 144))
94069	25167871	For reporter gene assays, cells seeded in 6-well plates were transiently transfected with XtremeGene9 (Roche) with 1 mug of either pJH26A (Notch responsive reporter) or pJH28A (Notch non-responsive reporter), kindly provided by Prof. D. Hayward, or in other experiments either pHES1 (+CBF1)-luc (addgene 41723; similar to pJH26A) or pHES1 lacking the CBF1 site (addgene 43805, similar to pJH28A).	('Notch', 'Gene', '4851;4853;4854;4855', (139, 144))	('pHES1', 'Chemical', '-', (277, 282))	('Notch', 'Gene', '4851;4853;4854;4855', (177, 182))	('pHES1', 'Chemical', '-', (333, 338))	('CBF1', 'Gene', '3516', (285, 289))	('CBF1', 'Gene', (285, 289))	('pJH28A', 'Var', (169, 175))	('CBF1', 'Gene', '3516', (351, 355))	('CBF1', 'Gene', (351, 355))	('pJH26A', 'Gene', (131, 137))	('Notch', 'Gene', (139, 144))	('mug', 'molecular_function', 'GO:0043739', ('117', '120'))	('Notch', 'Gene', (177, 182))
94073	25167871	Notch activity was determined as the ratio of wildtype to mutant plasmids and normalized to p850-luc and Renilla luciferase activity.	('mutant', 'Var', (58, 64))	('Notch', 'Gene', (0, 5))	('luciferase activity', 'molecular_function', 'GO:0047077', ('113', '132'))	('Notch', 'Gene', '4851;4853;4854;4855', (0, 5))	('luciferase activity', 'molecular_function', 'GO:0045289', ('113', '132'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('113', '132'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('113', '132'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('113', '132'))
94074	25167871	Briefly, urothelial cancer cell lines seeded in 6 well plates were co-transfected at 80% confluency with NOTCH1 full-length expression plasmid (or vector), the Notch-responsive reporters pJH26A or pJH28A and Renilla luciferase plasmid at a 1:1:0.1 ratio.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Notch', 'Gene', (160, 165))	('urothelial cancer', 'Disease', 'MESH:D014523', (9, 26))	('Notch', 'Gene', '4851;4853;4854;4855', (160, 165))	('NOTCH1', 'Gene', '4851', (105, 111))	('NOTCH1', 'Gene', (105, 111))	('pJH26A', 'Var', (187, 193))	('urothelial cancer', 'Disease', (9, 26))	('pJH28A', 'Var', (197, 203))	('Renilla luciferase plasmid', 'Disease', 'None', (208, 234))	('Renilla luciferase plasmid', 'Disease', (208, 234))
94076	25167871	For the colony forming assay 105 cells were seeded in 6 well plates and transfected with pIRES2-N1ICD or the corresponding pIRES2 empty vector, or with pcDNA4/to-Notch1 full-length (N1-FL) or the corresponding pcDNA4/to-lacZ plasmid.	('pIRES2-N1ICD', 'Var', (89, 101))	('Notch1', 'Gene', (162, 168))	('Notch1', 'Gene', '4851', (162, 168))
94115	25167871	NOTCH2 signals likely corresponding to full-length NOTCH2 and N2CTD were rather increased in cell lines with a mesenchymal phenotype (Figure 5).	('NOTCH2', 'Gene', (0, 6))	('mesenchymal', 'CPA', (111, 122))	('NOTCH2', 'Gene', (51, 57))	('increased', 'PosReg', (80, 89))	('NOTCH2', 'Gene', '4853', (0, 6))	('NOTCH2', 'Gene', '4853', (51, 57))	('N2CTD', 'Var', (62, 67))
94119	25167871	To measure canonical Notch signalling activity at its final step in the nucleus, we applied a pair of reporter gene plasmids with multiple binding sites for CBF1 functional in pJH26A, but mutated in pJH28A.	('CBF1', 'Gene', (157, 161))	('signalling', 'biological_process', 'GO:0023052', ('27', '37'))	('pJH26A', 'Disease', (176, 182))	('Notch', 'Gene', (21, 26))	('Notch', 'Gene', '4851;4853;4854;4855', (21, 26))	('nucleus', 'cellular_component', 'GO:0005634', ('72', '79'))	('mutated', 'Var', (188, 195))	('binding', 'molecular_function', 'GO:0005488', ('139', '146'))	('CBF1', 'Gene', '3516', (157, 161))
94121	25167871	Co-transfection of a plasmid expressing active N1ICD further increased Notch nuclear signalling in normal UPs (Figure 6C) and also in the UC cell lines showing that the Notch signalling pathway can in principle be activated by overexpression of NOTCH1.	('Notch', 'Gene', (71, 76))	('N1ICD', 'Gene', (47, 52))	('Notch', 'Gene', '4851;4853;4854;4855', (169, 174))	('active', 'Var', (40, 46))	('NOTCH1', 'Gene', '4851', (245, 251))	('Notch', 'Gene', '4851;4853;4854;4855', (71, 76))	('NOTCH1', 'Gene', (245, 251))	('signalling', 'biological_process', 'GO:0023052', ('85', '95'))	('increased', 'PosReg', (61, 70))	('Notch', 'Gene', (169, 174))	('Notch signalling pathway', 'biological_process', 'GO:0007219', ('169', '193'))
94124	25167871	To further investigate Notch signalling at the transcriptional level, we additionally applied another pair of reporters containing the natural HES1 promoter with intact or mutant CBF1 binding sites.	('mutant', 'Var', (172, 178))	('CBF1', 'Gene', '3516', (179, 183))	('Notch', 'Gene', '4851;4853;4854;4855', (23, 28))	('binding', 'molecular_function', 'GO:0005488', ('184', '191'))	('CBF1', 'Gene', (179, 183))	('HES1', 'Gene', (143, 147))	('signalling', 'biological_process', 'GO:0023052', ('29', '39'))	('HES1', 'Gene', '3280', (143, 147))	('Notch', 'Gene', (23, 28))
94129	25167871	As in the previous experiments, Notch signalling was induced by transfection of full-length NOTCH1, but neither further enhancement nor increased basal activity were achieved by exposure to the immobilized extracellular DLL1 domain (Figure 6H).	('transfection', 'Var', (64, 76))	('induced', 'Reg', (53, 60))	('NOTCH1', 'Gene', '4851', (92, 98))	('DLL1', 'Gene', (220, 224))	('Notch', 'Gene', '4851;4853;4854;4855', (32, 37))	('NOTCH1', 'Gene', (92, 98))	('signalling', 'biological_process', 'GO:0023052', ('38', '48'))	('DLL1', 'Gene', '28514', (220, 224))	('Notch', 'Gene', (32, 37))	('extracellular', 'cellular_component', 'GO:0005576', ('206', '219'))
94135	25167871	Whereas pharmacological Notch signalling inhibition did not diminish proliferation in urothelial cancer cell lines, overexpression of N1-FL or N1ICD diminished clonogenicity of urothelial carcinoma cell lines (Figure 8A).	('N1ICD', 'Var', (143, 148))	('urothelial carcinoma', 'Disease', (177, 197))	('Notch', 'Gene', (24, 29))	('N1-FL', 'Var', (134, 139))	('signalling', 'biological_process', 'GO:0023052', ('30', '40'))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('urothelial cancer', 'Disease', (86, 103))	('Notch', 'Gene', '4851;4853;4854;4855', (24, 29))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (177, 197))	('diminished', 'NegReg', (149, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('urothelial cancer', 'Disease', 'MESH:D014523', (86, 103))
94139	25167871	Sequencing data from the TCGA consortium (http://cancergenome.nih.gov/) indicate only few mutations in Notch pathway components in urothelial carcinoma (Additional file 1: Table S3).	('mutations', 'Var', (90, 99))	('urothelial carcinoma', 'Disease', (131, 151))	('Notch', 'Gene', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('Notch', 'Gene', '4851;4853;4854;4855', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (131, 151))	('cancer', 'Disease', (49, 55))
94140	25167871	The frequency of NOTCH1 mutations is about 5% and is thus considerably lower than in head-and-neck squamous cell carcinomas.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (99, 123))	('neck', 'cellular_component', 'GO:0044326', ('94', '98'))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (99, 123))	('NOTCH1', 'Gene', '4851', (17, 23))	('NOTCH1', 'Gene', (17, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('mutations', 'Var', (24, 33))	('head-and-neck', 'Disease', (85, 98))	('squamous cell carcinomas', 'Disease', (99, 123))	('lower', 'NegReg', (71, 76))
94141	25167871	A more likely cause of downregulation are copy number changes at chromosome 9q34 (where NOTCH1 is encoded) which occur in up to 30% of invasive UC.	('NOTCH1', 'Gene', '4851', (88, 94))	('NOTCH1', 'Gene', (88, 94))	('invasive UC', 'Disease', (135, 146))	('copy number changes', 'Var', (42, 61))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))
94162	25167871	In UC cell lines, a reporter plasmid driven by the HES1 promoter was similarly active, if the CBF sites were wild-type or mutant, supporting our conclusion that canonical Notch signalling is inactive.	('Notch', 'Gene', (171, 176))	('HES1', 'Gene', '3280', (51, 55))	('signalling', 'biological_process', 'GO:0023052', ('177', '187'))	('Notch', 'Gene', '4851;4853;4854;4855', (171, 176))	('HES1', 'Gene', (51, 55))	('mutant', 'Var', (122, 128))
94163	25167871	However, luciferase was induced by N1ICD cotransfection indicating that HES1 can be a target of an active Notch pathway in urothelial cells.	('luciferase', 'Enzyme', (9, 19))	('Notch', 'Gene', (106, 111))	('Notch', 'Gene', '4851;4853;4854;4855', (106, 111))	('HES1', 'Gene', '3280', (72, 76))	('N1ICD cotransfection', 'Var', (35, 55))	('induced', 'Reg', (24, 31))	('HES1', 'Gene', (72, 76))
94166	25167871	Rather, NOTCH1 transfected cells often showed misshaped or abnormally large nuclei or became obviously binuclear.	('NOTCH1', 'Gene', '4851', (8, 14))	('NOTCH1', 'Gene', (8, 14))	('misshaped', 'CPA', (46, 55))	('transfected', 'Var', (15, 26))	('showed', 'Reg', (39, 45))
94172	25167871	Collectively, our findings indicate that canonical Notch signalling is lost in urothelial carcinoma mainly via inactivation of NOTCH1, which in normal urothelium may promote specific steps of urothelial differentiation.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (79, 99))	('Notch', 'Gene', (51, 56))	('inactivation', 'Var', (111, 123))	('NOTCH1', 'Gene', (127, 133))	('NOTCH1', 'Gene', '4851', (127, 133))	('urothelial differentiation', 'CPA', (192, 218))	('Notch', 'Gene', '4851;4853;4854;4855', (51, 56))	('signalling', 'biological_process', 'GO:0023052', ('57', '67'))	('promote', 'PosReg', (166, 173))	('urothelial carcinoma', 'Disease', (79, 99))
94173	25167871	As it has been shown that inhibition of the gamma-secretase leads to hyperproliferation in tissues, where Notch signalling promotes differentiation, inhibition of Notch does therefore not appear to represent a useful therapeutic approach to UC.	('Notch', 'Gene', '4851;4853;4854;4855', (163, 168))	('promotes', 'PosReg', (123, 131))	('Notch', 'Gene', (106, 111))	('signalling', 'biological_process', 'GO:0023052', ('112', '122'))	('inhibition', 'Var', (26, 36))	('Notch', 'Gene', '4851;4853;4854;4855', (106, 111))	('hyperproliferation', 'Disease', (69, 87))	('differentiation', 'MPA', (132, 147))	('Notch', 'Gene', (163, 168))	('gamma-secretase', 'Protein', (44, 59))	('leads to', 'Reg', (60, 68))
11050	28749918	In murine models, expression of PD-L1 on the mastocytoma cell line increased apoptosis in active tumor-reactive T cells, suggesting a possible target for cancer immunotherapy.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('PD-L1', 'Gene', (32, 37))	('apoptosis', 'CPA', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('tumor', 'Disease', (97, 102))	('mastocytoma', 'Disease', 'MESH:D034801', (45, 56))	('increased', 'PosReg', (67, 76))	('murine', 'Species', '10090', (3, 9))	('mastocytoma', 'Disease', (45, 56))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('expression', 'Var', (18, 28))
94247	28749918	BCG can cause flu-like symptoms, fatigue, cystitis, and, occasionally, severe bleeding or bladder contracture.	('cause', 'Reg', (8, 13))	('BCG', 'Var', (0, 3))	('bleeding', 'Disease', 'MESH:D006470', (78, 86))	('fatigue', 'Disease', 'MESH:D005221', (33, 40))	('flu-like symptoms', 'Disease', (14, 31))	('bleeding', 'Disease', (78, 86))	('contracture', 'Phenotype', 'HP:0001371', (98, 109))	('bladder contracture', 'Disease', (90, 109))	('cystitis', 'Disease', (42, 50))	('cystitis', 'Disease', 'MESH:D003556', (42, 50))	('fatigue', 'Disease', (33, 40))	('BCG', 'Species', '33892', (0, 3))	('fatigue', 'Phenotype', 'HP:0012378', (33, 40))	('bladder contracture', 'Disease', 'MESH:D001745', (90, 109))
94282	28749918	Use of anti-PD-1 and anti-PD-L1 in combination with RT in the setting of breast and melanoma mouse xenograft models also has led to improved survival.	('anti-PD-L1', 'Var', (21, 31))	('mouse', 'Species', '10090', (93, 98))	('anti-PD-1', 'Var', (7, 16))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('improved', 'PosReg', (132, 140))	('survival', 'CPA', (141, 149))
94286	28749918	The combination of anti-CTLA-4 antibodies and RT has shown a benefit in distant disease control in syngeneic mouse models.	('benefit', 'PosReg', (61, 68))	('anti-CTLA-4', 'Gene', (19, 30))	('combination', 'Interaction', (4, 15))	('anti-CTLA-4', 'Var', (19, 30))	('distant disease control', 'CPA', (72, 95))	('mouse', 'Species', '10090', (109, 114))
94324	28749918	When these variants are in the minority relative to urothelial or transitional cancer, then the tumor generally responds like urothelial cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('urothelial', 'Disease', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('urothelial cancer', 'Disease', (126, 143))	('variants', 'Var', (11, 19))	('urothelial', 'Disease', 'MESH:D014522', (52, 62))	('tumor', 'Disease', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('urothelial cancer', 'Disease', 'MESH:D014523', (126, 143))	('cancer', 'Disease', (137, 143))	('urothelial', 'Disease', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('urothelial', 'Disease', 'MESH:D014522', (126, 136))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
94326	28749918	Cases in which the entire tumor has variant differentiation often behave differently than those with pure urothelial cancer, as exemplified by the use of different chemotherapy regimens in them: platin and etoposide in small cell, adding a taxane in squamous cell, and fluoropyrimidine use in adenonocarcinomas.	('etoposide', 'Chemical', 'MESH:D005047', (206, 215))	('fluoropyrimidine', 'Chemical', '-', (269, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('taxane', 'Chemical', 'MESH:C080625', (240, 246))	('platin', 'Chemical', '-', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('variant', 'Var', (36, 43))	('urothelial cancer', 'Disease', (106, 123))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('adenonocarcinomas', 'Disease', (293, 310))	('urothelial cancer', 'Disease', 'MESH:D014523', (106, 123))	('pure', 'molecular_function', 'GO:0034023', ('101', '105'))	('adenonocarcinomas', 'Disease', 'None', (293, 310))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('differently', 'Reg', (73, 84))	('men', 'Species', '9606', (181, 184))
94327	28749918	With regard to immunotherapy directed at T-cell checkpoints in variant histology tumors, there are anecdotal reports of durable response.	('variant', 'Var', (63, 70))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
94330	28749918	The use of PD-L1 expression, microsatellite instability, and/or mutational burden may provide justification for selecting these patients for these therapies outside a clinical trial.	('PD-L1', 'Protein', (11, 16))	('microsatellite instability', 'Var', (29, 55))	('patients', 'Species', '9606', (128, 136))	('mutational burden', 'Var', (64, 81))
94335	32213857	Pure Large Nested Variant of Urothelial Carcinoma (LNUC) Is the Prototype of an FGFR3 Mutated Aggressive Urothelial Carcinoma with Luminal-Papillary Phenotype Since 2016, large nested urothelial carcinoma (LNUC) has been included within the WHO classification of urothelial tumors.	('Carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('urothelial carcinoma', 'Disease', (184, 204))	('Urothelial Carcinoma', 'Disease', 'MESH:D014523', (29, 49))	('FGFR3', 'Gene', '2261', (80, 85))	('Urothelial Carcinoma', 'Disease', (29, 49))	('urothelial tumors', 'Disease', 'MESH:D001749', (263, 280))	('Carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('Aggressive Urothelial Carcinoma', 'Disease', (94, 125))	('Aggressive Urothelial Carcinoma', 'Disease', 'MESH:D014523', (94, 125))	('Urothelial Carcinoma', 'Disease', 'MESH:D014523', (105, 125))	('Luminal-Papillary', 'Disease', 'MESH:D002291', (131, 148))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('Pure', 'molecular_function', 'GO:0034023', ('0', '4'))	('Mutated', 'Var', (86, 93))	('Luminal-Papillary', 'Disease', (131, 148))	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('urothelial tumors', 'Disease', (263, 280))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (184, 204))	('FGFR3', 'Gene', (80, 85))
94336	32213857	We evaluated, for the first time, markers for new immunooncological or targeted therapies including FGFR3 mutational status and PD-L1 status, the frequency of TERT-promoter mutations and the molecular subtype in a cohort of 25 LNUC using SNaPshot analysis and immunohistochemistry.	('PD-L1', 'Gene', (128, 133))	('FGFR3', 'Gene', '2261', (100, 105))	('PD-L1', 'Gene', '29126', (128, 133))	('FGFR3', 'Gene', (100, 105))	('mutational', 'Var', (106, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('100', '104'))	('TERT', 'Gene', (159, 163))	('TERT', 'Gene', '7015', (159, 163))
94338	32213857	Of the 17 evaluable pure LNUCs, 16 were FGFR3-mutated with identical mutations in their concomitant papillary/papillary-like components.	('papillary-like component', 'Phenotype', 'HP:0007482', (110, 134))	('mutations', 'Var', (69, 78))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('FGFR3', 'Gene', (40, 45))	('papillary-like components', 'Phenotype', 'HP:0007482', (110, 135))	('pure', 'molecular_function', 'GO:0034023', ('20', '24'))	('FGFR3', 'Gene', '2261', (40, 45))
94339	32213857	An FGFR3 mutation was found in 1/7 evaluable mixed LNUCs combined with NVUC.	('mutation', 'Var', (9, 17))	('FGFR3', 'Gene', '2261', (3, 8))	('found', 'Reg', (22, 27))	('FGFR3', 'Gene', (3, 8))	('FGFR', 'molecular_function', 'GO:0005007', ('3', '7'))	('NVUC', 'Chemical', '-', (71, 75))
94343	32213857	In contrast, FGFR3 mutations seem to be rare in mixed LNUC, which may indicate a different pathway of tumor development.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mutations', 'Var', (19, 28))	('FGFR3', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('FGFR3', 'Gene', '2261', (13, 18))	('mixed LNUC', 'Disease', (48, 58))
94361	32213857	Seventeen of 23 (73.9%) evaluable cases were FGFR3 mutated, 16 of which were pure LNUC.	('pure', 'molecular_function', 'GO:0034023', ('77', '81'))	('FGFR3', 'Gene', '2261', (45, 50))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('FGFR3', 'Gene', (45, 50))	('mutated', 'Var', (51, 58))
94362	32213857	The only mixed LNUC with a FGFR3 mutation was an LNUC combined with NVUC.	('NVUC', 'Chemical', '-', (68, 72))	('FGFR3', 'Gene', '2261', (27, 32))	('mutation', 'Var', (33, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('FGFR3', 'Gene', (27, 32))
94363	32213857	In detail, a p.S249C FGFR3 mutation was found in eight (47.1%), p.Y375C in six (35.3%) and p.R248C in three (17.6%) cases; the mixed LNUC case had a p.S249C mutation.	('FGFR3', 'Gene', '2261', (21, 26))	('p.S249C', 'Mutation', 'rs121913483', (149, 156))	('p.R248C', 'Var', (91, 98))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('p.S249C', 'Var', (13, 20))	('FGFR3', 'Gene', (21, 26))	('found', 'Reg', (40, 45))	('p.S249C', 'Mutation', 'rs121913483', (13, 20))	('p.Y375C', 'Var', (64, 71))	('p.Y375C', 'Mutation', 'rs121913485', (64, 71))	('p.R248C', 'Mutation', 'rs121913482', (91, 98))	('p.S249C', 'Var', (149, 156))
94364	32213857	The FGFR3 mutations identified in the muscle-invasive component of pure LNUC matched with the mutations in their papillary-like components in all evaluable cases.	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('FGFR3', 'Gene', (4, 9))	('papillary-like component', 'Phenotype', 'HP:0007482', (113, 137))	('pure', 'molecular_function', 'GO:0034023', ('67', '71'))	('mutations', 'Var', (10, 19))	('FGFR3', 'Gene', '2261', (4, 9))	('papillary-like components', 'Phenotype', 'HP:0007482', (113, 138))
94365	32213857	The distribution of FGFR3 mutations within the tumor components is shown in Table 2.	('FGFR3', 'Gene', '2261', (20, 25))	('FGFR3', 'Gene', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mutations', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('20', '24'))
94366	32213857	Eighteen of 21 (85.7%) successfully investigated cases showed one of the hotspot promoter mutations of the TERT gene.	('TERT', 'Gene', (107, 111))	('hotspot promoter', 'PosReg', (73, 89))	('mutations', 'Var', (90, 99))	('TERT', 'Gene', '7015', (107, 111))
94372	32213857	FGFR3 expression was significantly more frequent in FGFR3 mutated cases (13/13 positive cases with an FGFR3 mutation; p < 0.001).	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('more frequent', 'PosReg', (35, 48))	('FGFR3', 'Gene', (102, 107))	('FGFR3', 'Gene', '2261', (52, 57))	('FGFR3', 'Gene', (0, 5))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('FGFR3', 'Gene', (52, 57))	('mutated', 'Var', (58, 65))	('FGFR3', 'Gene', '2261', (102, 107))	('FGFR3', 'Gene', '2261', (0, 5))
94380	32213857	This is the first molecular analysis on LNUC with a focus on FGFR3 mutations and PD-L1 expression, which are therapeutically relevant targets in UC.	('FGFR3', 'Gene', (61, 66))	('PD-L1', 'Gene', (81, 86))	('FGFR', 'molecular_function', 'GO:0005007', ('61', '65'))	('mutations', 'Var', (67, 76))	('PD-L1', 'Gene', '29126', (81, 86))	('FGFR3', 'Gene', '2261', (61, 66))
94386	32213857	However, recent studies reported an approximate frequency of 12%-15% FGFR3 mutations in MIBC.	('FGFR3', 'Gene', '2261', (69, 74))	('FGFR', 'molecular_function', 'GO:0005007', ('69', '73'))	('MIBC', 'Disease', (88, 92))	('FGFR3', 'Gene', (69, 74))	('mutations', 'Var', (75, 84))
94389	32213857	In our cohort, 16/17 (94.1%) pure LNUC cases presented with an activating FGFR3 mutation, regardless of the presence of a papillary or papillary-like component.	('FGFR3', 'Gene', (74, 79))	('pure', 'molecular_function', 'GO:0034023', ('29', '33'))	('papillary-like component', 'Phenotype', 'HP:0007482', (135, 159))	('pure LNUC', 'Disease', (29, 38))	('activating', 'PosReg', (63, 73))	('FGFR3', 'Gene', '2261', (74, 79))	('mutation', 'Var', (80, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))
94390	32213857	In contrast, FGFR3 mutation analysis of mixed LNUC revealed a mutation in the LNUC component of one case only, which was LNUC combined with NVUC.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('mutation', 'Var', (19, 27))	('NVUC', 'Chemical', '-', (140, 144))	('FGFR3', 'Gene', (13, 18))	('mutation', 'Var', (62, 70))	('FGFR3', 'Gene', '2261', (13, 18))
94391	32213857	This result is concordant with our recent study of an NVUC cohort, which presented FGFR3 mutations in one of 26 (3.8%) cases.	('FGFR3', 'Gene', '2261', (83, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('83', '87'))	('FGFR3', 'Gene', (83, 88))	('mutations', 'Var', (89, 98))	('NVUC', 'Chemical', '-', (54, 58))
94393	32213857	To sum up, the concordant findings at the clinical and molecular levels, with less aggressive behavior and FGFR3 mutations in pure compared to mixed LNUC, indicate the possibility of different tumor entities despite the histomorphologically concordant LNUC component.	('FGFR3', 'Gene', '2261', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('aggressive behavior', 'biological_process', 'GO:0002118', ('83', '102'))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('mutations', 'Var', (113, 122))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('FGFR3', 'Gene', (107, 112))	('aggressive behavior', 'Phenotype', 'HP:0000718', (83, 102))	('pure', 'molecular_function', 'GO:0034023', ('126', '130'))	('tumor', 'Disease', (193, 198))	('aggressive behavior', 'Disease', (83, 102))	('aggressive behavior', 'Disease', 'MESH:D001523', (83, 102))
94400	32213857	In the most recent consensus classification system by Kamoun et al., six molecular classes were proposed, among them the luminal papillary class which includes apparently uninflamed tumors with frequent papillary growth patterns and 40% FGFR3 mutations.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('papillary growth patterns', 'Phenotype', 'HP:0007482', (203, 228))	('FGFR3', 'Gene', '2261', (237, 242))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('luminal', 'Chemical', 'MESH:D010634', (121, 128))	('mutations', 'Var', (243, 252))	('FGFR3', 'Gene', (237, 242))	('FGFR', 'molecular_function', 'GO:0005007', ('237', '241'))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
94402	32213857	Moreover, LNUC samples showed an FGFR3 mutation frequency much higher than in conventional MIBC and points to the possibility of an FGFR3-driven scenario in pure LNUC cases.	('FGFR3', 'Gene', (132, 137))	('mutation', 'Var', (39, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('132', '136'))	('FGFR3', 'Gene', '2261', (33, 38))	('FGFR3', 'Gene', '2261', (132, 137))	('pure', 'molecular_function', 'GO:0034023', ('157', '161'))	('FGFR3', 'Gene', (33, 38))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))
94407	32213857	This is supported by the fact that LNUC represents the molecular subtype of luminal papillary bladder cancers, in which FGFR3 alterations are among the most important oncogenic mechanisms.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('FGFR3', 'Gene', (120, 125))	('LNUC', 'Disease', (35, 39))	('bladder cancers', 'Phenotype', 'HP:0009725', (94, 109))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('luminal papillary bladder cancers', 'Disease', 'MESH:D001749', (76, 109))	('FGFR', 'molecular_function', 'GO:0005007', ('120', '124'))	('luminal papillary bladder cancers', 'Disease', (76, 109))	('FGFR3', 'Gene', '2261', (120, 125))	('alterations', 'Var', (126, 137))
94409	32213857	However, combination therapies of FGFR inhibitors with immune checkpoint inhibitors give hope for enhanced therapeutic effects, by the modulation of the tumor micro-environment, inducing a T-cell-inflamed phenotype, which may result in a response to immune checkpoint inhibitors.	('inhibitors', 'Var', (39, 49))	('enhanced', 'PosReg', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('combination', 'Interaction', (9, 20))	('FGFR', 'Gene', (34, 38))	('therapeutic', 'MPA', (107, 118))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('inducing', 'PosReg', (178, 186))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('response', 'MPA', (238, 246))	('T-cell-inflamed phenotype', 'MPA', (189, 214))
94414	32213857	The mutation hotspots analyzed in our study should cover more than 90% of bladder-cancer-relevant gain-of-function mutations of the FGFR3 gene and ~80% of TERT promoter mutations, respectively.	('FGFR3', 'Gene', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('bladder-cancer', 'Phenotype', 'HP:0009725', (74, 88))	('mutations', 'Var', (115, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('132', '136'))	('gain-of-function', 'PosReg', (98, 114))	('bladder-cancer', 'Disease', 'MESH:D001749', (74, 88))	('FGFR3', 'Gene', '2261', (132, 137))	('TERT', 'Gene', (155, 159))	('TERT', 'Gene', '7015', (155, 159))	('bladder-cancer', 'Disease', (74, 88))
94421	32213857	Seven SNaPshot primers detecting the FGFR3 mutations p.S249C, p.R248C, p.G372C, p.Y375C, p.A393E, p.K652E, p.K652Q, p.K652M and p.K652T were annealed to the PCR products and extended with a labelled dideoxynucleotide.	('p.A393E', 'Mutation', 'rs28931615', (89, 96))	('p.R248C', 'Mutation', 'rs121913482', (62, 69))	('p.R248C', 'Var', (62, 69))	('p.K652Q', 'Mutation', 'rs78311289', (107, 114))	('FGFR3', 'Gene', (37, 42))	('p.G372C', 'Var', (71, 78))	('p.K652Q', 'Var', (107, 114))	('FGFR3', 'Gene', '2261', (37, 42))	('p.K652M', 'Var', (116, 123))	('p.K652T', 'Var', (128, 135))	('p.S249C', 'Var', (53, 60))	('p.G372C', 'Mutation', 'rs121913479', (71, 78))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('p.K652T', 'Mutation', 'rs121913105', (128, 135))	('p.S249C', 'Mutation', 'rs121913483', (53, 60))	('p.K652E', 'Var', (98, 105))	('p.K652E', 'Mutation', 'rs78311289', (98, 105))	('dideoxynucleotide', 'Chemical', 'MESH:D054306', (199, 216))	('p.Y375C', 'Var', (80, 87))	('p.Y375C', 'Mutation', 'rs121913485', (80, 87))	('p.A393E', 'Var', (89, 96))	('p.K652M', 'Mutation', 'rs121913105', (116, 123))
94433	32213857	In contrast, FGFR3 mutations seem to be rare in mixed LNUC cases, which indicates a different molecular background of pure versus mixed LNUC, thus the classification of LNUC as a separate variant of UC should be considered.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('mutations', 'Var', (19, 28))	('FGFR3', 'Gene', (13, 18))	('FGFR3', 'Gene', '2261', (13, 18))	('pure', 'molecular_function', 'GO:0034023', ('118', '122'))	('mixed LNUC', 'Disease', (48, 58))
94457	31802888	Recently, emerging evidence has indicated that circ-Foxo3 was detectable in multiple cancers, and that circ-Foxo3 was associated with cell cycle retardation or apoptosis.	('apoptosis', 'CPA', (160, 169))	('retardation', 'Disease', 'MESH:D008607', (145, 156))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('cell cycle retardation', 'Phenotype', 'HP:0011018', (134, 156))	('associated', 'Reg', (118, 128))	('circ-Foxo3', 'Var', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cell cycle', 'biological_process', 'GO:0007049', ('134', '144'))	('retardation', 'Disease', (145, 156))
94493	31802888	The following primary antibodies were used: anti-cleaved-caspase3 (1:1000), anti-Bcl2 (1:1000), anti-Bax (1:1000), and anti-GAPDH (1:1000) (all from Abcam, UK).	('Bcl2', 'molecular_function', 'GO:0015283', ('81', '85'))	('anti-Bcl2', 'Var', (76, 85))	('GAPDH', 'Gene', '2597', (124, 129))	('GAPDH', 'Gene', (124, 129))	('anti-Bax', 'Var', (96, 104))	('anti-cleaved-caspase3', 'Var', (44, 65))
94495	31802888	Targeted mutation of the vector was generated within the circ-Foxo3 3'-UTR sequence by a QuikChange Multi Site-Directed Mutagenesis Kit (Agilent Technologies, USA) resulting a mutant luciferase reporter vector (named pmirGlo-CREB1-MUT; MUT).	('CREB1', 'Gene', (225, 230))	('mutant', 'Var', (176, 182))	('Mutagenesis', 'biological_process', 'GO:0006280', ('120', '131'))	('CREB1', 'Gene', '1385', (225, 230))
94503	31802888	We first tested the level of apoptosis in J82 cells treated with doxorubicin, cisplatin or H2O2.	('H2O2', 'Chemical', 'MESH:D014867', (91, 95))	('J82', 'CellLine', 'CVCL:0359', (42, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('doxorubicin', 'Chemical', 'MESH:D004317', (65, 76))	('H2O2', 'Var', (91, 95))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))	('tested', 'Reg', (9, 15))
94518	31802888	To experimentally validate the interaction, we designed luciferase reporters coupled with either wild-type (WT) or mutant (MUT) 3'-UTR sequence of circ-Foxo3, and co-transfected the reporters with a miR-191-5p mimic or inhibitor in bladder cancer cells.	('bladder cancer', 'Disease', 'MESH:D001749', (232, 246))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('mutant', 'Var', (115, 121))	('men', 'Species', '9606', (9, 12))	('bladder cancer', 'Disease', (232, 246))	('miR-191-5p', 'Gene', (199, 209))	('luciferase', 'Enzyme', (56, 66))	('bladder cancer', 'Phenotype', 'HP:0009725', (232, 246))	('miR-191-5p', 'Gene', '100302129', (199, 209))
94522	31802888	Similarly, ectopic overexpression of miR-191 significantly suppressed the expression of circ-Foxo3 in T24, UM-UC-3 and J82 cells, while silencing of miR-191 significantly enhanced expression of circ-Foxo3 (Figure 5E).	('expression', 'MPA', (74, 84))	('miR-191', 'Gene', (37, 44))	('enhanced', 'PosReg', (171, 179))	('circ-Foxo3', 'Gene', (88, 98))	('expression', 'MPA', (180, 190))	('suppressed', 'NegReg', (59, 69))	('miR-191', 'Gene', '406966', (149, 156))	('miR-191', 'Gene', (149, 156))	('silencing', 'Var', (136, 145))	('miR-191', 'Gene', '406966', (37, 44))	('J82', 'CellLine', 'CVCL:0359', (119, 122))
94528	31802888	The primary finding of our study is that circ-Foxo3 regulated bladder cancer growth in vivo and in vitro.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('bladder cancer', 'Phenotype', 'HP:0009725', (62, 76))	('circ-Foxo3', 'Var', (41, 51))	('regulated bladder', 'Phenotype', 'HP:0100645', (52, 69))	('bladder cancer', 'Disease', 'MESH:D001749', (62, 76))	('bladder cancer', 'Disease', (62, 76))	('regulated', 'Reg', (52, 61))
94533	31802888	Our current data showed circ-Foxo3 was also dysregulated in bladder cancer and that the dysregulation of circ-Foxo3 could potentially contribute to various solid tumors as a common pathogenic factor.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('dysregulated', 'Reg', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('solid tumors', 'Disease', 'MESH:D009369', (156, 168))	('contribute', 'Reg', (134, 144))	('circ-Foxo3', 'Gene', (105, 115))	('bladder cancer', 'Disease', 'MESH:D001749', (60, 74))	('bladder cancer', 'Disease', (60, 74))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('solid tumors', 'Disease', (156, 168))	('dysregulation', 'Var', (88, 101))
94535	31802888	circ-Foxo3 has been shown to increase cellular senescence, to arrest cancer cell cycle progression by binding to the cell cycle proteins CDK2 and p21, and to inhibit angiogenesis.	('angiogenesis', 'biological_process', 'GO:0001525', ('166', '178'))	('binding', 'Interaction', (102, 109))	('CDK2', 'Gene', '1017', (137, 141))	('inhibit', 'NegReg', (158, 165))	('arrest cancer', 'Disease', 'MESH:D009369', (62, 75))	('circ-Foxo3', 'Var', (0, 10))	('CDK2', 'Gene', (137, 141))	('cell cycle', 'biological_process', 'GO:0007049', ('117', '127'))	('increase', 'PosReg', (29, 37))	('arrest cancer', 'Disease', (62, 75))	('CDK', 'molecular_function', 'GO:0004693', ('137', '140'))	('angiogenesis', 'CPA', (166, 178))	('binding', 'molecular_function', 'GO:0005488', ('102', '109'))	('cellular senescence', 'biological_process', 'GO:0090398', ('38', '57'))	('cell cycle', 'biological_process', 'GO:0007049', ('76', '86'))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('p21', 'Gene', (146, 149))	('cellular senescence', 'CPA', (38, 57))	('p21', 'Gene', '644914', (146, 149))
94536	31802888	Our data showed in bladder cancer tissue and bladder cancer cell lines, one major effect of circ-Foxo3 was the induction of apoptosis, indicated by increased cleaved-caspase3 and Bax/Bcl2 ratio.	('induction of apoptosis', 'biological_process', 'GO:0006915', ('111', '133'))	('bladder cancer', 'Disease', 'MESH:D001749', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('Bax/Bcl2 ratio', 'MPA', (179, 193))	('circ-Foxo3', 'Var', (92, 102))	('increased', 'PosReg', (148, 157))	('bladder cancer', 'Disease', (19, 33))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('Bcl2', 'molecular_function', 'GO:0015283', ('183', '187'))	('cleaved-caspase3', 'MPA', (158, 174))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (19, 33))	('apoptosis', 'CPA', (124, 133))	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('bladder cancer', 'Disease', (45, 59))
94537	31802888	Our results was consistent with the pro-apoptotic effect of circ-Foxo3 in breast carcinoma biopsies and in multiple cancer cell lines.	('pro-apoptotic effect', 'MPA', (36, 56))	('breast carcinoma', 'Disease', 'MESH:D001943', (74, 90))	('circ-Foxo3', 'Var', (60, 70))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('breast carcinoma', 'Phenotype', 'HP:0003002', (74, 90))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast carcinoma', 'Disease', (74, 90))
94538	31802888	Importantly, in breast cancer cells, circ-Foxo3 also increased Foxo3 protein level and promoted p53 ubiquitination and subsequent degradation, suggesting an alternative pathway by which circ-Foxo3 induces cancer cell apoptosis.	('p53', 'Gene', '7157', (96, 99))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('increased', 'PosReg', (53, 62))	('promoted', 'PosReg', (87, 95))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('circ-Foxo3', 'Var', (37, 47))	('protein level', 'MPA', (69, 82))	('breast cancer', 'Disease', (16, 29))	('p53', 'Gene', (96, 99))	('degradation', 'biological_process', 'GO:0009056', ('130', '141'))	('degradation', 'MPA', (130, 141))	('induces', 'PosReg', (197, 204))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('circ-Foxo3', 'Var', (186, 196))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', (23, 29))	('Foxo3', 'Gene', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('apoptosis', 'biological_process', 'GO:0097194', ('217', '226'))	('apoptosis', 'biological_process', 'GO:0006915', ('217', '226'))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
94544	31802888	First, there may be alternative pathways by which circ-Foxo3 promotes cancer apoptosis, which were not examined in our study.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('promotes', 'PosReg', (61, 69))	('circ-Foxo3', 'Var', (50, 60))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
94551	31221981	The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism Cancer driver genes involved in epigenetics Among the 299 driver genes mentioned by Bailey et al., only the epigenetics-related pathways have been sorted out a20/20+: Classifies genes as an oncogene, tumor suppressor gene, or as a nondriver gene using Random Forests, http://2020plus.readthedocs.org bBLCA (bladder urothelial carcinoma), BRCA (breast invasive carcinoma), CESC (cervical squamous cell carcinoma and endocervical adenocarcinoma), CHOL (cholangiocarcinoma), DLBC (lymphoid neoplasm diffuse large B-cell lymphoma), ESCA (esophageal carcinoma), GBM (glioblastoma multiforme), HNSC (head and neck squamous cell carcinoma), KIRC (kidney renal clear cell carcinoma), KIRP (kidney renal papillary cell carcinoma), LAML (acute myeloid leukemia), LGG (brain lower grade glioma), LIHC (liver hepatocellular carcinoma), LUAD (lung adenocarcinoma), LUSC (lung squamous cell carcinoma), MESO (mesothelioma), PAAD (pancreatic adenocarcinoma), PANCAN (Pan-cancer), PRAD (prostate adenocarcinoma), SKCM (skin cutaneous melanoma), THCA (thyroid carcinoma), UCEC (uterine corpus endometrial carcinoma) Recent studies on mutations in cancer genomes have distinguished driver mutations from passenger mutations, which occur as byproducts of cancer development.	('melanoma', 'Phenotype', 'HP:0002861', (1169, 1177))	('cancer', 'Phenotype', 'HP:0002664', (1281, 1287))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (948, 972))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (981, 1000))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (1227, 1248))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (1014, 1037))	('tumor', 'Disease', (351, 356))	('lung squamous cell carcinoma', 'Disease', (1009, 1037))	('JARID1C', 'Gene', (32, 39))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (713, 736))	('AML', 'Phenotype', 'HP:0004808', (874, 877))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('carcinoma', 'Phenotype', 'HP:0030731', (611, 620))	('LAML', 'Disease', (873, 877))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (495, 520))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (879, 901))	('UTX', 'Gene', '7403', (52, 55))	('Cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mesothelioma', 'Disease', (1046, 1058))	('LAML', 'Disease', 'None', (873, 877))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (1067, 1092))	('mutations', 'Var', (1322, 1331))	('mesothelioma', 'Disease', 'MESH:D008654', (1046, 1058))	('cancer', 'Phenotype', 'HP:0002664', (1107, 1113))	('lymphoid neoplasm', 'Disease', (629, 646))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (602, 620))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (1009, 1037))	('cancer', 'Disease', (4, 10))	('glioblastoma', 'Phenotype', 'HP:0012174', (713, 725))	('glioma', 'Phenotype', 'HP:0009733', (927, 933))	('lymphoid neoplasm', 'Disease', 'MESH:D008223', (629, 646))	('KDM6A', 'Gene', (57, 62))	('thyroid carcinoma', 'Disease', (1186, 1203))	('hypoxic', 'Disease', 'MESH:D000860', (108, 115))	('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))	('LIHC', 'Disease', 'None', (936, 940))	('cholangiocarcinoma', 'Disease', (602, 620))	('IDH1/2', 'Gene', (24, 30))	('lung adenocarcinoma', 'Disease', (981, 1000))	('kidney renal clear cell carcinoma', 'Disease', (791, 824))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (685, 705))	('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))	('Pan-cancer', 'Disease', 'MESH:C537931', (1103, 1113))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (1154, 1177))	('endometrial carcinoma', 'Disease', (1227, 1248))	('B-cell lymphoma', 'Disease', (661, 676))	('Cancer', 'Disease', (151, 157))	('CHOL', 'Disease', 'None', (596, 600))	('carcinoma', 'Phenotype', 'HP:0030731', (511, 520))
94554	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))
94556	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))
94560	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))
94570	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))
94574	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))
94575	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))	('KDM6A', 'Gene', (231, 236))	('cancer', 'Disease', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (302, 309))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancers', 'Disease', (302, 309))	('KDM5C', 'Gene', '8242', (217, 222))	('cancer', 'Disease', (302, 308))	('tumor', 'Disease', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('IDH', 'Gene', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('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))
94577	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))
94580	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))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 89))	('activities', 'MPA', (257, 267))	('alpha-KG', 'Chemical', 'MESH:D007656', (289, 297))	('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))
94582	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))
94583	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))
94586	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))	('excess', 'PosReg', (213, 219))	('IDH', 'Gene', (200, 203))	('AML', 'Disease', (273, 276))	('mutant', 'Var', (193, 199))	('D-2HG dehydrogenase', 'Gene', (101, 120))	('glioma', 'Disease', 'MESH:D005910', (262, 268))	('IDH', 'Gene', '3417', (200, 203))	('alpha-KG', 'Chemical', 'MESH:D007656', (174, 182))	('D-2HG', 'MPA', (220, 225))	('AML', 'Phenotype', 'HP:0004808', (273, 276))	('glioma', 'Phenotype', 'HP:0009733', (262, 268))	('patients', 'Species', '9606', (248, 256))	('catalytic activity', 'molecular_function', 'GO:0003824', ('68', '86'))	('D2HGDH', 'Gene', (122, 128))
94587	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))	('alpha-KG-dependent enzymes', 'Enzyme', (107, 133))	('L-2HG', 'Var', (39, 44))	('alpha-KG', 'Chemical', 'MESH:D007656', (107, 115))
94593	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))
94598	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'))
94599	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))
94600	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))	('L2HGDH', 'Gene', (49, 55))	('Systemic L-2HG', 'MPA', (0, 14))	('L2HGDH', 'Gene', '79944', (49, 55))
94616	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))
94619	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))
94622	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'))
94628	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'))
94632	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))
94633	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))
94637	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))
94638	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))
94641	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))
94645	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))
94659	31221981	JARID1D was considered a tumor suppressor because of its downregulation, mutation, or loss in prostate cancer and ccRCC.	('downregulation', 'NegReg', (57, 71))	('JARID1D', 'Gene', (0, 7))	('ccRCC', 'Disease', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('loss in prostate cancer', 'Disease', 'MESH:D011471', (86, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor 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))
94664	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))	('breast cancer', 'Disease', (187, 200))	('JARID1A', 'Gene', (176, 183))	('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))
94665	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))
94667	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))
94670	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))
94675	31221981	JARID1B knockdown leads to an initial acceleration of tumor growth, followed by exhaustion.	('acceleration', 'PosReg', (38, 50))	('JARID1B', 'Gene', '10765', (0, 7))	('knockdown', 'Var', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('JARID1B', 'Gene', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
94683	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.	('me1', 'Gene', '4199', (170, 173))	('me1', 'Gene', (170, 173))	('X chromosome', 'cellular_component', 'GO:0000805', ('83', '95'))	('KDM6B', 'Gene', (118, 123))	('JMJD3', 'Gene', (112, 117))	('me2', 'Gene', (160, 163))	('KDM6A', 'Gene', '7403', (102, 107))	('KDM6B', 'Gene', '23135', (118, 123))	('JMJD3', 'Gene', '23135', (112, 117))	('H3K27me3-', 'Var', (149, 158))	('KDM6A', 'Gene', (102, 107))	('me2', 'Gene', '4200', (160, 163))
94684	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))
94685	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))
94688	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))
94695	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))
94696	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))
94697	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))
94698	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))
94700	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', '2146', (56, 60))	('KDM6A', 'Gene', '7403', (7, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('H3K27me3 enrichment', 'Var', (114, 133))	('IGFBP3', 'Gene', '3486', (83, 89))	('EZH2', 'Gene', (56, 60))	('urothelial bladder carcinoma', 'Disease', (21, 49))
94703	31221981	EZH2 inhibition also restored the normal gene expression patterns and impaired the proliferation of tumor cells harboring mutations in an H3K4 methyltransferase, MLL3/KMT2C, or a tumor suppressor, BAP1, by rebalancing the H3K27me3 levels at MLL3/BAP1 target genes.	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('BAP1', 'Gene', '8314', (246, 250))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('MLL3', 'Gene', '58508', (162, 166))	('KMT2C', 'Gene', '58508', (167, 172))	('KMT2C', 'Gene', (167, 172))	('BAP1', 'Gene', '8314', (197, 201))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('BAP1', 'Gene', (246, 250))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('normal gene expression patterns', 'MPA', (34, 65))	('proliferation', 'CPA', (83, 96))	('restored', 'PosReg', (21, 29))	('MLL3', 'Gene', '58508', (241, 245))	('H3K4 methyltransferase', 'Enzyme', (138, 160))	('MLL3', 'Gene', (162, 166))	('impaired', 'NegReg', (70, 78))	('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))	('tumor', 'Disease', (179, 184))
94704	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))
94705	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))
94706	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))	('cancer', 'Disease', (9, 15))	('EZH2', 'Gene', (77, 81))	('reduction', 'NegReg', (51, 60))	('MLL3', 'Gene', '58508', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('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))	('EZH2', 'Gene', '2146', (77, 81))
94709	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))
94710	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'))	('p300', 'Gene', (286, 290))	('me1', 'Gene', (108, 111))	('me1', 'Gene', '4199', (108, 111))	('enhancer', 'PosReg', (81, 89))	('methyltransferase complex', 'cellular_component', 'GO:0034708', ('209', '234'))	('H3K27ac', 'Var', (116, 123))
94711	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))
94714	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))
94715	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))
94719	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))
94721	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))
94728	31221981	Specific methylation of the K810 residue of Rb facilitates its interaction with CDK4 protein kinase.	('methylation', 'Var', (9, 20))	('CDK4', 'Gene', (80, 84))	('facilitates', 'PosReg', (47, 58))	('CDK4', 'Gene', '1019', (80, 84))	('K810', 'Var', (28, 32))	('Rb', 'Chemical', 'MESH:D012413', (44, 46))	('interaction', 'Interaction', (63, 74))	('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'))
94729	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))	('CDK', 'molecular_function', 'GO:0004693', ('58', '61'))	('S807', 'Var', (88, 92))	('JMJD3', 'Gene', (0, 5))	('prevents', 'NegReg', (49, 57))	('K810', 'Var', (23, 27))	('S811 residues', 'Var', (97, 110))	('Rb', 'Chemical', 'MESH:D012413', (114, 116))	('phosphorylating', 'MPA', (68, 83))	('CDK4', 'Gene', (58, 62))	('JMJD3', 'Gene', '23135', (0, 5))	('Rb', 'Chemical', 'MESH:D012413', (39, 41))
94733	31221981	p53 increases the nuclear localization of JMJD3 via protein-protein interaction and recruits JMJD3 to its target genes, such as that encoding p21, where it demethylates the H3K27me3 repressive mark.	('p53', 'Gene', (0, 3))	('increases', 'PosReg', (4, 13))	('H3K27me3', 'Protein', (173, 181))	('p53', 'Gene', '7157', (0, 3))	('p21', 'Gene', '1026', (142, 145))	('JMJD3', 'Gene', '23135', (42, 47))	('JMJD3', 'Gene', '23135', (93, 98))	('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'))
94739	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))
94746	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))
94751	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))
94752	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))	('JMJD3', 'Gene', '23135', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('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))
94759	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))
94786	31321218	The histological examination of the biopsied cervical lymph node was consistent with metastasis of breast cancer with positivity for CK7, CK19, CK20, E-cadherin, and estrogen receptors, but negativity for progesterone receptors and c-ErbB2.	('cadherin', 'molecular_function', 'GO:0008014', ('152', '160'))	('CK19', 'Gene', (138, 142))	('CK20', 'Gene', '54474', (144, 148))	('metastasis of breast cancer', 'Disease', 'MESH:D009362', (85, 112))	('c-ErbB2', 'Gene', '2064', (232, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('CK7', 'Gene', (133, 136))	('E-cadherin', 'Gene', (150, 160))	('metastasis of breast cancer', 'Disease', (85, 112))	('E-cadherin', 'Gene', '999', (150, 160))	('CK19', 'Gene', '3880', (138, 142))	('CK7', 'Gene', '3855', (133, 136))	('c-ErbB2', 'Gene', (232, 239))	('estrogen receptors', 'Protein', (166, 184))	('positivity', 'Var', (118, 128))	('CK20', 'Gene', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
94818	31321218	The metastatic involvement of the bladder may present a broad spectrum of symptoms; namely dysuria, urgency, lower abdominal or flank pain, and gross or microscopic haematuria.	('flank pain', 'Phenotype', 'HP:0030157', (128, 138))	('dysuria', 'Disease', (91, 98))	('flank pain', 'Disease', (128, 138))	('flank pain', 'Disease', 'MESH:D021501', (128, 138))	('metastatic', 'Var', (4, 14))	('dysuria', 'Phenotype', 'HP:0100518', (91, 98))	('haematuria', 'Disease', (165, 175))	('dysuria', 'Disease', 'MESH:D053159', (91, 98))	('pain', 'Phenotype', 'HP:0012531', (134, 138))	('haematuria', 'Disease', 'MESH:D006417', (165, 175))	('urgency', 'Disease', (100, 107))	('microscopic haematuria', 'Phenotype', 'HP:0002907', (153, 175))
94824	31321218	The absence of simultaneous staining for CK7 and CK20, which is typical in 65% cases of urothelial carcinomas, positive staining for estrogen receptors and negative staining for uroplakin III confirmed the diagnosis of liver and bladder metastasis of breast cancer.	('CK7', 'Gene', '3855', (41, 44))	('urothelial carcinomas', 'Disease', (88, 109))	('CK20', 'Gene', (49, 53))	('CK20', 'Gene', '54474', (49, 53))	('uroplakin III', 'Gene', '7380', (178, 191))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (88, 109))	('CK7', 'Gene', (41, 44))	('uroplakin III', 'Gene', (178, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (251, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('positive', 'Var', (111, 119))	('liver and bladder metastasis of breast cancer', 'Disease', 'MESH:D009362', (219, 264))
94833	31190987	Results: Expression of PD-L1 on tumor cells (TCs) was associated with muscle-invasive disease (OR=3.67, 95% CI: 2.53-5.33), and inversely associated with the history of intravesical bacilli Calmette-Guerin therapy (OR=0.39, 95% CI: 0.18-0.82) in bladder cancer patients.	('muscle-invasive disease', 'Disease', (70, 93))	('patients', 'Species', '9606', (261, 269))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('inversely', 'NegReg', (128, 137))	('PD-L1', 'Gene', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('bladder cancer', 'Disease', (246, 260))	('bladder cancer', 'Disease', 'MESH:D001749', (246, 260))	('bladder cancer', 'Phenotype', 'HP:0009725', (246, 260))	('associated', 'Reg', (138, 148))	('Expression', 'Var', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('bacilli Calmette-Guerin', 'Chemical', '-', (182, 205))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (70, 93))	('tumor', 'Disease', (32, 37))	('TCs', 'Chemical', '-', (45, 48))	('associated', 'Reg', (54, 64))
94836	31190987	Conclusions: Expression of PD-L1 on TCs was associated with muscle-invasive disease in patients with bladder cancer.	('Expression', 'Var', (13, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('TCs', 'Chemical', '-', (36, 39))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (60, 83))	('patients', 'Species', '9606', (87, 95))	('bladder cancer', 'Disease', (101, 115))	('muscle-invasive disease', 'Disease', (60, 83))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))	('PD-L1', 'Gene', (27, 32))	('associated with', 'Reg', (44, 59))
94842	31190987	Therefore, it is hypothesized that blockade of the PD-1/PD-L1 pathway may restore the native anti-tumor function of T cells and facilitate tumor regression.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('PD-1', 'Gene', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PD-1', 'Gene', '5133', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('facilitate', 'PosReg', (128, 138))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('blockade', 'Var', (35, 43))	('tumor', 'Disease', (98, 103))	('restore', 'PosReg', (74, 81))
94847	31190987	Studies by Nakanishi et al revealed a higher risk of recurrence and shorter overall survival (OS) with high PD-L1 expression in patients with BC, though not all reports support this conclusion.	('PD-L1', 'Gene', (108, 113))	('overall survival', 'MPA', (76, 92))	('OS', 'Chemical', '-', (94, 96))	('high', 'Var', (103, 107))	('patients', 'Species', '9606', (128, 136))	('expression', 'MPA', (114, 124))	('shorter', 'NegReg', (68, 75))
94882	31190987	In subgroup analysis of receiving anti-PD-1/PD-L1 treatment, high PD-L1 expression on ICs was significantly associated with better OS for UC patients without (n=2, HR=0.47; 95% CI: 0.27-0.83; p=0.352; fixed-effects) (Figure 4B1) and with (n=5, HR =0.61; 95% CI: 0.52-0.72; p=0.099; fixed-effects) anti-PD-1/PD-L1 treatment (UC) (Figure 4B2).	('PD-1', 'Gene', (39, 43))	('PD-1', 'Gene', '5133', (39, 43))	('high', 'Var', (61, 65))	('OS', 'Chemical', '-', (131, 133))	('ICs', 'Chemical', '-', (86, 89))	('PD-1', 'Gene', (302, 306))	('expression', 'Var', (72, 82))	('PD-1', 'Gene', '5133', (302, 306))	('PD-L1', 'Gene', (66, 71))	('patients', 'Species', '9606', (141, 149))
94892	31190987	The pooled survival analysis results indicated that PD-L1 expression on ICs was a predictor of better OS for patients with and without anti-PD-1/PD-L1 antibody treatment.	('OS', 'Chemical', '-', (102, 104))	('antibody', 'cellular_component', 'GO:0042571', ('151', '159'))	('better OS', 'Disease', (95, 104))	('patients', 'Species', '9606', (109, 117))	('PD-1', 'Gene', (140, 144))	('antibody', 'cellular_component', 'GO:0019815', ('151', '159'))	('PD-1', 'Gene', '5133', (140, 144))	('antibody', 'cellular_component', 'GO:0019814', ('151', '159'))	('expression', 'Var', (58, 68))	('antibody', 'molecular_function', 'GO:0003823', ('151', '159'))	('PD-L1', 'Gene', (52, 57))	('ICs', 'Chemical', '-', (72, 75))
94893	31190987	Moreover, the studies also supported the hypothesis that positive PD-L1 expression based on staining different cellular populations (tumor cells, tumor-infiltrating ICs, or both) might be associated with improved response to PD-1/PD-L1 inhibitors in UC patients.	('positive', 'Var', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('patients', 'Species', '9606', (253, 261))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('ICs', 'Chemical', '-', (165, 168))	('improved', 'PosReg', (204, 212))	('response', 'MPA', (213, 221))	('tumor', 'Disease', (133, 138))	('PD-1', 'Gene', (225, 229))	('PD-L1', 'Gene', (66, 71))	('PD-1', 'Gene', '5133', (225, 229))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
94896	31190987	Forced or constitutive PD-L1 expression by tumors in vivo and in vitro leads to immune tolerance, while blockade of PD-L1/PD-1 enhances anti-tumor immunity and inhibits tumor growth.The presence of PD-L1 glycoprotein on the surface of UC cells may affect malignant stage progression via impairing host anti-tumor immunity, which may explain the positive correlation between PD-L1 expression and high-risk prognostic factors.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', (307, 312))	('impairing', 'NegReg', (287, 296))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('PD-1', 'Gene', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('PD-1', 'Gene', '5133', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('malignant stage progression', 'CPA', (255, 282))	('tumor', 'Disease', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('PD-L1 glycoprotein', 'Protein', (198, 216))	('affect', 'Reg', (248, 254))	('presence', 'Var', (186, 194))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
94901	31190987	In this meta-analysis, only two studies reported improved OS with PD-L1 expression on tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('OS', 'Chemical', '-', (58, 60))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('expression', 'Var', (72, 82))	('PD-L1', 'Gene', (66, 71))
94912	31190987	Our observation that PD-L1 positivity predicts postoperative mortality may help identify patients with organ-confined tumors who are at high risk for disease progression and who may benefit from treatment in addition to surgery.	('positivity', 'Var', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('patients', 'Species', '9606', (89, 97))	('PD-L1', 'Gene', (21, 26))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
94919	31190987	Evaluating both TCs and ICs in a combined definition of PD-L1 status (CPS) seemed to show that PD-L1 was a positive predictive factor for ORR (HR=0.92).	('ORR', 'Disease', (138, 141))	('TCs', 'Chemical', '-', (16, 19))	('PD-L1', 'Var', (95, 100))	('ICs', 'Chemical', '-', (24, 27))	('CPS', 'Disease', (70, 73))	('CPS', 'Disease', 'MESH:D020165', (70, 73))
94924	31190987	In conclusion, this meta-analysis suggests that PD-L1 expression on BC TCs is associated with more aggressive clinical features and reduced OS in patients with organ-confined disease.	('aggressive clinical features', 'CPA', (99, 127))	('OS', 'Chemical', '-', (140, 142))	('expression', 'Var', (54, 64))	('TCs', 'Chemical', '-', (71, 74))	('reduced', 'NegReg', (132, 139))	('PD-L1', 'Gene', (48, 53))	('patients', 'Species', '9606', (146, 154))
94954	30653154	Histopathological examination showed high-grade prostatic urothelial carcinoma [Immunohistochemistry: CK5/6(-), CK7(+), CgA(-), GATA-3(+,55%), P40(+), P504s(-), P63(+), PSA(-), Syn(-), uroplakim III(+), and CD56(-)] (Figs.	('CgA', 'Gene', '1113', (120, 123))	('GATA-3', 'Gene', (128, 134))	('CK5', 'Gene', '3852', (102, 105))	('Syn', 'Gene', (177, 180))	('P63', 'Gene', '8626', (161, 164))	('prostatic urothelial carcinoma', 'Disease', 'MESH:D011472', (48, 78))	('prostatic urothelial carcinoma', 'Disease', (48, 78))	('P40', 'Gene', (143, 146))	('P63', 'Gene', (161, 164))	('CK7', 'Gene', (112, 115))	('CgA', 'Gene', (120, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Syn', 'Gene', '23336', (177, 180))	('P40', 'Gene', '8626', (143, 146))	('CK7', 'Gene', '3855', (112, 115))	('P40', 'cellular_component', 'GO:0070743', ('143', '146'))	('P504s', 'Var', (151, 156))	('CK5', 'Gene', (102, 105))	('GATA-3', 'Gene', '2625', (128, 134))	('P40', 'cellular_component', 'GO:0043514', ('143', '146'))
94974	30653154	Moreover, prostatic urothelial carcinoma is generally negative for PSA and P504 s, which is also significant for differential diagnosis.	('P504 s', 'Var', (75, 81))	('PSA', 'Disease', (67, 70))	('negative', 'NegReg', (54, 62))	('prostatic urothelial carcinoma', 'Disease', 'MESH:D011472', (10, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('prostatic urothelial carcinoma', 'Disease', (10, 40))
95006	26430392	The regimen of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), the first breakthrough in the treatment of muscle-invasive UC, was associated with improved progression-free survival (PFS) and overall survival (OS) compared with single-agent cisplatin.	('MVAC', 'Chemical', '-', (69, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('improved', 'PosReg', (159, 167))	('progression-free survival', 'CPA', (168, 193))	('men', 'Species', '9606', (8, 11))	('men', 'Species', '9606', (111, 114))	('vinblastine', 'Chemical', 'MESH:D014747', (29, 40))	('methotrexate', 'Var', (15, 27))	('overall survival', 'CPA', (204, 220))	('cisplatin', 'Chemical', 'MESH:D002945', (253, 262))	('doxorubicin', 'Chemical', 'MESH:D004317', (42, 53))	('methotrexate', 'Chemical', 'MESH:D008727', (15, 27))	('cisplatin', 'Var', (58, 67))
95016	26430392	DD-MVAC regimen is currently being studied in the neoadjuvant setting prior to radical cystectomy for patients with muscle-invasive disease in a number of studies (NCT00808639, NCT01031420, and NCT00506155).	('NCT00808639', 'Var', (164, 175))	('DD-MVAC', 'Chemical', '-', (0, 7))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (116, 139))	('patients', 'Species', '9606', (102, 110))	('men', 'Species', '9606', (12, 15))	('muscle-invasive disease', 'Disease', (116, 139))	('NCT01031420', 'Var', (177, 188))
95027	26430392	demonstrated that in patients with advanced UC treated with cisplatin combination chemotherapy those with low levels of ERCC1 mRNA expression had a median survival of 25.4 months versus 15.4 months in those with high levels of expression.	('ERCC1', 'Gene', '2067', (120, 125))	('patients', 'Species', '9606', (21, 29))	('mRNA expression', 'MPA', (126, 141))	('low', 'Var', (106, 109))	('ERCC1', 'Gene', (120, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))
95030	26430392	Over-expression of the tumor suppressor p53 in a human bladder cancer cell line through adenoviral gene transfer has been effective in overcoming platinum resistance.	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('bladder cancer', 'Disease', (55, 69))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('platinum', 'Chemical', 'MESH:D010984', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('human', 'Species', '9606', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('p53', 'Gene', (40, 43))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('overcoming', 'PosReg', (135, 145))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('p53', 'Gene', '7157', (40, 43))	('Over-expression', 'Var', (0, 15))	('platinum', 'CPA', (146, 154))	('tumor', 'Disease', (23, 28))
95033	26430392	Accumulating evidence suggests that urothelial carcinomas which exhibit alterations in DNA repair pathways experience improved outcomes to platinum agents.	('DNA repair', 'biological_process', 'GO:0006281', ('87', '97'))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (36, 57))	('alterations', 'Var', (72, 83))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('improved', 'PosReg', (118, 126))	('DNA repair pathways', 'Pathway', (87, 106))	('outcomes', 'MPA', (127, 135))	('platinum', 'Chemical', 'MESH:D010984', (139, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('urothelial carcinomas', 'Disease', (36, 57))
95034	26430392	A recently reported retrospective series of patients with locally advanced UC treated with neoadjuvant cisplatin-based combination chemotherapy demonstrated improved survival following cystectomy for patients with low/intermediate BRCA1 mRNA compared to high BRCA1 mRNA levels (64% 5 year survival versus 12%).	('survival', 'MPA', (166, 174))	('patients', 'Species', '9606', (200, 208))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('patients', 'Species', '9606', (44, 52))	('BRCA1', 'Gene', '672', (231, 236))	('low/intermediate', 'Var', (214, 230))	('BRCA1', 'Gene', '672', (259, 264))	('BRCA1', 'Gene', (231, 236))	('improved', 'PosReg', (157, 165))	('BRCA1', 'Gene', (259, 264))
95039	26430392	Angiogenesis is a rational target in UC given that VEGF is produced by UC and VEGFR inhibition may sensitize UC to treatment with cisplatin.	('Angiogenesis', 'biological_process', 'GO:0001525', ('0', '12'))	('VEGFR', 'Gene', '3791', (78, 83))	('VEGFR', 'Gene', (78, 83))	('VEGF', 'Gene', '7422', (51, 55))	('VEGF', 'Gene', (78, 82))	('sensitize', 'Reg', (99, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('inhibition', 'Var', (84, 94))	('VEGF', 'Gene', '7422', (78, 82))	('VEGF', 'Gene', (51, 55))	('men', 'Species', '9606', (120, 123))
95051	26430392	The HER2/neu monoclonal antibody trastuzumab was evaluated in a phase II first-line study that required confirmation testing of HER2 overexpression, and the combination of trastuzumab together with PCG produced a response rate of 70% (31 of 44 patients), median time to progression of 9.3 months and overall survival of 14.1 months (Table 2).	('HER2', 'Gene', (128, 132))	('combination', 'Var', (157, 168))	('trastuzumab', 'Chemical', 'MESH:D000068878', (172, 183))	('HER2', 'Gene', '2064', (128, 132))	('antibody', 'cellular_component', 'GO:0019815', ('24', '32'))	('neu', 'Gene', '2064', (9, 12))	('neu', 'Gene', (9, 12))	('PCG', 'Chemical', '-', (198, 201))	('patients', 'Species', '9606', (244, 252))	('antibody', 'cellular_component', 'GO:0019814', ('24', '32'))	('antibody', 'molecular_function', 'GO:0003823', ('24', '32'))	('HER2', 'Gene', (4, 8))	('antibody', 'cellular_component', 'GO:0042571', ('24', '32'))	('HER2', 'Gene', '2064', (4, 8))	('trastuzumab', 'Chemical', 'MESH:D000068878', (33, 44))
95058	26430392	This agent has minimal renal excretion and therefore is being studied as a second-line therapy for patients with UC and renal dysfunction (NCT00365157), as well as first-line therapy in combination with GC (NCT01125749).	('NCT00365157', 'Var', (139, 150))	('patients', 'Species', '9606', (99, 107))	('renal dysfunction', 'Phenotype', 'HP:0000083', (120, 137))	('excretion', 'biological_process', 'GO:0007588', ('29', '38'))	('renal dysfunction', 'Disease', (120, 137))	('renal excretion', 'MPA', (23, 38))	('GC', 'Chemical', '-', (203, 205))
95082	23696716	According to the National Comprehensive Cancer Network guidelines, cisplatin is categorized as having a high risk of emesis, whereas nedaplatin is reported to have a moderate emetic risk in the clinical practice guidelines of the Japan Society of Clinical Oncology.	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('nedaplatin', 'Chemical', 'MESH:C053989', (133, 143))	('cisplatin', 'Var', (67, 76))	('Cancer', 'Disease', (40, 46))	('Cancer', 'Disease', 'MESH:D009369', (40, 46))	('Oncology', 'Phenotype', 'HP:0002664', (256, 264))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('emesis', 'Phenotype', 'HP:0002013', (117, 123))	('emesis', 'Disease', 'MESH:D014839', (117, 123))	('emesis', 'Disease', (117, 123))
95098	23696716	Further, deregulation of the genes encoding cytokeratins 14 and 19 reflects the characteristic renal papillary injury associated with nedaplatin.	('nedaplatin', 'Chemical', 'MESH:C053989', (134, 144))	('deregulation', 'Var', (9, 21))	('renal papillary injury', 'Disease', 'MESH:D007681', (95, 117))	('renal papillary injury', 'Disease', (95, 117))
95135	23696716	In patients with advanced NSCLC and high expression of epidermal growth factor receptor, cetuximab in combination with cisplatin-vinorelbine chemotherapy prolonged overall survival.	('high expression', 'Var', (36, 51))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('55', '78'))	('prolonged', 'PosReg', (154, 163))	('epidermal growth factor receptor', 'Gene', (55, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (26, 31))	('epidermal growth factor receptor', 'Gene', '1956', (55, 87))	('patients', 'Species', '9606', (3, 11))	('vinorelbine', 'Chemical', 'MESH:D000077235', (129, 140))	('cetuximab', 'Chemical', 'MESH:D000068818', (89, 98))	('NSCLC', 'Disease', (26, 31))	('overall survival', 'MPA', (164, 180))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))
95177	23696716	Gimeracil also has a radiosensitizing effect by inhibiting the repair of double-stranded DNA breaks.	('Gimeracil', 'Var', (0, 9))	('radiosensitizing', 'MPA', (21, 37))	('inhibiting', 'NegReg', (48, 58))	('Gimeracil', 'Chemical', 'MESH:C104201', (0, 9))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('repair of double-stranded DNA breaks', 'MPA', (63, 99))
95204	31950163	Prevalence and architecture of posttranscriptionally impaired synonymous mutations in 8,320 genomes across 22 cancer types Somatic synonymous mutations are one of the most frequent genetic variants occurring in the coding region of cancer genomes, while their contributions to cancer development remain largely unknown.	('mutations', 'Var', (142, 151))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', (232, 238))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('synonymous mutations', 'Var', (62, 82))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
95205	31950163	To assess whether synonymous mutations involved in post-transcriptional regulation contribute to the genetic etiology of cancers, we collected whole exome data from 8,320 patients across 22 cancer types.	('cancer', 'Disease', (190, 196))	('cancers', 'Disease', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('patients', 'Species', '9606', (171, 179))	('synonymous mutations', 'Var', (18, 38))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('regulation', 'biological_process', 'GO:0065007', ('72', '82'))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
95210	31950163	Somatic synonymous mutations, which do not alter the protein sequences of their host genes, are one of the most frequent but rarely investigated genetic changes that occur in the coding regions of human cancer genomes.	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('human', 'Species', '9606', (197, 202))	('synonymous mutations', 'Var', (8, 28))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
95213	31950163	RNA-binding proteins (RBPs) play versatile roles in posttranscriptional RNA regulation, including splicing, polyadenylation, mRNA stabilization, RNA structure, subcellular localization and transcription, and their aberrant expression may lead to chaos within the whole regulation network.	('lead to', 'Reg', (238, 245))	('mRNA', 'MPA', (125, 129))	('expression', 'MPA', (223, 233))	('chaos', 'MPA', (246, 251))	('splicing', 'biological_process', 'GO:0045292', ('98', '106'))	('regulation', 'biological_process', 'GO:0065007', ('76', '86'))	('mRNA stabilization', 'biological_process', 'GO:0048255', ('125', '143'))	('localization', 'biological_process', 'GO:0051179', ('172', '184'))	('transcription', 'biological_process', 'GO:0006351', ('189', '202'))	('regulation', 'biological_process', 'GO:0065007', ('269', '279'))	('RNA-binding', 'molecular_function', 'GO:0003723', ('0', '11'))	('RNA', 'cellular_component', 'GO:0005562', ('72', '75'))	('RBP', 'Gene', (22, 25))	('RNA', 'cellular_component', 'GO:0005562', ('145', '148'))	('aberrant', 'Var', (214, 222))	('RBP', 'Gene', '57794', (22, 25))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
95214	31950163	In several cancer types, the abnormal expression of RBPs was associated with patient prognosis, and numerous mutations occurred in coding regions of RBPs had been implicated in tumorigenesis and progression, such as KHDRBS1 and ELAVL1 (also known as HuR).	('implicated', 'Reg', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('HuR', 'Gene', '1994', (250, 253))	('ELAVL1', 'Gene', (228, 234))	('RBP', 'Gene', (52, 55))	('abnormal', 'Var', (29, 37))	('RBP', 'Gene', '57794', (149, 152))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('associated', 'Reg', (61, 71))	('patient', 'Species', '9606', (77, 84))	('tumor', 'Disease', (177, 182))	('KHDRBS1', 'Gene', '10657', (216, 223))	('expression', 'MPA', (38, 48))	('KHDRBS1', 'Gene', (216, 223))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('ELAVL1', 'Gene', '1994', (228, 234))	('mutations', 'Var', (109, 118))	('progression', 'CPA', (195, 206))	('RBP', 'Gene', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('HuR', 'Gene', (250, 253))	('cancer', 'Disease', (11, 17))	('RBP', 'Gene', '57794', (52, 55))
95219	31950163	It has been demonstrated that RBPs can recognize their RNA substrate via sequence-specific binding motifs; therefore, genetic mutations occurred in the binding motifs may disrupt the recognition between RBPs and RNA substrates, resulting in various human diseases.	('resulting in', 'Reg', (228, 240))	('RBP', 'Gene', '57794', (30, 33))	('genetic mutations', 'Var', (118, 135))	('recognition', 'MPA', (183, 194))	('RBP', 'Gene', (203, 206))	('binding', 'molecular_function', 'GO:0005488', ('152', '159'))	('RBP', 'Gene', '57794', (203, 206))	('human diseases', 'Disease', (249, 263))	('human', 'Species', '9606', (249, 254))	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))	('RNA', 'cellular_component', 'GO:0005562', ('55', '58'))	('RNA', 'cellular_component', 'GO:0005562', ('212', '215'))	('mutations', 'Var', (126, 135))	('disrupt', 'NegReg', (171, 178))	('RBP', 'Gene', (30, 33))
95220	31950163	For example, a mutation in the 3' untranslated region of FMR1 decreased neuronal activity-dependent translation of FMRP by disrupting the binding of HuR, leading to developmental delay in patients.	('FMR1', 'Gene', (57, 61))	('neuronal activity-dependent translation', 'MPA', (72, 111))	('decreased', 'NegReg', (62, 71))	('HuR', 'Gene', (149, 152))	('developmental delay', 'CPA', (165, 184))	('FMRP', 'Gene', (115, 119))	('mutation in', 'Var', (15, 26))	('disrupting', 'NegReg', (123, 133))	('HuR', 'Gene', '1994', (149, 152))	('binding', 'molecular_function', 'GO:0005488', ('138', '145'))	('leading to', 'Reg', (154, 164))	('binding', 'Interaction', (138, 145))	('patients', 'Species', '9606', (188, 196))	('developmental delay', 'Phenotype', 'HP:0001263', (165, 184))	('translation', 'biological_process', 'GO:0006412', ('100', '111'))	('FMRP', 'Gene', '2332', (115, 119))	('FMR1', 'Gene', '2332', (57, 61))
95222	31950163	To test whether synonymous mutations involved in posttranscriptional regulation contribute to the genetic etiology of cancers, we collected whole exome data from 8,320 patients across 22 cancer types.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (118, 124))	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('regulation', 'biological_process', 'GO:0065007', ('69', '79'))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('patients', 'Species', '9606', (168, 176))	('synonymous mutations', 'Var', (16, 36))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
95254	31950163	All genetic mutations occurred in 2,042 pisSNV-hosted genes across 22 cancer types were curated, and their functional consequences on protein were predicted using Varcards.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('genetic mutations', 'Var', (4, 21))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
95255	31950163	Protein damage mutations were then defined by loss-of-function mutations or missense mutations with a damaging score >=0.8 predicted using ReVe.	('mutations', 'Var', (63, 72))	('missense mutations', 'Var', (76, 94))	('Protein damage', 'Disease', (0, 14))	('Protein damage', 'Disease', 'MESH:D058495', (0, 14))	('loss-of-function', 'NegReg', (46, 62))
95264	31950163	Seventeen (62.96%) piSNVs and 11 (73.33%) pisSNVs obtained through our pipeline were overlapped with the allele-specific RBP-RNA interaction sites identified by ASPRIN (Figure 1B; Supplementary Table S3), which suggests that PIVar was more stringent for identifying the impact of genetic mutations on posttranscriptional regulation network.	('PIVar', 'Chemical', '-', (225, 230))	('RNA', 'cellular_component', 'GO:0005562', ('125', '128'))	('RBP', 'Gene', (121, 124))	('mutations', 'Var', (288, 297))	('RBP', 'Gene', '57794', (121, 124))	('regulation', 'biological_process', 'GO:0065007', ('321', '331'))
95265	31950163	Inspired by previous studies in which genetic mutations can disrupt the RBP recognition of RNA substrates and many RBPs play important roles in tumorigenesis, we then employed PIVar (Figure 1A) to analyze the somatic mutation spectrum of 22 cancer types to explore the correlation between mutations and binding of RBPs.	('tumor', 'Disease', (144, 149))	('binding', 'molecular_function', 'GO:0005488', ('303', '310'))	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('RBP', 'Gene', (72, 75))	('RBP', 'Gene', (115, 118))	('RBP', 'Gene', (314, 317))	('cancer', 'Disease', (241, 247))	('disrupt', 'NegReg', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('RBP', 'Gene', '57794', (314, 317))	('RBP', 'Gene', '57794', (72, 75))	('RNA', 'cellular_component', 'GO:0005562', ('91', '94'))	('PIVar', 'Chemical', '-', (176, 181))	('RBP', 'Gene', '57794', (115, 118))
95267	31950163	Synonymous mutations can function as driver mutations in human cancers by disrupting RNA splicing or RBP binding instead of altering the sequence of encoded proteins directly; thus, we focused on the previously neglected 'silent' mutations and observed a total of 22,948 synonymous piSNVs (pisSNVs) across 22 cancer types (Figure 1C; Supplementary Table S4).	('mutations', 'Var', (11, 20))	('disrupting', 'NegReg', (74, 84))	('altering', 'Reg', (124, 132))	('RBP', 'Gene', (101, 104))	('human', 'Species', '9606', (57, 62))	('RNA splicing', 'biological_process', 'GO:0008380', ('85', '97'))	('binding', 'molecular_function', 'GO:0005488', ('105', '112'))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancer', 'Disease', (63, 69))	('cancers', 'Disease', (63, 70))	('cancer', 'Disease', (309, 315))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('RBP', 'Gene', '57794', (101, 104))	('RNA splicing', 'MPA', (85, 97))	('RNA', 'cellular_component', 'GO:0005562', ('85', '88'))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
95269	31950163	Also, we observed synonymous mutations had a higher mutation load on posttranscriptional regulation comparing to non-synonymous mutations in 15 cancer types (Supplementary Figure S1).	('Supplementary Figure S1', 'Disease', (158, 181))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('synonymous mutations', 'Var', (18, 38))	('cancer', 'Disease', (144, 150))	('posttranscriptional regulation', 'MPA', (69, 99))	('regulation', 'biological_process', 'GO:0065007', ('89', '99'))	('mutation load', 'MPA', (52, 65))	('higher', 'PosReg', (45, 51))	('Supplementary Figure S1', 'Disease', 'MESH:D017034', (158, 181))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
95270	31950163	The significant distinction between cancer and normal control samples unveiled the prevalence of posttranscriptionally impaired synonymous mutations in cancer genomes, implying their contribution to cancer etiology.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('posttranscriptionally', 'MPA', (97, 118))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('synonymous mutations', 'Var', (128, 148))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
95276	31950163	It has been demonstrated that genetic mutations on RNA substrates can disrupt the RBP recognition toward them.	('RBP', 'Gene', (82, 85))	('RBP', 'Gene', '57794', (82, 85))	('disrupt', 'NegReg', (70, 77))	('genetic mutations', 'Var', (30, 47))	('RNA', 'cellular_component', 'GO:0005562', ('51', '54'))
95283	31950163	By screening the identified pisSNVs, we found that ADCY7, whose expression significantly correlated with the overall survival of acute myeloid leukemia patients, had a mutation from G to A at the second position of the above motif.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (129, 151))	('leukemia', 'Phenotype', 'HP:0001909', (143, 151))	('expression', 'MPA', (64, 74))	('acute myeloid leukemia', 'Disease', (129, 151))	('mutation from G to A', 'Var', (168, 188))	('ADCY7', 'Gene', '113', (51, 56))	('ADCY7', 'Gene', (51, 56))	('correlated', 'Reg', (89, 99))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (129, 151))	('patients', 'Species', '9606', (152, 160))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (135, 151))
95296	31950163	LRP1B was thought to function as a tumor suppressor, and microRNA-mediated inactivation of LRP1B could increase the growth and invasive capacity of cancer cells.	('cancer', 'Disease', (148, 154))	('inactivation', 'Var', (75, 87))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('increase', 'PosReg', (103, 111))	('LRP1B', 'Gene', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('LRP1B', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('tumor', 'Disease', (35, 40))	('LRP1B', 'Gene', '53353', (91, 96))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('LRP1B', 'Gene', '53353', (0, 5))
95302	31950163	When we summarized the gene-length corrected frequency of occurrence of 2,042 genes based on the status of posttranscriptional impact and/or function damage (Figure 4C), we found that 470 of 8,320 cancer patients carried protein-damaging mutations in LRP1B, the highest frequently occurred pisSNV-hosted gene.	('patients', 'Species', '9606', (204, 212))	('protein', 'cellular_component', 'GO:0003675', ('221', '228'))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('mutations', 'Var', (238, 247))	('protein-damaging', 'NegReg', (221, 237))	('LRP1B', 'Gene', (251, 256))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('LRP1B', 'Gene', '53353', (251, 256))
95313	31950163	Posttranscriptionally impaired synonymous mutations of MTOR, a reported oncogene in multiple cancers, co-occurred in 14 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancers', 'Disease', (93, 100))	('cancer', 'Disease', (93, 99))	('MTOR', 'Gene', '2475', (55, 59))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('co-occurred', 'Reg', (102, 113))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Disease', (120, 126))	('synonymous mutations', 'Var', (31, 51))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('MTOR', 'Gene', (55, 59))
95317	31950163	As shown in Figure 6A, high sensitivity (low IC50 value) for CAY10566, a steroyl-CoA desaturase 1 (SCD1) inhibitor which inhibits the conversion from saturated to monounsaturated, long-chain fatty acyl-CoAs, was significantly associated with IGSF3 c.891 G>A mutation.	('long-chain fatty acyl-CoAs', 'Chemical', '-', (180, 206))	('SCD1', 'Gene', '6319', (99, 103))	('associated', 'Reg', (226, 236))	('steroyl-CoA desaturase 1', 'Gene', (73, 97))	('inhibits', 'NegReg', (121, 129))	('c.891 G>A mutation', 'Var', (248, 266))	('IGSF3', 'Gene', (242, 247))	('conversion', 'MPA', (134, 144))	('CAY10566', 'Var', (61, 69))	('SCD1', 'Gene', (99, 103))	('steroyl-CoA desaturase 1', 'Gene', '6319', (73, 97))	('c.891 G>A', 'Mutation', 'rs61730485', (248, 257))	('CAY10566', 'Chemical', '-', (61, 69))	('IGSF3', 'Gene', '3321', (242, 247))
95318	31950163	In addition, Ara-G and SGC0946 had higher response to TTN c.22323 C>T mutated cell lines in comparison with wild-type cell lines (Figure 6B).	('TTN', 'Gene', (54, 57))	('TTN', 'Gene', '7273', (54, 57))	('Ara-G', 'Chemical', 'MESH:C028771', (13, 18))	('c.22323 C>T', 'Mutation', 'c.22323C>T', (58, 69))	('c.22323 C>T', 'Var', (58, 69))	('higher', 'PosReg', (35, 41))
95324	31950163	Recent studies have shown that synonymous mutations could function as cancer drivers by altering RNA splicing, RNA stability and protein translation.	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('RNA stability', 'MPA', (111, 124))	('protein translation', 'biological_process', 'GO:0006412', ('129', '148'))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('protein translation', 'MPA', (129, 148))	('RNA splicing', 'biological_process', 'GO:0008380', ('97', '109'))	('synonymous mutations', 'Var', (31, 51))	('RNA splicing', 'MPA', (97, 109))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('RNA', 'cellular_component', 'GO:0005562', ('97', '100'))	('altering', 'Reg', (88, 96))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
95326	31950163	Numerous studies have found that RBPs play an important role in posttranscriptional regulation, and in the cancer genome, abnormal expression of RBPs has a significant effect on cancer phenotype.	('RBP', 'Gene', '57794', (33, 36))	('abnormal', 'Var', (122, 130))	('regulation', 'biological_process', 'GO:0065007', ('84', '94'))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('posttranscriptional regulation', 'MPA', (64, 94))	('RBP', 'Gene', (145, 148))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('RBP', 'Gene', '57794', (145, 148))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('effect', 'Reg', (168, 174))	('RBP', 'Gene', (33, 36))
95327	31950163	Therefore, we speculated that the synonymous mutations present in the cancer genome may disrupt the binding of RBPs by altering the secondary structure of RNA, thereby affecting the translation, transportation or degradation of the RNA and ultimately resulting in the carcinogenesis and progression of cancer.	('progression', 'CPA', (287, 298))	('degradation', 'biological_process', 'GO:0009056', ('213', '224'))	('binding', 'Interaction', (100, 107))	('carcinogenesis', 'Disease', 'MESH:D063646', (268, 282))	('RNA', 'Protein', (155, 158))	('binding', 'molecular_function', 'GO:0005488', ('100', '107'))	('RNA', 'cellular_component', 'GO:0005562', ('155', '158'))	('cancer', 'Disease', (302, 308))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('secondary structure', 'MPA', (132, 151))	('translation', 'biological_process', 'GO:0006412', ('182', '193'))	('cancer', 'Disease', (70, 76))	('RBP', 'Gene', '57794', (111, 114))	('transportation', 'MPA', (195, 209))	('resulting in', 'Reg', (251, 263))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('translation', 'MPA', (182, 193))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('disrupt', 'NegReg', (88, 95))	('RNA', 'cellular_component', 'GO:0005562', ('232', '235'))	('altering', 'Reg', (119, 127))	('mutations', 'Var', (45, 54))	('affecting', 'Reg', (168, 177))	('degradation', 'MPA', (213, 224))	('RBP', 'Gene', (111, 114))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('carcinogenesis', 'Disease', (268, 282))
95328	31950163	To verify this, we presented a new approach, PIVar, according to the functional confidence of variants based on multi-omic experimental data, for identifying pisSNVs from pan-cancer genome data.	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('variants', 'Var', (94, 102))	('PIVar', 'Chemical', '-', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
95331	31950163	Thus, we provided an efficient and reliable tool for genome-wide deciphering of the role of these synonymous mutations in the development of cancers at the posttranscriptional regulation level.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('regulation', 'biological_process', 'GO:0065007', ('176', '186'))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('mutations', 'Var', (109, 118))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))
95336	31950163	For example, LRP1B, a member of low density lipoprotein receptor-related protein family, had the highest gene-length corrected frequency of occurrence as a pisSNV-hosted gene, while 470 of 8,320 cancer patients was also identified to carry protein damaging mutations of LRP1B.	('mutations', 'Var', (257, 266))	('LRP1B', 'Gene', (270, 275))	('LRP1B', 'Gene', (13, 18))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('protein', 'cellular_component', 'GO:0003675', ('240', '247'))	('patients', 'Species', '9606', (202, 210))	('LRP1B', 'Gene', '53353', (270, 275))	('LRP1B', 'Gene', '53353', (13, 18))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('low density lipoprotein', 'molecular_function', 'GO:0005322', ('32', '55'))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
95337	31950163	Down-regulation of LRP1B was reported to promote the growth and migration of colon cancer cells, and its deletion was associated with acquired chemotherapy resistance to liposomal doxorubicin in high-grade serous ovarian cancers.	('LRP1B', 'Gene', (19, 24))	('doxorubicin', 'Chemical', 'MESH:D004317', (180, 191))	('deletion', 'Var', (105, 113))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('serous ovarian cancers', 'Disease', 'MESH:D010051', (206, 228))	('colon cancer', 'Phenotype', 'HP:0003003', (77, 89))	('colon cancer', 'Disease', 'MESH:D015179', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('serous ovarian cancers', 'Disease', (206, 228))	('LRP1B', 'Gene', '53353', (19, 24))	('ovarian cancers', 'Phenotype', 'HP:0100615', (213, 228))	('promote', 'PosReg', (41, 48))	('Down-regulation', 'NegReg', (0, 15))	('regulation', 'biological_process', 'GO:0065007', ('5', '15'))	('growth', 'CPA', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('colon cancer', 'Disease', (77, 89))	('associated', 'Reg', (118, 128))
95341	31950163	Clinical implication analysis unveiled two drug-response associated pisSNVs and three pisSNV-associated compounds including CAY10566, Ara-G and SGC0946.	('Ara-G', 'Chemical', 'MESH:C028771', (134, 139))	('drug-response', 'Disease', (43, 56))	('CAY10566', 'Var', (124, 132))	('CAY10566', 'Chemical', '-', (124, 132))
95342	31950163	Of the compounds responding to TTN c.22323 C>T synonymous mutation, Ara-G is a metabolite of nelarabine, which could be used for chemotherapy in T-cell acute lymphoblastic leukemia.	('lymphoblastic leukemia', 'Disease', (158, 180))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (145, 180))	('TTN', 'Gene', (31, 34))	('leukemia', 'Phenotype', 'HP:0001909', (172, 180))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (152, 180))	('Ara-G', 'Chemical', 'MESH:C028771', (68, 73))	('nelarabine', 'Chemical', 'MESH:C104457', (93, 103))	('c.22323 C>T synonymous', 'Var', (35, 57))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (158, 180))	('TTN', 'Gene', '7273', (31, 34))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (158, 180))	('c.22323 C>T', 'Mutation', 'c.22323C>T', (35, 46))
95343	31950163	In addition, SGC0946 can work as an inhibitor of histone lysine methyltransferase for H3K79 and selectively kill mixed lineage leukemia cells.	('leukemia', 'Disease', (127, 135))	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('leukemia', 'Disease', 'MESH:D007938', (127, 135))	('kill', 'NegReg', (108, 112))	('H3K79', 'Protein', (86, 91))	('SGC0946', 'Var', (13, 20))
95365	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))
95384	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))
95461	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))
95473	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))	('ERK1/2', 'Gene', (344, 350))	('PI3K', 'Var', (203, 207))	('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))	('c-Jun N-terminal kinase', 'Gene', '5599', (405, 428))	('TGF-beta-activated kinase', 'Gene', '56911', (316, 341))	('MAPK', 'Gene', (268, 272))	('JNK', 'molecular_function', 'GO:0004705', ('400', '403'))	('JNK', 'Gene', '5599', (400, 403))	('PP2A', 'Gene', (237, 241))
95478	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.	('tumors', 'Disease', (19, 25))	('TGF-beta', 'Gene', (165, 173))	('TGF-beta', 'Gene', (79, 87))	('men', 'Species', '9606', (185, 188))	('mutations', 'Var', (121, 130))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('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))
95479	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))
95483	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))
95486	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))
95499	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))
95506	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'))
95512	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))
95515	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'))
95532	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))
95537	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'))
95543	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))	('S320X', 'Var', (186, 191))	('ACVR2B', 'Gene', (104, 110))	('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))	('losses', 'NegReg', (48, 54))	('S320X', 'Var', (193, 198))	('R522X', 'Var', (179, 184))	('S320X', 'Mutation', 'p.S320X', (193, 198))	('TGFB3', 'Gene', '7043', (81, 86))	('gains', 'PosReg', (58, 63))	('SMAD7', 'Gene', (133, 138))	('PITX2', 'Gene', (140, 145))	('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))
95544	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))
95549	31842336	In fetal testis, TGF-beta attenuates proliferation, indicating that aberrances of the TGF-beta pathway may lead to tumor development.	('TGF-beta', 'Gene', (17, 25))	('lead to', 'Reg', (107, 114))	('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))
95550	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))
95557	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))
95558	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))
95559	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))
95560	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.	('-509C > T', 'Mutation', 'rs1800469', (4, 13))	('plasma concentrations', 'MPA', (122, 143))	('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))
95561	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))
95567	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))
95568	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))	('c.29C > T', 'Var', (6, 15))	('bladder cancer', 'Disease', (78, 92))	('rs1800470', 'Mutation', 'rs1800470', (30, 39))	('rs1800470', 'Var', (30, 39))	('TGFB1', 'Gene', '7040', (0, 5))
95569	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))	('substitution', 'Var', (144, 156))	('leucine', 'MPA', (173, 180))	('proline', 'Chemical', 'MESH:C489032', (160, 167))
95570	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'))
95573	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))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('men', 'Species', '9606', (153, 156))	('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))
95578	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))
95593	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'))
95598	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))	('inhibits', 'NegReg', (25, 33))	('TGF-beta1-induced', 'Gene', (34, 51))	('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))
95602	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))	('invasiveness of T24 cells', 'CPA', (97, 122))	('pro-invasive', 'CPA', (159, 171))	('downregulation', 'NegReg', (141, 155))	('TGFBR1', 'Gene', (30, 36))	('rat', 'Species', '10116', (86, 89))
95610	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))
95614	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))
95626	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))
95628	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', (13, 19))	('Trim59', 'Gene', '286827', (145, 151))	('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))
95632	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))
95642	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))
95643	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', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (125, 131))	('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))
95644	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'))
95645	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))
95646	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))
95655	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))	('ectopic expression', 'Var', (14, 32))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('attenuated', 'NegReg', (71, 81))	('cell growth', 'CPA', (82, 93))	('GDF-9', 'Gene', (36, 41))	('reduced', 'NegReg', (99, 106))	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('bladder cancer', 'Disease', (45, 59))
95658	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))
95660	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))
95670	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))
95677	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))
95679	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))
95690	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))
95693	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))
95700	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))
95707	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))
95729	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))
95734	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))
95735	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))
95745	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))
95755	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))
95756	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))
95765	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))
95766	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))
95767	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))
95771	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))
95780	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))	('men', 'Species', '9606', (108, 111))	('miR', 'Gene', '220972', (157, 160))	('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))
95784	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))	('miR-93', 'Gene', '407051', (48, 54))	('rat', 'Species', '10116', (97, 100))	('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))
95800	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))	('inhibits', 'NegReg', (54, 62))	('TGF-beta signaling', 'MPA', (109, 127))	('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))
95818	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))	('USP9X', 'Gene', (98, 103))	('potentiates', 'PosReg', (51, 62))	('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))
95834	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))
95837	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'))
95840	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))
95841	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))
95842	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))
95844	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))	('patients', 'Species', '9606', (117, 125))	('rs1800469', 'Mutation', 'rs1800469', (90, 99))	('c.-1347C > T', 'Var', (61, 73))	('c.-1347C > T', 'Mutation', 'rs1800469', (61, 73))	('Bacillus Calmette-Guerin', 'Species', '33892', (143, 167))	('rs1800469', 'Var', (90, 99))	('-509C > T', 'Mutation', 'rs1800469', (75, 84))	('BCG', 'Species', '33892', (138, 141))	('TGF-beta +C28.', 'Gene', (0, 14))
95846	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))
95910	31649294	Among the 1263 high-risk NMIBC patients, 112 (8.8%) reported histologic variants in TURBT.	('TURBT', 'Gene', (84, 89))	('patients', 'Species', '9606', (31, 39))	('variants', 'Var', (72, 80))
95929	31649294	The patients with variant histology show significantly lower survival than pure urothelial carcinoma in both of OS (54.17 +- 0.54 months vs. 50.47 +- 1.87 months, p = 0.013) and CSS (55.41 +- 0.49 months vs. 52.78 +- 1.68 months, p = 0.038) in this cohort.	('pure', 'molecular_function', 'GO:0034023', ('75', '79'))	('urothelial carcinoma', 'Disease', (80, 100))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (80, 100))	('survival', 'MPA', (61, 69))	('lower', 'NegReg', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('patients', 'Species', '9606', (4, 12))	('variant', 'Var', (18, 25))
95942	31649294	Anderson study group reported early and follow-up data of micropapillary variants with urothelial carcinoma showing a poor response to BCG instillation therapy, prompting early radical cystectomy.	('BCG', 'Species', '33892', (135, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('micropapillary', 'Var', (58, 72))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (87, 107))	('urothelial carcinoma', 'Disease', (87, 107))
95947	31649294	among 41 high-risk NMIBC patients with histologic variants including 14 micropapillary, 13 squamous, 9 glandular and 7 nested variants, compared with 140 cases of pure urothelial carcinoma.	('NMIBC', 'Disease', (19, 24))	('pure', 'molecular_function', 'GO:0034023', ('163', '167'))	('micropapillary', 'Disease', (72, 86))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (168, 188))	('patients', 'Species', '9606', (25, 33))	('variants', 'Var', (50, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('urothelial carcinoma', 'Disease', (168, 188))
95999	30024509	Within group comparisons, the widowed group had the higher proportion of women (53.9%), white race (90.8%), older (>=60 years) patients (97.4%), bladder (primary site) (49.9%), low grade (46.7%), noninvasive papillary carcinoma (Oa) stage (47.9%), and surgery performed (95.5%), all of which were statistically significant (P < .001).	('women', 'Species', '9606', (73, 78))	('low', 'Var', (177, 180))	('surgery', 'Disease', (252, 259))	('papillary carcinoma', 'Disease', (208, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('patients', 'Species', '9606', (127, 135))	('papillary carcinoma', 'Disease', 'MESH:D002291', (208, 227))	('bladder', 'Disease', (145, 152))
96005	30024509	Female sex (P < .001), black race (P < .001), older patients (P < .001), dome of bladder (P < .001), high grade (P < .001), IV stage (P < .001), no surgery performed (P < .001), and the widowed group (P < .001) had been confirmed as significant risk predictors for poor survival on univariate analysis (Table 2).	('high', 'Var', (101, 105))	('dome', 'Disease', (73, 77))	('patients', 'Species', '9606', (52, 60))
96051	30024509	Similarly, the patients with low grade, the widowed group had worst 5-year CSS (88.5%) compared with married (95.1.0%), never married (94.1%), and divorced/separated (94.0%) patients (all P < .01).	('patients', 'Species', '9606', (15, 23))	('worst', 'NegReg', (62, 67))	('CSS', 'Chemical', '-', (75, 78))	('patients', 'Species', '9606', (174, 182))	('CSS', 'CPA', (75, 78))	('low grade', 'Var', (29, 38))
96251	27376138	In a phase 2 study of everolimus in previously treated patients, this mT0RC1 inhibitor resulted in a complete response in a patient with disease refractory to gemcitabine and cisplatin.	('mT0RC1', 'Gene', (70, 76))	('everolimus', 'Chemical', 'MESH:D000068338', (22, 32))	('gemcitabine', 'Chemical', 'MESH:C056507', (159, 170))	('patient', 'Species', '9606', (124, 131))	('patient', 'Species', '9606', (55, 62))	('patients', 'Species', '9606', (55, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('inhibitor', 'Var', (77, 86))
96252	27376138	Whole genome sequencing performed in this patient demonstrated both TSC1 and NF2 mutations identified as cooperative and resulting in exquisite sensitivity to this agent.	('TSC1', 'Gene', '7248', (68, 72))	('TSC1', 'Gene', (68, 72))	('patient', 'Species', '9606', (42, 49))	('NF2', 'Gene', (77, 80))	('mutations', 'Var', (81, 90))	('sensitivity to this agent', 'MPA', (144, 169))	('NF2', 'Gene', '4771', (77, 80))
96259	27376138	The initial study reported a response rate of 43% in tumors with high expression of PD-L1 and 11% in tumors with little or no expression of PD-L1.	('PD-L1', 'Gene', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('high expression', 'Var', (65, 80))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
96273	27376138	The proposed trials will seek to test two hypotheses: 1) Molecularly targeted therapy has clinical benefit in non-muscle invasive bladder cancer; and, 2) Novel immunotherapy has clinical benefit in non-muscle invasive bladder cancer.	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (198, 225))	('clinical', 'Species', '191496', (90, 98))	('-muscle invasive bladder cancer', 'Phenotype', 'HP:0006740', (201, 232))	('invasive bladder', 'Phenotype', 'HP:0100645', (209, 225))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (202, 232))	('-muscle invasive bladder cancer', 'Phenotype', 'HP:0006740', (113, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('muscle invasive bladder cancer', 'Disease', (202, 232))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (114, 144))	('clinical', 'Species', '191496', (178, 186))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (110, 137))	('invasive bladder', 'Phenotype', 'HP:0100645', (121, 137))	('bladder cancer', 'Phenotype', 'HP:0009725', (218, 232))	('muscle invasive bladder cancer', 'Disease', (114, 144))	('bladder cancer', 'Phenotype', 'HP:0009725', (130, 144))	('Molecularly', 'Var', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
96306	27376138	These studies have revealed that bladder cancer has a high mutation rate largely due to APOBEC-mediated mutagenesis.	('bladder cancer', 'Disease', 'MESH:D001749', (33, 47))	('mutagenesis', 'Var', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('bladder cancer', 'Disease', (33, 47))	('mutagenesis', 'biological_process', 'GO:0006280', ('104', '115'))	('APOBEC', 'cellular_component', 'GO:0030895', ('88', '94'))	('APOBEC-mediated', 'Protein', (88, 103))	('bladder cancer', 'Phenotype', 'HP:0009725', (33, 47))	('mutation', 'MPA', (59, 67))
96308	27376138	Focal genomic amplifications and deletions are also common in bladder cancer and target these same pathways.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('target', 'Reg', (81, 87))	('bladder cancer', 'Phenotype', 'HP:0009725', (62, 76))	('Focal genomic amplifications', 'Var', (0, 28))	('bladder cancer', 'Disease', 'MESH:D001749', (62, 76))	('bladder cancer', 'Disease', (62, 76))	('deletions', 'Var', (33, 42))
96309	27376138	Previous studies have shown that FGFR3 mutations are more common in NMIBC, while TP53 mutations are more common in muscle-invasive (MIBC) bladder cancer.	('common', 'Reg', (58, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('NMIBC', 'Chemical', '-', (68, 73))	('muscle-invasive (MIBC) bladder cancer', 'Disease', 'MESH:D001749', (115, 152))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('mutations', 'Var', (39, 48))	('FGFR3', 'Gene', '2261', (33, 38))	('common', 'Reg', (105, 111))	('NMIBC', 'Disease', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('TP53', 'Gene', '7157', (81, 85))	('FGFR3', 'Gene', (33, 38))	('TP53', 'Gene', (81, 85))
96310	27376138	Compilation of data from four studies employing whole exome sequencing including a total of 350 MIBC cases and 54 NMIBC cases indicates that both KDM6A and FGFR3 mutations are significantly more common in NMIBC than MIBC (42% vs. 23%, and 22% vs. 11%, respectively), while TP53 and MLL2 are significantly more frequent in MIBC than NMIBC (47% vs. 22%, and 22% vs. 4%, respectively) (Fig.	('NMIBC', 'Disease', (205, 210))	('NMIBC', 'Chemical', '-', (205, 210))	('MIBC', 'Chemical', '-', (206, 210))	('common', 'Reg', (195, 201))	('FGFR', 'molecular_function', 'GO:0005007', ('156', '160'))	('MIBC', 'Chemical', '-', (333, 337))	('MLL2', 'Gene', '9757', (282, 286))	('KDM6A', 'Gene', '7403', (146, 151))	('NMIBC', 'Chemical', '-', (114, 119))	('TP53', 'Gene', (273, 277))	('FGFR3', 'Gene', (156, 161))	('MIBC', 'Chemical', '-', (322, 326))	('FGFR3', 'Gene', '2261', (156, 161))	('MIBC', 'Chemical', '-', (115, 119))	('MLL2', 'Gene', (282, 286))	('mutations', 'Var', (162, 171))	('NMIBC', 'Chemical', '-', (332, 337))	('MIBC', 'Chemical', '-', (216, 220))	('KDM6A', 'Gene', (146, 151))	('MIBC', 'Chemical', '-', (96, 100))	('TP53', 'Gene', '7157', (273, 277))
96311	27376138	Mutations in several other genes also appear to be more common in MIBC but did not reach statistical significance: ERBB3, CDKN1A, CDKN2A, NFE2L2, TXNIP.	('NFE2L2', 'Gene', (138, 144))	('MIBC', 'Disease', (66, 70))	('common', 'Reg', (56, 62))	('CDKN1A', 'Gene', (122, 128))	('TXNIP', 'Gene', (146, 151))	('CDKN2A', 'Gene', (130, 136))	('CDKN1A', 'Gene', '1026', (122, 128))	('NFE2L2', 'Gene', '4780', (138, 144))	('CDKN2A', 'Gene', '1029', (130, 136))	('Mutations', 'Var', (0, 9))	('ERBB3', 'Gene', (115, 120))	('ERBB3', 'Gene', '2065', (115, 120))	('MIBC', 'Chemical', '-', (66, 70))	('TXNIP', 'Gene', '10628', (146, 151))
96312	27376138	Other studies have identified STAG2 mutations as occurring more often in NMIBC vs. MIBC.	('NMIBC', 'Chemical', '-', (73, 78))	('MIBC', 'Disease', (83, 87))	('MIBC', 'Chemical', '-', (74, 78))	('mutations', 'Var', (36, 45))	('MIBC', 'Chemical', '-', (83, 87))	('STAG2', 'Gene', (30, 35))	('STAG2', 'Gene', '10735', (30, 35))	('NMIBC', 'Disease', (73, 78))
96315	27376138	Sixty to 70% of stage Ta tumors and approximately 40% of stage T1 tumors have activating point mutations (most commonly S249C) that induce ligand-independent signaling.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('S249C', 'Mutation', 'rs121913483', (120, 125))	('signaling', 'biological_process', 'GO:0023052', ('158', '167'))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('ligand', 'molecular_function', 'GO:0005488', ('139', '145'))	('Ta tumors', 'Disease', (22, 31))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('induce', 'Reg', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('Ta tumors', 'Disease', 'MESH:D009369', (22, 31))	('ligand-independent signaling', 'MPA', (139, 167))	('S249C', 'Var', (120, 125))
96322	27376138	Although normal urothelial cells express low levels of FGFR3, they are not sensitive to the small molecule inhibitors tested (PD173074, AZD4547, TKI-258).	('FGFR3', 'Gene', '2261', (55, 60))	('PD173074', 'Var', (126, 134))	('PD173074', 'Chemical', 'MESH:C115711', (126, 134))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('FGFR3', 'Gene', (55, 60))	('AZD4547', 'Chemical', 'MESH:C572463', (136, 143))
96323	27376138	Tumor cell lines with point mutation and detectable FGFR3 protein expression show variable responses (e.g.	('protein', 'Protein', (58, 65))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('FGFR3', 'Gene', '2261', (52, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('FGFR3', 'Gene', (52, 57))	('responses', 'MPA', (91, 100))	('point mutation', 'Var', (22, 36))
96325	27376138	Three cell lines with FGFR3 fusions (RT4, RT112 and SW7800) show high sensitivity (IC50 5-50nM).	('FGFR3', 'Gene', (22, 27))	('sensitivity', 'MPA', (70, 81))	('SW780', 'CellLine', 'CVCL:1728', (52, 57))	('FGFR3', 'Gene', '2261', (22, 27))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('fusions', 'Var', (28, 35))
96327	27376138	RT112 (FGFR3 fusion-containing) can be rescued from the inhibitory effects of PD173074 by NRG1 and EGF, and from BGJ398 by HGF, NRG1, TGFalpha and EGF.	('FGFR3', 'Gene', '2261', (7, 12))	('HGF', 'Gene', (123, 126))	('PD173074', 'Var', (78, 86))	('NRG1', 'Gene', '3084', (128, 132))	('PD173074', 'Chemical', 'MESH:C115711', (78, 86))	('NRG1', 'Gene', '3084', (90, 94))	('EGF', 'Gene', (99, 102))	('EGF', 'Gene', (147, 150))	('HGF', 'Gene', '3082', (123, 126))	('EGF', 'molecular_function', 'GO:0005154', ('99', '102'))	('FGFR3', 'Gene', (7, 12))	('EGF', 'Gene', '1950', (99, 102))	('NRG1', 'Gene', (128, 132))	('EGF', 'Gene', '1950', (147, 150))	('TGFalpha and EGF', 'Gene', '7039;1950', (134, 150))	('FGFR', 'molecular_function', 'GO:0005007', ('7', '11'))	('EGF', 'molecular_function', 'GO:0005154', ('147', '150'))	('NRG1', 'Gene', (90, 94))
96328	27376138	EGFR knockdown was found by RNAi screening to increase sensitivity to PD173074 in FGFR3-dependent cell lines.	('FGFR3', 'Gene', (82, 87))	('EGFR', 'Gene', (0, 4))	('increase', 'PosReg', (46, 54))	('knockdown', 'Var', (5, 14))	('sensitivity', 'MPA', (55, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('82', '86'))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('FGFR3', 'Gene', '2261', (82, 87))	('PD173074', 'Var', (70, 78))	('RNAi', 'biological_process', 'GO:0016246', ('28', '32'))	('PD173074', 'Chemical', 'MESH:C115711', (70, 78))	('EGFR', 'Gene', '1956', (0, 4))
96333	27376138	Past reports have also examined copy number alterations and mutations in non-muscle invasive bladder cancer.	('-muscle invasive bladder cancer', 'Phenotype', 'HP:0006740', (76, 107))	('invasive bladder', 'Phenotype', 'HP:0100645', (84, 100))	('muscle invasive bladder cancer', 'Disease', (77, 107))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (73, 100))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('bladder cancer', 'Phenotype', 'HP:0009725', (93, 107))	('mutations', 'Var', (60, 69))	('copy number alterations', 'Var', (32, 55))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (77, 107))
96335	27376138	2) Comparison of the mutational frequency between NMIBC and MIBC showed that a number of genes (most notably FGFR3) are more frequently mutated in high-grade, NMIBC (Fig.	('FGFR3', 'Gene', (109, 114))	('MIBC', 'Chemical', '-', (60, 64))	('NMIBC', 'Chemical', '-', (50, 55))	('FGFR', 'molecular_function', 'GO:0005007', ('109', '113'))	('NMIBC', 'Chemical', '-', (159, 164))	('MIBC', 'Chemical', '-', (51, 55))	('mutated', 'Var', (136, 143))	('FGFR3', 'Gene', '2261', (109, 114))	('NMIBC', 'Disease', (159, 164))	('MIBC', 'Chemical', '-', (160, 164))
96338	27376138	Finally, recent research suggests that mutations in the DNA damage repair pathway may predict for response to cisplatin based chemotherapy in MIBC.	('predict', 'Reg', (86, 93))	('MIBC', 'Disease', (142, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('response to cisplatin based chemotherapy', 'MPA', (98, 138))	('DNA damage repair pathway', 'Pathway', (56, 81))	('mutations', 'Var', (39, 48))	('response to cisplatin', 'biological_process', 'GO:0072718', ('98', '119'))	('MIBC', 'Chemical', '-', (142, 146))
96341	27376138	Recent studies have identified frequent mutations in several targetable kinases including FGFR3, ERRB2, PIK3CA and others.	('ERRB2', 'Gene', (97, 102))	('FGFR3', 'Gene', '2261', (90, 95))	('PIK3CA', 'Gene', (104, 110))	('mutations', 'Var', (40, 49))	('FGFR3', 'Gene', (90, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))	('PIK3CA', 'Gene', '5290', (104, 110))
96344	27376138	For example, in the recently reported vemurafenib basket study, patients with multiple non-melanoma cancers whose tumor harbored a codon 600 BRAF mutation were eligible.	('BRAF', 'Gene', (141, 145))	('vemurafenib', 'Chemical', 'MESH:D000077484', (38, 49))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('patients', 'Species', '9606', (64, 72))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('non-melanoma cancers', 'Disease', (87, 107))	('tumor', 'Disease', (114, 119))	('codon 600', 'Var', (131, 140))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('non-melanoma cancers', 'Disease', 'MESH:D008545', (87, 107))	('BRAF', 'Gene', '673', (141, 145))
96351	27376138	For example, in patients with bladder cancer whose tumors are RB1 mutant, a promising targeted approach has yet to be identified.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutant', 'Var', (66, 72))	('RB1', 'Gene', '5925', (62, 65))	('patients', 'Species', '9606', (16, 24))	('bladder cancer', 'Disease', 'MESH:D001749', (30, 44))	('bladder cancer', 'Disease', (30, 44))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('RB1', 'Gene', (62, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))
96358	27376138	Several groups recently demonstrated that MIBCs can be assigned to intrinsic basal and luminal subtypes that are similar to the ones observed in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('MIBCs', 'Var', (42, 47))	('MIBCs', 'Chemical', '-', (42, 47))
96360	27376138	Conversely, a large fraction of luminal MIBCs, corresponding to TCGA's "papillary" subtype (cluster I) that is also characterized by enrichment with FGFR3 mutations and fusions, expresses particularly low levels of these same biomarkers, and results from a completed Phase 2 study of atezolizumab in patients with cisplatin-refractory advanced disease confirmed that these papillary luminal tumors were resistant to PD-L1 blockade.	('papillary luminal tumors', 'Disease', 'MESH:D002291', (373, 397))	('tumors', 'Phenotype', 'HP:0002664', (391, 397))	('mutations', 'Var', (155, 164))	('patients', 'Species', '9606', (300, 308))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('MIBCs', 'Chemical', '-', (40, 45))	('FGFR3', 'Gene', '2261', (149, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (314, 323))	('FGFR', 'molecular_function', 'GO:0005007', ('147', '151'))	('papillary luminal tumors', 'Disease', (373, 397))	('FGFR3', 'Gene', (149, 154))	('atezolizumab', 'Chemical', 'MESH:C000594389', (284, 296))
96376	27376138	Through mutation identification and case/control genomics algorithm development, we discovered and experimentally validated that somatic ERCC2 mutations correlated with cisplatin response in MIBC.	('MIBC', 'Chemical', '-', (191, 195))	('cisplatin response', 'MPA', (169, 187))	('ERCC2', 'Gene', (137, 142))	('MIBC', 'Disease', (191, 195))	('cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('correlated with', 'Reg', (153, 168))	('ERCC2', 'Gene', '2068', (137, 142))	('mutations', 'Var', (143, 152))
96382	27376138	Altered DNA methylation represents the most common epigenetic alteration in bladder cancer and CpG island hypermethylation of tumor-suppressor gene promoters is associated with transcriptional inactivation and may occur early in carcinogenesis, making it clinically valuable for early diagnosis and risk stratification.	('bladder cancer', 'Disease', (76, 90))	('transcriptional inactivation', 'MPA', (177, 205))	('carcinogenesis', 'Disease', 'MESH:D063646', (229, 243))	('carcinogenesis', 'Disease', (229, 243))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('126', '142'))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('126', '142'))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('clinical', 'Species', '191496', (255, 263))	('Altered DNA methylation', 'Var', (0, 23))	('DNA methylation', 'biological_process', 'GO:0006306', ('8', '23'))	('hypermethylation', 'Var', (106, 122))	('tumor', 'Disease', (126, 131))
96386	27376138	Most importantly DNA hypermethylation has been shown to carry prognostic information in NMIBC, with a variety of selected genes associated with disease recurrence, progression, or both (Table 5).	('hypermethylation', 'Var', (21, 37))	('NMIBC', 'Chemical', '-', (88, 93))	('NMIBC', 'Disease', (88, 93))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('17', '37'))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))
96391	27376138	In conclusion, DNA methylation is the most studied epigenetic modification in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (78, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('DNA methylation', 'Var', (15, 30))	('bladder cancer', 'Disease', 'MESH:D001749', (78, 92))	('bladder cancer', 'Disease', (78, 92))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))
96393	27376138	Epigenetic modifications can be used as biomarkers for bladder cancer detection, prognostication, and therapeutic benefit prediction.	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('bladder cancer', 'Disease', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('Epigenetic modifications', 'Var', (0, 24))
96395	27376138	Leading the way are activating mutations and translocations of FGFR3, which are present in up to 70% of these tumors, while mutations in KDM6A, PIK3CA and HRAS are also relatively common.	('KDM6A', 'Gene', (137, 142))	('translocations', 'Var', (45, 59))	('mutations', 'Var', (31, 40))	('FGFR3', 'Gene', '2261', (63, 68))	('HRAS', 'Gene', '3265', (155, 159))	('PIK3CA', 'Gene', (144, 150))	('PIK3CA', 'Gene', '5290', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('HRAS', 'Gene', (155, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('FGFR3', 'Gene', (63, 68))	('KDM6A', 'Gene', '7403', (137, 142))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('activating', 'MPA', (20, 30))
96408	27376138	Simultaneous to the rapid articulation of specific targetable driver genetic alterations in bladder cancer through efforts such as the TCGA project, equally accelerated investigations of the molecular biology and candidate targets has occurred in the field of immuno-oncology.	('genetic alterations', 'Var', (69, 88))	('oncology', 'Phenotype', 'HP:0002664', (267, 275))	('bladder cancer', 'Disease', 'MESH:D001749', (92, 106))	('bladder cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (92, 106))
96421	27376138	In addition, the safety and early efficacy of other checkpoint inhibitor and agonist targets (LAG3, IDO1, GITR, 4-1BB, OX40, CD27, KIR2DL, CSF1R, CD40) is currently being evaluated in ongoing phase I trials.	('CSF1', 'molecular_function', 'GO:0005011', ('139', '143'))	('IDO1', 'Gene', (100, 104))	('CD40', 'Gene', (146, 150))	('4-1BB', 'Gene', '3604', (112, 117))	('KIR2DL', 'Var', (131, 137))	('CSF1R', 'Gene', '1436', (139, 144))	('OX40', 'Gene', '7293', (119, 123))	('LAG3', 'Gene', (94, 98))	('CD40', 'Gene', '958', (146, 150))	('IDO', 'molecular_function', 'GO:0033754', ('100', '103'))	('GITR', 'Gene', '8784', (106, 110))	('CSF1R', 'Gene', (139, 144))	('GITR', 'Gene', (106, 110))	('IDO', 'molecular_function', 'GO:0047719', ('100', '103'))	('CD27', 'Gene', (125, 129))	('IDO1', 'Gene', '3620', (100, 104))	('OX40', 'Gene', (119, 123))	('CD27', 'Gene', '939', (125, 129))	('LAG3', 'Gene', '3902', (94, 98))	('4-1BB', 'Gene', (112, 117))
96445	27376138	Among the multiple immune checkpoints under study, that mediated by the interaction between PD-1 and its ligands PD-L1 and/or PD-L2 has risen to the forefront of clinical investigation; as antibody-mediated blockade of either PD-1 or PD-L1 induces objective responses in a number of tumor types.	('PD-1', 'Gene', (92, 96))	('PD-1', 'Gene', '5133', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('antibody', 'cellular_component', 'GO:0019814', ('189', '197'))	('PD-1', 'Gene', (226, 230))	('antibody', 'molecular_function', 'GO:0003823', ('189', '197'))	('PD-1', 'Gene', '5133', (226, 230))	('clinical', 'Species', '191496', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('antibody', 'cellular_component', 'GO:0042571', ('189', '197'))	('objective responses', 'CPA', (248, 267))	('antibody', 'cellular_component', 'GO:0019815', ('189', '197'))	('PD-L2', 'Gene', (126, 131))	('tumor', 'Disease', (283, 288))	('PD-L2', 'Gene', '574057', (126, 131))	('PD-L1', 'Gene', (234, 239))	('blockade', 'Var', (207, 215))
96470	27376138	Preliminary data suggest activity for the combination of anti-VEGF (Bevicizumab) and anti-PD-L1 (Atezolizumab) in RCC, with an interesting Phase II trial in (NCT01984242) now fully accrued.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('Bevicizumab', 'Chemical', '-', (68, 79))	('Atezolizumab', 'Chemical', 'MESH:C000594389', (97, 109))	('VEGF', 'Gene', '7422', (62, 66))	('anti-PD-L1', 'Var', (85, 95))	('VEGF', 'Gene', (62, 66))
96491	27376138	We reviewed data on peripheral blood correlates that have been investigated in patients with melanoma that have been treated with CTLA-4 blocking antibodies, including absolute lymphocyte count (ALC), myeloid derived suppressor cells (MDSC) and changes in phenotypic markers on peripheral T cells like ki67 .	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('antibodies', 'Var', (146, 156))	('melanoma', 'Disease', (93, 101))	('CTLA-4', 'Gene', '1493', (130, 136))	('changes', 'Reg', (245, 252))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('patients', 'Species', '9606', (79, 87))	('CTLA-4', 'Gene', (130, 136))
96552	27376138	SWOG successfully completed accrual to a non-intergroup randomized phase III trial of newly diagnosed or recurrent Grade 1-2, Ta or T1 transitional cell carcinoma (S0337, NCT00445601), averaging 7 patients per month.	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (135, 162))	('patients', 'Species', '9606', (197, 205))	('carcinoma', 'Disease', 'MESH:D002277', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinoma', 'Disease', (153, 162))	('S0337', 'Var', (164, 169))
96577	27376138	Many clinical trials have demonstrated that patients positive for PD-L1 expression have a higher radiologic response to anti-PD-1 or PD-L1 therapy compared to those who are PD-L1-negative.	('patients', 'Species', '9606', (44, 52))	('radiologic response', 'MPA', (97, 116))	('higher', 'PosReg', (90, 96))	('clinical', 'Species', '191496', (5, 13))	('PD-1', 'Gene', (125, 129))	('PD-1', 'Gene', '5133', (125, 129))	('expression', 'Var', (72, 82))	('PD-L1', 'Gene', (66, 71))
96581	27376138	This is a very important factor since many clinical trials of PD-1/PD-L1 inhibitors currently in development are in combination with chemotherapy, radiation, tyrosine kinase inhibitors, and other immunotherapies.	('tyrosine kinase', 'Gene', (158, 173))	('PD-1', 'Gene', (62, 66))	('PD-1', 'Gene', '5133', (62, 66))	('clinical', 'Species', '191496', (43, 51))	('man', 'Species', '9606', (38, 41))	('inhibitors', 'Var', (73, 83))	('tyrosine kinase', 'Gene', '7294', (158, 173))
96611	27376138	In this setting, a fee for service is required for biospecimen processing (including quality assurance) and distribution, as well as any additional testing (e.g., nucleic acid extractions, TMA creation).	('TMA creation', 'Disease', 'MESH:D000783', (189, 201))	('TMA creation', 'Disease', (189, 201))	('nucleic acid', 'Var', (163, 175))	('nucleic acid', 'cellular_component', 'GO:0005561', ('163', '175'))
96625	27376138	In closing, bladder cancer offers some similarities to squamous cell lung carcinoma as it may require screening of large numbers of tumors to find those with a specific actionable gene alteration, given the relatively low (10-15%) frequency of these alterations.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('bladder cancer', 'Disease', 'MESH:D001749', (12, 26))	('bladder cancer', 'Disease', (12, 26))	('alteration', 'Var', (185, 195))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (55, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (55, 83))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('squamous cell lung carcinoma', 'Disease', (55, 83))	('tumors', 'Disease', (132, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (12, 26))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
96628	27376138	FGFR3 activation appears to be an early event, and non-muscle-invasive tumors are highly enriched for activating mutations and fusions.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', '2261', (0, 5))	('FGFR3', 'Gene', (0, 5))	('fusions', 'Var', (127, 134))	('mutations', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('invasive tumors', 'Disease', (62, 77))	('activation', 'PosReg', (6, 16))	('invasive tumors', 'Disease', 'MESH:D009369', (62, 77))
96629	27376138	These FGFR3 alterations occur in 50-70% of non-muscle-invasive bladder cancer (NMIBC), and are more prevalent in tumors of low grade and low stage.	('FGFR3', 'Gene', '2261', (6, 11))	('occur', 'Reg', (24, 29))	('prevalent', 'Reg', (100, 109))	('alterations', 'Var', (12, 23))	('tumors', 'Disease', (113, 119))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (47, 77))	('muscle-invasive bladder cancer', 'Disease', (47, 77))	('FGFR3', 'Gene', (6, 11))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('bladder cancer', 'Phenotype', 'HP:0009725', (63, 77))	('NMIBC', 'Chemical', '-', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('6', '10'))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('invasive bladder', 'Phenotype', 'HP:0100645', (54, 70))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
96630	27376138	FGFR3 mutant tumors recur at the same frequency as FGFR3 wild-type tumors, but have a lower rate of progression to muscle invasion, with one study demonstrating a 5 year progression free survival of 91% in FGFR3 mutant patients compared to 74% in FGFR3 wild-type patients.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', '2261', (247, 252))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('FGFR3', 'Gene', (206, 211))	('FGFR', 'molecular_function', 'GO:0005007', ('247', '251'))	('FGFR3', 'Gene', '2261', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumors', 'Disease', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('FGFR3', 'Gene', (51, 56))	('tumors', 'Disease', (67, 73))	('mutant', 'Var', (212, 218))	('mutant', 'Var', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('FGFR3', 'Gene', '2261', (51, 56))	('patients', 'Species', '9606', (263, 271))	('FGFR3', 'Gene', (0, 5))	('FGFR3', 'Gene', (247, 252))	('FGFR', 'molecular_function', 'GO:0005007', ('206', '210'))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('FGFR3', 'Gene', '2261', (0, 5))
96631	27376138	The FGFR3 mutation status in bladder tumor recurrences is often concordant with the primary tumor.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('bladder tumor', 'Disease', 'MESH:D001749', (29, 42))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('tumor', 'Disease', (92, 97))	('bladder tumor', 'Phenotype', 'HP:0009725', (29, 42))	('FGFR3', 'Gene', (4, 9))	('mutation', 'Var', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('bladder tumor', 'Disease', (29, 42))	('FGFR3', 'Gene', '2261', (4, 9))
96638	27376138	Studies to demonstrate anti-tumor activity are required to determine whether systemic administration of FGFR3 inhibitors can lead to anticancer effects on tumors in the lining of the bladder.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (155, 160))	('FGFR3', 'Gene', '2261', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('104', '108'))	('tumors', 'Disease', (155, 161))	('cancer', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('FGFR3', 'Gene', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('inhibitors', 'Var', (110, 120))
96720	25993187	However, it contained thimerosal, a known organomercurial preservative with the potential for neurotoxicity.	('neurotoxicity', 'Disease', (94, 107))	('thimerosal', 'Var', (22, 32))	('thimerosal', 'Chemical', 'MESH:D013849', (22, 32))	('neurotoxicity', 'Disease', 'MESH:D020258', (94, 107))	('contained', 'Reg', (12, 21))
96743	25993187	Binding of PD-L1 and/or PD-L2 to PD-1 results in dephosphorylation of proximal signaling molecules downstream of the T-cell receptor complex via src homology region 2 domain- containing phosphatase (SHP)-1 and SHP-2 as well as augmentation of phosphatase and tensin homolog (PTEN), leading to decreased T-cell proliferation, survival, and protein synthesis.	('survival', 'CPA', (325, 333))	('PD-L1', 'Gene', '29126', (11, 16))	('T-cell proliferation', 'biological_process', 'GO:0042098', ('303', '323'))	('protein', 'cellular_component', 'GO:0003675', ('339', '346'))	('SHP-2', 'Gene', (210, 215))	('T-cell proliferation', 'CPA', (303, 323))	('decreased T-cell', 'Phenotype', 'HP:0005403', (293, 309))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('243', '273'))	('T-cell receptor complex', 'cellular_component', 'GO:0042101', ('117', '140'))	('Binding', 'Interaction', (0, 7))	('SHP)-1', 'Gene', (199, 205))	('dephosphorylation of proximal signaling molecules', 'MPA', (49, 98))	('dephosphorylation', 'biological_process', 'GO:0016311', ('49', '66'))	('augmentation', 'PosReg', (227, 239))	('protein synthesis', 'biological_process', 'GO:0006412', ('339', '356'))	('PD-1', 'Gene', (33, 37))	('decreased', 'NegReg', (293, 302))	('phosphatase', 'molecular_function', 'GO:0016791', ('186', '197'))	('PD-L2', 'Var', (24, 29))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('PD-L1', 'Gene', (11, 16))	('protein synthesis', 'CPA', (339, 356))	('PTEN', 'Gene', (275, 279))	('phosphatase', 'molecular_function', 'GO:0016791', ('243', '254'))
96757	25993187	Recently reported results from The Cancer Genome Atlas found that HER2 alterations were almost as frequent in urothelial carcinoma compared to the TCGA breast cancer study.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('HER2', 'Gene', '2064', (66, 70))	('HER2', 'Gene', (66, 70))	('frequent', 'Reg', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (110, 130))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('alterations', 'Var', (71, 82))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Cancer', 'Disease', (35, 41))	('breast cancer', 'Disease', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('Cancer', 'Disease', 'MESH:D009369', (35, 41))	('urothelial carcinoma', 'Disease', (110, 130))
96761	25993187	A randomized phase II study comparing adjuvant DN24 - 02 to the standard of care in patients with high-risk urothelial cell carcinoma met accrual and results are pending at this time.	('urothelial cell carcinoma met accrual', 'Disease', (108, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('patients', 'Species', '9606', (84, 92))	('DN24', 'Var', (47, 51))	('urothelial cell carcinoma met accrual', 'Disease', 'MESH:C538614', (108, 145))
96774	25993187	These vectors contain transgenes for both human T-cell costimulatory molecules and tumor-associated antigens against Mucin-1 (MUC-1) and carcinoembryonic antigen (CEA).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('transgenes', 'Var', (22, 32))	('Mucin-1', 'Gene', (117, 124))	('Mucin-1', 'Gene', '4582', (117, 124))	('CEA', 'Gene', (163, 166))	('carcinoembryonic antigen', 'Gene', '1084', (137, 161))	('human', 'Species', '9606', (42, 47))	('tumor', 'Disease', (83, 88))	('CEA', 'Gene', '1084', (163, 166))	('carcinoembryonic antigen', 'Gene', (137, 161))	('MUC-1', 'Gene', (126, 131))	('MUC-1', 'Gene', '4582', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
96782	25993187	A more novel approach applies extraction of TILs from tumors and whole-exomic sequencing of the tumors to identify mutations characteristic of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('mutations', 'Var', (115, 124))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
96783	25993187	This technology can be applied to any malignancy, and, given that urothelial cancer has the third highest rate of mutations, it is well positioned for this type of therapy.	('malignancy', 'Disease', 'MESH:D009369', (38, 48))	('malignancy', 'Disease', (38, 48))	('mutations', 'Var', (114, 123))	('urothelial cancer', 'Disease', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('urothelial cancer', 'Disease', 'MESH:D014523', (66, 83))
96785	25993187	As a result, genetic modification of the T-cell receptor (TCR) only requires isolation from peripheral blood, viral transduction to express a recombinant TCR specific for a tumor antigen, and reinfusion after expansion of these genetically engineered TCRs.	('genetic modification', 'Var', (13, 33))	('TCR', 'biological_process', 'GO:0006283', ('58', '61'))	('TCR', 'Gene', '6962', (154, 157))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('TCR', 'Gene', '6962', (58, 61))	('TCR', 'cellular_component', 'GO:0042101', ('154', '157'))	('TCR', 'Gene', '6962', (251, 254))	('tumor antigen', 'molecular_function', 'GO:0008222', ('173', '186'))	('TCR', 'Gene', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('TCR', 'biological_process', 'GO:0006283', ('154', '157'))	('TCR', 'Gene', (58, 61))	('TCR', 'cellular_component', 'GO:0042101', ('58', '61'))	('TCR', 'Gene', (251, 254))	('transduction', 'biological_process', 'GO:0009293', ('116', '128'))
96798	25993187	Monoclonal antibodies, and specifically checkpoint blockade inhibitors, have been especially exciting and are the newest therapies for metastatic urothelial cancer.	('urothelial cancer', 'Disease', (146, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Monoclonal', 'Var', (0, 10))	('urothelial cancer', 'Disease', 'MESH:D014523', (146, 163))
96801	25993187	Finally, adoptive T-cell therapy is very promising; although this area of immunotherapy has not been explored fully in urothelial cancer, the high rate of mutations in urothelial cancer and the prevalence of urothelial-speciffic TAAs make this a promising area of future research.	('urothelial cancer', 'Disease', (119, 136))	('mutations', 'Var', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('urothelial cancer', 'Disease', (168, 185))	('urothelial cancer', 'Disease', 'MESH:D014523', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('urothelial cancer', 'Disease', 'MESH:D014523', (168, 185))
96807	25877892	Although mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal "actionable" mutations, including BRAF(V600E), IDH1(R132H), PIK3CA(E545K), EGFR(L858R), and KRAS(G12D), which may compromise the efficacy of targeted therapy approaches.	('EGFR', 'Gene', (197, 201))	('EGFR', 'molecular_function', 'GO:0005006', ('195', '199'))	('E545K', 'Mutation', 'rs104886003', (189, 194))	('R132H', 'Mutation', 'rs121913500', (174, 179))	('IDH1', 'Gene', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PIK3CA', 'Gene', (182, 188))	('KRAS', 'Gene', (214, 218))	('G12D', 'Mutation', 'rs121913529', (219, 223))	('KRAS', 'Gene', '3845', (214, 218))	('IDH1', 'Gene', '3417', (169, 173))	('PIK3CA', 'Gene', '5290', (182, 188))	('L858R', 'Mutation', 'rs121434568', (202, 207))	('EGFR', 'Gene', '1956', (197, 201))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('V600E', 'SUBSTITUTION', 'None', (161, 166))	('V600E', 'Var', (161, 166))	('cancer', 'Disease', (69, 75))
96808	25877892	More than 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K(phosphatidylinositol 3-kinase)-AKT-mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal.	('glioblastomas', 'Disease', 'MESH:D005909', (35, 48))	('mammalian target of rapamycin', 'Gene', '2475', (133, 162))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('IDH1', 'Gene', '3417', (17, 21))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (92, 121))	('mammalian target of rapamycin', 'Gene', (133, 162))	('mTOR', 'Gene', (127, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('glioblastomas', 'Phenotype', 'HP:0012174', (35, 48))	('AKT', 'Gene', (123, 126))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))	('phosphatidylinositol 3-kinase', 'Gene', (92, 121))	('tumor', 'Disease', (190, 195))	('mutations', 'Var', (22, 31))	('mTOR', 'Gene', '2475', (127, 131))	('glioblastomas', 'Disease', (35, 48))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('AKT', 'Gene', '207', (123, 126))	('IDH1', 'Gene', (17, 21))	('PI3K', 'molecular_function', 'GO:0016303', ('87', '91'))
96809	25877892	Mutations in the RAS-MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTORsignaling.	('AKT', 'Gene', '207', (160, 163))	('PI3K', 'molecular_function', 'GO:0016303', ('155', '159'))	('RAS-MEK', 'Gene', (17, 24))	('Mutations', 'Var', (0, 9))	('AKT', 'Gene', (160, 163))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('mTOR', 'Gene', (164, 168))	('mTOR', 'Gene', '2475', (164, 168))
96810	25877892	Analysis of late mutations revealed a link between APOBEC-mediated mutagenesis and the acquisition of subclonal driver mutations and uncovered putative cancer genes involved in subclonal expansions, including CTNNA2 and ATXN1.	('cancer', 'Disease', (152, 158))	('ATXN1', 'Gene', '6310', (220, 225))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('CTNNA2', 'Gene', (209, 215))	('APOBEC', 'cellular_component', 'GO:0030895', ('51', '57'))	('mutagenesis', 'Var', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mutagenesis', 'biological_process', 'GO:0006280', ('67', '78'))	('APOBEC-mediated', 'Gene', (51, 66))	('CTNNA2', 'Gene', '1496', (209, 215))	('ATXN1', 'Gene', (220, 225))
96812	25877892	The frequent presence of subclonal driver mutations suggests the need to stratify targeted therapy response according to the proportion of tumor cells in which the driver is identified.	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mutations', 'Var', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))
96818	25877892	The presence of subclonal mutations may reduce the clinical benefit of cancer therapies.	('subclonal mutations', 'Var', (16, 35))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('reduce', 'NegReg', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
96819	25877892	For instance, in colorectal cancer, subclonal RAS mutations have been shown to precipitate resistance to cetuximab, and in glioblastomas, individual driver events can be present in distinct populations of cancer cells or subclones.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('precipitate', 'Reg', (79, 90))	('RAS', 'Gene', (46, 49))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))	('glioblastomas', 'Phenotype', 'HP:0012174', (123, 136))	('colorectal cancer', 'Disease', (17, 34))	('resistance to cetuximab', 'MPA', (91, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (123, 135))	('subclonal', 'Var', (36, 45))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('glioblastomas', 'Disease', (123, 136))	('cancer', 'Disease', (28, 34))	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (50, 59))	('glioblastomas', 'Disease', 'MESH:D005909', (123, 136))	('cetuximab', 'Chemical', 'MESH:D000068818', (105, 114))
96820	25877892	Furthermore, the use of targeted therapy against a subclonal driver present in a subset of cells within a tumor may lead to stimulation of wild-type subclones lacking the targeted mutation.	('targeted', 'Var', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('stimulation', 'PosReg', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
96822	25877892	However, although the clonal status of driver mutations has received attention in certain cancers, a broad understanding of the heterogeneity of driver genes, deciphering the clonal and subclonal frequencies, and the timing of mutational processes involved in tumor evolution is lacking.	('tumor', 'Disease', (260, 265))	('cancers', 'Disease', (90, 97))	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
96826	25877892	Mutations and copy number variants from TCGA were processed and filtered to obtain a pan-cancer data set representing 2694 tumors from nine major cancer types with both copy number and mutation data.	('cancer', 'Disease', (146, 152))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('TCGA', 'Gene', (40, 44))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
96827	25877892	To explore the relative timing of mutations, we first estimated the mutation copy number (the number of alleles harboring the mutation) and cancer cell fraction (the fraction of tumor cells with the mutation) of each single nucleotide variant.	('tumor', 'Disease', (178, 183))	('single nucleotide variant', 'Var', (217, 242))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cell fraction', 'cellular_component', 'GO:0000267', ('147', '160'))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
96828	25877892	Mutations were classified as clonal (present in all tumor cells sequenced) if the upper band of the 95% cancer cell fraction confidence interval was >= 1, and subclonal otherwise.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cell fraction', 'cellular_component', 'GO:0000267', ('111', '124'))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (52, 57))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
96829	25877892	Mutations were then classified as "early" or "late" based on the cancer cell fraction and the mutation copy number.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Mutations', 'Var', (0, 9))	('cell fraction', 'cellular_component', 'GO:0000267', ('68', '81'))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
96833	25877892	To explore the clonal status of mutations in established cancer genes, we first identified all nonsilent mutations that occurred in known cancer driver genes based on the recent pan-cancer analysis by Lawrence et al.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (105, 114))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
96834	25877892	In general, we observed a clear tendency for mutations in driver genes to be clonal compared to mutations in noncancer genes (Fig.	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (45, 54))	('cancer', 'Disease', (112, 118))
96835	25877892	In every cancer type, with the exception of KIRC, mutations in driver genes (considered in aggregate) were enriched to a statistically significant degree for clonal mutations, compared to mutations in nondriver genes (Fig.	('cancer', 'Disease', (9, 15))	('significant', 'Reg', (135, 146))	('mutations', 'Var', (50, 59))	('KIRC', 'Phenotype', 'HP:0005584', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
96836	25877892	In KIRC, we found that VHL was the only cancer gene that had a significantly higher proportion of clonal mutations than the background rate representing all nonsilent mutations, consistent with multiregion sequencing results in KIRC and supporting our approach to distinguish clonal from subclonal somatic events (P= 0.0147; fig.	('VHL', 'Disease', (23, 26))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('KIRC', 'Phenotype', 'HP:0005584', (228, 232))	('cancer', 'Disease', (40, 46))	('mutations', 'Var', (105, 114))	('KIRC', 'Phenotype', 'HP:0005584', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('VHL', 'Disease', 'MESH:D006623', (23, 26))
96837	25877892	Within other cancer types, we found that mutations in specific cancer genes showed a tendency to be clonal (Fig.	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
96838	25877892	For instance, in BRCA, mutations in CBFB were exclusively clonal, as were mutations in CDKN2A in LUSC and HNSC, and a similar trend was observed for mutations in ARID1A in BLCA.	('BRCA', 'Gene', (17, 21))	('CDKN2A', 'Gene', '1029', (87, 93))	('CBFB', 'Gene', '865', (36, 40))	('LUSC', 'Phenotype', 'HP:0030359', (97, 101))	('BRCA', 'Gene', '672', (17, 21))	('mutations', 'Var', (74, 83))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('mutations', 'Var', (23, 32))	('BLCA', 'Phenotype', 'HP:0009725', (172, 176))	('CBFB', 'Gene', (36, 40))	('ARID1A', 'Gene', '8289', (162, 168))	('BRCA', 'Phenotype', 'HP:0003002', (17, 21))	('ARID1A', 'Gene', (162, 168))	('CDKN2A', 'Gene', (87, 93))
96840	25877892	We also observed a significant enrichment of TP53 mutations in genome-doubled tumors (fig.	('tumors', 'Disease', (78, 84))	('genome-doubled', 'Disease', (63, 77))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('TP53', 'Gene', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('TP53', 'Gene', '7157', (45, 49))
96841	25877892	S4; P < 0.001, Fisher's exact test), and almost invariably (>90% cases), these mutations occurred before doubling, consistent with TP53 playing an important role in tolerance of genome doubling.	('TP53', 'Gene', (131, 135))	('occurred', 'Reg', (89, 97))	('mutations', 'Var', (79, 88))	('TP53', 'Gene', '7157', (131, 135))
96847	25877892	Mutations in PIK3R1 and MLL3 were frequently subclonal across cancer types, such that a higher proportion of subclonal mutations were observed in these genes compared to the background rate (fig.	('PIK3R1', 'Gene', '5295', (13, 19))	('MLL3', 'Gene', '58508', (24, 28))	('PIK3R1', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Mutations', 'Var', (0, 9))	('MLL3', 'Gene', (24, 28))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
96850	25877892	In GBM-28-2513, we identified two subclonal mutations in genes involved in the PI3K (phosphatidylinositol 3-kinase) signaling axis, with one mutation in PIK3R1 present in 54% of cancer cells and a mutation in PTEN present in only 36% of cancer cells.	('PTEN', 'Gene', (209, 213))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (85, 114))	('cancer', 'Disease', (178, 184))	('PIK3R1', 'Gene', (153, 159))	('phosphatidylinositol 3-kinase', 'Gene', (85, 114))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('PIK3R1', 'Gene', '5295', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('phosphatidylinositol 3-kinase) signaling', 'biological_process', 'GO:0014065', ('85', '125'))	('cancer', 'Disease', (237, 243))	('PI3K', 'molecular_function', 'GO:0016303', ('79', '83'))	('mutation', 'Var', (141, 149))	('PTEN', 'Gene', '5728', (209, 213))
96852	25877892	In further support of parallel evolution, in general, we found that when multiple nonsilent mutations were identified in the same cancer gene within one tumor sample, these mutations exhibited a significantly lower cancer cell fraction compared to mutations in cancer genes occurring only once in a cancer sample (fig.	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (215, 221))	('lower', 'NegReg', (209, 214))	('tumor', 'Disease', (153, 158))	('cancer', 'Disease', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('mutations', 'Var', (92, 101))	('mutations', 'Var', (173, 182))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', (130, 136))	('cell fraction', 'cellular_component', 'GO:0000267', ('222', '235'))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (261, 267))
96855	25877892	Signature 1A, reflecting a preponderance of C>T transitions at CpG sites, was identified in five cancer types (BLCA, BRCA, COAD, GBM, and HNSC).	('BRCA', 'Phenotype', 'HP:0003002', (117, 121))	('cancer', 'Disease', (97, 103))	('BRCA', 'Gene', (117, 121))	('BRCA', 'Gene', '672', (117, 121))	('COAD', 'Disease', 'MESH:D029424', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('GBM', 'Disease', (129, 132))	('BLCA', 'Phenotype', 'HP:0009725', (111, 115))	('BLCA', 'Disease', (111, 115))	('C>T', 'Var', (44, 47))	('HNSC', 'Phenotype', 'HP:0012288', (138, 142))	('COAD', 'Disease', (123, 127))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
96860	25877892	We also found a tendency for signature 2 to increase in frequency in later mutations in ER-negative BRCA (P= 0.0126), but not in ER-positive breast cancers (P= 0.597), highlighting the differences between these two subtypes of breast cancer.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('BRCA', 'Gene', '672', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('breast cancers', 'Phenotype', 'HP:0003002', (141, 155))	('BRCA', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancers', 'Disease', (141, 155))	('increase', 'PosReg', (44, 52))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('breast cancers', 'Disease', 'MESH:D001943', (141, 155))	('breast cancer', 'Disease', (227, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('ER-negative', 'Var', (88, 99))	('BRCA', 'Phenotype', 'HP:0003002', (100, 104))
96861	25877892	These data suggest that the APOBEC mutational process may foster subclonal expansions across several tumor types.	('mutational', 'Var', (35, 45))	('APOBEC', 'Gene', (28, 34))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('subclonal expansions', 'MPA', (65, 85))	('foster', 'PosReg', (58, 64))	('APOBEC', 'cellular_component', 'GO:0030895', ('28', '34'))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
96862	25877892	Notably, signature 2 was detected in both early and late mutations, albeit to a lesser degree in early mutations, suggesting that APOBEC activity is more than a transient event and does not simply represent a historical relic within the tumor genome, active at only one point in time during the disease course.	('APOBEC', 'cellular_component', 'GO:0030895', ('130', '136'))	('tumor', 'Disease', (237, 242))	('mutations', 'Var', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
96865	25877892	In SKCM, it is also worth noting that most samples were derived from metastatic sites; thus, many of the later mutations will likely have been acquired when tumor cells were no longer exposed to UV light.	('tumor', 'Disease', (157, 162))	('mutations', 'Var', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
96867	25877892	In both LUAD and LUSC, we found that more than 30% of clonal nonsilent mutations in cancer genes were C>A transversions, which can be attributed to tobacco smoke; for example, more than 40% of clonal mutations in TP53 were C>A transversions.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('LUSC', 'Phenotype', 'HP:0030359', (17, 21))	('TP53', 'Gene', (213, 217))	('cancer', 'Disease', (84, 90))	('LUAD', 'Phenotype', 'HP:0030078', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tobacco', 'Species', '4097', (148, 155))	('C>A', 'Var', (223, 226))	('TP53', 'Gene', '7157', (213, 217))
96871	25877892	Strikingly, in these cancers, more than 90% of subclonal mutations in PIK3CA occurred in an APOBEC context, and we also identified subclonal APOBEC mutations in multiple other cancer driver genes, including PTEN, EGFR, and TP53.	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('EGFR', 'Gene', '1956', (213, 217))	('TP53', 'Gene', '7157', (223, 227))	('APOBEC', 'cellular_component', 'GO:0030895', ('92', '98'))	('PIK3CA', 'Gene', '5290', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('mutations', 'Var', (148, 157))	('PTEN', 'Gene', (207, 211))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancers', 'Disease', (21, 28))	('cancer', 'Disease', (21, 27))	('EGFR', 'molecular_function', 'GO:0005006', ('213', '217'))	('APOBEC', 'cellular_component', 'GO:0030895', ('141', '147'))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('EGFR', 'Gene', (213, 217))	('TP53', 'Gene', (223, 227))	('PTEN', 'Gene', '5728', (207, 211))	('PIK3CA', 'Gene', (70, 76))	('occurred', 'Reg', (77, 85))	('cancer', 'Disease', (176, 182))
96873	25877892	Together, these data highlight the extent to which endogenous and exogenous mutational processes can fuel the acquisition of somatic events in cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutational', 'Var', (76, 86))	('fuel', 'PosReg', (101, 105))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
96874	25877892	Moreover, the dynamics of specific mutational processes may alter the subclonal architecture of a tumor by providing the mutational fuel upon which selection can act.	('mutational', 'Var', (35, 45))	('alter', 'Reg', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
96875	25877892	Given the tendency for mutations in many known cancer genes to be clonal and the observation that many clonal mutations likely occur before tumorigenesis, we reasoned that it might be possible to identify drivers of subclonal expansions by focusing exclusively on late or subclonal mutations.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('mutations', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (140, 145))
96879	25877892	Temporal dissection was required to uncover the cancer gene PIK3CA in HNSC, suggesting that mutations in this gene may often lead to, or be permissive for, subclonal expansions in this cancer type.	('HNSC', 'Phenotype', 'HP:0012288', (70, 74))	('PIK3CA', 'Gene', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('PIK3CA', 'Gene', '5290', (60, 66))	('mutations', 'Var', (92, 101))	('HNSC', 'Disease', (70, 74))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('lead to', 'Reg', (125, 132))
96882	25877892	CTNNA2 has previously been implicated in laryngeal cancer as a tumor suppressor, and its inactivation in HNSC cells is associated with migration and invasion advantages, consistent with it playing a role at later stages of tumor development.	('laryngeal cancer', 'Disease', (41, 57))	('tumor', 'Disease', (63, 68))	('invasion advantages', 'CPA', (149, 168))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (41, 57))	('tumor', 'Disease', (223, 228))	('CTNNA2', 'Gene', '1496', (0, 6))	('HNSC', 'Phenotype', 'HP:0012288', (105, 109))	('inactivation', 'Var', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('migration', 'CPA', (135, 144))	('CTNNA2', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('63', '79'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('laryngeal cancer', 'Disease', 'MESH:D007822', (41, 57))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor suppressor', 'biological_process', 'GO:0051726', ('63', '79'))
96883	25877892	In LUAD, we also identified mutations in NRXN3 as a putative subclonal driver event.	('NRXN3', 'Gene', '9369', (41, 46))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('mutations', 'Var', (28, 37))	('NRXN3', 'Gene', (41, 46))
96884	25877892	A polymorphic site of this gene (rs10146997) has been associated with higher risk of breast cancer development, and low expression of NRXN3 is associated with poorer survival in lung cancer (fig.	('rs10146997', 'Var', (33, 43))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('expression', 'MPA', (120, 130))	('lung cancer', 'Disease', (178, 189))	('breast cancer', 'Disease', (85, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('rs10146997', 'Mutation', 'rs10146997', (33, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('low', 'NegReg', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('poorer', 'NegReg', (159, 165))	('NRXN3', 'Gene', '9369', (134, 139))	('NRXN3', 'Gene', (134, 139))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
96886	25877892	The ATXN1 protein family plays an important role in transcriptional control of extracellular matrix remodeling, and mutations in ATXN1 have been putatively linked to cancer metastasis, consistent with its occurrence as a later event in COAD.	('cancer metastasis', 'Disease', (166, 183))	('COAD', 'Disease', 'MESH:D029424', (236, 240))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('79', '99'))	('ATXN1', 'Gene', (129, 134))	('linked', 'Reg', (156, 162))	('ATXN1', 'Gene', '6310', (129, 134))	('mutations', 'Var', (116, 125))	('cancer metastasis', 'Disease', 'MESH:D009362', (166, 183))	('ATXN1', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('ATXN1', 'Gene', '6310', (4, 9))	('COAD', 'Disease', (236, 240))	('transcriptional control', 'biological_process', 'GO:0006355', ('52', '75'))
96888	25877892	It has been suggested that LRP1B acts as a tumor suppressor gene, and in KIRC, its depletion leads to increased anchorage-independent growth, cell migration, and invasion in vitro.	('LRP1B', 'Gene', '53353', (27, 32))	('cell migration', 'biological_process', 'GO:0016477', ('142', '156'))	('anchorage-independent growth', 'CPA', (112, 140))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cell migration', 'CPA', (142, 156))	('LRP1B', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('depletion', 'Var', (83, 92))	('increased', 'PosReg', (102, 111))	('KIRC', 'Phenotype', 'HP:0005584', (73, 77))	('tumor', 'Disease', (43, 48))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))	('invasion', 'CPA', (162, 170))
96891	25877892	For instance, the presence of mutations that activate the PI3K-AKT-mTOR (mammalian target of rapamycin) pathway and contribute to carcinogenesis has engendered much interest in inhibitors of this signaling axis.	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('AKT', 'Gene', (63, 66))	('carcinogenesis', 'Disease', 'MESH:D063646', (130, 144))	('signaling', 'biological_process', 'GO:0023052', ('196', '205'))	('contribute', 'Reg', (116, 126))	('carcinogenesis', 'Disease', (130, 144))	('activate', 'PosReg', (45, 53))	('mTOR', 'Gene', (67, 71))	('mTOR', 'Gene', '2475', (67, 71))	('mutations', 'Var', (30, 39))	('mammalian target of rapamycin', 'Gene', '2475', (73, 102))	('mammalian target of rapamycin', 'Gene', (73, 102))	('AKT', 'Gene', '207', (63, 66))
96893	25877892	More than 10%of all nonsilent PIK3CA mutations and more than 20% of all nonsilent mutations in PTEN were found to be subclonal, and more than 15% of mutations in genes in the PI3K-AKT-mTOR pathway overall were subclonal (Fig.	('PIK3CA', 'Gene', (30, 36))	('mutations', 'Var', (149, 158))	('mTOR', 'Gene', '2475', (184, 188))	('PI3K', 'molecular_function', 'GO:0016303', ('175', '179'))	('mTOR', 'Gene', (184, 188))	('PIK3CA', 'Gene', '5290', (30, 36))	('mutations', 'Var', (37, 46))	('mutations', 'Var', (82, 91))	('AKT', 'Gene', (180, 183))	('PTEN', 'Gene', (95, 99))	('PTEN', 'Gene', '5728', (95, 99))	('AKT', 'Gene', '207', (180, 183))
96894	25877892	In GBM, the use of IDH-targeted therapies has been proposed for tumors with IDH1 or IDH2 mutations, and yet, we observed that more than 20% of IDH1 mutations are subclonal in GBM (Fig.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('IDH1', 'Gene', (143, 147))	('IDH1', 'Gene', '3417', (76, 80))	('IDH', 'Gene', '3417', (76, 79))	('IDH', 'Gene', '3417', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('IDH', 'Gene', (143, 146))	('tumors', 'Disease', (64, 70))	('IDH2', 'Gene', (84, 88))	('IDH2', 'Gene', '3418', (84, 88))	('IDH1', 'Gene', '3417', (143, 147))	('GBM', 'Disease', (175, 178))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (148, 157))	('IDH', 'Gene', '3417', (143, 146))	('IDH', 'Gene', (84, 87))	('IDH1', 'Gene', (76, 80))	('IDH', 'Gene', (76, 79))	('IDH', 'Gene', (19, 22))	('IDH', 'Gene', '3417', (84, 87))
96895	25877892	On the other hand, all IDH1 mutations detected in SKCM were clonal.	('mutations', 'Var', (28, 37))	('IDH1', 'Gene', (23, 27))	('IDH1', 'Gene', '3417', (23, 27))
96896	25877892	In KIRC, mTOR inhibition is a common therapeutic option; however, we found that more than 30% of mutations in mTOR were subclonal within this disease type within single tumor samples.	('mTOR', 'Gene', (110, 114))	('mutations', 'Var', (97, 106))	('mTOR', 'Gene', '2475', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('mTOR', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mTOR', 'Gene', '2475', (9, 13))	('tumor', 'Disease', (169, 174))	('KIRC', 'Phenotype', 'HP:0005584', (3, 7))
96899	25877892	Finally, we restricted our analysis to well-characterized mutations occurring in the database of curated mutations (DoCM; docm.genome.wustl.edu) and in at least three tumor samples within the cohort.	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mutations', 'Var', (58, 67))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (167, 172))
96900	25877892	For most of these mutations, we identified both clonal and subclonal mutations in at least one cancer type (fig.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('mutations', 'Var', (18, 27))
96901	25877892	We identified tumor samples with subclonal mutations in known sites with therapeutic relevance such as NRAS(Q61K, Q61R, Q61L), BRAF (V600E), KRAS (G12C, G12D, G12V), PIK3CA (E542K, 545K, H1047R), and IDH1 (R132H), as well as many subclonal loss-of-function mutations in tumor suppressor genes such as PTEN (Fig.	('G12V', 'Var', (159, 163))	('IDH1', 'Gene', (200, 204))	('NRAS', 'Gene', '4893', (103, 107))	('KRAS', 'Gene', (141, 145))	('E542K', 'Mutation', 'rs121913273', (174, 179))	('BRAF', 'Gene', '673', (127, 131))	('BRAF', 'Gene', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('V600E', 'Var', (133, 138))	('PTEN', 'Gene', '5728', (301, 305))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('270', '286'))	('E542K', 'Var', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('Q61R', 'Var', (114, 118))	('H1047R', 'Var', (187, 193))	('G12D', 'Var', (153, 157))	('Q61R', 'Mutation', 'rs11554290', (114, 118))	('IDH1', 'Gene', '3417', (200, 204))	('G12D', 'Mutation', 'rs121913529', (153, 157))	('loss-of-function', 'NegReg', (240, 256))	('tumor suppressor', 'biological_process', 'GO:0051726', ('270', '286'))	('Q61L', 'Mutation', 'rs11554290', (120, 124))	('H1047R', 'Mutation', 'rs121913279', (187, 193))	('NRAS', 'Gene', (103, 107))	('545K', 'Var', (181, 185))	('G12C', 'Mutation', 'rs121913530', (147, 151))	('PIK3CA', 'Gene', '5290', (166, 172))	('R132H', 'Mutation', 'rs121913500', (206, 211))	('Q61L', 'Var', (120, 124))	('tumor', 'Disease', (270, 275))	('tumor', 'Disease', (14, 19))	('KRAS', 'Gene', '3845', (141, 145))	('G12V', 'Mutation', 'rs121913529', (159, 163))	('V600E', 'Mutation', 'rs113488022', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('PTEN', 'Gene', (301, 305))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('PIK3CA', 'Gene', (166, 172))	('Q61K', 'Mutation', 'rs121913254', (108, 112))
96902	25877892	Identified subclonal driver mutations often occurred in tumors where clonal mutations in established cancer genes were also present [Fig.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancer', 'Disease', (101, 107))	('occurred', 'Reg', (44, 52))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (28, 37))
96903	25877892	For example, in patient HNSC-CV-7177, a PIK3CA (E545K) mutation in the highly conserved helical domain was estimated to be present in only 36% of cancer cells, whereas a mutation in TP53in the same tumor was found to be present in all cancer cells.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('TP53', 'Gene', '7157', (182, 186))	('PIK3CA', 'Gene', (40, 46))	('TP53', 'Gene', (182, 186))	('HNSC', 'Phenotype', 'HP:0012288', (24, 28))	('cancer', 'Disease', (235, 241))	('PIK3CA', 'Gene', '5290', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('E545K', 'Mutation', 'rs104886003', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('mutation', 'Var', (55, 63))	('tumor', 'Disease', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('patient', 'Species', '9606', (16, 23))
96904	25877892	Similarly, patient SKCM-ER-A2NE exhibited a clonal mutation in NRAS(Q61K), whereas a PTEN mutation (Y178*) was present only in 13% of cells.	('NRAS', 'Gene', '4893', (63, 67))	('Y178*', 'SUBSTITUTION', 'None', (100, 105))	('Y178*', 'Var', (100, 105))	('Q61K', 'Mutation', 'rs121913254', (68, 72))	('patient', 'Species', '9606', (11, 18))	('PTEN', 'Gene', (85, 89))	('NRAS', 'Gene', (63, 67))	('PTEN', 'Gene', '5728', (85, 89))
96906	25877892	Moreover, these results demonstrate that known driver mutations do not only play a role in tumor initiation but also likely influence tumor behavior after tumor branching within distinct subclones.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('play', 'Reg', (76, 80))	('tumor branching', 'Disease', 'MESH:D009369', (155, 170))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mutations', 'Var', (54, 63))	('tumor branching', 'Disease', (155, 170))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor initiation', 'Disease', 'MESH:D009369', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('influence', 'Reg', (124, 133))	('tumor', 'Disease', (91, 96))	('tumor initiation', 'Disease', (91, 107))	('tumor', 'Disease', (134, 139))
96911	25877892	Our results demonstrate the presence of considerable intratumor heterogeneity in driver events, including known canonical hotspot mutations, such as IDH1 (R132H) and PIK3CA (E545K).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('PIK3CA', 'Gene', '5290', (166, 172))	('R132H', 'Var', (155, 160))	('IDH1', 'Gene', (149, 153))	('E545K', 'Mutation', 'rs104886003', (174, 179))	('E545K', 'Var', (174, 179))	('R132H', 'Mutation', 'rs121913500', (155, 160))	('IDH1', 'Gene', '3417', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('PIK3CA', 'Gene', (166, 172))
96912	25877892	Strikingly, we find that almost every gene linked with a targeted therapy harbors subclonal mutations in at least one tumor within the cohort.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('subclonal mutations', 'Var', (82, 101))	('tumor', 'Disease', 'MESH:D009369', (118, 123))
96918	25877892	Nevertheless, despite extensive heterogeneity, we also demonstrate that mutations in established driver genes have a tendency to be clonal compared to mutations in nondriver genes, suggesting that these mutational events may often be required as early events in tumorigenesis and might represent suitable candidates for cancer screening approaches.	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', (262, 267))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('cancer', 'Disease', (320, 326))
96926	25877892	We also found evidence linking APOBEC-mediated mutagenesis with the acquisition of subclonal driver events, highlighting how this mutational process can alter tumor evolutionary trajectories.	('alter', 'Reg', (153, 158))	('mutagenesis', 'biological_process', 'GO:0006280', ('47', '58'))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mutagenesis', 'Var', (47, 58))	('APOBEC', 'cellular_component', 'GO:0030895', ('31', '37'))	('tumor', 'Disease', (159, 164))	('APOBEC-mediated', 'Gene', (31, 46))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
96928	25877892	As recently demonstrated in KIRC as well as in LUAD and LUSC, mutations from single biopsies may give the illusion of clonality, that is, although a mutation appears to be present in every cell from one tumor biopsy, it can be entirely absent from other regions of the same tumor.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('LUSC', 'Phenotype', 'HP:0030359', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('KIRC', 'Phenotype', 'HP:0005584', (28, 32))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('tumor', 'Disease', (274, 279))	('mutation', 'Var', (149, 157))	('mutations', 'Var', (62, 71))
96932	25877892	This was an observational study using publicly available mutation and copy number data from nine cancer types to explore the clonal status of driver mutations (including those linked to targeted therapies), the dynamics of mutational processes over time, and whether we could identify additional cancer genes through temporal and clonal dissection (Fig.	('mutations', 'Var', (149, 158))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancer', 'Disease', (296, 302))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
96940	25877892	To identify cancer genes, MutSigCV was applied separately to temporally and clonally dissected mutations within each cancer cohort (for details, see Supplementary Materials and Methods).	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mutations', 'Var', (95, 104))	('cancer', 'Disease', (117, 123))
96943	33322698	CDKN2A-Inactivated Pancreatic Ductal Adenocarcinoma Exhibits Therapeutic Sensitivity to Paclitaxel: A Bioinformatics Study The mutation of cyclin dependent kinase inhibitor 2A (CDKN2A) is frequently found in pancreatic ductal adenocarcinoma (PDAC).	('cyclin dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('139', '172'))	('CDKN2A', 'Gene', (177, 183))	('Pancreatic Ductal Adenocarcinoma', 'Disease', 'MESH:D021441', (19, 51))	('Pancreatic Ductal Adenocarcinoma', 'Disease', (19, 51))	('CDKN2A', 'Gene', '1029', (177, 183))	('mutation', 'Var', (127, 135))	('pancreatic ductal adenocarcinoma', 'Disease', (208, 240))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (208, 240))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (208, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('CDKN2A', 'Gene', (0, 6))	('found', 'Reg', (199, 204))	('PD', 'Disease', 'MESH:D010300', (242, 244))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('156', '172'))	('Pancreatic Ductal Adenocarcinoma', 'Phenotype', 'HP:0006725', (19, 51))	('Paclitaxel', 'Chemical', 'MESH:D017239', (88, 98))	('CDKN2A', 'Gene', '1029', (0, 6))
96945	33322698	In this study, we mined and integrated the cancer genomics and chemogenomics data to investigate the roles of CDKN2A genetic alterations in PDAC patients' prognosis and treatment.	('patients', 'Species', '9606', (145, 153))	('CDKN2A', 'Gene', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('PD', 'Disease', 'MESH:D010300', (140, 142))	('rat', 'Species', '10116', (129, 132))	('rat', 'Species', '10116', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('genetic alterations', 'Var', (117, 136))
96946	33322698	We found that functional CDKN2A inactivation caused by mutations and deep deletions predicted poor prognosis in PDAC patients.	('PD', 'Disease', 'MESH:D010300', (112, 114))	('deep deletions', 'Var', (69, 83))	('mutations', 'Var', (55, 64))	('inactivation', 'NegReg', (32, 44))	('CDKN2A', 'Gene', (25, 31))	('patients', 'Species', '9606', (117, 125))
96947	33322698	CDKN2A inactivation was associated with the upregulation of genes related to estrogen response, which can be overcome by CDKN2A restoration.	('upregulation', 'PosReg', (44, 56))	('inactivation', 'Var', (7, 19))	('rat', 'Species', '10116', (133, 136))	('CDKN2A', 'Gene', (0, 6))
96955	33322698	The major driver gene mutation for PDAC tumorigenesis are Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), tumor protein p53 (TP53), SMAD family member 4 (SMAD4), and cyclin dependent kinase inhibitor 2A (CDKN2A).	('SMAD4', 'Gene', (159, 164))	('KRAS', 'Gene', '24525', (104, 108))	('sarcoma', 'Disease', (70, 77))	('mutation', 'Var', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('SMAD family member 4', 'Gene', (137, 157))	('TP53', 'Gene', '24842', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('188', '204'))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('SMAD4', 'Gene', '50554', (159, 164))	('TP53', 'Gene', (130, 134))	('KRAS', 'Gene', (104, 108))	('SMAD family member 4', 'Gene', '50554', (137, 157))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (40, 45))	('rat', 'Species', '10116', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('PD', 'Disease', 'MESH:D010300', (35, 37))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('cyclin dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('171', '204'))
96960	33322698	CDKN2A is frequently inactivated in cancers due to genetic alterations by point mutation, homozygous deletion, promoter hypermethylation, and loss of heterozygosity.	('point mutation', 'Var', (74, 88))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('promoter', 'MPA', (111, 119))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('loss of heterozygosity', 'Var', (142, 164))	('homozygous deletion', 'Var', (90, 109))	('CDKN2A', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('rat', 'Species', '10116', (63, 66))
96961	33322698	In this study, we performed a bioinformatics analysis to investigate the prognostic and therapeutic impacts of CDKN2A inactivation in PDAC.	('inactivation', 'Var', (118, 130))	('PD', 'Disease', 'MESH:D010300', (134, 136))	('CDKN2A', 'Gene', (111, 117))
96964	33322698	The genetic (mutation, copy number variation, and mRNA expression) and prognostic (overall survival) data for cancer patients ("TCGA, PanCancer Atlas" data set) were obtained from the cBioPortal (accessed on 27 November 2020).	('copy number variation', 'Var', (23, 44))	('cancer', 'Disease', (110, 116))	('mRNA expression', 'MPA', (50, 65))	('Cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Cancer', 'Disease', 'MESH:D009369', (137, 143))	('patients', 'Species', '9606', (117, 125))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
96981	33322698	We obtained 168 PDAC patients with complete genomics data (mutations, copy number variations, and mRNA levels).	('patients', 'Species', '9606', (21, 29))	('mRNA levels', 'MPA', (98, 109))	('copy number variations', 'Var', (70, 92))	('PD', 'Disease', 'MESH:D010300', (16, 18))
96982	33322698	As shown in Figure 1a, 29% and 21% of PDAC patients harbored deep deletions and mutations of the CDKN2A gene, respectively.	('CDKN2A', 'Gene', (97, 103))	('mutations', 'Var', (80, 89))	('patients', 'Species', '9606', (43, 51))	('PD', 'Disease', 'MESH:D010300', (38, 40))	('deep deletions', 'Var', (61, 75))	('harbored', 'Reg', (52, 60))
96986	33322698	It has been suggested that the mutant CDKN2A genes may encode functionally inactivated proteins in cancer cells.	('mutant', 'Var', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('functionally inactivated proteins', 'MPA', (62, 95))	('CDKN2A', 'Gene', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
96987	33322698	The above results implied that CDKN2A mRNA expression itself was not a good prognostic biomarker for PDAC due to the high transcript levels of the mutant CDKN2A gene.	('mutant', 'Var', (147, 153))	('CDKN2A', 'Gene', (154, 160))	('high', 'PosReg', (117, 121))	('transcript levels', 'MPA', (122, 139))	('PD', 'Disease', 'MESH:D010300', (101, 103))
96990	33322698	Interestingly, PDAC patients with CDKN2A mutation (MUT) or deep deletion (DEEP LOSS) had poorer overall survivals compared with those with WT or shallow deletion (LOSS) of the CDKN2A gene (Figure 1d).	('PD', 'Disease', 'MESH:D010300', (15, 17))	('poorer', 'NegReg', (89, 95))	('overall', 'MPA', (96, 103))	('mutation', 'Var', (41, 49))	('CDKN2A', 'Gene', (34, 40))	('patients', 'Species', '9606', (20, 28))	('deep deletion', 'Var', (59, 72))
96991	33322698	Similarly, the primary therapy outcomes for PDAC patients with CDKN2A-MUT and CDKN2A-DEEP LOSS were worse than those with CDKN2A-WT and CDKN2A-LOSS (Figure 1e).	('PD', 'Disease', 'MESH:D010300', (44, 46))	('worse', 'NegReg', (100, 105))	('LOSS', 'NegReg', (90, 94))	('CDKN2A-DEEP', 'Var', (78, 89))	('patients', 'Species', '9606', (49, 57))	('CDKN2A-MUT', 'Var', (63, 73))
96994	33322698	As shown in Figure 1f,g, PDAC patients with inactivated CDKN2A had worse prognostic values in overall survivals and primary therapy outcomes than those with functional CDKN2A.	('overall survivals', 'CPA', (94, 111))	('inactivated', 'Var', (44, 55))	('PD', 'Disease', 'MESH:D010300', (25, 27))	('patients', 'Species', '9606', (30, 38))	('CDKN2A', 'Gene', (56, 62))
96996	33322698	We performed a pan-cancer analysis for CDKN2A alterations using the "TCGA, PanCancer Atlas" data set.	('Cancer', 'Disease', (78, 84))	('CDKN2A', 'Gene', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('Cancer', 'Disease', 'MESH:D009369', (78, 84))	('rat', 'Species', '10116', (50, 53))	('cancer', 'Disease', (19, 25))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('alterations', 'Var', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
96998	33322698	The cancer genomics (mutations, copy number variations, and mRNA levels) and patients' survival data (Table S1b-g) in these cancer types were analyzed for the role of CDKN2A.	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('copy number variations', 'Var', (32, 54))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('patients', 'Species', '9606', (77, 85))	('mRNA levels', 'MPA', (60, 71))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
96999	33322698	CDKN2A mutations also reduced CDKN2A gene levels in GBM and HNSC, but had no effects on the other four cancer types.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('CDKN2A', 'Gene', (30, 36))	('reduced', 'NegReg', (22, 29))	('CDKN2A', 'Gene', (0, 6))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('mutations', 'Var', (7, 16))
97002	33322698	Interestingly, the mutations and copy number variations of the CDKN2A gene did not affect the patients' overall survival in GBM, ESCA, SKCM, LUSC, and BLCA (Figure S4a,c-f).	('affect', 'Reg', (83, 89))	('patients', 'Species', '9606', (94, 102))	('copy number variations', 'Var', (33, 55))	('LUSC', 'Disease', (141, 145))	('SKCM', 'Disease', (135, 139))	('GBM', 'Disease', (124, 127))	('mutations', 'Var', (19, 28))	('BLCA', 'Disease', (151, 155))	('ESCA', 'Disease', (129, 133))	('CDKN2A', 'Gene', (63, 69))
97003	33322698	An exception was that HNSC patients with lower CDKN2A mRNA levels had a poorer overall survival (Figure S3b), which may be resulted from the shallow and deep deletions, and partly mutations, of the CDKN2A gene that exhibited prognostic impact on patients' overall survival (Figure S4b).	('CDKN2A', 'Gene', (198, 204))	('mutations', 'Var', (180, 189))	('patients', 'Species', '9606', (246, 254))	('overall', 'MPA', (79, 86))	('CDKN2A', 'Gene', (47, 53))	('lower', 'NegReg', (41, 46))	('resulted', 'Reg', (123, 131))	('poorer', 'NegReg', (72, 78))	('patients', 'Species', '9606', (27, 35))	('mRNA levels', 'MPA', (54, 65))
97004	33322698	Consistently, HNSC patients with CDKN2A gene mutations and deletions had worse primary therapy outcome (Figure S5).	('CDKN2A', 'Gene', (33, 39))	('mutations', 'Var', (45, 54))	('deletions', 'Var', (59, 68))	('patients', 'Species', '9606', (19, 27))
97005	33322698	Therefore, we conclude that the impact of CDKN2A genetic alterations is cancer type-specific.	('genetic alterations', 'Var', (49, 68))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('rat', 'Species', '10116', (61, 64))	('CDKN2A', 'Gene', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
97006	33322698	To further investigate the role of CDKN2A inactivation in PDAC, the gene expression profile in PDAC patients (TCGA-PAAD data set) with CDKN2A mutation and deep deletion (compared to those with CDKN2A wildtype and shallow deletion) were analyzed by GSEA for 50 cancer hallmark enrichment.	('CDKN2A', 'Gene', (135, 141))	('PD', 'Disease', 'MESH:D010300', (95, 97))	('GSEA', 'Chemical', '-', (248, 252))	('deep deletion', 'Var', (155, 168))	('PD', 'Disease', 'MESH:D010300', (58, 60))	('cancer hallmark enrichment', 'Disease', 'MESH:D009369', (260, 286))	('patients', 'Species', '9606', (100, 108))	('gene expression', 'biological_process', 'GO:0010467', ('68', '83'))	('mutation', 'Var', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer hallmark enrichment', 'Disease', (260, 286))
97007	33322698	We found that 4 cancer hallmarks (TGF-BETA_SIGNALING, NOTCH_SIGNALING, ESTROGEN_RESPONSE_EARLY, and ESTROGEN_RESPONSE_LATE) were significantly associated with CDKN2A inactivation (mutations and deep deletions) in PDAC patients (Figure 2a, the blue bars).	('ESTROGEN_RESPONSE_LATE', 'MPA', (100, 122))	('patients', 'Species', '9606', (218, 226))	('PD', 'Disease', 'MESH:D010300', (213, 215))	('SIGNALING', 'biological_process', 'GO:0023052', ('43', '52'))	('deep deletions', 'Var', (194, 208))	('inactivation', 'NegReg', (166, 178))	('NOTCH_SIGNALING', 'MPA', (54, 69))	('SIGNALING', 'biological_process', 'GO:0023052', ('60', '69'))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer hallmarks', 'Disease', (16, 32))	('cancer hallmarks', 'Disease', 'MESH:D009369', (16, 32))	('ESTROGEN_RESPONSE_EARLY', 'MPA', (71, 94))	('CDKN2A', 'Gene', (159, 165))
97011	33322698	Therefore, CDKN2A inactivation may alter the estrogen response in PDAC.	('inactivation', 'Var', (18, 30))	('estrogen response', 'MPA', (45, 62))	('PD', 'Disease', 'MESH:D010300', (66, 68))	('CDKN2A', 'Gene', (11, 17))	('alter', 'Reg', (35, 40))
97019	33322698	As shown in Figure S7, PDAC cells with copy numbers <-2 (deep deletion) had low CDKN2A expression levels.	('low CDKN2A expression', 'Phenotype', 'HP:0032421', (76, 97))	('PD', 'Disease', 'MESH:D010300', (23, 25))	('copy numbers <-2', 'Var', (39, 55))	('CDKN2A expression levels', 'MPA', (80, 104))	('low CDKN2A', 'Phenotype', 'HP:0032421', (76, 86))	('low', 'NegReg', (76, 79))
97023	33322698	Therefore, CDKN2A inactivation correlates with the increased sensitivity to cell cycle-targeting drugs in PDAC cell lines.	('sensitivity to cell cycle-targeting drugs', 'MPA', (61, 102))	('increased', 'PosReg', (51, 60))	('inactivation', 'Var', (18, 30))	('PD', 'Disease', 'MESH:D010300', (106, 108))	('cell cycle', 'biological_process', 'GO:0007049', ('76', '86'))	('CDKN2A', 'Gene', (11, 17))
97026	33322698	As shown in Table S2 and Figure 3b, CDKN2A-inactivated (MUT + DEEP LOSS) organoids were more sensitive to paclitaxel, SN-38, 5-FU, bortezomib, and LY2874455, which confirmed the in vitro effects of paclitaxel and SN-38 (Figure 3a).	('LY2874455', 'Chemical', 'MESH:C570663', (147, 156))	('SN-38', 'Chemical', 'MESH:D000077146', (118, 123))	('CDKN2A-inactivated', 'Gene', (36, 54))	('5-FU', 'Chemical', 'MESH:D005472', (125, 129))	('paclitaxel', 'Chemical', 'MESH:D017239', (198, 208))	('SN-38', 'Chemical', 'MESH:D000077146', (213, 218))	('bortezomib', 'Chemical', 'MESH:D000069286', (131, 141))	('LY2874455', 'Var', (147, 156))	('sensitive', 'MPA', (93, 102))	('paclitaxel', 'Chemical', 'MESH:D017239', (106, 116))
97028	33322698	To investigate whether CDKN2A inactivation in GBM, ESCA, SKCM, LUSC, and BLCA also led to the increased sensitivity to paclitaxel and SN-38, the correlation between CDKN2A gene copy number variation and drug sensitivity was analyzed using the data obtained from the CTRP database.	('inactivation', 'Var', (30, 42))	('increased', 'PosReg', (94, 103))	('CDKN2A', 'Gene', (23, 29))	('SN-38', 'Chemical', 'MESH:D000077146', (134, 139))	('paclitaxel', 'Chemical', 'MESH:D017239', (119, 129))	('drug sensitivity', 'Phenotype', 'HP:0020174', (203, 219))
97030	33322698	In contrast, the central nervous system (CNS) cancer cell lines with lower copy numbers were more resistant to both paclitaxel and SN-38.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('SN-38', 'Chemical', 'MESH:D000077146', (131, 136))	('cancer', 'Disease', (46, 52))	('copy numbers', 'Var', (75, 87))	('resistant', 'MPA', (98, 107))	('paclitaxel', 'Chemical', 'MESH:D017239', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
97031	33322698	Other cancer types did not exhibit a significant correlation between CDKN2A copy numbers and drug sensitivity.	('drug sensitivity', 'Phenotype', 'HP:0020174', (93, 109))	('copy numbers', 'Var', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('CDKN2A', 'Gene', (69, 75))
97032	33322698	Therefore, the observations from PDAC may not be applied to other cancer types with a high frequency of CDKN2A alterations.	('PD', 'Disease', 'MESH:D010300', (33, 35))	('rat', 'Species', '10116', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('alterations', 'Var', (111, 122))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('CDKN2A', 'Gene', (104, 110))	('cancer', 'Disease', (66, 72))
97044	33322698	The results suggest that the CDKN2A functional inactivation caused by mutations and deep deletions predicts poor prognosis in PDAC patients.	('CDKN2A', 'Gene', (29, 35))	('patients', 'Species', '9606', (131, 139))	('PD', 'Disease', 'MESH:D010300', (126, 128))	('mutations', 'Var', (70, 79))	('functional', 'MPA', (36, 46))
97045	33322698	Besides, CDKN2A inactivation results in the upregulation of estrogen response-related genes, which can be reversed by paclitaxel.	('estrogen response-related genes', 'Gene', (60, 91))	('paclitaxel', 'Chemical', 'MESH:D017239', (118, 128))	('upregulation', 'PosReg', (44, 56))	('inactivation', 'Var', (16, 28))	('CDKN2A', 'Gene', (9, 15))
97049	33322698	Genes correlated with paclitaxel and SN-38 drug sensitivity in PDAC cell lines, Figure S1: A pan-cancer analysis for the CDKN2A genetic alterations, Figure S2.	('cancer', 'Disease', (97, 103))	('SN-38', 'Chemical', 'MESH:D000077146', (37, 42))	('drug sensitivity', 'Phenotype', 'HP:0020174', (43, 59))	('paclitaxel', 'Chemical', 'MESH:D017239', (22, 32))	('PD', 'Disease', 'MESH:D010300', (63, 65))	('alterations', 'Var', (136, 147))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('rat', 'Species', '10116', (140, 143))	('CDKN2A', 'Gene', (121, 127))	('correlated', 'Reg', (6, 16))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
97050	33322698	Effect of genetic alterations on CDKN2A mRNA expression in cancers, Figure S3.	('genetic alterations', 'Var', (10, 29))	('CDKN2A', 'Gene', (33, 39))	('mRNA expression', 'MPA', (40, 55))	('rat', 'Species', '10116', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))	('Effect', 'Reg', (0, 6))
97052	33322698	Effect of CDKN2A genetic alterations on cancer patients' overall survival, Figure S5.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('patients', 'Species', '9606', (47, 55))	('rat', 'Species', '10116', (29, 32))	('cancer', 'Disease', (40, 46))	('genetic alterations', 'Var', (17, 36))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('CDKN2A', 'Gene', (10, 16))	('overall', 'MPA', (57, 64))	('Effect', 'Reg', (0, 6))
97053	33322698	Effect of CDKN2A genetic alterations on cancer patients' primary therapy outcome, Figure S6.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('patients', 'Species', '9606', (47, 55))	('rat', 'Species', '10116', (29, 32))	('cancer', 'Disease', (40, 46))	('genetic alterations', 'Var', (17, 36))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('CDKN2A', 'Gene', (10, 16))	('Effect', 'Reg', (0, 6))
97054	33322698	The functional impact of CDKN2A inactivation in head and neck squamous cell carcinoma, Figure S7.	('neck squamous cell carcinoma', 'Disease', (57, 85))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (57, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (48, 85))	('neck', 'cellular_component', 'GO:0044326', ('57', '61'))	('inactivation', 'Var', (32, 44))	('CDKN2A', 'Gene', (25, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))
97055	33322698	The correlation between CDKN2A copy number variation and mRNA expression levels in pancreatic ductal adenocarcinoma cell lines, Figure S8.	('mRNA expression levels', 'MPA', (57, 79))	('CDKN2A', 'Gene', (24, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (83, 115))	('copy number variation', 'Var', (31, 52))	('pancreatic ductal adenocarcinoma', 'Disease', (83, 115))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (83, 115))
97056	33322698	The correlation between CDKN2A copy number variation and paclitaxel drug activity in cancer cells, Figure S9.	('correlation', 'Interaction', (4, 15))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('paclitaxel drug activity', 'MPA', (57, 81))	('CDKN2A', 'Gene', (24, 30))	('cancer', 'Disease', (85, 91))	('paclitaxel', 'Chemical', 'MESH:D017239', (57, 67))	('copy number variation', 'Var', (31, 52))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
97057	33322698	The correlation between CDKN2A copy number variation and SN-38 drug activity in cancer cells.	('correlation', 'Interaction', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CDKN2A', 'Gene', (24, 30))	('SN-38', 'Chemical', 'MESH:D000077146', (57, 62))	('SN-38', 'Gene', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('copy number variation', 'Var', (31, 52))	('cancer', 'Disease', (80, 86))
97061	33322698	This research was funded by the Ministry of Science and Technology, grant numbers MOST109-2314-B-038-040 and MOST109-2314-B-195-006; the health and welfare surcharge of tobacco products (WanFang Hospital, Chi-Mei Medical Center, and Hualien Tzu-Chi Hospital Joint Cancer Center Grant-Focus on Colon Cancer Research), grant number MOHW109-TDU-B-212-134020.	('Cancer', 'Phenotype', 'HP:0002664', (299, 305))	('Colon Cancer', 'Phenotype', 'HP:0003003', (293, 305))	('Colon Cancer', 'Disease', 'MESH:D015179', (293, 305))	('Colon Cancer', 'Disease', (293, 305))	('MOST109-2314-B-195-006', 'Var', (109, 131))	('Cancer', 'Phenotype', 'HP:0002664', (264, 270))	('Cancer', 'Disease', (299, 305))	('Cancer', 'Disease', (264, 270))	('tobacco', 'Species', '4097', (169, 176))	('Cancer', 'Disease', 'MESH:D009369', (299, 305))	('Cancer', 'Disease', 'MESH:D009369', (264, 270))
97210	30642841	Kaplan-Meier survival analysis of COMT and IYD showed that low expression had significantly poor survival in TCGA BLCA smokers and did not show any significant difference in never smokers.	('COMT', 'Gene', '1312', (34, 38))	('survival', 'MPA', (97, 105))	('COMT', 'Gene', (34, 38))	('poor', 'NegReg', (92, 96))	('low expression', 'Var', (59, 73))	('IYD', 'Gene', (43, 46))	('IYD', 'Gene', '389434', (43, 46))
97211	30642841	BLCA smokers with high expression of TTL showed the worst prognosis compared to BLCA never smokers (Figure 5A and B).	('high expression', 'Var', (18, 33))	('TTL', 'Gene', '150465', (37, 40))	('TTL', 'Gene', (37, 40))
97257	29336367	Furthermore, TIP30 might predict postoperative OS.	('predict', 'Reg', (25, 32))	('OS', 'Chemical', '-', (47, 49))	('postoperative', 'Disease', (33, 46))	('TIP30', 'Var', (13, 18))
97263	29336367	The human gene Tat-interacting protein 30 (TIP30), also known as CC3 or HITATIP2, was first identified as a suppressor of variant small-cell lung carcinoma (vSCLC).	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('Tat-interacting protein 30', 'Gene', (15, 41))	('human', 'Species', '9606', (4, 9))	('small-cell lung carcinoma', 'Disease', (130, 155))	('CC3', 'Gene', (65, 68))	('TIP30', 'Gene', (43, 48))	('small-cell lung carcinoma', 'Disease', 'MESH:D055752', (130, 155))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (130, 155))	('variant', 'Var', (122, 129))	('Tat-interacting protein 30', 'Gene', '10553', (15, 41))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('CC3', 'Gene', '10553', (65, 68))
97299	29336367	TIP30 expression in patients treated with TUR was significantly higher than that in those treated with partial cystectomy (t = 4.02, P < 0.01).	('TUR', 'Var', (42, 45))	('higher', 'PosReg', (64, 70))	('expression', 'MPA', (6, 16))	('TIP30', 'Gene', (0, 5))	('patients', 'Species', '9606', (20, 28))
97303	29336367	Figures 2 and 3 show the Kaplan-Meier survival curves for patients with BUC tumors with high or low TIP30 expression.	('high', 'Var', (88, 92))	('BUC tumors', 'Disease', 'MESH:D009369', (72, 82))	('expression', 'MPA', (106, 116))	('BUC tumors', 'Disease', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('low', 'NegReg', (96, 99))	('patients', 'Species', '9606', (58, 66))	('TIP30', 'Gene', (100, 105))
97304	29336367	The OS of patients with low TIP30 expression was significantly lower than that of patients with high TIP30 protein expression (chi2 = 17.29, P < 0.001; Figure 2).	('lower', 'NegReg', (63, 68))	('OS', 'Chemical', '-', (4, 6))	('patients', 'Species', '9606', (82, 90))	('low TIP30', 'Var', (24, 33))	('TIP30', 'Var', (28, 33))	('patients', 'Species', '9606', (10, 18))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
97310	29336367	As a transcription cofactor, TIP30 may suppress the expression of genes that are involved in proliferation, apoptosis, angiogenesis, and metastasis, suggesting that TIP30 may act as a cancer suppressor.	('cancer', 'Disease', (184, 190))	('proliferation', 'CPA', (93, 106))	('expression of genes', 'MPA', (52, 71))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('angiogenesis', 'CPA', (119, 131))	('angiogenesis', 'biological_process', 'GO:0001525', ('119', '131'))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('transcription', 'biological_process', 'GO:0006351', ('5', '18'))	('suppress', 'NegReg', (39, 47))	('TIP30', 'Var', (29, 34))	('metastasis', 'CPA', (137, 147))	('apoptosis', 'CPA', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
97311	29336367	For example, overexpression of TIP30 has been shown to suppress tumor invasion through the extracellular matrix.	('extracellular matrix', 'cellular_component', 'GO:0031012', ('91', '111'))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('TIP30', 'Gene', (31, 36))	('suppress', 'NegReg', (55, 63))	('overexpression', 'Var', (13, 27))
97313	29336367	Downregulation of TIP30 has been found to lead to the expression of osteopontin, matrix metalloproteinase-2, and vascular endothelial growth factor, suggesting that downregulation of this protein promotes metastatic progression of lung cancer.	('lung cancer', 'Disease', (231, 242))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('113', '147'))	('promotes', 'PosReg', (196, 204))	('vascular endothelial growth factor', 'Gene', (113, 147))	('Downregulation', 'NegReg', (0, 14))	('matrix metalloproteinase-2', 'Gene', (81, 107))	('osteopontin', 'Gene', '6696', (68, 79))	('lung cancer', 'Disease', 'MESH:D008175', (231, 242))	('metastatic progression', 'CPA', (205, 227))	('osteopontin', 'Gene', (68, 79))	('TIP30', 'Gene', (18, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (231, 242))	('matrix metalloproteinase-2', 'Gene', '4313', (81, 107))	('lead', 'Reg', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('expression', 'MPA', (54, 64))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('downregulation', 'Var', (165, 179))	('vascular endothelial growth factor', 'Gene', '7422', (113, 147))
97314	29336367	Chen and Shtivelman found that inhibition of TIP30 expression allowed tumor cells to evade apoptosis through glucose deprivation, and studies on animal models showed that TIP30-/- mice spontaneously developed tumors faster than wild-type mice.	('developed', 'PosReg', (199, 208))	('glucose deprivation', 'Disease', 'MESH:D012892', (109, 128))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('mice', 'Species', '10090', (180, 184))	('TIP30-/-', 'Var', (171, 179))	('TIP30', 'Gene', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (209, 214))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('inhibition', 'Var', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Disease', (209, 215))	('tumor', 'Disease', (70, 75))	('glucose deprivation', 'Disease', (109, 128))	('mice', 'Species', '10090', (238, 242))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
97315	29336367	Meanwhile, TIP30 knockdown led to prolonged epidermal growth factor receptor (EGFR) signaling in early endosomes, along with delayed EGFR degradation and increased EGFR nuclear location, leading to increased expression of pAKT and pERK1/2 in human lung adenocarcinoma cells.	('EGFR', 'Gene', (164, 168))	('EGFR', 'molecular_function', 'GO:0005006', ('133', '137'))	('degradation', 'biological_process', 'GO:0009056', ('138', '149'))	('nuclear location', 'MPA', (169, 185))	('EGFR', 'Gene', '1956', (133, 137))	('expression', 'MPA', (208, 218))	('EGFR', 'Gene', '1956', (78, 82))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('44', '67'))	('TIP30', 'Gene', (11, 16))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('EGFR', 'Gene', '1956', (164, 168))	('increased', 'PosReg', (154, 163))	('epidermal growth factor receptor', 'Gene', (44, 76))	('epidermal growth factor receptor', 'Gene', '1956', (44, 76))	('lung adenocarcinoma', 'Disease', (248, 267))	('pAKT', 'Gene', (222, 226))	('knockdown', 'Var', (17, 26))	('pERK1/2', 'Gene', (231, 238))	('EGFR', 'Gene', (78, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('EGFR', 'Gene', (133, 137))	('EGFR', 'molecular_function', 'GO:0005006', ('164', '168'))	('prolonged', 'PosReg', (34, 43))	('increased', 'PosReg', (198, 207))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (248, 267))	('human', 'Species', '9606', (242, 247))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (248, 267))
97318	29336367	Human hepatocellular carcinoma with methylated TIP30 has shown a tendency toward significantly high recurrence and mortality rates and low DFS.	('methylated', 'Var', (36, 46))	('hepatocellular carcinoma', 'Disease', (6, 30))	('Human', 'Species', '9606', (0, 5))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (6, 30))	('TIP30', 'Gene', (47, 52))	('mortality rates', 'CPA', (115, 130))	('high', 'PosReg', (95, 99))	('recurrence', 'CPA', (100, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (6, 30))
97319	29336367	TIP30 can also induce apoptosis and mitochondrial dysfunction, probably through stabilization of p53 mRNA, and this mechanism is blocked by inhibition of p53 expression.	('mRNA', 'MPA', (101, 105))	('p53', 'Gene', (97, 100))	('apoptosis', 'biological_process', 'GO:0006915', ('22', '31'))	('TIP30', 'Var', (0, 5))	('apoptosis', 'CPA', (22, 31))	('p53', 'Gene', '7157', (97, 100))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (36, 61))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (36, 61))	('mitochondrial dysfunction', 'Disease', (36, 61))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('induce', 'Reg', (15, 21))	('stabilization', 'MPA', (80, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('22', '31'))
97320	29336367	Comparison of the TIP30 cDNA sequences in the National Center for Biotechnology Information databases revealed the presence of TIP30 missense mutation in approximately 24% of various types of cancer cells.	('cancer', 'Disease', (192, 198))	('TIP30', 'Gene', (127, 132))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('presence', 'Reg', (115, 123))	('missense mutation', 'Var', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
97323	29336367	The results showed significantly lower average expression levels of TIP30 in bladder cancer tissues than those in normal bladder mucosal tissues, suggesting that TIP30 expression might play an important role in bladder tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('bladder tumor', 'Disease', 'MESH:D001749', (211, 224))	('bladder tumor', 'Phenotype', 'HP:0009725', (211, 224))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('bladder cancer', 'Disease', (77, 91))	('TIP30', 'Var', (162, 167))	('TIP30', 'Gene', (68, 73))	('play', 'Reg', (185, 189))	('bladder tumor', 'Disease', (211, 224))	('lower', 'NegReg', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('expression levels', 'MPA', (47, 64))
97327	29336367	Patients with low TIP30 expression showed a higher incidence of disease progression than those with high TIP30 expression (P < 0.05).	('disease progression', 'CPA', (64, 83))	('TIP30', 'Gene', (18, 23))	('low', 'Var', (14, 17))	('Patients', 'Species', '9606', (0, 8))
97330	29336367	The mechanisms by which TIP30 inhibits the development of BUC remain elusive and further studies should be designed to evaluate these issues.	('men', 'Species', '9606', (50, 53))	('development of BUC', 'CPA', (43, 61))	('TIP30', 'Var', (24, 29))	('inhibits', 'NegReg', (30, 38))
97387	33085656	Similarly, GPX1 overexpression was also found to promote tumor growth and metastasis in a skin cancer mouse model.	('metastasis in a', 'CPA', (74, 89))	('GPX1', 'Gene', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('skin cancer', 'Phenotype', 'HP:0008069', (90, 101))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('overexpression', 'Var', (16, 30))	('skin cancer', 'Disease', (90, 101))	('promote', 'PosReg', (49, 56))	('skin cancer', 'Disease', 'MESH:D012878', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', (57, 62))	('mouse', 'Species', '10090', (102, 107))
97388	33085656	However, there is evidence indicating that high expression of GPX1 could inhibit pancreatic cancer cell proliferation.	('high expression', 'Var', (43, 58))	('GPX1', 'Gene', (62, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('cell proliferation', 'biological_process', 'GO:0008283', ('99', '117'))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('pancreatic cancer', 'Disease', (81, 98))	('inhibit', 'NegReg', (73, 80))
97418	33085656	GPX1 expression was sharply higher in high-grade, 1p/19q non-codel status, and IDH-wild-type status gliomas and in older patients; there was no statistically significant sex-based differences based on the TCGA (Figure 2E-2I) and CGGA (Figure 2J-2N) datasets.	('expression', 'MPA', (5, 15))	('GPX1', 'Gene', (0, 4))	('IDH', 'Gene', (79, 82))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('IDH', 'Gene', '3417', (79, 82))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('1p/19q non-codel status', 'Var', (50, 73))	('higher', 'PosReg', (28, 34))	('status gliomas', 'Disease', (93, 107))	('status gliomas', 'Disease', 'MESH:D005910', (93, 107))	('patients', 'Species', '9606', (121, 129))	('high-grade', 'Var', (38, 48))
97420	33085656	Univariate Cox regression analysis based on the TCGA dataset showed that the WHO grade, age, IDH status, 1p/19q status, and GPX1 expression were strongly associated with OS of patients.	('patients', 'Species', '9606', (176, 184))	('1p/19q status', 'Var', (105, 118))	('associated with', 'Reg', (154, 169))	('IDH', 'Gene', (93, 96))	('GPX1', 'Gene', (124, 128))	('IDH', 'Gene', '3417', (93, 96))	('OS of patients', 'Disease', (170, 184))
97423	33085656	The nomogram integrated age, grade, 1p19q status, IDH status, and GPX1 expression for gliomas in the TCGA dataset (Figure 3A), and the C-index was 0.861.	('p19', 'cellular_component', 'GO:0070743', ('37', '40'))	('gliomas', 'Disease', (86, 93))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('GPX1', 'Gene', (66, 70))	('IDH', 'Gene', (50, 53))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('IDH', 'Gene', '3417', (50, 53))	('1p19q status', 'Var', (36, 48))
97431	33085656	These analyses revealed that high expression levels of GPX1 could critically increase immune infiltrating levels of B cells (R=0.242, P=5.55e-07), CD4+ cells (R=0.158, P=1.21e-03), macrophages (R=0.236, P=1.09e-06), neutrophils (R=0.286, P=2.54e-09), and dendritic cells (R=0.343, P=5.65-13), while negative associations were found for levels of CD8+ T cells (R=-0.1777, P=2.83e-04) in GBM (Figure 5A).	('CD4', 'Gene', '920', (147, 150))	('GPX1', 'Gene', (55, 59))	('CD8', 'Gene', (346, 349))	('CD8', 'Gene', '925', (346, 349))	('immune infiltrating levels of B', 'MPA', (86, 117))	('increase', 'PosReg', (77, 85))	('high expression levels', 'Var', (29, 51))	('GBM', 'Phenotype', 'HP:0012174', (386, 389))	('CD4', 'Gene', (147, 150))
97452	33085656	The GPX1 expression level was positively correlated with older patients, and high-grade, 1p19q non-codel, and IDH-wild-type status glioma; this correlation may imply a previously unidentified molecular mechanism of GPX1 in glioma malignancies.	('status glioma', 'Disease', 'MESH:D005910', (124, 137))	('glioma malignancies', 'Disease', 'MESH:D005910', (223, 242))	('1p19q non-codel', 'Var', (89, 104))	('IDH', 'Gene', (110, 113))	('correlated', 'Interaction', (41, 51))	('GPX1', 'Gene', (4, 8))	('high-grade', 'Disease', (77, 87))	('expression level', 'MPA', (9, 25))	('status glioma', 'Disease', (124, 137))	('IDH', 'Gene', '3417', (110, 113))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('p19', 'cellular_component', 'GO:0070743', ('90', '93'))	('glioma malignancies', 'Disease', (223, 242))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('patients', 'Species', '9606', (63, 71))	('imply', 'Reg', (160, 165))
97454	33085656	In addition, some clinical characteristics also had a positive correlation with worse OS; these included patient age, glioma grade, and 1p/19q codel and IDH status.	('patient', 'Species', '9606', (105, 112))	('glioma', 'Disease', (118, 124))	('1p/19q codel', 'Var', (136, 148))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('IDH', 'Gene', (153, 156))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('IDH', 'Gene', '3417', (153, 156))
97459	33085656	We hypothesized that these signaling pathways have a critical role in malignancy progression of gliomas, and high GPX1 expression is correlated with these critical inflammatory signal pathways.	('expression', 'MPA', (119, 129))	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('high', 'Var', (109, 113))	('malignancy', 'Disease', 'MESH:D009369', (70, 80))	('malignancy', 'Disease', (70, 80))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('correlated', 'Reg', (133, 143))	('GPX1', 'Gene', (114, 118))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))
97476	33085656	Moreover, we also found that high GPX1 expression increases immune infiltration levels in GBM and LGG, which means that GPX1 is involved in the activation of immune infiltration in gliomas.	('high', 'Var', (29, 33))	('GPX1', 'Gene', (34, 38))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('expression', 'Var', (39, 49))	('immune infiltration levels', 'MPA', (60, 86))	('increases', 'PosReg', (50, 59))	('GBM', 'Phenotype', 'HP:0012174', (90, 93))	('gliomas', 'Disease', (181, 188))	('gliomas', 'Disease', 'MESH:D005910', (181, 188))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))
97486	31903146	Human B-cell CLL/lymphoma 6 (BCL6) gene, a transcription repressor, was originally identified through its involvement in chromosomal translocations and aberrant expression associated with B cell-derived non-Hodgkin lymphoma.	('lymphoma', 'Phenotype', 'HP:0002665', (215, 223))	('Human', 'Species', '9606', (0, 5))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (203, 223))	('expression', 'MPA', (161, 171))	('B-cell CLL/lymphoma', 'Phenotype', 'HP:0012191', (6, 25))	('associated', 'Reg', (172, 182))	('B-cell CLL/lymphoma 6', 'Gene', (6, 27))	('Hodgkin lymphoma', 'Disease', (207, 223))	('aberrant', 'Var', (152, 160))	('involvement', 'Reg', (106, 117))	('BCL6', 'Gene', (29, 33))	('B-cell CLL/lymphoma 6', 'Gene', '604', (6, 27))	('lymphoma', 'Phenotype', 'HP:0002665', (17, 25))	('transcription', 'biological_process', 'GO:0006351', ('43', '56'))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (207, 223))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (207, 223))
97502	31903146	The expression vector carrying BCL6 complete DNA (RC219007) with Myc-DDK-tag (pCMV6-BCL6) and its corresponding control pCMV6-Entry (PS100001) were obtained from Origene (Herford, Germany).	('RC219007', 'Chemical', 'MESH:C027867', (50, 58))	('Myc', 'Gene', '4609', (65, 68))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('Myc', 'Gene', (65, 68))	('PS100001', 'Chemical', 'MESH:C058647', (133, 141))	('RC219007', 'Var', (50, 58))	('DDK', 'cellular_component', 'GO:0031431', ('69', '72'))
97504	31903146	pHRIG-AKT1 (AKT serine/threonine kinase 1, #53583), pFOXO3 (forkhead box O3, #1787) and pFLAG-FOXO3(TM) (#8361, triple mutations: T32A/S253A/S315A, AKT-insensitive form) were obtained from Addgene (Watertown, MA, USA) and subcloned into the pHaloTag plasmid to generate pFOXO3-HaloTag and pFOXO3(TM)-HaloTag using the In-Fusion  HD Cloning Kit (#121416, Takara, Shiga, Japan).	('AKT1', 'Gene', '207', (6, 10))	('#121416', 'Var', (345, 352))	('HD', 'Disease', 'MESH:D006816', (329, 331))	('AKT', 'Gene', (6, 9))	('T32A', 'Var', (130, 134))	('AKT1', 'Gene', (6, 10))	('AKT', 'Gene', (148, 151))	('AKT', 'Gene', (12, 15))	('AKT serine/threonine kinase 1', 'Gene', (12, 41))	('forkhead box O3', 'Gene', (60, 75))	('S315A', 'Mutation', 'p.S315A', (141, 146))	('AKT', 'Gene', '207', (6, 9))	('S253A', 'SUBSTITUTION', 'None', (135, 140))	('AKT', 'Gene', '207', (148, 151))	('AKT', 'Gene', '207', (12, 15))	('T32A', 'SUBSTITUTION', 'None', (130, 134))	('S253A', 'Var', (135, 140))	('AKT serine/threonine kinase 1', 'Gene', '207', (12, 41))	('forkhead box O3', 'Gene', '2309', (60, 75))
97506	31903146	The plasmids targeting BCL6 (shBCL6#1/ TRCN0000013606: 5'-CCACAGTGACAAACCCTACAA-3' and shBCL6#2/TRCN00000235665: 5'-TGGACACTTGCCGGAAGTTTA-3') and FOXO3 (shFOXO3#1/TRCN0000040098: CAGACCCTCAAACTGACACAA and shFOXO3#2/TRCN0000235491: CTTGCTCATATCCCATATAAT) were used to knockdown BCL6 and FOXO3 genes, respectively.	('knockdown', 'Var', (267, 276))	('BCL6', 'Gene', (277, 281))	("5'-CCACAGTGACAAACCCTACAA", 'Chemical', 'MESH:C068492', (55, 79))	('FOXO3 genes', 'Gene', (286, 297))
97507	31903146	Flow cytometric, bromodeoxyuridine, cell proliferation, soft agar, anchorage-independent growth, wound-healing, transwell migration, transwell invasion and RNA expression profiling with the HumanHT-12v4 Expression BeadChip (Illumina, San Diego, CA, USA) assays were used to determine the alterations of cell cycle distribution, cell proliferation, colony formation/anchorage-independent cell growth, cell migration, cell invasion and mRNA levels after overexpression, knockdown of the BCL6, FOXO3 gene or treatments with inhibitors, respectively (Supplementary Methods).	('cell migration', 'CPA', (400, 414))	('Human', 'Species', '9606', (190, 195))	('RNA', 'cellular_component', 'GO:0005562', ('156', '159'))	('cell cycle', 'biological_process', 'GO:0007049', ('303', '313'))	('cell invasion', 'CPA', (416, 429))	('wound-healing', 'biological_process', 'GO:0042060', ('97', '110'))	('cell proliferation', 'biological_process', 'GO:0008283', ('328', '346'))	('colony formation/anchorage-independent cell growth', 'CPA', (348, 398))	('cell cycle distribution', 'CPA', (303, 326))	('cell growth', 'biological_process', 'GO:0016049', ('387', '398'))	('mRNA levels', 'MPA', (434, 445))	('knockdown', 'Var', (468, 477))	('FOXO3 gene', 'Gene', (491, 501))	('BCL6', 'Gene', (485, 489))	('bromodeoxyuridine', 'Chemical', 'MESH:D001973', (17, 34))	('cell proliferation', 'biological_process', 'GO:0008283', ('36', '54'))	('formation', 'biological_process', 'GO:0009058', ('355', '364'))	('cell migration', 'biological_process', 'GO:0016477', ('400', '414'))	('cell proliferation', 'CPA', (328, 346))
97515	31903146	Therefore, BCL6 gene amplification causes BCL6 mRNA and protein upregulation and confer poor prognosis in UBUC patients.	('upregulation', 'PosReg', (64, 76))	('BCL6 gene', 'Gene', (11, 20))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('amplification', 'Var', (21, 34))	('patients', 'Species', '9606', (111, 119))
97516	31903146	The BCL6 mRNA and BCL6 protein were highly expressed in RT4, BFTC905, BFTC909, J82 and/or T24 compared to normal HUC cell line (Supplementary Figure S1A, S1B).	('BFTC909', 'Var', (70, 77))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('expressed', 'MPA', (43, 52))	('T24', 'Var', (90, 93))	('highly', 'PosReg', (36, 42))	('BFTC909', 'CellLine', 'CVCL:1084', (70, 77))	('J82', 'CellLine', 'CVCL:0359', (79, 82))	('J82', 'Var', (79, 82))	('RT4', 'Var', (56, 59))	('BFTC905', 'CellLine', 'CVCL:1083', (61, 68))	('BFTC905', 'Var', (61, 68))
97517	31903146	Stable overexpression of the BCL6 gene in J82 and/or T24; knockdown in J82, BFTC905, BFTC909 cells significantly upregulated and downregulated BCL6 mRNA and protein levels, respectively (Supplementary Figure S1C, S1D).	('downregulated', 'NegReg', (129, 142))	('BFTC909', 'CellLine', 'CVCL:1084', (85, 92))	('upregulated', 'PosReg', (113, 124))	('BFTC905', 'CellLine', 'CVCL:1083', (76, 83))	('J82', 'CellLine', 'CVCL:0359', (71, 74))	('J82', 'CellLine', 'CVCL:0359', (42, 45))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('overexpression', 'PosReg', (7, 21))	('BFTC909', 'Gene', (85, 92))	('BFTC905', 'Gene', (76, 83))	('knockdown', 'Var', (58, 67))	('BCL6 gene', 'Gene', (29, 38))
97520	31903146	On the other hand, stable knockdown of the BCL6 gene in BFTC905 and BFTC909 cells showed opposite phenotypes and protein expression profiles to those in J82 and/or T24 cells (Figure 3J-3R, Supplementary Figure S2, S3, S4, S5).	('BFTC909', 'CellLine', 'CVCL:1084', (68, 75))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('S4', 'Chemical', 'MESH:D013455', (218, 220))	('knockdown', 'Var', (26, 35))	('BCL6 gene', 'Gene', (43, 52))	('J82', 'CellLine', 'CVCL:0359', (153, 156))	('BFTC905', 'CellLine', 'CVCL:1083', (56, 63))
97523	31903146	To evaluate whether FOXO3 plays a crucial role in BCL6-suppressed cytostasis, overexpression of the BCL6, wild type FOXO3 or FOXO3(TM) (triple mutations: T32A/S253A/S315A, AKT1-insensitive form) gene (Figure 4C) along with single or double knockdown of the BCL6 and FOXO3 gene were performed in vitro.	('S315A', 'Mutation', 'p.S315A', (165, 170))	('AKT1', 'Gene', '207', (172, 176))	('T32A', 'Var', (154, 158))	('S253A', 'Var', (159, 164))	('AKT1', 'Gene', (172, 176))	('T32A', 'SUBSTITUTION', 'None', (154, 158))	('S253A', 'SUBSTITUTION', 'None', (159, 164))	('FOXO3', 'Gene', (125, 130))
97533	31903146	Immunoblot analysis showed that BCL6 overexpression in T24 cells downregulated FOXO3, however, upregulated pAKT1(S473), pMAPK1/3(T202/Y204), pFOXO3(S253) and pFOXO3(S294) protein levels.	('MAPK1/3', 'Gene', '5603;5594;5595', (121, 128))	('upregulated', 'PosReg', (95, 106))	('overexpression', 'PosReg', (37, 51))	('pFOXO3', 'MPA', (141, 147))	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('AKT1', 'Gene', '207', (108, 112))	('downregulated', 'NegReg', (65, 78))	('FOXO3', 'Gene', (79, 84))	('S294', 'Chemical', 'MESH:C042606', (165, 169))	('MAPK1/3', 'Gene', (121, 128))	('AKT1', 'Gene', (108, 112))	('S253', 'Var', (148, 152))	('S4', 'Chemical', 'MESH:D013455', (113, 115))	('S253', 'Chemical', 'MESH:C513198', (148, 152))
97539	31903146	Alternatively, overexpression of the constitutively active AKT1 gene in BFTC905 cells (Figure 5N) increased BCL6 knockdown-suppressed cell proliferation (P < 0.001, P < 0.001; Figure 5O), upregulated pFOXO3(S253) while downregulated CDKN1A, CDKN1B protein (Figure 5P) and their corresponding mRNA (P < 0.01 to P < 0.001; Figure 5Q) levels, suggesting that BCL6 promotes cell proliferation may through modulation of the PI3K-AKT signaling pathway in BFTC905 cells.	('upregulated', 'PosReg', (188, 199))	('protein', 'cellular_component', 'GO:0003675', ('248', '255'))	('AKT signaling', 'biological_process', 'GO:0043491', ('424', '437'))	('AKT', 'Gene', '207', (424, 427))	('CDKN1A', 'Gene', (233, 239))	('CDKN1A', 'Gene', '1026', (233, 239))	('BCL6', 'Gene', (356, 360))	('AKT1', 'Gene', '207', (59, 63))	('BCL6', 'Gene', (108, 112))	('CDKN1B', 'Gene', (241, 247))	('modulation', 'Reg', (401, 411))	('signaling pathway', 'biological_process', 'GO:0007165', ('428', '445'))	('increased', 'PosReg', (98, 107))	('promotes', 'PosReg', (361, 369))	('knockdown-suppressed', 'Var', (113, 133))	('cell proliferation', 'biological_process', 'GO:0008283', ('370', '388'))	('S253', 'Chemical', 'MESH:C513198', (207, 211))	('cell proliferation', 'CPA', (134, 152))	('BFTC905', 'CellLine', 'CVCL:1083', (449, 456))	('AKT1', 'Gene', (59, 63))	('AKT', 'Gene', (59, 62))	('PI3K', 'molecular_function', 'GO:0016303', ('419', '423'))	('AKT', 'Gene', (424, 427))	('5O', 'Chemical', 'MESH:D013481', (183, 185))	('cell proliferation', 'biological_process', 'GO:0008283', ('134', '152'))	('CDKN1B', 'Gene', '1027', (241, 247))	('cell proliferation', 'CPA', (370, 388))	('downregulated', 'NegReg', (219, 232))	('AKT', 'Gene', '207', (59, 62))	('BFTC905', 'CellLine', 'CVCL:1083', (72, 79))
97540	31903146	Knockdown of the BCL6 gene notably upregulated PTEN with or without AKT1 overexpression (Figure 5P).	('AKT1', 'Gene', (68, 72))	('Knockdown', 'Var', (0, 9))	('BCL6 gene', 'Gene', (17, 26))	('upregulated', 'PosReg', (35, 46))	('PTEN', 'Gene', (47, 51))	('PTEN', 'Gene', '5728', (47, 51))	('AKT1', 'Gene', '207', (68, 72))
97544	31903146	Therefore, in vitro experiments and clinical correlation in 295 patients suggested that BCL6 enhances FOXO3 phosphorylation and phosphorylated-FOXO3 predicted worse survival rates.	('enhances', 'PosReg', (93, 101))	('FOXO3', 'Protein', (102, 107))	('patients', 'Species', '9606', (64, 72))	('phosphorylation', 'biological_process', 'GO:0016310', ('108', '123'))	('BCL6', 'Var', (88, 92))	('phosphorylation', 'MPA', (108, 123))
97548	31903146	Dysregulation of FOXO3 in different types of cancer including UBUC has been reported.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Dysregulation', 'Var', (0, 13))	('FOXO3', 'Gene', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('UBUC', 'Disease', (62, 66))	('cancer', 'Disease', (45, 51))
97562	31903146	It is well known that AKT1 phosphorylate T32, S253 and S315 whilst MAPK1/3 phosphorylates S284, S294, S325, S425 and T487 residues on the FOXO3 protein (reviewed in).	('MAPK1/3', 'Gene', '5603;5594;5595', (67, 74))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('T487 residues', 'Var', (117, 130))	('S294', 'Var', (96, 100))	('T32', 'Var', (41, 44))	('S315', 'Var', (55, 59))	('AKT1', 'Gene', '207', (22, 26))	('S253', 'Var', (46, 50))	('S4', 'Chemical', 'MESH:D013455', (108, 110))	('S284', 'Var', (90, 94))	('S425', 'Var', (108, 112))	('S325', 'Chemical', 'MESH:C010814', (102, 106))	('AKT1', 'Gene', (22, 26))	('S325', 'Var', (102, 106))	('MAPK', 'molecular_function', 'GO:0004707', ('67', '71'))	('S253', 'Chemical', 'MESH:C513198', (46, 50))	('S284', 'Chemical', 'MESH:C556877', (90, 94))	('MAPK1/3', 'Gene', (67, 74))	('S294', 'Chemical', 'MESH:C042606', (96, 100))
97563	31903146	In glioblastoma cells, knockdown of the BCL6 gene inhibited malignant phenotype and enhanced sensitivity to temozolomide through inhibition of the AKT pathway.	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('inhibited', 'NegReg', (50, 59))	('knockdown', 'Var', (23, 32))	('glioblastoma', 'Disease', (3, 15))	('malignant phenotype', 'CPA', (60, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('BCL6', 'Gene', (40, 44))	('inhibition', 'NegReg', (129, 139))	('AKT', 'Gene', '207', (147, 150))	('enhanced', 'PosReg', (84, 92))	('temozolomide', 'Chemical', 'MESH:C047246', (108, 120))	('sensitivity to temozolomide', 'MPA', (93, 120))	('AKT', 'Gene', (147, 150))
97569	31903146	Amplifications of the BCL6 gene were similarly found in follicular lymphoma, esophageal cancer, pancreatic tumor and glioma.	('pancreatic tumor', 'Disease', 'MESH:D010190', (96, 112))	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('lymphoma', 'Phenotype', 'HP:0002665', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('found', 'Reg', (47, 52))	('pancreatic tumor', 'Disease', (96, 112))	('Amplifications', 'Var', (0, 14))	('follicular lymphoma', 'Disease', 'MESH:D008224', (56, 75))	('follicular lymphoma', 'Disease', (56, 75))	('BCL6', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal cancer', 'Disease', (77, 94))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (96, 112))	('glioma', 'Disease', (117, 123))
97570	31903146	Accordingly, our studies confirmed that amplification of the BCL6 locus is a profound cause of BCL6 transcription and translation in muscle-invasive UBUC patients.	('translation', 'MPA', (118, 129))	('muscle-invasive UBUC', 'Disease', (133, 153))	('patients', 'Species', '9606', (154, 162))	('transcription', 'MPA', (100, 113))	('translation', 'biological_process', 'GO:0006412', ('118', '129'))	('cause', 'Reg', (86, 91))	('amplification', 'Var', (40, 53))	('transcription', 'biological_process', 'GO:0006351', ('100', '113'))	('BCL6', 'Gene', (95, 99))	('BCL6', 'Gene', (61, 65))
97595	29928337	Detailed messages were accessible as follows: Microarray data of miRNAs included 8 normal (GSM881439-GSM881446) and 8 case chips (GSM881455-GSM881462); and microarray data of mRNAs included 8 normal (GSM991923-GSM991930) and 8 case chips (GSM991939-GSM991946).	('GSM991923-GSM991930', 'Var', (200, 219))	('GSM991939-GSM991946', 'Var', (239, 258))	('GSM881455-GSM881462', 'Var', (130, 149))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('GSM881439-GSM881446', 'Var', (91, 110))
97596	29928337	The expression levels of miRNAs and mRNAs were previously studied in these samples on two platforms: GPL8227 Agilent-019118 Human miRNA Microarray 2.0 G4470B (miRNA ID version) and GPL13497 Agilent-026652 Whole Human Genome Microarray 4x44K v2 (Probe Name version) (both Agilent Technologies, Inc., Santa Clara, CA, USA).	('Human', 'Species', '9606', (211, 216))	('G4470B', 'Var', (151, 157))	('miR', 'Gene', '220972', (130, 133))	('miR', 'Gene', (130, 133))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', (25, 28))	('Human', 'Species', '9606', (124, 129))	('G4470B', 'SUBSTITUTION', 'None', (151, 157))	('miR', 'Gene', '220972', (159, 162))	('miR', 'Gene', (159, 162))
97623	29928337	miRNAs were reported to regulate the activity of ~30% of all protein-coding genes in the human genome, whereas the deregulation of miRNAs and their targeted mRNAs may serve an important function in the development of cancer.	('human', 'Species', '9606', (89, 94))	('protein-coding', 'Protein', (61, 75))	('deregulation', 'Var', (115, 127))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('activity', 'MPA', (37, 45))	('regulate', 'Reg', (24, 32))	('miR', 'Gene', '220972', (131, 134))	('miR', 'Gene', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
97624	29928337	It was previously revealed that aberrantly expressed miRNAs served significant roles in the initiation, development and metastasis of bladder cancer.	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('aberrantly expressed', 'Var', (32, 52))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('metastasis of bladder cancer', 'Disease', 'MESH:D009362', (120, 148))	('metastasis of bladder cancer', 'Disease', (120, 148))	('development', 'CPA', (104, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (134, 148))
97658	25160520	High-risk, typically high grade and T1 lesions, will progress to invade the muscularis propria in 20-25% of patients.	('patients', 'Species', '9606', (108, 116))	('high grade', 'Var', (21, 31))	('muscularis propria', 'Phenotype', 'HP:0030936', (76, 94))	('progress', 'PosReg', (53, 61))
97702	25160520	One possible mechanism may be that the genetic changes in tumors of patients with bone only or bone predominant metastases may be associated with either a specific treatment-sensitivity or a less aggressive disease phenotype.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('bone only', 'CPA', (82, 91))	('aggressive disease', 'Disease', 'MESH:D001523', (196, 214))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('metastases', 'Disease', (112, 122))	('patients', 'Species', '9606', (68, 76))	('aggressive disease', 'Disease', (196, 214))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('genetic changes', 'Var', (39, 54))	('associated', 'Reg', (130, 140))
97705	25160520	By utilizing gene sequencing panels to identify and subsequently target these actionable mutations, we may be able to achieve better long term outcomes, not only in bone-predominant disease, but all patients with metastatic urothelial carcinoma.	('bone-predominant disease', 'Disease', (165, 189))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (224, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (199, 207))	('urothelial carcinoma', 'Disease', (224, 244))
97711	20456984	We identified patients with clinical T4bN0 bladder cancer from our IRB-approved database of patients undergoing radical cystectomy (n =1194).	('bladder cancer', 'Disease', 'MESH:D001749', (43, 57))	('patients', 'Species', '9606', (92, 100))	('bladder cancer', 'Disease', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('patients', 'Species', '9606', (14, 22))	('bladder cancer', 'Phenotype', 'HP:0009725', (43, 57))	('T4bN0', 'Var', (37, 42))
97717	20456984	Eight of 17 patients with pT2-4 tumors succumbed to disease compared to none of 6 who were <= pT1 (p=0.04).	('pT1', 'Gene', '58492', (94, 97))	('patients', 'Species', '9606', (12, 20))	('pT2-4', 'Var', (26, 31))	('pT1', 'Gene', (94, 97))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
97719	20456984	Long-term survival can be achieved in a proportion of patients with cT4b bladder cancer undergoing chemotherapy and extirpative surgery.	('bladder cancer', 'Disease', (73, 87))	('cT4b', 'Var', (68, 72))	('patients', 'Species', '9606', (54, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))
97727	20456984	In order to evaluate the efficacy of consolidative surgery in cT4b bladder cancer, we retrospectively evaluated our experience with radical cystectomy in this cohort of patients.	('patients', 'Species', '9606', (169, 177))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cT4b', 'Var', (62, 66))
97731	20456984	Twenty-three patients underwent radical cystectomy, pelvic lymph node dissection and urinary diversion with curative intent for cT4b urothelial carcinoma of the bladder.	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (133, 168))	('urothelial carcinoma of the bladder', 'Disease', (133, 168))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (133, 168))	('patients', 'Species', '9606', (13, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('cT4b', 'Var', (128, 132))
97740	20456984	Twenty three patients with cT4bN0 bladder cancer underwent radical cystectomy (total n=1194) at M.D.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('cT4bN0', 'Var', (27, 33))	('patients', 'Species', '9606', (13, 21))	('bladder cancer', 'Disease', 'MESH:D001749', (34, 48))	('bladder cancer', 'Disease', (34, 48))
97764	20456984	As is shown in Figure 2, none of 6 patients with pT0/Tis/Ta/T1 carcinoma died of disease, compared to 8 of 17 with pT2/T3/T4 disease (p=0.04, log rank test).	('carcinoma', 'Disease', (63, 72))	('pT0/Tis/Ta/T1', 'Var', (49, 62))	('patients', 'Species', '9606', (35, 43))	('carcinoma', 'Disease', 'MESH:D002277', (63, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
97770	20456984	Our results suggest that surgical extirpation can be efficacious in a select group of patients with cT4b urothelial carcinoma of the bladder.	('urothelial carcinoma of the bladder', 'Disease', (105, 140))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (105, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cT4b', 'Var', (100, 104))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (105, 140))	('patients', 'Species', '9606', (86, 94))
97775	20456984	Not all patients presenting with clinical T4b bladder cancer will be candidates for cystectomy.	('bladder cancer', 'Disease', 'MESH:D001749', (46, 60))	('bladder cancer', 'Disease', (46, 60))	('T4b', 'Var', (42, 45))	('bladder cancer', 'Phenotype', 'HP:0009725', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('patients', 'Species', '9606', (8, 16))
97777	20456984	Since our database only includes patients who undergo cystectomy, we do not know what proportion of patients presented with cT4b bladder carcinoma but did not respond adequately to chemotherapy to permit surgical consolidation.	('bladder carcinoma', 'Disease', (129, 146))	('patients', 'Species', '9606', (33, 41))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (129, 146))	('patients', 'Species', '9606', (100, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('bladder carcinoma', 'Disease', 'MESH:D001749', (129, 146))	('cT4b', 'Var', (124, 128))
97787	20456984	reported on 32 patients who underwent radical cystectomy with cT4bNx and 48 with cT3N2-3 bladder cancer.	('cT4bNx', 'Var', (62, 68))	('patients', 'Species', '9606', (15, 23))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))
97796	20456984	Our results suggest that radical cystectomy can be efficacious in a select group of patients with cT4b bladder cancer.	('patients', 'Species', '9606', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cT4b', 'Var', (98, 102))	('bladder cancer', 'Phenotype', 'HP:0009725', (103, 117))	('bladder cancer', 'Disease', 'MESH:D001749', (103, 117))	('bladder cancer', 'Disease', (103, 117))
97813	31331377	Around 93% of bladder cancers (BLCA) display mutations in genes regulating cell cycle progression.	('bladder cancers', 'Disease', (14, 29))	('mutations', 'Var', (45, 54))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('bladder cancers', 'Phenotype', 'HP:0009725', (14, 29))	('bladder cancers', 'Disease', 'MESH:D001749', (14, 29))	('BLCA', 'Phenotype', 'HP:0009725', (31, 35))	('bladder cancer', 'Phenotype', 'HP:0009725', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cell cycle', 'biological_process', 'GO:0007049', ('75', '85'))
97838	31331377	T24 cells were transduced with lentivirus containing dCas9-VP64 and MS2-p65-HSF1 respectively.	('HSF1', 'Gene', (76, 80))	('p65', 'Gene', '5970', (72, 75))	('dCas9-VP64', 'Var', (53, 63))	('S', 'Chemical', 'MESH:D013455', (69, 70))	('S', 'Chemical', 'MESH:D013455', (77, 78))	('p65', 'Gene', (72, 75))	('HSF1', 'Gene', '3297', (76, 80))
97875	31331377	T24 cells were transduced with the dCas9-VP64 fusion protein and the MS2-p65-HSF1 activation helper and expression was confirmed by immunoblots and PCR (Additional file 1: Figure S1a).	('HSF1', 'Gene', (77, 81))	('p65', 'Gene', '5970', (73, 76))	('HSF1', 'Gene', '3297', (77, 81))	('S', 'Chemical', 'MESH:D013455', (70, 71))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('S', 'Chemical', 'MESH:D013455', (78, 79))	('S', 'Chemical', 'MESH:D013455', (179, 180))	('p65', 'Gene', (73, 76))	('dCas9-VP64', 'Var', (35, 45))
97896	31331377	Above results suggested that amplification of distinct pathways in bladder cancer can serve as indicators of resistance to Palbociclib.	('Palbociclib', 'Chemical', 'MESH:C500026', (123, 134))	('amplification', 'Var', (29, 42))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
97902	31331377	However, inhibitors against the JAK/STAT signaling pathway showed additive and even antagonistic effects.	('JAK/STAT signaling pathway', 'Pathway', (32, 58))	('S', 'Chemical', 'MESH:D013455', (36, 37))	('signaling pathway', 'biological_process', 'GO:0007165', ('41', '58'))	('JAK', 'molecular_function', 'GO:0004713', ('32', '35'))	('inhibitors', 'Var', (9, 19))
97903	31331377	Since treatment of cells with Palbociclib mostly arrests bladder cancer cells in G0/G1 cell cycle stage by inhibiting progression into S-Phase, we examined if the synergistic drug combinations with Axitinib, Erdafitinib, CI1040 and the PI3K/mTOR inhibitor NVP-BEZ235 could induce an even greater G0/G1 arrest than monotherapy.	('G0/G1', 'MPA', (296, 301))	('inhibiting', 'NegReg', (107, 117))	('S-Phase', 'biological_process', 'GO:0051320', ('135', '142'))	('combinations', 'Interaction', (180, 192))	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (208, 219))	('mTOR', 'Gene', (241, 245))	('Palbociclib mostly arrests bladder cancer', 'Disease', 'MESH:D001749', (30, 71))	('CI1040', 'Var', (221, 227))	('cell cycle', 'biological_process', 'GO:0007049', ('87', '97'))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('progression into S-Phase', 'MPA', (118, 142))	('mTOR', 'Gene', '2475', (241, 245))	('Palbociclib mostly arrests bladder cancer', 'Disease', (30, 71))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (256, 266))	('Axitinib', 'Chemical', 'MESH:D000077784', (198, 206))	('CI1040', 'Chemical', 'MESH:C120227', (221, 227))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('S', 'Chemical', 'MESH:D013455', (135, 136))	('PI3K', 'molecular_function', 'GO:0016303', ('236', '240'))
97906	31331377	In T24 cells only the combination with NVP-BEZ235 suppressed cell-cycle progression with only 5.3% of cells in S-phase compared to 11.2% in Palbociclib monotherapy, whereas in RT112 cells the combination with Axitinib, Erdafitinib or NVP-BEZ235 inhibited cell-cycle progression to 3.9, 3.7 and 2.88% in S phase compared to Palbociclib monotherapy (8.5%).	('Erdafitinib', 'Chemical', 'MESH:C000604580', (219, 230))	('cell-cycle progression', 'CPA', (61, 83))	('suppressed', 'NegReg', (50, 60))	('S', 'Chemical', 'MESH:D013455', (111, 112))	('Palbociclib', 'Chemical', 'MESH:C500026', (140, 151))	('NVP-BEZ235', 'Var', (234, 244))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (39, 49))	('cell-cycle', 'biological_process', 'GO:0007049', ('61', '71'))	('S', 'Chemical', 'MESH:D013455', (303, 304))	('S phase', 'biological_process', 'GO:0051320', ('303', '310'))	('cell-cycle progression', 'CPA', (255, 277))	('NVP-BEZ235', 'Var', (39, 49))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (234, 244))	('Palbociclib', 'Chemical', 'MESH:C500026', (323, 334))	('cell-cycle', 'biological_process', 'GO:0007049', ('255', '265'))	('Axitinib', 'Chemical', 'MESH:D000077784', (209, 217))	('inhibited', 'NegReg', (245, 254))	('S-phase', 'biological_process', 'GO:0051320', ('111', '118'))
97929	31331377	The diversity of different signaling events involved in the cellular response to CDK4/6 inhibitors reflect probably the diverse and complicated downstream signaling network of CDK4/6 as described only recently.	('CDK4/6', 'Gene', '1019;1021', (81, 87))	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('CDK', 'molecular_function', 'GO:0004693', ('81', '84'))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('CDK4/6', 'Gene', (81, 87))	('CDK4/6', 'Gene', '1019;1021', (176, 182))	('CDK4/6', 'Gene', (176, 182))	('CDK', 'molecular_function', 'GO:0004693', ('176', '179'))	('inhibitors', 'Var', (88, 98))
97943	31331377	This observation is also supported in patients with acquired resistance to CDK4/6 inhibitors in whom novel mutations in RB1 with predicated loss of function have been observed.	('CDK4/6', 'Gene', '1019;1021', (75, 81))	('mutations', 'Var', (107, 116))	('RB1', 'Gene', '5925', (120, 123))	('loss of function', 'NegReg', (140, 156))	('CDK', 'molecular_function', 'GO:0004693', ('75', '78'))	('CDK4/6', 'Gene', (75, 81))	('patients', 'Species', '9606', (38, 46))	('RB1', 'Gene', (120, 123))
97961	25018779	Upstaging, metastases and recurrence were correlated with high index in T1 and T2-4 tumours.	('T2-4', 'Gene', (79, 83))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('recurrence', 'CPA', (26, 36))	('tumours', 'Disease', 'MESH:D009369', (84, 91))	('tumours', 'Disease', (84, 91))	('metastases', 'Disease', 'MESH:D009362', (11, 21))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('high index', 'Var', (58, 68))	('metastases', 'Disease', (11, 21))	('T2-4', 'Gene', '292', (79, 83))	('Upstaging', 'CPA', (0, 9))
98060	22355497	Immunohistochemically, one case was characterized by positive cytokeratins, EMA, p53, Ki-67 (labeling=15%), alpha-methylacyl CoA racemase, CA19-9, and MUC1, and another case by positive cytokeratins, EMA, p63, p53, Ki-67 (lebeling=30%), CD10, CEA, and MUC1.	('p63', 'Gene', '8626', (205, 208))	('CD10', 'Gene', (237, 241))	('p53', 'Gene', '7157', (210, 213))	('alpha-methylacyl CoA racemase', 'Gene', '23600', (108, 137))	('CEA', 'Gene', '5670', (243, 246))	('alpha-methylacyl CoA racemase', 'Gene', (108, 137))	('CD10', 'Gene', '4311', (237, 241))	('CD10', 'molecular_function', 'GO:0004245', ('237', '241'))	('MUC1', 'Gene', (252, 256))	('Ki-67', 'Var', (86, 91))	('MUC1', 'Gene', '4582', (252, 256))	('CEA', 'Gene', (243, 246))	('MUC1', 'Gene', (151, 155))	('p53', 'Gene', (81, 84))	('MUC1', 'Gene', '4582', (151, 155))	('p53', 'Gene', '7157', (81, 84))	('p63', 'Gene', (205, 208))	('p53', 'Gene', (210, 213))
98078	22355497	Characteristic findings were positive cytokeratins, EMA, p53 (Figure 1C), Ki-67 (labeling=15%) (Figure 1D), alpha-methylacyl CoA racemase (AMACR), CA19-9, and MUC1 (Figure 1E) (Table 1).	('alpha-methylacyl CoA racemase', 'Gene', '23600', (108, 137))	('MUC1', 'Gene', (159, 163))	('MUC1', 'Gene', '4582', (159, 163))	('alpha-methylacyl CoA racemase', 'Gene', (108, 137))	('AMACR', 'Gene', (139, 144))	('AMACR', 'Gene', '23600', (139, 144))	('Ki-67', 'Gene', (74, 79))	('p53', 'Gene', (57, 60))	('CA19-9', 'Var', (147, 153))	('p53', 'Gene', '7157', (57, 60))
98106	22355497	The present cases, particularly in case #1, are different from nephrogenic metaplasia, because the present cases showed positive p53 and high Ki67 and negative CD10 in case #1.	('nephrogenic metaplasia', 'Disease', (63, 85))	('nephrogenic metaplasia', 'Disease', 'MESH:D008679', (63, 85))	('negative', 'NegReg', (151, 159))	('CD10', 'Gene', (160, 164))	('CD10', 'Gene', '4311', (160, 164))	('Ki67', 'Var', (142, 146))	('CD10', 'molecular_function', 'GO:0004245', ('160', '164'))	('Ki67', 'Chemical', '-', (142, 146))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '7157', (129, 132))	('metaplasia', 'biological_process', 'GO:0036074', ('75', '85'))
98139	31543783	Clival metastases may be clinically silent, but large lesions usually cause VI cranial nerve palsy due to the compression of the abducens nerve in Dorello's canal.	('VI cranial nerve palsy', 'Phenotype', 'HP:0006897', (76, 98))	('cranial nerve', 'Phenotype', 'HP:0001291', (79, 92))	('metastases', 'Disease', 'MESH:D009362', (7, 17))	('VI cranial nerve palsy', 'Disease', (76, 98))	('cause', 'Reg', (70, 75))	('VI cranial nerve palsy', 'Disease', 'MESH:D020434', (76, 98))	('metastases', 'Disease', (7, 17))	('lesions', 'Var', (54, 61))	('cranial nerve palsy', 'Phenotype', 'HP:0006824', (79, 98))
98238	29757570	Histologically, both tumors were intermediate risk adenocarcinomas {Gleason 7 (4+3) and Gleason 7 (3+4)}, both clinical stages IIB (T2cN0M0, an T2bN0M0, respectively).	('T2bN0M0', 'Var', (144, 151))	('Gleason', 'Chemical', '-', (68, 75))	('Gleason', 'Chemical', '-', (88, 95))	('adenocarcinomas', 'Disease', 'MESH:D000230', (51, 66))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('adenocarcinomas', 'Disease', (51, 66))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('Gleason', 'Var', (88, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
98251	29757570	Regarding histocompatibility, we found that of those sharing 0-haplotypes, 47.3% developed malignancies, while of those with 1 and 2 haplotypes, the frequency of tumors was 36.8% and 15.7%, respectively.	('0-haplotypes', 'Var', (61, 73))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('malignancies', 'Disease', (91, 103))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('malignancies', 'Disease', 'MESH:D009369', (91, 103))	('developed', 'PosReg', (81, 90))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))
98283	29757570	We found 2 cases with intermediate risk prostate cancer (Gleason 7 (4+3) and Gleason 7 (3+4)).	('Gleason', 'Chemical', '-', (77, 84))	('Gleason', 'Chemical', '-', (57, 64))	('prostate cancer', 'Disease', (40, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Gleason', 'Var', (77, 84))	('prostate cancer', 'Disease', 'MESH:D011471', (40, 55))	('prostate cancer', 'Phenotype', 'HP:0012125', (40, 55))
98320	29850366	Generally, the 5-year survival rates of patients with pTa or pT1 UUT-UC (Stage 0-I in the AJCC staging system) are over 60%, whereas the rate for patients with pT3-4 or N1-3 disease (Stage IV) is extremely poor (<5%).	('pT3', 'Gene', (160, 163))	('patients', 'Species', '9606', (40, 48))	('pTa', 'molecular_function', 'GO:0008959', ('54', '57'))	('pT1 UUT-UC', 'Gene', (61, 71))	('patients', 'Species', '9606', (146, 154))	('pT3', 'Gene', '7694', (160, 163))	('pTa', 'Var', (54, 57))	('pT1 UUT-UC', 'Gene', '58492', (61, 71))
98356	29850366	), with resistance to platinum-based chemotherapy, were also significantly reduced by GP-chemotherapy as a second-line treatment.	('platinum', 'Chemical', 'MESH:D010984', (22, 30))	('GP-chemotherapy', 'Var', (86, 101))	('reduced', 'NegReg', (75, 82))
98383	27246979	Cdc6 depletion can attenuate the malignant properties of bladder cancer cells, including DNA replication, migration and invasion.	('DNA replication', 'CPA', (89, 104))	('depletion', 'Var', (5, 14))	('Cdc6', 'Protein', (0, 4))	('bladder cancer', 'Disease', (57, 71))	('bladder cancer', 'Disease', 'MESH:D001749', (57, 71))	('invasion', 'CPA', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('DNA replication', 'biological_process', 'GO:0006260', ('89', '104'))	('attenuate', 'NegReg', (19, 28))	('malignant properties of', 'CPA', (33, 56))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))
98386	27246979	Cdc6 depletion abrogates S phase arrest caused by CDDP, leading to aberrant mitosis by inactivating ATR-Chk1-Cdc25C pathway.	('aberrant mitosis', 'Disease', 'MESH:D002869', (67, 83))	('depletion', 'Var', (5, 14))	('S phase', 'biological_process', 'GO:0051320', ('25', '32'))	('aberrant mitosis', 'Disease', (67, 83))	('mitosis', 'biological_process', 'GO:0000278', ('76', '83'))	('abrogates', 'NegReg', (15, 24))	('Cdc25C', 'Gene', (109, 115))	('Chk1', 'Gene', (104, 108))	('Cdc6', 'Gene', (0, 4))	('S phase arrest', 'CPA', (25, 39))	('ATR', 'Gene', '545', (100, 103))	('ATR', 'Gene', (100, 103))	('CDDP', 'Chemical', 'MESH:D002945', (50, 54))	('Chk1', 'Gene', '1111', (104, 108))	('inactivating', 'NegReg', (87, 99))	('Cdc25C', 'Gene', '995', (109, 115))
98400	27246979	In human cells, Cdc6 co-precipitates with ATR and more importantly, Cdc6 silencing impairs ATR-dependent checkpoint activation.	('silencing', 'Var', (73, 82))	('ATR', 'Gene', (91, 94))	('Cdc6', 'Gene', (68, 72))	('human', 'Species', '9606', (3, 8))	('ATR', 'Gene', '545', (42, 45))	('ATR', 'Gene', (42, 45))	('impairs', 'NegReg', (83, 90))	('ATR', 'Gene', '545', (91, 94))
98404	27246979	In addition, we explored the correlation between Cdc6 up-regulation and ATR pathway under CDDP stress, demonstrating that Cdc6 contributes to CDDP resistance by activating ATR-Chk1-Cdc25C pathway and Cdc6 depletion can promote DNA damage and lead to aberrant mitosis, thus reverse CDDP resistance.	('depletion', 'Var', (205, 214))	('CDDP', 'Chemical', 'MESH:D002945', (142, 146))	('activating', 'PosReg', (161, 171))	('CDDP', 'MPA', (281, 285))	('ATR', 'Gene', (72, 75))	('lead to', 'Reg', (242, 249))	('aberrant mitosis', 'Disease', 'MESH:D002869', (250, 266))	('DNA', 'cellular_component', 'GO:0005574', ('227', '230'))	('regulation', 'biological_process', 'GO:0065007', ('57', '67'))	('ATR', 'Gene', (172, 175))	('mitosis', 'biological_process', 'GO:0000278', ('259', '266'))	('Cdc25C', 'Gene', '995', (181, 187))	('aberrant mitosis', 'Disease', (250, 266))	('promote', 'PosReg', (219, 226))	('Cdc25C', 'Gene', (181, 187))	('ATR', 'Gene', '545', (72, 75))	('Chk1', 'Gene', (176, 180))	('CDDP', 'Chemical', 'MESH:D002945', (281, 285))	('Chk1', 'Gene', '1111', (176, 180))	('Cdc6', 'Gene', (122, 126))	('ATR', 'Gene', '545', (172, 175))	('CDDP', 'Chemical', 'MESH:D002945', (90, 94))	('DNA', 'MPA', (227, 230))	('Cdc6', 'Gene', (200, 204))
98422	27246979	These results indicate that Cdc6 depletion can reduce the malignant traits, including DNA replication, migration and invasion of bladder cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('depletion', 'Var', (33, 42))	('reduce', 'NegReg', (47, 53))	('DNA replication', 'CPA', (86, 101))	('bladder cancer', 'Disease', 'MESH:D001749', (129, 143))	('malignant traits', 'CPA', (58, 74))	('bladder cancer', 'Disease', (129, 143))	('DNA replication', 'biological_process', 'GO:0006260', ('86', '101'))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('Cdc6', 'Gene', (28, 32))	('invasion', 'CPA', (117, 125))	('migration', 'CPA', (103, 112))
98428	27246979	CDDP can lead to DNA damage by causing crosslinking of DNA, which ultimately triggers apoptosis.	('CDDP', 'Chemical', 'MESH:D002945', (0, 4))	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('causing', 'Reg', (31, 38))	('DNA', 'Protein', (55, 58))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('CDDP', 'Var', (0, 4))	('triggers', 'Reg', (77, 85))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('DNA damage', 'MPA', (17, 27))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('lead to', 'Reg', (9, 16))	('crosslinking', 'MPA', (39, 51))
98444	27246979	Therefore, we speculate that inhibition of Cdc6 may enhance the sensitivity of CDDP-resistant bladder cancer cells by disturbing the ATR checkpoint signal.	('sensitivity', 'CPA', (64, 75))	('bladder cancer', 'Disease', (94, 108))	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('CDDP', 'Chemical', 'MESH:D002945', (79, 83))	('ATR', 'Gene', '545', (133, 136))	('ATR', 'Gene', (133, 136))	('Cdc6', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('disturbing', 'Reg', (118, 128))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('enhance', 'PosReg', (52, 59))	('inhibition', 'Var', (29, 39))
98445	27246979	As shown in Figure 6, CDDP (4mug/ml) induced 20% apoptosis in UMUC-3 cells versus about 9% in UMUC3-R cells, showing lower response to CDDP in UMUC3-R cells.	('CDDP', 'Var', (22, 26))	('UMUC-3', 'CellLine', 'CVCL:1783', (62, 68))	('CDDP', 'Chemical', 'MESH:D002945', (135, 139))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))	('CDDP', 'Chemical', 'MESH:D002945', (22, 26))	('apoptosis', 'CPA', (49, 58))	('mug', 'molecular_function', 'GO:0043739', ('29', '32'))
98446	27246979	The combination of CDDP with Cdc6 RNAi leaded to over 21% apoptosis in UMUC3-R and 40% apoptosis in UMUC3 cells, which were significantly higher than the apoptosis rate caused by CDDP or Cdc6 siRNA alone, suggesting that Cdc6 RNAi combined with CDDP synergistically promotes apoptosis both in CDDP-resistant and non-resistant cells.	('apoptosis', 'biological_process', 'GO:0006915', ('275', '284'))	('apoptosis', 'biological_process', 'GO:0097194', ('154', '163'))	('CDDP', 'Chemical', 'MESH:D002945', (179, 183))	('apoptosis', 'biological_process', 'GO:0006915', ('154', '163'))	('CDDP', 'Chemical', 'MESH:D002945', (293, 297))	('RNAi', 'biological_process', 'GO:0016246', ('34', '38'))	('combination', 'Var', (4, 15))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))	('apoptosis', 'biological_process', 'GO:0097194', ('58', '67'))	('apoptosis', 'biological_process', 'GO:0006915', ('58', '67'))	('CDDP', 'Chemical', 'MESH:D002945', (19, 23))	('CDDP', 'Chemical', 'MESH:D002945', (245, 249))	('apoptosis', 'CPA', (275, 284))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('apoptosis', 'biological_process', 'GO:0097194', ('275', '284'))	('promotes', 'PosReg', (266, 274))	('RNAi', 'biological_process', 'GO:0016246', ('226', '230'))
98449	27246979	What's more, CDDP resulted in S phase accumulation (70% in S, 14.6% in G2/M), and BrdU-positive cells markedly decreased after CDDP treatment (Supplementary Figure S1), indicating that CDDP inhibits DNA replication and results in S phase arrest.	('S phase', 'CPA', (30, 37))	('Supplementary Figure S1', 'Disease', 'MESH:D017034', (143, 166))	('CDDP', 'Chemical', 'MESH:D002945', (185, 189))	('CDDP', 'Var', (13, 17))	('S phase', 'biological_process', 'GO:0051320', ('230', '237'))	('S phase arrest', 'CPA', (230, 244))	('decreased', 'NegReg', (111, 120))	('DNA replication', 'CPA', (199, 214))	('DNA replication', 'biological_process', 'GO:0006260', ('199', '214'))	('DNA', 'cellular_component', 'GO:0005574', ('199', '202'))	('CDDP', 'Var', (185, 189))	('results in', 'Reg', (219, 229))	('inhibits', 'NegReg', (190, 198))	('CDDP', 'Chemical', 'MESH:D002945', (127, 131))	('S phase', 'biological_process', 'GO:0051320', ('30', '37'))	('Supplementary Figure S1', 'Disease', (143, 166))	('CDDP', 'Chemical', 'MESH:D002945', (13, 17))
98450	27246979	Interestingly, Cdc6 depletion plus CDDP caused a substantial proportion of cells abrogated S phase arrest and progressed into G2/M phase (56.7% in S, 22.3% in G2/M) (Figure 7A).	('Cdc6', 'Gene', (15, 19))	('S phase arrest', 'CPA', (91, 105))	('CDDP', 'Gene', (35, 39))	('S phase', 'biological_process', 'GO:0051320', ('91', '98'))	('M phase', 'biological_process', 'GO:0000279', ('129', '136'))	('depletion', 'Var', (20, 29))	('CDDP', 'Chemical', 'MESH:D002945', (35, 39))	('abrogated', 'NegReg', (81, 90))	('progressed', 'PosReg', (110, 120))	('G2/M phase', 'CPA', (126, 136))
98451	27246979	Cell cycle analysis indicated that Cdc6 depletion led to aberrant progression of cancer cells into G2/M phase under CDDP exposure.	('M phase', 'biological_process', 'GO:0000279', ('102', '109'))	('depletion', 'Var', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('progression', 'CPA', (66, 77))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('Cdc6', 'Gene', (35, 39))	('CDDP', 'Chemical', 'MESH:D002945', (116, 120))
98452	27246979	Here, to further characterize aberrant mitosis with CDDP-induced DNA damage, we assess pH3 (a mitotic marker) and gammaH2AX (a DNA damage marker) by immunofluorescence.	('mitosis', 'biological_process', 'GO:0000278', ('39', '46'))	('gammaH2AX', 'Var', (114, 123))	('CDDP', 'Chemical', 'MESH:D002945', (52, 56))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('pH3', 'Gene', (87, 90))	('aberrant mitosis', 'Disease', (30, 46))	('aberrant mitosis', 'Disease', 'MESH:D002869', (30, 46))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))
98453	27246979	The results showed few pH3- but plenty of gammaH2AX-stained cells in CDDP treatment group, while combination of Cdc6 RNAi with CDDP gave rise to more gammaH2AX-positive cells (Figure 7B), indicating that Cdc6 depletion enhances DNA damage induced by CDDP.	('RNAi', 'biological_process', 'GO:0016246', ('117', '121'))	('DNA', 'cellular_component', 'GO:0005574', ('228', '231'))	('CDDP', 'Chemical', 'MESH:D002945', (69, 73))	('depletion', 'Var', (209, 218))	('DNA damage', 'MPA', (228, 238))	('enhances', 'PosReg', (219, 227))	('CDDP', 'Chemical', 'MESH:D002945', (250, 254))	('CDDP', 'Chemical', 'MESH:D002945', (127, 131))
98455	27246979	Our studies show that Cdc6 depletion abrogated S phase block induced by CDDP and resulted in aberrant mitosis with DNA damage.	('aberrant mitosis', 'Disease', (93, 109))	('resulted in', 'Reg', (81, 92))	('mitosis', 'biological_process', 'GO:0000278', ('102', '109'))	('Cdc6', 'Gene', (22, 26))	('CDDP', 'Chemical', 'MESH:D002945', (72, 76))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('abrogated', 'NegReg', (37, 46))	('depletion', 'Var', (27, 36))	('S phase', 'biological_process', 'GO:0051320', ('47', '54'))	('aberrant mitosis', 'Disease', 'MESH:D002869', (93, 109))
98456	27246979	So we speculate that inhibition of Cdc6 may impair activation of ATR-Chk1-Cdc25C pathway and abolish cell cycle arrest, leaving DNA damage unrepaired.	('impair', 'NegReg', (44, 50))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (101, 118))	('Cdc25C', 'Gene', (74, 80))	('abolish', 'NegReg', (93, 100))	('ATR', 'Gene', '545', (65, 68))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('inhibition', 'Var', (21, 31))	('Chk1', 'Gene', (69, 73))	('cell cycle arrest', 'CPA', (101, 118))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('101', '118'))	('DNA', 'MPA', (128, 131))	('ATR', 'Gene', (65, 68))	('Cdc25C', 'Gene', '995', (74, 80))	('Chk1', 'Gene', '1111', (69, 73))	('Cdc6', 'Gene', (35, 39))
98457	27246979	In accordance to previous reports, we found that CDDP can activate ATR-Chk1-Cdc25C pathway.	('Cdc25C', 'Gene', (76, 82))	('Chk1', 'Gene', (71, 75))	('CDDP', 'Chemical', 'MESH:D002945', (49, 53))	('Cdc25C', 'Gene', '995', (76, 82))	('activate', 'PosReg', (58, 66))	('Chk1', 'Gene', '1111', (71, 75))	('CDDP', 'Var', (49, 53))	('ATR', 'Gene', '545', (67, 70))	('ATR', 'Gene', (67, 70))
98460	27246979	As expectation, after Cdc6 RNAi transfection, chromatin-binding ATR, p-Chk1 and p-CDC25C were decreased (Figure 8B,C,D), indicating that the CDDP-activated ATR-Chk1-CDC25C pathway was inhibited by Cdc6 depletion.	('Chk1', 'Gene', (71, 75))	('ATR', 'Gene', (64, 67))	('Chk1', 'Gene', '1111', (71, 75))	('chromatin', 'cellular_component', 'GO:0000785', ('46', '55'))	('CDDP', 'Chemical', 'MESH:D002945', (141, 145))	('CDC25C', 'Gene', (165, 171))	('CDC25C', 'Gene', '995', (165, 171))	('inhibited', 'NegReg', (184, 193))	('ATR', 'Gene', (156, 159))	('ATR', 'Gene', '545', (64, 67))	('decreased', 'NegReg', (94, 103))	('Cdc6', 'Var', (22, 26))	('Chk1', 'Gene', (160, 164))	('chromatin-binding', 'molecular_function', 'GO:0003682', ('46', '63'))	('Chk1', 'Gene', '1111', (160, 164))	('CDC25C', 'Gene', (82, 88))	('CDC25C', 'Gene', '995', (82, 88))	('RNAi', 'biological_process', 'GO:0016246', ('27', '31'))	('ATR', 'Gene', '545', (156, 159))
98468	27246979	Furthermore, Cdc6 depletion not only can inhibit DNA replication, migration and invasion, but also reverse CDDP resistance of UMUC3R and cause aberrant mitosis, probably by inactivation of ATR-Chk1-Cdc25 pathway.	('Cdc25', 'Gene', (198, 203))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('aberrant mitosis', 'Disease', (143, 159))	('cause', 'Reg', (137, 142))	('DNA replication', 'MPA', (49, 64))	('Cdc6', 'Gene', (13, 17))	('Cdc25', 'Gene', '995', (198, 203))	('mitosis', 'biological_process', 'GO:0000278', ('152', '159'))	('depletion', 'Var', (18, 27))	('ATR', 'Gene', (189, 192))	('Chk1', 'Gene', (193, 197))	('Chk1', 'Gene', '1111', (193, 197))	('CDDP', 'Chemical', 'MESH:D002945', (107, 111))	('CDDP resistance', 'MPA', (107, 122))	('reverse', 'NegReg', (99, 106))	('invasion', 'CPA', (80, 88))	('migration', 'CPA', (66, 75))	('DNA replication', 'biological_process', 'GO:0006260', ('49', '64'))	('aberrant mitosis', 'Disease', 'MESH:D002869', (143, 159))	('ATR', 'Gene', '545', (189, 192))	('inhibit', 'NegReg', (41, 48))
98470	27246979	Dysregulation of DNA damage response (DDR) has been implicated in the CDDP-resistance in cancer treatment.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('CDDP', 'Chemical', 'MESH:D002945', (70, 74))	('cancer', 'Disease', (89, 95))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('DNA damage response', 'biological_process', 'GO:0006974', ('17', '36'))	('implicated', 'Reg', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
98478	27246979	Notably, CDDP-resistant UMUC3R cells expressed more chromatin-binding ATR and Cdc6 than UMUC3 after exposure to CDDP (Figure 5A and 5B), indicating Cdc6 may collaborate with ATR and contribute to CDDP resistance by facilitating activation of ATR pathway (Figure 9).	('ATR', 'Gene', '545', (242, 245))	('ATR', 'Gene', (242, 245))	('more', 'PosReg', (47, 51))	('Cdc6', 'Gene', (78, 82))	('ATR', 'Gene', '545', (174, 177))	('ATR', 'Gene', (174, 177))	('contribute', 'Reg', (182, 192))	('CDDP', 'Chemical', 'MESH:D002945', (9, 13))	('CDDP', 'Chemical', 'MESH:D002945', (196, 200))	('Cdc6', 'Var', (148, 152))	('ATR', 'Gene', '545', (70, 73))	('chromatin', 'cellular_component', 'GO:0000785', ('52', '61'))	('chromatin-binding', 'MPA', (52, 69))	('CDDP', 'Chemical', 'MESH:D002945', (112, 116))	('ATR', 'Gene', (70, 73))	('chromatin-binding', 'molecular_function', 'GO:0003682', ('52', '69'))
98480	27246979	Inhibition of ATR/Chk1 pathway has been shown to sensitize cancer cells to gemcitabine, cytarabine and 5-fluorouracil.	('cytarabine', 'MPA', (88, 98))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('gemcitabine', 'Chemical', 'MESH:C056507', (75, 86))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (103, 117))	('5-fluorouracil', 'MPA', (103, 117))	('gemcitabine', 'MPA', (75, 86))	('Inhibition', 'Var', (0, 10))	('ATR', 'Gene', (14, 17))	('Chk1', 'Gene', (18, 22))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', (59, 65))	('Chk1', 'Gene', '1111', (18, 22))	('cytarabine', 'Chemical', 'MESH:D003561', (88, 98))	('ATR', 'Gene', '545', (14, 17))	('sensitize', 'Reg', (49, 58))
98481	27246979	Here, we demonstrated that Cdc6 depletion can enhance sensitivity to CDDP by inactivating ATR-Chk1 pathway.	('Chk1', 'Gene', '1111', (94, 98))	('CDDP', 'Chemical', 'MESH:D002945', (69, 73))	('depletion', 'Var', (32, 41))	('inactivating', 'NegReg', (77, 89))	('ATR', 'Gene', (90, 93))	('Cdc6', 'Gene', (27, 31))	('sensitivity to CDDP', 'MPA', (54, 73))	('ATR', 'Gene', '545', (90, 93))	('enhance', 'PosReg', (46, 53))	('Chk1', 'Gene', (94, 98))
98483	27246979	Moreover, Cdc6 silence abrogated the S and S/G2 cell cycle checkpoint and caused cells to aberrantly enter mitosis with damage DNA (Figure 7).	('aberrantly enter mitosis', 'Disease', (90, 114))	('silence abrogated', 'NegReg', (15, 32))	('S/G2', 'Var', (43, 47))	('S/G2', 'SUBSTITUTION', 'None', (43, 47))	('Cdc6', 'Gene', (10, 14))	('aberrantly enter mitosis', 'Disease', 'MESH:D004751', (90, 114))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('48', '69'))	('mitosis', 'biological_process', 'GO:0000278', ('107', '114'))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))
98484	27246979	The Western blot results confirmed the inhibitory effect of Cdc6 depletion on ATR-Chk1-Cdc25C pathway (Figure 8).	('Cdc25C', 'Gene', (87, 93))	('Chk1', 'Gene', (82, 86))	('ATR', 'Gene', '545', (78, 81))	('ATR', 'Gene', (78, 81))	('Cdc6', 'Gene', (60, 64))	('Cdc25C', 'Gene', '995', (87, 93))	('Chk1', 'Gene', '1111', (82, 86))	('depletion', 'Var', (65, 74))
98485	27246979	So inhibition of Cdc6 may be a new promising strategy to inhibit ATR pathway for killing CDDP-resistant cancer cells.	('CDDP', 'Chemical', 'MESH:D002945', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Cdc6', 'Gene', (17, 21))	('inhibit', 'NegReg', (57, 64))	('inhibition', 'Var', (3, 13))	('ATR', 'Gene', '545', (65, 68))	('ATR', 'Gene', (65, 68))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
98494	27246979	Cdc6 inhibition can abolish S/G2 checkpoint and induce abnormal mitosis with damage DNA indicating silencing of Cdc6 might be cytotoxic to tumors as well as to normal cells.	('cytotoxic to tumors', 'Disease', (126, 145))	('abnormal mitosis', 'Disease', 'MESH:D000014', (55, 71))	('abolish', 'NegReg', (20, 27))	('mitosis', 'biological_process', 'GO:0000278', ('64', '71'))	('inhibition', 'Var', (5, 15))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('induce', 'Reg', (48, 54))	('Cdc6', 'Gene', (112, 116))	('Cdc6', 'Protein', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('silencing', 'Var', (99, 108))	('cytotoxic to tumors', 'Disease', 'MESH:D064420', (126, 145))	('abnormal mitosis', 'Disease', (55, 71))	('S/G2', 'Var', (28, 32))	('S/G2', 'SUBSTITUTION', 'None', (28, 32))
98504	27246979	Accordingly, inhibition of Cdc6 could enhance cytotoxicity of CDDP in both parent and CDDP-resistant bladder cancer cells.	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('cytotoxicity', 'Disease', 'MESH:D064420', (46, 58))	('CDDP', 'Chemical', 'MESH:D002945', (62, 66))	('inhibition', 'Var', (13, 23))	('enhance', 'PosReg', (38, 45))	('bladder cancer', 'Disease', (101, 115))	('CDDP', 'Chemical', 'MESH:D002945', (86, 90))	('Cdc6', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))	('cytotoxicity', 'Disease', (46, 58))
98506	27246979	Human bladder cancer UMUC3, T24 and 5637 cells were routinely maintained in MEM medium (Gibco BRL, Grand Island, NY, USA) containing 10% fetal bovine serum, penicillin (100U/ml), and streptomycin (100mug/ml) at 37 C in a balanced air humidified incubator with an atmosphere of 5% CO2.	('Human', 'Species', '9606', (0, 5))	('streptomycin', 'Chemical', 'MESH:D013307', (183, 195))	('bovine', 'Species', '9913', (143, 149))	('MEM medium', 'Chemical', '-', (76, 86))	('CO2', 'Chemical', '-', (280, 283))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('bladder cancer', 'Phenotype', 'HP:0009725', (6, 20))	('penicillin', 'Chemical', 'MESH:D010406', (157, 167))	('mug', 'molecular_function', 'GO:0043739', ('200', '203'))	('bladder cancer', 'Disease', 'MESH:D001749', (6, 20))	('100mug/ml', 'Var', (197, 206))	('bladder cancer', 'Disease', (6, 20))
98511	27246979	Total proteins (about 20 mug) were separated by SDS-PAGE (6% for ATR, 10% for other proteins) and transferred onto polyvinylidene fluoride membranes and incubated overnight at 4 C with antibody against Cdc6 (Abcam), ATR, gamma-H2AX (Abcam), p-Chk1 (Cell Signaling technology), pCdc25C (Cell Signaling technology), beta-actin (Cell Signaling technology) or histone H3 (Cell Signaling technology).	('Cdc25C', 'Gene', '995', (278, 284))	('antibody', 'cellular_component', 'GO:0042571', ('185', '193'))	('mug', 'molecular_function', 'GO:0043739', ('25', '28'))	('Cdc25C', 'Gene', (278, 284))	('antibody', 'molecular_function', 'GO:0003823', ('185', '193'))	('Chk1', 'Gene', (243, 247))	('beta-actin', 'Gene', (314, 324))	('Chk1', 'Gene', '1111', (243, 247))	('antibody', 'cellular_component', 'GO:0019815', ('185', '193'))	('ATR', 'Gene', '545', (216, 219))	('Signaling', 'biological_process', 'GO:0023052', ('254', '263'))	('ATR', 'Gene', '545', (65, 68))	('Signaling', 'biological_process', 'GO:0023052', ('291', '300'))	('Signaling', 'biological_process', 'GO:0023052', ('331', '340'))	('antibody', 'cellular_component', 'GO:0019814', ('185', '193'))	('SDS', 'Chemical', 'MESH:D012967', (48, 51))	('beta-actin', 'Gene', '728378', (314, 324))	('histone H3', 'Protein', (356, 366))	('gamma-H2AX', 'Var', (221, 231))	('polyvinylidene fluoride', 'Chemical', 'MESH:C024865', (115, 138))	('ATR', 'Gene', (216, 219))	('ATR', 'Gene', (65, 68))	('Signaling', 'biological_process', 'GO:0023052', ('373', '382'))
98519	27246979	Endogenous peroxidase activities were quenched by 3% H2O2 for 30 minutes, followed by rinsing twice in ddH2O and once with 0.1% Tween-20 in TBS and non-specific-binding sites were blocked with goat serum for 30 min.	('goat', 'Species', '9925', (193, 197))	('TBS', 'Chemical', 'MESH:D013725', (140, 143))	('Tween-20', 'Chemical', 'MESH:D011136', (128, 136))	('activities', 'MPA', (22, 32))	('quenched', 'NegReg', (38, 46))	('H2O2', 'Var', (53, 57))	('Endogenous', 'MPA', (0, 10))	('H2O2', 'Chemical', 'MESH:D006861', (53, 57))	('binding', 'molecular_function', 'GO:0005488', ('161', '168'))	('ddH2O', 'Chemical', '-', (103, 108))
98525	27246979	Three Cdc6-targeting siRNAs (si-Cdc6-1: 5'AGGCACUUGCUACCAGCAA dTdT 3', si-Cdc6-2: 5'CCAAGAAGGAGCACAAGAUdTdT3', si-Cdc6-3: 5'GACAAUCAGCUGACAAUUAdTdT 3'), were purchased from Guangzhou Ribobio tech.	('si-Cdc6-3', 'Var', (111, 120))	('si-Cdc6-2', 'Var', (71, 80))	('GC', 'Chemical', '-', (94, 96))	('GC', 'Chemical', '-', (132, 134))	('Cdc6-targeting', 'Disease', (6, 20))	('GC', 'Chemical', '-', (57, 59))	('GC', 'Chemical', '-', (44, 46))	('GC', 'Chemical', '-', (50, 52))	('si-Cdc6-1', 'Var', (29, 38))
98548	25960768	Tumor samples in different CIMP subclasses show distinctive correlations with gene expression profiles and recurrence of somatic mutations, copy number variations, and epigenetic silencing.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('epigenetic silencing', 'Var', (168, 188))	('copy number variations', 'Var', (140, 162))	('gene expression', 'biological_process', 'GO:0010467', ('78', '93'))	('CIMP', 'Chemical', '-', (27, 31))
98552	25960768	We present a comprehensive computational study of CIMP that reveals pan-cancer commonalities and tissue-specific differences underlying concurrent hypermethylation of CpG islands across tumors.	('hypermethylation', 'Var', (147, 163))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('CIMP', 'Chemical', '-', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumors', 'Disease', (186, 192))	('CpG', 'Gene', (167, 170))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
98555	25960768	Recurrent patterns of aberrant DNA methylation are commonly observed in cancerous cells, implying that this epigenetic alteration is inherently linked to general mechanisms of oncogenesis and tumor progression.	('aberrant', 'Var', (22, 30))	('tumor', 'Disease', (192, 197))	('cancerous', 'Disease', (72, 81))	('DNA', 'Gene', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancerous', 'Disease', 'MESH:D009369', (72, 81))	('DNA methylation', 'biological_process', 'GO:0006306', ('31', '46'))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('oncogenesis', 'biological_process', 'GO:0007048', ('176', '187'))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('linked', 'Reg', (144, 150))
98557	25960768	Concurrent and widespread hypermethylation of CpG islands in clinically distinct cancer subtypes is known as CpG island methylator phenotype (CIMP).	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('hypermethylation', 'Var', (26, 42))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('CIMP', 'Chemical', '-', (142, 146))
98562	25960768	For example, the inactivation of mismatch repair gene MLH1 correlates strongly with CIMP in colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('inactivation', 'Var', (17, 29))	('MLH1', 'Gene', '4292', (54, 58))	('MLH1', 'Gene', (54, 58))	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('CIMP', 'Chemical', '-', (84, 88))	('colon cancer', 'Disease', (92, 104))	('mismatch repair', 'biological_process', 'GO:0006298', ('33', '48'))	('CIMP', 'Disease', (84, 88))
98563	25960768	Glioblastoma exhibits mutations in epigenetic regulators such as IDH1/2 and in histone encoding genes such as H3F3A, whereas CIMP in leukemia is associated with TET2 mutations (for a review, see Witte et al.).	('leukemia', 'Disease', 'MESH:D007938', (133, 141))	('CIMP', 'Chemical', '-', (125, 129))	('Glioblastoma', 'Disease', (0, 12))	('epigenetic regulators', 'MPA', (35, 56))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('IDH1/2', 'Gene', '3417;3418', (65, 71))	('TET2', 'Gene', '54790', (161, 165))	('leukemia', 'Phenotype', 'HP:0001909', (133, 141))	('H3F3A', 'Gene', '3020', (110, 115))	('mutations', 'Var', (22, 31))	('TET2', 'Gene', (161, 165))	('H3F3A', 'Gene', (110, 115))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('IDH1/2', 'Gene', (65, 71))	('leukemia', 'Disease', (133, 141))
98606	25960768	An Ingenuity Pathway Analysis (IPA) evaluation of the genes associated with the differential methylation sites in individual cancers revealed a subset of canonical pathways that are collectively targeted in the CIMP probe sets (Figure 3A).	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('CIMP', 'Chemical', '-', (211, 215))	('canonical pathways', 'Pathway', (154, 172))	('sites', 'Var', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('methylation sites', 'Var', (93, 110))
98610	25960768	Using the IPA tool, we also identified a set of recurrent upstream regulators for the differentially methylated probe set associated with each cancer type (Figure 3B).	('associated', 'Reg', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('differentially methylated', 'Var', (86, 111))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
98619	25960768	Also, we noted a strong correlation between the differentially methylated probe set and the set of 89 tumor-derived pan-cancer loci (Figure 4G), which supports the consistency of our findings between the cell lines and the tumor data.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('differentially methylated', 'Var', (48, 73))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
98634	25960768	Furthermore, less than half of the CIMP +  Hyper regions in the gene-associated set collocated with known transcription start sites annotated by Illumina (and a comparable number overlapped gene bodies), suggesting that aberrant hypermethylation in CIMP is not exclusive to gene promoters.	('CIMP', 'Gene', (249, 253))	('CIMP', 'Chemical', '-', (35, 39))	('CIMP', 'Chemical', '-', (249, 253))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('aberrant hypermethylation', 'Var', (220, 245))
98636	25960768	A subset of 121 regions associated with 93 genes exhibited significant levels of Spearman correlation between methylation and expression in all 12 cancer types, with varying magnitudes of effect in terms of actual differential expression (Figure 5B).	('methylation', 'biological_process', 'GO:0032259', ('110', '121'))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('expression', 'MPA', (126, 136))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('methylation', 'Var', (110, 121))	('cancer', 'Disease', (147, 153))
98638	25960768	Additionally, FLI1 (which had been identified in our selected differentially methylated probe sets for 8 of 14 cancer types), contained a combination of CIMP +  Hyper and CIMP +  Hypo regions, which occurred at the gene promoter and the first exon, respectively.	('FLI1', 'Gene', '2313', (14, 18))	('CIMP +  Hyper', 'Var', (153, 166))	('FLI1', 'Gene', (14, 18))	('CIMP', 'Chemical', '-', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CIMP', 'Chemical', '-', (171, 175))	('CIMP +  Hypo regions', 'Var', (171, 191))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
98642	25960768	To address commonalities, we used characterizations of TCGA data generated by Ciriello et al., which consisted of 479 selected functional events (SFEs) including 116 copy number gains, 151 copy number losses, mutation of 199 genes, and epigenetic silencing of 13 genes (requiring promoter methylation and decreased expression).	('copy number', 'Var', (166, 177))	('expression', 'MPA', (315, 325))	('losses', 'NegReg', (201, 207))	('methylation', 'biological_process', 'GO:0032259', ('289', '300'))	('SFE', 'Gene', '4311', (146, 149))	('mutation', 'Var', (209, 217))	('copy number', 'Var', (189, 200))	('SFE', 'Gene', (146, 149))	('epigenetic silencing', 'Var', (236, 256))	('gains', 'PosReg', (178, 183))
98646	25960768	Events with strong effects in more than one tumor type included MGMT and MLH1 promoter methylation, as well as mutation of ARID1A, KRAS, BRAF, and PTEN.	('ARID1A', 'Gene', (123, 129))	('KRAS', 'Gene', '3845', (131, 135))	('MGMT', 'Gene', '4255', (64, 68))	('PTEN', 'Gene', (147, 151))	('tumor', 'Disease', (44, 49))	('ARID1A', 'Gene', '8289', (123, 129))	('KRAS', 'Gene', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('PTEN', 'Gene', '5728', (147, 151))	('methylation', 'biological_process', 'GO:0032259', ('87', '98'))	('MGMT', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('promoter methylation', 'MPA', (78, 98))	('mutation', 'Var', (111, 119))	('MLH1', 'Gene', (73, 77))	('MGMT', 'molecular_function', 'GO:0003908', ('64', '68'))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('MLH1', 'Gene', '4292', (73, 77))
98647	25960768	Events that were strong but gave mixed results towards the CIMP phenotype included mutation of TP53, PIK3CA, FBXW7, and several amplification and deletion regions.	('PIK3CA', 'Gene', '5290', (101, 107))	('FBXW7', 'Gene', '55294', (109, 114))	('PIK3CA', 'Gene', (101, 107))	('FBXW7', 'Gene', (109, 114))	('mutation', 'Var', (83, 91))	('CIMP', 'Chemical', '-', (59, 63))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
98651	25960768	In contrast, mutations in six genes (BRAF, PTEN, KRAS, SETD2, PIK3R1, and PBRM1) and two gene silencing events (MLH1 and MGMT, for which the smallest FDRs were recorded) were more frequent in CIMP+ samples.	('silencing', 'NegReg', (94, 103))	('MGMT', 'Gene', '4255', (121, 125))	('MLH1', 'Gene', '4292', (112, 116))	('gene silencing', 'biological_process', 'GO:0016458', ('89', '103'))	('KRAS', 'Gene', '3845', (49, 53))	('PIK3R1', 'Gene', '5295', (62, 68))	('PTEN', 'Gene', (43, 47))	('CIMP+', 'Chemical', '-', (192, 197))	('KRAS', 'Gene', (49, 53))	('BRAF', 'Gene', '673', (37, 41))	('MGMT', 'Gene', (121, 125))	('BRAF', 'Gene', (37, 41))	('PTEN', 'Gene', '5728', (43, 47))	('MGMT', 'molecular_function', 'GO:0003908', ('121', '125'))	('mutations', 'Var', (13, 22))	('SETD2', 'Gene', (55, 60))	('frequent', 'Reg', (180, 188))	('PBRM1', 'Gene', '55193', (74, 79))	('PIK3R1', 'Gene', (62, 68))	('MLH1', 'Gene', (112, 116))	('SETD2', 'Gene', '29072', (55, 60))	('PBRM1', 'Gene', (74, 79))
98653	25960768	The remaining mutations are well known due to their involvement in the PI3K/PTEN/AKT/mTOR and the Ras/Raf/MEK/ERK pathways.	('ERK', 'Gene', (110, 113))	('AKT', 'Gene', '207', (81, 84))	('MEK', 'Gene', (106, 109))	('PTEN', 'Gene', (76, 80))	('MEK', 'Gene', '5609', (106, 109))	('PTEN', 'Gene', '5728', (76, 80))	('ERK', 'molecular_function', 'GO:0004707', ('110', '113'))	('Raf', 'Gene', (102, 105))	('Raf', 'Gene', '22882', (102, 105))	('AKT', 'Gene', (81, 84))	('mTOR', 'Gene', '2475', (85, 89))	('ERK', 'Gene', '5594', (110, 113))	('mTOR', 'Gene', (85, 89))	('mutations', 'Var', (14, 23))	('involvement', 'Reg', (52, 63))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))
98654	25960768	In particular, both BRAF and KRAS mutations have been linked to CIMP status (high and low, respectively) in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('KRAS', 'Gene', (29, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('CIMP', 'Chemical', '-', (64, 68))	('BRAF', 'Gene', '673', (20, 24))	('KRAS', 'Gene', '3845', (29, 33))	('colorectal cancer', 'Disease', (108, 125))	('BRAF', 'Gene', (20, 24))	('linked', 'Reg', (54, 60))	('mutations', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
98657	25960768	CIMP+ samples for COAD, KIRC, LUSC, and READ exhibited a larger number of mutational events per sample than CIMP- samples, implicating impairment of DNA repair processes.	('CIMP-', 'Chemical', '-', (108, 113))	('DNA repair', 'biological_process', 'GO:0006281', ('149', '159'))	('COAD', 'Disease', (18, 22))	('mutational', 'Var', (74, 84))	('DNA', 'cellular_component', 'GO:0005574', ('149', '152'))	('LUSC', 'Phenotype', 'HP:0030359', (30, 34))	('COAD', 'Disease', 'MESH:D029424', (18, 22))	('CIMP+', 'Chemical', '-', (0, 5))
98658	25960768	In contrast, copy number variation showed significant effects in CIMP- samples, where amplifications occurred more frequently in COAD and UCEC tumors, and deletions occurred more frequently in BRCA and UCEC tumors.	('UCEC tumors', 'Disease', 'MESH:D009369', (202, 213))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('amplifications', 'MPA', (86, 100))	('COAD', 'Disease', 'MESH:D029424', (129, 133))	('UCEC tumors', 'Disease', (202, 213))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('BRCA', 'Phenotype', 'HP:0003002', (193, 197))	('BRCA', 'Gene', '672', (193, 197))	('UCEC tumors', 'Disease', (138, 149))	('UCEC tumors', 'Disease', 'MESH:D009369', (138, 149))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('deletions', 'Var', (155, 164))	('BRCA', 'Gene', (193, 197))	('CIMP-', 'Chemical', '-', (65, 70))	('COAD', 'Disease', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
98659	25960768	However, these events are not always positively correlated, as shown by the reduction in deletions in COAD CIMP- samples.	('COAD', 'Disease', (102, 106))	('reduction', 'NegReg', (76, 85))	('deletions', 'Var', (89, 98))	('COAD', 'Disease', 'MESH:D029424', (102, 106))	('CIMP-', 'Chemical', '-', (107, 112))
98663	25960768	For example, MLH1 promoter methylation is observed in a subset of COAD and UCEC tumors with a very strong majority of CIMP+ labels.	('UCEC tumors', 'Disease', (75, 86))	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('MLH1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('MLH1', 'Gene', '4292', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('COAD', 'Disease', (66, 70))	('CIMP+', 'Chemical', '-', (118, 123))	('methylation', 'Var', (27, 38))	('UCEC tumors', 'Disease', 'MESH:D009369', (75, 86))	('observed', 'Reg', (42, 50))	('COAD', 'Disease', 'MESH:D029424', (66, 70))
98664	25960768	Similarly, a high proportion of CIMP+ labels was observed in samples with MGMT promoter methylation, combined with either (a) FBXW7 mutations or (b) APC and KRAS mutations or (c) absence of FBXW7 and APC mutations (Figure 7).	('APC', 'Disease', (200, 203))	('APC', 'Disease', 'MESH:D011125', (149, 152))	('APC', 'Disease', (149, 152))	('FBXW7', 'Gene', (190, 195))	('FBXW7', 'Gene', (126, 131))	('MGMT', 'Gene', (74, 78))	('CIMP+', 'Chemical', '-', (32, 37))	('FBXW7', 'Gene', '55294', (190, 195))	('KRAS', 'Gene', '3845', (157, 161))	('mutations', 'Var', (162, 171))	('FBXW7', 'Gene', '55294', (126, 131))	('mutations', 'Var', (132, 141))	('MGMT', 'molecular_function', 'GO:0003908', ('74', '78'))	('APC', 'cellular_component', 'GO:0005680', ('200', '203'))	('MGMT', 'Gene', '4255', (74, 78))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('KRAS', 'Gene', (157, 161))	('APC', 'cellular_component', 'GO:0005680', ('149', '152'))	('APC', 'Disease', 'MESH:D011125', (200, 203))
98665	25960768	Of note, subgroups containing these alterations consisted entirely of tumors of the aero-digestive tract (HNSC, LUSC, COAD, and READ).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('COAD', 'Disease', 'MESH:D029424', (118, 122))	('LUSC', 'Phenotype', 'HP:0030359', (112, 116))	('alterations', 'Var', (36, 47))	('COAD', 'Disease', (118, 122))	('tumors of the aero-digestive tract', 'Phenotype', 'HP:0007378', (70, 104))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('LUSC', 'Disease', (112, 116))
98667	25960768	In our samples lacking MGMT and MLH1 promoter methylation, the highest proportions of CIMP+ samples were observed in a subgroup dominated by KIRC tumors that were characterized by a combination of SETD2 and PBRM1 mutations.	('MLH1', 'Gene', (32, 36))	('PBRM1', 'Gene', (207, 212))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('SETD2', 'Gene', '29072', (197, 202))	('PBRM1', 'Gene', '55193', (207, 212))	('CIMP+', 'Chemical', '-', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('SETD2', 'Gene', (197, 202))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('MGMT', 'Gene', '4255', (23, 27))	('MGMT', 'Gene', (23, 27))	('MGMT', 'molecular_function', 'GO:0003908', ('23', '27'))	('tumors', 'Disease', (146, 152))	('MLH1', 'Gene', '4292', (32, 36))	('mutations', 'Var', (213, 222))
98668	25960768	We found co-occurrence of CCNE1 amplification and TP53 mutations in a subgroup derived from a mixture of BLCA, BRCA, UCEC, and LUAD tumors where all the samples were labeled as CIMP-.	('mutations', 'Var', (55, 64))	('CCNE1', 'Gene', '898', (26, 31))	('CCNE1', 'Gene', (26, 31))	('BRCA', 'Phenotype', 'HP:0003002', (111, 115))	('BRCA', 'Gene', '672', (111, 115))	('CIMP-', 'Chemical', '-', (177, 182))	('amplification', 'Var', (32, 45))	('TP53', 'Gene', '7157', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('BRCA', 'Gene', (111, 115))	('LUAD tumors', 'Disease', (127, 138))	('LUAD tumors', 'Disease', 'MESH:D009369', (127, 138))	('TP53', 'Gene', (50, 54))	('BLCA', 'Chemical', '-', (105, 109))	('LUAD', 'Phenotype', 'HP:0030078', (127, 131))
98670	25960768	Other copy number events, such as amplification of the region containing NKX2 and FOXA1 or deletion of HERC2 were observed in subgroups with a majority of CIMP+ samples and a large fraction of LUAD but also a few BRCA tumors.	('BRCA tumors', 'Disease', 'MESH:D009369', (213, 224))	('NKX2', 'Gene', (73, 77))	('FOXA1', 'Gene', (82, 87))	('deletion', 'Var', (91, 99))	('BRCA', 'Phenotype', 'HP:0003002', (213, 217))	('BRCA tumors', 'Disease', (213, 224))	('CIMP+', 'Chemical', '-', (155, 160))	('FOXA1', 'Gene', '3169', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('LUAD', 'Phenotype', 'HP:0030078', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('HERC2', 'Gene', (103, 108))	('amplification', 'Var', (34, 47))	('HERC2', 'Gene', '8924', (103, 108))	('observed', 'Reg', (114, 122))
98671	25960768	Deletion of a region containing GALR1 was observed in a subset with a majority of CIMP+ tumors that came primarily from the COAD and HNSC types.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('GALR1', 'Gene', '2587', (32, 37))	('HNSC', 'Phenotype', 'HP:0012288', (133, 137))	('COAD', 'Disease', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CIMP+', 'Chemical', '-', (82, 87))	('GALR1', 'Gene', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('COAD', 'Disease', 'MESH:D029424', (124, 128))	('Deletion', 'Var', (0, 8))
98672	25960768	Our pan-cancer regression tree shows that VHL mutations correlate with significant reductions in average levels of CGI methylation in KIRC tumors (Additional file 1: Figure S2).	('reductions', 'NegReg', (83, 93))	('cancer', 'Disease', (8, 14))	('mutations', 'Var', (46, 55))	('CGI methylation', 'MPA', (115, 130))	('VHL', 'Disease', (42, 45))	('VHL', 'Disease', 'MESH:D006623', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
98673	25960768	Similarly, amplification of two chromosomal regions in chromosome 17, including ERBB2 (a.k.a.	('ERBB2', 'Gene', '2064', (80, 85))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('amplification', 'Var', (11, 24))	('ERBB2', 'Gene', (80, 85))
98677	25960768	For example, our classification tree for BLCA highlights alterations affecting RB1 and ARID1A in CIMP+ tumors (Additional file 1: Figure S3), consistent with previous independent analyses.	('BLCA', 'Chemical', '-', (41, 45))	('RB1', 'Gene', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('RB1', 'Gene', '5925', (79, 82))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('CIMP+', 'Chemical', '-', (97, 102))	('tumors', 'Disease', (103, 109))	('alterations', 'Var', (57, 68))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('ARID1A', 'Gene', '8289', (87, 93))	('ARID1A', 'Gene', (87, 93))
98678	25960768	In BRCA, we found a strong association between CCND1 amplification and CIMP status (Additional file 1: Figures S3 and S4).	('BRCA', 'Gene', (3, 7))	('BRCA', 'Gene', '672', (3, 7))	('amplification', 'Var', (53, 66))	('CIMP', 'Chemical', '-', (71, 75))	('CCND1', 'Gene', (47, 52))	('CCND1', 'Gene', '595', (47, 52))	('CIMP status', 'Disease', (71, 82))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))
98679	25960768	Also, the presence of MYC amplifications delineated a subset of samples that consisted entirely of CIMP- tumors (Additional file 1: Figure S3).	('MYC', 'Gene', '4609', (22, 25))	('CIMP- tumors', 'Disease', 'MESH:D009369', (99, 111))	('CIMP- tumors', 'Disease', (99, 111))	('delineated', 'Reg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('MYC', 'Gene', (22, 25))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('presence', 'Var', (10, 18))	('amplifications', 'Var', (26, 40))
98680	25960768	This is consistent with reports from TCGA identifying MYC amplification and high-expression in basal-like breast tumors, which tend to be hypomethylated.	('breast tumors', 'Phenotype', 'HP:0100013', (106, 119))	('MYC', 'Gene', '4609', (54, 57))	('breast tumors', 'Disease', 'MESH:D001943', (106, 119))	('breast tumors', 'Disease', (106, 119))	('MYC', 'Gene', (54, 57))	('high-expression', 'Var', (76, 91))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
98681	25960768	In KIRC, the presence of either mutations or deletions affecting gene SETD2 and methylation of the GSTP1 promoter correlate with an important increase in the frequency of CIMP+ cases (Additional file 1: Figures S3 and S4).	('GSTP1', 'Gene', (99, 104))	('increase', 'PosReg', (142, 150))	('methylation', 'MPA', (80, 91))	('GSTP1', 'Gene', '2950', (99, 104))	('deletions', 'Var', (45, 54))	('mutations', 'Var', (32, 41))	('CIMP+ cases', 'Disease', (171, 182))	('SETD2', 'Gene', '29072', (70, 75))	('methylation', 'biological_process', 'GO:0032259', ('80', '91'))	('SETD2', 'Gene', (70, 75))	('CIMP+', 'Chemical', '-', (171, 176))
98682	25960768	Also in KIRC, we found that deletion of a genomic region containing CDKN2A and CDKN2B on chromosome 9 is associated with increased levels of CGI methylation (Additional file 1: Figure S4).	('CDKN2B', 'Gene', '1030', (79, 85))	('increased', 'PosReg', (121, 130))	('CDKN2A', 'Gene', (68, 74))	('chromosome', 'cellular_component', 'GO:0005694', ('89', '99'))	('CDKN2A', 'Gene', '1029', (68, 74))	('methylation', 'biological_process', 'GO:0032259', ('145', '156'))	('deletion', 'Var', (28, 36))	('CGI methylation', 'MPA', (141, 156))	('CDKN2B', 'Gene', (79, 85))
98683	25960768	This kind of deletion has been linked to a more aggressive phenotype of clear cell carcinoma.	('linked to', 'Reg', (31, 40))	('deletion', 'Var', (13, 21))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (72, 92))	('clear cell carcinoma', 'Disease', (72, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
98684	25960768	In LUSC, methylation of the RBP1 promoter and amplification of a region containing KDM5A correlate with an increase in average CGI methylation (Additional file 1: Figure S4).	('KDM5A', 'Gene', (83, 88))	('methylation', 'Var', (9, 20))	('RBP1', 'Gene', (28, 32))	('increase', 'PosReg', (107, 115))	('KDM5A', 'Gene', '5927', (83, 88))	('RBP1', 'Gene', '5947', (28, 32))	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('CGI methylation', 'MPA', (127, 142))	('LUSC', 'Phenotype', 'HP:0030359', (3, 7))
98685	25960768	In UCEC, our data show that methylation of the MLH1 promoter results in a very high probability of CIMP+ status.	('MLH1', 'Gene', '4292', (47, 51))	('CIMP+ status', 'Disease', (99, 111))	('MLH1', 'Gene', (47, 51))	('methylation', 'Var', (28, 39))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('CIMP+', 'Chemical', '-', (99, 104))
98686	25960768	For samples that do not exhibit this trait, the presence of TP53 mutations is associated with the opposite outcome.	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('presence', 'Var', (48, 56))	('mutations', 'Var', (65, 74))
98687	25960768	Among the remaining samples, PIK3R1 mutations are linked to increased CIMP+ rates (Additional file 1: Figure S3).	('CIMP+ rates', 'MPA', (70, 81))	('CIMP+', 'Chemical', '-', (70, 75))	('mutations', 'Var', (36, 45))	('PIK3R1', 'Gene', '5295', (29, 35))	('PIK3R1', 'Gene', (29, 35))	('increased', 'PosReg', (60, 69))
98688	25960768	Thus, the presence of tumor-specific mutations provides a potential link to predicting methylation status.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('methylation', 'biological_process', 'GO:0032259', ('87', '98'))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', (22, 27))
98694	25960768	For these three types, the median age of CIMP+ patients is higher than the median age in CIMP- (consistent with an independent study of CIMP+ status in COAD).	('COAD', 'Disease', 'MESH:D029424', (152, 156))	('CIMP+', 'Chemical', '-', (41, 46))	('patients', 'Species', '9606', (47, 55))	('CIMP+', 'Var', (41, 46))	('COAD', 'Disease', (152, 156))	('CIMP-', 'Chemical', '-', (89, 94))	('higher', 'PosReg', (59, 65))	('CIMP+', 'Chemical', '-', (136, 141))
98695	25960768	We found no statistical association between CIMP status and gender in any cancer type, except KIRC (P = 0.025, Fisher's exact test with Holm's correction), where we observed a significantly higher frequency of CIMP+ labels in male samples (45%, 58 of 128) than in female samples (22%, 15 of 66).	('CIMP+', 'Chemical', '-', (210, 215))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('CIMP+ labels', 'Var', (210, 222))	('cancer', 'Disease', (74, 80))	('CIMP', 'Chemical', '-', (44, 48))	('CIMP', 'Chemical', '-', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('higher', 'PosReg', (190, 196))
98702	25960768	These results are consistent with independent reports of MSI in CIMP-high colorectal tumors and also with the division between UCEC serous and endometrioid samples (largely CIMP- and CIMP+ in our analysis, respectively), where endometrioid tumors carry microsatellite instability and serous tumors do not.	('serous tumors', 'Disease', 'MESH:D018284', (284, 297))	('MSI', 'Disease', (57, 60))	('CIMP-', 'Chemical', '-', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('endometrioid tumors', 'Disease', (227, 246))	('serous tumors', 'Disease', (284, 297))	('microsatellite instability', 'Var', (253, 279))	('colorectal tumors', 'Disease', 'MESH:D015179', (74, 91))	('tumors', 'Phenotype', 'HP:0002664', (291, 297))	('CIMP+', 'Chemical', '-', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('colorectal tumors', 'Disease', (74, 91))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('CIMP-', 'Chemical', '-', (64, 69))	('endometrioid tumors', 'Disease', 'MESH:D016889', (227, 246))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('MSI', 'Disease', 'None', (57, 60))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
98703	25960768	Thus, the MSI characteristic appears to be associated with CIMP+ status and mutually exclusive with TP53 mutations and copy number variation.	('CIMP+', 'Chemical', '-', (59, 64))	('TP53', 'Gene', '7157', (100, 104))	('copy number variation', 'Var', (119, 140))	('MSI', 'Disease', 'None', (10, 13))	('TP53', 'Gene', (100, 104))	('MSI', 'Disease', (10, 13))	('associated', 'Reg', (43, 53))	('CIMP+ status', 'Var', (59, 71))
98706	25960768	This conclusion is consistent with trends reported by TCGA, where many luminal B samples showed a hypermethylator phenotype while basal-like samples were hypomethylated and associated with very high rates of TP53 mutations.	('mutations', 'Var', (213, 222))	('hypermethylator phenotype', 'MPA', (98, 123))	('TP53', 'Gene', '7157', (208, 212))	('TP53', 'Gene', (208, 212))
98713	25960768	This variation appears to be proportional to distance along the intestinal tract and is consistent with a previous study of colorectal cancer samples collected from three anatomic locations and assessed at eight CIMP-specific promoters using MethyLight technology, as well as independent reports of a gradual decrease in the frequency of BRAF mutations and microsatellite instability within this same region of the intestinal tract.	('BRAF', 'Gene', '673', (338, 342))	('microsatellite instability', 'MPA', (357, 383))	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('colorectal cancer', 'Disease', (124, 141))	('CIMP-', 'Chemical', '-', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('decrease', 'NegReg', (309, 317))	('mutations', 'Var', (343, 352))	('BRAF', 'Gene', (338, 342))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))
98716	25960768	Also in HNSC, CIMP- samples exhibited significantly better survival curves for recurrence free status than CIMP+ samples (Additional file 1: Figure S5B).	('CIMP- samples', 'Var', (14, 27))	('HNSC', 'Phenotype', 'HP:0012288', (8, 12))	('CIMP+', 'Chemical', '-', (107, 112))	('better', 'PosReg', (52, 58))	('HNSC', 'Disease', (8, 12))	('S5B', 'Gene', '5711', (148, 151))	('CIMP-', 'Chemical', '-', (14, 19))	('recurrence free status', 'MPA', (79, 101))	('S5B', 'Gene', (148, 151))
98720	25960768	This is consistent with our finding of recurrent CDKN2A and CDKN2B deletions in CIMP+ samples from KIRC patients mentioned earlier (Additional file 1: Figure S4), which were independently linked to a more clinically aggressive phenotype of kidney clear cell carcinoma.	('kidney clear cell carcinoma', 'Disease', (240, 267))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (240, 267))	('CDKN2A', 'Gene', '1029', (49, 55))	('deletions', 'Var', (67, 76))	('CIMP+', 'Chemical', '-', (80, 85))	('CDKN2B', 'Gene', (60, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('CDKN2B', 'Gene', '1030', (60, 66))	('linked to', 'Reg', (188, 197))	('CDKN2A', 'Gene', (49, 55))	('patients', 'Species', '9606', (104, 112))
98723	25960768	In fact, the association between CIMP status and histological subtype extends to tumor grade (an indicator of how quickly a tumor is likely to grow and spread based on microscopic appearance), where CIMP- samples exhibit higher grades than CIMP+ samples (Additional file 1: Figure S6B, P = 9.6 x 10-4, Fisher's exact test, Bonferroni correction).	('CIMP+', 'Chemical', '-', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('CIMP', 'Chemical', '-', (33, 37))	('tumor', 'Disease', (124, 129))	('CIMP-', 'Var', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CIMP-', 'Chemical', '-', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CIMP', 'Chemical', '-', (240, 244))	('CIMP', 'Chemical', '-', (199, 203))	('tumor', 'Disease', (81, 86))	('higher', 'PosReg', (221, 227))
98725	25960768	Overall, our results support the existence of both commonalities and tissue-specific differences in CGI hypermethylation patterns across tumors.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('hypermethylation', 'Var', (104, 120))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
98726	25960768	The most important similarity found in our analysis is the existence of consistent levels of average CGI hypermethylation that correlate with CIMP status and are independent of cancer type (Figure 2B,C).	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('CGI', 'Protein', (101, 104))	('hypermethylation', 'Var', (105, 121))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('CIMP', 'Chemical', '-', (142, 146))
98728	25960768	Our genome-wide analyses (Additional file 1: Figure S1) show that much of the focal, cancer-related CGI hypermethylation occurs at loci that exhibit consistently baseline levels of methylation in control samples.	('hypermethylation', 'Var', (104, 120))	('CGI', 'Disease', (100, 103))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('methylation', 'biological_process', 'GO:0032259', ('181', '192'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
98732	25960768	For example, significantly recurrent functional events in CIMP+ samples correspond to mutated genes or silencing of MLH1 and MGMT, while recurrent events in CIMP- consist primarily of chromosomal amplifications and TP53 mutations (Table 2).	('MGMT', 'molecular_function', 'GO:0003908', ('125', '129'))	('CIMP+', 'Chemical', '-', (58, 63))	('MGMT', 'Gene', (125, 129))	('mutated genes', 'Var', (86, 99))	('MLH1', 'Gene', (116, 120))	('MGMT', 'Gene', '4255', (125, 129))	('MLH1', 'Gene', '4292', (116, 120))	('TP53', 'Gene', '7157', (215, 219))	('CIMP-', 'Chemical', '-', (157, 162))	('mutations', 'Var', (220, 229))	('TP53', 'Gene', (215, 219))	('silencing', 'NegReg', (103, 112))
98737	25960768	While mutations in gene H3F3A, which encodes histone variant H3.3, have been correlated with specific DNA methylation subgroups in pediatric glioblastoma, our analysis of upstream regulators implicates involvement in most of the cancer types that we evaluated, with the exception of LUAD and BLCA (Figure 3B).	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('H3F3A', 'Gene', '3020', (24, 29))	('BLCA', 'Chemical', '-', (292, 296))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (131, 153))	('correlated', 'Reg', (77, 87))	('DNA methylation', 'biological_process', 'GO:0006306', ('102', '117'))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('H3F3A', 'Gene', (24, 29))	('involvement', 'Reg', (202, 213))	('LUAD', 'Phenotype', 'HP:0030078', (283, 287))	('LUAD', 'Disease', (283, 287))	('BLCA', 'Disease', (292, 296))	('pediatric glioblastoma', 'Disease', (131, 153))	('mutations', 'Var', (6, 15))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
98739	25960768	Loss-of-function mutations in the demethylating enzyme TET2 have been previously associated to CIMP in leukemia, and our results reveal recurrence of this mutation in CIMP+ for other types such as UCEC and READ (Figure 6A).	('Loss-of-function', 'NegReg', (0, 16))	('CIMP', 'Disease', (95, 99))	('TET2', 'Gene', (55, 59))	('UCEC', 'Disease', (197, 201))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('leukemia', 'Disease', 'MESH:D007938', (103, 111))	('CIMP', 'Chemical', '-', (167, 171))	('CIMP', 'Chemical', '-', (95, 99))	('leukemia', 'Disease', (103, 111))	('READ', 'Disease', (206, 210))	('TET2', 'Gene', '54790', (55, 59))	('CIMP+', 'Chemical', '-', (167, 172))	('mutations', 'Var', (17, 26))
98740	25960768	Also, mutations of ARID1A have been linked to MSI and CIMP in gastrointestinal cancers, and our results indicate importance in UCEC and BLCA.	('MSI', 'Disease', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('CIMP', 'Chemical', '-', (54, 58))	('BLCA', 'Disease', (136, 140))	('ARID1A', 'Gene', (19, 25))	('MSI', 'Disease', 'None', (46, 49))	('UCEC', 'Disease', (127, 131))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (62, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('linked', 'Reg', (36, 42))	('gastrointestinal cancers', 'Disease', (62, 86))	('ARID1A', 'Gene', '8289', (19, 25))	('BLCA', 'Chemical', '-', (136, 140))	('mutations', 'Var', (6, 15))
98741	25960768	BRAF mutations, which are perhaps one of the most commonly accepted indicator events for CIMP in colorectal cancers, also appear to be relevant in LUAD, but not the other tumor types.	('colorectal cancers', 'Disease', (97, 115))	('LUAD', 'Disease', (147, 151))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mutations', 'Var', (5, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('BRAF', 'Gene', '673', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colorectal cancers', 'Disease', 'MESH:D015179', (97, 115))	('CIMP', 'Chemical', '-', (89, 93))	('BRAF', 'Gene', (0, 4))	('tumor', 'Disease', (171, 176))	('LUAD', 'Phenotype', 'HP:0030078', (147, 151))
98742	25960768	For example, amplification of genes PIK3CA and CCNE1 occur significantly more frequently in CIMP- samples.	('CCNE1', 'Gene', '898', (47, 52))	('PIK3CA', 'Gene', '5290', (36, 42))	('CCNE1', 'Gene', (47, 52))	('CIMP-', 'Chemical', '-', (92, 97))	('CIMP- samples', 'Disease', (92, 105))	('amplification', 'Var', (13, 26))	('PIK3CA', 'Gene', (36, 42))
98744	25960768	Our pan-cancer regression tree revealed global CGI hypomethylation in samples with mutated NSD1, which came primarily from the HNSC data set (Additional file 1: Figure S2).	('NSD1', 'Gene', (91, 95))	('mutated', 'Var', (83, 90))	('cancer', 'Disease', (8, 14))	('hypomethylation', 'Var', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('HNSC', 'Phenotype', 'HP:0012288', (127, 131))	('NSD1', 'Gene', '64324', (91, 95))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
98746	25960768	Our results also linked mutations in KDM6A, a H3K27me3 demethylase, to decreased CpG island methylation (Additional file 1: Figure S2).	('KDM6A', 'Gene', '7403', (37, 42))	('methylation', 'biological_process', 'GO:0032259', ('92', '103'))	('KDM6A', 'Gene', (37, 42))	('CpG island methylation', 'MPA', (81, 103))	('mutations', 'Var', (24, 33))	('decreased', 'NegReg', (71, 80))
98752	25960768	Our results help to clarify this apparent contradiction by showing that poor survival could be associated with luminal B patients with CIMP+ status and that luminal B patients with CIMP- can have good survival outcomes (Figure 8B).	('CIMP+ status', 'Var', (135, 147))	('patients', 'Species', '9606', (167, 175))	('CIMP+', 'Chemical', '-', (135, 140))	('CIMP-', 'Chemical', '-', (181, 186))	('patients', 'Species', '9606', (121, 129))	('poor', 'NegReg', (72, 76))
98753	25960768	Interestingly, the situation is reversed in luminal A tumors, where CIMP+ status is associated to good survival and CIMP- status is associated with poor survival (as originally reported by Fang et al.).	('poor', 'NegReg', (148, 152))	('luminal A tumors', 'Disease', 'MESH:D009369', (44, 60))	('CIMP-', 'Chemical', '-', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('luminal A tumors', 'Disease', (44, 60))	('CIMP+', 'Chemical', '-', (68, 73))	('CIMP- status', 'Var', (116, 128))
98770	25960768	In the case of the KIRP dataset, we excluded nine tumor samples that behaved as outliers based on PCA plots computed over variably methylated probes (these tumor samples clustered together with each other, away from the rest of tumors and closer to the set of controls; the actual sample IDs were TCGA-A4-7915-01, TCGA-F9-A4JJ-01, TCGA-G7-6793-01, TCGA-GL-7966-01, TCGA-P4-A5E8-01, TCGA-P4-A5EA-01, TCGA-BQ-5879-01, TCGA-BQ-5893-01, TCGA-BQ-5894-01).	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Disease', (156, 161))	('TCGA-G7-6793-01', 'CellLine', 'CVCL:4V47', (331, 346))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('TCGA-BQ-5893-01', 'Var', (416, 431))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('TCGA-G7-6793-01', 'Var', (331, 346))	('tumors', 'Disease', (228, 234))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('TCGA-F9-A4JJ-01', 'Var', (314, 329))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('TCGA-BQ-5893-01', 'CellLine', 'CVCL:6383', (416, 431))	('TCGA-P4-A5EA-01', 'Var', (382, 397))	('TCGA-GL-7966-01', 'CellLine', 'CVCL:Y146', (348, 363))	('EA-01', 'CellLine', 'CVCL:E575', (392, 397))	('TCGA-BQ-5879-01', 'CellLine', 'CVCL:6383', (399, 414))	('TCGA-BQ-5894-01', 'CellLine', 'CVCL:6383', (433, 448))	('tumor', 'Disease', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('TCGA-F9-A4JJ-01', 'CellLine', 'CVCL:D605', (314, 329))
98789	25960768	For every cancer type, we observe differences in beta values of at least 0.1 and 0.3 when the variably methylated set and the differentially methylated set, respectively, are used to estimate average per-probe methylation in the CIMP+ and CIMP- subsets of samples.	('CIMP-', 'Chemical', '-', (239, 244))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('CIMP+', 'Chemical', '-', (229, 234))	('methylation', 'Var', (210, 221))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))	('methylation', 'biological_process', 'GO:0032259', ('210', '221'))
98813	25960768	For the comparison of the average number of mutation, amplification and deletion events per sample shown in Figure 6B, we provide a bar plot showing mean number of events of each category for each individual cancer type.	('cancer', 'Disease', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('deletion', 'Var', (72, 80))	('amplification', 'MPA', (54, 67))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
98851	27076853	CSF2 also activates at least three signaling pathways: the Janus kinase (JAK) 2/STAT pathway, the ras/mitogen-activated protein kinase (MAP kinase) pathway, and the PI3K pathway.	('PI3K', 'molecular_function', 'GO:0016303', ('165', '169'))	('JAK', 'molecular_function', 'GO:0004713', ('73', '76'))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('CSF2', 'Var', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('Janus kinase (JAK) 2', 'Gene', (59, 79))	('MAP', 'molecular_function', 'GO:0004239', ('136', '139'))	('Janus kinase (JAK) 2', 'Gene', '3717', (59, 79))	('signaling pathways', 'Pathway', (35, 53))	('PI3K pathway', 'Pathway', (165, 177))	('activates', 'PosReg', (10, 19))
98904	27076853	Detailed information as summarized in Table S1, high pSTAT5 expression was associated with increment of pT (UTUC, P=0.004; UBUC, P<0.001), nodal status (UTUC, P=0.049; UBUC, P=0.004), and the presence of vascular permeation (UTUC, P=0.035; UBUC, P=0.001).	('UBUC', 'Chemical', '-', (240, 244))	('UBUC', 'Chemical', '-', (168, 172))	('increment', 'PosReg', (91, 100))	('vascular permeation', 'CPA', (204, 223))	('nodal', 'Gene', (139, 144))	('nodal', 'Gene', '4838', (139, 144))	('pSTAT5', 'Gene', (53, 59))	('pT', 'Chemical', '-', (104, 106))	('UBUC', 'Chemical', '-', (123, 127))	('high', 'Var', (48, 52))
98905	27076853	Interestingly, high CSF2 expression significantly correlated with pSTAT5 expression in both UTUC and UBUC (each P<0.001), suggesting a link between CSF2 expression and STAT5 activation.	('high', 'Var', (15, 19))	('pSTAT5', 'Gene', (66, 72))	('UBUC', 'Chemical', '-', (101, 105))	('expression', 'MPA', (25, 35))	('correlated', 'Reg', (50, 60))	('CSF2', 'Gene', (20, 24))
98914	27076853	In Table 3, cases with UTUC expressing high CSF2 cytoplasmic immunoreactivity had significantly inferior DSS (P=0.0001, Fig.	('DSS', 'Gene', (105, 108))	('high', 'Var', (39, 43))	('CSF2', 'Gene', (44, 48))	('DSS', 'Gene', '5376', (105, 108))	('inferior', 'NegReg', (96, 104))
98920	27076853	Furthermore, CSF2 was suggested to independently correlate with worse clinical outcomes, DSS and MeFS, in both UTUC and UBUC.	('CSF2', 'Var', (13, 17))	('DSS', 'Gene', (89, 92))	('DSS', 'Gene', '5376', (89, 92))	('MeFS', 'Disease', (97, 101))	('MeFS', 'Chemical', '-', (97, 101))	('UBUC', 'Chemical', '-', (120, 124))
98924	27076853	CSF2-dependent phosphorylation of JAK2 and the subsequent recruitment of STAT5 have been suggestive of affecting cellular differentiation, and are required steps in promoting oncogenesis.	('recruitment', 'MPA', (58, 69))	('phosphorylation', 'Var', (15, 30))	('JAK2', 'Gene', '3717', (34, 38))	('oncogenesis', 'CPA', (175, 186))	('affecting', 'Reg', (103, 112))	('oncogenesis', 'biological_process', 'GO:0007048', ('175', '186'))	('JAK2', 'Gene', (34, 38))	('phosphorylation', 'biological_process', 'GO:0016310', ('15', '30'))	('promoting', 'PosReg', (165, 174))	('JAK', 'molecular_function', 'GO:0004713', ('34', '37'))	('cellular differentiation', 'CPA', (113, 137))
98925	27076853	In the present study, both high pSTAT5 and CSF2 expression correlated with higher pT and nodal status in UTUCs and UBUCs but only CSF2 overexpression served as an inferior prognostic factor in multivariate analysis.	('CSF2', 'Gene', (43, 47))	('higher', 'PosReg', (75, 81))	('pSTAT5', 'Gene', (32, 38))	('pT', 'Chemical', '-', (82, 84))	('UBUC', 'Chemical', '-', (115, 119))	('high', 'Var', (27, 31))	('nodal', 'Gene', (89, 94))	('nodal', 'Gene', '4838', (89, 94))
98926	27076853	These findings indicate that CSF2 rather than STAT predicts a poor prognosis in patients with UCs.	('CSF2', 'Var', (29, 33))	('UCs', 'Disease', (94, 97))	('patients', 'Species', '9606', (80, 88))
98927	27076853	As we know, more than 70% of papillary non-invasive UCs and 10-20% invasive UCs harbor FGFR3 mutations.	('mutations', 'Var', (93, 102))	('FGFR3', 'Gene', '2261', (87, 92))	('papillary non-invasive UCs', 'Disease', (29, 55))	('FGFR3', 'Gene', (87, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))
98946	27076853	Wang et al indicated that aberrant Ras/ERK signaling results in proliferation of monocytic/granulocytic precursors, which are sufficient to induce CSF2-dependent STAT5 hypersensitivity in murine models.	('hypersensitivity in', 'Disease', 'MESH:D004342', (168, 187))	('induce', 'Reg', (140, 146))	('monocytic/granulocytic precursors', 'CPA', (81, 114))	('aberrant', 'Var', (26, 34))	('murine', 'Species', '10090', (188, 194))	('hypersensitivity', 'biological_process', 'GO:0002524', ('168', '184'))	('proliferation', 'CPA', (64, 77))	('ERK', 'molecular_function', 'GO:0004707', ('39', '42'))	('hypersensitivity in', 'Disease', (168, 187))	('signaling', 'biological_process', 'GO:0023052', ('43', '52'))	('Ras/ERK', 'Protein', (35, 42))
98947	27076853	Furthermore, Padron et al demonstrated 90% of chronic myelomonocytic leukemias with CSF2-dependent STAT5 hypersensitivity were enhanced by signaling mutations.	('enhanced', 'PosReg', (127, 135))	('mutations', 'Var', (149, 158))	('myelomonocytic leukemias', 'Disease', (54, 78))	('myelomonocytic leukemias', 'Disease', 'MESH:D054429', (54, 78))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('hypersensitivity', 'Disease', (105, 121))	('hypersensitivity', 'Disease', 'MESH:D004342', (105, 121))	('chronic myelomonocytic leukemias', 'Phenotype', 'HP:0012325', (46, 78))	('hypersensitivity', 'biological_process', 'GO:0002524', ('105', '121'))	('leukemias', 'Phenotype', 'HP:0001909', (69, 78))
98975	26366284	Aristolochic acids (AA) are potent human renal toxicants and upper urinary tract carcinogens.	('upper urinary tract carcinogens', 'Disease', (61, 92))	('human', 'Species', '9606', (35, 40))	('renal toxicants', 'Disease', (41, 56))	('renal toxicants', 'Disease', 'MESH:D007674', (41, 56))	('Aristolochic', 'Var', (0, 12))	('Aristolochic acids', 'Chemical', 'MESH:D034341', (0, 18))	('upper urinary tract carcinogens', 'Disease', 'MESH:D014552', (61, 92))
98981	26366284	Exfoliated urinary cells serve a dual purpose by providing a non-invasive approach to screen for AL-DNA adducts and detect mutations.	('AL-DNA', 'Chemical', '-', (97, 103))	('mutations', 'Var', (123, 132))	('AL-DNA adducts', 'Protein', (97, 111))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))
99005	26366284	There is compelling evidence that dA-AL adducts are carcinogenic lesions in humans.	('carcinogenic lesions', 'Disease', 'MESH:D051437', (52, 72))	('adducts', 'Var', (40, 47))	('carcinogenic lesions', 'Disease', (52, 72))	('dA-AL', 'Chemical', '-', (34, 39))	('humans', 'Species', '9606', (76, 82))
99007	26366284	These A-to-T transversions in the TP53 gene are otherwise rare mutational events in urothelial cancer.	('A-to-T transversions', 'Var', (6, 26))	('urothelial cancer', 'Disease', 'MESH:D014523', (84, 101))	('TP53', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('urothelial cancer', 'Disease', (84, 101))	('TP53', 'Gene', '7157', (34, 38))
99008	26366284	Among the 27,000 mutations in the IARC TP53 database, A-to-T TP53 mutations are found in 5.3% of all human cancers and only 1.4% of UTUCs overall.	('found', 'Reg', (80, 85))	('A-to-T', 'Var', (54, 60))	('cancers', 'Disease', (107, 114))	('mutations', 'Var', (66, 75))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('human', 'Species', '9606', (101, 106))	('TP53', 'Gene', '7157', (39, 43))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('TP53', 'Gene', '7157', (61, 65))	('mutations', 'Var', (17, 26))	('TP53', 'Gene', (61, 65))	('TP53', 'Gene', (39, 43))
99009	26366284	AL-DNA adducts are strongly resistant to global genomic nucleotide excision repair, which accounts for the strand bias in TP53 mutations.	('TP53', 'Gene', (122, 126))	('global genomic nucleotide excision repair', 'biological_process', 'GO:0070911', ('41', '82'))	('mutations', 'Var', (127, 136))	('TP53', 'Gene', '7157', (122, 126))	('DNA', 'cellular_component', 'GO:0005574', ('3', '6'))	('AL-DNA', 'Chemical', '-', (0, 6))
99012	26366284	Very recent studies, involving genome-wide sequencing of DNA in tumors of UTUCs from individuals with known exposure to AA, revealed an unusually large number of somatic mutations harboring this uncommon A-to-T transversion attributable to AA.	('tumors', 'Disease', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (170, 179))	('A-to-T', 'Var', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))
99013	26366284	Another recent study also reported a high frequency of A-to-T mutations, but also G-to-T transversions as a complementary signature mutation in TP53 of a group of non-smoking women from Belgium who ingested large amounts AA over a short period of time.	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (144, 148))	('A-to-T mutations', 'Var', (55, 71))	('women', 'Species', '9606', (175, 180))	('G-to-T transversions', 'Var', (82, 102))
99083	26366284	Aristolochic acid represents a highly relevant environmental toxicant model for translational studies of chemical carcinogenesis.	('carcinogenesis', 'Disease', (114, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (114, 128))	('Aristolochic', 'Var', (0, 12))	('Aristolochic acid', 'Chemical', 'MESH:C000228', (0, 17))
99090	26366284	Recent genome-wide sequence studies of tumors reveal the mutational signature associated with AA to be present in renal cell carcinomas from Romania and Croatia as well as hepatocellular carcinomas and intrahepatic cholangiocarcinomas from China.	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (172, 197))	('hepatocellular carcinomas', 'Disease', (172, 197))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (224, 234))	('mutational', 'Var', (57, 67))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (114, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('renal cell carcinomas', 'Disease', (114, 135))	('intrahepatic cholangiocarcinomas', 'Disease', (202, 234))	('Romania and Croatia', 'Disease', 'None', (141, 160))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (114, 135))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (172, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (202, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
99094	26366284	The ability to retrieve AL-DNA adducts quantitatively from FFPE tissue blocks represents an important technical breakthrough that allows identification of AL-DNA adducts at the time of early exposure, which is often 20-30 years prior to the development of the resulting urothelial cancer.	('urothelial cancer', 'Disease', (270, 287))	('AL-DNA', 'Chemical', '-', (155, 161))	('DNA', 'cellular_component', 'GO:0005574', ('158', '161'))	('urothelial cancer', 'Disease', 'MESH:D014523', (270, 287))	('AL-DNA', 'Var', (155, 161))	('AL-DNA', 'Chemical', '-', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))
99169	23599723	There are several important reasons for recognizing the micropapillary variant of urothelial carcinoma in exfoliative urinary specimens.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (82, 102))	('men', 'Species', '9606', (131, 134))	('micropapillary', 'Var', (56, 70))	('urothelial carcinoma', 'Disease', (82, 102))
99184	23599723	While no effect of ThinPrep  on the urothelial cluster formation and presence of urothelial cytoplasmic vacuoles has been reported, it is possible that ThinPrep  may at least partially disrupt epithelial cluster formation as it does in fine needle aspiration biopsy specimens of breast fibroadenoma.	('men', 'Species', '9606', (271, 274))	('aspiration', 'Phenotype', 'HP:0002835', (248, 258))	('disrupt', 'NegReg', (185, 192))	('ThinPrep', 'Var', (152, 160))	('breast fibroadenoma', 'Phenotype', 'HP:0010619', (279, 298))	('formation', 'biological_process', 'GO:0009058', ('212', '221'))	('breast fibroadenoma', 'Disease', (279, 298))	('formation', 'biological_process', 'GO:0009058', ('55', '64'))	('breast fibroadenoma', 'Disease', 'OMIM:615554', (279, 298))	('epithelial cluster formation', 'CPA', (193, 221))
99203	23599723	UroVysion  (Abbott Molecular, Des Plaines, IL, USA) is a multi-target multicolor fluorescent in situ hybridization assay that uses probes directed against pericentric regions of chromosomes known to be aneuploid in urothelial carcinoma, as well as to the 9p21 locus of the p16 tumor suppressor gene, which may also be overexpressed in urothelial carcinoma.	('aneuploid', 'Var', (202, 211))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (335, 355))	('p16', 'Gene', (273, 276))	('urothelial carcinoma', 'Disease', (215, 235))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor suppressor', 'biological_process', 'GO:0051726', ('277', '293'))	('urothelial carcinoma', 'Disease', (335, 355))	('carcinoma', 'Phenotype', 'HP:0030731', (346, 355))	('p16', 'Gene', '1029', (273, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('277', '293'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (215, 235))	('tumor', 'Disease', (277, 282))
99277	33805295	Furthermore, CRBP1 was demonstrated to be downregulated in BC through the CpG hypermethylation of the promoter region.	('CRBP1', 'Gene', (13, 18))	('downregulated', 'NegReg', (42, 55))	('rat', 'Species', '10116', (30, 33))	('CpG hypermethylation', 'Var', (74, 94))	('hypermethylation', 'Var', (78, 94))	('CRBP1', 'Gene', '5947', (13, 18))	('BC', 'Phenotype', 'HP:0009725', (59, 61))
99293	33805295	A meta-analysis of 25 studies investigating the quantitative effects of vitamin A on BC revealed that high vitamin A intake and high blood retinol levels were associated with a reduced risk of BC.	('high vitamin A', 'Phenotype', 'HP:0004905', (102, 116))	('vitamin A', 'Chemical', '-', (72, 81))	('retinol', 'Chemical', 'MESH:D014801', (139, 146))	('high', 'Var', (102, 106))	('vitamin A', 'Chemical', '-', (107, 116))	('BC', 'Phenotype', 'HP:0009725', (193, 195))	('reduced', 'NegReg', (177, 184))	('BC', 'Phenotype', 'HP:0009725', (85, 87))
99320	33805295	Synthetic retinoids (4-HPR and CD437-also known as Ro 472077) have been shown to have stronger effects on growth inhibition and apoptosis than naturally occurring retinoids, e.g., ATRA.	('Ro 472077', 'Chemical', '-', (51, 60))	('HPR', 'Gene', '3250', (23, 26))	('retinoids', 'Chemical', 'MESH:D012176', (10, 19))	('CD437-also', 'Var', (31, 41))	('apoptosis', 'biological_process', 'GO:0097194', ('128', '137'))	('growth inhibition', 'CPA', (106, 123))	('apoptosis', 'biological_process', 'GO:0006915', ('128', '137'))	('retinoids', 'Chemical', 'MESH:D012176', (163, 172))	('HPR', 'Gene', (23, 26))	('apoptosis', 'CPA', (128, 137))	('ATRA', 'Chemical', 'MESH:D014212', (180, 184))
99346	33805295	Therefore, inhibition of Oct4 could be a therapeutic strategy to overcome drug resistance and reduce the recurrence rate.	('recurrence rate', 'CPA', (105, 120))	('drug resistance', 'biological_process', 'GO:0009315', ('74', '89'))	('Oct4', 'Gene', (25, 29))	('drug resistance', 'biological_process', 'GO:0042493', ('74', '89'))	('Oct4', 'Gene', '5460', (25, 29))	('inhibition', 'Var', (11, 21))	('rat', 'Species', '10116', (116, 119))	('reduce', 'NegReg', (94, 100))	('rat', 'Species', '10116', (55, 58))	('drug resistance', 'Phenotype', 'HP:0020174', (74, 89))
99357	33805295	For example, conjugation of RA to nanoparticles such as RA-poly(ethylene glycol)-thiol gold nanoparticle conjugates showed superior activity against the cervical carcinoma cell line compared to free RA, which is attributed to increased rates of drug transport through nanoparticle uptake compared to passive diffusion of free drug.	('uptake', 'biological_process', 'GO:0098739', ('281', '287'))	('uptake', 'biological_process', 'GO:0098657', ('281', '287'))	('RA', 'Chemical', 'MESH:D014212', (199, 201))	('conjugation', 'Var', (13, 24))	('cervical carcinoma', 'Disease', 'MESH:D002583', (153, 171))	('activity', 'MPA', (132, 140))	('rat', 'Species', '10116', (236, 239))	('RA', 'Chemical', 'MESH:D014212', (56, 58))	('thiol gold', 'Chemical', '-', (81, 91))	('conjugation', 'biological_process', 'GO:0000746', ('13', '24'))	('RA', 'Chemical', 'MESH:D014212', (28, 30))	('drug transport', 'biological_process', 'GO:0015893', ('245', '259'))	('RA-poly(ethylene glycol)', 'Chemical', '-', (56, 80))	('increased', 'PosReg', (226, 235))	('cervical carcinoma', 'Disease', (153, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
99365	33805295	Finally, nanoencapsulation may enhance the effect of dietary vitamin A supplementation.	('enhance', 'PosReg', (31, 38))	('vitamin A', 'Chemical', '-', (61, 70))	('nanoencapsulation', 'Var', (9, 26))	('men', 'Species', '9606', (77, 80))
99371	33805295	Preclinical in vitro experiments showed that increased expression of RORC suppressed cell proliferation and glucose metabolism and induced apoptosis in BC cells.	('rat', 'Species', '10116', (97, 100))	('cell proliferation', 'CPA', (85, 103))	('induced', 'Reg', (131, 138))	('BC', 'Phenotype', 'HP:0009725', (152, 154))	('suppressed', 'NegReg', (74, 84))	('increased', 'PosReg', (45, 54))	('cell proliferation', 'biological_process', 'GO:0008283', ('85', '103'))	('apoptosis', 'biological_process', 'GO:0097194', ('139', '148'))	('apoptosis', 'biological_process', 'GO:0006915', ('139', '148'))	('expression', 'Var', (55, 65))	('glucose metabolism', 'biological_process', 'GO:0006006', ('108', '126'))	('RORC', 'Gene', (69, 73))	('glucose metabolism', 'Disease', 'MESH:D044882', (108, 126))	('men', 'Species', '9606', (27, 30))	('RORC', 'Gene', '6097', (69, 73))	('glucose metabolism', 'Disease', (108, 126))
99377	33805295	Inhibition of ALDH1A1 by ALDH inhibitors and silenced ALDH1A1 expression by shRNA lentiviral transfer suppressed proliferation and spheroid formation of cancer cells from long-term BC patients.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('ALDH1A1', 'Gene', '216', (54, 61))	('ALDH', 'molecular_function', 'GO:0004030', ('14', '18'))	('ALDH1A1', 'Gene', (14, 21))	('formation', 'biological_process', 'GO:0009058', ('140', '149'))	('cancer', 'Disease', (153, 159))	('silenced', 'Var', (45, 53))	('Inhibition', 'NegReg', (0, 10))	('patients', 'Species', '9606', (184, 192))	('ALDH', 'molecular_function', 'GO:0004030', ('25', '29'))	('suppressed', 'NegReg', (102, 112))	('ALDH1A1', 'Gene', '216', (14, 21))	('ALDH1A1', 'Gene', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('ALDH', 'molecular_function', 'GO:0004030', ('54', '58'))	('rat', 'Species', '10116', (120, 123))	('BC', 'Phenotype', 'HP:0009725', (181, 183))
99378	33805295	In addition, knockdown of TUBB3 also suppressed proliferation of these cells.	('rat', 'Species', '10116', (55, 58))	('proliferation of these cells', 'CPA', (48, 76))	('TUBB3', 'Gene', (26, 31))	('TUBB3', 'Gene', '10381', (26, 31))	('knockdown', 'Var', (13, 22))	('suppressed', 'NegReg', (37, 47))
99381	33805295	The study showed that inhibition of miR-29b suppressed cell proliferation, growth, migration, invasion, and tumour growth via RARbeta.	('inhibition', 'Var', (22, 32))	('invasion', 'CPA', (94, 102))	('suppressed', 'NegReg', (44, 54))	('tumour growth via RARbeta', 'Disease', 'MESH:D006130', (108, 133))	('rat', 'Species', '10116', (67, 70))	('miR-29b', 'Gene', (36, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('55', '73'))	('tumour growth via RARbeta', 'Disease', (108, 133))	('miR-29b', 'Gene', '407024', (36, 43))	('cell proliferation', 'CPA', (55, 73))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('growth', 'CPA', (75, 81))	('rat', 'Species', '10116', (86, 89))	('migration', 'CPA', (83, 92))
99383	33805295	Silencing of ING4 reversed the RARbeta-mediated suppression of cell migration and invasion.	('rat', 'Species', '10116', (71, 74))	('suppression', 'NegReg', (48, 59))	('cell migration', 'CPA', (63, 77))	('RARbeta', 'Gene', (31, 38))	('RARbeta', 'Gene', '5914', (31, 38))	('ING4', 'Gene', (13, 17))	('cell migration', 'biological_process', 'GO:0016477', ('63', '77'))	('ING4', 'Gene', '51147', (13, 17))	('Silencing', 'Var', (0, 9))
99393	33805295	The authors acknowledge financial support from the P3-0108, P3-0054, J7-2594, J3 2521, MRIC UL IP-0510 Infrastructure program of the Slovenian Research Agency ARRS.	('J7-2594', 'CellLine', 'CVCL:1V19', (69, 76))	('J3 2521', 'Var', (78, 85))	('P3-0054', 'Var', (60, 67))	('J7-2594', 'Var', (69, 76))
99446	31613226	Therefore, the dysfunction of Hippo/YAP1 pathway could imbalance the regulation, which could cause the cancer initiation.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('regulation', 'biological_process', 'GO:0065007', ('69', '79'))	('imbalance', 'NegReg', (55, 64))	('imbalance', 'Phenotype', 'HP:0002172', (55, 64))	('cause', 'Reg', (93, 98))	('YAP1', 'Gene', (36, 40))	('YAP1', 'Gene', '10413', (36, 40))	('dysfunction', 'Var', (15, 26))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('regulation', 'MPA', (69, 79))
99456	31613226	The results showed YAP1 expression was observed to be significantly related with worse OS, but not with DFS.	('related', 'Reg', (68, 75))	('expression', 'Var', (24, 34))	('YAP1', 'Gene', '10413', (19, 23))	('YAP1', 'Gene', (19, 23))	('worse OS', 'Disease', (81, 89))
99497	31528172	In case of invasive urothelial carcinoma, the FGFR3 positivity was observed in 18.2% of tumors (P<0.05).	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('invasive urothelial carcinoma', 'Disease', (11, 40))	('observed', 'Reg', (67, 75))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('positivity', 'Var', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('FGFR3', 'Gene', (46, 51))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (11, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
99509	31528172	Binding of the fibroblast growth factor receptor (FGFR) to the mutated FGFR3 tyrosine kinase receptor leads to the activation of downstream pathways including RAS- MAPK, PI3K and STAT6.	('PI3K', 'Pathway', (170, 174))	('mutated', 'Var', (63, 70))	('FGFR3', 'Gene', (71, 76))	('activation', 'PosReg', (115, 125))	('downstream pathways', 'Pathway', (129, 148))	('RAS- MAPK', 'Pathway', (159, 168))	('STAT6', 'Gene', '6778', (179, 184))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('FGFR', 'molecular_function', 'GO:0005007', ('50', '54'))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('15', '39'))	('STAT6', 'Gene', (179, 184))	('Binding', 'Interaction', (0, 7))	('MAPK', 'molecular_function', 'GO:0004707', ('164', '168'))	('PI3K', 'molecular_function', 'GO:0016303', ('170', '174'))
99510	31528172	FGFR3 mutations have been described in spermatocytic seminoma, multiple myeloma and cervical cancer.	('spermatocytic seminoma', 'Disease', 'MESH:C563236', (39, 61))	('multiple myeloma', 'Disease', 'MESH:D009101', (63, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('cervical cancer', 'Disease', 'MESH:D002583', (84, 99))	('multiple myeloma', 'Phenotype', 'HP:0006775', (63, 79))	('cervical cancer', 'Disease', (84, 99))	('FGFR3', 'Gene', (0, 5))	('multiple myeloma', 'Disease', (63, 79))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('spermatocytic seminoma', 'Disease', (39, 61))	('spermatocytic seminoma', 'Phenotype', 'HP:0100617', (39, 61))	('described', 'Reg', (26, 35))	('mutations', 'Var', (6, 15))
99511	31528172	Some cases of multiple myeloma are seen to express both mutation and over-expression of FGFR3.	('FGFR3', 'Gene', (88, 93))	('multiple myeloma', 'Phenotype', 'HP:0006775', (14, 30))	('multiple myeloma', 'Disease', 'MESH:D009101', (14, 30))	('multiple myeloma', 'Disease', (14, 30))	('over-expression', 'PosReg', (69, 84))	('mutation', 'Var', (56, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('88', '92'))
99512	31528172	Mutations of FGFR3 are found in around 80% of pTa tumors.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('pTa', 'molecular_function', 'GO:0008959', ('46', '49'))	('found', 'Reg', (23, 28))	('pTa tumors', 'Disease', (46, 56))	('FGFR3', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('pTa tumors', 'Disease', 'MESH:D009369', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
99513	31528172	FGFR3 mutations are present in 21% of pT1 and 16% of pT2-4 tumors.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('present', 'Reg', (20, 27))	('FGFR3', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('pT1', 'Gene', (38, 41))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('pT1', 'Gene', '58492', (38, 41))	('mutations', 'Var', (6, 15))
99521	31528172	Inclusion criteria  Microscopically proven cases of urothelial carcinomas including low grade non-invasive, high grade non-invasive, low grade invasive and high grade invasive.	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('invasive', 'Disease', (167, 175))	('urothelial carcinomas', 'Disease', (52, 73))	('high', 'Disease', (108, 112))	('high', 'Disease', (156, 160))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (52, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('low grade', 'Var', (133, 142))
99550	31528172	One case of LG non-invasive urothelial carcinoma had nuclear positivity for FGFR3.	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (19, 48))	('nuclear positivity', 'Var', (53, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('FGFR3', 'Gene', (76, 81))	('invasive urothelial carcinoma', 'Disease', (19, 48))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))
99552	31528172	In case of invasive urothelial carcinoma FGFR3 positivity was observed in 18.2% (4/22) of tumors, while 18 or 81.8% were negative.	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('invasive urothelial carcinoma', 'Disease', (11, 40))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('FGFR3', 'Gene', (41, 46))	('positivity', 'Var', (47, 57))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (11, 40))	('observed', 'Reg', (62, 70))
99595	31528172	Mutation studies done on two groups of the same have reported an association between mutations and a higher recurrence rate (Mhawech-Fauceglia P et al, Van Oers et al) , whereas others are contrary (van Rhijn BW et al, Hernandez S et al).	('van', 'Disease', (199, 202))	('higher', 'PosReg', (101, 107))	('recurrence rate', 'MPA', (108, 123))	('van', 'Disease', 'MESH:C536530', (199, 202))	('Mhawech-Fauceglia P', 'Disease', (125, 144))	('mutations', 'Var', (85, 94))	('Mhawech-Fauceglia P', 'Disease', 'MESH:C000656865', (125, 144))
99606	31528172	In the study done by Rotterud et al., in 2007, they concluded that nuclear positivity of FGFR3 led to the tumor genesis.	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('FGFR3', 'Gene', (89, 94))	('nuclear positivity', 'Var', (67, 85))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('led to', 'Reg', (95, 101))	('tumor', 'Disease', (106, 111))
99607	31528172	In a Korean study done in 2010, nuclear FGFR3 positivity was reported in 32.7% of the tumors but it failed to show prognostic power .	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('FGFR3', 'Gene', (40, 45))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('positivity', 'Var', (46, 56))	('nuclear FGFR3', 'Gene', (32, 45))
99610	30127891	The knockdown of the Mediator complex subunit MED15 restrains urothelial bladder cancer cells' malignancy The Mediator complex, a multi-subunit protein complex, plays an integral role in regulating transcription.	('restrains', 'NegReg', (52, 61))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (62, 87))	('Mediator complex', 'cellular_component', 'GO:0016592', ('21', '37'))	('MED15', 'Gene', '51586', (46, 51))	('MED15', 'Gene', (46, 51))	('protein complex', 'cellular_component', 'GO:0032991', ('144', '159'))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('Mediator complex', 'cellular_component', 'GO:0016592', ('110', '126'))	('transcription', 'biological_process', 'GO:0006351', ('198', '211'))	('urothelial bladder cancer', 'Disease', (62, 87))	('malignancy', 'Disease', 'MESH:D009369', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('knockdown', 'Var', (4, 13))	('malignancy', 'Disease', (95, 105))
99611	30127891	Genetic alterations of the mediator subunit 15 (MED15) in separate tumor entities have been described previously.	('Genetic alterations', 'Var', (0, 19))	('MED15', 'Gene', '51586', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('mediator subunit 15', 'Gene', (27, 46))	('mediator subunit 15', 'Gene', '51586', (27, 46))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('MED15', 'Gene', (48, 53))
99615	30127891	After the MED15 knockdown by small interfering (si)RNA, cell proliferation, migration and invasion were investigated.	('MED15', 'Gene', (10, 15))	('MED15', 'Gene', '51586', (10, 15))	('knockdown', 'Var', (16, 25))	('RNA', 'cellular_component', 'GO:0005562', ('51', '54'))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))
99619	30127891	In the functional analysis, proliferation, migration, and invasion were significantly reduced in BCa-cells following the transient siRNA-mediated MED15 knockdown.	('knockdown', 'Var', (152, 161))	('reduced', 'NegReg', (86, 93))	('MED15', 'Gene', (146, 151))	('proliferation', 'CPA', (28, 41))	('BCa', 'Phenotype', 'HP:0009725', (97, 100))	('MED15', 'Gene', '51586', (146, 151))	('invasion', 'CPA', (58, 66))	('migration', 'CPA', (43, 52))
99627	30127891	The mutational landscape of urothelial carcinoma, including specific mutations in pathways and driver genes, such as FGFR3, ERBB2, PIK3CA, TP53 (p53), and RB1, affects tumor aggressiveness and response to therapy.	('p53', 'Gene', (145, 148))	('FGFR3', 'Gene', (117, 122))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (28, 48))	('PIK3CA', 'Gene', (131, 137))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (168, 188))	('RB1', 'Gene', (155, 158))	('FGFR3', 'Gene', '2261', (117, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('FGFR', 'molecular_function', 'GO:0005007', ('117', '121'))	('TP53', 'Gene', (139, 143))	('mutations', 'Var', (69, 78))	('RB1', 'Gene', '5925', (155, 158))	('aggressiveness', 'Phenotype', 'HP:0000718', (174, 188))	('PIK3CA', 'Gene', '5290', (131, 137))	('urothelial carcinoma', 'Disease', (28, 48))	('ERBB2', 'Gene', (124, 129))	('affects', 'Reg', (160, 167))	('p53', 'Gene', '7157', (145, 148))	('tumor aggressiveness', 'Disease', (168, 188))	('TP53', 'Gene', '7157', (139, 143))	('ERBB2', 'Gene', '2064', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
99634	30127891	Additionally, the knockdown of MED19 leads to a reduced growth of the carcinoma cell lines.	('knockdown', 'Var', (18, 27))	('carcinoma', 'Disease', 'MESH:D002277', (70, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('MED19', 'Gene', '219541', (31, 36))	('reduced', 'NegReg', (48, 55))	('carcinoma', 'Disease', (70, 79))	('MED19', 'Gene', (31, 36))
99670	30127891	In both analyses, named 'Bladder Urothelial Carcinoma (TCGA, Provisional)' and 'Bladder Urothelial Carcinoma (TCGA, Nature 2014)', an alteration of MED15 is described in 2.9% (12/408) and 2.3% (3/129), respectively.	("'Bladder Urothelial Carcinoma", 'Disease', (79, 108))	("'Bladder Urothelial Carcinoma", 'Disease', (24, 53))	('alteration', 'Var', (134, 144))	('Carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('MED15', 'Gene', '51586', (148, 153))	('MED15', 'Gene', (148, 153))	('Carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	("'Bladder Urothelial Carcinoma", 'Disease', 'MESH:D001749', (79, 108))	("'Bladder Urothelial Carcinoma", 'Disease', 'MESH:D001749', (24, 53))
99681	30127891	To investigate the functional role of the subunit MED15 in malignant progression and metastasis, we performed in vitro siRNA-mediated knockdown of MED15 in the BCa cell lines T24 (P<=0.001) and TCCSUP (P<=0.001; Fig.	('MED15', 'Gene', '51586', (147, 152))	('MED15', 'Gene', (147, 152))	('BCa', 'Phenotype', 'HP:0009725', (160, 163))	('knockdown', 'Var', (134, 143))	('MED15', 'Gene', (50, 55))	('MED15', 'Gene', '51586', (50, 55))
99683	30127891	Further, migration and invasion were significantly reduced in T24 (migration P=0.003, invasion P<=0.001) and TCCSUP (migration P<=0.001, invasion P<=0.001) cells following the transient MED15 knockdown, compared to scrambled control cells (Fig.	('invasion', 'CPA', (23, 31))	('reduced', 'NegReg', (51, 58))	('migration', 'CPA', (9, 18))	('MED15', 'Gene', '51586', (186, 191))	('MED15', 'Gene', (186, 191))	('knockdown', 'Var', (192, 201))
99684	30127891	In conclusion, MED15 knockdown led to reduced malignant behaviour in the BCa cell lines T24 and TCCSUP.	('BCa', 'Phenotype', 'HP:0009725', (73, 76))	('reduced', 'NegReg', (38, 45))	('MED15', 'Gene', '51586', (15, 20))	('MED15', 'Gene', (15, 20))	('malignant behaviour in the BCa cell lines T24', 'CPA', (46, 91))	('behaviour', 'biological_process', 'GO:0007610', ('56', '65'))	('knockdown', 'Var', (21, 30))
99690	30127891	In our investigation, we found out that the knockdown of MED15 in BCa cell lines leads to a downregulation of the tumor parameters of proliferation, migration, and invasion in the functional analysis.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('BCa', 'Phenotype', 'HP:0009725', (66, 69))	('downregulation', 'NegReg', (92, 106))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('migration', 'CPA', (149, 158))	('tumor', 'Disease', (114, 119))	('MED15', 'Gene', (57, 62))	('invasion', 'CPA', (164, 172))	('knockdown', 'Var', (44, 53))	('MED15', 'Gene', '51586', (57, 62))
99696	30127891	In osteosarcoma, the knockdown of MED1 reduced the proliferation, whereas in non-small lung cancer the loss of MED1 led to an increase of invasion and metastases.	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('MED1', 'Gene', '5469', (34, 38))	('increase', 'PosReg', (126, 134))	('knockdown', 'Var', (21, 30))	('MED1', 'Gene', (111, 115))	('MED1', 'Gene', '5469', (111, 115))	('osteosarcoma', 'Disease', (3, 15))	('metastases', 'Disease', 'MESH:D009362', (151, 161))	('small lung', 'Phenotype', 'HP:0002089', (81, 91))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('reduced', 'NegReg', (39, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('non-small lung cancer', 'Disease', (77, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('metastases', 'Disease', (151, 161))	('loss', 'NegReg', (103, 107))	('proliferation', 'CPA', (51, 64))	('MED1', 'Gene', (34, 38))	('non-small lung cancer', 'Disease', 'MESH:D002289', (77, 98))
99705	30127891	We concluded that the knockdown of the Mediator complex subunit MED15 restrains urothelial BCa cells' malignancy.	('urothelial BCa', 'Disease', 'MESH:D014522', (80, 94))	('restrains', 'NegReg', (70, 79))	('MED15', 'Gene', '51586', (64, 69))	('malignancy', 'Disease', (102, 112))	('urothelial BCa', 'Disease', (80, 94))	('knockdown', 'Var', (22, 31))	('BCa', 'Phenotype', 'HP:0009725', (91, 94))	('Mediator complex', 'cellular_component', 'GO:0016592', ('39', '55'))	('malignancy', 'Disease', 'MESH:D009369', (102, 112))	('MED15', 'Gene', (64, 69))
99776	29642177	Companied P16 genetic and protein status together providing useful information on the clinical outcome of urinary bladder cancer SPEC P16/CEN3/7/17 Probe fluorescence-in-situ-hybridization (FISH) has become the most sensitive method in indentifying the urothelial tumors and loss of P16 has often been identified in low-grade urothelial lesions; however, little is known about the significations of other P16 genetic status (normal and amplification) in bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (114, 128))	('urothelial tumors', 'Disease', (253, 270))	('P16', 'Gene', (10, 13))	('urinary bladder cancer', 'Disease', (106, 128))	('P16', 'Gene', '1029', (405, 408))	('cancer', 'Phenotype', 'HP:0002664', (462, 468))	('bladder cancer', 'Phenotype', 'HP:0009725', (114, 128))	('bladder cancer', 'Disease', 'MESH:D001749', (454, 468))	('bladder cancer', 'Disease', (454, 468))	('loss', 'Var', (275, 279))	('P16', 'Gene', (405, 408))	('P16', 'Gene', '1029', (134, 137))	('bladder cancer', 'Phenotype', 'HP:0009725', (454, 468))	('SPEC', 'molecular_function', 'GO:0004586', ('129', '133'))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (106, 128))	('urothelial tumors', 'Disease', 'MESH:D001749', (253, 270))	('P16', 'Gene', (134, 137))	('P16', 'Gene', '1029', (283, 286))	('P16', 'Gene', (283, 286))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('P16', 'Gene', '1029', (10, 13))
99777	29642177	We detected P16 gene status by FISH in 259 urine samples and divided these samples into 3 groups: 1, normal P16; 2, loss of P16; and 3, amplified P16.	('P16', 'Gene', '1029', (12, 15))	('P16', 'Gene', (108, 111))	('P16', 'Gene', (146, 149))	('P16', 'Gene', (124, 127))	('amplified', 'Var', (136, 145))	('loss', 'NegReg', (116, 120))	('P16', 'Gene', '1029', (108, 111))	('P16', 'Gene', (12, 15))	('P16', 'Gene', '1029', (146, 149))	('P16', 'Gene', '1029', (124, 127))
99780	29642177	P16 genetic status was significantly associated with tumor grade and primary tumor status (P = .008 and .017), but not with pathological tumor stage, overall survival, and p16 protein expression.	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('P16', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('p16', 'Gene', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('P16', 'Gene', '1029', (0, 3))	('associated', 'Reg', (37, 47))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('genetic status', 'Var', (4, 18))	('p16', 'Gene', '1029', (172, 175))
99782	29642177	Studies show that the genetic status of P16 has a close relation with the stages of bladder cancer.	('P16', 'Gene', (40, 43))	('bladder cancer', 'Phenotype', 'HP:0009725', (84, 98))	('bladder cancer', 'Disease', 'MESH:D001749', (84, 98))	('bladder cancer', 'Disease', (84, 98))	('P16', 'Gene', '1029', (40, 43))	('genetic status', 'Var', (22, 36))	('relation', 'Reg', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
99783	29642177	Loss of P16 is associated with low-grade urothelial malignancy while amplified P16 donotes high-grade.	('P16', 'Gene', '1029', (8, 11))	('urothelial malignancy', 'Disease', 'MESH:D009369', (41, 62))	('amplified', 'Var', (69, 78))	('P16', 'Gene', (79, 82))	('associated', 'Reg', (15, 25))	('P16', 'Gene', (8, 11))	('P16', 'Gene', '1029', (79, 82))	('Loss', 'Var', (0, 4))	('urothelial malignancy', 'Disease', (41, 62))
99835	29642177	As shown in Table 1, p16 gene expression was observed in 26.2% (68/259) of cases, normal P16 gene in 32.4% (84/259) of the cases, and amplification of P16 gene in 42.7% (107/259) of all the samples.	('P16', 'Gene', (89, 92))	('P16', 'Gene', (151, 154))	('gene expression', 'biological_process', 'GO:0010467', ('25', '40'))	('p16', 'Gene', (21, 24))	('P16', 'Gene', '1029', (89, 92))	('P16', 'Gene', '1029', (151, 154))	('amplification', 'Var', (134, 147))	('observed', 'Reg', (45, 53))	('p16', 'Gene', '1029', (21, 24))
99837	29642177	The results indicated different P16 genetic status according to different stages of histology, deletion of P16 indicates low grade, amplified P16 indicates high-grade, whereas normal P16 fits between them.	('P16', 'Gene', '1029', (32, 35))	('deletion', 'Var', (95, 103))	('P16', 'Gene', '1029', (142, 145))	('fits', 'Disease', 'MESH:D012640', (187, 191))	('P16', 'Gene', (142, 145))	('P16', 'Gene', (107, 110))	('P16', 'Gene', (183, 186))	('amplified', 'MPA', (132, 141))	('P16', 'Gene', (32, 35))	('fits', 'Disease', (187, 191))	('P16', 'Gene', '1029', (107, 110))	('P16', 'Gene', '1029', (183, 186))
99847	29642177	P16 gene amplification accompanied p16INK4a overexpression group predicts a bad prognosis (P = .023), and loss of P16 accompanied loss of p16INK4a expression group has the tendency (P = .067) to predict a bad prognosis of urinary bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (230, 244))	('p16INK4a', 'Gene', '1029', (138, 146))	('P16', 'Gene', (0, 3))	('urinary bladder cancer', 'Disease', (222, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('P16', 'Gene', (114, 117))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (222, 244))	('P16', 'Gene', '1029', (0, 3))	('p16INK4a', 'Gene', (138, 146))	('p16INK4a', 'Gene', (35, 43))	('loss', 'NegReg', (130, 134))	('P16', 'Gene', '1029', (114, 117))	('loss', 'Var', (106, 110))	('p16INK4a', 'Gene', '1029', (35, 43))
99848	29642177	Aberrant p16 gene expression is known to affect carcinogenesis and progression of urothelial carcinoma, as demonstrated in this study.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('progression', 'CPA', (67, 78))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (82, 102))	('Aberrant', 'Var', (0, 8))	('gene expression', 'biological_process', 'GO:0010467', ('13', '28'))	('carcinogenesis', 'Disease', 'MESH:D063646', (48, 62))	('p16', 'Gene', '1029', (9, 12))	('urothelial carcinoma', 'Disease', (82, 102))	('carcinogenesis', 'Disease', (48, 62))	('affect', 'Reg', (41, 47))	('p16', 'Gene', (9, 12))
99862	29642177	Our data on p16 normal and amplified expression in urothelial carcinoma of the urine specimen have not been reported previously.	('amplified', 'Var', (27, 36))	('p16', 'Gene', '1029', (12, 15))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (51, 71))	('expression', 'MPA', (37, 47))	('p16', 'Gene', (12, 15))	('urothelial carcinoma', 'Disease', (51, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
99867	29642177	Second, increased p16INK4a expression by immunocytochemistry may be related to polyploidy of chromosome 9 or amplification of the 9p21 locus, which directly augments p16 gene expression at the protein level.	('gene expression', 'biological_process', 'GO:0010467', ('170', '185'))	('p16', 'Gene', '1029', (18, 21))	('p16INK4a', 'Gene', '1029', (18, 26))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('polyploidy', 'Disease', 'MESH:D011123', (79, 89))	('p16', 'Gene', '1029', (166, 169))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('expression', 'MPA', (27, 37))	('amplification', 'Var', (109, 122))	('9p21', 'Gene', (130, 134))	('increased', 'PosReg', (8, 17))	('p16', 'Gene', (18, 21))	('p16INK4a', 'Gene', (18, 26))	('augments', 'PosReg', (157, 165))	('p16', 'Gene', (166, 169))	('polyploidy', 'Disease', (79, 89))
99868	29642177	Finally, p16 gene dysfunction on self-regulation, such as abnormally high levels of cell proliferation, may cause a very long half-life of p16INK4a protein accumulated in cells, leading to strong immunoreactivity, but not the FISH detected p16 gene amplification.	('p16', 'Gene', '1029', (240, 243))	('half-life', 'MPA', (126, 135))	('p16INK4a', 'Gene', (139, 147))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('cell proliferation', 'biological_process', 'GO:0008283', ('84', '102'))	('gene dysfunction', 'Var', (13, 29))	('dysfunction', 'Var', (18, 29))	('p16', 'Gene', '1029', (139, 142))	('p16INK4a', 'Gene', '1029', (139, 147))	('p16', 'Gene', '1029', (9, 12))	('regulation', 'biological_process', 'GO:0065007', ('38', '48'))	('p16', 'Gene', (240, 243))	('immunoreactivity', 'MPA', (196, 212))	('cause', 'Reg', (108, 113))	('p16', 'Gene', (139, 142))	('p16', 'Gene', (9, 12))
99893	32560530	RNAi (RNA interference)-mediated depletion of ANLN causes furrow instability in D. melanogaster S2 cells.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('depletion', 'Var', (33, 42))	('furrow instability', 'CPA', (58, 76))	('D. melanogaster', 'Species', '7227', (80, 95))	('ANLN', 'Gene', (46, 50))	('furrow', 'cellular_component', 'GO:0097610', ('58', '64'))	('causes', 'Reg', (51, 57))	('RNA interference', 'biological_process', 'GO:0016246', ('6', '22'))	('RNAi', 'biological_process', 'GO:0016246', ('0', '4'))
99894	32560530	The loss of ANLN also promotes membrane blebbing and, in cases where a relatively stable furrow forms, a loss of stability of the midbody structure that forms after furrowing in D. melanogaster.	('midbody', 'cellular_component', 'GO:0030496', ('130', '137'))	('promotes', 'PosReg', (22, 30))	('D. melanogaster', 'Species', '7227', (178, 193))	('loss', 'NegReg', (105, 109))	('stability', 'CPA', (113, 122))	('membrane', 'cellular_component', 'GO:0016020', ('31', '39'))	('furrow', 'cellular_component', 'GO:0097610', ('89', '95'))	('ANLN', 'Gene', (12, 16))	('membrane blebbing', 'CPA', (31, 48))	('membrane blebbing', 'biological_process', 'GO:0032060', ('31', '48'))	('loss', 'Var', (4, 8))
99906	32560530	ANLN was characterized as a molecule that is specifically associated with F-actin.	('F-actin', 'cellular_component', 'GO:0031941', ('74', '81'))	('F-actin', 'Gene', (74, 81))	('F-actin', 'Gene', '40444', (74, 81))	('ANLN', 'Var', (0, 4))
99908	32560530	ANLN was also described as a binding site for F-actin and amino acids 246-371 bundle actin filaments.	('binding', 'molecular_function', 'GO:0005488', ('29', '36'))	('amino acids 246-371', 'Var', (58, 77))	('F-actin', 'cellular_component', 'GO:0031941', ('46', '53'))	('binding', 'Interaction', (29, 36))	('F-actin', 'Gene', '40444', (46, 53))	('F-actin', 'Gene', (46, 53))
99915	32560530	Taken together, this suggests that ANLN could have a direct or indirect impact on actin activities both outside and inside cytokinesis events, which could be related to cancer progression.	('cancer', 'Disease', (169, 175))	('actin activities', 'MPA', (82, 98))	('ANLN', 'Var', (35, 39))	('cytokinesis', 'biological_process', 'GO:0000910', ('123', '134'))	('related', 'Reg', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('impact', 'Reg', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
99917	32560530	ANLN may indirectly impact myosin through F-actin.	('myosin', 'MPA', (27, 33))	('F-actin', 'Gene', '40444', (42, 49))	('impact', 'Reg', (20, 26))	('F-actin', 'Gene', (42, 49))	('F-actin', 'cellular_component', 'GO:0031941', ('42', '49'))	('ANLN', 'Var', (0, 4))
99928	32560530	ANLN truncation occurs in human cells without the AH domain, which was considered as a factor mediating the interaction of septins, and showed the mislocalization of the poles in the span of oscillation like the event witnessed as a lack of myosin.	('human', 'Species', '9606', (26, 31))	('ANLN truncation', 'Var', (0, 15))	('mislocalization of the poles', 'MPA', (147, 175))
99938	32560530	The half of the ANLN N-terminal of ANLN was observed not to interact with any RacGAP constructs.	('RacGAP', 'Gene', '36538', (78, 84))	('ANLN', 'Var', (35, 39))	('RacGAP', 'Gene', (78, 84))
99939	32560530	Specific RacGAP deletions to abolish Pebble or MKLP1 binding was documented without any effect on the interaction with ANLN.	('deletions', 'Var', (16, 25))	('binding', 'molecular_function', 'GO:0005488', ('53', '60'))	('MKLP1', 'Gene', (47, 52))	('RacGAP', 'Gene', (9, 15))	('Pebble', 'Gene', (37, 43))	('RacGAP', 'Gene', '36538', (9, 15))	('Pebble', 'Gene', '38879', (37, 43))	('abolish', 'NegReg', (29, 36))	('binding', 'Interaction', (53, 60))
99940	32560530	The absence of ANLN leads to a loss of connection between the spindle-associated RacGAP and the equatorial cortex and to cytokinesis failure.	('cytokinesis', 'biological_process', 'GO:0000910', ('121', '132'))	('loss', 'NegReg', (31, 35))	('spindle', 'cellular_component', 'GO:0005819', ('62', '69'))	('RacGAP', 'Gene', (81, 87))	('cytokinesis failure', 'Disease', (121, 140))	('cytokinesis failure', 'Disease', 'MESH:D006333', (121, 140))	('absence', 'Var', (4, 11))	('ANLN', 'Gene', (15, 19))	('RacGAP', 'Gene', '36538', (81, 87))	('connection', 'Interaction', (39, 49))
99942	32560530	This was also underpinned by the evidence of phosphomimetic-mutant S635D, the negative charge of D at the 635 residues which partially recovered the localization.	('S635D', 'Var', (67, 72))	('negative charge', 'MPA', (78, 93))	('S635D', 'Mutation', 'p.S635D', (67, 72))	('localization', 'MPA', (149, 161))	('localization', 'biological_process', 'GO:0051179', ('149', '161'))
99943	32560530	S635 phosphorylation helps ANLN improve the efficacy of the Rho integration with its upstream and downstream regulators, which contributes to the success of cytokinesis.	('Rho', 'Protein', (60, 63))	('reg', 'Gene', (109, 112))	('efficacy', 'MPA', (44, 52))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('cytokinesis', 'biological_process', 'GO:0000910', ('157', '168'))	('phosphorylation', 'Var', (5, 20))	('S635 phosphorylation', 'Var', (0, 20))	('improve', 'PosReg', (32, 39))	('reg', 'Gene', '5967', (109, 112))
99963	32560530	The observations have suggested that ANLN acts as the intrinsic connection between PI3K/PTEN and KDR signaling, which represents two critical transitions in carcinogenesis.	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('KDR', 'Gene', (97, 100))	('PTEN', 'Gene', (88, 92))	('ANLN', 'Var', (37, 41))	('PTEN', 'Gene', '5728', (88, 92))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('KDR', 'Gene', '3791', (97, 100))
99964	32560530	The interaction between ANLN and KDR could act as ANLN and KDR jointly as a prognostic in cancer survival, which could be applied to control triple negative breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('KDR', 'Gene', (59, 62))	('interaction', 'Interaction', (4, 15))	('KDR', 'Gene', '3791', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ANLN', 'Var', (50, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('KDR', 'Gene', (33, 36))	('KDR', 'Gene', '3791', (59, 62))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
99973	32560530	TAF10 inactivation in liver tissue was observed to dissociate TFIID complexes individually, but genes affected by TAF10 inactivation were less than 5% of the active genes.	('TFIID', 'Gene', '6908', (62, 67))	('inactivation', 'Var', (120, 132))	('TFIID', 'Gene', (62, 67))
99975	32560530	Loss of function mutations decrease the repair of DNA double-strand breaks and thereby increases the mutation frequency and the risk of cancer.	('mutation', 'CPA', (101, 109))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('increases', 'PosReg', (87, 96))	('decrease', 'NegReg', (27, 35))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('Loss of function', 'NegReg', (0, 16))	('cancer', 'Disease', (136, 142))	('repair', 'MPA', (40, 46))	('mutations', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
99977	32560530	The BRCA1 mutation is found in breast cancer in young women, which is a triple negative breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('BRCA1', 'Gene', (4, 9))	('women', 'Species', '9606', (54, 59))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('mutation', 'Var', (10, 18))	('breast cancer', 'Disease', (31, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('BRCA1', 'Gene', '672', (4, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
99979	32560530	Therefore, there is a possibility that ANLN modulates DNA repair by interacting with BRCA1 in the nucleus.	('DNA repair', 'MPA', (54, 64))	('modulates', 'Reg', (44, 53))	('DNA repair', 'biological_process', 'GO:0006281', ('54', '64'))	('BRCA1', 'Gene', (85, 90))	('interacting', 'Interaction', (68, 79))	('ANLN', 'Var', (39, 43))	('nucleus', 'cellular_component', 'GO:0005634', ('98', '105'))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('BRCA1', 'Gene', '672', (85, 90))
99985	32560530	Onset of cytokinesis (metaphase): When nuclear envelopes are broken down, ANLN moves from the nuclei to peripheral stress fibers in mammalian cells, at which ANLN might mediate these fibers' disassembly and increase the round cortex of Drosophila cells.	('broken down', 'Phenotype', 'HP:0001061', (61, 72))	('Drosophila', 'Species', '7227', (236, 246))	('increase', 'PosReg', (207, 215))	('mammalian', 'Species', '9606', (132, 141))	('metaphase', 'biological_process', 'GO:0051323', ('22', '31'))	('cytokinesis', 'biological_process', 'GO:0000910', ('9', '20'))	('ANLN', 'Var', (158, 162))	('round cortex of Drosophila cells', 'CPA', (220, 252))
99987	32560530	ANLN depletion leads to a mislocalization of F-actin, like myosin, out of the equator in Drosophila spermatocytes, which could lead to a failure in cytokinesis.	('depletion', 'Var', (5, 14))	('mislocalization', 'MPA', (26, 41))	('F-actin', 'cellular_component', 'GO:0031941', ('45', '52'))	('ANLN depletion', 'Var', (0, 14))	('Drosophila', 'Species', '7227', (89, 99))	('cytokinesis', 'biological_process', 'GO:0000910', ('148', '159'))	('cytokinesis', 'MPA', (148, 159))	('lead to', 'Reg', (127, 134))	('F-actin', 'Gene', (45, 52))	('failure', 'NegReg', (137, 144))	('F-actin', 'Gene', '40444', (45, 52))
99988	32560530	In C. elegans, ANLN (ANI-1) is associated with an asymmetry of the division plane, which plays an important role in the perturbations of contractility during cytokinesis.	('ANI-1', 'Gene', (21, 26))	('cytokinesis', 'biological_process', 'GO:0000910', ('158', '169'))	('C. elegans', 'Species', '6239', (3, 13))	('ANI-1', 'Gene', '176672', (21, 26))	('ANLN', 'Var', (15, 19))	('asymmetry of the division plane', 'CPA', (50, 81))	('associated', 'Reg', (31, 41))
99989	32560530	Metazoan ANLN coordinates contractile ring assembly and organization by crosslinking with myosin septins and F-actin in the actin-myosin ring.	('F-actin', 'Gene', '40444', (109, 116))	('F-actin', 'Gene', (109, 116))	('actin-myosin ring', 'Phenotype', 'HP:0025200', (124, 141))	('contractile ring assembly', 'biological_process', 'GO:0000915', ('26', '51'))	('F-actin', 'cellular_component', 'GO:0031941', ('109', '116'))	('crosslinking', 'Var', (72, 84))	('myosin septins', 'Protein', (90, 104))	('contractile ring', 'cellular_component', 'GO:0070938', ('26', '42'))
99990	32560530	Although actin-myosin contractility still happens in both human and Drosophila cultured cells that have been depleted of ANLN, the depletion of ANLN leads to the lateral oscillation of cleavage furrow, or its failure cannot accurately maintain at the division plane.	('lateral oscillation', 'CPA', (162, 181))	('human', 'Species', '9606', (58, 63))	('ANLN', 'Gene', (144, 148))	('Drosophila', 'Species', '7227', (68, 78))	('cleavage furrow', 'cellular_component', 'GO:0032154', ('185', '200'))	('depletion', 'Var', (131, 140))	('leads to', 'Reg', (149, 157))	('cleavage furrow', 'CPA', (185, 200))
99991	32560530	The knockdown of ANLN in human cells and Drosophila ANLN mutants caused slow and abortive furrowing as well as slow ingression.	('slow ingression', 'CPA', (111, 126))	('human', 'Species', '9606', (25, 30))	('ANLN', 'Gene', (52, 56))	('Drosophila', 'Species', '7227', (41, 51))	('mutants', 'Var', (57, 64))
100013	32560530	Evidence has shown an association between poor tumour prognosis and highly expressed ANLN in the nucleus.	('highly', 'Var', (68, 74))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('nucleus', 'cellular_component', 'GO:0005634', ('97', '104'))	('tumour', 'Disease', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
100027	32560530	For example, mutations in the ANLN gene cause kidney disease and focal segmental glomerulosclerosis, which indicate a defect in podosomal matrix adhesions.	('kidney disease', 'Phenotype', 'HP:0000112', (46, 60))	('ANLN', 'Gene', (30, 34))	('cause', 'Reg', (40, 45))	('focal segmental glomerulosclerosis', 'Disease', 'MESH:D005923', (65, 99))	('focal segmental glomerulosclerosis', 'Phenotype', 'HP:0000097', (65, 99))	('kidney disease', 'Disease', (46, 60))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (81, 99))	('mutations', 'Var', (13, 22))	('focal segmental glomerulosclerosis', 'Disease', (65, 99))	('kidney disease', 'Disease', 'MESH:D007674', (46, 60))
100029	32560530	ANLN knockdown results in abnormal adherens junctions and tight junctions in Xenopus embryos.	('adherens', 'MPA', (35, 43))	('ANLN', 'Gene', (0, 4))	('results in', 'Reg', (15, 25))	('knockdown', 'Var', (5, 14))	('tight junctions', 'CPA', (58, 73))	('Xenopus', 'Species', '8355', (77, 84))
100034	32560530	Indeed, the overexpression of ANLN in the colon cancer cell lines SW480 and HT29 actually increased cell migration and invasion, which seems to be partly related to a decrease in the expression of E-cadherin.	('cell migration', 'biological_process', 'GO:0016477', ('100', '114'))	('E-cadherin', 'Gene', (197, 207))	('cell migration', 'CPA', (100, 114))	('E-cadherin', 'Gene', '37386', (197, 207))	('colon cancer', 'Phenotype', 'HP:0003003', (42, 54))	('overexpression', 'PosReg', (12, 26))	('HT29', 'CellLine', 'CVCL:0320', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cadherin', 'molecular_function', 'GO:0008014', ('199', '207'))	('colon cancer', 'Disease', 'MESH:D015179', (42, 54))	('expression', 'MPA', (183, 193))	('ANLN', 'Var', (30, 34))	('invasion', 'CPA', (119, 127))	('increased', 'PosReg', (90, 99))	('SW480', 'CellLine', 'CVCL:0546', (66, 71))	('colon cancer', 'Disease', (42, 54))	('decrease', 'NegReg', (167, 175))	('expression', 'Species', '29278', (183, 193))	('expression', 'Species', '29278', (16, 26))
100043	32560530	Hence, we highlight the hallmarks of cancer that are impacted by ANLN (Figure 5) and discuss them as follows.	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('ANLN', 'Var', (65, 69))
100044	32560530	There is evidence showing that ANLN plays a critical role in driving cell proliferation, and the absence of ANLN could hinder cancer cells from division.	('hinder', 'NegReg', (119, 125))	('absence', 'Var', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('ANLN', 'Gene', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cell proliferation', 'CPA', (69, 87))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))
100046	32560530	The analysis with flow cytometry indicated that ANLN knockdown in MDA-MB-231 cells inhibited the cell cycle progression, with an increasing amount of cells stuck at the G2/M phase because of phosphorylation of Cdc2 and an inhibition of Cyclin D1.	('Cyclin', 'molecular_function', 'GO:0016538', ('236', '242'))	('M phase', 'biological_process', 'GO:0000279', ('172', '179'))	('phosphorylation', 'biological_process', 'GO:0016310', ('191', '206'))	('increasing', 'PosReg', (129, 139))	('inhibition', 'NegReg', (222, 232))	('Cdc2', 'Gene', (210, 214))	('cell cycle progression', 'CPA', (97, 119))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (66, 76))	('Cyclin D1', 'Gene', '595', (236, 245))	('cell cycle', 'biological_process', 'GO:0007049', ('97', '107'))	('inhibited', 'NegReg', (83, 92))	('Cyclin D1', 'Gene', (236, 245))	('ANLN knockdown', 'Var', (48, 62))	('Cdc2', 'Gene', '983', (210, 214))	('phosphorylation', 'MPA', (191, 206))
100049	32560530	ANLN deletion led to an increase in polyploidy cells along with the activation of apoptosis and DNA damage.	('increase', 'PosReg', (24, 32))	('activation of apoptosis', 'biological_process', 'GO:0006915', ('68', '91'))	('apoptosis', 'CPA', (82, 91))	('DNA damage', 'CPA', (96, 106))	('activation', 'PosReg', (68, 78))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('activation of apoptosis', 'biological_process', 'GO:0043065', ('68', '91'))	('polyploidy', 'Disease', (36, 46))	('ANLN deletion', 'Var', (0, 13))	('polyploidy', 'Disease', 'MESH:D011123', (36, 46))
100050	32560530	In pancreatic cancer, ANLN deficiency led to the expression of miR218-5p while mir-218 caused the apoptosis of pancreatic cancer cells.	('pancreatic cancer', 'Disease', (3, 20))	('apoptosis', 'CPA', (98, 107))	('expression', 'Species', '29278', (49, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (111, 128))	('expression', 'MPA', (49, 59))	('mir-218', 'Var', (79, 86))	('caused', 'Reg', (87, 93))	('pancreatic cancer', 'Disease', (111, 128))	('miR218-5p', 'Var', (63, 72))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (111, 128))	('ANLN deficiency', 'Disease', (22, 37))	('ANLN deficiency', 'Disease', 'MESH:D007153', (22, 37))
100051	32560530	ANLN was known to be involved in PI3K/PTEN signaling.	('PTEN', 'Gene', '5728', (38, 42))	('PTEN', 'Gene', (38, 42))	('signaling', 'biological_process', 'GO:0023052', ('43', '52'))	('ANLN', 'Var', (0, 4))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))
100060	32560530	In addition, the incidence of metastasis in patients with a high ANLN expression was substantially higher than that in patients with low expression.	('patients', 'Species', '9606', (44, 52))	('ANLN', 'Protein', (65, 69))	('higher', 'PosReg', (99, 105))	('high', 'Var', (60, 64))	('patients', 'Species', '9606', (119, 127))	('expression', 'Species', '29278', (70, 80))	('metastasis', 'CPA', (30, 40))	('expression', 'Species', '29278', (137, 147))
100076	32560530	The deficiency of ANLN in U2OS cells progressively induced an increase in the number and intensity of 53BP1 foci in G1 nuclei, a phenomenon that could act as a marker for an increased number of DNA damage events.	('53BP1', 'Gene', (102, 107))	('DNA', 'cellular_component', 'GO:0005574', ('194', '197'))	('ANLN', 'Gene', (18, 22))	('deficiency', 'Var', (4, 14))	('U2OS', 'CellLine', 'CVCL:0042', (26, 30))	('increase', 'PosReg', (62, 70))
100077	32560530	ANLN interacts with BRCA1, so aberrant ANLN expression might affect genome instability and mutation.	('BRCA1', 'Gene', (20, 25))	('aberrant', 'Var', (30, 38))	('mutation', 'CPA', (91, 99))	('genome instability', 'CPA', (68, 86))	('affect', 'Reg', (61, 67))	('expression', 'Species', '29278', (44, 54))	('BRCA1', 'Gene', '672', (20, 25))	('ANLN', 'Gene', (39, 43))
100079	32560530	ANLN knockdown was documented to induce polyploid hepatocytes, which induce an upregulation of the genes controlling lipid metabolism and a downregulation of the genes controlling mitochondrial oxidation.	('genes', 'MPA', (99, 104))	('ANLN', 'Gene', (0, 4))	('lipid metabolism', 'biological_process', 'GO:0006629', ('117', '133'))	('knockdown', 'Var', (5, 14))	('reg', 'Gene', (144, 147))	('reg', 'Gene', '5967', (144, 147))	('lipid', 'Chemical', 'MESH:D008055', (117, 122))	('mitochondrial oxidation', 'MPA', (180, 203))	('lipid metabolism', 'MPA', (117, 133))	('reg', 'Gene', (81, 84))	('reg', 'Gene', '5967', (81, 84))	('induce', 'Reg', (33, 39))
100094	32560530	In a study on Dalmatian dogs, the loss of ANLN caused a familial fatal acute respiratory distress syndrome, which is a disease where inflammatory mediators such as IL-8, IL-6 are suggested as the potential culprits.	('acute respiratory distress syndrome', 'Phenotype', 'HP:0011948', (71, 106))	('loss', 'Var', (34, 38))	('IL-8', 'molecular_function', 'GO:0005153', ('164', '168'))	('familial fatal acute respiratory distress syndrome', 'Disease', (56, 106))	('ANLN', 'Gene', (42, 46))	('dogs', 'Species', '9615', (24, 28))	('IL-6', 'Gene', '403985', (170, 174))	('IL-8', 'Gene', (164, 168))	('familial fatal acute respiratory distress syndrome', 'Disease', 'MESH:D012128', (56, 106))	('respiratory distress', 'Phenotype', 'HP:0002098', (77, 97))	('caused', 'Reg', (47, 53))	('IL-8', 'Gene', '403850', (164, 168))	('IL-6', 'molecular_function', 'GO:0005138', ('170', '174'))	('IL-6', 'Gene', (170, 174))
100105	32560530	Another study also suggests a critical role in the immune response through a synergy between ANLN and KDR, which have prognostic value in breast cancer survival.	('synergy', 'Var', (77, 84))	('KDR', 'Gene', '3791', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('ANLN', 'Gene', (93, 97))	('immune response', 'biological_process', 'GO:0006955', ('51', '66'))	('breast cancer', 'Disease', (138, 151))	('KDR', 'Gene', (102, 105))
100110	32560530	ANLN facilitates septin assembly to prevent pathological outfoldings of central nervous system myelin.	('central nervous system myelin', 'Disease', 'MESH:D020278', (72, 101))	('central nervous system myelin', 'Disease', (72, 101))	('septin', 'Protein', (17, 23))	('facilitates', 'PosReg', (5, 16))	('ANLN', 'Var', (0, 4))
100128	32560530	In other research, there is evidence showing that ANLN is also related to metastasis in lung adenocarcinoma (A549, PC9).	('ANLN', 'Var', (50, 54))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('PC9', 'Gene', '255738', (115, 118))	('metastasis', 'CPA', (74, 84))	('lung adenocarcinoma', 'Disease', (88, 107))	('PC9', 'Gene', (115, 118))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('related', 'Reg', (63, 70))
100131	32560530	The Cancer Genome Atlas data analysis revealed 27 mutations in 446 patients with lung adenocarcinoma, with five mutations affecting the conserved amino acids of ANLN.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('patients', 'Species', '9606', (67, 75))	('mutations', 'Var', (50, 59))	('lung adenocarcinoma', 'Disease', (81, 100))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
100135	32560530	Based on the analysis of colorectal cancer tissues, ANLN is supposed to be associated with colorectal cancer development and with a poor prognosis.	('associated with', 'Reg', (75, 90))	('ANLN', 'Var', (52, 56))	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (25, 42))	('colorectal cancer', 'Disease', (25, 42))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (25, 42))
100137	32560530	An integrated bioinformatics analysis showed that ANLN could play a role as a key candidate in cervical cancer.	('ANLN', 'Var', (50, 54))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
100143	32560530	However, some studies have shown that both total ANLN and p-ANLN expression decreased by LY294002 (Sigma-Aldrich; 20 mumol/L for 16 h), a specific inhibitor of the catalytic subunit of PI3K, which is directed at the ATP-binding site of the kinase.	('ANLN', 'MPA', (49, 53))	('LY294002', 'Var', (89, 97))	('PI3K', 'molecular_function', 'GO:0016303', ('185', '189'))	('ATP-binding', 'molecular_function', 'GO:0005524', ('216', '227'))	('p-ANLN expression', 'MPA', (58, 75))	('expression', 'Species', '29278', (65, 75))	('decreased', 'NegReg', (76, 85))	('LY294002', 'Chemical', 'MESH:C085911', (89, 97))	('ATP', 'Chemical', 'MESH:D000255', (216, 219))
100152	32560530	The mechanism of the cytotoxicity of 5-FU has been depicted to cause the misincorporation of fluoronucleotides in RNA and DNA, and the suppression of the nucleotide synthetic enzyme thymidylate synthase.	('5-FU', 'Chemical', 'MESH:D005472', (37, 41))	('misincorporation of fluoronucleotides', 'MPA', (73, 110))	('cytotoxicity', 'Disease', (21, 33))	('thymidylate synthase', 'Gene', (182, 202))	('RNA', 'cellular_component', 'GO:0005562', ('114', '117'))	('suppression', 'NegReg', (135, 146))	('thymidylate synthase', 'Gene', '7298', (182, 202))	('5-FU', 'Var', (37, 41))	('cytotoxicity', 'Disease', 'MESH:D064420', (21, 33))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))	('fluoronucleotides', 'Chemical', '-', (93, 110))
100159	32560530	In support of this idea, there has been a recent report that ANLN knockdown lowers the incidence of liver cancer but does not affect liver regeneration.	('reg', 'Gene', (139, 142))	('ANLN knockdown', 'Var', (61, 75))	('liver cancer', 'Phenotype', 'HP:0002896', (100, 112))	('liver cancer', 'Disease', 'MESH:D006528', (100, 112))	('lowers', 'NegReg', (76, 82))	('liver regeneration', 'biological_process', 'GO:0097421', ('133', '151'))	('liver cancer', 'Disease', (100, 112))	('knockdown', 'Var', (66, 75))	('reg', 'Gene', '5967', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
100222	28766915	In stage comparison, MIBC appears to preferentially enhance cyclooxygenase (COX) and lipoxygenase (LOX) signaling, increase heme catabolism, and alter nicotinamide adenine dinucleotide (NAD+) synthesis with a possible influence from associated inflammatory cells.	('lipoxygenase', 'MPA', (85, 97))	('NAD+) synthesis', 'biological_process', 'GO:0009435', ('186', '201'))	('MIBC', 'Var', (21, 25))	('cyclooxygenase', 'MPA', (60, 74))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('heme catabolism', 'biological_process', 'GO:0042167', ('124', '139'))	('MIBC', 'Chemical', '-', (21, 25))	('increase heme catabolism', 'Disease', (115, 139))	('increase heme catabolism', 'Disease', 'MESH:D046351', (115, 139))	('enhance', 'PosReg', (52, 59))	('nicotinamide adenine dinucleotide', 'Chemical', 'MESH:D009243', (151, 184))	('NAD+', 'Chemical', 'MESH:D009243', (186, 190))	('alter', 'Reg', (145, 150))
100292	28766915	The hemoglobin catabolite bilirubin was significantly higher in MIBC (P = 0.0001 for bilirubin (Z,Z) and P = 0.0069 for bilirubin (E,E)), suggesting enhanced heme catabolism in higher stage tumors.	('bilirubin', 'Chemical', 'MESH:D001663', (85, 94))	('MIBC', 'Chemical', '-', (64, 68))	('bilirubin', 'Chemical', 'MESH:D001663', (120, 129))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('higher', 'PosReg', (54, 60))	('heme', 'Chemical', 'MESH:D006418', (158, 162))	('hemoglobin catabolite bilirubin', 'MPA', (4, 35))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('heme catabolism', 'biological_process', 'GO:0042167', ('158', '173'))	('heme catabolism', 'MPA', (158, 173))	('enhanced', 'PosReg', (149, 157))	('tumors', 'Disease', (190, 196))	('bilirubin', 'Chemical', 'MESH:D001663', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('MIBC', 'Var', (64, 68))
100353	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))
100371	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))
100392	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))
100405	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'))
100406	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'))
100420	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))
100424	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))
100436	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))
100470	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))
100495	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'))
100502	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))
100514	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))
100516	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))
100548	25862322	Elevating the Horizon: Emerging Molecular and Genomic Targets in the Treatment of Advanced Urothelial Carcinoma Despite recent advances in the identification of genomic alterations that lead to urothelial oncogenesis in vitro, advanced urothelial carcinomas continue to have poor clinical outcomes.	('lead to', 'Reg', (186, 193))	('urothelial carcinomas', 'Disease', (236, 257))	('alterations', 'Var', (169, 180))	('Carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('Advanced Urothelial Carcinoma', 'Disease', (82, 111))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (236, 257))	('oncogenesis', 'biological_process', 'GO:0007048', ('205', '216'))	('Advanced Urothelial Carcinoma', 'Disease', 'MESH:D020178', (82, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('carcinomas', 'Phenotype', 'HP:0030731', (247, 257))
100577	25862322	The data collected identified several currently targetable genomic changes that are also supported by other research groups as important pathways in urothelial oncogenesis, i.e., the PI3K/AKT/mTOR pathway and RTK/RAS pathways, including HER2, ERBB3, and FGFR3 (Table 1).	('FGFR3', 'Gene', '2261', (254, 259))	('HER2', 'Gene', '2064', (237, 241))	('changes', 'Var', (67, 74))	('ERBB3', 'Gene', '2065', (243, 248))	('RTK/RAS pathways', 'Pathway', (209, 225))	('PI3K', 'molecular_function', 'GO:0016303', ('183', '187'))	('FGFR3', 'Gene', (254, 259))	('ERBB3', 'Gene', (243, 248))	('urothelial oncogenesis', 'Disease', (149, 171))	('FGFR', 'molecular_function', 'GO:0005007', ('254', '258'))	('oncogenesis', 'biological_process', 'GO:0007048', ('160', '171'))	('AKT', 'Gene', '207', (188, 191))	('mTOR', 'Gene', (192, 196))	('mTOR', 'Gene', '2475', (192, 196))	('HER2', 'Gene', (237, 241))	('AKT', 'Gene', (188, 191))
100581	25862322	Cisplatin, the backbone of combination chemotherapy for urothelial carcinoma, acts by forming inter- and intra-strand crosslinks in DNA, resulting in DNA damage and consequent cell death.	('urothelial carcinoma', 'Disease', (56, 76))	('cell death', 'biological_process', 'GO:0008219', ('176', '186'))	('crosslinks', 'Var', (118, 128))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('DNA damage', 'MPA', (150, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (56, 76))	('cell death', 'CPA', (176, 186))	('DNA', 'cellular_component', 'GO:0005574', ('150', '153'))
100584	25862322	For example, somatic mutations of ERCC2, a gene involved in the nucleotide excision repair pathway, have been shown to correlate with cisplatin sensitivity, while activating missense mutations of ERBB2 are significantly more prevalent in tumor tissue from complete responders to neoadjuvant chemotherapy.	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('missense mutations', 'Var', (174, 192))	('ERCC2', 'Gene', (34, 39))	('cisplatin sensitivity', 'MPA', (134, 155))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('64', '90'))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('correlate', 'Reg', (119, 128))	('ERBB2', 'Gene', '2064', (196, 201))	('tumor', 'Disease', (238, 243))	('activating', 'PosReg', (163, 173))	('ERBB2', 'Gene', (196, 201))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('ERCC2', 'Gene', '2068', (34, 39))	('mutations', 'Var', (21, 30))
100601	25862322	Currently, only a few phase II trials are investigating the activity of novel cytotoxic agents (eribulin, amrubicin, cabazitaxel, and tesetaxel) in urothelial carcinoma that has relapsed after platinum-based therapy (NCT00365157, NCT01331824, NCT01437488, and NCT01215877, respectively).	('NCT01331824', 'Var', (230, 241))	('urothelial carcinoma', 'Disease', (148, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('cabazitaxel', 'Chemical', 'MESH:C552428', (117, 128))	('NCT01215877', 'Var', (260, 271))	('NCT00365157', 'Var', (217, 228))	('platinum', 'Chemical', 'MESH:D010984', (193, 201))	('NCT01437488', 'Var', (243, 254))	('eribulin', 'Chemical', 'MESH:C490954', (96, 104))	('amrubicin', 'Chemical', 'MESH:C055866', (106, 115))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (148, 168))	('tesetaxel', 'Chemical', 'MESH:C479543', (134, 143))
100633	25862322	Disappointingly, small molecule inhibitors that target multiple pathways, including VEGF, have shown minimal clinical benefit in an unselected population.	('small', 'Var', (17, 22))	('VEGF', 'Gene', (84, 88))	('VEGF', 'Gene', '7422', (84, 88))
100650	25862322	The significance of testing targeted therapies in select populations was demonstrated in a single-arm phase II study of the safety and efficacy of the antihuman EGFR-2 (HER2) antibody trastuzumab combined with gemcitabine, carboplatin, and paclitaxel in patients who had HER2 overexpression by immunohistochemistry, gene amplification, and/or elevated serum HER2.	('HER2', 'Gene', '2064', (358, 362))	('antibody', 'molecular_function', 'GO:0003823', ('175', '183'))	('overexpression', 'PosReg', (276, 290))	('HER2', 'Gene', '2064', (169, 173))	('gemcitabine', 'Chemical', 'MESH:C056507', (210, 221))	('antibody', 'cellular_component', 'GO:0042571', ('175', '183'))	('EGFR', 'Gene', (161, 165))	('elevated', 'PosReg', (343, 351))	('carboplatin', 'Chemical', 'MESH:D016190', (223, 234))	('gene amplification', 'Var', (316, 334))	('HER2', 'Gene', (271, 275))	('serum', 'MPA', (352, 357))	('HER2', 'Gene', (358, 362))	('antibody', 'cellular_component', 'GO:0019815', ('175', '183'))	('HER2', 'Gene', (169, 173))	('paclitaxel', 'Chemical', 'MESH:D017239', (240, 250))	('EGFR', 'Gene', '1956', (161, 165))	('antibody', 'cellular_component', 'GO:0019814', ('175', '183'))	('human', 'Species', '9606', (155, 160))	('HER2', 'Gene', '2064', (271, 275))	('trastuzumab', 'Chemical', 'MESH:D000068878', (184, 195))	('patients', 'Species', '9606', (254, 262))	('EGFR', 'molecular_function', 'GO:0005006', ('161', '165'))
100665	25862322	An integrated analysis of urothelial carcinoma by the Cancer Genome Atlas Research Network demonstrated that 42% of tumors had mutations, copy number alterations, or RNA expression changes in the PI3K/AKT/mTOR pathway.	('tumors', 'Disease', (116, 122))	('RNA expression', 'MPA', (166, 180))	('AKT', 'Gene', '207', (201, 204))	('urothelial carcinoma by the Cancer Genome Atlas', 'Disease', 'MESH:D014523', (26, 73))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('mTOR', 'Gene', (205, 209))	('mTOR', 'Gene', '2475', (205, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('PI3K', 'molecular_function', 'GO:0016303', ('196', '200'))	('AKT', 'Gene', (201, 204))	('changes', 'Reg', (181, 188))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('copy number alterations', 'Var', (138, 161))	('RNA', 'cellular_component', 'GO:0005562', ('166', '169'))	('urothelial carcinoma by the Cancer Genome Atlas', 'Disease', (26, 73))	('mutations', 'Var', (127, 136))
100666	25862322	Genomic changes included PI3K-alpha point mutations (17% of patients), mutation or deletion of tuberous sclerosis complex (TSC)-1 or TSC-2 (9%), and overexpression of AKT3 (10%).	('tuberous sclerosis', 'Disease', 'MESH:D014402', (95, 113))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('95', '121'))	('PI3K', 'molecular_function', 'GO:0016303', ('25', '29'))	('PI3K-alpha', 'Gene', (25, 35))	('mutation', 'Var', (71, 79))	('patients', 'Species', '9606', (60, 68))	('TSC-2', 'Gene', (133, 138))	('TSC)-1', 'Gene', '7248', (123, 129))	('TSC-2', 'Gene', '7249', (133, 138))	('tuberous sclerosis', 'Disease', (95, 113))	('deletion', 'Var', (83, 91))	('AKT3', 'Gene', (167, 171))	('PI3K-alpha', 'Gene', '5290', (25, 35))	('point mutations', 'Var', (36, 51))	('AKT3', 'Gene', '10000', (167, 171))	('overexpression', 'PosReg', (149, 163))
100667	25862322	Other studies have reported inactivating mutations of PTEN, which result in activation of the PI3K pathway, in 30% of muscle-invasive urothelial carcinomas.	('muscle-invasive urothelial carcinomas', 'Disease', 'MESH:D009217', (118, 155))	('inactivating mutations', 'Var', (28, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('PI3K pathway', 'Pathway', (94, 106))	('muscle-invasive urothelial carcinomas', 'Disease', (118, 155))	('PTEN', 'Gene', (54, 58))	('PI3K', 'molecular_function', 'GO:0016303', ('94', '98'))	('PTEN', 'Gene', '5728', (54, 58))	('activation', 'PosReg', (76, 86))
100671	25862322	Interestingly, in the second trial one patient with inactivating TSC-1 mutation had significant tumor shrinkage and a durable response, further highlighting the importance of patient selection in the use of targeted therapies.	('TSC-1', 'Gene', (65, 70))	('patient', 'Species', '9606', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mutation', 'Var', (71, 79))	('patient', 'Species', '9606', (175, 182))	('tumor', 'Disease', (96, 101))	('TSC-1', 'Gene', '7248', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('inactivating', 'Var', (52, 64))
100701	25862322	Based on data from the Cancer Genome Atlas Research Network and previous experience with molecular targeted agents (summarized above), this trial will initially focus on several of the most promising targets: FGFR3 fusion/mutation/amplification, Rb1 mutation, PIK3CA mutation, AKT1 mutation/amplification, mTOR mutation, TSC1 deletion/mutation, PTEN deletion/mutation, ERBB2 mutation/fusion/amplification, EGFR amplification, and histone acetyltransferase mutation (Figure 1).	('histone acetyltransferase', 'Enzyme', (430, 455))	('mutation', 'Var', (267, 275))	('Rb1', 'Gene', (246, 249))	('Cancer', 'Disease', (23, 29))	('PIK3CA', 'Gene', (260, 266))	('deletion/mutation', 'Var', (326, 343))	('mTOR', 'Gene', (306, 310))	('deletion/mutation', 'Var', (350, 367))	('EGFR', 'molecular_function', 'GO:0005006', ('406', '410'))	('FGFR', 'molecular_function', 'GO:0005007', ('209', '213'))	('AKT1', 'Gene', (277, 281))	('mutation', 'Var', (250, 258))	('mTOR', 'Gene', '2475', (306, 310))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('PTEN', 'Gene', (345, 349))	('TSC1', 'Gene', (321, 325))	('mutation/fusion/amplification', 'Var', (375, 404))	('EGFR', 'Gene', (406, 410))	('mutation', 'Reg', (456, 464))	('mutation', 'Var', (311, 319))	('TSC1', 'Gene', '7248', (321, 325))	('FGFR3', 'Gene', (209, 214))	('PIK3CA', 'Gene', '5290', (260, 266))	('PTEN', 'Gene', '5728', (345, 349))	('Rb1', 'Gene', '5925', (246, 249))	('fusion/mutation/amplification', 'Var', (215, 244))	('mutation/amplification', 'Var', (282, 304))	('FGFR3', 'Gene', '2261', (209, 214))	('ERBB2', 'Gene', (369, 374))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('EGFR', 'Gene', '1956', (406, 410))	('AKT1', 'Gene', '207', (277, 281))	('ERBB2', 'Gene', '2064', (369, 374))
100704	25862322	Tissue samples from urothelial tumors will be screened for expression of proteins (androgen receptor [AR]) and mutation (FGFR-3) during first-line chemotherapy (4 to 8 cycles of platinum-containing regimens).	('androgen receptor', 'Gene', (83, 100))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('FGFR-3', 'Gene', (121, 127))	('proteins', 'Protein', (73, 81))	('urothelial tumors', 'Disease', 'MESH:D001749', (20, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('121', '125'))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('FGFR-3', 'Gene', '2261', (121, 127))	('urothelial tumors', 'Disease', (20, 37))	('androgen receptor', 'Gene', '367', (83, 100))	('mutation', 'Var', (111, 119))	('platinum', 'Chemical', 'MESH:D010984', (178, 186))	('AR', 'Gene', '367', (102, 104))
100740	25158272	Approximately 15% to 30% of high grade NMIBC cases develop into MIBC, in addition to 30% with de novo MIBC presentation.	('MIBC', 'Chemical', '-', (64, 68))	('MIBC', 'Chemical', '-', (102, 106))	('high grade', 'Var', (28, 38))	('develop', 'Reg', (51, 58))	('MIBC', 'Disease', (64, 68))	('MIBC', 'Chemical', '-', (40, 44))
100744	25158272	A multicenter, randomized, controlled clinical trial showed 77-month median survival (57% 5-year survival rate) in patients with nonmetastatic MIBC treated with neoadjuvant chemotherapy combined with cystectomy compared to 46-month median survival (43% 5-year survival rate) in those treated with cystectomy alone.	('patients', 'Species', '9606', (115, 123))	('nonmetastatic', 'Var', (129, 142))	('MIBC', 'Gene', (143, 147))	('MIBC', 'Chemical', '-', (143, 147))
100769	25158272	Despite the presence of EGFR mutations in many other cancers a survey of 11 UC cell lines and 75 primary tumors demonstrated no mutations when analyzed by automated sequencing.	('EGFR', 'Gene', '1956', (24, 28))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('EGFR', 'Gene', (24, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('mutations', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('primary tumors', 'Disease', (97, 111))	('primary tumors', 'Disease', 'MESH:D009369', (97, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
100771	25158272	Furthermore, a study of 28 urothelial primary adenocarcinomas and another study in 8 cell lines showed no mutations in EGFR, indicating that mutations in EGFR are rare in primary UC.	('EGFR', 'Gene', (154, 158))	('EGFR', 'molecular_function', 'GO:0005006', ('119', '123'))	('mutations', 'Var', (141, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('urothelial primary adenocarcinomas', 'Disease', (27, 61))	('primary', 'Disease', (171, 178))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'molecular_function', 'GO:0005006', ('154', '158'))	('urothelial primary adenocarcinomas', 'Disease', 'MESH:D000230', (27, 61))	('EGFR', 'Gene', (119, 123))	('EGFR', 'Gene', '1956', (154, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
100772	25158272	However, in the TCGA study there was a 9% incidence of EGFR amplification in 131 MIBC samples.	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('amplification', 'Var', (60, 73))	('MIBC', 'Chemical', '-', (81, 85))	('EGFR', 'Gene', (55, 59))	('MIBC', 'Disease', (81, 85))
100773	25158272	Although to our knowledge the EGFR mutation rate in distant metastases is unknown, a study of 17 patients with MIBC (total of 22 primary tumors and 24 associated metastases) showed strong concordance (mean 75%) between the chromosomal aberrations in the primary tumors and their associated metastases.	('metastases', 'Disease', (162, 172))	('EGFR', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('metastases', 'Disease', (290, 300))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('metastases', 'Disease', (60, 70))	('mutation', 'Var', (35, 43))	('MIBC', 'Chemical', '-', (111, 115))	('primary tumors', 'Disease', (129, 143))	('primary tumors', 'Disease', (254, 268))	('chromosomal aberrations', 'Var', (223, 246))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (223, 246))	('EGFR', 'Gene', '1956', (30, 34))	('primary tumors', 'Disease', 'MESH:D009369', (129, 143))	('primary tumors', 'Disease', 'MESH:D009369', (254, 268))	('patients', 'Species', '9606', (97, 105))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('metastases', 'Disease', 'MESH:D009362', (162, 172))	('metastases', 'Disease', 'MESH:D009362', (60, 70))	('metastases', 'Disease', 'MESH:D009362', (290, 300))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
100774	25158272	Since mutations and gene amplifications of EGFR are a rare event in UC, it was hypothesized that EGFR over expression is due to deregulation of the protein recycling and degradation pathways.	('deregulation', 'MPA', (128, 140))	('over expression', 'PosReg', (102, 117))	('protein', 'Pathway', (148, 155))	('degradation', 'biological_process', 'GO:0009056', ('170', '181'))	('EGFR', 'Gene', '1956', (97, 101))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('degradation', 'MPA', (170, 181))	('EGFR', 'Gene', (97, 101))	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'Gene', (43, 47))	('mutations', 'Var', (6, 15))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))
100784	25158272	However, it was significantly over expressed in MIBC compared to normal tissue (1.55-fold change, p <0.0001).	('over expressed', 'PosReg', (30, 44))	('MIBC', 'Var', (48, 52))	('MIBC', 'Chemical', '-', (48, 52))
100787	25158272	A TCGA study of 131 MIBC bladder tumors corroborated this finding, indicating that ERBB2 mutation or amplification was present in 9% of samples, similar to levels in breast cancer, but with more mutations and fewer amplifications in bladder than in breast tumors.	('breast tumors', 'Phenotype', 'HP:0100013', (249, 262))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('breast cancer', 'Disease', (166, 179))	('bladder tumors', 'Phenotype', 'HP:0009725', (25, 39))	('mutations', 'MPA', (195, 204))	('bladder tumor', 'Phenotype', 'HP:0009725', (25, 38))	('mutation', 'Var', (89, 97))	('MIBC', 'Chemical', '-', (20, 24))	('ERBB2', 'Gene', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('bladder tumors', 'Disease', 'MESH:D001749', (25, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('amplification', 'MPA', (101, 114))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('breast tumors', 'Disease', (249, 262))	('breast tumors', 'Disease', 'MESH:D001943', (249, 262))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('ERBB2', 'Gene', '2064', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('amplifications', 'MPA', (215, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('bladder tumors', 'Disease', (25, 39))
100790	25158272	HER2 amplification was reported to be more common in associated metastases than in their corresponding primary tumors.	('metastases', 'Disease', 'MESH:D009362', (64, 74))	('primary tumors', 'Disease', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('amplification', 'Var', (5, 18))	('primary tumors', 'Disease', 'MESH:D009369', (103, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('common', 'Reg', (43, 49))	('HER2', 'Gene', (0, 4))	('metastases', 'Disease', (64, 74))	('HER2', 'Gene', '2064', (0, 4))
100801	25158272	Significantly a study of 131 MIBC samples demonstrated that mutations in ERBB3 were present in 6% of bladder tumors with similar levels of mutation having been previously reported.	('bladder tumors', 'Disease', 'MESH:D001749', (101, 115))	('bladder tumors', 'Phenotype', 'HP:0009725', (101, 115))	('bladder tumor', 'Phenotype', 'HP:0009725', (101, 114))	('bladder tumors', 'Disease', (101, 115))	('ERBB3', 'Gene', '2065', (73, 78))	('present', 'Reg', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('ERBB3', 'Gene', (73, 78))	('mutations', 'Var', (60, 69))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('MIBC', 'Chemical', '-', (29, 33))
100847	25158272	Therefore, dual inhibition of EGFR/ERBB2 seems to be more effective for UC than single agents alone, even in chemotherapy resistant patients in whom EGFR or ERBB3 is over expressed.	('over expressed', 'PosReg', (166, 180))	('EGFR', 'Gene', (30, 34))	('dual', 'Var', (11, 15))	('ERBB3', 'Gene', (157, 162))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('EGFR', 'Gene', '1956', (149, 153))	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('EGFR', 'Gene', (149, 153))	('ERBB2', 'Gene', (35, 40))	('ERBB2', 'Gene', '2064', (35, 40))	('EGFR', 'Gene', '1956', (30, 34))	('patients', 'Species', '9606', (132, 140))	('ERBB3', 'Gene', '2065', (157, 162))
100863	25158272	As noted mutations in EGFR are rare in UC but mutations in related genes may drive the resistance of these tumors to EGFR/ERBB2 inhibitors.	('resistance', 'MPA', (87, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('mutations', 'Var', (46, 55))	('ERBB2', 'Gene', '2064', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('EGFR', 'molecular_function', 'GO:0005006', ('117', '121'))	('EGFR', 'Gene', '1956', (117, 121))	('mutations', 'Var', (9, 18))	('EGFR', 'Gene', (117, 121))	('ERBB2', 'Gene', (122, 127))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))	('drive', 'Reg', (77, 82))
100900	22177163	Patients who underwent RNU were more likely than those who underwent PSUR to have preoperative radiographic evidence of hydronephrosis (p = 0.0006) and less likely to have had a history of transitional cell carcinoma in the bladder (p = 0.008).	('hydronephrosis', 'Disease', (120, 134))	('less', 'NegReg', (152, 156))	('cell carcinoma', 'Disease', 'MESH:C538614', (202, 216))	('RNU', 'Var', (23, 26))	('transitional cell carcinoma in the bladder', 'Phenotype', 'HP:0006740', (189, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('hydronephrosis', 'Phenotype', 'HP:0000126', (120, 134))	('Patients', 'Species', '9606', (0, 8))	('RNU', 'Chemical', '-', (23, 26))	('cell carcinoma', 'Disease', (202, 216))	('hydronephrosis', 'Disease', 'MESH:D006869', (120, 134))
100907	22177163	Patients who underwent RNU tended to have worse baseline renal function than those treated with PSUR (eGFR 51 vs 63 ml/minute/1.73 m2, p = 0.009, table 3).	('RNU', 'Var', (23, 26))	('eGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('renal function', 'MPA', (57, 71))	('Patients', 'Species', '9606', (0, 8))	('RNU', 'Chemical', '-', (23, 26))	('eGFR', 'Gene', '1956', (102, 106))	('eGFR', 'Gene', (102, 106))
100914	22177163	The development of metastatic disease was more frequent in patients who underwent RNU (20 patients, 23%) than in those who underwent PSUR (4 patients, 12%).	('metastatic disease', 'Disease', (19, 37))	('metastatic disease', 'Disease', 'MESH:C538445', (19, 37))	('RNU', 'Var', (82, 85))	('RNU', 'Chemical', '-', (82, 85))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (90, 98))	('patients', 'Species', '9606', (141, 149))
100915	22177163	The unadjusted 2-year recurrence rates could have been as much as 9% lower or 34% higher in patients treated with PSUR vs RNU.	('higher', 'PosReg', (82, 88))	('lower', 'NegReg', (69, 74))	('patients', 'Species', '9606', (92, 100))	('PSUR', 'Var', (114, 118))	('RNU', 'Chemical', '-', (122, 125))
100923	22177163	Chemotherapeutic agents, particularly cisplatin, a known nephrotoxic agent, have been demonstrated to be efficacious in the treatment of urothelial malignancy.	('nephrotoxic', 'Disease', 'MESH:D007674', (57, 68))	('nephrotoxic', 'Disease', (57, 68))	('cisplatin', 'Var', (38, 47))	('urothelial malignancy', 'Disease', 'MESH:D009369', (137, 158))	('urothelial malignancy', 'Disease', (137, 158))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))
100928	22177163	We previously demonstrated that RNU results in decreases in eGFR that are likely to impact the receipt of cisplatin based chemotherapy.	('impact', 'Reg', (84, 90))	('RNU', 'Var', (32, 35))	('RNU', 'Chemical', '-', (32, 35))	('receipt of cisplatin based chemotherapy', 'MPA', (95, 134))	('eGFR', 'Gene', '1956', (60, 64))	('eGFR', 'Gene', (60, 64))	('eGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('decreases', 'NegReg', (47, 56))
100935	22177163	While creatinine levels were similar between the groups, eGFR was lower in the RNU group (51 vs 63 ml/minute/1.73 m2).	('RNU', 'Chemical', '-', (79, 82))	('eGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('eGFR', 'Gene', '1956', (57, 61))	('lower', 'NegReg', (66, 71))	('creatinine', 'Chemical', 'MESH:D003404', (6, 16))	('creatinine levels', 'MPA', (6, 23))	('eGFR', 'Gene', (57, 61))	('RNU', 'Var', (79, 82))
100938	22177163	While patients who underwent RNU experienced a greater decline in renal function than those treated with PSUR, the overall decrease in eGFR associated with RNU of -7 was less than might be anticipated with uninephrectomy.	('RNU of -7', 'Var', (156, 165))	('eGFR', 'molecular_function', 'GO:0005006', ('135', '139'))	('eGFR', 'Gene', '1956', (135, 139))	('decrease', 'NegReg', (123, 131))	('decline', 'NegReg', (55, 62))	('RNU', 'Var', (29, 32))	('RNU', 'Chemical', '-', (156, 159))	('RNU', 'Chemical', '-', (29, 32))	('eGFR', 'Gene', (135, 139))	('patients', 'Species', '9606', (6, 14))	('renal function', 'MPA', (66, 80))
100974	33302606	BKPyV replication has been described to be a significant risk factor for bladder cancer development following kidney transplantation.	('replication', 'Var', (6, 17))	('bladder cancer', 'Disease', (73, 87))	('risk factor', 'Reg', (57, 68))	('BKPyV', 'Species', '1891762', (0, 5))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('BKPyV', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))
101005	33302606	Decoy cells in their urine were detected in the follow-up after the first presentation with UCC with a median period of 3.5 years (range 1-13 years) and were positive for the SV40 LTAg by immunohistochemistry, indicating the BKPyV-reactivation in urothelial cells (Figure 1C; Table 2; Supplementary Table S2).	('BKPyV', 'Species', '1891762', (225, 230))	('positive', 'Reg', (158, 166))	('SV40', 'Var', (175, 179))
101032	33302606	The reactivation of BKPyV can lead to BKPyV-associated nephropathy.	('lead to', 'Reg', (30, 37))	('nephropathy', 'Phenotype', 'HP:0000112', (55, 66))	('nephropathy', 'Disease', (55, 66))	('BKPyV', 'Species', '1891762', (20, 25))	('BKPyV', 'Species', '1891762', (38, 43))	('BKPyV', 'Gene', (20, 25))	('reactivation', 'Var', (4, 16))	('nephropathy', 'Disease', 'MESH:D007674', (55, 66))
101198	32640719	Furthermore, NRP2, PLXNC1 and PLXNB3 were also positively associated with cell sensitivity to Dabrafenib, which is the treatment for late-stage melanoma and metastatic non-small cell lung cancer with BRAF V600E or V600K mutations (Figure 5C and Table S5).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (172, 194))	('BRAF', 'Gene', (200, 204))	('Dabrafenib', 'Chemical', 'MESH:C561627', (94, 104))	('V600E', 'Mutation', 'rs113488022', (205, 210))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('NRP2', 'Gene', (13, 17))	('NRP', 'biological_process', 'GO:0085015', ('13', '16'))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('V600K', 'Var', (214, 219))	('cell sensitivity', 'MPA', (74, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('PLXNB3', 'Gene', '5365', (30, 36))	('PLXNC1', 'Gene', '10154', (19, 25))	('PLXNB3', 'Gene', (30, 36))	('PLXNC1', 'Gene', (19, 25))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('associated', 'Reg', (58, 68))	('NRP2', 'Gene', '8828', (13, 17))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (168, 194))	('lung cancer', 'Disease', (183, 194))	('V600K', 'Mutation', 'rs121913227', (214, 219))	('BRAF', 'Gene', '673', (200, 204))	('metastatic', 'CPA', (157, 167))
101210	32640719	Various cell types in the TME of breast cancer tumors might contribute to the dysregulated expression of SEMA3 and their receptors.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('expression', 'MPA', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer tumors', 'Disease', 'MESH:D001943', (33, 53))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (33, 52))	('SEMA', 'Gene', '7869', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('breast cancer tumors', 'Disease', (33, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('dysregulated', 'Var', (78, 90))	('SEMA', 'Gene', (105, 109))
101225	32640719	The semaphorin/neuropilin/plexin complexes control a wide range of biological processes and deregulation of these complexes is associated with multiple pathological statuses.	('sema', 'Gene', '7869', (4, 8))	('associated', 'Reg', (127, 137))	('control', 'Reg', (43, 50))	('sema', 'Gene', (4, 8))	('neuropilin', 'Gene', '8829', (15, 25))	('deregulation', 'Var', (92, 104))	('neuropilin', 'Gene', (15, 25))
101242	32640719	The dysregulated expression of NRPs and PLXNs in cancer tumors was generally associated with patient overall survival and progression free interval in 33 cancer types, while the direction of association is dependent on the cancer type tested and the genes queried.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancer tumors', 'Disease', (49, 62))	('PLXNs', 'Gene', (40, 45))	('cancer', 'Disease', (223, 229))	('dysregulated', 'Var', (4, 16))	('cancer', 'Disease', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('expression', 'MPA', (17, 27))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('associated', 'Reg', (77, 87))	('patient', 'Species', '9606', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer tumors', 'Disease', 'MESH:D009369', (49, 62))	('NRP', 'Gene', '8829', (31, 34))	('NRP', 'Gene', (31, 34))	('cancer', 'Disease', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
101319	31991631	Mutant ras genes induced urothelial hyperplasia at low copy numbers and papillary tumors at high copy numbers, while inactivation of the tumor protein p53 and retinoblastoma (RB1) pathways seem to induce carcinoma in situ (CIS) tumors, able to progress into invasive BCa.	('retinoblastoma', 'Disease', (159, 173))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('urothelial hyperplasia', 'Disease', 'MESH:D006965', (25, 47))	('inactivation', 'Var', (117, 129))	('induced', 'Reg', (17, 24))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (204, 221))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('papillary tumors', 'Phenotype', 'HP:0007482', (72, 88))	('tumor', 'Disease', (82, 87))	('p53', 'Gene', '7157', (151, 154))	('urothelial hyperplasia', 'Disease', (25, 47))	('RB1', 'Gene', '5925', (175, 178))	('papillary tumors', 'Disease', 'MESH:D002291', (72, 88))	('papillary tumors', 'Disease', (72, 88))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('carcinoma in situ (CIS) tumors', 'Disease', 'MESH:D002278', (204, 234))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('p53', 'Gene', (151, 154))	('tumor', 'Disease', (137, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('retinoblastoma', 'Disease', 'MESH:D012175', (159, 173))	('invasive BCa', 'Disease', (258, 270))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ras genes', 'Gene', (7, 16))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('induce', 'Reg', (197, 203))	('Mutant', 'Var', (0, 6))	('BCa', 'Phenotype', 'HP:0009725', (267, 270))	('CIS', 'Phenotype', 'HP:0030075', (223, 226))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', (228, 233))	('retinoblastoma', 'Phenotype', 'HP:0009919', (159, 173))	('RB1', 'Gene', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
101321	31991631	P53 alterations are involved in tumor progression to more aggressive forms and the RB1 pathway plays a critical role in the regulation of the cell cycle and cell death.	('alterations', 'Var', (4, 15))	('RB1', 'Gene', (83, 86))	('involved', 'Reg', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('cell death', 'biological_process', 'GO:0008219', ('157', '167'))	('cell cycle', 'biological_process', 'GO:0007049', ('142', '152'))	('P53', 'Gene', (0, 3))	('RB1', 'Gene', '5925', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('P53', 'Gene', '7157', (0, 3))	('regulation', 'biological_process', 'GO:0065007', ('124', '134'))	('tumor', 'Disease', (32, 37))
101325	31991631	In the present in silico analysis, we used six public access databases, the Cancer Genome Atlas (TCGA) and five mRNA microarray datasets from the Gene Expression Omnibus (GEO), to detect DEGs in bladder cancer tissues and noncancerous bladder tissues (further nominated controls).	('DEGs', 'Var', (187, 191))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('bladder cancer', 'Phenotype', 'HP:0009725', (195, 209))	('Gene Expression', 'biological_process', 'GO:0010467', ('146', '161'))	('cancer', 'Disease', (225, 231))	('bladder cancer', 'Disease', 'MESH:D001749', (195, 209))	('bladder cancer', 'Disease', (195, 209))	('cancer', 'Disease', (203, 209))	('Cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
101334	31991631	On the other hand, downregulated DEGs were associated with "pathways in cancer", "cGMP-PKG signaling pathway", and other signaling pathways, but also "focal adhesion" and "regulation of actin cytoskeleton" (Table S4).	('cGMP', 'Chemical', 'MESH:D006152', (82, 86))	('focal adhesion', 'CPA', (151, 165))	('DEGs', 'Var', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('PKG', 'Gene', '5592', (87, 90))	('PKG', 'Gene', (87, 90))	('downregulated', 'NegReg', (19, 32))	('cancer', 'Disease', (72, 78))
101381	31991631	That is intriguing, since infection with polyomavirus BK could induce PCa in normal prostate epithelium (RWPE-1), but was not needed for maintaining the phenotype of PC3 prostate cancer cells in vitro.	('infection', 'Disease', (26, 35))	('infection', 'Disease', 'MESH:D007239', (26, 35))	('polyomavirus BK', 'Var', (41, 56))	('prostate cancer', 'Disease', (170, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('induce', 'Reg', (63, 69))	('polyomavirus BK', 'Species', '1891762', (41, 56))	('prostate cancer', 'Disease', 'MESH:D011471', (170, 185))	('PCa', 'Disease', (70, 73))	('prostate cancer', 'Phenotype', 'HP:0012125', (170, 185))	('PC3', 'CellLine', 'CVCL:0035', (166, 169))
101412	31991631	reported that CCNB1 was closely correlated with GTSE1: after GTSE1 knockdown, CCNB1 and FoxM1 were significantly downregulated, while p53 expression was significantly increased in BCa.	('GTSE1', 'Gene', (61, 66))	('p53', 'Gene', '7157', (134, 137))	('GTSE1', 'Gene', '51512', (61, 66))	('BCa', 'Phenotype', 'HP:0009725', (180, 183))	('FoxM1', 'Gene', (88, 93))	('downregulated', 'NegReg', (113, 126))	('GTSE1', 'Gene', (48, 53))	('knockdown', 'Var', (67, 76))	('CCNB1', 'Gene', (78, 83))	('GTSE1', 'Gene', '51512', (48, 53))	('CCNB1', 'Gene', '891', (14, 19))	('p53', 'Gene', (134, 137))	('increased', 'PosReg', (167, 176))	('CCNB1', 'Gene', '891', (78, 83))	('expression', 'MPA', (138, 148))	('CCNB1', 'Gene', (14, 19))	('FoxM1', 'Gene', '2305', (88, 93))
101416	31991631	Furthermore, Li indicated that CCNA2 induced the EMT progression through the ROCK/AKT/beta-catenin/SNAIL pathway, and, in vitro, downregulated CCNA2 significantly repressed the proliferation and migration of BCa.	('CCNA2', 'Gene', (143, 148))	('CCNA2', 'Gene', (31, 36))	('downregulated', 'Var', (129, 142))	('repressed', 'NegReg', (163, 172))	('beta-catenin', 'Gene', (86, 98))	('beta-catenin', 'Gene', '1499', (86, 98))	('EMT', 'biological_process', 'GO:0001837', ('49', '52'))	('BCa', 'Phenotype', 'HP:0009725', (208, 211))	('AKT', 'Gene', '207', (82, 85))	('EMT progression', 'CPA', (49, 64))	('BCa', 'CPA', (208, 211))	('SNAIL', 'Gene', '6615', (99, 104))	('SNAIL', 'Gene', (99, 104))	('proliferation', 'CPA', (177, 190))	('CCNA2', 'Gene', '890', (143, 148))	('migration', 'CPA', (195, 204))	('CCNA2', 'Gene', '890', (31, 36))	('AKT', 'Gene', (82, 85))
101424	31991631	Even more, high expression of CDC20 was associated with high tumor grade.	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CDC20', 'Gene', (30, 35))	('CDC20', 'Gene', '991', (30, 35))	('high', 'Var', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('associated', 'Reg', (40, 50))
101505	29264185	Dr. Jun Luo is a pioneer who discovered spliced AR-V7 mRNA in CTC as a biomarker predictive of androgen antagonist therapy in prostate cancer patients.	('prostate cancer', 'Phenotype', 'HP:0012125', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('spliced', 'Var', (40, 47))	('prostate cancer', 'Disease', (126, 141))	('patients', 'Species', '9606', (142, 150))	('AR', 'Gene', '367', (48, 50))	('prostate cancer', 'Disease', 'MESH:D011471', (126, 141))
101507	29264185	Dr. Yun Qiu and her colleague Jin Xu provided mechanistic insights on the expression and the role of AR spliced variants in driving the progression of metastatic CRPC and how they contribute to disease relapse and therapeutic resistance.	('AR', 'Gene', '367', (101, 103))	('therapeutic resistance', 'CPA', (214, 236))	('CRPC', 'Disease', (162, 166))	('CRPC', 'Disease', 'None', (162, 166))	('contribute', 'Reg', (180, 190))	('variants', 'Var', (112, 120))
101547	28375787	The rationale for assessing immune checkpoint inhibitors in advanced urothelial cancer is supported by a high prevalence of tumor somatic mutations, which may generate neoantigens that are recognized by activated antitumor T cells.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('urothelial cancer', 'Disease', (69, 86))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('urothelial cancer', 'Disease', 'MESH:D014523', (69, 86))	('neoantigens', 'MPA', (168, 179))	('generate', 'Reg', (159, 167))	('mutations', 'Var', (138, 147))
101548	28375787	Such mutational signatures have been shown to correlate with response to PD-L1/PD-1 antibodies in a range of advanced solid tumors, including metastatic urothelial carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('solid tumors', 'Disease', 'MESH:D009369', (118, 130))	('urothelial carcinoma', 'Disease', (153, 173))	('PD-L1', 'Gene', '29126', (73, 78))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (153, 173))	('PD-1', 'Gene', (79, 83))	('mutational', 'Var', (5, 15))	('PD-1', 'Gene', '5133', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('solid tumors', 'Disease', (118, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('PD-L1', 'Gene', (73, 78))
101572	28375787	Other exceptions were transient (<= 6 hours) grade 3 flu-like symptoms or fever controlled with medical management; grade 3 fatigue, local reactions, headache, nausea, or emesis lasting <= 24 hours; grade >= 3 amylase or lipase abnormality not associated with symptoms or clinical manifestations of pancreatitis; tumor flare phenomena (local pain, irritation, or rash at site of tumor); and increase in Eastern Cooperative Oncology Group performance status to >= 3.	('rash', 'Disease', 'MESH:D005076', (363, 367))	('tumor', 'Disease', 'MESH:D009369', (379, 384))	('tumor', 'Disease', (313, 318))	('grade >= 3', 'Var', (199, 209))	('irritation', 'Disease', 'MESH:D001523', (348, 358))	('local', 'Disease', (133, 138))	('headache', 'Disease', 'MESH:D006261', (150, 158))	('abnormality', 'Var', (228, 239))	('amylase', 'Protein', (210, 217))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('nausea', 'Phenotype', 'HP:0002018', (160, 166))	('pancreatitis', 'Phenotype', 'HP:0001733', (299, 311))	('pain', 'Disease', (342, 346))	('flu-like', 'Disease', (53, 61))	('emesis', 'Disease', 'MESH:D014839', (171, 177))	('fatigue', 'Disease', (124, 131))	('emesis', 'Phenotype', 'HP:0002013', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (379, 384))	('emesis', 'Disease', (171, 177))	('pain', 'Phenotype', 'HP:0012531', (342, 346))	('fatigue', 'Phenotype', 'HP:0012378', (124, 131))	('nausea', 'Disease', (160, 166))	('fever', 'Disease', 'MESH:D005334', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('fever', 'Disease', (74, 79))	('pancreatitis', 'Disease', 'MESH:D010195', (299, 311))	('lipase', 'Enzyme', (221, 227))	('headache', 'Phenotype', 'HP:0002315', (150, 158))	('rash', 'Phenotype', 'HP:0000988', (363, 367))	('pancreatitis', 'Disease', (299, 311))	('increase', 'PosReg', (391, 399))	('pain', 'Disease', 'MESH:D010146', (342, 346))	('nausea', 'Disease', 'MESH:D009325', (160, 166))	('irritation', 'Disease', (348, 358))	('headache', 'Disease', (150, 158))	('fatigue', 'Disease', 'MESH:D005221', (124, 131))	('flu-like symptoms or fever', 'Phenotype', 'HP:0002373', (53, 79))	('fever', 'Phenotype', 'HP:0001945', (74, 79))	('rash', 'Disease', (363, 367))	('tumor', 'Disease', (379, 384))	('Oncology', 'Phenotype', 'HP:0002664', (423, 431))
101575	28375787	Tumors were categorized on the basis of quantity and intensity of PD-L1 staining using percentage thresholds of >= 1% (any intensity), >= 5% (any intensity), or >= 25% (>= 2+ staining intensity) in tumor cell membranes, and >= 10% in hotspots of tumor-associated immune cells (any intensity).	('>= 25%', 'Var', (161, 167))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PD-L1', 'Gene', '29126', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('>= 5%', 'Var', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (246, 251))	('PD-L1', 'Gene', (66, 71))
101679	34030708	For each oncogene, differences in Glycolysis score and OXPHOS score were computed between tumors with copy-number amplification and those without (Wilcoxon test, FDR < 0.05).	('OXPHOS', 'biological_process', 'GO:0002082', ('55', '61'))	('OXPHOS score', 'MPA', (55, 67))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('Glycolysis score', 'MPA', (34, 50))	('copy-number amplification', 'Var', (102, 127))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Disease', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Glycolysis', 'biological_process', 'GO:0006096', ('34', '44'))
101680	34030708	For each tumor-suppressor gene, differences in Glycolysis score and OXPHOS score were computed between tumors with copy-number loss and those without (Wilcoxon test, FDR < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('Glycolysis score', 'MPA', (47, 63))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('copy-number loss', 'Var', (115, 131))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor-suppressor', 'Gene', (9, 25))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('9', '25'))	('OXPHOS', 'biological_process', 'GO:0002082', ('68', '74'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('9', '25'))	('Glycolysis', 'biological_process', 'GO:0006096', ('47', '57'))	('OXPHOS score', 'MPA', (68, 80))	('tumor-suppressor', 'Gene', '7248', (9, 25))
101702	34030708	We classified all the cancer patients enrolled in this study into four metabolic subgroups according to their Glycolysis and OXPHOS scores: High-glycolysis and high OXPHOS (HGHO), High-glycolysis and low OXPHOS (HGLO), low-glycolysis and high OXPHOS (LGHO), and Low-Glycolysis & Low OXPHOS (LGLO) (Fig.	('high OXPHOS', 'MPA', (160, 171))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('Glycolysis', 'biological_process', 'GO:0006096', ('110', '120'))	('low OXPHOS', 'MPA', (200, 210))	('HGLO', 'Chemical', '-', (212, 216))	('glycolysis', 'biological_process', 'GO:0006096', ('185', '195'))	('patients', 'Species', '9606', (29, 37))	('OXPHOS', 'biological_process', 'GO:0002082', ('243', '249'))	('OXPHOS', 'biological_process', 'GO:0002082', ('204', '210'))	('low-glycolysis', 'Var', (219, 233))	('OXPHOS', 'biological_process', 'GO:0002082', ('125', '131'))	('Glycolysis', 'biological_process', 'GO:0006096', ('266', '276'))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('OXPHOS', 'biological_process', 'GO:0002082', ('165', '171'))	('LGLO', 'Chemical', '-', (291, 295))	('glycolysis', 'biological_process', 'GO:0006096', ('223', '233'))	('glycolysis', 'biological_process', 'GO:0006096', ('145', '155'))	('OXPHOS', 'biological_process', 'GO:0002082', ('283', '289'))	('High-glycolysis', 'Var', (180, 195))	('high OXPHOS', 'MPA', (238, 249))
101707	34030708	Unexpectedly, LGHO was significantly associated with worse survival in esophageal carcinoma (ESCA; HR: 3.69 (1.32-10.31), p = 0.012), suggesting the potential distinct metabolic feature of ESCA.	('ESCA', 'Phenotype', 'HP:0011459', (189, 193))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (71, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('ESCA', 'Phenotype', 'HP:0011459', (93, 97))	('worse', 'NegReg', (53, 58))	('esophageal carcinoma', 'Disease', (71, 91))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (71, 91))	('LGHO', 'Var', (14, 18))
101728	34030708	MiR-30c-5p (LGHO), miR-362-5p (LGHO), and miR-379-5p (HGLO) appear to be strong regulators of tumor glycolysis and OXPHOS since they were all dysregulated in 8 cancer types and targeted several metabolism-related DEGs.	('miR-379', 'Gene', '494328', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('HGLO', 'Chemical', '-', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Disease', (160, 166))	('metabolism', 'biological_process', 'GO:0008152', ('194', '204'))	('miR-379', 'Gene', (42, 49))	('OXPHOS', 'biological_process', 'GO:0002082', ('115', '121'))	('glycolysis', 'biological_process', 'GO:0006096', ('100', '110'))	('tumor glycolysis', 'Disease', 'MESH:C564972', (94, 110))	('dysregulated', 'Reg', (142, 154))	('MiR-30c-5p', 'Var', (0, 10))	('OXPHOS since', 'MPA', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('miR-362', 'Gene', '574030', (19, 26))	('tumor glycolysis', 'Disease', (94, 110))	('miR-362', 'Gene', (19, 26))
101731	34030708	The genes were classified into four groups based on the intersection between metabolism-associated DMGs and DEGs: hypermethylated and upregulated (hyper-up), hypermethylated, and downregulated (hyper-down), hypomethylated and upregulated (hypo-up), and hypomethylated and downregulated (hypo-down).	('DMGs', 'Chemical', '-', (99, 103))	('upregulated', 'PosReg', (226, 237))	('upregulated', 'PosReg', (134, 145))	('hypomethylated', 'Var', (207, 221))	('metabolism', 'biological_process', 'GO:0008152', ('77', '87'))	('hypermethylated', 'Var', (158, 173))	('downregulated', 'NegReg', (179, 192))	('hypomethylated', 'Var', (253, 267))	('downregulated', 'NegReg', (272, 285))	('hypermethylated', 'Var', (114, 129))
101744	34030708	For instance, it has been widely accepted that mutated TP53 and amplified MYC are linked to several anabolic and catabolic pathways.	('MYC', 'Gene', '4609', (74, 77))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('mutated', 'Var', (47, 54))	('MYC', 'Gene', (74, 77))	('linked', 'Reg', (82, 88))
101749	34030708	As for CNVs, we first focused on 131 cancer driver genes altered by CNVs and identified the oncogenes and tumor suppressors recurrently associated with tumor metabolism in multiple cancer types (Fig.	('associated', 'Reg', (136, 146))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('tumor metabolism', 'Disease', (152, 168))	('tumor metabolism', 'Disease', 'MESH:D008659', (152, 168))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('metabolism', 'biological_process', 'GO:0008152', ('158', '168'))	('tumor', 'Disease', (152, 157))	('CNVs', 'Var', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Disease', (181, 187))	('altered', 'Reg', (57, 64))	('tumor', 'Disease', (106, 111))
101750	34030708	For example, the amplification of the oncogene MYC was significantly associated with elevated Glycolysis score in four independent cancer types (FDR < 0.05).	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Glycolysis score', 'MPA', (94, 110))	('MYC', 'Gene', '4609', (47, 50))	('elevated', 'PosReg', (85, 93))	('amplification', 'Var', (17, 30))	('Glycolysis', 'biological_process', 'GO:0006096', ('94', '104'))	('MYC', 'Gene', (47, 50))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
101756	34030708	5E, F, in BRCA, tumors harboring amplification of PIK3CA, GATA3, MYC, and deletion of MAP3K1, CHAF1A are more likely to have higher Glycolysis score.	('PIK3CA', 'Gene', '5290', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('higher', 'PosReg', (125, 131))	('tumors', 'Disease', (16, 22))	('BRCA', 'Phenotype', 'HP:0003002', (10, 14))	('MYC', 'Gene', (65, 68))	('MAP3K1', 'Gene', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('PIK3CA', 'Gene', (50, 56))	('MAP3K1', 'Gene', '4214', (86, 92))	('BRCA', 'Gene', '672', (10, 14))	('amplification', 'Var', (33, 46))	('Glycolysis', 'biological_process', 'GO:0006096', ('132', '142'))	('MYC', 'Gene', '4609', (65, 68))	('GATA3', 'Gene', '2625', (58, 63))	('CHAF1A', 'Gene', (94, 100))	('CHAF1A', 'Gene', '10036', (94, 100))	('deletion', 'Var', (74, 82))	('BRCA', 'Gene', (10, 14))	('MAP3K', 'molecular_function', 'GO:0004709', ('86', '91'))	('Glycolysis score', 'MPA', (132, 148))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('GATA3', 'Gene', (58, 63))
101758	34030708	Tumors with amplification of PIK3CA and BCL6, or those with deletion of ARID1A and CH1F1A, are more likely to show lower OXPHOS score (Additional file 7: Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BCL6', 'Gene', '604', (40, 44))	('deletion', 'Var', (60, 68))	('OXPHOS', 'biological_process', 'GO:0002082', ('121', '127'))	('amplification', 'Var', (12, 25))	('OXPHOS score', 'MPA', (121, 133))	('CH1F1A', 'Gene', (83, 89))	('ARID1A', 'Gene', '8289', (72, 78))	('lower', 'NegReg', (115, 120))	('ARID1A', 'Gene', (72, 78))	('BCL6', 'Gene', (40, 44))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (29, 35))
101759	34030708	Additionally, TP53 point mutations are more common in low-OXPHOS tumors (OR = 2.63, P < 0.001).	('point mutations', 'Var', (19, 34))	('TP53', 'Gene', '7157', (14, 18))	('low-OXPHOS tumors', 'Disease', 'MESH:D009800', (54, 71))	('TP53', 'Gene', (14, 18))	('low-OXPHOS tumors', 'Disease', (54, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('OXPHOS', 'biological_process', 'GO:0002082', ('58', '64'))	('common', 'Reg', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
101788	34030708	Therefore, we inferred that tumor patients with HGLO or LGHO subtypes are more likely to have worse or better survival respectively, and the drivers or targets motivating this transition might harbor potential therapeutic value, thus benefiting selected tumor patients.	('LGHO', 'Disease', (56, 60))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('patients', 'Species', '9606', (260, 268))	('better', 'PosReg', (103, 109))	('patients', 'Species', '9606', (34, 42))	('HGLO', 'Chemical', '-', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('HGLO', 'Var', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
101789	34030708	In our study, we identified a series of molecular alterations showing consistency as pan-cancer correlates of metabolic status, as well as several differentially enriched metabolism-associated biological pathways.	('metabolism', 'biological_process', 'GO:0008152', ('171', '181'))	('alterations', 'Var', (50, 61))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
101794	34030708	As for others, such as somatic alterations, our result that the amplification of oncogene MYC and mutation of tumor suppressor gene TP53 are enriched in HGLO supports the idea that they were regarded as the driver of the initiation of tumor metabolic reprogramming.	('HGLO', 'Chemical', '-', (153, 157))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('mutation', 'Var', (98, 106))	('amplification', 'Var', (64, 77))	('MYC', 'Gene', (90, 93))	('TP53', 'Gene', '7157', (132, 136))	('tumor', 'Disease', (110, 115))	('TP53', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', (235, 240))	('MYC', 'Gene', '4609', (90, 93))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
101798	34030708	For example, one of the "core" drugs, the ATM kinase inhibitor KU55933, has been demonstrated to induces apoptosis and inhibits motility by blocking GLUT1-mediated glucose uptake in aggressive cancer cells.	('blocking', 'NegReg', (140, 148))	('GLUT1', 'Gene', '6513', (149, 154))	('aggressive cancer', 'Disease', (182, 199))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('KU55933', 'Var', (63, 70))	('motility', 'CPA', (128, 136))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('44', '60'))	('apoptosis', 'CPA', (105, 114))	('KU55933', 'Chemical', 'MESH:C495818', (63, 70))	('core', 'cellular_component', 'GO:0019013', ('24', '28'))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('induces', 'PosReg', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('glucose', 'Chemical', 'MESH:D005947', (164, 171))	('glucose uptake', 'biological_process', 'GO:0046323', ('162', '176'))	('GLUT1', 'Gene', (149, 154))	('aggressive cancer', 'Disease', 'MESH:D009369', (182, 199))	('inhibits', 'NegReg', (119, 127))
101912	33029111	The sensitivity of dabrafenib, a selective inhibitor of mutated forms of BRAF kinase for BRAF-mutated melanoma, thyroid cancer, and non-small-cell lung cancer, was found to be positively associated with PPARGC1A (correlation coefficient = 0.448, p < 0.001) and PPARGC1B (correlation coefficient = 0.377, p = 0.003).	('PPARGC1B', 'Gene', (261, 269))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (136, 158))	('sensitivity', 'MPA', (4, 15))	('mutated', 'Var', (56, 63))	('dabrafenib', 'Chemical', 'MESH:C561627', (19, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('BRAF', 'Gene', '673', (89, 93))	('PPARGC1A', 'Gene', (203, 211))	('BRAF', 'Gene', (89, 93))	('associated', 'Interaction', (187, 197))	('BRAF', 'Gene', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('PPARGC1A', 'Gene', '10891', (203, 211))	('thyroid cancer', 'Disease', (112, 126))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (132, 158))	('PPARGC1B', 'Gene', '133522', (261, 269))	('thyroid cancer', 'Disease', 'MESH:D013964', (112, 126))	('thyroid cancer', 'Phenotype', 'HP:0002890', (112, 126))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (132, 158))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('non-small-cell lung cancer', 'Disease', (132, 158))	('BRAF', 'Gene', '673', (73, 77))
101917	33029111	Statistically significant survival differences were observed between high and low PPAR-expressed patients in some types of cancers, suggesting that PPARs might become potential prognostic indicators for clinical applications.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('PPAR', 'Gene', (148, 152))	('PPAR', 'Gene', '5465', (82, 86))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('PPAR', 'Gene', (82, 86))	('cancers', 'Disease', (123, 130))	('high', 'Var', (69, 73))	('PPAR', 'Gene', '5465', (148, 152))	('patients', 'Species', '9606', (97, 105))
101954	28202506	Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types.	('deletions', 'Var', (211, 220))	('human', 'Species', '9606', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('DNA', 'cellular_component', 'GO:0005574', ('188', '191'))	('amplifications', 'Var', (192, 206))	('cancer', 'Disease', (236, 242))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('tumors', 'Disease', (146, 152))	('tumors', 'Disease', (53, 59))
101957	28202506	The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes.	('p53', 'Gene', (42, 45))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('mutations', 'Var', (46, 55))	('glycolytic genes', 'Gene', (126, 142))	('cancer', 'Disease', (153, 159))	('associated', 'Reg', (63, 73))	('glycolysis', 'biological_process', 'GO:0006096', ('79', '89'))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('glycolysis', 'MPA', (79, 89))	('amplification', 'PosReg', (109, 122))
101961	28202506	Modern cancer classification relies on molecular characterization, including examination of genomic DNA mutations and copy number alterations (CNAs; Stuart & Sellers, 2009).	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('copy number alterations', 'Var', (118, 141))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
101962	28202506	Although individual oncogenes and tumor suppressor genes are preferential targets of DNA amplifications and deletions, respectively, the recurrent CNA patterns in tumors cannot be fully explained by canonical cancer genes (Beroukhim et al, 2010; Muller et al, 2012; Davoli et al, 2013).	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('tumors', 'Disease', (163, 169))	('cancer', 'Disease', (209, 215))	('tumor', 'Disease', (163, 168))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('deletions', 'Var', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
101964	28202506	Reports that the cumulative phenotypic effects of many small gene dosage alterations across the genome can impact the resulting tumor copy number landscape (Solimini et al, 2012; Davoli et al, 2013) illustrate a need to consider more subtle and combinatorial effects to explain the remaining selective forces underlying recurrent CNA patterns observed in human cancers.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancers', 'Disease', (361, 368))	('small gene dosage alterations', 'Var', (55, 84))	('cancers', 'Disease', 'MESH:D009369', (361, 368))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('human', 'Species', '9606', (355, 360))	('impact', 'Reg', (107, 113))	('tumor', 'Disease', (128, 133))	('cancers', 'Phenotype', 'HP:0002664', (361, 368))
101970	28202506	Using an integrative analysis of CNA data from human tumors, mouse models of cancer, cancer cell lines, and a murine experimental immortalization system, here we show that the loci of metabolic genes impact the recurrent CNA changes observed in genomically unstable tumors.	('unstable tumors', 'Disease', (257, 272))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('impact', 'Reg', (200, 206))	('murine', 'Species', '10090', (110, 116))	('metabolic genes', 'Gene', (184, 199))	('CNA changes', 'MPA', (221, 232))	('unstable tumors', 'Disease', 'MESH:D000789', (257, 272))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mouse', 'Species', '10090', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('human', 'Species', '9606', (47, 52))	('tumors', 'Disease', (53, 59))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (266, 272))	('loci', 'Var', (176, 180))	('tumors', 'Disease', 'MESH:D009369', (266, 272))
101971	28202506	Our bioinformatic and experimental results support a tumorigenesis model in which copy number changes in metabolic genes contribute to an enhanced glycolytic and proliferative state (see Fig EV1 for a schematic of our overall approach).	('metabolic genes', 'Gene', (105, 120))	('EV1', 'Gene', '11322', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('copy number changes', 'Var', (82, 101))	('enhanced', 'PosReg', (138, 146))	('EV1', 'Gene', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('glycolytic and', 'MPA', (147, 161))	('tumor', 'Disease', (53, 58))
101976	28202506	In BRCA, signature A tumors were enriched for the basal subtype, p53 point mutations, high numbers of genomic breakpoints, and thus subchromosomal alterations (Figs 1B and D, and EV2D; P < 0.001, P < 0.001, P = 2 x 10-4, respectively).	('p53', 'Gene', (65, 68))	('BRCA', 'Gene', (3, 7))	('BRCA', 'Gene', '672', (3, 7))	('EV2', 'Gene', '147138', (179, 182))	('EV2', 'Gene', (179, 182))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('subchromosomal alterations', 'Var', (132, 158))	('point mutations', 'Var', (69, 84))	('A tumors', 'Disease', (19, 27))	('A tumors', 'Disease', 'MESH:D009369', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
101977	28202506	Signature B BRCA tumors, in contrast, were enriched for luminal type tumors (P < 0.001) and exhibited amplifications of the oncogenes MYC and MDM2 and deletion of the tumor suppressor CDKN2A (Fig 1B).	('tumor suppressor', 'biological_process', 'GO:0051726', ('167', '183'))	('MYC', 'Gene', '4609', (134, 137))	('deletion', 'Var', (151, 159))	('CDKN2A', 'Gene', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (17, 22))	('CDKN2A', 'Gene', '1029', (184, 190))	('BRCA tumors', 'Disease', (12, 23))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('luminal type tumors', 'Disease', (56, 75))	('BRCA tumors', 'Disease', 'MESH:D009369', (12, 23))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('MDM2', 'Gene', (142, 146))	('luminal type tumors', 'Disease', 'MESH:D009369', (56, 75))	('MYC', 'Gene', (134, 137))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (69, 74))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('167', '183'))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('MDM2', 'Gene', '4193', (142, 146))	('amplifications', 'MPA', (102, 116))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
101978	28202506	Amplification of MDM2 and loss of CDKN2A were generally mutually exclusive in signature B tumors (Fig EV2E), reflecting alternate mechanisms for disabling the p53/ARF axis (Sherr & Weber, 2000).	('Amplification', 'Var', (0, 13))	('EV2', 'Gene', '147138', (102, 105))	('B tumors', 'Disease', 'MESH:D006509', (88, 96))	('EV2', 'Gene', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('MDM2', 'Gene', '4193', (17, 21))	('disabling', 'NegReg', (145, 154))	('ARF axis', 'Disease', (163, 171))	('MDM2', 'Gene', (17, 21))	('CDKN2A', 'Gene', (34, 40))	('ARF axis', 'Disease', 'MESH:C566610', (163, 171))	('loss', 'NegReg', (26, 30))	('CDKN2A', 'Gene', '1029', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('B tumors', 'Disease', (88, 96))
101980	28202506	Overall, signature A tumors demonstrated enrichment of p53 mutations, more genomic breakpoints (BRCA, LU, and UCEC), and a higher degree of copy number alterations (LU, OV, and UCEC) than signature B tumors (Appendix Fig S2A and B, P-values indicated in figure).	('BRCA', 'Gene', '672', (96, 100))	('copy', 'MPA', (140, 144))	('p53', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('BRCA', 'Gene', (96, 100))	('B tumors', 'Disease', 'MESH:D006509', (198, 206))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('OV', 'Phenotype', 'HP:0012887', (169, 171))	('genomic breakpoints', 'CPA', (75, 94))	('mutations', 'Var', (59, 68))	('A tumors', 'Disease', (19, 27))	('B tumors', 'Disease', (198, 206))	('A tumors', 'Disease', 'MESH:D009369', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
101983	28202506	Unlike signature A tumors, the signature B CNA patterns were quite distinct between tumor types, although some commonalities were observed including point mutations in oncogenes such as KRAS (LU and UCEC) and amplification of MYC (BRCA, LU, and OV).	('OV', 'Phenotype', 'HP:0012887', (245, 247))	('MYC', 'Gene', (226, 229))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('A tumors', 'Disease', 'MESH:D009369', (17, 25))	('KRAS', 'Gene', (186, 190))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('BRCA', 'Gene', (231, 235))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('MYC', 'Gene', '4609', (226, 229))	('tumor', 'Disease', (84, 89))	('KRAS', 'Gene', '3845', (186, 190))	('BRCA', 'Gene', '672', (231, 235))	('tumor', 'Disease', (19, 24))	('amplification', 'Var', (209, 222))	('point mutations', 'Var', (149, 164))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('A tumors', 'Disease', (17, 25))
101987	28202506	Using CNA-based gene set enrichment analysis over all metabolic pathways defined by KEGG (Kanehisa et al, 2014), we found that the conserved profile of core signature A tumors (i.e., OV, BRCA, UCEC, LU) (Fig 1C) was significantly enriched for DNA amplifications of core glycolysis pathway genes (Fig 1E and F, and Table EV1; P = 0.024).	('UCEC', 'Disease', (193, 197))	('A tumors', 'Disease', 'MESH:D009369', (167, 175))	('EV1', 'Gene', '11322', (320, 323))	('core', 'cellular_component', 'GO:0019013', ('265', '269'))	('amplifications', 'Var', (247, 261))	('EV1', 'Gene', (320, 323))	('BRCA', 'Gene', '672', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('glycolysis', 'biological_process', 'GO:0006096', ('270', '280'))	('OV', 'Phenotype', 'HP:0012887', (183, 185))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('BRCA', 'Gene', (187, 191))	('core', 'cellular_component', 'GO:0019013', ('152', '156'))	('DNA', 'cellular_component', 'GO:0005574', ('243', '246'))	('DNA amplifications', 'Var', (243, 261))	('A tumors', 'Disease', (167, 175))
101988	28202506	For example, BRCA signature A tumors exhibited DNA amplification of most genes from the glycolytic pathway, as well as amplification of lactate dehydrogenase B, deletion of pyruvate dehydrogenase subunits A and B, and amplification of the glycolysis-regulating metabolic enzyme TIGAR (human gene C12orf5; Fig 1G).	('TIGAR', 'Gene', (278, 283))	('pyruvate dehydrogenase', 'Gene', '54704', (173, 195))	('pyruvate dehydrogenase', 'Gene', (173, 195))	('BRCA', 'Gene', (13, 17))	('glycolytic', 'Enzyme', (88, 98))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('A tumors', 'Disease', 'MESH:D009369', (28, 36))	('amplification', 'Var', (218, 231))	('lactate dehydrogenase B', 'Gene', '3945', (136, 159))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('TIGAR', 'Gene', '57103', (278, 283))	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('lactate dehydrogenase B', 'Gene', (136, 159))	('human', 'Species', '9606', (285, 290))	('amplification', 'PosReg', (51, 64))	('DNA amplification', 'biological_process', 'GO:0006277', ('47', '64'))	('genes', 'Gene', (73, 78))	('glycolysis', 'biological_process', 'GO:0006096', ('239', '249'))	('A tumors', 'Disease', (28, 36))	('C12orf5', 'Gene', '57103', (296, 303))	('deletion', 'Var', (161, 169))	('C12orf5', 'Gene', (296, 303))	('amplification', 'Var', (119, 132))	('BRCA', 'Gene', '672', (13, 17))
101991	28202506	Thus, PCA identified a shared signature from breast, lung, ovarian, and uterine carcinomas that was enriched for p53 mutations, higher numbers of genomic breakpoints, and CNA of genes from the core glycolysis pathway.	('mutations', 'Var', (117, 126))	('core glycolysis pathway', 'Pathway', (193, 216))	('breast', 'Disease', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('glycolysis', 'biological_process', 'GO:0006096', ('198', '208'))	('ovarian', 'Disease', (59, 66))	('core', 'cellular_component', 'GO:0019013', ('193', '197'))	('uterine carcinomas', 'Phenotype', 'HP:0010784', (72, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('carcinomas', 'Disease', (80, 90))	('carcinomas', 'Disease', 'MESH:D002277', (80, 90))	('lung', 'Disease', (53, 57))	('p53', 'Gene', (113, 116))
101992	28202506	While canonical oncogenes and tumor suppressor genes drive some recurrent DNA copy number alterations, many recurrent CNA regions cannot be fully explained by the presence of known cancer genes (Beroukhim et al, 2010; Muller et al, 2012; Davoli et al, 2013).	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('DNA', 'Gene', (74, 77))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('cancer', 'Disease', (181, 187))	('tumor', 'Disease', (30, 35))	('copy number alterations', 'Var', (78, 101))
102038	28202506	Returning to the result of the CNA-defined signature A being associated with increased FDG uptake in human primary tumors in vivo, we next asked which sets of metabolic gene loci copy number levels were most predictive of glycolytic phenotypes.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('FDG', 'Chemical', 'MESH:D019788', (87, 90))	('human', 'Species', '9606', (101, 106))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('copy number', 'Var', (179, 190))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('increased', 'PosReg', (77, 86))	('uptake', 'biological_process', 'GO:0098657', ('91', '97'))	('uptake', 'biological_process', 'GO:0098739', ('91', '97'))
102042	28202506	Averaging results across these two test cases revealed that genes from the glycolysis and pentose phosphate pathway were most predictive of these metabolic phenotypes (Fig 3C and Table EV4; P = 0.01).	('genes', 'Var', (60, 65))	('glycolysis', 'Enzyme', (75, 85))	('glycolysis', 'biological_process', 'GO:0006096', ('75', '85'))	('pentose phosphate', 'Chemical', 'MESH:D010428', (90, 107))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('90', '115'))
102054	28202506	In contrast, the MEF-derived signature B was characterized by amplification of Mdm2 or deletion of Cdkn2a (Ink4a/Arf) and fewer overall copy number alterations.	('amplification', 'PosReg', (62, 75))	('Cdkn2a', 'Gene', (99, 105))	('Mdm2', 'Gene', (79, 83))	('Ink4a/Arf', 'Gene', (107, 116))	('deletion', 'Var', (87, 95))	('Ink4a/Arf', 'Gene', '1029', (107, 116))
102056	28202506	As in human BRCA (Fig EV2E), amplification of Mdm2 and loss of Cdkn2a were generally mutually exclusive in signature B MEFs (Appendix Fig S6D), reflecting alternate mechanisms for disabling the p53/ARF axis (Sherr & Weber, 2000).	('Mdm2', 'Gene', (46, 50))	('human', 'Species', '9606', (6, 11))	('loss', 'NegReg', (55, 59))	('signature B', 'Disease', (107, 118))	('amplification', 'Var', (29, 42))	('MEFs', 'CellLine', 'CVCL:9115', (119, 123))	('ARF axis', 'Disease', (198, 206))	('BRCA', 'Gene', '672', (12, 16))	('ARF axis', 'Disease', 'MESH:C566610', (198, 206))	('EV2', 'Gene', '147138', (22, 25))	('BRCA', 'Gene', (12, 16))	('EV2', 'Gene', (22, 25))	('Cdkn2a', 'Gene', (63, 69))
102060	28202506	p53-/- MEFs do not undergo senescence (Olive et al, 2004), and consistent with this, we observed that they tended to have less strong copy number alterations.	('senescence', 'biological_process', 'GO:0010149', ('27', '37'))	('Olive', 'Species', '4146', (39, 44))	('less', 'NegReg', (122, 126))	('MEFs', 'CellLine', 'CVCL:9115', (7, 11))	('p53-/- MEFs', 'Var', (0, 11))
102061	28202506	In summary, strong p53 functional loss (p53 mutation or genetic loss) tends to lead to the CNA signature A pattern, which is associated with a higher degree of copy number alterations (higher integrated CNA score and more breakpoints) and Hk2 amplification, while weaker or less complete p53 functional loss (e.g., mediated by Mdm2 amplification or Cdkn2a loss) is associated with an alternative signature (signature B).	('CNA signature', 'Disease', (91, 104))	('mutation', 'Var', (44, 52))	('functional loss', 'NegReg', (23, 38))	('Hk2', 'molecular_function', 'GO:0008256', ('239', '242'))	('amplification', 'Var', (243, 256))	('Hk2', 'Gene', (239, 242))	('p53', 'Gene', (288, 291))	('Cdkn2a', 'Gene', (349, 355))	('copy', 'MPA', (160, 164))	('p53', 'Gene', (19, 22))	('functional loss', 'NegReg', (292, 307))	('lead', 'Reg', (79, 83))	('genetic loss', 'Disease', 'MESH:D030342', (56, 68))	('genetic loss', 'Disease', (56, 68))	('Mdm2', 'Gene', (327, 331))	('loss', 'NegReg', (356, 360))
102062	28202506	Next we sought to understand how CNA signatures revealed by CGH relate to numerical and structural aneuploidy (i.e., whole chromosomal and subchromosomal gains or losses, respectively).	('subchromosomal', 'Var', (139, 153))	('aneuploidy', 'Disease', 'MESH:D000782', (99, 109))	('losses', 'NegReg', (163, 169))	('aneuploidy', 'Disease', (99, 109))
102076	28202506	Furthermore, p53-/- cells did not undergo senescence (Olive et al, 2004) and exhibited less strong copy number alterations than wild-type signature A MEFs (Appendix Fig S7B; P = 9 x 10-4).	('senescence', 'biological_process', 'GO:0010149', ('42', '52'))	('copy number alterations', 'MPA', (99, 122))	('p53-/-', 'Var', (13, 19))	('MEFs', 'CellLine', 'CVCL:9115', (150, 154))	('Olive', 'Species', '4146', (54, 59))
102082	28202506	In cross-species pathway enrichment analysis, MEF CNA signatures added a similar amount of enrichment signal to human tumor signatures as do the non-MEF mouse model signatures, and when combined together, the enrichment was even stronger (e.g., glycolysis and core glycolysis pathways, Fig 4F).	('glycolysis', 'biological_process', 'GO:0006096', ('265', '275'))	('enrichment', 'MPA', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('core glycolysis pathways', 'Pathway', (260, 284))	('mouse', 'Species', '10090', (153, 158))	('core', 'cellular_component', 'GO:0019013', ('260', '264'))	('tumor', 'Disease', (118, 123))	('MEF', 'Var', (46, 49))	('glycolysis', 'biological_process', 'GO:0006096', ('245', '255'))	('human', 'Species', '9606', (112, 117))
102098	28202506	We found that three glycolytic genes (LDHB, TPI1, and GAPDH) and one oncogene (KRAS) exhibited strong DNA-RNA correlation (r > 0.66), three glycolytic genes (HK2, ENO2, and PGAM2) and three oncogenes (MYC, CHD4, and TRRAP) exhibited moderate correlation (0.2 < r < 0.5), and only one glycolytic gene (GCK) and one oncogene (GATA2) exhibited weak DNA-RNA correlation (r < 0.2) (Appendix Fig S10A and B).	('PGAM2', 'Gene', '5224', (173, 178))	('S10A', 'SUBSTITUTION', 'None', (390, 394))	('TPI1', 'Gene', (44, 48))	('TRRAP', 'Gene', '8295', (216, 221))	('GCK', 'Gene', '2645', (301, 304))	('MYC', 'Gene', (201, 204))	('S10A', 'Var', (390, 394))	('HK2', 'molecular_function', 'GO:0008256', ('158', '161'))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))	('PGAM2', 'Gene', (173, 178))	('RNA', 'cellular_component', 'GO:0005562', ('350', '353'))	('HK2', 'Gene', (158, 161))	('HK2', 'Gene', '3099', (158, 161))	('MYC', 'Gene', '4609', (201, 204))	('LDHB', 'Gene', (38, 42))	('KRAS', 'Gene', '3845', (79, 83))	('LDHB', 'Gene', '3945', (38, 42))	('RNA', 'cellular_component', 'GO:0005562', ('106', '109'))	('GAPDH', 'Gene', '2597', (54, 59))	('ENO2', 'Gene', '2026', (163, 167))	('CHD4', 'Gene', (206, 210))	('KRAS', 'Gene', (79, 83))	('DNA', 'cellular_component', 'GO:0005574', ('346', '349'))	('GCK', 'Gene', (301, 304))	('ENO2', 'Gene', (163, 167))	('CHD4', 'Gene', '1108', (206, 210))	('TRRAP', 'Gene', (216, 221))	('TPI1', 'Gene', '7167', (44, 48))	('GAPDH', 'Gene', (54, 59))
102099	28202506	This analysis indicates that gene copy number alterations at the DNA level generally lead to increased RNA expression in signature A tumors in BRCA, LU, and OV tumors, with a similar degree of correlation observed for both glycolysis genes and oncogenes.	('gene copy number alterations', 'Var', (29, 57))	('RNA', 'Gene', (103, 106))	('BRCA', 'Gene', (143, 147))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('OV tumors', 'Disease', 'MESH:D009369', (157, 166))	('OV', 'Phenotype', 'HP:0012887', (157, 159))	('RNA', 'cellular_component', 'GO:0005562', ('103', '106'))	('glycolysis', 'biological_process', 'GO:0006096', ('223', '233'))	('increased', 'PosReg', (93, 102))	('A tumors', 'Disease', (131, 139))	('expression', 'MPA', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('OV tumors', 'Disease', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('A tumors', 'Disease', 'MESH:D009369', (131, 139))	('BRCA', 'Gene', '672', (143, 147))
102104	28202506	Taken together, these results support a model in which the selection pressures shared during immortalization and tumorigenesis result in cross-species conservation of the glycolysis gene loci copy number alterations (Fig 4E and F, and Table EV2).	('tumor', 'Disease', (113, 118))	('copy number alterations', 'Var', (192, 215))	('EV2', 'Gene', (241, 244))	('EV2', 'Gene', '147138', (241, 244))	('glycolysis', 'biological_process', 'GO:0006096', ('171', '181'))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
102105	28202506	To test this hypothesis, we transduced pre-senescent MEFs with either wild-type HK2 or HK1, kinase-dead HK2 (D209A/D657A) (McCoy et al, 2014), or wild-type ENO2 and allowed the cells to senesce and immortalize in the presence of these exogenously expressed proteins (Appendix Fig S11).	('transduced', 'Reg', (28, 38))	('HK1', 'Gene', '3098', (87, 90))	('D657A', 'Var', (115, 120))	('HK2', 'Gene', '3099', (104, 107))	('HK2', 'Gene', (104, 107))	('pre', 'molecular_function', 'GO:0003904', ('39', '42'))	('HK2', 'molecular_function', 'GO:0008256', ('104', '107'))	('HK1', 'molecular_function', 'GO:0004673', ('87', '90'))	('HK2', 'molecular_function', 'GO:0008256', ('80', '83'))	('ENO2', 'Gene', '2026', (156, 160))	('ENO2', 'Gene', (156, 160))	('HK2', 'Gene', (80, 83))	('HK2', 'Gene', '3099', (80, 83))	('MEFs', 'CellLine', 'CVCL:9115', (53, 57))	('D209A', 'Var', (109, 114))	('immortalize', 'CPA', (198, 209))	('D657A', 'SUBSTITUTION', 'None', (115, 120))	('HK1', 'Gene', (87, 90))	('D209A', 'SUBSTITUTION', 'None', (109, 114))
102109	28202506	In this analysis, we found that cells expressing exogenous hexokinase demonstrated significantly reduced Hk2:Chr6 max ratios (P = 3 x 10-3) (Fig 5A and C).	('Hk2', 'molecular_function', 'GO:0008256', ('105', '108'))	('hexokinase', 'Gene', (59, 69))	('exogenous', 'Var', (49, 58))	('hexokinase', 'Gene', '3098', (59, 69))	('reduced', 'NegReg', (97, 104))	('Hk2:Chr6 max ratios', 'MPA', (105, 124))
102110	28202506	Additionally, a MEF subline expressing exogenous ENO2 exhibited deletion rather than amplification of the Eno2 locus on chr.	('ENO2', 'Gene', '2026', (49, 53))	('exhibited', 'Reg', (54, 63))	('deletion', 'Var', (64, 72))	('ENO2', 'Gene', (49, 53))
102119	28202506	As noted above, the evolving MEF CNA signature pattern was enriched for DNA amplifications of genes in the core glycolysis and glycolysis-associated pathways (Table EV2), particularly due to amplification of chromosome 6, which contains multiple metabolic gene loci including Hk2 and Eno2 (Fig 4A and E, and Appendix Fig S6B).	('Hk2', 'molecular_function', 'GO:0008256', ('276', '279'))	('Eno2', 'Gene', (284, 288))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('amplification', 'Var', (191, 204))	('glycolysis', 'biological_process', 'GO:0006096', ('127', '137'))	('Hk2', 'Gene', (276, 279))	('EV2', 'Gene', '147138', (165, 168))	('EV2', 'Gene', (165, 168))	('glycolysis', 'biological_process', 'GO:0006096', ('112', '122'))	('chromosome', 'cellular_component', 'GO:0005694', ('208', '218'))	('glycolysis-associated pathways', 'Pathway', (127, 157))	('core', 'cellular_component', 'GO:0019013', ('107', '111'))
102132	28202506	Chromosomal instability and high glycolysis characterize some of the most aggressive tumors, and the complexity and plasticity of the genomes in aggressive tumors can hinder molecularly targeted therapies (Nakamura et al, 2011; McGranahan et al, 2012; Shi et al, 2012).	('aggressive tumors', 'Disease', 'MESH:D001523', (74, 91))	('high glycolysis', 'MPA', (28, 43))	('aggressive tumors', 'Disease', (145, 162))	('aggressive tumors', 'Disease', (74, 91))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Chromosomal', 'Var', (0, 11))	('glycolysis', 'biological_process', 'GO:0006096', ('33', '43'))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('hinder', 'NegReg', (167, 173))	('aggressive tumors', 'Disease', 'MESH:D001523', (145, 162))
102135	28202506	We found that CNAs in core glycolysis enzymes (e.g., HK2) and other cancer-linked metabolic enzymes such as TIGAR are coordinately enriched in tumors with distinct CNA signatures.	('CNAs', 'Var', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('core', 'cellular_component', 'GO:0019013', ('22', '26'))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('HK2', 'molecular_function', 'GO:0008256', ('53', '56'))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', (143, 149))	('HK2', 'Gene', (53, 56))	('TIGAR', 'Gene', (108, 113))	('HK2', 'Gene', '3099', (53, 56))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('glycolysis', 'biological_process', 'GO:0006096', ('27', '37'))	('TIGAR', 'Gene', '57103', (108, 113))
102140	28202506	Combined with the observation that metabolic genes can facilitate cellular immortalization (Kondoh et al, 2005; Kondoh, 2009; Kaplon et al, 2013), our results implicate tumor metabolism as an additional fitness measure linked to how genomic instability can enable tumorigenesis.	('enable', 'PosReg', (257, 263))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('genomic instability', 'Var', (233, 252))	('metabolism', 'biological_process', 'GO:0008152', ('175', '185'))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (264, 269))
102142	28202506	Paradoxically, chromosomal instability can act either as an oncogene or as a tumor suppressor depending on the context (Weaver et al, 2007).	('tumor suppressor', 'molecular_function', 'GO:0008181', ('77', '93'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('chromosomal instability', 'Var', (15, 38))	('tumor', 'Disease', (77, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('77', '93'))	('chromosomal instability', 'Phenotype', 'HP:0040012', (15, 38))
102148	28202506	Numerous stimuli, including RAS mutations, matrix detachment, altered metabolism, and hypoxia, induce the accumulation of intracellular ROS (Lee et al, 1999; Schafer et al, 2009; Weinberg et al, 2010; Anastasiou et al, 2011).	('ROS', 'Chemical', 'MESH:D017382', (136, 139))	('accumulation', 'PosReg', (106, 118))	('RAS', 'Gene', (28, 31))	('intracellular', 'cellular_component', 'GO:0005622', ('122', '135'))	('metabolism', 'biological_process', 'GO:0008152', ('70', '80'))	('mutations', 'Var', (32, 41))	('hypoxia', 'Disease', (86, 93))	('hypoxia', 'Disease', 'MESH:D000860', (86, 93))	('intracellular ROS', 'MPA', (122, 139))
102154	28202506	RNA knockdown-based analyses have also been used to support a more systems-level model in which the selection for amplification and deletion of a particular DNA region is based on the cumulative effects of many positive and negative fitness gains from multiple genes within that genomic region (Solimini et al, 2012; Cai et al, 2016).	('deletion', 'Var', (132, 140))	('fitness gains', 'Disease', 'MESH:D015430', (233, 246))	('fitness gains', 'Disease', (233, 246))	('negative', 'NegReg', (224, 232))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
102158	28202506	The coordinated alterations of metabolic genes at the DNA level adds an additional mechanism, namely conserved sets of CNA changes, by which glycolysis is dysregulated to promote tumorigenesis.	('alterations', 'Reg', (16, 27))	('promote', 'PosReg', (171, 178))	('changes', 'Var', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('glycolysis', 'MPA', (141, 151))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('glycolysis', 'biological_process', 'GO:0006096', ('141', '151'))	('tumor', 'Disease', (179, 184))
102161	28202506	Across multiple tumor types, loss of p53 function through p53 mutation is associated with the high breakpoint signature A pattern.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('function', 'MPA', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('loss', 'NegReg', (29, 33))	('p53', 'Protein', (37, 40))	('mutation', 'Var', (62, 70))	('tumor', 'Disease', (16, 21))	('p53', 'Gene', (58, 61))	('high breakpoint signature A', 'MPA', (94, 121))
102162	28202506	In contrast, loss of the p53/ARF axis via other mechanisms (MDM2 amplification or CDKN2A deletion) in BRCA human tumors is associated with a different CNA signature (signature B) that in general has fewer breakpoints.	('MDM2', 'Gene', '4193', (60, 64))	('BRCA', 'Gene', (102, 106))	('MDM2', 'Gene', (60, 64))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('human', 'Species', '9606', (107, 112))	('CDKN2A', 'Gene', (82, 88))	('ARF axis', 'Disease', (29, 37))	('deletion', 'Var', (89, 97))	('CDKN2A', 'Gene', '1029', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('loss', 'NegReg', (13, 17))	('CNA signature', 'MPA', (151, 164))	('ARF axis', 'Disease', 'MESH:C566610', (29, 37))	('BRCA', 'Gene', '672', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
102163	28202506	Notably, the two mouse signatures and their associated phenotype strengths were defined by the initiating loss of tumor suppression event, namely Trp53 mutation versus either Mdm2 amplification or Cdkn2a loss.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('mouse', 'Species', '10090', (17, 22))	('Trp53', 'Gene', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('loss', 'NegReg', (204, 208))	('tumor', 'Disease', (114, 119))	('Trp53', 'Gene', '22059', (146, 151))	('loss', 'NegReg', (106, 110))	('mutation', 'Var', (152, 160))
102164	28202506	Thus, while the consequences of TP53 mutation and "MDM2 amplification/CDKN2A loss" are considered functionally similar and therefore mutually exclusive (Wade et al, 2013), our findings indicate they are not fully equivalent in terms of genomic instability and subsequent metabolic evolution.	('mutation', 'Var', (37, 45))	('TP53', 'Gene', '7157', (32, 36))	('MDM2', 'Gene', '4193', (51, 55))	('MDM2', 'Gene', (51, 55))	('TP53', 'Gene', (32, 36))	('loss', 'NegReg', (77, 81))	('CDKN2A', 'Gene', (70, 76))	('CDKN2A', 'Gene', '1029', (70, 76))
102165	28202506	The tolerance of more highly disrupted and rearranged genomes upon p53 mutation appears to allow more flexibility in the evolution of aneuploid cancer genomes, thereby resulting in stronger glycolysis and somewhat enhanced proliferation.	('glycolysis', 'MPA', (190, 200))	('glycolysis', 'biological_process', 'GO:0006096', ('190', '200'))	('proliferation', 'CPA', (223, 236))	('mutation', 'Var', (71, 79))	('aneuploid cancer', 'Disease', (134, 150))	('aneuploid cancer', 'Disease', 'MESH:D000782', (134, 150))	('p53', 'Gene', (67, 70))	('stronger', 'PosReg', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('enhanced', 'PosReg', (214, 222))
102169	28202506	The most copy number aberrant tumors tend to have fewer point mutations in canonical oncogenes (e.g., KRAS, Fig EV2A and C) and less canonical oncogene amplification (e.g., MYC, Fig 1B).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('point mutations', 'MPA', (56, 71))	('MYC', 'Gene', (173, 176))	('KRAS', 'Gene', '3845', (102, 106))	('Fig', 'Disease', (108, 111))	('fewer', 'NegReg', (50, 55))	('copy number aberrant', 'Var', (9, 29))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('EV2A and C', 'Gene', '2121', (112, 122))	('KRAS', 'Gene', (102, 106))	('MYC', 'Gene', '4609', (173, 176))
102170	28202506	Hence, genomic instability and subsequent coordinate alterations in multiple genes within a functional pathway may provide an alternate, more complex, pathway to acquisition of aggressive tumor phenotypes:with tumor evolution and selection guiding the trajectory (Ciriello et al, 2013).	('tumor', 'Disease', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('aggressive tumor', 'Disease', (177, 193))	('tumor', 'Disease', (210, 215))	('alterations', 'Var', (53, 64))	('genomic instability', 'Var', (7, 26))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('aggressive tumor', 'Disease', 'MESH:D001523', (177, 193))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
102171	28202506	In that KRAS mutation and MYC amplification can drive glycolysis (Ying et al, 2012; Dang, 2013), the findings that signature A tumors are de-enriched in these events relative to signature B tumors and enriched for glycolysis gene loci CNA amplifications support that tumor cells can meet their metabolic demands through distinct mechanisms, or combinations thereof.	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('A tumors', 'Disease', 'MESH:D009369', (125, 133))	('MYC', 'Gene', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('drive', 'Reg', (48, 53))	('glycolysis', 'MPA', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('glycolysis', 'biological_process', 'GO:0006096', ('214', '224'))	('glycolysis', 'biological_process', 'GO:0006096', ('54', '64'))	('B tumors', 'Disease', (188, 196))	('MYC', 'Gene', '4609', (26, 29))	('A tumors', 'Disease', (125, 133))	('B tumors', 'Disease', 'MESH:D006509', (188, 196))	('KRAS', 'Gene', '3845', (8, 12))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', (127, 132))	('mutation', 'Var', (13, 21))	('KRAS', 'Gene', (8, 12))	('tumor', 'Disease', (267, 272))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
102172	28202506	Future models of the most aggressive cases of cancer will need to incorporate aspects of spontaneous genomic instability (mediated by distinct instability mechanisms) and resulting copy number alterations.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('copy number alterations', 'Var', (181, 204))	('spontaneous genomic instability', 'MPA', (89, 120))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
102175	28202506	p53fl/fl MEFs were obtained at day E14.5 from p53fl/fl (FVB.129P2-Trp53tm1Brn/Nci) crossed with C57BL/6-129/SV mice.	('MEFs', 'CellLine', 'CVCL:9115', (9, 13))	('129/SV', 'Species', '10090', (104, 110))	('Trp53', 'Gene', (66, 71))	('mice', 'Species', '10090', (111, 115))	('Trp53', 'Gene', '22059', (66, 71))	('p53fl/fl', 'Var', (46, 54))
102179	28202506	Overexpression of HK1, HK2, kinase-dead HK2 (D209A/D657A), or ENO2 glycolysis enzymes and the MYC oncogene or the control protein RFP in CD1 MEFs was accomplished by transduction of non-immortalized cells with pDS-FB-neo retrovirus, followed by selection in 600 mug/ml G418.	('HK1', 'molecular_function', 'GO:0004673', ('18', '21'))	('RFP', 'Gene', (130, 133))	('HK2', 'molecular_function', 'GO:0008256', ('23', '26'))	('HK2, kinase-dead HK2', 'Gene', '3099', (23, 43))	('G418', 'Chemical', 'MESH:C010680', (269, 273))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('ENO2', 'Gene', '2026', (62, 66))	('RFP', 'Gene', '2358', (130, 133))	('HK1', 'Gene', (18, 21))	('MEFs', 'CellLine', 'CVCL:9115', (141, 145))	('D657A', 'Var', (51, 56))	('ENO2', 'Gene', (62, 66))	('mug', 'molecular_function', 'GO:0043739', ('262', '265'))	('MYC', 'Gene', (94, 97))	('HK2', 'molecular_function', 'GO:0008256', ('40', '43'))	('D209A', 'Var', (45, 50))	('transduction', 'biological_process', 'GO:0009293', ('166', '178'))	('HK1', 'Gene', '3098', (18, 21))	('glycolysis', 'biological_process', 'GO:0006096', ('67', '77'))	('D657A', 'SUBSTITUTION', 'None', (51, 56))	('MYC', 'Gene', '4609', (94, 97))	('D209A', 'SUBSTITUTION', 'None', (45, 50))
102180	28202506	Deletion of p53 in p53fl/fl MEFs was induced by infection of non-immortalized cells with either retroviral Cre-GFP or Cre-ERT2 plus treatment with 1 muM 4-OHT.	('4-OHT', 'Chemical', 'MESH:C032278', (153, 158))	('ERT2', 'Gene', '5595', (122, 126))	('induced', 'Reg', (37, 44))	('p53', 'Gene', (12, 15))	('MEFs', 'CellLine', 'CVCL:9115', (28, 32))	('ERT2', 'Gene', (122, 126))	('Deletion', 'Var', (0, 8))
102188	28202506	Molecular subtypes tested were as follows: BRCA: basal, luminal, claudin-low, and HER2-enriched (The Cancer Genome Atlas Research Network, 2012b); LUAD: bronchioid, magnoid, and squamoid (The Cancer Genome Atlas Research Network, 2014); LUSC: basal, classical, primitive, and secretory (The Cancer Genome Atlas Research Network, 2012a); OV: proliferative, immunoreactive, differentiated, and mesenchymal (The Cancer Genome Atlas Research Network, 2011); and UCEC: POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high (The Cancer Genome Atlas Research Network, 2013).	('AD', 'Disease', (149, 151))	('low', 'NegReg', (536, 539))	('copy number high', 'Var', (545, 561))	('LUSC', 'Phenotype', 'HP:0030359', (237, 241))	('Cancer', 'Phenotype', 'HP:0002664', (291, 297))	('copy number', 'Var', (524, 535))	('OV', 'Phenotype', 'HP:0012887', (337, 339))	('Cancer', 'Phenotype', 'HP:0002664', (192, 198))	('HER2', 'Gene', (82, 86))	('Cancer', 'Phenotype', 'HP:0002664', (567, 573))	('BRCA', 'Gene', '672', (43, 47))	('HER2', 'Gene', '2064', (82, 86))	('Cancer', 'Phenotype', 'HP:0002664', (409, 415))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('BRCA', 'Gene', (43, 47))	('AD', 'Disease', 'MESH:D000544', (149, 151))
102193	28202506	The signed absolute minimum consistency score (SAMCS) was defined as non-zero when all CNA summary signatures have the same sign across all tumor types, and the score is derived from the absolute value-based minimum summary metric and then re-signed positive for amplification or negative for deletion.	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('amplification', 'Var', (263, 276))	('tumor', 'Disease', (140, 145))
102194	28202506	Consistent amplifications or deletions were combined into a "consistent region", when absolute SAMCS values greater than 0.05 spanned at least 1 Mbp.	('deletions', 'Var', (29, 38))	('Mbp', 'Gene', (145, 148))	('Mbp', 'Gene', '4155', (145, 148))
102241	28202506	The genetically engineered mouse models with characterized CNA were obtained from public datasets: mammary (breast) tumors (Brca, 57 samples, GSE30710; 62 samples, GSE43997; 44 samples, GSE27101) (Drost et al, 2011; Herschkowitz et al, 2012); melanoma (Skcm, 30 samples, GSE58265) (Viros et al, 2014); glioblastoma/high-grade astrocytoma (Gbm, 72 samples, GSE22927) (Chow et al, 2011); and prostate tumors (Prad, 18 samples GSE35247; 55 samples, GSE61382) (Ding et al, 2012; Wanjala et al, 2015).	('glioblastoma', 'Phenotype', 'HP:0012174', (302, 314))	('melanoma', 'Disease', 'MESH:D008545', (243, 251))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('GSE35247', 'Var', (424, 432))	('prostate tumors', 'Disease', (390, 405))	('breast) tumors', 'Disease', 'MESH:D001943', (108, 122))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('prostate tumors', 'Disease', 'MESH:D011471', (390, 405))	('astrocytoma', 'Phenotype', 'HP:0009592', (326, 337))	('Brca', 'Gene', '672', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (243, 251))	('melanoma', 'Disease', (243, 251))	('tumors', 'Phenotype', 'HP:0002664', (399, 405))	('glioblastoma', 'Disease', 'MESH:D005909', (302, 314))	('Brca', 'Gene', (124, 128))	('mouse', 'Species', '10090', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (399, 404))	('glioblastoma', 'Disease', (302, 314))	('astrocytoma', 'Disease', 'MESH:D001254', (326, 337))	('astrocytoma', 'Disease', (326, 337))
102263	25409906	Both proliferating cells and transformed cells have been shown to favor expression of shortened 3' UTRs through APA, leading to activation of several proto-oncogenes, such as Cyclin D1.	('activation', 'PosReg', (128, 138))	('APA', 'Gene', (112, 115))	('favor', 'PosReg', (66, 71))	('shortened', 'Var', (86, 95))	('expression', 'MPA', (72, 82))	('Cyclin D1', 'Gene', '595', (175, 184))	('Cyclin', 'molecular_function', 'GO:0016538', ('175', '181'))	('Cyclin D1', 'Gene', (175, 184))
102298	25409906	For example, PolyA-seq is designed to amplify polyA tags; therefore, some dynamic APA events reported by PolyA-seq may have a small magnitude of changes that are not readily detectable by RNA-seq (Supplementary Fig.	('PolyA-seq', 'Chemical', '-', (105, 114))	('polyA', 'Chemical', 'MESH:D011061', (46, 51))	('PolyA-seq', 'Chemical', '-', (13, 22))	('PolyA-seq', 'Var', (105, 114))	('RNA', 'cellular_component', 'GO:0005562', ('188', '191'))	('APA', 'MPA', (82, 85))
102314	25409906	In addition, AATAAA and ATTAAA are the most prevalent motifs among variants of polyA signals (Supplementary Fig.	('polyA', 'Chemical', 'MESH:D011061', (79, 84))	('polyA signals', 'Gene', (79, 92))	('AATAAA', 'Disease', (13, 19))	('prevalent', 'Reg', (44, 53))	('variants', 'Var', (67, 75))
102361	25409906	The implication of the 3' UTR switch to GAC is that the expression of GLS is no longer regulated by miR-23 or MYC.	('GAC', 'Gene', '2744', (40, 43))	('GAC', 'Gene', (40, 43))	('GLS', 'Gene', (70, 73))	('MYC', 'Gene', (110, 113))	('miR-23', 'Chemical', '-', (100, 106))	('miR-23', 'Var', (100, 106))	('MYC', 'Gene', '4609', (110, 113))	('GLS', 'Gene', '2744', (70, 73))
102389	25409906	They reported 171 genes with lengthening in 3' UTRs upon knock down of CstF64, among which 46 genes from our analysis have shortened 3' UTRs in tumors where CstF64 is up-regulated (Fig.	('tumors', 'Disease', (144, 150))	('CstF64', 'Gene', '1478', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('CstF64', 'Gene', (157, 163))	('shortened', 'NegReg', (123, 132))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('CstF', 'molecular_function', 'GO:0030365', ('157', '161'))	('CstF64', 'Gene', '1478', (157, 163))	('knock down', 'Var', (57, 67))	('CstF', 'molecular_function', 'GO:0030365', ('71', '75'))	('CstF64', 'Gene', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('up-regulated', 'PosReg', (167, 179))
102414	25409906	Fourth, our study reveals a novel link between altered 3' UTR usage and cancer metabolism.	('metabolism', 'biological_process', 'GO:0008152', ('79', '89'))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('altered', 'Var', (47, 54))	('cancer', 'Disease', (72, 78))
102423	25409906	These RNA aberrations represent an illustrative case of genomic "dark matter" beyond coding regions, and thus may also provide new directions for tumor gene discovery.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('aberrations', 'Var', (10, 21))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
102473	22642265	While age at diagnosis, American Society of Anesthesiologists score, advanced stage, nodal involvement and high grade adversely affected recurrence-free survival, smoking status was not associated with risk of recurrence or death in multivariate analysis (P = 0.60).	('death', 'Disease', (224, 229))	('recurrence-free survival', 'CPA', (137, 161))	('high grade', 'Var', (107, 117))	('nodal', 'Gene', '4838', (85, 90))	('death', 'Disease', 'MESH:D003643', (224, 229))	('affected', 'Reg', (128, 136))	('nodal', 'Gene', (85, 90))
102481	22642265	Smoking is also an important modifier of genetic risk, as smokers who carry variants in NAT2 and GSMT1 are at highest risk of developing urothelial carcinoma.	('NAT2', 'Gene', (88, 92))	('GSMT1', 'Gene', (97, 102))	('urothelial carcinoma', 'Disease', (137, 157))	('variants', 'Var', (76, 84))	('NAT2', 'Gene', '10', (88, 92))	('GSMT', 'molecular_function', 'GO:0033804', ('97', '101'))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (137, 157))
102516	22642265	Increased age at diagnosis, ASA score >=3, advanced pT stage, positive nodal status, and high grade disease were all associated with decreased RFS probability in univariate analysis and remained associated with increased risk of recurrence or death in multivariate analysis.	('high grade', 'Var', (89, 99))	('death', 'Disease', 'MESH:D003643', (243, 248))	('RFS', 'Chemical', '-', (143, 146))	('RFS probability', 'MPA', (143, 158))	('death', 'Disease', (243, 248))	('nodal', 'Gene', (71, 76))	('nodal', 'Gene', '4838', (71, 76))	('ASA', 'Chemical', '-', (28, 31))	('ASA score', 'Gene', (28, 37))	('decreased', 'NegReg', (133, 142))
102521	22642265	Advanced pT stage, positive nodal status, and high grade disease were all associated with increased cumulative incidence of recurrence in univariate analysis and remained associated with increased risk of recurrence in multivariate analysis.	('nodal', 'Gene', '4838', (28, 33))	('nodal', 'Gene', (28, 33))	('high grade', 'Var', (46, 56))
102544	21571333	BMI was treated as a continuous and a categorical variable defined as normal weight (<25 kg/m2), overweight (25-29.9 kg/m2) or obese (>=30 kg/m2).	('25-29.9 kg/m2', 'Var', (109, 122))	('overweight', 'Phenotype', 'HP:0025502', (97, 107))	('obese', 'Disease', (127, 132))	('obese', 'Disease', 'MESH:D009765', (127, 132))
102549	21571333	In the postoperative model, tumor stage (p<0.001), positive lymph nodes (HR 2.52, 95% CI: 1.59-4.0, p<0.001), BMI 25-29 kg/m2 (HR 2.18, 95% CI: 1.27-3.73, p=0.005) and BMI >=30 kg/m2 (HR 3.52, 95% CI: 2.08-5.95, p<0.001) were associated with disease recurrence.	('tumor', 'Disease', (28, 33))	('associated', 'Reg', (226, 236))	('BMI 25-29 kg/m2', 'Var', (110, 125))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('BMI >=30 kg/m2', 'Var', (168, 182))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('disease recurrence', 'CPA', (242, 260))
102586	21571333	Pair-wise comparisons using the log-rank test (Mantel-Cox) showed that patients with BMI >=30 kg/m2 had a higher risk of disease recurrence compared to patients with BMI <25 kg/m2 (p<0.001) and those with BMI 25-29.9 kg/m2 (p<0.001).	('patients', 'Species', '9606', (71, 79))	('BMI >=30 kg/m2', 'Var', (85, 99))	('disease recurrence', 'CPA', (121, 139))	('patients', 'Species', '9606', (152, 160))	('Cox', 'Gene', '1351', (54, 57))	('Cox', 'Gene', (54, 57))
102587	21571333	Similarly, the probability estimate of cancer-specific death was higher in patients with BMI >=30 kg/m2 compared to those with BMI <25 kg/m2 (p<0.001) and those with BMI 25-29.9 kg/m2 (p<0.001).	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('patients', 'Species', '9606', (75, 83))	('BMI >=30 kg/m2', 'Var', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('higher', 'PosReg', (65, 71))
102590	21571333	BMI >= 30 kg/m2 was associated with cancer specific death (HR 4.24, 2.4-7.5, p<0.001).	('associated', 'Reg', (20, 30))	('BMI >= 30 kg/m2', 'Var', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
102593	21571333	Here, we observed that patients with pathologic stage T1 (HR 3.74, 95% CI 1.1-12.6, p=0.034), stage T2 (HR 4.04, 95% CI 1.2-13.6, p=0.024), and stage T3 or greater tumors (HR 9.41, 95% CI 2.82-31.5, p<0.001) are associated with decreased disease-free recurrence compared to stage Ta and Tis tumors.	('Tis tumors', 'Disease', 'MESH:D000072676', (287, 297))	('Tis tumors', 'Disease', (287, 297))	('stage T3 or greater', 'Var', (144, 163))	('tumors', 'Disease', (164, 170))	('patients', 'Species', '9606', (23, 31))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('disease-free recurrence', 'CPA', (238, 261))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (291, 297))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('tumors', 'Disease', 'MESH:D009369', (291, 297))	('decreased', 'NegReg', (228, 237))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumors', 'Disease', (291, 297))
102594	21571333	In addition, positive lymph nodes (HR 2.52, 95% CI: 1.59-4.0, p<0.001), patients with a BMI 25-29 kg/m2 (HR 2.18, 95% CI 1.27-3.73, p=0.005) and patients with a BMI >=30 kg/m2 (HR 3.52, 95% CI 2.08-5.95, p<0.001) experienced worse disease-free recurrence.	('patients', 'Species', '9606', (145, 153))	('positive lymph nodes', 'CPA', (13, 33))	('disease-free recurrence', 'CPA', (231, 254))	('BMI 25-29 kg/m2', 'Var', (88, 103))	('patients', 'Species', '9606', (72, 80))
102604	21571333	In addition, excess body fat is associated with systemic inflammation which may play a role in lower urinary urothelial carcinoma outcomes as suggested by studies that measured circulating levels of inflammatory markers.	('inflammation', 'biological_process', 'GO:0006954', ('57', '69'))	('urinary urothelial carcinoma', 'Disease', (101, 129))	('inflammation', 'Disease', 'MESH:D007249', (57, 69))	('excess', 'Var', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('associated', 'Reg', (32, 42))	('urinary urothelial carcinoma', 'Disease', 'MESH:D001749', (101, 129))	('inflammation', 'Disease', (57, 69))
102730	31816991	Four groups were formed: positive group: T24 + UCNP-LPG-MIL38; three negative controls: C3 + UCNP-LPG-MIL38 (negative cell line), T24 + UCNP-LPG-CRY104 (negative antibody), T24 + UCNP-LPG (no antibody).	('T24 + UCNP-LPG-CRY104', 'Var', (130, 151))	('antibody', 'cellular_component', 'GO:0019814', ('162', '170'))	('antibody', 'cellular_component', 'GO:0042571', ('192', '200'))	('N', 'Chemical', 'MESH:D009584', (49, 50))	('T24 + UCNP-LPG-MIL38', 'Var', (41, 61))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('N', 'Chemical', 'MESH:D009584', (181, 182))	('antibody', 'molecular_function', 'GO:0003823', ('162', '170'))	('antibody', 'cellular_component', 'GO:0019815', ('192', '200'))	('antibody', 'molecular_function', 'GO:0003823', ('192', '200'))	('antibody', 'cellular_component', 'GO:0019814', ('192', '200'))	('N', 'Chemical', 'MESH:D009584', (138, 139))	('T24 + UCNP-LPG', 'Var', (173, 187))	('antibody', 'cellular_component', 'GO:0042571', ('162', '170'))	('antibody', 'cellular_component', 'GO:0019815', ('162', '170'))
102736	31816991	To target T24 urothelial carcinoma cells, expressing Glypican-1, silica-coated UCNP (UCNP@SiO2) were conjugated with a Glypican-1 monoclonal antibody MIL-38, by using LPG linker, resulting in targeted upconversion nanoconjugates UCNP@SiO2-LPG-MIL-38 (Figure 1).	('Glypican-1', 'Gene', (119, 129))	('UCNP@SiO2-LPG-MIL-38', 'Var', (229, 249))	('upconversion', 'PosReg', (201, 213))	('Glypican-1', 'Gene', (53, 63))	('antibody', 'cellular_component', 'GO:0019814', ('141', '149'))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (14, 34))	('nanoconjugates', 'MPA', (214, 228))	('Glypican', 'molecular_function', 'GO:0015017', ('53', '61'))	('urothelial carcinoma', 'Disease', (14, 34))	('N', 'Chemical', 'MESH:D009584', (231, 232))	('antibody', 'molecular_function', 'GO:0003823', ('141', '149'))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('Glypican-1', 'Gene', '2817', (119, 129))	('antibody', 'cellular_component', 'GO:0042571', ('141', '149'))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('Glypican', 'molecular_function', 'GO:0015017', ('119', '127'))	('Glypican-1', 'Gene', '2817', (53, 63))	('silica', 'Chemical', 'MESH:D012822', (65, 71))	('antibody', 'cellular_component', 'GO:0019815', ('141', '149'))
102758	31816991	The success of the conjugation was confirmed by a positive shift of the zeta potential of UCNP@SiO2-LPG-MIL-38 to -5.75 mV (Table 1) and an increase of the hydrodynamic diameter of nanoconjugates (Figure 2E).	('hydrodynamic diameter', 'MPA', (156, 177))	('positive', 'PosReg', (50, 58))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('zeta potential', 'MPA', (72, 86))	('conjugation', 'biological_process', 'GO:0000746', ('19', '30'))	('increase', 'PosReg', (140, 148))	('UCNP@SiO2-LPG-MIL-38', 'Var', (90, 110))
102773	31816991	The mean PL intensity of all T24 cells incubated with nanoconjugates UCNP@SiO2-LPG-MIL-38 was found to be almost eight times higher than the mean PL intensity of C3 cells incubated with the same nanoconjugates and was more than five times higher than mean PL intensity of T24 cells incubated with control nanoconjugates UCNP@SiO2-LPG-CRY104 or UCNP@SiO2-LPG.	('PL intensity', 'MPA', (9, 21))	('N', 'Chemical', 'MESH:D009584', (322, 323))	('N', 'Chemical', 'MESH:D009584', (346, 347))	('higher', 'PosReg', (239, 245))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('higher', 'PosReg', (125, 131))	('PL intensity', 'MPA', (146, 158))	('UCNP@SiO2-LPG-MIL-38', 'Var', (69, 89))
102791	31816991	The increase of the mean hydrodynamic diameter of the antibody-coupled targeted upconversion nanoconjugates UCNP@SiO2-LPG-MIL38 can be interpreted by the attachment of MIL-38 to the surface of nanoparticles and by some degree of aggregation (as can be seen by a secondary peak centred at ~700 nm:see Figure 2E).	('attachment', 'Interaction', (154, 164))	('aggregation', 'MPA', (229, 240))	('mean hydrodynamic diameter', 'MPA', (20, 46))	('UCNP', 'Var', (108, 112))	('antibody', 'cellular_component', 'GO:0019815', ('54', '62'))	('antibody', 'cellular_component', 'GO:0019814', ('54', '62'))	('antibody', 'molecular_function', 'GO:0003823', ('54', '62'))	('men', 'Species', '9606', (160, 163))	('increase', 'PosReg', (4, 12))	('antibody', 'cellular_component', 'GO:0042571', ('54', '62'))	('N', 'Chemical', 'MESH:D009584', (110, 111))	('MIL-38', 'Gene', (168, 174))
102792	31816991	The incubation of urothelial carcinoma cells T24 with targeted nanoconjugates UCNP@SiO2-LPG-MIL-38 resulted in labelling of almost 90% of cells and PL of targeted cells with the intensity up to eight times higher than in the control groups.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (18, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('UCNP', 'Var', (78, 82))	('urothelial carcinoma', 'Disease', (18, 38))	('labelling', 'MPA', (111, 120))	('N', 'Chemical', 'MESH:D009584', (80, 81))
102795	31816991	In this study, we demonstrated the production of targeted upconversion photoluminescent nanoconjugates UCNP@SiO2-LPG-MIL-38 for photodynamic diagnosis of bladder cancer cells and assessed their selectivity and molecular specificity towards Glypican-1 positive urothelial carcinoma cells T24.	('UCNP', 'Var', (103, 107))	('bladder cancer', 'Phenotype', 'HP:0009725', (154, 168))	('upconversion', 'PosReg', (58, 70))	('urothelial carcinoma', 'Disease', (260, 280))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('Glypican', 'molecular_function', 'GO:0015017', ('240', '248'))	('Glypican-1', 'Gene', (240, 250))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (260, 280))	('bladder cancer', 'Disease', (154, 168))	('bladder cancer', 'Disease', 'MESH:D001749', (154, 168))	('Glypican-1', 'Gene', '2817', (240, 250))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))
102845	28824947	Positive margins were associated with worse OS (p = 0.049) and RFS (p = 0.02) (Fig.	('OS', 'Chemical', 'MESH:D009992', (44, 46))	('Positive margins', 'Var', (0, 16))	('RFS', 'Disease', (63, 66))
102846	28824947	In a multivariate cox-porportional hazards model, positive margins were associated with worse OS (HR 3.59; 95% CI 1.36-9.46) and RFS (HR 2.61; 95% CI 1.17-5.84).	('RFS', 'Disease', (129, 132))	('positive margins', 'Var', (50, 66))	('OS', 'Chemical', 'MESH:D009992', (94, 96))	('worse OS', 'Disease', (88, 96))
102863	28824947	All margins were negative and final pathology demonstrated pT3b, N0 sarcomatoid urothelial carcinoma invading the periversicular tissue.	('N0 sarcomatoid urothelial carcinoma', 'Disease', (65, 100))	('pT3b', 'Var', (59, 63))	('N0 sarcomatoid urothelial carcinoma', 'Disease', 'MESH:C538614', (65, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
102890	28824947	One can foresee a future where a patient with clinical T3/T4 bladder cancer undergoes neoadjuvant chemotherapy, has stable disease or disease progression, undergoes radical cystectomy with IORT and adjuvant immunotherapy.	('T3/T4', 'Var', (55, 60))	('patient', 'Species', '9606', (33, 40))	('undergoes', 'Reg', (155, 164))	('bladder cancer', 'Disease', 'MESH:D001749', (61, 75))	('stable disease', 'Disease', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('undergoes', 'Reg', (76, 85))	('bladder cancer', 'Disease', (61, 75))	('stable disease', 'Disease', 'MESH:D060050', (116, 130))	('bladder cancer', 'Phenotype', 'HP:0009725', (61, 75))
102906	26862755	Taken together, our data demonstrate for the first time that conditional activation of transgenic AR expression in bladder urothelium enhances carciongen-induced bladder tumor formation in mice.	('activation', 'PosReg', (73, 83))	('formation', 'biological_process', 'GO:0009058', ('176', '185'))	('bladder tumor', 'Disease', 'MESH:D001749', (162, 175))	('transgenic', 'Var', (87, 97))	('bladder tumor', 'Phenotype', 'HP:0009725', (162, 175))	('mice', 'Species', '10090', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('carciongen', 'Chemical', '-', (143, 153))	('enhances', 'PosReg', (134, 142))	('bladder tumor', 'Disease', (162, 175))
102935	26862755	Taken together, our data demonstrate for the first time that conditional activation of transgenic AR expression in bladder urothelium enhances carcinogen-induced bladder tumor formation in mice.	('activation', 'PosReg', (73, 83))	('formation', 'biological_process', 'GO:0009058', ('176', '185'))	('bladder tumor', 'Disease', 'MESH:D001749', (162, 175))	('transgenic', 'Var', (87, 97))	('bladder tumor', 'Phenotype', 'HP:0009725', (162, 175))	('mice', 'Species', '10090', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('enhances', 'PosReg', (134, 142))	('bladder tumor', 'Disease', (162, 175))
102965	26862755	To identify Upk3a expression cells, we generated Rosa26-mT/mG (R26RmT/mG):Upk3aGCE/+ mice by intercrossing R26RmT/mG and Upk3aGCE/+ mouse strains (Fig 1A).	('Upk3a', 'Gene', (121, 126))	('mice', 'Species', '10090', (85, 89))	('Upk3a', 'Gene', '22270', (12, 17))	('Upk3a', 'Gene', '22270', (74, 79))	('Upk3a', 'Gene', (12, 17))	('Upk3a', 'Gene', (74, 79))	('Rosa26', 'Gene', (49, 55))	('mouse', 'Species', '10090', (132, 137))	('R26RmT/mG', 'Var', (107, 116))	('Rosa26', 'Gene', '14910', (49, 55))	('Upk3a', 'Gene', '22270', (121, 126))
102971	26862755	Using co-immunofluorescence assays, we further characterized the cellular identity of mGFP expression cells in the bladder urothelium with Ck5, Ck8, and p63 antibodies (Fig 1E-1G").	('mGFP expression', 'Gene', (86, 101))	('Ck5', 'Gene', (139, 142))	('Ck8', 'Gene', (144, 147))	('Ck8', 'Gene', '16691', (144, 147))	('Ck5', 'Gene', '110308', (139, 142))	('p63 antibodies', 'Var', (153, 167))
102977	26862755	Using genomic PCR approaches, we confirmed the activity of CreER in bladder tissues, resulting in a 300 bp PCR fragment corresponding to the deletion of the LSL cassette through loxP/Cre recombination in bladder tissues of R26hARLoxP/+:Upk3aGCE/+ mice with TM induction, but not in those of R26hARLoxP/+ mice at 8 weeks of age (Fig 2C).	('mice', 'Species', '10090', (247, 251))	('deletion', 'Var', (141, 149))	('hAR', 'Gene', '10894', (294, 297))	('hAR', 'Gene', (294, 297))	('Upk3a', 'Gene', '22270', (236, 241))	('men', 'Species', '9606', (115, 118))	('Upk3a', 'Gene', (236, 241))	('LSL', 'Gene', (157, 160))	('hAR', 'Gene', '10894', (226, 229))	('hAR', 'Gene', (226, 229))	('mice', 'Species', '10090', (304, 308))	('TM', 'Chemical', 'MESH:D013629', (257, 259))
102982	26862755	These data indicate that expression of the AR transgene in bladder urothelium is a result of the LoxP/Cre recombination through TM-activated Cre transgene driven by the Upk3a promoter.	('TM', 'Chemical', 'MESH:D013629', (128, 130))	('Upk3a', 'Gene', (169, 174))	('LoxP/Cre', 'Var', (97, 105))	('Upk3a', 'Gene', '22270', (169, 174))
102986	26862755	Therefore, we assessed whether transgenic AR expression in bladder urothelium changes the susceptibility to BBN-induced tumorigenesis.	('changes', 'Reg', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('BBN', 'Chemical', 'MESH:D002085', (108, 111))	('tumor', 'Disease', (120, 125))	('AR expression', 'Var', (42, 55))
102993	26862755	These data demonstrate that conditional expression of transgenic AR in bladder urothelium cells enhances susceptibility to oncogenic transformation and tumor aggressiveness in both male and female R26hARLoxP/+:Upk3aGCE/+ mice with BBN induction.	('Upk3a', 'Gene', (210, 215))	('oncogenic transformation', 'CPA', (123, 147))	('BBN', 'Chemical', 'MESH:D002085', (231, 234))	('hAR', 'Gene', '10894', (200, 203))	('hAR', 'Gene', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor aggressiveness', 'Disease', (152, 172))	('mice', 'Species', '10090', (221, 225))	('enhances', 'PosReg', (96, 104))	('transgenic', 'Var', (54, 64))	('aggressiveness', 'Phenotype', 'HP:0000718', (158, 172))	('susceptibility', 'MPA', (105, 119))	('Upk3a', 'Gene', '22270', (210, 215))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (152, 172))
102996	26862755	As shown in Fig 4A-4D', tumor cells showed positive immunostaining with the human AR antibody (Fig 4A and 4A'), suggesting a link between transgenic AR expression and BBN-induced oncogenic transformation.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('antibody', 'molecular_function', 'GO:0003823', ('85', '93'))	('transgenic', 'Var', (138, 148))	('tumor', 'Disease', (24, 29))	('oncogenic transformation', 'CPA', (179, 203))	('antibody', 'cellular_component', 'GO:0042571', ('85', '93'))	('BBN', 'Chemical', 'MESH:D002085', (167, 170))	('human', 'Species', '9606', (76, 81))	('antibody', 'cellular_component', 'GO:0019814', ('85', '93'))	('antibody', 'cellular_component', 'GO:0019815', ('85', '93'))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
103008	26862755	These results implicate a promotional role of transgenic AR expression in cellular proliferation of BBN-induced bladder urothelial tumors.	('cellular proliferation', 'CPA', (74, 96))	('bladder urothelial tumors', 'Phenotype', 'HP:0009725', (112, 137))	('BBN-induced', 'Gene', (100, 111))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('transgenic', 'Var', (46, 56))	('promotional', 'PosReg', (26, 37))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('bladder urothelial tumors', 'Disease', (112, 137))	('bladder urothelial tumors', 'Disease', 'MESH:D001749', (112, 137))	('BBN', 'Chemical', 'MESH:D002085', (100, 103))
103020	26862755	Taken together, these data provide additional line of evidence demonstrating that the promotional effect of transgenic AR protein in BBN-induced bladder tumorigenesis is mediated through androgens.	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('transgenic', 'Var', (108, 118))	('bladder tumor', 'Disease', 'MESH:D001749', (145, 158))	('BBN-induced', 'Gene', (133, 144))	('BBN', 'Chemical', 'MESH:D002085', (133, 136))	('bladder tumor', 'Phenotype', 'HP:0009725', (145, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('bladder tumor', 'Disease', (145, 158))	('AR protein', 'Protein', (119, 129))	('promotional', 'PosReg', (86, 97))
103028	26862755	The data generated from this study provide the first line of evidence that demonstrates a promotional role of transgenic AR expression in enhancing the susceptibility to BBN-induced bladder urothelial carcinomas in mice.	('BBN', 'Chemical', 'MESH:D002085', (170, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('transgenic', 'Var', (110, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (201, 211))	('enhancing', 'PosReg', (138, 147))	('bladder urothelial carcinomas', 'Disease', (182, 211))	('susceptibility', 'MPA', (152, 166))	('mice', 'Species', '10090', (215, 219))	('bladder urothelial carcinomas', 'Disease', 'MESH:D001749', (182, 211))
103033	26862755	Earlier studies also showed decreased bladder tumor incidence in the Ar knockout mouse models, suggesting a protective role of AR deletion.	('bladder tumor', 'Phenotype', 'HP:0009725', (38, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('decreased', 'NegReg', (28, 37))	('decreased bladder', 'Phenotype', 'HP:0005343', (28, 45))	('bladder tumor', 'Disease', (38, 51))	('deletion', 'Var', (130, 138))	('mouse', 'Species', '10090', (81, 86))	('Ar', 'Gene', '10894', (69, 71))	('bladder tumor', 'Disease', 'MESH:D001749', (38, 51))
103037	26862755	These data suggest that dysregulation of AR activation may directly contribute to the sexual dimorphism observed in human bladder cancer development.	('men', 'Species', '9606', (144, 147))	('bladder cancer', 'Phenotype', 'HP:0009725', (122, 136))	('dysregulation', 'Var', (24, 37))	('contribute', 'Reg', (68, 78))	('bladder cancer', 'Disease', (122, 136))	('bladder cancer', 'Disease', 'MESH:D001749', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('human', 'Species', '9606', (116, 121))
103051	26862755	In the same study, it has been shown that deletion of CD24 reduced BBN-induced bladder carcinogenesis, and that tumor reduction effect was more striking in male than in female mice.	('BBN', 'Chemical', 'MESH:D002085', (67, 70))	('reduced', 'NegReg', (59, 66))	('CD24', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('CD24', 'Gene', '12484', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mice', 'Species', '10090', (176, 180))	('bladder carcinogenesis', 'Disease', 'MESH:D063646', (79, 101))	('tumor', 'Disease', (112, 117))	('deletion', 'Var', (42, 50))	('bladder carcinogenesis', 'Disease', (79, 101))
103060	26862755	Using different experimental approaches to manipulate endogenous androgen levels, we have shown that the effect of transgenic AR expression in bladder urothelial cells is mediated through androgens in both male and female mice.	('men', 'Species', '9606', (22, 25))	('mice', 'Species', '10090', (222, 226))	('mediated', 'Reg', (171, 179))	('transgenic', 'Var', (115, 125))
103068	24400102	Alterations in DNA methylation (DNAm) levels are among the earliest changes in human carcinogenesis, and hence offer novel strategies to identify individuals who might be at risk of developing such illnesses or individuals with early stage cancers.	('human', 'Species', '9606', (79, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('Alterations', 'Var', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('carcinogenesis', 'Disease', (85, 99))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))	('cancers', 'Disease', (240, 247))	('cancers', 'Disease', 'MESH:D009369', (240, 247))	('DNA methylation', 'MPA', (15, 30))
103073	24400102	We show that this measure associates significantly with overall survival outcome independent of known prognostic markers in several data sets and cancer types, and that groups of these significant gene-gene network interactions identify subnetwork modules, with a well-controlled false discovery rate.	('cancer', 'Disease', (146, 152))	('interactions', 'Var', (215, 227))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('false', 'biological_process', 'GO:0071877', ('280', '285'))	('overall', 'MPA', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('false', 'biological_process', 'GO:0071878', ('280', '285'))
103105	24400102	F5 is factor five, a protein of the coagulation system; its deficiency leads to predisposition for haemorrhage.	('haemorrhage', 'Disease', (99, 110))	('deficiency', 'Var', (60, 70))	('haemorrhage', 'Disease', 'MESH:D006470', (99, 110))	('coagulation', 'biological_process', 'GO:0050817', ('36', '47'))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
103133	24400102	The key point in this metazoan model is that, whereas the conventional model of tumourigenesis holds that proliferative characteristics acquired by cancers occur as a result of random genetic and epigenetic mutation, these archaic metazoan characteristics are present in humans all along, but lie dormant until they are released in cancer.	('cancer', 'Disease', (148, 154))	('tumour', 'Disease', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('epigenetic mutation', 'Var', (196, 215))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (332, 338))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('humans', 'Species', '9606', (271, 277))
103252	30662333	The Kaplan-Meier plots for SLIT3 expression in two datasets (GSE5287 and GSE13507) were extracted from the PRECOG database, as displayed in Figure 8A, indicating lower survival probability in bladder UC patients with low SLIT3 expression.	('GSE13507', 'Var', (73, 81))	('SLIT3', 'Gene', '6586', (27, 32))	('SLIT3', 'Gene', (27, 32))	('bladder UC', 'Disease', (192, 202))	('expression', 'MPA', (227, 237))	('SLIT3', 'Gene', '6586', (221, 226))	('lower', 'NegReg', (162, 167))	('survival', 'CPA', (168, 176))	('patients', 'Species', '9606', (203, 211))	('SLIT3', 'Gene', (221, 226))	('low', 'NegReg', (217, 220))	('GSE5287', 'Chemical', '-', (61, 68))
103255	30662333	The results indicated higher ranking of SLIT3 under-expression in infiltrating bladder UC across each dataset (Figure 8B).	('SLIT3', 'Gene', (40, 45))	('SLIT3', 'Gene', '6586', (40, 45))	('under-expression', 'Var', (46, 62))	('infiltrating bladder UC', 'Disease', (66, 89))
103270	30662333	Alteration in cell cycle checkpoint pathways increases the risk of carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (67, 81))	('carcinogenesis', 'Disease', (67, 81))	('Alteration', 'Var', (0, 10))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('14', '35'))	('cell cycle checkpoint pathways', 'Pathway', (14, 44))
103271	30662333	Similar molecular signatures of cell cycle and proliferative tissue markers between UC of bladder and upper urinary tract origin has been reported, and Ki-67, pRb, p53, and CDCA5 are of prognostic values.	('pRb', 'Gene', '5925', (159, 162))	('CDCA5', 'Gene', '113130', (173, 178))	('cell cycle', 'biological_process', 'GO:0007049', ('32', '42'))	('Ki-67', 'Var', (152, 157))	('cell cycle', 'CPA', (32, 42))	('p53', 'Gene', (164, 167))	('CDCA5', 'Gene', (173, 178))	('pRb', 'Gene', (159, 162))	('p53', 'Gene', '7157', (164, 167))
103278	30662333	Taken together, epigenetic regulation of PRC2/ EZH2 on cell cycle checkpoint related genes and downstream SLIT3 suppression may have potential contribution to cancer development.	('cancer', 'Disease', (159, 165))	('SLIT3', 'Gene', '6586', (106, 111))	('EZH2', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('epigenetic regulation', 'Var', (16, 37))	('contribution', 'Reg', (143, 155))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('55', '76'))	('cell cycle checkpoint related genes', 'Gene', (55, 90))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('suppression', 'NegReg', (112, 123))	('EZH2', 'Gene', '2146', (47, 51))	('regulation', 'biological_process', 'GO:0065007', ('27', '37'))	('SLIT3', 'Gene', (106, 111))
103280	30662333	SLIT3 is a tumor suppressor gene, where decreased expression of SLIT3 was observed in many human cancers through hypermethylation of SLIT3 promoter region or synergistic inhibitory effect with intronic miR-218, which also revealed an average 8.6-fold decreased expression in our dataset, leading to tumor invasion and progression.	('leading to', 'Reg', (288, 298))	('expression', 'MPA', (50, 60))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('progression', 'CPA', (318, 329))	('tumor', 'Disease', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('decreased', 'NegReg', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('SLIT3', 'Gene', '6586', (0, 5))	('SLIT3', 'Gene', (0, 5))	('expression', 'MPA', (261, 271))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('11', '27'))	('SLIT3', 'Gene', '6586', (133, 138))	('SLIT3', 'Gene', (133, 138))	('SLIT3', 'Gene', '6586', (64, 69))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('SLIT3', 'Gene', (64, 69))	('tumor', 'Disease', (299, 304))	('decreased', 'NegReg', (251, 260))	('tumor suppressor', 'biological_process', 'GO:0051726', ('11', '27'))	('hypermethylation', 'Var', (113, 129))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('human', 'Species', '9606', (91, 96))
103288	30662333	Literature supported miR-34a as a tumor suppressor miRNA targeting key regulators of cell cycle and apoptosis through p53-dependent and p53-independent pathways, being silenced due to CpG methylation of its promoter in many cancer cell lines, including UC.	('miR-34a', 'Gene', (21, 28))	('silenced', 'NegReg', (168, 176))	('miR-34a', 'Gene', '407040', (21, 28))	('cancer', 'Disease', (224, 230))	('p53', 'Gene', '7157', (136, 139))	('tumor', 'Disease', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('methylation', 'biological_process', 'GO:0032259', ('188', '199'))	('cell cycle', 'biological_process', 'GO:0007049', ('85', '95'))	('p53', 'Gene', '7157', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('apoptosis', 'CPA', (100, 109))	('p53', 'Gene', (136, 139))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('p53', 'Gene', (118, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))	('CpG methylation', 'Var', (184, 199))
103289	30662333	High expression of miR-34a was also reported to have reduced risk of bladder cancer recurrence.	('bladder cancer', 'Disease', 'MESH:D001749', (69, 83))	('bladder cancer', 'Disease', (69, 83))	('High', 'Var', (0, 4))	('miR-34a', 'Gene', '407040', (19, 26))	('reduced', 'NegReg', (53, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (69, 83))	('miR-34a', 'Gene', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (69, 94))
103300	30662333	The concept of TME holds true that tumor cells react to altered TME and affect gene expression of normal tissue adjacent to the tumor (NAT), and unique characteristics of NAT from healthy tissue has recently been reported.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('affect', 'Reg', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('gene expression', 'biological_process', 'GO:0010467', ('79', '94'))	('altered', 'Var', (56, 63))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('gene expression', 'MPA', (79, 94))	('TME', 'MPA', (64, 67))	('tumor', 'Disease', (128, 133))
103302	30662333	Our result may implicate the dysregulated genes in UTUC are potentially involved in altered ECM tumor microenvironment, while the mechanistic link between matrisome-associated genes and tumor related biological processes necessitate further investigation.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('matrisome', 'cellular_component', 'GO:0031012', ('155', '164'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (186, 191))	('UTUC', 'Gene', (51, 55))	('involved', 'Reg', (72, 80))	('dysregulated', 'Var', (29, 41))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('implicate', 'Reg', (15, 24))
103317	29371637	Urinary tract tumors develop resistance to apoptosis through diverse mechanisms, including Von-Hippel Lindau (VHL) mutations in clear cell kidney cancer and resistance to survival factor deprivation in prostate cancer.	('clear cell kidney cancer', 'Disease', (128, 152))	('prostate cancer', 'Disease', 'MESH:D011471', (202, 217))	('resistance', 'MPA', (29, 39))	('prostate cancer', 'Phenotype', 'HP:0012125', (202, 217))	('kidney cancer', 'Phenotype', 'HP:0009726', (139, 152))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (128, 152))	('prostate cancer', 'Disease', (202, 217))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('Urinary tract tumors', 'Disease', 'MESH:D014571', (0, 20))	('VHL', 'Gene', '7428', (110, 113))	('Von-Hippel Lindau', 'Gene', '7428', (91, 108))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('Von-Hippel Lindau', 'Gene', (91, 108))	('clear cell kidney cancer', 'Disease', 'MESH:D008649', (128, 152))	('Urinary tract tumors', 'Phenotype', 'HP:0010786', (0, 20))	('mutations', 'Var', (115, 124))	('Urinary tract tumors', 'Disease', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('VHL', 'Gene', (110, 113))
103334	29371637	The extrinsic pathway is triggered by ligation of death receptors by tumor necrosis factor superfamily (TNFSF) members, such as TNF, Fas ligand (FasL), TNF-related apoptosis-inducing ligand (TRAIL), and TNF-like weak inducer of apoptosis (TWEAK), leading to activation of caspase-8.	('TNF', 'Gene', (203, 206))	('Fas ligand', 'Gene', '356', (133, 143))	('apoptosis', 'biological_process', 'GO:0097194', ('228', '237'))	('TWEAK', 'Gene', (239, 244))	('Fas ligand', 'Gene', (133, 143))	('apoptosis', 'biological_process', 'GO:0006915', ('228', '237'))	('ligand', 'molecular_function', 'GO:0005488', ('183', '189'))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('TNF-related apoptosis-inducing ligand', 'Gene', (152, 189))	('TNF', 'Gene', (104, 107))	('caspase-8', 'Gene', (272, 281))	('tumor necrosis', 'Disease', 'MESH:D009336', (69, 83))	('TNF', 'Gene', (128, 131))	('TNF', 'Gene', '7124', (203, 206))	('TNF', 'Gene', (152, 155))	('FasL', 'Gene', (145, 149))	('necrosis', 'biological_process', 'GO:0008219', ('75', '83'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('69', '90'))	('TRAIL', 'Gene', '8743', (191, 196))	('tumor necrosis', 'Disease', (69, 83))	('extrinsic pathway', 'Pathway', (4, 21))	('FasL', 'Gene', '356', (145, 149))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('TNF', 'Gene', '7124', (128, 131))	('TNF', 'Gene', '7124', (104, 107))	('TNF-related apoptosis-inducing ligand', 'Gene', '8743', (152, 189))	('ligand', 'molecular_function', 'GO:0005488', ('137', '143'))	('TNF', 'Gene', '7124', (152, 155))	('TRAIL', 'Gene', (191, 196))	('necrosis', 'biological_process', 'GO:0008220', ('75', '83'))	('necrosis', 'biological_process', 'GO:0019835', ('75', '83'))	('caspase-8', 'Gene', '841', (272, 281))	('necrosis', 'biological_process', 'GO:0070265', ('75', '83'))	('activation', 'PosReg', (258, 268))	('ligation', 'Var', (38, 46))	('TWEAK', 'Gene', '8742', (239, 244))	('necrosis', 'biological_process', 'GO:0001906', ('75', '83'))
103344	29371637	MLKL phosphorylation results in plasma membrane translocation and subsequent recruitment of a yet not completely characterized complex machinery that promotes plasma membrane rupture.	('MLKL', 'Gene', '197259', (0, 4))	('plasma membrane translocation', 'MPA', (32, 61))	('MLKL', 'Gene', (0, 4))	('promotes', 'PosReg', (150, 158))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('phosphorylation', 'Var', (5, 20))	('results in', 'Reg', (21, 31))	('recruitment', 'MPA', (77, 88))	('plasma membrane rupture', 'MPA', (159, 182))	('plasma membrane', 'cellular_component', 'GO:0005886', ('159', '174'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('32', '47'))
103346	29371637	Ferroptosis is characterized by accumulation of lipid peroxidation products resulting from dysfunction of glutathione peroxidase 4 (GPX4) and requires free cellular iron.	('iron', 'Chemical', 'MESH:D007501', (165, 169))	('lipid', 'Chemical', 'MESH:D008055', (48, 53))	('glutathione peroxidase 4', 'Gene', '2879', (106, 130))	('GPX4', 'Gene', (132, 136))	('lipid peroxidation products', 'MPA', (48, 75))	('GPX4', 'Gene', '2879', (132, 136))	('accumulation', 'PosReg', (32, 44))	('glutathione peroxidase 4', 'Gene', (106, 130))	('Ferroptosis', 'Disease', (0, 11))	('dysfunction', 'Var', (91, 102))	('Ferroptosis', 'biological_process', 'GO:0097707', ('0', '11'))
103360	29371637	However, aberrant NETosis may trigger autoimmune disorders such as lupus erythematosus, vasculitis, or rheumatoid arthritis.	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (103, 123))	('rheumatoid arthritis', 'Disease', (103, 123))	('trigger', 'Reg', (30, 37))	('autoimmune disorders', 'Disease', (38, 58))	('vasculitis', 'Disease', 'MESH:D014657', (88, 98))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (103, 123))	('lupus erythematosus', 'Disease', 'MESH:D008180', (67, 86))	('vasculitis', 'Phenotype', 'HP:0002633', (88, 98))	('autoimmune disorders', 'Phenotype', 'HP:0002960', (38, 58))	('arthritis', 'Phenotype', 'HP:0001369', (114, 123))	('aberrant', 'Var', (9, 17))	('autoimmune disorders', 'Disease', 'MESH:D001327', (38, 58))	('lupus erythematosus', 'Phenotype', 'HP:0002725', (67, 86))	('lupus erythematosus', 'Disease', (67, 86))	('vasculitis', 'Disease', (88, 98))	('NETosis', 'MPA', (18, 25))
103363	29371637	Depending on the magnitude of live bacteria release, stage of the infection, and efficacy of antibiotics or extracellular antibacterial defenses, release of live bacteria may result in killing of bacteria in the extracellular space, infection of adjacent cells, recurrent infection, or triggering potentially more severe upper UTI.	('infection', 'Disease', (233, 242))	('infection', 'Disease', (272, 281))	('upper UTI', 'Disease', (321, 330))	('infection', 'Disease', 'MESH:D007239', (272, 281))	('infection', 'Disease', 'MESH:D007239', (233, 242))	('infection', 'Disease', (66, 75))	('recurrent infection', 'Phenotype', 'HP:0002719', (262, 281))	('triggering', 'Reg', (286, 296))	('infection', 'Disease', 'MESH:D007239', (66, 75))	('extracellular space', 'cellular_component', 'GO:0005615', ('212', '231'))	('result in', 'Reg', (175, 184))	('killing', 'CPA', (185, 192))	('extracellular', 'cellular_component', 'GO:0005576', ('108', '121'))	('release', 'Var', (146, 153))
103369	29371637	Inherited RCC syndromes and around 70% of non-familial RCC have mutations in the Von-Hippel Lindau (VHL) gene encoding the VHL protein (pVHL).	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('VHL', 'Gene', '7428', (137, 140))	('VHL', 'Gene', (123, 126))	('VHL', 'Gene', (137, 140))	('Inherited RCC syndromes', 'Disease', 'MESH:C538614', (0, 23))	('Von-Hippel Lindau', 'Gene', '7428', (81, 98))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('VHL', 'Gene', '7428', (123, 126))	('mutations', 'Var', (64, 73))	('Inherited RCC syndromes', 'Disease', (0, 23))	('Von-Hippel Lindau', 'Gene', (81, 98))	('VHL', 'Gene', (100, 103))	('RCC', 'Disease', (10, 13))	('pVHL', 'Gene', '7428', (136, 140))	('pVHL', 'Gene', (136, 140))	('VHL', 'Gene', '7428', (100, 103))	('RCC', 'Disease', 'MESH:C538614', (10, 13))
103372	29371637	Mutations in VHL provide resistance to cell death through a variety of molecular mechanisms.	('VHL', 'Gene', (13, 16))	('cell death', 'biological_process', 'GO:0008219', ('39', '49'))	('Mutations', 'Var', (0, 9))	('VHL', 'Gene', '7428', (13, 16))
103379	29371637	NFkappaB activation by interferon gamma (IFNgamma) promotes the expression of pro-survival genes in RCC cells, but an inhibitor of NFkappaB switches the response to IFNgamma from survival to necroptosis.	('interferon gamma (IFNgamma', 'Gene', (23, 49))	('IFNgamma', 'Gene', (165, 173))	('IFNgamma', 'Gene', '3458', (165, 173))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('NFkappaB', 'Gene', '4790', (131, 139))	('response', 'MPA', (153, 161))	('promotes', 'PosReg', (51, 59))	('inhibitor', 'Var', (118, 127))	('NFkappaB', 'Gene', (131, 139))	('expression', 'MPA', (64, 74))	('NFkappaB', 'Gene', '4790', (0, 8))	('interferon gamma (IFNgamma)', 'Gene', '3458', (23, 50))	('IFNgamma', 'Gene', '3458', (41, 49))	('IFNgamma', 'Gene', (41, 49))	('interferon gamma', 'molecular_function', 'GO:0005133', ('23', '39'))	('necroptosis', 'biological_process', 'GO:0070266', ('191', '202'))	('switches', 'Reg', (140, 148))	('NFkappaB', 'Gene', (0, 8))	('necroptosis', 'biological_process', 'GO:0097528', ('191', '202'))	('RCC', 'Disease', (100, 103))	('pro-survival', 'biological_process', 'GO:0043066', ('78', '90'))
103383	29371637	Knockdown of GPX4 using short interfering RNAs was sufficient to kill RCC cell lines, via a characteristic ferroptotic death.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('GPX4', 'Gene', (13, 17))	('GPX4', 'Gene', '2879', (13, 17))	('ferroptotic death', 'CPA', (107, 124))	('short interfering RNAs', 'Var', (24, 46))
103387	29371637	Additional oncogenes mutated in RCC or tumor-associated genes also promote resistance to apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('89', '98'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('resistance to apoptosis', 'CPA', (75, 98))	('tumor', 'Disease', (39, 44))	('mutated', 'Var', (21, 28))	('apoptosis', 'biological_process', 'GO:0006915', ('89', '98'))	('promote', 'PosReg', (67, 74))
103388	29371637	Thus, knockdown of astrocyte elevated gene-1 or zinc-finger protein X-linked leads to activation of Bax and caspase-3, and apoptosis in RCC.	('caspase-3', 'Gene', (108, 117))	('Bax', 'Gene', '581', (100, 103))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('caspase-3', 'Gene', '836', (108, 117))	('zinc-finger protein X-linked', 'Gene', '7543', (48, 76))	('astrocyte elevated gene-1', 'Gene', (19, 44))	('apoptosis', 'CPA', (123, 132))	('zinc-finger protein X-linked', 'Gene', (48, 76))	('knockdown', 'Var', (6, 15))	('astrocyte elevated gene-1', 'Gene', '92140', (19, 44))	('astrocyte elevated', 'Phenotype', 'HP:0002446', (19, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('Bax', 'Gene', (100, 103))	('activation', 'PosReg', (86, 96))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))
103391	29371637	Inhibition of autophagy and mammalian Target of Rapamycin promotes necroptosis, to which RCC cells may be sensitized, as indicated above.	('autophagy', 'CPA', (14, 23))	('autophagy', 'biological_process', 'GO:0006914', ('14', '23'))	('mammalian Target of Rapamycin', 'Gene', (28, 57))	('necroptosis', 'biological_process', 'GO:0070266', ('67', '78'))	('promotes', 'PosReg', (58, 66))	('RCC', 'Disease', (89, 92))	('Inhibition', 'Var', (0, 10))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('necroptosis', 'CPA', (67, 78))	('necroptosis', 'biological_process', 'GO:0097528', ('67', '78'))	('autophagy', 'biological_process', 'GO:0016236', ('14', '23'))	('mammalian Target of Rapamycin', 'Gene', '2475', (28, 57))
103410	29371637	Phosphorylation of the pro-apoptotic protein BAD by PI3K protects prostate cancer cells from apoptosis.	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('PI3K', 'molecular_function', 'GO:0016303', ('52', '56'))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('PI3K', 'Var', (52, 56))	('Phosphorylation', 'MPA', (0, 15))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('prostate cancer', 'Disease', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('apoptosis', 'CPA', (93, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))
103415	29371637	Expression of TRAIL and its lethal receptor TRAIL-R2 was higher and TRAIL decoy receptor lower in androgen ablation-treated patients than in untreated patients.	('ablation-treated', 'Var', (107, 123))	('TRAIL-R2', 'Gene', (44, 52))	('lower', 'NegReg', (89, 94))	('TRAIL', 'Gene', '8743', (68, 73))	('TRAIL', 'Gene', '8743', (14, 19))	('TRAIL', 'Gene', (44, 49))	('higher', 'PosReg', (57, 63))	('Expression', 'MPA', (0, 10))	('TRAIL', 'Gene', (68, 73))	('patients', 'Species', '9606', (151, 159))	('TRAIL', 'Gene', (14, 19))	('TRAIL-R2', 'Gene', '8795', (44, 52))	('decoy receptor', 'molecular_function', 'GO:0140319', ('74', '88'))	('androgen', 'Disease', (98, 106))	('TRAIL', 'Gene', '8743', (44, 49))	('patients', 'Species', '9606', (124, 132))
103431	29371637	The current standard of therapy for RCC exploits knowledge about the consequences of VHL mutations.	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('VHL', 'Gene', (85, 88))	('mutations', 'Var', (89, 98))	('VHL', 'Gene', '7428', (85, 88))
103436	29371637	mammalian Target of Rapamycin inhibition stimulates autophagy and eliminates RIPKs in RCCs, thus allowing scape from mammalian Target of Rapamycin inhibition.	('autophagy', 'biological_process', 'GO:0016236', ('52', '61'))	('autophagy', 'CPA', (52, 61))	('inhibition', 'Var', (30, 40))	('autophagy', 'biological_process', 'GO:0006914', ('52', '61'))	('mammalian Target of Rapamycin', 'Gene', (0, 29))	('mammalian Target of Rapamycin', 'Gene', (117, 146))	('eliminates', 'NegReg', (66, 76))	('stimulates', 'PosReg', (41, 51))	('RIPKs', 'MPA', (77, 82))	('mammalian Target of Rapamycin', 'Gene', '2475', (0, 29))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('mammalian Target of Rapamycin', 'Gene', '2475', (117, 146))
103439	29371637	Since mutated VHL signals through HIF, direct targeting of mutant VHL or of HIF has been considered.	('mutant', 'Var', (59, 65))	('VHL', 'Gene', (66, 69))	('VHL', 'Gene', (14, 17))	('VHL', 'Gene', '7428', (66, 69))	('mutated', 'Var', (6, 13))	('VHL', 'Gene', '7428', (14, 17))
103440	29371637	Indeed, restoration of functioning VHL restores many of the abnormalities of RCC cells with mutant alleles.	('mutant alleles', 'Var', (92, 106))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('VHL', 'Gene', (35, 38))	('abnormalities', 'MPA', (60, 73))	('VHL', 'Gene', '7428', (35, 38))
103443	29371637	However, a small molecule HIF-2 inhibitor (PT2399, PT2385) suppressed tumorigenesis in around 50% of human RCC lines and in a patient whose RCC was predicted to be sensitive to the drug.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('RCC', 'Disease', (107, 110))	('PT2399', 'Var', (43, 49))	('tumor', 'Disease', (70, 75))	('patient', 'Species', '9606', (126, 133))	('suppressed', 'NegReg', (59, 69))	('human', 'Species', '9606', (101, 106))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('HIF-2', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
103444	29371637	Mutations in HIF-2alpha and HIF-1beta accounted for tumor resistance to the drug in some patients.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (89, 97))	('HIF-2alpha and HIF-1beta', 'Disease', 'None', (13, 37))	('accounted for', 'Reg', (38, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
103457	29371637	The pro-mitotic protein PLK1 is upregulated in AR-independent prostate cancer cells, and PLK1 inhibitors promote necroptosis.	('promote', 'PosReg', (105, 112))	('PLK1', 'Gene', '5347', (24, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('PLK1', 'Gene', '5347', (89, 93))	('necroptosis', 'biological_process', 'GO:0070266', ('113', '124'))	('protein', 'cellular_component', 'GO:0003675', ('16', '23'))	('upregulated', 'PosReg', (32, 43))	('prostate cancer', 'Disease', 'MESH:D011471', (62, 77))	('prostate cancer', 'Disease', (62, 77))	('AR', 'Gene', '367', (47, 49))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('necroptosis', 'biological_process', 'GO:0097528', ('113', '124'))	('PLK1', 'Gene', (89, 93))	('PLK1', 'Gene', (24, 28))	('necroptosis', 'CPA', (113, 124))	('inhibitors', 'Var', (94, 104))
103463	29371637	Germline breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene mutations are implicated in prostate cancer predisposition and aggressiveness.	('mutations', 'Var', (66, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('aggressiveness', 'Disease', (129, 143))	('aggressiveness', 'Phenotype', 'HP:0000718', (129, 143))	('BRCA1', 'Gene', '672', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('aggressiveness', 'Disease', 'MESH:D001523', (129, 143))	('breast cancer', 'Disease', (37, 50))	('implicated', 'Reg', (80, 90))	('BRCA1', 'Gene', (26, 31))	('prostate cancer', 'Disease', 'MESH:D011471', (94, 109))	('prostate cancer', 'Phenotype', 'HP:0012125', (94, 109))	('BRCA2', 'Gene', (54, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('prostate cancer', 'Disease', (94, 109))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('breast cancer', 'Disease', (9, 22))	('BRCA2', 'Gene', '675', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
103464	29371637	Cancer cells with these mutations rely on PARP to repair DNA and divide.	('PARP', 'Gene', (42, 46))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (24, 33))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('PARP', 'Gene', '142', (42, 46))
103465	29371637	Olaparib is an oral PARP inhibitor in clinical use for ovary cancer that blocks DNA repair and, when coupled with BRCA mutations, results in tumor cell death.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('DNA repair', 'biological_process', 'GO:0006281', ('80', '90'))	('Olaparib', 'Chemical', 'MESH:C531550', (0, 8))	('results in', 'Reg', (130, 140))	('cell death', 'biological_process', 'GO:0008219', ('147', '157'))	('ovary cancer', 'Disease', 'MESH:D010051', (55, 67))	('PARP', 'Gene', '142', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('PARP', 'Gene', (20, 24))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('DNA repair', 'MPA', (80, 90))	('mutations', 'Var', (119, 128))	('ovary cancer', 'Phenotype', 'HP:0100615', (55, 67))	('BRCA', 'Gene', '672', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('blocks', 'NegReg', (73, 79))	('tumor', 'Disease', (141, 146))	('ovary cancer', 'Disease', (55, 67))	('BRCA', 'Gene', (114, 118))
103471	29371637	Tumors have incorporated mutations and changes in gene expression that allow them to evade a number of triggers of death (e.g., survival factor deprivation-induced apoptosis, hypoxia-induced apoptosis, killing by T cells, recruitment of autophagy to preserve cell survival).	('autophagy', 'CPA', (237, 246))	('mutations', 'Var', (25, 34))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('apoptosis', 'biological_process', 'GO:0097194', ('191', '200'))	('apoptosis', 'biological_process', 'GO:0006915', ('191', '200'))	('autophagy', 'biological_process', 'GO:0006914', ('237', '246'))	('recruitment', 'CPA', (222, 233))	('changes', 'Reg', (39, 46))	('hypoxia', 'Disease', 'MESH:D000860', (175, 182))	('killing', 'CPA', (202, 209))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('hypoxia', 'Disease', (175, 182))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('gene expression', 'biological_process', 'GO:0010467', ('50', '65'))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('autophagy', 'biological_process', 'GO:0016236', ('237', '246'))
103474	29371637	For RCC, these further developments may try to exploit the recently identified sensitivity of cells with VHL mutations to necroptosis and ferroptosis to develop novel antitumor strategies aimed at increasing RCC death.	('VHL', 'Gene', (105, 108))	('RCC death', 'Disease', (208, 217))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('RCC', 'Disease', (208, 211))	('necroptosis', 'biological_process', 'GO:0097528', ('122', '133'))	('VHL', 'Gene', '7428', (105, 108))	('tumor', 'Disease', (171, 176))	('ferroptosis', 'biological_process', 'GO:0097707', ('138', '149'))	('mutations', 'Var', (109, 118))	('necroptosis and ferroptosis', 'Disease', 'None', (122, 149))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('RCC', 'Disease', (4, 7))	('necroptosis', 'biological_process', 'GO:0070266', ('122', '133'))	('RCC', 'Disease', 'MESH:C538614', (4, 7))	('RCC death', 'Disease', 'MESH:C538614', (208, 217))
103481	29371637	A number of observations have described sensitivity of AR-resistant prostate cancer cells to death induced by certain triggers such as TWEAK, sorafenib, olaparib, and inhibition of BET proteins or PLK1, among others.	('AR', 'Gene', '367', (55, 57))	('sorafenib', 'Chemical', 'MESH:D000077157', (142, 151))	('inhibition', 'Var', (167, 177))	('BET proteins', 'Protein', (181, 193))	('olaparib', 'Chemical', 'MESH:C531550', (153, 161))	('TWEAK', 'Gene', (135, 140))	('prostate cancer', 'Disease', (68, 83))	('PLK1', 'Gene', (197, 201))	('TWEAK', 'Gene', '8742', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('PLK1', 'Gene', '5347', (197, 201))	('prostate cancer', 'Disease', 'MESH:D011471', (68, 83))	('prostate cancer', 'Phenotype', 'HP:0012125', (68, 83))
103489	29371637	Therapeutic approaches in clinical development aim at inactivating molecular mechanisms that help tumor cells withstand apoptosis triggered by survival factor deprivation, hypoxia, or lethal and proinflammatory cytokines, to prevent tumor cell-induced death or exhaustion of antitumor leukocytes and to exploit tumor cell sensitivity to necroptosis and ferroptosis, which sometimes is linked to the very same mechanisms that promote resistance to apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('necroptosis and ferroptosis', 'Disease', 'None', (337, 364))	('ferroptosis', 'biological_process', 'GO:0097707', ('353', '364'))	('help tumor', 'Disease', (93, 103))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Disease', (311, 316))	('inactivating', 'Var', (54, 66))	('tumor', 'Disease', (279, 284))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('help tumor', 'Disease', 'MESH:D009369', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('120', '129'))	('hypoxia', 'Disease', (172, 179))	('apoptosis', 'biological_process', 'GO:0006915', ('120', '129'))	('apoptosis', 'biological_process', 'GO:0097194', ('447', '456'))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('apoptosis', 'biological_process', 'GO:0006915', ('447', '456'))	('necroptosis', 'biological_process', 'GO:0070266', ('337', '348'))	('hypoxia', 'Disease', 'MESH:D000860', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('necroptosis', 'biological_process', 'GO:0097528', ('337', '348'))
103498	27677700	Dasatinib exerted similar effects on Src signaling in RT112 and RT112rGEMCI20 cells but RT112rGEMCI20 cells were less sensitive to dasatinib-induced anti-cancer effects (half maximal inhibitory concentration (IC50) of dasatinib in RT112 cells: 349.2 +- 67.2 nM; IC50 of dasatinib in RT112rGEMCI20 cells: 1081.1 +- 239.2 nM).	('RT112rGEMCI20', 'Var', (88, 101))	('Src', 'Gene', (37, 40))	('Src', 'Gene', '6714', (37, 40))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('Dasatinib', 'Chemical', 'MESH:D000069439', (0, 9))	('dasatinib', 'Chemical', 'MESH:D000069439', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('dasatinib', 'Chemical', 'MESH:D000069439', (218, 227))	('dasatinib', 'Chemical', 'MESH:D000069439', (270, 279))
103508	27677700	In other studies, however, Src inhibition increased bladder cancer cell migration and metastasis formation.	('increased', 'PosReg', (42, 51))	('formation', 'biological_process', 'GO:0009058', ('97', '106'))	('Src', 'Gene', (27, 30))	('Src', 'Gene', '6714', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('metastasis formation', 'CPA', (86, 106))	('inhibition', 'Var', (31, 41))	('cell migration', 'biological_process', 'GO:0016477', ('67', '81'))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('bladder cancer', 'Disease', (52, 66))
103514	27677700	RT112 cells were adapted to growth in presence of 20 ng/ml gemcitabine by continuous cultivation in the presence of increasing drug concentrations as previously described resulting in the gemcitabine-resistant subline RT112rGEMCI20.	('gemcitabine-resistant', 'MPA', (188, 209))	('gemcitabine', 'Chemical', 'MESH:C056507', (59, 70))	('RT112rGEMCI20', 'Var', (218, 231))	('gemcitabine', 'Chemical', 'MESH:C056507', (188, 199))
103520	27677700	Proteins were detected using specific antibodies against beta-actin (#A5441, Sigma-Aldrich, St. Louis, MO, USA), Src (#2123, Cell Signaling, Cambridge, UK), phosphorylated Src (Tyr416, #2101, Cell Signaling), Akt (#9272, Cell Signaling), and phosphorylated Akt (Thr308, #2965, Cell Signaling and Ser473, #04-736, EMD-Millipore, Billerica, MA, USA).	('Src', 'Gene', '6714', (113, 116))	('beta-actin', 'Gene', '728378', (57, 67))	('Ser473', 'Var', (296, 302))	('Ser473', 'Chemical', '-', (296, 302))	('Ser', 'cellular_component', 'GO:0005790', ('296', '299'))	('Src', 'Gene', (172, 175))	('Tyr416', 'Chemical', '-', (177, 183))	('Akt', 'Gene', (209, 212))	('Akt', 'Gene', (257, 260))	('Thr308', 'Var', (262, 268))	('Akt', 'Gene', '207', (209, 212))	('Akt', 'Gene', '207', (257, 260))	('Src', 'Gene', '6714', (172, 175))	('beta-actin', 'Gene', (57, 67))	('Signaling', 'biological_process', 'GO:0023052', ('226', '235'))	('Signaling', 'biological_process', 'GO:0023052', ('197', '206'))	('Signaling', 'biological_process', 'GO:0023052', ('282', '291'))	('Src', 'Gene', (113, 116))	('Thr308', 'Chemical', '-', (262, 268))	('Signaling', 'biological_process', 'GO:0023052', ('130', '139'))
103523	27677700	Mice were subdivided into four treatment arms: RT112luc control treatment (n = 15), RT112luc dasatinib treatment (n = 15), RT112rGEMCI20luc control treatment (n = 15), and RT112rGEMCI20luc dasatinib treatment (n = 14).	('RT112luc', 'Var', (84, 92))	('dasatinib', 'Chemical', 'MESH:D000069439', (189, 198))	('RT112rGEMCI20luc', 'Var', (123, 139))	('dasatinib', 'Chemical', 'MESH:D000069439', (93, 102))	('Mice', 'Species', '10090', (0, 4))	('RT112rGEMCI20luc', 'Var', (172, 188))
103535	27677700	Transduction with the luciferase plasmid, which is needed to monitor in vivo tumor growth, did not alter cell growth kinetics (doubling time RT112luc: 24.72 +- 5.04 h; doubling time RT112rGEMCI20luc: 27.36 +- 3.6 h) (Fig.	('cell growth', 'biological_process', 'GO:0016049', ('105', '116'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('Transduction', 'biological_process', 'GO:0009293', ('0', '12'))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('RT112rGEMCI20luc', 'Var', (182, 198))	('RT112luc', 'Var', (141, 149))	('tumor', 'Disease', (77, 82))
103536	27677700	RT112rGEMCI20 cells (IC50 = 125.40 +- 29.78 ng/ml) displayed a 77-fold increased resistance to gemcitabine compared to parental RT112 cells (IC50 = 1.63 +- 0.55 ng/ml).	('RT112rGEMCI20', 'Var', (0, 13))	('gemcitabine', 'Chemical', 'MESH:C056507', (95, 106))	('increased', 'PosReg', (71, 80))	('resistance to gemcitabine', 'MPA', (81, 106))
103537	27677700	There was a similar sensitivity to gemcitabine in the luciferase-transduced cell lines RT112luc and RT112rGEMCI20luc compared to RT112 and RT112rGEMCI20 [RT112luc (IC50: 1.94 +- 0.24) and RT112rGEMCI20luc (IC50: 114.39 +- 14.52)] (Table 1).	('gemcitabine', 'Chemical', 'MESH:C056507', (35, 46))	('RT112luc', 'Var', (87, 95))	('RT112rGEMCI20luc', 'Var', (100, 116))
103538	27677700	In vivo, growth of RT112luc and RT112rGEMCI20luc tumors was investigated in an established murine orthotopic xenograft model.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('RT112rGEMCI20luc', 'Var', (32, 48))	('murine', 'Species', '10090', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('RT112luc', 'Var', (19, 27))
103540	27677700	RT112rGEMCI20luc xenografts grew substantially slower than RT112luc xenografts resulting in a 6-fold smaller average tumor volume at day 25 (p < 0.0001) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('slower', 'NegReg', (47, 53))	('tumor', 'Disease', (117, 122))	('RT112rGEMCI20luc', 'Var', (0, 16))	('smaller', 'NegReg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('grew', 'CPA', (28, 32))
103541	27677700	RT112rGEMCI20 cells (IC50: 1081.1 +- 239.2 nM) showed a 3.1-fold decreased sensitivity to dasatinib compared to parental RT112 cells (IC50: 349.2 +- 67.2 nM).	('RT112rGEMCI20', 'Var', (0, 13))	('decreased', 'NegReg', (65, 74))	('sensitivity to dasatinib', 'MPA', (75, 99))	('dasatinib', 'Chemical', 'MESH:D000069439', (90, 99))
103542	27677700	In cell culture, dasatinib caused in RT112 and in RT112rGEMCI20 cells a dose-dependent reduction of Src phosphorylation.	('phosphorylation', 'biological_process', 'GO:0016310', ('104', '119'))	('Src', 'Gene', '6714', (100, 103))	('dasatinib', 'Chemical', 'MESH:D000069439', (17, 26))	('Src', 'Gene', (100, 103))	('reduction', 'NegReg', (87, 96))	('RT112rGEMCI20', 'Var', (50, 63))
103545	27677700	Since Src inhibition was described to increase migration in urothelial cancer, we evaluated migratory behavior using a wound healing scratch assay in RT112 and RT112rGEMCI20 cells with and without dasatinib treatment.	('increase', 'PosReg', (38, 46))	('urothelial cancer', 'Disease', 'MESH:D014523', (60, 77))	('wound healing', 'biological_process', 'GO:0042060', ('119', '132'))	('Src', 'Gene', (6, 9))	('Src', 'Gene', '6714', (6, 9))	('migration', 'CPA', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('inhibition', 'Var', (10, 20))	('dasatinib', 'Chemical', 'MESH:D000069439', (197, 206))	('urothelial cancer', 'Disease', (60, 77))
103546	27677700	Results indicated a similar time-dependent migration inhibition in response to dasatinib in RT112 and RT112rGEMCI20 cells resulting in >60 % inhibition of migration in both cell lines relative to untreated control (p < 0.0001) (Fig.	('inhibition', 'NegReg', (141, 151))	('migration', 'CPA', (155, 164))	('inhibition', 'NegReg', (53, 63))	('RT112rGEMCI20', 'Var', (102, 115))	('dasatinib', 'Chemical', 'MESH:D000069439', (79, 88))	('migration', 'CPA', (43, 52))
103547	27677700	Dasatinib treatment using 20 mg/kg twice daily caused a reduction of RT112luc xenograft size by 39 % (p = 0.036) relative to untreated control at day 25.	('Dasatinib', 'Chemical', 'MESH:D000069439', (0, 9))	('RT112luc', 'Var', (69, 77))	('reduction', 'NegReg', (56, 65))
103548	27677700	In contrast, dasatinib treatment induced a 4-fold increase in RT112rGEMCI20luc tumor size compared to vehicle treated RT112rGEMCI20luc xenografts at day 25 (p < 0.001) (Fig.	('RT112rGEMCI20luc', 'Var', (62, 78))	('tumor', 'Disease', (79, 84))	('dasatinib', 'Chemical', 'MESH:D000069439', (13, 22))	('increase', 'PosReg', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
103550	27677700	Untreated RT112luc tumors displayed muscle-invasive growth (pT2) (Fig.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('invasive growth', 'biological_process', 'GO:0001404', ('43', '58'))	('RT112luc', 'Var', (10, 18))	('invasive growth', 'biological_process', 'GO:0036267', ('43', '58'))	('muscle-invasive growth', 'CPA', (36, 58))	('invasive growth', 'biological_process', 'GO:0044412', ('43', '58'))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('invasive growth', 'biological_process', 'GO:0044409', ('43', '58'))	('invasive growth', 'biological_process', 'GO:0051831', ('43', '58'))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('invasive growth', 'biological_process', 'GO:0007125', ('43', '58'))
103552	27677700	The opposite pattern was observed in RT112rGEMCI20luc tumors.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('RT112rGEMCI20luc', 'Var', (37, 53))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
103553	27677700	Untreated RT112rGEMCI20luc tumors did not show muscle-invasive growth (pT1) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('invasive growth', 'biological_process', 'GO:0036267', ('54', '69'))	('pT1', 'Gene', '58492', (71, 74))	('invasive growth', 'biological_process', 'GO:0051831', ('54', '69'))	('invasive growth', 'biological_process', 'GO:0044409', ('54', '69'))	('muscle-invasive growth', 'CPA', (47, 69))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('invasive growth', 'biological_process', 'GO:0007125', ('54', '69'))	('invasive growth', 'biological_process', 'GO:0001404', ('54', '69'))	('pT1', 'Gene', (71, 74))	('invasive growth', 'biological_process', 'GO:0044412', ('54', '69'))	('RT112rGEMCI20luc', 'Var', (10, 26))
103554	27677700	4c), while dasatinib-treated RT112rGEMCI20luc xenografts displayed muscle invasive growth (pT2) (p < 0.001).	('invasive growth', 'biological_process', 'GO:0001404', ('74', '89'))	('invasive growth', 'biological_process', 'GO:0036267', ('74', '89'))	('invasive growth', 'biological_process', 'GO:0044412', ('74', '89'))	('RT112rGEMCI20luc', 'Var', (29, 45))	('invasive growth', 'biological_process', 'GO:0044409', ('74', '89'))	('dasatinib', 'Chemical', 'MESH:D000069439', (11, 20))	('invasive growth', 'biological_process', 'GO:0051831', ('74', '89'))	('muscle invasive growth', 'CPA', (67, 89))	('invasive growth', 'biological_process', 'GO:0007125', ('74', '89'))
103555	27677700	In dasatinib-treated RT112rGEMCI20luc xenografts, the bladder muscle was completely infiltrated by the tumor, and the bladder wall was not clearly visible anymore (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('RT112rGEMCI20luc', 'Var', (21, 37))	('dasatinib', 'Chemical', 'MESH:D000069439', (3, 12))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
103557	27677700	Dasatinib inhibited Src phosphorylation in RT112 and RT112rGEMCI20 cells at low nanomolar concentrations similar to those that had already been described to affect Src phosphorylation.	('RT112rGEMCI20', 'Var', (53, 66))	('Src', 'Gene', (164, 167))	('Src', 'Gene', '6714', (164, 167))	('inhibited', 'NegReg', (10, 19))	('Src', 'Gene', (20, 23))	('Dasatinib', 'Chemical', 'MESH:D000069439', (0, 9))	('Src', 'Gene', '6714', (20, 23))	('phosphorylation', 'biological_process', 'GO:0016310', ('168', '183'))	('phosphorylation', 'biological_process', 'GO:0016310', ('24', '39'))
103558	27677700	While dasatinib had previously been shown to interfere with the phosphorylation of Akt (Thr308 and Ser473) in squamous cell lung cancer, we only detected inhibition of phosphorylation of Akt (Thr308).	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (110, 135))	('phosphorylation', 'biological_process', 'GO:0016310', ('64', '79'))	('inhibition of phosphorylation', 'biological_process', 'GO:0042326', ('154', '183'))	('Ser', 'cellular_component', 'GO:0005790', ('99', '102'))	('Ser473', 'Var', (99, 105))	('phosphorylation', 'MPA', (168, 183))	('Ser473', 'Chemical', '-', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('phosphorylation', 'MPA', (64, 79))	('dasatinib', 'Chemical', 'MESH:D000069439', (6, 15))	('Akt', 'Gene', (187, 190))	('Thr308', 'Chemical', '-', (88, 94))	('Akt', 'Gene', '207', (187, 190))	('interfere', 'NegReg', (45, 54))	('Thr308', 'Chemical', '-', (192, 198))	('Akt', 'Gene', (83, 86))	('squamous cell lung cancer', 'Disease', (110, 135))	('Akt', 'Gene', '207', (83, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))
103559	27677700	Although dasatinib exerted similar effects on Src signaling in RT112 and RT112rGEMCI20 cells, its effects on cell viability differed between the two cell lines.	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('differed', 'Reg', (124, 132))	('Src', 'Gene', (46, 49))	('RT112rGEMCI20', 'Var', (73, 86))	('dasatinib', 'Chemical', 'MESH:D000069439', (9, 18))	('Src', 'Gene', '6714', (46, 49))
103561	27677700	This suggests that RT112rGEMCI20 cells have acquired resistance mechanisms that interfere with antitumoral effects of dasatinib downstream of Src signaling.	('tumor', 'Disease', (99, 104))	('RT112rGEMCI20', 'Var', (19, 32))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('Src', 'Gene', (142, 145))	('Src', 'Gene', '6714', (142, 145))	('signaling', 'biological_process', 'GO:0023052', ('146', '155'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('dasatinib', 'Chemical', 'MESH:D000069439', (118, 127))	('interfere', 'NegReg', (80, 89))
103562	27677700	In accordance, dasatinib treatment resulted in reduced inhibition of the phosphorylation of the Src downstream kinase Akt (Thr 308) in RT112rGEMCI20 cells compared to RT112 cells.	('RT112rGEMCI20', 'Var', (135, 148))	('phosphorylation', 'biological_process', 'GO:0016310', ('73', '88'))	('Thr', 'Chemical', 'MESH:D013912', (123, 126))	('Akt', 'Gene', (118, 121))	('Src', 'Gene', (96, 99))	('Src', 'Gene', '6714', (96, 99))	('reduced inhibition', 'NegReg', (47, 65))	('phosphorylation', 'MPA', (73, 88))	('Akt', 'Gene', '207', (118, 121))	('dasatinib', 'Chemical', 'MESH:D000069439', (15, 24))
103563	27677700	In nude mice, RT112rGEMCI20luc cells formed about 6-fold smaller tumors than RT112luc cells.	('smaller', 'NegReg', (57, 64))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('nude mice', 'Species', '10090', (3, 12))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('RT112rGEMCI20luc', 'Var', (14, 30))
103564	27677700	The most striking differences were found after oral dasatinib treatment of mice bearing orthotopic RT112luc or RT112rGEMCI20luc xenografts.	('dasatinib', 'Chemical', 'MESH:D000069439', (52, 61))	('RT112luc', 'Var', (99, 107))	('mice', 'Species', '10090', (75, 79))	('RT112rGEMCI20luc', 'Var', (111, 127))
103565	27677700	Dasatinib treatment of RT112luc bladder tumors resulted in a significant reduction of tumor size relative to untreated control.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('RT112luc', 'Var', (23, 31))	('bladder tumors', 'Disease', 'MESH:D001749', (32, 46))	('bladder tumors', 'Phenotype', 'HP:0009725', (32, 46))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('bladder tumors', 'Disease', (32, 46))	('Dasatinib', 'Chemical', 'MESH:D000069439', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('reduction', 'NegReg', (73, 82))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
103566	27677700	In contrast, dasatinib treatment of RT112rGEMCI20luc bladder tumors resulted in a dramatic increase of tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('bladder tumors', 'Disease', 'MESH:D001749', (53, 67))	('bladder tumors', 'Phenotype', 'HP:0009725', (53, 67))	('tumor', 'Disease', (103, 108))	('RT112rGEMCI20luc', 'Var', (36, 52))	('dasatinib', 'Chemical', 'MESH:D000069439', (13, 22))	('increase', 'PosReg', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('bladder tumors', 'Disease', (53, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (61, 66))
103567	27677700	In addition, the dasatinib treatment prevented muscle-invasive growth of RT112luc xenografts, but strongly induced muscle-invasive growth of RT112rGEMCI20luc xenografts.	('RT112rGEMCI20luc', 'Var', (141, 157))	('invasive growth', 'biological_process', 'GO:0051831', ('122', '137'))	('dasatinib', 'Chemical', 'MESH:D000069439', (17, 26))	('invasive growth', 'biological_process', 'GO:0007125', ('54', '69'))	('invasive growth', 'biological_process', 'GO:0036267', ('54', '69'))	('invasive growth', 'biological_process', 'GO:0007125', ('122', '137'))	('muscle-invasive growth', 'CPA', (47, 69))	('invasive growth', 'biological_process', 'GO:0036267', ('122', '137'))	('prevented', 'NegReg', (37, 46))	('invasive growth', 'biological_process', 'GO:0044409', ('54', '69'))	('RT112luc', 'Var', (73, 81))	('invasive growth', 'biological_process', 'GO:0001404', ('54', '69'))	('invasive growth', 'biological_process', 'GO:0044412', ('54', '69'))	('invasive growth', 'biological_process', 'GO:0044409', ('122', '137'))	('muscle-invasive growth', 'CPA', (115, 137))	('invasive growth', 'biological_process', 'GO:0051831', ('54', '69'))	('induced', 'PosReg', (107, 114))	('invasive growth', 'biological_process', 'GO:0001404', ('122', '137'))	('invasive growth', 'biological_process', 'GO:0044412', ('122', '137'))
103568	27677700	had reported that loss of Src increases metastasis formation in a bladder cancer model.	('Src', 'Gene', (26, 29))	('metastasis formation', 'CPA', (40, 60))	('loss', 'Var', (18, 22))	('Src', 'Gene', '6714', (26, 29))	('bladder cancer', 'Phenotype', 'HP:0009725', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('formation', 'biological_process', 'GO:0009058', ('51', '60'))	('bladder cancer', 'Disease', 'MESH:D001749', (66, 80))	('bladder cancer', 'Disease', (66, 80))	('increases', 'PosReg', (30, 39))
103570	27677700	However, dasatinib inhibited RT112 and RT112rGEMCI20 cell migration in a similar manner, similarly to other studies that reported on the effects of Src inhibition on cancer cell migration in models from different cancer entities.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('RT112rGEMCI20', 'Var', (39, 52))	('cancer', 'Disease', (166, 172))	('inhibited', 'NegReg', (19, 28))	('Src', 'Gene', '6714', (148, 151))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('RT112', 'Var', (29, 34))	('cell migration', 'biological_process', 'GO:0016477', ('53', '67'))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cell migration', 'biological_process', 'GO:0016477', ('173', '187'))	('dasatinib', 'Chemical', 'MESH:D000069439', (9, 18))	('Src', 'Gene', (148, 151))
103571	27677700	Therefore, it seems unlikely that the dasatinib-induced increased invasive growth of RT112rGEMCI20luc cells in the xenograft model may be caused by dasatinib-induced enhanced RT112rGEMCI20luc cell migration.	('invasive growth', 'biological_process', 'GO:0044409', ('66', '81'))	('increased', 'PosReg', (56, 65))	('invasive growth', 'biological_process', 'GO:0051831', ('66', '81'))	('invasive growth', 'CPA', (66, 81))	('dasatinib', 'Chemical', 'MESH:D000069439', (38, 47))	('invasive growth', 'biological_process', 'GO:0007125', ('66', '81'))	('cell migration', 'biological_process', 'GO:0016477', ('192', '206'))	('dasatinib', 'Chemical', 'MESH:D000069439', (148, 157))	('enhanced', 'PosReg', (166, 174))	('RT112rGEMCI20luc', 'Var', (175, 191))	('invasive growth', 'biological_process', 'GO:0001404', ('66', '81'))	('invasive growth', 'biological_process', 'GO:0036267', ('66', '81'))	('invasive growth', 'biological_process', 'GO:0044412', ('66', '81'))
103665	31965287	SSH-1 positivity was significantly associated with higher pathological grade (p = 0.020), lymphovascular invasion (p = 0.006), tumor recurrence (p < 0.001) and progression (p < 0.001) in bladder UC.	('bladder UC', 'Disease', 'MESH:D001745', (187, 197))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('higher', 'PosReg', (51, 57))	('tumor', 'Disease', (127, 132))	('positivity', 'Var', (6, 16))	('associated', 'Reg', (35, 45))	('SSH-1', 'Gene', '54434', (0, 5))	('pathological grade', 'CPA', (58, 76))	('SSH-1', 'Gene', (0, 5))	('bladder UC', 'Disease', (187, 197))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('progression', 'CPA', (160, 171))	('lymphovascular invasion', 'CPA', (90, 113))
103666	31965287	Besides, SSH-1 positivity predicted a shorter overall survival (OS, p = 0.024), recurrence-free survival (RFS, p < 0.001), progression-free survival (PFS, p = 0.002) and cancer-specific survival (CSS, p = 0.047).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('recurrence-free survival', 'CPA', (80, 104))	('cancer', 'Disease', (170, 176))	('RFS', 'Disease', (106, 109))	('SSH-1', 'Gene', (9, 14))	('shorter', 'NegReg', (38, 45))	('SSH-1', 'Gene', '54434', (9, 14))	('RFS', 'Disease', 'MESH:D005198', (106, 109))	('overall', 'MPA', (46, 53))	('positivity', 'Var', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('progression-free survival', 'CPA', (123, 148))	('CSS', 'Chemical', '-', (196, 199))
103674	31965287	Transurethral resection of bladder tumor (TUR-BT) has been the standard treatment for initial, non-muscle invasive bladder cancer (NMIBC), including carcinoma in situ (CIS), stage Ta and T1 BT.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('T1 BT', 'Var', (187, 192))	('age', 'Gene', '5973', (176, 179))	('BT', 'Phenotype', 'HP:0009725', (46, 48))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (149, 166))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (95, 122))	('bladder tumor', 'Phenotype', 'HP:0009725', (27, 40))	('invasive bladder', 'Phenotype', 'HP:0100645', (106, 122))	('-muscle invasive bladder cancer', 'Phenotype', 'HP:0006740', (98, 129))	('CIS', 'Phenotype', 'HP:0030075', (168, 171))	('TUR-BT', 'Chemical', '-', (42, 48))	('muscle invasive bladder cancer', 'Disease', (99, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('bladder tumor', 'Disease', (27, 40))	('men', 'Species', '9606', (77, 80))	('age', 'Gene', (176, 179))	('carcinoma', 'Disease', (149, 158))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (99, 129))	('bladder tumor', 'Disease', 'MESH:D001749', (27, 40))	('BT', 'Phenotype', 'HP:0009725', (190, 192))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('carcinoma', 'Disease', 'MESH:D009369', (149, 158))
103713	31965287	In subgroup of high-grade bladder UC, SSH-1 positivity was significantly associated with poor OS (p = 0.012), RFS (p = 0.002), PFS (p < 0.001) and CSS (p = 0.011) than SSH-1 negativity patients (Figs.	('SSH-1', 'Gene', '54434', (168, 173))	('SSH-1', 'Gene', (168, 173))	('bladder UC', 'Disease', (26, 36))	('SSH-1', 'Gene', (38, 43))	('SSH-1', 'Gene', '54434', (38, 43))	('bladder UC', 'Disease', 'MESH:D001745', (26, 36))	('PFS', 'Disease', (127, 130))	('CSS', 'Disease', (147, 150))	('RFS', 'Disease', (110, 113))	('patients', 'Species', '9606', (185, 193))	('CSS', 'Chemical', '-', (147, 150))	('positivity', 'Var', (44, 54))	('RFS', 'Disease', 'MESH:D005198', (110, 113))	('poor OS', 'Disease', (89, 96))
103732	31965287	found that the expression of SSH-1 was to be upregulated in pancreatic cancer cell lines with high metastatic potential, and loss of SSH-1 was correlated with an increase in the phosphorylation of cofilin-1 and the inhibition of cancerous cell migration (but not proliferation).	('inhibition', 'NegReg', (215, 225))	('upregulated', 'PosReg', (45, 56))	('SSH-1', 'Gene', '54434', (133, 138))	('cofilin-1', 'Gene', (197, 206))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('phosphorylation', 'biological_process', 'GO:0016310', ('178', '193'))	('cell migration', 'biological_process', 'GO:0016477', ('239', '253'))	('loss', 'Var', (125, 129))	('SSH-1', 'Gene', '54434', (29, 34))	('expression', 'MPA', (15, 25))	('pancreatic cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancerous', 'Disease', 'MESH:D009369', (229, 238))	('increase', 'PosReg', (162, 170))	('SSH-1', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cofilin-1', 'Gene', '1072', (197, 206))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('phosphorylation', 'MPA', (178, 193))	('cancerous', 'Disease', (229, 238))	('SSH-1', 'Gene', (29, 34))
103737	31965287	The presence of SSH-1 in bladder UC specimens was significantly associated with unfavorable clinic-pathological characteristics, including higher pathological grade, lymphovascular invasion, and incidence of tumor recurrence and progression.	('associated', 'Reg', (64, 74))	('lymphovascular invasion', 'CPA', (166, 189))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('bladder UC', 'Disease', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('SSH-1', 'Gene', (16, 21))	('bladder UC', 'Disease', 'MESH:D001745', (25, 35))	('higher pathological grade', 'CPA', (139, 164))	('tumor', 'Disease', (208, 213))	('SSH-1', 'Gene', '54434', (16, 21))	('presence', 'Var', (4, 12))	('men', 'Species', '9606', (41, 44))
103738	31965287	Through follow-up and survival analysis, we identified that bladder UC patients with SSH-1 expression had a significantly poor OS, RFS, PFS, and CSS.	('CSS', 'Chemical', '-', (145, 148))	('bladder UC', 'Disease', (60, 70))	('RFS', 'Disease', 'MESH:D005198', (131, 134))	('PFS', 'MPA', (136, 139))	('bladder UC', 'Disease', 'MESH:D001745', (60, 70))	('patients', 'Species', '9606', (71, 79))	('expression', 'Var', (91, 101))	('poor', 'NegReg', (122, 126))	('RFS', 'Disease', (131, 134))	('CSS', 'MPA', (145, 148))	('SSH-1', 'Gene', '54434', (85, 90))	('SSH-1', 'Gene', (85, 90))
103740	31965287	In the subgroup analysis, SSH-1 positivity patients were still statistically associated with poorer oncological outcomes than SSH-1 negativity subgroup.	('patients', 'Species', '9606', (43, 51))	('oncological outcomes', 'CPA', (100, 120))	('SSH-1', 'Gene', '54434', (126, 131))	('SSH-1', 'Gene', '54434', (26, 31))	('poorer', 'NegReg', (93, 99))	('positivity', 'Var', (32, 42))	('SSH-1', 'Gene', (126, 131))	('SSH-1', 'Gene', (26, 31))
103856	30380420	We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ.	('mutation', 'Var', (175, 183))	('TAZ', 'Gene', (171, 174))	('miR-590', 'Gene', '693175', (196, 203))	('YAP', 'Gene', (163, 166))	('effects', 'Reg', (184, 191))	('regulation', 'biological_process', 'GO:0065007', ('217', '227'))	('miR-200a', 'Gene', (208, 216))	('miR-590', 'Gene', (196, 203))	('miR-200a', 'Gene', '406983', (208, 216))
103859	30380420	Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns.	('squamous cell cancer', 'Phenotype', 'HP:0002860', (59, 79))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (59, 80))	('amplification', 'Var', (108, 121))	('YAP/TAZ', 'Gene', (125, 132))	('squamous cell cancers', 'Disease', 'MESH:D002294', (59, 80))	('Hippo signaling', 'biological_process', 'GO:0035329', ('40', '55'))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('expression', 'MPA', (139, 149))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('squamous cell cancers', 'Disease', (59, 80))
103865	30380420	Dysregulated signaling by the Hippo pathway has been reported in several cancer types such as breast, liver, lung, prostate, gastric, and colorectal tumors.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('colorectal tumors', 'Disease', (138, 155))	('signaling', 'biological_process', 'GO:0023052', ('13', '22'))	('liver', 'Disease', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast', 'Disease', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Hippo pathway', 'Pathway', (30, 43))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('Dysregulated', 'Var', (0, 12))	('gastric', 'Disease', (125, 132))	('lung', 'Disease', (109, 113))	('colorectal tumors', 'Disease', 'MESH:D015179', (138, 155))	('reported', 'Reg', (53, 61))	('prostate', 'Disease', (115, 123))
103875	30380420	Deep deletions occurred mostly in LATS1/2, consistent with their tumor suppressor role in cancer development.	('LATS1/2', 'Gene', '9113;26524', (34, 41))	('tumor', 'Disease', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor suppressor', 'biological_process', 'GO:0051726', ('65', '81'))	('LATS1/2', 'Gene', (34, 41))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('65', '81'))	('Deep deletions', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
103877	30380420	For oncogenes, the most significant amplification peak was an amplicon of 11q22.1 in cervical squamous cell carcinoma (CESC), driven by the amplification of YAP1 (Figure S1A).	('YAP1', 'Gene', (157, 161))	('YAP1', 'Gene', '10413', (157, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('11q22.1', 'Gene', (74, 81))	('amplification', 'Var', (140, 153))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 117))	('cervical squamous cell carcinoma', 'Disease', (85, 117))
103879	30380420	Regarding the mutational profile, NF2 (23.2%) and LATS2 (9.8%) showed the highest mutation frequencies in mesothelioma (MESO).	('NF2', 'Gene', (34, 37))	('mesothelioma', 'Disease', (106, 118))	('mutation', 'Var', (82, 90))	('LATS2', 'Gene', (50, 55))	('LATS2', 'Gene', '26524', (50, 55))	('NF2', 'Gene', '4771', (34, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))
103880	30380420	NF2 showed a striking pattern in MESO: all of the mutations were truncating mutations and led to reduced protein expression, indicating its loss-of-function effects (Figure S1C).	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('NF2', 'Gene', (0, 3))	('loss-of-function', 'NegReg', (140, 156))	('mutations', 'Var', (50, 59))	('NF2', 'Gene', '4771', (0, 3))	('reduced', 'NegReg', (97, 104))	('protein expression', 'MPA', (105, 123))
103883	30380420	To assess the cancer types in which Hippo pathway alterations are more (or less) prevalent than background expectation, we employed a random sampling approach (STAR Methods).	('cancer', 'Disease', (14, 20))	('Hippo pathway', 'Pathway', (36, 49))	('alterations', 'Var', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
103885	30380420	Among the hyper-altered cancer types, MESO, kidney renal papillary cell carcinoma (KIRP), and CESC were the most significant, which was probably due to the high frequency of NF2, LATS2, and SAV1 mutations and YAP1 amplification.	('hyper-altered cancer', 'Disease', 'MESH:D009369', (10, 30))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (44, 81))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('CESC', 'Disease', (94, 98))	('SAV1', 'Gene', (190, 194))	('YAP1', 'Gene', '10413', (209, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('LATS2', 'Gene', (179, 184))	('LATS2', 'Gene', '26524', (179, 184))	('NF2', 'Gene', '4771', (174, 177))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (51, 81))	('kidney renal papillary cell carcinoma', 'Disease', (44, 81))	('hyper-altered cancer', 'Disease', (10, 30))	('mutations', 'Var', (195, 204))	('MESO', 'Disease', (38, 42))	('NF2', 'Gene', (174, 177))	('SAV1', 'Gene', '60485', (190, 194))	('YAP1', 'Gene', (209, 213))
103891	30380420	Interestingly, the high-level amplifications of these two genes occurred in a mutually exclusive pattern in two squamous cell cancers (HNSC and CESC), collectively contributing to 14% and 19% of the tumor samples (Figure 2B).	('tumor', 'Disease', (199, 204))	('squamous cell cancers', 'Disease', 'MESH:D002294', (112, 133))	('amplifications', 'Var', (30, 44))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (112, 133))	('contributing', 'Reg', (164, 176))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('squamous cell cancers', 'Disease', (112, 133))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (112, 132))
103894	30380420	To understand the impact of YAP1/TAZ somatic mutations, we experimentally assessed the effect of each of 22 YAP1 and 19 TAZ non-silent mutations observed in the pan-cancer cohort using moderate-throughput, sensitive cell viability assays (Figures 2C and 2D; STAR Methods).	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('YAP1', 'Gene', (108, 112))	('mutations', 'Var', (135, 144))	('YAP1', 'Gene', (28, 32))	('YAP1', 'Gene', '10413', (28, 32))	('YAP1', 'Gene', '10413', (108, 112))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
103897	30380420	These results provide large-scale experimental evidence of YAP1/TAZ mutation effects, highlighting an underappreciated functional diversity of somatic mutations observed in human cancers.	('YAP1', 'Gene', (59, 63))	('mutation', 'Var', (68, 76))	('YAP1', 'Gene', '10413', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('effects', 'Reg', (77, 84))	('human', 'Species', '9606', (173, 178))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', (179, 186))
103916	30380420	To assess the clinical impact of a dysregulated Hippo pathway in cancer, we sought to examine the correlation of its activity with patients' overall survival times.	('patients', 'Species', '9606', (131, 139))	('dysregulated', 'Var', (35, 47))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Hippo pathway', 'Pathway', (48, 61))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
103939	30380420	Decreased NF2 expression level caused by NF2 truncating mutation was a dominant regulator of YAP/TAZ activity in MESO.	('NF2', 'Gene', (10, 13))	('NF2', 'Gene', (41, 44))	('Decreased', 'NegReg', (0, 9))	('NF2', 'Gene', '4771', (41, 44))	('NF2', 'Gene', '4771', (10, 13))	('truncating mutation', 'Var', (45, 64))	('expression level', 'MPA', (14, 30))
103940	30380420	Hyper-methylation of STK3, WWC1, and TAOK2 was predicted to strongly promote YAP/TAZ amplification in colorectal cancer, MESO, and BLCA, respectively.	('TAOK2', 'Gene', (37, 42))	('MESO', 'Disease', (121, 125))	('colorectal cancer', 'Disease', (102, 119))	('BLCA', 'Disease', (131, 135))	('STK', 'molecular_function', 'GO:0050359', ('21', '24'))	('STK3', 'Gene', (21, 25))	('YAP/TAZ amplification', 'MPA', (77, 98))	('Hyper-methylation', 'Var', (0, 17))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('TAOK2', 'Gene', '9344', (37, 42))	('promote', 'PosReg', (69, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('WWC1', 'Gene', '23286', (27, 31))	('WWC1', 'Gene', (27, 31))
103941	30380420	Furthermore, copy number loss for the TAOK family was a major cause of elevated YAP/TAZ activity in KIRP and LUSC.	('YAP/TAZ activity', 'MPA', (80, 96))	('TAOK', 'Gene', '57551;9344', (38, 42))	('TAOK', 'Gene', (38, 42))	('elevated', 'PosReg', (71, 79))	('copy number loss', 'Var', (13, 29))
103944	30380420	Other recurrently identified somatic driver events included ERBB2, RB1, and SOX2 copy number changes.	('ERBB2', 'Gene', '2064', (60, 65))	('SOX2', 'Gene', '6657', (76, 80))	('ERBB2', 'Gene', (60, 65))	('copy number changes', 'Var', (81, 100))	('SOX2', 'Gene', (76, 80))	('RB1', 'Gene', (67, 70))	('RB1', 'Gene', '5925', (67, 70))
103945	30380420	Besides SCNAs, IDH1 and FGFR3 mutations were predicted to be associated with YAP/TAZ activity in LGG and BLCA, respectively.	('associated with', 'Reg', (61, 76))	('FGFR3', 'Gene', '2261', (24, 29))	('IDH1', 'Gene', (15, 19))	('IDH1', 'Gene', '3417', (15, 19))	('FGFR3', 'Gene', (24, 29))	('YAP/TAZ activity', 'MPA', (77, 93))	('mutations', 'Var', (30, 39))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))
103946	30380420	Other identified associated somatic driver events included EGFR, KRAS, and PDGFR copy number changes, consistent with the reported functional coupling of these pathways with Hippo pathway signaling.	('EGFR', 'Gene', (59, 63))	('KRAS', 'Gene', '3845', (65, 69))	('copy number changes', 'Var', (81, 100))	('PDGFR', 'Gene', (75, 80))	('PDGFR', 'Gene', '5159', (75, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('EGFR', 'Gene', '1956', (59, 63))	('signaling', 'biological_process', 'GO:0023052', ('188', '197'))	('KRAS', 'Gene', (65, 69))
103948	30380420	Importantly, we found that Hippo pathway activity was associated with aberrations in a few clinically actionable genes with Food and Drug Administration (FDA)-approved drugs or compelling clinical evidence, which provides insights into clinical applications targeting the Hippo pathway in cancer therapy.	('aberrations', 'Var', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('Hippo', 'Gene', (27, 32))	('associated', 'Reg', (54, 64))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('activity', 'MPA', (41, 49))	('cancer', 'Disease', (289, 295))
103951	30380420	In total, we identified 11 non-silent mutations that affect cell viability and proliferation, filling a critical knowledge gap about YAP1/TAZ somatic mutations.	('proliferation', 'CPA', (79, 92))	('cell viability', 'CPA', (60, 74))	('affect', 'Reg', (53, 59))	('mutations', 'Var', (38, 47))	('YAP1', 'Gene', (133, 137))	('YAP1', 'Gene', '10413', (133, 137))
103954	30380420	Our analysis reveals that diverse mechanisms drive pathway dysregulation in tumor contexts.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('pathway dysregulation', 'Var', (51, 72))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
103956	30380420	Through our integrated analyses of BLCA, CESC, ESCA, LUSC, and HNSC, we reveal frequent YAP1/TAZ amplifications, high expression heterogeneity, and significant prognostic correlations.	('expression', 'MPA', (118, 128))	('amplifications', 'Var', (97, 111))	('YAP1', 'Gene', (88, 92))	('YAP1', 'Gene', '10413', (88, 92))
103958	30380420	Another cancer of particular interest is LGG, for which Hippo pathway activity shows the strongest correlation with patient survival times and the most extensive associations with known drivers such as IDH1 mutations.	('Hippo pathway', 'Pathway', (56, 69))	('LGG', 'Disease', (41, 44))	('cancer', 'Disease', (8, 14))	('activity', 'MPA', (70, 78))	('patient', 'Species', '9606', (116, 123))	('associations', 'Interaction', (162, 174))	('mutations', 'Var', (207, 216))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('IDH1', 'Gene', (202, 206))	('IDH1', 'Gene', '3417', (202, 206))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
103970	30380420	Cell lines were confirmed using Short Tandem Repeat (STR) analysis and were tested and negative for mycoplasma contamination.	('mycoplasma', 'Disease', 'MESH:D009175', (100, 110))	('Short Tandem', 'Var', (32, 44))	('mycoplasma', 'Disease', (100, 110))
103978	30380420	i) Only mutations with "PASS" in the "FILTER" column were retained for all cancer types except OV and LAML, and we allowed "wga" for these two cancer types.	('LAML', 'Disease', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('mutations', 'Var', (8, 17))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
103981	30380420	Functions of YAP1 and TAZ mutations were assayed in MCF10A cells, human non-tumorigenic mammary epithelial cells.	('MCF10A', 'CellLine', 'CVCL:0598', (52, 58))	('TAZ', 'Gene', (22, 25))	('YAP1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('human', 'Species', '9606', (66, 71))	('mutations', 'Var', (26, 35))	('YAP1', 'Gene', '10413', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
103982	30380420	The mutations, wild-types and silent controls of YAP1 (YAP) and TAZ (WWTR1) genes were cloned into pHAGE-PURO lentivirus vector by HiTMMoB technique as described previously.	('WWTR1', 'Gene', '25937', (69, 74))	('YAP1', 'Gene', (49, 53))	('YAP1', 'Gene', '10413', (49, 53))	('mutations', 'Var', (4, 13))	('WWTR1', 'Gene', (69, 74))
104026	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))
104028	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))
104029	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))
104034	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))
104040	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))
104041	33067881	PGC expression was upregulated with the increase of copy number in cholangiocarcinoma, esophageal carcinoma, and kidney renal papillary cell carcinoma, while in stomach adenocarcinoma, PGC was upregulated regardless of whether the copy number was increased or decreased.	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (120, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('expression', 'MPA', (4, 14))	('esophageal carcinoma', 'Disease', (87, 107))	('cholangiocarcinoma', 'Disease', (67, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('PGC', 'Gene', (185, 188))	('kidney renal papillary cell carcinoma', 'Disease', (113, 150))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (87, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (161, 183))	('upregulated', 'PosReg', (193, 204))	('PGC', 'Gene', (0, 3))	('upregulated', 'PosReg', (19, 30))	('PGC', 'Gene', '5225', (185, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('stomach adenocarcinoma', 'Disease', (161, 183))	('PGC', 'Gene', '5225', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('increase', 'PosReg', (40, 48))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (87, 107))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (113, 150))	('copy number', 'Var', (52, 63))
104045	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))
104047	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))
104067	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))
104068	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))
104073	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))
104086	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))
104098	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))
104109	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))
104133	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))
104136	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))
104137	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))
104138	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))
104139	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))
104142	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))
104143	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))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('gene expression', 'biological_process', 'GO:0010467', ('349', '364'))	('affect', 'Reg', (338, 344))	('associated', 'Reg', (211, 221))	('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))	('PGC', 'Gene', (328, 331))	('PGs', 'Chemical', 'MESH:D010715', (184, 187))
104162	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))
104164	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))
104185	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))
104186	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))
104187	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))
104188	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))
104190	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))
104191	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))
104193	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))
104207	32668393	Homozygous deletion of six genes in 9p21.3 characterized an LGG subtype with poor prognosis and contributed to the dysfunction of cancer-associated pathways in a complementary way.	('contributed', 'Reg', (96, 107))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('Homozygous', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('dysfunction', 'MPA', (115, 126))	('LGG', 'Disease', (60, 63))
104215	32668393	The accumulation of driver somatic genetic alterations gradually drives the evolution progression from normal to tumor cells.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('alterations', 'Var', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('drives', 'Reg', (65, 71))
104216	32668393	Somatic copy-number alterations (SCNAs), one important type of somatic genetic alterations, have been reported to activate oncogenes and inactivate tumor suppressors, which further made contributions to cancer progression.	('alterations', 'Var', (79, 90))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('inactivate', 'NegReg', (137, 147))	('activate', 'PosReg', (114, 122))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('copy-number alterations', 'Var', (8, 31))	('oncogenes', 'Protein', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
104221	32668393	showed that the co-amplifications and co-deletions of cancer-causing genes and metabolic genes contributed to reprogram cancer cell metabolism.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('metabolism', 'biological_process', 'GO:0008152', ('132', '142'))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (120, 126))	('co-amplifications', 'Var', (16, 33))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('co-deletions', 'Var', (38, 50))	('contributed', 'Reg', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
104223	32668393	The driver genetic alterations could induce the dysregulation of multilayer factor-mediated regulatory networks of gene expression and further cause disorder of cancer-associated functions.	('disorder', 'MPA', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('gene expression', 'biological_process', 'GO:0010467', ('115', '130'))	('multilayer factor-mediated regulatory networks of', 'Pathway', (65, 114))	('cause', 'Reg', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('induce', 'Reg', (37, 43))	('cancer', 'Disease', (161, 167))	('genetic alterations', 'Var', (11, 30))	('dysregulation', 'MPA', (48, 61))
104229	32668393	Copy number loss of both CNOT6LA and VAPA may downregulate PTEN in a miRNA-dependent manner.	('downregulate', 'NegReg', (46, 58))	('VAPA', 'Gene', '9218', (37, 41))	('VAPA', 'Gene', (37, 41))	('CNOT6LA', 'Gene', (25, 32))	('PTEN', 'Gene', (59, 63))	('PTEN', 'Gene', '5728', (59, 63))	('Copy number loss', 'Var', (0, 16))
104231	32668393	vIRF1 deletion increased miR-218-5p expression level and reduced the level of lnc-OIP5-AS1.	('OIP5-AS1', 'Gene', '729082;11339;5729', (82, 90))	('increased', 'PosReg', (15, 24))	('OIP5-AS1', 'Gene', (82, 90))	('deletion', 'Var', (6, 14))	('reduced', 'NegReg', (57, 64))	('vIRF1', 'Gene', (0, 5))	('miR-218-5p expression level', 'MPA', (25, 52))
104234	32668393	Homozygous deletion of six genes in 9p21.3 could characterize a LGG subtype with poor prognosis and contribute to the dysfunction of cancer-associated pathways in a complementary way.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('dysfunction', 'MPA', (118, 129))	('contribute', 'Reg', (100, 110))	('Homozygous deletion', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('LGG', 'Disease', (64, 67))
104244	32668393	The knocking down of COMMD9 was reported to inhibit cell proliferation and migration, and it arrested the cell cycle at the G1/S transition.	('knocking down', 'Var', (4, 17))	('cell cycle at the G1/S transition', 'CPA', (106, 139))	('arrest', 'Disease', 'MESH:D006323', (93, 99))	('inhibit', 'NegReg', (44, 51))	('cell proliferation', 'CPA', (52, 70))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('cell cycle', 'biological_process', 'GO:0007049', ('106', '116'))	('COMMD9', 'Gene', (21, 27))	('arrest', 'Disease', (93, 99))	('COMMD9', 'Gene', '29099', (21, 27))
104245	32668393	The depletion of CPSF1 suppressed cell viability and promoted cell apoptosis by inducing cell cycle arrest at the G0/G1 phase.	('promoted', 'PosReg', (53, 61))	('suppressed', 'NegReg', (23, 33))	('arrest', 'Disease', 'MESH:D006323', (100, 106))	('G1 phase', 'biological_process', 'GO:0051318', ('117', '125'))	('arrest', 'Disease', (100, 106))	('depletion', 'Var', (4, 13))	('CPSF1', 'Gene', '29894', (17, 22))	('CPSF1', 'Gene', (17, 22))	('cell apoptosis', 'CPA', (62, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('67', '76'))	('inducing', 'Reg', (80, 88))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (89, 106))	('apoptosis', 'biological_process', 'GO:0006915', ('67', '76'))	('CPSF', 'molecular_function', 'GO:0030364', ('17', '21'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('89', '106'))	('cell viability', 'CPA', (34, 48))
104247	32668393	HSF1 knockdown reduced cell migration and invasive ability, which were restored by HSF1 overexpression.	('invasive ability', 'CPA', (42, 58))	('cell migration', 'biological_process', 'GO:0016477', ('23', '37'))	('knockdown', 'Var', (5, 14))	('HSF1', 'Gene', (0, 4))	('HSF1', 'Gene', '3297', (0, 4))	('HSF1', 'Gene', (83, 87))	('reduced', 'NegReg', (15, 22))	('cell migration', 'CPA', (23, 37))	('HSF1', 'Gene', '3297', (83, 87))
104252	32668393	To investigate whether dysregulated ceRNA networks were associated with cancer hallmarks, we downloaded 50 hallmark signatures from MSigDB and identified the significantly enriched hallmark signatures by the deregulated ceRNA networks using R package clusterProfiler at a false discovery rate (FDR) of 0.05.	('deregulated', 'Var', (208, 219))	('MSigDB', 'Gene', (132, 138))	('false', 'biological_process', 'GO:0071878', ('272', '277'))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer hallmarks', 'Disease', (72, 88))	('cancer hallmarks', 'Disease', 'MESH:D009369', (72, 88))	('false', 'biological_process', 'GO:0071877', ('272', '277'))
104253	32668393	For example, the dysregulated ceRNA networks caused by lncRNA ZNF252P-AS1 amplification were significantly enriched in a DNA damage signature (DNA_REPAIR), proliferation signatures (E2F_TARGETS, G2M_CHECKPOINT, MITOTIC_SPINDLE, MYC_TARGETS_V1, and MYC_TARGETS_V2), and a pathway signature (UNFOLDED_PROTEIN_RESPONSE).	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('ZNF252P-AS1', 'Gene', (62, 73))	('MYC', 'Gene', '4609', (228, 231))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('G2M_CHECKPOINT', 'biological_process', 'GO:0000075', ('195', '209'))	('DNA_REPAIR', 'biological_process', 'GO:0006281', ('143', '153'))	('amplification', 'Var', (74, 87))	('MYC', 'Gene', (248, 251))	('MITOTIC_SPINDLE', 'cellular_component', 'GO:0072686', ('211', '226'))	('DNA damage signature', 'MPA', (121, 141))	('proliferation', 'MPA', (156, 169))	('ZNF252P-AS1', 'Gene', '286103', (62, 73))	('MYC', 'Gene', (228, 231))	('ceRNA', 'Gene', (30, 35))	('MYC', 'Gene', '4609', (248, 251))
104254	32668393	The most frequently enriched hallmark signatures across 37 dysregulated ceRNA networks were proliferation signatures, including E2F_TARGETS (30/37), G2M_CHECKPOINT (29/37), and MYC_TARGETS_V1 (25/37).	('MYC', 'Gene', '4609', (177, 180))	('MYC', 'Gene', (177, 180))	('E2F_TARGETS', 'Var', (128, 139))	('proliferation', 'CPA', (92, 105))	('G2M_CHECKPOINT', 'biological_process', 'GO:0000075', ('149', '163'))
104259	32668393	To further analyze the association of 9p21.3 deletions with LGG poor prognosis in spite of alterations in the rest of the driver genes, we classified the LGG patients into three subgroups based on the SCNA status of the 44 driver genes as follows: subgroup I, including patients without any SCNAs of the 44 driver genes; subgroup II, including patients with homozygous deletions of at least one of the six genes in 9p21.3; and subgroup III, including patients without homozygous deletions of the six genes but with homozygous deletions or high-level amplifications of the rest of the 38 driver genes.	('patients', 'Species', '9606', (270, 278))	('deletions', 'Var', (45, 54))	('patients', 'Species', '9606', (158, 166))	('deletions', 'Var', (369, 378))	('patients', 'Species', '9606', (344, 352))	('patients', 'Species', '9606', (451, 459))
104260	32668393	By preforming function enrichment analysis, we found that these six dysregulated ceRNA networks were consistently and significantly enriched in the proliferation hallmark signatures, including E2F_TARGETS, G2M_CHECKPOINT and MYC_TARGETS_V1 (Figure 4F).	('MYC', 'Gene', '4609', (225, 228))	('G2M_CHECKPOINT', 'biological_process', 'GO:0000075', ('206', '220'))	('MYC', 'Gene', (225, 228))	('E2F_TARGETS', 'Var', (193, 204))	('G2M_CHECKPOINT', 'Var', (206, 220))
104271	32668393	We found that amplification of lncRNA PVT1 could destroy its ceRNA networks in six cancer types, including OV, head and neck squamous cell carcinoma (HNSC), lung adenocarcinoma (LUAD), stomach adenocarcinoma (STAD), BRCA, and bladder urothelial carcinoma (BLCA) (Figures S5-S10).	('LUAD', 'Phenotype', 'HP:0030078', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('neck', 'cellular_component', 'GO:0044326', ('120', '124'))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('BRCA', 'Phenotype', 'HP:0003002', (216, 220))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('amplification', 'Var', (14, 27))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('neck squamous cell carcinoma', 'Disease', (120, 148))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (120, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('PVT1', 'Gene', (38, 42))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('ceRNA networks', 'CPA', (61, 75))	('PVT1', 'Gene', '5820', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('BRCA', 'Gene', '672', (216, 220))	('destroy', 'NegReg', (49, 56))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (185, 207))	('OV', 'Phenotype', 'HP:0012887', (107, 109))	('stomach adenocarcinoma', 'Disease', (185, 207))	('bladder urothelial carcinoma', 'Disease', (226, 254))	('BRCA', 'Gene', (216, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('lung adenocarcinoma', 'Disease', (157, 176))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (226, 254))	('cancer', 'Disease', (83, 89))
104274	32668393	Amplification of PVT1 could contribute to the development ovarian and breast cancer.	('Amplification', 'Var', (0, 13))	('PVT1', 'Gene', (17, 21))	('ovarian and breast cancer', 'Disease', 'MESH:D001943', (58, 83))	('PVT1', 'Gene', '5820', (17, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('contribute to', 'Reg', (28, 41))
104275	32668393	Knockdown of PVT1 could inhibit cell migration and proliferation.	('PVT1', 'Gene', (13, 17))	('cell migration', 'biological_process', 'GO:0016477', ('32', '46'))	('Knockdown', 'Var', (0, 9))	('PVT1', 'Gene', '5820', (13, 17))	('inhibit', 'NegReg', (24, 31))
104277	32668393	Compared with non-alteration status, amplification significantly elevated the expression levels of PVT1 (Figure 6B).	('PVT1', 'Gene', (99, 103))	('amplification', 'Var', (37, 50))	('PVT1', 'Gene', '5820', (99, 103))	('elevated', 'PosReg', (65, 73))	('expression levels', 'MPA', (78, 95))
104280	32668393	The amplification of PVT1 completely destroyed the active ceRNA networks, and the numbers of active ceRNA triples dropped to 0.	('active ceRNA networks', 'CPA', (51, 72))	('destroyed', 'NegReg', (37, 46))	('PVT1', 'Gene', (21, 25))	('amplification', 'Var', (4, 17))	('PVT1', 'Gene', '5820', (21, 25))
104290	32668393	Comparative analysis showed that MTAP deletion also disturbed distinct ceRNA triples in different cancers (Figure S11).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('MTAP', 'Gene', (33, 37))	('disturbed', 'Reg', (52, 61))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('ceRNA triples', 'MPA', (71, 84))	('MTAP', 'Gene', '4507', (33, 37))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('deletion', 'Var', (38, 46))
104293	32668393	This ceRNA triple was activated under non-alteration of PVT1 in HNSC.	('PVT1', 'Gene', '5820', (56, 60))	('PVT1', 'Gene', (56, 60))	('non-alteration', 'Var', (38, 52))
104295	32668393	However, the significant inverse relationships between hsa-miR-326 and both PVT1 and NEAT1 were destroyed by PVT1 amplification in HNSC.	('PVT1', 'Gene', '5820', (76, 80))	('amplification', 'Var', (114, 127))	('NEAT1', 'Gene', '283131', (85, 90))	('PVT1', 'Gene', '5820', (109, 113))	('NEAT1', 'Gene', (85, 90))	('hsa-miR-326', 'Gene', '442900', (55, 66))	('hsa-miR-326', 'Gene', (55, 66))	('PVT1', 'Gene', (76, 80))	('PVT1', 'Gene', (109, 113))
104297	32668393	These results suggested that SCNAs of lncRNAs/PGs could contribute to abnormal transformation of cancer by destroying their ceRNA networks through different miRNA-mediated ceRNAs.	('cancer', 'Disease', (97, 103))	('ceRNA networks', 'CPA', (124, 138))	('lncRNAs/PGs', 'Var', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('contribute', 'Reg', (56, 66))	('destroying', 'NegReg', (107, 117))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
104306	32668393	EGFR amplification was associated with poor prognosis in both GBM and HNSC (p = 0.0242 for GBM, p = 0.0314 for HNSC; Figure S13).	('GBM', 'Disease', (62, 65))	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('HNSC', 'Disease', (70, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))
104307	32668393	Compared with non-alteration, amplification significantly elevated EGFR expression levels in both GBM and HNSC (p = 3.6e-16 for GBM and p = 1.3e-9 for HNSC; Figure 8F).	('expression levels', 'MPA', (72, 89))	('amplification', 'Var', (30, 43))	('EGFR', 'molecular_function', 'GO:0005006', ('67', '71'))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('elevated', 'PosReg', (58, 66))
104308	32668393	However, EGFR did not participate in the ceRNA regulatory mechanism in spite of non-alteration or amplification in GBM (FDR = 0.05, PCC < 0; Figure 8G).	('PCC', 'cellular_component', 'GO:0120205', ('132', '135'))	('GBM', 'Gene', (115, 118))	('EGFR', 'Gene', '1956', (9, 13))	('amplification', 'Var', (98, 111))	('EGFR', 'Gene', (9, 13))	('non-alteration', 'Var', (80, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
104309	32668393	Under non-alteration of EGFR in HNSC, four miRNAs showed significant inverse correlations with EGFR while no inverse correlations were identified between any miRNA and EGFR under EGFR amplifications (FDR = 0.05, PCC < 0; Figure 8H; Figure S14).	('EGFR', 'Gene', (179, 183))	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('168', '172'))	('EGFR', 'molecular_function', 'GO:0005006', ('179', '183'))	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', (168, 172))	('EGFR', 'Gene', (24, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('non-alteration', 'Var', (6, 20))	('correlations', 'Interaction', (77, 89))	('EGFR', 'molecular_function', 'GO:0005006', ('95', '99'))	('EGFR', 'Gene', '1956', (95, 99))	('PCC', 'cellular_component', 'GO:0120205', ('212', '215'))	('inverse', 'NegReg', (69, 76))	('EGFR', 'Gene', '1956', (179, 183))	('EGFR', 'Gene', (95, 99))
104313	32668393	Due to the less frequent SCNAs of known cancer genes, we re-identified the driver genes in LGG for the threshold of alteration frequencies at 0.08, 0.06, 0.04, and 0.02, which also could significantly capture known cancer genes.	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('0.02', 'Var', (164, 168))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('LGG', 'Gene', (91, 94))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
104322	32668393	Analysis of ceRNA networks in previous studies explored ceRNA partners of PGs (PTEN) based on mRNA-mRNA ceRNA networks or predicted lncRNA functions based on lncRNA-mRNA ceRNA networks.	('PGs', 'Var', (74, 77))	('PTEN', 'Gene', '5728', (79, 83))	('PTEN', 'Gene', (79, 83))	('lncRNA functions', 'MPA', (132, 148))
104330	32668393	Amplification of EGFR could elevate EGFR expression levels in both HNSC and GBM.	('expression levels', 'MPA', (41, 58))	('Amplification', 'Var', (0, 13))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('EGFR', 'molecular_function', 'GO:0005006', ('17', '21'))	('elevate', 'PosReg', (28, 35))	('EGFR', 'Gene', '1956', (36, 40))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (36, 40))	('EGFR', 'Gene', (17, 21))
104331	32668393	EGFR amplification dysregulated the EGFR-associated ceRNA network in HNSC, while EGFR did not participate in the ceRNA regulatory mechanism in GBM.	('dysregulated', 'Reg', (19, 31))	('EGFR', 'Gene', (0, 4))	('HNSC', 'Disease', (69, 73))	('amplification', 'Var', (5, 18))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('EGFR', 'Gene', '1956', (36, 40))	('EGFR', 'molecular_function', 'GO:0005006', ('81', '85'))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', (36, 40))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
104332	32668393	In other case, SCNAs of genes or lncRNAs could disturb their associated ceRNA networks through different miRNAs and different ceRNA partners in different cancer types.	('SCNAs', 'Var', (15, 20))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('miRNAs', 'MPA', (105, 111))	('disturb', 'Reg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('ceRNA networks', 'Pathway', (72, 86))
104337	32668393	The copy number profiles of 12 cancer types involved 5,814 cancer samples in TCGA.	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('copy', 'Var', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
104353	32668393	According to copy number status of each candidate gene, we grouped cancer samples into subgroups and deleted the subgroups with fewer than five samples.	('copy', 'Var', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (67, 73))
104354	32668393	For a given PG or lncRNA, three SCNA status levels may be present across cancer populations: heterozygous deletion (-2), high-level amplification (2), and non-alterations (0).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('non-alterations', 'Var', (155, 170))
104355	32668393	According to SCNA status of the PG or lncRNA, the cancer patients were divided into subgroups as follows: one subgroup of patients with heterozygous deletion (-2) of the PG or lncRNA, one subgroup of patients with high-level amplification (2) of the PG or lncRNA, and one subgroup of patients with non-alteration (0) of the PG or lncRNA.	('deletion', 'Var', (149, 157))	('patients', 'Species', '9606', (200, 208))	('cancer', 'Disease', (50, 56))	('patients', 'Species', '9606', (284, 292))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
104357	31552026	Loss of Janus Associated Kinase 1 Alters Urothelial Cell Function and Facilitates the Development of Bladder Cancer Inherited Primary Immunodeficiency (PID) disorders are associated with increased risk of malignancy that may relate to impaired antitumor immune responses or a direct role for PID germline mutations in tumorigenesis.	('Facilitates', 'PosReg', (70, 81))	('germline', 'Var', (296, 304))	('malignancy', 'Disease', 'MESH:D009369', (205, 215))	('Development', 'CPA', (86, 97))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (101, 115))	('tumor', 'Disease', (248, 253))	('Loss', 'NegReg', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Disease', (318, 323))	('malignancy', 'Disease', (205, 215))	('Bladder Cancer', 'Disease', (101, 115))	('Urothelial Cell Function', 'CPA', (41, 65))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('Primary Immunodeficiency (PID) disorders', 'Disease', 'MESH:D051270', (126, 166))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('Bladder Cancer', 'Disease', 'MESH:D001749', (101, 115))	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Immunodeficiency', 'Phenotype', 'HP:0002721', (134, 150))	('Alters', 'Reg', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('PID', 'Gene', (292, 295))
104358	31552026	We recently identified germline loss of function mutations in Janus Associated Kinase 1 (JAK1) causing primary immunodeficiency characterized by infections and associated with early onset, fatal high-grade bladder carcinoma.	('bladder carcinoma', 'Phenotype', 'HP:0002862', (206, 223))	('JAK', 'molecular_function', 'GO:0004713', ('89', '92'))	('infections', 'Disease', (145, 155))	('mutations', 'Var', (49, 58))	('immunodeficiency', 'Phenotype', 'HP:0002721', (111, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('bladder carcinoma', 'Disease', 'MESH:D001749', (206, 223))	('immunodeficiency', 'Disease', (111, 127))	('immunodeficiency', 'Disease', 'MESH:D007153', (111, 127))	('bladder carcinoma', 'Disease', (206, 223))	('JAK1', 'Gene', (89, 93))	('infections', 'Disease', 'MESH:D007239', (145, 155))	('primary', 'Disease', (103, 110))	('loss of function', 'NegReg', (32, 48))	('associated', 'Reg', (160, 170))
104362	31552026	Our results have implications for patients with rare JAK1 PID and, more broadly, inform development of biomarker and targeted therapies for urothelial carcinoma.	('JAK', 'molecular_function', 'GO:0004713', ('53', '56'))	('JAK1 PID', 'Var', (53, 61))	('patients', 'Species', '9606', (34, 42))	('urothelial carcinoma', 'Disease', (140, 160))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (140, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
104366	31552026	We recently identified a new PID associated with compound homozygous loss of function mutations in the gene coding the signaling protein Janus-Associated Kinase 1 (JAK1) resulting in partial JAK1 deficiency.	('Janus-Associated Kinase 1', 'Gene', '3716', (137, 162))	('mutations', 'Var', (86, 95))	('JAK', 'molecular_function', 'GO:0004713', ('164', '167'))	('JAK', 'molecular_function', 'GO:0004713', ('191', '194'))	('loss of function', 'NegReg', (69, 85))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('deficiency', 'NegReg', (196, 206))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))	('Janus-Associated Kinase 1', 'Gene', (137, 162))	('JAK1', 'Gene', (191, 195))
104367	31552026	The clinical phenotype was characterized by immunodeficiency plus aggressive urothelial carcinoma that was fatal in the third decade of life, suggesting that impaired JAK1 function may be a predisposing factor for urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('urothelial carcinoma', 'Disease', (214, 234))	('immunodeficiency', 'Phenotype', 'HP:0002721', (44, 60))	('JAK1', 'Protein', (167, 171))	('immunodeficiency plus aggressive urothelial carcinoma', 'Disease', 'MESH:D001523', (44, 97))	('impaired', 'Var', (158, 166))	('urothelial carcinoma', 'Disease', (77, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (214, 234))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (77, 97))	('JAK', 'molecular_function', 'GO:0004713', ('167', '170'))
104371	31552026	Elucidating the non-redundant roles of JAK1 in cell biology has been complicated by the fact that complete JAK1-deficiency results in perinatal lethality as a result of neurological defects in murine models precluding detailed examination of immune competence or malignancy risk.	('murine', 'Species', '10090', (193, 199))	('JAK1-deficiency', 'Gene', (107, 122))	('neurological defects', 'Phenotype', 'HP:0000707', (169, 189))	('neurological defects', 'Disease', 'MESH:D009422', (169, 189))	('JAK', 'molecular_function', 'GO:0004713', ('107', '110'))	('malignancy', 'Disease', 'MESH:D009369', (263, 273))	('results in', 'Reg', (123, 133))	('JAK', 'molecular_function', 'GO:0004713', ('39', '42'))	('JAK1-deficiency', 'Var', (107, 122))	('malignancy', 'Disease', (263, 273))	('neurological defects', 'Disease', (169, 189))	('perinatal lethality', 'CPA', (134, 153))
104374	31552026	In mouse models, loss of IFNgamma signaling accelerated tumor initiation and progression, demonstrating a direct impact of IFNgamma signaling on tumorigenesis, the tumor microenvironment and metastatic dissemination.	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('progression', 'CPA', (77, 88))	('mouse', 'Species', '10090', (3, 8))	('tumor initiation', 'Disease', 'MESH:D009369', (56, 72))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('accelerated', 'PosReg', (44, 55))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('tumor', 'Disease', (145, 150))	('IFNgamma', 'Gene', (25, 33))	('tumor initiation', 'Disease', (56, 72))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('loss', 'Var', (17, 21))
104376	31552026	Somatic mutations in JAK1 have been identified in multiple tumor types including high-risk bladder cancer, endometrial, colorectal, stomach, and prostate carcinomas supporting the idea that alterations in JAK1 signaling, whether through loss or gain of function, could play a role in the pathogenesis of some epithelial cancers.	('tumor', 'Disease', (59, 64))	('endometrial', 'Disease', (107, 118))	('stomach', 'Disease', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('colorectal', 'Disease', (120, 130))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('signaling', 'biological_process', 'GO:0023052', ('210', '219'))	('mutations', 'Var', (8, 17))	('JAK1', 'Gene', (21, 25))	('prostate carcinomas', 'Disease', 'MESH:D011471', (145, 164))	('cancers', 'Disease', 'MESH:D009369', (320, 327))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('colorectal', 'Disease', 'MESH:D015179', (120, 130))	('play', 'Reg', (269, 273))	('JAK', 'molecular_function', 'GO:0004713', ('205', '208'))	('endometrial', 'Disease', 'MESH:D016889', (107, 118))	('JAK', 'molecular_function', 'GO:0004713', ('21', '24'))	('gain of function', 'PosReg', (245, 261))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('alterations', 'Var', (190, 201))	('bladder cancer', 'Disease', (91, 105))	('pathogenesis', 'biological_process', 'GO:0009405', ('288', '300'))	('cancers', 'Disease', (320, 327))	('prostate carcinomas', 'Disease', (145, 164))	('identified', 'Reg', (36, 46))	('cancers', 'Phenotype', 'HP:0002664', (320, 327))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('loss', 'NegReg', (237, 241))
104378	31552026	Although the cellular mechanisms have not been fully elucidated, truncating somatic JAK1 mutations in gynecological carcinomas reduced IFNgamma-induced MHC class I expression at the tumor cell surface, which could reduce immune recognition and facilitate immune evasion.	('MHC', 'Gene', (152, 155))	('facilitate', 'PosReg', (244, 254))	('cell surface', 'cellular_component', 'GO:0009986', ('188', '200'))	('immune evasion', 'biological_process', 'GO:0042783', ('255', '269'))	('JAK', 'molecular_function', 'GO:0004713', ('84', '87'))	('mutations', 'Var', (89, 98))	('immune evasion', 'biological_process', 'GO:0051842', ('255', '269'))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('carcinomas', 'Disease', (116, 126))	('MHC', 'Gene', '3107', (152, 155))	('immune evasion', 'MPA', (255, 269))	('truncating', 'Var', (65, 75))	('reduced', 'NegReg', (127, 134))	('JAK1', 'Gene', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('carcinomas', 'Disease', 'MESH:D002277', (116, 126))	('tumor', 'Disease', (182, 187))	('expression', 'MPA', (164, 174))	('immune recognition', 'MPA', (221, 239))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('reduce', 'NegReg', (214, 220))
104382	31552026	Variants which overlapped the predominant JAK1 transcript (ENST00000342505.5) were extracted and their impact assessed using the Ensembl Variant Effect Predictor including SIFT 4G and Poly-Phen 2, with additional analysis of deleterious effects using HMMvar v1.1.0.	('Variants', 'Var', (0, 8))	('HMMvar', 'Disease', 'None', (251, 257))	('HMMvar', 'Disease', (251, 257))	('JAK', 'molecular_function', 'GO:0004713', ('42', '45'))	('Poly-Phen', 'Chemical', 'MESH:C037153', (184, 193))
104387	31552026	shRNA technology permitted generation of cell lines with sub-total deficiency similar to the effect of loss of function mutations seen in our patient.	('sub-total deficiency', 'Disease', 'MESH:D007246', (57, 77))	('sub-total deficiency', 'Disease', (57, 77))	('mutations', 'Var', (120, 129))	('patient', 'Species', '9606', (142, 149))
104414	31552026	While our patient remains the only reported individual with partial JAK1 deficiency caused by germline loss of function mutations, somatic variants in JAK1 have been described in other patients with very high-risk bladder cancer.	('JAK', 'molecular_function', 'GO:0004713', ('151', '154'))	('bladder cancer', 'Disease', 'MESH:D001749', (214, 228))	('bladder cancer', 'Disease', (214, 228))	('JAK1', 'Gene', (68, 72))	('patient', 'Species', '9606', (185, 192))	('patient', 'Species', '9606', (10, 17))	('JAK1', 'Gene', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('loss of function', 'NegReg', (103, 119))	('bladder cancer', 'Phenotype', 'HP:0009725', (214, 228))	('JAK', 'molecular_function', 'GO:0004713', ('68', '71'))	('variants', 'Var', (139, 147))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (185, 193))	('deficiency', 'NegReg', (73, 83))
104415	31552026	Analysis of the muscle invasive bladder cancer (BLCA) cohort from The Cancer Genome Atlas (TCGA) identified 31 different JAK1 variants in 25/412 TCGA BLCA samples, including single nucleotide variants predicted to alter JAK1 protein function and non-sense/frameshift variants predicted to impair JAK1 signaling (Figure 1A).	('muscle invasive bladder cancer', 'Disease', (16, 46))	('JAK', 'molecular_function', 'GO:0004713', ('296', '299'))	('function', 'MPA', (233, 241))	('BLCA', 'Disease', 'MESH:D001749', (48, 52))	('BLCA', 'Disease', (150, 154))	('JAK1 signaling', 'MPA', (296, 310))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (16, 46))	('BLCA', 'Disease', 'MESH:D001749', (150, 154))	('JAK1 protein', 'Protein', (220, 232))	('JAK', 'molecular_function', 'GO:0004713', ('121', '124'))	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('alter', 'Reg', (214, 219))	('non-sense/frameshift', 'Var', (246, 266))	('JAK', 'molecular_function', 'GO:0004713', ('220', '223'))	('impair', 'NegReg', (289, 295))	('BLCA', 'Phenotype', 'HP:0009725', (48, 52))	('signaling', 'biological_process', 'GO:0023052', ('301', '310'))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('protein', 'cellular_component', 'GO:0003675', ('225', '232'))	('invasive bladder', 'Phenotype', 'HP:0100645', (23, 39))	('variants', 'Var', (126, 134))	('BLCA', 'Phenotype', 'HP:0009725', (150, 154))	('BLCA', 'Disease', (48, 52))	('JAK1', 'Gene', (121, 125))
104416	31552026	To model and test the impact of loss of JAK1 function in urothelial cells, we generated a JAK1 KD hTERT immortalized urothelial cell line using lentiviral vectors expressing shRNA sequences.	('JAK1 KD', 'Var', (90, 97))	('JAK', 'molecular_function', 'GO:0004713', ('90', '93'))	('hTERT', 'Gene', '7015', (98, 103))	('hTERT', 'Gene', (98, 103))	('JAK', 'molecular_function', 'GO:0004713', ('40', '43'))
104417	31552026	To confirm functional knock down of JAK1, we studied JAK1-mediated activation of STAT1 proteins in response to IFNgamma stimulation, using flow cytometry.	('JAK', 'molecular_function', 'GO:0004713', ('53', '56'))	('STAT1', 'Gene', '6772', (81, 86))	('knock', 'Var', (22, 27))	('STAT1', 'Gene', (81, 86))	('JAK', 'molecular_function', 'GO:0004713', ('36', '39'))
104419	31552026	The effect was similar to the reduced, but not abolished, STAT1 phosphorylation observed in fibroblasts of the patient with JAK1 deficiency following IFNgamma stimulation (Figure S1C).	('STAT1', 'Gene', (58, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('64', '79'))	('deficiency', 'Var', (129, 139))	('STAT1', 'Gene', '6772', (58, 63))	('patient', 'Species', '9606', (111, 118))	('JAK', 'molecular_function', 'GO:0004713', ('124', '127'))	('JAK1', 'Gene', (124, 128))
104420	31552026	Expression of mRNA for the interferon inducible transcription factor IRF1 was also significantly lower in KD than Sc urothelial cell lines following stimulation with IFNgamma, indicating impaired downstream gene regulation in JAK1 deficiency (Figure 1D).	('Figure 1D', 'Disease', (243, 252))	('deficiency', 'Var', (231, 241))	('transcription', 'biological_process', 'GO:0006351', ('48', '61'))	('Expression', 'MPA', (0, 10))	('transcription factor', 'molecular_function', 'GO:0000981', ('48', '68'))	('Figure 1D', 'Disease', 'MESH:C537985', (243, 252))	('IRF1', 'Gene', (69, 73))	('IRF1', 'Gene', '3659', (69, 73))	('lower', 'NegReg', (97, 102))	('regulation', 'biological_process', 'GO:0065007', ('212', '222'))	('mRNA', 'MPA', (14, 18))	('JAK', 'molecular_function', 'GO:0004713', ('226', '229'))	('impaired', 'NegReg', (187, 195))
104425	31552026	As described for gynecological cancer cells bearing somatic JAK1 mutations, we also observed lower surface MHC I expression by JAK1-deficient hTERT urothelial cells compared with control cells at baseline.	('JAK1-deficient', 'Gene', (127, 141))	('JAK', 'molecular_function', 'GO:0004713', ('60', '63'))	('hTERT', 'Gene', '7015', (142, 147))	('JAK1', 'Gene', (60, 64))	('MHC', 'Gene', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('JAK', 'molecular_function', 'GO:0004713', ('127', '130'))	('hTERT', 'Gene', (142, 147))	('MHC', 'Gene', '3107', (107, 110))	('lower', 'NegReg', (93, 98))	('lower surface MHC I expression', 'Phenotype', 'HP:0031390', (93, 123))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('mutations', 'Var', (65, 74))
104429	31552026	JAK1 KD had no effect on basal growth kinetics of immortalized hTERT urothelial cell lines assessed using an Alamar Blue (AB) reduction assay.	('JAK1 KD', 'Var', (0, 7))	('hTERT', 'Gene', (63, 68))	('JAK', 'molecular_function', 'GO:0004713', ('0', '3'))	('basal growth kinetics', 'CPA', (25, 46))	('hTERT', 'Gene', '7015', (63, 68))
104445	31552026	NHU cells were induced to differentiate by coactivation of PPARgamma and inhibition of EGFR signaling, using a combination of troglitazone and PD153035 (TZ/PD).	('troglitazone', 'Chemical', 'MESH:C057693', (126, 138))	('PD153035', 'Chemical', 'MESH:C088860', (143, 151))	('EGFR', 'Gene', '1956', (87, 91))	('coactivation', 'Var', (43, 55))	('inhibition', 'NegReg', (73, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('EGFR', 'Gene', (87, 91))	('TZ', 'Chemical', 'MESH:C057693', (153, 155))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('PPARgamma', 'Gene', (59, 68))	('PPARgamma', 'Gene', '5468', (59, 68))
104447	31552026	As IRF1 knock down limits uroplakin expression and IRF1 induction was impaired in JAK1-deficient cells (Figure 1B), we tested by RT-qPCR whether IFNgamma modulates expression of genes associated with IFNgamma signaling and urothelial cytodifferentiation pathways.	('modulates', 'Reg', (154, 163))	('expression', 'MPA', (164, 174))	('IRF1', 'Gene', '3659', (51, 55))	('tested', 'Reg', (119, 125))	('knock down', 'Var', (8, 18))	('IRF1', 'Gene', (3, 7))	('IRF1', 'Gene', '3659', (3, 7))	('IRF1', 'Gene', (51, 55))	('uroplakin expression', 'MPA', (26, 46))	('limits', 'NegReg', (19, 25))	('JAK', 'molecular_function', 'GO:0004713', ('82', '85'))	('signaling', 'biological_process', 'GO:0023052', ('209', '218'))
104451	31552026	These data suggest that the combination of both IFNgamma and TZ/PD significantly increases expression of transcription factors involved in urothelial cytodifferentiation and supports a previously unknown role for IFNgamma in modulating urothelial phenotype.	('expression', 'MPA', (91, 101))	('transcription', 'biological_process', 'GO:0006351', ('105', '118'))	('TZ/PD', 'Var', (61, 66))	('TZ', 'Chemical', 'MESH:C057693', (61, 63))	('increases', 'PosReg', (81, 90))
104453	31552026	We recently reported the first case of germline loss of function mutations causing partial JAK1 deficiency in humans which resulted in immunodeficiency characterized by mycobacterial infection, suggesting a dominant effect on the IFNgamma pathway, and high-grade bladder carcinoma.	('immunodeficiency', 'Phenotype', 'HP:0002721', (135, 151))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (263, 280))	('bladder carcinoma', 'Disease', 'MESH:D001749', (263, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('humans', 'Species', '9606', (110, 116))	('bladder carcinoma', 'Disease', (263, 280))	('resulted', 'Reg', (123, 131))	('immunodeficiency', 'Disease', (135, 151))	('loss of function', 'NegReg', (48, 64))	('mycobacterial infection', 'Disease', 'MESH:D009165', (169, 192))	('partial JAK1', 'Gene', (83, 95))	('mycobacterial infection', 'Disease', (169, 192))	('JAK1', 'Gene', (91, 95))	('deficiency', 'Var', (96, 106))	('immunodeficiency', 'Disease', 'MESH:D007153', (135, 151))	('JAK', 'molecular_function', 'GO:0004713', ('91', '94'))	('mycobacterial infection', 'Phenotype', 'HP:0011274', (169, 192))	('mutations', 'Var', (65, 74))	('IFNgamma pathway', 'Pathway', (230, 246))
104454	31552026	The early-onset and aggressive nature of the malignancy, along with the fact that JAK1 is a hotspot for damaging somatic mutations in bladder carcinoma, led us to investigate whether impaired JAK1 function may be a specific predisposing factor for urothelial carcinoma.	('bladder carcinoma', 'Disease', (134, 151))	('malignancy', 'Disease', 'MESH:D009369', (45, 55))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (248, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('JAK', 'molecular_function', 'GO:0004713', ('192', '195'))	('JAK1', 'Gene', (192, 196))	('malignancy', 'Disease', (45, 55))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (134, 151))	('function', 'MPA', (197, 205))	('JAK', 'molecular_function', 'GO:0004713', ('82', '85'))	('impaired', 'Var', (183, 191))	('urothelial carcinoma', 'Disease', (248, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('bladder carcinoma', 'Disease', 'MESH:D001749', (134, 151))
104455	31552026	The data presented here demonstrate that JAK1 is important for multiple aspects of urothelial cell biology and highlight mechanisms by which loss of JAK1 function may promote tumorigenesis in this cell type.	('tumor', 'Disease', (175, 180))	('JAK1', 'Gene', (149, 153))	('JAK', 'molecular_function', 'GO:0004713', ('149', '152'))	('promote', 'PosReg', (167, 174))	('loss', 'Var', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('JAK', 'molecular_function', 'GO:0004713', ('41', '44'))
104459	31552026	The absence of an immune infiltrate observed in the patient's tumor by immunohistochemistry supports our conclusion that loss of JAK1 in bladder cancer cells results in a poorly immunogenic tumor.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('immunogenic tumor', 'Disease', 'MESH:D009369', (178, 195))	('bladder cancer', 'Phenotype', 'HP:0009725', (137, 151))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('JAK1', 'Gene', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('loss', 'Var', (121, 125))	('tumor', 'Disease', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (137, 151))	('tumor', 'Disease', (190, 195))	('results in', 'Reg', (158, 168))	('patient', 'Species', '9606', (52, 59))	('immunogenic tumor', 'Disease', (178, 195))	('JAK', 'molecular_function', 'GO:0004713', ('129', '132'))	('bladder cancer', 'Disease', (137, 151))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
104461	31552026	It has already been reported that damaging mutations in the IFNgamma signaling pathway and antigen presentation pathway are associated with metastasis and higher resistance to the checkpoint blocking therapy with anti-PD-L1/PD-1 in a number of tumor types, including bladder cancer.	('resistance', 'MPA', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('IFNgamma signaling pathway', 'Pathway', (60, 86))	('PD-1', 'Gene', (224, 228))	('PD-1', 'Gene', '5133', (224, 228))	('metastasis', 'CPA', (140, 150))	('higher', 'PosReg', (155, 161))	('antigen presentation', 'biological_process', 'GO:0019882', ('91', '111'))	('bladder cancer', 'Disease', 'MESH:D001749', (267, 281))	('bladder cancer', 'Disease', (267, 281))	('associated', 'Reg', (124, 134))	('bladder cancer', 'Phenotype', 'HP:0009725', (267, 281))	('PD-L1', 'Gene', (218, 223))	('tumor', 'Disease', (244, 249))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('PD-L1', 'Gene', '29126', (218, 223))	('mutations', 'Var', (43, 52))	('signaling pathway', 'biological_process', 'GO:0007165', ('69', '86'))	('antigen presentation pathway', 'Pathway', (91, 119))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
104462	31552026	Our data suggest loss of function JAK1 mutations are a risk factor for lower tumor cell PD-L1 expression which could impair responsiveness to anti-PD-1 therapy used for advanced urothelial carcinoma.	('PD-1', 'Gene', (147, 151))	('PD-L1', 'Gene', (88, 93))	('loss of function', 'NegReg', (17, 33))	('PD-1', 'Gene', '5133', (147, 151))	('impair', 'NegReg', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mutations', 'Var', (39, 48))	('JAK', 'molecular_function', 'GO:0004713', ('34', '37'))	('PD-L1', 'Gene', '29126', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('urothelial carcinoma', 'Disease', (178, 198))	('expression', 'MPA', (94, 104))	('JAK1', 'Gene', (34, 38))	('responsiveness to', 'MPA', (124, 141))	('tumor', 'Disease', (77, 82))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (178, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('lower', 'NegReg', (71, 76))
104480	31008958	Based on the mutation of STK11 M51Ifs*106 detected by next generation sequencing (NGS), we started targeted therapy with everolimus.	('everolimus', 'Chemical', 'MESH:D000068338', (121, 131))	('STK11', 'molecular_function', 'GO:0033868', ('25', '30'))	('STK11', 'Gene', (25, 30))	('M51Ifs*106', 'Var', (31, 41))	('M51Ifs*106', 'Mutation', 'p.M51IfsX106', (31, 41))
104501	31008958	Tumor markers were detected as follows: total prostatic specific antigen (T-PSA) 0.55 ng/mL (normal: 0-4), carcinoembryonic antigen (CEA) >100.00 ng/mL (normal: <=5 ng/mL), carbohydrate antigen 125 (CA-125) 46.8 U/mL (normal: <= 35 U/mL), CA-153 157.8 U/mL (normal: <=31.3 U/mL), and squamous cell carcinoma associated antigen (SCC) 4.64 ng/mL (normal: 0-1.5 ng/mL).	('carcinoembryonic antigen', 'Gene', (107, 131))	('carcinoma associated antigen (SCC) 4', 'Gene', '23383', (298, 334))	('>100.00', 'Var', (138, 145))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('CEA', 'Gene', (133, 136))	('carcinoembryonic antigen', 'Gene', '1084', (107, 131))	('CA-153', 'Var', (239, 245))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (284, 307))	('squamous cell carcinoma', 'Disease', (284, 307))	('CEA', 'Gene', '1084', (133, 136))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (284, 307))
104511	31008958	Based on results of bone IHC, (Creatine Kinase) (CK)5/6+ scattered, CK7+, GATA binding protein 3 (GATA3)+, P40+ few, CK20-, Villin-, thyroid transcription factor-1 (TTF-1)-, CDX2-, Glypican3- and Alpha-1 Antitrypsin (AAT)+ few), liver IHC (CK7+, CK20-, Villin-, TTF-1-, paired-box-8 (PAX-8)-, GATA-3-, CDX-2+, Ki-67+ about 60%), and lung IHC (CK5/6-, P40-, CK20-, GATA-3+ partial, CK7+ strong and widespread, TTF-1-, NapsinA-, Ki-67+ 40%), it did not support adenocarcinoma or squamous cell carcinoma from lung, liver, intestines, or stomach.	('GATA-3', 'Gene', '2625', (364, 370))	('P40-', 'Var', (351, 355))	('TTF-1', 'Gene', (262, 267))	('GATA binding protein 3', 'Gene', (74, 96))	('CDX-2', 'Gene', (302, 307))	('GATA-3', 'Gene', '2625', (293, 299))	('CK7', 'Gene', '3855', (68, 71))	('CK20', 'Gene', (357, 361))	('TTF-1', 'Gene', (165, 170))	('TTF-1', 'Gene', '7080', (165, 170))	('CK7', 'Gene', (240, 243))	('adenocarcinoma', 'Disease', (459, 473))	('P40', 'cellular_component', 'GO:0070743', ('351', '354'))	('PAX-8', 'Gene', (284, 289))	('GATA-3', 'Gene', (364, 370))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (477, 500))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (477, 500))	('transcription factor', 'molecular_function', 'GO:0000981', ('141', '161'))	('thyroid transcription factor-1', 'Gene', (133, 163))	('PAX-8', 'Gene', '7849', (284, 289))	('GATA-3', 'Gene', (293, 299))	('CK20', 'Gene', (246, 250))	('P40', 'cellular_component', 'GO:0070743', ('107', '110'))	('TTF-1', 'Gene', '7080', (409, 414))	('AAT', 'molecular_function', 'GO:0004069', ('217', '220'))	('CK20', 'Gene', '54474', (357, 361))	('CK7', 'Gene', (381, 384))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('TTF-1', 'Gene', (409, 414))	('carcinoma', 'Phenotype', 'HP:0030731', (491, 500))	('P40', 'cellular_component', 'GO:0043514', ('351', '354'))	('bone IHC', 'Disease', (20, 28))	('CK7', 'Gene', '3855', (240, 243))	('squamous cell carcinoma', 'Disease', (477, 500))	('Alpha-1 Antitrypsin', 'Gene', (196, 215))	('Glypican3', 'Gene', (181, 190))	('CK20', 'Gene', (117, 121))	('CDX-2', 'Gene', '1045', (302, 307))	('paired-box-8', 'Gene', '7849', (270, 282))	('adenocarcinoma', 'Disease', 'MESH:D000230', (459, 473))	('Alpha-1 Antitrypsin', 'Gene', '5265', (196, 215))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('P40', 'cellular_component', 'GO:0043514', ('107', '110'))	('CK20', 'Gene', '54474', (246, 250))	('GATA3', 'Gene', '2625', (98, 103))	('CDX2', 'Gene', '1045', (174, 178))	('paired-box-8', 'Gene', (270, 282))	('thyroid transcription factor-1', 'Gene', '7080', (133, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (464, 473))	('CK5/6-', 'Var', (343, 349))	('CK7', 'Gene', '3855', (381, 384))	('CK20', 'Gene', '54474', (117, 121))	('Glypican3', 'Gene', '2719', (181, 190))	('CDX2', 'Gene', (174, 178))	('GATA3', 'Gene', (98, 103))	('CK7', 'Gene', (68, 71))	('liver IHC', 'Disease', 'MESH:D017093', (229, 238))	('transcription', 'biological_process', 'GO:0006351', ('141', '154'))	('GATA binding protein 3', 'Gene', '2625', (74, 96))	('Glypican', 'molecular_function', 'GO:0015017', ('181', '189'))	('bone IHC', 'Disease', 'MESH:D001847', (20, 28))	('liver IHC', 'Disease', (229, 238))	('TTF-1', 'Gene', '7080', (262, 267))
104525	31008958	Of the 450 tumor related genes that were identified, 7 clinically significant genetic variants, including MET amplification, STK11 M51Ifs*106 exon1, KRAS G12C exon2, NCOR1 S1952* exon37, RBM10 E832* exon22, SETD2 Q2030* exon13 and SUFU c.1022+1G>T, were detected.	('S1952*', 'SUBSTITUTION', 'None', (172, 178))	('KRAS', 'Gene', (149, 153))	('Q2030*', 'Var', (213, 219))	('RBM10', 'Gene', (187, 192))	('SUFU', 'Gene', '51684', (231, 235))	('E832*', 'SUBSTITUTION', 'None', (193, 198))	('MET', 'Var', (106, 109))	('Q2030*', 'SUBSTITUTION', 'None', (213, 219))	('STK11', 'molecular_function', 'GO:0033868', ('125', '130'))	('tumor', 'Disease', (11, 16))	('RBM10', 'Gene', '8241', (187, 192))	('c.1022+1G>T', 'Mutation', 'c.1022+1G>T', (236, 247))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('NCOR1', 'Gene', (166, 171))	('SETD2', 'Gene', (207, 212))	('S1952*', 'Var', (172, 178))	('M51Ifs*106 exon1', 'Var', (131, 147))	('NCOR1', 'Gene', '9611', (166, 171))	('SUFU', 'Gene', (231, 235))	('G12C', 'Mutation', 'rs121913530', (154, 158))	('SETD2', 'Gene', '29072', (207, 212))	('E832*', 'Var', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('KRAS', 'Gene', '3845', (149, 153))	('STK11', 'Gene', (125, 130))	('M51Ifs*106', 'Mutation', 'p.M51IfsX106', (131, 141))
104526	31008958	Based on the highest variation abundance of STK11 M51Ifs*106 exon1, the patient was given 10 mg qd.	('exon1', 'Protein', (61, 66))	('M51Ifs*106', 'Mutation', 'p.M51IfsX106', (50, 60))	('STK11 M51Ifs*106', 'Var', (44, 60))	('patient', 'Species', '9606', (72, 79))	('STK11', 'molecular_function', 'GO:0033868', ('44', '49'))
104549	31008958	Seven genetic variants with clinical significance, including MET amplification, STK11 M51Ifs*106 exon1, KRAS G12C exon2, NCOR1 S1952* exon37, RBM10 E832* exon22, SETD2 Q2030* exon13, and SUFU c.1022+1G>T were detected in 450 cancer related genes.	('SETD2', 'Gene', (162, 167))	('Q2030*', 'SUBSTITUTION', 'None', (168, 174))	('M51Ifs*106 exon1', 'Var', (86, 102))	('cancer', 'Disease', (225, 231))	('SUFU', 'Gene', (187, 191))	('G12C', 'Mutation', 'rs121913530', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('SETD2', 'Gene', '29072', (162, 167))	('E832*', 'Var', (148, 153))	('NCOR1', 'Gene', (121, 126))	('S1952*', 'Var', (127, 133))	('KRAS', 'Gene', '3845', (104, 108))	('NCOR1', 'Gene', '9611', (121, 126))	('KRAS', 'Gene', (104, 108))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('RBM10', 'Gene', (142, 147))	('E832*', 'SUBSTITUTION', 'None', (148, 153))	('STK11', 'Gene', (80, 85))	('SUFU', 'Gene', '51684', (187, 191))	('M51Ifs*106', 'Mutation', 'p.M51IfsX106', (86, 96))	('S1952*', 'SUBSTITUTION', 'None', (127, 133))	('RBM10', 'Gene', '8241', (142, 147))	('STK11', 'molecular_function', 'GO:0033868', ('80', '85'))	('Q2030*', 'Var', (168, 174))	('c.1022+1G>T', 'Mutation', 'c.1022+1G>T', (192, 203))
104552	31008958	In a normal physiological state, the combination of HGF and c-MET can activate a variety of downstream signaling pathways, including RAS/RAF/MAPK, PI3K/Akt/mTOR, SRC/FAK, and JUN, which can lead to the cell cycle process, proliferation, movement and migration, survival and cell transformation.MET gene mutations or amplification have been found in many human cancers, most commonly seen in lung and breast cancer.	('amplification', 'Var', (316, 329))	('mutations', 'Var', (303, 312))	('SRC', 'Gene', (162, 165))	('men', 'Species', '9606', (241, 244))	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('MAPK', 'molecular_function', 'GO:0004707', ('141', '145'))	('HGF', 'Gene', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('cancers', 'Phenotype', 'HP:0002664', (360, 367))	('cancers', 'Disease', (360, 367))	('transformation.MET', 'Gene', (279, 297))	('RAF', 'Gene', (137, 140))	('man', 'Species', '9606', (349, 352))	('breast cancer', 'Phenotype', 'HP:0003002', (400, 413))	('FAK', 'Gene', '5747', (166, 169))	('man', 'Species', '9606', (356, 359))	('found', 'Reg', (340, 345))	('breast cancer', 'Disease', 'MESH:D001943', (400, 413))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('breast cancer', 'Disease', (400, 413))	('cancers', 'Disease', 'MESH:D009369', (360, 367))	('FAK', 'molecular_function', 'GO:0004717', ('166', '169'))	('SRC', 'Gene', '6714', (162, 165))	('c-MET', 'Gene', '4233', (60, 65))	('FAK', 'Gene', (166, 169))	('Akt', 'Gene', (152, 155))	('human', 'Species', '9606', (354, 359))	('PI3K', 'molecular_function', 'GO:0016303', ('147', '151'))	('c-MET', 'Gene', (60, 65))	('cell cycle process', 'biological_process', 'GO:0022402', ('202', '220'))	('HGF', 'Gene', '3082', (52, 55))	('Akt', 'Gene', '207', (152, 155))	('RAF', 'Gene', '22882', (137, 140))	('lung', 'Disease', (391, 395))
104553	31008958	It can activate c-MET signaling and promote uncontrolled cell proliferation and tumor metastasis.MET gene amplification is often found in metastatic tumors, suggesting that it mainly plays a role in the process of tumor metastasis.MET gene variation (amplification or mutation), combined with overexpression of the protein, occurs in about 2% to 10% of bladder cancer cases and is associated with bladder cancer metastasis and poor survival.	('bladder cancer', 'Phenotype', 'HP:0009725', (353, 367))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('bladder cancer metastasis', 'Disease', 'MESH:D009362', (397, 422))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('bladder cancer metastasis', 'Disease', (397, 422))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('protein', 'cellular_component', 'GO:0003675', ('315', '322'))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('cell proliferation', 'biological_process', 'GO:0008283', ('57', '75'))	('cancer', 'Phenotype', 'HP:0002664', (405, 411))	('c-MET', 'Gene', '4233', (16, 21))	('bladder cancer', 'Disease', 'MESH:D001749', (397, 411))	('metastasis.MET gene variation', 'Var', (220, 249))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('associated', 'Reg', (381, 391))	('c-MET', 'Gene', (16, 21))	('tumors', 'Disease', (149, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (397, 411))	('tumor', 'Disease', (80, 85))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('tumor', 'Disease', (149, 154))	('bladder cancer', 'Disease', 'MESH:D001749', (353, 367))	('bladder cancer', 'Disease', (353, 367))
104554	31008958	In this report, the extensive multiple organ metastasis (including liver, bone, and lung) of occult urothelial carcinoma might be related to MET amplification.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('occult urothelial carcinoma', 'Disease', (93, 120))	('MET amplification', 'Var', (141, 158))	('occult urothelial carcinoma', 'Disease', 'MESH:D009382', (93, 120))	('bone', 'CPA', (74, 78))
104556	31008958	Cabozantinib can inhibit the proliferation of gastric cancer cell lines with MET amplification, but it is not effective for cell lines without MET amplification.	('MET amplification', 'Var', (77, 94))	('gastric cancer', 'Disease', (46, 60))	('gastric cancer', 'Disease', 'MESH:D013274', (46, 60))	('proliferation', 'CPA', (29, 42))	('inhibit', 'NegReg', (17, 24))	('Cabozantinib', 'Chemical', 'MESH:C558660', (0, 12))	('gastric cancer', 'Phenotype', 'HP:0012126', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
104557	31008958	A lung adenocarcinoma patient carrying MET gene amplification and 14 exon skipping mutation achieved complete remission after being treated with cabozantinib.	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('cabozantinib', 'Chemical', 'MESH:C558660', (145, 157))	('A lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 21))	('A lung adenocarcinoma', 'Disease', (0, 21))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (2, 21))	('patient', 'Species', '9606', (22, 29))	('MET gene amplification', 'Var', (39, 61))
104559	31008958	In this report, the STK11 M51Ifs*106 mutation can be described as the 51st codon of methionine changed into isoleucine and the 106th codon becoming a stop codon in the new open reading frame.	('M51Ifs*106', 'Var', (26, 36))	('methionine', 'Chemical', 'MESH:D008715', (84, 94))	('methionine', 'MPA', (84, 94))	('STK11', 'Gene', (20, 25))	('STK11', 'molecular_function', 'GO:0033868', ('20', '25'))	('isoleucine', 'MPA', (108, 118))	('isoleucine', 'Chemical', 'MESH:D007532', (108, 118))	('M51Ifs*106', 'Mutation', 'p.M51IfsX106', (26, 36))
104560	31008958	Although there are no anti-tumor drugs targeting the STK11 gene, the inhibition of mTOR can be used as a treatment for cancer patients with STK11 dysfunction.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mTOR', 'Gene', (83, 87))	('STK11', 'Gene', (140, 145))	('tumor', 'Disease', (27, 32))	('men', 'Species', '9606', (110, 113))	('STK11', 'molecular_function', 'GO:0033868', ('53', '58'))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('patients', 'Species', '9606', (126, 134))	('inhibition', 'Var', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('STK11', 'molecular_function', 'GO:0033868', ('140', '145'))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
104561	31008958	In the STK11-/- mouse breast cancer tumor model, mTOR inhibitor AZD8055 can inhibit tumor growth successfully.	('AZD8055', 'Var', (64, 71))	('breast cancer tumor', 'Disease', 'MESH:D001943', (22, 41))	('AZD8055', 'Chemical', 'MESH:C546624', (64, 71))	('inhibit', 'NegReg', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('STK11', 'molecular_function', 'GO:0033868', ('7', '12'))	('breast cancer tumor', 'Disease', (22, 41))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mouse', 'Species', '10090', (16, 21))	('tumor', 'Disease', (36, 41))
104562	31008958	A patient with metastatic atypical pituitary adenomas with STK11 F298L variation was treated with radiotherapy and everolimus, and MRI and positron emission tomography and computed tomography showed stable disease (SD) over 6 months.	('pituitary adenomas', 'Disease', 'MESH:D010911', (35, 53))	('F298L', 'Mutation', 'rs199681533', (65, 70))	('everolimus', 'Chemical', 'MESH:D000068338', (115, 125))	('STK11', 'molecular_function', 'GO:0033868', ('59', '64'))	('F298L', 'Var', (65, 70))	('STK11', 'Gene', (59, 64))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (35, 53))	('SD', 'Disease', 'MESH:D029461', (215, 217))	('pituitary adenomas', 'Disease', (35, 53))	('patient', 'Species', '9606', (2, 9))
104564	31008958	In this case, based on the mutation of STK11 M51Ifs*106, the patient was treated with everolimus, but it was not very effective and the patient's condition continued to deteriorate.	('patient', 'Species', '9606', (61, 68))	('everolimus', 'Chemical', 'MESH:D000068338', (86, 96))	('patient', 'Species', '9606', (136, 143))	('STK11', 'molecular_function', 'GO:0033868', ('39', '44'))	('mutation', 'Var', (27, 35))	('STK11', 'Gene', (39, 44))	('M51Ifs*106', 'Mutation', 'p.M51IfsX106', (45, 55))
104565	31008958	In addition, the patient carried a variety of tumor related gene mutations.	('carried', 'Reg', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('patient', 'Species', '9606', (17, 24))	('tumor', 'Disease', (46, 51))	('mutations', 'Var', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
104568	31008958	KRAS mutations mainly occur in the 12th, 13th and 61st codons, which may affect RAS mediated guanosine triphosphate (GTP) hydrolysis and lead to the continuous activation of RAS, promoting the malignant transformation of cells.	('GTP) hydrolysis', 'biological_process', 'GO:0006184', ('117', '132'))	('RAS', 'Protein', (174, 177))	('guanosine triphosphate', 'Chemical', 'MESH:D006160', (93, 115))	('affect', 'Reg', (73, 79))	('activation', 'PosReg', (160, 170))	('mutations', 'Var', (5, 14))	('GTP', 'Chemical', 'MESH:D006160', (117, 120))	('promoting', 'PosReg', (179, 188))	('malignant transformation of cells', 'CPA', (193, 226))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
104569	31008958	G12C is one of the most common mutations in KRAS located in the 2nd exon.	('KRAS', 'Gene', '3845', (44, 48))	('G12C', 'Mutation', 'rs121913530', (0, 4))	('KRAS', 'Gene', (44, 48))	('G12C', 'Var', (0, 4))
104571	31008958	Compared with the mutation of position 13, the mutation of the 12th position has a stronger ability to resist cell death and promote transformation of cancer cells.	('cell death', 'biological_process', 'GO:0008219', ('110', '120'))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutation', 'Var', (47, 55))	('resist cell death', 'CPA', (103, 120))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('promote', 'PosReg', (125, 132))
104572	31008958	Although there is no anti-tumor drug targeting the KRAS gene, MEK inhibitors and PI3K pathway inhibitors have a certain therapeutic effect in treating cancer patients with KRAS mutations.	('KRAS', 'Gene', (172, 176))	('KRAS', 'Gene', '3845', (51, 55))	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('MEK', 'Gene', (62, 65))	('KRAS', 'Gene', '3845', (172, 176))	('MEK', 'Gene', '5609', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('mutations', 'Var', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('patients', 'Species', '9606', (158, 166))	('tumor', 'Disease', (26, 31))	('KRAS', 'Gene', (51, 55))
104575	31008958	However, in breast cancer, patients with a high expression of NCOR1 have a better prognosis than those with low expression.	('breast cancer', 'Disease', (12, 25))	('NCOR1', 'Gene', (62, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('high expression', 'Var', (43, 58))	('NCOR1', 'Gene', '9611', (62, 67))	('patients', 'Species', '9606', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))
104576	31008958	In this case, the patient with occult urothelial carcinoma had a NCOR1 S1952* mutation which resulted in protein truncation.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('occult urothelial carcinoma', 'Disease', (31, 58))	('NCOR1', 'Gene', '9611', (65, 70))	('occult urothelial carcinoma', 'Disease', 'MESH:D009382', (31, 58))	('patient', 'Species', '9606', (18, 25))	('protein truncation', 'MPA', (105, 123))	('S1952*', 'SUBSTITUTION', 'None', (71, 77))	('S1952*', 'Var', (71, 77))	('NCOR1', 'Gene', (65, 70))
104577	31008958	The truncated NCOR1 lost the functional domain of the C1D interaction zone, RARA interaction region, and ID1 and ID2 region, meaning that this mutation may affect the normal function of NCOR1.	('NCOR1', 'Gene', (186, 191))	('truncated', 'Var', (4, 13))	('ID2', 'Gene', '3398', (113, 116))	('C1D', 'Gene', (54, 57))	('lost', 'NegReg', (20, 24))	('RARA', 'Gene', '5914', (76, 80))	('affect', 'Reg', (156, 162))	('ID1', 'Gene', '3397', (105, 108))	('mutation', 'Var', (143, 151))	('ID2', 'Gene', (113, 116))	('C1D', 'Gene', '10438', (54, 57))	('ID1', 'Gene', (105, 108))	('NCOR1', 'Gene', '9611', (14, 19))	('RARA', 'Gene', (76, 80))	('NCOR1', 'Gene', (14, 19))	('NCOR1', 'Gene', '9611', (186, 191))	('normal function', 'MPA', (167, 182))	('functional domain', 'MPA', (29, 46))
104581	31008958	The deletion or mutation of NUMB frequently occurs in lung cancer.RBM10 mutation often coexists with known drive gene mutations.	('RBM10', 'Gene', '8241', (66, 71))	('lung cancer', 'Disease', (54, 65))	('NUMB', 'Gene', (28, 32))	('RBM10', 'Gene', (66, 71))	('NUMB', 'Gene', '8650', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('mutation', 'Var', (72, 80))
104582	31008958	In this case, the mutation of RBM10 E832*, as a first reported novel mutation, produced a truncated protein, which lost the G-patch domain (858-904 amino acid residues).	('E832*', 'SUBSTITUTION', 'None', (36, 41))	('E832*', 'Var', (36, 41))	('RBM10', 'Gene', '8241', (30, 35))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('lost', 'NegReg', (115, 119))	('RBM10', 'Gene', (30, 35))
104583	31008958	The mutation of RBM10 E810*, which has been reported in lung adenocarcinoma, also produced a truncated protein with G-patch domain deletion.	('E810*', 'Var', (22, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('G-patch domain', 'MPA', (116, 130))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('lung adenocarcinoma', 'Disease', (56, 75))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (56, 75))	('RBM10', 'Gene', '8241', (16, 21))	('truncated', 'MPA', (93, 102))	('RBM10', 'Gene', (16, 21))	('E810*', 'SUBSTITUTION', 'None', (22, 27))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (56, 75))
104584	31008958	It was suggested that RBM10 E832* might be a harmful mutation affecting the normal function of RBM10 protein.	('normal function', 'MPA', (76, 91))	('E832*', 'SUBSTITUTION', 'None', (28, 33))	('RBM10', 'Gene', '8241', (22, 27))	('protein', 'Protein', (101, 108))	('E832*', 'Var', (28, 33))	('RBM10', 'Gene', (22, 27))	('RBM10', 'Gene', '8241', (95, 100))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('RBM10', 'Gene', (95, 100))
104586	31008958	The mutations or translocations of the histone methyltransferase SETD2 are found in leukemia and solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (97, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('SETD2', 'Gene', '29072', (65, 70))	('found', 'Reg', (75, 80))	('leukemia', 'Phenotype', 'HP:0001909', (84, 92))	('SETD2', 'Gene', (65, 70))	('translocations', 'Var', (17, 31))	('solid tumors', 'Disease', (97, 109))	('leukemia', 'Disease', (84, 92))	('mutations', 'Var', (4, 13))	('leukemia', 'Disease', 'MESH:D007938', (84, 92))
104587	31008958	There are many variants of SETD2 mutated at different sites in the same tumor and this will have a selective advantage in the process of renal cell carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('advantage', 'PosReg', (109, 118))	('renal cell carcinoma', 'Disease', (137, 157))	('mutated', 'Var', (33, 40))	('man', 'Species', '9606', (10, 13))	('SETD2', 'Gene', '29072', (27, 32))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (137, 157))	('SETD2', 'Gene', (27, 32))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (137, 157))	('variants', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
104588	31008958	In this case, the SETD2 Q2030* mutation caused the glutamine of position 2030 mutated to stop codon.	('glutamine', 'Chemical', 'MESH:D005973', (51, 60))	('Q2030*', 'SUBSTITUTION', 'None', (24, 30))	('mutated', 'MPA', (78, 85))	('SETD2', 'Gene', '29072', (18, 23))	('Q2030*', 'Var', (24, 30))	('glutamine', 'MPA', (51, 60))	('SETD2', 'Gene', (18, 23))
104590	31008958	It was suggested that the variation of SETD2 Q2030* might affect the normal function of SETD2.	('SETD2', 'Gene', '29072', (88, 93))	('SETD2', 'Gene', (39, 44))	('SETD2', 'Gene', '29072', (39, 44))	('Q2030*', 'SUBSTITUTION', 'None', (45, 51))	('normal function', 'MPA', (69, 84))	('SETD2', 'Gene', (88, 93))	('Q2030*', 'Var', (45, 51))	('affect', 'Reg', (58, 64))
104593	31008958	Abnormal activation of the Hh pathway is associated with tumor formation in various tissues.SUFU c.1022+1G>T mutation makes the G base in the splicing donor site into a T, which might cause abnormal mRNA splicing.	('formation', 'biological_process', 'GO:0009058', ('63', '72'))	('mRNA splicing', 'biological_process', 'GO:0000374', ('199', '212'))	('SUFU', 'Gene', '51684', (92, 96))	('mRNA splicing', 'biological_process', 'GO:0006371', ('199', '212'))	('c.1022+1G>T', 'Mutation', 'c.1022+1G>T', (97, 108))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('mRNA splicing', 'biological_process', 'GO:0000373', ('199', '212'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('199', '212'))	('splicing', 'biological_process', 'GO:0045292', ('142', '150'))	('mRNA splicing', 'biological_process', 'GO:0000372', ('199', '212'))	('c.1022+1G>T mutation', 'Var', (97, 117))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mRNA splicing', 'biological_process', 'GO:0000394', ('199', '212'))	('mRNA splicing', 'MPA', (199, 212))	('SUFU', 'Gene', (92, 96))	('tumor', 'Disease', (57, 62))	('cause', 'Reg', (184, 189))	('donor', 'Species', '9606', (151, 156))
104595	31008958	Real-time reverse transcription polymerase chain reaction confirms that SUFU c.1022+1G>T mutation causes SUFU exon 8 skipping, and forms a stop codon in the 9th exon.	('SUFU', 'Gene', '51684', (105, 109))	('c.1022+1G>T', 'Var', (77, 88))	('reverse transcription', 'biological_process', 'GO:0001171', ('10', '31'))	('SUFU', 'Gene', (72, 76))	('c.1022+1G>T', 'Mutation', 'c.1022+1G>T', (77, 88))	('SUFU', 'Gene', (105, 109))	('SUFU', 'Gene', '51684', (72, 76))	('skipping', 'NegReg', (117, 125))
104605	29103968	M7824 is a novel first-in-class bifunctional fusion protein comprising a monoclonal antibody against programmed death-ligand 1 (PD-L1, avelumab), fused to the extracellular domain of human transforming growth factor beta (TGFbeta) receptor 2, which functions as a TGFbeta "trap".	('TGFbeta', 'Gene', '7040', (264, 271))	('antibody', 'cellular_component', 'GO:0019814', ('84', '92'))	('transforming growth factor beta (TGFbeta) receptor 2', 'Gene', '7048', (189, 241))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))	('TGFbeta', 'Gene', (222, 229))	('extracellular', 'cellular_component', 'GO:0005576', ('159', '172'))	('TGFbeta', 'Gene', '7040', (222, 229))	('programmed death-ligand 1', 'Gene', (101, 126))	('programmed death-ligand 1', 'Gene', '29126', (101, 126))	('M7824', 'Var', (0, 5))	('human', 'Species', '9606', (183, 188))	('avelumab', 'Chemical', 'MESH:C000609138', (135, 143))	('antibody', 'molecular_function', 'GO:0003823', ('84', '92'))	('ligand', 'molecular_function', 'GO:0005488', ('118', '124'))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('189', '220'))	('TGFbeta', 'Gene', (264, 271))	('antibody', 'cellular_component', 'GO:0042571', ('84', '92'))	('antibody', 'cellular_component', 'GO:0019815', ('84', '92'))
104608	29103968	In this study, we explored the effect of M7824 on invasive urothelial carcinoma cell lines.	('urothelial carcinoma cell lines', 'Disease', 'MESH:C538614', (59, 90))	('M7824', 'Var', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('urothelial carcinoma cell lines', 'Disease', (59, 90))
104609	29103968	Human urothelial (transitional cell) carcinoma cell lines HTB-4, HTB-1, and HTB-5 were treated with M7824, M7824mut (M7824 that is mutated in the anti-PD-L1 portion of the molecule and thus does not bind PD-L1), anti-PD-L1 (avelumab), or IgG1 isotype control monoclonal antibody, and were assessed for gene expression, cell surface phenotype, and sensitivity to lysis by TRAIL, antigen-specific cytotoxic T lymphocytes and natural killer cells.	('Human', 'Species', '9606', (0, 5))	('cell surface', 'cellular_component', 'GO:0009986', ('319', '331'))	('IgG1', 'cellular_component', 'GO:0071735', ('238', '242'))	('antibody', 'cellular_component', 'GO:0019815', ('270', '278'))	('lysis', 'biological_process', 'GO:0019835', ('362', '367'))	('TRAIL', 'Gene', (371, 376))	('antibody', 'cellular_component', 'GO:0019814', ('270', '278'))	('avelumab', 'Chemical', 'MESH:C000609138', (224, 232))	('carcinoma', 'Disease', 'MESH:D002277', (37, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('antibody', 'molecular_function', 'GO:0003823', ('270', '278'))	('gene expression', 'biological_process', 'GO:0010467', ('302', '317'))	('carcinoma', 'Disease', (37, 46))	('antibody', 'cellular_component', 'GO:0042571', ('270', '278'))	('M7824', 'Var', (100, 105))	('M7824mut', 'Var', (107, 115))	('TRAIL', 'Gene', '8743', (371, 376))
104610	29103968	M7824 retains the ability to mediate antibody-dependent cellular cytotoxicity of tumor cells, although in some cases to a lesser extent than anti-PD-L1.	('cytotoxicity', 'Disease', 'MESH:D064420', (65, 77))	('antibody', 'cellular_component', 'GO:0042571', ('37', '45'))	('antibody', 'cellular_component', 'GO:0019815', ('37', '45'))	('M7824', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('antibody', 'cellular_component', 'GO:0019814', ('37', '45'))	('antibody', 'molecular_function', 'GO:0003823', ('37', '45'))	('cytotoxicity', 'Disease', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('antibody-dependent cellular cytotoxicity', 'biological_process', 'GO:0001788', ('37', '77'))	('tumor', 'Disease', (81, 86))
104611	29103968	However, compared to anti-PD-L1, M7824 increases (a) gene expression of molecules involved in T-cell trafficking in the tumor (e.g., CXCL11), (b) TRAIL-mediated tumor cell lysis, and (c) antigen-specific CD8+ T-cell mediated lysis of tumor cells.	('lysis', 'biological_process', 'GO:0019835', ('225', '230'))	('tumor', 'Disease', (234, 239))	('TRAIL', 'Gene', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', (161, 166))	('gene expression', 'MPA', (53, 68))	('gene expression', 'biological_process', 'GO:0010467', ('53', '68'))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', (120, 125))	('CD8', 'Gene', '925', (204, 207))	('M7824', 'Var', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('lysis', 'biological_process', 'GO:0019835', ('172', '177'))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('increases', 'PosReg', (39, 48))	('TRAIL', 'Gene', '8743', (146, 151))	('CXCL11', 'Gene', '6373', (133, 139))	('CXCL11', 'Gene', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CD8', 'Gene', (204, 207))
104612	29103968	These studies demonstrate the immunomodulatory properties of M7824 on both tumor cell phenotype and immune-mediated lysis.	('M7824', 'Var', (61, 66))	('lysis', 'biological_process', 'GO:0019835', ('116', '121'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
104613	29103968	Compared to anti-PD-L1 or M7824mut, M7824 induces immunogenic modulation of urothelial carcinoma cell lines, rendering them more susceptible to immune mediated recognition and lysis.	('susceptible', 'MPA', (129, 140))	('urothelial carcinoma cell lines', 'Disease', (76, 107))	('M7824', 'Var', (36, 41))	('urothelial carcinoma cell lines', 'Disease', 'MESH:C538614', (76, 107))	('lysis', 'biological_process', 'GO:0019835', ('176', '181'))	('more', 'PosReg', (124, 128))	('immunogenic modulation', 'MPA', (50, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
104627	29103968	M7824 is a novel first-in-class bifunctional fusion protein consisting of the extracellular domain of the human transforming growth factor beta (TGFbeta) receptor 2, which functions as a "trap" for all three TGFbeta isoforms, covalently linked to the C-terminus of the heavy chain of the anti-PD-L1 antibody derived from avelumab (Lan et al., manuscript submitted).	('TGFbeta', 'Gene', '7040', (145, 152))	('human', 'Species', '9606', (106, 111))	('antibody', 'cellular_component', 'GO:0019815', ('297', '305'))	('TGFbeta', 'Gene', (208, 215))	('antibody', 'cellular_component', 'GO:0019814', ('297', '305'))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('112', '143'))	('M7824', 'Var', (0, 5))	('TGFbeta', 'Gene', '7040', (208, 215))	('antibody', 'molecular_function', 'GO:0003823', ('297', '305'))	('TGFbeta', 'Gene', (145, 152))	('avelumab', 'Chemical', 'MESH:C000609138', (321, 329))	('transforming growth factor beta (TGFbeta) receptor 2', 'Gene', '7048', (112, 164))	('extracellular', 'cellular_component', 'GO:0005576', ('78', '91'))	('antibody', 'cellular_component', 'GO:0042571', ('297', '305'))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
104630	29103968	A recent study has shown that M7824 reverts features of TGFbeta-mediated mesenchymalization, including attenuating expression of mesenchymal markers, proliferation suppression, and chemo-resistance.	('attenuating', 'NegReg', (103, 114))	('TGFbeta', 'Gene', '7040', (56, 63))	('M7824', 'Var', (30, 35))	('proliferation suppression', 'CPA', (150, 175))	('chemo-resistance', 'CPA', (181, 197))	('expression', 'MPA', (115, 125))	('TGFbeta', 'Gene', (56, 63))
104631	29103968	In addition, in vitro studies have shown that M7824 is capable of mediating ADCC of human cervical, lung, breast, and prostate cancer cells.	('prostate cancer', 'Disease', (118, 133))	('breast', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung', 'Disease', (100, 104))	('ADCC', 'biological_process', 'GO:0001788', ('76', '80'))	('prostate cancer', 'Disease', 'MESH:D011471', (118, 133))	('ADCC', 'Disease', (76, 80))	('prostate cancer', 'Phenotype', 'HP:0012125', (118, 133))	('human', 'Species', '9606', (84, 89))	('M7824', 'Var', (46, 51))
104632	29103968	M7824 has also shown anti-tumor efficacy in various murine models (Lan et al., manuscript submitted; Knudson et al., manuscript in preparation).	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('M7824', 'Var', (0, 5))	('murine', 'Species', '10090', (52, 58))	('tumor', 'Disease', (26, 31))
104638	29103968	In this study, we explored the relevance of the dual blockade of PD-L1 and TGFbeta for the immunogenic modulation of tumor cells, and support the rationale for the use of M7824 alone and in combination with other therapies in clinical studies in patients with urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (260, 280))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('patients', 'Species', '9606', (246, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('tumor', 'Disease', (117, 122))	('urothelial carcinoma', 'Disease', (260, 280))	('M7824', 'Var', (171, 176))	('TGFbeta', 'Gene', '7040', (75, 82))	('PD-L1', 'Gene', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('TGFbeta', 'Gene', (75, 82))
104642	29103968	HTB-4, HTB-1, and HTB-5 cells were treated with M7824, M7824mut, anti-PD-L1 (avelumab), or the IgG1 isotype control MAb at 20 ug/ml for 72 hours.	('anti-PD-L1', 'Var', (65, 75))	('M7824', 'Var', (48, 53))	('IgG1', 'cellular_component', 'GO:0071735', ('95', '99'))	('M7824mut', 'Var', (55, 63))	('avelumab', 'Chemical', 'MESH:C000609138', (77, 85))
104643	29103968	M7824 is a bifunctional fusion protein consisting of the extracellular domain of the human TGFbetaR2 covalently linked to the C-terminus of the heavy chain of the anti-PDL1 antibody derived from avelumab.	('antibody', 'cellular_component', 'GO:0019814', ('173', '181'))	('antibody', 'molecular_function', 'GO:0003823', ('173', '181'))	('TGFbeta', 'Gene', (91, 98))	('extracellular', 'cellular_component', 'GO:0005576', ('57', '70'))	('avelumab', 'Chemical', 'MESH:C000609138', (195, 203))	('PDL1', 'Gene', '29126', (168, 172))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('91', '99'))	('antibody', 'cellular_component', 'GO:0042571', ('173', '181'))	('M7824', 'Var', (0, 5))	('TGFbeta', 'Gene', '7040', (91, 98))	('PDL1', 'Gene', (168, 172))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('antibody', 'cellular_component', 'GO:0019815', ('173', '181'))	('human', 'Species', '9606', (85, 90))
104644	29103968	In comparison, M7824mut is able to bind TGFbeta, but is mutated in the anti-PD-L1 portion of the molecule, so it does not bind PD-L1, while avelumab binds only to PD-L1.	('TGFbeta', 'Gene', (40, 47))	('avelumab', 'Chemical', 'MESH:C000609138', (140, 148))	('M7824mut', 'Var', (15, 23))	('bind', 'Interaction', (35, 39))	('TGFbeta', 'Gene', '7040', (40, 47))
104655	29103968	To analyze the effect of M7824, M7824mut and anti-PD-L1 on expression of genes potentially involved in cancer progression, RNA from treated cells was extracted and analyzed with the NanoString PanCancer Progression Panel.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Cancer', 'Phenotype', 'HP:0002664', (196, 202))	('Cancer', 'Disease', (196, 202))	('Cancer', 'Disease', 'MESH:D009369', (196, 202))	('RNA', 'cellular_component', 'GO:0005562', ('123', '126'))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('M7824', 'Var', (25, 30))	('M7824mut', 'Var', (32, 40))
104657	29103968	2B) a greater number of genes were uniquely altered with M7824 compared to anti-PD-L1 or M7824mut; however, in HTB-1 tumor cells, a similar number of genes changed among the different treatments (Fig.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('M7824', 'Var', (57, 62))	('tumor', 'Disease', (117, 122))	('changed', 'Reg', (156, 163))	('altered', 'Reg', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
104660	29103968	2E, CXCL11 was upregulated to a greater extent in cultures treated with M7824 compared to anti-PD-L1 or M7824mut.	('M7824', 'Var', (72, 77))	('CXCL11', 'Gene', (4, 10))	('upregulated', 'PosReg', (15, 26))	('CXCL11', 'Gene', '6373', (4, 10))
104662	29103968	M7824 is a human IgG1 derived from the anti-PD-L1 antibody, avelumab, that has the ability to mediate ADCC.	('antibody', 'cellular_component', 'GO:0019815', ('50', '58'))	('antibody', 'cellular_component', 'GO:0019814', ('50', '58'))	('human', 'Species', '9606', (11, 16))	('antibody', 'molecular_function', 'GO:0003823', ('50', '58'))	('IgG1', 'cellular_component', 'GO:0071735', ('17', '21'))	('M7824', 'Var', (0, 5))	('ADCC', 'biological_process', 'GO:0001788', ('102', '106'))	('antibody', 'cellular_component', 'GO:0042571', ('50', '58'))	('ADCC', 'Disease', (102, 106))	('avelumab', 'Chemical', 'MESH:C000609138', (60, 68))
104663	29103968	To determine if M7824 increases the sensitivity of urothelial carcinoma cell lines to NK lysis, HTB-4, HTB-5 and HTB-1 cells were incubated with M7824, M7824mut or anti-PD-L1, and then assessed for lysis by NK cells (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('M7824', 'Var', (16, 21))	('urothelial carcinoma cell lines', 'Disease', 'MESH:C538614', (51, 82))	('lysis', 'biological_process', 'GO:0019835', ('198', '203'))	('increases', 'PosReg', (22, 31))	('lysis', 'biological_process', 'GO:0019835', ('89', '94'))	('sensitivity', 'MPA', (36, 47))	('M7824', 'Var', (145, 150))	('urothelial carcinoma cell lines', 'Disease', (51, 82))	('M7824mut', 'Var', (152, 160))
104665	29103968	Two of three tumor cell lines treated with anti-PD-L1, however, showed higher levels of lysis compared to M7824.	('higher', 'PosReg', (71, 77))	('tumor', 'Disease', (13, 18))	('lysis', 'biological_process', 'GO:0019835', ('88', '93'))	('anti-PD-L1', 'Var', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('lysis', 'MPA', (88, 93))
104666	29103968	Employing HTB-4 cells, the difference observed in lysis between M7824 and anti-PD-L1 appear to be dependent upon the donor NK cells used.	('M7824', 'Var', (64, 69))	('donor', 'Species', '9606', (117, 122))	('lysis', 'biological_process', 'GO:0019835', ('50', '55'))	('lysis', 'MPA', (50, 55))
104667	29103968	Using NK cells from five healthy donors, four had a similar level of NK lysis with M7824 and anti-PD-L1, while one had a much higher level of lysis with anti-PD-L1 than M7824 (Table S1, Supplementary Material).	('anti-PD-L1', 'Var', (93, 103))	('donor', 'Species', '9606', (33, 38))	('lysis', 'biological_process', 'GO:0019835', ('142', '147'))	('M7824', 'Var', (83, 88))	('lysis', 'biological_process', 'GO:0019835', ('72', '77'))
104668	29103968	To confirm the ability of M7824 to mediate ADCC, human urothelial carcinoma cells treated with M7824, anti-PD-L1 or the IgG1 isotype control MAb were incubated with healthy donor NK cells that were pretreated with anti-CD16 blocking antibody.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('antibody', 'cellular_component', 'GO:0019814', ('233', '241'))	('IgG1', 'cellular_component', 'GO:0071735', ('120', '124'))	('antibody', 'molecular_function', 'GO:0003823', ('233', '241'))	('donor', 'Species', '9606', (173, 178))	('M7824', 'Var', (26, 31))	('human', 'Species', '9606', (49, 54))	('M7824', 'Var', (95, 100))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (55, 75))	('antibody', 'cellular_component', 'GO:0042571', ('233', '241'))	('CD16', 'Gene', '2214', (219, 223))	('ADCC', 'biological_process', 'GO:0001788', ('43', '47'))	('CD16', 'Gene', (219, 223))	('anti-PD-L1', 'Var', (102, 112))	('antibody', 'cellular_component', 'GO:0019815', ('233', '241'))	('urothelial carcinoma', 'Disease', (55, 75))
104669	29103968	The percentage of lysis was significantly reduced when tumor cells treated with M7824 or anti-PD-L1 were incubated with NK cells pretreated with the anti-CD16 blocking antibody (Fig.	('antibody', 'cellular_component', 'GO:0019814', ('168', '176'))	('M7824', 'Var', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('reduced', 'NegReg', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('lysis', 'MPA', (18, 23))	('antibody', 'molecular_function', 'GO:0003823', ('168', '176'))	('CD16', 'Gene', '2214', (154, 158))	('lysis', 'biological_process', 'GO:0019835', ('18', '23'))	('tumor', 'Disease', (55, 60))	('CD16', 'Gene', (154, 158))	('antibody', 'cellular_component', 'GO:0042571', ('168', '176'))	('anti-PD-L1', 'Var', (89, 99))	('antibody', 'cellular_component', 'GO:0019815', ('168', '176'))
104674	29103968	4D) cisplatin-resistant cells to NK killing, demonstrating that even cisplatin resistant cells treated with M7824 or anti-PD-L1 are susceptible to NK lysis.	('susceptible', 'Reg', (132, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('lysis', 'biological_process', 'GO:0019835', ('150', '155'))	('M7824', 'Var', (108, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('anti-PD-L1', 'Var', (117, 127))
104675	29103968	To examine the potential of M7824 to alter tumor cell phenotype, HTB-4 cells were exposed for 3 days to M7824, M7824mut or anti-PD-L1, and then analyzed by flow cytometry for the expression of several immunologically relevant molecules.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('M7824', 'Var', (28, 33))	('tumor', 'Disease', (43, 48))	('M7824mut', 'Var', (111, 119))	('M7824', 'Var', (104, 109))
104676	29103968	Relative to the isotype control, M7824 increased the expression (percent positive or MFI) of ICAM-1, CEA, and Fas in HTB-4 cells (Table 1).	('M7824', 'Var', (33, 38))	('ICAM-1', 'Gene', '3383', (93, 99))	('CEA', 'Gene', (101, 104))	('CEA', 'Gene', '1084', (101, 104))	('ICAM-1', 'Gene', (93, 99))	('increased', 'PosReg', (39, 48))	('expression', 'MPA', (53, 63))	('Fas', 'Chemical', 'MESH:C038178', (110, 113))
104678	29103968	In conclusion, M7824 induces an upregulation of molecules involved in immunogenic modulation of urothelial cancer cells, potentially rendering them more sensitive to immune-mediated killing.	('urothelial cancer', 'Disease', 'MESH:D014523', (96, 113))	('M7824', 'Var', (15, 20))	('upregulation', 'PosReg', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('urothelial cancer', 'Disease', (96, 113))	('more', 'PosReg', (148, 152))
104680	29103968	To determine whether M7824 could play a functional role in reverting resistance to TRAIL, HTB-4 cells were treated with M7824, M7824mut or anti-PD-L1 and assessed for sensitivity to TRAIL.	('TRAIL', 'Gene', '8743', (83, 88))	('TRAIL', 'Gene', '8743', (182, 187))	('M7824', 'Var', (120, 125))	('M7824mut', 'Var', (127, 135))	('TRAIL', 'Gene', (83, 88))	('TRAIL', 'Gene', (182, 187))
104682	29103968	Treatment with anti-PD-L1 did not alter sensitivity to TRAIL; however, exposure of HTB-4 cells to M7824 or M7824mut significantly increased sensitivity to TRAIL (Fig.	('sensitivity', 'MPA', (140, 151))	('TRAIL', 'Gene', '8743', (155, 160))	('TRAIL', 'Gene', '8743', (55, 60))	('M7824', 'Var', (98, 103))	('TRAIL', 'Gene', (155, 160))	('TRAIL', 'Gene', (55, 60))	('increased', 'PosReg', (130, 139))	('M7824mut', 'Var', (107, 115))
104683	29103968	These data indicate that the increased sensitivity to TRAIL lysis is mediated by the TGFbetaR2 component of M7824.	('sensitivity', 'MPA', (39, 50))	('TRAIL', 'Gene', '8743', (54, 59))	('TRAIL', 'Gene', (54, 59))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('85', '93'))	('TGFbeta', 'Gene', (85, 92))	('increased', 'PosReg', (29, 38))	('TGFbeta', 'Gene', '7040', (85, 92))	('M7824', 'Var', (108, 113))	('lysis', 'biological_process', 'GO:0019835', ('60', '65'))
104685	29103968	High levels of TGFbeta are also associated with immune escape due to a reduction of T-cell function.	('TGFbeta', 'Gene', (15, 22))	('reduction', 'NegReg', (71, 80))	('High levels', 'Var', (0, 11))	('TGFbeta', 'Gene', '7040', (15, 22))	('immune escape', 'CPA', (48, 61))	('T-cell function', 'CPA', (84, 99))
104686	29103968	To determine whether M7824 increases the sensitivity to antigen-specific CD8+ T cells, HTB-4 cells were treated with M7824, M7824mut, or anti-PD-L1, and assessed for their sensitivity to CEA-specific CD8+ T cells.	('CD8', 'Gene', '925', (73, 76))	('CEA', 'Gene', (187, 190))	('CD8', 'Gene', '925', (200, 203))	('CEA', 'Gene', '1084', (187, 190))	('increases', 'PosReg', (27, 36))	('sensitivity', 'MPA', (41, 52))	('M7824', 'Var', (21, 26))	('M7824', 'Var', (117, 122))	('CD8', 'Gene', (73, 76))	('M7824mut', 'Var', (124, 132))	('CD8', 'Gene', (200, 203))
104691	29103968	M7824 is a novel first-in-class bifunctional fusion protein composed of an MAb against PD-L1 (avelumab), fused to the extracellular domain of human TGFbeta receptor 2, which functions as a TGFbeta "trap".	('extracellular', 'cellular_component', 'GO:0005576', ('118', '131'))	('TGFbeta', 'Gene', '7040', (189, 196))	('TGFbeta', 'Gene', '7040', (148, 155))	('human', 'Species', '9606', (142, 147))	('M7824', 'Var', (0, 5))	('PD-L1', 'Gene', (87, 92))	('TGFbeta', 'Gene', (189, 196))	('TGFbeta', 'Gene', (148, 155))	('avelumab', 'Chemical', 'MESH:C000609138', (94, 102))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
104693	29103968	Specifically, M7824 blocks the PD-1/PD-L1 interaction between tumor cells and immune effector cells, and simultaneously removes TGFbeta from the tumor microenvironment, which, in addition to inhibiting T-cell function, suppresses the antitumor activity of innate immune cells including NK cells and dendritic cells.	('PD-1/PD-L1', 'Protein', (31, 41))	('blocks', 'NegReg', (20, 26))	('TGFbeta', 'Gene', '7040', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('T-cell function', 'CPA', (202, 217))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', (238, 243))	('inhibiting', 'NegReg', (191, 201))	('removes', 'NegReg', (120, 127))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('interaction', 'Interaction', (42, 53))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (62, 67))	('suppresses', 'NegReg', (219, 229))	('M7824', 'Var', (14, 19))	('TGFbeta', 'Gene', (128, 135))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
104695	29103968	Preclinical studies with M7824 have shown anti-tumor efficacy in several murine tumor models and associated modulation of immune infiltrate, including increases in CD8+ T cells and NK cells as well as reductions in suppressive immune cells including neutrophils and myeloid-derived suppressor cells (Lan et al., manuscript submitted; Knudson et al., manuscript in preparation).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('murine', 'Species', '10090', (73, 79))	('reductions', 'NegReg', (201, 211))	('increases', 'PosReg', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CD8', 'Gene', (164, 167))	('CD8', 'Gene', '925', (164, 167))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('suppressive immune cells', 'CPA', (215, 239))	('NK cells', 'CPA', (181, 189))	('M7824', 'Var', (25, 30))	('tumor', 'Disease', (47, 52))
104696	29103968	In the present study, we analyzed the immunomodulatory properties of M7824 on human invasive urothelial cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('invasive urothelial cancer', 'Disease', (84, 110))	('invasive urothelial cancer', 'Disease', 'MESH:D009362', (84, 110))	('M7824', 'Var', (69, 74))	('human', 'Species', '9606', (78, 83))
104698	29103968	Compared to avelumab, we show for the first time that M7824 is able to induce immunologically relevant changes on urothelial cancer cells, rendering them more susceptible to immune-mediated attack.	('urothelial cancer', 'Disease', 'MESH:D014523', (114, 131))	('M7824', 'Var', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('more', 'PosReg', (154, 158))	('susceptible', 'MPA', (159, 170))	('avelumab', 'Chemical', 'MESH:C000609138', (12, 20))	('urothelial cancer', 'Disease', (114, 131))	('immunologically', 'MPA', (78, 93))
104699	29103968	NanoString analysis shows that M7824 can influence multiple pathways related to the immune recognition of human urothelial cancer cells via mechanisms related to the remodeling of tumor vasculature, extracellular matrix and tumor stroma, and secretion of chemokines that potentially favor immune cell infiltration into the tumor.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('human', 'Species', '9606', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('199', '219'))	('influence', 'Reg', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor stroma', 'Disease', (224, 236))	('favor', 'PosReg', (283, 288))	('urothelial cancer', 'Disease', 'MESH:D014523', (112, 129))	('tumor stroma', 'Disease', 'MESH:D009369', (224, 236))	('tumor', 'Disease', (224, 229))	('secretion', 'MPA', (242, 251))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('urothelial cancer', 'Disease', (112, 129))	('secretion', 'biological_process', 'GO:0046903', ('242', '251'))	('tumor', 'Disease', (323, 328))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (323, 328))	('M7824', 'Var', (31, 36))	('immune cell infiltration', 'CPA', (289, 313))
104700	29103968	We show that M7824 induces upregulation of CXCL11, a molecule involved in the homing of T cells into the tumor.	('CXCL11', 'Gene', (43, 49))	('CXCL11', 'Gene', '6373', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('M7824', 'Var', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('upregulation', 'PosReg', (27, 39))	('tumor', 'Disease', (105, 110))
104702	29103968	Because avelumab is able to mediate ADCC, we also evaluated the ability of M7824 to induce ADCC of urothelial cancer cells.	('ADCC', 'biological_process', 'GO:0001788', ('91', '95'))	('urothelial cancer', 'Disease', (99, 116))	('ADCC', 'biological_process', 'GO:0001788', ('36', '40'))	('M7824', 'Var', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('urothelial cancer', 'Disease', 'MESH:D014523', (99, 116))	('avelumab', 'Chemical', 'MESH:C000609138', (8, 16))
104703	29103968	We confirmed that M7824 retains the biological ADCC activity of avelumab but to a lower extent, using NK cells from some healthy donors as effectors, presumably due to steric hindrance caused by fusion of anti-PD-L1 to the TGFbetaR2 portion of the molecule.	('TGFbeta', 'Gene', '7040', (223, 230))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('223', '231'))	('avelumab', 'Gene', (64, 72))	('fusion', 'Interaction', (195, 201))	('ADCC', 'biological_process', 'GO:0001788', ('47', '51'))	('donor', 'Species', '9606', (129, 134))	('biological ADCC activity', 'MPA', (36, 60))	('M7824', 'Var', (18, 23))	('TGFbeta', 'Gene', (223, 230))	('avelumab', 'Chemical', 'MESH:C000609138', (64, 72))	('anti-PD-L1', 'Gene', (205, 215))
104704	29103968	In the experiments performed with HTB-4 cells, the lysis by four of five different healthy donors was fairly similar between M7824 and anti-PD-L1.	('anti-PD-L1', 'Var', (135, 145))	('donor', 'Species', '9606', (91, 96))	('lysis', 'MPA', (51, 56))	('lysis', 'biological_process', 'GO:0019835', ('51', '56'))	('M7824', 'Var', (125, 130))
104706	29103968	We found that M7824 is able to mediate ADCC of resistant cells to a similar extent as non-resistant tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ADCC', 'CPA', (39, 43))	('tumor', 'Disease', (100, 105))	('ADCC', 'biological_process', 'GO:0001788', ('39', '43'))	('M7824', 'Var', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
104707	29103968	The studies reported here also showed the ability of M7824 to enhance cell death induced by TRAIL.	('cell death', 'biological_process', 'GO:0008219', ('70', '80'))	('TRAIL', 'Gene', (92, 97))	('M7824', 'Var', (53, 58))	('enhance', 'PosReg', (62, 69))	('cell death', 'CPA', (70, 80))	('TRAIL', 'Gene', '8743', (92, 97))
104708	29103968	HTB-4 urothelial cancer cells treated with M7824 were more sensitive to TRAIL-mediated lysis compared to tumor cells that were untreated, treated with the isotype control, or treated with anti-PD-L1.	('sensitive', 'Reg', (59, 68))	('urothelial cancer', 'Disease', (6, 23))	('TRAIL', 'Gene', '8743', (72, 77))	('M7824', 'Var', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('urothelial cancer', 'Disease', 'MESH:D014523', (6, 23))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('TRAIL', 'Gene', (72, 77))	('lysis', 'biological_process', 'GO:0019835', ('87', '92'))	('tumor', 'Disease', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
104709	29103968	The evidence that TRAIL-mediated lysis was partially enhanced also by M7824mut indicates that this effect is mediated by the TGFbetaR2 component of the molecule.	('TGFbetaR', 'molecular_function', 'GO:0005024', ('125', '133'))	('TRAIL', 'Gene', '8743', (18, 23))	('TRAIL', 'Gene', (18, 23))	('TGFbeta', 'Gene', '7040', (125, 132))	('lysis', 'biological_process', 'GO:0019835', ('33', '38'))	('enhanced', 'PosReg', (53, 61))	('M7824mut', 'Var', (70, 78))	('TGFbeta', 'Gene', (125, 132))
104710	29103968	It has previously been shown that treatment with certain agents, such as tyrosine kinase inhibitors, chemotherapy and radiation, can modulate the phenotype of immunologically relevant molecules on tumor cells, making them more sensitive to T-cell mediated killing in a process known as immunogenic modulation.	('T-cell mediated killing', 'CPA', (240, 263))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('more', 'PosReg', (222, 226))	('modulate', 'Reg', (133, 141))	('tyrosine', 'Var', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('sensitive', 'MPA', (227, 236))	('tumor', 'Disease', (197, 202))
104711	29103968	We found that HTB-4 cells treated with M7824 increased their expression of CEA, ICAM, and Fas.	('Fas', 'Gene', (90, 93))	('M7824', 'Var', (39, 44))	('increased', 'PosReg', (45, 54))	('ICAM', 'Gene', (80, 84))	('CEA', 'Gene', (75, 78))	('CEA', 'Gene', '1084', (75, 78))	('Fas', 'Chemical', 'MESH:C038178', (90, 93))	('expression', 'MPA', (61, 71))
104714	29103968	In addition, we show that M7824 mediates ADCC of tumor cells, although to a lesser extent than anti-PD-L1 alone, using NK cells as effectors from some donors.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('M7824', 'Var', (26, 31))	('tumor', 'Disease', (49, 54))	('ADCC', 'biological_process', 'GO:0001788', ('41', '45'))	('ADCC', 'CPA', (41, 45))	('donor', 'Species', '9606', (151, 156))
104716	29103968	M7824 could also be employed in patients with urothelial carcinoma in combination with recombinant vaccines directed against urothelial carcinoma associated antigens or vaccines directed against neo-antigens identified from patient tumor biopsies.	('patients', 'Species', '9606', (32, 40))	('urothelial carcinoma', 'Disease', (46, 66))	('urothelial carcinoma', 'Disease', (125, 145))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('patient', 'Species', '9606', (224, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('M7824', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (125, 145))	('tumor', 'Disease', (232, 237))	('patient', 'Species', '9606', (32, 39))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (46, 66))
104717	29103968	Since M7824 has also been shown in the present study to mediate ADCC of urothelial carcinoma cells, a potential combination therapy would consist of M7824 and the IL15 superagonist fusion protein ALT-803; ALT-803 has been shown in preclinical studies to enhance both the level of NK cells and their ability to mediate ADCC of carcinoma cells.	('enhance', 'PosReg', (254, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('ADCC', 'biological_process', 'GO:0001788', ('318', '322'))	('ALT', 'molecular_function', 'GO:0004021', ('205', '208'))	('carcinoma', 'Disease', 'MESH:D002277', (83, 92))	('carcinoma', 'Disease', (326, 335))	('urothelial carcinoma', 'Disease', (72, 92))	('IL15', 'Gene', '3600', (163, 167))	('IL15', 'molecular_function', 'GO:0016170', ('163', '167'))	('carcinoma', 'Disease', 'MESH:D002277', (326, 335))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (72, 92))	('ALT', 'Gene', (205, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('ALT', 'Gene', '76282', (205, 208))	('carcinoma', 'Disease', (83, 92))	('ALT', 'Gene', (196, 199))	('ADCC', 'biological_process', 'GO:0001788', ('64', '68'))	('M7824', 'Var', (6, 11))	('IL15', 'Gene', (163, 167))	('ALT', 'molecular_function', 'GO:0004021', ('196', '199'))	('ALT', 'Gene', '76282', (196, 199))
104718	29103968	Finally, a recent study has demonstrated that M7824 can alter the phenotype of carcinoma cells from a more mesenchymal to an epithelial phenotype, and consequently render tumor cells more sensitive to a range of chemotherapeutic agents.	('carcinoma', 'Disease', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('render', 'Reg', (164, 170))	('sensitive', 'MPA', (188, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('more', 'PosReg', (183, 187))	('alter', 'Reg', (56, 61))	('carcinoma', 'Disease', 'MESH:D002277', (79, 88))	('tumor', 'Disease', (171, 176))	('phenotype', 'MPA', (66, 75))	('M7824', 'Var', (46, 51))
104719	29103968	These findings also provide the rationale for potential clinical studies employing M7824 in combination with chemotherapy in patients with urothelial carcinoma.	('urothelial carcinoma', 'Disease', (139, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('M7824', 'Var', (83, 88))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (139, 159))	('patients', 'Species', '9606', (125, 133))
104720	29103968	The data presented here thus support the rationale for future clinical studies of M7824 in urothelial cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('M7824', 'Var', (82, 87))	('patients', 'Species', '9606', (109, 117))	('urothelial cancer', 'Disease', 'MESH:D014523', (91, 108))	('urothelial cancer', 'Disease', (91, 108))
104721	29103968	M7824 consists of anti-PD-L1 and TGFbetaR2 which functions as a TGFbeta "trap."	('TGFbetaR', 'molecular_function', 'GO:0005024', ('33', '41'))	('TGFbeta', 'Gene', (33, 40))	('TGFbeta', 'Gene', (64, 71))	('anti-PD-L1', 'Gene', (18, 28))	('M7824', 'Var', (0, 5))	('TGFbeta', 'Gene', '7040', (33, 40))	('TGFbeta', 'Gene', '7040', (64, 71))
104722	29103968	M7824 induces immunogenic modulation of urothelial carcinoma cells.	('urothelial carcinoma', 'Disease', (40, 60))	('M7824', 'Var', (0, 5))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (40, 60))	('immunogenic', 'MPA', (14, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
104723	29103968	M7824 increases T cell-mediated lysis of urothelial carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (41, 61))	('M7824', 'Var', (0, 5))	('lysis', 'biological_process', 'GO:0019835', ('32', '37'))	('urothelial carcinoma', 'Disease', (41, 61))	('increases', 'PosReg', (6, 15))
104724	29103968	M7824 mediates ADCC of urothelial carcinoma cells.	('mediates', 'Reg', (6, 14))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (23, 43))	('urothelial carcinoma', 'Disease', (23, 43))	('M7824', 'Var', (0, 5))	('ADCC', 'biological_process', 'GO:0001788', ('15', '19'))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))
104733	29304754	The cancer research community refers to 'cancer driver' genes as genes whose perturbation (in the expression levels or in the sequence) confers a selective advantage to tumour growth.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('selective advantage', 'CPA', (146, 165))	("'cancer", 'Disease', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('perturbation', 'Var', (77, 89))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumour growth', 'Disease', (169, 182))	("'cancer", 'Disease', 'MESH:D009369', (40, 47))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', (4, 10))	('tumour growth', 'Disease', 'MESH:D006130', (169, 182))
104735	29304754	those genes whose mutation does not give any fitness advantage to the tumour.	('fitness advantage to the tumour', 'Disease', 'MESH:D012640', (45, 76))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('mutation', 'Var', (18, 26))	('fitness advantage to the tumour', 'Disease', (45, 76))
104736	29304754	In cancer, driver genes are those that accumulate mutations, or those that are differentially expressed in tumours vs normal samples (differentially expressed genes).	('tumours', 'Disease', 'MESH:D009369', (107, 114))	('tumours', 'Disease', (107, 114))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (3, 9))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
104786	29304754	DNA2 nuclease has a role in the mechanism of double strand break repair and its mutation has been reported in gastric and colorectal carcinomas.	('double strand break repair', 'biological_process', 'GO:0006302', ('45', '71'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('gastric', 'Disease', (110, 117))	('colorectal carcinomas', 'Disease', (122, 143))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (122, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('double strand break repair', 'MPA', (45, 71))	('DNA2', 'Gene', (0, 4))	('DNA2', 'Gene', '1763', (0, 4))	('mutation', 'Var', (80, 88))	('reported', 'Reg', (98, 106))
104789	29304754	Since previous studies have shown that the absence of mutations in genes with a high degree centrality is vital for the organism survival, we found a list of 1322 network genes highly connected in at least two networks for each pathway, and we studied their behavior in 16 different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('cancer', 'Disease', (292, 298))	('connected', 'Reg', (184, 193))
104815	29304754	Polymorphisms in this gene are associated with different types of cancer (e.g.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Polymorphisms', 'Var', (0, 13))	('associated', 'Reg', (31, 41))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
104825	29304754	With these tools cancer drivers were defined as 1) genes with unexpected mutation rates in phosphorylation-specific regions (ActiveDriver), 2) proteins with higher-than-expected mutation rates regardless of the protein regions (OncodriveCLUST), 3) proteins with somatic missense mutations in different protein functional regions, such as domains and intrinsically disordered regions (e-Driver), 4) genes analyzing the impact of mutations on the protein function (OncodriveFM and Simon).	('missense mutations', 'Var', (270, 288))	('protein', 'cellular_component', 'GO:0003675', ('302', '309'))	('protein', 'cellular_component', 'GO:0003675', ('211', '218'))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('protein', 'cellular_component', 'GO:0003675', ('445', '452'))	('cancer', 'Disease', (17, 23))	('disordered', 'Disease', 'MESH:D030342', (364, 374))	('phosphorylation', 'biological_process', 'GO:0016310', ('91', '106'))	('mutation', 'Var', (73, 81))	('disordered', 'Disease', (364, 374))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
104826	29304754	The second group includes Dendrix and CoMDP, two software tools that use an alternative approach to identify cancer driver genes: they examine mutations in the context of functional pathways.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (109, 115))	('mutations', 'Var', (143, 152))	('cancer', 'Disease', 'MESH:D009369', (109, 115))
104842	33655556	The VEGF-VEGFR signalling is the most crucial pathway to induce angiogenesis, and inhibiting this cascade has already got success in treating tumours.	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('tumours', 'Disease', (142, 149))	('inhibiting', 'Var', (82, 92))	('angiogenesis', 'biological_process', 'GO:0001525', ('64', '76'))	('angiogenesis', 'CPA', (64, 76))	('VEGFR', 'Gene', '3791', (9, 14))	('signalling', 'biological_process', 'GO:0023052', ('15', '25'))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('induce', 'PosReg', (57, 63))	('VEGFR', 'Gene', (9, 14))
104843	33655556	While both their efficacy and antitumour spectrum are limited, combining FGF/FGFR inhibitors with VEGF/VEGFR inhibitors are an excellent way to optimize the curative effect and expand the antitumour range because their combination can target both tumour cells and the tumour microenvironment.	('inhibitors', 'Var', (82, 92))	('tumour', 'Phenotype', 'HP:0002664', (268, 274))	('tumour', 'Disease', 'MESH:D009369', (268, 274))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('tumour', 'Disease', (268, 274))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', (34, 40))	('FGFR', 'Gene', (77, 81))	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('curative effect', 'CPA', (157, 172))	('tumour', 'Disease', 'MESH:D009369', (247, 253))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('tumour', 'Disease', (247, 253))	('tumour', 'Disease', (192, 198))	('FGFR', 'Gene', '2260', (77, 81))	('VEGFR', 'Gene', '3791', (103, 108))	('VEGFR', 'Gene', (103, 108))
104845	33655556	Targeted therapies interfering with oncogenic driver alterations have achieved remarkable success in limited types of cancer with certain driver gene alterations (Nat Rev Clin Oncol, 2017; Lancet Oncol, 2018; Jama, 2019; Lancet, 2017).	('cancer', 'Disease', (118, 124))	('Jama', 'Gene', '50848', (209, 213))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('alterations', 'Var', (150, 161))	('Jama', 'Gene', (209, 213))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
104847	33655556	The FGF-FGFR signalling plays pivotal roles in both the physiological and oncogenic processes (Nat Rev Clin Oncol, 2019), but FGFRs are constitutively active in malignant cells because of the upregulation of FGF and FGFR genetic alterations (Nat Rev Clin Oncol, 2019).	('FGF', 'Gene', (208, 211))	('FGFR', 'Gene', (216, 220))	('FGFR', 'Gene', (126, 130))	('FGFR', 'Gene', '2260', (216, 220))	('genetic alterations', 'Var', (221, 240))	('FGFR', 'molecular_function', 'GO:0005007', ('216', '220'))	('FGFR', 'Gene', '2260', (126, 130))	('upregulation', 'PosReg', (192, 204))	('FGFR', 'molecular_function', 'GO:0005007', ('8', '12'))	('FGFR', 'Gene', (8, 12))	('signalling', 'biological_process', 'GO:0023052', ('13', '23'))	('FGFR', 'Gene', '2260', (8, 12))
104851	33655556	Accordingly, inhibition of the VEGF-VEGFR signalling pathway is believed to suppress tumour development (New Engl J Med, 1971).	('VEGFR', 'Gene', '3791', (36, 41))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('suppress', 'NegReg', (76, 84))	('VEGFR', 'Gene', (36, 41))	('tumour', 'Disease', (85, 91))	('inhibition', 'Var', (13, 23))	('signalling pathway', 'biological_process', 'GO:0007165', ('42', '60'))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
104854	33655556	FGFR/VEGFR inhibitors have better effects and broaden the indications in clinical use (Nat Commun, 2020; JAMA Oncol, 2018; The Lancet Oncology, 2020).	('JAMA', 'Gene', '50848', (105, 109))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'Gene', (0, 4))	('VEGFR', 'Gene', (5, 10))	('JAMA', 'Gene', (105, 109))	('FGFR', 'Gene', '2260', (0, 4))	('Oncology', 'Phenotype', 'HP:0002664', (134, 142))	('effects', 'MPA', (34, 41))	('inhibitors', 'Var', (11, 21))	('VEGFR', 'Gene', '3791', (5, 10))
104859	33655556	Anti-FGF or FGFR therapy is a promising way to treat tumours with FGF and (or) FGFR alterations.	('FGFR', 'Gene', '2260', (12, 16))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('FGFR', 'Gene', (79, 83))	('alterations', 'Var', (84, 95))	('FGF', 'Gene', (66, 69))	('FGFR', 'Gene', '2260', (79, 83))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('FGFR', 'Gene', (12, 16))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))
104860	33655556	5  With the accelerated approval of erdafitinib for FGFR-altered urothelial carcinoma in April 2019 and pemigatinib for cholangiocarcinoma with FGFR2 fusion or other rearrangements in April 2020, 6 ,  7  the FGF-FGFR signalling pathway has received more attention.	('FGFR', 'Gene', (144, 148))	('FGFR', 'Gene', (212, 216))	('FGFR', 'Gene', '2260', (144, 148))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (120, 138))	('pemigatinib', 'Chemical', '-', (104, 115))	('cholangiocarcinoma', 'Disease', (120, 138))	('FGFR2', 'Gene', (144, 149))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (120, 138))	('FGFR', 'Gene', '2260', (212, 216))	('FGFR', 'Gene', (52, 56))	('FGFR', 'molecular_function', 'GO:0005007', ('212', '216'))	('erdafitinib', 'Chemical', 'MESH:C000604580', (36, 47))	('FGFR2', 'Gene', '2263', (144, 149))	('fusion', 'Var', (150, 156))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (65, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('signalling pathway', 'biological_process', 'GO:0007165', ('217', '235'))	('FGFR', 'Gene', '2260', (52, 56))	('urothelial carcinoma', 'Disease', (65, 85))
104862	33655556	5  Combination of the inhibitory of the FGF-FGFR signalling pathway with other mechanisms is a promising way to solve this puzzle.	('signalling pathway', 'biological_process', 'GO:0007165', ('49', '67'))	('FGFR', 'Gene', (44, 48))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('FGFR', 'Gene', '2260', (44, 48))	('inhibitory', 'Var', (22, 32))
104873	33655556	19  Take FGFR1 as an example; seven phosphorylatable tyrosine residues have been identified, that is, Y463, Y583, Y585, Y653, Y654, Y730 and Y766.	('FGFR1', 'Gene', '2260', (9, 14))	('Y653', 'Var', (120, 124))	('Y585', 'Var', (114, 118))	('Y583', 'Var', (108, 112))	('FGFR', 'molecular_function', 'GO:0005007', ('9', '13'))	('tyrosine', 'Chemical', 'MESH:D014443', (53, 61))	('Y730', 'Var', (132, 136))	('Y654', 'Var', (126, 130))	('FGFR1', 'Gene', (9, 14))	('Y463', 'Var', (102, 106))
104892	33655556	The oncogenic role of FGF-FGFR signalling in driving cancer cell proliferation, survival, migration and invasion is mediated by the upregulation of FGF, FGFR genetic alterations, angiogenesis and immune evasion in the tumour microenvironment.	('FGFR', 'Gene', (26, 30))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('immune', 'MPA', (196, 202))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('survival', 'CPA', (80, 88))	('tumour', 'Disease', 'MESH:D009369', (218, 224))	('FGFR', 'Gene', '2260', (153, 157))	('FGFR', 'molecular_function', 'GO:0005007', ('153', '157'))	('FGFR', 'Gene', '2260', (26, 30))	('tumour', 'Disease', (218, 224))	('genetic alterations', 'Var', (158, 177))	('invasion', 'CPA', (104, 112))	('FGF', 'Gene', (148, 151))	('cancer', 'Disease', (53, 59))	('upregulation', 'PosReg', (132, 144))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('angiogenesis', 'biological_process', 'GO:0001525', ('179', '191'))	('signalling', 'biological_process', 'GO:0023052', ('31', '41'))	('immune evasion', 'biological_process', 'GO:0042783', ('196', '210'))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('migration', 'CPA', (90, 99))	('immune evasion', 'biological_process', 'GO:0051842', ('196', '210'))	('angiogenesis', 'CPA', (179, 191))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('FGFR', 'Gene', (153, 157))
104893	33655556	5   An analysis of 4,853 solid tumours by the next-generation sequencing technique demonstrated FGFR aberrations in 7.1% of cancers.	('solid tumours', 'Disease', (25, 38))	('aberrations', 'Var', (101, 112))	('FGFR', 'Gene', (96, 100))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('FGFR', 'Gene', '2260', (96, 100))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('solid tumours', 'Disease', 'MESH:D009369', (25, 38))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))
104895	33655556	33   Deregulated gene transcription or amplification can lead to elevated FGFR levels, which can activate FGF-FGFR signalling in a ligand-independent manner.	('FGFR', 'Gene', '2260', (74, 78))	('ligand', 'molecular_function', 'GO:0005488', ('131', '137'))	('FGFR', 'molecular_function', 'GO:0005007', ('110', '114'))	('amplification', 'Var', (39, 52))	('activate', 'PosReg', (97, 105))	('FGFR', 'Gene', '2260', (110, 114))	('FGFR', 'Gene', (110, 114))	('signalling', 'biological_process', 'GO:0023052', ('115', '125'))	('elevated', 'PosReg', (65, 73))	('Deregulated', 'Var', (5, 16))	('transcription', 'biological_process', 'GO:0006351', ('22', '35'))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))	('FGFR', 'Gene', (74, 78))
104897	33655556	34   Amplification of the FGFR1 gene is the most common in all types of FGFR gene alterations.	('FGFR', 'Gene', (26, 30))	('common', 'Reg', (49, 55))	('FGFR1', 'Gene', (26, 31))	('FGFR', 'Gene', '2260', (26, 30))	('FGFR1', 'Gene', '2260', (26, 31))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('FGFR', 'Gene', (72, 76))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('alterations', 'Var', (82, 93))	('FGFR', 'Gene', '2260', (72, 76))	('34   Amplification', 'Var', (0, 18))
104899	33655556	33  Recent studies described that the rate of FGFR1 amplification was significantly higher in squamous cell lung cancer (SqCLC) and Asians, and FGFR1 amplification may be a potential new therapeutic target for individual patients with specific lung cancer subtypes such as EGFR TKI for Asian patients with lung adenocarcinoma.	('patients', 'Species', '9606', (221, 229))	('lung adenocarcinoma', 'Disease', (306, 325))	('FGFR1', 'Gene', (144, 149))	('FGFR1', 'Gene', (46, 51))	('patients', 'Species', '9606', (292, 300))	('amplification', 'Var', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('higher', 'PosReg', (84, 90))	('EGFR', 'Gene', (273, 277))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (306, 325))	('lung cancer', 'Disease', (244, 255))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (306, 325))	('SqCLC', 'Phenotype', 'HP:0030359', (121, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (94, 119))	('squamous cell lung cancer', 'Disease', (94, 119))	('EGFR', 'molecular_function', 'GO:0005006', ('273', '277'))	('FGFR1', 'Gene', '2260', (144, 149))	('EGFR', 'Gene', '1956', (273, 277))	('FGFR1', 'Gene', '2260', (46, 51))	('lung cancer', 'Disease', 'MESH:D008175', (244, 255))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (94, 119))
104902	33655556	37  The relationship between amplification of FGFR1 and prognosis is still in doubt in NSCLC.	('NSCLC', 'Disease', (87, 92))	('amplification', 'Var', (29, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('SCLC', 'Phenotype', 'HP:0030357', (88, 92))	('FGFR1', 'Gene', (46, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('FGFR1', 'Gene', '2260', (46, 51))
104906	33655556	39  FGFR1 amplification is an independent biomarker of a poor prognosis in patients with ER (+) breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('FGFR1', 'Gene', (4, 9))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('patients', 'Species', '9606', (75, 83))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('ER', 'Gene', '2069', (89, 91))	('FGFR1', 'Gene', '2260', (4, 9))	('amplification', 'Var', (10, 23))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))
104908	33655556	42  What is more, allelic loss and amplification of FGFR1 can predict chemo- and radiotherapy response in breast cancer.	('amplification', 'Var', (35, 48))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('allelic loss', 'Var', (18, 30))	('FGFR1', 'Gene', (52, 57))	('FGFR1', 'Gene', '2260', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('predict', 'Reg', (62, 69))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
104909	33655556	43  FGFR1 amplification correlating with inadequate response to traditional treatments also happens in osteosarcoma, 44  and the expression of FGFR1 is associated with worse disease-free survival (DFS) and poor overall survival (OS) in head and neck squamous cell carcinoma (HNSCC), 45  oesophageal cancer 46  and colorectal cancer (CRC).	('HNSCC', 'Phenotype', 'HP:0012288', (275, 280))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (236, 273))	('FGFR1', 'Gene', '2260', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('cancer', 'Disease', (325, 331))	('osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (314, 331))	('FGFR1', 'Gene', (143, 148))	('colorectal cancer', 'Disease', (314, 331))	('neck squamous cell carcinoma', 'Disease', (245, 273))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('disease-free', 'Disease', (174, 186))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (245, 273))	('FGFR1', 'Gene', (4, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (250, 273))	('expression', 'Var', (129, 139))	('poor', 'NegReg', (206, 210))	('FGFR', 'molecular_function', 'GO:0005007', ('143', '147'))	('CRC', 'Phenotype', 'HP:0003003', (333, 336))	('cancer', 'Disease', (299, 305))	('neck', 'cellular_component', 'GO:0044326', ('245', '249'))	('worse', 'NegReg', (168, 173))	('colorectal cancer', 'Disease', 'MESH:D015179', (314, 331))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('osteosarcoma', 'Disease', (103, 115))	('osteosarcoma', 'Disease', 'MESH:D012516', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('overall', 'MPA', (211, 218))	('FGFR1', 'Gene', '2260', (143, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))
104911	33655556	FGFR2 amplification exists in several cancers.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('amplification', 'Var', (6, 19))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))	('cancers', 'Disease', (38, 45))
104913	33655556	48  High-level FGFR2 amplification is associated with the lower response, resistance to chemotherapy, shorter PFS and shorter OS in gastric cancers.	('shorter', 'NegReg', (102, 109))	('resistance', 'CPA', (74, 84))	('lower', 'NegReg', (58, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('response', 'MPA', (64, 72))	('FGFR2', 'Gene', (15, 20))	('FGFR2', 'Gene', '2263', (15, 20))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('gastric cancers', 'Disease', 'MESH:D013274', (132, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('amplification', 'Var', (21, 34))	('gastric cancers', 'Disease', (132, 147))	('gastric cancers', 'Phenotype', 'HP:0012126', (132, 147))
104919	33655556	51  FGFR3 amplification is also found in HNSCC, urothelial cancers and CRC.	('HNSCC', 'Phenotype', 'HP:0012288', (41, 46))	('CRC', 'Disease', (71, 74))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('found', 'Reg', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('HNSCC, urothelial cancers', 'Disease', 'MESH:D000077195', (41, 66))	('FGFR3', 'Gene', (4, 9))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('amplification', 'Var', (10, 23))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))
104920	33655556	33  High expression of FGFR3 is concerned with poor prognosis in papillary bladder cancers and oligometastatic CRC.	('FGFR3', 'Gene', (23, 28))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('High expression', 'Var', (4, 19))	('oligometastatic CRC', 'Disease', (95, 114))	('papillary bladder cancers', 'Disease', 'MESH:D001749', (65, 90))	('papillary bladder cancers', 'Disease', (65, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CRC', 'Phenotype', 'HP:0003003', (111, 114))	('bladder cancers', 'Phenotype', 'HP:0009725', (75, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))
104927	33655556	37   N546K mutation in the kinase domain of FGFR1 is the most common reported subtype among all the types of FGFR1 mutations.	('FGFR1', 'Gene', (44, 49))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('FGFR1', 'Gene', (109, 114))	('FGFR', 'molecular_function', 'GO:0005007', ('109', '113'))	('FGFR1', 'Gene', '2260', (44, 49))	('FGFR1', 'Gene', '2260', (109, 114))	('37   N546K', 'Var', (0, 10))	('N546K', 'Mutation', 'rs779707422', (5, 10))
104929	33655556	57 ,  58 ,  59  Other mutations in FGFR1, such as K565E, have also been reported in glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (84, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (84, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('K565E', 'Var', (50, 55))	('reported', 'Reg', (72, 80))	('K565E', 'Mutation', 'rs869320694', (50, 55))	('FGFR1', 'Gene', (35, 40))	('glioblastoma', 'Disease', (84, 96))	('FGFR1', 'Gene', '2260', (35, 40))
104931	33655556	57   Unlike the mutations in FGFR1, the most common mutations of FGFR2 are S252w and P253R occurring in the extracellular fragment, while K650E/M/N and N549K in FGFR2 are also found in the A-loop.	('extracellular', 'cellular_component', 'GO:0005576', ('108', '121'))	('FGFR2', 'Gene', (65, 70))	('FGFR2', 'Gene', '2263', (65, 70))	('FGFR1', 'Gene', '2260', (29, 34))	('N549K', 'Var', (152, 157))	('P253R', 'Mutation', 'rs77543610', (85, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('N549K', 'Mutation', 'rs121913476', (152, 157))	('P253R', 'Var', (85, 90))	('S252w', 'Var', (75, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('161', '165'))	('FGFR', 'molecular_function', 'GO:0005007', ('29', '33'))	('FGFR2', 'Gene', (161, 166))	('K650E', 'Var', (138, 143))	('FGFR2', 'Gene', '2263', (161, 166))	('FGFR1', 'Gene', (29, 34))	('K650E', 'SUBSTITUTION', 'None', (138, 143))
104932	33655556	FGFR2 mutations are found in up to 12% of endometrial carcinomas, 10% of gastric tumours, approximately 4% of NSCLCs and <2% of urothelial cancers.	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (42, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('urothelial cancers', 'Disease', 'MESH:D014523', (128, 146))	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('endometrial carcinomas', 'Disease', (42, 64))	('FGFR2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))	('NSCLCs', 'Disease', (110, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (54, 64))	('FGFR2', 'Gene', '2263', (0, 5))	('gastric tumours', 'Disease', 'MESH:D013274', (73, 88))	('urothelial cancers', 'Disease', (128, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (42, 64))	('SCLC', 'Phenotype', 'HP:0030357', (111, 115))	('NSCLCs', 'Disease', 'MESH:D002289', (110, 116))	('found', 'Reg', (20, 25))	('gastric tumours', 'Disease', (73, 88))
104933	33655556	61  FGFR2 mutation is an independent prognostic factor in endometrioid endometrial cancer through disrupting cell polarity to enhance migration and invasion.	('cell polarity', 'biological_process', 'GO:0007163', ('109', '122'))	('enhance', 'PosReg', (126, 133))	('endometrial cancer', 'Phenotype', 'HP:0012114', (71, 89))	('FGFR2', 'Gene', '2263', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('mutation', 'Var', (10, 18))	('endometrioid endometrial cancer', 'Disease', 'MESH:D016889', (58, 89))	('migration', 'CPA', (134, 143))	('cell polarity', 'CPA', (109, 122))	('endometrioid endometrial cancer', 'Disease', (58, 89))	('FGFR2', 'Gene', (4, 9))	('invasion', 'CPA', (148, 156))	('disrupting', 'NegReg', (98, 108))
104934	33655556	62  However, a phase II study failed to prove that the proportion of patients who were progression-free at 18 weeks was higher in advanced or metastatic endometrial cancer with FGFR mutations than in FGFR-non-mutated endometrial cancer when treated by dovitinib, a TK inhibitor (TKI) of FGFRs, VEGFRs, PDGFR-beta and c-KIT after first-line chemotherapy.	('FGFR', 'Gene', (287, 291))	('VEGFR', 'Gene', '3791', (294, 299))	('VEGFR', 'Gene', (294, 299))	('KIT', 'molecular_function', 'GO:0005020', ('319', '322'))	('patients', 'Species', '9606', (69, 77))	('FGFR', 'Gene', '2260', (200, 204))	('FGFR', 'Gene', '2260', (177, 181))	('FGFR', 'Gene', '2260', (287, 291))	('FGFR', 'molecular_function', 'GO:0005007', ('177', '181'))	('advanced', 'Disease', (130, 138))	('mutations', 'Var', (182, 191))	('FGFR', 'molecular_function', 'GO:0005007', ('200', '204'))	('endometrial cancer', 'Phenotype', 'HP:0012114', (217, 235))	('dovitinib', 'Chemical', 'MESH:C500007', (252, 261))	('PDGFR-beta', 'Gene', '5156', (302, 312))	('PDGFR-beta', 'Gene', (302, 312))	('endometrial cancer', 'Phenotype', 'HP:0012114', (153, 171))	('endometrial cancer', 'Disease', (217, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('c-KIT', 'Gene', (317, 322))	('endometrial cancer', 'Disease', (153, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('higher', 'PosReg', (120, 126))	('endometrial cancer', 'Disease', 'MESH:D016889', (217, 235))	('metastatic', 'CPA', (142, 152))	('c-KIT', 'Gene', '3815', (317, 322))	('endometrial cancer', 'Disease', 'MESH:D016889', (153, 171))	('FGFR', 'Gene', (200, 204))	('FGFR', 'Gene', (177, 181))
104935	33655556	63   FGFR3 mutations commonly occur in the extracellular (R248C, S249C) and TM (G370C, Y373C) domains of the receptor, which are found to have the ability to stimulate proliferation in cell lines and lead to the transformation of fibroblasts into tumour cells.	('transformation', 'CPA', (212, 226))	('R248C', 'Var', (58, 63))	('proliferation', 'CPA', (168, 181))	('lead to', 'Reg', (200, 207))	('mutations', 'Var', (11, 20))	('S249C', 'Var', (65, 70))	('R248C', 'Mutation', 'rs121913482', (58, 63))	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('G370C', 'Mutation', 'rs199740841', (80, 85))	('stimulate', 'PosReg', (158, 167))	('S249C', 'Mutation', 'rs121913483', (65, 70))	('tumour', 'Disease', 'MESH:D009369', (247, 253))	('Y373C', 'Mutation', 'rs121913485', (87, 92))	('tumour', 'Disease', (247, 253))	('extracellular', 'cellular_component', 'GO:0005576', ('43', '56'))	('FGFR', 'molecular_function', 'GO:0005007', ('5', '9'))	('G370C', 'Var', (80, 85))	('FGFR3', 'Gene', (5, 10))
104936	33655556	33  75% of muscle-non-invasive bladder cancers (MNIBC) have mutations in FGFR3, while the proportion is around 15% in muscle-invasive bladder cancers (MIBC).	('muscle-invasive bladder cancers', 'Disease', (118, 149))	('bladder cancers', 'Phenotype', 'HP:0009725', (134, 149))	('FGFR3', 'Gene', (73, 78))	('bladder cancers', 'Phenotype', 'HP:0009725', (31, 46))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('mutations', 'Var', (60, 69))	('muscle-non-invasive bladder cancers', 'Disease', 'MESH:D001749', (11, 46))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('muscle-invasive bladder cancers', 'Disease', 'MESH:D001749', (118, 149))	('FGFR', 'molecular_function', 'GO:0005007', ('73', '77'))	('MIBC', 'Disease', 'None', (151, 155))	('muscle-non-invasive bladder', 'Phenotype', 'HP:0000011', (11, 38))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('invasive bladder', 'Phenotype', 'HP:0100645', (125, 141))	('MIBC', 'Disease', (151, 155))	('muscle-non-invasive bladder cancers', 'Disease', (11, 46))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('invasive bladder', 'Phenotype', 'HP:0100645', (22, 38))
104937	33655556	64  Mutations in FGFR3 indicate a better prognosis in MNIBC, a better response to neoadjuvant chemotherapy in MIBC and disease occurrence or recurrence in bladder cancers.	('MIBC', 'Disease', (110, 114))	('better', 'PosReg', (34, 40))	('MNIBC', 'Disease', (54, 59))	('bladder cancers', 'Phenotype', 'HP:0009725', (155, 170))	('recurrence in bladder', 'Phenotype', 'HP:0012786', (141, 162))	('bladder cancers', 'Disease', 'MESH:D001749', (155, 170))	('MIBC', 'Disease', 'None', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('FGFR3', 'Gene', (17, 22))	('Mutations', 'Var', (4, 13))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('bladder cancers', 'Disease', (155, 170))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))
104938	33655556	65  At the same time, FGFR3 S249C mutation in urinary cell-free DNA could predict early-stage (<=pT1) of upper muscle-invasive urothelial carcinoma with 100% positive predictive value.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('FGFR3', 'Gene', (22, 27))	('S249C', 'Var', (28, 33))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('upper muscle-invasive urothelial carcinoma', 'Disease', (105, 147))	('S249C', 'Mutation', 'rs121913483', (28, 33))	('predict', 'Reg', (74, 81))	('upper muscle-invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (105, 147))
104939	33655556	66  Besides, FGFR3 mutations also occur in cervical, vulvar squamous cell carcinoma and breast cancer.	('cervical', 'Disease', (43, 51))	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('vulvar squamous cell carcinoma', 'Phenotype', 'HP:0030417', (53, 83))	('occur', 'Reg', (34, 39))	('vulvar squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 83))	('mutations', 'Var', (19, 28))	('FGFR3', 'Gene', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('vulvar squamous cell carcinoma', 'Disease', (53, 83))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
104940	33655556	67 ,  68 ,  69   The kinase domain mutations of FGFR4 (V550E/L and N535D/K) were described in 7% of rhabdomyosarcoma, leading to tumour growth in vivo and drug resistance to all type I and some type II inhibitors in patients.	('drug resistance', 'biological_process', 'GO:0009315', ('155', '170'))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (100, 116))	('drug resistance', 'Phenotype', 'HP:0020174', (155, 170))	('drug resistance', 'biological_process', 'GO:0042493', ('155', '170'))	('V550E', 'SUBSTITUTION', 'None', (55, 60))	('FGFR4', 'Gene', '2264', (48, 53))	('drug resistance to all', 'MPA', (155, 177))	('tumour growth', 'Disease', 'MESH:D006130', (129, 142))	('V550E', 'Var', (55, 60))	('N535D', 'SUBSTITUTION', 'None', (67, 72))	('N535D', 'Var', (67, 72))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('FGFR4', 'Gene', (48, 53))	('leading to', 'Reg', (118, 128))	('patients', 'Species', '9606', (216, 224))	('rhabdomyosarcoma', 'Disease', (100, 116))	('described', 'Reg', (81, 90))	('tumour growth', 'Disease', (129, 142))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (100, 116))
104941	33655556	70  Besides, variant rs351855-G/A can lead to germline FGFR4 G388R substitution, subsequently expose a membrane-proximal STAT3-binding site and trigger STAT3 signalling cascade, which can accelerate cancer progression and also contribute to tumour-extrinsic immune evasion.	('STAT3', 'Gene', '6774', (121, 126))	('STAT3', 'Gene', '6774', (152, 157))	('immune evasion', 'biological_process', 'GO:0051842', ('258', '272'))	('lead', 'Reg', (38, 42))	('contribute', 'Reg', (227, 237))	('cancer', 'Disease', (199, 205))	('membrane', 'cellular_component', 'GO:0016020', ('103', '111'))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('tumour', 'Disease', 'MESH:D009369', (241, 247))	('tumour', 'Disease', (241, 247))	('expose', 'PosReg', (94, 100))	('FGFR4', 'Gene', '2264', (55, 60))	('accelerate', 'PosReg', (188, 198))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('variant rs351855-G/A', 'Var', (13, 33))	('G388R', 'Var', (61, 66))	('STAT3', 'Gene', (121, 126))	('STAT3', 'Gene', (152, 157))	('FGFR4', 'Gene', (55, 60))	('rs351855', 'Mutation', 'rs351855', (21, 29))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('signalling cascade', 'biological_process', 'GO:0007165', ('158', '176'))	('trigger', 'Reg', (144, 151))	('binding', 'molecular_function', 'GO:0005488', ('127', '134'))	('G388R', 'Mutation', 'rs351855', (61, 66))	('immune evasion', 'biological_process', 'GO:0042783', ('258', '272'))
104942	33655556	71  FGFR4 G388R substitution is correlated with poor survival in resected colon cancer and lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('colon cancer', 'Phenotype', 'HP:0003003', (74, 86))	('G388R', 'Mutation', 'rs351855', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('colon cancer', 'Disease', 'MESH:D015179', (74, 86))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('G388R', 'Var', (10, 15))	('colon cancer', 'Disease', (74, 86))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('FGFR4', 'Gene', '2264', (4, 9))	('poor', 'NegReg', (48, 52))	('FGFR4', 'Gene', (4, 9))	('lung cancer', 'Disease', (91, 102))
104948	33655556	77   FGFR2 fusions occur in around 10%-20% of patients with intrahepatic cholangiocarcinoma.	('patients', 'Species', '9606', (46, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('FGFR2', 'Gene', (5, 10))	('FGFR2', 'Gene', '2263', (5, 10))	('FGFR', 'molecular_function', 'GO:0005007', ('5', '9'))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (60, 91))	('fusions', 'Var', (11, 18))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (73, 91))	('intrahepatic cholangiocarcinoma', 'Disease', (60, 91))
104949	33655556	The major fusion partners of FGFR2 are PPHLN1, AHCYL1, BICC1 and TACC3, which bring the probability of targeted therapy for the patients who have FGFR2 rearrangements.	('FGFR', 'molecular_function', 'GO:0005007', ('146', '150'))	('BICC1', 'Gene', '80114', (55, 60))	('TACC3', 'Gene', '10460', (65, 70))	('PPHLN1', 'Gene', (39, 45))	('AHCYL1', 'Gene', (47, 53))	('FGFR2', 'Gene', (146, 151))	('TACC3', 'Gene', (65, 70))	('FGFR2', 'Gene', '2263', (146, 151))	('FGFR', 'molecular_function', 'GO:0005007', ('29', '33'))	('FGFR2', 'Gene', (29, 34))	('AHCYL1', 'Gene', '10768', (47, 53))	('FGFR2', 'Gene', '2263', (29, 34))	('PPHLN1', 'Gene', '51535', (39, 45))	('rearrangements', 'Var', (152, 166))	('BICC1', 'Gene', (55, 60))	('patients', 'Species', '9606', (128, 136))
104950	33655556	78  Several FGFR inhibitors have been tested in phase I or II clinical trial and finally, pemigatinib, an FGFR1-3 inhibitor, received accelerated approval in April 2020 by the FDA for the treatment of patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangements based on FIGHT-202 phase II clinical trial, in which 35.5% of patients with FGFR2 fusions or rearrangements achieved an objective response.	('FGFR', 'Gene', '2260', (12, 16))	('FGFR', 'Gene', '2260', (106, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('FGFR2', 'Gene', (307, 312))	('FGFR1-3', 'Gene', (106, 113))	('fusions', 'Var', (426, 433))	('rearrangements', 'Var', (437, 451))	('FGFR', 'Gene', (420, 424))	('pemigatinib', 'Chemical', '-', (90, 101))	('FGFR', 'molecular_function', 'GO:0005007', ('307', '311'))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (280, 298))	('FGFR2', 'Gene', '2263', (307, 312))	('FGFR', 'Gene', (307, 311))	('cholangiocarcinoma', 'Disease', (280, 298))	('FGFR', 'Gene', '2260', (420, 424))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (280, 298))	('patients', 'Species', '9606', (201, 209))	('FGFR2', 'Gene', (420, 425))	('FGFR', 'Gene', '2260', (307, 311))	('FGFR', 'Gene', (12, 16))	('FGFR', 'Gene', (106, 110))	('patients', 'Species', '9606', (406, 414))	('FGFR', 'molecular_function', 'GO:0005007', ('420', '424'))	('FGFR2', 'Gene', '2263', (420, 425))	('FGFR1-3', 'Gene', '2260;2263;2261', (106, 113))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))
104951	33655556	7  Interestingly, FGFR2 fusions also have been found in breast, prostate and thyroid cancer.	('FGFR2', 'Gene', (18, 23))	('FGFR2', 'Gene', '2263', (18, 23))	('breast', 'Disease', (56, 62))	('prostate', 'Disease', (64, 72))	('thyroid cancer', 'Phenotype', 'HP:0002890', (77, 91))	('found', 'Reg', (47, 52))	('thyroid cancer', 'Disease', (77, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('thyroid cancer', 'Disease', 'MESH:D013964', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('fusions', 'Var', (24, 31))
104952	33655556	33   In addition to the presence of FGFR3 amplification and mutations in urothelial carcinoma, FGFR2/3 fusions have also been detected.	('fusions', 'Var', (103, 110))	('FGFR2/3', 'Gene', '2263;2261', (95, 102))	('urothelial carcinoma', 'Disease', (73, 93))	('FGFR3', 'Gene', (36, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('95', '99'))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (73, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('FGFR2/3', 'Gene', (95, 102))	('mutations', 'Var', (60, 69))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
104955	33655556	Other researchers found the fused protein can trigger the MAPK-ERK and JAK-STAT signalling pathways.	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('trigger', 'Reg', (46, 53))	('ERK', 'molecular_function', 'GO:0004707', ('63', '66'))	('protein', 'Protein', (34, 41))	('JAK-STAT signalling pathways', 'Pathway', (71, 99))	('MAPK', 'molecular_function', 'GO:0004707', ('58', '62'))	('JAK', 'molecular_function', 'GO:0004713', ('71', '74'))	('signalling', 'biological_process', 'GO:0023052', ('80', '90'))	('ERK', 'Gene', '5594', (63, 66))	('ERK', 'Gene', (63, 66))	('fused', 'Var', (28, 33))
104969	33655556	Neutralizing FGF2 and FGFRs inhibit neovascularization and tumour growth in vivo models.	('FGFR', 'Gene', (22, 26))	('FGFR', 'Gene', '2260', (22, 26))	('FGF2', 'Gene', (13, 17))	('tumour growth', 'Disease', (59, 72))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour growth', 'Disease', 'MESH:D006130', (59, 72))	('neovascularization', 'CPA', (36, 54))	('Neutralizing', 'Var', (0, 12))	('FGF2', 'Gene', '2247', (13, 17))	('inhibit', 'NegReg', (28, 35))
104973	33655556	According to their action mechanism, they can be divided into several categories: (a) small-molecule FGFR TKIs, (b) anti-FGFR antibodies and (c) and FGF ligand traps.	('FGFR', 'molecular_function', 'GO:0005007', ('121', '125'))	('ligand', 'molecular_function', 'GO:0005488', ('153', '159'))	('FGFR', 'Gene', (121, 125))	('FGFR', 'Gene', '2260', (121, 125))	('FGFR', 'Gene', (101, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))	('FGFR', 'Gene', '2260', (101, 105))	('small-molecule', 'Var', (86, 100))
104981	33655556	94  Responses to FGFR-targeted treatments may be hampered by the activation of bypass signalling pathways and the appearance of secondary drug-resistant FGFR mutations, FGFR amplification without alterations in protein expression, and intratumour heterogeneity.	('FGFR', 'Gene', '2260', (153, 157))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('FGFR', 'Gene', (17, 21))	('FGFR', 'molecular_function', 'GO:0005007', ('169', '173'))	('FGFR', 'molecular_function', 'GO:0005007', ('153', '157'))	('FGFR', 'Gene', '2260', (17, 21))	('protein', 'cellular_component', 'GO:0003675', ('211', '218'))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('tumour', 'Disease', 'MESH:D009369', (240, 246))	('amplification', 'Var', (174, 187))	('bypass signalling pathways', 'Pathway', (79, 105))	('signalling', 'biological_process', 'GO:0023052', ('86', '96'))	('FGFR', 'Gene', (169, 173))	('mutations', 'Var', (158, 167))	('FGFR', 'Gene', (153, 157))	('tumour', 'Disease', (240, 246))	('FGFR', 'Gene', '2260', (169, 173))
105006	33655556	Y1175, Y951 and Y1214 are the three major VEGFA-dependent phosphorylation sites in VEGFR2.	('Y951', 'Var', (7, 11))	('Y1175', 'Var', (0, 5))	('Y1214', 'Chemical', '-', (16, 21))	('VEGFA', 'Gene', '7422', (42, 47))	('Y1214', 'Var', (16, 21))	('VEGFR2', 'Gene', (83, 89))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('VEGFA', 'Gene', (42, 47))
105007	33655556	105  Phosphorylated Y1175 (pY1175) can bind PLC-gamma, the adaptor protein Shb and the adaptor protein Sck, further promoting the cascade signalling.	('Sck', 'Gene', (103, 106))	('PLC', 'cellular_component', 'GO:0042824', ('44', '47'))	('Sck', 'Gene', '25759', (103, 106))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('pY1175', 'Chemical', '-', (27, 33))	('signalling', 'biological_process', 'GO:0023052', ('138', '148'))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('bind', 'Interaction', (39, 43))	('PLC-gamma', 'Protein', (44, 53))	('Shb', 'Gene', (75, 78))	('promoting', 'PosReg', (116, 125))	('cascade signalling', 'MPA', (130, 148))	('Y1175 (pY1175', 'Var', (20, 33))	('Shb', 'Gene', '6461', (75, 78))
105010	33655556	Besides, pY1175 can recruit GAB1 to active the PI3K-AKT pathway.	('GAB1', 'Gene', (28, 32))	('pY1175', 'Var', (9, 15))	('AKT', 'Gene', (52, 55))	('GAB1', 'Gene', '2549', (28, 32))	('pY1175', 'Chemical', '-', (9, 15))	('active', 'PosReg', (36, 42))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('AKT', 'Gene', '207', (52, 55))
105013	33655556	102  Phosphorylated Y951 promotes the formation of complexes between Src through the adaptor protein VRAP/TSAd, resulting in the opening of inter-endothelial junctions, critical for cytoskeletal reorganization and migration.	('Y951', 'Var', (20, 24))	('VRAP', 'Gene', '9047', (101, 105))	('TSAd', 'Gene', (106, 110))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('promotes', 'PosReg', (25, 33))	('VRAP', 'Gene', (101, 105))	('opening of inter-endothelial junctions', 'MPA', (129, 167))	('TSAd', 'Gene', '9047', (106, 110))	('formation', 'biological_process', 'GO:0009058', ('38', '47'))	('complexes', 'Interaction', (51, 60))	('Src', 'Gene', (69, 72))	('Src', 'Gene', '6714', (69, 72))
105014	33655556	108  Phosphorylated Y1214 associates with VEGF-induced actin remodelling via binding the adaptor protein Nck.	('binding', 'molecular_function', 'GO:0005488', ('77', '84'))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('Nck', 'Gene', '4690', (105, 108))	('Nck', 'Gene', (105, 108))	('binding', 'Interaction', (77, 84))	('Y1214', 'Chemical', '-', (20, 25))	('Y1214', 'Var', (20, 25))
105035	33655556	120 ,  121 ,  122   Besides, a soluble VEGF decoy receptor (Aflibercept, Zaltrap) neutralizing VEGFA, VEGFB and PLGF was approved in 2012 by the FDA to treat metastatic CRC.	('PLGF', 'Gene', '5228', (112, 116))	('neutralizing', 'Var', (82, 94))	('VEGFB', 'Gene', '7423', (102, 107))	('VEGFA', 'Gene', '7422', (95, 100))	('VEGFB', 'Gene', (102, 107))	('CRC', 'Phenotype', 'HP:0003003', (169, 172))	('soluble', 'cellular_component', 'GO:0005625', ('31', '38'))	('decoy receptor', 'molecular_function', 'GO:0140319', ('44', '58'))	('VEGFA', 'Gene', (95, 100))	('PLGF', 'Gene', (112, 116))	('metastatic CRC', 'Disease', (158, 172))
105044	33655556	127  Researchers have found the combination of FGF-1 and VEGF induced a more significant angiogenic effect than the additive effects of FGF-1 or VEGF alone in vitro quantitative fibrin-based 3-dimensional angiogenesis system.	('FGF-1', 'Gene', '2246', (47, 52))	('FGF-1', 'Gene', (136, 141))	('FGF-1', 'Gene', '2246', (136, 141))	('angiogenesis', 'biological_process', 'GO:0001525', ('205', '217'))	('VEGF', 'Gene', (57, 61))	('combination', 'Var', (32, 43))	('angiogenic effect', 'CPA', (89, 106))	('FGF-1', 'Gene', (47, 52))
105046	33655556	FGF can also induce the VEGFR2 expression in an ERK1/2-dependent pathway, and the expression of VEGFR2 rapidly declines without this interaction.	('ERK1/2', 'Gene', (48, 54))	('induce', 'Reg', (13, 19))	('expression', 'MPA', (82, 92))	('VEGFR2', 'Gene', (24, 30))	('ERK1/2', 'Gene', '5595;5594', (48, 54))	('ERK1', 'molecular_function', 'GO:0004707', ('48', '52'))	('expression', 'MPA', (31, 41))	('FGF', 'Var', (0, 3))
105055	33655556	137  VEGF/VEGFR, FGF/FGFR and FGFR/VEGFR inhibitors can invert the TME from immunologically 'cold' tumours into 'hot' tumours through immune-supportive effects by decreasing immunosuppressive cells and enhancing infiltration of mature dendritic cells and cytotoxic T lymphocytes.	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('inhibitors', 'Var', (41, 51))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('decreasing', 'NegReg', (163, 173))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('FGFR', 'Gene', (21, 25))	('invert', 'NegReg', (56, 62))	('TME', 'Chemical', '-', (67, 70))	('immunosuppressive cells', 'CPA', (174, 197))	('tumours', 'Disease', (118, 125))	('VEGFR', 'Gene', '3791', (10, 15))	('FGFR', 'Gene', (30, 34))	('FGFR', 'Gene', '2260', (21, 25))	('VEGFR', 'Gene', '3791', (35, 40))	('VEGFR', 'Gene', (10, 15))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('VEGFR', 'Gene', (35, 40))	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('TME', 'CPA', (67, 70))	('FGFR', 'Gene', '2260', (30, 34))	('enhancing', 'PosReg', (202, 211))	('tumours', 'Disease', (99, 106))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))
105056	33655556	138 ,  139 ,  140   The FGFR/VEGFR inhibitors are also reported to arrest the cell cycle in the G0/G1 phase and cause tumour cell apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('cause', 'Reg', (112, 117))	('tumour', 'Disease', (118, 124))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('VEGFR', 'Gene', (29, 34))	('VEGFR', 'Gene', '3791', (29, 34))	('arrest', 'NegReg', (67, 73))	('FGFR', 'Gene', (24, 28))	('cell cycle', 'biological_process', 'GO:0007049', ('78', '88'))	('FGFR', 'Gene', '2260', (24, 28))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('G1 phase', 'biological_process', 'GO:0051318', ('99', '107'))	('inhibitors', 'Var', (35, 45))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))	('cell cycle in the G0/G1 phase', 'CPA', (78, 107))
105070	33655556	151  However, dovitinib did not show clinical benefit in endometrial cancer with FGFR2 mutations, glioblastoma with FGFR3-TACC3 gene fusion and urothelial carcinoma with FGFR3 mutations or overexpression.	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (144, 164))	('TACC3', 'Gene', '10460', (122, 127))	('urothelial carcinoma', 'Disease', (144, 164))	('mutations', 'Var', (87, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('170', '174'))	('TACC3', 'Gene', (122, 127))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('FGFR2', 'Gene', (81, 86))	('dovitinib', 'Chemical', 'MESH:C500007', (14, 23))	('FGFR', 'molecular_function', 'GO:0005007', ('116', '120'))	('glioblastoma', 'Disease', (98, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('FGFR2', 'Gene', '2263', (81, 86))	('endometrial cancer', 'Phenotype', 'HP:0012114', (57, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('endometrial cancer', 'Disease', (57, 75))	('endometrial cancer', 'Disease', 'MESH:D016889', (57, 75))
105072	33655556	153 ,  154   E7090 is an orally non-selective inhibitor of FGFR1-3 and has a slightly lower inhibitory activity on VEGFR2.	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('non-selective', 'NegReg', (32, 45))	('lower', 'NegReg', (86, 91))	('E7090', 'Chemical', '-', (13, 18))	('E7090', 'Var', (13, 18))	('FGFR1-3', 'Gene', (59, 66))	('FGFR1-3', 'Gene', '2260;2263;2261', (59, 66))	('inhibitory activity', 'MPA', (92, 111))
105074	33655556	156   Lenvatinib (E7080) is an oral multikinase inhibitor that targets VEGFR1-3, FGFR1-4, RET, c-kit and PDGFRa, obtained considerable success in clinical trials of different cancer types, including NSCLC, thyroid cancer, gastric cancer, HCC, RCC and endometrial cancer.	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('HCC', 'Phenotype', 'HP:0001402', (238, 241))	('FGFR1', 'Gene', (81, 86))	('gastric cancer', 'Disease', (222, 236))	('cancer', 'Disease', (263, 269))	('thyroid cancer', 'Disease', 'MESH:D013964', (206, 220))	('cancer', 'Disease', (175, 181))	('RCC', 'Disease', (243, 246))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('NSCLC', 'Phenotype', 'HP:0030358', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('Lenvatinib', 'Chemical', 'MESH:C531958', (6, 16))	('RET', 'Gene', (90, 93))	('thyroid cancer', 'Phenotype', 'HP:0002890', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('c-kit', 'Gene', '3815', (95, 100))	('cancer', 'Disease', (214, 220))	('E7080', 'Var', (18, 23))	('endometrial cancer', 'Phenotype', 'HP:0012114', (251, 269))	('gastric cancer', 'Disease', 'MESH:D013274', (222, 236))	('RCC', 'Disease', 'MESH:C538614', (243, 246))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', (230, 236))	('endometrial cancer', 'Disease', (251, 269))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('VEGFR1-3', 'Gene', '2321;3791;2324', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('endometrial cancer', 'Disease', 'MESH:D016889', (251, 269))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('PDGFRa', 'Gene', '5156', (105, 111))	('FGFR1', 'Gene', '2260', (81, 86))	('SCLC', 'Phenotype', 'HP:0030357', (200, 204))	('PDGFRa', 'Gene', (105, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (222, 236))	('VEGFR1-3', 'Gene', (71, 79))	('thyroid cancer', 'Disease', (206, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('c-kit', 'Gene', (95, 100))	('NSCLC', 'Disease', 'MESH:D002289', (199, 204))	('RET', 'Gene', '5979', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('E7080', 'Chemical', 'MESH:C531958', (18, 23))	('HCC', 'Disease', (238, 241))	('NSCLC', 'Disease', (199, 204))
105082	33655556	Nowadays, as lenvatinib was reported to decrease tumour-associated macrophages and increase infiltration of CD8+ T cells, many clinical trials combining the immune checkpoint inhibitors with lenvatinib are ongoing, and some of them have already got positive results (NCT03609359, NCT02501096).	('NCT03609359', 'Var', (267, 278))	('decrease', 'NegReg', (40, 48))	('increase', 'PosReg', (83, 91))	('lenvatinib', 'Chemical', 'MESH:C531958', (191, 201))	('lenvatinib', 'Gene', (13, 23))	('lenvatinib', 'Chemical', 'MESH:C531958', (13, 23))	('infiltration', 'CPA', (92, 104))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour', 'Disease', (49, 55))
105083	33655556	161 ,  162   Lucitanib (E3810 or AL3810) is a reversible, ATP-competitive TKI that targets FGFR1-2 and VEGFR1-3 in the nM range and exerts antitumour activity in multiple preclinical models, including colon, ovarian, renal and thyroid carcinoma and breast cancer.	('AL3810', 'Var', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('AL3810', 'Chemical', 'MESH:C000595232', (33, 39))	('FGFR', 'molecular_function', 'GO:0005007', ('91', '95'))	('ATP', 'Chemical', 'MESH:D000255', (58, 61))	('FGFR1', 'Gene', '2260', (91, 96))	('VEGFR1-3', 'Gene', '2321;3791;2324', (103, 111))	('E3810', 'Var', (24, 29))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (227, 244))	('colon, ovarian, renal and thyroid carcinoma', 'Disease', 'MESH:D010051', (201, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (249, 262))	('E3810', 'Chemical', 'MESH:D064750', (24, 29))	('VEGFR1-3', 'Gene', (103, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('breast cancer', 'Disease', 'MESH:D001943', (249, 262))	('breast cancer', 'Disease', (249, 262))	('FGFR1', 'Gene', (91, 96))	('Lucitanib', 'Chemical', 'MESH:C000595232', (13, 22))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('tumour', 'Disease', (143, 149))
105085	33655556	165  Subsequently, the phase II FINESSE study found the ORRs in lucitanib-treated HR+/HER2- metastatic breast cancer with FGFR1 amplification or 11q13 amplification or no amplification were 19%, 0%, and 15%, respectively.	('HER2', 'Gene', (86, 90))	('amplification', 'Var', (128, 141))	('HER2', 'Gene', '2064', (86, 90))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('FGFR1', 'Gene', (122, 127))	('FGFR1', 'Gene', '2260', (122, 127))	('lucitanib', 'Chemical', 'MESH:C000595232', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('122', '126'))
105086	33655556	39  What is more, the following analyses showed that the ORR in patients with high-level FGFR1 amplification was higher in patients without high-level FGFR1 amplification (22% vs 9%), indicating that FGFR1 may be a biomarker for FGFR inhibitor therapy.	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('FGFR', 'Gene', (89, 93))	('FGFR', 'Gene', (151, 155))	('FGFR1', 'Gene', (89, 94))	('FGFR', 'Gene', (229, 233))	('FGFR', 'Gene', '2260', (200, 204))	('FGFR', 'Gene', '2260', (89, 93))	('patients', 'Species', '9606', (123, 131))	('FGFR', 'Gene', '2260', (151, 155))	('FGFR1', 'Gene', (151, 156))	('FGFR', 'molecular_function', 'GO:0005007', ('229', '233'))	('FGFR1', 'Gene', '2260', (200, 205))	('ORR', 'MPA', (57, 60))	('FGFR', 'Gene', '2260', (229, 233))	('FGFR', 'molecular_function', 'GO:0005007', ('200', '204'))	('FGFR', 'molecular_function', 'GO:0005007', ('151', '155'))	('FGFR1', 'Gene', '2260', (89, 94))	('patients', 'Species', '9606', (64, 72))	('higher', 'PosReg', (113, 119))	('amplification', 'Var', (95, 108))	('FGFR1', 'Gene', (200, 205))	('FGFR', 'Gene', (200, 204))	('FGFR1', 'Gene', '2260', (151, 156))
105093	33655556	177   Ponatinib (AP24534) is a multi-TKI targeting SRC, ABL, FGFR, PDGFR and VEGFR, while the inhibition of BCR-ABL is the primary clinical use.	('AP24534', 'Var', (17, 24))	('ABL', 'Gene', '25', (56, 59))	('VEGFR', 'Gene', (77, 82))	('FGFR', 'Gene', (61, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('61', '65'))	('ABL', 'Gene', (56, 59))	('PDGFR', 'Gene', (67, 72))	('FGFR', 'Gene', '2260', (61, 65))	('PDGFR', 'Gene', '5159', (67, 72))	('ABL', 'Gene', '25', (112, 115))	('BCR-ABL', 'Gene', '25', (108, 115))	('Ponatinib', 'Chemical', 'MESH:C545373', (6, 15))	('ABL', 'Gene', (112, 115))	('SRC', 'Gene', '6714', (51, 54))	('BCR-ABL', 'Gene', (108, 115))	('SRC', 'Gene', (51, 54))	('AP24534', 'Chemical', 'MESH:C545373', (17, 24))	('VEGFR', 'Gene', '3791', (77, 82))
105096	33655556	181  Currently, researchers are trying to discover novel FGFRs inhibitors according to the structure of ponatinib, which have already displayed significant antitumour activities in FGFR1-amplificated H1581 and FGFR2-amplificated SNU-16 xenograft models.	('FGFR', 'Gene', '2260', (57, 61))	('tumour', 'Disease', (160, 166))	('FGFR', 'Gene', (181, 185))	('FGFR2', 'Gene', (210, 215))	('FGFR2', 'Gene', '2263', (210, 215))	('FGFR', 'Gene', (210, 214))	('FGFR', 'molecular_function', 'GO:0005007', ('210', '214'))	('FGFR1', 'Gene', (181, 186))	('FGFR', 'Gene', '2260', (181, 185))	('FGFR', 'molecular_function', 'GO:0005007', ('181', '185'))	('FGFR', 'Gene', '2260', (210, 214))	('FGFR1', 'Gene', '2260', (181, 186))	('inhibitors', 'Var', (63, 73))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('ponatinib', 'Chemical', 'MESH:C545373', (104, 113))	('FGFR', 'Gene', (57, 61))	('tumour', 'Disease', 'MESH:D009369', (160, 166))
105098	33655556	Because of the multiple targets of non-selective FGFR/VEGFR inhibitors, their antitumour effects are not limited to FGFR-addicted tumours.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('FGFR', 'molecular_function', 'GO:0005007', ('116', '120'))	('FGFR', 'Gene', (116, 120))	('inhibitors', 'Var', (60, 70))	('FGFR', 'Gene', '2260', (116, 120))	('tumour', 'Disease', (130, 136))	('VEGFR', 'Gene', (54, 59))	('FGFR', 'Gene', (49, 53))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('FGFR-addicted tumours', 'Disease', (116, 137))	('tumour', 'Disease', (82, 88))	('FGFR-addicted tumours', 'Disease', 'MESH:D009369', (116, 137))	('FGFR', 'Gene', '2260', (49, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('VEGFR', 'Gene', '3791', (54, 59))
105101	33655556	AZD4547 is a selective and reversible TKI of FGFR1-3 and also shows activity against VEGFR2 at nM concentration with IC50 equal to 24 nM.	('VEGFR2', 'Gene', (85, 91))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('activity', 'MPA', (68, 76))	('FGFR1-3', 'Gene', (45, 52))	('AZD4547', 'Var', (0, 7))	('FGFR1-3', 'Gene', '2260;2263;2261', (45, 52))
105102	33655556	182  Its antitumour effect has been confirmed in some preclinical tumour models, including oesophageal squamous, non-small-cell lung, breast, endometrial and colorectal tumours characterized by different kinds of FGFR alterations.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('tumour', 'Disease', (13, 19))	('oesophageal squamous', 'Disease', (91, 111))	('tumours', 'Phenotype', 'HP:0002664', (169, 176))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('FGFR', 'Gene', (213, 217))	('non-small-cell lung', 'Disease', (113, 132))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('alterations', 'Var', (218, 229))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('colorectal tumours', 'Disease', 'MESH:D015179', (158, 176))	('tumour', 'Disease', (66, 72))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('endometrial', 'Disease', (142, 153))	('tumour', 'Disease', (169, 175))	('FGFR', 'Gene', '2260', (213, 217))	('colorectal tumours', 'Disease', (158, 176))	('FGFR', 'molecular_function', 'GO:0005007', ('213', '217'))	('breast', 'Disease', (134, 140))
105104	33655556	However, minimal activities were achieved against tumours harbouring actionable aberration(s) in FGFR1-3, including FGFR1-amplified SqCLC and gastric adenocarcinoma with FGFR2 polysomy or gene amplification.	('FGFR1-3', 'Gene', '2260;2263;2261', (97, 104))	('SqCLC', 'Disease', (132, 137))	('FGFR1', 'Gene', '2260', (116, 121))	('FGFR2', 'Gene', (170, 175))	('tumours', 'Disease', (50, 57))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (142, 164))	('FGFR', 'molecular_function', 'GO:0005007', ('170', '174'))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('FGFR1-3', 'Gene', (97, 104))	('SqCLC', 'Phenotype', 'HP:0030359', (132, 137))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('polysomy', 'Var', (176, 184))	('FGFR2', 'Gene', '2263', (170, 175))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('gene amplification', 'Var', (188, 206))	('FGFR1', 'Gene', '2260', (97, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('116', '120'))	('FGFR1', 'Gene', (116, 121))	('gastric adenocarcinoma', 'Disease', (142, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('FGFR', 'molecular_function', 'GO:0005007', ('97', '101'))	('FGFR1', 'Gene', (97, 102))
105106	33655556	ASP5878 is a selective pan-FGFR inhibitor that exerts its antitumour activity towards tumours with FGFR genetic alterations.	('FGFR', 'Gene', (99, 103))	('genetic alterations', 'Var', (104, 123))	('ASP5878', 'Chemical', 'MESH:C000615784', (0, 7))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('FGFR', 'Gene', '2260', (99, 103))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('FGFR', 'Gene', (27, 31))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('FGFR', 'Gene', '2260', (27, 31))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('tumour', 'Disease', (62, 68))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumour', 'Disease', (86, 92))	('tumours', 'Disease', (86, 93))
105116	33655556	196  In phase I clinical trials, it showed clinical benefits in glioblastoma, cholangiocarcinoma, urothelial and endometrial cancer with FGFR mutations or fusions, while ORRs in other tumour types were below 10%.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('FGFR', 'Gene', '2260', (137, 141))	('endometrial cancer', 'Disease', 'MESH:D016889', (113, 131))	('fusions', 'Var', (155, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('urothelial', 'Disease', (98, 108))	('mutations', 'Var', (142, 151))	('FGFR', 'molecular_function', 'GO:0005007', ('137', '141'))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('tumour', 'Disease', (184, 190))	('benefits', 'PosReg', (52, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('FGFR', 'Gene', (137, 141))	('glioblastoma', 'Disease', (64, 76))	('endometrial cancer', 'Phenotype', 'HP:0012114', (113, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('endometrial cancer', 'Disease', (113, 131))	('cholangiocarcinoma', 'Disease', (78, 96))
105117	33655556	6 ,  197 ,  198  In April 2019, erdafitinib received accelerated approval by the FDA to treat patients with FGFR3 mutated or FGFR2/3 fusion-positive advanced or metastatic urothelial carcinoma after at least one prior platinum-based regimen.	('patients', 'Species', '9606', (94, 102))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (172, 192))	('FGFR2/3', 'Gene', (125, 132))	('mutated', 'Var', (114, 121))	('advanced', 'Disease', (149, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('FGFR', 'molecular_function', 'GO:0005007', ('125', '129'))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('platinum', 'Chemical', 'MESH:D010984', (218, 226))	('erdafitinib', 'Chemical', 'MESH:C000604580', (32, 43))	('urothelial carcinoma', 'Disease', (172, 192))	('FGFR2/3', 'Gene', '2263;2261', (125, 132))	('FGFR3', 'Gene', (108, 113))
105120	33655556	199   Ly2874455 is a selective pan-FGFR inhibitor, with similar values of IC50 in inhibiting FGFR1-4, which also has inhibitory activity towards VEGFR2 with IC50 equal to 7 nM.	('FGFR', 'Gene', '2260', (35, 39))	('inhibiting', 'NegReg', (82, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('Ly2874455', 'Var', (6, 15))	('Ly2874455', 'Chemical', 'MESH:C570663', (6, 15))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('FGFR1', 'Gene', (93, 98))	('FGFR', 'Gene', '2260', (93, 97))	('FGFR', 'Gene', (93, 97))	('FGFR', 'Gene', (35, 39))	('FGFR1', 'Gene', '2260', (93, 98))
105121	33655556	200  Interestingly, as the inhibition of FGF-induced Erk phosphorylation by Ly2874455 is much easier than that of VEGF-mediated target signalling in vivo, LY2874455 can avoid VEGFR2-mediated hypertension at efficacious doses.	('Ly2874455', 'Chemical', 'MESH:C570663', (76, 85))	('hypertension', 'Phenotype', 'HP:0000822', (191, 203))	('LY2874455', 'Chemical', 'MESH:C570663', (155, 164))	('LY2874455', 'Var', (155, 164))	('hypertension', 'Disease', (191, 203))	('signalling', 'biological_process', 'GO:0023052', ('135', '145'))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('hypertension', 'Disease', 'MESH:D006973', (191, 203))	('Erk', 'Gene', (53, 56))	('Erk', 'Gene', '5594', (53, 56))	('Ly2874455', 'Var', (76, 85))	('Erk', 'molecular_function', 'GO:0004707', ('53', '56'))
105124	33655556	141  SOMCL-286 starting from the structure of lucitanib is another FGFR and VEGR2 dual inhibitor and showed significant antitumour effects in SNU-16 xenograft model harbouring aberration in FGFR and VEGFR2.	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('FGFR', 'Gene', (67, 71))	('VEGFR2', 'Gene', (199, 205))	('FGFR', 'Gene', '2260', (67, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('190', '194'))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('aberration', 'Var', (176, 186))	('FGFR', 'Gene', (190, 194))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('FGFR', 'Gene', '2260', (190, 194))	('lucitanib', 'Chemical', 'MESH:C000595232', (46, 55))	('tumour', 'Disease', (124, 130))
105126	33655556	The clinical effects of these drugs vary with different types of FGFR genetic alterations.	('FGFR', 'Gene', (65, 69))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('genetic alterations', 'Var', (70, 89))	('FGFR', 'Gene', '2260', (65, 69))
105127	33655556	The effect of drugs targeting FGFR gene fusion and mutations seems to be better than that of gene amplification, probably mainly because gene amplification does not imply high protein expression.	('mutations', 'Var', (51, 60))	('FGFR', 'Gene', (30, 34))	('FGFR', 'Gene', '2260', (30, 34))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))
105129	33655556	FGF-FGFR signalling can be abnormally triggered by FGF and FGFR alterations.	('triggered', 'Reg', (38, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('FGFR', 'Gene', (59, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('FGFR', 'Gene', (4, 8))	('FGFR', 'Gene', '2260', (59, 63))	('FGFR', 'Gene', '2260', (4, 8))	('signalling', 'biological_process', 'GO:0023052', ('9', '19'))	('FGF', 'Gene', (51, 54))	('alterations', 'Var', (64, 75))
105137	33655556	The combination of lenvatinib and pembrolizumab has received accelerated approval in patients with advanced endometrial cancer and is undergoing phase III clinical trial in HCC and RCC (NCT03713593, NCT02811861).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('HCC', 'Disease', (173, 176))	('HCC', 'Phenotype', 'HP:0001402', (173, 176))	('endometrial cancer', 'Disease', (108, 126))	('lenvatinib', 'Chemical', 'MESH:C531958', (19, 29))	('patients', 'Species', '9606', (85, 93))	('endometrial cancer', 'Phenotype', 'HP:0012114', (108, 126))	('endometrial cancer', 'Disease', 'MESH:D016889', (108, 126))	('pembrolizumab', 'Chemical', 'MESH:C582435', (34, 47))	('NCT03713593', 'Var', (186, 197))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('RCC', 'Disease', (181, 184))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))
105142	31028363	UroSEEK is designed to detect alterations in 11 genes that includes most common genetic alterations in bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('bladder cancer', 'Phenotype', 'HP:0009725', (103, 117))	('alterations', 'Var', (30, 41))	('bladder cancer', 'Disease', 'MESH:D001749', (103, 117))	('bladder cancer', 'Disease', (103, 117))
105147	31028363	Seventy-two percent of pT1 and 63% of muscle-invasive bladder tumors harbored TERT promoter mutations with g.1295228C>T alteration being the most common in all groups.	('g.1295228C>T', 'Var', (107, 119))	('TERT', 'Gene', (78, 82))	('TERT', 'Gene', '7015', (78, 82))	('g.1295228C>T', 'Mutation', 'g.1295228C>T', (107, 119))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('pT1', 'Gene', '58492', (23, 26))	('common', 'Reg', (146, 152))	('muscle-invasive bladder tumors harbored', 'Disease', 'MESH:D001749', (38, 77))	('bladder tumors', 'Phenotype', 'HP:0009725', (54, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('bladder tumor', 'Phenotype', 'HP:0009725', (54, 67))	('invasive bladder', 'Phenotype', 'HP:0100645', (45, 61))	('muscle-invasive bladder tumors harbored', 'Disease', (38, 77))	('pT1', 'Gene', (23, 26))
105148	31028363	FGFR3 and PIK3CA mutations were more frequent in low-grade non-invasive papillary carcinomas compared to high-grade non-invasive papillary carcinomas and carcinomas in situ (p<0.0001), while the opposite was true for TP53 (p<0.0001).	('TP53', 'Gene', '7157', (217, 221))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('papillary carcinomas', 'Disease', (129, 149))	('carcinomas in situ', 'Disease', (154, 172))	('papillary carcinomas', 'Disease', 'MESH:D002291', (72, 92))	('PIK3CA', 'Gene', '5290', (10, 16))	('mutations', 'Var', (17, 26))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('papillary carcinomas and carcinomas', 'Disease', 'MESH:C538614', (129, 164))	('papillary carcinomas', 'Disease', (72, 92))	('TP53', 'Gene', (217, 221))	('PIK3CA', 'Gene', (10, 16))	('papillary carcinomas', 'Disease', 'MESH:D002291', (129, 149))	('carcinomas in situ', 'Disease', 'MESH:D002278', (154, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('frequent', 'Reg', (37, 45))	('FGFR3', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('FGFR3', 'Gene', '2261', (0, 5))
105149	31028363	Significantly higher rates of TP53 and CDKN2A mutation rates (p=0.005 and 0.035, respectively) were encountered in muscle-invasive bladder tumors compared to those of pT1 stage.	('pT1', 'Gene', (167, 170))	('TP53', 'Gene', (30, 34))	('CDKN2A', 'Gene', (39, 45))	('higher rates', 'PosReg', (14, 26))	('bladder tumors', 'Phenotype', 'HP:0009725', (131, 145))	('invasive bladder', 'Phenotype', 'HP:0100645', (122, 138))	('CDKN2A', 'Gene', '1029', (39, 45))	('muscle-invasive bladder tumors', 'Disease', 'MESH:D001749', (115, 145))	('bladder tumor', 'Phenotype', 'HP:0009725', (131, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('muscle-invasive bladder tumors', 'Disease', (115, 145))	('pT1', 'Gene', '58492', (167, 170))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('TP53', 'Gene', '7157', (30, 34))	('mutation', 'Var', (46, 54))
105150	31028363	The overwhelming majority of all investigated tumors showed at least one mutation among UroSEEK assay genes confirming the comprehensive coverage of the panel and supporting its potential utility as a non-invasive urine based assay.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', (46, 52))	('mutation', 'Var', (73, 81))	('UroSEEK assay genes', 'Gene', (88, 107))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
105177	31028363	As previously described, the classification of a sample's DNA status was based on two complementary criteria applied to each mutation: 1) the difference between the average mutant allele frequency in the sample of interest and the corresponding maximum mutant allele frequency observed for that same mutation in a set of controls; and 2) the Stouffer's Z-score obtained by comparing the mutant allele frequency in the sample of interest to a distribution of normal controls.	('men', 'Species', '9606', (92, 95))	('mutation', 'Var', (300, 308))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('mutation', 'Var', (125, 133))
105184	31028363	TERT promoter mutations were identified in 70% of all cases with the most common alteration being g.1295228C>T, followed by g.1295250C>T.	('g.1295250C>T', 'Var', (124, 136))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('g.1295228C>T', 'Mutation', 'g.1295228C>T', (98, 110))	('g.1295228C>T', 'Var', (98, 110))	('g.1295250C>T', 'Mutation', 'g.1295250C>T', (124, 136))
105186	31028363	A higher incidence of TERT promoter mutation was identified in low-grade non-invasive papillary carcinomas compared to high-grade non-invasive papillary carcinomas and carcinomas in situ (77% vs 65%; p=0.017; see Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('TERT', 'Gene', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('papillary carcinomas', 'Disease', 'MESH:D002291', (143, 163))	('papillary carcinomas', 'Disease', (143, 163))	('TERT', 'Gene', '7015', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('papillary carcinomas', 'Disease', (86, 106))	('papillary carcinomas and carcinomas', 'Disease', 'MESH:C538614', (143, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('carcinomas in situ', 'Disease', 'MESH:D002278', (168, 186))	('papillary carcinomas', 'Disease', 'MESH:D002291', (86, 106))	('carcinomas in situ', 'Disease', (168, 186))	('mutation', 'Var', (36, 44))
105188	31028363	Among the 10 genes included in the UroSeqS assay, FGFR3 and PIK3CA mutations occurred significantly more often in low-grade non-invasive papillary carcinoma tumors compared to high-grade non-invasive papillary carcinomas and carcinomas in situ (p<0.0001), while the reverse was true for TP53 (p<0.0001; see Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('carcinomas', 'Phenotype', 'HP:0030731', (210, 220))	('papillary carcinoma tumors', 'Disease', (137, 163))	('carcinomas in situ', 'Disease', 'MESH:D002278', (225, 243))	('carcinomas', 'Phenotype', 'HP:0030731', (225, 235))	('TP53', 'Gene', '7157', (287, 291))	('papillary carcinoma tumors', 'Disease', 'MESH:D002291', (137, 163))	('papillary carcinomas and carcinomas', 'Disease', 'MESH:C538614', (200, 235))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('PIK3CA', 'Gene', (60, 66))	('carcinomas in situ', 'Disease', (225, 243))	('TP53', 'Gene', (287, 291))	('FGFR3', 'Gene', (50, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('PIK3CA', 'Gene', '5290', (60, 66))	('mutations', 'Var', (67, 76))	('occurred', 'Reg', (77, 85))	('FGFR', 'molecular_function', 'GO:0005007', ('50', '54'))	('FGFR3', 'Gene', '2261', (50, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
105189	31028363	In invasive bladder cancer CDKN2A and TP53 mutations were more commonly observed in muscle-invasive bladder cancer compared to pT1 tumors (P= 0.035 and 0.005, respectively; see Table 2).	('invasive bladder', 'Phenotype', 'HP:0100645', (91, 107))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (84, 114))	('TP53', 'Gene', (38, 42))	('invasive bladder', 'Phenotype', 'HP:0100645', (3, 19))	('CDKN2A', 'Gene', (27, 33))	('observed', 'Reg', (72, 80))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (91, 114))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (3, 26))	('CDKN2A', 'Gene', '1029', (27, 33))	('TP53', 'Gene', '7157', (38, 42))	('muscle-invasive bladder cancer', 'Disease', (84, 114))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('invasive bladder cancer', 'Disease', (3, 26))	('pT1', 'Gene', '58492', (127, 130))	('tumors', 'Disease', (131, 137))	('pT1', 'Gene', (127, 130))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (43, 52))	('bladder cancer', 'Phenotype', 'HP:0009725', (100, 114))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('bladder cancer', 'Phenotype', 'HP:0009725', (12, 26))
105190	31028363	Regarding mutation variants, p.S249C was the most frequent FGFR3 mutation (67%), while p.E545K and p.H66P were the most common PIK3CA and CDKN2A mutations, (49% and 79%, respectively; see Supplementary Table S2).	('FGFR3', 'Gene', '2261', (59, 64))	('CDKN2A', 'Gene', (138, 144))	('CDKN2A', 'Gene', '1029', (138, 144))	('p.H66P', 'Mutation', 'rs756750256', (99, 105))	('p.S249C', 'Var', (29, 36))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('p.S249C', 'Mutation', 'rs121913483', (29, 36))	('FGFR3', 'Gene', (59, 64))	('PIK3CA', 'Gene', (127, 133))	('p.E545K', 'Var', (87, 94))	('men', 'Species', '9606', (194, 197))	('p.E545K', 'Mutation', 'rs104886003', (87, 94))	('PIK3CA', 'Gene', '5290', (127, 133))	('p.H66P', 'Var', (99, 105))
105191	31028363	Two hundred and nineteen tumors demonstrated co-occurrence of mutations in both assay components with 59% of tumors harboring TERT promoter mutation also showing a mutation in at least one UroSeqS gene (p=0.001).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('TERT', 'Gene', (126, 130))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('mutation', 'Var', (140, 148))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('TERT', 'Gene', '7015', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
105192	31028363	Finally, occasional cases demonstrated multiple variants of TERT promoter (13 tumors) and TP53 (14 tumors) mutations and one case displayed two FGFR3 variant mutations.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('FGFR3', 'Gene', '2261', (144, 149))	('mutations', 'Var', (107, 116))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('TERT', 'Gene', '7015', (60, 64))	('TP53', 'Gene', '7157', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('FGFR3', 'Gene', (144, 149))	('TP53', 'Gene', (90, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('TERT', 'Gene', (60, 64))	('tumors', 'Disease', (99, 105))
105196	31028363	Only 2 of 15 patients with observed FGFR3 mutations had the same mutation present across tumors.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('FGFR3', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('patients', 'Species', '9606', (13, 21))	('FGFR3', 'Gene', '2261', (36, 41))	('mutations', 'Var', (42, 51))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
105199	31028363	As shown, 94% of tumors with subsequent recurrence had mutation in at least one of the 11 genes included in UroSEEK.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mutation', 'Var', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
105202	31028363	Tumors with progression were less likely to harbor a mutation in one or more UroSEEK assay genes (81% vs. 96%; p=0.016).	('mutation', 'Var', (53, 61))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('UroSEEK assay genes', 'Gene', (77, 96))
105204	31028363	The TERTSeqS component detected mutations in the TERT promoter region in 70% of all tumors.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TERT', 'Gene', (4, 8))	('mutations', 'Var', (32, 41))	('TERT', 'Gene', (49, 53))	('TERT', 'Gene', '7015', (4, 8))	('TERT', 'Gene', '7015', (49, 53))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
105205	31028363	Combing these two components led to a capture rate for alteration of the UroSEEK assay in 92% of all tumors.	('UroSEEK assay', 'MPA', (73, 86))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('alteration', 'Var', (55, 65))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
105209	31028363	The current observation of 54% of TP53 mutation in muscle-invasive bladder cancer is in line with findings of recent studies such as The Cancer Genome Atlas and Kim et al.	('mutation', 'Var', (39, 47))	('TP53', 'Gene', (34, 38))	('Cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('invasive bladder', 'Phenotype', 'HP:0100645', (58, 74))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (51, 81))	('muscle-invasive bladder cancer', 'Disease', (51, 81))	('TP53', 'Gene', '7157', (34, 38))
105213	31028363	In this group, FGFR3 mutations were the most frequent (46%) among the 10 genes included in UroSeqS followed by PIK3CA mutation in 19%.	('FGFR3', 'Gene', (15, 20))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('PIK3CA', 'Gene', (111, 117))	('FGFR3', 'Gene', '2261', (15, 20))	('frequent', 'Reg', (45, 53))	('PIK3CA', 'Gene', '5290', (111, 117))	('mutations', 'Var', (21, 30))
105214	31028363	in their study of whole exome and targeted sequencing of 82 Ta tumors (79% and 54% for FGFR3 and PIK3CA mutations, respectively).	('Ta tumors', 'Disease', 'MESH:D009369', (60, 69))	('mutations', 'Var', (104, 113))	('FGFR3', 'Gene', '2261', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('FGFR3', 'Gene', (87, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('Ta tumors', 'Disease', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PIK3CA', 'Gene', (97, 103))	('PIK3CA', 'Gene', '5290', (97, 103))
105217	31028363	The here found distribution rates of TERT promoter mutations in non-invasive lesions is in line with our originally reported rates in conventional urothelial carcinoma in Kinde et al.	('mutations', 'Var', (51, 60))	('TERT', 'Gene', (37, 41))	('TERT', 'Gene', '7015', (37, 41))	('urothelial carcinoma', 'Disease', (147, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (147, 167))
105219	31028363	found TERT promoter mutations to be more frequent in their high-grade non-invasive papillary carcinoma cases compared to low-grade non-invasive papillary carcinomas (88% and 61 %, respectively).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('papillary carcinoma', 'Disease', 'MESH:D002291', (144, 163))	('papillary carcinoma', 'Disease', (83, 102))	('papillary carcinomas', 'Disease', 'MESH:D002291', (144, 164))	('papillary carcinomas', 'Disease', (144, 164))	('TERT', 'Gene', (6, 10))	('papillary carcinoma', 'Disease', 'MESH:D002291', (83, 102))	('TERT', 'Gene', '7015', (6, 10))	('frequent', 'Reg', (41, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('mutations', 'Var', (20, 29))
105220	31028363	Our analysis of sequential tumors in 36 patients unveiled an identical TERT promoter mutation across tumors in 22 of the 29 patients harboring TERT promoter mutations.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('TERT', 'Gene', (143, 147))	('TERT', 'Gene', (71, 75))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('TERT', 'Gene', '7015', (71, 75))	('patients', 'Species', '9606', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Disease', (27, 33))	('TERT', 'Gene', '7015', (143, 147))	('mutation', 'Var', (85, 93))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (124, 132))	('tumors', 'Disease', (101, 107))
105222	31028363	This consistency of TERT promoter alteration across tumors, if proven in a larger cohort of sequential tumors, suggests that assessment of the index tumor might be sufficient and could obviate the need for repeat sequential tumor testing.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (52, 57))	('men', 'Species', '9606', (131, 134))	('tumors', 'Disease', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('alteration', 'Var', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('TERT', 'Gene', (20, 24))	('TERT', 'Gene', '7015', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (103, 108))	('tumors', 'Disease', (52, 58))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Disease', (149, 154))
105228	31028363	In conclusion, the overwhelming majority of all investigated tumors showed at least one mutation among genes included in the recently reported UroSEEK assay, across tumor grade and stage.	('mutation', 'Var', (88, 96))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', (165, 170))
105247	30697528	Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II.	('types I', 'Disease', (67, 74))	('associated', 'Reg', (27, 37))	('Mutations', 'Var', (0, 9))	('Ehlers-Danlos syndrome', 'Disease', 'MESH:D004535', (43, 65))	('Ehlers-Danlos syndrome', 'Disease', (43, 65))
105271	30697528	Significant association was observed in two datasets (TCGA and CIT), both indicating worse prognosis in COL5A2 high expression group.	('high expression', 'Var', (111, 126))	('CIT', 'biological_process', 'GO:0106106', ('63', '66'))	('COL5A2', 'Gene', '1290', (104, 110))	('CIT', 'Gene', '11113', (63, 66))	('COL5A2', 'Gene', (104, 110))	('CIT', 'Gene', (63, 66))
105277	30697528	The FGFR3 mutation status was the only one with significance as defined by FDR < 0.05.	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('FGFR3', 'Gene', '2261', (4, 9))	('FGFR3', 'Gene', (4, 9))	('mutation', 'Var', (10, 18))
105301	30697528	On the other hand, we also performed differential mutational analysis and identified that FGFR3 mutation was significantly enriched in the COL5A2 low expression group.	('low expression', 'NegReg', (146, 160))	('FGFR3', 'Gene', '2261', (90, 95))	('mutation', 'Var', (96, 104))	('COL5A2', 'Gene', '1290', (139, 145))	('COL5A2', 'Gene', (139, 145))	('FGFR3', 'Gene', (90, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))
105302	30697528	Actually, it has been well-known that FGFR3 is one of the most frequently mutated genes in BC and is more frequent in lower tumor stage, with over 65% of NMIBC and about 15% of MIBC bearing an FGFR3 mutation.	('FGFR3', 'Gene', (193, 198))	('FGFR3', 'Gene', '2261', (38, 43))	('MIBC', 'Chemical', '-', (177, 181))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('NMIBC', 'Disease', (154, 159))	('BC', 'Phenotype', 'HP:0009725', (91, 93))	('tumor', 'Disease', (124, 129))	('mutation', 'Var', (199, 207))	('FGFR3', 'Gene', (38, 43))	('bearing', 'Reg', (182, 189))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('FGFR3', 'Gene', '2261', (193, 198))	('BC', 'Phenotype', 'HP:0009725', (179, 181))	('BC', 'Phenotype', 'HP:0009725', (157, 159))	('MIBC', 'Chemical', '-', (155, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('193', '197'))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
105328	29928414	This was further demonstrated by blocking MALAT-1 using antisense oligonucleotides after tumor implantation.	('MALAT-1', 'Gene', (42, 49))	('oligonucleotides', 'Chemical', 'MESH:D009841', (66, 82))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (89, 94))	('blocking', 'NegReg', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('antisense', 'Var', (56, 65))
105334	29928414	MALAT-1 was demonstrated to epigenetically bind to the RBD of PSF and release it from the promoter region of GAGE6, thus inhibiting its proto-oncogene activity in melanoma cells.	('GAGE6', 'Gene', '2578', (109, 114))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('PSF', 'Gene', '6421', (62, 65))	('epigenetically', 'Var', (28, 42))	('bind', 'Interaction', (43, 47))	('inhibiting', 'NegReg', (121, 131))	('proto-oncogene', 'MPA', (136, 150))	('PSF', 'Gene', (62, 65))	('GAGE6', 'Gene', (109, 114))	('MALAT-1', 'Gene', (0, 7))
105338	29928414	Subsequent analysis of the regulatory role of MALAT-1 upregulation in cell proliferation, migration and invasion via epigenetic regulation of the transcriptional activity of PSF on its downstream target gene, GAGE6, was performed.	('regulation', 'biological_process', 'GO:0065007', ('128', '138'))	('GAGE6', 'Gene', (209, 214))	('migration', 'CPA', (90, 99))	('MALAT-1', 'Gene', (46, 53))	('PSF', 'Gene', '6421', (174, 177))	('GAGE6', 'Gene', '2578', (209, 214))	('cell proliferation', 'CPA', (70, 88))	('upregulation', 'PosReg', (54, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('70', '88'))	('invasion', 'CPA', (104, 112))	('epigenetic regulation', 'Var', (117, 138))	('PSF', 'Gene', (174, 177))
105348	29928414	The PCR for beta-actin mRNA was performed using the following reaction conditions: 20 cycles of 95 C for 10 sec, 60 C for 60 sec.	('beta-actin', 'Gene', '728378', (12, 22))	('95 C', 'Var', (96, 100))	('beta-actin', 'Gene', (12, 22))
105383	29928414	In order to further confirm that upregulated MALAT-1 caused this dissociation, siMALAT-1 was introduced into hypoxia-exposed A549 cells and, 24 h later, the efficiency of MALAT-1 knockdown was detected by RT-qPCR (Fig.	('upregulated', 'PosReg', (33, 44))	('hypoxia', 'Disease', (109, 116))	('hypoxia', 'Disease', 'MESH:D000860', (109, 116))	('A549', 'CellLine', 'CVCL:0023', (125, 129))	('knockdown', 'Var', (179, 188))	('MALAT-1', 'Gene', (171, 178))
105388	29928414	3B); however, in normoxia-treated A549 cells, the knockdown of MALAT-1 led to only a marginal difference (P>0.05).	('knockdown', 'Var', (50, 59))	('A549', 'CellLine', 'CVCL:0023', (34, 38))	('MALAT-1', 'Gene', (63, 70))
105393	29928414	Following the removal of hypoxic conditions, upregulated MALAT-1 lncRNA persisted for >72 h. Notably, MALAT-1 epigenetically binds to the RBD of PSF, which is a tightly regulated region due to its DNA-binding activity.	('PSF', 'Gene', (145, 148))	('binds', 'Interaction', (125, 130))	('DNA', 'cellular_component', 'GO:0005574', ('197', '200'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('197', '208'))	('hypoxic conditions', 'Disease', (25, 43))	('hypoxic conditions', 'Disease', 'MESH:D009135', (25, 43))	('PSF', 'Gene', '6421', (145, 148))	('epigenetically', 'Var', (110, 124))	('MALAT-1', 'Gene', (102, 109))
105403	29928414	In D12 and R-18 melanoma, hypoxia exposure was reported to increase tumor progression.	('tumor', 'Disease', (68, 73))	('hypoxia', 'Disease', (26, 33))	('hypoxia', 'Disease', 'MESH:D000860', (26, 33))	('D12', 'Var', (3, 6))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('increase', 'PosReg', (59, 67))
105416	29928414	Furthermore, silencing MALAT-1 inhibited proliferation, migration and invasion in bladder urothelial carcinoma T24 and 5,637 cells.	('migration', 'CPA', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('silencing', 'Var', (13, 22))	('MALAT-1', 'Gene', (23, 30))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (82, 110))	('bladder urothelial carcinoma', 'Disease', (82, 110))	('inhibited', 'NegReg', (31, 40))	('invasion', 'CPA', (70, 78))	('proliferation', 'CPA', (41, 54))
105447	29653574	Immunohistochemical analysis indicated positivity of the tumour cells for vimentin, CK, EMA, CEA, CKH, GATA3, and P63 (Fig.	('tumour', 'Disease', (57, 63))	('CEA', 'Gene', (93, 96))	('GATA3', 'Gene', '2625', (103, 108))	('vimentin', 'cellular_component', 'GO:0045099', ('74', '82'))	('CEA', 'Gene', '1084', (93, 96))	('vimentin', 'Gene', '7431', (74, 82))	('P63', 'Gene', '8626', (114, 117))	('positivity', 'Var', (39, 49))	('vimentin', 'Gene', (74, 82))	('vimentin', 'cellular_component', 'GO:0045098', ('74', '82'))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('GATA3', 'Gene', (103, 108))	('P63', 'Gene', (114, 117))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
105511	26692678	The exact pathogenesis of LELC remains elusive, but an abnormality in p53 regulation and stem cell origin for the carcinoma has been suggested.	('LELC', 'Disease', (26, 30))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('carcinoma', 'Disease', 'MESH:D002277', (114, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('regulation', 'biological_process', 'GO:0065007', ('74', '84'))	('stem cell origin', 'CPA', (89, 105))	('regulation', 'MPA', (74, 84))	('carcinoma', 'Disease', (114, 123))	('abnormality', 'Var', (55, 66))	('pathogenesis', 'biological_process', 'GO:0009405', ('10', '22'))
105530	32328202	The hypo-methylations of EMP3 and SERPINE1 were contributing to the high expressions of EMP3 and SERPINE1 in old LGG patients.	('EMP3', 'Gene', (25, 29))	('SERPINE1', 'Gene', '5054', (97, 105))	('SERPINE1', 'Gene', (97, 105))	('EMP3', 'Gene', '2014', (25, 29))	('high', 'PosReg', (68, 72))	('expressions', 'MPA', (73, 84))	('hypo-methylations', 'Var', (4, 21))	('EMP3', 'Gene', (88, 92))	('patients', 'Species', '9606', (117, 125))	('LGG', 'Disease', (113, 116))	('SERPINE1', 'Gene', '5054', (34, 42))	('SERPINE1', 'Gene', (34, 42))	('EMP3', 'Gene', '2014', (88, 92))
105532	32328202	Moreover, high expressions of IGFBP2, EMP3, TIMP1 and SERPINE1 were associated with the worse prognosis of LGG patients.	('EMP3', 'Gene', (38, 42))	('associated', 'Reg', (68, 78))	('TIMP1', 'Gene', (44, 49))	('LGG', 'Disease', (107, 110))	('EMP3', 'Gene', '2014', (38, 42))	('IGFBP2', 'Gene', '3485', (30, 36))	('SERPINE1', 'Gene', '5054', (54, 62))	('SERPINE1', 'Gene', (54, 62))	('IGFBP2', 'Gene', (30, 36))	('TIMP1', 'Gene', '7076', (44, 49))	('high expressions', 'Var', (10, 26))	('patients', 'Species', '9606', (111, 119))
105533	32328202	Furthermore, we demonstrated that EMP3 and SERPINE1 were connected with each other and the combination of EMP3 and SERPINE1 had better prognostic effects in glioma patients.	('EMP3', 'Gene', '2014', (106, 110))	('EMP3', 'Gene', (34, 38))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('EMP3', 'Gene', '2014', (34, 38))	('SERPINE1', 'Gene', '5054', (115, 123))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('SERPINE1', 'Gene', (43, 51))	('SERPINE1', 'Gene', (115, 123))	('patients', 'Species', '9606', (164, 172))	('better', 'PosReg', (128, 134))	('glioma', 'Disease', (157, 163))	('SERPINE1', 'Gene', '5054', (43, 51))	('combination', 'Var', (91, 102))	('EMP3', 'Gene', (106, 110))
105556	32328202	At last, we demonstrate the prognostic effects of combination of EMP3 and SERPINE1 genes in glioma patients.	('EMP3', 'Gene', (65, 69))	('glioma', 'Disease', (92, 98))	('patients', 'Species', '9606', (99, 107))	('EMP3', 'Gene', '2014', (65, 69))	('SERPINE1', 'Gene', '5054', (74, 82))	('SERPINE1', 'Gene', (74, 82))	('combination', 'Var', (50, 61))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
105560	32328202	The gene expression series matrix of normal and cancerous brain tissues was downloaded from the Gene Expression Omnibus (GEO) website (www.ncbi.nlm.nih.gov/geo), and included the GEO datasets GSE4920, GSE16011 and GSE50161.	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))	('Gene Expression', 'biological_process', 'GO:0010467', ('96', '111'))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancerous', 'Disease', 'MESH:D009369', (48, 57))	('GSE50161', 'Var', (214, 222))	('GSE16011', 'Var', (201, 209))	('cancerous brain', 'Phenotype', 'HP:0030692', (48, 63))	('GSE4920', 'Var', (192, 199))	('cancerous', 'Disease', (48, 57))
105615	32328202	Similarly, age related gene SERPINE1 was hypo-methylated in old LGG patients, compared with young LGG patients (P=5.35e-05) (Figure 4B).	('SERPINE1', 'Gene', '5054', (28, 36))	('SERPINE1', 'Gene', (28, 36))	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (68, 76))	('hypo-methylated', 'Var', (41, 56))	('LGG', 'Disease', (64, 67))
105625	32328202	For example, high IGFBP2, EMP3, TIMP1 and SERPINE1 expressions were all positively associated with the overall survival of LGG patients, while, high SFRP2, IRX1, KLRC3 and LUZP2 expressions were all negatively associated with the overall survival of LGG patients (Table 2).	('IGFBP2', 'Gene', '3485', (18, 24))	('IRX1', 'Gene', '79192', (156, 160))	('TIMP1', 'Gene', (32, 37))	('LUZP2', 'Gene', '338645', (172, 177))	('SFRP2', 'Gene', (149, 154))	('positively', 'PosReg', (72, 82))	('SERPINE1', 'Gene', (42, 50))	('high', 'Var', (13, 17))	('IGFBP2', 'Gene', (18, 24))	('TIMP1', 'Gene', '7076', (32, 37))	('KLRC3', 'Gene', '3823', (162, 167))	('EMP3', 'Gene', (26, 30))	('KLRC3', 'Gene', (162, 167))	('SERPINE1', 'Gene', '5054', (42, 50))	('LGG', 'Disease', (250, 253))	('LGG', 'Disease', (123, 126))	('IRX1', 'Gene', (156, 160))	('EMP3', 'Gene', '2014', (26, 30))	('LUZP2', 'Gene', (172, 177))	('patients', 'Species', '9606', (127, 135))	('associated', 'Reg', (83, 93))	('SFRP2', 'Gene', '6423', (149, 154))	('patients', 'Species', '9606', (254, 262))
105636	32328202	We found that patients with both high EMP3 and SERPINE1 expressions were particular with lowest overall survival in glioma patients (Figure 7B).	('EMP3', 'Gene', (38, 42))	('high', 'Var', (33, 37))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Disease', (116, 122))	('lowest', 'NegReg', (89, 95))	('EMP3', 'Gene', '2014', (38, 42))	('patients', 'Species', '9606', (123, 131))	('overall survival', 'MPA', (96, 112))	('patients', 'Species', '9606', (14, 22))	('SERPINE1', 'Gene', '5054', (47, 55))	('SERPINE1', 'Gene', (47, 55))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
105637	32328202	Patients with the low expression of EMP3 or SERPINE1 had better clinical outcomes (Figure 7B).	('EMP3', 'Gene', (36, 40))	('Patients', 'Species', '9606', (0, 8))	('SERPINE1', 'Gene', '5054', (44, 52))	('SERPINE1', 'Gene', (44, 52))	('low expression', 'Var', (18, 32))	('EMP3', 'Gene', '2014', (36, 40))
105646	32328202	Moreover, EMP3 and SERPINE1 were highly correlated with each other (Figure 8D) and the combination of EMP3 and SERPINE1 genes had better survival prediction in Chinese patients with LGG (Figure 8E).	('EMP3', 'Gene', (10, 14))	('better', 'PosReg', (130, 136))	('survival', 'CPA', (137, 145))	('EMP3', 'Gene', '2014', (102, 106))	('SERPINE1', 'Gene', '5054', (111, 119))	('SERPINE1', 'Gene', (111, 119))	('EMP3', 'Gene', '2014', (10, 14))	('combination', 'Var', (87, 98))	('SERPINE1', 'Gene', '5054', (19, 27))	('SERPINE1', 'Gene', (19, 27))	('patients', 'Species', '9606', (168, 176))	('EMP3', 'Gene', (102, 106))	('LGG', 'Disease', (182, 185))
105665	32328202	Furthermore, high expressions of IGFBP2, EMP3, TIMP1 and SERPINE1 are associated with low overall survival of LGG patients (Figure 6).	('EMP3', 'Gene', (41, 45))	('patients', 'Species', '9606', (114, 122))	('high', 'Var', (13, 17))	('IGFBP2', 'Gene', '3485', (33, 39))	('TIMP1', 'Gene', (47, 52))	('LGG', 'Disease', (110, 113))	('EMP3', 'Gene', '2014', (41, 45))	('IGFBP2', 'Gene', (33, 39))	('TIMP1', 'Gene', '7076', (47, 52))	('SERPINE1', 'Gene', '5054', (57, 65))	('low', 'NegReg', (86, 89))	('SERPINE1', 'Gene', (57, 65))	('overall survival', 'MPA', (90, 106))
105666	32328202	Interestingly, EMP3 and SERPINE1 are connected with each other and the combination of EMP3 and SERPINE1 genes have better prognostic effects in glioma patients (Figure 7B and 7C).	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('SERPINE1', 'Gene', '5054', (24, 32))	('SERPINE1', 'Gene', (24, 32))	('patients', 'Species', '9606', (151, 159))	('EMP3', 'Gene', (86, 90))	('SERPINE1', 'Gene', (95, 103))	('SERPINE1', 'Gene', '5054', (95, 103))	('better', 'PosReg', (115, 121))	('EMP3', 'Gene', (15, 19))	('glioma', 'Disease', (144, 150))	('EMP3', 'Gene', '2014', (86, 90))	('combination', 'Var', (71, 82))	('EMP3', 'Gene', '2014', (15, 19))
105669	32328202	Although the expression of IGFBP2 is controlled by epigenetic DNA methylation in glioma patients, we find no significant different methylation intensity of IGFBP2 and TIMP1 genes between old and young LGG patients (Figure 4B).	('epigenetic', 'Var', (51, 61))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('IGFBP2', 'Gene', (27, 33))	('patients', 'Species', '9606', (205, 213))	('patients', 'Species', '9606', (88, 96))	('IGFBP2', 'Gene', (156, 162))	('IGFBP2', 'Gene', '3485', (156, 162))	('TIMP1', 'Gene', (167, 172))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('glioma', 'Disease', (81, 87))	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))	('LGG', 'Disease', (201, 204))	('TIMP1', 'Gene', '7076', (167, 172))	('DNA methylation', 'biological_process', 'GO:0006306', ('62', '77'))	('IGFBP2', 'Gene', '3485', (27, 33))	('controlled', 'Reg', (37, 47))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
105680	29867225	Up or downregulating the expression of RIPK4 enhanced or inhibited, respectively, the migration and invasion of BC cells in vitro and in vivo.	('RIPK4', 'Gene', '54101', (39, 44))	('downregulating', 'NegReg', (6, 20))	('invasion of BC cells', 'CPA', (100, 120))	('migration', 'CPA', (86, 95))	('inhibited', 'NegReg', (57, 66))	('RIPK4', 'Gene', (39, 44))	('enhanced', 'PosReg', (45, 53))	('expression', 'Var', (25, 35))
105689	29867225	Moreover, some studies have revealed that constitutive activation of nuclear factor kappa B (NF-kappaB) signalling has a vital role in the progression of BC, and blockade of the NF-kappaB pathway could suppress angiogenesis and metastasis in BC.	('angiogenesis', 'CPA', (211, 223))	('signalling', 'biological_process', 'GO:0023052', ('104', '114'))	('NF-kappaB', 'Gene', '4790', (178, 187))	('angiogenesis', 'biological_process', 'GO:0001525', ('211', '223'))	('metastasis', 'CPA', (228, 238))	('NF-kappaB', 'Gene', '4790', (93, 102))	('NF-kappaB', 'Gene', (178, 187))	('blockade', 'Var', (162, 170))	('activation', 'PosReg', (55, 65))	('NF-kappaB', 'Gene', (93, 102))	('suppress', 'NegReg', (202, 210))	('nuclear factor kappa B', 'Gene', '4790', (69, 91))	('nuclear factor kappa B', 'Gene', (69, 91))
105692	29867225	It was identified initially as an important regulator of keratinocyte differentiation, and its encoding gene is mutated in Bartsocas-Papas syndrome.	('mutated', 'Var', (112, 119))	('Bartsocas-Papas syndrome', 'Disease', (123, 147))	('Bartsocas-Papas syndrome', 'Disease', 'MESH:C564874', (123, 147))	('keratinocyte differentiation', 'biological_process', 'GO:0030216', ('57', '85'))
105700	29867225	Overexpression of RIPK4 induced, whereas silencing RIPK4 inhibited, the invasion and metastasis of BC in vitro and in vivo.	('silencing', 'Var', (41, 50))	('RIPK4', 'Gene', (51, 56))	('inhibited', 'NegReg', (57, 66))	('RIPK4', 'Gene', (18, 23))	('RIPK4', 'Gene', '54101', (18, 23))	('RIPK4', 'Gene', '54101', (51, 56))	('metastasis of BC', 'CPA', (85, 101))	('invasion', 'CPA', (72, 80))
105735	29867225	The results showed that a high RIPK4 level is an independent predictor of poor OS in patients with BC (P < 0.001; Supplementary Table S3).	('high', 'Var', (26, 30))	('RIPK4', 'Gene', (31, 36))	('patients', 'Species', '9606', (85, 93))	('RIPK4', 'Gene', '54101', (31, 36))	('poor OS', 'Disease', (74, 81))
105738	29867225	The wound healing and matrigel invasion assays indicated that RIPK4 knockdown by ShRNA-3 transfection reduced the migration and invasion abilities of T24 and RT4 cells significantly compared with the control shNC cells (Fig.	('RIPK4', 'Gene', (62, 67))	('migration', 'CPA', (114, 123))	('invasion abilities', 'CPA', (128, 146))	('knockdown', 'Var', (68, 77))	('ShRNA-3', 'Gene', (81, 88))	('RIPK4', 'Gene', '54101', (62, 67))	('reduced', 'NegReg', (102, 109))	('wound healing', 'biological_process', 'GO:0042060', ('4', '17'))
105740	29867225	More importantly, using a lung metastasis in vivo animal model, the sizes and numbers of metastatic nodules were significantly decreased after RIPK4 knockdown in both T24 and RT4 cells (Fig.	('sizes', 'CPA', (68, 73))	('decreased', 'NegReg', (127, 136))	('knockdown', 'Var', (149, 158))	('RIPK4', 'Gene', '54101', (143, 148))	('RIPK4', 'Gene', (143, 148))
105741	29867225	These results implied that knockdown of RIPK4 suppresses the invasiveness and metastasis of BC cells.	('RIPK4', 'Gene', '54101', (40, 45))	('knockdown', 'Var', (27, 36))	('RIPK4', 'Gene', (40, 45))	('suppresses', 'NegReg', (46, 56))
105748	29867225	To investigate the relationship between RIPK4 and EMT, after silencing RIPK4 in T24 and RT4 cells, the protein levels of two epithelial markers, E-cadherin and beta-catenin, were increased, whereas the levels of two mesenchymal markers, fibronectin and vimentin, were decreased, as shown by both western blotting (Supplementary Figure S1A and C) and immunofluorescence staining (Supplementary Figure S1B and D).	('protein levels', 'MPA', (103, 117))	('RIPK4', 'Gene', '54101', (71, 76))	('EMT', 'biological_process', 'GO:0001837', ('50', '53'))	('RIPK4', 'Gene', '54101', (40, 45))	('beta-catenin', 'Gene', (160, 172))	('beta-catenin', 'Gene', '1499', (160, 172))	('increased', 'PosReg', (179, 188))	('fibronectin', 'Gene', (237, 248))	('vimentin', 'cellular_component', 'GO:0045099', ('253', '261'))	('silencing', 'Var', (61, 70))	('E-cadherin', 'Gene', (145, 155))	('E-cadherin', 'Gene', '999', (145, 155))	('vimentin', 'Gene', '7431', (253, 261))	('decreased', 'NegReg', (268, 277))	('fibronectin', 'Gene', '2335', (237, 248))	('vimentin', 'Gene', (253, 261))	('levels', 'MPA', (202, 208))	('cadherin', 'molecular_function', 'GO:0008014', ('147', '155'))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('RIPK4', 'Gene', (71, 76))	('RIPK4', 'Gene', (40, 45))	('vimentin', 'cellular_component', 'GO:0045098', ('253', '261'))
105754	29867225	Western blotting also showed that knocking down RIPK4 using shRIPK4 transfection downregulated the VEGF-A level and increased the abundance of CD82 in T24 and RT4 cells significantly (Fig.	('RIPK4', 'Gene', (48, 53))	('RIPK4', 'Gene', (62, 67))	('VEGF-A', 'Gene', (99, 105))	('downregulated', 'NegReg', (81, 94))	('CD82', 'Gene', '3732', (143, 147))	('RIPK4', 'Gene', '54101', (62, 67))	('RIPK4', 'Gene', '54101', (48, 53))	('increased', 'PosReg', (116, 125))	('abundance', 'MPA', (130, 139))	('VEGF-A', 'Gene', '7422', (99, 105))	('CD82', 'Gene', (143, 147))	('knocking down', 'Var', (34, 47))
105755	29867225	Consistently, overexpression of RIPK4 by pcDNA-RIPK4 transfection significantly upregulated the VEGF-A level and decreased the CD82 level in BIU87 cells (Fig.	('transfection', 'Var', (53, 65))	('RIPK4', 'Gene', '54101', (32, 37))	('RIPK4', 'Gene', '54101', (47, 52))	('VEGF-A', 'Gene', '7422', (96, 102))	('VEGF-A', 'Gene', (96, 102))	('RIPK4', 'Gene', (32, 37))	('CD82', 'Gene', '3732', (127, 131))	('RIPK4', 'Gene', (47, 52))	('BIU87', 'Chemical', '-', (141, 146))	('upregulated', 'PosReg', (80, 91))	('CD82', 'Gene', (127, 131))	('overexpression', 'PosReg', (14, 28))	('decreased', 'NegReg', (113, 122))
105767	29867225	Overexpression of RIPK4 increased the activity of the NF-kappaB luciferase reporter gene significantly, whereas silencing of RIPK4 reduced the reporter activity significantly (Fig.	('NF-kappaB', 'Gene', (54, 63))	('activity', 'MPA', (38, 46))	('RIPK4', 'Gene', (125, 130))	('activity', 'MPA', (152, 160))	('reduced', 'NegReg', (131, 138))	('RIPK4', 'Gene', '54101', (18, 23))	('silencing', 'Var', (112, 121))	('NF-kappaB', 'Gene', '4790', (54, 63))	('RIPK4', 'Gene', '54101', (125, 130))	('RIPK4', 'Gene', (18, 23))	('increased', 'PosReg', (24, 33))
105769	29867225	By contrast, after the ectopic overexpression of RIPK4 in BIU87 cells, the level of NF-kappaB-p65 increased, whereas silencing of RIPK4 decreased the amount of NF-kappaB-p65, as evidenced by immunofluorescence staining (Fig.	('RIPK4', 'Gene', (49, 54))	('NF-kappaB', 'Gene', (160, 169))	('p65', 'Gene', (170, 173))	('NF-kappaB', 'Gene', '4790', (84, 93))	('NF-kappaB', 'Gene', (84, 93))	('silencing', 'Var', (117, 126))	('p65', 'Gene', '5970', (94, 97))	('BIU87', 'Chemical', '-', (58, 63))	('RIPK4', 'Gene', '54101', (130, 135))	('RIPK4', 'Gene', '54101', (49, 54))	('p65', 'Gene', '5970', (170, 173))	('increased', 'PosReg', (98, 107))	('RIPK4', 'Gene', (130, 135))	('NF-kappaB', 'Gene', '4790', (160, 169))	('p65', 'Gene', (94, 97))	('overexpression', 'PosReg', (31, 45))	('level', 'MPA', (75, 80))	('decreased', 'NegReg', (136, 145))
105784	29867225	Importantly, positivity for p-p65 was associated with poor survival in this BC cohort (P = 0.001, Supplementary Figure S3C).	('positivity', 'Var', (13, 23))	('p65', 'Gene', (30, 33))	('poor', 'NegReg', (54, 58))	('p65', 'Gene', '5970', (30, 33))	('survival', 'MPA', (59, 67))
105795	29867225	Silencing RIPK4 dramatically reduced, whereas overexpressing RIPK4 promoted, NF-kappaB activity.	('RIPK4', 'Gene', '54101', (61, 66))	('NF-kappaB', 'Gene', (77, 86))	('RIPK4', 'Gene', (61, 66))	('reduced', 'NegReg', (29, 36))	('RIPK4', 'Gene', '54101', (10, 15))	('Silencing', 'Var', (0, 9))	('RIPK4', 'Gene', (10, 15))	('NF-kappaB', 'Gene', '4790', (77, 86))
105799	29867225	Liu and colleagues reported that RIPK4 is overexpressed in cervical squamous cell cancer, and RIPK4 knockdown in vitro reduced cell migration and invasion.	('cell migration', 'CPA', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('knockdown', 'Var', (100, 109))	('cervical squamous cell cancer', 'Disease', (59, 88))	('overexpressed', 'PosReg', (42, 55))	('cervical squamous cell cancer', 'Disease', 'MESH:D002294', (59, 88))	('RIPK4', 'Gene', (94, 99))	('RIPK4', 'Gene', (33, 38))	('cell migration', 'biological_process', 'GO:0016477', ('127', '141'))	('RIPK4', 'Gene', '54101', (33, 38))	('RIPK4', 'Gene', '54101', (94, 99))	('reduced', 'NegReg', (119, 126))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (68, 88))	('invasion', 'CPA', (146, 154))
105804	29867225	Overexpressing RIPK4 promoted, but silencing RIPK4 reduced, BC EMT and invasion/metastasis.	('RIPK4', 'Gene', '54101', (15, 20))	('silencing', 'Var', (35, 44))	('reduced', 'NegReg', (51, 58))	('RIPK4', 'Gene', (45, 50))	('promoted', 'PosReg', (21, 29))	('RIPK4', 'Gene', (15, 20))	('invasion/metastasis', 'CPA', (71, 90))	('BC EMT', 'CPA', (60, 66))	('RIPK4', 'Gene', '54101', (45, 50))	('EMT', 'biological_process', 'GO:0001837', ('63', '66'))
105812	29867225	Recently, angiogenesis was identified an effective and important target of pharmacological strategies against BC; for example, using monoclonal antibodies against VEGF and the VEGF receptor.	('VEGF', 'Gene', (176, 180))	('angiogenesis', 'biological_process', 'GO:0001525', ('10', '22'))	('monoclonal antibodies', 'Var', (133, 154))	('VEGF', 'Gene', (163, 167))	('VEGF', 'Gene', '7422', (176, 180))	('VEGF', 'Gene', '7422', (163, 167))
105819	29867225	also demonstrated that RIPK4 upregulation in various diffuse large B-cell lymphoma cell lines caused activation of NF-kappaB, whereas RIPK4 inactivation led to a suppression of NF-kappaB, increased survival in vitro and sensitisation of these cell lines cells to treatment with chemotherapeutic agents.	('inactivation', 'Var', (140, 152))	('RIPK4', 'Gene', '54101', (23, 28))	('suppression', 'NegReg', (162, 173))	('RIPK4', 'Gene', '54101', (134, 139))	('NF-kappaB', 'Gene', (177, 186))	('activation', 'PosReg', (101, 111))	('lymphoma', 'Phenotype', 'HP:0002665', (74, 82))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('101', '124'))	('upregulation', 'PosReg', (29, 41))	('RIPK4', 'Gene', (23, 28))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (67, 82))	('RIPK4', 'Gene', (134, 139))	('NF-kappaB', 'Gene', '4790', (115, 124))	('NF-kappaB', 'Gene', (115, 124))	('increased', 'PosReg', (188, 197))	('survival', 'CPA', (198, 206))	('NF-kappaB', 'Gene', '4790', (177, 186))
105827	29867225	Combined with the data from previous studies, the results presented here provided strong evidence that RIPK4 dysregulation has important roles in many pathological processes.	('dysregulation', 'Var', (109, 122))	('RIPK4', 'Gene', '54101', (103, 108))	('roles', 'Reg', (137, 142))	('RIPK4', 'Gene', (103, 108))
105828	29867225	Moreover, our results showed that high expression of RIPK4 is a novel and independent prognostic factor for patients with BC, enabling clinicians to identify high-risk patients that require more intensive treatment.	('RIPK4', 'Gene', '54101', (53, 58))	('RIPK4', 'Gene', (53, 58))	('high', 'Var', (34, 38))	('patients', 'Species', '9606', (168, 176))	('patients', 'Species', '9606', (108, 116))
105846	28345830	All patients were categorized according to age, gender, histologic grade, tumor configuration, microscopic tumor extension (primary tumor, pT), recurrent tumors and patient age; <=40 years, 41 to 50 years, 51 to 60 years, 61 to 70 years, 71 to 80 years, and >81 years.	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', (74, 79))	('<=40 years', 'Var', (178, 188))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('patients', 'Species', '9606', (4, 12))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('patient', 'Species', '9606', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('to 7', 'Species', '1214577', (225, 229))	('tumors', 'Disease', (154, 160))	('patient', 'Species', '9606', (4, 11))
105912	26278805	Tumor and germline DNA from patients with UTUC (n = 83) and UCB (n = 102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy-number alterations in 300 cancer-associated genes.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', (201, 207))	('rat', 'Species', '10116', (186, 189))	('mutations', 'Var', (156, 165))	('UCB', 'Phenotype', 'HP:0006740', (60, 63))	('rat', 'Species', '10116', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('copy-number alterations', 'Var', (170, 193))	('patients', 'Species', '9606', (28, 36))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
105913	26278805	We described co-mutation patterns and copy-number alterations in UTUC.	('rat', 'Species', '10116', (54, 57))	('copy-number alterations', 'Var', (38, 61))	('co-mutation', 'Var', (13, 24))
105921	26278805	Comparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('upper tract urothelial carcinoma', 'Disease', (44, 76))	('cancer', 'Disease', (170, 176))	('mutations', 'Var', (139, 148))	('rat', 'Species', '10116', (23, 26))	('urothelial bladder cancer', 'Disease', (89, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('bladder cancer', 'Phenotype', 'HP:0009725', (100, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (89, 114))	('rat', 'Species', '10116', (265, 268))	('cancer', 'Disease', (108, 114))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (44, 76))
105922	26278805	UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('rat', 'Species', '10116', (38, 41))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
105942	26278805	For putative tumor suppressors, we included truncating mutations (nonsense, frameshift indels) and deletions.	('tumor', 'Disease', (13, 18))	('deletions', 'Var', (99, 108))	('frameshift indels', 'Var', (76, 93))	('truncating', 'MPA', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
105947	26278805	Analysis identified a hotspot mutation of the exonuclease domain of polymerase (DNA directed), epsilon, catalytic subunit (POLE), V411L, previously reported to be associated with an ultramutated phenotype in endometrial and colorectal cancers.	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('colorectal cancers', 'Disease', 'MESH:D015179', (224, 242))	('V411L', 'Mutation', 'rs765164423', (130, 135))	('endometrial', 'Disease', (208, 219))	('associated', 'Reg', (163, 173))	('V411L', 'Var', (130, 135))	('colorectal cancers', 'Disease', (224, 242))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
105951	26278805	All mutations identified in FGFR3, tuberous sclerosis 1 (TSC1), AT rich interactive domain 1A (SWI-like) (ARID1A), CREB binding protein (CREBBP), Harvey rat sarcoma viral oncogene homolog (HRAS), KDM6A, KMT2D, TP53, inositol polyphosphate-4-phosphatase, type I, 107kDa (INPP4A), and phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) were subsequently confirmed using an orthogonal MiSeq-based assay with 100% concordance.	('tuberous sclerosis 1', 'Gene', '60445', (35, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('INPP4A', 'Gene', '80849', (270, 276))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('CREB binding protein', 'Gene', '54244', (115, 135))	('INPP4A', 'Gene', (270, 276))	('rat', 'Species', '10116', (153, 156))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('tuberous sclerosis 1', 'Gene', (35, 55))	('AT', 'Disease', 'None', (64, 66))	('FGFR3', 'Gene', (28, 33))	('sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('phosphatase', 'molecular_function', 'GO:0016791', ('241', '252'))	('CREB binding protein', 'Gene', (115, 135))	('mutations', 'Var', (4, 13))	('CREB binding', 'molecular_function', 'GO:0008140', ('115', '127'))	('sarcoma', 'Disease', (157, 164))
105952	26278805	We also identified five intrachromosomal FGFR3-transforming, acidic coiled-coil containing protein 3 (TACC3) translocations predicted to result in activating gene fusions.	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('TACC3', 'Gene', (102, 107))	('FGFR3-transforming, acidic coiled-coil containing protein 3', 'Gene', '10460', (41, 100))	('activating gene fusions', 'MPA', (147, 170))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('translocations', 'Var', (109, 123))	('TACC3', 'Gene', '10460', (102, 107))
105958	26278805	A higher frequency of FGFR3-TACC3 fusions was identified in the UTUC cohort (8.5% vs 2.0%).	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('TACC3', 'Gene', '10460', (28, 33))	('fusions', 'Var', (34, 41))	('TACC3', 'Gene', (28, 33))
105960	26278805	Strikingly, we detected no retinoblastoma 1 (RB1) mutations in the UTUC cohort compared with an 18.6% frequency in UCB tumors (p < 0.001).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('UCB', 'Phenotype', 'HP:0006740', (115, 118))	('UCB tumors', 'Disease', (115, 125))	('mutations', 'Var', (50, 59))	('UCB tumors', 'Disease', 'MESH:D009369', (115, 125))	('retinoblastoma', 'Phenotype', 'HP:0009919', (27, 41))	('retinoblastoma 1 (RB1', 'Gene', '5925', (27, 48))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
105961	26278805	We also identified fewer TP53/MDM2 proto-oncogene, E3 ubiquitin protein ligase (MDM2) alterations in the UTUC cohort (35.6% vs 62.7%; p = 0.001).	('MDM2', 'Gene', (80, 84))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('MDM2', 'Gene', '4193', (30, 34))	('fewer', 'NegReg', (19, 24))	('ubiquitin', 'molecular_function', 'GO:0031386', ('54', '63'))	('MDM2', 'Gene', (30, 34))	('alterations', 'Var', (86, 97))	('MDM2', 'Gene', '4193', (80, 84))	('rat', 'Species', '10116', (90, 93))
105963	26278805	We also identified a trend toward differences between the UTUC and UCB cohorts in the frequency of alterations in several additional driver oncogenes and tumor suppressors including TSC1 (11.9% vs 3.9%; p = 0.100) and PIK3CA (10.2% vs 21.6%; p = 0.084).	('rat', 'Species', '10116', (103, 106))	('differences', 'Reg', (34, 45))	('alterations', 'Var', (99, 110))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('TSC1', 'Gene', (182, 186))	('UCB', 'Phenotype', 'HP:0006740', (67, 70))	('tumor', 'Disease', (154, 159))
105964	26278805	Consistent with recent next-generation sequencing analyses of UCB tumors, we also identified frequent mutations in chromatin-modifying genes (CMGs) including the histone demethylase KDM6A, the histone methyltransferases KMT2A (MLL), KMT2D (MLL2), and lysine (K)-specific methyltransferase 2C (KMT2C) (MLL3), the histone acetyltransferases CREBBP and E1A binding protein p300 (EP300), and the SWI/SNF complex genes ARID1A and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4).	('chromatin', 'cellular_component', 'GO:0000785', ('115', '124'))	('rat', 'Species', '10116', (32, 35))	('EP300', 'Gene', '2033', (376, 381))	('protein', 'cellular_component', 'GO:0003675', ('362', '369'))	('MLL', 'Gene', (240, 243))	('MLL', 'Gene', '4297', (240, 243))	('ARID1A', 'Gene', (414, 420))	('MLL', 'Gene', (301, 304))	('SMARCA4', 'Gene', (524, 531))	('MLL', 'Gene', '4297', (301, 304))	('MLL3', 'Gene', (301, 305))	('UCB tumors', 'Disease', 'MESH:D009369', (62, 72))	('KMT2A', 'Gene', (220, 225))	('binding', 'molecular_function', 'GO:0005488', ('354', '361'))	('UCB', 'Phenotype', 'HP:0006740', (62, 65))	('mutations', 'Var', (102, 111))	('EP300', 'Gene', (376, 381))	('methyltransferase 2', 'molecular_function', 'GO:0043851', ('271', '290'))	('SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4', 'Gene', '6597', (425, 522))	('KMT2A', 'Gene', '4297', (220, 225))	('UCB tumors', 'Disease', (62, 72))	('lysine (K)-specific methyltransferase 2C', 'Gene', '58508', (251, 291))	('KDM6A', 'Gene', (182, 187))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('E1A binding protein p300', 'Gene', (350, 374))	('KMT2C', 'Gene', '58508', (293, 298))	('KMT2C', 'Gene', (293, 298))	('SMARCA4', 'Gene', '6597', (524, 531))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('392', '407'))	('MLL2', 'Gene', '8085', (240, 244))	('E1A binding protein p300', 'Gene', '2033', (350, 374))	('chromatin', 'cellular_component', 'GO:0000785', ('490', '499'))	('MLL', 'Gene', (227, 230))	('MLL', 'Gene', '4297', (227, 230))	('MLL3', 'Gene', '58508', (301, 305))	('MLL2', 'Gene', (240, 244))
105965	26278805	With the exception of ARID1A, there was no significant difference in the frequency of mutations in these CMGs in UTUC versus UCB tumors.	('CMGs', 'Gene', (105, 109))	('mutations', 'Var', (86, 95))	('UCB tumors', 'Disease', (125, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('UCB tumors', 'Disease', 'MESH:D009369', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('UTUC', 'Disease', (113, 117))	('UCB', 'Phenotype', 'HP:0006740', (125, 128))
105968	26278805	These results in UTUC are consistent with previously reported data suggesting an association between aneuploidy and TP53 mutation in UCB.	('association', 'Interaction', (81, 92))	('TP53', 'Gene', (116, 120))	('UCB', 'Phenotype', 'HP:0006740', (133, 136))	('aneuploidy', 'Disease', (101, 111))	('mutation', 'Var', (121, 129))	('aneuploidy', 'Disease', 'MESH:D000782', (101, 111))
105972	26278805	Notably, TP53 mutations were found exclusively in high-grade tumors, whereas mutations in CMGs were common in both low-grade and high-grade tumors.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Disease', (140, 146))	('found', 'Reg', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('TP53', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CMGs', 'Gene', (90, 94))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (14, 23))
105973	26278805	These latter results suggest that CMG alterations are likely an early event in the pathogenesis of UTUC rather than drivers of progression to high-grade disease.	('pathogenesis', 'biological_process', 'GO:0009405', ('83', '95'))	('CMG', 'Gene', (34, 37))	('alterations', 'Var', (38, 49))	('UTUC', 'Disease', (99, 103))	('rat', 'Species', '10116', (42, 45))	('rat', 'Species', '10116', (104, 107))
105974	26278805	To determine whether the FGFR3 mutations identified were present in morphologically and spatially distinct components of the tumors, we performed microdissection of four UTUC cases to separate tumor components for additional sequencing.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('mutations', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumor', 'Disease', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('rat', 'Species', '10116', (188, 191))	('FGFR3', 'Gene', (25, 30))	('tumor', 'Disease', (193, 198))
105977	26278805	We found that mutations in TP53 (p = 0.008), FGFR3 (p < 0.001), CREBBP (p = 0.04), KMT2C (p = 0.02), and stromal antigen 2 (STAG2) (p = 0.006) were significantly associated with grade.	('KMT2C', 'Gene', (83, 88))	('TP53', 'Gene', (27, 31))	('STAG2', 'Gene', (124, 129))	('grade', 'Disease', (178, 183))	('stromal antigen 2', 'Gene', '10735', (105, 122))	('STAG2', 'Gene', '10735', (124, 129))	('associated', 'Reg', (162, 172))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('stromal antigen 2', 'Gene', (105, 122))	('FGFR3', 'Gene', (45, 50))	('KMT2C', 'Gene', '58508', (83, 88))	('mutations', 'Var', (14, 23))
105978	26278805	Tumors with TP53 mutations were more frequently high grade, whereas those with FGFR3, CREBBP, and STAG2 mutations were more frequently low grade.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('FGFR3', 'Gene', (79, 84))	('STAG2', 'Gene', (98, 103))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('high grade', 'CPA', (48, 58))	('STAG2', 'Gene', '10735', (98, 103))	('TP53', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
105980	26278805	Tumors with TP53, CCND1, ERBB2, ERBB3, and KRAS mutations were more frequently pT3/pT4, whereas those with FGFR3 mutations were more frequently pTa/pT1/pT2.	('pT1', 'Gene', '58492', (148, 151))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('pT3', 'Gene', '7694', (79, 82))	('CCND1', 'Gene', '595', (18, 23))	('pT1', 'Gene', (148, 151))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CCND1', 'Gene', (18, 23))	('ERBB2', 'Gene', (25, 30))	('KRAS', 'Gene', '3845', (43, 47))	('mutations', 'Var', (48, 57))	('Tumors', 'Disease', (0, 6))	('KRAS', 'Gene', (43, 47))	('ERBB2', 'Gene', '2064', (25, 30))	('TP53', 'Gene', (12, 16))	('pTa', 'molecular_function', 'GO:0008959', ('144', '147'))	('ERBB3', 'Gene', (32, 37))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('pT3', 'Gene', (79, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('ERBB3', 'Gene', '2065', (32, 37))
105985	26278805	Our comparison of high-grade UTUC with UCB identified more frequent mutations in FGFR3 and HRAS and less prevalent mutations in TP53 and RB1.	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('HRAS', 'Gene', (91, 95))	('RB1', 'Gene', '5925', (137, 140))	('UCB', 'Phenotype', 'HP:0006740', (39, 42))	('FGFR3', 'Gene', (81, 86))	('TP53', 'Gene', (128, 132))	('mutations', 'Var', (68, 77))	('RB1', 'Gene', (137, 140))
105986	26278805	To exclude the possibility that the higher fraction of high-grade UTUC tumors harboring FGFR3 and HRAS mutations was an artifact resulting from intratumoral heterogeneity, we compared multiple histologically and spatially distinct areas of four tumors.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('mutations', 'Var', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Disease', (245, 251))	('HRAS', 'Gene', (98, 102))	('rat', 'Species', '10116', (147, 150))	('tumor', 'Disease', (245, 250))	('tumor', 'Disease', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('FGFR', 'molecular_function', 'GO:0005007', ('88', '92'))	('FGFR3', 'Gene', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
105987	26278805	Also of note, CMG mutations were found at high frequency in low-grade UTUC tumors and in the noninvasive components of two high-grade UTUC tumors, suggesting such events could occur early as one form of disease pathogenesis in some tumors.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('CMG', 'Gene', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('pathogenesis', 'biological_process', 'GO:0009405', ('211', '223'))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('tumors', 'Disease', (232, 238))	('mutations', 'Var', (18, 27))
105989	26278805	In the first, low-grade tumors, which typically harbor mutations in FGFR3 and HRAS, acquire additional genetic and/or epigenetic alterations leading to a high-grade morphology, invasion, and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('high-grade morphology', 'CPA', (154, 175))	('invasion', 'CPA', (177, 185))	('tumors', 'Disease', (24, 30))	('mutations', 'Var', (55, 64))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('epigenetic alterations', 'Var', (118, 140))	('FGFR', 'molecular_function', 'GO:0005007', ('68', '72'))	('FGFR3', 'Gene', (68, 73))	('rat', 'Species', '10116', (133, 136))	('metastasis', 'CPA', (191, 201))	('HRAS', 'Gene', (78, 82))	('leading to', 'Reg', (141, 151))
105990	26278805	Alternatively, high-grade tumors may arise de novo, associated with mutations in TP53 and RB1.	('RB1', 'Gene', (90, 93))	('tumors', 'Disease', (26, 32))	('associated', 'Reg', (52, 62))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('RB1', 'Gene', '5925', (90, 93))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('mutations', 'Var', (68, 77))	('TP53', 'Gene', (81, 85))
105991	26278805	Consistent with this model, we identified activating FGFR3 mutations in 22 of 23 low-grade UTUC tumors.	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('activating', 'PosReg', (42, 52))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('mutations', 'Var', (59, 68))	('FGFR3', 'Gene', (53, 58))
105993	26278805	All five FGFR3-TACC3 translocations in the UTUC cohort were present in high-grade tumors.	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('9', '13'))	('TACC3', 'Gene', '10460', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('present', 'Reg', (60, 67))	('translocations', 'Var', (21, 35))	('TACC3', 'Gene', (15, 20))
105995	26278805	In sum, the results are consistent with a model in which low-grade FGFR3 and HRAS mutant tumors more frequently progress to high-grade invasive disease when they arise in the upper tract versus the bladder.	('progress', 'PosReg', (112, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('FGFR3', 'Gene', (67, 72))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('high-grade invasive disease', 'MPA', (124, 151))	('HRAS', 'Gene', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mutant', 'Var', (82, 88))
105998	26278805	Finally, epigenetic differences and/or differences in gene expression may be more important drivers of disease progression than genomic alterations, a possibility not addressed by our targeted DNA sequencing approach.	('DNA', 'cellular_component', 'GO:0005574', ('193', '196'))	('gene expression', 'MPA', (54, 69))	('epigenetic differences', 'Var', (9, 31))	('gene expression', 'biological_process', 'GO:0010467', ('54', '69'))	('rat', 'Species', '10116', (140, 143))
106000	26278805	Although the spectrum of genes mutated in UTUC and UCB was similar, we identified differences in the prevalence of alterations in several recurrently mutated genes including FGFR3, HRAS, TP53, and RB1.	('FGFR', 'molecular_function', 'GO:0005007', ('174', '178'))	('HRAS', 'Gene', (181, 185))	('RB1', 'Gene', (197, 200))	('FGFR3', 'Gene', (174, 179))	('alterations', 'Var', (115, 126))	('rat', 'Species', '10116', (119, 122))	('TP53', 'Gene', (187, 191))	('UCB', 'Phenotype', 'HP:0006740', (51, 54))	('RB1', 'Gene', '5925', (197, 200))
106004	26278805	Comparison with high-grade bladder cancer identified more frequent FGFR3, HRAS, and CDKN2B alterations and fewer TP53 and RB1 mutations in high-grade UTUC.	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('CDKN2B', 'Gene', (84, 90))	('fewer', 'NegReg', (107, 112))	('FGFR3', 'Gene', (67, 72))	('RB1', 'Gene', '5925', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('rat', 'Species', '10116', (95, 98))	('bladder cancer', 'Phenotype', 'HP:0009725', (27, 41))	('alterations', 'Var', (91, 102))	('bladder cancer', 'Disease', 'MESH:D001749', (27, 41))	('mutations', 'Var', (126, 135))	('RB1', 'Gene', (122, 125))	('HRAS', 'Gene', (74, 78))	('TP53', 'Gene', (113, 117))	('bladder cancer', 'Disease', (27, 41))
106132	31921631	In the RCx patients, high NLR was negatively associated with both disease status (extravesical extension and lymph-node positivity, OR: 1.14 and 1.43, respectively) and oncological outcomes [overall survival (OS), PFS], and cancer specific survival (CSS, HR: 1.18, 1.12, and 1.35, respectively).	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('high', 'Var', (21, 25))	('overall survival', 'CPA', (191, 207))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('patients', 'Species', '9606', (11, 19))	('negatively', 'NegReg', (34, 44))	('NLR', 'Gene', (26, 29))	('cancer', 'Disease', (224, 230))
106148	31921631	Some studies have suggested a link between high NLR with the pathologic stage of urothelial carcinoma, including muscle invasiveness, extravesical extension, and lymph-node positivity.	('high', 'Var', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('lymph-node positivity', 'Disease', (162, 183))	('NLR', 'Gene', (48, 51))	('muscle invasiveness', 'Disease', 'MESH:D019042', (113, 132))	('urothelial carcinoma', 'Disease', (81, 101))	('muscle invasiveness', 'Disease', (113, 132))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (81, 101))	('extravesical extension', 'Disease', (134, 156))
106239	31334127	In the survival analysis, we observed that patients with higher mRNAsi scores had better overall survival than those with lower mRNAsi scores (Figure 1E).	('patients', 'Species', '9606', (43, 51))	('mRNAsi', 'Var', (64, 70))	('better', 'PosReg', (82, 88))	('overall survival', 'MPA', (89, 105))
106273	31334127	In our survival analysis, we found that patients with higher corrected mRNAsi scores had lower overall survival rates, which was consistent with the poor prognosis associated with CSC characteristics.	('lower', 'NegReg', (89, 94))	('mRNAsi', 'Gene', (71, 77))	('patients', 'Species', '9606', (40, 48))	('overall survival', 'MPA', (95, 111))	('corrected', 'Var', (61, 70))
106299	31334127	Silencing of CDCA5 inhibits cell proliferation and induces G2/M cell cycle arrest in vitro, possibly through inhibition of the ERK/AKT pathway.	('cell proliferation', 'biological_process', 'GO:0008283', ('28', '46'))	('AKT', 'Gene', '207', (131, 134))	('CDCA5', 'Gene', (13, 18))	('ERK', 'Gene', '2048', (127, 130))	('G2/M cell cycle arrest', 'CPA', (59, 81))	('cell proliferation', 'CPA', (28, 46))	('AKT', 'Gene', (131, 134))	('induces', 'Reg', (51, 58))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('inhibition', 'NegReg', (109, 119))	('CDCA5', 'Gene', '113130', (13, 18))	('ERK', 'molecular_function', 'GO:0004707', ('127', '130'))	('ERK', 'Gene', (127, 130))	('inhibits', 'NegReg', (19, 27))	('Silencing', 'Var', (0, 9))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('64', '81'))
106329	29556581	The following beam arrangements were used: A30R, A10R, A15L, A40L, A65L, left lateral, P60L, P40L, P20L, and a posterior beam, wherein A vs. P designates anterior versus posterior and L vs. R designates left versus right of midline.	('A15L', 'Var', (55, 59))	('P40', 'cellular_component', 'GO:0043514', ('93', '96'))	('P60L', 'Var', (87, 91))	('P40L', 'Var', (93, 97))	('P40L', 'Mutation', 'p.P40L', (93, 97))	('A30R', 'Mutation', 'p.A30R', (43, 47))	('A10R', 'Mutation', 'p.A10R', (49, 53))	('A65L', 'Var', (67, 71))	('P20L', 'Mutation', 'p.P20L', (99, 103))	('A15L', 'Mutation', 'p.A15L', (55, 59))	('P20L', 'Var', (99, 103))	('A40L', 'Mutation', 'p.A40L', (61, 65))	('A65L', 'Mutation', 'p.A65L', (67, 71))	('midline', 'cellular_component', 'GO:0031430', ('224', '231'))	('A10R', 'Var', (49, 53))	('P60L', 'Mutation', 'rs199686405', (87, 91))	('P40', 'cellular_component', 'GO:0070743', ('93', '96'))	('A40L', 'Var', (61, 65))	('A30R', 'Var', (43, 47))
106330	29556581	Key constraint objectives with actual achieved values included cord V21.9 Gy [cc] < .03 cc (0 cc achieved), skin V30 Gy [cc] < 10 cc (0 cc achieved), stomach V16.5 Gy [cc] < 10 cc (0 cc achieved), small bowel V17.7 Gy [cc] < 5 cc (1.71 cc achieved), and V25.2 Gy [cc] < .03 cc (0 cc achieved), colon V 28.2 Gy [cc] < 1 cc (0.65 cc achieved), and V24 Gy [cc] < 20 cc (13.16 cc achieved), right kidney V10.5 Gy [%] <66% (0% achieved), and liver CV19.2 Gy [cc] > 700 cc (1299.4 cc achieved).	('small bowel V17', 'Disease', 'MESH:D015212', (197, 212))	('V25.2', 'Var', (254, 259))	('V10.5 Gy [%] <', 'Var', (400, 414))	('small bowel V17', 'Disease', (197, 212))	('V24', 'Var', (346, 349))
106363	20299035	Median time between prostate and bladder cancer diagnoses was longer in irradiated versus nonirradiated patients (59 months [IQR 25-88] versus 24 months [IQR 2-87], p = 0.007).	('bladder cancer', 'Disease', 'MESH:D001749', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('irradiated', 'Var', (72, 82))	('bladder cancer', 'Disease', (33, 47))	('prostate', 'Disease', (20, 28))	('bladder cancer', 'Phenotype', 'HP:0009725', (33, 47))	('patients', 'Species', '9606', (104, 112))
106392	20299035	The median time from prostate to bladder cancer diagnosis was longer in irradiated (n = 83) versus nonirradiated (n = 61) patients (59 months [IQR 25-88] versus 24 months [IQR 2- 87], p = 0.007).	('bladder cancer', 'Disease', 'MESH:D001749', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('irradiated', 'Var', (72, 82))	('bladder cancer', 'Disease', (33, 47))	('patients', 'Species', '9606', (122, 130))	('prostate', 'Disease', (21, 29))	('bladder cancer', 'Phenotype', 'HP:0009725', (33, 47))
106403	20299035	With regards to tumor location, irradiated patients had a higher risk of having urothelial cancer in the trigone or bladder neck area than nonirradiated patients (27% versus 0%, p = 0.007).	('neck', 'cellular_component', 'GO:0044326', ('124', '128'))	('urothelial cancer', 'Disease', 'MESH:D014523', (80, 97))	('patients', 'Species', '9606', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('patients', 'Species', '9606', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('irradiated', 'Var', (32, 42))	('tumor', 'Disease', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('urothelial cancer', 'Disease', (80, 97))
106421	20299035	Radiation has been shown to be associated with in vitro progression of low grade to high grade urothelial tumors and a higher rate of p53 mutations.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('low grade', 'CPA', (71, 80))	('p53', 'Gene', '7157', (134, 137))	('urothelial tumors', 'Disease', (95, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('p53', 'Gene', (134, 137))	('urothelial tumors', 'Disease', 'MESH:D001749', (95, 112))	('mutations', 'Var', (138, 147))
106453	20299035	They determined the relative risk of bladder cancer developing after EBRT, BT, and EBRT-BT compared to RP was 1.88, 1.52, and 1.85, respectively.	('BT', 'Chemical', 'MESH:C005465', (75, 77))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('bladder cancer', 'Phenotype', 'HP:0009725', (37, 51))	('BT', 'Chemical', 'MESH:C005465', (88, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (37, 51))	('bladder cancer', 'Disease', (37, 51))	('EBRT', 'Chemical', '-', (83, 87))	('EBRT', 'Chemical', '-', (69, 73))	('EBRT-BT', 'Var', (83, 90))
106475	24868547	After synthesis and modifications of uroplakins in the endoplasmic reticulum and the Golgi apparatus, respectively, urothelial plaques are gradually assembled in post-Golgi compartments.	('uroplakins in the endoplasmic reticulum', 'Disease', 'MESH:D008228', (37, 76))	('uroplakins in the endoplasmic reticulum', 'Disease', (37, 76))	('synthesis', 'biological_process', 'GO:0009058', ('6', '15'))	('Golgi apparatus', 'cellular_component', 'GO:0005794', ('85', '100'))	('Golgi', 'cellular_component', 'GO:0005794', ('167', '172'))	('modifications', 'Var', (20, 33))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('55', '76'))
106500	24868547	Immunolabeling was performed using the same antibodies as for Western blotting: antibodies against uroplakins (1 : 10.000), P2X3 (1 : 1000), P2X5 (1 : 200), TRPV1 (1 : 200), and TRPV4 (1 : 500).	('1 : 200', 'Var', (164, 171))	('P2X5', 'Gene', '5026', (141, 145))	('TRPV1', 'Gene', '7442', (157, 162))	('TRPV1', 'Gene', (157, 162))	('P2X3', 'Gene', (124, 128))	('1 : 10.000', 'Var', (111, 121))	('TRPV4', 'Gene', (178, 183))	('TRPV4', 'Gene', '59341', (178, 183))	('P2X5', 'Gene', (141, 145))	('P2X3', 'Gene', '5024', (124, 128))
106588	32580248	Comprehensive analysis of multicomponent data across reformed and current smokers identified a total of 85 differential expressed genes (DEGs) affected by different modes of genetic and epigenetic regulation, potentially representing cancer drivers in smokers.	('epigenetic', 'Var', (186, 196))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('regulation', 'biological_process', 'GO:0065007', ('197', '207'))	('affected', 'Reg', (143, 151))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))	('differential expressed genes', 'MPA', (107, 135))
106596	32580248	In addition to causing frequent gene mutations, tobacco smoking also appears to break the immune homeostasis, which may contribute to tumorigenesis [6].	('homeostasis', 'biological_process', 'GO:0042592', ('97', '108'))	('contribute', 'Reg', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('immune homeostasis', 'MPA', (90, 108))	('tobacco', 'Species', '4097', (48, 55))	('break', 'NegReg', (80, 85))	('tumor', 'Disease', (134, 139))
106613	32580248	In age-adjusted models, quitting smoking was significantly associated with longer survival time in CESC, HNSC, LUSC, and PAAD.	('longer', 'PosReg', (75, 81))	('HNSC', 'Phenotype', 'HP:0012288', (105, 109))	('LUSC', 'Disease', (111, 115))	('LUSC', 'Phenotype', 'HP:0030359', (111, 115))	('CESC', 'Disease', (99, 103))	('quitting', 'Var', (24, 32))	('HNSC', 'Disease', (105, 109))	('PAAD', 'Phenotype', 'HP:0006725', (121, 125))	('LUSC', 'Chemical', '-', (111, 115))	('PAAD', 'Disease', (121, 125))
106645	32580248	Many studies confirmed that variants in LIG1 may predispose to smoking-related lung cancer [31, 32].	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('predispose', 'Reg', (49, 59))	('variants', 'Var', (28, 36))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('LIG1', 'Gene', (40, 44))	('LIG1', 'Gene', '3978', (40, 44))
106664	32580248	confirmed that patients with high mutational smoking signature had poorer overall survival in HNSC (HR = 1.50, 95% CI = 1.23-1.81, P < 0.01), but the mutational smoking signature was not prognostic in LUSC (HR = 1.02, 95% CI = 0.71-1.46, P = 0.92) [52] and LUAD (HR = 1.18, 95% CI = 0.46-3.04, P = 0.74).	('LUAD', 'Phenotype', 'HP:0030078', (257, 261))	('patients', 'Species', '9606', (15, 23))	('high mutational', 'Var', (29, 44))	('LUAD', 'Disease', (257, 261))	('LUSC', 'Phenotype', 'HP:0030359', (201, 205))	('LUSC', 'Disease', (201, 205))	('HNSC', 'Disease', (94, 98))	('mutational', 'Var', (34, 44))	('poorer', 'NegReg', (67, 73))	('overall', 'MPA', (74, 81))	('LUSC', 'Chemical', '-', (201, 205))	('HNSC', 'Phenotype', 'HP:0012288', (94, 98))
106754	30501131	The regulation of miRNAs has been evaluated at different levels, including in studies of genetic mutations, epigenetic modifications, and alterations in the microprocessor components, such as DROSHA, DGCR8, and DICER1.	('DGCR8', 'Gene', (200, 205))	('mutations', 'Var', (97, 106))	('regulation', 'biological_process', 'GO:0065007', ('4', '14'))	('DROSHA', 'Gene', '29102', (192, 198))	('DROSHA', 'Gene', (192, 198))	('DGCR8', 'Gene', '54487', (200, 205))	('DICER1', 'Gene', (211, 217))	('DICER1', 'Gene', '23405', (211, 217))
106777	30501131	For each cancer type, we investigated whether miRNAs tend to be present in the SCNA regions because previous studies showed that miRNAs are more likely to be found in copy number-altered regions.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('copy number-altered', 'Var', (167, 186))
106780	30501131	Furthermore, we calculated the fractions of genomic regions with SCNAs across all genomes, which were shown to be higher than the fractions of miRNAs with SCNAs in all cancer types except for in KIRC samples.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('SCNAs', 'Var', (65, 70))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))
106806	30501131	investigated the co-deletion of mir-491 and CDKN2A in glioblastoma and demonstrated that the deletion of mir-491 was not just a passenger event and that mir-491 acts as a tumor suppressor.	('mir-491', 'Gene', (153, 160))	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('mir-491', 'Gene', (32, 39))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('CDKN2A', 'Gene', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mir-491', 'Gene', (105, 112))	('mir-491', 'Gene', '574444', (153, 160))	('CDKN2A', 'Gene', '1029', (44, 50))	('mir-491', 'Gene', '574444', (32, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('171', '187'))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('mir-491', 'Gene', '574444', (105, 112))	('deletion', 'Var', (93, 101))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('171', '187'))	('glioblastoma', 'Disease', (54, 66))
106808	30501131	These results suggest that co-deletion of hsa-mir-491 and CDKN2A plays an important role in BLCA, LUAD, and UCEC, and that co-deletion of mir-31 and CDKN2A is a crucial event in BLCA and LUSC.	('co-deletion', 'Var', (27, 38))	('CDKN2A', 'Gene', '1029', (149, 155))	('CDKN2A', 'Gene', (58, 64))	('LUAD', 'Disease', (98, 102))	('UCEC', 'Disease', (108, 112))	('hsa-mir-491', 'Gene', (42, 53))	('BLCA', 'Disease', (92, 96))	('role', 'Reg', (84, 88))	('BLCA', 'Phenotype', 'HP:0002862', (92, 96))	('mir-31', 'Gene', (138, 144))	('CDKN2A', 'Gene', '1029', (58, 64))	('LUSC', 'Phenotype', 'HP:0030359', (187, 191))	('BLCA', 'Disease', (178, 182))	('CDKN2A', 'Gene', (149, 155))	('hsa-mir-491', 'Gene', '574444', (42, 53))	('BLCA', 'Phenotype', 'HP:0002862', (178, 182))	('mir-31', 'Gene', '407035', (138, 144))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('co-deletion', 'Var', (123, 134))
106811	30501131	The survival of cancer patients was analyzed to determine whether copy number changes of 80 SCNA-miRNAs were associated with death by cancer (Figure 5).	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('patients', 'Species', '9606', (23, 31))	('cancer', 'Disease', (16, 22))	('cancer', 'Disease', (134, 140))	('SCNA-miRNAs', 'Gene', (92, 103))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('death by cancer', 'Disease', 'MESH:D003643', (125, 140))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('associated with', 'Reg', (109, 124))	('death by cancer', 'Disease', (125, 140))	('copy number changes', 'Var', (66, 85))
106819	30501131	For deleted miRNAs, for mir-31, the mean survival time of patients in the deletion group was shorter than that in the unchanged group of BRCA and KIRC patients (q = 0.0065 and 0.0024, respectively).	('BRCA', 'Gene', (137, 141))	('survival time', 'CPA', (41, 54))	('mir-31', 'Gene', '407035', (24, 30))	('deletion', 'Var', (74, 82))	('mir-31', 'Gene', (24, 30))	('patients', 'Species', '9606', (151, 159))	('shorter', 'NegReg', (93, 100))	('BRCA', 'Phenotype', 'HP:0003002', (137, 141))	('patients', 'Species', '9606', (58, 66))	('BRCA', 'Gene', '672', (137, 141))
106822	30501131	Mir-491 copy number alterations were shown to affect the survival of patients with BRCA and KIRC (q = 0.0071 and 0.023, respectively).	('BRCA', 'Phenotype', 'HP:0003002', (83, 87))	('BRCA', 'Gene', '672', (83, 87))	('Mir-491', 'Gene', '574444', (0, 7))	('Mir-491', 'Gene', (0, 7))	('BRCA', 'Gene', (83, 87))	('affect', 'Reg', (46, 52))	('copy number alterations', 'Var', (8, 31))	('patients', 'Species', '9606', (69, 77))	('survival', 'CPA', (57, 65))
106827	30501131	This suggests that alterations in these SCNA-miRNAs with a q-value < 0.05 affect patient survival by more than other miRNAs (p-value = 0.00254, Fisher's exact test).	('alterations', 'Var', (19, 30))	('patient', 'Species', '9606', (81, 88))	('patient survival', 'CPA', (81, 97))	('affect', 'Reg', (74, 80))
106859	30501131	Our results demonstrate that SCNA-miRNAs are more closely associated with cancer survival compared to other miRNAs.	('SCNA-miRNAs', 'Var', (29, 40))	('associated', 'Reg', (58, 68))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
106908	30501131	Table S1: Analysis of patient survival according to copy numbers of the 84 pairs of SCNA-miRNAs and cancer types.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('copy', 'Var', (52, 56))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patient', 'Species', '9606', (22, 29))
106909	30501131	Table S3: miRNAs commonly correlated with SCNAs across seven cancer types.	('correlated with', 'Reg', (26, 41))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('SCNAs', 'Disease', (42, 47))	('miRNAs', 'Var', (10, 16))
107014	28693610	Secondary EMPD caused by prostatic adenocarcinoma can be distinguished from primary EMPD by p501S (prostein) and GATA3.	('GATA3', 'Gene', (113, 118))	('prostatic adenocarcinoma', 'Disease', 'MESH:D011471', (25, 49))	('prostatic adenocarcinoma', 'Disease', (25, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('GATA3', 'Gene', '2625', (113, 118))	('p501S', 'Var', (92, 97))
107015	28693610	Prostatic adenocarcinoma is positive for p501S but negative for GATA3 whereas EMPD shows an opposite profile.	('GATA3', 'Gene', '2625', (64, 69))	('Prostatic adenocarcinoma', 'Disease', (0, 24))	('negative', 'NegReg', (51, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('Prostatic adenocarcinoma', 'Disease', 'MESH:D011471', (0, 24))	('GATA3', 'Gene', (64, 69))	('p501S', 'Var', (41, 46))
107022	28693610	Anorectal adenocarcinoma and primary vulvar EMPDs showed overlapping profiles in CK7 and CK20 though CK7 negativity favors the former and CK20 negativity favors the latter.	('CK7', 'Gene', (101, 104))	('negativity', 'Var', (105, 115))	('CK7', 'Gene', (81, 84))	('Anorectal adenocarcinoma', 'Disease', (0, 24))	('CK20', 'Gene', (138, 142))	('CK20', 'Gene', '54474', (138, 142))	('CK7', 'Gene', '3855', (101, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('CK7', 'Gene', '3855', (81, 84))	('CK20', 'Gene', '54474', (89, 93))	('Anorectal adenocarcinoma', 'Disease', 'MESH:D012002', (0, 24))	('PDs', 'Chemical', 'MESH:D010165', (46, 49))	('CK20', 'Gene', (89, 93))
107080	33550279	Suppression of p16 alleviates the senescence-associated secretory phenotype Oncogene-induced senescence (OIS) is characterized by increased expression of the cell cycle inhibitor p16, leading to a hallmark cell cycle arrest.	('p16', 'Gene', (15, 18))	('arrest', 'Disease', (217, 223))	('expression', 'MPA', (140, 150))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (206, 223))	('Suppression', 'Var', (0, 11))	('p16', 'Gene', (179, 182))	('cell cycle', 'biological_process', 'GO:0007049', ('158', '168'))	('alleviates', 'NegReg', (19, 29))	('p16', 'Gene', '1029', (15, 18))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('206', '223'))	('senescence', 'biological_process', 'GO:0010149', ('34', '44'))	('Oncogene-induced senescence', 'Disease', (76, 103))	('senescence', 'biological_process', 'GO:0010149', ('93', '103'))	('senescence-associated secretory', 'MPA', (34, 65))	('increased', 'PosReg', (130, 139))	('p16', 'Gene', '1029', (179, 182))	('OIS', 'biological_process', 'GO:0090402', ('105', '108'))	('arrest', 'Disease', 'MESH:D006323', (217, 223))
107082	33550279	Here, we show that knockdown of p16 decreases expression of the SASP factors and pro-inflammatory cytokines IL6 and CXCL8 in multiple models, including OIS and DNA damage-induced senescence.	('OIS', 'biological_process', 'GO:0090402', ('152', '155'))	('knockdown', 'Var', (19, 28))	('IL6', 'molecular_function', 'GO:0005138', ('108', '111'))	('decreases', 'NegReg', (36, 45))	('IL6', 'Gene', '3569', (108, 111))	('DNA', 'cellular_component', 'GO:0005574', ('160', '163'))	('IL6', 'Gene', (108, 111))	('senescence', 'biological_process', 'GO:0010149', ('179', '189'))	('expression', 'MPA', (46, 56))	('CXCL8', 'Gene', '3576', (116, 121))	('p16', 'Gene', (32, 35))	('CXCL8', 'Gene', (116, 121))	('SASP factors', 'Protein', (64, 76))
107090	33550279	Loss of p16 is a common event in human cancer that has been linked to senescence bypass, increased proliferation, and malignant transformation though both canonical and non-canonical (RB-independent) pathways.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('malignant transformation', 'CPA', (118, 142))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('human', 'Species', '9606', (33, 38))	('p16', 'Gene', (8, 11))	('senescence', 'biological_process', 'GO:0010149', ('70', '80'))	('senescence bypass', 'CPA', (70, 87))	('increased', 'PosReg', (89, 98))	('Loss', 'Var', (0, 4))	('proliferation', 'CPA', (99, 112))
107094	33550279	Therefore, changes in LMNB1 expression are tightly linked to SASP gene transcription.	('SASP gene', 'Gene', (61, 70))	('LMNB1', 'Gene', (22, 27))	('linked', 'Reg', (51, 57))	('expression', 'MPA', (28, 38))	('LMNB1', 'Gene', '4001', (22, 27))	('changes', 'Var', (11, 18))	('transcription', 'biological_process', 'GO:0006351', ('71', '84'))
107100	33550279	We found that knockdown of p16 leads to decreased IL6 and CXCL8 (encoding IL8) SASP gene expression in both HRASG12V and BRAFV600E models of OIS.	('IL6', 'Gene', (50, 53))	('CXCL8', 'Gene', '3576', (58, 63))	('expression', 'MPA', (89, 99))	('IL8', 'molecular_function', 'GO:0005153', ('74', '77'))	('HRAS', 'Gene', '3265', (108, 112))	('BRAFV600E', 'Mutation', 'rs113488022', (121, 130))	('CXCL8', 'Gene', (58, 63))	('IL6', 'molecular_function', 'GO:0005138', ('50', '53'))	('p16', 'Gene', (27, 30))	('HRAS', 'Gene', (108, 112))	('IL8', 'Gene', (74, 77))	('IL8', 'Gene', '3576', (74, 77))	('IL6', 'Gene', '3569', (50, 53))	('gene expression', 'biological_process', 'GO:0010467', ('84', '99'))	('OIS', 'biological_process', 'GO:0090402', ('141', '144'))	('knockdown', 'Var', (14, 23))	('decreased', 'NegReg', (40, 49))
107102	33550279	We confirmed these results in p16-wildtype melanoma cells upon knockdown of p16 and in DNA damage-induced senescence.	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('senescence', 'biological_process', 'GO:0010149', ('106', '116'))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('p16', 'Gene', (76, 79))	('knockdown', 'Var', (63, 72))
107104	33550279	Together, our results suggest that p16 may have a role in transcriptionally regulating SASP factors, which has implications for understanding how loss of p16 affects the senescent and tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('p16', 'Gene', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('transcriptionally regulating', 'MPA', (58, 86))	('loss', 'Var', (146, 150))	('affects', 'Reg', (158, 165))	('tumor', 'Disease', (184, 189))	('SASP', 'Protein', (87, 91))
107106	33550279	Knockdown of p16 with BRAFV600E or HRASG12V overexpression (Supplementary Figure 1A) decreased IL6 and CXCL8 expression and suppressed senescence-associated beta-galactosidase (SA-beta-gal) activity and the cell cycle arrest in IMR90 fibroblasts (Figure 1A-1J), a classical model of OIS.	('CXCL8', 'Gene', '3576', (103, 108))	('CXCL8', 'Gene', (103, 108))	('IL6', 'Gene', '3569', (95, 98))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (207, 224))	('OIS', 'biological_process', 'GO:0090402', ('283', '286'))	('activity', 'MPA', (190, 198))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('207', '224'))	('senescence', 'biological_process', 'GO:0010149', ('135', '145'))	('BRAFV600E', 'Mutation', 'rs113488022', (22, 31))	('arrest', 'Disease', (218, 224))	('IMR90', 'CellLine', 'CVCL:0347', (228, 233))	('IL6', 'Gene', (95, 98))	('HRAS', 'Gene', '3265', (35, 39))	('IL6', 'molecular_function', 'GO:0005138', ('95', '98'))	('HRAS', 'Gene', (35, 39))	('beta-galactosidase', 'Gene', '2720', (157, 175))	('beta-galactosidase', 'Gene', (157, 175))	('suppressed', 'NegReg', (124, 134))	('decreased', 'NegReg', (85, 94))	('arrest', 'Disease', 'MESH:D006323', (218, 224))	('BRAFV600E', 'Var', (22, 31))
107108	33550279	Additionally, knockdown of p16 in the BRAFV600E-induced senescence model decreased the expression of other SASP factors including growth factors, proteases, and ligands (Supplementary Figure 1I), suggesting that this is a broader phenomenon not limited to IL6 and CXCL8.	('IL6', 'Gene', (256, 259))	('CXCL8', 'Gene', '3576', (264, 269))	('BRAFV600E', 'Mutation', 'rs113488022', (38, 47))	('decreased', 'NegReg', (73, 82))	('IL6', 'Gene', '3569', (256, 259))	('CXCL8', 'Gene', (264, 269))	('BRAFV600E-induced', 'Var', (38, 55))	('p16', 'Gene', (27, 30))	('IL6', 'molecular_function', 'GO:0005138', ('256', '259'))	('expression', 'MPA', (87, 97))	('knockdown', 'Var', (14, 23))	('senescence', 'biological_process', 'GO:0010149', ('56', '66'))
107110	33550279	To investigate whether the observed decrease in IL6 and CXCL8 is a direct effect of p16 suppression and not simply a consequence of senescence bypass, we knocked down p16 at two time points after oncogene expression (Figure 2A and Supplementary Figure 2A-2C).	('senescence', 'biological_process', 'GO:0010149', ('132', '142'))	('p16', 'Gene', (167, 170))	('knocked', 'Var', (154, 161))	('CXCL8', 'Gene', '3576', (56, 61))	('CXCL8', 'Gene', (56, 61))	('IL6', 'Gene', '3569', (48, 51))	('IL6', 'molecular_function', 'GO:0005138', ('48', '51'))	('IL6', 'Gene', (48, 51))	('suppression', 'NegReg', (88, 99))	('p16', 'Protein', (84, 87))	('decrease', 'NegReg', (36, 44))
107111	33550279	Consistent with observations using knockdown of p16 prior to senescence induction (Figure 1), IL6 and CXCL8 expression were both decreased when p16 was knocked down at later time points (Figure 2E and Supplementary Figure 2H).	('CXCL8', 'Gene', (102, 107))	('CXCL8', 'Gene', '3576', (102, 107))	('senescence', 'biological_process', 'GO:0010149', ('61', '71'))	('IL6', 'molecular_function', 'GO:0005138', ('94', '97'))	('p16', 'Gene', (144, 147))	('IL6', 'Gene', '3569', (94, 97))	('IL6', 'Gene', (94, 97))	('knocked down', 'Var', (152, 164))	('decreased', 'NegReg', (129, 138))
107115	33550279	Consistent with our data in fibroblasts (Figures 1, 2), knockdown of p16 in the melanoma cells also decreased IL6 and CXCL8 (Figure 3B-3D).	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('IL6', 'Gene', '3569', (110, 113))	('p16', 'Gene', (69, 72))	('decreased', 'NegReg', (100, 109))	('CXCL8', 'Gene', '3576', (118, 123))	('CXCL8', 'Gene', (118, 123))	('IL6', 'Gene', (110, 113))	('knockdown', 'Var', (56, 65))	('IL6', 'molecular_function', 'GO:0005138', ('110', '113'))
107116	33550279	Finally, expression of IL6 and CXCL8 was also significantly reduced by stable knockdown of p16 in melanoma cells induced to senesce using etoposide (Figure 3E-3H).	('p16', 'Gene', (91, 94))	('IL6', 'Gene', (23, 26))	('etoposide', 'Chemical', 'MESH:D005047', (138, 147))	('IL6', 'molecular_function', 'GO:0005138', ('23', '26'))	('knockdown', 'Var', (78, 87))	('CXCL8', 'Gene', '3576', (31, 36))	('CXCL8', 'Gene', (31, 36))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('expression', 'MPA', (9, 19))	('reduced', 'NegReg', (60, 67))	('melanoma', 'Disease', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('IL6', 'Gene', '3569', (23, 26))
107121	33550279	Patients were classified according to their CDKN2A status (p16-low or p16-high, see Methods for details) (Table 1), and differential expression analysis was performed independently for each tumor type.	('p16-low', 'Var', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('p16-high', 'Var', (70, 78))	('CDKN2A', 'Gene', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('CDKN2A', 'Gene', '1029', (44, 50))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', (190, 195))
107122	33550279	Note that there were no significant differences in the number of normal and tumor cells between p16-high and p16-low tumors (Supplementary Figure 4A).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumors', 'Disease', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('p16-low', 'Var', (109, 116))	('p16-high', 'Var', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
107123	33550279	Most of the SASP factors profiled in a published database of RAS-induced senescence (including soluble factors and exosomes, 232 total unique genes) (Supplementary Table 1), were significantly downregulated in p16-low tumors (Supplementary Figure 4A and Supplementary Table 2).	('downregulated', 'NegReg', (193, 206))	('p16-low', 'Var', (210, 217))	('soluble', 'cellular_component', 'GO:0005625', ('95', '102'))	('senescence', 'biological_process', 'GO:0010149', ('73', '83'))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
107124	33550279	Gene Set Enrichment Analysis (GSEA) also showed a decrease in 'Senescence Associated Secretory Phenotype, SASP' (Figure 4B) in p16-low tumors.	("SASP'", 'MPA', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	("'Senescence Associated Secretory Phenotype", 'MPA', (62, 104))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('Senescence', 'biological_process', 'GO:0010149', ('63', '73'))	('GSEA', 'Chemical', '-', (30, 34))	('p16-low', 'Var', (127, 134))	('decrease', 'NegReg', (50, 58))
107125	33550279	Interestingly, 4 out of 6 tumors (PAAD, COADREAD, MESO, and BLCA) showed a decrease in pathways related to inflammation and the immune system such as 'Antigen Processing and Presentation' and 'Cytosolic DNA Sensing Pathway' in p16-low tumors (Supplementary Figure 4B).	('p16-low', 'Var', (227, 234))	('inflammation', 'Disease', (107, 119))	('DNA', 'cellular_component', 'GO:0005574', ('203', '206'))	('decrease', 'NegReg', (75, 83))	('tumors', 'Disease', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('pathways', 'Pathway', (87, 95))	('inflammation', 'biological_process', 'GO:0006954', ('107', '119'))	('Antigen Processing and Presentation', 'biological_process', 'GO:0019882', ('151', '186'))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('inflammation', 'Disease', 'MESH:D007249', (107, 119))	('tumors', 'Disease', (235, 241))	("'Cytosolic DNA Sensing Pathway", 'Pathway', (192, 222))
107126	33550279	These data demonstrate that p16 status correlates with expression of SASP factors in human tumor samples.	('p16', 'Var', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('expression', 'MPA', (55, 65))	('SASP factors', 'Protein', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('human', 'Species', '9606', (85, 90))
107127	33550279	Importantly, to rule out the possibility of less senescent tumor cells in the p16-low patient samples, we used GSEA to cross-compare p16-low vs. p16-high expression profiles with a previously published senescence expression signature.	('senescence', 'biological_process', 'GO:0010149', ('202', '212'))	('tumor', 'Disease', (59, 64))	('GSEA', 'Chemical', '-', (111, 115))	('patient', 'Species', '9606', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('p16-low', 'Var', (133, 140))
107131	33550279	To unravel whether this observation is due to a decrease of immune cell infiltration in p16-low vs. p16-high tumors, we compared the number of infiltrating lymphocytes, monocytes, and neutrophils seen on OCT-embedded tissue slides reported by TCGA in 5 out of 6 tumors (note that there is no available data for GBM).	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('immune cell infiltration', 'CPA', (60, 84))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Disease', (262, 268))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('OCT', 'Chemical', 'MESH:C051883', (204, 207))	('decrease', 'NegReg', (48, 56))	('decrease of immune cell', 'Phenotype', 'HP:0002721', (48, 71))	('p16-low', 'Var', (88, 95))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
107132	33550279	No significant differences were observed between p16-low and p16-high tumors (Supplementary Figure 4C).	('p16-low', 'Var', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('p16-high', 'Var', (61, 69))	('tumors', 'Disease', 'MESH:D009369', (70, 76))
107135	33550279	We did not observe a strong correlation between CDKN2A and LMNB1 expression (Figure 4C), suggesting that p16 regulation of this pathway and the SASP in tumors may not be directly through modulation of LMNB1.	('LMNB1', 'Gene', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('regulation', 'biological_process', 'GO:0065007', ('109', '119'))	('LMNB1', 'Gene', (59, 64))	('LMNB1', 'Gene', '4001', (201, 206))	('CDKN2A', 'Gene', '1029', (48, 54))	('CDKN2A', 'Gene', (48, 54))	('p16', 'Var', (105, 108))	('tumors', 'Disease', (152, 158))	('LMNB1', 'Gene', '4001', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
107138	33550279	Here we found that knockdown p16 decreases gene expression of two of the most well characterized SASP factors IL6 and CXCL8, in a manner that is uncoupled from senescence bypass (Figures 1, 2).	('p16', 'Gene', (29, 32))	('gene expression', 'biological_process', 'GO:0010467', ('43', '58'))	('gene expression', 'MPA', (43, 58))	('knockdown', 'Var', (19, 28))	('IL6', 'Gene', '3569', (110, 113))	('senescence', 'biological_process', 'GO:0010149', ('160', '170'))	('CXCL8', 'Gene', '3576', (118, 123))	('decreases', 'NegReg', (33, 42))	('CXCL8', 'Gene', (118, 123))	('IL6', 'Gene', (110, 113))	('IL6', 'molecular_function', 'GO:0005138', ('110', '113'))
107139	33550279	Knockdown of p16 or low expression of CDKN2A in patient tumors was also associated with lower expression of additional SASP factors.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('low', 'NegReg', (20, 23))	('patient', 'Species', '9606', (48, 55))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('CDKN2A', 'Gene', (38, 44))	('lower', 'NegReg', (88, 93))	('expression of', 'MPA', (94, 107))	('p16', 'Var', (13, 16))	('CDKN2A', 'Gene', '1029', (38, 44))
107142	33550279	Importantly, we found that knockdown of p16 decreased SASP gene expression, which was not a consequence of increased LMNB1 expression (Figure 2).	('p16', 'Gene', (40, 43))	('LMNB1', 'Gene', '4001', (117, 122))	('knockdown', 'Var', (27, 36))	('expression', 'MPA', (64, 74))	('LMNB1', 'Gene', (117, 122))	('gene expression', 'biological_process', 'GO:0010467', ('59', '74'))	('SASP gene', 'Gene', (54, 63))	('decreased', 'NegReg', (44, 53))
107144	33550279	Notably, we found that four out of the six tumor types analyzed here have decreased cytosolic DNA sensing pathway signaling in p16-low vs. p16-high tumors (Supplementary Figure 4B); however, no correlation was found between CDKN2A and LMNB1 mRNA expression (Figure 4C), suggesting that additional mechanisms are at play in tumors with low p16 expression.	('LMNB1', 'Gene', '4001', (235, 240))	('tumor', 'Disease', (43, 48))	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cytosolic DNA sensing', 'MPA', (84, 105))	('tumors', 'Phenotype', 'HP:0002664', (323, 329))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('CDKN2A', 'Gene', (224, 230))	('LMNB1', 'Gene', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (323, 329))	('tumors', 'Disease', (148, 154))	('p16-low', 'Var', (127, 134))	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('CDKN2A', 'Gene', '1029', (224, 230))	('tumor', 'Disease', (323, 328))	('tumor', 'Disease', (148, 153))	('tumors', 'Disease', 'MESH:D009369', (323, 329))	('decreased', 'NegReg', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (323, 328))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
107146	33550279	Loss of CDKN2A is often due to deletion or hypermethylation of the locus.	('CDKN2A', 'Gene', (8, 14))	('CDKN2A', 'Gene', '1029', (8, 14))	('Loss', 'NegReg', (0, 4))	('deletion', 'Var', (31, 39))	('hypermethylation', 'Var', (43, 59))
107147	33550279	Interestingly, previous work has suggested that melanomas with low MTAP have decreased cGAS-STING signaling, and MTAP is often co-deleted/silenced with CDKN2A.	('CDKN2A', 'Gene', (152, 158))	('cGAS', 'Gene', '115004', (87, 91))	('CDKN2A', 'Gene', '1029', (152, 158))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('MTAP', 'Gene', (113, 117))	('melanomas', 'Disease', (48, 57))	('MTAP', 'Gene', (67, 71))	('cGAS', 'Gene', (87, 91))	('MTAP', 'Gene', '4507', (113, 117))	('MTAP', 'Gene', '4507', (67, 71))	('low', 'Var', (63, 66))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('decreased', 'NegReg', (77, 86))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))
107149	33550279	Additionally, p16 can negatively regulate TP53 (encoding for p53) at the transcriptional level and also at the protein level by increasing Mdm2-dependent degradation of p53.	('TP53', 'Gene', '7157', (42, 46))	('Mdm2', 'Gene', (139, 143))	('Mdm2', 'Gene', '4193', (139, 143))	('p53', 'Gene', (169, 172))	('TP53', 'Gene', (42, 46))	('p16', 'Var', (14, 17))	('p53', 'Gene', '7157', (169, 172))	('negatively', 'NegReg', (22, 32))	('degradation', 'biological_process', 'GO:0009056', ('154', '165'))	('p53', 'Gene', '7157', (61, 64))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('increasing', 'PosReg', (128, 138))	('p53', 'Gene', (61, 64))
107152	33550279	In this regard, some studies have found that pharmacological inhibition of canonical downstream targets of p16, namely CDK4/6, leads to an induction of SASP factors, recruitment of antitumor immune cells, and senescence, suggesting that p16-loss-mediated regulation of SASP expression and the tumor immune microenvironment may be due to non-canonical (RB-independent) mechanisms.	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('recruitment', 'MPA', (166, 177))	('CDK4/6', 'Gene', (119, 125))	('p16', 'Gene', (107, 110))	('p16-loss-mediated', 'NegReg', (237, 254))	('tumor', 'Disease', (185, 190))	('CDK', 'molecular_function', 'GO:0004693', ('119', '122'))	('regulation', 'biological_process', 'GO:0065007', ('255', '265'))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('CDK4/6', 'Gene', '1019;1021', (119, 125))	('p16-loss-mediated', 'Gene', (237, 254))	('senescence', 'CPA', (209, 219))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('inhibition', 'Var', (61, 71))	('SASP factors', 'Protein', (152, 164))	('tumor', 'Disease', (293, 298))	('induction', 'Reg', (139, 148))	('senescence', 'biological_process', 'GO:0010149', ('209', '219'))
107153	33550279	On the contrary, other authors suggest that inhibition of CDK4/6 alone does not induce a SASP and immunologic responses.	('SASP', 'CPA', (89, 93))	('inhibition', 'Var', (44, 54))	('CDK4/6', 'Gene', '1019;1021', (58, 64))	('induce', 'Reg', (80, 86))	('CDK', 'molecular_function', 'GO:0004693', ('58', '61'))	('CDK4/6', 'Gene', (58, 64))
107155	33550279	Additionally, we demonstrated that knockdown of p16 in BRAFV600E-induced senescence in vitro corresponds with a decrease in different SASP factors including inflammatory factors, growth factors, metalloproteinases, and ligands (Figure 1I, 1J and Supplementary Figure 1I).	('senescence', 'CPA', (73, 83))	('decrease', 'NegReg', (112, 120))	('BRAFV600E', 'Mutation', 'rs113488022', (55, 64))	('SASP factors', 'MPA', (134, 146))	('inflammatory factors', 'MPA', (157, 177))	('senescence', 'biological_process', 'GO:0010149', ('73', '83'))	('p16', 'Gene', (48, 51))	('metalloproteinases', 'MPA', (195, 213))	('growth factors', 'MPA', (179, 193))	('BRAFV600E-induced', 'Var', (55, 72))
107157	33550279	Moreover, it will be important to determine whether these tumor-specific SASP signatures alter the clinical course of each tumor type or response to therapy.	('signatures', 'Var', (78, 88))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (123, 128))	('alter', 'Reg', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
107166	33550279	Thus, it is possible that in the context of certain tumor types such as those studied here, the decreased expression of SASP factors observed upon p16 knockdown or in CDKN2A-low patients may contribute to abrogation of senescence surveillance by immune cells, thereby promoting tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('promoting', 'PosReg', (268, 277))	('tumor', 'Disease', (52, 57))	('p16', 'Gene', (147, 150))	('CDKN2A', 'Gene', (167, 173))	('tumor', 'Disease', (278, 283))	('SASP', 'Protein', (120, 124))	('decreased', 'NegReg', (96, 105))	('senescence surveillance', 'MPA', (219, 242))	('expression', 'MPA', (106, 116))	('patients', 'Species', '9606', (178, 186))	('CDKN2A', 'Gene', '1029', (167, 173))	('abrogation', 'NegReg', (205, 215))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('senescence', 'biological_process', 'GO:0010149', ('219', '229'))	('knockdown', 'Var', (151, 160))
107167	33550279	Interestingly, a recent publication shows that depletion of p16 in tumor cells abrogates the cancer immune response and promotes immune checkpoint blockade resistance.	('p16', 'Gene', (60, 63))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('promotes', 'PosReg', (120, 128))	('depletion', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('immune response', 'biological_process', 'GO:0006955', ('100', '115'))	('abrogates', 'NegReg', (79, 88))	('immune', 'CPA', (129, 135))
107169	33550279	Although loss of p16 is one of the most common events in cancer (~50% of all human cancers), there are currently no approved targeted therapies.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Disease', (83, 90))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('p16', 'Gene', (17, 20))	('loss', 'Var', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancer', 'Disease', (83, 89))	('human', 'Species', '9606', (77, 82))
107172	33550279	For instance, we previously showed that inhibition of nucleotide metabolism through suppression of mTORC1 or the pentose phosphate pathway enzyme Ribose 5-Phosphate Isomerase A (RPIA) induces senescence specifically in p16-low cancers.	('nucleotide metabolism', 'MPA', (54, 75))	('senescence', 'biological_process', 'GO:0010149', ('192', '202'))	('nucleotide metabolism', 'biological_process', 'GO:0009117', ('54', '75'))	('mTORC1', 'Gene', (99, 105))	('mTORC1', 'Gene', '382056', (99, 105))	('senescence', 'MPA', (192, 202))	('Ribose 5-Phosphate Isomerase A', 'Gene', '22934', (146, 176))	('pentose phosphate', 'Chemical', 'MESH:D010428', (113, 130))	('cancers', 'Disease', 'MESH:D009369', (227, 234))	('mTORC1', 'cellular_component', 'GO:0031931', ('99', '105'))	('inhibition', 'Var', (40, 50))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('113', '138'))	('RPIA', 'Gene', '22934', (178, 182))	('suppression', 'NegReg', (84, 95))	('RPIA', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('Ribose 5-Phosphate Isomerase A', 'Gene', (146, 176))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('induces', 'Reg', (184, 191))	('cancers', 'Disease', (227, 234))
107173	33550279	Therefore, induction of senescence in p16-low cancers may be a valuable strategy to inhibit the cell cycle while not activating the potential deleterious effects of the SASP.	('cell cycle', 'biological_process', 'GO:0007049', ('96', '106'))	('p16-low', 'Var', (38, 45))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('senescence', 'MPA', (24, 34))	('cancers', 'Disease', (46, 53))	('induction', 'Reg', (11, 20))	('inhibit', 'NegReg', (84, 91))	('cell cycle', 'CPA', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('senescence', 'biological_process', 'GO:0010149', ('24', '34'))
107174	33550279	We found that this phenomenon also occurs in p16-wildtype tumor cells upon p16 knockdown, and there is a decrease in the SASP gene signature in multiple tumor types that are associated with low p16 expression.	('p16 knockdown', 'Var', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('SASP gene', 'Gene', (121, 130))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('knockdown', 'Var', (79, 88))	('decrease', 'NegReg', (105, 113))
107176	33550279	Normal diploid IMR90 human fibroblasts were obtained from ATCC (CCL-186) and cultured according to the ATCC protocol in DMEM (Corning, cat#10-017-CV) supplemented with 5% FBS (VWR, cat#97068-085), L-glutamine (Corning, cat#25-015-CI), non-essential amino acids (Corning, cat#25-025-CI), sodium pyruvate (Corning, cat#25-000-CI), and sodium bicarbonate (Corning, cat#25-035-CI).	('sodium pyruvate', 'MPA', (287, 302))	('CCL', 'molecular_function', 'GO:0044101', ('64', '67'))	('cat', 'molecular_function', 'GO:0004096', ('313', '316'))	('DMEM', 'Chemical', '-', (120, 124))	('cat#25-025-CI', 'Var', (271, 284))	('sodium bicarbonate', 'MPA', (333, 351))	('cat', 'molecular_function', 'GO:0004096', ('219', '222'))	('human', 'Species', '9606', (21, 26))	('cat', 'molecular_function', 'GO:0004096', ('362', '365'))	('cat', 'molecular_function', 'GO:0004096', ('271', '274'))	('cat', 'molecular_function', 'GO:0004096', ('181', '184'))	('cat', 'molecular_function', 'GO:0004096', ('135', '138'))	('non-essential amino acids', 'MPA', (235, 260))	('IMR90', 'CellLine', 'CVCL:0347', (15, 20))
107186	33550279	Briefly, cells were infected with pBabe empty vector control, pBabe BRAFV600E, or pBabe HRASG12V retroviral particles, and 24 hours later cells were infected with a second round of corresponding retroviral particles.	('BRAFV600E', 'Var', (68, 77))	('infected', 'Disease', 'MESH:D007239', (20, 28))	('infected', 'Disease', (20, 28))	('HRAS', 'Gene', '3265', (88, 92))	('infected', 'Disease', 'MESH:D007239', (149, 157))	('HRAS', 'Gene', (88, 92))	('BRAFV600E', 'Mutation', 'rs113488022', (68, 77))	('infected', 'Disease', (149, 157))
107187	33550279	Cells were infected with pLKO.1-shp16 or pLKO.1-shGFP when indicated in Supplementary Figure 1A and Supplementary Figure 2A.	('infected', 'Disease', (11, 19))	('infected', 'Disease', 'MESH:D007239', (11, 19))	('pLKO.1-shp16', 'Var', (25, 37))	('pLKO.1-shGFP', 'Gene', (41, 53))
107189	33550279	SKMel28 melanoma cells (p16-wildtype) with stable p16 knockdown (using shp16 hairpin #1) or control (shGFP) were treated with either DMSO or 1muM etoposide (Cayman Chemical, cat#12092) for 6 days (drug replacement every 2 days).	('melanoma', 'Disease', 'MESH:D008545', (8, 16))	('etoposide', 'Chemical', 'MESH:D005047', (146, 155))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanoma', 'Disease', (8, 16))	('knockdown', 'Var', (54, 63))	('DMSO', 'Chemical', 'MESH:D004121', (133, 137))	('SKMel28', 'Chemical', '-', (0, 7))	('cat', 'molecular_function', 'GO:0004096', ('174', '177'))	('p16', 'Gene', (50, 53))
107195	33550279	Antibodies used include: anti-BRAF (Santa Cruz Biotechnology, cat#sc-5284, 1:1000), anti-RAS (BD Sciences, cat#610001, 1:1000), anti-p16 (Abcam, cat#ab108349, 1:1000), anti-p21 (Abcam cat#ab109199, 1:1000), anti-cyclin A2 (Abcam cat#ab181591, 1:2000), anti-vinculin (Sigma-Aldrich cat#V9131, 1:1000), beta-Actin (Sigma-Aldrich, cat#A1978, 1:10000), anti-mouse HRP (Cell Signaling Technology, cat#cst7076, 1:10,000), and anti-rabbit HRP (Cell Signaling Technology, cat#cst7074, 1:5000).	('cat', 'molecular_function', 'GO:0004096', ('184', '187'))	('Signaling', 'biological_process', 'GO:0023052', ('370', '379'))	('cat', 'molecular_function', 'GO:0004096', ('229', '232'))	('anti-rabbit', 'Var', (420, 431))	('cat', 'molecular_function', 'GO:0004096', ('392', '395'))	('cyclin A2', 'Gene', '12428', (212, 221))	('beta-Actin', 'Gene', '11461', (301, 311))	('cyclin', 'molecular_function', 'GO:0016538', ('212', '218'))	('vinculin', 'Gene', '22330', (257, 265))	('p21', 'Gene', (173, 176))	('cat', 'molecular_function', 'GO:0004096', ('145', '148'))	('cat', 'molecular_function', 'GO:0004096', ('281', '284'))	('vinculin', 'Gene', (257, 265))	('mouse', 'Species', '10090', (354, 359))	('beta-Actin', 'Gene', (301, 311))	('cat', 'molecular_function', 'GO:0004096', ('107', '110'))	('cat', 'molecular_function', 'GO:0004096', ('328', '331'))	('cat', 'molecular_function', 'GO:0004096', ('62', '65'))	('cat', 'molecular_function', 'GO:0004096', ('464', '467'))	('cyclin A2', 'Gene', (212, 221))	('p21', 'Gene', '12575', (173, 176))	('anti-mouse HRP', 'Protein', (349, 363))	('Signaling', 'biological_process', 'GO:0023052', ('442', '451'))
107217	32586345	It is worth knowing and reporting that the Atyp.C assay may be used as an accessory test for patients with suspected urothelial carcinoma, based on its ability to identify high-risk patients who might need closer follow-up or additional medical treatment.	('urothelial carcinoma', 'Disease', (117, 137))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (117, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('Atyp.C', 'Var', (43, 49))	('men', 'Species', '9606', (250, 253))	('patients', 'Species', '9606', (182, 190))	('patients', 'Species', '9606', (93, 101))
107277	32586345	The false positive rate (17.9%) was relatively low in our study; false positive results could be due to the presence of cytoplasmic inclusion-bearing cells, virus-infected cells, or umbrella cells since these types of cells frequently are tetraploid, aneuploidy, or show chromosomal aberrations.	('aneuploidy', 'Disease', (251, 261))	('cytoplasmic inclusion', 'cellular_component', 'GO:0097413', ('120', '141'))	('false', 'biological_process', 'GO:0071877', ('65', '70'))	('aneuploidy', 'Disease', 'MESH:D000782', (251, 261))	('tetraploid', 'Var', (239, 249))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (271, 294))	('false', 'biological_process', 'GO:0071878', ('4', '9'))	('infected', 'Disease', 'MESH:D007239', (163, 171))	('false', 'biological_process', 'GO:0071878', ('65', '70'))	('chromosomal aberrations', 'CPA', (271, 294))	('false', 'biological_process', 'GO:0071877', ('4', '9'))	('infected', 'Disease', (163, 171))
107286	32586345	Therefore, greater consideration should be given to the presence of Atyp.C, regardless of symptoms associated with urothelial carcinoma.	('Atyp.C', 'Var', (68, 74))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (115, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('urothelial carcinoma', 'Disease', (115, 135))
107287	32586345	Based on our results, we presume that the Atyp.C assay may be useful as an accessory test in patients with a suspected diagnosis of urothelial carcinoma, or in patients requiring urothelial carcinoma surveillance, especially in identifying some high-risk patients who may need closer follow-up or additional medical treatment.	('patients', 'Species', '9606', (160, 168))	('urothelial carcinoma', 'Disease', (132, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (132, 152))	('patients', 'Species', '9606', (255, 263))	('men', 'Species', '9606', (321, 324))	('urothelial carcinoma', 'Disease', (179, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('patients', 'Species', '9606', (93, 101))	('Atyp.C', 'Var', (42, 48))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (179, 199))
107310	30374124	GAS5 is comprised of 12 exons, bearing a 5'-terminal oligopyrimidine (5'-TOP) sequence in exon 1, and beside several mature GAS5 variants, GAS5 encodes 10 C/D box snoRNAs (SNORD44, SNORD47, SNORD74-SNORD81) within its 11 introns.	('GAS5', 'Gene', '60674', (0, 4))	('GAS', 'molecular_function', 'GO:0034005', ('124', '127'))	('SNORD44', 'Gene', '26806', (172, 179))	('variants', 'Var', (129, 137))	('SNORD81', 'Gene', (198, 205))	('GAS5', 'Gene', '60674', (124, 128))	('GAS', 'molecular_function', 'GO:0034005', ('139', '142'))	('GAS5', 'Gene', (0, 4))	('GAS', 'molecular_function', 'GO:0034005', ('0', '3'))	('10 C/D', 'Var', (152, 158))	('SNORD47', 'Gene', (181, 188))	('GAS5', 'Gene', '60674', (139, 143))	("5'-TOP", 'Chemical', 'MESH:C040288', (70, 76))	('GAS5', 'Gene', (124, 128))	('SNORD47', 'Gene', '26802', (181, 188))	('SNORD44', 'Gene', (172, 179))	('10 C/D', 'SUBSTITUTION', 'None', (152, 158))	('SNORD74', 'Gene', (190, 197))	('SNORD81', 'Gene', '26769', (198, 205))	('SNORD74', 'Gene', '619498', (190, 197))	('GAS5', 'Gene', (139, 143))	("5'-terminal oligopyrimidine", 'Chemical', 'MESH:C040288', (41, 68))
107313	30374124	The well-characterised tumour suppressor of GAS5 has been documented in a wide variety of human malignancies and loss of GAS5 expression has been implicated both in tumorigenesis and disease progression, as well as in patients prognosis.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('GAS5', 'Gene', (44, 48))	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('tumorigenesis', 'Disease', 'MESH:D063646', (165, 178))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('patients', 'Species', '9606', (218, 226))	('disease progression', 'CPA', (183, 202))	('implicated', 'Reg', (146, 156))	('GAS5', 'Gene', '60674', (121, 125))	('malignancies', 'Disease', (96, 108))	('tumour', 'Disease', (23, 29))	('human', 'Species', '9606', (90, 95))	('GAS', 'molecular_function', 'GO:0034005', ('44', '47'))	('loss', 'Var', (113, 117))	('GAS5', 'Gene', '60674', (44, 48))	('GAS5', 'Gene', (121, 125))	('tumorigenesis', 'Disease', (165, 178))	('GAS', 'molecular_function', 'GO:0034005', ('121', '124'))
107315	30374124	Indeed, GAS5 silencing is associated with increased proportion of cells in the S/G2 phase as well as with attenuated apoptosis upon endogenous stimuli or chemotherapeutic agents.	('increased', 'PosReg', (42, 51))	('S/G2', 'SUBSTITUTION', 'None', (79, 83))	('GAS5', 'Gene', (8, 12))	('GAS', 'molecular_function', 'GO:0034005', ('8', '11'))	('attenuated', 'NegReg', (106, 116))	('apoptosis', 'biological_process', 'GO:0097194', ('117', '126'))	('apoptosis', 'biological_process', 'GO:0006915', ('117', '126'))	('GAS5', 'Gene', '60674', (8, 12))	('apoptosis', 'CPA', (117, 126))	('silencing', 'NegReg', (13, 22))	('G2 phase', 'biological_process', 'GO:0051319', ('81', '89'))	('S/G2', 'Var', (79, 83))
107399	30374124	Indeed, NMIBC patients underexpressing GAS5 were at significantly higher risk for disease short-term relapse and progression to invasive tumour stages.	('NMIBC', 'Disease', (8, 13))	('invasive tumour', 'Disease', 'MESH:D009361', (128, 143))	('GAS5', 'Gene', (39, 43))	('NMIBC', 'Disease', 'MESH:D001749', (8, 13))	('disease short-term relapse', 'CPA', (82, 108))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))	('GAS5', 'Gene', '60674', (39, 43))	('GAS', 'molecular_function', 'GO:0034005', ('39', '42'))	('patients', 'Species', '9606', (14, 22))	('invasive tumour', 'Disease', (128, 143))	('underexpressing', 'Var', (23, 38))
107403	30374124	validation cohort for NMIBC clearly verified the significantly worse PFS expectancy of the TaT1 patients underexpressing GAS5.	('worse', 'NegReg', (63, 68))	('TaT1', 'Gene', (91, 95))	('NMIBC', 'Disease', (22, 27))	('PFS expectancy', 'MPA', (69, 83))	('GAS5', 'Gene', '60674', (121, 125))	('NMIBC', 'Disease', 'MESH:D001749', (22, 27))	('patients', 'Species', '9606', (96, 104))	('GAS5', 'Gene', (121, 125))	('underexpressing', 'Var', (105, 120))	('GAS', 'molecular_function', 'GO:0034005', ('121', '124'))	('TaT1', 'Gene', '117247', (91, 95))
107408	30374124	Focusing on BlCa, silencing of GAS5 resulted in enhanced cell proliferation and increased percentage of cells in S/G2 cell-cycle phase, which was mediated by the increased expression of CDK6 (ref. )	('BlCa', 'Phenotype', 'HP:0009725', (12, 16))	('cell proliferation', 'biological_process', 'GO:0008283', ('57', '75'))	('CDK', 'molecular_function', 'GO:0004693', ('186', '189'))	('cell proliferation', 'CPA', (57, 75))	('increased', 'PosReg', (162, 171))	('GAS5', 'Gene', '60674', (31, 35))	('enhanced', 'PosReg', (48, 56))	('cell-cycle phase', 'biological_process', 'GO:0022403', ('118', '134'))	('BlCa', 'Disease', (12, 16))	('BlCa', 'Disease', 'MESH:D001749', (12, 16))	('GAS5', 'Gene', (31, 35))	('CDK6', 'Gene', '1021', (186, 190))	('silencing', 'Var', (18, 27))	('increased', 'PosReg', (80, 89))	('S/G2', 'Var', (113, 117))	('S/G2', 'SUBSTITUTION', 'None', (113, 117))	('expression', 'MPA', (172, 182))	('GAS', 'molecular_function', 'GO:0034005', ('31', '34'))	('CDK6', 'Gene', (186, 190))
107426	30374124	; acquired and managed patients: P.K.L., T.T.	('patients', 'Species', '9606', (23, 31))	('T.T', 'Disease', (41, 44))	('T.T', 'Disease', 'MESH:D001260', (41, 44))	('P.K.L.', 'Var', (33, 39))
107431	29843367	The combination of low CD151 expression and high RNASEH2A expression resulted in impaired proliferation in four kidney cancer cell lines, suggesting potential synthetic dosage lethality (SDL) interactions between the two genes.	('high', 'Var', (44, 48))	('kidney cancer', 'Disease', (112, 125))	('proliferation', 'CPA', (90, 103))	('low', 'NegReg', (19, 22))	('RNASEH2A', 'Gene', (49, 57))	('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))
107435	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))
107437	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'))
107447	29843367	It has been reported that certain genes have synthetic dosage lethality (SDL) interactions with genes that are frequently overexpressed in tumors and that inhibition of the SDL partners can decrease cancer proliferation.	('decrease', 'NegReg', (190, 198))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Disease', (139, 145))	('cancer', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('inhibition', 'Var', (155, 165))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('interactions', 'Interaction', (78, 90))
107456	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))
107460	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))
107461	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))
107462	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))
107463	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))
107466	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))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('MTT', 'Chemical', 'MESH:C070243', (222, 225))	('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))
107471	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))
107473	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).	('lower', 'NegReg', (133, 138))	('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))	('si', 'Chemical', 'MESH:D012825', (56, 58))
107481	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'))
107484	29843367	In contrast to CDK1 knockdown, transfection of RCC cell lines with either si-RNASEH2A or si-CD151 resulted in impaired tumor proliferation.	('RNASEH2A', 'Gene', '10535', (77, 85))	('CDK1', 'Gene', '983', (15, 19))	('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))
107485	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))
107493	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))
107532	28959653	p-Benzoquinone initiates non-invasive urothelial cancer through aberrant tyrosine phosphorylation of EGFR, MAP kinase activation and cell cycle deregulation: Prevention by vitamin C p-Benzoquinone induces non-invasive urothelial carcinoma in a guinea pig model.	('cell cycle', 'biological_process', 'GO:0007049', ('133', '143'))	('EGFR', 'Gene', '100725363', (101, 105))	('non-invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (205, 238))	('vitamin C', 'Chemical', 'MESH:D001205', (172, 181))	('tyrosine', 'Chemical', 'MESH:D014443', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('urothelial cancer', 'Disease', (38, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('EGFR', 'Gene', (101, 105))	('MAP', 'molecular_function', 'GO:0004239', ('107', '110'))	('EGFR', 'molecular_function', 'GO:0005006', ('101', '105'))	('non-invasive urothelial carcinoma', 'Disease', (205, 238))	('guinea pig', 'Species', '10141', (244, 254))	('p-Benzoquinone', 'Chemical', 'MESH:C004532', (0, 14))	('urothelial cancer', 'Disease', 'MESH:D014523', (38, 55))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))	('p-Benzoquinone', 'Chemical', 'MESH:C004532', (182, 196))	('p-Benzoquinone', 'Var', (182, 196))
107538	28959653	Here, using a guinea pig model we showed that prolonged treatment with p-BQ led to non-invasive UC, specifically carcinoma in situ (CIS) of the renal pelvis and dysplasia in the ureter and bladder.	('p-BQ', 'Chemical', 'MESH:C004532', (71, 75))	('CIS', 'Phenotype', 'HP:0030075', (132, 135))	('carcinoma in situ', 'Disease', 'MESH:D002278', (113, 130))	('renal pelvis and dysplasia in the ureter', 'Disease', 'MESH:D014516', (144, 184))	('led to', 'Reg', (76, 82))	('renal pelvis', 'Phenotype', 'HP:0000125', (144, 156))	('guinea pig', 'Species', '10141', (14, 24))	('p-BQ', 'Var', (71, 75))	('carcinoma in situ', 'Disease', (113, 130))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (113, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('men', 'Species', '9606', (61, 64))	('non-invasive UC', 'Disease', (83, 98))
107539	28959653	The mechanisms of carcinogenesis were p-BQ-induced oxidative damage and apoptosis that were later suppressed and followed by activation of epidermal growth factor receptor, aberrant phosphorylation of intracellular tyrosine residues, activation of MAP kinase pathway and persistent growth signaling.	('signaling', 'biological_process', 'GO:0023052', ('289', '298'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('139', '162'))	('intracellular', 'cellular_component', 'GO:0005622', ('201', '214'))	('activation', 'PosReg', (234, 244))	('activation of MAP kinase', 'biological_process', 'GO:0000187', ('234', '258'))	('p-BQ', 'Chemical', 'MESH:C004532', (38, 42))	('oxidative', 'MPA', (51, 60))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('p-BQ-induced', 'Var', (38, 50))	('MAP kinase pathway', 'Pathway', (248, 266))	('activation', 'PosReg', (125, 135))	('epidermal', 'Protein', (139, 148))	('carcinogenesis', 'Disease', (18, 32))	('MAP', 'molecular_function', 'GO:0004239', ('248', '251'))	('phosphorylation of intracellular tyrosine residues', 'MPA', (182, 232))	('growth signaling', 'CPA', (282, 298))	('tyrosine', 'Chemical', 'MESH:D014443', (215, 223))	('apoptosis', 'CPA', (72, 81))	('carcinogenesis', 'Disease', 'MESH:D063646', (18, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('182', '197'))
107541	28959653	UC has been characterised by histopathology and immunohistochemistry showing aberrant CK20, increased Ki-67, and marked p53 nuclear immunopositivity with uniformly negative labelling of CD44.	('CK20', 'Gene', (86, 90))	('CK20', 'Gene', '54474', (86, 90))	('Ki-67', 'MPA', (102, 107))	('increased', 'PosReg', (92, 101))	('p53', 'Gene', (120, 123))	('aberrant', 'Var', (77, 85))
107560	28959653	We have observed that in the lung, p-BQ closely mimics emphysema in a guinea pig model.	('emphysema', 'Disease', 'MESH:D004646', (55, 64))	('p-BQ', 'Var', (35, 39))	('guinea pig', 'Species', '10141', (70, 80))	('emphysema', 'Phenotype', 'HP:0002097', (55, 64))	('p-BQ', 'Chemical', 'MESH:C004532', (35, 39))	('emphysema', 'Disease', (55, 64))
107561	28959653	In the blood, p-BQ forms Michael adducts with serum albumin as well as haemoglobin resulting in alteration of structure and function of the proteins.	('alteration', 'Reg', (96, 106))	('p-BQ', 'Var', (14, 18))	('adducts', 'Interaction', (33, 40))	('function of the proteins', 'MPA', (124, 148))	('p-BQ', 'Chemical', 'MESH:C004532', (14, 18))	('rat', 'Species', '10116', (100, 103))
107562	28959653	In the systemic circulation, p-BQ reaches distant organs and causes myocardial damage and myelodysplastic syndromes (a type of cancer).	('p-BQ', 'Chemical', 'MESH:C004532', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('causes', 'Reg', (61, 67))	('p-BQ', 'Var', (29, 33))	('type of cancer', 'Disease', 'MESH:D009369', (119, 133))	('myocardial damage and myelodysplastic syndromes', 'Disease', 'MESH:D009202', (68, 115))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (90, 115))	('type of cancer', 'Disease', (119, 133))
107569	28959653	In this paper we demonstrate that prolonged p-BQ treatment produces non-invasive UC, particularly carcinoma in situ (CIS) in the renal pelvis and dysplasia in the ureter and bladder in a guinea pig model.	('renal pelvis and dysplasia in the ureter', 'Disease', 'MESH:D014516', (129, 169))	('p-BQ', 'Chemical', 'MESH:C004532', (44, 48))	('carcinoma in situ', 'Disease', 'MESH:D002278', (98, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('non-invasive UC', 'Disease', (68, 83))	('prolonged p-BQ', 'Phenotype', 'HP:0012248', (34, 48))	('carcinoma in situ', 'Disease', (98, 115))	('p-BQ', 'Var', (44, 48))	('guinea pig', 'Species', '10141', (187, 197))	('men', 'Species', '9606', (54, 57))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (98, 115))	('renal pelvis', 'Phenotype', 'HP:0000125', (129, 141))	('rat', 'Species', '10116', (24, 27))	('CIS', 'Phenotype', 'HP:0030075', (117, 120))
107573	28959653	Our preclinical study might reveal insights into the underlying molecular mechanisms how p-BQ, a major toxic quinone derived from CS, initiates UC and to formulate effective strategies for early intervention of the disease.	('quinone', 'Chemical', 'MESH:C004532', (109, 116))	('rat', 'Species', '10116', (176, 179))	('CS', 'Chemical', '-', (130, 132))	('p-BQ', 'Chemical', 'MESH:C004532', (89, 93))	('p-BQ', 'Var', (89, 93))	('initiates', 'PosReg', (134, 143))
107596	28959653	The membrane was blocked in 5% milk for 1 h and then incubated with primary antibody (1:1000 dilution) of p53, phospho p53, Bax, Bcl-2, caspase 3, cleaved caspase 3, PARP, p44/p42 MAPK, phospho p44/p42 MAPK, c-Myc, phospho (serine 62) c-Myc, p21 waf1/cip1, cyclin D1, phospho Rb (807/811) (Cell Signalling Technologies), anti-GTPase Hras (Abcam), respectively, as needed.	('cyclin D1', 'Gene', (257, 266))	('waf1', 'Gene', (246, 250))	('MAPK', 'molecular_function', 'GO:0004707', ('202', '206'))	('p21', 'Gene', '1026', (242, 245))	('caspase 3', 'Gene', '100718309', (155, 164))	('Hras', 'Gene', '100735038', (333, 337))	('waf1', 'Gene', '1026', (246, 250))	('caspase 3', 'Gene', (136, 145))	('Signalling', 'biological_process', 'GO:0023052', ('295', '305'))	('antibody', 'cellular_component', 'GO:0019815', ('76', '84'))	('Bcl-2', 'Gene', (129, 134))	('Bcl-2', 'molecular_function', 'GO:0015283', ('129', '134'))	('Hras', 'Gene', (333, 337))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))	('antibody', 'cellular_component', 'GO:0019814', ('76', '84'))	('caspase 3', 'Gene', '100718309', (136, 145))	('GTP', 'Chemical', 'MESH:D006160', (326, 329))	('Bax', 'Gene', '100730890', (124, 127))	('p21', 'Gene', (242, 245))	('serine', 'Chemical', 'MESH:D012694', (224, 230))	('cip1', 'Gene', '1026', (251, 255))	('p44/p42', 'Var', (172, 179))	('cyclin', 'molecular_function', 'GO:0016538', ('257', '263'))	('Bax', 'Gene', (124, 127))	('phospho', 'Var', (186, 193))	('Bcl-2', 'Gene', '100733337', (129, 134))	('antibody', 'molecular_function', 'GO:0003823', ('76', '84'))	('cyclin D1', 'Gene', '100729808', (257, 266))	('caspase 3', 'Gene', (155, 164))	('cip1', 'Gene', (251, 255))	('antibody', 'cellular_component', 'GO:0042571', ('76', '84'))	('MAPK', 'molecular_function', 'GO:0004707', ('180', '184'))
107602	28959653	The membrane was blocked in 5% milk for 1 h and then incubated with 1:1000 dilution of primary anti-p-BQ antibody (Abexome, India), anti-phospho-Tyr845, anti-phospho-Tyr 1045, anti-phospho-Tyr1068, anti-phospho-Tyr 1173, anti-c-Cbl and anti-ubiquitin antibody (Cell signaling Technologies) overnight at 4  C, and processed similarly like immunoblots.	('Tyr', 'Chemical', 'MESH:D014443', (189, 192))	('Cbl', 'Gene', (228, 231))	('anti-phospho-Tyr 1173', 'Var', (198, 219))	('Tyr', 'Chemical', 'MESH:D014443', (211, 214))	('antibody', 'cellular_component', 'GO:0019815', ('251', '259'))	('antibody', 'cellular_component', 'GO:0019815', ('105', '113'))	('anti-phospho-Tyr845', 'Var', (132, 151))	('Tyr', 'Chemical', 'MESH:D014443', (145, 148))	('p-BQ', 'Chemical', 'MESH:C004532', (100, 104))	('antibody', 'cellular_component', 'GO:0019814', ('105', '113'))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))	('antibody', 'cellular_component', 'GO:0019814', ('251', '259'))	('Tyr845', 'Chemical', '-', (145, 151))	('anti-phospho-Tyr1068', 'Var', (176, 196))	('Tyr1068', 'Chemical', '-', (189, 196))	('anti-phospho-Tyr 1045', 'Var', (153, 174))	('ubiquitin', 'molecular_function', 'GO:0031386', ('241', '250'))	('Cbl', 'Gene', '100725041', (228, 231))	('antibody', 'molecular_function', 'GO:0003823', ('251', '259'))	('antibody', 'molecular_function', 'GO:0003823', ('105', '113'))	('antibody', 'cellular_component', 'GO:0042571', ('251', '259'))	('Tyr', 'Chemical', 'MESH:D014443', (166, 169))	('antibody', 'cellular_component', 'GO:0042571', ('105', '113'))	('signaling', 'biological_process', 'GO:0023052', ('266', '275'))
107604	28959653	Five micron thick deparaffinized tissue sections were processed for antigen retrieval in10 mmol/L citrate buffer (pH 6.0) for 15 min for permeabilisation The slides were then blocked with 10% BSA and incubated overnight with relevant primary antibodies as follows: Ki-67(Abcam), 1:100, overnight at 4  C; p53(CST),1:100,overnight at 4  C, cytokeratin 20 (Abcam), 1:100, 1 h at room temperature; CD44 (Abcam) 1:100, 1 h at room temperature.	('rat', 'Species', '10116', (345, 348))	('rat', 'Species', '10116', (101, 104))	('CD44', 'Var', (395, 399))	('rat', 'Species', '10116', (387, 390))	('rat', 'Species', '10116', (432, 435))	('CS', 'Chemical', '-', (309, 311))	('cytokeratin 20', 'Gene', (339, 353))	('cytokeratin 20', 'Gene', '54474', (339, 353))
107608	28959653	We observed that daily intramuscular injection of p-BQ (25 mug/animal) for 4 weeks in vitamin C- restricted guinea pigs caused death of some epithelial cells of the renal pelvis as evidenced by hollowing of cells and missing nuclei (Fig.	('death', 'NegReg', (127, 132))	('p-BQ', 'Chemical', 'MESH:C004532', (50, 54))	('renal pelvis', 'Phenotype', 'HP:0000125', (165, 177))	('p-BQ', 'Var', (50, 54))	('vitamin C', 'Chemical', 'MESH:D001205', (86, 95))	('hollowing of cells', 'CPA', (194, 212))	('guinea pigs', 'Species', '10141', (108, 119))	('mug', 'molecular_function', 'GO:0043739', ('59', '62'))	('missing', 'NegReg', (217, 224))
107614	28959653	Here, we showed that after 2 and 4 weeks of treatment, p-BQ caused protein oxidation, as evidenced by significant formation of protein carbonyl (p < 0.005) after 2 and 4 weeks.	('protein oxidation', 'biological_process', 'GO:0018158', ('67', '84'))	('men', 'Species', '9606', (49, 52))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('protein carbonyl', 'MPA', (127, 143))	('p-BQ', 'Chemical', 'MESH:C004532', (55, 59))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('formation', 'MPA', (114, 123))	('protein oxidation', 'MPA', (67, 84))	('formation', 'biological_process', 'GO:0009058', ('114', '123'))	('p-BQ', 'Var', (55, 59))
107618	28959653	Compared to sham control and vitamin C-supplemented animals, p-BQ also caused significant apoptosis after 2 and 4 weeks of treatment (Fig.	('men', 'Species', '9606', (45, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('p-BQ', 'Chemical', 'MESH:C004532', (61, 65))	('men', 'Species', '9606', (128, 131))	('apoptosis', 'CPA', (90, 99))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('vitamin C', 'Chemical', 'MESH:D001205', (29, 38))	('p-BQ', 'Var', (61, 65))
107619	28959653	1B, C), as evidenced by immunoblotting using antibodies against proapoptotic markers phospho-p53 (p < 0.005), Bax (p < 0.005), cleaved caspase 3 (p < 0.005), and cleaved PARP (p < 0.005).	('Bax', 'Gene', '100730890', (110, 113))	('cleaved', 'Var', (162, 169))	('caspase 3', 'Gene', (135, 144))	('phospho-p53', 'Var', (85, 96))	('cleaved', 'MPA', (127, 134))	('caspase 3', 'Gene', '100718309', (135, 144))	('Bax', 'Gene', (110, 113))	('PARP', 'Protein', (170, 174))
107623	28959653	Suppression of apoptosis was accompanied by hyperplasia as evidenced by increased expression of phospho-p44/p42 MAPK after 8 weeks of p-BQ injections (p < 0.005) (Supplementary Fig.	('apoptosis', 'CPA', (15, 24))	('increased', 'PosReg', (72, 81))	('MAPK', 'Protein', (112, 116))	('expression', 'MPA', (82, 92))	('men', 'Species', '9606', (169, 172))	('p-BQ', 'Chemical', 'MESH:C004532', (134, 138))	('phospho-p44/p42', 'Var', (96, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('15', '24'))	('hyperplasia', 'Disease', (44, 55))	('apoptosis', 'biological_process', 'GO:0006915', ('15', '24'))	('Suppression', 'NegReg', (0, 11))	('hyperplasia', 'Disease', 'MESH:D006965', (44, 55))	('MAPK', 'molecular_function', 'GO:0004707', ('112', '116'))
107626	28959653	Since p-BQ treatment caused hyperplasia after 8 weeks, we continued the treatment for 24 weeks until the vitamin C-restricted animals showed a marked decrease in food intake and body weight (Supplementary Fig.	('food intake', 'CPA', (162, 173))	('hyperplasia', 'Disease', (28, 39))	('decrease', 'NegReg', (150, 158))	('body weight', 'CPA', (178, 189))	('p-BQ', 'Chemical', 'MESH:C004532', (6, 10))	('men', 'Species', '9606', (77, 80))	('men', 'Species', '9606', (16, 19))	('hyperplasia', 'Disease', 'MESH:D006965', (28, 39))	('men', 'Species', '9606', (197, 200))	('p-BQ', 'Var', (6, 10))	('vitamin C', 'Chemical', 'MESH:D001205', (105, 114))
107630	28959653	Accurate diagnosis of CIS in humans is done using immunostains for cytokeratin 20 (CK20) (a cytoplasmic protein), p53 (nuclear antigen), standard isoform of CD44 (expressed on the cellular membrane) and Ki67 (nuclear antigen).	('humans', 'Species', '9606', (29, 35))	('CIS', 'Phenotype', 'HP:0030075', (22, 25))	('CK20', 'Gene', (83, 87))	('CK20', 'Gene', '54474', (83, 87))	('p53', 'Gene', (114, 117))	('cellular membrane', 'cellular_component', 'GO:0005886', ('180', '197'))	('Ki67', 'Var', (203, 207))	('Ki67', 'Chemical', '-', (203, 207))	('CD44', 'Gene', (157, 161))	('cytokeratin 20', 'Gene', (67, 81))	('cytokeratin 20', 'Gene', '54474', (67, 81))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('rat', 'Species', '10116', (4, 7))	('rat', 'Species', '10116', (73, 76))
107635	28959653	p53 is generally absent in normal urothelium but is overexpressed in a large number of malignancies that is indicative of mutated p53 status.	('overexpressed', 'PosReg', (52, 65))	('malignancies', 'Disease', (87, 99))	('mutated', 'Var', (122, 129))	('malignancies', 'Disease', 'MESH:D009369', (87, 99))
107647	28959653	However, there was no significant change in phosphorylation pattern of Tyr 845 (p > 0.05), Tyr 1068 (p > 0.05) and Tyr 1173 (p > 0.05), compared to that of sham control and vitamin C-sufficient animals (Fig.	('phosphorylation', 'MPA', (44, 59))	('phosphorylation', 'biological_process', 'GO:0016310', ('44', '59'))	('Tyr 1173', 'Var', (115, 123))	('Tyr', 'Chemical', 'MESH:D014443', (115, 118))	('Tyr 1068', 'Var', (91, 99))	('Tyr', 'Chemical', 'MESH:D014443', (91, 94))	('Tyr', 'Chemical', 'MESH:D014443', (71, 74))	('vitamin C', 'Chemical', 'MESH:D001205', (173, 182))	('Tyr 845', 'Var', (71, 78))
107650	28959653	There was no change in phosphorylation of Tyr1173 (p>0.05) (Fig.	('phosphorylation', 'MPA', (23, 38))	('phosphorylation', 'biological_process', 'GO:0016310', ('23', '38'))	('Tyr1173', 'Var', (42, 49))	('Tyr1173', 'Chemical', '-', (42, 49))
107657	28959653	We showed that in the p-BQ-treated guinea pigs protein expression level of phosphorylated (activated) p44/p42 MAPK increased significantly after 8 weeks (p < 0.005) and 24 weeks (p < 0.005) (Supplementary Fig.	('p-BQ', 'Chemical', 'MESH:C004532', (22, 26))	('increased', 'PosReg', (115, 124))	('guinea pigs', 'Species', '10141', (35, 46))	('p44/p42', 'Var', (102, 109))	('men', 'Species', '9606', (197, 200))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('MAPK', 'molecular_function', 'GO:0004707', ('110', '114'))	('protein expression level', 'MPA', (47, 71))
107658	28959653	c-Myc is overexpressed in a number of tumors and phosphorylation at ser62 upon mitogen stimulation stabilizes c-Myc.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('ser62', 'Var', (68, 73))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('c-Myc', 'MPA', (110, 115))	('ser62', 'Chemical', '-', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('stabilizes', 'PosReg', (99, 109))	('phosphorylation', 'biological_process', 'GO:0016310', ('49', '64'))	('ser', 'cellular_component', 'GO:0005790', ('68', '71'))	('phosphorylation', 'Var', (49, 64))
107662	28959653	However, a number of reports indicate that in urothelial cancer cyclin D1 expression level decreases with p53 mutations and invasiveness of tumor.	('urothelial cancer', 'Disease', 'MESH:D014523', (46, 63))	('mutations', 'Var', (110, 119))	('invasiveness of tumor', 'Disease', 'MESH:D009369', (124, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('decreases', 'NegReg', (91, 100))	('cyclin', 'molecular_function', 'GO:0016538', ('64', '70'))	('expression level', 'MPA', (74, 90))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('urothelial cancer', 'Disease', (46, 63))	('cyclin D1', 'Gene', (64, 73))	('p53', 'Gene', (106, 109))	('cyclin D1', 'Gene', '100729808', (64, 73))	('invasiveness of tumor', 'Disease', (124, 145))
107669	28959653	Taken together our results indicated that prolonged treatment with p-BQ caused cell cycle progression through deregulation of G1/S checkpoint, the most important checkpoint in the mammalian cell cycle.	('deregulation', 'MPA', (110, 122))	('cell cycle progression', 'CPA', (79, 101))	('p-BQ', 'Chemical', 'MESH:C004532', (67, 71))	('cell cycle', 'biological_process', 'GO:0007049', ('79', '89'))	('mammalian', 'Species', '9606', (180, 189))	('p-BQ', 'Var', (67, 71))	('G1/S checkpoint', 'biological_process', 'GO:0000075', ('126', '141'))	('G1/S', 'MPA', (126, 130))	('men', 'Species', '9606', (57, 60))	('cell cycle', 'biological_process', 'GO:0007049', ('190', '200'))
107673	28959653	The aim of the study was to delineate the mechanism by which p-BQ, a major toxic quinone derived from CS, initiated non-invasive UC that was prevented by oral supplementation of vitamin C. Except several murine models used to study bladder cancer, till date there is little information about investigations on non-invasive UC in animal model.	('men', 'Species', '9606', (165, 168))	('murine', 'Species', '10090', (204, 210))	('bladder cancer', 'Disease', 'MESH:D001749', (232, 246))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('quinone', 'Chemical', 'MESH:C004532', (81, 88))	('p-BQ', 'Chemical', 'MESH:C004532', (61, 65))	('non-invasive', 'Disease', (116, 128))	('bladder cancer', 'Disease', (232, 246))	('CS', 'Chemical', '-', (102, 104))	('p-BQ', 'Var', (61, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (232, 246))	('vitamin C', 'Chemical', 'MESH:D001205', (178, 187))
107675	28959653	The mechanisms of carcinogenesis were oxidative damage and apoptosis that were later suppressed and followed by aberrant EGFR activation, persistent growth signaling, marked increase in immunoexpression of nuclear p53 indicating p53 mutation and cell cycle deregulation.	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('carcinogenesis', 'Disease', (18, 32))	('EGFR', 'Protein', (121, 125))	('cell cycle', 'biological_process', 'GO:0007049', ('246', '256'))	('immunoexpression', 'MPA', (186, 202))	('growth signaling', 'MPA', (149, 165))	('p53', 'Gene', (229, 232))	('mutation', 'Var', (233, 241))	('activation', 'PosReg', (126, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('121', '125'))	('increase', 'PosReg', (174, 182))	('carcinogenesis', 'Disease', 'MESH:D063646', (18, 32))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('nuclear p53', 'Protein', (206, 217))	('cell cycle deregulation', 'CPA', (246, 269))
107678	28959653	It is also reported that deregulated cell proliferation and suppressed cell death together provide the underlying platform for neoplastic progression.	('cell proliferation', 'biological_process', 'GO:0008283', ('37', '55'))	('cell death', 'CPA', (71, 81))	('cell death', 'biological_process', 'GO:0008219', ('71', '81'))	('deregulated', 'Var', (25, 36))	('rat', 'Species', '10116', (49, 52))	('cell proliferation', 'CPA', (37, 55))
107681	28959653	p-BQ is known to induce leukemia.	('induce', 'Reg', (17, 23))	('p-BQ', 'Chemical', 'MESH:C004532', (0, 4))	('leukemia', 'Phenotype', 'HP:0001909', (24, 32))	('leukemia', 'Disease', 'MESH:D007938', (24, 32))	('leukemia', 'Disease', (24, 32))	('p-BQ', 'Var', (0, 4))
107684	28959653	p-BQ is also mutagenic.	('p-BQ', 'Var', (0, 4))	('p-BQ', 'Chemical', 'MESH:C004532', (0, 4))	('mutagenic', 'Var', (13, 22))
107685	28959653	Moreover, p-BQ is an inhibitor of topoisomerase II, which has implications for the formation of deleterious translocation leading to leukemogenesis Furthermore, p-BQ is a redox cycling agent that leads to formation of reactive oxygen species (ROS) that may lead to single-strand breaks as well as oxidation of DNA bases.	('leukemogenesis', 'Disease', (133, 147))	('formation', 'biological_process', 'GO:0009058', ('205', '214'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (218, 241))	('p-BQ', 'Chemical', 'MESH:C004532', (161, 165))	('DNA', 'cellular_component', 'GO:0005574', ('310', '313'))	('formation', 'biological_process', 'GO:0009058', ('83', '92'))	('p-BQ', 'Chemical', 'MESH:C004532', (10, 14))	('topoisomerase II', 'molecular_function', 'GO:0003918', ('34', '50'))	('single-strand breaks', 'MPA', (265, 285))	('lead to', 'Reg', (257, 264))	('oxidation', 'MPA', (297, 306))	('p-BQ', 'Var', (161, 165))	('ROS', 'Chemical', 'MESH:D017382', (243, 246))
107686	28959653	Moreover, ROS causes oxidative stress within cells through the formation of oxidized cellular macromolecules, including proteins.	('formation', 'biological_process', 'GO:0009058', ('63', '72'))	('formation of oxidized cellular macromolecules', 'MPA', (63, 108))	('ROS', 'Var', (10, 13))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('oxidative stress', 'Phenotype', 'HP:0025464', (21, 37))	('causes', 'Reg', (14, 20))	('oxidative stress', 'MPA', (21, 37))	('proteins', 'Protein', (120, 128))
107688	28959653	Here, we showed that p-BQ initiated protein oxidation, which was accompanied by apoptosis.	('initiated', 'Reg', (26, 35))	('protein oxidation', 'MPA', (36, 53))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('p-BQ', 'Chemical', 'MESH:C004532', (21, 25))	('protein oxidation', 'biological_process', 'GO:0018158', ('36', '53'))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('p-BQ', 'Var', (21, 25))
107690	28959653	Majority of CIS in the urothelium is known to progress to invasive cancer with a higher risk of cancer-specific mortality.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('CIS', 'Var', (12, 15))	('cancer', 'Disease', (67, 73))	('CIS', 'Phenotype', 'HP:0030075', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('invasive cancer', 'Disease', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('progress', 'PosReg', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('invasive cancer', 'Disease', 'MESH:D009362', (58, 73))	('cancer', 'Disease', (96, 102))
107694	28959653	Increased nuclear accumulation of p53 protein indicates mutations of the TP53 gene, which is a common event in the development of urothelial CIS and invasive neoplasms.	('p53 protein', 'Protein', (34, 45))	('mutations', 'Var', (56, 65))	('urothelial CIS', 'Disease', 'MESH:D014522', (130, 144))	('urothelial CIS', 'Disease', (130, 144))	('invasive neoplasms', 'Disease', (149, 167))	('neoplasm', 'Phenotype', 'HP:0002664', (158, 166))	('TP53', 'Gene', (73, 77))	('TP53', 'Gene', '100379269', (73, 77))	('neoplasms', 'Phenotype', 'HP:0002664', (158, 167))	('Increased', 'PosReg', (0, 9))	('invasive neoplasms', 'Disease', 'MESH:D009361', (149, 167))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('CIS', 'Phenotype', 'HP:0030075', (141, 144))	('nuclear accumulation', 'MPA', (10, 30))	('men', 'Species', '9606', (122, 125))
107696	28959653	Here, we showed that p-BQ activated EGFR in the renal pelvis apparently by binding to cysteine or lysine residues of the extracellular domain and induced aberrant phosphorylation of cytoplasmic tyrosine residuesinsert reference.	('cysteine', 'MPA', (86, 94))	('lysine', 'Chemical', 'MESH:D008239', (98, 104))	('cysteine', 'Chemical', 'MESH:D003545', (86, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('renal pelvis', 'Phenotype', 'HP:0000125', (48, 60))	('binding', 'molecular_function', 'GO:0005488', ('75', '82'))	('p-BQ', 'Chemical', 'MESH:C004532', (21, 25))	('activated', 'PosReg', (26, 35))	('tyrosine', 'Chemical', 'MESH:D014443', (194, 202))	('extracellular', 'cellular_component', 'GO:0005576', ('121', '134'))	('EGFR', 'Gene', (36, 40))	('binding', 'Interaction', (75, 82))	('phosphorylation', 'MPA', (163, 178))	('phosphorylation', 'biological_process', 'GO:0016310', ('163', '178'))	('p-BQ', 'Var', (21, 25))	('induced', 'Reg', (146, 153))
107701	28959653	Tyrosine 1045 of the cytoplasmic domain of EGFR is essential for c-Cbl mediated degradation and downregulation of EGFR signaling.	('Tyrosine 1045', 'Var', (0, 13))	('Cbl', 'Gene', '100725041', (67, 70))	('degradation', 'MPA', (80, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('Cbl', 'Gene', (67, 70))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('Tyrosine', 'Chemical', 'MESH:D014443', (0, 8))	('downregulation', 'NegReg', (96, 110))	('degradation', 'biological_process', 'GO:0009056', ('80', '91'))	('EGFR signaling', 'Pathway', (114, 128))	('EGFR', 'Gene', (43, 47))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))
107702	28959653	Phosphorylation of Tyr 1045 acts as the docking site for E3 ubiquitin ligase c-Cbl.	('Tyr 1045', 'Var', (19, 27))	('Cbl', 'Gene', '100725041', (79, 82))	('Tyr', 'Chemical', 'MESH:D014443', (19, 22))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('60', '69'))	('Cbl', 'Gene', (79, 82))
107709	28959653	Similarly increased phosphorylation at Tyr 1068 is seen that acts as the docking site for Grb2 which activates GTPase Hras as well as p44/p42 MAPK leading to proliferation.	('Hras', 'Gene', '100735038', (118, 122))	('activates', 'PosReg', (101, 110))	('Hras', 'Gene', (118, 122))	('phosphorylation', 'biological_process', 'GO:0016310', ('20', '35'))	('Grb2', 'Gene', '100715453', (90, 94))	('Grb2', 'Gene', (90, 94))	('p44/p42 MAPK', 'Var', (134, 146))	('MAPK', 'molecular_function', 'GO:0004707', ('142', '146'))	('Tyr', 'Chemical', 'MESH:D014443', (39, 42))	('GTP', 'Chemical', 'MESH:D006160', (111, 114))	('rat', 'Species', '10116', (165, 168))	('proliferation', 'CPA', (158, 171))
107710	28959653	Overexpression of Ras protein has been associated with various cancers including UC.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Ras protein', 'Protein', (18, 29))	('associated', 'Reg', (39, 49))	('Overexpression', 'Var', (0, 14))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
107713	28959653	Ras/Raf/MAPK pathway plays a key role in stabilizing c-Myc by phosphorylation at ser62.	('ser62', 'Chemical', '-', (81, 86))	('ser', 'cellular_component', 'GO:0005790', ('81', '84'))	('phosphorylation', 'MPA', (62, 77))	('c-Myc', 'Protein', (53, 58))	('ser62', 'Var', (81, 86))	('MAPK', 'molecular_function', 'GO:0004707', ('8', '12'))	('stabilizing', 'MPA', (41, 52))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))
107720	28959653	It is reported that patients with p53 altered and p21 waf1/cip1-negative tumors have a high probability of recurrence and poor survival.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('cip1', 'Gene', (59, 63))	('waf1', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('p21', 'Gene', '1026', (50, 53))	('p53 altered', 'Var', (34, 45))	('cip1', 'Gene', '1026', (59, 63))	('waf1', 'Gene', '1026', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('patients', 'Species', '9606', (20, 28))	('tumors', 'Disease', (73, 79))	('p21', 'Gene', (50, 53))
107724	28959653	We have shown that in p-BQ-induced CIS, pRb is hyperphosphorylated, which results in cell cycle progression evading G1/S checkpoint.	('p-BQ', 'Chemical', 'MESH:C004532', (22, 26))	('cell cycle', 'biological_process', 'GO:0007049', ('85', '95'))	('cell', 'MPA', (85, 89))	('pRb', 'Gene', (40, 43))	('results in', 'Reg', (74, 84))	('G1/S checkpoint', 'biological_process', 'GO:0000075', ('116', '131'))	('G1/S checkpoint', 'MPA', (116, 131))	('p-BQ-induced', 'Var', (22, 34))	('CIS', 'Phenotype', 'HP:0030075', (35, 38))	('evading', 'NegReg', (108, 115))
107733	28959653	Our present investigation provides the mechanism how p-BQ initiates non-invasive urothelial neoplasm.	('urothelial neoplasm', 'Disease', (81, 100))	('initiates', 'Reg', (58, 67))	('p-BQ', 'Chemical', 'MESH:C004532', (53, 57))	('urothelial neoplasm', 'Disease', 'MESH:D014523', (81, 100))	('p-BQ', 'Var', (53, 57))	('neoplasm', 'Phenotype', 'HP:0002664', (92, 100))
107744	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))
107745	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))
107748	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))
107771	28912897	As per the study by Teng and colleagues, we classified TCGA samples of each cancer type into four TMITs by merging the mRNA expression levels of PD-L1 and CD8A, or PD-L1 and CYT as follows: type I, PD-L1 high expression and CD8A/CYT high expression; type II, PD-L1 low expression and CD8A/CYT low expression; type III, PD-L1 high expression and CD8A/CYT low expression; and type IV, PD-L1 low expression and CD8A/CYT high expression.	('CD8A', 'Gene', (408, 412))	('CD8A', 'Gene', (224, 228))	('CD8A', 'Gene', '925', (155, 159))	('CD8A', 'Gene', '925', (408, 412))	('CD8A', 'Gene', (155, 159))	('CD8A', 'Gene', '925', (345, 349))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CD8A', 'Gene', (345, 349))	('TMIT', 'Chemical', '-', (98, 102))	('CD8A', 'Gene', '925', (284, 288))	('low', 'NegReg', (389, 392))	('PD-L1', 'Var', (319, 324))	('CD8A', 'Gene', (284, 288))	('CD8A', 'Gene', '925', (224, 228))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
107777	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))
107782	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))
107788	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))
107789	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))
107793	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))	('CD8A', 'Gene', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (45, 50))	('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))	('tumor', 'Disease', (92, 97))	('BRCA', 'Gene', '672', (238, 242))	('BLCA', 'Chemical', '-', (232, 236))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
107798	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))	('neoantigen numbers', 'Var', (40, 58))	('mutation', 'Var', (28, 36))
107823	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))
107827	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))
107834	27785421	Lynch syndrome and exposure to aristolochic acid in upper-tract urothelial carcinoma: its clinical impact?	('upper-tract urothelial carcinoma', 'Disease', (52, 84))	('aristolochic acid', 'Chemical', 'MESH:C000228', (31, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Lynch syndrome', 'Disease', (0, 14))	('upper-tract urothelial carcinoma', 'Disease', 'MESH:D012141', (52, 84))	('aristolochic', 'Var', (31, 43))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))
107836	27785421	A systematic review of the scientific literature was performed using the Medline database (National Library of Medicine, PubMed) using the following keywords: epidemiology, risk factor, AA, Balkan nephropathy (BNe), LS, hereditary cancer, hereditary non-polyposis colorectal cancer (HNPCC), mismatch repair genes, urothelial carcinomas, upper urinary tract, renal pelvis, ureter, Amsterdam criteria, genetic counselling, mismatch repair genes, genetic instability, microsatellite, and Bethesda guidelines.	('hereditary cancer', 'Disease', (220, 237))	('Balkan nephropathy', 'Disease', 'MESH:D007674', (190, 208))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (314, 335))	('Balkan nephropathy', 'Disease', (190, 208))	('hereditary non-polyposis colorectal cancer', 'Disease', 'MESH:D015179', (239, 281))	('mismatch repair', 'biological_process', 'GO:0006298', ('421', '436'))	('hereditary cancer', 'Disease', 'MESH:D009369', (220, 237))	('HNPCC', 'Gene', (283, 288))	('mismatch repair genes', 'Gene', (421, 442))	('genetic', 'Var', (444, 451))	('HNPCC', 'Gene', '4436', (283, 288))	('HNPCC', 'Phenotype', 'HP:0006716', (283, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('carcinomas', 'Phenotype', 'HP:0030731', (325, 335))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('mismatch repair genes', 'Gene', (291, 312))	('colorectal cancer', 'Phenotype', 'HP:0003003', (264, 281))	('hereditary non-polyposis colorectal cancer', 'Disease', (239, 281))	('mismatch repair', 'biological_process', 'GO:0006298', ('291', '306'))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('renal pelvis', 'Phenotype', 'HP:0000125', (358, 370))	('nephropathy', 'Phenotype', 'HP:0000112', (197, 208))	('urothelial carcinomas', 'Disease', (314, 335))	('hereditary non-polyposis colorectal cancer', 'Phenotype', 'HP:0006716', (239, 281))
107838	27785421	Mutation of the MSH2 gene is the most commonly described cause of UTUC in LS.	('MSH2', 'Gene', (16, 20))	('MSH2', 'Gene', '4436', (16, 20))	('cause', 'Reg', (57, 62))	('UTUC', 'Disease', (66, 70))	('Mutation', 'Var', (0, 8))
107848	27785421	Ingestion of aristolochic acid (AA) is now recognized to be a carcinogenic agent that causes severe renal disease and UTUCs in exposed populations worldwide.	('aristolochic acid', 'Chemical', 'MESH:C000228', (13, 30))	('aristolochic acid', 'Var', (13, 30))	('UTUCs', 'Phenotype', 'HP:0010786', (118, 123))	('causes', 'Reg', (86, 92))	('UTUCs', 'Disease', (118, 123))	('renal disease', 'Disease', (100, 113))	('carcinogenic', 'Disease', 'MESH:D063646', (62, 74))	('renal disease', 'Disease', 'MESH:D007674', (100, 113))	('carcinogenic', 'Disease', (62, 74))	('renal disease', 'Phenotype', 'HP:0000112', (100, 113))
107860	27785421	LS is associated with a germline mutation of one of the six genes in the DNA-mismatch repair system (MMR): i.e., hMSH2, hMSH3, hMSH6, hMLH1, hPMS1, hPMS2.	('hMSH', 'molecular_function', 'GO:0018775', ('120', '124'))	('hMLH1', 'Gene', (134, 139))	('hMLH1', 'Gene', '4292', (134, 139))	('hMSH2', 'Gene', '4436', (113, 118))	('hPMS2', 'Gene', '5395', (148, 153))	('germline mutation', 'Var', (24, 41))	('hMSH2', 'Gene', (113, 118))	('mismatch repair', 'biological_process', 'GO:0006298', ('77', '92'))	('hPMS2', 'Gene', (148, 153))	('hMSH', 'molecular_function', 'GO:0018775', ('127', '131'))	('MMR', 'biological_process', 'GO:0006298', ('101', '104'))	('hPMS1', 'Gene', (141, 146))	('associated', 'Reg', (6, 16))	('hMSH', 'molecular_function', 'GO:0018775', ('113', '117'))	('hMSH6', 'Gene', (127, 132))	('hMSH3', 'Gene', '4437', (120, 125))	('hPMS1', 'Gene', '5378', (141, 146))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('hMSH3', 'Gene', (120, 125))	('hMSH6', 'Gene', '2956', (127, 132))
107861	27785421	This type of mutation is causes an unstable tumor phenotype that can be detected by assessing microsatellite instability (MSI).	('mutation', 'Var', (13, 21))	('microsatellite instability', 'MPA', (94, 120))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('MSI', 'Disease', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('MSI', 'Disease', 'None', (122, 125))
107874	27785421	An hMSH2 gene mutation is the most common (60%) in patients with LS and UTUC.	('hMSH', 'molecular_function', 'GO:0018775', ('3', '7'))	('common', 'Reg', (35, 41))	('UTUC', 'Disease', (72, 76))	('hMSH2', 'Gene', '4436', (3, 8))	('mutation', 'Var', (14, 22))	('hMSH2', 'Gene', (3, 8))	('patients', 'Species', '9606', (51, 59))
107876	27785421	Mutations of other genes (hMSH3, hPMS1, and hPSM2) are less common.	('hMSH', 'molecular_function', 'GO:0018775', ('26', '30'))	('hMSH3', 'Gene', '4437', (26, 31))	('hPMS1', 'Gene', (33, 38))	('hPSM2', 'Gene', (44, 49))	('hPMS1', 'Gene', '5378', (33, 38))	('Mutations', 'Var', (0, 9))	('hMSH3', 'Gene', (26, 31))
107888	27785421	Published data report that those with familial LS and patients carrying a MSH2 mutation are particularly at risk of carcinogenesis of the upper urinary tract and so should be monitored closely.	('MSH2', 'Gene', '4436', (74, 78))	('carcinogenesis', 'Disease', 'MESH:D063646', (116, 130))	('patients', 'Species', '9606', (54, 62))	('carcinogenesis', 'Disease', (116, 130))	('mutation', 'Var', (79, 87))	('risk', 'Reg', (108, 112))	('familial LS', 'Disease', (38, 49))	('MSH2', 'Gene', (74, 78))
107990	29702555	In addition to the effects on lung cancer, PFE may be a promising chemopreventive/chemotherapeutic agent against human prostate cancer as well.	('n', 'Chemical', 'MESH:D009584', (130, 131))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('human', 'Species', '9606', (113, 118))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('lung cancer', 'Disease', (30, 41))	('PFE', 'Chemical', 'MESH:D000074263', (43, 46))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('prostate cancer', 'Disease', 'MESH:D011471', (119, 134))	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('prostate cancer', 'Disease', (119, 134))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('PFE', 'Var', (43, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('n', 'Chemical', 'MESH:D009584', (76, 77))
108020	29702555	Hence, the EtOAc layer (4.5 g) was subjected directly to Diaion HP-20 column chromatography, eluted with water containing increasing proportions of ethanol to render eight fractions labeled PEPE1 (0.1256 g), PEPE2 (0.1064 g), PEPE3 (1.712 g), PEPE4 (1.4595 g), PEPE5 (0.3758 g), PEPE6 (0.1384 g), PEPE7 (0.1731 g), and PEPE8 (0.1567 g).	('PEPE', 'Gene', '5185', (279, 283))	('n', 'Chemical', 'MESH:D009584', (130, 131))	('n', 'Chemical', 'MESH:D009584', (161, 162))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('PEPE', 'Gene', '5185', (208, 212))	('EtOAc', 'Chemical', 'MESH:C007650', (11, 16))	('0.1731 g', 'Var', (304, 312))	('PEPE', 'Gene', (261, 265))	('PEPE', 'Gene', '5185', (319, 323))	('n', 'Chemical', 'MESH:D009584', (2, 3))	('water', 'Chemical', 'MESH:D014867', (105, 110))	('PEPE', 'Gene', (226, 230))	('PEPE', 'Gene', '5185', (190, 194))	('PEPE', 'Gene', (243, 247))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (142, 143))	('n', 'Chemical', 'MESH:D009584', (152, 153))	('ethanol', 'Chemical', 'MESH:D000431', (148, 155))	('PEPE', 'Gene', (297, 301))	('PEPE', 'Gene', '5185', (261, 265))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('PEPE', 'Gene', '5185', (226, 230))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('PEPE', 'Gene', '5185', (243, 247))	('PEPE', 'Gene', (279, 283))	('n', 'Chemical', 'MESH:D009584', (316, 317))	('0.3758 g', 'Var', (268, 276))	('PEPE', 'Gene', (208, 212))	('n', 'Chemical', 'MESH:D009584', (179, 180))	('PEPE', 'Gene', '5185', (297, 301))	('PEPE', 'Gene', (319, 323))	('PEPE', 'Gene', (190, 194))
108115	29702555	The hematoxylin/eosin (H/E) staining of H2O-treated tumors revealed large neoplastic areas while the 5 and 10 mg/kg treated counterparts showed less neoplastic areas comparatively (Figure 4B).	('H2O', 'Chemical', 'MESH:D014867', (40, 43))	('n', 'Chemical', 'MESH:D009584', (74, 75))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('neoplastic areas', 'CPA', (74, 90))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('n', 'Chemical', 'MESH:D009584', (20, 21))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('hematoxylin', 'Chemical', 'MESH:D006416', (4, 15))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('H2O-treated', 'Var', (40, 51))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('eosin', 'Chemical', 'MESH:D004801', (16, 21))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('n', 'Chemical', 'MESH:D009584', (149, 150))
108152	29702555	(2016) found that treatment of polyphenol of pomegranate peels can induce HepG2 cells apoptosis by increasing cytochrome c amount, p53 expression level, Bax/Bcl-2 and caspase-3/9 activities.	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('cytochrome c', 'molecular_function', 'GO:0009461', ('110', '122'))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('p53', 'Gene', (131, 134))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('caspase-3', 'Gene', (167, 176))	('Bcl-2', 'Gene', '596', (157, 162))	('HepG2 cells apoptosis', 'CPA', (74, 95))	('Bax', 'Gene', (153, 156))	('pomegranate', 'Species', '22663', (45, 56))	('cytochrome c', 'Gene', '54205', (110, 122))	('n', 'Chemical', 'MESH:D009584', (144, 145))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('Bax', 'Gene', '581', (153, 156))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('increasing', 'PosReg', (99, 109))	('men', 'Species', '9606', (23, 26))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('cytochrome c', 'molecular_function', 'GO:0045155', ('110', '122'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('157', '162'))	('cytochrome c', 'Gene', (110, 122))	('HepG2', 'CellLine', 'CVCL:0027', (74, 79))	('polyphenol', 'Chemical', 'MESH:D059808', (31, 41))	('p53', 'Gene', '7157', (131, 134))	('polyphenol', 'Var', (31, 41))	('n', 'Chemical', 'MESH:D009584', (164, 165))	('Bcl-2', 'Gene', (157, 162))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('caspase-3', 'Gene', '836', (167, 176))	('activities', 'MPA', (179, 189))	('induce', 'PosReg', (67, 73))
108160	29702555	PPE is also shown to alleviate the hepatic pathology, body weight, liver enzymes, and retard lipogenesis.	('body weight', 'CPA', (54, 65))	('n', 'Chemical', 'MESH:D009584', (74, 75))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('PPE', 'Chemical', '-', (0, 3))	('lipogenesis', 'biological_process', 'GO:0008610', ('93', '104'))	('liver enzymes', 'MPA', (67, 80))	('PPE', 'Var', (0, 3))	('n', 'Chemical', 'MESH:D009584', (99, 100))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('retard', 'NegReg', (86, 92))	('alleviate', 'NegReg', (21, 30))	('lipogenesis', 'MPA', (93, 104))	('hepatic pathology', 'MPA', (35, 52))
108280	9484825	The 1- and 3-year disease-free survival rates in the patients with high MMP-2/TIMP-2 ratios (50% and 12%) were significantly poorer than those of the patients with normal ratios (82% and 56%) (P = 0.0152).	('MMP-2', 'Gene', '4313', (72, 77))	('high', 'Var', (67, 71))	('patients', 'Species', '9606', (53, 61))	('poorer', 'NegReg', (125, 131))	('TIMP-2', 'Gene', (78, 84))	('disease-free survival', 'CPA', (18, 39))	('TIMP-2', 'Gene', '7077', (78, 84))	('MMP-2', 'Gene', (72, 77))	('patients', 'Species', '9606', (150, 158))	('MMP-2', 'molecular_function', 'GO:0004228', ('72', '77'))
108336	33738002	Based on the WHO grading system, patients with low risk disease are known to have unifocal disease, tumor size < 2 cm, low-grade cytology, low-grade URS biopsy and no invasive aspect on CT urography.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('patients', 'Species', '9606', (33, 41))	('low-grade cytology', 'Var', (119, 137))	('tumor', 'Disease', (100, 105))	('unifocal disease', 'Disease', (82, 98))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
108337	33738002	Characteristics of high-risk UTUC in patients included hydronephrosis, tumor size > 2 cm, high-grade cytology, high-grade URS biopsy, multifocal disease, previous radical cystectomy for bladder cancer and variant histology.	('bladder cancer', 'Disease', 'MESH:D001749', (186, 200))	('bladder cancer', 'Disease', (186, 200))	('multifocal disease', 'Disease', (134, 152))	('high-grade', 'Var', (111, 121))	('hydronephrosis', 'Phenotype', 'HP:0000126', (55, 69))	('patients', 'Species', '9606', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('hydronephrosis', 'Disease', 'MESH:D006869', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('hydronephrosis', 'Disease', (55, 69))	('high-grade cytology', 'Var', (90, 109))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('bladder cancer', 'Phenotype', 'HP:0009725', (186, 200))	('tumor', 'Disease', (71, 76))	('multifocal disease', 'Disease', 'MESH:D000080364', (134, 152))
108471	31379926	The gene sets identified by the other algorithms were related to different pathways such as "positive regulation of JNK cascade" (CoxPH), "central carbon metabolism in cancer" (Fisher score and Fscore), "O-glycan biosynthesis, mucin type core" (LLL21, RF, and XGBoost), "mitotic nuclear division" (Trace ratio), "regulation of gene silencing" (RFS), and "GPCR ligand binding" (SVM).	('JNK', 'Gene', '5599', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('O-glycan', 'Chemical', '-', (204, 212))	('Cox', 'Gene', '1351', (130, 133))	('Cox', 'Gene', (130, 133))	('carbon', 'Chemical', 'MESH:D002244', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('JNK', 'Gene', (116, 119))	('gene silencing', 'Var', (327, 341))
108512	30602657	Cardiac dysfunction is a recognized outcome of cancer-induced cachexia, with alterations in heart function leading to poor outcomes such as dyspnoea, fatigue, reduced quality of life, limited tolerance to therapeutics, and survival.	('heart function', 'MPA', (92, 106))	('cachexia', 'Disease', (62, 70))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('Cardiac dysfunction', 'Disease', (0, 19))	('reduced', 'NegReg', (159, 166))	('cancer', 'Disease', (47, 53))	('dyspnoea', 'Disease', (140, 148))	('dyspnoea', 'Disease', 'MESH:D004417', (140, 148))	('Cardiac dysfunction', 'Disease', 'MESH:D006331', (0, 19))	('cachexia', 'Phenotype', 'HP:0004326', (62, 70))	('alterations', 'Var', (77, 88))	('quality of life', 'CPA', (167, 182))	('fatigue', 'Disease', 'MESH:D005221', (150, 157))	('fatigue', 'Disease', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('fatigue', 'Phenotype', 'HP:0012378', (150, 157))	('cachexia', 'Disease', 'MESH:D002100', (62, 70))
108529	30602657	The incidence of urothelial lesions observed in exercised and sedentary mice exposed to BBN was also different: the incidence of invasive carcinoma was 5% lower in BBN+Ex and the incidence of preneoplastic lesions was also lower in BBN+Ex group (10% lower for simple hyperplasia and 25% lower for dysplasia) compared to BBN+Sed.	('BBN', 'Chemical', 'MESH:D002085', (88, 91))	('dysplasia', 'Disease', (297, 306))	('lower', 'NegReg', (155, 160))	('dysplasia', 'Disease', 'MESH:D004476', (297, 306))	('urothelial lesions', 'Disease', 'MESH:D004194', (17, 35))	('preneoplastic lesions', 'Disease', 'MESH:D011230', (192, 213))	('lower', 'NegReg', (250, 255))	('BBN+Ex', 'Var', (164, 170))	('BBN', 'Chemical', 'MESH:D002085', (164, 167))	('urothelial lesions', 'Disease', (17, 35))	('Ex', 'Chemical', '-', (236, 238))	('lower', 'NegReg', (287, 292))	('lower', 'NegReg', (223, 228))	('hyperplasia', 'Disease', (267, 278))	('BBN', 'Chemical', 'MESH:D002085', (320, 323))	('invasive carcinoma', 'Disease', (129, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('hyperplasia', 'Disease', 'MESH:D006965', (267, 278))	('BBN', 'Chemical', 'MESH:D002085', (232, 235))	('preneoplastic lesions', 'Disease', (192, 213))	('invasive carcinoma', 'Disease', 'MESH:D009361', (129, 147))	('mice', 'Species', '10090', (72, 76))	('Ex', 'Chemical', '-', (168, 170))
108556	30602657	Our data shows that BBN-induced urothelial carcinoma is associated with hemodynamic signs of cardiac dysfunction, further supported by histological evidences of fibrosis and significantly lower serum levels of the cardioprotector myokine irisin.	('BBN-induced', 'Var', (20, 31))	('cardiac dysfunction', 'Disease', (93, 112))	('urothelial carcinoma', 'Disease', (32, 52))	('lower', 'NegReg', (188, 193))	('fibrosis', 'Disease', 'MESH:D005355', (161, 169))	('fibrosis', 'Disease', (161, 169))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (93, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('BBN', 'Chemical', 'MESH:D002085', (20, 23))	('serum levels of the', 'MPA', (194, 213))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (32, 52))
108568	30602657	Derangements in cardiac energy metabolism contribute to the pathological remodeling of heart once the capacity of cardiac mitochondria to generate ATP is compromised and myocardial high-energy phosphate stores, specifically phosphocreatine levels, the main reservoir sources of ATP, are reduced.	('compromised', 'NegReg', (154, 165))	('metabolism', 'biological_process', 'GO:0008152', ('31', '41'))	('ATP', 'Chemical', 'MESH:D000255', (147, 150))	('mitochondria', 'cellular_component', 'GO:0005739', ('122', '134'))	('Derangements', 'Var', (0, 12))	('ATP', 'Chemical', 'MESH:D000255', (278, 281))	('phosphocreatine', 'Chemical', 'MESH:D010725', (224, 239))	('phosphocreatine levels', 'MPA', (224, 246))	('phosphate', 'Chemical', 'MESH:D010710', (193, 202))	('cardiac energy metabolism', 'MPA', (16, 41))	('reduced', 'NegReg', (287, 294))	('myocardial high-energy phosphate stores', 'MPA', (170, 209))
108605	30602657	Phosphatase and protease inhibitors (P2850, P5726, P8340; Sigma, Saint Louis, MO, USA) were added and all the procedures were performed at 4  C. Protein concentration was estimated with a colorimetric method (RC-DC protein assay, Bio-Rad, Hercules, CA, USA) using BSA as standard.	('P8340', 'Var', (51, 56))	('Rad', 'biological_process', 'GO:1990116', ('234', '237'))	('P5726', 'Var', (44, 49))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('P2850', 'Chemical', '-', (37, 42))	('Phosphatase', 'molecular_function', 'GO:0016791', ('0', '11'))	('P5726', 'Chemical', '-', (44, 49))	('P2850', 'Var', (37, 42))	('Rad', 'Gene', (234, 237))	('Rad', 'Gene', '56437', (234, 237))
108630	29354493	On the example of Her2 targeting, we aimed to indicate, that either a target is ineffective in MIBC or that the patient selection is insufficient.	('insufficient', 'Disease', (133, 145))	('patient', 'Species', '9606', (112, 119))	('targeting', 'Var', (23, 32))	('Her2', 'Gene', '2064', (18, 22))	('MIBC', 'Chemical', '-', (95, 99))	('MIBC', 'Disease', (95, 99))	('Her2', 'Gene', (18, 22))	('insufficient', 'Disease', 'MESH:D000309', (133, 145))
108648	29354493	Importantly, all levels of Her2 are enriched in luminal-like tumors, such as amplification rate, mRNA and protein overexpression.	('protein', 'Protein', (106, 113))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('amplification rate', 'Var', (77, 95))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('Her2', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Her2', 'Gene', '2064', (27, 31))	('mRNA and', 'MPA', (97, 105))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
108664	29354493	They mediate the signal from these growth factors that mediate an activation of several pathways e.g., Erk, Mek, MAPK, NF-kB, Ras, Raf, Stat3, PI3K.	('PI3K', 'Var', (143, 147))	('Erk', 'Gene', (103, 106))	('MAPK', 'Pathway', (113, 117))	('Erk', 'Gene', '5594', (103, 106))	('Stat3', 'Gene', '6774', (136, 141))	('MAPK', 'molecular_function', 'GO:0004707', ('113', '117'))	('Raf', 'Gene', '22882', (131, 134))	('PI3K', 'molecular_function', 'GO:0016303', ('143', '147'))	('Ras', 'Pathway', (126, 129))	('Stat3', 'Gene', (136, 141))	('Mek', 'Gene', '5609', (108, 111))	('Mek', 'Gene', (108, 111))	('Erk', 'molecular_function', 'GO:0004707', ('103', '106'))	('NF-kB', 'Gene', (119, 124))	('Raf', 'Gene', (131, 134))	('activation', 'PosReg', (66, 76))
108665	29354493	Urothelial carcinoma shows a high frequency of genetic alterations particularly in FGFR3.	('FGFR3', 'Gene', '2261', (83, 88))	('Urothelial carcinoma', 'Disease', 'MESH:D014526', (0, 20))	('FGFR', 'molecular_function', 'GO:0005007', ('83', '87'))	('Urothelial carcinoma', 'Disease', (0, 20))	('FGFR3', 'Gene', (83, 88))	('genetic alterations', 'Var', (47, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
108666	29354493	Activating mutations, amplification and fusions of FGFR3 often result in an FGFR3 overexpression.	('FGFR3', 'Gene', '2261', (51, 56))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('fusions', 'Var', (40, 47))	('FGFR3', 'Gene', (76, 81))	('FGFR3', 'Gene', '2261', (76, 81))	('amplification', 'Var', (22, 35))	('overexpression', 'PosReg', (82, 96))	('FGFR3', 'Gene', (51, 56))	('result in', 'Reg', (63, 72))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))
108673	29354493	LY3076226 is a FGFR3 antibody conjugated with microtubule inhibitor, DM4 (Table 1, No.	('FGFR3', 'Gene', (15, 20))	('antibody', 'cellular_component', 'GO:0019815', ('21', '29'))	('LY3076226', 'Chemical', '-', (0, 9))	('microtubule', 'cellular_component', 'GO:0005874', ('46', '57'))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('DM4', 'Chemical', 'MESH:D008453', (69, 72))	('antibody', 'cellular_component', 'GO:0019814', ('21', '29'))	('antibody', 'molecular_function', 'GO:0003823', ('21', '29'))	('LY3076226', 'Var', (0, 9))	('FGFR3', 'Gene', '2261', (15, 20))	('antibody', 'cellular_component', 'GO:0042571', ('21', '29'))
108674	29354493	In this trial, the tumors are screened for FGFR alterations.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('FGFR', 'Gene', (43, 47))	('alterations', 'Var', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
108675	29354493	For the three selective FGFR tyrosine kinase inhibitors, BAY1163877, JNJ-42756493 and BGJ398, patients are preselected for FGFR alterations.	('patients', 'Species', '9606', (94, 102))	('FGFR', 'Gene', (24, 28))	('BAY1163877', 'Chemical', '-', (57, 67))	('BGJ398', 'Gene', (86, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('123', '127'))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))	('BAY1163877', 'Var', (57, 67))
108676	29354493	4 and 5), patients are selected according to high FGFR expression levels and FGFR mutations in archival tumors.	('archival tumors', 'Disease', 'MESH:D009369', (95, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('expression levels', 'MPA', (55, 72))	('mutations', 'Var', (82, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('50', '54'))	('patients', 'Species', '9606', (10, 18))	('archival tumors', 'Disease', (95, 110))	('FGFR', 'Gene', (50, 54))	('FGFR', 'Gene', (77, 81))
108677	29354493	A phase 2/3 trial investigating BAY1163877 (Rogaratinib) in progressive cisplatin-resistant urothelial carcinoma is about to start recruitment.	('Rogaratinib', 'Chemical', '-', (44, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('BAY1163877', 'Chemical', '-', (32, 42))	('urothelial carcinoma', 'Disease', (92, 112))	('BAY1163877', 'Var', (32, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (92, 112))
108678	29354493	6), patients with tumors that harbor amplification in FGFR1 or FGFR2 or mutations in FGFR3 are included.	('mutations', 'Var', (72, 81))	('FGFR', 'molecular_function', 'GO:0005007', ('54', '58'))	('FGFR3', 'Gene', (85, 90))	('FGFR1', 'Gene', (54, 59))	('FGFR1', 'Gene', '2260', (54, 59))	('amplification', 'Var', (37, 50))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('patients', 'Species', '9606', (4, 12))	('FGFR2', 'Gene', '2263', (63, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('FGFR3', 'Gene', '2261', (85, 90))	('FGFR2', 'Gene', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
108682	29354493	Finally, AZD4547a selective FGFR1-3 tyrosine kinase inhibitor is used as one of 18 different treatments (Table 1, No.	('AZD4547a', 'Var', (9, 17))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('FGFR1', 'Gene', (28, 33))	('AZD4547a', 'Chemical', '-', (9, 17))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('45', '61'))	('FGFR1', 'Gene', '2260', (28, 33))
108685	29354493	In terms of FGFR, tumors with FGFR1-3 mutations or translocation receive FGFR Inhibitor AZD4547.	('FGFR1', 'Gene', (30, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('73', '77'))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))	('FGFR1', 'Gene', '2260', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('mutations', 'Var', (38, 47))	('AZD4547', 'Chemical', 'MESH:C572463', (88, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
108698	29354493	For example, V5-tagged rVAR2 can be used for detection of ofCS by immunohistochemistry or flow cytometry.	('CS', 'Chemical', 'MESH:D002809', (60, 62))	('rVAR2', 'Gene', (23, 28))	('V5-tagged', 'Var', (13, 22))
108722	29354493	Despite biological similarities between cancers of breast and bladder cancer, e.g., in terms of molecular subtyping, amplification status or protein expression of Her2 are predictive for successful treatment in one but not in the other disease.	('Her2', 'Gene', (163, 167))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('protein expression', 'MPA', (141, 159))	('Her2', 'Gene', '2064', (163, 167))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('bladder cancer', 'Phenotype', 'HP:0009725', (62, 76))	('amplification status', 'Var', (117, 137))	('cancers of breast and bladder cancer', 'Disease', 'MESH:D001749', (40, 76))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
108726	29354493	Although DNA alterations such as activating mutations and amplifications are most commonly found in MIBC, patient selection for these trials are based on gene expression analysis.	('gene expression', 'biological_process', 'GO:0010467', ('154', '169'))	('amplifications', 'Var', (58, 72))	('patient', 'Species', '9606', (106, 113))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('MIBC', 'Chemical', '-', (100, 104))	('MIBC', 'Disease', (100, 104))
108759	21762516	Primary bladder tumors with rhabdomyosarcomatous differentiation: tumor with pure rhabdomyoblastic differentiation a.k.a rhabdomyosarcoma (case 1) versus tumor with minor carcinomatous element, a.k.a rhabdomyosarcomatous carcinoma (cases 2 and 3).	('a.k.a', 'Var', (115, 120))	('rhabdomyosarcomatous carcinoma', 'Disease', (200, 230))	('rhabdomyosarcomatous differentiation', 'Disease', (28, 64))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (28, 44))	('tumor', 'Disease', (154, 159))	('rhabdomyosarcoma', 'Disease', (121, 137))	('rhabdomyosarcoma', 'Disease', (200, 216))	('Primary bladder tumors', 'Disease', 'MESH:D001749', (0, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('bladder tumors', 'Phenotype', 'HP:0009725', (8, 22))	('tumor', 'Disease', (66, 71))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (28, 44))	('rhabdomyosarcomatous carcinoma', 'Disease', 'MESH:D002277', (200, 230))	('carcinomatous', 'Disease', (171, 184))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('rhabdomyosarcomatous carcinoma', 'Phenotype', 'HP:0002859', (200, 230))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (121, 137))	('pure', 'molecular_function', 'GO:0034023', ('77', '81'))	('carcinomatous', 'Disease', 'MESH:D055756', (171, 184))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (200, 216))	('Primary bladder tumors', 'Disease', (0, 22))	('bladder tumor', 'Phenotype', 'HP:0009725', (8, 21))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (121, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('tumor', 'Disease', (16, 21))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (200, 216))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('men', 'Species', '9606', (188, 191))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('rhabdomyosarcomatous differentiation', 'Disease', 'MESH:D012734', (28, 64))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('rhabdomyosarcoma', 'Disease', (28, 44))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))
108776	21762516	As shown in the table, the rhabdomyosarcomatous areas of all of three rhabdomyosarcomatous tumors of the bladder showed positivity for myogenin and desmin.	('desmin', 'cellular_component', 'GO:0045100', ('148', '154'))	('rhabdomyosarcomatous tumors', 'Disease', (70, 97))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (70, 86))	('rhabdomyosarcomatous', 'Disease', (70, 90))	('myogenin', 'Gene', '4656', (135, 143))	('rhabdomyosarcomatous', 'Disease', (27, 47))	('rhabdomyosarcomatous tumors', 'Disease', 'MESH:D009369', (70, 97))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (27, 43))	('desmin', 'Gene', (148, 154))	('tumors of the bladder', 'Phenotype', 'HP:0009725', (91, 112))	('desmin', 'cellular_component', 'GO:0045098', ('148', '154'))	('rhabdomyosarcomatous tumors', 'Phenotype', 'HP:0002859', (70, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('rhabdomyosarcomatous', 'Disease', 'None', (70, 90))	('desmin', 'Gene', '1674', (148, 154))	('positivity', 'Var', (120, 130))	('rhabdomyosarcomatous', 'Disease', 'None', (27, 47))	('myogenin', 'Gene', (135, 143))	('rhabdomyosarcomatous tumor', 'Phenotype', 'HP:0002859', (70, 96))
108822	21762516	As reported, positivity for synaptophysin can also be detected in pure RMS, and hence has little utility to differentiate rhabdomyosarcomatous tumors from other mimics with neuroendocrine differentiation such as small cell carcinoma.	('neuroendocrine', 'Disease', (173, 187))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('pure', 'molecular_function', 'GO:0034023', ('66', '70'))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('positivity', 'Var', (13, 23))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (212, 232))	('rhabdomyosarcomatous tumor', 'Phenotype', 'HP:0002859', (122, 148))	('rhabdomyosarcomatous tumors', 'Disease', (122, 149))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (122, 138))	('rhabdomyosarcomatous tumors', 'Disease', 'MESH:D009369', (122, 149))	('small cell carcinoma', 'Disease', (212, 232))	('synaptophysin', 'Gene', (28, 41))	('RMS', 'Phenotype', 'HP:0002859', (71, 74))	('small cell carcinoma', 'Disease', 'MESH:D018288', (212, 232))	('detected', 'Reg', (54, 62))	('rhabdomyosarcomatous tumors', 'Phenotype', 'HP:0002859', (122, 149))	('synaptophysin', 'Gene', '6855', (28, 41))	('neuroendocrine', 'Disease', 'MESH:D018358', (173, 187))
108824	21762516	FISH analysis was performed on paraffin-embedded formalin-fixed tissue in three cases of rhabdomyosarcomatous tumor of the bladder tumors to detect rearrangement of the FKHR (13q14) region which is hallmark of alveolar rhabdomyosarcoma.	('formalin', 'Chemical', 'MESH:D005557', (49, 57))	('bladder tumor', 'Phenotype', 'HP:0009725', (123, 136))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (210, 235))	('tumor of the bladder', 'Phenotype', 'HP:0009725', (110, 130))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (219, 235))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (210, 235))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('rhabdomyosarcomatous tumor of the bladder tumors', 'Disease', (89, 137))	('FKHR', 'Gene', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('rhabdomyosarcomatous tumor', 'Phenotype', 'HP:0002859', (89, 115))	('men', 'Species', '9606', (157, 160))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (89, 105))	('paraffin', 'Chemical', 'MESH:D010232', (31, 39))	('rearrangement', 'Var', (148, 161))	('FKHR', 'Gene', '2308', (169, 173))	('bladder tumors', 'Phenotype', 'HP:0009725', (123, 137))	('rhabdomyosarcomatous tumor of the bladder tumors', 'Disease', 'MESH:D001749', (89, 137))	('alveolar rhabdomyosarcoma', 'Disease', (210, 235))
108972	29767328	However, the PD-1 inhibitor pembrolizumab is evaluated in combination with BCG for patients with NMIBC (NCT02808143 and NCT02324582).	('pembrolizumab', 'Chemical', 'MESH:C582435', (28, 41))	('NCT02324582', 'Var', (120, 131))	('BCG', 'Species', '33892', (75, 78))	('patients', 'Species', '9606', (83, 91))	('NMIBC', 'Disease', (97, 102))	('NCT02808143', 'Var', (104, 115))
108973	29767328	The PD-L1 antibody Atezolizumab is under investigation for the treatment of NMIBC (NCT02792192) as well as for patients with CIS (NCT02844816).	('antibody', 'cellular_component', 'GO:0042571', ('10', '18'))	('Atezolizumab', 'Chemical', 'MESH:C000594389', (19, 31))	('antibody', 'cellular_component', 'GO:0019815', ('10', '18'))	('PD-L1', 'Gene', (4, 9))	('antibody', 'cellular_component', 'GO:0019814', ('10', '18'))	('antibody', 'molecular_function', 'GO:0003823', ('10', '18'))	('NCT02792192', 'Var', (83, 94))	('NMIBC', 'Disease', (76, 81))	('PD-L1', 'Gene', '29126', (4, 9))	('patients', 'Species', '9606', (111, 119))
108984	29650026	Large-scale transcriptome sequence changes are known to be associated with cancer.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('associated', 'Reg', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('changes', 'Var', (35, 42))
108990	29650026	However, WGS data are not completely suitable for inferring TSVs since they neither inform which region is transcribed nor reveal how the transcribed sequence will change if SVs alter a splicing site or the stop codon.	('splicing site', 'MPA', (186, 199))	('SVs', 'Var', (174, 177))	('TSV', 'Chemical', '-', (60, 63))	('alter', 'Reg', (178, 183))	('splicing', 'biological_process', 'GO:0045292', ('186', '194'))
109006	29650026	Observed non-fusion-gene TSVs, for example, are more likely to be intra-chromosomal events.	('TSV', 'Chemical', '-', (25, 28))	('non-fusion-gene', 'Var', (9, 24))	('TSVs', 'Disease', (25, 29))
109007	29650026	Finally, we identify several novel non-fusion-gene TSVs that affect known tumor suppressor genes (TSGs), which may result in loss of function of corresponding proteins and play a role in tumorigenesis.	('TSVs', 'Var', (51, 55))	('tumor', 'Disease', (187, 192))	('tumor suppressor', 'Gene', '7248', (74, 90))	('tumor', 'Disease', (74, 79))	('TSG', 'Gene', '57045', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('TSG', 'Gene', (98, 101))	('role', 'Reg', (179, 183))	('proteins', 'Protein', (159, 167))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('TSV', 'Chemical', '-', (51, 54))	('play', 'Reg', (172, 176))	('non-fusion-gene TSVs', 'Var', (35, 55))	('tumor suppressor', 'Gene', (74, 90))	('loss of function', 'NegReg', (125, 141))
109020	29650026	Fusion genes, thus, exclude TSV events where a gene region is fused with an intergenic region or an anti-sense strand of another gene.	('Fusion', 'Var', (0, 6))	('TSV', 'Disease', (28, 31))	('TSV', 'Chemical', '-', (28, 31))
109021	29650026	Nevertheless, fusion genes have been implicated in playing a role in cancer.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('fusion genes', 'Var', (14, 26))	('cancer', 'Disease', (69, 75))
109026	29650026	We use publicly available RNA-seq data from the Sequencing Read Archive (SRA) of the National Institutes of Health (SRA accessions SRR2532344 and SRR925710 for HCC1954, and SRR2532336 for HCC1395).	('SRA', 'Chemical', '-', (73, 76))	('SRR2532336', 'Var', (173, 183))	('SRR2532344', 'Var', (131, 141))	('SRA', 'Chemical', '-', (116, 119))	('HCC1954', 'CellLine', 'CVCL:1259', (160, 167))	('HCC1395', 'CellLine', 'CVCL:1249', (188, 195))	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))	('SRR925710', 'Var', (146, 155))
109035	29650026	A considerable proportion of validated TSVs are non-fusion-gene TSVs.	('TSVs', 'Disease', (39, 43))	('TSV', 'Chemical', '-', (64, 67))	('TSV', 'Chemical', '-', (39, 42))	('non-fusion-gene', 'Var', (48, 63))
109036	29650026	Correctly predicted non-fusion-gene TSVs make up almost half of all correct predictions of SQUID (Fig.	('SQUID', 'Disease', (91, 96))	('TSV', 'Chemical', '-', (36, 39))	('non-fusion-gene', 'Var', (20, 35))
109045	29650026	We use WGS data for the corresponding cell lines to validate the novel TSVs predicted by SQUID (SRA accession numbers ERP000265 for HCC1954 and SRR892417 and SRR892296 for HCC1395).	('TSV', 'Chemical', '-', (71, 74))	('SRR892417', 'Var', (144, 153))	('SRR892296', 'Var', (158, 167))	('HCC1954', 'CellLine', 'CVCL:1259', (132, 139))	('SRA', 'Chemical', '-', (96, 99))	('HCC1395', 'CellLine', 'CVCL:1249', (172, 179))
109056	29650026	We find that most samples have ~18-23 TSVs, including ~3-4 non-fusion-gene TSVs among all four cancer types (Fig.	('TSV', 'Chemical', '-', (75, 78))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('non-fusion-gene', 'Var', (59, 74))	('cancer', 'Disease', (95, 101))	('TSV', 'Chemical', '-', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
109061	29650026	Non-fusion-gene TSVs are more likely to be intra-chromosomal events than fusion-gene TSVs (Fig.	('TSV', 'Chemical', '-', (85, 88))	('TSV', 'Chemical', '-', (16, 19))	('Non-fusion-gene', 'Var', (0, 15))	('TSVs', 'Disease', (16, 20))
109063	29650026	Prostate cancer is an exception in that, for non-fusion-gene TSVs, inter-chromosomal events are observed much more often than intra-chromosomal events.	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('TSV', 'Chemical', '-', (61, 64))	('Prostate cancer', 'Disease', (0, 15))	('non-fusion-gene', 'Var', (45, 60))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('Prostate cancer', 'Disease', 'MESH:D011471', (0, 15))
109064	29650026	Nevertheless, non-fusion-gene TSVs are more likely to be intra-chromosomal than fusion-gene TSVs, because the percentage of intra-chromosomal TSVs within non-fusion-gene TSVs is higher than that within all TSVs.	('non-fusion-gene', 'Var', (154, 169))	('TSV', 'Chemical', '-', (30, 33))	('TSV', 'Chemical', '-', (170, 173))	('TSV', 'Chemical', '-', (92, 95))	('higher', 'PosReg', (178, 184))	('TSV', 'Chemical', '-', (206, 209))	('TSVs', 'Var', (142, 146))	('TSV', 'Chemical', '-', (142, 145))
109068	29650026	Mutations in TSGs may lead to loss of function of the corresponding proteins and benefit tumor growth.	('TSG', 'Gene', '57045', (13, 16))	('loss of function', 'NegReg', (30, 46))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Mutations', 'Var', (0, 9))	('proteins', 'Protein', (68, 76))	('TSG', 'Gene', (13, 16))	('benefit', 'PosReg', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
109069	29650026	For example, a homozygous loss-of-function mutation in p53 is found in about half of cancer samples across various cancer types.	('cancer', 'Disease', (115, 121))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('mutation', 'Var', (43, 51))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('loss-of-function', 'NegReg', (26, 42))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
109080	29650026	Another example is given by the ASXL1 gene, which is essential for activating CDKN2B to inhibit tumorigenesis.	('CDKN2B', 'Gene', '1030', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('ASXL1', 'Gene', '171023', (32, 37))	('ASXL1', 'Gene', (32, 37))	('tumor', 'Disease', (96, 101))	('inhibit', 'NegReg', (88, 95))	('CDKN2B', 'Gene', (78, 84))	('activating', 'Var', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
109086	29650026	These non-fusion-gene examples are novel predicted TSV events, which are not typically detectable via traditional fusion-gene detection methods using RNA-seq data.	('TSV', 'Chemical', '-', (51, 54))	('RNA', 'cellular_component', 'GO:0005562', ('150', '153'))	('non-fusion-gene', 'Var', (6, 21))	('TSV', 'Disease', (51, 54))
109087	29650026	They suggest that non-fusion-gene events can also be involved in tumorigenesis by disrupting TSGs.	('TSG', 'Gene', (93, 96))	('involved', 'Reg', (53, 61))	('tumor', 'Disease', (65, 70))	('disrupting', 'NegReg', (82, 92))	('TSG', 'Gene', '57045', (93, 96))	('non-fusion-gene', 'Var', (18, 33))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
109093	29650026	By applying SQUID to TCGA RNA-seq data, we are able to detect TSVs in cancer samples, especially non-fusion-gene TSVs.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('detect', 'Reg', (55, 61))	('TSV', 'Chemical', '-', (113, 116))	('TSV', 'Chemical', '-', (62, 65))	('non-fusion-gene', 'Var', (97, 112))	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
109096	29650026	TSVs will impact the accuracy of transcriptome assembly and expression quantification, and methodological advances are needed to correct those downstream analyses for the effect of TSVs.	('TSVs', 'Var', (0, 4))	('accuracy', 'MPA', (21, 29))	('TSV', 'Chemical', '-', (181, 184))	('TSV', 'Chemical', '-', (0, 3))	('expression quantification', 'MPA', (60, 85))	('transcriptome assembly', 'MPA', (33, 55))	('impact', 'Reg', (10, 16))
109106	29650026	We observe that non-fusion-gene TSVs are more likely to be intra-chromosomal events than fusion-gene TSVs.	('TSV', 'Chemical', '-', (32, 35))	('TSV', 'Chemical', '-', (101, 104))	('non-fusion-gene', 'Var', (16, 31))	('TSVs', 'Disease', (32, 36))
109111	29650026	The large-scale variations of TSGs suggest that non-fusion-gene TSVs can potentially affect cancer genesis and progression, and needs to be studied more carefully.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('TSV', 'Chemical', '-', (64, 67))	('non-fusion-gene', 'Var', (48, 63))	('TSG', 'Gene', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('affect', 'Reg', (85, 91))	('progression', 'CPA', (111, 122))	('TSG', 'Gene', '57045', (30, 33))
109123	29650026	There is the possibility that some rearranged tumor transcripts will be outnumbered by normal counterparts.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('rearranged', 'Var', (35, 45))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
109135	29650026	An interleaving structure of exons from different regions (different genes) seems more likely to be a result of sequencing or alignment error rather than an SV.	('sequencing', 'Var', (112, 122))	('alignment error', 'Disease', 'MESH:D012030', (126, 141))	('alignment error', 'Disease', (126, 141))
109155	24642859	Subgroup analyses revealed that high NLR yielded a worse OS in RCC (HR = 1.9, 95%CI: 1.47-2.45; Pheterogeneity = 0.003) and a poor RFS/CSS in RCC (HR = 1.83, 95%CI: 1.35-2.48; Pheterogeneity = 0.709), bladder cancer (HR = 2.2, 95%CI: 1.27-3.8; Pheterogeneity = 0.447) and urothelial carcinoma (HR = 2.58, 95%CI: 1.66-4.01; Pheterogeneity = 0.784).	('high', 'Var', (32, 36))	('RCC', 'Disease', (63, 66))	('RCC', 'Disease', (142, 145))	('bladder cancer', 'Disease', 'MESH:D001749', (201, 215))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('bladder cancer', 'Disease', (201, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (272, 292))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('poor', 'NegReg', (126, 130))	('urothelial carcinoma', 'Disease', (272, 292))	('bladder cancer', 'Phenotype', 'HP:0009725', (201, 215))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
109177	24642859	Subgroup analyses by cancer type showed that high NLR yielded a worse OS in RCC (HR = 1.9, 95%CI: 1.47-2.45; Pheterogeneity = 0.003) and a poor RFS/CSS in RCC (HR = 1.83, 95%CI: 1.35-2.48; Pheterogeneity = 0.709), bladder cancer (HR = 2.2, 95%CI: 1.27-3.8; Pheterogeneity = 0.447) and urothelial carcinoma (HR = 2.58, 95%CI: 1.66-4.01; Pheterogeneity = 0.784).	('RCC', 'Disease', (155, 158))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('urothelial carcinoma', 'Disease', (285, 305))	('RCC', 'Disease', 'MESH:C538614', (155, 158))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('bladder cancer', 'Disease', 'MESH:D001749', (214, 228))	('bladder cancer', 'Disease', (214, 228))	('cancer', 'Disease', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('bladder cancer', 'Phenotype', 'HP:0009725', (214, 228))	('high NLR', 'Var', (45, 53))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (285, 305))	('cancer', 'Disease', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
109245	22289336	The causes of RCCs are unknown; environmental exposure to asbestos, solvents and cadmium, smoking and genetic mutation have been implicated.	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('asbestos', 'Chemical', 'MESH:D001194', (58, 66))	('genetic mutation', 'Var', (102, 118))	('cadmium', 'Chemical', 'MESH:D002104', (81, 88))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
109255	22289336	Genetic hypersensitivity, mutation or pharmacological carcinogenetic effects provide other possibilities for cancer development.	('hypersensitivity', 'biological_process', 'GO:0002524', ('8', '24'))	('hypersensitivity,', 'Disease', 'MESH:D004342', (8, 25))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('mutation', 'Var', (26, 34))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
109260	22289336	Cox-2 polymorphism has been shown to be a predictive marker of survival in non-small cell lung cancer patients treated with chemoradiotherapy or radiotherapy.	('polymorphism', 'Var', (6, 18))	('cell lung cancer', 'Disease', (85, 101))	('patients', 'Species', '9606', (102, 110))	('Cox-2', 'Gene', '4513', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('cell lung cancer', 'Disease', 'MESH:D008175', (85, 101))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (79, 101))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (75, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Cox-2', 'Gene', (0, 5))
109302	32799825	In the tumor microenvironment, S1P exhibits multiple functions: (a) it increases the survival of macrophages; (b) it serves as the "come-and-get-me" signal of dead cells, attracting and enhancing macrophage migration by combining with S1PR1; (c) it stimulates the polarization of TAM/M2 macrophages by activating S1PR1/2/4.	('polarization', 'CPA', (264, 276))	('S1PR1/2/4', 'Gene', (313, 322))	('S1P', 'Chemical', 'MESH:C060506', (313, 316))	('activating', 'PosReg', (302, 312))	('survival of macrophages', 'CPA', (85, 108))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('stimulates', 'PosReg', (249, 259))	('S1PR1', 'Gene', '1901', (235, 240))	('S1PR1', 'Gene', (235, 240))	('S1PR1', 'Gene', '1901', (313, 318))	('S1P', 'Chemical', 'MESH:C060506', (31, 34))	('S1PR1/2/4', 'Gene', '1901;9294;8698', (313, 322))	('S1PR1', 'Gene', (313, 318))	('macrophage migration', 'biological_process', 'GO:1905517', ('194', '214'))	('combining', 'Interaction', (220, 229))	('increases', 'PosReg', (71, 80))	('enhancing', 'PosReg', (186, 195))	('macrophage migration', 'CPA', (196, 216))	('S1P', 'Var', (31, 34))	('tumor', 'Disease', (7, 12))	('S1P', 'Chemical', 'MESH:C060506', (235, 238))	('tumor', 'Disease', 'MESH:D009369', (7, 12))
109341	32799825	Two probes (204642_at and 239401_at) matching S1PR1 were detected.	('S1PR1', 'Gene', '1901', (46, 51))	('S1PR1', 'Gene', (46, 51))	('204642_at', 'Var', (12, 21))	('239401_at', 'Var', (26, 35))
109342	32799825	Notably, in three breast cancer cohorts (GSE1456-GPL96, GSE7378, and GSE12276), low S1PR1 expression was significantly associated with a poorer prognosis breast cancer (Fig.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('low', 'NegReg', (80, 83))	('S1PR1', 'Gene', '1901', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('GSE12276', 'Var', (69, 77))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('breast cancer', 'Disease', (18, 31))	('S1PR1', 'Gene', (84, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('expression', 'MPA', (90, 100))	('GSE1456-GPL96', 'Var', (41, 54))
109346	32799825	In addition, low S1PR1 expression was also related to poor prognosis in two cohorts of patients with lung cancer (GSE31210 and GSE8894), as determined using two probes (204642_at and 239401_at) (Fig.	('S1PR1', 'Gene', (17, 22))	('low', 'NegReg', (13, 16))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('poor', 'NegReg', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('204642_at', 'Var', (169, 178))	('239401_at', 'Var', (183, 192))	('S1PR1', 'Gene', '1901', (17, 22))	('patients', 'Species', '9606', (87, 95))	('lung cancer', 'Disease', (101, 112))	('expression', 'MPA', (23, 33))
109347	32799825	Kaplan-Meier plotter database also showed that low expression of S1PR1 was an independent risk factor for poor prognosis of lung cancer (overall survival, HR = 0.7, P = 6.9e-08; recurrence-free survival, HR = 0.71, P = 0.00035), but not related to post-progression survival in lung cancer (HR = 0.82, P = 0.14) (Fig.	('low expression', 'Var', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('lung cancer', 'Disease', (277, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (277, 288))	('S1PR1', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('lung cancer', 'Disease', 'MESH:D008175', (277, 288))	('lung cancer', 'Disease', (124, 135))	('S1PR1', 'Gene', '1901', (65, 70))
109359	32799825	Taken together, high expression of S1PR1 could be considered a good prognostic indictor for breast and lung cancers depending on the clinical characteristics.	('S1PR1', 'Gene', '1901', (35, 40))	('high', 'Var', (16, 20))	('S1PR1', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('lung cancers', 'Phenotype', 'HP:0100526', (103, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('breast and lung cancers', 'Disease', 'MESH:D001943', (92, 115))
109373	32799825	cBioPortal database was used to determine the types and frequencies of S1PR1 alterations in BRCA, LUAD, and LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (108, 112))	('S1PR1', 'Gene', '1901', (71, 76))	('BRCA', 'Phenotype', 'HP:0003002', (92, 96))	('alterations', 'Var', (77, 88))	('BRCA', 'Gene', '672', (92, 96))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('BRCA', 'Gene', (92, 96))	('S1PR1', 'Gene', (71, 76))
109375	32799825	S1PR1 was altered in 6% of patients with LUAD and 2.3% of patients with LUSC, including mRNA missense mutations, truncating mutations, amplifications, and deletions (Fig.	('LUAD', 'Disease', (41, 45))	('altered', 'Reg', (10, 17))	('LUAD', 'Phenotype', 'HP:0030078', (41, 45))	('LUSC', 'Phenotype', 'HP:0030359', (72, 76))	('S1PR1', 'Gene', '1901', (0, 5))	('patients', 'Species', '9606', (27, 35))	('truncating', 'MPA', (113, 123))	('amplifications', 'Var', (135, 149))	('missense mutations', 'Var', (93, 111))	('deletions', 'Var', (155, 164))	('patients', 'Species', '9606', (58, 66))	('S1PR1', 'Gene', (0, 5))
109377	32799825	These results suggest that mutations in S1PR1 are associated with prognosis in LUAD.	('associated with', 'Reg', (50, 65))	('mutations', 'Var', (27, 36))	('LUAD', 'Disease', (79, 83))	('LUAD', 'Phenotype', 'HP:0030078', (79, 83))	('S1PR1', 'Gene', '1901', (40, 45))	('S1PR1', 'Gene', (40, 45))
109399	32799825	This further confirms that S1PR1 is significantly related to immune infiltrating cells in lung and breast cancer, suggesting that high levels of S1PR1 could induce immune activity in the lung and breast cancer microenvironment.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('S1PR1', 'Gene', '1901', (145, 150))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('breast cancer', 'Disease', (99, 112))	('S1PR1', 'Gene', (27, 32))	('S1PR1', 'Gene', (145, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('induce', 'PosReg', (157, 163))	('breast cancer', 'Disease', (196, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('high levels', 'Var', (130, 141))	('immune activity', 'CPA', (164, 179))	('S1PR1', 'Gene', '1901', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
109403	32799825	Prognostic data from Kaplan-Meier plotter showed that low levels of S1PR1 are significantly related to poor prognosis in breast cancer and lung cancer.	('S1PR1', 'Gene', (68, 73))	('lung cancer', 'Disease', (139, 150))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('S1PR1', 'Gene', '1901', (68, 73))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('low levels', 'Var', (54, 64))
109413	32799825	These studies support our findings that high expression of S1PR1 is beneficial for tumor survival.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('high expression', 'Var', (40, 55))	('S1PR1', 'Gene', (59, 64))	('tumor', 'Disease', (83, 88))	('S1PR1', 'Gene', '1901', (59, 64))	('beneficial', 'PosReg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
109422	32799825	As shown in recently reports, endothelial loss of S1PR1 led to a reduction in CD45+ cells, macrophages, and DCs, which influences tumor growth and metastasis.	('influences', 'Reg', (119, 129))	('loss', 'Var', (42, 46))	('CD45', 'Gene', '5788', (78, 82))	('DCs', 'MPA', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('S1PR1', 'Gene', '1901', (50, 55))	('CD45', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('S1PR1', 'Gene', (50, 55))	('tumor', 'Disease', (130, 135))	('reduction', 'NegReg', (65, 74))	('metastasis', 'CPA', (147, 157))
109423	32799825	In addition, S1P is involved in enhancing endocytosis and migration of mature dendritic cells through S1PR3, an event that may increase the immune response to cancer cells.	('cancer', 'Disease', (159, 165))	('enhancing', 'PosReg', (32, 41))	('endocytosis', 'MPA', (42, 53))	('S1PR3', 'Gene', '1903', (102, 107))	('S1PR3', 'Gene', (102, 107))	('immune response', 'biological_process', 'GO:0006955', ('140', '155'))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('increase', 'PosReg', (127, 135))	('S1P', 'Chemical', 'MESH:C060506', (13, 16))	('S1P', 'Chemical', 'MESH:C060506', (102, 105))	('S1P', 'Var', (13, 16))	('endocytosis', 'biological_process', 'GO:0006897', ('42', '53'))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('migration', 'CPA', (58, 67))
109432	32799825	This shows that S1PR1 defects promote the occurrence of VM, and the knockout of S1PR1 in breast cancer cells increases the number of VMs.	('S1PR1', 'Gene', '1901', (80, 85))	('promote', 'PosReg', (30, 37))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('S1PR1', 'Gene', '1901', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('knockout', 'Var', (68, 76))	('breast cancer', 'Disease', (89, 102))	('defects', 'Var', (22, 29))	('S1PR1', 'Gene', (80, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('S1PR1', 'Gene', (16, 21))	('increases', 'PosReg', (109, 118))	('VMs', 'Disease', (133, 136))
109433	32799825	More importantly, tumor cells with low S1PR1 expression receive nutrition through VM, and accelerate tumor growth in animal models.	('tumor', 'Disease', (18, 23))	('S1PR1', 'Gene', '1901', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('accelerate', 'PosReg', (90, 100))	('S1PR1', 'Gene', (39, 44))	('low', 'Var', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
109467	32677984	Furthermore, further experiments demonstrated that knockdown of CASC9 inhibited growth and metastasis of bladder cancer cells (BCCs) in vitro and in vivo.	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('metastasis of bladder cancer', 'Disease', (91, 119))	('BC', 'Phenotype', 'HP:0009725', (127, 129))	('metastasis of bladder cancer', 'Disease', 'MESH:D001749', (91, 119))	('CASC9', 'Gene', '101805492', (64, 69))	('inhibited', 'NegReg', (70, 79))	('CASC9', 'Gene', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('knockdown', 'Var', (51, 60))
109468	32677984	Mechanistically, we found CASC9 was mainly distributed in the cytoplasm and knockdown of CASC9 increased miR-497-5p expression and subsequently inhibited FZD6 expression, in a ceRNA-dependent way.	('miR-497', 'Gene', '574456', (105, 112))	('FZD6', 'Gene', '8323', (154, 158))	('CASC9', 'Gene', (89, 94))	('miR-497', 'Gene', (105, 112))	('knockdown', 'Var', (76, 85))	('5p', 'Chemical', '-', (113, 115))	('inhibited', 'NegReg', (144, 153))	('expression', 'MPA', (159, 169))	('CASC9', 'Gene', (26, 31))	('CASC9', 'Gene', '101805492', (26, 31))	('increased', 'PosReg', (95, 104))	('CASC9', 'Gene', '101805492', (89, 94))	('FZD6', 'Gene', (154, 158))
109499	32677984	Our results showed that knockdown of CASC9 inhibited the proliferation of BCCs (Fig.	('inhibited', 'NegReg', (43, 52))	('CASC9', 'Gene', '101805492', (37, 42))	('CASC9', 'Gene', (37, 42))	('BC', 'Phenotype', 'HP:0009725', (74, 76))	('knockdown', 'Var', (24, 33))
109502	32677984	Our result showed knockdown of CASC9 decreased tumor growth and tumor weight (Fig.	('knockdown', 'Var', (18, 27))	('tumor', 'Disease', (64, 69))	('CASC9', 'Gene', (31, 36))	('CASC9', 'Gene', '101805492', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('decreased tumor', 'Disease', (37, 52))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (47, 52))	('decreased tumor', 'Disease', 'MESH:D002303', (37, 52))
109504	32677984	Moreover, we found knockdown of CASC9 decreased Ki67 expression (Fig.	('decreased', 'NegReg', (38, 47))	('Ki67', 'Gene', '17345', (48, 52))	('knockdown', 'Var', (19, 28))	('CASC9', 'Gene', (32, 37))	('CASC9', 'Gene', '101805492', (32, 37))	('Ki67', 'Gene', (48, 52))
109510	32677984	We found that knockdown of CASC9 inhibited migration (Fig.	('CASC9', 'Gene', '101805492', (27, 32))	('CASC9', 'Gene', (27, 32))	('migration', 'CPA', (43, 52))	('knockdown', 'Var', (14, 23))	('inhibited', 'NegReg', (33, 42))
109513	32677984	Our result showed knockdown of CASC9 decreased luciferase signals (Fig.	('knockdown', 'Var', (18, 27))	('CASC9', 'Gene', (31, 36))	('CASC9', 'Gene', '101805492', (31, 36))	('luciferase', 'Enzyme', (47, 57))	('decreased', 'NegReg', (37, 46))
109516	32677984	Our results showed knockdown of CASC9 significantly reduced the number of pulmonary metastases and metastases size (Fig.	('reduced', 'NegReg', (52, 59))	('knockdown', 'Var', (19, 28))	('metastases', 'Disease', (84, 94))	('metastases', 'Disease', 'MESH:D009362', (84, 94))	('CASC9', 'Gene', (32, 37))	('CASC9', 'Gene', '101805492', (32, 37))	('metastases', 'Disease', (99, 109))	('pulmonary metastases', 'Disease', 'MESH:D009362', (74, 94))	('pulmonary metastases', 'Disease', (74, 94))	('metastases', 'Disease', 'MESH:D009362', (99, 109))
109517	32677984	Moreover, further results showed knockdown of CASC9 decreased Ki67 (Fig.	('Ki67', 'Gene', '17345', (62, 66))	('knockdown', 'Var', (33, 42))	('CASC9', 'Gene', (46, 51))	('decreased', 'NegReg', (52, 61))	('CASC9', 'Gene', '101805492', (46, 51))	('Ki67', 'Gene', (62, 66))
109523	32677984	Our result showed knockdown of CASC9 decreased FZD6, beta-catenin expression and inhibited EMT of BCCs (Fig.	('knockdown', 'Var', (18, 27))	('CASC9', 'Gene', (31, 36))	('CASC9', 'Gene', '101805492', (31, 36))	('inhibited', 'NegReg', (81, 90))	('beta-catenin', 'Gene', (53, 65))	('expression', 'MPA', (66, 76))	('BC', 'Phenotype', 'HP:0009725', (98, 100))	('EMT', 'biological_process', 'GO:0001837', ('91', '94'))	('EMT', 'Gene', (91, 94))	('FZD6', 'Gene', '8323', (47, 51))	('EMT', 'Gene', '3702', (91, 94))	('decreased', 'NegReg', (37, 46))	('FZD6', 'Gene', (47, 51))	('beta-catenin', 'Gene', '1499', (53, 65))
109524	32677984	Meanwhile, we found knockdown of CASC9 decreased FZD6 (Fig.	('FZD6', 'Gene', '8323', (49, 53))	('FZD6', 'Gene', (49, 53))	('CASC9', 'Gene', (33, 38))	('CASC9', 'Gene', '101805492', (33, 38))	('knockdown', 'Var', (20, 29))	('decreased', 'NegReg', (39, 48))
109533	32677984	Furthermore, further experimental results showed knockdown of CASC9 increased miR-497-5p expression (Fig.	('knockdown', 'Var', (49, 58))	('miR-497', 'Gene', '574456', (78, 85))	('CASC9', 'Gene', (62, 67))	('CASC9', 'Gene', '101805492', (62, 67))	('miR-497', 'Gene', (78, 85))	('increased', 'PosReg', (68, 77))	('5p', 'Chemical', '-', (86, 88))
109539	32677984	Our results showed that knockdown of miR-497-5p significantly reversed the proliferation (Fig.	('miR-497', 'Gene', (37, 44))	('miR-497', 'Gene', '574456', (37, 44))	('5p', 'Chemical', '-', (45, 47))	('reversed', 'NegReg', (62, 70))	('proliferation', 'CPA', (75, 88))	('knockdown', 'Var', (24, 33))
109542	32677984	Moreover, knockdown of miR-497-5p significantly reversed FZD6 (Fig.	('miR-497', 'Gene', (23, 30))	('miR-497', 'Gene', '574456', (23, 30))	('FZD6', 'Gene', '8323', (57, 61))	('5p', 'Chemical', '-', (31, 33))	('FZD6', 'Gene', (57, 61))	('knockdown', 'Var', (10, 19))
109550	32677984	For example, LncRNA LNMAT1 could recruit hnRNPL to CCL2 promoter and subsequently epigenetically activate CCL2 expression in BC.	('BC', 'Phenotype', 'HP:0009725', (125, 127))	('hnRNPL', 'Gene', (41, 47))	('CCL2', 'Gene', (106, 110))	('CCL2', 'Gene', (51, 55))	('hnRNPL', 'Gene', '3191', (41, 47))	('epigenetically', 'Var', (82, 96))	('activate', 'PosReg', (97, 105))	('expression', 'MPA', (111, 121))	('recruit', 'PosReg', (33, 40))	('ncRNA', 'Gene', (14, 19))	('CCL2', 'Gene', '6347', (106, 110))	('CCL', 'molecular_function', 'GO:0044101', ('51', '54'))	('CCL2', 'Gene', '6347', (51, 55))	('CCL', 'molecular_function', 'GO:0044101', ('106', '109'))	('ncRNA', 'Gene', '54719', (14, 19))
109555	32677984	Recently, CASC9 originally was identified as a key regulator and the differentially expressed CASC9 have become highlighted in some somatic cancers.	('differentially expressed', 'Var', (69, 93))	('CASC9', 'Gene', (94, 99))	('CASC9', 'Gene', '101805492', (94, 99))	('CASC9', 'Gene', '101805492', (10, 15))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('CASC9', 'Gene', (10, 15))
109558	32677984	Furthermore, our further experiments demonstrated that CASC9 deletion inhibited tumor growth and metastasis of BC in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('CASC9', 'Gene', (55, 60))	('metastasis of BC', 'CPA', (97, 113))	('CASC9', 'Gene', '101805492', (55, 60))	('BC', 'Phenotype', 'HP:0009725', (111, 113))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('deletion', 'Var', (61, 69))	('tumor', 'Disease', (80, 85))	('inhibited', 'NegReg', (70, 79))
109560	32677984	Meanwhile, FZD6 expression was also up-regulated in our dataset and knockdown of CASC9 decreased the expression of FZD6.	('FZD6', 'Gene', '8323', (11, 15))	('decreased', 'NegReg', (87, 96))	('FZD6', 'Gene', (11, 15))	('up-regulated', 'PosReg', (36, 48))	('FZD6', 'Gene', '8323', (115, 119))	('FZD6', 'Gene', (115, 119))	('knockdown', 'Var', (68, 77))	('CASC9', 'Gene', (81, 86))	('CASC9', 'Gene', '101805492', (81, 86))	('expression', 'MPA', (101, 111))	('expression', 'MPA', (16, 26))
109561	32677984	Furthermore, a great number of studies have indicated that FZD6 is a key regulator of Wnt/beta-catenin signaling pathway and knockdown of CASC9 decreases FZD6, beta-catenin expression and inhibits EMT in BCCs.	('decreases', 'NegReg', (144, 153))	('FZD6', 'Gene', '8323', (59, 63))	('knockdown', 'Var', (125, 134))	('CASC9', 'Gene', (138, 143))	('FZD6', 'Gene', (59, 63))	('CASC9', 'Gene', '101805492', (138, 143))	('FZD6', 'Gene', '8323', (154, 158))	('BC', 'Phenotype', 'HP:0009725', (204, 206))	('signaling pathway', 'biological_process', 'GO:0007165', ('103', '120'))	('beta-catenin', 'Gene', (90, 102))	('beta-catenin', 'Gene', (160, 172))	('EMT', 'Gene', (197, 200))	('EMT', 'biological_process', 'GO:0001837', ('197', '200'))	('beta-catenin', 'Gene', '1499', (90, 102))	('beta-catenin', 'Gene', '1499', (160, 172))	('EMT', 'Gene', '3702', (197, 200))	('inhibits', 'NegReg', (188, 196))	('FZD6', 'Gene', (154, 158))
109565	32677984	Moreover, knockdown of miR-497-5p reversed FZD6 expression and malignant phenotypes inhibition of BCCs induced by silencing CASC9.	('miR-497', 'Gene', (23, 30))	('miR-497', 'Gene', '574456', (23, 30))	('BCCs', 'Disease', (98, 102))	('CASC9', 'Gene', (124, 129))	('CASC9', 'Gene', '101805492', (124, 129))	('expression', 'MPA', (48, 58))	('silencing', 'Var', (114, 123))	('BC', 'Phenotype', 'HP:0009725', (98, 100))	('FZD6', 'Gene', '8323', (43, 47))	('5p', 'Chemical', '-', (31, 33))	('FZD6', 'Gene', (43, 47))
109586	31699107	Here, we present an unusual case of EMPD of the vulva, secondary to high-grade urothelial carcinoma, that presented 2 yr after the patient was diagnosed with low-grade bladder urothelial carcinoma, associated with massive dermal lymphatic carcinomatosis, cervical involvement, and lymph node metastasis.	('low-grade', 'Var', (158, 167))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (79, 99))	('lymph node metastasis', 'Disease', (281, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('dermal lymphatic carcinomatosis', 'Disease', 'MESH:D008206', (222, 253))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (176, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('cervical involvement', 'Disease', (255, 275))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (168, 196))	('dermal lymphatic carcinomatosis', 'Disease', (222, 253))	('patient', 'Species', '9606', (131, 138))	('bladder urothelial carcinoma', 'Disease', (168, 196))	('urothelial carcinoma', 'Disease', (79, 99))
109668	29037201	The dysregulation of lncRNAs plays pivotal roles in many kinds of diseases, particularly in cancer.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('dysregulation', 'Var', (4, 17))	('roles', 'Reg', (43, 48))	('lncRNAs', 'Protein', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
109718	25994056	Fortunately, enhancers can also be identified using patterns of 5-methylcytosine, an epigenetic mark that is maintained more stably than protein marks, and can be detected genome-wide in as few as 1,000 cells.	('patterns', 'Var', (52, 60))	('5-methylcytosine', 'Var', (64, 80))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (64, 80))
109741	25994056	To identify enhancers that displayed cancer-specific changes in DNA methylation, we applied a t-test to identify enhancer probes that were significantly hypermethylated or hypomethylated within tumor samples of each cancer type, relative to TCGA adjacent normal samples from the same tissue (Fig.	('hypermethylated', 'Var', (153, 168))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('changes in DNA methylation', 'biological_process', 'GO:0044728', ('53', '79'))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('hypomethylated within tumor', 'Disease', (172, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('hypomethylated within tumor', 'Disease', 'MESH:D001929', (172, 199))
109742	25994056	1b; see Methods for details); a list of the identified hypermethylated or hypomethylated enhancer probes for each tumor type can be found in Additional file 3.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('hypomethylated', 'Var', (74, 88))	('hypermethylated', 'Var', (55, 70))
109743	25994056	We identified many more hypomethylated enhancer probes than hypermethylated probes for each of the 10 cancer types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('enhancer', 'PosReg', (39, 47))	('hypomethylated', 'Var', (24, 38))
109744	25994056	Interestingly, most of the probes showing DNA methylation changes were found to have similar changes in DNA methylation in more than one cancer type.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('DNA methylation', 'biological_process', 'GO:0006306', ('42', '57'))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('changes', 'Var', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('changes in DNA methylation', 'biological_process', 'GO:0044728', ('93', '119'))	('changes', 'Reg', (93, 100))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('DNA methylation', 'MPA', (104, 119))
109745	25994056	However, some probes were uniquely hypermethylated or hypomethylated in only one of the 10 tumor types.	('hypomethylated', 'Var', (54, 68))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
109746	25994056	We note that it is not possible for us to be certain that the adjacent tissues collected by TCGA correspond to the same cell type from which the cancer arose, and therefore some of these methylation changes may correspond to tissue-specific differences rather than changes arising in the cancer.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', (288, 294))	('methylation', 'MPA', (187, 198))	('methylation', 'biological_process', 'GO:0032259', ('187', '198'))	('changes', 'Var', (199, 206))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))
109748	25994056	For example, in a ChIA-PET study using an antibody for RNA polymerase II, Li et al.	('antibody', 'cellular_component', 'GO:0019814', ('42', '50'))	('antibody', 'molecular_function', 'GO:0003823', ('42', '50'))	('RNA polymerase', 'Protein', (55, 69))	('antibody', 'cellular_component', 'GO:0042571', ('42', '50'))	('RNA', 'cellular_component', 'GO:0005562', ('55', '58'))	('ChIA', 'Gene', '27159', (18, 22))	('ChIA', 'Gene', (18, 22))	('antibody', 'cellular_component', 'GO:0019815', ('42', '50'))	('antibody', 'Var', (42, 50))
109754	25994056	Using this method, we identified a total of 11,972 hypomethylated probe-gene pairs and 2,308 hypermethylated probe-gene pairs in the set of 10 tumor types (Fig.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('hypomethylated', 'Var', (51, 65))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
109755	25994056	3a), with the number of hypomethylated probe-gene pairs ranging from 499 to 3,847 in different tumor types, and the number of hypermethylated probe-gene pairs ranging from 119 to 464 (see Additional file 5 for a breakdown by type).	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('hypomethylated', 'Var', (24, 38))	('breakdown', 'biological_process', 'GO:0009056', ('212', '221'))	('tumor', 'Disease', (95, 100))
109758	25994056	Although the enhancer-gene pairs that we identified were highly specific for a certain tumor type, we found that approximately 34 % of the genes identified as regulated by a hypomethylated probe and approximately 17 % of the genes identified as regulated by a hypermethylated probe were targets in more than one tumor type (Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('hypomethylated', 'Var', (174, 188))	('tumor', 'Disease', (312, 317))
109761	25994056	As indicated above, many of the genes that we identified as linked to enhancers with cancer-associated DNA methylation differences were actually identified in more than one cancer type, suggesting that they may have some common function in tumor initiation or progression.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('tumor initiation', 'Disease', 'MESH:D009369', (240, 256))	('cancer', 'Disease', (173, 179))	('DNA methylation', 'biological_process', 'GO:0006306', ('103', '118'))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('methylation differences', 'Var', (107, 130))	('tumor initiation', 'Disease', (240, 256))	('cancer', 'Disease', (85, 91))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('enhancers', 'PosReg', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
109763	25994056	The 1,959 genes linked to hypomethylated (activated) enhancer probes correspond to genes upregulated in cancer, and the 284 genes linked to hypermethylated (inactivated) probes correspond to genes downregulated in cancer.	('downregulated', 'NegReg', (197, 210))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('upregulated', 'PosReg', (89, 100))	('hypomethylated', 'Var', (26, 40))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('enhancer', 'PosReg', (53, 61))	('probes', 'Var', (62, 68))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
109770	25994056	Some of these motifs were common to various different cancers, such as AP1, which was enriched within nine of the 10 cancer types.	('AP1', 'Gene', '2353', (71, 74))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('motifs', 'Var', (14, 20))	('cancers', 'Disease', (54, 61))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('AP1', 'cellular_component', 'GO:0005907', ('71', '74'))	('cancer', 'Disease', (54, 60))	('common', 'Reg', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('AP1', 'Gene', (71, 74))
109779	25994056	In addition, GATA3 expression is correlated with longer disease-free survival and evidence suggests that it can prevent or reverse the epithelial to mesenchymal transition that is characteristic of cancer metastasis.	('epithelial to mesenchymal transition', 'CPA', (135, 171))	('prevent', 'NegReg', (112, 119))	('expression', 'Var', (19, 29))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('135', '171'))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer metastasis', 'Disease', (198, 215))	('GATA3', 'Gene', (13, 18))	('reverse', 'NegReg', (123, 130))	('GATA3', 'Gene', '2625', (13, 18))	('cancer metastasis', 'Disease', 'MESH:D009362', (198, 215))
109800	25994056	We identified from 5,147 to 26,787 hypomethylated probes in different tumor types, corresponding to between 4,841 and 21,374 distinct enhancer regions.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('hypomethylated probes', 'Var', (35, 56))	('enhancer', 'PosReg', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
109824	25994056	For instance, we found that GATA-containing enhancer hypomethylation occurred primarily in the subset of breast cancer cases belonging to the Luminal subtype, which also had high expression of the GATA3 gene (Fig.	('expression', 'MPA', (179, 189))	('breast cancer', 'Gene', '672', (105, 118))	('GATA', 'Gene', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('GATA3', 'Gene', (197, 202))	('breast cancer', 'Gene', (105, 118))	('GATA', 'Gene', '55278', (197, 201))	('enhancer', 'PosReg', (44, 52))	('hypomethylation', 'Var', (53, 68))	('GATA3', 'Gene', '2625', (197, 202))	('GATA', 'Gene', (28, 32))	('GATA', 'Gene', '55278', (28, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
109826	25994056	Understanding the genome-wide transcriptional consequences of molecular subtypes will be particularly relevant for those that are defined by genetic mutation of transcriptional regulators; indeed, transcription factors make up the largest functional class within the list of 127 cancer genes with so-called 'driver' mutations identified by TCGA.	("'driver'", 'PosReg', (307, 315))	('mutations', 'Var', (316, 325))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('transcription', 'biological_process', 'GO:0006351', ('197', '210'))	('TCGA', 'Gene', (340, 344))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))
109829	25994056	For instance, FOXA1 is most frequently mutated in Breast and Bladder cancer, and ELMER identified it in these specific cancers.	('FOXA1', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('Breast and Bladder cancer', 'Disease', 'MESH:D001749', (50, 75))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('mutated', 'Var', (39, 46))	('cancers', 'Disease', (119, 126))	('Bladder cancer', 'Phenotype', 'HP:0009725', (61, 75))	('FOXA1', 'Gene', '3169', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
109830	25994056	Likewise, FOXA2 and SOX17 are primarily mutated in endometrial cancers, and ELMER identified network alterations specifically in this cancer type (UCEC).	('FOXA2', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (134, 140))	('SOX17', 'Gene', '64321', (20, 25))	('endometrial cancers', 'Disease', 'MESH:D016889', (51, 70))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('endometrial cancer', 'Phenotype', 'HP:0012114', (51, 69))	('mutated', 'Var', (40, 47))	('endometrial cancers', 'Disease', (51, 70))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('FOXA2', 'Gene', '3170', (10, 15))	('cancer', 'Disease', (63, 69))	('SOX17', 'Gene', (20, 25))
109831	25994056	NFE2L2 is most frequently mutated in lung squamous cell carcinoma (LUSC), the same cancer type where ELMER detected NFE2L2 alterations.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 65))	('lung squamous cell carcinoma', 'Disease', (37, 65))	('NFE2L2', 'Gene', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('NFE2L2', 'Gene', '4780', (0, 6))	('mutated', 'Var', (26, 33))	('NFE2L2', 'Gene', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (37, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('NFE2L2', 'Gene', '4780', (116, 122))	('cancer', 'Disease', (83, 89))
109834	25994056	Our results indicate that hypomethylation of AP-1-containing enhancers is a common feature of many or most cancer types (including nine of our 10 cancer types, see Fig.	('AP-1', 'cellular_component', 'GO:0005907', ('45', '49'))	('cancer', 'Disease', (146, 152))	('AP-1-containing', 'Gene', (45, 60))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('hypomethylation', 'Var', (26, 41))	('cancer', 'Disease', (107, 113))
109837	25994056	Phosphorylation of JUN can lead to histone acetylation at AP-1 motif-containing enhancers by inhibiting their association with the Mbd3 component of the NuRD complex.	('histone acetylation', 'biological_process', 'GO:0016573', ('35', '54'))	('Phosphorylation', 'Var', (0, 15))	('JUN', 'Gene', (19, 22))	('association', 'Interaction', (110, 121))	('Mbd3', 'Gene', (131, 135))	('AP-1', 'Gene', (58, 62))	('lead to', 'Reg', (27, 34))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('AP-1', 'cellular_component', 'GO:0005907', ('58', '62'))	('NuRD complex', 'cellular_component', 'GO:0016581', ('153', '165'))	('inhibiting', 'NegReg', (93, 103))	('Mbd3', 'Gene', '53615', (131, 135))	('histone acetylation', 'MPA', (35, 54))
109841	25994056	Interestingly, high expression of ZNF703 has been shown to correlate with poor prognosis in patients with luminal B breast cancer.	('high', 'Var', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('breast cancer', 'Gene', '672', (116, 129))	('patients', 'Species', '9606', (92, 100))	('ZNF703', 'Gene', '80139', (34, 40))	('breast cancer', 'Gene', (116, 129))	('ZNF703', 'Gene', (34, 40))
109850	25994056	However, the most important output of this work may actually be the identification of enhancers in which mutations in individual transcription factor binding sites can be responsible for cancer risk or cancer progression.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', (187, 193))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('129', '157'))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('mutations', 'Var', (105, 114))	('responsible', 'Reg', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (202, 208))	('transcription', 'biological_process', 'GO:0006351', ('129', '142'))
109852	25994056	Somatic enhancer mutations are predicted to affect cancer progression, although these have not yet been identified due to the overwhelming use of exon sequencing as a means to identify new cancer mutations.	('enhancer', 'PosReg', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('affect', 'Reg', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (51, 57))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', (189, 195))
109874	25994056	Genes associated with hypo- or hypermethylated enhancer probes in more than one cancer type were selected for GO analysis.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('hypo-', 'Var', (22, 27))	('hypermethylated', 'Var', (31, 46))	('cancer', 'Disease', (80, 86))
109907	23121893	They attempted to analyze abnormal nuclear localization of beta-catenin in colonic adenocarcinomas (CA) due to dysregulation of the wnt pathway, in the setting of PBA.	('beta-catenin', 'Gene', '1499', (59, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('localization', 'biological_process', 'GO:0051179', ('43', '55'))	('dysregulation', 'Var', (111, 124))	('colonic adenocarcinomas', 'Disease', 'MESH:D003110', (75, 98))	('wnt pathway', 'Pathway', (132, 143))	('colonic adenocarcinomas', 'Disease', (75, 98))	('PBA', 'Chemical', '-', (163, 166))	('beta-catenin', 'Gene', (59, 71))
109954	23121893	The most frequent chromosomal abnormalities detected by UroVysion FISH in PBAs were 9p21 homozygous loss (HL) (6/9, 67%) (Figure 4) followed by Polysomy (PL) pattern (3/9, 33%) (Figure 5).	('PBA', 'Chemical', '-', (74, 77))	('Polysomy', 'Var', (144, 152))	('chromosomal abnormalities', 'Disease', (18, 43))	('9p21', 'Gene', (84, 88))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (18, 43))
109955	23121893	HL, PL and single chromosome gain of chromosome 3 (SG) were seen in 3/5 (60%), 1/5 (20%), and 1/5 (20%) of PBA cases, respectively.	('chromosome', 'cellular_component', 'GO:0005694', ('37', '47'))	('gain', 'PosReg', (29, 33))	('single chromosome', 'Var', (11, 28))	('chromosome', 'cellular_component', 'GO:0005694', ('18', '28'))	('PBA', 'Disease', (107, 110))	('PBA', 'Chemical', '-', (107, 110))
109974	23121893	Abnormal localization of beta-catenin has been well documented in colonic adenocarcinomas with mutation in APC tumor suppressor gene.	('colonic adenocarcinomas', 'Disease', 'MESH:D003110', (66, 89))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('111', '127'))	('localization', 'biological_process', 'GO:0051179', ('9', '21'))	('APC tumor', 'Disease', 'MESH:D011125', (107, 116))	('colonic adenocarcinomas', 'Disease', (66, 89))	('beta-catenin', 'Gene', '1499', (25, 37))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('APC tumor', 'Disease', (107, 116))	('APC', 'cellular_component', 'GO:0005680', ('107', '110'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('111', '127'))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('beta-catenin', 'Gene', (25, 37))	('mutation', 'Var', (95, 103))
109976	23121893	In patients with mutated or absent APC, beta-catenin translocates to the nucleus of the cell and acts as a transactivating factor for the transcriptional factor Tcf-4 to regulate the expression of a number of downstream target genes that are believed play a role in oncogenesis.	('beta-catenin', 'Gene', '1499', (40, 52))	('nucleus', 'cellular_component', 'GO:0005634', ('73', '80'))	('Tcf-4', 'Gene', '6925', (161, 166))	('translocates', 'MPA', (53, 65))	('APC', 'cellular_component', 'GO:0005680', ('35', '38'))	('oncogenesis', 'biological_process', 'GO:0007048', ('266', '277'))	('APC', 'Disease', 'MESH:D011125', (35, 38))	('Tcf-4', 'Gene', (161, 166))	('beta-catenin', 'Gene', (40, 52))	('patients', 'Species', '9606', (3, 11))	('expression', 'MPA', (183, 193))	('APC', 'Disease', (35, 38))	('regulate', 'Reg', (170, 178))	('mutated', 'Var', (17, 24))
109984	23121893	The e-cadherin molecule forms an important component of the cell-cell adhesion complex in association with other proteins including catenin molecules (alpha-, beta-, and gamma) and p120.	('cadherin', 'molecular_function', 'GO:0008014', ('6', '14'))	('gamma', 'Protein', (170, 175))	('e-cadherin', 'Gene', '999', (4, 14))	('e-cadherin', 'Gene', (4, 14))	('cell adhesion complex', 'cellular_component', 'GO:0098636', ('65', '86'))	('p120', 'Var', (181, 185))	('alpha-', 'Protein', (151, 157))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('60', '78'))
110002	23121893	Gastrointestinal tumors, including colonic and rectal adenocarcinomas, tend to be CK20+ and CK7-.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('colonic and rectal adenocarcinomas', 'Disease', 'MESH:D012004', (35, 69))	('Gastrointestinal tumors', 'Disease', 'MESH:D004067', (0, 23))	('Gastrointestinal tumors', 'Disease', (0, 23))	('Gastrointestinal tumors', 'Phenotype', 'HP:0007378', (0, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('CK7-', 'Var', (92, 96))	('CK20+', 'Var', (82, 87))
110005	23121893	Many PBA have been reported to show a CK20+ and CK7- profile, similar to colonic adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('colonic adenocarcinomas', 'Disease', 'MESH:D003110', (73, 96))	('PBA', 'Chemical', '-', (5, 8))	('CK20+', 'Var', (38, 43))	('colonic adenocarcinomas', 'Disease', (73, 96))	('CK7-', 'Var', (48, 52))
110009	23121893	Based on these findings, CK7 appeared to be of limited utility in distinguishing PBAs from secondary bladder adenocarcinomas and CK20 was not able to distinguish between the two tumor groups.	('PBAs', 'Disease', (81, 85))	('bladder adenocarcinomas', 'Disease', (101, 124))	('tumor', 'Disease', (178, 183))	('bladder adenocarcinomas', 'Disease', 'MESH:D001749', (101, 124))	('PBA', 'Chemical', '-', (81, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('CK7', 'Var', (25, 28))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (101, 123))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
110014	23121893	In their study, the most frequent abnormality documented in bladder adenocarcinoma was 9p21 homozygous loss followed by single gain only.	('bladder adenocarcinoma', 'Disease', (60, 82))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (60, 82))	('9p21', 'Gene', (87, 91))	('bladder adenocarcinoma', 'Disease', 'MESH:D001749', (60, 82))	('homozygous loss', 'Var', (92, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
110022	18997819	Inhibition of pituitary tumors in Rb mutant chimeras through E2f4-loss reveals a key suppressive role for the pRB/E2F pathway in urothelium and ganglionic carcinogenesis The retinoblastoma protein pRB suppresses tumorigenesis largely through regulation of the E2F transcription factors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('retinoblastoma', 'Gene', '5925', (174, 188))	('E2f4', 'Gene', '104394', (61, 65))	('retinoblastoma', 'Phenotype', 'HP:0009919', (174, 188))	('pRB', 'Gene', (110, 113))	('pRB', 'Gene', '19645', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('pRB', 'Gene', (197, 200))	('suppresses', 'NegReg', (201, 211))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('pRB', 'Gene', '19645', (197, 200))	('pituitary tumors', 'Disease', 'MESH:D010911', (14, 30))	('transcription', 'biological_process', 'GO:0006351', ('264', '277'))	('retinoblastoma', 'Gene', (174, 188))	('tumor', 'Disease', (24, 29))	('pituitary tumors', 'Disease', (14, 30))	('mutant', 'Var', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (212, 217))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('regulation', 'biological_process', 'GO:0065007', ('242', '252'))	('E2f4', 'Gene', (61, 65))
110023	18997819	In this study, we analyze how loss of E2f4 affects the tumorigenicity of pRB-deficient tissues.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('E2f4', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('affects', 'Reg', (43, 50))	('tumor', 'Disease', (55, 60))	('loss', 'Var', (30, 34))
110025	18997819	We found that loss of E2f4 had a differential effect on known Rb-associated neuroendocrine tumors.	('neuroendocrine tumors', 'Disease', (76, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('loss', 'Var', (14, 18))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (76, 97))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (76, 97))	('Rb', 'Chemical', 'MESH:D012413', (62, 64))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('E2f4', 'Gene', (22, 26))
110027	18997819	The most striking effect was in the pituitary where E2F4-loss delayed the development, and reduced the incidence, of Rb mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('incidence', 'MPA', (103, 112))	('tumors', 'Disease', (127, 133))	('development', 'CPA', (74, 85))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('delayed', 'NegReg', (62, 69))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('Rb', 'Chemical', 'MESH:D012413', (117, 119))	('reduced', 'NegReg', (91, 98))	('E2F4-loss', 'Var', (52, 61))	('mutant', 'Var', (120, 126))
110028	18997819	This tumor suppression increased the longevity of the Rb-/-;E2f4-/- chimeric animals allowing us to identify novel tumor types.	('Rb', 'Chemical', 'MESH:D012413', (54, 56))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('increased', 'PosReg', (23, 32))	('tumor', 'Disease', (5, 10))	('longevity', 'CPA', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('E2f4-/-', 'Var', (60, 67))
110029	18997819	We observed ganglionic neuroendocrine neoplasms, lesions not previously associated with mutation of either Rb or E2f4.	('mutation', 'Var', (88, 96))	('neuroendocrine neoplasms', 'Disease', 'MESH:D018358', (23, 47))	('neoplasm', 'Phenotype', 'HP:0002664', (38, 46))	('neuroendocrine neoplasms', 'Disease', (23, 47))	('Rb', 'Chemical', 'MESH:D012413', (107, 109))	('neoplasms', 'Phenotype', 'HP:0002664', (38, 47))	('neuroendocrine neoplasms', 'Phenotype', 'HP:0100634', (23, 47))	('E2f4', 'Gene', (113, 117))
110030	18997819	Moreover, a subset of the Rb-/-;E2f4-/- chimeras developed either low or high-grade carcinomas in the urothelium transitional epithelium supporting a key role for Rb in bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (169, 183))	('Rb', 'Chemical', 'MESH:D012413', (26, 28))	('bladder cancer', 'Disease', (169, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('Rb-/-;E2f4-/-', 'Var', (26, 39))	('carcinomas', 'Disease', 'MESH:D002277', (84, 94))	('carcinomas', 'Disease', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('bladder cancer', 'Phenotype', 'HP:0009725', (169, 183))	('Rb', 'Chemical', 'MESH:D012413', (163, 165))	('E2f4-/-', 'Var', (32, 39))
110031	18997819	The retinoblastoma tumor suppressor gene RB is mutated in approximately 30% of all human cancers and in more than 90% of retinoblastomas, osteosarcomas and small cell lung carcinomas.	('tumor suppressor', 'biological_process', 'GO:0051726', ('19', '35'))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('small cell lung carcinomas', 'Disease', (156, 182))	('osteosarcomas', 'Disease', (138, 151))	('cancers', 'Disease', (89, 96))	('retinoblastoma tumor', 'Disease', 'MESH:D012175', (4, 24))	('mutated', 'Var', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('retinoblastomas', 'Disease', 'MESH:D012175', (121, 136))	('small cell lung carcinomas', 'Disease', 'MESH:D055752', (156, 182))	('osteosarcomas', 'Phenotype', 'HP:0002669', (138, 151))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('retinoblastoma', 'Phenotype', 'HP:0009919', (121, 135))	('retinoblastoma tumor', 'Disease', (4, 24))	('retinoblastoma', 'Phenotype', 'HP:0009919', (4, 18))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (156, 181))	('retinoblastomas', 'Disease', (121, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('retinoblastomas', 'Phenotype', 'HP:0009919', (121, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('19', '35'))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (156, 182))	('human', 'Species', '9606', (83, 88))	('osteosarcomas', 'Disease', 'MESH:D012516', (138, 151))
110034	18997819	E2Fs control the expression of genes crucial for cell cycle re-entry, DNA replication and mitosis.	('mitosis', 'biological_process', 'GO:0000278', ('90', '97'))	('DNA replication', 'biological_process', 'GO:0006260', ('70', '85'))	('E2Fs', 'Var', (0, 4))	('mitosis', 'Disease', 'None', (90, 97))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('control', 'Reg', (5, 12))	('expression', 'MPA', (17, 27))	('cell cycle', 'biological_process', 'GO:0007049', ('49', '59'))	('mitosis', 'Disease', (90, 97))
110036	18997819	The second involves formation of E2F4- or E2F5-pocket protein complexes that bind to E2F-responsive promoters and actively repress their transcription, thereby promoting quiescence.	('repress', 'NegReg', (123, 130))	('quiescence', 'biological_process', 'GO:0044838', ('170', '180'))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('E2F5', 'Gene', '13559', (42, 46))	('promoting', 'PosReg', (160, 169))	('transcription', 'biological_process', 'GO:0006351', ('137', '150'))	('quiescence', 'MPA', (170, 180))	('E2F4-', 'Var', (33, 38))	('E2F5', 'Gene', (42, 46))	('formation', 'biological_process', 'GO:0009058', ('20', '29'))	('transcription', 'MPA', (137, 150))
110037	18997819	Consistent with these dual roles, Rb-/-;p107-/-;p130-/- and E2f4-/-;E2f5-/- mouse embryonic fibroblasts (MEFs) fail to respond to a variety of growth inhibitory signals, while MEFs lacking E2f1, E2f2, and/or E2f3 have impaired proliferative capacity.	('E2f1', 'Gene', '13555', (189, 193))	('E2f2', 'Gene', '242705', (195, 199))	('E2f5', 'Gene', (68, 72))	('E2f2', 'Gene', (195, 199))	('lacking', 'NegReg', (181, 188))	('p130-/-', 'Var', (48, 55))	('E2f5', 'Gene', '13559', (68, 72))	('impaired', 'NegReg', (218, 226))	('mouse', 'Species', '10090', (76, 81))	('Rb', 'Chemical', 'MESH:D012413', (34, 36))	('E2f1', 'Gene', (189, 193))	('Rb-/-;p107-/-;p130-/-', 'Var', (34, 55))	('respond', 'MPA', (119, 126))	('proliferative capacity', 'CPA', (227, 249))	('MEFs', 'CellLine', 'CVCL:9115', (176, 180))	('E2f3', 'Gene', '13557', (208, 212))	('MEFs', 'CellLine', 'CVCL:9115', (105, 109))	('E2f3', 'Gene', (208, 212))
110041	18997819	However, analysis of E2F's role in the context of Rb mutant tumors challenges this conclusion.	('Rb', 'Chemical', 'MESH:D012413', (50, 52))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutant', 'Var', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
110043	18997819	Loss of E2f4 suppresses development of both tumor types and thus, significantly expands the lifespan.	('expands', 'PosReg', (80, 87))	('lifespan', 'CPA', (92, 100))	('suppresses', 'NegReg', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('E2f4', 'Gene', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Loss', 'Var', (0, 4))	('tumor', 'Disease', (44, 49))
110044	18997819	First, E2F4 could behave as a trascriptional activator in the context of these tumor cells.	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('E2F4', 'Var', (7, 11))	('tumor', 'Disease', (79, 84))
110045	18997819	Second, there is evidence that E2F4 may influence tumorigenesis in a indirect manner: we found that the absence of E2F4 in Rb-/- cells allows p107 and p130 to associate with E2F1, E2F2 and E2F3 and presumably substitute for pRB in preventing these activator E2Fs from promoting proliferation and therefore tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('influence', 'Reg', (40, 49))	('p130', 'Var', (151, 155))	('promoting', 'PosReg', (268, 277))	('E2F4', 'Gene', (115, 119))	('p107', 'Var', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('E2F2', 'Gene', '242705', (180, 184))	('Rb', 'Chemical', 'MESH:D012413', (123, 125))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (306, 311))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('absence', 'Var', (104, 111))	('associate', 'Interaction', (159, 168))	('tumor', 'Disease', (50, 55))	('E2F2', 'Gene', (180, 184))
110048	18997819	To analyze tumorigenesis induced by combined loss of E2f4 and Rb, in this study we generate Rb-/-;E2f4-/- chimeric mice.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('E2f4-/-', 'Var', (98, 105))	('Rb', 'Chemical', 'MESH:D012413', (92, 94))	('tumor', 'Disease', (11, 16))	('Rb', 'Chemical', 'MESH:D012413', (62, 64))	('E2f4 and Rb', 'Gene', '104394;13983', (53, 64))	('mice', 'Species', '10090', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
110049	18997819	This model system overcomes the lethality of the Rb-/-;E2f4-/- germline animals and therefore eliminates the requirement for Rb LOH.	('lethality', 'CPA', (32, 41))	('overcomes', 'NegReg', (18, 27))	('E2f4-/-', 'Var', (55, 62))	('Rb', 'Chemical', 'MESH:D012413', (49, 51))	('Rb', 'Chemical', 'MESH:D012413', (125, 127))	('eliminates', 'NegReg', (94, 104))
110050	18997819	Consistent with previous observations in Rb+/-;E2f4-/- germline animals, we found that loss of E2f4 suppresses formation of pituitary tumors that are the predominant cause of death of the Rb-/- chimeras and therefore greatly expands the lifespan.	('expands', 'PosReg', (225, 232))	('pituitary tumors', 'Disease', 'MESH:D010911', (124, 140))	('loss', 'Var', (87, 91))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('Rb', 'Chemical', 'MESH:D012413', (188, 190))	('formation', 'biological_process', 'GO:0009058', ('111', '120'))	('death', 'Disease', 'MESH:D003643', (175, 180))	('death', 'Disease', (175, 180))	('formation', 'CPA', (111, 120))	('Rb', 'Chemical', 'MESH:D012413', (41, 43))	('pituitary tumors', 'Disease', (124, 140))	('suppresses', 'NegReg', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('E2f4', 'Gene', (95, 99))
110053	18997819	To study the contribution of E2f4 to the tumors that arise in Rb null tissues, we generated E2f4-/-;Rb-/- chimeric mice.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('E2f4-/-', 'Var', (92, 99))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('Rb', 'Chemical', 'MESH:D012413', (62, 64))	('Rb', 'Chemical', 'MESH:D012413', (100, 102))	('mice', 'Species', '10090', (115, 119))
110054	18997819	To obtain these animals, we intercrossed E2f4+/-;Rb+/- Rosa26 germline mutant animals and isolated E2f4-/-;Rb-/-Rosa26 embryonic stem (ES) cells by de novo derivation.	('Rosa26', 'Gene', '14910', (112, 118))	('Rosa26', 'Gene', (55, 61))	('E2f4+/-', 'Var', (41, 48))	('Rosa26', 'Gene', (112, 118))	('Rb', 'Chemical', 'MESH:D012413', (107, 109))	('Rb', 'Chemical', 'MESH:D012413', (49, 51))	('Rosa26', 'Gene', '14910', (55, 61))
110055	18997819	Two E2f4-/-;Rb-/- Rosa26 ES cell lines were injected into blastocysts giving rise to E2f4;Rb chimeras.	('Rb', 'Chemical', 'MESH:D012413', (12, 14))	('E2f4;Rb chimeras', 'Var', (85, 101))	('Rosa26 ES', 'CellLine', 'CVCL:8806', (18, 27))	('chimeras', 'Var', (93, 101))	('Rb', 'Chemical', 'MESH:D012413', (90, 92))
110057	18997819	E2f4-/-;Rb-/- ES cells also contributed to a variety of adult tissues (Figure 1b, data not shown).	('Rb', 'Chemical', 'MESH:D012413', (8, 10))	('contributed', 'Reg', (28, 39))	('E2f4-/-', 'Var', (0, 7))
110058	18997819	However, we observed that on average, our cohort of adult Rb-/-;E2f4-/- chimeric animals, had a lower degree of chimerism than the Rb-/- chimeric mice as judged by coat color (Table 1,).	('chimerism', 'CPA', (112, 121))	('E2f4-/-', 'Var', (64, 71))	('lower', 'NegReg', (96, 101))	('Rb', 'Chemical', 'MESH:D012413', (58, 60))	('mice', 'Species', '10090', (146, 150))	('Rb', 'Chemical', 'MESH:D012413', (131, 133))
110059	18997819	Since our Rb-/-;E2f4-/- ES cells are pluripotent, and we know that E2f4-/- animals can be viable, these findings suggest that additional loss of E2f4 decreases the viability of Rb-/- cells in chimeric mice.	('viability', 'CPA', (164, 173))	('E2f4', 'Gene', (145, 149))	('mice', 'Species', '10090', (201, 205))	('Rb', 'Chemical', 'MESH:D012413', (10, 12))	('loss', 'Var', (137, 141))	('decreases', 'NegReg', (150, 159))	('Rb', 'Chemical', 'MESH:D012413', (177, 179))
110060	18997819	To study the effects of E2f4-loss in Rb tumorigenesis we aged our cohort of Rb-/-;E2f4-/- chimeric animals and compared them to Rb-/- chimeric mice that we generated in parallel.	('Rb', 'Chemical', 'MESH:D012413', (37, 39))	('E2f4-/-', 'Var', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Rb', 'Chemical', 'MESH:D012413', (76, 78))	('Rb', 'Chemical', 'MESH:D012413', (128, 130))	('tumor', 'Disease', (40, 45))	('mice', 'Species', '10090', (143, 147))
110061	18997819	We found a striking difference in the lifespan of the Rb-/-;E2f4-/- versus Rb-/- chimeras.	('lifespan', 'CPA', (38, 46))	('Rb', 'Chemical', 'MESH:D012413', (54, 56))	('Rb', 'Chemical', 'MESH:D012413', (75, 77))	('E2f4-/-', 'Var', (60, 67))
110064	18997819	Accordingly, we found that less than half of the Rb-/-;E2f4-/- chimeric mice developed pituitary tumors and the affected animals were all greater than ten months of age (Figure 2b, Table 1).	('pituitary tumors', 'Disease', 'MESH:D010911', (87, 103))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('pituitary tumors', 'Disease', (87, 103))	('E2f4-/-', 'Var', (55, 62))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('Rb', 'Chemical', 'MESH:D012413', (49, 51))	('mice', 'Species', '10090', (72, 76))
110065	18997819	Histologically, the pituitary tumors that do develop in the Rb-/-;E2f4-/- animals are similar to the ones found in the Rb-/- chimeras.	('pituitary tumors', 'Disease', 'MESH:D010911', (20, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('Rb', 'Chemical', 'MESH:D012413', (60, 62))	('Rb-/-;E2f4-/-', 'Var', (60, 73))	('Rb', 'Chemical', 'MESH:D012413', (119, 121))	('E2f4-/-', 'Var', (66, 73))	('pituitary tumors', 'Disease', (20, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
110066	18997819	They originate from the pars intermedia of the pituitary, have the morphology of adenocarcinomas, and all derive from Rb-/-;E2f4-/- mutant cells as shown by beta-galactosidase staining (Figure 3a, b).	('adenocarcinomas', 'Disease', (81, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('Rb', 'Chemical', 'MESH:D012413', (118, 120))	('beta-galactosidase', 'Gene', '12091', (157, 175))	('beta-galactosidase', 'Gene', (157, 175))	('Rb-/-', 'Gene', (118, 123))	('adenocarcinomas', 'Disease', 'MESH:D000230', (81, 96))	('E2f4-/- mutant', 'Var', (124, 138))
110068	18997819	Analysis of pituitary tumor samples recovered from Rb-/- and Rb-/-;E2f4-/- chimeras at necropsy showed that there was a general absence of both apoptotic and proliferative cells (as judged by staining for TUNEL and Ki67 respectively) in both genotypes (data not shown).	('pituitary tumor', 'Disease', 'MESH:D010911', (12, 27))	('Rb', 'Chemical', 'MESH:D012413', (61, 63))	('apoptotic', 'CPA', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Rb', 'Chemical', 'MESH:D012413', (51, 53))	('pituitary tumor', 'Disease', (12, 27))	('absence', 'NegReg', (128, 135))	('proliferative cells', 'CPA', (158, 177))	('E2f4-/-', 'Var', (67, 74))
110070	18997819	Since we detect pituitary tumors in Rb-deficient mice with chimerism as low as 5%, we can be sure that the suppression of tumor development in Rb-/-;E2f4-/- chimeras is not merely the result of insufficient contribution of Rb-/-;E2f4-/- cells to the pituitary.	('Rb', 'Chemical', 'MESH:D012413', (36, 38))	('suppression', 'NegReg', (107, 118))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('Rb', 'Chemical', 'MESH:D012413', (223, 225))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mice', 'Species', '10090', (49, 53))	('Rb', 'Chemical', 'MESH:D012413', (143, 145))	('pituitary tumors', 'Disease', 'MESH:D010911', (16, 32))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('Rb-/-;E2f4-/-', 'Var', (143, 156))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('pituitary tumors', 'Disease', (16, 32))	('tumor', 'Disease', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
110072	18997819	E2f4-loss has been shown to completely suppress c-cell carcinomas of the thyroid in Rb+/-;E2f4-/- germline mice.	('Rb', 'Chemical', 'MESH:D012413', (84, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (55, 65))	('carcinomas of the thyroid', 'Phenotype', 'HP:0100031', (55, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('carcinomas of the thyroid', 'Disease', 'MESH:D013964', (55, 80))	('E2f4-/-', 'Var', (90, 97))	('E2f4-loss', 'Var', (0, 9))	('suppress', 'NegReg', (39, 47))	('mice', 'Species', '10090', (107, 111))	('carcinomas of the thyroid', 'Disease', (55, 80))
110076	18997819	Rb-/- chimeras develop additional neuroendocrine lesions in adrenal glands and in the lung.	('neuroendocrine lesions in adrenal glands', 'Phenotype', 'HP:0100631', (34, 74))	('neuroendocrine lesions', 'Phenotype', 'HP:0100634', (34, 56))	('neuroendocrine lesions', 'Disease', 'MESH:D018358', (34, 56))	('Rb', 'Chemical', 'MESH:D012413', (0, 2))	('neuroendocrine lesions', 'Disease', (34, 56))	('Rb-/-', 'Var', (0, 5))
110080	18997819	We found that Rb-/-;E2f4-/- chimeric animals also presented hyperplastic areas in the lung, but the severity of these lesions as well as the percentage of animals bearing them, was much lower when compared to than seen in the Rb-/- chimeras (Figure 4c, Table 1).	('hyperplastic areas in the lung', 'CPA', (60, 90))	('Rb', 'Chemical', 'MESH:D012413', (226, 228))	('E2f4-/-', 'Var', (20, 27))	('Rb', 'Chemical', 'MESH:D012413', (14, 16))	('lower', 'NegReg', (186, 191))
110083	18997819	The increased lifespan of the Rb-/-;E2f4-/- animals due to suppression of pituitary tumors, together with the ability to generate adult tissues simultaneously lacking Rb and E2f4, gave us the unique opportunity to identify new tumor types that might be modulated by these proteins.	('suppression', 'NegReg', (59, 70))	('E2f4-/-', 'Var', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('Rb', 'Chemical', 'MESH:D012413', (30, 32))	('Rb', 'Chemical', 'MESH:D012413', (167, 169))	('pituitary tumors', 'Disease', (74, 90))	('tumor', 'Disease', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('pituitary tumors', 'Disease', 'MESH:D010911', (74, 90))	('E2f4', 'Var', (174, 178))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('increased', 'PosReg', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
110084	18997819	We performed necropsy and whole histology on all the Rb-/-;E2f4-/- chimeric mice and found a distinct tumor spectrum in the older animals (Table 1).	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Rb-/-;E2f4-/-', 'Var', (53, 66))	('E2f4-/-', 'Var', (59, 66))	('mice', 'Species', '10090', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('Rb', 'Chemical', 'MESH:D012413', (53, 55))
110088	18997819	We did not detect any TUNEL-positive cells in the neoplastic lesions of the Rb-/-;E2f4-/- chimeras or the normal ganglia of either Rb-/- or Rb-/-;E2f4-/- chimeras (data not shown).	('Rb-/-;E2f4-/-', 'Var', (76, 89))	('E2f4-/-', 'Var', (82, 89))	('neoplastic lesions', 'Disease', (50, 68))	('Rb', 'Chemical', 'MESH:D012413', (140, 142))	('neoplastic lesions', 'Disease', 'MESH:D051437', (50, 68))	('Rb', 'Chemical', 'MESH:D012413', (76, 78))	('Rb', 'Chemical', 'MESH:D012413', (131, 133))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (50, 68))
110092	18997819	via differences in proliferative and/or apoptotic capacity of Rb-/-;E2f4-/- versus Rb mutant tissues) or an indirect effect (the extended lifespan of the Rb mutant chimeras) of E2f4 loss.	('loss', 'NegReg', (182, 186))	('E2f4-/-', 'Gene', (68, 75))	('mutant', 'Var', (157, 163))	('apoptotic capacity', 'CPA', (40, 58))	('mutant', 'Var', (86, 92))	('Rb', 'Chemical', 'MESH:D012413', (154, 156))	('proliferative', 'CPA', (19, 32))	('Rb', 'Chemical', 'MESH:D012413', (62, 64))	('differences', 'Reg', (4, 15))	('Rb', 'Chemical', 'MESH:D012413', (83, 85))	('E2f4', 'Gene', (177, 181))
110093	18997819	In addition to these ganglionic neoplasms, we also identified tumors in the urogenital epithelium of the Rb-/-;E2f4-/- chimeric mice (Table 1).	('Rb', 'Chemical', 'MESH:D012413', (105, 107))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('neoplasms', 'Phenotype', 'HP:0002664', (32, 41))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('mice', 'Species', '10090', (128, 132))	('neoplasm', 'Phenotype', 'HP:0002664', (32, 40))	('neoplasms', 'Disease', 'MESH:D009369', (32, 41))	('neoplasms', 'Disease', (32, 41))	('E2f4-/-', 'Var', (111, 118))
110098	18997819	Histological comparison of tumorigenic versus normal urothelium in the Rb-/-;E2f4-/- chimeras, revealed no apoptosis, but high levels of proliferation specifically within circumscribed regions of the tumors but not the normal urothelium (data not shown).	('E2f4-/-', 'Var', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('Rb', 'Chemical', 'MESH:D012413', (71, 73))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', (200, 205))	('Rb-/-;E2f4-/-', 'Var', (71, 84))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('proliferation', 'CPA', (137, 150))
110101	18997819	As we could not take advantage of beta-galactosidase staining due to problems of high background (kidney) or poor penetrability of the dye (ganglion) in the tissues surrounding the tumors, we assessed the contribution of mutant cells to the novel tumors by screening the tumor areas for the presence of the E2f4 mutant allele.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Disease', (247, 253))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('beta-galactosidase', 'Gene', '12091', (34, 52))	('tumor', 'Disease', (247, 252))	('tumors', 'Disease', (181, 187))	('tumor', 'Disease', (271, 276))	('mutant', 'Var', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('tumor', 'Disease', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('E2f4', 'Gene', (307, 311))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('beta-galactosidase', 'Gene', (34, 52))
110103	18997819	Specifically, the mutant band was relatively weak in the urothelium neoplasm which had a high non-epithelial component and much stronger in the ganglionic neoplasm which was more homogenous.	('neoplasm', 'Disease', 'MESH:D009369', (68, 76))	('neoplasm', 'Disease', (155, 163))	('neoplasm', 'Phenotype', 'HP:0002664', (155, 163))	('mutant', 'Var', (18, 24))	('neoplasm', 'Disease', 'MESH:D009369', (155, 163))	('stronger', 'PosReg', (128, 136))	('neoplasm', 'Disease', (68, 76))	('neoplasm', 'Phenotype', 'HP:0002664', (68, 76))	('weak', 'NegReg', (45, 49))
110107	18997819	Nevertheless, the finding that Rb-/-;E2f4-/- chimeric mice develop a papillary form of urothelial cancer represents the first direct evidence of a role for Rb in this cancer type and is concordant with the high incidence of Rb mutation in urothelial carcinoma of the bladder.	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (239, 274))	('cancer', 'Disease', (167, 173))	('Rb', 'Chemical', 'MESH:D012413', (31, 33))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('papillary form', 'Phenotype', 'HP:0007482', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('papillary form', 'Disease', (69, 83))	('Rb', 'Chemical', 'MESH:D012413', (156, 158))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (239, 274))	('E2f4-/-', 'Var', (37, 44))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('urothelial cancer', 'Disease', 'MESH:D014523', (87, 104))	('Rb-/-;E2f4-/-', 'Var', (31, 44))	('urothelial carcinoma of the bladder', 'Disease', (239, 274))	('urothelial cancer', 'Disease', (87, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('Rb', 'Chemical', 'MESH:D012413', (224, 226))	('mice', 'Species', '10090', (54, 58))
110109	18997819	Nevertheless, the extent to which the interaction of pRB with the E2Fs influences its role in cancer remains unclear due in part to the embryonic lethality of Rb-/- and Rb-/-;E2f-/- mutant animals.	('Rb-/-', 'Var', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Rb-/-;E2f-/- mutant', 'Var', (169, 188))	('Rb', 'Chemical', 'MESH:D012413', (159, 161))	('influences', 'Reg', (71, 81))	('Rb', 'Chemical', 'MESH:D012413', (169, 171))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
110113	18997819	We found that loss of E2f4 increased the lifespan of these animals by delaying the development and decreasing the incidence of pituitary tumors.	('loss', 'Var', (14, 18))	('increased', 'PosReg', (27, 36))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('pituitary tumors', 'Disease', (127, 143))	('decreasing', 'NegReg', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('delaying', 'NegReg', (70, 78))	('development', 'CPA', (83, 94))	('lifespan', 'CPA', (41, 49))	('E2f4', 'Gene', (22, 26))	('pituitary tumors', 'Disease', 'MESH:D010911', (127, 143))
110116	18997819	The function of E2F4 in cell division is thus still unclear; in vitro E2F4 acts as a proliferation inhibitor, while in vivo E2F4 functions to promote pituitary tumorigenesis.	('E2F4', 'Var', (124, 128))	('pituitary tumor', 'Disease', (150, 165))	('E2F4', 'Gene', (70, 74))	('pituitary tumor', 'Disease', 'MESH:D010911', (150, 165))	('cell division', 'biological_process', 'GO:0051301', ('24', '37'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('promote', 'PosReg', (142, 149))
110117	18997819	The first, called the "pocket protein reshuffling" model, stems from our finding that p107 and p130, normally unable to bind to the activator E2Fs, associate with these proteins in Rb;E2f4 deficient tissues.	('Rb', 'Chemical', 'MESH:D012413', (181, 183))	('p130', 'Var', (95, 99))	('associate', 'Interaction', (148, 157))	('p107', 'Var', (86, 90))
110118	18997819	These novel repressor complexes could prevent E2F1, E2F2 and E2F3 from activating target genes responsible for cell proliferation thus inhibiting tumor formation in Rb+/-;E2f4-/- mice.	('E2F1', 'Var', (46, 50))	('mice', 'Species', '10090', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cell proliferation', 'biological_process', 'GO:0008283', ('111', '129'))	('formation', 'biological_process', 'GO:0009058', ('152', '161'))	('tumor', 'Disease', (146, 151))	('E2F3', 'Var', (61, 65))	('E2F2', 'Gene', '242705', (52, 56))	('inhibiting', 'NegReg', (135, 145))	('prevent', 'NegReg', (38, 45))	('Rb', 'Chemical', 'MESH:D012413', (165, 167))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('activating', 'MPA', (71, 81))	('E2F2', 'Gene', (52, 56))
110119	18997819	The second model proposes that E2F4 functions as a transcriptional activator in certain contexts, including Rb mutant tumors, and this explains its oncogenic activity.	('transcriptional', 'MPA', (51, 66))	('mutant', 'Var', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('Rb', 'Chemical', 'MESH:D012413', (108, 110))	('tumors', 'Disease', (118, 124))	('E2F4', 'Protein', (31, 35))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
110120	18997819	Notably, we have recently found that E2F4 associates with the promoter of E2F-responsive genes in tumor cells, concordant with their transcriptional activation, raising support for this hypothesis (Iaquinta and J.	('E2F-responsive', 'Gene', (74, 88))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('E2F4', 'Var', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
110121	18997819	Our data also show that Rb-/- and Rb-/-;E2f4-/- chimeric mice developed thyroid tumors at a similar frequency.	('mice', 'Species', '10090', (57, 61))	('developed', 'PosReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Rb', 'Chemical', 'MESH:D012413', (34, 36))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('thyroid tumors', 'Disease', (72, 86))	('thyroid tumors', 'Disease', 'MESH:D013959', (72, 86))	('thyroid tumor', 'Phenotype', 'HP:0100031', (72, 85))	('Rb', 'Chemical', 'MESH:D012413', (24, 26))	('E2f4-/-', 'Var', (40, 47))
110122	18997819	This is in contrast to what previously found in Rb+/-;E2f4-/- germline animals where the thyroid tumors are fully suppressed.	('thyroid tumors', 'Disease', (89, 103))	('thyroid tumors', 'Disease', 'MESH:D013959', (89, 103))	('thyroid tumor', 'Phenotype', 'HP:0100031', (89, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Rb', 'Chemical', 'MESH:D012413', (48, 50))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('E2f4-/-', 'Var', (54, 61))
110123	18997819	It is hard to envisage how either the reshuffling or transcriptional activation mechanisms could account for tumor suppression in Rb+/-;E2f4-/- germline mice, but not in Rb-/-;E2f4-/- chimeras.	('Rb', 'Chemical', 'MESH:D012413', (130, 132))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('mice', 'Species', '10090', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('Rb+/-;E2f4-/-', 'Var', (130, 143))	('tumor', 'Disease', (109, 114))	('Rb', 'Chemical', 'MESH:D012413', (170, 172))
110124	18997819	Thus, two possibilities remain to explain the specific suppression of tumors in the Rb+/-;E2f4-/- thyroids.	('Rb', 'Chemical', 'MESH:D012413', (84, 86))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('suppression', 'NegReg', (55, 66))	('Rb+/-;E2f4-/-', 'Var', (84, 97))	('tumors', 'Disease', (70, 76))	('E2f4-/-', 'Var', (90, 97))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
110129	18997819	In fact, while previous Rb;E2f germline mutant mice assigned opposing roles for E2f3 and E2f4 in the development of thyroid tumors our studies in chimeric mice suggest that these E2fs are both fully dispensable for this tumor type.	('E2f3', 'Gene', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('thyroid tumors', 'Disease', (116, 130))	('thyroid tumors', 'Disease', 'MESH:D013959', (116, 130))	('thyroid tumor', 'Phenotype', 'HP:0100031', (116, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (220, 225))	('mice', 'Species', '10090', (47, 51))	('tumor', 'Disease', (124, 129))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('E2fs', 'FRAMESHIFT', 'None', (179, 183))	('E2fs', 'Var', (179, 183))	('E2f3', 'Gene', '13557', (80, 84))	('mice', 'Species', '10090', (155, 159))	('Rb', 'Chemical', 'MESH:D012413', (24, 26))	('E2f4', 'Var', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
110136	18997819	Thus, this suggests that E2F3 and E2F4 play a prominent role in the hyperplastic stage of small cell lung carcinoma.	('lung carcinoma', 'Disease', (101, 115))	('lung carcinoma', 'Disease', 'MESH:D008175', (101, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('E2F3', 'Var', (25, 29))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (90, 115))	('E2F4', 'Var', (34, 38))
110137	18997819	The extended longevity of Rb-/-;E2f4-/- chimeric mice due to suppression of pituitary tumors allowed us to identify two novel tumor types in these mice, ganglionic neuroendocrine neoplasms and urethelial cancer.	('urethelial cancer', 'Disease', 'MESH:D009369', (193, 210))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('neoplasms', 'Phenotype', 'HP:0002664', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mice', 'Species', '10090', (147, 151))	('neoplasm', 'Phenotype', 'HP:0002664', (179, 187))	('neuroendocrine neoplasms', 'Disease', 'MESH:D018358', (164, 188))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('mice', 'Species', '10090', (49, 53))	('pituitary tumors', 'Disease', 'MESH:D010911', (76, 92))	('urethelial cancer', 'Disease', (193, 210))	('neuroendocrine neoplasms', 'Phenotype', 'HP:0100634', (164, 188))	('neuroendocrine neoplasms', 'Disease', (164, 188))	('tumor', 'Disease', (126, 131))	('Rb', 'Chemical', 'MESH:D012413', (26, 28))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('pituitary tumors', 'Disease', (76, 92))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('E2f4-/-', 'Var', (32, 39))
110142	18997819	The other novel tumor in Rb-/-;E2f4-/- chimeric animals is urothelial transitional cell carcinoma.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('carcinoma', 'Disease', 'MESH:D002277', (88, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('E2f4-/-', 'Var', (31, 38))	('Rb', 'Chemical', 'MESH:D012413', (25, 27))	('tumor', 'Disease', (16, 21))	('carcinoma', 'Disease', (88, 97))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (70, 97))
110147	18997819	There is a strong correlation between Rb mutations and urothelial cancer.	('mutations', 'Var', (41, 50))	('urothelial cancer', 'Disease', 'MESH:D014523', (55, 72))	('Rb', 'Chemical', 'MESH:D012413', (38, 40))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('urothelial cancer', 'Disease', (55, 72))
110148	18997819	In humans Rb has been found inactivated in about 60% cases of human bladder cancer, although there is still a debate as to whether Rb mutation is associated with the low grade, non papillary form.	('bladder cancer', 'Phenotype', 'HP:0009725', (68, 82))	('human', 'Species', '9606', (3, 8))	('human', 'Species', '9606', (62, 67))	('mutation', 'Var', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('bladder cancer', 'Disease', 'MESH:D001749', (68, 82))	('bladder cancer', 'Disease', (68, 82))	('humans', 'Species', '9606', (3, 9))	('Rb', 'Chemical', 'MESH:D012413', (10, 12))	('associated', 'Reg', (146, 156))	('papillary form', 'Phenotype', 'HP:0007482', (181, 195))	('Rb', 'Chemical', 'MESH:D012413', (131, 133))	('non papillary form', 'Phenotype', 'HP:0007482', (177, 195))
110149	18997819	Despite the strong association between Rb mutations and urothelial cancer, only one animal model has investigated the role of pRB in this tumor type.	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('urothelial cancer', 'Disease', (56, 73))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('mutations', 'Var', (42, 51))	('urothelial cancer', 'Disease', 'MESH:D014523', (56, 73))	('Rb', 'Chemical', 'MESH:D012413', (39, 41))
110150	18997819	In this mutant mouse Rb and p53 are both inactivated in urothelial cells by transgenic expression of the SV40 Large T antigen, and this causes invasive carcinoma in situ.	('p53', 'Gene', (28, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('transgenic', 'Species', '10090', (76, 86))	('causes', 'Reg', (136, 142))	('p53', 'Gene', '22059', (28, 31))	('SV40', 'Gene', (105, 109))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (152, 169))	('mutant', 'Var', (8, 14))	('Rb', 'Chemical', 'MESH:D012413', (21, 23))	('mouse', 'Species', '10090', (15, 20))	('invasive carcinoma', 'Disease', 'MESH:D009361', (143, 161))	('invasive carcinoma in situ', 'Phenotype', 'HP:0030075', (143, 169))	('invasive carcinoma', 'Disease', (143, 161))
110151	18997819	In Rb-/-;E2f4-/- chimeras we found both invasive and non invasive papillary carcinomas, suggesting that Rb mutation may facilitate the switch from low grade to dysplastic, high grade tumors.	('dysplastic', 'Disease', 'MESH:D004416', (160, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('invasive papillary carcinomas', 'Disease', (57, 86))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('switch', 'MPA', (135, 141))	('Rb', 'Chemical', 'MESH:D012413', (3, 5))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('invasive papillary carcinomas', 'Disease', 'MESH:D002291', (57, 86))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('Rb', 'Chemical', 'MESH:D012413', (104, 106))	('dysplastic', 'Disease', (160, 170))	('tumors', 'Disease', (183, 189))	('mutation', 'Var', (107, 115))	('facilitate', 'PosReg', (120, 130))
110153	18997819	To conclude, we have learnt from the analysis of Rb-/-;E2f4-/- chimeric animal that E2f4 plays a role in the pituitary tumors as well as in lung neuroendocrine hyperplasia caused by loss of Rb, but not in thyroid and adrenal gland tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('pituitary tumors', 'Disease', (109, 125))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('loss', 'Var', (182, 186))	('lung neuroendocrine hyperplasia', 'Disease', 'MESH:D018358', (140, 171))	('adrenal gland tumors', 'Phenotype', 'HP:0100631', (217, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('adrenal gland tumors', 'Disease', (217, 237))	('E2f4', 'Var', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('adrenal gland tumors', 'Disease', 'MESH:D000310', (217, 237))	('pituitary tumors', 'Disease', 'MESH:D010911', (109, 125))	('Rb', 'Chemical', 'MESH:D012413', (49, 51))	('Rb', 'Chemical', 'MESH:D012413', (190, 192))	('lung neuroendocrine hyperplasia', 'Disease', (140, 171))
110160	18997819	E2f4+/-Rb+/- 129/Sv mice were crossed to 129/Sv Rosa beta-geo 26 (Rosa26) animals.	('129/Sv', 'Species', '10090', (41, 47))	('Rosa26', 'Gene', (66, 72))	('mice', 'Species', '10090', (20, 24))	('Rb', 'Chemical', 'MESH:D012413', (7, 9))	('Rosa26', 'Gene', '14910', (66, 72))	('E2f4+/-Rb+/-', 'Var', (0, 12))	('129/Sv', 'Species', '10090', (13, 19))	('beta-geo', 'Chemical', '-', (53, 61))
110162	18997819	E2f4-/-Rb-/- Rosa26 chimeric mice were generated by injecting 10-12 mutant ES cells into C57Bl/6 blastocysts.	('Rosa26', 'Gene', '14910', (13, 19))	('Rb', 'Chemical', 'MESH:D012413', (7, 9))	('mice', 'Species', '10090', (29, 33))	('Rosa26', 'Gene', (13, 19))	('mutant', 'Var', (68, 74))
110183	32579540	It was reported that dysregulation of immune status induced by tumors might be associated with glioblastoma progression.	('associated', 'Reg', (79, 89))	('glioblastoma', 'Disease', (95, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('immune status', 'MPA', (38, 51))	('dysregulation', 'Var', (21, 34))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('dysregulation of immune status', 'Phenotype', 'HP:0002958', (21, 51))
110189	32579540	Lnc-sox5 knock-down can directly increase the activity of regulatory T cells and their cytotoxicity is also dramatically enhanced in CRC.	('cytotoxicity', 'Disease', 'MESH:D064420', (87, 99))	('enhanced', 'PosReg', (121, 129))	('activity', 'MPA', (46, 54))	('CRC', 'Disease', (133, 136))	('increase', 'PosReg', (33, 41))	('cytotoxicity', 'Disease', (87, 99))	('sox5', 'Gene', (4, 8))	('knock-down', 'Var', (9, 19))	('sox5', 'Gene', '6660', (4, 8))	('CRC', 'Phenotype', 'HP:0003003', (133, 136))	('regulatory T cells', 'CPA', (58, 76))
110191	32579540	Therefore, aberrantly expressed lncRNAs may be potential prognostic biomarkers for BCa patients and may be served as potential therapeutic targets.	('lncRNAs', 'Protein', (32, 39))	('patients', 'Species', '9606', (87, 95))	('BCa', 'Disease', (83, 86))	('aberrantly expressed', 'Var', (11, 31))
110197	32579540	We found that they both had enrichments in negative regulation of immune system process (GO:0002683), G protein-coupled receptor binding (GO:0001664) and transcriptional misregulation in cancer (hsa05202), which indicated that the development of BCa was associated with immune system and immune response (Figure 3E).	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('G protein-coupled receptor binding', 'molecular_function', 'GO:0001664', ('102', '136'))	('negative regulation', 'NegReg', (43, 62))	('immune response', 'biological_process', 'GO:0006955', ('288', '303'))	('cancer', 'Disease', (187, 193))	('G protein-coupled receptor', 'Protein', (102, 128))	('immune', 'CPA', (66, 72))	('negative regulation of immune system process', 'biological_process', 'GO:0002683', ('43', '87'))	('misregulation', 'Var', (170, 183))	('negative regulation of immune system', 'Phenotype', 'HP:0002721', (43, 79))	('BCa', 'Disease', (246, 249))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))
110203	32579540	The other six are protective lncRNAs with univariate Cox HR < 1 (MIF-AS1, AC008735.2, AL357033.4, LINC00649, AC099343.2 and USP30-AS1), which indicated that high expression of the six lncRNAs might result in a better survival time.	('USP', 'molecular_function', 'GO:0051748', ('124', '127'))	('AC099343.2', 'Var', (109, 119))	('MIF-AS1', 'Gene', '284889', (65, 72))	('MIF-AS1', 'Gene', (65, 72))	('USP30', 'Gene', (124, 129))	('better', 'PosReg', (210, 216))	('LINC00649', 'Gene', (98, 107))	('survival time', 'CPA', (217, 230))	('AL357033.4', 'Var', (86, 96))	('USP30', 'Gene', '84749', (124, 129))	('AS1', 'Gene', '5729', (130, 133))	('AS1', 'Gene', (130, 133))	('LINC00649', 'Gene', '100506334', (98, 107))	('AS1', 'Gene', '5729', (69, 72))	('AS1', 'Gene', (69, 72))
110204	32579540	Based on the expression of these eight lncRNAs for overall survival (OS) prediction, we established a risk score of the 8-lncRNA signature with the following formula: Risk score = (0.231 x ExpressionWNT5A-AS1) + (0.420 x ExpressionAL136084.3) + (-0.564 x ExpressionMIF-AS1) + (-0.388 x ExpressionAC008735.2) + (-0.456 x ExpressionAL357033.4) + (-0.661 x ExpressionLINC00649) + (-0.633 x ExpressionAC099343.2) + (-0.263 x ExpressionUSP30-AS1).	('MIF-AS1', 'Gene', '284889', (265, 272))	('AS1', 'Gene', (205, 208))	('LINC00649', 'Gene', '100506334', (364, 373))	('AS1', 'Gene', (437, 440))	('AS1', 'Gene', '5729', (437, 440))	('AS1', 'Gene', '5729', (205, 208))	('MIF-AS1', 'Gene', (265, 272))	('WNT5A-AS1', 'Gene', (199, 208))	('WNT5A-AS1', 'Gene', '100874008', (199, 208))	('USP30', 'Gene', (431, 436))	('0.231', 'Var', (181, 186))	('USP30', 'Gene', '84749', (431, 436))	('LINC00649', 'Gene', (364, 373))	('AS1', 'Gene', '5729', (269, 272))	('AS1', 'Gene', (269, 272))
110212	32579540	In summary, the immune-related prognostic signature based on the eight lncRNAs targeting immune-related genes was significantly associated with the immune status of BCa, and high risk score of the signature was more likely to activate immune-related pathways in BCa patients.	('patients', 'Species', '9606', (266, 274))	('activate', 'PosReg', (226, 234))	('BCa', 'Disease', (262, 265))	('immune-related pathways', 'Pathway', (235, 258))	('associated', 'Reg', (128, 138))	('high risk score', 'Var', (174, 189))
110216	32579540	The KM curve showed that BCa patients in high-nomogram-score group had worse prognosis compared with low-nomogram-score group (P < 0.001) (Figure 10C).	('BCa', 'Disease', (25, 28))	('patients', 'Species', '9606', (29, 37))	('high-nomogram-score', 'Var', (41, 60))
110221	32579540	The KM curve showed that MIBC patients in high-nomogram-score group had worse prognosis compared with low-nomogram-score group (P < 0.001).	('high-nomogram-score', 'Var', (42, 61))	('patients', 'Species', '9606', (30, 38))	('MIBC', 'Disease', (25, 29))	('MIBC', 'Chemical', '-', (25, 29))
110223	32579540	Aberrantly expressed lncRNAs in cancer can be utilized as biomarkers for diagnosis, prognosis and target therapy.	('Aberrantly expressed', 'Var', (0, 20))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('lncRNAs', 'Protein', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
110225	32579540	Among the 20 lncRNAs, lnc-BOD1-1:7, -1:8, and -1:9, as well as lnc-GCH1-2:1, -2:2, and -2:3 were associated with both immune-related pathways and cancer-associated pathways.	('lnc-BOD1-1:7', 'Var', (22, 34))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('GCH1', 'Gene', '2643', (67, 71))	('immune-related pathways', 'Pathway', (118, 141))	('GCH1', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('associated', 'Reg', (97, 107))
110233	32579540	Next, we established an immune-related prognostic signature based on eight lncRNAs targeting immune-related genes (WNT5A-AS1, AL136084.3, MIF-AS1, AC008735.2, AL357033.4, LINC00649, AC099343.2 and USP30-AS1) in the training cohort.	('AS1', 'Gene', (142, 145))	('AS1', 'Gene', '5729', (121, 124))	('AS1', 'Gene', (121, 124))	('LINC00649', 'Gene', '100506334', (171, 180))	('MIF-AS1', 'Gene', '284889', (138, 145))	('USP', 'molecular_function', 'GO:0051748', ('197', '200'))	('MIF-AS1', 'Gene', (138, 145))	('USP30', 'Gene', (197, 202))	('WNT5A-AS1', 'Gene', '100874008', (115, 124))	('AS1', 'Gene', '5729', (142, 145))	('AC008735.2', 'Var', (147, 157))	('AL357033.4', 'Var', (159, 169))	('LINC00649', 'Gene', (171, 180))	('WNT5A-AS1', 'Gene', (115, 124))	('AS1', 'Gene', (203, 206))	('AS1', 'Gene', '5729', (203, 206))	('USP30', 'Gene', '84749', (197, 202))	('AL136084.3', 'Var', (126, 136))
110237	32579540	One explanation for this phenomenon is that most of the patients with low stage BCa had favourable prognosis with good survival and the heterogeneity of prognosis among them is small.	('patients', 'Species', '9606', (56, 64))	('BCa', 'Disease', (80, 83))	('low stage', 'Var', (70, 79))
110244	32579540	found mutations in LIG1 are identified to underlie a spectrum of immune deficiencies by in vitro studies and TBX1 mutation is responsible for most of the congenital immune defect seen in the mouse models and in patients.	('underlie', 'Reg', (42, 50))	('patients', 'Species', '9606', (211, 219))	('TBX1', 'Gene', (109, 113))	('responsible', 'Reg', (126, 137))	('immune deficiencies', 'Disease', 'MESH:D007153', (65, 84))	('mouse', 'Species', '10090', (191, 196))	('immune deficiencies', 'Disease', (65, 84))	('immune defect', 'Phenotype', 'HP:0002721', (165, 178))	('mutation', 'Var', (114, 122))	('immune deficiencies', 'Phenotype', 'HP:0002721', (65, 84))	('LIG1', 'Gene', (19, 23))	('mutations', 'Var', (6, 15))	('congenital immune defect', 'Disease', (154, 178))
110247	32579540	Among these eight lncRNAs, WNT5A-AS1 and AL136084.3 are risk lncRNAs, while MIF-AS1, AC008735.2, AL357033.4, LINC00649, AC099343.2 and USP30-AS1 are protective lncRNAs.	('USP30', 'Gene', (135, 140))	('LINC00649', 'Gene', '100506334', (109, 118))	('AS1', 'Gene', (80, 83))	('AL136084.3', 'Var', (41, 51))	('AS1', 'Gene', '5729', (80, 83))	('AS1', 'Gene', (33, 36))	('WNT5A-AS1', 'Gene', '100874008', (27, 36))	('AS1', 'Gene', '5729', (33, 36))	('MIF-AS1', 'Gene', '284889', (76, 83))	('MIF-AS1', 'Gene', (76, 83))	('LINC00649', 'Gene', (109, 118))	('WNT5A-AS1', 'Gene', (27, 36))	('USP30', 'Gene', '84749', (135, 140))	('USP', 'molecular_function', 'GO:0051748', ('135', '138'))	('AL357033.4', 'Var', (97, 107))	('AS1', 'Gene', '5729', (141, 144))	('AS1', 'Gene', (141, 144))
110259	32579540	Immune-related genes were extracted from Molecular Signatures Database v4.0 (http://www.broadinstitute.org/gsea/msigdb/index.jsp: Immune system process M13664, Immune response M19817).	('M13664', 'Var', (152, 158))	('msigdb', 'Disease', (112, 118))	('M19817', 'Var', (176, 182))	('msigdb', 'Disease', 'None', (112, 118))	('Immune system process', 'biological_process', 'GO:0002376', ('130', '151'))	('Immune response', 'biological_process', 'GO:0006955', ('160', '175'))
110267	32579540	FDR < 25% and nominal P-value < 0.05 were regarded as the cut-off criteria of sorting GO and KEGG pathway enrichments in GSEA.	('KEGG pathway', 'Pathway', (93, 105))	('KEGG', 'Chemical', '-', (93, 97))	('GSEA', 'Chemical', '-', (121, 125))	('FDR', 'Var', (0, 3))
110276	32579540	The relative lncRNA expression levels of WNT5A-AS1, AL136084.3, MIF-AS1, AC008735.2, AL357033.4, LINC00649, AC099343.2 and USP30-AS1 were calculated by 2-DeltaDeltaCt method.	('USP30', 'Gene', '84749', (123, 128))	('WNT5A-AS1', 'Gene', '100874008', (41, 50))	('AS1', 'Gene', '5729', (129, 132))	('AS1', 'Gene', (47, 50))	('MIF-AS1', 'Gene', '284889', (64, 71))	('lncRNA expression levels', 'MPA', (13, 37))	('AC008735.2', 'Var', (73, 83))	('AL357033.4', 'Var', (85, 95))	('AL136084.3', 'Var', (52, 62))	('AS1', 'Gene', (68, 71))	('AS1', 'Gene', (129, 132))	('AS1', 'Gene', '5729', (47, 50))	('LINC00649', 'Gene', '100506334', (97, 106))	('USP', 'molecular_function', 'GO:0051748', ('123', '126'))	('MIF-AS1', 'Gene', (64, 71))	('AS1', 'Gene', '5729', (68, 71))	('WNT5A-AS1', 'Gene', (41, 50))	('USP30', 'Gene', (123, 128))	('LINC00649', 'Gene', (97, 106))
110318	31867425	The pooled PR rate was 14% (95% CI 10% - 19%, I2 = 72%) overall, 17% (95% CI 14% - 20%, I2 = 15%) in PD-L1 positive and 11% (95% CI 8% - 16%, I2 = 72%) PD-L1 negative patients.	('PD-L1', 'Gene', '29126', (152, 157))	('PD-L1', 'Gene', '29126', (101, 106))	('patients', 'Species', '9606', (167, 175))	('positive', 'Var', (107, 115))	('PD-L1', 'Gene', (152, 157))	('PD-L1', 'Gene', (101, 106))
110319	31867425	The pooled ORR rate was 18% (95% CI 15% - 21%, I2 = 58%) overall, 25% (95% CI 22% - 28%, I2 =5%) in PD-L1 positive and 14% (95% CI 8% - 21%, I2 = 68%) in PD-L1 negative patients.	('patients', 'Species', '9606', (169, 177))	('positive', 'Var', (106, 114))	('PD-L1', 'Gene', '29126', (100, 105))	('PD-L1', 'Gene', (154, 159))	('PD-L1', 'Gene', '29126', (154, 159))	('PD-L1', 'Gene', (100, 105))
110330	31867425	We show that the response rates (CR, PR, and ORR) and survival outcomes (PFS and OS) are better in PD-L1 positive patients than in negative patients.	('better', 'PosReg', (89, 95))	('survival outcomes', 'CPA', (54, 71))	('response rates', 'CPA', (17, 31))	('PD-L1', 'Gene', (99, 104))	('CR', 'Chemical', '-', (33, 35))	('patients', 'Species', '9606', (140, 148))	('PD-L1', 'Gene', '29126', (99, 104))	('patients', 'Species', '9606', (114, 122))	('positive', 'Var', (105, 113))
110355	31530827	Estimating the Frequency of Single Point Driver Mutations across Common Solid Tumours For cancers, such as common solid tumours, variants in the genome give a selective growth advantage to certain cells.	('solid tumours', 'Disease', 'MESH:D009369', (114, 127))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('cancers', 'Disease', (90, 97))	('selective growth advantage', 'CPA', (159, 185))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Tumours', 'Disease', 'MESH:D009369', (78, 85))	('solid tumours', 'Disease', (114, 127))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('Tumours', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('Mutations', 'Var', (48, 57))	('Tumours', 'Disease', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('variants', 'Var', (129, 137))
110356	31530827	It has recently been argued that the mean count of coding single nucleotide variants acting as disease-drivers in common solid tumours is frequently small in size, but significantly variable by cancer type (hypermutation is excluded from this study).	('cancer', 'Disease', (194, 200))	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('solid tumours', 'Disease', (121, 134))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('single nucleotide variants', 'Var', (58, 84))	('solid tumours', 'Disease', 'MESH:D009369', (121, 134))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
110357	31530827	In this paper we investigate this proposal through the use of integrative machine-learning-based classifiers we have proposed recently for predicting the disease-driver status of single nucleotide variants (SNVs) in the human cancer genome.	('human', 'Species', '9606', (220, 225))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('single nucleotide variants', 'Var', (179, 205))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
110360	31530827	For common solid tumours, a number of variants in the coding regions of the human cancer genome can act as disease-drivers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('solid tumours', 'Disease', (11, 24))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('variants', 'Var', (38, 46))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('human', 'Species', '9606', (76, 81))	('solid tumours', 'Disease', 'MESH:D009369', (11, 24))
110363	31530827	argued for only a few sequential mutations in a study of lung and colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Disease', (66, 83))	('lung', 'Disease', (57, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
110366	31530827	An exception to this picture is the high mutation count which can stem from alterations to the proofreading domains of DNA polymerases POLE and POLD1, leading to hypermutation.	('alterations', 'Var', (76, 87))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('POLD1', 'Gene', '5424', (144, 149))	('POLD1', 'Gene', (144, 149))	('hypermutation', 'MPA', (162, 175))
110369	31530827	Catalogues covering documented instances of disease-traits associated with single nucleotide variants, across non-cancer diseases, indicate that approximately 90% of these are located in non-coding regions of the human genome and our previous tools predict a large proportion of disease-driver variants in non-coding regions in consequence.	('non-cancer diseases', 'Disease', (110, 129))	('human', 'Species', '9606', (213, 218))	('non-cancer diseases', 'Disease', 'MESH:D009369', (110, 129))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('single nucleotide variants', 'Var', (75, 101))
110370	31530827	we proposed CScape, a method for predicting the disease-driver status of single nucleotide variants in the coding and non-coding regions of the human cancer genome (the method is more fully described in Supplementary Section 1).	('human', 'Species', '9606', (144, 149))	('single nucleotide variants', 'Var', (73, 99))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
110384	31530827	Whereas CS-coding could be viewed as reasonably successful overall and apparently accurate with high confidence prediction, CS-noncoding is weak overall because of our current lack of understanding of the pathogenic impact of variants within non-coding regions of the cancer genome.	('cancer', 'Disease', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('variants', 'Var', (226, 234))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))
110389	31530827	Mutations driving cancer are typically random in occurrence and the mode of the distribution could be expected to lie at a lower SNV count than the median, as would be the case for a Poissonian distribution (excepting hypermutation, relatively fewer numbers of examples are observed with relatively larger mutation counts).	('cancer', 'Disease', (18, 24))	('driving', 'Reg', (10, 17))	('lower', 'NegReg', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('Mutations', 'Var', (0, 9))	('SNV count', 'MPA', (129, 138))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
110404	31530827	The prospective accumulation of SNV-driver mutations with stage of disease has been argued by many authors, though frequently via observation of tumour mutational burden (TMB), the number of non-synonymous mutations in coding regions of the cancer genome.	('tumour', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('mutations', 'Var', (43, 52))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (241, 247))
110406	31530827	Since many non-synonymous mutations are not disease-drivers, the TDB is obviously more insightful, but requires a method to separate passengers and drivers.	('TDB', 'Disease', (65, 68))	('non-synonymous mutations', 'Var', (11, 35))	('TDB', 'Disease', 'MESH:D009369', (65, 68))
110425	31530827	Thus somatically acquired mutations have been implicated in gliomas and chondrosarcomas.	('implicated', 'Reg', (46, 56))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('chondrosarcomas', 'Disease', 'MESH:D002813', (72, 87))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('mutations', 'Var', (26, 35))	('chondrosarcomas', 'Disease', (72, 87))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (72, 87))
110426	31530827	Excepting TP53, CScape predicts that all these single point mutations are disease drivers with confidence levels equal to, or exceeding, 0.829.	('TP53', 'Gene', (10, 14))	('mutations', 'Var', (60, 69))	('TP53', 'Gene', '7157', (10, 14))
110427	31530827	TP53 is different in that any alteration at some locations will act as a disease-driver (e.g.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('alteration', 'Var', (30, 40))
110431	31530827	A recurrent point mutation at chromosome 17, position 64738741 G   C, introduces a D463H amino acid substitution and this has been described as a hallmark of chordoid glioma.	('hallmark of chordoid glioma', 'Disease', 'MESH:D005910', (146, 173))	('D463H', 'Mutation', 'p.D463H', (83, 88))	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))	('hallmark of chordoid glioma', 'Disease', (146, 173))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('D463H', 'Var', (83, 88))	('chordoid glioma', 'Phenotype', 'HP:0010762', (158, 173))
110443	31530827	Mutations in BRAF are well known and studied in the context of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
110450	31530827	TTN mutations have been reported as highly predictive of patient survival with some cancers and TTN-AS1 has been recently argued as an oncogene across several cancers.	('cancers', 'Disease', (159, 166))	('TTN-AS1', 'Gene', '100506866', (96, 103))	('patient', 'Species', '9606', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('TTN', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancers', 'Disease', (84, 91))	('TTN', 'Gene', (96, 99))	('TTN', 'Gene', '7273', (0, 3))	('TTN', 'Gene', '7273', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TTN-AS1', 'Gene', (96, 103))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('mutations', 'Var', (4, 13))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('patient survival', 'CPA', (57, 73))	('predictive', 'Reg', (43, 53))
110459	31530827	As we have previously discussed, three mutations in the TERT promoter region have been characterised as disruptive to putative ETS (E26 transformation specific) family transcription factor binding sites and are verified drivers.	('binding sites', 'Interaction', (189, 202))	('mutations', 'Var', (39, 48))	('ETS', 'Protein', (127, 130))	('transcription', 'biological_process', 'GO:0006351', ('168', '181'))	('disruptive', 'NegReg', (104, 114))	('TERT', 'Gene', (56, 60))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('168', '196'))	('TERT', 'Gene', '7015', (56, 60))
110460	31530827	Five additional recurrent driver mutations in regulatory elements upstream of SDHD and PLEKHS1 have been documented.	('SDHD', 'Gene', '6392', (78, 82))	('SDHD', 'Gene', (78, 82))	('mutations', 'Var', (33, 42))	('PLEKHS1', 'Gene', (87, 94))	('PLEKHS1', 'Gene', '79949', (87, 94))
110461	31530827	The exception is one mutation for SDHD which is outside the core response element.	('SDHD', 'Gene', (34, 38))	('SDHD', 'Gene', '6392', (34, 38))	('core', 'cellular_component', 'GO:0019013', ('60', '64'))	('mutation', 'Var', (21, 29))
110465	31530827	This threshold could be cancer-type specific but would provide predictions of actual driver mutations in concordance with such an alternative model.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer-type', 'Disease', (24, 35))	('cancer-type', 'Disease', 'MESH:D009369', (24, 35))	('mutations', 'Var', (92, 101))
110480	31530827	Secondly, the above analysis supports the general message proposed by other groups, that the mean number of coding SNV-drivers for most cancers is typically very small in size, either single digits or low double digits.	('single digits', 'Var', (184, 197))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
110482	31530827	The indicated low driver set sizes, and the ability to partially identify members of these small sets, suggests an ability to identify many of the core variants in the cancer genome which drive the development of a particular tumour.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('core', 'cellular_component', 'GO:0019013', ('147', '151'))	('drive', 'Reg', (188, 193))	('particular tumour', 'Disease', (215, 232))	('particular tumour', 'Disease', 'MESH:D009369', (215, 232))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('variants', 'Var', (152, 160))	('cancer', 'Disease', (168, 174))
110492	26921031	MB49luc murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, nonmetastatic urothelial carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('nonmetastatic urothelial carcinomas', 'Disease', 'MESH:D014526', (121, 156))	('nonmetastatic urothelial carcinomas', 'Disease', (121, 156))	('MB49', 'CellLine', 'CVCL:7076', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (15, 20))	('non-muscle invasive', 'Disease', (100, 119))	('tumors', 'Disease', (43, 49))	('MB49luc', 'Var', (0, 7))	('tumor', 'Disease', (43, 48))	('murine', 'Species', '10090', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
110495	26921031	The findings suggest that in this bladder tumor model, interruption of the immune suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth.	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', (42, 47))	('interruption', 'Var', (55, 67))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('bladder tumor', 'Disease', (34, 47))	('PD-1/PD-L1', 'Gene', (94, 104))	('bladder tumor', 'Disease', 'MESH:D001749', (34, 47))	('adaptive immune response', 'biological_process', 'GO:0002250', ('130', '154'))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('reduces', 'NegReg', (170, 177))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('bladder tumor', 'Phenotype', 'HP:0009725', (34, 47))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('releases', 'PosReg', (113, 121))
110499	26921031	Although investigators realized that a large subset of patients had evidence of immune cell infiltrates within their tumor microenvironment, it was data highlighting CTLA-4 blockade with Ipilimumab that provided the crucial connection between an interruption of an immune cell checkpoint pathway and significant antitumor responses.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('CTLA-4', 'Gene', '1493', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (316, 321))	('blockade', 'Var', (173, 181))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (316, 321))	('interruption', 'NegReg', (246, 258))	('CTLA-4', 'Gene', (166, 172))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (187, 197))	('immune cell checkpoint pathway', 'Pathway', (265, 295))
110505	26921031	Interruption, or blockade, of the PD-1/PD-L1 interaction by the administration of an antibody to PD-1 or PD-L1 can overcome immune resistance in preclinical models and has been correlated with positive clinical outcomes in patients diagnosed with metastatic bladder cancer.	('antibody', 'molecular_function', 'GO:0003823', ('85', '93'))	('PD-L1', 'Gene', (105, 110))	('Interruption', 'Var', (0, 12))	('interaction', 'Interaction', (45, 56))	('immune resistance', 'MPA', (124, 141))	('bladder cancer', 'Phenotype', 'HP:0009725', (258, 272))	('antibody', 'cellular_component', 'GO:0042571', ('85', '93'))	('correlated', 'Reg', (177, 187))	('PD-1', 'Gene', (97, 101))	('bladder cancer', 'Disease', 'MESH:D001749', (258, 272))	('bladder cancer', 'Disease', (258, 272))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('antibody', 'cellular_component', 'GO:0019814', ('85', '93'))	('antibody', 'cellular_component', 'GO:0019815', ('85', '93'))	('patients', 'Species', '9606', (223, 231))
110512	26921031	Therefore, the presence of PD-L1 could conceivably play a role in abrogating host immune-related responses and result in bladder cancer progression, which infers a biological role for the PD-1/PD-L1 interaction as a new immunotherapeutic target.	('host immune-related responses', 'CPA', (77, 106))	('result in', 'Reg', (111, 120))	('bladder cancer', 'Disease', (121, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('interaction', 'Interaction', (199, 210))	('presence', 'Var', (15, 23))	('bladder cancer', 'Phenotype', 'HP:0009725', (121, 135))	('abrogating', 'NegReg', (66, 76))	('bladder cancer', 'Disease', 'MESH:D001749', (121, 135))	('PD-L1', 'Gene', (27, 32))
110558	26921031	Peptides included p15E (KSPWFTTL, H-2Kb) or control HY peptide (WMHHNMDLI, H-2Db).	('p15E', 'Var', (18, 22))	('H-2Kb', 'Gene', (34, 39))	('H-2Kb', 'Gene', '14972', (34, 39))
110560	26921031	For the CTL assay, splenocytes were plated in triplicate wells of round-bottom, 96-well plates along with EL-4 cells that had been labeled with Indium-111 and pulsed with p15E or control peptide VSV-NP (RGYVYQGL, H-2Kb).	('Indium-111', 'Chemical', 'MESH:C000615551', (144, 154))	('H-2Kb', 'Gene', '14972', (213, 218))	('EL-4', 'CellLine', 'CVCL:0255', (106, 110))	('p15E', 'Var', (171, 175))	('H-2Kb', 'Gene', (213, 218))
110587	26921031	As expected, the intravesical instillation of the MB49luc cells resulted in non-muscle invasive tumor formation on the mucosal surface of the bladder (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('resulted in', 'Reg', (64, 75))	('MB49luc', 'Var', (50, 57))	('tumor', 'Disease', (96, 101))	('formation', 'biological_process', 'GO:0009058', ('102', '111'))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('MB49', 'CellLine', 'CVCL:7076', (50, 54))
110641	26921031	Bladder cancer, the fifth most common cancer in the United States, has a high prevalence, along with melanoma and lung cancer, for somatic mutations, presumably due to DNA damage as a result of long-term exposure to extrinsic mutagens, i.e., smoking, carcinogenic chemicals, etc.. Coincident with those mutations, investigators have found a large number of tumor-infiltrating lymphocytes in bladder cancer.	('mutations', 'Var', (303, 312))	('cancer', 'Disease', (399, 405))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('Bladder cancer', 'Disease', (0, 14))	('carcinogenic', 'Disease', 'MESH:D063646', (251, 263))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (399, 405))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('bladder cancer', 'Disease', 'MESH:D001749', (391, 405))	('bladder cancer', 'Disease', (391, 405))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('cancer', 'Disease', (8, 14))	('bladder cancer', 'Phenotype', 'HP:0009725', (391, 405))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('DNA', 'cellular_component', 'GO:0005574', ('168', '171'))	('cancer', 'Disease', (38, 44))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (399, 405))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('lung cancer', 'Disease', (114, 125))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('tumor', 'Disease', (357, 362))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('carcinogenic', 'Disease', (251, 263))	('Bladder cancer', 'Disease', 'MESH:D001749', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (357, 362))
110655	26921031	Mechanistic studies clearly showed the need for an intact immune system, with depletion of either CD4 or CD8 T cells abrogating the antitumor effects of avelumab treatment.	('CD8', 'Gene', (105, 108))	('CD8', 'Gene', '925', (105, 108))	('depletion', 'Var', (78, 87))	('CD4', 'Gene', '12504', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('abrogating', 'NegReg', (117, 127))	('CD4', 'Gene', (98, 101))	('avelumab', 'Chemical', 'MESH:C000609138', (153, 161))	('tumor', 'Disease', (136, 141))
110656	26921031	Depletion of NK cells had no adverse effect on the antitumor properties of avelumab.	('avelumab', 'Chemical', 'MESH:C000609138', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Depletion', 'Var', (0, 9))	('tumor', 'Disease', (55, 60))
110659	26921031	Two possible tumor-associated antigens are the envelope protein p15E antigen associated with the active component of endogenous retroviruses and/or immune recognition of the HY antigens presented by the MB49 tumor cells implanted into female hosts.	('tumor', 'Disease', (13, 18))	('MB49 tumor', 'Disease', 'MESH:D009369', (203, 213))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('envelope', 'cellular_component', 'GO:0009274', ('47', '55'))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('p15E', 'Var', (64, 68))	('MB49 tumor', 'Disease', (203, 213))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', (208, 213))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('envelope', 'cellular_component', 'GO:0031975', ('47', '55'))
110661	26921031	Although a low, but measurable splenic CTL activity directed against the p15E epitope was found in untreated mice, it had very little effect in impeding tumor growth.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('p15E', 'Var', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('mice', 'Species', '10090', (109, 113))	('impeding', 'NegReg', (144, 152))
110664	26921031	The PD-1/PD-L1 axis seems to be a potent component and contributor to local immunosuppression, as blockade of that axis by avelumab suppressed both subcutaneous and orthotopic MB49 tumor growth, leading to increased overall survival.	('avelumab', 'Chemical', 'MESH:C000609138', (123, 131))	('blockade', 'Var', (98, 106))	('PD-L1 axis', 'Disease', (9, 19))	('increased', 'PosReg', (206, 215))	('avelumab', 'Gene', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('MB49 tumor', 'Disease', 'MESH:D009369', (176, 186))	('MB49 tumor', 'Disease', (176, 186))	('overall survival', 'CPA', (216, 232))	('PD-L1 axis', 'Disease', 'MESH:D010300', (9, 19))	('suppressed', 'NegReg', (132, 142))
110674	26921031	S3B, simple intravesical instillation of the MB49luc cells seems to upregulate PD-L1 expression levels within the different mucosal and submucosal layers of the bladder.	('upregulate', 'PosReg', (68, 78))	('MB49luc', 'Var', (45, 52))	('MB49', 'CellLine', 'CVCL:7076', (45, 49))	('PD-L1 expression levels', 'MPA', (79, 102))
110676	26921031	Use of the model might provide important insights into the cellular mechanisms involved in the nonresponders to immune cell check point immunotherapy, identification of effective immune-based combinations that would be expected to provide a more robust antitumor response than with immune cell checkpoint inhibitor monotherapy, and the PD-L1 function within a tumor microenvironment devoid of T cells.	('combinations', 'Var', (192, 204))	('tumor', 'Disease', (257, 262))	('tumor', 'Disease', (360, 365))	('PD-L1', 'Gene', (336, 341))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))
110698	33194654	Moreover, bladder tumor carries a high mutational load, which leads to the development of a high number of neoantigens, appearing as a good candidate for immunotherapy with checkpoint inhibitors (CPIs).	('neoantigens', 'MPA', (107, 118))	('leads to', 'Reg', (62, 70))	('bladder tumor', 'Disease', (10, 23))	('mutational', 'Var', (39, 49))	('development', 'MPA', (75, 86))	('CPIs', 'Chemical', '-', (196, 200))	('bladder tumor', 'Disease', 'MESH:D001749', (10, 23))	('bladder tumor', 'Phenotype', 'HP:0009725', (10, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
110727	33194654	The pCR rate was 29% (pT0 23%, Tis 6%) in all population and 40% in patients with high PD-L1 expression.	('pCR', 'Disease', (4, 7))	('PD-L1', 'Gene', '29126', (87, 92))	('high', 'Var', (82, 86))	('patients', 'Species', '9606', (68, 76))	('PD-L1', 'Gene', (87, 92))
110739	33194654	Moreover, chemotherapy induces immunologic cell death that augments the tumor antigens presentation through Major histocompatibility complex I (MHC-I).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('chemotherapy', 'Var', (10, 22))	('augments', 'NegReg', (59, 67))	('Major histocompatibility complex', 'biological_process', 'GO:0046776', ('108', '140'))	('complex I', 'cellular_component', 'GO:0030964', ('133', '142'))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cell death', 'biological_process', 'GO:0008219', ('43', '53'))
110752	33194654	Also the gene-targeted therapies may accentuate the anti-tumor response of immunotherapy through upregulated immune-mediated killing and inhibition of tumor-mediated immunosuppression.	('therapies', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('immune-mediated killing', 'CPA', (109, 132))	('inhibition', 'NegReg', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('upregulated', 'PosReg', (97, 108))	('gene-targeted therapies', 'Var', (9, 32))	('accentuate', 'PosReg', (37, 47))
110789	33194654	BMS-986205 is a potent, selective, and orally bioavailable indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, with a potential antineoplastic and immunomodulating activities.	('IDO1', 'Gene', '3620', (90, 94))	('IDO', 'molecular_function', 'GO:0047719', ('90', '93'))	('BMS-986205', 'Var', (0, 10))	('IDO1', 'Gene', (90, 94))	('indoleamine 2,3-dioxygenase 1', 'Gene', '3620', (59, 88))	('IDO', 'molecular_function', 'GO:0033754', ('90', '93'))
110791	33194654	By targeting and inhibiting IDO1 and decreasing kynurenine, BMS-986205 is able to determine a reduction in tumor-associated regulatory T cells (Tregs) and to restore and promote the activation and proliferation of several immune cells, such as natural killer cells, dendritic cells, and T lymphocytes cells.	('IDO', 'molecular_function', 'GO:0033754', ('28', '31'))	('decreasing', 'NegReg', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('restore', 'PosReg', (158, 165))	('reduction', 'NegReg', (94, 103))	('BMS-986205', 'Var', (60, 70))	('inhibiting', 'NegReg', (17, 27))	('IDO1', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('kynurenine', 'Chemical', 'MESH:D007737', (48, 58))	('IDO', 'molecular_function', 'GO:0047719', ('28', '31'))	('kynurenine', 'MPA', (48, 58))	('activation', 'CPA', (182, 192))	('proliferation', 'CPA', (197, 210))	('IDO1', 'Gene', '3620', (28, 32))	('promote', 'PosReg', (170, 177))
110825	33194654	Likewise, in the IMVigor-210 trial (a phase 2 trial investigating the clinical activity of PD-L1 blockade with atezolizumab in metastatic urothelial carcinoma), the median mutational load was higher in responders to atezolizumab than in non-responders (12.4 mut/Mb vs. 6.4 mut/Mb).	('PD-L1', 'Gene', (91, 96))	('atezolizumab', 'Chemical', 'MESH:C000594389', (216, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('higher', 'PosReg', (192, 198))	('atezolizumab in metastatic urothelial carcinoma', 'Disease', 'MESH:C538445', (111, 158))	('atezolizumab in metastatic urothelial carcinoma', 'Disease', (111, 158))	('PD-L1', 'Gene', '29126', (91, 96))	('atezolizumab', 'Chemical', 'MESH:C000594389', (111, 123))	('mutational', 'Var', (172, 182))
110851	33194654	Mutations in this family of genes are known to be associated with tumor development, progression, treatment response, and outcome in urothelial cancer.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('urothelial cancer', 'Disease', 'MESH:D014523', (133, 150))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('associated', 'Reg', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('urothelial cancer', 'Disease', (133, 150))
110852	33194654	In bladder cancer, tumors carrying DDR genes alterations achieved a higher ORR to cisplatinum-based neoadjuvant chemotherapy.	('alterations', 'Var', (45, 56))	('tumors', 'Disease', (19, 25))	('ORR to cisplatinum-based neoadjuvant chemotherapy', 'MPA', (75, 124))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('higher', 'PosReg', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('DDR genes', 'Gene', (35, 44))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('cisplatinum', 'Chemical', 'MESH:D002945', (82, 93))
110853	33194654	The association of DDR genes alterations with a higher mutational burden and increased gene copy number alterations justifies a better responsivity to immune CPIs, as observed in several solid tumors.	('CPIs', 'Chemical', '-', (158, 162))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('alterations', 'Var', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('gene copy', 'MPA', (87, 96))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('DDR genes', 'Gene', (19, 28))	('mutational burden', 'MPA', (55, 72))
110854	33194654	Unfortunately, the data supporting the predictive role of DDR gene mutations about response to immunotherapy in bladder carcinoma are still insufficient.	('bladder carcinoma', 'Disease', 'MESH:D001749', (112, 129))	('DDR gene', 'Gene', (58, 66))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (112, 129))	('mutations', 'Var', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('bladder carcinoma', 'Disease', (112, 129))
110855	33194654	Moreover, in the ABACUS trial, alteration status in DDR-related genes, observed at baseline and stratified by outcome, did not show a significant correlation with response to atezolizumab.	('atezolizumab', 'Chemical', 'MESH:C000594389', (175, 187))	('DDR-related genes', 'Gene', (52, 69))	('alteration', 'Var', (31, 41))
110856	33194654	The RB1 gene is a fundamental cell cycle regulator, whose inactivation is notoriously associated with cancer development.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('RB1', 'Gene', '5925', (4, 7))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('30', '50'))	('inactivation', 'Var', (58, 70))	('associated', 'Reg', (86, 96))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('30', '50'))	('RB1', 'Gene', (4, 7))
110860	33194654	In NSCLC patients, RB1 alterations have been correlated with the lack of response to second line nivolumab or first line pembrolizumab.	('patients', 'Species', '9606', (9, 17))	('pembrolizumab', 'Chemical', 'MESH:C582435', (121, 134))	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('RB1', 'Gene', (19, 22))	('alterations', 'Var', (23, 34))	('nivolumab', 'Chemical', 'MESH:D000077594', (97, 106))	('RB1', 'Gene', '5925', (19, 22))
110862	33194654	However, in the PURE-01 trial, the apparently strong association between DDR and/or RB1 genes alterations and response to immunotherapy (increasing of pCR rate up to 60% in patients with tumors carrying these alterations compared to 39.5% observed in unselected patients) resulted weakened when adjusted for TMB.	('alterations', 'Var', (94, 105))	('RB1', 'Gene', '5925', (84, 87))	('patients', 'Species', '9606', (173, 181))	('patients', 'Species', '9606', (262, 270))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('RB1', 'Gene', (84, 87))	('DDR', 'Gene', (73, 76))	('PURE', 'molecular_function', 'GO:0034023', ('16', '20'))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('alterations', 'Var', (209, 220))	('TMB', 'Chemical', '-', (308, 311))
110863	33194654	Therefore, further data are needed to explore the role of RB1 gene alterations.	('RB1', 'Gene', '5925', (58, 61))	('RB1', 'Gene', (58, 61))	('alterations', 'Var', (67, 78))
110868	33194654	On the basis of these analysis and especially of mRNA expression, four clusters were initially identified, but, in a subsequent analysis of 412 MIBC, published in 2017, the taxonomy of MIBC was expanded, identifying five molecular subtypes: (1) luminal-papillary (35%), enriched in mutation or amplification of FGFR3 or FGFR3 gene fusions with TACC3; (2) luminal-infiltrated (19%), with overexpression of extracellular matrix and smooth muscle gene and of immune markers, such as PD-L1 and CTLA-4 and with high level of immune infiltrates; (3) luminal (6%), with high expression of uroplakin genes, KRT20 and SNX31; (4) basal-squamous (35%), with high expression of basal marker genes (such as KRT5, KRT6A, and CD44), squamous differentiation markers, immune expression genes (such as CXCL11 and L1CAM) and TP53 mutations; (5) neuronal (5%), with high expression of neural differentiation and development genes (such as SOX2, MSI1, and GNG4) and high level of alterations in genes of the p53/cell-cycle pathway.	('CD44', 'Gene', (711, 715))	('GNG4', 'Gene', (936, 940))	('GNG4', 'Gene', '2786', (936, 940))	('FGFR', 'molecular_function', 'GO:0005007', ('311', '315'))	('expression', 'MPA', (852, 862))	('mutations', 'Var', (812, 821))	('MIBC', 'Chemical', '-', (144, 148))	('luminal', 'Chemical', 'MESH:D010634', (355, 362))	('L1CAM', 'Gene', (796, 801))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('405', '425'))	('KRT5', 'Gene', '3852', (694, 698))	('TP53', 'Gene', (807, 811))	('SNX31', 'Gene', (609, 614))	('TACC3', 'Gene', '10460', (344, 349))	('luminal', 'Chemical', 'MESH:D010634', (544, 551))	('MSI1', 'Gene', (926, 930))	('TACC3', 'Gene', (344, 349))	('SNX31', 'Gene', '169166', (609, 614))	('SOX2', 'Gene', '6657', (920, 924))	('SOX2', 'Gene', (920, 924))	('CXCL11', 'Gene', (785, 791))	('CXCL11', 'Gene', '6373', (785, 791))	('KRT20', 'Gene', '54474', (599, 604))	('KRT6A', 'Gene', '3853', (700, 705))	('KRT5', 'Gene', (694, 698))	('cell-cycle', 'biological_process', 'GO:0007049', ('992', '1002'))	('CTLA-4', 'Gene', (490, 496))	('neural differentiation', 'CPA', (866, 888))	('FGFR3', 'Gene', (320, 325))	('p53', 'Gene', '7157', (988, 991))	('KRT6A', 'Gene', (700, 705))	('L1CAM', 'Gene', '3897', (796, 801))	('KRT20', 'Gene', (599, 604))	('MSI1', 'Gene', '4440', (926, 930))	('FGFR3', 'Gene', (311, 316))	('luminal', 'Chemical', 'MESH:D010634', (245, 252))	('FGFR', 'molecular_function', 'GO:0005007', ('320', '324'))	('TP53', 'Gene', '7157', (807, 811))	('FGFR3', 'Gene', '2261', (320, 325))	('PD-L1', 'Gene', (480, 485))	('CTLA-4', 'Gene', '1493', (490, 496))	('MIBC', 'Chemical', '-', (185, 189))	('alterations', 'Reg', (960, 971))	('development', 'CPA', (893, 904))	('FGFR3', 'Gene', '2261', (311, 316))	('PD-L1', 'Gene', '29126', (480, 485))	('p53', 'Gene', (988, 991))	('CD44', 'Gene', '960', (711, 715))
110875	33194654	This specific subgroup presented distinct features of high mutation load, inhibited TGFbeta signaling, and activated cell cycle.	('TGFbeta', 'Gene', (84, 91))	('inhibited', 'NegReg', (74, 83))	('cell cycle', 'biological_process', 'GO:0007049', ('117', '127'))	('cell cycle', 'CPA', (117, 127))	('TGFbeta', 'Gene', '7039', (84, 91))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('high mutation load', 'Var', (54, 72))	('activated', 'PosReg', (107, 116))
110881	32292497	Aristolochic acid mutational signature defines the low-risk subtype in upper tract urothelial carcinoma Rationale: Dietary exposure to aristolochic acids and similar compounds (collectively, AA) is a significant risk factor for nephropathy and subsequent upper tract urothelial carcinoma (UTUC).	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('aristolochic acids', 'Chemical', 'MESH:D034341', (135, 153))	('Aristolochic acid', 'Chemical', 'MESH:C000228', (0, 17))	('nephropathy', 'Disease', 'MESH:D007674', (228, 239))	('upper tract urothelial carcinoma', 'Disease', (255, 287))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (255, 287))	('aristolochic acids', 'Var', (135, 153))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (71, 103))	('nephropathy', 'Phenotype', 'HP:0000112', (228, 239))	('nephropathy', 'Disease', (228, 239))	('upper tract urothelial carcinoma', 'Disease', (71, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))
110900	32292497	However, many genes listed in the Cancer Gene Census as known driver genes were affected by nonsilent mutations, including genes that are frequently mutated in Western UTUC patients, such as KMT2A, C and D (27%) and ARID1A (14%) (Figure S2C).	('patients', 'Species', '9606', (173, 181))	('KMT2A', 'Gene', (191, 196))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Cancer', 'Disease', (34, 40))	('ARID1A', 'Gene', '8289', (216, 222))	('KMT2A', 'Gene', '4297', (191, 196))	('ARID1A', 'Gene', (216, 222))	('Cancer', 'Disease', 'MESH:D009369', (34, 40))	('mutations', 'Var', (102, 111))	('affected', 'Reg', (80, 88))
110901	32292497	Consistent with a previous study, hotspot driver mutations in the promoter of TERT (22% of all the patients) and FGFR3 mutations (2%) were identified in our cohort but at a much lower frequency (Figure S2C).	('TERT', 'Gene', (78, 82))	('TERT', 'Gene', '7015', (78, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('113', '117'))	('mutations', 'Var', (49, 58))	('FGFR3', 'Gene', (113, 118))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (119, 128))	('FGFR3', 'Gene', '2261', (113, 118))
110907	32292497	We did find similar numbers of SNVs and indels in the morphologically normal urothelium specimens in the multifocal patient (Table S2).	('indels', 'Var', (40, 46))	('SNVs', 'Var', (31, 35))	('patient', 'Species', '9606', (116, 123))
110917	32292497	Moreover, it has been reported that lymphocyte infiltration, especially CD3+ lymphocytes, in the tumor region is associated with improved survival in a range of cancers, including urothelial cancer, and the number of tumor- infiltrating lymphocytes independently correlates with progression-free survival in non-small-cell lung carcinoma patients treated with nivolumab immunotherapy.	('urothelial cancer', 'Disease', 'MESH:D014523', (180, 197))	('CD3+ lymphocytes', 'Var', (72, 88))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (312, 337))	('urothelial cancer', 'Disease', (180, 197))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('progression-free', 'Disease', (279, 295))	('cancers', 'Disease', (161, 168))	('patients', 'Species', '9606', (338, 346))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (308, 337))	('tumor', 'Disease', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('lung carcinoma', 'Disease', (323, 337))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('lung carcinoma', 'Disease', 'MESH:D008175', (323, 337))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('nivolumab', 'Chemical', 'MESH:D000077594', (360, 369))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('improved', 'PosReg', (129, 137))
110920	32292497	First, we experimentally verified that AA alone, as a purified isolated compound, was sufficient to cause AA mutational signatures in human renal tubular cell HK-2 and human uroepithelium cell SV-HUC-1.	('human', 'Species', '9606', (134, 139))	('human', 'Species', '9606', (168, 173))	('HK-2', 'Gene', '3099', (159, 163))	('cause', 'Reg', (100, 105))	('mutational', 'Var', (109, 119))	('HK-2', 'Gene', (159, 163))	('HK-2', 'molecular_function', 'GO:0008256', ('159', '163'))	('SV-HUC-1', 'CellLine', 'CVCL:3798', (193, 201))
110923	32292497	Consistent with previous studies in several types of cells, we identified AA mutational signature mutations in HK-2 cells (Figure 4B).	('HK-2', 'molecular_function', 'GO:0008256', ('111', '115'))	('HK-2', 'Gene', '3099', (111, 115))	('HK-2', 'Gene', (111, 115))	('mutations', 'Var', (98, 107))	('mutational', 'Var', (77, 87))
110926	32292497	Copy number changes were also identified in AA-treated HK-2 cells but not in SV-HUC-1 cells (Figure S4B).	('HK-2', 'Gene', '3099', (55, 59))	('HK-2', 'molecular_function', 'GO:0008256', ('55', '59'))	('SV-HUC-1', 'CellLine', 'CVCL:3798', (77, 85))	('Copy number changes', 'Var', (0, 19))	('HK-2', 'Gene', (55, 59))
110933	32292497	Consistently, high proportion (>50%) of AA signature mutations was identified in matched tumor tissues in all 4 patients with high proportion (nearly >15%) of AA signature mutations in cfDNA but not in any of the 4 patients with low proportion (<5%) of AA signature mutations in cfDNA (Figure 4D).	('mutations', 'Var', (172, 181))	('cfDNA', 'Gene', (185, 190))	('patients', 'Species', '9606', (215, 223))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
110967	27870574	Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor.	('tumor', 'Disease', 'MESH:D009369', (578, 583))	('BGJ398', 'Gene', (601, 607))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('Kinase Inhibitor', 'biological_process', 'GO:0033673', ('62', '78'))	('tumors', 'Phenotype', 'HP:0002664', (340, 346))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('638', '654'))	('tumor', 'Phenotype', 'HP:0002664', (578, 583))	('FGFR1', 'Gene', '2260', (621, 626))	('tyrosine', 'Chemical', 'None', (629, 637))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('380', '404'))	('Advanced Solid Tumors Harboring', 'Disease', 'MESH:C537062', (97, 128))	('solid tumors', 'Disease', (334, 346))	('Advanced Solid Tumors Harboring', 'Disease', (97, 128))	('Fibroblast Growth Factor', 'molecular_function', 'GO:0005104', ('152', '176'))	('tumor', 'Disease', (340, 345))	('Tumors', 'Phenotype', 'HP:0002664', (112, 118))	('FGFR', 'molecular_function', 'GO:0005007', ('621', '625'))	('human', 'Species', '9606', (282, 287))	('Fibroblast Growth Factor', 'molecular_function', 'GO:0005104', ('24', '48'))	('alterations', 'Var', (365, 376))	('FGFR1', 'Gene', (621, 626))	('tumor', 'Disease', 'MESH:D009369', (340, 345))	('patients', 'Species', '9606', (311, 319))	('tumor', 'Disease', (578, 583))	('Patients', 'Species', '9606', (83, 91))	('Tumor', 'Phenotype', 'HP:0002664', (112, 117))	('solid tumors', 'Disease', 'MESH:D009369', (334, 346))
110969	27870574	During expansion at the MTD, patients with FGFR1-amplified squamous cell non-small-cell lung cancer (sqNSCLC; arm 1) or other solid tumors with FGFR genetic alterations (mutations/amplifications/fusions) received BGJ398 daily on a continuous schedule (arm 2), or on a 3-weeks-on/1-week-off schedule (arm 3).	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (77, 99))	('patients', 'Species', '9606', (29, 37))	('FGFR1', 'Gene', (43, 48))	('lung cancer', 'Disease', (88, 99))	('genetic alterations', 'Var', (149, 168))	('solid tumors', 'Disease', (126, 138))	('FGFR1', 'Gene', '2260', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('FGFR', 'Gene', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (73, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('solid tumors', 'Disease', 'MESH:D009369', (126, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
110978	27870574	Genomic alterations in FGFR1-3 (eg, gene amplifications, gain-of-function mutations, and chromosomal translocations) that trigger pathway activation have been identified in bladder cancer, squamous cell non-small-cell lung cancer (sqNSCLC), squamous cell cancer of the head and neck, endometrial cancer, cholangiocarcinoma, and breast cancer.	('squamous cell cancer of the head', 'Phenotype', 'HP:0030413', (241, 273))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('neck', 'cellular_component', 'GO:0044326', ('278', '282'))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (207, 229))	('endometrial cancer', 'Phenotype', 'HP:0012114', (284, 302))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('FGFR1', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('lung cancer', 'Phenotype', 'HP:0100526', (218, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (304, 322))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (203, 229))	('endometrial cancer', 'Disease', (284, 302))	('cholangiocarcinoma', 'Disease', (304, 322))	('bladder cancer', 'Disease', 'MESH:D001749', (173, 187))	('bladder cancer', 'Disease', (173, 187))	('endometrial cancer', 'Disease', 'MESH:D016889', (284, 302))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (304, 322))	('breast cancer', 'Phenotype', 'HP:0003002', (328, 341))	('squamous cell non-small-cell lung cancer (sqNSCLC), squamous cell cancer of the head', 'Disease', 'MESH:D018307', (189, 273))	('cancer of the head and neck', 'Phenotype', 'HP:0012288', (255, 282))	('bladder cancer', 'Phenotype', 'HP:0009725', (173, 187))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (241, 261))	('breast cancer', 'Disease', 'MESH:D001943', (328, 341))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('breast cancer', 'Disease', (328, 341))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('gain-of-function', 'PosReg', (57, 73))	('FGFR1', 'Gene', '2260', (23, 28))	('mutations', 'Var', (74, 83))
110980	27870574	BGJ398, an orally bioavailable, selective FGFR1 to 3 inhibitor (half maximal inhibitory concentration values range from 0.9 to 1.4 nM for FGFR1-3 to 60 nM for FGFR4), inhibits proliferation and tumor growth in preclinical cancer models bearing FGFR1-3 genetic alterations.	('FGFR', 'molecular_function', 'GO:0005007', ('244', '248'))	('tumor', 'Disease', (194, 199))	('FGFR1', 'Gene', '2260', (138, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('138', '142'))	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('cancer', 'Disease', (222, 228))	('FGFR4', 'Gene', '2264', (159, 164))	('FGFR1', 'Gene', (244, 249))	('FGFR1', 'Gene', '2260', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('FGFR4', 'Gene', (159, 164))	('genetic alterations', 'Var', (252, 271))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('FGFR1', 'Gene', (138, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('BGJ398', 'Gene', (0, 6))	('FGFR1', 'Gene', (42, 47))	('proliferation', 'CPA', (176, 189))	('FGFR1', 'Gene', '2260', (244, 249))	('inhibits', 'NegReg', (167, 175))
110981	27870574	On the basis of these preclinical data, we conducted a global, personalized phase I single-agent study to determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), schedule, safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of BGJ398 in patients with solid tumors bearing FGFR alterations (ClinicalTrials.gov identifier NCT01004224).	('solid tumors', 'Disease', (298, 310))	('BGJ398', 'Gene', (274, 280))	('patients', 'Species', '9606', (284, 292))	('alterations', 'Var', (324, 335))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('PD', 'Disease', 'MESH:D010300', (243, 245))	('FGFR', 'Gene', (319, 323))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('solid tumors', 'Disease', 'MESH:D009369', (298, 310))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('FGFR', 'molecular_function', 'GO:0005007', ('319', '323'))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Disease', (304, 309))	('tumors', 'Phenotype', 'HP:0002664', (304, 310))	('tumor', 'Disease', (256, 261))
110982	27870574	Adults with solid tumors harboring FGFR alterations (eg, amplification, mutation, fusion) for whom no effective standard therapy exists were enrolled.	('solid tumors', 'Disease', 'MESH:D009369', (12, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('fusion', 'Var', (82, 88))	('alterations', 'Var', (40, 51))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('solid tumors', 'Disease', (12, 24))	('mutation', 'Var', (72, 80))	('FGFR', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
110983	27870574	Patient selection criteria relative to FGFR genetic alterations are defined in the Appendix (online only).	('FGFR', 'Gene', (39, 43))	('FGFR', 'molecular_function', 'GO:0005007', ('39', '43'))	('Patient', 'Species', '9606', (0, 7))	('genetic alterations', 'Var', (44, 63))
110984	27870574	FGFR genetic alterations not specified in the protocol were compared with those in public databases (eg, COSMIC and dbSNP) and were adjudicated to determine suitability for enrollment, allowing for continual review and enrollment of patients with newly reported FGFR alterations suggestive of potential sensitivity to FGFR inhibition (Appendix Table A1, online only).	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'Gene', (0, 4))	('FGFR', 'molecular_function', 'GO:0005007', ('262', '266'))	('FGFR', 'Gene', (262, 266))	('FGFR', 'molecular_function', 'GO:0005007', ('318', '322'))	('alterations', 'Var', (267, 278))	('not specified', 'Species', '32644', (25, 38))	('patients', 'Species', '9606', (233, 241))
111038	27870574	Of 26 patients with breast cancer (FGFR1/2 amplified [n = 25]; FGFR3 mutant [n = 1]) with pre-and post-treatment target lesion measurements, four (15.4%) had reduced tumor burden.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('FGFR3', 'Gene', '2261', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('mutant', 'Var', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('breast cancer', 'Disease', (20, 33))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('tumor', 'Disease', (166, 171))	('FGFR3', 'Gene', (63, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('pre', 'molecular_function', 'GO:0003904', ('90', '93'))	('patients', 'Species', '9606', (6, 14))	('FGFR1', 'Gene', (35, 40))	('reduced', 'NegReg', (158, 165))	('FGFR1', 'Gene', '2260', (35, 40))
111039	27870574	In addition, all three patients with FGFR2-altered (fusion [n = 2] or mutation [n = 1]) cholangiocarcinoma with pre-and post-treatment target lesion assessments had reduced tumor burden (Fig 3).	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('patients', 'Species', '9606', (23, 31))	('FGFR2', 'Gene', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('cholangiocarcinoma', 'Disease', (88, 106))	('FGFR2', 'Gene', '2263', (37, 42))	('pre', 'molecular_function', 'GO:0003904', ('112', '115'))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('mutation', 'Var', (70, 78))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 106))	('reduced', 'NegReg', (165, 172))
111042	27870574	This global first-in-human study of the FGFR1-3 inhibitor BGJ398 demonstrated a tolerable safety profile in patients with advancedsolid tumors bearing FGFR amplifications, mutations, or fusions.	('advancedsolid tumors', 'Disease', (122, 142))	('mutations', 'Var', (172, 181))	('advancedsolid tumors', 'Disease', 'MESH:D009369', (122, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('fusions', 'Var', (186, 193))	('FGFR', 'molecular_function', 'GO:0005007', ('151', '155'))	('BGJ398', 'Gene', (58, 64))	('FGFR', 'Gene', (151, 155))	('FGFR1', 'Gene', (40, 45))	('human', 'Species', '9606', (21, 26))	('FGFR1', 'Gene', '2260', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('patients', 'Species', '9606', (108, 116))	('amplifications', 'Var', (156, 170))
111057	27870574	Despite preselecting for FGFR1 amplification, the response rate was lower than expected on the basis of preclinical data, suggesting that FGFR1 amplification may not function as a sole biomarker predicting clinical benefit.	('lower', 'NegReg', (68, 73))	('response', 'MPA', (50, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('FGFR1', 'Gene', (138, 143))	('FGFR1', 'Gene', (25, 30))	('FGFR1', 'Gene', '2260', (138, 143))	('FGFR1', 'Gene', '2260', (25, 30))	('FGFR', 'molecular_function', 'GO:0005007', ('138', '142'))	('amplification', 'Var', (31, 44))
111059	27870574	Responses observed in FGFR3-mutant bladder/urothelial cancer after failure of platinum-based chemotherapy (38% overall response rate, 75% DCR) strongly support a role for FGFR3 mutations as driver alterations in this molecular subgroup and the potent inhibitory function of BGJ398.	('bladder/urothelial cancer', 'Disease', (35, 60))	('FGFR3', 'Gene', (22, 27))	('FGFR3', 'Gene', (171, 176))	('mutations', 'Var', (177, 186))	('platinum', 'Chemical', 'MESH:D010984', (78, 86))	('FGFR', 'molecular_function', 'GO:0005007', ('171', '175'))	('bladder/urothelial cancer', 'Disease', 'MESH:D001749', (35, 60))	('FGFR3', 'Gene', '2261', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('DCR', 'Gene', (138, 141))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('FGFR3', 'Gene', '2261', (171, 176))	('DCR', 'Gene', '1637', (138, 141))
111061	27870574	To this end, a fourth expansion arm was opened to further evaluate BGJ398 activity in patients with urothelial cancer harboring an FGFR3 mutation or fusion.	('mutation', 'Var', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('FGFR3', 'Gene', '2261', (131, 136))	('FGFR', 'molecular_function', 'GO:0005007', ('131', '135'))	('activity', 'MPA', (74, 82))	('urothelial cancer', 'Disease', (100, 117))	('fusion', 'Var', (149, 155))	('BGJ398', 'Gene', (67, 73))	('FGFR3', 'Gene', (131, 136))	('urothelial cancer', 'Disease', 'MESH:D014523', (100, 117))	('patients', 'Species', '9606', (86, 94))
111062	27870574	SD with reduced tumor burden was also observed in patients with cholangiocarcinoma (FGFR2 fusions [n = 2], FGFR2 mutation [n = 1]) and FGFR1-amplified squamous head and neck cancer.	('FGFR2', 'Gene', (107, 112))	('FGFR2', 'Gene', '2263', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('neck', 'cellular_component', 'GO:0044326', ('169', '173'))	('FGFR1', 'Gene', (135, 140))	('mutation', 'Var', (113, 121))	('FGFR2', 'Gene', '2263', (107, 112))	('cancer', 'Disease', (174, 180))	('reduced', 'NegReg', (8, 15))	('FGFR', 'molecular_function', 'GO:0005007', ('84', '88'))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('fusions', 'Var', (90, 97))	('patients', 'Species', '9606', (50, 58))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('head and neck cancer', 'Phenotype', 'HP:0012288', (160, 180))	('tumor', 'Disease', (16, 21))	('cholangiocarcinoma', 'Disease', (64, 82))	('FGFR1', 'Gene', '2260', (135, 140))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 82))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('FGFR2', 'Gene', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('FGFR', 'molecular_function', 'GO:0005007', ('135', '139'))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
111064	27870574	Of interest, another patient with cholangiocarcinoma who was enrolled with a presumed FGFR3 mutation progressed rapidly and was later identified to be wild type for FGFR but as having a mutation in KRAS, a negative predictor (preclinically) for BGJ398 sensitivity.	('FGFR', 'molecular_function', 'GO:0005007', ('165', '169'))	('mutation', 'Var', (92, 100))	('patient', 'Species', '9606', (21, 28))	('FGFR3', 'Gene', '2261', (86, 91))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (34, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (34, 52))	('KRAS', 'Gene', (198, 202))	('mutation', 'Var', (186, 194))	('KRAS', 'Gene', '3845', (198, 202))	('FGFR3', 'Gene', (86, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('86', '90'))	('cholangiocarcinoma', 'Disease', (34, 52))	('progressed', 'PosReg', (101, 111))
111066	27870574	The lack of objective responses and the limited disease control observed with BGJ398 in patients with breast cancer challenge the idea of FGFR amplification as a sole oncogenic driver in this disease; however, BGJ398 may prove more effective against advanced breast cancer when combined with other endocrine or targeted agents.	('breast cancer', 'Disease', (102, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('BGJ398', 'Var', (210, 216))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('breast cancer', 'Disease', 'MESH:D001943', (259, 272))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('FGFR', 'molecular_function', 'GO:0005007', ('138', '142'))	('breast cancer', 'Disease', (259, 272))
111067	27870574	Certain FGFR alterations (eg, FGFR3 mutations/gene fusions in bladder/urothelial carcinoma and FGFR2 gene fusions in cholangiocarcinoma) are dominant oncogenic drivers and confer sensitivity to BGJ398-mediated FGFR inhibition, whereas FGFR1 amplification, observed in a number of tumor types including sqNSCLC and breast cancer, may not be sufficient to identify a BGJ398-sensitive population.	('FGFR1', 'Gene', '2260', (235, 240))	('bladder/urothelial carcinoma', 'Disease', 'MESH:D001749', (62, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('235', '239'))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('FGFR', 'Gene', (8, 12))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('FGFR3', 'Gene', (30, 35))	('bladder/urothelial carcinoma', 'Disease', (62, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (314, 327))	('tumor', 'Disease', (280, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('FGFR3', 'Gene', '2261', (30, 35))	('FGFR1', 'Gene', (235, 240))	('FGFR', 'molecular_function', 'GO:0005007', ('210', '214'))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('mutations/gene', 'Var', (36, 50))	('FGFR2', 'Gene', (95, 100))	('sqNSCLC and breast cancer', 'Disease', 'MESH:D001943', (302, 327))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (117, 135))	('FGFR', 'molecular_function', 'GO:0005007', ('95', '99'))	('cholangiocarcinoma', 'Disease', (117, 135))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (117, 135))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('FGFR', 'molecular_function', 'GO:0005007', ('8', '12'))	('alterations', 'Var', (13, 24))	('FGFR2', 'Gene', '2263', (95, 100))
111069	27870574	As the knowledge of FGFR biology and driver genetic alterations increased and assays for patient selection became available over the 6-year enrollment period, patient inclusion criteria were amended accordingly (Appendix Table A1).	('patient', 'Species', '9606', (89, 96))	('FGFR', 'Gene', (20, 24))	('genetic alterations', 'Var', (44, 63))	('patient', 'Species', '9606', (159, 166))	('FGFR', 'molecular_function', 'GO:0005007', ('20', '24'))
111071	27870574	Taken together, treatment with BGJ398 in patients with advanced solid tumors bearing FGFR alterations was tolerable, with manageable toxicity.	('solid tumors', 'Disease', (64, 76))	('toxicity', 'Disease', 'MESH:D064420', (133, 141))	('alterations', 'Var', (90, 101))	('toxicity', 'Disease', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('FGFR', 'Gene', (85, 89))	('BGJ398', 'Gene', (31, 37))	('solid tumors', 'Disease', 'MESH:D009369', (64, 76))	('patients', 'Species', '9606', (41, 49))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))
111073	27870574	BGJ398 clinical development is ongoing, including adding a fourth expansion arm to this study for patients with urothelial carcinoma and FGFR3 mutation/gene fusion and a phase II study in cholangiocarcinoma with FGFR2 gene fusion/other FGFR genetic alterations.	('FGFR3', 'Gene', '2261', (137, 142))	('genetic alterations', 'Var', (241, 260))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (188, 206))	('urothelial carcinoma', 'Disease', (112, 132))	('FGFR', 'molecular_function', 'GO:0005007', ('236', '240'))	('FGFR', 'molecular_function', 'GO:0005007', ('137', '141'))	('FGFR', 'Gene', (236, 240))	('gene fusion/other', 'Var', (218, 235))	('patients', 'Species', '9606', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('FGFR', 'molecular_function', 'GO:0005007', ('212', '216'))	('FGFR2', 'Gene', (212, 217))	('FGFR3', 'Gene', (137, 142))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (188, 206))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (112, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('FGFR2', 'Gene', '2263', (212, 217))	('mutation/gene', 'Var', (143, 156))	('cholangiocarcinoma', 'Disease', (188, 206))
111074	27870574	Patient eligibility was determined on the basis of FGFR alteration status as assessed centrally or locally using fresh and/or archival tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('FGFR', 'Gene', (51, 55))	('tumor', 'Disease', (135, 140))	('alteration', 'Var', (56, 66))	('Patient', 'Species', '9606', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
111076	27870574	Patients were eligible for enrollment if one of the following genetic alteration criteria was met: (1) FGFR1 or FGFR2 amplification was identified using fluorescence in situ hybridization (defined as a ratio of the respective FGFR to chromosome enumeration probe 8 [FGFR1] or chromosome enumeration probe 10 [FGFR2] of >= 2.2 or an average FGFR copy number of six or more signals/nucleus in >= 20 contiguous cells from two tumor areas); chromogenic or silver-enhanced in situ hybridization (defined as an average respective FGFR copy number of six or more signals/nucleus or a large gene cluster in >= 30% of tumor cells from >= 100 contiguous cells from two tumor areas); or quantitative polymerase chain reaction (defined as a respective FGFR copy number of at least six); (2) FGFR3 mutations were detected in exon 7 (R248C, S249C), exon 10 (G372C, A393E, Y375C), or exon 15 (K652M/T, K652E/Q); or (3) other FGFR genetic alterations, including gene fusions, were identified.	('FGFR', 'molecular_function', 'GO:0005007', ('103', '107'))	('tumor', 'Disease', 'MESH:D009369', (609, 614))	('S249C', 'Mutation', 'rs121913483', (827, 832))	('A393E', 'Mutation', 'rs28931615', (851, 856))	('chromosome', 'cellular_component', 'GO:0005694', ('234', '244'))	('FGFR', 'molecular_function', 'GO:0005007', ('112', '116'))	('FGFR', 'molecular_function', 'GO:0005007', ('266', '270'))	('FGFR1', 'Gene', (103, 108))	('A393E', 'Var', (851, 856))	('K652E', 'Var', (887, 892))	('K652M', 'SUBSTITUTION', 'None', (878, 883))	('R248C', 'Var', (820, 825))	('R248C', 'Mutation', 'rs121913482', (820, 825))	('Y375C', 'SUBSTITUTION', 'None', (858, 863))	('tumor', 'Disease', (423, 428))	('FGFR1', 'Gene', '2260', (266, 271))	('FGFR', 'molecular_function', 'GO:0005007', ('226', '230'))	('FGFR', 'Gene', (910, 914))	('tumor', 'Phenotype', 'HP:0002664', (609, 614))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (785, 794))	('FGFR2', 'Gene', (112, 117))	('FGFR', 'molecular_function', 'GO:0005007', ('524', '528'))	('tumor', 'Disease', 'MESH:D009369', (423, 428))	('FGFR2', 'Gene', (309, 314))	('tumor', 'Disease', (659, 664))	('nucleus', 'cellular_component', 'GO:0005634', ('564', '571'))	('chromosome', 'cellular_component', 'GO:0005694', ('276', '286'))	('FGFR', 'molecular_function', 'GO:0005007', ('740', '744'))	('tumor', 'Disease', 'MESH:D009369', (659, 664))	('Y375C', 'Var', (858, 863))	('G372C', 'Var', (844, 849))	('FGFR2', 'Gene', '2263', (112, 117))	('FGFR1', 'Gene', '2260', (103, 108))	('nucleus', 'cellular_component', 'GO:0005634', ('380', '387'))	('FGFR', 'molecular_function', 'GO:0005007', ('309', '313'))	('FGFR2', 'Gene', '2263', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (423, 428))	('FGFR1', 'Gene', (266, 271))	('FGFR', 'molecular_function', 'GO:0005007', ('779', '783'))	('K652E', 'SUBSTITUTION', 'None', (887, 892))	('FGFR', 'molecular_function', 'GO:0005007', ('340', '344'))	('FGFR', 'molecular_function', 'GO:0005007', ('910', '914'))	('FGFR3', 'Gene', (779, 784))	('K652M', 'Var', (878, 883))	('silver', 'Chemical', 'MESH:D012834', (452, 458))	('tumor', 'Disease', (609, 614))	('tumor', 'Phenotype', 'HP:0002664', (659, 664))	('G372C', 'Mutation', 'rs121913479', (844, 849))	('FGFR3', 'Gene', '2261', (779, 784))
111077	27870574	The intent of including unspecified FGFR alterations, such as fusions, in the prescreening evaluation was to adapt to the rapidly evolving understanding of the role of FGFR in various cancer types and to allow the enrollment of patients with previously unknown activating FGFR alterations (Appendix Table A1).	('cancer', 'Disease', (184, 190))	('unspecified', 'Species', '32644', (24, 35))	('patients', 'Species', '9606', (228, 236))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('activating', 'PosReg', (261, 271))	('FGFR', 'molecular_function', 'GO:0005007', ('272', '276'))	('FGFR', 'molecular_function', 'GO:0005007', ('168', '172'))	('FGFR', 'Gene', (272, 276))	('alterations', 'Var', (277, 288))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('alterations', 'Var', (41, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
111097	27870574	It was recognized that many patients required dose reduction over the course of their therapy for the management of chronic toxicities; however, given the fact that patients with FGFR alterations are rare and are not easily identified, we chose to initiate treatment with a dose most likely to provide clinical benefit.	('toxicities', 'Disease', (124, 134))	('FGFR', 'Gene', (179, 183))	('alterations', 'Var', (184, 195))	('FGFR', 'molecular_function', 'GO:0005007', ('179', '183'))	('patients', 'Species', '9606', (165, 173))	('toxicities', 'Disease', 'MESH:D064420', (124, 134))	('patients', 'Species', '9606', (28, 36))
111175	30064409	Fibroblast growth factor receptor 3 (FGFR3) aberrations in muscle-invasive urothelial carcinoma Recent studies suggest that FGFR3 is a potential therapeutic target in urothelial carcinoma (UC).	('FGFR3', 'Gene', (37, 42))	('Fibroblast growth factor', 'molecular_function', 'GO:0005104', ('0', '24'))	('muscle-invasive urothelial carcinoma', 'Disease', 'MESH:D009217', (59, 95))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (167, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('124', '128'))	('aberrations in muscle', 'Phenotype', 'HP:0011805', (44, 65))	('FGFR3', 'Gene', '2261', (124, 129))	('aberrations', 'Var', (44, 55))	('FGFR3', 'Gene', '2261', (37, 42))	('urothelial carcinoma', 'Disease', (167, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('Fibroblast growth factor receptor 3', 'Gene', (0, 35))	('muscle-invasive urothelial carcinoma', 'Disease', (59, 95))	('FGFR3', 'Gene', (124, 129))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (75, 95))	('Fibroblast growth factor receptor 3', 'Gene', '2261', (0, 35))
111176	30064409	The purpose of this study was to evaluate the rates and types of FGFR3 aberrations in patients with muscle-invasive UC who received radical resection.	('FGFR3', 'Gene', '2261', (65, 70))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('FGFR3', 'Gene', (65, 70))	('aberrations', 'Var', (71, 82))	('muscle-invasive UC', 'Disease', (100, 118))	('patients', 'Species', '9606', (86, 94))
111178	30064409	Ion AmpliSeq Cancer Hotspot Panel v2 and nCounter Copy Number Variation Assay were used to detect FGFR3 aberrations.	('aberrations', 'Var', (104, 115))	('FGFR3', 'Gene', (98, 103))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('98', '102'))	('FGFR3', 'Gene', '2261', (98, 103))
111180	30064409	Sixteen patients (22%) harbored FGFR3 alterations, the most common of which was FGFR3 mutations (n = 13): Y373C (n = 3), N532D (n = 3), R248C (n = 2), S249C (n = 1), G370C (n = 1), S657S (n = 1), A797P (n = 1), and 746_747insG (n = 1).	('Y373C', 'Mutation', 'rs121913485', (106, 111))	('FGFR3', 'Gene', (32, 37))	('S657S', 'Mutation', 'p.S657S', (181, 186))	('S249C', 'Var', (151, 156))	('G370C', 'Var', (166, 171))	('FGFR3', 'Gene', '2261', (80, 85))	('746_747insG', 'Var', (215, 226))	('FGFR3', 'Gene', '2261', (32, 37))	('Y373C', 'Var', (106, 111))	('A797P', 'Var', (196, 201))	('G370C', 'Mutation', 'rs199740841', (166, 171))	('S249C', 'Mutation', 'rs121913483', (151, 156))	('R248C', 'Var', (136, 141))	('S657S', 'Var', (181, 186))	('mutations', 'Var', (86, 95))	('R248C', 'Mutation', 'rs121913482', (136, 141))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('N532D', 'Var', (121, 126))	('A797P', 'Mutation', 'p.A797P', (196, 201))	('patients', 'Species', '9606', (8, 16))	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('746_747insG', 'Mutation', 'rs886041952', (215, 226))	('N532D', 'Mutation', 'rs1181247980', (121, 126))	('FGFR3', 'Gene', (80, 85))
111181	30064409	Three additional patients had a FGFR3-TACC3 rearrangement.	('FGFR3', 'Gene', (32, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('rearrangement', 'Var', (44, 57))	('TACC3', 'Gene', '10460', (38, 43))	('TACC3', 'Gene', (38, 43))	('patients', 'Species', '9606', (17, 25))	('FGFR3', 'Gene', '2261', (32, 37))
111182	30064409	The frequency of FGFR3 aberrations was higher in bladder UC (25%) than in UC of the renal pelvis and ureter (18%) but the difference was not statistically significant (P = 0.444).	('renal pelvis', 'Phenotype', 'HP:0000125', (84, 96))	('renal pelvis and ureter', 'Disease', 'MESH:D014516', (84, 107))	('FGFR3', 'Gene', '2261', (17, 22))	('higher', 'Reg', (39, 45))	('FGFR3', 'Gene', (17, 22))	('aberrations', 'Var', (23, 34))	('bladder UC', 'Disease', (49, 59))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))
111184	30064409	We report the frequency and types of FGFR3 aberrations in Korean patients with UC.	('FGFR3', 'Gene', (37, 42))	('FGFR3', 'Gene', '2261', (37, 42))	('patients', 'Species', '9606', (65, 73))	('aberrations', 'Var', (43, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))
111185	30064409	Patients with FGFR3 mutations or FGFR3-TACC3 fusion may constitute potential candidates for a novel FGFR-targeted therapy in the perioperative setting.	('FGFR3', 'Gene', '2261', (14, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('FGFR3', 'Gene', '2261', (33, 38))	('FGFR3', 'Gene', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('TACC3', 'Gene', '10460', (39, 44))	('FGFR3', 'Gene', (33, 38))	('TACC3', 'Gene', (39, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('100', '104'))	('mutations', 'Var', (20, 29))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))
111194	30064409	The most common types of FGFR3 aberrations in UC are activating mutations, followed by gene rearrangements and amplification.	('FGFR3', 'Gene', (25, 30))	('aberrations', 'Var', (31, 42))	('amplification', 'Var', (111, 124))	('FGFR3', 'Gene', '2261', (25, 30))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('activating', 'MPA', (53, 63))
111195	30064409	FGFR3 mutations are predominantly found in genetically stable UC, and have been associated with oncogenic progression in UC.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (0, 5))	('associated with', 'Reg', (80, 95))	('oncogenic progression', 'CPA', (96, 117))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
111196	30064409	FGFR3 gene rearrangements generate constitutively activated and oncogenic FGFR3 kinase protein products, and cellular dependence on these drivers confers sensitivity to selective FGFR inhibition.	('FGFR3', 'Gene', (74, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (0, 5))	('rearrangements', 'Var', (11, 25))	('FGFR3', 'Gene', '2261', (74, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('179', '183'))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))	('FGFR3', 'Gene', '2261', (0, 5))
111197	30064409	Furthermore, studies indicate that FGFR3 mutation status could be used to guide anti-FGFR3 therapy.	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR3', 'Gene', (85, 90))	('FGFR3', 'Gene', '2261', (35, 40))	('mutation', 'Var', (41, 49))	('FGFR3', 'Gene', (35, 40))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('FGFR3', 'Gene', '2261', (85, 90))
111199	30064409	Data on FGFR3 aberrations in the UTUC, particularly in the muscle invasive type, are not yet sufficient.	('aberrations', 'Var', (14, 25))	('FGFR3', 'Gene', '2261', (8, 13))	('FGFR', 'molecular_function', 'GO:0005007', ('8', '12'))	('muscle invasive type', 'Disease', (59, 79))	('FGFR3', 'Gene', (8, 13))
111200	30064409	Based on these considerations, this retrospective study aimed to evaluate the frequency and types of FGFR3 gene aberrations in radically resected UC.	('FGFR3', 'Gene', (101, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))	('aberrations', 'Var', (112, 123))	('FGFR3', 'Gene', '2261', (101, 106))
111206	30064409	We used the Ion Torrent Ampliseq  cancer panel v2 to detect frequent somatic mutations that were selected based on a literature review.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (34, 40))
111207	30064409	This panel examines 2855 mutations in 50 commonly mutated oncogenes and tumor suppressor genes (Additional file 1: Table S1).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mutations', 'Var', (25, 34))	('tumor suppressor', 'biological_process', 'GO:0051726', ('72', '88'))	('tumor', 'Disease', (72, 77))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('72', '88'))	('oncogenes', 'Gene', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
111221	30064409	Table 2 presents the clinical and pathological characteristics of the 16 patients with FGFR3 aberrations.	('FGFR3', 'Gene', '2261', (87, 92))	('aberrations', 'Var', (93, 104))	('FGFR3', 'Gene', (87, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('patients', 'Species', '9606', (73, 81))
111222	30064409	In addition to 13 patients with FGFR3 mutations, we identified three patients with translocation involving FGFR3-TACC3 (Chr4) which was already considered a promising therapeutic target.	('FGFR3', 'Gene', (32, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('TACC3', 'Gene', (113, 118))	('translocation', 'Var', (83, 96))	('FGFR3', 'Gene', '2261', (107, 112))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('FGFR3', 'Gene', (107, 112))	('FGFR3', 'Gene', '2261', (32, 37))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (69, 77))	('mutations', 'Var', (38, 47))	('TACC3', 'Gene', '10460', (113, 118))
111223	30064409	There was no significant difference in the frequency of FGFR3 aberrations between UTUC (18%) and UBUC (25%) cohorts (P = 0.444).	('FGFR', 'molecular_function', 'GO:0005007', ('56', '60'))	('FGFR3', 'Gene', '2261', (56, 61))	('UBUC', 'Chemical', '-', (97, 101))	('FGFR3', 'Gene', (56, 61))	('aberrations', 'Var', (62, 73))
111224	30064409	31% of tumors with FGFR3 aberrations were of grade 3 (i.e., poorly-differentiated, according to the WHO 1973 classification).	('aberrations', 'Var', (25, 36))	('poorly-differentiated', 'CPA', (60, 81))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('FGFR3', 'Gene', '2261', (19, 24))	('FGFR3', 'Gene', (19, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
111225	30064409	Grade 3 and lymphovascular invasion were associated with a lower frequency of FGFR3 aberrations (Table 3).	('lymphovascular invasion', 'CPA', (12, 35))	('FGFR3', 'Gene', (78, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('78', '82'))	('lower', 'NegReg', (59, 64))	('aberrations', 'Var', (84, 95))	('FGFR3', 'Gene', '2261', (78, 83))
111229	30064409	HRAS mutations were found in 7 patients.	('HRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (31, 39))	('found', 'Reg', (20, 25))	('HRAS', 'Gene', '3265', (0, 4))
111230	30064409	Interestingly, three of these HRAS mutations were found to be activating, actionable mutations (G12S, G13R and Q61R), unlike the previous study suggesting a mutual exclusion of RAS and FGFR3.	('HRAS', 'Gene', (30, 34))	('FGFR3', 'Gene', '2261', (185, 190))	('G12S', 'Mutation', 'rs104894229', (96, 100))	('Q61R', 'Mutation', 'rs121913233', (111, 115))	('FGFR', 'molecular_function', 'GO:0005007', ('185', '189'))	('G12S', 'Var', (96, 100))	('activating', 'PosReg', (62, 72))	('FGFR3', 'Gene', (185, 190))	('G13R', 'Mutation', 'rs104894228', (102, 106))	('Q61R', 'Var', (111, 115))	('HRAS', 'Gene', '3265', (30, 34))	('G13R', 'Var', (102, 106))	('mutations', 'Var', (35, 44))
111235	30064409	The present study demonstrated that FGFR3 abnormalities are present in 22% of patients with UC who underwent radical resection.	('abnormalities', 'Var', (42, 55))	('FGFR3', 'Gene', (36, 41))	('patients', 'Species', '9606', (78, 86))	('FGFR3', 'Gene', '2261', (36, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
111236	30064409	The majority of aberrations were FGFR3 point mutations.	('FGFR3', 'Gene', '2261', (33, 38))	('point mutations', 'Var', (39, 54))	('FGFR3', 'Gene', (33, 38))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))
111239	30064409	Our study focused on FGFR3 aberrations in muscle-invasive UC and compared UTUC with UBUC.	('FGFR3', 'Gene', '2261', (21, 26))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('FGFR3', 'Gene', (21, 26))	('UBUC', 'Chemical', '-', (84, 88))	('muscle-invasive UC', 'Disease', (42, 60))	('aberrations in muscle', 'Phenotype', 'HP:0011805', (27, 48))	('aberrations', 'Var', (27, 38))
111240	30064409	Compared to previous studies, relatively many cases of UTUB (n = 34) were included in the analysis and the results showed no significant difference in the frequency of FGFR3 aberrations between UBUC (25%) and UTUC (18%).	('FGFR3', 'Gene', '2261', (168, 173))	('FGFR3', 'Gene', (168, 173))	('UBUC', 'Chemical', '-', (194, 198))	('FGFR', 'molecular_function', 'GO:0005007', ('168', '172'))	('aberrations', 'Var', (174, 185))
111242	30064409	In a comprehensive study of the genetics of UTUC, whole exome sequencing was performed in samples from 27 patients; FGFR3 alteration was detected in 60% (9 of 15) of high-grade tumors and in 37.5% (3 of 8) of > pT2 tumors.	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('FGFR', 'molecular_function', 'GO:0005007', ('116', '120'))	('alteration', 'Var', (122, 132))	('FGFR3', 'Gene', '2261', (116, 121))	('FGFR3', 'Gene', (116, 121))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('detected', 'Reg', (137, 145))	('patients', 'Species', '9606', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', (215, 221))
111243	30064409	FGFR3 mutations are common in low grade and early stage UCs, while they are less common in muscle-invasive tumors.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('muscle-invasive tumors', 'Disease', (91, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('FGFR3', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('early stage UCs', 'Disease', (44, 59))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (91, 113))	('low grade', 'Disease', (30, 39))	('common', 'Reg', (20, 26))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
111244	30064409	In a previous meta-analysis for FGFR3 mutations in UBUC, the frequency of FGFR3 mutations decreased with increasing stage and grade: 65% in pTa, 30.2% in pT1, 11.5% in pT2-4 and 69.8% in G1, 68% in G2 and 18.6% in G3.	('FGFR3', 'Gene', (32, 37))	('FGFR3', 'Gene', (74, 79))	('UBUC', 'Chemical', '-', (51, 55))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('mutations', 'Var', (80, 89))	('decreased', 'NegReg', (90, 99))	('FGFR3', 'Gene', '2261', (74, 79))	('pTa', 'molecular_function', 'GO:0008959', ('140', '143'))	('FGFR3', 'Gene', '2261', (32, 37))	('mutations', 'Var', (38, 47))	('pTa', 'Disease', (140, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))
111245	30064409	The frequency of FGFR3 mutations in the present study was infrequent with 18%; it is explained by that in our study, 96 and 73% had pT2-4 and G3 disease, respectively.	('FGFR3', 'Gene', '2261', (17, 22))	('mutations', 'Var', (23, 32))	('FGFR3', 'Gene', (17, 22))	('pT2-4', 'Disease', (132, 137))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('G3 disease', 'Disease', (142, 152))
111246	30064409	We identified eight different mutations, including R248C, S249C, and Y373C, which consist more than 95% of mutations from radical cystectomy specimens in a previous study.	('Y373C', 'Var', (69, 74))	('R248C', 'Var', (51, 56))	('S249C', 'Var', (58, 63))	('Y373C', 'Mutation', 'rs121913485', (69, 74))	('S249C', 'Mutation', 'rs121913483', (58, 63))	('R248C', 'Mutation', 'rs121913482', (51, 56))
111248	30064409	Furthermore, we found four additional mutations (N532D, S676S, A797P, and 746_747insG) which have not been reported previously in the COSMIC database (accessed December 2017).	('N532D', 'Var', (49, 54))	('746_747insG', 'Mutation', 'rs886041952', (74, 85))	('N532D', 'Mutation', 'rs1181247980', (49, 54))	('S676S', 'Mutation', 'rs200980490', (56, 61))	('A797P', 'Mutation', 'p.A797P', (63, 68))	('A797P', 'Var', (63, 68))	('746_747insG', 'Var', (74, 85))	('S676S', 'Var', (56, 61))
111249	30064409	Further studies are needed in order to evaluate if these mutations are pathogenic and represent valid targets for anti-FGFR3 therapy.	('FGFR3', 'Gene', (119, 124))	('mutations', 'Var', (57, 66))	('FGFR3', 'Gene', '2261', (119, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))
111251	30064409	FGFR3 fusions with TACC3 and BAIAP2L1 have been reported in UC cell lines and tissues.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (0, 5))	('reported', 'Reg', (48, 56))	('BAIAP2L1', 'Gene', (29, 37))	('TACC3', 'Gene', '10460', (19, 24))	('BAIAP2L1', 'Gene', '55971', (29, 37))	('TACC3', 'Gene', (19, 24))	('fusions', 'Var', (6, 13))	('FGFR3', 'Gene', '2261', (0, 5))
111252	30064409	The clinical relevance of FGFR3-TACC3 fusion in UC has been highlighted by results from preclinical and early clinical studies reporting promising responses to the treatment with FGFR inhibitors.	('FGFR3', 'Gene', (26, 31))	('fusion', 'Var', (38, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('179', '183'))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('TACC3', 'Gene', '10460', (32, 37))	('FGFR3', 'Gene', '2261', (26, 31))	('TACC3', 'Gene', (32, 37))
111253	30064409	In a phase I trial with FGFR inhibitor JNJ-42756493 (n = 65), five responses were observed; two of them harbored FGFR3-TACC3 translocation.	('TACC3', 'Gene', (119, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('113', '117'))	('FGFR3', 'Gene', (113, 118))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))	('JNJ-42756493', 'Var', (39, 51))	('FGFR3', 'Gene', '2261', (113, 118))	('TACC3', 'Gene', '10460', (119, 124))
111256	30064409	In our study, FGFR3-TACC3 translocation was observed in three patients (4%): one patient with high-grade tumor and two patients with low-grade tumor.	('patient', 'Species', '9606', (119, 126))	('patient', 'Species', '9606', (81, 88))	('tumor', 'Disease', (143, 148))	('FGFR3', 'Gene', '2261', (14, 19))	('TACC3', 'Gene', (20, 25))	('observed', 'Reg', (44, 52))	('patients', 'Species', '9606', (119, 127))	('patient', 'Species', '9606', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('TACC3', 'Gene', '10460', (20, 25))	('patients', 'Species', '9606', (62, 70))	('FGFR3', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (105, 110))	('translocation', 'Var', (26, 39))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
111257	30064409	reported that all five FGFR3-TACC3 translocations were detected only in high-grade UTUCs (n = 59) but in no low-grade tumors (0 of 23).	('FGFR3', 'Gene', (23, 28))	('translocations', 'Var', (35, 49))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('detected', 'Reg', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('TACC3', 'Gene', '10460', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('FGFR3', 'Gene', '2261', (23, 28))	('TACC3', 'Gene', (29, 34))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
111258	30064409	Recent studies have reported encouraging data of FGFR3-targeted therapies in patients with advanced UC harboring FGFR3 alterations.	('FGFR', 'molecular_function', 'GO:0005007', ('113', '117'))	('FGFR3', 'Gene', (113, 118))	('FGFR3', 'Gene', '2261', (49, 54))	('patients', 'Species', '9606', (77, 85))	('FGFR3', 'Gene', (49, 54))	('advanced UC', 'Disease', (91, 102))	('alterations', 'Var', (119, 130))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('FGFR3', 'Gene', '2261', (113, 118))
111260	30064409	BGJ398 monotherapy was well tolerated and had response rate of 25.4% with a disease control rate of 64.2%.	('BGJ398', 'Chemical', 'MESH:C568950', (0, 6))	('BGJ398', 'Gene', (0, 6))	('monotherapy', 'Var', (7, 18))
111261	30064409	In a Phase II trial of erdafitinib, a pan-FGFR inhibitor, the 99 patients enrolled had a verified mutation in FGFR3 (74.7%) or fusion in FGFR2/FGFR3 (25.3%); 88.1% had received >=1 line of prior systemic treatment.	('FGFR2', 'Gene', (137, 142))	('FGFR2', 'Gene', '2263', (137, 142))	('FGFR3', 'Gene', '2261', (143, 148))	('mutation', 'Var', (98, 106))	('fusion', 'Var', (127, 133))	('FGFR', 'molecular_function', 'GO:0005007', ('137', '141'))	('FGFR', 'molecular_function', 'GO:0005007', ('110', '114'))	('FGFR3', 'Gene', (143, 148))	('FGFR3', 'Gene', '2261', (110, 115))	('FGFR', 'molecular_function', 'GO:0005007', ('143', '147'))	('patients', 'Species', '9606', (65, 73))	('FGFR3', 'Gene', (110, 115))	('erdafitinib', 'Chemical', 'MESH:C000604580', (23, 34))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))
111267	30064409	Similarly, it should be noted that previous intravesical therapy may influence the results of mutational analysis in UBUC, although our study included only three patients who had received intravesical therapy.	('patients', 'Species', '9606', (162, 170))	('UBUC', 'Chemical', '-', (117, 121))	('UBUC', 'Gene', (117, 121))	('influence', 'Reg', (69, 78))	('mutational analysis', 'Var', (94, 113))	('results', 'MPA', (83, 90))
111270	30064409	Further studies are warranted to reveal the functional significance of the FGFR3 aberrations and better define subset of patients that benefit from anti-FGFR therapy.	('FGFR3', 'Gene', (75, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('FGFR', 'molecular_function', 'GO:0005007', ('153', '157'))	('aberrations', 'Var', (81, 92))	('FGFR3', 'Gene', '2261', (75, 80))	('patients', 'Species', '9606', (121, 129))
111295	30008905	The risk score of each patient was calculated using the following formula: Risk score=(0.012050982x ZNF230) + (-0.124027149x BCL2L14) + (-0.251893959x AHNAK) + (0.264530911x TMEM109) + (0.133540278x APOL2) + (-0.19351212x AGER) + (-0.209706035x AOC2); where gene name represents the Z-score for that gene.	('AHNAK', 'Gene', '79026', (151, 156))	('TMEM109', 'Gene', (174, 181))	('AGER', 'Gene', '177', (222, 226))	('BCL2L14', 'Gene', (125, 132))	('APOL2', 'Gene', '23780', (199, 204))	('BCL2', 'molecular_function', 'GO:0015283', ('125', '129'))	('0.012050982x', 'Var', (87, 99))	('ZNF230', 'Gene', (100, 106))	('APOL2', 'Gene', (199, 204))	('AOC2', 'Gene', '314', (245, 249))	('ZNF230', 'Gene', '7773', (100, 106))	('TMEM109', 'Gene', '79073', (174, 181))	('AOC2', 'Gene', (245, 249))	('AGER', 'Gene', (222, 226))	('BCL2L14', 'Gene', '79370', (125, 132))	('AHNAK', 'Gene', (151, 156))	('patient', 'Species', '9606', (23, 30))
111303	30008905	It was possible that the model may have overfit to the training dataset; in order to test the robustness of the model, subsequent to locking the coefficients for each gene, risk scores of all patients in three independent test datasets (GSE31684, GSE48075 and E-MTAB-4321) were evaluated, and the median risk score value of each dataset was used as a cutoff.	('MTAB', 'molecular_function', 'GO:0047152', ('262', '266'))	('patients', 'Species', '9606', (192, 200))	('GSE31684', 'Var', (237, 245))	('GSE48075', 'Var', (247, 255))
111308	30008905	Of the 7 genes in the model, BCL2L14 has previously been associated with carcinogenesis and a single-nucleotide polymorphism in this gene has been associated with lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('carcinogenesis', 'Disease', (73, 87))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('BCL2L14', 'Gene', '79370', (29, 36))	('associated with', 'Reg', (147, 162))	('single-nucleotide polymorphism', 'Var', (94, 124))	('BCL2', 'molecular_function', 'GO:0015283', ('29', '33'))	('BCL2L14', 'Gene', (29, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('carcinogenesis', 'Disease', 'MESH:D063646', (73, 87))	('lung cancer', 'Disease', (163, 174))	('associated', 'Reg', (57, 67))
111321	33129231	PR-619 could inhibit ESCC cell growth and induce G2/M cell cycle arrest by downregulating cyclin B1 and upregulating p21.	('arrest', 'Disease', 'MESH:D006323', (65, 71))	('PR-619', 'Var', (0, 6))	('cell growth', 'biological_process', 'GO:0016049', ('26', '37'))	('cyclin', 'molecular_function', 'GO:0016538', ('90', '96'))	('p21', 'Gene', (117, 120))	('induce', 'PosReg', (42, 48))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('cyclin B1', 'Gene', '891', (90, 99))	('upregulating', 'PosReg', (104, 116))	('arrest', 'Disease', (65, 71))	('cyclin B1', 'Gene', (90, 99))	('ESCC', 'Disease', (21, 25))	('p21', 'Gene', '644914', (117, 120))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('54', '71'))	('downregulating', 'NegReg', (75, 89))	('inhibit', 'NegReg', (13, 20))	('PR-619', 'Chemical', 'MESH:C570894', (0, 6))
111322	33129231	Meanwhile, PR-619 led to the accumulation of ubiquitylated proteins, induced ER stress and triggered apoptosis by the ATF4-Noxa axis.	('PR-619', 'Var', (11, 17))	('ATF4', 'Gene', (118, 122))	('Noxa', 'Gene', '5366', (123, 127))	('Noxa', 'Gene', (123, 127))	('ER stress', 'MPA', (77, 86))	('ATF4', 'Gene', '468', (118, 122))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('ubiquitylated proteins', 'MPA', (45, 67))	('induced', 'Reg', (69, 76))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('apoptosis', 'CPA', (101, 110))	('accumulation', 'PosReg', (29, 41))	('triggered', 'Reg', (91, 100))	('PR-619', 'Chemical', 'MESH:C570894', (11, 17))
111324	33129231	Ubiquitin E1 inhibitor, PYR-41, could reduce the accumulation of ubi-proteins and alleviate ER stress, G2/M cell cycle arrest, apoptosis and autophagy in PR-619-treated ESCC cells.	('arrest', 'Disease', (119, 125))	('alleviate', 'NegReg', (82, 91))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (108, 125))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('108', '125'))	('autophagy', 'CPA', (141, 150))	('ER stress', 'MPA', (92, 101))	('autophagy', 'biological_process', 'GO:0016236', ('141', '150'))	('apoptosis', 'CPA', (127, 136))	('PYR-41', 'Var', (24, 30))	('reduce', 'NegReg', (38, 44))	('autophagy', 'biological_process', 'GO:0006914', ('141', '150'))	('PYR-41', 'Chemical', 'MESH:C523934', (24, 30))	('arrest', 'Disease', 'MESH:D006323', (119, 125))	('PR-619', 'Chemical', 'MESH:C570894', (154, 160))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('0', '9'))	('apoptosis', 'biological_process', 'GO:0097194', ('127', '136'))	('apoptosis', 'biological_process', 'GO:0006915', ('127', '136'))	('accumulation of ubi-proteins', 'MPA', (49, 77))
111325	33129231	Furthermore, blocking autophagy by chloroquine or bafilomycin A1 enhanced the cell growth inhibition effect and apoptosis induced by PR-619.	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('apoptosis', 'CPA', (112, 121))	('bafilomycin A1', 'Chemical', 'MESH:C040929', (50, 64))	('autophagy', 'biological_process', 'GO:0016236', ('22', '31'))	('cell growth inhibition effect', 'CPA', (78, 107))	('cell growth', 'biological_process', 'GO:0016049', ('78', '89'))	('enhanced', 'PosReg', (65, 73))	('chloroquine', 'Chemical', 'MESH:D002738', (35, 46))	('autophagy', 'biological_process', 'GO:0006914', ('22', '31'))	('PR-619', 'Chemical', 'MESH:C570894', (133, 139))	('blocking', 'NegReg', (13, 21))	('autophagy', 'CPA', (22, 31))	('PR-619', 'Var', (133, 139))
111327	33129231	PR-619 could inhibit oesophageal squamous cell carcinoma cell growth and induce G2/M cell cycle arrest by downregulating the expression of cyclin B1 and upregulating the protein level of p21.	('PR-619', 'Var', (0, 6))	('cell growth', 'biological_process', 'GO:0016049', ('57', '68'))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('arrest', 'Disease', 'MESH:D006323', (96, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('cyclin B1', 'Gene', '891', (139, 148))	('cyclin B1', 'Gene', (139, 148))	('inhibit', 'NegReg', (13, 20))	('upregulating', 'PosReg', (153, 165))	('induce', 'PosReg', (73, 79))	('PR-619', 'Chemical', 'MESH:C570894', (0, 6))	('downregulating', 'NegReg', (106, 120))	('cyclin', 'molecular_function', 'GO:0016538', ('139', '145'))	('p21', 'Gene', (187, 190))	('protein level', 'MPA', (170, 183))	('expression', 'MPA', (125, 135))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('85', '102'))	('p21', 'Gene', '644914', (187, 190))	('oesophageal squamous cell carcinoma', 'Disease', (21, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('arrest', 'Disease', (96, 102))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (21, 56))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (85, 102))
111338	33129231	Inactivation of DUBs by inhibitors showed promising antitumour activity in multiple tumours.	('antitumour activity', 'CPA', (52, 71))	('tumours', 'Disease', 'MESH:D009369', (84, 91))	('tumours', 'Disease', (84, 91))	('DUBs', 'Gene', (16, 20))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('Inactivation', 'Var', (0, 12))
111339	33129231	P5091 significantly inhibited cell growth of ovarian cancer, 19  oesophageal cancer 15  and colorectal cancer 20  in vitro and in vivo.	('cell growth', 'biological_process', 'GO:0016049', ('30', '41'))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('ovarian cancer', 'Phenotype', 'HP:0100615', (45, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('inhibited', 'NegReg', (20, 29))	('oesophageal cancer', 'Disease', (65, 83))	('cell growth', 'CPA', (30, 41))	('P5091', 'Var', (0, 5))	('oesophageal cancer', 'Disease', 'MESH:D009369', (65, 83))	('ovarian cancer', 'Disease', 'MESH:D010051', (45, 59))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('ovarian cancer', 'Disease', (45, 59))	('colorectal cancer', 'Disease', (92, 109))
111340	33129231	Meanwhile, P5091 induced apoptosis in multiple myeloma cells resistant to conventional and Bortezomib therapies.	('multiple myeloma', 'Disease', 'MESH:D009101', (38, 54))	('Bortezomib', 'Chemical', 'MESH:D000069286', (91, 101))	('multiple myeloma', 'Disease', (38, 54))	('apoptosis', 'biological_process', 'GO:0097194', ('25', '34'))	('apoptosis', 'biological_process', 'GO:0006915', ('25', '34'))	('apoptosis', 'CPA', (25, 34))	('P5091', 'Var', (11, 16))	('multiple myeloma', 'Phenotype', 'HP:0006775', (38, 54))
111342	33129231	21  And then, b-AP15 was identified as an anti-cancer deubiquitinase inhibitor in many cancers.	('cancers', 'Disease', (87, 94))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('b-AP15', 'Var', (14, 20))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('54', '68'))
111350	33129231	33  More recently, Kuo et al reported that PR-619 could effectively induce dose- and time-dependent cytotoxicity and ER stress-related apoptosis in metastatic bladder urothelial carcinoma (UC) and potentiate cisplatin-induced cytotoxicity in UC.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (159, 187))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('induce', 'PosReg', (68, 74))	('bladder urothelial carcinoma', 'Disease', (159, 187))	('PR-619', 'Chemical', 'MESH:C570894', (43, 49))	('cytotoxicity', 'Disease', (226, 238))	('cisplatin', 'Chemical', 'MESH:D002945', (208, 217))	('cytotoxicity', 'Disease', (100, 112))	('PR-619', 'Var', (43, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('cytotoxicity', 'Disease', 'MESH:D064420', (226, 238))	('potentiate', 'PosReg', (197, 207))	('cytotoxicity', 'Disease', 'MESH:D064420', (100, 112))
111356	33129231	Ubiquitin E1 inhibitor, PYR-41, could reduce the accumulation of ubiquitinated proteins and alleviate ER stress, G2/M cell cycle arrest, apoptosis and autophagy.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('118', '135'))	('arrest', 'Disease', (129, 135))	('alleviate', 'NegReg', (92, 101))	('apoptosis', 'CPA', (137, 146))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('autophagy', 'CPA', (151, 160))	('accumulation of ubiquitinated proteins', 'MPA', (49, 87))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('ER stress', 'MPA', (102, 111))	('PYR-41', 'Var', (24, 30))	('reduce', 'NegReg', (38, 44))	('arrest', 'Disease', 'MESH:D006323', (129, 135))	('autophagy', 'biological_process', 'GO:0016236', ('151', '160'))	('PYR-41', 'Chemical', 'MESH:C523934', (24, 30))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('0', '9'))	('autophagy', 'biological_process', 'GO:0006914', ('151', '160'))
111374	33129231	Cell lysates were prepared for Western blotting analysis, with antibodies against p21, p-WEE1 (Ser642), WEE1, Cyclin B1, p-Histone H3 (Ser10), Cdc25c, ATF4, BiP, p-ACC(Ser79), ACC, LC3, p-eIF2alpha (Ser51), eIF2alpha, FOXO3a, cleaved CASP9, cleaved CASP3, cleaved PARP, PARP, Bax, Bak, Bcl-xl, Mcl-1, XIAP, CIAP1, CIAP2 (Cell Signaling Technology, Inc, Boston, MA), Noxa (Millipore, Billerica, MA), c-Myc and Ub (Santa Cruz Biotechnology, Santa Cruz, CA), HIF-1alpha and AMPKalpha (Abgent, Shanghai, China), p-AMPKalpha (Thr172), Histone H3, Capase3 and Capase9 (Beyotime, China).	('p21', 'Gene', '644914', (82, 85))	('Noxa', 'Gene', (366, 370))	('AMPKalpha', 'Chemical', '-', (510, 519))	('eIF2', 'cellular_component', 'GO:0005850', ('207', '211'))	('CASP3', 'Gene', '836', (249, 254))	('eIF2alpha', 'Gene', (207, 216))	('c-Myc', 'Gene', (399, 404))	('WEE1', 'Gene', '7465', (89, 93))	('WEE1', 'Gene', '7465', (104, 108))	('CASP9', 'Gene', (234, 239))	('HIF-1alpha', 'Gene', '3091', (456, 466))	('p-ACC', 'Chemical', '-', (162, 167))	('Capase9', 'Gene', (554, 561))	('eIF2alpha', 'Gene', '83939', (207, 216))	('AMPKalpha', 'Chemical', '-', (471, 480))	('c-Myc', 'Gene', '4609', (399, 404))	('Ser', 'cellular_component', 'GO:0005790', ('199', '202'))	('CIAP2', 'Gene', (314, 319))	('Ser', 'cellular_component', 'GO:0005790', ('95', '98'))	('LC3', 'Gene', (181, 184))	('PARP', 'Gene', '1302', (264, 268))	('CASP9', 'Gene', '842', (234, 239))	('BiP', 'Gene', (157, 160))	('PARP', 'Gene', '1302', (270, 274))	('BiP', 'Gene', '2662', (157, 160))	('XIAP', 'Gene', '331', (301, 305))	('p21', 'Gene', (82, 85))	('Bak', 'Gene', '578', (281, 284))	('Ser', 'cellular_component', 'GO:0005790', ('135', '138'))	('WEE1', 'Gene', (104, 108))	('Ser10', 'Chemical', '-', (135, 140))	('eIF2alpha', 'Gene', (188, 197))	('HIF-1alpha', 'Gene', (456, 466))	('Ser', 'cellular_component', 'GO:0005790', ('168', '171'))	('Bax', 'Gene', (276, 279))	('CIAP1', 'Gene', '329', (307, 312))	('eIF2alpha', 'Gene', '83939', (188, 197))	('CIAP2', 'Gene', '330', (314, 319))	('ATF4', 'Gene', (151, 155))	('Bax', 'Gene', '581', (276, 279))	('Cyclin B1', 'Gene', (110, 119))	('PARP', 'Gene', (264, 268))	('Cyclin', 'molecular_function', 'GO:0016538', ('110', '116'))	('eIF2', 'cellular_component', 'GO:0005850', ('188', '192'))	('Signaling', 'biological_process', 'GO:0023052', ('326', '335'))	('Cdc25c', 'Gene', (143, 149))	('PARP', 'Gene', (270, 274))	('WEE1', 'Gene', (89, 93))	('ATF4', 'Gene', '468', (151, 155))	('FOXO3a', 'Gene', (218, 224))	('Cyclin B1', 'Gene', '891', (110, 119))	('Noxa', 'Gene', '5366', (366, 370))	('CIAP1', 'Gene', (307, 312))	('p-AMPKalpha', 'Chemical', '-', (508, 519))	('LC3', 'Gene', '84557', (181, 184))	('Bcl-xl', 'Gene', '598', (286, 292))	('Thr172', 'Chemical', '-', (521, 527))	('Bak', 'Gene', (281, 284))	('p-AMPKalpha', 'Var', (508, 519))	('XIAP', 'Gene', (301, 305))	('Cdc25c', 'Gene', '995', (143, 149))	('CASP3', 'Gene', (249, 254))	('Bcl-xl', 'Gene', (286, 292))	('FOXO3a', 'Gene', '2309', (218, 224))
111391	33129231	Results showed that PR-619 inhibited the growth of ESCC cells Kyse30, Kyse450, EC1 and EC109, as evidenced by dose-dependent inhibition of cell proliferation (Figure 1A) and colony formation (Figure 1B).	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('125', '157'))	('EC1', 'Gene', '4819', (79, 82))	('EC1', 'Gene', (79, 82))	('formation', 'biological_process', 'GO:0009058', ('181', '190'))	('colony formation', 'CPA', (174, 190))	('EC1', 'Gene', '4819', (87, 90))	('EC1', 'Gene', (87, 90))	('Kyse30', 'Var', (62, 68))	('Kyse450', 'Var', (70, 77))	('cell proliferation', 'CPA', (139, 157))	('inhibited', 'NegReg', (27, 36))	('growth', 'MPA', (41, 47))	('PR-619', 'Chemical', 'MESH:C570894', (20, 26))	('PR-619', 'Var', (20, 26))	('inhibition', 'NegReg', (125, 135))
111394	33129231	Results showed that PR-619 induced the phosphorylation of Wee1 (inhibitor of G2-M phase transition 38 ,  39 ), increased the protein level of p21 and decreased the expression of cyclin B1 and p-Histone H3, a hallmark of M-phase cells 39 ,  40  (Figure 1D), while PR-619 treatment has no obvious effect on the expression of Cdc25c (an essential regulator of G2/M transition 41 ,  42 ) and the total protein level of Wee1 and Histone H3 (Figure 1D).	('Cdc25c', 'Gene', (323, 329))	('PR-619', 'Chemical', 'MESH:C570894', (263, 269))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('PR-619', 'Var', (20, 26))	('Wee1', 'Gene', (415, 419))	('p-Histone', 'MPA', (192, 201))	('Wee1', 'Gene', (58, 62))	('Cdc25c', 'Gene', '995', (323, 329))	('protein level', 'MPA', (125, 138))	('p21', 'Gene', (142, 145))	('cyclin', 'molecular_function', 'GO:0016538', ('178', '184'))	('p21', 'Gene', '644914', (142, 145))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('M phase', 'biological_process', 'GO:0000279', ('80', '87'))	('cyclin B1', 'Gene', '891', (178, 187))	('cyclin B1', 'Gene', (178, 187))	('decreased', 'NegReg', (150, 159))	('phosphorylation', 'MPA', (39, 54))	('Wee1', 'Gene', '7465', (415, 419))	('Wee1', 'Gene', '7465', (58, 62))	('M-phase', 'biological_process', 'GO:0000279', ('220', '227'))	('PR-619', 'Chemical', 'MESH:C570894', (20, 26))	('increased', 'PosReg', (111, 120))	('protein', 'cellular_component', 'GO:0003675', ('398', '405'))	('expression', 'MPA', (164, 174))
111398	33129231	Besides, PR-619 effectively induced the cleavage of CASP9, CASP3 and PARP (Figure 2D).	('CASP3', 'Gene', '836', (59, 64))	('CASP9', 'Gene', (52, 57))	('CASP3', 'Gene', (59, 64))	('PR-619', 'Var', (9, 15))	('PR-619', 'Chemical', 'MESH:C570894', (9, 15))	('PARP', 'Gene', '1302', (69, 73))	('CASP9', 'Gene', '842', (52, 57))	('PARP', 'Gene', (69, 73))	('induced', 'Reg', (28, 35))	('cleavage', 'MPA', (40, 48))
111399	33129231	These results suggested that PR-619 triggered apoptosis in ESCC cells.	('apoptosis', 'CPA', (46, 55))	('PR-619', 'Chemical', 'MESH:C570894', (29, 35))	('PR-619', 'Var', (29, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))
111408	33129231	Furthermore, knockdown of ATF4 rescued PR-619-induced apoptosis (Figure 3D), downregulated the expression of Noxa and led to a lower level of c-PARP (Figure 3E).	('apoptosis', 'CPA', (54, 63))	('downregulated', 'NegReg', (77, 90))	('PARP', 'Gene', '1302', (144, 148))	('ATF4', 'Gene', '468', (26, 30))	('Noxa', 'Gene', (109, 113))	('Noxa', 'Gene', '5366', (109, 113))	('ATF4', 'Gene', (26, 30))	('PARP', 'Gene', (144, 148))	('lower', 'NegReg', (127, 132))	('PR-619', 'Chemical', 'MESH:C570894', (39, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('knockdown', 'Var', (13, 22))	('PR-619-induced', 'Var', (39, 53))	('expression', 'MPA', (95, 105))
111411	33129231	These results indicated that PR-619 triggered ER stress and induced ATF4-Noxa-mediated apoptosis in ESCC cells.	('ER stress', 'MPA', (46, 55))	('PR-619', 'Chemical', 'MESH:C570894', (29, 35))	('induced', 'Reg', (60, 67))	('PR-619', 'Var', (29, 35))	('ATF4', 'Gene', (68, 72))	('Noxa', 'Gene', '5366', (73, 77))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('ATF4', 'Gene', '468', (68, 72))	('Noxa', 'Gene', (73, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))
111415	33129231	Furthermore, we found that the inhibition of autophagy with either CQ or BafA1 significantly enhanced PR-619-induced inhibition of cell viability (Figure 4E) and PR-619-induced apoptosis (Figure 4F).	('inhibition', 'NegReg', (31, 41))	('autophagy', 'CPA', (45, 54))	('PR-619-induced', 'Var', (102, 116))	('BafA1', 'Gene', (73, 78))	('PR-619', 'Chemical', 'MESH:C570894', (162, 168))	('cell viability', 'CPA', (131, 145))	('enhanced PR', 'Phenotype', 'HP:0008151', (93, 104))	('autophagy', 'biological_process', 'GO:0006914', ('45', '54'))	('BafA1', 'Chemical', 'MESH:C040929', (73, 78))	('CQ', 'Chemical', 'MESH:D002738', (67, 69))	('enhanced', 'PosReg', (93, 101))	('inhibition', 'NegReg', (117, 127))	('PR-619', 'Chemical', 'MESH:C570894', (102, 108))	('apoptosis', 'biological_process', 'GO:0097194', ('177', '186'))	('apoptosis', 'biological_process', 'GO:0006915', ('177', '186'))	('autophagy', 'biological_process', 'GO:0016236', ('45', '54'))
111416	33129231	Co-treatment with CQ or BafA1 resulted in an increased level of cleaved PARP and caspase3 than treatment with PR-619 alone (Figure 4G) in both Kyse30 and Kyse450 cells.	('BafA1', 'Var', (24, 29))	('PR-619', 'Chemical', 'MESH:C570894', (110, 116))	('increased', 'PosReg', (45, 54))	('BafA1', 'Chemical', 'MESH:C040929', (24, 29))	('CQ', 'Chemical', 'MESH:D002738', (18, 20))	('PARP', 'Gene', '1302', (72, 76))	('PARP', 'Gene', (72, 76))	('caspase3', 'Gene', (81, 89))	('caspase3', 'Gene', '836', (81, 89))
111417	33129231	These results revealed that PR-619 activated pro-survival autophagy, and blockage of the autophagic response significantly enhanced the cell growth inhibition efficacy of PR-619 on ESCC cells.	('enhanced', 'PosReg', (123, 131))	('autophagy', 'biological_process', 'GO:0006914', ('58', '67'))	('pro-survival autophagy', 'CPA', (45, 67))	('autophagic response', 'CPA', (89, 108))	('cell growth inhibition efficacy', 'CPA', (136, 167))	('pro-survival', 'biological_process', 'GO:0043066', ('45', '57'))	('cell growth', 'biological_process', 'GO:0016049', ('136', '147'))	('PR-619', 'Chemical', 'MESH:C570894', (171, 177))	('ESCC', 'Disease', (181, 185))	('PR-619', 'Var', (171, 177))	('autophagy', 'biological_process', 'GO:0016236', ('58', '67'))	('PR-619', 'Chemical', 'MESH:C570894', (28, 34))	('activated', 'PosReg', (35, 44))	('blockage', 'NegReg', (73, 81))
111420	33129231	45 ,  46 ,  47  Therefore, we next investigate whether PR-619 induced autophagy through the activation of Ca2+-CaMKKbeta-AMPK signalling cascade.	('AMPK', 'Gene', (121, 125))	('Ca2+', 'Chemical', 'MESH:D000069285', (106, 110))	('signalling cascade', 'biological_process', 'GO:0007165', ('126', '144'))	('induced', 'PosReg', (62, 69))	('autophagy', 'biological_process', 'GO:0006914', ('70', '79'))	('autophagy', 'CPA', (70, 79))	('PR-619', 'Var', (55, 61))	('CaMKKbeta', 'Gene', (111, 120))	('PR-619', 'Chemical', 'MESH:C570894', (55, 61))	('AMPK', 'molecular_function', 'GO:0004691', ('121', '125'))	('AMPK', 'molecular_function', 'GO:0050405', ('121', '125'))	('AMPK', 'Gene', '5563', (121, 125))	('CaMKKbeta', 'molecular_function', 'GO:0004683', ('111', '120'))	('AMPK', 'molecular_function', 'GO:0047322', ('121', '125'))	('autophagy', 'biological_process', 'GO:0016236', ('70', '79'))	('CaMKKbeta', 'Gene', '84254', (111, 120))
111422	33129231	The fluorescence intensity of the Ca2+ dye and the number of Fluo-3+ cells also gradually increased in response to PR-619 (Figure 5B-C).	('PR-619', 'Chemical', 'MESH:C570894', (115, 121))	('increased', 'PosReg', (90, 99))	('Ca2+', 'Chemical', 'MESH:D000069285', (34, 38))	('PR-619', 'Var', (115, 121))	('fluorescence intensity of the Ca2+ dye', 'MPA', (4, 42))
111428	33129231	Meanwhile, AMPK inhibition significantly enhanced PR-619-induced cell growth inhibition (Figure 6B-C) and cell apoptosis (Figure 6D-E).	('AMPK', 'molecular_function', 'GO:0050405', ('11', '15'))	('AMPK', 'molecular_function', 'GO:0004691', ('11', '15'))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('enhanced', 'PosReg', (41, 49))	('AMPK', 'molecular_function', 'GO:0047322', ('11', '15'))	('cell apoptosis', 'CPA', (106, 120))	('cell growth', 'biological_process', 'GO:0016049', ('65', '76'))	('PR-619', 'Chemical', 'MESH:C570894', (50, 56))	('enhanced PR', 'Phenotype', 'HP:0008151', (41, 52))	('PR-619-induced', 'Gene', (50, 64))	('AMPK', 'Gene', '5563', (11, 15))	('cell growth inhibition', 'CPA', (65, 87))	('AMPK', 'Gene', (11, 15))	('inhibition', 'Var', (16, 26))
111430	33129231	AMPK inhibition enhanced PR-619-induced cytotoxicity, probably through blocking autophagy and facilitating cell apoptosis.	('inhibition', 'Var', (5, 15))	('autophagy', 'CPA', (80, 89))	('PR-619', 'Chemical', 'MESH:C570894', (25, 31))	('autophagy', 'biological_process', 'GO:0006914', ('80', '89'))	('cytotoxicity', 'Disease', (40, 52))	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('AMPK', 'Gene', '5563', (0, 4))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('AMPK', 'molecular_function', 'GO:0050405', ('0', '4'))	('cytotoxicity', 'Disease', 'MESH:D064420', (40, 52))	('enhanced', 'PosReg', (16, 24))	('AMPK', 'molecular_function', 'GO:0004691', ('0', '4'))	('AMPK', 'Gene', (0, 4))	('enhanced PR', 'Phenotype', 'HP:0008151', (16, 27))	('blocking', 'NegReg', (71, 79))	('PR-619-induced', 'Gene', (25, 39))	('AMPK', 'molecular_function', 'GO:0047322', ('0', '4'))	('autophagy', 'biological_process', 'GO:0016236', ('80', '89'))	('cell apoptosis', 'CPA', (107, 121))
111433	33129231	Results showed that PYR-41 treatment decreased apoptosis (Figure 7A), G2/M cell cycle arrest (Figure 7B) and autophagy (Figure 7C) in PR-619-treated cells.	('autophagy', 'biological_process', 'GO:0016236', ('109', '118'))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('autophagy', 'biological_process', 'GO:0006914', ('109', '118'))	('apoptosis', 'CPA', (47, 56))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('75', '92'))	('arrest', 'Disease', (86, 92))	('PYR-41', 'Var', (20, 26))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (75, 92))	('PR-619', 'Chemical', 'MESH:C570894', (134, 140))	('PYR-41', 'Chemical', 'MESH:C523934', (20, 26))	('autophagy', 'CPA', (109, 118))	('decreased', 'NegReg', (37, 46))
111434	33129231	PYR-41 effectively diminished the accumulation of conjugated ubiquitin and inhibited ER stress that induced by PR-619 (Figure 7D).	('PR-619', 'Chemical', 'MESH:C570894', (111, 117))	('ubiquitin', 'molecular_function', 'GO:0031386', ('61', '70'))	('diminished', 'NegReg', (19, 29))	('conjugated ubiquitin', 'MPA', (50, 70))	('inhibited', 'NegReg', (75, 84))	('ER stress', 'MPA', (85, 94))	('accumulation', 'MPA', (34, 46))	('PYR-41', 'Var', (0, 6))	('PYR-41', 'Chemical', 'MESH:C523934', (0, 6))
111435	33129231	Following the above results (Figures 1D, 3E and 5E), PYR-41 downregulated the expression of ATF4-Noxa and the cleavage of PARP; rescued the expression of Cyclin B1 and downregulated the protein level of p21; and decreased the expression of phosphorylated AMPKalpha and LC3II (Figure 7D) in PR-619-treated cells.	('Cyclin B1', 'Gene', (154, 163))	('ATF4', 'Gene', (92, 96))	('expression', 'MPA', (226, 236))	('LC3', 'Gene', (269, 272))	('ATF4', 'Gene', '468', (92, 96))	('Cyclin B1', 'Gene', '891', (154, 163))	('PARP', 'Gene', '1302', (122, 126))	('downregulated', 'NegReg', (168, 181))	('protein', 'cellular_component', 'GO:0003675', ('186', '193'))	('Cyclin', 'molecular_function', 'GO:0016538', ('154', '160'))	('decreased', 'NegReg', (212, 221))	('LC3', 'Gene', '84557', (269, 272))	('PARP', 'Gene', (122, 126))	('AMPKalpha', 'Chemical', '-', (255, 264))	('PYR-41', 'Chemical', 'MESH:C523934', (53, 59))	('protein level', 'MPA', (186, 199))	('cleavage', 'MPA', (110, 118))	('Noxa', 'Gene', '5366', (97, 101))	('downregulated', 'NegReg', (60, 73))	('rescued', 'PosReg', (128, 135))	('PYR-41', 'Var', (53, 59))	('p21', 'Gene', (203, 206))	('expression', 'MPA', (78, 88))	('expression', 'MPA', (140, 150))	('p21', 'Gene', '644914', (203, 206))	('PR-619', 'Chemical', 'MESH:C570894', (290, 296))	('Noxa', 'Gene', (97, 101))
111437	33129231	In previous studies, we demonstrated that inactivation of USP7 or USP14 with specific inhibitor led to the effective suppression of ESCC cell growth in vitro and in murine model.	('suppression', 'NegReg', (117, 128))	('USP', 'molecular_function', 'GO:0051748', ('58', '61'))	('USP', 'molecular_function', 'GO:0051748', ('66', '69'))	('USP14', 'Gene', (66, 71))	('inactivation', 'Var', (42, 54))	('USP7', 'Gene', (58, 62))	('murine', 'Species', '10090', (165, 171))	('cell growth', 'biological_process', 'GO:0016049', ('137', '148'))	('ESCC', 'Disease', (132, 136))
111438	33129231	13 ,  15  However, it is unknown whether broad-range DUB inhibitor PR-619 could also significantly inhibit ESCC cell growth via disrupting the dynamic balance of ubiquitin conjugation.	('ubiquitin', 'molecular_function', 'GO:0031386', ('162', '171'))	('inhibit', 'NegReg', (99, 106))	('PR-619', 'Var', (67, 73))	('PR-619', 'Chemical', 'MESH:C570894', (67, 73))	('cell growth', 'biological_process', 'GO:0016049', ('112', '123'))	('disrupting', 'NegReg', (128, 138))	('ESCC', 'Disease', (107, 111))	('conjugation', 'biological_process', 'GO:0000746', ('172', '183'))	('dynamic balance of ubiquitin conjugation', 'MPA', (143, 183))
111444	33129231	49 ,  50  Knocking-down of USP14 arrested cell cycle at G2/M phase.	('cell cycle', 'biological_process', 'GO:0007049', ('42', '52'))	('arrest', 'Disease', 'MESH:D006323', (33, 39))	('cell cycle at G2/M phase', 'CPA', (42, 66))	('USP', 'molecular_function', 'GO:0051748', ('27', '30'))	('Knocking-down', 'Var', (10, 23))	('M phase', 'biological_process', 'GO:0000279', ('59', '66'))	('arrest', 'Disease', (33, 39))	('USP14', 'Gene', (27, 32))
111446	33129231	However, Ling et al reported that knockdown of USP22 by siRNA induced cells G0/G1 cell cycle arrest via the c-Myc/cyclin D2 pathway in HepG2 cells.	('USP22', 'Gene', '23326', (47, 52))	('c-Myc', 'Gene', '4609', (108, 113))	('cyclin', 'molecular_function', 'GO:0016538', ('114', '120'))	('arrest', 'Disease', 'MESH:D006323', (93, 99))	('c-Myc', 'Gene', (108, 113))	('Ling', 'Species', '163112', (9, 13))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (82, 99))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('82', '99'))	('USP', 'molecular_function', 'GO:0051748', ('47', '50'))	('arrest', 'Disease', (93, 99))	('knockdown', 'Var', (34, 43))	('USP22', 'Gene', (47, 52))	('HepG2', 'CellLine', 'CVCL:0027', (135, 140))
111447	33129231	51  Most recently, Kuo et al revealed that PR-619 treatment induced G0/G1 cell cycle arrest in bladder urothelial carcinoma cells with decreased p-Histone H3 (Ser10) and increased p21 and phospho-CDK2 (Tyr15).	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (74, 91))	('p-Histone', 'MPA', (145, 154))	('bladder urothelial carcinoma', 'Disease', (95, 123))	('Ser', 'cellular_component', 'GO:0005790', ('159', '162'))	('arrest', 'Disease', (85, 91))	('increased', 'PosReg', (170, 179))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (95, 123))	('PR-619', 'Var', (43, 49))	('CDK', 'molecular_function', 'GO:0004693', ('196', '199'))	('decreased', 'NegReg', (135, 144))	('Ser10', 'Chemical', '-', (159, 164))	('Tyr15', 'Chemical', '-', (202, 207))	('p21', 'Gene', (180, 183))	('CDK2', 'Gene', '1017', (196, 200))	('p21', 'Gene', '644914', (180, 183))	('arrest', 'Disease', 'MESH:D006323', (85, 91))	('CDK2', 'Gene', (196, 200))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('74', '91'))	('PR-619', 'Chemical', 'MESH:C570894', (43, 49))
111450	33129231	Besides, ubiquitin E1 inhibitor PYR-41 rescued the expression of Cyclin B1, downregulated p21 and reduced the accumulation of G2/M phase cells in PR-619-treated ESCC cells, which implied that PR-619 triggered G2/M cell cycle arrest in ESCC by regulating the expression of cyclin B1 and p21.	('rescued', 'PosReg', (39, 46))	('PR-619', 'Chemical', 'MESH:C570894', (146, 152))	('Cyclin B1', 'Gene', (65, 74))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('214', '231'))	('arrest', 'Disease', 'MESH:D006323', (225, 231))	('expression', 'MPA', (51, 61))	('accumulation', 'MPA', (110, 122))	('reduced', 'NegReg', (98, 105))	('PR-619', 'Chemical', 'MESH:C570894', (192, 198))	('Cyclin B1', 'Gene', '891', (65, 74))	('Cyclin', 'molecular_function', 'GO:0016538', ('65', '71'))	('PYR-41', 'Chemical', 'MESH:C523934', (32, 38))	('p21', 'Gene', (286, 289))	('p21', 'Gene', '644914', (286, 289))	('G2/M phase cells', 'CPA', (126, 142))	('PYR-41', 'Var', (32, 38))	('cyclin B1', 'Gene', (272, 281))	('cyclin B1', 'Gene', '891', (272, 281))	('G2/M', 'CPA', (209, 213))	('regulating', 'Reg', (243, 253))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (214, 231))	('cyclin', 'molecular_function', 'GO:0016538', ('272', '278'))	('arrest', 'Disease', (225, 231))	('M phase', 'biological_process', 'GO:0000279', ('129', '136'))	('p21', 'Gene', (90, 93))	('p21', 'Gene', '644914', (90, 93))	('downregulated', 'NegReg', (76, 89))	('ubiquitin', 'molecular_function', 'GO:0031386', ('9', '18'))
111453	33129231	35 ,  54  In the present study, we found that PR-619 treatment led to the accumulation of poly-ubiquitinated proteins and triggered ER stress in ESCC cells, as evidenced by the increased expression of Bip, p-eIF2alpha and ATF4.	('Bip', 'Gene', (201, 204))	('Bip', 'Gene', '2662', (201, 204))	('ER stress', 'MPA', (132, 141))	('PR-619', 'Chemical', 'MESH:C570894', (46, 52))	('ATF4', 'Gene', (222, 226))	('increased', 'PosReg', (177, 186))	('eIF2', 'cellular_component', 'GO:0005850', ('208', '212'))	('PR-619', 'Var', (46, 52))	('eIF2alpha', 'Gene', (208, 217))	('ATF4', 'Gene', '468', (222, 226))	('expression', 'MPA', (187, 197))	('accumulation', 'PosReg', (74, 86))	('eIF2alpha', 'Gene', '83939', (208, 217))	('triggered', 'Reg', (122, 131))
111456	33129231	Furthermore, ubiquitin E1 inhibitor PYR-41 could alleviate the accumulation of conjugated ubiquitin, inhibit ER stress, decrease the expression of ATF4-Noxa and cleaved PARP in PR-619-treated cells.	('expression', 'MPA', (133, 143))	('PYR-41', 'Var', (36, 42))	('inhibit', 'NegReg', (101, 108))	('PR-619', 'Chemical', 'MESH:C570894', (177, 183))	('decrease', 'NegReg', (120, 128))	('ATF4', 'Gene', (147, 151))	('ubiquitin', 'molecular_function', 'GO:0031386', ('13', '22'))	('ER stress', 'MPA', (109, 118))	('PYR-41', 'Chemical', 'MESH:C523934', (36, 42))	('cleaved', 'MPA', (161, 168))	('ubiquitin', 'molecular_function', 'GO:0031386', ('90', '99'))	('PARP', 'Gene', '1302', (169, 173))	('Noxa', 'Gene', '5366', (152, 156))	('PARP', 'Gene', (169, 173))	('alleviate', 'NegReg', (49, 58))	('accumulation of conjugated ubiquitin', 'MPA', (63, 99))	('ATF4', 'Gene', '468', (147, 151))	('Noxa', 'Gene', (152, 156))
111465	33129231	PYR-41 could reduce the accumulation of ubiquitinated proteins, alleviate ER stress and decrease autophagy in PR-619-treated cells.	('decrease', 'NegReg', (88, 96))	('accumulation of ubiquitinated proteins', 'MPA', (24, 62))	('PR-619', 'Chemical', 'MESH:C570894', (110, 116))	('ER stress', 'MPA', (74, 83))	('alleviate', 'NegReg', (64, 73))	('reduce', 'NegReg', (13, 19))	('autophagy', 'CPA', (97, 106))	('autophagy', 'biological_process', 'GO:0016236', ('97', '106'))	('PYR-41', 'Var', (0, 6))	('autophagy', 'biological_process', 'GO:0006914', ('97', '106'))	('PYR-41', 'Chemical', 'MESH:C523934', (0, 6))
111466	33129231	Besides, the treatment of STO-609, a CaMKKbeta inhibitor, led to the inactivation of AMPKalpha induced by PR-619, decreased the expression of p-AMPKalpha and accompanied by reduced LC3-II.	('AMPKalpha', 'Chemical', '-', (144, 153))	('LC3', 'Gene', '84557', (181, 184))	('inactivation', 'NegReg', (69, 81))	('AMPKalpha', 'Chemical', '-', (85, 94))	('LC3', 'Gene', (181, 184))	('reduced', 'NegReg', (173, 180))	('p-AMPKalpha', 'Chemical', '-', (142, 153))	('CaMKKbeta', 'Gene', '84254', (37, 46))	('STO-609', 'Chemical', 'MESH:C458525', (26, 33))	('PR-619', 'Chemical', 'MESH:C570894', (106, 112))	('decreased', 'NegReg', (114, 123))	('AMPKalpha', 'Protein', (85, 94))	('CaMKKbeta', 'molecular_function', 'GO:0004683', ('37', '46'))	('expression', 'MPA', (128, 138))	('CaMKKbeta', 'Gene', (37, 46))	('p-AMPKalpha', 'MPA', (142, 153))	('PR-619', 'Var', (106, 112))
111469	33129231	Collectively, this study revealed the detailed mechanism of PR-619 in ESCC cells (Figure 8).	('PR-619', 'Var', (60, 66))	('PR-619', 'Chemical', 'MESH:C570894', (60, 66))	('ESCC', 'Disease', (70, 74))
111472	33129231	Besides, PR-619 could activate autophagy through Ca2+-CaMKKbeta-AMPK signalling.	('CaMKKbeta', 'molecular_function', 'GO:0004683', ('54', '63'))	('autophagy', 'biological_process', 'GO:0006914', ('31', '40'))	('CaMKKbeta', 'Gene', '84254', (54, 63))	('autophagy', 'CPA', (31, 40))	('AMPK', 'molecular_function', 'GO:0047322', ('64', '68'))	('PR-619', 'Var', (9, 15))	('AMPK', 'Gene', (64, 68))	('PR-619', 'Chemical', 'MESH:C570894', (9, 15))	('Ca2+', 'Chemical', 'MESH:D000069285', (49, 53))	('AMPK', 'molecular_function', 'GO:0004691', ('64', '68'))	('AMPK', 'molecular_function', 'GO:0050405', ('64', '68'))	('CaMKKbeta', 'Gene', (54, 63))	('signalling', 'biological_process', 'GO:0023052', ('69', '79'))	('autophagy', 'biological_process', 'GO:0016236', ('31', '40'))	('activate', 'PosReg', (22, 30))	('AMPK', 'Gene', '5563', (64, 68))
111596	27409839	Indeed, results from early phase clinical trials already indicate that a subset of patients with advanced tumors derive benefit from FGFR targeted therapies.	('FGFR', 'Gene', (133, 137))	('benefit', 'PosReg', (120, 127))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('targeted therapies', 'Var', (138, 156))	('FGFR', 'molecular_function', 'GO:0005007', ('133', '137'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('patients', 'Species', '9606', (83, 91))
111597	27409839	FGFR gene aberrations and FGFR gene rearrangements are relatively rare in solid malignancies.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR gene', 'Gene', (26, 35))	('malignancies', 'Disease', 'MESH:D009369', (80, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('FGFR gene', 'Gene', (0, 9))	('rearrangements', 'Var', (36, 50))	('malignancies', 'Disease', (80, 92))
111599	27409839	We summarize the prevalence data on FGFR3-TACC3 fusions among different histological tumor types and the preliminary evidence that this rearrangement represents a targetable molecular aberration in some patients with solid tumors.	('tumor', 'Disease', (85, 90))	('fusions', 'Var', (48, 55))	('TACC3', 'Gene', '10460', (42, 47))	('tumor', 'Disease', (223, 228))	('FGFR3', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('TACC3', 'Gene', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('solid tumors', 'Disease', (217, 229))	('patients', 'Species', '9606', (203, 211))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('FGFR3', 'Gene', '2261', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('solid tumors', 'Disease', 'MESH:D009369', (217, 229))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
111604	27409839	Anomalous signaling through FGFR can occur through overexpression of receptors, activating mutations, gene amplification, or by FGFR-containing translocations in wide array of solid tumors as discussed below.	('signaling', 'biological_process', 'GO:0023052', ('10', '19'))	('receptors', 'Protein', (69, 78))	('solid tumors', 'Disease', 'MESH:D009369', (176, 188))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('signaling', 'MPA', (10, 19))	('FGFR', 'Gene', (28, 32))	('FGFR', 'molecular_function', 'GO:0005007', ('128', '132'))	('mutations', 'Var', (91, 100))	('solid tumors', 'Disease', (176, 188))	('translocations', 'Var', (144, 158))	('gene amplification', 'Var', (102, 120))	('overexpression', 'PosReg', (51, 65))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
111605	27409839	Most importantly, these aberrations can represent important therapeutic targets in solid tumors and have supported the clinical development of several FGFR inhibitors and anti-FGFR drug conjugate (ADC) antibodies (Tables 3, 4, 5, 6, 7, 8, 9).	('inhibitors', 'Var', (156, 166))	('solid tumors', 'Disease', 'MESH:D009369', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('151', '155'))	('FGFR', 'Gene', (151, 155))	('FGFR', 'molecular_function', 'GO:0005007', ('176', '180'))	('solid tumors', 'Disease', (83, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
111606	27409839	Herein we review the current literature and describe the cancer pathobiology, the prevalence, the pre-clinical, and the clinical data supporting drug development targeting the recently described FGFR3-TACC3 fusion.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('FGFR3', 'Gene', (195, 200))	('pre', 'molecular_function', 'GO:0003904', ('98', '101'))	('FGFR', 'molecular_function', 'GO:0005007', ('195', '199'))	('TACC3', 'Gene', '10460', (201, 206))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('fusion', 'Var', (207, 213))	('TACC3', 'Gene', (201, 206))	('FGFR3', 'Gene', '2261', (195, 200))
111607	27409839	FGFR alterations relatively rare and were present in ~7% of a cohort of 4853 tumor samples including 47 different histological types.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('alterations', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
111608	27409839	When limiting to histologies with at least 75 samples analyzed, the frequencies of FGFR aberrations were higher among urothelial (31.7%), breast (17.4%), endometrial (11.3%), and endometrial/ovarian carcinomas (8.1%).	('breast', 'Disease', (138, 144))	('higher', 'Reg', (105, 111))	('FGFR', 'Gene', (83, 87))	('FGFR', 'molecular_function', 'GO:0005007', ('83', '87'))	('endometrial', 'Disease', (154, 165))	('aberrations', 'Var', (88, 99))	('endometrial/ovarian carcinomas', 'Disease', 'MESH:D016889', (179, 209))	('urothelial', 'Disease', (118, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('endometrial/ovarian carcinomas', 'Disease', (179, 209))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (191, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
111609	27409839	Evidence from early phase clinical trials support that FGFR aberrations can represent targetable events in solid tumors.	('FGFR', 'Gene', (55, 59))	('solid tumors', 'Disease', (107, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('aberrations', 'Var', (60, 71))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('solid tumors', 'Disease', 'MESH:D009369', (107, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
111611	27409839	Of 17 evaluable patients, 4 had radiologic tumor reduction and 3 had stable disease indicating that a subset of patients with FGFR pathway aberrations indeed benefits for FGFR targeted therapy.	('FGFR pathway', 'Gene', (126, 138))	('reduction', 'NegReg', (49, 58))	('patients', 'Species', '9606', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('FGFR', 'molecular_function', 'GO:0005007', ('171', '175'))	('aberrations', 'Var', (139, 150))	('FGFR', 'molecular_function', 'GO:0005007', ('126', '130'))	('benefits', 'PosReg', (158, 166))	('tumor', 'Disease', (43, 48))
111612	27409839	In another phase I trial BGJ398 also showed evidence of clinical activity in patients with solid tumors harboring FGFR aberrations, including 4 of 5 patients with urothelial cell carcinomas (4 of which originated in the bladder) with FGFR3-activating mutations.	('urothelial cell carcinomas', 'Disease', (163, 189))	('BGJ398', 'Chemical', 'MESH:C568950', (25, 31))	('patients', 'Species', '9606', (149, 157))	('FGFR', 'molecular_function', 'GO:0005007', ('234', '238'))	('solid tumors', 'Disease', 'MESH:D009369', (91, 103))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('BGJ398', 'Gene', (25, 31))	('FGFR3', 'Gene', (234, 239))	('FGFR', 'molecular_function', 'GO:0005007', ('114', '118'))	('patients', 'Species', '9606', (77, 85))	('urothelial cell carcinomas', 'Disease', 'MESH:C538614', (163, 189))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))	('aberrations', 'Var', (119, 130))	('FGFR', 'Gene', (114, 118))	('solid tumors', 'Disease', (91, 103))	('FGFR3', 'Gene', '2261', (234, 239))
111616	27409839	A small number of partial responses to FGFR targeted therapies have been documented among patients with sqNSCLC harboring FGFR1 amplification (BGJ398), cholangiocarcinoma harboring FGFR2 translocations (BGJ398), glioblastoma positive for FGFR3 translocation (JNJ-42756493), bladder cancer harboring FGFR3 mutations and translocations are sensitive to targeted therapies (JNJ-42756493 and BGJ398).	('FGFR3', 'Gene', (238, 243))	('bladder cancer', 'Phenotype', 'HP:0009725', (274, 288))	('JNJ-42756493', 'Var', (371, 383))	('BGJ398', 'Chemical', 'MESH:C568950', (143, 149))	('glioblastoma', 'Disease', (212, 224))	('FGFR', 'molecular_function', 'GO:0005007', ('238', '242'))	('glioblastoma', 'Phenotype', 'HP:0012174', (212, 224))	('FGFR3', 'Gene', (299, 304))	('FGFR3', 'Gene', '2261', (238, 243))	('FGFR', 'molecular_function', 'GO:0005007', ('122', '126'))	('BGJ398', 'Chemical', 'MESH:C568950', (203, 209))	('FGFR', 'molecular_function', 'GO:0005007', ('39', '43'))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (371, 383))	('FGFR3', 'Gene', '2261', (299, 304))	('FGFR1', 'Gene', '2260', (122, 127))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (259, 271))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (152, 170))	('FGFR', 'molecular_function', 'GO:0005007', ('299', '303'))	('cholangiocarcinoma', 'Disease', (152, 170))	('patients', 'Species', '9606', (90, 98))	('NSCLC', 'Disease', (106, 111))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (152, 170))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('FGFR1', 'Gene', (122, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (274, 288))	('glioblastoma', 'Disease', 'MESH:D005909', (212, 224))	('FGFR', 'molecular_function', 'GO:0005007', ('181', '185'))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('mutations', 'Var', (305, 314))	('bladder cancer', 'Disease', (274, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('BGJ398', 'Chemical', 'MESH:C568950', (388, 394))
111617	27409839	Fusions have been described in the FGFR1-3 genes with multiple partners (i.e., TACC1, TACC2, TACC3, BAIAP2L1, BICC1, NPM1, PPAPDC1A, AFF3, SLC45A3 and AHCYL1) in a wide spectrum of tumors (i.e., cholangiocarcinoma, breast, and prostate cancer, sqNSCLC, gastric adenocarcinoma, colorectal adenocarcinoma, carcinoma of unknown primary and glioblastoma).	('Fusions', 'Var', (0, 7))	('TACC1', 'Gene', '6867', (79, 84))	('carcinoma', 'Disease', 'MESH:D002277', (204, 213))	('BAIAP2L1', 'Gene', '55971', (100, 108))	('AFF3', 'Gene', '3899', (133, 137))	('NPM1', 'Gene', '4869', (117, 121))	('carcinoma', 'Disease', 'MESH:D002277', (293, 302))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (195, 213))	('NSCLC', 'Disease', (246, 251))	('SLC45A3', 'Gene', '85414', (139, 146))	('cholangiocarcinoma', 'Disease', (195, 213))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (253, 275))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('glioblastoma', 'Disease', 'MESH:D005909', (337, 349))	('colorectal adenocarcinoma', 'Disease', (277, 302))	('NSCLC', 'Phenotype', 'HP:0030358', (246, 251))	('PPAPDC1A', 'Gene', (123, 131))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('carcinoma', 'Disease', 'MESH:D002277', (304, 313))	('carcinoma', 'Disease', 'MESH:D002277', (266, 275))	('glioblastoma', 'Disease', (337, 349))	('NPM1', 'Gene', (117, 121))	('FGFR1', 'Gene', (35, 40))	('BAIAP2L1', 'Gene', (100, 108))	('AFF3', 'Gene', (133, 137))	('FGFR1', 'Gene', '2260', (35, 40))	('NSCLC', 'Disease', 'MESH:D002289', (246, 251))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (277, 302))	('glioblastoma', 'Phenotype', 'HP:0012174', (337, 349))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('tumors', 'Disease', (181, 187))	('TACC2', 'Gene', (86, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('TACC1', 'Gene', (79, 84))	('carcinoma', 'Disease', (293, 302))	('carcinoma', 'Disease', (204, 213))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('TACC2', 'Gene', '10579', (86, 91))	('gastric adenocarcinoma', 'Disease', (253, 275))	('prostate cancer', 'Disease', 'MESH:D011471', (227, 242))	('prostate cancer', 'Phenotype', 'HP:0012125', (227, 242))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('TACC3', 'Gene', '10460', (93, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (195, 213))	('PPAPDC1A', 'Gene', '196051', (123, 131))	('TACC3', 'Gene', (93, 98))	('prostate cancer', 'Disease', (227, 242))	('breast', 'Disease', (215, 221))	('SLC45A3', 'Gene', (139, 146))	('carcinoma', 'Disease', (304, 313))	('carcinoma', 'Disease', (266, 275))
111620	27409839	For instance stable cell lines harboring FGFR3-BAIAP2L1, FGFR3-TACC3, and FGFR2-CCDC6 fusions showed expression of active FGFR fusion kinases and activation of downstream mitogen-activated protein kinase ERK1/2 and the transcription factor STAT1.	('STAT1', 'Gene', (240, 245))	('BAIAP2L1', 'Gene', '55971', (47, 55))	('transcription', 'biological_process', 'GO:0006351', ('219', '232'))	('ERK1', 'molecular_function', 'GO:0004707', ('204', '208'))	('FGFR3', 'Gene', '2261', (41, 46))	('FGFR', 'molecular_function', 'GO:0005007', ('122', '126'))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('activation', 'PosReg', (146, 156))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('STAT1', 'Gene', '6772', (240, 245))	('BAIAP2L1', 'Gene', (47, 55))	('TACC3', 'Gene', '10460', (63, 68))	('TACC3', 'Gene', (63, 68))	('ERK1/2', 'Gene', (204, 210))	('ERK1/2', 'Gene', '5595;5594', (204, 210))	('FGFR2-CCDC6', 'Gene', (74, 85))	('FGFR3', 'Gene', (57, 62))	('FGFR', 'Gene', (122, 126))	('fusions', 'Var', (86, 93))	('transcription factor', 'molecular_function', 'GO:0000981', ('219', '239'))	('FGFR3', 'Gene', '2261', (57, 62))	('FGFR3', 'Gene', (41, 46))	('FGFR', 'molecular_function', 'GO:0005007', ('57', '61'))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))
111621	27409839	The presence of FGFR fusions (FGFR3-BAIAP2L1) not only enhanced tumor cell proliferation, but also led to significant sensitivity to small kinase inhibitors (PD173074) in pre-clinical cellular and xenograft bladder cancer models, in contrast with FGFR3 mutant cell lines, which were not sensitive to kinase inhibition.	('FGFR3', 'Gene', '2261', (247, 252))	('pre', 'molecular_function', 'GO:0003904', ('171', '174'))	('PD173074', 'Chemical', 'MESH:C115711', (158, 166))	('BAIAP2L1', 'Gene', '55971', (36, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('247', '251'))	('fusions', 'Var', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('FGFR', 'Gene', (16, 20))	('bladder cancer', 'Disease', 'MESH:D001749', (207, 221))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('FGFR3', 'Gene', (30, 35))	('enhanced', 'PosReg', (55, 63))	('bladder cancer', 'Disease', (207, 221))	('bladder cancer', 'Phenotype', 'HP:0009725', (207, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('FGFR3', 'Gene', '2261', (30, 35))	('BAIAP2L1', 'Gene', (36, 44))	('led', 'Reg', (99, 102))	('sensitivity', 'MPA', (118, 129))	('tumor', 'Disease', (64, 69))	('cell proliferation', 'biological_process', 'GO:0008283', ('70', '88'))	('FGFR3', 'Gene', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
111623	27409839	Cholangiocarcinoma mice model harboring FGFR2-AHCYL1, FGFR2-CCDC6, and FGFR2-BICC1 was sensitive to treatment with FGFR kinase inhibitors BGJ398 and PD173074.	('FGFR', 'molecular_function', 'GO:0005007', ('115', '119'))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('FGFR', 'molecular_function', 'GO:0005007', ('54', '58'))	('BGJ398', 'Chemical', 'MESH:C568950', (138, 144))	('PD173074', 'Chemical', 'MESH:C115711', (149, 157))	('FGFR2-BICC1', 'Var', (71, 82))	('FGFR2-CCDC6', 'Var', (54, 65))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 18))	('FGFR2-AHCYL1', 'Var', (40, 52))	('mice', 'Species', '10090', (19, 23))	('Cholangiocarcinoma', 'Disease', (0, 18))
111624	27409839	TACC3 gene has been identified as an important partner of these FGFR fusions and associated with the pathogenesis of several solid tumors.	('FGFR', 'Gene', (64, 68))	('solid tumors', 'Disease', 'MESH:D009369', (125, 137))	('TACC3', 'Gene', (0, 5))	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('pathogenesis', 'biological_process', 'GO:0009405', ('101', '113'))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('solid tumors', 'Disease', (125, 137))	('TACC3', 'Gene', '10460', (0, 5))	('associated', 'Reg', (81, 91))	('fusions', 'Var', (69, 76))
111627	27409839	FGFR3-TACC3 fusions were first described in glioblastoma multiforme (GBM) and bladder urothelial tumors.	('fusions', 'Var', (12, 19))	('TACC3', 'Gene', '10460', (6, 11))	('described', 'Reg', (31, 40))	('bladder urothelial tumors', 'Phenotype', 'HP:0009725', (78, 103))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('TACC3', 'Gene', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('glioblastoma multiforme', 'Disease', (44, 67))	('FGFR3', 'Gene', (0, 5))	('bladder urothelial tumors', 'Disease', 'MESH:D001749', (78, 103))	('glioblastoma', 'Phenotype', 'HP:0012174', (44, 56))	('bladder urothelial tumors', 'Disease', (78, 103))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (44, 67))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('FGFR3', 'Gene', '2261', (0, 5))
111630	27409839	only 28 exhibited FGFR gene fusions, and 14 samples had FGFR3-TACC3 fusions.	('FGFR gene', 'Gene', (18, 27))	('FGFR', 'molecular_function', 'GO:0005007', ('56', '60'))	('FGFR3', 'Gene', '2261', (56, 61))	('TACC3', 'Gene', '10460', (62, 67))	('TACC3', 'Gene', (62, 67))	('FGFR3', 'Gene', (56, 61))	('fusions', 'Interaction', (68, 75))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('fusions', 'Var', (28, 35))
111635	27409839	have also utilized immunostaining of the N terminus of FGFR3 and found uniform overexpression of FGFR3 in a subset of glioblastoma multiforme (GBM) cases with FGRF3-TACC fusions that were identified by RT-PCR.	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('FGFR3', 'Gene', (97, 102))	('fusions', 'Var', (170, 177))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (118, 141))	('FGFR3', 'Gene', '2261', (55, 60))	('FGFR3', 'Gene', '2261', (97, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('97', '101'))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('FGFR3', 'Gene', (55, 60))	('overexpression', 'PosReg', (79, 93))	('glioblastoma multiforme', 'Disease', (118, 141))	('FGRF3-TACC', 'Gene', (159, 169))
111636	27409839	Those findings demonstrate that detection of FGFR3 amplification by IHC or IF may serve as a method to screen for FGRF3-TACC fusions which is clinically relevant since RNA sequencing is not common practice.	('RNA', 'cellular_component', 'GO:0005562', ('168', '171'))	('FGFR3', 'Gene', '2261', (45, 50))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('FGFR3', 'Gene', (45, 50))	('amplification', 'Var', (51, 64))
111639	27409839	Moreover, preclinical and clinical results have shown that FGFR inhibitors can block the tyrosine kinase activity of this fusion protein.	('block', 'NegReg', (79, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('FGFR', 'Gene', (59, 63))	('kinase activity', 'molecular_function', 'GO:0016301', ('98', '113'))	('inhibitors', 'Var', (64, 74))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('tyrosine kinase activity', 'MPA', (89, 113))	('tyrosine', 'Chemical', 'MESH:D014443', (89, 97))
111641	27409839	RT4 urothelial carcinoma line harboring FGFR3-TACC3 fusion also exhibited sensitivity to this same FGFR inhibitor in a xenograft model.	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('FGFR3', 'Gene', (40, 45))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (4, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('TACC3', 'Gene', '10460', (46, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('fusion', 'Var', (52, 58))	('TACC3', 'Gene', (46, 51))	('urothelial carcinoma', 'Disease', (4, 24))	('FGFR3', 'Gene', '2261', (40, 45))	('exhibited', 'Reg', (64, 73))	('sensitivity', 'MPA', (74, 85))
111642	27409839	Similar results were seen in GBM in vivo and in vitro models carrying the FGFR3-TACC3 fusions, which was not only associated oncogenic transformation but also exhibited significant sensitivity to FGFR inhibitor JNJ-42756493.	('FGFR3', 'Gene', (74, 79))	('TACC3', 'Gene', '10460', (80, 85))	('FGFR3', 'Gene', '2261', (74, 79))	('TACC3', 'Gene', (80, 85))	('oncogenic transformation', 'CPA', (125, 149))	('associated', 'Reg', (114, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('196', '200'))	('fusions', 'Var', (86, 93))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (211, 223))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))
111644	27409839	For instance, the phase I trial with FGFR inhibitor JNJ-42756493 including 65 patients with advanced solid tumors included 4 patients with FGFR3-TACC3 translocation.	('solid tumors', 'Disease', 'MESH:D009369', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('JNJ-42756493', 'Var', (52, 64))	('patients', 'Species', '9606', (78, 86))	('TACC3', 'Gene', '10460', (145, 150))	('FGFR3', 'Gene', '2261', (139, 144))	('TACC3', 'Gene', (145, 150))	('solid tumors', 'Disease', (101, 113))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (52, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('FGFR', 'molecular_function', 'GO:0005007', ('139', '143'))	('FGFR3', 'Gene', (139, 144))	('patients', 'Species', '9606', (125, 133))
111645	27409839	Three partial responses (two confirmed and one unconfirmed) were seen among 3 patients with urothelial, two of which cancer harbored FGFR3-TACC3 fusion.	('FGFR3', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('TACC3', 'Gene', '10460', (139, 144))	('FGFR', 'molecular_function', 'GO:0005007', ('133', '137'))	('FGFR3', 'Gene', '2261', (133, 138))	('fusion', 'Var', (145, 151))	('cancer', 'Disease', (117, 123))	('TACC3', 'Gene', (139, 144))	('urothelial', 'Disease', (92, 102))
111651	27409839	A subsequent study with 795 cases of gliomas (584 GBMs and 211 grade II-III gliomas) described 17 cases (2.9%) of FGFR3-TACC3 genomic fusions among the GBM group, and 3 cases among lower grade gliomas.	('TACC3', 'Gene', (120, 125))	('gliomas', 'Disease', (193, 200))	('gliomas', 'Disease', (76, 83))	('gliomas', 'Disease', 'MESH:D005910', (193, 200))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('FGFR3', 'Gene', '2261', (114, 119))	('gliomas', 'Phenotype', 'HP:0009733', (193, 200))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('114', '118'))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Disease', (37, 44))	('genomic fusions', 'Var', (126, 141))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('TACC3', 'Gene', '10460', (120, 125))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('FGFR3', 'Gene', (114, 119))
111654	27409839	Epidermal growth factor receptor gene (EGFR) amplification showed significant negative correlation with FGFR3-TACC3 status; CDK4 and MDM2 amplification had significant positive correlation with FGFR3-TACC3 (CDK4 amplification was seen in 7/16 FGFR3-TACC3 positive cases).	('MDM2', 'Gene', '4193', (133, 137))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('0', '23'))	('FGFR3', 'Gene', '2261', (104, 109))	('FGFR', 'molecular_function', 'GO:0005007', ('104', '108'))	('TACC3', 'Gene', '10460', (249, 254))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('EGFR', 'Gene', '1956', (39, 43))	('amplification', 'Var', (138, 151))	('TACC3', 'Gene', (249, 254))	('CDK4', 'Gene', '1019', (124, 128))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('TACC3', 'Gene', '10460', (200, 205))	('TACC3', 'Gene', (200, 205))	('FGFR3', 'Gene', (194, 199))	('FGFR', 'molecular_function', 'GO:0005007', ('194', '198'))	('CDK4', 'Gene', (207, 211))	('CDK', 'molecular_function', 'GO:0004693', ('207', '210'))	('FGFR3', 'Gene', (243, 248))	('FGFR3', 'Gene', '2261', (194, 199))	('positive', 'PosReg', (168, 176))	('FGFR', 'molecular_function', 'GO:0005007', ('243', '247'))	('EGFR', 'Gene', (39, 43))	('FGFR3', 'Gene', '2261', (243, 248))	('CDK4', 'Gene', '1019', (207, 211))	('CDK', 'molecular_function', 'GO:0004693', ('124', '127'))	('TACC3', 'Gene', '10460', (110, 115))	('MDM2', 'Gene', (133, 137))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('TACC3', 'Gene', (110, 115))	('FGFR3', 'Gene', (104, 109))	('CDK4', 'Gene', (124, 128))
111655	27409839	No statistically significant correlation was seen between FGFR3-TACC3 fusions and other genetic and epigenetic alterations (CDKN2A deletion, TERT promoter mutations, gain of chromosome 7p, loss of chromosome 10q, and methylation of the MGMT promoter).	('CDKN2A', 'Gene', (124, 130))	('loss', 'Var', (189, 193))	('TACC3', 'Gene', '10460', (64, 69))	('FGFR3', 'Gene', '2261', (58, 63))	('TACC3', 'Gene', (64, 69))	('CDKN2A', 'Gene', '1029', (124, 130))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('gain', 'PosReg', (166, 170))	('FGFR3', 'Gene', (58, 63))	('chromosome', 'cellular_component', 'GO:0005694', ('197', '207'))	('chromosome', 'cellular_component', 'GO:0005694', ('174', '184'))	('MGMT', 'molecular_function', 'GO:0003908', ('236', '240'))	('MGMT', 'Gene', '4255', (236, 240))	('methylation', 'biological_process', 'GO:0032259', ('217', '228'))	('MGMT', 'Gene', (236, 240))	('TERT', 'Gene', (141, 145))	('TERT', 'Gene', '7015', (141, 145))	('deletion', 'Var', (131, 139))
111656	27409839	also reported higher frequency of FGFR3-TACC3 fusions in GBMs when compared to gliomas.	('gliomas', 'Disease', (79, 86))	('FGFR3', 'Gene', '2261', (34, 39))	('TACC3', 'Gene', (40, 45))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('fusions', 'Var', (46, 53))	('FGFR3', 'Gene', (34, 39))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('TACC3', 'Gene', '10460', (40, 45))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('GBMs', 'Disease', (57, 61))	('higher', 'PosReg', (14, 20))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
111658	27409839	In addition, 2 out 157 GBM (1.2%) and 2 out of 461 low grade gliomas (0.4%) samples from The Cancer Genome Atlas (TCGA) dataset tested positive for FGFR3-TACC3 fusions which reinforced the notion that this fusion is more common in high grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (93, 112))	('TACC3', 'Gene', (154, 159))	('gliomas', 'Disease', 'MESH:D005910', (242, 249))	('gliomas', 'Phenotype', 'HP:0009733', (242, 249))	('fusions', 'Var', (160, 167))	('gliomas', 'Disease', (242, 249))	('FGFR3', 'Gene', '2261', (148, 153))	('gliomas', 'Disease', (61, 68))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('positive', 'Reg', (135, 143))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('FGFR3', 'Gene', (148, 153))	('FGFR', 'molecular_function', 'GO:0005007', ('148', '152'))	('TACC3', 'Gene', '10460', (154, 159))	('Cancer Genome Atlas', 'Disease', (93, 112))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))
111660	27409839	reported 2 cases of GBM harboring FGFR3-TACC3 fusion from the TGCA database.	('FGFR3', 'Gene', '2261', (34, 39))	('TACC3', 'Gene', (40, 45))	('FGFR3', 'Gene', (34, 39))	('TACC3', 'Gene', '10460', (40, 45))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('fusion', 'Var', (46, 52))
111666	27409839	described 126 cases of urothelial carcinomas and 4 cases (3%) of FGFR3-TACC3 translocations were observed.	('FGFR3', 'Gene', '2261', (65, 70))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (23, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('FGFR3', 'Gene', (65, 70))	('translocations', 'Var', (77, 91))	('TACC3', 'Gene', '10460', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (34, 44))	('TACC3', 'Gene', (71, 76))	('urothelial carcinomas', 'Disease', (23, 44))
111667	27409839	reported results of analysis of 2 tumor samples positive for FGFR3 exon 18 and TACC3 exon 13 fusions among 32 selected bladder carcinoma samples.	('fusions', 'Var', (93, 100))	('FGFR3', 'Gene', (61, 66))	('tumor', 'Disease', (34, 39))	('TACC3', 'Gene', '10460', (79, 84))	('bladder carcinoma', 'Disease', 'MESH:D001749', (119, 136))	('bladder carcinoma', 'Disease', (119, 136))	('TACC3', 'Gene', (79, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('61', '65'))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('FGFR3', 'Gene', '2261', (61, 66))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (119, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
111669	27409839	RNA sequencing of 492 sqNSCLC from the TCGA showed only 3 cases of FGFR3-TACC3 fusions; none of 513 cases of adenocarcinomas harbored this translocation.	('adenocarcinomas', 'Disease', (109, 124))	('NSCLC', 'Disease', (24, 29))	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('FGFR3', 'Gene', (67, 72))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('TACC3', 'Gene', '10460', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('TACC3', 'Gene', (73, 78))	('FGFR3', 'Gene', '2261', (67, 72))	('fusions', 'Var', (79, 86))	('adenocarcinomas', 'Disease', 'MESH:D000230', (109, 124))
111671	27409839	reported through analysis of the TGCA dataset 4 cases of sqNSCLC harboring FGFR3-TACC3 fusion.	('TACC3', 'Gene', (81, 86))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('FGFR3', 'Gene', (75, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('FGFR3', 'Gene', '2261', (75, 80))	('fusion', 'Var', (87, 93))	('TACC3', 'Gene', '10460', (81, 86))	('NSCLC', 'Disease', (59, 64))
111673	27409839	Fusion variants identified included exon 17 FGFR3 to exon exon 8 of TACC3; exon 17 of FGFR3 and exon 11 of TACC3; and exon 17 of FGFR3 to exon 4 TACC3 resulting in an overall prevalence of 0.5%.	('FGFR3', 'Gene', (129, 134))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('FGFR3', 'Gene', (44, 49))	('TACC3', 'Gene', (68, 73))	('TACC3', 'Gene', '10460', (107, 112))	('FGFR3', 'Gene', '2261', (44, 49))	('TACC3', 'Gene', '10460', (145, 150))	('FGFR3', 'Gene', '2261', (86, 91))	('TACC3', 'Gene', (107, 112))	('FGFR', 'molecular_function', 'GO:0005007', ('129', '133'))	('exon', 'Var', (36, 40))	('TACC3', 'Gene', (145, 150))	('FGFR3', 'Gene', '2261', (129, 134))	('FGFR3', 'Gene', (86, 91))	('exon 17', 'Var', (118, 125))	('exon 17', 'Var', (75, 82))	('TACC3', 'Gene', '10460', (68, 73))	('FGFR', 'molecular_function', 'GO:0005007', ('86', '90'))
111674	27409839	An additional analysis of 1,328 NSCLC samples revealed 15 FGFR3-TACC3 fusion variants identified through RT-PCR.	('variants', 'Var', (77, 85))	('TACC3', 'Gene', '10460', (64, 69))	('FGFR3', 'Gene', '2261', (58, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (32, 37))	('TACC3', 'Gene', (64, 69))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('FGFR3', 'Gene', (58, 63))	('NSCLC', 'Disease', (32, 37))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))
111675	27409839	Histological distribution was as follows: 6/1016 (0.6%) adenocarcinomas and 9/312 (2.9%) squamous cell carcinoma of the lung suggesting the FGFR3-TACC3 fusions are more frequent in sqNSCLC.	('FGFR', 'molecular_function', 'GO:0005007', ('140', '144'))	('TACC3', 'Gene', '10460', (146, 151))	('NSCLC', 'Disease', (183, 188))	('TACC3', 'Gene', (146, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('FGFR3', 'Gene', (140, 145))	('frequent', 'Reg', (169, 177))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (103, 124))	('squamous cell carcinoma of the lung', 'Disease', (89, 124))	('FGFR3', 'Gene', '2261', (140, 145))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (89, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('fusions', 'Var', (152, 159))	('adenocarcinomas', 'Disease', 'MESH:D000230', (56, 71))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('adenocarcinomas', 'Disease', (56, 71))
111676	27409839	FGFR3-TACC3 fusion correlated with positive smoking history and male gender in univariate analysis.	('fusion', 'Var', (12, 18))	('TACC3', 'Gene', '10460', (6, 11))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('TACC3', 'Gene', (6, 11))	('FGFR3', 'Gene', (0, 5))	('FGFR3', 'Gene', '2261', (0, 5))
111677	27409839	Tumor size > 3cm correlated with FGFR3 fusions independently in multivariate modeling.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('fusions', 'Var', (39, 46))	('FGFR3', 'Gene', '2261', (33, 38))	('FGFR3', 'Gene', (33, 38))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))
111678	27409839	FGFR3-TACC3 fusions were distributed as follows: E18:E11 2 cases, E17:E11 9 cases, E17:E8 1 case, E17:E5 1 case, and E17:E10 2 cases.	('E18', 'Var', (49, 52))	('TACC3', 'Gene', '10460', (6, 11))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('E17', 'Var', (83, 86))	('TACC3', 'Gene', (6, 11))	('FGFR3', 'Gene', (0, 5))	('E17', 'Var', (66, 69))	('FGFR3', 'Gene', '2261', (0, 5))
111679	27409839	Another cohort of patients from Korea was analyzed and only 2 cases of FGFR3-TACC3 fusion were detected (E17:E8 and E18:E9).	('FGFR3', 'Gene', (71, 76))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('E18:E9', 'Var', (116, 122))	('FGFR3', 'Gene', '2261', (71, 76))	('patients', 'Species', '9606', (18, 26))	('TACC3', 'Gene', '10460', (77, 82))	('TACC3', 'Gene', (77, 82))
111680	27409839	Two more cases of FGFR3 E18 fused with TACC3 E10 were reported in sqNSCLC.	('FGFR3', 'Gene', '2261', (18, 23))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('E18', 'Var', (24, 27))	('FGFR3', 'Gene', (18, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('TACC3', 'Gene', '10460', (39, 44))	('reported', 'Reg', (54, 62))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('TACC3', 'Gene', (39, 44))	('NSCLC', 'Disease', (68, 73))
111682	27409839	In summary, FGFR3-TACC3 fusions are rare in NSCLC but seem to be more common in sqNSCLC histological type with an estimated prevalence consistently lower than 2.9%.	('FGFR3', 'Gene', (12, 17))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('common', 'Reg', (70, 76))	('TACC3', 'Gene', '10460', (18, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('TACC3', 'Gene', (18, 23))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('FGFR3', 'Gene', '2261', (12, 17))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', (44, 49))	('fusions', 'Var', (24, 31))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
111683	27409839	Three cases of TACC3-FGFR3 translocations break points in patients with advanced cervical carcinoma have been described with early evidence of clinical benefit from FGFR targeted treatment.	('FGFR3', 'Gene', '2261', (21, 26))	('translocations', 'Var', (27, 41))	('cervical carcinoma', 'Disease', (81, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('165', '169'))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('cervical carcinoma', 'Disease', 'MESH:D002575', (81, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('FGFR3', 'Gene', (21, 26))	('TACC3', 'Gene', '10460', (15, 20))	('patients', 'Species', '9606', (58, 66))	('TACC3', 'Gene', (15, 20))
111685	27409839	The metastatic tumor showed FGFR3-TACC3 fusion (break point intron 17 and TACC3 intron 10).	('fusion', 'Var', (40, 46))	('TACC3', 'Gene', '10460', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('FGFR3', 'Gene', '2261', (28, 33))	('TACC3', 'Gene', (34, 39))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('TACC3', 'Gene', '10460', (74, 79))	('FGFR3', 'Gene', (28, 33))	('tumor', 'Disease', (15, 20))	('TACC3', 'Gene', (74, 79))
111686	27409839	Associated genomic aberrations were: AKT1 missense mutation, mTOR point mutation, ATRX truncating nonsense mutation.	('AKT1', 'Gene', (37, 41))	('ATRX', 'Gene', (82, 86))	('AKT1', 'Gene', '207', (37, 41))	('missense mutation', 'Var', (42, 59))	('point mutation', 'Var', (66, 80))	('ATRX', 'Gene', '546', (82, 86))	('mTOR', 'Gene', (61, 65))	('mTOR', 'Gene', '2475', (61, 65))
111689	27409839	Tumor tissue from the original biopsy showed FGFR3-TACC3 fusion (break points FGFR3 intron 18 and TACC3 intron 7) as well as BRAF 3' tandem duplication, activating PIK3CA missense mutation, CDNK2A loss, and activating missense mutations in KRAS and HRAS.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('FGFR3', 'Gene', (78, 83))	('PIK3CA', 'Gene', (164, 170))	('loss', 'NegReg', (197, 201))	('TACC3', 'Gene', '10460', (98, 103))	('activating', 'PosReg', (207, 217))	('FGFR3', 'Gene', '2261', (78, 83))	('TACC3', 'Gene', (98, 103))	('KRAS', 'Gene', '3845', (240, 244))	('TACC3', 'Gene', '10460', (51, 56))	('TACC3', 'Gene', (51, 56))	('HRAS', 'Gene', '3265', (249, 253))	('FGFR3', 'Gene', (45, 50))	('HRAS', 'Gene', (249, 253))	('KRAS', 'Gene', (240, 244))	('BRAF', 'Gene', (125, 129))	('BRAF', 'Gene', '673', (125, 129))	('FGFR3', 'Gene', '2261', (45, 50))	('FGFR', 'molecular_function', 'GO:0005007', ('78', '82'))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('PIK3CA', 'Gene', '5290', (164, 170))	('missense mutations', 'Var', (218, 236))	('activating', 'PosReg', (153, 163))	('CDNK2A', 'Gene', (190, 196))	('missense mutation', 'Var', (171, 188))
111690	27409839	The third case was a squamous cell carcinoma of the cervix in which the following genomic aberrations were identified on hysterectomy specimen: FGFR3-TACC3 fusion (breakpoints at FGFR3 intron 17 and TACC intron 10) and partial loss of STK11, and RB1 loss.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('squamous cell carcinoma', 'Disease', (21, 44))	('FGFR3', 'Gene', '2261', (144, 149))	('RB1', 'Gene', '5925', (246, 249))	('fusion', 'Var', (156, 162))	('loss', 'NegReg', (227, 231))	('STK11', 'Gene', '6794', (235, 240))	('FGFR3', 'Gene', (179, 184))	('loss', 'NegReg', (250, 254))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (21, 44))	('FGFR3', 'Gene', '2261', (179, 184))	('TACC3', 'Gene', '10460', (150, 155))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (21, 44))	('TACC3', 'Gene', (150, 155))	('RB1', 'Gene', (246, 249))	('FGFR3', 'Gene', (144, 149))	('FGFR', 'molecular_function', 'GO:0005007', ('179', '183'))	('carcinoma of the cervix', 'Phenotype', 'HP:0030079', (35, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('STK11', 'Gene', (235, 240))	('STK11', 'molecular_function', 'GO:0033868', ('235', '240'))
111693	27409839	Other sporadic cases of FGFR3-TACC3 translocation in cervical carcinoma have been reported as part of genomic aberrations analysis of solid tumors: FGFR3-TACC3 fusion (intron 17-intron 7) one case of cervical carcinoma.	('cervical carcinoma', 'Disease', (53, 71))	('FGFR3', 'Gene', '2261', (24, 29))	('solid tumors', 'Disease', (134, 146))	('FGFR3', 'Gene', (148, 153))	('TACC3', 'Gene', '10460', (154, 159))	('cervical carcinoma', 'Disease', 'MESH:D002575', (53, 71))	('TACC3', 'Gene', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('FGFR3', 'Gene', '2261', (148, 153))	('cervical carcinoma', 'Disease', (200, 218))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('solid tumors', 'Disease', 'MESH:D009369', (134, 146))	('translocation', 'Var', (36, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('cervical carcinoma', 'Disease', 'MESH:D002575', (200, 218))	('FGFR3', 'Gene', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('TACC3', 'Gene', '10460', (30, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('148', '152'))	('TACC3', 'Gene', (30, 35))
111699	27409839	Single cases of carcinoma of unknown primary, endometrial carcinoma, renal cell carcinoma, gallbladder, papillary kidney tumor, and prostate adenocarcinoma harboring the FGFR3-TACC3 fusion have been described.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (69, 89))	('carcinoma', 'Disease', (58, 67))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (46, 67))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (132, 155))	('gallbladder', 'Disease', (91, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('170', '174'))	('carcinoma', 'Disease', 'MESH:D002277', (146, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('TACC3', 'Gene', '10460', (176, 181))	('TACC3', 'Gene', (176, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinoma', 'Disease', (80, 89))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (46, 67))	('FGFR3', 'Gene', (170, 175))	('carcinoma', 'Disease', 'MESH:D002277', (58, 67))	('carcinoma', 'Disease', (16, 25))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (69, 89))	('FGFR3', 'Gene', '2261', (170, 175))	('endometrial carcinoma', 'Disease', (46, 67))	('kidney tumor', 'Phenotype', 'HP:0009726', (114, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('carcinoma', 'Disease', 'MESH:D002277', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('papillary kidney tumor', 'Disease', 'MESH:D007681', (104, 126))	('prostate adenocarcinoma', 'Disease', (132, 155))	('fusion', 'Var', (182, 188))	('carcinoma', 'Disease', 'MESH:D002277', (16, 25))	('carcinoma', 'Disease', (146, 155))	('renal cell carcinoma', 'Disease', (69, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('papillary kidney tumor', 'Disease', (104, 126))
111705	27409839	The clinical relevance of FGFR3-TACC3 has been highlighted by 3 out of 4 partial responses among patients with tumors harboring FGFR3-TACC3 fusions treated with FGFR inhibitor JNJ-42756493.	('TACC3', 'Gene', (134, 139))	('FGFR3', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('161', '165'))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('TACC3', 'Gene', '10460', (134, 139))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('FGFR3', 'Gene', '2261', (128, 133))	('FGFR', 'molecular_function', 'GO:0005007', ('128', '132'))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('fusions', 'Var', (140, 147))	('TACC3', 'Gene', '10460', (32, 37))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (176, 188))	('FGFR3', 'Gene', '2261', (26, 31))	('TACC3', 'Gene', (32, 37))	('FGFR3', 'Gene', (128, 133))	('patients', 'Species', '9606', (97, 105))
111706	27409839	Furthermore taking into account the obvious limitation of the sparse clinical data thus far tumors harboring FGFR3-TACC3 fusions seem to be more sensitive FGFR targeted therapies when compared to other FGFR aberrations.	('fusions', 'Var', (121, 128))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('FGFR3', 'Gene', (109, 114))	('TACC3', 'Gene', '10460', (115, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('109', '113'))	('more', 'PosReg', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('155', '159'))	('TACC3', 'Gene', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('FGFR', 'molecular_function', 'GO:0005007', ('202', '206'))	('FGFR3', 'Gene', '2261', (109, 114))	('tumors', 'Disease', (92, 98))
111707	27409839	This is particularly important, as there are limited treatment options for patients with aggressive tumors in which FGFR3-TACC3 fusions have been described such as GBM and bladder cancer.	('fusions', 'Var', (128, 135))	('GBM', 'Disease', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('116', '120'))	('TACC3', 'Gene', (122, 127))	('FGFR3', 'Gene', '2261', (116, 121))	('aggressive tumors', 'Disease', (89, 106))	('FGFR3', 'Gene', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('bladder cancer', 'Phenotype', 'HP:0009725', (172, 186))	('patients', 'Species', '9606', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('aggressive tumors', 'Disease', 'MESH:D001523', (89, 106))	('bladder cancer', 'Disease', 'MESH:D001749', (172, 186))	('TACC3', 'Gene', '10460', (122, 127))	('bladder cancer', 'Disease', (172, 186))
111708	27409839	Future studies should take into account that FGFR3-TACC3 fusion has shown positive correlations with PI3K/AKT/mTOR pathway, cell cycle control (CDK4, CDK2, and CCND1), and MDM2 aberrations (Table 1).	('PI3K', 'molecular_function', 'GO:0016303', ('101', '105'))	('AKT', 'Gene', '207', (106, 109))	('cell cycle control', 'biological_process', 'GO:1901987', ('124', '142'))	('TACC3', 'Gene', '10460', (51, 56))	('TACC3', 'Gene', (51, 56))	('CDK', 'molecular_function', 'GO:0004693', ('144', '147'))	('FGFR3', 'Gene', (45, 50))	('fusion', 'Var', (57, 63))	('CCND1', 'Gene', '595', (160, 165))	('mTOR', 'Gene', (110, 114))	('FGFR3', 'Gene', '2261', (45, 50))	('CCND1', 'Gene', (160, 165))	('MDM2 aberrations', 'Disease', (172, 188))	('CDK2', 'Gene', '1017', (150, 154))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('CDK4', 'Gene', (144, 148))	('cell cycle control', 'CPA', (124, 142))	('correlations', 'Interaction', (83, 95))	('AKT', 'Gene', (106, 109))	('CDK2', 'Gene', (150, 154))	('mTOR', 'Gene', '2475', (110, 114))	('MDM2 aberrations', 'Disease', 'MESH:D002869', (172, 188))	('CDK', 'molecular_function', 'GO:0004693', ('150', '153'))	('CDK4', 'Gene', '1019', (144, 148))
111710	27409839	Notwithstanding its rarity, FGFR3-TACC3 fusions are present in wide array of solid tumor types and its analysis should be an integral part of screening procedures in FGFR targeted trials in solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TACC3', 'Gene', '10460', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('FGFR3', 'Gene', '2261', (28, 33))	('TACC3', 'Gene', (34, 39))	('solid tumor', 'Disease', (77, 88))	('fusions', 'Var', (40, 47))	('solid tumor', 'Disease', 'MESH:D009369', (77, 88))	('solid tumor', 'Disease', 'MESH:D009369', (190, 201))	('solid tumors', 'Disease', 'MESH:D009369', (190, 202))	('FGFR', 'molecular_function', 'GO:0005007', ('166', '170'))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('FGFR3', 'Gene', (28, 33))	('solid tumors', 'Disease', (190, 202))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
111711	27409839	Pre-clinical data suggest that FGFR3 mutations are exclusive to non-inflamed bladder cancers (~ 30% of tumors), a subgroup characterized by absence of CD8 tumor infiltrating lymphocytes (CD8 TILs), worsen prognosis, and lower chance of responding to PD-L1 blockade.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('CD8', 'Gene', '925', (151, 154))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', (103, 109))	('FGFR3', 'Gene', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('FGFR3', 'Gene', '2261', (31, 36))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('CD8', 'Gene', '925', (187, 190))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (103, 108))	('CD8', 'Gene', (151, 154))	('absence', 'NegReg', (140, 147))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('mutations', 'Var', (37, 46))	('bladder cancers', 'Phenotype', 'HP:0009725', (77, 92))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('non-inflamed bladder cancers', 'Disease', 'MESH:D001749', (64, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('worsen', 'PosReg', (198, 204))	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('PD-L1', 'Gene', (250, 255))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('PD-L1', 'Gene', '29126', (250, 255))	('CD8', 'Gene', (187, 190))	('non-inflamed bladder cancers', 'Disease', (64, 92))
111713	27409839	Nevertheless, these preliminary results highlight a possible link between FGFR pathway aberrations and immune modulation of tumor microenvironment that could be explored therapeutically.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('aberrations', 'Var', (87, 98))	('tumor', 'Disease', (124, 129))	('FGFR pathway', 'Gene', (74, 86))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
111724	26251629	In the following years, identification of the genes and gene mutations that drive tumorigenesis has been one of the mainstream focuses in cancer research.	('cancer', 'Disease', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
111744	26251629	Third, recent genomic studies have revealed that each tumor typically harbors tens to hundreds of mutations that affect protein products.	('protein', 'Protein', (120, 127))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mutations', 'Var', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('affect', 'Reg', (113, 119))	('tumor', 'Disease', (54, 59))
111750	26251629	A general expectation may have been to identify a handful of gene mutations in each tumor, which would point to an actionable therapy target.	('mutations', 'Var', (66, 75))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))
111751	26251629	The whole-genome-sequencing data revealed a more complicated picture of a tumor typically harboring an average of 3,000 mutations, compared to the normal cells of the same person (an average of one mutation per one million nucleotides).	('person', 'Species', '9606', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('harboring', 'Reg', (90, 99))	('a tumor', 'Disease', 'MESH:D009369', (72, 79))	('mutations', 'Var', (120, 129))	('a tumor', 'Disease', (72, 79))
111752	26251629	It is notable that the median number of non-synonymous mutations varies depending on the tumor type, ranging from several (eg, acute lymphoblastic leukemia) to hundreds (eg, melanoma, lung cancer).	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('acute lymphoblastic leukemia', 'Disease', (127, 155))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (127, 155))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (133, 155))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))	('non-synonymous mutations', 'Var', (40, 64))	('lung cancer', 'Disease', (184, 195))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (127, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('tumor', 'Disease', (89, 94))
111753	26251629	It is fitting that mutagens cause DNA mutations, and therefore result in the accumulation of many mutations in tumors.	('accumulation', 'PosReg', (77, 89))	('mutations', 'MPA', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('DNA mutations', 'MPA', (34, 47))	('cause', 'Reg', (28, 33))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('mutagens', 'Var', (19, 27))
111755	26251629	Nevertheless, it is widely accepted that the major portion of these mutations are "bystander" mutations that do not directly contribute to tumorigenesis.	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mutations', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))
111756	26251629	By the same token, considering the scale of sequence variations detected in tumors in general, it is thought that the average number of 30-60 non-synonymous mutations found in tumors also includes bystander mutations.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('non-synonymous mutations', 'Var', (142, 166))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
111757	26251629	How do we discern cancer-driving mutations from bystander mutations?	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))
111760	26251629	In other words, statistically, all cancers harbor mutations in one or more of these genes, signifying their functional contribution in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (135, 140))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
111761	26251629	It is estimated that a tumor contains an average of two to eight mutations in these cancer driver genes.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('a tumor', 'Disease', 'MESH:D009369', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('a tumor', 'Disease', (21, 28))	('mutations', 'Var', (65, 74))
111764	26251629	These mutations recur in multiple tumors, attesting to their functional importance in driving tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('multiple tumors', 'Disease', (25, 40))	('tumor', 'Disease', (34, 39))	('multiple tumors', 'Disease', 'MESH:D009369', (25, 40))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('mutations', 'Var', (6, 15))
111765	26251629	A well-known example is mutations in the KRAS gene found in multiple types of cancers, including colorectal cancer, lung cancer, melanoma, and endometrial cancer.	('endometrial cancer', 'Phenotype', 'HP:0012114', (143, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('colorectal cancer', 'Disease', 'MESH:D015179', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('colorectal cancer', 'Disease', (97, 114))	('mutations', 'Var', (24, 33))	('endometrial cancer', 'Disease', (143, 161))	('found', 'Reg', (51, 56))	('KRAS', 'Gene', '3845', (41, 45))	('endometrial cancer', 'Disease', 'MESH:D016889', (143, 161))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('KRAS', 'Gene', (41, 45))	('lung cancer', 'Disease', (116, 127))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))
111766	26251629	According to the Catalogue Of Somatic Mutations In Cancer (COSMIC) database, 83% of the KRAS mutations alter the amino acid residue glycine 12 (eg, G12D, G12V), and 14% alter the amino acid residue glycine 13.	('alter', 'Reg', (169, 174))	('mutations', 'Var', (93, 102))	('G12D', 'Mutation', 'rs121913529', (148, 152))	('Cancer', 'Disease', 'MESH:D009369', (51, 57))	('glycine', 'Chemical', 'MESH:D005998', (132, 139))	('G12V', 'Var', (154, 158))	('Cancer', 'Disease', (51, 57))	('KRAS', 'Gene', (88, 92))	('amino acid residue glycine 13', 'MPA', (179, 208))	('alter', 'Reg', (103, 108))	('G12V', 'Mutation', 'rs121913529', (154, 158))	('glycine', 'Chemical', 'MESH:D005998', (198, 205))	('G12D', 'Var', (148, 152))	('KRAS', 'Gene', '3845', (88, 92))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))
111767	26251629	Functional studies have shown that these amino acid substitutions affect the GTPase activity of k-ras, resulting in constitutively active k-ras in a GTP-bound state.	('affect', 'Reg', (66, 72))	('k-ras', 'Gene', '3845', (138, 143))	('k-ras', 'Gene', (96, 101))	('k-ras', 'Gene', (138, 143))	('k-ras', 'Gene', '3845', (96, 101))	('GTP', 'Chemical', 'MESH:D006160', (149, 152))	('GTPase activity', 'molecular_function', 'GO:0003924', ('77', '92'))	('activity', 'MPA', (84, 92))	('GTP', 'Chemical', 'MESH:D006160', (77, 80))	('amino acid substitutions', 'Var', (41, 65))	('GTPase', 'Enzyme', (77, 83))
111768	26251629	In contrast, tumor suppressor gene mutations are typically found distributed along the coding regions as missense or nonsense mutations, suggesting that any mutations that disable the protein product drive tumorigenesis.	('disable', 'NegReg', (172, 179))	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('protein', 'cellular_component', 'GO:0003675', ('184', '191'))	('tumor', 'Disease', (206, 211))	('mutations', 'Var', (157, 166))	('tumor suppressor', 'biological_process', 'GO:0051726', ('13', '29'))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('protein', 'Protein', (184, 191))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('13', '29'))	('mutations', 'Var', (35, 44))
111769	26251629	For example, mutations in the BRCA1 gene, a tumor suppressor gene associated with an increased risk of breast cancer, are found all over the coding region with no specific recurring mutations among the 389 BRCA1 mutations registered in the COSMIC database.	('a tumor', 'Disease', (42, 49))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('BRCA1', 'Gene', (30, 35))	('BRCA1', 'Gene', '672', (206, 211))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('BRCA1', 'Gene', (206, 211))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('a tumor', 'Disease', 'MESH:D009369', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('BRCA1', 'Gene', '672', (30, 35))	('mutations', 'Var', (13, 22))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))
111770	26251629	Thus, mutations distributed in the coding region of the gene are indicative of a tumor suppressor gene.	('a tumor', 'Disease', (79, 86))	('tumor suppressor', 'biological_process', 'GO:0051726', ('81', '97'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('81', '97'))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('a tumor', 'Disease', 'MESH:D009369', (79, 86))	('mutations', 'Var', (6, 15))
111777	26251629	What the current data do clearly show is that each gene does not have equal potential to drive tumorigenesis, as some of the gene mutations are vastly more prevalent than others.	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mutations', 'Var', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
111778	26251629	In keeping with the intent of this article to provide an overview, not a comprehensive review, we discuss the SMGs that are mutated in >5% of all cancers from the data available from Kandoth et al.	('SMG', 'Gene', '23034', (110, 113))	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('mutated', 'Var', (124, 131))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('SMG', 'Gene', (110, 113))
111779	26251629	Using >5% frequency is an arbitrary cutoff, but it translates to one in 20 tumors harboring the gene mutations which we thought should warrant recognition as to represent major pathways involved in tumorigenesis.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('mutations', 'Var', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (198, 203))	('tumors', 'Disease', (75, 81))	('tumor', 'Disease', (75, 80))
111782	26251629	It is not surprising, but striking, that TP53 is mutated in 42% of all cancers, attesting to its principal tumor suppressor function in a wide range of tissue types.	('TP53', 'Gene', '7157', (41, 45))	('mutated', 'Var', (49, 56))	('TP53', 'Gene', (41, 45))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor suppressor', 'biological_process', 'GO:0051726', ('107', '123'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('107', '123'))
111783	26251629	In ovarian serous carcinoma, over 95% of tumors harbor TP53 mutations in the absence of any other SMG mutations, suggesting that loss of TP53 is a major event that drives tumorigenesis in this tissue type.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumors', 'Disease', (41, 47))	('SMG', 'Gene', '23034', (98, 101))	('TP53', 'Gene', '7157', (55, 59))	('mutations', 'Var', (60, 69))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('ovarian serous carcinoma', 'Disease', (3, 27))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('TP53', 'Gene', (137, 141))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (3, 27))	('tumor', 'Disease', (41, 46))	('SMG', 'Gene', (98, 101))	('loss', 'Var', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (137, 141))	('tumor', 'Disease', (171, 176))
111784	26251629	High-frequency mutations in TP53 are also found in lung squamous cell carcinoma and head and neck squamous cell carcinoma with 80% and 70%, respectively (Table 1).	('TP53', 'Gene', '7157', (28, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (51, 79))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (84, 121))	('mutations', 'Var', (15, 24))	('TP53', 'Gene', (28, 32))	('neck', 'cellular_component', 'GO:0044326', ('93', '97'))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (51, 79))	('lung squamous cell carcinoma', 'Disease', (51, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('neck squamous cell carcinoma', 'Disease', (93, 121))	('found', 'Reg', (42, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (93, 121))
111795	26251629	Mutations in the PIK3CA gene are found to alter specific amino acid residues, including E545K, E542K, and H1047R.	('H1047R', 'Mutation', 'rs121913279', (106, 112))	('E542K', 'Mutation', 'rs121913273', (95, 100))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('E542K', 'Var', (95, 100))	('alter', 'Reg', (42, 47))	('H1047R', 'Var', (106, 112))	('E545K', 'Mutation', 'rs104886003', (88, 93))	('E545K', 'Var', (88, 93))
111796	26251629	These mutations confer an increase in the lipid kinase activity of PI3k, indicating gain-of-function mutations that result in active signaling.	('mutations', 'Var', (101, 110))	('lipid', 'Chemical', 'MESH:D008055', (42, 47))	('gain-of-function', 'PosReg', (84, 100))	('lipid kinase activity', 'MPA', (42, 63))	('signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('lipid kinase activity', 'molecular_function', 'GO:0001727', ('42', '63'))	('active signaling', 'MPA', (126, 142))	('PI3k', 'molecular_function', 'GO:0016303', ('67', '71'))	('increase', 'PosReg', (26, 34))	('mutations', 'Var', (6, 15))
111797	26251629	PIP3 generated by PI3k is a signaling lipid that activates downstream kinases, including phosphatidylinositol-dependent kinase (PDK1) and protein kinase B (PKB, also known as AKT), which in turn inhibit pro-apoptotic molecules (eg, BAD and BIM), thereby mediating cell survival.	('activates', 'PosReg', (49, 58))	('PDK1', 'Gene', '5163', (128, 132))	('protein kinase B', 'Enzyme', (138, 154))	('BIM', 'Gene', (240, 243))	('cell survival', 'CPA', (264, 277))	('PI3k', 'Var', (18, 22))	('phosphatidylinositol-dependent', 'Enzyme', (89, 119))	('PIP3', 'Chemical', '-', (0, 4))	('AKT', 'Gene', '207', (175, 178))	('BIM', 'Gene', '10018', (240, 243))	('PI3k', 'molecular_function', 'GO:0016303', ('18', '22'))	('PDK1', 'molecular_function', 'GO:0004740', ('128', '132'))	('inhibit', 'NegReg', (195, 202))	('signaling', 'biological_process', 'GO:0023052', ('28', '37'))	('PDK1', 'Gene', (128, 132))	('lipid', 'Chemical', 'MESH:D008055', (38, 43))	('mediating', 'Reg', (254, 263))	('PKB', 'Gene', (156, 159))	('PKB', 'Gene', '207', (156, 159))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('AKT', 'Gene', (175, 178))
111800	26251629	The common function between TP53 and PIK3CA is in the cell death/survival pathway, such that either gene mutations - TP53 loss or PIK3CA activation - result in aberrant cell survival under stress.	('PIK3CA', 'Gene', (130, 136))	('PIK3CA', 'Gene', '5290', (37, 43))	('TP53', 'Gene', '7157', (28, 32))	('cell survival under', 'CPA', (169, 188))	('PIK3CA', 'Gene', '5290', (130, 136))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('TP53', 'Gene', (28, 32))	('result in', 'Reg', (150, 159))	('mutations', 'Var', (105, 114))	('activation', 'PosReg', (137, 147))	('cell death/survival pathway', 'Pathway', (54, 81))	('loss', 'NegReg', (122, 126))	('cell death', 'biological_process', 'GO:0008219', ('54', '64'))	('PIK3CA', 'Gene', (37, 43))
111802	26251629	Interestingly, we observed that the tumor types with high-frequency mutations in TP53 had relatively low-frequency mutations in PIK3CA.	('PIK3CA', 'Gene', '5290', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('PIK3CA', 'Gene', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mutations', 'Var', (68, 77))	('TP53', 'Gene', '7157', (81, 85))	('tumor', 'Disease', (36, 41))	('TP53', 'Gene', (81, 85))
111803	26251629	Conversely, the tumor types with high-frequency mutations in PIK3CA had relatively low-frequency mutations in TP53 (Table 1).	('PIK3CA', 'Gene', (61, 67))	('TP53', 'Gene', '7157', (110, 114))	('PIK3CA', 'Gene', '5290', (61, 67))	('TP53', 'Gene', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('mutations', 'Var', (48, 57))
111805	26251629	This inverse relationship suggests that TP53 and PIK3CA mutations may occur mutually exclusive of one another in a given tumor type; that is, tumors that harbor TP53 mutations do not contain PIK3CA mutations and vice versa.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('TP53', 'Gene', (161, 165))	('PIK3CA', 'Gene', '5290', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('mutations', 'Var', (166, 175))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (121, 126))	('TP53', 'Gene', '7157', (40, 44))	('PIK3CA', 'Gene', (49, 55))	('TP53', 'Gene', (40, 44))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('PIK3CA', 'Gene', '5290', (49, 55))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('PIK3CA', 'Gene', (191, 197))	('TP53', 'Gene', '7157', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
111806	26251629	For example, KRAS (G12V or G12D) and BRAF(V600E) mutations are mutually exclusive in colorectal cancer, indicating that a mutation in either gene results in the same functional consequence, namely activation of the MAP kinase pathway leading to tumorigenesis.	('V600E', 'Var', (42, 47))	('V600E', 'SUBSTITUTION', 'None', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Disease', (85, 102))	('mutation', 'Var', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('activation', 'PosReg', (197, 207))	('MAP', 'molecular_function', 'GO:0004239', ('215', '218'))	('G12V', 'Mutation', 'rs121913529', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('G12D', 'Var', (27, 31))	('tumor', 'Disease', (245, 250))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('KRAS', 'Gene', (13, 17))	('MAP kinase pathway', 'Pathway', (215, 233))	('KRAS', 'Gene', '3845', (13, 17))	('G12D', 'Mutation', 'rs121913529', (27, 31))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
111807	26251629	In this logic, the genome data showing the mutual exclusivity between TP53 and PIK3CA mutations suggest that these two genes may function in the same genetic pathway, the deregulation of which by either gene mutations results in tumorigenesis.	('mutations', 'Var', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('TP53', 'Gene', '7157', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('results in', 'Reg', (218, 228))	('mutations', 'Var', (208, 217))	('PIK3CA', 'Gene', (79, 85))	('tumor', 'Disease', (229, 234))	('TP53', 'Gene', (70, 74))	('function', 'Reg', (129, 137))	('PIK3CA', 'Gene', '5290', (79, 85))
111808	26251629	Alternatively, TP53 or PIK3CA mutations may drive cancers originating from different cell types.	('drive', 'Reg', (44, 49))	('PIK3CA', 'Gene', (23, 29))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('PIK3CA', 'Gene', '5290', (23, 29))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
111809	26251629	For example, the ovarian cancer found with high-frequency mutations in TP53 (Table 1) is the serous epithelial ovarian carcinoma subtype that makes up >90% of ovarian cancer.	('mutations', 'Var', (58, 67))	('ovarian cancer', 'Disease', (159, 173))	('serous epithelial ovarian carcinoma subtype', 'Disease', (93, 136))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('ovarian cancer', 'Phenotype', 'HP:0100615', (17, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (17, 31))	('ovarian cancer', 'Phenotype', 'HP:0100615', (159, 173))	('ovarian cancer', 'Disease', (17, 31))	('serous epithelial ovarian carcinoma subtype', 'Disease', 'MESH:D000077216', (93, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('TP53', 'Gene', '7157', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('TP53', 'Gene', (71, 75))	('ovarian cancer', 'Disease', 'MESH:D010051', (159, 173))
111811	26251629	The clear cell ovarian-subtype tumors have been shown to contain largely wild-type TP53 but high-frequency mutations in PIK3CA, up to 40%.	('TP53', 'Gene', '7157', (83, 87))	('PIK3CA', 'Gene', (120, 126))	('ovarian-subtype tumors', 'Disease', 'MESH:D010051', (15, 37))	('ovarian-subtype tumors', 'Disease', (15, 37))	('mutations', 'Var', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('TP53', 'Gene', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('PIK3CA', 'Gene', '5290', (120, 126))
111812	26251629	Together, these may suggest that TP53 or PIK3CA mutations occur in different cell types, each driving a different subtype of cancer (serous ovarian cancer vs clear cell ovarian cancer).	('serous ovarian cancer', 'Disease', 'MESH:D010051', (133, 154))	('cancer', 'Disease', (177, 183))	('clear cell ovarian cancer', 'Disease', 'MESH:D008649', (158, 183))	('driving', 'Reg', (94, 101))	('TP53', 'Gene', '7157', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('PIK3CA', 'Gene', '5290', (41, 47))	('mutations', 'Var', (48, 57))	('ovarian cancer', 'Phenotype', 'HP:0100615', (140, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('serous ovarian cancer', 'Disease', (133, 154))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('PIK3CA', 'Gene', (41, 47))	('clear cell ovarian cancer', 'Disease', (158, 183))	('TP53', 'Gene', (33, 37))	('ovarian cancer', 'Phenotype', 'HP:0100615', (169, 183))	('cancer', 'Disease', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
111815	26251629	The basal-like subtype of breast cancer has a high frequency of TP53 mutations, 80%, as does serous ovarian cancer with 95%.	('breast cancer', 'Disease', (26, 39))	('mutations', 'Var', (69, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('serous ovarian cancer', 'Disease', (93, 114))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (93, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('basal-like', 'Disease', (4, 14))
111816	26251629	Thus, it appears to support the argument that TP53 mutation drives cancers originating from similar cell types.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('TP53', 'Gene', '7157', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('drives', 'Reg', (60, 66))	('TP53', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))
111818	26251629	Rather, the study points out that some cancers share the "p53 footprint" recognizable by gene expression patterns altered by the loss of p53.	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('loss', 'Var', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('p53', 'Gene', (58, 61))	('p53', 'Gene', (137, 140))	('p53', 'Gene', '7157', (137, 140))	('p53', 'Gene', '7157', (58, 61))
111820	26251629	In fact, all four molecular subtypes of breast cancers are found with mutations in TP53 or PIK3CA, albeit with different prevalence but in a mutually exclusive manner within each subtype.	('PIK3CA', 'Gene', (91, 97))	('breast cancers', 'Disease', (40, 54))	('TP53', 'Gene', '7157', (83, 87))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', (83, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('PIK3CA', 'Gene', '5290', (91, 97))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('found', 'Reg', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('breast cancers', 'Phenotype', 'HP:0003002', (40, 54))	('breast cancers', 'Disease', 'MESH:D001943', (40, 54))
111821	26251629	In addition, the two subtypes of lung cancers, squamous cell carcinoma and adenocarcinoma, also harbor mutations in both TP53 and PIK3CA.	('PIK3CA', 'Gene', (130, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('mutations', 'Var', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('lung cancers', 'Disease', 'MESH:D008175', (33, 45))	('PIK3CA', 'Gene', '5290', (130, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('lung cancers', 'Phenotype', 'HP:0100526', (33, 45))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('lung cancers', 'Disease', (33, 45))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('harbor', 'Reg', (96, 102))	('squamous cell carcinoma and adenocarcinoma', 'Disease', 'MESH:D002294', (47, 89))
111823	26251629	At any rate, as numerous studies have shown the functions of p53 and PI3k in multiple and diverse cell types, it would be hard-pressed to assign the biological functions of TP53 or PIK3CA to any specific cell types, such that each gene mutation drives different cancer types.	('cancer', 'Disease', (262, 268))	('drives', 'PosReg', (245, 251))	('mutation', 'Var', (236, 244))	('PI3k', 'molecular_function', 'GO:0016303', ('69', '73'))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('PIK3CA', 'Gene', (181, 187))	('PIK3CA', 'Gene', '5290', (181, 187))	('p53', 'Gene', '7157', (61, 64))	('TP53', 'Gene', '7157', (173, 177))	('TP53', 'Gene', (173, 177))	('p53', 'Gene', (61, 64))	('cancer', 'Disease', 'MESH:D009369', (262, 268))
111824	26251629	Taken together, it seems tenable that the mutual exclusivity between TP53 and PIK3CA mutations may be due to their function in the same genetic pathway, the deregulation of which leads to tumorigenesis.	('tumor', 'Disease', (188, 193))	('deregulation', 'Var', (157, 169))	('PIK3CA', 'Gene', (78, 84))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('leads to', 'Reg', (179, 187))	('function', 'Reg', (115, 123))	('PIK3CA', 'Gene', '5290', (78, 84))	('mutations', 'Var', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
111825	26251629	Considering that the mutation frequency of TP53 is 42%, dominantly higher than the one of PIK3CA, 18% (Table 1), it is tempting to speculate that TP53 is an upstream regulator of PIK3CA; TP53 regulates several major pathways that lead to tumorigenesis, with the PIK3CA pathway being one of the major pathways.	('TP53', 'Gene', '7157', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('PIK3CA', 'Gene', '5290', (262, 268))	('TP53', 'Gene', '7157', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('regulates', 'Reg', (192, 201))	('TP53', 'Gene', (146, 150))	('mutation', 'Var', (21, 29))	('lead to', 'Reg', (230, 237))	('PIK3CA', 'Gene', (179, 185))	('TP53', 'Gene', (187, 191))	('PIK3CA', 'Gene', (90, 96))	('tumor', 'Disease', (238, 243))	('PIK3CA', 'Gene', '5290', (179, 185))	('PIK3CA', 'Gene', (262, 268))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('PIK3CA', 'Gene', '5290', (90, 96))
111826	26251629	In this scenario, TP53 mutations alone could drive tumorigenesis, while PIK3CA mutations result in tumorigenesis if one or more pathways governed by TP53 are deregulated.	('tumor', 'Disease', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', '7157', (149, 153))	('tumor', 'Disease', (51, 56))	('TP53', 'Gene', (18, 22))	('PIK3CA', 'Gene', (72, 78))	('result in', 'Reg', (89, 98))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('TP53', 'Gene', (149, 153))	('PIK3CA', 'Gene', '5290', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('drive', 'PosReg', (45, 50))	('mutations', 'Var', (79, 88))
111827	26251629	The genomic data support this postulate, which show that PIK3CA mutations "co-occur" with other gene mutations such as PTEN and AKT, whereas TP53 mutations remain mutually exclusive with these other gene mutations.	('PIK3CA', 'Gene', '5290', (57, 63))	('TP53', 'Gene', '7157', (141, 145))	('AKT', 'Gene', (128, 131))	('TP53', 'Gene', (141, 145))	('PTEN', 'Gene', (119, 123))	('mutations', 'Var', (64, 73))	('PTEN', 'Gene', '5728', (119, 123))	('AKT', 'Gene', '207', (128, 131))	('PIK3CA', 'Gene', (57, 63))
111833	26251629	Conversely, PI3k activates Akt, which in turn activates Mdm2 to inhibit p53.	('Mdm2', 'Gene', '4193', (56, 60))	('Mdm2', 'Gene', (56, 60))	('activates', 'PosReg', (46, 55))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('Akt', 'Gene', '207', (27, 30))	('inhibit', 'NegReg', (64, 71))	('PI3k', 'molecular_function', 'GO:0016303', ('12', '16'))	('Akt', 'Gene', (27, 30))	('activates', 'PosReg', (17, 26))	('PI3k', 'Var', (12, 16))
111838	26251629	Considering that 42% of all human cancers harbor TP53 mutations with no targeted therapy available to date, the TP53/PIK3CA relationship warrants investigative scrutiny.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('human', 'Species', '9606', (28, 33))	('mutations', 'Var', (54, 63))	('PIK3CA', 'Gene', (117, 123))	('PIK3CA', 'Gene', '5290', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('TP53', 'Gene', '7157', (112, 116))	('cancers', 'Disease', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('TP53', 'Gene', (112, 116))
111841	26251629	GATA3 may belong to this group of genes as it is mutated in 11% of breast cancers but less than 5% in all other cancer types.	('GATA3', 'Gene', '2625', (0, 5))	('mutated', 'Var', (49, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Disease', (74, 80))	('breast cancers', 'Phenotype', 'HP:0003002', (67, 81))	('GATA3', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancers', 'Disease', 'MESH:D001943', (67, 81))	('breast cancers', 'Disease', (67, 81))
111843	26251629	Thus, the loss of APC results in expansion of aberrant cell population in intestinal epithelium, leading to colon cancer.	('loss', 'Var', (10, 14))	('colon cancer', 'Disease', (108, 120))	('leading to', 'Reg', (97, 107))	('expansion', 'PosReg', (33, 42))	('APC', 'Gene', (18, 21))	('colon cancer', 'Phenotype', 'HP:0003003', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('APC', 'Gene', '324', (18, 21))	('APC', 'cellular_component', 'GO:0005680', ('18', '21'))	('colon cancer', 'Disease', 'MESH:D015179', (108, 120))
111847	26251629	As cilia are required for the proper development and maintenance of nephrons in kidney, the absence of cilia due to the loss of VHL apparently results in the formation of lesions in kidney tissue, leading to tumorigenesis.	('formation', 'biological_process', 'GO:0009058', ('158', '167'))	('absence', 'NegReg', (92, 99))	('VHL', 'Gene', '7428', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('leading to', 'Reg', (197, 207))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('nephrons', 'Disease', 'MESH:D007683', (68, 76))	('nephrons', 'Disease', (68, 76))	('tumor', 'Disease', (208, 213))	('loss', 'Var', (120, 124))	('VHL', 'Gene', (128, 131))
111849	26251629	Interestingly, the mutations in these genes are loss-of-function mutations, suggesting their tumor suppressor functions.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('mutations', 'Var', (19, 28))	('loss-of-function', 'NegReg', (48, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('93', '109'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('93', '109'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
111850	26251629	APC has been referred to as a "gate keeper" because its functional loss inevitably leads to colon cancer, evidenced by the fact that patients with familiar adenomatous polyposis syndrome, who inherit a defective copy of APC, develop colon cancer with 100% penetrance.	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('patients', 'Species', '9606', (133, 141))	('colon cancer', 'Phenotype', 'HP:0003003', (233, 245))	('APC', 'Gene', '324', (220, 223))	('adenomatous polyposis syndrome', 'Phenotype', 'HP:0005227', (156, 186))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('familiar adenomatous polyposis syndrome', 'Disease', (147, 186))	('APC', 'Gene', (0, 3))	('loss', 'NegReg', (67, 71))	('colon cancer', 'Disease', (92, 104))	('colon cancer', 'Disease', 'MESH:D015179', (233, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('APC', 'Gene', (220, 223))	('familiar adenomatous polyposis syndrome', 'Disease', 'MESH:D011125', (147, 186))	('defective', 'Var', (202, 211))	('develop', 'Reg', (225, 232))	('colon cancer', 'Disease', (233, 245))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('APC', 'cellular_component', 'GO:0005680', ('0', '3'))	('leads to', 'Reg', (83, 91))	('APC', 'Gene', '324', (0, 3))
111851	26251629	Similarly, patients with von Hippel-Lindau syndrome, who inherit a mutated copy of VHL, develop clear cell renal cancer with a high frequency of 70%.	('von Hippel-Lindau syndrome', 'Disease', (25, 51))	('develop', 'Reg', (88, 95))	('VHL', 'Gene', '7428', (83, 86))	('clear cell renal cancer', 'Disease', 'MESH:C538614', (96, 119))	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (25, 51))	('clear cell renal cancer', 'Disease', (96, 119))	('mutated', 'Var', (67, 74))	('renal cancer', 'Phenotype', 'HP:0009726', (107, 119))	('clear cell renal cancer', 'Phenotype', 'HP:0006770', (96, 119))	('patients', 'Species', '9606', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('VHL', 'Gene', (83, 86))
111852	26251629	Thus, APC, VHL, PBRM1, GATA3, and other genes mutated in specific cancer types may qualify as the "gate keepers" of specific tissue type, the loss of which leads to the expansion of aberrant cell population and tumorigenesis.	('VHL', 'Gene', '7428', (11, 14))	('expansion', 'PosReg', (169, 178))	('PBRM1', 'Gene', '55193', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('APC', 'Gene', (6, 9))	('loss', 'Var', (142, 146))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('GATA3', 'Gene', (23, 28))	('APC', 'cellular_component', 'GO:0005680', ('6', '9'))	('VHL', 'Gene', (11, 14))	('APC', 'Gene', '324', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('GATA3', 'Gene', '2625', (23, 28))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('PBRM1', 'Gene', (16, 21))	('cancer', 'Disease', (66, 72))
111853	26251629	Acute myeloid leukemia (AML) is a cancer type that contains mutations in a unique set of genes, which includes NPM1 (27%), FLT3 (26%), DNMT3A (25%), and IDH2 (10%).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (0, 22))	('FLT3', 'Gene', (123, 127))	('NPM1', 'Gene', (111, 115))	('DNMT3A', 'Gene', '1788', (135, 141))	('mutations', 'Var', (60, 69))	('FLT3', 'Gene', '2322', (123, 127))	('leukemia', 'Phenotype', 'HP:0001909', (14, 22))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (6, 22))	('AML', 'Disease', 'MESH:D015470', (24, 27))	('AML', 'Disease', (24, 27))	('DNMT3A', 'Gene', (135, 141))	('IDH2', 'Gene', (153, 157))	('NPM1', 'Gene', '4869', (111, 115))	('IDH2', 'Gene', '3418', (153, 157))	('cancer', 'Disease', (34, 40))	('Acute myeloid leukemia', 'Disease', (0, 22))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (0, 22))
111854	26251629	Hematologic malignancies often have their unique set of gene mutations, suggesting that these cancers may arise from mutations in the genes involved in determining and/or maintaining specific hematopoietic cell lineage.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('mutations', 'Var', (117, 126))	('arise from', 'Reg', (106, 116))	('mutations', 'Var', (61, 70))	('Hematologic', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('malignancies', 'Disease', 'MESH:D009369', (12, 24))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('malignancies', 'Disease', (12, 24))	('cancers', 'Disease', (94, 101))
111855	26251629	Pediatric AML shares mutations in the NPM1 and FLT3 genes with the adult AML, supporting the role of NPM1 and FLT3 mutations in driving AML regardless of the age of disease onset.	('AML', 'Disease', 'MESH:D015470', (73, 76))	('AML', 'Disease', (10, 13))	('mutations', 'Var', (115, 124))	('AML', 'Disease', (73, 76))	('FLT3', 'Gene', (110, 114))	('NPM1', 'Gene', '4869', (101, 105))	('FLT3', 'Gene', '2322', (47, 51))	('NPM1', 'Gene', (38, 42))	('NPM1', 'Gene', '4869', (38, 42))	('AML', 'Disease', 'MESH:D015470', (136, 139))	('AML', 'Disease', 'MESH:D015470', (10, 13))	('FLT3', 'Gene', (47, 51))	('FLT3', 'Gene', '2322', (110, 114))	('NPM1', 'Gene', (101, 105))	('AML', 'Disease', (136, 139))
111862	26251629	When mutated, Idh1 or Idh2 produces an aberrant metabolite, 2-hydroxyglutarate, which results in the loss of 5-hydroxymethylcytosine at CpG islands in DNA, resulting in aberrant DNA methylation.	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('loss', 'NegReg', (101, 105))	('Idh1', 'Gene', (14, 18))	('DNA methylation', 'MPA', (178, 193))	('Idh2', 'Gene', '3418', (22, 26))	('5-hydroxymethylcytosine', 'MPA', (109, 132))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (109, 132))	('DNA methylation', 'biological_process', 'GO:0006306', ('178', '193'))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (60, 78))	('mutated', 'Var', (5, 12))	('Idh1', 'Gene', '3417', (14, 18))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))	('Idh2', 'Gene', (22, 26))
111863	26251629	Both DNMT3A and IDH2 have been found with recurrent mutations such as R882H/C and R140Q, respectively, associated with poor prognosis and disease relapse, indicating their oncogenic function in tumorigenesis.	('R140Q', 'Mutation', 'rs121913502', (82, 87))	('DNMT3A', 'Gene', (5, 11))	('associated', 'Reg', (103, 113))	('DNMT3A', 'Gene', '1788', (5, 11))	('R882H', 'SUBSTITUTION', 'None', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('IDH2', 'Gene', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('R140Q', 'Var', (82, 87))	('tumor', 'Disease', (194, 199))	('R882H', 'Var', (70, 75))	('IDH2', 'Gene', '3418', (16, 20))	('poor prognosis', 'CPA', (119, 133))	('disease relapse', 'CPA', (138, 153))
111864	26251629	Mapping of the CpG sites affected by these gene mutations may provide insight into the biology of adult myeloid cell lineage and AML tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('AML', 'Disease', 'MESH:D015470', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('AML', 'Disease', (129, 132))	('tumor', 'Disease', (133, 138))	('mutations', 'Var', (48, 57))
111869	26251629	MLL1, the first member of MLLs, was discovered due to the frequent gene rearrangement in aggressive leukemia, including in-frame chromosomal translocation, partial tandem gene duplication, and gene amplification.	('MLL', 'Gene', '4297', (26, 29))	('MLL', 'Gene', '4297', (0, 3))	('aggressive leukemia', 'Disease', 'MESH:D007938', (89, 108))	('MLL1', 'Gene', '4297', (0, 4))	('leukemia', 'Phenotype', 'HP:0001909', (100, 108))	('MLL', 'Gene', (0, 3))	('gene amplification', 'Var', (193, 211))	('aggressive leukemia', 'Disease', (89, 108))	('partial tandem gene duplication', 'Var', (156, 187))	('MLL1', 'Gene', (0, 4))	('MLL', 'Gene', (26, 29))
111871	26251629	As the HOX genes play a critical role in development, MLL1 knockout results in defective hematopoiesis and embryonic lethality.	('hematopoiesis', 'biological_process', 'GO:0030097', ('89', '102'))	('defective hematopoiesis', 'Phenotype', 'HP:0010972', (79, 102))	('MLL1', 'Gene', (54, 58))	('defective hematopoiesis', 'Disease', (79, 102))	('defective hematopoiesis', 'Disease', 'MESH:C536227', (79, 102))	('embryonic lethality', 'Disease', 'MESH:D020964', (107, 126))	('embryonic lethality', 'Disease', (107, 126))	('knockout', 'Var', (59, 67))	('MLL1', 'Gene', '4297', (54, 58))
111872	26251629	While MLL1 gain-of-function mutations drive cell transformation and leukemia, the mutations found in MLL2/MLL3 by genomic sequencing in solid tumors are mostly nonsense or frameshift loss of function mutations.	('MLL1', 'Gene', (6, 10))	('MLL2', 'Gene', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('leukemia', 'Disease', (68, 76))	('leukemia', 'Phenotype', 'HP:0001909', (68, 76))	('solid tumors', 'Disease', (136, 148))	('leukemia', 'Disease', 'MESH:D007938', (68, 76))	('MLL2', 'Gene', '9757', (101, 105))	('MLL3', 'Gene', (106, 110))	('nonsense', 'Var', (160, 168))	('MLL1', 'Gene', '4297', (6, 10))	('solid tumors', 'Disease', 'MESH:D009369', (136, 148))	('MLL3', 'Gene', '58508', (106, 110))	('cell transformation', 'CPA', (44, 63))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('gain-of-function', 'PosReg', (11, 27))	('frameshift', 'Var', (172, 182))	('mutations', 'Var', (28, 37))
111877	26251629	The mutations found in ARID1A are loss-of-function mutations, suggesting a tumor suppressor function.	('a tumor', 'Disease', (73, 80))	('ARID1A', 'Gene', '8289', (23, 29))	('ARID1A', 'Gene', (23, 29))	('loss-of-function', 'NegReg', (34, 50))	('tumor suppressor', 'biological_process', 'GO:0051726', ('75', '91'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('75', '91'))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutations', 'Var', (4, 13))	('a tumor', 'Disease', 'MESH:D009369', (73, 80))
111878	26251629	Consistent with a tumor suppressor function, several in vitro cell studies have shown that knock-down of ARID1A results in enhanced cell proliferation, whereas overexpression results in cell cycle arrest.	('enhanced', 'PosReg', (123, 131))	('ARID1A', 'Gene', '8289', (105, 111))	('a tumor', 'Disease', 'MESH:D009369', (16, 23))	('ARID1A', 'Gene', (105, 111))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (186, 203))	('a tumor', 'Disease', (16, 23))	('tumor suppressor', 'biological_process', 'GO:0051726', ('18', '34'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('186', '203'))	('cell proliferation', 'CPA', (132, 150))	('cell cycle arrest', 'CPA', (186, 203))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('18', '34'))	('cell proliferation', 'biological_process', 'GO:0008283', ('132', '150'))	('knock-down', 'Var', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
111880	26251629	For example, ARID1A knock-down in embryonic stem (ES) cells results in a differentiation block to certain cell types including cardiomyocytes and adipocytes but permits differentiation of ES cells into other cell types such as neurons.	('ARID1A', 'Gene', '8289', (13, 19))	('knock-down', 'Var', (20, 30))	('ARID1A', 'Gene', (13, 19))	('differentiation block', 'CPA', (73, 94))	('results in', 'Reg', (60, 70))
111881	26251629	These studies suggest that the loss of ARID1A drives tumorigenesis in specific tissue types, the differentiation of which depends on the function of ARID1A.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('loss', 'Var', (31, 35))	('drives', 'Reg', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('ARID1A', 'Gene', '8289', (149, 155))	('ARID1A', 'Gene', (149, 155))	('tumor', 'Disease', (53, 58))	('ARID1A', 'Gene', '8289', (39, 45))	('ARID1A', 'Gene', (39, 45))
111882	26251629	Supportive of this idea, ARID1A is found to be the most frequently mutated in two cancer types, uterine corpus endometrial carcinoma (30%) and bladder urothelial carcinoma (27.6%).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (104, 132))	('ARID1A', 'Gene', '8289', (25, 31))	('ARID1A', 'Gene', (25, 31))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutated', 'Var', (67, 74))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (143, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (111, 132))	('corpus endometrial carcinoma', 'Disease', (104, 132))	('bladder urothelial carcinoma', 'Disease', (143, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
111885	26251629	It is notable that PBRM1 (BAF180), frequently mutated in kidney renal cell carcinoma, is also a subunit of the same SWI/SNF complex, underscoring the importance of chromatin remodeling in tumorigenesis.	('tumor', 'Disease', (188, 193))	('PBRM1', 'Gene', '55193', (19, 24))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('164', '184'))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('116', '131'))	('mutated', 'Var', (46, 53))	('BAF180', 'Gene', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (64, 84))	('BAF180', 'Gene', '55193', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('kidney renal cell carcinoma', 'Disease', (57, 84))	('chromatin', 'cellular_component', 'GO:0000785', ('164', '173'))	('kidney renal cell carcinoma', 'Disease', 'MESH:D007674', (57, 84))	('PBRM1', 'Gene', (19, 24))
111889	26251629	For example, although imatinib is effective in achieving remission in >90% CML patients, those who do not respond or have partial response to imatinib were found to have leukemic cells with additional mutations in Bcr-Abl, specifically in the kinase domain of Abl.	('leukemic', 'Disease', (170, 178))	('imatinib', 'Chemical', 'MESH:D000068877', (142, 150))	('mutations', 'Var', (201, 210))	('Abl', 'Gene', (260, 263))	('CML', 'Disease', (75, 78))	('Abl', 'Gene', (218, 221))	('leukemic', 'Disease', 'MESH:D007938', (170, 178))	('Bcr-Abl', 'Gene', (214, 221))	('CML', 'Disease', 'MESH:D015464', (75, 78))	('patients', 'Species', '9606', (79, 87))	('imatinib', 'Chemical', 'MESH:D000068877', (22, 30))	('Bcr-Abl', 'Gene', '25', (214, 221))	('Abl', 'Gene', '25', (218, 221))	('Abl', 'Gene', '25', (260, 263))
111890	26251629	Several of these amino acid substitution mutations directly abrogate imatinib binding to Bcr-Abl, thereby rendering imatinib ineffective.	('binding', 'Interaction', (78, 85))	('Bcr-Abl', 'Gene', '25', (89, 96))	('abrogate', 'NegReg', (60, 68))	('amino acid substitution mutations', 'Var', (17, 50))	('binding', 'molecular_function', 'GO:0005488', ('78', '85'))	('imatinib', 'Protein', (69, 77))	('imatinib', 'Chemical', 'MESH:D000068877', (116, 124))	('Bcr-Abl', 'Gene', (89, 96))	('imatinib', 'Chemical', 'MESH:D000068877', (69, 77))
111891	26251629	Similarly, NSCLC patients who become resistant to gefitinib or erlotinib are found to have tumor cells that acquire mutations in Egfr in the kinase domain such as T790M mutation.	('NSCLC', 'Disease', (11, 16))	('NSCLC', 'Disease', 'MESH:D002289', (11, 16))	('Egfr', 'Gene', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('erlotinib', 'Chemical', 'MESH:D000069347', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('gefitinib', 'Chemical', 'MESH:D000077156', (50, 59))	('patients', 'Species', '9606', (17, 25))	('T790M mutation', 'Var', (163, 177))	('tumor', 'Disease', (91, 96))	('Egfr', 'Gene', '1956', (129, 133))	('T790M', 'Mutation', 'rs121434569', (163, 168))	('Egfr', 'molecular_function', 'GO:0005006', ('129', '133'))
111902	26251629	These include overexpression of the MYC oncogene, amplification of ERBB2/HER2, activation of the insulin/Igf receptor signaling, and mutations in the PI3k pathway molecules.	('HER2', 'Gene', '2064', (73, 77))	('ERBB2', 'Gene', '2064', (67, 72))	('amplification', 'Var', (50, 63))	('MYC', 'Gene', '4609', (36, 39))	('insulin', 'Gene', '3630', (97, 104))	('ERBB2', 'Gene', (67, 72))	('PI3k pathway', 'Pathway', (150, 162))	('PI3k', 'molecular_function', 'GO:0016303', ('150', '154'))	('MYC', 'Gene', (36, 39))	('mutations', 'Var', (133, 142))	('activation', 'PosReg', (79, 89))	('insulin', 'molecular_function', 'GO:0016088', ('97', '104'))	('signaling', 'biological_process', 'GO:0023052', ('118', '127'))	('overexpression', 'PosReg', (14, 28))	('HER2', 'Gene', (73, 77))	('insulin', 'Gene', (97, 104))
111903	26251629	However, genetic alterations of these genes and pathways have been implicated in other drug therapy resistance as well, suggesting that these may confer general cell growth/survival advantage mechanisms under unfavorable conditions, not tamoxifen resistance per se.	('implicated', 'Reg', (67, 77))	('genetic alterations', 'Var', (9, 28))	('tamoxifen', 'Chemical', 'MESH:D013629', (237, 246))	('drug therapy resistance', 'Phenotype', 'HP:0020174', (87, 110))	('cell growth/survival advantage', 'CPA', (161, 191))	('cell growth', 'biological_process', 'GO:0016049', ('161', '172'))
111904	26251629	More revealing are the specific mutations in the ESR1 gene that encodes ER, recently identified in 20%-50% of recurrent tumor samples from breast cancer patients who were treated with antiestrogen therapy of aromatase inhibitors and/or tamoxifen.	('tamoxifen', 'Chemical', 'MESH:D013629', (236, 245))	('patients', 'Species', '9606', (153, 161))	('ESR1', 'Gene', (49, 53))	('ER', 'Gene', '2099', (72, 74))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('mutations', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('breast cancer', 'Disease', (139, 152))	('ESR1', 'Gene', '2099', (49, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('tumor', 'Disease', (120, 125))
111907	26251629	The specific amino acid substitution mutations found in recurrent tumors result in mimicking the active conformation of ER without estrogen bound to it, rendering cancer cells to no longer require estrogen for growth.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mimicking', 'MPA', (83, 92))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('amino acid substitution mutations', 'Var', (13, 46))	('ER', 'Gene', '2099', (120, 122))	('active conformation', 'MPA', (97, 116))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
111908	26251629	Mutations in the ESR1 gene are rarely found in primary tumors, estimated less than 1% according to TCGA data.	('primary tumors', 'Disease', 'MESH:D009369', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('ESR1', 'Gene', '2099', (17, 21))	('Mutations', 'Var', (0, 9))	('primary tumors', 'Disease', (47, 61))	('ESR1', 'Gene', (17, 21))
111909	26251629	Thus, the ESR1 mutations found in recurrent tumors are de novo-acquired mutations under the selective pressure of antiestrogen therapy.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('ESR1', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ESR1', 'Gene', '2099', (10, 14))
111914	26251629	As is the case with tamoxifen-resistant breast cancer cells, it has been demonstrated that mutations and amplification of growth receptor genes including IGFR, MET, and FGFR family members confer resistance to various targeted therapies.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('169', '173'))	('breast cancer', 'Disease', (40, 53))	('amplification', 'Var', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('tamoxifen', 'Chemical', 'MESH:D013629', (20, 29))	('IGFR', 'Gene', '3480', (154, 158))	('mutations', 'Var', (91, 100))	('resistance', 'MPA', (196, 206))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('FGFR', 'Gene', (169, 173))	('IGFR', 'Gene', (154, 158))	('MET', 'Gene', (160, 163))	('FGFR', 'Gene', '2260', (169, 173))
111916	26251629	It has been shown that vemurafenib that targets BRAF(V600E) mutation is effective in treating melanoma but has limited success in treating colon cancer despite the same BRAF(V600E) mutation.	('vemurafenib', 'Chemical', 'MESH:D000077484', (23, 34))	('V600E', 'Var', (174, 179))	('V600E', 'SUBSTITUTION', 'None', (174, 179))	('colon cancer', 'Disease', 'MESH:D015179', (139, 151))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('colon cancer', 'Disease', (139, 151))	('melanoma', 'Disease', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('V600E', 'Var', (53, 58))	('V600E', 'SUBSTITUTION', 'None', (53, 58))	('colon cancer', 'Phenotype', 'HP:0003003', (139, 151))
111917	26251629	Subsequently, it was shown that vemurafenib-resistant colon cancer cells reactivate EGFR, an upstream activator of b-Raf, via amplification or overexpression, shortly after vemurafenib treatment.	('b-Raf', 'Gene', '673', (115, 120))	('reactivate', 'Reg', (73, 83))	('colon cancer', 'Disease', 'MESH:D015179', (54, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (54, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('colon cancer', 'Disease', (54, 66))	('b-Raf', 'Gene', (115, 120))	('overexpression', 'PosReg', (143, 157))	('EGFR', 'Gene', '1956', (84, 88))	('amplification', 'Var', (126, 139))	('vemurafenib', 'Chemical', 'MESH:D000077484', (173, 184))	('vemurafenib', 'Chemical', 'MESH:D000077484', (32, 43))	('EGFR', 'Gene', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
111921	26251629	It is not clear whether the time to resistance depends on therapeutics (eg, small-molecule kinase inhibitors vs hormone mimetics) or cancer cell types (NSCLC vs breast cancer) or both.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('breast cancer', 'Disease', (161, 174))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('NSCLC', 'Disease', (152, 157))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (133, 139))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('cancer', 'Disease', (168, 174))	('small-molecule', 'Var', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
111924	26251629	It is remarkable that the specific mutations in the kinase domain of Abl that confer imatinib resistance arise through seemingly a nonspecific tumor progression stage called blasting crisis without the drug selection.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('Abl', 'Gene', '25', (69, 72))	('imatinib resistance', 'MPA', (85, 104))	('Abl', 'Gene', (69, 72))	('mutations in', 'Var', (35, 47))	('imatinib', 'Chemical', 'MESH:D000068877', (85, 93))
111925	26251629	Consistent with this observation in CML, tumor cells with EGFR (T790M) mutation or MET-amplification that confers resistance to Egfr-targeted therapies were found in NSCLC patients prior to targeted therapies.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('Egfr', 'Gene', (128, 132))	('resistance', 'MPA', (114, 124))	('EGFR', 'Gene', '1956', (58, 62))	('Egfr', 'molecular_function', 'GO:0005006', ('128', '132'))	('MET-amplification', 'Var', (83, 100))	('tumor', 'Disease', (41, 46))	('CML', 'Disease', (36, 39))	('EGFR', 'Gene', (58, 62))	('NSCLC', 'Disease', (166, 171))	('T790M', 'Mutation', 'rs121434569', (64, 69))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('Egfr', 'Gene', '1956', (128, 132))	('CML', 'Disease', 'MESH:D015464', (36, 39))	('patients', 'Species', '9606', (172, 180))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('T790M) mutation', 'Var', (64, 79))
111926	26251629	These findings show that mutations that confer targeted therapy resistance can be acquired during tumor progression without the targeted therapy selection.	('tumor', 'Disease', (98, 103))	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))
111928	26251629	Detection of preexisting therapy-resistant mutations in sub-population within the primary tumor will enable the treatment of patients with multiple targeting agents at the time of initial targeted therapy.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('mutations', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('patients', 'Species', '9606', (125, 133))
111938	26251629	In this postulate, one could compare genetic alterations in metastatic lesions to its primary tumor origin and identify gene mutations uniquely present in metastatic lesions as metastasis-driving gene mutations.	('mutations', 'Var', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', (94, 99))
111940	26251629	These studies corroborated the postulate that metastases arise from primary tumors by acquiring additional mutations.	('primary tumors', 'Disease', (68, 82))	('mutations', 'Var', (107, 116))	('primary tumors', 'Disease', 'MESH:D009369', (68, 82))	('metastases', 'Disease', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('metastases', 'Disease', 'MESH:D009362', (46, 56))
111946	26251629	Consistent with this idea, recent genomic sequencing studies revealed that the same cancer driver mutations found in primary tumors such as KRAS, TP53, and ERBB2/HER2 are highly enriched in metastatic lesions of pancreatic cancer, renal carcinoma, and breast cancer, respectively.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('ERBB2', 'Gene', '2064', (156, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (212, 229))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('KRAS', 'Gene', '3845', (140, 144))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (223, 229))	('KRAS', 'Gene', (140, 144))	('pancreatic cancer', 'Disease', (212, 229))	('HER2', 'Gene', (162, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('TP53', 'Gene', (146, 150))	('metastatic lesions', 'CPA', (190, 208))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('cancer', 'Disease', (259, 265))	('breast cancer', 'Disease', (252, 265))	('primary tumors', 'Disease', (117, 131))	('cancer', 'Disease', (84, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (212, 229))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('renal carcinoma', 'Disease', 'MESH:C538614', (231, 246))	('HER2', 'Gene', '2064', (162, 166))	('renal carcinoma', 'Disease', (231, 246))	('TP53', 'Gene', '7157', (146, 150))	('ERBB2', 'Gene', (156, 161))	('renal carcinoma', 'Phenotype', 'HP:0005584', (231, 246))	('primary tumors', 'Disease', 'MESH:D009369', (117, 131))	('mutations', 'Var', (98, 107))
111947	26251629	These findings suggest that metastasis is driven by the same genetic alterations that drive tumorigenesis, likely by providing the same advantages in cell survival and proliferation through arduous metastatic processes of invasion, intravasation, extravasation, and colonization.	('cell survival', 'CPA', (150, 163))	('proliferation', 'CPA', (168, 181))	('alterations', 'Var', (69, 80))	('extravasation', 'CPA', (247, 260))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('metastatic', 'CPA', (198, 208))	('genetic alterations', 'Var', (61, 80))	('advantages', 'PosReg', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('metastasis', 'CPA', (28, 38))	('driven', 'Reg', (42, 48))
111957	26251629	Alternatively and/or additionally, metastatic progression including the colonization step may be largely driven by epigenetic changes in tumor cells, extrinsic local factors, and/or systemic state of each patient.	('driven by', 'Reg', (105, 114))	('tumor', 'Disease', (137, 142))	('metastatic progression', 'CPA', (35, 57))	('colonization step', 'CPA', (72, 89))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('patient', 'Species', '9606', (205, 212))	('epigenetic changes', 'Var', (115, 133))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
111960	26251629	The presence of CTCs in patients with metastatic breast cancer has been correlated with reduced progression-free survival and overall survival.	('overall survival', 'CPA', (126, 142))	('progression-free survival', 'CPA', (96, 121))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('patients', 'Species', '9606', (24, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('presence', 'Var', (4, 12))	('reduced', 'NegReg', (88, 95))
111961	26251629	Even in early breast cancer patients, CTCs have been detected in 24% of patients and were predictive of early recurrence and decreased overall survival.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('decreased', 'NegReg', (125, 134))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('CTCs', 'Var', (38, 42))	('overall', 'MPA', (135, 142))	('breast cancer', 'Disease', (14, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('patients', 'Species', '9606', (28, 36))	('patients', 'Species', '9606', (72, 80))
111971	26251629	It is possible that the very initial genetic alterations in tumorigenesis, presumably the ones that provide proliferation advantage, may also enable cell dissemination.	('enable', 'Reg', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('proliferation', 'CPA', (108, 121))	('genetic alterations', 'Var', (37, 56))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('cell dissemination', 'CPA', (149, 167))
111975	26251629	These findings suggest additional events such as mutations in "colonization genes" and/or factors in order for CTCs to become bona fide metastases.	('metastases', 'Disease', 'MESH:D009362', (136, 146))	('metastases', 'Disease', (136, 146))	('mutations', 'Var', (49, 58))
111978	26251629	Evidently, tumorigenesis is driven by mutations in two to eight of these cancer-driving genes.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('driven by', 'Reg', (28, 37))	('tumor', 'Disease', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
111979	26251629	These findings support the multistep tumorigenesis paradigm but also present an incredulous number of possible combinations of mutations that could give rise to cancer.	('give rise', 'Reg', (148, 157))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('mutations', 'Var', (127, 136))
111981	26251629	Furthermore, as we strive to target oncogene mutations via therapy development, we urgently need to think of innovative ways to treat cancers driven by the loss of tumor suppressor(s).	('tumor', 'Disease', (164, 169))	('mutations', 'Var', (45, 54))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('tumor suppressor', 'biological_process', 'GO:0051726', ('164', '180'))	('loss', 'NegReg', (156, 160))	('cancers', 'Disease', (134, 141))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('164', '180'))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
111983	26251629	Considering the "mutual exclusivity" between TP53 and PIK3CA gene mutations, we propose a TP53/PIK3CA common genetic pathway model as one of the critical decision points of cell death/survival in tumorigenesis.	('mutations', 'Var', (66, 75))	('PIK3CA', 'Gene', (95, 101))	('TP53', 'Gene', (45, 49))	('tumor', 'Disease', (196, 201))	('PIK3CA', 'Gene', '5290', (95, 101))	('PIK3CA', 'Gene', '5290', (54, 60))	('TP53', 'Gene', '7157', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('TP53', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('TP53', 'Gene', '7157', (45, 49))	('PIK3CA', 'Gene', (54, 60))
111987	26251629	As mutations in these genes are likely to affect global scale gene transcription, it will require innovative approaches to delineate the mechanisms of these gene mutations in tumorigenesis and even more ingenuity to develop targeted therapy for cancers driven by such gene mutations.	('affect', 'Reg', (42, 48))	('mutations', 'Var', (162, 171))	('global scale gene transcription', 'MPA', (49, 80))	('tumor', 'Disease', (175, 180))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('cancers', 'Disease', (245, 252))	('transcription', 'biological_process', 'GO:0006351', ('67', '80'))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('mutations', 'Var', (3, 12))
111990	26251629	Technological development to assess intra-tumor heterogeneity and evaluate relevant mutations in subpopulation of tumor cells, preferably in early stages of cancer, will enable us to better strategize to manage therapy resistance.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', (42, 47))	('intra-tumor', 'Disease', 'MESH:D009369', (36, 47))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', (114, 119))	('intra-tumor', 'Disease', (36, 47))	('cancer', 'Disease', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
112053	32509573	The results showed that a high pretreatment serum LDH was associated with an inferior overall survival (OS, HR 1.61, 95% CI 1.39-1.87, p < 0.001), cancer-specific survival (CSS, HR 1.41, 95% CI 1.05-1.90, p = 0.022), and disease-free survival (DFS, HR 1.64, 95% CI 1.04-2.59, p = 0.034) in UC.	('serum LDH', 'Protein', (44, 53))	('LDH', 'Protein', (50, 53))	('overall survival', 'CPA', (86, 102))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('high', 'Var', (26, 30))	('inferior', 'NegReg', (77, 85))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('disease-free survival', 'CPA', (221, 242))	('cancer', 'Disease', (147, 153))
112077	32509573	After merging HRs and 95% CIs, we identified that a high pretreatment serum LDH was associated with an inferior overall survival (HR 1.61, 95% CI 1.39-1.87, p < 0.001), cancer-specific survival (HR 1.41, 95% CI 1.05-1.90, p = 0.022), and disease-free survival (HR 1.64, 95% CI 1.04-2.59, p = 0.034) in patients with urothelial carcinoma (Figure 2).	('carcinoma', 'Phenotype', 'HP:0030731', (327, 336))	('cancer', 'Disease', (169, 175))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (316, 336))	('serum LDH', 'Protein', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('overall survival', 'CPA', (112, 128))	('high', 'Var', (52, 56))	('LDH', 'Protein', (76, 79))	('urothelial carcinoma', 'Disease', (316, 336))	('inferior', 'NegReg', (103, 111))	('disease-free survival', 'CPA', (238, 259))	('patients', 'Species', '9606', (302, 310))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
112104	32244410	Role of PA2G4P4 pseudogene in bladder cancer tumorigenesis Background: Many pseudogenes possess biological activities and play important roles in the pathogenesis of various types of cancer including bladder cancer (BlCa), which still lacks suitable molecular biomarkers.	('bladder cancer', 'Disease', 'MESH:D001749', (200, 214))	('bladder cancer', 'Disease', (200, 214))	('cancer', 'Disease', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('bladder cancer', 'Phenotype', 'HP:0009725', (200, 214))	('PA2G4P4', 'Gene', '647033', (8, 15))	('BlCa', 'Phenotype', 'HP:0009725', (216, 220))	('si', 'Chemical', 'MESH:D012825', (159, 161))	('cancer', 'Disease', (183, 189))	('pseudogenes', 'Var', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('roles', 'Reg', (137, 142))	('cancer', 'Disease', (38, 44))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (30, 44))	('bladder cancer', 'Disease', (30, 44))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('PA2G4P4', 'Gene', (8, 15))	('pathogenesis', 'biological_process', 'GO:0009405', ('150', '162'))	('cancer', 'Disease', 'MESH:D009369', (38, 44))
112105	32244410	Recently, pseudogenes were found to be significantly enriched in a pan-cancer classification based on the Cancer Genome Atlas gene expression data.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('cancer', 'Disease', (71, 77))	('Cancer', 'Disease', (106, 112))	('pseudogenes', 'Var', (10, 21))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('Cancer', 'Disease', 'MESH:D009369', (106, 112))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('gene expression', 'biological_process', 'GO:0010467', ('126', '141'))	('si', 'Chemical', 'MESH:D012825', (137, 139))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
112113	32244410	Moreover, we showed that PA2G4P4 knockdown affects both proliferation and migration of BlCa cells, highlighting its potential oncogenic role.	('PA2G4P4', 'Gene', (25, 32))	('BlCa', 'Phenotype', 'HP:0009725', (87, 91))	('migration of BlCa cells', 'CPA', (74, 97))	('knockdown', 'Var', (33, 42))	('PA2G4P4', 'Gene', '647033', (25, 32))	('affects', 'Reg', (43, 50))	('proliferation', 'CPA', (56, 69))
112116	32244410	Over the last decades, data from large transcriptomic studies have shown that most pseudogenes are not simply "genomic relicts", but are transcriptionally active and involved in important regulatory mechanisms.	('involved', 'Reg', (166, 174))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('pseudogenes', 'Var', (83, 94))
112120	32244410	Human genome encodes thousands of pseudogenes, many of which are differentially expressed in human cancers and in their normal tissue.	('pseudogenes', 'Var', (34, 45))	('Human', 'Species', '9606', (0, 5))	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
112167	32244410	RNA interference-mediated gene silencing.	('RNA interference', 'biological_process', 'GO:0016246', ('0', '16'))	('gene silencing', 'biological_process', 'GO:0016458', ('26', '40'))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('RNA', 'MPA', (0, 3))	('gene', 'Var', (26, 30))
112176	32244410	ABE043 Merck Millipore, Italy) used to detect the p48 isoform of the EBP1 protein, and anti-GAPDH mouse monoclonal antibody (G8795 Sigma-Aldrich, actually Merck) used for normalization.	('antibody', 'cellular_component', 'GO:0042571', ('115', '123'))	('p48', 'Var', (50, 53))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('antibody', 'cellular_component', 'GO:0019815', ('115', '123'))	('antibody', 'cellular_component', 'GO:0019814', ('115', '123'))	('EBP1', 'Gene', (69, 73))	('mouse', 'Species', '10090', (98, 103))	('antibody', 'molecular_function', 'GO:0003823', ('115', '123'))
112221	32244410	Furthermore, the pseudogene depletion did not affect the expression of the p48 isoform of the EBP1 protein (Supplementary Figure S3B).	('expression', 'MPA', (57, 67))	('pseudogene', 'Var', (17, 27))	('men', 'Species', '9606', (114, 117))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('EBP1', 'Gene', (94, 98))
112223	32244410	Cells were counted every 24 h, and as shown in Figure 4A, PA2G4P4 silencing led to the decreased proliferation of BlCa cells, as compared to the control.	('PA2G4P4', 'Gene', (58, 65))	('PA2G4P4', 'Gene', '647033', (58, 65))	('silencing', 'Var', (66, 75))	('decreased', 'NegReg', (87, 96))	('proliferation', 'CPA', (97, 110))	('BlCa', 'Phenotype', 'HP:0009725', (114, 118))	('si', 'Chemical', 'MESH:D012825', (66, 68))
112226	32244410	These data clearly indicated that following PA2G4P4 knockdown, J82 cells were retained in the G1 phase.	('G1 phase', 'biological_process', 'GO:0051318', ('94', '102'))	('J82', 'CellLine', 'CVCL:0359', (63, 66))	('PA2G4P4', 'Gene', (44, 51))	('knockdown', 'Var', (52, 61))	('PA2G4P4', 'Gene', '647033', (44, 51))
112229	32244410	It was observed that, 72 h following silencing, the percentage of PI+ cells increased from 4% in the control cell cohort to 23% in the cancer one (P < 0.001; Figure 4C).	('cancer', 'Disease', (135, 141))	('increased', 'PosReg', (76, 85))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('silencing', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('PI+ cells', 'CPA', (66, 75))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
112232	32244410	Imaging of cell migration revealed that pseudogene depletion decreased the motility of J82 cells in vitro by ~60% when compared with si-ctrl transfected cells (p < 0.001).	('pseudogene', 'Protein', (40, 50))	('cell migration', 'biological_process', 'GO:0016477', ('11', '25'))	('si', 'Chemical', 'MESH:D012825', (133, 135))	('J82', 'CellLine', 'CVCL:0359', (87, 90))	('decreased', 'NegReg', (61, 70))	('depletion', 'Var', (51, 60))	('motility', 'CPA', (75, 83))
112235	32244410	A growing body of evidence has suggested that individual pseudogenes are functionally involved in tumorigenesis and that can characterize tumor heterogeneity.	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('involved', 'Reg', (86, 94))	('pseudogenes', 'Var', (57, 68))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('si', 'Chemical', 'MESH:D012825', (108, 110))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
112250	32244410	Two isoforms of EBP1, p48 and p42, have been characterized so far, with opposite roles in tumorigenesis.	('si', 'Chemical', 'MESH:D012825', (76, 78))	('p42', 'Gene', (30, 33))	('EBP1', 'Gene', (16, 20))	('tumor', 'Disease', (90, 95))	('p48', 'Var', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('p42', 'Gene', '2038', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('si', 'Chemical', 'MESH:D012825', (100, 102))
112253	32244410	It was found that both were localized in the urothelium of bladder tumors and adjacent non-tumoral bladder tissues, but not in the endothelium of vessels, where only the protein was detected; this suggests a specific pseudogene expression in urothelial cells.	('tumoral bladder', 'Disease', (91, 106))	('bladder tumors', 'Disease', (59, 73))	('pseudogene', 'Var', (217, 227))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('tumoral bladder', 'Disease', 'MESH:D001749', (91, 106))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('bladder tumors', 'Disease', 'MESH:D001749', (59, 73))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('si', 'Chemical', 'MESH:D012825', (234, 236))	('tumoral bladder', 'Phenotype', 'HP:0009725', (91, 106))	('bladder tumors', 'Phenotype', 'HP:0009725', (59, 73))	('bladder tumor', 'Phenotype', 'HP:0009725', (59, 72))
112261	32244410	We also found an increase of apoptosis and a strong impairment of cell motility in J82 silenced cells, as compared to the control.	('apoptosis', 'CPA', (29, 38))	('si', 'Chemical', 'MESH:D012825', (87, 89))	('J82', 'Gene', (83, 86))	('impairment', 'NegReg', (52, 62))	('silenced', 'Var', (87, 95))	('si', 'Chemical', 'MESH:D012825', (35, 37))	('cell motility', 'CPA', (66, 79))	('J82', 'CellLine', 'CVCL:0359', (83, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('cell motility', 'biological_process', 'GO:0048870', ('66', '79'))	('increase', 'PosReg', (17, 25))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))	('men', 'Species', '9606', (58, 61))
112263	32244410	Increasing evidence from large transcriptomic studies have shown that most pseudogenes are transcriptionally active and involved in important regulatory mechanisms in cancer development and progression.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('involved', 'Reg', (120, 128))	('si', 'Chemical', 'MESH:D012825', (197, 199))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('pseudogenes', 'Var', (75, 86))	('si', 'Chemical', 'MESH:D012825', (6, 8))	('men', 'Species', '9606', (181, 184))
112273	32244410	(A) Analysis of PA2G4P4 mRNA depletion 48 and 72 h after J82 transfection with specific si-P4 (**p < 0.005).	('J82', 'CellLine', 'CVCL:0359', (57, 60))	('PA2G4P4', 'Gene', (16, 23))	('si-P4', 'Var', (88, 93))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('PA2G4P4', 'Gene', '647033', (16, 23))	('si-P4', 'Chemical', '-', (88, 93))
112316	28828122	Trihalomethanes formed as byproducts when chlorine or bromine is used to disinfect water for drinking, arsenic in drinking water, and consumption of Chinese herbs containing aristolochic acid have been associated with increased incidences of UBC.	('UBC', 'Disease', (242, 245))	('aristolochic acid', 'Chemical', 'MESH:C000228', (174, 191))	('aristolochic acid', 'Var', (174, 191))	('chlorine', 'Chemical', 'MESH:D002713', (42, 50))	('arsenic', 'Chemical', 'MESH:D001151', (103, 110))	('water', 'Chemical', 'MESH:D014867', (123, 128))	('water', 'Chemical', 'MESH:D014867', (83, 88))	('Trihalomethanes', 'Chemical', 'MESH:D022882', (0, 15))	('bromine', 'Chemical', 'MESH:D001966', (54, 61))
112393	27766936	Specifically, all the genes in the table were queried to get annotations of pathways using KEGG Mapper - Search Pathway, of gene ontology using Ensembl BioMart, of cancer-related diseases using Catalogue of Somatic Mutations In Cancer (COSMIC), and of human-related diseases using Online Mendelian Inheritance In Man (OMIM).	('Cancer', 'Disease', 'MESH:D009369', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('gene ontology', 'biological_process', 'GO:0003673', ('124', '137'))	('Mutations', 'Var', (215, 224))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('Man', 'Species', '9606', (313, 316))	('Cancer', 'Phenotype', 'HP:0002664', (228, 234))	('Cancer', 'Disease', (228, 234))	('human', 'Species', '9606', (252, 257))
112460	27766936	It is interesting that the HNSC_shared_GO_in_NH_TL and KICH_shared_GO_in_NH_TL have many common GO terms like mitotic sister chromatid segregation, G1/S transition of mitotic cell cycle, regulation of transcription involved in G1/S transition of mitotic cell cycle, and others.	('chromatid', 'cellular_component', 'GO:0005695', ('125', '134'))	('chromatid', 'cellular_component', 'GO:0005694', ('125', '134'))	('mitotic sister chromatid segregation', 'CPA', (110, 146))	('mitotic cell cycle, regulation', 'biological_process', 'GO:0007346', ('167', '197'))	('regulation of transcription involved in G1/S transition of mitotic cell cycle', 'biological_process', 'GO:0000083', ('187', '264'))	('G1/S transition of mitotic cell cycle', 'biological_process', 'GO:0000082', ('148', '185'))	('mitotic sister chromatid segregation', 'biological_process', 'GO:0000070', ('110', '146'))	('KICH_shared_GO_in_NH_TL', 'Var', (55, 78))	('KICH', 'Chemical', '-', (55, 59))
112461	27766936	HNSC_shared_GO_in_NL_TH and KICH_shared_GO_in_NL_TH have the exact two common GO terms, histone deacetylase complex and positive regulation of transporter activity.	('positive regulation', 'MPA', (120, 139))	('histone deacetylase complex', 'cellular_component', 'GO:0000118', ('88', '115'))	('transporter activity', 'molecular_function', 'GO:0005215', ('143', '163'))	('KICH_shared_GO_in_NL_TH', 'Var', (28, 51))	('KICH', 'Chemical', '-', (28, 32))	('positive regulation of transporter activity', 'biological_process', 'GO:0032411', ('120', '163'))
112465	27766936	Our study assumed that the tumor is activated via mRNAs mutation directly targeted by miRNAs.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('mRNAs', 'Gene', (50, 55))	('mutation', 'Var', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
112477	25613404	Contralateral upper tract urothelial carcinoma after nephroureterectomy: the predictive role of DNA methylation Aberrant methylation of genes is one of the most common epigenetic modifications involved in the development of urothelial carcinoma.	('methylation', 'biological_process', 'GO:0032259', ('121', '132'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (224, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('Aberrant methylation', 'Var', (112, 132))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('Contralateral upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (0, 46))	('Contralateral upper tract urothelial carcinoma', 'Disease', (0, 46))	('urothelial carcinoma', 'Disease', (224, 244))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (26, 46))	('DNA methylation', 'biological_process', 'GO:0006306', ('96', '111'))
112484	25613404	High MI (P = 0.007) was significantly correlated with poor cancer-specific survival.	('High MI', 'Var', (0, 7))	('poor', 'NegReg', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
112485	25613404	Multivariate analysis indicated that unmethylated RASSF1A (P = 0.039), lack of bladder recurrence prior to contralateral UTUC (P = 0.009), history of renal transplantation (P < 0.001), and preoperative renal insufficiency (P = 0.002) are independent risk factors for contralateral UTUC recurrence after RNU.	('lack of bladder', 'Phenotype', 'HP:0010477', (71, 86))	('RNU', 'Chemical', '-', (303, 306))	('contralateral UTUC recurrence', 'Disease', (267, 296))	('RASSF1A', 'Gene', '11186', (50, 57))	('renal insufficiency', 'Disease', (202, 221))	('renal insufficiency', 'Disease', 'MESH:D051437', (202, 221))	('RASSF1A', 'Gene', (50, 57))	('unmethylated', 'Var', (37, 49))	('renal insufficiency', 'Phenotype', 'HP:0000083', (202, 221))
112486	25613404	Our data suggest a potential role of DNA methylation in predicting contralateral UTUC recurrence after RNU.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('RNU', 'Chemical', '-', (103, 106))	('contralateral UTUC recurrence', 'Disease', (67, 96))	('DNA methylation', 'biological_process', 'GO:0006306', ('37', '52'))	('methylation', 'Var', (41, 52))
112492	25613404	A growing body of evidence indicates that aberrant methylation of cytosine-guanine dinucleotide (CpG) islands in the DNA promoter regions is one of the most common epigenetic modifications involved in the development of urothelial carcinoma.	('cytosine-guanine dinucleotide', 'Chemical', 'MESH:C015772', (66, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('methylation', 'MPA', (51, 62))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (220, 240))	('involved', 'Reg', (189, 197))	('aberrant', 'Var', (42, 50))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('urothelial carcinoma', 'Disease', (220, 240))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))
112530	25613404	Hypermethylation was associated with advanced tumor grade for BRCA1 (P = 0.003), CDH1 (P = 0.002), HSPA2 (P = 0.009), RASSF1A (P = 0.017), and THBS1 (P = 0.000), while methylated GDF15 (P = 0.002) promoter was associated with low tumor grade.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('HSPA2', 'Gene', '3306', (99, 104))	('Hypermethylation', 'Var', (0, 16))	('GDF15', 'Gene', (179, 184))	('HSPA2', 'Gene', (99, 104))	('tumor', 'Disease', (230, 235))	('THBS1', 'Gene', (143, 148))	('associated', 'Reg', (21, 31))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('THBS1', 'Gene', '7057', (143, 148))	('low tumor', 'Disease', 'MESH:D009800', (226, 235))	('RASSF1A', 'Gene', '11186', (118, 125))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('CDH1', 'Gene', '999', (81, 85))	('BRCA1', 'Gene', '672', (62, 67))	('BRCA1', 'Gene', (62, 67))	('RASSF1A', 'Gene', (118, 125))	('GDF15', 'Gene', '9518', (179, 184))	('CDH1', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('low tumor', 'Disease', (226, 235))
112531	25613404	Hypermethylation was associated with advanced tumor stage for ABCC6 (P = 0.050), BRCA1 (P = 0.032), CDH1 (P = 0.004), GDF15 (P = 0.005), HSPA2 (P = 0.000), RASSF1A (P = 0.003), TSHB1 (P = 0.018), and TMEFF2 (P = 0.002).	('TMEFF2', 'Gene', '23671', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CDH1', 'Gene', '999', (100, 104))	('Hypermethylation', 'Var', (0, 16))	('RASSF1A', 'Gene', (156, 163))	('CDH1', 'Gene', (100, 104))	('GDF15', 'Gene', (118, 123))	('HSPA2', 'Gene', '3306', (137, 142))	('BRCA1', 'Gene', '672', (81, 86))	('ABCC6', 'Gene', (62, 67))	('TMEFF2', 'Gene', (200, 206))	('TSHB1', 'Gene', (177, 182))	('BRCA1', 'Gene', (81, 86))	('associated', 'Reg', (21, 31))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('HSPA2', 'Gene', (137, 142))	('GDF15', 'Gene', '9518', (118, 123))	('ABCC6', 'Gene', '368', (62, 67))	('RASSF1A', 'Gene', '11186', (156, 163))
112535	25613404	Patients in the high-MI group had a poor cancer-specific survival (CSS, P = 0.007, Figure 1) than patients in the low-MI group.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('poor', 'NegReg', (36, 40))	('high-MI', 'Var', (16, 23))	('CSS', 'Chemical', '-', (67, 70))	('patients', 'Species', '9606', (98, 106))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
112537	25613404	In multivariate analysis, unmethylated RASSF1A (P = 0.039, Figure 2A), renal transplant history (P < 0.001, Figure 2B), preoperative renal insufficiency (P = 0.002, Figure 2C), and lack of bladder recurrence before the development of contralateral UTUC (P = 0.007, Figure 2D) were found to be independent risk factors of contralateral UTUC recurrence after RNU.	('renal insufficiency', 'Disease', (133, 152))	('RASSF1A', 'Gene', '11186', (39, 46))	('renal insufficiency', 'Disease', 'MESH:D051437', (133, 152))	('contralateral UTUC', 'Disease', (321, 339))	('renal insufficiency', 'Phenotype', 'HP:0000083', (133, 152))	('lack of bladder', 'Phenotype', 'HP:0010477', (181, 196))	('RNU', 'Chemical', '-', (357, 360))	('RASSF1A', 'Gene', (39, 46))	('unmethylated', 'Var', (26, 38))
112544	25613404	To our knowledge, this is the first study to investigate the predictive role of aberrant methylation to predict contralateral UTUC after RNU.	('contralateral UTUC', 'Disease', (112, 130))	('RNU', 'Chemical', '-', (137, 140))	('methylation', 'biological_process', 'GO:0032259', ('89', '100'))	('aberrant methylation', 'Var', (80, 100))
112545	25613404	Unmethylated RASSF1A, no bladder recurrence before the development of contralateral UTUC, renal transplant history, and preoperative renal insufficiency were independent risk factors for contralateral UTUC recurrence after RNU.	('RASSF1A', 'Gene', (13, 20))	('renal insufficiency', 'Disease', (133, 152))	('RNU', 'Chemical', '-', (223, 226))	('renal insufficiency', 'Disease', 'MESH:D051437', (133, 152))	('Unmethylated', 'Var', (0, 12))	('RASSF1A', 'Gene', '11186', (13, 20))	('renal insufficiency', 'Phenotype', 'HP:0000083', (133, 152))	('contralateral UTUC recurrence', 'Disease', (187, 216))
112551	25613404	Second, Chinese herbs containing aristolochic acid are used nationwide, which could bring nephrotoxic and carcinogenic toxins to induce neoplasms of the entire urothelial field.	('neoplasms', 'Disease', (136, 145))	('nephrotoxic and carcinogenic', 'Disease', 'MESH:D007674', (90, 118))	('induce', 'PosReg', (129, 135))	('neoplasms', 'Phenotype', 'HP:0002664', (136, 145))	('aristolochic acid', 'Var', (33, 50))	('aristolochic acid', 'Chemical', 'MESH:C000228', (33, 50))	('neoplasms', 'Disease', 'MESH:D009369', (136, 145))
112554	25613404	Consistent with our results, hypermethylation of RASSF1A is generally considered to correlate with poor prognostic parameters, such as advanced tumor grade or stage, muscle invasion, and disease progression in transitional cell carcinoma.	('muscle invasion', 'CPA', (166, 181))	('tumor', 'Disease', (144, 149))	('RASSF1A', 'Gene', (49, 56))	('carcinoma', 'Disease', 'MESH:D002277', (228, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('disease progression', 'CPA', (187, 206))	('hypermethylation', 'Var', (29, 45))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('RASSF1A', 'Gene', '11186', (49, 56))	('carcinoma', 'Disease', (228, 237))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (210, 237))
112555	25613404	However, we also found that unmethylated RASSF1A was an independent risk factor of contralateral UTUC recurrence.	('unmethylated', 'Var', (28, 40))	('RASSF1A', 'Gene', '11186', (41, 48))	('contralateral UTUC recurrence', 'Disease', (83, 112))	('RASSF1A', 'Gene', (41, 48))
112558	25613404	First, as hypermethylation of RASSF1A was correlated with poor prognostic parameters, patients with RASSF1A hypermethylation may die from tumor dissemination before developing contralateral UTUC recurrence.	('RASSF1A', 'Gene', '11186', (30, 37))	('tumor', 'Disease', (138, 143))	('hypermethylation', 'Var', (108, 124))	('RASSF1A', 'Gene', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('RASSF1A', 'Gene', '11186', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('RASSF1A', 'Gene', (30, 37))	('patients', 'Species', '9606', (86, 94))
112559	25613404	Second, aristolochic acid was proven to be associated with UTUC.	('aristolochic acid', 'Chemical', 'MESH:C000228', (8, 25))	('aristolochic acid', 'Var', (8, 25))	('UTUC', 'Disease', (59, 63))	('associated', 'Reg', (43, 53))
112561	25613404	Combining these results, we believe aristolochic acid-related UTUCs have the trend of developing the contralateral UTUC recurrence in this cohort.	('aristolochic acid', 'Chemical', 'MESH:C000228', (36, 53))	('developing', 'PosReg', (86, 96))	('aristolochic acid-related', 'Var', (36, 61))
112563	25613404	This result suggests that the aristolochic acid-related UTUCs may have lower malignancy potential.	('aristolochic acid', 'Chemical', 'MESH:C000228', (30, 47))	('malignancy', 'Disease', (77, 87))	('malignancy', 'Disease', 'MESH:D009369', (77, 87))	('aristolochic acid-related', 'Var', (30, 55))	('lower', 'NegReg', (71, 76))
112564	25613404	Our results revealed unmethylated RASSF1A was more prevalent in UTUCs with lower malignancy potential.	('prevalent', 'Reg', (51, 60))	('RASSF1A', 'Gene', (34, 41))	('RASSF1A', 'Gene', '11186', (34, 41))	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('malignancy', 'Disease', (81, 91))	('unmethylated', 'Var', (21, 33))
112565	25613404	Unmethylated RASSF1A may correlated with aristolochic acid-related UTUCs.	('RASSF1A', 'Gene', (13, 20))	('aristolochic acid-related UTUCs', 'Disease', (41, 72))	('aristolochic acid', 'Chemical', 'MESH:C000228', (41, 58))	('Unmethylated', 'Var', (0, 12))	('RASSF1A', 'Gene', '11186', (13, 20))	('correlated', 'Reg', (25, 35))
112566	25613404	Hence, unmethylated RASSF1A seemed to correlate with the development of contralateral UTUC recurrence.	('correlate with', 'Reg', (38, 52))	('unmethylated', 'Var', (7, 19))	('RASSF1A', 'Gene', (20, 27))	('RASSF1A', 'Gene', '11186', (20, 27))	('contralateral UTUC recurrence', 'Disease', (72, 101))
112567	25613404	The role of RASSF1A methylation in the recurrence of urothelial cancer, and the relationship between RASSF1A and aristolochic acid related urothelial cancer require further research.	('RASSF1A', 'Gene', '11186', (12, 19))	('RASSF1A', 'Gene', '11186', (101, 108))	('urothelial cancer', 'Disease', 'MESH:D014523', (139, 156))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('urothelial cancer', 'Disease', 'MESH:D014523', (53, 70))	('RASSF1A', 'Gene', (101, 108))	('RASSF1A', 'Gene', (12, 19))	('methylation', 'Var', (20, 31))	('aristolochic acid', 'Chemical', 'MESH:C000228', (113, 130))	('recurrence of urothelial cancer', 'Phenotype', 'HP:0000010', (39, 70))	('urothelial cancer', 'Disease', (139, 156))	('urothelial cancer', 'Disease', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
112572	25613404	In addition, aristolochic acid-related UTUCs may have lower MI due to the characteristics of lower malignancy potential, which could be another potential reason for contralateral UTUC recurrence with lower MI as aristolochic acid was extremely likely involved in the development of contralateral UTUC in this cohort.	('malignancy', 'Disease', (99, 109))	('aristolochic acid', 'Chemical', 'MESH:C000228', (212, 229))	('aristolochic acid', 'Chemical', 'MESH:C000228', (13, 30))	('aristolochic', 'Var', (13, 25))	('malignancy', 'Disease', 'MESH:D009369', (99, 109))	('lower', 'NegReg', (54, 59))
112586	25613404	Unmethylated RASSF1A, no bladder recurrence prior to contralateral UTUC, history of renal transplantation, and preoperative renal insufficiency are independent risk factors of contralateral UTUC recurrence after RNU.	('RASSF1A', 'Gene', (13, 20))	('renal insufficiency', 'Disease', 'MESH:D051437', (124, 143))	('Unmethylated', 'Var', (0, 12))	('RASSF1A', 'Gene', '11186', (13, 20))	('renal insufficiency', 'Disease', (124, 143))	('RNU', 'Chemical', '-', (212, 215))	('contralateral UTUC recurrence', 'Disease', (176, 205))	('renal insufficiency', 'Phenotype', 'HP:0000083', (124, 143))
112607	33123462	However, some patients with T1 high-grade bladder cancer have a low risk of metastasis and progression, and conservative treatment can be tried.	('men', 'Species', '9606', (126, 129))	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('T1 high-grade', 'Var', (28, 41))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('bladder cancer', 'Disease', 'MESH:D001749', (42, 56))	('bladder cancer', 'Disease', (42, 56))	('patients', 'Species', '9606', (14, 22))
112705	32329250	Elevations in carcinoembryonic antigen (CEA), CA19-9, CA125, CA724, CyFra21-1, and neuron-specific enolase (NSE) were observed in some patients (21%, 8.1%, 1.6%, 19.4%, 14.5%, and 4.8%, respectively).	('patients', 'Species', '9606', (135, 143))	('CA125', 'Gene', '94025', (54, 59))	('CEA', 'Gene', '1084', (40, 43))	('CA19-9', 'Var', (46, 52))	('Elevations', 'PosReg', (0, 10))	('CyFra21-1', 'Var', (68, 77))	('NSE', 'Gene', '2026', (108, 111))	('Elevations in carcinoembryonic antigen', 'Phenotype', 'HP:0031029', (0, 38))	('CA724', 'Chemical', '-', (61, 66))	('CA125', 'Gene', (54, 59))	('NSE', 'Gene', (108, 111))	('neuron-specific enolase', 'Gene', (83, 106))	('CEA', 'Gene', (40, 43))	('carcinoembryonic antigen', 'Gene', '1084', (14, 38))	('CA19-9', 'Chemical', 'MESH:C086528', (46, 52))	('CA724', 'Var', (61, 66))	('carcinoembryonic antigen', 'Gene', (14, 38))	('neuron-specific enolase', 'Gene', '2026', (83, 106))
112720	32329250	Elevations in some tumor markers, such as CEA, CA19-9, and CA125, were observed in some patients in this study (12 of 32 patients, five of 37, and one of 15, respectively).	('Elevations', 'PosReg', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('CA19-9', 'Var', (47, 53))	('patients', 'Species', '9606', (88, 96))	('CA125', 'Gene', '94025', (59, 64))	('CEA', 'Gene', '1084', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('CA19-9', 'Chemical', 'MESH:C086528', (47, 53))	('CA125', 'Gene', (59, 64))	('CEA', 'Gene', (42, 45))	('patients', 'Species', '9606', (121, 129))
112750	32391279	RNA sequencing data were analyzed from 8 papillary high-grade NMIUTUC specimens consisting of 4 CK14-positive and 4 CK14-negative tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('CK14-positive', 'Var', (96, 109))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
112751	32391279	Results: CK14 positivity was associated with a high TNM stage (p < 0.001) and a high World Health Organization grade (p = 0.003).	('positivity', 'Var', (14, 24))	('TNM', 'Gene', (52, 55))	('CK14', 'Gene', (9, 13))	('TNM', 'Gene', '10178', (52, 55))
112752	32391279	Survival analysis showed that CK14 positivity was significantly associated with poor progression-free survival (p = 0.015; hazard ratio [HR] = 2.990; 95% confidence interval [CI] = 1.180-7.580) and was marginally associated with poor cancer-specific survival (p = 0.052; HR = 3.77; 95% CI = 0.900-15.780).	('CK14', 'Protein', (30, 34))	('progression-free survival', 'CPA', (85, 110))	('poor', 'NegReg', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('poor', 'NegReg', (229, 233))	('positivity', 'Var', (35, 45))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('rat', 'Species', '10116', (130, 133))	('cancer', 'Disease', (234, 240))
112753	32391279	Gene set enrichment analysis demonstrated that the CK14-positive tumors were associated with a basal subtype of breast cancer, squamous cell carcinoma development, p40, tumor necrosis factor alpha-nuclear factor-kappaB, and p53 pathways, and embryonic stem cells; these characteristics are reminiscent of the BASQ subtype.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('p53', 'Gene', '7157', (224, 227))	('breast cancer', 'Disease', (112, 125))	('tumors', 'Disease', (65, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('169', '190'))	('embryonic', 'CPA', (242, 251))	('p53', 'Gene', (224, 227))	('nuclear factor-kappaB', 'Gene', '4790', (197, 218))	('p40', 'Gene', '3578', (164, 167))	('p40', 'cellular_component', 'GO:0070743', ('164', '167'))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('necrosis', 'biological_process', 'GO:0008219', ('175', '183'))	('nuclear factor-kappaB', 'Gene', (197, 218))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 150))	('associated', 'Reg', (77, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('p40', 'Gene', (164, 167))	('p40', 'cellular_component', 'GO:0043514', ('164', '167'))	('tumor necrosis', 'Disease', 'MESH:D009336', (169, 183))	('rat', 'Species', '10116', (36, 39))	('necrosis', 'biological_process', 'GO:0008220', ('175', '183'))	('CK14-positive', 'Var', (51, 64))	('squamous cell carcinoma', 'Disease', (127, 150))	('tumor necrosis', 'Disease', (169, 183))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('necrosis', 'biological_process', 'GO:0070265', ('175', '183'))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('necrosis', 'biological_process', 'GO:0019835', ('175', '183'))	('necrosis', 'biological_process', 'GO:0001906', ('175', '183'))
112754	32391279	In addition, with a p < 0.05 and  fold change  >=2 as the cutoffs, we identified 178 differentially expressed genes when comparing CK14-positive and CK14-negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('CK14-positive', 'Var', (131, 144))
112756	32391279	Consistent with these results, we demonstrated that the mean Ki-67 proliferative index was higher in CK14-positive tumors than it was in CK14-negative tumors (2.3 vs. 0.8%, respectively, p = 0.002).	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('higher', 'PosReg', (91, 97))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('rat', 'Species', '10116', (74, 77))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('proliferative index', 'MPA', (67, 86))	('rat', 'Species', '10116', (41, 44))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('CK14-positive', 'Var', (101, 114))	('Ki-67', 'Gene', (61, 66))
112757	32391279	Conclusion: CK14-positive papillary NMIUTUC is an aggressive subtype with BASQ-like molecular characteristics and dynamic proliferative activity.	('rat', 'Species', '10116', (129, 132))	('CK14-positive', 'Var', (12, 25))	('papillary NMIUTUC', 'Disease', (26, 43))
112766	32391279	In line with these results when studying the urinary bladder, we previously reported that papillary non-muscle-invasive upper tract urothelial carcinoma (NMIUTUC) with luminal-like, CK5/6-negative/CK20-positive, or CD44-negative/CK20-positive, immunophenotypes had distinctly poor prognoses that were probably associated with altered cell adhesion and late cell cycle/proliferation functions.	('luminal', 'Chemical', 'MESH:D010634', (168, 175))	('CD44', 'Gene', '960', (215, 219))	('CK5/6', 'Gene', (182, 187))	('cell cycle', 'biological_process', 'GO:0007049', ('357', '367'))	('luminal-like', 'Var', (168, 180))	('cell adhesion', 'biological_process', 'GO:0007155', ('334', '347'))	('CD44', 'Gene', (215, 219))	('CK20', 'Gene', '54474', (197, 201))	('CK20', 'Gene', (229, 233))	('CK20', 'Gene', '54474', (229, 233))	('CK20', 'Gene', (197, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('rat', 'Species', '10116', (375, 378))	('CK5/6', 'Gene', '3852', (182, 187))	('papillary non-muscle-invasive upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (90, 152))
112767	32391279	Despite these conflicting results observed regarding some of the subtype-defining markers in early urothelial carcinoma, high KRT14 levels were independently prognostic of poor survival both in NMIBC and in MIBC.	('NMIBC', 'Disease', (194, 199))	('MIBC', 'Phenotype', 'HP:0006740', (207, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('poor', 'NegReg', (172, 176))	('KRT14', 'Gene', '3861', (126, 131))	('urothelial carcinoma', 'Disease', (99, 119))	('MIBC', 'Chemical', '-', (195, 199))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (99, 119))	('MIBC', 'Phenotype', 'HP:0006740', (195, 199))	('KRT14', 'Gene', (126, 131))	('high', 'Var', (121, 125))	('MIBC', 'Chemical', '-', (207, 211))
112773	32391279	In addition, CK14 was associated with a poor prognosis of other malignancies, including breast cancer, squamous cell carcinoma, and salivary gland carcinoma, because it triggers proliferation, dedifferentiation, invasion, and metastasis of these cancers.	('dedifferentiation', 'CPA', (193, 210))	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('malignancies', 'Disease', (64, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('cancers', 'Disease', (246, 253))	('salivary gland carcinoma', 'Phenotype', 'HP:0100684', (132, 156))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('triggers', 'Reg', (169, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('CK14', 'Var', (13, 17))	('salivary gland carcinoma', 'Disease', (132, 156))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 126))	('dedifferentiation', 'biological_process', 'GO:0043696', ('193', '210'))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('salivary gland carcinoma', 'Disease', 'MESH:D012468', (132, 156))	('metastasis', 'CPA', (226, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('proliferation', 'CPA', (178, 191))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('squamous cell carcinoma', 'Disease', (103, 126))	('invasion', 'CPA', (212, 220))	('rat', 'Species', '10116', (185, 188))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))
112775	32391279	Furthermore, because of the rarity of upper tract urothelial carcinoma, which accounts for only 5-10% of the total urothelial carcinoma, CK14 expression and its clinicopathological and molecular significance in papillary NMIUTUC has not been studied.	('urothelial carcinoma', 'Disease', (115, 135))	('CK14', 'Var', (137, 141))	('upper tract urothelial carcinoma', 'Disease', (38, 70))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (50, 70))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (38, 70))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (115, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))
112796	32391279	CK14 positivity (IHC tumor cell score >0) and negativity (IHC tumor cell score = 0) were designated as above.	('IHC tumor', 'Disease', 'MESH:D009369', (58, 67))	('positivity', 'Var', (5, 15))	('IHC tumor', 'Disease', 'MESH:D009369', (17, 26))	('IHC tumor', 'Disease', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('IHC tumor', 'Disease', (17, 26))	('CK14 positivity', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
112805	32391279	CK14 positivity was associated with high (>=I) TNM stage (p < 0.001) and high WHO grade (p = 0.003).	('positivity', 'Var', (5, 15))	('CK14', 'Protein', (0, 4))	('TNM', 'Gene', (47, 50))	('TNM', 'Gene', '10178', (47, 50))	('high WHO grade', 'CPA', (73, 87))
112806	32391279	In addition, CK14 positivity was related to combined CK5/6-CK20 expression (p = 0.001), where CK5/6-negative/CK20-positive expression was more prevalent in CK14-positive tumors (45.8 vs. 23.8%).	('CK20', 'Gene', (59, 63))	('CK20', 'Gene', '54474', (59, 63))	('CK5/6', 'Gene', '3852', (94, 99))	('CK5/6', 'Gene', '3852', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('CK5/6', 'Gene', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('CK20', 'Gene', (109, 113))	('CK5/6', 'Gene', (53, 58))	('CK20', 'Gene', '54474', (109, 113))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', (170, 176))	('CK14-positive', 'Var', (156, 169))
112814	32391279	KRT14 gene was highly expressed in CK14-positive tumors compared to CK14-negative tumors (fold change = 40.2, p = 0.035).	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('KRT14', 'Gene', '3861', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('CK14-positive', 'Var', (35, 48))	('KRT14', 'Gene', (0, 5))
112817	32391279	IPA also identified significant enrichment of cellular movement/invasion and cell death functions, which were upregulated and downregulated, respectively, in CK14-positive tumors (Table 4).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('downregulated', 'NegReg', (126, 139))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('CK14-positive', 'Var', (158, 171))	('upregulated', 'PosReg', (110, 121))	('cell death functions', 'CPA', (77, 97))	('cell death', 'biological_process', 'GO:0008219', ('77', '87'))	('cellular movement/invasion', 'CPA', (46, 72))
112823	32391279	In agreement with the high-grade GEP cohort, cellular growth and proliferation overrepresented the biological functions associated with CK14 expression in the low-grade NMIBC cohort, as revealed by the IPA network search (Table 3, Supplementary Figure 5) and GO analysis (Figure 3B, Supplementary Table 2).	('proliferation', 'CPA', (65, 78))	('rat', 'Species', '10116', (72, 75))	('MIBC', 'Phenotype', 'HP:0006740', (170, 174))	('cellular growth', 'biological_process', 'GO:0016049', ('45', '60'))	('biological functions', 'MPA', (99, 119))	('overrepresented', 'PosReg', (79, 94))	('CK14', 'Gene', (136, 140))	('cellular growth', 'CPA', (45, 60))	('MIBC', 'Chemical', '-', (170, 174))	('expression', 'Var', (141, 151))
112825	32391279	CK14-positive tumors displayed a 2.3 +- 5.36% proliferative index (mean +- standard deviation), which was higher than 0.8 +- 2.06% index of CK14-negative tumors in the prognosis cohort (Mann-Whitney U, p = 0.002) (Figure 3E).	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('CK14-positive', 'Var', (0, 13))	('tumors', 'Disease', (14, 20))	('rat', 'Species', '10116', (53, 56))	('higher', 'PosReg', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('proliferative index', 'CPA', (46, 65))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
112826	32391279	In this study, we demonstrated that positive IHC staining for CK14 was associated with high-risk phenotypes of papillary NMIUTUC and was predictive for unfavorable survival rates.	('CK14', 'Gene', (62, 66))	('rat', 'Species', '10116', (173, 176))	('rat', 'Species', '10116', (25, 28))	('positive', 'Var', (36, 44))	('associated', 'Reg', (71, 81))	('papillary NMIUTUC', 'Disease', (111, 128))
112827	32391279	We found that CK14 positivity in papillary high-grade NMIUTUC marked transcriptional characteristics reminiscent of those in BASQ-type MIBC, including signatures of basal/stem cell and squamous cell carcinoma.	('positivity', 'Var', (19, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('MIBC', 'Phenotype', 'HP:0006740', (135, 139))	('squamous cell carcinoma', 'Disease', (185, 208))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (185, 208))	('CK14', 'Gene', (14, 18))	('basal/stem cell', 'CPA', (165, 180))	('MIBC', 'Chemical', '-', (135, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
112829	32391279	IHC staining for Ki-67 verified a much higher proliferative activity in CK14-positive tumors than what was seen in CK14-negative papillary NMIUTUC.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('higher', 'PosReg', (39, 45))	('proliferative activity', 'MPA', (46, 68))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('rat', 'Species', '10116', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('CK14-positive', 'Var', (72, 85))
112836	32391279	Consistent with these reports, we showed that CK14 positivity was associated with poor PFS in papillary NMIUTUC, which was in agreement with the characteristics of CK14-positive BASQ-type MIBC.	('MIBC', 'Chemical', '-', (188, 192))	('papillary NMIUTUC', 'Disease', (94, 111))	('CK14', 'Gene', (46, 50))	('positivity', 'Var', (51, 61))	('MIBC', 'Phenotype', 'HP:0006740', (188, 192))	('poor', 'NegReg', (82, 86))	('PFS', 'MPA', (87, 90))
112837	32391279	In addition, we demonstrated that CK14-positive papillary NMIUTUC had BASQ-like genetic features that were similar to those of basal-type breast cancer and those of squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (165, 188))	('squamous cell carcinoma', 'Disease', (165, 188))	('basal-type breast cancer', 'Disease', 'MESH:D001943', (127, 151))	('CK14-positive', 'Var', (34, 47))	('rat', 'Species', '10116', (23, 26))	('basal-type breast cancer', 'Disease', (127, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))
112838	32391279	Furthermore, CK14-positive papillary NMIUTUC shared other molecular hallmarks of BASQ-type MIBC: activated p40, c-myc, EGFR, and NF-kappaB pathways, which mediate growth and squamous differentiation of urothelial carcinoma.	('EGFR', 'molecular_function', 'GO:0005006', ('119', '123'))	('NF-kappaB', 'Gene', '4790', (129, 138))	('p40', 'cellular_component', 'GO:0043514', ('107', '110'))	('NF-kappaB', 'Gene', (129, 138))	('squamous differentiation of urothelial carcinoma', 'Disease', (174, 222))	('c-myc', 'Gene', (112, 117))	('MIBC', 'Chemical', '-', (91, 95))	('CK14-positive', 'Var', (13, 26))	('p40', 'cellular_component', 'GO:0070743', ('107', '110'))	('squamous differentiation of urothelial carcinoma', 'Disease', 'MESH:D002294', (174, 222))	('p40', 'Gene', (107, 110))	('EGFR', 'Gene', '1956', (119, 123))	('c-myc', 'Gene', '4609', (112, 117))	('MIBC', 'Phenotype', 'HP:0006740', (91, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('p40', 'Gene', '3578', (107, 110))	('EGFR', 'Gene', (119, 123))	('activated', 'PosReg', (97, 106))
112840	32391279	Network and functional enrichment analyses as well as Ki-67 IHC staining demonstrated that cellular growth and proliferative functions are particularly upregulated in CK14-positive papillary NMIUTUC, in accordance with previously reported high-risk phenotypes of NMIBC and NMIUTUC.	('upregulated', 'PosReg', (152, 163))	('CK14-positive papillary NMIUTUC', 'Var', (167, 198))	('cellular growth', 'CPA', (91, 106))	('rat', 'Species', '10116', (118, 121))	('rat', 'Species', '10116', (80, 83))	('proliferative functions', 'CPA', (111, 134))	('MIBC', 'Chemical', '-', (264, 268))	('cellular growth', 'biological_process', 'GO:0016049', ('91', '106'))	('MIBC', 'Phenotype', 'HP:0006740', (264, 268))
112842	32391279	Dysregulation of these genes modulates proliferation, survival, migration, EMT, or metastasis of urothelial carcinoma, and other malignancies, leading to poor prognoses of these tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('rat', 'Species', '10116', (67, 70))	('rat', 'Species', '10116', (46, 49))	('malignancies', 'Disease', (129, 141))	('Dysregulation', 'Var', (0, 13))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('metastasis of urothelial carcinoma', 'Disease', (83, 117))	('EMT', 'biological_process', 'GO:0001837', ('75', '78'))	('modulates', 'Reg', (29, 38))	('EMT', 'CPA', (75, 78))	('proliferation', 'CPA', (39, 52))	('malignancies', 'Disease', 'MESH:D009369', (129, 141))	('migration', 'CPA', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('metastasis of urothelial carcinoma', 'Disease', 'MESH:D009362', (83, 117))	('survival', 'CPA', (54, 62))
112846	32391279	Likewise, varied transcription activators and activation pathways (e.g., p40, c-myc, NF-kappaB, EGFR, Wnt, and mTORC1 signaling pathways) that were enriched in CK14-positive papillary NMIUTUC are linked to proliferation and/or malignant transformation of basal cells and embryonal stem cells.	('p40', 'Gene', (73, 76))	('rat', 'Species', '10116', (213, 216))	('p40', 'cellular_component', 'GO:0070743', ('73', '76'))	('signaling', 'biological_process', 'GO:0023052', ('118', '127'))	('c-myc', 'Gene', (78, 83))	('p40', 'cellular_component', 'GO:0043514', ('73', '76'))	('malignant transformation', 'CPA', (227, 251))	('EGFR', 'Gene', (96, 100))	('malignant transformation of basal cells', 'Phenotype', 'HP:0002671', (227, 266))	('transcription', 'biological_process', 'GO:0006351', ('17', '30'))	('mTORC1', 'Gene', (111, 117))	('mTORC1', 'cellular_component', 'GO:0031931', ('111', '117'))	('NF-kappaB', 'Gene', (85, 94))	('mTORC1', 'Gene', '382056', (111, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('c-myc', 'Gene', '4609', (78, 83))	('EGFR', 'Gene', '1956', (96, 100))	('linked', 'Reg', (196, 202))	('Wnt', 'Pathway', (102, 105))	('CK14-positive', 'Var', (160, 173))	('NF-kappaB', 'Gene', '4790', (85, 94))	('p40', 'Gene', '3578', (73, 76))
112847	32391279	For example, silencing of p40 inhibited c-myc-mediated proliferation of urothelial carcinoma, and high p63 expression was associated with poor prognosis in NMIBC.	('inhibited', 'NegReg', (30, 39))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (72, 92))	('rat', 'Species', '10116', (62, 65))	('c-myc', 'Gene', (40, 45))	('urothelial carcinoma', 'Disease', (72, 92))	('p40', 'cellular_component', 'GO:0070743', ('26', '29'))	('NMIBC', 'Disease', (156, 161))	('MIBC', 'Chemical', '-', (157, 161))	('p63', 'Gene', (103, 106))	('p40', 'cellular_component', 'GO:0043514', ('26', '29'))	('p63', 'Gene', '8626', (103, 106))	('silencing', 'Var', (13, 22))	('MIBC', 'Phenotype', 'HP:0006740', (157, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('c-myc', 'Gene', '4609', (40, 45))	('p40', 'Gene', '3578', (26, 29))	('high', 'Var', (98, 102))	('expression', 'MPA', (107, 117))	('p40', 'Gene', (26, 29))
112853	32391279	Interestingly, poorly differentiated properties associated with CK14 positivity might be partially opposed by our finding that CK14 positivity was associated with luminal-like CK5/6-negative/CK20-positive expression in papillary NMIUTUC.	('CK5/6', 'Gene', '3852', (176, 181))	('CK5/6', 'Gene', (176, 181))	('CK20', 'Gene', (191, 195))	('luminal', 'Chemical', 'MESH:D010634', (163, 170))	('CK20', 'Gene', '54474', (191, 195))	('CK14', 'Gene', (127, 131))	('positivity', 'Var', (132, 142))
112855	32391279	Similarly, low CK5/6 and high CK20 expression profiles were associated with high-risk phenotypes of both papillary NMIUTUC and NMIBC that exhibited altered adhesion, migration, and proliferation.	('rat', 'Species', '10116', (169, 172))	('papillary NMIUTUC', 'Disease', (105, 122))	('CK20', 'Gene', '54474', (30, 34))	('CK5/6', 'Gene', '3852', (15, 20))	('CK5/6', 'Gene', (15, 20))	('high', 'Var', (25, 29))	('low', 'NegReg', (11, 14))	('NMIBC', 'Disease', (127, 132))	('MIBC', 'Chemical', '-', (128, 132))	('rat', 'Species', '10116', (188, 191))	('MIBC', 'Phenotype', 'HP:0006740', (128, 132))	('CK20', 'Gene', (30, 34))
112856	32391279	Both CK14 and CK20 were suggested to direct the aggravation of early urothelial carcinoma via the carcinoma in situ-driven pathway.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('urothelial carcinoma via the carcinoma', 'Disease', 'MESH:D009369', (69, 107))	('CK20', 'Gene', '54474', (14, 18))	('CK20', 'Gene', (14, 18))	('urothelial carcinoma via the carcinoma', 'Disease', (69, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (98, 115))	('CK14', 'Var', (5, 9))
112866	32391279	In conclusion, CK14 positivity represents an aggressive BASQ-like subtype in papillary NMIUTUC that is enriched with brisk proliferative activity.	('CK14', 'Gene', (15, 19))	('rat', 'Species', '10116', (130, 133))	('positivity', 'Var', (20, 30))	('papillary NMIUTUC', 'Disease', (77, 94))
112867	32391279	CK14 IHC staining is a promising biomarker that can be applied in the management of non-muscle-invasive urothelial carcinoma in daily practice, with the aim of precision oncology.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('muscle-invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (88, 124))	('CK14', 'Var', (0, 4))	('muscle-invasive urothelial carcinoma', 'Disease', (88, 124))	('oncology', 'Phenotype', 'HP:0002664', (170, 178))
112949	31552180	analyzed lymph node-associated variables [pathological N stage (pN), lymph node ratio (LNR) and log odds (LODDDS)] in the patients with MIBC and found c-index that predicted the survival was 0.6769 (pN), 0.6794 (pN+ LNR), and 0.6855 (pN+LNR+LODDDS).	('0.6794', 'Var', (204, 210))	('0.6855', 'Var', (226, 232))	('patients', 'Species', '9606', (122, 130))	('0.6769', 'Var', (191, 197))	('MIBC', 'Disease', (136, 140))	('MIBC', 'Disease', 'MESH:D001749', (136, 140))
112963	31552180	The single nucleotide polymorphism rs721048(A>G) in EHBP1 is associated with an aggressive form of prostate cancer.	('associated with', 'Reg', (61, 76))	('EHBP1', 'Gene', (52, 57))	('rs721048(A>G)', 'SUBSTITUTION', 'None', (35, 48))	('rs721048(A>G', 'Var', (35, 47))	('prostate cancer', 'Disease', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('rs721048', 'Mutation', 'rs721048', (35, 43))	('EHBP1', 'Gene', '23301', (52, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (99, 114))	('prostate cancer', 'Phenotype', 'HP:0012125', (99, 114))
112993	29370105	These promising results of PD-1/PD-L1 inhibitors have encouraged many ongoing preclinical and clinical trials to explore the extent of antitumor activity, clinical efficacy and safety as well as to extend their applications.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('PD-1', 'Gene', (27, 31))	('PD-1', 'Gene', '5133', (27, 31))	('tumor', 'Disease', (139, 144))	('inhibitors', 'Var', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))
113003	29370105	Thus, the inhibition of these checkpoint proteins would activate the immune system against tumors.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('activate', 'PosReg', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('inhibition', 'Var', (10, 20))
113030	29370105	One of the phase III trials compared the efficacy of nivolumab to dacarbazine, a chemotherapeutic agent, as a first-line treatment in MM patients with negative B-RAF mutation.	('nivolumab', 'Chemical', 'MESH:D000077594', (53, 62))	('B-RAF', 'Gene', (160, 165))	('MM', 'Phenotype', 'HP:0002861', (134, 136))	('patients', 'Species', '9606', (137, 145))	('dacarbazine', 'Chemical', 'MESH:D003606', (66, 77))	('mutation', 'Var', (166, 174))	('B-RAF', 'Gene', '673', (160, 165))
113134	29370105	Unlike other PD-1 inhibitors, AMP-224 does not induce an immune response by solely blocking the PD-1 receptors; rather, it is suggested that it functions by eliminating exhausted effector cells, i.e., PD-1 highly expressed T cells.	('blocking', 'NegReg', (83, 91))	('PD-1', 'Gene', (13, 17))	('PD-1', 'Gene', '5133', (13, 17))	('PD-1', 'Gene', (96, 100))	('PD-1', 'Gene', '5133', (96, 100))	('immune response', 'biological_process', 'GO:0006955', ('57', '72'))	('PD-1', 'Gene', (201, 205))	('PD-1', 'Gene', '5133', (201, 205))	('AMP-224', 'Chemical', '-', (30, 37))	('eliminating', 'NegReg', (157, 168))	('AMP-224', 'Var', (30, 37))
113135	29370105	Therefore, AMP-224 might exhibit distinct safety and efficacy results as an anticancer agent compared to other PD-1 inhibitors, due to the differences in their biological nature and mechanisms of action.	('AMP-224', 'Chemical', '-', (11, 18))	('AMP-224', 'Var', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('PD-1', 'Gene', (111, 115))	('PD-1', 'Gene', '5133', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
113137	29370105	Other reports have displayed the application of AMP-224 in metastatic colorectal cancer, in which adequate peripheral anticancer activity was documented in colorectal cancer patients treated with radiation.	('colorectal cancer', 'Disease', 'MESH:D015179', (156, 173))	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('AMP-224', 'Chemical', '-', (48, 55))	('patients', 'Species', '9606', (174, 182))	('AMP-224', 'Var', (48, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (156, 173))	('colorectal cancer', 'Disease', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('colorectal cancer', 'Disease', (156, 173))
113138	29370105	However, this positive response upon the administration of AMP-224 might be due to the radiation-induced expression of PD-L1 and this is the current concern that the study is trying to resolve.	('AMP-224', 'Chemical', '-', (59, 66))	('AMP-224', 'Var', (59, 66))	('PD-L1', 'Gene', (119, 124))
113139	29370105	Among the specific reactions seen with the use of AMP-224 was infusion reactions, which can be explained by the unique nature of this agent.	('infusion', 'MPA', (62, 70))	('AMP-224', 'Chemical', '-', (50, 57))	('AMP-224', 'Var', (50, 57))
113144	29370105	Both agents AMP-224 and AMP-514 are in the early stages of clinical trials and their use as anticancer agents is currently under investigation.	('AMP-514', 'Chemical', '-', (24, 31))	('AMP-514', 'Var', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('AMP-224', 'Chemical', '-', (12, 19))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('AMP-224', 'Var', (12, 19))	('cancer', 'Disease', (96, 102))
113145	29370105	Atezolizumab (MPDL3280A/RG7446) is an IgG-1 humanized antibody that blocks the PD-1/PD-L1 interaction, by targeting the expressed PD-L1 on numerous kinds of malignant cells (Table 2).	('human', 'Species', '9606', (44, 49))	('blocks', 'NegReg', (68, 74))	('antibody', 'cellular_component', 'GO:0019815', ('54', '62'))	('Atezolizumab', 'Chemical', 'MESH:C000594389', (0, 12))	('targeting', 'Reg', (106, 115))	('PD-L1', 'Gene', (130, 135))	('antibody', 'cellular_component', 'GO:0019814', ('54', '62'))	('PD-1', 'Gene', (79, 83))	('antibody', 'molecular_function', 'GO:0003823', ('54', '62'))	('IgG-1', 'cellular_component', 'GO:0071735', ('38', '43'))	('PD-1', 'Gene', '5133', (79, 83))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (14, 23))	('MPDL3280A/RG7446', 'Var', (14, 30))	('antibody', 'cellular_component', 'GO:0042571', ('54', '62'))
113146	29370105	The blockage of the PD-1/PD-L1 pathway stimulates the immune defense mechanisms against tumors.	('stimulates', 'PosReg', (39, 49))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('PD-1', 'Gene', (20, 24))	('PD-1', 'Gene', '5133', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('blockage', 'Var', (4, 12))
113158	29370105	PD-L1-positive patients treated with atezolizumab presented an ORR (14%) which was better than the ORR (13%) for the docetaxel-treated group.	('atezolizumab', 'Chemical', 'MESH:C000594389', (37, 49))	('patients', 'Species', '9606', (15, 23))	('docetaxel', 'Chemical', 'MESH:D000077143', (117, 126))	('ORR', 'MPA', (63, 66))	('atezolizumab', 'Var', (37, 49))	('PD-L1-positive', 'Gene', (0, 14))
113275	32018225	Furthermore, overexpression of ETV4 rescued the inhibition of proliferation and invasion induced by PH4 silencing.	('invasion', 'CPA', (80, 88))	('silencing', 'Var', (104, 113))	('ETV4', 'Gene', (31, 35))	('ETV4', 'Gene', '2118', (31, 35))	('inhibition', 'NegReg', (48, 58))	('PH4', 'Gene', (100, 103))
113283	32018225	Subsequent studies detect antibodies against P3H4 in cases of interstitial cystitis, membranous nephropathy, prostate cancer, and meningeal cancer.	('P3H4', 'Protein', (45, 49))	('membranous nephropathy', 'Phenotype', 'HP:0012578', (85, 107))	('prostate cancer', 'Disease', (109, 124))	('antibodies', 'Var', (26, 36))	('interstitial cystitis', 'Disease', 'MESH:D018856', (62, 83))	('P3H', 'molecular_function', 'GO:0033763', ('45', '48'))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('nephropathy', 'Disease', (96, 107))	('nephropathy', 'Phenotype', 'HP:0000112', (96, 107))	('interstitial cystitis', 'Disease', (62, 83))	('detect', 'Reg', (19, 25))	('meningeal cancer', 'Disease', (130, 146))	('prostate cancer', 'Disease', 'MESH:D011471', (109, 124))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('nephropathy', 'Disease', 'MESH:D007674', (96, 107))	('prostate cancer', 'Phenotype', 'HP:0012125', (109, 124))	('meningeal cancer', 'Disease', 'MESH:D009369', (130, 146))
113288	32018225	In the present study, we found that P3H4 was significantly overexpressed in BC tissues, and knockdown of P3H4 inhibits BC cell proliferation, cell cycle, migration and invasion.	('P3H4', 'Gene', (105, 109))	('inhibits', 'NegReg', (110, 118))	('knockdown', 'Var', (92, 101))	('P3H', 'molecular_function', 'GO:0033763', ('105', '108'))	('cell proliferation', 'biological_process', 'GO:0008283', ('122', '140'))	('P3H', 'molecular_function', 'GO:0033763', ('36', '39'))	('cell cycle', 'biological_process', 'GO:0007049', ('142', '152'))	('cell cycle', 'CPA', (142, 152))	('BC', 'Disease', 'MESH:D001749', (119, 121))	('BC', 'Phenotype', 'HP:0009725', (119, 121))	('invasion', 'CPA', (168, 176))	('migration', 'CPA', (154, 163))	('BC', 'Disease', 'MESH:D001749', (76, 78))	('BC', 'Phenotype', 'HP:0009725', (76, 78))
113290	32018225	Overexpression of ETV4 rescued the inhibition of proliferation and invasion induced by PH4 silencing.	('PH4', 'Gene', (87, 90))	('invasion', 'CPA', (67, 75))	('proliferation', 'CPA', (49, 62))	('ETV4', 'Gene', (18, 22))	('ETV4', 'Gene', '2118', (18, 22))	('silencing', 'Var', (91, 100))	('inhibition', 'NegReg', (35, 45))
113301	32018225	As shown in Figure 1H and 1I, CCK8 assay showed that proliferation of EJ and T24 cells was inhibited when siP3H4 was transfected into cells.	('inhibited', 'NegReg', (91, 100))	('proliferation', 'CPA', (53, 66))	('siP3H4', 'Chemical', '-', (106, 112))	('siP3H4', 'Var', (106, 112))	('EJ', 'CellLine', 'CVCL:7039', (70, 72))
113302	32018225	Similarly, colony formation assay revealed that knockdown of P3H4 inhibited the colony forming ability of EJ and T24 cells (Figure 2A).	('P3H', 'molecular_function', 'GO:0033763', ('61', '64'))	('formation', 'biological_process', 'GO:0009058', ('18', '27'))	('P3H4', 'Gene', (61, 65))	('EJ', 'CellLine', 'CVCL:7039', (106, 108))	('inhibited', 'NegReg', (66, 75))	('knockdown', 'Var', (48, 57))
113303	32018225	Furthermore, we detected the action of P3H4 knockdown on the cell cycle and apoptosis of BC cells.	('cell cycle', 'biological_process', 'GO:0007049', ('61', '71'))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('BC', 'Disease', 'MESH:D001749', (89, 91))	('BC', 'Phenotype', 'HP:0009725', (89, 91))	('P3H4', 'Gene', (39, 43))	('P3H', 'molecular_function', 'GO:0033763', ('39', '42'))	('knockdown', 'Var', (44, 53))	('cell cycle', 'CPA', (61, 71))	('apoptosis', 'CPA', (76, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))
113304	32018225	As shown in Figure 2B and 2C, the proportion of cells in G0/G1 phase increased while the proportion of cells in S and G2/M phase decreased, when siP3H4 was transfected into cells.	('siP3H4', 'Var', (145, 151))	('M phase', 'biological_process', 'GO:0000279', ('121', '128'))	('G1 phase', 'biological_process', 'GO:0051318', ('60', '68'))	('decreased', 'NegReg', (129, 138))	('siP3H4', 'Chemical', '-', (145, 151))
113305	32018225	In addition, transfection of siP3H4 reduced the protein levels of Cyclin D1, Nusap1 and p70 (Figure 2D).	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('Cyclin', 'molecular_function', 'GO:0016538', ('66', '72'))	('transfection', 'Var', (13, 25))	('siP3H4', 'Gene', (29, 35))	('p70', 'Gene', (88, 91))	('p70', 'Gene', '309', (88, 91))	('Nusap1', 'Gene', '51203', (77, 83))	('reduced', 'NegReg', (36, 43))	('Nusap1', 'Gene', (77, 83))	('Cyclin D1', 'Gene', '595', (66, 75))	('protein levels', 'MPA', (48, 62))	('Cyclin D1', 'Gene', (66, 75))	('siP3H4', 'Chemical', '-', (29, 35))
113308	32018225	Finally, flow cytometry detection found that knockdown of P3H4 had no effect on the apoptosis of BC cells (Figure 2E).	('apoptosis', 'CPA', (84, 93))	('BC', 'Phenotype', 'HP:0009725', (97, 99))	('P3H', 'molecular_function', 'GO:0033763', ('58', '61'))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('P3H4', 'Gene', (58, 62))	('knockdown', 'Var', (45, 54))	('BC', 'Disease', 'MESH:D001749', (97, 99))
113309	32018225	These results demonstrate that the knockdown of P3H4 can inhibit BC cell proliferation by arresting cell cycle progression, but that it has no effect on the apoptosis of BC cells.	('knockdown', 'Var', (35, 44))	('P3H', 'molecular_function', 'GO:0033763', ('48', '51'))	('cell cycle', 'biological_process', 'GO:0007049', ('100', '110'))	('arresting', 'NegReg', (90, 99))	('BC', 'Disease', 'MESH:D001749', (170, 172))	('BC', 'Phenotype', 'HP:0009725', (170, 172))	('cell cycle progression', 'CPA', (100, 122))	('inhibit', 'NegReg', (57, 64))	('BC', 'Disease', 'MESH:D001749', (65, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('157', '166'))	('apoptosis', 'biological_process', 'GO:0006915', ('157', '166'))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))	('BC', 'Phenotype', 'HP:0009725', (65, 67))	('P3H4', 'Gene', (48, 52))
113312	32018225	Additionally, wound healing assay revealed that transfection of siP3H4 caused wound healing of EJ and T24 cells to be slower (Figure 3B and 3C).	('wound healing', 'biological_process', 'GO:0042060', ('78', '91'))	('wound healing', 'biological_process', 'GO:0042060', ('14', '27'))	('EJ', 'CellLine', 'CVCL:7039', (95, 97))	('siP3H4', 'Chemical', '-', (64, 70))	('siP3H4', 'Gene', (64, 70))	('transfection', 'Var', (48, 60))	('slower', 'NegReg', (118, 124))
113313	32018225	Moreover, the knockdown of P3H4 reduced protein levels of N-cadherin and Vimentin, as well as increased the protein levels of E-cadherin (Figure 3D-3F).	('cadherin', 'molecular_function', 'GO:0008014', ('60', '68'))	('Vimentin', 'Gene', (73, 81))	('Vimentin', 'cellular_component', 'GO:0045099', ('73', '81'))	('N-cadherin', 'Gene', (58, 68))	('increased', 'PosReg', (94, 103))	('reduced', 'NegReg', (32, 39))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('E-cadherin', 'Gene', (126, 136))	('N-cadherin', 'Gene', '1000', (58, 68))	('Vimentin', 'Gene', '7431', (73, 81))	('E-cadherin', 'Gene', '999', (126, 136))	('P3H', 'molecular_function', 'GO:0033763', ('27', '30'))	('P3H4', 'Gene', (27, 31))	('cadherin', 'molecular_function', 'GO:0008014', ('128', '136'))	('knockdown', 'Var', (14, 23))	('protein levels of', 'MPA', (40, 57))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('Vimentin', 'cellular_component', 'GO:0045098', ('73', '81'))
113317	32018225	As shown in Figure 3G, 3H, knockdown of P3H4 in EJ and T24 cells significantly inhibited BC growth.	('3H', 'Chemical', 'MESH:D014316', (23, 25))	('knockdown', 'Var', (27, 36))	('P3H4', 'Gene', (40, 44))	('P3H', 'molecular_function', 'GO:0033763', ('40', '43'))	('3H', 'Chemical', 'MESH:D014316', (41, 43))	('BC', 'Disease', 'MESH:D001749', (89, 91))	('BC', 'Phenotype', 'HP:0009725', (89, 91))	('inhibited', 'NegReg', (79, 88))	('EJ', 'CellLine', 'CVCL:7039', (48, 50))
113322	32018225	Furthermore, the promoter analysis revealed the presence of three binding regions for ETV4 on the promoter of P3H4, located at 697-705, 111-1019, and 1771-1779, respectively (Figure 4E).	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('111-1019', 'Var', (136, 144))	('ETV4', 'Gene', (86, 90))	('P3H', 'molecular_function', 'GO:0033763', ('110', '113'))	('1771-1779', 'Var', (150, 159))	('P3H4', 'Gene', (110, 114))	('ETV4', 'Gene', '2118', (86, 90))
113328	32018225	In addition, ETV4 overexpression partially restored the inhibitory of siP3H4 transfection on proliferation, colony formation and invasion ability of EJ and T24 cells (Figure 5C-5E).	('siP3H4', 'Gene', (70, 76))	('invasion ability', 'CPA', (129, 145))	('ETV4', 'Gene', (13, 17))	('EJ', 'CellLine', 'CVCL:7039', (149, 151))	('transfection', 'Var', (77, 89))	('proliferation', 'CPA', (93, 106))	('ETV4', 'Gene', '2118', (13, 17))	('formation', 'biological_process', 'GO:0009058', ('115', '124'))	('colony formation', 'CPA', (108, 124))	('inhibitory', 'MPA', (56, 66))	('siP3H4', 'Chemical', '-', (70, 76))
113333	32018225	In addition, knockdown of P3H4 also impeded migration and invasion of both EJ and T24 cells by inhibiting the EMT process.	('P3H', 'molecular_function', 'GO:0033763', ('26', '29'))	('impeded', 'NegReg', (36, 43))	('inhibiting', 'NegReg', (95, 105))	('EJ', 'CellLine', 'CVCL:7039', (75, 77))	('EMT process', 'CPA', (110, 121))	('invasion', 'CPA', (58, 66))	('P3H4', 'Protein', (26, 30))	('migration', 'CPA', (44, 53))	('EMT', 'biological_process', 'GO:0001837', ('110', '113'))	('knockdown', 'Var', (13, 22))
113334	32018225	The xenograft nude mouse model also showed that knockdown of P3H4 inhibited the growth of subcutaneous BC tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('P3H', 'molecular_function', 'GO:0033763', ('61', '64'))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('P3H4', 'Gene', (61, 65))	('BC', 'Disease', 'MESH:D001749', (103, 105))	('inhibited', 'NegReg', (66, 75))	('mouse', 'Species', '10090', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('BC', 'Phenotype', 'HP:0009725', (103, 105))	('knockdown', 'Var', (48, 57))
113336	32018225	Although studies have displayed that P3H4 may be associated with several tumors (prostate cancer and meningeal cancer), this study was the first to conduct experiments in vivo and in vitro to determine the role of P3H4 in BC.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('prostate cancer', 'Disease', (81, 96))	('P3H4', 'Var', (37, 41))	('BC', 'Disease', 'MESH:D001749', (222, 224))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('associated', 'Reg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('BC', 'Phenotype', 'HP:0009725', (222, 224))	('meningeal cancer', 'Disease', (101, 117))	('meningeal cancer', 'Disease', 'MESH:D009369', (101, 117))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('P3H', 'molecular_function', 'GO:0033763', ('37', '40'))	('tumors', 'Disease', (73, 79))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('P3H', 'molecular_function', 'GO:0033763', ('214', '217'))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))
113344	32018225	ETV4-related gene fusion may be an early event in prostate cancer and could define a new molecular subtype of prostate cancer.	('ETV4', 'Gene', (0, 4))	('prostate cancer', 'Disease', 'MESH:D011471', (110, 125))	('prostate cancer', 'Disease', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ETV4', 'Gene', '2118', (0, 4))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('fusion', 'Var', (18, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (50, 65))	('prostate cancer', 'Disease', (110, 125))	('prostate cancer', 'Phenotype', 'HP:0012125', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
113379	32018225	Anti-P3H4 (1:1000, 15288-1-AP), anti-E-cadherin (1:1000, 29874-1-AP) and anti-ETV4 (1:1000, 10684-1-AP) were purchased from Proteintech (Manchester, UK, USA).	('ETV4', 'Gene', (78, 82))	('E-cadherin', 'Gene', (37, 47))	('ETV4', 'Gene', '2118', (78, 82))	('cadherin', 'molecular_function', 'GO:0008014', ('39', '47'))	('1:1000', 'Var', (49, 55))	('E-cadherin', 'Gene', '999', (37, 47))	('P3H', 'molecular_function', 'GO:0033763', ('5', '8'))	('1:1000', 'Var', (84, 90))
113380	32018225	Anti-Cyclin D1 (1:1000, ab16663), anti-Nusap1 (1:1000, ab169083), anti-p70 (1:1000, ab131526), anti-N-cadherin (1:1000, ab18203), anti-Vimentin (1:1000, ab8978), anti-GAPDH (1:1000, ab181602) were purchased from Abcam (Cambridge, MA, USA).	('p70', 'Gene', (71, 74))	('Cyclin D1', 'Gene', '595', (5, 14))	('Cyclin', 'molecular_function', 'GO:0016538', ('5', '11'))	('Vimentin', 'cellular_component', 'GO:0045098', ('135', '143'))	('Cyclin D1', 'Gene', (5, 14))	('Vimentin', 'Gene', (135, 143))	('N-cadherin', 'Gene', (100, 110))	('Nusap1', 'Gene', '51203', (39, 45))	('Nusap1', 'Gene', (39, 45))	('1:1000', 'Var', (112, 118))	('Vimentin', 'Gene', '7431', (135, 143))	('p70', 'Gene', '309', (71, 74))	('Vimentin', 'cellular_component', 'GO:0045099', ('135', '143'))	('N-cadherin', 'Gene', '1000', (100, 110))	('1:1000', 'Var', (174, 180))	('cadherin', 'molecular_function', 'GO:0008014', ('102', '110'))
113414	30809286	Dysregulation of Wnt/beta-catenin signaling, which is necessary for many vital biological processes, such as embryonic development, organogenesis, tissue regeneration, hematopoiesis, cell survival, cellular proliferation and differentiation and stem cell renewal, is associated with many diseases, including osteoporosis, neurodegenerative diseases, and cardiovascular diseases, and numerous human malignancies.	('hematopoiesis', 'biological_process', 'GO:0030097', ('168', '181'))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('Dysregulation', 'Var', (0, 13))	('numerous human malignancies', 'Disease', (383, 410))	('osteoporosis', 'Phenotype', 'HP:0000939', (308, 320))	('osteoporosis', 'Disease', 'MESH:D010024', (308, 320))	('tissue regeneration', 'biological_process', 'GO:0042246', ('147', '166'))	('cardiovascular diseases', 'Disease', (354, 377))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (322, 348))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (354, 377))	('associated', 'Reg', (267, 277))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (322, 348))	('numerous human malignancies', 'Disease', 'MESH:D009369', (383, 410))	('organogenesis', 'biological_process', 'GO:0048513', ('132', '145'))	('stem cell renewal', 'biological_process', 'GO:0017145', ('245', '262'))	('hematopoiesis', 'Disease', 'MESH:C536227', (168, 181))	('hematopoiesis', 'Disease', (168, 181))	('neurodegenerative diseases', 'Disease', (322, 348))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (354, 377))	('osteoporosis', 'Disease', (308, 320))
113418	30809286	Further, RPRD1A was found to inhibit chicken DF-1 cell proliferation by downregulating the expression of downstream regulatory genes of the Wnt/beta-catenin pathway, including beta-catenin, TCF4, and cyclin D1.	('expression', 'MPA', (91, 101))	('beta-catenin', 'Protein', (176, 188))	('chicken', 'Species', '9031', (37, 44))	('downregulating', 'NegReg', (72, 86))	('DF-1', 'CellLine', 'CVCL:0570', (45, 49))	('cyclin D1', 'Gene', (200, 209))	('inhibit', 'NegReg', (29, 36))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('cyclin', 'molecular_function', 'GO:0016538', ('200', '206'))	('TCF4', 'Gene', (190, 194))	('RPRD1A', 'Var', (9, 15))	('chicken DF-1 cell proliferation', 'CPA', (37, 68))
113426	30809286	The breast cancer cell lines ZR-75-30, MCF-7, ZR-75-1, BT-549, BT-474, SKBR3, T47D, MDA-MB-415, MDA-MB-435, MDA-MB-468, MDA-MB-231 and MDA-MB-453 were purchased from the ATCC and maintained in DMEM (Gibco, Grand Island, NY) or RPMI-1640 (Gibco) supplemented with 10% FBS (HyClone, Logan, UT) and 1% penicillin/ streptomycin (Gibco).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (120, 130))	('T47D', 'CellLine', 'CVCL:0553', (78, 82))	('MDA-MB-415', 'Var', (84, 94))	('FBS', 'Disease', 'MESH:D005198', (267, 270))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('MDA-MB-415', 'CellLine', 'CVCL:0621', (84, 94))	('ZR-75-1', 'CellLine', 'CVCL:0588', (46, 53))	('SKBR3', 'CellLine', 'CVCL:0033', (71, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('BT-549', 'CellLine', 'CVCL:1092', (55, 61))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (108, 118))	('FBS', 'Disease', (267, 270))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (135, 145))	('MCF-7', 'CellLine', 'CVCL:0031', (39, 44))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (96, 106))
113445	30809286	Western blotting analysis was performed according to a standard method previously described, using anti-RPRD1A, anti-Axin2, anti-Dkk3, anti-SFRP1 (Abcam) or anti-E-cadherin, anti-alpha-catenin, anti-N-cadherin, anti-vimentin and anti-beta-catenin (Cell Signaling) antibodies.	('vimentin', 'cellular_component', 'GO:0045098', ('216', '224'))	('vimentin', 'Gene', '7431', (216, 224))	('E-cadherin', 'Gene', (162, 172))	('E-cadherin', 'Gene', '999', (162, 172))	('vimentin', 'Gene', (216, 224))	('Dkk3', 'Gene', '27122', (129, 133))	('vimentin', 'cellular_component', 'GO:0045099', ('216', '224'))	('Axin2', 'Gene', (117, 122))	('SFRP1', 'Gene', (140, 145))	('N-cadherin', 'Gene', (199, 209))	('N-cadherin', 'Gene', '1000', (199, 209))	('cadherin', 'molecular_function', 'GO:0008014', ('164', '172'))	('anti-alpha-catenin', 'Protein', (174, 192))	('anti-RPRD1A', 'Var', (99, 110))	('Axin2', 'Gene', '8313', (117, 122))	('Dkk3', 'Gene', (129, 133))	('cadherin', 'molecular_function', 'GO:0008014', ('201', '209'))	('SFRP1', 'Gene', '6422', (140, 145))	('Signaling', 'biological_process', 'GO:0023052', ('253', '262'))
113451	30809286	Stable cell lines expressing miR-454-3p or miRZip-454-3p were generated via retroviral infection using HEK293T cells and selected with 0.5 mug/mL puromycin for 10 days.	('miR-454', 'Gene', (29, 36))	('puromycin', 'Chemical', 'MESH:D011691', (146, 155))	('mug', 'molecular_function', 'GO:0043739', ('139', '142'))	('HEK293T', 'CellLine', 'CVCL:0063', (103, 110))	('miR-454', 'Gene', '768216', (29, 36))	('miRZip-454-3p', 'Var', (43, 56))
113461	30809286	IHC assay was performed using anti-RPRD1A, anti-AXIN2, anti-DKK3, anti-SFRP1 (Abcam) and anti-beta-catenin antibodies (Cell Signaling).	('SFRP1', 'Gene', (71, 76))	('AXIN2', 'Gene', (48, 53))	('AXIN2', 'Gene', '8313', (48, 53))	('anti-beta-catenin', 'Var', (89, 106))	('SFRP1', 'Gene', '6422', (71, 76))	('anti-RPRD1A', 'Var', (30, 41))	('DKK3', 'Gene', '27122', (60, 64))	('DKK3', 'Gene', (60, 64))	('Signaling', 'biological_process', 'GO:0023052', ('124', '133'))
113484	30809286	Since previous reports have demonstrated that RPRD1A acts as a negative regulator of Wnt/beta-catenin signaling, we investigated whether Wnt/beta-catenin signaling was involved in the molecular mechanism and found that the transactivity of beta-catenin and the expression of well-known beta-catenin downstream target genes were significantly decreased in the RPRD1A-overexpressing breast cancer cells but increased in the RPRD1A-silenced cells (Figure 1G and Figure S1C).	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('transactivity', 'MPA', (223, 236))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('breast cancer', 'Disease', 'MESH:D001943', (381, 394))	('decreased', 'NegReg', (342, 351))	('expression', 'MPA', (261, 271))	('breast cancer', 'Disease', (381, 394))	('breast cancer', 'Phenotype', 'HP:0003002', (381, 394))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('RPRD1A-overexpressing', 'Var', (359, 380))	('beta-catenin', 'Protein', (240, 252))
113490	30809286	Furthermore, the luciferase reporter assay showed that the luciferase activity of RPRD1A-3'UTR was drastically decreased in miR-454-3p -overexpressing breast cancer cells but increased in miR-454-silenced cells, whereas forced expression of a mutant miR-454-3p (miR-454-3p-mu: UUCAGCAAUAUUGCUUAUAGGGU) had no inhibitory effect on RPRD1A-3'UTR luciferase activity (Figure 2D).	('luciferase activity', 'molecular_function', 'GO:0050397', ('343', '362'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('343', '362'))	('miR-454', 'Gene', (188, 195))	('luciferase activity', 'molecular_function', 'GO:0047077', ('59', '78'))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('miR-454', 'Gene', '768216', (262, 269))	('miR-454', 'Gene', (124, 131))	('luciferase activity', 'molecular_function', 'GO:0045289', ('59', '78'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('59', '78'))	('miR-454', 'Gene', (250, 257))	('miR-454', 'Gene', '768216', (188, 195))	('decreased', 'NegReg', (111, 120))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('miR-454', 'Gene', '768216', (124, 131))	('breast cancer', 'Disease', (151, 164))	('luciferase activity', 'molecular_function', 'GO:0050397', ('59', '78'))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('miR-454', 'Gene', '768216', (250, 257))	('luciferase activity', 'molecular_function', 'GO:0050248', ('59', '78'))	('activity', 'MPA', (70, 78))	('luciferase activity', 'molecular_function', 'GO:0047077', ('343', '362'))	('increased', 'PosReg', (175, 184))	('luciferase', 'Enzyme', (59, 69))	('luciferase activity', 'molecular_function', 'GO:0045289', ('343', '362'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('343', '362'))	('miR-454', 'Gene', (262, 269))	('mutant', 'Var', (243, 249))
113505	30809286	We also found that overexpression of miR-454-3p reduced the reporter activities driven by the 3'-UTRs of the AXIN2, DKK3 and SFRP1 transcripts, while silencing of miR-454-3p elevated these activities (Figure 3E).	('DKK3', 'Gene', '27122', (116, 120))	('AXIN2', 'Gene', (109, 114))	('AXIN2', 'Gene', '8313', (109, 114))	('DKK3', 'Gene', (116, 120))	('miR-454', 'Gene', '768216', (37, 44))	('SFRP1', 'Gene', '6422', (125, 130))	('reporter activities driven', 'MPA', (60, 86))	('reduced', 'NegReg', (48, 55))	('miR-454', 'Gene', (37, 44))	('elevated', 'PosReg', (174, 182))	('silencing', 'Var', (150, 159))	('miR-454', 'Gene', '768216', (163, 170))	('SFRP1', 'Gene', (125, 130))	('miR-454', 'Gene', (163, 170))
113520	30809286	Further, mice injected with cells with high miR-454-3p expression had shorter survival than those injected with cells that had low miR-454-3p expression, while silencing of miR-454-3p significantly extended their survival (Figure 4G).	('survival', 'CPA', (78, 86))	('extended', 'PosReg', (198, 206))	('miR-454', 'Gene', (44, 51))	('shorter', 'NegReg', (70, 77))	('silencing', 'Var', (160, 169))	('survival', 'CPA', (213, 221))	('miR-454', 'Gene', '768216', (173, 180))	('mice', 'Species', '10090', (9, 13))	('miR-454', 'Gene', '768216', (131, 138))	('miR-454', 'Gene', (131, 138))	('miR-454', 'Gene', (173, 180))	('miR-454', 'Gene', '768216', (44, 51))
113527	30809286	In contrast, silencing of miR-454-3p drastically inhibited the local invasive capability of MDA-MB-231/vector tumors (Figure 5A).	('miR-454', 'Gene', (26, 33))	('local invasive capability', 'CPA', (63, 88))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (92, 102))	('miR-454', 'Gene', '768216', (26, 33))	('inhibited', 'NegReg', (49, 58))	('silencing', 'Var', (13, 22))
113535	30809286	Further, the average number of colonies recovered from the blood samples of the tumor-bearing mice was markedly higher in the MDA-MB-231/miRZip-V group (3.4 colonies/100 muL blood) than in the MDA-MB-231/miRZip-454-3p group (1 colony/100 muL blood) (Figure 5E).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (126, 136))	('MDA-MB-231/miRZip-V', 'Var', (126, 145))	('higher', 'PosReg', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('mice', 'Species', '10090', (94, 98))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (193, 203))
113546	30809286	As shown in Figure 6B, the number of tumor nests in the lungs formed by the miR-454-3p-transduced MCF-7 cells was significantly higher than that formed by the control cells; further, silencing of miR-454-3p drastically inhibited the capability of MDA-MB-231/vector cells to form lung metastases.	('lung metastases', 'Disease', (279, 294))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (247, 257))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('lung metastases', 'Disease', 'MESH:D009362', (279, 294))	('miR-454', 'Gene', '768216', (196, 203))	('silencing', 'Var', (183, 192))	('inhibited', 'NegReg', (219, 228))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('miR-454', 'Gene', (196, 203))	('MCF-7', 'CellLine', 'CVCL:0031', (98, 103))	('miR-454', 'Gene', '768216', (76, 83))	('miR-454', 'Gene', (76, 83))
113559	30809286	Overexpression of miR-454-3p significantly increased beta-catenin luciferase reporter activity in both the LIHC and KIRC cell lines, while silencing of miR-454-3p decreased this activity.	('miR-454', 'Gene', (152, 159))	('LIHC', 'Disease', 'None', (107, 111))	('silencing', 'Var', (139, 148))	('beta-catenin luciferase', 'Enzyme', (53, 76))	('reporter activity', 'MPA', (77, 94))	('decreased', 'NegReg', (163, 172))	('increased', 'PosReg', (43, 52))	('miR-454', 'Gene', '768216', (152, 159))	('miR-454', 'Gene', (18, 25))	('miR-454', 'Gene', '768216', (18, 25))	('LIHC', 'Disease', (107, 111))
113561	30809286	Taken together, these results demonstrate that aberrantly amplified miR-454-3p promotes cancer stem cell-like traits by activating the Wnt/beta-catenin pathways, thus resulting in poor outcomes in cancer patients.	('patients', 'Species', '9606', (204, 212))	('miR-454', 'Gene', '768216', (68, 75))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('miR-454', 'Gene', (68, 75))	('Wnt/beta-catenin pathways', 'Pathway', (135, 160))	('promotes', 'PosReg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('aberrantly amplified', 'Var', (47, 67))	('activating', 'PosReg', (120, 130))
113577	30809286	Moreover, dysregulation of multiple direct target genes of Wnt/beta-catenin signaling in immune cells and tumor cells has been demonstrated to be responsible for the failure of cancer immunotherapy.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('failure', 'Disease', 'MESH:D017093', (166, 173))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('dysregulation', 'Var', (10, 23))	('failure', 'Disease', (166, 173))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
113583	30809286	In one such study, inhibition of miR-122 was found to result in a substantial reduction in hepatitis C virus (HCV) infection load and reduction in liver damage.	('reduction in liver damage', 'Disease', (134, 159))	('inhibition', 'Var', (19, 29))	('reduction in hepatitis C virus (HCV) infection', 'Disease', 'MESH:D006526', (78, 124))	('miR-122', 'Gene', (33, 40))	('miR-122', 'Chemical', '-', (33, 40))	('reduction in liver damage', 'Disease', 'MESH:D056486', (134, 159))	('hepatitis', 'Phenotype', 'HP:0012115', (91, 100))
113584	30809286	Recently, two companies (Roche/Santaris and Regulus Therapeutics) have been engaged in clinical trials with anti-miR-122 LNAs as a therapeutic agent against HCV infections, and the projects have reached phase II trials for the treatment of hepatitis.	('hepatitis', 'Disease', (240, 249))	('anti-miR-122', 'Var', (108, 120))	('HCV infections', 'Disease', 'MESH:D006526', (157, 171))	('hepatitis', 'Disease', 'MESH:D056486', (240, 249))	('HCV infections', 'Disease', (157, 171))	('miR-122', 'Chemical', '-', (113, 120))	('hepatitis', 'Phenotype', 'HP:0012115', (240, 249))
113589	30809286	Inhibition of miR-454-3p resulted in inhibition of breast cancer metastasis in a mouse model, indicating its potential clinical applications as a therapeutic target.	('breast cancer metastasis', 'Disease', 'MESH:D009362', (51, 75))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('inhibition', 'NegReg', (37, 47))	('breast cancer metastasis', 'Disease', (51, 75))	('miR-454', 'Gene', '768216', (14, 21))	('Inhibition', 'Var', (0, 10))	('miR-454', 'Gene', (14, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('mouse', 'Species', '10090', (81, 86))
113590	30809286	Herein, we demonstrated that inhibition of miR-454-3p or ectopic expression of Wnt/beta-catenin antagonists, including RPRD1A, AXIN2, DKK3 and SFRP1, led to Wnt/beta-catenin signaling activity inhibition, which subsequently led to attenuation of breast cancer metastasis.	('miR-454', 'Gene', '768216', (43, 50))	('DKK3', 'Gene', '27122', (134, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('RPRD1A', 'Gene', (119, 125))	('DKK3', 'Gene', (134, 138))	('AXIN2', 'Gene', (127, 132))	('miR-454', 'Gene', (43, 50))	('SFRP1', 'Gene', (143, 148))	('inhibition', 'NegReg', (193, 203))	('Wnt/beta-catenin signaling activity', 'MPA', (157, 192))	('AXIN2', 'Gene', '8313', (127, 132))	('signaling', 'biological_process', 'GO:0023052', ('174', '183'))	('attenuation of breast cancer metastasis', 'Disease', (231, 270))	('attenuation of breast cancer metastasis', 'Disease', 'MESH:D009362', (231, 270))	('SFRP1', 'Gene', '6422', (143, 148))	('inhibition', 'Var', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
113595	30588104	Prognostic value of AIB1 and EIF5A2 in intravesical recurrence after surgery for upper tract urothelial carcinoma The aim of this study was to investigate the prognostic effect of amplified in AIB1 and EIF5A2 expression on postoperative intravesical recurrence for upper urinary tract urothelial carcinoma (UTUC) and improve postoperative risk stratification and prediction of intravesical chemotherapy benefit.	('AIB1', 'Gene', (20, 24))	('AIB1', 'Gene', '63897', (20, 24))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (81, 113))	('upper urinary tract urothelial carcinoma', 'Disease', (265, 305))	('EIF5A2', 'Gene', '56648', (202, 208))	('upper urinary tract urothelial carcinoma', 'Disease', 'MESH:D014552', (265, 305))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('amplified in', 'Var', (180, 192))	('AIB1', 'Gene', (193, 197))	('AIB1', 'Gene', '63897', (193, 197))	('EIF5A2', 'Gene', '56648', (29, 35))	('EIF5A2', 'Gene', (202, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))	('improve', 'PosReg', (317, 324))	('EIF5A2', 'Gene', (29, 35))	('upper tract urothelial carcinoma', 'Disease', (81, 113))
113599	30588104	In different subsets of UTUC patients, high expression of AIB1 was a prognostic indicator in high grade (P=0.006) and pT2-4 (P=0.007), and high expression of EIF5A2 for high grade (P=0.014), pT2-4 (P=0.002) and pN0 (P=0.009).	('high grade', 'Disease', (93, 103))	('patients', 'Species', '9606', (29, 37))	('EIF5A2', 'Gene', '56648', (158, 164))	('P', 'Gene', '8202', (105, 106))	('AIB1', 'Gene', '63897', (58, 62))	('P', 'Gene', '8202', (181, 182))	('high expression', 'Var', (39, 54))	('AIB1', 'Gene', (58, 62))	('EIF5A2', 'Gene', (158, 164))	('P', 'Gene', '8202', (216, 217))	('P', 'Gene', '8202', (125, 126))	('P', 'Gene', '8202', (198, 199))	('high', 'Var', (139, 143))
113604	30588104	High expression of AIB1 and EIF5A2 were independent predictors for intravesical recurrence after RNU and might be able to predict which patients benefit from postoperative intravesical chemotherapy.	('RNU', 'Chemical', '-', (97, 100))	('predictors', 'Reg', (52, 62))	('High', 'Var', (0, 4))	('EIF5A2', 'Gene', (28, 34))	('AIB1', 'Gene', (19, 23))	('patients', 'Species', '9606', (136, 144))	('AIB1', 'Gene', '63897', (19, 23))	('intravesical recurrence', 'Disease', (67, 90))	('EIF5A2', 'Gene', '56648', (28, 34))
113614	30588104	Overexpression of EIF5A2 was reported to predict poor prognosis in gastric adenocarcinomas, colorectal cancer, hepatocellular carcinomas, ovarian cancer and non-small-cell lung cancer.	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (157, 183))	('EIF5A2', 'Gene', '56648', (18, 24))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('EIF5A2', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ovarian cancer', 'Disease', 'MESH:D010051', (138, 152))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (111, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('non-small-cell lung cancer', 'Disease', (157, 183))	('ovarian cancer', 'Disease', (138, 152))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (157, 183))	('gastric adenocarcinomas', 'Disease', (67, 90))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (111, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('ovarian cancer', 'Phenotype', 'HP:0100615', (138, 152))	('hepatocellular carcinomas', 'Disease', (111, 136))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (67, 90))	('colorectal cancer', 'Disease', (92, 109))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (161, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))
113651	30588104	Median IVRFSs in the low and high AIB1 expression groups were observed to be 46 months (range 6-140) and 24 months (range 1-180), respectively.	('high', 'Var', (29, 33))	('AIB1', 'Gene', '63897', (34, 38))	('AIB1', 'Gene', (34, 38))	('IVRFSs', 'CPA', (7, 13))
113652	30588104	Statistically significant differences were observed between the low and high AIB1 expression groups in the 5-year IVRFS rate (90.5% vs 76.5%, P=0.021).	('P', 'Gene', '8202', (142, 143))	('low', 'Var', (64, 67))	('IVRFS rate', 'CPA', (114, 124))	('AIB1', 'Gene', '63897', (77, 81))	('high', 'Var', (72, 76))	('AIB1', 'Gene', (77, 81))
113653	30588104	The survival intervals in the low and high EIF5A2 expression groups were 39 months (range 2-131) and 28 months (range 1-180), respectively.	('EIF5A2', 'Gene', (43, 49))	('EIF5A2', 'Gene', '56648', (43, 49))	('high', 'Var', (38, 42))
113654	30588104	The 5-year IVRFS rates of the low and high EIF5A2 expression groups were 94.2% and 72.6% (P=0.002), as shown in Figure 2.	('EIF5A2', 'Gene', (43, 49))	('low', 'Var', (30, 33))	('high', 'Var', (38, 42))	('IVRFS', 'CPA', (11, 16))	('P', 'Gene', '8202', (90, 91))	('EIF5A2', 'Gene', '56648', (43, 49))
113660	30588104	The results showed that intravesical chemotherapy was a good prognostic factor for IVRFS of UTUC patients with high AIB1 and EIF5A2 expression (P=0.002; Figure 5).	('P', 'Gene', '8202', (144, 145))	('EIF5A2', 'Gene', '56648', (125, 131))	('AIB1', 'Gene', '63897', (116, 120))	('patients', 'Species', '9606', (97, 105))	('EIF5A2', 'Gene', (125, 131))	('AIB1', 'Gene', (116, 120))	('high', 'Var', (111, 115))	('IVRFS', 'Disease', (83, 88))
113661	30588104	In addition, patients with pT2-4 (16/20, 80%), pN+ (7/20, 35%) or high grade (13/20, 65%) were included in this subset.	('patients', 'Species', '9606', (13, 21))	('pT2-4', 'Var', (27, 32))	('pN+', 'Disease', (47, 50))
113662	30588104	In univariate analysis, lymph node metastasis and high-level AIB1 and EIF5A2 expression were significantly associated with intravesical recurrence (P<0.05).	('AIB1', 'Gene', '63897', (61, 65))	('expression', 'MPA', (77, 87))	('intravesical recurrence', 'Disease', (123, 146))	('EIF5A2', 'Gene', '56648', (70, 76))	('associated', 'Reg', (107, 117))	('EIF5A2', 'Gene', (70, 76))	('lymph node metastasis', 'CPA', (24, 45))	('P', 'Gene', '8202', (148, 149))	('high-level', 'Var', (50, 60))	('AIB1', 'Gene', (61, 65))
113663	30588104	Multivariate Cox proportional hazards regression analysis revealed that lymph node metastasis (P=0.009), high-level AIB1 expression (P=0.034) and high-level EIF5A2 expression (P=0.022) were significant risk factors for IVRFS.	('EIF5A2', 'Gene', '56648', (157, 163))	('P', 'Gene', '8202', (133, 134))	('Cox', 'Gene', (13, 16))	('Cox', 'Gene', '1351', (13, 16))	('expression', 'MPA', (164, 174))	('AIB1', 'Gene', '63897', (116, 120))	('expression', 'MPA', (121, 131))	('EIF5A2', 'Gene', (157, 163))	('P', 'Gene', '8202', (95, 96))	('P', 'Gene', '8202', (176, 177))	('high-level', 'Var', (146, 156))	('high-level', 'Var', (105, 115))	('AIB1', 'Gene', (116, 120))	('IVRFS', 'Disease', (219, 224))	('lymph node metastasis', 'CPA', (72, 93))
113674	30588104	The key findings in this study are that high expressions of AIB1 and EIF5A2 are strongly linked with intravesical recurrence after operation in patients with UTUC, especially in the subsets of high grade and high pathological stage.	('EIF5A2', 'Gene', '56648', (69, 75))	('high expressions', 'Var', (40, 56))	('linked with', 'Reg', (89, 100))	('intravesical recurrence', 'Disease', (101, 124))	('patients', 'Species', '9606', (144, 152))	('AIB1', 'Gene', (60, 64))	('AIB1', 'Gene', '63897', (60, 64))	('EIF5A2', 'Gene', (69, 75))
113687	30588104	In other words, AIB1 and EIF5A may be considered as underlying biological biomarkers to predict the development of UTUC, and the combination of both markers shows more powerful predictive value of bladder recurrence in UTUC.	('bladder recurrence', 'Disease', (197, 215))	('EIF5A', 'Gene', (25, 30))	('EIF5A', 'Gene', '1984', (25, 30))	('UTUC', 'Disease', (115, 119))	('AIB1', 'Gene', (16, 20))	('AIB1', 'Gene', '63897', (16, 20))	('combination', 'Var', (129, 140))
113696	30588104	In this study, we found a significant association between intravesical chemotherapy and the combination of AIB1 and EIF5A2.	('intravesical chemotherapy', 'Disease', (58, 83))	('EIF5A2', 'Gene', (116, 122))	('AIB1', 'Gene', (107, 111))	('AIB1', 'Gene', '63897', (107, 111))	('EIF5A2', 'Gene', '56648', (116, 122))	('combination', 'Var', (92, 103))
113699	30588104	The subset group of UTUC patients with high level of AIB1 and EIF5A2 might be inclined to implant dispersed intraluminal viable cancer cells or establish a significant new tumor, and intravesical chemotherapy should be more meaningful for this subset group of UTUC patients after surgery.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('EIF5A2', 'Gene', '56648', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('high level', 'Var', (39, 49))	('EIF5A2', 'Gene', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (265, 273))	('AIB1', 'Gene', (53, 57))	('AIB1', 'Gene', '63897', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('cancer', 'Disease', (128, 134))
113702	30588104	In this study, the presence of AIB1, EIF5A2 and pN+ was found to be associated with an elevated risk for intravesical recurrence, and surgical approach with RNU was considered as a protective factor for intravesical recurrence.	('pN+', 'Gene', (48, 51))	('EIF5A2', 'Gene', (37, 43))	('associated', 'Reg', (68, 78))	('AIB1', 'Gene', (31, 35))	('EIF5A2', 'Gene', '56648', (37, 43))	('presence', 'Var', (19, 27))	('AIB1', 'Gene', '63897', (31, 35))	('RNU', 'Chemical', '-', (157, 160))	('intravesical recurrence', 'Disease', (105, 128))
113706	30588104	We describe, for the first time, that AIB1 and EIF5A2 expressions are associated with shorter IVRFS time in UTUC.	('AIB1', 'Gene', (38, 42))	('AIB1', 'Gene', '63897', (38, 42))	('IVRFS time', 'CPA', (94, 104))	('EIF5A2', 'Gene', (47, 53))	('expressions', 'Var', (54, 65))	('shorter', 'NegReg', (86, 93))	('EIF5A2', 'Gene', '56648', (47, 53))
113713	29325739	Anti-PD-1/PD-L1 antibodies have shown favorable clinical activity and tolerability in patients with metastatic urothelial carcinoma refractory to platinum-based therapy or who are ineligible for cisplatin.	('urothelial carcinoma', 'Disease', (111, 131))	('antibodies', 'Var', (16, 26))	('platinum', 'Chemical', 'MESH:D010984', (146, 154))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (111, 131))	('Anti-PD-1/PD-L1 antibodies', 'Var', (0, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (195, 204))	('patients', 'Species', '9606', (86, 94))
113725	29325739	Nevertheless, these therapies helped to establish urothelial carcinoma as immunogenic, and CD4+ T cells, CD8+ cytotoxic T cells, and natural killer cells have been shown to drive antitumor activity in response to BCG therapy.	('CD4+', 'Var', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('urothelial carcinoma', 'Disease', (50, 70))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('BCG', 'Species', '33892', (213, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('tumor', 'Disease', (183, 188))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (50, 70))	('drive', 'PosReg', (173, 178))
113730	29325739	Preclinical studies support the use of checkpoint inhibitors in urothelial carcinoma and have shown that blocking the PD-L1/PD-1 interaction increases the numbers and cytolytic activity of tumor-specific T cells and modulates levels of proinflammatory and anti-inflammatory cytokines (Figure 2).	('modulates', 'Reg', (216, 225))	('tumor', 'Disease', (189, 194))	('increases', 'PosReg', (141, 150))	('PD-L1/PD-1', 'Gene', (118, 128))	('cytolytic activity', 'CPA', (167, 185))	('interaction', 'Interaction', (129, 140))	('urothelial carcinoma', 'Disease', (64, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('numbers', 'CPA', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('blocking', 'Var', (105, 113))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (64, 84))
113742	29325739	Ongoing trials are assessing the efficacy of first- and second-line use of anti-PD-L1/PD-1 therapies for all stages of bladder cancer, including NIMBC, MIBC, and metastatic urothelial carcinoma (Table 2).	('urothelial carcinoma', 'Disease', (173, 193))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('bladder cancer', 'Phenotype', 'HP:0009725', (119, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('MIBC', 'Disease', (152, 156))	('bladder cancer', 'Disease', 'MESH:D001749', (119, 133))	('NIMBC', 'Chemical', '-', (145, 150))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (173, 193))	('NIMBC', 'Disease', (145, 150))	('bladder cancer', 'Disease', (119, 133))	('anti-PD-L1/PD-1', 'Var', (75, 90))	('MIBC', 'Chemical', '-', (152, 156))
113746	29325739	Similarly, patients with baseline metastases and high PD-L1 expression had better responses to treatment than counterparts with low PD-L1 expression (32% compared with 12%).	('better', 'PosReg', (75, 81))	('PD-L1', 'Gene', (54, 59))	('high', 'Var', (49, 53))	('metastases', 'Disease', (34, 44))	('responses', 'MPA', (82, 91))	('patients', 'Species', '9606', (11, 19))	('metastases', 'Disease', 'MESH:D009362', (34, 44))
113774	29325739	The ORR in the subset of evaluable patients with PD-L1+ or PD-L1- staining in TCs and ICs was 24% and 0%, respectively.	('TCs', 'Disease', (78, 81))	('PD-L1+', 'Var', (49, 55))	('TCs', 'Chemical', 'MESH:D013667', (78, 81))	('patients', 'Species', '9606', (35, 43))	('ICs', 'Disease', (86, 89))
113793	29325739	OS, regardless of PD-L1 expression, was superior with pembrolizumab compared with chemotherapy (10.3 vs 7.4 months), and there was a 30% reduction in the risk of death.	('pembrolizumab', 'Chemical', 'MESH:C582435', (54, 67))	('pembrolizumab', 'Var', (54, 67))	('superior', 'PosReg', (40, 48))	('reduction', 'NegReg', (137, 146))
113796	29325739	Pembrolizumab was tolerated better than chemotherapy; 61% of patients in the pembrolizumab arm compared with 90% of patients in the chemotherapy arm experienced TRAEs of any grade, including those of grade >=3 (17% and 50% for pembrolizumab and chemotherapy, respectively).	('pembrolizumab', 'Chemical', 'MESH:C582435', (227, 240))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (61, 69))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('TRAEs', 'Disease', (161, 166))	('pembrolizumab', 'Var', (77, 90))	('pembrolizumab', 'Chemical', 'MESH:C582435', (77, 90))
113817	29325739	Safety was consistent with that of nivolumab monotherapy (grade >=3 TRAEs occurred in 31% and 23% of patients treated with N1I3 and N3I1, respectively, compared with 23% for nivolumab monotherapy).	('patients', 'Species', '9606', (101, 109))	('N1I3', 'Var', (123, 127))	('nivolumab', 'Chemical', 'MESH:D000077594', (174, 183))	('nivolumab', 'Chemical', 'MESH:D000077594', (35, 44))	('TRAEs', 'Disease', (68, 73))	('N3I1', 'Var', (132, 136))
113847	29325739	Among these studies are two phase 2 studies that are currently enrolling patients to receive atezolizumab (NCT02662309) or pembrolizumab (NCT02736266), with pathological complete response as the primary endpoint.	('patients', 'Species', '9606', (73, 81))	('NCT02736266', 'Var', (138, 149))	('atezolizumab', 'Chemical', 'MESH:C000594389', (93, 105))	('NCT02662309', 'Var', (107, 118))	('pembrolizumab', 'Chemical', 'MESH:C582435', (123, 136))
113857	29325739	In KEYNOTE-012 and KEYNOTE-052, pembrolizumab showed enhanced antitumor activity in patients with recurrent or metastatic PD-L1+ urothelial carcinoma based on >=1% and >=10% PD-L1 expression, respectively.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('metastatic', 'CPA', (111, 121))	('tumor', 'Disease', (66, 71))	('PD-L1+ urothelial carcinoma', 'Disease', (122, 149))	('>=1%', 'Var', (159, 163))	('patients', 'Species', '9606', (84, 92))	('PD-L1+ urothelial carcinoma', 'Disease', 'MESH:D010300', (122, 149))	('pembrolizumab', 'Chemical', 'MESH:C582435', (32, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('PD-L1', 'Protein', (174, 179))	('enhanced', 'PosReg', (53, 61))
113859	29325739	Durvalumab showed enhanced antitumor activity in a population of patients with >=25% PD-L1 expression on ICs or TCs as a combined measure.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('expression', 'Var', (91, 101))	('PD-L1', 'Gene', (85, 90))	('enhanced', 'PosReg', (18, 26))	('Durvalumab', 'Chemical', 'MESH:C000613593', (0, 10))	('TCs', 'Chemical', 'MESH:D013667', (112, 115))	('patients', 'Species', '9606', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
113867	29325739	In addition to tumor PD-L1 expression, mutational load has been explored for its association with clinical outcomes in patients treated with PD-L1/PD-1 checkpoint inhibitors.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('PD-L1', 'Gene', (21, 26))	('mutational load', 'Var', (39, 54))
113869	29325739	Studies to identify peripheral blood immune biomarkers have determined that blockade of the PD-L1/PD-1 axis can increase effector T-cell proliferation and production of inducible T-cell alpha chemoattractant, IFNgamma, and interleukin 18, although these responses were not indicative of significant response or progression.	('PD-L1/PD-1 axis', 'Gene', (92, 107))	('increase effector T-cell proliferation', 'Phenotype', 'HP:0031402', (112, 150))	('effector T-cell proliferation', 'CPA', (121, 150))	('increase', 'PosReg', (112, 120))	('T-cell proliferation', 'biological_process', 'GO:0042098', ('130', '150'))	('production', 'MPA', (155, 165))	('inducible T-cell alpha chemoattractant', 'MPA', (169, 207))	('blockade', 'Var', (76, 84))	('interleukin 18', 'Gene', '397057', (223, 237))	('interleukin 18', 'Gene', (223, 237))
113877	29325739	Finally, the BISCAY trial is exploring whether the addition of targeted small molecules to durvalumab treatment in patients with specific biomarkers may result in enhanced neoantigen release and immunosensitization.	('neoantigen release', 'MPA', (172, 190))	('patients', 'Species', '9606', (115, 123))	('durvalumab', 'Chemical', 'MESH:C000613593', (91, 101))	('small molecules', 'Var', (72, 87))	('enhanced', 'PosReg', (163, 171))	('immunosensitization', 'CPA', (195, 214))
113880	29325739	For example, in KEYNOTE-045, pembrolizumab was associated with improved HRQOL measures compared with chemotherapy, including increased rates of improvement for most social functioning and symptom domains (31.2% vs 22.0%) and lower rates of deterioration for all social functioning and symptom domains (28.9 vs 40.6%).	('improved', 'PosReg', (63, 71))	('increased', 'PosReg', (125, 134))	('pembrolizumab', 'Chemical', 'MESH:C582435', (29, 42))	('pembrolizumab', 'Var', (29, 42))	('HRQOL measures', 'MPA', (72, 86))	('social functioning', 'MPA', (165, 183))	('improvement', 'PosReg', (144, 155))
113901	29179467	TUG1 knockdown also depressed the Wnt/beta-catenin pathway, and the activation the Wnt/beta-catenin pathway partly reversed the inhibitory effects of TUG1 knockdown on Dox resistance in T24/Dox cells.	('depressed', 'NegReg', (20, 29))	('knockdown', 'Var', (155, 164))	('beta-catenin', 'Gene', (38, 50))	('beta-catenin', 'Gene', (87, 99))	('TUG1', 'Gene', (150, 154))	('TUG1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('Dox resistance', 'MPA', (168, 182))	('Dox', 'Chemical', 'MESH:D004317', (168, 171))	('beta-catenin', 'Gene', '1499', (38, 50))	('Dox', 'Chemical', 'MESH:D004317', (190, 193))	('activation', 'PosReg', (68, 78))	('beta-catenin', 'Gene', '1499', (87, 99))	('TUG1', 'Gene', '55000', (150, 154))	('TUG1', 'Gene', '55000', (0, 4))	('T24', 'Chemical', '-', (186, 189))
113902	29179467	In conclusion, up-regulation of lncRNA TUG1 was related with the poor response of BUC patients to Dox chemotherapy, knockdown of TUG1 inhibited the Dox resistance of BUC cells via Wnt/beta-catenin pathway.	('Dox', 'Chemical', 'MESH:D004317', (148, 151))	('up-regulation', 'PosReg', (15, 28))	('inhibited', 'NegReg', (134, 143))	('knockdown', 'Var', (116, 125))	('TUG1', 'Gene', '55000', (39, 43))	('beta-catenin', 'Gene', (184, 196))	('TUG1', 'Gene', '55000', (129, 133))	('regulation', 'biological_process', 'GO:0065007', ('18', '28'))	('beta-catenin', 'Gene', '1499', (184, 196))	('Dox', 'Chemical', 'MESH:D004317', (98, 101))	('TUG1', 'Gene', (39, 43))	('TUG1', 'Gene', (129, 133))	('Dox resistance of BUC cells', 'MPA', (148, 175))	('lncRNA', 'Protein', (32, 38))	('patients', 'Species', '9606', (86, 94))
113917	29179467	In the array, TUG1 showed an over seven-fold up-regulation in Dox (-) BUC samples compared with Dox (+) BUC samples (Figure 1A).	('up-regulation', 'PosReg', (45, 58))	('TUG1', 'Gene', (14, 18))	('regulation', 'biological_process', 'GO:0065007', ('48', '58'))	('Dox (-) BUC', 'Var', (62, 73))	('TUG1', 'Gene', '55000', (14, 18))	('Dox', 'Chemical', 'MESH:D004317', (62, 65))	('Dox', 'Chemical', 'MESH:D004317', (96, 99))
113923	29179467	In order to validate the vital roles of TUG1 on Dox resistance, ss-TUG1 was transfected into T24/Dox cells to knockdown the expression of TUG1 (Figure 2A).	('knockdown', 'Var', (110, 119))	('Dox', 'Chemical', 'MESH:D004317', (48, 51))	('ss-TUG1', 'Gene', (64, 71))	('Dox', 'Chemical', 'MESH:D004317', (97, 100))	('TUG1', 'Gene', (138, 142))	('TUG1', 'Gene', '55000', (40, 44))	('ss-TUG1', 'Gene', '55000', (64, 71))	('TUG1', 'Gene', '55000', (67, 71))	('T24', 'Chemical', '-', (93, 96))	('TUG1', 'Gene', (40, 44))	('TUG1', 'Gene', (67, 71))	('TUG1', 'Gene', '55000', (138, 142))
113924	29179467	The CCK8 assay showed knockdown of TUG1 inhibited the IC50 of T24/Dox cells to Dox from 3.08 +- 0.23 mg/L to 1.14 +- 0.17 mg/L (Figure 2B, P < 0.05), which demonstrated that knockdown of TUG1 depressed Dox resistance in T24/Dox cells.	('TUG1', 'Gene', '55000', (187, 191))	('Dox', 'Chemical', 'MESH:D004317', (79, 82))	('Dox', 'Chemical', 'MESH:D004317', (224, 227))	('T24', 'Chemical', '-', (62, 65))	('inhibited', 'NegReg', (40, 49))	('TUG1', 'Gene', '55000', (35, 39))	('T24', 'Chemical', '-', (220, 223))	('Dox resistance', 'MPA', (202, 216))	('TUG1', 'Gene', (35, 39))	('knockdown', 'Var', (22, 31))	('knockdown', 'Var', (174, 183))	('TUG1', 'Gene', (187, 191))	('IC50', 'MPA', (54, 58))	('Dox', 'Chemical', 'MESH:D004317', (202, 205))	('depressed', 'NegReg', (192, 201))	('Dox', 'Chemical', 'MESH:D004317', (66, 69))
113925	29179467	Furthermore, the T24/Dox cells were treated with Dox (0.5 mg/L), and the impacts of TUG1 knockdown on the Dox-induced cytotoxicity were detected.	('T24', 'Chemical', '-', (17, 20))	('cytotoxicity', 'Disease', 'MESH:D064420', (118, 130))	('TUG1', 'Gene', '55000', (84, 88))	('knockdown', 'Var', (89, 98))	('Dox', 'Chemical', 'MESH:D004317', (49, 52))	('TUG1', 'Gene', (84, 88))	('Dox', 'Chemical', 'MESH:D004317', (106, 109))	('cytotoxicity', 'Disease', (118, 130))	('Dox', 'Chemical', 'MESH:D004317', (21, 24))
113926	29179467	Firstly, knockdown of TUG1 restrained cell viability of T24/Dox cells by CCK8 assay (Figure 2C, P < 0.05).	('restrained', 'NegReg', (27, 37))	('knockdown', 'Var', (9, 18))	('Dox', 'Chemical', 'MESH:D004317', (60, 63))	('T24', 'Chemical', '-', (56, 59))	('TUG1', 'Gene', '55000', (22, 26))	('cell viability of T24/Dox cells', 'CPA', (38, 69))	('TUG1', 'Gene', (22, 26))
113927	29179467	Secondly, single label flow cytometry indicated T24/Dox cells with TUG1 knockdown showed a significant S phase block (Figure 2D, P < 0.05).	('Dox', 'Chemical', 'MESH:D004317', (52, 55))	('TUG1', 'Gene', '55000', (67, 71))	('S phase block', 'CPA', (103, 116))	('T24', 'Chemical', '-', (48, 51))	('S phase', 'biological_process', 'GO:0051320', ('103', '110'))	('TUG1', 'Gene', (67, 71))	('knockdown', 'Var', (72, 81))
113928	29179467	Thirdly, TUG1 knockdown advanced cell apoptosis of T24/Dox cells by double label flow cytometry (Figure 2E, P < 0.05).	('cell apoptosis', 'CPA', (33, 47))	('TUG1', 'Gene', '55000', (9, 13))	('apoptosis', 'biological_process', 'GO:0097194', ('38', '47'))	('T24', 'Chemical', '-', (51, 54))	('apoptosis', 'biological_process', 'GO:0006915', ('38', '47'))	('advanced', 'PosReg', (24, 32))	('TUG1', 'Gene', (9, 13))	('knockdown', 'Var', (14, 23))	('Dox', 'Chemical', 'MESH:D004317', (55, 58))
113929	29179467	Thus, it was identified that knockdown of TUG1 inhibited the Dox resistance in T24/Dox cells.	('inhibited', 'NegReg', (47, 56))	('knockdown', 'Var', (29, 38))	('Dox', 'Chemical', 'MESH:D004317', (83, 86))	('TUG1', 'Gene', (42, 46))	('T24', 'Chemical', '-', (79, 82))	('Dox', 'Chemical', 'MESH:D004317', (61, 64))	('Dox resistance', 'MPA', (61, 75))	('TUG1', 'Gene', '55000', (42, 46))
113935	29179467	Secondly, TUG1 knockdown decreased the expression of beta-catenin protein in T24/Dox cells (Figure 3B, P < 0.05).	('knockdown', 'Var', (15, 24))	('TUG1', 'Gene', (10, 14))	('decreased', 'NegReg', (25, 34))	('Dox', 'Chemical', 'MESH:D004317', (81, 84))	('beta-catenin', 'Gene', (53, 65))	('expression', 'MPA', (39, 49))	('TUG1', 'Gene', '55000', (10, 14))	('beta-catenin', 'Gene', '1499', (53, 65))	('T24', 'Chemical', '-', (77, 80))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
113936	29179467	Thirdly, the TOP/FOP Flash luciferase reporter assay showed TUG1 knockdown depressed the TOP/FOP ratio in T24/Dox cells significantly (Figure 3C, P < 0.05), which represented the transcriptional activity of Wnt/beta-catenin pathway.	('Dox', 'Chemical', 'MESH:D004317', (110, 113))	('TUG1', 'Gene', '55000', (60, 64))	('T24', 'Chemical', '-', (106, 109))	('beta-catenin', 'Gene', (211, 223))	('beta-catenin', 'Gene', '1499', (211, 223))	('depressed', 'NegReg', (75, 84))	('TOP/FOP ratio', 'MPA', (89, 102))	('knockdown', 'Var', (65, 74))	('TUG1', 'Gene', (60, 64))
113937	29179467	Together, the data demonstrated TUG1 knockdown restrained the activity of Wnt/beta-catenin pathway.	('activity', 'MPA', (62, 70))	('knockdown', 'Var', (37, 46))	('TUG1', 'Gene', '55000', (32, 36))	('TUG1', 'Gene', (32, 36))	('restrained', 'NegReg', (47, 57))	('beta-catenin', 'Gene', (78, 90))	('beta-catenin', 'Gene', '1499', (78, 90))
113944	29179467	Therefore, these results suggest that activation of Wnt/beta-catenin signal pathway could partly restore the effecting on Dox resistance induced by TUG1 knockdown in T24/Dox cells.	('Dox resistance', 'MPA', (122, 136))	('knockdown', 'Var', (153, 162))	('TUG1', 'Gene', '55000', (148, 152))	('beta-catenin', 'Gene', (56, 68))	('effecting', 'MPA', (109, 118))	('TUG1', 'Gene', (148, 152))	('Dox', 'Chemical', 'MESH:D004317', (170, 173))	('beta-catenin', 'Gene', '1499', (56, 68))	('T24', 'Chemical', '-', (166, 169))	('Dox', 'Chemical', 'MESH:D004317', (122, 125))
113949	29179467	For instance, lncARSR advanced the Dox resistance in hepatocellular carcinoma (HCC), and might be a potential prognostic biomarker and therapeutic target for HCC; lncRNA HOTAIR depressed the Dox sensitivity in BUC.	('lncRNA', 'Var', (163, 169))	('Dox', 'Chemical', 'MESH:D004317', (35, 38))	('Dox', 'Chemical', 'MESH:D004317', (191, 194))	('Dox resistance', 'MPA', (35, 49))	('HOTAIR', 'Gene', (170, 176))	('HOTAIR', 'Gene', '100124700', (170, 176))	('depressed', 'NegReg', (177, 186))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (53, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('hepatocellular carcinoma', 'Disease', (53, 77))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (53, 77))	('HCC', 'Phenotype', 'HP:0001402', (158, 161))	('HCC', 'Phenotype', 'HP:0001402', (79, 82))	('advanced', 'PosReg', (22, 30))
113953	29179467	Recent studies reported TUG1 was up-regulated in colorectal cancer resistant to methotrexate, knockdown of TUG1 re-sensitized the colorectal cancer cells to methotrexate; high TUG1 expression was related to chemoresistance in esophageal squamous cell carcinoma to platinum combined with 5-fluorouracil or paclitaxel.	('colorectal cancer', 'Disease', (130, 147))	('TUG1', 'Gene', '55000', (176, 180))	('methotrexate', 'Chemical', 'MESH:D008727', (80, 92))	('colorectal cancer', 'Disease', (49, 66))	('paclitaxel', 'Chemical', 'MESH:D017239', (305, 315))	('TUG1', 'Gene', '55000', (24, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (237, 260))	('methotrexate', 'Chemical', 'MESH:D008727', (157, 169))	('platinum', 'Chemical', 'MESH:D010984', (264, 272))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (226, 260))	('related to', 'Reg', (196, 206))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (287, 301))	('TUG1', 'Gene', (107, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (130, 147))	('colorectal cancer', 'Phenotype', 'HP:0003003', (49, 66))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('high', 'Var', (171, 175))	('TUG1', 'Gene', (176, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('TUG1', 'Gene', (24, 28))	('TUG1', 'Gene', '55000', (107, 111))	('esophageal squamous cell carcinoma', 'Disease', (226, 260))	('chemoresistance', 'CPA', (207, 222))	('colorectal cancer', 'Disease', 'MESH:D015179', (130, 147))	('up-regulated', 'PosReg', (33, 45))	('colorectal cancer', 'Disease', 'MESH:D015179', (49, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
113956	29179467	Knockdown of TUG1 restrained the IC50 of T24/Dox cells to Dox, and advanced the Dox-induced cytotoxicity, which demonstrated that TUG1 knockdown inhibited Dox resistance in T24/Dox cells.	('Dox', 'Chemical', 'MESH:D004317', (80, 83))	('Dox', 'Chemical', 'MESH:D004317', (45, 48))	('Dox', 'Chemical', 'MESH:D004317', (155, 158))	('IC50', 'MPA', (33, 37))	('TUG1', 'Gene', '55000', (13, 17))	('Dox', 'Chemical', 'MESH:D004317', (58, 61))	('TUG1', 'Gene', (130, 134))	('Dox-induced', 'MPA', (80, 91))	('inhibited', 'NegReg', (145, 154))	('T24', 'Chemical', '-', (41, 44))	('Dox', 'Chemical', 'MESH:D004317', (177, 180))	('cytotoxicity', 'Disease', (92, 104))	('restrained', 'NegReg', (18, 28))	('knockdown', 'Var', (135, 144))	('Dox resistance', 'MPA', (155, 169))	('TUG1', 'Gene', '55000', (130, 134))	('cytotoxicity', 'Disease', 'MESH:D064420', (92, 104))	('T24', 'Chemical', '-', (173, 176))	('TUG1', 'Gene', (13, 17))	('advanced', 'PosReg', (67, 75))
113962	29179467	Then, western blotting and TOP/FOP Flash luciferase reporter assay were used to confirm that TUG1 knockdown restrained the activity of Wnt/beta-catenin pathway.	('TUG1', 'Gene', '55000', (93, 97))	('restrained', 'NegReg', (108, 118))	('knockdown', 'Var', (98, 107))	('TUG1', 'Gene', (93, 97))	('beta-catenin', 'Gene', (139, 151))	('activity', 'MPA', (123, 131))	('beta-catenin', 'Gene', '1499', (139, 151))
113963	29179467	Based on above findings, we put forward hypothesis that knockdown of lncRNA TUG1 might inhibit Dox resistance of BUC via Wnt/beta-catenin pathway.	('TUG1', 'Gene', '55000', (76, 80))	('beta-catenin', 'Gene', (125, 137))	('TUG1', 'Gene', (76, 80))	('Dox', 'Chemical', 'MESH:D004317', (95, 98))	('Dox resistance of BUC', 'MPA', (95, 116))	('beta-catenin', 'Gene', '1499', (125, 137))	('knockdown', 'Var', (56, 65))	('inhibit', 'NegReg', (87, 94))
113964	29179467	Subsequent series of experiments confirmed that activating Wnt/beta-catenin pathway by upregulating beta-catenin reversed the effects of TUG1 knockdown on Dox resistance in T24/Dox cells, Wnt/beta-catenin pathway partially mediated effecting induced by TUG1 knockdown in 24/DR cells.	('beta-catenin', 'Gene', (63, 75))	('TUG1', 'Gene', (137, 141))	('beta-catenin', 'Gene', (100, 112))	('beta-catenin', 'Gene', '1499', (192, 204))	('Dox', 'Chemical', 'MESH:D004317', (155, 158))	('beta-catenin', 'Gene', '1499', (100, 112))	('Dox', 'Chemical', 'MESH:D004317', (177, 180))	('Dox resistance', 'MPA', (155, 169))	('beta-catenin', 'Gene', '1499', (63, 75))	('TUG1', 'Gene', '55000', (253, 257))	('TUG1', 'Gene', '55000', (137, 141))	('upregulating', 'PosReg', (87, 99))	('beta-catenin', 'Gene', (192, 204))	('TUG1', 'Gene', (253, 257))	('T24', 'Chemical', '-', (173, 176))	('knockdown', 'Var', (142, 151))
113965	29179467	In our previous study, knockdown of PVT1 gene could downregulate the expression of multidrug resistance protein 1 (MDR1) and multidrug resistance associated protein 1 (MRP1) expression in BUC cells through Wnt/beta-catenin pathway, and then participate in the formation of chemoresistance to Dox and cisplatin.	('Dox', 'Chemical', 'MESH:D004317', (292, 295))	('MRP1', 'Gene', (168, 172))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('participate in', 'Reg', (241, 255))	('multidrug resistance protein 1', 'Gene', '5243', (83, 113))	('MDR1', 'Gene', (115, 119))	('MDR', 'molecular_function', 'GO:0004745', ('115', '118'))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('multidrug resistance protein', 'molecular_function', 'GO:0008559', ('83', '111'))	('PVT1', 'Gene', (36, 40))	('downregulate', 'NegReg', (52, 64))	('PVT1', 'Gene', '5820', (36, 40))	('expression', 'MPA', (174, 184))	('cisplatin', 'Chemical', 'MESH:D002945', (300, 309))	('multidrug resistance associated protein 1', 'Gene', (125, 166))	('multidrug resistance associated protein 1', 'Gene', '4363', (125, 166))	('beta-catenin', 'Gene', (210, 222))	('MRP1', 'Gene', '4363', (168, 172))	('MDR1', 'Gene', '5243', (115, 119))	('formation', 'biological_process', 'GO:0009058', ('260', '269'))	('multidrug resistance protein 1', 'Gene', (83, 113))	('beta-catenin', 'Gene', '1499', (210, 222))	('knockdown', 'Var', (23, 32))	('expression', 'MPA', (69, 79))	('chemoresistance to', 'CPA', (273, 291))
113968	29179467	In conclusion, high-expression of lncRNA TUG1 was related with the poor response of BUC patients to Dox chemotherapy, knockdown of TUG1 inhibited Dox resistance of BUC via Wnt/beta-catenin pathway.	('Dox', 'Chemical', 'MESH:D004317', (100, 103))	('TUG1', 'Gene', (41, 45))	('knockdown', 'Var', (118, 127))	('TUG1', 'Gene', '55000', (131, 135))	('inhibited', 'NegReg', (136, 145))	('beta-catenin', 'Gene', (176, 188))	('Dox', 'Chemical', 'MESH:D004317', (146, 149))	('patients', 'Species', '9606', (88, 96))	('beta-catenin', 'Gene', '1499', (176, 188))	('TUG1', 'Gene', (131, 135))	('Dox resistance of BUC', 'MPA', (146, 167))	('TUG1', 'Gene', '55000', (41, 45))
72294	29179467	The TOP Flash and FOP FLASH luciferase reporter vectors which contain wild-type or mutant TCF binding sites were purchased from Biovector NTCC Ltd (Beijing, China).	('TCF', 'Gene', (90, 93))	('TCF', 'Gene', '3172', (90, 93))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('mutant', 'Var', (83, 89))
114001	28969069	PVT1 knockdown reduced proliferation and invasion by a DOX- and DDP-resistant T24/DR BUC cells, arrested cells in G1 phase, and increased apoptosis.	('DDP', 'Gene', (64, 67))	('G1 phase', 'biological_process', 'GO:0051318', ('114', '122'))	('DOX', 'Chemical', 'MESH:D004317', (55, 58))	('knockdown', 'Var', (5, 14))	('apoptosis', 'biological_process', 'GO:0097194', ('138', '147'))	('increased', 'PosReg', (128, 137))	('arrested', 'NegReg', (96, 104))	('PVT1', 'Gene', (0, 4))	('reduced', 'NegReg', (15, 22))	('DDP', 'Gene', '1678', (64, 67))	('apoptosis', 'CPA', (138, 147))	('apoptosis', 'biological_process', 'GO:0006915', ('138', '147'))	('cells in G1 phase', 'CPA', (105, 122))	('PVT1', 'Gene', '5820', (0, 4))
114002	28969069	PVT1 knockdown also sensitized T24/DR cells to DOX and DDP, and suppressed expression of multidrug resistance 1 (MDR1) and multidrug resistance associated protein 1 (MRP1).	('multidrug resistance 1', 'Gene', (89, 111))	('knockdown', 'Var', (5, 14))	('DDP', 'Gene', (55, 58))	('PVT1', 'Gene', (0, 4))	('MRP1', 'Gene', (166, 170))	('PVT1', 'Gene', '5820', (0, 4))	('MDR1', 'Gene', (113, 117))	('multidrug resistance 1', 'Gene', '5243', (89, 111))	('suppressed', 'NegReg', (64, 74))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('drug resistance', 'Phenotype', 'HP:0020174', (128, 143))	('multidrug resistance associated protein 1', 'Gene', (123, 164))	('DOX', 'Chemical', 'MESH:D004317', (47, 50))	('multidrug resistance associated protein 1', 'Gene', '4363', (123, 164))	('MDR', 'molecular_function', 'GO:0004745', ('113', '116'))	('sensitized', 'Reg', (20, 30))	('drug resistance', 'Phenotype', 'HP:0020174', (94, 109))	('expression', 'MPA', (75, 85))	('DDP', 'Gene', '1678', (55, 58))
114003	28969069	Wnt/beta-catenin pathway activation in T24/DR cells reversed the effects of PVT1 knockdown on metastasis-associated behavior and chemoresistance.	('PVT1', 'Gene', '5820', (76, 80))	('metastasis-associated behavior', 'CPA', (94, 124))	('knockdown', 'Var', (81, 90))	('chemoresistance', 'CPA', (129, 144))	('PVT1', 'Gene', (76, 80))
114004	28969069	In sum, lncRNA PVT1 is overexpressed in multidrug resistant BUC tissues and cell lines, and PVT1 knockdown reduces BUC cell proliferation, invasiveness, and chemoresistance by modulating Wnt/beta-catenin signaling.	('PVT1', 'Gene', (92, 96))	('knockdown', 'Var', (97, 106))	('PVT1', 'Gene', '5820', (15, 19))	('cell proliferation', 'biological_process', 'GO:0008283', ('119', '137'))	('PVT1', 'Gene', '5820', (92, 96))	('modulating', 'Reg', (176, 186))	('invasiveness', 'CPA', (139, 151))	('reduces', 'NegReg', (107, 114))	('BUC cell proliferation', 'CPA', (115, 137))	('chemoresistance', 'CPA', (157, 172))	('signaling', 'biological_process', 'GO:0023052', ('204', '213'))	('PVT1', 'Gene', (15, 19))
114009	28969069	Long noncoding RNA (lncRNA) dysregulation is associated with aberrant biological processes promoting a variety of diseases, including cancers.	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('dysregulation', 'Var', (28, 41))	('associated', 'Reg', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('RNA', 'cellular_component', 'GO:0005562', ('15', '18'))
114024	28969069	CCK8 assay results showed that PVT1 knockdown reduced T24/DR cell viability (P<0.05; Figure 2B), and arrested cells in G1 phase (P<0.05; Figure 2C).	('PVT1', 'Gene', '5820', (31, 35))	('G1 phase', 'biological_process', 'GO:0051318', ('119', '127'))	('cells in G1 phase', 'CPA', (110, 127))	('knockdown', 'Var', (36, 45))	('reduced', 'NegReg', (46, 53))	('PVT1', 'Gene', (31, 35))	('T24/DR cell viability', 'CPA', (54, 75))	('arrested', 'NegReg', (101, 109))
114026	28969069	Additionally, flow cytometry analyses found that PVT1 knockdown increased T24/DR cell apoptosis (P<0.05; Figure 2D).	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('T24/DR cell apoptosis', 'CPA', (74, 95))	('knockdown', 'Var', (54, 63))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('PVT1', 'Gene', (49, 53))	('increased', 'PosReg', (64, 73))	('PVT1', 'Gene', '5820', (49, 53))
114027	28969069	Finally, Transwell assays showed that PVT1 knockdown reduced T24/DR cell invasion compared to controls (P<0.05; Figure 2E).	('T24/DR cell invasion', 'CPA', (61, 81))	('PVT1', 'Gene', (38, 42))	('knockdown', 'Var', (43, 52))	('reduced', 'NegReg', (53, 60))	('PVT1', 'Gene', '5820', (38, 42))
114028	28969069	Together, these data demonstrated that PVT1 knockdown inhibited T24/DR cell malignant behaviors.	('inhibited', 'NegReg', (54, 63))	('PVT1', 'Gene', (39, 43))	('PVT1', 'Gene', '5820', (39, 43))	('T24/DR cell malignant behaviors', 'CPA', (64, 95))	('knockdown', 'Var', (44, 53))
114030	28969069	DOX and DDP IC50s in T24/DR cells were reduced following PVT1 knockdown, from 3.53+-0.57 mg/L and 80.31+-7.15 mg/L to 1.13+-0.15 mg/L and 39.52+-4.48 mg/L, respectively (P<0.05; Figure 3A-3B).	('DOX', 'Chemical', 'MESH:D004317', (0, 3))	('PVT1', 'Gene', (57, 61))	('DDP', 'Gene', '1678', (8, 11))	('50s', 'Species', '1214577', (14, 17))	('PVT1', 'Gene', '5820', (57, 61))	('DDP', 'Gene', (8, 11))	('reduced', 'NegReg', (39, 46))	('knockdown', 'Var', (62, 71))
114031	28969069	Western blotting also showed that PVT1 knockdown inhibited multidrug resistance protein 1 (MDR1) and multidrug resistance associated protein 1 (MRP1) expression in T24/DR cells (P<0.05; Figure 3C).	('multidrug resistance protein', 'molecular_function', 'GO:0008559', ('59', '87'))	('expression', 'MPA', (150, 160))	('multidrug resistance protein 1', 'Gene', (59, 89))	('MDR1', 'Gene', (91, 95))	('drug resistance', 'Phenotype', 'HP:0020174', (106, 121))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('MRP1', 'Gene', (144, 148))	('knockdown', 'Var', (39, 48))	('PVT1', 'Gene', (34, 38))	('MDR', 'molecular_function', 'GO:0004745', ('91', '94'))	('multidrug resistance associated protein 1', 'Gene', '4363', (101, 142))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('multidrug resistance associated protein 1', 'Gene', (101, 142))	('multidrug resistance protein 1', 'Gene', '5243', (59, 89))	('PVT1', 'Gene', '5820', (34, 38))	('inhibited', 'NegReg', (49, 58))	('drug resistance', 'Phenotype', 'HP:0020174', (64, 79))
114035	28969069	TOP/FOPflash luciferase reporter assay results showed that PVT1 knockdown suppressed the TOP/FOP ratio in T24/DR cells (P<0.05; Figure 4A).	('suppressed', 'NegReg', (74, 84))	('PVT1', 'Gene', (59, 63))	('PVT1', 'Gene', '5820', (59, 63))	('knockdown', 'Var', (64, 73))	('TOP/FOP ratio', 'MPA', (89, 102))
114036	28969069	PVT1 knockdown also reduced both cytoplasmic and nuclear beta-catenin levels (P<0.05; Figure 4B) and CyclinD1 expression, the target gene of beta-catenin (P<0.05; Figure 4B).	('reduced', 'NegReg', (20, 27))	('CyclinD1', 'Gene', (101, 109))	('knockdown', 'Var', (5, 14))	('PVT1', 'Gene', (0, 4))	('expression', 'MPA', (110, 120))	('PVT1', 'Gene', '5820', (0, 4))
114037	28969069	These results suggest that PVT1 knockdown reduced Wnt/beta-catenin signaling.	('reduced', 'NegReg', (42, 49))	('PVT1', 'Gene', (27, 31))	('knockdown', 'Var', (32, 41))	('Wnt/beta-catenin signaling', 'MPA', (50, 76))	('PVT1', 'Gene', '5820', (27, 31))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))
114039	28969069	Wnt/beta-catenin pathway activation reversed the effects of PVT1 knockdown on T24/DR cells, upregulating cell proliferation and invasion, and suppressing apoptosis (P<0.05; Figure 6A-6D).	('apoptosis', 'biological_process', 'GO:0097194', ('154', '163'))	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('apoptosis', 'biological_process', 'GO:0006915', ('154', '163'))	('PVT1', 'Gene', '5820', (60, 64))	('apoptosis', 'CPA', (154, 163))	('upregulating', 'PosReg', (92, 104))	('suppressing', 'NegReg', (142, 153))	('knockdown', 'Var', (65, 74))	('invasion', 'CPA', (128, 136))	('cell proliferation', 'CPA', (105, 123))	('PVT1', 'Gene', (60, 64))
114040	28969069	Wnt/beta-catenin pathway activation also largely restored T24/DR cell chemoresistance reduced by PVT1 knockdown.	('reduced', 'NegReg', (86, 93))	('knockdown', 'Var', (102, 111))	('T24/DR cell chemoresistance', 'CPA', (58, 85))	('restored', 'NegReg', (49, 57))	('PVT1', 'Gene', (97, 101))	('PVT1', 'Gene', '5820', (97, 101))
114042	28969069	Altered lncRNA expression contributes to human tumor development and progression, providing novel anti-tumor therapeutic target opportunities.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('human', 'Species', '9606', (41, 46))	('Altered', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('lncRNA expression', 'Protein', (8, 25))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('progression', 'CPA', (69, 80))	('contributes', 'Reg', (26, 37))	('tumor', 'Disease', (47, 52))
114046	28969069	lncRNA PVT1 was upregulated over eight-fold in T24/DR cells compared to parent (non-resistant) T24 cells.	('upregulated', 'PosReg', (16, 27))	('PVT1', 'Gene', (7, 11))	('T24/DR', 'Var', (47, 53))	('PVT1', 'Gene', '5820', (7, 11))
114049	28969069	PVT1 silencing inhibited BC cell growth and induced apoptosis, but the role of PVT1 in BUC chemoresistance was not assessed.	('BC cell growth', 'CPA', (25, 39))	('inhibited', 'NegReg', (15, 24))	('induced', 'Reg', (44, 51))	('silencing', 'Var', (5, 14))	('PVT1', 'Gene', (0, 4))	('cell growth', 'biological_process', 'GO:0016049', ('28', '39'))	('PVT1', 'Gene', (79, 83))	('apoptosis', 'CPA', (52, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('52', '61'))	('BC', 'Phenotype', 'HP:0009725', (25, 27))	('PVT1', 'Gene', '5820', (0, 4))	('PVT1', 'Gene', '5820', (79, 83))	('apoptosis', 'biological_process', 'GO:0006915', ('52', '61'))
114051	28969069	Similarly, we found that PVT1 knockdown inhibited T24/DR cell proliferation and invasion, and enhanced apoptosis, suggesting that PVT1 acts as a potential oncogene in BUC.	('invasion', 'CPA', (80, 88))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('PVT1', 'Gene', (130, 134))	('inhibited', 'NegReg', (40, 49))	('PVT1', 'Gene', (25, 29))	('enhanced', 'PosReg', (94, 102))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('T24/DR cell proliferation', 'CPA', (50, 75))	('PVT1', 'Gene', '5820', (130, 134))	('knockdown', 'Var', (30, 39))	('apoptosis', 'CPA', (103, 112))	('cell proliferation', 'biological_process', 'GO:0008283', ('57', '75'))	('PVT1', 'Gene', '5820', (25, 29))
114052	28969069	PVT1 knockdown also reduced T24/DR resistance to DOX and DDP, and downregulated MDR1 and MRP1 expression.	('reduced', 'NegReg', (20, 27))	('DDP', 'Gene', (57, 60))	('DOX', 'Chemical', 'MESH:D004317', (49, 52))	('knockdown', 'Var', (5, 14))	('MRP1', 'Gene', (89, 93))	('MDR', 'molecular_function', 'GO:0004745', ('80', '83'))	('PVT1', 'Gene', (0, 4))	('downregulated', 'NegReg', (66, 79))	('expression', 'MPA', (94, 104))	('DDP', 'Gene', '1678', (57, 60))	('PVT1', 'Gene', '5820', (0, 4))	('MDR1', 'Gene', (80, 84))
114056	28969069	We confirmed that PVT1 knockdown inhibited Wnt/beta-catenin signaling via the TOP/FOPflash luciferase reporter system and western blotting.	('knockdown', 'Var', (23, 32))	('PVT1', 'Gene', (18, 22))	('Wnt/beta-catenin signaling', 'MPA', (43, 69))	('PVT1', 'Gene', '5820', (18, 22))	('inhibited', 'NegReg', (33, 42))	('signaling', 'biological_process', 'GO:0023052', ('60', '69'))
114057	28969069	showed that PVT1 epigenetically silenced miR-200b expression to promote cervical cancer cell proliferation, migration, and cell cycle progression.	('cell cycle progression', 'CPA', (123, 145))	('migration', 'CPA', (108, 117))	('promote', 'PosReg', (64, 71))	('PVT1', 'Gene', '5820', (12, 16))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('miR-200b', 'Gene', '406984', (41, 49))	('cancer', 'Disease', (81, 87))	('epigenetically', 'Var', (17, 31))	('PVT1', 'Gene', (12, 16))	('miR-200b', 'Gene', (41, 49))	('cell proliferation', 'biological_process', 'GO:0008283', ('88', '106'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cell cycle', 'biological_process', 'GO:0007049', ('123', '133'))	('expression', 'MPA', (50, 60))
114059	28969069	We speculate that PVT1 knockdown inhibited Wnt/beta-catenin signaling in our study through the miR-200b/PAF axis.	('PAF', 'Gene', (104, 107))	('miR-200b', 'Gene', (95, 103))	('knockdown', 'Var', (23, 32))	('PAF', 'Gene', '9768', (104, 107))	('PVT1', 'Gene', (18, 22))	('Wnt/beta-catenin signaling', 'MPA', (43, 69))	('miR-200b', 'Gene', '406984', (95, 103))	('PVT1', 'Gene', '5820', (18, 22))	('inhibited', 'NegReg', (33, 42))	('signaling', 'biological_process', 'GO:0023052', ('60', '69'))
114062	28969069	We found that activating Wnt/beta-catenin signaling by upregulating beta-catenin reversed the effects of PVT1 knockdown in T24/DR cells, restoring chemoresistance in these cells.	('PVT1', 'Gene', (105, 109))	('knockdown', 'Var', (110, 119))	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('upregulating', 'PosReg', (55, 67))	('PVT1', 'Gene', '5820', (105, 109))	('activating', 'PosReg', (14, 24))	('beta-catenin', 'Protein', (68, 80))	('restoring', 'PosReg', (137, 146))	('chemoresistance', 'CPA', (147, 162))
114111	29472622	Aberrant methylated key genes of methyl group metabolism within the molecular etiology of urothelial carcinogenesis Urothelial carcinoma (UC), the most common cancer of the urinary bladder causes severe morbidity and mortality, e.g.	('cancer', 'Disease', (159, 165))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (90, 115))	('Urothelial carcinoma', 'Disease', (116, 136))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('metabolism', 'biological_process', 'GO:0008152', ('46', '56'))	('Aberrant methylated', 'Var', (0, 19))	('urothelial carcinogenesis', 'Disease', (90, 115))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('Urothelial carcinoma', 'Disease', 'MESH:D014526', (116, 136))
114113	29472622	Extensive aberrant  DNA methylation is described to prevail in urothelial carcinoma and is thought to contribute to genetic instability, altered gene expression and tumor progression.	('DNA methylation', 'biological_process', 'GO:0006306', ('20', '35'))	('genetic instability', 'MPA', (116, 135))	('altered gene expression', 'MPA', (137, 160))	('gene expression', 'biological_process', 'GO:0010467', ('145', '160'))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (63, 83))	('contribute', 'Reg', (102, 112))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('urothelial carcinoma', 'Disease', (63, 83))	('aberrant  DNA methylation', 'Var', (10, 35))	('tumor', 'Disease', (165, 170))
114116	29472622	We therefore infer that hypermethylation of methyl group metabolism genes acts in a feed-forward cycle to promote additional DNA methylation changes and suggest a new hypothesis on the molecular etiology of urothelial carcinoma.	('hypermethylation', 'Var', (24, 40))	('urothelial carcinoma', 'Disease', (207, 227))	('DNA methylation', 'biological_process', 'GO:0006306', ('125', '140'))	('DNA methylation changes', 'MPA', (125, 148))	('promote', 'PosReg', (106, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (207, 227))	('metabolism', 'biological_process', 'GO:0008152', ('57', '67'))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))
114126	29472622	In urothelial carcinoma, focal DNA hypermethylation events, often associated with gene repression, and genome-wide LINE-1 hypomethylation have been detected in non-muscle invasive as well as in more aggressive muscle-invasive tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (3, 23))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (210, 232))	('focal DNA', 'Var', (25, 34))	('detected', 'Reg', (148, 156))	('urothelial carcinoma', 'Disease', (3, 23))	('muscle-invasive tumors', 'Disease', (210, 232))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('31', '51'))	('non-muscle invasive', 'Disease', (160, 179))
114127	29472622	It may contribute to carcinogenesis in various ways, including induction of genomic instability and aberrant transcription patterns.	('induction', 'Reg', (63, 72))	('aberrant', 'Var', (100, 108))	('genomic instability', 'CPA', (76, 95))	('carcinogenesis', 'Disease', 'MESH:D063646', (21, 35))	('transcription', 'biological_process', 'GO:0006351', ('109', '122'))	('contribute', 'Reg', (7, 17))	('carcinogenesis', 'Disease', (21, 35))
114128	29472622	Exposure to various chemical carcinogens such as occupational exposure to aromatic amines, and polycyclic aromatic hydrocarbons, with different attributable risks, is recognized as an important risk factor in urothelial carcinogenesis.	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (95, 127))	('aromatic amines', 'Chemical', '-', (74, 89))	('urothelial carcinogenesis', 'Disease', (209, 234))	('polycyclic aromatic', 'Var', (95, 114))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (209, 234))
114129	29472622	In addition, exposure to arsenic in drinking water and aristolochic acid in food or remedies, have been recognized as further causes of UC.	('drinking water', 'Chemical', 'MESH:D060766', (36, 50))	('causes', 'Reg', (126, 132))	('arsenic', 'Chemical', 'MESH:D001151', (25, 32))	('aristolochic acid', 'Var', (55, 72))	('aristolochic acid', 'Chemical', 'MESH:C000228', (55, 72))
114132	29472622	They are thought to act as carcinogens by forming DNA adducts and causing mutations in key cancer-related genes.	('causing', 'Reg', (66, 73))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('mutations', 'Var', (74, 83))	('forming', 'Reg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
114135	29472622	Accumulating evidence indicates that aberrant DNA methylation occurs as a direct consequence of exposure of urothelial cells to tobacco smoke carcinogens in urine.	('DNA methylation', 'MPA', (46, 61))	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('smoke carcinogens', 'Disease', 'MESH:D000074607', (136, 153))	('tobacco', 'Species', '4097', (128, 135))	('DNA methylation', 'biological_process', 'GO:0006306', ('46', '61'))	('smoke carcinogens', 'Disease', (136, 153))	('aberrant', 'Var', (37, 45))
114137	29472622	Similarly, several studies have linked arsenic exposure with hypermethylation and hypomethylation events in urothelial carcinogenesis (see refs in Schulz & Goering).	('hypomethylation', 'Var', (82, 97))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (108, 133))	('hypermethylation', 'MPA', (61, 77))	('urothelial carcinogenesis', 'Disease', (108, 133))	('arsenic', 'Chemical', 'MESH:D001151', (39, 46))
114140	29472622	We were therefore intrigued to observe during a screen for DNA methylation alterations in early stage urothelial carcinoma and adjacent, morphologically normal urothelium that genes encoding crucial enzymes in methyl group metabolism pathways appeared themselves to be affected by aberrant DNA methylation.	('metabolism', 'biological_process', 'GO:0008152', ('223', '233'))	('DNA methylation', 'biological_process', 'GO:0006306', ('59', '74'))	('stage urothelial carcinoma', 'Disease', (96, 122))	('DNA methylation', 'biological_process', 'GO:0006306', ('290', '305'))	('affected by', 'Reg', (269, 280))	('aberrant DNA methylation', 'Var', (281, 305))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('genes', 'Gene', (176, 181))	('stage urothelial carcinoma', 'Disease', 'MESH:D062706', (96, 122))	('DNA', 'cellular_component', 'GO:0005574', ('290', '293'))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
114141	29472622	The results indeed provide evidence that key genes of methyl group metabolism are themselves affected by aberrant DNA methylation in their 5'-regulatory regions in early stage urothelial carcinoma.	('stage urothelial carcinoma', 'Disease', (170, 196))	('metabolism', 'biological_process', 'GO:0008152', ('67', '77'))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('affected by', 'Reg', (93, 104))	('DNA', 'Gene', (114, 117))	('DNA methylation', 'biological_process', 'GO:0006306', ('114', '129'))	('aberrant', 'Var', (105, 113))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('stage urothelial carcinoma', 'Disease', 'MESH:D062706', (170, 196))
114142	29472622	These findings implicate a new mechanism in the etiology of epigenetic alterations during UC carcinogenesis.	('epigenetic alterations', 'Var', (60, 82))	('carcinogenesis', 'Disease', (93, 107))	('carcinogenesis', 'Disease', 'MESH:D063646', (93, 107))
114144	29472622	TP53 mutant cells, and widespread epigenetic alterations, e.g.	('mutant', 'Var', (5, 11))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))
114145	29472622	hypermethylated genes which are also present in bladder cancer cells.	('bladder cancer', 'Disease', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('hypermethylated genes', 'Var', (0, 21))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))
114150	29472622	Twelve of 26 considered genes did not show statistically significant differential methylation in any of the sample groups compared to healthy urothelium, despite a trend towards hypermethylation in ARG1, BHMT, BHMT2, CBS, DNMT3A, DNMT3B, FOLR3, SHMT1 and SMOX, and a trend towards hypomethylation in FOLR1/2 and MAT2B and in the corresponding tumor-adjacent, histologically benign urothelium.	('CBS', 'Gene', (217, 220))	('ARG1', 'Gene', '383', (198, 202))	('MAT', 'molecular_function', 'GO:0004314', ('312', '315'))	('MAT2B', 'Gene', '27430', (312, 317))	('BHMT', 'Gene', (210, 214))	('FOLR1/2', 'Gene', '2348;2350', (300, 307))	('SHMT1', 'Gene', '6470', (245, 250))	('CBS', 'Gene', '875', (217, 220))	('BHMT2', 'Gene', (210, 215))	('MAT2B', 'Gene', (312, 317))	('DNMT3A', 'Gene', '1788', (222, 228))	('hypermethylation', 'MPA', (178, 194))	('FOLR3', 'Gene', (238, 243))	('DNMT3B', 'Gene', '1789', (230, 236))	('DNMT3B', 'Gene', (230, 236))	('BHMT', 'Gene', (204, 208))	('tumor', 'Disease', (343, 348))	('hypomethylation', 'Var', (281, 296))	('FOLR3', 'Gene', '2352', (238, 243))	('BHMT', 'Gene', '635', (204, 208))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('ARG1', 'Gene', (198, 202))	('BHMT', 'Gene', '635', (210, 214))	('DNMT3A', 'Gene', (222, 228))	('SHMT1', 'Gene', (245, 250))	('BHMT2', 'Gene', '23743', (210, 215))	('SMOX', 'Gene', (255, 259))	('methylation', 'biological_process', 'GO:0032259', ('82', '93'))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('FOLR1/2', 'Gene', (300, 307))	('SMOX', 'Gene', '54498', (255, 259))
114151	29472622	The second group consisted of genes with statistically significant hypermethylation in either unifocal or multifocal tumors, namely AMD1, DNMT1 and MGMT in unifocal tumors and UHRF1, AHCYL1 and TCN2 in multifocal tumors.	('unifocal', 'Disease', (94, 102))	('DNMT1', 'Gene', '1786', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('multifocal tumors', 'Disease', 'None', (106, 123))	('MGMT', 'Gene', (148, 152))	('AMD1', 'Gene', '262', (132, 136))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('multifocal tumors', 'Disease', 'None', (202, 219))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('multifocal tumors', 'Disease', (106, 123))	('multifocal tumors', 'Disease', (202, 219))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('unifocal tumors', 'Disease', 'MESH:D009369', (156, 171))	('UHRF1', 'Gene', '29128', (176, 181))	('DNMT1', 'Gene', (138, 143))	('significant', 'Reg', (55, 66))	('AHCYL1', 'Gene', (183, 189))	('AHCYL1', 'Gene', '10768', (183, 189))	('MGMT', 'Gene', '4255', (148, 152))	('TCN2', 'Gene', (194, 198))	('AMD1', 'Gene', (132, 136))	('hypermethylation', 'Var', (67, 83))	('UHRF1', 'Gene', (176, 181))	('MGMT', 'molecular_function', 'GO:0003908', ('148', '152'))	('TCN2', 'Gene', '6948', (194, 198))	('unifocal tumors', 'Disease', (156, 171))
114154	29472622	Finally ODC1, AHCY, MTHFR and AHCYL2 were significantly hypermethylated in their 5'-regulatory gene regions in unifocal as well as multifocal tumors.	('ODC1', 'Gene', (8, 12))	('AHCY', 'Gene', '191', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('hypermethylated', 'Var', (56, 71))	('MTHFR', 'Gene', '4524', (20, 25))	('AHCYL2', 'Gene', (30, 36))	('ODC1', 'Gene', '4953', (8, 12))	('AHCYL2', 'Gene', '23382', (30, 36))	('multifocal tumors', 'Disease', (131, 148))	('MTHFR', 'Gene', (20, 25))	('multifocal tumors', 'Disease', 'None', (131, 148))	('AHCY', 'Gene', (30, 34))	('AHCY', 'Gene', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('AHCY', 'Gene', '191', (30, 34))
114158	29472622	In order to confirm the hypermethylation detected in ODC1 and AHCY by MeDIP-array analyses and to reveal the detailed methylation patterns of these differentially methylated regions (DMRs) we used standard bisulfite sequencing.	('hypermethylation', 'Var', (24, 40))	('ODC1', 'Gene', (53, 57))	('AHCY', 'Gene', '191', (62, 66))	('ODC1', 'Gene', '4953', (53, 57))	('methylation', 'biological_process', 'GO:0032259', ('118', '129'))	('bisulfite', 'Chemical', 'MESH:C042345', (206, 215))	('AHCY', 'Gene', (62, 66))
114159	29472622	Specifically, ODC1 hypermethylation had been detected in two pTaLG (2xMT), in two pTaLGadj (1xMT, 1xUT), in three pTaHG (1xMT, 2xUT), in two pTaHGadj (2xUT), in four pT1HG (2xMT, 2xUT), and in three pT1HGadj (1xMT, 2xUT) tissue samples.	('detected', 'Reg', (45, 53))	('pT1', 'Gene', (199, 202))	('pT1', 'Gene', '58492', (166, 169))	('ODC1', 'Gene', (14, 18))	('pT1', 'Gene', (166, 169))	('ODC1', 'Gene', '4953', (14, 18))	('hypermethylation', 'Var', (19, 35))	('pT1', 'Gene', '58492', (199, 202))
114162	29472622	In all these cases DNA methylation array data had indicated DNA hypermethylation of the respective ODC1 5'-regulatory region.	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('60', '80'))	('ODC1', 'Gene', (99, 103))	('ODC1', 'Gene', '4953', (99, 103))	('DNA methylation', 'biological_process', 'GO:0006306', ('19', '34'))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('hypermethylation', 'Var', (64, 80))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
114164	29472622	Thus, hypermethylation at the 5'-region of ODC1 appears to occur in some, but not all early stage urothelial carcinoma specimens.	('occur', 'Reg', (59, 64))	('ODC1', 'Gene', (43, 47))	('hypermethylation', 'Var', (6, 22))	('stage urothelial carcinoma', 'Disease', 'MESH:D062706', (92, 118))	('men', 'Species', '9606', (124, 127))	('ODC1', 'Gene', '4953', (43, 47))	('stage urothelial carcinoma', 'Disease', (92, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))
114166	29472622	We confirmed by bisulfite sequencing dense DNA methylation of this region in one unifocal pTa low grade, one multifocal pTa low grade and one unifocal pT1 low grade UC tissue sample and in contrast, lack of methylation in intact, healthy urothelium (Fig.	('methylation', 'biological_process', 'GO:0032259', ('207', '218'))	('pT1', 'Gene', (151, 154))	('pTa', 'molecular_function', 'GO:0008959', ('90', '93'))	('bisulfite', 'Chemical', 'MESH:C042345', (16, 25))	('methylation', 'Var', (47, 58))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('multifocal pTa low', 'Phenotype', 'HP:0031165', (109, 127))	('pT1', 'Gene', '58492', (151, 154))	('pTa', 'molecular_function', 'GO:0008959', ('120', '123'))	('DNA methylation', 'biological_process', 'GO:0006306', ('43', '58'))
114181	29472622	This method allows a reliable comparison of LINE-1 methylation in tumor samples despite genetic heterogeneity and copy number changes.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('copy number changes', 'Var', (114, 133))
114183	29472622	as a tumor entity with numerous and diverse epigenetic aberrations and associated genetic abnormalities that are thought to originate in the early stages of the carcinogenesis process and spreading across the entire genome.	('genetic abnormalities', 'Disease', 'MESH:D030342', (82, 103))	('genetic abnormalities', 'Disease', (82, 103))	('epigenetic aberrations', 'Var', (44, 66))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('carcinogenesis', 'Disease', 'MESH:D063646', (161, 175))	('tumor', 'Disease', (5, 10))	('carcinogenesis', 'Disease', (161, 175))
114186	29472622	For instance, tobacco smoking, a main risk factor, is thought to exert its adverse effect by aromatic amines and other contained carcinogens, reaching urothelial cells via the urine, forming DNA adducts and causing mutations.	('aromatic amines', 'Chemical', '-', (93, 108))	('DNA adducts', 'MPA', (191, 202))	('DNA', 'cellular_component', 'GO:0005574', ('191', '194'))	('mutations', 'Var', (215, 224))	('forming', 'Reg', (183, 190))	('causing', 'Reg', (207, 214))	('tobacco', 'Species', '4097', (14, 21))
114194	29472622	Global hypomethylation is a characteristic of many cancers, related to genomic instability and is particularly prominent in urothelial carcinoma.	('prominent', 'Reg', (111, 120))	('related', 'Reg', (60, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('Global hypomethylation', 'Var', (0, 22))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (124, 144))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('urothelial carcinoma', 'Disease', (124, 144))
114195	29472622	Therefore, the hypermethylation of key methyl group metabolism genes in early urothelial carcinoma specimens may promote further epigenetic alterations such as global DNA hypomethylation.	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('167', '186'))	('men', 'Species', '9606', (104, 107))	('metabolism', 'biological_process', 'GO:0008152', ('52', '62'))	('promote', 'PosReg', (113, 120))	('urothelial carcinoma', 'Disease', (78, 98))	('DNA', 'cellular_component', 'GO:0005574', ('167', '170'))	('hypermethylation', 'Var', (15, 31))	('epigenetic alterations', 'MPA', (129, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('global DNA hypomethylation', 'Disease', (160, 186))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (78, 98))
114197	29472622	The first enzyme affected by these hypermethylation events, ODC1, ornithine decarboxylase, is the rate-limiting enzyme of polyamine biosynthesis.	('hypermethylation', 'Var', (35, 51))	('polyamine', 'Chemical', 'MESH:D011073', (122, 131))	('ODC1', 'Gene', '4953', (60, 64))	('polyamine biosynthesis', 'biological_process', 'GO:0006596', ('122', '144'))	('ornithine decarboxylase', 'Gene', '4953', (66, 89))	('ODC1', 'Gene', (60, 64))	('ornithine decarboxylase', 'Gene', (66, 89))
114198	29472622	In early work, a positive correlation between ODC1 gene hypomethylation and expression was observed, experimental methylation of ODC1 abolished expression and aberrant methylation was reported in malignant cells.	('ODC1', 'Gene', '4953', (46, 50))	('methylation', 'biological_process', 'GO:0032259', ('168', '179'))	('men', 'Species', '9606', (107, 110))	('ODC1', 'Gene', '4953', (129, 133))	('expression', 'MPA', (144, 154))	('methylation', 'biological_process', 'GO:0032259', ('114', '125'))	('ODC1', 'Gene', (46, 50))	('methylation', 'Var', (114, 125))	('ODC1', 'Gene', (129, 133))	('abolished', 'NegReg', (134, 143))
114205	29472622	Thus, the dense DNA methylation encompassing the ODC1 5'-regulatory region in most of the analyzed early urothelial carcinoma specimens would be expected to epigenetically impair ODC1 expression.	('urothelial carcinoma', 'Disease', (105, 125))	('DNA methylation', 'biological_process', 'GO:0006306', ('16', '31'))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('ODC1', 'Gene', (179, 183))	('epigenetically', 'Var', (157, 171))	('impair', 'NegReg', (172, 178))	('men', 'Species', '9606', (131, 134))	('ODC1', 'Gene', '4953', (179, 183))	('ODC1', 'Gene', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('ODC1', 'Gene', '4953', (49, 53))	('expression', 'MPA', (184, 194))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (105, 125))
114206	29472622	Second, we have documented here DNA methylation of the 5'-regulatory region of AHCY encoding S-adenosylhomocysteine hydrolase in urothelial carcinoma specimens.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (129, 149))	('men', 'Species', '9606', (155, 158))	('S-adenosylhomocysteine hydrolase', 'Gene', (93, 125))	('AHCY', 'Gene', '191', (79, 83))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('urothelial carcinoma', 'Disease', (129, 149))	('S-adenosylhomocysteine hydrolase', 'Gene', '191', (93, 125))	('AHCY', 'Gene', (79, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('DNA methylation', 'biological_process', 'GO:0006306', ('32', '47'))	('methylation', 'Var', (36, 47))	('men', 'Species', '9606', (20, 23))
114217	29472622	the two common functional polymorphisms A1298C (rs1801131) and C677T (rs1801133) which diminish enzymatic activity, are involved.	('rs1801133', 'Mutation', 'rs1801133', (70, 79))	('C677T (rs1801133', 'Var', (63, 79))	('diminish', 'NegReg', (87, 95))	('rs1801133', 'Var', (70, 79))	('enzymatic activity', 'MPA', (96, 114))	('C677T', 'Mutation', 'rs1801133', (63, 68))	('rs1801131', 'Mutation', 'rs1801131', (48, 57))	('A1298C', 'Mutation', 'rs1801131', (40, 46))	('rs1801131', 'Var', (48, 57))
114218	29472622	For instance, carriers of the MTHFR variant allele A1289C had 4% lower LINE-1 methylation compared to those carrying the more common genotypes of this SNP in histologically normal breast tissues.	('LINE-1', 'Protein', (71, 77))	('A1289C', 'Var', (51, 57))	('A1289C', 'Mutation', 'c.1289A>C', (51, 57))	('lower', 'NegReg', (65, 70))	('MTHFR', 'Gene', (30, 35))	('methylation', 'biological_process', 'GO:0032259', ('78', '89'))	('MTHFR', 'Gene', '4524', (30, 35))
114221	29472622	The 5'-region analyzed by us was identified as the site of focal epimutations in mothers of Down syndrome children associated with global LINE-1 hypomethylation in their blood cells.	('epimutations', 'Var', (65, 77))	('associated', 'Reg', (115, 125))	('Down syndrome', 'Disease', (92, 105))	('global LINE-1 hypomethylation', 'MPA', (131, 160))	('children', 'Species', '9606', (106, 114))
114222	29472622	In human lung cancer cells MTHFR methylation was inversely correlated with gene expression.	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('gene expression', 'MPA', (75, 90))	('methylation', 'Var', (33, 44))	('MTHFR', 'Gene', '4524', (27, 32))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('MTHFR', 'Gene', (27, 32))	('lung cancer', 'Disease', (9, 20))	('gene expression', 'biological_process', 'GO:0010467', ('75', '90'))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))
114226	29472622	Focal cytosine methylation at transcription factor binding sites may lead to altered gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('85', '100'))	('gene expression', 'MPA', (85, 100))	('cytosine methylation', 'biological_process', 'GO:0032776', ('6', '26'))	('Focal cytosine methylation', 'Var', (0, 26))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('30', '58'))	('cytosine', 'Chemical', 'MESH:D003596', (6, 14))	('transcription', 'biological_process', 'GO:0006351', ('30', '43'))	('lead to altered', 'Reg', (69, 84))
114227	29472622	Their altered expression is expected to interfere with methylome integrity and in a feed-forward loop may propagate the development of epigenetic abnormalities, e.g.	('interfere', 'NegReg', (40, 49))	('men', 'Species', '9606', (127, 130))	('genetic abnormalities', 'Disease', 'MESH:D030342', (138, 159))	('expression', 'MPA', (14, 24))	('genetic abnormalities', 'Disease', (138, 159))	('methylome integrity', 'MPA', (55, 74))	('altered', 'Var', (6, 13))
114228	29472622	LINE-1 hypomethylation and other epigenetic disturbances in early urothelial carcinoma.	('urothelial carcinoma', 'Disease', (66, 86))	('hypomethylation', 'Var', (7, 22))	('epigenetic disturbances', 'Var', (33, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (66, 86))	('LINE-1', 'Gene', (0, 6))
114232	29472622	This impairment causes regulation imbalances within the involved methyl group metabolic pathways, disturbances of the delicate SAM:SAH ratio and consequently genome-wide DNA methylation alterations, including LINE-1 hypomethylation, ultimately resulting in genetic instabilities and cellular transformation.	('cellular transformation', 'CPA', (283, 306))	('causes', 'Reg', (16, 22))	('methyl group metabolic pathways', 'Pathway', (65, 96))	('alterations', 'Var', (186, 197))	('SAH', 'Gene', '6296', (131, 134))	('SAH', 'Gene', (131, 134))	('DNA methylation', 'biological_process', 'GO:0006306', ('170', '185'))	('genetic instabilities', 'Disease', 'MESH:D030342', (257, 278))	('disturbances', 'Var', (98, 110))	('hypomethylation', 'Var', (216, 231))	('SAM', 'Chemical', 'MESH:D012436', (127, 130))	('imbalances', 'Phenotype', 'HP:0002172', (34, 44))	('resulting in', 'Reg', (244, 256))	('imbalances', 'Reg', (34, 44))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))	('regulation', 'biological_process', 'GO:0065007', ('23', '33'))	('regulation', 'MPA', (23, 33))	('men', 'Species', '9606', (11, 14))	('genetic instabilities', 'Disease', (257, 278))
114235	29472622	Finally, it should be noted that such epigenetic alterations of genes with key importance in methyl group metabolism appear to fit well with the broadly discussed "few hits"-theory of cancer initiation.	('cancer initiation', 'Disease', (184, 201))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('metabolism', 'biological_process', 'GO:0008152', ('106', '116'))	('epigenetic alterations', 'Var', (38, 60))	('cancer initiation', 'Disease', 'MESH:D009369', (184, 201))
114237	29472622	6 for colon cancer, and in addition epigenetic events are together responsible for cancer initiation.	('cancer initiation', 'Disease', (83, 100))	('responsible', 'Reg', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('epigenetic events', 'Var', (36, 53))	('colon cancer', 'Phenotype', 'HP:0003003', (6, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('colon cancer', 'Disease', 'MESH:D015179', (6, 18))	('cancer initiation', 'Disease', 'MESH:D009369', (83, 100))	('colon cancer', 'Disease', (6, 18))
114274	28030802	Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies.	('translocation', 'Var', (134, 147))	('gene amplification', 'Var', (89, 107))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('oncogenesis', 'biological_process', 'GO:0007048', ('73', '84'))	('activating', 'MPA', (109, 119))
114275	28030802	With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (55, 58))	('tied', 'Reg', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('cell proliferation', 'biological_process', 'GO:0008283', ('117', '135'))	('FGF', 'Gene', (55, 58))	('aberrations', 'Var', (60, 71))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
114276	28030802	Inhibition of FGFR signaling appears promising in preclinical studies, suggesting a pathway of clinical interest in the development of targeted therapy.	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('Inhibition', 'Var', (0, 10))	('FGF', 'Gene', (14, 17))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (14, 17))
114279	28030802	As we progress from the first generation of non-selective drugs to the second generation of selective FGFR inhibitors, it is clear that FGFR aberrations do not behave uniformly across cancer types; thus, a deeper understanding of biomarker strategies is undoubtedly warranted.	('cancer', 'Disease', (184, 190))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('FGFR', 'molecular_function', 'GO:0005007', ('136', '140'))	('FGF', 'Gene', (102, 105))	('FGF', 'Gene', (136, 139))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (102, 105))	('inhibitors', 'Var', (107, 117))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
114282	28030802	We will also discuss qualities that may be desirable in future generations of FGFR inhibitors, with the hope that overcoming these current barriers will expedite the availability of this novel class of medications.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (78, 81))	('FGF', 'Gene', (78, 81))	('FGFR', 'molecular_function', 'GO:0005007', ('78', '82'))	('inhibitors', 'Var', (83, 93))
114284	28030802	Many prior studies indicate that alterations in FGFR signaling are associated with a broad range of congenital craniofacial developmental disorders.	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('congenital craniofacial developmental disorders', 'Disease', 'MESH:D019465', (100, 147))	('congenital craniofacial developmental disorders', 'Disease', (100, 147))	('alterations', 'Var', (33, 44))	('associated', 'Reg', (67, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('FGF', 'Gene', (48, 51))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (48, 51))
114285	28030802	Relatively recently, we have come to understand that somatic mutations of FGFR also have a role in oncologic evolution which makes this pathway of interest when exploring the realm of cancer-directed therapy.	('cancer', 'Disease', (184, 190))	('FGF', 'Gene', (74, 77))	('oncologic evolution', 'Disease', (99, 118))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutations', 'Var', (61, 70))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (74, 77))	('role', 'Reg', (91, 95))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))
114288	28030802	We ultimately need to re-evaluate how we can better develop strategies to bring direct FGFR inhibitors into the clinical setting.	('FGF', 'Gene', (87, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (87, 90))	('inhibitors', 'Var', (92, 102))
114292	28030802	The members differ from one another in their ligand affinities and tissue distribution with variations in splicing of FGFR1-3 accounting for some additional diversity.	('FGFR1', 'Gene', '2260', (118, 123))	('FGFR', 'molecular_function', 'GO:0005007', ('118', '122'))	('FGFR1', 'Gene', (118, 123))	('splicing', 'biological_process', 'GO:0045292', ('106', '114'))	('ligand', 'molecular_function', 'GO:0005488', ('45', '51'))	('ligand affinities', 'Interaction', (45, 62))	('variations', 'Var', (92, 102))
114295	28030802	Upon ligand binding, FGFRs dimerize and trigger a cascade of downstream signaling pathways, including the mitogen activated protein kinase (MAPK), signal transducer and activator of transcription (STAT), the phosphoinositide-3-kinase (PI3K)/Akt pathways, and DAG-PKC and IP3-Ca2+ signaling branches via PLCgamma activation.	('dimerize', 'Var', (27, 35))	('MAPK', 'Gene', (140, 144))	('ligand', 'molecular_function', 'GO:0005488', ('5', '11'))	('PLCgamma', 'Enzyme', (303, 311))	('binding', 'Interaction', (12, 19))	('MAPK', 'Gene', '5594', (140, 144))	('binding', 'molecular_function', 'GO:0005488', ('12', '19'))	('FGF', 'Gene', (21, 24))	('PKC', 'molecular_function', 'GO:0004697', ('263', '266'))	('activation', 'PosReg', (312, 322))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('Akt', 'Gene', (241, 244))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('Akt', 'Gene', '207', (241, 244))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (21, 24))	('mitogen activated protein kinase', 'Pathway', (106, 138))	('IP3', 'Chemical', 'MESH:D015544', (271, 274))	('Ca2+', 'Chemical', 'MESH:D000069285', (275, 279))	('trigger', 'Reg', (40, 47))	('signaling', 'biological_process', 'GO:0023052', ('280', '289'))	('PI3K', 'molecular_function', 'GO:0016303', ('235', '239'))	('MAPK', 'molecular_function', 'GO:0004707', ('140', '144'))	('transcription', 'biological_process', 'GO:0006351', ('182', '195'))
114297	28030802	There are several proposed mechanisms for FGFR related oncogenesis including: (i) activating or "driver" mutations resulting in cell growth and survival; (ii) neo-angiogenesis; and (iii) acquired resistance to other cancer therapy.	('cell growth', 'CPA', (128, 139))	('oncogenesis', 'biological_process', 'GO:0007048', ('55', '66'))	('oncogenesis', 'Disease', (55, 66))	('activating', 'PosReg', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('neo-angiogenesis', 'CPA', (159, 175))	('angiogenesis', 'biological_process', 'GO:0001525', ('161', '173'))	('mutations', 'Var', (105, 114))	('cell growth', 'biological_process', 'GO:0016049', ('126', '137'))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('FGF', 'Gene', (42, 45))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('acquired resistance', 'CPA', (187, 206))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (42, 45))
114299	28030802	Receptor overexpression can be a result of gene amplification or changes in post-transcriptional processing; point mutations may result in constitutive receptor activation or decreased sensitivity to ligand binding; translocations can produce fusion proteins with constitutive activity; and isoform switching and alternative splicing can reduce specificity to FGFs.	('point mutations', 'Var', (109, 124))	('sensitivity to ligand binding', 'MPA', (185, 214))	('result', 'Reg', (129, 135))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (360, 363))	('specificity', 'MPA', (345, 356))	('translocations', 'Var', (216, 230))	('post-transcriptional processing', 'MPA', (76, 107))	('alternative splicing', 'Var', (313, 333))	('decreased', 'NegReg', (175, 184))	('ligand', 'molecular_function', 'GO:0005488', ('200', '206'))	('activation', 'PosReg', (161, 171))	('reduce', 'NegReg', (338, 344))	('overexpression', 'PosReg', (9, 23))	('fusion proteins', 'Protein', (243, 258))	('constitutive', 'Protein', (139, 151))	('splicing', 'biological_process', 'GO:0045292', ('325', '333'))	('changes', 'Reg', (65, 72))	('FGF', 'Gene', (360, 363))	('binding', 'molecular_function', 'GO:0005488', ('207', '214'))
114301	28030802	Using next generation sequencing (NGS) to detect FGFR anomalies, a comprehensive review of a cohort of nearly 5,000 cancer patients found aberrations in 7.1% of malignancies.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (49, 52))	('anomalies', 'Disease', 'MESH:D000014', (54, 63))	('cancer', 'Disease', (116, 122))	('aberrations', 'Var', (138, 149))	('malignancies', 'Disease', (161, 173))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('patients', 'Species', '9606', (123, 131))	('anomalies', 'Disease', (54, 63))	('FGF', 'Gene', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))
114303	28030802	Amplification of the chromosomal region 8p11-12, the genomic location of FGFR1, has been detected in 10% of breast cancers (predominantly in estrogen receptor (ER) positive cancers) and this finding has been related to higher FGFR1 expression levels correlating to worse prognosis.	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('FGFR1', 'Gene', '2260', (226, 231))	('estrogen receptor', 'Gene', (141, 158))	('ER', 'Gene', '2099', (160, 162))	('breast cancers', 'Disease', 'MESH:D001943', (108, 122))	('breast cancers', 'Disease', (108, 122))	('expression', 'MPA', (232, 242))	('FGFR1', 'Gene', (73, 78))	('breast cancers', 'Phenotype', 'HP:0003002', (108, 122))	('FGFR', 'molecular_function', 'GO:0005007', ('226', '230'))	('higher', 'PosReg', (219, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Disease', (173, 180))	('FGFR1', 'Gene', (226, 231))	('FGFR', 'molecular_function', 'GO:0005007', ('73', '77'))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('estrogen receptor', 'Gene', '2099', (141, 158))	('detected', 'Reg', (89, 97))	('Amplification', 'Var', (0, 13))	('FGFR1', 'Gene', '2260', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('chromosomal region', 'cellular_component', 'GO:0098687', ('21', '39'))
114304	28030802	Recently, it has also been reported that FGFR1 is amplified in as many as 19% of squamous non-small cell lung cancers (SqCLC).	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('lung cancers', 'Phenotype', 'HP:0100526', (105, 117))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (94, 117))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (94, 116))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (90, 117))	('squamous non-small cell lung cancers', 'Disease', (81, 117))	('squamous non-small cell lung cancers', 'Disease', 'MESH:D002289', (81, 117))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (90, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('amplified', 'Var', (50, 59))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('FGFR1', 'Gene', (41, 46))	('FGFR1', 'Gene', '2260', (41, 46))
114305	28030802	Moreover, preclinical studies have shown that a subset of FGFR1-amplified small cell lung cancer is extremely sensitive to FGFR inhibition by PD173074, a specific FGFR1 inhibitor.	('FGFR', 'molecular_function', 'GO:0005007', ('163', '167'))	('inhibition', 'NegReg', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (74, 96))	('PD173074', 'Var', (142, 150))	('FGFR1', 'Gene', '2260', (163, 168))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('FGFR1', 'Gene', '2260', (58, 63))	('FGF', 'Gene', (163, 166))	('FGF', 'Gene', (123, 126))	('small cell lung cancer', 'Disease', 'MESH:D055752', (74, 96))	('FGF', 'Gene', (58, 61))	('FGFR', 'molecular_function', 'GO:0005007', ('123', '127'))	('small cell lung cancer', 'Disease', (74, 96))	('FGFR1', 'Gene', (163, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (163, 166))	('FGFR1', 'Gene', (58, 63))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (123, 126))	('PD173074', 'Chemical', 'MESH:C115711', (142, 150))	('sensitive', 'Reg', (110, 119))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (58, 61))
114306	28030802	FGFR1 amplifications have also been reported in oral squamous cell carcinoma, ovarian cancer, bladder cancer and rhabdomyosarcoma.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('rhabdomyosarcoma', 'Disease', (113, 129))	('FGFR1', 'Gene', (0, 5))	('ovarian cancer', 'Disease', (78, 92))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (48, 76))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (113, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (113, 129))	('oral squamous cell carcinoma', 'Disease', (48, 76))	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('amplifications', 'Var', (6, 20))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('FGFR1', 'Gene', '2260', (0, 5))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ovarian cancer', 'Disease', 'MESH:D010051', (78, 92))	('reported', 'Reg', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))
114310	28030802	Amplification and activating mutations in FGFR4 have been identified in 7-8% of rhabdomyosarcoma patients and FGFR inhibitors are potentially effective in a rhabdomyosarcoma mouse model expressing mutated FGFR4.	('FGFR', 'molecular_function', 'GO:0005007', ('110', '114'))	('mutated', 'Var', (197, 204))	('activating', 'PosReg', (18, 28))	('FGF', 'Gene', (110, 113))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (42, 45))	('mouse', 'Species', '10090', (174, 179))	('FGF', 'Gene', (205, 208))	('FGFR', 'molecular_function', 'GO:0005007', ('205', '209'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (110, 113))	('rhabdomyosarcoma', 'Disease', (80, 96))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (205, 208))	('mutations', 'Var', (29, 38))	('rhabdomyosarcoma', 'Disease', (157, 173))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('patients', 'Species', '9606', (97, 105))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (80, 96))	('Amplification', 'Var', (0, 13))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (157, 173))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (80, 96))	('FGF', 'Gene', (42, 45))	('identified', 'Reg', (58, 68))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (157, 173))
114315	28030802	Inhibition of this axis is thus hypothesized to result in a disruption of bile acid homeostasis.	('bile acid homeostasis', 'MPA', (74, 95))	('result', 'Reg', (48, 54))	('bile acid', 'Chemical', 'MESH:D001647', (74, 83))	('Inhibition', 'Var', (0, 10))	('disruption', 'MPA', (60, 70))	('homeostasis', 'biological_process', 'GO:0042592', ('84', '95'))
114316	28030802	The same review mentioned above also noted that gene mutations and rearrangements affecting FGF/FGFR signaling were less common than amplification.	('FGF', 'Gene', (92, 95))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (92, 95))	('FGF', 'Gene', (96, 99))	('rearrangements', 'Var', (67, 81))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (96, 99))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))
114317	28030802	Mutations in FGFR 2 are implicated in a broad spectrum of malignant disease.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('malignant disease', 'Disease', 'MESH:D009369', (58, 75))	('FGFR 2', 'Gene', (13, 19))	('FGFR 2', 'Gene', '2263', (13, 19))	('Mutations', 'Var', (0, 9))	('malignant disease', 'Disease', (58, 75))	('implicated', 'Reg', (24, 34))
114318	28030802	Mutations are present in 12% of endometrial carcinomas and FGFR2 mutant endometrial cancer cell lines are highly sensitive to FGFR tyrosine kinase inhibitors, implicating FGFR2 as an innovative therapeutic target in endometrial carcinoma.	('FGFR2', 'Gene', (59, 64))	('endometrial cancer', 'Disease', (72, 90))	('sensitive', 'MPA', (113, 122))	('endometrial cancer', 'Disease', 'MESH:D016889', (72, 90))	('FGFR2', 'Gene', '2263', (171, 176))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (32, 54))	('endometrial carcinoma', 'Disease', (216, 237))	('FGFR2', 'Gene', '2263', (59, 64))	('mutant', 'Var', (65, 71))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (32, 54))	('FGF', 'Gene', (126, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('126', '130'))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (216, 237))	('tyrosine', 'Chemical', 'MESH:D014443', (131, 139))	('FGF', 'Gene', (171, 174))	('FGF', 'Gene', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (126, 129))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (32, 53))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (216, 237))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('endometrial cancer', 'Phenotype', 'HP:0012114', (72, 90))	('endometrial carcinomas', 'Disease', (32, 54))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (32, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('171', '175'))	('FGFR2', 'Gene', (171, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (171, 174))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (59, 62))
114319	28030802	Also, approximately 10% of cases of gastric cancer are associated with FGFR2 amplification and/or mutation; in particular amplification is suggestive of a poor prognosis and more widespread disease.	('mutation', 'Var', (98, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('gastric cancer', 'Disease', (36, 50))	('associated', 'Reg', (55, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('amplification', 'Var', (77, 90))	('amplification', 'Var', (122, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('FGFR2', 'Gene', (71, 76))	('FGFR2', 'Gene', '2263', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
114320	28030802	Gastric cancer cell lines with FGFR2 amplifications show evidence of ligand-independent signaling and are highly sensitive to FGFR inhibitors.	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (126, 129))	('cancer', 'Disease', (8, 14))	('signaling', 'biological_process', 'GO:0023052', ('88', '97'))	('FGFR2', 'Gene', (31, 36))	('FGFR2', 'Gene', '2263', (31, 36))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (31, 34))	('ligand-independent signaling', 'MPA', (69, 97))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('FGF', 'Gene', (126, 129))	('Gastric cancer', 'Phenotype', 'HP:0012126', (0, 14))	('FGFR', 'molecular_function', 'GO:0005007', ('126', '130'))	('FGF', 'Gene', (31, 34))	('ligand', 'molecular_function', 'GO:0005488', ('69', '75'))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('amplifications', 'Var', (37, 51))
114321	28030802	In breast cancer, single nucleotide polymorphisms (SNPs) in FGFR2 were found to be strongly associated with evidence of postmenopausal disease.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('postmenopausal disease', 'Phenotype', 'HP:0008209', (120, 142))	('postmenopausal disease', 'Disease', (120, 142))	('single nucleotide polymorphisms', 'Var', (18, 49))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('FGFR2', 'Gene', (60, 65))	('FGFR2', 'Gene', '2263', (60, 65))	('associated', 'Reg', (92, 102))
114322	28030802	FGFR2 amplification is also detected in 5% of triple-negative breast cancers, providing the possibility of specific targeted therapy when many other options are less efficacious by the nature of the disease profile.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('detected', 'Reg', (28, 36))	('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))	('amplification', 'Var', (6, 19))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
114323	28030802	Recently, several novel FGFR2 mutations have been identified in lung cancer, both in cases of adenocarcinoma and squamous cell carcinoma.	('lung cancer', 'Disease', (64, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('FGFR2', 'Gene', '2263', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('mutations', 'Var', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))	('identified', 'Reg', (50, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('FGFR2', 'Gene', (24, 29))
114326	28030802	As aforementioned, FGFR mutations do not always result in "driver" mutations alone.	('FGF', 'Gene', (19, 22))	('result', 'Reg', (48, 54))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (19, 22))	('mutations', 'Var', (24, 33))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))
114327	28030802	As seen 10% of melanoma, missense mutations of FGFR2 have been identified in BRAF-inhibitor treatment resistance.	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('BRAF', 'Gene', '673', (77, 81))	('identified', 'Reg', (63, 73))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('BRAF', 'Gene', (77, 81))	('treatment resistance', 'MPA', (92, 112))	('missense mutations', 'Var', (25, 43))	('FGFR2', 'Gene', (47, 52))	('FGFR2', 'Gene', '2263', (47, 52))
114328	28030802	FGFR3 mutations are found in approximately 70% of non-muscle-invasive bladder cancers and 10-20% of invasive bladder cancers.	('invasive bladder', 'Phenotype', 'HP:0100645', (61, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('invasive bladder cancers', 'Disease', (100, 124))	('invasive bladder cancers', 'Disease', (61, 85))	('non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (50, 77))	('mutations', 'Var', (6, 15))	('bladder cancers', 'Phenotype', 'HP:0009725', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (100, 124))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('bladder cancers', 'Phenotype', 'HP:0009725', (109, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (61, 85))	('FGFR3', 'Gene', (0, 5))	('invasive bladder', 'Phenotype', 'HP:0100645', (100, 116))	('found', 'Reg', (20, 25))
114329	28030802	The presence of an FGFR3 mutation strongly relates to low-grade, non-muscle-invasive tumors with a better prognosis, however the clinical viability of FGFR3 as a target for cancer directed therapy in this population is unclear and remains controversial.	('relates', 'Reg', (43, 50))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('low-grade', 'Disease', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (173, 179))	('FGFR', 'molecular_function', 'GO:0005007', ('151', '155'))	('mutation', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('FGFR3', 'Gene', (19, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))	('tumors', 'Disease', (85, 91))
114330	28030802	Interestingly, in patients with non-invasive bladder cancer after resection, the presence of an FGFR3 mutation in cells obtained from urinalysis at routine follow-up was predictive of disease recurrence.	('mutation', 'Var', (102, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('FGFR3', 'Gene', (96, 101))	('patients', 'Species', '9606', (18, 26))	('presence', 'Var', (81, 89))	('invasive bladder', 'Phenotype', 'HP:0100645', (36, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('bladder cancer', 'Disease', (45, 59))
114331	28030802	FGFR3 mutations have also been identified in many other cancer types, including 3% of squamous cell lung carcinoma, cervical cancers, multiple myeloma, prostate cancer and spermatocytic seminomas.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('spermatocytic seminomas', 'Phenotype', 'HP:0100617', (172, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('squamous cell lung carcinoma', 'Disease', (86, 114))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', (56, 62))	('spermatocytic seminomas', 'Disease', 'MESH:C563236', (172, 195))	('multiple myeloma', 'Disease', 'MESH:D009101', (134, 150))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (86, 114))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('prostate cancer', 'Disease', 'MESH:D011471', (152, 167))	('prostate cancer', 'Phenotype', 'HP:0012125', (152, 167))	('cancer', 'Disease', (125, 131))	('mutations', 'Var', (6, 15))	('spermatocytic seminomas', 'Disease', (172, 195))	('multiple myeloma', 'Disease', (134, 150))	('prostate cancer', 'Disease', (152, 167))	('identified', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cervical cancers', 'Disease', (116, 132))	('cervical cancers', 'Disease', 'MESH:D002583', (116, 132))	('FGFR3', 'Gene', (0, 5))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (86, 114))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('multiple myeloma', 'Phenotype', 'HP:0006775', (134, 150))
114332	28030802	In head and neck squamous cell carcinoma (HNSCC) that was positive for human papilloma virus (HPV, 42.5% of 120 tumor samples), genomic analysis using parallel sequencing technology revealed nearly 18% of tumors with mutations in FGFR2 or FGFR 3, which was notably different than in HPV negative samples.	('FGFR', 'molecular_function', 'GO:0005007', ('239', '243'))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('HPV', 'Species', '10566', (283, 286))	('FGFR', 'molecular_function', 'GO:0005007', ('230', '234'))	('neck', 'cellular_component', 'GO:0044326', ('12', '16'))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('HNSCC', 'Phenotype', 'HP:0012288', (42, 47))	('papilloma', 'Phenotype', 'HP:0012740', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (112, 117))	('tumors', 'Disease', (205, 211))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('FGFR2', 'Gene', (230, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('human papilloma virus', 'Species', '10566', (71, 92))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('neck squamous cell carcinoma', 'Disease', (12, 40))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (12, 40))	('FGFR 3', 'Gene', '2261', (239, 245))	('FGFR2', 'Gene', '2263', (230, 235))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('FGFR 3', 'Gene', (239, 245))	('HPV', 'Species', '10566', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (205, 210))	('mutations', 'Var', (217, 226))
114333	28030802	Interestingly, HPV negative cases that had FGFR3 mutations were not as responsive to FGFR inhibition as the single HPV positive case studied, suggesting further need for study in HNSCC based on HPV status.	('mutations', 'Var', (49, 58))	('FGF', 'Gene', (43, 46))	('FGF', 'Gene', (85, 88))	('HPV', 'Species', '10566', (15, 18))	('HPV', 'Species', '10566', (115, 118))	('HPV', 'Species', '10566', (194, 197))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (43, 46))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (85, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('HNSCC', 'Phenotype', 'HP:0012288', (179, 184))
114334	28030802	FGFR3-activating mutations are also found at a high frequency in epidermal nevi and seborrhoeic keratosis, which are benign skin conditions and do not progress to malignancy.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('seborrhoeic keratosis', 'Phenotype', 'HP:0031287', (84, 105))	('seborrhoeic keratosis', 'Disease', 'MESH:D007642', (84, 105))	('FGFR3-activating', 'Gene', (0, 16))	('epidermal nevi', 'Phenotype', 'HP:0010816', (65, 79))	('malignancy', 'Disease', 'MESH:D009369', (163, 173))	('epidermal nevi', 'Disease', (65, 79))	('malignancy', 'Disease', (163, 173))	('seborrhoeic keratosis', 'Disease', (84, 105))	('nevi', 'Phenotype', 'HP:0003764', (75, 79))	('mutations', 'Var', (17, 26))
114337	28030802	In a comprehensive survey of gene fusions across different solid tumor histologies, the authors described a wide-ranging distribution of FGFR1, FGFR2, and FGFR3 fusions across 8 of 20 tumor types analyzed.	('FGFR2', 'Gene', '2263', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('FGFR', 'molecular_function', 'GO:0005007', ('137', '141'))	('FGFR1', 'Gene', (137, 142))	('tumor', 'Disease', (184, 189))	('FGFR', 'molecular_function', 'GO:0005007', ('155', '159'))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('FGFR3', 'Gene', (155, 160))	('FGFR1', 'Gene', '2260', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('fusions', 'Var', (161, 168))	('FGFR2', 'Gene', (144, 149))
114342	28030802	Pre-clinical evidence suggests that FGFR inhibitors are able to reduce growth and induce apoptosis in cell lines harboring FGFR1 gene rearrangements.	('rearrangements', 'Var', (134, 148))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('induce', 'Reg', (82, 88))	('FGF', 'Gene', (36, 39))	('reduce', 'NegReg', (64, 70))	('apoptosis', 'CPA', (89, 98))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (36, 39))	('FGF', 'Gene', (123, 126))	('FGFR1', 'Gene', (123, 128))	('growth', 'CPA', (71, 77))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (123, 126))	('reduce growth', 'Phenotype', 'HP:0001510', (64, 77))	('FGFR1', 'Gene', '2260', (123, 128))	('FGFR', 'molecular_function', 'GO:0005007', ('123', '127'))	('apoptosis', 'biological_process', 'GO:0097194', ('89', '98'))	('apoptosis', 'biological_process', 'GO:0006915', ('89', '98'))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
114343	28030802	Intrahepatic cholangiocarcinoma demonstrates FGFR2 fusions in 13.6% of cases that are mutually exclusive with KRAS/BRAF mutations, and in vivo cellular studies confirm the oncogenic potential of this aberration.	('BRAF', 'Gene', '673', (115, 119))	('Intrahepatic cholangiocarcinoma', 'Disease', (0, 31))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 31))	('FGFR2', 'Gene', (45, 50))	('BRAF', 'Gene', (115, 119))	('FGFR2', 'Gene', '2263', (45, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('fusions', 'Var', (51, 58))
114348	28030802	The TACC3 gene (transforming acidic coiled-coil containing protein) was first identified as a component of FGFR3-TACC3 fusion in glioblastoma multiforme (GBM) and bladder urothelial tumors, this fusion protein is constitutively active and has been shown to affect mitosis by altering chromosomal segregation patterns.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('altering', 'Reg', (275, 283))	('mitosis', 'Disease', 'None', (264, 271))	('FGFR3-TACC3', 'Gene', (107, 118))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('bladder urothelial tumors', 'Phenotype', 'HP:0009725', (163, 188))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('mitosis', 'biological_process', 'GO:0000278', ('264', '271'))	('affect', 'Reg', (257, 263))	('bladder urothelial tumors', 'Disease', 'MESH:D001749', (163, 188))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('mitosis', 'Disease', (264, 271))	('glioblastoma multiforme', 'Disease', (129, 152))	('bladder urothelial tumors', 'Disease', (163, 188))	('fusion', 'Var', (119, 125))	('chromosomal segregation patterns', 'CPA', (284, 316))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (129, 152))
114349	28030802	In an analysis of nearly 600 cases of lung adenocarcinoma patients without any smoking history, investigators found an FGFR3-TACC3 fusion in a tissue sample from a patient that previously did not have any known oncogenic alteration.	('FGFR3-TACC3', 'Gene', (119, 130))	('patients', 'Species', '9606', (58, 66))	('patient', 'Species', '9606', (58, 65))	('patient', 'Species', '9606', (164, 171))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (38, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))	('fusion', 'Var', (131, 137))	('lung adenocarcinoma', 'Disease', (38, 57))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (38, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
114351	28030802	In vitro, these cells with an FGFR3-TACC3 fusion demonstrated sensitivity to pan-FGFR inhibitors, suggesting a possible subset of lung adenocarcinoma patients that may benefit from targeting this pathway.	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('FGF', 'Gene', (81, 84))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (130, 149))	('FGF', 'Gene', (30, 33))	('fusion', 'Var', (42, 48))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (30, 33))	('patients', 'Species', '9606', (150, 158))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (81, 84))	('lung adenocarcinoma', 'Disease', (130, 149))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (130, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))
114352	28030802	It is also worth mentioning that we described the first 3 cases of cervical cancer harboring the FGFR-TACC3 fusion, noting that one patient received treatment with FGFR targeted therapy and achieved stable disease for 4 cycles.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (97, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('97', '101'))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('164', '168'))	('FGF', 'Gene', (164, 167))	('fusion', 'Var', (108, 114))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (164, 167))	('patient', 'Species', '9606', (132, 139))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('FGF', 'Gene', (97, 100))
114353	28030802	However, ligand-dependent signaling may also occur and would suggest that ectopic expression of FGFs can promote cancer.	('promote', 'PosReg', (105, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('ectopic expression', 'Var', (74, 92))	('FGF', 'Gene', (96, 99))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (96, 99))	('ligand', 'molecular_function', 'GO:0005488', ('9', '15'))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
114358	28030802	Early development of FGFR inhibitors exhibits antitumor activity and present very specific toxicity profiles.	('inhibitors', 'Var', (26, 36))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('FGF', 'Gene', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('toxicity', 'Disease', 'MESH:D064420', (91, 99))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (21, 24))	('toxicity', 'Disease', (91, 99))	('tumor', 'Disease', (50, 55))
114359	28030802	Prior studies also indicate that FGFR inhibitors enhance tumor sensitivity to conventional anticancer drugs such as 5-fluorouracil, irinotecan, paclitaxel, and etoposide in human cancer cells acquiring anti-apoptotic potential based on aberrant FGFR activation.	('irinotecan', 'Chemical', 'MESH:D000077146', (132, 142))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('FGF', 'Gene', (33, 36))	('activation', 'PosReg', (250, 260))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('FGF', 'Gene', (245, 248))	('cancer', 'Disease', (95, 101))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (33, 36))	('inhibitors', 'Var', (38, 48))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', (57, 62))	('paclitaxel', 'Chemical', 'MESH:D017239', (144, 154))	('FGFR', 'molecular_function', 'GO:0005007', ('245', '249'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (245, 248))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('human', 'Species', '9606', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('etoposide', 'Chemical', 'MESH:D005047', (160, 169))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (116, 130))	('enhance', 'PosReg', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Disease', (179, 185))
114368	28030802	Pan-FGFR inhibitors such as lenvatinib (E7080), ponatinib (AP24534), regorafenib (BAY 73-4506), dovitinib (TKI258), lucitanib (E3810), cediranib (AZD2171), intedanib (BIBF 1120), brivanib (BMS-540215), and others are currently being studied in clinical trials.	('intedanib', 'Chemical', 'MESH:C530716', (156, 165))	('AP24534', 'Chemical', 'MESH:C545373', (59, 66))	('cediranib', 'Chemical', 'MESH:C500926', (135, 144))	('dovitinib', 'Chemical', 'MESH:C500007', (96, 105))	('ponatinib', 'Chemical', 'MESH:C545373', (48, 57))	('BIBF', 'Chemical', '-', (167, 171))	('AZD2171', 'Chemical', 'MESH:C500926', (146, 153))	('E7080', 'Chemical', 'MESH:C531958', (40, 45))	('TKI258', 'Chemical', 'MESH:C500007', (107, 113))	('FGF', 'Gene', (4, 7))	('E7080', 'Var', (40, 45))	('brivanib', 'Chemical', 'MESH:C509922', (179, 187))	('E3810', 'Var', (127, 132))	('BAY 73-4506', 'Chemical', 'MESH:C559147', (82, 93))	('lucitanib', 'Chemical', 'MESH:C000595232', (116, 125))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('regorafenib', 'Chemical', 'MESH:C559147', (69, 80))	('lenvatinib', 'Chemical', 'MESH:C531958', (28, 38))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (4, 7))
114375	28030802	Interestingly, despite the high potency against FGFRs, one Phase II trial in advanced urothelial carcinoma using dovitinib to treat FGFR3 mutated versus FGFR wild-type cancer failed to show a meaningful overall response rate and the study was terminated after concluding that dovitinib has limited single-agent activity in this population.	('FGF', 'Gene', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('dovitinib', 'Chemical', 'MESH:C500007', (276, 285))	('FGF', 'Gene', (153, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('153', '157'))	('mutated', 'Var', (138, 145))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (132, 135))	('FGFR', 'molecular_function', 'GO:0005007', ('132', '136'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (86, 106))	('dovitinib', 'Chemical', 'MESH:C500007', (113, 122))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (153, 156))	('cancer', 'Disease', (168, 174))	('FGF', 'Gene', (48, 51))	('urothelial carcinoma', 'Disease', (86, 106))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (48, 51))
114377	28030802	TKI258 recently underwent a series of clinical trials for its safety and efficacy in patients with breast cancer (NCT00958971), endometrial cancer (NCT01379534), and multiple myeloma (NCT01058434).	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('TKI258', 'Chemical', 'MESH:C500007', (0, 6))	('TKI258', 'Gene', (0, 6))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('endometrial cancer', 'Disease', (128, 146))	('multiple myeloma', 'Disease', 'MESH:D009101', (166, 182))	('multiple myeloma', 'Phenotype', 'HP:0006775', (166, 182))	('patients', 'Species', '9606', (85, 93))	('multiple myeloma', 'Disease', (166, 182))	('endometrial cancer', 'Phenotype', 'HP:0012114', (128, 146))	('endometrial cancer', 'Disease', 'MESH:D016889', (128, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('NCT01379534', 'Var', (148, 159))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
114378	28030802	Lenvatinib (E7080, Eisai) is another multikinase inhibitor, inhibiting FGFR1-4 as well as VEGFR1-3, RET, KIT and PDGFR-beta.	('inhibiting', 'NegReg', (60, 70))	('RET', 'Gene', '5979', (100, 103))	('FGFR1', 'Gene', (71, 76))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('PDGFR-beta', 'Gene', (113, 123))	('FGFR1', 'Gene', '2260', (71, 76))	('KIT', 'Gene', (105, 108))	('VEGFR1', 'Gene', '2321', (90, 96))	('E7080', 'Chemical', 'MESH:C531958', (12, 17))	('VEGFR1', 'Gene', (90, 96))	('KIT', 'molecular_function', 'GO:0005020', ('105', '108'))	('RET', 'Gene', (100, 103))	('Lenvatinib', 'Chemical', 'MESH:C531958', (0, 10))	('E7080', 'Var', (12, 17))	('PDGFR-beta', 'Gene', '5159', (113, 123))
114391	28030802	Ongoing Phase II/III clinical trials include a comparison of lenvatinib with sorafenib in hepatocellular carcinoma (NCT01761266), lenvatinib with everolimus in renal cell carcinoma (NCT02454478), and as monotherapy in unresectable biliary cancer (NCT02579616).	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (90, 114))	('biliary cancer', 'Disease', (231, 245))	('lenvatinib', 'Chemical', 'MESH:C531958', (61, 71))	('renal cell carcinoma', 'Disease', (160, 180))	('hepatocellular carcinoma', 'Disease', (90, 114))	('NCT01761266', 'Var', (116, 127))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (90, 114))	('everolimus', 'Chemical', 'MESH:D000068338', (146, 156))	('lenvatinib', 'Chemical', 'MESH:C531958', (130, 140))	('biliary cancer', 'Disease', 'MESH:D001661', (231, 245))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (160, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (160, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('sorafenib', 'Chemical', 'MESH:D000077157', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
114396	28030802	These include compounds like AZD4547, BGJ398, JNJ42756493, and PD173074.	('BGJ398', 'Var', (38, 44))	('JNJ42756493', 'Var', (46, 57))	('PD173074', 'Var', (63, 71))	('AZD4547', 'Var', (29, 36))	('PD173074', 'Chemical', 'MESH:C115711', (63, 71))	('AZD4547', 'Chemical', 'MESH:C572463', (29, 36))	('JNJ42756493', 'Chemical', 'MESH:C000604580', (46, 57))	('BGJ398', 'Chemical', 'MESH:C568950', (38, 44))
114397	28030802	AZD4547 is a small-molecule compound that is a selective FGFR (FGFR 1-3) inhibitor, delivered orally in capsule form.	('FGFR 1', 'Gene', '2260', (63, 69))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (63, 66))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('FGF', 'Gene', (57, 60))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (57, 60))	('FGF', 'Gene', (63, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('57', '61'))	('FGFR 1', 'Gene', (63, 69))	('AZD4547', 'Var', (0, 7))	('capsule', 'cellular_component', 'GO:0042603', ('104', '111'))
114399	28030802	Oral administration of AZD4547 has also resulted in prolonged survival of FGFR3-TACC3-transformed glioma xenografts by 28 days compared with mice treated with the vehicle control.	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('prolonged', 'PosReg', (52, 61))	('survival', 'CPA', (62, 70))	('FGFR3-TACC3-transformed', 'Gene', (74, 97))	('mice', 'Species', '10090', (141, 145))	('AZD4547', 'Var', (23, 30))	('glioma', 'Disease', (98, 104))	('AZD4547', 'Chemical', 'MESH:C572463', (23, 30))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))
114400	28030802	Furthermore, inhibition with AZD4547 resulted in a significant dose-dependent tumor growth inhibition and survival of gastric cancer carrying an FGFR2 gene amplification both in vitro and in vivo.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('FGFR2', 'Gene', (145, 150))	('gastric cancer', 'Disease', (118, 132))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('survival', 'CPA', (106, 114))	('gastric cancer', 'Disease', 'MESH:D013274', (118, 132))	('FGFR2', 'Gene', '2263', (145, 150))	('AZD4547', 'Var', (29, 36))	('inhibition', 'NegReg', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('tumor', 'Disease', (78, 83))	('AZD4547', 'Chemical', 'MESH:C572463', (29, 36))	('FGFR', 'molecular_function', 'GO:0005007', ('145', '149'))
114401	28030802	Other pre-clinical studies on xenograft models transplanted with transformed cells derived from FGFR1 amplified NSCLC cancer patients have shown that AZD4547 stops tumor growth and promotes regression.	('FGFR1', 'Gene', '2260', (96, 101))	('tumor', 'Disease', (164, 169))	('pre', 'molecular_function', 'GO:0003904', ('6', '9'))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))	('stops', 'NegReg', (158, 163))	('NSCLC cancer', 'Disease', (112, 124))	('AZD4547', 'Var', (150, 157))	('promotes', 'PosReg', (181, 189))	('regression', 'CPA', (190, 200))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('FGFR1', 'Gene', (96, 101))	('AZD4547', 'Chemical', 'MESH:C572463', (150, 157))	('NSCLC cancer', 'Disease', 'MESH:D009369', (112, 124))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('patients', 'Species', '9606', (125, 133))
114404	28030802	The increase in serum phosphate concentration observed in this phase I study provides evidence that AZD4547 at this dose leads to pharmacologic target inhibition.	('pharmacologic target inhibition', 'MPA', (130, 161))	('AZD4547', 'Var', (100, 107))	('AZD4547', 'Chemical', 'MESH:C572463', (100, 107))	('increase in serum phosphate concentration', 'Phenotype', 'HP:0002905', (4, 45))	('serum phosphate concentration', 'MPA', (16, 45))	('phosphate', 'Chemical', 'MESH:D010710', (22, 31))	('increase', 'PosReg', (4, 12))	('increase in serum phosphate', 'Phenotype', 'HP:0002905', (4, 31))
114406	28030802	Expansion cohorts to further assess safety and tolerability required tumors with FGFR 1 amplification as confirmed through FISH (FGFR: Centromeric ratio >= 2).	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('FGF', 'Gene', (81, 84))	('FGF', 'Gene', (129, 132))	('amplification', 'Var', (88, 101))	('FGFR 1', 'Gene', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('FGFR 1', 'Gene', '2260', (81, 87))	('FGFR', 'molecular_function', 'GO:0005007', ('129', '133'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (81, 84))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (129, 132))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
114407	28030802	In a cohort of 15 patients with FGFR1 amplified SqCLC, the most common adverse events (AEs) were dermatologic and GI related.	('amplified', 'Var', (38, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('FGFR1', 'Gene', (32, 37))	('SqCLC', 'MPA', (48, 53))	('FGFR1', 'Gene', '2260', (32, 37))	('patients', 'Species', '9606', (18, 26))	('AEs', 'Chemical', '-', (87, 90))
114412	28030802	Of note, partial response (PR, by RECIST criteria) was observed in tumors with a high burden of FGFR aberration including one SqCLC patient with FGFR1 amplification and another patient with FGFR2 amplified gastroesophageal cancer.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (145, 148))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (96, 99))	('gastroesophageal cancer', 'Disease', (206, 229))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (206, 229))	('FGF', 'Gene', (190, 193))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('FGFR1', 'Gene', '2260', (145, 150))	('FGFR', 'molecular_function', 'GO:0005007', ('145', '149'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (190, 193))	('FGFR2', 'Gene', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('FGF', 'Gene', (145, 148))	('patient', 'Species', '9606', (132, 139))	('tumors', 'Disease', (67, 73))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))	('FGFR2', 'Gene', '2263', (190, 195))	('FGF', 'Gene', (96, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('190', '194'))	('FGFR1', 'Gene', (145, 150))	('patient', 'Species', '9606', (177, 184))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('amplification', 'Var', (151, 164))
114414	28030802	AZD4547 is currently under a Phase II clinical trial to assess its activity in patients with FGFR1 or FGFR2 amplified breast, squamous lung, and stomach cancer whose cancers have progressed following previous chemotherapy (NCT01795768).	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('amplified', 'Var', (108, 117))	('breast', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('stomach cancer', 'Disease', (145, 159))	('FGFR1', 'Gene', (93, 98))	('squamous lung', 'Disease', 'MESH:D002294', (126, 139))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancers', 'Disease', (166, 173))	('squamous lung', 'Disease', (126, 139))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('FGFR2', 'Gene', (102, 107))	('stomach cancer', 'Disease', 'MESH:D013274', (145, 159))	('stomach cancer', 'Phenotype', 'HP:0012126', (145, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('patients', 'Species', '9606', (79, 87))	('FGFR2', 'Gene', '2263', (102, 107))	('FGFR1', 'Gene', '2260', (93, 98))
114415	28030802	285 patients with advanced cancer were screened, identifying FGFR1 amplification in 18% (20/111) HER2 negative breast cancer, 9.5% (4/42) NSCLC, and FGFR2 amplification in 7.6% (10/132) gastroesophageal (GC).	('negative', 'NegReg', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('HER2', 'Gene', '2064', (97, 101))	('FGFR1', 'Gene', '2260', (61, 66))	('FGFR2', 'Gene', '2263', (149, 154))	('gastroesophageal', 'Disease', 'MESH:D005764', (186, 202))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Disease', (111, 124))	('gastroesophageal', 'Disease', (186, 202))	('amplification', 'Var', (155, 168))	('amplification', 'Var', (67, 80))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('patients', 'Species', '9606', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('HER2', 'Gene', (97, 101))	('cancer', 'Disease', (118, 124))	('NSCLC', 'Disease', (138, 143))	('FGFR1', 'Gene', (61, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('149', '153'))	('FGFR', 'molecular_function', 'GO:0005007', ('61', '65'))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('FGFR2', 'Gene', (149, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
114421	28030802	A recently completed Phase II trial aimed to evaluate the safety and efficacy of AZD4547 versus paclitaxel in advanced gastric or gastro-oesophageal junction cancer; no results have been reported (NTC01457846).	('paclitaxel', 'Chemical', 'MESH:D017239', (96, 106))	('NTC', 'cellular_component', 'GO:0000974', ('197', '200'))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('gastro-oesophageal junction cancer', 'Disease', (130, 164))	('AZD4547', 'Var', (81, 88))	('gastro-oesophageal junction cancer', 'Disease', 'MESH:D005764', (130, 164))	('AZD4547', 'Chemical', 'MESH:C572463', (81, 88))	('advanced gastric', 'Disease', (110, 126))
114422	28030802	AZD4547 is also undergoing a Phase I/II clinical trial in combination with fulvestrant versus fulvestrant alone in ER+ breast cancer patients with FGFR1 amplification (NTC01202591).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('NTC', 'cellular_component', 'GO:0000974', ('168', '171'))	('breast cancer', 'Disease', (119, 132))	('fulvestrant', 'Chemical', 'MESH:D000077267', (94, 105))	('patients', 'Species', '9606', (133, 141))	('amplification', 'Var', (153, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('ER', 'Gene', '2099', (115, 117))	('FGFR1', 'Gene', (147, 152))	('FGFR1', 'Gene', '2260', (147, 152))	('FGFR', 'molecular_function', 'GO:0005007', ('147', '151'))	('fulvestrant', 'Chemical', 'MESH:D000077267', (75, 86))
114424	28030802	Of the 94 enrolled patients initially, partial responses were seen in 4 FGFR3 mutated bladder cancers, 2 FGFR1 amplified SqCLC, and a reduction in tumor burden was seen in FGFR2 fusion cholangiocarcinoma as well as in FGFR1 amplified breast cancer.	('FGFR1', 'Gene', (105, 110))	('FGFR2', 'Gene', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (185, 203))	('mutated', 'Var', (78, 85))	('FGFR', 'molecular_function', 'GO:0005007', ('172', '176'))	('FGFR', 'molecular_function', 'GO:0005007', ('218', '222'))	('tumor', 'Disease', (147, 152))	('FGFR2', 'Gene', '2263', (172, 177))	('cholangiocarcinoma', 'Disease', (185, 203))	('FGFR1', 'Gene', '2260', (218, 223))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (185, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))	('patients', 'Species', '9606', (19, 27))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('bladder cancers', 'Phenotype', 'HP:0009725', (86, 101))	('breast cancer', 'Disease', (234, 247))	('FGFR1', 'Gene', '2260', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('FGFR1', 'Gene', (218, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('reduction', 'NegReg', (134, 143))	('bladder cancers', 'Disease', 'MESH:D001749', (86, 101))	('FGFR3', 'Gene', (72, 77))	('bladder cancers', 'Disease', (86, 101))
114425	28030802	Investigators used FISH to screen for FGFR1 amplification, and in the cohort of 17 SqCLC (expansion arm) patients there were 4/17 PRs (2 after data cutoff date) and 3 patients with SD.	('patients', 'Species', '9606', (105, 113))	('patients', 'Species', '9606', (167, 175))	('PRs', 'Disease', (130, 133))	('amplification', 'Var', (44, 57))	('FGFR1', 'Gene', (38, 43))	('FGFR1', 'Gene', '2260', (38, 43))	('SD', 'Chemical', '-', (181, 183))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))
114429	28030802	Trials that are actively recruiting for study of BGJ398 alone exist for non-muscle invasive urothelial carcinoma (NCT02657486), recurrent glioblastoma (NCT01975701), and advanced cholangiocarcinoma (NCT02150967).	('NCT02657486', 'Var', (114, 125))	('BGJ398', 'Chemical', 'MESH:C568950', (49, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (179, 197))	('BGJ398', 'Gene', (49, 55))	('invasive urothelial carcinoma', 'Disease', (83, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('glioblastoma', 'Phenotype', 'HP:0012174', (138, 150))	('glioblastoma', 'Disease', (138, 150))	('NCT02150967', 'Var', (199, 210))	('glioblastoma', 'Disease', 'MESH:D005909', (138, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('NCT01975701', 'Var', (152, 163))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (83, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cholangiocarcinoma', 'Disease', (179, 197))
114431	28030802	JNJ-42756493 (Janssen) is another pan-FGFR inhibitor that is orally bioavailable.	('JNJ-42756493', 'Var', (0, 12))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (38, 41))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (0, 12))	('FGF', 'Gene', (38, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))
114436	28030802	All patients that responded demonstrated FGFR2 or FGFR3 translocations, and of the responses identified, 3 of the patients with partial responses harbored an FGFR3-TACC3 fusion alteration.	('FGFR3-TACC3', 'Gene', (158, 169))	('FGFR2', 'Gene', (41, 46))	('FGFR3', 'Gene', (50, 55))	('FGFR2', 'Gene', '2263', (41, 46))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('FGFR', 'molecular_function', 'GO:0005007', ('158', '162'))	('FGFR', 'molecular_function', 'GO:0005007', ('50', '54'))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (114, 122))	('translocations', 'Var', (56, 70))
114442	28030802	An FGFR2-IIIb-specific antibody, GP369, has been shown to inhibit the proliferation of human cancer cell lines and tumor xenografts with amplified or activated FGFR2 signaling.	('tumor', 'Disease', (115, 120))	('antibody', 'cellular_component', 'GO:0019815', ('23', '31'))	('FGFR', 'molecular_function', 'GO:0005007', ('3', '7'))	('signaling', 'biological_process', 'GO:0023052', ('166', '175'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('FGFR2', 'Gene', (3, 8))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('human', 'Species', '9606', (87, 92))	('proliferation', 'CPA', (70, 83))	('antibody', 'cellular_component', 'GO:0019814', ('23', '31'))	('FGFR', 'molecular_function', 'GO:0005007', ('160', '164'))	('FGFR2', 'Gene', '2263', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('inhibit', 'NegReg', (58, 65))	('FGFR2', 'Gene', (160, 165))	('antibody', 'molecular_function', 'GO:0003823', ('23', '31'))	('GP369', 'Var', (33, 38))	('cancer', 'Disease', (93, 99))	('antibody', 'cellular_component', 'GO:0042571', ('23', '31'))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('FGFR2', 'Gene', '2263', (160, 165))
114443	28030802	BAY1187982 (Bayer) also falls under the spectrum of exploiting the antibody/antigen relationship as a human anti-FGFR2-Ab that is conjugated to a cytotoxic agent (antibody-drug conjugate).	('antibody', 'cellular_component', 'GO:0042571', ('163', '171'))	('antibody', 'cellular_component', 'GO:0019815', ('67', '75'))	('FGFR', 'molecular_function', 'GO:0005007', ('113', '117'))	('FGFR2', 'Gene', (113, 118))	('BAY1187982', 'Chemical', 'MESH:C000621819', (0, 10))	('antibody', 'cellular_component', 'GO:0019814', ('67', '75'))	('falls', 'Phenotype', 'HP:0002527', (24, 29))	('antibody', 'molecular_function', 'GO:0003823', ('67', '75'))	('fall', 'Phenotype', 'HP:0002527', (24, 28))	('antibody', 'cellular_component', 'GO:0019815', ('163', '171'))	('antibody', 'cellular_component', 'GO:0019814', ('163', '171'))	('antibody', 'molecular_function', 'GO:0003823', ('163', '171'))	('antibody', 'cellular_component', 'GO:0042571', ('67', '75'))	('BAY1187982', 'Var', (0, 10))	('FGFR2', 'Gene', '2263', (113, 118))	('human', 'Species', '9606', (102, 107))
114446	28030802	Antibodies targeting FGFR3 have also been shown to have significant inhibitory effect on cell proliferation in bladder cancer cells and t (4; 14)-positive multiple myeloma.	('multiple myeloma', 'Disease', 'MESH:D009101', (155, 171))	('inhibitory effect', 'NegReg', (68, 85))	('bladder cancer', 'Disease', (111, 125))	('Antibodies', 'Var', (0, 10))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('multiple myeloma', 'Disease', (155, 171))	('FGFR3', 'Gene', (21, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (111, 125))	('cell proliferation', 'biological_process', 'GO:0008283', ('89', '107'))	('bladder cancer', 'Disease', 'MESH:D001749', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('multiple myeloma', 'Phenotype', 'HP:0006775', (155, 171))
114447	28030802	MFGR1877S (Genentech) is a human anti-FGFR3 monoclonal antibody that demonstrated activity in preclinical models of urothelial carcinoma harboring FGFR3 overexpression.	('overexpression', 'PosReg', (153, 167))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (116, 136))	('antibody', 'cellular_component', 'GO:0042571', ('55', '63'))	('MFGR1877S', 'Var', (0, 9))	('anti-FGFR3', 'Gene', (33, 43))	('human', 'Species', '9606', (27, 32))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('antibody', 'cellular_component', 'GO:0019815', ('55', '63'))	('FGFR3', 'Gene', (147, 152))	('urothelial carcinoma', 'Disease', (116, 136))	('antibody', 'cellular_component', 'GO:0019814', ('55', '63'))	('activity', 'MPA', (82, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('147', '151'))	('antibody', 'molecular_function', 'GO:0003823', ('55', '63'))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
114448	28030802	Subsequently there have been two Phase I trials completed, one in solid tumors (NCT01363024) and one in t(4; 14)-positive multiple myeloma (NCT01122875).	('solid tumors', 'Disease', 'MESH:D009369', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('solid tumors', 'Disease', (66, 78))	('NCT01363024', 'Var', (80, 91))	('multiple myeloma', 'Phenotype', 'HP:0006775', (122, 138))	('multiple myeloma', 'Disease', 'MESH:D009101', (122, 138))	('multiple myeloma', 'Disease', (122, 138))
114454	28030802	A subsequent Phase II trial is currently recruiting and is looking to evaluate FP-1039 in solid tumors alone, or in combination with docetaxel, or paclitaxel and carboplatin (NCT01868022).	('solid tumors', 'Disease', 'MESH:D009369', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('carboplatin', 'Chemical', 'MESH:D016190', (162, 173))	('docetaxel', 'Chemical', 'MESH:D000077143', (133, 142))	('solid tumors', 'Disease', (90, 102))	('paclitaxel', 'Chemical', 'MESH:D017239', (147, 157))	('FP-1039', 'Var', (79, 86))
114455	28030802	Given the broad scope of malignancies with FGF/FGFR pathway aberrations, proof of concept has been demonstrated for its role as a driver for oncogenesis, as a downstream key player in angiogenesis, and as a pathway responsible for acquired resistance to other anti-cancer therapies.	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('FGF', 'Gene', (43, 46))	('malignancies', 'Disease', 'MESH:D009369', (25, 37))	('FGF', 'Gene', (47, 50))	('oncogenesis', 'biological_process', 'GO:0007048', ('141', '152'))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('oncogenesis', 'CPA', (141, 152))	('malignancies', 'Disease', (25, 37))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (43, 46))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (47, 50))	('aberrations', 'Var', (60, 71))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('angiogenesis', 'biological_process', 'GO:0001525', ('184', '196'))
114456	28030802	Pre-clinical and clinical studies have shown that cancers harboring FGF/FGFR pathway aberrations are likely to be sensitive to FGFR inhibitors across various histologies.	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (72, 75))	('cancers', 'Disease', (50, 57))	('FGF', 'Gene', (68, 71))	('FGF', 'Gene', (127, 130))	('aberrations', 'Var', (85, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (68, 71))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (127, 130))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('FGFR', 'molecular_function', 'GO:0005007', ('127', '131'))	('sensitive', 'Reg', (114, 123))	('FGF', 'Gene', (72, 75))
114460	28030802	As aforementioned, a recent study used next generation sequencing (NGS) to characterize frequencies of FGFR aberrations in nearly 5,000 solid tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('FGFR', 'molecular_function', 'GO:0005007', ('103', '107'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (103, 106))	('aberrations', 'Var', (108, 119))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('FGF', 'Gene', (103, 106))
114461	28030802	They found that 7.1% of malignancies demonstrated detectable abnormalities with the most common being gene amplification, followed by mutations, then rearrangements.	('gene amplification', 'Var', (102, 120))	('malignancies', 'Disease', 'MESH:D009369', (24, 36))	('mutations', 'Var', (134, 143))	('malignancies', 'Disease', (24, 36))
114463	28030802	Within the cohort of malignancies analyzed, urothelial carcinoma exhibited the highest percentage of FGFR aberrancy (largely mutation, then amplification, followed by fusion) at 32%.	('FGF', 'Gene', (101, 104))	('malignancies', 'Disease', 'MESH:D009369', (21, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (101, 104))	('urothelial carcinoma', 'Disease', (44, 64))	('malignancies', 'Disease', (21, 33))	('amplification', 'Var', (140, 153))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (44, 64))	('mutation', 'Var', (125, 133))
114465	28030802	Notably there was no evaluation of FGF ligand dependent signaling, highlighting that a subset of patients with FGF/FGFR pathway aberrations may still benefit from FGFR targeted therapy but were not characterized in this study.	('FGF', 'Gene', (115, 118))	('FGFR', 'molecular_function', 'GO:0005007', ('115', '119'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (35, 38))	('FGFR', 'molecular_function', 'GO:0005007', ('163', '167'))	('aberrations', 'Var', (128, 139))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (163, 166))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (111, 114))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (115, 118))	('FGF', 'Gene', (35, 38))	('ligand', 'molecular_function', 'GO:0005488', ('39', '45'))	('benefit', 'PosReg', (150, 157))	('FGF', 'Gene', (163, 166))	('FGF', 'Gene', (111, 114))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))	('patients', 'Species', '9606', (97, 105))
114467	28030802	Ultimately, when evaluating all FGF/FGFR aberrations (mutations, amplifications, rearrangements, etc.)	('rearrangements', 'Var', (81, 95))	('FGF', 'Gene', (32, 35))	('FGF', 'Gene', (36, 39))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (36, 39))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (32, 35))	('amplifications', 'Var', (65, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
114469	28030802	Much of the pre-clinical and early clinical data come from trials in patient populations unselected for FGF/FGFR pathway abnormalities.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (104, 107))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (108, 111))	('abnormalities', 'Var', (121, 134))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('patient', 'Species', '9606', (69, 76))	('FGF', 'Gene', (108, 111))	('pre', 'molecular_function', 'GO:0003904', ('12', '15'))	('FGF', 'Gene', (104, 107))
114470	28030802	The true response rates or clinical benefits for those whose cancers harbor FGF/FGFR abnormalities may be higher than observed in unselected patient populations.	('FGF', 'Gene', (76, 79))	('FGF', 'Gene', (80, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('response', 'CPA', (9, 17))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (76, 79))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (80, 83))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('patient', 'Species', '9606', (141, 148))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('higher', 'PosReg', (106, 112))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('clinical benefits', 'CPA', (27, 44))	('abnormalities', 'Var', (85, 98))
114471	28030802	Many ongoing Phase I/II trials can be commended for aiming to select patients with specific FGF/FGFR alterations, and at this stage (appropriately so) there exist a variety in the methods including FISH, chromogenic in situ hybridization (CISH), quantitative real-time PCR, and NGS.	('alterations', 'Var', (101, 112))	('FGF', 'Gene', (92, 95))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (92, 95))	('FGF', 'Gene', (96, 99))	('patients', 'Species', '9606', (69, 77))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (96, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))
114475	28030802	We must additionally consider that FGF/FGFR pathway alterations likely vary in their role depending on tumor histology and interactions with other oncogenic pathways.	('interactions', 'Interaction', (123, 135))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('alterations', 'Var', (52, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('39', '43'))	('tumor', 'Disease', (103, 108))	('FGF', 'Gene', (39, 42))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (39, 42))	('FGF', 'Gene', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
114478	28030802	It was later found out that EGFR expression by IHC in colorectal cancer did not correlate with response to therapy, and subsequent investigation led to the identification of the KRAS mutation conferring resistance.	('KRAS', 'Gene', (178, 182))	('EGFR', 'Gene', '1956', (28, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (54, 71))	('EGFR', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (54, 71))	('mutation', 'Var', (183, 191))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))	('colorectal cancer', 'Disease', (54, 71))
114484	28030802	As further studies unfold, we need to utilize multiplex molecular testing such as NGS to screen tumors harboring specific molecular aberrations of interest and increase the likelihood of detecting actionable FGF/FGFR alterations in each patient.	('FGF', 'Gene', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('patient', 'Species', '9606', (237, 244))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (208, 211))	('FGF', 'Gene', (212, 215))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('212', '216'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (212, 215))	('alterations', 'Var', (217, 228))
114487	28030802	There are some studies that have identified a high concordance for actionable mutations between paired plasma and tumor specimens, especially for metastatic disease in non-small cell lung cancer, breast cancer, and colorectal cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (172, 194))	('colorectal cancer', 'Disease', 'MESH:D015179', (215, 232))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (168, 194))	('colorectal cancer', 'Disease', (215, 232))	('metastatic disease', 'Disease', (146, 164))	('mutations', 'Var', (78, 87))	('tumor', 'Disease', (114, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('non-small cell lung cancer', 'Disease', (168, 194))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('breast cancer', 'Disease', (196, 209))	('colorectal cancer', 'Phenotype', 'HP:0003003', (215, 232))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (168, 194))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
114492	28030802	The accessibility of testing would likely allow for frequent monitoring of tumor evolution, and the presence of novel molecular alterations while actively receiving anti-cancer treatment may predict upcoming resistance to therapy.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('alterations', 'Var', (128, 139))	('cancer', 'Disease', (170, 176))	('predict', 'Reg', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('resistance', 'CPA', (208, 218))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
114493	28030802	Already this has been described in a small cohort of patients with colorectal cancer initially demonstrating KRAS wild-type tumors, which subsequently were noted to have molecular alterations (via serum analysis) including KRAS, NRAS, EGFR, and BRAF after treatment with anti-EGFR therapies.	('EGFR', 'Gene', '1956', (276, 280))	('NRAS', 'Gene', '4893', (229, 233))	('BRAF', 'Gene', (245, 249))	('BRAF', 'Gene', '673', (245, 249))	('patients', 'Species', '9606', (53, 61))	('EGFR', 'Gene', '1956', (235, 239))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('KRAS', 'Disease', (223, 227))	('EGFR', 'molecular_function', 'GO:0005006', ('276', '280'))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('NRAS', 'Gene', (229, 233))	('tumors', 'Disease', (124, 130))	('EGFR', 'Gene', (276, 280))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('KRAS', 'Var', (109, 113))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('EGFR', 'Gene', (235, 239))	('EGFR', 'molecular_function', 'GO:0005006', ('235', '239'))	('colorectal cancer', 'Disease', (67, 84))
114496	28030802	Ideally, we could use this approach to monitor treatment response, disease recurrence, as well as pick up resistant clones in patients that have an FGFR alteration being treated with an FGFR inhibitor.	('alteration', 'Var', (153, 163))	('FGF', 'Gene', (186, 189))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (148, 151))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (186, 189))	('patients', 'Species', '9606', (126, 134))	('FGFR', 'molecular_function', 'GO:0005007', ('186', '190'))	('FGFR', 'molecular_function', 'GO:0005007', ('148', '152'))	('FGF', 'Gene', (148, 151))
114497	28030802	New trial designs and approaches are being developed in order to capture the many malignancies that may harbor an FGF/FGFR aberration.	('FGF', 'Gene', (118, 121))	('aberration', 'Var', (123, 133))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (114, 117))	('FGFR', 'molecular_function', 'GO:0005007', ('118', '122'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (118, 121))	('malignancies', 'Disease', (82, 94))	('FGF', 'Gene', (114, 117))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))
114503	28030802	Thus far we have discussed the use of FGFR inhibitors assuming that FGF/FGFR is the primary driver for oncogenesis in certain histologies or in certain molecular aberrations such as FGFR3 fusion in bladder cancer.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (38, 41))	('bladder cancer', 'Disease', 'MESH:D001749', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('fusion', 'Var', (188, 194))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (72, 75))	('bladder cancer', 'Disease', (198, 212))	('FGF', 'Gene', (182, 185))	('FGF', 'Gene', (68, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('FGFR', 'molecular_function', 'GO:0005007', ('182', '186'))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (68, 71))	('FGF', 'Gene', (38, 41))	('oncogenesis', 'biological_process', 'GO:0007048', ('103', '114'))	('bladder cancer', 'Phenotype', 'HP:0009725', (198, 212))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (182, 185))	('FGF', 'Gene', (72, 75))
114505	28030802	Additionally we must appreciate the evolving nature of cancer cells and the likelihood of resistance to FGFR inhibitors directly either by (i) compensatory signaling or (ii) via intrinsic gatekeeper mutations in the FGFR receptors themselves.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (104, 107))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('FGFR', 'molecular_function', 'GO:0005007', ('216', '220'))	('FGFR', 'molecular_function', 'GO:0005007', ('104', '108'))	('gatekeeper', 'Species', '111938', (188, 198))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (216, 219))	('FGF', 'Gene', (216, 219))	('mutations', 'Var', (199, 208))	('FGF', 'Gene', (104, 107))	('compensatory signaling', 'MPA', (143, 165))	('cancer', 'Disease', (55, 61))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))
114506	28030802	Recently, acquired resistance to EGFR specific inhibitors in NSCLC mutant cell lines has been hypothesized to relate to the activation of the FGFR1-FGF2 autocrine loop.	('FGF2', 'Gene', '2247', (148, 152))	('activation', 'PosReg', (124, 134))	('FGFR', 'molecular_function', 'GO:0005007', ('142', '146'))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('FGFR1', 'Gene', '2260', (142, 147))	('EGFR', 'Gene', '1956', (33, 37))	('FGF2', 'Gene', (148, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('33', '37'))	('FGFR1', 'Gene', (142, 147))	('NSCLC', 'Disease', (61, 66))	('mutant', 'Var', (67, 73))	('EGFR', 'Gene', (33, 37))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
114513	28030802	This effect was appreciated in cell lines and xenograft mouse models of KRAS-mutant lung adenocarcinoma and KRAS-mutant pancreatic carcinoma, but was not as significant in KRAS wild-type lung cancer cells or KRAS mutant colon cancer.	('KRAS-mutant', 'Var', (108, 119))	('KRAS-mutant', 'Var', (72, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (120, 140))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('mouse', 'Species', '10090', (56, 61))	('colon cancer', 'Phenotype', 'HP:0003003', (220, 232))	('lung adenocarcinoma', 'Disease', (84, 103))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('pancreatic carcinoma', 'Disease', (120, 140))	('colon cancer', 'Disease', 'MESH:D015179', (220, 232))	('colon cancer', 'Disease', (220, 232))	('lung cancer', 'Disease', (187, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
114517	28030802	Secondly, they hypothesize that a combination of MEK and FGFR inhibition would likely be a valid approach in the treatment of KRAS-mutant lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('MEK', 'Gene', (49, 52))	('FGF', 'Gene', (57, 60))	('MEK', 'Gene', '5609', (49, 52))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (57, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('57', '61'))	('lung cancer', 'Disease', (138, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('inhibition', 'NegReg', (62, 72))	('KRAS-mutant', 'Var', (126, 137))
114522	28030802	In breast cancer, FGFR1 amplification has been associated with endocrine resistance and poor prognosis.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('endocrine resistance', 'MPA', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('FGFR1', 'Gene', (18, 23))	('amplification', 'Var', (24, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('FGFR1', 'Gene', '2260', (18, 23))	('associated', 'Reg', (47, 57))
114525	28030802	In the development of a novel targeted therapy, we must also recognize the inevitability of acquiring resistance to the drug - either from up-regulation of compensatory pathways or innate mutations rendering the FGFR receptor resistant.	('regulation', 'biological_process', 'GO:0065007', ('142', '152'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (212, 215))	('nevi', 'Phenotype', 'HP:0003764', (76, 80))	('up-regulation', 'PosReg', (139, 152))	('FGF', 'Gene', (212, 215))	('FGFR', 'molecular_function', 'GO:0005007', ('212', '216'))	('mutations', 'Var', (188, 197))
114526	28030802	In a study using FGFR3-mutant cell lines, the investigators identified EGFR signaling as a key mechanism in limiting FGFR3 inhibition.	('FGFR3-mutant', 'Var', (17, 29))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('FGFR3', 'Gene', (117, 122))	('EGFR', 'Gene', '1956', (71, 75))	('inhibition', 'NegReg', (123, 133))	('FGFR', 'molecular_function', 'GO:0005007', ('117', '121'))	('EGFR', 'molecular_function', 'GO:0005006', ('71', '75'))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('EGFR', 'Gene', (71, 75))
114528	28030802	In EGFR dependent cell lines, they also identified that EGFR downstream signaling dominated, even in the presence of an activating FGFR3 mutation.	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'molecular_function', 'GO:0005006', ('3', '7'))	('EGFR', 'Gene', (3, 7))	('mutation', 'Var', (137, 145))	('EGFR', 'Gene', '1956', (56, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('131', '135'))	('EGFR', 'Gene', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('FGFR3', 'Gene', (131, 136))	('activating', 'PosReg', (120, 130))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))
114529	28030802	More recently, in SqCLC cell lines with FGFR1 amplification, investigators identified clonal cell populations that were resistant to treatment with AZD4547 or BAY1163877.	('BAY1163877', 'Chemical', '-', (159, 169))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('AZD4547', 'Var', (148, 155))	('amplification', 'Var', (46, 59))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('BAY1163877', 'Var', (159, 169))	('AZD4547', 'Chemical', 'MESH:C572463', (148, 155))
114531	28030802	In these AZD4547 treated cells, MET amplification was thought to lead to resistance through ErbB3 activation.	('resistance', 'Disease', (73, 83))	('activation', 'PosReg', (98, 108))	('lead to', 'Reg', (65, 72))	('AZD4547', 'Chemical', 'MESH:C572463', (9, 16))	('MET amplification', 'Var', (32, 49))	('ErbB3', 'Gene', (92, 97))	('ErbB3', 'Gene', '2065', (92, 97))
114533	28030802	Additionally, when the investigators forced ectopic expression of MET in the SqCLC cells, they found that this conferred resistance to targeted FGFR inhibition.	('MET', 'Var', (66, 69))	('ectopic expression', 'MPA', (44, 62))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('FGF', 'Gene', (144, 147))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (144, 147))	('resistance', 'MPA', (121, 131))
114535	28030802	In discussing innate mutations, the "gatekeeper" mutation is responsible for the most common type of kinase inhibitor resistance, these are mutations of a residue located in the ATP binding pocket of the RTK.	('ATP', 'Chemical', 'MESH:D000255', (178, 181))	('gatekeeper', 'Species', '111938', (37, 47))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('99', '115'))	('RTK', 'Gene', (204, 207))	('mutations', 'Var', (140, 149))	('ATP binding', 'molecular_function', 'GO:0005524', ('176', '187'))	('RTK', 'Gene', '5979', (204, 207))
114543	28030802	A similar pattern of drug development and understanding has unfolded in the targeted treatment of EGFR mutant NSCLC or ALK-rearranged NSCLC.	('EGFR', 'Gene', (98, 102))	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('ALK', 'Gene', '238', (119, 122))	('mutant', 'Var', (103, 109))	('ALK', 'Gene', (119, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (134, 139))	('NSCLC', 'Disease', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('NSCLC', 'Disease', (134, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
114544	28030802	In treating EGFR mutant NSCLC, the first generation EGFR tyrosine kinase inhibitors gefinitib and erlotinib (approved in 2003 and 2004 respectively), followed by the second-generation afatinib, have been widely used in treatment of advanced disease.	('NSCLC', 'Disease', (24, 29))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('erlotinib', 'Chemical', 'MESH:D000069347', (98, 107))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('EGFR', 'Gene', '1956', (12, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('afatinib', 'Chemical', 'MESH:D000077716', (184, 192))	('tyrosine', 'Chemical', 'MESH:D014443', (57, 65))	('gefinitib', 'Chemical', '-', (84, 93))	('EGFR', 'Gene', (12, 16))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))	('mutant', 'Var', (17, 23))
114545	28030802	In fact, the most common acquired EGFR mutation leading to decreased survival has been found to be the "gatekeeper" mutation T790M, with nearly 50-60% of resistant cases demonstrating this anomaly.	('gatekeeper', 'Species', '111938', (104, 114))	('mutation', 'Var', (39, 47))	('anomaly', 'Disease', (189, 196))	('EGFR', 'Gene', (34, 38))	('decreased', 'NegReg', (59, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('anomaly', 'Disease', 'MESH:D000014', (189, 196))	('T790M', 'Mutation', 'rs121434569', (125, 130))	('EGFR', 'Gene', '1956', (34, 38))	('survival', 'MPA', (69, 77))
114547	28030802	Continued development of EGFR inhibitor therapy led to the accelerated approval of the third generation EGFR inhibitor osimertinib for patients with metastatic EGFR T790M mutation-positive NSCLC that have progressed on or after previous EGFR inhibitor therapy.	('T790M mutation-positive', 'Var', (165, 188))	('patients', 'Species', '9606', (135, 143))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('NSCLC', 'Disease', (189, 194))	('EGFR', 'Gene', '1956', (237, 241))	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', (104, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('160', '164'))	('EGFR', 'Gene', (160, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (189, 194))	('osimertinib', 'Chemical', 'MESH:C000603933', (119, 130))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', '1956', (104, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('237', '241'))	('EGFR', 'Gene', (237, 241))	('EGFR', 'Gene', '1956', (160, 164))	('T790M', 'Mutation', 'rs121434569', (165, 170))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
114550	28030802	As observed in the aforementioned stories, resistance to ALK blockade also emerges in time by multiple mechanisms including: ALK kinase mutations (30%) at L1196M (gatekeeper), F1174L, and G1202R, as well as activation of alternate oncogenes with resulting bypass signaling.	('gatekeeper', 'Species', '111938', (163, 173))	('F1174L', 'Var', (176, 182))	('ALK', 'Gene', (57, 60))	('ALK', 'Gene', '238', (125, 128))	('G1202R', 'Var', (188, 194))	('G1202R', 'Mutation', 'rs1057519783', (188, 194))	('F1174L', 'Mutation', 'rs863225281', (176, 182))	('mutations', 'Var', (136, 145))	('L1196M', 'Mutation', 'rs1057519784', (155, 161))	('signaling', 'biological_process', 'GO:0023052', ('263', '272'))	('ALK', 'Gene', '238', (57, 60))	('ALK', 'Gene', (125, 128))
114552	28030802	With ceritinib, there already exists some emerging data that ALK-G1202R and F1174V/C mutations confer some resistance to therapy.	('resistance to therapy', 'MPA', (107, 128))	('F1174V', 'Var', (76, 82))	('ALK', 'Gene', (61, 64))	('F1174V', 'SUBSTITUTION', 'None', (76, 82))	('ceritinib', 'Chemical', 'MESH:C586847', (5, 14))	('ALK', 'Gene', '238', (61, 64))	('G1202R', 'Mutation', 'rs1057519783', (65, 71))
114555	28030802	Several pre-clinical studies have highlighted a significant gatekeeper mutation (FGFR1 V561M, FGFR2 V564I, FGFR3 V555M, FGFR4 V550M) that renders targeted therapy ineffective.	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('V561M', 'Mutation', 'p.V561M', (87, 92))	('FGFR1', 'Gene', (81, 86))	('FGFR2', 'Gene', (94, 99))	('V564I', 'Var', (100, 105))	('gatekeeper', 'Species', '111938', (60, 70))	('FGFR2', 'Gene', '2263', (94, 99))	('FGFR1', 'Gene', '2260', (81, 86))	('V550M', 'Mutation', 'rs774571806', (126, 131))	('pre', 'molecular_function', 'GO:0003904', ('8', '11'))	('V555M', 'Mutation', 'rs199544087', (113, 118))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('FGFR3', 'Gene', (107, 112))	('V555M', 'Var', (113, 118))	('V561M', 'Var', (87, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('120', '124'))	('FGFR', 'molecular_function', 'GO:0005007', ('94', '98'))	('V564I', 'Mutation', 'rs1057519797', (100, 105))
114556	28030802	Preclinical cellular models harboring the FGFR3 V555M mutation have demonstrated resistance to AZD4547.	('resistance', 'MPA', (81, 91))	('FGFR3', 'Gene', (42, 47))	('V555M', 'Mutation', 'rs199544087', (48, 53))	('AZD4547', 'Chemical', 'MESH:C572463', (95, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('V555M', 'Var', (48, 53))
114557	28030802	Recently, the FGFR1 V561M gatekeeper mutation was characterized at a structural and kinetic level where a 38-fold increase in autophosphorylation of the receptor was demonstrated.	('increase', 'PosReg', (114, 122))	('gatekeeper', 'Species', '111938', (26, 36))	('V561M', 'Var', (20, 25))	('FGFR1', 'Gene', (14, 19))	('autophosphorylation', 'MPA', (126, 145))	('FGFR1', 'Gene', '2260', (14, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('V561M', 'Mutation', 'p.V561M', (20, 25))
114558	28030802	Interestingly, the mutated receptor still maintained affinity for AZD4547.	('affinity', 'MPA', (53, 61))	('AZD4547', 'Chemical', 'MESH:C572463', (66, 73))	('AZD4547', 'Var', (66, 73))	('mutated', 'Var', (19, 26))
114559	28030802	Subsequent generations of FGFR inhibitors will need to be able to circumvent these cellular defense mechanisms, and there exist two compounds FIIN-2 and FIIN-3 developed in preclinical studies that have demonstrated potency against wild type FGFR1-4 as well as receptors with gatekeeper mutations.	('FGF', 'Gene', (26, 29))	('FGFR1', 'Gene', '2260', (242, 247))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (242, 245))	('gatekeeper', 'Species', '111938', (276, 286))	('FGFR', 'molecular_function', 'GO:0005007', ('242', '246'))	('potency', 'MPA', (216, 223))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (26, 29))	('mutations', 'Var', (287, 296))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('FGF', 'Gene', (242, 245))	('FGFR1', 'Gene', (242, 247))
114562	28030802	When designing clinical trials, we should exclude tumors with the aforementioned gatekeeper mutations of FGFR known to confer possible resistance to currently available selective FGFR inhibitors.	('FGF', 'Gene', (105, 108))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('gatekeeper', 'Species', '111938', (81, 91))	('mutations', 'Var', (92, 101))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (105, 108))	('FGFR', 'molecular_function', 'GO:0005007', ('179', '183'))	('FGF', 'Gene', (179, 182))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (179, 182))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))
114581	28030802	Already in other known targetable mutations discussed above, such as EGFR in colorectal cancer or BCR-ABL1 in CML, the use of next generation sequencing (NGS) has proved invaluable in identifying not only actionable mutations, but also for screening "gatekeeper" mutations that may confer resistance to therapy.	('EGFR', 'Gene', '1956', (69, 73))	('colorectal cancer', 'Disease', (77, 94))	('EGFR', 'Gene', (69, 73))	('BCR-ABL1', 'Gene', (98, 106))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('CML', 'Disease', 'MESH:D015464', (110, 113))	('CML', 'Phenotype', 'HP:0005506', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('gatekeeper', 'Species', '111938', (251, 261))	('EGFR', 'molecular_function', 'GO:0005006', ('69', '73'))	('mutations', 'Var', (216, 225))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('CML', 'Disease', (110, 113))
114582	28030802	As selective FGFR inhibitors get closer to routine clinical use, we can learn from the past especially with regards to patient selection as it predicts response to therapy.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('patient', 'Species', '9606', (119, 126))	('FGF', 'Gene', (13, 16))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (13, 16))	('inhibitors', 'Var', (18, 28))
114586	28030802	The use of massive parallel DNA sequencing technology allows for noting differences in disease response based on FGFR mutation or fusion in lung, which may be important in a minority of lung cancers and this detail would be easily missed with FISH or IHC.	('fusion', 'Var', (130, 136))	('lung cancers', 'Phenotype', 'HP:0100526', (186, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('FGFR', 'molecular_function', 'GO:0005007', ('113', '117'))	('FGF', 'Gene', (113, 116))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('lung cancers', 'Disease', (186, 198))	('mutation', 'Var', (118, 126))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('lung cancers', 'Disease', 'MESH:D008175', (186, 198))
114588	28030802	This is an ideal platform to discover unusual responders to FGFR inhibitor therapy with the goal of identifying new and relevant FGF/FGFR alterations, especially with the addition of rare tumors that might otherwise not have enrolled in a clinical trial.	('tumors', 'Disease', (188, 194))	('FGF', 'Gene', (129, 132))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('FGF', 'Gene', (60, 63))	('FGF', 'Gene', (133, 136))	('alterations', 'Var', (138, 149))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (60, 63))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (129, 132))	('FGFR', 'molecular_function', 'GO:0005007', ('133', '137'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
114589	28030802	Despite the advances in drug design to include the second-generation selective FGFR inhibitors, the biology of FGF/FGFR signaling is complex and we have seen that response to therapy is dependent on a multitude of factors.	('FGF', 'Gene', (115, 118))	('inhibitors', 'Var', (84, 94))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (79, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('115', '119'))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (111, 114))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (115, 118))	('FGF', 'Gene', (79, 82))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('FGF', 'Gene', (111, 114))
114590	28030802	At the present time, targeting FGFR fusion aberrations has demonstrated the best response; we see this in bladder cancer with encouraging results.	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('bladder cancer', 'Disease', 'MESH:D001749', (106, 120))	('bladder cancer', 'Disease', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('aberrations', 'Var', (43, 54))	('FGF', 'Gene', (31, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (106, 120))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (31, 34))
114592	28030802	This is of interest given that the tumors in which FGFR3-TACC3 mutations have been identified (2.6% of urothelial carcinoma cases, 1.2-8.3% of GBM) are on the more aggressive end of the spectrum with overall limited treatment options.	('mutations', 'Var', (63, 72))	('urothelial carcinoma', 'Disease', (103, 123))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('FGFR3-TACC3', 'Gene', (51, 62))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (103, 123))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
114630	24827579	Group 1 (non-diabetic control) is samples Ot3449-Ot3454 (CK-1 through CK-6); Group 2 (DM+LOS) is samples Ot3455-Ot3457 (CK-7 through CK-9); and Group 3 (DM alone) is samples Ot3458-Ot3460 (CK-10 through CK-12).	('CK-1', 'Species', '2498238', (57, 61))	('non-diabetic', 'Disease', (9, 21))	('non-diabetic', 'Disease', 'MESH:D003920', (9, 21))	('Ot3449-Ot3454', 'Var', (42, 55))	('CK-1', 'Species', '2498238', (189, 193))	('CK-1', 'Species', '2498238', (203, 207))	('Ot3455-Ot3457', 'Var', (105, 118))	('DM', 'Disease', 'MESH:D009223', (86, 88))	('DM', 'Disease', 'MESH:D009223', (153, 155))
114634	24827579	Probe sets (Invitrogen) were as follows: Gm6300_1, Mm03949676_m1 [23.30]; Gm6300_2, Mm03949677_m1 [23.44]; Slc7a12_1, Mm00499866_m1 [21.87]; Slc7a12_2, Mm01283157_m1 [17.91].	('Slc7a12', 'Gene', '140918', (141, 148))	('Slc7a12', 'Gene', (107, 114))	('Mm03949677_m1', 'Var', (84, 97))	('Slc7a12', 'Gene', '140918', (107, 114))	('Mm03949676_m1', 'Var', (51, 64))	('Gm6300', 'Gene', (74, 80))	('Gm6300', 'Gene', '622229', (74, 80))	('Mm01283157_m1', 'Var', (152, 165))	('Gm6300', 'Gene', (41, 47))	('Gm6300', 'Gene', '622229', (41, 47))	('Slc7a12', 'Gene', (141, 148))	('Mm00499866_m1', 'Var', (118, 131))
114675	24827579	Some gene products were expressed in the non-diabetic state but were completely absent from the vehicle-treated (Mup3, Ahsg, Mug1, Uox, Mup10, Mup21) or losartan-treated (Serpina3k, Mup3, Mug1, Mup9, Mup17, Uox, Ucp1, Mup21, LOC100048884) diabetic kidney, so fold-induction could not be determined (Table S26 in File S2).	('Mup21', 'Gene', (218, 223))	('Uox', 'Gene', '22262', (207, 210))	('Mup21', 'Gene', '381531', (218, 223))	('non-diabetic', 'Disease', (41, 53))	('diabetic kidney', 'Disease', (239, 254))	('non-diabetic', 'Disease', 'MESH:D003920', (41, 53))	('Ucp1', 'Gene', '22227', (212, 216))	('Mup3', 'Gene', (182, 186))	('Mup17', 'Gene', '100039206', (200, 205))	('Mup3', 'Gene', '17842', (182, 186))	('Serpina3k', 'Gene', (171, 180))	('Mug1', 'Gene', (188, 192))	('diabetic kidney', 'Disease', 'MESH:D003928', (239, 254))	('Ahsg', 'Gene', (119, 123))	('Ahsg', 'Gene', '11625', (119, 123))	('Mug1', 'Gene', (125, 129))	('Mup10', 'Gene', '100039008', (136, 141))	('Mup9', 'Gene', '100038948', (194, 198))	('Serpina3k', 'Gene', '20714', (171, 180))	('LOC100048884', 'Var', (225, 237))	('Mug1', 'Gene', '17836', (188, 192))	('Ucp1', 'Gene', (212, 216))	('Mup21', 'Gene', (143, 148))	('Mup3', 'Gene', (113, 117))	('Mup3', 'Gene', '17842', (113, 117))	('Uox', 'Gene', (131, 134))	('Mug', 'molecular_function', 'GO:0043739', ('125', '128'))	('Mup21', 'Gene', '381531', (143, 148))	('Mug1', 'Gene', '17836', (125, 129))	('losartan', 'Chemical', 'MESH:D019808', (153, 161))	('Mup10', 'Gene', (136, 141))	('Uox', 'Gene', '22262', (131, 134))	('Mug', 'molecular_function', 'GO:0043739', ('188', '191'))	('Mup9', 'Gene', (194, 198))	('Mup17', 'Gene', (200, 205))	('Uox', 'Gene', (207, 210))
114756	24827579	Among the broad patterns observed, it was notable that the most expression differences occurred between the non-diabetic and diabetic kidney; unexpectedly, however, over 70% of the diabetes-associated changes reflected downregulation and not upregulation in gene expression.	('diabetes', 'Disease', (181, 189))	('changes', 'Var', (201, 208))	('diabetic kidney', 'Disease', (125, 140))	('gene expression', 'biological_process', 'GO:0010467', ('258', '273'))	('diabetes', 'Disease', 'MESH:D003920', (181, 189))	('downregulation', 'NegReg', (219, 233))	('diabetic kidney', 'Disease', 'MESH:D003928', (125, 140))	('non-diabetic', 'Disease', (108, 120))	('non-diabetic', 'Disease', 'MESH:D003920', (108, 120))
114792	24827579	Angptl3 mutations - and lower levels of the protein - cause familial combined hypolipidemia.	('mutations -', 'Var', (8, 19))	('hypolipidemia', 'Phenotype', 'HP:0045014', (78, 91))	('cause', 'Reg', (54, 59))	('Angptl3', 'Gene', '30924', (0, 7))	('hypolipidemia', 'Disease', 'MESH:C565732', (78, 91))	('hypolipidemia', 'Disease', (78, 91))	('lower', 'NegReg', (24, 29))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('Angptl3', 'Gene', (0, 7))
114793	24827579	Polymorphisms in Angptl3 associate with higher triglyceride levels and may represent a cardiovascular risk factor.	('cardiovascular risk factor', 'Phenotype', 'HP:0001626', (87, 113))	('higher', 'PosReg', (40, 46))	('Polymorphisms', 'Var', (0, 13))	('triglyceride levels', 'MPA', (47, 66))	('triglyceride', 'Chemical', 'MESH:D014280', (47, 59))	('Angptl3', 'Gene', (17, 24))	('higher triglyceride levels', 'Phenotype', 'HP:0002155', (40, 66))	('Angptl3', 'Gene', '30924', (17, 24))
114861	24827579	Most diabetic changes in gene expression were unaffected by losartan, and the majority of losartan-associated changes served to ameliorate rather than exacerbate diabetes-associated changes ( Figure 3 ).	('diabetic', 'Disease', (5, 13))	('gene expression', 'biological_process', 'GO:0010467', ('25', '40'))	('rat', 'Species', '10116', (139, 142))	('losartan', 'Chemical', 'MESH:D019808', (90, 98))	('losartan', 'Chemical', 'MESH:D019808', (60, 68))	('diabetes', 'Disease', (162, 170))	('gene expression', 'MPA', (25, 40))	('diabetes', 'Disease', 'MESH:D003920', (162, 170))	('rat', 'Species', '10116', (134, 137))	('changes', 'Var', (110, 117))	('diabetic', 'Disease', 'MESH:D003920', (5, 13))	('ameliorate', 'PosReg', (128, 138))
114864	24827579	Inhibition of the type 1 angiotensin II receptor can ameliorate ER stress in the diabetic kidney, and block ER stress-induced apoptosis in an obstructive model of renal interstitial fibrosis.	('ameliorate', 'PosReg', (53, 63))	('diabetic kidney', 'Disease', 'MESH:D003928', (81, 96))	('renal interstitial fibrosis', 'Phenotype', 'HP:0005576', (163, 190))	('ER stress', 'MPA', (64, 73))	('renal interstitial fibrosis', 'Disease', (163, 190))	('ER stress-induced apoptosis', 'biological_process', 'GO:0070059', ('108', '135'))	('diabetic kidney', 'Disease', (81, 96))	('Inhibition', 'Var', (0, 10))	('renal interstitial fibrosis', 'Disease', 'MESH:D007674', (163, 190))	('rat', 'Species', '10116', (59, 62))	('block', 'NegReg', (102, 107))	('ER stress-induced', 'MPA', (108, 125))
114873	24827579	Furthermore, a Mep1b polymorphism associate with DM risk in Pima Indians.	('associate with', 'Reg', (34, 48))	('Mep1b', 'Gene', (15, 20))	('DM', 'Disease', 'MESH:D009223', (49, 51))	('Mep1b', 'Gene', '17288', (15, 20))	('polymorphism', 'Var', (21, 33))
114882	24827579	Thus, cells that exhibit increased expression of these three genes would be expected to be proliferative and prone to genomic instability.	('increased', 'PosReg', (25, 34))	('genomic instability', 'CPA', (118, 137))	('proliferative', 'CPA', (91, 104))	('rat', 'Species', '10116', (98, 101))	('expression', 'Var', (35, 45))
114900	24827579	In a retrospective assessment of 279 patients who underwent resection for known urothelial cancer, ACEi or ARB use associated with improved five-year metastasis-free survival rate.	('urothelial cancer', 'Disease', 'MESH:D014523', (80, 97))	('patients', 'Species', '9606', (37, 45))	('ACEi', 'Var', (99, 103))	('improved', 'PosReg', (131, 139))	('rat', 'Species', '10116', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ACEi', 'Chemical', '-', (99, 103))	('urothelial cancer', 'Disease', (80, 97))	('metastasis-free survival', 'CPA', (150, 174))
114904	24827579	The effect of losartan was tested in isolation and not in combination with other antidiabetic therapies (e.g., insulin supplementation); therefore, some or many of the diabetic gene changes unaffected by losartan may represent the renal consequences of hyperglycemia, per se.	('losartan', 'Chemical', 'MESH:D019808', (204, 212))	('diabetic', 'Disease', 'MESH:D003920', (85, 93))	('insulin', 'molecular_function', 'GO:0016088', ('111', '118'))	('hyperglycemia', 'Disease', (253, 266))	('diabetic', 'Disease', 'MESH:D003920', (168, 176))	('diabetic', 'Disease', (85, 93))	('changes', 'Var', (182, 189))	('diabetic', 'Disease', (168, 176))	('hyperglycemia', 'Phenotype', 'HP:0003074', (253, 266))	('losartan', 'Chemical', 'MESH:D019808', (14, 22))	('hyperglycemia', 'Disease', 'MESH:D006943', (253, 266))
114919	24220575	We subsequently define mutations in microRNA target sites using the AGO-CLIP microRNA target atlas and TCGA exome-sequencing data.	('mutations', 'Var', (23, 32))	('CLIP', 'Gene', '7461', (72, 76))	('CLIP', 'Gene', (72, 76))
115019	24220575	To define additional novel mechanisms of microRNA regulation in tumours, we next integrated the AGO-CLIP data set with TCGA mutation data to identify somatic SNVs in microRNA target sites across tumours.	('CLIP', 'Gene', '7461', (100, 104))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('regulation', 'biological_process', 'GO:0065007', ('50', '60'))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('TCGA', 'Gene', (119, 123))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('mutation', 'Var', (124, 132))	('CLIP', 'Gene', (100, 104))	('tumours', 'Disease', (195, 202))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
115020	24220575	In our analysis of COAD whole-genome sequencing (WGS) samples, 60% of mutations in coding mRNAs are in the 3'-UTR, highlighting the potential importance of mutations in these regions (Fig.	('COAD', 'Disease', 'MESH:D029424', (19, 23))	('mutations', 'Var', (70, 79))	('COAD', 'Disease', (19, 23))	('mRNAs', 'Gene', (90, 95))
115021	24220575	As such, analysing mutations intersecting with microRNA seed-complementary sites has the potential to greatly expand the search for relevant cancer mutations by imbuing silent mutations and 3'-UTR mutations with functional significance.	('silent mutations', 'Var', (169, 185))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
115024	24220575	Therefore, the majority of microRNA target mutations we define from the 12 pan-cancer tumours occur specifically in the coding region.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('pan-cancer', 'Disease', 'MESH:C537931', (75, 85))	('mutations', 'Var', (43, 52))	('cancer tumours', 'Disease', 'MESH:D009369', (79, 93))	('cancer tumours', 'Disease', (79, 93))	('pan-cancer', 'Disease', (75, 85))
115027	24220575	To demonstrate the ability of the AGO-CLIP technology and the miSNP algorithm to detect relevant microRNA target-site mutations, we selected six binding site mutations for experimental validation (Supplementary Data 10).	('binding', 'molecular_function', 'GO:0005488', ('145', '152'))	('mutations', 'Var', (118, 127))	('CLIP', 'Gene', (38, 42))	('mutations', 'Var', (158, 167))	('CLIP', 'Gene', '7461', (38, 42))
115028	24220575	These sites were chosen based on the number of times the specific binding site was identified in the AGO-CLIP atlas, the location of the seed in the coding region or 3'-UTR, whether TargetScan called the site as highly conserved and the relative location of the mutation within the seed-complementary region of the binding site.	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('CLIP', 'Gene', (105, 109))	('mutation', 'Var', (262, 270))	('CLIP', 'Gene', '7461', (105, 109))	('binding', 'molecular_function', 'GO:0005488', ('315', '322'))
115029	24220575	For the four target sites with validated target repression, we reproduced the endogenous tumour mutation in the 3'-UTR-luciferase construct.	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('mutation', 'Var', (96, 104))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', (89, 95))
115031	24220575	Mutations complementary to the Let-7 seed on ANP32E and miR-142 seed on FAM114A1 variably reduced, but did not ablate, the repressive ability of the microRNA on the luciferase reporter (Fig.	('FAM114A1', 'Gene', (72, 80))	('miR-142', 'Gene', '406934', (56, 63))	('reduced', 'NegReg', (90, 97))	('ANP32E', 'Gene', (45, 51))	('Let-7', 'Gene', (31, 36))	('repressive', 'MPA', (123, 133))	('miR-142', 'Gene', (56, 63))	('Mutations', 'Var', (0, 9))	('repressive ability', 'Phenotype', 'HP:0000716', (123, 141))	('ANP32E', 'Gene', '81611', (45, 51))	('FAM114A1', 'Gene', '92689', (72, 80))
115032	24220575	One microRNA target site mutation validated in our study was a deletion of a miR-17 seed family binding site in the SKI-like OC (SKIL/SnoN) 3'-UTR.	('SKIL', 'Gene', (129, 133))	('SnoN', 'Gene', (134, 138))	('binding', 'molecular_function', 'GO:0005488', ('96', '103'))	('miR-17', 'Gene', (77, 83))	('SKIL', 'Gene', '6498', (129, 133))	('deletion', 'Var', (63, 71))	('miR-17', 'Gene', '406952', (77, 83))	('SnoN', 'Gene', '6498', (134, 138))
115033	24220575	SKIL is a known OC and was ranked in the top 7% of pan-cancer OCs in our pan-cancer mRNA driver index due to expression gain and copy number amplification (Supplementary Data 6).	('expression', 'MPA', (109, 119))	('pan-cancer', 'Disease', 'MESH:C537931', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pan-cancer', 'Disease', 'MESH:C537931', (73, 83))	('SKIL', 'Gene', (0, 4))	('SKIL', 'Gene', '6498', (0, 4))	('pan-cancer', 'Disease', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('copy number amplification', 'Var', (129, 154))	('pan-cancer', 'Disease', (73, 83))	('gain', 'PosReg', (120, 124))
115036	24220575	Mutation of the miR-17 seed-family binding site on the SKIL 3'-UTR may represent a mechanism to allow escape from this feedback regulation, allowing unregulated SKIL expression while simultaneously enhancing the oncogenicity of the miR-17 seed family and creating enhanced suppression of the TGFbeta pathway (Fig.	('SKIL', 'Gene', '6498', (55, 59))	('regulation', 'biological_process', 'GO:0065007', ('128', '138'))	('miR-17', 'Gene', '406952', (16, 22))	('Mutation', 'Var', (0, 8))	('miR-17', 'Gene', (232, 238))	('SKIL', 'Gene', (161, 165))	('enhancing', 'PosReg', (198, 207))	('miR-17', 'Gene', (16, 22))	('enhanced', 'PosReg', (264, 272))	('TGFbeta', 'Gene', (292, 299))	('SKIL', 'Gene', '6498', (161, 165))	('SKIL', 'Gene', (55, 59))	('binding', 'molecular_function', 'GO:0005488', ('35', '42'))	('oncogenicity', 'CPA', (212, 224))	('miR-17', 'Gene', '406952', (232, 238))	('suppression', 'NegReg', (273, 284))	('allowing', 'PosReg', (140, 148))	('TGFbeta', 'Gene', '7040', (292, 299))
115045	24220575	These mutations were discovered in the exome-sequencing-defined coding-region mutations available from the Pan-Cancer project, a small number of 3'-UTR mutations available from KIRC exome sequencing and whole-genome 3'-UTR mutations from 36 COAD WGS samples.	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('COAD', 'Disease', (241, 245))	('COAD', 'Disease', 'MESH:D029424', (241, 245))	('mutations', 'Var', (78, 87))
115046	24220575	AGO-CLIP characterization of microRNA binding in additional tissue types and integration of additional 3'-UTR mutations from broader cohorts of WGS samples will improve the yield of relevant microRNA target site mutations in the future.	('microRNA binding', 'molecular_function', 'GO:0035198', ('29', '45'))	('mutations', 'Var', (110, 119))	('mutations', 'Var', (212, 221))	('CLIP', 'Gene', (4, 8))	('CLIP', 'Gene', '7461', (4, 8))
115048	24220575	Integration of the AGO-CLIP-defined microRNA-binding data with TCGA tumour data revealed several novel insights into microRNA regulation of human tumours, including the definition of a pan-cancer oncomiR superfamily and genome-wide identification of microRNA-binding site mutations.	('mutations', 'Var', (272, 281))	('tumours', 'Disease', (146, 153))	('microRNA-binding', 'molecular_function', 'GO:0035198', ('36', '52'))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('pan-cancer', 'Disease', (185, 195))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('microRNA-binding', 'molecular_function', 'GO:0035198', ('250', '266'))	('tumour', 'Disease', 'MESH:D009369', (146, 152))	('miR', 'Gene', '220972', (200, 203))	('tumour', 'Disease', (146, 152))	('regulation', 'biological_process', 'GO:0065007', ('126', '136'))	('CLIP', 'Gene', (23, 27))	('miR', 'Gene', (200, 203))	('human', 'Species', '9606', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('CLIP', 'Gene', '7461', (23, 27))	('pan-cancer', 'Disease', 'MESH:C537931', (185, 195))
115049	24220575	AGO-CLIP sequence read archive (SRR) files corresponding to all publicly available human AGO-CLIP experiments were downloaded from the NIH sequence read archive (SRR codes: SRR048973, SRR048974, SRR048975, SRR048976, SRR048977, SRR048978, SRR048979, SRR048980, SRR048981, SRR359787, SRR189786, SRR189787, SRR189784, SRR189785, SRR189782, SRR189783, SRR580362, SRR580363, SRR580352, SRR580353, SRR580354, SRR580355, SRR580359, SRR580360, SRR580361, SRR580356, SRR580357, SRR343336, SRR343337, SRR343334, SRR343335, SRR592689, SRR592688, SRR592687, SRR592686, SRR592685; data were downloaded on 11 January 2013).	('SRR580360', 'Var', (426, 435))	('SRR580353', 'Var', (382, 391))	('CLIP', 'Gene', '7461', (93, 97))	('SRR580355', 'Var', (404, 413))	('SRR592688', 'Var', (525, 534))	('SRR580359', 'Var', (415, 424))	('CLIP', 'Gene', '7461', (4, 8))	('SRR580354', 'Var', (393, 402))	('SRR580352', 'Var', (371, 380))	('SRR343337', 'Var', (481, 490))	('SRR580361', 'Var', (437, 446))	('SRR580356', 'Var', (448, 457))	('SRR592689', 'Var', (514, 523))	('SRR592687', 'Var', (536, 545))	('SRR343334', 'Var', (492, 501))	('SRR580363', 'Var', (360, 369))	('SRR592686', 'Var', (547, 556))	('SRR343335', 'Var', (503, 512))	('CLIP', 'Gene', (93, 97))	('SRR580362', 'Var', (349, 358))	('SRR580357', 'Var', (459, 468))	('human', 'Species', '9606', (83, 88))	('SRR343336', 'Var', (470, 479))	('CLIP', 'Gene', (4, 8))
115055	24220575	The difference between the two methods lies in the use of photoactivatable ribonucleoside analogues in PAR-CLIP data sets, which allow experimental determination of physical interlinkage between protein-RNA pairs through a mismatch repair defect initialized at crosslinked nucleoside analogues during complementary DNA synthesis, leading to T C transitions in the generated cDNA.	('CLIP', 'Gene', (107, 111))	('nucleoside', 'Chemical', 'MESH:D009705', (273, 283))	('T C transitions', 'MPA', (341, 356))	('ribonucleoside', 'Chemical', 'MESH:D012263', (75, 89))	('CLIP', 'Gene', '7461', (107, 111))	('mismatch', 'Var', (223, 231))	('nucleoside', 'Chemical', 'MESH:D009705', (79, 89))	('mismatch repair', 'biological_process', 'GO:0006298', ('223', '238'))	('defect', 'Var', (239, 245))	('DNA synthesis', 'biological_process', 'GO:0071897', ('315', '328'))	('RNA', 'cellular_component', 'GO:0005562', ('203', '206'))	('DNA', 'cellular_component', 'GO:0005574', ('315', '318'))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))
115080	24220575	This system equally weighted CNV, mRNA expression change and gene mutations as three orthogonal methods of identifying TS and OCs across tumours.	('mutations', 'Var', (66, 75))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('OCs across tumours', 'Disease', (126, 144))	('mRNA', 'MPA', (34, 38))	('OCs across tumours', 'Disease', 'MESH:D009369', (126, 144))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
115085	24220575	In sum, this analysis generated a continuous negative-to-positive scale that ranked pan-cancer drivers based on consistent mRNA, CNV or mutation changes across tumours.	('tumours', 'Disease', 'MESH:D009369', (160, 167))	('mutation', 'Var', (136, 144))	('CNV', 'MPA', (129, 132))	('tumours', 'Disease', (160, 167))	('pan-cancer', 'Disease', 'MESH:C537931', (84, 94))	('mRNA', 'MPA', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('pan-cancer', 'Disease', (84, 94))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))
115087	24220575	All tumours contain CNV data and mutation data.	('mutation', 'Var', (33, 41))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('CNV data', 'MPA', (20, 28))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('tumours', 'Disease', (4, 11))
115088	24220575	Mutation score is highly dominant in several genes such as TP53 with very high mutation frequencies (~50% of all tumours).	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('TP53', 'Gene', (59, 63))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('tumours', 'Disease', 'MESH:D009369', (113, 120))	('Mutation score', 'Var', (0, 14))	('tumours', 'Disease', (113, 120))	('TP53', 'Gene', '7157', (59, 63))
115098	24220575	It first partition the tumour samples into those that contain mutations in microRNA binding site; the algorithm can be customized to consider only particular mutation types (for example, coding, silent).	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('microRNA binding', 'molecular_function', 'GO:0035198', ('75', '91'))	('coding', 'Disease', (187, 193))	('tumour', 'Disease', (23, 29))	('silent', 'Disease', (195, 201))	('mutations', 'Var', (62, 71))
115099	24220575	Finally, it identifies genes for which the expression associates with the mutation status in microRNA binding sites by comparing the gene expression distributions of tumour samples with or without common sites using a two tailed Welch's t-test; miSNP reports both the fold-change and the t-test P-value for each gene.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('mutation', 'Var', (74, 82))	('tumour', 'Disease', (166, 172))	('microRNA binding', 'molecular_function', 'GO:0035198', ('93', '109'))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('gene expression', 'biological_process', 'GO:0010467', ('133', '148'))
115100	24220575	In the current paper, we analysed all AGO-CLIP-defined microRNA target sites for mutations to define a global perspective of possible interactions, but selected sites for validation only from interactions with >=3 occurrences corresponding to a non-random event.	('CLIP', 'Gene', '7461', (42, 46))	('CLIP', 'Gene', (42, 46))	('mutations', 'Var', (81, 90))	('interactions', 'Interaction', (134, 146))
115131	32532789	High tumor mutational burden (TMB) has been shown to correlate with response to immune checkpoint inhibitors across multiple tumor types, including untreated non-small cell lung cancer (NSCLC), previously treated urothelial carcinoma, and small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (250, 261))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('TMB', 'Chemical', '-', (30, 33))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (158, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (162, 184))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('small cell lung cancer', 'Disease', 'MESH:D055752', (239, 261))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (213, 233))	('mutational', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('small cell lung cancer', 'Disease', (239, 261))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('urothelial carcinoma', 'Disease', (213, 233))	('small cell lung cancer', 'Disease', 'MESH:D055752', (162, 184))	('NSCLC', 'Disease', (186, 191))	('small cell lung cancer', 'Disease', (162, 184))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (239, 261))	('High tumor', 'Disease', (0, 10))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('NSCLC', 'Phenotype', 'HP:0030358', (186, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', (5, 10))	('High tumor', 'Disease', 'MESH:D009369', (0, 10))
115132	32532789	In advanced melanoma, high TMB has been associated with response in patients receiving ipilimumab, nivolumab followed by ipilimumab, and nivolumab in ipilimumab-naive patients.	('ipilimumab', 'Chemical', 'MESH:D000074324', (121, 131))	('TMB', 'Chemical', '-', (27, 30))	('nivolumab', 'Chemical', 'MESH:D000077594', (137, 146))	('melanoma', 'Disease', (12, 20))	('nivolumab', 'Chemical', 'MESH:D000077594', (99, 108))	('high', 'Var', (22, 26))	('ipilimumab', 'Chemical', 'MESH:D000074324', (87, 97))	('patients', 'Species', '9606', (167, 175))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('patients', 'Species', '9606', (68, 76))	('ipilimumab', 'Chemical', 'MESH:D000074324', (150, 160))	('TMB', 'MPA', (27, 30))
115153	32532789	In this post hoc exploratory analysis, TMB was defined as the total number of missense somatic mutations per tumor and evaluated as a continuous variable, by tertiles (low <85, medium 85-169, high >=170), and using a median cutoff (low <113, high >=113).	('low <85', 'Var', (168, 175))	('high', 'Var', (192, 196))	('medium 85-169', 'Var', (177, 190))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('TMB', 'Chemical', '-', (39, 42))	('missense', 'Var', (78, 86))	('tumor', 'Disease', (109, 114))
115156	32532789	A previous study identified 30 validated mutational signatures across human cancers.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('human', 'Species', '9606', (70, 75))	('mutational', 'Var', (41, 51))
115208	32532789	Consistent with the initial report of this study, while ORR was numerically higher and median PFS and OS were numerically longer in patients with baseline tumor PD-L1 expression >=1%, efficacy was observed regardless of PD-L1 expression.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('PD-L1', 'Gene', '29126', (220, 225))	('longer', 'PosReg', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('PD-L1', 'Gene', (161, 166))	('ORR', 'MPA', (56, 59))	('PFS', 'CPA', (94, 97))	('PD-L1', 'Gene', (220, 225))	('higher', 'PosReg', (76, 82))	('PD-L1', 'Gene', '29126', (161, 166))	('>=1%', 'Var', (178, 182))	('patients', 'Species', '9606', (132, 140))
115209	32532789	In the retrospective exploratory biomarker analyses, we found that high TMB categorization by tertiles as assessed by whole exome sequencing was associated with higher ORR, longer PFS, and longer OS in patients treated with nivolumab, and patients with high TMB showed improved outcomes across baseline PD-L1 expression levels.	('PD-L1', 'Gene', (303, 308))	('high', 'Var', (67, 71))	('ORR', 'MPA', (168, 171))	('TMB', 'Gene', (72, 75))	('patients', 'Species', '9606', (239, 247))	('TMB', 'Chemical', '-', (258, 261))	('PD-L1', 'Gene', '29126', (303, 308))	('nivolumab', 'Chemical', 'MESH:D000077594', (224, 233))	('patients', 'Species', '9606', (202, 210))	('PFS', 'MPA', (180, 183))	('TMB', 'Chemical', '-', (72, 75))	('higher', 'PosReg', (161, 167))
115213	32532789	Furthermore, the analyses of TMB together with PD-L1 expression indicate that the combination of TMB and PD-L1 was a better predictor of PFS and OS than TMB or PD-L1 alone.	('PD-L1', 'Gene', (105, 110))	('TMB', 'Gene', (97, 100))	('PD-L1', 'Gene', (47, 52))	('PD-L1', 'Gene', (160, 165))	('TMB', 'Chemical', '-', (97, 100))	('PD-L1', 'Gene', '29126', (160, 165))	('PD-L1', 'Gene', '29126', (105, 110))	('PD-L1', 'Gene', '29126', (47, 52))	('TMB', 'Chemical', '-', (29, 32))	('PFS', 'Disease', (137, 140))	('TMB', 'Chemical', '-', (153, 156))	('combination', 'Var', (82, 93))
115218	32532789	Consistent with our findings, mutational signature 2 was previously shown to be associated with both TMB and improved response to immune checkpoint inhibitors in patients with non-small cell lung cancer.	('patients', 'Species', '9606', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (180, 202))	('TMB', 'Disease', (101, 104))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (176, 202))	('small cell lung cancer', 'Disease', (180, 202))	('response to immune checkpoint inhibitors', 'MPA', (118, 158))	('mutational', 'Var', (30, 40))	('improved', 'PosReg', (109, 117))	('TMB', 'Chemical', '-', (101, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('small cell lung cancer', 'Disease', 'MESH:D055752', (180, 202))
115224	32532789	In the KEYNOTE-010 and KEYNOTE-042 trials, high TMB was associated with ORR, PFS, and OS in patients receiving pembrolizumab for PD-L1-positive NSCLC.	('ORR', 'Disease', (72, 75))	('pembrolizumab', 'Chemical', 'MESH:C582435', (111, 124))	('high', 'Var', (43, 47))	('TMB', 'Chemical', '-', (48, 51))	('patients', 'Species', '9606', (92, 100))	('PFS', 'Disease', (77, 80))	('associated', 'Reg', (56, 66))	('PD-L1-positive NSCLC', 'Disease', (129, 149))	('PD-L1-positive NSCLC', 'Disease', 'MESH:D010300', (129, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))
115232	32532789	In exploratory biomarker analyses, high TMB (>=170 mutations per tumor) was associated with higher ORR, longer PFS, and longer OS in patients treated with nivolumab, and patients with high TMB showed improved outcomes across baseline PD-L1 expression levels.	('patients', 'Species', '9606', (170, 178))	('ORR', 'MPA', (99, 102))	('higher', 'PosReg', (92, 98))	('tumor', 'Disease', (65, 70))	('TMB', 'Chemical', '-', (189, 192))	('patients', 'Species', '9606', (133, 141))	('improved', 'PosReg', (200, 208))	('TMB', 'Chemical', '-', (40, 43))	('nivolumab', 'Chemical', 'MESH:D000077594', (155, 164))	('PD-L1', 'Gene', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('PD-L1', 'Gene', '29126', (234, 239))	('high', 'Var', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
115271	33692868	CGH is particularly useful as it enables researchers to identify copy number changes by comparing sample tumor genomes with control genomes, and hence determine which changes are consistent among tumor populations and may, therefore, be markers of disease.	('tumor', 'Disease', (196, 201))	('changes', 'Var', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('copy number changes', 'Var', (65, 84))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
115287	33692868	This is because SLP determines the presence or absence of an aberration cell by cell, whereas aCGH only detects it in the global population and it may be averaged out to a normal level if there are both insertions and deletions in the tumor.	('deletions', 'Var', (218, 227))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (235, 240))
115288	33692868	aCGH was also employed to assess the deletion status of the bone tumor suppressor gene disks large homolog 2, common to both human and canine osteosarcoma, which were found to occur in 42 and 56% of cases, respectively.	('canine', 'Species', '9615', (135, 141))	('disks large homolog 2', 'Gene', '1740', (87, 108))	('deletion', 'Var', (37, 45))	('bone tumor', 'Disease', (60, 70))	('bone tumor', 'Phenotype', 'HP:0010622', (60, 70))	('tumor suppressor', 'biological_process', 'GO:0051726', ('65', '81'))	('human', 'Species', '9606', (125, 130))	('osteosarcoma', 'Disease', (142, 154))	('bone tumor', 'Disease', 'MESH:D001859', (60, 70))	('disks large homolog 2', 'Gene', (87, 108))	('osteosarcoma', 'Phenotype', 'HP:0002669', (142, 154))	('osteosarcoma', 'Disease', 'MESH:D012516', (142, 154))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('65', '81'))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
115305	33692868	FISH is an early technology used to study chromosomal changes, such as translocations and deletions, and compare them with known changes in human cancer genomes.	('cancer', 'Disease', (146, 152))	('human', 'Species', '9606', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('translocations', 'Var', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('deletions', 'Var', (90, 99))
115307	33692868	In canines with Burkitt's lymphoma, a rearrangement homologous to the human t(8;14) one was found, and for canine chronic lymphocytic leukemia, the deletion at the RB transcriptional corepressor 1 locus known to occur in the human form was also located.	('deletion', 'Var', (148, 156))	('canines', 'Species', '9615', (3, 10))	('RB transcriptional corepressor 1', 'Gene', '476915', (164, 196))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (16, 34))	("Burkitt's lymphoma", 'Disease', (16, 34))	('leukemia', 'Phenotype', 'HP:0001909', (134, 142))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (114, 142))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (16, 34))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (114, 142))	('human', 'Species', '9606', (70, 75))	('lymphoma', 'Phenotype', 'HP:0002665', (26, 34))	('human', 'Species', '9606', (225, 230))	('chronic lymphocytic leukemia', 'Disease', (114, 142))	('canine', 'Species', '9615', (3, 9))	('canine', 'Species', '9615', (107, 113))	('RB transcriptional corepressor 1', 'Gene', (164, 196))
115318	33692868	Furthermore, the study screened for a KIT mutation often found in human MCTs and found that was often present in canine MCTs, and more so in tumors with a malignant phenotype.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('human', 'Species', '9606', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('canine', 'Species', '9615', (113, 119))	('MCTs', 'Phenotype', 'HP:0100495', (120, 124))	('mutation', 'Var', (42, 50))	('MCTs', 'Phenotype', 'HP:0100495', (72, 76))	('KIT', 'molecular_function', 'GO:0005020', ('38', '41'))
115334	33692868	Whilst changes were found throughout the genome, the majority of changes comprised gains of CFA13 and CFA36, and losses of CFA19 of the canine genome.	('losses', 'NegReg', (113, 119))	('canine', 'Species', '9615', (136, 142))	('changes', 'Var', (65, 72))	('CFA19', 'Gene', (123, 128))	('gains', 'PosReg', (83, 88))	('CFA13', 'Gene', (92, 97))	('CFA36', 'Gene', (102, 107))
115348	33692868	Changes in the P53 pathway such as mutations and aberrations were also found to be common to both species.	('P53', 'Gene', (15, 18))	('P53', 'Gene', '403869', (15, 18))	('aberrations', 'Var', (49, 60))	('mutations', 'Var', (35, 44))
115395	25909217	Urothelial carcinomas are genetically complex with various oncogenic drivers, numerous mutations within a single tumor, copy number alterations, gene fusion transcripts, and cytogenetic aberrations (Figure 1).	('Urothelial carcinomas', 'Disease', (0, 21))	('tumor', 'Disease', (113, 118))	('gene fusion transcripts', 'Var', (145, 168))	('Urothelial carcinomas', 'Disease', 'MESH:D014526', (0, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))	('mutations', 'Var', (87, 96))	('copy number alterations', 'Var', (120, 143))
115396	25909217	Muscle invasive urothelial carcinomas have more mutations, chromosomal aberrations, and aneuploidy than the non-invasive tumors, however, there are common genes implicated in the pathogenesis of both types.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (27, 37))	('Muscle invasive urothelial carcinomas', 'Disease', (0, 37))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('aneuploidy', 'Disease', (88, 98))	('chromosomal aberrations', 'Var', (59, 82))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (59, 82))	('invasive tumors', 'Disease', (112, 127))	('pathogenesis', 'biological_process', 'GO:0009405', ('179', '191'))	('Muscle invasive urothelial carcinomas', 'Disease', 'MESH:D009217', (0, 37))	('invasive tumors', 'Disease', 'MESH:D009369', (112, 127))	('aneuploidy', 'Disease', 'MESH:D000782', (88, 98))	('mutations', 'Var', (48, 57))
115399	25909217	The heat shock response prevents cancer cells from undergoing apoptosis, despite an accumulation of genomic mutations, and hostile hypoxic and/or acidotic tumor environments.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('shock', 'Phenotype', 'HP:0031273', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('genomic mutations', 'Var', (100, 117))	('acidotic tumor', 'Disease', (146, 160))	('hostile hypoxic', 'Disease', 'MESH:D000860', (123, 138))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('apoptosis', 'CPA', (62, 71))	('acidotic tumor', 'Disease', 'MESH:D006943', (146, 160))	('hostile hypoxic', 'Disease', (123, 138))	('prevents', 'NegReg', (24, 32))	('accumulation', 'PosReg', (84, 96))	('men', 'Species', '9606', (168, 171))
115401	25909217	Hsp90 plays an important role in urothelial carcinoma biology, as well as in carcinogenesis of other tumors, by its function as a molecular chaperone that cancer cells utilize to protect over-expressed or mutated oncoproteins from misfolding and degradation.	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('carcinogenesis of other tumors', 'Disease', (77, 107))	('oncoproteins', 'Protein', (213, 225))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('carcinogenesis of other tumors', 'Disease', 'MESH:D063646', (77, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mutated', 'Var', (205, 212))	('urothelial carcinoma', 'Disease', (33, 53))	('degradation', 'biological_process', 'GO:0009056', ('246', '257'))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('over-expressed', 'PosReg', (187, 201))	('Hsp90', 'Protein', (0, 5))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (33, 53))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
115403	25909217	Several Hsp90 client proteins act as drivers of urothelial carcinoma, and thus inhibitors or modulators of Hsp90 function may impede urothelial carcinoma pathogenesis (Figures 1 and 3).	('urothelial carcinoma', 'Disease', 'MESH:D014526', (133, 153))	('Hsp90', 'Gene', (107, 112))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (48, 68))	('urothelial carcinoma', 'Disease', (133, 153))	('inhibitors', 'Var', (79, 89))	('Hsp90', 'Protein', (8, 13))	('impede', 'NegReg', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('modulators', 'Var', (93, 103))	('pathogenesis', 'biological_process', 'GO:0009405', ('154', '166'))	('urothelial carcinoma', 'Disease', (48, 68))
115405	25909217	Urothelial carcinomas have somatic mutations of tumor suppressor genes, which include, but are not limited to TP53, RB1, PTEN, TSC1, and p16, and activation of oncogenic drivers (Figure 1).	('oncogenic drivers', 'CPA', (160, 177))	('TP53', 'Var', (110, 114))	('mutations', 'Var', (35, 44))	('activation', 'PosReg', (146, 156))	('p16', 'Gene', (137, 140))	('RB1', 'Gene', (116, 119))	('p16', 'Gene', '1029', (137, 140))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('48', '64'))	('Urothelial carcinomas', 'Disease', (0, 21))	('PTEN', 'Gene', (121, 125))	('tumor', 'Disease', (48, 53))	('Urothelial carcinomas', 'Disease', 'MESH:D014526', (0, 21))	('TSC1', 'Gene', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor suppressor', 'biological_process', 'GO:0051726', ('48', '64'))	('RB1', 'Gene', '5925', (116, 119))	('TSC1', 'Gene', '7248', (127, 131))	('PTEN', 'Gene', '5728', (121, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))
115406	25909217	While mutations in tumor suppressor genes allow for uncontrolled cell proliferation and cell cycle progression, the driver mutation present in many urothelial carcinomas is mutation or gene fusion of the fibroblast growth factor receptor 3 (FGFR3).	('tumor suppressor', 'biological_process', 'GO:0051726', ('19', '35'))	('gene fusion', 'Var', (185, 196))	('tumor', 'Disease', (19, 24))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('204', '228'))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('fibroblast growth factor receptor 3', 'Gene', (204, 239))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('urothelial carcinomas', 'Disease', (148, 169))	('cell proliferation', 'biological_process', 'GO:0008283', ('65', '83'))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (148, 169))	('cell cycle', 'biological_process', 'GO:0007049', ('88', '98'))	('FGFR3', 'Gene', '2261', (241, 246))	('fibroblast growth factor receptor 3', 'Gene', '2261', (204, 239))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('19', '35'))	('FGFR', 'molecular_function', 'GO:0005007', ('241', '245'))	('mutation', 'Var', (173, 181))
115410	25909217	It is upregulated by multiple mechanisms in bladder cancer cells: 1) somatic mutation, 2) over-expression of the wild-type protein, or 3) gene fusion with transforming acid coiled coil (TACC3) or BAI-1 associated protein 2-like 1 (BAI1AP2L1) partners.	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (44, 58))	('AP2', 'cellular_component', 'GO:0005908', ('235', '238'))	('BAI-1 associated protein 2-like 1', 'Gene', '55971', (196, 229))	('BAI1AP2L1', 'Gene', (231, 240))	('BAI1AP2L1', 'Gene', '55971', (231, 240))	('over-expression', 'PosReg', (90, 105))	('TACC3', 'Gene', '10460', (186, 191))	('protein', 'cellular_component', 'GO:0003675', ('213', '220'))	('bladder cancer', 'Disease', 'MESH:D001749', (44, 58))	('bladder cancer', 'Disease', (44, 58))	('upregulated', 'PosReg', (6, 17))	('BAI-1 associated protein 2-like 1', 'Gene', (196, 229))	('gene fusion', 'Var', (138, 149))	('TACC3', 'Gene', (186, 191))
115411	25909217	FGFR3-TACC3 or FGFR3-BAI1AP2L1 gene fusions can serve as the drivers of oncogenesis in bladder cancer cells, especially in non-muscle invasive bladder cancers, as they activate numerous downstream signaling pathways, including PI3K-Akt-mTOR, Ras, MAP kinases, STATs, and phospholipase-Cgamma.	('FGFR3', 'Gene', (15, 20))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('mTOR', 'Gene', '2475', (236, 240))	('FGFR3', 'Gene', '2261', (15, 20))	('bladder cancer', 'Disease', 'MESH:D001749', (87, 101))	('bladder cancer', 'Disease', (87, 101))	('PI3K', 'molecular_function', 'GO:0016303', ('227', '231'))	('MAP', 'molecular_function', 'GO:0004239', ('247', '250'))	('fusions', 'Var', (36, 43))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('signaling', 'biological_process', 'GO:0023052', ('197', '206'))	('bladder cancer', 'Disease', 'MESH:D001749', (143, 157))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('BAI1AP2L1', 'Gene', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('muscle invasive bladder cancers', 'Disease', 'MESH:D001749', (127, 158))	('bladder cancers', 'Phenotype', 'HP:0009725', (143, 158))	('AP2', 'cellular_component', 'GO:0005908', ('25', '28'))	('Ras', 'Pathway', (242, 245))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('bladder cancer', 'Phenotype', 'HP:0009725', (143, 157))	('Akt', 'Gene', (232, 235))	('STATs', 'Gene', (260, 265))	('phospholipase-Cgamma', 'Enzyme', (271, 291))	('MAP kinases', 'Pathway', (247, 258))	('BAI1AP2L1', 'Gene', '55971', (21, 30))	('Akt', 'Gene', '207', (232, 235))	('TACC3', 'Gene', '10460', (6, 11))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (123, 150))	('TACC3', 'Gene', (6, 11))	('invasive bladder', 'Phenotype', 'HP:0100645', (134, 150))	('FGFR3', 'Gene', (0, 5))	('STATs', 'Gene', '6774', (260, 265))	('activate', 'PosReg', (168, 176))	('oncogenesis', 'biological_process', 'GO:0007048', ('72', '83'))	('mTOR', 'Gene', (236, 240))	('muscle invasive bladder cancers', 'Disease', (127, 158))	('FGFR3', 'Gene', '2261', (0, 5))
115412	25909217	Loss of cell cycle control is characteristic of carcinogenesis in urothelial carcinoma, as in many other cancers, due to the inactivation of cell cycle-regulating tumor suppressor genes (including TP53, RB, ATM), mutation of cell cycle progression regulators (CDKN1A, CDKN2A, CCND1, and CCNE1), or activating mutations of genes promoting cell cycle progression (including MDM2 and E2F3).	('E2F3', 'Gene', '398159', (381, 385))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('tumor suppressor', 'biological_process', 'GO:0051726', ('163', '179'))	('carcinogenesis in urothelial carcinoma', 'Disease', 'MESH:D063646', (48, 86))	('tumor', 'Disease', (163, 168))	('CDKN2', 'Gene', (268, 273))	('cell', 'CPA', (338, 342))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TP53', 'Gene', (197, 201))	('RB', 'Gene', '5925', (203, 205))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('carcinogenesis in urothelial carcinoma', 'Disease', (48, 86))	('CCNE1', 'Gene', '397841', (287, 292))	('cell cycle control', 'biological_process', 'GO:1901987', ('8', '26'))	('Loss', 'NegReg', (0, 4))	('activating mutations', 'Var', (298, 318))	('cell cycle', 'CPA', (8, 18))	('cell cycle', 'biological_process', 'GO:0007049', ('141', '151'))	('E2F3', 'Gene', (381, 385))	('cell cycle', 'biological_process', 'GO:0007049', ('225', '235'))	('cell cycle', 'biological_process', 'GO:0007049', ('338', '348'))	('CCND1', 'Gene', (276, 281))	('cell cycle-regulating', 'Gene', (141, 162))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('CDKN2', 'Gene', '1029', (268, 273))	('MDM2', 'Gene', (372, 376))	('CDKN1A', 'Gene', (260, 266))	('CCNE1', 'Gene', (287, 292))	('mutation', 'Var', (213, 221))	('inactivation', 'NegReg', (125, 137))	('CDKN1A', 'Gene', '492305', (260, 266))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('163', '179'))	('CCND1', 'Gene', '379161', (276, 281))
115413	25909217	Inactivation of the cell cycle regulator p53 results in G1 to S cell cycle progression and uncontrolled cell growth in urothelial carcinomas.	('urothelial carcinomas', 'Disease', (119, 140))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('20', '40'))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (119, 140))	('p53', 'Gene', (41, 44))	('G1 to S cell cycle progression', 'CPA', (56, 86))	('cell growth', 'biological_process', 'GO:0016049', ('104', '115'))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('cell cycle', 'biological_process', 'GO:0007049', ('64', '74'))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('20', '40'))	('Inactivation', 'Var', (0, 12))	('uncontrolled cell growth', 'CPA', (91, 115))
115416	25909217	In lymphocytic leukaemia cells, inhibition of Hsp90 was found to have opposing effects on wild-type and mutant p53 proteins, with stabilization and increased expression of the wild-type protein.	('increased', 'PosReg', (148, 157))	('inhibition', 'NegReg', (32, 42))	('expression', 'MPA', (158, 168))	('stabilization', 'MPA', (130, 143))	('mutant', 'Var', (104, 110))	('p53', 'Gene', (111, 114))	('proteins', 'Protein', (115, 123))	('Hsp90', 'Protein', (46, 51))	('protein', 'cellular_component', 'GO:0003675', ('186', '193'))	('lymphocytic leukaemia', 'Disease', (3, 24))	('lymphocytic leukaemia', 'Disease', 'MESH:D007945', (3, 24))
115418	25909217	Inactivation of the retinoblastoma (RB) tumor suppressor gene is present in approximately 50 percent of high grade and muscle-invasive urothelial carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (20, 34))	('muscle-invasive urothelial carcinomas', 'Disease', 'MESH:D009217', (119, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('muscle-invasive urothelial carcinomas', 'Disease', (119, 156))	('retinoblastoma (RB) tumor', 'Disease', 'MESH:D012175', (20, 45))	('Inactivation', 'Var', (0, 12))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))
115421	25909217	In an animal model for urothelial carcinoma, mice deficient in both RB and P53, but not either tumor suppressor gene alone, were the most sensitive to carcinogen exposure.	('deficient', 'Var', (50, 59))	('RB', 'Gene', '5925', (68, 70))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (23, 43))	('mice', 'Species', '10090', (45, 49))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('urothelial carcinoma', 'Disease', (23, 43))	('sensitive', 'Reg', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('P53', 'Gene', (75, 78))	('tumor', 'Disease', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))
115427	25909217	CDK4 and CDK6 (both are Hsp90 clients) phosphorylate RB to stimulate G1 to S phase transition in the cell cycle, therefore, loss of p16 results in uninhibited cell growth.	('cell growth', 'biological_process', 'GO:0016049', ('159', '170'))	('cell cycle', 'biological_process', 'GO:0007049', ('101', '111'))	('loss', 'Var', (124, 128))	('p16', 'Gene', '1029', (132, 135))	('CDK', 'molecular_function', 'GO:0004693', ('0', '3'))	('CDK4', 'Gene', '1019', (0, 4))	('G1 to', 'CPA', (69, 74))	('stimulate', 'PosReg', (59, 68))	('CDK', 'molecular_function', 'GO:0004693', ('9', '12'))	('CDK4', 'Gene', (0, 4))	('RB', 'Gene', '5925', (53, 55))	('S phase', 'biological_process', 'GO:0051320', ('75', '82'))	('p16', 'Gene', (132, 135))	('CDK6', 'Gene', (9, 13))	('CDK6', 'Gene', '1021', (9, 13))
115428	25909217	Loss of p16 secondary to deletion occurs in 54 percent of urothelial carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('p16', 'Gene', '1029', (8, 11))	('urothelial carcinomas', 'Disease', (58, 79))	('Loss', 'NegReg', (0, 4))	('deletion', 'Var', (25, 33))	('p16', 'Gene', (8, 11))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (58, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
115429	25909217	A study of minimally invasive (T1a) urothelial carcinomas identified that loss of p16 was associated with a reduction in progression-free survival, but did not affect recurrence rates.	('urothelial carcinomas', 'Disease', 'MESH:D014526', (36, 57))	('p16', 'Gene', (82, 85))	('progression-free survival', 'CPA', (121, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('loss', 'Var', (74, 78))	('p16', 'Gene', '1029', (82, 85))	('urothelial carcinomas', 'Disease', (36, 57))	('reduction', 'NegReg', (108, 117))
115430	25909217	The loss of p16 was identified as an independent predictor of tumor progression at a given tumor stage and grade.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('p16', 'Gene', '1029', (12, 15))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('p16', 'Gene', (12, 15))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('loss', 'Var', (4, 8))
115432	25909217	Cells have evolved DNA repair mechanisms essential for the removal of damaged DNA caused by several endogenous (hydrolysis, reactive oxygen species, alkylation, DNA mismatches, insertions or deletions, strand breaks) and exogenous (ultraviolet light, ionizing radiation, chemotherapeutic drugs) sources.	('mismatches', 'Var', (165, 175))	('deletions', 'Var', (191, 200))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (124, 147))	('DNA repair', 'biological_process', 'GO:0006281', ('19', '29'))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))	('strand breaks', 'Var', (202, 215))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('insertions', 'Var', (177, 187))	('alkylation', 'MPA', (149, 159))
115434	25909217	Whole-exome sequencing studies identified somatic mutations in genes related to DNA repair pathways including P53, KDM6A, ATM, ERCC2, FANCD2, PALB2, BAP1, BRCA1 and -2).	('ERCC2', 'Gene', (127, 132))	('mutations', 'Var', (50, 59))	('DNA repair', 'biological_process', 'GO:0006281', ('80', '90'))	('BAP1', 'Gene', '8314', (149, 153))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('DNA repair pathways', 'Pathway', (80, 99))	('KDM6A', 'Gene', (115, 120))	('ERCC2', 'Gene', '2068', (127, 132))	('KDM6A', 'Gene', '7403', (115, 120))	('FANCD2', 'Gene', '2177', (134, 140))	('P53', 'Gene', (110, 113))	('BAP1', 'Gene', (149, 153))	('FANCD2', 'Gene', (134, 140))	('PALB2', 'Gene', '79728', (142, 147))	('BRCA1 and -2', 'Gene', '672;675', (155, 167))	('PALB2', 'Gene', (142, 147))
115435	25909217	Interestingly, these mutations seem to be correlated with recurrence-free survival in patients with muscle invasive bladder cancer.	('mutations', 'Var', (21, 30))	('bladder cancer', 'Phenotype', 'HP:0009725', (116, 130))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (100, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('muscle invasive bladder cancer', 'Disease', (100, 130))	('correlated', 'Reg', (42, 52))	('invasive bladder', 'Phenotype', 'HP:0100645', (107, 123))	('patients', 'Species', '9606', (86, 94))
115439	25909217	This usually occurs secondary to PTEN (phosphatase and tensin homolog) deletion, which results in increased activation of Akt by uninhibited PI3K activity.	('PI3K', 'molecular_function', 'GO:0016303', ('141', '145'))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('39', '69'))	('phosphatase', 'molecular_function', 'GO:0016791', ('39', '50'))	('PTEN', 'Gene', (33, 37))	('deletion', 'Var', (71, 79))	('Akt', 'Gene', '207', (122, 125))	('PTEN', 'Gene', '5728', (33, 37))	('Akt', 'Gene', (122, 125))	('activation', 'PosReg', (108, 118))
115446	25909217	Microdeletions at the 10q23 locus is often the source of PTEN LOH.	('PTEN', 'Gene', (57, 61))	('Microdeletions', 'Var', (0, 14))	('PTEN', 'Gene', '5728', (57, 61))
115448	25909217	Hsp90 stabilizes Akt and under Hsp90 inhibition, Akt is rapidly ubiquitinated, greatly shortening its half-life (to one-third) within treated cells.	('inhibition', 'Var', (37, 47))	('Hsp90', 'Protein', (31, 36))	('Akt', 'Gene', '207', (17, 20))	('half-life', 'MPA', (102, 111))	('shortening', 'NegReg', (87, 97))	('Akt', 'Gene', '207', (49, 52))	('Hsp90', 'Protein', (0, 5))	('Akt', 'Gene', (17, 20))	('Akt', 'Gene', (49, 52))
115454	25909217	There are numerous chromatin modifying or remodeling enzymes subject to frequent mutations in urothelial carcinoma, which include BAP1, UTX, MLL, NCOR1, ARID1A, CHD1 and 6, CREBBp, EP300, and the SWI/SNF complex.	('UTX', 'Gene', '7403', (136, 139))	('NCOR1', 'Gene', (146, 151))	('BAP1', 'Gene', (130, 134))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('196', '211'))	('EP300', 'Gene', (181, 186))	('chromatin modifying', 'Enzyme', (19, 38))	('NCOR1', 'Gene', '9611', (146, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('mutations', 'Var', (81, 90))	('ARID1A', 'Gene', (153, 159))	('MLL', 'Disease', (141, 144))	('urothelial carcinoma', 'Disease', (94, 114))	('CHD1 and 6', 'Gene', '1105;84181', (161, 171))	('ARID1A', 'Gene', '8289', (153, 159))	('CREBBp', 'Gene', '1387', (173, 179))	('MLL', 'Disease', 'None', (141, 144))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (94, 114))	('CREBBp', 'Gene', (173, 179))	('BAP1', 'Gene', '8314', (130, 134))	('EP300', 'Gene', '2033', (181, 186))	('chromatin', 'cellular_component', 'GO:0000785', ('19', '28'))	('UTX', 'Gene', (136, 139))
115455	25909217	Mutation causes inactivation of chromatin modifying enzymes in over 60 percent of urothelial carcinomas, with the most common mutations within members of the SWI/SNF complex.	('urothelial carcinomas', 'Disease', (82, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (82, 103))	('inactivation', 'MPA', (16, 28))	('Mutation', 'Var', (0, 8))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('158', '173'))	('chromatin modifying enzymes', 'Enzyme', (32, 59))	('chromatin', 'cellular_component', 'GO:0000785', ('32', '41'))
115483	25909217	Erlotinib primarily targets the epidermal growth factor receptor (EGFR), and was shown to have optimal use in the neoadjuvant setting, resulting in downstaging of the tumor prior to surgery.	('epidermal growth factor receptor', 'Gene', '1956', (32, 64))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('32', '55'))	('Erlotinib', 'Var', (0, 9))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))	('downstaging', 'NegReg', (148, 159))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('epidermal growth factor receptor', 'Gene', (32, 64))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
115506	25909217	Inhibitors of the mTOR have demonstrated anti-tumor activity alone and in combination with chemotherapy, as mTOR inhibition enhances chemosensitivity of urothelial carcinoma cells.	('mTOR', 'Gene', (18, 22))	('mTOR', 'Gene', (108, 112))	('mTOR', 'Gene', '2475', (18, 22))	('mTOR', 'Gene', '2475', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('urothelial carcinoma', 'Disease', (153, 173))	('tumor', 'Disease', (46, 51))	('Inhibitors', 'Var', (0, 10))	('inhibition', 'NegReg', (113, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('enhances', 'PosReg', (124, 132))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (153, 173))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
115533	25909217	More recently, bladder cancer cell lines with FGFR3 somatic mutation, FGFR3-TACC3 and FGFR3-BAI1AP2L1 gene fusions were all found to be sensitive to Hsp90 inhibition.	('FGFR3', 'Gene', '2261', (46, 51))	('TACC3', 'Gene', '10460', (76, 81))	('FGFR3', 'Gene', (70, 75))	('TACC3', 'Gene', (76, 81))	('FGFR3', 'Gene', (86, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('86', '90'))	('FGFR', 'molecular_function', 'GO:0005007', ('70', '74'))	('FGFR3', 'Gene', '2261', (70, 75))	('BAI1AP2L1', 'Gene', (92, 101))	('bladder cancer', 'Disease', (15, 29))	('Hsp90', 'Protein', (149, 154))	('bladder cancer', 'Disease', 'MESH:D001749', (15, 29))	('FGFR3', 'Gene', '2261', (86, 91))	('bladder cancer', 'Phenotype', 'HP:0009725', (15, 29))	('AP2', 'cellular_component', 'GO:0005908', ('96', '99'))	('fusions', 'Var', (107, 114))	('sensitive', 'Reg', (136, 145))	('BAI1AP2L1', 'Gene', '55971', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('FGFR3', 'Gene', (46, 51))
115534	25909217	Urothelial carcinoma cells with FGFR3 mutations that are insensitive to pan-FGFR inhibitors (those containing the FGFR3S249C or FGFR3Y375C mutations) were found to be sensitive to Hsp90 inhibitors.	('FGFR3', 'Gene', (32, 37))	('Hsp90', 'Protein', (180, 185))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('Urothelial carcinoma', 'Disease', 'MESH:D014526', (0, 20))	('FGFR3', 'Gene', '2261', (114, 119))	('FGFR3', 'Gene', (114, 119))	('Urothelial carcinoma', 'Disease', (0, 20))	('FGFR', 'molecular_function', 'GO:0005007', ('114', '118'))	('FGFR', 'molecular_function', 'GO:0005007', ('128', '132'))	('FGFR3', 'Gene', '2261', (128, 133))	('FGFR3', 'Gene', '2261', (32, 37))	('mutations', 'Var', (38, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('FGFR3', 'Gene', (128, 133))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))
115535	25909217	While both ganetespib and an FGFR inhibitor promoted regression of bladder cancer xenografts harboring the FGFR3-TACC3 fusion, combination of the two agents led to a further, significant reduction in tumor volume.	('FGFR', 'molecular_function', 'GO:0005007', ('29', '33'))	('ganetespib', 'Chemical', 'MESH:C533237', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('regression', 'CPA', (53, 63))	('reduction', 'NegReg', (187, 196))	('tumor', 'Disease', (200, 205))	('FGFR3', 'Gene', (107, 112))	('TACC3', 'Gene', '10460', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('promoted', 'PosReg', (44, 52))	('TACC3', 'Gene', (113, 118))	('FGFR3', 'Gene', '2261', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('fusion', 'Var', (119, 125))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('combination', 'Interaction', (127, 138))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))
115541	25909217	Hsp90 inhibitors provide synergism with cisplatin, and likewise, cisplatin improves clinical responses to Hsp90 inhibitors by preventing the compensatory heat shock response due to Hsp90 inhibition.	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('shock', 'Phenotype', 'HP:0031273', (159, 164))	('Hsp90', 'Protein', (181, 186))	('improves', 'PosReg', (75, 83))	('synergism', 'MPA', (25, 34))	('preventing', 'NegReg', (126, 136))	('cisplatin', 'Var', (65, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('Hsp90', 'Protein', (0, 5))	('Hsp90', 'Protein', (106, 111))	('compensatory heat shock response', 'MPA', (141, 173))	('clinical responses', 'MPA', (84, 102))
115548	25909217	In acting synergistically with chemotherapy, Hsp90 inhibitors may provide an alternative to adjunctive radiotherapy and may reduce morbidities, as a standard radiation dose (54 - 64 Gray) promotes radiation cystitis.	('cystitis', 'Disease', 'MESH:D003556', (207, 215))	('Hsp90', 'Protein', (45, 50))	('morbidities', 'MPA', (131, 142))	('promotes', 'PosReg', (188, 196))	('cystitis', 'Disease', (207, 215))	('inhibitors', 'Var', (51, 61))	('reduce', 'NegReg', (124, 130))
115549	25909217	Therefore, Hsp90 inhibitors can sensitize tumor cells to chemotherapy or radiotherapy.	('tumor', 'Disease', (42, 47))	('sensitize', 'Reg', (32, 41))	('inhibitors', 'Var', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('Hsp90', 'Protein', (11, 16))
115554	25909217	One mechanism of chemoradiosensitization by Hsp90 inhibitors is through reducing expression of the oncoproteins ErbB2 and NF-kB as they participate in resistance to chemoradiotherapy and are Hsp90 clients.	('ErbB2', 'Gene', (112, 117))	('inhibitors', 'Var', (50, 60))	('ErbB2', 'Gene', '2064', (112, 117))	('reducing', 'NegReg', (72, 80))	('Hsp90', 'Protein', (44, 49))	('NF-kB', 'Gene', (122, 127))	('expression', 'MPA', (81, 91))
115561	25909217	Inhibition of mTOR inhibits upregulation of heat shock factor (HSF) in response to Hsp90 inhibition, and would also serve as a means to reduce resistance.	('mTOR', 'Gene', '2475', (14, 18))	('HSF', 'Gene', (63, 66))	('shock', 'Phenotype', 'HP:0031273', (49, 54))	('heat shock factor', 'Gene', '3569', (44, 61))	('reduce', 'NegReg', (136, 142))	('HSF', 'Gene', '3569', (63, 66))	('Inhibition', 'Var', (0, 10))	('mTOR', 'Gene', (14, 18))	('resistance', 'MPA', (143, 153))	('inhibits', 'NegReg', (19, 27))	('heat shock factor', 'Gene', (44, 61))	('Hsp90', 'Protein', (83, 88))	('upregulation', 'PosReg', (28, 40))
115570	25909217	The inhibitors of the molecular chaperone Hsp90 have shown promise in clinical trials for other epithelial malignancies.	('epithelial malignancies', 'Phenotype', 'HP:0031492', (96, 119))	('epithelial malignancies', 'Disease', (96, 119))	('epithelial malignancies', 'Disease', 'MESH:D002277', (96, 119))	('inhibitors', 'Var', (4, 14))	('Hsp90', 'Protein', (42, 47))
115575	32429323	The cut-off PMI value for sarcopenia was defined as <=6.36 cm2/m2 for men and <=3.92 cm2/m2 for women.	('men', 'Species', '9606', (70, 73))	('sarcopenia', 'Disease', 'MESH:D055948', (26, 36))	('<=6.36', 'Var', (52, 58))	('sarcopenia', 'Disease', (26, 36))	('women', 'Species', '9606', (96, 101))	('<=3.92', 'Var', (78, 84))	('men', 'Species', '9606', (98, 101))
115641	32429323	Patients with high NLR values and sarcopenia had significantly poorer PFS and OS than those with low NLR values and without sarcopenia (Figure 3C-F).	('sarcopenia', 'Disease', 'MESH:D055948', (124, 134))	('sarcopenia', 'Disease', (124, 134))	('poorer', 'NegReg', (63, 69))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('sarcopenia', 'Disease', 'MESH:D055948', (34, 44))	('sarcopenia', 'Disease', (34, 44))
115669	32429323	PFS was significantly shorter in patients with an NLR >= 4.0 than in those with an NLR < 4.0 (p = 0.020) (Figure 3C).	('PFS', 'MPA', (0, 3))	('NLR', 'Var', (50, 53))	('shorter', 'NegReg', (22, 29))	('patients', 'Species', '9606', (33, 41))
115670	32429323	Furthermore, OS was significantly shorter in patients with an NLR >= 4.0 than in those with an NLR < 4.0 (p = 0.024) (Figure 3D).	('NLR', 'Var', (62, 65))	('shorter', 'NegReg', (34, 41))	('patients', 'Species', '9606', (45, 53))
115693	32429323	The results of our cross-sectional study revealed that OS was significantly shorter in patients with a PNI < 45 than in those with a PNI >= 45 (p = 0.046) (Table 3), and our longitudinal study revealed that an increased CONUT score value was a poor prognostic marker for OS (p = 0.024) (Table 4).	('shorter', 'NegReg', (76, 83))	('PNI < 45', 'Var', (103, 111))	('patients', 'Species', '9606', (87, 95))	('CONUT', 'MPA', (220, 225))
115705	29100438	Overall analysis indicated a significantly reduced risk of urothelial cancer for high intake of carrot (OR = 0.63, 95% CI 0.44-0.90).	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('urothelial cancer', 'Disease', (59, 76))	('high intake', 'Var', (81, 92))	('carrot', 'Species', '4039', (96, 102))	('urothelial cancer', 'Disease', 'MESH:D014523', (59, 76))	('reduced', 'NegReg', (43, 50))
115721	29100438	There was a significantly reduced risk of urothelial cancer for high consumption of carrot (OR = 0.63, 95% CI 0.44-0.90).	('carrot', 'Species', '4039', (84, 90))	('urothelial cancer', 'Disease', (42, 59))	('high consumption', 'Var', (64, 80))	('reduced', 'NegReg', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('urothelial cancer', 'Disease', 'MESH:D014523', (42, 59))
115725	29100438	The combined risk estimates of this meta-analysis provided limited evidence for a protective association of high carrot intake with urothelial cancer risk.	('urothelial cancer', 'Disease', 'MESH:D014523', (132, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('carrot', 'Species', '4039', (113, 119))	('high', 'Var', (108, 112))	('urothelial cancer', 'Disease', (132, 149))
115749	32332851	Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors.	('HER2', 'Gene', '2064', (14, 18))	('HER2', 'Gene', '2064', (87, 91))	('HER2', 'Gene', '2064', (138, 142))	('S310F-mutant', 'Var', (19, 31))	('S310F', 'Mutation', 'rs1057519816', (19, 24))	('antibody', 'molecular_function', 'GO:0003823', ('53', '61'))	('antibody', 'cellular_component', 'GO:0042571', ('53', '61'))	('antibody', 'cellular_component', 'GO:0019815', ('53', '61'))	('HER2', 'Gene', (14, 18))	('HER2', 'Gene', (87, 91))	('HER2', 'Gene', (138, 142))	('antibody', 'cellular_component', 'GO:0019814', ('53', '61'))
115755	32332851	Unlike UCB, UTUC is a Lynch Syndrome-associated malignancy, with the most recent study demonstrating 8.7% of UTUC patients having a pathogenic germline mutation in a Lynch Syndrome-associated gene.	('pathogenic', 'Reg', (132, 142))	('malignancy', 'Disease', (48, 58))	('germline mutation', 'Var', (143, 160))	('patients', 'Species', '9606', (114, 122))	('Lynch Syndrome-associated gene', 'Gene', (166, 196))	('malignancy', 'Disease', 'MESH:D009369', (48, 58))
115757	32332851	Recent genomic analyses of UTUC have identified a high incidence of potentially actionable genomic alterations including recurrent activating mutations in receptor tyrosine kinases (FGFR3, ERBB2), HRAS, PIK3CA and TSC1.	('TSC1', 'Gene', '7248', (214, 218))	('mutations', 'Var', (142, 151))	('PIK3CA', 'Gene', (203, 209))	('TSC1', 'Gene', (214, 218))	('FGFR3', 'Gene', '2261', (182, 187))	('ERBB2', 'Gene', '2064', (189, 194))	('activating', 'PosReg', (131, 141))	('ERBB2', 'Gene', (189, 194))	('HRAS', 'Gene', '3265', (197, 201))	('FGFR3', 'Gene', (182, 187))	('PIK3CA', 'Gene', '5290', (203, 209))	('FGFR', 'molecular_function', 'GO:0005007', ('182', '186'))	('HRAS', 'Gene', (197, 201))
115764	32332851	Although HER2 alterations are common in patients with urothelial cancer, HER2-targeted therapies have had only modest clinical impact in this disease.	('alterations', 'Var', (14, 25))	('HER2', 'Gene', '2064', (73, 77))	('urothelial cancer', 'Disease', 'MESH:D014523', (54, 71))	('HER2', 'Gene', (9, 13))	('patients', 'Species', '9606', (40, 48))	('HER2', 'Gene', '2064', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('HER2', 'Gene', (73, 77))	('urothelial cancer', 'Disease', (54, 71))
115767	32332851	MSK-IMPACT is a targeted capture-based next-generation sequencing (NGS) assay that can detect mutations, copy number alterations and select gene fusions in up to 468 cancer-associated genes.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('mutations', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('copy number alterations', 'Var', (105, 128))
115770	32332851	Consistent with prior studies in UTUC, we observed frequent mutations in potentially actionable genes including FGFR3 (47%), ERBB2 (9%), HRAS (12%), PIK3CA (16%) and TSC1 (14%).	('FGFR3', 'Gene', (112, 117))	('TSC1', 'Gene', (166, 170))	('TSC1', 'Gene', '7248', (166, 170))	('FGFR', 'molecular_function', 'GO:0005007', ('112', '116'))	('PIK3CA', 'Gene', (149, 155))	('ERBB2', 'Gene', '2064', (125, 130))	('HRAS', 'Gene', '3265', (137, 141))	('ERBB2', 'Gene', (125, 130))	('mutations', 'Var', (60, 69))	('FGFR3', 'Gene', '2261', (112, 117))	('PIK3CA', 'Gene', '5290', (149, 155))	('HRAS', 'Gene', (137, 141))
115782	32332851	Somatic FGFR3 mutations, which have previously been associated with a favorable prognostic outcome in UTUC, were only present in luminal subtype.	('luminal', 'Chemical', 'MESH:D010634', (129, 136))	('FGFR3', 'Gene', '2261', (8, 13))	('FGFR', 'molecular_function', 'GO:0005007', ('8', '12'))	('UTUC', 'Disease', (102, 106))	('mutations', 'Var', (14, 23))	('FGFR3', 'Gene', (8, 13))
115783	32332851	Conversely, there were no significant differences among the two subtypes in the percentage of patients with mutations in TP53 or other driver genes commonly present in UTUC.	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('patients', 'Species', '9606', (94, 102))	('mutations', 'Var', (108, 117))
115802	32332851	In 29% of the PDX, we observed PDX-specific deep deletions in CDKN2A/CDKN2B, consistent with selection for loss of these tumor suppressor genes during the process of PDX engraftment.	('CDKN2B', 'Gene', (69, 75))	('CDKN2B', 'Gene', '1030', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('121', '137'))	('tumor', 'Disease', (121, 126))	('tumor suppressor', 'biological_process', 'GO:0051726', ('121', '137'))	('CDKN2A', 'Gene', (62, 68))	('deep deletions', 'Var', (44, 58))	('CDKN2A', 'Gene', '1029', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
115807	32332851	Finally, the FGFR3 R248C hotspot mutation, which has previously been shown to be enriched in Lynch Syndrome-associated UTUC as compared to sporadic UTUC tumors, was present in 3 of the 4 MSI-H tumor/patient-matched PDX pairs (UCC17, UCC36 and UCC34).	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('MSI-H tumor', 'Disease', (187, 198))	('patient', 'Species', '9606', (199, 206))	('R248C', 'Var', (19, 24))	('FGFR3', 'Gene', (13, 18))	('Lynch Syndrome-associated UTUC', 'Disease', (93, 123))	('MSI-H tumor', 'Disease', 'MESH:D009369', (187, 198))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('R248C', 'Mutation', 'rs121913482', (19, 24))	('FGFR3', 'Gene', '2261', (13, 18))
115809	32332851	Phylogenetic analysis of the WES data provided evidence of both linear and branched evolution in the tumors and PDX/patient-derived cell lines, as demonstrated by the presence of both private and shared mutations among samples derived from the same patient (Fig.	('patient', 'Species', '9606', (249, 256))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('patient', 'Species', '9606', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (203, 212))	('tumors', 'Disease', (101, 107))	('presence', 'Reg', (167, 175))
115814	32332851	Among the top 15 most frequently altered genes in our PDX cohort, STAG2 and ERBB2 mutations were positively and negatively associated with successful engraftment respectively, although the differences were not statistically significant, possibly due to the small sample size (Fig.	('associated', 'Reg', (123, 133))	('STAG2', 'Gene', (66, 71))	('STAG2', 'Gene', '10735', (66, 71))	('successful engraftment', 'CPA', (139, 161))	('mutations', 'Var', (82, 91))	('negatively', 'NegReg', (112, 122))	('ERBB2', 'Gene', (76, 81))	('ERBB2', 'Gene', '2064', (76, 81))
115830	32332851	As DNA damage response (DDR) gene alterations have been associated with sensitivity to platinum-based chemotherapy and improved survival in patients with advanced UC patients, we assessed whether there was evidence of a likely pathogenic DDR gene alteration.	('survival', 'MPA', (128, 136))	('platinum', 'Chemical', 'MESH:D010984', (87, 95))	('DNA', 'cellular_component', 'GO:0005574', ('3', '6'))	('associated', 'Reg', (56, 66))	('DDR', 'Gene', (24, 27))	('DNA damage response', 'biological_process', 'GO:0006974', ('3', '22'))	('patients', 'Species', '9606', (140, 148))	('improved', 'PosReg', (119, 127))	('alterations', 'Var', (34, 45))	('patients', 'Species', '9606', (166, 174))
115831	32332851	Indeed, both the primary tumor and corresponding PDX harbored a truncating mutation in RECQL4 (F987*), a gene which has a role in DNA repair by homologous recombination.	('F987*', 'Var', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('F987*', 'SUBSTITUTION', 'None', (95, 100))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('homologous recombination', 'biological_process', 'GO:0035825', ('144', '168'))	('tumor', 'Disease', (25, 30))	('truncating', 'Var', (64, 74))	('RECQL4', 'Gene', (87, 93))	('DNA repair', 'biological_process', 'GO:0006281', ('130', '140'))	('RECQL4', 'Gene', '9401', (87, 93))	('harbored', 'Reg', (53, 61))
115839	32332851	Consistent with retrospective studies, prospective genomic profiling of 44,183 tumors including 1032 bladder and 204 UTUC at our institution using MSK-IMPACT revealed that mutations in ERBB2 (oncogenic/likely oncogenic) were more common in urothelial cancer (UC) than in other common solid tumors (10.3% in bladder and 5.9 % in UTUC as compared to 3.2% in breast, 2.9% in endometrial, 2.6% in colorectal, and 2.4% in NSCLC) (Fig.	('mutations', 'Var', (172, 181))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumors', 'Disease', (290, 296))	('tumors', 'Disease', 'MESH:D009369', (290, 296))	('bladder', 'Disease', (307, 314))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('ERBB2', 'Gene', '2064', (185, 190))	('ERBB2', 'Gene', (185, 190))	('urothelial cancer', 'Disease', (240, 257))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('NSCLC', 'Disease', (417, 422))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('urothelial cancer', 'Disease', 'MESH:D014523', (240, 257))	('NSCLC', 'Disease', 'MESH:D002289', (417, 422))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('common', 'Reg', (230, 236))
115840	32332851	ERBB2 amplification was also common in bladder cancer and UTUC (6.2%: 64 of 1032 bladder tumors and 4.4% of UTUC: 9 of 204 tumors, Fig.	('tumors', 'Disease', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('common', 'Reg', (29, 35))	('ERBB2', 'Gene', (0, 5))	('bladder tumors', 'Phenotype', 'HP:0009725', (81, 95))	('bladder cancer', 'Disease', 'MESH:D001749', (39, 53))	('ERBB2', 'Gene', '2064', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('bladder cancer', 'Disease', (39, 53))	('bladder cancer', 'Phenotype', 'HP:0009725', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('bladder tumors', 'Disease', 'MESH:D001749', (81, 95))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('UTUC', 'Disease', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', (123, 129))	('bladder tumors', 'Disease', (81, 95))	('amplification', 'Var', (6, 19))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
115846	32332851	Both UCC14-PDC (IC50 508.3 nM) and MGHU3 (an ERBB2 wildtype bladder cancer line, IC50 245.9 nM) were significantly less sensitive to neratinib as compared to CVX-4 (a HER2 S310F-mutant cervical cancer line, IC50 56.8 nM) and BT-474 (an ERBB2 amplified breast cancer cell line, IC50 0.1 nM)(Fig.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('less', 'NegReg', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('sensitive', 'MPA', (120, 129))	('HER2', 'Gene', '2064', (167, 171))	('S310F-mutant', 'Var', (172, 184))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('cancer', 'Disease', (259, 265))	('breast cancer', 'Disease', (252, 265))	('ERBB2', 'Gene', (236, 241))	('HER2', 'Gene', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('ERBB2', 'Gene', (45, 50))	('S310F', 'Mutation', 'rs1057519816', (172, 177))	('cancer', 'Disease', (194, 200))	('ERBB2', 'Gene', '2064', (236, 241))	('neratinib', 'Chemical', 'MESH:C487932', (133, 142))	('bladder cancer', 'Disease', 'MESH:D001749', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('bladder cancer', 'Disease', (60, 74))	('cancer', 'Disease', (68, 74))	('ERBB2', 'Gene', '2064', (45, 50))
115849	32332851	Finally, the limited sensitivity of the HER2 S310F-mutant UCC14-PDC to HER kinase inhibition in culture was consistent with the relative insensitivity of the UCC14-PDX to neratinib therapy in vivo (Fig.	('HER2', 'Gene', (40, 44))	('HER2', 'Gene', '2064', (40, 44))	('neratinib', 'Chemical', 'MESH:C487932', (171, 180))	('S310F-mutant', 'Var', (45, 57))	('S310F', 'Mutation', 'rs1057519816', (45, 50))
115864	32332851	Our prospective clinical sequencing experience of over 44,000 patient tumors indicates that activating ERBB2 mutations are more prevalent in both bladder and UTUC than in other common solid tumor types (Fig.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('bladder', 'Disease', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (70, 75))	('patient', 'Species', '9606', (62, 69))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Disease', (190, 195))	('ERBB2', 'Gene', (103, 108))	('ERBB2', 'Gene', '2064', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mutations', 'Var', (109, 118))	('UTUC', 'Disease', (158, 162))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('activating', 'PosReg', (92, 102))
115865	32332851	However, the lack of ERBB2 mutant models of UTUC has been a major impediment to the preclinical assessment of HER2-targeted therapies for UTUC patients.	('mutant', 'Var', (27, 33))	('patients', 'Species', '9606', (143, 151))	('ERBB2', 'Gene', '2064', (21, 26))	('ERBB2', 'Gene', (21, 26))	('HER2', 'Gene', (110, 114))	('HER2', 'Gene', '2064', (110, 114))
115866	32332851	As the UCC14-PDX and patient tumor from which it was derived harbored an activating hotspot mutation in the extracellular domain of HER2 (S310F), we leveraged this model to explore the biological basis for the limited clinical activity of HER kinase inhibitors observed to date in HER2-mutant UC patients.	('HER2', 'Gene', '2064', (132, 136))	('HER2', 'Gene', '2064', (281, 285))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('patient', 'Species', '9606', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('patient', 'Species', '9606', (296, 303))	('S310F', 'Var', (138, 143))	('activating hotspot', 'PosReg', (73, 91))	('tumor', 'Disease', (29, 34))	('HER2', 'Gene', (281, 285))	('extracellular', 'cellular_component', 'GO:0005576', ('108', '121'))	('S310F', 'Mutation', 'rs1057519816', (138, 143))	('patients', 'Species', '9606', (296, 304))	('HER2', 'Gene', (132, 136))
115867	32332851	Consistent with the poor response of HER2-mutant UC patients to the HER kinase inhibitor neratinib as compared to HER2-mutant breast and cervical cancer patients, the HER2 S310F-mutant cell line UCC14-PDC was significantly less sensitive to neratinib than the HER2-amplified BT-474 breast cancer and HER2 S310F-mutant CVX-4 cervical cancer cell lines.	('cancer', 'Disease', (146, 152))	('HER2', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('CVX-4 cervical cancer', 'Disease', 'MESH:D002583', (318, 339))	('HER2', 'Gene', '2064', (114, 118))	('HER2', 'Gene', (260, 264))	('HER2', 'Gene', '2064', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('S310F-mutant', 'Var', (172, 184))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('72', '88'))	('cancer', 'Disease', (333, 339))	('breast cancer', 'Phenotype', 'HP:0003002', (282, 295))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('less', 'NegReg', (223, 227))	('neratinib', 'Chemical', 'MESH:C487932', (241, 250))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('patients', 'Species', '9606', (52, 60))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('HER2', 'Gene', '2064', (300, 304))	('HER2', 'Gene', (114, 118))	('HER2', 'Gene', (167, 171))	('HER2', 'Gene', '2064', (37, 41))	('neratinib', 'Chemical', 'MESH:C487932', (89, 98))	('breast cancer', 'Disease', 'MESH:D001943', (282, 295))	('breast cancer', 'Disease', (282, 295))	('HER2', 'Gene', '2064', (260, 264))	('CVX-4 cervical cancer', 'Disease', (318, 339))	('S310F', 'Mutation', 'rs1057519816', (172, 177))	('patients', 'Species', '9606', (153, 161))	('cancer', 'Disease', 'MESH:D009369', (333, 339))	('S310F', 'Mutation', 'rs1057519816', (305, 310))	('sensitive to', 'MPA', (228, 240))	('cancer', 'Disease', (289, 295))	('HER2', 'Gene', (300, 304))
115871	32332851	One hypothesis as to why HER2-mutant tumors with low HER2 expression are sensitive to T-DM1 is that mutation of HER2 may increase the efficiency of receptor internalization following antibody binding.	('antibody', 'cellular_component', 'GO:0019815', ('183', '191'))	('HER2', 'Gene', (53, 57))	('HER2', 'Gene', '2064', (112, 116))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('receptor internalization following', 'MPA', (148, 182))	('receptor internalization', 'biological_process', 'GO:0031623', ('148', '172'))	('antibody', 'cellular_component', 'GO:0019814', ('183', '191'))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('HER2', 'Gene', (25, 29))	('tumors', 'Disease', (37, 43))	('T-DM1', 'Chemical', 'MESH:C550911', (86, 91))	('antibody', 'molecular_function', 'GO:0003823', ('183', '191'))	('HER2', 'Gene', (112, 116))	('HER2', 'Gene', '2064', (53, 57))	('binding', 'molecular_function', 'GO:0005488', ('192', '199'))	('antibody', 'cellular_component', 'GO:0042571', ('183', '191'))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('increase', 'PosReg', (121, 129))	('mutation', 'Var', (100, 108))	('HER2', 'Gene', '2064', (25, 29))
115913	32332851	Once tumors reached an average volume of 100 mm3, mice were randomized to receive either vehicle control (0.5% methylcellulose/0.2% Tween 80 for neratinib, PBS for DS-8201a), neratinib, or DS-8201a (Daiichi-Sankyo).	('PBS', 'Chemical', 'MESH:D007854', (156, 159))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('Tween 80', 'Chemical', 'MESH:D011136', (132, 140))	('DS-8201a', 'Var', (164, 172))	('DS-8201a', 'Var', (189, 197))	('neratinib', 'Chemical', 'MESH:C487932', (175, 184))	('methylcellulose', 'Chemical', 'MESH:D008747', (111, 126))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mice', 'Species', '10090', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('neratinib', 'Chemical', 'MESH:C487932', (145, 154))
115917	32332851	ERK (#9102), p-ERK (T202/Y204) (#9101), AKT (#9272) and p-AKT (Ser473) (#9271) antibodies were from Cell Signaling Technology.	('ERK', 'molecular_function', 'GO:0004707', ('15', '18'))	('#9271', 'Var', (72, 77))	('Signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('ERK', 'Gene', '2048', (15, 18))	('AKT', 'Gene', '207', (40, 43))	('Ser', 'cellular_component', 'GO:0005790', ('63', '66'))	('ERK', 'Gene', (15, 18))	('ERK', 'Gene', '2048', (0, 3))	('AKT', 'Gene', '207', (58, 61))	('AKT', 'Gene', (40, 43))	('ERK', 'Gene', (0, 3))	('Ser473', 'Chemical', '-', (63, 69))	('#9101', 'Var', (32, 37))	('ERK', 'molecular_function', 'GO:0004707', ('0', '3'))	('#9272', 'Var', (45, 50))	('AKT', 'Gene', (58, 61))
115928	31238579	Prognostic Impact of Canonical TGF-beta Signaling in Urothelial Bladder Cancer Background and objectives: Dysregulation of TGF-beta signaling plays multiple roles in cancer development and progression.	('TGF-beta', 'Gene', (31, 39))	('Dysregulation', 'Var', (106, 119))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('Signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (64, 78))	('men', 'Species', '9606', (180, 183))	('TGF-beta', 'Gene', '7040', (123, 131))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('TGF-beta', 'Gene', '7040', (31, 39))	('Cancer', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('TGF-beta', 'Gene', (123, 131))	('Cancer', 'Disease', 'MESH:D009369', (72, 78))
115935	31238579	Smad2 showed an inverse correlation with variant morphology and divergent differentiation of urothelial tumors (p = 0.014).	('urothelial tumors', 'Disease', (93, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Smad2', 'Gene', '4087', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('urothelial tumors', 'Disease', 'MESH:D001749', (93, 110))	('Smad2', 'Gene', (0, 5))	('variant', 'Var', (41, 48))	('inverse', 'NegReg', (16, 23))
115936	31238579	High TGF-beta1 correlated directly, while Smad2 and Smad4 correlated inversely to cancer-specific death (p = 0.043, p = 0.003, and p = 0.022, respectively).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Smad4', 'Gene', (52, 57))	('High', 'Var', (0, 4))	('Smad4', 'Gene', '4089', (52, 57))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('TGF-beta1', 'Gene', (5, 14))	('Smad2', 'Gene', '4087', (42, 47))	('inversely', 'NegReg', (69, 78))	('Smad2', 'Gene', (42, 47))
115938	31238579	Survival analyses showed that high Smad2 and Smad4 expression was associated with longer overall survival (p = 0.003, p = 0.034, respectively), while in multivariate regression analysis TGF-beta1 manifested as an independent predictor of poor outcome.	('Smad2', 'Gene', (35, 40))	('longer', 'PosReg', (82, 88))	('Smad4', 'Gene', (45, 50))	('Smad4', 'Gene', '4089', (45, 50))	('high', 'Var', (30, 34))	('expression', 'MPA', (51, 61))	('overall survival', 'MPA', (89, 105))	('Smad2', 'Gene', '4087', (35, 40))
115947	31238579	Dysregulation of TGF-beta signaling pathway plays multiple roles in cancer development and progression.	('TGF-beta', 'Gene', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('signaling pathway', 'biological_process', 'GO:0007165', ('26', '43'))	('TGF-beta', 'Gene', '7040', (17, 25))	('cancer', 'Disease', (68, 74))	('men', 'Species', '9606', (82, 85))
115956	31238579	Genetic variations of several components of the TGF-beta canonical pathway have been significantly linked to bladder cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('TGF-beta', 'Gene', (48, 56))	('bladder cancer', 'Disease', 'MESH:D001749', (109, 123))	('bladder cancer', 'Disease', (109, 123))	('Genetic variations', 'Var', (0, 18))	('linked', 'Reg', (99, 105))	('TGF-beta', 'Gene', '7040', (48, 56))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))
115957	31238579	Mutations of SMAD2 are infrequent in cancer, they are found in a small fraction of colorectal carcinoma, while, on the other hand, SMAD4/DPC4 is considered an important tumor-suppressor gene.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('tumor-suppressor', 'Gene', (169, 185))	('SMAD2', 'Gene', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('cancer', 'Disease', (37, 43))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (83, 103))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('DPC4', 'Gene', '4089', (137, 141))	('found', 'Reg', (54, 59))	('Mutations', 'Var', (0, 9))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('169', '185'))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('169', '185'))	('tumor-suppressor', 'Gene', '7248', (169, 185))	('colorectal carcinoma', 'Disease', (83, 103))	('DPC4', 'Gene', (137, 141))
115958	31238579	The loss of heterozygosity of chromosomal locus 18q21:which contains SMAD2 and SMAD4 genes:is a common event in pancreatic and colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('pancreatic', 'Disease', 'MESH:D010195', (112, 122))	('SMAD2', 'Gene', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colorectal cancer', 'Disease', (127, 144))	('pancreatic', 'Disease', (112, 122))	('SMAD4', 'Gene', (79, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('loss', 'Var', (4, 8))
115959	31238579	The alterations in Smad2 and Smad4 expression have been recently described in UBC, but their association with clinicopathologic features and their clinical significance have not been elucidated so far.	('Smad2', 'Gene', '4087', (19, 24))	('alterations', 'Var', (4, 15))	('Smad2', 'Gene', (19, 24))	('UBC', 'Disease', (78, 81))	('Smad4', 'Gene', (29, 34))	('Smad4', 'Gene', '4089', (29, 34))	('UBC', 'Chemical', '-', (78, 81))
115970	31238579	Immunohistochemical analysis was performed using the primary antibodies to TGF-beta1 (clone TGFB17, Leica Biosystems Newcastle, 1:40 dilution), Smad2 (ab63576, Abcam, 1:100 dilution), and Smad4 (ab236321, Abcam, 1:100 dilution).	('Smad2', 'Gene', '4087', (144, 149))	('Smad2', 'Gene', (144, 149))	('ab63576', 'Var', (151, 158))	('Smad4', 'Gene', (188, 193))	('Smad4', 'Gene', '4089', (188, 193))	('TGF-beta1', 'Gene', (75, 84))
115981	31238579	The majority of urothelial tumors with high TGF-beta1 expression were classified as high-grade neoplasms (70.5%).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('high', 'Var', (39, 43))	('urothelial tumors', 'Disease', (16, 33))	('neoplasms', 'Phenotype', 'HP:0002664', (95, 104))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('neoplasm', 'Phenotype', 'HP:0002664', (95, 103))	('neoplasms', 'Disease', 'MESH:D009369', (95, 104))	('neoplasms', 'Disease', (95, 104))	('urothelial tumors', 'Disease', 'MESH:D001749', (16, 33))	('TGF-beta1', 'Gene', (44, 53))
115985	31238579	High Smad2 and Smad4 nuclear expression with or without cytoplasmic staining in urothelial cancer (Figure 1) was associated with low tumor grade (p = 0.003, p = 0.048, respectively).	('Smad2', 'Gene', '4087', (5, 10))	('urothelial cancer', 'Disease', 'MESH:D014523', (80, 97))	('High', 'Var', (0, 4))	('Smad2', 'Gene', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('low tumor', 'Disease', 'MESH:D009800', (129, 138))	('Smad4', 'Gene', (15, 20))	('Smad4', 'Gene', '4089', (15, 20))	('low tumor', 'Disease', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('urothelial cancer', 'Disease', (80, 97))
115988	31238579	Smad2 immunoreactivity showed an inverse correlation with the increasing stage: high Smad2 was found in 44.3% (43/97) of pTa, 36.4% (71/195) pT1, and only 12.5% (14/112) of pT2 tumors.	('pTa', 'molecular_function', 'GO:0008959', ('121', '124'))	('pTa', 'Disease', (121, 124))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('Smad2', 'Gene', '4087', (0, 5))	('pT1', 'Gene', (141, 144))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('Smad2', 'Gene', '4087', (85, 90))	('Smad2', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('Smad2', 'Gene', (85, 90))	('pT1', 'Gene', '58492', (141, 144))	('tumors', 'Disease', (177, 183))	('high', 'Var', (80, 84))
115991	31238579	Moreover, Smad2 showed a strong inverse correlation with variant morphology and divergent differentiation of urothelial tumors (p = 0.014).	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('variant morphology', 'Var', (57, 75))	('urothelial tumors', 'Disease', (109, 126))	('Smad2', 'Gene', (10, 15))	('Smad2', 'Gene', '4087', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('inverse', 'NegReg', (32, 39))	('urothelial tumors', 'Disease', 'MESH:D001749', (109, 126))
115995	31238579	Overexpression of TGF-beta1 directly correlated to cancer-specific death (p = 0.043).	('TGF-beta1', 'Gene', (18, 27))	('correlated', 'Reg', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
116000	31238579	High Smad2 expression indicated a high probability of further treatment with intravesical instillation of BCG vaccine (p = 0.007), while its loss correlated with radical cystectomy (p = 0.004).	('Smad2', 'Gene', '4087', (5, 10))	('High', 'Var', (0, 4))	('loss', 'NegReg', (141, 145))	('expression', 'MPA', (11, 21))	('Smad2', 'Gene', (5, 10))	('men', 'Species', '9606', (67, 70))	('BCG', 'Species', '33892', (106, 109))	('radical cystectomy', 'Disease', (162, 180))
116004	31238579	Survival analyses showed that high Smad2 expression was associated with longer overall survival (p = 0.003).	('Smad2', 'Gene', (35, 40))	('expression', 'MPA', (41, 51))	('high', 'Var', (30, 34))	('longer', 'PosReg', (72, 78))	('Smad2', 'Gene', '4087', (35, 40))	('overall survival', 'MPA', (79, 95))
116005	31238579	High expression of Smad4 was also linked to better prognosis (p = 0.034).	('better', 'PosReg', (44, 50))	('Smad4', 'Gene', (19, 24))	('Smad4', 'Gene', '4089', (19, 24))	('High', 'Var', (0, 4))
116015	31238579	Alterations of TGF-beta signaling result in production of cytokines that support tumor growth and spread, and in modification of microenvironment that stimulates EMT.	('spread', 'CPA', (98, 104))	('support', 'PosReg', (73, 80))	('men', 'Species', '9606', (141, 144))	('production of cytokines', 'MPA', (44, 67))	('Alterations', 'Var', (0, 11))	('TGF-beta', 'Gene', '7040', (15, 23))	('EMT', 'biological_process', 'GO:0001837', ('162', '165'))	('EMT', 'CPA', (162, 165))	('TGF-beta', 'Gene', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('stimulates', 'PosReg', (151, 161))	('tumor', 'Disease', (81, 86))	('signaling', 'biological_process', 'GO:0023052', ('24', '33'))
116017	31238579	Several other studies emphasized the importance of EMT for the pathogenesis of UBC, where TGF-beta/Smad pathway was marked as the main inducer of EMT, and its ablation lead to inhibition of dissemination propensities.	('inhibition', 'NegReg', (176, 186))	('UBC', 'Disease', (79, 82))	('dissemination propensities', 'CPA', (190, 216))	('TGF-beta', 'Gene', '7040', (90, 98))	('UBC', 'Chemical', '-', (79, 82))	('pathogenesis', 'biological_process', 'GO:0009405', ('63', '75'))	('EMT', 'biological_process', 'GO:0001837', ('51', '54'))	('TGF-beta', 'Gene', (90, 98))	('EMT', 'biological_process', 'GO:0001837', ('146', '149'))	('Smad', 'Gene', '4089;4089;17128', (99, 103))	('Smad', 'Gene', (99, 103))	('ablation', 'Var', (159, 167))
116027	31238579	However, high Smad2 expression significantly correlated with the classic tumor morphology and the absence of variant morphological features or divergent differentiation.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('expression', 'MPA', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Smad2', 'Gene', '4087', (14, 19))	('tumor', 'Disease', (73, 78))	('Smad2', 'Gene', (14, 19))	('correlated', 'Reg', (45, 55))	('high', 'Var', (9, 13))
116029	31238579	We found that high TGF-beta1 was strongly connected to the invasive tumor stage, which is also in accordance with previous results.	('invasive tumor', 'Disease', (59, 73))	('invasive tumor', 'Disease', 'MESH:D009369', (59, 73))	('high', 'Var', (14, 18))	('connected', 'Reg', (42, 51))	('TGF-beta1', 'Gene', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
116035	31238579	Not only the defect of TGF-beta1, but also deletion of SMAD2 and SMAD4 genes in a murine model, renders animals more likely to spontaneously develop neoplastic growth.	('more', 'PosReg', (112, 116))	('deletion', 'Var', (43, 51))	('murine', 'Species', '10090', (82, 88))	('SMAD2', 'Gene', (55, 60))	('SMAD4', 'Gene', (65, 70))	('defect', 'Var', (13, 19))	('TGF-beta1', 'Gene', (23, 32))	('spontaneously develop neoplastic growth', 'CPA', (127, 166))
116037	31238579	No significant correlation between high p-Smad2/3and clinicopathologic features of the patients was found.	('Smad2', 'Gene', '4087', (42, 47))	('patients', 'Species', '9606', (87, 95))	('high', 'Var', (35, 39))	('Smad2', 'Gene', (42, 47))
116038	31238579	Another study suggested that the highest levels of phosphorylated Smad2 were present in high-grade urothelial carcinoma and were associated with increased recurrence rate.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (99, 119))	('associated', 'Reg', (129, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('urothelial carcinoma', 'Disease', (99, 119))	('increased', 'PosReg', (145, 154))	('phosphorylated', 'Var', (51, 65))	('Smad2', 'Gene', '4087', (66, 71))	('Smad2', 'Gene', (66, 71))
116040	31238579	Juvenile polyposis syndrome, the appearance of multiple hamartomatous polyps in the gastrointestinal tract associated with the increased risk of adenocarcinoma, is caused by mutations in SMAD4 gene.	('SMAD4', 'Gene', (187, 192))	('Juvenile polyposis syndrome', 'Phenotype', 'HP:0004784', (0, 27))	('hamartomatous polyps in the gastrointestinal tract', 'Disease', 'MESH:D011127', (56, 106))	('polyps in the gastrointestinal tract', 'Phenotype', 'HP:0200008', (70, 106))	('hamartomatous polyps', 'Phenotype', 'HP:0004390', (56, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('Juvenile polyposis syndrome', 'Disease', 'MESH:C537702', (0, 27))	('adenocarcinoma', 'Disease', (145, 159))	('caused by', 'Reg', (164, 173))	('mutations', 'Var', (174, 183))	('hamartomatous polyps in the gastrointestinal tract', 'Disease', (56, 106))	('Juvenile polyposis syndrome', 'Disease', (0, 27))	('adenocarcinoma', 'Disease', 'MESH:D000230', (145, 159))
116041	31238579	Inactivation of SMAD4 by mutation or deletion is well described as an important and common event in the development of pancreatic and colorectal carcinoma, and less frequently is observed in cancers of numerous other localizations, including urinary bladder.	('colorectal carcinoma', 'Disease', 'MESH:D015179', (134, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('SMAD4', 'Gene', (16, 21))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('deletion', 'Var', (37, 45))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Disease', (191, 198))	('mutation', 'Var', (25, 33))	('men', 'Species', '9606', (111, 114))	('pancreatic', 'Disease', 'MESH:D010195', (119, 129))	('urinary bladder', 'Disease', (242, 257))	('pancreatic', 'Disease', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('colorectal carcinoma', 'Disease', (134, 154))	('Inactivation', 'Var', (0, 12))
116050	31238579	High Smad4, as well as Smad2 staining, indicates less aggressive tumors and longer cancer-specific survival.	('aggressive tumors', 'Disease', 'MESH:D001523', (54, 71))	('Smad2', 'Gene', (23, 28))	('High', 'Var', (0, 4))	('Smad2', 'Gene', '4087', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('aggressive tumors', 'Disease', (54, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('Smad4', 'Gene', (5, 10))	('longer', 'PosReg', (76, 82))	('Smad4', 'Gene', '4089', (5, 10))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('less', 'NegReg', (49, 53))	('cancer', 'Disease', (83, 89))
116057	31238579	Conversely, high Smad2 expression indicated further treatment with intravesical immunotherapy with BCG vaccine.	('high', 'Var', (12, 16))	('BCG', 'Species', '33892', (99, 102))	('Smad2', 'Gene', '4087', (17, 22))	('indicated', 'Reg', (34, 43))	('Smad2', 'Gene', (17, 22))	('men', 'Species', '9606', (57, 60))	('expression', 'MPA', (23, 33))
116066	31238579	High TGF-beta1 is associated with cancer-specific death, and represents the independent predictor of adverse prognosis.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('High', 'Var', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('TGF-beta1', 'Gene', (5, 14))	('associated', 'Reg', (18, 28))	('cancer', 'Disease', (34, 40))
116076	28035325	In multivariable analysis, NAC was significantly associated with a decrease of at least one CKD stage from baseline to post-op (p = 0.009), but not to the 6-12 months follow-up time point (p = 0.050).	('NAC', 'Var', (27, 30))	('CKD stage', 'MPA', (92, 101))	('NAC', 'Chemical', '-', (27, 30))	('CKD', 'Phenotype', 'HP:0012622', (92, 95))	('decrease', 'NegReg', (67, 75))	('NAC', 'cellular_component', 'GO:0005854', ('27', '30'))
116115	28035325	However, when looking specifically at patients who received cisplatin-based NAC compared to carboplatin-based NAC, cisplatin-based NAC was an independent predictor of worsening of at least one CKD stage from baseline to the post-operative time point (OR 3.726, p = 0.001) and to the 6-12 month follow-up time point (OR 3.313, p = 0.017), while carboplatin-based NAC was not (OR 0.301, p = 0.261; 0.223, p = 0.219, respectively) (Table 3B).	('cisplatin-based', 'Var', (115, 130))	('carboplatin', 'Chemical', 'MESH:D016190', (92, 103))	('CKD stage', 'MPA', (193, 202))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('NAC', 'cellular_component', 'GO:0005854', ('76', '79'))	('NAC', 'cellular_component', 'GO:0005854', ('131', '134'))	('NAC', 'cellular_component', 'GO:0005854', ('362', '365'))	('NAC', 'Chemical', '-', (110, 113))	('carboplatin', 'Chemical', 'MESH:D016190', (344, 355))	('NAC', 'Chemical', '-', (362, 365))	('NAC', 'Chemical', '-', (131, 134))	('NAC', 'Chemical', '-', (76, 79))	('NAC', 'cellular_component', 'GO:0005854', ('110', '113'))	('patients', 'Species', '9606', (38, 46))	('CKD', 'Phenotype', 'HP:0012622', (193, 196))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('worsening', 'NegReg', (167, 176))
116117	28035325	Univariate logistic regression analysis identified NAC as a significant predictor of worsening CKD stage from baseline to post-operatively (OR 2.175, p = 0.046), which was confirmed on multivariable logistic regression (OR 2.226, p = 0.044).	('worsening', 'NegReg', (85, 94))	('NAC', 'Var', (51, 54))	('NAC', 'Chemical', '-', (51, 54))	('CKD stage', 'Disease', (95, 104))	('NAC', 'cellular_component', 'GO:0005854', ('51', '54'))	('CKD', 'Phenotype', 'HP:0012622', (95, 98))
116145	28035325	Our data suggests that administration of NAC may cause an initial insult to renal function, but their long-term renal function is no different than patients who undergo RC alone.	('NAC', 'Var', (41, 44))	('patients', 'Species', '9606', (148, 156))	('NAC', 'Chemical', '-', (41, 44))	('renal function', 'MPA', (76, 90))	('NAC', 'cellular_component', 'GO:0005854', ('41', '44'))	('insult', 'MPA', (66, 72))
116168	22489102	Compared with low-grade carcinomas, most high-grade cases showed larger and more variable nuclear size, more frequent polysomy of centromere enumeration probes (CEPs) 3, 7 and 17, and the loss of the 9p21 locus.	('carcinomas', 'Disease', 'MESH:D002277', (24, 34))	('centromere', 'cellular_component', 'GO:0005698', ('130', '140'))	('carcinomas', 'Disease', (24, 34))	('9p21 locus', 'Gene', (200, 210))	('centromere', 'cellular_component', 'GO:0000775', ('130', '140'))	('polysomy', 'Var', (118, 126))	('loss', 'NegReg', (188, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
116178	22489102	Furthermore, genetic anomalies or aberrant expression of genes such as Her2/neu, p53, p16INK4, cytokeratins and fibroblast growth factor receptor 3 (FGFR3) have been found to exist in urothelial carcinoma.	('p16INK4', 'Var', (86, 93))	('FGFR', 'molecular_function', 'GO:0005007', ('149', '153'))	('aberrant', 'Var', (34, 42))	('genetic anomalies', 'Disease', (13, 30))	('urothelial carcinoma', 'Disease', (184, 204))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (184, 204))	('p53', 'Gene', (81, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('genetic anomalies', 'Disease', 'MESH:D030342', (13, 30))	('expression', 'MPA', (43, 53))	('FGFR3', 'Gene', (149, 154))	('Her2/neu', 'Protein', (71, 79))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('112', '136'))
116180	22489102	UroVysion, a modification of the FISH technique for urothelial carcinomas, has been used successfully to assess aberrations in chromosomes 3, 7, and 17 by centromere enumeration probes (CEPs), and to detect deletions of p16 at the 9p21 locus.	('deletions', 'Var', (207, 216))	('centromere', 'cellular_component', 'GO:0005698', ('155', '165'))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('detect', 'Reg', (200, 206))	('centromere', 'cellular_component', 'GO:0000775', ('155', '165'))	('p16', 'Gene', (220, 223))	('urothelial carcinomas', 'Disease', (52, 73))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (52, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
116199	22489102	Among five non-invasive low-grade urothelial carcinomas, one showed polysomy and another indicated loss of 9p21.	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('urothelial carcinomas', 'Disease', (34, 55))	('9p21', 'Protein', (107, 111))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (34, 55))	('loss', 'NegReg', (99, 103))	('polysomy', 'Var', (68, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
116200	22489102	In seven high-grade urothelial carcinomas, six revealed polysomy, and five indicated loss of 9p21.	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('polysomy', 'Var', (56, 64))	('revealed', 'Reg', (47, 55))	('urothelial carcinomas', 'Disease', (20, 41))	('9p21', 'Protein', (93, 97))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (20, 41))	('loss', 'NegReg', (85, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
116216	22489102	This conclusion is supported by the observation that papillary thyroid carcinoma cells with only point mutation or transformation without any evident increase of chromosomes show negligible changes in nuclear morphology.	('papillary thyroid carcinoma', 'Disease', (53, 80))	('changes', 'Reg', (190, 197))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (53, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('nuclear morphology', 'CPA', (201, 219))	('point mutation', 'Var', (97, 111))	('nuclear morphology', 'biological_process', 'GO:0006997', ('201', '219'))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (53, 80))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (63, 80))
116218	32160708	Pan-Cancer Analysis Reveals the Diverse Landscape of Novel Sense and Antisense Fusion Transcripts Gene fusions that contribute to oncogenicity can be explored for identifying cancer biomarkers and potential drug targets.	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('Antisense Fusion Transcripts', 'Var', (69, 97))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Sense', 'Var', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
116221	32160708	The majority of the recurrent non-canonical fusions found in our study are novel, unexplored, and exhibited highly variable profiles across cancers, with breast cancer and glioblastoma having the highest and lowest rates, respectively.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('glioblastoma', 'Disease', (172, 184))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (172, 184))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('non-canonical', 'Var', (30, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))
116223	32160708	Genomic instability, a hallmark of cancer, leads to the accumulation of dynamic changes in the genome manifested as structural variants (SVs) that include quantitative (copy number variations [CNVs]), positional (translocations), or orientational (inversions) rearrangements.	('hallmark of cancer', 'Disease', 'MESH:D009369', (23, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('hallmark of cancer', 'Disease', (23, 41))	('translocations', 'Var', (213, 227))
116225	32160708	Fusion transcripts that originate from fusion genes are likely unique to a cancer type, which can be exploited to understand the underlying mechanisms of malignancy and can serve as effective diagnostic or prognostic markers.	('cancer type', 'Disease', 'MESH:D009369', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('fusion genes', 'Var', (39, 51))	('malignancy', 'Disease', 'MESH:D009369', (154, 164))	('cancer type', 'Disease', (75, 86))	('malignancy', 'Disease', (154, 164))
116226	32160708	These chimeras could contribute to oncogenicity by altering the expression of tumor suppressor or proto-oncogenes, or by modifying the original function of a protein resulting in an abnormal chimeric protein that stimulates tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('contribute', 'Reg', (21, 31))	('protein', 'cellular_component', 'GO:0003675', ('158', '165'))	('modifying', 'Reg', (121, 130))	('abnormal', 'Var', (182, 190))	('tumor suppressor', 'Gene', (78, 94))	('altering', 'Reg', (51, 59))	('expression', 'MPA', (64, 74))	('stimulates', 'PosReg', (213, 223))	('tumor', 'Disease', (224, 229))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('tumor suppressor', 'Gene', '7248', (78, 94))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('tumor', 'Disease', (78, 83))	('chimeric protein', 'MPA', (191, 207))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('78', '94'))
116227	32160708	Examples of established cancer-specific biomarkers include the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion transcript for the identification of NPM-ALK-positive anaplastic large cell lymphoma (ALCL), and BCR-ABL1 fusion in chronic myeloid leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (262, 270))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (254, 270))	('cancer', 'Disease', (24, 30))	('NPM', 'Gene', (114, 117))	('NPM', 'Gene', '4869', (114, 117))	('ALK', 'Gene', '238', (171, 174))	('BCR-ABL1', 'Gene', (227, 235))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('lymphoma', 'Phenotype', 'HP:0002665', (88, 96))	('ALK', 'Gene', (171, 174))	('cell lymphoma', 'Phenotype', 'HP:0012191', (201, 214))	('lymphoma', 'Phenotype', 'HP:0002665', (206, 214))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (184, 214))	('anaplastic large cell lymphoma', 'Disease', (184, 214))	('chronic myeloid leukemia', 'Disease', (246, 270))	('NPM', 'Gene', (167, 170))	('NPM', 'Gene', '4869', (167, 170))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (77, 96))	('ALCL', 'Phenotype', 'HP:0012193', (216, 220))	('ALK', 'Gene', '238', (118, 121))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (246, 270))	('ALK', 'Gene', (118, 121))	('fusion', 'Var', (236, 242))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (246, 270))
116232	32160708	Although fusions were initially found to be more prevalent in liquid cancers, later they were discovered to be prominent in solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (124, 136))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('prevalent', 'Reg', (49, 58))	('fusions', 'Var', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('solid tumors', 'Disease', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
116233	32160708	Furthermore, fusion transcripts were initially assumed to be exclusive to cancer cells, but several reports identified a large number of fusion transcripts in non-cancerous cells, suggesting that they are prevalent in normal cells as well.	('fusion', 'Var', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
116238	32160708	ChimeRScope employs short k-mer-based unique transcript fingerprints to serve as a reference to match with k-mers from cancer transcriptome reads and identify fusion transcripts in cancer cells that harbor frequent chromosomal abnormalities and mutations.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('mutations', 'Var', (245, 254))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('chromosomal abnormalities', 'Disease', (215, 240))	('mers', 'Species', '1335626', (109, 113))	('cancer', 'Disease', (181, 187))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (215, 240))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
116242	32160708	We also screened for fusions that are recurrent in the common cancer cell lines (CCLE) as a means to corroborate fusions that are co-occurring in corresponding primary tumors.	('CCLE', 'Chemical', '-', (81, 85))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('primary tumors', 'Disease', 'MESH:D001932', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('fusions', 'Var', (113, 120))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('primary tumors', 'Disease', (160, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
116243	32160708	Fusions in CCLE that are also detected in TCGA patients serve as a valuable resource to carry out mechanistic studies aimed at exploring the functional significance of these events.	('Fusions', 'Var', (0, 7))	('CCLE', 'Gene', (11, 15))	('patients', 'Species', '9606', (47, 55))	('CCLE', 'Chemical', '-', (11, 15))
116245	32160708	In addition to fusion detection from 33 cancer types, we also experimentally validated some of the predicted fusions by Sanger sequencing of fusion transcripts identified from CCLE cell lines.	('cancer type', 'Disease', 'MESH:D009369', (40, 51))	('fusions', 'Var', (109, 116))	('CCLE', 'Chemical', '-', (176, 180))	('cancer type', 'Disease', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
116265	32160708	In general, a very high percentage of CCLE samples contained recurrent fusions across all cancers compared to those of TCGA (Figure 1B).	('cancers', 'Disease', (90, 97))	('CCLE', 'Disease', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('fusions', 'Var', (71, 78))	('CCLE', 'Chemical', '-', (38, 42))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
116267	32160708	MESO (mesothelioma) and PAAD (pancreatic adenocarcinoma) had more non-canonical fusions in CCLE than did corresponding primary tumors in TCGA.	('non-canonical fusions', 'Var', (66, 87))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010195', (30, 55))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mesothelioma', 'Disease', (6, 18))	('CCLE', 'Chemical', '-', (91, 95))	('pancreatic adenocarcinoma', 'Disease', (30, 55))	('primary tumors', 'Disease', 'MESH:D001932', (119, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (30, 55))	('mesothelioma', 'Disease', 'MESH:D008654', (6, 18))	('primary tumors', 'Disease', (119, 133))	('CCLE', 'Disease', (91, 95))
116276	32160708	FGFR3-TACC3 (fibroblast growth factor receptor 3 and transforming acidic coiled-coil containing protein 3) fusion associated with multiple cancers was also found to be recurrent in BLCA, ESCA (esophageal carcinoma), CESC (cervical squamous cell carcinoma and endocervical adenocarcinoma), HNSC, LIHC (liver hepatocellular carcinoma), and LUSC.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (307, 331))	('HNSC', 'Disease', (289, 293))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('fusion', 'Var', (107, 113))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('BLCA', 'Disease', (181, 185))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('13', '37'))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (301, 331))	('LUSC', 'Disease', (338, 342))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('endocervical adenocarcinoma', 'Disease', (259, 286))	('multiple cancers', 'Disease', (130, 146))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (193, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('esophageal carcinoma', 'Disease', (193, 213))	('liver hepatocellular carcinoma', 'Disease', (301, 331))	('cervical squamous cell carcinoma', 'Disease', (222, 254))	('TACC3', 'Gene', '10460', (6, 11))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (259, 286))	('TACC3', 'Gene', (6, 11))	('FGFR3', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('associated', 'Reg', (114, 124))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (222, 254))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (193, 213))	('multiple cancers', 'Disease', 'MESH:D009369', (130, 146))	('FGFR3', 'Gene', '2261', (0, 5))
116277	32160708	The occurrence of FGFR3-TACC3 fusion in CESC, ESCA, and LIHC has not been reported previously, signifying that this common fusion is prevalent in more tissue types than previously discovered.	('FGFR3', 'Gene', '2261', (18, 23))	('fusion', 'Var', (30, 36))	('TACC3', 'Gene', '10460', (24, 29))	('CESC', 'Disease', (40, 44))	('TACC3', 'Gene', (24, 29))	('FGFR3', 'Gene', (18, 23))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('ESCA', 'Disease', (46, 50))
116278	32160708	Other FGFR fusions partnering with BicC family RNA binding protein 1 (BICC1), shootin 1 (SHTN1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and arginyltransferase 1 (ATE1) have also been detected in multiple cancers from our analysis.	('ATE1', 'Gene', (173, 177))	('GAPDH', 'Gene', (139, 144))	('RNA', 'cellular_component', 'GO:0005562', ('47', '50'))	('FGF', 'Gene', '2247', (6, 9))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('shootin 1', 'Gene', (78, 87))	('SHTN1', 'Gene', (89, 94))	('multiple cancers', 'Disease', 'MESH:D009369', (206, 222))	('RNA binding', 'molecular_function', 'GO:0003723', ('47', '58'))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('detected', 'Reg', (194, 202))	('SHTN1', 'Gene', '57698', (89, 94))	('FGF', 'Gene', (6, 9))	('FGFR', 'molecular_function', 'GO:0005007', ('6', '10'))	('fusions', 'Var', (11, 18))	('arginyltransferase 1', 'Gene', (151, 171))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ATE1', 'Gene', '11101', (173, 177))	('shootin 1', 'Gene', '57698', (78, 87))	('multiple cancers', 'Disease', (206, 222))	('BICC1', 'Gene', '80114', (70, 75))	('GAPDH', 'Gene', '2597', (139, 144))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (97, 137))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (97, 137))	('BICC1', 'Gene', (70, 75))	('arginyltransferase 1', 'Gene', '11101', (151, 171))
116279	32160708	Several of these FGFR fusions have been identified as activating fusions that have been linked to activation of downstream genes.	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('FGF', 'Gene', (17, 20))	('FGF', 'Gene', '2247', (17, 20))	('fusions', 'Var', (22, 29))
116280	32160708	Following the same trend, ETV6-NTRK3 (ETS variant 6 and neurotrophic tyrosine kinase, receptor, type 3) fusions were also identified in multiple cancers including breast, colon, skin, and thyroid cancers.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('thyroid cancers', 'Disease', 'MESH:D013964', (188, 203))	('colon', 'Disease', (171, 176))	('ETV6', 'Gene', '2120', (26, 30))	('fusions', 'Var', (104, 111))	('multiple cancers', 'Disease', 'MESH:D009369', (136, 152))	('breast', 'Disease', (163, 169))	('NTRK3', 'Gene', '4916', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('NTRK3', 'Gene', (31, 36))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('thyroid cancer', 'Phenotype', 'HP:0002890', (188, 202))	('identified', 'Reg', (122, 132))	('multiple cancers', 'Disease', (136, 152))	('ETV6', 'Gene', (26, 30))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('skin', 'Disease', (178, 182))	('thyroid cancers', 'Disease', (188, 203))
116281	32160708	This ETV6 fusion with NTRK3 has also been identified as oncogenic by the activation of the Ras-MAPK and phosphatidylinositol 3-kinase (PI3K)-AKT pathways.	('phosphatidylinositol 3-kinase', 'Gene', (104, 133))	('activation', 'PosReg', (73, 83))	('MAPK', 'Gene', (95, 99))	('phosphatidylinositol 3-kinase', 'Gene', '5295', (104, 133))	('NTRK3', 'Gene', '4916', (22, 27))	('AKT', 'Gene', (141, 144))	('MAPK', 'molecular_function', 'GO:0004707', ('95', '99'))	('fusion', 'Var', (10, 16))	('ETV6', 'Gene', (5, 9))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('AKT', 'Gene', '207', (141, 144))	('NTRK3', 'Gene', (22, 27))	('MAPK', 'Gene', '5594', (95, 99))	('ETV6', 'Gene', '2120', (5, 9))
116282	32160708	In contrast, most of the ESR1 (estrogen receptor 1) fusions except for ESR1-CCDC170 (coiled-coil domain containing 170) were found to be exclusively present in breast cancer.	('ESR1', 'Gene', (25, 29))	('coiled-coil domain containing 170', 'Gene', '80129', (85, 118))	('ESR1', 'Gene', '2099', (71, 75))	('estrogen receptor 1', 'Gene', '2099', (31, 50))	('CCDC170', 'Gene', '80129', (76, 83))	('present', 'Reg', (149, 156))	('estrogen receptor 1', 'Gene', (31, 50))	('ESR1', 'Gene', '2099', (25, 29))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('coiled-coil domain containing 170', 'Gene', (85, 118))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('ESR1', 'Gene', (71, 75))	('CCDC170', 'Gene', (76, 83))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('fusions', 'Var', (52, 59))
116294	32160708	IL34 expression has been associated with the progression of tumor growth, metastasis, and poor prognosis in several cancers.	('associated', 'Reg', (25, 35))	('IL34', 'Gene', (0, 4))	('expression', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('metastasis', 'CPA', (74, 84))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('tumor', 'Disease', (60, 65))	('IL34', 'Gene', '146433', (0, 4))
116302	32160708	An earlier report also identified a high percentage of recurrent kinase fusions in thyroid cancer, indicating that kinase fusions could be explored as biomarkers or therapeutic targets in this cancer.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('thyroid cancer', 'Disease', 'MESH:D013964', (83, 97))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('thyroid cancer', 'Phenotype', 'HP:0002890', (83, 97))	('thyroid cancer', 'Disease', (83, 97))	('kinase fusions', 'Var', (65, 79))
116307	32160708	EML4 (echinoderm microtubule-associated protein-like 4) fusions with ALK (ALK receptor tyrosine kinase) that were previously associated with non-small-cell lung cancer (NSCLC) were identified in LUAD along with KIRP and THCA at low frequency.	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('fusions', 'Var', (56, 63))	('ALK', 'Gene', '238', (69, 72))	('echinoderm microtubule-associated protein-like 4', 'Gene', (6, 54))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (141, 167))	('ALK', 'Gene', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('associated', 'Reg', (125, 135))	('ALK', 'Gene', '238', (74, 77))	('microtubule', 'cellular_component', 'GO:0005874', ('17', '28'))	('ALK', 'Gene', (74, 77))	('non-small-cell lung cancer', 'Disease', (141, 167))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (141, 167))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('KIRP', 'Chemical', '-', (211, 215))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (6, 54))	('EML4', 'Gene', (0, 4))	('NSCLC', 'Disease', (169, 174))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (145, 167))	('EML4', 'Gene', '27436', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))
116312	32160708	Since alteration of oncogene or tumor suppressor functions can be key to the initiation and progression of cancer, we also screened for these fusions in our dataset.	('tumor suppressor', 'Gene', (32, 48))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('tumor suppressor', 'Gene', '7248', (32, 48))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('oncogene', 'Protein', (20, 28))	('alteration', 'Var', (6, 16))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
116315	32160708	CCDC6-RET fusions in thyroid and CBFB-MYH11 (core-binding factor, beta subunit and myosin heavy chain 11) fusions in LAML (acute myeloid leukemia) were recurrent.	('leukemia', 'Phenotype', 'HP:0001909', (137, 145))	('RET', 'Gene', '5979', (6, 9))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (129, 145))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (123, 145))	('CBFB', 'Gene', '865', (33, 37))	('MYH11', 'Gene', (38, 43))	('acute myeloid leukemia', 'Disease', (123, 145))	('RET', 'Gene', (6, 9))	('CCDC6', 'Gene', '8030', (0, 5))	('CBFB', 'Gene', (33, 37))	('fusions', 'Var', (106, 113))	('CCDC6', 'Gene', (0, 5))	('binding', 'molecular_function', 'GO:0005488', ('50', '57'))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (123, 145))	('MYH11', 'Gene', '4629', (38, 43))	('core', 'cellular_component', 'GO:0019013', ('45', '49'))	('fusions', 'Var', (10, 17))
116320	32160708	PRKAR1A fusions were recurrent across and within several cancer types.	('cancer type', 'Disease', 'MESH:D009369', (57, 68))	('fusions', 'Var', (8, 15))	('PRKAR1A', 'Gene', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer type', 'Disease', (57, 68))	('PRKAR1A', 'Gene', '5573', (0, 7))
116322	32160708	The percentage of TSG/oncogene fusions among the recurrent non-canonical fusions predicted was similar to those in the canonical fusions, although the majority of these fusions were identified from BRCA (Table S11).	('S11', 'Gene', (210, 213))	('TSG', 'Gene', (18, 21))	('S11', 'Gene', '6267', (210, 213))	('TSG', 'Gene', '57045', (18, 21))	('BRCA', 'Gene', '672', (198, 202))	('BRCA', 'Gene', (198, 202))	('fusions', 'Var', (31, 38))
116325	32160708	Another interesting observation of breast cancer was the occurrence of ErbB2 fusions.	('ErbB2', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('fusions', 'Var', (77, 84))	('ErbB2', 'Gene', '2064', (71, 76))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
116326	32160708	BRCA samples that are HER2 positive or the HER2-E PAM50 subtype had statistically higher ErbB2 fusions (Fisher's exact test p = 0.004 and 0.002, respectively).	('BRCA', 'Gene', (0, 4))	('HER2', 'Gene', (43, 47))	('ErbB2', 'Gene', (89, 94))	('HER2', 'Gene', (22, 26))	('PAM50', 'Var', (50, 55))	('higher', 'PosReg', (82, 88))	('HER2', 'Gene', '2064', (43, 47))	('HER2', 'Gene', '2064', (22, 26))	('ErbB2', 'Gene', '2064', (89, 94))	('BRCA', 'Gene', '672', (0, 4))
116328	32160708	Overexpression of ErbB2, a receptor tyrosine kinase with intrinsic tyrosine kinase activity, is associated with breast cancer metastasis and lower survival rates.	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer metastasis', 'Disease', (112, 136))	('associated', 'Reg', (96, 106))	('ErbB2', 'Gene', (18, 23))	('kinase activity', 'molecular_function', 'GO:0016301', ('76', '91'))	('lower', 'NegReg', (141, 146))	('Overexpression', 'Var', (0, 14))	('breast cancer metastasis', 'Disease', 'MESH:D001943', (112, 136))	('ErbB2', 'Gene', '2064', (18, 23))	('survival rates', 'CPA', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
116329	32160708	These observations indicate the need to investigate ErbB2 fusions in breast cancer and their association with gene expression and patient survival.	('patient', 'Species', '9606', (130, 137))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ErbB2', 'Gene', (52, 57))	('breast cancer', 'Disease', (69, 82))	('fusions', 'Var', (58, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('ErbB2', 'Gene', '2064', (52, 57))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))
116330	32160708	To investigate oncogenic pathways that are affected by fusions in each TCGA cancer type, we cataloged recurrent fusions identified across 10 important oncogenic pathways (selection based on a previous report).	('cancer type', 'Disease', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('fusions', 'Var', (112, 119))	('oncogenic pathways', 'Pathway', (151, 169))	('cancer type', 'Disease', 'MESH:D009369', (76, 87))
116331	32160708	RTKRAS, NOTCH, PI3K, and HIPPO signaling pathways were found to be the most affected oncogenic pathways by recurrent canonical fusions (Figure 3A; Table S12).	('PI3K', 'molecular_function', 'GO:0016303', ('15', '19'))	('HIPPO signaling pathways', 'Pathway', (25, 49))	('PI3K', 'Pathway', (15, 19))	('S12', 'Gene', (153, 156))	('oncogenic pathways', 'Pathway', (85, 103))	('S12', 'Gene', '6268', (153, 156))	('HIPPO signaling', 'biological_process', 'GO:0035329', ('25', '40'))	('affected', 'Reg', (76, 84))	('canonical fusions', 'Var', (117, 134))	('NOTCH', 'Pathway', (8, 13))
116332	32160708	Thyroid cancer had more than 50% of the recurrent canonical fusions in the RTK (receptor tyrosine kinase)-RAS pathway, with a high frequency of CCDC-RET fusion.	('RET', 'Gene', '5979', (149, 152))	('Thyroid cancer', 'Disease', 'MESH:D013964', (0, 14))	('fusions', 'Var', (60, 67))	('Thyroid cancer', 'Phenotype', 'HP:0002890', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Thyroid cancer', 'Disease', (0, 14))	('RET', 'Gene', (149, 152))
116335	32160708	OV, ESCA, and LAML mainly contributed to the pool of read-through fusions (>40%) while some cancers have none (Table S1).	('ESCA', 'Disease', (4, 8))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('read-through fusions', 'Var', (53, 73))	('fusions', 'Var', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
116337	32160708	For example, ZCCHC8-RSRC2 fusion was detected in five cancers (BLCA, BRCA, CESC, HNSC, and PAAD) at very low frequency (Table S13).	('fusion', 'Var', (26, 32))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('BRCA', 'Gene', '672', (69, 73))	('HNSC', 'Disease', (81, 85))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('BRCA', 'Gene', (69, 73))	('RSRC2', 'Gene', (20, 25))	('RSRC2', 'Gene', '65117', (20, 25))	('CESC', 'Disease', (75, 79))	('detected', 'Reg', (37, 45))	('ZCCHC8', 'Gene', '55596', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('ZCCHC8', 'Gene', (13, 19))
116349	32160708	LUSC and THYM shared 39 recurrent fusions, including RAB3IP (interactor of the Ras-like GTPase Rab3A) and CHRM3 as recurrent 5' fusion partners with other genes in both cancers.	('Rab3A', 'Gene', '5864', (95, 100))	('cancers', 'Disease', (169, 176))	('Ras-like GTPase', 'Gene', '282808', (79, 94))	('Rab3A', 'Gene', (95, 100))	('CHRM3', 'Gene', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('RAB3IP', 'Gene', (53, 59))	('RAB3IP', 'Gene', '117177', (53, 59))	('CHRM3', 'Gene', '1131', (106, 111))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('Ras-like GTPase', 'Gene', (79, 94))	('fusions', 'Var', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
116351	32160708	We also identified RAB3IP fusions in gastrointestinal (GI) cancers, including STAD, COAD, CHOL, and LIHC.	('gastrointestinal (GI) cancers', 'Disease', 'MESH:D005770', (37, 66))	('RAB3IP', 'Gene', '117177', (19, 25))	('fusions', 'Var', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('RAB3IP', 'Gene', (19, 25))	('CHOL', 'CellLine', 'None', (90, 94))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('COAD', 'Disease', (84, 88))	('CHOL', 'Disease', (90, 94))	('STAD', 'Disease', (78, 82))	('LIHC', 'Disease', (100, 104))
116361	32160708	Fusions involving CHRM3 were expressed in several GI tract cancers studied.	('Fusions', 'Var', (0, 7))	('GI tract cancers', 'Disease', 'MESH:D005770', (50, 66))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('expressed', 'Reg', (29, 38))	('GI tract cancers', 'Disease', (50, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('CHRM3', 'Gene', (18, 23))	('CHRM3', 'Gene', '1131', (18, 23))
116365	32160708	RXR is a master regulator and plays a central role in nuclear signaling, and a truncated RXR has been associated with oncogenicity.	('associated', 'Reg', (102, 112))	('oncogenicity', 'CPA', (118, 130))	('RXR', 'molecular_function', 'GO:0004879', ('89', '92'))	('truncated', 'Var', (79, 88))	('RXR', 'Gene', '6256', (89, 92))	('signaling', 'biological_process', 'GO:0023052', ('62', '71'))	('RXR', 'molecular_function', 'GO:0004879', ('0', '3'))	('RXR', 'Gene', '6256', (0, 3))	('RXR', 'Gene', (89, 92))	('RXR', 'Gene', (0, 3))
116376	32160708	Among the recurrent non-canonical fusions, ErBB2 and ESR1 fusions were druggable and were only identified in breast cancer samples.	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('ErBB2', 'Gene', '2064', (43, 48))	('ESR1', 'Gene', '2099', (53, 57))	('fusions', 'Var', (58, 65))	('ErBB2', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ESR1', 'Gene', (53, 57))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
116385	32160708	We identified 2,524 unique recurrent fusions from these cell lines with approximately equal distribution of canonical and non-canonical fusions (Figure 1; Tables S16 and S17).	('S17', 'Gene', '6218', (170, 173))	('S16', 'Gene', (162, 165))	('S16', 'Gene', '6217', (162, 165))	('fusions', 'Var', (37, 44))	('S17', 'Gene', (170, 173))
116388	32160708	A large number of recurrent canonical fusions (91 fusions) were identified in more than 35% of the cancer cell lines analyzed across cancers, indicating that fusions present in cell lines are more pervasive across cancers than the ones identified in primary tumors.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('cancer', 'Disease', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('primary tumors', 'Disease', 'MESH:D001932', (250, 264))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancers', 'Disease', (214, 221))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancer', 'Disease', (133, 139))	('cancers', 'Disease', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Disease', (99, 105))	('fusions', 'Var', (158, 165))	('primary tumors', 'Disease', (250, 264))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
116394	32160708	We also identified a high frequency of chromosome Y genes in non-canonical fusions in lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (86, 114))	('chromosome Y genes', 'Gene', (39, 57))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('lung squamous cell carcinoma', 'Disease', (86, 114))	('non-canonical fusions', 'Var', (61, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))
116397	32160708	Hierarchical clustering analysis of recurrent canonical or non-canonical fusions in CCLE revealed different patterns, except for some cancers of squamous origin (ESCA and HNSC), which clustered together in both groups (Figures S10A, S10B, S11A, and S11B).	('S10A', 'SUBSTITUTION', 'None', (227, 231))	('S10B', 'SUBSTITUTION', 'None', (233, 237))	('S11A', 'SUBSTITUTION', 'None', (239, 243))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('S10A', 'Var', (227, 231))	('S10B', 'Var', (233, 237))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('S11A', 'Var', (239, 243))	('S11B', 'SUBSTITUTION', 'None', (249, 253))	('S11B', 'Var', (249, 253))	('CCLE', 'Chemical', '-', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
116399	32160708	The pool of recurrent fusions identified from CCLE samples was vastly different from those identified in TCGA tumors, with minimal overlap (Figures S12A and S12B).	('S12B', 'SUBSTITUTION', 'None', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('CCLE', 'Disease', (46, 50))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('CCLE', 'Chemical', '-', (46, 50))	('S12A', 'Var', (148, 152))	('S12B', 'Var', (157, 161))	('S12A', 'SUBSTITUTION', 'None', (148, 152))
116400	32160708	Of the common fusions identified between the two groups, canonical fusions were found to be more common (9%) than non-canonical fusions (2%) (Table S18).	('canonical', 'Var', (57, 66))	('S18', 'Gene', '6222', (148, 151))	('S18', 'Gene', (148, 151))
116401	32160708	Hierarchical clustering analysis of recurrent fusions identified in CCLE and TCGA also revealed separate clusters for primary tumor and cell lines for both canonical and non-canonical fusions, indicating that fusions in cell lines are vastly different from the primary tumors (Figures 5A-5D).	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('primary tumors', 'Disease', (261, 275))	('fusions', 'Var', (46, 53))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('tumor', 'Disease', (269, 274))	('TCGA', 'Gene', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('CCLE', 'Gene', (68, 72))	('primary tumors', 'Disease', 'MESH:D001932', (261, 275))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('CCLE', 'Chemical', '-', (68, 72))	('tumor', 'Disease', (126, 131))
116405	32160708	In contrast to other cancers, breast cancer also had a high frequency of recurrent non-canonical fusions that were common between CCLE and TCGA samples.	('non-canonical fusions', 'Var', (83, 104))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('breast cancer', 'Disease', (30, 43))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancers', 'Disease', (21, 28))	('CCLE', 'Chemical', '-', (130, 134))
116407	32160708	Most of the reported fusions in TCGA that are also common between cell lines and TCGA primary tumors were non-recurrent canonical fusions.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('primary tumors', 'Disease', (86, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('primary tumors', 'Disease', 'MESH:D001932', (86, 100))	('fusions', 'Var', (21, 28))	('TCGA', 'Disease', (32, 36))
116412	32160708	Among the samples screened for structural variations using BreakDancer, inter-chromosomal translocations (CTXs) and insertions (INSs) were relatively rare compared to other structural variations within a cancer (Table S20).	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('insertions', 'Var', (116, 126))	('S20', 'Gene', (218, 221))	('S20', 'Gene', '6224', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))
116413	32160708	Breast cancer displayed the highest percentage of both intra-chromosomal translocations (ITXs) and inversions (INVs), accounting for the majority of non-canonical fusions identified in these samples.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('intra-chromosomal', 'Var', (55, 72))	('inversions', 'Var', (99, 109))	('Breast cancer', 'Disease', (0, 13))
116419	32160708	We were also able to validate the existence of non-canonical fusions (at least one partner in antisense orientation: GBA-MTX1, DNHD1-RRP8, PRDM4-PWP1, RPL39L-ST6GAL1, BOP1-MROH1, SPDYE3-UPK3B) in CCLE cell lines, indicating that ChimeRScope can accurately predict fusions containing antisense genes along with canonical fusions (Figure S15).	('RRP8', 'Gene', '23378', (133, 137))	('BOP1', 'Gene', (167, 171))	('RRP8', 'Gene', (133, 137))	('ST6GAL1', 'Gene', '6480', (158, 165))	('RPL39L', 'Gene', '116832', (151, 157))	('MTX1', 'Gene', (121, 125))	('ST6GAL1', 'Gene', (158, 165))	('S15', 'Gene', '2202', (336, 339))	('UPK3B', 'Gene', (186, 191))	('UPK3B', 'Gene', '80761', (186, 191))	('PRDM4', 'Gene', '11108', (139, 144))	('BOP1', 'Gene', '23246', (167, 171))	('GBA', 'Gene', (117, 120))	('PRDM4', 'Gene', (139, 144))	('MROH1', 'Gene', '727957', (172, 177))	('MTX1', 'Gene', '4580', (121, 125))	('S15', 'Gene', (336, 339))	('CCLE', 'Chemical', '-', (196, 200))	('DNHD1', 'Gene', '144132', (127, 132))	('MROH1', 'Gene', (172, 177))	('GBA', 'Gene', '2629', (117, 120))	('SPDYE3', 'Gene', (179, 185))	('RPL39L', 'Gene', (151, 157))	('fusions', 'Var', (264, 271))	('SPDYE3', 'Gene', '441272', (179, 185))	('PWP1', 'Gene', (145, 149))	('RRP', 'cellular_component', 'GO:1990474', ('133', '136'))	('PWP1', 'Gene', '11137', (145, 149))	('antisense genes', 'Var', (283, 298))	('DNHD1', 'Gene', (127, 132))
116421	32160708	Within these recurrent fusions, non-canonical fusions were more prevalent than canonical fusions in this cancer (Table S1).	('cancer', 'Disease', (105, 111))	('non-canonical fusions', 'Var', (32, 53))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('prevalent', 'Reg', (64, 73))
116426	32160708	Mutual exclusivity of mutations and fusions was recently identified as an important driver of genes in cancer.	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (22, 31))
116428	32160708	TP53 mutations were found to be significantly lower in the samples with high fusion category (23%) when compared to low fusion samples (51%, adjusted p = 0.01) (Figure 7).	('TP53', 'Gene', '7157', (0, 4))	('lower', 'NegReg', (46, 51))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
116430	32160708	We limited our analysis only to fusion transcripts that were recurrent (n >= 2) either within or across cancers and generated a catalog of frequent high-confidence fusions across pan-cancer primary tumor and cell line samples.	('cancer', 'Disease', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('fusions', 'Var', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('tumor', 'Disease', (198, 203))	('cancer', 'Disease', (104, 110))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
116432	32160708	ChimeRScope also detected fusions in several of the normal samples, which is consistent with a recent report that fusions are also common in non-tumor cells.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('fusions', 'Var', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('detected', 'Reg', (17, 25))
116437	32160708	This observation is consistent with earlier reports that suggest breast cancer harbors a large number of structural variations compared to other cancers, specifically intrachromosomal translocations and inversions being the most common types.	('cancers', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', (65, 78))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('intrachromosomal', 'Var', (167, 183))	('inversions', 'Var', (203, 213))
116438	32160708	We also detected a high incidence of inversions and intrachromosomal variations in the BRCA-WGS data, which supports a large number of non-canonical fusions identified in breast cancer compared to other cancers (Table S20).	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Disease', (171, 184))	('BRCA', 'Gene', '672', (87, 91))	('S20', 'Gene', (218, 221))	('inversions', 'Var', (37, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('S20', 'Gene', '6224', (218, 221))	('BRCA', 'Gene', (87, 91))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('intrachromosomal variations', 'Var', (52, 79))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
116439	32160708	A recent report on the transcriptional costs of structural variation in breast cancer identified the presence of genes in opposite transcriptional orientation resulting in stable antisense transcription.	('antisense transcription', 'MPA', (179, 202))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('structural variation', 'Var', (48, 68))	('transcription', 'biological_process', 'GO:0006351', ('189', '202'))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
116442	32160708	The pervasive expression of antisense transcripts has been reported in many cancers, which accounts for about 38% of the annotated transcripts.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('reported', 'Reg', (59, 67))	('antisense transcripts', 'Var', (28, 49))	('cancers', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
116446	32160708	Nevertheless, BreakDancer was selected as a structural variation detection tool for validation because this tool was able to detect more translocations, deletions, and inversions compared to other popular tools, such as SVDetect, DELLY, and Meerkat.	('translocations', 'Var', (137, 151))	('Meerkat', 'Species', '37032', (241, 248))	('deletions', 'Var', (153, 162))	('inversions', 'Var', (168, 178))
116451	32160708	We also identified several transcriptional read-through fusions that are recurrent in various cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('fusions', 'Var', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
116457	32160708	Our data reconfirm the previous observation that thyroid cancer is one of the cancers that have the highest percentage of recurrent kinase fusions.	('thyroid cancer', 'Phenotype', 'HP:0002890', (49, 63))	('thyroid cancer', 'Disease', (49, 63))	('kinase fusions', 'Var', (132, 146))	('thyroid cancer', 'Disease', 'MESH:D013964', (49, 63))	('fusions', 'Var', (139, 146))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
116461	32160708	Understanding the possible involvement of SMG1 fusions in the accumulation of non-canonical fusions containing antisense transcripts requires further investigation.	('SMG1', 'Gene', '23049', (42, 46))	('fusions', 'Var', (47, 54))	('SMG1', 'Gene', (42, 46))
116464	32160708	It is also interesting that most of the recurrent fusions (78%) were recurrent only within breast cancer and are not found in other TCGA cancer samples (Table S2).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('fusions', 'Var', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (98, 104))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
116466	32160708	In addition, TP53 mutations were almost doubled in patients with low fusions, indicating that mutations on major oncogenes might be mutually exclusive with fusions.	('TP53', 'Gene', (13, 17))	('patients', 'Species', '9606', (51, 59))	('low fusions', 'Var', (65, 76))	('TP53', 'Gene', '7157', (13, 17))	('doubled', 'PosReg', (40, 47))	('mutations', 'Var', (18, 27))
116467	32160708	A recent study also found that fusions and mutations in driver genes are mutually exclusive across cancer types in TGCA.	('TGCA', 'Disease', (115, 119))	('cancer type', 'Disease', 'MESH:D009369', (99, 110))	('cancer type', 'Disease', (99, 110))	('fusions', 'Var', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
116468	32160708	Analysis of fusions in 802 tumor-derived cell lines from CCLE using ChimeRScope revealed a high frequency of recurrent fusions across several cell lines irrespective of the tissue of origin.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('fusions', 'Var', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('CCLE', 'Chemical', '-', (57, 61))
116469	32160708	Several reports, including a recent study on recurrent fusions across multiple cancer types, also identified fusions that were frequent across cell lines, but the mechanism behind this phenomenon is unexplored.	('cancer type', 'Disease', 'MESH:D009369', (79, 90))	('cancer type', 'Disease', (79, 90))	('fusions', 'Var', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
116471	32160708	We were able to identify only 150 (including both canonical and non-canonical) recurrent fusions that were common between TCGA and CCLE.	('CCLE', 'Disease', (131, 135))	('TCGA', 'Disease', (122, 126))	('fusions', 'Var', (89, 96))	('CCLE', 'Chemical', '-', (131, 135))
116474	32160708	Most of these studies have compared gene expression profiles, copy number variations, and mutation profiles but have not investigated the differences in fusion profiles among the primary tumor and tumor-derived cell lines.	('gene expression', 'MPA', (36, 51))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('copy number variations', 'Var', (62, 84))	('gene expression', 'biological_process', 'GO:0010467', ('36', '51'))
116477	32160708	Our analysis using ChimeRScope identified several recurrent fusion transcripts that are common across cancers, reemphasizing the need for identifying therapy focused on actionable targets.	('fusion', 'Var', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))
116516	32160708	Gene set enrichment analysis (GSEA) was used to identify enriched upregulated and downregulated pathways among the high and low fusion groups.	('high', 'Var', (115, 119))	('downregulated', 'NegReg', (82, 95))	('upregulated', 'PosReg', (66, 77))	('low', 'NegReg', (124, 127))	('GSEA', 'Chemical', '-', (30, 34))
116541	27664126	The role of adjuvant chemotherapy is more controversial but a meta-analysis of nine randomized trials and a large observational study suggested Disease-Free Survival and Overall Survival (OS) benefits for the patients who received cisplatin-based adjuvant chemotherapy.	('Disease-Free Survival', 'CPA', (144, 165))	('cisplatin-based', 'Var', (231, 246))	('Overall Survival', 'CPA', (170, 186))	('cisplatin', 'Chemical', 'MESH:D002945', (231, 240))	('benefits', 'PosReg', (192, 200))	('patients', 'Species', '9606', (209, 217))	('OS', 'Chemical', '-', (188, 190))
116767	21468353	The first term describes the bending energy due to the mismatch between the membrane curvature and the spontaneous curvature of the CTB-GM1 complex.	('CTB', 'Gene', (132, 135))	('bending energy', 'MPA', (29, 43))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('membrane', 'cellular_component', 'GO:0016020', ('76', '84'))	('mismatch', 'Var', (55, 63))	('CTB', 'Gene', '1486', (132, 135))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('n', 'Chemical', 'MESH:D009584', (106, 107))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('GM1', 'Chemical', 'MESH:D005677', (136, 139))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('membrane curvature', 'biological_process', 'GO:0097753', ('76', '94'))
116775	21468353	Results of our numerical simulations revealed that the coupling between the CTB-GM1 density and the membrane curvature led to the formation of membrane protrusions, which coalesced into a larger membrane protrusion (Figure 6).	('n', 'Chemical', 'MESH:D009584', (161, 162))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('n', 'Chemical', 'MESH:D009584', (106, 107))	('n', 'Chemical', 'MESH:D009584', (201, 202))	('GM1', 'Chemical', 'MESH:D005677', (80, 83))	('CTB', 'Gene', '1486', (76, 79))	('membrane', 'cellular_component', 'GO:0016020', ('100', '108'))	('led to', 'Reg', (119, 125))	('formation', 'biological_process', 'GO:0009058', ('130', '139'))	('membrane', 'cellular_component', 'GO:0016020', ('143', '151'))	('n', 'Chemical', 'MESH:D009584', (15, 16))	('n', 'Chemical', 'MESH:D009584', (213, 214))	('n', 'Chemical', 'MESH:D009584', (182, 183))	('membrane curvature', 'biological_process', 'GO:0097753', ('100', '118'))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('CTB', 'Gene', (76, 79))	('coupling', 'Interaction', (55, 63))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('membrane', 'cellular_component', 'GO:0016020', ('195', '203'))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('density', 'Var', (84, 91))
116800	21468353	Accordingly, we propose that the aggregation of GM1 molecules may generate the positive membrane curvature mediating the initial growth of membrane nanotubes (Figures 5 and 6).	('n', 'Chemical', 'MESH:D009584', (170, 171))	('n', 'Chemical', 'MESH:D009584', (148, 149))	('positive membrane curvature', 'MPA', (79, 106))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('GM1', 'Gene', (48, 51))	('membrane curvature', 'biological_process', 'GO:0097753', ('88', '106'))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('membrane', 'cellular_component', 'GO:0016020', ('139', '147'))	('aggregation', 'Var', (33, 44))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('membrane', 'cellular_component', 'GO:0016020', ('88', '96'))	('GM1', 'Chemical', 'MESH:D005677', (48, 51))	('n', 'Chemical', 'MESH:D009584', (94, 95))	('n', 'Chemical', 'MESH:D009584', (114, 115))	('n', 'Chemical', 'MESH:D009584', (145, 146))
116807	21468353	The present dynamic model shows that a positive spontaneous curvature of CTB-GM1 could drive a positive feedback loop in which the aggregation of CTB-GM1 complexes would not only bend the membrane but also lead to further attraction of CTB-GM1 complexes.	('n', 'Chemical', 'MESH:D009584', (194, 195))	('GM1', 'Chemical', 'MESH:D005677', (150, 153))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('n', 'Chemical', 'MESH:D009584', (231, 232))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('CTB', 'Gene', '1486', (146, 149))	('CTB', 'Gene', (236, 239))	('GM1', 'Chemical', 'MESH:D005677', (77, 80))	('n', 'Chemical', 'MESH:D009584', (175, 176))	('membrane', 'cellular_component', 'GO:0016020', ('188', '196'))	('CTB', 'Gene', '1486', (73, 76))	('membrane', 'MPA', (188, 196))	('attraction', 'PosReg', (222, 232))	('n', 'Chemical', 'MESH:D009584', (181, 182))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('bend', 'PosReg', (179, 183))	('CTB', 'Gene', (146, 149))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('aggregation', 'Var', (131, 142))	('CTB', 'Gene', '1486', (236, 239))	('lead to', 'Reg', (206, 213))	('GM1', 'Chemical', 'MESH:D005677', (240, 243))	('CTB', 'Gene', (73, 76))	('n', 'Chemical', 'MESH:D009584', (170, 171))
116813	21468353	Besides the curvature-generation mechanism of GM1s initiating the formation of membrane nanotubes, GM1s may also have an indirect effect through the recruitment of I-BAR domain proteins attached to the inner membrane surface (Figure 8).	('n', 'Chemical', 'MESH:D009584', (74, 75))	('membrane', 'cellular_component', 'GO:0016020', ('208', '216'))	('GM1s', 'Var', (99, 103))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('n', 'Chemical', 'MESH:D009584', (88, 89))	('n', 'Chemical', 'MESH:D009584', (175, 176))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('I-BAR domain proteins', 'Protein', (164, 185))	('GM1s', 'Chemical', 'MESH:D005677', (99, 103))	('membrane', 'cellular_component', 'GO:0016020', ('79', '87'))	('n', 'Chemical', 'MESH:D009584', (183, 184))	('n', 'Chemical', 'MESH:D009584', (214, 215))	('formation', 'biological_process', 'GO:0009058', ('66', '75'))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('n', 'Chemical', 'MESH:D009584', (158, 159))	('recruitment', 'PosReg', (149, 160))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('n', 'Chemical', 'MESH:D009584', (204, 205))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('GM1s', 'Chemical', 'MESH:D005677', (46, 50))	('n', 'Chemical', 'MESH:D009584', (203, 204))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('n', 'Chemical', 'MESH:D009584', (52, 53))
116817	21468353	To conclude, the outward membrane bending during the initial growth of a membrane nanotube may be generated by GM1s and I-BARs at the outer and inner leaflets of cell membranes, respectively.	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('outward membrane bending', 'CPA', (17, 41))	('membrane', 'cellular_component', 'GO:0016020', ('25', '33'))	('n', 'Chemical', 'MESH:D009584', (145, 146))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('membrane nanotube', 'cellular_component', 'GO:0035230', ('73', '90'))	('GM1s', 'Var', (111, 115))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('n', 'Chemical', 'MESH:D009584', (173, 174))	('n', 'Chemical', 'MESH:D009584', (84, 85))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('GM1s', 'Chemical', 'MESH:D005677', (111, 115))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('n', 'Chemical', 'MESH:D009584', (146, 147))	('membrane bending', 'biological_process', 'GO:0097753', ('25', '41'))
116852	21468353	The first term gives the bending energy due to the mismatch between the membrane curvature and the spontaneous curvature of a CTB-GM1 complex.	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('membrane', 'cellular_component', 'GO:0016020', ('72', '80'))	('mismatch', 'Var', (51, 59))	('GM1', 'Chemical', 'MESH:D005677', (130, 133))	('CTB', 'Gene', (126, 129))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('n', 'Chemical', 'MESH:D009584', (66, 67))	('membrane curvature', 'biological_process', 'GO:0097753', ('72', '90'))	('CTB', 'Gene', '1486', (126, 129))	('bending energy', 'MPA', (25, 39))
116862	21468353	The following is the list of parameter values incorporated in our model: xi = 125 s-1gr, D = 0.002 mum2s-1, Lambda = D/kBT, alpha = 0.013 gr s-2, gamma = 0.0004 grs-2, ns = 10 mum-2, k = 100 kBT, H = 5 mum-1, J = 0.00035 grs-2, and sigma = 0.001 grs-2.	('H = 5 mum-1', 'Var', (196, 207))	('grs-2', 'Gene', '26003', (221, 226))	('n', 'Chemical', 'MESH:D009584', (60, 61))	('ns = 10 mum-2', 'Var', (168, 181))	('grs-2', 'Gene', '26003', (246, 251))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('D = 0.002 mum2s-1', 'Var', (89, 106))	('grs-2', 'Gene', '26003', (161, 166))	('grs-2', 'Gene', (221, 226))	('n', 'Chemical', 'MESH:D009584', (229, 230))	('n', 'Chemical', 'MESH:D009584', (168, 169))	('grs-2', 'Gene', (246, 251))	('grs-2', 'Gene', (161, 166))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('k = 100 kBT', 'Var', (183, 194))
116888	21468353	In this case the change in the density due to length changes is removed, as it is assumed to be balanced by the currents into/out of the reservoir.	('n', 'Chemical', 'MESH:D009584', (1, 2))	('changes', 'Var', (53, 60))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('n', 'Chemical', 'MESH:D009584', (20, 21))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('density', 'MPA', (31, 38))	('n', 'Chemical', 'MESH:D009584', (25, 26))
116895	21468353	The first and second derivatives of the function along the x direction were calculated using the following explicit Euler method: where the subscripts n, n+1, n-1 represent the current, next, and previous nodes, respectively.	('n', 'Chemical', 'MESH:D009584', (170, 171))	('n+1', 'Var', (154, 157))	('n', 'Chemical', 'MESH:D009584', (205, 206))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('n', 'Chemical', 'MESH:D009584', (154, 155))	('n-1', 'Var', (159, 162))	('n', 'Chemical', 'MESH:D009584', (186, 187))	('n', 'Chemical', 'MESH:D009584', (42, 43))	('n', 'Chemical', 'MESH:D009584', (151, 152))	('n', 'Chemical', 'MESH:D009584', (182, 183))	('n', 'Chemical', 'MESH:D009584', (18, 19))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('n', 'Chemical', 'MESH:D009584', (159, 160))	('n', 'Chemical', 'MESH:D009584', (193, 194))
116908	32658903	Late stage breast cancer patients expressing PKClambdahigh and ALDH1A3high had poorer disease-specific survival than those expressing PKClambdalow and ALDH1A3low (p = 0.018, log rank test for Kaplan-Meier survival curves: hazard ratio 2.58, 95% CI 1.24-5.37, p = 0.011, multivariate Cox regression analysis).	('PKClambda', 'Gene', (134, 143))	('ALDH', 'molecular_function', 'GO:0004030', ('63', '67'))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('poorer', 'NegReg', (79, 85))	('ALDH', 'molecular_function', 'GO:0004030', ('151', '155'))	('PKClambda', 'Gene', '18759', (134, 143))	('PKClambdahigh', 'Disease', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancer', 'Disease', (11, 24))	('disease-specific survival', 'CPA', (86, 111))	('ALDH1A3high', 'Var', (63, 74))	('patients', 'Species', '9606', (25, 33))	('PKClambda', 'Gene', (45, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('PKClambdahigh', 'Disease', 'None', (45, 58))	('PKClambda', 'Gene', '18759', (45, 54))
116909	32658903	Functional inhibition of PKClambda through siRNA-mediated knockdown or CRISPR-Cas9-mediated knockout in ALDH1high MDA-MB 157 and MDA-MB 468 basal-like breast cancer cells led to increases in the numbers of trypan blue-positive and active-caspase 3-positive cells, as well as suppression of tumor-sphere formation and cell migration.	('trypan blue', 'Chemical', 'MESH:D014343', (206, 217))	('cell migration', 'biological_process', 'GO:0016477', ('317', '331'))	('knockout', 'Var', (92, 100))	('ALDH', 'molecular_function', 'GO:0004030', ('104', '108'))	('ALDH1high', 'Gene', (104, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('MDA-MB 157', 'CellLine', 'CVCL:0618', (114, 124))	('increases', 'PosReg', (178, 187))	('tumor', 'Disease', (290, 295))	('MDA-MB 468', 'CellLine', 'CVCL:0419', (129, 139))	('caspase 3', 'Gene', (238, 247))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('Cas', 'cellular_component', 'GO:0005650', ('78', '81'))	('breast cancer', 'Disease', (151, 164))	('caspase 3', 'Gene', '836', (238, 247))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('suppression', 'NegReg', (275, 286))	('formation', 'biological_process', 'GO:0009058', ('303', '312'))	('cell migration', 'CPA', (317, 331))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('inhibition', 'NegReg', (11, 21))	('trypan blue-positive', 'MPA', (206, 226))	('PKClambda', 'Gene', (25, 34))	('PKClambda', 'Gene', '18759', (25, 34))
116912	32658903	In addition, PKClambda knockdown led to increases in cellular ROS levels in ALDH1high cells.	('ALDH', 'molecular_function', 'GO:0004030', ('76', '80'))	('ROS', 'Chemical', 'MESH:D017382', (62, 65))	('PKClambda', 'Gene', (13, 22))	('knockdown', 'Var', (23, 32))	('cellular ROS levels', 'MPA', (53, 72))	('PKClambda', 'Gene', '18759', (13, 22))	('increases', 'PosReg', (40, 49))
116926	32658903	For example, CSCs make up the metastatic niche and generate bulk tumor at distant organs.	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('CSCs', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))
116953	32658903	Expression of PKClambda mRNA (reporter: A_23_P18392) and PKCzeta mRNA (A_23_P51186) was compared between normal and cancerous tissues, both of which were available from TCGA breast cancer dataset, using the Wilcoxon signed rank test.	('A_23_P51186', 'Var', (71, 82))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('cancerous', 'Disease', 'MESH:D009369', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('PKCzeta', 'molecular_function', 'GO:0004697', ('57', '64'))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('PKCzeta', 'Gene', (57, 64))	('PKClambda', 'Gene', (14, 23))	('PKCzeta', 'Gene', '5590', (57, 64))	('cancerous', 'Disease', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('PKClambda', 'Gene', '18759', (14, 23))
116970	32658903	To detect ALDH1A3, Akt, pS473-Akt, pT308-Akt, p44/42 MAPK, p-p44/42 MAPK, PKClambda, and beta-actin, aliquots of cell lysate containing approximately 20 mug of total proteins were subjected to SDS-PAGE (8% or 12% gel) and transferred (2 mA/cm2, 1 h) to Immobilon-P PVDF membranes (Milipore, IPVH00010).	('pS473-Akt', 'Var', (24, 33))	('p44', 'Gene', (46, 49))	('SDS', 'Chemical', 'MESH:D012967', (193, 196))	('MAPK', 'molecular_function', 'GO:0004707', ('53', '57'))	('PKClambda', 'Gene', '18759', (74, 83))	('p44', 'Gene', (61, 64))	('p44', 'Gene', '10561', (46, 49))	('ALDH', 'molecular_function', 'GO:0004030', ('10', '14'))	('ALDH1A3', 'Gene', (10, 17))	('PVDF', 'Chemical', 'MESH:C024865', (265, 269))	('mug', 'molecular_function', 'GO:0043739', ('153', '156'))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))	('p44', 'Gene', '10561', (61, 64))	('PKClambda', 'Gene', (74, 83))
116979	32658903	PKClambda knockdown in breast cancer cell lines was achieved by transfection of siRNAs (SIGMA) as previously described.	('breast cancer', 'Disease', (23, 36))	('transfection', 'Var', (64, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('PKClambda', 'Gene', (0, 9))	('PKClambda', 'Gene', '18759', (0, 9))	('siRNAs', 'Gene', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
116985	32658903	To stain for cleaved (active) caspase-3, ALDH1high cells were isolated after knock down PKClambda for 48 h using targeted siRNA and then plated for 24 h in 8-well Lab-Tek chambers (Thermo) at a density of 5 x 103 cells/well.	('Tek', 'Gene', (167, 170))	('ALDH', 'molecular_function', 'GO:0004030', ('41', '45'))	('PKClambda', 'Gene', '18759', (88, 97))	('knock down', 'Var', (77, 87))	('Tek', 'Gene', '7010', (167, 170))	('PKClambda', 'Gene', (88, 97))
117003	32658903	Earlier immunohistochemical analyses showed that PKClambda protein is overexpressed in a variety of human cancers, including breast cancer, and that amplification of its gene occurs in lung and ovarian cancers.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('PKClambda', 'Gene', '18759', (49, 58))	('occurs', 'Reg', (175, 181))	('amplification', 'Var', (149, 162))	('lung and ovarian cancers', 'Disease', 'MESH:D055370', (185, 209))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('ovarian cancers', 'Phenotype', 'HP:0100615', (194, 209))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Disease', (125, 138))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('protein', 'Protein', (59, 66))	('overexpressed', 'PosReg', (70, 83))	('human', 'Species', '9606', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancers', 'Disease', (202, 209))	('PKClambda', 'Gene', (49, 58))
117005	32658903	We first compared PKClambda gene alterations in breast cancers to those in lung and ovarian cancers.	('ovarian cancers', 'Phenotype', 'HP:0100615', (84, 99))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('breast cancers', 'Phenotype', 'HP:0003002', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancers', 'Disease', 'MESH:D001943', (48, 62))	('breast cancers', 'Disease', (48, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('PKClambda', 'Gene', (18, 27))	('alterations', 'Var', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('lung and ovarian cancers', 'Disease', 'MESH:D055370', (75, 99))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('PKClambda', 'Gene', '18759', (18, 27))
117007	32658903	In addition, there are few genetic mutations (0.1% in TCGA) and no deletions (0% in TCGA and METABRIC) in the breast cancer datasets.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('TCGA', 'Gene', (54, 58))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('breast cancer', 'Disease', (110, 123))	('genetic mutations', 'Var', (27, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
117026	32658903	Multivariate analysis of DSS showed that patients expressing only PKClambdahigh (HR 1.91, 95% CI 1.18-3.08, p = 0.0079) or both PKClambdahigh and ALDH1A3high (HR 2.58, 95% CI 1.24-5.37, p = 0.011) had poorer prognoses at stages III-IV (Fig 2C).	('DSS', 'Chemical', '-', (25, 28))	('ALDH', 'molecular_function', 'GO:0004030', ('146', '150'))	('ALDH1A3high', 'Var', (146, 157))	('patients', 'Species', '9606', (41, 49))	('PKClambdahigh', 'Disease', (66, 79))	('PKClambdahigh', 'Disease', (128, 141))	('PKClambdahigh', 'Disease', 'None', (66, 79))	('PKClambdahigh', 'Disease', 'None', (128, 141))	('stages III-IV', 'Disease', (221, 234))
117032	32658903	Therefore, to further investigate the role of PKClambda in ALDH1-positive CSCs, we used two methods to inhibit the enzyme: siRNA-mediated knockdown (KD) and CRISPR-Cas9-mediated knockout (KO).	('knockdown', 'Var', (138, 147))	('PKClambda', 'Gene', '18759', (46, 55))	('ALDH', 'molecular_function', 'GO:0004030', ('59', '63'))	('Cas', 'cellular_component', 'GO:0005650', ('164', '167'))	('PKClambda', 'Gene', (46, 55))	('ALDH1-positive', 'Gene', (59, 73))	('KD', 'Disease', 'MESH:C537017', (149, 151))	('inhibit', 'NegReg', (103, 110))
117036	32658903	PKClambda depletion in ALDH1high cells led to decreases in both the number and size of tumor-spheres (Fig 3F-3H).	('ALDH', 'molecular_function', 'GO:0004030', ('23', '27'))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('PKClambda', 'Gene', (0, 9))	('tumor', 'Disease', (87, 92))	('depletion', 'Var', (10, 19))	('decreases', 'NegReg', (46, 55))	('PKClambda', 'Gene', '18759', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('ALDH1high', 'Gene', (23, 32))
117041	32658903	We found that PKClambda depletion in ALDH1high cells led to a decrease in the number of migrated cells (Fig 3I), which suggests that PKClambda is required for ALDH1-positive basal-like breast CSC migration.	('ALDH', 'molecular_function', 'GO:0004030', ('159', '163'))	('basal-like breast CSC migration', 'CPA', (174, 205))	('PKClambda', 'Gene', '18759', (133, 142))	('PKClambda', 'Gene', (14, 23))	('depletion', 'Var', (24, 33))	('ALDH1high', 'Gene', (37, 46))	('decrease', 'NegReg', (62, 70))	('number of migrated cells', 'CPA', (78, 102))	('ALDH', 'molecular_function', 'GO:0004030', ('37', '41'))	('PKClambda', 'Gene', '18759', (14, 23))	('PKClambda', 'Gene', (133, 142))
117042	32658903	To determine the reason why PKClambda depletion led to decreases in the number of ALDH1high cells and in tumor-sphere formation by ALDH1high cells, we performed trypan blue assays with PKClambda-depleted ALDH1high cells.	('trypan blue', 'Chemical', 'MESH:D014343', (161, 172))	('PKClambda', 'Gene', '18759', (28, 37))	('PKClambda', 'Gene', (185, 194))	('ALDH', 'molecular_function', 'GO:0004030', ('131', '135'))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('PKClambda', 'Gene', (28, 37))	('decreases', 'NegReg', (55, 64))	('depletion', 'Var', (38, 47))	('formation', 'biological_process', 'GO:0009058', ('118', '127'))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('ALDH', 'molecular_function', 'GO:0004030', ('204', '208'))	('ALDH', 'molecular_function', 'GO:0004030', ('82', '86'))	('PKClambda', 'Gene', '18759', (185, 194))	('tumor', 'Disease', (105, 110))
117046	32658903	The levels of phospho-Akt (T308) were differed in between ALDH1high PKClambda KD MDA-MB468 cells and PKClambda KO cells (S3 Fig).	('PKClambda', 'Gene', '18759', (101, 110))	('ALDH', 'molecular_function', 'GO:0004030', ('58', '62'))	('PKClambda', 'Gene', (68, 77))	('ALDH1high', 'Var', (58, 67))	('MDA-MB468', 'CellLine', 'CVCL:0419', (81, 90))	('PKClambda', 'Gene', (101, 110))	('PKClambda', 'Gene', '18759', (68, 77))	('PKClambda KD', 'Disease', (68, 80))	('PKClambda KD', 'Disease', 'MESH:C537017', (68, 80))
117049	32658903	To determine more specifically how PKClambda depletion led to an increase in ALDH1high cell death, we next considered whether PKClambda contributes to apoptosis in ALDH1high cells.	('PKClambda', 'Gene', (126, 135))	('apoptosis', 'biological_process', 'GO:0097194', ('151', '160'))	('apoptosis', 'biological_process', 'GO:0006915', ('151', '160'))	('ALDH', 'molecular_function', 'GO:0004030', ('77', '81'))	('PKClambda', 'Gene', (35, 44))	('ALDH1high cell death', 'CPA', (77, 97))	('ALDH', 'molecular_function', 'GO:0004030', ('164', '168'))	('cell death', 'biological_process', 'GO:0008219', ('87', '97'))	('PKClambda', 'Gene', '18759', (126, 135))	('depletion', 'Var', (45, 54))	('PKClambda', 'Gene', '18759', (35, 44))
117051	32658903	PKClambda depletion also led to higher levels of cleaved caspase-3 protein (Fig 4B) as well as higher levels Casp3 and PARP mRNA in ALDH1high cells (Fig 4C and 4D).	('Casp3', 'Gene', '836', (109, 114))	('ALDH', 'molecular_function', 'GO:0004030', ('132', '136'))	('PARP', 'Gene', (119, 123))	('PKClambda', 'Gene', (0, 9))	('higher', 'PosReg', (32, 38))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('higher', 'PosReg', (95, 101))	('levels', 'MPA', (39, 45))	('depletion', 'Var', (10, 19))	('Casp3', 'Gene', (109, 114))	('PKClambda', 'Gene', '18759', (0, 9))	('cleaved caspase-3', 'MPA', (49, 66))	('PARP', 'Gene', '1302', (119, 123))
117058	32658903	PKClambda was detected in both the asymmetric and symmetric fractions (High/Low, 19.4%; High/High, 59.1%; Low/Low, 21.5%) (Fig 5A and 5B).	('High/High', 'Var', (88, 97))	('PKClambda', 'Gene', '18759', (0, 9))	('PKClambda', 'Gene', (0, 9))
117063	32658903	Interestingly, PKClambda depletion caused a decrease in the asymmetric distribution of ALDH1A3 (High/Low; 17.3% to 8.4%) and an increase in the symmetric distribution (High/High, 35.7% to 45.8%; Low/Low, 36.9% to 55.9%) (Fig 5E).	('increase', 'PosReg', (128, 136))	('decrease', 'NegReg', (44, 52))	('asymmetric distribution', 'MPA', (60, 83))	('symmetric distribution', 'MPA', (144, 166))	('PKClambda', 'Gene', '18759', (15, 24))	('ALDH1A3', 'Gene', (87, 94))	('depletion', 'Var', (25, 34))	('ALDH', 'molecular_function', 'GO:0004030', ('87', '91'))	('PKClambda', 'Gene', (15, 24))
117069	32658903	In MDA-MB 468 cells, ROS levels did not differ between ALDH1high and ALDH1low cells.	('ROS', 'Chemical', 'MESH:D017382', (21, 24))	('ALDH', 'molecular_function', 'GO:0004030', ('69', '73'))	('MDA-MB 468', 'CellLine', 'CVCL:0419', (3, 13))	('ALDH1high', 'Var', (55, 64))	('ROS', 'MPA', (21, 24))	('ALDH', 'molecular_function', 'GO:0004030', ('55', '59'))
117071	32658903	In addition, we proposed that depletion PKClambda may lead to enhanced expression of ROS defense genes, including SOD1, SOD2 and Gpx1, in response to ROS accumulation.	('expression', 'MPA', (71, 81))	('PKClambda', 'Gene', (40, 49))	('SOD1', 'molecular_function', 'GO:0004784', ('114', '118'))	('depletion', 'Var', (30, 39))	('ROS defense genes', 'Gene', (85, 102))	('Gpx1', 'Gene', (129, 133))	('enhanced', 'PosReg', (62, 70))	('SOD1', 'Gene', (114, 118))	('SOD1', 'Gene', '6647', (114, 118))	('PKClambda', 'Gene', '18759', (40, 49))	('SOD2', 'molecular_function', 'GO:0004784', ('120', '124'))	('response to ROS', 'biological_process', 'GO:0000302', ('138', '153'))	('Gpx1', 'Gene', '2876', (129, 133))	('SOD2', 'Gene', '6648', (120, 124))	('SOD2', 'Gene', (120, 124))	('ROS', 'Chemical', 'MESH:D017382', (85, 88))	('ROS', 'Chemical', 'MESH:D017382', (150, 153))
117074	32658903	Our findings show that breast cancer patients expressing both PKClambdahigh and ALDH1A3high exhibit poorer clinical outcomes at late-stage than those expressing PKClambdalow and ALDH1A3low (Fig 2B and 2C).	('breast cancer', 'Disease', (23, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('ALDH', 'molecular_function', 'GO:0004030', ('80', '84'))	('PKClambda', 'Gene', (161, 170))	('patients', 'Species', '9606', (37, 45))	('PKClambda', 'Gene', (62, 71))	('PKClambdahigh', 'Disease', (62, 75))	('poorer', 'NegReg', (100, 106))	('PKClambda', 'Gene', '18759', (161, 170))	('ALDH1A3high', 'Var', (80, 91))	('clinical outcomes', 'CPA', (107, 124))	('PKClambdahigh', 'Disease', 'None', (62, 75))	('ALDH', 'molecular_function', 'GO:0004030', ('178', '182'))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('PKClambda', 'Gene', '18759', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
117087	32658903	As shown in Fig 2A, PKClambda, MET, NOTCH1, CD133, MYC, ALDH1A3, NOTCH3, OCT4, and CD44 were all enriched in stage III-IV basal-like breast cancers.	('OCT4', 'Gene', (73, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('breast cancers', 'Disease', 'MESH:D001943', (133, 147))	('MYC', 'Gene', (51, 54))	('breast cancers', 'Disease', (133, 147))	('breast cancers', 'Phenotype', 'HP:0003002', (133, 147))	('PKClambda', 'Gene', (20, 29))	('PKClambda', 'Gene', '18759', (20, 29))	('MYC', 'Gene', '4609', (51, 54))	('ALDH1A3', 'Gene', (56, 63))	('ALDH', 'molecular_function', 'GO:0004030', ('56', '60'))	('MET', 'Var', (31, 34))	('NOTCH1', 'Gene', (36, 42))	('NOTCH3', 'Gene', '4854', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('NOTCH1', 'Gene', '4851', (36, 42))	('OCT4', 'Gene', '5460', (73, 77))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('CD44', 'Gene', '960', (83, 87))	('NOTCH3', 'Gene', (65, 71))	('CD133', 'Gene', (44, 49))	('CD133', 'Gene', '8842', (44, 49))	('CD44', 'Gene', (83, 87))
117092	32658903	Immunohistochemical studies indicate that patients exhibiting high PKClambda expression have poor prognoses in a variety of cancers.	('PKClambda', 'Gene', (67, 76))	('PKClambda', 'Gene', '18759', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('high', 'Var', (62, 66))	('patients', 'Species', '9606', (42, 50))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
117101	32658903	Nonetheless, late-stage breast cancer patients expressing PKCzetahigh and ALDH1A3high had poorer clinical outcomes than patients expressing PKCzetalow and ALDH1A3high (S6 Fig).	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('poorer', 'NegReg', (90, 96))	('breast cancer', 'Disease', (24, 37))	('ALDH', 'molecular_function', 'GO:0004030', ('155', '159'))	('PKCzeta', 'Gene', (140, 147))	('PKCzeta', 'Gene', '5590', (58, 65))	('patients', 'Species', '9606', (120, 128))	('PKCzeta', 'Gene', (58, 65))	('PKCzeta', 'Gene', '5590', (140, 147))	('patients', 'Species', '9606', (38, 46))	('ALDH', 'molecular_function', 'GO:0004030', ('74', '78'))	('ALDH1A3high', 'Var', (74, 85))
117108	32658903	Deletion of PKClambda suppresses migration of MDA-MB 231, a TNBC cell line.	('suppresses', 'NegReg', (22, 32))	('MDA-MB', 'CellLine', 'CVCL:0062', (46, 52))	('PKClambda', 'Gene', '18759', (12, 21))	('migration', 'CPA', (33, 42))	('PKClambda', 'Gene', (12, 21))	('Deletion', 'Var', (0, 8))
117113	32658903	In addition, PI3K activates PKClambda.	('PI3K', 'Var', (13, 17))	('PKClambda', 'Gene', (28, 37))	('PI3K', 'molecular_function', 'GO:0016303', ('13', '17'))	('PKClambda', 'Gene', '18759', (28, 37))	('activates', 'PosReg', (18, 27))
117128	32658903	Inhibition of ALDH1 in breast cancer cells is associated with increased ROS levels.	('breast cancer', 'Disease', (23, 36))	('increased', 'PosReg', (62, 71))	('ALDH', 'molecular_function', 'GO:0004030', ('14', '18'))	('increased ROS levels', 'Phenotype', 'HP:0025464', (62, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('ROS levels', 'MPA', (72, 82))	('ROS', 'Chemical', 'MESH:D017382', (72, 75))	('Inhibition', 'Var', (0, 10))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('ALDH1', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
117139	32658903	On the other hand, PKClambda knockdown suppressed ROS levels in MDA-MB157 ALDH1low cells, but did not change ROS levels in MDA-MB 468 ALDH1low cells (Fig 6).	('ALDH', 'molecular_function', 'GO:0004030', ('74', '78'))	('knockdown', 'Var', (29, 38))	('PKClambda', 'Gene', '18759', (19, 28))	('ROS', 'Chemical', 'MESH:D017382', (50, 53))	('MDA-MB 468', 'CellLine', 'CVCL:0419', (123, 133))	('ROS levels', 'MPA', (50, 60))	('ALDH', 'molecular_function', 'GO:0004030', ('134', '138'))	('PKClambda', 'Gene', (19, 28))	('ROS', 'Chemical', 'MESH:D017382', (109, 112))	('suppressed', 'NegReg', (39, 49))	('MDA-MB157 ALDH1', 'CellLine', 'CVCL:0618', (64, 79))
117142	32658903	PKClambda depletion in ALDH1high cells leads to increases in the numbers of apoptotic and dead cells (Fig 3J, 3K and Fig 4) and a corresponding increase in intracellular ROS (Fig 6).	('ALDH', 'molecular_function', 'GO:0004030', ('23', '27'))	('increases', 'PosReg', (48, 57))	('PKClambda', 'Gene', (0, 9))	('intracellular ROS', 'MPA', (156, 173))	('depletion', 'Var', (10, 19))	('PKClambda', 'Gene', '18759', (0, 9))	('ROS', 'Chemical', 'MESH:D017382', (170, 173))	('ALDH1high', 'Gene', (23, 32))	('increase', 'PosReg', (144, 152))	('intracellular', 'cellular_component', 'GO:0005622', ('156', '169'))
117147	32658903	In this study, we have shown that patients with stage III-IV breast cancer expressing PKClambdahigh and ALDH1A3high have poorer clinical outcomes than those expressing PKClambdalow and ALDH1A3low.	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('PKClambda', 'Gene', '18759', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('ALDH', 'molecular_function', 'GO:0004030', ('185', '189'))	('poorer', 'NegReg', (121, 127))	('ALDH', 'molecular_function', 'GO:0004030', ('104', '108'))	('PKClambda', 'Gene', (168, 177))	('ALDH1A3high', 'Var', (104, 115))	('PKClambda', 'Gene', (86, 95))	('PKClambdahigh', 'Disease', (86, 99))	('patients', 'Species', '9606', (34, 42))	('PKClambda', 'Gene', '18759', (168, 177))	('PKClambdahigh', 'Disease', 'None', (86, 99))
117150	30987093	Methylation of SPARCL1 Is Associated with Oncologic Outcome of Advanced Upper Urinary Tract Urothelial Carcinoma Advanced upper urinary tract urothelial carcinoma (UTUC) is often associated with poor oncologic outcomes.	('upper urinary tract urothelial carcinoma', 'Disease', 'MESH:D014552', (122, 162))	('Methylation', 'Var', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('Carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('SPARCL1', 'Gene', '8404', (15, 22))	('SPARCL1', 'Gene', (15, 22))	('Advanced Upper Urinary Tract Urothelial Carcinoma', 'Disease', (63, 112))	('Associated', 'Reg', (26, 36))	('upper urinary tract urothelial carcinoma', 'Disease', (122, 162))	('Advanced Upper Urinary Tract Urothelial Carcinoma', 'Disease', 'MESH:D014552', (63, 112))
117167	30987093	It is also a tumour suppressor as it induces cell differentiation possibly via MET, which represses the aggressiveness of CRCs.	('MET', 'Var', (79, 82))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('cell differentiation', 'biological_process', 'GO:0030154', ('45', '65'))	('cell differentiation', 'CPA', (45, 65))	('aggressiveness', 'Disease', 'MESH:D001523', (104, 118))	('represses', 'NegReg', (90, 99))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('tumour', 'Disease', (13, 19))	('aggressiveness', 'Disease', (104, 118))	('aggressiveness', 'Phenotype', 'HP:0000718', (104, 118))
117175	30987093	It has also been reported that DNA methylation is the reason for the downregulation of SPARCL1 and demethylation of the gene partially reversed the abnormal expression in pancreatic cancer and osteosarcoma.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('expression', 'MPA', (157, 167))	('SPARCL1', 'Gene', '8404', (87, 94))	('demethylation', 'Var', (99, 112))	('pancreatic cancer', 'Disease', 'MESH:D010190', (171, 188))	('SPARCL1', 'Gene', (87, 94))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (171, 188))	('demethylation', 'biological_process', 'GO:0070988', ('99', '112'))	('DNA methylation', 'biological_process', 'GO:0006306', ('31', '46'))	('osteosarcoma', 'Phenotype', 'HP:0002669', (193, 205))	('osteosarcoma', 'Disease', (193, 205))	('osteosarcoma', 'Disease', 'MESH:D012516', (193, 205))	('pancreatic cancer', 'Disease', (171, 188))	('downregulation', 'NegReg', (69, 83))	('reversed', 'NegReg', (135, 143))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))
117200	30987093	The migration of BFTC909 cells was significantly enhanced by SPARCL1 knockdown, while overexpression of SPARCL1 inhibited cell migration (Figure 4B), indicating that the tumour behaviour of BFTC909 cells was less aggressive after SPARCL1 overexpression.	('SPARCL1', 'Gene', (61, 68))	('behaviour', 'biological_process', 'GO:0007610', ('177', '186'))	('SPARCL1', 'Gene', '8404', (230, 237))	('SPARCL1', 'Gene', (230, 237))	('cell migration', 'CPA', (122, 136))	('BFTC909', 'CellLine', 'CVCL:1084', (17, 24))	('tumour', 'Disease', (170, 176))	('SPARCL1', 'Gene', (104, 111))	('migration', 'CPA', (4, 13))	('enhanced', 'PosReg', (49, 57))	('SPARCL1', 'Gene', '8404', (104, 111))	('cell migration', 'biological_process', 'GO:0016477', ('122', '136'))	('SPARCL1', 'Gene', '8404', (61, 68))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('BFTC909', 'CellLine', 'CVCL:1084', (190, 197))	('knockdown', 'Var', (69, 78))	('tumour', 'Disease', 'MESH:D009369', (170, 176))
117218	30987093	Therefore, the hypermethylation of tumour suppressor genes may be associated with tumorigenesis due to epigenetic change.	('associated', 'Reg', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('hypermethylation', 'Var', (15, 31))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('epigenetic change', 'Var', (103, 120))	('tumor', 'Disease', (82, 87))	('tumour', 'Disease', (35, 41))
117222	30987093	Pyrosequencing-based analysis of our prospectively collected UTUC and normal urothelial tissue samples further proved significant SPARCL1 hypermethylation in UTUC.	('SPARCL1', 'Gene', (130, 137))	('SPARCL1', 'Gene', '8404', (130, 137))	('hypermethylation', 'Var', (138, 154))
117223	30987093	Such a high prevalence of SPARCL1 hypermethylation in the UTUC samples indicates that the loss of SPARCL1 function might be considered to have clinical utility in the assessment of UTUC behavior.	('hypermethylation', 'Var', (34, 50))	('function', 'MPA', (106, 114))	('loss', 'NegReg', (90, 94))	('SPARCL1', 'Gene', '8404', (98, 105))	('SPARCL1', 'Gene', '8404', (26, 33))	('SPARCL1', 'Gene', (26, 33))	('clinical', 'Species', '191496', (143, 151))	('SPARCL1', 'Gene', (98, 105))
117238	30987093	We examined the status of SPARCL1 methylation status of several UC cell lines and found that SPARCL1 methylation was more common in aggressive UC cell lines.	('SPARCL1', 'Gene', '8404', (93, 100))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('SPARCL1', 'Gene', (93, 100))	('common', 'Reg', (122, 128))	('SPARCL1', 'Gene', '8404', (26, 33))	('SPARCL1', 'Gene', (26, 33))	('methylation', 'Var', (101, 112))	('methylation', 'biological_process', 'GO:0032259', ('101', '112'))
117280	30987093	The primary antibodies were used: SPARCL1 (1:500), Vimentin (1:1000), N-cadherin (1:1000), E-cadherin (1:1000), beta-actin (1:5000) and GAPDH (1:5000).	('Vimentin', 'Gene', (51, 59))	('1:1000', 'Var', (103, 109))	('SPARCL1', 'Gene', '8404', (34, 41))	('SPARCL1', 'Gene', (34, 41))	('beta-actin', 'Gene', '728378', (112, 122))	('N-cadherin', 'Gene', (70, 80))	('beta-actin', 'Gene', (112, 122))	('E-cadherin', 'Gene', (91, 101))	('E-cadherin', 'Gene', '999', (91, 101))	('Vimentin', 'Gene', '7431', (51, 59))	('Vimentin', 'cellular_component', 'GO:0045098', ('51', '59'))	('cadherin', 'molecular_function', 'GO:0008014', ('93', '101'))	('1:1000', 'Var', (82, 88))	('cadherin', 'molecular_function', 'GO:0008014', ('72', '80'))	('GAPDH', 'Protein', (136, 141))	('Vimentin', 'cellular_component', 'GO:0045099', ('51', '59'))	('N-cadherin', 'Gene', '1000', (70, 80))	('1:5000', 'Var', (124, 130))
117289	30987093	Cells of different conditions (Control or SPARCL1 knockdown/overexpression).	('knockdown/overexpression', 'Var', (50, 74))	('SPARCL1', 'Gene', '8404', (42, 49))	('SPARCL1', 'Gene', (42, 49))
117293	30987093	In addition, positive SPARCL1 expression was an independent prognostic biomarker for locally advanced UTUC in our clinical cohort.	('positive', 'Var', (13, 21))	('expression', 'MPA', (30, 40))	('clinical', 'Species', '191496', (114, 122))	('SPARCL1', 'Gene', '8404', (22, 29))	('locally advanced UTUC', 'Disease', (85, 106))	('SPARCL1', 'Gene', (22, 29))
117334	25470039	This is paradoxically followed by a significant increase in IdU+ LRCCs that were simultaneously incorporated with CldU (Fig.	('LRCC', 'Gene', '2271', (65, 69))	('IdU', 'Chemical', '-', (60, 63))	('CldU', 'Chemical', '-', (114, 118))	('IdU+', 'Var', (60, 64))	('LRCC', 'Gene', (65, 69))	('increase', 'PosReg', (48, 56))
117358	25470039	Because more than 70% of patients with advanced bladder cancer do not benefit from neoadjuvant chemotherapy, and celecoxib is a US Food and Drug Administration (FDA)-approved drug, we evaluated whether the attenuation of PGE2 signalling in vivo could enhance chemotherapeutic response (Fig.	('bladder cancer', 'Disease', (48, 62))	('enhance', 'PosReg', (251, 258))	('attenuation', 'Var', (206, 217))	('celecoxib', 'Chemical', 'MESH:D000068579', (113, 122))	('signalling', 'biological_process', 'GO:0023052', ('226', '236'))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('patients', 'Species', '9606', (25, 33))	('PGE2', 'Chemical', 'MESH:D015232', (221, 225))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))	('chemotherapeutic response', 'CPA', (259, 284))	('PGE2', 'Gene', (221, 225))
117446	20610280	The 9p region contains the p16/ARF locus, and studies have confirmed that p16 is frequently inactivated by LOH plus homozygous deletion or methylation independently of stage or grade in both superficial and muscle-invasive bladder cancers.	('muscle-invasive bladder cancers', 'Disease', (207, 238))	('p16', 'Gene', (74, 77))	('invasive bladder', 'Phenotype', 'HP:0100645', (214, 230))	('bladder cancers', 'Phenotype', 'HP:0009725', (223, 238))	('p16', 'Gene', '1029', (27, 30))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('muscle-invasive bladder cancers', 'Disease', 'MESH:D001749', (207, 238))	('bladder cancer', 'Phenotype', 'HP:0009725', (223, 237))	('p16', 'Gene', (27, 30))	('p16', 'Gene', '1029', (74, 77))	('methylation', 'biological_process', 'GO:0032259', ('139', '150'))	('ARF', 'Disease', 'MESH:D058186', (31, 34))	('LOH', 'Var', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('inactivated', 'NegReg', (92, 103))	('ARF', 'Disease', (31, 34))	('methylation', 'Var', (139, 150))
117448	20610280	Given that IFNalpha can induce apoptosis in bladder cancer cells, inactivation of the IFNalpha gene might also contribute to disease progression.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (44, 58))	('bladder cancer', 'Disease', 'MESH:D001749', (44, 58))	('bladder cancer', 'Disease', (44, 58))	('inactivation', 'Var', (66, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('31', '40'))	('IFNalpha', 'Gene', (86, 94))	('IFNalpha', 'Gene', (11, 19))	('IFNalpha', 'Gene', '3439', (11, 19))	('apoptosis', 'biological_process', 'GO:0006915', ('31', '40'))	('contribute', 'Reg', (111, 121))	('IFNalpha', 'Gene', '3439', (86, 94))	('apoptosis', 'CPA', (31, 40))
117450	20610280	Overall, LOH at 9q remains one of the earliest events in bladder cancer progression identified to date.	('bladder cancer', 'Disease', 'MESH:D001749', (57, 71))	('bladder cancer', 'Disease', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('LOH at 9q', 'Var', (9, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))
117452	20610280	Bladder cancer progression appears to involve an accumulation of stereotyped phenotypic and molecular alterations in a manner that is similar to the more familiar progression model developed for colorectal cancers, where progression from adenoma to carcinoma involves accumulation of epigenetic and genetic damage.	('genetic damage', 'Disease', (299, 313))	('colorectal cancers', 'Disease', 'MESH:D015179', (195, 213))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('colorectal cancers', 'Disease', (195, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('epigenetic', 'Var', (284, 294))	('adenoma to carcinoma', 'Disease', 'MESH:D000236', (238, 258))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('accumulation', 'PosReg', (268, 280))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('adenoma to carcinoma', 'Disease', (238, 258))	('cancer', 'Disease', (206, 212))	('genetic damage', 'Disease', 'MESH:D030342', (299, 313))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
117458	20610280	Typically this downregulation involved LOH of one allele and methylation of the other; for example, in cell lines the frequency of ITM2B methylation was approximately 40%.	('LOH', 'Var', (39, 42))	('downregulation', 'NegReg', (15, 29))	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('methylation', 'Var', (137, 148))	('ITM2B', 'Gene', (131, 136))	('ITM2B', 'Gene', '9445', (131, 136))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))
117461	20610280	Interestingly, another group identified a SNP within this same genomic locus (rs2227311) that is predicted to downregulate P2RY5 gene expression and is a risk factor for developing invasive ovarian cancer.	('P2RY5', 'Gene', '10161', (123, 128))	('rs2227311', 'Mutation', 'rs2227311', (78, 87))	('invasive ovarian cancer', 'Disease', 'MESH:D010051', (181, 204))	('expression', 'MPA', (134, 144))	('invasive ovarian cancer', 'Phenotype', 'HP:0025318', (181, 204))	('gene expression', 'biological_process', 'GO:0010467', ('129', '144'))	('P2RY5', 'Gene', (123, 128))	('invasive ovarian cancer', 'Disease', (181, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('rs2227311', 'Var', (78, 87))	('risk factor', 'Reg', (154, 165))	('downregulate', 'NegReg', (110, 122))
117462	20610280	Similarly, a polymorphic site (G1722T) located within the P2RY5 coding sequence was detected in several bladder tumors and non-tumor DNA from the same patient.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('bladder tumors', 'Disease', (104, 118))	('non-tumor', 'Disease', 'MESH:D009369', (123, 132))	('patient', 'Species', '9606', (151, 158))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('P2RY5', 'Gene', (58, 63))	('bladder tumors', 'Phenotype', 'HP:0009725', (104, 118))	('detected', 'Reg', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('G1722T', 'Var', (31, 37))	('G1722T', 'Mutation', 'c.1722G>T', (31, 37))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('non-tumor', 'Disease', (123, 132))	('bladder tumors', 'Disease', 'MESH:D001749', (104, 118))	('P2RY5', 'Gene', '10161', (58, 63))
117467	20610280	In the first, bladder-specific expression of mutant active H-ras led to the development of bladder hyperplasia/dysplasia or papillary tumors in a manner that was related to gene dosage (i.e., high copy numbers induced tumors).	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('H-ras', 'Gene', '3265', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Disease', (134, 140))	('led to', 'Reg', (65, 71))	('papillary tumors', 'Phenotype', 'HP:0007482', (124, 140))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('active', 'Gene', (52, 58))	('papillary tumors', 'Disease', 'MESH:D002291', (124, 140))	('papillary tumors', 'Disease', (124, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('development of bladder hyperplasia', 'Phenotype', 'HP:0008635', (76, 110))	('bladder hyperplasia/dysplasia', 'Disease', 'MESH:D001745', (91, 120))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Disease', (218, 224))	('bladder hyperplasia/dysplasia', 'Disease', (91, 120))	('mutant', 'Var', (45, 51))	('induced', 'PosReg', (210, 217))	('H-ras', 'Gene', (59, 64))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
117468	20610280	When the same promoter was used to drive expression of the SV40 large T antigen (thereby inactivating the p53 and Rb tumor suppressors), mice bearing low copy numbers developed CIS, whereas mice bearing high copy numbers developed muscle-invasive tumors with 100% penetrance.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('CIS', 'Phenotype', 'HP:0030075', (177, 180))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Rb tumor', 'Disease', 'MESH:D009369', (114, 122))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('SV40', 'Var', (59, 63))	('CIS', 'CPA', (177, 180))	('inactivating', 'NegReg', (89, 101))	('p53', 'Protein', (106, 109))	('mice', 'Species', '10090', (190, 194))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (231, 253))	('mice', 'Species', '10090', (137, 141))	('Rb tumor', 'Disease', (114, 122))	('low copy numbers', 'Var', (150, 166))	('muscle-invasive tumors', 'Disease', (231, 253))
117470	20610280	Likewise, complete loss of p53 on the mutant H-ras background accelerated the development of both low-grade and high-grade superficial tumors but did not support the development of muscle-invasive disease.	('mutant', 'Var', (38, 44))	('development', 'CPA', (78, 89))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('loss', 'NegReg', (19, 23))	('H-ras', 'Gene', '3265', (45, 50))	('tumors', 'Disease', (135, 141))	('accelerated', 'PosReg', (62, 73))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('H-ras', 'Gene', (45, 50))	('muscle-invasive disease', 'Disease', (181, 204))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (181, 204))	('p53', 'Gene', (27, 30))
117471	20610280	Again, additional genetic events must be present in the high copy number SV40T mice that drive progression to muscle invasion.	('muscle invasion', 'CPA', (110, 125))	('high copy number SV40T', 'Var', (56, 78))	('mice', 'Species', '10090', (79, 83))	('SV40T', 'Var', (73, 78))
117474	20610280	Similarly, elimination of p53 and PTEN function in human urothelial cells also made them tumorigenic, and the group's own analysis of primary tumors from patients confirmed that PTEN disruption and AKT pathway activation are common features of muscle-invasive disease, consistent with previous studies (see below).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('human', 'Species', '9606', (51, 56))	('muscle-invasive disease', 'Disease', (244, 267))	('PTEN', 'Protein', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('PTEN', 'Protein', (178, 182))	('activation', 'PosReg', (210, 220))	('elimination', 'Var', (11, 22))	('primary tumors', 'Disease', (134, 148))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', (142, 147))	('disruption', 'NegReg', (183, 193))	('patients', 'Species', '9606', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (244, 267))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('primary tumors', 'Disease', 'MESH:D009369', (134, 148))	('AKT pathway', 'Pathway', (198, 209))	('p53', 'Protein', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
117479	20610280	For example, in one cohort of 67 tumors activating codon 12 Hras mutations were detected in almost half.	('activating', 'PosReg', (40, 50))	('Hras', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('mutations', 'Var', (65, 74))
117480	20610280	These mutations were more common in high-grade (II or III) tumors, and 7 contained synchronous mutations at position 2719 of Hras intron D. This phenotype mirrored the mutations in Hras that were previously detected in the human T24 cell line, and in these tumors overall levels of Hras protein were 10-fold higher than were present in tumors that lacked the intron D mutation.	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('tumors', 'Disease', (336, 342))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('protein', 'Protein', (287, 294))	('mutations', 'Var', (168, 177))	('higher', 'PosReg', (308, 314))	('human', 'Species', '9606', (223, 228))	('tumors', 'Disease', 'MESH:D009369', (336, 342))	('Hras', 'Gene', (181, 185))	('protein', 'cellular_component', 'GO:0003675', ('287', '294'))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('levels', 'MPA', (272, 278))	('tumors', 'Phenotype', 'HP:0002664', (336, 342))	('tumors', 'Disease', (257, 263))	('tumors', 'Disease', (59, 65))
117481	20610280	However, in a subsequent study the frequency of activating Hras mutations was much lower, and an even more recent study of 35 consecutive Iranian urothelial tumors failed to identify mutations in Hras, Kras, or Nras in any of them, suggesting that HRas mutational frequencies vary significantly in different populations.	('urothelial tumors', 'Disease', (146, 163))	('Nras', 'Gene', '4893', (211, 215))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('Hras', 'Gene', (196, 200))	('HRas', 'Gene', '3265', (248, 252))	('HRas', 'Gene', (248, 252))	('Kras', 'Gene', (202, 206))	('urothelial tumors', 'Disease', 'MESH:D001749', (146, 163))	('mutations', 'Var', (64, 73))	('Kras', 'Gene', '3845', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('Nras', 'Gene', (211, 215))
117483	20610280	However, the data do not address the issue of whether mutational activation of Hras drives the formation of superficial as opposed to muscle-invasive cancer.	('muscle-invasive cancer', 'Disease', (134, 156))	('formation', 'biological_process', 'GO:0009058', ('95', '104'))	('mutational activation', 'Var', (54, 75))	('Hras', 'Gene', (79, 83))	('muscle-invasive cancer', 'Disease', 'MESH:D009217', (134, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
117486	20610280	Activating mutations in the type 3 receptor for fibroblast growth factors (FGFR3) occur frequently (>= 50%) in superficial but more rarely (<= 20%) in muscle-invasive tumors (P. Black et al, manuscript in preparation).	('FGFR3', 'Gene', (75, 80))	('superficial but', 'Disease', (111, 126))	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('Activating mutations', 'Var', (0, 20))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (151, 173))	('muscle-invasive tumors', 'Disease', (151, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('FGFR3', 'Gene', '2261', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
117487	20610280	The most common is a codon 7 mutation (S249C) that forms disulfide-linked homodimers that exhibit ligand-independent signaling activity.	('disulfide', 'Chemical', 'MESH:D004220', (57, 66))	('S249C', 'Var', (39, 44))	('ligand', 'molecular_function', 'GO:0005488', ('98', '104'))	('ligand-independent', 'MPA', (98, 116))	('S249C', 'Mutation', 'rs121913483', (39, 44))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))
117490	20610280	Therefore, the fraction of superficial tumors that is dependent on FGFR3 signaling is probably higher than the proportion of tumors that expresses mutant FGFR3.	('mutant', 'Var', (147, 153))	('tumors', 'Disease', (39, 45))	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('FGFR3', 'Gene', (67, 72))	('FGFR3', 'Gene', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('154', '158'))	('FGFR3', 'Gene', '2261', (67, 72))	('FGFR3', 'Gene', '2261', (154, 159))	('superficial', 'Disease', (27, 38))
117492	20610280	In the preclinical models, loss of p53 promotes CIS and contributes to progression to muscle-invasive disease.	('CIS', 'CPA', (48, 51))	('loss', 'Var', (27, 31))	('promotes', 'PosReg', (39, 47))	('p53', 'Gene', (35, 38))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (86, 109))	('CIS', 'Phenotype', 'HP:0030075', (48, 51))	('contributes', 'Reg', (56, 67))	('muscle-invasive disease', 'Disease', (86, 109))
117493	20610280	Similarly, early work established that LOH on 17p distinguished high grade from low grade cancers, and many other studies have demonstrated that mutational inactivation of p53 or p53 pathway disruption (via loss of its downstream target, p21) appears to contribute to poor clinical outcome in both organ-confined and muscle-invasive disease, although as a prognostic marker its effects are stronger in lower-stage tumors (T1-T2, N0).	('p53 pathway', 'Pathway', (179, 190))	('p53', 'Pathway', (172, 175))	('cancers', 'Disease', (90, 97))	('muscle-invasive disease', 'Disease', (317, 340))	('tumor', 'Phenotype', 'HP:0002664', (414, 419))	('loss', 'NegReg', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('disruption', 'NegReg', (191, 201))	('tumors', 'Phenotype', 'HP:0002664', (414, 420))	('organ-confined', 'Disease', (298, 312))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (317, 340))	('lower-stage tumors', 'Disease', 'MESH:D062706', (402, 420))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('mutational inactivation', 'Var', (145, 168))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('lower-stage tumors', 'Disease', (402, 420))
117494	20610280	An interesting exception may be found in tumors that contain exon 5 p53 mutations; in one study clinical outcomes in this group were similar to those observed in patients whose tumors expressed wild-type p53.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Disease', (177, 183))	('patients', 'Species', '9606', (162, 170))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('exon 5', 'Var', (61, 67))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('p53', 'Gene', (68, 71))	('tumors', 'Disease', 'MESH:D009369', (177, 183))
117495	20610280	Similarly, the phenotype of the uroplakin-SV40T transgenic mice strongly suggests that loss of Rb function also contributes to CIS and muscle invasive-disease.	('loss', 'Var', (87, 91))	('contributes', 'Reg', (112, 123))	('muscle invasive-disease', 'Disease', (135, 158))	('CIS', 'Phenotype', 'HP:0030075', (127, 130))	('muscle invasive-disease', 'Disease', 'MESH:D009135', (135, 158))	('CIS', 'Disease', (127, 130))	('transgenic mice', 'Species', '10090', (48, 63))
117496	20610280	In patient tumors Rb pathway disruption occurs frequently due to mutational inactivation of Rb itself or of its upstream regulator, p16.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('p16', 'Gene', '1029', (132, 135))	('patient', 'Species', '9606', (3, 10))	('disruption', 'Reg', (29, 39))	('tumors Rb', 'Disease', (11, 20))	('tumors Rb', 'Disease', 'MESH:D009369', (11, 20))	('p16', 'Gene', (132, 135))	('mutational inactivation', 'Var', (65, 88))
117497	20610280	Predictably, loss of Rb cooperates with p53 to promote tumor recurrence and patient mortality.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('promote', 'PosReg', (47, 54))	('patient mortality', 'CPA', (76, 93))	('tumor', 'Disease', (55, 60))	('patient', 'Species', '9606', (76, 83))	('loss', 'Var', (13, 17))
117501	20610280	Interestingly, mutational inactivation of the other TSC1 allele is not a particularly common event, even in tumor subsets selected for LOH at 9q.	('TSC1', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('LOH at', 'Var', (135, 141))	('tumor', 'Disease', (108, 113))	('TSC1', 'Gene', '7248', (52, 56))
117505	20610280	On the other hand, and more consistent with predictions made by the preclinical models, LOH within the PTEN locus on chromosome 10 appears to be much more common in muscle-invasive as compared with superficial tumors, and a genetic signature of PTEN loss predicts a poor clinical outcome.	('PTEN', 'Gene', (103, 107))	('common', 'Reg', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('chromosome', 'cellular_component', 'GO:0005694', ('117', '127'))	('tumors', 'Disease', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('PTEN', 'Gene', (245, 249))	('loss', 'NegReg', (250, 254))	('muscle-invasive', 'Disease', (165, 180))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('LOH', 'Var', (88, 91))
117508	20610280	Cross-species comparisons of gene expression confirm that the papillary tumors that arise in the Hras transgenics are highly similar to superficial (Ta and T1) lesions in patients in 3 independent datasets (Woonyoung Choi, manuscript in preparation).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('papillary tumors', 'Disease', 'MESH:D002291', (62, 78))	('papillary tumors', 'Disease', (62, 78))	('transgenics', 'Var', (102, 113))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('patients', 'Species', '9606', (171, 179))	('papillary tumors', 'Phenotype', 'HP:0007482', (62, 78))	('gene expression', 'biological_process', 'GO:0010467', ('29', '44'))	('transgenic', 'Species', '10090', (102, 112))	('Hras', 'Gene', (97, 101))
117531	20610280	We renewed our EMT studies as a result of our longstanding interest in the effects of inhibitors of the epidermal growth factor receptor (EGFR) in preclinical bladder cancer models.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('104', '127'))	('bladder cancer', 'Disease', 'MESH:D001749', (159, 173))	('bladder cancer', 'Disease', (159, 173))	('EGFR', 'Gene', '1956', (138, 142))	('epidermal growth factor receptor', 'Gene', (104, 136))	('EGFR', 'Gene', (138, 142))	('EMT', 'biological_process', 'GO:0001837', ('15', '18'))	('EGFR', 'molecular_function', 'GO:0005006', ('138', '142'))	('bladder cancer', 'Phenotype', 'HP:0009725', (159, 173))	('epidermal growth factor receptor', 'Gene', '1956', (104, 136))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('inhibitors', 'Var', (86, 96))
117538	20610280	Furthermore, knockdown of E-cadherin in the EGFR inhibitor-sensitive cells made them resistant to the drugs, demonstrating a cause-effect relationship between the two.	('E-cadherin', 'Gene', (26, 36))	('E-cadherin', 'Gene', '999', (26, 36))	('EGFR', 'Gene', '1956', (44, 48))	('resistant to', 'MPA', (85, 97))	('EGFR', 'Gene', (44, 48))	('knockdown', 'Var', (13, 22))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))	('cadherin', 'molecular_function', 'GO:0008014', ('28', '36'))
117571	20610280	Furthermore, whether the two "tracks" of cancer are driven by different oncogenic events (FGFR3 mutation versus p53/Rb/PTEN loss) that occur within the same target cell (presumably the basal cell), or by different oncogenic events that target different progenitors (basal versus intermediate cell) remains unclear.	('loss', 'NegReg', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutation', 'Var', (96, 104))	('FGFR3', 'Gene', '2261', (90, 95))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('FGFR3', 'Gene', (90, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('88', '92'))
117577	20610280	We have also attempted to provide some context with respect to other recent developments in the field, including insights into how differences in molecular genetics (FGFR3 mutations versus p53/Rb/PTEN/mTOR pathway alterations) might mediate the progression along the two independent tracks (papillary and non-papillary) of progression.	('mutations', 'Var', (172, 181))	('FGFR', 'molecular_function', 'GO:0005007', ('166', '170'))	('FGFR3', 'Gene', '2261', (166, 171))	('mediate', 'Reg', (233, 240))	('FGFR3', 'Gene', (166, 171))
117704	29127397	sPAGM: inferring subpathway activity by integrating gene and miRNA expression-robust functional signature identification for melanoma prognoses MicroRNAs (miRNAs) regulate biological pathways by inhibiting gene expression.	('regulate', 'Reg', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('inhibiting', 'NegReg', (195, 205))	('gene expression', 'MPA', (206, 221))	('biological pathways', 'Pathway', (172, 191))	('gene expression', 'biological_process', 'GO:0010467', ('206', '221'))	('MicroRNAs', 'Var', (144, 153))
117749	29127397	Moreover, the Path: 05206 graph could be divided into many subpathways according to the tumor type, which were compared with the corresponding cancer pathways (gene components involved) (e.g., Path: 05214 for gliomas).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('Path: 05206', 'Var', (14, 25))	('gliomas', 'Phenotype', 'HP:0009733', (209, 216))	('gliomas', 'Disease', (209, 216))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('gliomas', 'Disease', 'MESH:D005910', (209, 216))	('Path: 05214', 'Var', (193, 204))	('tumor', 'Disease', (88, 93))
117762	29127397	Five tumor pathways were obtained from the KEGG database, and each pathway graph corresponded to one or more tumor types involving Path: 05219 (bladder cancer, BLCA type), Path: 05211 (renal cell carcinoma, KICH, KIRC, and KIRP types), Path: 05223 (non-small cell lung cancer, LUAD and LUSC types), Path: 05215 (prostate cancer, PRAD type), and Path: 05216 (thyroid cancer, THCA type).	('thyroid cancer', 'Phenotype', 'HP:0002890', (358, 372))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (185, 205))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('non-small cell lung cancer', 'Disease', (249, 275))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('BLCA', 'Chemical', '-', (160, 164))	('bladder cancer', 'Disease', 'MESH:D001749', (144, 158))	('bladder cancer', 'Disease', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('prostate cancer', 'Disease', 'MESH:D011471', (312, 327))	('prostate cancer', 'Phenotype', 'HP:0012125', (312, 327))	('bladder cancer', 'Phenotype', 'HP:0009725', (144, 158))	('LUSC', 'Phenotype', 'HP:0030359', (286, 290))	('prostate cancer', 'Disease', (312, 327))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('Path: 05219', 'Var', (131, 142))	('Path: 05215', 'Var', (299, 310))	('lung cancer', 'Phenotype', 'HP:0100526', (264, 275))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (249, 275))	('renal cell carcinoma', 'Disease', (185, 205))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (185, 205))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('KICH', 'Disease', 'None', (207, 211))	('thyroid cancer', 'Disease', (358, 372))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('Path: 05211', 'Var', (172, 183))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (253, 275))	('LUAD', 'Disease', (277, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('BLCA', 'Disease', (160, 164))	('Path: 05216', 'Var', (345, 356))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (249, 275))	('Path: 05223', 'Var', (236, 247))	('THCA', 'Phenotype', 'HP:0002890', (374, 378))	('KICH', 'Disease', (207, 211))	('thyroid cancer', 'Disease', 'MESH:D013964', (358, 372))	('tumor', 'Disease', (5, 10))	('LUAD', 'Disease', 'None', (277, 281))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('tumor', 'Disease', (109, 114))
117768	29127397	Figure 2C shows that the third subpathway of Path: 05219 was more active in tumor conditions (P = 0.0226), and the fifth subpathway was more active in normal conditions (P = 1.22E-07).	('active', 'MPA', (66, 72))	('more', 'PosReg', (61, 65))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('Path: 05219', 'Var', (45, 56))
117818	26316886	Genetic and epigenetic differences between cancer cells within a tumour might explain why some tumour cells are more aggressive and difficult to eradicate in patients treated with chemotherapy.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (43, 49))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('Genetic', 'Var', (0, 7))	('tumour', 'Disease', (95, 101))	('epigenetic differences', 'Var', (12, 34))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('patients', 'Species', '9606', (158, 166))	('tumour', 'Disease', (65, 71))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
117820	26316886	Most tumours initiate from a single cell which has acquired driver mutations necessary for malignant transformation.	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('tumours', 'Disease', (5, 12))	('mutations', 'Var', (67, 76))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))
117821	26316886	However, additional mutations can be acquired during the neoplastic process leading to genetic diversity within the tumour population i.e.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('tumour', 'Disease', (116, 122))	('neoplastic process', 'Phenotype', 'HP:0002664', (57, 75))	('genetic diversity', 'MPA', (87, 104))	('leading to', 'Reg', (76, 86))	('mutations', 'Var', (20, 29))
117864	26316886	It is generally known that because of mutational instability of tumour cells and/or drug-induced selection, drug resistance almost always develops under therapy.	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('drug resistance', 'biological_process', 'GO:0009315', ('108', '123'))	('drug resistance', 'Phenotype', 'HP:0020174', (108, 123))	('develops', 'Reg', (138, 146))	('drug resistance', 'biological_process', 'GO:0042493', ('108', '123'))	('mutational instability', 'Var', (38, 60))	('drug resistance', 'MPA', (108, 123))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
117884	26316886	This approach allowed the identification of rearrangements involving previously described ETS genes in 51.5%, 7%, 1%, and 0.5% for ERG, ETV1, ETV4, and ETV5 respectively.	('ETV1', 'Gene', (136, 140))	('ETS genes', 'Gene', (90, 99))	('ETV5', 'Gene', (152, 156))	('ETV1', 'Gene', '2115', (136, 140))	('ERG', 'Gene', '2078', (131, 134))	('ETV4', 'Gene', (142, 146))	('ERG', 'Gene', (131, 134))	('ETV4', 'Gene', '2118', (142, 146))	('rearrangements', 'Var', (44, 58))	('ETV5', 'Gene', '2119', (152, 156))
117889	26316886	Moreover, to evaluate genetic markers of prognosis we studied a series of 200 diagnostic needle-biopsies with confirmed PCa with detailed clinicopathological data, including a ten-year disease-specific survival follow-up, in which the frequency of ERG rearrangements and relative 8q chromosomal gains were assessed by FISH.	('ERG', 'Gene', '2078', (248, 251))	('ERG', 'Gene', (248, 251))	('rearrangements', 'Var', (252, 266))	('PCa', 'Disease', (120, 123))
117892	26316886	Our work showed that effective knockdown of GRPR in LNCaP and VCaP cells attenuates their aggressive oncogenic properties by decreasing proliferation, invasion, and anchorage-independent growth, while increasing apoptosis.	('increasing', 'PosReg', (201, 211))	('apoptosis', 'biological_process', 'GO:0006915', ('212', '221'))	('GRPR', 'Gene', (44, 48))	('apoptosis', 'CPA', (212, 221))	('anchorage-independent growth', 'CPA', (165, 193))	('attenuates', 'NegReg', (73, 83))	('GRPR', 'Gene', '2925', (44, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('212', '221'))	('invasion', 'CPA', (151, 159))	('VCaP', 'CellLine', 'CVCL:2235', (62, 66))	('decreasing', 'NegReg', (125, 135))	('LNCaP', 'CellLine', 'CVCL:0395', (52, 57))	('knockdown', 'Var', (31, 40))	('aggressive oncogenic properties', 'CPA', (90, 121))
117894	26316886	We show that overexpression of these GRPR targets is restricted to prostate carcinomas harbouring ERG and/or ETV1 rearrangements, establishing their potential as therapeutic targets for these particular molecular subsets of the disease.	('ETV1', 'Gene', '2115', (109, 113))	('ERG', 'Gene', (98, 101))	('prostate carcinomas', 'Disease', 'MESH:D011472', (67, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('GRPR', 'Gene', (37, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('GRPR', 'Gene', '2925', (37, 41))	('overexpression', 'PosReg', (13, 27))	('rearrangements', 'Var', (114, 128))	('ERG', 'Gene', '2078', (98, 101))	('ETV1', 'Gene', (109, 113))	('prostate carcinomas', 'Disease', (67, 86))
117897	26316886	This is attributed to the fact that cancer exosomes carry molecular signatures and effectors of the disease, such as mutant oncoproteins, oncogenic transcripts, non-coding RNAS (microRNAs, long non-coding RNAS, transfer RNAs, etc...) and double-stranded DNA.	('DNA', 'cellular_component', 'GO:0005574', ('254', '257'))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('mutant', 'Var', (117, 123))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
117909	26316886	GPC1 crExos from patients and from mice with spontaneous pancreatic tumours carry specific KRAS mutations and reliably detect pancreatic intraepithelial lesions in mice despite negative signals by MRI.	('pancreatic tumours', 'Disease', 'MESH:D010190', (57, 75))	('pancreatic intraepithelial lesions', 'Disease', 'MESH:D010182', (126, 160))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('mice', 'Species', '10090', (164, 168))	('pancreatic intraepithelial lesions', 'Disease', (126, 160))	('mice', 'Species', '10090', (35, 39))	('patients', 'Species', '9606', (17, 25))	('GPC1', 'Gene', (0, 4))	('KRAS', 'Gene', (91, 95))	('detect', 'Reg', (119, 125))	('pancreatic tumours', 'Disease', (57, 75))	('mutations', 'Var', (96, 105))	('GPC1', 'Gene', '2817', (0, 4))
117916	26316886	On several loci, we detected somatic mutations with 100% variant frequency in sorted tumour cell populations clearly indicating LoH and confirming 100% purity of sorted cells.	('variant', 'Var', (57, 64))	('tumour', 'Disease', (85, 91))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
117935	26316886	Recently the mutational landscape of HER-2 heterogeneous carcinomas with two separate clones have been analysed and distinct driver genetic alterations in the different components have been demonstrated suggesting that HER-2 negative components are likely driven by genetic alterations not present in the HER-2+ components, including BRF2 and DSN1 amplification and HER-2 I767M somatic mutations.	('amplification', 'Var', (348, 361))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('DSN1', 'Gene', '79980', (343, 347))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('carcinomas', 'Disease', 'MESH:D002277', (57, 67))	('I767M', 'Mutation', 'p.I767M', (372, 377))	('HER-2', 'Gene', '2064', (37, 42))	('BRF2', 'Gene', '55290', (334, 338))	('HER-2', 'Gene', (37, 42))	('HER-2', 'Gene', '2064', (219, 224))	('BRF2', 'Gene', (334, 338))	('negative', 'NegReg', (225, 233))	('HER-2', 'Gene', (219, 224))	('DSN1', 'Gene', (343, 347))	('HER-2', 'Gene', '2064', (305, 310))	('HER-2', 'Gene', (305, 310))	('carcinomas', 'Disease', (57, 67))	('I767M somatic mutations', 'Var', (372, 395))	('HER-2', 'Gene', '2064', (366, 371))	('HER-2', 'Gene', (366, 371))
117952	26316886	NGS demonstrated the coexistence of TP53/KRAS/CTNNB1/SMAD4/MET mutations with mutated EGFR.	('SMAD4', 'Gene', (53, 58))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('mutated', 'Var', (78, 85))	('TP53', 'Gene', '7157', (36, 40))	('CTNNB1', 'Gene', '1499', (46, 52))	('EGFR', 'Gene', (86, 90))	('SMAD4', 'Gene', '4089', (53, 58))	('TP53', 'Gene', (36, 40))	('CTNNB1', 'Gene', (46, 52))
117953	26316886	This may explain the variable response of the EGFR mutated tumours to the respective inhibitors.	('EGFR', 'Gene', '1956', (46, 50))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('EGFR', 'Gene', (46, 50))	('tumours', 'Disease', (59, 66))	('mutated', 'Var', (51, 58))
117956	26316886	When combining IHC and molecular pathology, the following cascades have been demonstrated in pulmonary carcinomas: epidermoid carcinoma-epidermal growth factor receptor (EGFR) and HER-2 polysomy, and CK7/vimentin for EMT non-pure epidermoid carcinomas; bronchial-pulmonary adenocarcinomas -non-smoking female:mut EGFR and excision repair cross complement group 1 (ERCC1) expression; micropapillary pattern with VIM/RB/ERCC1 expression; acinar/BA:lepidic/micropappilary patterns express TTF1, and mutated EGFR.	('ERCC1', 'Gene', (418, 423))	('RB', 'Disease', 'MESH:D012175', (415, 417))	('pulmonary carcinomas', 'Disease', 'MESH:D008175', (93, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('carcinomas', 'Phenotype', 'HP:0030731', (241, 251))	('vimentin', 'cellular_component', 'GO:0045099', ('204', '212'))	('EGFR', 'Gene', (313, 317))	('EGFR', 'molecular_function', 'GO:0005006', ('504', '508'))	('EGFR', 'molecular_function', 'GO:0005006', ('170', '174'))	('carcinoma-epidermal growth factor receptor', 'Gene', '1956', (126, 168))	('EGFR', 'Gene', (170, 174))	('HER-2', 'Gene', '2064', (180, 185))	('excision repair cross complement group 1', 'Gene', '2067', (322, 362))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (278, 288))	('HER-2', 'Gene', (180, 185))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('CK7', 'Gene', (200, 203))	('TTF1', 'Gene', '7270', (486, 490))	('epidermoid carcinomas', 'Disease', (230, 251))	('EGFR', 'Gene', '1956', (504, 508))	('mutated', 'Var', (496, 503))	('bronchial-pulmonary adenocarcinomas', 'Disease', 'MESH:D001984', (253, 288))	('excision repair cross complement group 1', 'Gene', (322, 362))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('313', '317'))	('ERCC1', 'Gene', '2067', (364, 369))	('EGFR', 'Gene', '1956', (313, 317))	('EGFR', 'Gene', '1956', (170, 174))	('vimentin', 'cellular_component', 'GO:0045098', ('204', '212'))	('CK7', 'Gene', '3855', (200, 203))	('bronchial-pulmonary adenocarcinomas', 'Disease', (253, 288))	('epidermoid carcinomas', 'Disease', 'MESH:D002294', (230, 251))	('TTF1', 'Gene', (486, 490))	('ERCC1', 'Gene', (364, 369))	('ERCC1', 'Gene', '2067', (418, 423))	('vimentin', 'Gene', '7431', (204, 212))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('136', '159'))	('EMT', 'biological_process', 'GO:0001837', ('217', '220'))	('VIM', 'Gene', '7431', (411, 414))	('vimentin', 'Gene', (204, 212))	('pure', 'molecular_function', 'GO:0034023', ('225', '229'))	('pulmonary carcinomas', 'Disease', (93, 113))	('EGFR', 'Gene', (504, 508))	('carcinoma-epidermal growth factor receptor', 'Gene', (126, 168))	('VIM', 'Gene', (411, 414))
117957	26316886	Higher ki67 and APC/ERCC1 expression correlates with stages IIA/IIIA while lower TTF1expression relates with mutated KRAS, mainly in papillary and solid patterns.	('expression', 'MPA', (26, 36))	('ERCC1', 'Gene', '2067', (20, 25))	('ERCC1', 'Gene', (20, 25))	('TTF1', 'Gene', (81, 85))	('TTF1', 'Gene', '7270', (81, 85))	('APC', 'cellular_component', 'GO:0005680', ('16', '19'))	('stages IIA/IIIA', 'Disease', (53, 68))	('mutated', 'Var', (109, 116))	('APC', 'Disease', 'MESH:D011125', (16, 19))	('papillary', 'Disease', (133, 142))	('KRAS', 'Disease', (117, 121))	('APC', 'Disease', (16, 19))
117962	26316886	This type of urothelial carcinoma shows only very infrequent genetic alterations which are limited to deletions of chromosome 9 and oncogenic driver mutations, like FGFR3 or PIK3Ca inducing proliferation.	('FGFR3', 'Gene', '2261', (165, 170))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (13, 33))	('FGFR', 'molecular_function', 'GO:0005007', ('165', '169'))	('mutations', 'Var', (149, 158))	('chromosome', 'cellular_component', 'GO:0005694', ('115', '125'))	('FGFR3', 'Gene', (165, 170))	('urothelial carcinoma', 'Disease', (13, 33))	('PIK3Ca', 'Gene', (174, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('PIK3Ca', 'Gene', '5290', (174, 180))	('inducing', 'PosReg', (181, 189))
117970	26316886	Both intrinsic subtypes are associated with distinct genomic alterations like FGFR3and TSC1 mutations in the luminal and retinoblastoma (RB) alteration in the basal subtype.	('retinoblastoma', 'Disease', 'MESH:D012175', (121, 135))	('retinoblastoma', 'Disease', (121, 135))	('FGFR3', 'Gene', (78, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('78', '82'))	('mutations', 'Var', (92, 101))	('retinoblastoma', 'Phenotype', 'HP:0009919', (121, 135))	('TSC1', 'Gene', '7248', (87, 91))	('FGFR3', 'Gene', '2261', (78, 83))	('RB', 'Disease', 'MESH:D012175', (137, 139))	('TSC1', 'Gene', (87, 91))
117986	26316886	These techniques open the doors to highly precise quantitation, and they are suitable to identify rare DNA sequence variants in plasma that may reflect the presence of minimal residual malignant disease.	('variants', 'Var', (116, 124))	('malignant disease', 'Disease', 'MESH:D009369', (185, 202))	('malignant disease', 'Disease', (185, 202))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('DNA sequence', 'Gene', (103, 115))
117989	23593348	Multiplex inversion probe (MIP) analysis, a recently developed genomic technique, was used to study 80 urothelial carcinomas to identify mutations and copy number changes.	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('urothelial carcinomas', 'Disease', (103, 124))	('MIP', 'molecular_function', 'GO:0004243', ('27', '30'))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (103, 124))	('copy number changes', 'Var', (151, 170))
118008	23593348	Subsequently, TP53 mutations were identified, the CDKN2A gene was shown to be a consistent target of deletion, and mutations were found in both the TSC1 and FGFR3 genes in bladder cancer, as well as many other genetic changes.	('deletion', 'Var', (101, 109))	('TP53', 'Gene', '7157', (14, 18))	('CDKN2A', 'Gene', (50, 56))	('TP53', 'Gene', (14, 18))	('mutations', 'Var', (115, 124))	('FGFR3', 'Gene', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('CDKN2A', 'Gene', '1029', (50, 56))	('bladder cancer', 'Phenotype', 'HP:0009725', (172, 186))	('found', 'Reg', (130, 135))	('bladder cancer', 'Disease', (172, 186))	('bladder cancer', 'Disease', 'MESH:D001749', (172, 186))	('TSC1', 'Gene', '7248', (148, 152))	('FGFR3', 'Gene', '2261', (157, 162))	('TSC1', 'Gene', (148, 152))	('FGFR', 'molecular_function', 'GO:0005007', ('157', '161'))
118009	23593348	In addition, comparative genomic hybridization has been used extensively to identify regions of chromosomal gain and loss in bladder cancer with identification of many consistent changes of potential importance in tumor development although the resolution of these technologies was limited.	('loss', 'NegReg', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('men', 'Species', '9606', (227, 230))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('gain', 'PosReg', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('tumor', 'Disease', (214, 219))	('chromosomal', 'Var', (96, 107))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))
118012	23593348	We identified 44 regions of copy number change in a discovery cohort of 80 urothelial carcinoma samples, and then focused on 9 genomic regions showing significant and relatively common amplification of genes that may function as 'driver' events for urothelial carcinoma development.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (249, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('copy number change', 'Var', (28, 46))	('urothelial carcinoma', 'Disease', (75, 95))	('urothelial carcinoma', 'Disease', (249, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('men', 'Species', '9606', (277, 280))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (75, 95))
118014	23593348	We found that genomic copy number changes were significantly more common in Ta grade 3 and higher stage/grade tumors than in stage Ta grades 1 and 1-2 tumors.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('common', 'Reg', (66, 72))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('1-2 tumors', 'Disease', 'MESH:D009369', (147, 157))	('genomic copy number changes', 'Var', (14, 41))	('1-2 tumors', 'Disease', (147, 157))
118028	23593348	The 412 cancer gene mutations are listed in Table S2.	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (8, 14))	('mutations', 'Var', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
118033	23593348	Recurrent copy number alterations were identified using Genomic Identification of Significant Targets in Cancer (GISTIC), implemented in both GenePattern 3.3.3 and in Nexus v6.0.	('Cancer', 'Disease', (105, 111))	('Cancer', 'Disease', 'MESH:D009369', (105, 111))	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	('copy number alterations', 'Var', (10, 33))	('men', 'Species', '9606', (127, 130))
118034	23593348	GISTIC identifies regions of the genome that are significantly amplified or deleted across a set of cancer samples.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('deleted', 'Var', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))
118043	23593348	The discovery cohort of 80 samples included cystectomy, nephroureterectomy, and transurethral resection specimens, and had tumor stages ranging from Ta to T4 (Table 1), but were nearly all T1 or higher stage to permit robust detection of mutations associated with invasive urothelial carcinoma.	('nephroureterectomy', 'Disease', 'None', (56, 74))	('tumor', 'Disease', (123, 128))	('invasive urothelial carcinoma', 'Disease', (264, 293))	('nephroureterectomy', 'Disease', (56, 74))	('mutations', 'Var', (238, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('associated', 'Reg', (248, 258))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('men', 'Species', '9606', (109, 112))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (264, 293))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
118048	23593348	Thirty-two mutations in 7 genes were identified in 28 urothelial carcinoma samples by Affymetrix criteria (scores>=9.0, and <50) as being probable mutations in the 80 urothelial carcinoma FFPE samples.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('mutations', 'Var', (11, 20))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (167, 187))	('urothelial carcinoma', 'Disease', (54, 74))	('urothelial carcinoma', 'Disease', (167, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (54, 74))
118065	23593348	Six (22%) cell lines showed amplification of CCND1, while 5 each showed amplification of some or all of the genes on 1q23.3 and of E2F3-SOX4.	('CCND1', 'Gene', (45, 50))	('CCND1', 'Gene', '595', (45, 50))	('E2F3', 'Gene', (131, 135))	('E2F3', 'Gene', '1871', (131, 135))	('amplification', 'MPA', (72, 85))	('SOX4', 'Gene', (136, 140))	('SOX4', 'Gene', '6659', (136, 140))	('amplification', 'Var', (28, 41))
118069	23593348	Concordant results were seen for amplification in 8 of the 9 genomic regions analyzed for one or more cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('amplification', 'Var', (33, 46))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))
118072	23593348	Furthermore, we examined the possibility that genomic amplification of these regions would be associated with stage of disease, and thus might provide a potential prognostic measure for clinical use.	('clinical', 'Species', '191496', (186, 194))	('genomic amplification', 'Var', (46, 67))	('associated', 'Reg', (94, 104))	('stage of disease', 'Disease', (110, 126))
118077	23593348	In contrast, amplifications were seen in 11 of 20 (55%) Ta grade 3 cancers, and in 20 of 41 (49%) T2 grade 2 cancers.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('amplifications', 'Var', (13, 27))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
118078	23593348	SOX4 was the only individual marker which showed amplification at a significantly higher rate in Ta grade 3+T2 grade 2 cancers (11 of 61) than in Ta grade 1 or 1-2 cancers (0 of 23, p = 0.03).	('amplification', 'Var', (49, 62))	('1-2 cancers', 'Disease', (160, 171))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (119, 126))	('cancers', 'Disease', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('SOX4', 'Gene', (0, 4))	('1-2 cancers', 'Disease', 'MESH:D009369', (160, 171))	('SOX4', 'Gene', '6659', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
118081	23593348	Ten of 11 samples examined (4 grade 1 and 7 grade 1-2) had mutations in FGFR3: 1 had R248C, 8 had S249C, and 1 had Y373C, consistent with previous studies of early stage bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (170, 184))	('bladder cancer', 'Disease', (170, 184))	('Y373C', 'Var', (115, 120))	('R248C', 'Mutation', 'rs121913482', (85, 90))	('S249C', 'Mutation', 'rs121913483', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('FGFR3', 'Gene', '2261', (72, 77))	('Y373C', 'Mutation', 'rs121913485', (115, 120))	('bladder cancer', 'Phenotype', 'HP:0009725', (170, 184))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('FGFR3', 'Gene', (72, 77))	('S249C', 'Var', (98, 103))	('R248C', 'Var', (85, 90))
118083	23593348	Most mutations identified here were in the 12 most commonly mutated genes reported by the Catalogue of Somatic Mutations in Cancer (COSMIC) in bladder cancer.	('Cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('bladder cancer', 'Phenotype', 'HP:0009725', (143, 157))	('bladder cancer', 'Disease', (143, 157))	('mutations', 'Var', (5, 14))	('bladder cancer', 'Disease', 'MESH:D001749', (143, 157))	('Cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Cancer', 'Disease', (124, 130))
118084	23593348	However, we also identified mutations in two other genes not reported in COSMIC for bladder cancer, ATM and FBXW7.	('bladder cancer', 'Phenotype', 'HP:0009725', (84, 98))	('bladder cancer', 'Disease', 'MESH:D001749', (84, 98))	('bladder cancer', 'Disease', (84, 98))	('ATM', 'Gene', '472', (100, 103))	('FBXW7', 'Gene', '55294', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ATM', 'Gene', (100, 103))	('FBXW7', 'Gene', (108, 113))	('mutations', 'Var', (28, 37))
118085	23593348	Relatively few mutations in FGFR3 were seen in this cohort, four Y373C (5%), likely due to the inclusion of only three Ta samples, two of which arose in the renal pelvis.	('Y373C', 'Var', (65, 70))	('FGFR3', 'Gene', '2261', (28, 33))	('renal pelvis', 'Disease', 'MESH:D010386', (157, 169))	('Y373C', 'Mutation', 'rs121913485', (65, 70))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('renal pelvis', 'Disease', (157, 169))	('FGFR3', 'Gene', (28, 33))	('renal pelvis', 'Phenotype', 'HP:0000125', (157, 169))
118086	23593348	MIP screening for mutation and copy number change has recently been reported for multiple other cancer types.	('MIP', 'molecular_function', 'GO:0004243', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('copy number change', 'Var', (31, 49))	('mutation', 'Var', (18, 26))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
118092	23593348	Amplification was seen significantly more frequently in advanced stage tumors (Ta grade 3, or higher stage) than in early stage tumors (Ta grade 1 or 1-2).	('Amplification', 'Var', (0, 13))	('stage tumors', 'Disease', (122, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('stage tumors', 'Disease', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('stage tumors', 'Disease', 'MESH:D062706', (122, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('stage tumors', 'Disease', 'MESH:D062706', (65, 77))
118095	23593348	In our validation cohort, we identified MYCL1 and POLB amplification in 3 and 4 samples, respectively.	('POLB', 'Gene', (50, 54))	('amplification', 'Var', (55, 68))	('MYCL1', 'Gene', '4610', (40, 45))	('POLB', 'Gene', '5423', (50, 54))	('MYCL1', 'Gene', (40, 45))
118098	23593348	Non-invasive Ta papillary tumors commonly have activating mutations in FGFR3 (as seen here), or mutation in one of the RAS genes (mutually exclusive with FGFR3 mutation), and loss of one chromosome 9.	('FGFR3', 'Gene', (71, 76))	('FGFR3', 'Gene', (154, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('papillary tumors', 'Phenotype', 'HP:0007482', (16, 32))	('chromosome', 'cellular_component', 'GO:0005694', ('187', '197'))	('mutation', 'Var', (96, 104))	('FGFR', 'molecular_function', 'GO:0005007', ('154', '158'))	('Non-invasive Ta papillary tumors', 'Disease', 'MESH:D002291', (0, 32))	('FGFR3', 'Gene', '2261', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('FGFR3', 'Gene', '2261', (154, 159))	('Non-invasive Ta papillary tumors', 'Disease', (0, 32))	('activating', 'PosReg', (47, 57))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
118100	23593348	In contrast, many genetic events have been identified in muscle-invasive bladder cancer, including common deletion and mutations in TSC1, PTEN, RB1, and particularly TP53.	('invasive bladder', 'Phenotype', 'HP:0100645', (64, 80))	('PTEN', 'Gene', (138, 142))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (57, 87))	('muscle-invasive bladder cancer', 'Disease', (57, 87))	('PTEN', 'Gene', '5728', (138, 142))	('RB1', 'Gene', '5925', (144, 147))	('TP53', 'Gene', '7157', (166, 170))	('deletion', 'Var', (106, 114))	('RB1', 'Gene', (144, 147))	('TP53', 'Gene', (166, 170))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('TSC1', 'Gene', '7248', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (119, 128))	('TSC1', 'Gene', (132, 136))
118101	23593348	In addition, recent studies have emphasized the common involvement of the PI3K-mTOR pathway in this disease, and common mutation in chromatin remodeling genes in invasive bladder cancer.	('mTOR', 'Gene', (79, 83))	('men', 'Species', '9606', (62, 65))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (162, 185))	('mTOR', 'Gene', '2475', (79, 83))	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('chromatin', 'cellular_component', 'GO:0000785', ('132', '141'))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mutation', 'Var', (120, 128))	('invasive bladder', 'Phenotype', 'HP:0100645', (162, 178))	('PI3K', 'molecular_function', 'GO:0016303', ('74', '78'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('132', '152'))	('invasive bladder cancer', 'Disease', (162, 185))	('involvement', 'Reg', (55, 66))
118107	23593348	In our study, we demonstrated that MIP technology can be used to study routine FFPE cancer specimens, providing a great deal of mutational and copy number information.	('men', 'Species', '9606', (96, 99))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('MIP', 'molecular_function', 'GO:0004243', ('35', '38'))	('copy number', 'Var', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
118110	23593348	Hence detection of amplification in these genes in bladder cancer might also lead to targeted therapy.	('bladder cancer', 'Disease', (51, 65))	('lead to', 'Reg', (77, 84))	('amplification', 'Var', (19, 32))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('bladder cancer', 'Disease', 'MESH:D001749', (51, 65))
118224	33614501	Knockdown of this lncRNA induced glioma cell cycle arrest and apoptosis via epigenetically regulating CDKN1A (p21).	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('p21', 'Gene', '1026', (110, 113))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('epigenetically regulating', 'Var', (76, 101))	('glioma cell cycle arrest', 'Disease', (33, 57))	('p21', 'Gene', (110, 113))	('CDKN1A', 'Gene', (102, 108))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (40, 57))	('apoptosis', 'CPA', (62, 71))	('CDKN1A', 'Gene', '1026', (102, 108))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('40', '57'))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('glioma cell cycle arrest', 'Disease', 'MESH:D006323', (33, 57))
118259	33614501	As shown in  Figure 2 , we found AR peaks in FAM83H-AS1 loci significantly increased after DHT treatment compared to the control group by analyzing GSE55062 ( Figure 2B ).	('GSE55062', 'Var', (148, 156))	('AR', 'Gene', '367', (33, 35))	('FAM83H-AS1', 'Gene', '100128338', (45, 55))	('DHT', 'Chemical', '-', (91, 94))	('increased', 'PosReg', (75, 84))	('FAM83H-AS1', 'Gene', (45, 55))
118263	33614501	Moreover, we revealed that AR knockdown remarkably decreased FAM83H-AS1 levels in LNCaP and LNCaP-AI cells ( Figures 2F, G ).	('LNCaP', 'CellLine', 'CVCL:0395', (82, 87))	('LNCaP', 'CellLine', 'CVCL:0395', (92, 97))	('decreased', 'NegReg', (51, 60))	('FAM83H-AS1', 'Gene', (61, 71))	('knockdown', 'Var', (30, 39))	('AR', 'Gene', '367', (27, 29))	('FAM83H-AS1', 'Gene', '100128338', (61, 71))
118272	33614501	Then, the CCK-8 assay was employed, and the results show FAM83H-AS1 knockdown significantly inhibited the proliferation rate in LNCaP ( Figure 4E ), PC-3 ( Figure 4F ), and DU145 ( Figure 4G ).	('FAM83H-AS1', 'Gene', '100128338', (57, 67))	('LNCaP', 'CellLine', 'CVCL:0395', (128, 133))	('inhibited', 'NegReg', (92, 101))	('FAM83H-AS1', 'Gene', (57, 67))	('knockdown', 'Var', (68, 77))	('proliferation rate', 'CPA', (106, 124))	('CCK-8', 'Chemical', 'MESH:D012844', (10, 15))
118273	33614501	In addition, a flow cytometry assay showed knockdown of FAM83H-AS1 contributed to the increase of cells in the G1 phase and the decreased of cells in S phase in LNCaP ( Figure 4H ,  Figure S1A ) and DU145 ( Figure 4I ,  Figure S1B ) cells.	('S phase', 'biological_process', 'GO:0051320', ('150', '157'))	('cells in the G1 phase', 'CPA', (98, 119))	('increase', 'PosReg', (86, 94))	('G1 phase', 'biological_process', 'GO:0051318', ('111', '119'))	('LNCaP', 'CPA', (161, 166))	('knockdown', 'Var', (43, 52))	('FAM83H-AS1', 'Gene', '100128338', (56, 66))	('LNCaP', 'CellLine', 'CVCL:0395', (161, 166))	('cells in S phase', 'CPA', (141, 157))	('decreased', 'NegReg', (128, 137))	('FAM83H-AS1', 'Gene', (56, 66))
118275	33614501	Moreover, a transwell assay showed silencing of FAM83H-AS1 suppressed PC-3 ( Figures 5A, B ) and DU145 cell migration ( Figures 5C, D ).	('silencing', 'Var', (35, 44))	('PC-3', 'CPA', (70, 74))	('FAM83H-AS1', 'Gene', '100128338', (48, 58))	('cell migration', 'biological_process', 'GO:0016477', ('103', '117'))	('suppressed', 'NegReg', (59, 69))	('FAM83H-AS1', 'Gene', (48, 58))
118286	33614501	In addition, our results report that silencing of FAM83H-AS1 suppressed CCNE2 expression in PC-3 and DU145 cells ( Figures 7H-J ).	('suppressed', 'NegReg', (61, 71))	('CCNE2', 'Gene', '9134', (72, 77))	('expression', 'MPA', (78, 88))	('FAM83H-AS1', 'Gene', (50, 60))	('silencing', 'Var', (37, 46))	('CCNE2', 'Gene', (72, 77))	('FAM83H-AS1', 'Gene', '100128338', (50, 60))
118310	33614501	FAM83H-AS1 knockdown reduces PCa cell proliferation but promotes cell cycle arrest and apoptosis.	('arrest', 'Disease', 'MESH:D006323', (76, 82))	('cell proliferation', 'biological_process', 'GO:0008283', ('33', '51'))	('PCa', 'Phenotype', 'HP:0012125', (29, 32))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (65, 82))	('FAM83H-AS1', 'Gene', '100128338', (0, 10))	('arrest', 'Disease', (76, 82))	('apoptosis', 'CPA', (87, 96))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('65', '82'))	('promotes', 'PosReg', (56, 64))	('PCa', 'Disease', (29, 32))	('FAM83H-AS1', 'Gene', (0, 10))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))	('knockdown', 'Var', (11, 20))	('reduces', 'NegReg', (21, 28))
118313	33614501	This study demonstrates that FAM83H-AS1 silencing suppresses PC-3 and DU145 migration.	('suppresses', 'NegReg', (50, 60))	('FAM83H-AS1', 'Gene', (29, 39))	('FAM83H-AS1', 'Gene', '100128338', (29, 39))	('silencing', 'Var', (40, 49))
118384	31871155	Genetic alterations mimicked by PARCB factors are relevant to bladder cancer.	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('bladder cancer', 'Phenotype', 'HP:0009725', (62, 76))	('bladder cancer', 'Disease', 'MESH:D001749', (62, 76))	('bladder cancer', 'Disease', (62, 76))
118385	31871155	Mutations in TP53 and loss of RB1 are frequently found in SCCB samples.	('TP53', 'Gene', (13, 17))	('loss', 'NegReg', (22, 26))	('Mutations', 'Var', (0, 9))	('RB1', 'Gene', (30, 33))	('SCCB', 'Disease', (58, 62))	('TP53', 'Gene', '7157', (13, 17))	('RB1', 'Gene', '5925', (30, 33))
118387	31871155	A recent mutation study showed that mutations on the PTEN, RB1, TERT, promoter, and TP53 can present concurrently in clinical SCCB samples.	('TERT', 'Gene', (64, 68))	('RB1', 'Gene', (59, 62))	('clinical', 'Species', '191496', (117, 125))	('TERT', 'Gene', '7015', (64, 68))	('mutations', 'Var', (36, 45))	('RB1', 'Gene', '5925', (59, 62))	('TP53', 'Gene', '7157', (84, 88))	('present', 'Reg', (93, 100))	('PTEN', 'Gene', (53, 57))	('PTEN', 'Gene', '5728', (53, 57))	('TP53', 'Gene', (84, 88))
118396	31871155	These epithelial cells also generated tumors in NSG mice after the transduction of the PARCB factors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('transduction', 'biological_process', 'GO:0009293', ('67', '79'))	('generated', 'Reg', (28, 37))	('mice', 'Species', '10090', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('PARCB factors', 'Gene', (87, 100))	('transduction', 'Var', (67, 79))
118397	31871155	We noticed that the urothelial cells from prostatic urethra may be contaminated by prostate basal cells that also express CD49f and EPCAM.	('prostatic urethra', 'Disease', (42, 59))	('prostatic urethra', 'Disease', 'MESH:D014523', (42, 59))	('CD49f', 'Var', (122, 127))	('EPCAM', 'Var', (132, 137))
118475	31871155	The transdifferentiation of cancer cells can be dictated by epigenetic modification in neuroblastoma and nonsmall cell lung cancer.	('cancer', 'Disease', (124, 130))	('epigenetic modification', 'Var', (60, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('neuroblastoma', 'Phenotype', 'HP:0003006', (87, 100))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (108, 130))	('nonsmall cell lung cancer', 'Disease', (105, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (105, 130))	('transdifferentiation', 'biological_process', 'GO:0060290', ('4', '24'))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('neuroblastoma', 'Disease', 'MESH:D009447', (87, 100))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('neuroblastoma', 'Disease', (87, 100))
118476	31871155	Importantly, mutations on epigenetic modifiers KDM6A, ARID1A, CREBBP, EP300, and KMT2A/C/D are present in more than 70% of SCCB samples.	('CREBBP', 'Gene', '1387', (62, 68))	('ARID1A', 'Gene', (54, 60))	('KDM6A', 'Gene', '7403', (47, 52))	('KMT2A', 'Gene', (81, 86))	('EP300', 'Gene', (70, 75))	('EP300', 'Gene', '2033', (70, 75))	('KMT2A', 'Gene', '4297', (81, 86))	('CREBBP', 'Gene', (62, 68))	('KDM6A', 'Gene', (47, 52))	('mutations', 'Var', (13, 22))	('ARID1A', 'Gene', '8289', (54, 60))
118478	31871155	Emerging evidence shows that targeting the epigenetic regulation as a promising therapeutic strategy for blood, liver, and colorectal cancers.	('blood', 'Disease', (105, 110))	('liver', 'Disease', (112, 117))	('colorectal cancers', 'Disease', 'MESH:D015179', (123, 141))	('regulation', 'biological_process', 'GO:0065007', ('54', '64'))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('colorectal cancers', 'Disease', (123, 141))	('epigenetic regulation', 'Var', (43, 64))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
118479	31871155	Therefore, our cell lines provided a useful tool to further investigate the epigenetic modification in dictating bladder cancer phenotypes and may lead to novel therapeutic strategies for aggressive bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (199, 213))	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('aggressive bladder cancer', 'Disease', 'MESH:D001749', (188, 213))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('lead to', 'Reg', (147, 154))	('epigenetic modification', 'Var', (76, 99))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('dictating bladder cancer', 'Disease', 'MESH:D001749', (103, 127))	('aggressive bladder cancer', 'Disease', (188, 213))	('dictating bladder cancer', 'Disease', (103, 127))	('dictating bladder', 'Phenotype', 'HP:0100645', (103, 120))
118483	31871155	We found that most SCCB samples had more than 5% PD-L1 positivity in TILs, suggesting a potential response to PD-1/PD-L1-targeted treatment.	('PD-L1', 'Gene', '29126', (49, 54))	('PD-L1', 'Gene', '29126', (115, 120))	('positivity', 'Var', (55, 65))	('PD-1', 'Gene', (110, 114))	('PD-1', 'Gene', '5133', (110, 114))	('PD-L1', 'Gene', (49, 54))	('PD-L1', 'Gene', (115, 120))
118535	31871155	The CSP associated with a specific phenotype is determined by the P < 0.05 and LFC >0 (SCCB) or LFC < 0 (non-SCCB) in DESeq2 analysis.	('CSP', 'Gene', (4, 7))	('LFC < 0', 'Var', (96, 103))	('CSP', 'Gene', '80331', (4, 7))	('LFC >0', 'Var', (79, 85))
118547	31186635	Interestingly, survival analysis based on NEAT1 expression in several cancer tissues revealed that the p53 wild-type group with high NEAT1 expression had a good prognosis, while poor prognosis or no correlation between NEAT1 expression and survival was observed in the p53-mutated group.	('p53', 'Gene', (269, 272))	('p53', 'Gene', '7157', (269, 272))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('NEAT1', 'Gene', '283131', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('NEAT1', 'Gene', '283131', (219, 224))	('NEAT1', 'Gene', (42, 47))	('NEAT1', 'Gene', '283131', (133, 138))	('NEAT1', 'Gene', (219, 224))	('high', 'Var', (128, 132))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('expression', 'MPA', (139, 149))	('NEAT1', 'Gene', (133, 138))
118552	31186635	Furthermore, abnormality of p53 such as mutation or deletion causes poor prognosis and resistance to various cancer therapies.	('p53', 'Gene', (28, 31))	('mutation', 'Var', (40, 48))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('p53', 'Gene', '7157', (28, 31))	('cancer', 'Disease', (109, 115))	('resistance', 'CPA', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('deletion', 'Var', (52, 60))
118559	31186635	NEAT1 knockdown had an effect on p53-induced transactivation and enhanced cancer cell growth.	('transactivation', 'MPA', (45, 60))	('NEAT1', 'Gene', (0, 5))	('NEAT1', 'Gene', '283131', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('enhanced', 'PosReg', (65, 73))	('cancer', 'Disease', (74, 80))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('knockdown', 'Var', (6, 15))	('cell growth', 'biological_process', 'GO:0016049', ('81', '92'))	('transactivation', 'biological_process', 'GO:2000144', ('45', '60'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
118568	31186635	Total 11,095 RNA-seq files were analyzed using a series of cufflinks software programs, cuffquant and cuffnorm to quantify and normalize the expression of NEAT1, NEAT1_2 (NR_131012), CDKN1A, and MDM2 genes.	('CDKN1A', 'Gene', '1026', (183, 189))	('MDM2', 'Gene', '4193', (195, 199))	('MDM2', 'Gene', (195, 199))	('NEAT1', 'Gene', '283131', (162, 167))	('NEAT1', 'Gene', '283131', (155, 160))	('NEAT1', 'Gene', (162, 167))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('NR_131012', 'Var', (171, 180))	('NEAT1', 'Gene', (155, 160))	('CDKN1A', 'Gene', (183, 189))
118576	31186635	RNA-seq data of tumors were divided into two groups, wild-type p53 or mutated p53 (including homologous deletion) groups, and then, the expression of NEAT1 and two major p53 transcriptional targets, CDKN1A (encoding p21) and MDM2, was analyzed and compared among the groups (Figure 2 and Supplementary Figure 1).	('p21', 'Gene', (216, 219))	('p53', 'Gene', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', (16, 22))	('MDM2', 'Gene', (225, 229))	('p53', 'Gene', '7157', (63, 66))	('CDKN1A', 'Gene', (199, 205))	('CDKN1A', 'Gene', '1026', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('p53', 'Gene', '7157', (78, 81))	('MDM2', 'Gene', '4193', (225, 229))	('p21', 'Gene', '1026', (216, 219))	('p53', 'Gene', (63, 66))	('NEAT1', 'Gene', (150, 155))	('p53', 'Gene', (78, 81))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('p53', 'Gene', '7157', (170, 173))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('mutated', 'Var', (70, 77))	('NEAT1', 'Gene', '283131', (150, 155))
118590	31186635	Among 32 cancer tissues, in 11 cancer types (BLCA, BRCA, head and neck squamous cell carcinoma (HNSC), LIHC, LUAD, MESO, OV, rectal adenocarcinoma (READ), SARC, skin cutaneous melanoma (SKCM), and STAD), the rate of survival was significantly higher among patients whose tumors had high levels of NEAT1 expression compared with those with low NEAT1-expressing tumors ("Good" in "Total" column of Table 1).	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (161, 184))	('cancer', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (360, 366))	('NEAT1', 'Gene', (297, 302))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Disease', (271, 277))	('SARC', 'Disease', (155, 159))	('skin cutaneous melanoma', 'Disease', (161, 184))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (125, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (166, 184))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('READ', 'Disease', 'None', (148, 152))	('survival', 'MPA', (216, 224))	('BRCA', 'Gene', '672', (51, 55))	('neck', 'cellular_component', 'GO:0044326', ('66', '70'))	('NEAT1', 'Gene', (343, 348))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('expression', 'MPA', (303, 313))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('LIHC', 'Disease', (103, 107))	('NEAT1', 'Gene', '283131', (297, 302))	('SARC', 'Phenotype', 'HP:0100242', (155, 159))	('tumors', 'Phenotype', 'HP:0002664', (360, 366))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('BRCA', 'Gene', (51, 55))	('rectal adenocarcinoma', 'Disease', (125, 146))	('higher', 'PosReg', (243, 249))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (57, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('high', 'Var', (282, 286))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('NEAT1', 'Gene', '283131', (343, 348))	('LIHC', 'Disease', 'None', (103, 107))	('tumors', 'Disease', (360, 366))	('READ', 'Disease', (148, 152))	('neck squamous cell carcinoma', 'Disease', (66, 94))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (66, 94))	('patients', 'Species', '9606', (256, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('BRCA', 'Phenotype', 'HP:0003002', (51, 55))
118591	31186635	On the other hand, in 7 cancer types, the survival rate was significantly lower among patients whose tumors had high levels of NEAT1 expression than among those with low NEAT1 expression in tumors (colon adenocarcinoma (COAD), glioblastoma multiforme (GBM), KIRC, lower grade glioma (LGG), THYM, uterine corpus endometrial carcinoma (UCEC), and uveal melanoma (UVM)) ("Poor" in "Total" column of Table 1).	('uveal melanoma', 'Disease', 'MESH:C536494', (345, 359))	('THYM', 'Phenotype', 'HP:0100522', (290, 294))	('uveal melanoma', 'Disease', (345, 359))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('NEAT1', 'Gene', '283131', (127, 132))	('high', 'Var', (112, 116))	('cancer', 'Disease', (24, 30))	('COAD', 'Disease', 'MESH:D029424', (220, 224))	('tumors', 'Disease', (190, 196))	('lower', 'NegReg', (74, 79))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('patients', 'Species', '9606', (86, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (345, 359))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('colon adenocarcinoma', 'Disease', (198, 218))	('NEAT1', 'Gene', '283131', (170, 175))	('glioblastoma multiforme', 'Disease', (227, 250))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('glioblastoma', 'Phenotype', 'HP:0012174', (227, 239))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (227, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('endometrial carcinoma', 'Disease', (311, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (323, 332))	('COAD', 'Disease', (220, 224))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('NEAT1', 'Gene', (127, 132))	('tumors', 'Disease', (101, 107))	('expression', 'MPA', (133, 143))	('glioma', 'Disease', (276, 282))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (311, 332))	('survival', 'CPA', (42, 50))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (198, 218))	('glioma', 'Disease', 'MESH:D005910', (276, 282))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (311, 332))	('NEAT1', 'Gene', (170, 175))	('melanoma', 'Phenotype', 'HP:0002861', (351, 359))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
118594	31186635	To clarify the p53 dependency of the prognostic effect of NEAT1, tumors were divided into two groups, wild-type p53 and mutated p53 (including homologous deletion) groups, and then, prognosis was analyzed in 18 cancer tissues that had sufficient sample numbers of both wild-type and mutated p53 tumor tissues.	('p53', 'Gene', '7157', (128, 131))	('NEAT1', 'Gene', (58, 63))	('mutated', 'Var', (283, 290))	('tumors', 'Disease', (65, 71))	('p53', 'Gene', '7157', (112, 115))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('tumor', 'Disease', (65, 70))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (15, 18))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('p53', 'Gene', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (295, 300))	('NEAT1', 'Gene', '283131', (58, 63))	('p53', 'Gene', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('p53', 'Gene', '7157', (291, 294))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('cancer', 'Disease', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('p53', 'Gene', (291, 294))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
118595	31186635	Interestingly, in BRCA and OV, the p53 wild-type group with high NEAT1 expression had a good prognosis compared with those with low NEAT1 expression, while poor prognosis was indicated in the p53-mutated group with high NEAT1 expression compared with low NEAT1 expression (Figure 3 and Table 1).	('BRCA', 'Phenotype', 'HP:0003002', (18, 22))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('high', 'Var', (60, 64))	('BRCA', 'Gene', '672', (18, 22))	('NEAT1', 'Gene', '283131', (65, 70))	('NEAT1', 'Gene', '283131', (220, 225))	('p53', 'Gene', '7157', (192, 195))	('BRCA', 'Gene', (18, 22))	('NEAT1', 'Gene', (65, 70))	('NEAT1', 'Gene', '283131', (255, 260))	('NEAT1', 'Gene', (220, 225))	('NEAT1', 'Gene', '283131', (132, 137))	('NEAT1', 'Gene', (255, 260))	('p53', 'Gene', (192, 195))	('NEAT1', 'Gene', (132, 137))
118597	31186635	Furthermore, in BLCA, lung squamous cell carcinoma (LUSC), and SKCM, the p53 wild-type group with high NEAT1 expression had a good prognosis compared with the group with low NEAT1 expression, while the p53-mutated groups did not exhibit a significant prognosis difference based on NEAT1 expression (Supplementary Figure 4).	('NEAT1', 'Gene', '283131', (281, 286))	('lung squamous cell carcinoma', 'Disease', (22, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('LUSC', 'Phenotype', 'HP:0030359', (52, 56))	('NEAT1', 'Gene', (281, 286))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('NEAT1', 'Gene', (174, 179))	('NEAT1', 'Gene', '283131', (174, 179))	('high', 'Var', (98, 102))	('NEAT1', 'Gene', '283131', (103, 108))	('expression', 'Var', (109, 119))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (22, 50))	('NEAT1', 'Gene', (103, 108))	('p53', 'Gene', '7157', (202, 205))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (22, 50))	('p53', 'Gene', (202, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (27, 50))
118616	31186635	In 11 of 32 cancer types (BLCA, BRCA, HNSC, LIHC, LUAD, MESO, OV, READ, SARC, SKCM, and STAD), high NEAT1 expression suggested a good prognosis but suggested a poor prognosis in seven other cancer types (COAD, GBM, KIRC, LGG, THYM, UCEC, and UVM) (Table 1, Supplementary Figure 3).	('GBM', 'Disease', (210, 213))	('SARC', 'Phenotype', 'HP:0100242', (72, 76))	('THYM', 'Phenotype', 'HP:0100522', (226, 230))	('LIHC', 'Disease', 'None', (44, 48))	('cancer', 'Disease', (190, 196))	('READ', 'Disease', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('COAD', 'Disease', 'MESH:D029424', (204, 208))	('high', 'Var', (95, 99))	('NEAT1', 'Gene', '283131', (100, 105))	('BRCA', 'Phenotype', 'HP:0003002', (32, 36))	('LGG', 'Disease', (221, 224))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('THYM', 'Disease', (226, 230))	('KIRC', 'Disease', (215, 219))	('READ', 'Disease', 'None', (66, 70))	('BRCA', 'Gene', '672', (32, 36))	('COAD', 'Disease', (204, 208))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', (12, 18))	('UCEC', 'Disease', (232, 236))	('LIHC', 'Disease', (44, 48))	('LUAD', 'Phenotype', 'HP:0030078', (50, 54))	('NEAT1', 'Gene', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('BRCA', 'Gene', (32, 36))
118618	31186635	Therefore, considering p53 mutational status, we divided tumors into two groups, wild-type p53 and mutated p53 groups, and then, prognosis was analyzed.	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mutated', 'Var', (99, 106))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
118619	31186635	Surprisingly, in seven cancer types (BLCA, BRCA, LUSC, OV, SARC, SKCM and STAD), the p53 wild-type group with high NEAT1 expression had a good prognosis, while the opposite result or no correlation between NEAT1 expression and survival was observed in the p53-mutated group (Figure 3, Table 1, Supplementary Figure 4).	('SARC', 'Disease', (59, 63))	('LUSC', 'Phenotype', 'HP:0030359', (49, 53))	('NEAT1', 'Gene', '283131', (206, 211))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('BRCA', 'Phenotype', 'HP:0003002', (43, 47))	('p53', 'Gene', (256, 259))	('high', 'Var', (110, 114))	('BRCA', 'Gene', '672', (43, 47))	('NEAT1', 'Gene', '283131', (115, 120))	('p53', 'Gene', '7157', (85, 88))	('SARC', 'Phenotype', 'HP:0100242', (59, 63))	('cancer', 'Disease', (23, 29))	('NEAT1', 'Gene', (206, 211))	('p53', 'Gene', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('BRCA', 'Gene', (43, 47))	('LUSC', 'Disease', (49, 53))	('p53', 'Gene', '7157', (256, 259))	('NEAT1', 'Gene', (115, 120))	('SKCM', 'Disease', (65, 69))
118632	26791567	Non-muscle-invasive bladder carcinoma (NMIBC) accounts for about 75 % of bladder cancers, and high-grade T1 is the subtype of NMIBC at highest risk, with patients facing long-term cancer-specific mortality rates as high as 34 %.	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Disease', (81, 87))	('muscle-invasive bladder carcinoma', 'Phenotype', 'HP:0006740', (4, 37))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('Non-muscle-invasive bladder carcinoma', 'Disease', 'MESH:D001749', (0, 37))	('high-grade', 'Var', (94, 104))	('bladder cancers', 'Phenotype', 'HP:0009725', (73, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('invasive bladder', 'Phenotype', 'HP:0100645', (11, 27))	('cancer', 'Disease', (180, 186))	('Non-muscle-invasive bladder carcinoma', 'Disease', (0, 37))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('patients', 'Species', '9606', (154, 162))	('Non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (0, 27))	('bladder cancers', 'Disease', 'MESH:D001749', (73, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (20, 37))	('T1', 'Gene', '291', (105, 107))	('bladder cancers', 'Disease', (73, 88))	('cancer', 'Disease', 'MESH:D009369', (180, 186))
118723	26770009	In this paper, we mainly review immunohistochemical studies showing associations between alterations of steroid hormone receptors in urothelial tumors and patient outcomes.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('urothelial tumors', 'Disease', (133, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('patient', 'Species', '9606', (155, 162))	('steroid', 'Chemical', 'MESH:D013256', (104, 111))	('associations', 'Interaction', (68, 80))	('alterations', 'Var', (89, 100))	('urothelial tumors', 'Disease', 'MESH:D001749', (133, 150))
118734	26770009	Despite the promoting effects of AR signals on tumorigenesis, two studies showed a significant correlation and a tendency, respectively, between AR expression and lower risks of bladder tumor recurrence.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('AR expression', 'Var', (145, 158))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('bladder tumor', 'Disease', (178, 191))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('promoting', 'PosReg', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('lower', 'NegReg', (163, 168))	('bladder tumor', 'Disease', 'MESH:D001749', (178, 191))	('tumor', 'Disease', (47, 52))	('bladder tumor', 'Phenotype', 'HP:0009725', (178, 191))
118738	26770009	For instance, significantly higher incidence of bladder cancer was observed in BBN-treated ERalpha knockout female mice, compared with wild-type female littermates, suggesting the preventive role of ERalpha in bladder cancer development.	('bladder cancer', 'Disease', (48, 62))	('bladder cancer', 'Disease', (210, 224))	('bladder cancer', 'Disease', 'MESH:D001749', (210, 224))	('BBN', 'Chemical', '-', (79, 82))	('men', 'Species', '9606', (232, 235))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (210, 224))	('higher', 'PosReg', (28, 34))	('knockout', 'Var', (99, 107))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('ERalpha', 'Gene', (91, 98))	('mice', 'Species', '10090', (115, 119))
118739	26770009	Selective ER modulators, such as tamoxifen and raloxifen, were also shown to inhibit the growth of bladder cancer cell lines expressing ERbeta.	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('raloxifen', 'Chemical', '-', (47, 56))	('inhibit', 'NegReg', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('growth', 'MPA', (89, 95))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('ERbeta', 'Var', (136, 142))	('bladder cancer', 'Disease', (99, 113))	('tamoxifen', 'Chemical', 'MESH:D013629', (33, 42))
118763	26770009	Multivariate analysis identified low GR expression as a predictor for recurrence of non-muscle-invasive bladder tumors (hazard ratio (HR) = 2.252; P = 0.034) and progression of muscle-invasive bladder tumors (HR = 3.690; P = 0.077).	('expression', 'MPA', (40, 50))	('invasive bladder', 'Phenotype', 'HP:0100645', (95, 111))	('bladder tumor', 'Phenotype', 'HP:0009725', (104, 117))	('bladder tumors', 'Phenotype', 'HP:0009725', (193, 207))	('muscle-invasive bladder tumors', 'Disease', 'MESH:D001749', (88, 118))	('low', 'Var', (33, 36))	('non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (84, 111))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('bladder tumors', 'Phenotype', 'HP:0009725', (104, 118))	('GR', 'Gene', '2908', (37, 39))	('muscle-invasive bladder tumors', 'Disease', (177, 207))	('muscle-invasive bladder tumors', 'Disease', (88, 118))	('muscle-invasive bladder tumors', 'Disease', 'MESH:D001749', (177, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('bladder tumor', 'Phenotype', 'HP:0009725', (193, 206))	('invasive bladder', 'Phenotype', 'HP:0100645', (184, 200))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
118776	26770009	VDR gene polymorphism resulting in reduction of receptor activity has also been correlated with higher incidence of bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (116, 130))	('VDR gene', 'Gene', (0, 8))	('bladder cancer', 'Disease', (116, 130))	('polymorphism', 'Var', (9, 21))	('bladder cancer', 'Disease', 'MESH:D001749', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('receptor activity', 'molecular_function', 'GO:0038024', ('48', '65'))	('receptor activity', 'MPA', (48, 65))	('receptor activity', 'molecular_function', 'GO:0038023', ('48', '65'))	('reduction', 'NegReg', (35, 44))
118788	26770009	In addition, methylated RARbeta was frequently found in bladder cancer tissues and urine samples from bladder cancer patients, suggesting its utility as a urine marker.	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('methylated', 'Var', (13, 23))	('RARbeta', 'Gene', '5915', (24, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('found', 'Reg', (47, 52))	('bladder cancer', 'Disease', (102, 116))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('RARbeta', 'Gene', (24, 31))	('patients', 'Species', '9606', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('bladder cancer', 'Disease', (56, 70))
118799	26770009	Moreover, high cytoplasmic Nurr1 expression, but not total expression, was an independent prognosticator of cancer-specific mortality (HR = 4.894; P < 0.001).	('high cytoplasmic', 'Var', (10, 26))	('Nurr1', 'Gene', (27, 32))	('Nurr1', 'Gene', '4929', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
118805	26770009	In animal models, CD24 overexpression and knockdown resulted in stimulation and inhibition, respectively, of the development of primary bladder cancer and its metastasis.	('overexpression', 'PosReg', (23, 37))	('stimulation', 'PosReg', (64, 75))	('inhibition', 'NegReg', (80, 90))	('metastasis', 'CPA', (159, 169))	('development', 'CPA', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('primary bladder cancer', 'Disease', 'MESH:D001749', (128, 150))	('primary bladder cancer', 'Disease', (128, 150))	('CD24', 'Gene', '100133941', (18, 22))	('CD24', 'Gene', (18, 22))	('knockdown', 'Var', (42, 51))	('men', 'Species', '9606', (120, 123))
118824	26770009	Alterations of the EGFR family, such as protein overexpression and gene amplification or mutation, have been extensively studied in bladder cancer specimens, providing mixed results regarding their prognostic values.	('bladder cancer', 'Disease', 'MESH:D001749', (132, 146))	('bladder cancer', 'Disease', (132, 146))	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('mutation', 'Var', (89, 97))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('EGFR', 'Gene', '1956', (19, 23))	('men', 'Species', '9606', (152, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (132, 146))	('overexpression', 'PosReg', (48, 62))	('EGFR', 'Gene', (19, 23))	('protein', 'Protein', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('gene amplification', 'Var', (67, 85))
118837	26770009	While there were no significant correlations between the levels of ELK1 or phospho-ELK1 and tumor grades or stages, phospho-ELK1 positivity precisely predicted the recurrence of non-muscle-invasive tumors in a univariate setting (P = 0.043) as well as a worse outcome of muscle-invasive tumors in both univariate (P = 0.045 for disease progression; P = 0.008 for cancer-specific mortality) and multivariate (HR = 2.693; P = 0.021 for cancer-specific mortality) settings.	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (271, 293))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('ELK1', 'Gene', (67, 71))	('muscle-invasive tumors', 'Disease', (271, 293))	('cancer', 'Disease', 'MESH:D009369', (363, 369))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (182, 204))	('ELK1', 'Gene', '2002', (124, 128))	('muscle-invasive tumors', 'Disease', (182, 204))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (287, 292))	('ELK1', 'Gene', '2002', (83, 87))	('cancer', 'Disease', (434, 440))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('cancer', 'Disease', (363, 369))	('cancer', 'Phenotype', 'HP:0002664', (434, 440))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('ELK1', 'Gene', '2002', (67, 71))	('tumor', 'Disease', (198, 203))	('predicted', 'Reg', (150, 159))	('positivity', 'Var', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('ELK1', 'Gene', (83, 87))	('ELK1', 'Gene', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('cancer', 'Disease', 'MESH:D009369', (434, 440))
118838	26770009	Subsequent immunohistochemistry in bladder cancer specimens from patients who received neoadjuvant chemotherapy revealed that phospho-ELK1 positivity strongly correlated with chemoresistance.	('bladder cancer', 'Disease', (35, 49))	('men', 'Species', '9606', (55, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (35, 49))	('correlated with', 'Reg', (159, 174))	('ELK1', 'Gene', (134, 138))	('chemoresistance', 'CPA', (175, 190))	('positivity', 'Var', (139, 149))	('patients', 'Species', '9606', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('bladder cancer', 'Disease', 'MESH:D001749', (35, 49))	('ELK1', 'Gene', '2002', (134, 138))
118839	26770009	Indeed, ELK1 inactivation resulted in enhancement of the cytotoxic activity of cisplatin in bladder cancer cells.	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('inactivation', 'Var', (13, 25))	('men', 'Species', '9606', (45, 48))	('bladder cancer', 'Disease', 'MESH:D001749', (92, 106))	('bladder cancer', 'Disease', (92, 106))	('ELK1', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('ELK1', 'Gene', '2002', (8, 12))	('enhancement', 'PosReg', (38, 49))	('bladder cancer', 'Phenotype', 'HP:0009725', (92, 106))	('cytotoxic', 'CPA', (57, 66))
118842	26770009	GATA3 knockdown in SVHUC exposed to the chemical carcinogen resulted in downregulation of the molecules that play a protective role in bladder tumorigenesis, such as UGT1A, PTEN, p53, and p21, and upregulation of oncogenic genes, such as c-myc, cyclins D1/D3/E, and FGFR3.	('GATA3', 'Gene', '2625', (0, 5))	('p53', 'Gene', (179, 182))	('bladder tumor', 'Disease', 'MESH:D001749', (135, 148))	('PTEN', 'Gene', (173, 177))	('FGFR', 'molecular_function', 'GO:0005007', ('266', '270'))	('GATA3', 'Gene', (0, 5))	('c-myc', 'Gene', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('upregulation', 'PosReg', (197, 209))	('molecules', 'Protein', (94, 103))	('PTEN', 'Gene', '5728', (173, 177))	('cyclins D1/D3/E', 'Gene', (245, 260))	('p21', 'Gene', (188, 191))	('UGT1A', 'Gene', (166, 171))	('p21', 'Gene', '644914', (188, 191))	('bladder tumor', 'Phenotype', 'HP:0009725', (135, 148))	('FGFR3', 'Gene', (266, 271))	('c-myc', 'Gene', '4609', (238, 243))	('FGFR3', 'Gene', '2261', (266, 271))	('p53', 'Gene', '7157', (179, 182))	('knockdown', 'Var', (6, 15))	('oncogenic genes', 'Gene', (213, 228))	('downregulation', 'NegReg', (72, 86))	('bladder tumor', 'Disease', (135, 148))
118844	26770009	GATA3 knockdown in bladder cancer lines also resulted in promotion of cell invasion and migration as well as induction of the expression of their related molecules, such as MMP-2 and MMP-9, while androgens did not significantly change the levels of GATA3 expression in these cells.	('GATA3', 'Gene', '2625', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('MMP-2', 'Gene', '4313', (173, 178))	('promotion', 'PosReg', (57, 66))	('GATA3', 'Gene', (0, 5))	('MMP-2', 'Gene', (173, 178))	('expression', 'MPA', (126, 136))	('MMP-2', 'molecular_function', 'GO:0004228', ('173', '178'))	('GATA3', 'Gene', '2625', (249, 254))	('bladder cancer', 'Disease', 'MESH:D001749', (19, 33))	('bladder cancer', 'Disease', (19, 33))	('GATA3', 'Gene', (249, 254))	('cell invasion', 'CPA', (70, 83))	('MMP-9', 'Gene', (183, 188))	('migration', 'CPA', (88, 97))	('MMP-9', 'Gene', '4318', (183, 188))	('bladder cancer', 'Phenotype', 'HP:0009725', (19, 33))	('knockdown', 'Var', (6, 15))	('MMP-9', 'molecular_function', 'GO:0004229', ('183', '188'))
118863	22743166	The cumulative smoking exposure was categorized as light-short-term (<=19 CPD and <=19.9 yr), moderate (all combinations except light-short-term and heavy-long-term), and heavy-long-term (>= 20CPD and >= 20 yr).	('<=19', 'Var', (69, 73))	('CPD', 'Disease', (193, 196))	('CPD', 'Disease', 'MESH:C565865', (193, 196))	('CPD', 'Disease', 'MESH:C565865', (74, 77))	('CPD', 'Disease', (74, 77))
118867	22743166	Current smoking status, smoking >=20CPD >=20 yr, and heavy-long-term smoking were associated with advanced disease (p values <=0.004), greater likelihood of disease recurrence (p values <=0.01), and cancer-specific mortality (p values <=0.05) on multivariable analyses that adjusted for standard features.	('heavy-long-term', 'Var', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('disease recurrence', 'CPA', (157, 175))	('CPD', 'Disease', 'MESH:C565865', (36, 39))	('CPD', 'Disease', (36, 39))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('advanced', 'Disease', (98, 106))	('cancer', 'Disease', (199, 205))	('greater', 'PosReg', (135, 142))
118903	22743166	We categorized patients based on their cumulative smoking exposure into four groups: never smoker, light-short-term smoker (<=19 CPD and <=19.9 yr), moderate smoker (>=20 CPD and <=19.9 yr or <=19 CPD and >=20 yr), and heavy-long-term smokers (>=20 CPD and >=20 yr).	('patients', 'Species', '9606', (15, 23))	('<=19', 'Var', (124, 128))	('CPD', 'Disease', (171, 174))	('>=20', 'Var', (166, 170))	('CPD', 'Disease', (197, 200))	('CPD', 'Disease', 'MESH:C565865', (197, 200))	('CPD', 'Disease', (249, 252))	('CPD', 'Disease', 'MESH:C565865', (129, 132))	('CPD', 'Disease', 'MESH:C565865', (249, 252))	('CPD', 'Disease', (129, 132))	('CPD', 'Disease', 'MESH:C565865', (171, 174))
118904	22743166	Using multivariable logistic regression analyses, the association of smoking with pathologic stage and lymph node metastasis at the time of RNU was assessed in two models (end points: prediction of >=pT2 and/or pN+, >=pT3, and/or pN+).	('pT3', 'Gene', '7694', (218, 221))	('pT3', 'Gene', (218, 221))	('RNU', 'Chemical', '-', (140, 143))	('>=pT2', 'Var', (198, 203))	('pN+', 'Disease', (211, 214))
118941	22743166	Although the exact mechanisms of smoking-induced urothelial carcinogenesis remain unknown, accumulating evidence suggests that dose escalation and longer duration might increase not only the risk of development of UC but also its aggressiveness and the risk of progression to advanced disease.	('dose escalation', 'Var', (127, 142))	('aggressiveness', 'Disease', (230, 244))	('urothelial carcinogenesis', 'Disease', (49, 74))	('increase', 'PosReg', (169, 177))	('aggressiveness', 'Phenotype', 'HP:0000718', (230, 244))	('aggressiveness', 'Disease', 'MESH:D001523', (230, 244))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (49, 74))
118951	24409280	Reproducibility and Prognostic Value of WHO1973 and WHO2004 Grading Systems in TaT1 Urothelial Carcinoma of the Urinary Bladder European treatment guidelines of TaT1 urinary bladder urothelial carcinomas depend highly on stage and WHO1973-grade but grading reproducibility is wanting.	('WHO1973', 'CellLine', 'CVCL:E046', (231, 238))	('urinary bladder urothelial carcinomas', 'Disease', 'MESH:D001749', (166, 203))	('Carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('TaT1', 'Gene', '116369', (161, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('TaT1 Urothelial Carcinoma', 'Disease', (79, 104))	('TaT1', 'Gene', (161, 165))	('urinary bladder urothelial carcinomas', 'Disease', (166, 203))	('TaT1', 'Gene', (79, 83))	('TaT1', 'Gene', '116369', (79, 83))	('WHO1973-grade', 'Var', (231, 244))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('TaT1 Urothelial Carcinoma', 'Disease', 'MESH:D014526', (79, 104))	('WHO1973', 'CellLine', 'CVCL:E046', (40, 47))
118952	24409280	To compare reproducibility and prognostic value (of stage progression) of the WHO1973 and WHO2004.	('WHO1973', 'CellLine', 'CVCL:E046', (78, 85))	('WHO1973', 'Var', (78, 85))	('WHO2004', 'Var', (90, 97))
118961	24409280	Therefore, the aims of the current study were to compare the inter-observer reproducibility and prognostic value (on stage progression) of the WHO73 and WHO04 in patients with TaT1 urothelial urinary bladder cancer and the clinical significance of distinguishing PUNLMP and low grade cancers.	('patients', 'Species', '9606', (162, 170))	('urothelial urinary bladder cancer', 'Disease', (181, 214))	('cancers', 'Disease', 'MESH:D009369', (284, 291))	('cancers', 'Phenotype', 'HP:0002664', (284, 291))	('cancers', 'Disease', (284, 291))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('WHO04', 'Var', (153, 158))	('bladder cancer', 'Phenotype', 'HP:0009725', (200, 214))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('urothelial urinary bladder cancer', 'Disease', 'MESH:D001749', (181, 214))	('TaT1', 'Gene', '116369', (176, 180))	('WHO73', 'Var', (143, 148))	('TaT1', 'Gene', (176, 180))
118979	24409280	Median ages for patients with different WHO73 or WHO04 grade tumours were compared by Mann Whitney U tests.	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('patients', 'Species', '9606', (16, 24))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('WHO73', 'Var', (40, 45))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('tumours', 'Disease', (61, 68))	('WHO04 grade', 'Var', (49, 60))
118987	24409280	For WHO04, the median age was 71.0 years for low grade and 75.5 years for high grade tumours (p = 0.006).	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('tumours', 'Disease', 'MESH:D009369', (85, 92))	('tumours', 'Disease', (85, 92))	('WHO04', 'Var', (4, 9))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
118996	24409280	On consensus diagnosis, all WHO73 grade 1 tumours were classified as low grade.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('tumours', 'Disease', 'MESH:D009369', (42, 49))	('WHO73', 'Var', (28, 33))	('tumours', 'Disease', (42, 49))
119000	24409280	When analysing progression in the two stages separately, for pTa tumours there were significant differences between the grades of both the WHO73 (grades 1&2 versus 3) and the WHO04, but more so in the WHO73 (p<0.001 versus p = 0.015, Figure 2).	('pTa tumours', 'Disease', (61, 72))	('pTa', 'molecular_function', 'GO:0008959', ('61', '64'))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('WHO73', 'Var', (139, 144))	('pTa tumours', 'Disease', 'MESH:D009369', (61, 72))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('differences', 'Reg', (96, 107))
119014	24409280	The WHO04 has many more high-grade tumours (n = 74) than the WHO73 (grade 3, n = 51).	('tumours', 'Disease', (35, 42))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('tumours', 'Disease', 'MESH:D009369', (35, 42))	('WHO04', 'Var', (4, 9))
119017	24409280	The proportion of WHO73 grade 3 tumours was 26% whereas there were 38% WHO04 high grade tumours, both considerably higher than the overall progression rate of 9%.	('tumours', 'Disease', 'MESH:D009369', (32, 39))	('tumours', 'Disease', (32, 39))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('tumours', 'Disease', (88, 95))	('WHO04', 'Var', (71, 76))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('WHO73', 'Var', (18, 23))
119018	24409280	For patients with otherwise similar risk factors for progression (multiplicity, tumour size, progression rate, and stage), this could lead to overtreatment if the WHO04 high grade tumours were treated similarly to the WHO73 grade 3 tumours.	('tumours', 'Disease', 'MESH:D009369', (180, 187))	('tumours', 'Disease', (232, 239))	('lead', 'Reg', (134, 138))	('tumours', 'Phenotype', 'HP:0002664', (232, 239))	('tumours', 'Disease', 'MESH:D009369', (232, 239))	('overtreatment', 'PosReg', (142, 155))	('patients', 'Species', '9606', (4, 12))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('tumour', 'Disease', 'MESH:D009369', (232, 238))	('tumour', 'Disease', (232, 238))	('WHO04', 'Var', (163, 168))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('tumour', 'Disease', (80, 86))	('tumours', 'Disease', (180, 187))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('tumours', 'Phenotype', 'HP:0002664', (180, 187))	('tumour', 'Disease', (180, 186))
119020	24409280	In 2010, van Rhijn et al showed that using a molecular grade, consisting of a combination of FGFR3 mutations status and Ki67%, could predict recurrence and progression more accurately and more reproducibly.	('mutations status', 'Var', (99, 115))	('FGFR3', 'Gene', '2261', (93, 98))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('FGFR3', 'Gene', (93, 98))	('recurrence', 'CPA', (141, 151))
119168	32344898	In addition, we demonstrate that cells expressing PAI1 protein are more sensitive to the PIM inhibitor AZD1208, suggesting that PAI1 could be used to predict response to treatment with PIM inhibitors and to complement radiotherapy in rectal tumors.	('rectal tumors', 'Disease', 'MESH:D012004', (234, 247))	('PIM', 'Gene', (89, 92))	('PIM', 'Gene', '5292', (89, 92))	('PAI1', 'Gene', (128, 132))	('rectal tumors', 'Disease', (234, 247))	('rectal tumors', 'Phenotype', 'HP:0100743', (234, 247))	('PAI1', 'Gene', (50, 54))	('PIM', 'Gene', (185, 188))	('PIM', 'Gene', '5292', (185, 188))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('PAI1', 'Gene', '5054', (128, 132))	('protein', 'Var', (55, 62))	('PAI1', 'Gene', '5054', (50, 54))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('sensitive', 'MPA', (72, 81))	('rectal tumor', 'Phenotype', 'HP:0100743', (234, 246))	('AZD1208', 'Chemical', 'MESH:C587575', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
119181	32344898	Moreover, deregulation of PAI1 expression has been involved in cardiovascular diseases, obesity, metabolic syndrome and various types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('deregulation', 'Var', (10, 22))	('obesity', 'Disease', 'MESH:D009765', (88, 95))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('obesity', 'Disease', (88, 95))	('cardiovascular diseases', 'Disease', (63, 86))	('involved', 'Reg', (51, 59))	('expression', 'MPA', (31, 41))	('cancer', 'Disease', (137, 143))	('PAI1', 'Gene', (26, 30))	('metabolic syndrome', 'Disease', (97, 115))	('metabolic syndrome', 'Disease', 'MESH:D024821', (97, 115))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (63, 86))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (63, 86))	('obesity', 'Phenotype', 'HP:0001513', (88, 95))	('PAI1', 'Gene', '5054', (26, 30))
119185	32344898	Moreover, PAI1 expression is also correlated with poor outcome in several other cancer subtypes, such as node-negative breast cancer and ovarian serous carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('expression', 'Var', (15, 25))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (137, 161))	('PAI1', 'Gene', '5054', (10, 14))	('breast cancer', 'Disease', (119, 132))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('ovarian serous carcinoma', 'Disease', (137, 161))	('correlated', 'Reg', (34, 44))	('PAI1', 'Gene', (10, 14))	('cancer', 'Disease', (80, 86))
119201	32344898	Eligible patients were those with locally advanced rectal cancer T3-4 N+ M0 (stages II-III) that had completed the neoadjuvant chemoradiotherapy plan before resection with curative intention.	('rectal cancer', 'Phenotype', 'HP:0100743', (51, 64))	('patients', 'Species', '9606', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('T3-4 N+ M0', 'Var', (65, 75))
119212	32344898	Briefly, SW48, SW480, T84, LS180, LOVO, HT29 HCT116 and COLO205 were cultured in the corresponding medium and incubated at 37  C in 5% CO2 in a humidified atmosphere.	('T84', 'Var', (22, 25))	('SW480', 'Var', (15, 20))	('SW48', 'CellLine', 'CVCL:1724', (9, 13))	('SW48', 'CellLine', 'CVCL:1724', (15, 19))	('SW48', 'Var', (9, 13))	('SW480', 'CellLine', 'CVCL:0546', (15, 20))	('CO2', 'Chemical', 'MESH:D002245', (135, 138))	('HT29 HCT116', 'CellLine', 'CVCL:0291', (40, 51))
119223	32344898	To study the potential of PAI1 as a marker in rectal cancer, we first analyzed PAI1 expression levels in four public rectal cancer databases: GSE35452, GSE8671 and GSE2109 (Table S3).	('GSE35452', 'Var', (142, 150))	('PAI1', 'Gene', (79, 83))	('cancer', 'Disease', (124, 130))	('rectal cancer', 'Phenotype', 'HP:0100743', (46, 59))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('GSE8671', 'Var', (152, 159))	('PAI1', 'Gene', '5054', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('PAI1', 'Gene', (26, 30))	('rectal cancer', 'Phenotype', 'HP:0100743', (117, 130))	('GSE2109', 'Var', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('PAI1', 'Gene', '5054', (26, 30))
119226	32344898	We extended this analysis to colorectal cancer patients in GSE8671 and four additional databases with paired non-tumor and tumor samples (GSE21510, GSE4183, GSE201916 and GSE33114).	('GSE8671', 'Var', (59, 66))	('GSE201916', 'Var', (157, 166))	('GSE4183', 'Var', (148, 155))	('tumor', 'Disease', (113, 118))	('GSE21510', 'Var', (138, 146))	('tumor', 'Disease', (123, 128))	('GSE4183', 'Chemical', '-', (148, 155))	('rectal cancer', 'Phenotype', 'HP:0100743', (33, 46))	('colorectal cancer', 'Disease', 'MESH:D015179', (29, 46))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (29, 46))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('colorectal cancer', 'Disease', (29, 46))	('GSE33114', 'Var', (171, 179))
119232	32344898	We found that patients in our cohort with higher PAI1 expression showed a decrease in disease-free survival (DFS) compared to that in patients with lower PAI1 expression, although it did not reach statistical significance (Figure 1G; p = 0.076).	('decrease', 'NegReg', (74, 82))	('PAI1', 'Gene', (49, 53))	('PAI1', 'Gene', '5054', (154, 158))	('PAI1', 'Gene', '5054', (49, 53))	('expression', 'Var', (54, 64))	('higher', 'Var', (42, 48))	('patients', 'Species', '9606', (134, 142))	('disease-free survival', 'CPA', (86, 107))	('patients', 'Species', '9606', (14, 22))	('PAI1', 'Gene', (154, 158))
119242	32344898	To explore this possibility, we visualized in a heatmap the expression levels of EMT-associated genes that significantly correlated with PAI1 expression in two representative patient databases with available microarray expression data: GSE35452 and TCGA (Figure 2B) (Note that microarray data are not available for the HUVR-IBIS cohort).	('correlated', 'Reg', (121, 131))	('patient', 'Species', '9606', (175, 182))	('GSE35452', 'Var', (236, 244))	('expression levels', 'MPA', (60, 77))	('PAI1', 'Gene', (137, 141))	('EMT', 'biological_process', 'GO:0001837', ('81', '84'))	('expression', 'MPA', (142, 152))	('B) (Note', 'Species', '1054174', (263, 271))	('PAI1', 'Gene', '5054', (137, 141))
119258	32344898	FGFR1 (R = 0.61, p < 0.0001; Figure 4C) is a member of the Fibroblast Growth Factor family whose alterations have been recently identified as likely mechanisms of primary and secondary resistance to therapy using anti-EGFR antibody in CRC.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('antibody', 'cellular_component', 'GO:0042571', ('223', '231'))	('Fibroblast Growth Factor', 'molecular_function', 'GO:0005104', ('59', '83'))	('alterations', 'Var', (97, 108))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('antibody', 'cellular_component', 'GO:0019814', ('223', '231'))	('EGFR', 'molecular_function', 'GO:0005006', ('218', '222'))	('EGFR', 'Gene', '1956', (218, 222))	('antibody', 'cellular_component', 'GO:0019815', ('223', '231'))	('antibody', 'molecular_function', 'GO:0003823', ('223', '231'))	('EGFR', 'Gene', (218, 222))
119261	32344898	Finally, the BRAF gene (R = 0.38, p < 0.0001; Figure 4C) encodes a serine/threonine kinase and BRAF mutations have been associated with poor prognosis and less response to treatment in metastatic CRC.	('mutations', 'Var', (100, 109))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', '673', (95, 99))	('BRAF', 'Gene', (13, 17))	('BRAF', 'Gene', (95, 99))	('metastatic CRC', 'Disease', (185, 199))	('serine', 'Chemical', 'MESH:D012694', (67, 73))
119268	32344898	Vemurafenib is the first BRAF serine-threonine kinase protein inhibitor authorized for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E positive mutation.	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('V600E positive', 'Var', (172, 186))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('BRAF', 'Gene', '673', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('BRAF', 'Gene', (25, 29))	('V600E', 'Mutation', 'rs113488022', (172, 177))	('patients', 'Species', '9606', (110, 118))	('serine', 'Chemical', 'MESH:D012694', (30, 36))
119269	32344898	Mutations in the BRAF gene substitute the amino acid valine for glutamic acid at position 600 and lead to the oncogenic activation of BRAF proteins.	('amino acid valine', 'MPA', (42, 59))	('oncogenic activation', 'MPA', (110, 130))	('lead to', 'Reg', (98, 105))	('glutamic acid', 'MPA', (64, 77))	('BRAF', 'Gene', '673', (134, 138))	('BRAF', 'Gene', '673', (17, 21))	('proteins', 'Protein', (139, 147))	('BRAF', 'Gene', (134, 138))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (17, 21))	('valine for glutamic acid at position 600', 'Mutation', 'rs113488022', (53, 93))
119270	32344898	AZD1208 is a potent and selective inhibitor that affects all three isoforms of serine-threonine Pim kinases.	('Pim', 'Gene', (96, 99))	('serine', 'Chemical', 'MESH:D012694', (79, 85))	('affects', 'Reg', (49, 56))	('AZD1208', 'Chemical', 'MESH:C587575', (0, 7))	('Pim', 'Gene', '5292', (96, 99))	('AZD1208', 'Var', (0, 7))
119276	32344898	Interestingly, the analysis with the Pim inhibitor AZD1208 showed that, although the IC50 was negatively correlated with PAI1 protein levels, most of the cell lines expressing PAI1 were similarly affected by AZD1208 treatment, in contrast to cell lines expressing undetectable levels (Figure 5C; Table S4), indicating that PAI1 expression determines sensitivity to AZD1208-mediated PIM inhibition.	('PAI1', 'Gene', (121, 125))	('AZD1208', 'Chemical', 'MESH:C587575', (365, 372))	('PAI1', 'Gene', (323, 327))	('PAI1', 'Gene', (176, 180))	('affected', 'Reg', (196, 204))	('Pim', 'Gene', (37, 40))	('AZD1208', 'Chemical', 'MESH:C587575', (208, 215))	('PAI1', 'Gene', '5054', (121, 125))	('PIM', 'Gene', '5292', (382, 385))	('PAI1', 'Gene', '5054', (323, 327))	('Pim', 'Gene', '5292', (37, 40))	('PAI1', 'Gene', '5054', (176, 180))	('AZD1208', 'Var', (208, 215))	('PIM', 'Gene', (382, 385))	('AZD1208', 'Chemical', 'MESH:C587575', (51, 58))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))
119277	32344898	The mutation status of KRAS, BRAF and PI3KCA did not seem to be related to the degree of sensitivity of these cell lines to AZD1208.	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('KRAS', 'Gene', '3845', (23, 27))	('KRAS', 'Gene', (23, 27))	('AZD1208', 'Chemical', 'MESH:C587575', (124, 131))	('PI3KCA', 'Var', (38, 44))
119286	32344898	PAI1 deregulation has been associated with cardiovascular diseases, obesity, metabolic syndrome and various types of cancer.	('obesity', 'Phenotype', 'HP:0001513', (68, 75))	('cardiovascular diseases', 'Disease', (43, 66))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (43, 66))	('PAI1', 'Gene', '5054', (0, 4))	('metabolic syndrome', 'Disease', 'MESH:D024821', (77, 95))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (43, 66))	('PAI1', 'Gene', (0, 4))	('metabolic syndrome', 'Disease', (77, 95))	('obesity', 'Disease', 'MESH:D009765', (68, 75))	('associated', 'Reg', (27, 37))	('obesity', 'Disease', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('deregulation', 'Var', (5, 17))	('cancer', 'Disease', (117, 123))
119288	32344898	Patients with higher PAI1 expression show a decrease in the survival probability in our patient database, as compared to patients with lower PAI1 expression.	('patient', 'Species', '9606', (88, 95))	('PAI1', 'Gene', (141, 145))	('decrease', 'NegReg', (44, 52))	('PAI1', 'Gene', '5054', (21, 25))	('expression', 'Var', (26, 36))	('PAI1', 'Gene', '5054', (141, 145))	('survival', 'MPA', (60, 68))	('Patients', 'Species', '9606', (0, 8))	('patient', 'Species', '9606', (121, 128))	('patients', 'Species', '9606', (121, 129))	('PAI1', 'Gene', (21, 25))
119291	32344898	Moreover, PAI1 expression is also correlated with poor outcome in several other cancer subtypes, particularly in ovarian serous carcinoma and node-negative breast cancer.	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (113, 137))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('expression', 'Var', (15, 25))	('PAI1', 'Gene', '5054', (10, 14))	('correlated', 'Reg', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('ovarian serous carcinoma', 'Disease', (113, 137))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('cancer', 'Disease', (163, 169))	('PAI1', 'Gene', (10, 14))	('cancer', 'Disease', (80, 86))
119311	32344898	Overexpression of PIM kinases is common in many types of tumors, including CRCs.	('PIM', 'Gene', '5292', (18, 21))	('common', 'Reg', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('PIM', 'Gene', (18, 21))	('Overexpression', 'Var', (0, 14))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('CRCs', 'Disease', (75, 79))
119314	32344898	The pan-PIM kinase inhibitor AZD1208 acts over the serine/threonine kinases PIM1, 2 and 3, which may result in cell cycle arrest and apoptosis when those kinases are overexpressed.	('PIM1', 'Gene', (76, 80))	('PIM1', 'Gene', '5292', (76, 80))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (111, 128))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('AZD1208', 'Chemical', 'MESH:C587575', (29, 36))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('111', '128'))	('apoptosis', 'CPA', (133, 142))	('serine', 'Chemical', 'MESH:D012694', (51, 57))	('arrest', 'Disease', 'MESH:D006323', (122, 128))	('PIM', 'Gene', '5292', (76, 79))	('AZD1208', 'Var', (29, 36))	('PIM', 'Gene', (8, 11))	('PIM', 'Gene', '5292', (8, 11))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('12', '28'))	('PIM', 'Gene', (76, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('result in', 'Reg', (101, 110))	('arrest', 'Disease', (122, 128))
119370	28732212	Molecular signature: In case of prostate adenocarcinoma, 246 primary prostate tumor samples were divided into seven subtypes defined by ERG (ETS transcription factor), ETV1/4 (ETS variant 1/4) and FLI1 (Fli-1 proto-oncogene, ETS transcription factor) gene fusions and SPOP (speckle type BTB/POZ protein), FOXA1 (forkhead box A1) and IDH1 (isocitrate dehydrogenase (NADP(+)) 1, cytosolic) mutations.	('transcription', 'biological_process', 'GO:0006351', ('145', '158'))	('ERG', 'Gene', '2078', (136, 139))	('SPOP', 'Gene', (268, 272))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ETV1/4', 'Gene', '2115;2118', (168, 174))	('Fli-1 proto-oncogene', 'Gene', '2313', (203, 223))	('ETS variant 1/4', 'Gene', (176, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('transcription', 'biological_process', 'GO:0006351', ('229', '242'))	('ETS variant 1/4', 'Gene', '2115;2118', (176, 191))	('ETV1/4', 'Gene', (168, 174))	('prostate adenocarcinoma', 'Disease', (32, 55))	('IDH1', 'Gene', (333, 337))	('mutations', 'Var', (388, 397))	('FLI1', 'Gene', (197, 201))	('Fli-1 proto-oncogene', 'Gene', (203, 223))	('forkhead box A1', 'Gene', (312, 327))	('forkhead box A1', 'Gene', '3169', (312, 327))	('FOXA1', 'Gene', '3169', (305, 310))	('FLI1', 'Gene', '2313', (197, 201))	('FOXA1', 'Gene', (305, 310))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (32, 55))	('IDH1', 'Gene', '3417', (333, 337))	('prostate tumor', 'Disease', (69, 83))	('ERG', 'Gene', (136, 139))	('transcription factor', 'molecular_function', 'GO:0000981', ('145', '165'))	('prostate tumor', 'Disease', 'MESH:D011471', (69, 83))	('protein', 'cellular_component', 'GO:0003675', ('295', '302'))	('prostate tumor', 'Phenotype', 'HP:0100787', (69, 83))	('transcription factor', 'molecular_function', 'GO:0000981', ('229', '249'))
119421	28732212	The KM plot depicting the effect of high and low/medium CDKN1A expression on overall survival of African American, Caucasian, and Asian patients shows a cumulative significance of 0.039.	('low/medium', 'Var', (45, 55))	('patients', 'Species', '9606', (136, 144))	('CDKN1A', 'Gene', (56, 62))	('high', 'Var', (36, 40))	('CDKN1A', 'Gene', '1026', (56, 62))
119423	28732212	On careful observation of the KM plots, one can observe that high expression of CDKN1A significantly (P = .023) correlates with overall survival in Caucasian HNSC patients.	('patients', 'Species', '9606', (163, 171))	('high', 'Var', (61, 65))	('overall survival', 'CPA', (128, 144))	('correlates with', 'Reg', (112, 127))	('CDKN1A', 'Gene', (80, 86))	('CDKN1A', 'Gene', '1026', (80, 86))
119479	27471555	The C1s immunoreactivity median H score was applied as the cutoff point to bisect the two groups, UCUTs and UCUBs, into two subgroups, high- and low-C1s expression, respectively.	('C1s', 'Gene', '716', (4, 7))	('C1s', 'Gene', (4, 7))	('C1s', 'Gene', '716', (149, 152))	('C1s', 'Gene', (149, 152))	('high-', 'Var', (135, 140))
119483	27471555	1 shows that tumors with downregulated USP31, AGBL2, SPPL2B, and MMP28 as well as upregulated C1S, FAP, PCSKS, CPXM1, PCSK1, CPE, ADAMTS3, and PRSS35 tended to have a more advanced pT status and more frequent metastatic events compared with other tumors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('PCSK1', 'Gene', '5122', (118, 123))	('MMP28', 'Gene', '79148', (65, 70))	('tumors', 'Disease', (247, 253))	('CPXM1', 'Gene', (111, 116))	('PRSS35', 'Gene', '167681', (143, 149))	('AGBL2', 'Gene', '79841', (46, 51))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('PCSKS', 'Var', (104, 109))	('ADAMTS3', 'Gene', (130, 137))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('AGBL2', 'Gene', (46, 51))	('SPPL2B', 'Gene', (53, 59))	('PCSK1', 'Gene', (118, 123))	('downregulated', 'NegReg', (25, 38))	('USP31', 'Gene', (39, 44))	('CPE', 'Gene', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumors', 'Disease', (13, 19))	('PRSS35', 'Gene', (143, 149))	('USP31', 'Gene', '57478', (39, 44))	('upregulated', 'PosReg', (82, 93))	('FAP', 'Disease', (99, 102))	('SPPL2B', 'Gene', '56928', (53, 59))	('USP', 'molecular_function', 'GO:0051748', ('39', '42'))	('metastatic events', 'CPA', (209, 226))	('MMP28', 'Gene', (65, 70))	('C1S', 'Gene', (94, 97))	('FAP', 'Disease', 'MESH:C567782', (99, 102))	('MMP', 'molecular_function', 'GO:0004235', ('65', '68'))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('pT status', 'Disease', (181, 190))	('ADAMTS3', 'Gene', '9508', (130, 137))	('CPE', 'Gene', '1363', (125, 128))	('CPXM1', 'Gene', '56265', (111, 116))
119506	27471555	ROS cause oxidative stress and an oxidation-reduction imbalance.	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('imbalance', 'Phenotype', 'HP:0002172', (54, 63))	('cause', 'Reg', (4, 9))	('oxidation-reduction', 'biological_process', 'GO:0055114', ('34', '53'))	('oxidation-reduction imbalance', 'MPA', (34, 63))	('oxidative stress', 'Phenotype', 'HP:0025464', (10, 26))	('oxidative stress', 'MPA', (10, 26))
119514	27471555	reported that when hamster complement C1s cDNA was transfected into BALB/c mouse fibroblast A31 cells, the transfectants formed tumors in BALB/c-nu/nu mice.	('complement C1s', 'molecular_function', 'GO:0003816', ('27', '41'))	('C1s', 'Gene', '716', (38, 41))	('mice', 'Species', '10090', (151, 155))	('C1s', 'Gene', (38, 41))	('hamster', 'Species', '10034', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('transfectants', 'Var', (107, 120))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('mouse', 'Species', '10090', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('formed', 'Reg', (121, 127))
119515	27471555	In a subsequent study, the same authors transfected mutant C1s cDNA into A31 cells.	('C1s', 'Gene', '716', (59, 62))	('C1s', 'Gene', (59, 62))	('mutant', 'Var', (52, 58))
119518	27471555	Furthermore, conformationally altered hyaluronan (HA) inhibited C1s activation and other components of the complement system in DU145 prostate cancer cells.	('inhibited', 'NegReg', (54, 63))	('DU145', 'CellLine', 'CVCL:0105', (128, 133))	('activation', 'MPA', (68, 78))	('C1s', 'Gene', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('hyaluronan', 'Chemical', 'MESH:D006820', (38, 48))	('HA', 'Chemical', 'MESH:D006820', (50, 52))	('prostate cancer', 'Disease', (134, 149))	('prostate cancer', 'Disease', 'MESH:D011471', (134, 149))	('conformationally altered', 'Var', (13, 37))	('prostate cancer', 'Phenotype', 'HP:0012125', (134, 149))	('C1s', 'Gene', '716', (64, 67))
119519	27471555	The underexpression of HA synthase 3 (HAS3), one of the three HA synthases, is associated with adverse outcome and advanced disease in both UCUTs and UCUBs.	('HA', 'Chemical', 'MESH:D006820', (23, 25))	('HA', 'Chemical', 'MESH:D006820', (38, 40))	('HA', 'Chemical', 'MESH:D006820', (62, 64))	('associated with', 'Reg', (79, 94))	('underexpression', 'Var', (4, 19))	('advanced disease', 'Disease', (115, 131))	('HA synthase 3', 'Gene', '3038', (23, 36))	('HA synthase 3', 'Gene', (23, 36))	('HAS3', 'Gene', (38, 42))	('advanced disease', 'Disease', 'MESH:D020178', (115, 131))	('HAS3', 'Gene', '3038', (38, 42))
119529	24949951	Quantitative IHC examinations revealed that MACC1 abnormal abundance in cancerous tissues might represent a biological indicator clinically suggestive of tumor malignancy in the renal pelvis.	('tumor malignancy in the renal pelvis', 'Disease', (154, 190))	('cancerous', 'Disease', (72, 81))	('MACC1', 'Gene', (44, 49))	('MACC1', 'Gene', '346389', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancerous', 'Disease', 'MESH:D009369', (72, 81))	('tumor malignancy in the renal pelvis', 'Disease', 'MESH:D010386', (154, 190))	('abnormal', 'Var', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor malignancy in the renal pelvis', 'Phenotype', 'HP:0006762', (154, 190))	('renal pelvis', 'Phenotype', 'HP:0000125', (178, 190))
119531	24949951	Moreover, both disease-free survival and overall survival for the patients in the high MACC1 expression group were significantly lower than those in the low expression group.	('high', 'Var', (82, 86))	('MACC1', 'Gene', '346389', (87, 92))	('patients', 'Species', '9606', (66, 74))	('MACC1', 'Gene', (87, 92))	('expression', 'MPA', (93, 103))	('disease-free survival', 'CPA', (15, 36))	('overall survival', 'CPA', (41, 57))	('lower', 'NegReg', (129, 134))
119546	24949951	Originally discovered in colon cancer, MACC1 overexpression has been demonstrated to promote tumor proliferation, invasion, and metastasis in a wide spectrum of solid tumors including gastrointestinal cancers (e.g.	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('metastasis', 'CPA', (128, 138))	('overexpression', 'Var', (45, 59))	('colon cancer', 'Phenotype', 'HP:0003003', (25, 37))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('invasion', 'CPA', (114, 122))	('MACC1', 'Gene', '346389', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (184, 208))	('colon cancer', 'Disease', 'MESH:D015179', (25, 37))	('tumor', 'Disease', (167, 172))	('gastrointestinal cancers', 'Disease', (184, 208))	('solid tumors', 'Disease', (161, 173))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('promote', 'PosReg', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('MACC1', 'Gene', (39, 44))	('colon cancer', 'Disease', (25, 37))	('tumor', 'Disease', (93, 98))	('solid tumors', 'Disease', 'MESH:D009369', (161, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
119602	24949951	As shown in Table 1, the AOD reading of MACC1 was shown as 0.0648+-0.0312 in RPC tissues, 0.0218+-0.0144 in ANRPETs, and 0.0210+-0.0151 in NRPETs, respectively.	('0.0210+-0.0151', 'Var', (121, 135))	('MACC1', 'Gene', '346389', (40, 45))	('MACC1', 'Gene', (40, 45))	('0.0218+-0.0144', 'Var', (90, 104))	('0.0648+-0.0312', 'Var', (59, 73))	('RPC', 'Phenotype', 'HP:0006762', (77, 80))
119603	24949951	These results suggest that MACC1 abnormal abundance might represent a biological indicator clinically suggestive of tumor malignancy in renal pelvis tissues.	('abnormal abundance', 'Var', (33, 51))	('renal pelvis', 'Phenotype', 'HP:0000125', (136, 148))	('tumor malignancy', 'Disease', 'MESH:D018198', (116, 132))	('MACC1', 'Gene', (27, 32))	('MACC1', 'Gene', '346389', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor malignancy', 'Disease', (116, 132))
119605	24949951	As shown in Table 2, elevated MACC1 protein levels appeared to be associated with higher aggressiveness of RPC, with the AOD score of MACC1 in TNM stage Ta, I, II, and III-IV revealed as 0.0355+-0.0247, 0.0563+-0.0281, 0.0752+-0.0264, and 0.0965+-0.0185, respectively.	('0.0752+-0.0264', 'Var', (219, 233))	('MACC1', 'Gene', (30, 35))	('MACC1', 'Gene', (134, 139))	('0.0563+-0.0281', 'Var', (203, 217))	('aggressiveness of RPC', 'Disease', (89, 110))	('MACC1', 'Gene', '346389', (30, 35))	('MACC1', 'Gene', '346389', (134, 139))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('higher', 'PosReg', (82, 88))	('0.0965+-0.0185', 'Var', (239, 253))	('0.0355+-0.0247', 'Var', (187, 201))	('aggressiveness', 'Phenotype', 'HP:0000718', (89, 103))	('elevated', 'PosReg', (21, 29))	('RPC', 'Phenotype', 'HP:0006762', (107, 110))	('aggressiveness of RPC', 'Disease', 'MESH:D001523', (89, 110))
119610	24949951	In contrast, although MACC1 exhibited an increased protein level in the group of older patients (>61 years old) with the AOD score measured as 0.0654+-0.0298 when compared to the group of younger patients (<61 years old) (AOD score: 0.0628+-0.0343), no statistically significant difference was observed between these two groups (p>0.05).	('MACC1', 'Gene', '346389', (22, 27))	('MACC1', 'Gene', (22, 27))	('increased', 'PosReg', (41, 50))	('protein level', 'MPA', (51, 64))	('patients', 'Species', '9606', (196, 204))	('patients', 'Species', '9606', (87, 95))	('0.0654+-0.0298', 'Var', (143, 157))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
119612	24949951	To facilitate statistical analysis, RPC patients were divided into three groups according to the visual assessment of the immunohistochemical staining strength in tissue sections we examined (negative, low MACC1 expression group, and high MACC1 expression group, respectively).	('MACC1', 'Gene', '346389', (239, 244))	('patients', 'Species', '9606', (40, 48))	('expression', 'MPA', (212, 222))	('MACC1', 'Gene', (206, 211))	('MACC1', 'Gene', '346389', (206, 211))	('RPC', 'Phenotype', 'HP:0006762', (36, 39))	('low', 'Var', (202, 205))	('MACC1', 'Gene', (239, 244))
119618	24949951	3A & B, patients with high MACC1 expression level determined by visual assessment scoring system showed a significantly shorter OS (p<0.001) and DFS (p<0.001) than the group of patients with low MACC1 expression level.	('with', 'Var', (17, 21))	('MACC1', 'Gene', '346389', (195, 200))	('MACC1', 'Gene', (195, 200))	('and', 'CPA', (141, 144))	('patients', 'Species', '9606', (177, 185))	('MACC1', 'Gene', (27, 32))	('shorter', 'CPA', (120, 127))	('high', 'Gene', (22, 26))	('MACC1', 'Gene', '346389', (27, 32))	('significantly', 'NegReg', (106, 119))	('patients', 'Species', '9606', (8, 16))
119619	24949951	3A, in the high MACC1 expression group, the mean OS rate was 29.9 months with the 5-year OS rate approximating 70%.	('MACC1', 'Gene', '346389', (16, 21))	('MACC1', 'Gene', (16, 21))	('high', 'Var', (11, 15))
119620	24949951	For patients in the low MACC1 expression group, the mean OS rate was 45.6 months, ~50% higher than the high MACC1 group.	('MACC1', 'Gene', '346389', (24, 29))	('MACC1', 'Gene', (24, 29))	('low', 'Var', (20, 23))	('patients', 'Species', '9606', (4, 12))	('MACC1', 'Gene', (108, 113))	('MACC1', 'Gene', '346389', (108, 113))	('higher', 'PosReg', (87, 93))
119623	24949951	Conclusively, high MACC1 expression level is significantly correlated with decreased overall survival and disease-free survival in RPC patients as revealed in the quantitative immunohistochemical analyses.	('MACC1', 'Gene', '346389', (19, 24))	('patients', 'Species', '9606', (135, 143))	('disease-free survival', 'CPA', (106, 127))	('high', 'Var', (14, 18))	('RPC', 'Phenotype', 'HP:0006762', (131, 134))	('overall survival', 'CPA', (85, 101))	('MACC1', 'Gene', (19, 24))	('expression level', 'MPA', (25, 41))	('decreased', 'NegReg', (75, 84))
119643	24949951	Since at this stage we have no effective treatment for patients with metastatic renal pelvis carcinoma, the detection of high levels of MACC1 might help to predict the progression and the prognosis of the disease.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('renal pelvis carcinoma', 'Phenotype', 'HP:0006762', (80, 102))	('MACC1', 'Gene', '346389', (136, 141))	('high levels', 'Var', (121, 132))	('metastatic renal pelvis carcinoma', 'Disease', (69, 102))	('MACC1', 'Gene', (136, 141))	('renal pelvis', 'Phenotype', 'HP:0000125', (80, 92))	('metastatic renal pelvis carcinoma', 'Disease', 'MESH:C538445', (69, 102))	('patients', 'Species', '9606', (55, 63))	('help', 'Reg', (148, 152))	('pelvis carcinoma', 'Phenotype', 'HP:0006762', (86, 102))
119645	24949951	Indeed, MACC1 translocation from the cytoplasm to the nucleus has been indicated to be intimately associated with metastasis in colon cancer cells and may very well indicate the higher malignancy in the case of glioma cells.	('MACC1', 'Gene', '346389', (8, 13))	('malignancy', 'Disease', 'MESH:D009369', (185, 195))	('metastasis', 'CPA', (114, 124))	('colon cancer', 'Disease', (128, 140))	('translocation', 'Var', (14, 27))	('malignancy', 'Disease', (185, 195))	('cytoplasm', 'cellular_component', 'GO:0005737', ('37', '46'))	('nucleus', 'cellular_component', 'GO:0005634', ('54', '61'))	('glioma', 'Disease', (211, 217))	('associated', 'Reg', (98, 108))	('glioma', 'Phenotype', 'HP:0009733', (211, 217))	('colon cancer', 'Phenotype', 'HP:0003003', (128, 140))	('colon cancer', 'Disease', 'MESH:D015179', (128, 140))	('MACC1', 'Gene', (8, 13))	('glioma', 'Disease', 'MESH:D005910', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
119652	24949951	As it is well known that chromosomal aneuploidy has been observed frequently in carcinomas, it is not surprising that abnormal amplification, rearrangement of chromosome 7, or gain of the p-arm (particularly 7p21), has been discovered in a wide spectrum of cancers, such as gastric, intestinal, colorectal, pancreatic cancers and astrocytic tumors   (also reviewed in).	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('colorectal', 'Disease', (295, 305))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('cancers', 'Phenotype', 'HP:0002664', (318, 325))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('gain', 'PosReg', (176, 180))	('cancers', 'Disease', (318, 325))	('carcinomas', 'Disease', 'MESH:D002277', (80, 90))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (307, 325))	('cancers', 'Disease', 'MESH:D009369', (257, 264))	('pancreatic cancers', 'Disease', (307, 325))	('colorectal', 'Disease', 'MESH:D015179', (295, 305))	('intestinal', 'Disease', (283, 293))	('rearrangement', 'Var', (142, 155))	('chromosome', 'cellular_component', 'GO:0005694', ('159', '169'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (307, 324))	('p21', 'Gene', (209, 212))	('astrocytic tumors', 'Disease', (330, 347))	('p21', 'Gene', '644914', (209, 212))	('pancreatic cancers', 'Disease', 'MESH:D010190', (307, 325))	('tumors', 'Phenotype', 'HP:0002664', (341, 347))	('carcinomas', 'Disease', (80, 90))	('astrocytic tumors', 'Disease', 'MESH:D001254', (330, 347))	('cancers', 'Disease', 'MESH:D009369', (318, 325))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('cancers', 'Disease', (257, 264))	('gastric', 'Disease', (274, 281))
119653	24949951	Indeed, there are many lines of evidence indicating that the pathological amplification or rearrangement of chromosome 7p may very well underlie the increased abundance of MACC1 mRNA and is intimately associated with a concomitant overexpression of the protein throughout tumor growth, invasion, metastasis, and tumor recurrence     (also reviewed in).	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('protein', 'cellular_component', 'GO:0003675', ('253', '260'))	('rearrangement', 'Var', (91, 104))	('overexpression', 'PosReg', (231, 245))	('abundance', 'MPA', (159, 168))	('increased', 'PosReg', (149, 158))	('tumor', 'Disease', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('MACC1', 'Gene', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('MACC1', 'Gene', '346389', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('associated', 'Reg', (201, 211))	('chromosome', 'cellular_component', 'GO:0005694', ('108', '118'))	('tumor', 'Disease', (312, 317))	('mRNA', 'MPA', (178, 182))
119654	24949951	It would certainly be of great interest in the near future to examine whether there is indeed a high level of aberrant genomic DNA amplification and/or rearrangement in the genomic DNA fragment containing the MACC1 locus in patients with renal pelvis carcinoma.	('DNA', 'cellular_component', 'GO:0005574', ('181', '184'))	('renal pelvis carcinoma', 'Disease', 'MESH:D010386', (238, 260))	('MACC1', 'Gene', '346389', (209, 214))	('renal pelvis carcinoma', 'Phenotype', 'HP:0006762', (238, 260))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))	('MACC1', 'Gene', (209, 214))	('DNA amplification', 'biological_process', 'GO:0006277', ('127', '144'))	('renal pelvis', 'Phenotype', 'HP:0000125', (238, 250))	('rearrangement', 'Var', (152, 165))	('patients', 'Species', '9606', (224, 232))	('renal pelvis carcinoma', 'Disease', (238, 260))	('pelvis carcinoma', 'Phenotype', 'HP:0006762', (244, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))
119671	33923231	A recent comprehensive analysis of different molecular subtypes in a cohort of 412 muscle-invasive bladder cancers (BLCA) revealed that approximately 90% of these tumors displayed genetic alterations in regulatory elements of the cell cycle pathway.	('muscle-invasive bladder cancers', 'Disease', 'MESH:D001749', (83, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cell cycle pathway', 'Pathway', (230, 248))	('BLCA', 'Phenotype', 'HP:0009725', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('genetic alterations', 'Var', (180, 199))	('invasive bladder', 'Phenotype', 'HP:0100645', (90, 106))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('cell cycle', 'biological_process', 'GO:0007049', ('230', '240'))	('regulatory elements', 'MPA', (203, 222))	('bladder cancers', 'Phenotype', 'HP:0009725', (99, 114))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('muscle-invasive bladder cancers', 'Disease', (83, 114))
119680	33923231	This suggested that the combination of CDK4/6 inhibitors and inhibitors against DNA repair mechanisms might improve response to Palbociclib monotherapy.	('CDK', 'molecular_function', 'GO:0004693', ('39', '42'))	('inhibitors', 'Var', (61, 71))	('CDK4/6', 'Gene', (39, 45))	('DNA repair', 'biological_process', 'GO:0006281', ('80', '90'))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('DNA repair', 'Gene', (80, 90))	('response', 'MPA', (116, 124))	('improve', 'PosReg', (108, 115))	('Palbociclib', 'Chemical', 'MESH:C500026', (128, 139))	('CDK4/6', 'Gene', '1019;1021', (39, 45))
119682	33923231	Small-molecule inhibitors against PARP have been developed and approved by the Food and Drug Administration (FDA) for the treatment of ovarian or prostate cancer with the inclusion criteria of germline BRCA1/2 mutation.	('BRCA1/2', 'Gene', '672;675', (202, 209))	('ovarian or prostate cancer', 'Disease', (135, 161))	('PARP', 'Gene', (34, 38))	('ovarian or prostate cancer', 'Disease', 'MESH:D011472', (135, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('prostate cancer', 'Phenotype', 'HP:0012125', (146, 161))	('germline', 'Var', (193, 201))	('BRCA1/2', 'Gene', (202, 209))	('PARP', 'Gene', '142', (34, 38))
119693	33923231	Several clinical trials are currently investigating the PARP inhibitors Olaparib (NCT03459846, NCT02546661, NCT04579133, NCT03375307, NCT03448718) and Niraparib (NCT03945084, NCT03425201) in bladder or urothelial cancer as monotherapies or in combination with immune checkpoint blockade.	('NCT03425201', 'Var', (175, 186))	('bladder or urothelial cancer', 'Disease', (191, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('NCT02546661', 'Var', (95, 106))	('PARP', 'Gene', '142', (56, 60))	('NCT03945084', 'Var', (162, 173))	('NCT03448718', 'Var', (134, 145))	('NCT03375307', 'Var', (121, 132))	('NCT03459846', 'Var', (82, 93))	('bladder or urothelial cancer', 'Disease', 'MESH:D001749', (191, 219))	('PARP', 'Gene', (56, 60))	('Olaparib', 'Chemical', 'MESH:C531550', (72, 80))	('NCT04579133', 'Var', (108, 119))	('Niraparib', 'Chemical', 'MESH:C545685', (151, 160))
119694	33923231	Because the clinical benefit of CDK4/6 or PARP-1 targeted inhibition as respective monotherapies might be, as also shown in other tumor entities, limited for BLCA, suitable combination therapies for these compounds are necessary for sufficient therapeutic efficiency.	('PARP-1', 'Gene', '142', (42, 48))	('CDK', 'molecular_function', 'GO:0004693', ('32', '35'))	('targeted', 'Var', (49, 57))	('CDK4/6', 'Gene', (32, 38))	('BLCA', 'Phenotype', 'HP:0009725', (158, 162))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('CDK4/6', 'Gene', '1019;1021', (32, 38))	('PARP-1', 'Gene', (42, 48))
119736	33923231	To evaluate the influence of RB depletion for Talazoparib/Palbociclib combinatory therapy, we additionally studied the RB-negative BLCA cell line 5637, which harbors a loss of function mutation in the RB1 gene.	('RB1', 'Gene', (201, 204))	('Palbociclib', 'Chemical', 'MESH:C500026', (58, 69))	('mutation', 'Var', (185, 193))	('loss of function', 'NegReg', (168, 184))	('Talazoparib', 'Chemical', 'MESH:C586365', (46, 57))	('RB1', 'Gene', '5925', (201, 204))	('BLCA', 'Phenotype', 'HP:0009725', (131, 135))
119740	33923231	CDK4/6 inhibitors represent a new generation of successful anticancer drugs.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('CDK', 'molecular_function', 'GO:0004693', ('0', '3'))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('inhibitors', 'Var', (7, 17))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('CDK4/6', 'Gene', (0, 6))	('cancer', 'Disease', (63, 69))
119750	33923231	While Talazoparib has been extensively studied in cancers of ovarian, prostate, or breast that emerge with a high population of germline deficiencies in homologous repair pathways, the effect of Talazoparib in BLCA has only been evaluated on the verge of other research foci.	('Talazoparib', 'Chemical', 'MESH:C586365', (195, 206))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('Talazoparib', 'Chemical', 'MESH:C586365', (6, 17))	('breast', 'Disease', (83, 89))	('BLCA', 'Phenotype', 'HP:0009725', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancers of ovarian, prostate', 'Disease', 'MESH:D011472', (50, 78))	('deficiencies', 'Var', (137, 149))	('homologous repair pathways', 'Pathway', (153, 179))
119757	33923231	When analyzing protein expression, we noticed that Palbociclib seems to reduce the total protein level of PARP-1.	('Palbociclib', 'Var', (51, 62))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('total protein level', 'MPA', (83, 102))	('Palbociclib', 'Chemical', 'MESH:C500026', (51, 62))	('PARP-1', 'Gene', (106, 112))	('reduce', 'NegReg', (72, 78))	('PARP-1', 'Gene', '142', (106, 112))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
119773	33923231	Further, the phospho-RB-dependent exit of senescence activates DNA repair via Nonhomologous End Joining, and its disruption leads to apoptosis.	('DNA repair', 'biological_process', 'GO:0006281', ('63', '73'))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('senescence', 'biological_process', 'GO:0010149', ('42', '52'))	('phospho-RB', 'Chemical', '-', (13, 23))	('apoptosis', 'CPA', (133, 142))	('leads to', 'Reg', (124, 132))	('disruption', 'Var', (113, 123))	('activates', 'PosReg', (53, 62))	('DNA', 'MPA', (63, 66))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('Nonhomologous End Joining', 'MPA', (78, 103))
119779	33923231	We conclude a crucial role for RB, as its knockdown or expression as a dysfunctional mutant in 5637 cells reversed both, the synergism and the retention of apoptosis induction in the combinatory treatment.	('dysfunctional', 'Disease', 'MESH:D009461', (71, 84))	('apoptosis', 'CPA', (156, 165))	('apoptosis', 'biological_process', 'GO:0097194', ('156', '165'))	('dysfunctional', 'Disease', (71, 84))	('apoptosis', 'biological_process', 'GO:0006915', ('156', '165'))	('knockdown', 'Var', (42, 51))	('synergism', 'MPA', (125, 134))	('retention', 'biological_process', 'GO:0051235', ('143', '152'))
119784	33923231	Additionally, it has been demonstrated that responsiveness to PARP inhibitors is increased in tumors bearing mutations in homologous repair pathways.	('homologous', 'Pathway', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PARP', 'Gene', (62, 66))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('mutations', 'Var', (109, 118))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('increased', 'PosReg', (81, 90))	('responsiveness', 'MPA', (44, 58))	('PARP', 'Gene', '142', (62, 66))
119807	33923231	A total of 1.5 million HEK 293T cells were seeded in 10 cm dishes and after 24 h were transfected with 15 microg of psPAX2 (Addgene #12260), 6 microg of pMD2.G (Addgene #12259), and 20 microg of scramble shRNA (Addgene #1864) or pLKO-RB1-shRNA-19 (Addgene #25640) or pLKO-RB1-shRNA-63 (Addgene #25641) using 2.5 M CaCl2 and 2x HBS as described previously.	('RB1', 'Gene', (234, 237))	('RB1', 'Gene', (272, 275))	('RB1', 'Gene', '5925', (234, 237))	('RB1', 'Gene', '5925', (272, 275))	('HEK 293T', 'CellLine', 'CVCL:0063', (23, 31))	('Addgene #25640', 'Var', (248, 262))	('Addgene #25641', 'Var', (286, 300))
119890	32884355	A previous study showed that high NLR significantly increased the risk for CSS, RFS, and overall survival (OS); these results were consistent with our results.	('high', 'Var', (29, 33))	('RFS', 'Disease', 'MESH:D005198', (80, 83))	('NLR', 'Gene', (34, 37))	('CSS', 'Disease', (75, 78))	('RFS', 'Disease', (80, 83))	('overall survival', 'CPA', (89, 105))
119892	32884355	Therefore, our females have a higher risk of exposure to a potent carcinogen in some herbal medicine, aristolochic acid, which is well-known to cause UTUC.	('herbal medicine', 'Species', '1407750', (85, 100))	('cause', 'Reg', (144, 149))	('exposure', 'MPA', (45, 53))	('aristolochic acid', 'Var', (102, 119))	('UTUC', 'Disease', (150, 154))	('aristolochic acid', 'Chemical', 'MESH:C000228', (102, 119))
119901	32120844	Hypermethylation of UCHL1 Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing Degradation of Cortactin (CTTN) Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC), but the epigenetic mechanisms underlying NPC metastasis remain poorly understood.	('Promotes', 'PosReg', (26, 34))	('CTTN', 'Gene', (115, 119))	('Hypermethylation', 'Var', (0, 16))	('Carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('UCHL1', 'Gene', (20, 25))	('Nasopharyngeal Carcinoma', 'Phenotype', 'HP:0100630', (49, 73))	('Degradation', 'MPA', (89, 100))	('Cortactin', 'Gene', '2017', (104, 113))	('Suppressing', 'NegReg', (77, 88))	('Cortactin', 'Gene', (104, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('Carcinoma', 'Disease', (64, 73))	('Carcinoma', 'Disease', 'MESH:D009369', (64, 73))	('carcinoma', 'Disease', (220, 229))	('CTTN', 'Gene', '2017', (115, 119))	('NPC', 'cellular_component', 'GO:0005643', ('278', '281'))	('Metastasis', 'CPA', (35, 45))	('NPC', 'cellular_component', 'GO:0005643', ('231', '234'))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (205, 229))	('carcinoma', 'Disease', 'MESH:D009369', (220, 229))	('regulation', 'biological_process', 'GO:0065007', ('132', '142'))	('UCHL1', 'Gene', '7398', (20, 25))
119910	32120844	Hypermethylation of the UCHL1 promoter leads to low UCHL1 expression, and promotes cell proliferation by regulating the stability of p53 and MDM2 in hepatocellular cancer (HCC) and NPC.	('promotes', 'PosReg', (74, 82))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (149, 170))	('regulating', 'Reg', (105, 115))	('low', 'NegReg', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('NPC', 'cellular_component', 'GO:0005643', ('181', '184'))	('expression', 'MPA', (58, 68))	('Hypermethylation', 'Var', (0, 16))	('cell proliferation', 'CPA', (83, 101))	('MDM2', 'Gene', (141, 145))	('stability', 'MPA', (120, 129))	('p53', 'Gene', '7157', (133, 136))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (149, 170))	('cell proliferation', 'biological_process', 'GO:0008283', ('83', '101'))	('p53', 'Gene', (133, 136))	('MDM2', 'Gene', '4193', (141, 145))	('hepatocellular cancer', 'Disease', (149, 170))	('UCHL1', 'Gene', (52, 57))
119913	32120844	Not surprisingly, dysregulation of CTTN expression caused by post-translation modification can contribute to the pathogenesis of human diseases, including cancer.	('expression', 'MPA', (40, 50))	('CTTN', 'Gene', (35, 39))	('contribute', 'Reg', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('translation', 'biological_process', 'GO:0006412', ('66', '77'))	('pathogenesis', 'biological_process', 'GO:0009405', ('113', '125'))	('dysregulation', 'Var', (18, 31))	('human', 'Species', '9606', (129, 134))	('post-translation modification', 'Var', (61, 90))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
119916	32120844	In this study, UCHL1 promoter hypermethylation was confirmed in NPC tissues by bisulfite pyrosequencing, corroborating our previous work and public microarray data.	('UCHL1', 'Gene', (15, 20))	('bisulfite', 'Chemical', 'MESH:C042345', (79, 88))	('NPC', 'cellular_component', 'GO:0005643', ('64', '67'))	('hypermethylation', 'Var', (30, 46))	('NPC', 'Disease', (64, 67))
119923	32120844	Anti-CTTN (Proteintech, Whuhan, China, 11381-1-AP), HRP-conjugated goat anti-mouse IgG (CST, Boston, MA, USA, 7076), HRP-conjugated goat anti-rabbit IgG (CST, 7074), anti-GFP (Proteintech, 50430-2-AP), anti-alpha-tubulin (Proteintech, 11224-1-AP), anti-FLAG (Sigma, St. Louis, MO, USA, F3165), anti-HA (Proteintech, 51064-2-AP), anti-UCHL1 (CST, 13179S), anti-Ub (Santa Cruz, Dallas, TX, USA, sc-8017), Goat-anti-mouse Alexa Fluor  488 IgG (Life Technologies, Carlsbad, CA, USA, A-10684), Goat-anti-rabbit, and Alexa Fluor  594 IgG (Life Technologies, A-11079), MG132 (Sigma, 474787), DAC (Sigma, 189825), CHX (Sigma, 5087390001), and puromycin (Thermo, Waltham, MA, USA, A1113802) were purchased from the indicated manufacturers.	('MG132', 'Chemical', 'MESH:C072553', (562, 567))	('Sigma', 'Var', (590, 595))	('alpha-tubulin', 'Gene', (207, 220))	('mouse', 'Species', '10090', (413, 418))	('alpha-tubulin', 'Gene', '10376', (207, 220))	('CST', 'Gene', '12854', (341, 344))	('CST', 'Gene', (341, 344))	('puromycin', 'Chemical', 'MESH:D011691', (635, 644))	('CST', 'Gene', '12854', (88, 91))	('CST', 'Gene', '12854', (154, 157))	('mouse', 'Species', '10090', (77, 82))	('CST', 'Gene', (154, 157))	('CST', 'Gene', (88, 91))
119932	32120844	PRK-HA-Ub, PRK-HA-Ub(K48O), and PRK-HA-Ub(K63O) were generously provided by Professor Bo Zhong (Wuhan University, Whuhan, China).	('K63O', 'Var', (42, 46))	('PRK', 'Gene', '1263', (32, 35))	('PRK', 'Gene', (32, 35))	('PRK', 'Gene', (11, 14))	('PRK', 'Gene', '1263', (11, 14))	('PRK', 'molecular_function', 'GO:0008974', ('0', '3'))	('PRK', 'molecular_function', 'GO:0008974', ('11', '14'))	('PRK', 'molecular_function', 'GO:0008974', ('32', '35'))	('PRK', 'Gene', '1263', (0, 3))	('PRK', 'Gene', (0, 3))
119966	32120844	In contrast, knockdown of UCHL1 markedly increased SUNE1 and HONE1 migration and invasion (Figure 3D-H).	('HONE1', 'CellLine', 'CVCL:8706', (61, 66))	('increased', 'PosReg', (41, 50))	('invasion', 'CPA', (81, 89))	('HONE1 migration', 'CPA', (61, 76))	('SUNE1', 'Chemical', '-', (51, 56))	('UCHL1', 'Gene', (26, 31))	('SUNE1', 'CPA', (51, 56))	('knockdown', 'Var', (13, 22))
119972	32120844	It has been reported that the UCHL1 (C90S) mutant is an enzymatically inactive mutant with significantly decreased ligase activity.	('ligase activity', 'molecular_function', 'GO:0016874', ('115', '130'))	('C90S', 'Mutation', 'p.C90S', (37, 41))	('UCHL1', 'Gene', (30, 35))	('decreased', 'NegReg', (105, 114))	('ligase', 'Protein', (115, 121))	('C90S', 'Var', (37, 41))	('activity', 'MPA', (122, 130))
119973	32120844	We constructed the UCHL1 (C90S) mutant, and found that overexpression of UCHL1, but not UCHL1 (C90S), could significantly increase the ubiquitination of CTTN (Figure 5F and Supplementary Figure S4B).	('overexpression', 'PosReg', (55, 69))	('CTTN', 'Protein', (153, 157))	('C90S', 'Mutation', 'p.C90S', (26, 30))	('UCHL1', 'Gene', (73, 78))	('C90S', 'Mutation', 'p.C90S', (95, 99))	('mutant', 'Var', (32, 38))	('ubiquitination', 'MPA', (135, 149))	('increase', 'PosReg', (122, 130))
119974	32120844	Moreover, overexpression of UCHL1 but not UCHL1 (C90S) promoted CTTN degradation, and degradation of CTTN was completely blocked by the proteasome inhibitor MG132 (Figure 5G).	('MG132', 'Chemical', 'MESH:C072553', (157, 162))	('proteasome', 'cellular_component', 'GO:0000502', ('136', '146'))	('degradation', 'biological_process', 'GO:0009056', ('69', '80'))	('degradation', 'biological_process', 'GO:0009056', ('86', '97'))	('UCHL1', 'Var', (28, 33))	('promoted', 'PosReg', (55, 63))	('C90S', 'Mutation', 'p.C90S', (49, 53))	('overexpression', 'PosReg', (10, 24))	('CTTN degradation', 'MPA', (64, 80))	('proteasome', 'molecular_function', 'GO:0004299', ('136', '146'))
119976	32120844	As expected, mutation of the Lys48 site on ubiquitin (K48O) significantly increased UCHL1-mediated CTTN ubiquitination, whereas the K63O ubiquitin mutation had no effect (Figure 5H and Supplementary Figure S4C).	('ubiquitin', 'molecular_function', 'GO:0031386', ('43', '52'))	('K63O', 'Var', (132, 136))	('mutation', 'Var', (13, 21))	('UCHL1-mediated CTTN ubiquitination', 'MPA', (84, 118))	('increased', 'PosReg', (74, 83))	('ubiquitin', 'molecular_function', 'GO:0031386', ('137', '146'))	('K48O', 'Var', (54, 58))	('Lys48', 'Chemical', '-', (29, 34))
119977	32120844	To examine whether the ligase activity of UCHL1 is involved in suppressing NPC cell migration and invasion, we performed transwell assays with wild-type UCHL1 and the enzymatically inactive mutant UCHL1 (C90S) in SUNE1 and HONE1 cells exhibiting stable UCHL1 knockdown.	('C90S', 'Mutation', 'p.C90S', (204, 208))	('SUNE1', 'Chemical', '-', (213, 218))	('cell migration', 'biological_process', 'GO:0016477', ('79', '93'))	('UCHL1', 'Gene', (153, 158))	('HONE1', 'CellLine', 'CVCL:8706', (223, 228))	('NPC', 'cellular_component', 'GO:0005643', ('75', '78'))	('UCHL1', 'Gene', (197, 202))	('suppressing', 'NegReg', (63, 74))	('C90S', 'Var', (204, 208))	('ligase activity', 'molecular_function', 'GO:0016874', ('23', '38'))
119978	32120844	Transfection with the UCHL1(C90S) mutant failed to rescue the tumor-promoting effect of NPC cell migration and invasion (Figure 6A,B), which implied that the ligase activity of UCHL1 is indispensable for UCHL1 mediated-suppressive effects on NPC cell migration and invasion.	('cell migration', 'biological_process', 'GO:0016477', ('92', '106'))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('UCHL1', 'Gene', (22, 27))	('NPC', 'cellular_component', 'GO:0005643', ('242', '245'))	('C90S', 'Mutation', 'p.C90S', (28, 32))	('NPC', 'cellular_component', 'GO:0005643', ('88', '91'))	('ligase activity', 'molecular_function', 'GO:0016874', ('158', '173'))	('cell migration', 'biological_process', 'GO:0016477', ('246', '260'))	('mutant', 'Var', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
119983	32120844	H&E staining exhibited that the primary tumors in the UCHL1 knockdown group showed a more aggressive phenotype with invasion of the tumor cells towards the skin and muscle than the tumors in the shControl group (Figure 7B).	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Disease', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('UCHL1', 'Var', (54, 59))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumors', 'Disease', (181, 187))	('H&E', 'Chemical', '-', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (40, 45))	('with', 'CPA', (111, 115))	('tumor', 'Disease', (181, 186))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('the', 'Gene', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
119984	32120844	Furthermore, the volumes of the popliteal lymph nodes were bigger, and the pan-cytokeratin-positive tumor cells were more in the UCHL1 knockdown group than in the shControl group (Figure 7C,D).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('knockdown', 'Var', (135, 144))	('volumes of the popliteal lymph nodes', 'CPA', (17, 53))	('tumor', 'Disease', (100, 105))	('UCHL1', 'Gene', (129, 134))	('more', 'PosReg', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('bigger', 'PosReg', (59, 65))
119989	32120844	We have previously reported that hypermethylation of the HOPX, RAB37, and SHISA3 genes might serve as molecular biomarkers to predict NPC metastasis.	('NPC', 'cellular_component', 'GO:0005643', ('134', '137'))	('NPC', 'Disease', (134, 137))	('HOPX', 'Gene', (57, 61))	('RAB37', 'Gene', (63, 68))	('SHISA3', 'Gene', (74, 80))	('SHISA3', 'Gene', '152573', (74, 80))	('hypermethylation', 'Var', (33, 49))	('HOPX', 'Gene', '84525', (57, 61))	('RAB37', 'Gene', '326624', (63, 68))
119990	32120844	Dysregulation of protein ubiquitination is associated with a wide range of human diseases, including cancer.	('protein', 'Protein', (17, 24))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('Dysregulation', 'Var', (0, 13))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('protein ubiquitination', 'biological_process', 'GO:0016567', ('17', '39'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('associated', 'Reg', (43, 53))	('human', 'Species', '9606', (75, 80))
119991	32120844	UCHL1 inhibits cell proliferation by deubiquitinating p53/HIF-a in hepatocellular carcinoma and by ubiquitinating MDM-2 in NPC.	('deubiquitinating', 'MPA', (37, 53))	('MDM-2', 'Gene', (114, 119))	('MDM-2', 'Gene', '4193', (114, 119))	('inhibits', 'NegReg', (6, 14))	('cell proliferation', 'biological_process', 'GO:0008283', ('15', '33'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (67, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('hepatocellular carcinoma', 'Disease', (67, 91))	('p53', 'Gene', (54, 57))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (67, 91))	('NPC', 'cellular_component', 'GO:0005643', ('123', '126'))	('cell proliferation', 'CPA', (15, 33))	('p53', 'Gene', '7157', (54, 57))	('UCHL1', 'Gene', (0, 5))	('ubiquitinating', 'Var', (99, 113))
119993	32120844	The MethHC database showed that the UCHL1 promoter is also hypermethylated in these cancers, and there are strong negative correlations between UCHL1 promoter methylation and mRNA expression in these cancers as well (Supplementary Figure S3B and S3C).	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('methylation', 'biological_process', 'GO:0032259', ('159', '170'))	('cancers', 'Disease', (84, 91))	('negative', 'NegReg', (114, 122))	('mRNA expression', 'MPA', (175, 190))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('UCHL1', 'Gene', (36, 41))	('methylation', 'Var', (159, 170))	('hypermethylated', 'Var', (59, 74))	('UCHL1', 'Gene', (144, 149))
119996	32120844	Therefore, dysregulation of CTTN causes many diseases, especially cancer.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('dysregulation', 'Var', (11, 24))	('diseases', 'Disease', (45, 53))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('CTTN', 'Gene', (28, 32))	('cancer', 'Disease', (66, 72))	('causes', 'Reg', (33, 39))
119999	32120844	Further ubiquitin assays showed that UCHL1 (WT) but not UCHL1 (C90S) mutant could increase the K48-linked ubiquitin level of CTTN, confirming that UCHL1 regulated the stability of CTTN through ubiquitin-proteasome pathway (Figure 5E-H).	('UCHL1', 'Gene', (56, 61))	('mutant', 'Var', (69, 75))	('proteasome', 'molecular_function', 'GO:0004299', ('203', '213'))	('proteasome', 'cellular_component', 'GO:0000502', ('203', '213'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('8', '17'))	('C90S', 'Mutation', 'p.C90S', (63, 67))	('ubiquitin', 'molecular_function', 'GO:0031386', ('193', '202'))	('increase', 'PosReg', (82, 90))	('K48-linked ubiquitin level', 'MPA', (95, 121))	('proteasome pathway', 'biological_process', 'GO:0043161', ('203', '221'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('106', '115'))	('stability', 'MPA', (167, 176))
120002	32120844	The following are available online at , Figure S1: The UCHL1 is hypermethylated in nasopharyngeal carcinoma tissues.	('UCHL1', 'Gene', (55, 60))	('carcinoma', 'Disease', 'MESH:D009369', (98, 107))	('hypermethylated', 'Var', (64, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (83, 107))	('carcinoma', 'Disease', (98, 107))
120004	32120844	Figure S3: Promoter hypermethylation mediates downregulation of UCHL1 in four types of solid tumor.	('downregulation', 'NegReg', (46, 60))	('Promoter hypermethylation', 'Var', (11, 36))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('UCHL1', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
120019	29723992	The myriad of carcinogens in cigarette smoke includes tobacco nitrosoamine, which may affect tumorigenesis in diverse organs.	('tobacco', 'Species', '4097', (54, 61))	('affect', 'Reg', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('nitrosoamine', 'Chemical', '-', (62, 74))	('tobacco nitrosoamine', 'Var', (54, 74))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
120033	29723992	Environmental factors, including diet, smoking, alcohol consumption, stress, infectious agents, and environmental carcinogens, are important in the pathogenesis of cancers through epigenetic modifications.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('epigenetic modifications', 'Var', (180, 204))	('pathogenesis', 'biological_process', 'GO:0009405', ('148', '160'))	('alcohol', 'Chemical', 'MESH:D000438', (48, 55))
120039	29723992	At variable steps of DNA breaks, the aberrant expression patterns of miRNAs can be oncogenic or antioncogenic factors and are associated with cellular dysfunction and onset of disease.	('associated with', 'Reg', (126, 141))	('cellular dysfunction', 'Disease', (142, 162))	('aberrant expression patterns', 'Var', (37, 65))	('cellular dysfunction', 'Disease', 'MESH:D004806', (142, 162))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('miRNAs', 'Gene', (69, 75))
120045	29723992	Alterations in the expression of miR-125b, a tumor-suppressing miRNA, trigger an early event in prostate carcinoma.	('miR-125b', 'Gene', (33, 41))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (96, 114))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', (45, 50))	('prostate carcinoma', 'Disease', (96, 114))	('prostate carcinoma', 'Disease', 'MESH:D011472', (96, 114))	('trigger', 'Reg', (70, 77))	('miR-125b', 'Chemical', '-', (33, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
120046	29723992	miR-125b directly targets ErbB2/B3 and MET, and loss of miR-125b results in enhanced signaling via the MET-regulated phosphoinositol-3-kinase/protein kinase B and RAS/pMEK pathways.	('protein kinase B', 'Gene', (142, 158))	('RAS/pMEK pathways', 'Pathway', (163, 180))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('loss', 'Var', (48, 52))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('miR-125b', 'Chemical', '-', (56, 64))	('signaling', 'MPA', (85, 94))	('ErbB2', 'Gene', (26, 31))	('protein kinase B', 'Gene', '2185', (142, 158))	('enhanced', 'PosReg', (76, 84))	('MET-regulated', 'MPA', (103, 116))	('ErbB2', 'Gene', '2064', (26, 31))	('miR-125b', 'Gene', (56, 64))	('miR-125b', 'Chemical', '-', (0, 8))
120048	29723992	These molecular dysfunctions mediate apoptosis, cell senescence, and/or autophagy or carcinogenesis by aberrant genomic expression.	('mediate', 'Reg', (29, 36))	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('autophagy', 'biological_process', 'GO:0006914', ('72', '81'))	('autophagy', 'CPA', (72, 81))	('apoptosis', 'CPA', (37, 46))	('senescence', 'biological_process', 'GO:0010149', ('53', '63'))	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('aberrant genomic expression', 'Var', (103, 130))	('carcinogenesis', 'Disease', (85, 99))	('autophagy', 'biological_process', 'GO:0016236', ('72', '81'))	('cell senescence', 'CPA', (48, 63))
120065	29723992	On the basis of molecular pathology, lung carcinoma occurs after multiple processes including genomic instability, mutations, deletions, insertions, modifications (such as methylation and sialylation), and gene silencing by miRNAs.	('sialylation', 'biological_process', 'GO:0097503', ('188', '199'))	('mutations', 'Var', (115, 124))	('insertions', 'Var', (137, 147))	('lung carcinoma', 'Disease', 'MESH:D008175', (37, 51))	('gene', 'Var', (206, 210))	('deletions', 'Var', (126, 135))	('lung carcinoma', 'Disease', (37, 51))	('gene silencing', 'biological_process', 'GO:0016458', ('206', '220'))	('methylation', 'Var', (172, 183))	('methylation', 'biological_process', 'GO:0032259', ('172', '183'))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
120066	29723992	During the early steps in the oncogenesis of lung carcinoma, mutations of tumor suppressor or enhancer genes have been identified.	('lung carcinoma', 'Disease', (45, 59))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutations', 'Var', (61, 70))	('oncogenesis', 'biological_process', 'GO:0007048', ('30', '41'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('tumor', 'Disease', (74, 79))	('lung carcinoma', 'Disease', 'MESH:D008175', (45, 59))
120067	29723992	Once the repair of DNA damage fails, these intrinsic mutations may be important carcinogens underlying genomic instability and may accelerate cancer progression.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutations', 'Var', (53, 62))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))	('accelerate', 'PosReg', (131, 141))	('cancer', 'Disease', (142, 148))
120068	29723992	miRNA-486-5p is a tumor suppressor miRNA that is often downregulated, and which correlated with ankyrin 1 (ANK1) expression in NSCLC.	('NSCLC', 'Disease', (127, 132))	('expression', 'MPA', (113, 123))	('correlated', 'Reg', (80, 90))	('ANK1', 'Gene', (107, 111))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('tumor', 'Disease', (18, 23))	('ANK1', 'Gene', '286', (107, 111))	('miRNA-486-5p', 'Var', (0, 12))	('tumor suppressor', 'biological_process', 'GO:0051726', ('18', '34'))	('ankyrin 1', 'Gene', '286', (96, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('downregulated', 'NegReg', (55, 68))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('18', '34'))	('ankyrin 1', 'Gene', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
120073	29723992	ANK1 methylation is significantly more prevalent in adenocarcinoma compared to squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('methylation', 'biological_process', 'GO:0032259', ('5', '16'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('methylation', 'Var', (5, 16))	('squamous cell carcinoma', 'Disease', (79, 102))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (79, 102))	('prevalent', 'Reg', (39, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('adenocarcinoma', 'Disease', (52, 66))	('adenocarcinoma', 'Disease', 'MESH:D000230', (52, 66))	('ANK1', 'Gene', (0, 4))	('ANK1', 'Gene', '286', (0, 4))
120076	29723992	Cigarette smoking for many decades leads to genetic mutations or deletions of bronchial epithelial cells, which can result in dysplasia and subsequent carcinoma.	('carcinoma', 'Disease', (151, 160))	('carcinoma', 'Disease', 'MESH:D002277', (151, 160))	('result in', 'Reg', (116, 125))	('genetic mutations', 'Var', (44, 61))	('deletions', 'Var', (65, 74))	('dysplasia', 'Disease', (126, 135))	('dysplasia', 'Disease', 'MESH:D004476', (126, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
120077	29723992	Gene mutations most closely related to carcinogenesis occur due to exposure to some cigarette carcinogens.	('carcinogenesis', 'Disease', 'MESH:D063646', (39, 53))	('mutations', 'Var', (5, 14))	('carcinogenesis', 'Disease', (39, 53))
120078	29723992	A spectrum of TP53 mutations have been documented in cancers arising in active as well as former smokers, with greater prevalence in women with a history of heavy smoking.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('cancers', 'Disease', (53, 60))	('women', 'Species', '9606', (133, 138))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
120087	29723992	The other is EGFR mutations based on the DNA modification and mutations in lung cancer.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('DNA modification', 'biological_process', 'GO:0006304', ('41', '57'))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('mutations', 'Var', (62, 71))
120111	29723992	NBS1 has been found to increase NBS1 gene expression and associated NBS1 polymorphisms in smoking-related cancers, such as those of the lungs, liver, esophagus, head, and neck.	('NBS1', 'Gene', (32, 36))	('NBS1', 'Gene', '4683', (0, 4))	('NBS1', 'Gene', (68, 72))	('neck', 'cellular_component', 'GO:0044326', ('171', '175'))	('expression', 'MPA', (42, 52))	('gene expression', 'biological_process', 'GO:0010467', ('37', '52'))	('head', 'Disease', (161, 165))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('liver', 'Disease', (143, 148))	('increase', 'PosReg', (23, 31))	('polymorphisms', 'Var', (73, 86))	('cancers', 'Disease', (106, 113))	('NBS1', 'Gene', (0, 4))	('NBS1', 'Gene', '4683', (32, 36))	('esophagus', 'Disease', (150, 159))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('NBS1', 'Gene', '4683', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
120112	29723992	These findings support the hypothesis that genetic variation plays a critical role in smoking-related carcinogenesis.	('genetic variation', 'Var', (43, 60))	('carcinogenesis', 'Disease', (102, 116))	('carcinogenesis', 'Disease', 'MESH:D063646', (102, 116))
120114	29723992	Cigarette smoking has cancer-promoting effects that include the induction of mutations.	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (22, 28))
120120	29723992	Features of genetic change, cellular dysfunction, and carcinogenesis in aging cells are biologically similar to the characteristics observed during the carcinogenesis arising from cigarette smoking (Figure 2).	('carcinogenesis', 'Disease', 'MESH:D063646', (54, 68))	('carcinogenesis', 'Disease', (152, 166))	('carcinogenesis', 'Disease', (54, 68))	('cellular dysfunction', 'Disease', (28, 48))	('cellular dysfunction', 'Disease', 'MESH:D004806', (28, 48))	('genetic', 'Var', (12, 19))	('aging', 'biological_process', 'GO:0007568', ('72', '77'))	('carcinogenesis', 'Disease', 'MESH:D063646', (152, 166))
120129	29723992	An analysis of the expression of miRNAs in plasma from ALK-positive NSCLC patients identified mir-660-5p and miR-362-5p as potential predictors for the response to crizotinib treatment.	('mir-660-5p', 'Var', (94, 104))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('patients', 'Species', '9606', (74, 82))	('miR-362-5p', 'Var', (109, 119))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('crizotinib', 'Chemical', 'MESH:D000077547', (164, 174))	('NSCLC', 'Disease', (68, 73))
120136	29723992	Similar mechanisms involving aberrant expression and mutations of genes due to smoking, leading to urothelial carcinoma in the urinary tract, have been reported (Table 1).	('urothelial carcinoma', 'Disease', 'MESH:D014526', (99, 119))	('leading to', 'Reg', (88, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('urothelial carcinoma', 'Disease', (99, 119))	('carcinoma in the urinary tract', 'Phenotype', 'HP:0010786', (110, 140))	('mutations', 'Var', (53, 62))	('aberrant', 'Var', (29, 37))
120138	29723992	Therefore, cancer-related molecules controlled by miRNA are involved in carcinogenesis and cancer progression and could be the leading cause of smoking-related carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('carcinogenesis', 'Disease', (160, 174))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('carcinogenesis', 'Disease', 'MESH:D063646', (72, 86))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('carcinogenesis', 'Disease', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (11, 17))	('miRNA', 'Var', (50, 55))	('involved', 'Reg', (60, 68))
120219	25011684	Deregulation of HDAC8 is frequent in urothelial cancer, but neither specific pharmacological inhibition nor siRNA-mediated knockdown of HDAC8 impaired viability of urothelial cancer cell lines in a therapeutic useful manner.	('urothelial cancer', 'Disease', 'MESH:D014523', (37, 54))	('HDAC8 impaired viability of urothelial cancer', 'Disease', 'MESH:D009422', (136, 181))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('urothelial cancer', 'Disease', 'MESH:D014523', (164, 181))	('urothelial cancer', 'Disease', (37, 54))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('HDAC8 impaired viability of urothelial cancer', 'Disease', (136, 181))
120225	25011684	Epigenetic alterations have been proposed as a driving force of malignancy [-].	('Epigenetic alterations', 'Var', (0, 22))	('malignancy', 'Disease', (64, 74))	('malignancy', 'Disease', 'MESH:D009369', (64, 74))
120232	25011684	Although many HDACs deacetylate histones the analysis of the human acetylome indicates that the deacetylation of non-histone proteins represents a considerable part of their action .	('HDAC', 'Gene', (14, 18))	('non-histone proteins', 'Protein', (113, 133))	('HDAC', 'Gene', '9734', (14, 18))	('histones', 'Protein', (32, 40))	('deacetylate', 'Var', (20, 31))	('deacetylation', 'MPA', (96, 109))	('human', 'Species', '9606', (61, 66))
120242	25011684	In cultured neuroblastoma cells knockdown and pharmacological inhibition of HDAC8 resulted in inhibition of proliferation, reduced clonogenic growth, cell cycle arrest and differentiation .	('differentiation', 'CPA', (172, 187))	('cell cycle arrest', 'CPA', (150, 167))	('HDAC8', 'Gene', (76, 81))	('inhibition', 'NegReg', (94, 104))	('neuroblastoma', 'Disease', 'MESH:D009447', (12, 25))	('neuroblastoma', 'Disease', (12, 25))	('proliferation', 'CPA', (108, 121))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('150', '167'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (150, 167))	('neuroblastoma', 'Phenotype', 'HP:0003006', (12, 25))	('inhibition', 'Var', (62, 72))	('clonogenic growth', 'CPA', (131, 148))	('reduced', 'NegReg', (123, 130))
120245	25011684	HDAC8 knockdown inhibits proliferation and enhances apoptosis in hepatocellular carcinoma cells via up-regulation of p53 .	('up-regulation', 'PosReg', (100, 113))	('hepatocellular carcinoma', 'Disease', (65, 89))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (65, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('proliferation', 'CPA', (25, 38))	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('enhances', 'PosReg', (43, 51))	('HDAC8', 'Gene', (0, 5))	('apoptosis', 'CPA', (52, 61))	('inhibits', 'NegReg', (16, 24))	('knockdown', 'Var', (6, 15))	('apoptosis', 'biological_process', 'GO:0097194', ('52', '61'))	('apoptosis', 'biological_process', 'GO:0006915', ('52', '61'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (65, 89))	('regulation', 'biological_process', 'GO:0065007', ('103', '113'))
120255	25011684	Cells were transfected with 10 nM HDAC8 Silencer  Select validated siRNA (#4390824, s31698, Ambion, Life Technologies, Darmstadt, Germany) or a Silencer  Select Negative Control #2 validated siRNA (#4390846, Ambion, Life Technologies, Darmstadt, Germany) using Lipofectamine RNAi MAX (Invitrogen, Life Technologies, Darmstadt, Germany), according to the manufacturer's protocol.	('#4390824', 'Var', (74, 82))	('Lipofectamine', 'Chemical', 'MESH:C086724', (261, 274))	('RNAi', 'biological_process', 'GO:0016246', ('275', '279'))	('#4390846', 'Var', (198, 206))
120257	25011684	UCCs were seeded into 96-well plates and grown for 24 h before inhibitor treatment with the indicated drug concentration or DMSO and further grown for 72 h. In another experiment, cells were plated in 6-well plates and grown for 24 h before siRNA-mediated knockdown of HDAC8.	('knockdown', 'Var', (256, 265))	('DMSO', 'Chemical', 'MESH:D004121', (124, 128))	('HDAC8', 'Gene', (269, 274))
120285	25011684	The transfection of HDAC8 siRNA in VM-CUB1 and UM-UC-3 cells caused a moderate reduction of colony numbers compared to transfection of irrelevant siRNA by up to 30%.	('UM-UC-3', 'CellLine', 'CVCL:1783', (47, 54))	('colony numbers', 'CPA', (92, 106))	('transfection', 'Var', (4, 16))	('HDAC8', 'Gene', (20, 25))	('reduction', 'NegReg', (79, 88))
120286	25011684	In VM-CUB1, SW-1710, RT-112 and UM-UC-3 cells the colony size remains constant between irrelevant control and HDAC8 siRNA transfection (data not shown).	('transfection', 'Var', (122, 134))	('RT-112', 'Chemical', '-', (21, 27))	('SW-1710', 'CellLine', 'CVCL:1721', (12, 19))	('UM-UC-3', 'CellLine', 'CVCL:1783', (32, 39))	('colony size', 'CPA', (50, 61))
120289	25011684	The expression of TS 72 h after HDAC8 knockdown was only slightly reduced in SW-1710, 639-V and UM-UC-3 cells.	('reduced', 'NegReg', (66, 73))	('HDAC8', 'Gene', (32, 37))	('UM-UC-3', 'CellLine', 'CVCL:1783', (96, 103))	('expression', 'MPA', (4, 14))	('SW-1710', 'CellLine', 'CVCL:1721', (77, 84))	('knockdown', 'Var', (38, 47))	('TS', 'Gene', '7298', (18, 20))
120291	25011684	Effects on cleavage of PARP could only be detected in UM-UC-3 cells after HDAC8 knockdown.	('knockdown', 'Var', (80, 89))	('PARP', 'Gene', (23, 27))	('HDAC8', 'Gene', (74, 79))	('PARP', 'Gene', '142', (23, 27))	('cleavage', 'MPA', (11, 19))	('UM-UC-3', 'CellLine', 'CVCL:1783', (54, 61))
120294	25011684	An increase of acetylated alpha-tubulin could be detected in all cell lines after HDAC8 siRNA transfection (Figure 4).	('acetylated', 'MPA', (15, 25))	('alpha-tubulin', 'Gene', '10376', (26, 39))	('HDAC8', 'Gene', (82, 87))	('alpha-tubulin', 'Gene', (26, 39))	('transfection', 'Var', (94, 106))	('increase', 'PosReg', (3, 11))
120295	25011684	Based on the observation that the HDAC8 knockdown inhibited proliferation of urothelial carcinoma cells we investigated the sensitivity of several UCCs to three different HDAC8 inhibitors .	('urothelial carcinoma', 'Disease', 'MESH:D014526', (77, 97))	('knockdown', 'Var', (40, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('urothelial carcinoma', 'Disease', (77, 97))	('HDAC8', 'Gene', (34, 39))	('inhibited', 'NegReg', (50, 59))
120312	25011684	In contrast, acetylation of H4 increased after inhibitor treatment in RT-112 (Figure 10B).	('inhibitor treatment', 'Var', (47, 66))	('acetylation', 'MPA', (13, 24))	('RT-112', 'Chemical', '-', (70, 76))	('increased', 'PosReg', (31, 40))
120314	25011684	In brief, HDAC1, HDAC2 and HDAC3 mRNA levels exhibited variable changes after siRNA-mediated knockdown of HDAC8.	('knockdown', 'Var', (93, 102))	('HDAC3', 'Gene', '8841', (27, 32))	('HDAC3', 'Gene', (27, 32))	('changes', 'Reg', (64, 71))	('HDAC2', 'Gene', (17, 22))	('HDAC1', 'Gene', (10, 15))	('HDAC2', 'Gene', '3066', (17, 22))	('HDAC8', 'Gene', (106, 111))	('HDAC1', 'Gene', '3065', (10, 15))
120316	25011684	In particular, either HDAC1 or HDAC2 seems to become upregulated after HDAC8 knockdown (Figure 11A).	('HDAC1', 'Gene', (22, 27))	('knockdown', 'Var', (77, 86))	('HDAC1', 'Gene', '3065', (22, 27))	('HDAC8', 'Gene', (71, 76))	('HDAC2', 'Gene', (31, 36))	('HDAC2', 'Gene', '3066', (31, 36))	('upregulated', 'PosReg', (53, 64))
120324	25011684	SiRNA-mediated knockdown and pharmacological inhibition of HDAC8 in neuroblastoma significantly decreased proliferation rate and reduced clonogenic growth, cell cycle arrest, and differentiation .	('cell cycle arrest', 'Phenotype', 'HP:0011018', (156, 173))	('pharmacological', 'Var', (29, 44))	('differentiation', 'CPA', (179, 194))	('clonogenic growth', 'CPA', (137, 154))	('neuroblastoma', 'Phenotype', 'HP:0003006', (68, 81))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('156', '173'))	('decreased', 'NegReg', (96, 105))	('neuroblastoma', 'Disease', (68, 81))	('cell cycle arrest', 'CPA', (156, 173))	('neuroblastoma', 'Disease', 'MESH:D009447', (68, 81))	('reduced', 'NegReg', (129, 136))	('proliferation rate', 'CPA', (106, 124))	('HDAC8', 'Gene', (59, 64))
120325	25011684	In hepatocellular carcinoma HDAC8 knockdown also suppresses cell proliferation and enhances apoptosis via elevated expression of p53 and acetylation of p53 at Lys382 .	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('cell proliferation', 'CPA', (60, 78))	('p53', 'Gene', '7157', (152, 155))	('p53', 'Gene', (129, 132))	('HDAC8', 'Gene', (28, 33))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('apoptosis', 'CPA', (92, 101))	('p53', 'Gene', (152, 155))	('elevated', 'PosReg', (106, 114))	('Lys382', 'Chemical', '-', (159, 165))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('suppresses', 'NegReg', (49, 59))	('Lys382', 'Var', (159, 165))	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('hepatocellular carcinoma', 'Disease', (3, 27))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('acetylation', 'MPA', (137, 148))	('expression', 'MPA', (115, 125))	('enhances', 'PosReg', (83, 91))	('p53', 'Gene', '7157', (129, 132))
120343	25011684	Comparing expression levels of further class I HDACs after knockdown of HDAC8 as well as after pharmacological inhibition, only minor changes were observed.	('HDAC', 'Gene', (72, 76))	('expression levels', 'MPA', (10, 27))	('HDAC', 'Gene', '9734', (72, 76))	('HDAC', 'Gene', (47, 51))	('HDAC', 'Gene', '9734', (47, 51))	('knockdown', 'Var', (59, 68))
120344	25011684	Although upregulation of HDAC1 or HDAC2 was a little more consistently observed after HDAC8 knockdown, they can hardly explain the difference between knockdown and inhibition by c5 or c6.	('HDAC8', 'Gene', (86, 91))	('HDAC1', 'Gene', '3065', (25, 30))	('upregulation', 'PosReg', (9, 21))	('knockdown', 'Var', (92, 101))	('HDAC2', 'Gene', (34, 39))	('HDAC2', 'Gene', '3066', (34, 39))	('HDAC1', 'Gene', (25, 30))
120345	25011684	Neither HDAC8 knockdown nor pharmacological treatment with any compound (except the SAHA control) led to a change in histone H3 or H4 acetylation, a widely used surrogate marker for intracellular HDAC inhibition.	('HDAC', 'Gene', '9734', (196, 200))	('intracellular', 'cellular_component', 'GO:0005622', ('182', '195'))	('histone', 'MPA', (117, 124))	('SAHA', 'Chemical', 'MESH:D000077337', (84, 88))	('HDAC', 'Gene', (8, 12))	('HDAC', 'Gene', '9734', (8, 12))	('knockdown', 'Var', (14, 23))	('HDAC', 'Gene', (196, 200))
120348	25011684	Global Histone H4 acetylation was not affected by HDAC8 knockdown or by selective inhibitor treatment .	('Histone H4', 'Gene', (7, 17))	('Histone H4', 'Gene', '8294', (7, 17))	('HDAC8', 'Gene', (50, 55))	('Histone H4 acetylation', 'biological_process', 'GO:0043967', ('7', '29'))	('knockdown', 'Var', (56, 65))
120349	25011684	In contrast, HDAC8 knockdown in some cell lines and treatment with c5 or c6 resulted in a strong increase of acetylated alpha-tubulin.	('increase', 'PosReg', (97, 105))	('alpha-tubulin', 'Gene', '10376', (120, 133))	('knockdown', 'Var', (19, 28))	('HDAC8', 'Gene', (13, 18))	('alpha-tubulin', 'Gene', (120, 133))
120358	25011684	The effects of siRNA mediated knockdown of HDAC8 on cell cycle and apoptosis were limited and few significant effects were seen, such as a decreased S-phase fraction in VM-CUB1 and small changes in thymidylate synthase and p21 expression.	('thymidylate synthase', 'Gene', (198, 218))	('S-phase fraction', 'MPA', (149, 165))	('cell cycle', 'biological_process', 'GO:0007049', ('52', '62'))	('p21', 'Gene', (223, 226))	('S-phase', 'biological_process', 'GO:0051320', ('149', '156'))	('expression', 'MPA', (227, 237))	('thymidylate synthase', 'Gene', '7298', (198, 218))	('p21', 'Gene', '644914', (223, 226))	('HDAC8', 'Gene', (43, 48))	('decreased', 'NegReg', (139, 148))	('apoptosis', 'biological_process', 'GO:0097194', ('67', '76'))	('knockdown', 'Var', (30, 39))	('apoptosis', 'biological_process', 'GO:0006915', ('67', '76'))	('changes', 'Reg', (187, 194))
120359	25011684	In the neuroblastoma cell line BE (2)-C, a G0/G1 arrest has been detected after siRNA-mediated knockdown of HDAC8.	('neuroblastoma', 'Disease', (7, 20))	('neuroblastoma', 'Phenotype', 'HP:0003006', (7, 20))	('HDAC8', 'Gene', (108, 113))	('knockdown', 'Var', (95, 104))	('G0/G1 arrest', 'CPA', (43, 55))	('neuroblastoma', 'Disease', 'MESH:D009447', (7, 20))
120360	25011684	This G0/G1 arrest induced by HDAC8 knockdown was associated with p21 mRNA upregulation .	('knockdown', 'Var', (35, 44))	('p21', 'Gene', (65, 68))	('p21', 'Gene', '644914', (65, 68))	('HDAC8', 'Gene', (29, 34))	('upregulation', 'PosReg', (74, 86))	('G0/G1 arrest', 'CPA', (5, 17))
120362	25011684	This observation fits with our own marginal effects after siRNA-mediated HDAC8 knockdown.	('fits', 'Disease', (17, 21))	('knockdown', 'Var', (79, 88))	('HDAC8', 'Gene', (73, 78))	('fits', 'Disease', 'MESH:D012640', (17, 21))
120367	25011684	Furthermore, pharmacological inhibition of HDAC8 induced a G2/M-arrest.	('M-arrest', 'Disease', 'MESH:D006323', (62, 70))	('pharmacological', 'Var', (13, 28))	('HDAC8', 'Gene', (43, 48))	('induced', 'Reg', (49, 56))	('M-arrest', 'Disease', (62, 70))
120378	30053901	Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO.	('mutations', 'Var', (131, 140))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cancer', 'Disease', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('protein/phosphoprotein', 'MPA', (172, 194))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mRNA expression', 'MPA', (142, 157))
120382	30053901	Further, our analyses showed co-occurring potentially druggable multi-omics alterations in 32% of tumors, indicating a role for individualized combinational therapy, with evidence supporting mTOR/PI3K/ESR1 co-inhibition and BRAF/AKT co-inhibition in 1.6 and 0.8% of tumors, respectively.	('alterations', 'Var', (76, 87))	('tumors', 'Disease', (98, 104))	('ESR1', 'Gene', '2099', (201, 205))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('mTOR', 'Gene', (191, 195))	('AKT', 'Gene', '207', (229, 232))	('mTOR', 'Gene', '2475', (191, 195))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('PI3K', 'molecular_function', 'GO:0016303', ('196', '200'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ESR1', 'Gene', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('BRAF', 'Gene', (224, 228))	('AKT', 'Gene', (229, 232))	('BRAF', 'Gene', '673', (224, 228))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('tumors', 'Disease', (266, 272))
120383	30053901	We experimentally validated a subset of putative druggable mutations in BRAF identified by a protein structure-based computational tool.	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (72, 76))	('mutations', 'Var', (59, 68))
120392	30053901	The Cancer Genome Atlas (TCGA), the Clinical Proteomic Tumor Analysis Consortium (CPTAC), and other large-scale sequencing data sets represent an opportunity to identify "druggable" variants, i.e., variants that render a cancer type susceptible to a drug.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', (221, 227))	('render', 'Reg', (212, 218))	('variants', 'Var', (182, 190))	('Tumor', 'Phenotype', 'HP:0002664', (55, 60))	('variants', 'Var', (198, 206))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('Cancer Genome Atlas', 'Disease', (4, 23))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))
120395	30053901	We identified tumors with drug-associated mutations and found considerable opportunity for repurposing of drugs across cancer types.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', (119, 125))	('drug-associated', 'Reg', (26, 41))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('mutations', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
120396	30053901	We used a structure-based computational tool to identify putative druggable mutations based on proximity to known druggable mutations and experimentally validated a subset of putative druggable mutations in BRAF.	('BRAF', 'Gene', (207, 211))	('BRAF', 'Gene', '673', (207, 211))	('mutations', 'Var', (76, 85))	('mutations', 'Var', (194, 203))
120404	30053901	Tumor type is included for each variant/drug entry because, with infrequent exception, a variant's effect on a tumor's response to a given drug has only been rigorously studied in one or only a few cancer type(s).	('response to a given drug', 'MPA', (119, 143))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('variant', 'Var', (89, 96))	('tumor', 'Disease', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))
120405	30053901	For a variant/drug entry based on preclinical data, tumor type was either inferred from the xenograft or cell line, or left unspecified.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('variant/drug', 'Var', (6, 18))	('tumor', 'Disease', (52, 57))	('unspecified', 'Species', '32644', (124, 135))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
120406	30053901	Copy number amplifications (CNA) and losses (CNL), high expression outliers in oncogenes, low expression outliers in tumor suppressors, and fusions that may lead to druggability are also included.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('druggability', 'MPA', (165, 177))	('losses', 'NegReg', (37, 43))	('tumor', 'Disease', (117, 122))	('lead to', 'Reg', (157, 164))	('Copy number amplifications', 'Var', (0, 26))	('oncogenes', 'Gene', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
120407	30053901	Effect describes whether a variant correlates with increased sensitivity of a tumor to a drug or increased resistance of a tumor to a drug.	('increased', 'PosReg', (97, 106))	('tumor', 'Disease', (123, 128))	('increased', 'PosReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('sensitivity', 'MPA', (61, 72))	('tumor', 'Disease', (78, 83))	('variant', 'Var', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('resistance', 'MPA', (107, 117))
120408	30053901	A given drug entry in DEPO could be associated with multiple drug families to allow for the possibility of combining therapies (e.g., dabrafenib [B-Raf inhibitor] and trametinib [MEK inhibitor] for BRAF V600E/K-mutant melanoma) and multi-targeted tyrosine kinase inhibitors (e.g., afatinib as a dual HER2 and EGFR inhibitor).	('EGFR', 'Gene', '1956', (309, 313))	('BRAF', 'Gene', '673', (198, 202))	('BRAF', 'Gene', (198, 202))	('MEK', 'Gene', '5609', (179, 182))	('dabrafenib', 'Chemical', 'MESH:C561627', (134, 144))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('B-Raf', 'Gene', '673', (146, 151))	('V600E', 'Var', (203, 208))	('HER2', 'Gene', '2064', (300, 304))	('EGFR', 'molecular_function', 'GO:0005006', ('309', '313'))	('MEK', 'Gene', (179, 182))	('EGFR', 'Gene', (309, 313))	('tyrosine kinase', 'Gene', (247, 262))	('tyrosine kinase', 'Gene', '7294', (247, 262))	('afatinib', 'Chemical', 'MESH:D000077716', (281, 289))	('trametinib', 'Chemical', 'MESH:C560077', (167, 177))	('V600E', 'SUBSTITUTION', 'None', (203, 208))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('B-Raf', 'Gene', (146, 151))	('HER2', 'Gene', (300, 304))
120412	30053901	Variant calls were obtained from the TCGA Genome Data Analysis Centers (GDAC), Data Coordinating Center (DCC), and previously published TCGA marker papers until the end of 2014 (https://cancergenome.nih.gov/publications).	('Variant', 'Var', (0, 7))	('GDAC', 'Chemical', '-', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('DCC', 'cellular_component', 'GO:0120206', ('105', '108'))	('DCC', 'Chemical', '-', (105, 108))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
120416	30053901	We identified tumors in our pan-cancer cohort that harbored one or more drug-associated SNP or indel.	('indel', 'Var', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('SNP', 'Var', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
120417	30053901	Iterating through a mutation annotation format (MAF) file containing all variants in our pan-cancer cohort, we performed two actions for each entry in the MAF.	('cancer', 'Disease', (93, 99))	('variants', 'Var', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
120418	30053901	First, we queried a hash table containing all druggable, unambiguous mutations in DEPO (e.g., BRAF V600E) and a separate hash table containing all druggable, ambiguous, single-residue mutations in DEPO (e.g., BRAF V600).	('single-residue', 'Var', (169, 183))	('mutations', 'Var', (69, 78))	('BRAF', 'Gene', (94, 98))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))	('DEPO', 'Gene', (197, 201))	('BRAF', 'Gene', '673', (94, 98))	('DEPO', 'Gene', (82, 86))
120419	30053901	Second, we queried several classes of mutations that occur in a specific exon or segment of a gene (EGFR exon 19 in-frame deletion).	('mutations', 'Var', (38, 47))	('EGFR', 'Gene', '1956', (100, 104))	('EGFR', 'Gene', (100, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))
120421	30053901	In some cases, DEPO contains multiple entries per gene/mutation pair to reflect possible druggability of a gene/mutation pair in more than one tumor type, or that it may confer an effect (e.g., sensitivity or resistance) that depends on tumor type or other therapeutic context.	('resistance', 'CPA', (209, 219))	('tumor', 'Disease', (237, 242))	('tumor', 'Disease', (143, 148))	('druggability', 'MPA', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('gene/mutation', 'Var', (107, 120))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('sensitivity', 'MPA', (194, 205))
120422	30053901	For example, when visualizing "drug repurposing" across tumor types, a given mutation could be associated with > 1 "cancer-type-specific" tumor type, if a given gene/mutation pair had druggability information in DEPO in multiple tumor types at the same level of evidence.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (138, 143))	('mutation', 'Var', (77, 85))	('cancer', 'Disease', (116, 122))	('tumor', 'Disease', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('associated', 'Reg', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
120426	30053901	When considering potential druggable events in the cancer-type-non-specific setting, the drug with the highest level of evidence found across all tumor types was used for a specific variant (Additional file 2: Table S3).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('variant', 'Var', (182, 189))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
120428	30053901	If any sensitive interaction for a variant was found regardless of the tumor type and level, it was considered a "druggable" event for these analyses.	('variant', 'Var', (35, 42))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
120429	30053901	HotSpot3D was used to spatially cluster "known" drug-associated mutations in DEPO with putative druggable mutations in our pan-cancer cohort.	('DEPO', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', (127, 133))
120443	30053901	The distribution of LN(IC50) values of cell lines with DEPO mutations (both sensitive and resistant) for both the cancer-type-specific and non-specific settings were compared to a background distribution using the Mann-Whitney U test.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('DEPO', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (60, 69))	('cancer', 'Disease', (114, 120))
120450	30053901	Constructions expressing BRAF variants were generated from a plasmid expressing a wild-type BRAF (Addgene, #40775) with an N-terminal Flag tag using Q5 site-directed mutagenesis (New England BioLabs).	('variants', 'Var', (30, 38))	('BRAF', 'Gene', '673', (92, 96))	('BRAF', 'Gene', (92, 96))	('mutagenesis', 'biological_process', 'GO:0006280', ('166', '177'))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))
120451	30053901	Cells were transiently transfected with wild-type or mutant BRAF constructs using Lipofectamine 2000 reagent (Life Technologies) in six-well plates.	('BRAF', 'Gene', (60, 64))	('Lipofectamine 2000 reagent', 'Chemical', '-', (82, 108))	('BRAF', 'Gene', '673', (60, 64))	('mutant', 'Var', (53, 59))
120458	30053901	For each tumor, we mapped its "druggable" variants against one or more drugs, which were then mapped to one or more drug classes (Additional file 2: Table S8).	('variants', 'Var', (42, 50))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (9, 14))
120459	30053901	For each variant, we used the drug that had the highest level of evidence in DEPO regardless of cancer type (Additional file 2: Table S3).	('variant', 'Var', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('DEPO', 'Disease', (77, 81))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
120460	30053901	For the purposes of visualization, we only considered ten FDA-approved drug classes (Additional file 2: Table S9) mapping to the largest number of variants across our pan-cancer cohort (Additional file 2: Table S10).	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('variants', 'Var', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (171, 177))
120466	30053901	Further, a substantial number (~ 25%) of sensitive variant/drug interactions are approved by the FDA for a particular cancer type or are based on late-stage clinical studies.	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('particular cancer type', 'Disease', (107, 129))	('particular cancer type', 'Disease', 'MESH:D009369', (107, 129))	('variant/drug', 'Var', (51, 63))
120467	30053901	Several genes account for a large proportion of variant/drug interactions (e.g., EGFR, KIT, ERBB2, BRCA1, PDGFRA), reflecting interest in therapeutically exploiting a relatively limited number of cancer driver genes (Fig.	('ERBB2', 'Gene', '2064', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('KIT', 'Gene', (87, 90))	('PDGFRA', 'Gene', '5156', (106, 112))	('ERBB2', 'Gene', (92, 97))	('BRCA1', 'Gene', (99, 104))	('KIT', 'molecular_function', 'GO:0005020', ('87', '90'))	('variant/drug', 'Var', (48, 60))	('EGFR', 'Gene', '1956', (81, 85))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('EGFR', 'molecular_function', 'GO:0005006', ('81', '85'))	('cancer', 'Disease', (196, 202))	('BRCA', 'Phenotype', 'HP:0003002', (99, 103))	('BRCA1', 'Gene', '672', (99, 104))	('PDGFRA', 'Gene', (106, 112))	('EGFR', 'Gene', (81, 85))
120469	30053901	Our analysis reveals 2364 mutations across 2114 tumors that are associated with sensitivity to one or more drugs (mean = 1.12/tumor) (Additional file 2: Table S2).	('associated', 'Reg', (64, 74))	('tumor', 'Disease', (48, 53))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('sensitivity', 'MPA', (80, 91))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (126, 131))
120470	30053901	The low fraction of drug-associated mutations likely reflects the large number of passengers in cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (36, 45))
120471	30053901	Thirty-two percent of tumors had at least one drug-associated mutation, a percentage that is consistent with the 28% of screened patients that could be matched with a targeted therapy or trial.	('patients', 'Species', '9606', (129, 137))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutation', 'Var', (62, 70))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
120473	30053901	2), that is, tumors with mutations associated with a known drug response in the cancer type with the highest level of evidence.	('mutations', 'Var', (25, 34))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Disease', (80, 86))
120474	30053901	Only 3.3% of the samples contain a druggable mutation known to be FDA approved; however, if we consider less mature evidence: clinical trials, preclinical, and case reports, we could potentially increase the percentage of tumors with drug-associated mutations to 8.2, 8.5, and 10.5%, respectively.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('drug-associated', 'Reg', (234, 249))	('mutations', 'Var', (250, 259))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('increase', 'PosReg', (195, 203))
120475	30053901	Here, skin cutaneous melanoma (SKCM) is the cancer type with the largest fraction of drug-associated mutations (78%).	('mutations', 'Var', (101, 110))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (11, 29))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (6, 29))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('skin cutaneous melanoma', 'Disease', (6, 29))	('CM', 'Disease', 'MESH:D009202', (33, 35))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
120476	30053901	SKCM with a BRAF V600E/K mutation (40% of patients) can be treated with BRAF and MEK inhibitors based on FDA approval.	('BRAF', 'Gene', (72, 76))	('V600E', 'Var', (17, 22))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('V600E', 'SUBSTITUTION', 'None', (17, 22))	('CM', 'Disease', 'MESH:D009202', (2, 4))	('patients', 'Species', '9606', (42, 50))	('MEK', 'Gene', (81, 84))	('BRAF', 'Gene', '673', (72, 76))	('MEK', 'Gene', '5609', (81, 84))
120477	30053901	The NRAS Q61 mutations found in 12% of SKCM patients are more challenging to treat, as is any RAS-mutant cancer due to activation of multiple signaling pathways.	('patients', 'Species', '9606', (44, 52))	('signaling', 'biological_process', 'GO:0023052', ('142', '151'))	('cancer', 'Disease', (105, 111))	('CM', 'Disease', 'MESH:D009202', (41, 43))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('activation', 'PosReg', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('NRAS', 'Gene', (4, 8))	('mutations', 'Var', (13, 22))	('NRAS', 'Gene', '4893', (4, 8))
120479	30053901	In colon and rectal carcinoma (COADREAD), glioblastoma multiforme (GBM), and lung adenocarcinoma (LUAD), 21, 14, and 40% of their respective tumors contain a drug-associated mutation in a cancer-type-specific setting.	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('colon and rectal carcinoma', 'Disease', 'MESH:D012004', (3, 29))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (13, 29))	('mutation', 'Var', (174, 182))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('glioblastoma multiforme', 'Disease', (42, 65))	('cancer', 'Disease', (188, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (42, 65))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('lung adenocarcinoma', 'Disease', (77, 96))	('contain', 'Reg', (148, 155))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('drug-associated', 'Reg', (158, 173))
120480	30053901	In COADREAD, drug-associated variants PIK3CA E542K, E545K, and H1047R are present in 2.1, 5.2, and 1.8% of tumors, respectively, and are associated with sensitivity to PI3K/AKT/mTOR pathway inhibitors in early-stage trials and aspirin in observational studies.	('H1047R', 'Mutation', 'rs121913279', (63, 69))	('AKT', 'Gene', (173, 176))	('sensitivity', 'MPA', (153, 164))	('associated with', 'Reg', (137, 152))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('mTOR', 'Gene', (177, 181))	('E542K', 'Mutation', 'rs121913273', (45, 50))	('aspirin', 'Chemical', 'MESH:D001241', (227, 234))	('E545K', 'Mutation', 'rs104886003', (52, 57))	('PIK3CA', 'Gene', '5290', (38, 44))	('E542K', 'Var', (45, 50))	('AKT', 'Gene', '207', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('mTOR', 'Gene', '2475', (177, 181))	('E545K', 'Var', (52, 57))	('PI3K', 'molecular_function', 'GO:0016303', ('168', '172'))	('PIK3CA', 'Gene', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('H1047R', 'Var', (63, 69))
120482	30053901	In GBM, the EGFR extracellular mutations (A289V, G598V, and R108K) and IDH1 mutation R132H are present in 10 and 4.5% of tumors, respectively, and are associated with drug response based on preclinical data.	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('G598V', 'Mutation', 'rs139236063', (49, 54))	('R132H', 'Var', (85, 90))	('A289V', 'Mutation', 'rs149840192', (42, 47))	('EGFR', 'Gene', (12, 16))	('R108K', 'Var', (60, 65))	('associated', 'Reg', (151, 161))	('IDH1', 'Gene', (71, 75))	('A289V', 'Var', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('G598V', 'Var', (49, 54))	('R108K', 'Mutation', 'rs1057519828', (60, 65))	('EGFR', 'Gene', '1956', (12, 16))	('IDH1', 'Gene', '3417', (71, 75))	('R132H', 'Mutation', 'rs121913500', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('extracellular', 'cellular_component', 'GO:0005576', ('17', '30'))
120483	30053901	In non-small cell lung cancer, EGFR inhibitors (e.g., erlotinib) are FDA approved for tumors with activating EGFR mutations, which are present at 10 and 1% in our LUAD and lung squamous cell carcinoma (LUSC) cohorts, respectively.	('mutations', 'Var', (114, 123))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('EGFR', 'Gene', '1956', (109, 113))	('non-small cell lung cancer', 'Disease', (3, 29))	('EGFR', 'molecular_function', 'GO:0005006', ('109', '113'))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('EGFR', 'Gene', '1956', (31, 35))	('tumors', 'Disease', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (172, 200))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('erlotinib', 'Chemical', 'MESH:D000069347', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('EGFR', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('LUSC', 'Phenotype', 'HP:0030359', (202, 206))	('activating', 'PosReg', (98, 108))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('EGFR', 'Gene', (31, 35))	('lung squamous cell carcinoma', 'Disease', (172, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 200))	('LUAD', 'Phenotype', 'HP:0030078', (163, 167))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))
120484	30053901	Despite the promise of targeted therapy, only 10.5% of this pan-cancer cohort contains potential drug-associated mutations in a cancer-type-specific setting.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('drug-associated', 'Reg', (97, 112))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (128, 134))
120485	30053901	With drug repurposing across cancer types, in which a drug used primarily in cancer type A with mutation X is repurposed for cancer type B with mutation X, we find that an additional 5.4% of patients may be treated with a FDA-approved drug-variant interaction (Figs.	('cancer', 'Disease', (29, 35))	('patients', 'Species', '9606', (191, 199))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutation', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
120487	30053901	In this cancer-type-non-specific setting, cancer types in which at least 40% of tumors have drug-associated mutations include low-grade glioma (LGG, 76%), thyroid carcinoma (THCA, 70%), and colorectal adenocarcinoma (COADREAD, 42%).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('THCA', 'Phenotype', 'HP:0002890', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (80, 86))	('colorectal adenocarcinoma', 'Disease', (190, 215))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (155, 172))	('cancer', 'Disease', (8, 14))	('thyroid carcinoma', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('glioma', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (190, 215))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (155, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('mutations', 'Var', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (42, 48))
120488	30053901	A small number of drug-associated mutations occur at high frequency in these cancer types.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutations', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
120491	30053901	However, BRAF V600E also occurs at a lower frequency in HNSC, KIRP, LGG, and GBM, indicating significant repurposing potential for BRAF inhibitors (Fig.	('HNSC', 'Phenotype', 'HP:0012288', (56, 60))	('BRAF', 'Gene', (131, 135))	('V600E', 'Var', (14, 19))	('BRAF', 'Gene', (9, 13))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', '673', (9, 13))
120492	30053901	However, COADREAD has been difficult to treat due to a large presence of KRAS and BRAF mutations; EGFR inhibition as monotherapy is used for COADREAD, but only in tumors with wild-type KRAS.	('EGFR', 'Gene', (98, 102))	('KRAS', 'Gene', '3845', (185, 189))	('KRAS', 'Gene', (73, 77))	('BRAF', 'Gene', '673', (82, 86))	('KRAS', 'Gene', '3845', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('BRAF', 'Gene', (82, 86))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('mutations', 'Var', (87, 96))	('KRAS', 'Gene', (185, 189))
120496	30053901	COADREAD or other cancer types having RAS mutations, such as cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), acute myeloid leukemia (AML), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC), could benefit from further exploration of combinatorial therapies targeting downstream targets of KRAS (Fig.	('corpus endometrial carcinoma', 'Disease', (207, 235))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (207, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('acute myeloid leukemia', 'Disease', (134, 156))	('cancer', 'Disease', (18, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (61, 125))	('RAS', 'Gene', (38, 41))	('AML', 'Disease', 'MESH:D015470', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('AML', 'Disease', (158, 161))	('stomach adenocarcinoma', 'Disease', (164, 186))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (134, 156))	('AML', 'Phenotype', 'HP:0004808', (158, 161))	('KRAS', 'Gene', '3845', (342, 346))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (134, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (140, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('KRAS', 'Gene', (342, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (164, 186))	('mutations', 'Var', (42, 51))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (214, 235))
120499	30053901	Together, cancer-type-specific and non-specific mutational analyses identified potential therapeutic targets in 2114 tumors (32%), some of which will be considered druggable only with further clinical development and FDA approval.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('mutational', 'Var', (48, 58))	('cancer', 'Disease', (10, 16))
120500	30053901	We applied a structure-based clustering tool, HotSpot3D, to the pan-cancer dataset to reveal putative functional mutations (Additional file 2: Table S13).	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('mutations', 'Var', (113, 122))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))
120501	30053901	HotSpot3D's utility in predicting functional mutations is supported by experimental evidence using cell lines expressing one of several EGFR-mutant proteins.	('mutations', 'Var', (45, 54))	('EGFR', 'Gene', (136, 140))	('proteins', 'Protein', (148, 156))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('136', '140'))
120502	30053901	Among all genes in our analysis, EGFR contains the highest number of putative sensitive mutations, with 36 mutations that clustered with 19 mutations in DEPO from seven different clusters (Fig.	('mutations', 'Var', (107, 116))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('33', '37'))	('DEPO', 'Gene', (153, 157))	('EGFR', 'Gene', (33, 37))
120504	30053901	This procedure yielded four different clusters with a "resistant" mutation in AKT1, MAP2K1, and RAC1; these four clusters contained 14 putative resistant mutations clustering with four known resistant mutations (Additional file 2: Table S13).	('AKT1', 'Gene', (78, 82))	('MAP2K', 'molecular_function', 'GO:0004708', ('82', '87'))	('contained', 'Reg', (122, 131))	('MAP2K1', 'Gene', (84, 90))	('RAC1', 'Gene', '5879', (96, 100))	('AKT1', 'Gene', '207', (78, 82))	('mutation', 'Var', (66, 74))	('RAC1', 'Gene', (96, 100))	('MAP2K1', 'Gene', '5604', (84, 90))
120505	30053901	RAC1 yielded the largest cluster, with RAC1 P29S mediating resistance to BRAF inhibitors in BRAF-mutant SKCM.	('BRAF', 'Gene', '673', (73, 77))	('P29S', 'Mutation', 'rs1057519874', (44, 48))	('resistance to', 'MPA', (59, 72))	('BRAF', 'Gene', '673', (92, 96))	('CM', 'Disease', 'MESH:D009202', (106, 108))	('RAC1', 'Gene', '5879', (39, 43))	('BRAF', 'Gene', (92, 96))	('RAC1', 'Gene', (39, 43))	('RAC1', 'Gene', '5879', (0, 4))	('P29S', 'Var', (44, 48))	('BRAF', 'Gene', (73, 77))	('RAC1', 'Gene', (0, 4))	('mediating', 'Reg', (49, 58))
120506	30053901	Other mutations in this cluster that may affect binding affinity of BRAF inhibitors (or that may mediate resistance to BRAF inhibitors) are C18Y, E31D, A159V, P29L/T, and P34S.	('P29L', 'SUBSTITUTION', 'None', (159, 163))	('C18Y', 'SUBSTITUTION', 'None', (140, 144))	('binding', 'molecular_function', 'GO:0005488', ('48', '55'))	('BRAF', 'Gene', '673', (68, 72))	('E31D', 'Var', (146, 150))	('BRAF', 'Gene', '673', (119, 123))	('A159V', 'Mutation', 'p.A159V', (152, 157))	('binding', 'Interaction', (48, 55))	('BRAF', 'Gene', (68, 72))	('P34S', 'Var', (171, 175))	('BRAF', 'Gene', (119, 123))	('C18Y', 'Var', (140, 144))	('P34S', 'Mutation', 'p.P34S', (171, 175))	('E31D', 'Mutation', 'p.E31D', (146, 150))	('P29L', 'Var', (159, 163))	('affect', 'Reg', (41, 47))	('A159V', 'Var', (152, 157))
120507	30053901	For example, KIT has multiple clusters with known mutations; one of which has three known mutations (E490D, Y494C, S476G) in the same cluster, which are FDA approved as sensitive to combined therapy of imatinib, sunitinib, and regorafenib (KIT and angiogenesis inhibitor).	('KIT', 'molecular_function', 'GO:0005020', ('13', '16'))	('E490D', 'Mutation', 'p.E490D', (101, 106))	('S476G', 'Var', (115, 120))	('regorafenib', 'Chemical', 'MESH:C559147', (227, 238))	('angiogenesis', 'biological_process', 'GO:0001525', ('248', '260'))	('E490D', 'Var', (101, 106))	('Y494C', 'Var', (108, 113))	('sunitinib', 'Chemical', 'MESH:D000077210', (212, 221))	('KIT', 'molecular_function', 'GO:0005020', ('240', '243'))	('Y494C', 'Mutation', 'p.Y494C', (108, 113))	('S476G', 'Mutation', 'p.S476G', (115, 120))	('imatinib', 'Chemical', 'MESH:D000068877', (202, 210))
120508	30053901	In addition, this cluster contains two other unique mutations (D439H, I438L) not in DEPO that, based on our analysis using HotSpot3D, could also affect binding affinity and potentially tumor sensitivity to KIT combined with angiogenesis inhibitors (Additional file 2: Table S13).	('tumor', 'Disease', (185, 190))	('I438L', 'Var', (70, 75))	('D439H', 'Mutation', 'p.D439H', (63, 68))	('affect', 'Reg', (145, 151))	('binding affinity', 'Interaction', (152, 168))	('I438L', 'Mutation', 'p.I438L', (70, 75))	('KIT', 'molecular_function', 'GO:0005020', ('206', '209'))	('binding', 'molecular_function', 'GO:0005488', ('152', '159'))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('D439H', 'Var', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('angiogenesis', 'biological_process', 'GO:0001525', ('224', '236'))
120509	30053901	To do this, we assessed the activity and drug sensitivity of a set of six BRAF mutations (F635I, G596D, K601E, W604L, L613F, G596R) in close spatial proximity to the well-studied V600E pathogenic mutation (Fig.	('L613F', 'Mutation', 'p.L613F', (118, 123))	('G596D', 'Mutation', 'rs397507483', (97, 102))	('W604L', 'Mutation', 'p.W604L', (111, 116))	('K601E', 'Mutation', 'rs121913364', (104, 109))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('F635I', 'Mutation', 'p.F635I', (90, 95))	('L613F', 'Var', (118, 123))	('K601E', 'Var', (104, 109))	('G596R', 'Mutation', 'rs121913361', (125, 130))	('G596R', 'Var', (125, 130))	('G596D', 'Var', (97, 102))	('V600E', 'Mutation', 'rs113488022', (179, 184))	('F635I', 'Var', (90, 95))	('drug sensitivity', 'Phenotype', 'HP:0020174', (41, 57))	('W604L', 'Var', (111, 116))
120511	30053901	Therefore, we transfected BRAF mutations, along with wild-type BRAF and BRAF V600E, into HEK293T cells in the presence or absence of BRAF inhibitor dabrafenib, and used phosphorylation changes in MEK1/2 as an indicator of BRAF activity.	('BRAF', 'Gene', '673', (26, 30))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('BRAF', 'Gene', (26, 30))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (72, 76))	('MEK1/2', 'Gene', '5604;5605', (196, 202))	('MEK1/2', 'Gene', (196, 202))	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (222, 226))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (133, 137))	('BRAF', 'Gene', (222, 226))	('mutations', 'Var', (31, 40))	('phosphorylation', 'biological_process', 'GO:0016310', ('169', '184'))	('dabrafenib', 'Chemical', 'MESH:C561627', (148, 158))	('HEK293T', 'CellLine', 'CVCL:0063', (89, 96))	('phosphorylation', 'MPA', (169, 184))	('MEK1', 'molecular_function', 'GO:0004708', ('196', '200'))
120512	30053901	The undetectable level of endogenous BRAF in HEK293T cells eliminates potential ambiguity in interpreting the effects of transfected BRAF mutations.	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (37, 41))	('BRAF', 'Gene', (133, 137))	('HEK293T', 'CellLine', 'CVCL:0063', (45, 52))	('mutations', 'Var', (138, 147))
120513	30053901	As expected, BRAF V600E caused drastically increased phosphorylation in MEK1/2 that is reduced by dabrafenib (Fig.	('V600E', 'Var', (18, 23))	('MEK1/2', 'Gene', '5604;5605', (72, 78))	('MEK1/2', 'Gene', (72, 78))	('BRAF', 'Gene', '673', (13, 17))	('dabrafenib', 'Chemical', 'MESH:C561627', (98, 108))	('BRAF', 'Gene', (13, 17))	('increased', 'PosReg', (43, 52))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('MEK1', 'molecular_function', 'GO:0004708', ('72', '76'))	('phosphorylation', 'MPA', (53, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))
120514	30053901	Three (G596D, K601E, and W604L) out of six other transfected BRAF mutations also showed higher levels of MEK1/2 phosphorylation and sensitivity to dabrafenib than wild-type BRAF, suggesting that a high percentage of mutations identified by Hotspot3D in close spatial proximity to V600E are activated and similarly sensitive to dabrafenib.	('mutations', 'Var', (66, 75))	('MEK1', 'molecular_function', 'GO:0004708', ('105', '109'))	('K601E', 'Var', (14, 19))	('dabrafenib', 'Chemical', 'MESH:C561627', (327, 337))	('W604L', 'Var', (25, 30))	('G596D', 'Mutation', 'rs397507483', (7, 12))	('BRAF', 'Gene', '673', (173, 177))	('V600E', 'Mutation', 'rs113488022', (280, 285))	('BRAF', 'Gene', '673', (61, 65))	('BRAF', 'Gene', (173, 177))	('BRAF', 'Gene', (61, 65))	('MEK1/2', 'Gene', '5604;5605', (105, 111))	('MEK1/2', 'Gene', (105, 111))	('phosphorylation', 'biological_process', 'GO:0016310', ('112', '127'))	('higher', 'PosReg', (88, 94))	('W604L', 'Mutation', 'p.W604L', (25, 30))	('G596D', 'Var', (7, 12))	('sensitivity', 'MPA', (132, 143))	('dabrafenib', 'Chemical', 'MESH:C561627', (147, 157))	('V600E', 'Var', (280, 285))	('K601E', 'Mutation', 'rs121913364', (14, 19))
120515	30053901	Notably, BRAF G596R-transfected cells appeared to have a much lower level of MEK1/2 phosphorylation when compared to those transfected with wild-type BRAF, supporting prior findings that G596R results in BRAF loss of function.	('loss of function', 'NegReg', (209, 225))	('BRAF', 'Gene', (204, 208))	('BRAF', 'Gene', (9, 13))	('BRAF', 'Gene', '673', (9, 13))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('G596R', 'Mutation', 'rs121913361', (14, 19))	('BRAF', 'Gene', (150, 154))	('lower', 'NegReg', (62, 67))	('BRAF', 'Gene', '673', (150, 154))	('MEK1', 'molecular_function', 'GO:0004708', ('77', '81'))	('G596R', 'Mutation', 'rs121913361', (187, 192))	('G596R', 'Var', (187, 192))	('MEK1/2', 'Gene', '5604;5605', (77, 83))	('MEK1/2', 'Gene', (77, 83))	('G596R-transfected', 'Var', (14, 31))	('BRAF', 'Gene', '673', (204, 208))
120517	30053901	For example, in the case of breast cancer, elevated mRNA expression and copy number amplification of ESR1 correlate with elevated protein expression of ER, as well as with sensitivity to hormonal therapy with tamoxifen.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('ESR1', 'Gene', '2099', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('elevated', 'PosReg', (43, 51))	('elevated', 'PosReg', (121, 129))	('copy number amplification', 'Var', (72, 97))	('tamoxifen', 'Chemical', 'MESH:D013629', (209, 218))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('ESR1', 'Gene', (101, 105))	('mRNA expression', 'MPA', (52, 67))	('protein expression', 'MPA', (130, 148))
120523	30053901	Interestingly, tumors with "druggable" gene fusions tend to express elevated levels of the corresponding druggable gene (Additional file 2: Table S15, Additional file 3: Figure S1), suggesting that fusions may be one of several drivers of gene and protein expression.	('levels of', 'MPA', (77, 86))	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('fusions', 'Var', (44, 51))	('elevated', 'PosReg', (68, 76))	('protein', 'cellular_component', 'GO:0003675', ('246', '253'))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
120535	30053901	Similarly, 26 and 52% of BRCA and UCEC, respectively, show elevated activity at ESR1's p.S118 phosphosite.	('BRCA', 'Gene', (25, 29))	('ESR1', 'Gene', '2099', (80, 84))	('p.S118', 'Var', (87, 93))	('S118 phosphosite', 'Chemical', '-', (89, 105))	('activity', 'MPA', (68, 76))	('ESR1', 'Gene', (80, 84))	('elevated', 'PosReg', (59, 67))	('BRCA', 'Phenotype', 'HP:0003002', (25, 29))	('BRCA', 'Gene', '672', (25, 29))
120538	30053901	EGFR phosphosites p.Y1068 and p.Y1173 are active in GBM, head and neck squamous cell carcinoma (HNSC), KIRC, LUAD, and LUSC.	('p.Y1068', 'Var', (18, 25))	('EGFR', 'Gene', (0, 4))	('neck', 'cellular_component', 'GO:0044326', ('66', '70'))	('neck squamous cell carcinoma', 'Disease', (66, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('GBM', 'Disease', (52, 55))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (66, 94))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (57, 94))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('HNSC', 'Phenotype', 'HP:0012288', (96, 100))	('LUSC', 'Phenotype', 'HP:0030359', (119, 123))	('phosphosite', 'Chemical', '-', (5, 16))	('p.Y1173', 'Var', (30, 37))	('EGFR', 'Gene', '1956', (0, 4))
120548	30053901	RAC1 P29S co-occurs with mutations in BRAF and MEK1 in four SKCM tumors (Additional file 2: Table S17, Additional file 3: Figure S3).	('mutations', 'Var', (25, 34))	('MEK1', 'Gene', '5604', (47, 51))	('MEK1', 'molecular_function', 'GO:0004708', ('47', '51'))	('SKCM tumors', 'Disease', 'MESH:D009369', (60, 71))	('MEK1', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (38, 42))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('SKCM tumors', 'Disease', (60, 71))	('BRAF', 'Gene', (38, 42))	('RAC1', 'Gene', '5879', (0, 4))	('P29S', 'Var', (5, 9))	('RAC1', 'Gene', (0, 4))	('P29S', 'Mutation', 'rs1057519874', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
120549	30053901	RAC1 P29S renders SKCM resistant to BRAF/MEK inhibition; testing for RAC1 P29S may identify patients with BRAF V600E SKCM unlikely to benefit from BRAF/MEK inhibitor.	('CM', 'Disease', 'MESH:D009202', (20, 22))	('V600E', 'Var', (111, 116))	('P29S', 'Mutation', 'rs1057519874', (5, 9))	('patients', 'Species', '9606', (92, 100))	('RAC1', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (36, 40))	('P29S', 'Mutation', 'rs1057519874', (74, 78))	('BRAF', 'Gene', (36, 40))	('MEK', 'Gene', '5609', (41, 44))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('RAC1', 'Gene', '5879', (0, 4))	('MEK', 'Gene', '5609', (152, 155))	('RAC1', 'Gene', (69, 73))	('V600E', 'Mutation', 'rs113488022', (111, 116))	('CM', 'Disease', 'MESH:D009202', (119, 121))	('MEK', 'Gene', (41, 44))	('BRAF', 'Gene', '673', (106, 110))	('MEK', 'Gene', (152, 155))	('BRAF', 'Gene', (106, 110))	('RAC1', 'Gene', '5879', (69, 73))
120551	30053901	AKT1 E17K co-occurs with BRAF V600E in five tumors (Additional file 2: Table S17, Additional file 3: Figure S3).	('tumors', 'Disease', (44, 50))	('E17K', 'SUBSTITUTION', 'None', (5, 9))	('AKT1', 'Gene', '207', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('AKT1', 'Gene', (0, 4))	('V600E', 'Mutation', 'rs113488022', (30, 35))	('BRAF', 'Gene', '673', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('BRAF', 'Gene', (25, 29))	('E17K', 'Var', (5, 9))
120553	30053901	Transcriptomic and proteomic expression profiling reveals 48 additional tumors with BRAF V600E/K and elevated AKT (AKT1/2/3) expression at the mRNA or protein/phosphoprotein levels; these may also benefit from BRAF/AKT inhibition (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('elevated', 'PosReg', (101, 109))	('AKT', 'Gene', '207', (115, 118))	('AKT1/2/3', 'Gene', (115, 123))	('AKT', 'Gene', (110, 113))	('tumors', 'Disease', (72, 78))	('V600E', 'SUBSTITUTION', 'None', (89, 94))	('AKT', 'Gene', '207', (215, 218))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('AKT', 'Gene', '207', (110, 113))	('AKT1/2/3', 'Gene', '207;208;10000', (115, 123))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('AKT', 'Gene', (115, 118))	('BRAF', 'Gene', (210, 214))	('BRAF', 'Gene', '673', (210, 214))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('AKT', 'Gene', (215, 218))	('V600E', 'Var', (89, 94))
120556	30053901	Additionally, 105 tumors contain activating PIK3CA mutations co-occurring with elevated mRNA or protein expression of ESR1 or PGR.	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (51, 60))	('PGR', 'Gene', '5241', (126, 129))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('ESR1', 'Gene', '2099', (118, 122))	('PIK3CA', 'Gene', '5290', (44, 50))	('mRNA or protein expression', 'MPA', (88, 114))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('activating', 'PosReg', (33, 43))	('elevated', 'PosReg', (79, 87))	('ESR1', 'Gene', (118, 122))	('PGR', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
120562	30053901	Overall, the mean LN(IC50) for cell lines that contain a sensitive mutation from DEPO was significantly lower than background LN(IC50) in both the cancer-type-specific and non-specific setting (Mann-Whitney U test, P = 1.1e-96 and P = 1.3e-109, respectively) (Fig.	('DEPO', 'Gene', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mutation', 'Var', (67, 75))	('lower', 'NegReg', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
120564	30053901	In both the cancer-type-specific and non-specific settings, 19 variant/drug combinations had significantly lower mean LN(IC50) than background LN(IC50) for the corresponding drug.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('variant/drug', 'Var', (63, 75))	('lower', 'NegReg', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('combinations', 'Var', (76, 88))
120566	30053901	For example, cell lines with BRAF V600E were associated with sensitivity to BRAF inhibitors PLX4720 (1), PLX4720 (2), and dabrafenib in both the cancer-type-specific (SKCM) and non-specific settings (BRCA, COADREAD, GBM, LGG, LIHC, and THCA) (Fig.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('LIHC', 'Disease', 'None', (226, 230))	('THCA', 'Phenotype', 'HP:0002890', (236, 240))	('BRCA', 'Phenotype', 'HP:0003002', (200, 204))	('PLX4720', 'Var', (105, 112))	('CM', 'Disease', 'MESH:D009202', (169, 171))	('V600E', 'Mutation', 'rs113488022', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('BRCA', 'Gene', '672', (200, 204))	('sensitivity', 'MPA', (61, 72))	('V600E', 'Var', (34, 39))	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('dabrafenib', 'Chemical', 'MESH:C561627', (122, 132))	('LIHC', 'Disease', (226, 230))	('BRCA', 'Gene', (200, 204))	('PLX4720', 'Gene', (92, 99))
120567	30053901	Two out of six mutations (PIK3CA H1047R and KRAS G12C) was associated with sensitivity in either the cancer-type-specific or the non-specific setting.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('H1047R', 'Var', (33, 39))	('G12C', 'Mutation', 'rs121913530', (49, 53))	('cancer', 'Disease', (101, 107))	('PIK3CA', 'Gene', '5290', (26, 32))	('sensitivity', 'Disease', (75, 86))	('associated', 'Reg', (59, 69))	('H1047R', 'Mutation', 'rs121913279', (33, 39))	('KRAS', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('KRAS', 'Gene', '3845', (44, 48))	('PIK3CA', 'Gene', (26, 32))
120582	30053901	First, with DEPO, our analysis of druggability in a given tumor is exclusively based on mutation/drug interactions rather than gene/drug interactions, with variants including both predefined mutations (e.g., BRAF V600E) and categories of mutations (e.g., EGFR exon 19 deletions).	('EGFR', 'Gene', '1956', (255, 259))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('EGFR', 'Gene', (255, 259))	('BRAF', 'Gene', '673', (208, 212))	('BRAF', 'Gene', (208, 212))	('EGFR', 'molecular_function', 'GO:0005006', ('255', '259'))	('deletions', 'Var', (268, 277))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('V600E', 'Mutation', 'rs113488022', (213, 218))
120585	30053901	Third, it uses an analytic tool to create a set of putative druggable mutations, of which a subset occurring in BRAF were tested and validated in vitro.	('mutations', 'Var', (70, 79))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))
120589	30053901	Realistically, only a fraction of the 48% of tumors with potential drug-associated omics alterations will be clinically druggable because the mere presence of a shared genetic biomarker (mutation, mRNA/protein expression outlier) does not guarantee clinical efficacy across cancer types, nor does it guarantee acceptable clinical toxicity.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('tumors', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('toxicity', 'Disease', 'MESH:D064420', (330, 338))	('toxicity', 'Disease', (330, 338))	('cancer', 'Disease', (274, 280))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('alterations', 'Var', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
120590	30053901	Further, we recognize that our computational survey of the landscape of potential drug-associated omics alterations may include some controversial drug/biomarker relationships (e.g., PI3K inhibitors in PIK3CA-mutant cancers), some of which have either failed clinical trials and/or are still being actively developed in clinical trials.	('alterations', 'Var', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('PI3K', 'molecular_function', 'GO:0016303', ('183', '187'))	('PIK3CA', 'Gene', (202, 208))	('PIK3CA', 'Gene', '5290', (202, 208))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('cancers', 'Disease', 'MESH:D009369', (216, 223))
120593	30053901	Second, our analysis does not account for clonal heterogeneity, which is not unreasonable given that therapies targeting genomic alterations with high variant allele frequencies can induce substantial tumor regression.	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('variant', 'Var', (151, 158))
120603	30053901	ACC Adrenocortical carcinoma AML/LAML Acute myeloid leukemia BLCA Bladder urothelial carcinoma BRCA Breast adenocarcinoma CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma CNA Copy number amplification CNL Copy number loss CNV Copy number variation COADREAD Colon and rectal carcinoma CPTAC Clinical Proteomic Tumor Analysis Consortium DCC Data Coordinating Center DEPO Database of Evidence for Precision Oncology FBS Fetal bovine serum FDA Food and Drug Administration FFPE Formalin-fixed, paraffin-embedded GBM Glioblastoma multiforme GDAC Genome Data Analysis Centers GDSC Genomics of Drug Sensitivity in Cancer HNSC Head and neck squamous cell carcinoma IQR Interquartile range KICH Kidney chromophobe KIRC Kidney renal clear cell carcinoma KIRP Kidney renal papillary cell carcinoma LGG Low-grade glioma LIHC Liver hepatocellular carcinoma LUAD Lung adenocarcinoma LUSC Lung squamous cell carcinoma MAF Mutation annotation file NGS Next-generation sequencing NSCLC Non-small cell lung cancer OV Ovarian serous carcinoma PNNL Pacific Northwest National Laboratory PRAD Prostate adenocarcinoma RBN Replicates-based normalization RPPA Reverse phase protein array SKCM Skin cutaneous melanoma SNP Single nucleotide polymorphism STAD Stomach adenocarcinoma STR Short tandem repeat TCGA The Cancer Genome Atlas TCPA The Cancer Protein Atlas THCA Thyroid carcinoma TKI Tyrosine kinase inhibitor UCEC Uterine corpus endometrial carcinoma UCS Uterine carcinosarcoma VCF Variant call format LD designed and supervised the research.	('adenocarcinoma', 'Disease', (1262, 1276))	('Kidney renal clear cell carcinoma', 'Disease', (731, 764))	('carcinosarcoma', 'Disease', (1467, 1481))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (1310, 1329))	('adenocarcinoma', 'Disease', (1102, 1116))	('RBN', 'Chemical', '-', (1117, 1120))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (777, 807))	('cancer', 'Phenotype', 'HP:0002664', (1010, 1016))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinoma', 'Disease', 'MESH:D002277', (85, 94))	('DCC', 'Chemical', '-', (356, 359))	('Adrenocortical carcinoma', 'Disease', (4, 28))	('carcinoma', 'Disease', (1445, 1454))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (38, 60))	('squamous cell carcinoma', 'Disease', (900, 923))	('carcinoma', 'Disease', 'MESH:D002277', (798, 807))	('CM', 'Disease', 'MESH:D009202', (1187, 1189))	('adenocarcinoma', 'Disease', 'MESH:D000230', (1262, 1276))	('Cancer', 'Disease', 'MESH:D009369', (1339, 1345))	('glioma', 'Phenotype', 'HP:0009733', (822, 828))	('bovine', 'Species', '9913', (444, 450))	('Cancer', 'Phenotype', 'HP:0002664', (1310, 1316))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (44, 60))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (1426, 1454))	('VCF', 'Gene', '6899', (1482, 1485))	('PNNL', 'Chemical', '-', (1045, 1049))	('Breast adenocarcinoma', 'Disease', 'MESH:D000230', (100, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (1195, 1213))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (1365, 1382))	('adenocarcinoma', 'Disease', (177, 191))	('Kidney renal papillary cell carcinoma', 'Disease', (770, 807))	('neck', 'cellular_component', 'GO:0044326', ('649', '653'))	('Non-small cell lung cancer', 'Disease', (990, 1016))	('carcinoma', 'Disease', (85, 94))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (288, 304))	('Skin cutaneous melanoma', 'Disease', (1190, 1213))	('Ovarian serous carcinoma', 'Disease', (1020, 1044))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (770, 807))	('urothelial carcinoma', 'Disease', (74, 94))	('FBS', 'Disease', (434, 437))	('AML', 'Phenotype', 'HP:0004808', (29, 32))	('VCF', 'Gene', (1482, 1485))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (990, 1016))	('Uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (1459, 1481))	('NSCLC', 'Disease', 'MESH:D002289', (984, 989))	('Cancer Protein Atlas', 'Disease', 'MESH:D009369', (1339, 1359))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (1433, 1454))	('Cancer', 'Disease', (1339, 1345))	('AML', 'Disease', 'MESH:D015470', (34, 37))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (74, 94))	('AML', 'Phenotype', 'HP:0004808', (34, 37))	('Cancer Genome Atlas', 'Disease', (1310, 1329))	('Ovarian serous carcinoma', 'Disease', 'MESH:D010051', (1020, 1044))	('THCA', 'Phenotype', 'HP:0002890', (1360, 1364))	('UCEC Uterine corpus', 'Phenotype', 'HP:0000139', (1413, 1432))	('adenocarcinoma', 'Disease', (107, 121))	('squamous cell carcinoma', 'Disease', (136, 159))	('adenocarcinoma', 'Disease', 'MESH:D000230', (1102, 1116))	('paraffin', 'Chemical', 'MESH:D010232', (511, 519))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (990, 1016))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (608, 624))	('corpus endometrial carcinoma', 'Disease', (1426, 1454))	('KICH', 'Chemical', '-', (702, 706))	('Tumor', 'Phenotype', 'HP:0002664', (330, 335))	('Kidney chromophobe', 'Disease', 'MESH:D000238', (707, 725))	('Cancer', 'Disease', (628, 634))	('adenocarcinoma', 'Disease', (875, 889))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (649, 677))	('carcinoma', 'Disease', 'MESH:D002277', (755, 764))	('Kidney chromophobe', 'Disease', (707, 725))	('BRCA', 'Phenotype', 'HP:0003002', (95, 99))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (1093, 1116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (900, 923))	('Liver hepatocellular carcinoma', 'Disease', (834, 864))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (834, 864))	('carcinoma', 'Disease', 'MESH:D002277', (150, 159))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (4, 28))	('adenocarcinoma', 'Disease', 'MESH:D000230', (875, 889))	('Cancer', 'Disease', 'MESH:D009369', (628, 634))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (654, 677))	('Cancer', 'Phenotype', 'HP:0002664', (1339, 1345))	('protein', 'cellular_component', 'GO:0003675', ('1171', '1178'))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (164, 191))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('1396', '1412'))	('LUSC', 'Phenotype', 'HP:0030359', (890, 894))	('LIHC', 'Disease', (829, 833))	('Formalin', 'Chemical', 'MESH:D005557', (495, 503))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (900, 923))	('adenocarcinoma', 'Disease', 'MESH:D000230', (177, 191))	('carcinosarcoma', 'Disease', 'MESH:D002296', (1467, 1481))	('carcinoma', 'Disease', (19, 28))	('glioma', 'Disease', 'MESH:D005910', (822, 828))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (654, 677))	('carcinoma', 'Disease', 'MESH:D002277', (1267, 1276))	('NSCLC', 'Disease', (984, 989))	('carcinoma', 'Disease', (755, 764))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (994, 1016))	('Cancer', 'Phenotype', 'HP:0002664', (628, 634))	('DCC', 'cellular_component', 'GO:0120206', ('356', '359'))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('Tyrosine kinase', 'Gene', '7294', (1387, 1402))	('Stomach adenocarcinoma', 'Disease', 'MESH:D013274', (1254, 1276))	('NSCLC', 'Phenotype', 'HP:0030358', (984, 989))	('melanoma', 'Phenotype', 'HP:0002861', (1205, 1213))	('Breast adenocarcinoma', 'Phenotype', 'HP:0003002', (100, 121))	('carcinoma', 'Disease', 'MESH:D002277', (914, 923))	('carcinoma', 'Disease', (150, 159))	('carcinoma', 'Disease', (1373, 1382))	('carcinoma', 'Disease', 'MESH:D002277', (668, 677))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (731, 764))	('carcinoma', 'Disease', 'MESH:D002277', (295, 304))	('HNSC', 'Phenotype', 'HP:0012288', (635, 639))	('Glioblastoma multiforme', 'Disease', (533, 556))	('Variant', 'Var', (1486, 1493))	('Cancer', 'Disease', (1310, 1316))	('Stomach adenocarcinoma', 'Disease', (1254, 1276))	('GDAC', 'Chemical', '-', (557, 561))	('lung cancer', 'Phenotype', 'HP:0100526', (1005, 1016))	('carcinoma', 'Disease', (1267, 1276))	('carcinoma', 'Disease', (1035, 1044))	('LGG Low', 'Phenotype', 'HP:0004315', (808, 815))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('Breast adenocarcinoma', 'Disease', (100, 121))	('carcinoma', 'Disease', (1107, 1116))	('AML', 'Disease', (29, 32))	('carcinoma', 'Disease', 'MESH:D002277', (1373, 1382))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (1190, 1213))	('carcinoma', 'Disease', 'MESH:D002277', (182, 191))	('FBS', 'Disease', 'MESH:D005198', (434, 437))	('Cancer', 'Disease', 'MESH:D009369', (1310, 1316))	('carcinoma', 'Disease', (914, 923))	('glioma', 'Disease', (822, 828))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (533, 556))	('carcinoma', 'Disease', (668, 677))	('carcinoma', 'Disease', (112, 121))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))	('LUAD', 'Phenotype', 'HP:0030078', (865, 869))	('Acute myeloid leukemia', 'Disease', (38, 60))	('carcinoma', 'Disease', (295, 304))	('AML', 'Disease', (34, 37))	('BRCA', 'Gene', (95, 99))	('LIHC', 'Disease', 'None', (829, 833))	('carcinoma', 'Disease', 'MESH:D002277', (1035, 1044))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (38, 60))	('carcinoma', 'Disease', 'MESH:D002277', (19, 28))	('carcinoma', 'Disease', 'MESH:D002277', (1107, 1116))	('carcinoma', 'Disease', (880, 889))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('carcinoma', 'Disease', (855, 864))	('endocervical adenocarcinoma', 'Disease', (164, 191))	('Tyrosine kinase', 'Gene', (1387, 1402))	('carcinoma', 'Disease', (182, 191))	('neck squamous cell carcinoma', 'Disease', (649, 677))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (870, 889))	('carcinoma', 'Disease', 'MESH:D002277', (1445, 1454))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (4, 28))	('carcinoma', 'Disease', 'MESH:D002277', (112, 121))	('leukemia', 'Phenotype', 'HP:0001909', (52, 60))	('Oncology', 'Phenotype', 'HP:0002664', (425, 433))	('UCS', 'Phenotype', 'HP:0002891', (1455, 1458))	('BLCA', 'Chemical', '-', (61, 65))	('AML', 'Disease', 'MESH:D015470', (29, 32))	('Glioblastoma', 'Phenotype', 'HP:0012174', (533, 545))	('Prostate adenocarcinoma', 'Disease', (1093, 1116))	('carcinoma', 'Disease', 'MESH:D002277', (880, 889))	('TCPA', 'Chemical', '-', (1330, 1334))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (840, 864))	('carcinoma', 'Disease', (798, 807))	('carcinoma', 'Disease', 'MESH:D002277', (855, 864))	('Cancer Protein Atlas', 'Disease', (1339, 1359))	('BRCA', 'Gene', '672', (95, 99))
120637	30089999	Positivity for cytokeratins CK7 and CK20 has been shown to indicate urothelial and rule out prostate cancer.	('rule out', 'NegReg', (83, 91))	('CK7', 'Gene', '3855', (28, 31))	('prostate cancer', 'Phenotype', 'HP:0012125', (92, 107))	('urothelial', 'Disease', (68, 78))	('prostate cancer', 'Disease', (92, 107))	('CK20', 'Gene', (36, 40))	('CK20', 'Gene', '54474', (36, 40))	('indicate', 'Reg', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Positivity', 'Var', (0, 10))	('prostate cancer', 'Disease', 'MESH:D011471', (92, 107))	('CK7', 'Gene', (28, 31))
120643	30089999	found 82.9% of 35 high-grade urothelial tumors to be positive for p63 variants versus <2% positivity of the 38 prostate cancers.	('positive', 'Reg', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancers', 'Disease', (111, 127))	('p63', 'Gene', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('urothelial tumors', 'Disease', (29, 46))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('prostate cancers', 'Disease', 'MESH:D011471', (111, 127))	('variants', 'Var', (70, 78))	('p63', 'Gene', '8626', (66, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('urothelial tumors', 'Disease', 'MESH:D001749', (29, 46))	('prostate cancers', 'Phenotype', 'HP:0012125', (111, 127))
120683	29587848	In the present study we found that CK5/6 expression is low in urothelial carcinoma in our set up; however, its positivity signifies adverse prognostic features like higher tumor grade and muscularis propria invasion.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('expression', 'MPA', (41, 51))	('tumor', 'Disease', (172, 177))	('CK5/6', 'Gene', (35, 40))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (62, 82))	('muscularis propria', 'Phenotype', 'HP:0030936', (188, 206))	('positivity', 'Var', (111, 121))	('low', 'NegReg', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('CK5/6', 'Gene', '3852', (35, 40))	('urothelial carcinoma', 'Disease', (62, 82))	('muscularis propria invasion', 'CPA', (188, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
120766	23798862	The carbohydrate antigen CA19.9 (Sialyl Le-a) is a blood group-related antigen and its expression requires the expression of Lewis a blood group antigen which is a cancer-associated phenomenon, CA19.9 is also known to be a ligand for the cell adhesion molecule called ELAM-1, involved in the extravasation of cells from the bloodstream and of particular importance in the adhesion of human epithelial cancer cells to vascular endothelial cells.	('human', 'Species', '9606', (384, 389))	('epithelial cancer', 'Phenotype', 'HP:0031492', (390, 407))	('CA19.9', 'Var', (194, 200))	('ELAM-1', 'Gene', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('ELAM-1', 'Gene', '6401', (268, 274))	('blood group antigen', 'Phenotype', 'HP:0010970', (133, 152))	('blood group antigen', 'molecular_function', 'GO:0005555', ('133', '152'))	('cell adhesion', 'biological_process', 'GO:0007155', ('238', '251'))	('cancer', 'Phenotype', 'HP:0002664', (401, 407))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('238', '260'))	('ligand', 'molecular_function', 'GO:0005488', ('223', '229'))
120771	23798862	For positive control, sections from normal liver were stained for CD10, while sections from colorectal carcinoma were considered as positive control for CA19.9.	('CD10', 'Var', (66, 70))	('CD10', 'molecular_function', 'GO:0004245', ('66', '70'))	('colorectal carcinoma', 'Disease', (92, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (92, 112))
120831	20890425	Kaplan-Meier univariate analysis demonstrated worse survival with altered expression of pRb (P=0.040) (Fig.	('expression', 'MPA', (74, 84))	('altered', 'Var', (66, 73))	('pRb', 'Gene', (88, 91))	('pRb', 'Gene', '5925', (88, 91))	('worse', 'NegReg', (46, 51))
120832	20890425	Altered expression of p53, p16 and cyclin D1 did not have a significant impact on patient survival time (P=0.123, P=0.804, P=0.741, respectively), although mean survival time with altered expression of cyclin D1 was reduced (data not shown).	('reduced', 'NegReg', (216, 223))	('cyclin D1', 'Gene', '595', (35, 44))	('cyclin D1', 'Gene', (202, 211))	('cyclin D1', 'Gene', (35, 44))	('cyclin', 'molecular_function', 'GO:0016538', ('202', '208'))	('expression', 'MPA', (188, 198))	('patient', 'Species', '9606', (82, 89))	('cyclin', 'molecular_function', 'GO:0016538', ('35', '41'))	('p53', 'Gene', (22, 25))	('p16', 'Gene', (27, 30))	('altered', 'Var', (180, 187))	('p53', 'Gene', '7157', (22, 25))	('cyclin D1', 'Gene', '595', (202, 211))	('p16', 'Gene', '1029', (27, 30))
120836	20890425	We found that patients whose tumors had altered expression of all four markers had worse survival than those whose tumors had altered expression of none (P=0.029) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('worse', 'NegReg', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('altered', 'Var', (40, 47))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', (29, 35))	('survival', 'MPA', (89, 97))	('patients', 'Species', '9606', (14, 22))
120837	20890425	We also found that patients whose tumors had altered expression of two markers appeared to have decreased survival compared to those whose tumors had altered expression of only one marker; however, this observation was of borderline statistical significance (P=0.052).	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('patients', 'Species', '9606', (19, 27))	('altered', 'Var', (45, 52))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('decreased', 'NegReg', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('survival', 'MPA', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
120842	20890425	Molecular changes in bladder tumors involve three main mechanisms: chromosomal alteration (the initial event in carcinogenesis), tumor proliferation due to loss of cell cycle regulation, and metastasis aided by processes such as angiogenesis and the loss of cell adhesion.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('loss', 'NegReg', (156, 160))	('metastasis', 'CPA', (191, 201))	('bladder tumors', 'Disease', 'MESH:D001749', (21, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (129, 134))	('chromosomal alteration', 'Var', (67, 89))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('164', '185'))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('loss', 'NegReg', (250, 254))	('bladder tumors', 'Disease', (21, 35))	('cell adhesion', 'CPA', (258, 271))	('carcinogenesis', 'Disease', (112, 126))	('angiogenesis', 'CPA', (229, 241))	('cell cycle regulation', 'CPA', (164, 185))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('bladder tumors', 'Phenotype', 'HP:0009725', (21, 35))	('cell adhesion', 'biological_process', 'GO:0007155', ('258', '271'))	('carcinogenesis', 'Disease', 'MESH:D063646', (112, 126))	('angiogenesis', 'biological_process', 'GO:0001525', ('229', '241'))	('tumor', 'Disease', (29, 34))
120843	20890425	Aberrations in G1/S regulatory proteins are common in various tumors, and aberrant expression of cyclin D1 and cyclin E, down-regulation of p16 and p27, and mutation of the Rb and p53 genes have been frequently observed in several types of cancer.	('cyclin D1', 'Gene', (97, 106))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('p16', 'Gene', (140, 143))	('expression', 'MPA', (83, 93))	('cyclin', 'molecular_function', 'GO:0016538', ('111', '117'))	('cancer', 'Disease', (240, 246))	('p16', 'Gene', '1029', (140, 143))	('cyclin D1', 'Gene', '595', (97, 106))	('Rb', 'Chemical', 'MESH:D012413', (173, 175))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('p27', 'Gene', '3429', (148, 151))	('p27', 'Gene', (148, 151))	('Aberrations', 'Var', (0, 11))	('various tumors', 'Disease', (54, 68))	('cyclin', 'molecular_function', 'GO:0016538', ('97', '103'))	('various tumors', 'Disease', 'MESH:D009369', (54, 68))	('p53', 'Gene', '7157', (180, 183))	('regulation', 'biological_process', 'GO:0065007', ('126', '136'))	('cyclin E', 'Protein', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('down-regulation', 'NegReg', (121, 136))	('p53', 'Gene', (180, 183))	('mutation', 'Var', (157, 165))	('G1/S', 'Protein', (15, 19))
120844	20890425	Therefore, it has been suggested that G1/S defects might be obligatory for tumor development.	('defects', 'Var', (43, 50))	('tumor', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))
120852	20890425	In this present study, we included early and advanced carcinoma and found that the combined expression of pRb and p53 was an independent prognostic factor, and patients whose tumors had altered expression of all four markers had significantly worse survival compared to those whose tumors had altered expression of none.	('tumors', 'Disease', (175, 181))	('p53', 'Gene', (114, 117))	('survival', 'MPA', (249, 257))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('carcinoma', 'Disease', (54, 63))	('pRb', 'Gene', (106, 109))	('worse', 'NegReg', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumors', 'Disease', (282, 288))	('altered', 'Var', (186, 193))	('pRb', 'Gene', '5925', (106, 109))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('patients', 'Species', '9606', (160, 168))	('carcinoma', 'Disease', 'MESH:D002277', (54, 63))	('p53', 'Gene', '7157', (114, 117))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
120853	20890425	Patients whose tumors had altered expression of two markers appeared to have diminished survival compared to those whose tumors had altered expression of one marker, but this observation was of borderline statistical significance.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('diminished', 'NegReg', (77, 87))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('survival', 'MPA', (88, 96))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('Patients', 'Species', '9606', (0, 8))	('altered', 'Var', (26, 33))	('tumors', 'Disease', (15, 21))
120858	20890425	Absence of pRb reactivity is indicative of loss of gene expression, generally through mutation, and pRb overexpression reflects an alteration in the Rb pathway resulting in loss of several cyclin dependent kinase inhibitors.	('pRb', 'Gene', '5925', (100, 103))	('Rb', 'Chemical', 'MESH:D012413', (101, 103))	('Rb', 'Chemical', 'MESH:D012413', (12, 14))	('cyclin', 'molecular_function', 'GO:0016538', ('189', '195'))	('alteration', 'Reg', (131, 141))	('pRb', 'Gene', (11, 14))	('gene expression', 'biological_process', 'GO:0010467', ('51', '66'))	('Rb', 'Chemical', 'MESH:D012413', (149, 151))	('gene expression', 'MPA', (51, 66))	('loss', 'NegReg', (173, 177))	('cyclin', 'Enzyme', (189, 195))	('loss', 'NegReg', (43, 47))	('Rb pathway', 'Pathway', (149, 159))	('mutation', 'Var', (86, 94))	('pRb', 'Gene', '5925', (11, 14))	('pRb', 'Gene', (100, 103))	('overexpression', 'PosReg', (104, 118))
120868	20890425	It is well known that high expression of p16 can lead to loss of the pRb protein, and it has been reported that these two factors are inversely correlated in urothelial carcinoma.	('pRb', 'Gene', (69, 72))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (158, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('high', 'Var', (22, 26))	('expression', 'MPA', (27, 37))	('p16', 'Gene', (41, 44))	('urothelial carcinoma', 'Disease', (158, 178))	('loss', 'NegReg', (57, 61))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('p16', 'Gene', '1029', (41, 44))	('pRb', 'Gene', '5925', (69, 72))
120869	20890425	reported there was relationship between LOH at 9p21 ( the locus of the MTS-1/INK 4a gene encoding for p16) and/or homozygous deletions/mutations within the MTS-1 gene and p16 or pRb status as determined by immunohistochemistry.	('MTS-1', 'Gene', '1029', (156, 161))	('p21', 'Gene', '1026', (48, 51))	('INK 4a', 'Gene', '1029', (77, 83))	('MTS-1', 'Gene', '1029', (71, 76))	('p16', 'Gene', (171, 174))	('p16', 'Gene', (102, 105))	('p16', 'Gene', '1029', (102, 105))	('p21', 'Gene', (48, 51))	('pRb', 'Gene', '5925', (178, 181))	('INK 4a', 'Gene', (77, 83))	('pRb', 'Gene', (178, 181))	('MTS-1', 'Gene', (156, 161))	('p16', 'Gene', '1029', (171, 174))	('MTS-1', 'Gene', (71, 76))	('deletions/mutations', 'Var', (125, 144))
120956	30374279	MetS could decrease insulin sensitivity and induce a permanent state of excess insulin secretion.	('insulin', 'molecular_function', 'GO:0016088', ('79', '86'))	('insulin secretion', 'biological_process', 'GO:0030073', ('79', '96'))	('insulin', 'molecular_function', 'GO:0016088', ('20', '27'))	('MetS', 'Var', (0, 4))	('decrease', 'NegReg', (11, 19))	('insulin', 'Gene', (20, 27))	('insulin', 'Gene', (79, 86))	('excess insulin secretion', 'Disease', 'MESH:D007333', (72, 96))	('excess insulin secretion', 'Disease', (72, 96))	('insulin', 'Gene', '3630', (20, 27))	('insulin', 'Gene', '3630', (79, 86))	('induce', 'Reg', (44, 50))
120958	30374279	Although the reports about the association between low HDL levels and arteriosclerosis are common, reports about the association between low HDL levels and malignant disease are rare.	('arteriosclerosis', 'Phenotype', 'HP:0002634', (70, 86))	('HDL', 'molecular_function', 'GO:0005321', ('55', '58'))	('arteriosclerosis', 'Disease', 'MESH:D001161', (70, 86))	('arteriosclerosis', 'Disease', (70, 86))	('HDL', 'molecular_function', 'GO:0005321', ('141', '144'))	('low HDL', 'Phenotype', 'HP:0003233', (137, 144))	('low HDL', 'Phenotype', 'HP:0003233', (51, 58))	('low', 'Var', (51, 54))
120965	30374279	After all, the mechanism through which low HDL levels induce the upstaging of urothelial carcinoma of the bladder might be same as the mechanism by which MetS induces the worsening of the pathological stage of urothelial carcinoma of the bladder.	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (78, 113))	('urothelial carcinoma of the bladder', 'Disease', (78, 113))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (78, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('upstaging', 'PosReg', (65, 74))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (210, 245))	('urothelial carcinoma of the bladder', 'Disease', (210, 245))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (210, 245))	('low', 'Var', (39, 42))	('low HDL', 'Phenotype', 'HP:0003233', (39, 46))	('HDL', 'Protein', (43, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('HDL', 'molecular_function', 'GO:0005321', ('43', '46'))
120970	30374279	On the other hand, physicians should also keep in mind that a low HDL level can worsen a patient's metabolic disorder; without proper treatment, this has the potential to lead to MetS and a worsening of urothelial carcinoma of the bladder.	('metabolic disorder', 'Phenotype', 'HP:0001939', (99, 117))	('patient', 'Species', '9606', (89, 96))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (203, 238))	('urothelial carcinoma of the bladder', 'Disease', (203, 238))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (203, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('lead to', 'Reg', (171, 178))	('metabolic disorder', 'Disease', (99, 117))	('HDL', 'MPA', (66, 69))	('worsen', 'Reg', (80, 86))	('low', 'Var', (62, 65))	('HDL', 'molecular_function', 'GO:0005321', ('66', '69'))	('low HDL', 'Phenotype', 'HP:0003233', (62, 69))	('MetS', 'Disease', (179, 183))	('metabolic disorder', 'Disease', 'MESH:D008659', (99, 117))
120973	26202601	Identification of a multi-cancer gene expression biomarker for cancer clinical outcomes using a network-based algorithm Cancer types are commonly classified by histopathology and more recently through molecular characteristics such as gene expression, mutations, copy number variations, and epigenetic alterations.	('gene expression', 'biological_process', 'GO:0010467', ('235', '250'))	('Cancer', 'Disease', (120, 126))	('multi-cancer', 'Disease', 'MESH:D009369', (20, 32))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('Cancer', 'Disease', 'MESH:D009369', (120, 126))	('copy number variations', 'Var', (263, 285))	('multi-cancer', 'Disease', (20, 32))	('epigenetic alterations', 'Var', (291, 313))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (252, 261))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('gene expression', 'biological_process', 'GO:0010467', ('33', '48'))	('cancer', 'Disease', (63, 69))
120980	26202601	Cancer is typically classified by tissue-specific scores such as the Gleason score in prostate cancer, the Dukes or Astler-Coller in colon cancer, or Figo in cervical cancer.	('Gleason score', 'Var', (69, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (86, 101))	('colon cancer', 'Disease', 'MESH:D015179', (133, 145))	('colon cancer', 'Phenotype', 'HP:0003003', (133, 145))	('prostate cancer', 'Phenotype', 'HP:0012125', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cervical cancer', 'Disease', (158, 173))	('colon cancer', 'Disease', (133, 145))	('Cancer', 'Disease', (0, 6))	('cervical cancer', 'Disease', 'MESH:D002583', (158, 173))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('prostate cancer', 'Disease', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
120983	26202601	Several cancer types have been divided into subtypes using TCGA data about gene expression, mutations, copy number alterations, microRNA expression, pseudogenes, or even biological processes such as inflammation.	('cancer', 'Disease', (8, 14))	('microRNA expression', 'MPA', (128, 147))	('inflammation', 'biological_process', 'GO:0006954', ('199', '211'))	('mutations', 'Var', (92, 101))	('pseudogenes', 'Var', (149, 160))	('copy number alterations', 'Var', (103, 126))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('inflammation', 'Disease', 'MESH:D007249', (199, 211))	('gene expression', 'biological_process', 'GO:0010467', ('75', '90'))	('inflammation', 'Disease', (199, 211))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
121052	26202601	The C-index of the multi-NCA biomarker was almost always better than those of the cancer type-specific biomarkers (Fig.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('multi-NCA', 'Var', (19, 28))	('C-index', 'MPA', (4, 11))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('better', 'PosReg', (57, 63))
121094	26202601	For instance, high expression of CALR has been associated with high risk in bladder cancer.	('bladder cancer', 'Disease', (76, 90))	('CALR', 'Gene', (33, 37))	('CALR', 'Gene', '811', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('high expression', 'Var', (14, 29))	('associated', 'Reg', (47, 57))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))
121138	33924987	In bladder carcinogenesis, we previously demonstrated epigenetic inactivation of ITIH5 associated with advanced tumor stages predicting unfavorable prognosis of patients diagnosed with a papillary (pT1) urothelial high-grade tumor.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Disease', (112, 117))	('epigenetic inactivation', 'Var', (54, 77))	('ITIH5', 'Gene', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('bladder carcinogenesis', 'Disease', 'MESH:D001749', (3, 25))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (225, 230))	('associated', 'Reg', (87, 97))	('pT1', 'Gene', '58492', (198, 201))	('patients', 'Species', '9606', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('bladder carcinogenesis', 'Disease', (3, 25))	('pT1', 'Gene', (198, 201))
121139	33924987	ITIH5 promoter methylation was also characterized as putative biomarker for non-invasive detection of breast and bladder cancer via plasma and urine samples, respectively.	('breast', 'Disease', (102, 108))	('methylation', 'Var', (15, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ITIH5', 'Gene', (0, 5))	('bladder cancer', 'Disease', 'MESH:D001749', (113, 127))	('bladder cancer', 'Disease', (113, 127))
121150	33924987	In contrast ITIH5 expression was associated with poor patients' outcome in case of lacking CD44 expression.	('ITIH5', 'Var', (12, 17))	('patients', 'Species', '9606', (54, 62))	('CD44', 'Gene', '960', (91, 95))	('expression', 'MPA', (96, 106))	('lacking', 'NegReg', (83, 90))	('CD44', 'Gene', (91, 95))
121168	33924987	In parallel, studying cell migration by performing a wound healing assay, we showed a reduced cell migration capability of basal-type SCaBER cells upon forced ITIH5 expression, i.e., SCaBER DeltapBK-mock clones repopulated the wounded area notably faster than corresponding ITIH5-expressing single-cell clones over three days (72 h).	('cell migration', 'biological_process', 'GO:0016477', ('22', '36'))	('reduced', 'NegReg', (86, 93))	('forced', 'Var', (152, 158))	('cell migration capability', 'CPA', (94, 119))	('faster', 'PosReg', (248, 254))	('repopulated', 'CPA', (211, 222))	('pBK', 'Gene', '55872', (195, 198))	('wound healing', 'biological_process', 'GO:0042060', ('53', '66'))	('pBK', 'Gene', (195, 198))	('ITIH5', 'Gene', (159, 164))	('cell migration', 'biological_process', 'GO:0016477', ('94', '108'))
121184	33924987	Consistent with previous reports, ITIH5 expression impaired tumor cell and colony growth as well as cell capacities to colonize an artificial wound in vitro.	('impaired tumor', 'Disease', (51, 65))	('expression', 'Var', (40, 50))	('impaired tumor', 'Disease', 'MESH:D060825', (51, 65))	('ITIH5', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cell capacities to colonize an artificial wound', 'CPA', (100, 147))
121189	33924987	This was validated by a substantial reduction of cell migration in our wound healing assays, indicating a low invasive bladder cell phenotype after ITIH5 re-expression.	('cell migration', 'biological_process', 'GO:0016477', ('49', '63'))	('cell migration', 'CPA', (49, 63))	('invasive bladder', 'Disease', (110, 126))	('reduction', 'NegReg', (36, 45))	('invasive bladder', 'Phenotype', 'HP:0100645', (110, 126))	('wound healing', 'biological_process', 'GO:0042060', ('71', '84'))	('ITIH5', 'Var', (148, 153))	('invasive bladder', 'Disease', 'MESH:D001745', (110, 126))
121198	33924987	In line with that, ITIH5 expression associated with altered ECM-cell interaction significantly enhanced sensitivity of SCaBER to both cisplatin and gemcitabine up to 15-fold.	('sensitivity', 'MPA', (104, 115))	('gemcitabine', 'Chemical', 'MESH:C056507', (148, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('enhanced', 'PosReg', (95, 103))	('expression', 'Var', (25, 35))	('ITIH5', 'Gene', (19, 24))
121201	33924987	ITIH5 DNA methylation, which was shown to be useful as biomarker to detect bladder cancer via urine, may further hold information for predicting chemo-response of bladder cancer patients.	('bladder cancer', 'Disease', 'MESH:D001749', (163, 177))	('DNA methylation', 'biological_process', 'GO:0006306', ('6', '21'))	('bladder cancer', 'Disease', (163, 177))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('ITIH5', 'Var', (0, 5))	('information', 'Reg', (118, 129))	('patients', 'Species', '9606', (178, 186))	('DNA', 'cellular_component', 'GO:0005574', ('6', '9'))	('bladder cancer', 'Phenotype', 'HP:0009725', (163, 177))	('methylation', 'Var', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))
121239	30268436	A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-beta Superfamily We present an integromic analysis of gene alterations that modulate transforming growth factor beta (TGF-beta)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA).	('cancer', 'Disease', (287, 293))	('TGF-beta', 'Gene', '7040', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('modulate', 'Reg', (178, 186))	('transforming growth factor beta', 'Gene', (187, 218))	('signaling', 'biological_process', 'GO:0023052', ('244', '253'))	('tumor', 'Disease', (263, 268))	('Signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('TGF-beta', 'Gene', (98, 106))	('alterations', 'Var', (161, 172))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('187', '218'))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('transforming growth factor beta', 'Gene', '7040', (187, 218))	('TGF-beta', 'Gene', '7040', (220, 228))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('Cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Cancer', 'Phenotype', 'HP:0002664', (307, 313))	('TGF-beta', 'Gene', (220, 228))
121240	30268436	Focusing on genes that encode mediators and regulators of TGF-beta signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('TGF-beta', 'Gene', (58, 66))	('mutation', 'Var', (120, 128))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (216, 240))	('amplification', 'Var', (154, 167))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('gastrointestinal cancers', 'Disease', (216, 240))	('frequencies', 'Reg', (201, 212))	('TGF-beta', 'Gene', '7040', (58, 66))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))
121242	30268436	Alterations in the TGF-beta superfamily correlated positively with expression of metastasis-associated genes and with decreased survival.	('Alterations', 'Var', (0, 11))	('TGF-beta', 'Gene', '7040', (19, 27))	('metastasis-associated genes', 'Gene', (81, 108))	('decreased', 'NegReg', (118, 127))	('survival', 'CPA', (128, 136))	('expression', 'MPA', (67, 77))	('TGF-beta', 'Gene', (19, 27))
121243	30268436	Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-beta signaling in each cancer type.	('miR', 'Gene', (105, 108))	('signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('TGF-beta', 'Gene', '7040', (153, 161))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('deletion', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('mutation', 'Var', (49, 57))	('DNA methylation', 'biological_process', 'GO:0006306', ('84', '99'))	('TGF-beta', 'Gene', (153, 161))	('transcriptional activity', 'MPA', (125, 149))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('amplification', 'Var', (59, 72))	('cancer', 'Disease', (180, 186))	('miR', 'Gene', '220972', (105, 108))
121259	30268436	We analyzed multiple data types: somatic copy number variation (CNV), point mutation, DNA methylation, mRNA expression (from mRNA-seq), miRNA expression (from miRNA-seq), and, for correlative analyses, protein expression (from reverse-phase protein arrays; RPPA).	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('miR', 'Gene', '220972', (136, 139))	('DNA methylation', 'biological_process', 'GO:0006306', ('86', '101'))	('miR', 'Gene', (136, 139))	('point mutation', 'Var', (70, 84))	('protein', 'cellular_component', 'GO:0003675', ('241', '248'))	('miR', 'Gene', '220972', (159, 162))	('miR', 'Gene', (159, 162))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('mRNA expression', 'MPA', (103, 118))
121265	30268436	Using the cBioPortal definitions, genomic alterations were classified as gene amplifications, gains (low-level amplifications), deep deletions (equivalent to homozygous deletions for non-aneuploidy cases), shallow deletions (heterozygous loss), truncating mutations, inframe mutations, or missense mutations.	('non-aneuploidy', 'Disease', (183, 197))	('truncating', 'Disease', (245, 255))	('deep', 'Disease', (128, 132))	('gains', 'Disease', (94, 99))	('inframe mutations', 'Var', (267, 284))	('missense mutations', 'Var', (289, 307))	('shallow', 'Disease', (206, 213))	('non-aneuploidy', 'Disease', 'MESH:D000782', (183, 197))
121267	30268436	Although alteration frequencies were low, 39% of the tumors contained an alteration in at least one of the 43 genes.	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('alteration', 'Var', (73, 83))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
121271	30268436	When excluding those six, cumulative mutation frequency (23%) in the TGF-beta core pathways was significantly higher than expected for a randomly selected set of 37 genes (Figure S1C, S1D).	('TGF-beta', 'Gene', (69, 77))	('mutation frequency', 'Var', (37, 55))	('core', 'cellular_component', 'GO:0019013', ('78', '82'))	('TGF-beta', 'Gene', '7040', (69, 77))	('higher', 'PosReg', (110, 116))
121275	30268436	The frequency and type of genomic alteration varied widely across tumor types (Figure 2A and S2A), from no alterations in testicular germline tumors (TGCT) to all three types of alterations (mutation, deletion, and amplification) in urothelial bladder cancers (BLCA).	('deletion', 'Var', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('tumor', 'Disease', (66, 71))	('bladder cancers', 'Phenotype', 'HP:0009725', (244, 259))	('tumor', 'Disease', (142, 147))	('amplification', 'Var', (215, 228))	('urothelial bladder cancers', 'Disease', (233, 259))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('BLCA', 'Phenotype', 'HP:0009725', (261, 265))	('urothelial bladder cancers', 'Disease', 'MESH:D001749', (233, 259))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
121276	30268436	There were genomic alterations of TGF-beta pathway genes in more than 50% of samples in 12 tumor types (Figure 2A, Tables S2-S4).	('TGF-beta', 'Gene', (34, 42))	('genomic alterations', 'Var', (11, 30))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TGF-beta', 'Gene', '7040', (34, 42))	('tumor', 'Disease', (91, 96))
121278	30268436	Without adjusting for background alteration burden, among the 39% of TCGA cases that carried TGF-beta pathway gene alterations, SKCM (70%), COAD (65%), and ESCA (65%) had the highest percentages of alterations; THCA (4%), KICH (6%), and TGCT (9%) had the lowest (Table S3).	('TGF-beta', 'Gene', '7040', (93, 101))	('COAD', 'Disease', (140, 144))	('TGF-beta', 'Gene', (93, 101))	('alterations', 'Reg', (198, 209))	('alterations', 'Var', (115, 126))	('KICH', 'Disease', 'None', (222, 226))	('ESCA', 'Phenotype', 'HP:0011459', (156, 160))	('COAD', 'Disease', 'MESH:D029424', (140, 144))	('KICH', 'Disease', (222, 226))
121279	30268436	We observed non-silent SMAD4 mutations in 24% and SMAD4 deletions in 13% of pancreatic adenocarcinoma (PAAD) samples (Figure 2A, 2C; Table S4).	('SMAD4', 'Gene', (23, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mutations', 'Var', (29, 38))	('SMAD4', 'Gene', (50, 55))	('pancreatic adenocarcinoma', 'Disease', (76, 101))	('deletions', 'Var', (56, 65))	('PAAD', 'Phenotype', 'HP:0006725', (103, 107))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (76, 101))	('SMAD4', 'Gene', '4089', (23, 28))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (76, 101))	('SMAD4', 'Gene', '4089', (50, 55))
121280	30268436	Because SMAD4 is the Co-Smad required for transducing the Smad signal to downstream effectors, loss of SMAD4 in PAAD by mutation or deletion suggests a tumor-suppressive role for TGF-beta signaling in PAAD, which is consistent with other reports.	('TGF-beta', 'Gene', (179, 187))	('deletion', 'Var', (132, 140))	('SMAD4', 'Gene', (8, 13))	('a tumor', 'Disease', 'MESH:D009369', (150, 157))	('PAAD', 'Phenotype', 'HP:0006725', (112, 116))	('SMAD4', 'Gene', '4089', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutation', 'Var', (120, 128))	('a tumor', 'Disease', (150, 157))	('SMAD4', 'Gene', '4089', (8, 13))	('TGF-beta', 'Gene', '7040', (179, 187))	('signaling', 'biological_process', 'GO:0023052', ('188', '197'))	('loss', 'NegReg', (95, 99))	('SMAD4', 'Gene', (103, 108))	('PAAD', 'Disease', (201, 205))	('PAAD', 'Phenotype', 'HP:0006725', (201, 205))
121284	30268436	Diffuse large B-cell lymphoma (DLBC) had a high frequency of deletions spanning different levels of the pathway:: ligands (TGFB2, INHBB, GDF1), receptors or receptor-associated proteins (BMPR1A, ACVR1, ACVR1C, ACV2A, ACVR2B, TGFBRAP1), and Smads (SMAD9):, indicative of a tumor-suppressive role for TGF-beta signaling in these early-stage DLBC cases in the TCGA cohort.	('deletions', 'Var', (61, 70))	('TGF-beta', 'Gene', (299, 307))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (14, 29))	('TGFB2', 'Gene', '7042', (123, 128))	('ACVR1C', 'Gene', (202, 208))	('ACVR1C', 'Gene', '130399', (202, 208))	('INHBB', 'Gene', (130, 135))	('BMPR1A', 'Gene', '657', (187, 193))	('ACV', 'Gene', (195, 198))	('ACV', 'Gene', (210, 213))	('ACV', 'Gene', (202, 205))	('ACVR1', 'Gene', (195, 200))	('a tumor', 'Disease', 'MESH:D009369', (270, 277))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (14, 29))	('signaling', 'biological_process', 'GO:0023052', ('308', '317'))	('TGFB2', 'Gene', (123, 128))	('TGFBRAP1', 'Gene', '9392', (225, 233))	('ACV', 'Gene', '83729', (202, 205))	('ACV', 'Gene', '83729', (195, 198))	('GDF1', 'Gene', (137, 141))	('ACVR2B', 'Gene', '93', (217, 223))	('ACV', 'Gene', '83729', (210, 213))	('ACVR1', 'Gene', '90', (202, 207))	('INHBB', 'Gene', '3625', (130, 135))	('B-cell lymphoma', 'Disease', (14, 29))	('ACV', 'Gene', (217, 220))	('early-stage DLBC', 'Disease', (327, 343))	('a tumor', 'Disease', (270, 277))	('BMPR1A', 'Gene', (187, 193))	('lymphoma', 'Phenotype', 'HP:0002665', (21, 29))	('ACVR1', 'Gene', (202, 207))	('ACVR1', 'Gene', '90', (195, 200))	('SMAD9', 'Gene', (247, 252))	('GDF1', 'Gene', '2657', (137, 141))	('TGF-beta', 'Gene', '7040', (299, 307))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('ACV', 'Gene', '83729', (217, 220))	('ACVR2B', 'Gene', (217, 223))	('SMAD9', 'Gene', '4093', (247, 252))	('TGFBRAP1', 'Gene', (225, 233))
121290	30268436	PAAD had deletions associated with 14 TGF-beta core genes, suggesting synergistic effects from ligands (BMP family), receptors (BMPR, TGFBR), and SMAD4.	('TGFBR', 'Gene', '7046;7048;7049', (134, 139))	('TGF-beta', 'Gene', (38, 46))	('BMP', 'Gene', (128, 131))	('BMP', 'Gene', (104, 107))	('TGFBR', 'Gene', (134, 139))	('SMAD4', 'Gene', '4089', (146, 151))	('PAAD', 'Phenotype', 'HP:0006725', (0, 4))	('core', 'cellular_component', 'GO:0019013', ('47', '51'))	('TGF-beta', 'Gene', '7040', (38, 46))	('deletions', 'Var', (9, 18))	('BMP', 'Gene', '649', (104, 107))	('SMAD4', 'Gene', (146, 151))	('BMP', 'Gene', '649', (128, 131))
121291	30268436	Colorectal cancers (COAD and READ) were marked by SMAD4 and SMAD3 deletions.	('COAD', 'Disease', (20, 24))	('SMAD3', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Colorectal cancers', 'Disease', (0, 18))	('SMAD4', 'Gene', (50, 55))	('Colorectal cancers', 'Disease', 'MESH:D015179', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('COAD', 'Disease', 'MESH:D029424', (20, 24))	('deletions', 'Var', (66, 75))	('SMAD3', 'Gene', '4088', (60, 65))	('SMAD4', 'Gene', '4089', (50, 55))
121292	30268436	Deletions in genomic regions covering all ACVR genes except ACVR2B were identified as significant in DLBC.	('significant', 'Reg', (86, 97))	('ACV', 'Gene', '83729', (42, 45))	('ACVR2B', 'Gene', (60, 66))	('DLBC', 'Disease', (101, 105))	('ACV', 'Gene', (42, 45))	('ACV', 'Gene', '83729', (60, 63))	('ACVR2B', 'Gene', '93', (60, 66))	('ACV', 'Gene', (60, 63))	('Deletions', 'Var', (0, 9))
121293	30268436	To understand how gene alterations affect transcriptional output of the pathways, we analyzed the mRNA expression of 50 downstream targets of Smad signaling with defined roles as tumor promoters or tumor suppressors (Table S1).	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('alterations', 'Var', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (198, 203))	('signaling', 'biological_process', 'GO:0023052', ('147', '156'))	('tumor', 'Disease', (179, 184))
121294	30268436	Surprisingly, the directionality of target-gene change was consistent for all mutations, even for mutations in the inhibitors SMAD6/7.	('SMAD6/7', 'Gene', (126, 133))	('SMAD6/7', 'Gene', '4091;4092', (126, 133))	('mutations', 'Var', (78, 87))
121295	30268436	An explanation is that mutations in pathway activators, like TGFB1/2/3 and TGFBR1/2/3, may result in gain of function, whereas mutations in the inhibitors SMAD6 and SMAD7 may result in loss of inhibitory function.	('TGFBR1/2/3', 'Gene', (75, 85))	('gain of function', 'PosReg', (101, 117))	('TGFBR1/2/3', 'Gene', '7046;7048;7049', (75, 85))	('TGFB1/2/3', 'Gene', (61, 70))	('SMAD7', 'Gene', (165, 170))	('mutations', 'Var', (23, 32))	('SMAD7', 'Gene', '4092', (165, 170))	('SMAD6', 'Gene', '4091', (155, 160))	('TGFB1/2/3', 'Gene', '7040;7042;7043', (61, 70))	('SMAD6', 'Gene', (155, 160))	('inhibitory function', 'MPA', (193, 212))
121297	30268436	Similarly, SMAD3 was generally co-amplified with SMAD6; both are in proximal cytogenetic bands, 15q22.33 and 15q22.31, respectively.	('SMAD3', 'Gene', '4088', (11, 16))	('SMAD3', 'Gene', (11, 16))	('SMAD6', 'Gene', '4091', (49, 54))	('15q22.33', 'Var', (96, 104))	('SMAD6', 'Gene', (49, 54))	('15q22.31', 'Var', (109, 117))
121298	30268436	In support of that hypothesis, both the amplification and deletion profiles (rows in Figure 2H-I) of those gene pairs were similar, and, consequently, SMAD2 and SMAD7 are co-clustered, whereas SMAD3 and SMAD6 clustered close to each other.	('SMAD7', 'Gene', (161, 166))	('SMAD7', 'Gene', '4092', (161, 166))	('SMAD2', 'Gene', (151, 156))	('SMAD2', 'Gene', '4087', (151, 156))	('SMAD6', 'Gene', '4091', (203, 208))	('deletion', 'Var', (58, 66))	('SMAD6', 'Gene', (203, 208))	('SMAD3', 'Gene', '4088', (193, 198))	('SMAD3', 'Gene', (193, 198))
121299	30268436	The effect of TGF-beta pathway amplification events on target gene mRNA expression was similar to that of mutations (Figure 2H), suggesting that most mutations in TGF-beta pathway activators are gain of function.	('TGF-beta', 'Gene', '7040', (163, 171))	('TGF-beta', 'Gene', (14, 22))	('gain of function', 'PosReg', (195, 211))	('TGF-beta', 'Gene', (163, 171))	('mutations', 'Var', (150, 159))	('TGF-beta', 'Gene', '7040', (14, 22))
121300	30268436	HMGA2 was overexpressed in samples with either mutations or amplifications in the TGF-beta pathway genes, with the exception of tumors with amplifications in TGFB2, TGFBR2, ACVR2B, SMAD4, SMAD5, or SMAD6.	('TGFBR2', 'Gene', (165, 171))	('SMAD6', 'Gene', (198, 203))	('ACVR2B', 'Gene', '93', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('TGF-beta', 'Gene', '7040', (82, 90))	('SMAD4', 'Gene', (181, 186))	('tumors', 'Disease', (128, 134))	('overexpressed', 'PosReg', (10, 23))	('HMGA2', 'Gene', '8091', (0, 5))	('SMAD5', 'Gene', (188, 193))	('mutations', 'Var', (47, 56))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('TGF-beta', 'Gene', (82, 90))	('ACVR2B', 'Gene', (173, 179))	('SMAD6', 'Gene', '4091', (198, 203))	('SMAD4', 'Gene', '4089', (181, 186))	('amplifications', 'Var', (140, 154))	('TGFB2', 'Gene', '7042', (158, 163))	('TGFBR2', 'Gene', '7048', (165, 171))	('SMAD5', 'Gene', '4090', (188, 193))	('amplifications', 'Var', (60, 74))	('TGFB2', 'Gene', (158, 163))	('HMGA2', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
121305	30268436	SMAD5 amplification was associated with increased CDH2 expression; 36 other amplifications were associated with decreased CDH2 expression.	('CDH2', 'Gene', (50, 54))	('CDH2', 'Gene', '1000', (50, 54))	('SMAD5', 'Gene', (0, 5))	('expression', 'MPA', (127, 137))	('CDH2', 'Gene', (122, 126))	('expression', 'MPA', (55, 65))	('CDH2', 'Gene', '1000', (122, 126))	('SMAD5', 'Gene', '4090', (0, 5))	('increased', 'PosReg', (40, 49))	('amplification', 'Var', (6, 19))	('decreased', 'NegReg', (112, 121))
121307	30268436	Another exception was reduced HMGA2 expression in samples with amplifications of SMAD4 or TGFBR2, whereas HMGA2 expression increased in samples with mutations in SMAD4 or TGFBR2 (Figure 2G).	('increased', 'PosReg', (123, 132))	('mutations', 'Var', (149, 158))	('HMGA2', 'Gene', '8091', (30, 35))	('TGFBR2', 'Gene', (90, 96))	('HMGA2', 'Gene', '8091', (106, 111))	('SMAD4', 'Gene', '4089', (162, 167))	('TGFBR2', 'Gene', '7048', (171, 177))	('SMAD4', 'Gene', (81, 86))	('HMGA2', 'Gene', (30, 35))	('HMGA2', 'Gene', (106, 111))	('amplifications', 'Var', (63, 77))	('reduced', 'NegReg', (22, 29))	('TGFBR2', 'Gene', (171, 177))	('TGFBR2', 'Gene', '7048', (90, 96))	('SMAD4', 'Gene', (162, 167))	('expression', 'MPA', (36, 46))	('SMAD4', 'Gene', '4089', (81, 86))	('expression', 'MPA', (112, 122))
121309	30268436	The analysis identified 6genes with hotspot mutations, representing all levels of the TGF-beta pathway (Figure 3A-E).	('TGF-beta', 'Gene', '7040', (86, 94))	('TGF-beta', 'Gene', (86, 94))	('mutations', 'Var', (44, 53))
121311	30268436	Hotspot mutations of BMP5 occurred in 13 cases across 7 cancers.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (8, 17))	('occurred', 'Reg', (26, 34))	('BMP5', 'Gene', (21, 25))	('BMP5', 'Gene', '653', (21, 25))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('Hotspot', 'PosReg', (0, 7))
121312	30268436	BMP5 is synthesized as a proprotein, and an R321 stop-codon mutation (4 cases) (Figure 3A) results in loss of the functional, secreted ligand.	('R321 stop-codon', 'Var', (44, 59))	('ligand', 'molecular_function', 'GO:0005488', ('135', '141'))	('BMP5', 'Gene', (0, 4))	('loss', 'NegReg', (102, 106))	('BMP5', 'Gene', '653', (0, 4))
121313	30268436	Frameshift mutations in ACVR2A at the K437 hotspot generate the variants K437Efs*19 (7 cases in 2 cancers) and K437Rfs*5 (69 cases in 5 cancers), resulting in premature stop codons and deletion of two C-terminal helices of the 4-helix bundle (Figure 3A, 3D), which likely disrupt ACV signaling (; Yosef et al., 2017).	('ACV', 'Gene', '83729', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('signaling', 'biological_process', 'GO:0023052', ('284', '293'))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', (98, 105))	('K437Efs*19', 'Var', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('K437Efs', 'Mutation', 'p.K437,FSE', (73, 80))	('ACV', 'Gene', (280, 283))	('disrupt', 'NegReg', (272, 279))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('ACV', 'Gene', '83729', (280, 283))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('K437Rfs*5', 'Var', (111, 120))	('stop codons', 'MPA', (169, 180))	('ACVR2A', 'Gene', '92', (24, 30))	('ACV', 'Gene', (24, 27))	('deletion', 'Var', (185, 193))	('ACVR2A', 'Gene', (24, 30))	('K437Rfs', 'Mutation', 'p.K437,FSR', (111, 118))	('Frameshift mutations', 'Var', (0, 20))
121314	30268436	Type I receptors ACVR1B and ACVR1C have similar C-terminal frameshift mutation hotspots at R485 (6 cases) and R441 (5 cases), respectively (Figure S3).	('ACVR1B', 'Gene', '91', (17, 23))	('ACVR1B', 'Gene', (17, 23))	('R441', 'Var', (110, 114))	('ACVR1C', 'Gene', (28, 34))	('ACVR1C', 'Gene', '130399', (28, 34))	('R485', 'Var', (91, 95))
121315	30268436	TGFBR2 R553 to C or H mutations and BMPR2 N583 frameshift might disrupt interaction with other receptor subunits or binding proteins.	('binding', 'molecular_function', 'GO:0005488', ('116', '123'))	('BMPR2', 'Gene', '659', (36, 41))	('binding', 'Interaction', (116, 123))	('N583 frameshift', 'Var', (42, 57))	('interaction', 'Interaction', (72, 83))	('TGFBR2', 'Gene', (0, 6))	('R553 to C or H mutations', 'Var', (7, 31))	('frameshift', 'Var', (47, 57))	('TGFBR2', 'Gene', '7048', (0, 6))	('disrupt', 'NegReg', (64, 71))	('BMPR2', 'Gene', (36, 41))
121316	30268436	Hotspots in SMAD4 at R361 and D537 (two conserved sites in R-Smads) normally stabilize homo- or heterotrimer oligomerization (Figure 3C).	('SMAD4', 'Gene', (12, 17))	('stabilize', 'Reg', (77, 86))	('D537', 'Var', (30, 34))	('homo- or heterotrimer oligomerization', 'MPA', (87, 124))	('SMAD4', 'Gene', '4089', (12, 17))
121317	30268436	Those mutations could have widespread effects, because SMAD4 is a binding partner for all Smad-dependent transcriptional regulation.	('regulation', 'biological_process', 'GO:0065007', ('121', '131'))	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('SMAD4', 'Gene', '4089', (55, 60))	('mutations', 'Var', (6, 15))	('SMAD4', 'Gene', (55, 60))
121318	30268436	Mutation at either R361 or D537 in SMAD4 correlates with metastasis and decreased survival in colon cancer.	('survival', 'CPA', (82, 90))	('colon cancer', 'Disease', (94, 106))	('decreased', 'NegReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('SMAD4', 'Gene', '4089', (35, 40))	('D537', 'Var', (27, 31))	('metastasis', 'CPA', (57, 67))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('SMAD4', 'Gene', (35, 40))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))
121319	30268436	SMAD2 exhibited 13 truncating mutations at S464 (Figure 3A).	('SMAD2', 'Gene', (0, 5))	('SMAD2', 'Gene', '4087', (0, 5))	('S464', 'Var', (43, 47))
121321	30268436	S464 is necessary for proper positioning of SMAD2 for phosphorylation at S465 and S467, both of which mediate interaction of SMAD2 with SMAD4 and dissociation of SMAD2 from TGFBR1 and the adaptor SARA (encoded by ZFYVE9).	('SARA', 'Gene', '9372', (196, 200))	('interaction', 'Interaction', (110, 121))	('SMAD2', 'Gene', (162, 167))	('SMAD4', 'Gene', '4089', (136, 141))	('SMAD2', 'Gene', (44, 49))	('dissociation', 'MPA', (146, 158))	('TGFBR1', 'Gene', '7046', (173, 179))	('mediate', 'Reg', (102, 109))	('TGFBR1', 'Gene', (173, 179))	('S467', 'Var', (82, 86))	('SARA', 'Gene', (196, 200))	('ZFYVE9', 'Gene', '9372', (213, 219))	('SMAD2', 'Gene', '4087', (125, 130))	('ZFYVE9', 'Gene', (213, 219))	('SMAD4', 'Gene', (136, 141))	('SMAD2', 'Gene', '4087', (162, 167))	('SMAD2', 'Gene', (125, 130))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('SMAD2', 'Gene', '4087', (44, 49))
121322	30268436	Hence, S464 mutations may prevent dissociation of SMAD2 from the receptor-adaptor complex, blocking the downstream signal (Figure 3E).	('SMAD2', 'Gene', (50, 55))	('S464 mutations', 'Var', (7, 21))	('downstream signal', 'MPA', (104, 121))	('blocking', 'NegReg', (91, 99))	('SMAD2', 'Gene', '4087', (50, 55))	('dissociation', 'MPA', (34, 46))	('prevent', 'NegReg', (26, 33))
121323	30268436	Of 176 mutations at hotspot sites across 6 genes, 115 (65%) were in cancers of the GI system (Figure S3): 60 in ESCA, 51 in COAD, 3 in PAAD, and 1 in LIHC.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers of the GI system', 'Phenotype', 'HP:0007378', (68, 92))	('PAAD', 'Phenotype', 'HP:0006725', (135, 139))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('COAD', 'Disease', (124, 128))	('cancers of the GI system', 'Disease', 'MESH:D009369', (68, 92))	('cancers of the GI system', 'Disease', (68, 92))	('LIHC', 'Disease', (150, 154))	('ESCA', 'Phenotype', 'HP:0011459', (112, 116))	('LIHC', 'Disease', 'None', (150, 154))	('ESCA', 'Disease', (112, 116))	('COAD', 'Disease', 'MESH:D029424', (124, 128))	('mutations', 'Var', (7, 16))
121326	30268436	To determine if GI cancers possess a unique signature of altered TGF-beta pathway activity, we compared changes in the expression of 50 downstream genes related to mutations at hotspot sites (Figure 3B).	('TGF-beta', 'Gene', (65, 73))	('expression', 'MPA', (119, 129))	('GI cancers', 'Disease', (16, 26))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('GI cancers', 'Disease', 'MESH:D009369', (16, 26))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('activity', 'MPA', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (164, 173))	('TGF-beta', 'Gene', '7040', (65, 73))
121328	30268436	Notably, CDH2 exhibited an overall reduction in expression except in the context of the BMP5 hotspot mutation.	('CDH2', 'Gene', (9, 13))	('CDH2', 'Gene', '1000', (9, 13))	('BMP5', 'Gene', (88, 92))	('expression', 'MPA', (48, 58))	('BMP5', 'Gene', '653', (88, 92))	('mutation', 'Var', (101, 109))	('reduction', 'NegReg', (35, 44))
121332	30268436	Guided by the enrichment of hotspot mutations in GI cancers, we tested for enrichment of TGF-beta pathway point mutations in GI cancers.	('GI cancers', 'Disease', 'MESH:D009369', (49, 59))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('GI cancers', 'Disease', 'MESH:D009369', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('GI cancer', 'Phenotype', 'HP:0007378', (49, 58))	('GI cancer', 'Phenotype', 'HP:0007378', (125, 134))	('tested', 'Reg', (64, 70))	('point mutations', 'Var', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('TGF-beta', 'Gene', '7040', (89, 97))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('GI cancers', 'Disease', (49, 59))	('GI cancers', 'Disease', (125, 135))	('TGF-beta', 'Gene', (89, 97))
121333	30268436	Non-silent mutations were significantly more common in GI cancers (596 of 1,511) than in the non-GI cancers (1,606 of 7,614).	('GI cancers', 'Disease', 'MESH:D009369', (55, 65))	('common', 'Reg', (45, 51))	('non-GI cancers', 'Disease', 'MESH:D009369', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('GI cancer', 'Phenotype', 'HP:0007378', (55, 64))	('GI cancer', 'Phenotype', 'HP:0007378', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('Non-silent mutations', 'Var', (0, 20))	('GI cancers', 'Disease', 'MESH:D009369', (97, 107))	('GI cancers', 'Disease', (55, 65))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('non-GI cancers', 'Disease', (93, 107))
121334	30268436	Deep deletions and amplifications were also significantly enriched in GI cancers.	('GI cancer', 'Phenotype', 'HP:0007378', (70, 79))	('GI cancers', 'Disease', 'MESH:D009369', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('GI cancers', 'Disease', (70, 80))	('Deep deletions', 'Var', (0, 14))	('amplifications', 'Var', (19, 33))
121335	30268436	COAD, READ, and STAD had recurrent aberrations in genes at each level of the pathway (ligands, receptors, and SMADs) and all axes (TGFBR, BMPR, ACVR), whereas PAAD had frequent mutations in only SMAD4 and TGFBR2 (Figure S4A).	('TGFBR', 'Gene', (205, 210))	('COAD', 'Disease', (0, 4))	('SMAD4', 'Gene', '4089', (195, 200))	('aberrations', 'Var', (35, 46))	('TGFBR2', 'Gene', '7048', (205, 211))	('ACV', 'Gene', (144, 147))	('mutations', 'Var', (177, 186))	('BMP', 'Gene', (138, 141))	('TGFBR', 'Gene', '7046;7048;7049', (131, 136))	('TGFBR2', 'Gene', (205, 211))	('SMAD4', 'Gene', (195, 200))	('COAD', 'Disease', 'MESH:D029424', (0, 4))	('TGFBR', 'Gene', '7046;7048;7049', (205, 210))	('PAAD', 'Phenotype', 'HP:0006725', (159, 163))	('BMP', 'Gene', '649', (138, 141))	('ACV', 'Gene', '83729', (144, 147))	('TGFBR', 'Gene', (131, 136))
121336	30268436	To compare the TGF-beta pathway transcriptional signatures in GI vs. other cancers, we calculated the target gene expression signatures associated with TGF-beta pathway mutations in both groups (Figure 4A-B).	('gene expression', 'biological_process', 'GO:0010467', ('109', '124'))	('TGF-beta', 'Gene', '7040', (152, 160))	('mutations', 'Var', (169, 178))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('TGF-beta', 'Gene', '7040', (15, 23))	('cancers', 'Disease', (75, 82))	('TGF-beta', 'Gene', (15, 23))	('TGF-beta', 'Gene', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
121338	30268436	Whereas IL6 mRNA was increased in most non-GI cancers with TGF-beta pathway mutations, IL6 upregulation was significantly greater in GI cancers than non-GI cancers (Figure S4B), and within GI cancers IL6 expression was greater in samples with alterations in the TGF-beta pathway genes than those without alterations in the TGF-beta pathway genes.	('non-GI cancers', 'Disease', (39, 53))	('GI cancers', 'Disease', 'MESH:D009369', (189, 199))	('GI cancers than non-GI cancers', 'Disease', 'MESH:D009369', (133, 163))	('non-GI cancers', 'Disease', 'MESH:D009369', (39, 53))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('IL6', 'molecular_function', 'GO:0005138', ('87', '90'))	('TGF-beta', 'Gene', (323, 331))	('GI cancers', 'Disease', 'MESH:D009369', (43, 53))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('IL6', 'Gene', '3569', (8, 11))	('alterations', 'Var', (243, 254))	('IL6', 'Gene', '3569', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('TGF-beta', 'Gene', (59, 67))	('increased', 'PosReg', (21, 30))	('non-GI cancers', 'Disease', 'MESH:D009369', (149, 163))	('GI cancers', 'Disease', 'MESH:D009369', (153, 163))	('IL6', 'Gene', '3569', (87, 90))	('GI cancer', 'Phenotype', 'HP:0007378', (43, 52))	('IL6', 'Gene', (8, 11))	('TGF-beta', 'Gene', '7040', (262, 270))	('IL6', 'Gene', (200, 203))	('GI cancers than non-GI cancers', 'Disease', (133, 163))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('GI cancer', 'Phenotype', 'HP:0007378', (153, 162))	('upregulation', 'PosReg', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('IL6', 'Gene', (87, 90))	('expression', 'MPA', (204, 214))	('GI cancers', 'Disease', (189, 199))	('IL6', 'molecular_function', 'GO:0005138', ('200', '203'))	('greater', 'PosReg', (122, 129))	('TGF-beta', 'Gene', '7040', (323, 331))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('mutations', 'Var', (76, 85))	('TGF-beta', 'Gene', (262, 270))	('GI cancer', 'Phenotype', 'HP:0007378', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('GI cancers', 'Disease', 'MESH:D009369', (133, 143))	('IL6', 'molecular_function', 'GO:0005138', ('8', '11'))	('GI cancer', 'Phenotype', 'HP:0007378', (189, 198))	('TGF-beta', 'Gene', '7040', (59, 67))
121339	30268436	Notably, in non-GI cancers associated with GDF1 mutations, IL6 mRNA expression was markedly decreased, suggesting that GDF1 may play different roles in GI and non-GI cancers.	('non-GI cancers', 'Disease', 'MESH:D009369', (159, 173))	('non-GI cancers', 'Disease', (159, 173))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('IL6', 'Gene', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (48, 57))	('GI cancer', 'Phenotype', 'HP:0007378', (163, 172))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('GDF1', 'Gene', (43, 47))	('non-GI cancers', 'Disease', (12, 26))	('non-GI cancers', 'Disease', 'MESH:D009369', (12, 26))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('decreased', 'NegReg', (92, 101))	('GDF1', 'Gene', '2657', (43, 47))	('GDF1', 'Gene', (119, 123))	('IL6', 'molecular_function', 'GO:0005138', ('59', '62'))	('IL6', 'Gene', '3569', (59, 62))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('GDF1', 'Gene', '2657', (119, 123))
121341	30268436	In GI cancers, most TGF-beta pathway gene mutations were associated with increased FOS expression; exceptions were TGFBRAP1, SMAD7, SMAD5, GDF1, BMP5, and ACVRL1.	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))	('TGF-beta', 'Gene', (20, 28))	('ACVRL1', 'Gene', (155, 161))	('SMAD7', 'Gene', '4092', (125, 130))	('BMP5', 'Gene', (145, 149))	('BMP5', 'Gene', '653', (145, 149))	('TGFBRAP1', 'Gene', '9392', (115, 123))	('GDF1', 'Gene', (139, 143))	('SMAD5', 'Gene', (132, 137))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('increased', 'PosReg', (73, 82))	('ACVRL1', 'Gene', '94', (155, 161))	('GDF1', 'Gene', '2657', (139, 143))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('SMAD5', 'Gene', '4090', (132, 137))	('FOS', 'Gene', (83, 86))	('SMAD7', 'Gene', (125, 130))	('GI cancers', 'Disease', (3, 13))	('TGF-beta', 'Gene', '7040', (20, 28))	('FOS', 'Gene', '2353', (83, 86))	('TGFBRAP1', 'Gene', (115, 123))	('mutations', 'Var', (42, 51))
121342	30268436	In non-GI cancers, only mutations in TGFBR2 were associated with increased FOS expression; all other TGF-beta pathway gene mutations were associated with decreased FOS expression.	('decreased', 'NegReg', (154, 163))	('increased', 'PosReg', (65, 74))	('FOS', 'Gene', (164, 167))	('TGF-beta', 'Gene', '7040', (101, 109))	('TGFBR2', 'Gene', '7048', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('FOS', 'Gene', '2353', (164, 167))	('TGF-beta', 'Gene', (101, 109))	('non-GI cancers', 'Disease', (3, 17))	('FOS', 'Gene', (75, 78))	('TGFBR2', 'Gene', (37, 43))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('mutations', 'Var', (24, 33))	('non-GI cancers', 'Disease', 'MESH:D009369', (3, 17))	('GI cancer', 'Phenotype', 'HP:0007378', (7, 16))	('FOS', 'Gene', '2353', (75, 78))
121343	30268436	To compare the transcriptional output resulting from mutations in GI and non-GI cancers, we calculated differences in expression of the 50 target genes associated with mutations in the 43 genes (Figure 4C).	('non-GI cancers', 'Disease', 'MESH:D009369', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GI cancer', 'Phenotype', 'HP:0007378', (77, 86))	('differences', 'Reg', (103, 114))	('expression', 'MPA', (118, 128))	('non-GI cancers', 'Disease', (73, 87))	('mutations', 'Var', (168, 177))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
121344	30268436	The analysis revealed a shift toward repression of transcriptional output in GI cancers with the most significant shifts occurring with mutations in ACVR2B, INHBA, SMAD3, or GDF2.	('GDF2', 'Gene', (174, 178))	('repression', 'NegReg', (37, 47))	('GI cancers', 'Disease', (77, 87))	('SMAD3', 'Gene', '4088', (164, 169))	('INHBA', 'Gene', '3624', (157, 162))	('ACVR2B', 'Gene', '93', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('transcriptional output', 'MPA', (51, 73))	('SMAD3', 'Gene', (164, 169))	('GI cancer', 'Phenotype', 'HP:0007378', (77, 86))	('INHBA', 'Gene', (157, 162))	('mutations', 'Var', (136, 145))	('GI cancers', 'Disease', 'MESH:D009369', (77, 87))	('ACVR2B', 'Gene', (149, 155))	('GDF2', 'Gene', '2658', (174, 178))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
121345	30268436	In GI cancers, mutations in GDF1 were associated with significantly increased target gene transcription.	('GDF1', 'Gene', '2657', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('GDF1', 'Gene', (28, 32))	('mutations', 'Var', (15, 24))	('target gene transcription', 'MPA', (78, 103))	('GI cancers', 'Disease', (3, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('increased', 'PosReg', (68, 77))	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))	('transcription', 'biological_process', 'GO:0006351', ('90', '103'))
121346	30268436	Mutations in any of the 43 genes were associated with reduced mRNA expression in GI cancers compared with non-GI cancers for most target genes with the largest reductions found for HMGA2 and TERT.	('GI cancer', 'Phenotype', 'HP:0007378', (110, 119))	('GI cancers', 'Disease', 'MESH:D009369', (110, 120))	('GI cancers', 'Disease', (81, 91))	('HMGA2', 'Gene', '8091', (181, 186))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('non-GI cancers', 'Disease', 'MESH:D009369', (106, 120))	('non-GI cancers', 'Disease', (106, 120))	('GI cancers', 'Disease', 'MESH:D009369', (81, 91))	('reduced', 'NegReg', (54, 61))	('HMGA2', 'Gene', (181, 186))	('Mutations', 'Var', (0, 9))	('mRNA expression', 'MPA', (62, 77))	('GI cancer', 'Phenotype', 'HP:0007378', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TERT', 'Gene', (191, 195))	('TERT', 'Gene', '7015', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
121347	30268436	Compared to non-GI cancers, GI cancers had fewer genes with increased expression resulting from pathway mutations.	('non-GI cancers', 'Disease', (12, 26))	('mutations', 'Var', (104, 113))	('GI cancers', 'Disease', 'MESH:D009369', (28, 38))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('non-GI cancers', 'Disease', 'MESH:D009369', (12, 26))	('GI cancers', 'Disease', 'MESH:D009369', (16, 26))	('expression', 'MPA', (70, 80))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('GI cancers', 'Disease', (28, 38))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('GI cancer', 'Phenotype', 'HP:0007378', (28, 37))	('increased', 'PosReg', (60, 69))
121348	30268436	In GI cancers, mutations in any of the 43 genes were associated with a significantly increased expression of FOS, IL6, ZEB2, and ZEB1 compared to expression changes of the same genes resulting from pathway mutations in non-GI cancers.	('IL6', 'molecular_function', 'GO:0005138', ('114', '117'))	('ZEB1', 'Gene', '6935', (129, 133))	('IL6', 'Gene', (114, 117))	('increased', 'PosReg', (85, 94))	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))	('mutations', 'Var', (15, 24))	('non-GI cancers', 'Disease', (219, 233))	('non-GI cancers', 'Disease', 'MESH:D009369', (219, 233))	('FOS', 'Gene', (109, 112))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('GI cancers', 'Disease', 'MESH:D009369', (223, 233))	('expression', 'MPA', (95, 105))	('FOS', 'Gene', '2353', (109, 112))	('ZEB1', 'Gene', (129, 133))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('GI cancer', 'Phenotype', 'HP:0007378', (223, 232))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('ZEB2', 'Gene', (119, 123))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('IL6', 'Gene', '3569', (114, 117))	('GI cancers', 'Disease', (3, 13))	('ZEB2', 'Gene', '9839', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
121349	30268436	Finally, we probed for associations between transcriptional output and TGF-beta pathway gene alterations for all cancers and the GI and non-GI subsets (Figure 4E).	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('alterations', 'Var', (93, 104))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('probed', 'Reg', (12, 18))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('TGF-beta', 'Gene', '7040', (71, 79))	('TGF-beta', 'Gene', (71, 79))
121352	30268436	To explore TGF-beta signaling pathway variation across the 33 cancers in the PanCancer cohort, we computed a "pathway activity score" based on mRNA expression of the 43 genes.	('TGF-beta', 'Gene', '7040', (11, 19))	('TGF-beta', 'Gene', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('variation', 'Var', (38, 47))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('signaling pathway', 'biological_process', 'GO:0007165', ('20', '37'))
121374	30268436	We attribute this observation to co-occurring amplifications or deletions of SMAD7 and SMAD2 and co-occurring amplifications of SMAD6 and SMAD3 (Figure 1B).	('amplifications', 'Var', (46, 60))	('SMAD7', 'Gene', (77, 82))	('SMAD6', 'Gene', (128, 133))	('SMAD3', 'Gene', '4088', (138, 143))	('SMAD2', 'Gene', '4087', (87, 92))	('deletions', 'Var', (64, 73))	('SMAD7', 'Gene', '4092', (77, 82))	('SMAD2', 'Gene', (87, 92))	('SMAD3', 'Gene', (138, 143))	('SMAD6', 'Gene', '4091', (128, 133))
121381	30268436	We analyzed the combined impact of TGF-beta target gene expression and the 43 core gene alterations on patient survival across the PanCancer cohort.	('TGF-beta', 'Gene', (35, 43))	('gene expression', 'biological_process', 'GO:0010467', ('51', '66'))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('alterations', 'Var', (88, 99))	('core', 'cellular_component', 'GO:0019013', ('78', '82'))	('patient', 'Species', '9606', (103, 110))	('TGF-beta', 'Gene', '7040', (35, 43))
121382	30268436	We compared the survival of patients with 3 different cancer profiles: those with high expression of HMGA2 and alterations in any one of the 43 TGF-beta pathway genes (Figure 6C, High HMGA2/TGF-beta mutant), those with high HMGA2 expression and no alterations in any of the 43 genes (Figure 6C, High HMGA2/TGF-beta wild-type), and those with low expression of HMGA2 without considering alterations in TGF-beta pathway genes (Figure 6C, Low HMGA2 expression).	('TGF-beta', 'Gene', '7040', (306, 314))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('HMGA2', 'Gene', '8091', (360, 365))	('high', 'PosReg', (82, 86))	('HMGA2', 'Gene', '8091', (184, 189))	('HMGA2', 'Gene', '8091', (440, 445))	('HMGA2', 'Gene', (300, 305))	('TGF-beta', 'Gene', (401, 409))	('mutant', 'Var', (199, 205))	('HMGA2', 'Gene', (101, 106))	('TGF-beta', 'Gene', (306, 314))	('HMGA2', 'Gene', '8091', (224, 229))	('TGF-beta', 'Gene', '7040', (144, 152))	('patients', 'Species', '9606', (28, 36))	('TGF-beta', 'Gene', '7040', (190, 198))	('cancer', 'Disease', (54, 60))	('HMGA2', 'Gene', (360, 365))	('HMGA2', 'Gene', '8091', (300, 305))	('HMGA2', 'Gene', '8091', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('TGF-beta', 'Gene', (144, 152))	('HMGA2', 'Gene', (184, 189))	('HMGA2', 'Gene', (440, 445))	('alterations', 'Var', (111, 122))	('TGF-beta', 'Gene', (190, 198))	('TGF-beta', 'Gene', '7040', (401, 409))	('HMGA2', 'Gene', (224, 229))
121386	30268436	We saw the opposite for cancers with downregulated CDH2; the worst outcome was associated with low CDH2 expression and mutations in 43 genes (Figure S6B).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('low', 'NegReg', (95, 98))	('CDH2', 'Gene', (99, 103))	('CDH2', 'Gene', (51, 55))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('expression', 'MPA', (104, 114))	('CDH2', 'Gene', '1000', (99, 103))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('mutations', 'Var', (119, 128))	('CDH2', 'Gene', '1000', (51, 55))	('cancers', 'Disease', (24, 31))
121387	30268436	Thus, the expression profile of specific target genes and alterations in the TGF-beta superfamily genes cooperated to increase tumor aggressiveness.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor aggressiveness', 'Disease', (127, 147))	('increase', 'PosReg', (118, 126))	('TGF-beta', 'Gene', '7040', (77, 85))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (127, 147))	('aggressiveness', 'Phenotype', 'HP:0000718', (133, 147))	('TGF-beta', 'Gene', (77, 85))	('alterations', 'Var', (58, 69))
121389	30268436	Because of the association of collagen overexpression and alterations in TGF-beta pathway genes with poor survival, we hypothesize that altered signaling through the TGF-beta superfamily pathways remodels the extracellular matrix to drive metastasis in multiple cancer contexts.	('cancer', 'Disease', (262, 268))	('overexpression', 'PosReg', (39, 53))	('TGF-beta', 'Gene', '7040', (73, 81))	('TGF-beta', 'Gene', '7040', (166, 174))	('remodels', 'Reg', (196, 204))	('TGF-beta', 'Gene', (73, 81))	('collagen', 'molecular_function', 'GO:0005202', ('30', '38'))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('209', '229'))	('drive', 'PosReg', (233, 238))	('TGF-beta', 'Gene', (166, 174))	('metastasis', 'CPA', (239, 249))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('alterations', 'Var', (58, 69))
121391	30268436	In the GI cohort, only ZEB2 combined with TGF-beta pathway gene alteration yielded a significant difference, with low ZEB2 expression corresponding to a survival benefit.	('ZEB2', 'Gene', '9839', (23, 27))	('ZEB2', 'Gene', (118, 122))	('TGF-beta', 'Gene', (42, 50))	('expression', 'MPA', (123, 133))	('ZEB2', 'Gene', (23, 27))	('alteration', 'Var', (64, 74))	('benefit', 'PosReg', (162, 169))	('low', 'NegReg', (114, 117))	('TGF-beta', 'Gene', '7040', (42, 50))	('ZEB2', 'Gene', '9839', (118, 122))
121393	30268436	Thus, although TGF-beta pathway mutations may not occur as commonly in non-GI cancers, they may be important contributors to mortality.	('non-GI cancers', 'Disease', (71, 85))	('non-GI cancers', 'Disease', 'MESH:D009369', (71, 85))	('contributors', 'Reg', (109, 121))	('TGF-beta', 'Gene', '7040', (15, 23))	('TGF-beta', 'Gene', (15, 23))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('mutations', 'Var', (32, 41))	('GI cancer', 'Phenotype', 'HP:0007378', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
121411	30268436	We also identified BMPR2 and TGFBR2 as genes with hotspot sites of mutations that were common in STAD and COAD.	('COAD', 'Disease', (106, 110))	('STAD', 'Disease', (97, 101))	('COAD', 'Disease', 'MESH:D029424', (106, 110))	('mutations', 'Var', (67, 76))	('TGFBR2', 'Gene', (29, 35))	('BMPR2', 'Gene', (19, 24))	('BMPR2', 'Gene', '659', (19, 24))	('TGFBR2', 'Gene', '7048', (29, 35))
121412	30268436	The cancers with high frequencies of hotspot mutations in those two genes did not have high expression of miRNA 92a-3p, suggesting that there is little selective pressure for both mutation and downregulation by that miRNA.	('downregulation', 'NegReg', (193, 207))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('miR', 'Gene', (106, 109))	('miR', 'Gene', '220972', (216, 219))	('miR', 'Gene', (216, 219))	('miR', 'Gene', '220972', (106, 109))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (4, 11))
121413	30268436	To examine the contribution of mutations, amplifications, deletions, DNA methylation and miRNAs to the pathway activity score across tumor types, we computed Pearson's correlations between the pathway activity score and (i) levels of DNA methylation or miRNA expression and (ii) percentages of mutations or CNVs in each tumor type and plotted the results in order of increasing pathway activity score (Figure 7F).	('miR', 'Gene', '220972', (253, 256))	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('miR', 'Gene', (253, 256))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('CNVs', 'Var', (307, 311))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (320, 325))	('tumor', 'Disease', (133, 138))	('DNA methylation', 'biological_process', 'GO:0006306', ('234', '249'))	('DNA methylation', 'biological_process', 'GO:0006306', ('69', '84'))	('DNA', 'cellular_component', 'GO:0005574', ('234', '237'))	('mutations', 'Var', (294, 303))
121415	30268436	DNA methylation was dominant in DLBC, STAD, BRCA, and COAD.	('STAD', 'Disease', (38, 42))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('COAD', 'Disease', 'MESH:D029424', (54, 58))	('methylation', 'Var', (4, 15))	('dominant', 'Reg', (20, 28))	('DLBC', 'Disease', (32, 36))	('BRCA', 'Gene', '672', (44, 48))	('BRCA', 'Gene', (44, 48))	('COAD', 'Disease', (54, 58))
121420	30268436	Some of the key findings of the study were that (i) 39% of the cancers carried TGF-beta pathway gene alterations; (ii) the genomic alterations appeared to affect expression of metastatic and EMT genes; (iii) six hotspot mutations were identified in six genes; (iv) the pathway was most frequently aberrant in GI cancers, which exhibited 115 of the 176 hotspot mutations identified; (iv) high expression of downstream target genes coupled with mutations in the TGF-beta pathway genes was associated with poor outcome, suggesting a net tumor-promoting role of the superfamily across the PanCancer cohort; (v) apparent gene silencing by DNA methylation and deletion of TGF-beta pathway genes were observed most frequently in DLBC, whereas miRNA silencing was seen most often in LAML.	('gene silencing', 'NegReg', (616, 630))	('gene silencing', 'biological_process', 'GO:0016458', ('616', '630'))	('cancers', 'Phenotype', 'HP:0002664', (312, 319))	('cancers', 'Disease', (312, 319))	('GI cancers', 'Disease', (309, 319))	('tumor', 'Disease', (534, 539))	('miR', 'Gene', (736, 739))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('tumor', 'Disease', 'MESH:D009369', (534, 539))	('DLBC', 'Disease', (722, 726))	('DNA methylation', 'biological_process', 'GO:0006306', ('634', '649'))	('TGF-beta', 'Gene', '7040', (666, 674))	('TGF-beta', 'Gene', '7040', (460, 468))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('DNA', 'cellular_component', 'GO:0005574', ('634', '637'))	('GI cancers', 'Disease', 'MESH:D009369', (309, 319))	('TGF-beta', 'Gene', '7040', (79, 87))	('cancers', 'Disease', (63, 70))	('Cancer', 'Phenotype', 'HP:0002664', (588, 594))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('methylation', 'Var', (638, 649))	('tumor', 'Phenotype', 'HP:0002664', (534, 539))	('cancers', 'Disease', 'MESH:D009369', (312, 319))	('TGF-beta', 'Gene', (666, 674))	('TGF-beta', 'Gene', (460, 468))	('TGF-beta', 'Gene', (79, 87))	('GI cancer', 'Phenotype', 'HP:0007378', (309, 318))	('deletion', 'Var', (654, 662))	('EMT', 'biological_process', 'GO:0001837', ('191', '194'))	('DNA methylation', 'Var', (634, 649))	('miR', 'Gene', '220972', (736, 739))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
121422	30268436	Although 39% of the cancers had genomic alterations in at least one of the TGF-beta pathway genes, GI cancers were particularly enriched for them.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GI cancers', 'Disease', (99, 109))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('GI cancers', 'Disease', 'MESH:D009369', (99, 109))	('genomic alterations', 'Var', (32, 51))	('TGF-beta', 'Gene', '7040', (75, 83))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('TGF-beta', 'Gene', (75, 83))	('GI cancer', 'Phenotype', 'HP:0007378', (99, 108))	('cancers', 'Disease', (20, 27))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
121423	30268436	GI cancers were most influenced by recurrent hotspot mutations in 6 genes, SMAD4, SMAD2, BMPR2, BMP5, TGFBR2, and ACVR2A.	('BMP5', 'Gene', (96, 100))	('SMAD2', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('BMP5', 'Gene', '653', (96, 100))	('BMPR2', 'Gene', (89, 94))	('GI cancers', 'Disease', (0, 10))	('SMAD4', 'Gene', (75, 80))	('TGFBR2', 'Gene', '7048', (102, 108))	('mutations', 'Var', (53, 62))	('hotspot', 'PosReg', (45, 52))	('ACVR2A', 'Gene', '92', (114, 120))	('GI cancer', 'Phenotype', 'HP:0007378', (0, 9))	('influenced', 'Reg', (21, 31))	('GI cancers', 'Disease', 'MESH:D009369', (0, 10))	('BMPR2', 'Gene', '659', (89, 94))	('ACVR2A', 'Gene', (114, 120))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('SMAD4', 'Gene', '4089', (75, 80))	('SMAD2', 'Gene', '4087', (82, 87))	('TGFBR2', 'Gene', (102, 108))
121424	30268436	The hotspot mutations in BMP5 and TGFBR2 had not been identified previously, and their function in GI cancer should be explored.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GI cancer', 'Disease', (99, 108))	('mutations', 'Var', (12, 21))	('TGFBR2', 'Gene', '7048', (34, 40))	('GI cancer', 'Disease', 'MESH:D009369', (99, 108))	('BMP5', 'Gene', (25, 29))	('GI cancer', 'Phenotype', 'HP:0007378', (99, 108))	('TGFBR2', 'Gene', (34, 40))	('BMP5', 'Gene', '653', (25, 29))
121439	30268436	We selected the list of core TGF-beta superfamily genes used in the paper by searching for the keyword "TGF-beta" in 4 databases: (i) BIOCARTA_TGFB_PATHWAY from GSEA (http://software.broadinstitute.org/gsea/msigdb/cards/BIOCARTA_TGFB_PATHWAY), (ii) KEGG_TGF_BETA_SIGNALING_PATHWAY from GSEA (http://software.broadinstitute.org/gsea/msigdb/cards/KEGG_TGF_BETA_SIGNALING_PATHWAY), (iii) GO_0007179 full gene set from BioMart, and (iv) subset of GO_0007179 (filtered by "experimental evidence") from AmiGo.	('core', 'cellular_component', 'GO:0019013', ('24', '28'))	('SIGNALING_PATHWAY', 'biological_process', 'GO:0007165', ('261', '278'))	('AmiGo', 'Gene', '57463', (497, 502))	('TGF-beta', 'Gene', (104, 112))	('AmiGo', 'Gene', (497, 502))	('TGF-beta', 'Gene', '7040', (29, 37))	('TGF-beta', 'Gene', (29, 37))	('SIGNALING_PATHWAY', 'biological_process', 'GO:0007165', ('357', '374'))	('TGF-beta', 'Gene', '7040', (104, 112))	('GO_0007179', 'Var', (385, 395))
121440	30268436	(ii) We then performed extensive literature searches and kept only those genes that satisfied any of the following conditions: (a) the gene had previously been implicated in cancer, or (b) the gene was involved in direct binding to and regulation of Smad function, or (c) the gene was phenotypically associated with the TGF-beta superfamily, where mutations or deletions of the gene had resulted in phenotypes similar to those from loss of function of the TGF-beta superfamily pathways.	('TGF-beta', 'Gene', '7040', (320, 328))	('binding', 'molecular_function', 'GO:0005488', ('221', '228'))	('TGF-beta', 'Gene', (456, 464))	('mutations', 'Var', (348, 357))	('implicated', 'Reg', (160, 170))	('TGF-beta', 'Gene', (320, 328))	('involved', 'Reg', (202, 210))	('associated', 'Reg', (300, 310))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('resulted', 'Reg', (387, 395))	('binding', 'Interaction', (221, 228))	('deletions', 'Var', (361, 370))	('TGF-beta', 'Gene', '7040', (456, 464))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('regulation', 'biological_process', 'GO:0065007', ('236', '246'))
121457	30268436	Copy-number alterations (CNA) were assessed as deviations in the tumor sample from the paired normal tissue sample, so they only reflected somatic changes.	('Copy-number alterations', 'Var', (0, 23))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
52234	30268436	This step realigns reads at sites that potentially harbor small insertions or deletions in either the tumor or the matched normal, to decrease the number of false positive single nucleotide variations caused by misaligned reads.	('false', 'biological_process', 'GO:0071878', ('157', '162'))	('insertions', 'Var', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('false', 'biological_process', 'GO:0071877', ('157', '162'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('deletions', 'Var', (78, 87))
121466	30268436	Firehose (http://www.broadinstitute.org/cancer/cga/Firehose) takes the BAM files for the tumor and patient- matched normal samples and performs analyses including quality control, local realignment, mutation calling, small insertion and deletion identification, rearrangement detection, coverage calculations and others as described briefly below.	('patient', 'Species', '9606', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('rearrangement', 'Var', (262, 275))	('cancer', 'Disease', (40, 46))	('mutation calling', 'Var', (199, 215))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cga', 'Gene', '1113', (47, 50))	('deletion', 'Var', (237, 245))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('cga', 'Gene', (47, 50))	('small insertion', 'Var', (217, 232))
121469	30268436	Each oncoprint visualizes and quantifies the somatic mutation and copy number events in 9,125 patients with 33 cancer types for each gene family in the pathway.	('patients', 'Species', '9606', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('copy number', 'Var', (66, 77))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
121470	30268436	The hotspot mutations are extracted from MC3 MAF file first programmatically for any hotspot site with more than nine counts and validated through a systematic mining in the cBioPortal.	('MC3', 'Gene', '4159', (41, 44))	('mutations', 'Var', (12, 21))	('MAF', 'Gene', '4094', (45, 48))	('MAF', 'Gene', (45, 48))	('MC3', 'Gene', (41, 44))
121471	30268436	For ACVR2A and SMAD4 hotspot mutations are mapped onto the respective protein structures (pdb IDs: 4ASX for ACVR2A and 1DD1 for SMAD4) using the UCSF chimera software.	('SMAD4', 'Gene', (15, 20))	('ACVR2A', 'Gene', (108, 114))	('ACVR2A and 1DD1', 'Gene', '92', (108, 123))	('SMAD4', 'Gene', (128, 133))	('ACVR2A', 'Gene', '92', (4, 10))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('mutations', 'Var', (29, 38))	('ACVR2A', 'Gene', '92', (108, 114))	('SMAD4', 'Gene', '4089', (15, 20))	('SMAD4', 'Gene', '4089', (128, 133))	('ACVR2A', 'Gene', (4, 10))
121481	30268436	Tumor types for which few tumors have been profiled and that have infrequently occurring copy number alterations, GISTIC may fail to identify rare but important somatic events.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('copy number alterations', 'Var', (89, 112))	('tumors', 'Disease', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
121482	30268436	As more copy number profiles become available through large-scale tumor sequencing efforts, the ability to detect these rare but significant events will increase.	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('copy number', 'Var', (8, 19))
121484	30268436	The genomic alteration frequencies for copy number gains or losses and mutations are extracted from the cBioPortal and programmatically form the MC3 MAF file.	('MC3', 'Gene', '4159', (145, 148))	('MC3', 'Gene', (145, 148))	('MAF', 'Gene', '4094', (149, 152))	('mutations', 'Var', (71, 80))	('losses', 'NegReg', (60, 66))	('MAF', 'Gene', (149, 152))	('copy number gains', 'Var', (39, 56))
121486	30268436	The samples with alterations in each core gene and wild type for all TGF-beta pathway genes are extracted from the MC3 MAF file.	('MAF', 'Gene', '4094', (119, 122))	('MAF', 'Gene', (119, 122))	('TGF-beta', 'Gene', (69, 77))	('core', 'cellular_component', 'GO:0019013', ('37', '41'))	('MC3', 'Gene', '4159', (115, 118))	('MC3', 'Gene', (115, 118))	('TGF-beta', 'Gene', '7040', (69, 77))	('alterations', 'Var', (17, 28))
121487	30268436	The median fold change of transcriptional changes are calculated as the ratio of expression of downstream genes among all core pathway gene mutated, amplified and deleted samples to expression levels in TGF-beta pathway wild type samples.	('TGF-beta', 'Gene', (203, 211))	('core', 'cellular_component', 'GO:0019013', ('122', '126'))	('deleted', 'Var', (163, 170))	('TGF-beta', 'Gene', '7040', (203, 211))	('expression', 'MPA', (81, 91))	('mutated', 'Var', (140, 147))
121491	30268436	The enrichment of genomic TGF-beta pathway genomic alterations in the GI cancers was statistically assessed using a one tailed Fisher's exact test, where the null hypothesis was the odds ratio of alterations in GI vs other cancers was not greater than 1.	('cancers', 'Disease', (223, 230))	('cancers', 'Disease', (73, 80))	('alterations', 'Var', (51, 62))	('GI cancer', 'Phenotype', 'HP:0007378', (70, 79))	('GI cancers', 'Disease', 'MESH:D009369', (70, 80))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('TGF-beta', 'Gene', '7040', (26, 34))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('GI cancers', 'Disease', (70, 80))	('TGF-beta', 'Gene', (26, 34))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
121492	30268436	The transcriptional outcome of GI cancers with TGF-beta pathway disruptions were quantified using the same method and downstream target gene list as we did in the analysis of transcriptional output from all cancers.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('GI cancer', 'Phenotype', 'HP:0007378', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('GI cancers', 'Disease', 'MESH:D009369', (31, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancers', 'Disease', (207, 214))	('disruptions', 'Var', (64, 75))	('TGF-beta', 'Gene', '7040', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('TGF-beta', 'Gene', (47, 55))	('cancers', 'Disease', (34, 41))	('GI cancers', 'Disease', (31, 41))
121516	30268436	We particularly focused on mRNA expression distribution of HMGA2, MMP9, collagens (COL1A1, COL1A2, COL3A1), TERT, FOXP3, CDH2 as the expression of these genes varied significantly between TGF-beta pathway mutated vs. wild type samples.	('mutated', 'Var', (205, 212))	('COL1A2', 'Gene', '1278', (91, 97))	('TERT', 'Gene', (108, 112))	('varied', 'Reg', (159, 165))	('TERT', 'Gene', '7015', (108, 112))	('CDH2', 'Gene', (121, 125))	('MMP9', 'molecular_function', 'GO:0004229', ('66', '70'))	('FOXP3', 'Gene', (114, 119))	('HMGA2', 'Gene', (59, 64))	('COL1A2', 'Gene', (91, 97))	('COL1A1', 'Gene', '1277', (83, 89))	('CDH2', 'Gene', '1000', (121, 125))	('COL3A1', 'Gene', '1281', (99, 105))	('TGF-beta', 'Gene', '7040', (188, 196))	('FOXP3', 'Gene', '50943', (114, 119))	('expression', 'MPA', (133, 143))	('COL1A1', 'Gene', (83, 89))	('MMP9', 'Gene', (66, 70))	('HMGA2', 'Gene', '8091', (59, 64))	('MMP9', 'Gene', '4318', (66, 70))	('TGF-beta', 'Gene', (188, 196))	('COL3A1', 'Gene', (99, 105))
121518	30268436	The resulting thresholds divided the cohorts into three groups as TGF-beta expression, TGF-beta mutant/high target expression, TGF-beta wt/high target expression and low target gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('177', '192'))	('TGF-beta', 'Gene', (87, 95))	('TGF-beta', 'Gene', (66, 74))	('TGF-beta', 'Gene', '7040', (127, 135))	('mutant/high', 'Var', (96, 107))	('TGF-beta', 'Gene', '7040', (87, 95))	('TGF-beta', 'Gene', (127, 135))	('TGF-beta', 'Gene', '7040', (66, 74))
121519	30268436	We merged the TGF-beta mutant/low target expression and TGF-beta wt/low expression cohorts as discriminating between these sets do not inform on the combined effect of TGF-beta mutations and target expression.	('TGF-beta', 'Gene', (168, 176))	('TGF-beta', 'Gene', '7040', (56, 64))	('TGF-beta', 'Gene', (14, 22))	('mutant/low', 'Var', (23, 33))	('mutant/low', 'NegReg', (23, 33))	('TGF-beta', 'Gene', (56, 64))	('TGF-beta', 'Gene', '7040', (14, 22))	('TGF-beta', 'Gene', '7040', (168, 176))
121535	30081681	Two of the primary areas of inquiry typically addressed in TCGA cancer type-specific studies involved: 1) the set of "significant" DNA-level alterations, which may involve mutations, copy number alterations, or gene fusions; and 2) the molecular subtypes of the disease, which could be defined in a number of ways and may involve different molecular types including mRNA, microRNA, DNA methylation, protein, and copy number alterations.	('mutations', 'Var', (172, 181))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('protein', 'cellular_component', 'GO:0003675', ('397', '404'))	('DNA', 'cellular_component', 'GO:0005574', ('129', '132'))	('DNA', 'cellular_component', 'GO:0005574', ('380', '383'))	('DNA methylation', 'biological_process', 'GO:0006306', ('380', '395'))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
121536	30081681	As most every gene may be found altered at the DNA level in at least one or two cases, algorithms may be used to identify recurrent and non-random patterns of mutation or copy alterations across a set of cancer cases.	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('copy alterations', 'Var', (171, 187))
121540	30081681	A large number of genes have been implicated in bladder cancer through mutation analysis of TCGA data, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signaling pathways.	('bladder cancer', 'Disease', (48, 62))	('TCGA data', 'Gene', (92, 101))	('signaling', 'biological_process', 'GO:0023052', ('196', '205'))	('mutation analysis', 'Var', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('implicated', 'Reg', (34, 44))	('cell-cycle regulation', 'biological_process', 'GO:0051726', ('140', '161'))	('chromatin', 'cellular_component', 'GO:0000785', ('163', '172'))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))	('regulation', 'biological_process', 'GO:0065007', ('173', '183'))
121541	30081681	Through DNA alterations, on the order of 70% of bladder cancer cases would harbor potential therapeutic targets, most of these involving either PI3K/AKT/mTOR or RTK/MAPK pathways.	('bladder cancer', 'Disease', (48, 62))	('RTK', 'Gene', '5979', (161, 164))	('alterations', 'Var', (12, 23))	('mTOR', 'Gene', (153, 157))	('AKT', 'Gene', (149, 152))	('mTOR', 'Gene', '2475', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('MAPK', 'molecular_function', 'GO:0004707', ('165', '169'))	('PI3K', 'molecular_function', 'GO:0016303', ('144', '148'))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))	('RTK', 'Gene', (161, 164))	('AKT', 'Gene', '207', (149, 152))
121542	30081681	Recently, for pathway members in ten selected pathways, gene-level alterations (involving copy-number alterations, mutations, fusions or epigenetic silencing) across the entire TCGA pan-cancer cohort (involving all 32 cancer types) were catalogued.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('copy-number alterations', 'Var', (90, 113))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('fusions', 'Var', (126, 133))	('epigenetic silencing', 'Var', (137, 157))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
121544	30081681	However, even genes with a low frequency of DNA alterations may be critical in individual cancer cases and have a cumulative effect on pathway-level alterations.	('effect', 'Reg', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('alterations', 'Var', (48, 59))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
121546	30081681	Different mutational processes often generate different combinations of mutation types, termed "signatures," and analysis of whole exome sequencing data can reveal the presence of these signatures within a particular cancer sample, potentially providing clues as to the specific processes at work in that cancer.	('mutational', 'Var', (10, 20))	('cancer', 'Disease', (305, 311))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
121547	30081681	In the most recent TCGA BLCA marker paper, the 412 bladder cancers cases analyzed could be separated into four major groups, each with a distinct mutational signature, including one associated with mutation of the DNA repair gene ERCC2 and two others associated with patterns of mutagenesis by APOBEC Cytidine Deaminases.	('APOBEC Cytidine', 'Chemical', 'MESH:D003562', (294, 309))	('ERCC2', 'Gene', (230, 235))	('associated', 'Reg', (182, 192))	('bladder cancers', 'Phenotype', 'HP:0009725', (51, 66))	('DNA', 'cellular_component', 'GO:0005574', ('214', '217'))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('APOBEC', 'cellular_component', 'GO:0030895', ('294', '300'))	('bladder cancers', 'Disease', 'MESH:D001749', (51, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('mutagenesis', 'biological_process', 'GO:0006280', ('279', '290'))	('ERCC2', 'Gene', '2068', (230, 235))	('DNA repair', 'biological_process', 'GO:0006281', ('214', '224'))	('bladder cancers', 'Disease', (51, 66))	('mutation', 'Var', (198, 206))
121548	30081681	APOBEC-related mutational signature, high mutational burden, and high neoantigen load were each associated with better patient survival.	('patient', 'Species', '9606', (119, 126))	('high', 'Var', (37, 41))	('mutational', 'Var', (15, 25))	('APOBEC-related', 'Gene', (0, 14))	('neoantigen load', 'MPA', (70, 85))	('mutational burden', 'MPA', (42, 59))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('better', 'PosReg', (112, 118))
121550	30081681	on the basis of mutations in specific genes or of the presence of mutational signatures), "phenotypic" subtyping may define disease subsets on the basis of gene expression or DNA methylation, which represent molecular states that, in principle, may be changeable or subject to contributions from non-cancer cellular components.	('gene expression', 'biological_process', 'GO:0010467', ('154', '169'))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('mutations', 'Var', (16, 25))	('DNA methylation', 'biological_process', 'GO:0006306', ('173', '188'))	('DNA', 'cellular_component', 'GO:0005574', ('173', '176'))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('cancer', 'Disease', (300, 306))
121551	30081681	In the initial TCGA BLCA marker paper of 131 cases, RNA expression analysis revealed four expression subtypes, including: a "luminal" subtype enriched for luminal breast and urothelial differentiation factors, a "luminal-papillary" subtype with luminal markers and enriched for cases with papillary morphology as well as FGFR3-related alterations, and a basal/squamous-like subtype with squamous histology and expression of epithelial lineage genes and stem/progenitor cytokeratins.	('FGFR3', 'Gene', (321, 326))	('papillary morphology', 'Phenotype', 'HP:0007482', (289, 309))	('FGFR', 'molecular_function', 'GO:0005007', ('317', '321'))	('epithelial lineage genes', 'Gene', (424, 448))	('alterations', 'Var', (335, 346))	('FGFR3', 'Gene', '2261', (321, 326))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))
121575	30081681	The mutations and gene fusions detected (including FGFR3 fusions, most notably FGFR3-TACC3) represent targetable pathways such as PI3K/AKT/mTOR pathway or receptor tyrosine kinases, and the relevant alterations as cataloged by TCGA may be incorporated into precision medicine approaches as applied to bladder cancer.	('FGFR3', 'Gene', '2261', (79, 84))	('PI3K', 'molecular_function', 'GO:0016303', ('130', '134'))	('TACC3', 'Gene', (85, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('mTOR', 'Gene', (139, 143))	('receptor tyrosine kinase', 'Gene', (155, 179))	('AKT', 'Gene', (135, 138))	('bladder cancer', 'Disease', 'MESH:D001749', (301, 315))	('bladder cancer', 'Disease', (301, 315))	('mTOR', 'Gene', '2475', (139, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (301, 315))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('AKT', 'Gene', '207', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('FGFR3', 'Gene', (51, 56))	('FGFR3', 'Gene', '2261', (51, 56))	('FGFR3', 'Gene', (79, 84))	('receptor tyrosine kinase', 'Gene', '5979', (155, 179))	('fusions', 'Var', (57, 64))	('TACC3', 'Gene', '10460', (85, 90))
121581	30081681	NCT02853305, NCT02807636, NCT02516241, NCT03036098) should shed light on candidate biomarkers of response, which might include PD-L1 expression and immune cell infiltration (which may be considered surrogate markers of the luminal-infiltrated and basal-squamous subtypes) as well as mutation burden and neoantigen load.	('immune cell infiltration', 'CPA', (148, 172))	('NCT02516241', 'Var', (26, 37))	('NCT02853305', 'Var', (0, 11))	('NCT02807636', 'Var', (13, 24))	('NCT02807636', 'Chemical', 'MESH:C079985', (13, 24))	('NCT03036098', 'Chemical', 'MESH:C079985', (39, 50))	('NCT03036098', 'Var', (39, 50))	('PD-L1', 'Gene', (127, 132))	('shed', 'Reg', (59, 63))	('PD-L1', 'Gene', '29126', (127, 132))
121582	30081681	In a recent phase 2 clinical trial of patients with metastatic bladder cancer treated with PD-L1 inhibitor atezolizumab (NCT02108652), increased levels of PD-L1 expression on immune cells and mutation load were each associated with increased response.	('bladder cancer', 'Disease', 'MESH:D001749', (63, 77))	('response', 'Disease', (242, 250))	('bladder cancer', 'Disease', (63, 77))	('PD-L1', 'Gene', '29126', (155, 160))	('PD-L1', 'Gene', (91, 96))	('mutation load', 'Var', (192, 205))	('bladder cancer', 'Phenotype', 'HP:0009725', (63, 77))	('increased', 'PosReg', (135, 144))	('PD-L1', 'Gene', '29126', (91, 96))	('increased', 'PosReg', (232, 241))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('patients', 'Species', '9606', (38, 46))	('PD-L1', 'Gene', (155, 160))
121583	30081681	Regarding FGFR3 DNA-level alterations (including mutations, fusions with TACC3, and/or amplification), enriched within the BLCA luminal-papillary subtype, a number of planned or ongoing phase 1 and phase 2 clinical trials aim to target the FGFR family in bladder cancer (e.g.	('FGFR3', 'Gene', '2261', (10, 15))	('mutations', 'Var', (49, 58))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('FGFR', 'Gene', (240, 244))	('fusions', 'Var', (60, 67))	('FGFR', 'Gene', '2261', (240, 244))	('FGFR', 'Gene', (10, 14))	('FGFR', 'Gene', '2261', (10, 14))	('FGFR', 'molecular_function', 'GO:0005007', ('10', '14'))	('FGFR3', 'Gene', (10, 15))	('TACC3', 'Gene', '10460', (73, 78))	('bladder cancer', 'Phenotype', 'HP:0009725', (255, 269))	('FGFR', 'molecular_function', 'GO:0005007', ('240', '244'))	('TACC3', 'Gene', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('bladder cancer', 'Disease', 'MESH:D001749', (255, 269))	('bladder cancer', 'Disease', (255, 269))
121584	30081681	NCT03123055, NCT02401542, NCT02365597, NCT02465060).	('NCT03123055', 'Var', (0, 11))	('NCT02365597', 'Chemical', 'MESH:C079985', (26, 37))	('NCT02465060', 'Var', (39, 50))	('NCT02365597', 'Var', (26, 37))	('NCT02401542', 'Var', (13, 24))
121585	30081681	ERCC2 mutation) with sensitivity to DNA damaging-based therapy such as cisplatin, which could also help inform clinical trial design.	('mutation', 'Var', (6, 14))	('ERCC2', 'Gene', '2068', (0, 5))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('cisplatin', 'Chemical', 'MESH:D002945', (71, 80))	('ERCC2', 'Gene', (0, 5))
121594	30081681	Genes shown to be functionally relevant in the laboratory setting could also be examined in TCGA to ascertain their relevance in the setting of human disease; for example, whether expression or alteration of a gene is associated with more aggressive disease or with molecular subtype, or whether two functionally-related genes also appear correlated in expression with each other across human cancer samples.	('cancer', 'Disease', (393, 399))	('human', 'Species', '9606', (387, 392))	('human', 'Species', '9606', (144, 149))	('aggressive disease', 'Disease', 'MESH:D001523', (239, 257))	('cancer', 'Phenotype', 'HP:0002664', (393, 399))	('expression', 'MPA', (180, 190))	('aggressive disease', 'Disease', (239, 257))	('associated', 'Reg', (218, 228))	('cancer', 'Disease', 'MESH:D009369', (393, 399))	('alteration', 'Var', (194, 204))
121600	30081681	The catalogue of DNA-level alterations in bladder cancer involves pathways such as PI3K/AKT/mTOR, receptor tyrosine kinase (RTK) signaling, cell cycle, and p53, and can greatly inform precision medicine approaches.	('cell cycle', 'biological_process', 'GO:0007049', ('140', '150'))	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('mTOR', 'Gene', '2475', (92, 96))	('AKT', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('receptor tyrosine kinase', 'Gene', '5979', (98, 122))	('alterations', 'Var', (27, 38))	('inform', 'Reg', (177, 183))	('AKT', 'Gene', '207', (88, 91))	('receptor tyrosine kinase', 'Gene', (98, 122))	('p53', 'Gene', '7157', (156, 159))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('cell cycle', 'CPA', (140, 150))	('RTK', 'Gene', (124, 127))	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('p53', 'Gene', (156, 159))	('signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('mTOR', 'Gene', (92, 96))	('RTK', 'Gene', '5979', (124, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (42, 56))	('bladder cancer', 'Disease', (42, 56))
121607	28662677	Preclinical and clinical evidence suggests that radiotherapy has a systemic anti-cancer immune effect and can increase the level of PD-L1 and tumor infiltrating lymphocytes in the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('increase', 'PosReg', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('level', 'MPA', (123, 128))	('PD-L1', 'Gene', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (142, 147))	('cancer', 'Disease', (81, 87))	('tumor', 'Disease', (180, 185))	('PD-L1', 'Gene', '29126', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('radiotherapy', 'Var', (48, 60))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
121724	28662677	Several pre-clinical and clinical evidence indicate that radiotherapy instigates a systemic anti-cancer immune effect.	('cancer', 'Disease', (97, 103))	('pre', 'molecular_function', 'GO:0003904', ('8', '11'))	('radiotherapy', 'Var', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
121894	26264044	It is a heterogeneous group of disorders and in systemic form, amyloid may infiltrate the retroperitoneal and pelvic soft tissues and undergo gradually progressive calcification over time with formation of soft tissue thickening, encasing the urinary tract and involving renal sinus.	('renal sinus', 'Disease', (271, 282))	('calcification', 'Disease', (164, 177))	('amyloid', 'Var', (63, 70))	('formation', 'biological_process', 'GO:0009058', ('193', '202'))	('renal sinus', 'Disease', 'MESH:D007674', (271, 282))	('calcification', 'Disease', 'MESH:D002114', (164, 177))	('undergo', 'Reg', (134, 141))
121912	33976291	An increase in the absolute quantity of tumor mutations and neoantigens has been associated with favorable response to checkpoint immunotherapy and has led to a tumor histology-agnostic regulatory drug approval.	('mutations', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', (161, 166))	('increase', 'PosReg', (3, 11))
121914	33976291	Thus, an individual patient's prognosis is likely to be influenced not only by the quantity of neoantigens, but by the presence of neoantigens that are most likely to result in an effective anti-tumor immune response.	('tumor', 'Disease', (195, 200))	('immune response', 'biological_process', 'GO:0006955', ('201', '216'))	('patient', 'Species', '9606', (20, 27))	('neoantigens', 'Var', (131, 142))	('presence', 'Var', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('influenced', 'Reg', (56, 66))	('result', 'Reg', (167, 173))
121919	33976291	TCR-facing amino acids that contain sequences resembling the unaltered human genome have been shown to modulate immunity by activating a tolerizing response.	('modulate', 'Reg', (103, 111))	('tolerizing', 'MPA', (137, 147))	('amino acids', 'Var', (11, 22))	('TCR', 'biological_process', 'GO:0006283', ('0', '3'))	('activating', 'Reg', (124, 134))	('TCR', 'cellular_component', 'GO:0042101', ('0', '3'))	('immunity', 'CPA', (112, 120))	('human', 'Species', '9606', (71, 76))
121925	33976291	We hypothesized that the presence of a mutation alone is not sufficient to generate an immunogenic neoepitope, but that significant differences must exist at the HLA- and/or TCR-interfaces of the neoepitope as compared to (1) the non-mutated form of the neoepitope, and (2) to other self-epitopes, in order to be recognized as non-self by the immune system.	('HLA', 'Gene', (162, 165))	('TCR', 'cellular_component', 'GO:0042101', ('174', '177'))	('mutation', 'Var', (39, 47))	('TCR', 'biological_process', 'GO:0006283', ('174', '177'))	('HLA', 'Gene', '3123', (162, 165))
121952	33976291	Therefore, most bladder cancer patients present a sufficiently high number of mutations and would be eligible for standard neoantigen-based vaccinations designed by Ancer.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('bladder cancer', 'Disease', 'MESH:D001749', (16, 30))	('bladder cancer', 'Disease', (16, 30))	('mutations', 'Var', (78, 87))	('patients', 'Species', '9606', (31, 39))	('bladder cancer', 'Phenotype', 'HP:0009725', (16, 30))
121969	33976291	The largest differential in median overall survival was obtained with the Ancer pipeline and was more than double the difference in median overall survival observed when stratifying patients using NetMHCpan (70 versus 34 months).	('NetMHCpan', 'Chemical', '-', (197, 206))	('overall', 'MPA', (35, 42))	('patients', 'Species', '9606', (182, 190))	('Ancer pipeline', 'Var', (74, 88))
122006	33976291	Mutations generating Treg neoepitopes, or neo-Tregitopes, may camouflage tumors from the immune system.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('Treg', 'Chemical', '-', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('camouflage', 'NegReg', (62, 72))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('Treg', 'Chemical', '-', (21, 25))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', (73, 79))
122019	33976291	Five-year survival classification of BLCA patients based on Ancer HLA I and HLA II neoepitope contents appeared again to be superior compared to classifications based on NetMHCpan neoepitope content or based on TMB (Fig.	('BLCA', 'Phenotype', 'HP:0009725', (37, 41))	('HLA', 'Gene', (76, 79))	('Ancer', 'Var', (60, 65))	('HLA', 'Gene', '3123', (66, 69))	('TMB', 'Chemical', '-', (211, 214))	('NetMHCpan', 'Chemical', '-', (170, 179))	('patients', 'Species', '9606', (42, 50))	('HLA', 'Gene', (66, 69))	('HLA', 'Gene', '3123', (76, 79))
122046	33976291	Mutated and normal matched sequences are then compared to identify tumor-specific neoepitopes that significantly differ from their normal matched counterparts at the HLA- and/or TCR-interfaces.	('HLA', 'Gene', (166, 169))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('TCR', 'cellular_component', 'GO:0042101', ('178', '181'))	('tumor', 'Disease', (67, 72))	('differ', 'Reg', (113, 119))	('Mutated', 'Var', (0, 7))	('TCR', 'biological_process', 'GO:0006283', ('178', '181'))	('HLA', 'Gene', '3123', (166, 169))
122052	33976291	As neoepitopes analyses are restricted to the HLA-A, HLA-B, and HLA-DBR1 genes within the Ancer pipeline, we applied the same restrictions when analyzing mutations with NetMHCpan and NetMHCIIpan for comparative purposes.	('NetMHCIIpan', 'Chemical', '-', (183, 194))	('HLA', 'Gene', (46, 49))	('HLA', 'Gene', '3123', (53, 56))	('HLA', 'Gene', '3123', (64, 67))	('HLA-A', 'Gene', '3105', (46, 51))	('DBR1', 'Gene', '51163', (68, 72))	('DBR1', 'Gene', (68, 72))	('HLA', 'Gene', (53, 56))	('HLA', 'Gene', (64, 67))	('HLA-B', 'Gene', '3106', (53, 58))	('HLA-B', 'Gene', (53, 58))	('NetMHCpan', 'Gene', (169, 178))	('mutations', 'Var', (154, 163))	('NetMHCpan', 'Chemical', '-', (169, 178))	('HLA-A', 'Gene', (46, 51))	('HLA', 'Gene', '3123', (46, 49))
122071	27283768	Mutations of KRAS, NRAS, BRAF, EGFR, and PIK3CA genes in urachal carcinoma: Occurence and prognostic significance Targeted therapy represents an attractive alternative for rare tumors such as urachal carcinoma (UrC).	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('NRAS', 'Gene', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('PIK3CA', 'Gene', '5290', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumors', 'Disease', (177, 183))	('EGFR', 'Gene', '1956', (31, 35))	('urachal carcinoma', 'Disease', (192, 209))	('UrC', 'Phenotype', 'HP:0012618', (211, 214))	('Mutations', 'Var', (0, 9))	('urachal carcinoma', 'Disease', 'MESH:C536475', (192, 209))	('urachal carcinoma', 'Phenotype', 'HP:0012618', (192, 209))	('urachal carcinoma', 'Disease', (57, 74))	('PIK3CA', 'Gene', (41, 47))	('NRAS', 'Gene', '4893', (19, 23))	('urachal carcinoma', 'Disease', 'MESH:C536475', (57, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('urachal carcinoma', 'Phenotype', 'HP:0012618', (57, 74))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('KRAS', 'Gene', '3845', (13, 17))	('EGFR', 'Gene', (31, 35))	('BRAF', 'Gene', '673', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('BRAF', 'Gene', (25, 29))	('KRAS', 'Gene', (13, 17))
122072	27283768	The aim of this study was to assess the mutations of the most commonly affected 5 genes in the targetable EGFR-pathway in UrC and comapre their frequencies to those of found in urothelial and colorectal cancer.	('colorectal cancer', 'Disease', (192, 209))	('EGFR', 'molecular_function', 'GO:0005006', ('106', '110'))	('mutations', 'Var', (40, 49))	('colorectal cancer', 'Disease', 'MESH:D015179', (192, 209))	('EGFR', 'Gene', '1956', (106, 110))	('UrC', 'Phenotype', 'HP:0012618', (122, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (192, 209))	('UrC', 'Disease', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('EGFR', 'Gene', (106, 110))
122079	27283768	The high occurence of EGFR-pathway mutations warrants the testing for KRAS and BRAF mutations when considering anti-EGFR therapy in UrC.	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('EGFR', 'Gene', '1956', (116, 120))	('KRAS', 'Gene', (70, 74))	('KRAS', 'Gene', '3845', (70, 74))	('UrC', 'Phenotype', 'HP:0012618', (132, 135))	('BRAF', 'Gene', '673', (79, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('116', '120'))	('EGFR', 'Gene', '1956', (22, 26))	('BRAF', 'Gene', (79, 83))	('EGFR', 'Gene', (116, 120))	('EGFR', 'Gene', (22, 26))	('mutations', 'Var', (35, 44))
122096	27283768	Mutated intracellular domain of EGFR is a therapeutic target in several malignancies including CRC as EGFR-inhibitors can silence mutation-activated EGFR signaling.	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('silence', 'NegReg', (122, 129))	('CRC', 'Disease', (95, 98))	('EGFR', 'Gene', '1956', (149, 153))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('malignancies', 'Disease', 'MESH:D009369', (72, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('EGFR', 'Gene', (32, 36))	('EGFR', 'Gene', (149, 153))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('malignancies', 'Disease', (72, 84))	('intracellular', 'cellular_component', 'GO:0005622', ('8', '21'))	('EGFR', 'Gene', '1956', (102, 106))	('Mutated', 'Var', (0, 7))	('EGFR', 'Gene', (102, 106))
122098	27283768	A number of mutations of these downstream pathways are able to impair anti-EGFR treatment.	('mutations', 'Var', (12, 21))	('impair', 'NegReg', (63, 69))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('EGFR', 'Gene', '1956', (75, 79))	('men', 'Species', '9606', (85, 88))	('EGFR', 'Gene', (75, 79))
122099	27283768	Therefore, mutation analyses of the EGFR-pathway are widely used for guiding treatment decisions.	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('EGFR', 'Gene', (36, 40))	('EGFR', 'Gene', '1956', (36, 40))	('mutation', 'Var', (11, 19))	('men', 'Species', '9606', (82, 85))
122100	27283768	The prevalence and prognostic significance of the mutations in genes of the EGFR pathway in UrC remain poorly understood.	('UrC', 'Phenotype', 'HP:0012618', (92, 95))	('mutations', 'Var', (50, 59))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('76', '80'))	('EGFR', 'Gene', (76, 80))	('UrC', 'Disease', (92, 95))
122106	27283768	KRAS was the most frequently affected gene with 6 mutations (6/22; 27%), followed by BRAF with 4 mutations (4/22; 18%) and NRAS with one case (1/22; 5%) (Tables 1, 2).	('affected', 'Reg', (29, 37))	('mutations', 'Var', (50, 59))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('NRAS', 'Gene', (123, 127))	('NRAS', 'Gene', '4893', (123, 127))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
122107	27283768	In one case co-occurrence of an NRAS and a BRAF mutation was observed.	('NRAS', 'Gene', (32, 36))	('BRAF', 'Gene', '673', (43, 47))	('NRAS', 'Gene', '4893', (32, 36))	('BRAF', 'Gene', (43, 47))	('mutation', 'Var', (48, 56))
122118	27283768	reported cetuximab treatment to be effective for eight months in a patient with metastatic UrC bearing EGFR amplification and wild-type KRAS.	('amplification', 'Var', (108, 121))	('men', 'Species', '9606', (24, 27))	('metastatic UrC bearing', 'Disease', (80, 102))	('KRAS', 'Gene', '3845', (136, 140))	('EGFR', 'Gene', '1956', (103, 107))	('EGFR', 'Gene', (103, 107))	('cetuximab', 'Chemical', 'MESH:D000068818', (9, 18))	('KRAS', 'Gene', (136, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('UrC', 'Phenotype', 'HP:0012618', (91, 94))	('patient', 'Species', '9606', (67, 74))
122120	27283768	Primary resistance to EGFR inhibitors is mostly related to the presence of wild-type EGFR, as these tumors often harbor mutations in other genes downstream of EGFR such as KRAS and BRAF.	('KRAS', 'Gene', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('EGFR', 'Gene', (85, 89))	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('KRAS', 'Gene', '3845', (172, 176))	('EGFR', 'Gene', '1956', (159, 163))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('EGFR', 'molecular_function', 'GO:0005006', ('159', '163'))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('BRAF', 'Gene', (181, 185))	('EGFR', 'Gene', (159, 163))	('BRAF', 'Gene', '673', (181, 185))	('EGFR', 'Gene', '1956', (22, 26))	('mutations', 'Var', (120, 129))	('EGFR', 'Gene', '1956', (85, 89))	('EGFR', 'Gene', (22, 26))
122121	27283768	EGFR mutations were found to be absent in urothelial and primary bladder ADC and was reported to be also rare in CRC.	('EGFR', 'Gene', (0, 4))	('urothelial', 'Disease', (42, 52))	('mutations', 'Var', (5, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('absent', 'NegReg', (32, 38))	('EGFR', 'Gene', '1956', (0, 4))
122126	27283768	In contrast to wild-type RAS proteins, which are deactivated after a short time, mutated RAS proteins cause continuous activation of RAS signaling pathways also without the upstream stimulation of EGFR or HER1 receptor.	('HER1', 'Gene', '1956', (205, 209))	('RAS signaling pathways', 'Pathway', (133, 155))	('mutated', 'Var', (81, 88))	('activation', 'PosReg', (119, 129))	('EGFR', 'Gene', '1956', (197, 201))	('signaling', 'biological_process', 'GO:0023052', ('137', '146'))	('EGFR', 'molecular_function', 'GO:0005006', ('197', '201'))	('EGFR', 'Gene', (197, 201))	('RAS', 'Gene', (89, 92))	('HER1', 'Gene', (205, 209))
122127	27283768	A somatic missense mutation in codon 12 of the KRAS gene, results in a single amino acid substitution (Gly12Val) representing the most frequently occurring mutation in CRC.	('CRC', 'Gene', (168, 171))	('Gly12Val', 'SUBSTITUTION', 'None', (103, 111))	('KRAS', 'Gene', (47, 51))	('Gly12Val', 'Var', (103, 111))	('KRAS', 'Gene', '3845', (47, 51))
122129	27283768	These KRAS mutant cases were unlikely to benefit from anti-EGFR therapy.	('KRAS', 'Gene', '3845', (6, 10))	('mutant', 'Var', (11, 17))	('EGFR', 'Gene', (59, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('KRAS', 'Gene', (6, 10))	('EGFR', 'Gene', '1956', (59, 63))
122130	27283768	In contrast to CRC, KRAS mutations are rare in urothelial carcinomas and primary bladder ADCs (~5% and ~10% respectively).	('KRAS', 'Gene', '3845', (20, 24))	('primary bladder ADCs', 'Disease', 'MESH:D001749', (73, 93))	('mutations', 'Var', (25, 34))	('urothelial carcinomas', 'Disease', (47, 68))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (47, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('primary bladder ADCs', 'Disease', (73, 93))	('KRAS', 'Gene', (20, 24))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
122132	27283768	found mutation in 1 of 5 UrC patients (20%).	('patients', 'Species', '9606', (29, 37))	('mutation', 'Var', (6, 14))	('UrC', 'Phenotype', 'HP:0012618', (25, 28))	('UrC', 'Disease', (25, 28))
122134	27283768	Based on these, KRAS mutations - similar to CRC but in contrast to urothelial carcinomas - seems to be frequent in UrC.	('urothelial carcinomas', 'Disease', 'MESH:D014526', (67, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('UrC', 'Disease', (115, 118))	('UrC', 'Phenotype', 'HP:0012618', (115, 118))	('KRAS', 'Gene', (16, 20))	('KRAS', 'Gene', '3845', (16, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('frequent', 'Reg', (103, 111))	('urothelial carcinomas', 'Disease', (67, 88))	('mutations', 'Var', (21, 30))
122135	27283768	However, 3 of the 6 KRAS mutations we observed were located at codons 61 and 146 which are rarely (< 5%) affected in CRC.	('KRAS', 'Gene', '3845', (20, 24))	('mutations', 'Var', (25, 34))	('KRAS', 'Gene', (20, 24))
122137	27283768	In these cases, mutated BRAF gene - which is present in ~10% of cases - can affect response to anti-EGFR treatment.	('affect', 'Reg', (76, 82))	('EGFR', 'Gene', '1956', (100, 104))	('men', 'Species', '9606', (110, 113))	('EGFR', 'Gene', (100, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('mutated', 'Var', (16, 23))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('response', 'MPA', (83, 91))
122138	27283768	BRAF mutations were found to be absent in urothelial carcinoma, while, to best of our knowledge, there are no available data on the occurrence of its mutations in primary ADC of the bladder.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (42, 62))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('BRAF', 'Gene', (0, 4))	('primary ADC of the bladder', 'Disease', (163, 189))	('urothelial carcinoma', 'Disease', (42, 62))
122139	27283768	In the present analysis, we found BRAF mutations in 4 of 22 (18%) UrC cases, which frequency seems to be similar to that of in CRC.	('UrC', 'Disease', (66, 69))	('UrC', 'Phenotype', 'HP:0012618', (66, 69))	('mutations', 'Var', (39, 48))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))
122140	27283768	In contrast, others found no BRAF mutations in UrC.	('BRAF', 'Gene', '673', (29, 33))	('mutations', 'Var', (34, 43))	('UrC', 'Phenotype', 'HP:0012618', (47, 50))	('BRAF', 'Gene', (29, 33))
122141	27283768	Low case number of that study together with the relative low abundance of BRAF mutation might be the reason for this discrepancy.	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('mutation', 'Var', (79, 87))
122143	27283768	Our analysis revealed one single UrC with NRAS mutation (1/22, 5%), suggesting, that these mutations are rare also in UrC similar to those of CRC and urothelial carcinoma (5% and 1% respectively).	('NRAS', 'Gene', '4893', (42, 46))	('mutation', 'Var', (47, 55))	('urothelial carcinoma', 'Disease', (150, 170))	('UrC', 'Phenotype', 'HP:0012618', (118, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('UrC', 'Phenotype', 'HP:0012618', (33, 36))	('NRAS', 'Gene', (42, 46))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (150, 170))	('CRC', 'Disease', (142, 145))
122145	27283768	PIK3CA mutations in CRC are associated with clinical resistance to EGFR-targeted monoclonal antibodies.	('associated', 'Reg', (28, 38))	('clinical resistance', 'MPA', (44, 63))	('PIK3CA', 'Gene', (0, 6))	('clinical', 'Species', '191496', (44, 52))	('EGFR', 'molecular_function', 'GO:0005006', ('67', '71'))	('PIK3CA', 'Gene', '5290', (0, 6))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('CRC', 'Gene', (20, 23))	('mutations', 'Var', (7, 16))
122148	27283768	In accordance, PIK3CA mutant CRCs were found to benefit from adjuvant aspirin therapy in contrast to patients with wild-type PIK3CA gene.	('patients', 'Species', '9606', (101, 109))	('PIK3CA', 'Gene', '5290', (15, 21))	('PIK3CA', 'Gene', (125, 131))	('benefit', 'PosReg', (48, 55))	('aspirin', 'Chemical', 'MESH:D001241', (70, 77))	('mutant', 'Var', (22, 28))	('PIK3CA', 'Gene', '5290', (125, 131))	('PIK3CA', 'Gene', (15, 21))
122149	27283768	We found no PIK3CA mutations in any of the analyzed UrCs.	('UrC', 'Phenotype', 'HP:0012618', (52, 55))	('PIK3CA', 'Gene', '5290', (12, 18))	('mutations', 'Var', (19, 28))	('PIK3CA', 'Gene', (12, 18))
122150	27283768	In contrast, both urothelial and colorectal cancers were reported to bear PIK3CA mutations with a probability of 15-20% (Tables 2, 3).	('colorectal cancers', 'Disease', (33, 51))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('PIK3CA', 'Gene', '5290', (74, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (33, 50))	('urothelial', 'Disease', (18, 28))	('mutations', 'Var', (81, 90))	('colorectal cancers', 'Disease', 'MESH:D015179', (33, 51))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('PIK3CA', 'Gene', (74, 80))
122153	27283768	recently analyzed KRAS and BRAF mutations in 7 cases of UrC and found a better survival in patients with mutated KRAS gene.	('patients', 'Species', '9606', (91, 99))	('KRAS', 'Gene', (18, 22))	('KRAS', 'Gene', '3845', (18, 22))	('UrC', 'Phenotype', 'HP:0012618', (56, 59))	('better', 'PosReg', (72, 78))	('BRAF', 'Gene', '673', (27, 31))	('KRAS', 'Gene', (113, 117))	('mutated', 'Var', (105, 112))	('BRAF', 'Gene', (27, 31))	('KRAS', 'Gene', '3845', (113, 117))	('survival', 'MPA', (79, 87))
122154	27283768	This observation, however, is in contrast to those made in CRC and lung adenocarcinoma where KRAS mutations were associated with adverse prognosis.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('KRAS', 'Gene', (93, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('KRAS', 'Gene', '3845', (93, 97))	('mutations', 'Var', (98, 107))	('lung adenocarcinoma', 'Disease', (67, 86))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (67, 86))
122157	27283768	identified recurrent mutations in NF1, APC and RNF43 genes suggesting the involvement of MAPK and Wnt/beta-catenin pathways in UrC formation.	('UrC formation', 'Disease', (127, 140))	('APC', 'Disease', 'MESH:D011125', (39, 42))	('APC', 'Disease', (39, 42))	('beta-catenin', 'Gene', '1499', (102, 114))	('UrC', 'Phenotype', 'HP:0012618', (127, 130))	('formation', 'biological_process', 'GO:0009058', ('131', '140'))	('RNF43', 'Gene', '54894', (47, 52))	('APC', 'cellular_component', 'GO:0005680', ('39', '42'))	('RNF43', 'Gene', (47, 52))	('involvement', 'Reg', (74, 85))	('men', 'Species', '9606', (81, 84))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('NF1', 'Gene', (34, 37))	('beta-catenin', 'Gene', (102, 114))	('NF1', 'Gene', '4763', (34, 37))	('mutations', 'Var', (21, 30))
122160	27283768	On the one hand, KRAS and BRAF mutations occurred in UrC with similar frequencies as in CRC, in contrast to urothelial carcinoma, where both of these mutations are infrequent.	('urothelial carcinoma', 'Disease', (108, 128))	('mutations', 'Var', (31, 40))	('BRAF', 'Gene', '673', (26, 30))	('BRAF', 'Gene', (26, 30))	('occurred', 'Reg', (41, 49))	('CRC', 'Disease', (88, 91))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (108, 128))	('UrC', 'Phenotype', 'HP:0012618', (53, 56))	('KRAS', 'Gene', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('UrC', 'Disease', (53, 56))	('KRAS', 'Gene', '3845', (17, 21))
122165	27283768	Furthermore, our data suggest that patients with metastatic UrC, who are being considered for an anti-EGFR antibody therapy, should be tested for the presence of KRAS and BRAF mutations prior to therapy.	('antibody', 'molecular_function', 'GO:0003823', ('107', '115'))	('KRAS', 'Gene', (162, 166))	('mutations', 'Var', (176, 185))	('metastatic UrC', 'Disease', (49, 63))	('KRAS', 'Gene', '3845', (162, 166))	('BRAF', 'Gene', '673', (171, 175))	('antibody', 'cellular_component', 'GO:0042571', ('107', '115'))	('BRAF', 'Gene', (171, 175))	('UrC', 'Phenotype', 'HP:0012618', (60, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('patients', 'Species', '9606', (35, 43))	('antibody', 'cellular_component', 'GO:0019815', ('107', '115'))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('tested', 'Reg', (135, 141))	('antibody', 'cellular_component', 'GO:0019814', ('107', '115'))
122183	27283768	Pyrosequencing primers were designed to test codons 12, 13, 59, 61 and 146 for KRAS, codons 12, 13, 59, 61, 117 and 146 for NRAS, codon 600 for BRAF, codons 719, 744-750, 768, 790 and 858-861 for EGFR and codons 542, 545 and 1047 for PIK3CA.	('EGFR', 'Gene', (196, 200))	('EGFR', 'molecular_function', 'GO:0005006', ('196', '200'))	('NRAS', 'Gene', '4893', (124, 128))	('KRAS', 'Gene', '3845', (79, 83))	('codon 600', 'Var', (130, 139))	('codons', 'Var', (150, 156))	('PIK3CA', 'Gene', (234, 240))	('BRAF', 'Gene', '673', (144, 148))	('PIK3CA', 'Gene', '5290', (234, 240))	('BRAF', 'Gene', (144, 148))	('EGFR', 'Gene', '1956', (196, 200))	('KRAS', 'Gene', (79, 83))	('NRAS', 'Gene', (124, 128))
122267	25412849	Importantly, the ICUD makes a general recommendation in favor of reporting variant morphology for urothelial carcinoma, especially as recent studies suggest it may be underreported in routine practice.	('variant', 'Var', (75, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('urothelial carcinoma', 'Disease', (98, 118))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (98, 118))
122293	25412849	Although other variant morphologies have been reported to be associated with aggressive course, especially high-stage disease, micropapillary urothelial carcinoma remains the variant where the prognostic implications are more clearly defined and where therapeutic, and, recently, molecular considerations are most salient.	('micropapillary urothelial carcinoma', 'Disease', 'MESH:D014526', (127, 162))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (132, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('variant', 'Var', (15, 22))	('micropapillary urothelial carcinoma', 'Disease', (127, 162))	('associated', 'Reg', (61, 71))	('high-stage disease', 'Disease', (107, 125))
122300	25412849	Most promising for this disease, going forward, are recent molecular observations, which suggest a high prevalence of lesions involving ERBB2, the HER2 oncogene, which may be amplified or mutated, providing a therapeutically tractable target.	('ERBB2', 'Gene', '2064', (136, 141))	('ERBB2', 'Gene', (136, 141))	('HER2', 'Gene', '2064', (147, 151))	('HER2', 'Gene', (147, 151))	('lesions', 'Var', (118, 125))
122320	25412849	Distinctive molecular features: ERBB2 mutation and amplification.	('ERBB2', 'Gene', (32, 37))	('mutation', 'Var', (38, 46))	('amplification', 'MPA', (51, 64))	('ERBB2', 'Gene', '2064', (32, 37))
122326	26816829	Similarly to UCB, smoking increases the risk of UTUC and worsens its prognosis, whereas aristolochic acid (AA) exposure and mismatch repair genes abnormality are UTUC specific risk factors.	('UTUC', 'Disease', (48, 52))	('prognosis', 'MPA', (69, 78))	('UCB', 'Phenotype', 'HP:0006740', (13, 16))	('UCB', 'Chemical', '-', (13, 16))	('worsens', 'NegReg', (57, 64))	('abnormality', 'Var', (146, 157))	('mismatch repair genes', 'Gene', (124, 145))	('mismatch repair', 'biological_process', 'GO:0006298', ('124', '139'))	('increases', 'PosReg', (26, 35))	('aristolochic acid', 'Chemical', 'MESH:C000228', (88, 105))
122348	26816829	Alterations of mismatch repair genes, responsible for HNPCC, could also be involved in sporadic UTUC as a potential initiating event.	('involved', 'Reg', (75, 83))	('Alterations', 'Var', (0, 11))	('mismatch repair', 'biological_process', 'GO:0006298', ('15', '30'))	('HNPCC', 'Phenotype', 'HP:0006716', (54, 59))	('sporadic UTUC', 'Disease', (87, 100))	('HNPCC', 'Disease', 'None', (54, 59))	('HNPCC', 'Disease', (54, 59))	('mismatch repair genes', 'Gene', (15, 36))
122353	26816829	reported in 475 patients treated with RNU that Ki-67 was an independent prognosticator of recurrence free survival (RFS) and CSS for high grade tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('RNU', 'Chemical', '-', (38, 41))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('recurrence free', 'Disease', (90, 105))	('patients', 'Species', '9606', (16, 24))	('CSS', 'Chemical', '-', (125, 128))	('RFS', 'Chemical', '-', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('Ki-67', 'Var', (47, 52))
122354	26816829	similarly demonstrated that both PI3K and cyclin D, two mTOR biomarkers, were associated with adverse pathologic results and worse oncological outcomes in a cohort of 620 patients who underwent RNU or partial ureterectomy.	('associated', 'Reg', (78, 88))	('mTOR', 'Gene', (56, 60))	('mTOR', 'Gene', '2475', (56, 60))	('RNU', 'Chemical', '-', (194, 197))	('patients', 'Species', '9606', (171, 179))	('cyclin', 'molecular_function', 'GO:0016538', ('42', '48'))	('PI3K', 'Var', (33, 37))	('cyclin D', 'Protein', (42, 50))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))
122399	26816829	In high risk UTUC (pT3N0, pT4N0 and/or N+ and/or M+), positive margins have been identified as an independent prognostic factor for CSS and OS.	('pT3', 'Gene', (19, 22))	('pT4N0', 'Var', (26, 31))	('M+', 'Var', (49, 51))	('CSS', 'Chemical', '-', (132, 135))	('OS', 'Chemical', '-', (140, 142))	('CSS', 'Disease', (132, 135))	('pT3', 'Gene', '7694', (19, 22))
122429	26816829	demonstrated, in a prospective multicentre randomized study, that a single post-operative intravesical dose of MMC after RNU decreased the relative risk of bladder tumor by 40% within the first year.	('bladder tumor', 'Disease', 'MESH:D001749', (156, 169))	('RNU', 'Chemical', '-', (121, 124))	('MMC', 'Var', (111, 114))	('decreased', 'NegReg', (125, 134))	('bladder tumor', 'Phenotype', 'HP:0009725', (156, 169))	('bladder tumor', 'Disease', (156, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('MMC', 'Chemical', 'MESH:D016685', (111, 114))
122470	25501392	By illuminating these rare combinations of mutations, Pan-Cancer network analyses provide a roadmap to investigate new diagnostic and therapeutic opportunities across cancer types.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
122475	25501392	Clustering of mutations on known pathways is illustrated in many cancer sequencing papers, but typically without a measure of statistical significance.	('cancer', 'Disease', (65, 71))	('mutations', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
122476	25501392	This approach combines: (1) a new algorithm, HotNet2, for identification of mutated subnetworks in a genome-scale interaction network; (2) a large TCGA Pan-Cancer dataset of somatic single nucleotide variants, small indels, and copy number aberrations measured in 3,281 samples from 12 cancer types.	('Cancer', 'Phenotype', 'HP:0002664', (156, 162))	('copy number aberrations', 'Disease', 'MESH:D002869', (228, 251))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('copy number aberrations', 'Disease', (228, 251))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cancer', 'Disease', (286, 292))	('single nucleotide variants', 'Var', (182, 208))
122480	25501392	clustering in protein sequence/structure or an excess of inactivating mutations) that lend additional support for their role in cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('inactivating mutations', 'Var', (57, 79))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('cancer', 'Disease', (128, 134))
122483	25501392	We assembled a TCGA Pan-Cancer dataset of exome sequencing, array copy number, and RNA-seq data from 3,281 samples from 12 cancer types, analyzing single nucleotide variants (SNVs), small indels, and copy number aberrations (CNAs) in 19,424 transcripts (Figure 1a and Supplementary Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('single nucleotide variants', 'Var', (147, 173))	('copy number aberrations', 'Disease', 'MESH:D002869', (200, 223))	('RNA', 'cellular_component', 'GO:0005562', ('83', '86'))	('small indels', 'Var', (182, 194))	('Cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('copy number aberrations', 'Disease', (200, 223))	('cancer', 'Disease', (123, 129))
122491	25501392	The MHC Class I subnetwork (Supplementary Figure 12) is an example of the ability of HotNet2 ability to identify rarely mutated cancer genes; all of the genes in the subnetwork are mutated in fewer than 35 samples (1.1%), yet four of the five genes have recently been proposed as novel cancer genes.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('mutated', 'Var', (181, 188))	('cancer', 'Disease', (286, 292))	('cancer', 'Disease', (128, 134))
122492	25501392	Many of the subnetworks exhibit a significant enrichment for mutations in a subset of cancer types, including many previously unreported associations (Supplementary Tables 6-18).	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (61, 70))	('cancer', 'Disease', (86, 92))
122493	25501392	We also identify genes within these subnetworks enriched for mutations in particular cancer types.	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (61, 70))
122498	25501392	Consistent with this model, we find that 4 pairs of subnetworks, including TP53 and NOTCH signaling, TP53 and RTK signaling, PI3K signaling and cohesin complex, and PI3K and ASCOM complex exhibit significant co-occurrence (P < 0.05, multiple hypotheses corrected) across the Pan-Cancer cohort (Figure 2b) or in individual cancer types (Figure 2c).	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('signaling', 'biological_process', 'GO:0023052', ('90', '99'))	('PI3K', 'molecular_function', 'GO:0016303', ('165', '169'))	('NOTCH signaling', 'MPA', (84, 99))	('PI3K', 'Var', (165, 169))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('PI3K', 'molecular_function', 'GO:0016303', ('125', '129'))	('co-occurrence', 'Reg', (208, 221))	('cancer', 'Disease', (322, 328))	('TP53', 'Gene', '7157', (101, 105))	('cohesin complex', 'cellular_component', 'GO:0008278', ('144', '159'))	('Cancer', 'Phenotype', 'HP:0002664', (279, 285))	('TP53', 'Gene', (101, 105))	('PI3K signaling', 'biological_process', 'GO:0014065', ('125', '139'))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('TP53', 'Gene', (75, 79))	('TP53', 'Gene', '7157', (75, 79))	('RTK', 'MPA', (110, 113))
122500	25501392	This exclusivity was largely due to LUAD samples with mutually exclusive EGFR and KEAP1 mutations (Supplementary Figure 15).	('KEAP1', 'Gene', (82, 87))	('EGFR', 'Gene', '1956', (73, 77))	('mutations', 'Var', (88, 97))	('EGFR', 'Gene', (73, 77))	('KEAP1', 'Gene', '9817', (82, 87))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))
122501	25501392	This observation is consistent with reports of exclusivity between EGFR mutations and NFE2L2 expression in LUAD and also that NFE2L2 expression is downstream of EGFR signaling.	('mutations', 'Var', (72, 81))	('NFE2L2', 'Gene', '4780', (126, 132))	('EGFR', 'Gene', (161, 165))	('NFE2L2', 'Gene', (126, 132))	('NFE2L2', 'Gene', '4780', (86, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('67', '71'))	('signaling', 'biological_process', 'GO:0023052', ('166', '175'))	('NFE2L2', 'Gene', (86, 92))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('EGFR', 'Gene', '1956', (161, 165))	('EGFR', 'molecular_function', 'GO:0005006', ('161', '165'))
122509	25501392	CUL9 sequesters p53 in the cytoplasm, and we find a cluster of 45 missense mutations (P = 1.32 x 10-8) as well as a cluster in protein structure (FDR = 0.025).	('p53', 'Gene', (16, 19))	('missense mutations', 'Var', (66, 84))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('p53', 'Gene', '7157', (16, 19))	('CUL9', 'Gene', '23113', (0, 4))	('cytoplasm', 'cellular_component', 'GO:0005737', ('27', '36'))	('CUL9', 'Gene', (0, 4))
122512	25501392	We find three independent signals of CHD8 inactivation across samples: CHD8 is deleted in 9 samples in a focal peak from GISTIC; 18/58 (31%) of its mutations as inactivating; and has a wide cluster of missense mutations (P = 6.37 x 10-5).	('CHD8', 'Gene', '57680', (37, 41))	('CHD8', 'Gene', '57680', (71, 75))	('mutations', 'Var', (148, 157))	('CHD8', 'Gene', (37, 41))	('CHD8', 'Gene', (71, 75))	('missense mutations', 'Var', (201, 219))
122513	25501392	In the NOTCH subnetwork, we find rare mutations in JAG1 and DLL1, which interact with the NOTCH receptors and have some reports of a role in cancer.	('JAG1', 'Gene', '182', (51, 55))	('JAG1', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (38, 47))	('DLL1', 'Gene', '28514', (60, 64))	('DLL1', 'Gene', (60, 64))	('role', 'Reg', (133, 137))	('interact', 'Reg', (72, 80))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
122514	25501392	Moreover, 11/24 mutations in JAG1 are inactivating.	('JAG1', 'Gene', (29, 33))	('mutations', 'Var', (16, 25))	('JAG1', 'Gene', '182', (29, 33))	('inactivating', 'Var', (38, 50))
122515	25501392	The NOTCH subnetwork also includes SHPRH, which has a significant (P < 8x10-5) cluster of missense mutations (Supplementary Figure 18).	('missense mutations', 'Var', (90, 108))	('SHPRH', 'Gene', (35, 40))	('SHPRH', 'Gene', '257218', (35, 40))
122516	25501392	Mutations in this complex have previously been reported in several cancers, including TCGA samples.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('TCGA samples', 'Disease', (86, 98))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('reported', 'Reg', (47, 55))
122517	25501392	Our HotNet2 Pan-Cancer analysis demonstrates the prevalence of mutations in SWI/SNF: at least 1.5% of the samples from each of the 12 cancer types contain a mutation in this subnetwork.	('mutations', 'Var', (63, 72))	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mutation', 'Var', (157, 165))	('SWI/SNF', 'Gene', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
122518	25501392	KIRC (P<10-15), UCEC (P=7x10-10), and BLCA (P=1.8x10-8) were enriched for mutations in this subnetwork and several genes were enriched for mutations in specific cancer types including PBRM1 in KIRC (P<10-15) and ARID1A in both BLCA (P=4.8x10-8) and UCEC (P<10-15).	('PBRM1', 'Gene', '55193', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('mutations', 'Var', (139, 148))	('ARID1A', 'Gene', '8289', (212, 218))	('ARID1A', 'Gene', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('PBRM1', 'Gene', (184, 189))
122519	25501392	The subnetwork also contains ARID1B, which is reported to have somatic mutations in juvenile neuroblastoma and germline mutations in Coffin-Siris syndrome.	('neuroblastoma', 'Disease', (93, 106))	('Coffin-Siris syndrome', 'Disease', (133, 154))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (133, 154))	('neuroblastoma', 'Phenotype', 'HP:0003006', (93, 106))	('ARID1B', 'Gene', (29, 35))	('mutations', 'Var', (71, 80))	('ARID1B', 'Gene', '57492', (29, 35))	('neuroblastoma', 'Disease', 'MESH:D009447', (93, 106))
122521	25501392	ADNP mutations have not previously been reported in cancer and were not considered significant by the three individual gene-scoring methods.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ADNP', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('ADNP', 'Gene', '23394', (0, 4))
122522	25501392	However, ADNP has a known interaction with SWI/SNF and protects against oxidative stress in neuronal cells, suggesting that in rare cases ADNP mutations contribute to tumorigenesis.	('ADNP', 'Gene', '23394', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('ADNP', 'Gene', '23394', (9, 13))	('ADNP', 'Gene', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('ADNP', 'Gene', (9, 13))	('oxidative stress', 'Phenotype', 'HP:0025464', (72, 88))	('tumor', 'Disease', (167, 172))	('mutations', 'Var', (143, 152))	('contribute', 'Reg', (153, 163))
122523	25501392	Thus, HotNet2 analyses broaden the view of mutations in SWI/SNF to additional cancer types and additional interacting proteins.	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('SWI/SNF', 'Gene', (56, 63))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
122527	25501392	This subnetwork is mutated in at least 6 samples from each cancer type, demonstrating the breadth of mutations in the BAP1 complex.	('mutations', 'Var', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('BAP1', 'Gene', '8314', (118, 122))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', (59, 65))	('BAP1', 'Gene', (118, 122))
122529	25501392	Consistent with Pena-Llopis et al., we find that mutations in the BAP1 gene are mutually exclusive (P<7.2x10-3) of mutations in the PBRM1 gene in KIRC.	('PBRM1', 'Gene', '55193', (132, 137))	('BAP1', 'Gene', '8314', (66, 70))	('mutations', 'Var', (49, 58))	('BAP1', 'Gene', (66, 70))	('PBRM1', 'Gene', (132, 137))
122530	25501392	We find that mutations in the SWI/SNF and BAP1 complexes show even greater mutual exclusivity (P=9.4x10-5) in KIRC because of mutations in additional genes in these complexes besides BAP1 and PBRM1, respectively (Supplementary Note Section 5.8.1).	('BAP1', 'Gene', '8314', (42, 46))	('BAP1', 'Gene', '8314', (183, 187))	('PBRM1', 'Gene', (192, 197))	('BAP1', 'Gene', (42, 46))	('mutual exclusivity', 'MPA', (75, 93))	('BAP1', 'Gene', (183, 187))	('PBRM1', 'Gene', '55193', (192, 197))	('mutations', 'Var', (126, 135))	('mutations', 'Var', (13, 22))	('SWI/SNF', 'Gene', (30, 37))
122531	25501392	This mutual exclusivity suggests that mutations in these complexes define different subtypes of kidney cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('kidney cancer', 'Disease', 'MESH:D007680', (96, 109))	('kidney cancer', 'Phenotype', 'HP:0009726', (96, 109))	('kidney cancer', 'Disease', (96, 109))	('mutations', 'Var', (38, 47))
122532	25501392	Supporting this hypothesis, we observe that inactivating mutations in the BAP1 complex are enriched (P<3.4x10-8) for samples in the third mRNA expression subtype from (Figure 3c).	('BAP1', 'Gene', '8314', (74, 78))	('BAP1', 'Gene', (74, 78))	('inactivating mutations', 'Var', (44, 66))
122533	25501392	We find that a large fraction of the mutations in BAP1, ASXL1, and ASXL2 in different cancer types are inactivating mutations, demonstrating alternative strategies for inactivation of the BAP1 complex.	('BAP1', 'Gene', (188, 192))	('ASXL1', 'Gene', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('BAP1', 'Gene', '8314', (50, 54))	('BAP1', 'Gene', '8314', (188, 192))	('mutations', 'Var', (37, 46))	('ASXL2', 'Gene', '55252', (67, 72))	('BAP1', 'Gene', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('ASXL1', 'Gene', '171023', (56, 61))	('ASXL2', 'Gene', (67, 72))	('cancer', 'Disease', (86, 92))
122534	25501392	In addition, 6/13 missense mutations in FOXK2 are in the forkhead transcription factor domain or forkhead associated domain, which may inactivate the DNA-binding properties of FOXK2.	('FOXK2', 'Gene', (176, 181))	('DNA-binding', 'molecular_function', 'GO:0003677', ('150', '161'))	('transcription', 'biological_process', 'GO:0006351', ('66', '79'))	('FOXK2', 'Gene', '3607', (40, 45))	('transcription factor', 'molecular_function', 'GO:0000981', ('66', '86'))	('FOXK2', 'Gene', (40, 45))	('DNA', 'cellular_component', 'GO:0005574', ('150', '153'))	('DNA-binding', 'Interaction', (150, 161))	('FOXK2', 'Gene', '3607', (176, 181))	('missense mutations', 'Var', (18, 36))	('inactivate', 'NegReg', (135, 145))
122535	25501392	Finally, we examined the mutations in KDM1B, a gene that is involved in H3K4-methylation, but not considered a core part of the BAP1 complex.	('mutations', 'Var', (25, 34))	('methylation', 'biological_process', 'GO:0032259', ('77', '88'))	('BAP1', 'Gene', '8314', (128, 132))	('KDM1B', 'Gene', (38, 43))	('KDM1B', 'Gene', '221656', (38, 43))	('BAP1', 'Gene', (128, 132))	('core', 'cellular_component', 'GO:0019013', ('111', '115'))
122536	25501392	We find that 12/19 mutations in KDM1B (including 10/16 missense mutations) fall in the C-terminal amino-oxidase domain that is important for lysine-specific demethylation of histones.	('KDM1B', 'Gene', '221656', (32, 37))	('lysine', 'Chemical', 'MESH:D008239', (141, 147))	('fall', 'Phenotype', 'HP:0002527', (75, 79))	('mutations', 'Var', (19, 28))	('demethylation', 'biological_process', 'GO:0070988', ('157', '170'))	('KDM1B', 'Gene', (32, 37))
122537	25501392	Moreover, 2 of the 3 KDM1B mutations in LUSC and LUAD are inactivating, and these are also exclusive of BAP1 inactivating mutations, suggesting that KDM1B mutations might play a role in cancer.	('mutations', 'Var', (27, 36))	('BAP1', 'Gene', '8314', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('KDM1B', 'Gene', (21, 26))	('BAP1', 'Gene', (104, 108))	('play', 'Reg', (171, 175))	('KDM1B', 'Gene', '221656', (21, 26))	('KDM1B', 'Gene', (149, 154))	('KDM1B', 'Gene', '221656', (149, 154))	('role', 'Reg', (178, 182))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
122540	25501392	This pattern of mutations complicates the identification of recurrent mutations in individual genes, and indeed only half of the genes in the complex (STAG2, SMC1A, and RAD21) were significant by at least one of the three gene scores.	('SMC', 'cellular_component', 'GO:0016029', ('158', '161'))	('STAG2', 'Gene', (151, 156))	('STAG2', 'Gene', '10735', (151, 156))	('RAD21', 'Gene', (169, 174))	('RAD', 'biological_process', 'GO:1990116', ('169', '172'))	('SMC1A', 'Gene', (158, 163))	('mutations', 'Var', (16, 25))	('RAD21', 'Gene', '5885', (169, 174))	('SMC1A', 'Gene', '8243', (158, 163))
122541	25501392	Mutations in some of these genes have recently been reported to be significant in several cancers.	('cancers', 'Disease', (90, 97))	('significant', 'Reg', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
122542	25501392	We find enrichment for mutations in the subnetwork in BLCA (P=7x10-4); this enrichment derives largely from enrichment for mutations in STAG2 in BLCA (P=0.005), which was recently reported.	('BLCA', 'Gene', (145, 149))	('STAG2', 'Gene', '10735', (136, 141))	('STAG2', 'Gene', (136, 141))	('mutations', 'Var', (123, 132))
122545	25501392	All mutations in RAD21 in LAML samples were inactivating, and BRCA and KIRC harbor inactivating mutations in STAG1.	('STAG1', 'Gene', (109, 114))	('RAD', 'biological_process', 'GO:1990116', ('17', '20'))	('BRCA', 'Gene', '672', (62, 66))	('inactivating', 'NegReg', (44, 56))	('BRCA', 'Gene', (62, 66))	('STAG1', 'Gene', '10274', (109, 114))	('mutations', 'Var', (4, 13))	('RAD21', 'Gene', (17, 22))	('RAD21', 'Gene', '5885', (17, 22))
122546	25501392	In addition, we observed a significant clustering of missense mutations in STAG1 (P=6x10-5), and the broad span of the cluster (135 residues) is indicative of inactivation.	('STAG1', 'Gene', (75, 80))	('STAG1', 'Gene', '10274', (75, 80))	('missense mutations', 'Var', (53, 71))
122547	25501392	STAG1 has been shown to function as a transcriptional coactivator, and thus mutation of STAG1 may play another role in cancer apart from genome stability.	('STAG1', 'Gene', (0, 5))	('STAG1', 'Gene', '10274', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('play', 'Reg', (98, 102))	('cancer', 'Disease', (119, 125))	('STAG1', 'Gene', '10274', (0, 5))	('STAG1', 'Gene', (88, 93))	('mutation', 'Var', (76, 84))	('transcriptional', 'MPA', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
122548	25501392	Together, these results show that mutational inactivation of the cohesin complex occurs broadly across cancer types and across genes within the complex.	('cohesin complex', 'Protein', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutational inactivation', 'Var', (34, 57))	('cohesin complex', 'cellular_component', 'GO:0008278', ('65', '80'))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
122550	25501392	A subnetwork consisting of NCAPD2, SMC2, and SMC4, both members of Condensin I form of the complex, was significantly mutated in BLCA (P= 6.2 x 10-6).	('SMC2', 'Gene', (35, 39))	('BLCA', 'Disease', (129, 133))	('SMC', 'cellular_component', 'GO:0016029', ('35', '38'))	('SMC', 'cellular_component', 'GO:0016029', ('45', '48'))	('SMC4', 'Gene', '10051', (45, 49))	('mutated', 'Var', (118, 125))	('SMC4', 'Gene', (45, 49))	('NCAPD2', 'Gene', (27, 33))	('SMC2', 'Gene', '10592', (35, 39))	('NCAPD2', 'Gene', '9918', (27, 33))
122551	25501392	Condensin I is thought to primarily be involved in the sister chromatid condensation during mitosis, suggesting that these mutations promote genome instability.	('chromatid', 'cellular_component', 'GO:0005694', ('62', '71'))	('genome instability', 'MPA', (141, 159))	('promote', 'PosReg', (133, 140))	('mitosis', 'Disease', (92, 99))	('mitosis', 'biological_process', 'GO:0000278', ('92', '99'))	('mitosis', 'Disease', 'None', (92, 99))	('mutations', 'Var', (123, 132))	('chromatid', 'cellular_component', 'GO:0005695', ('62', '71'))
122552	25501392	In contrast, a subnetwork consisting of NCAPD3, NCAPG2 and NCAPH2, all members of Condensin II form of the complex, was significantly mutated in LUAD (P=0.04) and LUSC (P=0.002) and the majority (4/7) of NCAPG2 mutations in LUSC are inactivating.	('NCAPD3', 'Gene', '23310', (40, 46))	('NCAPG2', 'Gene', '54892', (48, 54))	('NCAPH2', 'Gene', '29781', (59, 65))	('NCAPD3', 'Gene', (40, 46))	('mutations', 'Var', (211, 220))	('mutated', 'Var', (134, 141))	('NCAPG2', 'Gene', '54892', (204, 210))	('NCAPG2', 'Gene', (48, 54))	('NCAPH2', 'Gene', (59, 65))	('NCAPG2', 'Gene', (204, 210))
122553	25501392	In addition, we found a significant (P= 0.002) cluster of missense mutations in NCAPH2 (Figure 4b), implying that mutations in this region of unknown function may be important for the deregulation of condensin.	('missense mutations', 'Var', (58, 76))	('NCAPH2', 'Gene', (80, 86))	('NCAPH2', 'Gene', '29781', (80, 86))
122554	25501392	We also note that it was recently observed that expression of NCAPD3 was positively associated with recurrence-free survival.	('recurrence-free survival', 'CPA', (100, 124))	('NCAPD3', 'Gene', '23310', (62, 68))	('associated', 'Reg', (84, 94))	('expression', 'Var', (48, 58))	('NCAPD3', 'Gene', (62, 68))
122555	25501392	Finally, RNA-seq and whole-genome sequencing data from the same samples provide further validation of the somatic mutations in SMC2, SMC4, NCAPD2, NCAPD3, NCAPH2, and NCAPG2 and show that some of these mutations are expressed (Supplementary Note Section 6 and Supplementary Table 39).	('SMC4', 'Gene', '10051', (133, 137))	('NCAPH2', 'Gene', (155, 161))	('NCAPD2', 'Gene', '9918', (139, 145))	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('SMC4', 'Gene', (133, 137))	('SMC2', 'Gene', '10592', (127, 131))	('mutations', 'Var', (114, 123))	('NCAPG2', 'Gene', (167, 173))	('NCAPH2', 'Gene', '29781', (155, 161))	('SMC2', 'Gene', (127, 131))	('SMC', 'cellular_component', 'GO:0016029', ('133', '136'))	('NCAPD3', 'Gene', '23310', (147, 153))	('NCAPD2', 'Gene', (139, 145))	('NCAPG2', 'Gene', '54892', (167, 173))	('SMC', 'cellular_component', 'GO:0016029', ('127', '130'))	('NCAPD3', 'Gene', (147, 153))
122556	25501392	Our HotNet2 Pan-Cancer analysis suggests that multiple cancer types harbor rare mutations in the cohesin and condensin complexes, supporting a proposed tumor suppressor role for these complexes.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutations', 'Var', (80, 89))	('cohesin', 'Protein', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('tumor', 'Disease', (152, 157))	('condensin complexes', 'Protein', (109, 128))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
122559	25501392	We recover many classic cancer pathways like TP53, PI3K, NOTCH, and RTK automatically from a large-scale interaction network, demonstrating the power of the Pan-Cancer network approach.	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('TP53', 'Gene', (45, 49))	('NOTCH', 'Disease', (57, 62))	('PI3K', 'Var', (51, 55))	('RTK', 'Disease', (68, 71))	('Cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('TP53', 'Gene', '7157', (45, 49))
122562	25501392	These subnetworks have rare mutations in nearly all cancer types, making them difficult to detect without a sensitive Pan-Cancer network approach that examines combinations of genes across multiple cancer types.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (198, 204))	('Cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mutations', 'Var', (28, 37))
122566	25501392	In addition, we find that well-characterized mutations in a single gene in one cancer type (e.g.	('cancer', 'Disease', (79, 85))	('mutations', 'Var', (45, 54))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
122567	25501392	inactivating mutations BAP1 in KIRC) are replaced in other cancer types by rare mutations in other members of the same complex (e.g.	('BAP1', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('BAP1', 'Gene', '8314', (23, 27))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('inactivating mutations', 'Var', (0, 22))
122568	25501392	inactivating mutations in ASXL1, ASXL2, FOXK2, KDM1B).	('KDM1B', 'Gene', (47, 52))	('KDM1B', 'Gene', '221656', (47, 52))	('FOXK2', 'Gene', '3607', (40, 45))	('ASXL2', 'Gene', '55252', (33, 38))	('ASXL1', 'Gene', '171023', (26, 31))	('FOXK2', 'Gene', (40, 45))	('ASXL1', 'Gene', (26, 31))	('ASXL2', 'Gene', (33, 38))	('inactivating mutations', 'Var', (0, 22))
122570	25501392	The HotNet2 Pan-Cancer network approach identifies combinations of rare and common mutations in groups of interacting genes; combinations that were not apparent by analysis of single genes, known pathways, or single cancer types.	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))
122574	25501392	In particular, genome-wide association studies (GWAS) and other studies of genetic diseases face an analogous problem of identification of combinations of genetic variants with a statistically significant association to a phenotype.	('genetic diseases', 'Disease', (75, 91))	('variants', 'Var', (163, 171))	('genetic diseases', 'Disease', 'MESH:D030342', (75, 91))
122575	25501392	SNVs, indels, and splice-site mutations were extracted from TCGA Pan-Cancer analysis on Synapse (syn1710680), and copy number aberrations (CNAs) from GISTIC2 output via Firehose.	('Synapse', 'cellular_component', 'GO:0045202', ('88', '95'))	('syn1710680', 'Var', (97, 107))	('copy number aberrations', 'Disease', 'MESH:D002869', (114, 137))	('copy number aberrations', 'Disease', (114, 137))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))
122577	25501392	Finally, we used only those genes that had at least 3 reads from RNA-seq data in at least 70% of samples of at least one of the cancer types, as described in syn1734155 (See URLs).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('RNA', 'cellular_component', 'GO:0005562', ('65', '68'))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('syn1734155', 'Var', (158, 168))	('cancer', 'Disease', (128, 134))
122593	25278252	Both low cytoplasmic and membranous ezrin staining were associated with a significantly reduced 5-year OS (HR = 1.65; 95% CI 1.06-2.57 and HR = 2.51, 95% CI 1.52-4.17), but only low membranous ezrin remained prognostic after adjustment for age, sex, stage, grade and smoking status (HR = 1.69, 95% CI 1.00-2.85).	('ezrin', 'Gene', '7430', (193, 198))	('ezrin', 'Gene', (193, 198))	('OS', 'Chemical', '-', (103, 105))	('ezrin', 'Gene', '7430', (36, 41))	('ezrin', 'Gene', (36, 41))	('men', 'Species', '9606', (231, 234))	('low cytoplasmic', 'Var', (5, 20))	('5-year OS', 'CPA', (96, 105))	('reduced', 'NegReg', (88, 95))
122609	25278252	found that reduced membranous expression of the membrane-cytoskeletal linking protein ezrin was associated with adverse tumour characteristics and a worse prognosis in 92 patients with T1G3 urothelial cell carcinoma of the bladder.	('urothelial cell carcinoma of the bladder', 'Disease', (190, 230))	('reduced', 'NegReg', (11, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('membrane', 'cellular_component', 'GO:0016020', ('48', '56'))	('adverse tumour', 'Disease', (112, 126))	('urothelial cell carcinoma of the bladder', 'Phenotype', 'HP:0006740', (190, 230))	('T1G3', 'Var', (185, 189))	('patients', 'Species', '9606', (171, 179))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('urothelial cell carcinoma of the bladder', 'Disease', 'MESH:D001749', (190, 230))	('ezrin', 'Gene', '7430', (86, 91))	('membranous expression', 'MPA', (19, 40))	('ezrin', 'Gene', (86, 91))	('adverse tumour', 'Disease', 'MESH:D064420', (112, 126))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
122610	25278252	Another recent study on 104 bladder cancer cases of varying stages and grades, loss of membranous ezrin was found to correlate with adverse tumour characteristics, but the prognostic impact was not evaluated.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('adverse tumour', 'Disease', (132, 146))	('loss', 'Var', (79, 83))	('ezrin', 'Gene', '7430', (98, 103))	('bladder cancer', 'Phenotype', 'HP:0009725', (28, 42))	('ezrin', 'Gene', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('bladder cancer', 'Disease', 'MESH:D001749', (28, 42))	('bladder cancer', 'Disease', (28, 42))	('adverse tumour', 'Disease', 'MESH:D064420', (132, 146))
122632	25278252	Kaplan-Meier analysis and log rank test were used to illustrate differences in five-year OS according to high and low ezrin expression.	('ezrin', 'Gene', '7430', (118, 123))	('high', 'Var', (105, 109))	('ezrin', 'Gene', (118, 123))	('expression', 'MPA', (124, 134))	('low', 'NegReg', (114, 117))	('OS', 'Chemical', '-', (89, 91))
122646	25278252	CRT analysis determined optimal prognostic cut-offs at 0.988 for mean cytoplasmic and 0.538 for mean membranous ezrin expression in relation to 5-year OS (Additional file 1A and B).	('OS', 'Chemical', '-', (151, 153))	('ezrin', 'Gene', '7430', (112, 117))	('ezrin', 'Gene', (112, 117))	('0.988', 'Var', (55, 60))	('0.538', 'Var', (86, 91))
122653	25278252	In tumours of pT2 stage and beyond cytoplasmic ezrin was not prognostic (data not shown), whereas loss of membranous ezrin was borderline prognostic (univariable and multivariable HR = 2.72, 95% CI 0.97-7.63).	('ezrin', 'Gene', '7430', (47, 52))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('ezrin', 'Gene', (47, 52))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('ezrin', 'Gene', '7430', (117, 122))	('ezrin', 'Gene', (117, 122))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))	('loss', 'Var', (98, 102))
122664	25278252	In this study, cytoplasmic ezrin expression was also found to be associated with adverse tumour characteristics and survival, although the prognostic value did not remain independent of conventional clinicopathological factors.	('adverse tumour', 'Disease', 'MESH:D064420', (81, 95))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('survival', 'CPA', (116, 124))	('cytoplasmic', 'Var', (15, 26))	('adverse tumour', 'Disease', (81, 95))	('ezrin', 'Gene', '7430', (27, 32))	('associated', 'Reg', (65, 75))	('ezrin', 'Gene', (27, 32))
122681	25278252	Despite the small sample size, the finding of a significant reduction of membranous ezrin expression in recurrent tumours further supports the increasing body of evidence demonstrating that loss of ezrin is associated with tumour progression.	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('tumour', 'Disease', (114, 120))	('tumours', 'Disease', (114, 121))	('ezrin', 'Gene', (84, 89))	('ezrin', 'Gene', (198, 203))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('ezrin', 'Gene', '7430', (198, 203))	('membranous', 'MPA', (73, 83))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('reduction', 'NegReg', (60, 69))	('loss', 'Var', (190, 194))	('expression', 'MPA', (90, 100))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Disease', (223, 229))	('associated', 'Reg', (207, 217))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('ezrin', 'Gene', '7430', (84, 89))
122683	25278252	This finding may well be due to chance, given the small sample size, but is also in line with the observation of cytoplasmic ezrin seemingly being more weakly associated with aggressive tumour features.	('associated', 'Reg', (159, 169))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('cytoplasmic', 'Var', (113, 124))	('weakly', 'NegReg', (152, 158))	('aggressive tumour', 'Disease', 'MESH:D001523', (175, 192))	('ezrin', 'Gene', '7430', (125, 130))	('ezrin', 'Gene', (125, 130))	('aggressive tumour', 'Disease', (175, 192))
122702	25031072	Aristolochic acid, which is a component of Aristolochia herbal remedies and widely used in traditional Chinese medicine, is thought to be associated with the higher incidence of UTUC in Taiwan .	('associated', 'Reg', (138, 148))	('UTUC', 'Disease', (178, 182))	('Aristolochic', 'Var', (0, 12))	('Aristolochic acid', 'Chemical', 'MESH:C000228', (0, 17))
122758	33810347	Transcriptional and epigenetic dysregulation is significantly associated with cancer stemness.	('cancer stemness', 'Disease', 'MESH:D009369', (78, 93))	('associated', 'Reg', (62, 72))	('epigenetic dysregulation', 'Var', (20, 44))	('cancer stemness', 'Disease', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
122761	33810347	Our results indicate that only TIF1beta (also known as Tripartite Motif protein 28, TRIM28) high expression is consequently associated with a "stemness high" phenotype, regardless of the tumor type, resulting in a worse prognosis for cancer patients.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('TIF1beta', 'Gene', (31, 39))	('high expression', 'Var', (92, 107))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('TIF1beta', 'Gene', '8805', (31, 39))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('TRIM28', 'Gene', (84, 90))	('tumor', 'Disease', (187, 192))	('associated with', 'Reg', (124, 139))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))	('TRIM28', 'Gene', '10155', (84, 90))	('patients', 'Species', '9606', (241, 249))
122764	33810347	Our results demonstrate that the association between high TRIM28 expression and an enriched cancer stem cell-like phenotype is a common phenomenon across solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('TRIM28', 'Gene', (58, 64))	('high', 'Var', (53, 57))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('solid tumors', 'Disease', (154, 166))	('TRIM28', 'Gene', '10155', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('expression', 'MPA', (65, 75))	('solid tumors', 'Disease', 'MESH:D009369', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
122766	33810347	Cancer de-differentiation and the acquisition of stemness features are mediated by the transcriptional and epigenetic dysregulation of cancer cells.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('epigenetic dysregulation', 'Var', (107, 131))	('stemness features', 'CPA', (49, 66))
122782	33810347	Reactivation of the ESC-like program in cancer strongly predicts metastatic potential and patient death.	('death', 'Disease', 'MESH:D003643', (98, 103))	('metastatic potential', 'CPA', (65, 85))	('death', 'Disease', (98, 103))	('predicts', 'Reg', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('Reactivation', 'Var', (0, 12))	('patient', 'Species', '9606', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ESC-like program', 'Gene', (20, 36))
122783	33810347	Cell de-differentiation and the acquisition of stemness features is mediated by the transcriptional and epigenetic dysregulation of cancer cells.	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('epigenetic dysregulation', 'Var', (104, 128))	('stemness features', 'CPA', (47, 64))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('Cell de-differentiation', 'CPA', (0, 23))
122790	33810347	TIF1 members are aberrantly expressed or mutated in multiple cancer types; however, their role in cancer stem cells is still not fully understood.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutated', 'Var', (41, 48))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('TIF1', 'Gene', '8805', (0, 4))	('TIF1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
122806	33810347	Among other TIF1 family members, only high TRIM28 expression might serve as a marker for stemness-associated traits of solid tumors.	('TIF1', 'Gene', '8805', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('TIF1', 'Gene', (12, 16))	('high', 'Var', (38, 42))	('solid tumors', 'Disease', 'MESH:D009369', (119, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('TRIM28', 'Gene', (43, 49))	('TRIM28', 'Gene', '10155', (43, 49))	('solid tumors', 'Disease', (119, 131))
122812	33810347	The representative results of immunohistochemistry staining of Prostate Adenocarcinoma (PRAD) samples with anti-TRIM24 (antibody name: HPA043495), anti-TRIM28 (HPA064033), anti-TRIM33 (HPA004345), and anti-TRIM66 (HPA027420) antibodies were downloaded from the Human Protein Atlas database (, accessed on 10 October 2020).	('anti-TRIM24', 'Var', (107, 118))	('antibody', 'cellular_component', 'GO:0019814', ('120', '128'))	('antibody', 'molecular_function', 'GO:0003823', ('120', '128'))	('antibody', 'cellular_component', 'GO:0042571', ('120', '128'))	('TRIM66', 'Gene', (206, 212))	('HPA004345', 'Var', (185, 194))	('antibody', 'cellular_component', 'GO:0019815', ('120', '128'))	('TRIM28', 'Gene', (152, 158))	('Human', 'Species', '9606', (261, 266))	('Prostate Adenocarcinoma', 'Disease', (63, 86))	('TRIM33', 'Gene', (177, 183))	('TRIM33', 'Gene', '51592', (177, 183))	('TRIM66', 'Gene', '9866', (206, 212))	('TRIM28', 'Gene', '10155', (152, 158))	('Prostate Adenocarcinoma', 'Disease', 'MESH:D011471', (63, 86))
122818	33810347	All datasets were analyzed online using the R2 Platform (, accessed on 10 October 2020) to find genes that correlate with TRIM24, TRIM28, TRIM33, or TRIM66 expression.	('TRIM24', 'Var', (122, 128))	('TRIM33', 'Gene', '51592', (138, 144))	('TRIM28', 'Gene', (130, 136))	('TRIM33', 'Gene', (138, 144))	('TRIM66', 'Gene', (149, 155))	('TRIM66', 'Gene', '9866', (149, 155))	('TRIM28', 'Gene', '10155', (130, 136))
122825	33810347	Higher TRIM28 expression is significantly associated with worse survival for Kidney Renal Clear Cell Carcinoma (KIRC), Kidney Renal Papillary Cell Carcinoma (KIRP), LIHC, Lung Adenocarcinoma (LUAD), MESO, Adrenocortical Carcinoma (ACC), Skin Cutaneous Melanoma (SKCM), and Bladder Urothelial Carcinoma (BLCA), and with better survival for THYM, Uveal Melanoma (UVM), and Testicular Germ Cell Tumor (TGCT) patients (Figure 1B).	('UVM', 'Phenotype', 'HP:0007716', (361, 364))	('Bladder Urothelial Carcinoma', 'Disease', 'MESH:D001749', (273, 301))	('Carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('THYM', 'Phenotype', 'HP:0100522', (339, 343))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (171, 190))	('Melanoma', 'Disease', (351, 359))	('Carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('Carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('Kidney Renal Papillary Cell Carcinoma', 'Disease', 'MESH:C538614', (119, 156))	('MESO', 'Disease', (199, 203))	('TRIM28', 'Gene', (7, 13))	('expression', 'Var', (14, 24))	('Kidney Renal Clear Cell Carcinoma', 'Disease', 'MESH:C538614', (77, 110))	('ACC', 'Phenotype', 'HP:0006744', (231, 234))	('Melanoma', 'Phenotype', 'HP:0002861', (351, 359))	('Germ Cell Tumor', 'Phenotype', 'HP:0100728', (382, 397))	('Skin Cutaneous Melanoma', 'Disease', (237, 260))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (205, 229))	('Kidney Renal Clear Cell Carcinoma', 'Disease', (77, 110))	('Lung Adenocarcinoma', 'Disease', (171, 190))	('Melanoma', 'Disease', 'MESH:D008545', (252, 260))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (242, 260))	('Tumor', 'Phenotype', 'HP:0002664', (392, 397))	('Bladder Urothelial Carcinoma', 'Disease', (273, 301))	('TRIM28', 'Gene', '10155', (7, 13))	('Carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (345, 359))	('Renal Papillary Cell Carcinoma', 'Phenotype', 'HP:0006766', (126, 156))	('LIHC', 'Disease', (165, 169))	('Melanoma', 'Disease', (252, 260))	('Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (205, 229))	('Kidney Renal Papillary Cell Carcinoma', 'Disease', (119, 156))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (171, 190))	('patients', 'Species', '9606', (405, 413))	('Melanoma', 'Disease', 'MESH:D008545', (351, 359))	('Melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (237, 260))	('Adrenocortical Carcinoma', 'Disease', (205, 229))	('LUAD', 'Phenotype', 'HP:0030078', (192, 196))
122829	33810347	Using the cBioportal data, we observed that across all tested tumor types (10,506 profiled samples in 27 solid TCGA tumor types), the frequencies of alterations (missense mutations, amplifications, deletions) in TIF1 member-encoding genes were relatively low (Figure S1A), with 2.6%, 2.2%, 1.8%, and 0.9% genetic alterations in profiled samples for TRIM24, TRIM28, TRIM33, and TRIM66, respectively.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('TRIM28', 'Gene', '10155', (357, 363))	('TRIM66', 'Gene', (377, 383))	('TRIM24', 'Var', (349, 355))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('TIF1', 'Gene', '8805', (212, 216))	('TRIM33', 'Gene', '51592', (365, 371))	('TRIM33', 'Gene', (365, 371))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('TRIM66', 'Gene', '9866', (377, 383))	('TIF1', 'Gene', (212, 216))	('tumor', 'Disease', (116, 121))	('TRIM28', 'Gene', (357, 363))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
122830	33810347	In most cancer types, the frequency of alterations did not exceed 5% for each of the tested genes (Figure S1B-E), except for TRIM24 in Ovarian Serous Cystadenocarcinoma (OV) (10.98%) and SKCM (8.05%), and TRIM28 and TRIM33 in Esophageal Carcinoma (ESCA) (5.41% and 5.41% of altered samples, respectively), suggesting that genetic alterations in TIF1 members are not of great importance in cancer development.	('TIF1', 'Gene', (345, 349))	('Carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('Ovarian Serous Cystadenocarcinoma', 'Phenotype', 'HP:0012887', (135, 168))	('cancer', 'Disease', (389, 395))	('TIF1', 'Gene', '8805', (345, 349))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('Ovarian Serous Cystadenocarcinoma', 'Disease', (135, 168))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('TRIM28', 'Gene', (205, 211))	('TRIM24', 'Var', (125, 131))	('Carcinoma', 'Disease', (237, 246))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (226, 246))	('Carcinoma', 'Disease', 'MESH:D009369', (237, 246))	('ESCA', 'Phenotype', 'HP:0011459', (248, 252))	('TRIM33', 'Gene', (216, 222))	('Ovarian Serous Cystadenocarcinoma', 'Disease', 'MESH:D018284', (135, 168))	('TRIM28', 'Gene', '10155', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (389, 395))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('TRIM33', 'Gene', '51592', (216, 222))	('OV', 'Phenotype', 'HP:0012887', (170, 172))
122833	33810347	For TRIM24 and TRIM28 expression, we mostly observed positive Spearman's correlation with stemness indices (Figure 2B,C), while for TRIM33 and TRIM66 expression, the correlation with stemness indices was primarily negative (Figure 2D,E).	('TRIM28', 'Gene', '10155', (15, 21))	('TRIM66', 'Gene', (143, 149))	('correlation', 'Interaction', (73, 84))	('TRIM24', 'Var', (4, 10))	('TRIM28', 'Gene', (15, 21))	('TRIM33', 'Gene', '51592', (132, 138))	('TRIM33', 'Gene', (132, 138))	('TRIM66', 'Gene', '9866', (143, 149))	('expression', 'MPA', (22, 32))	('stemness indices', 'MPA', (90, 106))
122847	33810347	The number of genes that are significantly correlated with the expression of TRIM24, TRIM28, TRIM33, or TRIM66 are presented in Figure S2.	('TRIM28', 'Gene', '10155', (85, 91))	('TRIM24', 'Var', (77, 83))	('TRIM66', 'Gene', (104, 110))	('TRIM33', 'Gene', '51592', (93, 99))	('TRIM33', 'Gene', (93, 99))	('TRIM28', 'Gene', (85, 91))	('TRIM66', 'Gene', '9866', (104, 110))
122886	33810347	We have previously shown that high TRIM28 expression is strictly related to the stem cell-like phenotype of breast cancer and melanomas.	('melanomas', 'Disease', 'MESH:D008545', (126, 135))	('TRIM28', 'Gene', (35, 41))	('melanomas', 'Disease', (126, 135))	('expression', 'MPA', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('high', 'Var', (30, 34))	('TRIM28', 'Gene', '10155', (35, 41))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanomas', 'Phenotype', 'HP:0002861', (126, 135))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('related', 'Reg', (65, 72))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
122889	33810347	Here, we reported for the first time that the association between high TRIM28 expression and an enriched stem cell-like phenotype is a common phenomenon across solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('TRIM28', 'Gene', (71, 77))	('association', 'Interaction', (46, 57))	('high', 'Var', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('TRIM28', 'Gene', '10155', (71, 77))	('solid tumors', 'Disease', (160, 172))
122912	33810347	As presented by Massague et al., the loss of TRIM33 expression does not affect stem cell self-renewal, but it impairs the differentiation process.	('differentiation process', 'CPA', (122, 145))	('TRIM33', 'Gene', '51592', (45, 51))	('TRIM33', 'Gene', (45, 51))	('impairs', 'NegReg', (110, 117))	('loss', 'Var', (37, 41))
122923	33810347	TRIM24 and TRIM28 are generally positively associated, while TRIM33 and TRIM66 are mostly negatively associated with cancer stemness in solid tumors.	('cancer stemness', 'Disease', (117, 132))	('TRIM28', 'Gene', (11, 17))	('associated', 'Interaction', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('solid tumors', 'Disease', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('negatively', 'NegReg', (90, 100))	('TRIM66', 'Gene', '9866', (72, 78))	('TRIM28', 'Gene', '10155', (11, 17))	('cancer stemness', 'Disease', 'MESH:D009369', (117, 132))	('TRIM24', 'Var', (0, 6))	('TRIM66', 'Gene', (72, 78))	('solid tumors', 'Disease', 'MESH:D009369', (136, 148))	('associated', 'Reg', (101, 111))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('TRIM33', 'Gene', '51592', (61, 67))	('TRIM33', 'Gene', (61, 67))
122996	29417045	Although chemotherapy regimens are still considered to be the best first-line approach for most eligible patients, PD-L1 and PD-1 inhibitors may yield more durable responses than conventional chemotherapy and continue to show promising results as new treatment options.	('patients', 'Species', '9606', (105, 113))	('inhibitors', 'Var', (130, 140))	('men', 'Species', '9606', (256, 259))	('PD-1', 'Gene', (125, 129))	('men', 'Species', '9606', (26, 29))	('PD-1', 'Gene', '5133', (125, 129))	('PD-L1', 'Gene', (115, 120))
123006	29417045	At a median follow-up of 14.4 months, ORR was 14.8% in the 310 treated patients, with higher ORR seen in the patients with high PD-L1 expression by immunohistochemistry (IHC) staining (26%), though responses were noted even in the absence of tumor-infiltrating cells PD-L1 expression.	('PD-L1', 'Gene', (128, 133))	('expression', 'MPA', (134, 144))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('patients', 'Species', '9606', (71, 79))	('high', 'Var', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', (242, 247))
123029	29417045	In the pembrolizumab arm, OS was significantly increased at 10.3 months compared with 7.4 months with chemotherapy.	('increased', 'PosReg', (47, 56))	('pembrolizumab', 'Chemical', 'MESH:C582435', (7, 20))	('pembrolizumab', 'Var', (7, 20))	('OS', 'Chemical', '-', (26, 28))
123030	29417045	In the subgroup with PD-L1 expression >=10%, median OS was 8.0 months compared with 5.2 months with other systemic therapy drugs.	('OS', 'Chemical', '-', (52, 54))	('expression >=10%', 'Var', (27, 43))	('PD-L1', 'Gene', (21, 26))
123057	29417045	Antibody-dependent cellular cytotoxicity is decreased via the creation of mutations in the Fc domain of the drug.	('cytotoxicity', 'Disease', 'MESH:D064420', (28, 40))	('mutations in', 'Var', (74, 86))	('Fc domain', 'Gene', (91, 100))	('Antibody-dependent cellular cytotoxicity', 'biological_process', 'GO:0001788', ('0', '40'))	('cytotoxicity', 'Disease', (28, 40))	('decreased', 'NegReg', (44, 53))
123063	29417045	Response rate did correlate with PD-L1 expression, with an ORR of 27.6% for tumors with high expression compared with 5.1% for tumors with low or no expression.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('PD-L1', 'Gene', (33, 38))	('high expression', 'Var', (88, 103))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
123100	29417045	The neuronal subtype, which accounted for approximately 5% of cases, had no histopathologic distinction from other specimens in most cases to aid in its identification, though expressed high frequencies of TP53 and RB1 mutations as seen in other types of small cell carcinomas.	('TP53', 'Gene', '7157', (206, 210))	('TP53', 'Gene', (206, 210))	('aid', 'Gene', '57379', (142, 145))	('small cell carcinomas', 'Disease', 'MESH:D018288', (255, 276))	('small cell carcinomas', 'Disease', (255, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('RB1', 'Gene', (215, 218))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (255, 276))	('carcinomas', 'Phenotype', 'HP:0030731', (266, 276))	('aid', 'Gene', (142, 145))	('mutations', 'Var', (219, 228))	('RB1', 'Gene', '5925', (215, 218))	('men', 'Species', '9606', (120, 123))
123102	29417045	Fibroblast growth factor receptor 3 mutations are common in the luminal subtype and may make a better therapeutic target for this population.	('Fibroblast growth factor', 'molecular_function', 'GO:0005104', ('0', '24'))	('Fibroblast growth factor receptor 3', 'Gene', (0, 35))	('mutations', 'Var', (36, 45))	('Fibroblast growth factor receptor 3', 'Gene', '2261', (0, 35))
123124	28903380	In this study, we did a thorough search for novel fusion transcripts in bladder cancer using RNA sequencing and sought to determine the effect of mex3a expression on the overall survival of BLCA.	('fusion transcripts', 'Var', (50, 68))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mex3a', 'Gene', (146, 151))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('BLCA', 'Chemical', '-', (190, 194))	('RNA', 'cellular_component', 'GO:0005562', ('93', '96'))	('mex3a', 'Gene', '92312', (146, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (72, 86))	('bladder cancer', 'Disease', (72, 86))
123136	28903380	It was demonstrated that the mean normalized expression of mex3a was 1191.153 +- 1556.508 in cancer and 167.466 +- 323.095 in adjacent normal tissues.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('mex3a', 'Gene', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mex3a', 'Gene', '92312', (59, 64))	('1191.153 +- 1556.508', 'Var', (69, 89))
123147	28903380	The result of logistic regression analysis indicated that high mex3a expression was associated with the papillary type of BLCA (P=0.006, odds ratio [OR]=1.854) (Figure 7) and the older age group diagnosed with BLCA (P=0.027, OR=1.617) (Figure 8), but was not associated with tumor status (P=0.968) or pathologic stage (P=0.816).	('BLCA', 'Chemical', '-', (210, 214))	('tumor', 'Disease', (275, 280))	('mex3a', 'Gene', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('mex3a', 'Gene', '92312', (63, 68))	('expression', 'MPA', (69, 79))	('BLCA', 'Disease', (210, 214))	('papillary type of BLCA', 'Disease', (104, 126))	('associated', 'Reg', (84, 94))	('high', 'Var', (58, 62))	('papillary type', 'Phenotype', 'HP:0007482', (104, 118))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('BLCA', 'Chemical', '-', (122, 126))
123157	28903380	Mex3a is located at complement (156,072,013-156,081,998) and has 9986 base pairs.	('156,072,013-156,081,998', 'Var', (32, 55))	('Mex3a', 'Gene', '92312', (0, 5))	('Mex3a', 'Gene', (0, 5))	('men', 'Species', '9606', (26, 29))
123159	28903380	It was reported that the inactivation of mex-3 by mutations could lead to embryonic death and defects in the anterior blastomere of the descendants.	('embryonic death', 'Disease', 'MESH:D003643', (74, 89))	('inactivation', 'Var', (25, 37))	('mutations', 'Var', (50, 59))	('embryonic death', 'Disease', (74, 89))	('mex-3', 'Gene', (41, 46))	('lead to', 'Reg', (66, 73))	('defects', 'NegReg', (94, 101))
123160	28903380	indicated that the knockout of gene hMex3a reduced the colony-forming ability of gastric cells in soft agar.	('hMex3a', 'Gene', (36, 42))	('knockout', 'Var', (19, 27))	('agar', 'Chemical', 'MESH:D000362', (103, 107))	('reduced', 'NegReg', (43, 50))	('hMex3a', 'Gene', '92312', (36, 42))
123161	28903380	Furthermore, transwell chamber and wound healing assays indicated that the knockout of hMex3a significantly affected the viability of cancer cells, and clinical correlation analysis indicated that the expression of hMex3a was significantly higher in cancer tissues than in normal tissues.	('hMex3a', 'Gene', (87, 93))	('expression', 'MPA', (201, 211))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('hMex3a', 'Gene', (215, 221))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', (134, 140))	('knockout', 'Var', (75, 83))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('hMex3a', 'Gene', '92312', (87, 93))	('wound healing', 'biological_process', 'GO:0042060', ('35', '48'))	('affected', 'Reg', (108, 116))	('higher', 'PosReg', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('hMex3a', 'Gene', '92312', (215, 221))
123162	28903380	demonstrated that hMex3a was involved in the regulation of tumorigenesis and that the aberrant activation of mex3a in human gastric cancer cells promoted cell proliferation and migration.	('cell proliferation', 'CPA', (154, 172))	('tumor', 'Disease', (59, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('hMex3a', 'Gene', '92312', (18, 24))	('mex3a', 'Gene', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('mex3a', 'Gene', '92312', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('gastric cancer', 'Disease', (124, 138))	('activation', 'PosReg', (95, 105))	('aberrant', 'Var', (86, 94))	('human', 'Species', '9606', (118, 123))	('hMex3a', 'Gene', (18, 24))	('gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('regulation', 'biological_process', 'GO:0065007', ('45', '55'))	('migration', 'CPA', (177, 186))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))	('promoted', 'PosReg', (145, 153))
123170	28903380	The univariate Cox model showed that the high expression of mex3a decreased the risk of death by 8.5% (relative risk [RR]=0.914) and the multivariate Cox model showed that the high expression of mex3a decreased the risk of death by 39.4% (RR=0.606) although the differences were not significant.	('mex3a', 'Gene', (60, 65))	('Cox', 'Gene', (150, 153))	('mex3a', 'Gene', (195, 200))	('mex3a', 'Gene', '92312', (60, 65))	('death', 'Disease', (88, 93))	('decreased', 'NegReg', (66, 75))	('high expression', 'Var', (41, 56))	('decreased', 'NegReg', (201, 210))	('death', 'Disease', 'MESH:D003643', (223, 228))	('death', 'Disease', (223, 228))	('mex3a', 'Gene', '92312', (195, 200))	('Cox', 'Gene', '1351', (15, 18))	('Cox', 'Gene', '1351', (150, 153))	('death', 'Disease', 'MESH:D003643', (88, 93))	('Cox', 'Gene', (15, 18))
57588	22613180	This cell line has been used to show that both Cd+2 and As+3 can cause the malignant transformation of human urothelial cells.	('Cd+2', 'Var', (47, 51))	('human', 'Species', '9606', (103, 108))	('cause', 'Reg', (65, 70))	('As+3', 'Chemical', '-', (56, 60))	('malignant transformation of human urothelial cells', 'CPA', (75, 125))	('As+3', 'Var', (56, 60))
123344	22613180	The level of ENO1 protein did not appear to be reduced in the As+3-transformed cell line which appeared to have a reduction in ENO1 mRNA.	('As+3-', 'Chemical', '-', (62, 67))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('ENO1', 'Var', (127, 131))	('reduction', 'NegReg', (114, 123))
123412	22613180	The uniform and extensive staining of ENO2 in the undifferentiated tumor cells proves evidence that cells expressing ENO2 may have an advantage in tumor initiation and subsequent growth.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor initiation', 'Disease', (147, 163))	('advantage', 'PosReg', (134, 143))	('growth', 'CPA', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (67, 72))	('tumor initiation', 'Disease', 'MESH:D009369', (147, 163))	('ENO2', 'Var', (117, 121))
123434	21303554	One, to determine if epigenetic modifications control urothelial MT-3 gene expression and if regulation is altered by malignant transformation by Cd+2 or As+3.	('regulation', 'biological_process', 'GO:0065007', ('93', '103'))	('As+3', 'Chemical', '-', (154, 158))	('epigenetic modifications', 'Var', (21, 45))	('control', 'Reg', (46, 53))	('urothelial MT-3 gene', 'Gene', (54, 74))	('gene expression', 'biological_process', 'GO:0010467', ('70', '85'))	('Cd+2', 'Var', (146, 150))	('expression', 'MPA', (75, 85))
123438	21303554	Histone modifications at acetyl H4, trimethyl H3K4, trimethyl H3K27, and trimethyl H3K9 were compared between the parental and transformed cell lines in the presence and absence of MS-275.	('trimethyl H3K9', 'Var', (73, 87))	('acetyl H4', 'Chemical', '-', (25, 34))	('MS-275', 'Chemical', 'MESH:C118739', (181, 187))	('Histone', 'MPA', (0, 7))
123457	21303554	This analysis demonstrated that parental UROtsa cells treated with MS-275 expressed increased levels of MT-3 mRNA compared to control cells (Figure 1A, D).	('levels', 'MPA', (94, 100))	('MT-3 mRNA', 'MPA', (104, 113))	('MS-275', 'Var', (67, 73))	('increased', 'PosReg', (84, 93))	('MS-275', 'Chemical', 'MESH:C118739', (67, 73))
123475	21303554	In the distal region 2, it was shown that the modification of acetyl H4 was increased in the parental UROtsa cells and both transformed cell lines following treatment with MS-275 (Figure 5A-E).	('MS-275', 'Var', (172, 178))	('acetyl H4', 'Chemical', '-', (62, 71))	('modification', 'MPA', (46, 58))	('MS-275', 'Chemical', 'MESH:C118739', (172, 178))	('acetyl H4', 'MPA', (62, 71))
123478	21303554	There was modification of trimethyl H3K4 in both the normal and transformed UROtsa cell lines under basal conditions and the level of modification increased for the parental UROtsa cells and the Cd+2 transformed cell line following treatment with MS-275 (Figure 5B, E).	('MS-275', 'Chemical', 'MESH:C118739', (247, 253))	('MS-275', 'Var', (247, 253))	('trimethyl H3K4', 'Protein', (26, 40))
123491	21303554	A similar analysis of the MREc element in the MT-3 promoter showed a low amount of MTF-1 binding to parental UROtsa cells not treated with MS-275 and a significant increase in binding following treatment with MS-275 (Figure 7B).	('binding', 'Interaction', (89, 96))	('MS-275', 'Var', (209, 215))	('binding', 'molecular_function', 'GO:0005488', ('176', '183'))	('binding', 'molecular_function', 'GO:0005488', ('89', '96'))	('MTF-1', 'Gene', '4520', (83, 88))	('MS-275', 'Chemical', 'MESH:C118739', (209, 215))	('MTF-1', 'Gene', (83, 88))	('binding', 'Interaction', (176, 183))	('increase', 'PosReg', (164, 172))	('MS-275', 'Chemical', 'MESH:C118739', (139, 145))
123493	21303554	Treatment with MS-275 had no further effect on MTF-1 binding to the MREc element of the MT-3 promoter for the Cd+2 transformed cells and only a small increase for the As+3 transformed cells (Figure 7B).	('MTF-1', 'Gene', (47, 52))	('MS-275', 'Chemical', 'MESH:C118739', (15, 21))	('binding', 'molecular_function', 'GO:0005488', ('53', '60'))	('Cd+2', 'Var', (110, 114))	('binding', 'Interaction', (53, 60))	('As+3', 'Chemical', '-', (167, 171))	('MTF-1', 'Gene', '4520', (47, 52))
123512	21303554	The second goal of the study was to determine if the accessibility of the MREs of the MT-3 promoter to a transcription factor were different between the parental UROtsa cell line and the UROtsa cell lines malignantly transformed by either Cd+2 or As+3.	('As+3', 'Chemical', '-', (247, 251))	('accessibility', 'MPA', (53, 66))	('transcription factor', 'molecular_function', 'GO:0000981', ('105', '125'))	('Cd+2', 'Var', (239, 243))	('transcription', 'biological_process', 'GO:0006351', ('105', '118'))
123513	21303554	The initial indication that the integrity of the MT-3 promoter may be different between the parent and transformed UROtsa cells, was that MT-3 mRNA expression could be further induced by Zn+2 in the transformed cell lines following treatment with MS-275, but was not induced by an identical treatment in the parental UROtsa cell line.	('MT-3', 'Gene', (138, 142))	('MS-275', 'Var', (247, 253))	('Zn+2', 'Chemical', 'MESH:D015032', (187, 191))	('induced', 'PosReg', (176, 183))	('MS-275', 'Chemical', 'MESH:C118739', (247, 253))	('mRNA expression', 'MPA', (143, 158))
123521	21303554	A similar analysis of MTF-1 binding to MREc in the MT-3 promoter showed the parental cells to have limited binding under basal conditions and an increased interaction following treatment with MS-275.	('MTF-1', 'Gene', (22, 27))	('interaction', 'Interaction', (155, 166))	('MS-275', 'Var', (192, 198))	('increased', 'PosReg', (145, 154))	('MS-275', 'Chemical', 'MESH:C118739', (192, 198))	('binding', 'Interaction', (107, 114))	('binding', 'molecular_function', 'GO:0005488', ('28', '35'))	('binding', 'molecular_function', 'GO:0005488', ('107', '114'))	('MTF-1', 'Gene', '4520', (22, 27))
123522	21303554	In contrast, the Cd+2 and As+3 transformed cell lines were shown to have increased binding of MTF-1 to MREc of the MT-3 promoter under both basal conditions with no increase in interaction following treatment with MS-275.	('increased', 'PosReg', (73, 82))	('Cd+2', 'Var', (17, 21))	('binding', 'Interaction', (83, 90))	('MTF-1', 'Gene', '4520', (94, 99))	('binding', 'molecular_function', 'GO:0005488', ('83', '90'))	('MTF-1', 'Gene', (94, 99))	('MS-275', 'Chemical', 'MESH:C118739', (214, 220))	('As+3', 'Chemical', '-', (26, 30))
123524	21303554	In contrast, MREe, f, g of the MT-3 promoter were able to bind MTF-1 under basal conditions, which was increased following treatment with MS-275.	('bind', 'Interaction', (58, 62))	('increased', 'PosReg', (103, 112))	('MTF-1', 'Gene', '4520', (63, 68))	('MTF-1', 'Gene', (63, 68))	('MS-275', 'Var', (138, 144))	('MS-275', 'Chemical', 'MESH:C118739', (138, 144))
123528	21303554	Several common histone modifications, acetyl H4, trimethyl H3K4, trimethyl H3K27, and trimethyl H3K9, associated with gene activation were analyzed in two regions of the MT-3 promoter for the parental UROtsa cells and the Cd+2 and As+3 transformed cell lines.	('acetyl H4', 'Chemical', '-', (38, 47))	('As+3', 'Chemical', '-', (231, 235))	('trimethyl H3K4', 'Var', (49, 63))	('trimethyl H3K9', 'Var', (86, 100))	('trimethyl H3K27', 'Var', (65, 80))
123529	21303554	The level of histone H4 acetylation was always increased in both the parental and transformed cell lines in the presence of MT-275.	('histone', 'MPA', (13, 20))	('MT-275', 'Var', (124, 130))	('MT-275', 'Chemical', '-', (124, 130))	('increased', 'PosReg', (47, 56))	('histone H4 acetylation', 'biological_process', 'GO:0043967', ('13', '35'))
123555	21303554	For the exposure and recovery experiment, the cells were exposed to 3 or 10 muM MS-275 until they reached confluency (2-3 days), fed fresh media without drug for 24 h, and then dosed with 100 muM ZnSO4(Sigma-Aldrich) for 24 h and harvested for RNA isolation.	('ZnSO4', 'Chemical', 'MESH:D019287', (196, 201))	('RNA', 'cellular_component', 'GO:0005562', ('244', '247'))	('muM', 'Gene', (192, 195))	('MS-275', 'Var', (80, 86))	('muM', 'Gene', '56925', (76, 79))	('MS-275', 'Chemical', 'MESH:C118739', (80, 86))	('muM', 'Gene', (76, 79))	('muM', 'Gene', '56925', (192, 195))
123563	21303554	The following antibodies were used in the immunoprecipitations: MTF-1 (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), Histone H3 trimethyl Lys9, Histone H3 trimethyl Lys4, Histone H3 trimethyl Lys27, (Active Motif) and Anti-acetyl-Histone H4 (Millipore, Billerica, MA).	('Anti-acetyl-Histone', 'Var', (221, 240))	('MTF-1', 'Gene', '4520', (64, 69))	('MTF-1', 'Gene', (64, 69))	('acetyl-Histone', 'Chemical', '-', (226, 240))	('Lys4', 'molecular_function', 'GO:0004409', ('168', '172'))	('Lys9', 'Chemical', '-', (141, 145))	('Lys4', 'Chemical', '-', (168, 172))	('Lys27', 'Chemical', '-', (195, 200))
123579	32323836	Furthermore, patients with pathological T1 stage and iCluster2 molecular subtype of LIHC expressed particularly low levels of E2F family genes.	('iCluster2', 'Var', (53, 62))	('E2F', 'Protein', (126, 129))	('LIHC', 'Disease', (84, 88))	('low', 'NegReg', (112, 115))	('patients', 'Species', '9606', (13, 21))	('LIHC', 'Disease', 'MESH:D006528', (84, 88))
123580	32323836	The present study demonstrated that hypo-DNA methylation, DNA amplification and TP53 mutation contributed to the high expression levels of E2F family genes in cancer cells.	('cancer', 'Disease', (159, 165))	('high expression levels', 'MPA', (113, 135))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('TP53', 'Gene', '7157', (80, 84))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('mutation', 'Var', (85, 93))	('TP53', 'Gene', (80, 84))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('E2F family genes', 'Gene', (139, 155))	('DNA amplification', 'biological_process', 'GO:0006277', ('58', '75'))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('DNA methylation', 'biological_process', 'GO:0006306', ('41', '56'))
123585	32323836	For example, E2F1 and E2F3 are increased in liver cancer, and the overexpression of E2F1 or E2F3 could induce spontaneous liver cancer development in mice.	('liver cancer', 'Disease', (44, 56))	('liver cancer', 'Disease', 'MESH:D006528', (122, 134))	('mice', 'Species', '10090', (150, 154))	('liver cancer', 'Phenotype', 'HP:0002896', (122, 134))	('liver cancer', 'Disease', (122, 134))	('E2F1', 'Var', (84, 88))	('E2F3', 'Var', (92, 96))	('E2F1', 'Var', (13, 17))	('E2F3', 'Var', (22, 26))	('induce', 'PosReg', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('liver cancer', 'Phenotype', 'HP:0002896', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('overexpression', 'PosReg', (66, 80))	('liver cancer', 'Disease', 'MESH:D006528', (44, 56))
123586	32323836	Furthermore, knockout of E2F8 could protect mice against the development of liver cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('knockout', 'Var', (13, 21))	('liver cancer', 'Phenotype', 'HP:0002896', (76, 88))	('liver cancer', 'Disease', 'MESH:D006528', (76, 88))	('E2F8', 'Gene', (25, 29))	('mice', 'Species', '10090', (44, 48))	('liver cancer', 'Disease', (76, 88))
123591	32323836	Restoring the balance between E2F1 and E2F7 is a therapeutic strategy in head and neck squamous cell carcinomas.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (73, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('neck', 'cellular_component', 'GO:0044326', ('82', '86'))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (82, 111))	('E2F1', 'Var', (30, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('E2F7', 'Gene', '144455', (39, 43))	('neck squamous cell carcinomas', 'Disease', (82, 111))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (87, 111))	('E2F7', 'Gene', (39, 43))
123631	32323836	Furthermore, the Kaplan-Meier survival analysis revealed that E2F1, E2F2, E2F4, E2F7 and E2F8 were all associated with overall survival in patients with LUAD (Fig.	('LUAD', 'Disease', 'MESH:D000077192', (153, 157))	('patients', 'Species', '9606', (139, 147))	('E2F2', 'Gene', (68, 72))	('E2F7', 'Gene', '144455', (80, 84))	('E2F4', 'Gene', (74, 78))	('LUAD', 'Disease', (153, 157))	('E2F2', 'Gene', '1870', (68, 72))	('LUAD', 'Phenotype', 'HP:0030078', (153, 157))	('associated with', 'Reg', (103, 118))	('E2F7', 'Gene', (80, 84))	('E2F8', 'Var', (89, 93))	('E2F1', 'Var', (62, 66))	('overall survival', 'MPA', (119, 135))	('E2F4', 'Gene', '1874', (74, 78))
123636	32323836	The Spearman's correlation test demonstrated a high correlation between E2F1, E2F7 and E2F8 in LIHC and LUAD expression datasets (Fig.	('LUAD', 'Disease', (104, 108))	('LUAD', 'Phenotype', 'HP:0030078', (104, 108))	('LIHC', 'Disease', (95, 99))	('LUAD', 'Disease', 'MESH:D000077192', (104, 108))	('E2F8', 'Var', (87, 91))	('E2F7', 'Gene', '144455', (78, 82))	('LIHC', 'Disease', 'MESH:D006528', (95, 99))	('E2F7', 'Gene', (78, 82))	('E2F1', 'Var', (72, 76))
123637	32323836	E2F2 was also highly correlated with E2F7 and E2F8 in LIHC and LUAD.	('E2F2', 'Gene', '1870', (0, 4))	('LUAD', 'Phenotype', 'HP:0030078', (63, 67))	('E2F8', 'Var', (46, 50))	('LUAD', 'Disease', (63, 67))	('LIHC', 'Disease', (54, 58))	('LIHC', 'Disease', 'MESH:D006528', (54, 58))	('E2F2', 'Gene', (0, 4))	('LUAD', 'Disease', 'MESH:D000077192', (63, 67))	('E2F7', 'Gene', '144455', (37, 41))	('correlated', 'Reg', (21, 31))	('E2F7', 'Gene', (37, 41))
123638	32323836	Additionally, E2F7 and E2F8 were correlated with each other (Fig.	('E2F7', 'Gene', (14, 18))	('E2F8', 'Var', (23, 27))	('E2F7', 'Gene', '144455', (14, 18))
123648	32323836	However, the expression levels of E2F5 and E2F8 in patients with T1 and T2 stage LIHC were not different.	('E2F5', 'Gene', '1875', (34, 38))	('E2F8', 'Var', (43, 47))	('E2F5', 'Gene', (34, 38))	('LIHC', 'Disease', (81, 85))	('patients', 'Species', '9606', (51, 59))	('LIHC', 'Disease', 'MESH:D006528', (81, 85))
123657	32323836	E2F2 and E2F8 were highly expressed in patients with T2 stage LUAD compared with patients with T1 stage (Fig.	('E2F2', 'Gene', '1870', (0, 4))	('E2F8', 'Var', (9, 13))	('patients', 'Species', '9606', (39, 47))	('LUAD', 'Phenotype', 'HP:0030078', (62, 66))	('LUAD', 'Disease', (62, 66))	('patients', 'Species', '9606', (81, 89))	('E2F2', 'Gene', (0, 4))	('LUAD', 'Disease', 'MESH:D000077192', (62, 66))
123660	32323836	Particularly LIHC, E2F2, E2F4, E2F5, E2F5 and E2F8 genes exhibited hypo-DNA methylation in tumor samples (Fig.	('E2F5', 'Gene', (37, 41))	('hypo-DNA methylation', 'MPA', (67, 87))	('E2F8', 'Var', (46, 50))	('E2F2', 'Gene', (19, 23))	('E2F4', 'Gene', '1874', (25, 29))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('E2F5', 'Gene', '1875', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('E2F5', 'Gene', (31, 35))	('E2F2', 'Gene', '1870', (19, 23))	('LIHC', 'Disease', (13, 17))	('LIHC', 'Disease', 'MESH:D006528', (13, 17))	('E2F5', 'Gene', '1875', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('E2F4', 'Gene', (25, 29))	('DNA methylation', 'biological_process', 'GO:0006306', ('72', '87'))	('tumor', 'Disease', (91, 96))
123664	32323836	It was revealed that the E2F1 and E2F3 genes were present in higher proportions of DNA amplification in BLCA (Fig.	('DNA amplification', 'biological_process', 'GO:0006277', ('83', '100'))	('BLCA', 'Disease', 'MESH:D001749', (104, 108))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('DNA', 'MPA', (83, 86))	('E2F3', 'Var', (34, 38))	('BLCA', 'Disease', (104, 108))	('E2F1', 'Gene', (25, 29))
123666	32323836	TP53 is a driver of mutations in several types of tumor.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('mutations', 'Var', (20, 29))
123669	32323836	It was revealed that, except for E2F5, the other E2F family genes were all highly expressed in patients with TP53 mutant LIHC and LUAD, compared with those patients with TP53 wild-type LIHC and LUAD (Fig.	('mutant', 'Var', (114, 120))	('LUAD', 'Disease', (194, 198))	('LIHC', 'Disease', (185, 189))	('LUAD', 'Disease', (130, 134))	('LIHC', 'Disease', (121, 125))	('patients', 'Species', '9606', (156, 164))	('TP53', 'Gene', '7157', (109, 113))	('TP53', 'Gene', (170, 174))	('E2F5', 'Gene', (33, 37))	('highly expressed', 'PosReg', (75, 91))	('LIHC', 'Disease', 'MESH:D006528', (185, 189))	('LIHC', 'Disease', 'MESH:D006528', (121, 125))	('TP53', 'Gene', (109, 113))	('LUAD', 'Disease', 'MESH:D000077192', (194, 198))	('patients', 'Species', '9606', (95, 103))	('LUAD', 'Disease', 'MESH:D000077192', (130, 134))	('TP53', 'Gene', '7157', (170, 174))	('LUAD', 'Phenotype', 'HP:0030078', (194, 198))	('E2F5', 'Gene', '1875', (33, 37))	('LUAD', 'Phenotype', 'HP:0030078', (130, 134))
123670	32323836	Overall, the present study speculated that hypo-DNA methylation, DNA amplification and TP53 mutation were contributing to the high expression levels of E2F family genes in cancer cells.	('TP53', 'Gene', '7157', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('mutation', 'Var', (92, 100))	('high expression levels', 'MPA', (126, 148))	('TP53', 'Gene', (87, 91))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('E2F family genes', 'Gene', (152, 168))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('DNA amplification', 'biological_process', 'GO:0006277', ('65', '82'))	('DNA methylation', 'biological_process', 'GO:0006306', ('48', '63'))	('cancer', 'Disease', (172, 178))
123679	32323836	It was revealed that, compared with other tumor types, E2F2-4, E2F7 and E2F8 were all expressed at relatively low levels in LIHC tumors (Fig.	('LIHC', 'Disease', (124, 128))	('E2F8', 'Var', (72, 76))	('tumor', 'Disease', (42, 47))	('tumors', 'Disease', (129, 135))	('LIHC', 'Disease', 'MESH:D006528', (124, 128))	('E2F7', 'Gene', '144455', (63, 67))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('E2F2-4', 'Gene', '1870;1871;1874', (55, 61))	('E2F7', 'Gene', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('E2F2-4', 'Gene', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
123683	32323836	E2F3 was highly expressed, while the expression levels of E2F7 and E2F8 were relatively lower in liver tissues (Fig.	('E2F8', 'Var', (67, 71))	('E2F7', 'Gene', '144455', (58, 62))	('E2F7', 'Gene', (58, 62))	('expression levels', 'MPA', (37, 54))	('lower', 'NegReg', (88, 93))	('E2F3', 'Gene', (0, 4))
123686	32323836	Similar to liver tissues, E2F3 was highly expressed, while the expression levels of E2F7 and E2F8 were relatively lower in normal lung or malignant tissues (Fig.	('expression levels', 'MPA', (63, 80))	('lower', 'NegReg', (114, 119))	('E2F7', 'Gene', '144455', (84, 88))	('E2F7', 'Gene', (84, 88))	('E2F8', 'Var', (93, 97))
123689	32323836	Similar to TCGA data, high expression levels of the E2F family genes E2F1, E2F2, E2F4, E2F7 and E2F8 were all associated with low overall survival in patients with lung cancer, while, high expression levels of E2F3, E2F5 and E2F6 were associated with an improved prognosis in patients with LUAD (Fig.	('patients', 'Species', '9606', (276, 284))	('E2F2', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('patients', 'Species', '9606', (150, 158))	('E2F3', 'Var', (210, 214))	('E2F2', 'Gene', '1870', (75, 79))	('E2F7', 'Gene', '144455', (87, 91))	('lung cancer', 'Disease', (164, 175))	('E2F5', 'Gene', (216, 220))	('E2F8', 'Var', (96, 100))	('E2F1', 'Gene', (69, 73))	('LUAD', 'Disease', 'MESH:D000077192', (290, 294))	('low', 'NegReg', (126, 129))	('E2F4', 'Gene', (81, 85))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('LUAD', 'Phenotype', 'HP:0030078', (290, 294))	('E2F5', 'Gene', '1875', (216, 220))	('E2F4', 'Gene', '1874', (81, 85))	('expression levels', 'MPA', (27, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('E2F7', 'Gene', (87, 91))	('E2F6', 'Gene', '1876', (225, 229))	('overall survival', 'MPA', (130, 146))	('E2F6', 'Gene', (225, 229))	('LUAD', 'Disease', (290, 294))
123693	32323836	Results derived from this dataset suggested a strong correlation among E2F1, E2F7 and E2F8 (Fig.	('E2F7', 'Gene', (77, 81))	('E2F8', 'Var', (86, 90))	('E2F7', 'Gene', '144455', (77, 81))	('E2F1', 'Var', (71, 75))
123694	32323836	E2F2 was also strongly correlated with E2F7 and E2F8.	('E2F2', 'Gene', '1870', (0, 4))	('correlated', 'Reg', (23, 33))	('E2F2', 'Gene', (0, 4))	('E2F7', 'Gene', '144455', (39, 43))	('E2F7', 'Gene', (39, 43))	('E2F8', 'Var', (48, 52))
123695	32323836	In addition, E2F7 and E2F8 were correlated with each other (Fig.	('E2F7', 'Gene', (13, 17))	('E2F7', 'Gene', '144455', (13, 17))	('E2F8', 'Var', (22, 26))
123697	32323836	Only E2F4 and E2F8 were independent prognostic markers (Fig.	('E2F4', 'Gene', '1874', (5, 9))	('E2F4', 'Gene', (5, 9))	('E2F8', 'Var', (14, 18))
123704	32323836	For example, higher E2F1, E2F3, E2F5, E2F7 and E2F8 expression levels were significantly associated with lower overall survival in patients with breast cancer.	('lower', 'NegReg', (105, 110))	('E2F7', 'Gene', '144455', (38, 42))	('patients', 'Species', '9606', (131, 139))	('E2F7', 'Gene', (38, 42))	('overall survival', 'MPA', (111, 127))	('E2F3', 'Var', (26, 30))	('higher', 'PosReg', (13, 19))	('E2F8', 'Var', (47, 51))	('expression', 'MPA', (52, 62))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('E2F1', 'Var', (20, 24))	('E2F5', 'Gene', '1875', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('E2F5', 'Gene', (32, 36))
123705	32323836	E2F1, E2F3 and E2F4 were significantly associated with unfavorable outcomes in patients with gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('E2F4', 'Gene', (15, 19))	('E2F1', 'Var', (0, 4))	('associated', 'Reg', (39, 49))	('patients', 'Species', '9606', (79, 87))	('E2F3', 'Var', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('E2F4', 'Gene', '1874', (15, 19))	('gastric cancer', 'Disease', (93, 107))
123709	32323836	In patients with LUAD, E2F1, E2F2, E2F4, E2F7 and E2F8, were significantly associated with unfavorable outcomes.	('E2F8', 'Var', (50, 54))	('E2F7', 'Gene', '144455', (41, 45))	('E2F2', 'Gene', (29, 33))	('E2F7', 'Gene', (41, 45))	('E2F1', 'Var', (23, 27))	('E2F4', 'Gene', (35, 39))	('LUAD', 'Disease', 'MESH:D000077192', (17, 21))	('E2F4', 'Gene', '1874', (35, 39))	('patients', 'Species', '9606', (3, 11))	('E2F2', 'Gene', '1870', (29, 33))	('LUAD', 'Phenotype', 'HP:0030078', (17, 21))	('associated', 'Reg', (75, 85))	('LUAD', 'Disease', (17, 21))
123713	32323836	The present study demonstrated that, in LIHC and LUAD patients, the hypomethylation of the E2F family genes in tumor samples may explain the high expression levels of these genes in the tumor tissues.	('hypomethylation', 'Var', (68, 83))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('LUAD', 'Phenotype', 'HP:0030078', (49, 53))	('LIHC', 'Disease', (40, 44))	('LUAD', 'Disease', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('expression levels', 'MPA', (146, 163))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', (111, 116))	('E2F family genes', 'Gene', (91, 107))	('LIHC', 'Disease', 'MESH:D006528', (40, 44))	('LUAD', 'Disease', 'MESH:D000077192', (49, 53))
123719	32323836	The present study demonstrated that, except for E2F5, the E2F family genes were all highly expressed in patients with TP53 mutant LIHC and LUAD, compared with patients with TP53 wild-type LIHC and LUAD.	('E2F5', 'Gene', '1875', (48, 52))	('LUAD', 'Disease', (139, 143))	('TP53', 'Gene', (118, 122))	('LIHC', 'Disease', (130, 134))	('TP53', 'Gene', (173, 177))	('highly expressed', 'PosReg', (84, 100))	('E2F family', 'Gene', (58, 68))	('LIHC', 'Disease', 'MESH:D006528', (130, 134))	('LUAD', 'Disease', 'MESH:D000077192', (197, 201))	('LIHC', 'Disease', (188, 192))	('TP53', 'Gene', '7157', (118, 122))	('E2F5', 'Gene', (48, 52))	('TP53', 'Gene', '7157', (173, 177))	('LUAD', 'Phenotype', 'HP:0030078', (197, 201))	('patients', 'Species', '9606', (159, 167))	('patients', 'Species', '9606', (104, 112))	('LUAD', 'Disease', 'MESH:D000077192', (139, 143))	('LUAD', 'Phenotype', 'HP:0030078', (139, 143))	('LIHC', 'Disease', 'MESH:D006528', (188, 192))	('LUAD', 'Disease', (197, 201))	('mutant', 'Var', (123, 129))
123729	29601842	We conclude that ERBB2 amplification and HER2 overexpression are preferentially but not exclusively identified in the MP component compared to the NOS component within the same tumor.	('overexpression', 'PosReg', (46, 60))	('amplification', 'Var', (23, 36))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('ERBB2', 'Gene', '2064', (17, 22))	('HER2', 'Gene', (41, 45))	('ERBB2', 'Gene', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('HER2', 'Gene', '2064', (41, 45))	('tumor', 'Disease', (177, 182))
123730	29601842	Our findings identify the presence of intratumoral heterogeneity of ERBB2 amplification and HER2 expression in MPUC and provide grounds for further investigation into the mechanisms underlying the development of MPUC.	('MPUC', 'Disease', (111, 115))	('amplification', 'Var', (74, 87))	('ERBB2', 'Gene', '2064', (68, 73))	('HER2', 'Gene', '2064', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('HER2', 'Gene', (92, 96))	('ERBB2', 'Gene', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('expression', 'MPA', (97, 107))
123736	29601842	HER2 protein overexpression and ERBB2 amplification have also been reported in several other cancers though the therapeutic relevance of such alterations remains to be defined.	('cancers', 'Disease', (93, 100))	('ERBB2', 'Gene', (32, 37))	('ERBB2', 'Gene', '2064', (32, 37))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('overexpression', 'PosReg', (13, 27))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('amplification', 'Var', (38, 51))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
123741	29601842	All tumors were subjected to fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) to detect ERBB2 amplification and HER2 protein expression, respectively.	('ERBB2', 'Gene', '2064', (112, 117))	('amplification', 'Var', (118, 131))	('ERBB2', 'Gene', (112, 117))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('HER2', 'Gene', (136, 140))	('expression', 'MPA', (149, 159))	('HER2', 'Gene', '2064', (136, 140))
123744	29601842	The probe mix consisted of BAC clones containing the ERBB2 gene (RP11-94L15, RP11-62N23 and CTD-3211L18; labeled with Red dUTP) and a centromeric repeat plasmid for Chr17 (clone p17H8p; labeled with Green dUTP) served as the control.	('ERBB2', 'Gene', '2064', (53, 58))	('dUTP', 'Chemical', 'MESH:C027078', (205, 209))	('RP11', 'Gene', '26121', (65, 69))	('CTD-3211L18', 'Var', (92, 103))	('RP11', 'Gene', (77, 81))	('dUTP', 'Chemical', 'MESH:C027078', (122, 126))	('RP11', 'Gene', '26121', (77, 81))	('RP11', 'Gene', (65, 69))	('ERBB2', 'Gene', (53, 58))
123753	29601842	The association between ERBB2 amplification and HER2 protein expression was evaluated using Spearman's rank correlation coefficients.	('HER2', 'Gene', '2064', (48, 52))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('amplification', 'Var', (30, 43))	('ERBB2', 'Gene', (24, 29))	('ERBB2', 'Gene', '2064', (24, 29))	('HER2', 'Gene', (48, 52))
123754	29601842	Kaplan-Meier survival plots were created to demonstrate the ability of the pathologic variables, amount of MP component, ERBB2 amplification and HER2 expression in the MP component to predict overall survival.	('HER2', 'Gene', (145, 149))	('HER2', 'Gene', '2064', (145, 149))	('ERBB2', 'Gene', '2064', (121, 126))	('overall', 'MPA', (192, 199))	('amplification', 'Var', (127, 140))	('ERBB2', 'Gene', (121, 126))
123761	29601842	Overall, ERBB2 amplification was more commonly present in the MP component compared to the NOS component within the same tumor [23 of 34 tumors (67.6%) vs. 15 of 34 tumors (44.1%), p=0.057, Figure 5].	('tumors', 'Disease', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('ERBB2', 'Gene', '2064', (9, 14))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('present', 'Reg', (47, 54))	('tumor', 'Disease', (137, 142))	('tumors', 'Disease', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (165, 170))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('amplification', 'Var', (15, 28))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('ERBB2', 'Gene', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
123765	29601842	An example of polysomy pattern ERBB2 amplification is depicted in Figure 4.	('ERBB2', 'Gene', (31, 36))	('amplification', 'Var', (37, 50))	('ERBB2', 'Gene', '2064', (31, 36))	('polysomy', 'Var', (14, 22))
123766	29601842	In the 12 tumors with ERBB2 amplification in both MP and NOS components, concordant HSR amplification was observed in 8 tumors.	('ERBB2', 'Gene', '2064', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('ERBB2', 'Gene', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('amplification', 'Var', (28, 41))
123767	29601842	Interestingly, 4 tumors displayed different patterns of ERBB2 amplification in the MP and NOS components: in 2 tumors, high polysomy type amplification was observed in the MP component and HSR in the NOS component and the reverse occurred in 2 cases.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('ERBB2', 'Gene', '2064', (56, 61))	('high polysomy type', 'Var', (119, 137))	('ERBB2', 'Gene', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
123768	29601842	In summary, our results indicate that HSR-type amplification of ERBB2 is more prevalent in MPUC.	('ERBB2', 'Gene', (64, 69))	('prevalent', 'Reg', (78, 87))	('ERBB2', 'Gene', '2064', (64, 69))	('HSR-type amplification', 'Var', (38, 60))	('MPUC', 'Disease', (91, 95))
123776	29601842	In tumors with an IHC score of 2+, ERBB2 amplification was noted in 71.4% (10 of 14) of MP and 83.3% (5 of 6) of NOS areas respectively.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('amplification', 'Var', (41, 54))	('ERBB2', 'Gene', (35, 40))	('ERBB2', 'Gene', '2064', (35, 40))	('noted', 'Reg', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
123777	29601842	In tumors with an IHC score of 1+, ERBB2 amplification was noted in 33.3% (3 of 9) of MP and 29.4% (5 of 17) of NOS components respectively.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('amplification', 'Var', (41, 54))	('ERBB2', 'Gene', (35, 40))	('ERBB2', 'Gene', '2064', (35, 40))	('noted', 'Reg', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
123779	29601842	In the 8 cases with MP histology only, 3 tumors had HSR type ERBB2 amplification; 2 of which had HER2 IHC score 3+ and 1 tumor had 2+ score.	('HER2', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('ERBB2', 'Gene', (61, 66))	('HER2', 'Gene', '2064', (97, 101))	('ERBB2', 'Gene', '2064', (61, 66))	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('amplification', 'Var', (67, 80))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('tumor', 'Disease', (121, 126))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('HSR type', 'Var', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
123780	29601842	Two tumors displayed high polysomy type ERBB2 amplification, with 1 tumor characterized as HER2 IHC score 2+ and 1 tumor 1+.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (68, 73))	('ERBB2', 'Gene', '2064', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('ERBB2', 'Gene', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Disease', (4, 10))	('tumor', 'Disease', (115, 120))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('HER2', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('HER2', 'Gene', '2064', (91, 95))	('amplification', 'MPA', (46, 59))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('polysomy type', 'Var', (26, 39))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
123786	29601842	Supplementary Figure 1 shows Kaplan-Meier overall survival plots as a function of tumor stage, lymph node status, amount of MP component, ERBB2 amplification and HER2 protein expression in the MP component.	('HER2', 'Gene', '2064', (162, 166))	('HER2', 'Gene', (162, 166))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('ERBB2', 'Gene', '2064', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('amplification', 'Var', (144, 157))	('ERBB2', 'Gene', (138, 143))	('tumor', 'Disease', (82, 87))
123789	29601842	In this study, we examined 43 MPUC cases for evidence of ERBB2 amplification and HER2 overexpression.	('ERBB2', 'Gene', '2064', (57, 62))	('ERBB2', 'Gene', (57, 62))	('HER2', 'Gene', (81, 85))	('HER2', 'Gene', '2064', (81, 85))	('overexpression', 'PosReg', (86, 100))	('amplification', 'Var', (63, 76))
123790	29601842	We identified ERBB2 amplification and HER2 overexpression in nearly two-thirds of cases, which is significantly higher than what has been reported in classic urothelial carcinoma [- ].	('classic urothelial carcinoma', 'Disease', (150, 178))	('classic urothelial carcinoma', 'Disease', 'MESH:D005693', (150, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('overexpression', 'PosReg', (43, 57))	('amplification', 'Var', (20, 33))	('ERBB2', 'Gene', '2064', (14, 19))	('ERBB2', 'Gene', (14, 19))	('HER2', 'Gene', (38, 42))	('HER2', 'Gene', '2064', (38, 42))
123791	29601842	The high rate of ERBB2 amplification in MPUC suggests that agents that inhibit HER2 signaling may be a potential targeted therapeutic approach for this histologic subtype.	('HER2', 'Gene', '2064', (79, 83))	('amplification', 'Var', (23, 36))	('ERBB2', 'Gene', '2064', (17, 22))	('MPUC', 'Disease', (40, 44))	('ERBB2', 'Gene', (17, 22))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('HER2', 'Gene', (79, 83))
123792	29601842	Recently, Choudhury et al reported that treatment of urothelial tumors containing ERBB2 or ERBB3 alterations with afatinib (an oral irreversible inhibitor of the ERBB family) significantly increased progression free survival duration in patients with platinum-refractory urothelial carcinoma.	('ERBB3', 'Gene', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('ERBB2', 'Gene', '2064', (82, 87))	('patients', 'Species', '9606', (237, 245))	('ERBB', 'Gene', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('progression free survival duration', 'CPA', (199, 233))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (271, 291))	('ERBB', 'Gene', '1956', (162, 166))	('ERBB', 'Gene', (82, 86))	('ERBB', 'Gene', (91, 95))	('urothelial tumors', 'Disease', (53, 70))	('ERBB', 'Gene', '1956', (91, 95))	('ERBB3', 'Gene', '2065', (91, 96))	('ERBB', 'Gene', '1956', (82, 86))	('alterations', 'Var', (97, 108))	('afatinib', 'Chemical', 'MESH:D000077716', (114, 122))	('urothelial tumors', 'Disease', 'MESH:D001749', (53, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('ERBB2', 'Gene', (82, 87))	('urothelial carcinoma', 'Disease', (271, 291))	('increased', 'PosReg', (189, 198))
123793	29601842	Notably, this is the first study to assess ERBB2 amplification in NOS component of MPUC.	('ERBB2', 'Gene', (43, 48))	('ERBB2', 'Gene', '2064', (43, 48))	('amplification', 'Var', (49, 62))
123795	29601842	In this study, we showed that ERBB2 amplification and HER2 overexpression are more frequently present in the MP component than in the NOS component within the same tumor (67.6% vs. 44.1%, p=0.057; 68.6% vs. 34.3%, p=0.012 respectively).	('tumor', 'Disease', (164, 169))	('ERBB2', 'Gene', '2064', (30, 35))	('HER2', 'Gene', (54, 58))	('ERBB2', 'Gene', (30, 35))	('HER2', 'Gene', '2064', (54, 58))	('amplification', 'Var', (36, 49))	('overexpression', 'PosReg', (59, 73))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
123797	29601842	Further, this indicates that ERBB2 amplification is a common genetic event in both the MP and NOS components although it is more frequently associated with the former.	('amplification', 'Var', (35, 48))	('ERBB2', 'Gene', (29, 34))	('ERBB2', 'Gene', '2064', (29, 34))
123801	29601842	In our study, only MP/NOS areas with IHC scores of 0 were not associated with ERBB2 amplification.	('ERBB2', 'Gene', '2064', (78, 83))	('amplification', 'Var', (84, 97))	('ERBB2', 'Gene', (78, 83))
123802	29601842	The majority of MPUC in this cohort were associated with HSR-type of ERBB2 amplification and there was no correlation between the type of amplification and clinical outcome.	('associated', 'Reg', (41, 51))	('HSR-type', 'Var', (57, 65))	('MPUC', 'Disease', (16, 20))	('amplification', 'Var', (75, 88))	('ERBB2', 'Gene', '2064', (69, 74))	('ERBB2', 'Gene', (69, 74))
123806	29601842	Therefore, this study is the first to report on the presence of intratumoral heterogeneity in ERBB2 amplification and HER2 overexpression in MPUC in relation to morphologic heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('amplification', 'Var', (100, 113))	('tumor', 'Disease', (69, 74))	('HER2', 'Gene', (118, 122))	('overexpression', 'PosReg', (123, 137))	('HER2', 'Gene', '2064', (118, 122))	('ERBB2', 'Gene', '2064', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('ERBB2', 'Gene', (94, 99))
123807	29601842	It has been recently suggested that MPUC also harbors higher rates of activating ERBB2 mutations, but this observation requires further independent validation.	('ERBB2', 'Gene', '2064', (81, 86))	('activating', 'MPA', (70, 80))	('mutations', 'Var', (87, 96))	('ERBB2', 'Gene', (81, 86))
123810	29601842	A large multi-institutional study incorporating multi-platform genomic analysis of MPUC is required to better delineate the prevalence, clonality, and intra- and inter-tumoral heterogeneity of ERBB2 amplification and HER2 overexpression in this rare variant histologic subtype.	('HER2', 'Gene', (217, 221))	('ERBB2', 'Gene', '2064', (193, 198))	('overexpression', 'PosReg', (222, 236))	('tumor', 'Disease', (168, 173))	('ERBB2', 'Gene', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('amplification', 'Var', (199, 212))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('HER2', 'Gene', '2064', (217, 221))
123812	29601842	ERBB2 amplification is very common in micropapillary bladder cancer.	('common', 'Reg', (28, 34))	('ERBB2', 'Gene', '2064', (0, 5))	('ERBB2', 'Gene', (0, 5))	('micropapillary bladder cancer', 'Disease', 'MESH:D001749', (38, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('amplification', 'Var', (6, 19))	('micropapillary bladder cancer', 'Disease', (38, 67))	('bladder cancer', 'Phenotype', 'HP:0009725', (53, 67))
123813	29601842	There is intratumoral heterogeneity of ERBB2 amplification in micropapillary bladder cancer.	('ERBB2', 'Gene', '2064', (39, 44))	('micropapillary bladder cancer', 'Disease', (62, 91))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('micropapillary bladder cancer', 'Disease', 'MESH:D001749', (62, 91))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('amplification', 'Var', (45, 58))	('ERBB2', 'Gene', (39, 44))
123814	29601842	ERBB2 amplification is more common in micropapillary component of tumors with mixed histology.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('common', 'Reg', (28, 34))	('micropapillary component of tumors', 'Disease', 'MESH:D009369', (38, 72))	('ERBB2', 'Gene', '2064', (0, 5))	('micropapillary component of tumors', 'Disease', (38, 72))	('ERBB2', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('amplification', 'Var', (6, 19))
124008	27042108	Azuma et al revealed that recurrence-free survival and CSS rates of patients in the high-NLR group (>=2.5) were lower than those in the low-NLR group (<2.5).	('recurrence-free survival', 'CPA', (26, 50))	('patients', 'Species', '9606', (68, 76))	('high-NLR', 'Var', (84, 92))	('lower', 'NegReg', (112, 117))	('CSS rates', 'CPA', (55, 64))	('CSS', 'Chemical', '-', (55, 58))
124011	27042108	Using a cutoff value of 2.2, the patients in the high-NLR group had poorer DFS and PFS than those in the low-NLR group.	('patients', 'Species', '9606', (33, 41))	('high-NLR', 'Var', (49, 57))	('poorer', 'NegReg', (68, 74))	('PFS', 'MPA', (83, 86))	('DFS', 'MPA', (75, 78))
124015	27042108	Similarly, we found that LMR could be an independent predictor of DFS and PFS in patients with UUTUC.	('LMR', 'Var', (25, 28))	('DFS', 'Disease', (66, 69))	('PFS', 'Disease', (74, 77))	('patients', 'Species', '9606', (81, 89))
124018	27042108	European guidelines on UUTUC state that tumor stage and grade, age, LVI, extensive tumor necrosis, tumor architecture (eg, papillary vs sessile), concomitant carcinoma in situ, and some molecular markers such as microsatellite instability are closely related to the prognosis of UUTUC.	('carcinoma in situ', 'Phenotype', 'HP:0030075', (158, 175))	('tumor', 'Disease', (83, 88))	('related', 'Reg', (251, 258))	('LVI', 'Disease', (68, 71))	('necrosis', 'biological_process', 'GO:0070265', ('89', '97'))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor necrosis', 'Disease', 'MESH:D009336', (83, 97))	('necrosis', 'biological_process', 'GO:0019835', ('89', '97'))	('tumor', 'Disease', (99, 104))	('necrosis', 'biological_process', 'GO:0001906', ('89', '97'))	('tumor necrosis', 'Disease', (83, 97))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('carcinoma', 'Disease', (158, 167))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (40, 45))	('necrosis', 'biological_process', 'GO:0008219', ('89', '97'))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('carcinoma', 'Disease', 'MESH:D002277', (158, 167))	('microsatellite instability', 'Var', (212, 238))	('necrosis', 'biological_process', 'GO:0008220', ('89', '97'))
124027	26869805	Intravenous chemotherapy combined with intravesical chemotherapy to treat T1G3 bladder urothelial carcinoma after transurethral resection of bladder tumor: results of a retrospective study The management of stage 1 and grade 3 (T1G3) bladder cancer continues to be controversial.	('T1G3', 'Var', (74, 78))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (79, 107))	('bladder tumor', 'Disease', 'MESH:D001749', (141, 154))	('bladder tumor', 'Phenotype', 'HP:0009725', (141, 154))	('bladder urothelial carcinoma', 'Disease', (79, 107))	('bladder cancer', 'Phenotype', 'HP:0009725', (234, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('bladder tumor', 'Disease', (141, 154))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('bladder cancer', 'Disease', 'MESH:D001749', (234, 248))	('bladder cancer', 'Disease', (234, 248))
124028	26869805	Although the transurethral resection of bladder tumor (TURBT) followed by intravesical chemotherapy is a conservative strategy for treatment of T1G3 bladder cancer, a relatively high risk of tumor recurrence and progression remains regarding the therapy.	('bladder cancer', 'Disease', 'MESH:D001749', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('bladder tumor', 'Disease', (40, 53))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('T1G3', 'Var', (144, 148))	('bladder cancer', 'Disease', (149, 163))	('bladder tumor', 'Disease', 'MESH:D001749', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('bladder cancer', 'Phenotype', 'HP:0009725', (149, 163))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('bladder tumor', 'Phenotype', 'HP:0009725', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
124030	26869805	We retrospectively reviewed the cases of 457 patients who were newly diagnosed with T1G3 bladder urothelial carcinoma between January 2009 and March 2014.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (89, 117))	('patients', 'Species', '9606', (45, 53))	('bladder urothelial carcinoma', 'Disease', (89, 117))	('T1G3', 'Var', (84, 88))
124036	26869805	Intravenous chemotherapy combined with intravesical chemotherapy offers a better oncologic outcome than the intravesical chemotherapy alone for patients with T1G3 bladder urothelial carcinoma after TURBT, and it may be considered as a new therapy strategy for T1G3 bladder cancer.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (163, 191))	('T1G3', 'Var', (158, 162))	('bladder urothelial carcinoma', 'Disease', (163, 191))	('bladder cancer', 'Phenotype', 'HP:0009725', (265, 279))	('patients', 'Species', '9606', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('bladder cancer', 'Disease', 'MESH:D001749', (265, 279))	('bladder cancer', 'Disease', (265, 279))
124038	26869805	Although surgical urologists and oncologists are dedicating to improve and innovate the treatments for T1G3 bladder cancer, they have not reached an agreement on the optimal management of patients with the neoplasm.	('neoplasm', 'Disease', (206, 214))	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('bladder cancer', 'Disease', (108, 122))	('neoplasm', 'Phenotype', 'HP:0002664', (206, 214))	('neoplasm', 'Disease', 'MESH:D009369', (206, 214))	('T1G3', 'Var', (103, 107))	('patients', 'Species', '9606', (188, 196))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
124039	26869805	Several studies have recommended the immediate radical cystectomy for patients with T1G3 bladder cancer and the radical cystectomy has proven an improvement in outcome of long-term tumor specific survival.	('patients', 'Species', '9606', (70, 78))	('improvement', 'PosReg', (145, 156))	('tumor', 'Disease', (181, 186))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('T1G3', 'Var', (84, 88))
124047	26869805	In this retrospective study, the tumor recurrence and progression outcomes of patients with T1G3 bladder cancer who underwent intravenous chemotherapy combined with intravesical chemotherapy after TURBT were compared with those of patients who received intravesical chemotherapy alone after TURBT.	('patients', 'Species', '9606', (231, 239))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('bladder cancer', 'Disease', 'MESH:D001749', (97, 111))	('bladder cancer', 'Disease', (97, 111))	('patients', 'Species', '9606', (78, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('T1G3', 'Var', (92, 96))
124048	26869805	To the best of our knowledge, this is the first report to assess the impact of intravenous chemotherapy combined with intravesical chemotherapy in the outcomes of tumor recurrence and progression for patients with T1G3 bladder cancer.	('patients', 'Species', '9606', (200, 208))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('bladder cancer', 'Phenotype', 'HP:0009725', (219, 233))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('bladder cancer', 'Disease', 'MESH:D001749', (219, 233))	('T1G3', 'Var', (214, 218))	('bladder cancer', 'Disease', (219, 233))
124079	26869805	The treatment of T1G3 bladder cancer continues to be debated by urologists, as it has a high risk of recurrence and progression.	('T1G3', 'Var', (17, 21))	('bladder cancer', 'Disease', 'MESH:D001749', (22, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('bladder cancer', 'Disease', (22, 36))	('bladder cancer', 'Phenotype', 'HP:0009725', (22, 36))
124080	26869805	Currently, T1G3 bladder cancer is treated with early radical cystectomy or TURBT followed by adjuvant intravesical therapy with BCG, or followed by the intra-arterial chemotherapy combined with intravesical chemotherapy or radiation therapy with or without chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('bladder cancer', 'Disease', 'MESH:D001749', (16, 30))	('bladder cancer', 'Disease', (16, 30))	('T1G3', 'Var', (11, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (16, 30))	('BCG', 'Species', '33892', (128, 131))
124082	26869805	As quite a few patients with T1G3 bladder cancer do not accept radical cystectomy as the initial treatment, conservative therapies of high efficacy and safety are greatly anticipated.	('patients', 'Species', '9606', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('bladder cancer', 'Disease', 'MESH:D001749', (34, 48))	('T1G3', 'Var', (29, 33))	('bladder cancer', 'Disease', (34, 48))
124084	26869805	Our analysis shows that compared to intravesical chemotherapy alone after TURBT that had a recurrence rate of 36.7%, intravenous chemotherapy in combination with intravesical chemotherapy effectively decreased the tumor recurrence in patients with T1G3 bladder cancer, showing a lower rate of 19.9% (P<0.001).	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('bladder cancer', 'Disease', 'MESH:D001749', (253, 267))	('bladder cancer', 'Disease', (253, 267))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('T1G3', 'Var', (248, 252))	('decreased', 'NegReg', (200, 209))	('patients', 'Species', '9606', (234, 242))	('tumor', 'Disease', (214, 219))	('bladder cancer', 'Phenotype', 'HP:0009725', (253, 267))
124094	26869805	Although conservative treatments for T1G3 bladder cancer have been shown to effectively prevent the progression in literatures, the relatively short duration of follow-up and the small size of patient cohort in the studies should be taken into account when interpreting the data.	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('bladder cancer', 'Disease', 'MESH:D001749', (42, 56))	('bladder cancer', 'Disease', (42, 56))	('patient', 'Species', '9606', (193, 200))	('T1G3', 'Var', (37, 41))
124096	26869805	In our series of 457 T1G3 bladder cancer patients, tumor progression occurred in 10.6% of the patients treated with intravesical chemotherapy alone after TURBT and 2.3% of the patients treated with intravesical combined with intravenous chemotherapy after TURBT (P=0.003), suggesting that the combined chemotherapies have a considerably improved efficacy in preventing tumor from progression.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (176, 184))	('bladder cancer', 'Phenotype', 'HP:0009725', (26, 40))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('patients', 'Species', '9606', (94, 102))	('T1G3', 'Var', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (369, 374))	('tumor', 'Disease', (51, 56))	('bladder cancer', 'Disease', (26, 40))	('bladder cancer', 'Disease', 'MESH:D001749', (26, 40))	('tumor', 'Phenotype', 'HP:0002664', (369, 374))	('patients', 'Species', '9606', (41, 49))	('tumor', 'Disease', (369, 374))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
124102	26869805	Considering the advantage of oxaliplatin that it can be administered to patients with renal impairment, we adopted oxaliplatin for intravenous chemotherapy to treat patients with T1G3 bladder urothelial carcinoma.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (184, 212))	('renal impairment', 'Phenotype', 'HP:0000083', (86, 102))	('T1G3', 'Var', (179, 183))	('patients', 'Species', '9606', (72, 80))	('bladder urothelial carcinoma', 'Disease', (184, 212))	('renal impairment', 'Disease', (86, 102))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (115, 126))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (29, 40))	('patients', 'Species', '9606', (165, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('renal impairment', 'Disease', 'MESH:D007674', (86, 102))
124108	26436532	Systematic analysis of somatic mutations impacting gene expression in 12 tumour types We present a novel hierarchical Bayes statistical model, xseq, to systematically quantify the impact of somatic mutations on expression profiles.	('tumour', 'Disease', (73, 79))	('mutations', 'Var', (31, 40))	('gene expression', 'biological_process', 'GO:0010467', ('51', '66'))	('impacting', 'Reg', (41, 50))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))
124109	26436532	We then use xseq to analyse thousands of tumour data sets available through The Cancer Genome Atlas, to systematically quantify somatic mutations impacting expression profiles.	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('Cancer Genome Atlas', 'Disease', (80, 99))	('expression profiles', 'MPA', (156, 175))	('mutations', 'Var', (136, 145))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('impacting', 'Reg', (146, 155))	('tumour', 'Disease', (41, 47))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (80, 99))
124110	26436532	We identify 30 novel cis-effect tumour suppressor gene candidates, enriched in loss-of-function mutations and biallelic inactivation.	('tumour', 'Disease', (32, 38))	('loss-of-function', 'NegReg', (79, 95))	('biallelic inactivation', 'Var', (110, 132))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('mutations', 'Var', (96, 105))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
124111	26436532	We reveal two important novel characteristics of mutation impact on expression: (1) patients harbouring known driver mutations exhibit different downstream gene expression consequences; (2) expression patterns for some mutations are stable across tumour types.	('mutations', 'Var', (117, 126))	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('patients', 'Species', '9606', (84, 92))	('tumour type', 'Disease', 'MESH:D009369', (247, 258))	('tumour type', 'Disease', (247, 258))	('gene expression', 'biological_process', 'GO:0010467', ('156', '171'))	('mutations', 'Var', (219, 228))
124112	26436532	These results have critical implications for identification and interpretation of mutations with consequent impact on transcription in cancer.	('cancer', 'Disease', (135, 141))	('transcription', 'biological_process', 'GO:0006351', ('118', '131'))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (82, 91))	('transcription', 'MPA', (118, 131))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('impact', 'Reg', (108, 114))
124113	26436532	Assessing functional impact of mutations in cancer on gene expression can improve our understanding of cancer biology and may identify potential therapeutic targets.	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('improve', 'PosReg', (74, 81))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('gene expression', 'biological_process', 'GO:0010467', ('54', '69'))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
124115	26436532	describe a novel statistical model named xseq for a systematic survey of how mutations impact transcriptome landscapes across 12 different tumour types.	('tumour type', 'Disease', 'MESH:D009369', (139, 150))	('tumour type', 'Disease', (139, 150))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('mutations', 'Var', (77, 86))	('transcriptome landscapes', 'MPA', (94, 118))	('impact', 'Reg', (87, 93))
124116	26436532	Human cancers acquire malignant properties following a stepwise accumulation of somatic genomic alterations and subsequent evolutionary selection on resultant phenotypic changes.	('Human', 'Species', '9606', (0, 5))	('alterations', 'Var', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('malignant properties', 'CPA', (22, 42))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))
124118	26436532	We have assessed the impact of mutations on gene expression as a means of quantifying potential phenotypic effects, and for novel cancer gene discovery.	('mutations', 'Var', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('gene expression', 'biological_process', 'GO:0010467', ('44', '59'))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
124119	26436532	This concept is motivated by biological hypotheses predicting that some functional mutations will exhibit a 'transcriptional shadow', resulting from a mechanistic impact on the gene expression profile of a tumour.	('mutations', 'Var', (83, 92))	('gene expression', 'biological_process', 'GO:0010467', ('177', '192'))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('gene expression profile', 'MPA', (177, 200))	('tumour', 'Disease', 'MESH:D009369', (206, 212))	('tumour', 'Disease', (206, 212))	('impact', 'Reg', (163, 169))
124120	26436532	For example, loss-of-function mutations (nonsense mutations, frame-shifting indels, splice site mutations or homozygous copy number deletions) occurring in tumour suppressor genes such as TP53 can cause loss of expression due to nonsense-mediated messenger RNA (mRNA) decay or gene dosage effects.	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('loss-of-function', 'NegReg', (13, 29))	('tumour', 'Disease', (156, 162))	('loss', 'NegReg', (203, 207))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('mRNA) decay', 'biological_process', 'GO:0006402', ('262', '273'))	('RNA', 'cellular_component', 'GO:0005562', ('257', '260'))	('mutations', 'Var', (30, 39))	('frame-shifting', 'Var', (61, 75))	('TP53', 'Gene', '7157', (188, 192))	('TP53', 'Gene', (188, 192))	('expression', 'MPA', (211, 221))	('mutations', 'Var', (96, 105))
124121	26436532	beta-Catenin (CTNNB1) mutations, which drive constitutive activation of Wnt signalling in several cancer types, are a potent example of mutational impact on gene expression.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gene expression', 'biological_process', 'GO:0010467', ('157', '172'))	('CTNNB1', 'Gene', '1499', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Wnt signalling', 'MPA', (72, 86))	('beta-Catenin', 'Gene', (0, 12))	('beta-Catenin', 'Gene', '1499', (0, 12))	('signalling', 'biological_process', 'GO:0023052', ('76', '86'))	('cancer', 'Disease', (98, 104))	('mutations', 'Var', (22, 31))	('CTNNB1', 'Gene', (14, 20))	('activation', 'PosReg', (58, 68))
124122	26436532	Large-scale data sets generated by international consortia provide opportunities to define the landscape of mutations impacting gene expression in thousands of tumours across the major cancer types.	('tumours across the major cancer', 'Disease', (160, 191))	('gene expression', 'biological_process', 'GO:0010467', ('128', '143'))	('mutations', 'Var', (108, 117))	('tumours across the major cancer', 'Disease', 'MESH:D009369', (160, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('gene expression', 'MPA', (128, 143))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('impacting', 'Reg', (118, 127))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))
124123	26436532	The Cancer Genome Atlas (TCGA) projects have generated genomic and transcriptomic data from multiple cancer types, providing a systematic characterization of somatic mutations, copy number alterations, oncogenic processes, mutated sub-networks or pathways, and genomic signature-defined tumour subtypes.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('mutated', 'Var', (223, 230))	('mutations', 'Var', (166, 175))	('cancer', 'Disease', (101, 107))	('tumour', 'Disease', (287, 293))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('sub-networks', 'Pathway', (231, 243))	('copy number alterations', 'Var', (177, 200))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Cancer Genome Atlas', 'Disease', (4, 23))	('tumour', 'Phenotype', 'HP:0002664', (287, 293))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('tumour', 'Disease', 'MESH:D009369', (287, 293))
124124	26436532	MOCA detects differently expressed genes in the presence of mutations in a gene, and tests the significance of the correlation (between mutation and gene differential expression).	('mutations', 'Var', (60, 69))	('detects', 'Reg', (5, 12))	('MOCA', 'Gene', '1795', (0, 4))	('MOCA', 'Gene', (0, 4))
124128	26436532	We identify 30 novel cis-effect tumour suppressor gene candidates, enriched in loss-of-function mutations and frequent biallelic inactivations.	('tumour', 'Disease', (32, 38))	('loss-of-function', 'NegReg', (79, 95))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('mutations', 'Var', (96, 105))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
124131	26436532	On the basis of the trans-analysis, we find two important characteristics of mutations impacting gene expression that could not be revealed with other methods: (1) a stratification of patients harbouring known driver mutations, but that exhibit different downstream gene expression consequences; (2) identification of mutations driving expression patterns that are stable across tumour types, thereby nominating important molecular targets for therapeutic intervention, transcending anatomic sites of origin.	('gene expression', 'biological_process', 'GO:0010467', ('266', '281'))	('gene expression', 'biological_process', 'GO:0010467', ('97', '112'))	('patients', 'Species', '9606', (184, 192))	('impacting', 'Reg', (87, 96))	('mutations', 'Var', (318, 327))	('tumour', 'Phenotype', 'HP:0002664', (379, 385))	('mutations', 'Var', (77, 86))	('tumour type', 'Disease', (379, 390))	('gene expression', 'MPA', (97, 112))	('tumour type', 'Disease', 'MESH:D009369', (379, 390))
124137	26436532	The output of xseq consists of: (a) the probability that a recurrently mutated gene g influences gene expression across the population of patients (denoted by P(Dg=1), Supplementary Table 2); and (b) the probability that an individual mutation in gene g in an individual patient m influences expression within that patient (denoted by P(Fg,m=1)).	('mutation', 'Var', (235, 243))	('gene expression', 'biological_process', 'GO:0010467', ('97', '112'))	('patient', 'Species', '9606', (315, 322))	('influences', 'Reg', (86, 96))	('patient', 'Species', '9606', (271, 278))	('expression', 'MPA', (292, 302))	('patient', 'Species', '9606', (138, 145))	('m influences', 'Reg', (279, 291))	('gene expression', 'MPA', (97, 112))	('patients', 'Species', '9606', (138, 146))
124139	26436532	Gg,m,n {downregulation, neutral, upregulation} denotes the status of the nth gene connected to gene g in patient m. The central assumption is that a mutation in gene g of patient m impacting gene expression (denoted by Fg,m=1) more frequently co-associates with non-neutral states in its connected genes, compared with the mutations that do not impact expression.	('gene expression', 'MPA', (191, 206))	('patient', 'Species', '9606', (105, 112))	('patient', 'Species', '9606', (171, 178))	('impacting', 'Reg', (181, 190))	('mutation', 'Var', (149, 157))	('gene expression', 'biological_process', 'GO:0010467', ('191', '206'))
124140	26436532	To represent a recurrent pattern of expression impact across multiple patients, we consider information across all patients with a mutation in gene g. This allows for borrowing of statistical strength across multiple gene expression patterns co-associating with mutations to generalize whether a mutated gene is impacting expression across the population (denoted by Dg=1).	('patients', 'Species', '9606', (70, 78))	('patients', 'Species', '9606', (115, 123))	('mutation', 'Var', (131, 139))	('gene expression', 'biological_process', 'GO:0010467', ('217', '232'))	('impacting', 'Reg', (312, 321))	('expression', 'MPA', (322, 332))	('mutated', 'Var', (296, 303))
124141	26436532	The learning problem is to estimate the conditional probabilities of a variable given its parents, for example, thetaF=1 D=1:the probability of a mutation impacting expression in a specific patient given that this gene's mutations impact expression across patients (Fig.	('mutations', 'Var', (221, 230))	('impact', 'Reg', (231, 237))	('expression', 'MPA', (165, 175))	('patients', 'Species', '9606', (256, 264))	('impacting', 'Reg', (155, 164))	('expression', 'MPA', (238, 248))	('mutation', 'Var', (146, 154))	('patient', 'Species', '9606', (256, 263))	('patient', 'Species', '9606', (190, 197))
124143	26436532	The classifiers were motivated by the pattern of distributed loss-of-function mutations across a gene for tumour suppressors (for example, TP53) and hotspot mutations at one or relatively few loci for oncogenes (for example, KRAS).	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('KRAS', 'Gene', (225, 229))	('TP53', 'Gene', '7157', (139, 143))	('mutations', 'Var', (78, 87))	('KRAS', 'Gene', '3845', (225, 229))	('tumour', 'Disease', (106, 112))	('TP53', 'Gene', (139, 143))	('loss-of-function', 'NegReg', (61, 77))
124149	26436532	To examine how the model would translate to independently generated data, we used the METABRIC data to validate the predicted copy number alterations from TCGA in breast cancer.	('TCGA', 'Gene', (155, 159))	('copy number alterations', 'Var', (126, 149))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('breast cancer', 'Disease', (163, 176))
124157	26436532	We next characterized the tumour suppressor properties of the 65 xseq cis-effect predictions for consistency with known patterns of enrichment for loss-of-function mutations (Methods).	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('tumour', 'Disease', (26, 32))	('loss-of-function', 'NegReg', (147, 163))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (164, 173))
124167	26436532	Of the 30 novel predictions, 18 genes accumulated enriched loss-of-function mutations (P(TSG)>=0.2, P value<0.001), 10 genes encode transcription factors (P value<0.05), 21 genes (P value<0.001) encode human phosphoproteins, three genes reside on the X chromosome (P value<0.1).	('mutations', 'Var', (76, 85))	('transcription', 'biological_process', 'GO:0006351', ('132', '145'))	('human', 'Species', '9606', (202, 207))	('loss-of-function', 'NegReg', (59, 75))	('X chromosome', 'cellular_component', 'GO:0000805', ('251', '263'))	('TSG', 'Gene', (89, 92))	('TSG', 'Gene', '57045', (89, 92))
124171	26436532	We next estimated the proportion of known tumour suppressor genes harbouring cis-effect loss-of-function mutations.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('mutations', 'Var', (105, 114))	('tumour', 'Disease', (42, 48))	('loss-of-function', 'NegReg', (88, 104))
124173	26436532	We found that 23/131 genes (significant enrichment of cis-effect genes, P value<0.001) were predicted to exhibit cis-expression effects indicating that loss-of-function mutations in ~17.6% of tumour suppressor genes yield concomitant changes in mRNA expression levels.	('mRNA expression levels', 'MPA', (245, 267))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('mutations', 'Var', (169, 178))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('tumour', 'Disease', (192, 198))	('loss-of-function', 'NegReg', (152, 168))	('changes', 'Reg', (234, 241))
124174	26436532	Application of xseq to predict mutations impacting expression in trans resulted in a total of 150 genes across the 12 cancer types (P(D)>=0.8; Supplementary Table 7; Supplementary Fig.	('cancer', 'Disease', (118, 124))	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('impacting', 'Reg', (41, 50))	('expression', 'MPA', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
124182	26436532	The gene which harboured the largest number of high-probability mutations was KPNA2 in breast cancer (Supplementary Fig.	('KPNA2', 'Gene', (78, 83))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('KPNA2', 'Gene', '3838', (78, 83))	('breast cancer', 'Disease', (87, 100))	('mutations', 'Var', (64, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))
124183	26436532	To examine other sources of evidence of functional effects, we analysed high-probability missense mutations across all the tumour types, and computed the enrichment of phosphorylation-related SNVs (pSNVs).	('tumour type', 'Disease', (123, 134))	('missense mutations', 'Var', (89, 107))	('tumour type', 'Disease', 'MESH:D009369', (123, 134))	('phosphorylation', 'biological_process', 'GO:0016310', ('168', '183'))	('phosphorylation-related', 'MPA', (168, 191))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
124186	26436532	The Pan-Cancer data set included 241,700 (236,367 unique) missense mutations.	('missense mutations', 'Var', (58, 76))	('Cancer', 'Disease', 'MESH:D009369', (8, 14))	('Cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Cancer', 'Disease', (8, 14))
124188	26436532	We asked whether these mutations across tumour types correlated with the dysregulation of the same set of genes.	('tumour type', 'Disease', 'MESH:D009369', (40, 51))	('tumour type', 'Disease', (40, 51))	('correlated', 'Reg', (53, 63))	('mutations', 'Var', (23, 32))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('dysregulation', 'MPA', (73, 86))
124189	26436532	We focused on those genes whose mutations were predicted to influence gene expression in multiple tumour types.	('multiple tumour', 'Disease', (89, 104))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumour type', 'Disease', (98, 109))	('tumour type', 'Disease', 'MESH:D009369', (98, 109))	('influence', 'Reg', (60, 69))	('mutations', 'Var', (32, 41))	('gene expression', 'biological_process', 'GO:0010467', ('70', '85'))	('multiple tumour', 'Disease', 'MESH:D009369', (89, 104))
124190	26436532	For each gene connected to the mutated gene g in a tumour type, we counted how many times this gene was dysregulated (P(G='upregulation')>=0.5 or P(G='downregulation')>=0.5) in the presence of high-probability mutations (P(F)>=0.5).	('mutations', 'Var', (210, 219))	('dysregulated', 'PosReg', (104, 116))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumour type', 'Disease', 'MESH:D009369', (51, 62))	("G='upregulation", 'PosReg', (120, 135))	('tumour type', 'Disease', (51, 62))
124192	26436532	Mutations in RB1 correlated with the same group of gene dysregulations across several tumour types.	('RB1', 'Gene', '5925', (13, 16))	('gene dysregulations', 'MPA', (51, 70))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('Mutations', 'Var', (0, 9))	('tumour type', 'Disease', (86, 97))	('tumour type', 'Disease', 'MESH:D009369', (86, 97))	('RB1', 'Gene', (13, 16))	('correlated', 'Reg', (17, 27))
124193	26436532	In particular, we observed that RB1 mutations correlated with E2F family gene upregulations (for example, E2F1; Supplementary Data 7; Supplementary Fig.	('upregulations', 'PosReg', (78, 91))	('RB1', 'Gene', (32, 35))	('mutations', 'Var', (36, 45))	('E2F1', 'Gene', '1869', (106, 110))	('E2F1', 'Gene', (106, 110))	('E2F family gene', 'Gene', (62, 77))	('RB1', 'Gene', '5925', (32, 35))
124196	26436532	To confirm these correlations, for each gene connected to RB1 in the original full influence graph (Methods), in each tumour type, we compared the expression of this gene in the patients with RB1 mutations to the patients without RB1 mutations using the Limma package.	('tumour type', 'Disease', 'MESH:D009369', (118, 129))	('RB1', 'Gene', (230, 233))	('RB1', 'Gene', '5925', (58, 61))	('RB1', 'Gene', '5925', (192, 195))	('RB1', 'Gene', '5925', (230, 233))	('patients', 'Species', '9606', (178, 186))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('patients', 'Species', '9606', (213, 221))	('tumour type', 'Disease', (118, 129))	('RB1', 'Gene', (58, 61))	('RB1', 'Gene', (192, 195))	('mutations', 'Var', (196, 205))	('compared', 'Reg', (134, 142))
124200	26436532	In addition, aberrations (mutations and amplifications) in the transcription factor NFE2L2 in six different tumour types (BLCA, head and neck squamous cell carcinoma, kidney renal clear cell carcinoma, lung adenocarcinoma, LUSC and UCEC) exhibited trans-effects on gene expression (P(D)>=0.8).	('trans-effects', 'Reg', (248, 261))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (137, 165))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (167, 200))	('lung adenocarcinoma', 'Disease', (202, 221))	('NFE2L2', 'Gene', (84, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('transcription', 'biological_process', 'GO:0006351', ('63', '76'))	('gene expression', 'biological_process', 'GO:0010467', ('265', '280'))	('aberrations', 'Var', (13, 24))	('kidney renal clear cell carcinoma', 'Disease', (167, 200))	('neck', 'cellular_component', 'GO:0044326', ('137', '141'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (202, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('gene expression', 'MPA', (265, 280))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('tumour type', 'Disease', 'MESH:D009369', (108, 119))	('transcription factor', 'molecular_function', 'GO:0000981', ('63', '83'))	('NFE2L2', 'Gene', '4780', (84, 90))	('tumour type', 'Disease', (108, 119))	('neck squamous cell carcinoma', 'Disease', (137, 165))
124202	26436532	26) were significantly upregulated in five and four tumour types, respectively, in the presence of NFE2L2 aberrations (FDR<0.1; Supplementary Data 7).	('upregulated', 'PosReg', (23, 34))	('NFE2L2', 'Gene', (99, 105))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour type', 'Disease', 'MESH:D009369', (52, 63))	('tumour type', 'Disease', (52, 63))	('aberrations', 'Var', (106, 117))	('NFE2L2', 'Gene', '4780', (99, 105))
124205	26436532	28 show the correlation between NFE2L2 aberrations and its direct regulator and binding partner, KEAP1 expression upregulation.	('upregulation', 'PosReg', (114, 126))	('NFE2L2', 'Gene', (32, 38))	('KEAP1', 'Gene', '9817', (97, 102))	('binding', 'molecular_function', 'GO:0005488', ('80', '87'))	('KEAP1', 'Gene', (97, 102))	('aberrations', 'Var', (39, 50))	('NFE2L2', 'Gene', '4780', (32, 38))
124206	26436532	We investigated whether xseq probabilities P(F) could stratify patients harbouring mutations in the same cancer driver gene.	('mutations', 'Var', (83, 92))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (63, 71))
124207	26436532	in each tumour type for the presence of bimodal xseq P(F) distributions over patients harbouring mutations in the genes of interest (Supplementary Methods).	('mutations', 'Var', (97, 106))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('patients', 'Species', '9606', (77, 85))	('tumour type', 'Disease', (8, 19))	('tumour type', 'Disease', 'MESH:D009369', (8, 19))
124209	26436532	This was particularly evident for CTNNB1 mutations in UCEC (Fig.	('mutations', 'Var', (41, 50))	('UCEC', 'Disease', (54, 58))	('CTNNB1', 'Gene', (34, 40))	('CTNNB1', 'Gene', '1499', (34, 40))
124210	26436532	6a); 53/72 patients harboured high-probability CTNNB1 mutations (P(F)>=0.5), with all 53 patients harbouring CTNNB1 hotspot mutations (mutations hitting codons between 31 and 45).	('CTNNB1', 'Gene', (47, 53))	('CTNNB1', 'Gene', (109, 115))	('mutations', 'Var', (54, 63))	('mutations', 'Var', (135, 144))	('patients', 'Species', '9606', (89, 97))	('CTNNB1', 'Gene', '1499', (47, 53))	('CTNNB1', 'Gene', '1499', (109, 115))	('patients', 'Species', '9606', (11, 19))
124211	26436532	By contrast, only 9/19 patients without high xseq probability CTNNB1 mutations harboured hotspot mutations (Fig.	('mutations', 'Var', (69, 78))	('mutations', 'Var', (97, 106))	('patients', 'Species', '9606', (23, 31))	('CTNNB1', 'Gene', (62, 68))	('CTNNB1', 'Gene', '1499', (62, 68))
124212	26436532	In addition, 9/19 patients harboured POLE mutations, or were annotated as 'ultramutated' (tumours with more mutations than Q3+IQR x 4.5, where Q3 is the third quartile of mutation counts across a corresponding tumour type, and IQR is the interquartile range, as defined in syn1729383), suggesting that the CTNNB1 mutations were inconsequential passenger mutations (Supplementary Fig.	('CTNNB1', 'Gene', '1499', (306, 312))	('mutations', 'Var', (108, 117))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('tumour type', 'Disease', (210, 221))	('tumours', 'Disease', (90, 97))	('CTNNB1', 'Gene', (306, 312))	('patients', 'Species', '9606', (18, 26))	('tumour type', 'Disease', 'MESH:D009369', (210, 221))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('mutations', 'Var', (313, 322))
124215	26436532	Similar results for RB1 mutations in UCEC are shown in Fig.	('UCEC', 'Disease', (37, 41))	('mutations', 'Var', (24, 33))	('RB1', 'Gene', (20, 23))	('RB1', 'Gene', '5925', (20, 23))
124216	26436532	All 11 loss-of-function mutations (in eight patients) were predicted to have high probabilities (P(F)>=0.5); however, only 2/13 patients that did not harbour loss-of-function mutations were predicted to accumulate high-probability mutations (P(F)>=0.5, Fig.	('patients', 'Species', '9606', (44, 52))	('mutations', 'Var', (231, 240))	('loss-of-function', 'NegReg', (7, 23))	('mutations', 'Var', (24, 33))	('patients', 'Species', '9606', (128, 136))
124218	26436532	As such, patients' tumours with these 'inert' mutations do not exhibit expected pathway dysregulation.	('patients', 'Species', '9606', (9, 17))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('mutations', 'Var', (46, 55))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
124220	26436532	TP53 mutations in UCEC also showed bimodal distributions (Supplementary Fig.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
124221	26436532	TP53 frequently accumulates both loss-of-function mutations and missense mutations.	('TP53', 'Gene', '7157', (0, 4))	('missense mutations', 'Var', (64, 82))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (50, 59))	('loss-of-function', 'NegReg', (33, 49))
124222	26436532	However, patients with P(F)>=0.5 were more likely to harbour copy number hemizygous deletions (36 patients harboured co-occurring hemizygous deletions, compared with eight patients with P(F)<0.5; only nine patients lacked copy number alterations in the group with P(F)>=0.5 compared with 12 in the group with P(F)<0.5, P value<0.005.)	('P(F)>=0.5', 'Var', (23, 32))	('patients', 'Species', '9606', (9, 17))	('copy number', 'Var', (61, 72))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (206, 214))	('patients', 'Species', '9606', (172, 180))
124223	26436532	We developed a probabilistic model, xseq to quantitatively assess the association of mutations with dysregulated gene expression in 12 tumour types.	('tumour type', 'Disease', 'MESH:D009369', (135, 146))	('association', 'Interaction', (70, 81))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('gene expression', 'biological_process', 'GO:0010467', ('113', '128'))	('mutations', 'Var', (85, 94))	('tumour type', 'Disease', (135, 146))
124226	26436532	These genes showed the hallmarks of tumour suppressor genes including a distribution of loss-of-function mutations, and biallelic inactivation through loss-of-function mutations and heterozygous deletions.	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('loss-of-function', 'NegReg', (151, 167))	('mutations', 'Var', (105, 114))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('loss-of-function', 'NegReg', (88, 104))	('mutations', 'Var', (168, 177))
124227	26436532	In addition, we assessed the landscape of mutations impacting gene expression in trans across the 12 tumour types.	('gene expression', 'biological_process', 'GO:0010467', ('62', '77'))	('tumour type', 'Disease', (101, 112))	('gene expression', 'MPA', (62, 77))	('impacting', 'Reg', (52, 61))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (42, 51))	('tumour type', 'Disease', 'MESH:D009369', (101, 112))
124229	26436532	Recent synthesis of mutation rates and discovery 'saturation' in genome-wide sequencing studies has indicated that current standard of study design has under-sampled important mutations, and that for some 50 tumour types, sequencing of >2,000 cases are needed to reach comprehensive sampling.	('mutations', 'Var', (176, 185))	('synthesis', 'biological_process', 'GO:0009058', ('7', '16'))	('tumour type', 'Disease', 'MESH:D009369', (208, 219))	('under-sampled', 'NegReg', (152, 165))	('tumour type', 'Disease', (208, 219))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))
124232	26436532	In our analysis, constitutive activation of Wnt signalling genes due to CTNNB1 mutation segregates almost exclusively with known hotspot mutations.	('activation', 'PosReg', (30, 40))	('Wnt signalling genes', 'Gene', (44, 64))	('CTNNB1', 'Gene', (72, 78))	('mutation', 'Var', (79, 87))	('signalling', 'biological_process', 'GO:0023052', ('48', '58'))	('CTNNB1', 'Gene', '1499', (72, 78))
124233	26436532	However, several cases exhibited mutation in CTNNB1 without evidence of Wnt activation, resulting in low xseq probabilities.	('CTNNB1', 'Gene', '1499', (45, 51))	('mutation', 'Var', (33, 41))	('CTNNB1', 'Gene', (45, 51))	('exhibited', 'Reg', (23, 32))	('low xseq probabilities', 'MPA', (101, 123))
124237	26436532	Despite distinct histologies and cell contexts of source tumours, RB1 loss-of-function mutations and NFE2L2 mutations/amplifications exhibited similar expression patterns.	('NFE2L2', 'Gene', (101, 107))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('RB1', 'Gene', '5925', (66, 69))	('mutations/amplifications', 'Var', (108, 132))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumours', 'Disease', (57, 64))	('loss-of-function', 'NegReg', (70, 86))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('NFE2L2', 'Gene', '4780', (101, 107))	('mutations', 'Var', (87, 96))	('RB1', 'Gene', (66, 69))
124239	26436532	Accordingly, we observed that RB1 mutations correlated with E2F family gene upregulation across tumour types.	('upregulation', 'PosReg', (76, 88))	('E2F family gene', 'Gene', (60, 75))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour type', 'Disease', (96, 107))	('RB1', 'Gene', (30, 33))	('tumour type', 'Disease', 'MESH:D009369', (96, 107))	('mutations', 'Var', (34, 43))	('RB1', 'Gene', '5925', (30, 33))
124241	26436532	We observed NFE2L2 mutations correlated with upregulation of KEAP1, as well as of oxidative stress genes (for example, GCLM, GCLC, TXNRD1, GPX2 and NQO1).	('KEAP1', 'Gene', (61, 66))	('NQO1', 'Gene', '1728', (148, 152))	('NFE2L2', 'Gene', (12, 18))	('GPX2', 'Gene', '2877', (139, 143))	('oxidative stress', 'Phenotype', 'HP:0025464', (82, 98))	('NQO1', 'molecular_function', 'GO:0003955', ('148', '152'))	('GCLM', 'Gene', (119, 123))	('TXNRD1', 'Gene', (131, 137))	('mutations', 'Var', (19, 28))	('GPX2', 'Gene', (139, 143))	('TXNRD1', 'Gene', '7296', (131, 137))	('GCLM', 'Gene', '2730', (119, 123))	('KEAP1', 'Gene', '9817', (61, 66))	('upregulation', 'PosReg', (45, 57))	('NQO1', 'Gene', (148, 152))	('NFE2L2', 'Gene', '4780', (12, 18))	('GCLC', 'Gene', (125, 129))	('GCLC', 'Gene', '2729', (125, 129))
124242	26436532	While therapeutic responses to targeted inhibitors administered against the same mutation can have variable effects due to intrinsic gene expression context (for example, BRAF inhibition in melanoma and colorectal cancer), the mutations we outlined (such as RB1 and NFE2L2 mutations) exhibit stable profiles and represent important targets for future development of broadly applicable therapeutics.	('RB1', 'Gene', (258, 261))	('NFE2L2', 'Gene', (266, 272))	('melanoma', 'Disease', (190, 198))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('colorectal cancer', 'Phenotype', 'HP:0003003', (203, 220))	('RB1', 'Gene', '5925', (258, 261))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('BRAF', 'Gene', '673', (171, 175))	('mutations', 'Var', (273, 282))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('colorectal cancer', 'Disease', (203, 220))	('BRAF', 'Gene', (171, 175))	('gene expression', 'biological_process', 'GO:0010467', ('133', '148'))	('colorectal cancer', 'Disease', 'MESH:D015179', (203, 220))	('NFE2L2', 'Gene', '4780', (266, 272))
124243	26436532	An intriguing evolutionary implication arises from these mutations: phenotypic impact is selected for in multiple heterogeneous tumour microenvironments, indicating independent convergence of phenotype transcending cell context.	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Disease', (128, 134))	('mutations', 'Var', (57, 66))	('tumour', 'Disease', 'MESH:D009369', (128, 134))
124245	26436532	Although genes are rarely mutated multiple times within a single patient, some large tumour suppressor genes (such as ARID1A) accumulate multiple mutations, as a result of their long coding sequences.	('mutations', 'Var', (146, 155))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Disease', (85, 91))	('patient', 'Species', '9606', (65, 72))	('ARID1A', 'Gene', '8289', (118, 124))	('accumulate', 'PosReg', (126, 136))	('ARID1A', 'Gene', (118, 124))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
124246	26436532	Similarly, in glioblastoma and lung cancers, EGFR is frequently mutated multiple times in single patients, often due to the emergence of clonal populations following the administration of EGFR inhibitors.	('EGFR', 'Gene', (45, 49))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('EGFR', 'Gene', '1956', (188, 192))	('EGFR', 'molecular_function', 'GO:0005006', ('188', '192'))	('lung cancers', 'Phenotype', 'HP:0100526', (31, 43))	('glioblastoma and lung cancers', 'Disease', 'MESH:D005909', (14, 43))	('mutated', 'Var', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (14, 26))	('EGFR', 'Gene', (188, 192))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('EGFR', 'Gene', '1956', (45, 49))	('patients', 'Species', '9606', (97, 105))
124248	26436532	Direct, model-based integration of mutations and co-acquired gene expression measurements from tumour samples enhances interpretation capacity of discovered mutations leading to optimal selectivity of targets for functional studies and development of novel therapeutics.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('interpretation', 'MPA', (119, 133))	('tumour', 'Disease', (95, 101))	('mutations', 'Var', (157, 166))	('enhances', 'PosReg', (110, 118))	('gene expression', 'biological_process', 'GO:0010467', ('61', '76'))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
124249	26436532	The xseq model specifies how the expression Y of a group of genes in a patient is influenced by the somatic mutation status of a gene g in the patient (Fig.	('patient', 'Species', '9606', (143, 150))	('influenced', 'Reg', (82, 92))	('expression', 'MPA', (33, 43))	('mutation', 'Var', (108, 116))	('patient', 'Species', '9606', (71, 78))
124252	26436532	In our experiments, to systematically analyse all the data sets, for the nth gene connected to gene g, we estimate the upregulation probability by , where m is the mth patients harbouring gene g mutations, M is the total number of patients harbouring gene g mutations and ym,n is the expression of the nth gene connected to g in patient m.  means downregulation, neutral and upregulation of the nth gene connected to g in patient m, respectively.	('mutations', 'Var', (258, 267))	('patient', 'Species', '9606', (329, 336))	('patients', 'Species', '9606', (231, 239))	('patient', 'Species', '9606', (422, 429))	('upregulation', 'PosReg', (375, 387))	('nth gene', 'Gene', (395, 403))	('patient', 'Species', '9606', (168, 175))	('mutations', 'Var', (195, 204))	('downregulation', 'NegReg', (347, 361))	('patients', 'Species', '9606', (168, 176))	('patient', 'Species', '9606', (231, 238))
124257	26436532	We can see that some patients without RUNX1 mutations still showed similar expression pattern to those with RUNX1 mutations.	('RUNX1', 'Gene', '861', (38, 43))	('RUNX1', 'Gene', (108, 113))	('mutations', 'Var', (114, 123))	('RUNX1', 'Gene', '861', (108, 113))	('patients', 'Species', '9606', (21, 29))	('mutations', 'Var', (44, 53))	('RUNX1', 'Gene', (38, 43))	('expression', 'MPA', (75, 85))
124259	26436532	Phenocopying may be a common event in cancer because of DNA methylation and other epigenetic alterations, and it may suggest novel treatment opportunities.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('DNA methylation', 'Var', (56, 71))	('alterations', 'Var', (93, 104))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('DNA methylation', 'biological_process', 'GO:0006306', ('56', '71'))	('cancer', 'Disease', (38, 44))
124265	26436532	In a recent review, a '20/20 rule' is used to identify driver genes: for oncogenes, at least 20% of all the mutations are required to be hotspot missense mutations or in-frame indels; for tumour suppressor genes, at least 20% of all the mutations are required to be loss-of-function mutations.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('mutations', 'Var', (108, 117))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('in-frame indels', 'Var', (167, 182))	('tumour', 'Disease', (188, 194))	('loss-of-function', 'NegReg', (266, 282))	('missense mutations', 'Var', (145, 163))	('mutations', 'Var', (237, 246))
124267	26436532	Similarly, when predicting tumour suppressor genes, we first count the number of loss-of-function mutations ng,loss in gene g, and Ng.	('loss', 'NegReg', (111, 115))	('loss-of-function', 'NegReg', (81, 97))	('mutations ng', 'Var', (98, 110))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('tumour', 'Disease', (27, 33))
124273	26436532	Some mutated genes are not expressed in cancer cells, and therefore the mutations in these genes are less likely to be pathogenic.	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))
124277	26436532	Here we use the 90th percentile instead of median considering the gene dosage effects of copy number deletions on expression in cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('copy number deletions', 'Var', (89, 110))	('cancer', 'Disease', (128, 134))
124285	26436532	Before analysing the trans-effects of somatic mutations, we first remove the cis-effects of copy number alterations on expression; copy number alterations are common in cancer and the majority have cis-effects on expression.	('cancer', 'Disease', (169, 175))	('expression', 'MPA', (213, 223))	('copy number alterations', 'Var', (131, 154))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
124452	32251318	However, the functions of the many variants of these proteins in cancer remain incompletely understood.	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('variants', 'Var', (35, 43))
124454	32251318	Although the mutation rate of the netrin family is low in pan-cancer, among the tumor patients with netrin mutations, the highest number are Uterine Corpus Endometrial Carcinoma patients, accounting for 13.6% of cases (54 of 397).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('netrin', 'Gene', (100, 106))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (178, 186))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (149, 177))	('Carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('tumor', 'Disease', (80, 85))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('Corpus Endometrial Carcinoma', 'Disease', (149, 177))	('patients', 'Species', '9606', (86, 94))
124462	32251318	HGF inhibits the treatment of RAF inhibitors of BRAF mutant melanoma.	('inhibits', 'NegReg', (4, 12))	('RAF', 'Gene', '22882', (49, 52))	('HGF', 'Gene', (0, 3))	('RAF', 'Gene', (49, 52))	('treatment of', 'MPA', (17, 29))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('HGF', 'Gene', '3082', (0, 3))	('melanoma', 'Disease', (60, 68))	('RAF', 'Gene', '22882', (30, 33))	('mutant', 'Var', (53, 59))	('RAF', 'Gene', (30, 33))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
124481	32251318	Mutations in the netrins were identified in the 33 cancers included in TCGA (Fig.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('netrins', 'Gene', (17, 24))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('identified', 'Reg', (30, 40))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
124482	32251318	At the cancer level, netrins associated with uterine corpus endometrial carcinoma (UCEC) exhibited the highest number of mutations (54), followed by colon adenocarcinoma (COAD) (49), skin cutaneous melanoma (SKCM) (47), stomach adenocarcinoma (STAD) (42), lung adenocarcinoma (LUAD) (38), and lung squamous cell carcinoma (LUSC)(36).	('mutations', 'Var', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (60, 81))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('lung adenocarcinoma', 'Disease', (256, 275))	('cancer', 'Disease', (7, 13))	('associated', 'Reg', (29, 39))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (188, 206))	('stomach adenocarcinoma', 'Disease', (220, 242))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (220, 242))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (256, 275))	('corpus endometrial carcinoma', 'Disease', (53, 81))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (53, 81))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (293, 321))	('colon adenocarcinoma (COAD) (49), skin cutaneous melanoma', 'Disease', 'MESH:D029424', (149, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (298, 321))	('lung squamous cell carcinoma', 'Disease', (293, 321))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (256, 275))	('netrins', 'Gene', (21, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
124483	32251318	The total mutation rates of Netrin family members in the above six cancers were 10.19%, 12.28%, 10.06%, 9.61%, 6.70% and 7.32%, respectively.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('Netrin family', 'Gene', (28, 41))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('mutation', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
124485	32251318	However, the hot spot mutation P201Qfs*15 of NTN3 was identified in three patients, each with a different cancer (ESCA, STAD, UCEC), and encodes a truncated protein.	('STAD', 'Disease', (120, 124))	('P201Qfs*15', 'Var', (31, 41))	('NTN3', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('ESCA', 'Phenotype', 'HP:0011459', (114, 118))	('cancer', 'Disease', (106, 112))	('NTN3', 'Gene', '4917', (45, 49))
124486	32251318	E59K, one of the hotspot mutations of NTN4, was detected in four patients with three cancers (READ, COAD, and UCEC) and both VEST3 and REVEL algorithms indicated this change was dual-damaging.	('READ', 'Disease', (94, 98))	('detected', 'Reg', (48, 56))	('COAD', 'Disease', (100, 104))	('NTN4', 'Gene', (38, 42))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('E59K', 'Var', (0, 4))	('cancers', 'Disease', (85, 92))	('NTN4', 'Gene', '59277', (38, 42))	('E59K', 'Mutation', 'rs762617558', (0, 4))	('patients', 'Species', '9606', (65, 73))	('READ', 'Disease', '-', (94, 98))	('COAD', 'Disease', 'MESH:D029424', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
124487	32251318	The hot spot mutation X342_splice of NTN5 occurred in two cancers (SKCM and UCEC) in two patients, and also encodes a truncated protein.	('occurred', 'Reg', (42, 50))	('NTN5', 'Gene', '126147', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('NTN5', 'Gene', (37, 41))	('patients', 'Species', '9606', (89, 97))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('X342_splice', 'Var', (22, 33))
124488	32251318	The hot spot mutation R238C/H of NTNG1 was detected in three patients with three cancers (COAD, STAD, and UCEC), and R238C was predicted as damaging in VEST3 and REVEL algorithms.	('STAD', 'Disease', (96, 100))	('R238C', 'SUBSTITUTION', 'None', (117, 122))	('R238C', 'Var', (117, 122))	('COAD', 'Disease', 'MESH:D029424', (90, 94))	('NTNG1', 'Gene', '22854', (33, 38))	('NTNG1', 'Gene', (33, 38))	('R238C', 'Mutation', 'p.R238C', (117, 122))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('patients', 'Species', '9606', (61, 69))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('R238C', 'Var', (22, 27))	('COAD', 'Disease', (90, 94))	('R238C', 'Mutation', 'p.R238C', (22, 27))	('R238C', 'SUBSTITUTION', 'None', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
124489	32251318	The NTNG2 hotspot mutation D226N/Rfs*141 occurred in three patients with three cancers (LAML, GBM, and COAD), and NTN1 hotspot mutation P459T was detected in three patients with two cancers (STAD, READ).The mutations in NTN1, NTN3, NTN4, NTNG1, and NTNG2 were mainly in the laminin-N domain, and most mutations of NTN5 were concentrated in the laminin_EGF2 domain.	('NTNG1', 'Gene', '22854', (238, 243))	('NTNG2', 'Gene', (249, 254))	('NTN1', 'Gene', '9423', (114, 118))	('P459T', 'Mutation', 'rs376278603', (136, 141))	('NTN4', 'Gene', (232, 236))	('NTN1', 'Gene', (220, 224))	('COAD', 'Disease', (103, 107))	('NTN5', 'Gene', (314, 318))	('D226N', 'SUBSTITUTION', 'None', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('mutations', 'Var', (207, 216))	('patients', 'Species', '9606', (59, 67))	('cancers', 'Disease', (182, 189))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('NTN5', 'Gene', '126147', (314, 318))	('patients', 'Species', '9606', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Disease', (79, 86))	('NTN1', 'Gene', '9423', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('NTN4', 'Gene', '59277', (232, 236))	('NTNG2', 'Gene', '84628', (4, 9))	('EGF', 'molecular_function', 'GO:0005154', ('352', '355'))	('D226N', 'Var', (27, 32))	('NTN3', 'Gene', '4917', (226, 230))	('NTNG2', 'Gene', '84628', (249, 254))	('NTNG1', 'Gene', (238, 243))	('NTN1', 'Gene', (114, 118))	('READ', 'Disease', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('COAD', 'Disease', 'MESH:D029424', (103, 107))	('READ', 'Disease', '-', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('NTN3', 'Gene', (226, 230))	('NTNG2', 'Gene', (4, 9))
124490	32251318	After screening by genetic ancestry groups and non-synonymous mutations, 62 patients had complete mutation information (64 mutations) for NTN1, 34 patients were included with complete mutation information (37 mutations) for NTN3, and 107 patients had complete mutation information (120 mutations) for NTN4.	('NTN4', 'Gene', (301, 305))	('patients', 'Species', '9606', (76, 84))	('NTN3', 'Gene', '4917', (224, 228))	('NTN1', 'Gene', (138, 142))	('NTN3', 'Gene', (224, 228))	('NTN4', 'Gene', '59277', (301, 305))	('NTN1', 'Gene', '9423', (138, 142))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (238, 246))	('mutations', 'Var', (123, 132))
124491	32251318	Additionally, the data included 33 patients with 33 mutations in NTN5, 152 patient and 161 mutations in NTNG1, and 91 patients with 98 mutations in (Fig.	('mutations', 'Var', (52, 61))	('NTNG1', 'Gene', '22854', (104, 109))	('patient', 'Species', '9606', (75, 82))	('patient', 'Species', '9606', (35, 42))	('NTN5', 'Gene', '126147', (65, 69))	('patients', 'Species', '9606', (35, 43))	('patient', 'Species', '9606', (118, 125))	('patients', 'Species', '9606', (118, 126))	('NTN5', 'Gene', (65, 69))	('NTNG1', 'Gene', (104, 109))
124492	32251318	By comparing the data, we found that up to four netrin family members in individual patients contained mutations in four patients, three UCEC patients and one STAD patient with mutations in both NTN1 and NTNG2.	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (84, 92))	('NTNG2', 'Gene', (204, 209))	('patient', 'Species', '9606', (164, 171))	('patient', 'Species', '9606', (121, 128))	('NTNG2', 'Gene', '84628', (204, 209))	('patient', 'Species', '9606', (142, 149))	('contained', 'Reg', (93, 102))	('NTN1', 'Gene', (195, 199))	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (121, 129))	('patient', 'Species', '9606', (84, 91))	('NTN1', 'Gene', '9423', (195, 199))
124493	32251318	In cancer studies with at least five mutations in members of netrin genes (Fig.	('netrin genes', 'Gene', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
124494	32251318	2b), UCEC patients were one of the two highest among the cancers associated with the netrin family mutations, with most mutations in NTNG1.	('NTNG1', 'Gene', '22854', (133, 138))	('UCEC', 'Disease', (5, 9))	('NTNG1', 'Gene', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (10, 18))
124495	32251318	SKCM has the most mutations in NTN4.	('NTN4', 'Gene', '59277', (31, 35))	('NTN4', 'Gene', (31, 35))	('mutations', 'Var', (18, 27))
124496	32251318	2c), the highest number of cancer mutations among the four genetic ancestry groups was UCEC, and the netrin family mutations in STAD were mainly distributed in EAA and NA.	('netrin family', 'Gene', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('mutations', 'Var', (34, 43))
124497	32251318	Most netrin mutations in COAD occur in EA and AA.	('mutations', 'Var', (12, 21))	('COAD', 'Disease', (25, 29))	('COAD', 'Disease', 'MESH:D029424', (25, 29))	('netrin', 'Gene', (5, 11))
124498	32251318	2d,e) revealed that most mutations in netrins were in the laminin N-terminal domain, except for NTN5.	('NTN5', 'Gene', '126147', (96, 100))	('mutations', 'Var', (25, 34))	('netrins', 'Gene', (38, 45))	('NTN5', 'Gene', (96, 100))
124499	32251318	In the laminin EGF domains of NTN1, NTN3, NTN4, and NTN5, most mutations were in the laminin EGF-like 2 domain.	('mutations', 'Var', (63, 72))	('EGF', 'molecular_function', 'GO:0005154', ('15', '18'))	('NTN4', 'Gene', (42, 46))	('EGF', 'molecular_function', 'GO:0005154', ('93', '96'))	('NTN5', 'Gene', '126147', (52, 56))	('NTN3', 'Gene', '4917', (36, 40))	('NTN4', 'Gene', '59277', (42, 46))	('NTN3', 'Gene', (36, 40))	('NTN1', 'Gene', (30, 34))	('NTN1', 'Gene', '9423', (30, 34))	('NTN5', 'Gene', (52, 56))
124500	32251318	In the NTNG1 laminin EGF domains, the mutation of laminin EGF-like 3 was the most frequent, and in the NTNG2 laminin EGF domains, the mutation of laminin EGF-like 1 was the most frequent.	('NTNG2', 'Gene', (103, 108))	('EGF', 'molecular_function', 'GO:0005154', ('58', '61'))	('EGF', 'molecular_function', 'GO:0005154', ('21', '24'))	('mutation', 'Var', (134, 142))	('frequent', 'Reg', (82, 90))	('frequent', 'Reg', (178, 186))	('laminin EGF-like 3', 'Gene', (50, 68))	('EGF', 'molecular_function', 'GO:0005154', ('154', '157'))	('NTNG1', 'Gene', '22854', (7, 12))	('mutation', 'Var', (38, 46))	('NTNG2', 'Gene', '84628', (103, 108))	('EGF', 'molecular_function', 'GO:0005154', ('117', '120'))	('NTNG1', 'Gene', (7, 12))
124501	32251318	The mutations in the NTR domain were mainly concentrated in NTN1 and 4.	('NTR', 'Gene', (21, 24))	('NTN1', 'Gene', (60, 64))	('NTN1', 'Gene', '9423', (60, 64))	('NTR', 'Gene', '4923', (21, 24))	('mutations', 'Var', (4, 13))
124511	32251318	Additionally, MLK1 enhanced cancer cell migration and invasion by epigenetic activation of MMP9 transcription in lung cancer.	('MLK1', 'Gene', (14, 18))	('transcription', 'MPA', (96, 109))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('MMP9', 'molecular_function', 'GO:0004229', ('91', '95'))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('transcription', 'biological_process', 'GO:0006351', ('96', '109'))	('epigenetic activation', 'Var', (66, 87))	('MLK1', 'Gene', '4293', (14, 18))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cell migration', 'biological_process', 'GO:0016477', ('35', '49'))	('MMP9', 'Gene', (91, 95))	('cancer', 'Disease', (28, 34))	('MMP9', 'Gene', '4318', (91, 95))	('lung cancer', 'Disease', (113, 124))	('invasion', 'CPA', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('enhanced', 'PosReg', (19, 27))
124546	32251318	5c) showed the survival was worse for hypomethylation of NTN1 in kidney renal papillary cell carcinoma (KIRP) and worse for NTNG1 in kidney renal clear cell carcinoma (KIRC), which is consistent with the correlation of high expression of NTN1 in KIRP and NTNG1 in KIRC with worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('hypomethylation', 'Var', (38, 53))	('kidney renal papillary cell carcinoma', 'Disease', (65, 102))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (65, 102))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (133, 166))	('NTN1', 'Gene', (238, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('NTN1', 'Gene', '9423', (238, 242))	('NTN1', 'Gene', '9423', (57, 61))	('NTN1', 'Gene', (57, 61))	('NTNG1', 'Gene', '22854', (255, 260))	('NTNG1', 'Gene', (255, 260))	('NTNG1', 'Gene', '22854', (124, 129))	('kidney renal clear cell carcinoma', 'Disease', (133, 166))	('NTNG1', 'Gene', (124, 129))
124549	32251318	Methylation of NTN1, NTN3, NTN4, NTN5, and NTNG1 was associated with radiation therapy and overall survival of LGG.	('NTN3', 'Gene', (21, 25))	('NTN4', 'Gene', (27, 31))	('NTNG1', 'Gene', '22854', (43, 48))	('Methylation', 'Var', (0, 11))	('NTNG1', 'Gene', (43, 48))	('NTN5', 'Gene', (33, 37))	('NTN1', 'Gene', (15, 19))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('NTN4', 'Gene', '59277', (27, 31))	('radiation therapy', 'CPA', (69, 86))	('NTN1', 'Gene', '9423', (15, 19))	('associated with', 'Reg', (53, 68))	('NTN3', 'Gene', '4917', (21, 25))	('NTN5', 'Gene', '126147', (33, 37))
124551	32251318	In pan-kidney (KIRP and KIRC), methylation of NTN4 was associated with pathology T stage and overall survival of KIRP and KIRC.	('NTN4', 'Gene', '59277', (46, 50))	('associated', 'Reg', (55, 65))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('methylation', 'Var', (31, 42))	('NTN4', 'Gene', (46, 50))
124552	32251318	Methylation of NTN1 and NTNG1 was associated with pathology T stage and pathology N stage of KIRP.	('associated', 'Reg', (34, 44))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('NTNG1', 'Gene', (24, 29))	('NTN1', 'Gene', '9423', (15, 19))	('NTNG1', 'Gene', '22854', (24, 29))
124554	32251318	Methylation of NTN1 and NTN3 was associated with radiation therapy and pathology T stage of ESCA.	('radiation', 'CPA', (49, 58))	('NTN3', 'Gene', '4917', (24, 28))	('NTN3', 'Gene', (24, 28))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('associated', 'Reg', (33, 43))	('NTN1', 'Gene', '9423', (15, 19))	('ESCA', 'Phenotype', 'HP:0011459', (92, 96))
124555	32251318	Methylation of NTN3 was associated with pathology T stage, pathology N stage and number of lymph nodes of PRAD.	('associated', 'Reg', (24, 34))	('Methylation', 'Var', (0, 11))	('NTN3', 'Gene', '4917', (15, 19))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('NTN3', 'Gene', (15, 19))
124556	32251318	Methylation of NTN1, NTN3, NTN4, and NTNG1 was associated with PAM50 typing of BRCA, and NTNG1 was also associated with ER.Status and PR.Status.	('NTNG1', 'Gene', (37, 42))	('ER.Status', 'Disease', (120, 129))	('BRCA', 'Gene', (79, 83))	('associated', 'Reg', (104, 114))	('NTN1', 'Gene', (15, 19))	('NTN4', 'Gene', '59277', (27, 31))	('associated', 'Reg', (47, 57))	('NTNG1', 'Gene', '22854', (37, 42))	('Methylation', 'Var', (0, 11))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('NTN1', 'Gene', '9423', (15, 19))	('NTN3', 'Gene', '4917', (21, 25))	('BRCA', 'Phenotype', 'HP:0003002', (79, 83))	('NTNG1', 'Gene', (89, 94))	('PAM50 typing', 'Var', (63, 75))	('NTN3', 'Gene', (21, 25))	('BRCA', 'Gene', '672', (79, 83))	('NTN4', 'Gene', (27, 31))	('PR.Status', 'Disease', (134, 143))	('NTNG1', 'Gene', '22854', (89, 94))
124557	32251318	In UCEC, methylation of NTN3, NTN4, NTNG1, and NTNG2 was associated with MSI phenotype.	('methylation', 'Var', (9, 20))	('NTN3', 'Gene', '4917', (24, 28))	('NTN4', 'Gene', (30, 34))	('MSI', 'Disease', '-', (73, 76))	('NTN3', 'Gene', (24, 28))	('NTNG2', 'Gene', '84628', (47, 52))	('NTNG1', 'Gene', '22854', (36, 41))	('NTN4', 'Gene', '59277', (30, 34))	('NTNG1', 'Gene', (36, 41))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('NTNG2', 'Gene', (47, 52))	('MSI', 'Disease', (73, 76))	('associated', 'Reg', (57, 67))
124561	32251318	Overexpression of EZH2 is also associated with the development of prostate cancer, and phosphorylated EZH2 can act as a co-activator of transcription factors, such as promoting the expression of AR.	('EZH2', 'Gene', (102, 106))	('EZH2', 'Gene', '2146', (102, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('expression', 'MPA', (181, 191))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('EZH2', 'Gene', '2146', (18, 22))	('associated', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('phosphorylated', 'Var', (87, 101))	('transcription', 'biological_process', 'GO:0006351', ('136', '149'))	('EZH2', 'Gene', (18, 22))	('AR', 'Gene', '367', (195, 197))	('prostate cancer', 'Disease', (66, 81))	('promoting', 'PosReg', (167, 176))
124576	32251318	Among the many statistically significant results, hsa-miR-361-3p had the strongest inhibitory effect on NTN1 in TCGT (r = 0.612), hsa-miR-33a-5p had the strongest inhibitory effect on NTN4 in TCGT and ESCA (r = -0.494), and hsa-miR-20b-5p had the strongest inhibitory effect on NTNG1 in DLBC (r = -0.528).	('inhibitory effect', 'MPA', (83, 100))	('NTN4', 'Gene', '59277', (184, 188))	('NTN1', 'Gene', (104, 108))	('hsa-miR-361-3p', 'Gene', '100500908', (50, 64))	('NTN1', 'Gene', '9423', (104, 108))	('inhibitory effect', 'MPA', (163, 180))	('hsa-miR-33a-5p', 'Var', (130, 144))	('ESCA', 'Phenotype', 'HP:0011459', (201, 205))	('NTN4', 'Gene', (184, 188))	('NTNG1', 'Gene', '22854', (278, 283))	('hsa-miR-361-3p', 'Gene', (50, 64))	('NTNG1', 'Gene', (278, 283))	('BC', 'Phenotype', 'HP:0003002', (289, 291))
124582	32251318	The expression of NTN5 was affected by eQTL in BRCA, COAD, KIRC, KIRP, LGG, PRAD, and THCA.	('expression', 'MPA', (4, 14))	('COAD', 'Disease', 'MESH:D029424', (53, 57))	('eQTL', 'Var', (39, 43))	('affected', 'Reg', (27, 35))	('NTN5', 'Gene', '126147', (18, 22))	('BRCA', 'Phenotype', 'HP:0003002', (47, 51))	('THCA', 'Phenotype', 'HP:0002890', (86, 90))	('BRCA', 'Gene', '672', (47, 51))	('COAD', 'Disease', (53, 57))	('NTN5', 'Gene', (18, 22))	('BRCA', 'Gene', (47, 51))
124585	32251318	Of these, 186 (74.4%) NTNG1 eQTLs were associated with AIDS and 57 (22.9%) were associated with non-obstructive azoospermia.	('NTNG1', 'Gene', '22854', (22, 27))	('non-obstructive azoospermia', 'Disease', 'MESH:D053713', (96, 123))	('NTNG1', 'Gene', (22, 27))	('obstructive azoospermia', 'Phenotype', 'HP:0011962', (100, 123))	('azoospermia', 'Phenotype', 'HP:0000027', (112, 123))	('AIDS', 'Disease', (55, 59))	('non-obstructive azoospermia', 'Disease', (96, 123))	('associated', 'Reg', (80, 90))	('associated', 'Reg', (39, 49))	('AIDS', 'Disease', 'MESH:D000163', (55, 59))	('eQTLs', 'Var', (28, 33))	('non-obstructive azoospermia', 'Phenotype', 'HP:0011961', (96, 123))
124588	32251318	Further, three eQTLs (rs9894790, rs9901637, and rs11650713) were found to affect the binding of MYC, TCF12, EBF1, EGR1, and NR2F2.	('rs11650713', 'Var', (48, 58))	('EBF1', 'Gene', '1879', (108, 112))	('rs9901637', 'Var', (33, 42))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('EBF1', 'Gene', (108, 112))	('MYC', 'Gene', (96, 99))	('rs9894790', 'Var', (22, 31))	('NR2F2', 'Gene', '7026', (124, 129))	('NR2F2', 'Gene', (124, 129))	('TCF12', 'Gene', (101, 106))	('TCF12', 'Gene', '6938', (101, 106))	('MYC', 'Gene', '4609', (96, 99))	('affect', 'Reg', (74, 80))	('rs9894790', 'Mutation', 'rs9894790', (22, 31))	('rs9901637', 'Mutation', 'rs9901637', (33, 42))	('rs11650713', 'Mutation', 'rs11650713', (48, 58))	('EGR1', 'Gene', (114, 118))	('EGR1', 'Gene', '1958', (114, 118))	('binding', 'Interaction', (85, 92))
124589	32251318	Additionally, high expression of NTN1 in thyroid carcinoma was correlated with a worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (41, 58))	('NTN1', 'Gene', '9423', (33, 37))	('high', 'Var', (14, 18))	('NTN1', 'Gene', (33, 37))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (41, 58))	('thyroid carcinoma', 'Disease', (41, 58))
124597	32251318	Highly expressed NTN4 is more sensitive to SRC inhibitors such as Dasatinib, WH-4-023, and AZD0530.	('NTN4', 'Gene', (17, 21))	('SRC', 'Gene', '6714', (43, 46))	('SRC', 'Gene', (43, 46))	('more', 'PosReg', (25, 29))	('NTN4', 'Gene', '59277', (17, 21))	('WH-4-023', 'Chemical', '-', (77, 85))	('AZD0530', 'Var', (91, 98))	('AZD0530', 'Chemical', 'MESH:C515233', (91, 98))	('Dasatinib', 'Chemical', 'MESH:D000069439', (66, 75))
124609	32251318	In particular, ML162 and ML210 are compounds that target and change the mesenchymal state, inhibit GPX4 activity, and promote apoptosis.	('change', 'Reg', (61, 67))	('GPX4', 'Gene', (99, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('GPX4', 'Gene', '2879', (99, 103))	('inhibit', 'NegReg', (91, 98))	('apoptosis', 'CPA', (126, 135))	('ML162', 'Var', (15, 20))	('mesenchymal state', 'CPA', (72, 89))	('promote', 'PosReg', (118, 125))	('ML210', 'Var', (25, 30))
124618	32251318	Our findings are as follows: (1) members of the Netrin family are tightly regulated by multiple mechanisms at the genetic, transcriptional, and post-transcriptional levels; (2) mutations of members of the Netrin family correlate with tumor genetic characteristics; (3) Netrins may play important roles in the occurrence and development of endocrine system-related tumors and sex hormone targeting tumors; (4) Netrin family members may be promising prognostic indicators and potential therapeutic targets for lung and kidney cancer; (5) NTNG1 and NTNG2 are potential diagnostic markers and therapeutic targets that should be further studied systematically.	('tumor', 'Disease', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (364, 370))	('mutations', 'Var', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumors', 'Disease', (397, 403))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('kidney cancer', 'Disease', 'MESH:D007680', (517, 530))	('NTNG1', 'Gene', (536, 541))	('tumors', 'Disease', (364, 370))	('lung', 'Disease', (508, 512))	('NTNG2', 'Gene', '84628', (546, 551))	('tumors', 'Disease', 'MESH:D009369', (397, 403))	('cancer', 'Phenotype', 'HP:0002664', (524, 530))	('NTNG1', 'Gene', '22854', (536, 541))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('kidney cancer', 'Phenotype', 'HP:0009726', (517, 530))	('kidney cancer', 'Disease', (517, 530))	('tumors', 'Disease', 'MESH:D009369', (364, 370))	('tumor', 'Disease', (397, 402))	('tumor', 'Disease', (364, 369))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('NTNG2', 'Gene', (546, 551))	('tumors', 'Phenotype', 'HP:0002664', (397, 403))	('tumor', 'Disease', 'MESH:D009369', (364, 369))
124621	32251318	This study was the first comprehensive analysis of tumor genetic characteristics of mutations in members of the Netrin family.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('Netrin', 'Gene', (112, 118))
124622	32251318	We found that tumor mutations of members of the Netrin family showed a unique distribution pattern for cancer type, protein structure, and ethnic group.	('tumor', 'Disease', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (20, 29))
124623	32251318	It is worth noting that a significant number of missense or truncating mutations have been found in the Laminin N-terminal and EGF domains that interact with related receptors and the regulatory localization of the NTR domain.	('interact', 'Interaction', (144, 152))	('truncating mutations', 'Var', (60, 80))	('NTR', 'Gene', '4923', (215, 218))	('missense', 'Var', (48, 56))	('localization', 'biological_process', 'GO:0051179', ('195', '207'))	('EGF', 'molecular_function', 'GO:0005154', ('127', '130'))	('NTR', 'Gene', (215, 218))	('Laminin', 'Protein', (104, 111))
124626	32251318	Our mutation analysis found highly enriched mutation of netrin family genes in uterine corpus endometrial carcinoma.	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (87, 115))	('corpus endometrial carcinoma', 'Disease', (87, 115))	('mutation', 'Var', (44, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (94, 115))	('netrin family genes', 'Gene', (56, 75))
124634	32251318	This study found that the NTN family not only has a high overall mutation rate in lung cancer, but that netrin activity is also closely related to the survival and clinical parameters of kidney cancer and non-small cell lung cancer.	('kidney cancer', 'Disease', (187, 200))	('clinical', 'Species', '191496', (164, 172))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (205, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('related', 'Reg', (136, 143))	('lung cancer', 'Disease', (82, 93))	('non-small cell lung cancer', 'Disease', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('kidney cancer', 'Disease', 'MESH:D007680', (187, 200))	('mutation', 'Var', (65, 73))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (209, 231))	('kidney cancer', 'Phenotype', 'HP:0009726', (187, 200))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
124642	32251318	Here we find that the expression or methylation of NTNG1 and NTNG2 is associated with survival and other clinical parameters of more than 10 types of cancer.	('NTNG1', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('NTNG2', 'Gene', '84628', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('clinical', 'Species', '191496', (105, 113))	('associated', 'Reg', (70, 80))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('cancer', 'Disease', (150, 156))	('NTNG2', 'Gene', (61, 66))	('NTNG1', 'Gene', '22854', (51, 56))	('expression', 'MPA', (22, 32))	('methylation', 'Var', (36, 47))
124643	32251318	There are also important epigenetic and transcriptional modifications of netrins that occur in pan-cancer that are related to the activation of the EMT pathway.	('EMT', 'biological_process', 'GO:0001837', ('148', '151'))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('activation', 'PosReg', (130, 140))	('EMT', 'Gene', (148, 151))	('cancer', 'Disease', (99, 105))	('EMT', 'Gene', '3702', (148, 151))	('netrins', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('epigenetic', 'Var', (25, 35))
124645	32251318	It is worth noting that the mutations and potential mirRNA targeting of NTNG1 and NTNG2 in cancer exhibit rates that are much higher than those predicted for NTN1 and NTN4.	('NTN4', 'Gene', (167, 171))	('NTN1', 'Gene', '9423', (158, 162))	('NTNG2', 'Gene', '84628', (82, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('higher', 'PosReg', (126, 132))	('NTN4', 'Gene', '59277', (167, 171))	('NTNG2', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NTNG1', 'Gene', '22854', (72, 77))	('NTNG1', 'Gene', (72, 77))	('mutations', 'Var', (28, 37))	('NTN1', 'Gene', (158, 162))
124646	32251318	TCGA fusion transcripts analysis suggests the presence of fusion transcripts composed of NTNG1 or NTNG2 in multiple cancers.	('multiple cancers', 'Disease', (107, 123))	('NTNG2', 'Gene', '84628', (98, 103))	('NTNG1', 'Gene', '22854', (89, 94))	('multiple cancers', 'Disease', 'MESH:D009369', (107, 123))	('NTNG1', 'Gene', (89, 94))	('fusion transcripts', 'Var', (58, 76))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('NTNG2', 'Gene', (98, 103))
124650	32251318	However, in some cancers, the selective inhibition of this receptor-dependent apoptosis pathway depends on the silencing of pro-apoptotic proteins.	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('silencing', 'Var', (111, 120))	('receptor-dependent apoptosis pathway', 'Pathway', (59, 95))	('inhibition', 'NegReg', (40, 50))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
124680	28978030	Our results showed that PinX1 deletion accounted for the most alterations, with the frequency of its deletion regularly occurring in pathological types of carcinosarcoma and adenocarcinoma.	('carcinosarcoma and adenocarcinoma', 'Disease', 'MESH:D002296', (155, 188))	('occurring', 'Reg', (120, 129))	('PinX1', 'Gene', (24, 29))	('deletion', 'Var', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('PinX1', 'Gene', '54984', (24, 29))
124681	28978030	We found few instances of PinX1 gene mutations and 3D structural analysis demonstrated that these mutation sites were always located within telomerase inhibitor domains.	('mutations', 'Var', (37, 46))	('telomerase inhibitor', 'biological_process', 'GO:0051974', ('140', '160'))	('PinX1', 'Gene', (26, 31))	('PinX1', 'Gene', '54984', (26, 31))
124683	28978030	The status of PinX1 genetic alterations was correlated with prognosis and may be tumor-type specific.	('PinX1', 'Gene', '54984', (14, 19))	('PinX1', 'Gene', (14, 19))	('correlated', 'Reg', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('genetic alterations', 'Var', (20, 39))
124689	28978030	Many studies have shown that telomere shortening or dysfunction is often acquired during the process of tumorigenesis.	('telomere', 'cellular_component', 'GO:0000781', ('29', '37'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('telomere', 'cellular_component', 'GO:0005696', ('29', '37'))	('telomere shortening', 'Var', (29, 48))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
124699	28978030	Additional work has shown that depletion of endogenous PinX1 or its TID domain elongates telomeres, induces immortalization, and increases tumorigenicity.	('TID', 'Disease', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('induces', 'PosReg', (100, 107))	('immortalization', 'CPA', (108, 123))	('PinX1', 'Gene', '54984', (55, 60))	('elongates', 'PosReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('increases', 'PosReg', (129, 138))	('PinX1', 'Gene', (55, 60))	('depletion', 'Var', (31, 40))	('TID', 'Disease', 'None', (68, 71))
124700	28978030	Furthermore, PinX1 knockdown leads to chromosomal instability, as its loss can cause delayed mitotic entry during mitosis, thereby abrogating faithful chromosome segregation.	('chromosomal instability', 'Phenotype', 'HP:0040012', (38, 61))	('loss', 'NegReg', (70, 74))	('mitosis', 'Disease', (114, 121))	('PinX1', 'Gene', (13, 18))	('knockdown', 'Var', (19, 28))	('mitosis', 'Disease', 'None', (114, 121))	('mitosis', 'biological_process', 'GO:0000278', ('114', '121'))	('chromosome segregation', 'biological_process', 'GO:0007059', ('151', '173'))	('cause', 'Reg', (79, 84))	('chromosomal instability', 'MPA', (38, 61))	('mitotic entry', 'biological_process', 'GO:0051727', ('93', '106'))	('leads to', 'Reg', (29, 37))	('faithful chromosome segregation', 'CPA', (142, 173))	('chromosome', 'cellular_component', 'GO:0005694', ('151', '161'))	('abrogating', 'NegReg', (131, 141))	('PinX1', 'Gene', '54984', (13, 18))
124708	28978030	PinX1 gene alterations were detected in 105 separate studies using the online resource cBioportal Web.	('alterations', 'Var', (11, 22))	('PinX1', 'Gene', (0, 5))	('PinX1', 'Gene', '54984', (0, 5))
124709	28978030	PinX1 deletion accounted for the most alterations, with the highest ratio of 12.5% (Uterine Carcinosarcoma, TCGA, Provisional).	('PinX1', 'Gene', (0, 5))	('Uterine Carcinosarcoma', 'Phenotype', 'HP:0002891', (84, 106))	('deletion', 'Var', (6, 14))	('Carcinosarcoma', 'Disease', 'MESH:D002296', (92, 106))	('TCGA', 'Disease', (108, 112))	('PinX1', 'Gene', '54984', (0, 5))	('Carcinosarcoma', 'Disease', (92, 106))
124710	28978030	Furthermore, the frequency of PinX1 deletion often occurred in the two specific pathological types of carcinosarcoma and adenocarcinoma.	('PinX1', 'Gene', (30, 35))	('deletion', 'Var', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('PinX1', 'Gene', '54984', (30, 35))	('occurred', 'Reg', (51, 59))	('carcinosarcoma and adenocarcinoma', 'Disease', 'MESH:D002296', (102, 135))
124711	28978030	In addition, the frequency of PinX1 gene deletion in adenocarcinoma was more than squamous carcinoma in some solid tumors, such as 6.1% (TCGA, Nature), 5.5% (Broad, Cell), and 5.7% (TCGA, Provisional) in lung adenocarcinoma versus 1.7% (TCGA, Provisional) in lung squamous cell carcinoma.	('solid tumors', 'Disease', (109, 121))	('PinX1', 'Gene', (30, 35))	('lung squamous cell carcinoma', 'Disease', (259, 287))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (264, 287))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (204, 223))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (204, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('adenocarcinoma', 'Disease', (53, 67))	('squamous carcinoma', 'Disease', (82, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('solid tumors', 'Disease', 'MESH:D009369', (109, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('adenocarcinoma', 'Disease', 'MESH:D000230', (53, 67))	('adenocarcinoma', 'Disease', (209, 223))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (82, 100))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (259, 287))	('squamous carcinoma', 'Disease', 'MESH:D002294', (82, 100))	('lung adenocarcinoma', 'Disease', (204, 223))	('deletion', 'Var', (41, 49))	('adenocarcinoma', 'Disease', 'MESH:D000230', (209, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (259, 287))	('PinX1', 'Gene', '54984', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
124712	28978030	When compared with the high frequency of PinX1 genetic deletions, there were few, frequent PinX1 gene mutations the in 105 studies examined using cBioportal Web.	('PinX1', 'Gene', (91, 96))	('PinX1', 'Gene', '54984', (41, 46))	('PinX1', 'Gene', (41, 46))	('PinX1', 'Gene', '54984', (91, 96))	('mutations', 'Var', (102, 111))
124713	28978030	Of these, only three sites (S161N/R, A175T, R209C/H) had reached mutation level 2 (the number of patients with the same mutation site).	('A175T', 'Var', (37, 42))	('R209C', 'Var', (44, 49))	('S161N', 'Var', (28, 33))	('R209C', 'SUBSTITUTION', 'None', (44, 49))	('A175T', 'Mutation', 'rs750737817', (37, 42))	('S161N', 'SUBSTITUTION', 'None', (28, 33))	('patients', 'Species', '9606', (97, 105))
124719	28978030	As shown in Figure 4, there were no significant correlations between PinX1 gene alteration and overall survival and/or disease-free survival in prostate adenocarcinoma (TCGA, Provisional) (P>0.05, Figure 4A), colorectal adenocarcinoma (TCGA, Provisional) (P>0.05, Figure 4B), head and neck squamous cell carcinoma (TCGA, Provisional) (P>0.05, Figure 4C), kidney renal clear cell carcinoma (TCGA, Provisional) (P>0.05, Figure 4D), and lung squamous cell carcinoma (TCGA, Provisional) (P>0.05, Figure 4F).	('lung squamous cell carcinoma', 'Disease', (434, 462))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (209, 234))	('prostate adenocarcinoma', 'Disease', (144, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (453, 462))	('neck', 'cellular_component', 'GO:0044326', ('285', '289'))	('neck squamous cell carcinoma', 'Disease', (285, 313))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (285, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (144, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (379, 388))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (355, 388))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (290, 313))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (434, 462))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (439, 462))	('alteration', 'Var', (80, 90))	('PinX1', 'Gene', '54984', (69, 74))	('colorectal adenocarcinoma', 'Disease', (209, 234))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (276, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('kidney renal clear cell carcinoma', 'Disease', (355, 388))	('PinX1', 'Gene', (69, 74))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (434, 462))
124720	28978030	There was also no significant correlation between PinX1 gene alteration and overall survival in bladder urothelial carcinoma (TCGA, Provisional) (P>0.05, Figure 4G) and disease-free survival in ovarian serous cystadenocarcinoma (TCGA, Provisional) (P>0.05, Figure 4H).	('ovarian serous cystadenocarcinoma', 'Disease', (194, 227))	('PinX1', 'Gene', (50, 55))	('bladder urothelial carcinoma', 'Disease', (96, 124))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (194, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('alteration', 'Var', (61, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('PinX1', 'Gene', '54984', (50, 55))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (194, 227))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (96, 124))
124721	28978030	However, PinX1 gene alteration was significantly correlated with poor overall survival and/or disease-free survival in lung adenocarcinoma (TCGA, Provisional) (P<0.05, Figure 4E), poor overall survival in bladder urothelial carcinoma (TCGA, Provisional) (P<0.05, Figure 4G), and poor disease-free survival ovarian serous cystadenocarcinoma (TCGA, Provisional) (P<0.05, Figure 4H).	('carcinoma', 'Phenotype', 'HP:0030731', (330, 339))	('poor', 'NegReg', (180, 184))	('alteration', 'Var', (20, 30))	('PinX1', 'Gene', '54984', (9, 14))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (205, 233))	('poor disease-free survival ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (279, 339))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('bladder urothelial carcinoma', 'Disease', (205, 233))	('lung adenocarcinoma', 'Disease', (119, 138))	('PinX1', 'Gene', (9, 14))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (119, 138))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (306, 339))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('poor', 'NegReg', (65, 69))
124734	28978030	We then continued our study in vitro to investigate whether knock-down of PinX1 expression promotes cell proliferation in cancer cell lines.	('promotes', 'PosReg', (91, 99))	('knock-down', 'Var', (60, 70))	('cell proliferation', 'biological_process', 'GO:0008283', ('100', '118'))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('PinX1', 'Gene', '54984', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('PinX1', 'Gene', (74, 79))
124740	28978030	For example, one study demonstrated that high expression of PinX1 in esophageal squamous cell carcinoma is associated with a patient's chemoradiotherapy resistance and can predict his/her survival.	('predict', 'Reg', (172, 179))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (69, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('associated', 'Reg', (107, 117))	('high expression', 'Var', (41, 56))	('esophageal squamous cell carcinoma', 'Disease', (69, 103))	('patient', 'Species', '9606', (125, 132))	('PinX1', 'Gene', '54984', (60, 65))	('PinX1', 'Gene', (60, 65))
124748	28978030	Our results indicated that PinX1 deletion is a common genotype in human cancer patients, leading us to believe that insufficient PinX1 may be involved in the progression of a variety of human cancers.	('deletion', 'Var', (33, 41))	('human', 'Species', '9606', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('PinX1', 'Gene', '54984', (129, 134))	('cancers', 'Disease', (192, 199))	('cancer', 'Disease', (192, 198))	('PinX1', 'Gene', (129, 134))	('PinX1', 'Gene', '54984', (27, 32))	('cancer', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('insufficient', 'Disease', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('PinX1', 'Gene', (27, 32))	('involved', 'Reg', (142, 150))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('insufficient', 'Disease', 'MESH:D000309', (116, 128))	('human', 'Species', '9606', (186, 191))	('patients', 'Species', '9606', (79, 87))
124751	28978030	With the exception of the high frequency of PinX1 gene deletion, we also found that PinX1 genetic mutations occurred in some types of human cancers, including bladder urothelial carcinoma, lung adenocarcinoma, and melanoma.	('lung adenocarcinoma', 'Disease', (189, 208))	('bladder urothelial carcinoma', 'Disease', (159, 187))	('deletion', 'Var', (55, 63))	('PinX1', 'Gene', '54984', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (159, 187))	('PinX1', 'Gene', (44, 49))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (189, 208))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('melanoma', 'Disease', (214, 222))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (189, 208))	('human', 'Species', '9606', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('occurred', 'Reg', (108, 116))	('PinX1', 'Gene', '54984', (84, 89))	('mutations', 'Var', (98, 107))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('PinX1', 'Gene', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))
124752	28978030	However, the number of cases having a PinX1 gene mutation was very few.	('PinX1', 'Gene', '54984', (38, 43))	('PinX1', 'Gene', (38, 43))	('mutation', 'Var', (49, 57))
124755	28978030	Additional work performing 3D structural analysis showed that that these mutation sites may influence this structural domain, which is specifically recognized by the TRFH domain of TRF1 via both hydrophobic and hydrophilic interactions.	('TRF1', 'Gene', (181, 185))	('mutation sites', 'Var', (73, 87))	('influence', 'Reg', (92, 101))	('hydrophobic', 'MPA', (195, 206))	('structural domain', 'MPA', (107, 124))	('TRF1', 'Gene', '7013', (181, 185))
124756	28978030	Thus, such mutations could break the PinX1-TRF1-TERT complex, thereby promoting telomere elongation in cells.	('mutations', 'Var', (11, 20))	('telomere', 'cellular_component', 'GO:0000781', ('80', '88'))	('promoting', 'PosReg', (70, 79))	('telomere elongation', 'CPA', (80, 99))	('TERT', 'Gene', (48, 52))	('PinX1', 'Gene', '54984', (37, 42))	('telomere', 'cellular_component', 'GO:0005696', ('80', '88'))	('break', 'NegReg', (27, 32))	('TRF1', 'Gene', (43, 47))	('TRF1', 'Gene', '7013', (43, 47))	('TERT', 'Gene', '7015', (48, 52))	('PinX1', 'Gene', (37, 42))
124759	28978030	Since the deletion of PinX1 accounts for the most observed alterations, we next randomly selected six studies to better understand the relationship between PinX1 gene copy number and mRNA levels.	('mRNA levels', 'MPA', (183, 194))	('PinX1', 'Gene', '54984', (22, 27))	('PinX1', 'Gene', '54984', (156, 161))	('deletion', 'Var', (10, 18))	('PinX1', 'Gene', (22, 27))	('PinX1', 'Gene', (156, 161))
124760	28978030	Among the five types of copy numbers we examined (deep deletion, shallow deletion, diploid, gain and amplification), we found that the frequency of PinX1 homozygous depletion as well as PinX1 heterozygous deficiency were the main reasons for the frequency of PinX1 deletion in a wide variety of tumor tissues.	('PinX1', 'Gene', '54984', (148, 153))	('PinX1', 'Gene', '54984', (186, 191))	('PinX1', 'Gene', '54984', (259, 264))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('PinX1', 'Gene', (148, 153))	('PinX1', 'Gene', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('deletion', 'Var', (265, 273))	('PinX1', 'Gene', (259, 264))	('tumor', 'Disease', (295, 300))
124763	28978030	According to our mutation data, PinX1 mutations in gastric, colorectal, prostate, breast, and lung carcinomas may not actually contribute to development of these carcinomas due to their low incidence of mutational events seen in the database.	('gastric', 'Disease', (51, 58))	('prostate', 'Disease', (72, 80))	('colorectal', 'Disease', 'MESH:D015179', (60, 70))	('carcinomas', 'Disease', (162, 172))	('mutations', 'Var', (38, 47))	('lung carcinomas', 'Disease', 'MESH:D008175', (94, 109))	('carcinomas', 'Disease', (99, 109))	('lung carcinomas', 'Disease', (94, 109))	('PinX1', 'Gene', '54984', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('PinX1', 'Gene', (32, 37))	('breast', 'Disease', (82, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('carcinomas', 'Disease', 'MESH:D002277', (162, 172))	('colorectal', 'Disease', (60, 70))	('contribute', 'Reg', (127, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('carcinomas', 'Disease', 'MESH:D002277', (99, 109))
124765	28978030	Rather, loss of hetereozygosity seems to play a major role in the inactivation of PinX1 in human cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('hetereozygosity', 'Var', (16, 31))	('inactivation', 'NegReg', (66, 78))	('loss', 'NegReg', (8, 12))	('PinX1', 'Gene', '54984', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('human', 'Species', '9606', (91, 96))	('PinX1', 'Gene', (82, 87))
124767	28978030	Thus, we used a Kaplan-Meier analysis to determine the relationship between PinX1 gene alterations and patient survival.	('PinX1', 'Gene', (76, 81))	('PinX1', 'Gene', '54984', (76, 81))	('alterations', 'Var', (87, 98))	('patient', 'Species', '9606', (103, 110))
124768	28978030	Our results demonstrated that PinX1 gene alterations were correlated with poor survival in patients with lung adenocarcinoma (overall survival and disease-free survival) and as well as those diagnosed with bladder urothelial carcinoma (disease-free survival only).	('PinX1', 'Gene', (30, 35))	('bladder urothelial carcinoma', 'Disease', (206, 234))	('patients', 'Species', '9606', (91, 99))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('poor', 'NegReg', (74, 78))	('lung adenocarcinoma', 'Disease', (105, 124))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (206, 234))	('PinX1', 'Gene', '54984', (30, 35))	('alterations', 'Var', (41, 52))
124769	28978030	However, there were no significant correlations between PinX1 alterations and overall survival and/or disease-free survival in the other seven types of tested human cancers.	('PinX1', 'Gene', '54984', (56, 61))	('disease-free survival', 'CPA', (102, 123))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('PinX1', 'Gene', (56, 61))	('alterations', 'Var', (62, 73))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))
124770	28978030	These results showed that the status of PinX1 gene alteration was correlated with prognosis; importantly, that this correlation may be tumor-type specific.	('correlated', 'Reg', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('alteration', 'Var', (51, 61))	('PinX1', 'Gene', '54984', (40, 45))	('PinX1', 'Gene', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
124783	28978030	It has been reported that PinX1 suppress tumor growth and depletion of endogenous PinX1 can enhance tumorigenicity.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('PinX1', 'Gene', (26, 31))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', (100, 105))	('suppress', 'NegReg', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('PinX1', 'Gene', '54984', (82, 87))	('depletion', 'Var', (58, 67))	('PinX1', 'Gene', '54984', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('enhance', 'PosReg', (92, 99))	('PinX1', 'Gene', (82, 87))
124784	28978030	We also observed that knockdown of PinX1 could also enhance cell proliferation in nine types of cancer cell lines in vitro.	('PinX1', 'Gene', '54984', (35, 40))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('knockdown', 'Var', (22, 31))	('PinX1', 'Gene', (35, 40))	('enhance', 'PosReg', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
124788	28978030	Thus, loss of PinX1 abrogates faithful chromosome segregation, suggesting a novel function outside of its established roles.	('chromosome segregation', 'biological_process', 'GO:0007059', ('39', '61'))	('PinX1', 'Gene', '54984', (14, 19))	('loss', 'Var', (6, 10))	('PinX1', 'Gene', (14, 19))	('abrogates', 'NegReg', (20, 29))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('faithful chromosome segregation', 'CPA', (30, 61))
124794	28978030	Analysis of PinX1 gene alterations, mutation levels, genetic profiles, 3D structural analyses, clinical impacts, gene co-expression, and integrated networks from this database was then performed in silico.	('PinX1', 'Gene', '54984', (12, 17))	('alterations', 'Var', (23, 34))	('PinX1', 'Gene', (12, 17))
124807	26041878	Patient tumor and PDX were processed for analysis of copy number variations by aCGH, gene expression by microarray, and expression of target pathways by immunohistochemistry (IHC).	('gene expression', 'biological_process', 'GO:0010467', ('85', '100'))	('copy number variations', 'Var', (53, 75))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('aCGH', 'Gene', (79, 83))	('Patient', 'Species', '9606', (0, 7))
124838	26041878	Copy number changes in the PDX models were more prominent, presumably due to reduction in the contribution of non-tumor cells such as macrophages and lymphocytes.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('reduction', 'NegReg', (77, 86))	('tumor', 'Disease', (114, 119))	('Copy number', 'Var', (0, 11))
124840	26041878	Remarkably, 19 of these 20 genes showed congruent copy number change in at least one of our xenograft tumors, although only four genes were affected by high copy gain or homozygous loss (CDKN2A, CCND1, ZNF703 and YAP1) [Figure 1C].	('ZNF703', 'Gene', (202, 208))	('CDKN2A', 'Gene', (187, 193))	('tumors', 'Disease', (102, 108))	('CDKN2A', 'Gene', '1029', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('YAP1', 'Gene', (213, 217))	('YAP1', 'Gene', '10413', (213, 217))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('CCND1', 'Gene', (195, 200))	('copy number change', 'Var', (50, 68))	('ZNF703', 'Gene', '80139', (202, 208))	('CCND1', 'Gene', '595', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
124841	26041878	Especially the copy number loss of CDKN2A in all models histologically classified as urothelial carcinoma (4/5 models) is in concordance with the TCGA data where 47% of non-squamous tumors exhibit this specific alteration.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('CDKN2A', 'Gene', '1029', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (85, 105))	('copy number loss', 'Var', (15, 31))	('urothelial carcinoma', 'Disease', (85, 105))	('non-squamous tumors', 'Disease', 'MESH:D002294', (169, 188))	('non-squamous tumors', 'Disease', (169, 188))	('CDKN2A', 'Gene', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
124842	26041878	This demonstrates the potential utility of our models to recapitulate the chromosomal copy number variation commonly detected in patient tumors.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('chromosomal copy number variation', 'Var', (74, 107))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('patient', 'Species', '9606', (129, 136))
124843	26041878	As mutations in the FGFR3 regularly occur in urothelial cancer of the bladder and are amenable to targeted therapies the primary tumors and their corresponding PDX were analyzed for mutations in this gene by direct sequencing.	('cancer of the bladder', 'Phenotype', 'HP:0009725', (56, 77))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('men', 'Species', '9606', (87, 90))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('urothelial cancer of the bladder', 'Disease', (45, 77))	('FGFR3', 'Gene', (20, 25))	('urothelial cancer of the bladder', 'Disease', 'MESH:D001749', (45, 77))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('occur', 'Reg', (36, 41))	('mutations', 'Var', (3, 12))	('FGFR', 'molecular_function', 'GO:0005007', ('20', '24'))
124851	26041878	This clustering revealed that corresponding pairs (patient tumors and corresponding PDX) tended to cluster together, although primary tumors LTL490 and LTL543 as well as PDX LTL490 and LTL543 clustered together.	('LTL543', 'Gene', (152, 158))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('LTL490', 'Var', (141, 147))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('patient', 'Species', '9606', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
124861	26041878	Significantly smaller tumor volumes were observed after 18 days of treatment with R3Mab compared to control antibody, and these differences persisted until the end of the experiment (p < 0.05 [Figure 4B, 4D]).	('antibody', 'cellular_component', 'GO:0042571', ('108', '116'))	('antibody', 'cellular_component', 'GO:0019815', ('108', '116'))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('men', 'Species', '9606', (72, 75))	('smaller', 'NegReg', (14, 21))	('antibody', 'cellular_component', 'GO:0019814', ('108', '116'))	('R3Mab', 'Var', (82, 87))	('men', 'Species', '9606', (177, 180))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('antibody', 'molecular_function', 'GO:0003823', ('108', '116'))
124875	26041878	Nevertheless we were able to demonstrate that even our few models recapitulated a large proportion of the chromosomal copy variation commonly detected in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (154, 168))	('chromosomal copy variation', 'Var', (106, 132))	('bladder cancer', 'Disease', 'MESH:D001749', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('bladder cancer', 'Disease', (154, 168))
124905	26041878	After blocking (Odyssey Blocking buffer; LI-COR Biosciences (Lincoln, NE)) the blots were incubated with the following primary antibodies: rabbit monoclonal anti-phospho-Akt (1:1000, #4060, Cell Signalling), mouse monoclonal anti- phospho- Erk1/2 (1:1000, #4374, Cell Signalling), mouse monoclonal anti-phosphotyrosine (1:1000, 05-321X, EMD Milipore (Darmstadt, Germany) and rabbit polyclonal anti-Vinculin (1:2, 500, PA5-19842, Thermo Scientific).	('Signalling', 'biological_process', 'GO:0023052', ('195', '205'))	('Erk1/2', 'Gene', '5595;5594', (240, 246))	('rabbit', 'Species', '9986', (375, 381))	('rabbit', 'Species', '9986', (139, 145))	('Vinculin', 'Gene', '7414', (398, 406))	('Erk1', 'molecular_function', 'GO:0004707', ('240', '244'))	('1:1000', 'Var', (320, 326))	('Vinculin', 'Gene', (398, 406))	('Erk1/2', 'Gene', (240, 246))	('mouse', 'Species', '10090', (208, 213))	('mouse', 'Species', '10090', (281, 286))	('Signalling', 'biological_process', 'GO:0023052', ('268', '278'))
124959	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))
125027	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))
125034	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))
125068	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'))
125071	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))
125075	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))
125092	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))	('benign tumors', 'Disease', 'MESH:D009369', (235, 248))	('SRMs', 'Disease', 'None', (226, 230))	('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))
125107	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))	('reducing', 'NegReg', (97, 105))	('DTT', 'Var', (13, 16))	('alter', 'Reg', (21, 26))	('complexes', 'Interaction', (70, 79))	('disulfide', 'Chemical', 'MESH:D004220', (106, 115))	('disulfide bonds', 'MPA', (106, 121))	('influence', 'Reg', (138, 147))
125156	29430515	Study Start Date: November 2, 2015 Estimated Study Completion Date: September 23, 2019 Study Title: A Phase 3, Open-label, Randomized Study of Nivolumab Combined with Ipilimumab, or with Standard of Care Chemotherapy, Versus Standard of Care Chemotherapy in Participants with Previously Untreated Unresectable or Metastatic Urothelial Cancer (Checkmate-901) Clinicaltrials.gov identifier: NCT03036098 Sponsor: Bristol-Myers Squibb + Ono Pharmaceutical Co. Ltd Enrollment: 897 Rationale: The purpose of this study is to determine whether immunotherapy with a PD-1 inhibitor, Nivolumab, in combination with ipilimumab, a CTLA-4 inhibitor, or in combination with standard of care chemotherapy is more effective than standard of care chemotherapy alone in treating patients with previously untreated inoperable or metastatic urothelial cancer.	('CTLA-4', 'Gene', '1493', (619, 625))	('Metastatic Urothelial Cancer', 'Disease', (313, 341))	('inhibitor', 'Var', (563, 572))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (167, 177))	('Metastatic Urothelial Cancer', 'Disease', 'MESH:C538445', (313, 341))	('Nivolumab', 'Chemical', 'MESH:D000077594', (143, 152))	('CTLA-4', 'Gene', (619, 625))	('ipilimumab', 'Chemical', 'MESH:D000074324', (605, 615))	('Cancer', 'Phenotype', 'HP:0002664', (335, 341))	('urothelial cancer', 'Disease', (821, 838))	('patients', 'Species', '9606', (761, 769))	('cancer', 'Phenotype', 'HP:0002664', (832, 838))	('Participants', 'Species', '9606', (258, 270))	('previously untreated inoperable', 'Disease', (775, 806))	('urothelial cancer', 'Disease', 'MESH:D014523', (821, 838))	('PD-1', 'Gene', (558, 562))	('Nivolumab', 'Chemical', 'MESH:D000077594', (574, 583))
125162	29430515	Confirmed objective response was observed in 23 (28.4%) of 81 patients with PD-L1 expression > 5%, 29 (23.8%) of 122 patients with PD-L1 expression > 1%, and 23 (16.1%) of 143 patients with PD-L1 expression <1% PD-L1 expression.	('patients', 'Species', '9606', (176, 184))	('PD-L1', 'Gene', (190, 195))	('PD-L1', 'Gene', (211, 216))	('PD-L1', 'Gene', '29126', (131, 136))	('PD-L1', 'Gene', '29126', (190, 195))	('PD-L1', 'Gene', '29126', (76, 81))	('PD-L1', 'Gene', '29126', (211, 216))	('> 5%', 'Var', (93, 97))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (62, 70))	('PD-L1', 'Gene', (131, 136))	('PD-L1', 'Gene', (76, 81))
125173	28212060	Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (232, 252))	('Pembrolizumab', 'Var', (0, 13))	('longer', 'PosReg', (48, 54))	('overall', 'MPA', (55, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('urothelial carcinoma', 'Disease', (232, 252))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('platinum', 'Chemical', 'MESH:D010984', (203, 211))
125238	28212060	Treatment-related events of grade 3, 4, or 5 severity were less frequent in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4% of patients), as was treatment-related discontinuation of therapy (5.6% vs. 11.0%).	('pembrolizumab', 'Var', (80, 93))	('less', 'NegReg', (59, 63))	('pembrolizumab', 'Chemical', 'MESH:C582435', (80, 93))	('patients', 'Species', '9606', (151, 159))
125247	28212060	In this randomized, phase 3 study involving patients with advanced urothelial cancer that progressed during or after platinum-based chemotherapy, pembrolizumab resulted in significantly longer overall survival : by approximately 3 months : than the investigator's choice of paclitaxel, docetaxel, or vinflunine (10.3 months vs. 7.4 months).	('overall survival', 'MPA', (193, 209))	('patients', 'Species', '9606', (44, 52))	('platinum', 'Chemical', 'MESH:D010984', (117, 125))	('pembrolizumab', 'Var', (146, 159))	('docetaxel', 'Chemical', 'MESH:D000077143', (286, 295))	('pembrolizumab', 'Chemical', 'MESH:C582435', (146, 159))	('urothelial cancer', 'Disease', 'MESH:D014523', (67, 84))	('vinflunine', 'Chemical', 'MESH:C111217', (300, 310))	('paclitaxel', 'Chemical', 'MESH:D017239', (274, 284))	('longer', 'PosReg', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('urothelial cancer', 'Disease', (67, 84))
125254	28212060	The relationship between smoking and the relative benefit of immunotherapy has also been observed in patients with other advanced cancers and may reflect a high mutational load in current and former smokers.	('mutational load', 'Var', (161, 176))	('patients', 'Species', '9606', (101, 109))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
125270	28212060	Overall, the incidence of treatment-related adverse events was substantially lower with pembrolizumab than with standard chemotherapy, including fewer events of grade 3, 4, or 5 severity and fewer events that resulted in the discontinuation of treatment.	('lower', 'NegReg', (77, 82))	('pembrolizumab', 'Chemical', 'MESH:C582435', (88, 101))	('pembrolizumab', 'Var', (88, 101))
125271	28212060	The number of treatment-related deaths was the same in the pembrolizumab group and the chemotherapy group, which probably reflects the poor prognosis of patients in this population.	('pembrolizumab', 'Var', (59, 72))	('death', 'Disease', (32, 37))	('patients', 'Species', '9606', (153, 161))	('pembrolizumab', 'Chemical', 'MESH:C582435', (59, 72))	('death', 'Disease', 'MESH:D003643', (32, 37))
125274	28212060	Currently, pembrolizumab and other PD-1 and PD-L1 inhibitors are being evaluated as adjuvant therapy and as first-line therapy for advanced disease in ongoing clinical trials (e.g., ClinicalTrials.gov numbers, NCT02450331, NCT02516241, NCT02632409, NCT02807636, and NCT02853305).	('pembrolizumab', 'Chemical', 'MESH:C582435', (11, 24))	('NCT02632409', 'Var', (236, 247))	('NCT02450331', 'Var', (210, 221))	('NCT02807636', 'Var', (249, 260))	('NCT02516241', 'Var', (223, 234))	('PD-L1', 'Gene', (44, 49))	('NCT02853305', 'Var', (266, 277))	('PD-1', 'Gene', (35, 39))	('PD-L1', 'Gene', '29126', (44, 49))	('PD-1', 'Gene', '5133', (35, 39))
125275	28212060	In conclusion, pembrolizumab resulted in significantly longer overall survival : by approximately 3 months : than the investigator's choice of paclitaxel, docetaxel, or vinflunine and was associated with a higher rate of objective response and a lower rate of treatment-related adverse events than chemotherapy as second-line therapy in patients with advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy, regardless of tumor PD-L1 expression status.	('vinflunine', 'Chemical', 'MESH:C111217', (169, 179))	('paclitaxel', 'Chemical', 'MESH:D017239', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (456, 461))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (360, 380))	('platinum', 'Chemical', 'MESH:D010984', (413, 421))	('docetaxel', 'Chemical', 'MESH:D000077143', (155, 164))	('PD-L1', 'Gene', (462, 467))	('pembrolizumab', 'Chemical', 'MESH:C582435', (15, 28))	('tumor', 'Phenotype', 'HP:0002664', (456, 461))	('pembrolizumab', 'Var', (15, 28))	('tumor', 'Disease', (456, 461))	('carcinoma', 'Phenotype', 'HP:0030731', (371, 380))	('PD-L1', 'Gene', '29126', (462, 467))	('longer', 'PosReg', (55, 61))	('urothelial carcinoma', 'Disease', (360, 380))	('patients', 'Species', '9606', (337, 345))
125327	26279824	Significant independent predictors for recurrence in the multivariate analysis were multiplicity, prior tumor, female gender, and presence of associated CIS.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('CIS', 'Phenotype', 'HP:0030075', (153, 156))	('tumor', 'Disease', (104, 109))	('multiplicity', 'Var', (84, 96))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
125339	26279824	A mutant genotype of p53 was found to be a predictor for recurrence in a study by Shariat et al., whereas the wild-type of p53 was associated with more recurrence in the Moonen et al.	('mutant', 'Var', (2, 8))	('p53', 'Gene', (123, 126))	('p53', 'Gene', (21, 24))	('p53', 'Gene', '7157', (123, 126))	('p53', 'Gene', '7157', (21, 24))
125345	26279824	The micropapillary variant of urothelial cancer and lympho-vascular invasion are other significant factors related to aggressiveness and can predict progression to muscle invasion.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('lympho-vascular invasion', 'CPA', (52, 76))	('aggressiveness', 'Phenotype', 'HP:0000718', (118, 132))	('urothelial cancer', 'Disease', (30, 47))	('micropapillary', 'Var', (4, 18))	('muscle invasion', 'CPA', (164, 179))	('urothelial cancer', 'Disease', 'MESH:D014523', (30, 47))	('aggressiveness', 'Disease', 'MESH:D001523', (118, 132))	('aggressiveness', 'Disease', (118, 132))
125361	26279824	The proportion of altered p53 was shown to increase progressively in specimens from normal urothelium, NMI BC, CIS, muscle-invasive BC, and metastatic lymph nodes in specimens from over 400 patients with BC using tissue microarray.	('BC', 'Phenotype', 'HP:0009725', (204, 206))	('BC', 'Phenotype', 'HP:0009725', (132, 134))	('CIS', 'Phenotype', 'HP:0030075', (111, 114))	('altered', 'Var', (18, 25))	('patients', 'Species', '9606', (190, 198))	('p53', 'Gene', (26, 29))	('increase', 'PosReg', (43, 51))	('men', 'Species', '9606', (74, 77))	('p53', 'Gene', '7157', (26, 29))	('men', 'Species', '9606', (171, 174))	('BC', 'Phenotype', 'HP:0009725', (107, 109))
125367	26279824	Altered p21 expression is independently associated with BC recurrence and progression.	('Altered', 'Var', (0, 7))	('BC recurrence', 'Disease', (56, 69))	('p21', 'Gene', (8, 11))	('p21', 'Gene', '644914', (8, 11))	('expression', 'MPA', (12, 22))	('BC', 'Phenotype', 'HP:0009725', (56, 58))	('associated', 'Reg', (40, 50))
125370	26279824	showed that patients with high MVD (>100 microvessels/HPF) and no p53 abnormalities showed the highest risk of disease recurrence and cancer-specific mortality compared with patients with low MVD.	('abnormalities', 'Var', (70, 83))	('patients', 'Species', '9606', (12, 20))	('p53', 'Gene', '7157', (66, 69))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('disease recurrence', 'CPA', (111, 129))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('p53', 'Gene', (66, 69))
125373	26279824	Approximately two-thirds of NMI UC cases are FGFR3 mutants.	('mutants', 'Var', (51, 58))	('FGFR3', 'Gene', '2261', (45, 50))	('NMI UC cases', 'Disease', (28, 40))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('FGFR3', 'Gene', (45, 50))
125374	26279824	Several studies have shown that FGFR3 mutation is a genetic event that leads to favorable pathways in BC with protection against disease progression.	('FGFR3', 'Gene', (32, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('favorable pathways', 'Pathway', (80, 98))	('FGFR3', 'Gene', '2261', (32, 37))	('mutation', 'Var', (38, 46))	('BC', 'Phenotype', 'HP:0009725', (102, 104))	('leads to', 'Reg', (71, 79))
125376	26279824	They proposed that analysis of FGFR3 mutation could decrease the frequency of cystoscopic surveillance.	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('FGFR3', 'Gene', '2261', (31, 36))	('mutation', 'Var', (37, 45))	('cystoscopic surveillance', 'Disease', (78, 102))	('decrease', 'NegReg', (52, 60))	('FGFR3', 'Gene', (31, 36))
125383	26279824	Detection of amplification of Her-2 by fluorescence in situ hybridization (FISH) is associated with markedly aggressive behavior in NMI UC with high risk of progression.	('associated with', 'Reg', (84, 99))	('aggressive behavior', 'CPA', (109, 128))	('aggressive behavior', 'Phenotype', 'HP:0000718', (109, 128))	('Her-2', 'Gene', '2064', (30, 35))	('amplification', 'Var', (13, 26))	('Her-2', 'Gene', (30, 35))	('aggressive behavior', 'biological_process', 'GO:0002118', ('109', '128'))
125418	26279824	The UroVysion test uses the FISH technique to detect aneuploidy in chromosomes 3, 7, 17, and loss of the 9p21 locus of the p16 tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor suppressor', 'biological_process', 'GO:0051726', ('127', '143'))	('tumor', 'Disease', (127, 132))	('p21', 'Gene', '644914', (106, 109))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('127', '143'))	('loss', 'Var', (93, 97))	('aneuploidy', 'Disease', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('aneuploidy', 'Disease', 'MESH:D000782', (53, 63))	('p21', 'Gene', (106, 109))
125509	23705833	Urothelial carcinoma has been associated with chemicals such as aniline dyes and aromatic amines associated with occupational exposure, a fact which is observed more frequently in developed countries than developing countries.	('associated', 'Reg', (30, 40))	('aniline', 'Chemical', 'MESH:C023650', (64, 71))	('aromatic amines', 'Chemical', '-', (81, 96))	('Urothelial carcinoma', 'Disease', 'MESH:D014526', (0, 20))	('aromatic', 'Var', (81, 89))	('Urothelial carcinoma', 'Disease', (0, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
125655	32358407	Of these 25 patients who received NAC, 80% had any reduction in tumor size observed by imaging.	('patients', 'Species', '9606', (12, 20))	('NAC', 'Var', (34, 37))	('reduction', 'NegReg', (51, 60))	('tumor', 'Disease', (64, 69))	('NAC', 'Chemical', '-', (34, 37))	('NAC', 'cellular_component', 'GO:0005854', ('34', '37'))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
125665	32358407	Statistical analysis showed that the pooled HR was 0.47 (95% CI: 0.34-0.64; P < .00001), which indicated that NAC plus RNU was associated with a significant OS improvement as compared with those that underwent RNU alone (Fig.	('RNU', 'Var', (119, 122))	('improvement', 'PosReg', (160, 171))	('NAC', 'Var', (110, 113))	('NAC', 'Chemical', '-', (110, 113))	('NAC', 'cellular_component', 'GO:0005854', ('110', '113'))	('RNU', 'Chemical', '-', (119, 122))	('RNU', 'Chemical', '-', (210, 213))
125666	32358407	The meta-analysis revealed that pooled HR was 0.50 (95% CI:0.37-0.66; P < .00001), which indicated that NAC plus RNU was also associated with a significant RFS improvement as compared those that received RNU alone (Fig.	('NAC', 'Var', (104, 107))	('RNU', 'Chemical', '-', (204, 207))	('improvement', 'PosReg', (160, 171))	('NAC', 'Chemical', '-', (104, 107))	('RFS', 'MPA', (156, 159))	('NAC', 'cellular_component', 'GO:0005854', ('104', '107'))	('RNU', 'Chemical', '-', (113, 116))
125667	32358407	The pooled HR was 0.37 (95% CI: 0.25-0.54; P < .00001), which indicated that NAC plus RNU was also associated with significant CSS improvement as compared with those that underwent RNU alone (Fig.	('CSS', 'CPA', (127, 130))	('improvement', 'PosReg', (131, 142))	('NAC', 'Var', (77, 80))	('NAC', 'cellular_component', 'GO:0005854', ('77', '80'))	('NAC', 'Chemical', '-', (77, 80))	('RNU', 'Var', (86, 89))	('RNU', 'Chemical', '-', (86, 89))	('RNU', 'Chemical', '-', (181, 184))
125669	32358407	These results inform us that the NAC group had a 6.58-fold higher possibility of having T stage down-grading (T3/4 to <=T2) as compared the control group.	('T stage down-grading', 'CPA', (88, 108))	('NAC', 'Var', (33, 36))	('NAC', 'cellular_component', 'GO:0005854', ('33', '36'))	('NAC', 'Chemical', '-', (33, 36))
125671	32358407	The results illustrate that the NAC group had a 5.24-fold higher possibility of having a declining incidence of lymph node-positive disease as compared the control group.	('NAC', 'Var', (32, 35))	('lymph node-positive disease', 'Disease', (112, 139))	('NAC', 'Chemical', '-', (32, 35))	('NAC', 'cellular_component', 'GO:0005854', ('32', '35'))
125684	32358407	After comprehensively searching for the relationship between NAC and survival prognosis in UTUC patients, 2 meta-analyses showed significant improvements in OS and CSS in the NAC group as compared to controls.	('NAC', 'Var', (175, 178))	('CSS', 'CPA', (164, 167))	('NAC', 'Chemical', '-', (175, 178))	('NAC', 'cellular_component', 'GO:0005854', ('61', '64'))	('improvements', 'PosReg', (141, 153))	('UTUC', 'Chemical', '-', (91, 95))	('NAC', 'cellular_component', 'GO:0005854', ('175', '178'))	('patients', 'Species', '9606', (96, 104))	('NAC', 'Chemical', '-', (61, 64))
125686	32358407	Patients who received NAC before surgery had significantly improved overall and disease-free survival.	('improved', 'PosReg', (59, 67))	('NAC', 'cellular_component', 'GO:0005854', ('22', '25'))	('overall', 'CPA', (68, 75))	('NAC', 'Var', (22, 25))	('Patients', 'Species', '9606', (0, 8))	('disease-free survival', 'CPA', (80, 101))	('NAC', 'Chemical', '-', (22, 25))
125691	32358407	Another study reported that NAC led to a pathologic down-staging in twelve (75%) of sixteen patients with upper tract cancer.	('NAC', 'cellular_component', 'GO:0005854', ('28', '31'))	('cancer', 'Disease', (118, 124))	('NAC', 'Var', (28, 31))	('NAC', 'Chemical', '-', (28, 31))	('patients', 'Species', '9606', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('down-staging', 'NegReg', (52, 64))
125694	32358407	These findings from the meta-analysis indicated that when compared with control subjects, NAC was significantly beneficial on OS, RFS, and CSS.	('CSS', 'Disease', (139, 142))	('RFS', 'Disease', (130, 133))	('NAC', 'Var', (90, 93))	('NAC', 'Chemical', '-', (90, 93))	('beneficial', 'PosReg', (112, 122))	('NAC', 'cellular_component', 'GO:0005854', ('90', '93'))
125695	32358407	With regard the pathological changes, the date showed that the NAC group had a 6.58-fold higher probablity of having T stage down-grading (T3/4 to <=T2) and had a 5.24-fold higher probablity of demonstrating a declining incidence of lymph node-positive disease as compared the control group.	('NAC', 'Var', (63, 66))	('NAC', 'Chemical', '-', (63, 66))	('NAC', 'cellular_component', 'GO:0005854', ('63', '66'))	('higher', 'PosReg', (89, 95))	('T stage', 'CPA', (117, 124))
125826	26613881	The investigators indicated, however, a potential association between high baseline Ktrans and a prolonged time to progression or death.	('death', 'Disease', 'MESH:D003643', (130, 135))	('death', 'Disease', (130, 135))	('Ktrans', 'Protein', (84, 90))	('Ktrans', 'Chemical', '-', (84, 90))	('time to progression', 'CPA', (107, 126))	('high', 'Var', (70, 74))
125857	26613881	Hyperintense detrusor muscle signal underlying tumor on T2-weighted and/or DWIs suggests muscle invasion.	('muscle invasion', 'CPA', (89, 104))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Hyperintense', 'Var', (0, 12))	('tumor', 'Disease', (47, 52))
125890	29791078	Pathological data, microsatellite instability, anatomic location, and overall survival data were analyzed and compared with sporadic bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('microsatellite', 'Var', (19, 33))	('sporadic bladder cancer', 'Disease', (124, 147))	('sporadic bladder cancer', 'Disease', 'MESH:D001749', (124, 147))
125900	29791078	Development of UC in Lynch syndrome is associated with mutations in the MSH2 gene with such mutations in 65-70% of the UC in Lynch syndrome (Engel et al., 2012; Joost et al., 2015; van der Post et al., 2010; Skeldon et al., 2013).	('Lynch syndrome', 'Disease', 'MESH:D003123', (21, 35))	('Lynch syndrome', 'Disease', (125, 139))	('mutations', 'Var', (55, 64))	('Lynch syndrome', 'Disease', 'MESH:D003123', (125, 139))	('mutations', 'Var', (92, 101))	('MSH2', 'Gene', (72, 76))	('associated', 'Reg', (39, 49))	('MSH2', 'Gene', '4436', (72, 76))	('Lynch syndrome', 'Disease', (21, 35))
125902	29791078	Differences in mutational profiles have been reported in high-grade tumors with more frequent mutations in FGFR3, HRAS, and CDKN2B in UTUC and in TP53 and RB1 in bladder UC (Sanford et al., 2015; Sfakianos et al., 2015).	('TP53', 'Gene', '7157', (146, 150))	('tumors', 'Disease', (68, 74))	('RB1', 'Gene', (155, 158))	('mutations', 'Var', (94, 103))	('CDKN2B', 'Gene', '1030', (124, 130))	('FGFR3', 'Gene', '2261', (107, 112))	('RB1', 'Gene', '5925', (155, 158))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', (146, 150))	('HRAS', 'Gene', '3265', (114, 118))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('bladder UC', 'Disease', (162, 172))	('FGFR3', 'Gene', (107, 112))	('HRAS', 'Gene', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CDKN2B', 'Gene', (124, 130))
125903	29791078	In assumingly sporadic tumors, defective mismatch-repair (MMR) is found in 11% of UTUC and in variable frequencies, most likely reflecting diverse assessment principles, in bladder UC (Catto et al., 2003; Metcalfe et al., 2018).	('sporadic tumors', 'Disease', (14, 29))	('MMR', 'biological_process', 'GO:0006298', ('58', '61'))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('sporadic tumors', 'Disease', 'MESH:D009369', (14, 29))	('defective mismatch-repair', 'Var', (31, 56))	('bladder UC', 'Disease', (173, 183))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('mismatch-repair', 'biological_process', 'GO:0006298', ('41', '56'))
125909	29791078	The tumors developed in MMR mutation carriers (n = 40) or in deceased first-degree relatives, in which gene carrier status could not be evaluated through tumor analyses (n = 1).	('tumor', 'Disease', (4, 9))	('MMR', 'biological_process', 'GO:0006298', ('24', '27'))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('carrier', 'molecular_function', 'GO:0005215', ('108', '115'))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('mutation', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('MMR', 'Gene', (24, 27))	('tumor', 'Disease', (154, 159))
125924	29791078	The majority of tumors (71%) developed in MSH2 mutation carriers.	('tumors', 'Disease', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('mutation', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('MSH2', 'Gene', (42, 46))	('MSH2', 'Gene', '4436', (42, 46))	('developed', 'Reg', (29, 38))	('tumors', 'Disease', 'MESH:D009369', (16, 22))
125933	29791078	None of the clusters were specifically associated with mutations in MSH6, MLH1, or MSH2, but there was a significant difference in the rate of microsatellite instability (MSI) among the clusters, with Cluster 3 showing the lowest proportion of MSI (Fisher's exact test, P = 0.01).	('MSH6', 'Gene', '2956', (68, 72))	('microsatellite instability', 'MPA', (143, 169))	('MLH1', 'Gene', '4292', (74, 78))	('mutations', 'Var', (55, 64))	('MLH1', 'Gene', (74, 78))	('MSH2', 'Gene', (83, 87))	('MSH2', 'Gene', '4436', (83, 87))	('MSH6', 'Gene', (68, 72))
125961	29791078	Mutations in UTUC and bladder UC differed only for HRAS, CDKN2B, TP53, RB1, and ARID1A when investigated in a set of 59 high-grade UTUC and 102 high-grade bladder UC (Sanford et al., 2015; Sfakianos et al., 2015).	('TP53', 'Gene', '7157', (65, 69))	('HRAS', 'Gene', (51, 55))	('TP53', 'Gene', (65, 69))	('CDKN2B', 'Gene', (57, 63))	('ARID1A', 'Gene', '8289', (80, 86))	('CDKN2B', 'Gene', '1030', (57, 63))	('RB1', 'Gene', (71, 74))	('Mutations', 'Var', (0, 9))	('RB1', 'Gene', '5925', (71, 74))	('ARID1A', 'Gene', (80, 86))	('HRAS', 'Gene', '3265', (51, 55))
125975	29791078	This report represents the first molecular subtyping of UC in Lynch syndrome and despite limited in size represents a large collection of this rare tumor entity with disease-predisposing MMR gene mutations/MMR protein loss in concordance with the germline mutation proven in 98% of the tumors.	('Lynch syndrome', 'Disease', (62, 76))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('MMR', 'biological_process', 'GO:0006298', ('187', '190'))	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('Lynch syndrome', 'Disease', 'MESH:D003123', (62, 76))	('tumor', 'Disease', (148, 153))	('loss', 'NegReg', (218, 222))	('tumors', 'Disease', (286, 292))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('MMR gene', 'Gene', (187, 195))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('mutations/MMR', 'Var', (196, 209))	('MMR', 'biological_process', 'GO:0006298', ('206', '209'))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
126006	27347540	AE1/AE3 (pancytokeratin), CAM5.2, CK7, CK20, and EMA; CA-125, PAX8, and PAX2 (89% to 100%); weak positive staining with PSA or PAP (33%), variable positivity with P504S; luminal mucin is PAS positive and mucicarmine positive.	('PSA', 'Gene', (120, 123))	('PAP', 'Gene', '10914', (127, 130))	('PAP', 'molecular_function', 'GO:0043751', ('127', '130'))	('PAX8', 'Gene', '7849', (62, 66))	('PAS', 'cellular_component', 'GO:0000407', ('187', '190'))	('CK7', 'Gene', (34, 37))	('PAP', 'Gene', (127, 130))	('AE3', 'Gene', (4, 7))	('CK20', 'Gene', (39, 43))	('CK7', 'Gene', '3855', (34, 37))	('P504S', 'Mutation', 'p.P504S', (163, 168))	('PSA', 'Gene', '354', (120, 123))	('AE1', 'Gene', '6521', (0, 3))	('P504S', 'Var', (163, 168))	('PAS', 'Chemical', 'MESH:D011478', (187, 190))	('AE3', 'Gene', '6508', (4, 7))	('CK20', 'Gene', '54474', (39, 43))	('AE1', 'Gene', (0, 3))	('PAX8', 'Gene', (62, 66))	('mucicarmine', 'Chemical', 'MESH:C029618', (204, 215))
126007	27347540	Nephrogenic adenoma of the urinary bladder stains positively with the ensuing  CK903, p63, and CD10 (may be focally positive).	('p63', 'Gene', (86, 89))	('CK903', 'Var', (79, 84))	('Nephrogenic adenoma of the urinary bladder', 'Disease', (0, 42))	('CD10', 'Gene', (95, 99))	('p63', 'Gene', '8626', (86, 89))	('CD10', 'Gene', '4311', (95, 99))	('CD10', 'molecular_function', 'GO:0004245', ('95', '99'))
126012	27347540	Nested variant of urothelial carcinoma of the bladder may resemble nephrogenic adenoma of the bladder but characteristically in nested variant of urothelial carcinoma there is cystic degeneration of nests and not a single layer and there is marked atypia.	('nephrogenic adenoma of the bladder', 'Disease', 'MESH:D000236', (67, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('cystic degeneration', 'Disease', 'MESH:C538364', (176, 195))	('cystic degeneration', 'Phenotype', 'HP:0007667', (176, 195))	('cystic degeneration', 'Disease', (176, 195))	('nephrogenic adenoma of the bladder', 'Disease', (67, 101))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (18, 53))	('urothelial carcinoma of the bladder', 'Disease', (18, 53))	('nested variant', 'Var', (128, 142))	('urothelial', 'Gene', (146, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))
126060	27347540	Nephrogenic adenomas are typically positive with cytokeratin 7 (CK7), alpha-methylacyl-CoA racemase (AMACR), P504S, PAX2, and epithelial membrane antigen and are usually negative with p63 (Figures 3(e) and 3(f)).	('Nephrogenic adenomas', 'Disease', (0, 20))	('cytokeratin 7', 'Gene', (49, 62))	('positive', 'Reg', (35, 43))	('epithelial', 'Protein', (126, 136))	('alpha-methylacyl-CoA racemase', 'Gene', '23600', (70, 99))	('membrane', 'cellular_component', 'GO:0016020', ('137', '145'))	('alpha-methylacyl-CoA racemase', 'Gene', (70, 99))	('P504S', 'Var', (109, 114))	('CK7', 'Gene', (64, 67))	('cytokeratin 7', 'Gene', '3855', (49, 62))	('P504S', 'SUBSTITUTION', 'None', (109, 114))
126064	27347540	Immunohistochemical staining of the tumour was strongly positive for CK7, P504S, CD10, and EMA but negative for CK20, PSA, and P63.	('P504S', 'Var', (74, 79))	('P504S', 'SUBSTITUTION', 'None', (74, 79))	('P63', 'Gene', (127, 130))	('positive', 'Reg', (56, 64))	('CD10', 'Var', (81, 85))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('CD10', 'molecular_function', 'GO:0004245', ('81', '85'))	('CK7', 'Var', (69, 72))	('P63', 'Gene', '8626', (127, 130))
126076	26951070	Cystoscopy detected a non-papillary tumor, and a transurethral resection of the bladder tumor (TUR-Bt) and a magnetic resonance imaging (MRI) scan revealed cT3N0M0 bladder cancer.	('bladder tumor', 'Disease', 'MESH:D001749', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('bladder cancer', 'Phenotype', 'HP:0009725', (164, 178))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('bladder tumor', 'Phenotype', 'HP:0009725', (80, 93))	('cT3N0M0', 'Var', (156, 163))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('bladder tumor', 'Disease', (80, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('bladder cancer', 'Disease', 'MESH:D001749', (164, 178))	('bladder cancer', 'Disease', (164, 178))	('-papillary tumor', 'Phenotype', 'HP:0007482', (25, 41))	('tumor', 'Disease', (88, 93))	('non-papillary', 'Disease', (22, 35))	('tumor', 'Disease', (36, 41))
126089	26951070	Two months after the total cystectomy, adjuvant chemotherapy with gemcitabine and cisplatin was administered (G: 2,000 mg/m2, C: 63 mg/m2).	('C: 63 mg/m2', 'Var', (126, 137))	('gemcitabine', 'Chemical', 'MESH:C056507', (66, 77))	('G: 2,000', 'Var', (110, 118))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))
126100	26951070	However, it has been reported that tumors with variant histology are associated with a higher risk of progression than conventional high-grade UC.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('variant', 'Var', (47, 54))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
126213	33247676	Only those curves are presented herein which showed significant differences in overall survival (p<0.05) of patients with high cut-off values compared to those with low cut-off values.	('patients', 'Species', '9606', (108, 116))	('high cut-off values', 'Var', (122, 141))	('differences', 'Reg', (64, 75))
126223	33247676	For mutation, it provides mutation ID, details of genetic change, protein change, type of mutation and its VEP impact across all available TCGA tumour data sets.	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('mutation', 'Var', (26, 34))	('tumour', 'Disease', (144, 150))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
126259	33247676	TC2N mutation profile in pan-cancer  Our analyses show several frequent somatic mutations in TC2N gene in various cancers.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancer', 'Disease', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('mutations', 'Var', (80, 89))	('TC2N', 'Gene', '123036', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('TC2N', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('TC2N', 'Gene', '123036', (93, 97))	('TC2N', 'Gene', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (114, 120))
126260	33247676	A total of 142 mutations were identified across 145 cases in a total of 18 TCGA tumour types.	('tumour', 'Disease', (80, 86))	('mutations', 'Var', (15, 24))	('TCGA', 'Disease', (75, 79))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('identified', 'Reg', (30, 40))
126261	33247676	Highest pathogenic mutation rates of TC2N were present in SKCM, UCEC, COAD, BLCA and BRCA (Table 3).	('BLCA', 'Disease', (76, 80))	('COAD', 'Disease', 'MESH:D029424', (70, 74))	('BRCA', 'Gene', (85, 89))	('mutation', 'Var', (19, 27))	('pathogenic', 'Reg', (8, 18))	('TC2N', 'Gene', (37, 41))	('BRCA', 'Gene', '672;675', (85, 89))	('UCEC', 'Disease', (64, 68))	('COAD', 'Disease', (70, 74))	('TC2N', 'Gene', '123036', (37, 41))	('SKCM', 'Disease', (58, 62))
126272	33247676	Promoter hypermethylation is a key feature for transcriptional silencing of several genes in cancer (Park, 2010).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Promoter hypermethylation', 'Var', (0, 25))
126273	33247676	In particular, tumour suppressor genes are silenced via hypermethylation in several caners (Nag and Yu, 2015).	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Disease', (15, 21))	('hypermethylation', 'Var', (56, 72))	('Nag', 'Gene', (92, 95))	('silenced', 'NegReg', (43, 51))	('Nag', 'Gene', '51594', (92, 95))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
126274	33247676	We also found TC2N promoter hypomethylation in HNSC and KIRC.	('TC2N', 'Gene', (14, 18))	('hypomethylation', 'Var', (28, 43))	('TC2N', 'Gene', '123036', (14, 18))
126275	33247676	There are evidence that hypomethylation may lead to increased genomic stability that may contribute towards carcinogenesis (Pfeifer, 2018).	('increased', 'PosReg', (52, 61))	('genomic stability', 'CPA', (62, 79))	('contribute', 'Reg', (89, 99))	('hypomethylation', 'Var', (24, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('carcinogenesis', 'Disease', (108, 122))
126276	33247676	Moreover, DNA hypomethylation also leads to overexpression of proinvasive, antiapoptotic and angiogenic factors in prostate cancer (Vestergaar et al., 2010).	('prostate cancer', 'Disease', (115, 130))	('hypomethylation', 'Var', (14, 29))	('overexpression', 'PosReg', (44, 58))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('10', '29'))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('DNA', 'Var', (10, 13))
126277	33247676	In summary, TC2N promoter hyper and hypo-methylation are important findings of this study demanding further exploration.	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('hyper', 'Var', (26, 31))	('hypo-methylation', 'Var', (36, 52))	('TC2N', 'Gene', '123036', (12, 16))	('TC2N', 'Gene', (12, 16))
126286	33247676	In a recent study that recruited 28 highly-aggregated-extended-highrisk-familial-lung-cancer (HRFLC) families, highest cluster of genetic variants associated with lung cancer were identified within CATSPERB gene (14q32) (Musolf et al., 2019).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('associated', 'Reg', (147, 157))	('familial-lung-cancer', 'Disease', (72, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CATSPERB', 'Gene', (198, 206))	('variants', 'Var', (138, 146))	('familial-lung-cancer', 'Disease', 'MESH:D008175', (72, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (163, 174))	('CATSPERB', 'Gene', '79820', (198, 206))
126290	33247676	We identified a range of genetic alterations in the TC2N gene in several cancers.	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TC2N', 'Gene', '123036', (52, 56))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('TC2N', 'Gene', (52, 56))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('genetic alterations', 'Var', (25, 44))
126291	33247676	The highest pathogenic non-synonymous mutation rates were observed in SKCM, UCEC, COAD, BLCA and BRCA.	('COAD', 'Disease', (82, 86))	('UCEC', 'Disease', (76, 80))	('non-synonymous mutation', 'Var', (23, 46))	('SKCM', 'Disease', (70, 74))	('pathogenic', 'Reg', (12, 22))	('BLCA', 'Disease', (88, 92))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('BRCA', 'Gene', (97, 101))	('BRCA', 'Gene', '672;675', (97, 101))
126292	33247676	Whether these genetic mutations are causative or a sequel of cancer processes needs to be investigated.	('genetic mutations', 'Var', (14, 31))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
126293	33247676	It is important to note that cancer cells are susceptible to accumulate several mutations for multiple reasons such as increased cellular turnover, inflammatory tumour microenvironment, altered metabolic wiring, increased reactive oxygen species, increased susceptibility to DNA damage and decreased capacity of DNA damage repair amongst others (Loeb and Loeb, 2000; Hanahan and Weinberg, 2011; Fouad and Anani, 2017).	('decreased', 'NegReg', (290, 299))	('oxygen', 'Chemical', 'MESH:D010100', (231, 237))	('increased reactive oxygen species', 'Phenotype', 'HP:0025464', (212, 245))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', (29, 35))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('DNA', 'cellular_component', 'GO:0005574', ('312', '315'))	('tumour', 'Disease', (161, 167))	('DNA', 'cellular_component', 'GO:0005574', ('275', '278'))	('susceptibility', 'MPA', (257, 271))	('metabolic wiring', 'CPA', (194, 210))	('altered', 'Reg', (186, 193))	('increased', 'PosReg', (212, 221))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('reactive oxygen species', 'MPA', (222, 245))	('increased', 'PosReg', (119, 128))	('cellular turnover', 'CPA', (129, 146))
126332	31640266	As with CTLA-4 inhibitors, PD-1 inhibitors work by enhancing the patient's natural anti-tumor immune response.	('immune response', 'biological_process', 'GO:0006955', ('94', '109'))	('inhibitors', 'Var', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CTLA-4', 'Gene', (8, 14))	('PD-1', 'Gene', (27, 31))	('patient', 'Species', '9606', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('enhancing', 'PosReg', (51, 60))	('tumor', 'Disease', (88, 93))	('CTLA-4', 'Gene', '1493', (8, 14))
126357	31640266	Agents in this class include Sym023 (Symphogen), TSR-022 (Tesaro/AnaptysBio), MBG453 (Novartis), LY3321367 (Lilly), and BGB-A425 (BeiGene).	('BGB-A425', 'Gene', (120, 128))	('LY3321367', 'Chemical', 'MESH:C430423', (97, 106))	('TSR', 'molecular_function', 'GO:0047362', ('49', '52'))	('MBG453', 'Gene', (78, 84))	('LY3321367', 'Var', (97, 106))	('MBG453', 'Chemical', 'MESH:C015473', (78, 84))
126361	31640266	TIM-3 inhibitors block these responses, mitigating the immune inhibition mediated through this pathway.	('TIM-3', 'Gene', '84868', (0, 5))	('mitigating', 'NegReg', (40, 50))	('inhibitors', 'Var', (6, 16))	('immune inhibition', 'MPA', (55, 72))	('TIM-3', 'Gene', (0, 5))
126437	31640266	ORR was 15.5% in the PD-L1 positive group, and 6.4% in the PD-L1 negative group.	('positive', 'Var', (27, 35))	('PD-L1', 'Gene', (59, 64))	('PD-L1', 'Gene', (21, 26))	('PD-L1', 'Gene', '29126', (59, 64))	('PD-L1', 'Gene', '29126', (21, 26))
126438	31640266	The median duration of response was 16.3 months in the PD-L1 positive group and 6.9 months in the PD-L1 negative group.	('positive', 'Var', (61, 69))	('PD-L1', 'Gene', '29126', (55, 60))	('PD-L1', 'Gene', (98, 103))	('PD-L1', 'Gene', '29126', (98, 103))	('PD-L1', 'Gene', (55, 60))
126449	31640266	It currently has indications as part of combination first-line treatment for metastatic NsqNSCLC and sqNSCLC, as well as first-line treatment for stage III disease in patients who are not candidates for surgical resection or definitive chemoradiation, whose tumors have no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations, and whose tumors are known to express PD-L1.	('sqNSCLC', 'Disease', (101, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('307', '311'))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('PD-L1', 'Gene', (398, 403))	('SCLC', 'Phenotype', 'HP:0030357', (92, 96))	('lymphoma', 'Phenotype', 'HP:0002665', (327, 335))	('PD-L1', 'Gene', '29126', (398, 403))	('tumors', 'Phenotype', 'HP:0002664', (370, 376))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('273', '296'))	('ALK', 'Gene', '238', (344, 347))	('EGFR', 'Gene', '1956', (307, 311))	('sqNSCLC', 'Disease', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (370, 375))	('ALK', 'Gene', (344, 347))	('mutations', 'Var', (349, 358))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumors', 'Disease', (370, 376))	('SCLC', 'Phenotype', 'HP:0030357', (104, 108))	('tumors', 'Disease', (258, 264))	('sqNSCLC', 'Disease', 'MESH:D002289', (101, 108))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (316, 335))	('epidermal growth factor receptor', 'Gene', (273, 305))	('tumors', 'Disease', 'MESH:D009369', (370, 376))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('patients', 'Species', '9606', (167, 175))	('EGFR', 'Gene', (307, 311))	('epidermal growth factor receptor', 'Gene', '1956', (273, 305))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('anaplastic lymphoma kinase', 'Gene', '238', (316, 342))	('sqNSCLC', 'Disease', 'MESH:D002289', (89, 96))	('anaplastic lymphoma kinase', 'Gene', (316, 342))
126455	31640266	In 2017, the FDA approved pembrolizumab as the first tissue-agnostic cancer therapy for unresectable or metastatic solid cancers expressing MSI-H or dMMR, marking the first FDA approval based on biomarker expression rather than on specific disease.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('unresectable', 'Disease', (88, 100))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('dMMR', 'Var', (149, 153))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('MSI', 'Gene', (140, 143))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('cancer', 'Disease', (121, 127))	('MSI', 'Gene', '5928', (140, 143))	('cancer', 'Disease', (69, 75))
126498	31640266	APX005M in combination with nivolumab is under current exploration in the treatment of metastatic melanoma.	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('APX005M', 'Var', (0, 7))	('melanoma', 'Disease', (98, 106))
126528	31640266	Investigatory studies have shown promise for combination anti-PD-1 + anti-LAG-3 and anti-PD-1 + CD40 agonist therapies in patients with known PD-1/PD-L1-refractory disease states.	('PD-L1', 'Gene', '29126', (147, 152))	('LAG-3', 'Gene', '3902', (74, 79))	('CD40', 'Gene', (96, 100))	('LAG-3', 'Gene', (74, 79))	('patients', 'Species', '9606', (122, 130))	('PD-L1', 'Gene', (147, 152))	('anti-PD-1', 'Var', (84, 93))	('anti-PD-1', 'Var', (57, 66))	('CD40', 'Gene', '958', (96, 100))
126536	31640266	Somewhat paradoxically, infiltration of the TME by various myeloid lineages has been associated with inhibited anti-tumor immunity, pro-tumor effects, and poorer overall prognoses.	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('infiltration', 'Var', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('inhibited', 'NegReg', (101, 110))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (136, 141))
126540	31640266	Understandably, the prospect of limiting these effects is appealing in cancer therapy, and depletion of myeloid cells has been shown in mice to correlate to decreased tumor growth.	('mice', 'Species', '10090', (136, 140))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('depletion', 'Var', (91, 100))	('cancer', 'Disease', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('decreased', 'NegReg', (157, 166))	('tumor', 'Disease', (167, 172))
126589	28495553	In addition, phosphorylation of intracellular immunoreceptor tyrosine-based inhibitory motif of PD-1 leads to SHP-2 activation, which in turn inhibits the PI3K/Akt pathway activated by CD28 signaling.	('Akt', 'Gene', '207', (160, 163))	('signaling', 'biological_process', 'GO:0023052', ('190', '199'))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('PD-1', 'Gene', (96, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('155', '159'))	('inhibits', 'NegReg', (142, 150))	('SHP-2', 'Gene', (110, 115))	('SHP-2', 'Gene', '5781', (110, 115))	('CD28', 'Gene', (185, 189))	('phosphorylation', 'Var', (13, 28))	('Akt', 'Gene', (160, 163))	('activation', 'PosReg', (116, 126))	('intracellular', 'cellular_component', 'GO:0005622', ('32', '45'))	('tyrosine', 'Chemical', 'MESH:D014443', (61, 69))	('CD28', 'Gene', '940', (185, 189))
126603	28495553	Mutated cellular transcripts are processed into tumor neoantigens that are presented on the surface of APCs.	('tumor', 'Disease', (48, 53))	('APC', 'Disease', 'MESH:D011125', (103, 106))	('APC', 'Disease', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('Mutated', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
126610	28495553	The objective response rate was 43% in PD-L1 high expression tumors and 11% in PD-L1 low expression tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', (61, 67))	('PD-L1', 'Gene', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Disease', (100, 106))	('PD-L1', 'Gene', '29126', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('PD-L1', 'Gene', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('high expression', 'Var', (45, 60))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('PD-L1', 'Gene', '29126', (79, 84))
126622	28495553	Although there are no data published yet regarding outcomes for combination immunotherapy in urothelial carcinoma, combination therapy has led to clinical remission in metastatic melanoma, although there is significant cumulative toxicity associated with dual therapy.	('toxicity', 'Disease', 'MESH:D064420', (230, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('toxicity', 'Disease', (230, 238))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (93, 113))	('combination', 'Var', (115, 126))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Disease', (179, 187))	('urothelial carcinoma', 'Disease', (93, 113))
126648	28495553	Radioimmunoconjugated 8H9 with cytotoxic I131 is currently in phase I trials for central nervous system and peritoneal tumors (NCT01099644 and NCT01502917), and other groups are testing 8H9 with other toxic conjugates in murine models.	('peritoneal tumors', 'Disease', 'MESH:D010534', (108, 125))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('murine', 'Species', '10090', (221, 227))	('peritoneal tumors', 'Disease', (108, 125))	('NCT01099644', 'Var', (127, 138))	('8H9', 'Chemical', '-', (186, 189))	('8H9', 'Chemical', '-', (22, 25))	('NCT01502917', 'Var', (143, 154))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
126650	28495553	Thus, targeting B7-H3 has been effective in preclinical models, and depending on the results of ongoing clinical trials, may be a viable treatment option for bladder cancer in the future.	('bladder cancer', 'Phenotype', 'HP:0009725', (158, 172))	('B7-H3', 'Gene', (16, 21))	('B7-H3', 'Gene', '80381', (16, 21))	('targeting', 'Var', (6, 15))	('bladder cancer', 'Disease', 'MESH:D001749', (158, 172))	('bladder cancer', 'Disease', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
126654	28495553	Despite its restricted expression on healthy somatic tissues, B7x is frequently expressed in many cancer types including those of the breast, lung, colon, ovary, endometrium, kidney, pancreas, prostate, and bladder.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('colon', 'Disease', 'MESH:D015179', (148, 153))	('bladder', 'Disease', (207, 214))	('kidney', 'Disease', (175, 181))	('lung', 'Disease', (142, 146))	('ovary', 'Disease', (155, 160))	('endometrium', 'Disease', (162, 173))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('pancreas', 'Disease', (183, 191))	('colon', 'Disease', (148, 153))	('B7x', 'Var', (62, 65))	('ovary', 'Disease', 'MESH:D010051', (155, 160))	('breast', 'Disease', (134, 140))	('prostate', 'Disease', (193, 201))
126655	28495553	B7x expression in renal cell carcinoma is associated with a greater cancer progression and decreased overall survival.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (18, 38))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('decreased', 'NegReg', (91, 100))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (18, 38))	('B7x expression', 'Var', (0, 14))	('overall', 'MPA', (101, 108))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('greater', 'PosReg', (60, 67))	('renal cell carcinoma', 'Disease', (18, 38))
126657	28495553	In urothelial carcinoma, B7x overexpression is associated with increased TNM stage, pathological grade, and poorer outcomes.	('increased', 'PosReg', (63, 72))	('pathological grade', 'CPA', (84, 102))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (3, 23))	('TNM', 'Gene', '10178', (73, 76))	('urothelial carcinoma', 'Disease', (3, 23))	('TNM', 'Gene', (73, 76))	('B7x overexpression', 'Var', (25, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
126659	28495553	Considering the immunosuppressive effects of B7x and its expression profile in human cancers, it is a prime target for immunotherapy.	('human', 'Species', '9606', (79, 84))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Disease', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('B7x', 'Var', (45, 48))
126660	28495553	Anti-B7x monoclonal antibodies reduce lung metastases of B7x-expressing colon cancer cells in a mouse experimental metastasis model.	('Anti-B7x', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colon cancer', 'Disease', (72, 84))	('B7x-expressing', 'Var', (57, 71))	('mouse', 'Species', '10090', (96, 101))	('metastases', 'Disease', (43, 53))	('reduce', 'NegReg', (31, 37))	('metastases', 'Disease', 'MESH:D009362', (43, 53))	('colon cancer', 'Phenotype', 'HP:0003003', (72, 84))	('colon cancer', 'Disease', 'MESH:D015179', (72, 84))
126661	28495553	Similarly, anti-B7x scFVs reduced the growth of ovarian tumor xenografts.	('ovarian tumor', 'Disease', 'MESH:D010051', (48, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ovarian tumor', 'Disease', (48, 61))	('reduced', 'NegReg', (26, 33))	('anti-B7x', 'Var', (11, 19))	('ovarian tumor', 'Phenotype', 'HP:0100615', (48, 61))	('growth of', 'CPA', (38, 47))
126662	28495553	B7x-targeted CAR T-cell therapy proved to be effective in eliminating xenografts of B7x-expressing ovarian tumors, but also caused lethal, delayed toxicity 6 to 8 weeks postengraftment.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('CAR', 'cellular_component', 'GO:0005826', ('13', '16'))	('toxicity', 'Disease', 'MESH:D064420', (147, 155))	('toxicity', 'Disease', (147, 155))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('ovarian tumors', 'Disease', (99, 113))	('ovarian tumors', 'Phenotype', 'HP:0100615', (99, 113))	('ovarian tumor', 'Phenotype', 'HP:0100615', (99, 112))	('CAR T', 'Gene', (13, 18))	('B7x-expressing', 'Var', (84, 98))	('ovarian tumors', 'Disease', 'MESH:D010051', (99, 113))	('CAR T', 'Gene', '9607', (13, 18))
126664	28495553	Taken together, B7x shows promise as an anticancer target, but further research is needed to refine the treatment strategies.	('B7x', 'Var', (16, 19))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
126677	28495553	Similarly, EGFR mutational status and high tumor-infiltrating lymphocyte density are associated with HHLA2 expression in non-small cell lung carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('HHLA2', 'Gene', '11148', (101, 106))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (121, 150))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (121, 150))	('EGFR', 'molecular_function', 'GO:0005006', ('11', '15'))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('mutational', 'Var', (16, 26))	('expression', 'MPA', (107, 117))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('non-small cell lung carcinoma', 'Disease', (121, 150))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (125, 150))	('tumor', 'Disease', (43, 48))	('HHLA2', 'Gene', (101, 106))	('associated', 'Reg', (85, 95))
126837	23947922	Aberrant Wnt signaling has been implicated in pathological conditions such as cancer and inflammatory diseases .	('inflammatory diseases', 'Disease', 'MESH:D007249', (89, 110))	('Aberrant', 'Var', (0, 8))	('implicated', 'Reg', (32, 42))	('signaling', 'biological_process', 'GO:0023052', ('13', '22'))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('inflammatory diseases', 'Disease', (89, 110))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Wnt signaling', 'Pathway', (9, 22))
126839	23947922	In the context of bladder cancers the hypermethylation of Wnt antagonist genes such as Wnt inhibitory factor 1 (WIF1), mutations in adenomatous polyposis coli (APC) and aberrant expression of beta-catenin have been reported to be associated with increased aggressiveness and poor prognosis .	('beta-catenin', 'Gene', '1499', (192, 204))	('APC', 'Disease', (160, 163))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('aggressiveness', 'Disease', (256, 270))	('associated', 'Reg', (230, 240))	('aggressiveness', 'Phenotype', 'HP:0000718', (256, 270))	('bladder cancers', 'Phenotype', 'HP:0009725', (18, 33))	('APC', 'cellular_component', 'GO:0005680', ('160', '163'))	('Wnt inhibitory factor 1', 'Gene', (87, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (18, 32))	('aggressiveness', 'Disease', 'MESH:D001523', (256, 270))	('mutations', 'Var', (119, 128))	('hypermethylation', 'Var', (38, 54))	('Wnt inhibitory factor 1', 'Gene', '11197', (87, 110))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (132, 158))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (132, 158))	('bladder cancers', 'Disease', 'MESH:D001749', (18, 33))	('adenomatous polyposis coli', 'Disease', (132, 158))	('WIF1', 'Gene', '11197', (112, 116))	('bladder cancers', 'Disease', (18, 33))	('increased', 'PosReg', (246, 255))	('beta-catenin', 'Gene', (192, 204))	('WIF1', 'Gene', (112, 116))	('aberrant expression', 'Var', (169, 188))	('APC', 'Phenotype', 'HP:0005227', (160, 163))	('APC', 'Disease', 'MESH:D011125', (160, 163))
126840	23947922	Recently, epigenetic deregulation of Wnt pathway inhibitors has been implicated in abnormal activation of the canonical Wnt signaling pathway in bladder tumors .	('bladder tumors', 'Phenotype', 'HP:0009725', (145, 159))	('canonical Wnt signaling pathway', 'biological_process', 'GO:0060070', ('110', '141'))	('bladder tumors', 'Disease', (145, 159))	('activation', 'PosReg', (92, 102))	('canonical Wnt signaling pathway', 'Pathway', (110, 141))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('epigenetic deregulation', 'Var', (10, 33))	('bladder tumors', 'Disease', 'MESH:D001749', (145, 159))	('implicated', 'Reg', (69, 79))
126847	23947922	reported the role of Wnt5a as a tumor suppressor gene in UC because ectopic expression of human Wnt5a in a UC cell line lacking the chromosomal region where Wnt5a resides abolished the cell's tumorigenic capacity .	('abolished', 'NegReg', (171, 180))	('tumor', 'Disease', (192, 197))	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('human', 'Species', '9606', (90, 95))	('chromosomal region', 'cellular_component', 'GO:0098687', ('132', '150'))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Wnt5a', 'Gene', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('ectopic expression', 'Var', (68, 86))	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
126856	23947922	Histological grade was defined based on architecture, polarity, thickness, and cohesiveness, as well as cytologic features including pleomorphism, chromasia, presence of nucleoli, mitosis and umbrella cells.	('chromasia', 'Disease', (147, 156))	('pleomorphism', 'Var', (133, 145))	('chromasia', 'Disease', 'None', (147, 156))	('mitosis', 'Disease', (180, 187))	('mitosis', 'Disease', 'None', (180, 187))	('mitosis', 'biological_process', 'GO:0000278', ('180', '187'))
126875	23947922	Wnt5a (Hs00180103_m1) and the following six potential housekeeping genes were assayed: HPRT (Hs99999909), GAPDH (Hs99999905), ACTB (Hs99999903), B2M (Hs99999907), UBC (Hs00824723), and SDHA (Hs00188166).	('UBC', 'Gene', (163, 166))	('SDHA', 'Gene', (185, 189))	('Hs99999905', 'Var', (113, 123))	('HPRT', 'molecular_function', 'GO:0004422', ('87', '91'))	('B2M', 'Gene', '567', (145, 148))	('SDHA', 'Gene', '6389', (185, 189))	('GAPDH', 'Gene', (106, 111))	('Hs99999903', 'Var', (132, 142))	('Hs00180103_m1', 'Var', (7, 20))	('HPRT', 'Gene', (87, 91))	('ACTB', 'Gene', '60', (126, 130))	('ACTB', 'Gene', (126, 130))	('Hs99999907', 'Var', (150, 160))	('UBC', 'Gene', '7316', (163, 166))	('Hs00188166', 'Var', (191, 201))	('Hs00824723', 'Var', (168, 178))	('HPRT', 'Gene', '3251', (87, 91))	('B2M', 'Gene', (145, 148))	('GAPDH', 'Gene', '2597', (106, 111))	('Hs99999909', 'Var', (93, 103))
126905	23947922	Multiple biomarkers used for other cancers have been described with potential diagnostic or prognostic value for UC as well, including p53, cytokeratin 20, E-cadherin, Ki67, CD44 and survivin .	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('E-cadherin', 'Gene', (156, 166))	('E-cadherin', 'Gene', '999', (156, 166))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('survivin', 'Protein', (183, 191))	('cadherin', 'molecular_function', 'GO:0008014', ('158', '166'))	('Ki67', 'Var', (168, 172))	('CD44', 'Gene', '960', (174, 178))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('CD44', 'Gene', (174, 178))	('cytokeratin 20', 'Gene', (140, 154))	('cytokeratin 20', 'Gene', '54474', (140, 154))	('cancers', 'Disease', (35, 42))
126956	23074377	Hematologic variables: hemoglobin >=10 g/dl, leukocyte count >= 3000 /mm3, platelet count >= 100000 /mm3; creatinine clearance >= 30 ml/min.	('>= 3000 /mm3', 'Var', (61, 73))	('creatinine', 'Chemical', 'MESH:D003404', (106, 116))	('>=10', 'Var', (34, 38))	('creatinine clearance', 'MPA', (106, 126))	('leukocyte', 'MPA', (45, 54))	('hemoglobin', 'MPA', (23, 33))	('>= 100000 /mm3', 'Var', (90, 104))
127041	33972391	Pan-cancer landscape of CD274 (PD-L1) copy number changes in 244 584 patient samples and the correlation with PD-L1 protein expression Several studies have shown clinical outcomes data that support the use of CD274 (PD-L1) copy-number (CN) gains and/or losses as a biomarker for immune checkpoint inhibitor (ICPI).	('PD-L1', 'Gene', (110, 115))	('copy-number', 'Var', (223, 234))	('CD274', 'Gene', '29126', (209, 214))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('CD274', 'Gene', '29126', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('PD-L1', 'Gene', '29126', (31, 36))	('PD-L1', 'Gene', '29126', (110, 115))	('PD-L1', 'Gene', '29126', (216, 221))	('PD-L1', 'Gene', (216, 221))	('CD274', 'Gene', (209, 214))	('losses', 'NegReg', (253, 259))	('CD274', 'Gene', (24, 29))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('gains', 'PosReg', (240, 245))	('patient', 'Species', '9606', (69, 76))	('cancer', 'Disease', (4, 10))	('PD-L1', 'Gene', (31, 36))
127042	33972391	Here, we present the landscape of CD274 CN changes across a large cohort of solid tumor cases and correlate these with PD-L1 protein expression by immunohistochemistry.	('CN changes', 'Var', (40, 50))	('CD274', 'Gene', '29126', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('PD-L1', 'Gene', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('CD274', 'Gene', (34, 39))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('PD-L1', 'Gene', '29126', (119, 124))	('tumor', 'Disease', (82, 87))
127046	33972391	Using different CN cut offs to define CD274 positivity resulted in different prevalence estimates: ploidy +1, 17.4% (42 636/244 584); ploidy +2, 6.2% (15 183/244 584); ploidy +3, 2.2% (5375/244 584); ploidy +4, 1.1% (2712/244 584); and ploidy +8, 0.2% (434/244 584).	('ploidy +2', 'Var', (134, 143))	('CD274', 'Gene', '29126', (38, 43))	('ploidy +4', 'Var', (200, 209))	('ploidy +3', 'Var', (168, 177))	('ploidy', 'Var', (99, 105))	('CD274', 'Gene', (38, 43))	('positivity', 'Var', (44, 54))	('ploidy +8', 'Var', (236, 245))
127048	33972391	CD274 CN gains were significantly associated with PD-L1 positivity in NSCLC, urothelial carcinoma, breast carcinoma, cervical carcinoma, esophagus squamous cell carcinoma (SCC) and head and neck SCC (ORs 3.3, 3.0, 2.0, 4.5.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 170))	('PD-L1', 'Gene', (50, 55))	('breast carcinoma', 'Phenotype', 'HP:0003002', (99, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('neck', 'cellular_component', 'GO:0044326', ('190', '194'))	('PD-L1', 'Gene', '29126', (50, 55))	('breast carcinoma', 'Disease', (99, 115))	('squamous cell carcinoma', 'Disease', (147, 170))	('NSCLC', 'Disease', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (77, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('CD274', 'Gene', '29126', (0, 5))	('SCC', 'Phenotype', 'HP:0002860', (172, 175))	('urothelial carcinoma', 'Disease', (77, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('cervical carcinoma', 'Disease', 'MESH:D002583', (117, 135))	('breast carcinoma', 'Disease', 'MESH:D001943', (99, 115))	('SCC', 'Phenotype', 'HP:0002860', (195, 198))	('positivity', 'Var', (56, 66))	('cervical carcinoma', 'Disease', (117, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('CD274', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
127052	33972391	These prevalence data on CD274 CN changes across a large cohort of different solid tumors can be used to design future clinical studies to assess whether CD274 CN changes could be a potential biomarker for ICPI.	('changes', 'Var', (163, 170))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('CD274', 'Gene', '29126', (154, 159))	('solid tumors', 'Disease', (77, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('CD274', 'Gene', '29126', (25, 30))	('CD274', 'Gene', (154, 159))	('solid tumors', 'Disease', 'MESH:D009369', (77, 89))	('CD274', 'Gene', (25, 30))
127055	33972391	One promising but not as well studied biomarker for ICPI is CD274 (PD-L1) gene copy number (CN) changes.	('PD-L1', 'Gene', (67, 72))	('CD274', 'Gene', (60, 65))	('changes', 'Var', (96, 103))	('PD-L1', 'Gene', '29126', (67, 72))	('CD274', 'Gene', '29126', (60, 65))
127058	33972391	More recently, in the SAFIR02-IMMUNO Randomized Phase II Trial, exploratory analysis has shown that CD274 amplification (defined as CN >=5) and CN gains (CN 3-4) were predictors of durvalumab response in metastatic breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (215, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('breast cancer', 'Disease', (215, 228))	('CN gains', 'Var', (144, 152))	('CD274', 'Gene', '29126', (100, 105))	('durvalumab', 'Chemical', 'MESH:C000613593', (181, 191))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('CD274', 'Gene', (100, 105))
127071	33972391	We also explored prevalence rates of different CN cut offs (ploidy +1 (CN 3), ploidy +2 (CN 4), ploidy +3 (CN 5), ploidy +4 (CN 6), and ploidy +8 (CN 10)) to define CD274 CN positivity.	('ploidy +2', 'Var', (78, 87))	('CD274', 'Gene', '29126', (165, 170))	('ploidy +4', 'Var', (114, 123))	('ploidy +3', 'Var', (96, 105))	('CD274', 'Gene', (165, 170))	('ploidy +8', 'Var', (136, 145))
127098	33972391	When compared with PD-L1 IHC, CD274 CN positivity (at different CN cut-offs) is highly specific and has high positive predictive value (figure 4B and online supplemental table 3).	('CD274', 'Gene', '29126', (30, 35))	('PD-L1', 'Gene', (19, 24))	('PD-L1', 'Gene', '29126', (19, 24))	('CD274', 'Gene', (30, 35))	('positivity', 'Var', (39, 49))
127099	33972391	Importantly, the sensitivity, specificity, positive predictive value, and negative predictive value varied depending on which cut-off we used to define CD274 CN positivity and varied depending on tumor type/PD-L1 CDx assay and scoring algorithm used (figure 4B and online supplemental table 3).	('CD274', 'Gene', (152, 157))	('PD-L1', 'Gene', (207, 212))	('tumor', 'Disease', (196, 201))	('positivity', 'Var', (161, 171))	('PD-L1', 'Gene', '29126', (207, 212))	('CD274', 'Gene', '29126', (152, 157))	('CDx', 'Chemical', '-', (213, 216))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
127104	33972391	In this study, we present prevalence data on CD274 CN losses, gains, and positivity (defined by different CD274 CN cut-offs) in over 240 000 patient samples across 290 solid tumor types.	('tumor', 'Disease', (174, 179))	('CD274', 'Gene', (45, 50))	('CD274', 'Gene', '29126', (106, 111))	('patient', 'Species', '9606', (141, 148))	('CD274', 'Gene', '29126', (45, 50))	('losses', 'NegReg', (54, 60))	('positivity', 'Var', (73, 83))	('CD274', 'Gene', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('gains', 'PosReg', (62, 67))
127105	33972391	While Goodman et al previously presented data on CD274 amplification status (defined as ploidy +4) on a large cohort of patients, recent clinical data suggests that CN loss, CN gain, and amplification based on different cut offs can represent both negative and positive predictive biomarkers for ICPI response.	('loss', 'NegReg', (168, 172))	('amplification', 'Var', (187, 200))	('ICPI', 'Disease', (296, 300))	('patients', 'Species', '9606', (120, 128))	('gain', 'PosReg', (177, 181))	('CD274', 'Gene', '29126', (49, 54))	('CD274', 'Gene', (49, 54))
127109	33972391	The prevalence and diversity of CD274 CN changes in this study can serve as a basis for future clinical studies when further exploring CD274 CN changes.	('CD274', 'Gene', (135, 140))	('CD274', 'Gene', (32, 37))	('CD274', 'Gene', '29126', (135, 140))	('changes', 'Var', (41, 48))	('CD274', 'Gene', '29126', (32, 37))
127130	30938068	Patients treated with radiotherapy were older, had more advanced comorbidity, and had a higher risk of death as compared to patients treated with RC (relative risks of 1.5-1.6).	('RC', 'Chemical', '-', (146, 148))	('Patients', 'Species', '9606', (0, 8))	('death', 'Disease', 'MESH:D003643', (103, 108))	('radiotherapy', 'Var', (22, 34))	('death', 'Disease', (103, 108))	('patients', 'Species', '9606', (124, 132))
127143	30938068	This group (less than 3% of patients with muscle-invasive bladder cancer) was in the analysis categorized as N1 if they had grade 1, 2, or T category T2, and as N3 if they were M1, and the remaining node-positive patients were categorized as N2.	('grade 1', 'Var', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('invasive bladder', 'Phenotype', 'HP:0100645', (49, 65))	('patients', 'Species', '9606', (213, 221))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (42, 72))	('muscle-invasive bladder cancer', 'Disease', (42, 72))	('patients', 'Species', '9606', (28, 36))
127205	29696234	The characteristics of high-risk UUT disease are: high-grade tumor at biopsy, multifocalitiy, positive urinary cytology, transmural disease, hydro-nephrosis on imaging and a tumor size >=1 cm.	('hydro-nephrosis', 'Disease', (141, 156))	('tumor', 'Disease', (174, 179))	('nephrosis', 'Phenotype', 'HP:0000100', (147, 156))	('positive urinary cytology', 'Phenotype', 'HP:0012614', (94, 119))	('hydro-nephrosis', 'Disease', 'MESH:D009401', (141, 156))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('multifocalitiy', 'Disease', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('high-grade', 'Var', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('transmural disease', 'Disease', (121, 139))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('UUT disease', 'Phenotype', 'HP:0001997', (33, 44))	('UUT disease', 'Disease', (33, 44))	('tumor', 'Disease', (61, 66))
127235	29696234	By modified intention-to-treat analysis, 21 of 120 patients (17%) in the Mitomycin arm developed a bladder recurrence in the first year versus 32 of 119 patients (27%) in the standard of care arm (p = 0.055).	('patients', 'Species', '9606', (153, 161))	('bladder recurrence', 'Disease', (99, 117))	('patients', 'Species', '9606', (51, 59))	('Mitomycin', 'Var', (73, 82))	('Mitomycin', 'Chemical', 'MESH:D016685', (73, 82))
127236	29696234	By treatment as per protocol analysis, 17 of 105 patients (16%) in the Mitomycin arm and 31 of 115 patients (27%) in the standard treatment arm developed a bladder recurrence (p = 0.03).	('Mitomycin', 'Var', (71, 80))	('bladder', 'Disease', (156, 163))	('patients', 'Species', '9606', (99, 107))	('Mitomycin', 'Chemical', 'MESH:D016685', (71, 80))	('patients', 'Species', '9606', (49, 57))
127281	29696234	In high-grade urothelial carcinoma of the UUT FGFR3 and HRAS were more frequently mutated, whereas mutations in TP53 and RB1 were less prevalent compared to high-grade UCB.	('urothelial carcinoma of the UUT', 'Disease', (14, 45))	('UCB', 'Chemical', '-', (168, 171))	('RB1', 'Gene', (121, 124))	('HRAS', 'Gene', '3265', (56, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('FGFR3', 'Gene', '2261', (46, 51))	('RB1', 'Gene', '5925', (121, 124))	('HRAS', 'Gene', (56, 60))	('mutations', 'Var', (99, 108))	('mutated', 'Var', (82, 89))	('urothelial carcinoma of the UUT', 'Disease', 'MESH:D014526', (14, 45))	('TP53', 'Gene', '7157', (112, 116))	('FGFR3', 'Gene', (46, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('TP53', 'Gene', (112, 116))
127285	29696234	Furthermore, alterations in the mTOR-pathway, and the genes HER2, BCAT1, CDCA5 and p53 might play a role in the prognosis of high grade urothelial carcinoma of the UUT, but the impact of these biomarkers hasn't been sufficiently validated because of the small portion of samples in single-institution cohorts.	('urothelial carcinoma of the UUT', 'Disease', 'MESH:D014526', (136, 167))	('p53', 'Gene', (83, 86))	('BCAT1', 'Gene', '586', (66, 71))	('p53', 'Gene', '7157', (83, 86))	('CDCA5', 'Gene', '113130', (73, 78))	('mTOR', 'Gene', '2475', (32, 36))	('HER2', 'Gene', (60, 64))	('mTOR', 'Gene', (32, 36))	('HER2', 'Gene', '2064', (60, 64))	('BCAT1', 'Gene', (66, 71))	('CDCA5', 'Gene', (73, 78))	('alterations', 'Var', (13, 24))	('BCAT', 'molecular_function', 'GO:0043840', ('66', '70'))	('urothelial carcinoma of the UUT', 'Disease', (136, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('play', 'Reg', (93, 97))
127334	29696234	tumor-specific mutations.	('mutations', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (0, 5))
127355	26169799	Aberrant miRNA expression is involved in the pathogenesis of several human diseases.	('Aberrant', 'Var', (0, 8))	('human', 'Species', '9606', (69, 74))	('miRNA expression', 'Protein', (9, 25))	('pathogenesis', 'biological_process', 'GO:0009405', ('45', '57'))	('involved', 'Reg', (29, 37))
127456	25598935	Specifically, there was a significant difference in survival after AC in patients with T3-4 and LVI but not in those with T1-2 and LVI.	('LVI', 'Chemical', '-', (131, 134))	('T3-4', 'Var', (87, 91))	('LVI', 'Chemical', '-', (96, 99))	('patients', 'Species', '9606', (73, 81))	('LVI', 'Disease', (96, 99))
127465	25598935	The prospective randomized controlled perioperative chemotherapy versus surveillance in upper tract urothelial cancer (POUT) trial has enrolled patients with UTUC staged pT2-pT4 N0-3 M0 or pTany N1-3 M0 after RNU starting in 2012.	('pT2-pT4 N0-3 M0', 'Var', (170, 185))	('pTany N1-3 M0', 'Var', (189, 202))	('upper tract urothelial cancer', 'Disease', 'MESH:D012141', (88, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('RNU', 'Chemical', '-', (209, 212))	('patients', 'Species', '9606', (144, 152))	('upper tract urothelial cancer', 'Disease', (88, 117))
127470	25598935	A recent retrospective analysis suggested that AC had no survival benefit for CSS and OS in patients with advanced UTUC (pT3N0, pT4N0, and/or lymph node positive).	('OS', 'Chemical', '-', (86, 88))	('patients', 'Species', '9606', (92, 100))	('CSS', 'Disease', (78, 81))	('pT3', 'Gene', '7694', (121, 124))	('pT3', 'Gene', (121, 124))	('CSS', 'Chemical', '-', (78, 81))	('pT4N0', 'Var', (128, 133))
127472	25598935	However, this study presents a favorable response to AC in patients with LVI+ and pT3-pT4N0/x.	('pT3', 'Gene', '7694', (82, 85))	('LVI+', 'Chemical', '-', (73, 77))	('pT3', 'Gene', (82, 85))	('LVI+', 'Var', (73, 77))	('patients', 'Species', '9606', (59, 67))
127498	25598935	The subgroup of patients with T3-4 and LVI is the target population for AC.	('T3-4', 'Var', (30, 34))	('LVI', 'Disease', (39, 42))	('patients', 'Species', '9606', (16, 24))	('LVI', 'Chemical', '-', (39, 42))
127503	33558879	Inhibition of glycolysis might be a promising assistant for immunotherapy in bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('Inhibition of glycolysis', 'biological_process', 'GO:0045820', ('0', '24'))	('bladder cancer', 'Disease', (77, 91))	('Inhibition', 'Var', (0, 10))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('glycolysis', 'MPA', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
127551	33558879	Therefore, we hypothesized that high glycolysis might lead to tumor cells' resistance to immune function, resulting in immune evasion.	('high', 'Var', (32, 36))	('glycolysis', 'MPA', (37, 47))	('immune evasion', 'MPA', (119, 133))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('lead to', 'Reg', (54, 61))	('resistance to immune function', 'Phenotype', 'HP:0002721', (75, 104))	('immune evasion', 'biological_process', 'GO:0042783', ('119', '133'))	('tumor', 'Disease', (62, 67))	('immune evasion', 'biological_process', 'GO:0051842', ('119', '133'))	('glycolysis', 'biological_process', 'GO:0006096', ('37', '47'))	('resistance', 'CPA', (75, 85))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
127562	33558879	Previous studies have confirmed that the expression of GLUT1 in human bladder cancer is associated with poor prognosis and a low survival rate, which was considered a marker of aggressive biologic potential for BLCA meanwhile.	('human', 'Species', '9606', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('bladder cancer', 'Disease', 'MESH:D001749', (70, 84))	('GLUT1', 'Gene', (55, 60))	('expression', 'Var', (41, 51))	('GLUT1', 'Gene', '6513', (55, 60))	('low', 'NegReg', (125, 128))	('survival rate', 'CPA', (129, 142))	('bladder cancer', 'Disease', (70, 84))
127567	33558879	In BLCA, once MCT1 was knocked out, the proliferation, migration, and invasion of bladder cancer cells were inhibited.	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('migration', 'CPA', (55, 64))	('MCT1', 'Gene', (14, 18))	('invasion of', 'CPA', (70, 81))	('knocked out', 'Var', (23, 34))	('bladder cancer', 'Disease', (82, 96))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))	('MCT1', 'Gene', '6566', (14, 18))	('MCT', 'biological_process', 'GO:0120197', ('14', '17'))	('proliferation', 'CPA', (40, 53))	('inhibited', 'NegReg', (108, 117))
127615	32725802	The objective of our study was to investigate the regulatory relationship between EZH2 and DLC1 in BC and to determine whether curcumin can inhibit the growth of TNBC cells by silencing EZH2 to restore the expression of DLC1.	('EZH2', 'Gene', (82, 86))	('silencing', 'Var', (176, 185))	('growth', 'MPA', (152, 158))	('EZH2', 'Gene', '2146', (82, 86))	('DLC1', 'Gene', '10395', (220, 224))	('DLC1', 'Gene', (91, 95))	('BC', 'Phenotype', 'HP:0003002', (99, 101))	('BC', 'Phenotype', 'HP:0003002', (164, 166))	('expression', 'MPA', (206, 216))	('curcumin', 'Chemical', 'MESH:D003474', (127, 135))	('DLC1', 'Gene', (220, 224))	('inhibit', 'NegReg', (140, 147))	('EZH2', 'Gene', (186, 190))	('EZH2', 'Gene', '2146', (186, 190))	('DLC1', 'Gene', '10395', (91, 95))	('restore', 'PosReg', (194, 201))
127677	32725802	To further verify that EZH2 can inhibit the expression of DLC1 by mediating H3K27me3, we used EZH2 siRNA1 to transfect 231 cells and found that EZH2 knockdown can inhibit the expression of H3K27me3 protein (Figure 4D).	('inhibit', 'NegReg', (163, 170))	('expression', 'MPA', (175, 185))	('inhibit', 'NegReg', (32, 39))	('knockdown', 'Var', (149, 158))	('EZH2', 'Gene', (144, 148))	('DLC1', 'Gene', '10395', (58, 62))	('H3K27me3 protein', 'Protein', (189, 205))	('EZH2', 'Gene', '2146', (144, 148))	('EZH2', 'Gene', '2146', (94, 98))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('DLC1', 'Gene', (58, 62))	('EZH2', 'Gene', (94, 98))	('EZH2', 'Gene', '2146', (23, 27))	('EZH2', 'Gene', (23, 27))
127678	32725802	ChIP assays showed that H3K27me3 was enriched in the DLC1 promoter region of MDA-MB-231 cells, while the knockdown of EZH2 reduced the enrichment of H3K27me3 in the promoter region of DLC1 (Figure 4E).	('DLC1', 'Gene', (53, 57))	('knockdown', 'Var', (105, 114))	('DLC1', 'Gene', '10395', (184, 188))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (77, 87))	('enrichment', 'MPA', (135, 145))	('DLC1', 'Gene', '10395', (53, 57))	('H3K27me3', 'Var', (24, 32))	('EZH2', 'Gene', (118, 122))	('EZH2', 'Gene', '2146', (118, 122))	('DLC1', 'Gene', (184, 188))	('reduced', 'NegReg', (123, 130))
127679	32725802	These results suggest that knockdown of EZH2 can restore the expression of DLC1 by reducing the enrichment of H3K27me3 in the DLC1 promoter.	('DLC1', 'Gene', '10395', (126, 130))	('knockdown', 'Var', (27, 36))	('DLC1', 'Gene', (75, 79))	('DLC1', 'Gene', (126, 130))	('restore', 'PosReg', (49, 56))	('reducing', 'NegReg', (83, 91))	('H3K27me3', 'Protein', (110, 118))	('EZH2', 'Gene', (40, 44))	('EZH2', 'Gene', '2146', (40, 44))	('expression', 'MPA', (61, 71))	('DLC1', 'Gene', '10395', (75, 79))	('enrichment of', 'MPA', (96, 109))
127683	32725802	Transwell and wound healing assays showed that knockdown of EZH2 by transfection with EZH2 siRNA inhibited the invasion and migration of MDA-MB-231 cells (Figure 5A,C) and MDA-MB-468 cells (Figure S1).	('EZH2', 'Gene', (60, 64))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (137, 147))	('wound healing', 'biological_process', 'GO:0042060', ('14', '27'))	('knockdown', 'Var', (47, 56))	('EZH2', 'Gene', '2146', (86, 90))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (172, 182))	('EZH2', 'Gene', '2146', (60, 64))	('EZH2', 'Gene', (86, 90))	('inhibited', 'NegReg', (97, 106))	('invasion', 'CPA', (111, 119))
127684	32725802	Moreover, the results of the CCK-8 assay demonstrated that knockdown of EZH2 inhibited the proliferation of MDA-MB-231 cells (Figure 5B) and MDA-MB-468 cells (Figure S1).	('MDA-MB-468', 'CellLine', 'CVCL:0419', (141, 151))	('CCK-8', 'Chemical', 'MESH:D012844', (29, 34))	('inhibited', 'NegReg', (77, 86))	('EZH2', 'Gene', '2146', (72, 76))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (108, 118))	('EZH2', 'Gene', (72, 76))	('proliferation', 'CPA', (91, 104))	('knockdown', 'Var', (59, 68))
127686	32725802	The results showed that knocking down EZH2 by EZH2 siRNA increased the apoptosis of MDA-MB-231 cells (Figure 5D) and MDA-MB-468 cells (Figure S1) and blocked MDA-MB-231 cells (Figure 5E) and MDA-MB-468 cells (Figure S1) in G2 phase compared with NC-siRNA.	('knocking down', 'Var', (24, 37))	('G2 phase', 'CPA', (223, 231))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (191, 201))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (158, 168))	('apoptosis', 'CPA', (71, 80))	('EZH2', 'Gene', '2146', (38, 42))	('blocked', 'NegReg', (150, 157))	('EZH2', 'Gene', (38, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (117, 127))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (84, 94))	('EZH2', 'Gene', '2146', (46, 50))	('increased', 'PosReg', (57, 66))	('EZH2', 'Gene', (46, 50))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('G2 phase', 'biological_process', 'GO:0051319', ('223', '231'))
127688	32725802	In addition, we used EZH2 inhibitors to treat MDA-MB-231 cells and MDA-MB-468 cells and found that the EZH2 inhibitor can inhibit the migration, invasion and proliferation of MDA-MB-231 cells and MDA-MB-468 cells, promote apoptosis and block the cell cycle (Figure S2).	('apoptosis', 'CPA', (222, 231))	('migration', 'CPA', (134, 143))	('block', 'NegReg', (236, 241))	('EZH2', 'Gene', '2146', (103, 107))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (196, 206))	('EZH2', 'Gene', (103, 107))	('cell cycle', 'CPA', (246, 256))	('invasion', 'CPA', (145, 153))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (175, 185))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (67, 77))	('promote', 'PosReg', (214, 221))	('EZH2', 'Gene', (21, 25))	('EZH2', 'Gene', '2146', (21, 25))	('inhibitor', 'Var', (108, 117))	('apoptosis', 'biological_process', 'GO:0097194', ('222', '231'))	('apoptosis', 'biological_process', 'GO:0006915', ('222', '231'))	('cell cycle', 'biological_process', 'GO:0007049', ('246', '256'))	('inhibit', 'NegReg', (122, 129))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (46, 56))
127710	32725802	Functional assays further proved that knocking down EZH2 inhibited the invasion, migration and proliferation of MDA-MB-231 cells, promoted cell apoptosis and blocked the cell cycle.	('knocking down', 'Var', (38, 51))	('apoptosis', 'biological_process', 'GO:0006915', ('144', '153'))	('inhibited', 'NegReg', (57, 66))	('cell cycle', 'biological_process', 'GO:0007049', ('170', '180'))	('invasion', 'CPA', (71, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('144', '153'))	('EZH2', 'Gene', (52, 56))	('promoted', 'PosReg', (130, 138))	('blocked', 'NegReg', (158, 165))	('EZH2', 'Gene', '2146', (52, 56))	('proliferation', 'CPA', (95, 108))	('cell cycle', 'CPA', (170, 180))	('migration', 'CPA', (81, 90))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (112, 122))	('cell apoptosis', 'CPA', (139, 153))
127715	32725802	33  In many cancer cells, the inactivation of RhoGAP caused by DLC1 gene silencing can activate RhoGAP protein, which can continuously transmit growth signals to cells, which may be one of the main mechanisms of tumorigenesis.	('gene silencing', 'biological_process', 'GO:0016458', ('68', '82'))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('RhoGAP', 'Gene', '392', (96, 102))	('inactivation', 'Var', (30, 42))	('cancer', 'Disease', (12, 18))	('DLC1', 'Gene', '10395', (63, 67))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('gene silencing', 'Var', (68, 82))	('protein', 'Protein', (103, 110))	('RhoGAP', 'Gene', (96, 102))	('RhoGAP', 'Gene', '392', (46, 52))	('activate', 'PosReg', (87, 95))	('DLC1', 'Gene', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('RhoGAP', 'Gene', (46, 52))
127716	32725802	34  However, inactivation of the DLC1 gene occurs not only in liver cancer 35  and lung cancer, 36  but its low expression or loss of expression in gastric cancer, BC and prostate cancer results in its malignant phenotype.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('inactivation', 'Var', (13, 25))	('BC and prostate cancer', 'Disease', 'MESH:D011471', (164, 186))	('prostate cancer', 'Phenotype', 'HP:0012125', (171, 186))	('liver cancer', 'Phenotype', 'HP:0002896', (62, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('liver cancer', 'Disease', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('expression', 'MPA', (112, 122))	('DLC1', 'Gene', '10395', (33, 37))	('DLC1', 'Gene', (33, 37))	('loss of expression', 'NegReg', (126, 144))	('gastric cancer', 'Disease', (148, 162))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Disease', (83, 94))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('BC', 'Phenotype', 'HP:0003002', (164, 166))	('malignant phenotype', 'MPA', (202, 221))	('liver cancer', 'Disease', 'MESH:D006528', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
127718	32725802	39 ,  40  Our study found that knocking down EZH2 up-regulated the expression of DLC1, which may be another reason why knocking down EZH2 promotes the apoptosis of MDA-MB-231 cells and inhibits their migration and proliferation.	('knocking', 'Var', (31, 39))	('EZH2', 'Gene', (133, 137))	('EZH2', 'Gene', '2146', (45, 49))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (164, 174))	('inhibits', 'NegReg', (185, 193))	('DLC1', 'Gene', (81, 85))	('EZH2', 'Gene', (45, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('151', '160'))	('apoptosis', 'biological_process', 'GO:0006915', ('151', '160'))	('up-regulated', 'PosReg', (50, 62))	('promotes', 'PosReg', (138, 146))	('expression', 'MPA', (67, 77))	('apoptosis', 'CPA', (151, 160))	('knocking down', 'Var', (119, 132))	('EZH2', 'Gene', '2146', (133, 137))	('DLC1', 'Gene', '10395', (81, 85))
127758	25684323	In the subset of patients with preoperatively identified CIS in the bladder, the sensitivity of frozen section analysis for the detection of UC and adverse pathology was improved from 43.3 to 72.7% and from 59.1 to 68.0%, respectively.	('CIS', 'Phenotype', 'HP:0030075', (57, 60))	('patients', 'Species', '9606', (17, 25))	('improved', 'PosReg', (170, 178))	('CIS', 'Var', (57, 60))
127906	30754663	Moreover, sarcopenia can contribute to higher rates of treatment-related complications in various cancers, including those due to surgical treatment, chemotherapy, or tyrosine kinase inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tyrosine', 'Var', (167, 175))	('higher', 'PosReg', (39, 45))	('rat', 'Species', '10116', (46, 49))	('sarcopenia', 'Disease', (10, 20))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('sarcopenia', 'Disease', 'MESH:D055948', (10, 20))
127938	30754663	Previous studies on ATGL- or HSL-deficient animal models showed that the absence of ATGL, and, to a lesser degree, HSL, reduces fatty acid mobilization and ameliorates the depletion of adipose tissue, resulting in the inhibition of skeletal muscle wasting.	('ATGL', 'Gene', '57104', (20, 24))	('fatty acid mobilization', 'MPA', (128, 151))	('skeletal muscle wasting', 'CPA', (232, 255))	('HSL', 'molecular_function', 'GO:0033878', ('29', '32'))	('absence', 'Var', (73, 80))	('ameliorates', 'PosReg', (156, 167))	('HSL', 'molecular_function', 'GO:0033878', ('115', '118'))	('HSL-deficient', 'Disease', 'MESH:D007153', (29, 42))	('muscle wasting', 'Phenotype', 'HP:0003202', (241, 255))	('adipose', 'Gene', '230796', (185, 192))	('HSL', 'Gene', (29, 32))	('reduces', 'NegReg', (120, 127))	('inhibition', 'NegReg', (218, 228))	('fatty acid', 'Chemical', 'MESH:D005227', (128, 138))	('HSL', 'Gene', '3991', (29, 32))	('ATGL', 'Gene', (84, 88))	('HSL-deficient', 'Disease', (29, 42))	('HSL', 'Gene', (115, 118))	('ATGL', 'Gene', (20, 24))	('HSL', 'Gene', '3991', (115, 118))	('rat', 'Species', '10116', (162, 165))	('adipose', 'Gene', (185, 192))	('ATGL', 'Gene', '57104', (84, 88))
127953	30754663	Apoptotic loss of skeletal muscle mass can lead to lipid droplet accumulation in skeletal muscle tissues, which is associated with poor skeletal muscle function.	('lipid droplet', 'cellular_component', 'GO:0005811', ('51', '64'))	('loss of skeletal muscle mass', 'Disease', (10, 38))	('lead to', 'Reg', (43, 50))	('lipid', 'Chemical', 'MESH:D008055', (51, 56))	('accumulation in skeletal muscle', 'Phenotype', 'HP:0009058', (65, 96))	('Apoptotic', 'Var', (0, 9))	('loss of skeletal muscle mass', 'Disease', 'MESH:D005207', (10, 38))	('lipid droplet accumulation', 'MPA', (51, 77))
127957	30754663	Apoptosis of satellite cells in aging skeletal muscle can also induce a loss of skeletal muscle mass and function.	('Apoptosis', 'Var', (0, 9))	('aging', 'biological_process', 'GO:0007568', ('32', '37'))	('loss of skeletal muscle mass', 'Disease', (72, 100))	('loss of skeletal muscle mass', 'Disease', 'MESH:D005207', (72, 100))	('function', 'CPA', (105, 113))
128015	30754663	n-3 fatty acids, including eicosapentaenoic acid and docosahexaenoic acid, can improve sarcopenia by antagonizing superoxide dismutase.	('docosahexaenoic acid', 'Chemical', 'MESH:D004281', (53, 73))	('n-3 fatty acids', 'Chemical', 'MESH:D015525', (0, 15))	('sarcopenia', 'Disease', (87, 97))	('improve', 'PosReg', (79, 86))	('eicosapentaenoic acid', 'Chemical', 'MESH:D015118', (27, 48))	('superoxide dismutase', 'MPA', (114, 134))	('antagonizing', 'NegReg', (101, 113))	('eicosapentaenoic', 'Var', (27, 43))	('sarcopenia', 'Disease', 'MESH:D055948', (87, 97))
128016	30754663	Excessive fatty acid oxidation can cause skeletal muscle depletion by increasing ROS production in myofibers.	('ROS production', 'MPA', (81, 95))	('fatty acid oxidation', 'MPA', (10, 30))	('Excessive', 'Var', (0, 9))	('fatty acid', 'Chemical', 'MESH:D005227', (10, 20))	('muscle depletion', 'Phenotype', 'HP:0003202', (50, 66))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('10', '30'))	('increasing', 'PosReg', (70, 80))	('skeletal muscle depletion', 'MPA', (41, 66))	('cause', 'Reg', (35, 40))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))	('increasing ROS production', 'Phenotype', 'HP:0025464', (70, 95))
128018	30754663	Because myostatin binds to and activates ActR2B, ActR2B antagonists may promote skeletal muscle mass recovery by improving the regenerative capacity of satellite cells.	('myostatin', 'Gene', (8, 17))	('activates', 'PosReg', (31, 40))	('binds', 'Interaction', (18, 23))	('myostatin', 'Gene', '2660', (8, 17))	('ActR2B', 'Gene', (41, 47))	('antagonists', 'Var', (56, 67))	('rat', 'Species', '10116', (133, 136))	('improving', 'PosReg', (113, 122))	('promote', 'PosReg', (72, 79))	('skeletal muscle mass recovery', 'CPA', (80, 109))	('regenerative capacity of satellite cells', 'CPA', (127, 167))
128040	27260798	Copy number analysis of whole-genome data using BIC-seq2 and its application to detection of cancer susceptibility variants Whole-genome sequencing data allow detection of copy number variation (CNV) at high resolution.	('copy number', 'Var', (172, 183))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
128044	27260798	Analysis of colorectal cancer genomes in particular reveals novel recurrent CNVs including deletions at two chromatin-remodeling genes RERE and NPM2.	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('108', '128'))	('colorectal cancer', 'Disease', (12, 29))	('RERE', 'Gene', '473', (135, 139))	('chromatin', 'cellular_component', 'GO:0000785', ('108', '117'))	('NPM2', 'Gene', '10361', (144, 148))	('RERE', 'Gene', (135, 139))	('deletions', 'Var', (91, 100))	('NPM2', 'Gene', (144, 148))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
128047	27260798	deletion of tumor suppressors or amplification of oncogenes can drive tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('oncogenes', 'Gene', (50, 59))	('amplification', 'Var', (33, 46))	('tumor', 'Disease', (70, 75))	('drive', 'PosReg', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('deletion', 'Var', (0, 8))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
128109	27260798	Several known arm level alterations have been identified previously, including gains of 7p/q, 8p/q, 13q, 20p/q, deletions of 1p, 4q, 14q, 15q, 17p (including TP53), 21q.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('deletions', 'Var', (112, 121))	('20p/q', 'Var', (105, 110))	('8p/q', 'Var', (94, 98))	('gains', 'PosReg', (79, 84))
128112	27260798	The genes with concordant transcript up-regulation and chromosomal amplification include known oncogenes MYC, IGF2, ERBB2 and HNF4A (Supplementary Figure S10A).	('HNF4A', 'Gene', (126, 131))	('S10A', 'Var', (154, 158))	('IGF2', 'Gene', (110, 114))	('ERBB2', 'Gene', '2064', (116, 121))	('MYC', 'Gene', '4609', (105, 108))	('regulation', 'biological_process', 'GO:0065007', ('40', '50'))	('ERBB2', 'Gene', (116, 121))	('up-regulation', 'PosReg', (37, 50))	('MYC', 'Gene', (105, 108))	('IGF2', 'Gene', '3481', (110, 114))	('HNF4A', 'Gene', '3172', (126, 131))	('S10A', 'SUBSTITUTION', 'None', (154, 158))
128115	27260798	Overexpression of PIP4K2B can confer proliferation advantage to tumor cells and it may therefore serve as a drug target for preventing and treating cancers with mutations in TP53.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('tumor', 'Disease', (64, 69))	('PIP4K2B', 'Gene', (18, 25))	('cancers', 'Disease', (148, 155))	('proliferation advantage', 'CPA', (37, 60))	('TP53', 'Gene', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('PIP4K', 'molecular_function', 'GO:0016309', ('18', '23'))	('mutations', 'Var', (161, 170))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('PIP4K2B', 'Gene', '8396', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('TP53', 'Gene', '7157', (174, 178))
128116	27260798	Genes whose transcripts show down-regulation coupled with chromosomal deletions include cancer-related genes such as ARID1A, SDHB, MAP2K4, FLCN (Supplementary Figure S10B).	('S10B', 'Var', (166, 170))	('SDHB', 'Gene', (125, 129))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('MAP2K4', 'Gene', '6416', (131, 137))	('MAP2K', 'molecular_function', 'GO:0004708', ('131', '136'))	('down-regulation', 'NegReg', (29, 44))	('MAP2K4', 'Gene', (131, 137))	('S10B', 'SUBSTITUTION', 'None', (166, 170))	('FLCN', 'Gene', (139, 143))	('ARID1A', 'Gene', '8289', (117, 123))	('ARID1A', 'Gene', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('regulation', 'biological_process', 'GO:0065007', ('34', '44'))	('FLCN', 'Gene', '201163', (139, 143))	('SDHB', 'Gene', '6390', (125, 129))
128121	27260798	Over-expression of RERE was shown to trigger apoptosis and frequent methylation of NPM2 was observed in melanoma and leukemia.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('RERE', 'Gene', (19, 23))	('RERE', 'Gene', '473', (19, 23))	('NPM2', 'Gene', '10361', (83, 87))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('observed', 'Reg', (92, 100))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('NPM2', 'Gene', (83, 87))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('Over-expression', 'Var', (0, 15))	('methylation', 'MPA', (68, 79))	('melanoma and leukemia', 'Disease', 'MESH:D008545', (104, 125))
128123	27260798	Here, we applied our algorithm to identify germline CNVs that may confer cancer susceptibility.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('germline CNVs', 'Var', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
128131	27260798	Among the known CNVRs, the most significant is the 7p14.1 deletion CNVR overlapping with the gene TARP (Supplementary Figure S11A).	('TARP', 'Gene', (98, 102))	('TARP', 'Gene', '445347', (98, 102))	('S11A', 'Var', (125, 129))	('deletion', 'Var', (58, 66))	('S11A', 'SUBSTITUTION', 'None', (125, 129))
128133	27260798	The 7q34 deletion CNVR (Supplementary Figure S11B) harboring the gene PIP was previously identified as a potential cancer-predisposing variation by screening of high-risk cancer patients.	('cancer', 'Disease', (115, 121))	('S11B', 'Var', (45, 49))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('CNVR', 'Gene', (18, 22))	('patients', 'Species', '9606', (178, 186))	('S11B', 'SUBSTITUTION', 'None', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('PIP', 'Gene', (70, 73))	('cancer', 'Disease', (171, 177))	('PIP', 'Gene', '5304', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
128134	27260798	It was also shown that the expression of PIP is significantly associated with good prognosis factors of breast cancer such as lower tumor grade and lower pN stage.	('PIP', 'Gene', '5304', (41, 44))	('associated', 'Reg', (62, 72))	('lower tumor', 'Disease', 'MESH:D009369', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('lower tumor', 'Disease', (126, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('expression', 'Var', (27, 37))	('PIP', 'Gene', (41, 44))
128135	27260798	The 6q37 amplification CNVR (Supplementary Figure S11C) is also known and is significantly enriched in Li-Fraumeni symdrome.	('Li-Fraumeni', 'Disease', (103, 114))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (103, 114))	('S11C', 'SUBSTITUTION', 'None', (50, 54))	('S11C', 'Var', (50, 54))
128137	27260798	Novel CNVRs include the most significant CNVR located at 7q36.1 overlapping with KMT2C (MLL3) (Supplementary Figure S12A).	('MLL3', 'Gene', (88, 92))	('KMT2C', 'Gene', (81, 86))	('S12A', 'SUBSTITUTION', 'None', (116, 120))	('S12A', 'Var', (116, 120))	('KMT2C', 'Gene', '58508', (81, 86))	('MLL3', 'Gene', '58508', (88, 92))
128139	27260798	Recent studies showed that germline mutations in KMT2C might be associated with ovarian cancer, colorectal cancer and acute myeloid leukemia.	('ovarian cancer', 'Disease', (80, 94))	('associated', 'Reg', (64, 74))	('KMT2C', 'Gene', (49, 54))	('KMT2C', 'Gene', '58508', (49, 54))	('acute myeloid leukemia', 'Disease', (118, 140))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (118, 140))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (124, 140))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('colorectal cancer', 'Disease', (96, 113))	('leukemia', 'Phenotype', 'HP:0001909', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ovarian cancer', 'Disease', 'MESH:D010051', (80, 94))	('germline mutations', 'Var', (27, 45))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (118, 140))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
128142	27260798	High frequency of GOLPH3 amplification was observed in several solid tumor types such as lung, ovarian, breast, pancreatic, prostate and skin cancers.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('lung', 'Disease', (89, 93))	('skin cancers', 'Phenotype', 'HP:0008069', (137, 149))	('skin cancers', 'Disease', (137, 149))	('tumor', 'Disease', (69, 74))	('breast', 'Disease', (104, 110))	('observed', 'Reg', (43, 51))	('GOLPH3', 'Gene', (18, 24))	('pancreatic, prostate', 'Disease', 'MESH:D010190', (112, 132))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('GOLPH3', 'Gene', '64083', (18, 24))	('skin cancers', 'Disease', 'MESH:D012878', (137, 149))	('ovarian', 'Disease', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('amplification', 'Var', (25, 38))
128150	27260798	In addition, we also identified less significant but novel CNVRs that overlap with known cancer genes.	('CNVRs', 'Var', (59, 64))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
128159	27260798	Germline mutations of ERBB2 that may confer cancer risk were also identified previously, such as in familial lung adenocarcinomas.	('Germline mutations', 'Var', (0, 18))	('ERBB2', 'Gene', '2064', (22, 27))	('ERBB2', 'Gene', (22, 27))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (109, 128))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('familial lung adenocarcinomas', 'Disease', (100, 129))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (109, 129))	('familial lung adenocarcinomas', 'Disease', 'MESH:D000077192', (100, 129))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
128172	27260798	In fact, the germline deletion of APOBEC3A and APOBEC3B is known to be associated with modestly increased cancer risk, but it was filtered because 6 individuals in the 1000 Genome control data have this deletion (Supplementary Figure S12B).	('APOBEC', 'cellular_component', 'GO:0030895', ('47', '53'))	('APOBEC3B', 'Gene', (47, 55))	('APOBEC3A', 'Gene', '200315', (34, 42))	('S12B', 'SUBSTITUTION', 'None', (234, 238))	('APOBEC3B', 'Gene', '9582', (47, 55))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('APOBEC', 'cellular_component', 'GO:0030895', ('34', '40'))	('APOBEC3A', 'Gene', (34, 42))	('S12B', 'Var', (234, 238))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
128173	27260798	The method used in this work has allowed us discover both known and novel cancer predisposing CNVRs, but the highly significant CNVRs might still contain copy number polymorphism.	('copy number polymorphism', 'Var', (154, 178))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('contain', 'Reg', (146, 153))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
128179	27260798	On the other hand, among the 16 patients with the amplification at TFG, 5 of them (2 BLCA patients, 1 LGG patient and 2 STAD patients) had data on family history in their clinical annotations.	('amplification', 'Var', (50, 63))	('patients', 'Species', '9606', (32, 40))	('patient', 'Species', '9606', (106, 113))	('TFG', 'Gene', '10342', (67, 70))	('patient', 'Species', '9606', (90, 97))	('TFG', 'Gene', (67, 70))	('patient', 'Species', '9606', (125, 132))	('patient', 'Species', '9606', (32, 39))	('patients', 'Species', '9606', (90, 98))	('patients', 'Species', '9606', (125, 133))
128215	27500201	Supporting that low BMI might be indicative of cachexia in metastatic urothelial cancer patients is that our data show that patients with a BMI <18.5 were more likely to have worse ECOG functional status scores, a marker of poor prognosis.	('low BMI', 'Phenotype', 'HP:0045082', (16, 23))	('cachexia in metastatic urothelial cancer', 'Disease', 'MESH:D002100', (47, 87))	('cachexia', 'Phenotype', 'HP:0004326', (47, 55))	('cachexia in metastatic urothelial cancer', 'Disease', (47, 87))	('<18.5', 'Var', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ECOG functional status scores', 'MPA', (181, 210))
128248	25657556	Saito reported a patient with T1G2 urothelial carcinoma treated with resection and bladder infiltration of BCG.	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('T1G2', 'Var', (30, 34))	('patient', 'Species', '9606', (17, 24))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (35, 55))	('urothelial carcinoma', 'Disease', (35, 55))
128267	22745731	After validation by RT-qPCR, miR-101, miR-125a-5p, miR-148b, miR-151-5p, miR-181a, miR-181b, miR-29c, miR-324-3p, miR-424, miR-874, RNU6B, RNU48, and Z30 were used for geNorm, NormFinder, and BestKeeper analyses that gave different combinations of recommended reference genes for normalization.	('miR-151', 'Gene', '442893', (61, 68))	('miR-101', 'Chemical', '-', (29, 36))	('Z30', 'Gene', '692076', (150, 153))	('miR-324', 'Gene', '442898', (102, 109))	('miR-151', 'Gene', (61, 68))	('miR-29c', 'Gene', '407026', (93, 100))	('Z30', 'Gene', (150, 153))	('miR-424', 'Gene', (114, 121))	('miR-424', 'Gene', '494336', (114, 121))	('miR-29c', 'Gene', (93, 100))	('RNU6B', 'Gene', (132, 137))	('RNU48', 'Gene', (139, 144))	('RNU48', 'Gene', '26801', (139, 144))	('miR-874', 'Gene', (123, 130))	('RNU6B', 'Gene', '26826', (132, 137))	('miR-148b', 'Gene', '442892', (51, 59))	('miR-148b', 'Gene', (51, 59))	('miR-125a', 'Gene', '406910', (38, 46))	('miR-324', 'Gene', (102, 109))	('miR-181b', 'Var', (83, 91))	('miR-874', 'Gene', '100126343', (123, 130))	('miR-125a', 'Gene', (38, 46))
128270	22745731	The combination of four (miR-101, miR-125a-5p, miR-148b, and miR-151-5p) or three (miR-148b, miR-181b, and miR-874,) reference miRNAs is recommended for normalization.	('miR-874', 'Gene', (107, 114))	('miR-101', 'Var', (25, 32))	('miR-148b', 'Gene', '442892', (83, 91))	('miR-125a', 'Gene', '406910', (34, 42))	('miR-874', 'Gene', '100126343', (107, 114))	('miR-148b', 'Gene', (83, 91))	('miR-151', 'Gene', '442893', (61, 68))	('miR-125a', 'Gene', (34, 42))	('miR-181b', 'Var', (93, 101))	('miR-151', 'Gene', (61, 68))	('miR-148b', 'Gene', '442892', (47, 55))	('miR-101', 'Chemical', '-', (25, 32))	('miR-148b', 'Gene', (47, 55))
128298	22745731	The intra-run precision for the finally considered candidate reference miRNAs miR-29c, miR-101, miR-125a-5p, miR-148b, miR-151-3p, miR-151-5p, miR-181a, miR-181b, miR-324-3p, miR-424, and miR-874 as well as the investigated small nuclear RNU6B, RNU48, and Z30 ranged from 0.15% to 0.35% for mean Cq values between 21.93 to 26.65.	('RNU48', 'Gene', (245, 250))	('Z30', 'Gene', (256, 259))	('RNU6B', 'Gene', (238, 243))	('RNU48', 'Gene', '26801', (245, 250))	('miR-29c', 'Gene', '407026', (78, 85))	('RNU6B', 'Gene', '26826', (238, 243))	('miR-181b', 'Var', (153, 161))	('miR-324', 'Gene', '442898', (163, 170))	('miR-151', 'Gene', '442893', (131, 138))	('miR-125a', 'Gene', '406910', (96, 104))	('miR-151', 'Gene', (131, 138))	('miR-148b', 'Gene', '442892', (109, 117))	('miR-874', 'Gene', (188, 195))	('miR-29c', 'Gene', (78, 85))	('miR-125a', 'Gene', (96, 104))	('miR-148b', 'Gene', (109, 117))	('miR-151', 'Gene', '442893', (119, 126))	('miR-151', 'Gene', (119, 126))	('miR-181a', 'Var', (143, 151))	('miR-874', 'Gene', '100126343', (188, 195))	('miR-424', 'Gene', (175, 182))	('miR-101', 'Chemical', '-', (87, 94))	('miR-424', 'Gene', '494336', (175, 182))	('miR-101', 'Var', (87, 94))	('Z30', 'Gene', '692076', (256, 259))	('miR-324', 'Gene', (163, 170))
128305	22745731	miR-15a, miR-20b, miR-107, miR-513a-5p, and miR-939 showed Cq values >35 in the pools and were excluded from further analyses because accurate quantification would be questionable.	('miR-513a-5p', 'Var', (27, 38))	('miR-15a', 'Gene', (0, 7))	('miR-20b', 'Gene', '574032', (9, 16))	('miR-107', 'Gene', (18, 25))	('miR-939', 'Gene', (44, 51))	('Cq values', 'MPA', (59, 68))	('miR-20b', 'Gene', (9, 16))	('miR-939', 'Gene', '100126351', (44, 51))	('miR-15a', 'Gene', '406948', (0, 7))	('miR-107', 'Gene', '406901', (18, 25))
128306	22745731	By this preselection, 11 putative reference miRNAs (Table 1: miR-29c, miR-101, miR-125a-5p, miR-148b, miR-151-3p, miR-151-5p, miR-181a, miR-181b, miR-324-3p, miR-424, and miR-874) as well as RNU6B, RNU48, and Z30 were further investigated and showed Cq values ranging from 22 (RNU48) to 28 (miR-324-3p).	('miR-324', 'Gene', (291, 298))	('RNU6B', 'Gene', (191, 196))	('RNU48', 'Gene', (198, 203))	('RNU48', 'Gene', '26801', (198, 203))	('RNU48', 'Gene', (277, 282))	('RNU48', 'Gene', '26801', (277, 282))	('miR-324', 'Gene', (146, 153))	('miR-151', 'Gene', '442893', (114, 121))	('miR-151', 'Gene', (114, 121))	('RNU6B', 'Gene', '26826', (191, 196))	('miR-181b', 'Var', (136, 144))	('miR-29c', 'Gene', '407026', (61, 68))	('miR-324', 'Gene', '442898', (291, 298))	('miR-125a', 'Gene', '406910', (79, 87))	('miR-324', 'Gene', '442898', (146, 153))	('miR-29c', 'Gene', (61, 68))	('miR-874', 'Gene', (171, 178))	('miR-148b', 'Gene', '442892', (92, 100))	('miR-125a', 'Gene', (79, 87))	('Z30', 'Gene', '692076', (209, 212))	('miR-424', 'Gene', (158, 165))	('miR-101', 'Chemical', '-', (70, 77))	('miR-148b', 'Gene', (92, 100))	('Z30', 'Gene', (209, 212))	('miR-101', 'Var', (70, 77))	('miR-424', 'Gene', '494336', (158, 165))	('miR-151', 'Gene', '442893', (102, 109))	('miR-181a', 'Var', (126, 134))	('miR-874', 'Gene', '100126343', (171, 178))	('miR-151', 'Gene', (102, 109))
128307	22745731	The expression levels significantly differed for miR-29c (P = 0.0012), miR-101 (P = 0.0007), miR-125a-5p (P<0.0001), miR-151-5p (P<0.0001), miR-324-3p (P<0.0001), and RNU6B (P = 0.0101) between nonmalignant and malignant samples.	('expression levels', 'MPA', (4, 21))	('miR-151', 'Gene', (117, 124))	('RNU6B', 'Gene', '26826', (167, 172))	('miR-324', 'Gene', (140, 147))	('RNU6B', 'Gene', (167, 172))	('miR-101', 'Chemical', '-', (71, 78))	('miR-125a', 'Gene', '406910', (93, 101))	('miR-101', 'Var', (71, 78))	('miR-324', 'Gene', '442898', (140, 147))	('miR-29c', 'Gene', (49, 56))	('miR-151', 'Gene', '442893', (117, 124))	('miR-125a', 'Gene', (93, 101))	('differed', 'Reg', (36, 44))	('miR-29c', 'Gene', '407026', (49, 56))
128308	22745731	The remaining eight miRNAs, namely miR-148b, miR-151-3p, miR-181a, miR-181b, miR-424, miR-874, RNU48, and Z30, revealed no significant differences between nonmalignant and malignant samples (P>0.05).	('miR-151', 'Gene', (45, 52))	('miR-148b', 'Gene', '442892', (35, 43))	('miR-148b', 'Gene', (35, 43))	('Z30', 'Gene', (106, 109))	('miR-181a', 'Var', (57, 65))	('miR-424', 'Gene', (77, 84))	('miR-874', 'Gene', (86, 93))	('RNU48', 'Gene', (95, 100))	('RNU48', 'Gene', '26801', (95, 100))	('miR-151', 'Gene', '442893', (45, 52))	('miR-424', 'Gene', '494336', (77, 84))	('Z30', 'Gene', '692076', (106, 109))	('miR-874', 'Gene', '100126343', (86, 93))	('miR-181b', 'Var', (67, 75))
128311	22745731	Classifying miRNA pairs with coefficients >=0.60 as co-expressed, we identified this characteristic co-expression feature among the four miRNAs miR-101, miR-125a-5p, miR-151-5p and miR-324-3p as well as between miR-148 and miR-151-3p, and between miR-181a and miR-181b.	('miR-101', 'Chemical', '-', (144, 151))	('miR-101', 'Var', (144, 151))	('miR-151', 'Gene', '442893', (223, 230))	('miR-125a', 'Gene', (153, 161))	('miR-181b', 'Var', (260, 268))	('miR-151', 'Gene', (166, 173))	('miR-324', 'Gene', (181, 188))	('miR-151', 'Gene', '442893', (166, 173))	('miR-125a', 'Gene', '406910', (153, 161))	('miR-181a', 'Var', (247, 255))	('miR-148', 'Var', (211, 218))	('miR-324', 'Gene', '442898', (181, 188))	('miR-151', 'Gene', (223, 230))
128312	22745731	The correlation between miR-101, miR-151-5p, and miR-324-3p was remarkable.	('miR-151', 'Gene', '442893', (33, 40))	('miR-101', 'Var', (24, 31))	('miR-324', 'Gene', (49, 56))	('miR-151', 'Gene', (33, 40))	('miR-324', 'Gene', '442898', (49, 56))	('miR-101', 'Chemical', '-', (24, 31))
128314	22745731	Differences in expression between low-grade and high-grade tumors were found for miR-29c (down-regulated, P = 0.005), miR-874 (down-regulated, P = 0.019), miR-181a (up-regulated, P = 0.031), and miR-181b (up-regulated, P = 0.0008), while all other miRNAs were not differentially expressed (P values from 0.092 to 0.826).	('down-regulated', 'NegReg', (127, 141))	('miR-874', 'Gene', '100126343', (118, 125))	('miR-29c', 'Gene', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('miR-181b', 'Var', (195, 203))	('miR-29c', 'Gene', '407026', (81, 88))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('down-regulated', 'NegReg', (90, 104))	('expression', 'MPA', (15, 25))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('miR-874', 'Gene', (118, 125))	('miR-181a', 'Var', (155, 163))
128315	22745731	miR-181a (M = 1.511) showed the highest M value, whereas miR-151-5p (M = 0.622) and miR-125a-5p (M = 0.663) showed the lowest M values.	('miR-125a', 'Gene', (84, 92))	('miR-151', 'Gene', '442893', (57, 64))	('miR-151', 'Gene', (57, 64))	('miR-125a', 'Gene', '406910', (84, 92))	('miR-181a', 'Var', (0, 8))
128316	22745731	Consequently, miR-181a had the least stable expression while miR-125a-5p and miR-151-5p had the most stable expression.	('miR-181a', 'Var', (14, 22))	('expression', 'MPA', (44, 54))	('least', 'NegReg', (31, 36))	('miR-151', 'Gene', '442893', (77, 84))	('miR-125a', 'Gene', (61, 69))	('miR-151', 'Gene', (77, 84))	('miR-125a', 'Gene', '406910', (61, 69))
128318	22745731	NormFinder ranked the four best reference genes for normalization as miR-148, miR-874, miR-181b, and Z30.	('Z30', 'Gene', '692076', (101, 104))	('miR-874', 'Gene', (78, 85))	('miR-148', 'Var', (69, 76))	('miR-874', 'Gene', '100126343', (78, 85))	('miR-181b', 'Var', (87, 95))	('Z30', 'Gene', (101, 104))
128329	22745731	The NormFinder recommended approaches were the following: (d) the best two reference gene combination (miR-125a-5p and Z30); (e) the three best ranked reference miRNAs (miR-148b, miR-181b, and miR-874), and (f) the best single miRNA miR-148b.	('miR-125a', 'Gene', (103, 111))	('Z30', 'Gene', (119, 122))	('miR-148b', 'Gene', (233, 241))	('miR-874', 'Gene', (193, 200))	('miR-874', 'Gene', '100126343', (193, 200))	('miR-125a', 'Gene', '406910', (103, 111))	('miR-181b', 'Var', (179, 187))	('miR-148b', 'Gene', '442892', (169, 177))	('Z30', 'Gene', '692076', (119, 122))	('miR-148b', 'Gene', (169, 177))	('miR-148b', 'Gene', '442892', (233, 241))
128335	22745731	Thus, although all reference miRNA suggestions by geNorm and NormFinder were obviously suited to be appropriate for normalization, we recommend the use of more than two reference miRNAs preferring the use of four miRNAs (miR-101, miR-148b, miR-125a-5p, and miR-151-5p) as recommended by geNorm or the combination of three miRNAs (miR-148b, miR-181b, and miR-874) suggested by NormFinder.	('miR-148b', 'Gene', (230, 238))	('miR-874', 'Gene', (354, 361))	('miR-125a', 'Gene', '406910', (240, 248))	('miR-148b', 'Gene', (330, 338))	('miR-101', 'Chemical', '-', (221, 228))	('miR-181b', 'Var', (340, 348))	('miR-101', 'Var', (221, 228))	('miR-125a', 'Gene', (240, 248))	('miR-151', 'Gene', '442893', (257, 264))	('miR-151', 'Gene', (257, 264))	('miR-148b', 'Gene', '442892', (330, 338))	('miR-148b', 'Gene', '442892', (230, 238))	('miR-874', 'Gene', '100126343', (354, 361))
128357	22745731	However, we recommend the combination of four (miR-101, miR-125a-5p, miR-148b, and miR-151-5p) or three (miR-148b, miR-181b, and miR-874) reference miRNAs.	('miR-125a', 'Gene', (56, 64))	('miR-151', 'Gene', '442893', (83, 90))	('miR-151', 'Gene', (83, 90))	('miR-874', 'Gene', (129, 136))	('miR-148b', 'Gene', (69, 77))	('miR-125a', 'Gene', '406910', (56, 64))	('miR-148b', 'Gene', '442892', (105, 113))	('miR-101', 'Chemical', '-', (47, 54))	('miR-874', 'Gene', '100126343', (129, 136))	('miR-148b', 'Gene', (105, 113))	('miR-181b', 'Var', (115, 123))	('miR-101', 'Var', (47, 54))	('miR-148b', 'Gene', '442892', (69, 77))
128419	33468084	Animal studies suggested that dimethylarsinic acid (DMAV) could induce bladder carcinogenesis in rats with the generation of a reactive metabolite (DMA (II I)).	('bladder carcinogenesis', 'Disease', 'MESH:D001749', (71, 93))	('induce', 'PosReg', (64, 70))	('DMA', 'Chemical', 'MESH:C405765', (148, 151))	('bladder carcinogenesis', 'Disease', (71, 93))	('dimethylarsinic acid', 'Var', (30, 50))	('DMA', 'Chemical', 'MESH:C405765', (52, 55))	('dimethylarsinic acid', 'Chemical', 'MESH:D002101', (30, 50))	('DMAV', 'Chemical', '-', (52, 56))
128445	32486001	Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are important immune checkpoint molecules, and blocking PD-1/PD-L1 reduces the tumor burden and indicate promising outcomes in many tumor types.	('ligand', 'molecular_function', 'GO:0005488', ('65', '71'))	('PD-1/PD-L1 reduces the tumor', 'Disease', 'MESH:D010300', (138, 166))	('PD-L1', 'Gene', '574058', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('programmed cell death ligand 1', 'Gene', '574058', (43, 73))	('Programmed cell death protein 1', 'Gene', '100533201', (0, 31))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('PD-L1', 'Gene', (143, 148))	('programmed cell death', 'biological_process', 'GO:0012501', ('43', '64'))	('PD-1/PD-L1 reduces the tumor', 'Disease', (138, 166))	('Programmed cell death', 'biological_process', 'GO:0012501', ('0', '21'))	('PD-L1', 'Gene', '574058', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (214, 219))	('blocking', 'Var', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('PD-L1', 'Gene', (75, 80))	('Programmed cell death protein 1', 'Gene', (0, 31))	('programmed cell death ligand 1', 'Gene', (43, 73))
128448	32486001	Growing evidence points to the aberrant activity of STAT3 in cancer providing a potential therapeutic option.	('STAT3', 'Gene', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('aberrant activity', 'Var', (31, 48))
128495	32486001	Similarly, the moderate or strong correlations between STAT3 and infiltrating levels were shown, involving neutrophils (r = 0.47) and DC (r = 0.476) in COAD; B-cell (r = 0.534) and DC (r = 0.742) in KICH; neutrophils (r = 0.411) in KIRC; CD8+ T-cells (r = 0.567), macrophages (r = 0.497), neutrophils (r = 0.505) and DCs (r = 0.502) in PRAD; DCs (r = 0.463) in READ (Figure 3).	('COAD', 'Disease', 'MESH:D029424', (152, 156))	('KICH', 'Disease', (199, 203))	('r = 0.502', 'Var', (322, 331))	('KICH', 'Disease', 'None', (199, 203))	('COAD', 'Disease', (152, 156))	('CD8', 'Gene', (238, 241))	('CD8', 'Gene', '925', (238, 241))
128538	32486001	Several compounds were targeting the PI3K/AKT pathway, such as rigosertib, MK-2206, AZD6482, TGX-221, NVP-BEZ235, and targeting the JAK/STAT pathway, like ruxolitinib and AZD1480, which were significantly correlated to STAT3 expression in cancer cell lines.	('AZD1480', 'Chemical', 'MESH:C545606', (171, 178))	('JAK', 'molecular_function', 'GO:0004713', ('132', '135'))	('STAT', 'Gene', '6772;6774;20848;6775', (136, 140))	('AKT', 'Gene', '207', (42, 45))	('STAT', 'Gene', (136, 140))	('PI3K', 'molecular_function', 'GO:0016303', ('37', '41'))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('AZD6482', 'Var', (84, 91))	('ruxolitinib', 'Chemical', 'MESH:C540383', (155, 166))	('rigosertib', 'Chemical', 'MESH:C507134', (63, 73))	('STAT', 'Gene', '6772;6774;20848;6775', (219, 223))	('rigosertib', 'Gene', (63, 73))	('targeting', 'Reg', (23, 32))	('AKT', 'Gene', (42, 45))	('AZD6482', 'Chemical', 'MESH:C578518', (84, 91))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('MK-2206', 'Var', (75, 82))	('MK-2206', 'Chemical', 'MESH:C548887', (75, 82))	('STAT', 'Gene', (219, 223))
128555	32486001	The expression level of p-STAT3 could reflect the activity in cancer progression better than total STAT3 protein expression.	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('expression', 'MPA', (4, 14))	('p-STAT3', 'Var', (24, 31))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
128601	32486001	Based on the above findings, we made the conclusion that STAT3 was particularly correlated with immune suppression in the tumor microenvironment.	('correlated', 'Reg', (80, 90))	('immune suppression', 'CPA', (96, 114))	('STAT3', 'Var', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
128614	28881595	Kaplan-Meier survival analysis demonstrated that patients exhibiting high Kindlin-2 expression had shorter survival times than those with low Kindlin-2 expression (p < 0.01).	('shorter', 'NegReg', (99, 106))	('Kindlin-2', 'Gene', '10979', (142, 151))	('Kindlin-2', 'Gene', (74, 83))	('survival times', 'CPA', (107, 121))	('Kindlin-2', 'Gene', '10979', (74, 83))	('high', 'Var', (69, 73))	('patients', 'Species', '9606', (49, 57))	('Kindlin-2', 'Gene', (142, 151))
128615	28881595	Multivariate analysis revealed that high Kindlin-2 expression leads to poor prognosis in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('expression', 'MPA', (51, 61))	('high', 'Var', (36, 40))	('Kindlin-2', 'Gene', (41, 50))	('Kindlin-2', 'Gene', '10979', (41, 50))
128616	28881595	Using cancer-associated fibroblasts (CAFs) isolated from human bladder cancer tissue, we observed that Kindlin-2 knockdown decreased CAFs activation, resulting in decreased expression of alpha-smooth muscle actin (alpha-SMA) and the extracellular matrix protein fibronectin.	('decreased', 'NegReg', (123, 132))	('CAF', 'Gene', (133, 136))	('CAF', 'Gene', '8850', (37, 40))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('human', 'Species', '9606', (57, 62))	('fibronectin', 'Gene', (262, 273))	('CAF', 'Gene', (37, 40))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Kindlin-2', 'Gene', (103, 112))	('alpha-smooth muscle actin', 'Protein', (187, 212))	('bladder cancer', 'Disease', 'MESH:D001749', (63, 77))	('bladder cancer', 'Disease', (63, 77))	('bladder cancer', 'Phenotype', 'HP:0009725', (63, 77))	('activation', 'MPA', (138, 148))	('knockdown', 'Var', (113, 122))	('protein', 'cellular_component', 'GO:0003675', ('254', '261'))	('expression', 'MPA', (173, 183))	('fibronectin', 'Gene', '2335', (262, 273))	('cancer', 'Disease', (6, 12))	('Kindlin-2', 'Gene', '10979', (103, 112))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('233', '253'))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('CAF', 'Gene', '8850', (133, 136))	('decreased', 'NegReg', (163, 172))
128629	28881595	However, high stromal expression of Kindlin-2 is correlated with poor prognosis in patients with pancreatic ductal adenocarcinomas, and stimulates cancer progression and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('stimulates', 'PosReg', (136, 146))	('pancreatic ductal adenocarcinomas', 'Disease', (97, 130))	('patients', 'Species', '9606', (83, 91))	('metastasis', 'CPA', (170, 180))	('Kindlin-2', 'Gene', (36, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('Kindlin-2', 'Gene', '10979', (36, 45))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (97, 130))	('cancer', 'Disease', (147, 153))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('high', 'Var', (9, 13))
128639	28881595	However, high expression of Kindlin-2 in bladder cancer samples was positively correlated with high grade (p < 0.001), advanced stage (p = 0.011), and recurrence (p = 0.023).	('Kindlin-2', 'Gene', '10979', (28, 37))	('high grade', 'CPA', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('bladder cancer', 'Phenotype', 'HP:0009725', (41, 55))	('Kindlin-2', 'Gene', (28, 37))	('advanced stage', 'CPA', (119, 133))	('correlated', 'Reg', (79, 89))	('recurrence', 'CPA', (151, 161))	('bladder cancer', 'Disease', 'MESH:D001749', (41, 55))	('bladder cancer', 'Disease', (41, 55))	('high', 'Var', (9, 13))
128642	28881595	As presented in Figure 2A, patients with high Kindlin-2 expression had a worse overall survival (OS) than those with low Kindlin-2 expression (p < 0.001).	('Kindlin-2', 'Gene', (46, 55))	('Kindlin-2', 'Gene', '10979', (121, 130))	('Kindlin-2', 'Gene', '10979', (46, 55))	('high', 'Var', (41, 45))	('worse', 'NegReg', (73, 78))	('patients', 'Species', '9606', (27, 35))	('Kindlin-2', 'Gene', (121, 130))	('overall survival', 'MPA', (79, 95))
128643	28881595	Moreover, cancer-specific survival (Figure 2B) and disease-free survival (Figure 2C) were shorter in patients with high Kindlin-2 expression than those with low Kindlin-2 expression (both p < 0.01).	('high', 'Var', (115, 119))	('expression', 'MPA', (130, 140))	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('shorter', 'NegReg', (90, 97))	('disease-free survival', 'CPA', (51, 72))	('Kindlin-2', 'Gene', (120, 129))	('Kindlin-2', 'Gene', (161, 170))	('Kindlin-2', 'Gene', '10979', (120, 129))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('Kindlin-2', 'Gene', '10979', (161, 170))	('cancer', 'Disease', (10, 16))
128658	28881595	Compared with control, Kindlin-2 knockdown in CAFs resulted in decreased alpha-SMA, fibroblast activation protein (FAP), vimentin, and fibronectin (Figure 3E and 3F).	('FAP', 'Gene', (115, 118))	('fibroblast activation protein', 'Gene', '2191', (84, 113))	('fibroblast activation', 'biological_process', 'GO:0072537', ('84', '105'))	('vimentin', 'Gene', '7431', (121, 129))	('alpha-SMA', 'MPA', (73, 82))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('vimentin', 'Gene', (121, 129))	('decreased', 'NegReg', (63, 72))	('fibronectin', 'Gene', (135, 146))	('FAP', 'Gene', '2191', (115, 118))	('vimentin', 'cellular_component', 'GO:0045098', ('121', '129'))	('Kindlin-2', 'Gene', (23, 32))	('knockdown', 'Var', (33, 42))	('fibroblast activation protein', 'Gene', (84, 113))	('fibronectin', 'Gene', '2335', (135, 146))	('CAF', 'Gene', '8850', (46, 49))	('Kindlin-2', 'Gene', '10979', (23, 32))	('vimentin', 'cellular_component', 'GO:0045099', ('121', '129'))	('CAF', 'Gene', (46, 49))
128661	28881595	We examined whether CAFs can induce an attenuated effect on bladder cancer cell migration and invasion after Kindlin-2 knockdown.	('invasion', 'CPA', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('Kindlin-2', 'Gene', (109, 118))	('CAF', 'Gene', (20, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (60, 74))	('attenuated', 'NegReg', (39, 49))	('bladder cancer', 'Disease', (60, 74))	('knockdown', 'Var', (119, 128))	('CAF', 'Gene', '8850', (20, 23))	('Kindlin-2', 'Gene', '10979', (109, 118))	('cell migration', 'biological_process', 'GO:0016477', ('75', '89'))
128663	28881595	In the transwell experiments, both the T24 and 5637 cells co-cultured with shK-treated CAFs had fewer migrated and invaded cells than the cells co-cultured with shNC-treated CAF (Figure 4B and 4C).	('fewer', 'NegReg', (96, 101))	('CAF', 'Gene', '8850', (87, 90))	('CAF', 'Gene', (174, 177))	('CAF', 'Gene', '8850', (174, 177))	('CAF', 'Gene', (87, 90))	('shK-treated', 'Var', (75, 86))
128672	28881595	After 72 h co-culture, we observed that Kindlin-2 knockdown decreased the mRNA expression of the epithelial marker E-cadherin, but increased expression of N-cadherin and vimentin (Figure 5B).	('decreased', 'NegReg', (60, 69))	('increased', 'PosReg', (131, 140))	('vimentin', 'Gene', '7431', (170, 178))	('vimentin', 'cellular_component', 'GO:0045098', ('170', '178'))	('knockdown', 'Var', (50, 59))	('vimentin', 'Gene', (170, 178))	('cadherin', 'molecular_function', 'GO:0008014', ('157', '165'))	('N-cadherin', 'Gene', (155, 165))	('Kindlin-2', 'Gene', (40, 49))	('Kindlin-2', 'Gene', '10979', (40, 49))	('expression', 'MPA', (141, 151))	('N-cadherin', 'Gene', '1000', (155, 165))	('cadherin', 'molecular_function', 'GO:0008014', ('117', '125'))	('vimentin', 'cellular_component', 'GO:0045099', ('170', '178'))	('E-cadherin', 'Gene', (115, 125))	('E-cadherin', 'Gene', '999', (115, 125))
128673	28881595	Decreased bladder cancer cell migration and invasion from Kindlin-2 knockdown can be rescued by addition of TGF-beta1 (Figure 6A and 6B).	('Kindlin-2', 'Gene', '10979', (58, 67))	('Decreased bladder cancer', 'Disease', (0, 24))	('Decreased bladder cancer', 'Disease', 'MESH:D001749', (0, 24))	('cell migration', 'biological_process', 'GO:0016477', ('25', '39'))	('TGF-beta1', 'Gene', '7040', (108, 117))	('invasion', 'CPA', (44, 52))	('Decreased bladder', 'Phenotype', 'HP:0005343', (0, 17))	('TGF-beta1', 'Gene', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('bladder cancer', 'Phenotype', 'HP:0009725', (10, 24))	('knockdown', 'Var', (68, 77))	('Kindlin-2', 'Gene', (58, 67))
128678	28881595	Kaplan-Meier survival curves and log-rank tests revealed that high Kindlin-2 expression was also correlated with the cancer-specific survival, disease-free survival, and overall survival of patients with bladder cancer (Figure 2).	('expression', 'MPA', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('bladder cancer', 'Disease', (204, 218))	('disease-free survival', 'CPA', (143, 164))	('cancer', 'Disease', (117, 123))	('patients', 'Species', '9606', (190, 198))	('Kindlin-2', 'Gene', (67, 76))	('Kindlin-2', 'Gene', '10979', (67, 76))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('bladder cancer', 'Phenotype', 'HP:0009725', (204, 218))	('correlated with', 'Reg', (97, 112))	('high', 'Var', (62, 66))	('bladder cancer', 'Disease', 'MESH:D001749', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
128682	28881595	Markers of CAF such as alpha-SMA, FAP, and vimentin were reduced upon knockdown of Kindlin-2 in CAFs.	('Kindlin-2', 'Gene', '10979', (83, 92))	('vimentin', 'cellular_component', 'GO:0045098', ('43', '51'))	('FAP', 'Gene', '2191', (34, 37))	('knockdown', 'Var', (70, 79))	('CAF', 'Gene', (11, 14))	('vimentin', 'cellular_component', 'GO:0045099', ('43', '51'))	('CAF', 'Gene', (96, 99))	('vimentin', 'Gene', '7431', (43, 51))	('vimentin', 'Gene', (43, 51))	('alpha-SMA', 'Disease', (23, 32))	('Kindlin-2', 'Gene', (83, 92))	('reduced', 'NegReg', (57, 64))	('FAP', 'Gene', (34, 37))	('CAF', 'Gene', '8850', (11, 14))	('CAF', 'Gene', '8850', (96, 99))
128683	28881595	The expression of extracellular matrix protein fibronectin was also suppressed following depletion of Kindlin-2.	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('depletion', 'Var', (89, 98))	('fibronectin', 'Gene', '2335', (47, 58))	('suppressed', 'NegReg', (68, 78))	('Kindlin-2', 'Gene', (102, 111))	('Kindlin-2', 'Gene', '10979', (102, 111))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('18', '38'))	('fibronectin', 'Gene', (47, 58))
128687	28881595	The data showed that CAFs enhance the migration of T24 and 5637 cells, and Kindlin-2 knockdown in CAFs abolished CAF-induced cancer cell migration.	('CAF', 'Gene', (98, 101))	('CAF', 'Gene', (113, 116))	('abolished', 'NegReg', (103, 112))	('Kindlin-2', 'Gene', (75, 84))	('CAF', 'Gene', '8850', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('CAF', 'Gene', (21, 24))	('CAF', 'Gene', '8850', (98, 101))	('cell migration', 'biological_process', 'GO:0016477', ('132', '146'))	('knockdown', 'Var', (85, 94))	('Kindlin-2', 'Gene', '10979', (75, 84))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('CAF', 'Gene', '8850', (21, 24))	('migration', 'CPA', (38, 47))	('enhance', 'PosReg', (26, 33))
128693	28881595	In our study, TGF-beta1secretion by CAFs decreased following Kindlin-2 knockdown, and cell migration and invasion capacity were suppressed.	('TGF-beta1', 'Gene', '7040', (14, 23))	('TGF-beta1', 'Gene', (14, 23))	('CAF', 'Gene', '8850', (36, 39))	('decreased', 'NegReg', (41, 50))	('Kindlin-2', 'Gene', (61, 70))	('knockdown', 'Var', (71, 80))	('Kindlin-2', 'Gene', '10979', (61, 70))	('suppressed', 'NegReg', (128, 138))	('secretion', 'biological_process', 'GO:0046903', ('23', '32'))	('cell migration', 'biological_process', 'GO:0016477', ('86', '100'))	('CAF', 'Gene', (36, 39))
128698	28881595	In this study, the results showed that knocking down Kindlin-2 in CAFs led to increased E-cadherin expression, and decreased N-cadherin and vimentin expression in co-cultured bladder cancer cells.	('expression', 'MPA', (99, 109))	('Kindlin-2', 'Gene', '10979', (53, 62))	('bladder cancer', 'Disease', 'MESH:D001749', (175, 189))	('bladder cancer', 'Disease', (175, 189))	('CAF', 'Gene', '8850', (66, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (175, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('CAF', 'Gene', (66, 69))	('vimentin', 'cellular_component', 'GO:0045098', ('140', '148'))	('knocking down', 'Var', (39, 52))	('E-cadherin', 'Gene', (88, 98))	('E-cadherin', 'Gene', '999', (88, 98))	('cadherin', 'molecular_function', 'GO:0008014', ('127', '135'))	('expression', 'MPA', (149, 159))	('cadherin', 'molecular_function', 'GO:0008014', ('90', '98'))	('Kindlin-2', 'Gene', (53, 62))	('decreased', 'NegReg', (115, 124))	('vimentin', 'cellular_component', 'GO:0045099', ('140', '148'))	('N-cadherin', 'Gene', (125, 135))	('increased', 'PosReg', (78, 87))	('vimentin', 'Gene', '7431', (140, 148))	('N-cadherin', 'Gene', '1000', (125, 135))	('vimentin', 'Gene', (140, 148))
128699	28881595	However, the inhibition effect in co-cultured bladder cancer cells following Kindlin-2 knockdown in CAFs can be rescued by addition of TGF-beta1.	('Kindlin-2', 'Gene', (77, 86))	('TGF-beta1', 'Gene', '7040', (135, 144))	('bladder cancer', 'Disease', 'MESH:D001749', (46, 60))	('bladder cancer', 'Disease', (46, 60))	('TGF-beta1', 'Gene', (135, 144))	('CAF', 'Gene', (100, 103))	('Kindlin-2', 'Gene', '10979', (77, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('CAF', 'Gene', '8850', (100, 103))	('knockdown', 'Var', (87, 96))
128727	28881595	To knockdown Kindlin-2 in CAFs, we employed the lentivirus infection strategy.	('CAF', 'Gene', (26, 29))	('lentivirus infection', 'Disease', 'MESH:D016180', (48, 68))	('knockdown', 'Var', (3, 12))	('CAF', 'Gene', '8850', (26, 29))	('Kindlin-2', 'Gene', (13, 22))	('Kindlin-2', 'Gene', '10979', (13, 22))	('lentivirus infection', 'Disease', (48, 68))
128741	28881595	The primary antibodies used for western blot were anti-Kindlin-2 antibody (1:3000; Santa Cruz, CA, USA), alpha-SMA (1:2000; Sigma, MO, USA), vimentin (1:2000; Santa Cruz, CA, USA), E-cadherin (1:300; Abcam, Cambridge, UK), N-cadherin (1:1000; Cell Signalling, MA, USA) and beta-actin (1:2000; Santa Cruz, CA, USA).	('antibody', 'cellular_component', 'GO:0042571', ('65', '73'))	('Kindlin-2', 'Gene', '10979', (55, 64))	('cadherin', 'molecular_function', 'GO:0008014', ('183', '191'))	('vimentin', 'cellular_component', 'GO:0045098', ('141', '149'))	('Cell Signalling', 'CPA', (243, 258))	('beta-actin', 'Gene', (273, 283))	('antibody', 'cellular_component', 'GO:0019815', ('65', '73'))	('1:2000;', 'Var', (285, 292))	('cadherin', 'molecular_function', 'GO:0008014', ('225', '233'))	('1:1000;', 'Var', (235, 242))	('vimentin', 'cellular_component', 'GO:0045099', ('141', '149'))	('N-cadherin', 'Gene', (223, 233))	('N-cadherin', 'Gene', '1000', (223, 233))	('antibody', 'cellular_component', 'GO:0019814', ('65', '73'))	('vimentin', 'Gene', '7431', (141, 149))	('Kindlin-2', 'Gene', (55, 64))	('Signalling', 'biological_process', 'GO:0023052', ('248', '258'))	('beta-actin', 'Gene', '728378', (273, 283))	('vimentin', 'Gene', (141, 149))	('E-cadherin', 'Gene', (181, 191))	('E-cadherin', 'Gene', '999', (181, 191))	('antibody', 'molecular_function', 'GO:0003823', ('65', '73'))
128769	28449665	Final pathology report showed three high-grade tumor foci in the bladder with the largest being high-grade urothelial carcinoma located in the right lateral wall measuring 2.8 cm, another tumor located in the posterior wall measuring 0.9 cm with areas of squamous differentiation, and the smallest tumor located at the dome measuring 0.6 cm with pathology consistent with LEL urothelial carcinoma.	('tumor', 'Disease', (188, 193))	('high-grade', 'Var', (96, 106))	('tumor', 'Disease', (298, 303))	('LEL urothelial carcinoma', 'Disease', (372, 396))	('LEL urothelial carcinoma', 'Disease', 'MESH:D014526', (372, 396))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (387, 396))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (107, 127))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (376, 396))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('tumor', 'Disease', (47, 52))	('urothelial carcinoma', 'Disease', (107, 127))
128807	33628089	Conclusions: HNF4a plays different roles in different malignancies, and the abnormal expression of HNF4a has a great correlation with the biological characteristics of BLCA.	('expression', 'MPA', (85, 95))	('malignancies', 'Disease', (54, 66))	('BLCA', 'Disease', (168, 172))	('abnormal', 'Var', (76, 84))	('malignancies', 'Disease', 'MESH:D009369', (54, 66))	('correlation', 'Reg', (117, 128))	('HNF4a', 'Gene', (99, 104))
128812	33628089	It has been shown that HNF4a can not only reduce or inhibit cell proliferation but can also accelerate the differentiation speed of poorly differentiated liver cancer by re-expressing HNF4a in liver cancer and maintaining a highly differentiated phenotype, which reduces its invasiveness.	('cell proliferation', 'CPA', (60, 78))	('liver cancer', 'Disease', 'MESH:D006528', (193, 205))	('re-expressing', 'Var', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('liver cancer', 'Disease', 'MESH:D006528', (154, 166))	('liver cancer', 'Phenotype', 'HP:0002896', (193, 205))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('reduces', 'NegReg', (263, 270))	('maintaining', 'Reg', (210, 221))	('accelerate', 'PosReg', (92, 102))	('liver cancer', 'Disease', (193, 205))	('differentiation speed', 'CPA', (107, 128))	('liver cancer', 'Phenotype', 'HP:0002896', (154, 166))	('HNF4a', 'Gene', (184, 189))	('liver cancer', 'Disease', (154, 166))	('reduce', 'NegReg', (42, 48))	('invasiveness', 'CPA', (275, 287))	('inhibit', 'NegReg', (52, 59))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))
128825	33628089	It was shown in our study that patients with high HNF4a expression showed a significantly longer overall survival (OS, p < 0.05) than patients with low HNF4a expression in BLCA, KIRC, and READ, while patients with high expression of HNF4a exhibited a significantly shorter OS (p < 0.05) than patients with low expression of HNF4a in LUSC (Figure 1).	('patients', 'Species', '9606', (200, 208))	('overall survival', 'MPA', (97, 113))	('patients', 'Species', '9606', (134, 142))	('high', 'Var', (45, 49))	('longer', 'PosReg', (90, 96))	('patients', 'Species', '9606', (31, 39))	('HNF4a', 'Gene', (50, 55))	('patients', 'Species', '9606', (292, 300))
128853	33628089	The overall survival time of patients with high expression of the HNF4a protein is long, whereas, the overall survival time of patients with low HNF4a protein expression is short.	('patients', 'Species', '9606', (29, 37))	('HNF4a', 'Gene', (66, 71))	('high', 'Var', (43, 47))	('expression', 'MPA', (48, 58))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('patients', 'Species', '9606', (127, 135))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))
128910	29984253	Moreover, intravesical treatment with CDC and CDC+BCG results in a lower percentage of tumors (60% and 68%, respectively) compared to BCG (75%) or control (85%).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CDC+BCG', 'Var', (46, 53))	('CDC', 'Var', (38, 41))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('lower', 'NegReg', (67, 72))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
128979	29725469	The presence of Survivin was able to discriminate bladder cancer from benign disease.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Survivin', 'Protein', (16, 24))	('bladder cancer', 'Disease', 'MESH:D001749', (50, 64))	('bladder cancer', 'Disease', (50, 64))	('discriminate', 'Reg', (37, 49))	('presence', 'Var', (4, 12))	('benign disease', 'Disease', (70, 84))	('bladder cancer', 'Phenotype', 'HP:0009725', (50, 64))	('benign disease', 'Disease', 'MESH:D009369', (70, 84))
129185	33925460	reported that AZ7328, an AKT inhibitor, induced autophagy in human bladder cancer cell lines, which protected cancer cells from AZ7328-induced apoptosis.	('autophagy', 'CPA', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('AKT', 'Gene', '207', (25, 28))	('induced', 'Reg', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('AZ7328', 'Var', (14, 20))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('AZ7328', 'Chemical', '-', (14, 20))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('cancer', 'Disease', (110, 116))	('autophagy', 'biological_process', 'GO:0016236', ('48', '57'))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('human', 'Species', '9606', (61, 66))	('AKT', 'Gene', (25, 28))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('cancer', 'Disease', (75, 81))	('autophagy', 'biological_process', 'GO:0006914', ('48', '57'))	('AZ7328', 'Chemical', '-', (128, 134))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
129196	33925460	By analyzing RNA-seq data of bladder cancer patients and their clinical follow-up information, obtained from TCGA, we identified the prognosis-related ARGs that were highly associated with overall survival.	('patients', 'Species', '9606', (44, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (29, 43))	('bladder cancer', 'Disease', (29, 43))	('overall', 'MPA', (189, 196))	('associated with', 'Reg', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('ARGs', 'Chemical', '-', (151, 155))	('ARGs', 'Var', (151, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (29, 43))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))
129232	33925460	Univariate Cox regression analysis showed that API was significantly associated with patient prognosis in both training cohorts (p-value <0.001) and validation cohorts (p-value < 0.001) (Table 3, Figure 4A).	('API', 'Var', (47, 50))	('associated with', 'Reg', (69, 84))	('patient', 'Species', '9606', (85, 92))	('patient prognosis', 'CPA', (85, 102))
129240	33925460	For example, a 60-year-old stage II BLCA patient with API of -2 would yield a total of 87.5 (10 points for age, 27.5 points for stage II, and 50 for -2 API score), with predicted 1-year, 3-year, and 5-year overall survival rates around 0.92, 0.80, and 0.73.	('API of -2', 'Var', (54, 63))	('age', 'Gene', (130, 133))	('age', 'Gene', '5973', (29, 32))	('patient', 'Species', '9606', (41, 48))	('age', 'Gene', '5973', (130, 133))	('age', 'Gene', (107, 110))	('age', 'Gene', (29, 32))	('age', 'Gene', '5973', (107, 110))
129252	33925460	In the context of cancer, dysfunction of autophagy may lead to increased free radicals and aggregated macromolecules, which may result in elevated DNA damage, mutation, metabolic deficiencies, and global cellular damage.	('increased', 'PosReg', (63, 72))	('free radicals', 'MPA', (73, 86))	('age', 'Gene', (154, 157))	('autophagy', 'CPA', (41, 50))	('metabolic deficiencies', 'Disease', 'MESH:D024821', (169, 191))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('autophagy', 'biological_process', 'GO:0016236', ('41', '50'))	('age', 'Gene', (216, 219))	('elevated', 'PosReg', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('age', 'Gene', '5973', (154, 157))	('autophagy', 'biological_process', 'GO:0006914', ('41', '50'))	('dysfunction', 'Var', (26, 37))	('age', 'Gene', '5973', (216, 219))	('mutation', 'MPA', (159, 167))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('metabolic deficiencies', 'Disease', (169, 191))
129253	33925460	On the other hand, abnormal autophagy could help cancer cells resistant to cell death.	('autophagy', 'CPA', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('help', 'PosReg', (44, 48))	('cell death', 'biological_process', 'GO:0008219', ('75', '85'))	('autophagy', 'biological_process', 'GO:0016236', ('28', '37'))	('abnormal', 'Var', (19, 27))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('death', 'Disease', 'MESH:D003643', (80, 85))	('death', 'Disease', (80, 85))	('autophagy', 'biological_process', 'GO:0006914', ('28', '37'))	('cancer', 'Disease', (49, 55))
129255	33925460	In the present study, we identified 32 ARGs that were significantly associated with the overall survival of bladder cancer patients.	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('bladder cancer', 'Disease', (108, 122))	('associated with', 'Reg', (68, 83))	('ARGs', 'Chemical', '-', (39, 43))	('ARGs', 'Var', (39, 43))	('patients', 'Species', '9606', (123, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
129279	33925460	APOL1 genetic variants are reported to be a major drive of kidney diseases, but their function in bladder cancer has not been reported.	('kidney diseases', 'Disease', 'MESH:D007674', (59, 74))	('APOL1', 'Gene', '8542', (0, 5))	('kidney diseases', 'Phenotype', 'HP:0000112', (59, 74))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('genetic variants', 'Var', (6, 22))	('kidney diseases', 'Disease', (59, 74))	('function in bladder', 'Phenotype', 'HP:0000009', (86, 105))	('APOL1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
129283	33925460	Silencing ITGA3 inhibited tumor cell migration and invasion through regulating FAK/PI3K/AKT and FAK/Src signaling mechanisms.	('ITGA3', 'Gene', '3675', (10, 15))	('Silencing', 'Var', (0, 9))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('AKT', 'Gene', '207', (88, 91))	('Src', 'Gene', (100, 103))	('FAK', 'Gene', (96, 99))	('tumor', 'Disease', (26, 31))	('ITGA3', 'Gene', (10, 15))	('cell migration', 'biological_process', 'GO:0016477', ('32', '46'))	('regulating', 'Reg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('Src', 'Gene', '6714', (100, 103))	('FAK', 'Gene', '5747', (96, 99))	('FAK', 'Gene', (79, 82))	('FAK', 'molecular_function', 'GO:0004717', ('79', '82'))	('inhibited', 'NegReg', (16, 25))	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('FAK', 'molecular_function', 'GO:0004717', ('96', '99'))	('FAK', 'Gene', '5747', (79, 82))	('AKT', 'Gene', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))
129285	33925460	ULK2 knockdown inhibited autophagy and apoptosis in bladder cancer cells.	('inhibited', 'NegReg', (15, 24))	('apoptosis', 'CPA', (39, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('knockdown', 'Var', (5, 14))	('ULK2', 'Gene', '9706', (0, 4))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('autophagy', 'biological_process', 'GO:0016236', ('25', '34'))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('bladder cancer', 'Disease', (52, 66))	('ULK2', 'Gene', (0, 4))	('autophagy', 'biological_process', 'GO:0006914', ('25', '34'))
129290	33925460	P4HB was found to be significantly correlated with a high frequency of TP53 mutations in glioma cells.	('correlated', 'Reg', (35, 45))	('P4HB', 'Gene', (0, 4))	('mutations', 'Var', (76, 85))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('glioma', 'Disease', (89, 95))	('P4HB', 'Gene', '5034', (0, 4))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))
129291	33925460	It is worth noting that high TP53 mutations is a hallmark of muscle-invasive bladder cancer.	('invasive bladder', 'Phenotype', 'HP:0100645', (68, 84))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (61, 91))	('muscle-invasive bladder cancer', 'Disease', (61, 91))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('high', 'Var', (24, 28))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (34, 43))
129295	33925460	Despite the favorable survival rate observed in the high expression group of DRAM1, BAG1, and KLHL24, the correlations are less significant.	('survival', 'CPA', (22, 30))	('KLHL24', 'Gene', (94, 100))	('favorable', 'PosReg', (12, 21))	('KLHL24', 'Gene', '54800', (94, 100))	('BAG1', 'Gene', (84, 88))	('DRAM1', 'Gene', (77, 82))	('high expression', 'Var', (52, 67))	('DRAM1', 'Gene', '55332', (77, 82))
129311	33925460	The following is available online at: , Figure S1: The Kaplan-Meier survival curve analysis of individual genes of 11-gene ARG signature, Figure S2: Boxplot showing the mRNA expression levels of 11 genes in high-risk and low-risk groups, Figure S3: Summary of mutations in bladder cancer patients, Table S1: 213 autophagy-related genes (ARGs) obtained from the Human Autophagy Database, Table S2: Summary of patients' survival information, 11-ARG signature genes expression and risk score in training and validation cohorts.	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('ARGs', 'Chemical', '-', (337, 341))	('autophagy', 'biological_process', 'GO:0006914', ('312', '321'))	('Autophagy', 'biological_process', 'GO:0016236', ('367', '376'))	('Autophagy', 'biological_process', 'GO:0006914', ('367', '376'))	('patients', 'Species', '9606', (288, 296))	('bladder cancer', 'Disease', 'MESH:D001749', (273, 287))	('bladder cancer', 'Disease', (273, 287))	('ARG', 'Chemical', '-', (443, 446))	('ARG', 'Chemical', '-', (123, 126))	('patients', 'Species', '9606', (408, 416))	('Human', 'Species', '9606', (361, 366))	('bladder cancer', 'Phenotype', 'HP:0009725', (273, 287))	('mutations', 'Var', (260, 269))	('autophagy', 'biological_process', 'GO:0016236', ('312', '321'))	('11-ARG', 'Chemical', '-', (440, 446))	('ARG', 'Chemical', '-', (337, 340))
129385	31530825	Data obtained from bladder histological analysis confirmed that animals from BBN groups developed urothelial lesions whereas animals from control groups did not develop any lesion.	('BBN', 'Var', (77, 80))	('urothelial lesions', 'Disease', (98, 116))	('urothelial lesions', 'Disease', 'MESH:D014522', (98, 116))	('BBN', 'Chemical', 'MESH:D002085', (77, 80))
129389	31530825	No significant effect of BBN exposure was noticed on gastrocnemius mass; however, an approximately 10% increase of the ratio between gastrocnemius mass to body weight was noticed in BBNex group (p < 0.05 vs CTex; Table 1).	('increase', 'PosReg', (103, 111))	('ratio', 'MPA', (119, 124))	('BBN', 'Chemical', 'MESH:D002085', (182, 185))	('rat', 'Species', '10116', (119, 122))	('BBN', 'Chemical', 'MESH:D002085', (25, 28))	('BBNex', 'Var', (182, 187))
129415	31530825	The volcano plot displays significantly expressed phospholipid abundances against fold-change (log2 (ratio)) and p-value (-log10 (p-value), based on Mann-Whitney statistics for two treatments) (Fig.	('phospholipid abundances', 'MPA', (50, 73))	('rat', 'Species', '10116', (101, 104))	('p-value', 'Var', (113, 120))	('fold-change', 'MPA', (82, 93))
129421	31530825	These PS contained shorter fatty acids (one C34, two C36 and two C38) than those that were upregulated (PS with C40 and C42).	('fatty acid', 'Chemical', 'MESH:D005227', (27, 37))	('C34', 'Var', (44, 47))	('C42', 'Gene', (120, 123))	('PS', 'Chemical', 'MESH:D010718', (6, 8))	('PS', 'Chemical', 'MESH:D010718', (104, 106))	('C36', 'Var', (53, 56))	('C38', 'Gene', (65, 68))	('C42', 'molecular_function', 'GO:0003813', ('120', '123'))	('C42', 'Gene', '406161', (120, 123))	('fatty acids', 'MPA', (27, 38))	('C38', 'Gene', '361675', (65, 68))	('shorter', 'NegReg', (19, 26))
129424	31530825	The downregulated phospholipids comprised 6 PS with shorter chain fatty acid (four C36 and two C38) and one PA. Of the upregulated group, cardiolipins (17species), with lower fold changes and lower p-values were the most significant feature.	('fatty acid', 'Chemical', 'MESH:D005227', (66, 76))	('cardiolipins', 'Chemical', 'MESH:D002308', (138, 150))	('downregulated', 'NegReg', (4, 17))	('lower', 'NegReg', (192, 197))	('C38', 'Gene', '361675', (95, 98))	('shorter', 'NegReg', (52, 59))	('PA', 'Chemical', 'MESH:D010712', (108, 110))	('fold changes', 'MPA', (175, 187))	('C38', 'Gene', (95, 98))	('PS', 'Chemical', 'MESH:D010718', (44, 46))	('p-values', 'MPA', (198, 206))	('C36', 'Var', (83, 86))
129433	31530825	In the present study, we report a comprehensive analysis of the variation of the mitochondrial phospholipidome of the skeletal muscle from rats with urothelial carcinoma, using high-resolution LC-MS, aiming to evaluate the beneficial effect of the exercise in cachexia.	('cachexia', 'Phenotype', 'HP:0004326', (260, 268))	('variation', 'Var', (64, 73))	('urothelial carcinoma', 'Disease', (149, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (149, 169))	('cachexia', 'Disease', 'MESH:D002100', (260, 268))	('mitochondrial phospholipidome', 'MPA', (81, 110))	('cachexia', 'Disease', (260, 268))	('rats', 'Species', '10116', (139, 143))
129456	31530825	Alterations of PS profile in mitochondria have been scarcely addressed, and its effect in the mitochondrial function is still unknown.	('PS profile', 'MPA', (15, 25))	('mitochondria', 'cellular_component', 'GO:0005739', ('29', '41'))	('Alterations', 'Var', (0, 11))	('PS', 'Chemical', 'MESH:D010718', (15, 17))	('rat', 'Species', '10116', (4, 7))
129462	31530825	Interestingly, we saw an increase of LPE species when BBNex is compared with BBNsed (Fig.	('BBN', 'Chemical', 'MESH:D002085', (54, 57))	('BBN', 'Chemical', 'MESH:D002085', (77, 80))	('LPE species', 'MPA', (37, 48))	('BBNex', 'Var', (54, 59))	('increase', 'PosReg', (25, 33))
129477	30642115	Epigenetic Mechanisms Influencing Epithelial to Mesenchymal Transition in Bladder Cancer Bladder cancer is one of the most incident neoplasms worldwide, and its treatment remains a significant challenge, since the mechanisms underlying disease progression are still poorly understood.	('neoplasms', 'Phenotype', 'HP:0002664', (132, 141))	('Bladder Cancer', 'Disease', (74, 88))	('Epigenetic Mechanisms', 'Var', (0, 21))	('Influencing', 'Reg', (22, 33))	('Bladder cancer', 'Disease', (89, 103))	('Bladder Cancer', 'Disease', 'MESH:D001749', (74, 88))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (74, 88))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('neoplasms', 'Disease', (132, 141))	('Bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Epithelial to Mesenchymal Transition', 'biological_process', 'GO:0001837', ('34', '70'))	('neoplasms', 'Disease', 'MESH:D009369', (132, 141))	('Bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('Epithelial to Mesenchymal Transition', 'CPA', (34, 70))
129479	30642115	Several studies have reported the importance of epigenetic mechanisms and enzymes, which orchestrate them in several features of cancer cells and, specifically, in EMT.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('epigenetic', 'Var', (48, 58))	('EMT', 'biological_process', 'GO:0001837', ('164', '167'))
129501	30642115	DNA methylation and chromatin remodelling deregulation in cancer result from aberrant epigenetic enzymes' activity that ultimately lead to abnormal gene expression, which empowers tumors to quickly evolve.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('epigenetic enzymes', 'Enzyme', (86, 104))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('20', '41'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('chromatin', 'CPA', (20, 29))	('chromatin', 'cellular_component', 'GO:0000785', ('20', '29'))	('deregulation', 'NegReg', (42, 54))	('gene expression', 'biological_process', 'GO:0010467', ('148', '163'))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('abnormal', 'Var', (139, 147))	('cancer', 'Disease', (58, 64))	('activity', 'MPA', (106, 114))	('lead to', 'Reg', (131, 138))
129502	30642115	Overall, while the importance of these epigenetic enzymes in promoting bladder cancer transformation has been already acknowledged, only a limited number of studies have characterized its role in the context of EMT process in this tumor model.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('bladder cancer', 'Disease', 'MESH:D001749', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('EMT', 'biological_process', 'GO:0001837', ('211', '214'))	('bladder cancer', 'Disease', (71, 85))	('epigenetic enzymes', 'Var', (39, 57))	('tumor', 'Disease', (231, 236))	('promoting', 'PosReg', (61, 70))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))
129505	30642115	demonstrated EZH2 and H3K23me3 enrichment within CDH1 promoter in BlCa cells even though no clues were yet provided on how PRC2 is specifically recruited to CDH1.	('EZH2', 'Gene', (13, 17))	('EZH2', 'Gene', '2146', (13, 17))	('CDH1', 'Gene', (49, 53))	('CDH1', 'Gene', '999', (157, 161))	('H3K23me3', 'Var', (22, 30))	('BlCa', 'Phenotype', 'HP:0009725', (66, 70))	('CDH1', 'Gene', '999', (49, 53))	('CDH1', 'Gene', (157, 161))
129514	30642115	Specifically, EZH2 inhibition might restrain the progression of non-muscle to muscle invasive disease.	('invasive disease', 'Disease', (85, 101))	('inhibition', 'Var', (19, 29))	('EZH2', 'Gene', (14, 18))	('restrain', 'NegReg', (36, 44))	('EZH2', 'Gene', '2146', (14, 18))	('invasive disease', 'Disease', 'MESH:D009362', (85, 101))
129516	30642115	Several cancer-related genes were reported to be regulated by promoter methylation, some of which were implicated in BlCa EMT (Table 1).	('cancer', 'Disease', (8, 14))	('promoter methylation', 'Var', (62, 82))	('BlCa', 'Phenotype', 'HP:0009725', (117, 121))	('EMT', 'biological_process', 'GO:0001837', ('122', '125'))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('implicated', 'Reg', (103, 113))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
129517	30642115	Among these, serine protease PRSS8 was found to be downregulated by promoter methylation in high-grade BlCa tissues, and its overexpression in cell lines was associated with E-Cadherin upregulation, which suggests an interplay between these two proteins during epithelial differentiation.	('BlCa', 'Phenotype', 'HP:0009725', (103, 107))	('methylation', 'biological_process', 'GO:0032259', ('77', '88'))	('E-Cadherin', 'Gene', '999', (174, 184))	('Cadherin', 'molecular_function', 'GO:0008014', ('176', '184'))	('PRSS8', 'Gene', (29, 34))	('E-Cadherin', 'Gene', (174, 184))	('overexpression', 'PosReg', (125, 139))	('promoter methylation', 'Var', (68, 88))	('downregulated', 'NegReg', (51, 64))	('PRSS8', 'Gene', '5652', (29, 34))	('upregulation', 'PosReg', (185, 197))
129523	30642115	Thus, the discovery of epigenetically downregulated genes in MIBC provides new insights about BlCa progression and metastasis.	('BlCa', 'Phenotype', 'HP:0009725', (94, 98))	('MIBC', 'Chemical', '-', (61, 65))	('BlCa', 'Disease', (94, 98))	('MIBC', 'Gene', (61, 65))	('epigenetically', 'Var', (23, 37))
129525	30642115	Specifically, KLF4 was found to be repressed by promoter methylation.	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('promoter methylation', 'Var', (48, 68))	('KLF4', 'Gene', (14, 18))	('KLF4', 'Gene', '9314', (14, 18))
129527	30642115	However, epigenetic editing (e.g., residue specific methylation or demethylation) would be more suitable for assessing the specific role of KLF4 promoter methylation in gene expression regulation.	('demethylation', 'Var', (67, 80))	('KLF4', 'Gene', (140, 144))	('KLF4', 'Gene', '9314', (140, 144))	('methylation', 'biological_process', 'GO:0032259', ('154', '165'))	('gene expression', 'biological_process', 'GO:0010467', ('169', '184'))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('demethylation', 'biological_process', 'GO:0070988', ('67', '80'))	('methylation', 'Var', (52, 63))	('regulation', 'biological_process', 'GO:0065007', ('185', '195'))
129547	30642115	miR-148a-3p, a BlCa tumor suppressor, and an EMT inhibitor, by targeting the ERBB3/AKT2/c-MYC axis, was shown to be downregulated by DNMT1-induced methylation.	('AKT2', 'Gene', '208', (83, 87))	('DNMT1', 'Gene', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('EMT', 'biological_process', 'GO:0001837', ('45', '48'))	('ERBB3', 'Gene', '2065', (77, 82))	('AKT2', 'Gene', (83, 87))	('c-MYC', 'Gene', '4609', (88, 93))	('c-MYC', 'Gene', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('DNMT1', 'Gene', '1786', (133, 138))	('miR', 'Gene', '220972', (0, 3))	('BlCa', 'Phenotype', 'HP:0009725', (15, 19))	('methylation', 'Var', (147, 158))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('methylation', 'biological_process', 'GO:0032259', ('147', '158'))	('ERBB3', 'Gene', (77, 82))	('downregulated', 'NegReg', (116, 129))	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('miR', 'Gene', (0, 3))	('tumor', 'Disease', (20, 25))
129550	30642115	DNMT1 inhibition resulted in substantial miR424 upregulation, which, in turn, promoted epithelial characteristics of BlCa cells (changing the relative expression levels of E-cadherin and Twist) and resulted in reduced invasion ability.	('invasion ability', 'CPA', (218, 234))	('epithelial characteristics of BlCa cells', 'CPA', (87, 127))	('reduced', 'NegReg', (210, 217))	('BlCa', 'Phenotype', 'HP:0009725', (117, 121))	('miR424', 'Gene', (41, 47))	('promoted', 'PosReg', (78, 86))	('changing', 'Reg', (129, 137))	('cadherin', 'molecular_function', 'GO:0008014', ('174', '182'))	('expression levels', 'MPA', (151, 168))	('miR424', 'Gene', '494336', (41, 47))	('DNMT1', 'Gene', (0, 5))	('inhibition', 'Var', (6, 16))	('DNMT1', 'Gene', '1786', (0, 5))	('Twist', 'Gene', '7291', (187, 192))	('E-cadherin', 'Gene', (172, 182))	('E-cadherin', 'Gene', '999', (172, 182))	('Twist', 'Gene', (187, 192))	('upregulation', 'PosReg', (48, 60))
129553	30642115	On the other hand, miR-323a-3p is downregulated by aberrant methylation of the intergenic differential methylated region (IG-DMR).	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', (19, 22))	('downregulated', 'NegReg', (34, 47))	('methylation', 'Var', (60, 71))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('aberrant methylation', 'Var', (51, 71))
129598	27725745	In one study by Chung et al., patients were divided into three groups: absence of chronic kidney disease (CKD), stage 1-4 CKD, and stage 5 CKD.	('chronic kidney disease', 'Disease', 'MESH:D051436', (82, 104))	('CKD', 'Phenotype', 'HP:0012622', (122, 125))	('CKD', 'Phenotype', 'HP:0012622', (106, 109))	('CKD', 'Var', (139, 142))	('patients', 'Species', '9606', (30, 38))	('chronic kidney disease', 'Disease', (82, 104))	('kidney disease', 'Phenotype', 'HP:0000112', (90, 104))	('CKD', 'Var', (122, 125))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (82, 104))	('CKD', 'Phenotype', 'HP:0012622', (139, 142))
129671	22629005	CA19-9 is now a well-known marker for pancreatic carcinoma and has also been reported to be positive in gastrointestinal cancers, papillary carcinoma of thyroid, and endometrial adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('papillary carcinoma of thyroid', 'Phenotype', 'HP:0002895', (130, 160))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (38, 58))	('papillary carcinoma of thyroid', 'Disease', 'MESH:D000077273', (130, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('papillary carcinoma of thyroid', 'Disease', (130, 160))	('endometrial adenocarcinomas', 'Disease', 'MESH:D016889', (166, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('endometrial adenocarcinomas', 'Disease', (166, 193))	('CA19-9', 'Var', (0, 6))	('gastrointestinal cancers', 'Disease', (104, 128))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (104, 128))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('pancreatic carcinoma', 'Disease', (38, 58))
129773	33639858	Except cg23646375 and cg07434244, nine CpG sites (cg02638691, cg06616057, cg08158408, cg08185241, cg09666230, cg14824901, cg17710021, cg26050864 and cg27176828) are among the top 5% important features of DNA methylation.	('cg26050864', 'Var', (134, 144))	('cg23646375', 'Chemical', '-', (7, 17))	('cg02638691', 'Var', (50, 60))	('DNA', 'cellular_component', 'GO:0005574', ('204', '207'))	('DNA methylation', 'biological_process', 'GO:0006306', ('204', '219'))	('cg27176828', 'Var', (149, 159))	('cg09666230', 'Var', (98, 108))	('cg14824901', 'Var', (110, 120))	('cg08185241', 'Var', (86, 96))	('cg17710021', 'Var', (122, 132))	('cg06616057', 'Var', (62, 72))	('cg08158408', 'Var', (74, 84))
129774	33639858	This suggests that G0S2 methylation may be one of the biological characteristics of the subtype 1.	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('G0S2', 'Gene', (19, 23))	('G0S2', 'Gene', '50486', (19, 23))	('methylation', 'Var', (24, 35))
129775	33639858	Indeed, a recent study confirmed that hypermethylation of the G0S2 locus and decreased G0S2 expression are hallmarks of rapidly recurrent or fatal ACC.	('hypermethylation', 'Var', (38, 54))	('G0S2', 'Gene', '50486', (62, 66))	('G0S2', 'Gene', '50486', (87, 91))	('ACC', 'Phenotype', 'HP:0006744', (147, 150))	('G0S2', 'Gene', (62, 66))	('G0S2', 'Gene', (87, 91))	('decreased', 'NegReg', (77, 86))	('expression', 'MPA', (92, 102))
129776	33639858	Moreover, G0S2 hypermethylation and silencing is exclusive to ACC.	('G0S2', 'Gene', '50486', (10, 14))	('G0S2', 'Gene', (10, 14))	('hypermethylation', 'Var', (15, 31))	('ACC', 'Phenotype', 'HP:0006744', (62, 65))	('silencing', 'MPA', (36, 45))
129778	33639858	Among the top important features of miRNA expression in this study, four miRNAs (miR-125b-5p, miR-139-3p, miR-139-5p and miR-335-5p) are shown as potential biomarkers in ACC according to previous researches.	('miR-139-3p', 'Gene', (94, 104))	('miR-335', 'Gene', (121, 128))	('ACC', 'Phenotype', 'HP:0006744', (170, 173))	('ACC', 'Disease', (170, 173))	('miR-139-5p', 'Var', (106, 116))	('miR-335', 'Gene', '442904', (121, 128))	('miR-125b-5p', 'Var', (81, 92))	('miR-139-3p', 'Gene', '406931', (94, 104))
129779	33639858	Overexpressed miR-139-5p, and underexpressed miR-125b-5p, miR-139-3p and miR-335-5p were found associated with ACC aggressiveness and poor prognosis.	('miR-139-3p', 'Gene', (58, 68))	('miR-125b-5p', 'Var', (45, 56))	('ACC', 'Phenotype', 'HP:0006744', (111, 114))	('miR-335', 'Gene', (73, 80))	('aggressiveness', 'Disease', 'MESH:D001523', (115, 129))	('miR-139-3p', 'Gene', '406931', (58, 68))	('miR-335', 'Gene', '442904', (73, 80))	('aggressiveness', 'Disease', (115, 129))	('miR-139-5p', 'Var', (14, 24))	('associated', 'Reg', (95, 105))	('aggressiveness', 'Phenotype', 'HP:0000718', (115, 129))
129783	33639858	A recent study has shown that the genomes of rapidly recurrent carcinomas are characterized by aberrant methylation directed to promoter CpG islands.	('carcinomas', 'Disease', 'MESH:D009369', (63, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('methylation', 'MPA', (104, 115))	('carcinomas', 'Disease', (63, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('aberrant', 'Var', (95, 103))	('methylation', 'biological_process', 'GO:0032259', ('104', '115'))
129791	33021006	The identification of FGFR fusions and other alterations in a wide range of solid tumors, including cholangiocarcinoma and bladder cancer, has resulted in the development of several selective FGFR inhibitors for use in these indications, for example, infigratinib, erdafitinib, derazantinib, pemigatinib, and futibatinib.	('infigratinib', 'Chemical', 'MESH:C568950', (251, 263))	('alterations', 'Var', (45, 56))	('tumors', 'Disease', (82, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('fusions', 'Var', (27, 34))	('FGFR', 'Gene', (22, 26))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))	('cholangiocarcinoma and bladder cancer', 'Disease', 'MESH:D001749', (100, 137))	('men', 'Species', '9606', (166, 169))	('pemigatinib', 'Chemical', '-', (292, 303))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('FGFR', 'molecular_function', 'GO:0005007', ('192', '196'))	('futibatinib', 'Chemical', '-', (309, 320))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('FGFR', 'Gene', (192, 196))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('erdafitinib', 'Chemical', 'MESH:C000604580', (265, 276))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('derazantinib', 'Chemical', 'MESH:C000621805', (278, 290))
129795	33021006	Identification of fibroblast growth factor receptor (FGFR) aberrations in cholangiocarcinoma and bladder cancer led to development of selective FGFR inhibitors for these indications, based on clinical benefit and safety profiles.	('men', 'Species', '9606', (126, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('FGFR', 'Gene', (53, 57))	('aberrations', 'Var', (59, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (74, 92))	('FGFR', 'Gene', (144, 148))	('inhibitors', 'NegReg', (149, 159))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('18', '42'))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('cholangiocarcinoma and bladder cancer', 'Disease', 'MESH:D001749', (74, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
129796	33021006	This work reviewed skin AEs reported with FGFR inhibitors and provides management guidelines for physicians, aiming to increase awareness of skin events and provide effective treatment strategies.	('skin AEs', 'Disease', 'MESH:D012871', (19, 27))	('inhibitors', 'Var', (47, 57))	('men', 'Species', '9606', (77, 80))	('men', 'Species', '9606', (180, 183))	('skin AEs', 'Disease', (19, 27))	('FGFR', 'Gene', (42, 46))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))
129798	33021006	This review provides oncologists with an understanding of dermatologic adverse events related to the use of FGFR inhibitors and proposes guidelines for treatment.	('inhibitors', 'Var', (113, 123))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('FGFR', 'Gene', (108, 112))	('men', 'Species', '9606', (157, 160))
129801	33021006	FGFR fusions and other alterations have been reported in a wide range of solid tumors, including cholangiocarcinoma [4], bladder cancer [5], lung cancer [6], and glioblastoma [7].	('bladder cancer', 'Disease', (121, 135))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'Gene', (0, 4))	('bladder cancer', 'Phenotype', 'HP:0009725', (121, 135))	('lung cancer', 'Disease', (141, 152))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('glioblastoma', 'Disease', 'MESH:D005909', (162, 174))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('fusions', 'Var', (5, 12))	('tumors', 'Disease', (79, 85))	('glioblastoma', 'Disease', (162, 174))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cholangiocarcinoma', 'Disease', (97, 115))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (97, 115))	('reported', 'Reg', (45, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('alterations', 'Var', (23, 34))	('bladder cancer', 'Disease', 'MESH:D001749', (121, 135))
129802	33021006	Identification of targetable genomic alterations has resulted in the development of several FGF/FGFR-directed therapies, primarily small-molecule tyrosine kinase inhibitors (TKIs) or multikinase inhibitors, with differing profiles (Table 1).	('FGF/FGFR-directed', 'Gene', (92, 109))	('alterations', 'Var', (37, 48))	('men', 'Species', '9606', (76, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))
129804	33021006	As FGFs act with other signaling molecules to orchestrate processes such as tissue regeneration and healing, inhibition of FGFR signaling has the potential to lead to on-target adverse events such as hyperphosphatemia, which is believed to result from inhibition of FGFR signaling in the proximal renal tubule, as well as others associated with off-target effects, including alopecia, dry mouth/xerostomia, nail changes, and other dermatologic events [8, 9].	('hyperphosphatemia', 'Phenotype', 'HP:0002905', (200, 217))	('tissue regeneration', 'biological_process', 'GO:0042246', ('76', '95'))	('FGFR', 'molecular_function', 'GO:0005007', ('266', '270'))	('dry mouth/xerostomia', 'Disease', (385, 405))	('inhibition', 'NegReg', (252, 262))	('alopecia', 'Disease', (375, 383))	('FGFR', 'Gene', (123, 127))	('hyperphosphatemia', 'Disease', 'MESH:D054559', (200, 217))	('dry mouth', 'Phenotype', 'HP:0000217', (385, 394))	('lead to', 'Reg', (159, 166))	('FGFR', 'molecular_function', 'GO:0005007', ('123', '127'))	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('nail changes', 'Disease', (407, 419))	('xerostomia', 'Phenotype', 'HP:0000217', (395, 405))	('signaling', 'biological_process', 'GO:0023052', ('271', '280'))	('inhibition', 'Var', (109, 119))	('dry mouth/xerostomia', 'Disease', 'MESH:D014987', (385, 405))	('alopecia', 'Phenotype', 'HP:0001596', (375, 383))	('hyperphosphatemia', 'Disease', (200, 217))	('signaling', 'biological_process', 'GO:0023052', ('23', '32'))
129805	33021006	Depending on the breadth of their inhibitory targets, adverse events associated with anti-FGFR TKIs can also include those related to vascular endothelial growth factor receptor (VEGFR) inhibition (e.g., hypertension, cardiovascular events, and proteinuria), as seen with earlier-generation multikinase inhibitors, and others commonly reported with TKIs (e.g., gastrointestinal disorders, such as vomiting and diarrhea, skin reactions, and ocular effects, such as dry eye and retinal pigment epithelium detachment).	('hypertension', 'Disease', (204, 216))	('vomiting', 'Disease', 'MESH:D014839', (397, 405))	('hypertension', 'Disease', 'MESH:D006973', (204, 216))	('dry eye', 'Disease', (464, 471))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('134', '168'))	('diarrhea', 'Disease', (410, 418))	('vomiting', 'Phenotype', 'HP:0002013', (397, 405))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))	('gastrointestinal disorders', 'Phenotype', 'HP:0011024', (361, 387))	('vomiting', 'Disease', (397, 405))	('VEGFR', 'Gene', '3791', (179, 184))	('hypertension', 'Phenotype', 'HP:0000822', (204, 216))	('VEGFR', 'Gene', (179, 184))	('gastrointestinal disorders', 'Disease', 'MESH:D005767', (361, 387))	('cardiovascular events', 'Disease', (218, 239))	('diarrhea', 'Disease', 'MESH:D003967', (410, 418))	('inhibition', 'NegReg', (186, 196))	('dry eye', 'Disease', 'MESH:D015352', (464, 471))	('cardiovascular events', 'Phenotype', 'HP:0001626', (218, 239))	('epithelium detachment', 'Phenotype', 'HP:0032156', (492, 513))	('proteinuria', 'Disease', (245, 256))	('TKIs', 'Gene', (95, 99))	('ocular effects', 'Disease', (440, 454))	('skin reactions', 'Phenotype', 'HP:0011123', (420, 434))	('proteinuria', 'Disease', 'MESH:D011507', (245, 256))	('dry eye', 'Phenotype', 'HP:0001097', (464, 471))	('skin reaction', 'Phenotype', 'HP:0011123', (420, 433))	('vascular endothelial growth factor receptor', 'Gene', '3791', (134, 177))	('vascular endothelial growth factor receptor', 'Gene', (134, 177))	('skin reactions', 'Disease', (420, 434))	('proteinuria', 'Phenotype', 'HP:0000093', (245, 256))	('gastrointestinal disorders', 'Disease', (361, 387))	('diarrhea', 'Phenotype', 'HP:0002014', (410, 418))	('retinal pigment epithelium detachment', 'Disease', (476, 513))	('anti-FGFR', 'Var', (85, 94))	('retinal pigment epithelium detachment', 'Disease', 'MESH:D012163', (476, 513))
129806	33021006	The aim of this review is to provide oncologists with an understanding of the dermatologic events associated with FGFR inhibitors currently in clinical development or approved by regulatory agencies for the treatment of cholangiocarcinoma and urothelial cancers.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('men', 'Species', '9606', (159, 162))	('inhibitors', 'Var', (119, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('FGFR', 'molecular_function', 'GO:0005007', ('114', '118'))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('cholangiocarcinoma and urothelial cancers', 'Disease', 'MESH:D014523', (220, 261))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (220, 238))	('FGFR', 'Gene', (114, 118))	('men', 'Species', '9606', (212, 215))
129816	33021006	Alterations in genes encoding FGFRs are common in patients with cholangiocarcinoma, the most common being FGFR2 fusions, FGFR19 amplifications, and FGFR2 mutations [20].	('FGFR2', 'Gene', '2263', (148, 153))	('Alterations', 'Var', (0, 11))	('amplifications', 'Var', (128, 142))	('FGFR2', 'Gene', (106, 111))	('common', 'Reg', (40, 46))	('FGFR2', 'Gene', '2263', (106, 111))	('FGFR1', 'Gene', '2260', (121, 126))	('FGFRs', 'Gene', (30, 35))	('patients', 'Species', '9606', (50, 58))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('cholangiocarcinoma', 'Disease', (64, 82))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('121', '125'))	('FGFR2', 'Gene', (148, 153))	('fusions', 'Var', (112, 119))	('FGFR1', 'Gene', (121, 126))	('mutations', 'Var', (154, 163))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('FGFR', 'molecular_function', 'GO:0005007', ('148', '152'))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
129817	33021006	FGFR2 fusions are present in 13%-25% of patients with cholangiocarcinoma [20, 21] and therefore represent a promising target for therapy in enriched patient populations.	('patient', 'Species', '9606', (40, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (54, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('patients', 'Species', '9606', (40, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('patient', 'Species', '9606', (149, 156))	('cholangiocarcinoma', 'Disease', (54, 72))	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))	('FGFR2', 'Gene', '2263', (0, 5))
129819	33021006	Pemigatinib was approved for use in patients with FGFR2 fusion or rearrangement in April 2020, based on the results of the phase II FIGHT-202 study [22].	('Pemigatinib', 'Chemical', '-', (0, 11))	('patients', 'Species', '9606', (36, 44))	('rearrangement', 'Var', (66, 79))	('FGFR2', 'Gene', '2263', (50, 55))	('men', 'Species', '9606', (75, 78))	('fusion', 'Var', (56, 62))	('FGFR', 'molecular_function', 'GO:0005007', ('50', '54'))	('FGFR2', 'Gene', (50, 55))
129829	33021006	Several possible mechanisms have been proposed, including inhibition of FGFR in keratinocytes, inducing dysregulation of hair-follicle homeostasis and epidermal proliferation and/or differentiation with downregulation of tight junction gene expression, as demonstrated in FGFR-deficient mice [29] and by inhibiting hormonal (nonpathological) FGF signaling by FGF19, FGF21, and FGF23 [30].	('epidermal proliferation', 'CPA', (151, 174))	('inhibition', 'Var', (58, 68))	('expression', 'MPA', (241, 251))	('FGFR', 'Gene', (72, 76))	('tight junction gene', 'Gene', (221, 240))	('FGF19', 'Gene', '14170', (359, 364))	('FGF21', 'Gene', (366, 371))	('signaling', 'biological_process', 'GO:0023052', ('346', '355'))	('homeostasis', 'biological_process', 'GO:0042592', ('135', '146'))	('downregulation', 'NegReg', (203, 217))	('hormonal', 'MPA', (315, 323))	('inducing', 'PosReg', (95, 103))	('tight junction', 'cellular_component', 'GO:0070160', ('221', '235'))	('FGF21', 'Gene', '56636', (366, 371))	('dysregulation', 'MPA', (104, 117))	('inhibiting', 'NegReg', (304, 314))	('gene expression', 'biological_process', 'GO:0010467', ('236', '251'))	('FGF23', 'Gene', '64654', (377, 382))	('FGFR', 'molecular_function', 'GO:0005007', ('272', '276'))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('FGF19', 'Gene', (359, 364))	('hair-follicle', 'CPA', (121, 134))	('mice', 'Species', '10090', (287, 291))	('FGF23', 'Gene', (377, 382))
129841	33021006	Other body hair can also be adversely affected in patients undergoing treatment with FGFR inhibitors (e.g., eyelash trichomegaly has been reported with infigratinib) [33].	('eyelash trichomegaly', 'Disease', (108, 128))	('FGFR', 'Gene', (85, 89))	('patients', 'Species', '9606', (50, 58))	('infigratinib', 'Chemical', 'MESH:C568950', (152, 164))	('men', 'Species', '9606', (75, 78))	('eyelash trichomegaly', 'Phenotype', 'HP:0000527', (108, 128))	('eyelash trichomegaly', 'Disease', 'MESH:C536554', (108, 128))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('inhibitors', 'Var', (90, 100))
129848	33021006	Conversely, with FGFR inhibitors, the ventral aspect of the distal digits and lateral aspects of the palms and soles are affected by erythema and pain, accompanied by onycholysis and secondary paronychia, reminiscent of changes observed with microtubule inhibitors (i.e., taxanes).	('pain', 'Phenotype', 'HP:0012531', (146, 150))	('FGFR', 'Gene', (17, 21))	('taxanes', 'Chemical', 'MESH:D043823', (272, 279))	('inhibitors', 'Var', (22, 32))	('pain', 'Disease', 'MESH:D010146', (146, 150))	('pain', 'Disease', (146, 150))	('microtubule', 'cellular_component', 'GO:0005874', ('242', '253'))	('erythema', 'Phenotype', 'HP:0010783', (133, 141))	('erythema', 'Disease', 'MESH:D004890', (133, 141))	('ventral aspect of the distal digits', 'CPA', (38, 73))	('onycholysis', 'Phenotype', 'HP:0001806', (167, 178))	('erythema', 'Disease', (133, 141))	('affected', 'Reg', (121, 129))	('secondary paronychia', 'Disease', (183, 203))	('paronychia', 'Phenotype', 'HP:0001818', (193, 203))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('onycholysis', 'Disease', (167, 178))
129849	33021006	PPES often presents as a mild to moderate cutaneous edema, erythema, and hyperkeratosis with FGFR inhibitors; this evolves into painful digits that can impact patients' quality of life [46, 47] and can ultimately limit daily functioning and lead to a reduction of the duration and intensity of treatment or its discontinuation [48].	('quality of life', 'CPA', (169, 184))	('painful', 'Disease', 'MESH:D010146', (128, 135))	('reduction', 'NegReg', (251, 260))	('limit daily functioning', 'Phenotype', 'HP:0031058', (213, 236))	('edema', 'Phenotype', 'HP:0000969', (52, 57))	('cutaneous edema', 'Disease', 'MESH:D004487', (42, 57))	('erythema', 'Disease', (59, 67))	('pain', 'Phenotype', 'HP:0012531', (128, 132))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (73, 87))	('erythema', 'Phenotype', 'HP:0010783', (59, 67))	('erythema', 'Disease', 'MESH:D004890', (59, 67))	('FGFR', 'Gene', (93, 97))	('painful', 'Disease', (128, 135))	('daily functioning', 'CPA', (219, 236))	('hyperkeratosis', 'Disease', (73, 87))	('impact', 'Reg', (152, 158))	('PPES', 'Disease', (0, 4))	('hyperkeratosis', 'Disease', 'MESH:D017488', (73, 87))	('patients', 'Species', '9606', (159, 167))	('limit', 'NegReg', (213, 218))	('men', 'Species', '9606', (299, 302))	('inhibitors', 'Var', (98, 108))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('cutaneous edema', 'Disease', (42, 57))
129850	33021006	Stomatitis is one of the most commonly observed adverse events in patients treated with FGFR inhibitors, with lesions appearing rapidly after treatment initiation.	('Stomatitis', 'Disease', (0, 10))	('Stomatitis', 'Phenotype', 'HP:0010280', (0, 10))	('Stomatitis', 'Disease', 'MESH:D013280', (0, 10))	('FGFR', 'molecular_function', 'GO:0005007', ('88', '92'))	('inhibitors', 'Var', (93, 103))	('men', 'Species', '9606', (147, 150))	('patients', 'Species', '9606', (66, 74))	('FGFR', 'Gene', (88, 92))
129853	33021006	Among patients with urothelial carcinoma, the incidence of stomatitis ranged from 12% with rogaratinib [49] to 58% with erdafitinib [28].	('erdafitinib', 'Chemical', 'MESH:C000604580', (120, 131))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (20, 40))	('stomatitis', 'Disease', 'MESH:D013280', (59, 69))	('stomatitis', 'Disease', (59, 69))	('patients', 'Species', '9606', (6, 14))	('stomatitis', 'Phenotype', 'HP:0010280', (59, 69))	('urothelial carcinoma', 'Disease', (20, 40))	('rogaratinib', 'Var', (91, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
129858	33021006	Although severe or life-threatening complications are uncommon, low-grade xerosis can result in dose delays or discontinuations, potentially impacting the overall efficacy of treatment.	('impacting', 'NegReg', (141, 150))	('xerosis', 'Disease', (74, 81))	('xerosis', 'Phenotype', 'HP:0000958', (74, 81))	('men', 'Species', '9606', (180, 183))	('xerosis', 'Disease', 'None', (74, 81))	('discontinuations', 'MPA', (111, 127))	('low-grade', 'Var', (64, 73))	('dose', 'MPA', (96, 100))
129859	33021006	The incidence of dry skin in patients with cholangiocarcinoma treated with the FGFR inhibitors ranged from 10% in derazantinib-treated patients [39] to 35% in erdafitinib-treated patients [42], whereas for those with urothelial cancer, dry skin was reported in 12% of infigratinib-treated patients [40] and 32% of erdafitinib-treated patients [34].	('patients', 'Species', '9606', (135, 143))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (43, 61))	('dry skin', 'Disease', (17, 25))	('dry skin', 'Disease', 'MESH:D012871', (236, 244))	('infigratinib', 'Chemical', 'MESH:C568950', (268, 280))	('erdafitinib', 'Chemical', 'MESH:C000604580', (159, 170))	('FGFR', 'Gene', (79, 83))	('cholangiocarcinoma', 'Disease', (43, 61))	('dry skin', 'Phenotype', 'HP:0000958', (236, 244))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (43, 61))	('patients', 'Species', '9606', (29, 37))	('dry skin', 'Disease', 'MESH:D012871', (17, 25))	('patients', 'Species', '9606', (179, 187))	('urothelial cancer', 'Disease', 'MESH:D014523', (217, 234))	('patients', 'Species', '9606', (289, 297))	('derazantinib', 'Chemical', 'MESH:C000621805', (114, 126))	('inhibitors', 'Var', (84, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('dry skin', 'Phenotype', 'HP:0000958', (17, 25))	('urothelial cancer', 'Disease', (217, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('patients', 'Species', '9606', (334, 342))	('dry skin', 'Disease', (236, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('erdafitinib', 'Chemical', 'MESH:C000604580', (314, 325))
129863	33021006	Dry mouth, generally grade 1 or 2, was common in patients treated with FGFR inhibitors, occurring in 23%-59% of patients with cholangiocarcinoma and 31%-46% of patients with urothelial cancers (Tables 3, 4).	('Dry mouth', 'Disease', (0, 9))	('Dry mouth', 'Disease', 'MESH:D014987', (0, 9))	('patients', 'Species', '9606', (160, 168))	('Dry mouth', 'Phenotype', 'HP:0000217', (0, 9))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (126, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('patients', 'Species', '9606', (112, 120))	('FGFR', 'Gene', (71, 75))	('urothelial cancers', 'Disease', (174, 192))	('urothelial cancers', 'Disease', 'MESH:D014523', (174, 192))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (126, 144))	('inhibitors', 'Var', (76, 86))	('patients', 'Species', '9606', (49, 57))	('cholangiocarcinoma', 'Disease', (126, 144))
129864	33021006	A rare skin/soft tissue reaction that has been observed in patients undergoing treatment with FGFR inhibitors is calcinosis cutis, a condition in which calcium salts are deposited in the skin and subcutaneous tissues.	('calcinosis cutis', 'Phenotype', 'HP:0025520', (113, 129))	('calcium', 'Chemical', 'MESH:D002118', (152, 159))	('inhibitors', 'Var', (99, 109))	('calcinosis cutis', 'Disease', 'MESH:D002114', (113, 129))	('men', 'Species', '9606', (84, 87))	('patients', 'Species', '9606', (59, 67))	('calcinosis cutis', 'Disease', (113, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('94', '98'))	('FGFR', 'Gene', (94, 98))	('calcinosis', 'Phenotype', 'HP:0003761', (113, 123))
129871	33021006	Prevention and early treatment of dermatologic adverse events are key to maximizing adherence to therapy and optimizing outcomes in patients undergoing treatment with FGFR inhibitors; however, data specific to preventive therapies for use with FGFR-targeted therapy are scarce.	('FGFR', 'Gene', (167, 171))	('FGFR', 'molecular_function', 'GO:0005007', ('244', '248'))	('inhibitors', 'Var', (172, 182))	('men', 'Species', '9606', (26, 29))	('men', 'Species', '9606', (157, 160))	('patients', 'Species', '9606', (132, 140))	('FGFR', 'molecular_function', 'GO:0005007', ('167', '171'))
129875	33021006	Counseling and education on the potential for nail changes are essential before initiation of treatment with FGFR inhibitors.	('inhibitors', 'Var', (114, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('109', '113'))	('FGFR', 'Gene', (109, 113))	('men', 'Species', '9606', (99, 102))
129883	33021006	Preventive measures normally considered for patients undergoing traditional chemotherapy regimens, for example, scalp compression, scalp cooling, and medications, are not applicable to patients receiving FGFR inhibitors, and the health care provider's attention should be focused on early identification and management of symptoms.	('patients', 'Species', '9606', (44, 52))	('men', 'Species', '9606', (93, 96))	('inhibitors', 'Var', (209, 219))	('men', 'Species', '9606', (314, 317))	('FGFR', 'molecular_function', 'GO:0005007', ('204', '208'))	('patients', 'Species', '9606', (185, 193))	('FGFR', 'Gene', (204, 208))
129943	33114616	Structurally, PD-1 consists of an immunoglobulin V (IgV)-like extracellular domain, a trans-membrane domain, and a cytoplasmic tyrosine kinase domain that, upon phosphorylation, negatively regulates T cell receptor (TCR) signals by phosphorylating Src homology phosphatase-1 (SHP-1) and SHP-22.	('SHP-22', 'Gene', (287, 293))	('phosphorylation', 'biological_process', 'GO:0016310', ('161', '176'))	('Src homology phosphatase-1', 'Gene', (248, 274))	('TCR', 'cellular_component', 'GO:0042101', ('216', '219'))	('Src homology phosphatase-1', 'Gene', '5777', (248, 274))	('PD-1', 'Gene', (14, 18))	('SHP-1', 'Gene', '5777', (276, 281))	('negatively regulates', 'NegReg', (178, 198))	('extracellular', 'cellular_component', 'GO:0005576', ('62', '75'))	('membrane', 'cellular_component', 'GO:0016020', ('92', '100'))	('SHP-1', 'Gene', (276, 281))	('phosphorylating', 'Var', (232, 247))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('34', '48'))	('phosphatase', 'molecular_function', 'GO:0016791', ('261', '272'))	('TCR', 'biological_process', 'GO:0006283', ('216', '219'))
129967	33114616	The ORR was 28.4%, 23.8%, and 16.1% in patients with PD-L1 >= 5%, PD-L1 >= 1%, and PD-L1 < 1%, respectively.	('PD-L1 >= 1%', 'Var', (66, 77))	('PD-L1 >= 5%', 'Var', (53, 64))	('patients', 'Species', '9606', (39, 47))
130011	33114616	Single nucleotide variant (SNV) count is defined as the number of exonic non-synonymous mutations per sample, including indels, non-sense mutations, splice site mutations, and non-synonymous mis-sense variants, often referred to as tumor mutational burden (TMB).	('TMB', 'Chemical', '-', (257, 260))	('non-synonymous mis-sense variants', 'Var', (176, 209))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('non-sense mutations', 'Var', (128, 147))	('tumor', 'Disease', (232, 237))
130014	33114616	In mUC, data from IMvigor 210 further suggest that high TMB may not be only prognostic of survival, but potentially predictive of a response.	('high', 'Var', (51, 55))	('TMB', 'MPA', (56, 59))	('TMB', 'Chemical', '-', (56, 59))
130017	33114616	Recently, high TMB was also found in mUC patients who also harbored ERBB2 (HER2) and ERBB3 (HER3) mutations.	('ERBB3', 'Gene', '2065', (85, 90))	('ERBB3', 'Gene', (85, 90))	('ERBB2', 'Gene', '2064', (68, 73))	('HER2', 'Gene', (75, 79))	('ERBB2', 'Gene', (68, 73))	('mutations', 'Var', (98, 107))	('patients', 'Species', '9606', (41, 49))	('HER2', 'Gene', '2064', (75, 79))	('HER3', 'Gene', (92, 96))	('TMB', 'Chemical', '-', (15, 18))	('HER3', 'Gene', '2065', (92, 96))
130024	33114616	The association between copy number variant (CNV), characterized by homozygous deletions and amplifications (defined as > six copies) and ICI response, has recently been analyzed in several cancer types.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('deletions', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('ICI response', 'MPA', (138, 150))	('copy number', 'Var', (24, 35))
130025	33114616	In Nassar et al., homozygous deletion of CDKN2A and CDKN2B was the most common CNV event related to no clinical benefit.	('CDKN2A', 'Gene', '1029', (41, 47))	('CDKN2A', 'Gene', (41, 47))	('homozygous deletion', 'Var', (18, 37))	('CDKN2B', 'Gene', (52, 58))	('CDKN2B', 'Gene', '1030', (52, 58))
130027	33114616	Furthermore, analysis of the interaction between SNV and CNV counts and ICI response revealed that patients with high SNV and low CNV benefitted more from ICI therapy than patients with low SNV and high CNV counts.	('benefitted', 'PosReg', (134, 144))	('high SNV', 'Var', (113, 121))	('patients', 'Species', '9606', (99, 107))	('ICI therapy', 'MPA', (155, 166))	('low', 'Var', (126, 129))	('patients', 'Species', '9606', (172, 180))
130028	33114616	Mutation of genes involved in the DNA MMR pathway causes defective DNA damage repair (dMMR), which has been shown to be a predictive biomarker for response to ICIs.	('defective', 'NegReg', (57, 66))	('Mutation', 'Var', (0, 8))	('MMR', 'biological_process', 'GO:0006298', ('38', '41'))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('DNA damage repair', 'Disease', (67, 84))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('dMMR', 'Chemical', '-', (86, 90))
130029	33114616	Microsatellite instability (MSI) in the tumor with dMMR, particularly deleterious mutations, was related to a higher sensitivity to ICI treatment regardless of the tissue of origin.	('dMMR', 'Var', (51, 55))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Microsatellite instability', 'Disease', (0, 26))	('dMMR', 'Chemical', '-', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('higher', 'PosReg', (110, 116))	('sensitivity to ICI treatment', 'MPA', (117, 145))
130030	33114616	MSI positive cancers are TMB-high tumors in which dMMR generates an elevated load of insertion and deletion mutations.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('insertion', 'Var', (85, 94))	('TMB', 'Chemical', '-', (25, 28))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('deletion mutations', 'Var', (99, 117))	('cancers', 'Disease', (13, 20))	('dMMR', 'Chemical', '-', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
130031	33114616	In clinical trials performed in mUC patients treated with nivolumab or atezolizumab, defective DNA damage repair was strongly associated with a response to anti PD-1 and anti PD-L1 agents and survival outcome, proving to be superior to TMB.	('atezolizumab', 'Chemical', 'MESH:C000594389', (71, 83))	('associated', 'Reg', (126, 136))	('defective', 'Var', (85, 94))	('patients', 'Species', '9606', (36, 44))	('DNA damage repair', 'MPA', (95, 112))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('response', 'MPA', (144, 152))	('nivolumab', 'Chemical', 'MESH:D000077594', (58, 67))	('TMB', 'Chemical', '-', (236, 239))
130168	31627281	In addition to its role in tumor growth, inhibition of A2BAR genetically or pharmacologically dramatically decreased lung metastasis after implantation of breast cancer cells into the mammary fat pad of immunodeficient mice.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('decreased lung metastasis', 'Disease', (107, 132))	('A2BAR', 'Gene', (55, 60))	('mice', 'Species', '10090', (219, 223))	('tumor', 'Disease', (27, 32))	('A2BAR', 'Gene', '11541', (55, 60))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('decreased lung', 'Phenotype', 'HP:0002089', (107, 121))	('inhibition', 'Var', (41, 51))	('immunodeficient', 'Disease', 'MESH:D007153', (203, 218))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('immunodeficient', 'Disease', (203, 218))	('breast cancer', 'Disease', (155, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('decreased lung metastasis', 'Disease', 'MESH:D009362', (107, 132))
130178	31627281	However, A2AAR deletion does not inhibit the growth of all tumor types and might have the opposite effect.	('A2AAR', 'Gene', (9, 14))	('tumor', 'Disease', (59, 64))	('deletion', 'Var', (15, 23))	('AAR', 'molecular_function', 'GO:0004043', ('11', '14'))	('A2AAR', 'Gene', '11540', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
130194	31627281	suggested that high A2BAR expression is associated with worse prognoses in triple-negative breast cancer (TNBC).	('expression', 'MPA', (26, 36))	('high', 'Var', (15, 19))	('breast cancer', 'Disease', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('A2BAR', 'Gene', (20, 25))	('A2BAR', 'Gene', '11541', (20, 25))
130195	31627281	In a TNBC mouse model, A2BAR activation increased metastasis, while A2BAR antagonism in mouse models reduced the tumor burden by immune mechanisms and action on tumor cells.	('A2BAR', 'Gene', '11541', (68, 73))	('tumor', 'Disease', (113, 118))	('mouse', 'Species', '10090', (10, 15))	('antagonism', 'Var', (74, 84))	('activation increased', 'PosReg', (29, 49))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('A2BAR', 'Gene', (23, 28))	('metastasis', 'CPA', (50, 60))	('reduced', 'NegReg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('mouse', 'Species', '10090', (88, 93))	('A2BAR', 'Gene', '11541', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (161, 166))	('A2BAR', 'Gene', (68, 73))
130203	31627281	found that genetic or pharmacological inhibition of A2BAR expression or activity dramatically impaired tumor initiation and lung metastasis in mice.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('A2BAR', 'Gene', (52, 57))	('A2BAR', 'Gene', '11541', (52, 57))	('activity', 'MPA', (72, 80))	('inhibition', 'Var', (38, 48))	('impaired tumor initiation and lung metastasis', 'Disease', 'MESH:D009362', (94, 139))	('mice', 'Species', '10090', (143, 147))
130236	31627281	The non-adenosine 3,5-dicyanopyridine class of A2BAR agonists that are commercially available include BAY60-6583 8, LUF5834 7 and BAY68-4986 (A1AR agonist Capadenoson 6).	('BAY68-4986', 'Var', (130, 140))	('BAY60-6583', 'Chemical', 'MESH:C518875', (102, 112))	('BAY60-6583', 'Var', (102, 112))	('Capadenoson', 'Chemical', 'MESH:C575871', (155, 166))	('A2BAR', 'Gene', (47, 52))	('adenosine 3,5-dicyanopyridine', 'Chemical', 'MESH:D000241', (8, 37))	('A2BAR', 'Gene', '11541', (47, 52))	('BAY68-4986', 'Chemical', 'MESH:C575871', (130, 140))
130237	31627281	BAY60-6583 is an A2BAR-selective agonist but shows variable agonist Emax and potencies in different types of cells and tissues (.	('A2BAR', 'Gene', (17, 22))	('A2BAR', 'Gene', '11541', (17, 22))	('agonist', 'MPA', (60, 67))	('BAY60-6583', 'Chemical', 'MESH:C518875', (0, 10))	('BAY60-6583', 'Var', (0, 10))
130239	31627281	In cAMP accumulation assays, 5'-substituted nucleosides NECA and CPCA, and non-adenosine agonists BAY60-6583 and BAY68-4986 are all full agonists in cells overexpressing the recombinant human A2BAR.	('A2BAR', 'Gene', (192, 197))	('BAY68-4986', 'Var', (113, 123))	('nucleoside', 'Chemical', 'MESH:D009705', (44, 54))	('A2BAR', 'Gene', '11541', (192, 197))	('BAY60-6583', 'Var', (98, 108))	('NECA', 'Chemical', 'MESH:D019830', (56, 60))	('BAY60-6583', 'Chemical', 'MESH:C518875', (98, 108))	('cAMP', 'Gene', (3, 7))	('BAY68-4986', 'Chemical', 'MESH:C575871', (113, 123))	('human', 'Species', '9606', (186, 191))	('cAMP', 'Gene', '820', (3, 7))	('adenosine', 'Chemical', 'MESH:D000241', (79, 88))
130241	31627281	A quantitative operational model characterized BAY60-6583 as an ERK1/2-biased agonist and N6-substituted agonists as biased against calcium and beta-arrestin pathways.	('rat', 'Species', '10116', (18, 21))	('BAY60-6583', 'Chemical', 'MESH:C518875', (47, 57))	('calcium', 'Chemical', 'MESH:D002118', (132, 139))	('BAY60-6583', 'Var', (47, 57))	('ERK1/2', 'Gene', '5595;5594', (64, 70))	('ERK1/2', 'Gene', (64, 70))	('ERK1', 'molecular_function', 'GO:0004707', ('64', '68'))
130242	31627281	Interestingly, a partial A2BAR agonist BAY60-6583 behaved as an A2BAR antagonist in MIN-6 mouse pancreatic beta cells expressing low A2BAR levels, to induce insulin release.	('BAY60-6583', 'Var', (39, 49))	('induce', 'PosReg', (150, 156))	('A2BAR', 'Gene', (25, 30))	('A2BAR', 'Gene', '11541', (25, 30))	('A2BAR', 'Gene', '11541', (64, 69))	('mouse', 'Species', '10090', (90, 95))	('A2BAR', 'Gene', (133, 138))	('insulin release', 'MPA', (157, 172))	('A2BAR', 'Gene', '11541', (133, 138))	('A2BAR', 'Gene', (64, 69))	('BAY60-6583', 'Chemical', 'MESH:C518875', (39, 49))	('insulin', 'molecular_function', 'GO:0016088', ('157', '164'))
130243	31627281	It remains to be determined whether BAY60-6583 behaves as a partial agonist or an antagonist in other cell types endogenously expressing low levels of the A2BAR.	('A2BAR', 'Gene', '11541', (155, 160))	('BAY60-6583', 'Chemical', 'MESH:C518875', (36, 46))	('A2BAR', 'Gene', (155, 160))	('BAY60-6583', 'Var', (36, 46))
130245	31627281	BAY60-6583 was found to be a partial agonist in stimulating cAMP accumulation in several cell types endogenously expressing the A2BAR.	('cAMP', 'Gene', (60, 64))	('cAMP', 'Gene', '820', (60, 64))	('stimulating', 'MPA', (48, 59))	('BAY60-6583', 'Chemical', 'MESH:C518875', (0, 10))	('A2BAR', 'Gene', (128, 133))	('A2BAR', 'Gene', '11541', (128, 133))	('BAY60-6583', 'Var', (0, 10))
130246	31627281	For example, in an assay of cAMP accumulation in HEK293 cells endogenously expressing the A2BAR, the EC50 and agonist Emax values of BAY60-6583 are 242 nM and 73%, respectively.	('BAY60-6583', 'Chemical', 'MESH:C518875', (133, 143))	('A2BAR', 'Gene', (90, 95))	('BAY60-6583', 'Var', (133, 143))	('A2BAR', 'Gene', '11541', (90, 95))	('cAMP', 'Gene', '820', (28, 32))	('cAMP', 'Gene', (28, 32))	('HEK293', 'CellLine', 'CVCL:0045', (49, 55))
130247	31627281	However, in HEK293 cells overexpressing the recombinant A2BAR, the EC50 and Emax of BAY60-6583 are 6.1 nM and 102%, respectively.	('EC50', 'MPA', (67, 71))	('BAY60-6583', 'Var', (84, 94))	('HEK293', 'CellLine', 'CVCL:0045', (12, 18))	('A2BAR', 'Gene', (56, 61))	('Emax', 'MPA', (76, 80))	('A2BAR', 'Gene', '11541', (56, 61))	('BAY60-6583', 'Chemical', 'MESH:C518875', (84, 94))
130248	31627281	BAY60-6583 did not show any agonist activity in stimulating calcium mobilization or ERK1/2 phosphorylation in T24 bladder cancer cells.	('phosphorylation', 'MPA', (91, 106))	('bladder cancer', 'Disease', 'MESH:D001749', (114, 128))	('bladder cancer', 'Disease', (114, 128))	('BAY60-6583', 'Chemical', 'MESH:C518875', (0, 10))	('calcium', 'Chemical', 'MESH:D002118', (60, 67))	('ERK1/2', 'Gene', (84, 90))	('ERK1', 'molecular_function', 'GO:0004707', ('84', '88'))	('BAY60-6583', 'Var', (0, 10))	('ERK1/2', 'Gene', '5595;5594', (84, 90))	('phosphorylation', 'biological_process', 'GO:0016310', ('91', '106'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('bladder cancer', 'Phenotype', 'HP:0009725', (114, 128))	('stimulating calcium mobilization', 'MPA', (48, 80))	('calcium mobilization', 'biological_process', 'GO:0051209', ('60', '80'))
130249	31627281	BAY60-6583 also did not show any agonist activity in stimulating calcium transients in HEK293 cells, although it showed a robust effect in stimulating cAMP accumulation and ERK1/2 activity.	('activity', 'MPA', (180, 188))	('stimulating', 'Reg', (139, 150))	('BAY60-6583', 'Chemical', 'MESH:C518875', (0, 10))	('ERK1/2', 'Gene', (173, 179))	('cAMP', 'Gene', (151, 155))	('cAMP', 'Gene', '820', (151, 155))	('calcium transients', 'MPA', (65, 83))	('BAY60-6583', 'Var', (0, 10))	('ERK1/2', 'Gene', '5595;5594', (173, 179))	('HEK293', 'CellLine', 'CVCL:0045', (87, 93))	('ERK1', 'molecular_function', 'GO:0004707', ('173', '177'))	('calcium', 'Chemical', 'MESH:D002118', (65, 72))
130250	31627281	LUF5834 has been reported as a nonselective A2BAR agonist showing an EC50 of 12 nM in cAMP accumulation and an agonist Emax of 74% in comparison with NECA (Emax = 100%).	('cAMP', 'Gene', (86, 90))	('LUF5834', 'Var', (0, 7))	('cAMP', 'Gene', '820', (86, 90))	('A2BAR', 'Gene', (44, 49))	('NECA', 'Chemical', 'MESH:D019830', (150, 154))	('A2BAR', 'Gene', '11541', (44, 49))
130252	31627281	(2017) found that the A1AR agonist BAY68-4986 shows potent A2BAR agonist activity in stimulating cAMP accumulation, with an EC50 of 1.1 nM.	('cAMP', 'Gene', '820', (97, 101))	('A2BAR', 'Gene', '11541', (59, 64))	('BAY68-4986', 'Var', (35, 45))	('BAY68-4986', 'Chemical', 'MESH:C575871', (35, 45))	('cAMP', 'Gene', (97, 101))	('A2BAR', 'Gene', (59, 64))
130253	31627281	However, when tested in cAMP accumulation in HEK293 cells endogenously expressing the A2BAR, BAY68-4986 showed an EC50 of 500 nM and Emax of 95% (Gao and Jacobson, unpublished data).	('EC50', 'MPA', (114, 118))	('A2BAR', 'Gene', (86, 91))	('A2BAR', 'Gene', '11541', (86, 91))	('cAMP', 'Gene', (24, 28))	('cAMP', 'Gene', '820', (24, 28))	('BAY68-4986', 'Var', (93, 103))	('Emax', 'MPA', (133, 137))	('HEK293', 'CellLine', 'CVCL:0045', (45, 51))	('BAY68-4986', 'Chemical', 'MESH:C575871', (93, 103))
130254	31627281	Thus, for all nucleoside and non-nucleoside A2BAR agonists commercially available, only the partial agonist BAY60-6583 is A2BAR selective, which may show agonist activity in some signaling pathways, and antagonist properties in other signaling events.	('signaling pathways', 'Pathway', (179, 197))	('nucleoside', 'Chemical', 'MESH:D009705', (33, 43))	('signaling', 'biological_process', 'GO:0023052', ('179', '188'))	('agonist activity', 'MPA', (154, 170))	('A2BAR', 'Gene', '11541', (122, 127))	('BAY60-6583', 'Chemical', 'MESH:C518875', (108, 118))	('nucleoside', 'Chemical', 'MESH:D009705', (14, 24))	('BAY60-6583', 'Var', (108, 118))	('A2BAR', 'Gene', (122, 127))	('A2BAR', 'Gene', '11541', (44, 49))	('signaling', 'biological_process', 'GO:0023052', ('234', '243'))	('A2BAR', 'Gene', (44, 49))
130258	31627281	Commercially available A2BAR antagonists as pharmacological tools include 8-arylxanthine derivatives MRS1754 13, MRS1706 14, GS6201 18, PSB-1115 21, PSB-603 22a and PSB-0788 23.	('PSB-0788', 'Chemical', 'MESH:C438613', (165, 173))	('MRS1706', 'CellLine', 'CVCL:9H10', (113, 120))	('A2BAR', 'Gene', (23, 28))	('PSB-1115', 'Chemical', 'MESH:C518874', (136, 144))	('MRS1706', 'Var', (113, 120))	('A2BAR', 'Gene', '11541', (23, 28))	('PSB-603', 'Chemical', 'MESH:C000592275', (149, 156))	('8-arylxanthine', 'Chemical', 'MESH:C090700', (74, 88))	('MRS1754', 'Var', (101, 108))
130307	31627281	It has been suggested that adenosine increases endothelial cell proliferation, chemotaxis and capillary tube formation.	('adenosine', 'Chemical', 'MESH:D000241', (27, 36))	('rat', 'Species', '10116', (71, 74))	('endothelial cell proliferation', 'biological_process', 'GO:0001935', ('47', '77'))	('endothelial cell proliferation', 'CPA', (47, 77))	('chemotaxis', 'biological_process', 'GO:0006935', ('79', '89'))	('capillary tube formation', 'CPA', (94, 118))	('increases', 'PosReg', (37, 46))	('tube formation', 'biological_process', 'GO:0035148', ('104', '118'))	('adenosine', 'Var', (27, 36))	('chemotaxis', 'CPA', (79, 89))
130310	31627281	Bay60-6583, a selective A2BAR agonist, was demonstrated to induce in tumor expression of VEGF-A.	('A2BAR', 'Gene', '11541', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('VEGF-A', 'Gene', (89, 95))	('tumor', 'Disease', (69, 74))	('rat', 'Species', '10116', (50, 53))	('induce', 'PosReg', (59, 65))	('Bay60-6583', 'Var', (0, 10))	('Bay60-6583', 'Chemical', 'MESH:C518875', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('VEGF-A', 'Gene', '7422', (89, 95))	('A2BAR', 'Gene', (24, 29))
130332	31627281	The pharmacologic inhibition or the genetic deletion of the A2BAR results in a hyperinflammatory response to TLR ligation, similar to IFN-gamma treatment of macrophages, suggesting the NECA-mediated effect is via A2BAR, but not A2AAR.	('A2BAR', 'Gene', '11541', (213, 218))	('hyperinflammatory response', 'MPA', (79, 105))	('A2AAR', 'Gene', (228, 233))	('hyperinflammatory response', 'Phenotype', 'HP:0012649', (79, 105))	('IFN-gamma', 'Gene', '3458', (134, 143))	('IFN-gamma', 'Gene', (134, 143))	('AAR', 'molecular_function', 'GO:0004043', ('230', '233'))	('A2BAR', 'Gene', (60, 65))	('genetic deletion', 'Var', (36, 52))	('A2BAR', 'Gene', '11541', (60, 65))	('A2AAR', 'Gene', '11540', (228, 233))	('A2BAR', 'Gene', (213, 218))	('NECA', 'Chemical', 'MESH:D019830', (185, 189))
130336	31627281	Inhibition of A2BAR activation by PSB-603 was shown to suppress regulatory T cell (Treg) differentiation and IL-10 production, without affecting effector T cell activation measured by IL-2 production and CD25 expression.	('A2BAR', 'Gene', (14, 19))	('IL-2 production', 'biological_process', 'GO:0032623', ('184', '199'))	('A2BAR', 'Gene', '11541', (14, 19))	('IL-10 production', 'MPA', (109, 125))	('PSB-603', 'Chemical', 'MESH:C000592275', (34, 41))	('CD25', 'Gene', '3559', (204, 208))	('PSB-603', 'Gene', (34, 41))	('IL-2', 'Gene', (184, 188))	('IL-2', 'Gene', '3558', (184, 188))	('IL-10', 'molecular_function', 'GO:0005141', ('109', '114'))	('IL-2', 'molecular_function', 'GO:0005134', ('184', '188'))	('Inhibition', 'Var', (0, 10))	('T cell activation', 'biological_process', 'GO:0042110', ('154', '171'))	('IL-10 production', 'biological_process', 'GO:0032613', ('109', '125'))	('CD25', 'Gene', (204, 208))	('suppress', 'NegReg', (55, 63))
130339	31627281	MHC-II expression is required for CD4+ T cell anti-tumor responses, and loss of MHC-II is associated with aggressiveness of colorectal cancer and decreased levels of tumor-infiltrating lymphocytes.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (166, 171))	('loss', 'Var', (72, 76))	('decreased', 'NegReg', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('aggressiveness', 'Phenotype', 'HP:0000718', (106, 120))	('MHC-II', 'Gene', (80, 86))	('rat', 'Species', '10116', (178, 181))	('aggressiveness of colorectal cancer', 'Disease', (106, 141))	('aggressiveness of colorectal cancer', 'Disease', 'MESH:D015179', (106, 141))
130347	31627281	showed that melanoma-bearing mice treated with the selective A2BAR agonist BAY60-6583 had increased melanoma growth, which was associated with higher levels of immune regulatory mediators IL-10 and monocyte chemoattractant protein 1 and accumulation of tumor-associated CD11b+ and Gr1+ cells and myeloid-derived suppressor cells.	('protein', 'cellular_component', 'GO:0003675', ('223', '230'))	('levels of immune regulatory mediators IL-10', 'MPA', (150, 193))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('melanoma growth', 'Disease', (100, 115))	('higher', 'PosReg', (143, 149))	('mice', 'Species', '10090', (29, 33))	('BAY60-6583', 'Chemical', 'MESH:C518875', (75, 85))	('A2BAR', 'Gene', '11541', (61, 66))	('BAY60-6583', 'Var', (75, 85))	('IL-10', 'molecular_function', 'GO:0005141', ('188', '193'))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('CD11b', 'Gene', '3684', (270, 275))	('melanoma', 'Disease', (100, 108))	('CD11b', 'Gene', (270, 275))	('monocyte chemoattractant protein 1', 'Gene', (198, 232))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('increased', 'PosReg', (90, 99))	('A2BAR', 'Gene', (61, 66))	('tumor', 'Disease', (253, 258))	('melanoma growth', 'Disease', 'MESH:D008545', (100, 115))	('monocyte chemoattractant protein 1', 'Gene', '20296', (198, 232))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('accumulation', 'PosReg', (237, 249))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
130357	31627281	Antagonists in clinical trials for cancer patients (ClinicalTrials.gov NCT Identifier) include the mixed A2AAR/A2BAR antagonist AB928 26 (Phase 1, lung cancer, 03846310; Phase 1, breast and ovarian cancer, 03719326; Phase 1, gastrointestinal cancer, 03720678; Phase 1, advanced cancer, 03629756), PBF-1129 (structure not disclosed; Phase 1, non-small cell lung cancer, 03274479) and theophylline 11 (see below).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (345, 367))	('AB928', 'Gene', (128, 133))	('gastrointestinal cancer', 'Disease', (225, 248))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (225, 248))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (225, 248))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('PBF', 'Gene', '55893', (297, 300))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (341, 367))	('cancer', 'Disease', (278, 284))	('A2AAR', 'Gene', '11540', (105, 110))	('PBF', 'Gene', (297, 300))	('cancer', 'Disease', 'MESH:D009369', (361, 367))	('cancer', 'Disease', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Disease', (198, 204))	('A2BAR', 'Gene', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('breast and ovarian cancer', 'Disease', 'MESH:D061325', (179, 204))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('non-small cell lung cancer', 'Disease', (341, 367))	('lung cancer', 'Disease', (147, 158))	('A2AAR', 'Gene', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('theophylline', 'Chemical', 'MESH:D013806', (383, 395))	('patients', 'Species', '9606', (42, 50))	('cancer', 'Disease', (361, 367))	('lung cancer', 'Disease', 'MESH:D008175', (356, 367))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('AAR', 'molecular_function', 'GO:0004043', ('107', '110'))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', (242, 248))	('03629756', 'Var', (286, 294))	('lung cancer', 'Phenotype', 'HP:0100526', (356, 367))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (341, 367))	('A2BAR', 'Gene', '11541', (111, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('cancer', 'Disease', (35, 41))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
130361	31627281	AB928 was able to produce maximal AR blockade assessed as a function of NECA-stimulated pCREB induction in peripheral blood CD8+ T cells.	('NECA', 'Chemical', 'MESH:D019830', (72, 76))	('CREB', 'Gene', (89, 93))	('AB928', 'Var', (0, 5))	('CD8', 'Gene', (124, 127))	('CREB', 'Gene', '1385', (89, 93))	('CD8', 'Gene', '925', (124, 127))	('AR blockade', 'MPA', (34, 45))
130372	31627281	Thus, A2BAR antagonists are potentially a novel anticancer therapy, either in combination with other anticancer drugs or as a mono-therapy.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('antagonists', 'Var', (12, 23))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('A2BAR', 'Gene', (6, 11))	('A2BAR', 'Gene', '11541', (6, 11))
130377	31627281	Thus, A2BAR antagonism is a promising direction for the development of new cancer therapeutics.	('antagonism', 'Var', (12, 22))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('A2BAR', 'Gene', (6, 11))	('A2BAR', 'Gene', '11541', (6, 11))
130429	29207678	We also performed subgroup analyses categorized by the number of patients (> 400 and < 400), cut-off values (>= 150, < 150 and Per 100 unit), and ethnicity (Asian and Caucasion).	('patients', 'Species', '9606', (65, 73))	('> 400', 'Var', (75, 80))	('>= 150', 'Var', (109, 115))	('< 150', 'Var', (117, 122))
130606	24198628	In this context, the fact that five patients responded (irrespective of prior platinum compound) is encouraging and indicates that the substitution of MVAC for GC can partially reverse refractoriness to platinum compounds.	('substitution', 'Var', (135, 147))	('patients', 'Species', '9606', (36, 44))	('platinum', 'Chemical', 'MESH:D010984', (78, 86))	('GC', 'Chemical', '-', (160, 162))	('refractoriness', 'MPA', (185, 199))	('MVAC', 'Chemical', '-', (151, 155))	('platinum', 'Chemical', 'MESH:D010984', (203, 211))
130694	24009632	We also found scattered single cells in all cases, but, the number of scattered single cells was smaller in the MPUC group than in the HGUC group.	('MPUC', 'Var', (112, 116))	('C', 'Chemical', 'MESH:D002244', (138, 139))	('C', 'Chemical', 'MESH:D002244', (115, 116))	('MPUC', 'Chemical', '-', (112, 116))	('smaller', 'NegReg', (97, 104))
130730	33273457	Common germline-somatic variant interactions in advanced urothelial cancer The prevalence and biological consequences of deleterious germline variants in urothelial cancer (UC) are not fully characterized.	('urothelial cancer', 'Disease', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('urothelial cancer', 'Disease', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('urothelial cancer', 'Disease', 'MESH:D014523', (57, 74))	('urothelial cancer', 'Disease', 'MESH:D014523', (154, 171))	('interactions', 'Reg', (32, 44))	('variant', 'Var', (24, 31))
130739	33273457	Recent work using targeted sequencing of known cancer susceptibility genes revealed a 14-24% prevalence of germline variants in UC patients, which accounts for only a fraction of the genetic predisposition for the disease.	('patients', 'Species', '9606', (131, 139))	('variants', 'Var', (116, 124))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
130740	33273457	To define the spectrum of germline variants affecting protein-coding genes and germline-somatic interactions (GSIs) in UC patients, we performed WES of prospectively collected germline DNA samples and 157 tumors from 80 UC patients at Weill Cornell Medicine (WCM-UC cohort) (Figs.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('DNA', 'cellular_component', 'GO:0005574', ('185', '188'))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('variants', 'Var', (35, 43))	('patients', 'Species', '9606', (122, 130))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (205, 211))	('patients', 'Species', '9606', (223, 231))
130743	33273457	To focus on functionally consequential germline variants, we adopted an approach to identify and prioritize germline variants that truncate tumor suppressor proteins.	('tumor suppressor', 'biological_process', 'GO:0051726', ('140', '156'))	('variants', 'Var', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('140', '156'))	('truncate', 'NegReg', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
130750	33273457	We reasoned that variants that truncate tumor suppressor proteins would increase predisposition to cancer and potentially play an important role in tumor progression in the context of the classical two-hit model.	('increase', 'PosReg', (72, 80))	('variants', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('predisposition', 'MPA', (81, 95))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancer', 'Disease', (99, 105))	('play', 'Reg', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))
130773	33273457	The WCM-UC-EUR (Odds ratio (OR) = 2.12, p = 2.4e-4) and TCGA-BLCA-EUR (OR = 2.04, p = 7.4e-17) cancer patients were more likely to harbor pDGVs in this gene set compared to SPARK-EUR non-cancer subjects.	('non-cancer', 'Disease', (183, 193))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('Odds ratio (OR) = 2.12', 'Gene', '81078', (16, 38))	('non-cancer', 'Disease', 'MESH:D009369', (183, 193))	('BLCA', 'Phenotype', 'HP:0009725', (61, 65))	('cancer', 'Disease', (187, 193))	('pDGVs', 'Var', (138, 143))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Disease', (95, 101))	('Odds ratio (OR) = 2.12', 'Gene', (16, 38))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('WCM-UC-EUR', 'Disease', (4, 14))
130774	33273457	Similarly, WCM-UC-AJ (OR = 1.75, p = 0.038) and TCGA-BLCA-AJ (OR = 1.61, p = 0.019) cancer patients were more likely to harbor pDGVs in this gene set compared to the SPARK-AJ non-cancer subjects (Online Methods) (Fig.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('patients', 'Species', '9606', (91, 99))	('BLCA', 'Phenotype', 'HP:0009725', (53, 57))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('pDGVs', 'Var', (127, 132))	('WCM-UC-AJ', 'Disease', (11, 20))	('non-cancer', 'Disease', (175, 185))	('non-cancer', 'Disease', 'MESH:D009369', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('WCM-UC-AJ', 'Disease', 'MESH:D003093', (11, 20))	('cancer', 'Disease', (179, 185))
130779	33273457	Genomic variants that confer a fitness advantage on tumor cells tend to aggregate in functionally significant domains.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('variants', 'Var', (8, 16))	('aggregate', 'MPA', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('fitness', 'Disease', (31, 38))	('fitness', 'Disease', 'MESH:D012640', (31, 38))
130781	33273457	Six pDGVs in the PINX1, MOB1A, CLTCL1, PRR5, CCDC136, and TRIM32 genes involved the exact amino acid residues affected by known somatic cancer variants (Supplementary Data 12).	('TRIM32', 'Gene', (58, 64))	('PINX1', 'Gene', (17, 22))	('PRR5', 'Gene', '55615', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('PRR', 'molecular_function', 'GO:0038187', ('39', '42'))	('MOB1A', 'Gene', (24, 29))	('CLTCL1', 'Gene', (31, 37))	('CCDC136', 'Gene', '64753', (45, 52))	('TRIM32', 'Gene', '22954', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('MOB1A', 'Gene', '55233', (24, 29))	('CCDC136', 'Gene', (45, 52))	('cancer', 'Disease', (136, 142))	('PINX1', 'Gene', '54984', (17, 22))	('CLTCL1', 'Gene', '8218', (31, 37))	('PRR5', 'Gene', (39, 43))	('variants', 'Var', (143, 151))
130782	33273457	We identified a pDGV in the Xeroderma-Pigmentosum Group A-Complementing gene (XPA) gene in a UC patient.	('Xeroderma-Pigmentosum', 'Disease', 'MESH:D014983', (28, 49))	('pDGV', 'Var', (16, 20))	('Xeroderma-Pigmentosum', 'Disease', (28, 49))	('patient', 'Species', '9606', (96, 103))	('XPA', 'Gene', (78, 81))
130784	33273457	This pDGV resulted in an L200* stop codon clustered with other known somatic variants that target the DNA binding domain of XPA spanning codons 104-225 (Fig.	('variants', 'Var', (77, 85))	('XPA', 'Gene', (124, 127))	('L200*', 'Var', (25, 30))	('L200*', 'SUBSTITUTION', 'None', (25, 30))	('DNA binding', 'molecular_function', 'GO:0003677', ('102', '113'))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
130788	33273457	To predict the functional impact of the L200* XPA pDGV within this complex, we superimposed it on the recently published XPA-TFIIH complex structure obtained by cryogenic electron microscopy (cryo-EM) (Fig.	('TFIIH', 'Gene', (125, 130))	('TFIIH', 'Gene', '2071', (125, 130))	('L200*', 'Var', (40, 45))	('L200*', 'SUBSTITUTION', 'None', (40, 45))
130789	33273457	This model predicts that L200* eliminates the entire DNA-binding alpha-helix domain of XPA.	('XPA', 'Gene', (87, 90))	('entire DNA-binding alpha-helix domain', 'MPA', (46, 83))	('L200*', 'Var', (25, 30))	('L200*', 'SUBSTITUTION', 'None', (25, 30))	('eliminates', 'NegReg', (31, 41))	('DNA-binding', 'molecular_function', 'GO:0003677', ('53', '64'))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))
130790	33273457	This suggests that the L200* pDGV potentially causes significant disruption of DNA binding, which is required for nucleotide-excision repair(Fig.	('disruption', 'NegReg', (65, 75))	('nucleotide-excision repair', 'biological_process', 'GO:0006289', ('114', '140'))	('pDGV', 'Gene', (29, 33))	('L200*', 'SUBSTITUTION', 'None', (23, 28))	('DNA binding', 'Interaction', (79, 90))	('DNA binding', 'molecular_function', 'GO:0003677', ('79', '90'))	('L200*', 'Var', (23, 28))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
130805	33273457	For example, these variants can transmit genetic information that mediates hereditary cancer predisposition.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('variants', 'Var', (19, 27))	('hereditary cancer', 'Disease', (75, 92))	('hereditary cancer', 'Disease', 'MESH:D009369', (75, 92))
130810	33273457	Recent studies using targeted sequencing approaches showed that 7.3%-24% of UC patients carry pathogenic germline variants.	('germline', 'Var', (105, 113))	('pathogenic', 'Reg', (94, 104))	('patients', 'Species', '9606', (79, 87))
130814	33273457	We prioritized germline variants defined as pathogenic or likely pathogenic by ClinVar or those resulting in truncated proteins encoded by known TSGs.	('TSG', 'Gene', (145, 148))	('TSG', 'Gene', '57045', (145, 148))	('truncated', 'MPA', (109, 118))	('variants', 'Var', (24, 32))
130815	33273457	Our DGVar framework expands the definition of putative pathogenicity to include variants that eliminate critical domains of TSGs, likely resulting in loss of function.	('TSG', 'Gene', (124, 127))	('critical domains', 'MPA', (104, 120))	('eliminate', 'NegReg', (94, 103))	('TSG', 'Gene', '57045', (124, 127))	('variants', 'Var', (80, 88))
130816	33273457	We reasoned that germline variants that truncate tumor suppressor proteins would potentially predispose to UC and play a critical role in tumor progression in the context of the two-hit carcinogenesis model.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (138, 143))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('49', '65'))	('predispose', 'Reg', (93, 103))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor suppressor', 'biological_process', 'GO:0051726', ('49', '65'))	('role', 'Reg', (130, 134))	('truncate', 'NegReg', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('variants', 'Var', (26, 34))
130818	33273457	We identified a pDGV affecting exon 5 of XPA in a UC patient using WES and confirmed it using Sanger sequencing of the patient's germline DNA.	('patient', 'Species', '9606', (119, 126))	('pDGV affecting', 'Var', (16, 30))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('XPA', 'Gene', (41, 44))	('patient', 'Species', '9606', (53, 60))
130819	33273457	Functional modeling predicted that this pDGV (L200*) eliminates the protein's DNA-binding domain critical for nucleotide-excision repair.	('eliminates', 'NegReg', (53, 63))	('pDGV', 'Gene', (40, 44))	('nucleotide-excision repair', 'MPA', (110, 136))	('L200*', 'Var', (46, 51))	('DNA-binding', 'molecular_function', 'GO:0003677', ('78', '89'))	('nucleotide-excision repair', 'biological_process', 'GO:0006289', ('110', '136'))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('protein', 'Protein', (68, 75))	('L200*', 'SUBSTITUTION', 'None', (46, 51))
130821	33273457	The exon 6 XPA germline variants R228* and H244R, which primarily affect the TFIIH-interacting region in the protein's c-terminus, have been previously associated with a mild xeroderma pigmentosum phenotype.	('xeroderma pigmentosum', 'Disease', (175, 196))	('R228*', 'SUBSTITUTION', 'None', (33, 38))	('R228*', 'Var', (33, 38))	('H244R', 'Mutation', 'rs144725456', (43, 48))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('TFIIH', 'Gene', '2071', (77, 82))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (175, 196))	('associated with', 'Reg', (152, 167))	('H244R', 'Var', (43, 48))	('TFIIH', 'Gene', (77, 82))
130822	33273457	Clinical and mouse model data suggest that heterozygous carriers of XPA mutations have a higher risk for developing cancer.	('mutations', 'Var', (72, 81))	('mouse', 'Species', '10090', (13, 18))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('XPA', 'Gene', (68, 71))
130823	33273457	It is possible that the L200* truncating mutation we identified in XPA results in nonsense-mediated decay decreasing the relative abundance of the XPA protein.	('L200*', 'Var', (24, 29))	('nonsense-mediated decay', 'MPA', (82, 105))	('relative abundance', 'MPA', (121, 139))	('XPA', 'Gene', (67, 70))	('L200*', 'SUBSTITUTION', 'None', (24, 29))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('decreasing', 'NegReg', (106, 116))
130825	33273457	We identified a TRIM32 R500* pDGV that eliminated its NHL domain.	('eliminated', 'NegReg', (39, 49))	('R500*', 'SUBSTITUTION', 'None', (23, 28))	('R500*', 'Var', (23, 28))	('TRIM32', 'Gene', (16, 22))	('TRIM32', 'Gene', '22954', (16, 22))	('NHL domain', 'MPA', (54, 64))
130829	33273457	Knockout of Trim32 resulted in a higher incidence of medulloblastoma formation in the Ptch1 +- mice and the upregulation of SHH target genes, suggesting a tumor suppressor effect from antagonizing SHH signaling.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('155', '171'))	('Trim32', 'Gene', (12, 18))	('medulloblastoma', 'Disease', (53, 68))	('mice', 'Species', '10090', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('formation', 'biological_process', 'GO:0009058', ('69', '78'))	('Trim32', 'Gene', '69807', (12, 18))	('Ptch1', 'Gene', '19206', (86, 91))	('tumor', 'Disease', (155, 160))	('tumor suppressor', 'biological_process', 'GO:0051726', ('155', '171'))	('Knockout', 'Var', (0, 8))	('medulloblastoma', 'Disease', 'MESH:D008527', (53, 68))	('signaling', 'biological_process', 'GO:0023052', ('201', '210'))	('upregulation', 'PosReg', (108, 120))	('Ptch1', 'Gene', (86, 91))	('medulloblastoma', 'Phenotype', 'HP:0002885', (53, 68))
130831	33273457	KLK6 re-expression in breast cancer cells reversed their malignant phenotype by inhibiting epithelial-to-mesenchymal transition consistent with a tumor suppressor role.	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('91', '127'))	('breast cancer', 'Disease', (22, 35))	('re-expression', 'Var', (5, 18))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('tumor suppressor', 'biological_process', 'GO:0051726', ('146', '162'))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('KLK6', 'Gene', '5653', (0, 4))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('146', '162'))	('epithelial-to-mesenchymal transition', 'CPA', (91, 127))	('inhibiting', 'NegReg', (80, 90))	('KLK6', 'Gene', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
130838	33273457	First, we examined LOH, a hallmark of pDGV pathogenicity within the Knudson two-hit hypothesis, which suggests that most TSGs require inactivation of both alleles to cause a phenotypic change.	('TSG', 'Gene', (121, 124))	('inactivation', 'Var', (134, 146))	('TSG', 'Gene', '57045', (121, 124))
130850	33273457	A randomized phase III study in patients with castrate-resistant prostate cancer recruited patients with alterations in the homologous recombination pathway.	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (91, 99))	('homologous recombination', 'biological_process', 'GO:0035825', ('124', '148'))	('prostate cancer', 'Disease', 'MESH:D011471', (65, 80))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('alterations', 'Var', (105, 116))	('homologous recombination pathway', 'Pathway', (124, 156))	('prostate cancer', 'Disease', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
130854	33273457	By expanding the repertoire of pDGVs in DNA damage repair genes, our results open the door to trials of these targeted therapeutic strategies in properly selected UC patients.	('DNA damage repair genes', 'Gene', (40, 63))	('pDGVs', 'Var', (31, 36))	('patients', 'Species', '9606', (166, 174))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))
130867	33273457	The gene harboring each variant and the corresponding effect on transcript products were annotated using SnpEff v4.2 with the pre-built GRCh37.75 database.	('pre', 'molecular_function', 'GO:0003904', ('126', '129'))	('v4.2', 'Gene', (112, 116))	('transcript products', 'MPA', (64, 83))	('variant', 'Var', (24, 31))	('v4.2', 'Gene', '28781', (112, 116))
130871	33273457	ClinVar pathogenic variants associated with non-cancer conditions were manually reviewed and excluded.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('ClinVar', 'Gene', (0, 7))	('non-cancer', 'Disease', (44, 54))	('non-cancer', 'Disease', 'MESH:D009369', (44, 54))	('variants', 'Var', (19, 27))
130872	33273457	We then screened TSGs for protein-truncating variants (stop gain or frameshift) that pass the "inbreeding coefficient" and" "VQS" filters in ExAC.	('TSG', 'Gene', (17, 20))	('frameshift', 'Var', (68, 78))	('TSG', 'Gene', '57045', (17, 20))
130889	33273457	Somatic SNVs and indels were identified using our in-house consensus multi-tool pipeline, which integrated four different somatic variant callers: MuTect2, Strelka, VarScan, and SomaticSniper; these tools identified SNVs in a paired analysis of the tumor and its matched normal sample.	('SNVs', 'Var', (216, 220))	('tumor', 'Disease', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))
130890	33273457	Strelka and VarScan were also used to identify indels in the tumor sample.	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('indels', 'Var', (47, 53))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))
130914	33273457	First, gene-level events were evaluated by searching for germline and somatic variants that affect the same TSG.	('TSG', 'Gene', '57045', (108, 111))	('TSG', 'Gene', (108, 111))	('variants', 'Var', (78, 86))
130915	33273457	Second, this concept was extended to a pathway-level analysis by identifying germline and somatic variants affecting TSG or oncogenes belonging to the same pathway.	('TSG', 'Gene', '57045', (117, 120))	('TSG', 'Gene', (117, 120))	('variants', 'Var', (98, 106))
130918	33273457	When searching for both gene-level and pathway-level GSIs, variants in TSGs were required to be protein-truncating (loss of function of TSG) and variants in oncogenes to be non-truncating.	('loss of function', 'NegReg', (116, 132))	('TSG', 'Gene', '57045', (136, 139))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('variants', 'Var', (59, 67))	('TSG', 'Gene', (71, 74))	('TSG', 'Gene', (136, 139))	('TSG', 'Gene', '57045', (71, 74))	('protein-truncating', 'NegReg', (96, 114))
130929	33178590	A total of 10,967 tumor samples comprising 32 cancer types from The Cancer Genome Atlas (TCGA) datasets were analyzed for MET abnormal expression, mutations, and copy number variants (CNVs).	('MET', 'Gene', '79811', (122, 125))	('mutations', 'Var', (147, 156))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', (18, 23))	('cancer', 'Disease', (46, 52))	('MET', 'Gene', (122, 125))	('Cancer', 'Disease', 'MESH:D009369', (68, 74))	('Cancer', 'Disease', (68, 74))	('copy number variants', 'Var', (162, 182))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
130931	33178590	Lung adenocarcinoma (LUAD) has most targetable mutations located in the juxtamembrane domain, and both high expression and amplification of MET are significantly associated with poor prognosis.	('MET', 'Gene', '79811', (140, 143))	('LUAD', 'Phenotype', 'HP:0030078', (21, 25))	('MET', 'Gene', (140, 143))	('juxtamembrane', 'cellular_component', 'GO:0005886', ('72', '85'))	('mutations', 'Var', (47, 56))	('associated', 'Reg', (162, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('juxtamembrane', 'cellular_component', 'GO:0019897', ('72', '85'))	('juxtamembrane', 'cellular_component', 'GO:0009898', ('72', '85'))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('amplification', 'Var', (123, 136))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('juxtamembrane', 'cellular_component', 'GO:0009897', ('72', '85'))
130936	33178590	This study provided significant and comprehensive information regarding MET abnormal expression, alterations (mutations and CNVs), and their clinical associations among 32 cancer types and offered insights into the full MET alteration spectrum and its implications for prognosis and treatment.	('MET', 'Gene', '79811', (220, 223))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('abnormal', 'Var', (76, 84))	('MET', 'Gene', (220, 223))	('cancer', 'Disease', (172, 178))	('alterations', 'Var', (97, 108))	('MET', 'Gene', '79811', (72, 75))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('MET', 'Gene', (72, 75))	('associations', 'Interaction', (150, 162))
130939	33178590	It is frequently activated in human tumors by various mechanisms, such as mutations, amplification, and overexpression, thus leading to malignant transformation and metastasis.	('malignant transformation', 'CPA', (136, 160))	('metastasis', 'CPA', (165, 175))	('leading to', 'Reg', (125, 135))	('human', 'Species', '9606', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('overexpression', 'Var', (104, 118))	('mutations', 'Var', (74, 83))	('activated', 'PosReg', (17, 26))	('amplification', 'Var', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
130942	33178590	Moreover, in esophageal carcinoma (ESCA) and kidney renal papillary cell carcinoma (KIRP), gene amplification with consequent protein overexpression and constitutive kinase activation of MET has been reported.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (13, 33))	('protein', 'Protein', (126, 133))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (13, 33))	('overexpression', 'PosReg', (134, 148))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (52, 82))	('MET', 'Gene', '79811', (187, 190))	('ESCA', 'Phenotype', 'HP:0011459', (35, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('MET', 'Gene', (187, 190))	('kidney renal papillary cell carcinoma', 'Disease', (45, 82))	('gene amplification', 'Var', (91, 109))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (45, 82))	('esophageal carcinoma', 'Disease', (13, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
130945	33178590	Especially in lung cancer, inhibition of MET receptor activity has shown promising results and has become a standard therapy for patients.	('receptor activity', 'molecular_function', 'GO:0038023', ('45', '62'))	('patients', 'Species', '9606', (129, 137))	('MET', 'Gene', (41, 44))	('lung cancer', 'Disease', (14, 25))	('MET', 'Gene', '79811', (41, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('inhibition', 'Var', (27, 37))	('activity', 'MPA', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('receptor activity', 'molecular_function', 'GO:0038024', ('45', '62'))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))
130959	33178590	Especially, in single- and cross-cancer queries, OQL algorithm can be utilized to accurately identify copy number alterations, mutations, mRNA, and protein expression profiles.	('mRNA', 'MPA', (138, 142))	('copy number alterations', 'Var', (102, 125))	('cross-cancer', 'Disease', (27, 39))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('cross-cancer', 'Disease', 'MESH:D009369', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (127, 136))
130977	33178590	MET mutations were observed most commonly in UCEC (12.3%), SKCM (10.5%), KIRP (8.8%), bladder urothelial carcinoma (BLCA, 4.4%), COADREAD (4.4%), and LUAD (4.2%).	('KIRP', 'Disease', (73, 77))	('MET', 'Gene', '79811', (0, 3))	('bladder urothelial carcinoma', 'Disease', (86, 114))	('observed', 'Reg', (19, 27))	('COADREAD', 'Disease', (129, 137))	('MET', 'Gene', (0, 3))	('UCEC', 'Disease', (45, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('mutations', 'Var', (4, 13))	('SKCM', 'Disease', (59, 63))	('LUAD', 'Phenotype', 'HP:0030078', (150, 154))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (86, 114))
130983	33178590	The most common domains were the other domain (91 samples), Sema domain (83 samples), Pkinase-Tyr domain (69 samples), TIG domain (563-654 aa, 18 samples), TIG domain (742-815 aa, 17 samples), TIG domain (657-728 aa, 12 samples), and PSI domain (7 samples).	('Tyr', 'Chemical', 'MESH:D014443', (94, 97))	('657-728 aa', 'Var', (205, 215))	('Sema', 'Gene', (60, 64))	('Sema', 'Gene', '7869', (60, 64))	('TIG', 'Disease', (119, 122))
130985	33178590	Mutations in KIRP were primarily located in the Pkinase-Tyr domain, approximately three times more than the mutations located in the other domain.	('Tyr', 'Chemical', 'MESH:D014443', (56, 59))	('Mutations', 'Var', (0, 9))	('KIRP', 'Gene', (13, 17))
130986	33178590	Mutations in COADREAD and GBM were mainly located in the Sema domain (Figure 2B and Supplementary Table S3).	('Mutations', 'Var', (0, 9))	('Sema', 'Gene', (57, 61))	('Sema', 'Gene', '7869', (57, 61))	('COADREAD', 'Gene', (13, 21))
130989	33178590	For example, the 1,010-aa mutation was found in seven samples (six samples with X1010 splice, one with D1010fs) and occurred almost exclusively in LUAD (6/7) (Supplementary Figure S2B).	('D1010fs', 'Var', (103, 110))	('D1010fs', 'Mutation', 'p.D1010fsX', (103, 110))	('X1010 splice', 'Var', (80, 92))	('LUAD', 'Phenotype', 'HP:0030078', (147, 151))
130992	33178590	The only other tumor with mutations at this position was LGG (one sample with X1010_splice), but its role was almost unknown to this cancer.	('LGG', 'Disease', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', (133, 139))	('tumor', 'Disease', (15, 20))	('X1010_splice', 'Var', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
130993	33178590	The 1,148-aa mutation in the Pkinase-Tyr domain was also observed in seven samples [six samples with R1148Q (three SKCMs, one BLCA, one BRCA, one COADREAD), one sample with R1148* (one UCEC)].	('R1148*', 'Var', (173, 179))	('observed', 'Reg', (57, 65))	('Pkinase-Tyr', 'Enzyme', (29, 40))	('R1148Q', 'Var', (101, 107))	('R1148Q', 'Mutation', 'p.R1148Q', (101, 107))	('Tyr', 'Chemical', 'MESH:D014443', (37, 40))	('R1148*', 'SUBSTITUTION', 'None', (173, 179))
130995	33178590	The most mutated positions in KIRP (17 of 25 mutations) were located at the Pkinase Tyr domain, especially at the 1,250-aa position (four samples with M1250T) and the 1,092- to 1,094-aa position (three with V1092I, three with H1094Y).	('H1094Y', 'Var', (226, 232))	('V1092I', 'Var', (207, 213))	('M1250T', 'Var', (151, 157))	('V1092I', 'Mutation', 'p.V1092I', (207, 213))	('H1094Y', 'Mutation', 'p.H1094Y', (226, 232))	('Tyr', 'Chemical', 'MESH:D014443', (84, 87))	('M1250T', 'Mutation', 'p.M1250T', (151, 157))	('mutated', 'Reg', (9, 16))
130997	33178590	The most mutated positions in UCEC (3 of 78 mutations) were located at the Pkinase-Tyr domain at the 1,186-aa position (one with L1186F, one with L1186I, one with L1186R), but its oncogenic role was considered unknown.	('L1186F', 'Mutation', 'p.L1186F', (129, 135))	('L1186F', 'Var', (129, 135))	('L1186I', 'Mutation', 'p.L1186I', (146, 152))	('Tyr', 'Chemical', 'MESH:D014443', (83, 86))	('L1186R', 'Mutation', 'p.L1186R', (163, 169))	('L1186I', 'Var', (146, 152))	('L1186R', 'Var', (163, 169))	('mutated', 'Reg', (9, 16))
130998	33178590	D1228Y/A and T222K alterations were found in UCEC (one with D1228Y, one with D1228A, one with T222K) and known to be likely oncogenic and predicted oncogenic, respectively (Supplementary Figure S2D).	('D1228Y', 'SUBSTITUTION', 'None', (60, 66))	('D1228Y', 'Var', (60, 66))	('D1228A', 'Var', (77, 83))	('T222K', 'Var', (13, 18))	('T222K', 'Mutation', 'p.T222K', (94, 99))	('D1228Y', 'Mutation', 'p.D1228Y', (0, 6))	('D1228A', 'Mutation', 'p.D1228A', (77, 83))	('D1228Y', 'SUBSTITUTION', 'None', (0, 6))	('D1228Y', 'Var', (0, 6))	('UCEC', 'Disease', (45, 49))	('D1228Y', 'Mutation', 'p.D1228Y', (60, 66))	('T222K', 'Mutation', 'p.T222K', (13, 18))
131000	33178590	Next, we analyzed the clinical targeted therapy implications of MET mutation using cBioPortal, which could provide the annotation of variants from different databases, including COSMIC, Cancer Hotspots method, CIViC, My Cancer Genome, and OncoKB.	('MET', 'Gene', (64, 67))	('MET', 'Gene', '79811', (64, 67))	('CIViC', 'Disease', 'None', (210, 215))	('Cancer', 'Phenotype', 'HP:0002664', (186, 192))	('CIViC', 'Disease', (210, 215))	('Cancer', 'Disease', (220, 226))	('Cancer', 'Disease', (186, 192))	('Cancer', 'Disease', 'MESH:D009369', (186, 192))	('Cancer', 'Disease', 'MESH:D009369', (220, 226))	('Cancer', 'Phenotype', 'HP:0002664', (220, 226))	('variants', 'Var', (133, 141))
131001	33178590	Thus, for the clinical targeted therapy implications, each MET somatic mutation could be classified into four levels as defined by OncoKB: level 2 (seven mutations), level 3B (one mutation), level 4 (13 mutations), and level NA (290 mutations) (Figure 4A and Supplementary Table S2).	('MET', 'Gene', '79811', (59, 62))	('MET', 'Gene', (59, 62))	('mutations', 'Var', (154, 163))
131008	33178590	Among the 311 samples with MET mutations mentioned above, 129 also harbored MET CNVs (108 with gain, nine with amplification, and 12 with shallow deletion).	('mutations', 'Var', (31, 40))	('MET', 'Gene', (27, 30))	('MET', 'Gene', '79811', (76, 79))	('MET', 'Gene', (76, 79))	('gain', 'PosReg', (95, 99))	('MET', 'Gene', '79811', (27, 30))
131010	33178590	As shown in Figure 5A and Figures 1A,B, KIRP harbored a very high proportion of gain and was also the cancer type with higher MET expression.	('MET', 'Gene', '79811', (126, 129))	('KIRP', 'Var', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('MET', 'Gene', (126, 129))	('cancer', 'Disease', (102, 108))	('gain', 'PosReg', (80, 84))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
131015	33178590	MET alterations were observed most commonly in UCEC (10.21%), SKCM (10.14%), and KIRP (9.89%), in which mutations were more common.	('SKCM', 'Disease', (62, 66))	('MET', 'Gene', '79811', (0, 3))	('alterations', 'Var', (4, 15))	('UCEC', 'Disease', (47, 51))	('MET', 'Gene', (0, 3))	('KIRP', 'Disease', (81, 85))	('observed', 'Reg', (21, 29))
131016	33178590	Other cancer types with dominant MET mutations but at much lower mutation rates included LUAD (3.53%), BLCA (3.89%), COADREAD (3.2%), UCS (3.51%), and PAAD (0.54%).	('COADREAD', 'Disease', (117, 125))	('LUAD', 'Disease', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('UCS', 'Disease', (134, 137))	('PAAD', 'Phenotype', 'HP:0006725', (151, 155))	('PAAD', 'Disease', (151, 155))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('BLCA', 'Disease', (103, 107))	('MET', 'Gene', '79811', (33, 36))	('cancer', 'Disease', (6, 12))	('MET', 'Gene', (33, 36))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))
131019	33178590	Approximately half of the mutations (29 of 67 mutations) in the Pkinase-Tyr domain also had MET copy gain, while nearly half of the mutations (44 of 90 mutations) in the other function-unknown domain were accompanied by amplification, gain, and shallow deletion.	('Pkinase-Tyr', 'Gene', (64, 75))	('copy', 'MPA', (96, 100))	('mutations', 'Var', (46, 55))	('MET', 'Gene', (92, 95))	('mutations', 'Var', (132, 141))	('gain', 'PosReg', (101, 105))	('amplification', 'MPA', (220, 233))	('Tyr', 'Chemical', 'MESH:D014443', (72, 75))	('mutations', 'Var', (26, 35))	('gain', 'PosReg', (235, 239))	('MET', 'Gene', '79811', (92, 95))
131026	33178590	Moreover, when the survival association analysis was performed only for MET mutation status, MET mutations were associated with poor prognosis in LUAD (Figure 7D).	('mutations', 'Var', (97, 106))	('LUAD', 'Phenotype', 'HP:0030078', (146, 150))	('MET', 'Gene', '79811', (93, 96))	('LUAD', 'Disease', (146, 150))	('MET', 'Gene', '79811', (72, 75))	('MET', 'Gene', (93, 96))	('MET', 'Gene', (72, 75))
131028	33178590	UCEC, SKCM, and KIRP had the highest MET alteration, and mutations accounted for the major proportion.	('MET', 'Gene', (37, 40))	('mutations', 'Var', (57, 66))	('MET', 'Gene', '79811', (37, 40))
131029	33178590	While mutations in UCEC and SKCM were most commonly located in the Sema domain and the other function-unknown domain, mutations in KIRP were primarily located in the Pkinase-Tyr domain, which is more important for treatment selection.	('KIRP', 'Gene', (131, 135))	('located', 'Reg', (52, 59))	('Sema', 'Gene', (67, 71))	('mutations', 'Var', (118, 127))	('Sema', 'Gene', '7869', (67, 71))	('Tyr', 'Chemical', 'MESH:D014443', (174, 177))	('mutations', 'Var', (6, 15))	('UCEC', 'Gene', (19, 23))
131031	33178590	Other cancer types, including LUAD, BLCA, COADREAD, and UCS harbored similar characteristics; all their alteration frequency was between 4 and 6%, and mutation was the primary alteration.	('LUAD', 'Disease', (30, 34))	('BLCA', 'Disease', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutation', 'Var', (151, 159))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('COADREAD', 'Disease', (42, 50))	('UCS', 'Disease', (56, 59))	('LUAD', 'Phenotype', 'HP:0030078', (30, 34))
131032	33178590	Mutations in LUAD are mainly X1010_splices, which are in exon 14, and mutations in this region are known for targeted therapy in clinical practice in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('LUAD', 'Gene', (13, 17))	('X1010_splices', 'Var', (29, 42))	('NSCLC', 'Disease', (150, 155))	('LUAD', 'Phenotype', 'HP:0030078', (13, 17))
131040	33178590	In addition, the prognostic role of MET in LUAD was quite clear, and both high expression and amplification of MET were significantly associated with poor prognosis.	('associated', 'Reg', (134, 144))	('amplification', 'Var', (94, 107))	('high', 'Var', (74, 78))	('MET', 'Gene', '79811', (111, 114))	('MET', 'Gene', (111, 114))	('MET', 'Gene', '79811', (36, 39))	('MET', 'Gene', (36, 39))	('LUAD', 'Phenotype', 'HP:0030078', (43, 47))
131043	33178590	Compared with other cancer types, mutations in KIRP were primarily located in the Pkinase-Tyr domain, which is known for targeted therapy with TKIs.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Tyr', 'Chemical', 'MESH:D014443', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('mutations', 'Var', (34, 43))
131046	33178590	In addition, high expression of MET was discovered in KIRP, and most mutations in KIRP were oncogenic and likely oncogenic; however, there was no association observed between MET expression and patient prognosis in this dataset, although some reports indicated otherwise.	('MET', 'Gene', '79811', (175, 178))	('mutations', 'Var', (69, 78))	('patient', 'Species', '9606', (194, 201))	('MET', 'Gene', (175, 178))	('KIRP', 'Gene', (82, 86))	('MET', 'Gene', '79811', (32, 35))	('MET', 'Gene', (32, 35))
131047	33178590	This paradox could be due to the absence of well-known responsive mutations and the presence of alternative compensatory pathways interacting with MET pathways, such as the MAPK/ERK and PI3K/AKT pathways, which inspired further research on combinatorial therapy strategies in KIRP.	('mutations', 'Var', (66, 75))	('MET', 'Gene', '79811', (147, 150))	('AKT', 'Gene', '207', (191, 194))	('MET', 'Gene', (147, 150))	('MAPK', 'molecular_function', 'GO:0004707', ('173', '177'))	('AKT', 'Gene', (191, 194))	('ERK', 'Gene', '2048', (178, 181))	('PI3K', 'molecular_function', 'GO:0016303', ('186', '190'))	('ERK', 'Gene', (178, 181))	('ERK', 'molecular_function', 'GO:0004707', ('178', '181'))
131052	33178590	However, several recent reports have showed that passenger mutations may also have critical functional roles in driving cancer, with some authors describing them as mini drivers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (120, 126))	('mutations', 'Var', (59, 68))
131053	33178590	They found that the aggregated impact of putative passenger mutations could provide significant predictive power to distinguish cancer from non-cancer phenotypes.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('non-cancer', 'Disease', 'MESH:D009369', (140, 150))	('cancer', 'Disease', (144, 150))	('non-cancer', 'Disease', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (128, 134))
131054	33178590	The above content implied to us that in some types of cancers, such as UCEC, even most of these mutations belonged to the unknown class; more efforts are needed to determine the meanings of these mutations, which might be found to also have important functional roles in driving tumorigenesis.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('cancers', 'Disease', (54, 61))	('UCEC', 'Disease', (71, 75))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('tumor', 'Disease', (279, 284))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('mutations', 'Var', (196, 205))
131055	33178590	In addition, several reports have showed that some gene mutations, like BRAF mutation and ERBB2 mutation, were associated with MSI status in several cancer types.	('cancer', 'Disease', (149, 155))	('BRAF', 'Gene', (72, 76))	('MSI status', 'Disease', (127, 137))	('mutation', 'Var', (77, 85))	('associated', 'Reg', (111, 121))	('mutation', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('BRAF', 'Gene', '673', (72, 76))	('ERBB2', 'Gene', '2064', (90, 95))	('ERBB2', 'Gene', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
131075	33178590	Some alterations are more involved in the development of tumors, while others participate more in targeted therapy.	('involved', 'Reg', (26, 34))	('participate', 'Reg', (78, 89))	('alterations', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
131080	32805727	Univariate and multivariate Cox regression analyses showed significant correlations between five autophagy-related lncRNAs, LINC02178, AC108449.2, Z83843.1, FAM13A-AS1 and USP30-AS1, and overall survival (OS) among BCLA patients.	('USP', 'molecular_function', 'GO:0051748', ('172', '175'))	('FAM13A-AS1', 'Gene', '285512', (157, 167))	('ncRNA', 'Gene', (116, 121))	('USP30', 'Gene', '84749', (172, 177))	('overall', 'MPA', (187, 194))	('autophagy', 'biological_process', 'GO:0016236', ('97', '106'))	('correlations', 'Interaction', (71, 83))	('Z83843.1', 'Var', (147, 155))	('AS1', 'Gene', (164, 167))	('FAM13A-AS1', 'Gene', (157, 167))	('AS1', 'Gene', (178, 181))	('AS1', 'Gene', '5729', (164, 167))	('AS1', 'Gene', '5729', (178, 181))	('ncRNA', 'Gene', '54719', (116, 121))	('patients', 'Species', '9606', (220, 228))	('autophagy', 'biological_process', 'GO:0006914', ('97', '106'))	('USP30', 'Gene', (172, 177))
131091	32805727	However, dysregulation of autophagy is implicated in several human diseases, such as cancer, neurodegenerative disorders, cardiovascular diseases, and inflammatory disorders related to infectious diseases.	('autophagy', 'biological_process', 'GO:0006914', ('26', '35'))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (122, 145))	('infectious diseases', 'Disease', 'MESH:D003141', (185, 204))	('implicated', 'Reg', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (93, 120))	('neurodegenerative disorders', 'Disease', (93, 120))	('cancer', 'Disease', (85, 91))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (93, 120))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('autophagy', 'CPA', (26, 35))	('infectious diseases', 'Disease', (185, 204))	('inflammatory disorders', 'Disease', (151, 173))	('autophagy', 'biological_process', 'GO:0016236', ('26', '35'))	('human', 'Species', '9606', (61, 66))	('dysregulation', 'Var', (9, 22))	('cardiovascular diseases', 'Disease', (122, 145))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (122, 145))
131093	32805727	Recent studies show that modulation of autophagy improves the sensitivity of BCLA tumors to chemotherapeutic agents.	('modulation', 'Var', (25, 35))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('sensitivity', 'MPA', (62, 73))	('autophagy', 'biological_process', 'GO:0016236', ('39', '48'))	('improves', 'PosReg', (49, 57))	('autophagy', 'CPA', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('autophagy', 'biological_process', 'GO:0006914', ('39', '48'))
131110	32805727	Univariate Cox regression analysis of the 49 autophagy-related lncRNAs showed that expression of 7 lncRNAs, namely, AC002553.2, Z83843.1, LINC02178, FAM13A-AS1, USP30-AS1, AC108449.2 and AC243960.1 significantly correlated with the overall survival (OS) of BLCA patients (P < 0.05; Figure 1A).	('USP', 'molecular_function', 'GO:0051748', ('161', '164'))	('USP30', 'Gene', '84749', (161, 166))	('FAM13A-AS1', 'Gene', (149, 159))	('ncRNA', 'Gene', (100, 105))	('Z83843.1', 'Var', (128, 136))	('ncRNA', 'Gene', '54719', (100, 105))	('AS1', 'Gene', (156, 159))	('AS1', 'Gene', '5729', (167, 170))	('autophagy', 'biological_process', 'GO:0016236', ('45', '54'))	('correlated with', 'Reg', (212, 227))	('patients', 'Species', '9606', (262, 270))	('AC243960.1', 'Var', (187, 197))	('LINC02178', 'Var', (138, 147))	('AC002553.2', 'Var', (116, 126))	('AS1', 'Gene', '5729', (156, 159))	('autophagy', 'biological_process', 'GO:0006914', ('45', '54'))	('ncRNA', 'Gene', (64, 69))	('FAM13A-AS1', 'Gene', '285512', (149, 159))	('USP30', 'Gene', (161, 166))	('AS1', 'Gene', (167, 170))	('AC108449.2', 'Var', (172, 182))	('overall survival', 'CPA', (232, 248))	('ncRNA', 'Gene', '54719', (64, 69))
131112	32805727	Among the 5 autophagy-related lncRNAs that were included in the prognostic signature, LINC02178 and AC108449.2 were considered as risk factors with HR values greater than 1, whereas the remaining 3 lncRNAs, Z83843.1, FAM13A-AS1 and USP30-AS1, were considered as protective factors with HR values less than 1.	('USP30', 'Gene', '84749', (232, 237))	('USP', 'molecular_function', 'GO:0051748', ('232', '235'))	('Z83843.1', 'Var', (207, 215))	('AS1', 'Gene', (238, 241))	('AS1', 'Gene', '5729', (238, 241))	('ncRNA', 'Gene', '54719', (31, 36))	('autophagy', 'biological_process', 'GO:0016236', ('12', '21'))	('FAM13A-AS1', 'Gene', '285512', (217, 227))	('autophagy', 'biological_process', 'GO:0006914', ('12', '21'))	('USP30', 'Gene', (232, 237))	('FAM13A-AS1', 'Gene', (217, 227))	('ncRNA', 'Gene', (199, 204))	('LINC02178', 'Var', (86, 95))	('AC108449.2', 'Var', (100, 110))	('ncRNA', 'Gene', '54719', (199, 204))	('ncRNA', 'Gene', (31, 36))	('AS1', 'Gene', '5729', (224, 227))	('AS1', 'Gene', (224, 227))
131113	32805727	The risk score for each BCLA patient in the TCGA dataset was calculated using the following formula for the autophagy-related lncRNA signature: risk score = (-0.677 x expression level of Z83843.1) + (0.162 x expression level of LINC02178) + (-0.403 x expression level of FAM13A-AS1) + (-0.307 x expression level of USP30-AS1) + (0.489 x expression level of AC108449.2).	('patient', 'Species', '9606', (29, 36))	('ncRNA', 'Gene', '54719', (127, 132))	('FAM13A-AS1', 'Gene', '285512', (271, 281))	('USP30', 'Gene', '84749', (315, 320))	('AS1', 'Gene', (321, 324))	('AS1', 'Gene', '5729', (321, 324))	('USP', 'molecular_function', 'GO:0051748', ('315', '318'))	('-0.677', 'Var', (158, 164))	('FAM13A-AS1', 'Gene', (271, 281))	('USP30', 'Gene', (315, 320))	('ncRNA', 'Gene', (127, 132))	('autophagy', 'biological_process', 'GO:0016236', ('108', '117'))	('Z83843.1) + (0.162', 'Var', (187, 205))	('autophagy', 'biological_process', 'GO:0006914', ('108', '117'))	('AS1', 'Gene', '5729', (278, 281))	('AS1', 'Gene', (278, 281))
131115	32805727	Kaplan-Meier survival curve analysis showed that the OS of BCLA patients with high-risk scores was significantly shorter than those with low-risk scores (Figure 1B).	('high-risk scores', 'Var', (78, 94))	('shorter', 'NegReg', (113, 120))	('BCLA', 'Gene', (59, 63))	('patients', 'Species', '9606', (64, 72))
131122	32805727	High-risk patients expressed higher levels of risk factors (AC108449.2 and LINC02178), while low-risk patients expressed higher levels of protective factors (Z83843.1, FAM13A-AS1 and USP30-AS1) (Figure 1G).	('higher', 'PosReg', (29, 35))	('USP30', 'Gene', '84749', (183, 188))	('LINC02178', 'Var', (75, 84))	('FAM13A-AS1', 'Gene', '285512', (168, 178))	('AC108449.2', 'Var', (60, 70))	('USP30', 'Gene', (183, 188))	('AS1', 'Gene', '5729', (175, 178))	('patients', 'Species', '9606', (102, 110))	('USP', 'molecular_function', 'GO:0051748', ('183', '186'))	('FAM13A-AS1', 'Gene', (168, 178))	('AS1', 'Gene', (175, 178))	('patients', 'Species', '9606', (10, 18))	('Z83843.1', 'Var', (158, 166))	('AS1', 'Gene', (189, 192))	('AS1', 'Gene', '5729', (189, 192))
131130	32805727	The patients were grouped according to age (<= 65 and > 65), gender (female and male), tumor grade (low grade and high grade), AJCC stage (stages I and II and stages III and IV), T stage (T1/T2 and T3/T4) and N stage (N0 and N1/N2/N3).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('T3/T4', 'Var', (198, 203))	('tumor', 'Disease', (87, 92))	('T1/T2', 'Var', (188, 193))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('AJCC', 'Disease', (127, 131))
131132	32805727	However, the OS rate between the high- and low-risk groups based on the prognostic signature were similar for patients with ages <= 65 (P = 1.744e-01), low grade (P = 1e+00), AJCC stages I and II (P = 9.596e-02), T1-2 stages (P = 4.257e-01) and N1-3 stages (P = 2.438e-01), probably because of the smaller sample size.	('low grade', 'Var', (152, 161))	('AJCC', 'Disease', (175, 179))	('patients', 'Species', '9606', (110, 118))	('T1-2', 'Disease', (213, 217))
131164	32805727	Furthermore, 5 autophagy-related lncRNAs, Z83843.1, LINC02178, FAM13A-AS1, USP30-AS1 and AC108449.2 were selected to construct a prognostic signature based on their performance in the multivariate Cox regression analysis.	('AS1', 'Gene', '5729', (70, 73))	('AS1', 'Gene', (70, 73))	('USP', 'molecular_function', 'GO:0051748', ('75', '78'))	('autophagy', 'biological_process', 'GO:0006914', ('15', '24'))	('AC108449.2', 'Var', (89, 99))	('AS1', 'Gene', '5729', (81, 84))	('AS1', 'Gene', (81, 84))	('ncRNA', 'Gene', (34, 39))	('FAM13A-AS1', 'Gene', '285512', (63, 73))	('USP30', 'Gene', (75, 80))	('USP30', 'Gene', '84749', (75, 80))	('FAM13A-AS1', 'Gene', (63, 73))	('Z83843.1', 'Var', (42, 50))	('autophagy', 'biological_process', 'GO:0016236', ('15', '24'))	('ncRNA', 'Gene', '54719', (34, 39))
131253	31331003	When no intravesical chemotherapy was considered as the reference for comparison, pirarubicin 30 mg single instillation (HR: 0.26; 95% CrI: 0.08-0.92) was associated with significantly better intravesical recurrence-free survival (Figure 6B).	('pirarubicin', 'Chemical', 'MESH:C027260', (82, 93))	('better', 'PosReg', (185, 191))	('intravesical recurrence-free survival', 'CPA', (192, 229))	('pirarubicin', 'Var', (82, 93))
131325	30541754	Cisplatin ineligibility was defined as one of the following: (a) impaired renal function (glomerular filtration rate >30 but <60 mL/minute), (b) greater than or equal to grade 2 hearing loss, (c) greater than or equal to grade 2 peripheral neuropathy, or (d) ECOG performance score of 2.	('peripheral neuropathy', 'Disease', (229, 250))	('impaired renal function', 'Disease', (65, 88))	('hearing', 'biological_process', 'GO:0007605', ('178', '185'))	('glomerular filtration', 'biological_process', 'GO:0003094', ('90', '111'))	('hearing loss', 'Phenotype', 'HP:0000365', (178, 190))	('glomerular filtration rate >30', 'MPA', (90, 120))	('hearing loss', 'Disease', (178, 190))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('hearing loss', 'Disease', 'MESH:D034381', (178, 190))	('greater', 'Var', (145, 152))	('impaired renal function', 'Disease', 'MESH:D007674', (65, 88))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (229, 250))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (229, 250))
131504	28738880	Nuclear pleomorphism showed borderline significance for association with recurrence of PUC-Ta (Table 3).	('PUC-Ta', 'Chemical', '-', (87, 93))	('PUC-Ta', 'Disease', (87, 93))	('association', 'Interaction', (56, 67))	('Nuclear pleomorphism', 'Var', (0, 20))
131512	28738880	In cases with any additional unfavorable histological features, including increased mitotic count (> 10/10 high-power fields), significant nuclear pleomorphism (smallest-to largest-ratio of tumor nuclei of >20), presence of divergent histology, and significant capillary proliferation (> 20 capillary lumina per papillary core), the tumors were upgraded: for example, grade 1 became grade 2, grade 2 became grade 3, and grade 3 became grade 4.	('tumor', 'Disease', (333, 338))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('papillary core', 'Phenotype', 'HP:0007482', (312, 326))	('tumors', 'Disease', (333, 339))	('tumors', 'Disease', 'MESH:D009369', (333, 339))	('core', 'cellular_component', 'GO:0019013', ('322', '326'))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('increased', 'PosReg', (74, 83))	('capillary proliferation', 'CPA', (261, 284))	('mitotic count', 'CPA', (84, 97))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('presence', 'Var', (212, 220))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('tumors', 'Phenotype', 'HP:0002664', (333, 339))
131535	28738880	We assigned tumors as grade 4 when high-level mitosis, with more than 10 mitoses per 10 high-power fields, and any of the following were present: divergent histology, nuclear pleomorphism of more than 20-fold, and more than 20 capillary lumens per papillary core.	('nuclear pleomorphism', 'Var', (167, 187))	('mitosis', 'biological_process', 'GO:0000278', ('46', '53'))	('mitosis', 'Disease', (46, 53))	('mitosis', 'Disease', 'None', (46, 53))	('core', 'cellular_component', 'GO:0019013', ('258', '262'))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('papillary core', 'Phenotype', 'HP:0007482', (248, 262))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
131559	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))
131570	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))
131598	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))
131660	30944635	Interestingly, patients who had received 5-FU, especially those whose primary tumors had lower levels of DPD expression, had better OS and PFS rates (Fig.	('5-FU', 'Var', (41, 45))	('lower', 'NegReg', (89, 94))	('patients', 'Species', '9606', (15, 23))	('DPD', 'Gene', (105, 108))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('5-FU', 'Chemical', 'MESH:D005472', (41, 45))	('OS', 'Chemical', '-', (132, 134))	('primary tumors', 'Disease', (70, 84))	('better', 'PosReg', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('primary tumors', 'Disease', 'MESH:D009369', (70, 84))	('DPD', 'Gene', '1806', (105, 108))	('PFS rates', 'CPA', (139, 148))	('DPD', 'molecular_function', 'GO:0017113', ('105', '108'))
131677	30944635	Interestingly, despite the small number of UC-UUT patients we studied, those with LVI who had received adjuvant 5-FU did not develop visceral metastases, in contrast to those who had not received it.	('visceral metastases', 'Disease', (133, 152))	('patients', 'Species', '9606', (50, 58))	('develop', 'PosReg', (125, 132))	('LVI', 'Disease', (82, 85))	('visceral metastases', 'Disease', 'MESH:D009362', (133, 152))	('5-FU', 'Var', (112, 116))	('5-FU', 'Chemical', 'MESH:D005472', (112, 116))
131681	30944635	In urothelial carcinoma, underexpression of OPRT, overexpression of TS and overexpression of DPD are reported to be associated with 5-FU resistance in vitro and in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('OPRT', 'Gene', (44, 48))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (3, 23))	('overexpression', 'PosReg', (50, 64))	('TS', 'Gene', '7298', (68, 70))	('DPD', 'molecular_function', 'GO:0017113', ('93', '96'))	('underexpression', 'Var', (25, 40))	('urothelial carcinoma', 'Disease', (3, 23))	('DPD', 'Gene', '1806', (93, 96))	('5-FU', 'Chemical', 'MESH:D005472', (132, 136))	('DPD', 'Gene', (93, 96))	('5-FU resistance', 'MPA', (132, 147))	('associated', 'Reg', (116, 126))
131711	21592330	Treatment with the COX2 inhibitor or knockdown of COX2 reduced expression of casein kinase (CK) 2 alpha, a phophorylated Akt and urokinase type plasminogen activator (uPA), resulting in p27 induction, cell cycle arrest at G1 phase and cell growth suppression in human urothelial carcinoma cell lines expressing COX2.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (201, 218))	('casein kinase (CK) 2 alpha', 'Gene', (77, 103))	('knockdown', 'Var', (37, 46))	('casein kinase (CK) 2 alpha', 'Gene', '1459', (77, 103))	('G1 phase', 'biological_process', 'GO:0051318', ('222', '230'))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('human', 'Species', '9606', (262, 267))	('uPA', 'molecular_function', 'GO:0008243', ('167', '170'))	('urokinase type plasminogen activator', 'Gene', (129, 165))	('p27', 'Protein', (186, 189))	('induction', 'PosReg', (190, 199))	('urothelial carcinoma', 'Disease', (268, 288))	('COX2', 'Gene', (50, 54))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('201', '218'))	('reduced', 'NegReg', (55, 62))	('urokinase type plasminogen activator', 'Gene', '5328', (129, 165))	('expression', 'MPA', (63, 73))	('urokinase type plasminogen activator', 'molecular_function', 'GO:0008243', ('129', '165'))	('cell cycle arrest at G1 phase', 'CPA', (201, 230))	('cell growth suppression', 'CPA', (235, 258))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (268, 288))	('cell growth', 'biological_process', 'GO:0016049', ('235', '246'))
131712	21592330	Silencing of CK2alpha exhibited the similar effects.	('CK2alpha', 'Gene', '1459', (13, 21))	('Silencing', 'Var', (0, 9))	('CK2alpha', 'Gene', (13, 21))
131714	21592330	The mouse orthotropic bladder cancer model demonstrated that the COX2 inhibitor, meloxicam significantly reduced CK2alpha, phosphorylated Akt and uPA expression, whereas induced p27 by which growth and invasiveness of bladder cancer cells were strongly inhibited.	('phosphorylated', 'MPA', (123, 137))	('induced', 'Reg', (170, 177))	('uPA', 'PosReg', (146, 149))	('invasiveness of bladder cancer', 'Disease', 'MESH:D001749', (202, 232))	('reduced', 'NegReg', (105, 112))	('meloxicam', 'Chemical', 'MESH:D000077239', (81, 90))	('growth', 'CPA', (191, 197))	('mouse', 'Species', '10090', (4, 9))	('p27', 'Var', (178, 181))	('bladder cancer', 'Disease', 'MESH:D001749', (22, 36))	('CK2alpha', 'Gene', (113, 121))	('uPA', 'molecular_function', 'GO:0008243', ('146', '149'))	('bladder cancer', 'Disease', (22, 36))	('bladder cancer', 'Phenotype', 'HP:0009725', (22, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('inhibited', 'NegReg', (253, 262))	('bladder cancer', 'Disease', 'MESH:D001749', (218, 232))	('CK2alpha', 'Gene', '1459', (113, 121))	('invasiveness of bladder cancer', 'Disease', (202, 232))	('bladder cancer', 'Phenotype', 'HP:0009725', (218, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
131719	21592330	Aberrant expression of COX2 as well as deregulation of WNT/beta-catenin signaling occurs in the majority of colorectal tumor.	('colorectal tumor', 'Disease', (108, 124))	('Aberrant', 'Var', (0, 8))	('COX2', 'Gene', (23, 27))	('beta-catenin', 'Gene', '1499', (59, 71))	('colorectal tumor', 'Disease', 'MESH:D015179', (108, 124))	('deregulation', 'MPA', (39, 51))	('expression', 'MPA', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('beta-catenin', 'Gene', (59, 71))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))
131720	21592330	Deregulation of COX-2 expression leads to an increased abundance of eicosanoids that affect the hallmarks of cancer.	('increased', 'PosReg', (45, 54))	('Deregulation', 'Var', (0, 12))	('COX-2', 'Gene', '4513', (16, 21))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('abundance of eicosanoids', 'MPA', (55, 79))	('COX-2', 'Gene', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('eicosanoids', 'Chemical', 'MESH:D015777', (68, 79))
131729	21592330	However, COX2-mediated signals involved in urothelial carcinoma cell survival remain fully undetermined, in addition, the fact that COX2 inhibitors have both COX2 -dependent and -independent cytotoxic effects make us much difficult to understand the biological roles.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (43, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('urothelial carcinoma', 'Disease', (43, 63))	('inhibitors', 'Var', (137, 147))	('COX2', 'Gene', (132, 136))
131730	21592330	Casein kinase (CK) 2 is a ubiquitous serine/threonine protein kinase, and its heterotetrameric structure consists of two catalytic subunits (~42 kDa alphaand 38 kDa alpha') and two regulatory subunits (~28 kDa beta) in alpha2beta2, alphaalpha'beta2, or alpha'2beta2 configurations.	('~42', 'Var', (141, 144))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('Casein kinase', 'Gene', '149420', (0, 13))	('Casein kinase', 'Gene', (0, 13))	('threonine', 'Chemical', 'MESH:D013912', (44, 53))	('serine', 'Chemical', 'MESH:D012694', (37, 43))
131736	21592330	Silencing or inhibition of COX2 successfully inhibits CK2alpha-Akt/uPA axis, resulting in cell cycle arrest and growth suppression of bladder cancer cells in vitro and in vivo.	('growth suppression', 'CPA', (112, 130))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('90', '107'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (90, 107))	('inhibits', 'NegReg', (45, 53))	('CK2alpha', 'Gene', '1459', (54, 62))	('bladder cancer', 'Disease', 'MESH:D001749', (134, 148))	('CK2alpha', 'Gene', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('COX2', 'Gene', (27, 31))	('uPA', 'molecular_function', 'GO:0008243', ('67', '70'))	('bladder cancer', 'Disease', (134, 148))	('cell cycle arrest', 'CPA', (90, 107))	('inhibition', 'NegReg', (13, 23))	('Silencing', 'Var', (0, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (134, 148))
131737	21592330	Interestingly, even in urothelial carcinoma cells lacking COX2 gene, COX2 inhibitors reduced expression of CK2alpha and cell viability.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (23, 43))	('inhibitors', 'Var', (74, 84))	('urothelial carcinoma', 'Disease', (23, 43))	('expression', 'MPA', (93, 103))	('COX2', 'Gene', (58, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('reduced', 'NegReg', (85, 92))	('CK2alpha', 'Gene', '1459', (107, 115))	('CK2alpha', 'Gene', (107, 115))	('cell viability', 'CPA', (120, 134))
131745	21592330	COX2 selective inhibitor, CAY10404 or DuP-697 was from Cayman (Ann Arbor, USA).	('DuP-697', 'Var', (38, 45))	('DuP-697', 'Chemical', 'MESH:C064874', (38, 45))	('CAY10404', 'Chemical', 'MESH:C501048', (26, 34))	('CAY10404', 'Var', (26, 34))
131772	21592330	COX2 inhibitors, DuP-697 and CAY10404 at more than 25 muM significantly suppressed viability of human urothelial carcinoma cell line, UMUC2 expressing wild type COX2 as assessed by MTS assay (Figure 1(A)).	('muM', 'Gene', (54, 57))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (102, 122))	('UMUC2', 'CellLine', 'CVCL:8155', (134, 139))	('viability', 'CPA', (83, 92))	('human', 'Species', '9606', (96, 101))	('CAY10404', 'Chemical', 'MESH:C501048', (29, 37))	('DuP-697', 'Var', (17, 24))	('urothelial carcinoma', 'Disease', (102, 122))	('MTS', 'Gene', (181, 184))	('suppressed', 'NegReg', (72, 82))	('muM', 'Gene', '56925', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('CAY10404', 'Var', (29, 37))	('DuP-697', 'Chemical', 'MESH:C064874', (17, 24))	('MTS', 'Gene', '8201', (181, 184))
131774	21592330	From western blotting, p27 was found to be induced in response to COX2 gene silencing (Figure 1(D)), but other molecules associated with cell cycle arrest including p53, p21, p16 or Rb protein were not significantly modified (data not shown).	('cell cycle arrest', 'biological_process', 'GO:0007050', ('137', '154'))	('p53', 'Gene', (165, 168))	('p27', 'Gene', (23, 26))	('p53', 'Gene', '7157', (165, 168))	('gene silencing', 'Var', (71, 85))	('p16', 'Gene', (175, 178))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (137, 154))	('p21', 'Gene', (170, 173))	('COX2', 'Gene', (66, 70))	('p16', 'Gene', '1029', (175, 178))	('p21', 'Gene', '644914', (170, 173))	('gene silencing', 'biological_process', 'GO:0016458', ('71', '85'))	('induced', 'PosReg', (43, 50))
131777	21592330	In addition, we found that COX2 contributes to the expression of CK2alpha, an upstream molecule of uPA and G1 cell cycle arrest was induced by silencing the CK2alpha gene as well as COX2 (Figures 2B,C and 2D).	('cell cycle arrest', 'biological_process', 'GO:0007050', ('110', '127'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (110, 127))	('CK2alpha', 'Gene', '1459', (157, 165))	('CK2alpha', 'Gene', (157, 165))	('uPA', 'molecular_function', 'GO:0008243', ('99', '102'))	('expression', 'MPA', (51, 61))	('CK2alpha', 'Gene', '1459', (65, 73))	('silencing', 'Var', (143, 152))	('CK2alpha', 'Gene', (65, 73))	('induced', 'Reg', (132, 139))
131781	21592330	Both COX2 and CK2alpha knockdowns inhibited Akt activation, but its baseline expression was not significantly changed (Figure 3B).	('knockdowns', 'Var', (23, 33))	('inhibited', 'NegReg', (34, 43))	('COX2', 'Protein', (5, 9))	('activation', 'PosReg', (48, 58))	('Akt', 'Pathway', (44, 47))	('CK2alpha', 'Gene', '1459', (14, 22))	('CK2alpha', 'Gene', (14, 22))
131782	21592330	Reduced uPA activity and cell cycle arrest at G1 phase through p27 induction was mediated by Akt inhibitor treatment as well as COX2 or CK2alpha gene silencing in UMUC6R cells (Figure 3C).	('induction', 'PosReg', (67, 76))	('COX2', 'Protein', (128, 132))	('G1 phase', 'biological_process', 'GO:0051318', ('46', '54'))	('UMUC6R', 'CellLine', 'CVCL:2751', (163, 169))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('25', '42'))	('uPA activity', 'CPA', (8, 20))	('Reduced', 'NegReg', (0, 7))	('uPA', 'molecular_function', 'GO:0008243', ('8', '11'))	('CK2alpha', 'Gene', '1459', (136, 144))	('p27', 'Gene', (63, 66))	('CK2alpha', 'Gene', (136, 144))	('gene silencing', 'Var', (145, 159))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (25, 42))	('cell cycle arrest at G1 phase', 'CPA', (25, 54))	('gene silencing', 'biological_process', 'GO:0016458', ('145', '159'))
131783	21592330	The human urothelial carcinoma cell line, UMUC3 lacks the COX2 gene, COX2 inhibitors, CAY10404 and DuP-697 significantly suppressed cancer cell growth in a dose dependent manner through the induction of cell cycle arrest at G1 phase (Figure 3A and 3B).	('G1 phase', 'biological_process', 'GO:0051318', ('224', '232'))	('COX2 gene', 'Gene', (58, 67))	('lacks', 'NegReg', (48, 53))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('203', '220'))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cell growth', 'biological_process', 'GO:0016049', ('139', '150'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (10, 30))	('DuP-697', 'Chemical', 'MESH:C064874', (99, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('cancer', 'Disease', (132, 138))	('cell cycle arrest at G1 phase', 'CPA', (203, 232))	('human', 'Species', '9606', (4, 9))	('DuP-697', 'Var', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('CAY10404', 'Var', (86, 94))	('suppressed', 'NegReg', (121, 131))	('UMUC3', 'CellLine', 'CVCL:1783', (42, 47))	('CAY10404', 'Chemical', 'MESH:C501048', (86, 94))	('urothelial carcinoma', 'Disease', (10, 30))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (203, 220))
131784	21592330	Expression of CK2alpha and phosphorylated Akt was down-regulated by COX2 inhibitors and knockdown of CK2 (Figure 4C).	('CK2', 'Gene', (101, 104))	('Expression', 'MPA', (0, 10))	('CK2alpha', 'Gene', (14, 22))	('knockdown', 'Var', (88, 97))	('CK2alpha', 'Gene', '1459', (14, 22))	('down-regulated', 'NegReg', (50, 64))
131785	21592330	Interestingly, uPA activity was reduced by COX2 inhibitors, and p21 was induced in response to COX2 inhibitors treatment or CK2alpha gene silencing in addition to p27.	('p21', 'Gene', '644914', (64, 67))	('induced', 'PosReg', (72, 79))	('gene silencing', 'biological_process', 'GO:0016458', ('133', '147'))	('uPA', 'molecular_function', 'GO:0008243', ('15', '18'))	('reduced', 'NegReg', (32, 39))	('uPA', 'CPA', (15, 18))	('gene', 'Var', (133, 137))	('CK2alpha', 'Gene', '1459', (124, 132))	('p21', 'Gene', (64, 67))	('CK2alpha', 'Gene', (124, 132))
131790	21592330	Invasion depth from the top to bottom of implanted tumor foci was strongly reduced by COX2 inhibitor treatment.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('reduced', 'NegReg', (75, 82))	('Invasion depth from the', 'CPA', (0, 23))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('COX2', 'Gene', (86, 90))	('inhibitor', 'Var', (91, 100))
131802	21592330	Our current data indicated reduced expression of CK2alpha following COX2 inhibitor or the gene silencing, but phosphorylation of p65 was not observed (data not shown).	('reduced', 'NegReg', (27, 34))	('gene silencing', 'biological_process', 'GO:0016458', ('90', '104'))	('p65', 'Gene', (129, 132))	('expression', 'MPA', (35, 45))	('p65', 'Gene', '5970', (129, 132))	('CK2alpha', 'Gene', '1459', (49, 57))	('gene silencing', 'Var', (90, 104))	('CK2alpha', 'Gene', (49, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('110', '125'))
131805	21592330	CK2 has been previously reported to increase association of Akt to the Heat shock protein (HSP) 90 which maintains stability of phosphorylated Akt at threonine 308 or serine 473 by inhibiting dephosphorylation by protein phosphatase2A.	('dephosphorylation', 'MPA', (192, 209))	('Heat shock protein (HSP) 90', 'Gene', '3320', (71, 98))	('dephosphorylation', 'biological_process', 'GO:0016311', ('192', '209'))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('association', 'Interaction', (45, 56))	('shock', 'Phenotype', 'HP:0031273', (76, 81))	('inhibiting', 'NegReg', (181, 191))	('increase', 'PosReg', (36, 44))	('serine 473', 'MPA', (167, 177))	('stability', 'MPA', (115, 124))	('protein', 'cellular_component', 'GO:0003675', ('213', '220'))	('CK2', 'Var', (0, 3))	('protein phosphatase2A', 'Enzyme', (213, 234))	('serine', 'Chemical', 'MESH:D012694', (167, 173))	('threonine', 'Chemical', 'MESH:D013912', (150, 159))	('protein phosphatase2A', 'molecular_function', 'GO:0050115', ('213', '234'))	('Heat shock protein (HSP) 90', 'Gene', (71, 98))
131811	21592330	IC50 values of CAY10404 and DuP-649 for COX1 are 500 muM and 9 muM, respectively.	('muM', 'Gene', '56925', (63, 66))	('muM', 'Gene', (53, 56))	('DuP-649', 'Var', (28, 35))	('CAY10404', 'Chemical', 'MESH:C501048', (15, 23))	('muM', 'Gene', (63, 66))	('COX1', 'Gene', (40, 44))	('CAY10404', 'Var', (15, 23))	('muM', 'Gene', '56925', (53, 56))	('COX1', 'Gene', '4512', (40, 44))
131816	21592330	The results showed both CAY10404 and DuP-649 similarly suppressed cell survival of KU-7, UMUC6 and UMUC6R cells at the concentrations more than 25 muM (data not shown).	('KU-7', 'CellLine', 'CVCL:4714', (83, 87))	('CAY10404', 'Var', (24, 32))	('muM', 'Gene', (147, 150))	('cell survival', 'CPA', (66, 79))	('CAY10404', 'Chemical', 'MESH:C501048', (24, 32))	('UMUC6R', 'CellLine', 'CVCL:2751', (99, 105))	('suppressed', 'NegReg', (55, 65))	('muM', 'Gene', '56925', (147, 150))	('DuP-649', 'Var', (37, 44))
131865	33490290	The miRNA-target network was associated with (TCCGTCC) MIR-184, (TGCACGA) MIR-517, (GTGGTGA) MIR-197, (CCAGGGG) MIR-331, and (CAGCAGG) MIR-370.	('MIR-331', 'Gene', '442903', (112, 119))	('associated', 'Interaction', (29, 39))	('MIR-197', 'Gene', '406974', (93, 100))	('MIR-331', 'Gene', (112, 119))	('MIR-184', 'Gene', (55, 62))	('MIR-370', 'Gene', (135, 142))	('MIR-184', 'Gene', '406960', (55, 62))	('MIR-370', 'Gene', '442915', (135, 142))	('MIR-197', 'Gene', (93, 100))	('MIR-517', 'Var', (74, 81))
131893	32258034	Furthermore, anti-PD-1/PDL-1 agents tend to yield longer lasting responses over anti-CTLA-4 agents.	('CTLA-4', 'Gene', '1493', (85, 91))	('responses', 'MPA', (65, 74))	('CTLA-4', 'Gene', (85, 91))	('anti-PD-1/PDL-1', 'Var', (13, 28))
131921	32258034	In other cancer types as well, such as head and neck squamous cell, and Merkel carcinoma, PDL-1 positivity favors a response to PD-1 blockade.	('cancer', 'Disease', (9, 15))	('Merkel carcinoma', 'Disease', (72, 88))	('positivity', 'Var', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('neck', 'cellular_component', 'GO:0044326', ('48', '52'))	('response', 'MPA', (116, 124))	('PD-1', 'Gene', (128, 132))	('Merkel carcinoma', 'Disease', 'MESH:D015266', (72, 88))	('PD-1', 'Gene', '5133', (128, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('PDL-1', 'Gene', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('favors', 'PosReg', (107, 113))
131923	32258034	Meta-analyses of eight randomized controlled trials with avelumab, atezolizumab, durvalumab, nivolumab, and pembrolizumab, encompassing >4000 patients with advanced or metastatic cancers, confirmed that in both patients that were PDL-1 positive and PDL-1 negative, the long term clinical benefits from PD-1 or PDL-1 blockade could be observed.	('atezolizumab', 'Chemical', 'MESH:C000594389', (67, 79))	('PDL-1', 'Gene', (249, 254))	('PDL-1', 'Gene', (310, 315))	('positive', 'Var', (236, 244))	('patients', 'Species', '9606', (211, 219))	('durvalumab', 'Chemical', 'MESH:C000613593', (81, 91))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('pembrolizumab', 'Chemical', 'MESH:C582435', (108, 121))	('PDL-1', 'Gene', (230, 235))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('PD-1', 'Gene', (302, 306))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('patients', 'Species', '9606', (142, 150))	('PD-1', 'Gene', '5133', (302, 306))	('cancers', 'Disease', (179, 186))	('nivolumab', 'Chemical', 'MESH:D000077594', (93, 102))	('avelumab', 'Chemical', 'MESH:C000609138', (57, 65))
131931	32258034	For example, in urothelial carcinoma, CPS >=10 renders the tumor PDL-1 positive, while in other carcinoma types, it is the CPS of >=1.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinoma', 'Disease', 'MESH:D002277', (27, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('tumor', 'Disease', (59, 64))	('urothelial carcinoma', 'Disease', (16, 36))	('carcinoma', 'Disease', (96, 105))	('CPS >=10', 'Var', (38, 46))	('carcinoma', 'Disease', (27, 36))	('PDL-1', 'Gene', (65, 70))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (16, 36))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('carcinoma', 'Disease', 'MESH:D002277', (96, 105))
131935	32258034	For NSCLC, both the tumor and the immune cells need to be scored and PDL-1 expression of >=50% on tumor cells or >=10% on immune cells is linked to better survival outcomes on atezolizumab.	('PDL-1', 'Gene', (69, 74))	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('>=10%', 'Var', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('atezolizumab', 'Chemical', 'MESH:C000594389', (176, 188))	('NSCLC', 'Phenotype', 'HP:0030358', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('better', 'PosReg', (148, 154))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (20, 25))	('survival', 'MPA', (155, 163))	('NSCLC', 'Disease', (4, 9))
131948	32258034	For example, in melanoma patients, there was a strong association of objective response rate to high PDL-1 RNA-seq expression, even regardless of PDL-1 IHC results.	('objective response', 'MPA', (69, 87))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('RNA', 'cellular_component', 'GO:0005562', ('107', '110'))	('expression', 'MPA', (115, 125))	('high', 'Var', (96, 100))	('patients', 'Species', '9606', (25, 33))	('PDL-1', 'Gene', (101, 106))	('N', 'Chemical', 'MESH:D009584', (108, 109))
131953	32258034	It can be detected using standard ELISA assays in patient blood, with high PDL-1 levels associating to adverse prognosis in multiple tumor types.	('multiple tumor', 'Disease', (124, 138))	('multiple tumor', 'Disease', 'MESH:D009369', (124, 138))	('PDL-1', 'Gene', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('associating', 'Reg', (88, 99))	('high', 'Var', (70, 74))	('patient', 'Species', '9606', (50, 57))
131954	32258034	In NSCLC for example, high soluble PDL-1 is associated with adverse prognosis, and studies in melanoma suggest it could even be utilized as a dynamic predictor of durable efficacy to checkpoint inhibitors.	('NSCLC', 'Disease', (3, 8))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('high soluble', 'Var', (22, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('soluble', 'cellular_component', 'GO:0005625', ('27', '34'))	('PDL-1', 'Gene', (35, 40))
131960	32258034	Although baseline exosomal PDL-1 may not correlate with clinicopathologic characteristics and melanoma tumor burden, exosomal PDL-1variations before and after treatment seem to correlate with tumor response to CPIs and to survival.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('exosomal', 'Var', (117, 125))	('tumor', 'Disease', (192, 197))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('correlate with', 'Reg', (177, 191))	('PDL-1variations', 'Gene', (126, 141))	('CPIs', 'Chemical', 'MESH:C110747', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('melanoma tumor', 'Disease', (94, 108))	('melanoma tumor', 'Disease', 'MESH:D008545', (94, 108))
131970	32258034	In 2017, FDA granted an umbrella approval for pembrolizumab for the treatment of patients with unresectable/metastatic, both adult and pediatric solid tumors harboring microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) tumors.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('MSI-H', 'Disease', (201, 206))	('solid tumors', 'Disease', 'MESH:D009369', (145, 157))	('microsatellite instability', 'Var', (168, 194))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('pembrolizumab', 'Chemical', 'MESH:C582435', (46, 59))	('mismatch repair deficient', 'Disease', (211, 236))	('MSI-H', 'Disease', 'MESH:D000848', (201, 206))	('patients', 'Species', '9606', (81, 89))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('solid tumors', 'Disease', (145, 157))	('tumors', 'Disease', (244, 250))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('mismatch repair', 'biological_process', 'GO:0006298', ('211', '226'))
131974	32258034	On the other hand, the same proteins' cognate genes can be inactivated due to germline (hyper)mutational changes, effectively resulting in what we refer to as high microsatellite instability (MSI-H).	('resulting in', 'Reg', (126, 138))	('high microsatellite instability', 'MPA', (159, 190))	('MSI-H', 'Disease', (192, 197))	('mutational changes', 'Var', (94, 112))	('hyper', 'Disease', 'MESH:D053307', (88, 93))	('hyper', 'Disease', (88, 93))	('MSI-H', 'Disease', 'MESH:D000848', (192, 197))
131975	32258034	Common sites which are found mutated and hence are routinely tested in MSI panels are BAT25 andBAT26 (two nucleotide repeats) and D5S346, D2S123, and D17S250 (three dinucleotide repeats).	('MSI', 'Disease', (71, 74))	('andBAT26', 'Gene', (92, 100))	('D2S123', 'Var', (138, 144))	('MSI', 'Disease', '-', (71, 74))	('BAT25', 'Gene', (86, 91))	('D5S346', 'Var', (130, 136))	('D17S250', 'Var', (150, 157))
131978	32258034	It is well known that malignant tumors harbor somatic mutations which can be measured as, and reflected by the so called neoantigen load or tumor mutational burden (TMB).	('malignant tumors', 'Disease', (22, 38))	('malignant tumors', 'Disease', 'MESH:D018198', (22, 38))	('TMB', 'Chemical', '-', (165, 168))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('neoantigen', 'MPA', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (140, 145))
131993	32258034	Data stemming from the NSCLC CheckMate-026 and similar trials, for example suggest that TMB and PD-L1 are likely complementary biomarkers, since patients with high TMB and PDL-1 >=50% had the best response of 75%, while only 16% of patients with lower TMB and PDL-1 levels benefited from therapy.	('patients', 'Species', '9606', (145, 153))	('TMB', 'Chemical', '-', (164, 167))	('TMB', 'Chemical', '-', (88, 91))	('PD-L1', 'Gene', '29126', (96, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (23, 28))	('patients', 'Species', '9606', (232, 240))	('NSCLC', 'Disease', (23, 28))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))	('TMB', 'Chemical', '-', (252, 255))	('PD-L1', 'Gene', (96, 101))	('high', 'Var', (159, 163))
132023	32258034	Interestingly, in patients treated with anti-PD1, a more "focused" TCR repertoire is associated with response .	('anti-PD1', 'Var', (40, 48))	('TCR', 'biological_process', 'GO:0006283', ('65', '68'))	('TCR', 'Gene', (67, 70))	('patients', 'Species', '9606', (18, 26))	('TCR', 'Gene', '6962', (67, 70))	('TCR', 'cellular_component', 'GO:0042101', ('65', '68'))
132028	32258034	A seminal paper in 2014 revealed that mutational load increases the probability of response to CPIs (p = 0.01), but that as a stand-alone, it is not sufficient to predict favorable outcome.	('response', 'MPA', (83, 91))	('mutational load', 'Var', (38, 53))	('increases', 'PosReg', (54, 63))	('CPIs', 'Chemical', 'MESH:C110747', (95, 99))
132031	32258034	A technology named MANAFEST (Mutation-Associated Neoantigen Functional Expansion of Specific T Cells), incorporates multiple techniques including WES, T cell receptor sequencing and comprehensive bioinformatics, proposes actionable tumor mutations and even includes peptide-stimulated cultures, to ultimately achieve an all-encompassing, anti-tumor immunity surveillance.	('T cell receptor', 'Gene', (151, 166))	('mutations', 'Var', (238, 247))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('T cell receptor', 'Gene', '6962', (151, 166))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('N', 'Chemical', 'MESH:D009584', (49, 50))	('N', 'Chemical', 'MESH:D009584', (21, 22))	('tumor', 'Disease', (232, 237))	('tumor', 'Disease', (343, 348))
132036	32258034	Pooled analysis of PD-1/PDL-1 inhibitors' efficacy in a total of five hundred and eighty nine HPV-positive and -negative head and neck squamous cell carcinoma patients, from six trials (CheckMate-141, KEYNOTE-012, KEYNOTE-012 Expansion 11, KEYNOTE-055, NCT01693562, and NCT0137584212), showed a 21.9% vs. 14.1% response rate in favor of HPV + tumors.	('N', 'Chemical', 'MESH:D009584', (204, 205))	('tumors', 'Disease', (343, 349))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('NCT01693562', 'Var', (253, 264))	('NCT01693562', 'CellLine', '-0.03749742074385625', (253, 264))	('tumors', 'Disease', 'MESH:D009369', (343, 349))	('HPV', 'Species', '10566', (337, 340))	('NCT0137584212', 'Var', (270, 283))	('N', 'Chemical', 'MESH:D009584', (243, 244))	('N', 'Chemical', 'MESH:D009584', (217, 218))	('neck', 'cellular_component', 'GO:0044326', ('130', '134'))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (121, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('patients', 'Species', '9606', (159, 167))	('neck squamous cell carcinoma', 'Disease', (130, 158))	('PD-1/PDL-1', 'Gene', (19, 29))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (130, 158))	('tumors', 'Phenotype', 'HP:0002664', (343, 349))	('N', 'Chemical', 'MESH:D009584', (253, 254))	('N', 'Chemical', 'MESH:D009584', (270, 271))	('HPV', 'Species', '10566', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))
132059	32258034	Selected genes reflect not only the immune state (degree of activation versus immune evasion), but also confer mechanistic information about pathways present in the tumor, which may overall be impacted through therapeutic intervention.	('immune evasion', 'biological_process', 'GO:0042783', ('78', '92'))	('immune evasion', 'biological_process', 'GO:0051842', ('78', '92'))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('impacted', 'Reg', (193, 201))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('genes', 'Var', (9, 14))	('tumor', 'Disease', (165, 170))
132069	32258034	Patients with metastatic, KRAS-mutated lung cancer, treated with at least one cycle of a PD-1 inhibitor or an anti-PD-1/PDL-1 and anti-CTLA-4 combination regimen, had STK11/LKB1 mutations largely drive the primary resistance to PD-1 blockade, in any regimen.	('PD-1', 'Gene', (228, 232))	('PD-1', 'Gene', (115, 119))	('PD-1', 'Gene', '5133', (115, 119))	('LKB1', 'Gene', (173, 177))	('lung cancer', 'Disease', (39, 50))	('Patients', 'Species', '9606', (0, 8))	('KRAS', 'Gene', '3845', (26, 30))	('CTLA-4', 'Gene', '1493', (135, 141))	('primary resistance', 'MPA', (206, 224))	('STK11', 'Gene', (167, 172))	('PD-1', 'Gene', (89, 93))	('CTLA-4', 'Gene', (135, 141))	('PD-1', 'Gene', '5133', (89, 93))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('STK11', 'molecular_function', 'GO:0033868', ('167', '172'))	('KRAS', 'Gene', (26, 30))	('metastatic', 'Disease', (14, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('LKB1', 'Gene', '6794', (173, 177))	('drive', 'Reg', (196, 201))	('STK11', 'Gene', '6794', (167, 172))	('mutations', 'Var', (178, 187))	('PD-1', 'Gene', '5133', (228, 232))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
132070	32258034	Interestingly, in patients with combined TP53 and STK11 alterations, response was far superior (57% response rate) than in KRAS-STK11 mutation carriers (0% response rate), who were virtually non-responders, in the CheckMate-057 trial.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('superior', 'PosReg', (86, 94))	('STK11', 'Gene', (50, 55))	('STK11', 'molecular_function', 'GO:0033868', ('128', '133'))	('alterations', 'Var', (56, 67))	('STK11', 'Gene', '6794', (128, 133))	('STK11', 'Gene', '6794', (50, 55))	('KRAS', 'Gene', (123, 127))	('STK11', 'Gene', (128, 133))	('response', 'MPA', (69, 77))	('patients', 'Species', '9606', (18, 26))	('KRAS', 'Gene', '3845', (123, 127))	('STK11', 'molecular_function', 'GO:0033868', ('50', '55'))
132071	32258034	Besides the newly acknowledged relevance of STK11 in lung cancer, this disease is characterized by other, well known genetic abnormalities, such as EGFR, BRAFv600E mutations, ALK, ROS, or RET rearrangements, as well as METexon 14 mutations.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('rearrangements', 'Var', (192, 206))	('lung cancer', 'Disease', (53, 64))	('STK11', 'Gene', (44, 49))	('BRAFv600E', 'Gene', (154, 163))	('EGFR', 'Gene', '1956', (148, 152))	('genetic abnormalities', 'Disease', 'MESH:D030342', (117, 138))	('ROS', 'Chemical', '-', (180, 183))	('genetic abnormalities', 'Disease', (117, 138))	('RET', 'Gene', '5979', (188, 191))	('BRAFv600E', 'Mutation', 'rs113488022', (154, 163))	('ROS', 'Disease', (180, 183))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('STK11', 'Gene', '6794', (44, 49))	('mutations', 'Var', (164, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('ALK', 'Gene', '238', (175, 178))	('ALK', 'Gene', (175, 178))	('RET', 'Gene', (188, 191))	('EGFR', 'Gene', (148, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('148', '152'))	('STK11', 'molecular_function', 'GO:0033868', ('44', '49'))
132072	32258034	EGFR mutant tumors have worse response to overall CPIs, though outcomes can vary by allele.	('EGFR', 'Gene', (0, 4))	('CPIs', 'Chemical', 'MESH:C110747', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('response', 'MPA', (30, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('mutant', 'Var', (5, 11))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('EGFR', 'Gene', '1956', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
132073	32258034	Overall, experience has demonstrated that patients with tumors harboring an exon 19 deletion have lower response rates to CPIs than patients with tumors that are EGFR wild type or have the EGFRL858R mutation).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('EGFR', 'Gene', (162, 166))	('tumors', 'Disease', (56, 62))	('response rates', 'MPA', (104, 118))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('patients', 'Species', '9606', (132, 140))	('lower', 'NegReg', (98, 103))	('EGFR', 'Gene', '1956', (189, 193))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('exon 19 deletion', 'Var', (76, 92))	('EGFRL858R', 'Mutation', 'rs121434568', (189, 198))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'molecular_function', 'GO:0005006', ('162', '166'))	('CPIs', 'Chemical', 'MESH:C110747', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('patients', 'Species', '9606', (42, 50))	('EGFR', 'Gene', (189, 193))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', (146, 152))
132079	32258034	Globally, in patients with gene mutations conferring oncogene addiction, response rates to single agent immunotherapy are impaired compared with wild-type patients, and combination strategies should be considered and implemented.	('gene mutations', 'Var', (27, 41))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (155, 163))	('impaired', 'Disease', 'MESH:D009422', (122, 130))	('impaired', 'Disease', (122, 130))
132080	32258034	Epigenetic studies in lung cancer have shown that promoter regions of the CTLA-4, PD-1, and PDL-1 genes can be hypomethylated, which in turn associates with upregulated expression of these genes in the tumor microenvironment.	('hypomethylated', 'Var', (111, 125))	('lung cancer', 'Disease', (22, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('PD-1', 'Gene', (82, 86))	('PDL-1', 'Gene', (92, 97))	('tumor', 'Disease', (202, 207))	('PD-1', 'Gene', '5133', (82, 86))	('CTLA-4', 'Gene', '1493', (74, 80))	('upregulated', 'PosReg', (157, 168))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))	('CTLA-4', 'Gene', (74, 80))	('expression', 'MPA', (169, 179))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
132098	32258034	Memory B cell like profiles (MBL) and links to CPI response have been studied in urothelial carcinoma patients on anti-PDL-1 (n = 25), melanoma patients on anti-PD-1 (n = 28), and anti-CTLA-4 therapies (n = 42).	('MBL', 'Gene', '4153', (29, 32))	('PD-1', 'Gene', (161, 165))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (81, 101))	('CTLA-4', 'Gene', (185, 191))	('melanoma', 'Disease', (135, 143))	('MBL', 'Gene', (29, 32))	('PD-1', 'Gene', '5133', (161, 165))	('patients', 'Species', '9606', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('patients', 'Species', '9606', (144, 152))	('CPI', 'Chemical', 'MESH:C110747', (47, 50))	('CTLA-4', 'Gene', '1493', (185, 191))	('urothelial carcinoma', 'Disease', (81, 101))	('anti-PDL-1', 'Var', (114, 124))
132112	32258034	Immunosuppressive gammadelta1 T cells are observed in high percentages in blood and among TILs in many solid tumor types (7.2-75.7%; mean 33.2%), and are involved in inflammation-induced cancer progression.	('solid tumor', 'Disease', 'MESH:D009369', (103, 114))	('gammadelta1', 'Var', (18, 29))	('involved', 'Reg', (154, 162))	('inflammation-induced cancer', 'Disease', 'MESH:D007249', (166, 193))	('TIL', 'Gene', '7096', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('inflammation', 'biological_process', 'GO:0006954', ('166', '178'))	('TIL', 'Gene', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('inflammation-induced cancer', 'Disease', (166, 193))	('solid tumor', 'Disease', (103, 114))
132113	32258034	More specifically, melanoma patients with higher percentage of Vdelta1 + cells in peripheral blood (>=30%) had poorer survival and a lower rate of clinical benefit on ipilimumab.	('Vdelta1 + cells', 'Var', (63, 78))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('poorer', 'NegReg', (111, 117))	('clinical benefit', 'MPA', (147, 163))	('ipilimumab', 'Chemical', 'MESH:D000074324', (167, 177))	('lower', 'NegReg', (133, 138))	('patients', 'Species', '9606', (28, 36))
132165	32042266	In terms of 2 studies incorporating 1727 patients and 1955 patients, we found that the patients with a higher De Ritis ratio had a significantly increased risk of progression and recurrence compared with those with lower De Ritis ratio.	('lower De Ritis', 'Disease', (215, 229))	('recurrence', 'CPA', (179, 189))	('patients', 'Species', '9606', (41, 49))	('higher', 'Var', (103, 109))	('patients', 'Species', '9606', (59, 67))	('progression', 'CPA', (163, 174))	('patients', 'Species', '9606', (87, 95))	('lower De Ritis', 'Disease', 'MESH:D005862', (215, 229))
132228	31788428	Infiltrated plaques or nodularity have been commonly associated with cutaneous metastases of urological cancers.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('metastases of urological cancers', 'Disease', 'MESH:D014571', (79, 111))	('nodularity', 'Var', (23, 33))	('associated', 'Reg', (53, 63))	('cutaneous', 'Disease', (69, 78))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('metastases of urological cancers', 'Disease', (79, 111))
132243	31697689	Assessing reliability of intra-tumor heterogeneity estimates from single sample whole exome sequencing data Tumors are made of evolving and heterogeneous populations of cells which arise from successive appearance and expansion of subclonal populations, following acquisition of mutations conferring them a selective advantage.	('intra-tumor', 'Disease', (25, 36))	('mutations', 'Var', (279, 288))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('intra-tumor', 'Disease', 'MESH:D009369', (25, 36))	('Tumors', 'Disease', (108, 114))	('Tumors', 'Disease', 'MESH:D009369', (108, 114))	('Tumors', 'Phenotype', 'HP:0002664', (108, 114))	('ran', 'Gene', (208, 211))	('ran', 'Gene', '5901', (208, 211))
132253	31697689	A consequence of this progressive accumulation of mutations is intra-tumor heterogeneity.	('mutations', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('intra-tumor', 'Disease', 'MESH:D009369', (63, 74))	('intra-tumor', 'Disease', (63, 74))
132254	31697689	Indeed, when a new mutation occurs in a tumor cell and provides an evolutionary advantage, this cell tends to have a higher probability to survive and divide, hence seeding a new clonal population.	('mutation', 'Var', (19, 27))	('survive', 'CPA', (139, 146))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('seeding', 'Reg', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
132275	31697689	A coverage filter was added, and we kept SNVs with at least 6 reads at the position in the normal sample, of which 1 maximum reports the alternative nucleotide (or with a variant allele frequency (VAF) <0.01), and for the tumor sample, at least 8 reads covering the position, of which at least 3 reporting the variant, or a VAF>0.2.	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('variant', 'Var', (310, 317))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (222, 227))
132290	31697689	The raw data for 7 normal-tumor WES samples analyzed jointly with matching single cell sequencing were downloaded from the NCBI SRA platform https://www.ncbi.nlm.nih.gov/sra and processed into fastq format using the tool fastq-dump for the two acute lymphoblastic leukemia (ALL) patients (accession numbers: SRR1517761, SRR1517762, SRR1517763, SRR1517764), or directly downloaded in the fastq format from the EBI ENA platform https://www.ebi.ac.uk/ena for the Triple Negative Breast Cancer patient (TNBC) (accession number: SRR1163508 and SRR1298936), and the two samples (primary tumor and liver metastasis) from the two colorectal cancer patients (CRC) (accession number: SRR3472566, SRR3472567, SRR3472569, SRR3472571, SRR3472796, SRR3472798, SRR3472799, SRR3472800).	('SRA', 'Gene', (128, 131))	('SRR3472799', 'Var', (746, 756))	('SRR1517763', 'Chemical', 'MESH:C105415', (332, 342))	('colorectal cancer', 'Disease', (622, 639))	('patient', 'Species', '9606', (279, 286))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (250, 272))	('Breast Cancer', 'Phenotype', 'HP:0003002', (476, 489))	('sra', 'Gene', (170, 173))	('SRA', 'Gene', '10011', (128, 131))	('lymphoblastic leukemia', 'Disease', (250, 272))	('patients', 'Species', '9606', (640, 648))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (244, 272))	('SRR1517764', 'Chemical', 'MESH:C105415', (344, 354))	('SRR3472571', 'Var', (710, 720))	('tumor', 'Disease', (581, 586))	('SRR1517762', 'Chemical', 'MESH:C105415', (320, 330))	('tumor', 'Disease', (26, 31))	('SRR3472567', 'Chemical', 'MESH:C105415', (686, 696))	('tumor', 'Disease', 'MESH:D009369', (581, 586))	('SRR3472569', 'Var', (698, 708))	('patient', 'Species', '9606', (490, 497))	('colorectal cancer', 'Phenotype', 'HP:0003003', (622, 639))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('SRR3472571', 'Chemical', 'MESH:C105415', (710, 720))	('Breast Cancer', 'Disease', 'MESH:D001943', (476, 489))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (250, 272))	('SRR3472800', 'Var', (758, 768))	('patients', 'Species', '9606', (279, 287))	('cancer', 'Phenotype', 'HP:0002664', (633, 639))	('SRR3472796', 'Var', (722, 732))	('Breast Cancer', 'Disease', (476, 489))	('patient', 'Species', '9606', (640, 647))	('SRR3472798', 'Var', (734, 744))	('SRR3472567', 'Var', (686, 696))	('ALL', 'Phenotype', 'HP:0006721', (274, 277))	('tumor', 'Phenotype', 'HP:0002664', (581, 586))	('Cancer', 'Phenotype', 'HP:0002664', (483, 489))	('leukemia', 'Phenotype', 'HP:0001909', (264, 272))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (622, 639))	('sra', 'Gene', '10011', (170, 173))
132292	31697689	Those variants and the copy number profile were then passed to PyClone, SciClone, PhyloWGS and Expands for ITH deconvolution.	('WGS', 'Disease', 'None', (87, 90))	('variants', 'Var', (6, 14))	('WGS', 'Disease', (87, 90))
132298	31697689	We assess ITH in each sample using 6 representative computational methods: PyClone, SciClone, PhyloWGS EXPANDS, the mutant-allele tumor heterogeneity (MATH) score, and CSR, a method providing a consensus of all of the above results (except MATH which is not compatible, see Methods).	('WGS', 'Disease', 'None', (99, 102))	('WGS', 'Disease', (99, 102))	('mutant-allele', 'Var', (116, 129))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
132306	31697689	PyClone and PhyloWGS runtime rises very quickly with the number of mutations in tumor sample, which can be a limitation for applications to heavily mutated tumors.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('WGS', 'Disease', 'None', (17, 20))	('WGS', 'Disease', (17, 20))	('tumor', 'Disease', (80, 85))	('mutations', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (156, 161))	('tumors', 'Disease', (156, 162))
132310	31697689	In addition, we add to the comparison 5 measures directly extracted from the NGS analysis, namely, the number of mutations in the protected and in the public sets, the percentage of non-diploid cells (estimated by ASCAT and ABSOLUTE), the purity (estimated by ASCAT and ABSOLUTE), and the inv_T_cell (estimated from gene expression signatures).	('inv', 'Gene', (289, 292))	('inv', 'Gene', '27130', (289, 292))	('mutations', 'Var', (113, 122))	('purity', 'CPA', (239, 245))	('gene expression', 'biological_process', 'GO:0010467', ('316', '331'))
132314	31697689	SciClone is different from PyClone and PhyloWGS in two ways: it only relies on mutations that are in regions without copy number alterations; and it does not correct for tumor purity.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('WGS', 'Disease', 'None', (44, 47))	('WGS', 'Disease', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('mutations', 'Var', (79, 88))
132320	31697689	Each group of ITH methods is highly correlated to distinct genomic metrics, mutation load and CNV abundance (perc_non_diploid) for the first group (MATH, Expands), and purity (and the opposite of immune cells infiltration (inv_T_cells)) for the latter (PyClone, SciClone, PhyloWGS CSR).	('inv', 'Gene', '27130', (223, 226))	('WGS', 'Disease', 'None', (277, 280))	('WGS', 'Disease', (277, 280))	('mutation', 'Var', (76, 84))	('inv', 'Gene', (223, 226))
132340	31697689	They obtain significant prognostic association for all variant calling results in only one cancer type: UCEC, and already report some lack of robustness in the results.	('variant', 'Var', (55, 62))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('UCEC', 'Disease', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
132387	30697554	Intraoperative patient repositioning or redocking of the robot has been shown to add, on average, an additional 30-60 minutes to the operative time.	('repositioning', 'Var', (23, 36))	('redocking', 'Var', (40, 49))	('patient', 'Species', '9606', (15, 22))
132427	30697554	Patients undergoing RALNU were also shown to be significantly less likely to have any complication during hospitalization compared to patients receiving laparoscopic NU.	('patients', 'Species', '9606', (134, 142))	('Patients', 'Species', '9606', (0, 8))	('RALNU', 'Var', (20, 25))	('RALNU', 'Chemical', '-', (20, 25))	('less', 'NegReg', (62, 66))
132473	29739808	In 1996, the same team found that the protein (PD-1 or CD279) produced by this gene is a trans-membranous heavily glycosylated receptor of 50-55 kDa, which contains an immune receptor tyrosine-based inhibitory motif in its cytoplasmic tail.	('CD279', 'Gene', (55, 60))	('tyrosine', 'Chemical', 'MESH:D014443', (184, 192))	('gene', 'Var', (79, 83))	('CD279', 'Gene', '5133', (55, 60))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))
132485	29739808	PD-1 antibodies interrupt PD-1 interaction with its ligands PD-L1 and PD-L2, whereas anti-PD-L1 Ab blocks the interaction of PD-L1 with both PD-1 and B7-1 (CD80), which is a member of the B7 family on the APC and has a downregulatory role on the T-cell response.	('interrupt', 'NegReg', (16, 25))	('CD80', 'Gene', '941', (156, 160))	('blocks', 'NegReg', (99, 105))	('APC', 'Disease', (205, 208))	('PD-1', 'Gene', (0, 4))	('interaction', 'Interaction', (31, 42))	('antibodies', 'Var', (5, 15))	('interaction', 'Interaction', (110, 121))	('APC', 'cellular_component', 'GO:0005680', ('205', '208'))	('CD80', 'Gene', (156, 160))	('PD-1 and B7-1', 'Gene', '5133;941', (141, 154))	('APC', 'Disease', 'MESH:D011125', (205, 208))	('PD-1', 'Protein', (26, 30))	('PD-L2', 'Gene', (70, 75))	('PD-L2', 'Gene', '80380', (70, 75))
132502	29739808	Few other studies have also illustrated the beneficial antitumor effect in PD-L1 selected advanced NSCLC.	('tumor', 'Disease', (59, 64))	('PD-L1', 'Var', (75, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('beneficial', 'PosReg', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('NSCLC', 'Disease', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
132537	29739808	It is worth noting that the clear majority of PD-1 and PD-L1 induced dysthyroidism was of grade I or II, whereas grades III and IV were very rare and no grade V was reported in all the trials in this review.	('PD-1', 'Var', (46, 50))	('dysthyroidism', 'Disease', 'MESH:D049970', (69, 82))	('PD-L1', 'Gene', (55, 60))	('dysthyroidism', 'Disease', (69, 82))
132538	29739808	Table 5 summarizes the time to onset, and when it is available, the rate and time to resolution of hyperT and hypothyroidism induced by PD-1 and PD-L1 Ab based on available data on the FDA drug information site in September 2017.	('hypothyroidism', 'Phenotype', 'HP:0000821', (110, 124))	('PD-1', 'Gene', (136, 140))	('hyperT and hypothyroidism', 'Disease', 'MESH:D007037', (99, 124))	('PD-L1', 'Var', (145, 150))	('hyperT', 'Phenotype', 'HP:0000836', (99, 105))
132555	29739808	One of the major adverse events of PD-1/PD-L1 Ab is fatigue which represents an important symptom of dysthyroidism.	('fatigue', 'Disease', 'MESH:D005221', (52, 59))	('PD-1/PD-L1 Ab', 'Var', (35, 48))	('fatigue', 'Disease', (52, 59))	('dysthyroidism', 'Disease', (101, 114))	('dysthyroidism', 'Disease', 'MESH:D049970', (101, 114))	('fatigue', 'Phenotype', 'HP:0012378', (52, 59))
132562	29739808	Due to the non-negligible frequency of thyroid irAEs in patients treated with PD-1 and PD-L1 Ab, and the paucity of specific symptoms, manufacturers and health authorities recommend to assess thyroid function at baseline and before every treatment.	('PD-L1 Ab', 'Var', (87, 95))	('PD-1', 'Gene', (78, 82))	('patients', 'Species', '9606', (56, 64))	('thyroid irAEs', 'Disease', (39, 52))
132573	29739808	The incidental thyroid findings when using F-18 FDG PET/CT for cancer initial assessment and follow-up have been mentioned in some studies.	('F-18 FDG', 'Var', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('thyroid findings', 'Phenotype', 'HP:0000820', (15, 31))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('thyroid findings', 'Disease', (15, 31))	('cancer', 'Disease', (63, 69))
132576	29739808	This finding is in line with results obtained from an earlier study and indicates that PD-1/PD-L1 Ab induce thyroid inflammation.	('inflammation', 'biological_process', 'GO:0006954', ('116', '128'))	('PD-1/PD-L1', 'Var', (87, 97))	('thyroid inflammation', 'Disease', (108, 128))	('thyroid inflammation', 'Disease', 'MESH:D007249', (108, 128))	('thyroid inflammation', 'Phenotype', 'HP:0100646', (108, 128))	('induce', 'PosReg', (101, 107))
132578	29739808	It was hypothesized that the presence of anti-thyroid antibodies such as TPO and thyroglobulin (Tg) antibodies is a positive predictive factor for developing hypothyroidism in 5 patients who developed hypothyroidism in a Japanese cohort of 64 patients with advanced NSCLC treated with nivolumab.	('TPO', 'Gene', '7173', (73, 76))	('TPO', 'Gene', (73, 76))	('thyroglobulin', 'Gene', (81, 94))	('patients', 'Species', '9606', (243, 251))	('patients', 'Species', '9606', (178, 186))	('Tg', 'Gene', '7038', (96, 98))	('hypothyroidism', 'Disease', (201, 215))	('nivolumab', 'Chemical', 'MESH:D000077594', (285, 294))	('NSCLC', 'Disease', 'MESH:D002289', (266, 271))	('hypothyroidism', 'Disease', 'MESH:D007037', (201, 215))	('presence', 'Var', (29, 37))	('hypothyroidism', 'Phenotype', 'HP:0000821', (201, 215))	('NSCLC', 'Disease', (266, 271))	('hypothyroidism', 'Disease', (158, 172))	('-thyroid antibodies', 'Phenotype', 'HP:0002930', (45, 64))	('thyroglobulin', 'Gene', '7038', (81, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (266, 271))	('hypothyroidism', 'Disease', 'MESH:D007037', (158, 172))	('hypothyroidism', 'Phenotype', 'HP:0000821', (158, 172))
132585	29739808	In another recent study, the presence of mRNA and protein expression of PD-L1 and PD-L2 was found in normal thyroid tissue by reverse transcription polymerase chain reaction and Western blotting, and the authors hypothesized that anti-PD-1 decreases the immune tolerance of T cells to normal thyroid tissue and leads to development of thyroiditis.	('decreases', 'NegReg', (240, 249))	('anti-PD-1', 'Var', (230, 239))	('reverse transcription', 'biological_process', 'GO:0001171', ('126', '147'))	('thyroiditis', 'Disease', (335, 346))	('thyroiditis', 'Phenotype', 'HP:0100646', (335, 346))	('PD-L2', 'Gene', (82, 87))	('PD-L2', 'Gene', '80380', (82, 87))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('thyroiditis', 'Disease', 'MESH:D013959', (335, 346))	('immune tolerance', 'CPA', (254, 270))	('leads to', 'Reg', (311, 319))
132586	29739808	A recent study compared the presenting patterns and the dynamic evolution of thyroid disorders in 46 patients treated with either anti-PD-1 alone or in combination with anti-CTLA-4.	('thyroid disorders', 'Disease', 'MESH:D013959', (77, 94))	('patients', 'Species', '9606', (101, 109))	('thyroid disorders', 'Phenotype', 'HP:0000820', (77, 94))	('CTLA-4', 'Gene', '1493', (174, 180))	('CTLA-4', 'Gene', (174, 180))	('thyroid disorders', 'Disease', (77, 94))	('anti-PD-1', 'Var', (130, 139))
132638	29020960	The immunosuppressive action of the PD1 receptor is activated in the effector phase of the interaction between T lymphocytes and tumour cells, and the blockade of this receptor seems to be more effective towards T-cell-activation than CTLA-4 blockade.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('T-cell-activation', 'biological_process', 'GO:0042110', ('212', '229'))	('CTLA-4', 'Gene', '1493', (235, 241))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('blockade', 'Var', (151, 159))	('tumour', 'Disease', (129, 135))	('PD1', 'Gene', (36, 39))	('CTLA-4', 'Gene', (235, 241))	('activated', 'PosReg', (52, 61))	('interaction', 'Interaction', (91, 102))	('immunosuppressive action', 'MPA', (4, 28))
132664	29020960	additional treatment given after the primary treatment for melanoma to reduce the risk of relapses) for patients with completely resected stage III melanoma at high risk of recurrence: median recurrence-free survival was 26.1 months (95% CI 19.3-39.3) in the ipilimumab group versus 17.1 months (95% CI 13.4-21.6) in the placebo group (HR 0.75; 95% CI 0.64-0.90; p = 0.0013); 3-year recurrence-free survival was 46.5% (95% CI 41.5-51.3) in the ipilimumab group versus 34.8% (30.1-39.5) in the placebo group.	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('ipilimumab', 'Var', (444, 454))	('melanoma', 'Disease', (148, 156))	('ipilimumab', 'Chemical', 'MESH:D000074324', (259, 269))	('ipilimumab', 'Chemical', 'MESH:D000074324', (444, 454))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('patients', 'Species', '9606', (104, 112))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
132665	29020960	The rate of OS at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (HR for death, 0.72; 95.1% CI 0.58-0.88; p = 0.001), and the rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (HR for death or distant metastasis, 0.76; 95.8% CI 0.64-0.92; p = 0.002).	('death', 'Disease', 'MESH:D003643', (305, 310))	('death', 'Disease', (305, 310))	('death', 'Disease', 'MESH:D003643', (113, 118))	('OS', 'Gene', '17451', (12, 14))	('death', 'Disease', (113, 118))	('ipilimumab', 'Var', (235, 245))	('ipilimumab', 'Chemical', 'MESH:D000074324', (43, 53))	('distant metastasis-free', 'CPA', (174, 197))	('ipilimumab', 'Chemical', 'MESH:D000074324', (235, 245))
132685	29020960	In the KEYNOTE-010 study, the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced NSCLC was assessed: pembrolizumab prolonged OS and had a favorable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced NSCLC, introducing pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection.	('NSCLC', 'Disease', (272, 277))	('PD-L1', 'Gene', (375, 380))	('PD-L1', 'Gene', (94, 99))	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('pembrolizumab', 'Chemical', 'MESH:C582435', (42, 55))	('PD-L1', 'Gene', '29126', (375, 380))	('NSCLC', 'Disease', 'MESH:D002289', (272, 277))	('OS', 'Gene', '17451', (163, 165))	('patients', 'Species', '9606', (60, 68))	('pembrolizumab', 'Var', (139, 152))	('PD-L1', 'Gene', '29126', (94, 99))	('pembrolizumab', 'Chemical', 'MESH:C582435', (139, 152))	('PD-L1', 'Gene', (247, 252))	('patients', 'Species', '9606', (213, 221))	('pembrolizumab', 'Chemical', 'MESH:C582435', (291, 304))	('prolonged', 'PosReg', (153, 162))	('NSCLC', 'Disease', (119, 124))	('PD-L1', 'Gene', '29126', (247, 252))
132686	29020960	In the total population, mOS was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg and 8.5 months with docetaxel.	('mOS', 'Gene', (25, 28))	('mOS', 'Gene', '17451', (25, 28))	('pembrolizumab', 'Chemical', 'MESH:C582435', (90, 103))	('pembrolizumab', 'Var', (50, 63))	('pembrolizumab', 'Chemical', 'MESH:C582435', (50, 63))	('docetaxel', 'Chemical', 'MESH:D000077143', (133, 142))
132701	29020960	In the 423 patients with 5% or greater PD-L1 expression, PFS was 4.2 months with nivolumab and 5.9 months with chemotherapy (HR 1.15, 95% CI 0.91-1.45, p = 0.25).	('PD-L1', 'Gene', (39, 44))	('nivolumab', 'Chemical', 'MESH:D000077594', (81, 90))	('PD-L1', 'Gene', '29126', (39, 44))	('patients', 'Species', '9606', (11, 19))	('expression', 'Var', (45, 55))
132705	29020960	A very relevant phase III trial (KEYNOTE 024) explored pembrolizumab as first line treatment compared to standard of care with platinum-based chemotherapy in untreated patients with advanced NSCLC and high PD-L1 expression (defined as expression in at least 50% of tumour cells).	('PD-L1', 'Gene', '29126', (206, 211))	('pembrolizumab', 'Chemical', 'MESH:C582435', (55, 68))	('expression', 'MPA', (212, 222))	('tumour', 'Phenotype', 'HP:0002664', (265, 271))	('tumour', 'Disease', 'MESH:D009369', (265, 271))	('NSCLC', 'Disease', (191, 196))	('patients', 'Species', '9606', (168, 176))	('PD-L1', 'Gene', (206, 211))	('platinum', 'Chemical', 'MESH:D010984', (127, 135))	('high', 'Var', (201, 205))	('NSCLC', 'Disease', 'MESH:D002289', (191, 196))	('tumour', 'Disease', (265, 271))
132731	29020960	until progression disease versus definite number of cycles), role in first-line as single agent and combined to chemotherapy, role in maintenance strategy, combination of immunotherapies, trials on Medium level of priority in the research can be given to studies on predictive role of IHC (produced by DAKO) PD-L1 expression for all anti PD-1 and anti PD-L1 inhibitors CT scan at definite time versus CT scan at clinically indication, neoadjuvant setting and combination with targeted therapies.	('PD-L1', 'Gene', (352, 357))	('PD-L1', 'Gene', (308, 313))	('PD-1', 'Gene', (338, 342))	('PD-L1', 'Gene', '29126', (352, 357))	('PD-L1', 'Gene', '29126', (308, 313))	('PD-1', 'Gene', '5133', (338, 342))	('inhibitors', 'Var', (358, 368))
132736	29020960	Multiple studies have elucidated the specific genetic background of HNSCC, establishing subclasses of tumors alongside HPV infection and/or TP53 mutations.	('HPV infection', 'Disease', 'MESH:D030361', (119, 132))	('TP53', 'Gene', (140, 144))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('mutations', 'Var', (145, 154))	('HPV infection', 'Disease', (119, 132))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('HNSCC', 'Disease', (68, 73))	('TP53', 'Gene', '7157', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
132743	29020960	HPV DNA has been found in 15-25% of HNSCC and the association differs depending on the site of the tumor; HPV DNA is detected in 45-67% of cases of cancers of the tonsil, in 13-25% of hypopharyngeal cancer, in 12-18% of the cancers of oral cavity and in 3-7% of carcinoma larynx and it may be associated with prognosis of disease, especially in tonsillar cancers.	('detected', 'Reg', (117, 125))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('HPV DNA', 'Var', (106, 113))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('tonsillar cancers', 'Disease', 'MESH:D014067', (345, 362))	('cancers', 'Disease', (224, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('tumor', 'Disease', (99, 104))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancers', 'Disease', 'MESH:D009369', (355, 362))	('carcinoma larynx', 'Disease', 'MESH:D007822', (262, 278))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('associated', 'Reg', (293, 303))	('hypopharyngeal cancer', 'Disease', (184, 205))	('tonsillar cancers', 'Disease', (345, 362))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cancers', 'Phenotype', 'HP:0002664', (355, 362))	('carcinoma larynx', 'Disease', (262, 278))	('cancers', 'Disease', (355, 362))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('carcinoma larynx', 'Phenotype', 'HP:0012118', (262, 278))	('DNA', 'cellular_component', 'GO:0005574', ('110', '113'))	('hypopharyngeal cancer', 'Disease', 'MESH:D007012', (184, 205))
132753	29020960	OS was significantly longer with nivolumab than with standard therapy (HR for death, 0.70; 97.73% CI 0.51-0.96; p = 0.01), and the estimates of the 1-year survival rate were approximately 19% higher with nivolumab than with standard therapy (36.0% vs. 16.6%).	('death', 'Disease', 'MESH:D003643', (78, 83))	('death', 'Disease', (78, 83))	('higher', 'PosReg', (192, 198))	('nivolumab', 'Var', (33, 42))	('nivolumab', 'Chemical', 'MESH:D000077594', (204, 213))	('OS', 'Gene', '17451', (0, 2))	('nivolumab', 'Chemical', 'MESH:D000077594', (33, 42))
132755	29020960	The rate of PFS at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy.	('nivolumab', 'Chemical', 'MESH:D000077594', (43, 52))	('PFS', 'Disease', (12, 15))	('nivolumab', 'Var', (43, 52))
132758	29020960	Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group.	('nivolumab', 'Chemical', 'MESH:D000077594', (57, 66))	('nivolumab', 'Var', (57, 66))	('Physical', 'CPA', (0, 8))
132776	29020960	Anti-PD1/PDL1 is the backbone of future combination immunotherapies and anti-PD1/PDL1 combination therapies are expected to disrupt the current treatment paradigms in kidney cancer.	('anti-PD1/PDL1', 'Var', (72, 85))	('kidney cancer', 'Disease', (167, 180))	('kidney cancer', 'Disease', 'MESH:D007680', (167, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('kidney cancer', 'Phenotype', 'HP:0009726', (167, 180))
132806	29020960	Hepatocarcinogenesis is a multistep process depending on a sequence of epigenetic and genetic alterations leading to activation or inhibition of p53, WNT, beta-catenin, MYC, the ErbB family, as well as chromatin modifications.	('beta-catenin', 'Gene', (155, 167))	('MYC', 'Gene', '4609', (169, 172))	('ErbB', 'Gene', '1956;2064', (178, 182))	('alterations', 'Var', (94, 105))	('p53', 'Gene', (145, 148))	('p53', 'Gene', '7157', (145, 148))	('chromatin', 'cellular_component', 'GO:0000785', ('202', '211'))	('MYC', 'Gene', (169, 172))	('beta-catenin', 'Gene', '1499', (155, 167))	('Hepatocarcinogenesis', 'Disease', (0, 20))	('ErbB', 'Gene', (178, 182))	('Hepatocarcinogenesis', 'Disease', 'MESH:D063646', (0, 20))	('activation', 'PosReg', (117, 127))	('inhibition', 'NegReg', (131, 141))
132843	29020960	The Cancer Genome Atlas project has analysed has analyzed the DNA sequences of exons IN 489 high-grade serous ovarian adenocarcinomas from coding genes in 316 of these tumors and reported that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumors (96%).	('tumors', 'Disease', (168, 174))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (204, 225))	('serous ovarian adenocarcinomas', 'Phenotype', 'HP:0012887', (103, 133))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('Cancer', 'Disease', (4, 10))	('ovarian cancer', 'Phenotype', 'HP:0100615', (211, 225))	('TP53', 'Gene', '7157', (246, 250))	('serous ovarian adenocarcinomas', 'Disease', (103, 133))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('serous ovarian cancer', 'Disease', (204, 225))	('tumors', 'Disease', (275, 281))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('mutations', 'Var', (251, 260))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('serous ovarian adenocarcinomas', 'Disease', 'MESH:D010051', (103, 133))	('tumors', 'Disease', 'MESH:D009369', (275, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('TP53', 'Gene', (246, 250))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
132846	29020960	A meta-analysis of studies (N = 1815 patients) evaluating the prognostic value of TIL on survival confirmed TILs are a robust predictor of outcome in ovarian cancer and define a specific class of patients.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('ovarian cancer', 'Disease', 'MESH:D010051', (150, 164))	('TILs', 'Var', (108, 112))	('patients', 'Species', '9606', (37, 45))	('ovarian cancer', 'Disease', (150, 164))	('patients', 'Species', '9606', (196, 204))	('ovarian cancer', 'Phenotype', 'HP:0100615', (150, 164))
132848	29020960	Type I cancers have wild-type p53 and BRCA1/2, but also mutations of Ras and Raf as well as expression of IGFR and phosphatidylinositol-3-kinase (PI3K) pathway; type II cancers have mutations of p53 and BRCA1/2.	('p53', 'Gene', (195, 198))	('BRCA1/2', 'Gene', (203, 210))	('BRCA1/2', 'Gene', '672;675', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Type I cancers', 'Disease', 'MESH:D009369', (0, 14))	('PI3K', 'molecular_function', 'GO:0016303', ('146', '150'))	('type II cancers', 'Disease', (161, 176))	('Type I cancers', 'Disease', (0, 14))	('BRCA1/2', 'Gene', '672;675', (203, 210))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('p53', 'Gene', '7157', (30, 33))	('mutations', 'Var', (182, 191))	('Raf', 'Gene', (77, 80))	('type II cancers', 'Disease', 'MESH:D009369', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('p53', 'Gene', (30, 33))	('phosphatidylinositol-3-kinase', 'Gene', '5293', (115, 144))	('BRCA1/2', 'Gene', (38, 45))	('p53', 'Gene', '7157', (195, 198))	('phosphatidylinositol-3-kinase', 'Gene', (115, 144))	('IGFR', 'Gene', '3480', (106, 110))	('Raf', 'Gene', '22882', (77, 80))	('IGFR', 'Gene', (106, 110))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
132855	29020960	The potential relationship between biomarkers, such as germline BRCA mutational status, and the probability of response is under investigation.	('BRCA', 'Gene', (64, 68))	('BRCA', 'Gene', '672', (64, 68))	('mutational', 'Var', (69, 79))
132861	29020960	Heterogeneous techniques in the measurement of PD-L1 and different timing of assessments subgroups may benefit more from immune checkpoint inhibitors: somatic and germline BRCA mutation carriers.	('mutation', 'Var', (177, 185))	('BRCA', 'Gene', '672', (172, 176))	('PD-L1', 'Gene', (47, 52))	('BRCA', 'Gene', (172, 176))	('PD-L1', 'Gene', '29126', (47, 52))
132867	29020960	Cell ovarian cancers are frequently associated with MicroSatellite Instability (MSI) leading to a higher number of CD3+ TILs and PD-1+ TILs.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('ovarian cancers', 'Phenotype', 'HP:0100615', (5, 20))	('CD3', 'Gene', '397455', (115, 118))	('MicroSatellite Instability', 'Var', (52, 78))	('Cell ovarian cancers', 'Disease', 'MESH:D010051', (0, 20))	('MSI', 'Disease', 'None', (80, 83))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('Cell ovarian cancers', 'Disease', (0, 20))	('CD3', 'Gene', (115, 118))	('associated', 'Reg', (36, 46))	('MSI', 'Disease', (80, 83))	('PD-1', 'Gene', (129, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (5, 19))	('PD-1', 'Gene', '5133', (129, 133))
132878	29020960	The presence of high rates of somatic mutations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens.	('increased', 'PosReg', (147, 156))	('ability', 'MPA', (64, 71))	('somatic mutations', 'Var', (30, 47))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('antigens', 'MPA', (167, 175))	('enhance', 'PosReg', (52, 59))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Disease', (111, 117))
132939	29020960	In the 182 patients, the confirmed ORR was 26.3% (95% CI 17.8, 36.4) in 95 patients with a high PD-L1 score and 4.1% (95% CI 0.9, 11.5) in 73 patients with a low or negative PD-L1 score.	('PD-L1', 'Gene', '29126', (96, 101))	('high', 'Var', (91, 95))	('patients', 'Species', '9606', (75, 83))	('PD-L1', 'Gene', (174, 179))	('patients', 'Species', '9606', (11, 19))	('PD-L1', 'Gene', (96, 101))	('patients', 'Species', '9606', (142, 150))	('score', 'Var', (102, 107))	('PD-L1', 'Gene', '29126', (174, 179))
133088	33036162	Nearly 15% of cases of bladder cancer have a mutation of HRAS.	('bladder cancer', 'Disease', 'MESH:D001749', (23, 37))	('bladder cancer', 'Disease', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('HRAS', 'Gene', '3265', (57, 61))	('mutation', 'Var', (45, 53))	('HRAS', 'Gene', (57, 61))	('bladder cancer', 'Phenotype', 'HP:0009725', (23, 37))
133090	33036162	Using our novel gene expression screening platform, pterostilbene was identified to sensitize cisplatin-resistant bladder cancer cells with HRAS alterations via RAS-related autophagy and cell senescence pathways, suggesting a potentially chemotherapeutic role of pterostilbene for cisplatin treatment of human bladder cancer with oncogenic HRAS.	('bladder cancer', 'Disease', 'MESH:D001749', (114, 128))	('bladder cancer', 'Disease', (114, 128))	('HRAS', 'Gene', (340, 344))	('senescence', 'biological_process', 'GO:0010149', ('192', '202'))	('human', 'Species', '9606', (304, 309))	('gene expression', 'biological_process', 'GO:0010467', ('16', '31'))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('bladder cancer', 'Phenotype', 'HP:0009725', (114, 128))	('autophagy', 'biological_process', 'GO:0016236', ('173', '182'))	('HRAS', 'Gene', '3265', (140, 144))	('bladder cancer', 'Disease', 'MESH:D001749', (310, 324))	('bladder cancer', 'Disease', (310, 324))	('pterostilbene', 'Chemical', 'MESH:C107773', (52, 65))	('HRAS', 'Gene', (140, 144))	('alterations', 'Var', (145, 156))	('bladder cancer', 'Phenotype', 'HP:0009725', (310, 324))	('autophagy', 'biological_process', 'GO:0006914', ('173', '182'))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('pterostilbene', 'Chemical', 'MESH:C107773', (263, 276))	('cell senescence', 'CPA', (187, 202))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cisplatin', 'Chemical', 'MESH:D002945', (281, 290))	('HRAS', 'Gene', '3265', (340, 344))
133093	33036162	Our data make HRAS a good candidate for modulation by pterostilbene for targeted cancer therapy in combination with conventional chemotherapeutic agents cisplatin plus gemcitabine.	('gemcitabine', 'Chemical', 'MESH:C056507', (168, 179))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('HRAS', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('cancer', 'Disease', (81, 87))	('pterostilbene', 'Chemical', 'MESH:C107773', (54, 67))	('modulation', 'Var', (40, 50))	('HRAS', 'Gene', '3265', (14, 18))
133094	33036162	Analysis of various public databases revealed that HRAS gene mutation frequency and mRNA expression are higher in bladder urothelial carcinoma.	('mRNA expression', 'MPA', (84, 99))	('HRAS', 'Gene', (51, 55))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (114, 142))	('mutation', 'Var', (61, 69))	('bladder urothelial carcinoma', 'Disease', (114, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('higher', 'Reg', (104, 110))	('HRAS', 'Gene', '3265', (51, 55))
133109	33036162	The mutation of RAS impairs the intrinsic GTPase activity of RAS and prevents GTP hydrolysis to GDP, causing the constitutively active GTP-bound RAS proteins to trigger downstream signaling, which leads to uncontrolled cell proliferation and formation of tumor.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('GDP', 'Chemical', 'MESH:D006153', (96, 99))	('mutation', 'Var', (4, 12))	('downstream signaling', 'MPA', (169, 189))	('prevents', 'NegReg', (69, 77))	('intrinsic', 'MPA', (32, 41))	('causing', 'Reg', (101, 108))	('impairs', 'NegReg', (20, 27))	('signaling', 'biological_process', 'GO:0023052', ('180', '189'))	('leads to', 'Reg', (197, 205))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('78', '92'))	('GTPase activity', 'molecular_function', 'GO:0003924', ('42', '57'))	('tumor', 'Disease', (255, 260))	('trigger', 'Reg', (161, 168))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('GTP hydrolysis to GDP', 'MPA', (78, 99))	('cell proliferation', 'biological_process', 'GO:0008283', ('219', '237'))	('RAS', 'Gene', (16, 19))	('formation', 'biological_process', 'GO:0009058', ('242', '251'))
133110	33036162	Nearly 15% of cases of bladder cancer have a mutation of HRAS, and the active HRAS protein contributes to the tumor progression and is associated with the risk of recurrence.	('bladder cancer', 'Disease', 'MESH:D001749', (23, 37))	('bladder cancer', 'Disease', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('protein', 'Protein', (83, 90))	('tumor', 'Disease', (110, 115))	('HRAS', 'Gene', '3265', (78, 82))	('HRAS', 'Gene', '3265', (57, 61))	('mutation', 'Var', (45, 53))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('active', 'MPA', (71, 77))	('associated with', 'Reg', (135, 150))	('HRAS', 'Gene', (57, 61))	('bladder cancer', 'Phenotype', 'HP:0009725', (23, 37))	('HRAS', 'Gene', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
133129	33036162	Besides the HRAS gene, TP53 gene mutations have been reported to be the first genetic alterations in invasive bladder cancers.	('invasive bladder cancers', 'Disease', (101, 125))	('mutations', 'Var', (33, 42))	('bladder cancers', 'Phenotype', 'HP:0009725', (110, 125))	('HRAS', 'Gene', '3265', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (101, 125))	('bladder cancer', 'Phenotype', 'HP:0009725', (110, 124))	('TP53', 'Gene', '7157', (23, 27))	('HRAS', 'Gene', (12, 16))	('TP53', 'Gene', (23, 27))	('invasive bladder', 'Phenotype', 'HP:0100645', (101, 117))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
133131	33036162	Gene analysis using DepMap further revealed that although the TP53 mutation confers resistance of bladder cancer cells to cisplatin, it has no significant effect on the sensitivity to gemcitabine or pterostilbene (Figure 2B), suggesting that pterostilbene may have an effect on bladder cancer cells despite the presence of the TP53 genotype.	('resistance', 'MPA', (84, 94))	('TP53', 'Gene', '7157', (327, 331))	('TP53', 'Gene', (62, 66))	('bladder cancer', 'Disease', 'MESH:D001749', (278, 292))	('bladder cancer', 'Disease', (278, 292))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('mutation', 'Var', (67, 75))	('effect', 'Reg', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('bladder cancer', 'Phenotype', 'HP:0009725', (278, 292))	('pterostilbene', 'Chemical', 'MESH:C107773', (242, 255))	('gemcitabine', 'Chemical', 'MESH:C056507', (184, 195))	('TP53', 'Gene', '7157', (62, 66))	('TP53', 'Gene', (327, 331))	('pterostilbene', 'Chemical', 'MESH:C107773', (199, 212))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))
133134	33036162	Two of the cell lines (VMCUB1 and SW1710) most resistant to cisplatin express a low level of HRAS, and the other two cell lines (HT1376 and 5637) with less resistance to cisplatin express a high level of HRAS (Figure 1D and Figure 2C), suggesting that the TP53 mutant bladder cancer cells with a higher expression level of HRAS were less resistant to cisplatin, although the elevated HRAS expression had no beneficial effect in all of the cisplatin-treated bladder cancer cell lines stored in the database despite the TP53 genotype (Figure 1C).	('SW1710', 'CellLine', 'CVCL:1721', (34, 40))	('HRAS', 'Gene', '3265', (93, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (351, 360))	('HRAS', 'Gene', '3265', (323, 327))	('HT1376', 'CellLine', 'CVCL:1292', (129, 135))	('HRAS', 'Gene', (323, 327))	('HRAS', 'Gene', '3265', (204, 208))	('HRAS', 'Gene', (93, 97))	('TP53', 'Gene', '7157', (256, 260))	('HRAS', 'Gene', (204, 208))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('TP53', 'Gene', (518, 522))	('bladder cancer', 'Disease', 'MESH:D001749', (268, 282))	('HRAS', 'Gene', '3265', (384, 388))	('bladder cancer', 'Disease', (268, 282))	('HRAS', 'Gene', (384, 388))	('mutant', 'Var', (261, 267))	('bladder cancer', 'Phenotype', 'HP:0009725', (268, 282))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('TP53', 'Gene', (256, 260))	('bladder cancer', 'Disease', 'MESH:D001749', (457, 471))	('bladder cancer', 'Disease', (457, 471))	('bladder cancer', 'Phenotype', 'HP:0009725', (457, 471))	('cisplatin', 'Chemical', 'MESH:D002945', (170, 179))	('TP53', 'Gene', '7157', (518, 522))	('cancer', 'Phenotype', 'HP:0002664', (465, 471))	('cisplatin', 'Chemical', 'MESH:D002945', (439, 448))
133140	33036162	To study the role of the HRAS cancer target and cisplatin resistance in bladder cancer, a T24 cell line with mutant HRAS (G12V, ATCC), expressing the highest level of HRAS (Figure 1D), and displaying the best sensitivity to pterostilbene was chosen for further experiments.	('HRAS', 'Gene', (116, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('HRAS', 'Gene', (25, 29))	('a T24', 'CellLine', 'CVCL:0554', (88, 93))	('HRAS cancer', 'Disease', 'MESH:D009369', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('HRAS', 'Gene', '3265', (116, 120))	('G12V', 'Mutation', 'rs104894230', (122, 126))	('bladder cancer', 'Disease', 'MESH:D001749', (72, 86))	('mutant', 'Var', (109, 115))	('HRAS', 'Gene', '3265', (167, 171))	('HRAS cancer', 'Disease', (25, 36))	('pterostilbene', 'Chemical', 'MESH:C107773', (224, 237))	('HRAS', 'Gene', '3265', (25, 29))	('HRAS', 'Gene', (167, 171))	('bladder cancer', 'Disease', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
133146	33036162	These data confirm our prediction results (Figure 1D and Figure 2C) which suggest that pterostilbene may overcome cisplatin resistance in the human bladder cell line with HRAS alternations.	('alternations', 'Var', (176, 188))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('human', 'Species', '9606', (142, 147))	('pterostilbene', 'Chemical', 'MESH:C107773', (87, 100))	('cisplatin resistance', 'MPA', (114, 134))	('overcome', 'PosReg', (105, 113))	('HRAS', 'Gene', '3265', (171, 175))	('HRAS', 'Gene', (171, 175))
133156	33036162	Phosphorylation of class I PI3K and its downstream molecules mTOR and p70S6K has been reported to inhibit autophagy, whereas phosphorylation of MEK and ERK induces autophagy.	('autophagy', 'biological_process', 'GO:0016236', ('164', '173'))	('PI3K', 'Var', (27, 31))	('MEK', 'Gene', (144, 147))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('mTOR', 'Gene', '2475', (61, 65))	('ERK', 'Gene', '5594', (152, 155))	('Phosphorylation', 'Var', (0, 15))	('autophagy', 'biological_process', 'GO:0006914', ('164', '173'))	('p70S6K', 'Gene', (70, 76))	('autophagy', 'biological_process', 'GO:0016236', ('106', '115'))	('autophagy', 'CPA', (164, 173))	('ERK', 'molecular_function', 'GO:0004707', ('152', '155'))	('ERK', 'Gene', (152, 155))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('autophagy', 'CPA', (106, 115))	('PI3K', 'molecular_function', 'GO:0016303', ('27', '31'))	('autophagy', 'biological_process', 'GO:0006914', ('106', '115'))	('MEK', 'Gene', '5609', (144, 147))	('inhibit', 'NegReg', (98, 105))	('p70S6K', 'Gene', '6198', (70, 76))	('mTOR', 'Gene', (61, 65))
133160	33036162	Therefore, the constitutively active HRAS protein due to the HRAS mutation in T24 cells, as compared to the HRAS wild-type in E7 cells (Figure 3C), may strengthen autophagy induction (Figure 3B).	('HRAS', 'Gene', (61, 65))	('T24', 'Chemical', '-', (78, 81))	('HRAS', 'Gene', '3265', (108, 112))	('autophagy induction', 'CPA', (163, 182))	('autophagy', 'biological_process', 'GO:0016236', ('163', '172'))	('E7', 'CellLine', 'CVCL:J153', (126, 128))	('HRAS', 'Gene', (108, 112))	('HRAS', 'Gene', '3265', (37, 41))	('autophagy', 'biological_process', 'GO:0006914', ('163', '172'))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('HRAS', 'Gene', '3265', (61, 65))	('mutation', 'Var', (66, 74))	('strengthen', 'PosReg', (152, 162))	('HRAS', 'Gene', (37, 41))
133161	33036162	These results confirm the role of mutant HRAS in pterostilbene-induced autophagy for sensitizing the cells to cisplatin (Figure 1D and Figure 2C,D).	('pterostilbene', 'Chemical', 'MESH:C107773', (49, 62))	('autophagy', 'biological_process', 'GO:0016236', ('71', '80'))	('autophagy', 'biological_process', 'GO:0006914', ('71', '80'))	('HRAS', 'Gene', (41, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('sensitizing', 'MPA', (85, 96))	('autophagy', 'CPA', (71, 80))	('HRAS', 'Gene', '3265', (41, 45))	('mutant', 'Var', (34, 40))
133164	33036162	As shown in Figure 5A, the addition of U0126 and 3-MA separately significantly decreased (p < 0.05) the cytotoxic response of T24 to the treatment with cisplatin/gemcitabine/pterostilbene or carboplatin/gemcitabine/pterostilbene, suggesting that pterostilbene-induced autophagy was cytotoxic.	('U0126', 'Var', (39, 44))	('3-MA', 'Chemical', '-', (49, 53))	('cytotoxic response', 'CPA', (104, 122))	('T24', 'Chemical', '-', (126, 129))	('decreased', 'NegReg', (79, 88))	('gemcitabine', 'Chemical', 'MESH:C056507', (203, 214))	('cisplatin', 'Chemical', 'MESH:D002945', (152, 161))	('autophagy', 'biological_process', 'GO:0016236', ('268', '277'))	('pterostilbene', 'Chemical', 'MESH:C107773', (246, 259))	('autophagy', 'biological_process', 'GO:0006914', ('268', '277'))	('gemcitabine', 'Chemical', 'MESH:C056507', (162, 173))	('pterostilbene', 'Chemical', 'MESH:C107773', (215, 228))	('U0126', 'Chemical', 'MESH:C113580', (39, 44))	('carboplatin', 'Chemical', 'MESH:D016190', (191, 202))	('pterostilbene', 'Chemical', 'MESH:C107773', (174, 187))
133174	33036162	Figure 5E shows that pterostilbene elevated the expression of phospho-Thr288-Aurora-A in T24 cells treated with carboplatin plus gemcitabine.	('pterostilbene', 'Chemical', 'MESH:C107773', (21, 34))	('carboplatin', 'Chemical', 'MESH:D016190', (112, 123))	('T24', 'Chemical', '-', (89, 92))	('Thr288', 'Chemical', '-', (70, 76))	('expression', 'MPA', (48, 58))	('elevated', 'PosReg', (35, 43))	('phospho-Thr288-Aurora-A', 'Var', (62, 85))	('gemcitabine', 'Chemical', 'MESH:C056507', (129, 140))
133175	33036162	These data suggest that the pterostilbene-enhanced senescence in T24 cells treated with cisplatin/or carboplatin plus gemcitabine may proceed, at least in part, via hypophosphorylation of RB, overexpression of RAS, and/or activation of Aurora-A.	('Aurora-A', 'Gene', (236, 244))	('hypophosphorylation', 'Var', (165, 184))	('senescence', 'biological_process', 'GO:0010149', ('51', '61'))	('senescence', 'MPA', (51, 61))	('activation', 'PosReg', (222, 232))	('T24', 'Chemical', '-', (65, 68))	('RAS', 'Protein', (210, 213))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('gemcitabine', 'Chemical', 'MESH:C056507', (118, 129))	('overexpression', 'PosReg', (192, 206))	('carboplatin', 'Chemical', 'MESH:D016190', (101, 112))	('RB', 'Chemical', '-', (188, 190))	('pterostilbene', 'Chemical', 'MESH:C107773', (28, 41))
133176	33036162	The constitutively active mutant HRAS signaling in HRAS mutated T24 cells may benefit the enhancement of senescence in response to pterostilbene compared to HRAS wild-type E7 cells.	('enhancement', 'PosReg', (90, 101))	('signaling', 'biological_process', 'GO:0023052', ('38', '47'))	('response to pterostilbene', 'MPA', (119, 144))	('pterostilbene', 'Chemical', 'MESH:C107773', (131, 144))	('HRAS', 'Gene', (51, 55))	('HRAS', 'Gene', (157, 161))	('T24', 'Chemical', '-', (64, 67))	('HRAS', 'Gene', '3265', (33, 37))	('senescence', 'biological_process', 'GO:0010149', ('105', '115'))	('HRAS', 'Gene', (33, 37))	('E7', 'CellLine', 'CVCL:J153', (172, 174))	('HRAS', 'Gene', '3265', (157, 161))	('mutant', 'Var', (26, 32))	('benefit', 'PosReg', (78, 85))	('senescence', 'MPA', (105, 115))	('HRAS', 'Gene', '3265', (51, 55))
133183	33036162	The decrease in tumor expression of p-class I PI3K/p-mTOR/p-p70S6K and increase of p-ERK (Figure 6F) validated the results using bioinformatics analysis and confirmed the observation in vitro (Figure 7), further highlighting the role of mutant HRAS in cisplatin sensitivity of T24 xenografts in response to pterostilbene.	('HRAS', 'Gene', (244, 248))	('T24', 'Chemical', '-', (277, 280))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mTOR', 'Gene', '2475', (53, 57))	('increase', 'PosReg', (71, 79))	('p70S6K', 'Gene', '6198', (60, 66))	('decrease', 'NegReg', (4, 12))	('ERK', 'molecular_function', 'GO:0004707', ('85', '88'))	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('mutant', 'Var', (237, 243))	('p-class', 'Var', (36, 43))	('ERK', 'Gene', '5594', (85, 88))	('tumor', 'Disease', (16, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (252, 261))	('p70S6K', 'Gene', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('ERK', 'Gene', (85, 88))	('mTOR', 'Gene', (53, 57))	('HRAS', 'Gene', '3265', (244, 248))	('pterostilbene', 'Chemical', 'MESH:C107773', (307, 320))
133185	33036162	Among the bladder cancer cell lines stored in the PRISM database, the most effective cell line against pterostilbene is T24 (Figure 2C), a grade III human bladder cancer cell with mutant HRAS protein (G12V, ATCC).	('bladder cancer', 'Disease', (155, 169))	('bladder cancer', 'Disease', (10, 24))	('pterostilbene', 'Chemical', 'MESH:C107773', (103, 116))	('T24', 'Chemical', '-', (120, 123))	('G12V', 'Mutation', 'rs104894230', (201, 205))	('HRAS', 'Gene', '3265', (187, 191))	('PRISM', 'Gene', (50, 55))	('PRISM', 'Gene', '93166', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('HRAS', 'Gene', (187, 191))	('human', 'Species', '9606', (149, 154))	('bladder cancer', 'Disease', 'MESH:D001749', (155, 169))	('bladder cancer', 'Phenotype', 'HP:0009725', (155, 169))	('bladder cancer', 'Phenotype', 'HP:0009725', (10, 24))	('protein', 'cellular_component', 'GO:0003675', ('192', '199'))	('bladder cancer', 'Disease', 'MESH:D001749', (10, 24))	('G12V', 'Var', (201, 205))
133188	33036162	These results demonstrate that overexpression of the HRAS gene correlated well with the sensitivity of pterostilbene in bladder cancer cells, and mutation of the HRAS gene was associated with the highest sensitivity to pterostilbene.	('HRAS', 'Gene', '3265', (162, 166))	('pterostilbene', 'Chemical', 'MESH:C107773', (103, 116))	('pterostilbene', 'Chemical', 'MESH:C107773', (219, 232))	('bladder cancer', 'Disease', 'MESH:D001749', (120, 134))	('sensitivity of pterostilbene', 'MPA', (88, 116))	('associated', 'Reg', (176, 186))	('HRAS', 'Gene', (162, 166))	('bladder cancer', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('HRAS', 'Gene', '3265', (53, 57))	('sensitivity', 'MPA', (204, 215))	('mutation', 'Var', (146, 154))	('overexpression', 'PosReg', (31, 45))	('HRAS', 'Gene', (53, 57))	('bladder cancer', 'Phenotype', 'HP:0009725', (120, 134))
133193	33036162	The TP53 mutation (lost-of-function mutations) leads to less activation of autophagy and/or senescence, conferring resistance of bladder cancer cells to cisplatin.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('TP53', 'Gene', (4, 8))	('autophagy', 'biological_process', 'GO:0016236', ('75', '84'))	('bladder cancer', 'Disease', 'MESH:D001749', (129, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('senescence', 'CPA', (92, 102))	('mutations', 'Var', (36, 45))	('autophagy', 'biological_process', 'GO:0006914', ('75', '84'))	('bladder cancer', 'Disease', (129, 143))	('senescence', 'biological_process', 'GO:0010149', ('92', '102'))	('autophagy', 'CPA', (75, 84))	('resistance', 'MPA', (115, 125))	('TP53', 'Gene', '7157', (4, 8))
133194	33036162	In a p53 mutated cell line with a high expression level of HRAS, either due to HRAS mutation (gain-of-function mutations) or overexpressing the wild-type gene, pterostilbene utilizes the high expression level of HRAS protein to elevate the RAS signaling for induction of autophagy and senescence by causing the activation of MEK/ERK and accumulation of p16, respectively.	('HRAS', 'Gene', (212, 216))	('autophagy', 'CPA', (271, 280))	('p16', 'Gene', (353, 356))	('accumulation', 'PosReg', (337, 349))	('ERK', 'Gene', (329, 332))	('elevate', 'PosReg', (228, 235))	('p16', 'Gene', '1029', (353, 356))	('HRAS', 'Gene', '3265', (59, 63))	('autophagy', 'biological_process', 'GO:0016236', ('271', '280'))	('mutations', 'Var', (111, 120))	('senescence', 'CPA', (285, 295))	('HRAS', 'Gene', (59, 63))	('senescence', 'biological_process', 'GO:0010149', ('285', '295'))	('signaling', 'biological_process', 'GO:0023052', ('244', '253'))	('activation', 'PosReg', (311, 321))	('protein', 'cellular_component', 'GO:0003675', ('217', '224'))	('ERK', 'molecular_function', 'GO:0004707', ('329', '332'))	('pterostilbene', 'Chemical', 'MESH:C107773', (160, 173))	('autophagy', 'biological_process', 'GO:0006914', ('271', '280'))	('RAS signaling', 'MPA', (240, 253))	('MEK', 'Gene', '5609', (325, 328))	('HRAS', 'Gene', '3265', (79, 83))	('ERK', 'Gene', '5594', (329, 332))	('HRAS', 'Gene', (79, 83))	('HRAS', 'Gene', '3265', (212, 216))	('MEK', 'Gene', (325, 328))	('mutation', 'Var', (84, 92))
133201	33036162	Inhibition of autophagy enhanced the death of these cancer cells, suggesting that pterostilbene-induced autophagy is cytoprotective (resistant to therapy).	('autophagy', 'CPA', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('death', 'Disease', (37, 42))	('autophagy', 'biological_process', 'GO:0006914', ('14', '23'))	('autophagy', 'biological_process', 'GO:0016236', ('104', '113'))	('autophagy', 'biological_process', 'GO:0006914', ('104', '113'))	('enhanced', 'PosReg', (24, 32))	('pterostilbene', 'Chemical', 'MESH:C107773', (82, 95))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('death', 'Disease', 'MESH:D003643', (37, 42))	('autophagy', 'biological_process', 'GO:0016236', ('14', '23'))
133202	33036162	However, our gene analysis results reveal that pterostilbene-induced autophagy has the potential to sensitize HRAS mutant bladder cancer cells to cisplatin (Figure 2C), suggesting the pterostilbene-induced autophagy is cytotoxic.	('autophagy', 'biological_process', 'GO:0016236', ('206', '215'))	('pterostilbene', 'Chemical', 'MESH:C107773', (184, 197))	('bladder cancer', 'Phenotype', 'HP:0009725', (122, 136))	('autophagy', 'biological_process', 'GO:0006914', ('206', '215'))	('cisplatin', 'Chemical', 'MESH:D002945', (146, 155))	('autophagy', 'biological_process', 'GO:0016236', ('69', '78'))	('mutant', 'Var', (115, 121))	('HRAS', 'Gene', (110, 114))	('bladder cancer', 'Disease', 'MESH:D001749', (122, 136))	('bladder cancer', 'Disease', (122, 136))	('pterostilbene', 'Chemical', 'MESH:C107773', (47, 60))	('autophagy', 'biological_process', 'GO:0006914', ('69', '78'))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('HRAS', 'Gene', '3265', (110, 114))
133203	33036162	Administration of autophagy inhibitor 3-MA and U0126 separately indeed reduced the cytotoxic response of T24 cells to treatment with cisplatin/gemcitabine/pterostilbene or carboplatin/gemcitabine/pterostilbene (Figure 5A), further validating that pterostilbene induced a cytotoxic form of autophagy.	('autophagy', 'biological_process', 'GO:0016236', ('289', '298'))	('gemcitabine', 'Chemical', 'MESH:C056507', (143, 154))	('carboplatin', 'Chemical', 'MESH:D016190', (172, 183))	('U0126', 'Var', (47, 52))	('pterostilbene', 'Chemical', 'MESH:C107773', (155, 168))	('autophagy', 'biological_process', 'GO:0006914', ('289', '298'))	('autophagy', 'biological_process', 'GO:0016236', ('18', '27'))	('autophagy', 'biological_process', 'GO:0006914', ('18', '27'))	('reduced', 'NegReg', (71, 78))	('T24', 'Chemical', '-', (105, 108))	('gemcitabine', 'Chemical', 'MESH:C056507', (184, 195))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('pterostilbene', 'Chemical', 'MESH:C107773', (196, 209))	('U0126', 'Chemical', 'MESH:C113580', (47, 52))	('pterostilbene', 'Chemical', 'MESH:C107773', (247, 260))	('cytotoxic response', 'CPA', (83, 101))	('3-MA', 'Chemical', '-', (38, 42))
133217	33036162	Though T24 cells carry mutated TP53, the mutation of which results in the in-frame deletion of tyrosine at the residue 126 of p53, preventing it from binding with SV40 large T antigen but may still possess some functions of the wild-type counterparts.	('preventing', 'NegReg', (131, 141))	('T24', 'Chemical', '-', (7, 10))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('mutation', 'Var', (41, 49))	('tyrosine', 'Chemical', 'MESH:D014443', (95, 103))	('deletion', 'Var', (83, 91))	('p53', 'Gene', (126, 129))	('tyrosine', 'Var', (95, 103))	('binding', 'molecular_function', 'GO:0005488', ('150', '157'))	('binding', 'Interaction', (150, 157))
133222	33036162	In contrast, Aurora-A inhibition has also been reported to induce senescence of glioblastoma neurosphere and many types of human cells in vitro and in vivo.	('inhibition', 'Var', (22, 32))	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('human', 'Species', '9606', (123, 128))	('Aurora-A', 'Gene', (13, 21))	('senescence', 'biological_process', 'GO:0010149', ('66', '76'))	('glioblastoma', 'Disease', (80, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))	('senescence', 'CPA', (66, 76))
133254	33036162	Our data indicate that pterostilbene-enhanced biosensitivity of HRAS mutant T24 cells against cisplatin/carboplatin plus gemcitabine was associated with induction of the cytotoxic form of autophagy (promoting cell death) and cell senescence.	('cell senescence', 'CPA', (225, 240))	('gemcitabine', 'Chemical', 'MESH:C056507', (121, 132))	('biosensitivity', 'MPA', (46, 60))	('induction', 'PosReg', (153, 162))	('autophagy', 'biological_process', 'GO:0006914', ('188', '197'))	('death', 'Disease', (214, 219))	('carboplatin', 'Chemical', 'MESH:D016190', (104, 115))	('T24', 'Chemical', '-', (76, 79))	('senescence', 'biological_process', 'GO:0010149', ('230', '240'))	('cell death', 'biological_process', 'GO:0008219', ('209', '219'))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('HRAS', 'Gene', '3265', (64, 68))	('pterostilbene-enhanced', 'PosReg', (23, 45))	('cytotoxic form of autophagy', 'CPA', (170, 197))	('HRAS', 'Gene', (64, 68))	('death', 'Disease', 'MESH:D003643', (214, 219))	('mutant', 'Var', (69, 75))	('pterostilbene', 'Chemical', 'MESH:C107773', (23, 36))	('autophagy', 'biological_process', 'GO:0016236', ('188', '197'))
133266	31998650	Although FUNDC1 showed a protective effect on pan-cancer, a high expression level of FUNDC1 was detrimental to the survival of LIHC patients.	('FUNDC1', 'Gene', (9, 15))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('high', 'Var', (60, 64))	('FUNDC1', 'Gene', (85, 91))	('FUNDC1', 'Gene', '139341', (9, 15))	('LIHC', 'Disease', (127, 131))	('detrimental', 'NegReg', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('LIHC', 'Disease', 'MESH:D006528', (127, 131))	('FUNDC1', 'Gene', '139341', (85, 91))	('patients', 'Species', '9606', (132, 140))
133284	31998650	For example, cytotoxic T lymphocyte associated antigen 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PD-L1) inhibitors were found to have promising antitumor effects on malignant melanoma and non-small-cell lung carcinoma.	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('programmed death ligand-1', 'Gene', (97, 122))	('malignant melanoma', 'Phenotype', 'HP:0002861', (192, 210))	('ligand', 'molecular_function', 'GO:0005488', ('114', '120'))	('non-small-cell lung carcinoma', 'Disease', (215, 244))	('programmed death-1', 'Gene', '5133', (66, 84))	('non-small-cell lung carcinoma', 'Disease', 'MESH:D002289', (215, 244))	('programmed death-1', 'Gene', (66, 84))	('cytotoxic T lymphocyte associated antigen 4', 'Gene', (13, 56))	('programmed death ligand-1', 'Gene', '29126', (97, 122))	('tumor', 'Disease', (175, 180))	('CTLA4', 'Gene', '1493', (58, 63))	('cytotoxic T lymphocyte associated antigen 4', 'Gene', '1493', (13, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('melanoma', 'Disease', (202, 210))	('inhibitors', 'Var', (131, 141))	('PD-L1', 'Gene', (124, 129))	('PD-L1', 'Gene', '29126', (124, 129))	('CTLA4', 'Gene', (58, 63))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (219, 244))	('PD-1', 'Gene', (86, 90))	('PD-1', 'Gene', '5133', (86, 90))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (215, 244))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
133325	31998650	The findings for lung cancer were partly different from those using PrognoScan, as a high expression of FUNDC1 only benefited LUSC (OS: HR = 0.64, 95 % CI from 0.48 to 0.85 logrank P = 0.0017; RFS: HR = 0.55, 95% CI from 0.33 to 0.91, logrank P = 0.019) (Figures 2C,D) and not LUAD (OS: HR = 0.8, 95% CI from 0.6 to 1.08, logrank P = 0.15; RFS: HR = 1.41, 95% CI from 0.91 to 2.19, logrank P = 0.13) (Figures 3M,N).	('LUSC', 'Disease', (126, 130))	('FUNDC1', 'Gene', (104, 110))	('lung cancer', 'Disease', (17, 28))	('benefited', 'PosReg', (116, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('FUNDC1', 'Gene', '139341', (104, 110))	('LUSC', 'Phenotype', 'HP:0030359', (126, 130))	('high', 'Var', (85, 89))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('LUAD', 'Disease', (277, 281))	('LUAD', 'Disease', 'MESH:C538231', (277, 281))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('LUSC', 'Disease', 'MESH:D002294', (126, 130))
133341	31998650	For progression-free survival (PFS), FUNDC1 expression was significantly hazardous to LIHC patients without hepatitis virus infection (n = 167, HR = 2.1, 95% CI from 1.3 to 3.38, P = 0.0019) but became protective to LIHC patients at stage 2 (n = 84, HR = 0.52, 95% CI from 0.28 to 0.98, P = 0.039) and grade 3 (n = 119, HR = 0.6, 95% CI from 0.36 to 0.98, P = 0.041) (Figure 4).	('LIHC', 'Disease', (86, 90))	('patients', 'Species', '9606', (221, 229))	('hepatitis virus infection', 'Disease', (108, 133))	('patients', 'Species', '9606', (91, 99))	('LIHC', 'Disease', 'MESH:D006528', (86, 90))	('hepatitis', 'Phenotype', 'HP:0012115', (108, 117))	('FUNDC1', 'Gene', (37, 43))	('expression', 'Var', (44, 54))	('FUNDC1', 'Gene', '139341', (37, 43))	('LIHC', 'Disease', (216, 220))	('LIHC', 'Disease', 'MESH:D006528', (216, 220))	('hepatitis virus infection', 'Disease', 'MESH:D006525', (108, 133))
133365	31998650	Mitochondria are essential for human immunity, and aberrant mitochondrial activity affects immune responses.	('aberrant', 'Var', (51, 59))	('mitochondrial activity', 'MPA', (60, 82))	('Mitochondria', 'cellular_component', 'GO:0005739', ('0', '12'))	('human', 'Species', '9606', (31, 36))	('immune responses', 'CPA', (91, 107))	('affects', 'Reg', (83, 90))
133366	31998650	For example, some studies have demonstrated that viruses (e.g., HBV in LIHC) can manipulate mitophagy, which enables viruses to promote persistent infection and attenuate the innate immune responses.	('attenuate', 'NegReg', (161, 170))	('innate immune responses', 'CPA', (175, 198))	('mitophagy', 'CPA', (92, 101))	('manipulate', 'Reg', (81, 91))	('infection', 'Disease', (147, 156))	('mitophagy', 'biological_process', 'GO:0000422', ('92', '101'))	('LIHC', 'Disease', (71, 75))	('infection', 'Disease', 'MESH:D007239', (147, 156))	('persistent infection', 'Phenotype', 'HP:0031035', (136, 156))	('viruses', 'Var', (117, 124))	('mitophagy', 'biological_process', 'GO:0000423', ('92', '101'))	('LIHC', 'Disease', 'MESH:D006528', (71, 75))	('promote', 'PosReg', (128, 135))
133369	31998650	FUNDC1-mediated mitophagy is negatively regulated by the phosphorylation of FUNDC1, as the phosphorylation of Tyr 18 in the FUNDC1 LC3-interacting region motif can weaken the binding affinity of FUNDC1 to LC3.	('phosphorylation', 'Var', (91, 106))	('FUNDC1', 'Gene', '139341', (76, 82))	('FUNDC1', 'Gene', '139341', (124, 130))	('phosphorylation', 'biological_process', 'GO:0016310', ('91', '106'))	('mitophagy', 'biological_process', 'GO:0000422', ('16', '25'))	('weaken', 'NegReg', (164, 170))	('Tyr', 'Chemical', 'MESH:C042696', (110, 113))	('mitophagy', 'biological_process', 'GO:0000423', ('16', '25'))	('binding', 'molecular_function', 'GO:0005488', ('175', '182'))	('FUNDC1', 'Gene', (0, 6))	('Tyr 18', 'Var', (110, 116))	('binding affinity', 'Interaction', (175, 191))	('FUNDC1', 'Gene', (195, 201))	('LC3', 'Protein', (205, 208))	('FUNDC1', 'Gene', (76, 82))	('FUNDC1', 'Gene', (124, 130))	('mitophagy', 'CPA', (16, 25))	('FUNDC1', 'Gene', '139341', (0, 6))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('FUNDC1', 'Gene', '139341', (195, 201))
133377	31998650	Thus, it is reasonable to surmise that FUNDC1 expression may influence patient survival through tumor cell proliferation.	('expression', 'Var', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('influence', 'Reg', (61, 70))	('tumor', 'Disease', (96, 101))	('FUNDC1', 'Gene', (39, 45))	('cell proliferation', 'biological_process', 'GO:0008283', ('102', '120'))	('FUNDC1', 'Gene', '139341', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('patient', 'Species', '9606', (71, 78))	('patient survival', 'CPA', (71, 87))
133381	31998650	One previous study has demonstrated that FUNDC1-mediated mitophagy can suppress hepatocarcinogenesis.	('FUNDC1', 'Gene', (41, 47))	('FUNDC1', 'Gene', '139341', (41, 47))	('mitophagy', 'biological_process', 'GO:0000422', ('57', '66'))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (80, 100))	('mitophagy', 'Var', (57, 66))	('suppress', 'NegReg', (71, 79))	('mitophagy', 'biological_process', 'GO:0000423', ('57', '66'))	('hepatocarcinogenesis', 'Disease', (80, 100))
133382	31998650	This study found that the specific knockout of FUNDC1 in hepatocytes promotes the initiation and progression of chemical carcinogen diethylnitrosamine-induced HCC.	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (132, 150))	('promotes', 'PosReg', (69, 77))	('FUNDC1', 'Gene', (47, 53))	('progression', 'CPA', (97, 108))	('knockout', 'Var', (35, 43))	('FUNDC1', 'Gene', '139341', (47, 53))
133383	31998650	The study also found that FUNDC1 transgenic hepatocytes protect against the development of HCC.	('FUNDC1', 'Gene', (26, 32))	('HCC', 'Disease', (91, 94))	('transgenic', 'Var', (33, 43))	('FUNDC1', 'Gene', '139341', (26, 32))
133406	31998650	In 8 datasets in PrognoScan, high FUNDC1 expression levels could be used as an independent risk factor for a poor prognosis in brain, breast, colorectal, and skin cancers (Figure 2).	('high', 'Var', (29, 33))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('colorectal', 'Disease', (142, 152))	('expression', 'MPA', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('skin cancers', 'Disease', (158, 170))	('skin cancers', 'Phenotype', 'HP:0008069', (158, 170))	('brain', 'Disease', (127, 132))	('FUNDC1', 'Gene', (34, 40))	('skin cancers', 'Disease', 'MESH:D012878', (158, 170))	('breast', 'Disease', (134, 140))	('FUNDC1', 'Gene', '139341', (34, 40))
133407	31998650	In addition, a high level of FUNDC1 expression was shown to be related to a poor prognosis in LIHC with micro-vascular invasion but a favorable prognosis in LIHC with AJCC T2 (Figure 4).	('high', 'Var', (15, 19))	('LIHC', 'Disease', (94, 98))	('FUNDC1', 'Gene', (29, 35))	('LIHC', 'Disease', 'MESH:D006528', (94, 98))	('LIHC', 'Disease', (157, 161))	('FUNDC1', 'Gene', '139341', (29, 35))	('LIHC', 'Disease', 'MESH:D006528', (157, 161))	('expression', 'MPA', (36, 46))
133409	31998650	Another major finding from this study is that FUNDC1 expression correlates with diverse immune infiltration levels in cancers, especially in LIHC and LUSC.	('LIHC', 'Disease', (141, 145))	('cancers', 'Disease', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('correlates with', 'Reg', (64, 79))	('expression', 'Var', (53, 63))	('immune infiltration levels', 'MPA', (88, 114))	('FUNDC1', 'Gene', (46, 52))	('LIHC', 'Disease', 'MESH:D006528', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('FUNDC1', 'Gene', '139341', (46, 52))	('LUSC', 'Disease', 'MESH:D002294', (150, 154))	('LUSC', 'Disease', (150, 154))	('LUSC', 'Phenotype', 'HP:0030359', (150, 154))
133433	31998650	These interactions between tumor cells and infiltrating immune cells help explain the findings from this study indicating that TAMs have a positive correlation with FUNDC1 expression in LIHC and that the high expression of FUNDC1 is associated with a worse LIHC patient prognosis.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('FUNDC1', 'Gene', '139341', (223, 229))	('FUNDC1', 'Gene', '139341', (165, 171))	('LIHC', 'Disease', (186, 190))	('tumor', 'Disease', (27, 32))	('FUNDC1', 'Gene', (165, 171))	('associated with', 'Reg', (233, 248))	('LIHC', 'Disease', 'MESH:D006528', (186, 190))	('TAM', 'Gene', '8205', (127, 130))	('expression', 'MPA', (172, 182))	('FUNDC1', 'Gene', (223, 229))	('patient', 'Species', '9606', (262, 269))	('LIHC', 'Disease', (257, 261))	('LIHC', 'Disease', 'MESH:D006528', (257, 261))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('TAM', 'Gene', (127, 130))	('high expression', 'Var', (204, 219))
133451	31900418	Interpreting pathways to discover cancer driver genes with Moonlight Cancer driver gene alterations influence cancer development, occurring in oncogenes, tumor suppressors, and dual role genes.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', (110, 116))	('Cancer', 'Gene', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('alterations', 'Var', (88, 99))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cancer', 'Disease', (34, 40))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('influence', 'Reg', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('tumor', 'Disease', (154, 159))
133458	31900418	We discover inactivation of tumor suppressors in intron regions and that tissue type and subtype indicate dual role status.	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (28, 33))	('inactivation', 'Var', (12, 24))
133465	31900418	Cancer progression is accelerated by the accumulation of genomic abnormalities in two different categories of cancer driver genes: oncogenes or tumor suppressors.	('genomic abnormalities', 'Var', (57, 78))	('tumor', 'Disease', (144, 149))	('cancer', 'Disease', (110, 116))	('accelerated', 'PosReg', (22, 33))	('accumulation', 'PosReg', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('Cancer progression', 'CPA', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
133470	31900418	In addition, it has been shown that concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis.	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('90', '126'))	('Notch', 'MPA', (48, 53))	('epithelial-to-mesenchymal transition', 'CPA', (90, 126))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('activation', 'PosReg', (54, 64))	('deletion', 'Var', (73, 81))	('trigger', 'PosReg', (82, 89))
133519	31900418	Moonlight detected 233 genes associated with hypermethylation (tumor-suppressor critical) and 404 with hypomethylation (oncogene critical).	('tumor-suppressor', 'Gene', (63, 79))	('hypermethylation', 'Var', (45, 61))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('63', '79'))	('tumor-suppressor', 'Gene', '7248', (63, 79))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('63', '79'))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
133523	31900418	These findings were confirmed by data on lung cancer, and associated with copy-number changes in head-and-neck cancer cell lines, but it has not been validated yet as oncogene for head-and-neck tumors, suggesting an interesting target for future studies.	('neck', 'cellular_component', 'GO:0044326', ('189', '193'))	('head-and-neck cancer', 'Disease', 'MESH:D006258', (97, 117))	('head-and-neck cancer', 'Disease', (97, 117))	('neck cancer', 'Phenotype', 'HP:0012288', (106, 117))	('lung cancer', 'Disease', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('neck', 'cellular_component', 'GO:0044326', ('106', '110'))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('copy-number changes', 'Var', (74, 93))	('tumors', 'Disease', (194, 200))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))
133524	31900418	For breast cancer, we found that 231 (30%) of the predicted oncogenic mediators experienced epigenetic changes.	('epigenetic changes', 'Var', (92, 110))	('experienced', 'Reg', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))
133525	31900418	Of these genes, 54 tumor suppressors showed hypermethylation while 80 oncogenes showed hypomethylation.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('hypermethylation', 'Var', (44, 60))	('tumor', 'Disease', (19, 24))
133533	31900418	Recently, it was shown that knockdown of RRM2 led to intrinsic apoptosis in head-and-neck squamous cell carcinoma and non-small cell lung cancer cell lines, confirming our findings.	('intrinsic apoptosis', 'CPA', (53, 72))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (118, 144))	('RRM2', 'Gene', (41, 45))	('RRM2', 'Gene', '6241', (41, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('squamous cell carcinoma', 'Disease', (90, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('non-small cell lung cancer', 'Disease', (118, 144))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 113))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('intrinsic apoptosis', 'biological_process', 'GO:0097193', ('53', '72'))	('neck', 'cellular_component', 'GO:0044326', ('85', '89'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (122, 144))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (118, 144))	('knockdown', 'Var', (28, 37))
133535	31900418	We also found hypermethylation of colon adenocarcinoma and lung adenocarcinoma, specifically in two CpG loci associated with FLI1: cg11017065 (colon cancer) and cg04691908 (lung adenocarcinoma).	('colon adenocarcinoma and lung adenocarcinoma', 'Disease', 'MESH:C538231', (34, 78))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (59, 78))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (173, 192))	('lung adenocarcinoma', 'Disease', (59, 78))	('colon cancer', 'Phenotype', 'HP:0003003', (143, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('FLI1', 'Gene', (125, 129))	('cg11017065', 'Var', (131, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('hypermethylation', 'Var', (14, 30))	('FLI1', 'Gene', '2313', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('colon cancer', 'Disease', 'MESH:D015179', (143, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (173, 192))	('lung adenocarcinoma', 'Disease', (173, 192))	('cg04691908', 'Var', (161, 171))	('colon cancer', 'Disease', (143, 155))
133536	31900418	We hypothesize that differentially methylated CpG islands, or hypermethylation of the FLI1 promoter, may also lead to inactivation of FLI1's tumor-suppressor ability.	('FLI1', 'Gene', (134, 138))	('hypermethylation', 'Var', (62, 78))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor-suppressor', 'Gene', (141, 157))	('inactivation', 'NegReg', (118, 130))	('FLI1', 'Gene', (86, 90))	('FLI1', 'Gene', '2313', (86, 90))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('141', '157'))	('tumor-suppressor', 'Gene', '7248', (141, 157))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('141', '157'))	('FLI1', 'Gene', '2313', (134, 138))
133538	31900418	Hypermethylation, especially in tumor suppressors, is a well-known epigenetic control mechanism that is important for gene inactivation in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('cancer', 'Disease', (139, 145))
133539	31900418	Furthermore, DNA hypomethylation can be found early in carcinogenesis, and is often associated with tumor progression and oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('tumor', 'Disease', (100, 105))	('associated', 'Reg', (84, 94))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('13', '32'))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('DNA hypomethylation', 'Var', (13, 32))	('carcinogenesis', 'Disease', (55, 69))
133540	31900418	Therefore, Moonlight's highlighted mechanisms on CpG-island promoter regions can be summarized as follows: (i) oncogene activation is associated with DNA hypomethylation at the promoter sites, and (ii) tumor-suppressor inactivation is associated with DNA hypermethylation at the promoter sites.	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('251', '271'))	('oncogene', 'Gene', (111, 119))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('202', '218'))	('tumor-suppressor', 'Gene', '7248', (202, 218))	('activation', 'PosReg', (120, 130))	('DNA', 'cellular_component', 'GO:0005574', ('150', '153'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('202', '218'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('DNA', 'cellular_component', 'GO:0005574', ('251', '254'))	('tumor-suppressor', 'Gene', (202, 218))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('150', '169'))	('hypomethylation', 'Var', (154, 169))
133548	31900418	We also reported overall higher chromatin peaks signal for oncogenes when compared with tumor suppressors (Fig.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('oncogenes', 'Var', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('higher', 'PosReg', (25, 31))	('chromatin peaks signal', 'MPA', (32, 54))	('chromatin', 'cellular_component', 'GO:0000785', ('32', '41'))
133554	31900418	In particular, among 151 dual-role genes detected by Moonlight one interesting gene, ANGPTL4, was predicted to be an oncogene in kidney cancers with associated promoter peaks as well as a tumor suppressor in prostate adenocarcinoma with hypermethylation in the promoter region (Supplementary Data 7, 8; Methods).	('tumor', 'Disease', (188, 193))	('kidney cancers', 'Disease', (129, 143))	('ANGPTL4', 'Gene', '51129', (85, 92))	('ANGPTL4', 'Gene', (85, 92))	('kidney cancers', 'Phenotype', 'HP:0009726', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('prostate adenocarcinoma', 'Disease', (208, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('promoter', 'MPA', (160, 168))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (208, 231))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('188', '204'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('188', '204'))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('hypermethylation', 'Var', (237, 253))	('kidney cancers', 'Disease', 'MESH:D007680', (129, 143))
133557	31900418	The relationship between DNA hypomethylation of oncogenes, hypermethylation of tumor suppressors, and copy-number amplification or deletion is another well-known mechanism to modulate cancer driver genes.	('cancer', 'Disease', (184, 190))	('tumor', 'Disease', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('copy-number amplification', 'Var', (102, 127))	('modulate', 'Reg', (175, 183))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('25', '44'))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('deletion', 'Var', (131, 139))
133559	31900418	For the 3123 mediators predicted by Moonlight within 18 cancer types, 848 showed copy-number changes and 358 showed critical copy-number cancer driver genes (eg.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('copy-number changes', 'Var', (81, 100))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
133560	31900418	observed amplification of oncogenes and deletion of tumor suppressors) (Supplementary Data 9).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('deletion', 'Var', (40, 48))	('oncogenes', 'Gene', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('amplification', 'MPA', (9, 22))
133561	31900418	For example, we observed amplification of the oncogenes CCND1 (supported by study) and CCNE1 in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('CCND1', 'Gene', '595', (56, 61))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Disease', (96, 109))	('CCNE1', 'Gene', (87, 92))	('CCNE1', 'Gene', '898', (87, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('CCND1', 'Gene', (56, 61))	('amplification', 'Var', (25, 38))
133562	31900418	Moreover, we identified deletions in tumor suppressors, such as DACT2 and TGFBR3 (Fig.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('DACT2', 'Gene', '168002', (64, 69))	('TGFBR3', 'Gene', '7049', (74, 80))	('deletions', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('DACT2', 'Gene', (64, 69))	('TGFBR3', 'Gene', (74, 80))
133563	31900418	In addition, Moonlight predicted FOXM1 as an oncogene with associated amplification in colon adenocarcinoma and lung squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('FOXM1', 'Gene', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('FOXM1', 'Gene', '2305', (33, 38))	('colon adenocarcinoma and lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (87, 140))	('amplification', 'Var', (70, 83))
133564	31900418	Among the 151 predicted dual-role genes, 19 were identified with associated copy-number changes, while 12 genes were critical copy-number cancer driver genes, including ADAM6, BCL2, CACNA2D2, CDKN2B, CLEC1A, DIXDC1, FAM129A, GPSM2, IQGAP2, MAP1B, PALM, and TSPAN4.	('cancer', 'Disease', (138, 144))	('ADAM6', 'Gene', '8755', (169, 174))	('CACNA2D2', 'Gene', (182, 190))	('FAM129A', 'Gene', (216, 223))	('CACNA2D2', 'Gene', '9254', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('GPSM2', 'Gene', (225, 230))	('CDKN2B', 'Gene', '1030', (192, 198))	('MAP1B', 'Gene', '4131', (240, 245))	('CLEC1A', 'Gene', '51267', (200, 206))	('IQGAP2', 'Gene', (232, 238))	('BCL2', 'Gene', '596', (176, 180))	('MAP', 'molecular_function', 'GO:0004239', ('240', '243'))	('BCL2', 'molecular_function', 'GO:0015283', ('176', '180'))	('GPSM2', 'Gene', '29899', (225, 230))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('copy-number', 'Var', (76, 87))	('BCL2', 'Gene', (176, 180))	('MAP1B', 'Gene', (240, 245))	('DIXDC1', 'Gene', '85458', (208, 214))	('TSPAN4', 'Gene', (257, 263))	('TSPAN4', 'Gene', '7106', (257, 263))	('DIXDC1', 'Gene', (208, 214))	('ADAM6', 'Gene', (169, 174))	('changes', 'Var', (88, 95))	('FAM129A', 'Gene', '116496', (216, 223))	('IQGAP2', 'Gene', '10788', (232, 238))	('CDKN2B', 'Gene', (192, 198))	('CLEC1A', 'Gene', (200, 206))
133568	31900418	Moonlight also identified BCL2 as a tumor suppressor in prostate adenocarcinoma with promoter hypermethylation, deletion, and associated with increased apoptosis (Supplementary Data 7, 9).	('BCL2', 'Gene', (26, 30))	('prostate adenocarcinoma', 'Disease', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('increased', 'PosReg', (142, 151))	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('deletion', 'Var', (112, 120))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (56, 79))	('BCL2', 'molecular_function', 'GO:0015283', ('26', '30'))	('BCL2', 'Gene', '596', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('apoptosis', 'CPA', (152, 161))	('tumor', 'Disease', (36, 41))
133570	31900418	While it has been shown that highly mutated genes promote cancer progression, it is yet unknown if methylation and copy-number changes to cancer driver genes directly imply that these genes have been mutated.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('promote', 'PosReg', (50, 57))	('methylation', 'biological_process', 'GO:0032259', ('99', '110'))	('genes', 'Var', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
133572	31900418	Moonlight applied to pan-cancer data revealed mutations in intron region (Fig.	('intron region', 'Gene', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))
133573	31900418	4b) for tumor suppressors and mutations in promoter regions for oncogenes.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('oncogenes', 'Gene', (64, 73))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (8, 13))
133575	31900418	Moonlight identified three oncogenes, CMYA5, ASPM, and ERBB2, showing 34, 30, and 29 samples with missense mutations, respectively (Methods; Supplementary Data 10).	('missense mutations', 'Var', (98, 116))	('ASPM', 'Gene', '259266', (45, 49))	('CMYA5', 'Gene', (38, 43))	('CMYA5', 'Gene', '202333', (38, 43))	('ERBB2', 'Gene', (55, 60))	('ASPM', 'Gene', (45, 49))	('ERBB2', 'Gene', '2064', (55, 60))
133579	31900418	Interestingly, Moonlight detected GATA3 as an oncogene in breast cancer with several mutated samples: frameshift insertion, deletion, and splice site.	('GATA3', 'Gene', '2625', (34, 39))	('frameshift insertion', 'Var', (102, 122))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('splice site', 'Var', (138, 149))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('GATA3', 'Gene', (34, 39))	('deletion', 'Var', (124, 132))
133580	31900418	In particular, we observed that GATA3 showed the highest mutation rate in breast-cancer samples in splice-site and frameshift insertions.	('mutation', 'Var', (57, 65))	('breast-cancer', 'Disease', 'MESH:D001943', (74, 87))	('frameshift insertions', 'Var', (115, 136))	('GATA3', 'Gene', (32, 37))	('highest', 'Reg', (49, 56))	('breast-cancer', 'Disease', (74, 87))	('GATA3', 'Gene', '2625', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('splice-site', 'Var', (99, 110))
133581	31900418	Therefore, we show the mutation site (x308, D335, p408) for the GATA3 gene (Supplementary Fig.	('GATA3', 'Gene', '2625', (64, 69))	('p408', 'Var', (50, 54))	('GATA3', 'Gene', (64, 69))	('x308', 'Var', (38, 42))
133584	31900418	In a recent study, we applied Moonlight to discover several pathways that are differentially expressed between wild-type GATA3 and GATA3 with frameshift/nonsense or missense mutations in breast-cancer samples.	('breast-cancer', 'Disease', 'MESH:D001943', (187, 200))	('GATA3', 'Gene', (131, 136))	('GATA3', 'Gene', '2625', (121, 126))	('GATA3', 'Gene', '2625', (131, 136))	('frameshift/nonsense', 'Var', (142, 161))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('breast-cancer', 'Disease', (187, 200))	('GATA3', 'Gene', (121, 126))
133587	31900418	It is well known that highly expressed oncogenes in cancer patients are associated with a worse prognosis, negatively impacting survival outcomes, whereas tumor suppressors present better outcomes.	('survival', 'MPA', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('negatively', 'NegReg', (107, 117))	('tumor', 'Disease', (155, 160))	('highly expressed', 'Var', (22, 38))	('patients', 'Species', '9606', (59, 67))	('oncogenes', 'Protein', (39, 48))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('impacting', 'Reg', (118, 127))
133627	31900418	To aid in effective cancer treatments which concurrently activate tumor suppressors and inactivate oncogenes, novel drug-combination therapies are required.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('oncogenes', 'Gene', (99, 108))	('cancer', 'Disease', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('inactivate', 'Var', (88, 98))	('activate', 'PosReg', (57, 65))
133641	31900418	For instance, Moonlight extracted mutation-context differences in samples with and without mutations (somatic or germline) of BRCA1 and/or BRCA2, as well as in known cancer driver-gene mutations (e.g., missense or frameshift/nonsense).	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('BRCA1', 'Gene', (126, 131))	('missense', 'Var', (202, 210))	('BRCA2', 'Gene', (139, 144))	('BRCA', 'Phenotype', 'HP:0003002', (139, 143))	('BRCA2', 'Gene', '675', (139, 144))	('frameshift/nonsense', 'Var', (214, 233))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('BRCA1', 'Gene', '672', (126, 131))	('BRCA', 'Phenotype', 'HP:0003002', (126, 130))
133651	31900418	Moonlight identified hypermethylated tumor suppressors and hypomethylated oncogenes.	('hypomethylated', 'Var', (59, 73))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('oncogenes', 'Gene', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('hypermethylated', 'Var', (21, 36))	('tumor', 'Disease', (37, 42))
133653	31900418	Also, Moonlight identified more mutations in intron regions than in promoter regions for tumor-suppressor genes.	('tumor-suppressor', 'Gene', '7248', (89, 105))	('mutations', 'Var', (32, 41))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('89', '105'))	('tumor-suppressor', 'Gene', (89, 105))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('89', '105'))
133658	31900418	Therefore, our findings support that differential chromatin accessibility is an underlying biological mechanism of tumor suppressors and oncogenes.	('differential', 'Var', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('chromatin', 'cellular_component', 'GO:0000785', ('50', '59'))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('chromatin accessibility', 'MPA', (50, 73))
133672	31900418	Among the state-of-the-art methods to identify cancer driver genes (CDGs), three of them have predicted the role of a CDG, such as TSG or OCG including 20/20, 20/20+, and OncodriveRole.	('TSG', 'Disease', (131, 134))	('OncodriveRole', 'Disease', (171, 184))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('20/20+', 'Var', (159, 165))	('cancer', 'Disease', (47, 53))	('20/20', 'Var', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
133692	31900418	Genes were identified as significantly differentially expressed if  logFC  >= 1 and FDR < 0.01 in at least one tumor type of the 18 different tumor types, which yielded 13,182 unique genes in total.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (111, 116))	('FDR < 0.01', 'Var', (84, 94))	('logFC  >= 1', 'Var', (68, 79))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
133699	31900418	This function carries out two differential phenotypes analysis: if dataType is selected as "Gene Expression", it detects DEGs wrapping the function TCGAanalyze_DEA from TCGAbiolinks.	('DEGs', 'Var', (121, 125))	('DEGs', 'Chemical', 'MESH:C062694', (121, 125))	('TCG', 'Chemical', 'MESH:C068682', (169, 172))	('TCG', 'Chemical', 'MESH:C068682', (148, 151))	('TCGAanalyze_DEA', 'Gene', (148, 163))
133725	31900418	The MC3 effort provided consensus calls of variants from seven software packages: MuTect, MuSE, VarScan2, Radia, Pindel, Somatic Sniper, and Indelocator.	('variants', 'Var', (43, 51))	('MuSE', 'Gene', '399806', (90, 94))	('MuSE', 'Gene', (90, 94))
133771	31628300	Indeed, in TCGA PAAD, when we evaluated the hematoxylin and eosin (H&E) slides for the presence or absence of immune infiltrate and tertiary lymphoid structures within the tumor, samples with high immune weights showed apparent infiltration, which was absent in low immune-weighted samples (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('TCGA PAAD', 'Chemical', 'MESH:C070654', (11, 20))	('hematoxylin', 'Chemical', 'MESH:D006416', (44, 55))	('with high immune', 'Var', (187, 203))	('tumor', 'Disease', (172, 177))	('eosin', 'Chemical', 'MESH:D004801', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
133772	31628300	In addition, high immune weights predict better overall survival in TCGA PAAD, as well as a subset of the 33 cancer types (Supplementary Fig.	('overall survival', 'MPA', (48, 64))	('high', 'Var', (13, 17))	('cancer type', 'Disease', 'MESH:D009369', (109, 120))	('better', 'PosReg', (41, 47))	('TCGA PAAD', 'Chemical', 'MESH:C070654', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('immune weights', 'MPA', (18, 32))	('TCGA PAAD', 'Disease', (68, 77))	('cancer type', 'Disease', (109, 120))
133774	31628300	Based on previous tumor subtype calls (the Moffitt schema) derived by consensus clustering using exemplar genes for these samples, we show that Moffitt Basal-like samples (n = 37) are associated with higher DECODER basal compartment weights and Moffitt Classical samples (n = 113) with higher DECODER classical compartment weights (Fig.	('tumor', 'Disease', (18, 23))	('DECODER basal compartment weights', 'MPA', (207, 240))	('Moffitt', 'Var', (144, 151))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('higher', 'PosReg', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
133798	31628300	Comparing with ATAC-seq clusters and iClusters, D29.13:GBM + LGG(Brain) was associated with A5:Brain, and C11:LGG(IDH1 mut) or C23:GBM/LGG(IDH1 wt), respectively.	('IDH1', 'Gene', (114, 118))	('IDH1', 'Gene', (139, 143))	('D29.13', 'Var', (48, 54))	('C11:LGG', 'Var', (106, 113))	('C23', 'Chemical', 'MESH:C038399', (127, 130))	('IDH1', 'Gene', '3417', (139, 143))	('IDH1', 'Gene', '3417', (114, 118))	('C23:GBM/LGG', 'Var', (127, 138))	('GBM +', 'Gene', (55, 60))
133800	31628300	Similarly, D21.5:COAD + STAD + ESCA(Pan-GI) and D29.26:STAD + ESCA(Digestive) were found to be related to the pan-GI system and clusters, with D21.5:COAD + STAD + ESCA(Pan-GI) exhibiting the highest weights in colon adenocarcinoma (COAD) and stomach adenocarcinoma (STAD), and the second highest weights in esophageal carcinoma (ESCA).	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('D29.26', 'Var', (48, 54))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (242, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('stomach adenocarcinoma', 'Disease', (242, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (318, 327))	('esophageal carcinoma', 'Disease', (307, 327))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (307, 327))	('D21.5:COAD + STAD + ESCA', 'Var', (143, 167))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (307, 327))	('colon adenocarcinoma', 'Disease', 'MESH:D015179', (210, 230))	('D21.5', 'Var', (11, 16))	('colon adenocarcinoma', 'Disease', (210, 230))
133802	31628300	Interestingly, while D16.12:Pan-Squamous showed the second highest weights in BLCA, we found that the cancer-specific D29.24:BLCA compartment was overrepresented as well.	('cancer', 'Disease', (102, 108))	('D29.24', 'Var', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
133803	31628300	Compartments D27.24:BRCA-Basal, D20.18:BRCA-Her2 + , D28.11:BRCA-Chr8qAmp, and D27.13:BRCA-Luminal were all found to be associated with breast invasive carcinoma (BRCA) (N = 141), enabled by sample sufficiency in the data set and as expected by its known heterogeneity.	('BRCA', 'Gene', (39, 43))	('BRCA', 'Gene', '672', (20, 24))	('breast invasive carcinoma', 'Disease', (136, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (136, 161))	('BRCA', 'Gene', (20, 24))	('associated with', 'Reg', (120, 135))	('BRCA', 'Gene', '672', (86, 90))	('D20.18', 'Var', (32, 38))	('BRCA', 'Gene', '672', (163, 167))	('BRCA', 'Gene', (86, 90))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (136, 161))	('BRCA', 'Gene', (163, 167))	('BRCA', 'Gene', '672', (60, 64))	('BRCA', 'Gene', '672', (39, 43))	('D27.24', 'Var', (13, 19))	('BRCA', 'Gene', (60, 64))
133860	31645905	Biomarkers have been developed to predict patients' responsivity to immunotherapy treatments, such as genome-wide mutational load, PD-L1 protein expression in infiltrating immune cells, the number of cytotoxic T cells in a tumor microenvironment, or MSI status.	('men', 'Species', '9606', (241, 244))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('men', 'Species', '9606', (87, 90))	('PD-L1', 'Gene', '29126', (131, 136))	('MSI', 'Gene', '5928', (250, 253))	('MSI', 'Gene', (250, 253))	('mutational load', 'Var', (114, 129))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('patients', 'Species', '9606', (42, 50))	('protein', 'Protein', (137, 144))	('PD-L1', 'Gene', (131, 136))
133900	31645905	In head and neck squamous cell carcinoma (HNSC, P = 0.0044, adjusted) and skin cutaneous melanoma (SKCM, P = 0.0044, adjusted), patients with T3/4 had significantly lower immune response than those with T1/2, while kidney renal clear cell carcinoma (KIRC, P = 0.0044, adjusted) showed the opposite trend.	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (215, 248))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('skin cutaneous melanoma', 'Disease', (74, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('neck', 'cellular_component', 'GO:0044326', ('12', '16'))	('KIRC', 'Disease', (250, 254))	('SKCM', 'Disease', 'MESH:C562393', (99, 103))	('kidney renal clear cell carcinoma', 'Disease', (215, 248))	('HNSC', 'Phenotype', 'HP:0012288', (42, 46))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('immune response', 'biological_process', 'GO:0006955', ('171', '186'))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('KIRC', 'Disease', 'MESH:D002292', (250, 254))	('immune response', 'MPA', (171, 186))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (12, 40))	('neck squamous cell carcinoma', 'Disease', (12, 40))	('T3/4', 'Var', (142, 146))	('patients', 'Species', '9606', (128, 136))	('lower', 'NegReg', (165, 170))	('lower immune response', 'Phenotype', 'HP:0002721', (165, 186))	('SKCM', 'Disease', (99, 103))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (74, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))
133918	31645905	It appears that the hypermutated (HM) colon adenocarcinoma (COAD) patients had the significantly highest immune response among the three different molecular subtypes (CIN, GS, HM) (P = 1.04 x 10-06, Figure 8C).	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('immune response', 'biological_process', 'GO:0006955', ('105', '120'))	('immune response', 'MPA', (105, 120))	('hypermutated', 'Var', (20, 32))	('COAD', 'Disease', 'MESH:D015179', (60, 64))	('HM) colon adenocarcinoma', 'Disease', 'MESH:D015179', (34, 58))	('COAD', 'Disease', (60, 64))	('CIN', 'Phenotype', 'HP:0040012', (167, 170))	('highest', 'PosReg', (97, 104))	('patients', 'Species', '9606', (66, 74))
133935	31645905	Our results further demonstrated that the hypermutated (HM) subtype in colon adenocarcinoma (COAD) had a significantly higher immune response than either the chromosomal instability (CIN) or genome stable (GS) subtypes, making such patients potential candidates for immunotherapeutic treatments.	('COAD', 'Disease', 'MESH:D015179', (93, 97))	('chromosomal instability', 'Phenotype', 'HP:0040012', (158, 181))	('CIN', 'Phenotype', 'HP:0040012', (183, 186))	('patients', 'Species', '9606', (232, 240))	('immune', 'MPA', (126, 132))	('men', 'Species', '9606', (289, 292))	('immune response', 'biological_process', 'GO:0006955', ('126', '141'))	('colon adenocarcinoma', 'Disease', (71, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('higher', 'PosReg', (119, 125))	('colon adenocarcinoma', 'Disease', 'MESH:D015179', (71, 91))	('COAD', 'Disease', (93, 97))	('hypermutated', 'Var', (42, 54))
133962	31645905	For the same reason, the molecular subtypes investigated in detail in this study included: Basal/Her2/LumA/LumB in breast invasive carcinoma (BRCA) patients, CIN/GS/HM-indel/HM-SNV or /EBV in gastrointestinal cancer patients, IDH mutation status in glioma patients, and POLE/MSI/CN_Low/CN_High in uterine corpus endometrial carcinoma (UCEC) patients.	('patients', 'Species', '9606', (341, 349))	('IDH', 'Gene', '3417', (226, 229))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (192, 215))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (115, 140))	('gastrointestinal cancer', 'Disease', (192, 215))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (192, 215))	('CIN', 'Phenotype', 'HP:0040012', (158, 161))	('patients', 'Species', '9606', (148, 156))	('LumA', 'Gene', '79188', (102, 106))	('breast invasive carcinoma (BRCA', 'Gene', (115, 146))	('glioma', 'Disease', (249, 255))	('breast invasive carcinoma (BRCA)', 'Gene', '672', (115, 147))	('MSI', 'Gene', (275, 278))	('MSI', 'Gene', '5928', (275, 278))	('glioma', 'Disease', 'MESH:D005910', (249, 255))	('BRCA', 'Phenotype', 'HP:0003002', (142, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (312, 333))	('corpus endometrial carcinoma', 'Disease', (305, 333))	('patients', 'Species', '9606', (216, 224))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (305, 333))	('LumA', 'Gene', (102, 106))	('IDH', 'Gene', (226, 229))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('Her2', 'Gene', '2064', (97, 101))	('patients', 'Species', '9606', (256, 264))	('CIN/GS/HM-indel/HM-SNV', 'Var', (158, 180))	('Her2', 'Gene', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
133965	31645905	The Normal subtype in breast invasive carcinoma (BRCA) and IDH mutant group in glioblastoma multiforme (GBM) typically had a small number of patients, and as such were excluded from downstream analyses.	('BRCA', 'Phenotype', 'HP:0003002', (49, 53))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (79, 102))	('breast invasive carcinoma (BRCA)', 'Gene', '672', (22, 54))	('IDH', 'Gene', (59, 62))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (22, 47))	('mutant', 'Var', (63, 69))	('GBM', 'Disease', (104, 107))	('IDH', 'Gene', '3417', (59, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('GBM', 'Disease', 'MESH:D005909', (104, 107))	('breast invasive carcinoma (BRCA', 'Gene', (22, 53))	('glioblastoma multiforme', 'Disease', (79, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('patients', 'Species', '9606', (141, 149))
133969	31645905	CIN Chromosomal instability GS genome stable HM hypermutated MSI microsatellite instability EBV Epstein-Barr virus SNV single-nucleotide variant HPV human papillomavirus	('single-nucleotide variant', 'Var', (119, 144))	('Epstein-Barr virus', 'Disease', 'MESH:D020031', (96, 114))	('HPV', 'Species', '10566', (145, 148))	('MSI', 'Gene', '5928', (61, 64))	('MSI', 'Gene', (61, 64))	('human papillomavirus', 'Species', '10566', (149, 169))	('Epstein-Barr virus', 'Disease', (96, 114))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (4, 27))	('CIN', 'Phenotype', 'HP:0040012', (0, 3))
133975	25839164	We characterized drebrin function in urothelial cancer cell lines and showed that drebrin is critical for progranulin-dependent activation of the Akt and MAPK pathways and modulates motility, invasion and anchorage-independent growth.	('activation', 'PosReg', (128, 138))	('progranulin', 'Gene', '2896', (106, 117))	('motility', 'CPA', (182, 190))	('progranulin', 'Gene', (106, 117))	('urothelial cancer', 'Disease', 'MESH:D014523', (37, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('MAPK pathways', 'Pathway', (154, 167))	('modulates', 'Reg', (172, 181))	('Akt', 'Gene', (146, 149))	('invasion', 'CPA', (192, 200))	('drebrin', 'Var', (82, 89))	('Akt', 'Gene', '207', (146, 149))	('anchorage-independent growth', 'CPA', (205, 233))	('urothelial cancer', 'Disease', (37, 54))	('MAPK', 'molecular_function', 'GO:0004707', ('154', '158'))
133998	25839164	In addition, in the presence of CpG-ONDs progranulin proteolytic fragments are soluble cofactors for Toll-like receptor 9 (TLR9) and contribute to innate immunity.	('innate immunity', 'CPA', (147, 162))	('progranulin', 'Gene', '2896', (41, 52))	('CpG-ONDs', 'Var', (32, 40))	('contribute', 'Reg', (133, 143))	('progranulin', 'Gene', (41, 52))	('TLR9', 'Gene', (123, 127))	('soluble', 'cellular_component', 'GO:0005625', ('79', '86'))	('innate immunity', 'biological_process', 'GO:0045087', ('147', '162'))	('Toll-like receptor 9', 'Gene', '54106', (101, 121))	('Toll-like receptor 9', 'Gene', (101, 121))	('TLR9', 'Gene', '54106', (123, 127))
134004	25839164	Significantly, drebrin depletion in tumorigenic urothelial cancer cells inhibits motility, anchorage-independent growth and tumor formation in vivo.	('drebrin', 'Protein', (15, 22))	('anchorage-independent growth', 'CPA', (91, 119))	('tumorigenic urothelial cancer', 'Disease', 'MESH:D002471', (36, 65))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('depletion', 'Var', (23, 32))	('tumor', 'Disease', (124, 129))	('tumorigenic urothelial cancer', 'Disease', (36, 65))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('inhibits', 'NegReg', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('motility', 'CPA', (81, 89))	('formation', 'biological_process', 'GO:0009058', ('130', '139'))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
134027	25839164	Following exposure to progranulin (40 nM), there was a marked increase in the ability of vehicle- and control oligo-transfected 5637 cells to invade a 3D matrix (Figure 3D) while drebrin knock-down significantly (**p < 0.01) reduced the invasive capacity of these cells (Figure 3D).	('invasive capacity', 'CPA', (237, 254))	('reduced', 'NegReg', (225, 232))	('invade a 3D matrix', 'CPA', (142, 160))	('progranulin', 'Gene', '2896', (22, 33))	('knock-down', 'Var', (187, 197))	('progranulin', 'Gene', (22, 33))	('increase', 'PosReg', (62, 70))
134029	25839164	Drebrin knockdown almost completely abolished progranulin-induced Akt activation, and caused > 50% reduction in ERK1/2 phosphorylation as compared to vehicle or siRNA control-transfected 5637 cells (Figure 3E).	('Akt', 'Gene', (66, 69))	('phosphorylation', 'MPA', (119, 134))	('knockdown', 'Var', (8, 17))	('ERK1', 'molecular_function', 'GO:0004707', ('112', '116'))	('ERK1/2', 'Gene', '5595;5594', (112, 118))	('Akt', 'Gene', '207', (66, 69))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('reduction', 'NegReg', (99, 108))	('ERK1/2', 'Gene', (112, 118))	('Drebrin', 'Gene', '1627', (0, 7))	('progranulin', 'Gene', '2896', (46, 57))	('progranulin', 'Gene', (46, 57))	('activation', 'PosReg', (70, 80))	('Drebrin', 'Gene', (0, 7))	('abolished', 'NegReg', (36, 45))
134086	25839164	Drebrin is essential for progranulin-induced signaling of urothelial cancer cells as in fact drebrin depletion significantly inhibits the activation of both the Akt and MAPK pathways, which are essential for progranulin-dependent motility and invasion of urothelial cancer cells.	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('MAPK pathways', 'Pathway', (169, 182))	('Drebrin', 'Gene', (0, 7))	('inhibits', 'NegReg', (125, 133))	('urothelial cancer', 'Disease', 'MESH:D014523', (58, 75))	('progranulin', 'Gene', '2896', (25, 36))	('progranulin', 'Gene', (25, 36))	('urothelial cancer', 'Disease', (58, 75))	('Drebrin', 'Gene', '1627', (0, 7))	('progranulin', 'Gene', '2896', (208, 219))	('urothelial cancer', 'Disease', 'MESH:D014523', (255, 272))	('Akt', 'Gene', (161, 164))	('progranulin', 'Gene', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('MAPK', 'molecular_function', 'GO:0004707', ('169', '173'))	('Akt', 'Gene', '207', (161, 164))	('urothelial cancer', 'Disease', (255, 272))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('depletion', 'Var', (101, 110))
134143	24363668	Paz and associates described the clinical and histological features of 12 transitional cell carcinomas of the urinary bladder with microcysts and concluded that microcystic variant of transitional cell carcinoma was linked with high-stage and high-grade urinary bladder tumours and with other primary tumours, especially those of the colon.	('bladder tumour', 'Disease', 'MESH:D001749', (262, 276))	('carcinomas', 'Disease', (92, 102))	('linked', 'Reg', (216, 222))	('tumours', 'Disease', (301, 308))	('urinary bladder tumours', 'Disease', 'MESH:D001749', (254, 277))	('tumours', 'Disease', (270, 277))	('carcinomas of the urinary bladder', 'Disease', 'MESH:D001749', (92, 125))	('primary tumours', 'Disease', (293, 308))	('primary tumours', 'Disease', 'MESH:D009369', (293, 308))	('urinary bladder tumours', 'Disease', (254, 277))	('tumours', 'Phenotype', 'HP:0002664', (301, 308))	('microcystic variant', 'Var', (161, 180))	('tumours', 'Phenotype', 'HP:0002664', (270, 277))	('tumours', 'Disease', 'MESH:D009369', (270, 277))	('tumours', 'Disease', 'MESH:D009369', (301, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('high-stage', 'Disease', (228, 238))	('carcinomas of the urinary bladder', 'Disease', (92, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('carcinomas', 'Disease', 'MESH:D002277', (92, 102))	('tumour', 'Phenotype', 'HP:0002664', (301, 307))	('tumour', 'Phenotype', 'HP:0002664', (270, 276))	('bladder tumour', 'Phenotype', 'HP:0009725', (262, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('high-grade', 'CPA', (243, 253))
134163	24363668	Leroy and associates stated that urothelial carcinoma can present many variable features, which can pose diagnostic difficulties, and that some variants mimicking benign lesions such as cystitis cystica or nephrogenic metaplasia have been described as deceptively bland bladder carcinoma.	('variants', 'Var', (144, 152))	('bland bladder carcinoma', 'Disease', 'MESH:D001749', (264, 287))	('bland bladder carcinoma', 'Disease', (264, 287))	('cystitis cystica', 'Disease', (186, 202))	('urothelial carcinoma', 'Disease', (33, 53))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (270, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('metaplasia', 'biological_process', 'GO:0036074', ('218', '228'))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('nephrogenic metaplasia', 'Disease', (206, 228))	('deceptively', 'Disease', (252, 263))
134249	22228636	As an example, with the model applied to the dataset by Kim et al., there was a 5-fold increase in the risk of death in those classified as high-risk (HR 5.05, 95% CI 2.26 - 11.3, P < 0.008) compared to those classified as low-risk.	('death', 'Disease', 'MESH:D003643', (111, 116))	('high-risk', 'Var', (140, 149))	('death', 'Disease', (111, 116))
134263	22228636	For example, inhibitors of MAP2K1 (i.e.	('MAP2K1', 'Gene', (27, 33))	('inhibitors', 'Var', (13, 23))	('MAP2K', 'molecular_function', 'GO:0004708', ('27', '32'))	('MAP2K1', 'Gene', '5604', (27, 33))
134283	22228636	Their investigation, which included whole genome and specific mutational analyses, identified a greater number of genomic alterations in the MS2 group, containing nearly all of the MI samples.	('alterations', 'Var', (122, 133))	('MS2', 'Gene', '100271694', (141, 144))	('MS2', 'Gene', (141, 144))
134303	30791227	Dysregulation, functional implications, and prognostic ability of the circadian clock across cancers It has been proposed that the circadian rhythm generally plays important roles in tumor suppression, but there is also evidence that disruption of the canonical circadian pathway has anticancer effects.	('cancer', 'Disease', (93, 99))	('cancers', 'Disease', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('canonical circadian pathway', 'Pathway', (252, 279))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', (288, 294))	('disruption', 'Var', (234, 244))	('tumor', 'Disease', (183, 188))	('circadian rhythm', 'biological_process', 'GO:0007623', ('131', '147'))	('clock', 'Gene', '9575', (80, 85))	('clock', 'Gene', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
134312	30791227	The 2017 Nobel Prize in Physiology or Medicine was awarded to Jeffrey C. Hall, Michael Rosbash and Michael W. Young for their leading discoveries of the molecular mechanisms controlling the circadian rhythm.1, 2 The circadian clock is critical for the normal physiological functions of cells, and disruption of the circadian system has been proposed to pose an important cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('clock', 'Gene', '9575', (226, 231))	('clock', 'Gene', (226, 231))	('circadian rhythm', 'biological_process', 'GO:0007623', ('190', '206'))	('cancer', 'Disease', (371, 377))	('cancer', 'Disease', 'MESH:D009369', (371, 377))	('disruption', 'Var', (297, 307))
134317	30791227	The results revealed that the circadian clock genes were most often dysregulated through DNA hypermethylation-based disruption of expression rather than mutations or copy number alterations.	('expression', 'MPA', (130, 140))	('DNA hypermethylation-based', 'Var', (89, 115))	('clock', 'Gene', (40, 45))	('clock', 'Gene', '9575', (40, 45))	('dysregulated', 'Reg', (68, 80))	('disruption', 'NegReg', (116, 126))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('89', '109'))	('hypermethylation-based', 'Var', (93, 115))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))
134327	30791227	The correlation between mutations of 375 driver genes40 and the CCI was analyzed by regression method, while cancer types and tumor mutation burden were adjusted.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Disease', (126, 131))	('cancer', 'Disease', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (24, 33))	('CCI', 'Chemical', '-', (64, 67))	('CCI', 'Disease', (64, 67))
134331	30791227	To test whether the mutational status of the driver genes40, 43 was significantly associated with the CCI, rank-transformed CCI was modeled via linear regression as a function of the gene's mutational status, and the rank-transformed mutation burden was used to diminish confounding effects.	('associated', 'Reg', (82, 92))	('CCI', 'Chemical', '-', (124, 127))	('genes40', 'Var', (52, 59))	('CCI', 'Chemical', '-', (102, 105))	('CCI', 'Disease', (102, 105))
134336	30791227	Thus, since the mutation rates of core clock genes were found to be low, the circadian rhythm system might not be disrupted by mutation in cancers.	('clock', 'Gene', '9575', (39, 44))	('core', 'cellular_component', 'GO:0019013', ('34', '38'))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('mutation', 'Var', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('mutation', 'MPA', (16, 24))	('circadian rhythm', 'biological_process', 'GO:0007623', ('77', '93'))	('clock', 'Gene', (39, 44))
134337	30791227	In general, PER1/2/3 exhibited the highest mutation frequencies among the core clock genes.	('PER1/2/3', 'Gene', '5187;8864;8863', (12, 20))	('PER1/2/3', 'Gene', (12, 20))	('mutation', 'Var', (43, 51))	('core', 'cellular_component', 'GO:0019013', ('74', '78'))	('clock', 'Gene', (79, 84))	('clock', 'Gene', '9575', (79, 84))
134339	30791227	Furthermore, the mutation rates of other CCMCCs in cancer were also low (Figure S1 and S8).	('mutation', 'Var', (17, 25))	('low', 'NegReg', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
134340	30791227	To further dissect the genomic alterations of circadian rhythm, the copy number variations of core clock genes were also analyzed (Figure 1B), and the results showed that the copy number alterations of core clock genes were limited, although both amplifications and deletions of core clock genes were observed.	('deletions', 'Var', (266, 275))	('clock', 'Gene', (284, 289))	('clock', 'Gene', '9575', (207, 212))	('core', 'cellular_component', 'GO:0019013', ('94', '98'))	('clock', 'Gene', (99, 104))	('clock', 'Gene', '9575', (284, 289))	('core', 'cellular_component', 'GO:0019013', ('202', '206'))	('circadian rhythm', 'biological_process', 'GO:0007623', ('46', '62'))	('clock', 'Gene', '9575', (99, 104))	('core', 'cellular_component', 'GO:0019013', ('279', '283'))	('clock', 'Gene', (207, 212))
134343	30791227	To investigate aberrances in rhythmic genes across cancers, the mutations in the 1350 experimentally identified rhythmic genes curated from the CGDB were systematically analyzed in various cancers.	('CGDB', 'Gene', (144, 148))	('various cancers', 'Disease', 'MESH:D009369', (181, 196))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('various cancers', 'Disease', (181, 196))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('analyzed', 'Reg', (169, 177))	('mutations', 'Var', (64, 73))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('cancers', 'Disease', (189, 196))
134367	30791227	As the results shown in Figure 2D, the CCI was negatively correlated with mutations of driver genes including TP53 in BRCA, LIHC, and LUAD, XIRP2 in STAD, MUC4 in KIRC and FAM46C in HNSC, while negatively correlations were observed for RNF43 in CESC, PIK3CA in BRCA, FRG1 in HNSC, and EGFR in BLCA.	('EGFR', 'Gene', '1956', (285, 289))	('FAM46C', 'Gene', '54855', (172, 178))	('PIK3CA', 'Gene', (251, 257))	('LUAD', 'Gene', (134, 138))	('BRCA', 'Gene', '672', (261, 265))	('BRCA', 'Gene', '672', (118, 122))	('TP53', 'Gene', '7157', (110, 114))	('MUC4', 'Gene', '4585', (155, 159))	('RNF43', 'Gene', '54894', (236, 241))	('XIRP2', 'Gene', (140, 145))	('BRCA', 'Gene', (261, 265))	('MUC4', 'Gene', (155, 159))	('FRG1', 'Gene', '2483', (267, 271))	('BRCA', 'Gene', (118, 122))	('CCI', 'Chemical', '-', (39, 42))	('FRG1', 'Gene', (267, 271))	('LUAD', 'Phenotype', 'HP:0030078', (134, 138))	('EGFR', 'Gene', (285, 289))	('RNF43', 'Gene', (236, 241))	('PIK3CA', 'Gene', '5290', (251, 257))	('FAM46C', 'Gene', (172, 178))	('CCI', 'Disease', (39, 42))	('negatively', 'NegReg', (47, 57))	('TP53', 'Gene', (110, 114))	('BRCA', 'Phenotype', 'HP:0003002', (261, 265))	('mutations', 'Var', (74, 83))	('BRCA', 'Phenotype', 'HP:0003002', (118, 122))	('HNSC', 'Phenotype', 'HP:0012288', (275, 279))	('HNSC', 'Phenotype', 'HP:0012288', (182, 186))	('EGFR', 'molecular_function', 'GO:0005006', ('285', '289'))	('XIRP2', 'Gene', '129446', (140, 145))
134368	30791227	Furthermore, the expression and methylation of CCMCCs were analyzed, and the results presented in Figure S8 show that the expression of CCMCCs was disrupted in tumors and that hypermethylation contributed substantially to this disruption.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('expression', 'MPA', (122, 132))	('hypermethylation', 'Var', (176, 192))	('CCMCCs', 'Gene', (136, 142))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('disrupted', 'NegReg', (147, 156))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
134369	30791227	In tumor tissues, dysregulated circadian rhythm would disrupt the oscillatory expression of circadian genes; therefore, it was necessary to investigate the differential expression of rhythmic genes.	('dysregulated', 'Var', (18, 30))	('tumor', 'Disease', (3, 8))	('oscillatory expression', 'MPA', (66, 88))	('circadian genes', 'Gene', (92, 107))	('disrupt', 'NegReg', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('circadian rhythm', 'biological_process', 'GO:0007623', ('31', '47'))
134371	30791227	Enrichment analyses of DEGs in rhythmic genes across cancers were based on using a hypergeometric test.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('DEGs', 'Var', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
134379	30791227	Furthermore, CCI was positively correlated with a large number of metabolic pathways in LIHC (Figure S4A), which was consistent with the findings of previous studies.46, 47, 48, 49, 50  The circadian rhythm recently emerged as an important regulator of the immune system.51, 52 The GSEA results showed that a number of immune pathways were differentially activated in high- and low-CCI tumor tissues (Figure 3B).	('GSEA', 'Chemical', '-', (282, 286))	('high-', 'Var', (368, 373))	('low-CCI tumor', 'Disease', 'MESH:D009800', (378, 391))	('circadian rhythm', 'biological_process', 'GO:0007623', ('190', '206'))	('CCI', 'Chemical', '-', (382, 385))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('low-CCI tumor', 'Disease', (378, 391))	('immune pathways', 'Pathway', (319, 334))	('CCI', 'Chemical', '-', (13, 16))	('activated', 'PosReg', (355, 364))
134381	30791227	Various pathways, including natural killer cell-mediated cytotoxicity, T- and B-cell receptor signaling pathways, Toll-like receptor signaling pathway, and primary immunodeficiency, were upregulated in high-CCI tumor tissues compared with low-CCI tumor tissues in BLCA and CESC.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('Toll-like receptor signaling pathway', 'biological_process', 'GO:0002224', ('114', '150'))	('CCI', 'Chemical', '-', (207, 210))	('tumor', 'Disease', (211, 216))	('primary immunodeficiency', 'Disease', 'MESH:D007153', (156, 180))	('low-CCI tumor', 'Disease', 'MESH:D009800', (239, 252))	('upregulated', 'PosReg', (187, 198))	('Toll-like receptor signaling pathway', 'Pathway', (114, 150))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cytotoxicity', 'Disease', (57, 69))	('cytotoxicity', 'Disease', 'MESH:D064420', (57, 69))	('high-CCI', 'Var', (202, 210))	('natural killer cell-mediated cytotoxicity', 'biological_process', 'GO:0042267', ('28', '69'))	('immunodeficiency', 'Phenotype', 'HP:0002721', (164, 180))	('tumor', 'Disease', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('CCI', 'Chemical', '-', (243, 246))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('low-CCI tumor', 'Disease', (239, 252))	('primary immunodeficiency', 'Disease', (156, 180))	('signaling', 'biological_process', 'GO:0023052', ('94', '103'))
134382	30791227	Fc gamma R-mediated phagocytosis was upregulated in high-CCI tumor tissues compared with low-CCI tumor tissues in BLCA and STAD.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('upregulated', 'PosReg', (37, 48))	('high-CCI', 'Var', (52, 60))	('low-CCI tumor', 'Disease', 'MESH:D009800', (89, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CCI', 'Chemical', '-', (93, 96))	('low-CCI tumor', 'Disease', (89, 102))	('Fc gamma R-mediated', 'Protein', (0, 19))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CCI', 'Chemical', '-', (57, 60))	('tumor', 'Disease', (61, 66))	('phagocytosis', 'biological_process', 'GO:0006909', ('20', '32'))
134383	30791227	The NOD-like receptor signaling pathway was upregulated in high-CCI tumor tissues compared with low-CCI tumor tissues in BLCA.	('tumor', 'Disease', (68, 73))	('CCI', 'Chemical', '-', (100, 103))	('NOD-like receptor signaling pathway', 'Pathway', (4, 39))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('NOD-like receptor signaling pathway', 'biological_process', 'GO:0035872', ('4', '39'))	('upregulated', 'PosReg', (44, 55))	('tumor', 'Disease', (104, 109))	('low-CCI tumor', 'Disease', 'MESH:D009800', (96, 109))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('low-CCI tumor', 'Disease', (96, 109))	('CCI', 'Chemical', '-', (64, 67))	('high-CCI', 'Var', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
134384	30791227	In BLCA and THCA, antigen processing and presentation were upregulated and downregulated in high-CCI tumor tissues compared with low-CCI tumor tissues, respectively.	('CCI', 'Chemical', '-', (133, 136))	('THCA', 'Phenotype', 'HP:0002890', (12, 16))	('tumor', 'Disease', (137, 142))	('downregulated', 'NegReg', (75, 88))	('low-CCI tumor', 'Disease', (129, 142))	('tumor', 'Disease', (101, 106))	('presentation', 'MPA', (41, 53))	('CCI', 'Chemical', '-', (97, 100))	('high-CCI', 'Var', (92, 100))	('upregulated', 'PosReg', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('antigen processing and presentation', 'biological_process', 'GO:0019882', ('18', '53'))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('antigen processing', 'MPA', (18, 36))	('low-CCI tumor', 'Disease', 'MESH:D009800', (129, 142))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
134397	30791227	A previous study found that the circadian rhythm is associated with survival in colorectal cancer patients.8 For circadian rhythm is crucial to cell physiology and the core clock genes were dysregulated at mutation, SCNA, DNA methylation and expression levels, the prognostic ability of the circadian system in cancers should be investigated.	('circadian rhythm', 'biological_process', 'GO:0007623', ('113', '129'))	('cell physiology', 'biological_process', 'GO:0009987', ('144', '159'))	('DNA methylation', 'biological_process', 'GO:0006306', ('222', '237'))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('circadian rhythm', 'biological_process', 'GO:0007623', ('32', '48'))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('patients', 'Species', '9606', (98, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('DNA', 'cellular_component', 'GO:0005574', ('222', '225'))	('cancers', 'Disease', (311, 318))	('mutation', 'Var', (206, 214))	('core', 'cellular_component', 'GO:0019013', ('168', '172'))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))	('clock', 'Gene', '9575', (173, 178))	('clock', 'Gene', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
134403	30791227	The survival analysis with the best cutoff value showed that a high CCI predicted better survival in BRCA, CESC, KIRP, and LIHC (Figure 4B-E).	('CESC', 'Disease', (107, 111))	('high CCI', 'Var', (63, 71))	('better', 'PosReg', (82, 88))	('BRCA', 'Phenotype', 'HP:0003002', (101, 105))	('CCI', 'Var', (68, 71))	('BRCA', 'Gene', '672', (101, 105))	('KIRP', 'Disease', (113, 117))	('BRCA', 'Gene', (101, 105))	('CCI', 'Chemical', '-', (68, 71))
134410	30791227	For example, in KIRC, high expression level of FBXL3 predicted better survival, while RORB, CSNK1D, and CSNK1E significantly predicted poor survival (Figure S7).	('RORB', 'Gene', (86, 90))	('CSNK1E', 'Gene', (104, 110))	('high', 'Var', (22, 26))	('expression', 'MPA', (27, 37))	('CSNK1E', 'Gene', '1454', (104, 110))	('better', 'PosReg', (63, 69))	('RORB', 'Gene', '6096', (86, 90))	('survival', 'CPA', (70, 78))	('FBXL3', 'Gene', (47, 52))	('CSNK1D', 'Gene', (92, 98))	('CSNK1D', 'Gene', '1453', (92, 98))	('FBXL3', 'Gene', '26224', (47, 52))
134411	30791227	However, high expression of FBXL3 was related to poor survival in STAD (Figure S7).	('FBXL3', 'Gene', (28, 33))	('FBXL3', 'Gene', '26224', (28, 33))	('STAD', 'Disease', (66, 70))	('poor', 'NegReg', (49, 53))	('high', 'Var', (9, 13))
134417	30791227	reported that in hematologic malignancies ARNTL was transcriptionally silenced by the hypermethylation of its promoter CpG island.30 TCGA data showed that the expression of ARNTL was significantly lower in most solid tumors than in nontumor tissues; in addition, hypermethylation of ARNTL was also observed in PRAD (Figure 2A) and STAD, while the methylation status of ARNTL in other cancers was not available.	('lower', 'NegReg', (197, 202))	('ARNTL', 'Gene', '406', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('hypermethylation', 'Var', (263, 279))	('solid tumors', 'Disease', (211, 223))	('tumor', 'Disease', (217, 222))	('methylation', 'biological_process', 'GO:0032259', ('347', '358'))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cancers', 'Disease', 'MESH:D009369', (384, 391))	('expression', 'MPA', (159, 169))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('solid tumors', 'Disease', 'MESH:D009369', (211, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('ARNTL', 'Gene', (283, 288))	('ARNTL', 'Gene', '406', (173, 178))	('ARNTL', 'Gene', (173, 178))	('ARNTL', 'Gene', '406', (283, 288))	('hematologic malignancies', 'Disease', (17, 41))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('ARNTL', 'Gene', '406', (369, 374))	('ARNTL', 'Gene', (369, 374))	('STAD', 'Disease', (331, 335))	('cancers', 'Phenotype', 'HP:0002664', (384, 391))	('cancers', 'Disease', (384, 391))	('tumor', 'Disease', (235, 240))	('hematologic malignancies', 'Disease', 'MESH:D019337', (17, 41))	('ARNTL', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (384, 390))
134419	30791227	Thus, the main cause of the lower expression levels of circadian clock genes might be hypermethylation of ARNTL and PER1/PER2/PER3, while the mechanisms for CLOCK and CRY1/CRY2 require further investigation.	('PER3', 'Gene', '8863', (126, 130))	('hypermethylation', 'Var', (86, 102))	('PER2', 'Gene', (121, 125))	('CRY2', 'Gene', (172, 176))	('lower', 'NegReg', (28, 33))	('clock', 'Gene', (65, 70))	('CRY1', 'Gene', (167, 171))	('PER2', 'Gene', '8864', (121, 125))	('PER3', 'Gene', (126, 130))	('clock', 'Gene', '9575', (65, 70))	('ARNTL', 'Gene', '406', (106, 111))	('CLOCK', 'Gene', '9575', (157, 162))	('ARNTL', 'Gene', (106, 111))	('CRY1', 'Gene', '1407', (167, 171))	('CRY2', 'Gene', '1408', (172, 176))	('CLOCK', 'Gene', (157, 162))	('expression levels', 'MPA', (34, 51))
134426	30791227	Thus, further detailed investigations should be performed to determine the mechanisms and functions of the dysregulation of the circadian clock in different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('clock', 'Gene', '9575', (138, 143))	('clock', 'Gene', (138, 143))	('cancer', 'Disease', (157, 163))	('dysregulation', 'Var', (107, 120))
134446	29107929	In addition, integration of viral DNA is a hallmark of tumorigenesis for some viruses.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('integration', 'Var', (13, 24))
134464	29107929	All of the HPV species detected were high-risk alpha-papillomaviruses except for a few samples containing HPV30, HPV73, or HPV111 (Figure 3, Supp Figure 3A).	('HPV', 'Species', '10566', (11, 14))	('HPV30', 'Var', (106, 111))	('HPV73', 'Var', (113, 118))	('HPV111', 'Var', (123, 129))	('HPV', 'Species', '10566', (123, 126))	('HPV', 'Species', '10566', (113, 116))	('HPV', 'Species', '10566', (106, 109))
134498	29107929	The mutation rate of Rb, CDKN2A and p53 in non-viral tumors was 16%, 7% and 49%, respectively.	('non-viral tumors', 'Disease', (43, 59))	('non-viral tumors', 'Disease', 'MESH:D001102', (43, 59))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('mutation', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('CDKN2A', 'Gene', (25, 31))	('CDKN2A', 'Gene', '1029', (25, 31))
134499	29107929	However, none of the BLCA viral tumors had a mutation in Rb, CDKN2A nor p53 (Table 3).	('viral tumors', 'Disease', 'MESH:D001102', (26, 38))	('CDKN2A', 'Gene', (61, 67))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('viral tumors', 'Disease', (26, 38))	('CDKN2A', 'Gene', '1029', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mutation', 'Var', (45, 53))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))
134511	29107929	Next we hypothesized that non-viral tumors in group B would have a similar impact on the mutation status of Rb, CDKN2A and p53.	('CDKN2A', 'Gene', (112, 118))	('impact', 'Reg', (75, 81))	('non-viral tumors', 'Disease', 'MESH:D001102', (26, 42))	('mutation', 'Var', (89, 97))	('CDKN2A', 'Gene', '1029', (112, 118))	('p53', 'Gene', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('p53', 'Gene', '7157', (123, 126))	('non-viral tumors', 'Disease', (26, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
134512	29107929	We found that all tumors with mutated Rb were found in the non-viral tumors of group B and was not mutated in Group A tumors (Table 4).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('A tumors', 'Disease', 'MESH:D009369', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('non-viral tumors', 'Disease', (59, 75))	('mutated', 'Var', (30, 37))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('non-viral tumors', 'Disease', 'MESH:D001102', (59, 75))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumors', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('A tumors', 'Disease', (116, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
134513	29107929	p53 was mutated in a higher percentage of non-viral group B tumors (54%, 88/162) than in group A tumors (24%, 8/34).	('non-viral', 'Var', (42, 51))	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutated', 'Var', (8, 15))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('A tumors', 'Disease', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('A tumors', 'Disease', 'MESH:D009369', (95, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumors', 'Disease', (60, 66))
134539	29107929	Second, we detected chimeric junctions indicating viral integration of HPV16, HPV45, HPV56 in some patients.	('chimeric junctions', 'Var', (20, 38))	('detected', 'Reg', (11, 19))	('HPV16', 'Gene', (71, 76))	('HPV16', 'Species', '333760', (71, 76))	('viral integration', 'MPA', (50, 67))	('HPV56', 'Gene', (85, 90))	('patients', 'Species', '9606', (99, 107))	('HPV', 'Species', '10566', (71, 74))	('HPV', 'Species', '10566', (78, 81))	('HPV45', 'Gene', (78, 83))	('HPV', 'Species', '10566', (85, 88))
134542	29107929	An analysis of mutational profiles revealed that nonviral bladder tumors harbored mutations in pRb (16%), CDKN2A (7%), and p53 (49%) indicating that the Rb and p53 pathways are compromised.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('bladder tumor', 'Phenotype', 'HP:0009725', (58, 71))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('pRb', 'Gene', '5925', (95, 98))	('p53', 'Gene', (160, 163))	('CDKN2A', 'Gene', (106, 112))	('mutations', 'Var', (82, 91))	('pRb', 'Gene', (95, 98))	('p53', 'Gene', (123, 126))	('bladder tumors', 'Disease', 'MESH:D001749', (58, 72))	('p53', 'Gene', '7157', (160, 163))	('bladder tumors', 'Phenotype', 'HP:0009725', (58, 72))	('CDKN2A', 'Gene', '1029', (106, 112))	('p53', 'Gene', '7157', (123, 126))	('bladder tumors', 'Disease', (58, 72))
134543	29107929	In contrast, none of the HPV-associated tumors, nor the BKV-associated tumor, carried mutations in these genes.	('mutations', 'Var', (86, 95))	('HPV-associated', 'Disease', (25, 39))	('HPV', 'Species', '10566', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', (71, 76))	('tumors', 'Disease', (40, 46))
134545	29107929	This inactivation can occur either by mutation of key genes in these pathways (Rb, CDKN2A, p53) or by the expression of the HPV E7 and E6 proteins or the BKV LT.	('CDKN2A', 'Gene', '1029', (83, 89))	('Rb', 'Gene', (79, 81))	('HPV', 'Species', '10566', (124, 127))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('mutation', 'Var', (38, 46))	('CDKN2A', 'Gene', (83, 89))
134546	29107929	Consistent with this hypothesis, we found that E2F-dependent cellular genes (ERGs) that are normally repressed by Rb, are over-expressed in virus-positive tumors and in the subset of virus-negative tumors that carry Rb or CDKN2A mutations.	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('CDKN2A', 'Gene', (222, 228))	('mutations', 'Var', (229, 238))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('CDKN2A', 'Gene', '1029', (222, 228))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('over-expressed', 'PosReg', (122, 136))
134609	24707363	showed that loss of CD44 on surface of prostate PCSC is independent prognostic predictor of clinical recurrence.	('PC', 'Phenotype', 'HP:0012125', (48, 50))	('loss', 'Var', (12, 16))	('CD44', 'Gene', '960', (20, 24))	('CD44', 'Gene', (20, 24))
134615	24707363	According to this concept, urothelial cells undergo field malignant transformation that affects the entire urothelium within urinary tracts and causes a myriad of independent mutations responsible for further simultaneous tumors growth.	('tumors growth', 'Disease', (222, 235))	('affects', 'Reg', (88, 95))	('causes', 'Reg', (144, 150))	('mutations', 'Var', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors growth', 'Disease', 'MESH:D006130', (222, 235))
134619	24707363	In this case, mutation of gene encoding structure of FGF receptor is first hit, which initiate urothelial hyperplasia.	('urothelial hyperplasia', 'Disease', 'MESH:D006965', (95, 117))	('initiate', 'Reg', (86, 94))	('mutation', 'Var', (14, 22))	('urothelial hyperplasia', 'Disease', (95, 117))	('FGF receptor', 'Gene', (53, 65))
134620	24707363	Subsequent mutations in two major tumor suppressors p53 and retinoblastoma (Rb), which occurred in 15% of low-grade cases, lead to genomic instability and tumor progression to high-grade.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('mutations', 'Var', (11, 20))	('retinoblastoma', 'Gene', (60, 74))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('retinoblastoma', 'Phenotype', 'HP:0009919', (60, 74))	('lead to', 'Reg', (123, 130))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('tumor', 'Disease', (155, 160))	('genomic', 'MPA', (131, 138))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('Rb', 'Phenotype', 'HP:0009919', (76, 78))	('Rb', 'Gene', '5925', (76, 78))	('retinoblastoma', 'Gene', '5925', (60, 74))
134684	23717626	Further analysis reveals genes identified as differentially regulated by miRNAs to be enriched in cancer pathways, thus suggesting biologically interesting interactions.	('miRNAs', 'Var', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('interactions', 'Interaction', (156, 168))
134690	23717626	On the molecular level, most non-invasive UCC are associated with FGFR3 mutation and chromosome 9 loss whereas the inactivation of p53 and PTEN function plays an important role in the progression of invasive UCC.	('non-invasive UCC', 'Disease', (29, 45))	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('FGFR3', 'Gene', '2261', (66, 71))	('PTEN', 'Gene', (139, 143))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('PTEN', 'Gene', '5728', (139, 143))	('loss', 'NegReg', (98, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('FGFR3', 'Gene', (66, 71))	('mutation', 'Var', (72, 80))	('associated', 'Reg', (50, 60))
134753	23717626	These interactions include miR-7, miR-24, miR-26b, miR-29b, miR-29c and miR-30b.	('miR-7', 'Gene', (27, 32))	('miR-30b', 'Gene', '407030', (72, 79))	('miR-30b', 'Gene', (72, 79))	('miR-29b', 'Gene', '407024', (51, 58))	('miR-24', 'Var', (34, 40))	('miR-29c', 'Gene', '407026', (60, 67))	('miR-7', 'Gene', '10859', (27, 32))	('miR-29c', 'Gene', (60, 67))	('miR-29b', 'Gene', (51, 58))	('miR-26b', 'Gene', '407017', (42, 49))	('miR-26b', 'Gene', (42, 49))
134768	23717626	Furthermore, the oncogenes NRAS and ERBB2 are up-regulated in bladder cancer, hypothetically, due to lower of expression of miR-28-5p and miR-125b, respectively.	('NRAS', 'Gene', '4893', (27, 31))	('ERBB2', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('ERBB2', 'Gene', '2064', (36, 41))	('up-regulated', 'PosReg', (46, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (62, 76))	('miR-28-5p', 'Var', (124, 133))	('lower', 'NegReg', (101, 106))	('expression', 'MPA', (110, 120))	('miR-1', 'Gene', '79187', (138, 143))	('bladder cancer', 'Disease', 'MESH:D001749', (62, 76))	('bladder cancer', 'Disease', (62, 76))	('NRAS', 'Gene', (27, 31))	('miR-1', 'Gene', (138, 143))
134771	23717626	To examine whether there is a relationship between the performance of classifiers and Jaccard-indexes independently of the size of the model, we generated models by randomly selecting a defined number of interactions within a range of Jaccard-indexes using the bladder cancer training and test sets (collective I and collective II) and evaluated their performance.	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('bladder cancer', 'Phenotype', 'HP:0009725', (261, 275))	('interactions', 'Var', (204, 216))	('bladder cancer', 'Disease', 'MESH:D001749', (261, 275))	('bladder cancer', 'Disease', (261, 275))
134792	23717626	To distinguish invasive from non-invasive bladder cancer, 319 interactions with a Jaccard-index equal to or higher than 0.4 remain involving 34 miRNAs, but there are just twelve interactions with a Jaccard-index equal to or higher than 0.7 that comprise six miRNAs, namely miR-24, miR-26b, miR-29b, miR-29c, miR-30b and miR-7.	('miR-24', 'Var', (273, 279))	('invasive bladder', 'Phenotype', 'HP:0100645', (33, 49))	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('miR-29b', 'Gene', (290, 297))	('miR-7', 'Gene', (320, 325))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (33, 56))	('miR-30b', 'Gene', '407030', (308, 315))	('miR-7', 'Gene', '10859', (320, 325))	('miR-30b', 'Gene', (308, 315))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('miR-26b', 'Gene', (281, 288))	('miR-29b', 'Gene', '407024', (290, 297))	('miR-29c', 'Gene', '407026', (299, 306))	('invasive bladder cancer', 'Disease', (33, 56))	('miR-26b', 'Gene', '407017', (281, 288))	('invasive', 'Disease', (15, 23))	('miR-29c', 'Gene', (299, 306))
134799	23717626	We suspect, that the postulated hypermethylation-mediated reduction of DAPK1 mRNA expression in bladder cancer is more than compensated by the mRNA-miRNA interfering effect caused by the reduction of DAPK1 interfering miRNAs.	('bladder cancer', 'Disease', 'MESH:D001749', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mRNA expression', 'MPA', (77, 92))	('DAPK1', 'Gene', (200, 205))	('mRNA-miRNA interfering', 'MPA', (143, 165))	('DAPK1', 'Gene', (71, 76))	('hypermethylation-mediated', 'Var', (32, 57))	('bladder cancer', 'Phenotype', 'HP:0009725', (96, 110))	('reduction', 'NegReg', (58, 67))	('bladder cancer', 'Disease', (96, 110))	('DAPK1', 'Gene', '1612', (200, 205))	('DAPK1', 'Gene', '1612', (71, 76))
134804	23717626	In KEGG bladder cancer pathway, the oncogenes NRAS and ERBB2 were found up-regulated, hypothetically, due to lower of expression of miR-28-5p and miR-125b, respectively.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('bladder cancer', 'Disease', 'MESH:D001749', (8, 22))	('lower', 'NegReg', (109, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (8, 22))	('miR-1', 'Gene', (146, 151))	('NRAS', 'Gene', (46, 50))	('up-regulated', 'PosReg', (72, 84))	('bladder cancer', 'Disease', (8, 22))	('NRAS', 'Gene', '4893', (46, 50))	('miR-1', 'Gene', '79187', (146, 151))	('miR-28-5p', 'Var', (132, 141))	('ERBB2', 'Gene', (55, 60))	('ERBB2', 'Gene', '2064', (55, 60))	('expression', 'MPA', (118, 128))
134814	32529761	According to the survival analyses, the MPUC group also had lower survival probability in both cancer-specific mortality (CSM) (P < .0001) and overall mortality (OM) analyses (P < .0001).	('survival', 'MPA', (66, 74))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('MPUC', 'Chemical', '-', (40, 44))	('mortality', 'Disease', 'MESH:D003643', (151, 160))	('mortality', 'Disease', 'MESH:D003643', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mortality', 'Disease', (151, 160))	('MPUC', 'Var', (40, 44))	('mortality', 'Disease', (111, 120))	('lower', 'NegReg', (60, 65))
134855	32529761	After adjustments for age, sex, TNM stage, tumor site, and treatment method, the adjusted model II showed that the MPUC group had a significantly higher risk of OM compared with the TCC group (HR = 1.39, 95% CI = 1.22-1.57, P < .0001), while no difference in CSM was observed between the two groups (HR = 1.18, 95% CI = 1.00-1.40, P = .0505).	('TCC', 'cellular_component', 'GO:0005579', ('182', '185'))	('MPUC', 'Chemical', '-', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('men', 'Species', '9606', (12, 15))	('TCC', 'Phenotype', 'HP:0006740', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('MPUC', 'Var', (115, 119))	('men', 'Species', '9606', (64, 67))	('tumor', 'Disease', (43, 48))
134904	32123240	Recently we discovered that several genes encoding key enzymes of methyl group and polyamine metabolism, including Ornithine Decarboxylase 1 (ODC1), are affected by DNA methylation in early stage UC.	('Ornithine Decarboxylase 1', 'Gene', (115, 140))	('Ornithine Decarboxylase 1', 'Gene', '4953', (115, 140))	('DNA methylation', 'biological_process', 'GO:0006306', ('165', '180'))	('polyamine metabolism', 'biological_process', 'GO:0006595', ('83', '103'))	('polyamine', 'Chemical', 'MESH:D011073', (83, 92))	('UC', 'Disease', 'MESH:D014523', (196, 198))	('ODC1', 'Gene', (142, 146))	('methylation', 'Var', (169, 180))	('ODC1', 'Gene', '4953', (142, 146))	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))	('DNA methylation', 'Var', (165, 180))	('affected', 'Reg', (153, 161))
134905	32123240	In this study, we investigated the hypothesis that these epigenetic alterations act in a feed-forward fashion to promote aberrant DNA methylation in UC.	('UC', 'Disease', 'MESH:D014523', (149, 151))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('promote', 'PosReg', (113, 120))	('DNA methylation', 'biological_process', 'GO:0006306', ('130', '145'))	('epigenetic alterations', 'Var', (57, 79))	('aberrant DNA methylation', 'MPA', (121, 145))
134906	32123240	We demonstrate that siRNA-mediated knockdown of ODC1 expression elicits genome-wide LINE-1 demethylation, induction of LINE-1 transcripts and double-strand DNA breaks and decreases viability in primary cultured uroepithelial cells.	('knockdown', 'Var', (35, 44))	('LINE-1', 'Gene', (84, 90))	('induction', 'PosReg', (106, 115))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('demethylation', 'MPA', (91, 104))	('demethylation', 'biological_process', 'GO:0070988', ('91', '104'))	('ODC1', 'Gene', (48, 52))	('viability', 'MPA', (181, 190))	('LINE-1', 'Gene', (119, 125))	('double-strand DNA breaks', 'MPA', (142, 166))	('elicits', 'Reg', (64, 71))	('ODC1', 'Gene', '4953', (48, 52))	('decreases', 'NegReg', (171, 180))
134907	32123240	Similarly, following siRNA-mediated knockdown of ODC1, UC cells undergo double-strand DNA breaks and apoptosis.	('undergo', 'Reg', (64, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('knockdown', 'Var', (36, 45))	('ODC1', 'Gene', (49, 53))	('apoptosis', 'CPA', (101, 110))	('ODC1', 'Gene', '4953', (49, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('double-strand', 'CPA', (72, 85))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('UC', 'Disease', 'MESH:D014523', (55, 57))
134908	32123240	Collectively, our findings provide evidence that ODC1 gene hypermethylation could be a starting point for the onset of genome-wide epigenetic aberrations in urothelial carcinogenesis.	('hypermethylation', 'Var', (59, 75))	('urothelial carcinogenesis', 'Disease', (157, 182))	('ODC1', 'Gene', (49, 53))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (157, 182))	('ODC1', 'Gene', '4953', (49, 53))
134914	32123240	Aromatic amines such as 2-naphthylamin and polycyclic aromatic hydrocarbons in cigarette smoke cause mutations in key cancer-related genes by forming DNA adducts.	('cancer', 'Disease', (118, 124))	('mutations', 'Var', (101, 110))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (43, 75))	('cause', 'Reg', (95, 100))	('DNA adducts', 'MPA', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('2-naphthylamin', 'Chemical', 'MESH:D015081', (24, 38))	('DNA', 'cellular_component', 'GO:0005574', ('150', '153'))	('Aromatic amines', 'Chemical', '-', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
134919	32123240	Focal DNA methylation changes affect among others tumor suppressor genes and may therefore causally contribute to the development and progression of UC.	('Focal DNA', 'Gene', (0, 9))	('UC', 'Disease', 'MESH:D014523', (149, 151))	('DNA methylation', 'biological_process', 'GO:0006306', ('6', '21'))	('changes', 'Var', (22, 29))	('DNA', 'cellular_component', 'GO:0005574', ('6', '9'))	('methylation changes', 'Var', (10, 29))	('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'))	('contribute to', 'Reg', (100, 113))	('affect', 'Reg', (30, 36))	('tumor', 'Disease', (50, 55))
134921	32123240	In particular, substantial global LINE-1 DNA hypomethylation in bladder cancer is accompanied by a shift toward expression of full-length LINE-1 elements.	('DNA hypomethylation', 'Var', (41, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (64, 78))	('shift', 'Reg', (99, 104))	('hypomethylation', 'Var', (45, 60))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('bladder cancer', 'Disease', 'MESH:D001749', (64, 78))	('bladder cancer', 'Disease', (64, 78))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('41', '60'))	('expression', 'MPA', (112, 122))
134923	32123240	It has been proposed that LINE-1 hypomethylation and activation may play a causative role in urothelial carcinogenesis by inducing genetic instability which accompanies cancer progression, especially in high-stage and high-grade cancer.	('inducing', 'Reg', (122, 130))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (93, 118))	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', (229, 235))	('activation', 'PosReg', (53, 63))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('LINE-1', 'Gene', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('genetic instability', 'MPA', (131, 150))	('urothelial carcinogenesis', 'Disease', (93, 118))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('high-stage', 'Disease', (203, 213))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('hypomethylation', 'Var', (33, 48))
134925	32123240	Despite clear evidence for the involvement of an abnormal methylome and particularly LINE-1 hypomethylation in urothelial carcinogenesis it remains unknown how this process is initiated.	('methylome', 'MPA', (58, 67))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (111, 136))	('LINE-1', 'Gene', (85, 91))	('urothelial carcinogenesis', 'Disease', (111, 136))	('involvement', 'Reg', (31, 42))	('hypomethylation', 'Var', (92, 107))
134926	32123240	To date, suitable in vitro models to investigate this issue are lacking, but are urgently required to understand both, how these epigenetic alterations are caused and how they promote cancer progression.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('epigenetic alterations', 'Var', (129, 151))	('promote', 'PosReg', (176, 183))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
134927	32123240	Recently, we have provided evidence that aberrant epigenetic regulation of key enzymes of methyl group and polyamine metabolism could be involved in establishing aberrant methylomes in UC.	('involved', 'Reg', (137, 145))	('aberrant', 'Var', (41, 49))	('methylomes', 'MPA', (171, 181))	('polyamine', 'Chemical', 'MESH:D011073', (107, 116))	('polyamine metabolism', 'biological_process', 'GO:0006595', ('107', '127'))	('regulation', 'biological_process', 'GO:0065007', ('61', '71'))	('UC', 'Disease', 'MESH:D014523', (185, 187))	('epigenetic regulation', 'MPA', (50, 71))
134931	32123240	Disturbances of these key enzymes are known to lead to grave imbalances in the delicate intracellular SAM:SAH ratio resulting in genome wide DNA methylation alterations, including genome-wide LINE-1 hypomethylation.	('SAH', 'Gene', (106, 109))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('hypomethylation', 'Var', (199, 214))	('lead', 'Reg', (47, 51))	('Disturbances', 'Var', (0, 12))	('intracellular', 'cellular_component', 'GO:0005622', ('88', '101'))	('DNA methylation', 'biological_process', 'GO:0006306', ('141', '156'))	('imbalances', 'MPA', (61, 71))	('SAH', 'Gene', '6296', (106, 109))	('imbalances', 'Phenotype', 'HP:0002172', (61, 71))	('SAM', 'Chemical', 'MESH:D012436', (102, 105))
134932	32123240	Therefore, we hypothesized that our observation may provide an explanation for the mechanisms involved in hypomethylation of LINE-1 retrotransposons, a hallmark of early urothelial cancer.	('hallmark of early urothelial cancer', 'Disease', (152, 187))	('hypomethylation', 'Var', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('hallmark of early urothelial cancer', 'Disease', 'MESH:D014523', (152, 187))	('LINE-1', 'Gene', (125, 131))
134935	32123240	We observed LINE-1 hypomethylation in 6 pTa and 6 pT1 urothelial carcinoma samples compared to 3 samples of healthy urothelium and 4 samples of tumor-adjacent uroepithelial tissue.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('tumor', 'Disease', (144, 149))	('pT1', 'Gene', '58492', (50, 53))	('urothelial carcinoma', 'Disease', (54, 74))	('LINE-1', 'Gene', (12, 18))	('pTa', 'Disease', (40, 43))	('pTa', 'Disease', 'None', (40, 43))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (54, 74))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('pT1', 'Gene', (50, 53))	('observed', 'Reg', (3, 11))	('pTa', 'molecular_function', 'GO:0008959', ('40', '43'))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('hypomethylation', 'Var', (19, 34))
134949	32123240	Interestingly, data from TCGA suggest that p21 is significantly frequently mutated in bladder cancer, a. o., the HT1376 UC cell line used here does not express p21 protein due to a frame shift mutation.	('bladder cancer', 'Disease', (86, 100))	('frame shift mutation', 'Var', (181, 201))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('p21', 'Gene', '1026', (43, 46))	('p21', 'Gene', '1026', (160, 163))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('p21', 'Gene', (160, 163))	('HT1376 UC', 'CellLine', 'CVCL:1292', (113, 122))	('mutated', 'Reg', (75, 82))	('p21', 'Gene', (43, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))
134951	32123240	The decrease in cell numbers was accompanied by a 2-fold increase of p21 transcripts at all time points in siRNA-treated cells compared to control siRNA-treated cells, in which p21 mRNA notably increased over time (Fig.	('p21', 'Gene', (69, 72))	('cell numbers', 'CPA', (16, 28))	('p21', 'Gene', '1026', (177, 180))	('p21', 'Gene', (177, 180))	('decrease', 'NegReg', (4, 12))	('increased', 'PosReg', (194, 203))	('increase', 'PosReg', (57, 65))	('siRNA-treated', 'Var', (107, 120))	('p21', 'Gene', '1026', (69, 72))
134953	32123240	To investigate whether DNA damage and apoptosis may underlie the observed decrease in cellular viability following ODC1 downregulation, we assayed gammaH2AX, an established biomarker of DNA damage response at DNA double-strand breaks.	('DNA', 'cellular_component', 'GO:0005574', ('209', '212'))	('ODC1', 'Gene', '4953', (115, 119))	('decrease', 'NegReg', (74, 82))	('downregulation', 'NegReg', (120, 134))	('DNA', 'cellular_component', 'GO:0005574', ('186', '189'))	('apoptosis', 'biological_process', 'GO:0097194', ('38', '47'))	('apoptosis', 'biological_process', 'GO:0006915', ('38', '47'))	('cellular', 'MPA', (86, 94))	('gammaH2AX', 'Chemical', '-', (147, 156))	('DNA damage response', 'biological_process', 'GO:0006974', ('186', '205'))	('gammaH2AX', 'Var', (147, 156))	('ODC1', 'Gene', (115, 119))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))
134960	32123240	Previously, we showed that ODC1 gene repression by promoter DNA methylation may be one of the first epigenetic hits in urothelial carcinogenesis (PrimeEpiHit (PEH) hypothesis).	('DNA methylation', 'biological_process', 'GO:0006306', ('60', '75'))	('urothelial carcinogenesis', 'Disease', (119, 144))	('repression', 'NegReg', (37, 47))	('promoter DNA methylation', 'Var', (51, 75))	('ODC1', 'Gene', (27, 31))	('ODC1', 'Gene', '4953', (27, 31))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (119, 144))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))
134976	32123240	In early studies a positive correlation between ODC1 gene hypomethylation and expression was reported and experimental methylation of the ODC1 gene abolished its expression.	('hypomethylation', 'Var', (58, 73))	('expression', 'MPA', (78, 88))	('methylation', 'Var', (119, 130))	('abolished', 'NegReg', (148, 157))	('ODC1', 'Gene', (48, 52))	('ODC1', 'Gene', (138, 142))	('expression', 'MPA', (162, 172))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))	('ODC1', 'Gene', '4953', (48, 52))	('ODC1', 'Gene', '4953', (138, 142))
134977	32123240	Furthermore aberrant ODC1 methylation has been reported in malignant cells.	('ODC1', 'Gene', (21, 25))	('ODC1', 'Gene', '4953', (21, 25))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('aberrant', 'Var', (12, 20))	('methylation', 'MPA', (26, 37))
134979	32123240	Thus we concluded that dense DNA methylation, epigenetically impairs ODC1 expression.	('expression', 'MPA', (74, 84))	('epigenetically', 'Var', (46, 60))	('impairs', 'NegReg', (61, 68))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('DNA methylation', 'biological_process', 'GO:0006306', ('29', '44'))	('ODC1', 'Gene', (69, 73))	('ODC1', 'Gene', '4953', (69, 73))
134981	32123240	Thus, hypermethylation of ODC1 impairing ODC1 gene expression in early urothelial cancer could act in a feed-forward fashion to promote further changes in methylation patterns, global DNA and LINE-1 hypomethylation.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ODC1', 'Gene', (26, 30))	('urothelial cancer', 'Disease', (71, 88))	('impairing', 'NegReg', (31, 40))	('hypermethylation', 'Var', (6, 22))	('gene expression', 'biological_process', 'GO:0010467', ('46', '61'))	('DNA', 'cellular_component', 'GO:0005574', ('184', '187'))	('ODC1', 'Gene', (41, 45))	('urothelial cancer', 'Disease', 'MESH:D014523', (71, 88))	('global DNA', 'MPA', (177, 187))	('ODC1', 'Gene', '4953', (26, 30))	('ODC1', 'Gene', '4953', (41, 45))	('expression', 'MPA', (51, 61))	('changes', 'Reg', (144, 151))	('methylation patterns', 'MPA', (155, 175))	('methylation', 'biological_process', 'GO:0032259', ('155', '166'))
134982	32123240	LINE-1 hypomethylation and activation which are established as widespread and early events in urothelial carcinogenesis would be facilitated by ODC1 repression.	('LINE-1', 'Gene', (0, 6))	('hypomethylation', 'Var', (7, 22))	('ODC1', 'Gene', (144, 148))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (94, 119))	('facilitated', 'PosReg', (129, 140))	('ODC1', 'Gene', '4953', (144, 148))	('urothelial carcinogenesis', 'Disease', (94, 119))	('activation', 'PosReg', (27, 37))	('repression', 'NegReg', (149, 159))
134987	32123240	This suggests that normal urothelial cells can respond to imbalances in methyl-group and polyamine metabolism as well as DNA damage by appropriate mechanisms, e.g.	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('polyamine metabolism', 'MPA', (89, 109))	('DNA damage', 'MPA', (121, 131))	('polyamine metabolism', 'biological_process', 'GO:0006595', ('89', '109'))	('imbalances', 'Phenotype', 'HP:0002172', (58, 68))	('polyamine', 'Chemical', 'MESH:D011073', (89, 98))	('methyl-group', 'MPA', (72, 84))	('imbalances', 'Var', (58, 68))
134989	32123240	Nevertheless, if ODC1 deficiency is a frequent phenomenon in urothelial carcinogenesis, later on in the course of tumor progression, tumor cells need to adapt to it, counter or overcome it by still unknown mechanisms, which may include the impediment of checkpoints characteristic of advanced bladder cancers.	('bladder cancers', 'Disease', (293, 308))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cancers', 'Phenotype', 'HP:0002664', (301, 308))	('urothelial carcinogenesis', 'Disease', (61, 86))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('ODC1', 'Gene', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('bladder cancers', 'Phenotype', 'HP:0009725', (293, 308))	('ODC1', 'Gene', '4953', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (114, 119))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (61, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (293, 307))	('tumor', 'Disease', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('bladder cancers', 'Disease', 'MESH:D001749', (293, 308))	('deficiency', 'Var', (22, 32))
134990	32123240	Obviously, this difference in response to ODC1 repression or inhibition may provide a therapeutic window, which deserves further exploration.	('ODC1', 'Gene', '4953', (42, 46))	('repression', 'Var', (47, 57))	('ODC1', 'Gene', (42, 46))	('inhibition', 'Var', (61, 71))
134991	32123240	Interference with ODC1, a key gene of polyamine metabolism, results in global demethylation and genetic instability.	('demethylation', 'biological_process', 'GO:0070988', ('78', '91'))	('global demethylation', 'MPA', (71, 91))	('ODC1', 'Gene', '4953', (18, 22))	('results in', 'Reg', (60, 70))	('polyamine', 'Chemical', 'MESH:D011073', (38, 47))	('ODC1', 'Gene', (18, 22))	('polyamine metabolism', 'biological_process', 'GO:0006595', ('38', '58'))	('Interference', 'Var', (0, 12))	('genetic instability', 'CPA', (96, 115))
134995	32123240	In addition, using the same model we will explore the role of other methyl group metabolism genes that we found concomitantly hypermethylated with ODC1 in urothelial carcinoma, like AHCY and AHCYL2.	('urothelial carcinoma', 'Disease', (155, 175))	('AHCYL2', 'Gene', '23382', (191, 197))	('AHCY', 'Gene', '191', (182, 186))	('ODC1', 'Gene', (147, 151))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (155, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('AHCY', 'Gene', '191', (191, 195))	('metabolism', 'biological_process', 'GO:0008152', ('81', '91'))	('ODC1', 'Gene', '4953', (147, 151))	('AHCY', 'Gene', (182, 186))	('hypermethylated', 'Var', (126, 141))	('AHCYL2', 'Gene', (191, 197))	('AHCY', 'Gene', (191, 195))
134996	32123240	We therefore hypothesize that further genes of methyl group metabolism in addition to ODC1 contribute to disturbances of the methylome and thereby promote tumor progression.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('promote', 'PosReg', (147, 154))	('methylome', 'MPA', (125, 134))	('tumor', 'Disease', (155, 160))	('genes', 'Var', (38, 43))	('ODC1', 'Gene', (86, 90))	('disturbances', 'MPA', (105, 117))	('metabolism', 'biological_process', 'GO:0008152', ('60', '70'))	('ODC1', 'Gene', '4953', (86, 90))
134999	32123240	Finally, LINE-1 hypomethylation and activation is a common phenomenon in many different cancers.	('LINE-1', 'Protein', (9, 15))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('activation', 'PosReg', (36, 46))	('cancers', 'Disease', (88, 95))	('hypomethylation', 'Var', (16, 31))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
135000	32123240	Models analogous to ours may therefore yield insights in the relationship between epigenetic alterations and carcinogenesis in other cancer types as well.	('yield', 'Reg', (39, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (109, 123))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('carcinogenesis', 'Disease', (109, 123))	('cancer', 'Disease', (133, 139))	('epigenetic alterations', 'Var', (82, 104))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
135001	32123240	Our results highlight the question to which extent, presumably temporary, disturbances in methyl-group metabolism and polyamine biosynthesis contribute to LINE-1 hypomethylation in other cancers.	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('disturbances', 'Reg', (74, 86))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('cancers', 'Disease', (187, 194))	('metabolism', 'biological_process', 'GO:0008152', ('103', '113'))	('methyl-group metabolism', 'MPA', (90, 113))	('polyamine', 'MPA', (118, 127))	('polyamine biosynthesis', 'biological_process', 'GO:0006596', ('118', '140'))	('hypomethylation', 'Var', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('LINE-1', 'Var', (155, 161))	('polyamine', 'Chemical', 'MESH:D011073', (118, 127))
135002	32123240	If so, the ODC1 RNAi approach we describe here may be suitable to study the functional consequences of LINE-1 hypomethylation and its role in the carcinogenesis process of many other cancer entities as well.	('carcinogenesis', 'Disease', (146, 160))	('cancer', 'Disease', (183, 189))	('hypomethylation', 'Var', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('ODC1', 'Gene', (11, 15))	('RNAi', 'biological_process', 'GO:0016246', ('16', '20'))	('ODC1', 'Gene', '4953', (11, 15))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('LINE-1', 'Gene', (103, 109))
135032	29662235	Overexpression of PLAGL2 can be an independent predictor for lymph node metastasis and patient survival.	('patient', 'Species', '9606', (87, 94))	('lymph node metastasis', 'CPA', (61, 82))	('Overexpression', 'Var', (0, 14))	('PLAGL2', 'Gene', (18, 24))
135132	29130146	This technique involves the analysis of exfoliated urothelial cells present in the urine and examines them for aneuploidy of chromosomes 3, 7 and 17 and loss of the 9p21 locus, all of which chromosomal aberrations commonly observed in bladder cancer cells.	('bladder cancer', 'Phenotype', 'HP:0009725', (235, 249))	('aneuploidy', 'Disease', (111, 121))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (190, 213))	('bladder cancer', 'Disease', 'MESH:D001749', (235, 249))	('bladder cancer', 'Disease', (235, 249))	('loss', 'Var', (153, 157))	('aneuploidy', 'Disease', 'MESH:D000782', (111, 121))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('9p21 locus', 'Gene', (165, 175))
135145	29130146	For example, several immunological assays have been developed to detect the presence of fragments of cytokeratin 8 and 18 in the urine.	('men', 'Species', '9606', (92, 95))	('cytokeratin 8', 'Gene', (101, 114))	('fragments', 'Var', (88, 97))	('cytokeratin 8', 'Gene', '3856', (101, 114))
135152	29130146	Although bladder cancers display a great deal of genetic heterogeneity in comparison to many other types of tumour, non-muscle invasive bladder tumours display a high frequency of mutations in the FGFR3 oncogene, resulting in dysregulation of the RAS-MAPK pathway, whilst mutations in the RAS oncogenes (HRAS, KRAS, NRAS) are observed in approximately 13% of all bladder tumours.	('tumour', 'Phenotype', 'HP:0002664', (371, 377))	('tumour', 'Disease', 'MESH:D009369', (371, 377))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (9, 23))	('tumour', 'Disease', (371, 377))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('bladder tumours', 'Disease', 'MESH:D001749', (363, 378))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', (108, 114))	('bladder tumour', 'Phenotype', 'HP:0009725', (363, 377))	('FGFR3', 'Gene', (197, 202))	('NRAS', 'Gene', '4893', (316, 320))	('HRAS', 'Gene', '3265', (304, 308))	('bladder cancers', 'Phenotype', 'HP:0009725', (9, 24))	('HRAS', 'Gene', (304, 308))	('FGFR3', 'Gene', '2261', (197, 202))	('invasive bladder tumours', 'Disease', 'MESH:D001749', (127, 151))	('invasive bladder tumours', 'Disease', (127, 151))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (116, 143))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('MAPK', 'molecular_function', 'GO:0004707', ('251', '255'))	('RAS-MAPK pathway', 'Pathway', (247, 263))	('mutations', 'Var', (180, 189))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('invasive bladder', 'Phenotype', 'HP:0100645', (127, 143))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('KRAS', 'Gene', '3845', (310, 314))	('FGFR', 'molecular_function', 'GO:0005007', ('197', '201'))	('tumour', 'Disease', (144, 150))	('bladder tumour', 'Phenotype', 'HP:0009725', (136, 150))	('bladder tumours', 'Disease', 'MESH:D001749', (136, 151))	('bladder cancers', 'Disease', 'MESH:D001749', (9, 24))	('NRAS', 'Gene', (316, 320))	('bladder cancers', 'Disease', (9, 24))	('KRAS', 'Gene', (310, 314))	('tumours', 'Phenotype', 'HP:0002664', (371, 378))	('dysregulation', 'MPA', (226, 239))	('bladder tumours', 'Disease', (363, 378))
135153	29130146	Indeed, FGFR3 mutation analysis of voided urine has been performed and demonstrated a sensitivity of 58% for detecting bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('bladder cancer', 'Phenotype', 'HP:0009725', (119, 133))	('bladder cancer', 'Disease', 'MESH:D001749', (119, 133))	('FGFR3', 'Gene', '2261', (8, 13))	('mutation', 'Var', (14, 22))	('FGFR', 'molecular_function', 'GO:0005007', ('8', '12'))	('bladder cancer', 'Disease', (119, 133))	('FGFR3', 'Gene', (8, 13))
135154	29130146	Therefore, FGFR3 mutation analysis may hold some promise as a non-invasive tool for diagnosing and predicting recurrence.	('FGFR3', 'Gene', (11, 16))	('FGFR', 'molecular_function', 'GO:0005007', ('11', '15'))	('mutation analysis', 'Var', (17, 34))	('FGFR3', 'Gene', '2261', (11, 16))
135155	29130146	Epigenetic alterations are a frequent observation in most cancers and the most well-characterised epigenetic phenomenon is DNA methylation.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('men', 'Species', '9606', (114, 117))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('DNA methylation', 'biological_process', 'GO:0006306', ('123', '138'))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))
135156	29130146	Alterations in DNA methylation are often observed in cancers and may lead to dysregulation of gene expression.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('methylation', 'Var', (19, 30))	('cancers', 'Disease', (53, 60))	('gene expression', 'biological_process', 'GO:0010467', ('94', '109'))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('Alterations', 'Var', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('dysregulation of gene expression', 'MPA', (77, 109))	('DNA', 'Protein', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('observed', 'Reg', (41, 49))	('lead to', 'Reg', (69, 76))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))
135160	29130146	For example, one study found that detection of hyper-methylation of the genes VAX1, KCNV1, TAL1, PPOX1 and CFTR in DNA found in urine was able to predict primary and recurrent disease with a sensitivity of 89% and a specificity of 88%.	('KCNV1', 'Gene', '27012', (84, 89))	('CFTR', 'Gene', '1080', (107, 111))	('predict', 'Reg', (146, 153))	('VAX1', 'Gene', (78, 82))	('PPOX1', 'Gene', (97, 102))	('TAL1', 'Gene', '6886', (91, 95))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('hyper-methylation', 'Var', (47, 64))	('CFTR', 'Gene', (107, 111))	('VAX1', 'Gene', '11023', (78, 82))	('TAL1', 'Gene', (91, 95))	('KCNV1', 'Gene', (84, 89))
135195	22140553	A Systematic Analysis on DNA Methylation and the Expression of Both mRNA and microRNA in Bladder Cancer DNA methylation aberration and microRNA (miRNA) deregulation have been observed in many types of cancers.	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('aberration', 'Var', (120, 130))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('Bladder Cancer', 'Disease', (89, 103))	('microRNA', 'MPA', (135, 143))	('cancers', 'Disease', (201, 208))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('DNA Methylation', 'biological_process', 'GO:0006306', ('25', '40'))	('Bladder Cancer', 'Disease', 'MESH:D001749', (89, 103))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (89, 103))	('DNA', 'Gene', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('DNA methylation', 'biological_process', 'GO:0006306', ('104', '119'))
135202	22140553	As genetic and epigenetic abnormalities have been observed in the development of cancer cells, it has been theorized that they both play important roles in oncogenesis, inducing changes in gene activity and chromosome structure.	('oncogenesis', 'biological_process', 'GO:0007048', ('156', '167'))	('chromosome structure', 'CPA', (207, 227))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('epigenetic abnormalities', 'Var', (15, 39))	('cancer', 'Disease', (81, 87))	('gene activity', 'MPA', (189, 202))	('abnormalities', 'Var', (26, 39))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('207', '217'))	('inducing changes', 'Reg', (169, 185))
135206	22140553	In addition to DNA methylation, deregulated miRNAs in cancer may affect the expression of genes and pathways that are involved in cancer pathogenesis all the way from initiation to metastasis.	('affect', 'Reg', (65, 71))	('deregulated', 'Var', (32, 43))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (130, 136))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('pathogenesis', 'biological_process', 'GO:0009405', ('137', '149'))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('expression of', 'MPA', (76, 89))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
135213	22140553	Inappropriate silencing of these genes by promoter hypermethylation contributes to cancer initiation, progression, invasion, and metastasis.	('contributes', 'Reg', (68, 79))	('cancer initiation', 'Disease', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('progression', 'CPA', (102, 113))	('metastasis', 'CPA', (129, 139))	('silencing', 'NegReg', (14, 23))	('cancer initiation', 'Disease', 'MESH:D009369', (83, 100))	('invasion', 'CPA', (115, 123))	('promoter hypermethylation', 'Var', (42, 67))
135216	22140553	The tumor-suppressor and oncogenic functions of miRNAs have been observed in bladder cancer as well.	('oncogenic functions', 'CPA', (25, 44))	('tumor', 'Disease', (4, 9))	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('4', '20'))	('bladder cancer', 'Disease', (77, 91))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('4', '20'))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('miRNAs', 'Var', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
135236	22140553	Remarkably, the tumor suppressors miR-1 and miR-133a were both significantly under-expressed in our study, resulting in the activation of the predicted target gene transgelin 2 (TAGLN2), which has been identified as a potential oncogene.	('TAGLN2', 'Gene', (178, 184))	('activation', 'PosReg', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('miR-133a', 'Var', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('transgelin 2', 'Gene', '8407', (164, 176))	('TAGLN2', 'Gene', '8407', (178, 184))	('tumor', 'Disease', (16, 21))	('miR-1', 'Gene', (34, 39))	('transgelin 2', 'Gene', (164, 176))
135241	22140553	This result suggests an important mechanism of epigenetic abnormality in neuron genes that play a role in bladder cancer, as cancer-related axonogenesis and neurogenesis has been observed in prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('axonogenesis', 'biological_process', 'GO:0007409', ('140', '152'))	('prostate cancer', 'Disease', 'MESH:D011471', (191, 206))	('neurogenesis', 'biological_process', 'GO:0022008', ('157', '169'))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('prostate cancer', 'Phenotype', 'HP:0012125', (191, 206))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('prostate cancer', 'Disease', (191, 206))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('neurogenesis', 'CPA', (157, 169))	('cancer', 'Disease', (114, 120))	('bladder cancer', 'Disease', 'MESH:D001749', (106, 120))	('bladder cancer', 'Disease', (106, 120))	('epigenetic abnormality', 'Var', (47, 69))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', (200, 206))	('bladder cancer', 'Phenotype', 'HP:0009725', (106, 120))
135250	22140553	Besides, we found that RAS protein activator like 1 (RASAL1) and keratin 17 (KRT17) were clearly hypomethylated in the promoter region and over-expressed in the tumor samples compared to the controls.	('RAS protein activator like 1', 'Gene', '8437', (23, 51))	('KRT17', 'Gene', '3872', (77, 82))	('hypomethylated', 'Var', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('RAS protein activator like 1', 'Gene', (23, 51))	('RASAL1', 'Gene', (53, 59))	('RASAL1', 'Gene', '8437', (53, 59))	('keratin 17', 'Gene', '3872', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('over-expressed', 'PosReg', (139, 153))	('keratin 17', 'Gene', (65, 75))	('KRT17', 'Gene', (77, 82))	('tumor', 'Disease', (161, 166))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))
135253	22140553	As shown in Figure 2B, aberration of regional promoter methylation was tightly associated with altered gene expression in these four genes in bladder cancer.	('associated', 'Reg', (79, 89))	('bladder cancer', 'Disease', (142, 156))	('aberration', 'Var', (23, 33))	('bladder cancer', 'Disease', 'MESH:D001749', (142, 156))	('altered', 'Reg', (95, 102))	('gene expression', 'MPA', (103, 118))	('bladder cancer', 'Phenotype', 'HP:0009725', (142, 156))	('gene expression', 'biological_process', 'GO:0010467', ('103', '118'))	('regional promoter', 'MPA', (37, 54))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
135255	22140553	Hypermethylation of the SLIT2 promoter was observed in 58.6% (17/29) cases, and a significant reduction of expression was detected at a rate of 86.2% (25/29).	('SLIT2', 'Gene', (24, 29))	('reduction', 'NegReg', (94, 103))	('SLIT2', 'Gene', '9353', (24, 29))	('Hypermethylation', 'Var', (0, 16))	('expression', 'MPA', (107, 117))
135259	22140553	Meanwhile, hypomethylation of the RASAL1 and KRT17 promoters and down-regulation of their expression were detected at rates of 63.3% and 75.8%, respectively.	('regulation', 'biological_process', 'GO:0065007', ('70', '80'))	('KRT17', 'Gene', (45, 50))	('hypomethylation', 'Var', (11, 26))	('expression', 'MPA', (90, 100))	('RASAL1', 'Gene', '8437', (34, 40))	('down-regulation', 'NegReg', (65, 80))	('KRT17', 'Gene', '3872', (45, 50))	('RASAL1', 'Gene', (34, 40))
135263	22140553	In gene level, it's well known that inactivation of tumor-suppressor genes by site-specific hypermethylation contributes to the initiation and progression of human malignancies.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('contributes', 'Reg', (109, 120))	('malignancies', 'Disease', 'MESH:D009369', (164, 176))	('human', 'Species', '9606', (158, 163))	('tumor', 'Disease', (52, 57))	('progression', 'CPA', (143, 154))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('52', '68'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('52', '68'))	('human', 'Disease', (158, 163))	('malignancies', 'Disease', (164, 176))	('hypermethylation', 'Var', (92, 108))	('inactivation', 'Var', (36, 48))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
135264	22140553	Hypermethylation of HIC1 and the associated decrease in HIC1 expression is a common feature in several cancers, such as human breast cancer, acute myeloid leukemia, and prostate cancer.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('HIC1', 'Gene', '3090', (20, 24))	('Hypermethylation', 'Var', (0, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('prostate cancer', 'Disease', 'MESH:D011471', (169, 184))	('prostate cancer', 'Phenotype', 'HP:0012125', (169, 184))	('acute myeloid leukemia', 'Disease', (141, 163))	('human', 'Species', '9606', (120, 125))	('prostate cancer', 'Disease', (169, 184))	('decrease', 'NegReg', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('leukemia', 'Phenotype', 'HP:0001909', (155, 163))	('breast cancer', 'Disease', (126, 139))	('HIC1', 'Gene', (56, 60))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (141, 163))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (147, 163))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (141, 163))	('HIC1', 'Gene', '3090', (56, 60))	('expression', 'MPA', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('HIC1', 'Gene', (20, 24))
135266	22140553	found that the methylation frequencies of HIC1 promoter in malignant and normal urothelium were 21.9% and 16.7%, respectively.	('HIC1', 'Gene', (42, 46))	('methylation', 'Var', (15, 26))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('HIC1', 'Gene', '3090', (42, 46))
135267	22140553	Here, we reported the hypermethylation of HIC1 and the resulting decreased expression of HIC1 mRNA in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('decreased', 'NegReg', (65, 74))	('HIC1', 'Gene', (89, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('hypermethylation', 'Var', (22, 38))	('bladder cancer', 'Disease', (102, 116))	('HIC1', 'Gene', (42, 46))	('HIC1', 'Gene', '3090', (42, 46))	('HIC1', 'Gene', '3090', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('expression', 'MPA', (75, 85))
135272	22140553	Epigenetic inactivation of HIC1 would induce the deacetylation of p53, disrupting its function and resulting in a reduced apoptotic response to DNA damage, leading to oncogenesis and promoting tumor progression.	('reduced', 'NegReg', (114, 121))	('deacetylation', 'MPA', (49, 62))	('HIC1', 'Gene', '3090', (27, 31))	('oncogenesis', 'biological_process', 'GO:0007048', ('167', '178'))	('disrupting', 'NegReg', (71, 81))	('tumor', 'Disease', (193, 198))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('Epigenetic inactivation', 'Var', (0, 23))	('induce', 'Reg', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('function', 'MPA', (86, 94))	('p53', 'Gene', '7157', (66, 69))	('oncogenesis', 'CPA', (167, 178))	('leading to', 'Reg', (156, 166))	('HIC1', 'Gene', (27, 31))	('apoptotic response to DNA damage', 'MPA', (122, 154))	('promoting', 'PosReg', (183, 192))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('p53', 'Gene', (66, 69))
135273	22140553	Therefore, our research indicated that promoter CpG island hypermethylation caused HIC1 transcription inactivation and might disrupt the complex HIC1-p53 signaling pathway in bladder cancer.	('inactivation', 'NegReg', (102, 114))	('hypermethylation', 'Var', (59, 75))	('bladder cancer', 'Phenotype', 'HP:0009725', (175, 189))	('p53 signaling pathway', 'biological_process', 'GO:0030330', ('150', '171'))	('transcription', 'biological_process', 'GO:0006351', ('88', '101'))	('disrupt', 'NegReg', (125, 132))	('HIC1', 'Gene', '3090', (83, 87))	('HIC1', 'Gene', (83, 87))	('bladder cancer', 'Disease', 'MESH:D001749', (175, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('p53', 'Gene', (150, 153))	('p53', 'Gene', '7157', (150, 153))	('HIC1', 'Gene', (145, 149))	('bladder cancer', 'Disease', (175, 189))	('transcription', 'MPA', (88, 101))	('HIC1', 'Gene', '3090', (145, 149))
135275	22140553	A number of studies have demonstrated that SLIT2 is epigenetically silenced by hypermethylation of the promoter region in a broad spectrum of other tumors, such as lung, breast, glioma, colon, and cervical cancers, leading to inactivation of SLIT2 expression.	('glioma', 'Disease', (178, 184))	('colon', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('hypermethylation', 'Var', (79, 95))	('expression', 'MPA', (248, 258))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('cervical cancers', 'Disease', (197, 213))	('cervical cancers', 'Disease', 'MESH:D002583', (197, 213))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('silenced', 'NegReg', (67, 75))	('breast', 'Disease', (170, 176))	('tumors', 'Disease', (148, 154))	('SLIT2', 'Gene', (242, 247))	('SLIT2', 'Gene', (43, 48))	('lung', 'Disease', (164, 168))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('SLIT2', 'Gene', '9353', (242, 247))	('SLIT2', 'Gene', '9353', (43, 48))	('inactivation', 'NegReg', (226, 238))
135278	22140553	Hypermethylation at the promoters of genes (SLIT1, SLIT2, SLIT3, ROBO1, and ROBO3) involved in Slit-Robo pathway resulting in down-regulated gene expression was also indentified in invasive cervical cancer.	('Robo', 'Gene', (100, 104))	('Hypermethylation', 'Var', (0, 16))	('SLIT2', 'Gene', '9353', (51, 56))	('ROBO1', 'Gene', '6091', (65, 70))	('gene expression', 'MPA', (141, 156))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('SLIT3', 'Gene', '6586', (58, 63))	('down-regulated', 'NegReg', (126, 140))	('SLIT1', 'Gene', (44, 49))	('SLIT3', 'Gene', (58, 63))	('invasive cervical cancer', 'Disease', (181, 205))	('ROBO3', 'Gene', '64221', (76, 81))	('SLIT1', 'Gene', '6585', (44, 49))	('Robo', 'Gene', '6091;64221', (100, 104))	('ROBO3', 'Gene', (76, 81))	('invasive cervical cancer', 'Disease', 'MESH:D002583', (181, 205))	('SLIT2', 'Gene', (51, 56))	('ROBO1', 'Gene', (65, 70))	('gene expression', 'biological_process', 'GO:0010467', ('141', '156'))
135279	22140553	This work identified that the tumor suppressor gene, SLIT2, which inhibited tumor growth and metastasis, was found inactivated by promoter hypermethylation in bladder urothelial carcinoma as well.	('SLIT2', 'Gene', '9353', (53, 58))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (159, 187))	('bladder urothelial carcinoma', 'Disease', (159, 187))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('promoter hypermethylation', 'Var', (130, 155))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('inhibited', 'NegReg', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('SLIT2', 'Gene', (53, 58))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
135283	22140553	In contrast to hypermethylation, DNA hypomethylation contributes to tumorigenesis by activating proto-oncogenes, which contributes to cancer development and progression.	('tumor', 'Disease', (68, 73))	('activating', 'PosReg', (85, 95))	('contributes', 'Reg', (119, 130))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('33', '52'))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('proto-oncogenes', 'Gene', (96, 111))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('hypomethylation', 'Var', (37, 52))
135289	22140553	Further studies are needed to address the mechanisms that underlie the RASAL1 over-expression and epigenetic aberration in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('RASAL1', 'Gene', '8437', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('bladder cancer', 'Disease', 'MESH:D001749', (123, 137))	('RASAL1', 'Gene', (71, 77))	('bladder cancer', 'Disease', (123, 137))	('over-expression', 'PosReg', (78, 93))	('epigenetic aberration', 'Var', (98, 119))
135296	22140553	We also observed hypomethylation of the KRT17 promoter in bladder urothelial carcinoma.	('bladder urothelial carcinoma', 'Disease', (58, 86))	('hypomethylation', 'Var', (17, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('KRT17', 'Gene', '3872', (40, 45))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (58, 86))	('KRT17', 'Gene', (40, 45))
135297	22140553	KRT17 might be a putative oncogene that is activated through hypomethylation at the promoter.	('KRT17', 'Gene', (0, 5))	('hypomethylation', 'Var', (61, 76))	('KRT17', 'Gene', '3872', (0, 5))
135303	22140553	Therefore, characterization of the oncogenes targeted by miRNAs would be of great value in improving our understanding of the pathogenic mechanisms underlying bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (159, 173))	('bladder cancer', 'Disease', (159, 173))	('miRNAs', 'Var', (57, 63))	('bladder cancer', 'Phenotype', 'HP:0009725', (159, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
135332	22140553	The bisulfite conversion products were amplified using the following PCR program: 94 C for 4 min, followed by 35 cycles of 94 C for 30 sec, 55 C for 30 sec, 72 C for 30 sec and then extension at 72 C for 10 min.	('bisulfite', 'Chemical', 'MESH:C042345', (4, 13))	('bisulfite', 'MPA', (4, 13))	('94 C', 'Var', (123, 127))
135340	33311496	Moreover, the results of a series of functional assays showed that LINC01116 knockdown suppressed the proliferation, migration, and invasion of BCa cells.	('suppressed', 'NegReg', (87, 97))	('LINC01116', 'Gene', '375295', (67, 76))	('BCa', 'Phenotype', 'HP:0009725', (144, 147))	('migration', 'CPA', (117, 126))	('invasion of BCa cells', 'CPA', (132, 153))	('knockdown', 'Var', (77, 86))	('LINC01116', 'Gene', (67, 76))	('proliferation', 'CPA', (102, 115))
135344	33311496	Rescue experiments further demonstrated that the restraining influence of LINC01116 knockdown on the progression of BCa, was partly rescued by ELK3 promotion, but absolutely reversed by the co-enhancement of ELK3 and HOXD8.	('HOXD8', 'Gene', (217, 222))	('HOXD8', 'Gene', '3234', (217, 222))	('ELK3', 'Gene', '2004', (208, 212))	('promotion', 'PosReg', (148, 157))	('LINC01116', 'Gene', '375295', (74, 83))	('ELK3', 'Gene', (208, 212))	('knockdown', 'Var', (84, 93))	('ELK3', 'Gene', (143, 147))	('ELK3', 'Gene', '2004', (143, 147))	('LINC01116', 'Gene', (74, 83))	('BCa', 'Phenotype', 'HP:0009725', (116, 119))	('BCa', 'Disease', (116, 119))
135349	33311496	Many factors participate in the tumorigenesis and progression of BCa, such as smoking, chemicals, and abnormal expression of genes.	('BCa', 'Phenotype', 'HP:0009725', (65, 68))	('abnormal', 'Var', (102, 110))	('BCa', 'Disease', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('participate', 'Reg', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
135398	33311496	The LINC01116 or ELK3 fragment covering the miR-3612 target sites (wild-type or mutant) was inserted into the pmirGLO vector.	('miR-3612', 'Gene', (44, 52))	('miR-3612', 'Gene', '100500817', (44, 52))	('mutant', 'Var', (80, 86))	('LINC01116', 'Gene', '375295', (4, 13))	('ELK3', 'Gene', '2004', (17, 21))	('ELK3', 'Gene', (17, 21))	('LINC01116', 'Gene', (4, 13))
135412	33311496	Next, we performed colony formation assay and EdU assay to test whether LINC01116 knockdown affect the proliferation ability of BCa cells.	('BCa', 'Phenotype', 'HP:0009725', (128, 131))	('LINC01116', 'Gene', (72, 81))	('proliferation ability', 'CPA', (103, 124))	('knockdown', 'Var', (82, 91))	('formation', 'biological_process', 'GO:0009058', ('26', '35'))	('affect', 'Reg', (92, 98))	('LINC01116', 'Gene', '375295', (72, 81))
135414	33311496	Furthermore, the results of the JC-1 assay and flow cytometry analysis revealed that LINC01116 knockdown increased the apoptosis rate of both J28 and T24 cells (Fig.	('LINC01116', 'Gene', (85, 94))	('LINC01116', 'Gene', '375295', (85, 94))	('apoptosis rate', 'CPA', (119, 133))	('apoptosis', 'biological_process', 'GO:0097194', ('119', '128'))	('knockdown', 'Var', (95, 104))	('apoptosis', 'biological_process', 'GO:0006915', ('119', '128'))	('increased', 'PosReg', (105, 114))
135415	33311496	In addition, we also found that silencing of LINC01116 inhibited the growth of tumors in vivo (Fig.	('LINC01116', 'Gene', (45, 54))	('silencing', 'Var', (32, 41))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('LINC01116', 'Gene', '375295', (45, 54))	('inhibited', 'NegReg', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
135422	33311496	2a, b, silencing of LINC01116 suppressed the capacity of migration and invasion in BCa cells.	('LINC01116', 'Gene', (20, 29))	('suppressed', 'NegReg', (30, 40))	('BCa', 'Phenotype', 'HP:0009725', (83, 86))	('LINC01116', 'Gene', '375295', (20, 29))	('silencing', 'Var', (7, 16))
135424	33311496	The results demonstrated that LINC01116 deficiency obviously increased the expression of E-cadherin in both J82 and T24 cells, while decreased N-cadherin and Vimentin levels (Fig.	('deficiency', 'Var', (40, 50))	('cadherin', 'molecular_function', 'GO:0008014', ('91', '99'))	('Vimentin', 'cellular_component', 'GO:0045098', ('158', '166'))	('N-cadherin', 'Gene', (143, 153))	('LINC01116', 'Gene', '375295', (30, 39))	('expression', 'MPA', (75, 85))	('Vimentin', 'Gene', '7431', (158, 166))	('E-cadherin', 'Gene', (89, 99))	('E-cadherin', 'Gene', '999', (89, 99))	('N-cadherin', 'Gene', '1000', (143, 153))	('Vimentin', 'cellular_component', 'GO:0045099', ('158', '166'))	('increased', 'PosReg', (61, 70))	('cadherin', 'molecular_function', 'GO:0008014', ('145', '153'))	('LINC01116', 'Gene', (30, 39))	('Vimentin', 'Gene', (158, 166))	('decreased', 'NegReg', (133, 142))
135427	33311496	All these results suggested that silencing of LINC01116 hinders the migration, invasion, and EMT process in BCa cells.	('hinders', 'NegReg', (56, 63))	('BCa', 'Phenotype', 'HP:0009725', (108, 111))	('EMT', 'biological_process', 'GO:0001837', ('93', '96'))	('silencing', 'Var', (33, 42))	('EMT', 'Gene', (93, 96))	('EMT', 'Gene', '3702', (93, 96))	('LINC01116', 'Gene', (46, 55))	('invasion', 'CPA', (79, 87))	('migration', 'CPA', (68, 77))	('LINC01116', 'Gene', '375295', (46, 55))
135448	33311496	More importantly, silencing LINC01116 in J82 and T24 cells blocked the binding of miR-3612 to LINC01116 but facilitated the interaction of miR-3612 with ELK3 (Fig.	('miR-3612', 'Gene', (139, 147))	('LINC01116', 'Gene', (28, 37))	('miR-3612', 'Gene', (82, 90))	('ELK3', 'Gene', (153, 157))	('silencing', 'Var', (18, 27))	('ELK3', 'Gene', '2004', (153, 157))	('miR-3612', 'Gene', '100500817', (139, 147))	('miR-3612', 'Gene', '100500817', (82, 90))	('interaction', 'Interaction', (124, 135))	('LINC01116', 'Gene', (94, 103))	('LINC01116', 'Gene', '375295', (28, 37))	('binding', 'Interaction', (71, 78))	('blocked', 'NegReg', (59, 66))	('LINC01116', 'Gene', '375295', (94, 103))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))	('facilitated', 'PosReg', (108, 119))
135456	33311496	Next, the outcomes of colony formation and EdU assays displayed that silencing of LINC01116 suppressed the proliferation of BCa cells, and this effect was partly reversed by a miR-3612 inhibitor (Fig.	('suppressed', 'NegReg', (92, 102))	('LINC01116', 'Gene', '375295', (82, 91))	('BCa', 'Phenotype', 'HP:0009725', (124, 127))	('proliferation', 'CPA', (107, 120))	('miR-3612', 'Gene', (176, 184))	('LINC01116', 'Gene', (82, 91))	('miR-3612', 'Gene', '100500817', (176, 184))	('formation', 'biological_process', 'GO:0009058', ('29', '38'))	('silencing', 'Var', (69, 78))
135457	33311496	Furthermore, flow cytometry analyzed that miR-3612 inhibitor restored the partial promoting effect of LINC01116 knockdown on cell apoptosis (Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('LINC01116', 'Gene', '375295', (102, 111))	('miR-3612', 'Gene', (42, 50))	('knockdown', 'Var', (112, 121))	('miR-3612', 'Gene', '100500817', (42, 50))	('promoting', 'PosReg', (82, 91))	('cell apoptosis', 'CPA', (125, 139))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('LINC01116', 'Gene', (102, 111))
135458	33311496	In addition, the results of transwell assays signified that silencing of LINC01116 inhibited the migration and invasion capacity of J82 and T24 cells, which was reversed by a miR-3612 inhibitor to some extent (Fig.	('LINC01116', 'Gene', (73, 82))	('miR-3612', 'Gene', (175, 183))	('miR-3612', 'Gene', '100500817', (175, 183))	('inhibited', 'NegReg', (83, 92))	('LINC01116', 'Gene', '375295', (73, 82))	('silencing', 'Var', (60, 69))
135460	33311496	Intriguingly, we verified that miR-3612 inhibition fully reversed the suppression of deficient LINC01116 on ELK3 expression (Fig.	('LINC01116', 'Gene', '375295', (95, 104))	('deficient', 'Var', (85, 94))	('miR-3612', 'Gene', (31, 39))	('miR-3612', 'Gene', '100500817', (31, 39))	('ELK3', 'Gene', '2004', (108, 112))	('LINC01116', 'Gene', (95, 104))	('ELK3', 'Gene', (108, 112))
135475	33311496	The results demonstrated that the stability of HOXD8 was significantly reduced after the knockdown of LINC01116 or DKC1 compared to the control group (Fig.	('DKC1', 'Gene', (115, 119))	('LINC01116', 'Gene', '375295', (102, 111))	('stability of', 'CPA', (34, 46))	('DKC1', 'Gene', '1736', (115, 119))	('reduced', 'NegReg', (71, 78))	('HOXD8', 'Gene', (47, 52))	('knockdown', 'Var', (89, 98))	('LINC01116', 'Gene', (102, 111))	('HOXD8', 'Gene', '3234', (47, 52))
135480	33311496	The results of colony formation assay showed that the relative colony formation efficiency was obviously reduced by LINC01116 knockdown, but was then partly rescued by ELK3 overexpression while absolutely reversed by the promotion of both ELK3 and HOXD8 (Fig.	('HOXD8', 'Gene', (248, 253))	('HOXD8', 'Gene', '3234', (248, 253))	('LINC01116', 'Gene', '375295', (116, 125))	('formation', 'biological_process', 'GO:0009058', ('22', '31'))	('colony formation efficiency', 'CPA', (63, 90))	('ELK3', 'Gene', (239, 243))	('ELK3', 'Gene', '2004', (239, 243))	('reduced', 'NegReg', (105, 112))	('formation', 'biological_process', 'GO:0009058', ('70', '79'))	('ELK3', 'Gene', '2004', (168, 172))	('knockdown', 'Var', (126, 135))	('LINC01116', 'Gene', (116, 125))	('ELK3', 'Gene', (168, 172))
135484	33311496	The results revealed that the upregulation of E-cadherin induced by silencing of LINC01116 was abolished by elevated ELK3 in part, and was fully reversed by the co-transfection with pcDNA3.1/ELK3 and pcDNA3.1/HOXD8.	('ELK3', 'Gene', '2004', (117, 121))	('cadherin', 'molecular_function', 'GO:0008014', ('48', '56'))	('ELK3', 'Gene', (191, 195))	('E-cadherin', 'Gene', (46, 56))	('abolished', 'NegReg', (95, 104))	('ELK3', 'Gene', '2004', (191, 195))	('HOXD8', 'Gene', '3234', (209, 214))	('LINC01116', 'Gene', '375295', (81, 90))	('E-cadherin', 'Gene', '999', (46, 56))	('silencing', 'Var', (68, 77))	('upregulation', 'PosReg', (30, 42))	('elevated', 'PosReg', (108, 116))	('HOXD8', 'Gene', (209, 214))	('LINC01116', 'Gene', (81, 90))	('ELK3', 'Gene', (117, 121))
135496	33311496	Moreover, luciferase reporter assays also showed that loss of HOXD8 suppressed the luciferase activity of the P1-WT reporter vector but barely affected that of the P1-MUT reporter vector (Fig.	('luciferase activity', 'molecular_function', 'GO:0047077', ('83', '102'))	('HOXD8', 'Gene', (62, 67))	('HOXD8', 'Gene', '3234', (62, 67))	('suppressed', 'NegReg', (68, 78))	('luciferase activity', 'molecular_function', 'GO:0045289', ('83', '102'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('83', '102'))	('activity', 'MPA', (94, 102))	('loss', 'Var', (54, 58))	('luciferase activity', 'molecular_function', 'GO:0050248', ('83', '102'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('83', '102'))	('luciferase', 'Enzyme', (83, 93))
135509	33311496	Inconsistent with these findings, our present study verified that LINC01116 was overexpressed in BCa cells, and silencing of LINC01116 significantly inhibited cell proliferation, migration, and invasion, as well as the EMT process in BCa.	('BCa', 'Disease', (234, 237))	('EMT', 'biological_process', 'GO:0001837', ('219', '222'))	('EMT', 'Gene', (219, 222))	('cell proliferation', 'biological_process', 'GO:0008283', ('159', '177'))	('EMT', 'Gene', '3702', (219, 222))	('LINC01116', 'Gene', (66, 75))	('invasion', 'CPA', (194, 202))	('LINC01116', 'Gene', (125, 134))	('BCa', 'Phenotype', 'HP:0009725', (97, 100))	('cell proliferation', 'CPA', (159, 177))	('LINC01116', 'Gene', '375295', (66, 75))	('silencing', 'Var', (112, 121))	('LINC01116', 'Gene', '375295', (125, 134))	('inhibited', 'NegReg', (149, 158))	('BCa', 'Phenotype', 'HP:0009725', (234, 237))
135513	33311496	Further, we verified that the 3'UTR activity of both mRNAs was declined by silenced LINC01116, proving the post-transcriptional regulation of LINC01116 on these two genes.	('regulation', 'biological_process', 'GO:0065007', ('128', '138'))	('LINC01116', 'Gene', '375295', (84, 93))	("3'UTR activity", 'MPA', (30, 44))	('LINC01116', 'Gene', (142, 151))	('LINC01116', 'Gene', '375295', (142, 151))	('LINC01116', 'Gene', (84, 93))	('declined', 'NegReg', (63, 71))	('silenced', 'Var', (75, 83))
135517	33311496	In our study, we confirmed that ELK3 knockdown could markedly suppress cell growth and metastasis in BCa.	('suppress', 'NegReg', (62, 70))	('ELK3', 'Gene', '2004', (32, 36))	('ELK3', 'Gene', (32, 36))	('knockdown', 'Var', (37, 46))	('BCa', 'Phenotype', 'HP:0009725', (101, 104))	('BCa', 'Disease', (101, 104))
135524	33311496	In this study, we proved that inhibiting HOXD8 hampered BCa cell proliferation, migration, invasion, and EMT, revealing HOXD8 as a tumor-facilitator in BCa.	('hampered', 'NegReg', (47, 55))	('BCa cell proliferation', 'CPA', (56, 78))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('HOXD8', 'Gene', (41, 46))	('invasion', 'CPA', (91, 99))	('HOXD8', 'Gene', '3234', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('migration', 'CPA', (80, 89))	('BCa', 'Phenotype', 'HP:0009725', (56, 59))	('BCa', 'Phenotype', 'HP:0009725', (152, 155))	('tumor', 'Disease', (131, 136))	('HOXD8', 'Gene', (120, 125))	('EMT', 'biological_process', 'GO:0001837', ('105', '108'))	('EMT', 'Gene', (105, 108))	('EMT', 'Gene', '3702', (105, 108))	('HOXD8', 'Gene', '3234', (120, 125))	('inhibiting', 'Var', (30, 40))
135525	33311496	Moreover, DCK1 was previously reported to function in the nucleus, but in our study, knockdown of DKC1 could suppress the expression of HOXD8, and LINC01116-DKC1 complex could effectively regulate the stability of HOXD8.	('stability', 'CPA', (201, 210))	('expression', 'MPA', (122, 132))	('LINC01116', 'Gene', (147, 156))	('DKC1', 'Gene', (98, 102))	('suppress', 'NegReg', (109, 117))	('DKC1', 'Gene', (157, 161))	('regulate', 'Reg', (188, 196))	('HOXD8', 'Gene', (214, 219))	('knockdown', 'Var', (85, 94))	('HOXD8', 'Gene', '3234', (214, 219))	('LINC01116', 'Gene', '375295', (147, 156))	('DKC1', 'Gene', '1736', (98, 102))	('nucleus', 'cellular_component', 'GO:0005634', ('58', '65'))	('HOXD8', 'Gene', (136, 141))	('HOXD8', 'Gene', '3234', (136, 141))	('DKC1', 'Gene', '1736', (157, 161))
135528	33311496	In summary, our results revealed that knockdown of LINC01116 could suppress the malignant progression of BCa both in vitro and in vivo, and its role in BCa depended on two pathways.	('LINC01116', 'Gene', (51, 60))	('suppress', 'NegReg', (67, 75))	('BCa', 'Phenotype', 'HP:0009725', (152, 155))	('BCa', 'Phenotype', 'HP:0009725', (105, 108))	('BCa', 'Disease', (105, 108))	('malignant progression of', 'CPA', (80, 104))	('LINC01116', 'Gene', '375295', (51, 60))	('knockdown', 'Var', (38, 47))
135542	29731962	High expression of KLgamma was significantly associated with higher stage and grade cancer and the presence of lymphovascular invasion compared to patients with lower expression of KLgamma.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('KLgamma', 'Gene', (19, 26))	('High', 'Var', (0, 4))	('cancer', 'Disease', (84, 90))	('lymphovascular invasion', 'CPA', (111, 134))	('associated', 'Reg', (45, 55))	('patients', 'Species', '9606', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('KLgamma', 'Chemical', '-', (19, 26))	('KLgamma', 'Chemical', '-', (181, 188))
135578	29731962	Significant tumor weight loss was observed in mice treated with KLgamma siRNA compared with the no treatment group (Figure 3D).	('tumor weight loss', 'Disease', (12, 29))	('men', 'Species', '9606', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mice', 'Species', '10090', (46, 50))	('KLgamma', 'Chemical', '-', (64, 71))	('tumor weight loss', 'Disease', 'MESH:D015431', (12, 29))	('weight loss', 'Phenotype', 'HP:0001824', (18, 29))	('KLgamma', 'Var', (64, 71))
135579	29731962	The tumor growth rate during the treatment was significantly lower in mice treated with KLgamma siRNA compared with the no treatment group (Figure 3E).	('tumor', 'Disease', (4, 9))	('lower', 'NegReg', (61, 66))	('men', 'Species', '9606', (38, 41))	('men', 'Species', '9606', (128, 131))	('mice', 'Species', '10090', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('KLgamma', 'Chemical', '-', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('KLgamma', 'Var', (88, 95))
135582	29731962	Xenografts of mice treated with KLgamma siRNA showed significantly lower expression of Ki67 and an increase in apoptotic cells compared with those of mice with no treatment (P = 0.0050, Supplementary Figure 1B; P = 0.0063, Supplementary Figure 1C, respectively).	('mice', 'Species', '10090', (150, 154))	('Ki67', 'Gene', '17345', (87, 91))	('mice', 'Species', '10090', (14, 18))	('KLgamma', 'Chemical', '-', (32, 39))	('expression', 'MPA', (73, 83))	('KLgamma', 'Var', (32, 39))	('men', 'Species', '9606', (229, 232))	('apoptotic cells', 'CPA', (111, 126))	('men', 'Species', '9606', (192, 195))	('Ki67', 'Gene', (87, 91))	('increase', 'PosReg', (99, 107))	('lower', 'NegReg', (67, 72))	('men', 'Species', '9606', (168, 171))
135583	29731962	Xenografts of mice treated with KLgamma siRNA also showed significantly higher expression of E-cadherin compared with that of mice with no treatment (P = 0.0099; Supplementary Figure 1D).	('men', 'Species', '9606', (144, 147))	('mice', 'Species', '10090', (126, 130))	('expression', 'MPA', (79, 89))	('E-cadherin', 'Protein', (93, 103))	('mice', 'Species', '10090', (14, 18))	('KLgamma', 'Chemical', '-', (32, 39))	('KLgamma', 'Var', (32, 39))	('higher', 'PosReg', (72, 78))	('cadherin', 'molecular_function', 'GO:0008014', ('95', '103'))	('men', 'Species', '9606', (168, 171))
135589	29731962	Phosphorylation levels of AKT and ERK1/2 were not affected significantly by the transfection of KLg siRNA (Figure 4C).	('AKT', 'Gene', '207', (26, 29))	('ERK1/2', 'Pathway', (34, 40))	('Phosphorylation levels', 'MPA', (0, 22))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('ERK1', 'molecular_function', 'GO:0004707', ('34', '38'))	('AKT', 'Gene', (26, 29))	('transfection', 'Var', (80, 92))
135594	29731962	The pathological data, such as tumor category, tumor grade, and lymphovascular invasion (LVI), were significantly different between patients with low and high KLgamma expression.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('KLgamma', 'Protein', (159, 166))	('low', 'Var', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('KLgamma', 'Chemical', '-', (159, 166))	('tumor', 'Disease', (31, 36))	('high', 'Var', (154, 158))	('lymphovascular invasion', 'CPA', (64, 87))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('different', 'Reg', (114, 123))	('patients', 'Species', '9606', (132, 140))	('tumor', 'Disease', (47, 52))
135601	29731962	With regard to the intravesical recurrence- and progression-free survival in patients with high or low KLgamma expression, intravesical recurrence was tended to be more in patients with high KLgamma expression and intravesical progression significantly increased in patients with high KLgamma expression (P = 0.067, Figure 5C; P = 0.013, Figure 5D, respectively).	('intravesical recurrence', 'CPA', (123, 146))	('patients', 'Species', '9606', (266, 274))	('high KLgamma', 'Var', (280, 292))	('KLgamma', 'Chemical', '-', (285, 292))	('KLgamma', 'Chemical', '-', (103, 110))	('KLgamma', 'Chemical', '-', (191, 198))	('patients', 'Species', '9606', (77, 85))	('increased', 'PosReg', (253, 262))	('patients', 'Species', '9606', (172, 180))	('high KLgamma', 'Var', (186, 198))
135603	29731962	With regard to the recurrence-free, disease-specific, and overall survival in patients with high or low KLgamma expression, there was no significant difference between the two groups (P = 0.069, Figure 5E; P = 0.84, Figure 5F; P = 0.82, Figure 5G, respectively).	('high', 'Var', (92, 96))	('KLgamma', 'Chemical', '-', (104, 111))	('patients', 'Species', '9606', (78, 86))	('low', 'NegReg', (100, 103))	('KLgamma', 'Protein', (104, 111))
135606	29731962	The multivariate analysis showed that INF and high KLgamma expression were independent prognostic factors for the intravesical progression-free survival in NMIBC patients.	('high', 'Var', (46, 50))	('patients', 'Species', '9606', (162, 170))	('KLgamma', 'Chemical', '-', (51, 58))	('NMIBC', 'Disease', (156, 161))	('MIBC', 'Chemical', '-', (157, 161))
135616	29731962	The present study also showed that patients with high KLgamma expression had a significantly higher stage and grade of UCB and a higher risk rate of the intravesical progression.	('higher', 'PosReg', (93, 99))	('UCB', 'Chemical', '-', (119, 122))	('UCB', 'Phenotype', 'HP:0006740', (119, 122))	('KLgamma', 'Protein', (54, 61))	('UCB', 'Disease', (119, 122))	('grade', 'CPA', (110, 115))	('KLgamma', 'Chemical', '-', (54, 61))	('high', 'Var', (49, 53))	('patients', 'Species', '9606', (35, 43))
135632	29731962	reported that KLgamma is an important factor for cell proliferation and that the presence of various KL members affects the degree of activation of signaling pathways in colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (170, 182))	('colon cancer', 'Disease', 'MESH:D015179', (170, 182))	('KLgamma', 'Chemical', '-', (14, 21))	('KL members', 'Gene', (101, 111))	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('affects', 'Reg', (112, 119))	('colon cancer', 'Disease', (170, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('activation', 'PosReg', (134, 144))	('signaling', 'biological_process', 'GO:0023052', ('148', '157'))	('presence', 'Var', (81, 89))	('signaling pathways', 'Pathway', (148, 166))
135633	29731962	showed that, in patients with triple negative breast cancer, the expression level of KLgamma was high and correlates with poor progression, that KLgamma was a necessary factor for cell survival, and that depletion of KLgamma resulted in cell cycle arrest, apoptosis, and persistent activation of the ERK1/2 signaling pathway.	('KLgamma', 'Chemical', '-', (145, 152))	('activation', 'PosReg', (282, 292))	('patients', 'Species', '9606', (16, 24))	('ERK1', 'molecular_function', 'GO:0004707', ('300', '304'))	('depletion', 'Var', (204, 213))	('signaling pathway', 'biological_process', 'GO:0007165', ('307', '324'))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Disease', (46, 59))	('cell cycle arrest', 'CPA', (237, 254))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('237', '254'))	('KLgamma', 'Gene', (217, 224))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('KLgamma', 'Chemical', '-', (85, 92))	('ERK1/2 signaling pathway', 'Pathway', (300, 324))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (237, 254))	('apoptosis', 'biological_process', 'GO:0097194', ('256', '265'))	('apoptosis', 'biological_process', 'GO:0006915', ('256', '265'))	('apoptosis', 'CPA', (256, 265))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('KLgamma', 'Chemical', '-', (217, 224))	('expression level', 'MPA', (65, 81))
135639	29731962	Thus, we hypothesized that high expression of KLgamma promoted EMT in bladder cancer, resulting in poor prognosis.	('promoted', 'PosReg', (54, 62))	('KLgamma', 'Gene', (46, 53))	('EMT', 'CPA', (63, 66))	('high expression', 'Var', (27, 42))	('KLgamma', 'Chemical', '-', (46, 53))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('EMT', 'biological_process', 'GO:0001837', ('63', '66'))	('bladder cancer', 'Disease', 'MESH:D001749', (70, 84))	('bladder cancer', 'Disease', (70, 84))
135724	28327458	However, the positive rates of NFATc1 expression tended to be higher in renal pelvic tumors (60%) than in ureteral tumors (42%; P = .080) as well as in pN+ tumors (75%) than in pN0 tumors (49%; P = .089).	('higher', 'PosReg', (62, 68))	('NFATc1', 'Gene', (31, 37))	('positive', 'MPA', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('ureteral tumors', 'Phenotype', 'HP:0100516', (106, 121))	('ureteral tumors', 'Disease', 'MESH:D014516', (106, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('NFATc1', 'Gene', '4772', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Disease', (85, 91))	('ureteral tumors', 'Disease', (106, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('expression', 'MPA', (38, 48))	('tumors', 'Disease', (181, 187))	('pN+', 'Var', (152, 155))	('renal pelvic tumors', 'Disease', 'MESH:D007674', (72, 91))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', (156, 162))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('renal pelvic tumors', 'Disease', (72, 91))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
135737	28327458	NFATc1 knockdown in bladder cancer lines also resulted in significant reduction of cell viability and invasion, suggesting its direct regulation of tumor growth without involvement of immune system.	('reduction', 'NegReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (20, 34))	('cell viability', 'CPA', (83, 97))	('tumor', 'Disease', (148, 153))	('invasion', 'CPA', (102, 110))	('involvement of immune system', 'Phenotype', 'HP:0002715', (169, 197))	('regulation', 'biological_process', 'GO:0065007', ('134', '144'))	('bladder cancer', 'Disease', 'MESH:D001749', (20, 34))	('NFATc1', 'Gene', (0, 6))	('NFATc1', 'Gene', '4772', (0, 6))	('bladder cancer', 'Disease', (20, 34))	('knockdown', 'Var', (7, 16))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
135755	28327458	Six (40%) of 15 low-grade versus 45 (54%) of 84 high-grade UUTUCs (P = .332) and 16 (43%) of 37 non-muscle-invasive versus 35 (56%) of 62 muscle-invasive UUTUCs (P = .203) were immunoreactive for NFATc1.	('NFATc1', 'Gene', '4772', (196, 202))	('immunoreactive', 'Var', (177, 191))	('NFATc1', 'Gene', (196, 202))
135757	28327458	Additionally, NFATc1 positivity was marginally increased (P = .080) in renal pelvic tumors (60%) compared with ureteral tumors (42%).	('ureteral tumors', 'Disease', 'MESH:D014516', (111, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('positivity', 'Var', (21, 31))	('ureteral tumors', 'Phenotype', 'HP:0100516', (111, 126))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('ureteral tumors', 'Disease', (111, 126))	('increased', 'PosReg', (47, 56))	('renal pelvic tumors', 'Disease', (71, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('NFATc1', 'Gene', (14, 20))	('NFATc1', 'Gene', '4772', (14, 20))	('renal pelvic tumors', 'Disease', 'MESH:D007674', (71, 90))
135760	28327458	There were no statistically significant differences in tumor progression (P = .390; Figure 2A) or cancer-specific mortality (P = .318; Figure 2B) between NFATc1 positivity and negativity.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('NFATc1', 'Gene', (154, 160))	('positivity', 'Var', (161, 171))	('NFATc1', 'Gene', '4772', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', (55, 60))	('cancer', 'Disease', (98, 104))
135761	28327458	However, patients with high (2+/3+) NFATc1 tumor had a significantly higher risk of tumor progression (P = .032; Figure 3A) or cancer-specific mortality (P = .005; Figure 3B) compared to those with low (0/1+) NFATc1 tumor.	('tumor', 'Disease', (216, 221))	('high (2+/3+', 'Var', (23, 34))	('patients', 'Species', '9606', (9, 17))	('NFATc1', 'Gene', '4772', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('NFATc1', 'Gene', (209, 215))	('NFATc1', 'Gene', '4772', (209, 215))	('tumor', 'Disease', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancer', 'Disease', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', (43, 48))	('NFATc1', 'Gene', (36, 42))
135762	28327458	In 62 patients with muscle-invasive tumor, moderate (2+) to strong (3+) NFATc1 expression was also strongly associated with a lower cancer-specific survival rate (P = .024) but not with a lower progression-free survival rate (P = .118).	('muscle-invasive tumor', 'Disease', (20, 41))	('moderate (2+', 'Var', (43, 55))	('cancer', 'Disease', (132, 138))	('lower', 'NegReg', (126, 131))	('expression', 'MPA', (79, 89))	('muscle-invasive tumor', 'Disease', 'MESH:D009217', (20, 41))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('NFATc1', 'Gene', (72, 78))	('NFATc1', 'Gene', '4772', (72, 78))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
135771	28327458	In accordance with our previous findings in bladder specimens, NFATc1 expression was found to be considerably elevated in UUTUCs compared with nonneoplastic urothelial tissues.	('UUTUCs', 'Var', (122, 128))	('nonneoplastic urothelial tissues', 'Disease', 'MESH:D014522', (143, 175))	('expression', 'MPA', (70, 80))	('NFATc1', 'Gene', (63, 69))	('nonneoplastic urothelial tissues', 'Disease', (143, 175))	('NFATc1', 'Gene', '4772', (63, 69))	('elevated', 'PosReg', (110, 118))
135776	28327458	NFATc1 positivity in muscle-invasive bladder cancer was shown to correlate with the risk of tumor progression after radical cystectomy.	('positivity', 'Var', (7, 17))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('invasive bladder', 'Phenotype', 'HP:0100645', (28, 44))	('NFATc1', 'Gene', (0, 6))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (21, 51))	('NFATc1', 'Gene', '4772', (0, 6))	('muscle-invasive bladder cancer', 'Disease', (21, 51))	('tumor', 'Disease', (92, 97))	('bladder cancer', 'Phenotype', 'HP:0009725', (37, 51))
135800	25349966	Mutant PIK3CA controls DUSP1-dependent ERK 1/2 activity to confer response to AKT target therapy Alterations in the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway are frequent in urothelial bladder cancer (BLCA) and thus provide a potential target for novel therapeutic strategies.	('mTOR', 'Gene', (186, 190))	('AKT', 'Gene', (142, 145))	('DUSP1', 'Gene', (23, 28))	('signalling pathway', 'biological_process', 'GO:0007165', ('192', '210'))	('PI3K', 'molecular_function', 'GO:0016303', ('177', '181'))	('AKT', 'Gene', (78, 81))	('frequent', 'Reg', (215, 223))	('PI3', 'Gene', (177, 180))	('ERK 1/2', 'Gene', '5595;5594', (39, 46))	('Alterations', 'Reg', (97, 108))	('mTOR', 'Gene', '2475', (186, 190))	('ERK 1', 'molecular_function', 'GO:0004707', ('39', '44'))	('AKT', 'Gene', '207', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('mammalian target of rapamycin', 'Gene', '2475', (146, 175))	('PIK3CA', 'Gene', '5290', (7, 13))	('AKT', 'Gene', '207', (142, 145))	('bladder cancer', 'Phenotype', 'HP:0009725', (238, 252))	('BLCA', 'Phenotype', 'HP:0009725', (254, 258))	('AKT', 'Gene', '207', (78, 81))	('Mutant', 'Var', (0, 6))	('DUSP1', 'Gene', '1843', (23, 28))	('mammalian target of rapamycin', 'Gene', (146, 175))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (227, 252))	('ERK 1/2', 'Gene', (39, 46))	('PIK3CA', 'Gene', (7, 13))	('PI3', 'Gene', '5266', (177, 180))	('urothelial bladder cancer', 'Disease', (227, 252))	('AKT', 'Gene', (182, 185))
135802	25349966	Biochemical and functional effects of the AKT inhibitor MK-2206 were analysed on a panel of 11 BLCA cell lines possessing different genetic alterations.	('BLCA', 'Phenotype', 'HP:0009725', (95, 99))	('AKT', 'Gene', (42, 45))	('MK-2206', 'Chemical', 'MESH:C548887', (56, 63))	('MK-2206', 'Var', (56, 63))	('AKT', 'Gene', '207', (42, 45))
135804	25349966	cDNA or siRNA transfections were used to manipulate the expression of specific proteins such as wild-type or mutant PIK3CA, DUSP1 or CREB.	('PIK3CA', 'Gene', (116, 122))	('CREB', 'Gene', (133, 137))	('CREB', 'Gene', '1385', (133, 137))	('DUSP1', 'Gene', (124, 129))	('PIK3CA', 'Gene', '5290', (116, 122))	('expression', 'MPA', (56, 66))	('DUSP1', 'Gene', '1843', (124, 129))	('mutant', 'Var', (109, 115))
135806	25349966	Treatment with MK-2206 suppressed AKT and S6K1 but not 4E-BP1 phosphorylation in all cell lines.	('AKT', 'Gene', (34, 37))	('suppressed', 'NegReg', (23, 33))	('4E-BP1', 'Gene', (55, 61))	('S6K1', 'Gene', (42, 46))	('S6K1', 'Gene', '6198', (42, 46))	('MK-2206', 'Chemical', 'MESH:C548887', (15, 22))	('MK-2206', 'Var', (15, 22))	('4E-BP1', 'Gene', '1978', (55, 61))	('AKT', 'Gene', '207', (34, 37))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))
135807	25349966	Functionally, only cell lines bearing mutations in the hotspot helical domain of PIK3CA were sensitive to the drug, independent of other genetic alterations in the PI3K or MAPK signalling pathway.	('PIK3CA', 'Gene', (81, 87))	('MAPK', 'molecular_function', 'GO:0004707', ('172', '176'))	('PI3', 'Gene', '5266', (164, 167))	('PIK3CA', 'Gene', '5290', (81, 87))	('PI3K', 'molecular_function', 'GO:0016303', ('164', '168'))	('MAPK', 'Gene', (172, 176))	('MAPK', 'Gene', '5595;5594;5595', (172, 176))	('PI3', 'Gene', (164, 167))	('MAPK signalling', 'biological_process', 'GO:0000165', ('172', '187'))	('mutations in', 'Var', (38, 50))	('signalling pathway', 'biological_process', 'GO:0007165', ('177', '195'))	('sensitive', 'MPA', (93, 102))
135808	25349966	Following MK-2206 treatment, the presence of mutant PIK3CA resulted in an increase in DUSP1 expression that induced a decrease in ERK 1/2 phosphorylation.	('phosphorylation', 'biological_process', 'GO:0016310', ('138', '153'))	('mutant', 'Var', (45, 51))	('ERK 1/2', 'Gene', '5595;5594', (130, 137))	('MK-2206', 'Chemical', 'MESH:C548887', (10, 17))	('DUSP1', 'Gene', (86, 91))	('ERK 1/2', 'Gene', (130, 137))	('PIK3CA', 'Gene', (52, 58))	('increase', 'PosReg', (74, 82))	('DUSP1', 'Gene', '1843', (86, 91))	('ERK 1', 'molecular_function', 'GO:0004707', ('130', '135'))	('decrease', 'NegReg', (118, 126))	('PIK3CA', 'Gene', '5290', (52, 58))	('expression', 'MPA', (92, 102))
135809	25349966	Manipulating the expression of mutant or wild-type PIK3CA or DUSP1 confirmed that this mechanism is responsible for the induction of apoptosis and the inhibition of tumour proliferation in vitro and in vivo, to sensitise cells to AKT target therapy.	('his', 'Chemical', 'MESH:D006639', (83, 86))	('mutant', 'Var', (31, 37))	('AKT', 'Gene', (230, 233))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('apoptosis', 'CPA', (133, 142))	('PIK3CA', 'Gene', (51, 57))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('DUSP1', 'Gene', (61, 66))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('120', '142'))	('tumour', 'Disease', (165, 171))	('AKT', 'Gene', '207', (230, 233))	('inhibition', 'NegReg', (151, 161))	('PIK3CA', 'Gene', '5290', (51, 57))	('DUSP1', 'Gene', '1843', (61, 66))
135810	25349966	PIK3CA mutations confer sensitivity to AKT target therapy in BLCA by regulating DUSP1 expression and subsequent ERK1/2 dephosphorylation and can potentially serve as a stratifying biomarker for treatment.	('dephosphorylation', 'MPA', (119, 136))	('BLCA', 'Phenotype', 'HP:0009725', (61, 65))	('dephosphorylation', 'biological_process', 'GO:0016311', ('119', '136'))	('ERK1', 'molecular_function', 'GO:0004707', ('112', '116'))	('DUSP1', 'Gene', (80, 85))	('AKT', 'Gene', '207', (39, 42))	('PIK3CA', 'Gene', (0, 6))	('expression', 'MPA', (86, 96))	('DUSP1', 'Gene', '1843', (80, 85))	('PIK3CA', 'Gene', '5290', (0, 6))	('ERK1/2', 'Gene', (112, 118))	('regulating', 'Reg', (69, 79))	('AKT', 'Gene', (39, 42))	('ERK1/2', 'Gene', '5595;5594', (112, 118))	('mutations', 'Var', (7, 16))
135812	25349966	Molecular alterations resulting in the hyperactivation of this pathway have been observed frequently in human cancer making it particularly suited for targeted therapy.	('cancer', 'Disease', (110, 116))	('alterations', 'Var', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('human', 'Species', '9606', (104, 109))	('hyperactivation', 'PosReg', (39, 54))	('his', 'Chemical', 'MESH:D006639', (59, 62))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
135822	25349966	Preclinical data in various tumour entities suggest that it is effective only in a subset of tumours possessing specific molecular alterations in PI3K or MAPK signalling.	('PI3K', 'molecular_function', 'GO:0016303', ('146', '150'))	('MAPK', 'Gene', (154, 158))	('PI3', 'Gene', (146, 149))	('tumours', 'Disease', (93, 100))	('MAPK', 'Gene', '5595;5594;5595', (154, 158))	('tumour entities', 'Disease', (28, 43))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumour entities', 'Disease', 'MESH:D009369', (28, 43))	('alterations', 'Var', (131, 142))	('MAPK signalling', 'biological_process', 'GO:0000165', ('154', '169'))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('PI3', 'Gene', '5266', (146, 149))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('tumours', 'Disease', 'MESH:D009369', (93, 100))	('MAPK', 'molecular_function', 'GO:0004707', ('154', '158'))
135824	25349966	Thus, the complexity behind the signalling events that contribute to the selective efficacy of AKT inhibition in the presence of specific genetic alterations remains to be understood.	('signalling', 'biological_process', 'GO:0023052', ('32', '42'))	('AKT', 'Gene', '207', (95, 98))	('alterations', 'Var', (146, 157))	('inhibition', 'NegReg', (99, 109))	('AKT', 'Gene', (95, 98))
135825	25349966	MK-2206 is now being tested in phase II trials in which patients are pre-stratified for PIK3CA, AKT or PTEN mutations in breast and lung cancer or thymic malignancies, those with KRAS wild type (WT) and PIK3CA mutations in metastatic colorectal cancer, or PIK3CA mutations in advanced endometrial cancer.	('KRAS', 'Gene', '3845', (179, 183))	('patients', 'Species', '9606', (56, 64))	('PTEN', 'Gene', '5728', (103, 107))	('PIK3CA', 'Gene', '5290', (88, 94))	('mutations', 'Var', (210, 219))	('PIK3CA', 'Gene', '5290', (256, 262))	('breast and lung cancer', 'Disease', 'MESH:D001943', (121, 143))	('PIK3CA', 'Gene', (203, 209))	('mutations', 'Var', (263, 272))	('endometrial cancer', 'Phenotype', 'HP:0012114', (285, 303))	('KRAS', 'Gene', (179, 183))	('AKT', 'Gene', '207', (96, 99))	('pre', 'molecular_function', 'GO:0003904', ('69', '72'))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('colorectal cancer', 'Phenotype', 'HP:0003003', (234, 251))	('endometrial cancer', 'Disease', (285, 303))	('endometrial cancer', 'Disease', 'MESH:D016889', (285, 303))	('PIK3CA', 'Gene', (88, 94))	('PIK3CA', 'Gene', (256, 262))	('MK-2206', 'Chemical', 'MESH:C548887', (0, 7))	('PIK3CA', 'Gene', '5290', (203, 209))	('colorectal cancer', 'Disease', 'MESH:D015179', (234, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('PTEN', 'Gene', (103, 107))	('AKT', 'Gene', (96, 99))	('mutations', 'Var', (108, 117))	('colorectal cancer', 'Disease', (234, 251))	('thymic malignancies', 'Disease', 'MESH:D013953', (147, 166))	('thymic malignancies', 'Disease', (147, 166))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))
135832	25349966	About 50-70% of BLCA tumours possess molecular alterations that affect PI3K/AKT/mTOR signalling, including activating PIK3CA mutations in 20-25%, inactivating TSC1 mutations in 8-16% and inactivating PTEN mutations or loss of expression in 13-16%.	('AKT', 'Gene', '207', (76, 79))	('inactivating', 'Var', (146, 158))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('BLCA tumours', 'Disease', (16, 28))	('PI3', 'Gene', '5266', (71, 74))	('signalling', 'biological_process', 'GO:0023052', ('85', '95'))	('BLCA tumours', 'Disease', 'MESH:D009369', (16, 28))	('PIK3CA', 'Gene', '5290', (118, 124))	('mutations', 'Var', (125, 134))	('mTOR', 'Gene', (80, 84))	('PI3', 'Gene', (71, 74))	('activating', 'PosReg', (107, 117))	('mutations', 'Var', (205, 214))	('PTEN', 'Gene', (200, 204))	('AKT', 'Gene', (76, 79))	('mutations', 'Var', (164, 173))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))	('inactivating', 'Var', (187, 199))	('TSC1', 'Gene', (159, 163))	('BLCA', 'Phenotype', 'HP:0009725', (16, 20))	('PTEN', 'Gene', '5728', (200, 204))	('mTOR', 'Gene', '2475', (80, 84))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('loss of expression', 'NegReg', (218, 236))	('PIK3CA', 'Gene', (118, 124))	('affect', 'Reg', (64, 70))	('TSC1', 'Gene', '7248', (159, 163))
135836	25349966	A potential association between the presence of TSC1 mutations and response to rapalogues in BLCA has been reported and demonstrates that a thorough understanding of the signalling events initiated by the PI3K/AKT/mTOR pathway is required to maximise the potential benefit of available inhibitors in patients.	('AKT', 'Gene', (210, 213))	('PI3', 'Gene', (205, 208))	('patients', 'Species', '9606', (300, 308))	('PI3K', 'molecular_function', 'GO:0016303', ('205', '209'))	('signalling', 'biological_process', 'GO:0023052', ('170', '180'))	('mutations', 'Var', (53, 62))	('mTOR', 'Gene', (214, 218))	('mTOR', 'Gene', '2475', (214, 218))	('BLCA', 'Phenotype', 'HP:0009725', (93, 97))	('TSC1', 'Gene', '7248', (48, 52))	('AKT', 'Gene', '207', (210, 213))	('response to rapalogues', 'MPA', (67, 89))	('PI3', 'Gene', '5266', (205, 208))	('TSC1', 'Gene', (48, 52))
135865	25349966	The greatest effect was seen after silencing the expression of all three isoforms (Figure 1C), indicating heterogeneous contribution of AKT isoforms to the regulation of cell growth and viability.	('regulation of cell growth', 'biological_process', 'GO:0001558', ('156', '181'))	('AKT', 'Gene', '207', (136, 139))	('silencing', 'Var', (35, 44))	('AKT', 'Gene', (136, 139))
135869	25349966	Although RT4 cells had no detectable phosphorylated AKT, they responded with a similar dephosphorylation of S6K1 upon MK-2206 treatment.	('dephosphorylation', 'MPA', (87, 104))	('AKT', 'Gene', (52, 55))	('MK-2206', 'Chemical', 'MESH:C548887', (118, 125))	('S6K1', 'Gene', '6198', (108, 112))	('MK-2206', 'Var', (118, 125))	('dephosphorylation', 'biological_process', 'GO:0016311', ('87', '104'))	('S6K1', 'Gene', (108, 112))	('AKT', 'Gene', '207', (52, 55))
135870	25349966	Interestingly, none of the cell lines showed an effect on 4E-BP-1 phosphorylation of the amino acid residues Thr 37/46, Ser 65 and Thr 70.	('Thr', 'Chemical', 'MESH:D013912', (131, 134))	('Thr 37/46', 'Var', (109, 118))	('Ser 65', 'Var', (120, 126))	('Ser', 'Chemical', 'MESH:D012694', (120, 123))	('Thr', 'Chemical', 'MESH:D013912', (109, 112))	('Ser', 'cellular_component', 'GO:0005790', ('120', '123'))	('4E-BP-1', 'Gene', (58, 65))	('phosphorylation', 'biological_process', 'GO:0016310', ('66', '81'))	('Thr 70', 'Var', (131, 137))	('4E-BP-1', 'Gene', '1978', (58, 65))
135871	25349966	Although the biochemical data did not differ among the various cell lines, only three cell lines, 253J, HT1197 and VmCUB1, responded with a decrease of 40-60% in viability after MK-2206 treatment (Figure 2B) with an absolute IC50 of 674, 242 and 1469 nM respectively (Figure 2C).	('HT1197', 'CellLine', 'CVCL:1291', (104, 110))	('decrease', 'NegReg', (140, 148))	('MK-2206', 'Var', (178, 185))	('MK-2206', 'Chemical', 'MESH:C548887', (178, 185))	('viability', 'MPA', (162, 171))
135873	25349966	253 J, HT1197 and VmCUB1 cells showed a decrease of 37-48% after MK-2206 treatment but no such decrease was observed in 647V, RT112 and T24 cells (Supplementary Figure 1A).	('HT1197', 'CellLine', 'CVCL:1291', (7, 13))	('MK-2206', 'Var', (65, 72))	('decrease', 'NegReg', (40, 48))	('MK-2206', 'Chemical', 'MESH:C548887', (65, 72))
135887	25349966	Additionally, upon DUSP1 silencing, previously sensitive cells became resistant to MK-2206 treatment (Figure 4B).	('silencing', 'Var', (25, 34))	('DUSP1', 'Gene', (19, 24))	('DUSP1', 'Gene', '1843', (19, 24))	('MK-2206', 'Chemical', 'MESH:C548887', (83, 90))
135892	25349966	Using public databases, we analysed the panel of cell lines used in this study for correlation of alterations in PTEN, PIK3CA, TSC1, RAS and FGFR3 with the response to MK-2206 in order to explain the differential sensitivity to AKT inhibition (Table 1).	('TSC1', 'Gene', '7248', (127, 131))	('PIK3CA', 'Gene', (119, 125))	('AKT', 'Gene', '207', (228, 231))	('FGFR3', 'Gene', '2261', (141, 146))	('PIK3CA', 'Gene', '5290', (119, 125))	('TSC1', 'Gene', (127, 131))	('PTEN', 'Gene', (113, 117))	('AKT', 'Gene', (228, 231))	('PTEN', 'Gene', '5728', (113, 117))	('FGFR3', 'Gene', (141, 146))	('his', 'Chemical', 'MESH:D006639', (69, 72))	('FGFR', 'molecular_function', 'GO:0005007', ('141', '145'))	('alterations', 'Var', (98, 109))	('RAS', 'Gene', (133, 136))	('MK-2206', 'Chemical', 'MESH:C548887', (168, 175))
135893	25349966	All three cell lines sensitive to MK-2206 possess activating hotspot mutations in the helical domain (HD) of the PIK3CA gene that encodes for the p110 alpha subunit of PI3K.	('mutations', 'Var', (69, 78))	('MK-2206', 'Chemical', 'MESH:C548887', (34, 41))	('PIK3CA', 'Gene', (113, 119))	('PI3', 'Gene', '5266', (168, 171))	('PIK3CA', 'Gene', '5290', (113, 119))	('PI3K', 'molecular_function', 'GO:0016303', ('168', '172'))	('HD', 'Disease', 'MESH:D006816', (102, 104))	('activating hotspot', 'PosReg', (50, 68))	('PI3', 'Gene', (168, 171))
135894	25349966	In contrast, mutations in other PIK3CA domains, TSC1, RAS, or alterations in PTEN or FGFR3, did not correlate with sensitivity to MK-2206.	('PIK3CA', 'Gene', '5290', (32, 38))	('FGFR3', 'Gene', (85, 90))	('PTEN', 'Gene', (77, 81))	('MK-2206', 'Chemical', 'MESH:C548887', (130, 137))	('PTEN', 'Gene', '5728', (77, 81))	('TSC1', 'Gene', '7248', (48, 52))	('mutations', 'Var', (13, 22))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('FGFR3', 'Gene', '2261', (85, 90))	('TSC1', 'Gene', (48, 52))	('PIK3CA', 'Gene', (32, 38))
135895	25349966	In order to examine the correlation between mutations in the HD of PIK3CA and response to MK-2206 at a molecular level, we used two different strategies of genetic manipulation.	('PIK3CA', 'Gene', '5290', (67, 73))	('MK-2206', 'Chemical', 'MESH:C548887', (90, 97))	('HD', 'Disease', 'MESH:D006816', (61, 63))	('mutations', 'Var', (44, 53))	('PIK3CA', 'Gene', (67, 73))
135896	25349966	First, we expressed a PIK3CA E545K mutation in 647V, RT112 and T24 cells that are WT for PIK3CA and examined the biochemical and functional response after MK-2206 treatment (Figure 5A).	('PIK3CA', 'Gene', '5290', (22, 28))	('MK-2206', 'Chemical', 'MESH:C548887', (155, 162))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))	('PIK3CA', 'Gene', (22, 28))	('E545K', 'Mutation', 'rs104886003', (29, 34))	('E545K', 'Var', (29, 34))
135897	25349966	Expression of the activating mutation led to an increase in phosphorylated AKT and ERK 1/2 as compared with WT cells (comparing lane 1 and 3), demonstrating that the presence of mutant PIK3CA results not only in hyperphosphorylation of AKT but also in the activation of ERK signalling.	('mutant', 'Var', (178, 184))	('AKT', 'Gene', (236, 239))	('PIK3CA', 'Gene', '5290', (185, 191))	('ERK 1/2', 'Gene', (83, 90))	('ERK', 'Gene', (83, 86))	('presence', 'Var', (166, 174))	('ERK', 'molecular_function', 'GO:0004707', ('270', '273'))	('ERK', 'Gene', '5594', (270, 273))	('activation', 'PosReg', (256, 266))	('AKT', 'Gene', (75, 78))	('hyperphosphorylation', 'biological_process', 'GO:0048151', ('212', '232'))	('AKT', 'Gene', '207', (236, 239))	('ERK', 'Gene', (270, 273))	('signalling', 'biological_process', 'GO:0023052', ('274', '284'))	('PIK3CA', 'Gene', (185, 191))	('ERK 1', 'molecular_function', 'GO:0004707', ('83', '88'))	('ERK 1/2', 'Gene', '5595;5594', (83, 90))	('hyperphosphorylation', 'MPA', (212, 232))	('AKT', 'Gene', '207', (75, 78))	('ERK', 'Gene', '5594', (83, 86))	('phosphorylated', 'MPA', (60, 74))	('increase', 'PosReg', (48, 56))
135898	25349966	After MK-2206 treatment in the presence of the PIK3CA mutation, levels of phosphorylated ERK remained unchanged in 647V cells, whereas RT112 and T24 cells showed a decrease, resembling the observed biochemical response in MK-2206-sensitive PIK3CA mutant cells (as shown in Figure 3).	('mutation', 'Var', (54, 62))	('PIK3CA', 'Gene', (47, 53))	('MK-2206', 'Chemical', 'MESH:C548887', (6, 13))	('PIK3CA', 'Gene', '5290', (47, 53))	('ERK', 'Gene', '5594', (89, 92))	('ERK', 'molecular_function', 'GO:0004707', ('89', '92'))	('PIK3CA', 'Gene', (240, 246))	('decrease', 'NegReg', (164, 172))	('ERK', 'Gene', (89, 92))	('PIK3CA', 'Gene', '5290', (240, 246))	('MK-2206', 'Chemical', 'MESH:C548887', (222, 229))
135899	25349966	Furthermore, the PIK3CA-transfected cells responded to MK-2206 treatment with a 37-68% decrease in cell viability (Figure 5B).	('MK-2206', 'Chemical', 'MESH:C548887', (55, 62))	('PIK3CA', 'Gene', (17, 23))	('MK-2206', 'Var', (55, 62))	('PIK3CA', 'Gene', '5290', (17, 23))	('decrease', 'NegReg', (87, 95))	('cell viability', 'CPA', (99, 113))
135904	25349966	Upon MK-2206 treatment, cells negative for the PIK3CA mutation no longer showed dephosphorylation of ERK 1/2.	('mutation', 'Var', (54, 62))	('PIK3CA', 'Gene', (47, 53))	('ERK 1/2', 'Gene', '5595;5594', (101, 108))	('PIK3CA', 'Gene', '5290', (47, 53))	('ERK 1/2', 'Gene', (101, 108))	('dephosphorylation', 'biological_process', 'GO:0016311', ('80', '97'))	('dephosphorylation', 'MPA', (80, 97))	('ERK 1', 'molecular_function', 'GO:0004707', ('101', '106'))	('MK-2206', 'Chemical', 'MESH:C548887', (5, 12))
135905	25349966	Additionally, previously sensitive cells became resistant to treatment in the absence of the mutant PIK3CA (Figure 6C).	('PIK3CA', 'Gene', '5290', (100, 106))	('mutant', 'Var', (93, 99))	('PIK3CA', 'Gene', (100, 106))
135906	25349966	These observations demonstrate that sensitivity to MK-2206 requires the presence of mutant PIK3CA that regulates a biochemical response mechanism involving ERK 1/2 phosphorylation.	('PIK3CA', 'Gene', (91, 97))	('biochemical response mechanism', 'MPA', (115, 145))	('ERK 1/2', 'Gene', '5595;5594', (156, 163))	('ERK 1', 'molecular_function', 'GO:0004707', ('156', '161'))	('MK-2206', 'Chemical', 'MESH:C548887', (51, 58))	('PIK3CA', 'Gene', '5290', (91, 97))	('ERK 1/2', 'Gene', (156, 163))	('mutant', 'Var', (84, 90))	('regulates', 'Reg', (103, 112))	('phosphorylation', 'biological_process', 'GO:0016310', ('164', '179'))
135910	25349966	Upon treatment, tumour weights were significantly reduced by about 50% in HT1197 cells, whereas RT112 tumours showed no such decrease (Figure 7A).	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', (16, 22))	('HT1197', 'Var', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('tumours', 'Disease', 'MESH:D009369', (102, 109))	('tumour', 'Disease', (102, 108))	('reduced', 'NegReg', (50, 57))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumours', 'Disease', (102, 109))	('HT1197', 'CellLine', 'CVCL:1291', (74, 80))
135911	25349966	MK-2206 induced a decrease in AKT phosphorylation of around 50-70% in both and a reduction of Ki-67 expression by 54% in HT1197 tumours, with no significant change in RT112 tumours (Figure 7B, Supplementary Figure 4B).	('HT1197 tumours', 'Disease', 'MESH:D009369', (121, 135))	('AKT', 'Gene', (30, 33))	('tumours', 'Disease', (128, 135))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('MK-2206', 'Var', (0, 7))	('tumours', 'Disease', 'MESH:D009369', (128, 135))	('MK-2206', 'Chemical', 'MESH:C548887', (0, 7))	('tumours', 'Disease', (173, 180))	('Ki-67', 'Gene', (94, 99))	('AKT', 'Gene', '207', (30, 33))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('reduction', 'NegReg', (81, 90))	('decrease', 'NegReg', (18, 26))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('HT1197 tumours', 'Disease', (121, 135))	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('expression', 'MPA', (100, 110))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))
135912	25349966	We then grafted RT112 cells transfected with a control vector or with PIK3CA E545K and treated the tumours with MK-2206.	('E545K', 'Var', (77, 82))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('PIK3CA', 'Gene', (70, 76))	('tumours', 'Disease', (99, 106))	('MK-2206', 'Chemical', 'MESH:C548887', (112, 119))	('PIK3CA', 'Gene', '5290', (70, 76))	('E545K', 'Mutation', 'rs104886003', (77, 82))
135913	25349966	While tumours containing the control vector did not respond to MK-2206, cells expressing the mutant PIK3CA showed a 56% decrease in weight after treatment (Figure 7C).	('weight', 'MPA', (132, 138))	('MK-2206', 'Chemical', 'MESH:C548887', (63, 70))	('decrease in weight', 'Phenotype', 'HP:0004325', (120, 138))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('decrease', 'NegReg', (120, 128))	('PIK3CA', 'Gene', (100, 106))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('mutant', 'Var', (93, 99))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('PIK3CA', 'Gene', '5290', (100, 106))	('tumours', 'Disease', (6, 13))
135914	25349966	While MK-2206 induced a decrease in AKT phosphorylation of around 80% in both, Ki-67 expression was significantly reduced by 55% only in cells containing PIK3CA E545K (Supplementary Figure 4C).	('MK-2206', 'Var', (6, 13))	('expression', 'MPA', (85, 95))	('Ki-67', 'Gene', (79, 84))	('PIK3CA', 'Gene', (154, 160))	('MK-2206', 'Chemical', 'MESH:C548887', (6, 13))	('E545K', 'Mutation', 'rs104886003', (161, 166))	('E545K', 'Var', (161, 166))	('AKT', 'Gene', '207', (36, 39))	('reduced', 'NegReg', (114, 121))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('PIK3CA', 'Gene', '5290', (154, 160))	('decrease', 'NegReg', (24, 32))	('AKT', 'Gene', (36, 39))
135916	25349966	We first demonstrated in a panel of 11 cell lines with characterised genomic alterations that all AKT isoforms are expressed and that they contribute heterogeneously to active phosphorylated AKT.	('AKT', 'Gene', '207', (191, 194))	('heterogeneously', 'MPA', (150, 165))	('active phosphorylated', 'MPA', (169, 190))	('AKT', 'Gene', '207', (98, 101))	('alterations', 'Var', (77, 88))	('AKT', 'Gene', (191, 194))	('AKT', 'Gene', (98, 101))	('contribute', 'Reg', (139, 149))
135920	25349966	Upon treatment with MK-2206, decreased phosphorylation of AKT and its downstream mTOR substrate S6K1 could be observed.	('phosphorylation', 'MPA', (39, 54))	('MK-2206', 'Chemical', 'MESH:C548887', (20, 27))	('MK-2206', 'Var', (20, 27))	('S6K1', 'Gene', (96, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('S6K1', 'Gene', '6198', (96, 100))	('AKT', 'Gene', '207', (58, 61))	('decreased', 'NegReg', (29, 38))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))	('AKT', 'Gene', (58, 61))
135922	25349966	We have previously shown that rapalogues (RAD001, CCI-779) or shRNA-mediated silencing of mTOR affects only the phosphorylation of S6K1 and not 4E-BP1 in BLCA.	('phosphorylation', 'MPA', (112, 127))	('mTOR', 'Gene', (90, 94))	('mTOR', 'Gene', '2475', (90, 94))	('4E-BP1', 'Gene', '1978', (144, 150))	('affects', 'Reg', (95, 102))	('BLCA', 'Phenotype', 'HP:0009725', (154, 158))	('silencing', 'Var', (77, 86))	('S6K1', 'Gene', (131, 135))	('S6K1', 'Gene', '6198', (131, 135))	('RAD', 'biological_process', 'GO:1990116', ('42', '45'))	('4E-BP1', 'Gene', (144, 150))	('phosphorylation', 'biological_process', 'GO:0016310', ('112', '127'))
135923	25349966	However, dual PI3K inhibitors such as NVP-BEZ235 did result in dephosphorylation of both S6K1 and 4E-BP1.	('dephosphorylation', 'MPA', (63, 80))	('BEZ235', 'Chemical', 'MESH:C531198', (42, 48))	('S6K1 and 4E-BP1', 'Gene', '6198;1978', (89, 104))	('dephosphorylation', 'biological_process', 'GO:0016311', ('63', '80'))	('PI3K', 'molecular_function', 'GO:0016303', ('14', '18'))	('PI3', 'Gene', '5266', (14, 17))	('PI3', 'Gene', (14, 17))	('NVP-BEZ235', 'Var', (38, 48))
135927	25349966	On a functional level, despite successful downregulation of AKT phosphorylation, MK-2206 treatment inhibited cell viability only in cell lines possessing mutations in the HD of PIK3CA that result in constitutive activation of PI3K.	('PIK3CA', 'Gene', '5290', (177, 183))	('phosphorylation', 'biological_process', 'GO:0016310', ('64', '79'))	('inhibited', 'NegReg', (99, 108))	('AKT', 'Gene', '207', (60, 63))	('PI3K', 'molecular_function', 'GO:0016303', ('226', '230'))	('PI3', 'Gene', '5266', (226, 229))	('downregulation', 'NegReg', (42, 56))	('PI3', 'Gene', (226, 229))	('mutations', 'Var', (154, 163))	('MK-2206', 'Chemical', 'MESH:C548887', (81, 88))	('PIK3CA', 'Gene', (177, 183))	('HD', 'Disease', 'MESH:D006816', (171, 173))	('activation', 'PosReg', (212, 222))	('AKT', 'Gene', (60, 63))	('cell viability', 'CPA', (109, 123))
135928	25349966	Mutations found in non-hotspot regions of the HD result in AKT activation to a lesser degree and were not associated with sensitivity to MK-2206 in our panel of cell lines (Table 1).	('AKT', 'Gene', (59, 62))	('HD', 'Disease', 'MESH:D006816', (46, 48))	('Mutations', 'Var', (0, 9))	('AKT', 'Gene', '207', (59, 62))	('MK-2206', 'Chemical', 'MESH:C548887', (137, 144))	('activation', 'PosReg', (63, 73))
135929	25349966	Bladder cancer possesses a different spectrum of PIK3CA mutations compared with other tumour entities, with about 80% occurring in hotspot regions of the HD.	('tumour entities', 'Disease', 'MESH:D009369', (86, 101))	('mutations', 'Var', (56, 65))	('Bladder cancer', 'Disease', (0, 14))	('tumour entities', 'Disease', (86, 101))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('HD', 'Disease', 'MESH:D006816', (154, 156))	('Bladder cancer', 'Disease', 'MESH:D001749', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('PIK3CA', 'Gene', (49, 55))	('PIK3CA', 'Gene', '5290', (49, 55))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('occurring', 'Reg', (118, 127))
135930	25349966	Around 15-20% of BLCA patients are predicted to bear these mutations and thus have the potential to benefit from AKT target therapy.	('benefit', 'PosReg', (100, 107))	('BLCA', 'Phenotype', 'HP:0009725', (17, 21))	('BLCA', 'Disease', (17, 21))	('AKT', 'Gene', '207', (113, 116))	('patients', 'Species', '9606', (22, 30))	('mutations', 'Var', (59, 68))	('AKT', 'Gene', (113, 116))
135931	25349966	Representative sensitive and resistant cell lines showed a modest decrease in cell cycle progression after MK-2206 treatment, as described previously for breast cancer and T-cell leukaemia.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('T-cell leukaemia', 'Disease', (172, 188))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('T-cell leukaemia', 'Disease', 'MESH:D015458', (172, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('MK-2206', 'Chemical', 'MESH:C548887', (107, 114))	('cell cycle', 'biological_process', 'GO:0007049', ('78', '88'))	('MK-2206', 'Var', (107, 114))	('decrease', 'NegReg', (66, 74))	('cell cycle progression', 'CPA', (78, 100))
135933	25349966	The association between sensitivity to AKT inhibition and specific PIK3CA mutations has also been observed in thyroid and breast cancer.	('PIK3CA', 'Gene', '5290', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('mutations', 'Var', (74, 83))	('AKT', 'Gene', '207', (39, 42))	('thyroid', 'Disease', (110, 117))	('observed', 'Reg', (98, 106))	('AKT', 'Gene', (39, 42))	('PIK3CA', 'Gene', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
135934	25349966	However, in these studies, sensitivity also correlated with PTEN and in thyroid cancer also with RAS mutations.	('thyroid cancer', 'Phenotype', 'HP:0002890', (72, 86))	('mutations', 'Var', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('sensitivity', 'MPA', (27, 38))	('thyroid cancer', 'Disease', 'MESH:D013964', (72, 86))	('correlated', 'Reg', (44, 54))	('RAS', 'Gene', (97, 100))	('PTEN', 'Gene', (60, 64))	('PTEN', 'Gene', '5728', (60, 64))	('thyroid cancer', 'Disease', (72, 86))
135939	25349966	In this study, no clear predictable pattern of associations between the presence of alterations in PIK3CA and the sensitivity to AKT inhibition was observed, although cells possessing mutant PIK3CA did respond with a lower IC50 for growth inhibition.	('PIK3CA', 'Gene', '5290', (191, 197))	('lower', 'NegReg', (217, 222))	('mutant', 'Var', (184, 190))	('PIK3CA', 'Gene', '5290', (99, 105))	('AKT', 'Gene', '207', (129, 132))	('his', 'Chemical', 'MESH:D006639', (4, 7))	('PIK3CA', 'Gene', (191, 197))	('AKT', 'Gene', (129, 132))	('IC50 for growth inhibition', 'MPA', (223, 249))	('PIK3CA', 'Gene', (99, 105))
135942	25349966	Mutations in PIK3CA or AKT1 correlated with sensitivity to the drug, whereas PTEN and TSC1 alterations did not.	('TSC1', 'Gene', (86, 90))	('AKT1', 'Gene', (23, 27))	('PIK3CA', 'Gene', (13, 19))	('PTEN', 'Gene', (77, 81))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', '5290', (13, 19))	('PTEN', 'Gene', '5728', (77, 81))	('AKT1', 'Gene', '207', (23, 27))	('sensitivity to the drug', 'MPA', (44, 67))	('TSC1', 'Gene', '7248', (86, 90))	('correlated', 'Reg', (28, 38))
135945	25349966	Upon treatment with MK-2206, activation of the MAPK signalling pathway by an increase in Raf-1 phosphorylation was observed in both WT and mutant PIK3CA expressing cells.	('MAPK', 'Gene', (47, 51))	('activation', 'PosReg', (29, 39))	('MK-2206', 'Chemical', 'MESH:C548887', (20, 27))	('PIK3CA', 'Gene', '5290', (146, 152))	('signalling pathway', 'biological_process', 'GO:0007165', ('52', '70'))	('MK-2206', 'Var', (20, 27))	('MAPK', 'molecular_function', 'GO:0004707', ('47', '51'))	('mutant', 'Var', (139, 145))	('phosphorylation', 'biological_process', 'GO:0016310', ('95', '110'))	('MAPK signalling', 'biological_process', 'GO:0000165', ('47', '62'))	('Raf-1', 'Gene', (89, 94))	('increase', 'PosReg', (77, 85))	('PIK3CA', 'Gene', (146, 152))	('Raf-1', 'Gene', '5894', (89, 94))	('phosphorylation', 'MPA', (95, 110))	('MAPK', 'Gene', '5595;5594;5595', (47, 51))
135947	25349966	Also, introduction of the mutant PIK3CA E545K resulted in an increase in ERK phosphorylation confirming a recent study that demonstrated crosstalk between PI3K and MAPK signalling.	('PI3', 'Gene', (155, 158))	('E545K', 'Mutation', 'rs104886003', (40, 45))	('E545K', 'Var', (40, 45))	('PIK3CA', 'Gene', '5290', (33, 39))	('ERK', 'molecular_function', 'GO:0004707', ('73', '76'))	('MAPK', 'Gene', (164, 168))	('ERK', 'Gene', (73, 76))	('MAPK', 'Gene', '5595;5594;5595', (164, 168))	('PI3K', 'molecular_function', 'GO:0016303', ('155', '159'))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('PI3', 'Gene', '5266', (155, 158))	('increase', 'PosReg', (61, 69))	('MAPK signalling', 'biological_process', 'GO:0000165', ('164', '179'))	('PIK3CA', 'Gene', (33, 39))	('MAPK', 'molecular_function', 'GO:0004707', ('164', '168'))	('ERK', 'Gene', '5594', (73, 76))
135948	25349966	However, we show here that expression of PIK3CA E545K has a regulatory role in DUSP1 expression.	('expression', 'MPA', (85, 95))	('DUSP1', 'Gene', '1843', (79, 84))	('regulatory', 'MPA', (60, 70))	('PIK3CA', 'Gene', (41, 47))	('E545K', 'Mutation', 'rs104886003', (48, 53))	('E545K', 'Var', (48, 53))	('PIK3CA', 'Gene', '5290', (41, 47))	('DUSP1', 'Gene', (79, 84))
135949	25349966	Inhibition of AKT in this situation results in a downregulation of ERK 1/2 and subsequently induces apoptosis.	('ERK 1/2', 'Gene', '5595;5594', (67, 74))	('ERK 1/2', 'Gene', (67, 74))	('induces', 'Reg', (92, 99))	('AKT', 'Gene', (14, 17))	('his', 'Chemical', 'MESH:D006639', (22, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('ERK 1', 'molecular_function', 'GO:0004707', ('67', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('downregulation', 'NegReg', (49, 63))	('Inhibition', 'Var', (0, 10))	('AKT', 'Gene', '207', (14, 17))
135952	25349966	It remains to be examined whether AKT inhibition in the presence of mutant PIK3CA influences DUSP1 expression due to hyperactivation of the PI3K or MAPK signalling pathway or due to other properties of the mutant such as protein complex formation.	('influences', 'Reg', (82, 92))	('expression', 'MPA', (99, 109))	('AKT', 'Gene', '207', (34, 37))	('inhibition', 'NegReg', (38, 48))	('PI3', 'Gene', (140, 143))	('PIK3CA', 'Gene', (75, 81))	('DUSP1', 'Gene', (93, 98))	('protein complex', 'cellular_component', 'GO:0032991', ('221', '236'))	('protein complex formation', 'biological_process', 'GO:0065003', ('221', '246'))	('MAPK signalling', 'biological_process', 'GO:0000165', ('148', '163'))	('MAPK', 'Gene', '5595;5594;5595', (148, 152))	('signalling pathway', 'biological_process', 'GO:0007165', ('153', '171'))	('PI3K', 'molecular_function', 'GO:0016303', ('140', '144'))	('AKT', 'Gene', (34, 37))	('hyperactivation', 'PosReg', (117, 132))	('MAPK', 'molecular_function', 'GO:0004707', ('148', '152'))	('PIK3CA', 'Gene', '5290', (75, 81))	('DUSP1', 'Gene', '1843', (93, 98))	('PI3', 'Gene', '5266', (140, 143))	('MAPK', 'Gene', (148, 152))	('mutant', 'Var', (68, 74))
135955	25349966	The interplay between mutant PIK3CA, DUSP1, ERK phosphorylation and AKT inhibition demonstrates the complexity in cell signalling involving a non-linear signalling cascade and crosstalk between the PI3K and MAPK pathways, which ultimately influences therapy response.	('MAPK', 'molecular_function', 'GO:0004707', ('207', '211'))	('ERK', 'Gene', (44, 47))	('MAPK', 'Gene', '5595;5594;5595', (207, 211))	('PI3K', 'molecular_function', 'GO:0016303', ('198', '202'))	('influences', 'Reg', (239, 249))	('signalling', 'biological_process', 'GO:0023052', ('119', '129'))	('signalling cascade', 'biological_process', 'GO:0007165', ('153', '171'))	('DUSP1', 'Gene', (37, 42))	('crosstalk', 'Reg', (176, 185))	('MAPK', 'Gene', (207, 211))	('PIK3CA', 'Gene', '5290', (29, 35))	('AKT', 'Gene', (68, 71))	('PI3', 'Gene', '5266', (198, 201))	('ERK', 'molecular_function', 'GO:0004707', ('44', '47'))	('mutant', 'Var', (22, 28))	('ERK', 'Gene', '5594', (44, 47))	('PI3', 'Gene', (198, 201))	('AKT', 'Gene', '207', (68, 71))	('PIK3CA', 'Gene', (29, 35))	('DUSP1', 'Gene', '1843', (37, 42))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))
135958	25349966	In BLCA, a disease for which target therapy is still in early stages of development, our data suggest that AKT therapy can benefit patients possessing hotspot HD PIK3CA mutations.	('patients', 'Species', '9606', (131, 139))	('HD', 'Disease', 'MESH:D006816', (159, 161))	('benefit', 'PosReg', (123, 130))	('PIK3CA', 'Gene', '5290', (162, 168))	('AKT', 'Gene', '207', (107, 110))	('mutations', 'Var', (169, 178))	('AKT', 'Gene', (107, 110))	('BLCA', 'Phenotype', 'HP:0009725', (3, 7))	('BLCA', 'Disease', (3, 7))	('PIK3CA', 'Gene', (162, 168))
135966	24871328	The overarching goal is to elucidate the landscape of DNA and RNA aberrations within and across tumor lineages and integrate the information with clinical characteristics, including patient outcome.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('clinical', 'Species', '191496', (146, 154))	('patient', 'Species', '9606', (182, 189))	('tumor', 'Disease', (96, 101))	('RNA', 'Gene', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('DNA', 'Gene', (54, 57))	('RNA', 'cellular_component', 'GO:0005562', ('62', '65'))	('aberrations', 'Var', (66, 77))
135990	24871328	Besides diversity in methodology, a number of cancer specific hypotheses, including post-translational regulation of HER2 expression, cytoplasmic HER2 localization, intratumoral heterogeneity of HER2 amplification or polysomy 17 have been suggested.	('localization', 'biological_process', 'GO:0051179', ('151', '163'))	('HER2', 'Gene', (117, 121))	('amplification', 'Var', (200, 213))	('HER2', 'Gene', '2064', (146, 150))	('polysomy 17', 'Var', (217, 228))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('HER2', 'Gene', '2064', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('cancer', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('HER2', 'Gene', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('HER2', 'Gene', '2064', (195, 199))	('HER2', 'Gene', (146, 150))	('regulation', 'biological_process', 'GO:0065007', ('103', '113'))
135992	24871328	With the advent of TDM1 toxin conjugate therapy (trastuzumab emtansine), the higher frequency of elevated HER2 protein levels in BLCA, LUAD, endometrial, and colorectal cancers supports the (pre)clinical exploration of TDM1, which binds HER2 to deliver a potent cell-cycle toxin (a mechanism of activity independent from trastuzumab, a drug with limited activity in endometrial cancer in previous studies) in these tumor lineages.	('colorectal cancer', 'Phenotype', 'HP:0003003', (158, 175))	('cell-cycle', 'biological_process', 'GO:0007049', ('262', '272'))	('endometrial cancer', 'Disease', 'MESH:D016889', (366, 384))	('colorectal cancers', 'Disease', (158, 176))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('TDM1', 'Var', (219, 223))	('pre', 'molecular_function', 'GO:0003904', ('191', '194'))	('tumor', 'Disease', (415, 420))	('HER2', 'Gene', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (415, 420))	('trastuzumab', 'Chemical', 'MESH:D000068878', (321, 332))	('elevated', 'PosReg', (97, 105))	('colorectal cancers', 'Disease', 'MESH:D015179', (158, 176))	('HER2', 'Gene', '2064', (237, 241))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('tumor', 'Phenotype', 'HP:0002664', (415, 420))	('clinical', 'Species', '191496', (195, 203))	('endometrial cancer', 'Phenotype', 'HP:0012114', (366, 384))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('trastuzumab', 'Chemical', 'MESH:D000068878', (49, 60))	('HER2', 'Gene', '2064', (106, 110))	('endometrial cancer', 'Disease', (366, 384))	('HER2', 'Gene', (237, 241))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
135995	24871328	Associations of specific mutations and copy number changes with the clusters were primarily based on known associations of mutations and copy number changes with tumor lineage.	('mutations', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Associations', 'Interaction', (0, 12))	('tumor', 'Disease', (162, 167))	('copy number', 'Var', (39, 50))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
135996	24871328	Cluster_E includes 70% of basal-like breast cancers, the majority of HER2 positive breast cancers (87%) and the largest group of bladder cancers (35%), including many with amplified HER2 (Fig.	('breast cancers', 'Disease', (37, 51))	('amplified', 'Var', (172, 181))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancers', 'Disease', 'MESH:D001943', (83, 97))	('breast cancers', 'Disease', (83, 97))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('breast cancers', 'Phenotype', 'HP:0003002', (37, 51))	('bladder cancers', 'Phenotype', 'HP:0009725', (129, 144))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('breast cancers', 'Phenotype', 'HP:0003002', (83, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('HER2', 'Gene', '2064', (69, 73))	('HER2', 'Gene', '2064', (182, 186))	('bladder cancers', 'Disease', 'MESH:D001749', (129, 144))	('bladder cancers', 'Disease', (129, 144))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('HER2', 'Gene', (69, 73))	('HER2', 'Gene', (182, 186))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('breast cancers', 'Disease', 'MESH:D001943', (37, 51))
135997	24871328	Cluster_E is defined by TP53 mutations, elevated HER2, cyclinB1 and Rab25 protein levels and low ER and PR levels (Supplementary Table 2).	('cyclinB1', 'Gene', (55, 63))	('cyclinB1', 'Gene', '891', (55, 63))	('TP53', 'Gene', (24, 28))	('elevated', 'PosReg', (40, 48))	('mutations', 'Var', (29, 38))	('HER2', 'Gene', '2064', (49, 53))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('Rab25', 'Gene', '57111', (68, 73))	('HER2', 'Gene', (49, 53))	('low', 'NegReg', (93, 96))	('Rab25', 'Gene', (68, 73))	('TP53', 'Gene', '7157', (24, 28))
136001	24871328	Membership in cluster_F is associated with TP53 mutations and elevated total and phosphorylated EGFR (EGFRp1068 and EGFRp1173), phosphorylated SRC (SRCpY527) and low ER and PR levels.	('EGFR', 'Protein', (96, 100))	('EGFRp1173', 'Var', (116, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('elevated', 'PosReg', (62, 70))	('mutations', 'Var', (48, 57))	('low', 'NegReg', (162, 165))
136002	24871328	Although TP53 mutations are usually associated with copy number changes and a limited number of recurrent mutations in cancer genes, cluster_F is unexpectedly enriched in recurrent cancer gene mutations (Supplementary Table 6).	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('TP53', 'Gene', '7157', (9, 13))	('mutations', 'Var', (193, 202))	('TP53', 'Gene', (9, 13))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('associated', 'Reg', (36, 46))	('mutations', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
136003	24871328	3), tumors with TP53 mutations show significantly higher rates of co-mutations in the top-25 driver mutations (Methods, P<0.0001, t-test, n=162).	('higher', 'PosReg', (50, 56))	('tumors', 'Disease', (4, 10))	('co-mutations', 'MPA', (66, 78))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('TP53', 'Gene', '7157', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
136010	24871328	2d) may be due to the absence of VHL mutations (Fisher's exact test (FE), P = 0.008, n=454), which has been associated with a worse outcome in kidney cancer.	('absence', 'NegReg', (22, 29))	('kidney cancer', 'Disease', (143, 156))	('VHL', 'Gene', (33, 36))	('mutations', 'Var', (37, 46))	('VHL', 'Gene', '7428', (33, 36))	('kidney cancer', 'Disease', 'MESH:D007680', (143, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('kidney cancer', 'Phenotype', 'HP:0009726', (143, 156))
136011	24871328	Bladder cancers in cluster_B show worse survival compared to all other BLCA, which may be due to associations with TP53 mutation (FE, P<0.001) and cMYC amplification (FE, P = 0.042) (n=127) (Fig.	('cMYC', 'Gene', (147, 151))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('Bladder cancers', 'Phenotype', 'HP:0009725', (0, 15))	('worse', 'NegReg', (34, 39))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('cMYC', 'Gene', '4609', (147, 151))	('TP53', 'Gene', '7157', (115, 119))	('mutation', 'Var', (120, 128))	('associations', 'Interaction', (97, 109))	('survival', 'MPA', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('TP53', 'Gene', (115, 119))	('Bladder cancers', 'Disease', (0, 15))	('Bladder cancers', 'Disease', 'MESH:D001749', (0, 15))
136017	24871328	Cluster_I was primarily driven by phosphoPEA15, YB1, EEF2 and ETS1 proteins (Supplementary Table 9), which were markedly elevated in a subset of colorectal tumors (18%).	('EEF2', 'Gene', (53, 57))	('colorectal tumors', 'Disease', 'MESH:D015179', (145, 162))	('ETS1', 'Gene', '2113', (62, 66))	('ETS1', 'Gene', (62, 66))	('YB1', 'Gene', (48, 51))	('phosphoPEA15', 'Var', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('colorectal tumors', 'Disease', (145, 162))	('YB1', 'Gene', '4904', (48, 51))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('EEF2', 'Gene', '1938', (53, 57))	('elevated', 'PosReg', (121, 129))
136022	24871328	Tumors in cluster_IIb were enriched in EGFR mutations, contained few PTEN mutations, and had elevated RTK pathway and suppressed mTOR pathway signatures.	('RTK pathway', 'Pathway', (102, 113))	('PTEN', 'Gene', '5728', (69, 73))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('suppressed', 'NegReg', (118, 128))	('mTOR', 'Gene', '2475', (129, 133))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('mTOR', 'Gene', (129, 133))	('mutations', 'Var', (44, 53))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('EGFR', 'Gene', (39, 43))	('elevated', 'PosReg', (93, 101))	('PTEN', 'Gene', (69, 73))
136028	24871328	Cluster_III also had high beta-catenin levels, suggesting activation of the canonical Wnt-signaling pathway.	('beta-catenin', 'Gene', '1499', (26, 38))	('Cluster_III', 'Var', (0, 11))	('canonical Wnt-signaling pathway', 'Pathway', (76, 107))	('high', 'PosReg', (21, 25))	('beta-catenin', 'Gene', (26, 38))	('activation', 'PosReg', (58, 68))	('canonical Wnt-signaling pathway', 'biological_process', 'GO:0060070', ('76', '107'))
136029	24871328	Cluster_IV also had high beta-catenin, as well as activated AKT, MAPK and mTOR pathways, but suppressed DNA damage, apoptosis, EMT and cell cycle pathways.	('beta-catenin', 'Gene', '1499', (25, 37))	('mTOR', 'Gene', (74, 78))	('DNA', 'MPA', (104, 107))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('EMT', 'biological_process', 'GO:0001837', ('127', '130'))	('activated', 'PosReg', (50, 59))	('apoptosis', 'CPA', (116, 125))	('mTOR', 'Gene', '2475', (74, 78))	('Cluster_IV', 'Var', (0, 10))	('AKT', 'Gene', (60, 63))	('EMT', 'Gene', (127, 130))	('EMT', 'Gene', '3702', (127, 130))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('cell cycle', 'biological_process', 'GO:0007049', ('135', '145'))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('suppressed', 'NegReg', (93, 103))	('AKT', 'Gene', '207', (60, 63))	('high', 'PosReg', (20, 24))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('beta-catenin', 'Gene', (25, 37))	('MAPK', 'Pathway', (65, 69))	('cell cycle pathways', 'CPA', (135, 154))
136035	24871328	COAD in cluster_V had better outcome compared to COAD located in other clusters (Fig.	('COAD', 'Disease', (0, 4))	('cluster_V', 'Var', (8, 17))	('COAD', 'Disease', (49, 53))	('COAD', 'Disease', 'MESH:D029424', (0, 4))	('COAD', 'Disease', 'MESH:D029424', (49, 53))
136036	24871328	3g) (n=334), which may, in part, be due to depletion of mutations in TP53 (6% vs. 15%, Fisher's Exact (FE) P = 0.05), APC (14% vs. 25%, FE P = 0.044) and KRAS (5% vs. 16%, FE P = 0.013), consistent with previous literature showing these are associated with a worse outcome.	('KRAS', 'Gene', '3845', (154, 158))	('mutations', 'Var', (56, 65))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('depletion', 'MPA', (43, 52))	('APC', 'cellular_component', 'GO:0005680', ('118', '121'))	('APC', 'Disease', 'MESH:D011125', (118, 121))	('APC', 'Disease', (118, 121))	('KRAS', 'Gene', (154, 158))
136037	24871328	The poor outcome for KIRC in cluster_VII may be partly due to enrichment of TP53 mutations (6% vs. 0.8%, FE P = 0.005, n=454) (Fig.	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))
136041	24871328	In general in the RBN analysis, pathway scores were associated with tumor lineage (Fig.	('tumor', 'Disease', (68, 73))	('associated', 'Reg', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('pathway scores', 'Var', (32, 46))
136072	24871328	PhosphoSRC (SRCpY416) and the transferrin receptor (TFRC) showed an association in three diseases suggesting particular importance for outcome.	('transferrin receptor', 'Gene', '7037', (30, 50))	('association', 'Interaction', (68, 79))	('TFRC', 'Gene', '7037', (52, 56))	('PhosphoSRC (SRCpY416', 'Var', (0, 20))	('TFRC', 'Gene', (52, 56))	('transferrin receptor', 'Gene', (30, 50))	('three diseases', 'Disease', (83, 97))
136078	24871328	Other expected links were seen in only a subset of tumors such as pAKT with pPRAS40 and pTSC2 (tuberinPT1462), consistent with differential wiring of signaling pathways in different cancers.	('AKT', 'Gene', '207', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('TSC', 'Gene', (89, 92))	('TSC', 'Gene', '7248', (89, 92))	('AKT', 'Gene', (67, 70))	('pPRAS40', 'Var', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('signaling', 'biological_process', 'GO:0023052', ('150', '159'))
136104	24871328	This mainly concerns EGFRpY1068 (but not EGFRpY1173), which cross-reacts with overexpressed HER2pY1248.	('EGFRpY1068', 'Var', (21, 31))	('HER2', 'Gene', '2064', (92, 96))	('HER2', 'Gene', (92, 96))
136120	24871328	We therefore compared samples in which HER2 was amplified vs. not amplified, aiming to find a threshold that might be reasonable to test.	('HER2', 'Gene', '2064', (39, 43))	('amplified', 'Var', (48, 57))	('HER2', 'Gene', (39, 43))
136128	24871328	Significantly mutated genes (present in more than 5% of tumors in the dataset, resulting in 16 genes) are included as are the two most frequently observed amplifications.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mutated', 'Var', (14, 21))	('tumors', 'Disease', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))
136157	33461172	Dysregulation of USP18/FTO/PYCR1 signaling network promotes bladder cancer development and progression N6-methyladenosine refers to a methylation of adenosine base at the 6th nitrogen position, which is the dominant methylation modification in both message and non-coding RNAs.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('Dysregulation', 'Var', (0, 13))	('USP', 'molecular_function', 'GO:0051748', ('17', '20'))	('nitrogen', 'Chemical', 'MESH:D009584', (175, 183))	('signaling', 'biological_process', 'GO:0023052', ('33', '42'))	('promotes', 'PosReg', (51, 59))	('methylation', 'biological_process', 'GO:0032259', ('134', '145'))	('USP18', 'Gene', '11274', (17, 22))	('adenosine', 'Chemical', 'MESH:D000241', (112, 121))	('USP18', 'Gene', (17, 22))	('PYCR1', 'Gene', (27, 32))	('PYCR1', 'Gene', '5831', (27, 32))	('FTO', 'Gene', '79068', (23, 26))	('FTO', 'Gene', (23, 26))	('adenosine', 'Chemical', 'MESH:D000241', (149, 158))	('bladder cancer', 'Disease', 'MESH:D001749', (60, 74))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (103, 121))	('methylation', 'biological_process', 'GO:0032259', ('216', '227'))	('bladder cancer', 'Disease', (60, 74))	('N6-methyladenosine', 'Var', (103, 121))
136158	33461172	Dysregulation of RNA m6A methylation causes tumorigenesis in humans.	('m6A', 'Chemical', '-', (21, 24))	('Dysregulation', 'Var', (0, 13))	('RNA', 'cellular_component', 'GO:0005562', ('17', '20'))	('humans', 'Species', '9606', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('methylation', 'Var', (25, 36))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('RNA m6A', 'Gene', (17, 24))	('causes', 'Reg', (37, 43))	('tumor', 'Disease', (44, 49))
136159	33461172	The key N6-methyladenosine demethylase fat-mass and obesity-associated protein (FTO) is negatively correlated with the overall survival of bladder cancer patients, but the underlying mechanism remains poorly understood.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('correlated with', 'Reg', (99, 114))	('bladder cancer', 'Disease', 'MESH:D001749', (139, 153))	('obesity', 'Disease', (52, 59))	('bladder cancer', 'Disease', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('patients', 'Species', '9606', (154, 162))	('negatively', 'NegReg', (88, 98))	('obesity', 'Phenotype', 'HP:0001513', (52, 59))	('demethylase', 'Gene', (27, 38))	('obesity', 'Disease', 'MESH:D009765', (52, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (139, 153))	('demethylase', 'Gene', '8932', (27, 38))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (8, 26))	('N6-methyladenosine', 'Var', (8, 26))
136161	33461172	As a result, FTO decreased N6-methyladenosine methylation level in PYCR1 through its demethylase enzymatic activity and stabilized PYCR1 transcript to promote bladder cancer initiation and progression.	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('demethylase', 'Gene', (85, 96))	('decreased', 'NegReg', (17, 26))	('bladder cancer initiation', 'Disease', 'MESH:D001749', (159, 184))	('PYCR1', 'Gene', '5831', (67, 72))	('FTO', 'Var', (13, 16))	('PYCR1', 'Gene', '5831', (131, 136))	('demethylase', 'Gene', '8932', (85, 96))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (27, 45))	('PYCR1', 'Gene', (131, 136))	('bladder cancer', 'Phenotype', 'HP:0009725', (159, 173))	('progression', 'CPA', (189, 200))	('promote', 'PosReg', (151, 158))	('N6-methyladenosine methylation level', 'MPA', (27, 63))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('bladder cancer initiation', 'Disease', (159, 184))	('PYCR1', 'Gene', (67, 72))
136162	33461172	Our work shows the importance of N6-methyladenosine RNA modification in bladder cancer development, and highlights UPS18/FTO/PYCR1 signaling network as potential therapeutic targets of bladder cancer.	('N6-methyladenosine', 'Var', (33, 51))	('bladder cancer', 'Phenotype', 'HP:0009725', (185, 199))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('RNA modification', 'biological_process', 'GO:0009451', ('52', '68'))	('PYCR1', 'Gene', (125, 130))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('PYCR1', 'Gene', '5831', (125, 130))	('bladder cancer', 'Disease', 'MESH:D001749', (185, 199))	('bladder cancer', 'Disease', (185, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('bladder cancer', 'Disease', 'MESH:D001749', (72, 86))	('bladder cancer', 'Disease', (72, 86))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (33, 51))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))
136164	33461172	Similar to DNA and histone methylation, RNA m6A methylation is a dynamic and reversible epi-regulation.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('regulation', 'biological_process', 'GO:0065007', ('92', '102'))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('RNA m6A', 'Gene', (40, 47))	('m6A', 'Chemical', '-', (44, 47))	('methylation', 'Var', (48, 59))	('histone methylation', 'biological_process', 'GO:0016571', ('19', '38'))
136170	33461172	Unlike epigenetic modifications of DNA and histones, which play critical roles in transcription, RNA m6A methylation mainly regulates gene expression at the post-transcriptional level.	('methylation', 'Var', (105, 116))	('gene expression', 'MPA', (134, 149))	('RNA m6A', 'Gene', (97, 104))	('methylation', 'biological_process', 'GO:0032259', ('105', '116'))	('m6A', 'Chemical', '-', (101, 104))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('transcription', 'biological_process', 'GO:0006351', ('82', '95'))	('RNA', 'cellular_component', 'GO:0005562', ('97', '100'))	('regulates', 'Reg', (124, 133))	('gene expression', 'biological_process', 'GO:0010467', ('134', '149'))
136171	33461172	Because it accounts for over 80% of all RNA methylation, m6A RNA methylation is important in regulating stress reaction, cell proliferation, stem cell differentiation, immunity, inflammation and development and so on.	('m6A', 'Chemical', '-', (57, 60))	('RNA methylation', 'biological_process', 'GO:0001510', ('40', '55'))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('cell proliferation', 'biological_process', 'GO:0008283', ('121', '139'))	('inflammation', 'biological_process', 'GO:0006954', ('178', '190'))	('important', 'Reg', (80, 89))	('stem cell differentiation', 'biological_process', 'GO:0048863', ('141', '166'))	('RNA methylation', 'biological_process', 'GO:0001510', ('61', '76'))	('inflammation', 'Disease', 'MESH:D007249', (178, 190))	('m6A', 'Var', (57, 60))	('inflammation', 'Disease', (178, 190))	('RNA', 'cellular_component', 'GO:0005562', ('61', '64'))
136172	33461172	Aberrant changes in the expression of writers and/or erasers of m6A methylation cause diseases such as diabetes, obesity, neurodegeneration and cancer.	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('expression', 'MPA', (24, 34))	('methylation', 'Var', (68, 79))	('obesity', 'Disease', 'MESH:D009765', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('diabetes', 'Disease', (103, 111))	('neurodegeneration', 'Phenotype', 'HP:0002180', (122, 139))	('obesity', 'Disease', (113, 120))	('cancer', 'Disease', (144, 150))	('diabetes', 'Disease', 'MESH:D003920', (103, 111))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('m6A', 'Gene', (64, 67))	('Aberrant changes', 'Var', (0, 16))	('neurodegeneration', 'Disease', (122, 139))	('cause', 'Reg', (80, 85))	('neurodegeneration', 'Disease', 'MESH:D019636', (122, 139))	('obesity', 'Phenotype', 'HP:0001513', (113, 120))	('m6A', 'Chemical', '-', (64, 67))
136174	33461172	Multiple single nucleotide polymorphisms (SNPs) in its first intron are closely related to the occurrence of obesity.	('related', 'Reg', (80, 87))	('obesity', 'Disease', 'MESH:D009765', (109, 116))	('obesity', 'Disease', (109, 116))	('Multiple single nucleotide polymorphisms', 'Var', (0, 40))	('obesity', 'Phenotype', 'HP:0001513', (109, 116))
136175	33461172	FTO overexpression causes obesity, whereas loss of FTO leads to growth retardation and high early mortality in rodents.	('obesity', 'Disease', 'MESH:D009765', (26, 33))	('causes', 'Reg', (19, 25))	('growth retardation', 'Disease', 'MESH:D006130', (64, 82))	('obesity', 'Disease', (26, 33))	('mortality', 'Disease', (98, 107))	('growth retardation', 'Disease', (64, 82))	('FTO', 'Gene', (51, 54))	('overexpression', 'PosReg', (4, 18))	('growth retardation', 'Phenotype', 'HP:0001510', (64, 82))	('loss', 'Var', (43, 47))	('obesity', 'Phenotype', 'HP:0001513', (26, 33))	('mortality', 'Disease', 'MESH:D003643', (98, 107))
136182	33461172	Methyltransferase complex (MTC) acts as a writer to install m6A, while demethylase removes m6A like an eraser.	('demethylase', 'Gene', '8932', (71, 82))	('Methyltransferase complex', 'cellular_component', 'GO:0034708', ('0', '25'))	('m6A', 'Chemical', '-', (91, 94))	('m6A', 'Var', (60, 63))	('m6A', 'Chemical', '-', (60, 63))	('demethylase', 'Gene', (71, 82))
136197	33461172	Meanwhile, overexpress FTO increased the yield of the immunoprecipitated USP18 without changing its expression, indicating the strong interaction between the two proteins.	('USP18', 'Gene', '11274', (73, 78))	('USP18', 'Gene', (73, 78))	('overexpress', 'Var', (11, 22))	('FTO', 'Gene', (23, 26))	('USP', 'molecular_function', 'GO:0051748', ('73', '76'))	('interaction', 'Interaction', (134, 145))
136204	33461172	However, USP18 silencing blocked the proliferation and migration induced by FTO.	('USP18', 'Gene', (9, 14))	('USP', 'molecular_function', 'GO:0051748', ('9', '12'))	('USP18', 'Gene', '11274', (9, 14))	('silencing', 'Var', (15, 24))	('proliferation', 'CPA', (37, 50))	('blocked', 'NegReg', (25, 32))
136212	33461172	PYCR1 expression was decreased upon silencing either USP18 (Figure 5G) or FTO (Figure 6A).	('PYCR1', 'Gene', (0, 5))	('USP18', 'Gene', (53, 58))	('USP18', 'Gene', '11274', (53, 58))	('decreased', 'NegReg', (21, 30))	('expression', 'MPA', (6, 16))	('FTO', 'Gene', (74, 77))	('PYCR1', 'Gene', '5831', (0, 5))	('USP', 'molecular_function', 'GO:0051748', ('53', '56'))	('silencing', 'Var', (36, 45))
136215	33461172	It was predicted by m6Avar that a few highly scored m6A-methylation sites in human PYCR1 orthologous gene (Table 2).	('m6A', 'Chemical', '-', (20, 23))	('m6A', 'Chemical', '-', (52, 55))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('PYCR1', 'Gene', (83, 88))	('PYCR1', 'Gene', '5831', (83, 88))	('human', 'Species', '9606', (77, 82))	('m6A-methylation', 'Var', (52, 67))
136216	33461172	Indeed, knockdown of FTO increased the global mRNA m6A level in both T24 and EJ cells, while the opposite was true when overexpressing FTO, which could be rescued by forced expression of N6-adenosine-methyltransferase catalytic subunit METTL3 (Figure 6D).	('m6A', 'Chemical', '-', (51, 54))	('increased', 'PosReg', (25, 34))	('knockdown', 'Var', (8, 17))	('adenosine', 'Chemical', 'MESH:D000241', (190, 199))	('EJ', 'CellLine', 'CVCL:7039', (77, 79))	('METTL3', 'Gene', '56339', (236, 242))	('FTO', 'Gene', (21, 24))	('mRNA m6A level', 'MPA', (46, 60))	('METTL3', 'Gene', (236, 242))
136219	33461172	Furthermore, mRNA stability assay showed that loss of FTO accelerated the degradation of PYCR1 mRNA, whereas gain of FTO extended its half-life indicating an increase in mRNA stability (Figure 6F).	('PYCR1', 'Gene', (89, 94))	('FTO', 'Gene', (54, 57))	('loss', 'Var', (46, 50))	('extended', 'PosReg', (121, 129))	('degradation', 'MPA', (74, 85))	('PYCR1', 'Gene', '5831', (89, 94))	('mRNA stability', 'MPA', (170, 184))	('accelerated', 'PosReg', (58, 69))	('gain', 'PosReg', (109, 113))	('FTO', 'Gene', (117, 120))	('half-life', 'MPA', (134, 143))	('increase', 'PosReg', (158, 166))	('degradation', 'biological_process', 'GO:0009056', ('74', '85'))
136221	33461172	We hypothesized that it might be mediated by PYCR1 because ectopic PYCR1 expression facilitated tumor cell proliferation (Figure 7A) and migration (Figure 7B).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('PYCR1', 'Gene', '5831', (67, 72))	('tumor', 'Disease', (96, 101))	('facilitated', 'PosReg', (84, 95))	('PYCR1', 'Gene', (45, 50))	('cell proliferation', 'biological_process', 'GO:0008283', ('102', '120'))	('migration', 'CPA', (137, 146))	('ectopic', 'Var', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('PYCR1', 'Gene', (67, 72))	('PYCR1', 'Gene', '5831', (45, 50))
136224	33461172	As expected, loss of FTO significantly compromised xenograft tumor growth in nude mice compared to the control group (Figure 8A, 8B, 8C).	('compromised', 'NegReg', (39, 50))	('nude mice', 'Species', '10090', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('FTO', 'Gene', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('loss', 'Var', (13, 17))	('tumor', 'Disease', (61, 66))
136230	33461172	Emerging evidence indicate that changes in these m6A-regulating proteins promote cancer cell proliferation, survival, tumor initiation and progression by inducing the expression of key oncogenic genes.	('progression', 'CPA', (139, 150))	('oncogenic genes', 'Gene', (185, 200))	('m6A', 'Chemical', '-', (49, 52))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor initiation', 'Disease', 'MESH:D009369', (118, 134))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cancer', 'Disease', (81, 87))	('promote', 'PosReg', (73, 80))	('tumor initiation', 'Disease', (118, 134))	('survival', 'CPA', (108, 116))	('cell proliferation', 'biological_process', 'GO:0008283', ('88', '106'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('inducing', 'PosReg', (154, 162))	('expression', 'MPA', (167, 177))	('changes', 'Var', (32, 39))
136232	33461172	FTO is highly expressed in many types of cancer such as acute myeloid leukemia with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA fusion, FLT3-ITD or NPM1 mutation, human cervical squamous cell carcinoma tissue and gastric cancer etc.	('squamous cell carcinoma', 'Disease', (181, 204))	('NPM1', 'Gene', (151, 155))	('FLT3-ITD', 'Disease', 'None', (139, 147))	('PML', 'Gene', (122, 125))	('gastric cancer', 'Disease', 'MESH:D013274', (216, 230))	('cancer', 'Disease', (41, 47))	('rearrangements', 'Var', (97, 111))	('cancer', 'Disease', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (56, 78))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('human', 'Species', '9606', (166, 171))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (56, 78))	('FLT3-ITD', 'Disease', (139, 147))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (62, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('PML', 'Gene', '5371', (122, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (216, 230))	('MLL', 'Gene', '4297', (93, 96))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('MLL', 'Gene', (93, 96))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('NPM1', 'Gene', '4869', (151, 155))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (181, 204))	('gastric cancer', 'Disease', (216, 230))	('acute myeloid leukemia', 'Disease', (56, 78))
136239	33461172	FTO was initially identified because of the strong association of multiple SNPs in its first intron with type 2 diabetes.	('diabetes', 'Disease', 'MESH:D003920', (112, 120))	('multiple SNPs', 'Var', (66, 79))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (105, 120))	('association', 'Interaction', (51, 62))	('diabetes', 'Disease', (112, 120))
136241	33461172	Generally, m6A deposition decreases the expression of methylated mRNAs and shortens their half-lives, while loss of m6A boosts gene transcription and increases RNA stability.	('expression', 'MPA', (40, 50))	('gene transcription', 'MPA', (127, 145))	('increases', 'PosReg', (150, 159))	('m6A', 'Chemical', '-', (116, 119))	('boosts', 'PosReg', (120, 126))	('RNA stability', 'CPA', (160, 173))	('m6A', 'Chemical', '-', (11, 14))	('RNA', 'cellular_component', 'GO:0005562', ('160', '163'))	('loss', 'Var', (108, 112))	('transcription', 'biological_process', 'GO:0006351', ('132', '145'))	('methylated mRNAs', 'MPA', (54, 70))	('half-lives', 'MPA', (90, 100))	('decreases', 'NegReg', (26, 35))	('m6A', 'Gene', (116, 119))	('shortens', 'NegReg', (75, 83))
136286	33536782	Many studies have reported that Dkk1 is abnormally expressed in tumor cells, and abnormal expression of Dkk1 can inhibit cell proliferation or induce apoptosis through pro-apoptotic factors, However, due to the differences in tumor environment and the complex regulatory mechanisms in different tumors, Dkk1 has different effects on the progression of different tumors.	('tumors', 'Disease', (295, 301))	('apoptosis', 'CPA', (150, 159))	('cell proliferation', 'CPA', (121, 139))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Disease', (362, 367))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('cell proliferation', 'biological_process', 'GO:0008283', ('121', '139'))	('tumor', 'Disease', 'MESH:D009369', (362, 367))	('tumors', 'Phenotype', 'HP:0002664', (362, 368))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (295, 300))	('induce', 'Reg', (143, 149))	('Dkk1', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (362, 367))	('tumors', 'Disease', (362, 368))	('effects', 'Reg', (322, 329))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('abnormal expression', 'Var', (81, 100))	('tumor', 'Disease', (64, 69))	('apoptosis', 'biological_process', 'GO:0097194', ('150', '159'))	('inhibit', 'NegReg', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('apoptosis', 'biological_process', 'GO:0006915', ('150', '159'))	('tumors', 'Disease', 'MESH:D009369', (362, 368))	('tumor', 'Disease', (226, 231))
136287	33536782	In many tumors, high expression of Dkk1 may promote tumor metastasis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('promote', 'PosReg', (44, 51))	('high', 'Var', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor metastasis', 'Disease', 'MESH:D009362', (52, 68))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('Dkk1', 'Gene', (35, 39))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumor metastasis', 'Disease', (52, 68))
136302	33536782	IP3 triggers the release of calcium ions (Ca2+) from the endoplasmic reticulum activating calmodulin and subsequently CAMKII (calcium/calmodulin-dependent kinase II), TAK-1 (TGF-beta activated kinase 1) and NLK (Nemo-like kinase) thereby inhibiting the canonical Wnt pathway.	('CAMKII', 'cellular_component', 'GO:0005954', ('118', '124'))	('TGF-beta activated kinase 1', 'Gene', (174, 201))	('calcium/calmodulin-dependent kinase II', 'Gene', (126, 164))	('CAMKII', 'Gene', '818', (118, 124))	('calcium', 'Chemical', 'MESH:D002118', (28, 35))	('IP3', 'Var', (0, 3))	('Nemo-like kinase', 'Gene', '51701', (212, 228))	('calcium/calmodulin-dependent kinase II', 'Gene', '818', (126, 164))	('Ca2+', 'Chemical', 'MESH:D000069285', (42, 46))	('CAMKII', 'molecular_function', 'GO:0004683', ('118', '124'))	('Nemo-like kinase', 'Gene', (212, 228))	('TAK-1', 'Gene', '6885', (167, 172))	('release', 'MPA', (17, 24))	('inhibiting', 'NegReg', (238, 248))	('NLK', 'Gene', '51701', (207, 210))	('NLK', 'Gene', (207, 210))	('Wnt', 'Gene', (263, 266))	('Wnt', 'Gene', '114487', (263, 266))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('57', '78'))	('CAMKII', 'Gene', (118, 124))	('calcium', 'Chemical', 'MESH:D002118', (126, 133))	('TGF-beta activated kinase 1', 'Gene', '6885', (174, 201))	('TAK-1', 'Gene', (167, 172))	('IP3', 'Chemical', 'MESH:D015544', (0, 3))
136304	33536782	In the Wnt pathway, mutations at key sites, methylation of the promoter and stability of beta-catenin have been shown to be associated with tumor progression and low survival in patients: The progression of chronic phase CML toward blastic crisis phase due to GSK3beta mutations and beta-catenin stabilization in GMP cells (granulocyte-macrophage progenitor cells).	('CML', 'Disease', (221, 224))	('mutations', 'Var', (269, 278))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('patients', 'Species', '9606', (178, 186))	('Wnt', 'Gene', (7, 10))	('associated', 'Reg', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('GSK3beta', 'Gene', (260, 268))	('GSK3beta', 'Gene', '2931', (260, 268))	('Wnt', 'Gene', '114487', (7, 10))	('methylation', 'biological_process', 'GO:0032259', ('44', '55'))	('GSK', 'molecular_function', 'GO:0050321', ('260', '263'))	('mutations', 'Var', (20, 29))	('tumor', 'Disease', (140, 145))
136305	33536782	And Wnt pathway inhibitor promoters (ie, SFRP,DKK and WIF-1) are hypermethylated in ALL and AML and are associated with low survival in patients.	('survival', 'MPA', (124, 132))	('AML', 'Disease', 'MESH:D015470', (92, 95))	('WIF-1', 'Gene', '11197', (54, 59))	('DKK', 'Gene', (46, 49))	('low', 'NegReg', (120, 123))	('patients', 'Species', '9606', (136, 144))	('Wnt', 'Gene', (4, 7))	('hypermethylated', 'Var', (65, 80))	('AML', 'Disease', (92, 95))	('WIF-1', 'Gene', (54, 59))	('Wnt', 'Gene', '114487', (4, 7))
136306	33536782	Loss-of-function mutations in APC and RNF43 and gain-of-function mutations in RSPO (characterized by gene fusions) and CTNNB1 was reported in the vast majority of colorectal cancers (CRC).	('Loss-of-function', 'NegReg', (0, 16))	('APC', 'Disease', 'MESH:D011125', (30, 33))	('APC', 'cellular_component', 'GO:0005680', ('30', '33'))	('APC', 'Disease', (30, 33))	('CTNNB1', 'Gene', (119, 125))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('RSPO', 'Gene', (78, 82))	('CTNNB1', 'Gene', '1499', (119, 125))	('colorectal cancers', 'Disease', 'MESH:D015179', (163, 181))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('gain-of-function', 'PosReg', (48, 64))	('RNF43', 'Gene', '54894', (38, 43))	('colorectal cancers', 'Disease', (163, 181))	('RNF43', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('mutations', 'Var', (17, 26))	('RSPO', 'Gene', '284654', (78, 82))	('mutations', 'Var', (65, 74))
136309	33536782	But in other tumors, the expression of Dkk1 exists as a tumor suppressor.	('tumor', 'Disease', (13, 18))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('56', '72'))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (13, 19))	('Dkk1', 'Gene', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('expression', 'Var', (25, 35))	('tumor suppressor', 'biological_process', 'GO:0051726', ('56', '72'))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
136317	33536782	The data showed that CSC phenotype was related to VM and Dkk1 overexpression, and in vivo studies showed that lung cancer cells overexpressing Dkk1 had more CSC phenotype and more invasiveness than normal lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('Dkk1', 'Var', (143, 147))	('more', 'PosReg', (175, 179))	('lung cancer', 'Disease', 'MESH:D008175', (205, 216))	('invasiveness', 'CPA', (180, 192))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('lung cancer', 'Disease', (205, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('CSC', 'Disease', (157, 160))	('more', 'PosReg', (152, 156))
136322	33536782	Cox regression analysis showed that antibodies against Pep B subtype were independent prognostic factors of NSCLC.	('antibodies', 'Var', (36, 46))	('NSCLC', 'Disease', (108, 113))	('Pep B', 'Gene', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('Pep B', 'cellular_component', 'GO:0000344', ('55', '60'))	('Pep B', 'Gene', '5182', (55, 60))
136331	33536782	By comparing the serum Dkk1 levels of 831 test cohort participants and 453 validation cohort participants, and the liver tissue Dkk1 mRNA and protein levels of HCC patients and non-cancer patients, Professor Qin Wenxin found that Dkk1 can complement the measurement of AFP in HCC diagnosis, improve the differentiation of AFP-negative HCC patients, and distinguish HCC from non-malignant chronic liver disease.	('AFP', 'Gene', (322, 325))	('AFP', 'Gene', '174', (322, 325))	('patients', 'Species', '9606', (188, 196))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('chronic liver disease', 'Disease', (388, 409))	('Qin', 'Gene', '2290', (208, 211))	('HCC', 'Disease', (365, 368))	('HCC', 'Disease', (276, 279))	('chronic liver disease', 'Disease', 'MESH:D058625', (388, 409))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('Qin', 'Gene', (208, 211))	('patients', 'Species', '9606', (339, 347))	('patients', 'Species', '9606', (164, 172))	('improve', 'PosReg', (291, 298))	('AFP', 'Gene', (269, 272))	('cancer', 'Disease', (181, 187))	('AFP', 'Gene', '174', (269, 272))	('participants', 'Species', '9606', (54, 66))	('liver disease', 'Phenotype', 'HP:0001392', (396, 409))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('distinguish', 'Reg', (353, 364))	('Dkk1', 'Var', (230, 234))	('participants', 'Species', '9606', (93, 105))
136339	33536782	It was found that after TACE treatment, the serum Dkk1 and CTCs in the reaction group were significantly lower than those before treatment, and the overall survival time, disease-free survival time and 5-year survival rate of patients with positive serum Dkk1 and CTC before treatment were significantly lower than those before treatment.	('lower', 'NegReg', (105, 110))	('TACE', 'Chemical', '-', (24, 28))	('CTCs', 'MPA', (59, 63))	('positive serum Dkk1', 'Var', (240, 259))	('patients', 'Species', '9606', (226, 234))	('5-year survival rate', 'CPA', (202, 222))	('serum', 'MPA', (44, 49))	('lower', 'NegReg', (304, 309))	('overall survival time', 'CPA', (148, 169))	('disease-free survival time', 'CPA', (171, 197))
136346	33536782	The proportion of S phase and G2/M phase increased, while the proportion of G0/G1 decreased, and the overexpression of Dkk1 led to the enhancement of invasive ability of EC9706 cells.	('overexpression', 'PosReg', (101, 115))	('S phase', 'biological_process', 'GO:0051320', ('18', '25'))	('Dkk1', 'Var', (119, 123))	('invasive ability', 'CPA', (150, 166))	('enhancement', 'PosReg', (135, 146))	('S phase', 'CPA', (18, 25))	('G2/M phase', 'CPA', (30, 40))	('M phase', 'biological_process', 'GO:0000279', ('33', '40'))	('EC9706', 'CellLine', 'CVCL:E307', (170, 176))
136349	33536782	The expression of Dkk1 protein in resected specimens of ESCC patients was compared with various clinicopathological parameters and prognosis (the relationship between disease-free survival (DFS)) showed that the DFS of patients with Dkk1-positive tumors was worse than that of ESCC-negative patients (5-year DFS;1.5% vs 53.6% DFS;1.5% 0.0062), indicating that Dkk1 can be used as a new predictor of poor prognosis in patients with ESCC after radical resection.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumors', 'Disease', (247, 253))	('worse', 'NegReg', (258, 263))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('ESCC', 'Disease', (431, 435))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('patients', 'Species', '9606', (61, 69))	('Dkk1', 'Var', (360, 364))	('patients', 'Species', '9606', (291, 299))	('patients', 'Species', '9606', (219, 227))	('patients', 'Species', '9606', (417, 425))
136363	33536782	After examining the relationship between the co-expression of Dkk1 and beta-catenin in gastric cancer and clinical prognosis, it was found that the co-expression of Dkk1 and beta-catenin was significantly correlated with high N stage (N2 and N3).	('high N stage', 'Disease', (221, 233))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('correlated', 'Reg', (205, 215))	('Dkk1', 'Gene', (165, 169))	('beta-catenin', 'Protein', (174, 186))	('co-expression', 'Var', (148, 161))	('gastric cancer', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))
136364	33536782	The overall survival (OS) and DFS of patients with high expression of Dkk1 were poor.	('overall survival', 'CPA', (4, 20))	('poor', 'NegReg', (80, 84))	('patients', 'Species', '9606', (37, 45))	('high expression', 'Var', (51, 66))	('Dkk1', 'Gene', (70, 74))
136365	33536782	Multivariate analysis showed that high expression of Dkk1 alone or high expression of Dkk1 with beta-catenin positive were independent prognostic factors for tumor recurrence and overall survival, indicating that high expression of Dkk1 was an important prognostic factor for tumor recurrence and survival in resected AGC patients, regardless of the positivity of beta-catenin.	('Dkk1', 'Gene', (232, 236))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('patients', 'Species', '9606', (322, 330))	('tumor', 'Disease', (276, 281))	('high', 'Var', (213, 217))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('Dkk1', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
136369	33536782	After Dkk1 was introduced into CD44+ cells, it effectively inhibited the endogenous Wnt/beta-catenin signal transduction and reduced the tumorigenicity of CD44+ cells in vivo, which verified the effectiveness of gene therapy targeting Wnt/beta-catenin signal pathway in CSC cells.	('Wnt', 'Gene', (84, 87))	('tumor', 'Disease', (137, 142))	('Wnt', 'Gene', (235, 238))	('inhibited', 'NegReg', (59, 68))	('Dkk1', 'Var', (6, 10))	('reduced', 'NegReg', (125, 132))	('Wnt', 'Gene', '114487', (84, 87))	('Wnt', 'Gene', '114487', (235, 238))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('signal transduction', 'biological_process', 'GO:0007165', ('101', '120'))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
136377	33536782	At the same time, in vitro culture showed that HCT116 with overexpression of Dkk1 inhibited the formation of the tubular structure of human umbilical vein endothelial cells and down-regulated the expression of VEGF, and the tumor size, microvessel density and VEGF expression of CRC cells with high expression of Dkk1 decreased.	('formation', 'biological_process', 'GO:0009058', ('96', '105'))	('HCT116', 'CellLine', 'CVCL:0291', (47, 53))	('Dkk1', 'Gene', (77, 81))	('human', 'Species', '9606', (134, 139))	('VEGF', 'Gene', '7422', (260, 264))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('inhibited', 'NegReg', (82, 91))	('VEGF', 'Gene', '7422', (210, 214))	('tumor', 'Disease', (224, 229))	('expression', 'MPA', (196, 206))	('HCT116', 'Var', (47, 53))	('expression', 'MPA', (265, 275))	('decreased', 'NegReg', (318, 327))	('microvessel density', 'CPA', (236, 255))	('VEGF', 'Gene', (260, 264))	('down-regulated', 'NegReg', (177, 191))	('VEGF', 'Gene', (210, 214))
136381	33536782	Microarray analysis of CRC cell lines showed that the expression of Dkk1 and the level of Dkk1 protein depended on the increase of Dkk1 secretion after CSN5 gene knockout, which affected the Wnt signal transduction of SW480 cells.	('SW480', 'CellLine', 'CVCL:0546', (218, 223))	('Wnt', 'Gene', (191, 194))	('Dkk1 secretion', 'MPA', (131, 145))	('Wnt', 'Gene', '114487', (191, 194))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('CSN', 'cellular_component', 'GO:0008180', ('152', '155'))	('CSN5', 'Gene', (152, 156))	('signal transduction', 'biological_process', 'GO:0007165', ('195', '214'))	('increase', 'PosReg', (119, 127))	('CSN5', 'Gene', '10987', (152, 156))	('secretion', 'biological_process', 'GO:0046903', ('136', '145'))	('knockout', 'Var', (162, 170))
136386	33536782	Knocking down miR-410 can promote the expression of Dkk1, inhibit the proliferation, migration and invasion of CRC cells, and induce apoptosis, while the overexpression of miR-410 shows the contrary.	('promote', 'PosReg', (26, 33))	('induce', 'Reg', (126, 132))	('miR-410', 'Gene', (14, 21))	('miR-410', 'Gene', '574434', (172, 179))	('Knocking down', 'Var', (0, 13))	('miR-410', 'Gene', '574434', (14, 21))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('expression', 'MPA', (38, 48))	('apoptosis', 'CPA', (133, 142))	('proliferation', 'CPA', (70, 83))	('inhibit', 'NegReg', (58, 65))	('Dkk1', 'Gene', (52, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('miR-410', 'Gene', (172, 179))
136388	33536782	Silencing the expression of HotTip can inhibit the migration and invasion of colorectal cancer cells.	('HotTip', 'Gene', '100316868', (28, 34))	('colorectal cancer', 'Disease', (77, 94))	('inhibit', 'NegReg', (39, 46))	('expression', 'MPA', (14, 24))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('HotTip', 'Gene', (28, 34))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('Silencing', 'Var', (0, 9))
136396	33536782	Further in vitro experiment found that the invasiveness of PC tumor cells with Dkk1 knockout was significantly decreased.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('knockout', 'Var', (84, 92))	('decreased', 'NegReg', (111, 120))	('Dkk1', 'Gene', (79, 83))	('invasiveness of PC tumor', 'Disease', 'MESH:D015324', (43, 67))	('invasiveness of PC tumor', 'Disease', (43, 67))
136397	33536782	In terms of the mechanism of Dkk1 regulating PC, gene chip analysis showed that Dkk1 was an abnormal gene associated with GATA6 gene knockout.	('GATA6', 'Gene', (122, 127))	('knockout', 'Var', (133, 141))	('GATA6', 'Gene', '2627', (122, 127))	('Dkk1', 'Gene', (80, 84))
136399	33536782	In the case of low GATA6 knock down, it was found that the mRNA expression of Dkk1 and the secretion of Dkk1 protein increased.	('knock down', 'Var', (25, 35))	('GATA6', 'Gene', (19, 24))	('increased', 'PosReg', (117, 126))	('secretion', 'MPA', (91, 100))	('GATA6', 'Gene', '2627', (19, 24))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('secretion', 'biological_process', 'GO:0046903', ('91', '100'))	('mRNA expression', 'MPA', (59, 74))	('Dkk1', 'Gene', (78, 82))
136402	33536782	This study found that serum Dkk1 and CA19-9 were increased in patients with advanced PC and chronic pancreatitis, but Dkk1 was more effective in distinguishing PC from chronic pancreatitis than CA19-9, and the survival rate of patients with high expression of Dkk1 was significantly lower than that of patients with low expression of Dkk1.	('pancreatitis', 'Phenotype', 'HP:0001733', (176, 188))	('pancreatitis', 'Disease', 'MESH:D010195', (176, 188))	('pancreatitis', 'Disease', (100, 112))	('survival rate', 'CPA', (210, 223))	('CA19-9', 'Chemical', 'MESH:C086528', (194, 200))	('pancreatitis', 'Disease', (176, 188))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (92, 112))	('high expression', 'Var', (241, 256))	('CA19-9', 'Chemical', 'MESH:C086528', (37, 43))	('pancreatitis', 'Disease', 'MESH:D010195', (100, 112))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (168, 188))	('lower', 'NegReg', (283, 288))	('pancreatitis', 'Phenotype', 'HP:0001733', (100, 112))	('patients', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (302, 310))	('patients', 'Species', '9606', (227, 235))
136403	33536782	Kaplan-Meier analysis of Dkk1 expression and patient clinical data showed that OS and relapse-free survival (RFS) decreased in patients with high Dkk1 expression, and the expression of Dkk1 was significantly correlated with T stage and lymph node metastasis.	('relapse-free survival', 'CPA', (86, 107))	('correlated', 'Reg', (208, 218))	('patient', 'Species', '9606', (127, 134))	('RFS', 'Disease', 'MESH:D005198', (109, 112))	('expression', 'MPA', (151, 161))	('patients', 'Species', '9606', (127, 135))	('lymph node metastasis', 'CPA', (236, 257))	('decreased', 'NegReg', (114, 123))	('patient', 'Species', '9606', (45, 52))	('Dkk1', 'Gene', (146, 150))	('T stage', 'CPA', (224, 231))	('high', 'Var', (141, 145))	('RFS', 'Disease', (109, 112))
136416	33536782	It can be used for the detection and diagnosis of CC, and for the prognosis evaluation of CC patients In view of the important role of lncRNA in the pathological process of cancer, some scholars have studied the role of lncRNA in CC and found that the promoting effect of SNHG7 on the development of CC depends on the activation of Wnt pathway mediated by Dkk1, while the binding of EZH2 and Dkk1 promoter and the share of H3K27me3 in Dkk1 promoter are decreased after SNHG7 silencing.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('Wnt', 'Gene', (332, 335))	('SNHG7', 'Gene', '84973', (469, 474))	('EZH2', 'Gene', '2146', (383, 387))	('promoting', 'PosReg', (252, 261))	('Wnt', 'Gene', '114487', (332, 335))	('EZH2', 'Gene', (383, 387))	('patients', 'Species', '9606', (93, 101))	('binding', 'molecular_function', 'GO:0005488', ('372', '379'))	('died', 'Disease', (203, 207))	('silencing', 'Var', (475, 484))	('decreased', 'NegReg', (453, 462))	('SNHG7', 'Gene', (272, 277))	('cancer', 'Disease', (173, 179))	('SNHG7', 'Gene', (469, 474))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('died', 'Disease', 'MESH:D003643', (203, 207))	('binding', 'Interaction', (372, 379))	('Dkk1', 'Protein', (392, 396))	('H3K27me3', 'Var', (423, 431))	('SNHG7', 'Gene', '84973', (272, 277))
136433	33536782	It was found that overexpression of DKN-01 had no significant effect on tumor cell phenotype and tumor load, but overexpression of Dkk1 reduced the infiltration of CD45+ leukocytes into the peritoneum and omentum, reduced natural killer (NK) and CD8T cells, and decreased the expression of interferon-gamma (IFN-gamma) on activated CD8T cells.	('infiltration', 'CPA', (148, 160))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('290', '306'))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (72, 77))	('interferon-gamma', 'Gene', '3458', (290, 306))	('decreased', 'NegReg', (262, 271))	('tumor', 'Disease', (97, 102))	('interferon-gamma', 'Gene', (290, 306))	('IFN-gamma', 'Gene', (308, 317))	('IFN-gamma', 'Gene', '3458', (308, 317))	('reduced', 'NegReg', (214, 221))	('reduced', 'NegReg', (136, 143))	('Dkk1', 'Var', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('natural killer', 'CPA', (222, 236))
136446	33536782	In the study of mesenchymal stem cell (MSC), it was found that MSCs from the rib perichondrium (PMSCs)-conditioned medium could significantly inhibit the growth, migration and invasion of breast cancer cells, and down-regulate the expression of Wnt/beta-catenin pathway and its target genes, while neutralizing Dkk1 in PMSC-conditioned medium could significantly reduce its inhibitory effect on tumor cells.	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('tumor', 'Disease', (395, 400))	('inhibit', 'NegReg', (142, 149))	('Wnt', 'Gene', (245, 248))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('neutralizing', 'Var', (298, 310))	('breast cancer', 'Disease', (188, 201))	('Dkk1', 'Gene', (311, 315))	('down-regulate', 'NegReg', (213, 226))	('MSCs', 'molecular_function', 'GO:0043854', ('63', '67'))	('Wnt', 'Gene', '114487', (245, 248))	('tumor', 'Disease', 'MESH:D009369', (395, 400))	('invasion', 'CPA', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (395, 400))	('growth', 'CPA', (154, 160))	('expression', 'MPA', (231, 241))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
136448	33536782	By comparing the serum Dkk1 and CA15-3 between breast cancer patients and healthy subjects, it was found that in the early stage of breast cancer, the sensitivity and specificity of Dkk1 were higher than that of CA15-3, while the expression of Dkk1 in HER-2-, ER-, and PR-positive patients was lower than that in HER-2-, ER- and PR- negative patients.	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('CA15-3', 'Gene', (212, 218))	('Dkk1', 'Var', (182, 186))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('breast cancer', 'Disease', (47, 60))	('HER-2', 'Gene', '2064', (252, 257))	('patients', 'Species', '9606', (61, 69))	('HER-2', 'Gene', (252, 257))	('HER-2', 'Gene', '2064', (313, 318))	('HER-2', 'Gene', (313, 318))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('specificity', 'MPA', (167, 178))	('CA15-3', 'Gene', '4582', (32, 38))	('sensitivity', 'MPA', (151, 162))	('patients', 'Species', '9606', (281, 289))	('expression', 'MPA', (230, 240))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Disease', (132, 145))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('lower', 'NegReg', (294, 299))	('CA15-3', 'Gene', (32, 38))	('patients', 'Species', '9606', (342, 350))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('higher', 'PosReg', (192, 198))	('CA15-3', 'Gene', '4582', (212, 218))
136459	33536782	Multivariate analysis showed that serum Dkk1 was an independent prognostic factor for OS of bladder cancer.	('OS of bladder cancer', 'Disease', 'MESH:D001749', (86, 106))	('Dkk1', 'Protein', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('OS of bladder cancer', 'Disease', (86, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (92, 106))	('serum', 'Var', (34, 39))
136460	33536782	Gao et al demonstrated that up-regulation of miR-543-3p in bladder cancer can activate Wnt/beta-catenin signal by directly targeting Dkk1, while the expression of miR-543-3p is up-regulated in bladder cancer tissues and cells, and is positively correlated with high-grade bladder cancer, suggesting a potential tumor intervention target.	('Dkk1', 'Gene', (133, 137))	('Wnt', 'Gene', '114487', (87, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (193, 207))	('bladder cancer', 'Phenotype', 'HP:0009725', (272, 286))	('bladder cancer', 'Phenotype', 'HP:0009725', (59, 73))	('bladder cancer', 'Disease', (193, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('bladder cancer', 'Phenotype', 'HP:0009725', (193, 207))	('targeting', 'Reg', (123, 132))	('regulation', 'biological_process', 'GO:0065007', ('31', '41'))	('tumor', 'Disease', (311, 316))	('correlated', 'Reg', (245, 255))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('up-regulation', 'PosReg', (28, 41))	('miR-543-3p', 'Var', (45, 55))	('miR-543-3p', 'Var', (163, 173))	('up-regulated', 'PosReg', (177, 189))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('bladder cancer', 'Disease', 'MESH:D001749', (59, 73))	('Wnt', 'Gene', (87, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (272, 286))	('bladder cancer', 'Disease', (272, 286))	('activate', 'PosReg', (78, 86))	('bladder cancer', 'Disease', (59, 73))
136464	33536782	Specifically, through the above research, we can find that Dkk1 has been shown to promote tumor metastasis in the following tumors: NSCLC, HCC, EC, GC, PC, CC, Breast cancer, and BUC.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('BUC', 'Disease', (179, 182))	('promote', 'PosReg', (82, 89))	('HCC', 'Disease', (139, 142))	('Breast cancer', 'Disease', (160, 173))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('Dkk1', 'Var', (59, 63))	('tumor metastasis', 'Disease', 'MESH:D009362', (90, 106))	('tumor metastasis', 'Disease', (90, 106))	('tumors', 'Disease', (124, 130))	('NSCLC', 'Disease', (132, 137))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('Breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('Breast cancer', 'Disease', 'MESH:D001943', (160, 173))
136466	33536782	By comparing the serum samples of tumor patients and normal subjects, we also confirmed the protective effect of high expression of Dkk1 on CRC patients.	('tumor', 'Disease', (34, 39))	('high expression', 'Var', (113, 128))	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (144, 152))	('CRC', 'Disease', (140, 143))	('Dkk1', 'Gene', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
136467	33536782	However, high expression of Dkk1 was shown in other tumors to promote tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (70, 75))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('Dkk1', 'Gene', (28, 32))	('promote', 'PosReg', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('high', 'Var', (9, 13))
136477	33536782	However, in other tumor studies, it has been found that Dkk1 can inhibit the biological effect of tumor.	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', (98, 103))	('inhibit', 'NegReg', (65, 72))	('Dkk1', 'Var', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
136479	33536782	In this case, it can be assumed that Dkk1 cannot inhibit the transduction of the classical Wnt signal pathway, thus eliminating its potential antitumor activity.	('Dkk1', 'Var', (37, 41))	('Wnt', 'Gene', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('Wnt', 'Gene', '114487', (91, 94))	('transduction', 'biological_process', 'GO:0009293', ('61', '73'))	('eliminating', 'NegReg', (116, 127))	('transduction', 'MPA', (61, 73))	('inhibit', 'NegReg', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
136481	33536782	The close relationship between the expression level of Dkk1 in serum of clinical tumor patients and prognosis makes Dkk1 an attractive target for tumor therapy, and blocking the activity of Dkk1 in mice can significantly reduce the ability of tumor invasion and metastasis in vivo.	('reduce', 'NegReg', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('blocking', 'Var', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mice', 'Species', '10090', (198, 202))	('activity', 'MPA', (178, 186))	('Dkk1', 'Gene', (190, 194))	('patients', 'Species', '9606', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', (243, 248))
136500	32256669	p53 is the product of the tumor suppressor gene TP53, and nuclear overexpression of p53 indicates the presence of TP53 gene mutation.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('TP53', 'Gene', '7157', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('TP53', 'Gene', (48, 52))	('TP53', 'Gene', '7157', (114, 118))	('tumor suppressor', 'biological_process', 'GO:0051726', ('26', '42'))	('p53', 'Gene', (84, 87))	('mutation', 'Var', (124, 132))	('p53', 'Gene', '7157', (84, 87))	('TP53', 'Gene', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('26', '42'))
136501	32256669	TP53 mutation is involved in several stages of UC development.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('involved', 'Reg', (17, 25))	('men', 'Species', '9606', (57, 60))	('mutation', 'Var', (5, 13))
136550	32256669	In the present study, 13 (65%) of 20 cases of atypia in urine cytology showed positivity for p53 or CK20.	('positivity', 'Var', (78, 88))	('CK20', 'Gene', '54474', (100, 104))	('CK20', 'Gene', (100, 104))	('p53', 'Gene', '7157', (93, 96))	('p53', 'Gene', (93, 96))
136576	30177858	There are several oral agents available for patients who harbor specific mutations, but little is known about mutations and affected pathways in HIV-infected patients with lung cancer.	('patients', 'Species', '9606', (44, 52))	('lung cancer', 'Disease', (172, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('HIV-infected', 'Disease', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('HIV-infected', 'Disease', 'MESH:D015658', (145, 157))	('patients', 'Species', '9606', (158, 166))	('mutations', 'Var', (73, 82))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))
136598	30177858	Our analysis results suggest that alterations in these 10 candidate genes interact in at least a subset of tumors.	('interact', 'Reg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('alterations', 'Var', (34, 45))
136613	30177858	To better distinguish the cancer tissue from the surrounding tissue, we finally stained with p63 and TTF-1 as lung cancer cell specific markers and found that all the two SCC cases showed strong positive staining for p63 (Fig.	('SCC', 'Gene', (171, 174))	('p63', 'Var', (217, 220))	('cancer', 'Disease', (115, 121))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('SCC', 'Gene', '6317', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
136618	30177858	A comprehensive network and pathway analysis of the DEGs revealed that these genes were associated with four network functions and six canonical pathways relevant to the development of HIV lung cancer.	('canonical pathways', 'Pathway', (135, 153))	('genes', 'Var', (77, 82))	('network', 'Pathway', (109, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('men', 'Species', '9606', (177, 180))	('HIV lung cancer', 'Disease', 'MESH:D008175', (185, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('associated', 'Reg', (88, 98))	('HIV lung cancer', 'Disease', (185, 200))
136629	30177858	These results implied that TNM was not only a major prognostic factor in the general population but also in HIV and might yield a survival benefit, although our study population was small.	('survival benefit', 'CPA', (130, 146))	('HIV', 'Disease', (108, 111))	('TNM', 'Var', (27, 30))	('HIV', 'Disease', 'MESH:D015658', (108, 111))
136648	30177858	SYNPO2 (synaptopodin-2) is a repressor of tumor cell invasion, being predominant in prostate acinar epithelial and basal cells, and induces formation of complex stress fiber networks in the cell body.	('tumor', 'Disease', (42, 47))	('stress fiber', 'cellular_component', 'GO:0001725', ('161', '173'))	('SYNPO2', 'Var', (0, 6))	('cell body', 'cellular_component', 'GO:0044297', ('190', '199'))	('induces', 'Reg', (132, 139))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('stress fiber networks', 'CPA', (161, 182))	('formation', 'biological_process', 'GO:0009058', ('140', '149'))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
136670	30177858	This was followed by a PBS wash and incubation with Anti-TFAP2A (Abcam, ab108311), Anti-TTF-1 (Dako Corporation, CA), Anti-p63 (Novocastra Laboratories Ltd, UK), or Anti-SIX1 (Cell Signaling Technology, #16960, Danvers, MA) antibodies for IHC analysis.	('SIX1', 'Gene', '6495', (170, 174))	('Signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('Anti-TFAP2A', 'Var', (52, 63))	('PBS', 'Chemical', 'MESH:D007854', (23, 26))	('Anti-p63', 'Var', (118, 126))	('Anti-TTF-1', 'Var', (83, 93))	('SIX1', 'Gene', (170, 174))
136672	30177858	SIX1, TTF-1, p63 and TFAP2A proteins appeared as brownish granules after staining.	('appeared', 'Reg', (37, 45))	('proteins', 'Protein', (28, 36))	('TFAP2A', 'Gene', (21, 27))	('SIX1', 'Gene', (0, 4))	('SIX1', 'Gene', '6495', (0, 4))	('p63', 'Var', (13, 16))	('TTF-1', 'Gene', (6, 11))
136675	30177858	planned overall concepts and designed experiments; L.W., Z.C., Z.P., Z.L., X.Z., D.Y., Q.X.	('Z.P.', 'Var', (63, 67))	('Z.C.', 'Var', (57, 61))	('D.Y.', 'Var', (81, 85))	('X.Z.', 'Var', (75, 79))	('men', 'Species', '9606', (44, 47))	('Z.L.', 'Var', (69, 73))
136676	30177858	performed experiments; Z.Z., Y.F., Y.S., W.C., X.Y.Z., J.X.	('men', 'Species', '9606', (16, 19))	('W.C.', 'Var', (41, 45))	('X.Y.Z.', 'Var', (47, 53))
136767	26604437	Patients with positive NMP22 and negative cystoscopy have a 9.57-times greater risk of recurrence during 1 year of follow-up compared with patients with a negative test result.	('patients', 'Species', '9606', (139, 147))	('NMP22', 'Gene', (23, 28))	('NMP22', 'Gene', '4926', (23, 28))	('Patients', 'Species', '9606', (0, 8))	('positive', 'Var', (14, 22))
136773	26604437	The accumulation of copy number variations (CNVs, represented as DNA loss or gain) during the development of bladder cancer can begin 3 years before diagnosis, but the extent required for a positive UroVysion  test is usually achieved no earlier than 1 year before diagnosis.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gain', 'Disease', (77, 81))	('gain', 'Disease', 'MESH:D015430', (77, 81))	('men', 'Species', '9606', (101, 104))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('bladder cancer', 'Disease', 'MESH:D001749', (109, 123))	('bladder cancer', 'Disease', (109, 123))	('copy number variations', 'Var', (20, 42))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))
136790	26604437	Cyfra 21.1 is an ELISA-based assay that detects fragments of CK19 in urine with monoclonal antibodies.	('men', 'Species', '9606', (52, 55))	('CK19', 'Gene', (61, 65))	('fragments', 'Var', (48, 57))	('CK19', 'Gene', '3880', (61, 65))
136803	26604437	Low-grade, papillary, non-invasive tumors are generally characterized by constitutive activation of the receptor tyrosine kinase-Ras pathway, such as activating mutations in the HRAS and fibroblast growth factor receptor 3 (FGFR3) genes.	('HRAS', 'Gene', '3265', (178, 182))	('FGFR', 'molecular_function', 'GO:0005007', ('224', '228'))	('fibroblast growth factor receptor 3', 'Gene', '2261', (187, 222))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('FGFR3', 'Gene', '2261', (224, 229))	('HRAS', 'Gene', (178, 182))	('papillary', 'Disease', (11, 20))	('invasive tumors', 'Disease', (26, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('Low-grade', 'Disease', (0, 9))	('fibroblast growth factor receptor 3', 'Gene', (187, 222))	('mutations', 'Var', (161, 170))	('FGFR3', 'Gene', (224, 229))	('invasive tumors', 'Disease', 'MESH:D009369', (26, 41))	('activating', 'Reg', (150, 160))	('activation', 'PosReg', (86, 96))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('187', '211'))	('receptor tyrosine kinase-Ras pathway', 'Pathway', (104, 140))
136807	26604437	The most common focal deletion contained CDKN2A and was observed in approximately 50% of bladder cancer samples.	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('deletion', 'Var', (22, 30))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('CDKN2A', 'Gene', (41, 47))	('CDKN2A', 'Gene', '1029', (41, 47))
136808	26604437	Three clusters have been identified based on somatic mutations and focal copy number alterations (CNAs): Cluster A was enriched in focal somatic CNAs in several genes and mutations in MLL2.	('mutations', 'Var', (171, 180))	('MLL2', 'Gene', '8085', (184, 188))	('MLL2', 'Gene', (184, 188))	('CNAs', 'Var', (145, 149))
136809	26604437	Cluster B was characterized by deletion of CDKN2A and mutations in FGFR3 and papillary morphology.	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('FGFR3', 'Gene', (67, 72))	('CDKN2A', 'Gene', (43, 49))	('mutations', 'Var', (54, 63))	('CDKN2A', 'Gene', '1029', (43, 49))	('deletion', 'Var', (31, 39))	('FGFR3', 'Gene', '2261', (67, 72))	('papillary morphology', 'Phenotype', 'HP:0007482', (77, 97))
136810	26604437	Cluster C showed TP53 mutations as well as enrichment with RB1 mutations and amplifications of E2F3 and CCNE1.	('mutations', 'Var', (63, 72))	('RB1', 'Gene', (59, 62))	('men', 'Species', '9606', (49, 52))	('E2F3', 'Gene', '1871', (95, 99))	('RB1', 'Gene', '5925', (59, 62))	('CCNE1', 'Gene', (104, 109))	('CCNE1', 'Gene', '898', (104, 109))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', '7157', (17, 21))	('E2F3', 'Gene', (95, 99))	('TP53', 'Gene', (17, 21))
136812	26604437	Mutations in individual genes were not overly prevalent (11-63%), but mutations in one or more target genes were found in 88% of primary tumors and 88% of recurrent tumors.	('tumors', 'Disease', (137, 143))	('mutations', 'Var', (70, 79))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('found', 'Reg', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
136814	26604437	Epigenetic alterations, such as DNA methylation, are frequently observed in tumors.	('DNA methylation', 'Var', (32, 47))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('tumors', 'Disease', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('DNA methylation', 'biological_process', 'GO:0006306', ('32', '47'))
136815	26604437	DNA methylation is associated with downregulation of tumor suppressor genes and may contribute to the development of bladder cancer.	('contribute', 'Reg', (84, 94))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (117, 131))	('methylation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('downregulation', 'NegReg', (35, 49))	('bladder cancer', 'Disease', 'MESH:D001749', (117, 131))	('tumor', 'Disease', (53, 58))	('men', 'Species', '9606', (109, 112))	('bladder cancer', 'Disease', (117, 131))	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))
136819	26604437	Methylation of CDH1, FHIT, LAMC2, RASSF1A, TIMP3, SFRP1, SOX9, PMF1 and RUNX3 genes is associated with poor survival in muscle-invasive bladder cancer.	('SFRP1', 'Gene', (50, 55))	('SOX9', 'Gene', '6662', (57, 61))	('RUNX3', 'Gene', (72, 77))	('TIMP3', 'Gene', '7078', (43, 48))	('muscle-invasive bladder cancer', 'Disease', (120, 150))	('TIMP3', 'Gene', (43, 48))	('FHIT', 'Gene', (21, 25))	('CDH1', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('LAMC2', 'Gene', (27, 32))	('Methylation', 'Var', (0, 11))	('associated', 'Reg', (87, 97))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('FHIT', 'Gene', '2272', (21, 25))	('RASSF1A', 'Gene', '11186', (34, 41))	('SFRP1', 'Gene', '6422', (50, 55))	('PMF1', 'Gene', (63, 67))	('invasive bladder', 'Phenotype', 'HP:0100645', (127, 143))	('PMF1', 'Gene', '11243', (63, 67))	('LAMC2', 'Gene', '3918', (27, 32))	('RASSF1A', 'Gene', (34, 41))	('RUNX3', 'Gene', '864', (72, 77))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (120, 150))	('poor', 'NegReg', (103, 107))	('SOX9', 'Gene', (57, 61))	('CDH1', 'Gene', '999', (15, 19))
136820	26604437	Methylation of RASSF1A and HOXB2 were associated with bladder tumor stage, grade and tumor progression.	('grade', 'CPA', (75, 80))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('associated', 'Reg', (38, 48))	('RASSF1A', 'Gene', '11186', (15, 22))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', (62, 67))	('bladder tumor', 'Disease', 'MESH:D001749', (54, 67))	('bladder tumor', 'Phenotype', 'HP:0009725', (54, 67))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('HOXB2', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('RASSF1A', 'Gene', (15, 22))	('HOXB2', 'Gene', '3212', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('bladder tumor', 'Disease', (54, 67))
136822	26604437	Methylation of VAX1, KCNV1, TAL1, PPOX1 and CFTR in 212 urine samples from patients (157 with primary tumors and 55 with recurrent tumors) and 190 samples from healthy controls was found to detect both primary and recurrent disease, with a sensitivity of 89% and a specificity of 88%.	('VAX1', 'Gene', (15, 19))	('CFTR', 'Gene', '1080', (44, 48))	('PPOX1', 'Gene', (34, 39))	('TAL1', 'Gene', '6886', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('CFTR', 'Gene', (44, 48))	('recurrent disease', 'Disease', (214, 231))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('Methylation', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('KCNV1', 'Gene', (21, 26))	('KCNV1', 'Gene', '27012', (21, 26))	('TAL1', 'Gene', (28, 32))	('tumors', 'Disease', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('patients', 'Species', '9606', (75, 83))	('primary', 'Disease', (202, 209))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('detect', 'Reg', (190, 196))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('VAX1', 'Gene', '11023', (15, 19))
136823	26604437	studied the use of APC, TERT and EDNRB methylation in a urinary test for the detection of recurrent bladder cancer.	('APC', 'Gene', (19, 22))	('bladder cancer', 'Disease', (100, 114))	('methylation', 'Var', (39, 50))	('APC', 'Gene', '324', (19, 22))	('recurrent bladder', 'Phenotype', 'HP:0012786', (90, 107))	('TERT', 'Gene', (24, 28))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('EDNRB', 'Gene', '1910', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (100, 114))	('TERT', 'Gene', '7015', (24, 28))	('bladder cancer', 'Disease', 'MESH:D001749', (100, 114))	('EDNRB', 'Gene', (33, 38))	('APC', 'cellular_component', 'GO:0005680', ('19', '22'))
136824	26604437	In conclusion, methylation markers for bladder cancer diagnosis are still at an early stage compared with other FDA-approved markers and need further validation.	('methylation', 'Var', (15, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (39, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (39, 53))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('bladder cancer', 'Disease', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
136840	26604437	Downregulation of miRNAs, including those that target the FGFR3 pathway, such as miR-145, miR-101, miR-100 and miR-99a, may be associated with increased expression of FGFR3 in the absence of FGFR3 mutation and has been observed in low-grade NMIBC.	('increased', 'PosReg', (143, 152))	('FGFR3', 'Gene', (191, 196))	('miR-99a', 'Gene', (111, 118))	('Downregulation', 'NegReg', (0, 14))	('FGFR3', 'Gene', '2261', (191, 196))	('expression', 'MPA', (153, 163))	('miR-101', 'Var', (90, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('miR-100', 'Gene', '406892', (99, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('191', '195'))	('miR-99a', 'Gene', '407055', (111, 118))	('miR-145', 'Gene', '406937', (81, 88))	('FGFR3', 'Gene', (58, 63))	('low-grade NMIBC', 'Disease', (231, 246))	('mutation', 'Var', (197, 205))	('FGFR3', 'Gene', (167, 172))	('FGFR3', 'Gene', '2261', (58, 63))	('miR-145', 'Gene', (81, 88))	('FGFR3', 'Gene', '2261', (167, 172))	('miR-100', 'Gene', (99, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('167', '171'))
136842	26604437	screened 723 miRNAs for potential diagnostic and prognostic value in bladder cancer and found seven upregulated miRNAs (miR-20a, miR-106b, miR-130b, miR-141, miR-200a, miR-200a and miR-205) and eight downregulated miRNAs (miR-100, miR-125b, miR-130a, miR-139-5p, miR-145, miR-199a-3p, miR-214 and miR-222).	('miR-214', 'Gene', (285, 292))	('miR-200a', 'Gene', (158, 166))	('miR-145', 'Gene', (263, 270))	('miR-130b', 'Gene', '406920', (139, 147))	('miR-100', 'Gene', '406892', (222, 229))	('miR-130b', 'Gene', (139, 147))	('upregulated', 'PosReg', (100, 111))	('miR-222', 'Gene', '407007', (297, 304))	('miR-130a', 'Gene', '406919', (241, 249))	('miR-205', 'Gene', '406988', (181, 188))	('miR-130a', 'Gene', (241, 249))	('miR-199a-3p', 'Gene', (272, 283))	('miR-200a', 'Gene', '406983', (168, 176))	('miR-139-5p', 'Var', (251, 261))	('miR-199a-3p', 'Gene', '406977', (272, 283))	('miR-141', 'Gene', '406933', (149, 156))	('miR-20a', 'Gene', (120, 127))	('miR-106b', 'Gene', '406900', (129, 137))	('miR-20a', 'Gene', '406982', (120, 127))	('miR-214', 'Gene', '406996', (285, 292))	('miR-200a', 'Gene', '406983', (158, 166))	('miR-205', 'Gene', (181, 188))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('miR-100', 'Gene', (222, 229))	('miR-106b', 'Gene', (129, 137))	('miR-141', 'Gene', (149, 156))	('bladder cancer', 'Disease', 'MESH:D001749', (69, 83))	('bladder cancer', 'Disease', (69, 83))	('miR-222', 'Gene', (297, 304))	('miR-200a', 'Gene', (168, 176))	('miR-145', 'Gene', '406937', (263, 270))	('bladder cancer', 'Phenotype', 'HP:0009725', (69, 83))	('miR-125b', 'Var', (231, 239))
136844	26604437	The combination of four miRNAs (miR-130b, miR-141, miR-199-3p and miR-205) resulted in correct classification of 100% of tissue samples.	('miR-141', 'Gene', '406933', (42, 49))	('miR-130b', 'Gene', '406920', (32, 40))	('miR-130b', 'Gene', (32, 40))	('miR-205', 'Gene', (66, 73))	('miR-141', 'Gene', (42, 49))	('miR-199-3p', 'Var', (51, 61))	('miR-205', 'Gene', '406988', (66, 73))
136850	26604437	Another panel of miRNAs including miR-135b, miR-15b and miR-1224-3p could detect bladder cancer with 94% sensitivity and 51% specificity.	('bladder cancer', 'Phenotype', 'HP:0009725', (81, 95))	('miR-1224-3p', 'Var', (56, 67))	('miR-135b', 'Gene', (34, 42))	('miR-15b', 'Gene', (44, 51))	('bladder cancer', 'Disease', (81, 95))	('bladder cancer', 'Disease', 'MESH:D001749', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('detect', 'Reg', (74, 80))	('miR-135b', 'Gene', '442891', (34, 42))	('miR-15b', 'Gene', '406949', (44, 51))
136856	26604437	Identification of novel genomic alterations and advances in molecular techniques may result in the development of a new generation of molecules that could be used in clinical practice.	('alterations', 'Var', (32, 43))	('result in', 'Reg', (85, 94))	('men', 'Species', '9606', (106, 109))
136978	24671186	Aberrant expression, localization and glycosylation of mucins are characteristic events of multiple malignancies (pancreatic, ovarian, prostate and gastric, lung, and breast).	('prostate', 'Disease', (135, 143))	('ovarian', 'Disease', (126, 133))	('pancreatic', 'Disease', 'MESH:D010195', (114, 124))	('Aberrant', 'Var', (0, 8))	('glycosylation', 'biological_process', 'GO:0070085', ('38', '51'))	('pancreatic', 'Disease', (114, 124))	('mucin', 'Gene', '100508689', (55, 60))	('multiple malignancies', 'Disease', 'MESH:D009369', (91, 112))	('localization', 'biological_process', 'GO:0051179', ('21', '33'))	('multiple malignancies', 'Disease', (91, 112))	('glycosylation', 'MPA', (38, 51))	('gastric', 'Disease', (148, 155))	('mucin', 'Gene', (55, 60))	('lung', 'Disease', (157, 161))	('localization', 'MPA', (21, 33))
136984	24671186	Deregulated expression of MUC1 is a prominent characteristic of various types of cancers and inflammatory diseases.	('Deregulated', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('expression', 'MPA', (12, 22))	('MUC1', 'Gene', (26, 30))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('MUC1', 'Gene', '4582', (26, 30))	('inflammatory diseases', 'Disease', (93, 114))
137014	24671186	Since the loss of MUC4 expression was observed in non-invasive papillary UC and urothelial CIS cases, the present study suggests that loss of MUC4 might be one of the early events during development of urothelial carcinoma.	('MUC4', 'Gene', '4585', (18, 22))	('MUC4', 'Gene', '4585', (142, 146))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (202, 222))	('MUC4', 'Gene', (18, 22))	('MUC4', 'Gene', (142, 146))	('non-invasive papillary UC', 'Disease', (50, 75))	('urothelial CIS', 'Disease', (80, 94))	('urothelial carcinoma', 'Disease', (202, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('loss', 'Var', (134, 138))
137018	24671186	Singh et al, suggested the epigenetic mechanism might be regulating the MUC4 expression during pathogenesis of prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('expression', 'MPA', (77, 87))	('regulating', 'Reg', (57, 67))	('prostate cancer', 'Disease', (111, 126))	('MUC4', 'Gene', '4585', (72, 76))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('MUC4', 'Gene', (72, 76))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('pathogenesis', 'biological_process', 'GO:0009405', ('95', '107'))	('epigenetic', 'Var', (27, 37))
137067	19887917	Staining of carcinoid tumors was also significantly higher with SPT24 clone, which detected 14 of 23 (60.8%) cases as opposed to the 8G7G3/1 clone which detected 4 of 23 (17.4%) cases (P=0.003)(Figure 1c).	('Staining', 'MPA', (0, 8))	('SPT24 clone', 'Var', (64, 75))	('carcinoid tumors', 'Disease', (12, 28))	('carcinoid tumors', 'Disease', 'MESH:D002276', (12, 28))	('SPT', 'molecular_function', 'GO:0004758', ('64', '67'))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('SPT', 'molecular_function', 'GO:0004760', ('64', '67'))	('carcinoid', 'Phenotype', 'HP:0100570', (12, 21))	('higher', 'PosReg', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))
137092	19887917	For instance, 14 of 28 glioblastoma multiforme tumors stained with TTF-1 clone SPT24, while all of these cases were negative using the 8G7G3-1 TTF-1 clone.	('SPT', 'molecular_function', 'GO:0004760', ('79', '82'))	('SPT', 'molecular_function', 'GO:0004758', ('79', '82'))	('glioblastoma multiforme tumors', 'Disease', (23, 53))	('glioblastoma', 'Phenotype', 'HP:0012174', (23, 35))	('glioblastoma multiforme tumors', 'Disease', 'MESH:D005909', (23, 53))	('TTF-1', 'Gene', (67, 72))	('stained', 'Reg', (54, 61))	('SPT24', 'Var', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
137119	32729250	 CD8 lymphocytes in tumors and nonsynonymous mutational load correlate with prognosis of bladder cancer patients treated with immune checkpoint inhibitors Anti-programed cell death 1 checkpoint inhibitors have recently demonstrated effectiveness against metastatic cancers including urothelial carcinoma.	('CD8', 'Gene', '925', (1, 4))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('cell death', 'biological_process', 'GO:0008219', ('170', '180'))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('nonsynonymous mutational', 'Var', (31, 55))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (283, 303))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('cancers', 'Disease', 'MESH:D009369', (265, 272))	('CD8', 'Gene', (1, 4))	('tumors', 'Disease', (20, 26))	('urothelial carcinoma', 'Disease', (283, 303))	('patients', 'Species', '9606', (104, 112))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('cancers', 'Disease', (265, 272))
137124	32729250	We performed whole exome sequencing of 14 cases and found that patients carrying higher numbers of somatic mutations received greater benefit from immunotherapy (P = .034) and one patient who had high microsatellite instability has survived for 1034 days.	('mutations', 'Var', (107, 116))	('patient', 'Species', '9606', (63, 70))	('patients', 'Species', '9606', (63, 71))	('benefit', 'PosReg', (134, 141))	('patient', 'Species', '9606', (180, 187))
137125	32729250	CD8 infiltration in tumors and nonsynonymous mutation load might be useful predictive markers for immune checkpoint inhibitors for bladder cancer patients.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('bladder cancer', 'Disease', (131, 145))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', '925', (0, 3))	('bladder cancer', 'Phenotype', 'HP:0009725', (131, 145))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('nonsynonymous mutation load', 'Var', (31, 58))	('patients', 'Species', '9606', (146, 154))	('bladder cancer', 'Disease', 'MESH:D001749', (131, 145))
137143	32729250	CD8 positivity in the tumor tissues was significantly associated with longer cancer-specific survival (Figures 2A and S1).	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('positivity', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('CD8', 'Gene', (0, 3))	('longer', 'PosReg', (70, 76))	('CD8', 'Gene', '925', (0, 3))	('tumor', 'Disease', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
137145	32729250	On the other hand, the PD-L1 positivity showed no significant association with the cancer-specific survival (Figure 2B).	('PD-L1', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('PD-L1', 'Gene', '29126', (23, 28))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('positivity', 'Var', (29, 39))	('cancer', 'Disease', (83, 89))
137151	32729250	We obtained an average sequencing depth of 73.8x per base and identified a total of 2856 nonsynonymous mutations (8 to 674 mutations per tumor).	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', (137, 142))	('nonsynonymous mutations', 'Var', (89, 112))	('tumor', 'Disease', 'MESH:D009369', (137, 142))
137152	32729250	The numbers of nonsynonymous mutations showed significant correlation with cancer-specific survival (Figure 3B, R = 0.588, P = .034).	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('nonsynonymous mutations', 'Var', (15, 38))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
137156	32729250	Eight patients carried mutations in DNA damage repair genes, FANCA, RECQL4, RECQL5, ATM, TP53, ERCC6, or XPA, and 1 showed a mutation in the DNA polymerase epsilon (POLE) gene.	('TP53', 'Gene', '7157', (89, 93))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('TP53', 'Gene', (89, 93))	('ATM', 'Gene', (84, 87))	('ERCC6', 'Gene', '2074', (95, 100))	('FANCA', 'Gene', '2175', (61, 66))	('RECQL4', 'Gene', '9401', (68, 74))	('XPA, and 1', 'Gene', '7507;11169', (105, 115))	('ERCC6', 'Gene', (95, 100))	('mutations', 'Var', (23, 32))	('ATM', 'Gene', '472', (84, 87))	('FANCA', 'Gene', (61, 66))	('patients', 'Species', '9606', (6, 14))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('RECQL5', 'Gene', '9400', (76, 82))	('POLE', 'Gene', (165, 169))	('RECQL4', 'Gene', (68, 74))	('RECQL5', 'Gene', (76, 82))
137157	32729250	Five of these 8 patients had a higher number of somatic mutations (216 to 674 mutations) and showed the tendency of a longer cancer-specific survival (601 to 1133 d).	('patients', 'Species', '9606', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('216', 'Var', (67, 70))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('longer', 'PosReg', (118, 124))	('somatic', 'MPA', (48, 55))
137158	32729250	The patient who carried the POLE mutation had a total of 187 nonsynonymous mutations, showed PR, but was excluded from the survival analysis because of death from a non-cancer-related disease.	('cancer-related disease', 'Disease', 'MESH:D009369', (169, 191))	('cancer-related disease', 'Disease', (169, 191))	('mutation', 'Var', (33, 41))	('nonsynonymous', 'MPA', (61, 74))	('patient', 'Species', '9606', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))
137167	32729250	However, in the future, PD-L1 might be more useful when it is used together with the other parameters or could be applied by semiquantitative algorithms.28  Nonsynonymous mutational burdens as well as the number of the possible neoantigens have also been reported as possible useful predictors in melanoma, non-small cell lung cancer, and bladder cancer.	('lung cancer', 'Disease', (322, 333))	('lung cancer', 'Phenotype', 'HP:0100526', (322, 333))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('bladder cancer', 'Phenotype', 'HP:0009725', (339, 353))	('melanoma', 'Disease', 'MESH:D008545', (297, 305))	('melanoma', 'Phenotype', 'HP:0002861', (297, 305))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('melanoma', 'Disease', (297, 305))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (311, 333))	('PD-L1', 'Gene', (24, 29))	('bladder cancer', 'Disease', 'MESH:D001749', (339, 353))	('bladder cancer', 'Disease', (339, 353))	('lung cancer', 'Disease', 'MESH:D008175', (322, 333))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (307, 333))	('Nonsynonymous mutational burdens', 'Var', (157, 189))	('PD-L1', 'Gene', '29126', (24, 29))
137168	32729250	Such tumors possessing higher numbers of somatic mutations are expected to have more immunogenic neoantigens attracting T cells, facilitating clinical response by immune checkpoint blockades.29, 30, 31, 32 A phase 2 trial of atezolizumab in locally advanced and metastatic urothelial cancer revealed the importance of mutational load as a biomarker of response.17 In our study, we identified a total of 2856 nonsynonymous mutations in 14 tumors and also found a statistically significant correlation between nonsynonymous mutation load and cancer-specific survival.	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('tumors', 'Disease', 'MESH:D009369', (438, 444))	('cancer', 'Disease', (540, 546))	('nonsynonymous mutations', 'Var', (408, 431))	('urothelial cancer', 'Disease', 'MESH:D014523', (273, 290))	('cancer', 'Phenotype', 'HP:0002664', (540, 546))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('nonsynonymous mutation load', 'Var', (508, 535))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('urothelial cancer', 'Disease', (273, 290))	('cancer', 'Disease', (284, 290))	('tumors', 'Phenotype', 'HP:0002664', (438, 444))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('cancer', 'Disease', 'MESH:D009369', (540, 546))	('tumors', 'Disease', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (438, 443))	('atezolizumab', 'Chemical', 'MESH:C000594389', (225, 237))	('tumors', 'Disease', (438, 444))
137176	32729250	Our previous work in muscle-invasive bladder cancer showed that the low TCRbeta diversity (oligoclonal TIL expansion) was a good biomarker for longer relapse-free survival in combination with the neoantigen load.18 In this current study, we also show a tendency that oligoclonal expanded TILs in tumor microenvironments might lead to better prognosis among immune checkpoint inhibitor-treated bladder cancer patients (P = .055), though the number of the patients studied was small.	('invasive bladder', 'Phenotype', 'HP:0100645', (28, 44))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (21, 51))	('TCRbeta', 'Gene', '28695', (72, 79))	('tumor', 'Disease', (296, 301))	('patients', 'Species', '9606', (408, 416))	('oligoclonal expanded', 'Var', (267, 287))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('bladder cancer', 'Disease', 'MESH:D001749', (37, 51))	('better', 'PosReg', (334, 340))	('muscle-invasive bladder cancer', 'Disease', (21, 51))	('cancer', 'Phenotype', 'HP:0002664', (401, 407))	('bladder cancer', 'Phenotype', 'HP:0009725', (37, 51))	('patients', 'Species', '9606', (454, 462))	('TCRbeta', 'Gene', (72, 79))	('bladder cancer', 'Disease', 'MESH:D001749', (393, 407))	('bladder cancer', 'Disease', (393, 407))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('bladder cancer', 'Phenotype', 'HP:0009725', (393, 407))
137177	32729250	It has been suggested that the higher mutational load in tumors may be one of the key predictors for good clinical responses in the cancer immunotherapy.31, 32 A phase 2 trial of atezolizumab in locally advanced and metastatic urothelial cancer revealed the importance of mutational load as a biomarker of response.16 In our study, we identified a total of 2856 nonsynonymous mutations in 14 tumors and found the statistically significant correlation between the nonsynonymous mutation load and the cancer-specific survival.	('nonsynonymous mutations', 'Var', (362, 385))	('tumors', 'Disease', 'MESH:D009369', (392, 398))	('urothelial cancer', 'Disease', 'MESH:D014523', (227, 244))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('urothelial cancer', 'Disease', (227, 244))	('cancer', 'Disease', (499, 505))	('tumor', 'Phenotype', 'HP:0002664', (392, 397))	('cancer', 'Phenotype', 'HP:0002664', (499, 505))	('tumors', 'Phenotype', 'HP:0002664', (392, 398))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('atezolizumab', 'Chemical', 'MESH:C000594389', (179, 191))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', (392, 398))	('cancer', 'Disease', 'MESH:D009369', (499, 505))
137178	32729250	The US FDA already approved the MSI test for selection of patients for anti-PD1 drug (pembrolizumab) both pediatric and adult patients, regardless to tissue origins of cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('pembrolizumab', 'Chemical', 'MESH:C582435', (86, 99))	('anti-PD1', 'Var', (71, 79))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (58, 66))
137180	32729250	Taken together, we have investigated various immune-related factors in tumors from patients treated with immune checkpoint inhibitors and found that the extent of CD8+ infiltration into tumor tissues and the number of nonsynonymous mutations, but not PD-L1 status, were good predictors of clinical outcomes.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('PD-L1', 'Gene', '29126', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('patients', 'Species', '9606', (83, 91))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('nonsynonymous mutations', 'Var', (218, 241))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('PD-L1', 'Gene', (251, 256))	('tumors', 'Disease', (71, 77))	('CD8', 'Gene', (163, 166))	('tumor', 'Disease', (71, 76))	('CD8', 'Gene', '925', (163, 166))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
137213	31788070	Each tumor harbors unique mutations, presents variable clinical outcomes and is associated with specific risk factors.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (5, 10))	('harbors', 'Reg', (11, 18))
137228	31788070	GSE9844 included 26 OTSCC and 12 normal tissues, GSE13601 included 31 OTSCC and 26 normal tissues, GSE31056 included 22 OTSCC and 24 normal tissues, and GSE75538 included 14 OTSCC and 14 normal tissues.	('OTSCC', 'Disease', 'MESH:D002294', (20, 25))	('OTSCC', 'Disease', 'MESH:D002294', (120, 125))	('OTSCC', 'Disease', 'MESH:D002294', (174, 179))	('GSE75538', 'Var', (153, 161))	('OTSCC', 'Disease', (20, 25))	('OTSCC', 'Disease', (120, 125))	('OTSCC', 'Disease', (174, 179))	('GSE9844', 'Var', (0, 7))	('OTSCC', 'Disease', 'MESH:D002294', (70, 75))	('OTSCC', 'Disease', (70, 75))	('GSE31056', 'Var', (99, 107))	('GSE13601', 'Var', (49, 57))
137267	31788070	These genes serve important functions in numerous physiological and pathological processes involved in tumor progression and can promote tumor-induced angiogenesis and extracellular matrix disassembly, enhancing therefore tumor invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('extracellular matrix disassembly', 'CPA', (168, 200))	('tumor', 'Disease', (137, 142))	('promote', 'PosReg', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', (103, 108))	('genes', 'Var', (6, 11))	('enhancing', 'PosReg', (202, 211))	('extracellular matrix disassembly', 'biological_process', 'GO:0022617', ('168', '200'))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('angiogenesis', 'biological_process', 'GO:0001525', ('151', '163'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('168', '188'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
137305	28643244	Eli Lilly's ramucirumab, galunisertib, LY2510924 or LY3022855 in solid tumours (August and October 2015).	('solid tumours', 'Disease', (65, 78))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))	('LY2510924', 'Chemical', 'MESH:C000595455', (39, 48))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('ramucirumab', 'Chemical', 'MESH:C543333', (12, 23))	('solid tumours', 'Disease', 'MESH:D009369', (65, 78))	('LY3022855', 'Chemical', '-', (52, 61))	('LY3022855', 'Var', (52, 61))	('galunisertib', 'Chemical', 'MESH:C557799', (25, 37))	('LY2510924', 'Var', (39, 48))
137341	28643244	In a phase I study (NCT02088112), a combination of durvalumab and gefitinib showed early clinical activity in tyrosine kinase inhibitor-naive patients with EGFR mutant advanced NSCLC.	('mutant', 'Var', (161, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('156', '160'))	('gefitinib', 'Chemical', 'MESH:D000077156', (66, 75))	('EGFR', 'Gene', '1956', (156, 160))	('EGFR', 'Gene', (156, 160))	('NSCLC', 'Disease', (177, 182))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('119', '135'))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('durvalumab', 'Chemical', 'MESH:C000613593', (51, 61))	('patients', 'Species', '9606', (142, 150))
137349	28643244	Durvalumab plus darafenib plus trametinib in a phase I/II trial (NCT02027961) in patients with BRAF mutant or wild type metastatic or unresectable melanoma.	('mutant', 'Var', (100, 106))	('metastatic', 'Disease', (120, 130))	('darafenib', 'Chemical', '-', (16, 25))	('BRAF', 'Gene', '673', (95, 99))	('patients', 'Species', '9606', (81, 89))	('Durvalumab', 'Chemical', 'MESH:C000613593', (0, 10))	('trametinib', 'Chemical', 'MESH:C560077', (31, 41))	('BRAF', 'Gene', (95, 99))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))
137352	28643244	Durvalumab plus AZD9150 (antisense oligonucleotide against STAT3) or AZD5069 (CXCR2 antagonist) in a phase Ib/II trial (NCT02499328) in patients with advanced malignancies.	('AZD5069', 'Chemical', 'MESH:C000597960', (69, 76))	('AZD5069', 'Var', (69, 76))	('malignancies', 'Disease', 'MESH:D009369', (159, 171))	('AZD9150', 'Var', (16, 23))	('oligonucleotide', 'Chemical', 'MESH:D009841', (35, 50))	('Durvalumab', 'Chemical', 'MESH:C000613593', (0, 10))	('STAT3', 'Gene', '6774', (59, 64))	('malignancies', 'Disease', (159, 171))	('patients', 'Species', '9606', (136, 144))	('CXCR2', 'Gene', '3579', (78, 83))	('STAT3', 'Gene', (59, 64))	('AZD9150', 'Chemical', 'MESH:C000610954', (16, 23))	('CXCR2', 'Gene', (78, 83))
137375	28643244	Furthermore, a biomarker-directed phase Ib trial (BISCAY; NCT02546661) is evaluating durvalumab alone or in combination with AZD4547 (fibroblast growth factor receptor tyrosine kinase 1, 2 and 3 inhibitor), AZD1775 (WEE1 tyrosine kinase inhibitor), olaparib or vistusertib in patients with muscle invasive bladder cancer.	('patients', 'Species', '9606', (276, 284))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (290, 320))	('muscle invasive bladder cancer', 'Disease', (290, 320))	('AZD4547', 'Var', (125, 132))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('230', '246'))	('durvalumab', 'Chemical', 'MESH:C000613593', (85, 95))	('AZD4547', 'Chemical', 'MESH:C572463', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('WEE1', 'Gene', '7465', (216, 220))	('AZD1775', 'Var', (207, 214))	('AZD1775', 'Chemical', 'MESH:C549567', (207, 214))	('bladder cancer', 'Phenotype', 'HP:0009725', (306, 320))	('vistusertib', 'Chemical', 'MESH:C585537', (261, 272))	('invasive bladder', 'Phenotype', 'HP:0100645', (297, 313))	('WEE1', 'Gene', (216, 220))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('134', '158'))	('olaparib', 'Chemical', 'MESH:C531550', (249, 257))
137383	28643244	2.3.4), MEDI0526 (NCT02705482), monalizumab (NCT02671435), selumetinib (NCT02586987), AZD1775 (NCT02617277), MEDI9447 (NCT02503774), tremelimumab in Japanese patients (NCT01938612) and tremelimumab plus first-line chemotherapy (NCT02658214) in advanced solid tumours.	('tumours', 'Phenotype', 'HP:0002664', (259, 266))	('NCT02617277', 'Var', (95, 106))	('tremelimumab', 'Chemical', 'MESH:C520704', (133, 145))	('MEDI9447', 'Chemical', '-', (109, 117))	('advanced solid tumours', 'Disease', 'MESH:D006223', (244, 266))	('NCT02671435', 'Var', (45, 56))	('NCT02705482', 'Var', (18, 29))	('MEDI0526', 'Chemical', '-', (8, 16))	('NCT02586987', 'Var', (72, 83))	('AZD1775', 'Chemical', 'MESH:C549567', (86, 93))	('tremelimumab', 'Chemical', 'MESH:C520704', (185, 197))	('NCT02503774', 'Var', (119, 130))	('tumour', 'Phenotype', 'HP:0002664', (259, 265))	('advanced solid tumours', 'Disease', (244, 266))	('monalizumab', 'Chemical', '-', (32, 43))	('patients', 'Species', '9606', (158, 166))	('selumetinib', 'Chemical', 'MESH:C517975', (59, 70))
137414	27267581	Alkylating agents were associated with the lowest VTE rates at 1.3% [0.1-3.7%].	('VTE', 'Disease', 'MESH:D054556', (50, 53))	('VTE', 'Disease', (50, 53))	('lowest', 'NegReg', (43, 49))	('Alkylating', 'Var', (0, 10))
137450	27267581	Monoclonal antibodies were found to be associated with a higher risk (RR 1.34) of thrombosis than oral tyrosine kinase inhibitors (RR 1.16).	('thrombosis', 'Disease', 'MESH:D013927', (82, 92))	('thrombosis', 'Disease', (82, 92))	('Monoclonal antibodies', 'Var', (0, 21))
137472	32795296	Tyrosine-kinase deregulations are observed during tumor progressions via mutations, amplification, and chromosomal abnormalities which introduces these factors as important candidates of anti-cancer therapies.	('deregulations', 'PosReg', (16, 29))	('Tyrosine-kinase', 'Gene', (0, 15))	('amplification', 'Var', (84, 97))	('chromosomal abnormalities', 'Disease', (103, 128))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('mutations', 'Var', (73, 82))	('cancer', 'Disease', (192, 198))	('Tyrosine-kinase', 'Gene', '7294', (0, 15))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (103, 128))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
137481	32795296	Over the past decades, mutations in kinases have been shown to be engaged in bladder malignancies.	('bladder malignancies', 'Disease', 'MESH:D001749', (77, 97))	('bladder malignancies', 'Disease', (77, 97))	('bladder malignancies', 'Phenotype', 'HP:0009725', (77, 97))	('mutations', 'Var', (23, 32))	('kinases', 'Enzyme', (36, 43))	('engaged', 'Reg', (66, 73))
137487	32795296	Dysregulation of TKs by gain of function mutations or over expression occurs in various malignancies like BCa which accelerates tumor proliferation and progression.	('mutations', 'Var', (41, 50))	('BCa', 'Disease', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('over expression', 'PosReg', (54, 69))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))	('malignancies', 'Disease', (88, 100))	('accelerates', 'PosReg', (116, 127))	('TKs', 'Gene', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('gain of function', 'PosReg', (24, 40))	('tumor', 'Disease', (128, 133))	('progression', 'CPA', (152, 163))	('BCa', 'Phenotype', 'HP:0009725', (106, 109))
137496	32795296	HER2 up regulation is mainly due to gene amplification which triggers intracellular pathways that promote cell proliferation, migration, and aggressiveness of tumor cells.	('cell proliferation', 'CPA', (106, 124))	('regulation', 'biological_process', 'GO:0065007', ('8', '18'))	('promote', 'PosReg', (98, 105))	('aggressiveness of tumor', 'Disease', 'MESH:D001523', (141, 164))	('intracellular', 'cellular_component', 'GO:0005622', ('70', '83'))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('up regulation', 'PosReg', (5, 18))	('triggers', 'Reg', (61, 69))	('aggressiveness of tumor', 'Disease', (141, 164))	('HER2', 'Gene', (0, 4))	('gene amplification', 'Var', (36, 54))	('HER2', 'Gene', '2064', (0, 4))	('migration', 'CPA', (126, 135))	('aggressiveness', 'Phenotype', 'HP:0000718', (141, 155))	('cell proliferation', 'biological_process', 'GO:0008283', ('106', '124'))
137497	32795296	Various studies have been reported that there were significant associations between tumor grade and HER-2 up regulation or gene amplification among different population of BCa patients.	('BCa', 'Disease', (172, 175))	('patients', 'Species', '9606', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('regulation', 'biological_process', 'GO:0065007', ('109', '119'))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('up regulation', 'PosReg', (106, 119))	('HER-2', 'Gene', '2064', (100, 105))	('HER-2', 'Gene', (100, 105))	('BCa', 'Phenotype', 'HP:0009725', (172, 175))	('gene amplification', 'Var', (123, 141))
137498	32795296	The pT2 tumors have a considerable amount of mutations compared with pTa/Ti tumors.	('pTa', 'molecular_function', 'GO:0008959', ('69', '72'))	('mutations', 'Var', (45, 54))	('pT2', 'Disease', (4, 7))	('Ti tumors', 'Disease', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('pTa', 'Gene', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('pTa', 'Gene', '171558', (69, 72))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('Ti tumors', 'Disease', 'MESH:D000072676', (73, 82))
137500	32795296	A significant high frequency of chromosome 17 polysomy (97%) and increased HER2/neu copy number (92%) were also observed in a sample of BCa patients.	('BCa', 'Disease', (136, 139))	('increased', 'PosReg', (65, 74))	('chromosome', 'Var', (32, 42))	('polysomy', 'Var', (46, 54))	('HER2/neu', 'Gene', '2064', (75, 83))	('copy', 'MPA', (84, 88))	('patients', 'Species', '9606', (140, 148))	('HER2/neu', 'Gene', (75, 83))	('BCa', 'Phenotype', 'HP:0009725', (136, 139))	('chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))
137501	32795296	Polysomy 17 and HER2/neu up regulation were frequent in G3 pT2 tumors.	('Polysomy 17', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('HER2/neu', 'Gene', '2064', (16, 24))	('regulation', 'biological_process', 'GO:0065007', ('28', '38'))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('HER2/neu', 'Gene', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('G3 pT2', 'Gene', (56, 62))	('up regulation', 'PosReg', (25, 38))
137502	32795296	Another study has been shown that there was HER2/neu abnormality in pT2 BCa tumors before muscle invasion.	('HER2/neu', 'Gene', '2064', (44, 52))	('pT2', 'Gene', (68, 71))	('BCa', 'Phenotype', 'HP:0009725', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('HER2/neu', 'Gene', (44, 52))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('BCa tumors', 'Disease', (72, 82))	('BCa tumors', 'Disease', 'MESH:D009369', (72, 82))	('abnormality', 'Var', (53, 64))
137503	32795296	Polysomy 17 and HER2/neu amplification and up regulation were correlated with advanced disease.	('regulation', 'biological_process', 'GO:0065007', ('46', '56'))	('Polysomy 17', 'Var', (0, 11))	('HER2/neu', 'Gene', '2064', (16, 24))	('up regulation', 'PosReg', (43, 56))	('advanced disease', 'Disease', (78, 94))	('HER2/neu', 'Gene', (16, 24))	('amplification', 'Var', (25, 38))
137505	32795296	A quarter of patients experiencing cystectomy and lymphadenectomy for N0M0 staged BCa showed lymph node metastases which resulted in death among two thirds of patients.	('death', 'Disease', (133, 138))	('metastases', 'Disease', (104, 114))	('metastases', 'Disease', 'MESH:D009362', (104, 114))	('patients', 'Species', '9606', (13, 21))	('N0M0', 'Var', (70, 74))	('resulted in', 'Reg', (121, 132))	('patients', 'Species', '9606', (159, 167))	('BCa', 'Phenotype', 'HP:0009725', (82, 85))	('death', 'Disease', 'MESH:D003643', (133, 138))	('BCa', 'Disease', (82, 85))
137508	32795296	HER2 amplification was also significantly associated with poor prognosis.	('associated', 'Reg', (42, 52))	('amplification', 'Var', (5, 18))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
137522	32795296	HER2 positive patients had markedly lower progression-free survival in comparison with HER2 negative cases.	('HER2', 'Gene', '2064', (87, 91))	('lower', 'NegReg', (36, 41))	('progression-free survival', 'CPA', (42, 67))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('patients', 'Species', '9606', (14, 22))	('HER2', 'Gene', (87, 91))	('positive', 'Var', (5, 13))
137526	32795296	It has been reported that the patients with positive HER2 expression had significantly shorter disease-free survival compared with negative HER2 expression cases in a sample of MIBC patients.	('disease-free survival', 'CPA', (95, 116))	('MIBC', 'Chemical', '-', (177, 181))	('HER2', 'Gene', (53, 57))	('shorter', 'NegReg', (87, 94))	('expression', 'Var', (58, 68))	('HER2', 'Gene', '2064', (53, 57))	('patients', 'Species', '9606', (30, 38))	('patients', 'Species', '9606', (182, 190))	('HER2', 'Gene', (140, 144))	('HER2', 'Gene', '2064', (140, 144))	('positive', 'Var', (44, 52))
137537	32795296	It has been shown that there was significant association between HER2 protein up regulation, gene amplification, grade, and shorter recurrence period.	('HER2', 'Gene', '2064', (65, 69))	('regulation', 'biological_process', 'GO:0065007', ('81', '91'))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('up regulation', 'PosReg', (78, 91))	('gene amplification', 'Var', (93, 111))	('HER2', 'Gene', (65, 69))
137538	32795296	HER2 positivity was more in patients over 70 years old compared with patients under 70 years old.	('positivity', 'Var', (5, 15))	('HER2', 'Gene', (0, 4))	('patients', 'Species', '9606', (69, 77))	('HER2', 'Gene', '2064', (0, 4))	('patients', 'Species', '9606', (28, 36))
137543	32795296	Patients with high HER3 and HER4 expressions had increased survival rate.	('survival rate', 'CPA', (59, 72))	('increased', 'PosReg', (49, 58))	('high', 'Var', (14, 18))	('HER3', 'Gene', (19, 23))	('HER4', 'Gene', '2066', (28, 32))	('HER4', 'Gene', (28, 32))	('Patients', 'Species', '9606', (0, 8))	('HER3', 'Gene', '2065', (19, 23))
137552	32795296	Progression free survival rate in patients without any progression were significantly lower among EGFR positive cases.	('EGFR', 'Gene', (98, 102))	('lower', 'NegReg', (86, 91))	('positive', 'Var', (103, 111))	('Progression free survival', 'CPA', (0, 25))	('patients', 'Species', '9606', (34, 42))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))
137556	32795296	A significant association was also observed between high expression of EGFR and P53.	('P53', 'Gene', '7157', (80, 83))	('EGFR', 'Gene', '1956', (71, 75))	('high', 'Var', (52, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('71', '75'))	('EGFR', 'Gene', (71, 75))	('P53', 'Gene', (80, 83))
137558	32795296	Therefore, highly expressed EGFR is typically a delayed event during BCa progression due to genomic instability.	('EGFR', 'Gene', '1956', (28, 32))	('BCa', 'Phenotype', 'HP:0009725', (69, 72))	('BCa', 'Disease', (69, 72))	('highly expressed', 'Var', (11, 27))	('EGFR', 'Gene', (28, 32))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))
137581	32795296	There was also a significant correlation regarding EGFR_03 and EGFR_05 variants with a higher risk of BCa progression, and EGFR_05 and EGFR_1808 variants with a prolonged survival.	('variants', 'Var', (71, 79))	('EGFR', 'Gene', (123, 127))	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', (51, 55))	('EGFR', 'molecular_function', 'GO:0005006', ('135', '139'))	('EGFR', 'Gene', (63, 67))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('EGFR', 'Gene', '1956', (135, 139))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('EGFR', 'Gene', (135, 139))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('EGFR', 'Gene', '1956', (123, 127))	('BCa', 'Phenotype', 'HP:0009725', (102, 105))	('EGFR', 'Gene', '1956', (51, 55))	('BCa', 'Disease', (102, 105))
137582	32795296	EGFR_03 and EGFR_05 polymorphisms were correlated with higher BCa risk.	('BCa', 'Phenotype', 'HP:0009725', (62, 65))	('BCa', 'Disease', (62, 65))	('EGFR', 'Gene', (0, 4))	('correlated', 'Reg', (39, 49))	('polymorphisms', 'Var', (20, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('EGFR', 'Gene', '1956', (12, 16))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', (12, 16))	('EGFR', 'Gene', '1956', (0, 4))
137583	32795296	Patients with polymorphic EGFR alleles showed higher survival rate than patients with wild-type EGFR.	('EGFR', 'Gene', (26, 30))	('higher', 'PosReg', (46, 52))	('EGFR', 'Gene', (96, 100))	('alleles', 'Var', (31, 38))	('patients', 'Species', '9606', (72, 80))	('polymorphic', 'Var', (14, 25))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', '1956', (26, 30))	('survival rate', 'CPA', (53, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))	('EGFR', 'Gene', '1956', (96, 100))
137592	32795296	It has been reported that there was a significant association between nuclear positivity of c-MYC and HER2 up regulation among a group of transitional cell BCa patients.	('nuclear positivity', 'Var', (70, 88))	('up regulation', 'PosReg', (107, 120))	('patients', 'Species', '9606', (160, 168))	('BCa', 'Phenotype', 'HP:0009725', (156, 159))	('transitional cell BCa', 'Disease', (138, 159))	('HER2', 'Gene', (102, 106))	('c-MYC', 'Gene', (92, 97))	('regulation', 'biological_process', 'GO:0065007', ('110', '120'))	('HER2', 'Gene', '2064', (102, 106))	('c-MYC', 'Gene', '4609', (92, 97))
137605	32795296	There was a negative association between pT classification and IGF1R expression in which the IGF1R over expression was less in pT4 cases compared with lower pT categories.	('IGF1R', 'Gene', '3480', (93, 98))	('lower pT', 'Phenotype', 'HP:0032198', (151, 159))	('over expression', 'PosReg', (99, 114))	('pT4', 'Var', (127, 130))	('less', 'NegReg', (119, 123))	('IGF1R', 'Gene', (63, 68))	('IGF1R', 'Gene', (93, 98))	('IGF1R', 'Gene', '3480', (63, 68))
137620	32795296	It has been reported that the PIK3CA mutations and amplification were a preliminary and prevalent occurrence among NMIBC patients which were correlated with reduced tumor relapse.	('PIK3CA', 'Gene', (30, 36))	('tumor', 'Disease', (165, 170))	('MIBC', 'Chemical', '-', (116, 120))	('PIK3CA', 'Gene', '5290', (30, 36))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('amplification', 'Var', (51, 64))	('patients', 'Species', '9606', (121, 129))	('NMIBC', 'Disease', (115, 120))	('reduced', 'NegReg', (157, 164))
137621	32795296	In low-grade tumors there was also a correlation between PIK3CA and FGFR3 mutations.	('FGFR3', 'Gene', '2261', (68, 73))	('PIK3CA', 'Gene', '5290', (57, 63))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('68', '72'))	('mutations', 'Var', (74, 83))	('correlation', 'Reg', (37, 48))	('FGFR3', 'Gene', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('PIK3CA', 'Gene', (57, 63))
137622	32795296	Moreover, patients with wt PIK3CA and FGFR3 mutated tumors had significantly higher recurrence rates.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('FGFR3', 'Gene', '2261', (38, 43))	('recurrence rates', 'CPA', (84, 100))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('higher', 'PosReg', (77, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('tumors', 'Disease', (52, 58))	('PIK3CA', 'Gene', (27, 33))	('mutated', 'Var', (44, 51))	('FGFR3', 'Gene', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('patients', 'Species', '9606', (10, 18))	('PIK3CA', 'Gene', '5290', (27, 33))
137623	32795296	An exceptionally high rate of PIK3CA mutations and gene amplifications were particularly found in T1 and T2 tumors.	('PIK3CA', 'Gene', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PIK3CA', 'Gene', '5290', (30, 36))	('mutations', 'Var', (37, 46))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('found', 'Reg', (89, 94))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
137624	32795296	Mutations and amplifications in PIK3CA induced AKT function.	('AKT', 'Gene', (47, 50))	('PIK3CA', 'Gene', '5290', (32, 38))	('induced', 'Reg', (39, 46))	('AKT', 'Gene', '207', (47, 50))	('amplifications', 'Var', (14, 28))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', (32, 38))
137626	32795296	It has been shown that the majority of UCC cases had mutations in PIK3CA, FGFR3, HRAS, KRAS, BRAF, and AKT1 genes.	('BRAF', 'Gene', (93, 97))	('FGFR3', 'Gene', (74, 79))	('KRAS', 'Gene', (87, 91))	('UCC', 'Disease', (39, 42))	('HRAS', 'Gene', (81, 85))	('KRAS', 'Gene', '3845', (87, 91))	('AKT1', 'Gene', '207', (103, 107))	('AKT1', 'Gene', (103, 107))	('PIK3CA', 'Gene', (66, 72))	('mutations', 'Var', (53, 62))	('FGFR3', 'Gene', '2261', (74, 79))	('HRAS', 'Gene', '3265', (81, 85))	('PIK3CA', 'Gene', '5290', (66, 72))	('BRAF', 'Gene', '673', (93, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))
137627	32795296	Mutations were significantly more frequent in FGFR3, PIK3CA, and FGFR3.	('FGFR3', 'Gene', '2261', (65, 70))	('PIK3CA', 'Gene', '5290', (53, 59))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('FGFR3', 'Gene', (65, 70))	('FGFR3', 'Gene', '2261', (46, 51))	('frequent', 'Reg', (34, 42))	('Mutations', 'Var', (0, 9))	('FGFR3', 'Gene', (46, 51))	('PIK3CA', 'Gene', (53, 59))
137631	32795296	It has been observed that there was significant correlations between mutated FGFR3 and lower tumor stage/grade.	('FGFR3', 'Gene', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('mutated', 'Var', (69, 76))	('tumor', 'Disease', (93, 98))	('FGFR3', 'Gene', '2261', (77, 82))	('correlations', 'Interaction', (48, 60))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
137632	32795296	BCa patients with mutated FGFR3 had higher rate of vascularization in comparison with wild-type FGFR3.	('BCa', 'Disease', (0, 3))	('higher', 'PosReg', (36, 42))	('FGFR3', 'Gene', (26, 31))	('mutated', 'Var', (18, 25))	('FGFR3', 'Gene', '2261', (96, 101))	('vascularization', 'CPA', (51, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('FGFR3', 'Gene', (96, 101))	('patients', 'Species', '9606', (4, 12))	('FGFR3', 'Gene', '2261', (26, 31))	('BCa', 'Phenotype', 'HP:0009725', (0, 3))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))
137633	32795296	FVIII up regulation was the only angiogenic factor associated with mutated FGFR3.	('FVIII', 'Gene', '2157', (0, 5))	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('FGFR3', 'Gene', (75, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('mutated', 'Var', (67, 74))	('FVIII', 'Gene', (0, 5))	('FGFR3', 'Gene', '2261', (75, 80))	('up regulation', 'PosReg', (6, 19))
137634	32795296	The T1 MIBC patients with mutated FGFR3 had significantly higher risk of recurrence compared with wild-type FGFR3 carriers.	('FGFR3', 'Gene', '2261', (34, 39))	('patients', 'Species', '9606', (12, 20))	('FGFR3', 'Gene', '2261', (108, 113))	('FGFR3', 'Gene', (34, 39))	('MIBC', 'Chemical', '-', (7, 11))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('mutated', 'Var', (26, 33))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('T1 MIBC', 'Disease', (4, 11))	('FGFR3', 'Gene', (108, 113))
137638	32795296	FGFR3 mutations are more common in pTa bladder tumors, less regular in pT1G3 tumors, and rare in carcinoma in situ (pTis).	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('pTa bladder tumors', 'Disease', 'MESH:D001749', (35, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', (47, 53))	('carcinoma in situ', 'Disease', (97, 114))	('bladder tumors', 'Phenotype', 'HP:0009725', (39, 53))	('pTa bladder', 'Phenotype', 'HP:0000384', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutations', 'Var', (6, 15))	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('pT1', 'Gene', '58492', (71, 74))	('pTa bladder tumors', 'Disease', (35, 53))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (97, 114))	('bladder tumor', 'Phenotype', 'HP:0009725', (39, 52))	('pT1', 'Gene', (71, 74))	('carcinoma in situ', 'Disease', 'MESH:D002278', (97, 114))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('common', 'Reg', (25, 31))	('FGFR3', 'Gene', (0, 5))	('pTa', 'molecular_function', 'GO:0008959', ('35', '38'))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('FGFR3', 'Gene', '2261', (0, 5))
137639	32795296	The BCa patients with a FGFR3 mutation appeared to have a better outcome compared with mutation free patients.	('BCa', 'Phenotype', 'HP:0009725', (4, 7))	('patients', 'Species', '9606', (101, 109))	('FGFR3', 'Gene', '2261', (24, 29))	('BCa', 'Disease', (4, 7))	('mutation', 'Var', (30, 38))	('FGFR3', 'Gene', (24, 29))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))	('patients', 'Species', '9606', (8, 16))
137640	32795296	It has been reported that the FGFR3 and CK20 were efficient prognostic factors of pTa bladder tumors, since it can distinguish the differentiated tumors with FGFR3 mutations.	('CK20', 'Gene', (40, 44))	('FGFR3', 'Gene', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('pTa bladder tumors', 'Disease', 'MESH:D001749', (82, 100))	('FGFR3', 'Gene', '2261', (158, 163))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('FGFR3', 'Gene', (30, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('158', '162'))	('pTa', 'molecular_function', 'GO:0008959', ('82', '85'))	('CK20', 'Gene', '54474', (40, 44))	('tumors', 'Disease', (94, 100))	('FGFR3', 'Gene', '2261', (30, 35))	('bladder tumors', 'Phenotype', 'HP:0009725', (86, 100))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('pTa bladder', 'Phenotype', 'HP:0000384', (82, 93))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('pTa bladder tumors', 'Disease', (82, 100))	('mutations', 'Var', (164, 173))	('bladder tumor', 'Phenotype', 'HP:0009725', (86, 99))	('tumors', 'Disease', (146, 152))
137641	32795296	The FGFR3 mutation with a normal CK20 expression pattern was observed in low-grade non-invasive papillary tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('papillary tumors', 'Phenotype', 'HP:0007482', (96, 112))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('FGFR3', 'Gene', (4, 9))	('observed', 'Reg', (61, 69))	('mutation', 'Var', (10, 18))	('CK20', 'Gene', (33, 37))	('CK20', 'Gene', '54474', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('papillary tumors', 'Disease', (96, 112))	('FGFR3', 'Gene', '2261', (4, 9))	('papillary tumors', 'Disease', 'MESH:D002291', (96, 112))
137642	32795296	It has been observed that the FGFR3 mutations were significantly more common in pTa BCa tumors.	('pTa BCa tumors', 'Disease', (80, 94))	('FGFR3', 'Gene', (30, 35))	('more common', 'Reg', (65, 76))	('pTa', 'molecular_function', 'GO:0008959', ('80', '83'))	('mutations', 'Var', (36, 45))	('pTa BCa tumors', 'Disease', 'MESH:D009369', (80, 94))	('BCa', 'Phenotype', 'HP:0009725', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('FGFR3', 'Gene', '2261', (30, 35))
137643	32795296	The patients with mutant FGFR3 had significantly lower death rate.	('FGFR3', 'Gene', '2261', (25, 30))	('mutant', 'Var', (18, 24))	('death', 'Disease', 'MESH:D003643', (55, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('lower', 'NegReg', (49, 54))	('patients', 'Species', '9606', (4, 12))	('FGFR3', 'Gene', (25, 30))	('death', 'Disease', (55, 60))
137644	32795296	The FGFR3 mutations can precisely determine patients with invasive tumor who were at lower risk of progression.	('invasive tumor', 'Disease', (58, 72))	('patients', 'Species', '9606', (44, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('FGFR3', 'Gene', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('invasive tumor', 'Disease', 'MESH:D009361', (58, 72))	('mutations', 'Var', (10, 19))	('FGFR3', 'Gene', '2261', (4, 9))
137645	32795296	The carriers of FGFR3 mutations had better prognosis.	('FGFR3', 'Gene', (16, 21))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('mutations', 'Var', (22, 31))	('FGFR3', 'Gene', '2261', (16, 21))	('carriers', 'Reg', (4, 12))
137646	32795296	Another study has been shown that the prevalence of FGFR3 mutation was significantly higher in pTa tumors compared with carcinoma in situ (CIS), pT1, and pT2-4 among a sub population of BCa patients.	('patients', 'Species', '9606', (190, 198))	('pTa', 'molecular_function', 'GO:0008959', ('95', '98'))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('higher', 'Reg', (85, 91))	('pT1', 'Gene', '58492', (145, 148))	('pT1', 'Gene', (145, 148))	('CIS', 'Phenotype', 'HP:0030075', (139, 142))	('mutation', 'Var', (58, 66))	('pTa tumors', 'Disease', (95, 105))	('carcinoma in situ', 'Disease', (120, 137))	('FGFR3', 'Gene', (52, 57))	('pTa tumors', 'Disease', 'MESH:D009369', (95, 105))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('FGFR3', 'Gene', '2261', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (120, 137))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('carcinoma in situ', 'Disease', 'MESH:D002278', (120, 137))	('BCa', 'Phenotype', 'HP:0009725', (186, 189))
137647	32795296	There were also significant correlations between FGFR3 mutations and low grade tumors.	('mutations', 'Var', (55, 64))	('FGFR3', 'Gene', '2261', (49, 54))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('FGFR3', 'Gene', (49, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('correlations', 'Interaction', (28, 40))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
137656	32795296	Moreover, there was association between mutation and FGFR3 over expression which were frequent in primary stage (pTa and pT1) and low grade (G1 and G2) BCa tumors.	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('mutation', 'Var', (40, 48))	('BCa tumors', 'Disease', 'MESH:D009369', (152, 162))	('pTa', 'molecular_function', 'GO:0008959', ('113', '116'))	('pTa', 'Gene', '171558', (113, 116))	('pT1', 'Gene', (121, 124))	('FGFR3', 'Gene', (53, 58))	('over expression', 'PosReg', (59, 74))	('BCa', 'Phenotype', 'HP:0009725', (152, 155))	('FGFR3', 'Gene', '2261', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('primary stage', 'Disease', (98, 111))	('pT1', 'Gene', '58492', (121, 124))	('pTa', 'Gene', (113, 116))	('BCa tumors', 'Disease', (152, 162))
137659	32795296	Moreover, the up regulations of FGFR3, PI3Kp110, PI3KClassIII, and AKT were also correlated with recurrence free survival among T1 BCa patients.	('FGFR3', 'Gene', (32, 37))	('PI3Kp110', 'Var', (39, 47))	('up regulations', 'PosReg', (14, 28))	('patients', 'Species', '9606', (135, 143))	('AKT', 'Gene', '207', (67, 70))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('recurrence free survival', 'CPA', (97, 121))	('BCa', 'Phenotype', 'HP:0009725', (131, 134))	('AKT', 'Gene', (67, 70))	('FGFR3', 'Gene', '2261', (32, 37))
137660	32795296	ERCC1 over expression and FGFR3 mutation were associated with a better response to the non-adjuvant chemotherapy in a group of MIBC patients.	('ERCC1', 'Gene', '2067', (0, 5))	('ERCC1', 'Gene', (0, 5))	('MIBC', 'Chemical', '-', (127, 131))	('FGFR3', 'Gene', (26, 31))	('over expression', 'PosReg', (6, 21))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('MIBC', 'Disease', (127, 131))	('FGFR3', 'Gene', '2261', (26, 31))	('mutation', 'Var', (32, 40))	('patients', 'Species', '9606', (132, 140))
137688	32795296	Deregulation of EphB4 has been demonstrated in various tumors of breast, prostate, and lung.	('EphB4', 'Gene', (16, 21))	('EphB4', 'Gene', '2050', (16, 21))	('Deregulation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('lung', 'Disease', (87, 91))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors of breast', 'Disease', 'MESH:D001943', (55, 71))	('tumors of breast', 'Disease', (55, 71))	('demonstrated', 'Reg', (31, 43))	('prostate', 'Disease', (73, 81))
137695	32795296	Moreover, they observed BCL-XL down regulation following the EphB4 knockdown in BCa cells.	('down regulation', 'NegReg', (31, 46))	('EphB4', 'Gene', (61, 66))	('knockdown', 'Var', (67, 76))	('BCL-XL', 'Gene', (24, 30))	('EphB4', 'Gene', '2050', (61, 66))	('BCa', 'Phenotype', 'HP:0009725', (80, 83))	('BCL-XL', 'Gene', '598', (24, 30))	('regulation', 'biological_process', 'GO:0065007', ('36', '46'))
137699	32795296	A high level of DDR1 in solid malignant tumors was associated with poor prognosis.	('DDR1', 'Gene', '780', (16, 20))	('malignant tumors', 'Disease', (30, 46))	('malignant tumors', 'Disease', 'MESH:D009369', (30, 46))	('DDR1', 'Gene', (16, 20))	('high level', 'Var', (2, 12))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
137778	32503466	High expression of TRIM44 protein in malignant tissues was found to be strongly associated with poor OS (HR = 1.94, 95% CI: 1.60-2.35, p < 0.0001), and the heterogeneity test revealed a mild heterogeneity (I2 = 32.6%; PQ = 0.139).	('High', 'Var', (0, 4))	('poor OS', 'Disease', (96, 103))	('TRIM44', 'Gene', '54765', (19, 25))	('associated', 'Reg', (80, 90))	('TRIM44', 'Gene', (19, 25))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('PQ', 'Chemical', '-', (218, 220))	('protein', 'Protein', (26, 33))
137792	32503466	When combined with all data from 33 different types of malignant tumors in GEPIA, the Kaplan-Meier analysis suggested that cancer patients with a high expression level of TRIM44 exhibited poorer OS, compared with cases expressing a low level of TRIM44 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TRIM44', 'Gene', '54765', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('TRIM44', 'Gene', '54765', (171, 177))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (123, 129))	('TRIM44', 'Gene', (245, 251))	('malignant tumors', 'Disease', (55, 71))	('TRIM44', 'Gene', (171, 177))	('malignant tumors', 'Disease', 'MESH:D009369', (55, 71))	('high expression', 'Var', (146, 161))
137800	32503466	TRIM44 amplification is correlated with unfavorable prognosis and advanced clinicopathological parameters of malignancies.	('TRIM44', 'Gene', (0, 6))	('malignancies', 'Disease', (109, 121))	('TRIM44', 'Gene', '54765', (0, 6))	('amplification', 'Var', (7, 20))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))
137810	32503466	Overexpression of TRIM44 has been shown to induce a similar change in hallmark characteristics of EMT in other cancers, such as ICC and HEC.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('ICC', 'Disease', (128, 131))	('HEC', 'CellLine', 'CVCL:N814', (136, 139))	('TRIM44', 'Gene', '54765', (18, 24))	('cancers', 'Disease', (111, 118))	('change', 'Reg', (60, 66))	('hallmark characteristics of', 'MPA', (70, 97))	('HEC', 'Disease', (136, 139))	('TRIM44', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Overexpression', 'Var', (0, 14))	('EMT', 'biological_process', 'GO:0001837', ('98', '101'))
137812	32503466	TRIM44 expression positively affects the expression of cyclins and CDKs, suggesting that TRIM44 is involved in the regulation of cell cycle G1/s transformation.	('TRIM44', 'Gene', (0, 6))	('affects', 'Reg', (29, 36))	('expression', 'MPA', (41, 51))	('regulation of cell cycle', 'biological_process', 'GO:0051726', ('115', '139'))	('involved', 'Reg', (99, 107))	('TRIM44', 'Gene', '54765', (89, 95))	('cyclin', 'Gene', '5111', (55, 61))	('expression', 'Var', (7, 17))	('TRIM44', 'Gene', '54765', (0, 6))	('CDKs', 'Gene', '23097', (67, 71))	('TRIM44', 'Gene', (89, 95))	('cyclin', 'Gene', (55, 61))	('CDKs', 'Gene', (67, 71))
137814	32503466	Indeed, ectopic expression of TRIM44 promotes cell proliferation by accelerating the G1/S-phase transition in HCC.	('accelerating', 'PosReg', (68, 80))	('HCC', 'Gene', '619501', (110, 113))	('ectopic expression', 'Var', (8, 26))	('G1/S-phase transition', 'CPA', (85, 106))	('S-phase', 'biological_process', 'GO:0051320', ('88', '95'))	('HCC', 'Gene', (110, 113))	('TRIM44', 'Gene', '54765', (30, 36))	('TRIM44', 'Gene', (30, 36))	('cell proliferation', 'CPA', (46, 64))	('promotes', 'PosReg', (37, 45))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
137815	32503466	In colony formation assays, knockdown of TRIM44 in Huh7 cells significantly decreased the expression levels of cyclin D1 and cyclin E, which have been shown to play a crucial role in accelerating the G1/S-phase transition.	('G1/S-phase transition', 'CPA', (200, 221))	('cyclin D1', 'Gene', (111, 120))	('formation', 'biological_process', 'GO:0009058', ('10', '19'))	('TRIM44', 'Gene', (41, 47))	('Huh7', 'CellLine', 'CVCL:0336', (51, 55))	('expression levels', 'MPA', (90, 107))	('decreased', 'NegReg', (76, 85))	('cyclin D1', 'Gene', '595', (111, 120))	('cyclin', 'Gene', '5111', (111, 117))	('cyclin', 'Gene', '5111', (125, 131))	('knockdown', 'Var', (28, 37))	('cyclin', 'molecular_function', 'GO:0016538', ('111', '117'))	('accelerating', 'PosReg', (183, 195))	('S-phase', 'biological_process', 'GO:0051320', ('203', '210'))	('cyclin', 'molecular_function', 'GO:0016538', ('125', '131'))	('cyclin', 'Gene', (125, 131))	('TRIM44', 'Gene', '54765', (41, 47))	('cyclin', 'Gene', (111, 117))
137817	32503466	Knock-down of TRIM44 in glioma cells induces an increase in p21/p27 expression,and then it inhibited cell division.	('p27', 'Gene', '10671', (64, 67))	('TRIM44', 'Gene', '54765', (14, 20))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('cell division', 'CPA', (101, 114))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('p21', 'Gene', '644914', (60, 63))	('expression', 'MPA', (68, 78))	('p27', 'Gene', (64, 67))	('inhibited', 'NegReg', (91, 100))	('TRIM44', 'Gene', (14, 20))	('Knock-down', 'Var', (0, 10))	('cell division', 'biological_process', 'GO:0051301', ('101', '114'))	('glioma', 'Disease', (24, 30))	('p21', 'Gene', (60, 63))	('increase', 'PosReg', (48, 56))
137818	32503466	Further, the critical p21/p27 regulator AKT is inactivated after TRIM44 is knocked down, but it is activated in glioma cells that overexpress TRIM44.	('inactivated', 'NegReg', (47, 58))	('TRIM44', 'Gene', '54765', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('TRIM44', 'Gene', '54765', (142, 148))	('knocked', 'Var', (75, 82))	('AKT', 'Gene', '207', (40, 43))	('TRIM44', 'Gene', (65, 71))	('TRIM44', 'Gene', (142, 148))	('activated', 'PosReg', (99, 108))	('glioma', 'Disease', (112, 118))	('p21', 'Gene', (22, 25))	('p27', 'Gene', '10671', (26, 29))	('AKT', 'Gene', (40, 43))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('p21', 'Gene', '644914', (22, 25))	('p27', 'Gene', (26, 29))	('overexpress', 'PosReg', (130, 141))
137820	32503466	The phosphorylation of downstream mTOR substrates, including p-Akt (Ser473) and p-p70S6K (Thr389), in TRIM44-knockdown cells was markedly inhibited, indicating that TRIM44 functions upstream of the mTOR signaling pathway by phosphorylating mTOR.	('TRIM44', 'Gene', (102, 108))	('TRIM44', 'Gene', (165, 171))	('p70S6K', 'Gene', (82, 88))	('Ser473', 'Var', (68, 74))	('inhibited', 'NegReg', (138, 147))	('Akt', 'Gene', '207', (63, 66))	('Ser473', 'Chemical', '-', (68, 74))	('mTOR', 'Gene', (34, 38))	('mTOR', 'Gene', (240, 244))	('signaling pathway', 'biological_process', 'GO:0007165', ('203', '220'))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', '2475', (240, 244))	('Thr389', 'Var', (90, 96))	('p70S6K', 'Gene', '6198', (82, 88))	('mTOR', 'Gene', (198, 202))	('Thr389', 'Chemical', '-', (90, 96))	('phosphorylation', 'MPA', (4, 19))	('mTOR', 'Gene', '2475', (198, 202))	('TRIM44', 'Gene', '54765', (102, 108))	('TRIM44', 'Gene', '54765', (165, 171))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('Ser', 'cellular_component', 'GO:0005790', ('68', '71'))	('Akt', 'Gene', (63, 66))
137831	32503466	Microarray analysis showed that TRIM44 knockdown is associated with the dysregulation of NUPR1, CDK19, CADM1, INHBA, TNFSF10, and DDIT4, which could normally activate the apoptotic cell pathways.	('activate', 'PosReg', (158, 166))	('CADM1', 'Gene', '23705', (103, 108))	('INHBA', 'Gene', '3624', (110, 115))	('NUPR1', 'Gene', (89, 94))	('CDK19', 'Gene', (96, 101))	('dysregulation', 'MPA', (72, 85))	('TNFSF10', 'Gene', (117, 124))	('INHBA', 'Gene', (110, 115))	('TRIM44', 'Gene', '54765', (32, 38))	('TRIM44', 'Gene', (32, 38))	('CDK', 'molecular_function', 'GO:0004693', ('96', '99'))	('NUPR1', 'Gene', '26471', (89, 94))	('apoptotic cell pathways', 'Pathway', (171, 194))	('TNFSF10', 'Gene', '8743', (117, 124))	('CADM1', 'Gene', (103, 108))	('DDIT4', 'Gene', (130, 135))	('knockdown', 'Var', (39, 48))	('CDK19', 'Gene', '23097', (96, 101))	('DDIT4', 'Gene', '54541', (130, 135))
137840	32503466	A previous report has shown that the silencing of TRIM44 could decrease the c-IAP1, c-IAP2, and XIAP expression levels, especially in the presence of doxorubicin.	('c-IAP1', 'Gene', (76, 82))	('XIAP', 'Gene', '331', (96, 100))	('c-IAP1', 'Gene', '329', (76, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (150, 161))	('TRIM44', 'Gene', '54765', (50, 56))	('silencing', 'Var', (37, 46))	('c-IAP2', 'Gene', (84, 90))	('decrease', 'NegReg', (63, 71))	('c-IAP2', 'Gene', '330', (84, 90))	('TRIM44', 'Gene', (50, 56))	('XIAP', 'Gene', (96, 100))
137847	32503466	Moreover, miR-26b-5p is the upstream regulatory gene of TRIM44, which acts as a suppressor.	('miR-26b-5p', 'Var', (10, 20))	('TRIM44', 'Gene', '54765', (56, 62))	('TRIM44', 'Gene', (56, 62))
137939	31753727	Similar to the primary progression-free survival analysis of the first 437 randomly assigned patients, many patients had one or more adverse prognostic risk factors, including liver metastases (147 [28%] of 530 patients), haemoglobin less than 10 g/dL (70 [13%]), and ECOG performance status score greater than zero (281 [53%]) and time since completion or discontinuation of previous therapy of less than 3 months (241 [45%]; table 1).	('metastases', 'Disease', 'MESH:D009362', (182, 192))	('patients', 'Species', '9606', (211, 219))	('metastases', 'Disease', (182, 192))	('patients', 'Species', '9606', (108, 116))	('less than 10 g/dL', 'Var', (234, 251))	('patients', 'Species', '9606', (93, 101))	('haemoglobin less than 10', 'Phenotype', 'HP:0001903', (222, 246))
137975	31753727	Despite a higher proportion of patients discontinuing treatment in the ramucirumab group than in the placebo group, time to treatment discontinuation was longer in the ramucirumab group than in the placebo group (median 3 4 months [95% CI 2 8-4 1] vs 2 8 months [2 4-2 9]); unstratified HR 0 835, 95% CI 0 702-0 993; p=0 042).	('ramucirumab', 'Chemical', 'MESH:C543333', (168, 179))	('discontinuing', 'NegReg', (40, 53))	('patients', 'Species', '9606', (31, 39))	('ramucirumab', 'Var', (168, 179))	('ramucirumab', 'Chemical', 'MESH:C543333', (71, 82))
137997	31753727	Exploratory efficacy analyses by PD-L1 expression showed that ramucirumab led to longer progression-free survival in patients with high PD-L1 expression (table 4).	('PD-L1', 'Gene', (33, 38))	('longer', 'PosReg', (81, 87))	('ramucirumab', 'Chemical', 'MESH:C543333', (62, 73))	('PD-L1', 'Gene', '29126', (33, 38))	('PD-L1', 'Gene', (136, 141))	('ramucirumab', 'Gene', (62, 73))	('progression-free survival', 'CPA', (88, 113))	('expression', 'MPA', (142, 152))	('patients', 'Species', '9606', (117, 125))	('PD-L1', 'Gene', '29126', (136, 141))	('high', 'Var', (131, 135))
138016	31753727	Patients from east Asia also had a lower proportion of bladder primary tumours (42% in the ramucirumab group and 49% in the placebo group) compared with patients from other geographical regions (where bladder primary tumours ranged from 67-76%).	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('patients', 'Species', '9606', (153, 161))	('tumours', 'Phenotype', 'HP:0002664', (217, 224))	('ramucirumab', 'Var', (91, 102))	('bladder primary tumours', 'Disease', (55, 78))	('Patients', 'Species', '9606', (0, 8))	('bladder primary tumours', 'Disease', 'MESH:D001749', (55, 78))	('lower', 'NegReg', (35, 40))	('bladder primary tumours', 'Disease', 'MESH:D001749', (201, 224))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('bladder primary tumours', 'Disease', (201, 224))	('lower proportion of bladder', 'Phenotype', 'HP:0005343', (35, 62))	('ramucirumab', 'Chemical', 'MESH:C543333', (91, 102))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
138044	31753727	Findings from a randomised phase 2 study  in patients with platinum-refractory advanced or metastatic urothelial carcinoma showed that ramucirumab plus docetaxel significantly improved median progression-free survival versus docetaxel alone, and provided support for the phase 3 RANGE clinical trial.	('platinum', 'Chemical', 'MESH:D010984', (59, 67))	('ramucirumab', 'Var', (135, 146))	('docetaxel', 'Chemical', 'MESH:D000077143', (152, 161))	('improved', 'PosReg', (176, 184))	('docetaxel', 'Chemical', 'MESH:D000077143', (225, 234))	('urothelial carcinoma', 'Disease', (102, 122))	('patients', 'Species', '9606', (45, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (102, 122))	('ramucirumab', 'Chemical', 'MESH:C543333', (135, 146))	('progression-free survival', 'CPA', (192, 217))
138051	31753727	The subgroup of patients with high baseline PD-L1 expression also had a greater clinical benefit compared with patients with lower baseline PD-L1 expression.	('patients', 'Species', '9606', (16, 24))	('clinical benefit', 'CPA', (80, 96))	('expression', 'Var', (50, 60))	('PD-L1', 'Gene', (44, 49))	('high', 'Var', (30, 34))	('PD-L1', 'Gene', (140, 145))	('PD-L1', 'Gene', '29126', (140, 145))	('PD-L1', 'Gene', '29126', (44, 49))	('patients', 'Species', '9606', (111, 119))
138055	30290033	Urea transport B gene induces melanoma B16 cell death via activation of p53 and mitochondrial apoptosis Urea Transporter B (UT-B) is a membrane channel protein that mediates the rapid transmembrane transport of urea and participates in urine concentration.	('Urea transport', 'biological_process', 'GO:0015840', ('0', '14'))	('urea', 'Chemical', 'MESH:D014508', (211, 215))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('activation', 'PosReg', (58, 68))	('gene', 'Var', (17, 21))	('induces', 'Reg', (22, 29))	('UT-B', 'Gene', (124, 128))	('p53', 'Gene', '7157', (72, 75))	('membrane', 'cellular_component', 'GO:0016020', ('135', '143'))	('B16', 'CellLine', 'CVCL:N540', (39, 42))	('Urea Transporter B', 'Gene', '108052', (104, 122))	('p53', 'Gene', (72, 75))	('transmembrane', 'cellular_component', 'GO:0016021', ('184', '197'))	('UT-B', 'Gene', '108052', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))	('cell death', 'biological_process', 'GO:0008219', ('43', '53'))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))	('transmembrane', 'cellular_component', 'GO:0044214', ('184', '197'))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('transmembrane transport', 'biological_process', 'GO:0055085', ('184', '207'))	('Urea Transporter B', 'Gene', (104, 122))
138059	30290033	We show that UT-B overexpression causes increased reactive oxygen species production, which may be caused by mitochondria dysfunction.	('UT-B', 'Gene', '108052', (13, 17))	('mitochondria', 'cellular_component', 'GO:0005739', ('109', '121'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (50, 73))	('overexpression', 'Var', (18, 32))	('increased reactive oxygen species production', 'Phenotype', 'HP:0025464', (40, 84))	('mitochondria dysfunction', 'Disease', 'MESH:C564925', (109, 133))	('increased', 'PosReg', (40, 49))	('mitochondria dysfunction', 'Disease', (109, 133))	('reactive oxygen species production', 'MPA', (50, 84))	('UT-B', 'Gene', (13, 17))
138154	30290033	After tumor injection for 14 days, mice were killed by intraperitoneal administration of an anesthetic drug cocktail (240 mg/kg) followed by cervical dislocation.	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('mice', 'Species', '10090', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('240', 'Var', (118, 121))
138165	30290033	As shown in Figure 2A,B, the mRNA and protein levels of UT-B in B16 cells were significantly increased after transfection compared with B16 cells transfected with the control vector (pcDNA3.1).	('transfection', 'Var', (109, 121))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('increased', 'PosReg', (93, 102))	('UT-B', 'Gene', (56, 60))	('UT-B', 'Gene', '108052', (56, 60))	('B16', 'CellLine', 'CVCL:N540', (64, 67))	('B16', 'CellLine', 'CVCL:N540', (136, 139))
138173	30290033	Overexpression of UT-B may cause irreversible damage to the cells, so the addition of the inhibitor did not completely rescue cell survival, which may also be related to the fact that the inhibitor does not completely inhibit UT-B function.	('UT-B', 'Gene', (226, 230))	('UT-B', 'Gene', '108052', (226, 230))	('UT-B', 'Gene', (18, 22))	('UT-B', 'Gene', '108052', (18, 22))	('cause', 'Reg', (27, 32))	('Overexpression', 'Var', (0, 14))
138177	30290033	Hoechst staining showed that after transfection with pcDNA3.1-UT-B, the number of cells undergoing apoptosis was increased (Figure 3E,F).	('UT-B', 'Gene', (62, 66))	('transfection', 'Var', (35, 47))	('UT-B', 'Gene', '108052', (62, 66))	('Hoechst', 'Chemical', '-', (0, 7))	('increased', 'PosReg', (113, 122))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))
138206	30290033	PQ-U group tumor volume and weight were significantly reduced (Figure 7D,E).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('PQ-U', 'Var', (0, 4))	('reduced', 'NegReg', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
138226	30290033	Therefore, in this study, re-expression of UT-B in melanoma B16 cells affected the proliferation of tumor cells, possibly through urea-related metabolism.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('re-expression', 'Var', (26, 39))	('urea', 'Chemical', 'MESH:D014508', (130, 134))	('UT-B', 'Gene', '108052', (43, 47))	('B16', 'CellLine', 'CVCL:N540', (60, 63))	('metabolism', 'biological_process', 'GO:0008152', ('143', '153'))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('affected', 'Reg', (70, 78))	('melanoma', 'Disease', (51, 59))	('UT-B', 'Gene', (43, 47))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
138231	30290033	The formation of mitochondrial ROS is an important component of cell metabolism and plays an important role in cell physiology.23 Increased ROS is responsible for the accumulation of ROS-related lesions in DNA, proteins and lipids, which may lead to progressive cell dysfunction, resulting in apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('293', '302'))	('lipids', 'Chemical', 'MESH:D008055', (224, 230))	('accumulation', 'PosReg', (167, 179))	('ROS', 'Chemical', 'MESH:D017382', (140, 143))	('DNA', 'cellular_component', 'GO:0005574', ('206', '209'))	('apoptosis', 'biological_process', 'GO:0006915', ('293', '302'))	('ROS', 'Chemical', 'MESH:D017382', (31, 34))	('lesions', 'Var', (195, 202))	('Increased', 'PosReg', (130, 139))	('ROS', 'Gene', (140, 143))	('ROS', 'Chemical', 'MESH:D017382', (183, 186))	('formation', 'biological_process', 'GO:0009058', ('4', '13'))	('cell dysfunction', 'Disease', (262, 278))	('metabolism', 'biological_process', 'GO:0008152', ('69', '79'))	('cell dysfunction', 'Disease', 'MESH:C538614', (262, 278))	('cell physiology', 'biological_process', 'GO:0009987', ('111', '126'))	('lead to', 'Reg', (242, 249))	('apoptosis', 'CPA', (293, 302))
138243	30290033	We have confirmed the role of UT-B in the development of skin melanoma, and how changes in UT-B function may seriously affect the long-term health of skin.	('skin melanoma', 'Disease', (57, 70))	('changes', 'Var', (80, 87))	('UT-B', 'Gene', '108052', (91, 95))	('UT-B', 'Gene', (30, 34))	('long-term health', 'CPA', (130, 146))	('UT-B', 'Gene', '108052', (30, 34))	('skin melanoma', 'Disease', 'MESH:D008545', (57, 70))	('affect', 'Reg', (119, 125))	('UT-B', 'Gene', (91, 95))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
138250	27649287	In HNSCC patients, high-EFNB2 mRNA expression was associated with tumor HPV negativity, oral cavity location, alcohol intake, higher TP53 mutation, and EGFR amplification.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('oral cavity location', 'Disease', (88, 108))	('patients', 'Species', '9606', (9, 17))	('alcohol intake', 'Disease', (110, 124))	('EFNB2', 'Gene', (24, 29))	('EFNB2', 'Gene', '1948', (24, 29))	('tumor', 'Disease', (66, 71))	('mRNA expression', 'MPA', (30, 45))	('higher', 'PosReg', (126, 132))	('EGFR', 'Gene', '1956', (152, 156))	('mutation', 'Var', (138, 146))	('EGFR', 'Gene', (152, 156))	('alcohol', 'Chemical', 'MESH:D000438', (110, 117))	('TP53', 'Gene', '7157', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('TP53', 'Gene', (133, 137))	('EGFR', 'molecular_function', 'GO:0005006', ('152', '156'))
138262	27649287	The cancer genome atlas (TCGA) comprises a database of over 10,000 primary tumors categorized based on cancer type and containing data related to gene expression, gene copy number amplification, mutation status, methylation status as well as response to chemo, and radiotherapy.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('gene expression', 'biological_process', 'GO:0010467', ('146', '161'))	('methylation', 'biological_process', 'GO:0032259', ('212', '223'))	('mutation', 'Var', (195, 203))	('cancer genome atlas', 'Disease', 'MESH:D009369', (4, 23))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('cancer genome atlas', 'Disease', (4, 23))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (75, 81))	('cancer', 'Disease', (4, 10))
138264	27649287	We also hypothesized that EFNB2 blockade can inhibit tumor growth and improve survival in patient-derived xenograft (PDX) tumor models.	('EFNB2', 'Gene', '1948', (26, 31))	('survival', 'CPA', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('improve', 'PosReg', (70, 77))	('patient', 'Species', '9606', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (53, 58))	('inhibit', 'NegReg', (45, 52))	('blockade', 'Var', (32, 40))	('tumor', 'Disease', (122, 127))	('EFNB2', 'Gene', (26, 31))
138298	27649287	In addition, EFNB2 expression correlated with reduced disease-free survival in the same populations (Figure 1).	('expression', 'Var', (19, 29))	('EFNB2', 'Gene', (13, 18))	('reduced', 'NegReg', (46, 53))	('disease-free survival', 'CPA', (54, 75))	('EFNB2', 'Gene', '1948', (13, 18))
138307	27649287	EFNB2 expression correlated significantly with the presence of TP53 mutations (P = 0.0003) and EGFR amplification (P = 0.0126).	('EFNB2', 'Gene', (0, 5))	('amplification', 'Var', (100, 113))	('EFNB2', 'Gene', '1948', (0, 5))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('expression', 'MPA', (6, 16))	('EGFR', 'molecular_function', 'GO:0005006', ('95', '99'))	('EGFR', 'Gene', '1956', (95, 99))	('mutations', 'Var', (68, 77))	('EGFR', 'Gene', (95, 99))
138308	27649287	Subgroup analysis comparing patients with stage T1-T2 and stage T3-T4 tumors (according to the neoplasm American Joint Committee on Cancer clinical primary tumor T stage) revealed a significant difference in OS in patients with high-EFNB2 expression compared to patients with low-EFNB2 expression (Figure 2B).	('patients', 'Species', '9606', (214, 222))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', (156, 161))	('neoplasm', 'Disease', 'MESH:D009369', (95, 103))	('Cancer', 'Disease', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('EFNB2', 'Gene', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('neoplasm', 'Disease', (95, 103))	('tumors', 'Disease', (70, 76))	('EFNB2', 'Gene', (280, 285))	('patients', 'Species', '9606', (28, 36))	('Cancer', 'Disease', 'MESH:D009369', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('neoplasm', 'Phenotype', 'HP:0002664', (95, 103))	('EFNB2', 'Gene', '1948', (233, 238))	('tumor', 'Disease', (70, 75))	('expression', 'Var', (239, 249))	('EFNB2', 'Gene', '1948', (280, 285))	('patients', 'Species', '9606', (262, 270))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
138309	27649287	Median OS for stage T1-T2 patients with high EFNB2 was 35.51 months compared to 57.88 months for stage T1-T2 patients with low-EFNB2 expression (P = 0.0019).	('high', 'Var', (40, 44))	('EFNB2', 'Gene', (127, 132))	('patients', 'Species', '9606', (109, 117))	('EFNB2', 'Gene', '1948', (127, 132))	('EFNB2', 'Gene', (45, 50))	('EFNB2', 'Gene', '1948', (45, 50))	('patients', 'Species', '9606', (26, 34))
138310	27649287	In addition, subgroup analysis based on nodal status showed significantly decreased OS and DFS in N1-N2b patients with high-EFNB2 expression compared to N1-N2b patients with low-EFNB2 expression (Figure 2C).	('EFNB2', 'Gene', (178, 183))	('EFNB2', 'Gene', '1948', (178, 183))	('patients', 'Species', '9606', (160, 168))	('patients', 'Species', '9606', (105, 113))	('N1-N2b', 'Var', (98, 104))	('EFNB2', 'Gene', (124, 129))	('EFNB2', 'Gene', '1948', (124, 129))	('DFS', 'CPA', (91, 94))	('decreased', 'NegReg', (74, 83))
138311	27649287	Median OS for N1-N2b patients with high EFNB2 was 18.96 months compared to 71.16 months in N1-N2b patients with low EFNB2 (P = 0.0005).	('EFNB2', 'Gene', '1948', (116, 121))	('N1-N2b', 'Disease', (14, 20))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (21, 29))	('EFNB2', 'Gene', (116, 121))	('high', 'Var', (35, 39))	('EFNB2', 'Gene', (40, 45))	('EFNB2', 'Gene', '1948', (40, 45))
138318	27649287	Radiotherapy data (for curative intent) was available for 112 patients with high EFNB2 and 173 patients with low EFNB2 (Figure 3A).	('patients', 'Species', '9606', (95, 103))	('EFNB2', 'Gene', (81, 86))	('EFNB2', 'Gene', '1948', (113, 118))	('high', 'Var', (76, 80))	('patients', 'Species', '9606', (62, 70))	('EFNB2', 'Gene', '1948', (81, 86))	('EFNB2', 'Gene', (113, 118))
138323	27649287	Patients with high EFNB2 who were treated with chemotherapy had significantly worse OS (median survival 25.9 months compared to 56.9 months, P = 0.0087, HR = 1.94, HR range = 1.2-3.2) and progression-free survival (median time to progression 18.4 months compared to 45.0 months, P = 0.0397, HR = 1.66, HR range = 1.03-2.68).	('worse', 'NegReg', (78, 83))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('EFNB2', 'Gene', (19, 24))	('EFNB2', 'Gene', '1948', (19, 24))	('progression-free survival', 'CPA', (188, 213))
138328	27649287	Out of the three HPV+ patients with high EFNB2, one was negative for HPV based on in situ hybridization analysis while the there was no ISH data available on the remaining two patients.	('patients', 'Species', '9606', (176, 184))	('patients', 'Species', '9606', (22, 30))	('EFNB2', 'Gene', (41, 46))	('EFNB2', 'Gene', '1948', (41, 46))	('high', 'Var', (36, 40))
138343	27649287	EphrinB2 blockade resulted in significant inhibition of tumor growth in the patient-derived CUHN004 xenograft compared to PBS-treated animals (Figure 5C).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('EphrinB2', 'Gene', (0, 8))	('tumor', 'Disease', (56, 61))	('PBS', 'Chemical', 'MESH:D007854', (122, 125))	('EphrinB2', 'Gene', '1948', (0, 8))	('patient', 'Species', '9606', (76, 83))	('inhibition', 'NegReg', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('blockade', 'Var', (9, 17))
138347	27649287	We chose to focus on the cohort of HNSCC patients due to the presence of a large sample size in both high and low EFNB2 expressing patients.	('patients', 'Species', '9606', (131, 139))	('HNSCC', 'Disease', (35, 40))	('EFNB2', 'Gene', (114, 119))	('EFNB2', 'Gene', '1948', (114, 119))	('patients', 'Species', '9606', (41, 49))	('high', 'Var', (101, 105))	('low', 'NegReg', (110, 113))
138351	27649287	Blockade of EFNB2 in PDX tumor derived from a patient with relapsed oral cavity caner, inhibited tumor proliferation, and increased animal survival.	('patient', 'Species', '9606', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (25, 30))	('Blockade', 'Var', (0, 8))	('tumor', 'Disease', (97, 102))	('inhibited', 'NegReg', (87, 96))	('animal survival', 'CPA', (132, 147))	('EFNB2', 'Gene', (12, 17))	('increased', 'PosReg', (122, 131))	('EFNB2', 'Gene', '1948', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
138354	29435122	APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response APOBEC enzymes are responsible for a mutation signature (TCW>T/G) implicated in a wide variety of tumors.	('mutations', 'Var', (90, 99))	('DNA damage response', 'biological_process', 'GO:0006974', ('103', '122'))	('tumors', 'Disease', (248, 254))	('urothelial carcinoma', 'Disease', (31, 51))	('survival', 'CPA', (80, 88))	('APOBEC', 'cellular_component', 'GO:0030895', ('150', '156'))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('improved', 'PosReg', (71, 79))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (31, 51))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('TCW>T/G', 'Var', (207, 214))	('APOBEC-mediated', 'Gene', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('immune response', 'biological_process', 'GO:0006955', ('134', '149'))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('mutagenesis', 'Var', (16, 27))	('mutagenesis', 'biological_process', 'GO:0006280', ('16', '27'))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
138358	29435122	APOBEC-high tumors are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2) and chromatin regulatory genes (ARID1A, MLL, MLL3), while APOBEC-low tumors are more likely to have mutations in FGFR3 and KRAS.	('ARID1A', 'Gene', '8289', (133, 139))	('FGFR3', 'Gene', (214, 219))	('chromatin', 'cellular_component', 'GO:0000785', ('105', '114'))	('APOBEC-high', 'Disease', (0, 11))	('FGFR3', 'Gene', '2261', (214, 219))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('KRAS', 'Gene', '3845', (224, 228))	('MLL3', 'Gene', '58508', (146, 150))	('FGFR', 'molecular_function', 'GO:0005007', ('214', '218'))	('ATR', 'Gene', '545', (89, 92))	('TP53', 'Gene', (83, 87))	('MLL', 'Gene', '4297', (141, 144))	('MLL', 'Gene', (141, 144))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('KRAS', 'Gene', (224, 228))	('BRCA2', 'Gene', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('DNA damage response', 'biological_process', 'GO:0006974', ('56', '75'))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('APOBEC', 'cellular_component', 'GO:0030895', ('159', '165'))	('tumors', 'Disease', (12, 18))	('MLL3', 'Gene', (146, 150))	('TP53', 'Gene', '7157', (83, 87))	('ARID1A', 'Gene', (133, 139))	('ATR', 'Gene', (89, 92))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('mutations', 'Var', (43, 52))	('BRCA2', 'Gene', '675', (94, 99))	('MLL', 'Gene', '4297', (146, 149))	('MLL', 'Gene', (146, 149))	('tumors', 'Disease', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
138360	29435122	APOBEC mutagenesis is associated with increased expression of immune signatures, including interferon signaling, and expression of APOBEC3B is increased after stimulation of APOBEC-high bladder cancer cell lines with IFNgamma.	('increased', 'PosReg', (143, 152))	('mutagenesis', 'Var', (7, 18))	('APOBEC', 'cellular_component', 'GO:0030895', ('131', '137'))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('interferon signaling', 'MPA', (91, 111))	('expression', 'MPA', (48, 58))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('APOBEC3B', 'Gene', '9582', (131, 139))	('expression', 'MPA', (117, 127))	('mutagenesis', 'biological_process', 'GO:0006280', ('7', '18'))	('APOBEC', 'Gene', (0, 6))	('IFNgamma', 'Gene', (217, 225))	('IFNgamma', 'Gene', '3458', (217, 225))	('bladder cancer', 'Disease', 'MESH:D001749', (186, 200))	('bladder cancer', 'Disease', (186, 200))	('APOBEC', 'cellular_component', 'GO:0030895', ('174', '180'))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('bladder cancer', 'Phenotype', 'HP:0009725', (186, 200))	('APOBEC3B', 'Gene', (131, 139))	('increased', 'PosReg', (38, 47))
138361	29435122	In summary, APOBEC-high tumors are more likely to have mutations in DNA damage response and chromatin regulatory genes, potentially providing more substrate for APOBEC enzymes, leading to a hypermutational phenotype and the subsequent enhanced immune response.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('hypermutational phenotype', 'MPA', (190, 215))	('chromatin regulatory genes', 'Gene', (92, 118))	('APOBEC-high', 'Gene', (12, 23))	('tumors', 'Disease', (24, 30))	('mutations', 'Var', (55, 64))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('DNA damage response', 'biological_process', 'GO:0006974', ('68', '87'))	('DNA damage response', 'Gene', (68, 87))	('APOBEC', 'cellular_component', 'GO:0030895', ('12', '18'))	('immune response', 'CPA', (244, 259))	('enhanced', 'PosReg', (235, 243))	('immune response', 'biological_process', 'GO:0006955', ('244', '259'))	('APOBEC', 'cellular_component', 'GO:0030895', ('161', '167'))	('chromatin', 'cellular_component', 'GO:0000785', ('92', '101'))
138364	29435122	This mutational pattern is the predominant pattern in muscle-invasive bladder cancer (approximately 80% of bladder tumors in the TCGA have an APOBEC mutation signature) and is also frequently found in breast, cervical, head and neck, and lung cancers.	('invasive bladder', 'Phenotype', 'HP:0100645', (61, 77))	('bladder tumor', 'Phenotype', 'HP:0009725', (107, 120))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (54, 84))	('bladder tumors', 'Disease', 'MESH:D001749', (107, 121))	('lung cancers', 'Disease', 'MESH:D008175', (238, 250))	('lung cancers', 'Disease', (238, 250))	('cervical', 'Disease', (209, 217))	('APOBEC', 'cellular_component', 'GO:0030895', ('142', '148'))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('found', 'Reg', (192, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (238, 249))	('bladder tumors', 'Disease', (107, 121))	('lung cancers', 'Phenotype', 'HP:0100526', (238, 250))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('neck', 'cellular_component', 'GO:0044326', ('228', '232'))	('muscle-invasive bladder cancer', 'Disease', (54, 84))	('breast', 'Disease', (201, 207))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('APOBEC', 'Gene', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('bladder tumors', 'Phenotype', 'HP:0009725', (107, 121))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('mutation', 'Var', (149, 157))
138371	29435122	In TCGA breast and bladder cancers, DNA replication stress and mutations in DNA repair genes have been linked to APOBEC-mediated mutagenesis, potentially due to increased availability of ssDNA substrate for enzymatic deamination.	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('linked', 'Reg', (103, 109))	('bladder cancers', 'Disease', 'MESH:D001749', (19, 34))	('DNA repair', 'Gene', (76, 86))	('mutagenesis', 'biological_process', 'GO:0006280', ('129', '140'))	('DNA replication', 'biological_process', 'GO:0006260', ('36', '51'))	('breast', 'Disease', (8, 14))	('DNA repair', 'biological_process', 'GO:0006281', ('76', '86'))	('bladder cancers', 'Disease', (19, 34))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('bladder cancers', 'Phenotype', 'HP:0009725', (19, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (19, 33))	('increased', 'PosReg', (161, 170))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('APOBEC', 'cellular_component', 'GO:0030895', ('113', '119'))
138372	29435122	Furthermore, a mutation in TP53 or other DNA damage response genes may be a prerequisite for cancer cells to survive in the setting of APOBEC-driven kataegis.	('TP53', 'Gene', '7157', (27, 31))	('mutation', 'Var', (15, 23))	('TP53', 'Gene', (27, 31))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('APOBEC', 'cellular_component', 'GO:0030895', ('135', '141'))	('DNA damage response', 'biological_process', 'GO:0006974', ('41', '60'))
138373	29435122	In this study, we investigate the APOBEC mutational signature in the TCGA, Beijing Genomics Institute (BGI), and Cancer Cell Line Encyclopedia (CCLE) bladder cancer datasets and its relationship with specific mutations, molecular subtype, gene expression, and survival.	('gene expression', 'biological_process', 'GO:0010467', ('239', '254'))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('APOBEC', 'Gene', (34, 40))	('Cancer', 'Phenotype', 'HP:0002664', (113, 119))	('APOBEC', 'cellular_component', 'GO:0030895', ('34', '40'))	('Cancer Cell Line Encyclopedia (CCLE) bladder cancer', 'Disease', 'MESH:D001749', (113, 164))	('bladder cancer', 'Phenotype', 'HP:0009725', (150, 164))	('mutational', 'Var', (41, 51))
138374	29435122	We hypothesized that tumors with high levels of APOBEC-mediated mutagenesis would be enriched for mutations in DNA damage response genes and express genes related to activation of the immune system at higher levels, while tumors with low levels of APOBEC-mediated mutagenesis may have enrichments for oncogenes.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('mutagenesis', 'biological_process', 'GO:0006280', ('264', '275'))	('mutagenesis', 'biological_process', 'GO:0006280', ('64', '75'))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('DNA damage response genes', 'Gene', (111, 136))	('mutations', 'Var', (98, 107))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('APOBEC', 'cellular_component', 'GO:0030895', ('48', '54'))	('DNA damage response', 'biological_process', 'GO:0006974', ('111', '130'))	('tumors', 'Disease', (222, 228))	('APOBEC', 'cellular_component', 'GO:0030895', ('248', '254'))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
138376	29435122	When compared across all patients, we found the frequency of the nucleotide conversion C>G mutations is directly related to total mutation burden in bladder cancer (Figure 1A).	('bladder cancer', 'Disease', 'MESH:D001749', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('bladder cancer', 'Disease', (149, 163))	('patients', 'Species', '9606', (25, 33))	('bladder cancer', 'Phenotype', 'HP:0009725', (149, 163))	('nucleotide conversion C>G mutations', 'Var', (65, 100))
138377	29435122	Of 388 tumors in the provisional TCGA bladder urothelial carcinoma dataset, 324 are enriched for APOBEC mutagenesis ("APOBEC-high") vs. 64 with low or no enrichment ("ABPOEC-low").	('mutagenesis', 'Var', (104, 115))	('APOBEC', 'cellular_component', 'GO:0030895', ('97', '103'))	('bladder urothelial carcinoma', 'Disease', (38, 66))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('mutagenesis', 'biological_process', 'GO:0006280', ('104', '115'))	('APOBEC', 'Gene', (97, 103))	('APOBEC', 'cellular_component', 'GO:0030895', ('117', '123'))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (38, 66))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
138379	29435122	TCGA APOBEC-high tumors have a higher number of variants per sample, a higher proportion of C>T and C>G mutations, and a higher proportion of catalogue of somatic mutations in cancer (COSMIC) signatures 2 and 13, as expected (Figure 1C-1D).	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('variants', 'Var', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('APOBEC', 'cellular_component', 'GO:0030895', ('5', '11'))	('C>G mutations', 'Var', (100, 113))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('C>T', 'Var', (92, 95))
138389	29435122	After correction for multiple comparisons, TCGA APOBEC-high tumors were more likely to have mutations in TP53, PIK3CA, ATR, BRCA2, MLL, MLL3, and ARID1A while TCGA APOBEC-low tumors were more likely to have mutations in KRAS and FGFR3 (Figure 3A-3B; Supplementary Table 2).	('FGFR3', 'Gene', (229, 234))	('tumors', 'Disease', (175, 181))	('ATR', 'Gene', (119, 122))	('MLL3', 'Gene', (136, 140))	('BRCA2', 'Gene', '675', (124, 129))	('FGFR3', 'Gene', '2261', (229, 234))	('APOBEC', 'cellular_component', 'GO:0030895', ('48', '54'))	('PIK3CA', 'Gene', '5290', (111, 117))	('APOBEC', 'cellular_component', 'GO:0030895', ('164', '170'))	('ARID1A', 'Gene', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('MLL', 'Gene', (136, 139))	('MLL', 'Gene', '4297', (136, 139))	('TP53', 'Gene', (105, 109))	('ARID1A', 'Gene', '8289', (146, 152))	('FGFR', 'molecular_function', 'GO:0005007', ('229', '233'))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('ATR', 'Gene', '545', (119, 122))	('PIK3CA', 'Gene', (111, 117))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MLL3', 'Gene', '58508', (136, 140))	('tumors', 'Disease', (60, 66))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('BRCA2', 'Gene', (124, 129))	('KRAS', 'Gene', '3845', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('TCGA', 'Gene', (43, 47))	('TP53', 'Gene', '7157', (105, 109))	('MLL', 'Gene', '4297', (131, 134))	('KRAS', 'Gene', (220, 224))	('MLL', 'Gene', (131, 134))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
138390	29435122	Functional annotation of differentially mutated genes demonstrates that APOBEC-high tumors are enriched for mutations in DNA damage repair genes and chromatin modification genes (Supplementary Table 3).	('chromatin modification genes', 'Gene', (149, 177))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('mutations', 'Var', (108, 117))	('DNA damage repair genes', 'Gene', (121, 144))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('chromatin modification', 'biological_process', 'GO:0006325', ('149', '171'))	('chromatin', 'cellular_component', 'GO:0000785', ('149', '158'))	('chromatin modification', 'biological_process', 'GO:0016569', ('149', '171'))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('APOBEC', 'cellular_component', 'GO:0030895', ('72', '78'))	('APOBEC-high', 'Gene', (72, 83))
138392	29435122	The most frequent mutations in the BGI APOBEC-high tumors were TP53 (35%), KDM6A (33%), PIK3CA (32%), and ARID1A (20%), whereas the most frequent mutations in the APOBEC-low tumors were KDM6A (30%), ZNF83 (23%), FGFR3 (20%), and HRAS (17%).	('ZNF83', 'Gene', '55769', (199, 204))	('PIK3CA', 'Gene', '5290', (88, 94))	('FGFR3', 'Gene', (212, 217))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('HRAS', 'Gene', (229, 233))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('APOBEC', 'cellular_component', 'GO:0030895', ('39', '45'))	('FGFR3', 'Gene', '2261', (212, 217))	('tumors', 'Disease', (174, 180))	('TP53', 'Gene', '7157', (63, 67))	('ARID1A', 'Gene', (106, 112))	('PIK3CA', 'Gene', (88, 94))	('KDM6A', 'Gene', '7403', (186, 191))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('KDM6A', 'Gene', '7403', (75, 80))	('ARID1A', 'Gene', '8289', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('ZNF83', 'Gene', (199, 204))	('FGFR', 'molecular_function', 'GO:0005007', ('212', '216'))	('APOBEC', 'cellular_component', 'GO:0030895', ('163', '169'))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('TP53', 'Gene', (63, 67))	('HRAS', 'Gene', '3265', (229, 233))	('KDM6A', 'Gene', (186, 191))	('tumors', 'Disease', (51, 57))	('KDM6A', 'Gene', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('mutations', 'Var', (18, 27))
138393	29435122	BGI APOBEC-high tumors were significantly more likely to have mutations in PIK3CA, ERBB2, TP53, and ARID1A (Figure 3C; Supplementary Table 4).	('PIK3CA', 'Gene', (75, 81))	('PIK3CA', 'Gene', '5290', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('TP53', 'Gene', '7157', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('ARID1A', 'Gene', '8289', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('ERBB2', 'Gene', (83, 88))	('ARID1A', 'Gene', (100, 106))	('TP53', 'Gene', (90, 94))	('ERBB2', 'Gene', '2064', (83, 88))	('APOBEC', 'cellular_component', 'GO:0030895', ('4', '10'))	('tumors', 'Disease', (16, 22))	('mutations', 'Var', (62, 71))
138394	29435122	Non-synonymous mutations in KRAS and FGFR3 are mutually exclusive in both the BGI and TCGA cohorts (Figure 3A and 3C).	('FGFR3', 'Gene', (37, 42))	('KRAS', 'Gene', (28, 32))	('KRAS', 'Gene', '3845', (28, 32))	('Non-synonymous mutations', 'Var', (0, 24))	('FGFR3', 'Gene', '2261', (37, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))
138395	29435122	Mutations in PIK3CA occurred primarily at E542K and E545K in both the TCGA and BGI cohorts, which are APOBEC TCW motifs (Figure 3E and 3G), suggesting these mutations may be a result of APOBEC-mediated mutagenesis rather than a driver of the APOBEC mutational signature.	('PIK3CA', 'Gene', (13, 19))	('E542K', 'Mutation', 'rs121913273', (42, 47))	('E545K', 'Mutation', 'rs104886003', (52, 57))	('PIK3CA', 'Gene', '5290', (13, 19))	('mutagenesis', 'biological_process', 'GO:0006280', ('202', '213'))	('E545K', 'Var', (52, 57))	('E542K', 'Var', (42, 47))	('APOBEC', 'cellular_component', 'GO:0030895', ('242', '248'))	('APOBEC', 'cellular_component', 'GO:0030895', ('186', '192'))	('APOBEC', 'cellular_component', 'GO:0030895', ('102', '108'))
138397	29435122	Of 20 bladder cancer cell lines, 9 were enriched for APOBEC mutagenesis, and had frequent mutations in TP53 (89%) and ARID1A (33%), while 11 cell lines were not enriched for APOBEC mutagenesis and had frequent mutations in FGFR3 (27%) and NRAS (27%) (Figure 3F).	('mutations', 'Var', (90, 99))	('FGFR3', 'Gene', '2261', (223, 228))	('mutations', 'Reg', (210, 219))	('TP53', 'Gene', '7157', (103, 107))	('NRAS', 'Gene', (239, 243))	('FGFR', 'molecular_function', 'GO:0005007', ('223', '227'))	('mutagenesis', 'biological_process', 'GO:0006280', ('181', '192'))	('APOBEC', 'cellular_component', 'GO:0030895', ('53', '59'))	('bladder cancer', 'Disease', 'MESH:D001749', (6, 20))	('ARID1A', 'Gene', (118, 124))	('bladder cancer', 'Disease', (6, 20))	('mutagenesis', 'biological_process', 'GO:0006280', ('60', '71'))	('TP53', 'Gene', (103, 107))	('APOBEC', 'cellular_component', 'GO:0030895', ('174', '180'))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('bladder cancer', 'Phenotype', 'HP:0009725', (6, 20))	('FGFR3', 'Gene', (223, 228))	('NRAS', 'Gene', '4893', (239, 243))	('ARID1A', 'Gene', '8289', (118, 124))
138398	29435122	To determine the relationship between APOBEC mutagenesis, APOBEC gene expression, and molecular subtype, we next investigated the association of APOBEC3 enzyme expression with total mutations in both the entire TCGA bladder cancer dataset and in the four molecular subtypes (luminal, p53-like, basal, and claudin-low; Supplementary Figure 1).	('APOBEC', 'cellular_component', 'GO:0030895', ('145', '151'))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('bladder cancer', 'Phenotype', 'HP:0009725', (216, 230))	('bladder cancer', 'Disease', 'MESH:D001749', (216, 230))	('gene expression', 'biological_process', 'GO:0010467', ('65', '80'))	('mutagenesis', 'biological_process', 'GO:0006280', ('45', '56'))	('p53', 'Gene', (284, 287))	('mutations', 'Var', (182, 191))	('p53', 'Gene', '7157', (284, 287))	('APOBEC', 'cellular_component', 'GO:0030895', ('58', '64'))	('investigated', 'Reg', (113, 125))	('bladder cancer', 'Disease', (216, 230))	('APOBEC', 'cellular_component', 'GO:0030895', ('38', '44'))	('association', 'Interaction', (130, 141))	('APOBEC3', 'Gene', (145, 152))
138411	29435122	APOBEC mutagenesis is the predominant mutational pattern in bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('mutagenesis', 'Var', (7, 18))	('APOBEC', 'Disease', (0, 6))	('bladder cancer', 'Disease', 'MESH:D001749', (60, 74))	('mutagenesis', 'biological_process', 'GO:0006280', ('7', '18'))	('bladder cancer', 'Disease', (60, 74))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))
138412	29435122	In this paper, we demonstrate that tumors enriched for APOBEC mutagenesis (APOBEC-high tumors) have better survival and are more likely to have mutations in DNA damage repair genes and chromatin regulation genes, while tumors not featuring the APOBEC mutational pattern (APOBEC-low tumors) are significantly more likely to harbor mutations in FGFR3 and KRAS/HRAS/NRAS, which are mutually exclusive.	('mutagenesis', 'Var', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('APOBEC', 'cellular_component', 'GO:0030895', ('55', '61'))	('regulation', 'biological_process', 'GO:0065007', ('195', '205'))	('better', 'PosReg', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('KRAS', 'Gene', (353, 357))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('NRAS', 'Gene', '4893', (363, 367))	('mutations', 'Var', (144, 153))	('chromatin regulation genes', 'Gene', (185, 211))	('APOBEC', 'cellular_component', 'GO:0030895', ('75', '81'))	('APOBEC', 'cellular_component', 'GO:0030895', ('244', '250'))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('mutagenesis', 'biological_process', 'GO:0006280', ('62', '73'))	('tumors', 'Disease', (87, 93))	('APOBEC', 'cellular_component', 'GO:0030895', ('271', '277'))	('DNA damage repair genes', 'Gene', (157, 180))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('HRAS', 'Gene', '3265', (358, 362))	('tumors', 'Disease', (219, 225))	('tumors', 'Disease', (282, 288))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('HRAS', 'Gene', (358, 362))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('NRAS', 'Gene', (363, 367))	('survival', 'CPA', (107, 115))	('APOBEC', 'Gene', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('chromatin', 'cellular_component', 'GO:0000785', ('185', '194'))	('FGFR', 'molecular_function', 'GO:0005007', ('343', '347'))	('mutations', 'Var', (330, 339))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('FGFR3', 'Gene', (343, 348))	('tumors', 'Disease', (35, 41))	('FGFR3', 'Gene', '2261', (343, 348))	('KRAS', 'Gene', '3845', (353, 357))
138413	29435122	Expression of APOBEC3A and APOBEC3B correlates with overall mutation load in bladder cancer, regardless of molecular subtype.	('APOBEC', 'cellular_component', 'GO:0030895', ('27', '33'))	('mutation', 'Var', (60, 68))	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('APOBEC', 'cellular_component', 'GO:0030895', ('14', '20'))	('APOBEC3B', 'Gene', (27, 35))	('bladder cancer', 'Disease', (77, 91))	('APOBEC3A', 'Gene', '200315', (14, 22))	('APOBEC3B', 'Gene', '9582', (27, 35))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('APOBEC3A', 'Gene', (14, 22))
138416	29435122	Furthermore, knockdown of APOBEC3B with short hairpin RNA in breast cancer cell lines decreases total number of uracil lesions, TP53 mutations, and C>T mutations.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('TP53', 'Gene', '7157', (128, 132))	('APOBEC3B', 'Gene', (26, 34))	('TP53', 'Gene', (128, 132))	('uracil lesions', 'Phenotype', 'HP:0012127', (112, 126))	('decreases', 'NegReg', (86, 95))	('APOBEC3B', 'Gene', '9582', (26, 34))	('APOBEC', 'cellular_component', 'GO:0030895', ('26', '32'))	('RNA', 'cellular_component', 'GO:0005562', ('54', '57'))	('mutations', 'Var', (133, 142))	('C>T mutations', 'Var', (148, 161))	('uracil', 'Chemical', 'MESH:D014498', (112, 118))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
138418	29435122	APOBEC3A expression was not initially detectable in breast cancer cell lines, and APOBEC3B expression correlates strongly with overall mutations in multiple malignancies, leading many to initially believe that APOBEC3B is responsible for the majority of the APOBEC mutational signature.	('APOBEC', 'cellular_component', 'GO:0030895', ('210', '216'))	('APOBEC', 'Disease', (258, 264))	('malignancies', 'Disease', 'MESH:D009369', (157, 169))	('APOBEC', 'cellular_component', 'GO:0030895', ('82', '88'))	('APOBEC', 'cellular_component', 'GO:0030895', ('258', '264'))	('APOBEC3A', 'Gene', '200315', (0, 8))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('APOBEC3B', 'Gene', (82, 90))	('APOBEC3B', 'Gene', '9582', (82, 90))	('mutations', 'Var', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('malignancies', 'Disease', (157, 169))	('breast cancer', 'Disease', (52, 65))	('APOBEC3B', 'Gene', (210, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('APOBEC3B', 'Gene', '9582', (210, 218))	('APOBEC3A', 'Gene', (0, 8))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))
138421	29435122	This group also used the TCGA bladder cancer dataset to demonstrate that APOBEC mutagenesis is associated with improved overall survival, and that APOBEC-high tumors are enriched for TP53 and PIK3CA mutations.	('TP53', 'Gene', '7157', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('PIK3CA', 'Gene', '5290', (192, 198))	('APOBEC', 'cellular_component', 'GO:0030895', ('147', '153'))	('improved', 'PosReg', (111, 119))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('APOBEC', 'Gene', (73, 79))	('overall', 'MPA', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('PIK3CA', 'Gene', (192, 198))	('TP53', 'Gene', (183, 187))	('bladder cancer', 'Disease', (30, 44))	('bladder cancer', 'Disease', 'MESH:D001749', (30, 44))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))	('mutagenesis', 'Var', (80, 91))	('mutagenesis', 'biological_process', 'GO:0006280', ('80', '91'))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('APOBEC', 'cellular_component', 'GO:0030895', ('73', '79'))
138422	29435122	We demonstrate that bladder tumors not enriched for APOBEC mutagenesis frequently harbor mutations in FGFR3 or the RAS family of oncogenes, and we also demonstrate that APOBEC3A is expressed at significantly higher levels in the basal subtype of bladder cancer, compared to other subtypes.	('FGFR3', 'Gene', (102, 107))	('bladder tumors', 'Disease', 'MESH:D001749', (20, 34))	('mutations', 'Var', (89, 98))	('FGFR3', 'Gene', '2261', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('mutagenesis', 'biological_process', 'GO:0006280', ('59', '70'))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('bladder cancer', 'Disease', 'MESH:D001749', (246, 260))	('bladder cancer', 'Disease', (246, 260))	('bladder cancer', 'Phenotype', 'HP:0009725', (246, 260))	('bladder tumors', 'Disease', (20, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('higher levels', 'PosReg', (208, 221))	('APOBEC3A', 'Gene', (169, 177))	('bladder tumors', 'Phenotype', 'HP:0009725', (20, 34))	('APOBEC', 'cellular_component', 'GO:0030895', ('169', '175'))	('APOBEC3A', 'Gene', '200315', (169, 177))	('APOBEC', 'cellular_component', 'GO:0030895', ('52', '58'))	('bladder tumor', 'Phenotype', 'HP:0009725', (20, 33))
138423	29435122	APOBEC-high tumors are more likely to have mutations in genes related to DNA repair and chromatin regulation, including TP53, NCOR1, MLL3 (KMT2C), MLL (KMT2A), ATR, BRCA2, and ARID1A in the TCGA dataset.	('KMT2C', 'Gene', '58508', (139, 144))	('KMT2C', 'Gene', (139, 144))	('ATR', 'Gene', (160, 163))	('regulation', 'biological_process', 'GO:0065007', ('98', '108'))	('ARID1A', 'Gene', (176, 182))	('KMT2A', 'Gene', (152, 157))	('TP53', 'Gene', '7157', (120, 124))	('MLL3', 'Gene', (133, 137))	('ARID1A', 'Gene', '8289', (176, 182))	('BRCA2', 'Gene', (165, 170))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('APOBEC-high', 'Gene', (0, 11))	('ATR', 'Gene', '545', (160, 163))	('DNA repair', 'biological_process', 'GO:0006281', ('73', '83'))	('MLL', 'Gene', (133, 136))	('MLL', 'Gene', '4297', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('NCOR1', 'Gene', (126, 131))	('tumors', 'Disease', (12, 18))	('chromatin', 'cellular_component', 'GO:0000785', ('88', '97'))	('TP53', 'Gene', (120, 124))	('KMT2A', 'Gene', '4297', (152, 157))	('BRCA2', 'Gene', '675', (165, 170))	('NCOR1', 'Gene', '9611', (126, 131))	('MLL', 'Gene', (147, 150))	('MLL', 'Gene', '4297', (147, 150))	('mutations', 'Var', (43, 52))	('MLL3', 'Gene', '58508', (133, 137))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
138424	29435122	In the smaller BGI dataset, APOBEC-high tumors are more likely to have mutations in TP53 and ARID1A.	('APOBEC-high', 'Gene', (28, 39))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('TP53', 'Gene', '7157', (84, 88))	('mutations', 'Var', (71, 80))	('ARID1A', 'Gene', '8289', (93, 99))	('TP53', 'Gene', (84, 88))	('APOBEC', 'cellular_component', 'GO:0030895', ('28', '34'))	('ARID1A', 'Gene', (93, 99))	('tumors', 'Disease', (40, 46))
138425	29435122	We also demonstrate a higher frequency of PIK3CA mutations in APOBEC-high tumors in both the TCGA and BGI datasets.	('APOBEC', 'cellular_component', 'GO:0030895', ('62', '68'))	('mutations', 'Var', (49, 58))	('PIK3CA', 'Gene', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('PIK3CA', 'Gene', '5290', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
138426	29435122	PIK3CA has been previously reported to be mutated at a high frequency in specific TCW-containing helical motifs across a number of tumor types.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mutated', 'Var', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('PIK3CA', 'Gene', (0, 6))	('tumor', 'Disease', (131, 136))	('PIK3CA', 'Gene', '5290', (0, 6))
138427	29435122	Our analysis supports these results, with the majority of PIK3CA mutations in APOBEC-high tumors occurring in the helical domain at E542 and E545.	('E545', 'Var', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('APOBEC', 'cellular_component', 'GO:0030895', ('78', '84'))	('PIK3CA', 'Gene', (58, 64))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('PIK3CA', 'Gene', '5290', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('E542', 'Var', (132, 136))	('occurring', 'Reg', (97, 106))
138428	29435122	These specific mutations in E542 and E545 have also been reported as hotspot mutations in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('E542', 'Var', (28, 32))	('E545', 'Var', (37, 41))
138429	29435122	The location of these mutations in APOBEC motifs suggests that these PIK3CA mutations may be a result of APOBEC-mediated mutagenesis, rather than supporting or driving APOBEC-mutagenesis.	('mutations', 'Var', (76, 85))	('result', 'Reg', (95, 101))	('mutagenesis', 'biological_process', 'GO:0006280', ('121', '132'))	('APOBEC', 'cellular_component', 'GO:0030895', ('35', '41'))	('PIK3CA', 'Gene', (69, 75))	('APOBEC', 'cellular_component', 'GO:0030895', ('105', '111'))	('PIK3CA', 'Gene', '5290', (69, 75))	('APOBEC', 'cellular_component', 'GO:0030895', ('168', '174'))	('mutagenesis', 'biological_process', 'GO:0006280', ('175', '186'))
138430	29435122	Interestingly, APOBEC-low tumors in this study were more likely to be low-grade and have mutations in FGFR3 and the RAS family of oncogenes.	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('APOBEC', 'cellular_component', 'GO:0030895', ('15', '21'))	('FGFR3', 'Gene', (102, 107))	('FGFR3', 'Gene', '2261', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('low-grade', 'CPA', (70, 79))	('mutations', 'Var', (89, 98))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('APOBEC-low', 'Gene', (15, 25))	('tumors', 'Disease', (26, 32))
138433	29435122	Alternatively, APOBEC-mediated mutagenesis may arrest tumor cells that do not possess inactivated TP53 or other tumor suppressors.	('mutagenesis', 'Var', (31, 42))	('APOBEC', 'cellular_component', 'GO:0030895', ('15', '21'))	('APOBEC-mediated', 'Gene', (15, 30))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('arrest tumor', 'Disease', 'MESH:D006323', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('arrest tumor', 'Disease', (47, 59))	('TP53', 'Gene', '7157', (98, 102))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (54, 59))	('mutagenesis', 'biological_process', 'GO:0006280', ('31', '42'))	('TP53', 'Gene', (98, 102))
138441	29435122	Accumulation of mutations in TP53, ARID1A, ATR, BRCA2, and/or other DNA damage response genes or chromatin regulation genes may result in the accumulation of ssDNA substrate for APOBEC3A and APOBEC3B, leading to a high level of APOBEC-mediated mutagenesis and a hypermutation phenotype.	('regulation', 'biological_process', 'GO:0065007', ('107', '117'))	('DNA damage response', 'biological_process', 'GO:0006974', ('68', '87'))	('TP53', 'Gene', (29, 33))	('ARID1A', 'Gene', (35, 41))	('APOBEC3A', 'Gene', (178, 186))	('APOBEC', 'cellular_component', 'GO:0030895', ('178', '184'))	('BRCA2', 'Gene', (48, 53))	('APOBEC3B', 'Gene', (191, 199))	('APOBEC3A', 'Gene', '200315', (178, 186))	('ATR', 'Gene', '545', (43, 46))	('APOBEC', 'cellular_component', 'GO:0030895', ('228', '234'))	('mutations', 'Var', (16, 25))	('APOBEC', 'cellular_component', 'GO:0030895', ('191', '197'))	('ARID1A', 'Gene', '8289', (35, 41))	('APOBEC-mediated mutagenesis', 'MPA', (228, 255))	('chromatin', 'cellular_component', 'GO:0000785', ('97', '106'))	('BRCA2', 'Gene', '675', (48, 53))	('TP53', 'Gene', '7157', (29, 33))	('accumulation', 'PosReg', (142, 154))	('mutagenesis', 'biological_process', 'GO:0006280', ('244', '255'))	('ATR', 'Gene', (43, 46))	('APOBEC3B', 'Gene', '9582', (191, 199))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))
138443	29435122	In contrast, other tumors with mutations in the FGFR3/RAS pathway or other oncogenes may not expose sufficient substrate ssDNA to APOBEC enzymes to undergo significant APOBEC mutagenesis.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('mutations', 'Var', (31, 40))	('APOBEC', 'cellular_component', 'GO:0030895', ('130', '136'))	('FGFR3', 'Gene', '2261', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('FGFR3', 'Gene', (48, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('APOBEC', 'cellular_component', 'GO:0030895', ('168', '174'))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('mutagenesis', 'biological_process', 'GO:0006280', ('175', '186'))
138444	29435122	These APOBEC-low tumors have poor survival, despite an enrichment for FGFR3 mutations and low-grade tumors, which were classically considered more benign phenotypes.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mutations', 'Var', (76, 85))	('APOBEC', 'cellular_component', 'GO:0030895', ('6', '12'))	('FGFR3', 'Gene', '2261', (70, 75))	('FGFR', 'molecular_function', 'GO:0005007', ('70', '74'))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('FGFR3', 'Gene', (70, 75))	('APOBEC-low', 'Gene', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
138445	29435122	However, mutations in ERCC2 and other DNA repair genes are associated with response to platinum-based therapy, and further investigation into the role of APOBEC mutagenesis and response to both cytotoxic chemotherapy and immunotherapy is warranted.	('platinum', 'Chemical', 'MESH:D010984', (87, 95))	('APOBEC', 'cellular_component', 'GO:0030895', ('154', '160'))	('mutations', 'Var', (9, 18))	('response', 'MPA', (75, 83))	('ERCC2', 'Gene', '2068', (22, 27))	('DNA repair', 'biological_process', 'GO:0006281', ('38', '48'))	('associated', 'Reg', (59, 69))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('ERCC2', 'Gene', (22, 27))	('mutagenesis', 'biological_process', 'GO:0006280', ('161', '172'))	('response to platinum', 'biological_process', 'GO:0070541', ('75', '95'))
138449	29435122	In summary, APOBEC enzymes are a major source of mutation in bladder cancer.	('APOBEC', 'Protein', (12, 18))	('bladder cancer', 'Disease', 'MESH:D001749', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutation', 'Var', (49, 57))	('bladder cancer', 'Disease', (61, 75))	('APOBEC', 'cellular_component', 'GO:0030895', ('12', '18'))	('bladder cancer', 'Phenotype', 'HP:0009725', (61, 75))
138450	29435122	Tumors enriched for APOBEC mutagenesis have better survival and are more likely to have mutations in DNA damage repair genes and chromatin modifying genes.	('chromatin', 'cellular_component', 'GO:0000785', ('129', '138'))	('better', 'PosReg', (44, 50))	('mutagenesis', 'Var', (27, 38))	('APOBEC', 'Gene', (20, 26))	('mutations', 'Var', (88, 97))	('APOBEC', 'cellular_component', 'GO:0030895', ('20', '26'))	('mutagenesis', 'biological_process', 'GO:0006280', ('27', '38'))	('Tumors', 'Disease', (0, 6))	('survival', 'CPA', (51, 59))	('DNA damage repair genes', 'Gene', (101, 124))	('chromatin modifying genes', 'Gene', (129, 154))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))
138451	29435122	Bladder tumors not enriched for APOBEC mutagenesis are more likely to have mutations in FGFR3 and the RAS family of oncogenes, which are mutually exclusive, and these patients have poor overall survival.	('FGFR3', 'Gene', (88, 93))	('Bladder tumors', 'Phenotype', 'HP:0009725', (0, 14))	('Bladder tumors', 'Disease', 'MESH:D001749', (0, 14))	('patients', 'Species', '9606', (167, 175))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('mutations', 'Var', (75, 84))	('Bladder tumors', 'Disease', (0, 14))	('FGFR3', 'Gene', '2261', (88, 93))	('APOBEC', 'cellular_component', 'GO:0030895', ('32', '38'))	('FGFR', 'molecular_function', 'GO:0005007', ('88', '92'))	('mutagenesis', 'biological_process', 'GO:0006280', ('39', '50'))
138458	29435122	Analysis and visualization of mutations was performed using R v3.3.3, Bioconductor v3.4 (http://www.Bioconductor.org), and MAFtools v1.0.55.	('v3.4', 'Gene', '28774', (83, 87))	('MAF', 'Gene', (123, 126))	('v3.3', 'Gene', '28775', (62, 66))	('mutations', 'Var', (30, 39))	('v3.4', 'Gene', (83, 87))	('v3.3', 'Gene', (62, 66))	('MAF', 'Gene', '4094', (123, 126))
138470	29435122	Expression level of APOBEC3B and endogenous control GAPDH was measured using BioRad PrimePCR Probe Assays (qHsaCIP0039581 and qHsaCEP0041396) using BioRad CFX Connect RT-PCR Detection System.	('GAPDH', 'Gene', '2597', (52, 57))	('GAPDH', 'Gene', (52, 57))	('qHsaCIP0039581', 'Var', (107, 121))	('Expression level', 'MPA', (0, 16))	('APOBEC', 'cellular_component', 'GO:0030895', ('20', '26'))	('APOBEC3B', 'Gene', (20, 28))	('APOBEC3B', 'Gene', '9582', (20, 28))	('qHsaCEP0041396', 'Var', (126, 140))
138478	27780919	Evaluation of 340 UTUC and 296 UBUC tissue samples, respectively, demonstrated that high MCM10 immunoexpression was significantly associated with advanced primary tumors, nodal status, and the presence of vascular invasion in both groups of UCs.	('high', 'Var', (84, 88))	('MCM10', 'Gene', '55388', (89, 94))	('primary tumors', 'Disease', (155, 169))	('nodal status', 'CPA', (171, 183))	('associated', 'Reg', (130, 140))	('vascular invasion', 'CPA', (205, 222))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('primary tumors', 'Disease', 'MESH:D009369', (155, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('MCM10', 'Gene', (89, 94))
138480	27780919	In vitro, knockdown of MCM10 gene significantly suppressed cell proliferation in both J82 and TCCSUP cells.	('cell proliferation in', 'CPA', (59, 80))	('suppressed', 'NegReg', (48, 58))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('MCM10', 'Gene', '55388', (23, 28))	('MCM10', 'Gene', (23, 28))	('knockdown', 'Var', (10, 19))
138520	27780919	More importantly, patients with high MCM10 expression had significantly worse DSS and MeFS in both univariate (P<0.0001, Figure 5A and 5B) and multivariate analyses (P=0.013 and P<0.001, respectively).	('high', 'Var', (32, 36))	('DSS', 'MPA', (78, 81))	('MeFS', 'CPA', (86, 90))	('worse', 'NegReg', (72, 77))	('MCM10', 'Gene', (37, 42))	('MCM10', 'Gene', '55388', (37, 42))	('patients', 'Species', '9606', (18, 26))	('DSS', 'Chemical', '-', (78, 81))
138534	27780919	We demonstrated that MCM10 immunoexpression was significantly associated with aggressive pathological features, including advanced primary tumor status, vascular invasion, and nodal metastasis in both groups of UCs.	('MCM10', 'Gene', (21, 26))	('MCM10', 'Gene', '55388', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('immunoexpression', 'Var', (27, 43))	('associated', 'Reg', (62, 72))	('nodal metastasis', 'CPA', (176, 192))	('vascular invasion', 'CPA', (153, 170))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('advanced', 'Disease', (122, 130))
138551	27780919	One study found that checkpoint activation was defective following the depletion of Mcm10.	('defective', 'NegReg', (47, 56))	('depletion', 'Var', (71, 80))	('Mcm10', 'Gene', '55388', (84, 89))	('Mcm10', 'Gene', (84, 89))	('checkpoint activation', 'CPA', (21, 42))
138562	27780919	Our results provide the first data suggesting that MCM10 expression could provide an early warning for poor outcomes in UC, as it is expressed before histological changes are observable and may indicate the need of a more aggressive treatment plan.	('expression', 'Var', (57, 67))	('MCM10', 'Gene', '55388', (51, 56))	('MCM10', 'Gene', (51, 56))
138565	27780919	To date, several studies have reported that anti-MCM small molecules are potentially effective against a broad spectrum of cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('small molecules', 'Var', (53, 68))	('cancers', 'Disease', (123, 130))
138574	27780919	The slides were subsequently incubated with a primary antibody targeting one of two significant candidate genes, MCM2 (1:100, N-19, Santa Cruz) or MCM10 (1:150, H-41, Santa Cruz), for one hour.	('MCM10', 'Gene', (147, 152))	('MCM10', 'Gene', '55388', (147, 152))	('MCM2', 'Gene', '4171', (113, 117))	('antibody', 'cellular_component', 'GO:0019815', ('54', '62'))	('MCM2', 'Gene', (113, 117))	('antibody', 'cellular_component', 'GO:0019814', ('54', '62'))	('H-41', 'Gene', '55573', (161, 165))	('antibody', 'molecular_function', 'GO:0003823', ('54', '62'))	('1:100', 'Var', (119, 124))	('antibody', 'cellular_component', 'GO:0042571', ('54', '62'))	('H-41', 'Gene', (161, 165))	('1:150', 'Var', (154, 159))
138584	27780919	Real-time PCR assay to quantify the expression level of MCM10 transcript was performed using pre-designed TaqMan assay reagents (MCM10 Hs00218560_m1, and POLR2A Hs01108291_m1 from Applied Biosystems, Foster City, CA).	('pre', 'molecular_function', 'GO:0003904', ('93', '96'))	('POLR2A', 'Gene', '5430', (154, 160))	('MCM10', 'Gene', (56, 61))	('MCM10', 'Gene', '55388', (56, 61))	('MCM10', 'Gene', (129, 134))	('MCM10', 'Gene', '55388', (129, 134))	('POLR2A', 'Gene', (154, 160))	('Hs00218560_m1', 'Var', (135, 148))
138586	27780919	After normalization to POLR2A, the relative expression fold of MCM transcript was then given by 2-DeltaDeltaCp, where DeltaDeltaCT = DeltaCT (UC cells)- DeltaCT (calibrator), DeltaCT represented the CT of MCM10 subtracted from the CT of POLR2A, and the calibrator was RT4 cell.	('POLR2A', 'Gene', (237, 243))	('DeltaDeltaCT', 'Var', (118, 130))	('POLR2A', 'Gene', '5430', (23, 29))	('POLR2A', 'Gene', '5430', (237, 243))	('DeltaCT', 'Var', (133, 140))	('DeltaCT', 'Var', (175, 182))	('POLR2A', 'Gene', (23, 29))	('MCM10', 'Gene', (205, 210))	('MCM10', 'Gene', '55388', (205, 210))	('RT4', 'CellLine', 'CVCL:0036', (268, 271))
138588	27780919	The western blotting assay was performed based on that of our previous publications to evaluate the endogenous MCM10 expression and the efficiency of MCM10 knockdown in J82 and TCCSUP cell lines.	('knockdown', 'Var', (156, 165))	('MCM10', 'Gene', (111, 116))	('MCM10', 'Gene', '55388', (111, 116))	('MCM10', 'Gene', '55388', (150, 155))	('MCM10', 'Gene', (150, 155))
138591	27780919	To establish stably silenced clones of MCM10-amplified J82 and TCCSUP cell lines with the short-hairpin RNAs against MCM10 expression (shMCM10), the lentiviral vectors were obtained from Taiwan National RNAi Core Facility, including pLKO.1-shLacZ (TRCN0000072223: 5'-TGTTCGCATTAT CCGAACCAT-3') and pLKO.1-shMCM10 (TRCN0000245425: 5'-TCATCCTCAGAAGG TCTTAAT-3'; TRCN0000245426: 5'-GACGGCGACGG TGAATCTTAT-3').	('MCM10', 'Gene', (137, 142))	('MCM10', 'Gene', '55388', (137, 142))	('MCM10', 'Gene', (117, 122))	('MCM10', 'Gene', '55388', (117, 122))	('RNAi', 'biological_process', 'GO:0016246', ('203', '207'))	('MCM10', 'Gene', (307, 312))	('MCM10', 'Gene', '55388', (307, 312))	('MCM10', 'Gene', (39, 44))	('MCM10', 'Gene', '55388', (39, 44))	('TRCN0000245426', 'Var', (360, 374))
138602	27880943	We show that TP53 is the most frequently mutated gene in a number of cancers, and its mutations appear to be early events in cancer initiation.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('mutations', 'Var', (86, 95))	('TP53', 'Gene', (13, 17))	('cancer initiation', 'Disease', (125, 142))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('TP53', 'Gene', '7157', (13, 17))	('cancer initiation', 'Disease', 'MESH:D009369', (125, 142))
138605	27880943	This study shows that while TP53-truncating mutations often result in decreased TP53 expression, other non-truncating TP53 mutations result in increased TP53 expression in some cancers.	('expression', 'MPA', (85, 95))	('increased', 'PosReg', (143, 152))	('TP53', 'Gene', '7157', (28, 32))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('expression', 'MPA', (158, 168))	('cancers', 'Disease', (177, 184))	('TP53', 'Gene', (28, 32))	('decreased', 'NegReg', (70, 79))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('TP53', 'Gene', '7157', (153, 157))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('TP53', 'Gene', (153, 157))	('mutations', 'Var', (123, 132))
138606	27880943	Survival analyses in a number of cancers show that patients with TP53 mutations are more likely to have worse prognoses than TP53-wildtype patients, and that elevated TP53 expression often leads to poor clinical outcomes.	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('leads to', 'Reg', (189, 197))	('patients', 'Species', '9606', (139, 147))	('TP53', 'Gene', '7157', (125, 129))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('TP53', 'Gene', (125, 129))	('expression', 'MPA', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('poor clinical outcomes', 'MPA', (198, 220))	('TP53', 'Gene', '7157', (167, 171))	('patients', 'Species', '9606', (51, 59))	('elevated', 'PosReg', (158, 166))	('TP53', 'Gene', (167, 171))
138609	27880943	TP53 mutations and dysfunction occur in more than half of all human cancer cases, and are independent markers of poor prognoses in some cancers.	('TP53', 'Gene', '7157', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('human', 'Species', '9606', (62, 67))	('cancers', 'Disease', (136, 143))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('mutations', 'Var', (5, 14))	('occur', 'Reg', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
138610	27880943	In addition to mutations in TP53 itself, mutations in p53 pathway genes are significantly enriched in cancer.	('mutations', 'Var', (41, 50))	('TP53', 'Gene', '7157', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('TP53', 'Gene', (28, 32))	('p53', 'Gene', (54, 57))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('p53', 'Gene', '7157', (54, 57))	('enriched', 'Reg', (90, 98))
138617	27880943	Some therapeutic strategies have been proposed to treat TP53-mutated cancers, such as restoring wild-type activity to; promoting the degradation of; or targeting pathways regulated by mutant p53.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('degradation', 'biological_process', 'GO:0009056', ('133', '144'))	('degradation of', 'MPA', (133, 147))	('wild-type', 'MPA', (96, 105))	('mutant', 'Var', (184, 190))	('TP53', 'Gene', '7157', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('p53', 'Gene', (191, 194))	('TP53', 'Gene', (56, 60))	('p53', 'Gene', '7157', (191, 194))	('targeting', 'Reg', (152, 161))	('pathways', 'Pathway', (162, 170))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('promoting', 'PosReg', (119, 128))	('cancers', 'Disease', (69, 76))
138619	27880943	Thus, the targeted disruption of a gene that is SL for TP53 should selectively kill cancer cells with somatic mutations in TP53, but spare normal TP53-wildtype cells.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('TP53', 'Gene', '7157', (146, 150))	('mutations', 'Var', (110, 119))	('disruption', 'Var', (19, 29))	('kill', 'NegReg', (79, 83))	('cancer', 'Disease', (84, 90))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
138622	27880943	We analyzed TP53 mutation and gene expression data to identify potential nodes in TP53 interaction networks, and performed survival analyses based on TP53 mutations and expression profiles across the 33 cancer types, respectively.	('TP53', 'Gene', (82, 86))	('TP53', 'Gene', (150, 154))	('mutations', 'Var', (155, 164))	('TP53', 'Gene', '7157', (12, 16))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (12, 16))	('TP53', 'Gene', '7157', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('gene expression', 'biological_process', 'GO:0010467', ('30', '45'))
138625	27880943	Almost one-third of cancer types have a TP53 mutation rate greater than 50%, and more than one-half have a rate greater than 30%.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('TP53', 'Gene', '7157', (40, 44))	('mutation', 'Var', (45, 53))	('TP53', 'Gene', (40, 44))	('cancer', 'Disease', (20, 26))
138626	27880943	The two cancer types with the highest TP53 mutation rates affect women: uterine carcino-sarcoma (UCS) (91.2%) and ovarian serous cystadeno-carcinoma (OV) (83%).	('ovarian serous cystadeno-carcinoma', 'Disease', (114, 148))	('cancer', 'Disease', (8, 14))	('uterine carcino-sarcoma', 'Phenotype', 'HP:0002891', (72, 95))	('mutation', 'Var', (43, 51))	('TP53', 'Gene', (38, 42))	('carcino-sarcoma', 'Disease', 'MESH:D012509', (80, 95))	('TP53', 'Gene', '7157', (38, 42))	('ovarian serous cystadeno-carcinoma', 'Disease', 'MESH:D010051', (114, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('carcino-sarcoma', 'Disease', (80, 95))	('women', 'Species', '9606', (65, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('ovarian serous cystadeno-carcinoma', 'Phenotype', 'HP:0012887', (114, 148))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
138627	27880943	The other eight cancer types with a TP53 mutation rate that exceeds 50% include four gastro-intestinal cancers: esophageal carcinoma (ESCA), rectal adeno-carcinoma (READ), pancreatic adeno-carcinoma (PAAD) and colon adeno-carcinoma (COAD); two lung cancers: lung squamous-cell carcinoma (LUSC) and lung adeno-carcinoma (LUAD); and head-and-neck squamous-cell carcinoma (HNSC) and brain lower-grade glioma (LGG).	('COAD', 'Disease', (233, 237))	('gastro-intestinal cancers', 'Disease', 'MESH:D007414', (85, 110))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('colon adeno-carcinoma', 'Disease', (210, 231))	('cancer', 'Disease', (249, 255))	('TP53', 'Gene', (36, 40))	('cancer', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('lung adeno-carcinoma', 'Disease', (298, 318))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (112, 132))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung squamous-cell carcinoma', 'Phenotype', 'HP:0030359', (258, 286))	('lung adeno-carcinoma', 'Phenotype', 'HP:0030078', (298, 318))	('cancer', 'Disease', (16, 22))	('gastro-intestinal cancers', 'Disease', (85, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('mutation', 'Var', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('glioma', 'Disease', (398, 404))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('glioma', 'Disease', 'MESH:D005910', (398, 404))	('colon adeno-carcinoma', 'Disease', 'MESH:D015179', (210, 231))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('TP53', 'Gene', '7157', (36, 40))	('lung squamous-cell carcinoma', 'Disease', 'MESH:D002294', (258, 286))	('lung cancers', 'Disease', 'MESH:D008175', (244, 256))	('lung adeno-carcinoma', 'Disease', 'MESH:D008175', (298, 318))	('COAD', 'Disease', 'MESH:D029424', (233, 237))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (263, 286))	('squamous-cell carcinoma (HNSC)', 'Disease', 'MESH:D002294', (345, 375))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (112, 132))	('lung cancers', 'Disease', (244, 256))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('glioma', 'Phenotype', 'HP:0009733', (398, 404))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (345, 368))	('adeno-carcinoma (READ), pancreatic adeno-carcinoma', 'Disease', 'MESH:C562463', (148, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('pancreatic adeno-carcinoma', 'Phenotype', 'HP:0006725', (172, 198))	('lung cancers', 'Phenotype', 'HP:0100526', (244, 256))	('lung squamous-cell carcinoma', 'Disease', (258, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('esophageal carcinoma', 'Disease', (112, 132))	('neck', 'cellular_component', 'GO:0044326', ('340', '344'))
138629	27880943	We found that TP53 has the highest mutation rate in six cancer types: UCS, OV, ESCA, LUSC, HNSC and sarcoma (SARC), and the second-highest mutation rate in seven other cancer types: READ, LUAD, LGG, bladder urothelial carcinoma (BLCA), stomach adeno-carcinoma (STAD), liver hepato-cellular carcinoma (LIHC), and breast-invasive carcinoma (BRCA).	('TP53', 'Gene', (14, 18))	('breast-invasive carcinoma (BRCA)', 'Gene', '672', (312, 344))	('cancer', 'Disease', (168, 174))	('mutation', 'Var', (35, 43))	('cancer', 'Disease', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('bladder urothelial carcinoma', 'Disease', (199, 227))	('ESCA', 'Disease', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('LUSC', 'Disease', (85, 89))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (199, 227))	('TP53', 'Gene', '7157', (14, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('stomach adeno-carcinoma (STAD), liver hepato-cellular carcinoma', 'Disease', 'MESH:D006528', (236, 299))	('breast-invasive carcinoma (BRCA', 'Gene', (312, 343))	('hepato-cellular carcinoma', 'Phenotype', 'HP:0001402', (274, 299))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('LUAD', 'Disease', (188, 192))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('UCS', 'Disease', (70, 73))	('READ', 'Disease', (182, 186))	('HNSC and sarcoma', 'Disease', 'MESH:D012509', (91, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('LGG', 'Disease', (194, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))
138634	27880943	Surprisingly, there are marked differences in the TP53 mutation rates in cancers from the same organ but different cell types, e.g., in KIRP, KIRC, and kidney chromophobe (KICH), with rates of 2.5%, 2.4% and 33.3%, respectively.	('cancers', 'Disease', (73, 80))	('TP53', 'Gene', (50, 54))	('KICH', 'Disease', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TP53', 'Gene', '7157', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('kidney chromophobe', 'Disease', (152, 170))	('mutation', 'Var', (55, 63))	('KICH', 'Disease', 'None', (172, 176))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('kidney chromophobe', 'Disease', 'MESH:D000238', (152, 170))
138635	27880943	TP53 mutations are comprised of eight classes: missense, nonsense, frame-shift deletion, frame-shift insertion, in-frame deletion, in-frame insertion, silent and splice-site.	('missense', 'Var', (47, 55))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('frame-shift insertion', 'Var', (89, 110))	('mutations', 'Var', (5, 14))	('frame-shift deletion', 'Var', (67, 87))	('nonsense', 'Var', (57, 65))	('in-frame insertion', 'Var', (131, 149))	('silent and', 'Var', (151, 161))	('in-frame deletion', 'Var', (112, 129))
138636	27880943	Figure 1 summarizes the proportion of each class of TP53 mutations in all 33 TCGA cancer types.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TP53', 'Gene', '7157', (52, 56))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('TP53', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))
138637	27880943	The most frequent classes of TP53 mutations are missense (62%), nonsense (14%) and frame-shift deletions (9%).	('frame-shift deletions', 'Var', (83, 104))	('missense', 'Var', (48, 56))	('nonsense', 'Var', (64, 72))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))
138638	27880943	The proportions of each class of mutations in all of the TP53 mutations in each cancer type are listed in Supplementary Table S2.	('TP53', 'Gene', '7157', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('cancer', 'Disease', (80, 86))
138639	27880943	In general, nonsense mutations, frame-shift deletions, frame-shift insertions and splice-site mutations are all highly deleterious, and 34.5% of all TP53 mutations fall into one of these classes.	('frame-shift deletions', 'Var', (32, 53))	('TP53', 'Gene', '7157', (149, 153))	('fall', 'Phenotype', 'HP:0002527', (164, 168))	('nonsense mutations', 'Var', (12, 30))	('TP53', 'Gene', (149, 153))	('mutations', 'Var', (154, 163))	('frame-shift', 'Var', (55, 66))
138640	27880943	In contrast, in-frame deletions, in-frame insertions, and silent mutations have comparatively much less deleterious effects, but only 3.5% of all TP53 mutations fall into one of these mutation classes.	('TP53', 'Gene', '7157', (146, 150))	('in-frame insertions', 'Var', (33, 52))	('fall', 'Phenotype', 'HP:0002527', (161, 165))	('TP53', 'Gene', (146, 150))	('mutations', 'Var', (151, 160))
138641	27880943	Since most TP53 missense mutations are deleterious, we can conclude that deleterious or altered-function mutations predominate among TP53 mutations discovered in cancers.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('missense mutations', 'Var', (16, 34))	('cancers', 'Disease', (162, 169))	('TP53', 'Gene', '7157', (11, 15))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('TP53', 'Gene', (11, 15))	('mutations', 'Var', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('TP53', 'Gene', '7157', (133, 137))	('altered-function', 'Reg', (88, 104))	('TP53', 'Gene', (133, 137))
138644	27880943	Once mutations compromise p53's transcriptional repression function, genes that are usually repressed by it should have elevated expression in TP53-mutated cancers compared to TP53-wildtype cancers or normal tissue.	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('TP53', 'Gene', '7157', (176, 180))	('p53', 'Gene', (26, 29))	('TP53', 'Gene', '7157', (143, 147))	('compromise', 'NegReg', (15, 25))	('TP53-wildtype cancers', 'Disease', (176, 197))	('expression', 'MPA', (129, 139))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('mutations', 'Var', (5, 14))	('TP53', 'Gene', (176, 180))	('elevated', 'PosReg', (120, 128))	('TP53', 'Gene', (143, 147))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('TP53-wildtype cancers', 'Disease', 'MESH:D009369', (176, 197))	('cancers', 'Disease', (156, 163))	('transcriptional repression function', 'MPA', (32, 67))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('p53', 'Gene', '7157', (26, 29))
138645	27880943	We identified genes potentially repressed by p53 by comparing gene expression levels in cancers with non-silent (functionally significant) TP53 mutations compared to TP53-wildtype cancers in the TCGA datasets.	('TP53-wildtype cancers', 'Disease', 'MESH:D009369', (166, 187))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('gene expression levels', 'MPA', (62, 84))	('mutations', 'Var', (144, 153))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('TP53', 'Gene', '7157', (166, 170))	('cancers', 'Disease', (88, 95))	('TP53', 'Gene', (139, 143))	('p53', 'Gene', '7157', (45, 48))	('gene expression', 'biological_process', 'GO:0010467', ('62', '77'))	('TP53-wildtype cancers', 'Disease', (166, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('p53', 'Gene', (45, 48))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancers', 'Disease', (180, 187))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('TP53', 'Gene', '7157', (139, 143))	('TP53', 'Gene', (166, 170))
138660	27880943	The products of these eight genes are of particular interest as targets for the development of small-molecule kinase inhibitors, a strategy adopted by several cancer therapies.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('small-molecule', 'Var', (95, 109))
138664	27880943	Using the PANTHER Classification System, we categorized the 120 TP53-MW genes into eight molecular function classes: binding (GO:0005488), catalytic activity (GO:0003824), channel regulator activity (GO:0016247), enzyme regulator activity (GO:0030234), nucleic acid binding transcription factor activity (GO:0001071), receptor activity (GO:0004872), structural molecule activity (GO:0005198), and transporter activity (GO:0005215).	('catalytic activity', 'MPA', (139, 157))	('GO:0001071', 'Var', (305, 315))	('structural molecule activity', 'molecular_function', 'GO:0005198', ('350', '378'))	('binding', 'Interaction', (117, 124))	('TP53', 'Gene', '7157', (64, 68))	('transcription', 'biological_process', 'GO:0006351', ('274', '287'))	('catalytic activity', 'molecular_function', 'GO:0003824', ('139', '157'))	('molecular function', 'molecular_function', 'GO:0003674', ('89', '107'))	('transporter activity', 'molecular_function', 'GO:0005215', ('397', '417'))	('nucleic', 'MPA', (253, 260))	('structural molecule activity', 'MPA', (350, 378))	('GO:0030234', 'Var', (240, 250))	('channel regulator activity', 'MPA', (172, 198))	('channel regulator activity', 'molecular_function', 'GO:0016247', ('172', '198'))	('receptor activity', 'MPA', (318, 335))	('receptor activity', 'molecular_function', 'GO:0038024', ('318', '335'))	('GO:0005198', 'Var', (380, 390))	('TP53', 'Gene', (64, 68))	('GO:0016247', 'Var', (200, 210))	('nucleic acid binding transcription factor activity', 'molecular_function', 'GO:0003700', ('253', '303'))	('GO:0003824', 'Var', (159, 169))	('transporter activity', 'MPA', (397, 417))	('GO:0005488', 'Var', (126, 136))	('GO:0004872', 'Var', (337, 347))	('receptor activity', 'molecular_function', 'GO:0038023', ('318', '335'))	('enzyme regulator activity', 'MPA', (213, 238))	('binding', 'molecular_function', 'GO:0005488', ('117', '124'))	('enzyme regulator activity', 'molecular_function', 'GO:0030234', ('213', '238'))	('nucleic acid', 'cellular_component', 'GO:0005561', ('253', '265'))
138680	27880943	Our results indicate that p53 may in turn inhibit TTK by a negative feedback loop, since TP53 mutations seem to cause the elevated expression of TTK.	('negative feedback loop', 'MPA', (59, 81))	('TP53', 'Gene', '7157', (89, 93))	('TTK', 'Gene', (145, 148))	('TP53', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('TTK', 'molecular_function', 'GO:0050321', ('145', '148'))	('TTK', 'molecular_function', 'GO:0050321', ('50', '53'))	('p53', 'Gene', (26, 29))	('TTK', 'Gene', (50, 53))	('expression', 'MPA', (131, 141))	('TTK', 'Gene', '7272', (145, 148))	('elevated', 'PosReg', (122, 130))	('p53', 'Gene', '7157', (26, 29))	('inhibit', 'NegReg', (42, 49))	('TTK', 'Gene', '7272', (50, 53))
138683	27880943	We are interested in these genes because the mechanism underlying the elevated expression of TP53-MSN genes could be specifically related to TP53 mutations.	('elevated', 'PosReg', (70, 78))	('mutations', 'Var', (146, 155))	('expression', 'MPA', (79, 89))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (93, 97))	('TP53', 'Gene', (141, 145))	('MSN', 'Gene', '4478', (98, 101))	('MSN', 'Gene', (98, 101))
138688	27880943	In addition, our results suggest that TP53 may also inhibit other TP53-MSN genes, and that TP53 mutations may contribute to their elevated expression in a number of different cancer types.	('inhibit', 'NegReg', (52, 59))	('TP53', 'Gene', (91, 95))	('TP53', 'Gene', '7157', (66, 70))	('MSN', 'Gene', '4478', (71, 74))	('TP53', 'Gene', (66, 70))	('TP53', 'Gene', (38, 42))	('MSN', 'Gene', (71, 74))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('elevated', 'PosReg', (130, 138))	('expression', 'MPA', (139, 149))	('TP53', 'Gene', '7157', (91, 95))	('mutations', 'Var', (96, 105))	('TP53', 'Gene', '7157', (38, 42))
138689	27880943	We compared the TP53 mutation rates among different clinical phenotypes of cancer patients including gender, race, tumor stage, size or direct extent of the primary tumor (T), lymph nodes (N), and metastasis (M) in 18 cancer types: ACC, BLCA, BRCA, CESC, CHOL, COAD, DLBC, ESCA, GBM, HNSC, KICH, KIRC, KIRP, LAML, LGG, LIHC, LUAD, and LUSC (Supplementary Table S11).	('KICH', 'Disease', 'None', (290, 294))	('tumor', 'Disease', (115, 120))	('CHOL', 'Disease', (255, 259))	('BRCA', 'Gene', '672', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('COAD', 'Disease', 'MESH:D029424', (261, 265))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('TP53', 'Gene', '7157', (16, 20))	('KICH', 'Disease', (290, 294))	('BRCA', 'Gene', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('patients', 'Species', '9606', (82, 90))	('COAD', 'Disease', (261, 265))	('tumor', 'Disease', (165, 170))	('CHOL', 'Disease', 'None', (255, 259))	('cancer', 'Disease', (218, 224))	('cancer', 'Disease', (75, 81))	('mutation', 'Var', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('TP53', 'Gene', (16, 20))
138691	27880943	In DLBC the TP53 mutation rate is lower in male than female subjects (unadjusted P-value = 0.05, odds ratio = 0), while in LIHC the rate is higher in male than female subjects (unadjusted P-value = 0.0007, odds ratio = 2.4).	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', (12, 16))	('lower', 'NegReg', (34, 39))	('mutation', 'Var', (17, 25))
138693	27880943	For the race phenotype, only HNSC shows a significantly higher TP53 mutation rate in African-American than in White-American subjects (unadjusted P-value = 0.03, odds ratio = 2.48).	('mutation', 'Var', (68, 76))	('higher', 'PosReg', (56, 62))	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (63, 67))
138694	27880943	We did not find significant differences in the TP53 mutation rates among different stages, T, N, or M status of tumor except that ACC shows a significantly higher TP53 mutation rate in large-size cancers (T3, T4) than small-size cancers (T1, T2) (unadjusted P-value = 0.04, odds ratio = 3.42).	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('higher', 'PosReg', (156, 162))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('TP53', 'Gene', '7157', (163, 167))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('cancers', 'Disease', (229, 236))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutation', 'Var', (168, 176))	('TP53', 'Gene', (163, 167))	('cancers', 'Disease', (196, 203))	('TP53', 'Gene', '7157', (47, 51))	('tumor', 'Disease', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('TP53', 'Gene', (47, 51))
138695	27880943	Since the phenotypes tumor stage, T, N, and M reflect the development or progress status of tumors, our results indicate that TP53 mutations are probably early events in tumorigenesis and drive its progression.	('mutations', 'Var', (131, 140))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('TP53', 'Gene', (126, 130))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumors', 'Disease', (92, 98))	('TP53', 'Gene', '7157', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
138697	27880943	Kaplan-Meier survival curves (Figure 6) show that patients with TP53 mutations have significantly worse OS prognoses compared with those without TP53 mutations in seven cancer types: ACC, COAD, HNSC, KIRC, LAML, LUAD, and PAAD; however, they have better OS prognoses in GBM (log-rank test, unadjusted P-value < 0.05).	('COAD', 'Disease', (188, 192))	('mutations', 'Var', (69, 78))	('cancer', 'Disease', (169, 175))	('patients', 'Species', '9606', (50, 58))	('COAD', 'Disease', 'MESH:D029424', (188, 192))	('TP53', 'Gene', '7157', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('TP53', 'Gene', (145, 149))	('GBM', 'Disease', (270, 273))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
138699	27880943	Kaplan-Meier survival curves (Figure 6) show that patients with TP53 mutations have significantly worse DFS prognoses compared with those without TP53 mutations in three cancer types: ACC, PAAD, and UCEC (log-rank test, unadjusted P-value < 0.05).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('mutations', 'Var', (69, 78))	('TP53', 'Gene', '7157', (146, 150))	('cancer', 'Disease', (170, 176))	('patients', 'Species', '9606', (50, 58))	('ACC', 'Disease', (184, 187))	('TP53', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('PAAD', 'Disease', (189, 193))	('DFS', 'MPA', (104, 107))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('worse', 'NegReg', (98, 103))
138700	27880943	These results confirm that TP53 mutations lead to poor clinical outcomes in a number of cancers.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('mutations', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
138712	27880943	It makes sense that some TP53 mutations compromise p53 tumor suppressor function by reducing TP53 expression.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('TP53', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('compromise', 'NegReg', (40, 50))	('tumor suppressor', 'biological_process', 'GO:0051726', ('55', '71'))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('tumor', 'Disease', (55, 60))	('TP53', 'Gene', '7157', (25, 29))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('55', '71'))	('mutations', 'Var', (30, 39))	('reducing', 'NegReg', (84, 92))	('expression', 'MPA', (98, 108))
138714	27880943	The explanation for these results could be that some TP53 mutations result in overexpression of mutant forms of TP53 while other mutations simply inactivate TP53.	('TP53', 'Gene', (157, 161))	('mutations', 'Var', (58, 67))	('mutant', 'Var', (96, 102))	('TP53', 'Gene', '7157', (157, 161))	('overexpression', 'MPA', (78, 92))	('result in', 'Reg', (68, 77))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', '7157', (112, 116))	('TP53', 'Gene', (53, 57))	('TP53', 'Gene', (112, 116))
138718	27880943	We then divided TP53 mutations into truncating and non-truncating classes to observe their respective effects on TP53 expression.	('TP53', 'Gene', '7157', (113, 117))	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (113, 117))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
138723	27880943	In contrast, TP53 non-truncating mutations may result in increased TP53 expression.	('TP53', 'Gene', (13, 17))	('expression', 'MPA', (72, 82))	('non-truncating mutations', 'Var', (18, 42))	('TP53', 'Gene', '7157', (67, 71))	('increased', 'PosReg', (57, 66))	('TP53', 'Gene', (67, 71))	('TP53', 'Gene', '7157', (13, 17))
138758	27880943	We found that BI-2536, GW843682X, Epothilone B, Afatinib and Gefitinib have significantly lower IC50 values in TP53-mutated cancer cell lines than in TP53-wildtype cancer cell lines (P-value < 0.05, FDR < 0.2, Supplementary Table S21).	('TP53', 'Gene', (150, 154))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('TP53', 'Gene', '7157', (111, 115))	('Epothilone B', 'Chemical', 'MESH:C093788', (34, 46))	('lower', 'NegReg', (90, 95))	('Afatinib', 'Chemical', 'MESH:D000077716', (48, 56))	('TP53', 'Gene', '7157', (150, 154))	('GW843682X', 'Var', (23, 32))	('GW843682X', 'Chemical', 'MESH:C524135', (23, 32))	('IC50 values', 'MPA', (96, 107))	('BI-2536', 'Var', (14, 21))	('cancer', 'Disease', (164, 170))	('BI-2536', 'Chemical', 'MESH:C518477', (14, 21))	('cancer', 'Disease', (124, 130))	('Gefitinib', 'Chemical', 'MESH:D000077156', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('TP53', 'Gene', (111, 115))
138763	27880943	In our study we performed extensive analyses of TP53 mutation, gene expression, and clinical data from 33 TCGA cancer type-specific datasets.	('TP53', 'Gene', '7157', (48, 52))	('gene expression', 'biological_process', 'GO:0010467', ('63', '78'))	('mutation', 'Var', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('TP53', 'Gene', (48, 52))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
138764	27880943	We identified potential TP53 interaction networks, the association between patient survival and TP53 mutation or gene expression status, and potential druggable SL partners of TP53.	('TP53', 'Gene', (96, 100))	('TP53', 'Gene', (24, 28))	('TP53', 'Gene', '7157', (176, 180))	('gene expression', 'biological_process', 'GO:0010467', ('113', '128'))	('association', 'Interaction', (55, 66))	('TP53', 'Gene', (176, 180))	('interaction', 'Interaction', (29, 40))	('mutation', 'Var', (101, 109))	('patient', 'Species', '9606', (75, 82))	('TP53', 'Gene', '7157', (96, 100))	('TP53', 'Gene', '7157', (24, 28))
138766	27880943	This indicates that TP53-truncating mutations reduce TP53 expression but some non-truncating mutations are capable of increasing it.	('reduce', 'NegReg', (46, 52))	('TP53', 'Gene', (20, 24))	('expression', 'MPA', (58, 68))	('mutations', 'Var', (36, 45))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', (53, 57))
138767	27880943	However, we did not find significant survival time (OS or DFS) differences between TP53-truncated and TP53-mutated but TP53-non-truncated classes of cancer patients, indicating that both types of TP53 mutations are equally deleterious and lead to poor clinical outcomes.	('TP53', 'Gene', (196, 200))	('patients', 'Species', '9606', (156, 164))	('TP53', 'Gene', (102, 106))	('cancer', 'Disease', (149, 155))	('mutations', 'Var', (201, 210))	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('TP53', 'Gene', '7157', (196, 200))	('TP53', 'Gene', '7157', (102, 106))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
138788	27880943	We performed survival analyses of TCGA patients based on TP53 mutation data and TP53 gene expression data, respectively.	('gene expression', 'biological_process', 'GO:0010467', ('85', '100'))	('patients', 'Species', '9606', (39, 47))	('TCGA', 'Disease', (34, 38))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('mutation', 'Var', (62, 70))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))
138821	26055179	Drug-resistant sublines were established by continuous exposure to increasing drug concentrations and are part of the Resistant Cancer Cell Line (RCCL) collection (http://www.kent.ac.uk/stms/cmp/RCCL/RCCLabout): RT112rCDDP1000 (cisplatin-resistant, 1000 ng/ml cisplatin), RT112rGEMCI20 (gemcitabine-resistant, 20 ng/ml gemcitabine), RT4rCDDP1000, RT4rGEMCI10, 5637rCDDP1000, 5637rGEMCI20, T24rCDDP1000, T24rGEMCI20, T24rVBL20 (vinblastine-resistant, 20 ng/ml vinblastine), HT1376rCDDP1000, HT1376rGEMCI20, TCC-SUPrCDDP1000, TCC-SUPrGEMCI20, and TCC-SUPrVBL20.	('TCC', 'cellular_component', 'GO:0005579', ('545', '548'))	('SUPrGEMCI20', 'Gene', '9709', (528, 539))	('gemcitabine', 'Chemical', 'MESH:C056507', (287, 298))	('HT1376rCDDP1000', 'Var', (473, 488))	('RT112rCDDP1000', 'Var', (212, 226))	('RCCL', 'Disease', (200, 204))	('RCCL', 'Disease', 'None', (195, 199))	('T24rCDDP1000', 'Var', (389, 401))	('gemcitabine', 'Chemical', 'MESH:C056507', (319, 330))	('RCCL', 'Disease', 'None', (146, 150))	('vinblastine', 'Chemical', 'MESH:D014747', (427, 438))	('vinblastine', 'Chemical', 'MESH:D014747', (459, 470))	('Cancer', 'Phenotype', 'HP:0002664', (128, 134))	('HT1376rGEMCI20', 'Var', (490, 504))	('T24rGEMCI20', 'Var', (403, 414))	('RCCL', 'Disease', 'None', (200, 204))	('HT1376', 'CellLine', 'CVCL:1292', (490, 496))	('cisplatin', 'Chemical', 'MESH:D002945', (228, 237))	('HT1376rGEMCI20', 'CellLine', 'CVCL:1292', (490, 504))	('SUPrGEMCI20', 'Gene', (528, 539))	('cisplatin', 'Chemical', 'MESH:D002945', (260, 269))	('HT1376', 'CellLine', 'CVCL:1292', (473, 479))	('5637rGEMCI20', 'Var', (375, 387))	('RCCL', 'Disease', (195, 199))	('T24rVBL20', 'Var', (416, 425))	('RCCL', 'Disease', (146, 150))	('TCC', 'cellular_component', 'GO:0005579', ('506', '509'))	('TCC', 'cellular_component', 'GO:0005579', ('524', '527'))
138833	26055179	Three of six cisplatin-resistant sublines [RT112rCDDP1000 (DT: 0.96 day), RT4rCDDP1000 (DT: 1.65 day), and TCC-SUPrCDDP1000 (DT: 1.30 day)] displayed enhanced growth rates compared to their parental cell lines, while growth rate of 5637rCDDP1000 (DT: 1.23 day) cells was decreased relative to 5637 cells.	('enhanced', 'PosReg', (150, 158))	('RT4rCDDP1000', 'Var', (74, 86))	('growth', 'MPA', (159, 165))	('TCC', 'cellular_component', 'GO:0005579', ('107', '110'))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))
138834	26055179	For HT1376 vs HT1376rCDDP1000 (DT: 1.30 day) and T24 vs T24rCDDP1000 (DT: 1.03 day), no significant difference in growth rate was found (Figure 1).	('T24 vs T24rCDDP1000', 'Var', (49, 68))	('HT1376rCDDP1000', 'Var', (14, 29))	('HT1376', 'CellLine', 'CVCL:1292', (4, 10))	('HT1376', 'CellLine', 'CVCL:1292', (14, 20))	('HT1376 vs HT1376rCDDP1000', 'Var', (4, 29))
138837	26055179	Gemcitabine-resistant cell lines displayed resistance factors to gemcitabine ranging from 7.11 (RT4rGEMCI10) to 73.28 (RT112rGEMCI20) relative to parental cell lines (Suppl.	('Gemcitabine', 'Chemical', 'MESH:C056507', (0, 11))	('resistance', 'MPA', (43, 53))	('gemcitabine', 'Chemical', 'MESH:C056507', (65, 76))	('RT112rGEMCI20', 'Var', (119, 132))	('Suppl', 'Chemical', '-', (167, 172))
138840	26055179	Cisplatin-resistant sublines were resistant to three (RT4rCDDP1000: cisplatin, carboplatin, and 5-fluorouracil) and four (5637rCDDP1000: cisplatin, carboplatin, methotrexate, and topotecan) of the 16 drugs (Suppl.	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('resistant', 'MPA', (34, 43))	('5637rCDDP1000', 'Var', (122, 135))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('carboplatin', 'Chemical', 'MESH:D016190', (79, 90))	('Suppl', 'Chemical', '-', (207, 212))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))	('carboplatin', 'Chemical', 'MESH:D016190', (148, 159))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (96, 110))	('methotrexate', 'Chemical', 'MESH:D008727', (161, 173))	('topotecan', 'Chemical', 'MESH:D019772', (179, 188))
138846	26055179	TCC-SUPrGEMCI20 and T24rGEMCI20 cells showed cross-resistance to ABCB1 substrates docetaxel, paclitaxel, and doxorubicin (Suppl.	('SUPrGEMCI20', 'Gene', '9709', (4, 15))	('doxorubicin', 'Chemical', 'MESH:D004317', (109, 120))	('SUPrGEMCI20', 'Gene', (4, 15))	('TCC', 'cellular_component', 'GO:0005579', ('0', '3'))	('ABCB1', 'Gene', (65, 70))	('paclitaxel', 'Chemical', 'MESH:D017239', (93, 103))	('ABCB1', 'Gene', '5243', (65, 70))	('docetaxel', 'Chemical', 'MESH:D000077143', (82, 91))	('cross-resistance', 'MPA', (45, 61))	('Suppl', 'Chemical', '-', (122, 127))	('T24rGEMCI20', 'Var', (20, 31))
138849	26055179	In accordance, the relative resistance IC50 TCC-SUPrGEMCI20/IC50 TCC-SUP and IC50 T24rGEMCI20/IC50 T24 was lower for vinflunine than for vinblastine (Suppl.	('SUPrGEMCI20', 'Gene', '9709', (48, 59))	('SUPrGEMCI20', 'Gene', (48, 59))	('vinflunine', 'Var', (117, 127))	('lower', 'NegReg', (107, 112))	('TCC', 'cellular_component', 'GO:0005579', ('65', '68'))	('vinflunine', 'Chemical', 'MESH:C111217', (117, 127))	('Suppl', 'Chemical', '-', (150, 155))	('TCC', 'cellular_component', 'GO:0005579', ('44', '47'))	('vinblastine', 'Chemical', 'MESH:D014747', (137, 148))
138850	26055179	R123 is a fluorescent dye that is transported by ABCB1.	('ABCB1', 'Gene', (49, 54))	('R123', 'Var', (0, 4))	('ABCB1', 'Gene', '5243', (49, 54))
138874	26055179	TCC-SUPrGEMCI20 and T24rGEMCI20 cells displayed cross-resistance to docetaxel, paclitaxel, and larotaxel, another taxane under clinical evaluation.	('docetaxel', 'Chemical', 'MESH:D000077143', (68, 77))	('SUPrGEMCI20', 'Gene', '9709', (4, 15))	('paclitaxel', 'Chemical', 'MESH:D017239', (79, 89))	('SUPrGEMCI20', 'Gene', (4, 15))	('TCC', 'cellular_component', 'GO:0005579', ('0', '3'))	('taxane', 'Chemical', 'MESH:C080625', (114, 120))	('larotaxel', 'Chemical', 'MESH:C531079', (95, 104))	('T24rGEMCI20', 'Var', (20, 31))	('cross-resistance', 'MPA', (48, 64))
138876	26055179	In contrast, RT112rGEMCI20 and RT112rCDDP1000 cells showed cross-resistance to cabazitaxel.	('cabazitaxel', 'Chemical', 'MESH:C552428', (79, 90))	('cross-resistance', 'MPA', (59, 75))	('RT112rGEMCI20', 'Var', (13, 26))	('RT112rCDDP1000', 'Var', (31, 45))
138882	26055179	Interestingly, also three of six gemcitabine-resistant sublines displayed decreased sensitivity to cisplatin (RT112rGEMCI20, TCC-SUPrGEMCI20, and T24rGEMCI20), and additionally, three of six gemcitabine-resistant sublines showed reduced sensitivity to carboplatin (RT112rGEMCI20, TCC-SUPrGEMCI20, and RT4rGEMCI10).	('RT112rGEMCI20', 'Var', (110, 123))	('sensitivity to carboplatin', 'MPA', (237, 263))	('TCC', 'cellular_component', 'GO:0005579', ('280', '283'))	('RT4rGEMCI10', 'Var', (301, 312))	('SUPrGEMCI20', 'Gene', '9709', (284, 295))	('reduced', 'NegReg', (229, 236))	('SUPrGEMCI20', 'Gene', '9709', (129, 140))	('gemcitabine', 'Chemical', 'MESH:C056507', (191, 202))	('SUPrGEMCI20', 'Gene', (284, 295))	('TCC', 'cellular_component', 'GO:0005579', ('125', '128'))	('SUPrGEMCI20', 'Gene', (129, 140))	('RT112rGEMCI20', 'Var', (265, 278))	('decreased', 'NegReg', (74, 83))	('gemcitabine', 'Chemical', 'MESH:C056507', (33, 44))	('sensitivity', 'MPA', (84, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))	('carboplatin', 'Chemical', 'MESH:D016190', (252, 263))	('T24rGEMCI20', 'Var', (146, 157))
138897	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))
138900	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))
138909	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))
138910	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))	('inactivation', 'Var', (20, 32))	('sarcomas', 'Disease', (161, 169))	('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))
138915	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))
138917	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))
138918	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))
138921	32359397	Of the 1165 genes mutated in untreated primary RMC tumors from a total of 31 patients, only 22 were known tumor suppressors or oncogenes listed in the Catalogue of Somatic Mutations in Cancer (COSMIC) database (Figure S1B and Supplementary Table 1).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutated', 'Var', (18, 25))	('tumor', 'Disease', (51, 56))	('men', 'Species', '9606', (232, 235))	('RMC tumors', 'Disease', 'MESH:D009369', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('patients', 'Species', '9606', (77, 85))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('Cancer', 'Disease', (185, 191))	('Cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('Cancer', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', (106, 111))	('RMC tumors', 'Disease', (47, 57))
138925	32359397	SETD2 was mutated in 2/31 (6.5%) of RMC tumors and was the only established gene driver of other renal cell carcinomas to be altered in RMC (Figure 1 and Supplementary Table 1).	('mutated', 'Var', (10, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('RMC', 'Chemical', '-', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('renal cell carcinomas', 'Disease', (97, 118))	('SETD2', 'Gene', '29072', (0, 5))	('RMC tumors', 'Disease', 'MESH:D009369', (36, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('SETD2', 'Gene', (0, 5))	('men', 'Species', '9606', (160, 163))	('RMC', 'Chemical', '-', (36, 39))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (97, 118))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (97, 118))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('RMC tumors', 'Disease', (36, 46))
138927	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))
138935	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))
138938	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))
138940	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))	('downregulated', 'NegReg', (196, 209))	('upregulated', 'PosReg', (181, 192))	('men', 'Species', '9606', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('RMC tumors', 'Disease', (228, 238))	('loss', 'NegReg', (140, 144))
138941	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))
138944	32359397	Less frequent were deletion of both SMARCB1 alleles (6/38 patients; 15.8%), deletion of one SMARCB1 allele and inDel of the second SMARCB1 allele (5/38 patients; 13.2%), and deletion of one SMARCB1 allele and truncating nonsense mutation of the second SMARCB1 allele (1/38 patients; 2.6%).	('deletion', 'Var', (76, 84))	('patients', 'Species', '9606', (273, 281))	('SMARCB1', 'Gene', (190, 197))	('deletion', 'Var', (19, 27))	('SMARCB1', 'Gene', (252, 259))	('truncating nonsense mutation', 'Var', (209, 237))	('SMARCB1', 'Gene', (36, 43))	('deletion', 'Var', (174, 182))	('SMARCB1', 'Gene', (92, 99))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (152, 160))
138946	32359397	In addition, we determined that this pattern for SMARCB1 inactivation (inactivating translocation combined with hemizygous deletion) occurred not only in primary tumors but also in lymph node and liver mestastases of patients RMC38 and RMC32, respectively.	('inactivation', 'NegReg', (57, 69))	('liver mestastases', 'Disease', (196, 213))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('RMC', 'Chemical', '-', (226, 229))	('patients', 'Species', '9606', (217, 225))	('RMC', 'Chemical', '-', (236, 239))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('RMC38', 'Var', (226, 231))	('liver mestastases', 'Disease', 'MESH:D017093', (196, 213))	('SMARCB1', 'Gene', (49, 56))
138947	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))
138950	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))	('MED5T', 'CellLine', 'CVCL:M137', (65, 70))	('RMC', 'Chemical', '-', (166, 169))	('MED1', 'Gene', (51, 55))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('inactivating translocations', 'Var', (86, 113))
138954	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'))
138957	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))
138991	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))
138992	32359397	However, patient age did not strongly correlate with the number of C > T mutations (Spearman rank correlation = 0.395, p = 0.145), suggesting that they are instead caused by replication stress in the setting of high cell turnover.	('patient', 'Species', '9606', (9, 16))	('caused by', 'Reg', (164, 173))	('C > T mutations', 'Var', (67, 82))
138993	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))
139000	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))
139004	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))
139005	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))
139014	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))
139020	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))
139023	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))
139033	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))
139084	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))
139091	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))
139106	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))
139132	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))
139133	32359397	Partial SMARCB1 deletion was defined as loss of either green or orange probes in >= 15% of tumor nuclei.	('SMARCB1', 'Gene', (8, 15))	('orange probes', 'MPA', (64, 77))	('deletion', 'Var', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('loss', 'NegReg', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('green', 'MPA', (55, 60))	('Partial', 'Var', (0, 7))
139233	32117435	Up to 30% of urothelial cancer (UC) specimens have demonstrated differential expression in PD-L1, which is associated with increased all-cause mortality.	('differential', 'Var', (64, 76))	('expression', 'MPA', (77, 87))	('increased', 'PosReg', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('PD-L1', 'Gene', (91, 96))	('UC', 'Disease', 'MESH:D014523', (32, 34))	('urothelial cancer', 'Disease', (13, 30))	('PD-L1', 'Gene', '29126', (91, 96))	('urothelial cancer', 'Disease', 'MESH:D014523', (13, 30))	('associated with', 'Reg', (107, 122))
139288	32117435	High expression of EDNRA was found to be associated with poor outcome in patients with advanced BLCA in a bioinformatics report.	('EDNRA', 'Gene', (19, 24))	('High', 'Var', (0, 4))	('BLCA', 'Disease', 'MESH:D001749', (96, 100))	('EDNRA', 'Gene', '1909', (19, 24))	('BLCA', 'Phenotype', 'HP:0009725', (96, 100))	('BLCA', 'Disease', (96, 100))	('patients', 'Species', '9606', (73, 81))
139312	31038863	The patients were stratified into three groups with Glasgow Prognostic Score: The Group-1, albumin >=3.5g/dL and C-reactive protein < 1.0mg/dL; Group-2, albumin < 3.5g/dL or C-reactive protein >=1.0mg/dL; Group-3, albumin < 3.5g/dL and C-reactive protein >=1.0mg/dL.	('albumin', 'Gene', (214, 221))	('C-reactive protein', 'Gene', '1401', (236, 254))	('albumin', 'Gene', (91, 98))	('C-reactive protein', 'Gene', (113, 131))	('albumin', 'Gene', (153, 160))	('patients', 'Species', '9606', (4, 12))	('albumin', 'Gene', '213', (214, 221))	('>=1.0mg/dL', 'Var', (193, 203))	('< 3.5g/dL', 'Var', (161, 170))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('protein', 'cellular_component', 'GO:0003675', ('247', '254'))	('C-reactive protein', 'Gene', '1401', (113, 131))	('>=3.5g/dL', 'Var', (99, 108))	('C-reactive protein', 'Gene', (174, 192))	('>=1.0mg/dL', 'Var', (255, 265))	('albumin', 'Gene', '213', (91, 98))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('C-reactive protein', 'Gene', (236, 254))	('albumin', 'Gene', '213', (153, 160))	('C-reactive protein', 'Gene', '1401', (174, 192))
139334	31038863	The patients were stratified into three groups with Glasgow prognostic score (GPS): The Group-1, albumin >= 3.5g/dL and CRP < 1.0mg/dL; Group-2, albumin < 3.5g/dL or CRP >= 1.0mg/dL; Group-3, albumin < 3.5g/dL and CRP >= 1.0mg/dL.	('>= 3.5g/dL', 'Var', (105, 115))	('CRP', 'Gene', (166, 169))	('albumin', 'Gene', (192, 199))	('albumin', 'Gene', '213', (192, 199))	('CRP', 'Gene', '1401', (166, 169))	('CRP < 1', 'Gene', (120, 127))	('CRP', 'Gene', (214, 217))	('albumin', 'Gene', (145, 152))	('CRP', 'Gene', (120, 123))	('albumin', 'Gene', '213', (145, 152))	('CRP', 'Gene', '1401', (214, 217))	('albumin', 'Gene', (97, 104))	('albumin', 'Gene', '213', (97, 104))	('patients', 'Species', '9606', (4, 12))	('CRP', 'Gene', '1401', (120, 123))	('CRP < 1', 'Gene', '1396', (120, 127))
139424	28753857	In a large cohort of patients treated with RC, we found that the presence of PCV was associated with adverse pathologic features but was not associated with worse overall mortality compared with pure UC on multivariable analysis.	('pure UC', 'Disease', (195, 202))	('pure', 'molecular_function', 'GO:0034023', ('195', '199'))	('patients', 'Species', '9606', (21, 29))	('PCV', 'Gene', (77, 80))	('PCV', 'Species', '28355', (77, 80))	('pure UC', 'Disease', 'MESH:C536289', (195, 202))	('associated', 'Reg', (85, 95))	('presence', 'Var', (65, 73))
139436	28753857	Similarly, we found that the presence of PCV was associated with locally advanced stage disease (54% vs 37%), a higher rate of positive surgical margins (21% vs 4%), and more positive lymph node involvement (30% vs 20%) compared with pure UC.	('positive lymph node involvement', 'CPA', (175, 206))	('PCV', 'Species', '28355', (41, 44))	('pure UC', 'Disease', (234, 241))	('presence', 'Var', (29, 37))	('stage disease', 'Disease', (82, 95))	('stage disease', 'Disease', 'MESH:D007676', (82, 95))	('pure', 'molecular_function', 'GO:0034023', ('234', '238'))	('pure UC', 'Disease', 'MESH:C536289', (234, 241))	('PCV', 'Gene', (41, 44))
139446	28753857	Earlier studies suggest that variant histology, for example, micropapillary, nested, or nonsquamous, are associated with cancer-specific mortality in univariable analysis, but they are not independent predictors of outcomes.	('nested', 'CPA', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('nonsquamous', 'Disease', (88, 99))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('associated', 'Reg', (105, 115))	('cancer', 'Disease', (121, 127))	('micropapillary', 'Var', (61, 75))
139510	27836245	Increasing evidence suggests that the mechanism for the clinical responses to immune checkpoint inhibitors in malignancies with high mutational burden is through the production of a variety of tumor-specific neoantigens capable of eliciting a T-cell response.	('malignancies', 'Disease', 'MESH:D009369', (110, 122))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('malignancies', 'Disease', (110, 122))	('mutational', 'Var', (133, 143))	('tumor', 'Disease', (193, 198))
139519	27836245	In the KEYNOTE-012 study, patients with >= 1% PD-L1 staining on tumor cells, had a 33% ORR in contrast to only 9% in < 1% PD-L1 staining patients treated with pembrolizumab using the 22C3 antibody on IHC.	('PD-L1', 'Gene', (46, 51))	('tumor', 'Disease', (64, 69))	('antibody', 'cellular_component', 'GO:0042571', ('188', '196'))	('pembrolizumab', 'Chemical', 'MESH:C582435', (159, 172))	('antibody', 'cellular_component', 'GO:0019815', ('188', '196'))	('staining', 'Var', (52, 60))	('PD-L1', 'Gene', '29126', (46, 51))	('patients', 'Species', '9606', (137, 145))	('PD-L1', 'Gene', (122, 127))	('patients', 'Species', '9606', (26, 34))	('antibody', 'cellular_component', 'GO:0019814', ('188', '196'))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('antibody', 'molecular_function', 'GO:0003823', ('188', '196'))	('PD-L1', 'Gene', '29126', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
139543	27836245	Accordingly, patients with a luminal I subtype should be considered for clinical trials utilizing FGFR inhibitors.	('FGFR', 'molecular_function', 'GO:0005007', ('98', '102'))	('patients', 'Species', '9606', (13, 21))	('FGFR', 'Gene', (98, 102))	('inhibitors', 'Var', (103, 113))
139547	27836245	Monoclonal antibodies against TIM-3 and LAG3 are in early clinical development as monotherapy or in combination with PD-1 inhibitors (NCT03608268, NCT01968109, and NCT02460224).	('LAG3', 'Gene', '3902', (40, 44))	('NCT02460224', 'Var', (164, 175))	('LAG3', 'Gene', (40, 44))	('NCT03608268', 'Var', (134, 145))	('PD-1', 'Gene', (117, 121))	('PD-1', 'Gene', '5133', (117, 121))	('NCT01968109', 'Var', (147, 158))	('TIM-3', 'Gene', '84868', (30, 35))	('TIM-3', 'Gene', (30, 35))
139569	21860767	In the multivariate analysis, strong phosS6 expression predicted shorter progression (p<0.01; hazard ratio [HR], 2.516) and disease-specific survival (p<0.01; HR, 2.396) but not overall survival (p=0.112), whereas strong phos4E-BP1 expression was a predictor of disease-specific survival (p<0.05; HR, 2.105).	('phosS6 expression', 'Var', (37, 54))	('shorter', 'NegReg', (65, 72))	('4E-BP1', 'Gene', (225, 231))	('disease-specific survival', 'CPA', (124, 149))	('progression', 'CPA', (73, 84))	('4E-BP1', 'Gene', '1978', (225, 231))
139570	21860767	Moreover, strong phosS6 expression predicted shorter recurrence-free (p<0.05) and progression-free (p<0.05) survival in the superficial bladder cancer cohort.	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('progression-free', 'CPA', (82, 98))	('shorter', 'NegReg', (45, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (136, 150))	('bladder cancer', 'Disease', (136, 150))	('recurrence-free', 'CPA', (53, 68))	('phosS6 expression', 'Var', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
139595	21860767	In univariate and multivariate analyses, a cutoff value of expression of each marker was used according to the mean tumor H-score (H-score>=141, 125, and 44, for mTOR, phos4E-BP1, and phosS6, respectively).	('mTOR', 'Gene', (162, 166))	('mTOR', 'Gene', '2475', (162, 166))	('4E-BP1', 'Gene', '1978', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('phosS6', 'Var', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('4E-BP1', 'Gene', (172, 178))	('tumor', 'Disease', (116, 121))
139601	21860767	1A, mTOR, phos4E-BP1, and phosS6 were expressed in the cytoplasm of bladder cancer cells and in benign urothelium.	('bladder cancer', 'Phenotype', 'HP:0009725', (68, 82))	('4E-BP1', 'Gene', (14, 20))	('cytoplasm', 'cellular_component', 'GO:0005737', ('55', '64'))	('mTOR', 'Gene', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('4E-BP1', 'Gene', '1978', (14, 20))	('bladder cancer', 'Disease', 'MESH:D001749', (68, 82))	('bladder cancer', 'Disease', (68, 82))	('phosS6', 'Var', (26, 32))	('mTOR', 'Gene', '2475', (4, 8))
139603	21860767	Phos4E-BP1 and phosS6 were expressed in 96.2% and 72.6% of bladder cancer cohort samples, respectively, and in 71.4% and 94.3% of benign cohort samples, respectively.	('4E-BP1', 'Gene', '1978', (4, 10))	('bladder cancer', 'Phenotype', 'HP:0009725', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (59, 73))	('phosS6', 'Var', (15, 21))	('4E-BP1', 'Gene', (4, 10))	('bladder cancer', 'Disease', (59, 73))
139609	21860767	1C shows the mean H-scores of phosS6 and phos4EBP1 in relation to mTOR H-scores in bladder cancer.	('mTOR', 'Gene', (66, 70))	('phosS6', 'Var', (30, 36))	('mTOR', 'Gene', '2475', (66, 70))	('BP1', 'Gene', '474256', (47, 50))	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('BP1', 'Gene', (47, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('bladder cancer', 'Disease', (83, 97))
139613	21860767	Among mTOR pathway-related markers, only phosS6 was a significant predictor of progression, DSS, and OS, although mTOR was a predictor of OS, and phos4E-BP1 was a predictor of DSS.	('DSS', 'Disease', (92, 95))	('4E-BP1', 'Gene', '1978', (150, 156))	('phosS6', 'Var', (41, 47))	('progression', 'Disease', (79, 90))	('OS', 'Chemical', '-', (138, 140))	('mTOR', 'Gene', '2475', (114, 118))	('mTOR', 'Gene', (114, 118))	('4E-BP1', 'Gene', (150, 156))	('DSS', 'Chemical', '-', (176, 179))	('OS', 'Chemical', '-', (101, 103))	('mTOR', 'Gene', '2475', (6, 10))	('DSS', 'Chemical', '-', (92, 95))	('mTOR', 'Gene', (6, 10))
139615	21860767	Among the markers, strong phosS6 expression predicted shorter progression (p<0.01; hazard ratio [HR], 2.516) and DSS (p<0.01; HR, 2.396), but not OS (p=0.112), whereas strong phos4E-BP1 expression was a predictor of DSS (p<0.05; HR, 2.105).	('4E-BP1', 'Gene', (179, 185))	('DSS', 'Chemical', '-', (216, 219))	('OS', 'Chemical', '-', (146, 148))	('progression', 'CPA', (62, 73))	('phosS6 expression', 'Var', (26, 43))	('DSS', 'CPA', (113, 116))	('4E-BP1', 'Gene', '1978', (179, 185))	('shorter', 'NegReg', (54, 61))	('DSS', 'Chemical', '-', (113, 116))
139622	21860767	Superficial tumors are thought to be driven by Ras pathway activation, most often (in up to 65% of cases) via the accumulation of activating mutations in the type 3 fibroblast growth factor receptor and less often via mutations in PI3K or Ras.	('activating', 'PosReg', (130, 140))	('mutations', 'Var', (141, 150))	('Ras pathway', 'Pathway', (47, 58))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('165', '189'))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('activation', 'PosReg', (59, 69))	('PI3K', 'molecular_function', 'GO:0016303', ('231', '235'))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
139623	21860767	The second progression track involves the inactivation of major tumor suppressors [p53, Rb, and PTEN], which produces tumors that are highly invasive and metastatic.	('PTEN', 'Gene', '5728', (96, 100))	('invasive', 'CPA', (141, 149))	('tumor', 'Disease', (64, 69))	('p53', 'Gene', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('p53', 'Gene', '7157', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('inactivation', 'Var', (42, 54))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumors', 'Disease', (118, 124))	('produces', 'Reg', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('PTEN', 'Gene', (96, 100))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
139639	21860767	PhosS6 expression was also significantly higher in high-grade bladder cancer cells.	('PhosS6', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('bladder cancer', 'Phenotype', 'HP:0009725', (62, 76))	('higher', 'PosReg', (41, 47))	('bladder cancer', 'Disease', 'MESH:D001749', (62, 76))	('bladder cancer', 'Disease', (62, 76))
139641	21860767	Among the mTOR pathway-related markers that we evaluated, phosS6 was a significant predictor of progression and DSS in the multivariate survival analysis, and phos4E-BP1 was a significant predictor of DSS.	('DSS', 'Chemical', '-', (112, 115))	('mTOR', 'Gene', (10, 14))	('4E-BP1', 'Gene', (163, 169))	('DSS', 'Disease', (112, 115))	('progression', 'Disease', (96, 107))	('phosS6', 'Var', (58, 64))	('4E-BP1', 'Gene', '1978', (163, 169))	('DSS', 'Chemical', '-', (201, 204))	('mTOR', 'Gene', '2475', (10, 14))
139649	21860767	In our study, strong phosS6 expression predicted shorter recurrence-free and progression-free survival in 145 patients with superficial bladder cancer who had undergone TURB, demonstrating that the mTOR pathway is involved in bladder cancer recurrence and progression.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('patients', 'Species', '9606', (110, 118))	('shorter', 'NegReg', (49, 56))	('mTOR', 'Gene', '2475', (198, 202))	('bladder cancer', 'Disease', 'MESH:D001749', (136, 150))	('bladder cancer', 'Disease', (136, 150))	('bladder cancer', 'Disease', 'MESH:D001749', (226, 240))	('bladder cancer', 'Disease', (226, 240))	('mTOR', 'Gene', (198, 202))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (226, 251))	('phosS6 expression', 'Var', (21, 38))	('progression-free survival', 'CPA', (77, 102))	('bladder cancer', 'Phenotype', 'HP:0009725', (226, 240))
139651	21860767	Seager et al reported that rapamycin, an mTOR inhibitor, prevented progression of carcinoma in situ to invasive bladder cancer in an animal model; furthermore, intravesical delivery of rapamycin into the bladder lumen was highly effective at suppressing bladder cancer recurrence.	('rapamycin', 'Var', (185, 194))	('bladder cancer', 'Disease', 'MESH:D001749', (112, 126))	('carcinoma in situ', 'Disease', (82, 99))	('bladder cancer', 'Disease', 'MESH:D001749', (254, 268))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (254, 279))	('rapamycin', 'Chemical', 'MESH:D020123', (185, 194))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))	('bladder cancer', 'Disease', (254, 268))	('suppressing', 'NegReg', (242, 253))	('mTOR', 'Gene', (41, 45))	('invasive bladder cancer', 'Disease', (103, 126))	('rapamycin', 'Chemical', 'MESH:D020123', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('bladder cancer', 'Phenotype', 'HP:0009725', (254, 268))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (82, 99))	('mTOR', 'Gene', '2475', (41, 45))	('carcinoma in situ', 'Disease', 'MESH:D002278', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('invasive bladder', 'Phenotype', 'HP:0100645', (103, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (103, 126))
139675	33665361	From the molecular side, bladder cancer is composed of a multitude of heterogenetic characteristics, including gene mutations, gene copy number alterations, and neoantigens, as well as the infiltration of immunocytes.	('gene copy number alterations', 'Var', (127, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('bladder cancer', 'Disease', 'MESH:D001749', (25, 39))	('bladder cancer', 'Disease', (25, 39))
139696	33665361	Especially during the late stages of tumors, genetic and epigenetic alterations of tumor cells are driven by activated stromal components.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (83, 88))	('epigenetic alterations', 'Var', (57, 79))	('genetic', 'Var', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumors', 'Disease', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
139708	33665361	Gene copy number alteration (CNA), tumor mutant burden (TMB), and neoantigens were reported to exhibit crosstalk with tumor immune activation.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('Gene copy number alteration', 'Var', (0, 27))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (35, 40))	('TMB', 'Chemical', '-', (56, 59))	('tumor', 'Disease', (118, 123))
139710	33665361	With the online tool TIMER, we twice confirmed that the association between immune infiltration and gene CNA deletion; deep deletion and arm-level deletion of PD-1, PD-L1 and CTLA-4; and the three major immune checkpoints were linked with decreased immunocyte infiltration, especially for CD4+ T cells, neutrophils, and dendritic cells (Figure S3).	('immune infiltration', 'CPA', (76, 95))	('deletion', 'Var', (109, 117))	('CD4', 'Gene', (289, 292))	('CTLA-4', 'Gene', '1493', (175, 181))	('PD-L1', 'Gene', (165, 170))	('PD-1', 'Gene', (159, 163))	('gene CNA', 'Gene', (100, 108))	('immunocyte infiltration', 'CPA', (249, 272))	('CTLA-4', 'Gene', (175, 181))	('decreased', 'NegReg', (239, 248))	('deep deletion', 'Var', (119, 132))	('CD4', 'Gene', '920', (289, 292))	('PD-L1', 'Gene', '29126', (165, 170))
139712	33665361	Mutations of TP53 (53.5% versus 43.1%, p = 0.051), TTN (52.9% versus 39.5%, p = 0.011), PIK3CA (28.0% versus 17.0%, p = 0.007), and RB1 (26.0% versus 13.0%, p < 0.001) appeared more frequently in the immune class than in the non-immune class (Figure S4B).	('TP53', 'Gene', (13, 17))	('PIK3CA', 'Gene', '5290', (88, 94))	('RB1', 'Gene', (132, 135))	('TP53', 'Gene', '7157', (13, 17))	('TTN', 'Gene', (51, 54))	('Mutations', 'Var', (0, 9))	('RB1', 'Gene', '5925', (132, 135))	('TTN', 'Gene', '7273', (51, 54))	('PIK3CA', 'Gene', (88, 94))	('immune class', 'Disease', (200, 212))
139713	33665361	ERBB2 (p = 0.035), KMT2A (p = 0.013), PKHD1 (p = 0.007), and MDN1 (p = 0.015) were the specific mutations noted in the immune-activated subgroup (Figure 3G), and patients with EP300 (p = 0.020), HMCN1 (p = 0.014), AKAP9 (p = 0.003), and MACF1 (p = 0.016) mutations were more highly enriched in the immune-exhausted subgroups (Figure 3H).	('KMT2A', 'Gene', (19, 24))	('HMCN1', 'Gene', (195, 200))	('MDN1', 'Gene', '23195', (61, 65))	('ERBB2', 'Gene', (0, 5))	('MACF1', 'Gene', '23499', (237, 242))	('mutations', 'Var', (255, 264))	('ERBB2', 'Gene', '2064', (0, 5))	('EP300', 'Gene', '2033', (176, 181))	('MACF1', 'Gene', (237, 242))	('patients', 'Species', '9606', (162, 170))	('immune-exhausted', 'Disease', (298, 314))	('HMCN1', 'Gene', '83872', (195, 200))	('KMT2A', 'Gene', '4297', (19, 24))	('AKAP9', 'Gene', '10142', (214, 219))	('EP300', 'Gene', (176, 181))	('AKAP9', 'Gene', (214, 219))	('MDN1', 'Gene', (61, 65))	('3H', 'Chemical', 'MESH:D014316', (333, 335))	('PKHD1', 'Gene', (38, 43))	('PKHD1', 'Gene', '5314', (38, 43))
139714	33665361	The mutation of EP300 lead to the increased expression of EP300 (Figure S4C).	('expression', 'MPA', (44, 54))	('EP300', 'Gene', (58, 63))	('EP300', 'Gene', '2033', (58, 63))	('mutation', 'Var', (4, 12))	('EP300', 'Gene', '2033', (16, 21))	('increased', 'PosReg', (34, 43))	('EP300', 'Gene', (16, 21))
139777	33665361	These alterations in the TME could lead to the escape from immune recognition by blocking immune checkpoints, which is related to unfavorable overall survival for patients.	('alterations', 'Var', (6, 17))	('patients', 'Species', '9606', (163, 171))	('escape', 'MPA', (47, 53))	('immune checkpoints', 'MPA', (90, 108))	('lead to', 'Reg', (35, 42))	('blocking', 'NegReg', (81, 89))
139779	33665361	As expected, patients in the immune-activated subgroup could benefit from anti-PD-1 therapy, but this was not the case for patients in the non-immune-activated subgroup, which included the combined immune-exhausted and non-immune classes.	('benefit', 'PosReg', (61, 68))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (123, 131))	('anti-PD-1', 'Var', (74, 83))
139781	33665361	Patients in the immune class showed a lower CNA burden with gene deletion at the arm and focal levels.	('CNA burden', 'MPA', (44, 54))	('gene deletion', 'Var', (60, 73))	('lower', 'NegReg', (38, 43))	('Patients', 'Species', '9606', (0, 8))
139782	33665361	The association was verified twice by the deletion copy numbers of PD-1 and PD-L1, and CTLA-4 was positively associated with the decreased infiltration level of immunocytes.	('PD-1', 'Gene', (67, 71))	('infiltration level of immunocytes', 'MPA', (139, 172))	('PD-L1', 'Gene', '29126', (76, 81))	('CTLA-4', 'Gene', (87, 93))	('deletion copy numbers', 'Var', (42, 63))	('CTLA-4', 'Gene', '1493', (87, 93))	('decreased', 'NegReg', (129, 138))	('PD-L1', 'Gene', (76, 81))
139783	33665361	found that antigen presentation through the major histocompatibility complex (MHC) class I pathway was suppressed in tumors with high chromosomal instability, also known as high CNA, which plays a pivotal role in immune evasion.	('immune evasion', 'biological_process', 'GO:0051842', ('213', '227'))	('chromosomal instability', 'Phenotype', 'HP:0040012', (134, 157))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('high chromosomal instability', 'Var', (129, 157))	('antigen presentation', 'biological_process', 'GO:0019882', ('11', '31'))	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('44', '76'))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('antigen presentation', 'MPA', (11, 31))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('suppressed', 'NegReg', (103, 113))	('immune evasion', 'biological_process', 'GO:0042783', ('213', '227'))
139785	33665361	The proportions of mutant TP53, TTN, PIC3CA, and RB1 were higher in the immune class than that in the non-immune class.	('TP53', 'Gene', (26, 30))	('PIC3CA', 'Var', (37, 43))	('RB1', 'Gene', (49, 52))	('RB1', 'Gene', '5925', (49, 52))	('mutant', 'Var', (19, 25))	('PIC', 'cellular_component', 'GO:0019035', ('37', '40'))	('higher', 'PosReg', (58, 64))	('TP53', 'Gene', '7157', (26, 30))	('TTN', 'Gene', (32, 35))	('PIC', 'cellular_component', 'GO:0097550', ('37', '40'))	('TTN', 'Gene', '7273', (32, 35))
139786	33665361	Oncol., abstract) reported that colorectal cancer patients with mutant PIK3CA had higher median densities of CD3+ and CD8+ cells, as well as a high rate of clinical benefit from immunotherapy (50% versus 8.6%).	('benefit', 'PosReg', (165, 172))	('colorectal cancer', 'Disease', (32, 49))	('PIK3CA', 'Gene', '5290', (71, 77))	('patients', 'Species', '9606', (50, 58))	('colorectal cancer', 'Phenotype', 'HP:0003003', (32, 49))	('colorectal cancer', 'Disease', 'MESH:D015179', (32, 49))	('higher', 'PosReg', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('CD8', 'Gene', (118, 121))	('CD8', 'Gene', '925', (118, 121))	('mutant', 'Var', (64, 70))	('PIK3CA', 'Gene', (71, 77))
139787	33665361	Furthermore, we observed a high rate of ERBB2 mutations in the immune-activated subgroup.	('ERBB2', 'Gene', (40, 45))	('immune-activated', 'Disease', (63, 79))	('ERBB2', 'Gene', '2064', (40, 45))	('mutations', 'Var', (46, 55))
139789	33665361	The V659E mutation of the ERBB2 gene has also been reported to be associated with altered sensitivity to afatinib and lapatinib treatment in vitro.	('V659E', 'Var', (4, 9))	('ERBB2', 'Gene', (26, 31))	('ERBB2', 'Gene', '2064', (26, 31))	('associated', 'Reg', (66, 76))	('lapatinib', 'Chemical', 'MESH:D000077341', (118, 127))	('afatinib', 'Chemical', 'MESH:D000077716', (105, 113))	('V659E', 'Mutation', 'p.V659E', (4, 9))	('altered', 'Reg', (82, 89))
139802	33665361	The different genetic types among the immune and non-immune classes were evaluated, including TIL abundance, PD-L1 expression, CNAs, TMB, neoantigens, and mutant genes.	('TMB', 'Chemical', '-', (133, 136))	('PD-L1', 'Gene', (109, 114))	('mutant genes', 'Var', (155, 167))	('PD-L1', 'Gene', '29126', (109, 114))
139829	32793789	Investigators found that the median overall survival was approximately 3 months longer in patients treated with pembrolizumab (10.3 months [95% confidence interval, 8.0 to 11.8]) than those treated with chemotherapy (7.4 months [95% CI, 6.1 to 8.3]).	('overall survival', 'MPA', (36, 52))	('pembrolizumab', 'Var', (112, 125))	('pembrolizumab', 'Chemical', 'MESH:C582435', (112, 125))	('longer', 'PosReg', (80, 86))	('patients', 'Species', '9606', (90, 98))
139834	32793789	To date, a number of clinical trials are underway in this vein (NCT02812420, NCT02845323, NCT02365766, NCT02690558), although dose-dense MVAC (ddMVAC) and GC remain the standard of care treatments in this setting.	('GC', 'Chemical', '-', (155, 157))	('MVAC', 'Chemical', '-', (145, 149))	('NCT02690558', 'Var', (103, 114))	('NCT02365766', 'Var', (90, 101))	('men', 'Species', '9606', (191, 194))	('ddMVAC', 'Chemical', '-', (143, 149))	('MVAC', 'Chemical', '-', (137, 141))	('NCT02812420', 'Var', (64, 75))
139862	32793789	The phase II study included 227 eligible patients diagnosed with T2-T4aN0M0 urothelial carcinoma who were planning to undergo cystectomy (Fig.	('T2-T4aN0M0', 'Var', (65, 75))	('urothelial carcinoma', 'Disease', (76, 96))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (76, 96))	('patients', 'Species', '9606', (41, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
139904	32793789	These assessments included genetic, single nucleotide polymorphism (SNP) and circulating tumor cell (CTC) analyses.	('single nucleotide polymorphism', 'Var', (36, 66))	('men', 'Species', '9606', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
139906	32793789	In evaluating the prognostic and predictive capabilities of the MVAC and GC COXEN biomarkers in the neoadjuvant setting of bladder cancer, SWOG 1314 represents a novel example of translating an in vitro biomarker directly into clinical application.	('SWOG', 'Var', (139, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('GC', 'Chemical', '-', (73, 75))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('bladder cancer', 'Disease', 'MESH:D001749', (123, 137))	('MVAC', 'Chemical', '-', (64, 68))	('bladder cancer', 'Disease', (123, 137))
139911	32793789	Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180888 and U10CA180819.	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('U10CA180819', 'Var', (166, 177))	('Cancer', 'Disease', (76, 82))	('U10CA180888', 'Var', (150, 161))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))
139917	32580338	ICIs increased antitumor T cells' responses and showed a key role in reducing the acquired immune system tolerance which is overexpressed by cancer and tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('acquired immune system tolerance', 'CPA', (82, 114))	('reducing', 'NegReg', (69, 77))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('ICIs', 'Var', (0, 4))	('increased', 'PosReg', (5, 14))	('tumor', 'Disease', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
139924	32580338	Chemotherapy was the first identified therapeutic approach that systemically delivered chemical agents into tumor tissue and destroyed the large mass, but did not eliminate the disease.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('large mass', 'MPA', (139, 149))	('destroyed', 'NegReg', (125, 134))	('chemical agents', 'Var', (87, 102))
139944	32580338	CTLA-4 is the earliest known immune checkpoint and in vivo experiments showed that mice died after 3-4 weeks CTLA-4 deletion for immunosuppression, showing its important roles in immune responses and T cell activation.	('T cell activation', 'biological_process', 'GO:0042110', ('200', '217'))	('mice', 'Species', '10090', (83, 87))	('died', 'Disease', (88, 92))	('deletion', 'Var', (116, 124))	('CTLA-4', 'Gene', (109, 115))	('died', 'Disease', 'MESH:D003643', (88, 92))
139951	32580338	Recently, monoclonal antibodies against CTLA-4, ipilimumab, and tremelimumab, alone or in combination with PD-1/L-1 inhibitors, significantly increased antitumor effects and improved the survival of several malignancies (Figure 1).	('L-1', 'Gene', (112, 115))	('malignancies', 'Disease', (207, 219))	('ipilimumab', 'Chemical', 'MESH:D000074324', (48, 58))	('L-1', 'Gene', '28938', (112, 115))	('increased', 'PosReg', (142, 151))	('tremelimumab', 'Chemical', 'MESH:C520704', (64, 76))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('monoclonal antibodies', 'Var', (10, 31))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('CTLA-4', 'Gene', (40, 46))	('malignancies', 'Disease', 'MESH:D009369', (207, 219))	('tumor', 'Disease', (156, 161))	('improved', 'PosReg', (174, 182))
139977	32580338	Hepatic side effects (elevated AST (28%), elevated alkaline phosphatase (22%), elevated ALT (16%)) appear along with gastrointestinal side effects (diarrhea or colitis (21%)), respiratory side effects (cough (17%), upper respiratory tract infection (17%)), cardiovascular side effects (peripheral edema (10%)), and endocrine side effects (hypothyroidism and hyperthyroidism) (Figure 2).	('Hepatic side effects', 'MPA', (0, 20))	('AST', 'Gene', '26503', (31, 34))	('colitis', 'Disease', (160, 167))	('diarrhea', 'Disease', (148, 156))	('hypothyroidism', 'Phenotype', 'HP:0000821', (339, 353))	('ALT', 'MPA', (88, 91))	('elevated', 'Var', (79, 87))	('ALT', 'molecular_function', 'GO:0004021', ('88', '91'))	('upper respiratory tract infection', 'Disease', (215, 248))	('upper respiratory tract infection', 'Disease', 'MESH:D012141', (215, 248))	('colitis', 'Disease', 'MESH:D003092', (160, 167))	('edema', 'Phenotype', 'HP:0000969', (297, 302))	('cough', 'Disease', 'MESH:D003371', (202, 207))	('diarrhea', 'Disease', 'MESH:D003967', (148, 156))	('elevated', 'PosReg', (42, 50))	('cough', 'Disease', (202, 207))	('hyperthyroidism', 'Phenotype', 'HP:0000836', (358, 373))	('upper respiratory tract infection', 'Phenotype', 'HP:0002788', (215, 248))	('AST', 'Gene', (31, 34))	('elevated ALT', 'Phenotype', 'HP:0031964', (79, 91))	('edema', 'Disease', 'MESH:D004487', (297, 302))	('peripheral edema', 'Phenotype', 'HP:0012398', (286, 302))	('respiratory tract infection', 'Phenotype', 'HP:0011947', (221, 248))	('edema', 'Disease', (297, 302))	('colitis', 'Phenotype', 'HP:0002583', (160, 167))	('phosphatase', 'molecular_function', 'GO:0016791', ('60', '71'))	('elevated alkaline phosphatase', 'Phenotype', 'HP:0003155', (42, 71))	('diarrhea', 'Phenotype', 'HP:0002014', (148, 156))	('cough', 'Phenotype', 'HP:0012735', (202, 207))	('hypothyroidism and hyperthyroidism', 'Disease', 'MESH:D006980', (339, 373))	('gastrointestinal', 'MPA', (117, 133))
139993	32580338	Their results showed that OS was increased by 15.1 months in patients who received ipilimumab as compared to 7.8 months in other patients.	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (61, 69))	('ipilimumab', 'Chemical', 'MESH:D000074324', (83, 93))	('increased', 'PosReg', (33, 42))	('ipilimumab', 'Var', (83, 93))
140110	32580338	Genetic modifications of the PD-L1/PD-L2 along with JAK2 locus in the 9p24.1 region have been described and could contribute to the overexpression of PD-L1 and PD-L2.	('PD-L2', 'Gene', (35, 40))	('PD-L2', 'Gene', '80380', (35, 40))	('overexpression', 'PosReg', (132, 146))	('modifications', 'Var', (8, 21))	('PD-L2', 'Gene', (160, 165))	('PD-L2', 'Gene', '80380', (160, 165))	('JAK2', 'Gene', '3717', (52, 56))	('JAK', 'molecular_function', 'GO:0004713', ('52', '55'))	('JAK2', 'Gene', (52, 56))	('contribute', 'Reg', (114, 124))
140122	32580338	For example, resistance to radiotherapy remains an important cause of poor survival rates in HNC, or EGFR inhibitors have poor efficacy with resistance to the innate and acquired immune systems.	('HNC', 'Phenotype', 'HP:0012288', (93, 96))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'molecular_function', 'GO:0005006', ('101', '105'))	('EGFR', 'Gene', (101, 105))	('HNC', 'Disease', (93, 96))	('inhibitors', 'Var', (106, 116))
140156	32580338	Based on the evidence, up to 90% of patients treated with an anti-CTLA-4 antibody and 70% of patients treated with a PD-1/PD-L1 antibody develop irAEs, which affect any of the body organs including thyroiditis, dermatitis, pneumonitis, colitis, hepatitis, hypophysitis, uveitis, polyneuritis, and pancreatitis.	('pancreatitis', 'Disease', (297, 309))	('polyneuritis', 'Phenotype', 'HP:0031003', (279, 291))	('PD-1/PD-L1', 'Disease', (117, 127))	('antibody', 'cellular_component', 'GO:0019814', ('128', '136'))	('polyneuritis', 'Disease', (279, 291))	('hypophysitis', 'Disease', 'MESH:D000072659', (256, 268))	('patients', 'Species', '9606', (93, 101))	('antibody', 'cellular_component', 'GO:0019815', ('73', '81'))	('antibody', 'cellular_component', 'GO:0019814', ('73', '81'))	('thyroiditis', 'Disease', (198, 209))	('patients', 'Species', '9606', (36, 44))	('anti-CTLA-4', 'Gene', (61, 72))	('hepatitis', 'Phenotype', 'HP:0012115', (245, 254))	('colitis', 'Disease', (236, 243))	('antibody', 'molecular_function', 'GO:0003823', ('128', '136'))	('hepatitis', 'Disease', 'MESH:D056486', (245, 254))	('anti-CTLA-4', 'Var', (61, 72))	('uveitis', 'Disease', 'MESH:D014605', (270, 277))	('antibody', 'molecular_function', 'GO:0003823', ('73', '81'))	('antibody', 'cellular_component', 'GO:0042571', ('128', '136'))	('pneumonitis', 'Disease', 'MESH:D011014', (223, 234))	('uveitis', 'Disease', (270, 277))	('pancreatitis', 'Phenotype', 'HP:0001733', (297, 309))	('dermatitis', 'Disease', 'MESH:D003872', (211, 221))	('dermatitis', 'Disease', (211, 221))	('colitis', 'Disease', 'MESH:D003092', (236, 243))	('hepatitis', 'Disease', (245, 254))	('thyroiditis', 'Disease', 'MESH:D013959', (198, 209))	('antibody', 'cellular_component', 'GO:0042571', ('73', '81'))	('pneumonitis', 'Disease', (223, 234))	('hypophysitis', 'Disease', (256, 268))	('PD-1/PD-L1', 'Disease', 'MESH:D010300', (117, 127))	('antibody', 'cellular_component', 'GO:0019815', ('128', '136'))	('thyroiditis', 'Phenotype', 'HP:0100646', (198, 209))	('pancreatitis', 'Disease', 'MESH:D010195', (297, 309))	('uveitis', 'Phenotype', 'HP:0000554', (270, 277))	('polyneuritis', 'Disease', 'MESH:D009443', (279, 291))	('affect', 'Reg', (158, 164))	('dermatitis', 'Phenotype', 'HP:0011123', (211, 221))	('colitis', 'Phenotype', 'HP:0002583', (236, 243))
140158	32580338	Rash and erythema are the most common cutaneous irAE (40%) for patients who are treated with combination therapy compared to 25% in anti-CTLA-4, and 15% in anti-PD1 monotherapies.	('erythema', 'Phenotype', 'HP:0010783', (9, 17))	('erythema', 'Disease', 'MESH:D004890', (9, 17))	('erythema', 'Disease', (9, 17))	('Rash', 'Disease', (0, 4))	('combination', 'Var', (93, 104))	('patients', 'Species', '9606', (63, 71))	('PD1', 'Gene', '5133', (161, 164))	('Rash', 'Disease', 'MESH:D005076', (0, 4))	('Rash', 'Phenotype', 'HP:0000988', (0, 4))	('PD1', 'Gene', (161, 164))
140166	32580338	In addition, hepatitis is higher in patients who were treated with combination therapy (14-18%) than patients who were treated with anti-CTLA4 (4-9%) or anti-PD1 (1-4%) monotherapy.	('hepatitis', 'Disease', (13, 22))	('patients', 'Species', '9606', (101, 109))	('CTLA4', 'Gene', '1493', (137, 142))	('hepatitis', 'Phenotype', 'HP:0012115', (13, 22))	('higher', 'PosReg', (26, 32))	('patients', 'Species', '9606', (36, 44))	('CTLA4', 'Gene', (137, 142))	('hepatitis', 'Disease', 'MESH:D056486', (13, 22))	('combination', 'Var', (67, 78))	('PD1', 'Gene', (158, 161))	('PD1', 'Gene', '5133', (158, 161))
140194	32580338	For example, PD-L1 expression, high mutational load, selective CD8+ T cell infiltration, and distribution at tumor invasive margins correlate with clinical response to anti-PD-1/PD-L1treatment.	('expression', 'MPA', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('high mutational load', 'Var', (31, 51))	('CD8', 'Gene', (63, 66))	('PD-L1', 'Gene', (13, 18))	('PD-1/PD-L1', 'Disease', 'MESH:D010300', (173, 183))	('CD8', 'Gene', '925', (63, 66))	('PD-1/PD-L1', 'Disease', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
140211	30607140	Despite the fact that tremendous somatic mutations in a variety of cancer types can give chances for personalized treatment targeting at patients' specific mutations, these mutations can eventually translate into new antigens for possible anti-tumor immune response.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('translate', 'Reg', (198, 207))	('cancer', 'Disease', (67, 73))	('tumor', 'Disease', (244, 249))	('mutations', 'Var', (156, 165))	('patients', 'Species', '9606', (137, 145))	('mutations', 'Var', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('immune response', 'biological_process', 'GO:0006955', ('250', '265'))
140217	30607140	Thus, monoclonal antibodies blocking PD-1 have arisen as an impressive treatment strategy for cancer patients and have been approved by the U.S. Food and Drug Administration (FDA) for human use.	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (184, 189))	('monoclonal', 'Var', (6, 16))	('PD-1', 'Gene', (37, 41))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
140286	30607140	The combination of PD-1 and CTLA-4 blockade has demonstrated higher response rates in advanced melanoma, while combination with LAG3 blockade are still carrying on clinical trials (NCT03250832, NCT02658981, NCT01968109, NCT03005782).	('LAG3', 'Gene', '3902', (128, 132))	('advanced melanoma', 'Disease', 'MESH:D008545', (86, 103))	('higher', 'PosReg', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('advanced melanoma', 'Disease', (86, 103))	('NCT03250832', 'Var', (181, 192))	('CTLA-4', 'Gene', '1493', (28, 34))	('PD-1', 'Gene', (19, 23))	('LAG3', 'Gene', (128, 132))	('CTLA-4', 'Gene', (28, 34))
140290	30607140	Therefore, we can infer that the high expression of LFA-1 may improve the efficacy of T cells that have been released from the "brake" of PD-1 by PD-1 blockade.	('LFA-1', 'Gene', (52, 57))	('high expression', 'Var', (33, 48))	('improve', 'PosReg', (62, 69))	('efficacy', 'CPA', (74, 82))	('LFA-1', 'Gene', '3689', (52, 57))
140314	29738475	Cancer is considered as a complex disease driven by genome alterations that include gene mutations, copy number alterations, and so on.	('gene mutations', 'Var', (84, 98))	('copy number alterations', 'Var', (100, 123))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
140315	29738475	A key challenge is to detect driver mutations, which contribute to the development of cancer, from passenger mutations, which are functionally neutral.	('contribute', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
140318	29738475	De novo methods identify combinatorial patterns of cancer mutations without any prior knowledge but utilize two properties of a driver gene set: high coverage and high mutual exclusivity.	('mutations', 'Var', (58, 67))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))
140323	29738475	give a comprehensive analysis of oncogenic driver genes and mutations across 33 cancer types, and identify 299 cancer driver genes.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', (111, 117))	('mutations', 'Var', (60, 69))	('cancer', 'Disease', (80, 86))
140327	29738475	present an integrated analysis of genetic alterations in ten signaling pathways across 33 cancer types, which denotes that different cancer types have similarities and differences in frequencies of alteration of individual pathways.	('signaling pathways', 'Pathway', (61, 79))	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('genetic alterations', 'Var', (34, 53))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
140370	29738475	The internal coverage of this specific driver module also has the largest value in all cancers, which is 0.448, and denotes that the mutated samples of BRCA accounted for 45% of the total sample size of BRCA (Figure 3c).	('cancers', 'Disease', (87, 94))	('BRCA', 'Gene', '672', (203, 207))	('BRCA', 'Phenotype', 'HP:0003002', (152, 156))	('BRCA', 'Gene', (203, 207))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('BRCA', 'Gene', '672', (152, 156))	('mutated', 'Var', (133, 140))	('BRCA', 'Gene', (152, 156))	('BRCA', 'Phenotype', 'HP:0003002', (203, 207))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
140377	29738475	About a third of the samples in which GFOD1 is mutated are samples of BRCA.	('GFOD1', 'Gene', (38, 43))	('BRCA', 'Phenotype', 'HP:0003002', (70, 74))	('GFOD1', 'Gene', '54438', (38, 43))	('BRCA', 'Gene', '672', (70, 74))	('BRCA', 'Gene', (70, 74))	('mutated', 'Var', (47, 54))
140383	29738475	All driver genes involved in driver modules detected by CSDM in BRCA are enriched in 107 pathways, with a statistically significant p-value < 0.01, while the results obtained by employing SPECifIC in BRCA are enriched in 73 pathways using KEGG pathway terms with the statistically significant p-value < 0.01.	('BRCA', 'Phenotype', 'HP:0003002', (200, 204))	('BRCA', 'Gene', '672', (200, 204))	('BRCA', 'Gene', '672', (64, 68))	('BRCA', 'Phenotype', 'HP:0003002', (64, 68))	('BRCA', 'Gene', (200, 204))	('CSDM', 'Var', (56, 60))	('enriched', 'Reg', (73, 81))	('BRCA', 'Gene', (64, 68))
140389	29738475	ELF3 and CDKN1A are genes downregulated in HeLa cells after knockdown of MED1 by RNAi, and they are both regulated by hypoxia.	('downregulated', 'NegReg', (26, 39))	('RNAi', 'biological_process', 'GO:0016246', ('81', '85'))	('hypoxia', 'Disease', 'MESH:D000860', (118, 125))	('HeLa', 'CellLine', 'CVCL:0030', (43, 47))	('knockdown', 'Var', (60, 69))	('MED1', 'Gene', (73, 77))	('CDKN1A', 'Gene', '1026', (9, 15))	('MED1', 'Gene', '5469', (73, 77))	('ELF3', 'Gene', '1999', (0, 4))	('CDKN1A', 'Gene', (9, 15))	('hypoxia', 'Disease', (118, 125))	('ELF3', 'Gene', (0, 4))
140394	29738475	The mutations of NPM1, RUNX1, and CEBPA are proven to be associated with LAML.	('RUNX1', 'Gene', (23, 28))	('LAML', 'Disease', (73, 77))	('NPM1', 'Gene', (17, 21))	('NPM1', 'Gene', '4869', (17, 21))	('RUNX1', 'Gene', '861', (23, 28))	('CEBPA', 'Gene', (34, 39))	('mutations', 'Var', (4, 13))	('CEBPA', 'Gene', '1050', (34, 39))	('associated', 'Reg', (57, 67))
140396	29738475	RUNX1 mutations predict for resistance to chemotherapy, and they are significantly associated with distinct biological and clinical features.	('predict', 'Reg', (16, 23))	('associated', 'Reg', (83, 93))	('RUNX1', 'Gene', (0, 5))	('resistance to chemotherapy', 'CPA', (28, 54))	('mutations', 'Var', (6, 15))	('RUNX1', 'Gene', '861', (0, 5))
140397	29738475	Patients with a biallelic mutation in CEBPA are defined as a clinicopathologic entity that is associated with a favorable prognosis.	('Patients', 'Species', '9606', (0, 8))	('biallelic mutation', 'Var', (16, 34))	('CEBPA', 'Gene', (38, 43))	('CEBPA', 'Gene', '1050', (38, 43))
140423	29738475	It is the fraction of samples with at least one mutation in gene  or  in cancer , based on all samples with mutations in  or gj in  cancer types, defined as follows: The specific coverage of  in cancer  to other  cancer types is the geometric mean of internal coverage and external coverage, and is denoted by , defined as follows: The larger the specific coverage, the more specific the gene pair is to a particular cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (417, 423))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('mutations', 'Var', (108, 117))	('particular cancer', 'Disease', (406, 423))	('cancer', 'Disease', (195, 201))	('particular cancer', 'Disease', 'MESH:D009369', (406, 423))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (417, 423))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (417, 423))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
140444	29738475	We permute the mutations of each gene among samples in a certain cancer type independently to hold the mutation frequency of each gene.	('mutations', 'Var', (15, 24))	('cancer', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
140446	29738475	Then, we permute samples with mutations for each gene in cancer  independently for 1000 times.	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
140469	26639198	For example, in the intergroup trial, neoadjuvant MVAC was associated with a significantly increased pT0 rate (38% vs. 15%), and patients who successfully attained a pT0 response achieved a more durable survival benefit (5-year survival rate of 85%).	('patients', 'Species', '9606', (129, 137))	('MVAC', 'Chemical', '-', (50, 54))	('neoadjuvant', 'Var', (38, 49))	('pT0 rate', 'CPA', (101, 109))	('increased', 'PosReg', (91, 100))
140472	26639198	Therefore, dual-inhibition of EGFR and HER-2 represents an attractive therapeutic strategy for management of urothelial carcinoma.	('dual-inhibition', 'Var', (11, 26))	('EGFR', 'Gene', (30, 34))	('HER-2', 'Gene', '2064', (39, 44))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('urothelial carcinoma', 'Disease', (109, 129))	('HER-2', 'Gene', (39, 44))	('men', 'Species', '9606', (101, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('EGFR', 'Gene', '1956', (30, 34))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (109, 129))
140563	26639198	In a histology-independent randomized discontinuation study of lapatinib monotherapy in HER-2 amplified tumors, including nine patients with advanced bladder cancer, the objective response rate was 3%, and 28% of patients achieved stable disease (including three bladder cancer patients).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('bladder cancer', 'Disease', 'MESH:D001749', (263, 277))	('bladder cancer', 'Disease', (263, 277))	('tumors', 'Disease', (104, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (263, 277))	('patients', 'Species', '9606', (213, 221))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('bladder cancer', 'Disease', 'MESH:D001749', (150, 164))	('bladder cancer', 'Disease', (150, 164))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lapatinib', 'Chemical', 'MESH:D000077341', (63, 72))	('amplified', 'Var', (94, 103))	('HER-2', 'Gene', '2064', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('HER-2', 'Gene', (88, 93))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (278, 286))
140574	26639198	The results of future and ongoing studies are needed to determine whether dual-inhibition of EGFR and HER-2 in combination with cisplatin-based chemotherapy is a safe and effective therapeutic strategy in MIBC.	('EGFR', 'molecular_function', 'GO:0005006', ('93', '97'))	('EGFR', 'Gene', '1956', (93, 97))	('MIBC', 'Disease', (205, 209))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('EGFR', 'Gene', (93, 97))	('HER-2', 'Gene', (102, 107))	('HER-2', 'Gene', '2064', (102, 107))	('dual-inhibition', 'Var', (74, 89))	('MIBC', 'Chemical', '-', (205, 209))
140658	25956057	High KPNA2 immunoreactivity was identified as a predictor of bladder recurrence (hazard ratio [HR]: 2.017, 95% CI 1.13-3.61, p = 0.018), poor disease-free survival (DFS, HR: 2.754, 95% CI 1.68-4.51, p = 0.001) and poor overall survival (OS, HR: 4.480, 95% CI 1.84-10.89, p = 0.001) for patients with UTUC after RNU.	('High', 'Var', (0, 4))	('KPNA2', 'Gene', (5, 10))	('KPNA2', 'Gene', '3838', (5, 10))	('poor', 'NegReg', (137, 141))	('bladder', 'Disease', (61, 68))	('RNU', 'Chemical', '-', (311, 314))	('disease-free survival', 'CPA', (142, 163))	('OS', 'Chemical', '-', (237, 239))	('patients', 'Species', '9606', (286, 294))
140712	25956057	Survival curves for patients with low or high KPNA2 expression were plotted using the Kaplan-Meier method, with log-rank tests for statistical significance.	('high', 'Var', (41, 45))	('KPNA2', 'Gene', '3838', (46, 51))	('patients', 'Species', '9606', (20, 28))	('KPNA2', 'Gene', (46, 51))
140732	25956057	A univariate Cox regression analysis (Table 3) revealed that male sex (P = 0.004), tumors located in the ureter (P = 0.015), multiple tumor foci (P = 0.009),high stage(P = 0.012) and high KPNA2 expression (P < 0.001) were highly associated with a shorter DFS.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Cox', 'Gene', (13, 16))	('multiple tumor foci', 'Disease', (125, 144))	('multiple tumor foci', 'Disease', 'MESH:C565785', (125, 144))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('DFS', 'MPA', (255, 258))	('KPNA2', 'Gene', (188, 193))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('high', 'Var', (183, 187))	('expression', 'MPA', (194, 204))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('KPNA2', 'Gene', '3838', (188, 193))	('Cox', 'Gene', '1351', (13, 16))
140733	25956057	In the multivariate Cox regression analysis, only high KPNA2 expression (P = 0.001), male gender (P = 0.002), multiple tumor foci (P = 0.013) and tumor stage(p = 0.022) remained significant.	('KPNA2', 'Gene', (55, 60))	('tumor', 'Disease', (119, 124))	('KPNA2', 'Gene', '3838', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('multiple tumor foci', 'Disease', (110, 129))	('Cox', 'Gene', '1351', (20, 23))	('Cox', 'Gene', (20, 23))	('expression', 'MPA', (61, 71))	('tumor', 'Disease', (146, 151))	('multiple tumor foci', 'Disease', 'MESH:C565785', (110, 129))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('high', 'Var', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
140734	25956057	Male sex (P = 0.001), a tumor diameter larger than 3.5 cm (P = 0.005),,high stage(P = 0.001) and high KPNA2 expression (P = 0.001) were significantly associated with shorter OS both in the uni- and multi-variable Cox regression analyses (in Table 4).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Cox', 'Gene', (213, 216))	('shorter OS', 'Disease', (166, 176))	('tumor', 'Disease', (24, 29))	('KPNA2', 'Gene', (102, 107))	('expression', 'MPA', (108, 118))	('KPNA2', 'Gene', '3838', (102, 107))	('OS', 'Chemical', '-', (174, 176))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('high', 'Var', (97, 101))	('Cox', 'Gene', '1351', (213, 216))
140738	25956057	siRNA technology was used to knockdown KPNA2 in T24 and J82 cells.	('KPNA2', 'Gene', (39, 44))	('J82', 'CellLine', 'CVCL:0359', (56, 59))	('KPNA2', 'Gene', '3838', (39, 44))	('knockdown', 'Var', (29, 38))
140739	25956057	Western blot analysis showed that following KPNA2-directed siRNA transfection, KPNA2 protein expression was significantly lower than in cells transfected with control RNA (Figure 2B).	('lower', 'NegReg', (122, 127))	('protein', 'Protein', (85, 92))	('KPNA2', 'Gene', (44, 49))	('KPNA2', 'Gene', '3838', (44, 49))	('transfection', 'Var', (65, 77))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('KPNA2', 'Gene', (79, 84))	('KPNA2', 'Gene', '3838', (79, 84))	('RNA', 'cellular_component', 'GO:0005562', ('167', '170'))
140741	25956057	Following knockdown of KPNA2, the viability of the cells was significantly lower than that of control cells, as assessed by a proliferation assay (Figure 2C and D).	('lower', 'NegReg', (75, 80))	('KPNA2', 'Gene', (23, 28))	('viability', 'CPA', (34, 43))	('KPNA2', 'Gene', '3838', (23, 28))	('knockdown', 'Var', (10, 19))
140743	25956057	As shown in Figure 2E and F, the number of migrating cells was significantly lower in KPNA2 knockdown cells than in control cells.	('lower', 'NegReg', (77, 82))	('knockdown', 'Var', (92, 101))	('KPNA2', 'Gene', (86, 91))	('KPNA2', 'Gene', '3838', (86, 91))
140744	25956057	These studies showed that knockdown of KPNA2 resulted in decreased proliferation and migration of urothelial carcinoma cells.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (98, 118))	('KPNA2', 'Gene', (39, 44))	('KPNA2', 'Gene', '3838', (39, 44))	('urothelial carcinoma', 'Disease', (98, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('proliferation', 'CPA', (67, 80))	('knockdown', 'Var', (26, 35))	('decreased', 'NegReg', (57, 66))
140745	25956057	To assess whether increased apoptosis was involved in the significant decrease in cell viability following KPNA2 knockdown, we employed an apoptosis assay using Annexin V-FITC and propidium iodide double staining, followed by flow cytometry analysis.	('cell viability', 'CPA', (82, 96))	('Annexin V', 'Gene', '308', (161, 170))	('Annexin V', 'Gene', (161, 170))	('propidium iodide', 'Chemical', 'MESH:D011419', (180, 196))	('KPNA2', 'Gene', '3838', (107, 112))	('apoptosis', 'biological_process', 'GO:0097194', ('139', '148'))	('apoptosis', 'biological_process', 'GO:0097194', ('28', '37'))	('apoptosis', 'biological_process', 'GO:0006915', ('139', '148'))	('apoptosis', 'biological_process', 'GO:0006915', ('28', '37'))	('knockdown', 'Var', (113, 122))	('KPNA2', 'Gene', (107, 112))	('decrease', 'NegReg', (70, 78))
140746	25956057	As shown in Figure 3A and B, the apoptosis rate in KPNA2 knockdown cells was significantly higher than in control cells.	('KPNA2', 'Gene', '3838', (51, 56))	('apoptosis rate', 'CPA', (33, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('33', '42'))	('higher', 'PosReg', (91, 97))	('apoptosis', 'biological_process', 'GO:0006915', ('33', '42'))	('knockdown', 'Var', (57, 66))	('KPNA2', 'Gene', (51, 56))
140747	25956057	Consistently, KPNA2 knockdown induced a significant increase in the disruption of the mitochondrial Deltapsim compared with control cells, which was suggested to be an early event in the apoptotic process [12766472] (Figure 3C, D).Furthermore, the activity of caspase-3 and -7, which are executioners of apoptosis, was also significantly increased after KPNA2 knockdown (Figure 3E).	('KPNA2', 'Gene', (354, 359))	('KPNA2', 'Gene', '3838', (354, 359))	('activity', 'MPA', (248, 256))	('apoptosis', 'biological_process', 'GO:0097194', ('304', '313'))	('apoptosis', 'biological_process', 'GO:0006915', ('304', '313'))	('caspase-3 and -7', 'Gene', '836;840', (260, 276))	('increased', 'PosReg', (338, 347))	('KPNA2', 'Gene', (14, 19))	('knockdown', 'Var', (360, 369))	('apoptotic process', 'biological_process', 'GO:0006915', ('187', '204'))	('KPNA2', 'Gene', '3838', (14, 19))
140748	25956057	Consistently, the cleavage of PARP, a marker of apoptosis, was significantly increased in KPNA2 knockdown cells as demonstrated by a western blot assay (Figure 3F).	('knockdown', 'Var', (96, 105))	('PARP', 'Gene', '1302', (30, 34))	('PARP', 'Gene', (30, 34))	('KPNA2', 'Gene', '3838', (90, 95))	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('cleavage', 'MPA', (18, 26))	('increased', 'PosReg', (77, 86))	('KPNA2', 'Gene', (90, 95))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))
140749	25956057	The expression of PCNA, a marker of proliferation, was decreased in KPNA2 knockdown cells (Figure 3F).	('expression', 'MPA', (4, 14))	('knockdown', 'Var', (74, 83))	('PCNA', 'molecular_function', 'GO:0003892', ('18', '22'))	('decreased', 'NegReg', (55, 64))	('KPNA2', 'Gene', (68, 73))	('PCNA', 'Gene', (18, 22))	('KPNA2', 'Gene', '3838', (68, 73))	('PCNA', 'Gene', '5111', (18, 22))
140750	25956057	Taken together, these data show that KPNA2 knockdown activated the apoptosis pathway and decreased the proliferation of urothelial carcinoma cells.	('KPNA2', 'Gene', (37, 42))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (120, 140))	('activated', 'PosReg', (53, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('apoptosis pathway', 'Pathway', (67, 84))	('knockdown', 'Var', (43, 52))	('KPNA2', 'Gene', '3838', (37, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('67', '76'))	('urothelial carcinoma', 'Disease', (120, 140))	('apoptosis', 'biological_process', 'GO:0006915', ('67', '76'))	('decreased', 'NegReg', (89, 98))
140753	25956057	Moreover, high nuclear KPNA2 immunoreactivity was identified as a novel predictor of bladder recurrence and poor DFS and OS of UTUC patients after RNU, and its predictive ability was independent of the conventional predictive factors such as sex, tumor location, tumor size, and tumor multiplicity.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('KPNA2', 'Gene', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('OS', 'Chemical', '-', (121, 123))	('tumor', 'Disease', (247, 252))	('bladder recurrence', 'Disease', (85, 103))	('tumor', 'Disease', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('poor DFS', 'CPA', (108, 116))	('KPNA2', 'Gene', '3838', (23, 28))	('high nuclear', 'Var', (10, 22))	('tumor', 'Disease', (263, 268))	('RNU', 'Chemical', '-', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('patients', 'Species', '9606', (132, 140))	('tumor', 'Disease', 'MESH:D009369', (279, 284))
140754	25956057	Additionally, KPNA2 knockdown resulted in decreased cell proliferation and migration and increased apoptosis in urothelial carcinoma cells.	('decreased', 'NegReg', (42, 51))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('cell proliferation', 'CPA', (52, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('apoptosis', 'CPA', (99, 108))	('urothelial carcinoma', 'Disease', (112, 132))	('KPNA2', 'Gene', (14, 19))	('knockdown', 'Var', (20, 29))	('increased', 'PosReg', (89, 98))	('KPNA2', 'Gene', '3838', (14, 19))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (112, 132))
140771	25956057	Therefore, the inhibited proliferation and migration and the increased apoptosis after KPNA2 silencing in our in vitro model may be due to the decreased nuclear translocation of NF-kappaB p65 by KPNA2.	('KPNA2', 'Gene', '3838', (87, 92))	('inhibited', 'NegReg', (15, 24))	('silencing', 'Var', (93, 102))	('NF-kappaB', 'Gene', '4790', (178, 187))	('apoptosis', 'CPA', (71, 80))	('decreased', 'NegReg', (143, 152))	('p65', 'Gene', (188, 191))	('p65', 'Gene', '5970', (188, 191))	('NF-kappaB', 'Gene', (178, 187))	('nuclear translocation', 'MPA', (153, 174))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('KPNA2', 'Gene', (195, 200))	('KPNA2', 'Gene', (87, 92))	('KPNA2', 'Gene', '3838', (195, 200))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))
140794	33665207	The results showed that ZIC2 also acted as a risk prognostic factor in bladder, breast and lung cancer Table 1.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('bladder', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('ZIC2', 'Var', (24, 28))	('breast and lung cancer', 'Disease', 'MESH:D001943', (80, 102))	('lung cancer', 'Disease', (91, 102))
140801	33665207	The results revealed that multiple tumor- and immune-related pathways were differentially enriched in ZIC2 high or low expression phenotype in a variety of tumors including complement and coagulation cascades, P53 signaling pathway, basal cell carcinoma, PPAR signaling pathway, tight junction, etc (Figure 10).	('tight junction', 'Disease', (279, 293))	('PPAR', 'Gene', '5465', (255, 259))	('ZIC2', 'Gene', (102, 106))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (233, 253))	('coagulation', 'biological_process', 'GO:0050817', ('188', '199'))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (233, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('carcinoma', 'Disease', (244, 253))	('P53', 'Gene', (210, 213))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('basal cell carcinoma', 'Disease', (233, 253))	('high', 'Var', (107, 111))	('PPAR', 'Gene', (255, 259))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tight junction', 'cellular_component', 'GO:0070160', ('279', '293'))	('PPAR signaling pathway', 'biological_process', 'GO:0035357', ('255', '277'))	('carcinoma', 'Disease', 'MESH:D009369', (244, 253))	('P53 signaling pathway', 'biological_process', 'GO:0030330', ('210', '231'))	('P53', 'Gene', '7157', (210, 213))	('enriched', 'Reg', (90, 98))	('low', 'NegReg', (115, 118))
140857	32211391	While predictive performances for three methods were comparable, CLING consistently generated the highest AUC score, followed by Endeavor and DRS, for each cancer type (Supplementary Table S3).	('DRS', 'Gene', '8406', (142, 145))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('CLING', 'Var', (65, 70))	('AUC score', 'MPA', (106, 115))	('DRS', 'Gene', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
140976	30456182	In a study by Brunocilla et al., who compared preoperative 11C-choline-PET/CT to contrast-enhanced CT in 26 BC patients, 11C-choline-PET/CT was shown to have much greater sensitivity than CT, while demonstrating similar specificity.	('11C-choline', 'Chemical', '-', (121, 132))	('BC', 'Phenotype', 'HP:0009725', (108, 110))	('sensitivity', 'MPA', (171, 182))	('11C-choline-PET/CT', 'Var', (121, 139))	('11C-choline', 'Chemical', '-', (59, 70))	('patients', 'Species', '9606', (111, 119))
140996	30456182	However, the results of the studies included into this review tend to suggest that the use of DW-MR for urothelial carcinoma nodal staging may yield relatively high sensitivity values, with no significant deterioration in terms specificity, and thus its use may result in lower rates of understaging compared to the golden-standard of CT.	('lower', 'NegReg', (272, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('DW-MR', 'Var', (94, 99))	('urothelial carcinoma nodal', 'Disease', 'MESH:D013611', (104, 130))	('understaging', 'MPA', (287, 299))	('urothelial carcinoma nodal', 'Disease', (104, 130))
141003	30456182	Kollberg et al., who investigated the results of PET/CT scans performed before and after neoadjuvant chemotherapy in 50 bladder cancer patients, reported PET/CT to demonstrate an 86% rate of correct prediction of the histological nodal chemotherapy response.	('histological nodal chemotherapy response', 'CPA', (217, 257))	('PET/CT', 'Var', (154, 160))	('patients', 'Species', '9606', (135, 143))	('bladder cancer', 'Disease', 'MESH:D001749', (120, 134))	('bladder cancer', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('bladder cancer', 'Phenotype', 'HP:0009725', (120, 134))
141067	26514209	miR-145 transfection slightly changed the morphological characteristics of T24 and KU7 cells.	('morphological characteristics', 'CPA', (42, 71))	('changed', 'Reg', (30, 37))	('miR-145', 'Gene', (0, 7))	('miR-145', 'Gene', '406937', (0, 7))	('transfection', 'Var', (8, 20))
141069	26514209	In addition, miR-145 transfection increased mRNA expression of some differentiation markers, including p63, TP63, and cytokeratin 5, which are markers of squamous cells, as well as MUC-1, MUC-2, and MUC-5 AC, which are markers of glandular cells.	('cytokeratin 5', 'Gene', '3852', (118, 131))	('TP63', 'Gene', '8626', (108, 112))	('mRNA expression', 'MPA', (44, 59))	('MUC-5 AC', 'Gene', '4586', (199, 207))	('transfection', 'Var', (21, 33))	('p63', 'Gene', (103, 106))	('MUC-2', 'Gene', '4583', (188, 193))	('MUC-2', 'Gene', (188, 193))	('MUC-1', 'Gene', (181, 186))	('MUC-5 AC', 'Gene', (199, 207))	('miR-145', 'Gene', (13, 20))	('miR-145', 'Gene', '406937', (13, 20))	('MUC-1', 'Gene', '4582', (181, 186))	('increased', 'PosReg', (34, 43))	('cytokeratin 5', 'Gene', (118, 131))	('p63', 'Gene', '8626', (103, 106))	('TP63', 'Gene', (108, 112))
141076	26514209	Similarly, silencing of syndecan-1 by siRNA up-regulated some stem cell and differentiation markers (Fig.	('silencing', 'Var', (11, 20))	('syndecan-1', 'Gene', '6382', (24, 34))	('syndecan-1', 'Gene', (24, 34))	('syndecan', 'molecular_function', 'GO:0015023', ('24', '32'))	('up-regulated', 'PosReg', (44, 56))
141088	26514209	An isoform of p63, a marker of squamous cells, transactivates p53 target genes and induces cell cycle arrest and apoptosis.	('arrest', 'Disease', (102, 108))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('91', '108'))	('apoptosis', 'CPA', (113, 122))	('induces', 'PosReg', (83, 90))	('p63', 'Gene', (14, 17))	('transactivates', 'Var', (47, 61))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (91, 108))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('p63', 'Gene', '8626', (14, 17))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))	('arrest', 'Disease', 'MESH:D006323', (102, 108))
141102	26514209	The capacity of such cancers to invade other tissues depends on intrinsic genetic factors, such as mutations in Ras or fibroblast growth factor receptor 3, as well as expression of p53 and RB tumor suppressor.	('p53', 'Gene', (181, 184))	('p53', 'Gene', '7157', (181, 184))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('119', '143'))	('RB tumor', 'Disease', (189, 197))	('RB tumor', 'Disease', 'MESH:D012175', (189, 197))	('tumor suppressor', 'biological_process', 'GO:0051726', ('192', '208'))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('mutations', 'Var', (99, 108))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancers', 'Disease', (21, 28))	('fibroblast growth factor receptor 3', 'Gene', '2261', (119, 154))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('192', '208'))	('Ras', 'Gene', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('fibroblast growth factor receptor 3', 'Gene', (119, 154))
141178	33841505	Multivariate COX analysis showed that T stage still had independent prognostic ability in four cohorts, while TRIB3 had independent prognostic ability in cohort TCGA-BLCA, GSE32548, and GSE32894.	('TRIB3', 'Gene', (110, 115))	('TRIB3', 'Gene', '57761', (110, 115))	('age', 'Gene', (42, 45))	('GSE32894', 'Var', (186, 194))	('age', 'Gene', '5973', (42, 45))
141187	33841505	In cohort GSE32548 and GSE32894, the expression of TRIB3 was different only in different grades and T stages (p < 0.05, Figures 3A,B).	('GSE32894', 'Var', (23, 31))	('TRIB3', 'Gene', '57761', (51, 56))	('GSE32548', 'Var', (10, 18))	('age', 'Gene', (104, 107))	('expression', 'MPA', (37, 47))	('TRIB3', 'Gene', (51, 56))	('age', 'Gene', '5973', (104, 107))
141231	33841505	This experiment suggests that expression of TRIB3 plays a tumor-promoting role in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('expression', 'Var', (30, 40))	('TRIB3', 'Gene', (44, 49))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))	('bladder cancer', 'Disease', (82, 96))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('TRIB3', 'Gene', '57761', (44, 49))	('men', 'Species', '9606', (11, 14))
141233	33841505	Knockout of TRIB3 inhibits tumorigenesis and cancer progression.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', (27, 32))	('inhibits', 'NegReg', (18, 26))	('TRIB3', 'Gene', (12, 17))	('TRIB3', 'Gene', '57761', (12, 17))	('Knockout', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))
141251	31258770	This study will research the regulatory roles and molecular mechanism of miR-101-3p in BUC chemoresistance.	('BUC chemoresistance', 'Disease', (87, 106))	('miR-101-3p', 'Chemical', '-', (73, 83))	('miR-101-3p', 'Var', (73, 83))
141253	31258770	Luciferase reporter assay was used to verify the combination between miR-101-3p and EZH2.	('EZH2', 'Gene', '2146', (84, 88))	('miR-101-3p', 'Chemical', '-', (69, 79))	('miR-101-3p', 'Var', (69, 79))	('EZH2', 'Gene', (84, 88))
141255	31258770	In T24/CDDP cells, the up-regulation of miR-101-3p decreased the half maximal inhibitory concentration (IC50) to CDDP, depressed the expression of MRP1 protein, promote the CDDP-induced cytotoxicity, and advanced CDDP sensitivity.	('cytotoxicity', 'Disease', 'MESH:D064420', (186, 198))	('decreased', 'NegReg', (51, 60))	('promote', 'PosReg', (161, 168))	('CDDP sensitivity', 'CPA', (213, 229))	('MRP1', 'Gene', '4363', (147, 151))	('depressed', 'NegReg', (119, 128))	('miR-101-3p', 'Chemical', '-', (40, 50))	('CDDP', 'Chemical', 'MESH:D002945', (7, 11))	('CDDP', 'Chemical', 'MESH:D002945', (213, 217))	('up-regulation', 'PosReg', (23, 36))	('CDDP', 'Chemical', 'MESH:D002945', (173, 177))	('miR-101-3p', 'Var', (40, 50))	('MRP1', 'Gene', (147, 151))	('half maximal inhibitory concentration', 'MPA', (65, 102))	('CDDP', 'Chemical', 'MESH:D002945', (113, 117))	('advanced', 'PosReg', (204, 212))	('regulation', 'biological_process', 'GO:0065007', ('26', '36'))	('expression', 'MPA', (133, 143))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('cytotoxicity', 'Disease', (186, 198))
141256	31258770	A series of in vitro experiments certified the EZH2 gene was a target gene of miR-101-3p, including luciferase reporter assay, western blotting and so on.	('EZH2', 'Gene', (47, 51))	('EZH2', 'Gene', '2146', (47, 51))	('miR-101-3p', 'Chemical', '-', (78, 88))	('miR-101-3p', 'Var', (78, 88))
141257	31258770	Up-regulation of EZH2 largely reversed the regulatory effects of miR-101-3p enhancement on CDDP sensitivity in T24/CDDP cells.	('enhancement', 'PosReg', (76, 87))	('regulation', 'biological_process', 'GO:0065007', ('3', '13'))	('EZH2', 'Gene', (17, 21))	('miR-101-3p', 'Var', (65, 75))	('miR-101-3p', 'Chemical', '-', (65, 75))	('CDDP sensitivity', 'MPA', (91, 107))	('CDDP', 'Chemical', 'MESH:D002945', (115, 119))	('Up-regulation', 'PosReg', (0, 13))	('EZH2', 'Gene', '2146', (17, 21))	('CDDP', 'Chemical', 'MESH:D002945', (91, 95))
141258	31258770	Conclusion: The expression of miR-101-3p is positively related to CDDP sensitivity of BUC, miR-101-3p advances sensitivity of BUC to CDDP through targeted silencing EZH2.	('silencing', 'NegReg', (155, 164))	('CDDP sensitivity', 'MPA', (66, 82))	('EZH2', 'Gene', (165, 169))	('EZH2', 'Gene', '2146', (165, 169))	('CDDP', 'Chemical', 'MESH:D002945', (66, 70))	('sensitivity', 'MPA', (111, 122))	('advances', 'PosReg', (102, 110))	('miR-101-3p', 'Var', (91, 101))	('CDDP', 'Chemical', 'MESH:D002945', (133, 137))	('related', 'Reg', (55, 62))	('miR-101-3p', 'Chemical', '-', (91, 101))	('miR-101-3p', 'Chemical', '-', (30, 40))
141263	31258770	Recent literatures reported miR-101-3p was low-expressed and acted as a tumor-suppressing gene in diverse malignant cancers, including bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('miR-101-3p', 'Var', (28, 38))	('malignant cancers', 'Disease', (106, 123))	('tumor', 'Disease', (72, 77))	('bladder cancer', 'Disease', (135, 149))	('miR-101-3p', 'Chemical', '-', (28, 38))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('bladder cancer', 'Phenotype', 'HP:0009725', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('malignant cancers', 'Disease', 'MESH:D009369', (106, 123))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
141264	31258770	MiR-101-3p inhibited the invasion and migration of bladder cancer 253J-BV cells.	('bladder cancer', 'Disease', (51, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('MiR-101-3p', 'Var', (0, 10))	('inhibited', 'NegReg', (11, 20))	('J-BV', 'CellLine', 'CVCL:0182', (69, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (51, 65))
141265	31258770	Whether miR-101-3p is involved in chemoresistance of BUC and the underlying mechanism is still unknown.	('miR-101-3p', 'Var', (8, 18))	('miR-101-3p', 'Chemical', '-', (8, 18))	('involved', 'Reg', (22, 30))
141266	31258770	Through bioinformatics analysis, the Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2) gene might be a target gene of miR-101-3p.	('miR-101-3p', 'Chemical', '-', (133, 143))	('EZH2', 'Gene', '2146', (96, 100))	('EZH2', 'Gene', (96, 100))	('Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit', 'Gene', '2146', (37, 94))	('miR-101-3p', 'Var', (133, 143))
141271	31258770	Remaining BUC specimens were stored at -80 C with RNAlater Stabilization Solution (Thermo Fisher Scientific, USA) and used to detect the expression of miR-101-3p and EZH2.	('EZH2', 'Gene', '2146', (166, 170))	('EZH2', 'Gene', (166, 170))	('miR-101-3p', 'Chemical', '-', (151, 161))	('miR-101-3p', 'Var', (151, 161))
141290	31258770	The luciferase reporter vectors (EZH2-M, containing mutant binding site and EZH2-W, containing wild-type binding site) were designed and synthesized by the Genescript company (China).	('binding', 'molecular_function', 'GO:0005488', ('105', '112'))	('binding', 'molecular_function', 'GO:0005488', ('59', '66'))	('binding', 'Interaction', (59, 66))	('mutant', 'Var', (52, 58))	('EZH2', 'Gene', '2146', (76, 80))	('EZH2', 'Gene', '2146', (33, 37))	('EZH2', 'Gene', (76, 80))	('EZH2', 'Gene', (33, 37))
141298	31258770	The expression of miR-101-3p in T24/CDDP cells was much lower than that in T24 cells (Fig.	('expression', 'MPA', (4, 14))	('miR-101-3p', 'Var', (18, 28))	('lower', 'NegReg', (56, 61))	('CDDP', 'Chemical', 'MESH:D002945', (36, 40))	('miR-101-3p', 'Chemical', '-', (18, 28))
141299	31258770	These findings reveal the expression of miR-101-3p is positively related to CDDP sensitivity of BUC, miR-101-3p plays an important role in chemoresistance of BUC to CDDP.	('expression', 'MPA', (26, 36))	('CDDP', 'Chemical', 'MESH:D002945', (165, 169))	('miR-101-3p', 'Chemical', '-', (40, 50))	('CDDP sensitivity', 'Disease', (76, 92))	('CDDP', 'Chemical', 'MESH:D002945', (76, 80))	('miR-101-3p', 'Var', (101, 111))	('related', 'Reg', (65, 72))	('miR-101-3p', 'Var', (40, 50))	('miR-101-3p', 'Chemical', '-', (101, 111))
141301	31258770	The miR-101-3p enhancement decreased the IC50 of T24/CDDP cells to CDDP from 81.06+-7.09 mg/L to 38.72+-3.25 mg/L (P<0.05, Fig.	('miR-101-3p', 'Var', (4, 14))	('decreased', 'NegReg', (27, 36))	('enhancement', 'PosReg', (15, 26))	('CDDP', 'Chemical', 'MESH:D002945', (53, 57))	('miR-101-3p', 'Chemical', '-', (4, 14))	('CDDP', 'Chemical', 'MESH:D002945', (67, 71))	('IC50', 'MPA', (41, 45))
141303	31258770	Furthermore, in the T24/CDDP cells treating with CDDP (10 mg/L), the miR-101-3p enhancement depressed cell viability (Fig.2C, P<0.05), and promoted cell apoptosis (Fig.	('enhancement', 'PosReg', (80, 91))	('promoted', 'PosReg', (139, 147))	('CDDP', 'Chemical', 'MESH:D002945', (49, 53))	('CDDP', 'Chemical', 'MESH:D002945', (24, 28))	('miR-101-3p', 'Var', (69, 79))	('depressed', 'NegReg', (92, 101))	('miR-101-3p', 'Chemical', '-', (69, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('153', '162'))	('cell viability', 'CPA', (102, 116))	('apoptosis', 'biological_process', 'GO:0006915', ('153', '162'))	('cell apoptosis', 'CPA', (148, 162))
141305	31258770	Luciferase reporter assay proved miR-101-3p could specifically combine with wild-type binding site to restrain the luciferase activity (Fig.	('luciferase', 'Enzyme', (115, 125))	('luciferase activity', 'molecular_function', 'GO:0047077', ('115', '134'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('115', '134'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('115', '134'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('115', '134'))	('miR-101-3p', 'Var', (33, 43))	('luciferase activity', 'molecular_function', 'GO:0050248', ('115', '134'))	('restrain', 'NegReg', (102, 110))	('binding', 'molecular_function', 'GO:0005488', ('86', '93'))	('miR-101-3p', 'Chemical', '-', (33, 43))	('activity', 'MPA', (126, 134))	('combine', 'Interaction', (63, 70))
141306	31258770	And, miR-101-3p enhancement depressed obviously the expression of EZH2 protein in T24/CDDP cells (Fig.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('miR-101-3p', 'Chemical', '-', (5, 15))	('CDDP', 'Chemical', 'MESH:D002945', (86, 90))	('EZH2', 'Gene', (66, 70))	('expression', 'MPA', (52, 62))	('EZH2', 'Gene', '2146', (66, 70))	('protein', 'Protein', (71, 78))	('miR-101-3p', 'Var', (5, 15))	('depressed', 'NegReg', (28, 37))
141308	31258770	And, the EZH2 expression showed an inverse correlation with the expression of miR-101-3p (P<0.01).	('expression', 'MPA', (64, 74))	('miR-101-3p', 'Chemical', '-', (78, 88))	('expression', 'MPA', (14, 24))	('inverse', 'NegReg', (35, 42))	('EZH2', 'Gene', (9, 13))	('EZH2', 'Gene', '2146', (9, 13))	('miR-101-3p', 'Var', (78, 88))
141309	31258770	In addition, the co-expression patterns analysis showed a negative correlation between miR-101-3p and EZH2 in BUC tissues (Fig.	('EZH2', 'Gene', (102, 106))	('EZH2', 'Gene', '2146', (102, 106))	('miR-101-3p', 'Var', (87, 97))	('negative', 'NegReg', (58, 66))	('miR-101-3p', 'Chemical', '-', (87, 97))
141310	31258770	These results confirmed that miR-101-3p could bind to EZH2 and negatively regulate the expression of EZH2, and EZH2 was a target gene of miR-101-3p.	('EZH2', 'Gene', (54, 58))	('regulate', 'Reg', (74, 82))	('miR-101-3p', 'Chemical', '-', (137, 147))	('negatively', 'NegReg', (63, 73))	('bind', 'Interaction', (46, 50))	('EZH2', 'Gene', '2146', (111, 115))	('EZH2', 'Gene', (101, 105))	('expression', 'MPA', (87, 97))	('EZH2', 'Gene', '2146', (101, 105))	('miR-101-3p', 'Var', (29, 39))	('EZH2', 'Gene', (111, 115))	('EZH2', 'Gene', '2146', (54, 58))	('miR-101-3p', 'Chemical', '-', (29, 39))
141311	31258770	To determine whether EZH2 mediates the regulatory effects of miR-101-3p on chemosensitivity, knockdown of EZH2 by miR-101-3p enhancement was rescued by transfection with pUC-EZH2 prior to the detection of CDDP sensitivity, MRP1 expression and cytotoxicity induced by CDDP.	('knockdown', 'Var', (93, 102))	('EZH2', 'Gene', (106, 110))	('MRP1', 'Gene', (223, 227))	('miR-101-3p', 'Var', (114, 124))	('pUC-EZH2', 'Gene', '2146', (170, 178))	('CDDP', 'Chemical', 'MESH:D002945', (205, 209))	('CDDP', 'Chemical', 'MESH:D002945', (267, 271))	('miR-101-3p', 'Chemical', '-', (61, 71))	('EZH2', 'Gene', (174, 178))	('EZH2', 'Gene', (21, 25))	('EZH2', 'Gene', '2146', (174, 178))	('EZH2', 'Gene', '2146', (21, 25))	('enhancement', 'PosReg', (125, 136))	('pUC-EZH2', 'Gene', (170, 178))	('expression', 'MPA', (228, 238))	('MRP1', 'Gene', '4363', (223, 227))	('cytotoxicity', 'Disease', (243, 255))	('miR-101-3p', 'Chemical', '-', (114, 124))	('cytotoxicity', 'Disease', 'MESH:D064420', (243, 255))	('EZH2', 'Gene', '2146', (106, 110))
141312	31258770	Compared with agomiR-101-3p + pUC-NC group, the IC50 of agomiR-101-3p + pUC-EZH2 group to CDDP raised significantly (Fig.4A, P<0.05), and the expression of MRP1 protein increased remarkably (Fig.4B, P<0.05).	('pUC-EZH2', 'Gene', '2146', (72, 80))	('agomiR-101-3p', 'Var', (56, 69))	('IC50', 'MPA', (48, 52))	('increased', 'PosReg', (169, 178))	('expression', 'MPA', (142, 152))	('raised', 'PosReg', (95, 101))	('MRP1', 'Gene', '4363', (156, 160))	('miR-101-3p', 'Chemical', '-', (59, 69))	('miR-101-3p', 'Chemical', '-', (17, 27))	('CDDP', 'Chemical', 'MESH:D002945', (90, 94))	('pUC-EZH2', 'Gene', (72, 80))	('MRP1', 'Gene', (156, 160))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))
141316	31258770	Our study firstly found miR-101-3p was low-expressed in CDDP resistant BUC patients and cell line, revealed the miR-101-3p expression was positively related to CDDP sensitivity of BUC.	('miR-101-3p', 'Var', (112, 122))	('expression', 'MPA', (123, 133))	('CDDP sensitivity', 'Disease', (160, 176))	('miR-101-3p', 'Chemical', '-', (24, 34))	('patients', 'Species', '9606', (75, 83))	('CDDP', 'Chemical', 'MESH:D002945', (56, 60))	('CDDP', 'Chemical', 'MESH:D002945', (160, 164))	('related', 'Reg', (149, 156))	('miR-101-3p', 'Chemical', '-', (112, 122))
141317	31258770	CDDP interferes with DNA replication, kills the fastest proliferating tumor cells, and is used widely in chemotherapy of many malignant cancers.	('CDDP', 'Chemical', 'MESH:D002945', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('DNA replication', 'CPA', (21, 36))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('DNA replication', 'biological_process', 'GO:0006260', ('21', '36'))	('malignant cancers', 'Disease', (126, 143))	('tumor', 'Disease', (70, 75))	('CDDP', 'Var', (0, 4))	('kills', 'NegReg', (38, 43))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('malignant cancers', 'Disease', 'MESH:D009369', (126, 143))	('interferes', 'NegReg', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
141318	31258770	Following experiment validated that miR-101-3p enhancement could inhibit the IC50 of T24/CDDP cells to CDDP, and promote the cytotoxicity induced by CDDP, which proved miR-101-3p played an important role in chemoresistance of BUC to CDDP.	('miR-101-3p', 'Chemical', '-', (36, 46))	('CDDP', 'Chemical', 'MESH:D002945', (89, 93))	('IC50', 'CPA', (77, 81))	('cytotoxicity', 'Disease', 'MESH:D064420', (125, 137))	('cytotoxicity', 'Disease', (125, 137))	('CDDP', 'Chemical', 'MESH:D002945', (233, 237))	('promote', 'PosReg', (113, 120))	('CDDP', 'Chemical', 'MESH:D002945', (103, 107))	('miR-101-3p', 'Chemical', '-', (168, 178))	('CDDP', 'Chemical', 'MESH:D002945', (149, 153))	('enhancement', 'PosReg', (47, 58))	('miR-101-3p', 'Var', (36, 46))	('inhibit', 'NegReg', (65, 72))
141319	31258770	Furthermore, the up-regulation of miR-101-3p also depressed the expression of MRP1 protein.	('miR-101-3p', 'Var', (34, 44))	('expression', 'MPA', (64, 74))	('miR-101-3p', 'Chemical', '-', (34, 44))	('depressed', 'NegReg', (50, 59))	('MRP1', 'Gene', '4363', (78, 82))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('regulation', 'biological_process', 'GO:0065007', ('20', '30'))	('up-regulation', 'PosReg', (17, 30))	('MRP1', 'Gene', (78, 82))
141321	31258770	Together, miR-101-3p advances CDDP sensitivity through silencing MRP1 expression, but the underlying mechanism is still unknown.	('CDDP', 'Chemical', 'MESH:D002945', (30, 34))	('silencing', 'NegReg', (55, 64))	('MRP1', 'Gene', '4363', (65, 69))	('miR-101-3p', 'Var', (10, 20))	('MRP1', 'Gene', (65, 69))	('miR-101-3p', 'Chemical', '-', (10, 20))	('expression', 'MPA', (70, 80))	('advances', 'PosReg', (21, 29))	('CDDP sensitivity', 'MPA', (30, 46))
141323	31258770	And, Hou Y reported miR-101-3p could regulate the proliferation of lung squamous carcinoma via targeting EZH2.	('miR-101-3p', 'Var', (20, 30))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (67, 90))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (67, 90))	('regulate', 'Reg', (37, 45))	('miR-101-3p', 'Chemical', '-', (20, 30))	('targeting', 'Reg', (95, 104))	('lung squamous carcinoma', 'Disease', (67, 90))	('proliferation', 'CPA', (50, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('EZH2', 'Gene', '2146', (105, 109))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (72, 90))	('EZH2', 'Gene', (105, 109))
141326	31258770	A series of following gain-of-function experiments, such as luciferase reporter assay and western blotting, proved EZH2 gene was the target gene of miR-101-3p.	('gain-of-function', 'PosReg', (22, 38))	('miR-101-3p', 'Var', (148, 158))	('EZH2', 'Gene', '2146', (115, 119))	('EZH2', 'Gene', (115, 119))	('miR-101-3p', 'Chemical', '-', (148, 158))
141327	31258770	Lv Y reported knockdown of EZH2 reduced the expression of MRP1 and advanced cisplatin sensitivity in lung adenocarcinoma.	('expression', 'MPA', (44, 54))	('MRP1', 'Gene', '4363', (58, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (101, 120))	('EZH2', 'Gene', (27, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('EZH2', 'Gene', '2146', (27, 31))	('lung adenocarcinoma', 'Disease', (101, 120))	('reduced', 'NegReg', (32, 39))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (101, 120))	('MRP1', 'Gene', (58, 62))	('cisplatin sensitivity', 'MPA', (76, 97))	('knockdown', 'Var', (14, 23))	('advanced', 'PosReg', (67, 75))
141328	31258770	To sum up, we speculate miR-101-3p might modulate the CDDP resistance of BUC cells through targeted silencing EZH2.	('silencing', 'NegReg', (100, 109))	('miR-101-3p', 'Var', (24, 34))	('CDDP resistance', 'CPA', (54, 69))	('miR-101-3p', 'Chemical', '-', (24, 34))	('EZH2', 'Gene', (110, 114))	('EZH2', 'Gene', '2146', (110, 114))	('CDDP', 'Chemical', 'MESH:D002945', (54, 58))	('modulate', 'Reg', (41, 49))
141329	31258770	To verify this hypothesis, knockdown of EZH2 by miR-101-3p enhancement was rescued by transfection with pUC-EZH2.	('pUC-EZH2', 'Gene', '2146', (104, 112))	('knockdown', 'Var', (27, 36))	('miR-101-3p', 'Var', (48, 58))	('pUC-EZH2', 'Gene', (104, 112))	('EZH2', 'Gene', (108, 112))	('miR-101-3p', 'Chemical', '-', (48, 58))	('EZH2', 'Gene', '2146', (108, 112))	('EZH2', 'Gene', (40, 44))	('EZH2', 'Gene', '2146', (40, 44))	('enhancement', 'PosReg', (59, 70))
141332	31258770	In summary, the expression of miR-101-3p is positively related to CDDP sensitivity of BUC, miR-101-3p advances sensitivity of BUC on CDDP through targeted silencing EZH2.	('silencing', 'NegReg', (155, 164))	('CDDP sensitivity', 'MPA', (66, 82))	('EZH2', 'Gene', (165, 169))	('EZH2', 'Gene', '2146', (165, 169))	('CDDP', 'Chemical', 'MESH:D002945', (66, 70))	('sensitivity', 'MPA', (111, 122))	('advances', 'PosReg', (102, 110))	('miR-101-3p', 'Var', (91, 101))	('CDDP', 'Chemical', 'MESH:D002945', (133, 137))	('related', 'Reg', (55, 62))	('miR-101-3p', 'Chemical', '-', (91, 101))	('miR-101-3p', 'Chemical', '-', (30, 40))
141333	29385995	Variant isoforms of CD44 involves acquisition of chemoresistance to cisplatin and has potential as a novel indicator for identifying a cisplatin-resistant population in urothelial cancer Cisplatin is the most commonly used chemotherapeutic agent in the treatment of patients with metastatic and/or recurrent urothelial cancer.	('chemoresistance to cisplatin', 'MPA', (49, 77))	('Variant', 'Var', (0, 7))	('patients', 'Species', '9606', (266, 274))	('metastatic', 'Disease', (280, 290))	('urothelial cancer', 'Disease', 'MESH:D014523', (169, 186))	('Cisplatin', 'Chemical', 'MESH:D002945', (187, 196))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('acquisition', 'PosReg', (34, 45))	('CD44', 'Gene', '960', (20, 24))	('urothelial cancer', 'Disease', 'MESH:D014523', (308, 325))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('CD44', 'Gene', (20, 24))	('urothelial cancer', 'Disease', (169, 186))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('urothelial cancer', 'Disease', (308, 325))
141340	29385995	Multivariate analyses revealed that CD44v9 positivity was an independent risk factor of cancer-specific survival (P = 0.024, hazard ratio = 5.16) in urothelial cancer patients who had recurrence and/or metastasis and received cisplatin-based chemotherapy.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('rat', 'Species', '10116', (132, 135))	('urothelial cancer', 'Disease', 'MESH:D014523', (149, 166))	('CD44', 'Gene', (36, 40))	('cancer', 'Disease', (160, 166))	('patients', 'Species', '9606', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('urothelial cancer', 'Disease', (149, 166))	('positivity', 'Var', (43, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (226, 235))	('metastasis', 'CPA', (202, 212))	('CD44', 'Gene', '960', (36, 40))
141341	29385995	The expression of CD44v8-10 and xCT was stronger in T24PR cells than in T24 cells.	('xCT', 'Gene', '23657', (32, 35))	('expression', 'MPA', (4, 14))	('CD44', 'Gene', '960', (18, 22))	('T24PR', 'Var', (52, 57))	('xCT', 'Gene', (32, 35))	('stronger', 'PosReg', (40, 48))	('CD44', 'Gene', (18, 22))
141342	29385995	The amount of intracellular glutathione was significantly higher in T24PR cells than in T24 cells (p < 0.001), and intracellular reactive oxygen species production by cisplatin was lower in T24PR cells than in T24 cells.	('T24PR', 'Var', (190, 195))	('amount of intracellular glutathione', 'MPA', (4, 39))	('intracellular reactive oxygen species production', 'MPA', (115, 163))	('lower', 'NegReg', (181, 186))	('glutathione', 'Chemical', 'MESH:D005978', (28, 39))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (129, 152))	('T24PR', 'Var', (68, 73))	('intracellular', 'cellular_component', 'GO:0005622', ('115', '128'))	('intracellular', 'cellular_component', 'GO:0005622', ('14', '27'))	('higher', 'PosReg', (58, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))
141343	29385995	Furthermore, the knockdown of CD44v8-10 by siRNA led to the recovery of cisplatin sensitivity in T24PR cells.	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('recovery', 'MPA', (60, 68))	('CD44', 'Gene', '960', (30, 34))	('cisplatin sensitivity', 'MPA', (72, 93))	('CD44', 'Gene', (30, 34))	('knockdown', 'Var', (17, 26))
141353	29385995	CD44 exists in numerous variant isoforms generated through the alternative mRNA splicing of different combinations of 10 exons (v1-10), and the variant isoforms of CD44 containing v8-v10 (CD44v8-10) have been identified as new cell surface markers for CSCs.	('CD44', 'Gene', '960', (188, 192))	('cell surface', 'cellular_component', 'GO:0009986', ('227', '239'))	('mRNA splicing', 'biological_process', 'GO:0006371', ('75', '88'))	('mRNA splicing', 'biological_process', 'GO:0000373', ('75', '88'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('75', '88'))	('mRNA splicing', 'biological_process', 'GO:0000372', ('75', '88'))	('CD44', 'Gene', (188, 192))	('CD44', 'Gene', '960', (164, 168))	('CD44', 'Gene', '960', (0, 4))	('mRNA splicing', 'biological_process', 'GO:0000394', ('75', '88'))	('v8-v10', 'Var', (180, 186))	('CSCs', 'Disease', (252, 256))	('CD44', 'Gene', (164, 168))	('CD44', 'Gene', (0, 4))	('mRNA splicing', 'biological_process', 'GO:0000374', ('75', '88'))	('rat', 'Species', '10116', (45, 48))
141407	29385995	Regarding cellular GSH measurements, 1 x 104 T24 or T24PR cells in 100 muL of culture medium were plated on each well of a 96-multiwell white plate, allowed to attach for 24 h, and each well was then washed three times with PBS.	('PBS', 'Gene', '1131', (224, 227))	('PBS', 'Gene', (224, 227))	('GSH', 'Chemical', 'MESH:D005978', (19, 22))	('T24PR', 'Var', (52, 57))
141434	29385995	The signal intensity of CD44v8-10 protein expression was stronger in T24PR cells that acquired resistance to CDDP than in their corresponding parent cells, T24 (p < 0.001).	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('stronger', 'PosReg', (57, 65))	('protein', 'Protein', (34, 41))	('expression', 'MPA', (42, 52))	('CDDP', 'Chemical', '-', (109, 113))	('signal intensity', 'MPA', (4, 20))	('CD44', 'Gene', '960', (24, 28))	('T24PR', 'Var', (69, 74))	('CD44', 'Gene', (24, 28))
141436	29385995	The signal intensity of xCT protein expression was also stronger in T24PR cells than in T24 cells (p < 0.001).	('xCT', 'Gene', (24, 27))	('signal intensity', 'MPA', (4, 20))	('T24PR', 'Var', (68, 73))	('xCT', 'Gene', '23657', (24, 27))	('stronger', 'PosReg', (56, 64))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
141439	29385995	However, significant cytotoxic reduction was only observed in T24PR cells treated with CDDP at a concentration of 5muM or higher as compared to those treated with the vehicle control.	('CDDP', 'Chemical', '-', (87, 91))	('reduction', 'NegReg', (31, 40))	('muM', 'Gene', '56925', (115, 118))	('CDDP', 'Var', (87, 91))	('muM', 'Gene', (115, 118))	('rat', 'Species', '10116', (104, 107))
141442	29385995	Intracellular GSH levels were significantly higher in T24PR cells than in T24 cells (p < 0.001, Fig.	('Intracellular GSH levels', 'MPA', (0, 24))	('Intracellular', 'cellular_component', 'GO:0005622', ('0', '13'))	('T24PR', 'Var', (54, 59))	('higher', 'PosReg', (44, 50))	('GSH', 'Chemical', 'MESH:D005978', (14, 17))
141445	29385995	In order to determine whether the knockdown of CD44v8-10 expression affects CDDP resistance in T24PR cells, we evaluated the cytotoxic effects of CDDP in T24PR treated with siRNA specific for CD44v8-10.	('CDDP', 'Chemical', '-', (146, 150))	('CD44', 'Gene', '960', (192, 196))	('CD44', 'Gene', '960', (47, 51))	('CDDP resistance', 'MPA', (76, 91))	('CDDP', 'Chemical', '-', (76, 80))	('affects', 'Reg', (68, 75))	('CD44', 'Gene', (192, 196))	('CD44', 'Gene', (47, 51))	('knockdown', 'Var', (34, 43))
141455	29385995	Our results revealed that patients with positive CD44v9 expression had significantly lower CSS rates and thus, CD44v9 positivity in tumor specimens was identified as an independent predictor for a poor prognosis in UC patients who received CDDP-based chemotherapy.	('CD44', 'Gene', (111, 115))	('positive', 'Var', (40, 48))	('CDDP', 'Chemical', '-', (240, 244))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('lower', 'NegReg', (85, 90))	('patients', 'Species', '9606', (218, 226))	('CSS rates', 'CPA', (91, 100))	('rat', 'Species', '10116', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('patients', 'Species', '9606', (26, 34))	('CD44', 'Gene', '960', (49, 53))	('CSS', 'Chemical', '-', (91, 94))	('tumor', 'Disease', (132, 137))	('CD44', 'Gene', '960', (111, 115))	('CD44', 'Gene', (49, 53))
141461	29385995	We evaluated CD44v8-10 expression levels in a T24PR cell line that acquired resistance to CDDP in order to elucidate the involvement of CD44v8-10 in the process of obtaining CDDP resistance, and found that CD44v8-10 expression levels were higher in T24PR cells than those in their parent cell line, T24.	('expression levels', 'MPA', (216, 233))	('T24PR', 'Var', (249, 254))	('CDDP', 'Chemical', '-', (90, 94))	('higher', 'PosReg', (239, 245))	('CD44', 'Gene', '960', (13, 17))	('CD44', 'Gene', '960', (136, 140))	('CD44', 'Gene', '960', (206, 210))	('CD44', 'Gene', (136, 140))	('CD44', 'Gene', (13, 17))	('CD44', 'Gene', (206, 210))	('CDDP', 'Chemical', '-', (174, 178))
141462	29385995	Furthermore, cytotoxicity for CDDP was almost 5-fold lower in T24PR cells than in T24 cells.	('cytotoxicity', 'Disease', (13, 25))	('T24PR', 'Var', (62, 67))	('cytotoxicity', 'Disease', 'MESH:D064420', (13, 25))	('CDDP', 'Chemical', '-', (30, 34))	('lower', 'NegReg', (53, 58))
141464	29385995	Our results revealed that the expression of xCT was higher in T24PR cells in which CD44v8-10 expression was highly elevated.	('expression', 'MPA', (30, 40))	('elevated', 'PosReg', (115, 123))	('xCT', 'Gene', '23657', (44, 47))	('CD44', 'Gene', (83, 87))	('CD44', 'Gene', '960', (83, 87))	('expression', 'MPA', (93, 103))	('T24PR', 'Var', (62, 67))	('higher', 'PosReg', (52, 58))	('xCT', 'Gene', (44, 47))
141465	29385995	Previous studies indicated that the expression of xCT was associated with tumor recurrence and poor survival in patients with various types of solid malignancies, including colorectal cancer, hepatocellular cancer, and esophageal squamous cell cancer.	('hepatocellular cancer', 'Disease', 'MESH:D006528', (192, 213))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('esophageal squamous cell cancer', 'Disease', (219, 250))	('solid malignancies', 'Disease', 'MESH:D009369', (143, 161))	('tumor', 'Disease', (74, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (173, 190))	('solid malignancies', 'Disease', (143, 161))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (230, 250))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('expression', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('xCT', 'Gene', '23657', (50, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (173, 190))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (219, 250))	('colorectal cancer', 'Disease', (173, 190))	('associated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('poor', 'NegReg', (95, 99))	('patients', 'Species', '9606', (112, 120))	('hepatocellular cancer', 'Disease', (192, 213))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (192, 213))	('xCT', 'Gene', (50, 53))
141467	29385995	We then evaluated whether the knockdown of CD44v8-10 improves CDDP chemosensitivity through the suppression of xCT in T24PR cells, and found down-regulated expression of CD44v8-10 and xCT as well as the recovery of CDDP chemosensitivity in T24PR cells transfected with siRNA specific for CD44v8-10.	('CDDP', 'Chemical', '-', (62, 66))	('CD44', 'Gene', (170, 174))	('suppression', 'NegReg', (96, 107))	('CD44', 'Gene', '960', (43, 47))	('CD44', 'Gene', '960', (288, 292))	('expression', 'MPA', (156, 166))	('improves', 'PosReg', (53, 61))	('CD44', 'Gene', (288, 292))	('CD44', 'Gene', (43, 47))	('CDDP', 'Chemical', '-', (215, 219))	('xCT', 'Gene', (111, 114))	('down-regulated', 'NegReg', (141, 155))	('knockdown', 'Var', (30, 39))	('CDDP chemosensitivity', 'MPA', (62, 83))	('xCT', 'Gene', (184, 187))	('CD44', 'Gene', '960', (170, 174))	('xCT', 'Gene', '23657', (111, 114))	('xCT', 'Gene', '23657', (184, 187))
141527	23928991	Twenty-four percent of the remaining GOF mutants (29 out of 122) had macroscopically discernable tumors within the bladder lumen; 11 had a single tumor and 18 had multi-foci tumors (Fig.	('tumor', 'Disease', (146, 151))	('multi-foci tumors', 'Disease', (163, 180))	('tumors', 'Disease', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumors', 'Disease', (174, 180))	('tumor', 'Disease', (97, 102))	('multi-foci tumors', 'Disease', 'MESH:C565785', (163, 180))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('mutants', 'Var', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('men', 'Species', '9606', (125, 128))	('GOF', 'PosReg', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
141531	23928991	Intriguingly, we noticed a striking sex difference in the rate of tumorigenesis, as we found that 45% (27/60) male GOF mice developed tumors, compared to a mere 3% (2/62) in females (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mice', 'Species', '10090', (119, 123))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Disease', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('GOF', 'Var', (115, 118))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (134, 139))
141543	23928991	The GOF urothelia were highly proliferative as 33% of urothelial cells were Ki67-positive, compared to near-zero in controls (Supplemental Fig.	('GOF', 'Var', (4, 7))	('Ki67-positive', 'Var', (76, 89))	('men', 'Species', '9606', (132, 135))
141554	23928991	Moreover, these cells showed distinct signaling activity, evidenced by p-S6 expression, an established target of the mTOR pathway (Supplemental Fig.	('mTOR', 'Gene', (117, 121))	('mTOR', 'Gene', '2475', (117, 121))	('signaling activity', 'MPA', (38, 56))	('p-S6', 'Var', (71, 75))	('men', 'Species', '9606', (137, 140))	('signaling', 'biological_process', 'GO:0023052', ('38', '47'))
141578	23928991	Therefore, we speculate that the dysplastic cells in the GOF urothelium with nuclear AR expression might express higher level of beta-catenin protein compared to their neighboring cells.	('nuclear AR expression', 'Var', (77, 98))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('higher', 'PosReg', (113, 119))	('dysplastic', 'Disease', (33, 43))	('dysplastic', 'Disease', 'MESH:D004416', (33, 43))	('level of beta-catenin protein', 'MPA', (120, 149))
141584	23928991	To determine whether abnormally expressed AR plays a role in promoting beta-catenin-induced tumorigenesis in male mice, we castrated GOF male mice 15 days after starting Dox treatment and determined its effect on tumor development (Fig.	('tumor', 'Disease', (213, 218))	('men', 'Species', '9606', (179, 182))	('abnormally', 'Var', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('men', 'Species', '9606', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mice', 'Species', '10090', (142, 146))	('Dox', 'Chemical', 'MESH:D004318', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('mice', 'Species', '10090', (114, 118))	('tumor', 'Disease', (92, 97))	('promoting', 'PosReg', (61, 70))	('beta-catenin-induced', 'Protein', (71, 91))
141587	23928991	These results indicated that misregulation of androgen-AR signaling contributed to beta-catenin-induced male-specific bladder tumorigenesis.	('misregulation', 'Var', (29, 42))	('bladder tumor', 'Disease', 'MESH:D001749', (118, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('beta-catenin-induced', 'Protein', (83, 103))	('bladder tumor', 'Phenotype', 'HP:0009725', (118, 131))	('androgen-AR signaling', 'MPA', (46, 67))	('bladder tumor', 'Disease', (118, 131))	('signaling', 'biological_process', 'GO:0023052', ('58', '67'))
141617	23928991	It is possible that aberrant expression of these genes might have contributed to enhanced bladder tumorigenesis in males.	('bladder tumor', 'Disease', 'MESH:D001749', (90, 103))	('enhanced', 'PosReg', (81, 89))	('bladder tumor', 'Phenotype', 'HP:0009725', (90, 103))	('aberrant', 'Var', (20, 28))	('bladder tumor', 'Disease', (90, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('expression', 'MPA', (29, 39))
141635	23928991	In addition, through histological analyses at sequential time points, we found that the exophytic bladder tumors developed in the GOF mutant were indeed evolved from small but highly proliferative clusters of dysplastic KRT5+;KRT7- cells (Fig.	('dysplastic', 'Disease', (209, 219))	('bladder tumors', 'Disease', 'MESH:D001749', (98, 112))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('KRT7', 'Gene', '3855', (226, 230))	('dysplastic', 'Disease', 'MESH:D004416', (209, 219))	('bladder tumors', 'Phenotype', 'HP:0009725', (98, 112))	('KRT7', 'Gene', (226, 230))	('bladder tumors', 'Disease', (98, 112))	('KRT5', 'Gene', (220, 224))	('bladder tumor', 'Phenotype', 'HP:0009725', (98, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('KRT5', 'Gene', '3852', (220, 224))	('mutant', 'Var', (134, 140))
141644	23928991	On the other hand, liganded-AR can facilitate nuclear translocation of beta-catenin and its binding to AR responsive promoter elements.	('binding', 'Interaction', (92, 99))	('facilitate', 'PosReg', (35, 45))	('binding', 'molecular_function', 'GO:0005488', ('92', '99'))	('nuclear translocation', 'MPA', (46, 67))	('beta-catenin', 'Protein', (71, 83))	('men', 'Species', '9606', (129, 132))	('liganded-AR', 'Var', (19, 30))
141707	31737562	During the development of tumor immunity, tumors show many alterations, including suppression of identity characteristics and stress, induction of immune cell apoptosis, attraction of Tregs, and neutralization of complement.	('identity characteristics', 'CPA', (97, 121))	('tumor', 'Disease', (42, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('159', '168'))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('attraction', 'CPA', (170, 180))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('stress', 'CPA', (126, 132))	('apoptosis', 'biological_process', 'GO:0006915', ('159', '168'))	('neutralization', 'Var', (195, 209))	('Tregs', 'CPA', (184, 189))	('immune cell apoptosis', 'CPA', (147, 168))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('suppression', 'NegReg', (82, 93))
141821	31702432	Furthermore, in a retrospective multicenter study, neoadjuvant aMVAC was associated with a 28% pCR rate compared to 15% for neoadjuvant cisplatin and gemcitabine.	('pCR', 'Disease', (95, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('neoadjuvant', 'Var', (51, 62))	('gemcitabine', 'Chemical', 'MESH:C056507', (150, 161))	('aMVAC', 'Chemical', '-', (63, 68))
141826	31702432	The Cancer Genome Atlas (TCGA) and other annotated bladder cancer sequencing datasets show in bladder cancer, tumors inof the luminal-papillary subset have high FGFR3 mutations, fusions and amplifications, and low chemotherapy response.	('bladder cancer', 'Disease', (51, 65))	('tumors inof', 'Disease', 'MESH:D009369', (110, 121))	('luminal', 'Chemical', 'MESH:D010634', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (167, 176))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('161', '165'))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('amplifications', 'Var', (190, 204))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('Cancer', 'Disease', (4, 10))	('fusions', 'Var', (178, 185))	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('FGFR3', 'Gene', (161, 166))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('tumors inof', 'Disease', (110, 121))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('FGFR3', 'Gene', '2261', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('bladder cancer', 'Disease', 'MESH:D001749', (51, 65))
141827	31702432	UTUC has higher FGFR3 aberrations rate than bladder cancer, and therefore possibly more of the papillary luminal subset unlikely to respond to chemotherapy.	('FGFR3', 'Gene', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (44, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('bladder cancer', 'Disease', 'MESH:D001749', (44, 58))	('bladder cancer', 'Disease', (44, 58))	('aberrations', 'Var', (22, 33))	('luminal', 'Chemical', 'MESH:D010634', (105, 112))	('FGFR3', 'Gene', '2261', (16, 21))	('higher', 'PosReg', (9, 15))
141834	31702432	Ongoing perioperative Perioperative practice informing urothelial studies \ (NCT01261728, NCT02876861, NCT02969083), and a chemo-immunotherapy NAC UTUC intergroup trial is in late-stage planning.	('NCT01261728', 'Var', (77, 88))	('NAC', 'Gene', (143, 146))	('NAC', 'Gene', '7504', (143, 146))	('NCT02876861', 'Var', (90, 101))	('NAC', 'cellular_component', 'GO:0005854', ('143', '146'))
141839	28599410	These include reduced function of pro-apoptotic proteins, mutations of tubulin and overexpression of the drug transporter adenosine 5'-triphosphate-binding cassette transporter subfamily B, member 1 (ABCB1).	('mutations', 'Var', (58, 67))	('tubulin', 'Protein', (71, 78))	('reduced', 'NegReg', (14, 21))	('binding', 'molecular_function', 'GO:0005488', ('148', '155'))	('ABCB1', 'Gene', '5243', (200, 205))	('overexpression', 'PosReg', (83, 97))	('ABCB1', 'Gene', (200, 205))	('function', 'MPA', (22, 30))
141846	28599410	Additionally, small molecules may overcome resistance to anticancer drugs that are substrates of ABCB1.	('small', 'Var', (14, 19))	('overcome', 'PosReg', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('ABCB1', 'Gene', (97, 102))	('ABCB1', 'Gene', '5243', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
141851	28599410	Nab-paclitaxel achieved a marked overall response rate of 27.7% in patients with metastatic urothelial cancer of the bladder who were pretreated with cisplatin, and may be more effective than conventional paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('urothelial cancer', 'Disease', (92, 109))	('cancer of the bladder', 'Phenotype', 'HP:0009725', (103, 124))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('patients', 'Species', '9606', (67, 75))	('Nab-paclitaxel', 'Var', (0, 14))	('urothelial cancer', 'Disease', 'MESH:D014523', (92, 109))	('paclitaxel', 'Chemical', 'MESH:D017239', (205, 215))	('metastatic urothelial cancer of the bladder', 'Phenotype', 'HP:0006740', (81, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))
141859	28599410	Resistance to nab-paclitaxel may be overcome by inhibitors of ABCB1 transporters, including cabozantinib and crizotinib, two FDA-approved small molecule inhibitors being tested at present as second-line therapy for urothelial carcinoma (NCT nos., 02612194, 01688999 and 02496208).	('urothelial carcinoma', 'Disease', (215, 235))	('crizotinib', 'Chemical', 'MESH:D000077547', (109, 119))	('ABCB1', 'Gene', (62, 67))	('02612194', 'Var', (247, 255))	('ABCB1', 'Gene', '5243', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('inhibitors', 'Var', (48, 58))	('02496208', 'Var', (270, 278))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (215, 235))	('cabozantinib', 'Chemical', 'MESH:C558660', (92, 104))	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (14, 28))	('01688999', 'Var', (257, 265))
141863	28599410	Drug-resistant sublines were established by continuous exposure to increasing drug concentrations as described previously and are part of the Resistant Cancer Cell Line collection (Institute of Medical Virology, University Hospital Frankfurt, Frankfurt, Germany): T24rGEMCI20 (gemcitabine-resistant, 20 ng gemcitabine/ml), T24rVBL20 (vinblastine-resistant, 20 ng vinblastine/ml), TCC-SUPrGEMCI20 and TCC-SUPrVBL20 (vinblastine-resistant, 20 ng vinblastine/ml).	('Cancer', 'Phenotype', 'HP:0002664', (152, 158))	('TCC', 'cellular_component', 'GO:0005579', ('400', '403'))	('T24rGEMCI20', 'Var', (264, 275))	('TCC-SUPrVBL20', 'Gene', (400, 413))	('vinblastine', 'Chemical', 'MESH:D014747', (334, 345))	('gemcitabine', 'Chemical', 'MESH:C056507', (306, 317))	('TCC', 'cellular_component', 'GO:0005579', ('380', '383'))	('vinblastine', 'Chemical', 'MESH:D014747', (363, 374))	('vinblastine', 'Chemical', 'MESH:D014747', (444, 455))	('SUPrGEMCI20', 'Gene', '9709', (384, 395))	('SUPrGEMCI20', 'Gene', (384, 395))	('T24rVBL20', 'Var', (323, 332))	('vinblastine', 'Chemical', 'MESH:D014747', (415, 426))	('gemcitabine', 'Chemical', 'MESH:C056507', (277, 288))
141892	28599410	Acquired taxane resistance is considered to be mediated by multiple mechanisms, including overexpression of drug pumps such as ABCB1, variations in tubulin structure, altered signal transduction and apoptotic pathways.	('variations', 'Var', (134, 144))	('taxane', 'Chemical', 'MESH:C080625', (9, 15))	('signal transduction', 'biological_process', 'GO:0007165', ('175', '194'))	('apoptotic', 'CPA', (199, 208))	('ABCB1', 'Gene', (127, 132))	('ABCB1', 'Gene', '5243', (127, 132))	('altered', 'Reg', (167, 174))	('overexpression', 'PosReg', (90, 104))	('signal transduction', 'MPA', (175, 194))	('tubulin structure', 'Protein', (148, 165))
141910	28599410	Therefore, the reason for ABCB1-mediated resistance to nab-paclitaxel may be the aforementioned dissociation of paclitaxel from albumin subsequent to endocytosis, and nab-paclitaxel may cause the same cytotoxicity to tumor cells as unbound paclitaxel.	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (55, 69))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('endocytosis', 'biological_process', 'GO:0006897', ('150', '161'))	('ABCB1', 'Gene', (26, 31))	('paclitaxel', 'Chemical', 'MESH:D017239', (240, 250))	('ABCB1', 'Gene', '5243', (26, 31))	('cytotoxicity', 'Disease', 'MESH:D064420', (201, 213))	('dissociation of paclitaxel', 'MPA', (96, 122))	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (167, 181))	('nab-paclitaxel', 'Var', (167, 181))	('paclitaxel', 'Chemical', 'MESH:D017239', (59, 69))	('paclitaxel', 'Chemical', 'MESH:D017239', (112, 122))	('albumin subsequent to endocytosis', 'MPA', (128, 161))	('paclitaxel', 'Chemical', 'MESH:D017239', (171, 181))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('cause', 'Reg', (186, 191))	('cytotoxicity', 'Disease', (201, 213))
141913	28599410	At present, several clinical trials are ongoing to evaluate the clinical role of ABCB1 inhibitors to prevent drug resistance.	('ABCB1', 'Gene', (81, 86))	('ABCB1', 'Gene', '5243', (81, 86))	('drug resistance', 'biological_process', 'GO:0042493', ('109', '124'))	('drug resistance', 'MPA', (109, 124))	('drug resistance', 'Phenotype', 'HP:0020174', (109, 124))	('inhibitors', 'Var', (87, 97))	('drug resistance', 'biological_process', 'GO:0009315', ('109', '124'))
141928	28599410	The data of the present study suggest that the previously identified beneficial clinical effects of nab-paclitaxel compared with those of paclitaxel are possibly due to improved pharmacokinetics and decreased systemic toxicity.	('toxicity', 'Disease', (218, 226))	('paclitaxel', 'Chemical', 'MESH:D017239', (104, 114))	('paclitaxel', 'Chemical', 'MESH:D017239', (138, 148))	('decreased', 'NegReg', (199, 208))	('systemic', 'MPA', (209, 217))	('improved', 'PosReg', (169, 177))	('toxicity', 'Disease', 'MESH:D064420', (218, 226))	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (100, 114))	('nab-paclitaxel', 'Var', (100, 114))	('pharmacokinetics', 'MPA', (178, 194))
141931	27994654	Overexpression of p53 is associated with poor prognosis in UC.	('p53', 'Gene', '7157', (18, 21))	('p53', 'Gene', (18, 21))	('Overexpression', 'Var', (0, 14))
141940	27994654	Low expression of RNF128 was an adverse prognosticator for DSS (UTUC, p<0.0001; UBUC, p<0.0001) and MeFS (UTUC, p<0.0001; UBUC, p=0.0002).	('RNF128', 'Gene', (18, 24))	('UBUC', 'Chemical', '-', (80, 84))	('MeFS', 'Disease', (100, 104))	('DSS', 'Chemical', '-', (59, 62))	('DSS', 'Disease', (59, 62))	('RNF128', 'Gene', '79589', (18, 24))	('UBUC', 'Chemical', '-', (122, 126))	('Low expression', 'Var', (0, 14))
141971	27994654	Pre-designed TaqMan probes targeting RNF128 (Hs00226053_m1) were used to measure the mRNA levels with an ABI StepOnePlus  System as described in our previous studies.	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('Hs00226053_m1', 'Var', (45, 58))	('mRNA levels', 'MPA', (85, 96))	('RNF128', 'Gene', (37, 43))	('RNF128', 'Gene', '79589', (37, 43))
141999	27994654	Univariate analysis indicated that poor DSS was significantly associated with tumor location (p=00079), multifocality (p=0.0026), higher pT status (p<0.0001), nodal metastasis (p<0.0001), high histological grade (p= 0.0215), vascular invasion (p<0.0001) and perineural invasion (p<0.0001) in UTUCs.	('nodal metastasis', 'CPA', (159, 175))	('multifocality', 'Disease', (104, 117))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('vascular invasion', 'CPA', (225, 242))	('high histological grade', 'CPA', (188, 211))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('poor', 'Var', (35, 39))	('DSS', 'Chemical', '-', (40, 43))	('perineural invasion', 'CPA', (258, 277))
142002	27994654	In the UBUC group, univariate analysis showed that poor DSS was significantly associated with higher pT status (p<0.0001), nodal metastasis (p=0.0002), high histological grade (p= 0.0013), vascular invasion (p=0.0024), perineural invasion (p<0.0001) and high mitotic rate (p<0.0001).	('pT status', 'CPA', (101, 110))	('poor DSS', 'Var', (51, 59))	('high histological grade', 'CPA', (152, 175))	('UBUC', 'Chemical', '-', (7, 11))	('high mitotic rate', 'CPA', (254, 271))	('DSS', 'Chemical', '-', (56, 59))	('nodal metastasis', 'CPA', (123, 139))	('perineural invasion', 'CPA', (219, 238))	('higher', 'PosReg', (94, 100))	('vascular invasion', 'CPA', (189, 206))
142014	27994654	These results are consistent with those of Chen et al.. Their unpublished data showed that RNF128 expression appeared to be downregulated in oral cancers through epigenetic modifications.	('oral cancers', 'Disease', (141, 153))	('oral cancers', 'Disease', 'MESH:D009062', (141, 153))	('RNF128', 'Gene', '79589', (91, 97))	('downregulated', 'NegReg', (124, 137))	('RNF128', 'Gene', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('epigenetic modifications', 'Var', (162, 186))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('expression', 'MPA', (98, 108))
142020	27994654	Alterations of the TP53 tumor suppressor gene play a central role in the carcinogenesis of many tumors, including UC.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (24, 29))	('Alterations', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (96, 101))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('role', 'Reg', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('carcinogenesis of many tumors', 'Disease', 'MESH:D063646', (73, 102))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('carcinogenesis of many tumors', 'Disease', (73, 102))
142022	27994654	TP53 mutations result in a series of downstream effects, including decreased expression of p21.	('expression', 'MPA', (77, 87))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('p21', 'Gene', '1026', (91, 94))	('mutations', 'Var', (5, 14))	('p21', 'Gene', (91, 94))	('decreased', 'NegReg', (67, 76))
142023	27994654	TP53 mutations in UC are also related to higher tumor grade, advanced stage, and worse disease outcomes.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', (48, 53))	('related', 'Reg', (30, 37))	('mutations', 'Var', (5, 14))	('advanced stage', 'CPA', (61, 75))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
142026	27994654	These results suggest that downregulation of RNF128 provides a growth advantage during UC tumorigenesis via p53 inactivation.	('inactivation', 'Var', (112, 124))	('RNF128', 'Gene', (45, 51))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('RNF128', 'Gene', '79589', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('downregulation', 'NegReg', (27, 41))	('growth advantage', 'CPA', (63, 79))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
142033	27994654	TP53 mutation and MDM2 amplification were mutually exclusive events in the tumorigenesis of UC, both were correlated with greater recurrence and lower survival rate.	('greater', 'PosReg', (122, 129))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('survival rate', 'CPA', (151, 164))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('MDM2', 'Gene', '4193', (18, 22))	('lower', 'NegReg', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('MDM2', 'Gene', (18, 22))	('mutation', 'Var', (5, 13))	('tumor', 'Disease', (75, 80))
142037	27994654	Deregulated cell-cycle control and alterations in the ubiquitylation of cell-cycle regulators such as E3 ubiquitin ligases might lead to uncontrolled cell proliferation as well as genomic instability and have been shown to be implicated in many human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (251, 263))	('E3 ubiquitin ligases', 'Protein', (102, 122))	('ubiquitylation', 'MPA', (54, 68))	('alterations', 'Reg', (35, 46))	('Deregulated', 'Var', (0, 11))	('lead to', 'Reg', (129, 136))	('cell-cycle control', 'CPA', (12, 30))	('malignancies', 'Disease', (251, 263))	('cell-cycle', 'biological_process', 'GO:0007049', ('72', '82'))	('genomic instability', 'CPA', (180, 199))	('ubiquitin', 'molecular_function', 'GO:0031386', ('105', '114'))	('human', 'Species', '9606', (245, 250))	('cell proliferation', 'biological_process', 'GO:0008283', ('150', '168'))	('implicated', 'Reg', (226, 236))	('uncontrolled', 'MPA', (137, 149))	('cell-cycle control', 'biological_process', 'GO:1901987', ('12', '30'))
142050	27994654	Further evaluation to elucidate the biological significance of dysregulated RNF128 expression in UC is needed to explore the potential of RNF128-targeted therapy in UC.	('dysregulated', 'Var', (63, 75))	('RNF128', 'Gene', (76, 82))	('RNF128', 'Gene', (138, 144))	('RNF128', 'Gene', '79589', (76, 82))	('RNF128', 'Gene', '79589', (138, 144))
142054	27326411	While apoptosis deregulation has long been an established pathway for cancer progression, nonapoptotic pathways have gained prominence of late.	('apoptosis', 'biological_process', 'GO:0006915', ('6', '15'))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('deregulation', 'Var', (16, 28))	('apoptosis', 'CPA', (6, 15))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('6', '15'))
142091	27326411	LC3 reactivity and SLS concentration was higher in HG NMIBC than in LG MIBC, and more importantly, was significantly higher in MIBC.	('LC3', 'Gene', '84557', (0, 3))	('MIBC', 'Chemical', '-', (71, 75))	('MIBC', 'Chemical', '-', (127, 131))	('HG NMIBC', 'Var', (51, 59))	('LC3', 'Gene', (0, 3))	('SLS', 'Disease', 'MESH:D016111', (19, 22))	('rat', 'Species', '10116', (30, 33))	('SLS', 'Disease', (19, 22))	('MIBC', 'Disease', (127, 131))	('higher', 'PosReg', (41, 47))	('MIBC', 'Chemical', '-', (55, 59))	('higher', 'PosReg', (117, 123))
142093	27326411	Autophagy inhibition with Baf (bafilomycin) A1 or knockdown of Atg-7 resulted in cell death in those same cell lines, due to apoptosis induction.	('Atg-7', 'Gene', (63, 68))	('Autophagy', 'biological_process', 'GO:0006914', ('0', '9'))	('cell death', 'CPA', (81, 91))	('Autophagy', 'biological_process', 'GO:0016236', ('0', '9'))	('knockdown', 'Var', (50, 59))	('bafilomycin', 'Chemical', '-', (31, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('125', '134'))	('apoptosis', 'biological_process', 'GO:0006915', ('125', '134'))	('Baf', 'Chemical', '-', (26, 29))	('apoptosis', 'CPA', (125, 134))	('Atg-7', 'Gene', '10533', (63, 68))	('Autophagy', 'CPA', (0, 9))	('cell death', 'biological_process', 'GO:0008219', ('81', '91'))
142102	27326411	SMYD3 inhibition markedly decreased the activation of autophagy in bladder cancer cell lines as well.	('SMYD3', 'Gene', (0, 5))	('autophagy', 'biological_process', 'GO:0006914', ('54', '63'))	('SMYD3', 'Gene', '64754', (0, 5))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('autophagy', 'CPA', (54, 63))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('inhibition', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('decreased', 'NegReg', (26, 35))	('autophagy', 'biological_process', 'GO:0016236', ('54', '63'))
142124	27326411	Monocytes previously exposed to BCG had a much higher cytokine release after the B. burgdorferi exposure than those pretreated with placebo.	('BCG', 'Species', '33892', (32, 35))	('higher', 'PosReg', (47, 53))	('exposure', 'Var', (96, 104))	('cytokine release', 'MPA', (54, 70))	('B. burgdorferi', 'Species', '139', (81, 95))
142126	27326411	Specific single nucleotide polymorphisms were identified in autophagy-related genes Atg2B and Atg5 that negatively influenced trained immunity in response to BCG, which correlated to a decrease in autophagosome production in the monocytes.	('autophagy', 'biological_process', 'GO:0016236', ('60', '69'))	('Atg2B', 'Gene', (84, 89))	('negatively', 'NegReg', (104, 114))	('autophagy', 'biological_process', 'GO:0006914', ('60', '69'))	('single nucleotide polymorphisms', 'Var', (9, 40))	('decrease', 'NegReg', (185, 193))	('Atg5', 'Gene', (94, 98))	('BCG', 'Species', '33892', (158, 161))	('autophagosome production in the monocytes', 'CPA', (197, 238))	('autophagosome', 'cellular_component', 'GO:0005776', ('197', '210'))	('Atg2B', 'Gene', '55102', (84, 89))	('trained immunity', 'CPA', (126, 142))	('influenced', 'Reg', (115, 125))
142127	27326411	More importantly, they found that in a cohort of 192 NMIBC patients treated with at least six instillations of BCG (equivalent to an induction course), patients that carry one or two C alleles for the rs3759601 Atg2B mutation showed increased risk of recurrence and progression.	('progression', 'CPA', (266, 277))	('MIBC', 'Chemical', '-', (54, 58))	('BCG', 'Species', '33892', (111, 114))	('rs3759601', 'Var', (201, 210))	('rs3759601', 'Mutation', 'rs3759601', (201, 210))	('Atg2B', 'Gene', (211, 216))	('recurrence', 'CPA', (251, 261))	('patients', 'Species', '9606', (59, 67))	('Atg2B', 'Gene', '55102', (211, 216))	('patients', 'Species', '9606', (152, 160))
142144	27326411	Autophagy inhibition with 3MA or hydroxychloroquine significantly increased apoptosis in pirarubicin-treated bladder cancer cells, and pirarubicin-induced autophagy was mediated via the mammalian target of rapamycin (mTOR)/p70S6K/4E-BP1 signaling pathway.	('inhibition', 'NegReg', (10, 20))	('Autophagy', 'CPA', (0, 9))	('mTOR', 'Gene', (217, 221))	('hydroxychloroquine', 'Chemical', 'MESH:D006886', (33, 51))	('pirarubicin', 'Chemical', 'MESH:C027260', (89, 100))	('Autophagy', 'biological_process', 'GO:0016236', ('0', '9'))	('hydroxychloroquine', 'Var', (33, 51))	('autophagy', 'biological_process', 'GO:0016236', ('155', '164'))	('3MA', 'Chemical', 'MESH:C025946', (26, 29))	('apoptosis', 'CPA', (76, 85))	('mTOR', 'Gene', '2475', (217, 221))	('mammalian target of rapamycin', 'Gene', '2475', (186, 215))	('signaling pathway', 'biological_process', 'GO:0007165', ('237', '254'))	('increased', 'PosReg', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('autophagy', 'CPA', (155, 164))	('bladder cancer', 'Disease', 'MESH:D001749', (109, 123))	('bladder cancer', 'Disease', (109, 123))	('autophagy', 'biological_process', 'GO:0006914', ('155', '164'))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('pirarubicin', 'Chemical', 'MESH:C027260', (135, 146))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))	('mammalian target of rapamycin', 'Gene', (186, 215))	('Autophagy', 'biological_process', 'GO:0006914', ('0', '9'))
142145	27326411	Knockdown of Atg3 generated similar results.	('Atg3', 'Gene', '64422', (13, 17))	('Atg3', 'Gene', (13, 17))	('Knockdown', 'Var', (0, 9))	('rat', 'Species', '10116', (22, 25))
142170	27326411	While they primarily established that YM155 had significant cytotoxic efficacy in the gemcitabine resistant bladder cancer lines, they did also demonstrate that YM155 mediates significant LC3 conversion independently, suggesting its efficacy is in part mediated by autophagy activation.	('LC3', 'Gene', (188, 191))	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('bladder cancer', 'Disease', (108, 122))	('autophagy', 'biological_process', 'GO:0016236', ('265', '274'))	('autophagy', 'biological_process', 'GO:0006914', ('265', '274'))	('YM155', 'Chemical', 'MESH:C523798', (161, 166))	('gemcitabine', 'Chemical', 'MESH:C056507', (86, 97))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('YM155', 'Var', (161, 166))	('YM155', 'Chemical', 'MESH:C523798', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('YM155', 'Var', (38, 43))	('rat', 'Species', '10116', (151, 154))	('LC3', 'Gene', '84557', (188, 191))	('cytotoxic', 'CPA', (60, 69))
142174	27326411	They also demonstrated in an earlier study that the dual phosphatidylinositol 3-kinase (PI3K) and mTOR inhibitor NVP-BEZ235 inhibits UC cell growth by activating autophagic flux; it increased production of acidic vesicular organelle development but did not increase LC3 conversion.	('increased', 'PosReg', (182, 191))	('LC3', 'Gene', '84557', (266, 269))	('autophagic flux', 'CPA', (162, 177))	('inhibits', 'NegReg', (124, 132))	('production', 'MPA', (192, 202))	('activating', 'PosReg', (151, 161))	('organelle', 'cellular_component', 'GO:0043226', ('223', '232'))	('BEZ235', 'Chemical', 'MESH:C531198', (117, 123))	('cell growth', 'biological_process', 'GO:0016049', ('136', '147'))	('UC cell growth', 'CPA', (133, 147))	('mTOR', 'Gene', '2475', (98, 102))	('PI3K', 'molecular_function', 'GO:0016303', ('88', '92'))	('acidic vesicular organelle', 'MPA', (206, 232))	('rat', 'Species', '10116', (17, 20))	('mTOR', 'Gene', (98, 102))	('LC3', 'Gene', (266, 269))	('NVP-BEZ235', 'Var', (113, 123))
142175	27326411	Of note, administration of chloraquine counteracted the effect of NVP-BEZ235, demonstrating that the anticancer efficacy of NVP-BEZ235 is due to autophagic flux and cotreatment with chloroquine counteracts the cytotoxic effect.	('autophagic flux', 'CPA', (145, 160))	('chloroquine', 'Chemical', 'MESH:D002738', (182, 193))	('NVP-BEZ235', 'Var', (124, 134))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('rat', 'Species', '10116', (85, 88))	('BEZ235', 'Chemical', 'MESH:C531198', (70, 76))	('BEZ235', 'Chemical', 'MESH:C531198', (128, 134))	('chloraquine', 'Chemical', 'MESH:D002738', (27, 38))	('rat', 'Species', '10116', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
142181	27326411	miR-222 overexpression dramatically reduced cisplatin-mediated autophagy in both UC cell lines, demonstrated by the decreased LC3-II levels, thereby indicating that miR-222 might block cisplatin-induced autophagy in bladder cancer cells.	('autophagy', 'biological_process', 'GO:0016236', ('203', '212'))	('autophagy', 'biological_process', 'GO:0006914', ('63', '72'))	('bladder cancer', 'Disease', 'MESH:D001749', (216, 230))	('bladder cancer', 'Disease', (216, 230))	('block', 'NegReg', (179, 184))	('rat', 'Species', '10116', (103, 106))	('LC3', 'Gene', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('bladder cancer', 'Phenotype', 'HP:0009725', (216, 230))	('miR-222', 'Chemical', '-', (0, 7))	('autophagy', 'biological_process', 'GO:0006914', ('203', '212'))	('miR-222', 'Gene', (0, 7))	('cisplatin-mediated', 'MPA', (44, 62))	('miR-222', 'Chemical', '-', (165, 172))	('decreased', 'NegReg', (116, 125))	('overexpression', 'PosReg', (8, 22))	('LC3', 'Gene', '84557', (126, 129))	('autophagy', 'biological_process', 'GO:0016236', ('63', '72'))	('miR-222', 'Var', (165, 172))	('reduced', 'NegReg', (36, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))
142191	27326411	Indeed, with HMGB1 knockdown, >1.5-fold sensitization to radiation therapy was achieved, and autophagy was inhibited more than 3 folds (as measured by LC3 conversion).	('LC3', 'Gene', '84557', (151, 154))	('HMGB1', 'Gene', (13, 18))	('LC3', 'Gene', (151, 154))	('autophagy', 'CPA', (93, 102))	('knockdown', 'Var', (19, 28))	('autophagy', 'biological_process', 'GO:0016236', ('93', '102'))	('sensitization', 'MPA', (40, 53))	('autophagy', 'biological_process', 'GO:0006914', ('93', '102'))	('sensitization', 'biological_process', 'GO:0046960', ('40', '53'))	('inhibited', 'NegReg', (107, 116))
142192	27326411	HMGB1 knockdown tumors in their mouse xenograft model showed a significantly better response to radiation therapy and decreased autophagy as compared to controls.	('better', 'PosReg', (77, 83))	('response', 'CPA', (84, 92))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('HMGB1', 'Gene', (0, 5))	('autophagy', 'biological_process', 'GO:0006914', ('128', '137'))	('response to radiation', 'biological_process', 'GO:0009314', ('84', '105'))	('autophagy', 'CPA', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('mouse', 'Species', '10090', (32, 37))	('decreased', 'NegReg', (118, 127))	('knockdown', 'Var', (6, 15))	('tumors', 'Disease', (16, 22))	('autophagy', 'biological_process', 'GO:0016236', ('128', '137'))
142238	19534791	The presence of MPC in urothelial carcinoma was found to be associated with an advanced stage of disease at the time of presentation and an aggressive clinical course.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (23, 43))	('MPC', 'Chemical', '-', (16, 19))	('urothelial carcinoma', 'Disease', (23, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('presence', 'Var', (4, 12))	('associated', 'Reg', (60, 70))
142299	32751328	PD-L1 positivity was significantly higher in females (p = 0.034), whereas there was no association between PD-L1 positivity and other clinicopathological characteristics (Supplementary Table S1).	('PD-L1', 'Gene', '29126', (107, 112))	('positivity', 'Var', (6, 16))	('PD-L1', 'Gene', (0, 5))	('PD-L1', 'Gene', (107, 112))	('PD-L1', 'Gene', '29126', (0, 5))	('higher', 'Reg', (35, 41))
142302	32751328	We found no significant difference in tumor progression (Figure 4A) or cancer-specific mortality (Figure 4B) in patients with Nectin-4 positive tumors and those with Nectin-4 negative tumors.	('tumors', 'Disease', (144, 150))	('mortality', 'Disease', 'MESH:D003643', (87, 96))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (71, 77))	('tumor', 'Disease', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('positive', 'Var', (135, 143))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('Nectin-4', 'Gene', '81607', (166, 174))	('Nectin-4', 'Gene', (166, 174))	('mortality', 'Disease', (87, 96))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Disease', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('Nectin-4', 'Gene', '81607', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('patients', 'Species', '9606', (112, 120))	('tumors', 'Disease', (184, 190))	('Nectin-4', 'Gene', (126, 134))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
142303	32751328	However, patients with strong Nectin-4 expression in tumors had a significantly higher risk of tumor progression (Log-rank test, p = 0.031; Figure 4C) or cancer-specific mortality (Log-rank test, p = 0.036; Figure 4D) than patients who did not show strong Nectin-4 expression in tumors (0/1+/2+ vs. 3+).	('Nectin-4', 'Gene', '81607', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('Nectin-4', 'Gene', (30, 38))	('tumors', 'Disease', (279, 285))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mortality', 'Disease', (170, 179))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (279, 285))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Disease', (53, 59))	('Nectin-4', 'Gene', '81607', (256, 264))	('Nectin-4', 'Gene', (256, 264))	('tumor', 'Disease', (279, 284))	('mortality', 'Disease', 'MESH:D003643', (170, 179))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('tumor', 'Disease', (95, 100))	('patients', 'Species', '9606', (9, 17))	('expression', 'Var', (39, 49))	('cancer', 'Disease', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (53, 58))	('patients', 'Species', '9606', (223, 231))	('higher', 'PosReg', (80, 86))
142318	32751328	Overexpression of Nectin-4 is reportedly implicated in disease progression and poor prognosis in several types of cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Nectin-4', 'Gene', '81607', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Nectin-4', 'Gene', (18, 26))	('Overexpression', 'Var', (0, 14))	('implicated', 'Reg', (41, 51))	('cancer', 'Disease', (114, 120))
142337	32751328	Other factors, such as the aging of TMA, could also affect the rate of Netin4 positivity.	('Netin4', 'Protein', (71, 77))	('positivity', 'Var', (78, 88))	('aging', 'biological_process', 'GO:0007568', ('27', '32'))	('affect', 'Reg', (52, 58))	('TMA', 'Chemical', '-', (36, 39))	('Netin4', 'Chemical', '-', (71, 77))
142347	32751328	Primary antibodies against Nectin-4 (1:3000; EPR15613-68; Abcam, Cambridge, UK) and PD-L1 (1:100; E1L3N; Cell Signalling, Danvers, MA, USA) were added and incubated overnight at 4  C. Then, we used EnVision + System-HRP labeled polymer anti-rabbit (DAKO, Glostrup, Denmark) according to the manufacturer's instructions.	('PD-L1', 'Gene', (84, 89))	('Nectin-4', 'Gene', '81607', (27, 35))	('Nectin-4', 'Gene', (27, 35))	('PD-L1', 'Gene', '29126', (84, 89))	('EPR15613-68', 'Var', (45, 56))	('polymer', 'Chemical', 'MESH:D011108', (228, 235))	('Signalling', 'biological_process', 'GO:0023052', ('110', '120'))
142373	31092844	MB49-I BC cells displayed aggressively invasive behavior in vitro and in vivo, and such invasiveness is probably due to elevated expression levels of decorin (DCN), yet its relevance to human BC has not yet been confirmed.	('MB49', 'CellLine', 'CVCL:7076', (0, 4))	('invasive behavior', 'CPA', (39, 56))	('MB49-I', 'Var', (0, 6))	('human', 'Species', '9606', (186, 191))	('BC', 'Phenotype', 'HP:0009725', (192, 194))	('elevated', 'PosReg', (120, 128))	('BC', 'Phenotype', 'HP:0009725', (7, 9))	('expression levels', 'MPA', (129, 146))	('aggressively', 'PosReg', (26, 38))
142444	31092844	Similarly, it has been reported that the expression of Snail and Twist in breast cancer cells can induce EMT and a stem cell-like character that would lead to increased metastatic potential.	('breast cancer', 'Disease', (74, 87))	('metastatic potential', 'CPA', (169, 189))	('induce', 'PosReg', (98, 104))	('stem cell-like character', 'CPA', (115, 139))	('Twist', 'Gene', (65, 70))	('Snail', 'Gene', (55, 60))	('increased', 'PosReg', (159, 168))	('EMT', 'CPA', (105, 108))	('Snail', 'Gene', '20613', (55, 60))	('EMT', 'biological_process', 'GO:0001837', ('105', '108'))	('expression', 'Var', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
142484	30578357	Using this targeted sequencing approach, we detected a median of 6 mutations per BLCA patient and observed surprisingly frequent mutations of the PLEKHS1 promoter (46%), suggesting these mutations represent a useful biomarker for detection of BLCA.	('BLCA', 'Phenotype', 'HP:0009725', (243, 247))	('PLEKHS1', 'Gene', (146, 153))	('PLEKHS1', 'Gene', '79949', (146, 153))	('BLCA', 'Phenotype', 'HP:0009725', (81, 85))	('mutations', 'Var', (129, 138))	('BLCA', 'Disease', (243, 247))	('mutations', 'Var', (67, 76))	('mutations', 'Var', (187, 196))	('patient', 'Species', '9606', (86, 93))
142503	30578357	Next, we tested the concordance of mutations detected in tumor tissue and urine using 18 patients for whom paired urine and tumor tissue were available.	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('patients', 'Species', '9606', (89, 97))	('tumor', 'Disease', (57, 62))	('tested', 'Reg', (9, 15))	('mutations', 'Var', (35, 44))
142504	30578357	Across these cases, a median of 66.7% mutations that were found in tumor tissue were also identified in utDNA while a median of 73.2% of mutations that were found in utDNA were also detected in paired tumor (Fig.	('utDNA', 'Disease', (104, 109))	('identified', 'Reg', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (201, 206))	('mutations', 'Var', (38, 47))
142505	30578357	Within tumor tissue, mutations that were also found in urine had higher median allele fractions than those not found in urine (27.2% vs. 9.2%, p<0.0001; Fig.	('mutations', 'Var', (21, 30))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('higher', 'PosReg', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
142506	30578357	Taken together, these results suggest that overall concordance between mutations found in bladder tumors and utDNA is high and is likely higher for truncal mutations than subclonal variants.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('bladder tumors', 'Disease', (90, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutations', 'Var', (71, 80))	('utDNA', 'Disease', (109, 114))	('higher', 'Reg', (137, 143))	('bladder tumors', 'Phenotype', 'HP:0009725', (90, 104))	('bladder tumors', 'Disease', 'MESH:D001749', (90, 104))
142509	30578357	PLEKHS1 was originally described as a recurrent noncoding mutation in cancers by Weinhold and colleagues in an analysis of whole genome sequencing data, with mutations at one of two single-nucleotide hotspots (hg19 chr10:g.115511590 and 115511593) found in 20/863 (~2%) of cancers, including 8/20 of BLCAs.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('hg19 chr10', 'Gene', (210, 220))	('115511593', 'Var', (237, 246))	('cancers', 'Disease', 'MESH:D009369', (273, 280))	('cancers', 'Phenotype', 'HP:0002664', (273, 280))	('PLEKHS1', 'Gene', (0, 7))	('cancers', 'Disease', (273, 280))	('g.115511590', 'Var', (221, 232))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('PLEKHS1', 'Gene', '79949', (0, 7))	('BLCA', 'Phenotype', 'HP:0009725', (300, 304))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('cancers', 'Disease', (70, 77))
142510	30578357	We identified PLEKHS1 promoter mutations in 37/81 (46%) of cases in our group, with all mutations clustered at these two previously described hotspots (Fig.	('PLEKHS1', 'Gene', (14, 21))	('mutations', 'Var', (31, 40))	('PLEKHS1', 'Gene', '79949', (14, 21))
142512	30578357	Consistent with prior studies, we observed a significantly higher frequency of TP53 mutations in high versus low grade tumors (59.2% vs. 12.5%; p<0.0001), and conversely, found disproportionately more FGFR3 mutations in low versus high grade cases (59.4% vs. 10.2%; p<0.0001) (Fig.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('mutations', 'Var', (84, 93))	('mutations', 'Var', (207, 216))	('FGFR3', 'Gene', '2261', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('201', '205'))	('FGFR3', 'Gene', (201, 206))
142513	30578357	We also assessed copy number variants across genes known to be significantly altered in BLCA that were covered in our panel and found deletions involving chromosome 9p21 in 27% of cases, amplifications of ERBB2 in 7%, and deletions of RB1 in 2% (Fig.	('deletions', 'Var', (222, 231))	('ERBB2', 'Gene', (205, 210))	('deletions', 'Var', (134, 143))	('BLCA', 'Phenotype', 'HP:0009725', (88, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('154', '164'))	('RB1', 'Gene', (235, 238))	('amplifications', 'Var', (187, 201))	('RB1', 'Gene', '5925', (235, 238))	('ERBB2', 'Gene', '2064', (205, 210))
142515	30578357	Since prior work had demonstrated enrichment of an APOBEC-related mutational signature in BLCA tumors by whole exome sequencing, we tested whether this signature was evident in utDNA by more targeted sequencing.	('BLCA tumors', 'Disease', 'MESH:D009369', (90, 101))	('APOBEC-related', 'Gene', (51, 65))	('BLCA tumors', 'Disease', (90, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('BLCA', 'Phenotype', 'HP:0009725', (90, 94))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('mutational', 'Var', (66, 76))	('APOBEC', 'cellular_component', 'GO:0030895', ('51', '57'))
142518	30578357	S5) and, if validated, could suggest that cancer-related mutational signatures identified in cfDNA might serve as biomarkers for the presence of cancer.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cfDNA', 'Disease', (93, 98))	('mutational', 'Var', (57, 67))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
142520	30578357	We applied two different approaches to the detection of mutations in urine cfDNA, here designated "tumor-informed" and "tumor-naive" profiling.	('tumor', 'Disease', (99, 104))	('mutations', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cfDNA', 'Gene', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (120, 125))
142521	30578357	The tumor-informed approach leverages prior knowledge by first sequencing a patient's tumor specimen and germline tissue and then testing for the presence of these mutations in a urine sample using a Monte Carlo-based statistical approach, as previously described.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('testing', 'Reg', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('patient', 'Species', '9606', (76, 83))	('mutations', 'Var', (164, 173))
142522	30578357	In contrast, the tumor-naive approach is designed to detect putative driver mutations without prior knowledge of the tumor genotype (see Supplemental Methods).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutations', 'Var', (76, 85))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
142526	30578357	Using the tumor-naive approach, we detected 134 putative driver mutations in the urine of cases and only 1 in the controls (Fig.	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('mutations', 'Var', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))
142536	30578357	Using tumor-naive utDNA profiling, we observed 88 putative driver mutations among patients experiencing disease recurrence and only 1 among those who did not (Fig.	('mutations', 'Var', (66, 75))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
142537	30578357	The 1 mutation detected in a patient who did not recur was a STAG2 nonsense mutation that was near the terminal end of the protein (residue 1029/1268) and therefore may not actually inactivate it.	('residue 1029/1268', 'Var', (132, 149))	('patient', 'Species', '9606', (29, 36))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('STAG2', 'Gene', '10735', (61, 66))	('STAG2', 'Gene', (61, 66))
142544	30578357	We detected mutant DNA in 1/27 patients who had at least nine months of negative follow-up, resulting in a specificity of 96% (Fig.	('detected', 'Reg', (3, 11))	('mutant', 'Var', (12, 18))	('patients', 'Species', '9606', (31, 39))	('DNA', 'Gene', (19, 22))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
142556	30578357	Our approach demonstrates high concordance for mutations between tumor and utDNA and enables genotyping of multiple somatic aberration types across a broad genomic space in a single integrated assay.	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mutations', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))
142557	30578357	Using this approach, we demonstrate that PLEKHS1 promoter mutations are among the most common somatic alterations in BLCA and are shed into the urine.	('mutations', 'Var', (58, 67))	('PLEKHS1', 'Gene', '79949', (41, 48))	('BLCA', 'Phenotype', 'HP:0009725', (117, 121))	('PLEKHS1', 'Gene', (41, 48))
142595	27034533	HER2 Protein Overexpression and Gene Amplification in Plasmacytoid Urothelial Carcinoma of the Urinary Bladder Aim.	('Overexpression', 'PosReg', (13, 27))	('Urothelial Carcinoma', 'Disease', (67, 87))	('HER2', 'Gene', (0, 4))	('Gene Amplification', 'Var', (32, 50))	('Urothelial Carcinoma', 'Disease', 'MESH:D014526', (67, 87))	('HER2', 'Gene', '2064', (0, 4))	('Carcinoma', 'Phenotype', 'HP:0030731', (78, 87))
142609	24199183	Molecular grading of tumors of the upper urothelial tract using FGFR3 mutation status identifies patients with favorable prognosis Mutations in FGFR3 have been shown to occur in tumors of the upper urothelial tract and may be indicative of a good prognosis.	('FGFR3', 'Gene', '2261', (144, 149))	('FGFR3', 'Gene', (64, 69))	('tumors of the upper urothelial tract', 'Disease', 'MESH:D012141', (178, 214))	('tumors of the upper urothelial tract', 'Disease', (21, 57))	('FGFR3', 'Gene', '2261', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors of the upper urothelial tract', 'Disease', (178, 214))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumors of the upper urothelial tract', 'Phenotype', 'HP:0010935', (21, 57))	('tumors of the upper urothelial', 'Disease', 'MESH:D001749', (21, 51))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('patients', 'Species', '9606', (97, 105))	('tumors of the upper urothelial tract', 'Phenotype', 'HP:0010935', (178, 214))	('tumors of the upper urothelial', 'Disease', 'MESH:D001749', (178, 208))	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('FGFR3', 'Gene', (144, 149))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('tumors of the upper urothelial tract', 'Disease', 'MESH:D012141', (21, 57))	('Mutations', 'Var', (131, 140))
142610	24199183	In bladder tumors, the combination of FGFR3 mutation status and Ki-67 level has been used to define a tumor's molecular grade and predict survival.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('FGFR3', 'Gene', '2261', (38, 43))	('mutation', 'Var', (44, 52))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('FGFR3', 'Gene', (38, 43))	('bladder tumors', 'Disease', 'MESH:D001749', (3, 17))	('bladder tumors', 'Phenotype', 'HP:0009725', (3, 17))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('bladder tumors', 'Disease', (3, 17))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
142612	24199183	This study investigated the association with prognosis of FGFR3 mutations alone and in combination with Ki-67 in this patient population.	('FGFR3', 'Gene', '2261', (58, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('FGFR3', 'Gene', (58, 63))	('mutations', 'Var', (64, 73))	('patient', 'Species', '9606', (118, 125))
142614	24199183	The presence of mutation in FGFR3 was evaluated using real-time polymerase chain reaction.	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('FGFR3', 'Gene', (28, 33))	('mutation', 'Var', (16, 24))	('FGFR3', 'Gene', '2261', (28, 33))
142615	24199183	Kaplan-Meier survival analysis evaluated the relationship of FGFR3 mutations and Ki-67 levels with survival.	('FGFR3', 'Gene', '2261', (61, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('61', '65'))	('FGFR3', 'Gene', (61, 66))	('mutations', 'Var', (67, 76))
142616	24199183	FGFR3 mutations were identified in 40% of tumors and were predominantly associated with noninvasive tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('FGFR3', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('associated', 'Reg', (72, 82))	('invasive tumors', 'Disease', (91, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('invasive tumors', 'Disease', 'MESH:D009369', (91, 106))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
142617	24199183	Overall survival was higher in patients with FGFR3 mutant tumors (P = 0.02) and in molecular grade 1 tumors as determined by FGFR3 and Ki-67 (P = 0.02).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumors', 'Disease', (58, 64))	('FGFR3', 'Gene', '2261', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mutant', 'Var', (51, 57))	('FGFR3', 'Gene', '2261', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('125', '129'))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('higher', 'PosReg', (21, 27))	('patients', 'Species', '9606', (31, 39))	('FGFR3', 'Gene', (125, 130))	('Overall survival', 'MPA', (0, 16))	('FGFR3', 'Gene', (45, 50))	('tumors', 'Disease', (101, 107))
142618	24199183	In this study, we confirm the occurrence of FGFR3 mutations in tumors of the upper urothelial tract and its association with a good prognosis.	('association', 'Reg', (108, 119))	('tumors of the upper urothelial tract', 'Disease', 'MESH:D012141', (63, 99))	('tumors of the upper urothelial tract', 'Phenotype', 'HP:0010935', (63, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('mutations', 'Var', (50, 59))	('FGFR3', 'Gene', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('FGFR3', 'Gene', '2261', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumors of the upper urothelial tract', 'Disease', (63, 99))
142624	24199183	Activating mutations in the fibroblast growth factor receptor 3 gene (FGFR3) are one of the most frequent somatic mutations found in bladder cancer.	('fibroblast growth factor receptor 3', 'Gene', (28, 63))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('28', '52'))	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('FGFR', 'molecular_function', 'GO:0005007', ('70', '74'))	('FGFR3', 'Gene', '2261', (70, 75))	('Activating mutations', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('FGFR3', 'Gene', (70, 75))	('bladder cancer', 'Disease', 'MESH:D001749', (133, 147))	('bladder cancer', 'Disease', (133, 147))	('fibroblast growth factor receptor 3', 'Gene', '2261', (28, 63))
142625	24199183	Eight FGFR3 mutations in three exons (exons 7, 10, and 15) are associated with >90% of all known mutant FGFR3-positive bladder cancers and are also common in upper urinary tract cancers.FGFR3 mutations occur in about 50% of primary bladder and upper tract tumors and are associated with low-stage tumors of the bladder and ureter.FGFR3 mutations are also associated with a milder disease course in both bladder and upper urothelial cancers, as well as better survival in patients with invasive urothelial cancer of the upper tract.	('FGFR', 'molecular_function', 'GO:0005007', ('330', '334'))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (432, 438))	('upper tract tumors', 'Disease', (244, 262))	('FGFR3', 'Gene', (6, 11))	('FGFR3', 'Gene', '2261', (104, 109))	('FGFR', 'molecular_function', 'GO:0005007', ('104', '108'))	('upper urothelial cancer', 'Phenotype', 'HP:0010935', (415, 438))	('FGFR', 'molecular_function', 'GO:0005007', ('186', '190'))	('FGFR3', 'Gene', '2261', (6, 11))	('invasive urothelial cancer', 'Disease', (485, 511))	('upper urinary tract cancers', 'Disease', (158, 185))	('upper urinary tract cancers', 'Disease', 'MESH:D014571', (158, 185))	('tumors of the bladder', 'Phenotype', 'HP:0009725', (297, 318))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (164, 184))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('FGFR', 'molecular_function', 'GO:0005007', ('6', '10'))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('FGFR3', 'Gene', (330, 335))	('bladder cancers', 'Phenotype', 'HP:0009725', (119, 134))	('FGFR3', 'Gene', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('bladder cancer', 'Phenotype', 'HP:0009725', (119, 133))	('upper tract tumors', 'Disease', 'MESH:D012141', (244, 262))	('FGFR3', 'Gene', '2261', (330, 335))	('FGFR3', 'Gene', '2261', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('bladder and upper urothelial cancers', 'Disease', 'MESH:D001749', (403, 439))	('patients', 'Species', '9606', (471, 479))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('upper urinary tract cancer', 'Phenotype', 'HP:0010935', (158, 184))	('bladder cancers', 'Disease', 'MESH:D001749', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (505, 511))	('invasive urothelial cancer', 'Disease', 'MESH:D009362', (485, 511))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('positive bladder', 'Phenotype', 'HP:0100645', (110, 126))	('bladder cancers', 'Disease', (119, 134))	('mutations', 'Var', (336, 345))	('low-stage tumors of the bladder and ureter', 'Disease', 'MESH:D001749', (287, 329))	('cancers', 'Phenotype', 'HP:0002664', (432, 439))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('FGFR3', 'Gene', (104, 109))
142628	24199183	In this study, we used both FGFR3 mutational analysis and immunohistochemistry for the Ki-67 antigen to evaluate the prognosis of patients with upper urothelial cancer.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('upper urothelial cancer', 'Phenotype', 'HP:0010935', (144, 167))	('FGFR3', 'Gene', '2261', (28, 33))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('upper urothelial cancer', 'Disease', 'MESH:D014523', (144, 167))	('upper urothelial cancer', 'Disease', (144, 167))	('FGFR3', 'Gene', (28, 33))	('patients', 'Species', '9606', (130, 138))	('mutational', 'Var', (34, 44))
142637	24199183	A second multiplexed PCR was carried out to identify FGFR3 mutations.	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('mutations', 'Var', (59, 68))	('FGFR3', 'Gene', '2261', (53, 58))	('FGFR3', 'Gene', (53, 58))
142638	24199183	This PCR reaction used primers that encoded wild-type sequence with locked nucleic acid (LNA) bases surrounding and including a known mutation site in exon 7, 10, or 15 (exon 7 [R248C and S249C], exon 10 [G372C, S373C and Y375C], and exon 15 [K652E, K652M, K652T and K652Q]), and real-time PCR primers specific for each exon with dual-labeled fluorescent probes.	('[K652E', 'Var', (242, 248))	('Y375C', 'Mutation', 'rs121913485', (222, 227))	('K652T', 'Mutation', 'rs121913105', (257, 262))	('R248C', 'Mutation', 'rs121913482', (178, 183))	('K652E', 'Mutation', 'rs78311289', (243, 248))	('K652T', 'Var', (257, 262))	('K652M', 'Var', (250, 255))	('K652Q]', 'Var', (267, 273))	('S249C', 'Mutation', 'rs121913483', (188, 193))	('nucleic acid', 'cellular_component', 'GO:0005561', ('75', '87'))	('G372C', 'Mutation', 'rs121913479', (205, 210))	('S373C', 'Mutation', 'rs121913484', (212, 217))	('[G372C', 'Var', (204, 210))	('exon', 'Var', (170, 174))	('Y375C]', 'Var', (222, 228))	('K652M', 'Mutation', 'rs121913105', (250, 255))	('K652Q', 'Mutation', 'rs78311289', (267, 272))
142639	24199183	A ratio between the amplification cycles of positive controls (plasmids containing known FGFR3 mutations) and negative controls (wild-type DNA) were included in each assay to determine if a sample did or did not contain a mutation.	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('FGFR3', 'Gene', (89, 94))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('mutations', 'Var', (95, 104))	('FGFR3', 'Gene', '2261', (89, 94))
142643	24199183	In brief, molecular grade 1 is defined as a sample that is positive for an FGFR3 mutation and has low Ki-67 staining.	('FGFR3', 'Gene', (75, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('mutation', 'Var', (81, 89))	('positive', 'Reg', (59, 67))	('FGFR3', 'Gene', '2261', (75, 80))
142644	24199183	Molecular grade 2 is defined as samples that are positive for an FGFR3 mutation but have high Ki-67 staining, or are wild-type for FGFR3 and have low Ki-67 staining.	('FGFR3', 'Gene', '2261', (65, 70))	('Ki-67 staining', 'MPA', (94, 108))	('mutation', 'Var', (71, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('positive', 'Reg', (49, 57))	('FGFR3', 'Gene', '2261', (131, 136))	('FGFR3', 'Gene', (65, 70))	('FGFR', 'molecular_function', 'GO:0005007', ('131', '135'))	('FGFR3', 'Gene', (131, 136))
142647	24199183	Overall survival probability was estimated by the Kaplan-Meier method for each patient group classified by the FGFR3 mutation status or classified according to the molecular grade defined by the combination of FGFR3 and Ki-67.	('FGFR3', 'Gene', '2261', (210, 215))	('FGFR', 'molecular_function', 'GO:0005007', ('210', '214'))	('FGFR3', 'Gene', '2261', (111, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('patient', 'Species', '9606', (79, 86))	('FGFR3', 'Gene', (210, 215))	('FGFR3', 'Gene', (111, 116))	('mutation', 'Var', (117, 125))
142649	24199183	The Cox proportional hazard model was used to assess the simultaneous contribution of the following baseline covariates: age, gender, tumor stage, morphological grade, site, FGFR3 mutation status, Ki-67, and molecular grade.	('FGFR', 'molecular_function', 'GO:0005007', ('174', '178'))	('FGFR3', 'Gene', '2261', (174, 179))	('mutation status', 'Var', (180, 195))	('FGFR3', 'Gene', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
142651	24199183	Although many studies have shown that FGFR3 mutations are common in bladder cancer, only one other study has shown that tumors of upper urothelial origin can also harbor FGFR3 mutations.	('common', 'Reg', (58, 64))	('bladder cancer', 'Phenotype', 'HP:0009725', (68, 82))	('tumors', 'Disease', (120, 126))	('mutations', 'Var', (176, 185))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('FGFR3', 'Gene', '2261', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('FGFR3', 'Gene', '2261', (170, 175))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('FGFR3', 'Gene', (38, 43))	('bladder cancer', 'Disease', 'MESH:D001749', (68, 82))	('bladder cancer', 'Disease', (68, 82))	('mutations', 'Var', (44, 53))	('tumors of upper urothelial origin', 'Phenotype', 'HP:0010935', (120, 153))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('FGFR3', 'Gene', (170, 175))	('FGFR', 'molecular_function', 'GO:0005007', ('170', '174'))
142652	24199183	In this study, 80 tumors from patients with upper urothelial cancer were analyzed for mutations in FGFR3.	('mutations', 'Var', (86, 95))	('upper urothelial cancer', 'Phenotype', 'HP:0010935', (44, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('FGFR3', 'Gene', (99, 104))	('upper urothelial cancer', 'Disease', 'MESH:D014523', (44, 67))	('upper urothelial cancer', 'Disease', (44, 67))	('tumors', 'Disease', (18, 24))	('patients', 'Species', '9606', (30, 38))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('FGFR3', 'Gene', '2261', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
142654	24199183	Of the 80 patients, 32 had tumors with FGFR3 mutations, indicating a mutation frequency of 40% (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (45, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('39', '43'))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('FGFR3', 'Gene', '2261', (39, 44))	('patients', 'Species', '9606', (10, 18))	('FGFR3', 'Gene', (39, 44))
142656	24199183	FGFR3 mutations were more frequent in noninvasive tumors (53% [21/40]) compared with 28% [21/40] in invasive tumors and were associated with low-grade disease (71% [12/17] of low-grade tumors carried mutations compared with 32% [20/63] of high-grade tumors), regardless of tumor site and in contrast with previous studies.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('mutations', 'Var', (200, 209))	('tumors', 'Disease', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (273, 278))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Disease', (250, 255))	('invasive tumors', 'Disease', (100, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', (185, 190))	('invasive tumors', 'Disease', 'MESH:D009369', (100, 115))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('tumors', 'Disease', (109, 115))	('tumor', 'Disease', (50, 55))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('associated with', 'Reg', (125, 140))	('invasive tumors', 'Disease', (41, 56))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumors', 'Disease', (250, 256))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('invasive tumors', 'Disease', 'MESH:D009369', (41, 56))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('low-grade disease', 'Disease', (141, 158))	('FGFR3', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Disease', (50, 56))	('tumor', 'Disease', (109, 114))	('FGFR3', 'Gene', '2261', (0, 5))
142659	24199183	Therefore, we analyzed survival as a function of FGFR3 mutation status using Kaplan-Meier survival plots.	('FGFR3', 'Gene', '2261', (49, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('FGFR3', 'Gene', (49, 54))	('mutation', 'Var', (55, 63))
142660	24199183	Patients whose tumors contained an FGFR3 mutation had better overall survival than those whose tumors did not have a mutation (Figure 1, P = 0.02), consistent with previous findings.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR3', 'Gene', '2261', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('mutation', 'Var', (41, 49))	('Patients', 'Species', '9606', (0, 8))	('FGFR3', 'Gene', (35, 40))	('overall survival', 'MPA', (61, 77))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('tumors', 'Disease', (15, 21))	('better', 'PosReg', (54, 60))
142668	24199183	Previous studies have shown that FGFR3 mutations are associated with an improved prognosis in invasive tumors of the upper urinary tract, while increased Ki67 levels have been associated with a poor prognosis.	('invasive tumors', 'Disease', (94, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors of the upper urinary tract', 'Phenotype', 'HP:0010935', (103, 136))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('invasive tumors', 'Disease', 'MESH:D009369', (94, 109))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('improved', 'PosReg', (72, 80))	('mutations', 'Var', (39, 48))	('FGFR3', 'Gene', '2261', (33, 38))	('Ki67 levels', 'MPA', (154, 165))	('FGFR3', 'Gene', (33, 38))	('increased', 'PosReg', (144, 153))
142670	24199183	In this study, we confirm the association of FGFR3 mutations with improved prognosis in a cohort of both invasive and noninvasive urothelial tumors of the upper urinary tract and apply the use of molecular grade to determine whether this approach can be indicative of a good prognosis.	('prognosis', 'MPA', (75, 84))	('urothelial tumors', 'Disease', 'MESH:D001749', (130, 147))	('mutations', 'Var', (51, 60))	('FGFR3', 'Gene', '2261', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('improved', 'PosReg', (66, 74))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('urothelial tumors', 'Disease', (130, 147))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('FGFR3', 'Gene', (45, 50))	('tumors of the upper urinary tract', 'Phenotype', 'HP:0010935', (141, 174))
142671	24199183	The results of our FGFR3 mutation assay are consistent with other methods reported to have similar analytical sensitivity.	('FGFR3', 'Gene', '2261', (19, 24))	('mutation', 'Var', (25, 33))	('FGFR3', 'Gene', (19, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))
142673	24199183	Both FGFR3 mutation and low molecular grade were associated with improved survival.	('improved', 'PosReg', (65, 73))	('survival', 'MPA', (74, 82))	('FGFR3', 'Gene', '2261', (5, 10))	('FGFR', 'molecular_function', 'GO:0005007', ('5', '9'))	('mutation', 'Var', (11, 19))	('FGFR3', 'Gene', (5, 10))
142677	24199183	These findings are consistent with prior results that found that the combination of FGFR3 and Ki-67 were good predictors of bladder cancer prognosis.	('bladder cancer', 'Disease', 'MESH:D001749', (124, 138))	('bladder cancer', 'Disease', (124, 138))	('Ki-67', 'Gene', (94, 99))	('combination', 'Var', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('FGFR3', 'Gene', '2261', (84, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (124, 138))	('FGFR', 'molecular_function', 'GO:0005007', ('84', '88'))	('FGFR3', 'Gene', (84, 89))
142678	24199183	Given its known association with bladder cancer, the FGFR3 mutation detection assay has been developed as a diagnostic tool for both molecular grading of bladder cancer tissues and for urine-based assays used in the evaluation of patients with hematuria or for cancer recurrence in patients who had been previously treated for bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (33, 47))	('cancer', 'Disease', (162, 168))	('bladder cancer', 'Phenotype', 'HP:0009725', (154, 168))	('association', 'Reg', (16, 27))	('bladder cancer', 'Disease', (33, 47))	('cancer', 'Disease', (335, 341))	('mutation', 'Var', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Disease', (41, 47))	('bladder cancer', 'Phenotype', 'HP:0009725', (33, 47))	('FGFR3', 'Gene', (53, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('bladder cancer', 'Disease', 'MESH:D001749', (327, 341))	('bladder cancer', 'Disease', (327, 341))	('hematuria', 'Disease', (244, 253))	('FGFR3', 'Gene', '2261', (53, 58))	('cancer', 'Disease', (261, 267))	('patients', 'Species', '9606', (282, 290))	('bladder cancer', 'Phenotype', 'HP:0009725', (327, 341))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('hematuria', 'Disease', 'MESH:D006417', (244, 253))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('hematuria', 'Phenotype', 'HP:0000790', (244, 253))	('patients', 'Species', '9606', (230, 238))	('bladder cancer', 'Disease', 'MESH:D001749', (154, 168))	('bladder cancer', 'Disease', (154, 168))	('cancer', 'Disease', 'MESH:D009369', (261, 267))
142680	24199183	It is possible that detection of FGFR3 mutations in urine may also be useful in diagnosing cancer of the upper urinary tract.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer of the upper urinary tract', 'Phenotype', 'HP:0010935', (91, 124))	('mutations', 'Var', (39, 48))	('FGFR3', 'Gene', '2261', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('FGFR3', 'Gene', (33, 38))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))
142681	24199183	In fact, a recent report showed that in a community-based clinical setting, FGFR3 mutation analysis was used to diagnose an upper urothelial carcinoma in a patient in whom standard diagnostic methods were inconclusive.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (130, 150))	('mutation analysis', 'Var', (82, 99))	('FGFR3', 'Gene', '2261', (76, 81))	('urothelial carcinoma', 'Disease', (130, 150))	('FGFR3', 'Gene', (76, 81))	('diagnose', 'Reg', (112, 120))	('patient', 'Species', '9606', (156, 163))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))
142682	24199183	The results of this study are consistent with previous findings that FGFR3 mutations are present in tumors of the upper urinary tract, and are indicative of a good prognosis.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('FGFR3', 'Gene', '2261', (69, 74))	('FGFR', 'molecular_function', 'GO:0005007', ('69', '73'))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('FGFR3', 'Gene', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (75, 84))	('tumors of the upper urinary tract', 'Phenotype', 'HP:0010935', (100, 133))	('present', 'Reg', (89, 96))
142693	33937395	In the bladder cancer, high expression of NRP2 is associated with chemoresistance and epithelial-to-mesenchymal transition and poor patient prognosis.	('epithelial-to-mesenchymal transition', 'CPA', (86, 122))	('high expression', 'Var', (23, 38))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('86', '122'))	('NRP', 'biological_process', 'GO:0085015', ('42', '45'))	('bladder cancer', 'Phenotype', 'HP:0009725', (7, 21))	('NRP2', 'Gene', (42, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (7, 21))	('bladder cancer', 'Disease', (7, 21))	('patient', 'Species', '9606', (132, 139))	('associated', 'Reg', (50, 60))	('chemoresistance', 'CPA', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
142706	33937395	In addition, high NRP1 expression was associated with higher stroma, microenvironment, and immune scores, as well as more endothelial cell infiltration in most tumours.	('tumours', 'Disease', 'MESH:D009369', (160, 167))	('higher', 'PosReg', (54, 60))	('high', 'Var', (13, 17))	('tumours', 'Disease', (160, 167))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))	('stroma', 'CPA', (61, 67))	('immune scores', 'CPA', (91, 104))	('NRP1', 'Gene', (18, 22))	('NRP', 'biological_process', 'GO:0085015', ('18', '21'))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('expression', 'MPA', (23, 33))
142707	33937395	In KIRC, a high NRP1 expression was associated with a larger tumour size, higher risk of distant metastases, and worse stage staging and grade staging.	('metastases', 'Disease', (97, 107))	('NRP1', 'Protein', (16, 20))	('NRP', 'biological_process', 'GO:0085015', ('16', '19'))	('expression', 'MPA', (21, 31))	('tumour size', 'CPA', (61, 72))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('high', 'Var', (11, 15))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
142710	33937395	Anti-NRP1 therapy can block tumour angiogenesis and upregulate the antitumour immune response.	('Anti-NRP1', 'Var', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('immune response', 'biological_process', 'GO:0006955', ('78', '93'))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('angiogenesis', 'biological_process', 'GO:0001525', ('35', '47'))	('antitumour immune response', 'CPA', (67, 93))	('upregulate', 'PosReg', (52, 62))	('block tumour', 'Disease', (22, 34))	('NRP', 'biological_process', 'GO:0085015', ('5', '8'))	('block tumour', 'Disease', 'MESH:D006327', (22, 34))
142711	33937395	NRP2 has also been found to be closely associated with metastasis and BRAFV600E in thyroid cancer.	('NRP2', 'Gene', (0, 4))	('metastasis', 'CPA', (55, 65))	('thyroid cancer', 'Disease', 'MESH:D013964', (83, 97))	('BRAFV600E', 'Var', (70, 79))	('BRAFV600E', 'Mutation', 'rs113488022', (70, 79))	('NRP', 'biological_process', 'GO:0085015', ('0', '3'))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('thyroid cancer', 'Phenotype', 'HP:0002890', (83, 97))	('thyroid cancer', 'Disease', (83, 97))
142771	29956810	The patients were principally divided into 3 groups on the basis of BMI: Underweight (<18.5 kg/m2), normal (>=18.5 to <25.0 kg/m2) and high (>=25.0 kg/m2).	('>=18.5 to <25.0', 'Var', (108, 123))	('<18.5 kg/m2', 'Var', (86, 97))	('patients', 'Species', '9606', (4, 12))
142772	29956810	The high group included two sub-groups: Overweight (>=25 to <30 kg/m2) and obese (>=30 kg/m2).	('obese', 'Disease', 'MESH:D009765', (75, 80))	('Overweight', 'Phenotype', 'HP:0025502', (40, 50))	('>=30 kg/m2', 'Var', (82, 92))	('obese', 'Disease', (75, 80))	('>=25', 'Var', (52, 56))
142810	29956810	The result suggested that high BMI (>=25) was a high risk factor for cancer in the gallbladder, rectum, kidney and uterus.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('high', 'Var', (26, 30))
142849	29956810	We identified a positive correlation between a high BMI and the corresponding two/five-year survival rate in cancer samples (r=0.53, Spearman correlation coefficient, Figs.	('BMI', 'MPA', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('high', 'Var', (47, 51))	('cancer', 'Disease', (109, 115))	('two/five-year survival rate', 'CPA', (78, 105))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
142863	29956810	For example, high levels of testosterone, and estrogen and progesterone are risk factors for prostate cancer and breast cancer, respectively.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (93, 108))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('risk factors', 'Reg', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (113, 126))	('high', 'Var', (13, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('testosterone', 'Chemical', 'MESH:D013739', (28, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (93, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))
142871	29956810	In the present study, we found that high BMI (<=25) is potentially a risk factor for many types of cancer.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('types', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('high', 'Var', (36, 40))	('risk', 'Reg', (69, 73))
142873	29956810	Patients with a low BMI (<18.5) had a reduced incidence for all 38 types of cancer.	('low BMI', 'Phenotype', 'HP:0045082', (16, 23))	('reduced', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Patients', 'Species', '9606', (0, 8))	('<18.5', 'Var', (25, 30))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
142910	29950003	Driver gene mutations based clustering of tumors: methods and applications Somatic mutations in proto-oncogenes and tumor suppressor genes constitute a major category of causal genetic abnormalities in tumor cells.	('tumor', 'Disease', (42, 47))	('Somatic', 'Var', (75, 82))	('tumor', 'Disease', (202, 207))	('genetic abnormalities', 'Disease', (177, 198))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor suppressor', 'biological_process', 'GO:0051726', ('116', '132'))	('proto-oncogenes', 'Gene', (96, 111))	('genetic abnormalities', 'Disease', 'MESH:D030342', (177, 198))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('116', '132'))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
142926	29950003	Third, the relevance of a non-synonymous mutation to the formation and progression of tumors intuitively depends on the confidence in its host gene as a true cancer gene.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('formation', 'biological_process', 'GO:0009058', ('57', '66'))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (158, 164))	('non-synonymous', 'Var', (26, 40))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
142953	29950003	wild and mutant) of the two most frequently mutated cancer driver genes for the specific cancer type.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutant', 'Var', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
142961	29950003	M3 is a zero-one filled matrix, indicating the mutation status of the driver genes in the tumor samples of a cancer patient cohort.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('patient', 'Species', '9606', (116, 123))	('mutation', 'Var', (47, 55))	('tumor', 'Disease', (90, 95))	('cancer', 'Disease', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
142964	29950003	Step-2M4 is adjusted to obtain a weighted between-gene similarity matrix (M5) by the Equation M5 The ith row jth column element of M5, represents the 'strength' of the genes gi and gj for connecting two tumor samples that have a mutation on either of them, respectively.	('mutation', 'Var', (229, 237))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (203, 208))
142978	29950003	While some tumors in the TCGA data have over 10 mutations in the putative cancer genes, a recent study showed that most cancer types only require 3 driver mutations.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (11, 17))	('cancer', 'Disease', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('mutations', 'Var', (48, 57))
142990	29950003	For example, the survival stratification of the partition obtained by ccpwModel in LIHC is much clearer than that from nbsModel.	('ccpwModel', 'Var', (70, 79))	('nbs', 'Gene', (119, 122))	('nbs', 'Gene', '4830', (119, 122))
142992	29950003	It clearly shows that the UCEC patients with tumors in which both PTEN and PICK3A genes are mutated demonstrate a desired survival curve, a highly useful signature for predicting the prognosis of UCEC patients (Page-15 of Supplementary Material).	('patients', 'Species', '9606', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('PTEN', 'Gene', (66, 70))	('PTEN', 'Gene', '5728', (66, 70))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('patients', 'Species', '9606', (31, 39))	('mutated', 'Var', (92, 99))	('PICK3A genes', 'Gene', (75, 87))
143000	29950003	Among them, Cluster-3 is of our special interest because ~95% of patients in this group have mutated TP53 gene and its survival profile is poorer than that of the other clusters with a modest significance (P = 0.07, logRank test).	('survival profile', 'CPA', (119, 135))	('mutated', 'Var', (93, 100))	('TP53', 'Gene', '7157', (101, 105))	('poorer', 'NegReg', (139, 145))	('TP53', 'Gene', (101, 105))	('patients', 'Species', '9606', (65, 73))
143008	29950003	Using ccpwModel, we identify a lethal LIHC sub-type (Cluster 4), in which tumor cells are characterized by the mutation-disturbed RAS/PI3K pathways (Fig.	('RAS/PI3K pathways', 'Pathway', (130, 147))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('PI3K', 'molecular_function', 'GO:0016303', ('134', '138'))	('mutation-disturbed', 'Var', (111, 129))
143009	29950003	Another sub-type (Cluster-3), in which tumor cells are characterized by the mutation-disturbed DNA damage control and cell cycle/apoptosis mechanisms, has a relatively low short-term (within 20 months) survival rate.	('mutation-disturbed', 'Var', (76, 94))	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('DNA damage control', 'MPA', (95, 113))	('low', 'NegReg', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('cell cycle', 'biological_process', 'GO:0007049', ('118', '128'))	('tumor', 'Disease', (39, 44))	('cell cycle/apoptosis', 'CPA', (118, 138))
143021	29950003	In this study, we find statistically significant associations between the mutation-based tumor clusters and the racial groups of patients in six cancer types.	('cancer', 'Disease', (145, 151))	('mutation-based', 'Var', (74, 88))	('significant associations', 'Reg', (37, 61))	('patients', 'Species', '9606', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
143029	29950003	Another unique aspect of this study is that it demonstrates a way to integrate the results of mutations based tumor clustering with the widely available gene expression data for prognostic signature identification.	('gene expression', 'biological_process', 'GO:0010467', ('153', '168'))	('mutations', 'Var', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
143031	29950003	For example, the signature in LIHC is selected based on the lethal outcome of patients whose tumors are characterized by mutation-disturbed DNA damage control or RAS/PI3K pathways.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('PI3K', 'molecular_function', 'GO:0016303', ('166', '170'))	('DNA', 'MPA', (140, 143))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('patients', 'Species', '9606', (78, 86))	('RAS/PI3K pathways', 'Pathway', (162, 179))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('tumors', 'Disease', (93, 99))	('mutation-disturbed', 'Var', (121, 139))
143032	29950003	have showed that RAS mutation predicts early lung recurrence and worse survival after curative resection of colorectal liver metastases.	('worse', 'NegReg', (65, 70))	('RAS', 'Gene', (17, 20))	('mutation', 'Var', (21, 29))	('colorectal liver metastases', 'Disease', (108, 135))	('lung recurrence', 'Disease', (45, 60))	('colorectal liver metastases', 'Disease', 'MESH:D009362', (108, 135))
143038	24268029	Overexpression of PinX1 resulted in G1/S phase arrest and cell growth/proliferation inhibition, while silencing PinX1 led to acceleration of G1/S transition, and cell growth/proliferation promotion by inhibiting/enhancing telomerase activity and via the p16/cyclin D1 pathway.	('cell growth', 'biological_process', 'GO:0016049', ('162', '173'))	('cell growth', 'biological_process', 'GO:0016049', ('58', '69'))	('cyclin', 'molecular_function', 'GO:0016538', ('258', '264'))	('silencing', 'Var', (102, 111))	('telomerase activity', 'molecular_function', 'GO:0003720', ('222', '241'))	('inhibition', 'NegReg', (84, 94))	('telomerase activity', 'CPA', (222, 241))	('PinX1', 'Gene', (18, 23))	('PinX1', 'Gene', (112, 117))	('G1/S transition', 'CPA', (141, 156))	('inhibiting/enhancing', 'PosReg', (201, 221))	('acceleration', 'PosReg', (125, 137))	('S phase', 'biological_process', 'GO:0051320', ('39', '46'))	('p16', 'Gene', (254, 257))	('cell growth/proliferation', 'CPA', (162, 187))	('promotion', 'PosReg', (188, 197))	('cyclin D1', 'Gene', (258, 267))	('p16', 'Gene', '1029', (254, 257))	('G1/S phase arrest', 'CPA', (36, 53))	('cell growth/proliferation', 'CPA', (58, 83))	('inhibiting/enhancing', 'NegReg', (201, 221))	('cyclin D1', 'Gene', '595', (258, 267))
143047	24268029	reported that high significance between a single-nucleotide polymorphism on the PinX1 gene and lower bladder cancer risk.	('lower', 'NegReg', (95, 100))	('single-nucleotide polymorphism', 'Var', (42, 72))	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('bladder cancer', 'Disease', (101, 115))	('PinX1', 'Gene', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))
143097	24268029	Interestingly, we found that patients with negative PinX1 expression had a much higher risk of recurrence than did patients with positive PinX1 expression.	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (29, 37))	('recurrence', 'CPA', (95, 105))	('PinX1', 'Gene', (52, 57))	('expression', 'Var', (58, 68))	('negative', 'NegReg', (43, 51))
143101	24268029	In the MTT assay, EJ-PinX1 and T24-PinX1 cells grew more slowly, with 1.4-fold and 1.7-fold fewer cells than the EJ-Vector and T24-Vector control cells respectively, by day 5 after plating (Figure 3C and 3D).	('MTT', 'Chemical', '-', (7, 10))	('EJ', 'CellLine', 'CVCL:7039', (18, 20))	('slowly', 'NegReg', (57, 63))	('EJ', 'CellLine', 'CVCL:7039', (113, 115))	('grew', 'CPA', (47, 51))	('fewer', 'NegReg', (92, 97))	('cells', 'CPA', (98, 103))	('T24-PinX1', 'Var', (31, 40))
143102	24268029	In the colony-formation assay, EJ-PinX1 and T24-PinX1 cells also formed fewer and smaller colonies than the EJ-Vector and T24-Vector cells, respectively.	('smaller', 'NegReg', (82, 89))	('fewer', 'NegReg', (72, 77))	('T24-PinX1', 'Var', (44, 53))	('EJ-PinX1', 'Var', (31, 39))	('formation', 'biological_process', 'GO:0009058', ('14', '23'))	('EJ', 'CellLine', 'CVCL:7039', (31, 33))	('EJ', 'CellLine', 'CVCL:7039', (108, 110))
143103	24268029	Furthermore, knocking-down of endogenous PinX1 in 5637 cells by shRNA significantly decreased PinX1 protein expression (Figure 3G) and increased 5637 cell viability, as analyzed by the MTT and colony-formation assays (Figure 3H and 3I).	('5637 cell viability', 'CPA', (145, 164))	('protein', 'Protein', (100, 107))	('PinX1', 'Gene', (41, 46))	('formation', 'biological_process', 'GO:0009058', ('200', '209'))	('increased', 'PosReg', (135, 144))	('PinX1', 'Gene', (94, 99))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('knocking-down', 'Var', (13, 26))	('decreased', 'NegReg', (84, 93))	('MTT', 'Chemical', '-', (185, 188))
143104	24268029	Tumors formed from EJ-PinX1 and T24-PinX1 cells implanted in nude mice grew more slowly and weighed substantially less than those formed by EJ-Vector and T24-Vector cells respectively, after 48 days (Figure 4A and 4B).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('less', 'NegReg', (114, 118))	('slowly', 'NegReg', (81, 87))	('T24-PinX1', 'Var', (32, 41))	('EJ', 'CellLine', 'CVCL:7039', (19, 21))	('grew', 'CPA', (71, 75))	('nude mice', 'Species', '10090', (61, 70))	('EJ', 'CellLine', 'CVCL:7039', (140, 142))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('weighed', 'CPA', (92, 99))
143105	24268029	Furthermore, tumors derived from 5637 cells transduced with retroviruses expressing PinX1-shRNA grew much faster and weighed significantly more at day 48 than those formed by 5637-Scramble cells (Figure 4C).	('faster', 'PosReg', (106, 112))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('weighed', 'CPA', (117, 124))	('PinX1-shRNA', 'Var', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('grew', 'CPA', (96, 100))	('more', 'PosReg', (139, 143))
143107	24268029	Annexin V binds to those cells that express phosphatidylserine on the outer layer of the cell membrane, which is a characteristic feature of cells entering the process of apoptosis.	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('apoptosis', 'biological_process', 'GO:0006915', ('171', '180'))	('phosphatidylserine', 'Var', (44, 62))	('cell membrane', 'cellular_component', 'GO:0005886', ('89', '102'))	('apoptosis', 'biological_process', 'GO:0097194', ('171', '180'))	('binds', 'Interaction', (10, 15))
143131	24268029	Multivariate analysis showed that the loss of PinX1 protein expression could be used as an independent prognostic predictor for UCB patients.	('loss', 'Var', (38, 42))	('expression', 'MPA', (60, 70))	('protein', 'Protein', (52, 59))	('PinX1', 'Gene', (46, 51))	('UCB', 'Phenotype', 'HP:0006740', (128, 131))	('patients', 'Species', '9606', (132, 140))	('UCB', 'Disease', (128, 131))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
143137	24268029	Overexpression of PinX1 in tumor cells could inhibit telomerase activity, shorten telomeres, and suppress tumor growth, while depletion of endogenous PinX1 increased telomerase activity, elongated telomeres, and enhanced tumorigenicity in telomerase-positive HT1080 cancer cells.	('shorten', 'NegReg', (74, 81))	('telomerase activity', 'MPA', (166, 185))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('increased', 'PosReg', (156, 165))	('activity', 'MPA', (64, 72))	('tumor', 'Disease', (106, 111))	('HT1080', 'CellLine', 'CVCL:0317', (259, 265))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('suppress', 'NegReg', (97, 105))	('tumor', 'Disease', (27, 32))	('PinX1', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('inhibit', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('telomerase activity', 'molecular_function', 'GO:0003720', ('166', '185'))	('enhanced', 'PosReg', (212, 220))	('telomeres', 'MPA', (82, 91))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('telomerase', 'Protein', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('PinX1', 'Gene', (150, 155))	('elongated', 'PosReg', (187, 196))	('cancer', 'Disease', (266, 272))	('depletion', 'Var', (126, 135))	('shorten telomeres', 'Phenotype', 'HP:0031413', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('telomerase activity', 'molecular_function', 'GO:0003720', ('53', '72'))
143138	24268029	Disruption of the PinX1-dependent telomere maintenance pathway could reduce carcinogenesis and enhance chemotherapeutic sensitivity in telomerase-positive human cancer cells as well.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('telomere', 'cellular_component', 'GO:0000781', ('34', '42'))	('human', 'Species', '9606', (155, 160))	('telomere maintenance', 'biological_process', 'GO:0000723', ('34', '54'))	('reduce', 'NegReg', (69, 75))	('chemotherapeutic sensitivity', 'CPA', (103, 131))	('PinX1-dependent', 'Gene', (18, 33))	('telomere', 'cellular_component', 'GO:0005696', ('34', '42'))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('carcinogenesis', 'Disease', (76, 90))	('carcinogenesis', 'Disease', 'MESH:D063646', (76, 90))	('cancer', 'Disease', (161, 167))	('enhance', 'PosReg', (95, 102))	('Disruption', 'Var', (0, 10))
143139	24268029	In the present study, we found that overexpression of PinX1 by transfection of pBABE-PinX1 into EJ and T24 cells significantly reduced cell growth, and arrested cells in the G0/G1 phase via the inhibition of telomerase activity and shortening of telomeres.	('activity', 'MPA', (219, 227))	('inhibition', 'NegReg', (194, 204))	('telomerase', 'CPA', (208, 218))	('overexpression', 'PosReg', (36, 50))	('pBABE-PinX1', 'Gene', (79, 90))	('G1 phase', 'biological_process', 'GO:0051318', ('177', '185'))	('cell growth', 'CPA', (135, 146))	('cells in the G0/G1 phase', 'CPA', (161, 185))	('transfection', 'Var', (63, 75))	('inhibition of telomerase activity', 'biological_process', 'GO:0051974', ('194', '227'))	('cell growth', 'biological_process', 'GO:0016049', ('135', '146'))	('shortening', 'CPA', (232, 242))	('EJ', 'CellLine', 'CVCL:7039', (96, 98))	('arrested', 'PosReg', (152, 160))	('shortening of telomeres', 'Phenotype', 'HP:0031413', (232, 255))	('reduced', 'NegReg', (127, 134))	('telomerase activity', 'molecular_function', 'GO:0003720', ('208', '227'))	('PinX1', 'Gene', (54, 59))
143151	24268029	Dysfunction of the proteins involved in the p16 pathway such as deletion of the p16 gene and overexpression of CDKs of cyclin D1 will lead to Rb phosphorylation, subsequent progression of G1/S phase transition and promotion of uncontrolled cell growth/proliferation.	('G1/S phase transition', 'CPA', (188, 209))	('p16', 'Gene', (44, 47))	('phosphorylation', 'biological_process', 'GO:0016310', ('145', '160'))	('deletion', 'Var', (64, 72))	('p16', 'Gene', '1029', (44, 47))	('S phase', 'biological_process', 'GO:0051320', ('191', '198'))	('overexpression', 'PosReg', (93, 107))	('cyclin', 'molecular_function', 'GO:0016538', ('119', '125'))	('promotion', 'PosReg', (214, 223))	('CDKs', 'Gene', (111, 115))	('progression', 'PosReg', (173, 184))	('cyclin D1', 'Gene', (119, 128))	('uncontrolled cell growth/proliferation', 'CPA', (227, 265))	('cyclin D1', 'Gene', '595', (119, 128))	('CDKs', 'Gene', '1019', (111, 115))	('p16', 'Gene', (80, 83))	('Rb', 'Gene', '5925', (142, 144))	('lead to', 'Reg', (134, 141))	('cell growth', 'biological_process', 'GO:0016049', ('240', '251'))	('p16', 'Gene', '1029', (80, 83))	('phosphorylation', 'MPA', (145, 160))	('Rb', 'Phenotype', 'HP:0009919', (142, 144))
143165	23433042	Our results also demonstrate that GFW interferes with cell cycle progression through the activation of CHK2 and P21 and induces apoptosis in these bladder cancer cells.	('interferes', 'NegReg', (38, 48))	('GFW', 'Var', (34, 37))	('induces', 'Reg', (120, 127))	('P21', 'Gene', '1026', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('bladder cancer', 'Phenotype', 'HP:0009725', (147, 161))	('cell cycle', 'biological_process', 'GO:0007049', ('54', '64'))	('apoptosis', 'biological_process', 'GO:0097194', ('128', '137'))	('activation', 'PosReg', (89, 99))	('bladder cancer', 'Disease', 'MESH:D001749', (147, 161))	('CHK2', 'Gene', (103, 107))	('bladder cancer', 'Disease', (147, 161))	('apoptosis', 'biological_process', 'GO:0006915', ('128', '137'))	('P21', 'Gene', (112, 115))	('cell cycle progression', 'CPA', (54, 76))	('CHK2', 'Gene', '11200', (103, 107))	('apoptosis', 'CPA', (128, 137))
143170	23433042	Unfortunately, intravesical chemotherapy, such as mitomycin C or thiotepa, commonly produce severe side effects, including urinary frequency, urinary urgency, cystitis, and hematuria.	('urinary urgency', 'Disease', (142, 157))	('mitomycin', 'Var', (50, 59))	('hematuria', 'Disease', 'MESH:D006417', (173, 182))	('mitomycin C', 'Chemical', 'MESH:D016685', (50, 61))	('urinary urgency', 'Phenotype', 'HP:0000012', (142, 157))	('thiotepa', 'Chemical', 'MESH:D013852', (65, 73))	('cystitis', 'Disease', 'MESH:D003556', (159, 167))	('hematuria', 'Phenotype', 'HP:0000790', (173, 182))	('cystitis', 'Disease', (159, 167))	('hematuria', 'Disease', (173, 182))	('urinary frequency', 'Disease', (123, 140))
143208	23433042	Compared with the untreated control, the CCK-8 assay revealed that the cytotoxicity of GFW to TSGH 8301 and BFTC 905 urothelial cancer cells is comparable to that of the three other chemotherapeutic agents with different IC50 values (P< 0.001, one-way ANOVA) (Table 2 and Figure 3).	('GFW', 'Var', (87, 90))	('cytotoxicity', 'Disease', (71, 83))	('urothelial cancer', 'Disease', (117, 134))	('BFTC', 'Chemical', '-', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cytotoxicity', 'Disease', 'MESH:D064420', (71, 83))	('urothelial cancer', 'Disease', 'MESH:D014523', (117, 134))
143214	23433042	These results suggest that GFW leads to the cell cycle arrest at the G1 to S transition of BFTC 905 cells and at the S to G2/M transition in TSGH 8301 cells.	('BFTC', 'Chemical', '-', (91, 95))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('44', '61'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (44, 61))	('cell cycle arrest', 'CPA', (44, 61))	('GFW', 'Var', (27, 30))
143215	23433042	Accordingly, the increase in the number of BFTC 905 cells in S phase was significant at 0.5 and 1 mg/ml of GFW (p<0.01), which correlates with a reduction in the number of cells in G2/M phase for these concentrations.	('S phase', 'CPA', (61, 68))	('reduction', 'NegReg', (145, 154))	('S phase', 'biological_process', 'GO:0051320', ('61', '68'))	('GFW', 'Gene', (107, 110))	('1 mg/ml', 'Var', (96, 103))	('0.5', 'Var', (88, 91))	('increase', 'PosReg', (17, 25))	('BFTC', 'Chemical', '-', (43, 47))	('M phase', 'biological_process', 'GO:0000279', ('184', '191'))
143229	23433042	In terms of its anti-cancer effect, GFW has been shown to inhibit the growth of hepatocellular carcinoma and cervical cancer.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cervical cancer', 'Disease', 'MESH:D002583', (109, 124))	('cervical cancer', 'Disease', (109, 124))	('GFW', 'Var', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (80, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('hepatocellular carcinoma', 'Disease', (80, 104))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (80, 104))	('cancer', 'Disease', (21, 27))	('inhibit', 'NegReg', (58, 65))	('growth', 'MPA', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
143238	23433042	Cell cycle analysis results indicate that GFW led to cell cycle arrest in BFTC 905 in the S-phase, while cell cycle arrest in TSGH 8301 occurred in G2/M phase (Figures 4A and 4B).	('GFW', 'Var', (42, 45))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (105, 122))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (53, 70))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('53', '70'))	('M phase', 'biological_process', 'GO:0000279', ('151', '158'))	('BFTC 905', 'Gene', (74, 82))	('S-phase', 'biological_process', 'GO:0051320', ('90', '97'))	('cell cycle arrest', 'CPA', (53, 70))	('BFTC', 'Chemical', '-', (74, 78))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('105', '122'))
143252	23433042	We suspect that GFW may cause very early genotoxic stress responses in highly replicating cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('GFW', 'Var', (16, 19))	('cause', 'Reg', (24, 29))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
143256	23433042	Treatment with 1 mg/ml of GFW resulted in significantly higher levels of apoptosis than what was observed in the untreated control group, indicating that GFW is a potent inducer of apoptosis in both BFTC 905 and TSGH 8301 cells.	('apoptosis', 'biological_process', 'GO:0097194', ('181', '190'))	('levels', 'MPA', (63, 69))	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('BFTC', 'Chemical', '-', (199, 203))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('apoptosis', 'biological_process', 'GO:0006915', ('181', '190'))	('inducer', 'PosReg', (170, 177))	('apoptosis', 'MPA', (73, 82))	('GFW', 'Var', (154, 157))	('higher', 'PosReg', (56, 62))
143262	23433042	We have also demonstrated that GFW interferes with cell cycle progression via the activation of CHK2/P21 pathway and induces apoptosis in these bladder cancer cells.	('GFW', 'Var', (31, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (144, 158))	('interferes', 'NegReg', (35, 45))	('cell cycle progression', 'CPA', (51, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('125', '134'))	('P21', 'Gene', (101, 104))	('apoptosis', 'biological_process', 'GO:0006915', ('125', '134'))	('activation', 'PosReg', (82, 92))	('induces', 'Reg', (117, 124))	('cell cycle', 'biological_process', 'GO:0007049', ('51', '61'))	('CHK2', 'Gene', (96, 100))	('bladder cancer', 'Disease', 'MESH:D001749', (144, 158))	('apoptosis', 'CPA', (125, 134))	('bladder cancer', 'Disease', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('CHK2', 'Gene', '11200', (96, 100))	('P21', 'Gene', '1026', (101, 104))
143290	33086575	The aggressiveness of luminal-like NMIBC is known to stem from the enrichment of the cell cycle, changes in junctional complexes, or high copy number alteration.	('junctional complexes', 'MPA', (108, 128))	('changes', 'Reg', (97, 104))	('aggressiveness', 'Disease', 'MESH:D001523', (4, 18))	('cell cycle', 'biological_process', 'GO:0007049', ('85', '95'))	('aggressiveness', 'Disease', (4, 18))	('luminal', 'Chemical', 'MESH:D010634', (22, 29))	('NMIBC', 'Chemical', '-', (35, 40))	('high copy number alteration', 'Var', (133, 160))	('aggressiveness', 'Phenotype', 'HP:0000718', (4, 18))
143291	33086575	K5/6 and K20 have been widely used as surrogate markers of intrinsic subtypes of NMIBC, and their expression is significantly associated with the clinical outcomes of NMIBC.	('K20', 'Gene', '54474', (9, 12))	('associated with', 'Reg', (126, 141))	('NMIBC', 'Chemical', '-', (167, 172))	('NMIBC', 'Chemical', '-', (81, 86))	('K5/6', 'Var', (0, 4))	('K20', 'Gene', (9, 12))	('expression', 'MPA', (98, 108))
143292	33086575	In addition, it was demonstrated that immunohistochemical (IHC) expression of K5/6 and K20 was associated with the molecular biology of non-muscle-invasive upper tract urothelial carcinoma (NMIUTUC), including proliferation, cell adhesion, and the mitogen-activated protein kinase (MAPK) pathway.	('muscle-invasive upper tract urothelial carcinoma', 'Disease', (140, 188))	('K5/6', 'Var', (78, 82))	('proliferation', 'CPA', (210, 223))	('muscle-invasive upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (140, 188))	('MAPK', 'molecular_function', 'GO:0004707', ('282', '286'))	('protein', 'cellular_component', 'GO:0003675', ('266', '273'))	('cell adhesion', 'biological_process', 'GO:0007155', ('225', '238'))	('K20', 'Gene', '54474', (87, 90))	('cell adhesion', 'CPA', (225, 238))	('K20', 'Gene', (87, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('associated', 'Reg', (95, 105))
143303	33086575	The overexpression pattern of p53 was observed in 0%, 75%, 50%, and 25% of K5/6-only, K20-only, double-high, and double-low group tumors, respectively.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('double-high', 'Var', (96, 107))	('K20', 'Gene', (86, 89))	('K20', 'Gene', '54474', (86, 89))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('K5/6-only', 'Var', (75, 84))	('double-low', 'Var', (113, 123))
143305	33086575	We identified 1462 DEGs across the NMIBC groups (K20-only vs. K5/6-only, K20-only vs. double-high, K5/6-only vs. double-high, K20-only vs. double-low, and K5/6-only vs. double-low), as illustrated in Figure S3.	('K20', 'Gene', (126, 129))	('K20', 'Gene', '54474', (126, 129))	('K5/6-only vs. double-high', 'Var', (99, 124))	('K5/6-only', 'Var', (155, 164))	('K20', 'Gene', '54474', (49, 52))	('K20', 'Gene', (49, 52))	('K20', 'Gene', (73, 76))	('NMIBC', 'Chemical', '-', (35, 40))	('K20', 'Gene', '54474', (73, 76))	('double-high', 'Var', (113, 124))
143307	33086575	Conversely, relative to the K20-only group, cell cycle arrest and/or cell death were enriched in DEGs upregulated in the K5/6-only group (e.g., GO "intrinsic apoptotic signaling pathway by p53 class mediator" and "positive regulation of cell death"; KEGG "apoptosis") and in the double-high group (e.g., GO "positive regulation of cell cycle arrest" and "DNA damage response signal transduction by p53 class mediator").	('cell death', 'biological_process', 'GO:0008219', ('69', '79'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (331, 348))	('arrest', 'Disease', 'MESH:D006323', (55, 61))	('p53', 'Gene', '7157', (189, 192))	('p53', 'Gene', '7157', (398, 401))	('DEGs', 'Gene', (97, 101))	('upregulated', 'PosReg', (102, 113))	('K5/6-only', 'Var', (121, 130))	('arrest', 'Disease', 'MESH:D006323', (342, 348))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('44', '61'))	('arrest', 'Disease', (55, 61))	('K20', 'Gene', '54474', (28, 31))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (44, 61))	('K20', 'Gene', (28, 31))	('cell death', 'CPA', (69, 79))	('arrest', 'Disease', (342, 348))	('p53', 'Gene', (398, 401))	('p53', 'Gene', (189, 192))
143308	33086575	Second, genes significantly overexpressed in the double-high group (vs. K20-only or K5/6-only) and the double-low group (vs. K20-only) were skewed toward functions related to protein synthesis/metabolism (e.g., GO "protein targeting to ER", "cellular nitrogen compound biosynthetic process", and "positive regulation of nitrogen compound metabolic process"; KEGG "ribosome').	('nitrogen compound metabolic process', 'MPA', (320, 355))	('overexpressed', 'PosReg', (28, 41))	('nitrogen', 'Chemical', 'MESH:D009584', (320, 328))	('double-high', 'Var', (49, 60))	('nitrogen', 'Chemical', 'MESH:D009584', (251, 259))	('protein synthesis/metabolism', 'MPA', (175, 203))	('K20', 'Gene', '54474', (72, 75))	('K20', 'Gene', (125, 128))	('K20', 'Gene', (72, 75))	('K20', 'Gene', '54474', (125, 128))
143309	33086575	In addition, DEGs found to be highly expressed in the K5/6-only or double-high groups compared to the K20-only or double-low groups were overrepresented by tissue morphogenesis and cell/substrate binding functions (e.g., GO "tissue morphogenesis" and "cell-substrate adhesion"; KEGG "focal adhesion" and "tight junction").	('binding', 'molecular_function', 'GO:0005488', ('196', '203'))	('K20', 'Gene', (102, 105))	('overrepresented', 'PosReg', (137, 152))	('cell/substrate binding', 'CPA', (181, 203))	('K20', 'Gene', '54474', (102, 105))	('tissue morphogenesis', 'biological_process', 'GO:0048729', ('156', '176'))	('GO "tissue morphogenesis" and "cell-substrate adhesion"', 'CPA', (221, 276))	('double-high', 'Var', (67, 78))	('K5/6-only', 'Var', (54, 63))
143310	33086575	Signaling pathways, such as the PI3K-Akt, MAPK, and HIF pathways, were related to the upregulated genes of the K5/6-only group and, to a lesser extent, to those of the double-high group compared to the K20-only or double-low groups.	('MAPK', 'Pathway', (42, 46))	('PI3K', 'molecular_function', 'GO:0016303', ('32', '36'))	('HIF pathways', 'Pathway', (52, 64))	('Akt', 'Gene', '207', (37, 40))	('K5/6-only', 'Var', (111, 120))	('K20', 'Gene', (202, 205))	('MAPK', 'molecular_function', 'GO:0004707', ('42', '46'))	('K20', 'Gene', '54474', (202, 205))	('Akt', 'Gene', (37, 40))	('upregulated', 'PosReg', (86, 97))	('Signaling pathways', 'Pathway', (0, 18))	('Signaling', 'biological_process', 'GO:0023052', ('0', '9'))
143314	33086575	Likewise, Gene Set Enrichment Analysis (GSEA) demonstrated enrichment of cell proliferation and related machinery in the K20-only group and also in the double-low group relative to the K5/6-only or double-high groups (Figure 2a,b, Figure S4).	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('GSEA', 'Chemical', '-', (40, 44))	('cell proliferation', 'CPA', (73, 91))	('K20', 'Gene', '54474', (121, 124))	('K20', 'Gene', (121, 124))	('double-low', 'Var', (152, 162))
143330	33086575	Similar to the results of our NMIBC cohorts, the K20-only_Lund group was overrepresented by cell cycle and E2F functions compared to the other groups; however, compared to the K20-only_Lund group, the K5/6-only_Lund group had increased levels of genes involved in epithelium morphogenesis and cellular biologic processes (Figure 3; Table S5).	('NMIBC', 'Chemical', '-', (30, 35))	('epithelium morphogenesis', 'biological_process', 'GO:0002009', ('264', '288'))	('K20', 'Gene', '54474', (49, 52))	('K20', 'Gene', (49, 52))	('K5/6-only_Lund', 'Var', (201, 215))	('K20', 'Gene', (176, 179))	('cell cycle', 'biological_process', 'GO:0007049', ('92', '102'))	('K20', 'Gene', '54474', (176, 179))	('increased', 'PosReg', (226, 235))	('levels of genes', 'MPA', (236, 251))
143332	33086575	In addition, consistent with the foregoing findings for the K5/6-only group, activation of KDM5B was predicted in the K5/6-only_Lund group compared to the K20-only_Lund or double-high_Lund groups (Table 2).	('KDM5B', 'Gene', '10765', (91, 96))	('activation', 'PosReg', (77, 87))	('KDM5B', 'Gene', (91, 96))	('K20', 'Gene', (155, 158))	('K5/6-only_Lund', 'Var', (118, 132))	('K20', 'Gene', '54474', (155, 158))
143335	33086575	In addition to their correlation to molecular profiles of bladder cancer, immunostains for K5/6 and K20 have an advantage in that they are widely used in real-world practice.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('K5/6', 'Var', (91, 95))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('K20', 'Gene', (100, 103))	('K20', 'Gene', '54474', (100, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('bladder cancer', 'Disease', (58, 72))
143338	33086575	On the other hand, the transcriptional characteristics of the double-high group included cell cycle arrest, apoptosis, tissue morphogenesis, and protein synthesis/metabolism.	('arrest', 'Disease', 'MESH:D006323', (100, 106))	('metabolism', 'biological_process', 'GO:0008152', ('163', '173'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('89', '106'))	('protein synthesis/metabolism', 'CPA', (145, 173))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('arrest', 'Disease', (100, 106))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('tissue morphogenesis', 'CPA', (119, 139))	('protein synthesis', 'biological_process', 'GO:0006412', ('145', '162'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (89, 106))	('double-high group', 'Var', (62, 79))	('tissue morphogenesis', 'biological_process', 'GO:0048729', ('119', '139'))	('apoptosis', 'CPA', (108, 117))
143346	33086575	: GSEA clearly connected our K20-only and double-high groups to Lindgren's cluster 3 and cluster 1, respectively.	('K20', 'Gene', '54474', (29, 32))	('GSEA', 'Chemical', '-', (2, 6))	('K20', 'Gene', (29, 32))	('double-high', 'Var', (42, 53))
143352	33086575	In mice, activation of E2F3 driven by deregulated Rb-induced high-grade papillary bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('activation', 'PosReg', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('deregulated', 'Var', (38, 49))	('mice', 'Species', '10090', (3, 7))	('papillary bladder cancer', 'Disease', 'MESH:D001749', (72, 96))	('Rb', 'Gene', '19645', (50, 52))	('papillary bladder cancer', 'Disease', (72, 96))	('E2F3 driven', 'Gene', (23, 34))
143353	33086575	E2F3, as a contributor to early cell cycle progression, may regulate early cell cycle genes in the K20-only group (e.g., ID2 and ID3).	('early cell cycle genes', 'Gene', (69, 91))	('ID2', 'Gene', (121, 124))	('K20', 'Gene', '54474', (99, 102))	('K20', 'Gene', (99, 102))	('cell cycle', 'biological_process', 'GO:0007049', ('32', '42'))	('regulate', 'Reg', (60, 68))	('ID3', 'Gene', (129, 132))	('E2F3', 'Var', (0, 4))	('cell cycle', 'biological_process', 'GO:0007049', ('75', '85'))
143358	33086575	FGFR3 alteration is one of the molecular hallmarks of early carcinogenesis of the urothelium and is associated with increased survival in NMIBC.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('carcinogenesis', 'Disease', 'MESH:D063646', (60, 74))	('FGFR3', 'Gene', (0, 5))	('associated', 'Reg', (100, 110))	('carcinogenesis', 'Disease', (60, 74))	('NMIBC', 'Chemical', '-', (138, 143))	('alteration', 'Var', (6, 16))	('increased', 'PosReg', (116, 125))	('FGFR3', 'Gene', '2261', (0, 5))
143359	33086575	We demonstrated that both the FGFR3 gene ( fold change  = 4.7, p = 0.04, double-high vs. K20-only) and its associated signatures were downregulated in the K20-only group but enriched in the double-high group.	('K20', 'Gene', '54474', (89, 92))	('downregulated', 'NegReg', (134, 147))	('K20', 'Gene', (89, 92))	('FGFR3', 'Gene', (30, 35))	('double-high', 'Var', (73, 84))	('K20', 'Gene', (155, 158))	('K20', 'Gene', '54474', (155, 158))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('FGFR3', 'Gene', '2261', (30, 35))
143360	33086575	Notably, Lindgren's cluster 1 is more closely related to FGFR3 alteration, such as a higher mutation rate and expression level, than Lindgren's cluster 3.	('expression level', 'MPA', (110, 126))	('FGFR3', 'Gene', (57, 62))	('higher', 'PosReg', (85, 91))	('mutation rate', 'MPA', (92, 105))	('FGFR3', 'Gene', '2261', (57, 62))	('alteration', 'Var', (63, 73))	('FGFR', 'molecular_function', 'GO:0005007', ('57', '61'))
143361	33086575	Mutation-driven hyperactivation of FGFR3 is one of the major triggers of low-risk NMIBC that frequently co-occurs with PIK3CA mutation.	('Mutation-driven hyperactivation', 'Var', (0, 31))	('NMIBC', 'Disease', (82, 87))	('NMIBC', 'Chemical', '-', (82, 87))	('PIK3CA', 'Gene', (119, 125))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR3', 'Gene', '2261', (35, 40))	('PIK3CA', 'Gene', '5290', (119, 125))	('triggers', 'Reg', (61, 69))	('mutation', 'Var', (126, 134))	('hyperactivation', 'Var', (16, 31))	('FGFR3', 'Gene', (35, 40))
143362	33086575	Consistent with this, we found that the double-high group was enriched in PI3K-Akt signaling.	('Akt signaling', 'biological_process', 'GO:0043491', ('79', '92'))	('Akt', 'Gene', '207', (79, 82))	('double-high', 'Var', (40, 51))	('PI3K', 'molecular_function', 'GO:0016303', ('74', '78'))	('Akt', 'Gene', (79, 82))
143364	33086575	In addition, previous studies showed that K5/6 and K20 dual positivity marked well-differentiated tumors that maintained tissue architectural hierarchy, which was demonstrated to be a favorable prognostic factor for early urothelial carcinoma.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tissue architectural hierarchy', 'CPA', (121, 151))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('urothelial carcinoma', 'Disease', (222, 242))	('K20', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('K5/6', 'Var', (42, 46))	('K20', 'Gene', '54474', (51, 54))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (222, 242))
143367	33086575	High levels of K14 in the K5/6-only group indicate its connection to the basal-like state and migratory function, in accordance with previous reports that K14 was mainly expressed in tumors with high K5/6 and low K20 expression and K14 expression identified stemness and basal/squamous-like characteristics, including activated cellular movement, in urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (350, 370))	('K20', 'Gene', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('K14', 'Gene', (15, 18))	('urothelial carcinoma', 'Disease', (350, 370))	('basal/squamous-like characteristics', 'CPA', (271, 306))	('tumors', 'Disease', (183, 189))	('K14', 'Gene', '3861', (15, 18))	('identified', 'Reg', (247, 257))	('K14', 'Gene', (155, 158))	('K14', 'Gene', '3861', (155, 158))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('high K5/6', 'Var', (195, 204))	('K20', 'Gene', '54474', (213, 216))	('K14', 'Gene', (232, 235))	('stemness', 'CPA', (258, 266))	('K14', 'Gene', '3861', (232, 235))	('activated cellular movement', 'CPA', (318, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (361, 370))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))
143368	33086575	Parallel to this, we also found a trend of tumors showing p53-wildtype staining clustered in the K5/6-only group compared to the K20-only group, which frequently displayed p53 overexpression.	('K20', 'Gene', (129, 132))	('p53', 'Gene', '7157', (58, 61))	('K20', 'Gene', '54474', (129, 132))	('p53', 'Gene', '7157', (172, 175))	('K5/6-only', 'Var', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))	('p53', 'Gene', (58, 61))	('p53', 'Gene', (172, 175))
143369	33086575	Aberrant expression of p53 differs among NMIBC subtypes and can indicate impending stage progression of the "genomically unstable" or "urothelial-like C" subtypes that are genetically similar to our K20-only group.	('Aberrant', 'Var', (0, 8))	('indicate', 'Reg', (64, 72))	('K20', 'Gene', '54474', (199, 202))	('K20', 'Gene', (199, 202))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('NMIBC', 'Chemical', '-', (41, 46))
143376	33086575	Instead, we revealed that the double-low group had a moderate expression of cell cycle progression-relate genes, in between that of the K20-only group and that of the K5/6-only group, and had a higher level of a protein synthetic/metabolic signature genes than the K20-only group.	('double-low', 'Var', (30, 40))	('higher', 'PosReg', (194, 200))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('K20', 'Gene', '54474', (136, 139))	('expression', 'MPA', (62, 72))	('K20', 'Gene', (136, 139))	('K20', 'Gene', (265, 268))	('K20', 'Gene', '54474', (265, 268))	('protein synthetic/metabolic signature genes', 'MPA', (212, 255))	('cell cycle', 'biological_process', 'GO:0007049', ('76', '86'))	('cell cycle progression-relate genes', 'Gene', (76, 111))
143377	33086575	IHC staining for K5/6 was reactive in some of the basal cells in the double-low group tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('double-low group', 'Var', (69, 85))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', (86, 92))
143379	33086575	In view of these findings, we hypothesize that the double-low group may indicate an advanced state of the K5/6-only group that is not yet as progressed as the K20-only group.	('double-low', 'Var', (51, 61))	('K20', 'Gene', '54474', (159, 162))	('K20', 'Gene', (159, 162))
143384	33086575	Aberrant expression of p53 (1:1000, DO-7, Dako) was defined as homogenous overexpression, complete absence, or cytoplasmic staining following a previous study.	('Aberrant', 'Var', (0, 8))	('absence', 'NegReg', (99, 106))	('overexpression', 'PosReg', (74, 88))	('p53', 'Gene', '7157', (23, 26))	('p53', 'Gene', (23, 26))
143400	33086575	IHC staining for K5/6 and K20 is an indicator of molecular traits profoundly affected in NMIBC and closely associated with NMIBC subtypes; thus, we propose K5/6 and K20 as promising biomarkers in the management of patients with NMIBC.	('K20', 'Gene', '54474', (26, 29))	('NMIBC', 'Chemical', '-', (228, 233))	('K20', 'Gene', (26, 29))	('patients', 'Species', '9606', (214, 222))	('affected', 'Reg', (77, 85))	('associated', 'Reg', (107, 117))	('K20', 'Gene', '54474', (165, 168))	('NMIBC', 'Disease', (89, 94))	('K20', 'Gene', (165, 168))	('NMIBC', 'Chemical', '-', (89, 94))	('NMIBC', 'Chemical', '-', (123, 128))	('K5/6', 'Var', (156, 160))
143406	31627336	Our results showed that PR-619 effectively induced dose- and time-dependent cytotoxicity, apoptosis, and ER-stress related apoptosis in human UC (T24 and BFTC-905) cells.	('human', 'Species', '9606', (136, 141))	('ER-stress related apoptosis', 'CPA', (105, 132))	('BFTC-905', 'CellLine', 'CVCL:1083', (154, 162))	('cytotoxicity', 'Disease', 'MESH:D064420', (76, 88))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('apoptosis', 'CPA', (90, 99))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('PR-619', 'Var', (24, 30))	('cytotoxicity', 'Disease', (76, 88))	('UC', 'Disease', 'MESH:D014523', (142, 144))
143407	31627336	Additionally, co-treatment of PR-619 with cisplatin potentiated cisplatin-induced cytotoxicity in UC cells and was accompanied by the concurrent suppression of Bcl-2.	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('co-treatment', 'Var', (14, 26))	('potentiated', 'PosReg', (52, 63))	('suppression', 'NegReg', (145, 156))	('cytotoxicity', 'Disease', (82, 94))	('UC', 'Disease', 'MESH:D014523', (98, 100))	('cisplatin-induced', 'MPA', (64, 81))	('Bcl-2', 'Gene', (160, 165))	('cytotoxicity', 'Disease', 'MESH:D064420', (82, 94))	('Bcl-2', 'Gene', '596', (160, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('Bcl-2', 'molecular_function', 'GO:0015283', ('160', '165'))
143409	31627336	In a xenograft mice model, we confirmed that PR-619 enhanced the antitumor effect of cisplatin on cisplatin-naive and cisplatin-resistant UCs.	('UC', 'Disease', 'MESH:D014523', (138, 140))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('PR-619', 'Var', (45, 51))	('tumor', 'Disease', (69, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (118, 127))	('enhanced', 'PosReg', (52, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('mice', 'Species', '10090', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
143410	31627336	Our results demonstrated that PR-619 effectively enhanced the cisplatin-induced antitumor effect via concurrent suppression of the Bcl-2 level.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cisplatin-induced', 'MPA', (62, 79))	('Bcl-2', 'Gene', (131, 136))	('Bcl-2', 'Gene', '596', (131, 136))	('enhanced', 'PosReg', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Bcl-2', 'molecular_function', 'GO:0015283', ('131', '136'))	('tumor', 'Disease', (84, 89))	('PR-619', 'Var', (30, 36))	('suppression', 'NegReg', (112, 123))
143421	31627336	PR-619, as a pan-DUB inhibitor, has been reported to be an effective treatment in some cancers.	('cancers', 'Disease', (87, 94))	('PR-619', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
143433	31627336	For Western blot analysis, the antibodies against CHOP (#2895), Bcl-2 (#2827), P21 (#2947), and cleaved-PARP (#5625) were obtained from Cell Signaling Technology (Danvers, MA, USA).	('P21', 'Gene', (79, 82))	('Signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('PARP', 'Gene', '1302', (104, 108))	('CHOP', 'Gene', (50, 54))	('#2827', 'Var', (71, 76))	('Bcl-2', 'Gene', (64, 69))	('P21', 'Gene', '1026', (79, 82))	('Bcl-2', 'molecular_function', 'GO:0015283', ('64', '69'))	('PARP', 'Gene', (104, 108))	('#2895', 'Var', (56, 61))	('#5625', 'Var', (110, 115))	('Bcl-2', 'Gene', '596', (64, 69))	('CHOP', 'Gene', '1649', (50, 54))
143461	31627336	As illustrated in Figure 1A,B, PR-619 effectively induced cytotoxicity and apoptosis in both T24 and BFTC cells in a dose- and time-dependent manner.	('induced', 'Reg', (50, 57))	('PR-619', 'Var', (31, 37))	('apoptosis', 'biological_process', 'GO:0006915', ('75', '84'))	('apoptosis', 'CPA', (75, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('75', '84'))	('cytotoxicity', 'Disease', (58, 70))	('cytotoxicity', 'Disease', 'MESH:D064420', (58, 70))
143462	31627336	Additionally, we found that PR-619 induced cytotoxicity in low-grade RT-4 UC cells and cisplatin-resistant UC cells (T24/R) in a dose- and time-dependent manner (Figures S1 and S2).	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('PR-619', 'Var', (28, 34))	('cytotoxicity', 'Disease', (43, 55))	('UC', 'Disease', 'MESH:D014523', (74, 76))	('T24/R', 'Mutation', 'p.T24R', (117, 122))	('cytotoxicity', 'Disease', 'MESH:D064420', (43, 55))	('UC', 'Disease', 'MESH:D014523', (107, 109))
143463	31627336	We also overserved less cytotoxicity of PR-619 on SV-HUC-1 cell line, which is a neoplastic transformation of SV40-immortalized human urothelial cell line (Figure S3).	('cytotoxicity', 'Disease', (24, 36))	('human', 'Species', '9606', (128, 133))	('PR-619', 'Var', (40, 46))	('SV-HUC-1', 'CellLine', 'CVCL:3798', (50, 58))	('cytotoxicity', 'Disease', 'MESH:D064420', (24, 36))
143466	31627336	In addition to the apoptotic effect of PR-619 on UC cells, the endoplasmic reticulum (ER)-stress-related apoptosis proteins (CHOP and caspase-4) increased after PR-619 treatment.	('caspase-4', 'Gene', (134, 143))	('PR-619', 'Var', (161, 167))	('CHOP', 'Gene', (125, 129))	('caspase-4', 'Gene', '837', (134, 143))	('apoptosis', 'biological_process', 'GO:0097194', ('105', '114'))	('increased', 'PosReg', (145, 154))	('endoplasmic', 'MPA', (63, 74))	('apoptosis', 'biological_process', 'GO:0006915', ('105', '114'))	('CHOP', 'Gene', '1649', (125, 129))	('UC', 'Disease', 'MESH:D014523', (49, 51))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('63', '84'))
143468	31627336	We assumed that PR-619 disturbed protein homeostasis of UC cells and induced ER stress, followed by apoptosis in UC cells.	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('ER stress', 'MPA', (77, 86))	('UC', 'Disease', 'MESH:D014523', (113, 115))	('protein homeostasis', 'MPA', (33, 52))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('PR-619', 'Var', (16, 22))	('UC', 'Disease', 'MESH:D014523', (56, 58))	('disturbed', 'Reg', (23, 32))	('induced', 'Reg', (69, 76))	('homeostasis', 'biological_process', 'GO:0042592', ('41', '52'))
143471	31627336	UC cells treated by 7.5 uM PR-619 for 24 h decreased phospho-Histone H3 (Ser10); meanwhile, increased p21, a cyclin-dependent kinase (CDK) inhibitor, and phospho-CDK2 (Tyr15), a G0/G1 arrest marker, in both UC cells.	('PR-619', 'Var', (27, 33))	('cyclin', 'molecular_function', 'GO:0016538', ('109', '115'))	('phospho', 'Chemical', 'MESH:C033601', (53, 60))	('UC', 'Disease', 'MESH:D014523', (207, 209))	('CDK) inhibitor', 'molecular_function', 'GO:0004861', ('134', '148'))	('phospho-Histone H3 (Ser10)', 'MPA', (53, 79))	('Tyr15', 'Chemical', 'MESH:C042696', (168, 173))	('CDK', 'molecular_function', 'GO:0004693', ('162', '165'))	('Ser10', 'Chemical', 'MESH:C530429', (73, 78))	('phospho', 'Chemical', 'MESH:C033601', (154, 161))	('CDK2', 'Gene', (162, 166))	('Ser', 'cellular_component', 'GO:0005790', ('73', '76'))	('increased', 'PosReg', (92, 101))	('UC', 'Disease', 'MESH:D014523', (0, 2))	('p21', 'Gene', '1026', (102, 105))	('CDK2', 'Gene', '1017', (162, 166))	('p21', 'Gene', (102, 105))	('decreased', 'NegReg', (43, 52))
143472	31627336	All these results consistently indicated that PR-619 induced G0/G1 arrest in UC cells (Figure 3C).	('UC', 'Disease', 'MESH:D014523', (77, 79))	('G0/G1 arrest', 'CPA', (61, 73))	('PR-619', 'Var', (46, 52))
143474	31627336	PR-619 in combination with cisplatin significantly potentiated apoptosis compared to that of cisplatin alone (Figure 4A-C).	('potentiated', 'PosReg', (51, 62))	('PR-619', 'Var', (0, 6))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('apoptosis', 'CPA', (63, 72))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))
143476	31627336	These data consistently indicated that PR-619 potentiated the apoptotic effect of cisplatin on UC cells.	('potentiated', 'PosReg', (46, 57))	('UC', 'Disease', 'MESH:D014523', (95, 97))	('PR-619', 'Var', (39, 45))	('apoptotic effect', 'CPA', (62, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))
143478	31627336	This data indicated that suppression of Bcl-2 is essential for PR-619-induced cytotoxicity in UC cells (Figure S4).	('Bcl-2', 'molecular_function', 'GO:0015283', ('40', '45'))	('cytotoxicity', 'Disease', (78, 90))	('cytotoxicity', 'Disease', 'MESH:D064420', (78, 90))	('Bcl-2', 'Gene', (40, 45))	('Bcl-2', 'Gene', '596', (40, 45))	('PR-619-induced', 'Var', (63, 77))	('UC', 'Disease', 'MESH:D014523', (94, 96))
143479	31627336	Additionally, T24 and BFTC-905 cells treated with PR-619 in combination with cisplatin at a 1:2 ratio for 24 h showed that PR-619 enhanced cisplatin-induced cytotoxicity (Figure 4G,H).	('enhanced', 'PosReg', (130, 138))	('BFTC-905', 'CellLine', 'CVCL:1083', (22, 30))	('cytotoxicity', 'Disease', (157, 169))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('cytotoxicity', 'Disease', 'MESH:D064420', (157, 169))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('PR-619', 'Var', (123, 129))
143484	31627336	We evaluated the antitumor effects of treatment with cisplatin, PR-619, or combined treatment with cisplatin and PR-619 in vivo by using a xenograft mouse model.	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('mouse', 'Species', '10090', (149, 154))	('PR-619', 'Var', (113, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
143487	31627336	Combined treatment with cisplatin and PR-619 showed the most significant antitumor effect on xenograft tumors of both T24 and BFTC-905 compared to single agent (cisplatin or PR-619) treatment (Figure 6A,B).	('PR-619', 'Var', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('BFTC-905', 'CellLine', 'CVCL:1083', (126, 134))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (161, 170))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))
143494	31627336	In this study, we demonstrated that the DUB inhibitor, PR-619, exhibited an antitumor effect on human UCs and cisplatin-resistant UCs.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('PR-619', 'Var', (55, 61))	('UC', 'Disease', 'MESH:D014523', (130, 132))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('human', 'Species', '9606', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('UC', 'Disease', 'MESH:D014523', (102, 104))
143495	31627336	PR-619 enhanced cisplatin-induced cytotoxicity in UCs.	('cytotoxicity', 'Disease', 'MESH:D064420', (34, 46))	('PR-619', 'Var', (0, 6))	('UC', 'Disease', 'MESH:D014523', (50, 52))	('enhanced', 'PosReg', (7, 15))	('cytotoxicity', 'Disease', (34, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (16, 25))
143496	31627336	PR-619 was previously shown to exert a broad DUB-inhibitory profile in living cells, resulting in an accumulation of polyubiquitinated proteins and 26S proteasome complexes.	('PR-619', 'Var', (0, 6))	('polyubiquitinated proteins', 'Disease', 'MESH:D058495', (117, 143))	('26S proteasome', 'cellular_component', 'GO:0000502', ('148', '162'))	('proteasome', 'molecular_function', 'GO:0004299', ('152', '162'))	('polyubiquitinated proteins', 'Disease', (117, 143))	('accumulation', 'PosReg', (101, 113))	('26S proteasome', 'cellular_component', 'GO:0000504', ('148', '162'))	('26S proteasome complexes', 'Enzyme', (148, 172))	('26S proteasome', 'cellular_component', 'GO:0005837', ('148', '162'))
143499	31627336	Approximately 76% of all primary bladder tumors display mutations in at least one chromatin regulatory gene.	('bladder tumors', 'Disease', 'MESH:D001749', (33, 47))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutations', 'Var', (56, 65))	('chromatin regulatory gene', 'Gene', (82, 107))	('bladder tumors', 'Phenotype', 'HP:0009725', (33, 47))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('bladder tumors', 'Disease', (33, 47))	('chromatin', 'cellular_component', 'GO:0000785', ('82', '91'))
143507	31627336	Our study also supported the phenomenon that PR-619 enhanced cisplatin-induced cytotoxicity with the concurrent suppression of Bcl-2.	('cytotoxicity', 'Disease', 'MESH:D064420', (79, 91))	('PR-619', 'Var', (45, 51))	('Bcl-2', 'molecular_function', 'GO:0015283', ('127', '132'))	('cytotoxicity', 'Disease', (79, 91))	('enhanced', 'PosReg', (52, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('suppression', 'NegReg', (112, 123))	('Bcl-2', 'Gene', (127, 132))	('Bcl-2', 'Gene', '596', (127, 132))
143508	31627336	The aberrant Bcl-2 expression in UC cells after chemotherapy provides a reason to develop Bcl-2-targeting strategies to improve clinical outcomes.	('expression', 'MPA', (19, 29))	('UC', 'Disease', 'MESH:D014523', (33, 35))	('Bcl-2', 'Gene', (90, 95))	('Bcl-2', 'Gene', '596', (90, 95))	('aberrant', 'Var', (4, 12))	('Bcl-2', 'molecular_function', 'GO:0015283', ('13', '18'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('90', '95'))	('Bcl-2', 'Gene', (13, 18))	('Bcl-2', 'Gene', '596', (13, 18))
143510	31627336	In summary, PR-619 enhances the cytotoxicity of cisplatin and effectively inhibits the tumor growth of cisplatin-resistant UC.	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('enhances', 'PosReg', (19, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (32, 44))	('tumor', 'Disease', (87, 92))	('PR-619', 'Var', (12, 18))	('UC', 'Disease', 'MESH:D014523', (123, 125))	('inhibits', 'NegReg', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cytotoxicity', 'Disease', (32, 44))
143511	31627336	The aberrant expression of Bcl-2 related to chemotherapy provides a promising target to find out a strategy to improve the therapeutic efficacy and circumvent chemotherapy in human UCs.	('human', 'Species', '9606', (175, 180))	('Bcl-2', 'Gene', (27, 32))	('Bcl-2', 'molecular_function', 'GO:0015283', ('27', '32'))	('aberrant expression', 'Var', (4, 23))	('UC', 'Disease', 'MESH:D014523', (181, 183))	('improve', 'PosReg', (111, 118))	('Bcl-2', 'Gene', '596', (27, 32))
143515	31627336	PR-619 effectively inhibited the cell viability and tumor growth of cisplatin-resistant UC (T24/R) in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('T24/R', 'Mutation', 'p.T24R', (92, 97))	('PR-619', 'Var', (0, 6))	('inhibited', 'NegReg', (19, 28))	('tumor', 'Disease', (52, 57))	('UC', 'Disease', 'MESH:D014523', (88, 90))	('cell viability', 'CPA', (33, 47))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
143522	31627336	PR-619 elicited selective cytotoxic effects on UC cells compared to those on simian virus 40-transformed and immortalized human urothelial (SV-HUC-1) cells.	('human', 'Species', '9606', (122, 127))	('PR-619', 'Var', (0, 6))	('SV-HUC-1', 'CellLine', 'CVCL:3798', (140, 148))	('simian virus 40', 'Species', '1891767', (77, 92))	('UC', 'Disease', 'MESH:D014523', (144, 146))	('UC', 'Disease', 'MESH:D014523', (47, 49))	('cytotoxic effects', 'CPA', (26, 43))
143528	31627336	This work was supported by National Taiwan University Hospital (108-4104, 108-M4137, and 107-S3784), the Taiwan Ministry and Science and Technology (107-2321-B-008-001, 107-2314-B-002-268-MY2, and 108-2314-B-002-054) and New Taipei City Hospital (108).	('108-2314-B-002-054', 'Chemical', 'MESH:C545088', (197, 215))	('107-2321-B-008', 'Chemical', 'MESH:C067675', (149, 163))	('108-4104', 'Var', (64, 72))	('107-2321-B-008-001', 'Var', (149, 167))	('107-2314-B-002-268', 'Chemical', 'MESH:C545088', (169, 187))	('107-S3784', 'Chemical', 'MESH:C540746', (89, 98))
143545	31086186	Clinically, tumor (T) staging defines the invasiveness of human bladder urothelial carcinoma cells into smooth muscle and perivesical tissues pathologically, with Ta/T1 defining non-muscle invasive bladder carcinomas (NMIBCs), and T2-T4 representing muscle-invasive bladder carcinomas (MIBCs).	('human', 'Species', '9606', (58, 63))	('invasive bladder', 'Phenotype', 'HP:0100645', (257, 273))	('muscle-invasive bladder carcinomas', 'Phenotype', 'HP:0006740', (250, 284))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (266, 284))	('Ta/T1', 'Var', (163, 168))	('tumor', 'Disease', (12, 17))	('bladder urothelial carcinoma', 'Disease', (64, 92))	('MIBCs', 'Chemical', '-', (219, 224))	('invasive bladder carcinomas', 'Disease', (189, 216))	('T2-T4', 'Var', (231, 236))	('invasive bladder carcinomas', 'Disease', 'MESH:D001749', (189, 216))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('MIBCs', 'Phenotype', 'HP:0006740', (219, 224))	('muscle invasive bladder carcinomas', 'Phenotype', 'HP:0006740', (182, 216))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (64, 92))	('invasive bladder carcinomas', 'Disease', (257, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('invasive bladder carcinomas', 'Disease', 'MESH:D001749', (257, 284))	('carcinomas', 'Phenotype', 'HP:0030731', (206, 216))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (198, 216))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('MIBCs', 'Chemical', '-', (286, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (178, 205))	('invasive bladder', 'Phenotype', 'HP:0100645', (189, 205))	('MIBCs', 'Phenotype', 'HP:0006740', (286, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('carcinomas', 'Phenotype', 'HP:0030731', (274, 284))
143558	31086186	Collectively, extracellular COL1 consistently increases cell migration in 2D; however, its functional impact on cancer cells is much more pronounced within a 3D matrix.	('extracellular', 'cellular_component', 'GO:0005576', ('14', '27'))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('increases', 'PosReg', (46, 55))	('COL1', 'Gene', (28, 32))	('extracellular', 'Var', (14, 27))	('cell migration in 2D', 'CPA', (56, 76))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cell migration', 'biological_process', 'GO:0016477', ('56', '70'))
143648	31086186	Enhancement of metastatic potential in this T24-LungMet subline associated with a significant increase in CD167a protein expression, which corresponded with an elevated phospho-tyrosine level of Stat3 at a.a. pY705 (Fig.	('Enhancement', 'PosReg', (0, 11))	('elevated', 'PosReg', (160, 168))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('increase', 'PosReg', (94, 102))	('expression', 'MPA', (121, 131))	('metastatic potential', 'CPA', (15, 35))	('CD167a', 'Gene', (106, 112))	('tyrosine', 'Chemical', 'MESH:D014443', (177, 185))	('phospho-tyrosine level', 'MPA', (169, 191))	('CD167a', 'Gene', '12305', (106, 112))	('men', 'Species', '9606', (7, 10))	('pY705', 'Chemical', '-', (209, 214))	('a.a. pY705', 'Var', (204, 214))
143674	31086186	Napabucasin (BBI-608) is currently approved by the FDA as an anti-cancer drug in use for Phase II/III clinical trials (https://www.cancer.gov/about-cancer/treatment/clinical-trials/intervention/napabucasin) and had been shown to prolong the survival of patients with colorectal cancer tumors expressing Stat3.	('colorectal cancer tumors', 'Disease', 'MESH:D015179', (267, 291))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('BBI-608', 'Chemical', 'MESH:C000621033', (13, 20))	('patients', 'Species', '9606', (253, 261))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('napabucasin', 'Chemical', 'MESH:C000621033', (194, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (267, 284))	('cancer', 'Disease', (278, 284))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('Stat3', 'Var', (303, 308))	('men', 'Species', '9606', (160, 163))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('colorectal cancer tumors', 'Disease', (267, 291))	('prolong', 'PosReg', (229, 236))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', (148, 154))	('Napabucasin', 'Chemical', 'MESH:C000621033', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('survival', 'CPA', (241, 249))	('cancer', 'Disease', (66, 72))
143739	31086186	For immunofluorescence analysis, goat anti-rabbit Alexa Fluor 488 (Z25302) and goat anti-mouse Alexa Fluor 594 (Z25207) were from Invitrogen.	('Z25207', 'Var', (112, 118))	('rabbit', 'Species', '9986', (43, 49))	('Z25207', 'Chemical', '-', (112, 118))	('Z25302', 'Var', (67, 73))	('Alexa Fluor 488', 'Chemical', '-', (50, 65))	('Alexa Fluor 594', 'Chemical', '-', (95, 110))	('goat', 'Species', '9925', (79, 83))	('Z25302', 'Chemical', '-', (67, 73))	('mouse', 'Species', '10090', (89, 94))	('goat', 'Species', '9925', (33, 37))
143818	29338688	Patients who met the following criteria were excluded: (1) age < 50 years or >90 years, (2) a diagnosis of prostate cancer (ICD-9-CM code 185.xx) or bladder cancer (ICD-9-CM code 188.xx) before the index date, (3) regularly receiving alpha-blockers for more than 6 months before the index date, and (4) long-term use of an indwelling urinary catheter.	('bladder cancer', 'Disease', 'MESH:D001749', (149, 163))	('prostate cancer', 'Disease', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('bladder cancer', 'Disease', (149, 163))	('prostate cancer', 'Disease', 'MESH:D011471', (107, 122))	('ICD-9-CM', 'Var', (165, 173))	('Patients', 'Species', '9606', (0, 8))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('bladder cancer', 'Phenotype', 'HP:0009725', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
143823	29338688	The following comorbidities were included in this study: diabetes mellitus (ICD-9-CM code 250.xx), hypertension (ICD-9-CM codes 401.xx-405.xx), dyslipidemia (ICD-9-CM code 272.4), chronic obstructive pulmonary disease (ICD-9-CM codes 491.xx, 492.xx, and 496.xx), Parkinson disease (ICD-9-CM code 332.xx), chronic renal disease or renal failure (ICD-9-CM codes 584.xx and 585.xx), ischemic heart disease (ICD-9-CM codes 410.xx-414.xx), stroke (ICD-9-CM codes 430.xx-437.xx), and heart failure (ICD-9-CM 428.xx).	('stroke', 'Disease', (435, 441))	('hypertension', 'Disease', (99, 111))	('dyslipidemia', 'Phenotype', 'HP:0003119', (144, 156))	('diabetes mellitus', 'Disease', (57, 74))	('chronic renal disease', 'Disease', (305, 326))	('dyslipidemia', 'Disease', (144, 156))	('ischemic heart disease', 'Disease', (380, 402))	('hypertension', 'Phenotype', 'HP:0000822', (99, 111))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (180, 217))	('Parkinson disease', 'Disease', 'MESH:D010300', (263, 280))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (180, 217))	('ischemic heart disease', 'Disease', 'MESH:D003324', (380, 402))	('heart failure', 'Disease', 'MESH:D006333', (478, 491))	('diabetes mellitus', 'Disease', 'MESH:D003920', (57, 74))	('ICD-9-CM', 'Var', (404, 412))	('heart failure', 'Phenotype', 'HP:0001635', (478, 491))	('renal failure', 'Phenotype', 'HP:0000083', (330, 343))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (57, 74))	('ICD-9-CM', 'Var', (443, 451))	('chronic obstructive pulmonary disease', 'Disease', (180, 217))	('chronic renal disease', 'Disease', 'MESH:D051436', (305, 326))	('renal failure', 'Disease', 'MESH:D051437', (330, 343))	('renal failure', 'Disease', (330, 343))	('stroke', 'Phenotype', 'HP:0001297', (435, 441))	('heart failure', 'Disease', (478, 491))	('Parkinson disease', 'Disease', (263, 280))	('dyslipidemia', 'Disease', 'MESH:D050171', (144, 156))	('stroke', 'Disease', 'MESH:D020521', (435, 441))	('renal disease', 'Phenotype', 'HP:0000112', (313, 326))	('hypertension', 'Disease', 'MESH:D006973', (99, 111))
143826	29338688	UTI was defined as hospitalization or an emergency department or outpatient visit with a UTI-related diagnosis (ICD-9-CM codes 599.0x and 595.0x) and antibiotic prescription.	('UTI', 'Phenotype', 'HP:0000010', (0, 3))	('UTI', 'Disease', (0, 3))	('599.0x', 'Var', (127, 133))	('595.0x', 'Var', (138, 144))	('UTI', 'Phenotype', 'HP:0000010', (89, 92))	('men', 'Species', '9606', (57, 60))	('outpatient', 'Species', '9606', (65, 75))	('UTI-related', 'Disease', (89, 100))
143827	29338688	Other geriatric adverse events that were compared included inguinal hernia (Taiwan NHI codes 75606B, 75607C, 75613C, 75614C, and 75610B), hemorrhoids (Taiwan NHI codes 74406C, 74407C, 74410C, 74411C, 74412C, and 74417C), stroke (ICD-9-CM codes 430.xx-437.xx), and acute myocardial infarction (ICD-9-CM code 410.xx).	('75607C', 'Var', (101, 107))	('hernia', 'Phenotype', 'HP:0100790', (68, 74))	('inguinal hernia', 'Disease', (59, 74))	('75610B', 'Var', (129, 135))	('74412C', 'Var', (200, 206))	('myocardial infarction', 'Phenotype', 'HP:0001658', (270, 291))	('hemorrhoids', 'Disease', (138, 149))	('inguinal hernia', 'Disease', 'MESH:D006552', (59, 74))	('hemorrhoids', 'Disease', 'MESH:D006484', (138, 149))	('75613C', 'Var', (109, 115))	('stroke', 'Phenotype', 'HP:0001297', (221, 227))	('75614C', 'Var', (117, 123))	('74417C', 'Var', (212, 218))	('74410C', 'Var', (184, 190))	('acute myocardial infarction', 'Disease', 'MESH:D009203', (264, 291))	('74411C', 'Var', (192, 198))	('74407C', 'Var', (176, 182))	('inguinal hernia', 'Phenotype', 'HP:0000023', (59, 74))	('hemorrhoids', 'Phenotype', 'HP:0032551', (138, 149))	('stroke', 'Disease', 'MESH:D020521', (221, 227))	('Taiwan', 'Var', (151, 157))	('acute myocardial infarction', 'Disease', (264, 291))	('stroke', 'Disease', (221, 227))
143828	29338688	We also compared the incidence of emergent bone fracture, which was defined as visiting the emergency department or hospitalization with a principal diagnosis of skeletal fracture (ICD-9-CM code 805.xx-829.xx), between the two cohorts, as well as the incidence of urological malignancies after the index date, including prostate cancer (ICD-9-CM code 185.xx) and bladder cancer (ICD-9-CM code 188.9x).	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('emergent bone fracture', 'Disease', 'MESH:D050723', (34, 56))	('bladder cancer', 'Phenotype', 'HP:0009725', (363, 377))	('men', 'Species', '9606', (108, 111))	('prostate cancer', 'Disease', 'MESH:D011471', (320, 335))	('urological malignancies', 'Disease', (264, 287))	('bone fracture', 'Phenotype', 'HP:0020110', (43, 56))	('emergent bone fracture', 'Disease', (34, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (320, 335))	('skeletal fracture', 'Disease', 'MESH:D050723', (162, 179))	('bladder cancer', 'Disease', 'MESH:D001749', (363, 377))	('bladder cancer', 'Disease', (363, 377))	('skeletal fracture', 'Disease', (162, 179))	('ICD-9-CM', 'Var', (337, 345))	('urological malignancies', 'Disease', 'MESH:D014570', (264, 287))	('prostate cancer', 'Disease', (320, 335))
143869	29338688	TURP appears to reduce the urge and prompt sensation to void and the number of times a patient gets up to visit the toilet at night, thus preventing them from the risk of falls.	('falls', 'Disease', (171, 176))	('preventing', 'NegReg', (138, 148))	('falls', 'Phenotype', 'HP:0002527', (171, 176))	('reduce', 'NegReg', (16, 22))	('fall', 'Phenotype', 'HP:0002527', (171, 175))	('UR', 'Phenotype', 'HP:0000016', (1, 3))	('falls', 'Disease', 'MESH:C537863', (171, 176))	('patient', 'Species', '9606', (87, 94))	('TURP', 'Var', (0, 4))
144032	30756528	As previously mentioned, endothelial cells are a critical component for the establishment of primary tumors and progression to metastatic sites and previous studies have shown that their dysfunction directly contributes to these processes (Franses et al.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('primary tumors', 'Disease', (93, 107))	('primary tumors', 'Disease', 'MESH:D009369', (93, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('dysfunction', 'Var', (187, 198))	('contributes', 'Reg', (208, 219))
144047	28507621	Expression of FGFR3 Protein and Gene Amplification in Urinary Bladder Lesions in Relation to Schistosomiasis Bladder cancer represents the fifth most common malignancy worldwide and a major cause of cancer-related morbidity and death.	('FGFR3', 'Gene', (14, 19))	('Gene Amplification', 'Var', (32, 50))	('cancer', 'Disease', (199, 205))	('malignancy', 'Disease', 'MESH:D009369', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('Protein', 'Protein', (20, 27))	('FGFR3', 'Gene', '2261', (14, 19))	('Schistosomiasis Bladder', 'Phenotype', 'HP:0001981', (93, 116))	('Schistosomiasis', 'Disease', (93, 108))	('cancer', 'Disease', (117, 123))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('death', 'Disease', (228, 233))	('malignancy', 'Disease', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('Schistosomiasis', 'Disease', 'MESH:D012552', (93, 108))	('Bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('death', 'Disease', 'MESH:D003643', (228, 233))
144056	28507621	FGFR3 gene amplification was reported mainly in low grade and NNMBIC tumours.	('tumours', 'Disease', (69, 76))	('low grade', 'Disease', (48, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', '2261', (0, 5))	('FGFR3', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('amplification', 'Var', (11, 24))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
144065	28507621	Activating mutations and overexpression of FGFR3 are common in urothelial tumours with low malignant potential and low-stage and -grade urothelial carcinomas and are associated with a lower risk of progression and better survival in some subgroups.	('urothelial carcinomas', 'Disease', (136, 157))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('FGFR3', 'Gene', (43, 48))	('Activating mutations', 'Var', (0, 20))	('urothelial tumours', 'Disease', (63, 81))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (136, 157))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('FGFR3', 'Gene', '2261', (43, 48))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('urothelial tumours', 'Disease', 'MESH:D014523', (63, 81))	('overexpression', 'PosReg', (25, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))
144066	28507621	FGFR3 mutations are linked to favourable (low grade/stage) pTa bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (63, 77))	('bladder cancer', 'Disease', (63, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', '2261', (0, 5))	('pTa', 'molecular_function', 'GO:0008959', ('59', '62'))	('FGFR3', 'Gene', (0, 5))	('pTa bladder', 'Phenotype', 'HP:0000384', (59, 70))	('bladder cancer', 'Phenotype', 'HP:0009725', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (6, 15))	('linked', 'Reg', (20, 26))
144067	28507621	Fibroblast Growth Factor receptor 3 (FGFR3) mutations are most common in low-risk NMIBC (non-muscle invasive bladder cancer), a subset of MIBC (muscle invasive bladder cancer) that carries FGFR3 mutations shows particularly poor prognosis.	('common', 'Reg', (63, 69))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (144, 174))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (89, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('189', '193'))	('FGFR3', 'Gene', (189, 194))	('muscle invasive bladder cancer', 'Disease', (93, 123))	('FGFR3', 'Gene', '2261', (189, 194))	('FGFR3', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('NMIBC', 'Disease', (82, 87))	('NMIBC', 'Chemical', '-', (82, 87))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (93, 123))	('FGFR3', 'Gene', '2261', (37, 42))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('Fibroblast Growth Factor receptor 3', 'Gene', (0, 35))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('invasive bladder', 'Phenotype', 'HP:0100645', (151, 167))	('Fibroblast Growth Factor', 'molecular_function', 'GO:0005104', ('0', '24'))	('MIBC', 'Chemical', '-', (83, 87))	('mutations', 'Var', (195, 204))	('MIBC', 'Chemical', '-', (138, 142))	('Fibroblast Growth Factor receptor 3', 'Gene', '2261', (0, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))	('-muscle invasive bladder cancer', 'Phenotype', 'HP:0006740', (92, 123))	('muscle invasive bladder cancer', 'Disease', (144, 174))	('invasive bladder', 'Phenotype', 'HP:0100645', (100, 116))	('mutations', 'Var', (44, 53))
144070	28507621	Subsequent larger studies established that FGFR3 mutations occur in around 50% of both lower and upper urinary tract tumours and these cluster in three distinct hotspots in exons 7, 10, and 15.	('mutations', 'Var', (49, 58))	('FGFR3', 'Gene', (43, 48))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('upper urinary tract tumours', 'Disease', (97, 124))	('upper urinary tract tumours', 'Phenotype', 'HP:0010935', (97, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('FGFR3', 'Gene', '2261', (43, 48))	('upper urinary tract tumours', 'Disease', 'MESH:D014571', (97, 124))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))
144071	28507621	FGFR3 mutations are thought to induce a conformational change in the kinase domain resulting in ligand-independent receptor activation and signalling; they have also been shown to alter FGFR3 cellular localisation, inducing aberrant signalling from the endoplasmic reticulum.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('253', '274'))	('FGFR', 'molecular_function', 'GO:0005007', ('186', '190'))	('FGFR3', 'Gene', (0, 5))	('ligand', 'molecular_function', 'GO:0005488', ('96', '102'))	('cellular localisation', 'MPA', (192, 213))	('FGFR3', 'Gene', '2261', (186, 191))	('cellular localisation', 'biological_process', 'GO:0051641', ('192', '213'))	('FGFR3', 'Gene', (186, 191))	('signalling from the endoplasmic reticulum', 'MPA', (233, 274))	('inducing', 'Reg', (215, 223))	('signalling', 'biological_process', 'GO:0023052', ('233', '243'))	('alter', 'Reg', (180, 185))	('signalling', 'biological_process', 'GO:0023052', ('139', '149'))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
144072	28507621	FGFR3 mutation status was the strongest predictor of recurrence when compared with stage and grade.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('FGFR3', 'Gene', '2261', (0, 5))
144073	28507621	This is the first mutation in bladder cancer that selectively identifies patients with favourable disease characteristics.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('bladder cancer', 'Disease', 'MESH:D001749', (30, 44))	('bladder cancer', 'Disease', (30, 44))	('mutation', 'Var', (18, 26))	('patients', 'Species', '9606', (73, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))
144074	28507621	While FGFR3 mutation or copy number gain is a rare event, studies of these tumours may shed light on how FGFR3 signalling contributes to urothelial carcinoma growth and proliferation.	('FGFR3', 'Gene', '2261', (6, 11))	('FGFR3', 'Gene', (105, 110))	('urothelial carcinoma growth', 'Disease', (137, 164))	('contributes', 'Reg', (122, 133))	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('tumours', 'Disease', (75, 82))	('FGFR3', 'Gene', (6, 11))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('proliferation', 'CPA', (169, 182))	('urothelial carcinoma growth', 'Disease', 'MESH:D006130', (137, 164))	('copy number', 'Var', (24, 35))	('FGFR3', 'Gene', '2261', (105, 110))	('FGFR', 'molecular_function', 'GO:0005007', ('6', '10'))	('mutation', 'Var', (12, 20))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('signalling', 'biological_process', 'GO:0023052', ('111', '121'))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))
144078	28507621	In our study, we are aiming to evaluate the association of FGFR3 expression and gene mutation and its risk in the development of urothelial carcinoma (bilharzial and non-bilharzial), the effect on grading and staging of the tumour and the benefit of using this marker as a therapeutic target and diagnostic tool in bladder cancer patients.	('FGFR3', 'Gene', '2261', (59, 64))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (129, 149))	('bilharzial', 'Chemical', '-', (151, 161))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('FGFR3', 'Gene', (59, 64))	('bilharzial', 'Chemical', '-', (170, 180))	('mutation', 'Var', (85, 93))	('urothelial carcinoma', 'Disease', (129, 149))	('bladder cancer', 'Disease', (315, 329))	('bladder cancer', 'Disease', 'MESH:D001749', (315, 329))	('tumour', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('patients', 'Species', '9606', (330, 338))	('tumour', 'Disease', (224, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('association', 'Interaction', (44, 55))	('bladder cancer', 'Phenotype', 'HP:0009725', (315, 329))
144090	28507621	Cells with membrane cytoplasmic staining were considered positive: The intensity and extent of cells stained positively for FGFR3 was evaluated by assessing 10 high-power microscopic fields by two independent pathologists (OH &TA): *Score 0: All tumor cells are negative; *Score +1: Weak but detectable positivity in some or all cells; *Score +2: moderate but extensive positivity; and *Score +3: strong positivity (regardless of extent).	('membrane', 'cellular_component', 'GO:0016020', ('11', '19'))	('FGFR', 'molecular_function', 'GO:0005007', ('124', '128'))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('FGFR3', 'Gene', '2261', (124, 129))	('extensive', 'MPA', (360, 369))	('; *Score +2', 'Var', (334, 345))	('; *Score +1', 'Var', (270, 281))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('detectable', 'MPA', (292, 302))	('tumor', 'Disease', (246, 251))	('FGFR3', 'Gene', (124, 129))	('are', 'NegReg', (258, 261))
144114	28507621	While all cases of SCC have FGFR3 gene amplification, most of the positive cases were of high grade and belong to the MIBC group (83.3%) with a significant difference at p-value < 0.01 compared to high grade and NMIBC group.	('SCC', 'Gene', '6317', (19, 22))	('FGFR3', 'Gene', '2261', (28, 33))	('NMIBC', 'Chemical', '-', (212, 217))	('amplification', 'Var', (39, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('MIBC', 'Disease', (118, 122))	('MIBC', 'Chemical', '-', (213, 217))	('FGFR3', 'Gene', (28, 33))	('SCC', 'Gene', (19, 22))	('MIBC', 'Chemical', '-', (118, 122))
144115	28507621	Almost all cases of SCC and TCC associated with bilharziasis report FGFR3 gene amplification with a significant difference between TCC on bilharzial compared to TCC bilharzial groups at P value < 0.05 (Table 5).	('FGFR3', 'Gene', '2261', (68, 73))	('bilharzial', 'Chemical', '-', (165, 175))	('bilharzial', 'Chemical', '-', (138, 148))	('SCC', 'Gene', (20, 23))	('TCC', 'cellular_component', 'GO:0005579', ('28', '31'))	('bilharziasis', 'Disease', 'MESH:D012552', (48, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('68', '72'))	('FGFR3', 'Gene', (68, 73))	('SCC', 'Gene', '6317', (20, 23))	('TCC', 'cellular_component', 'GO:0005579', ('131', '134'))	('bilharziasis', 'Disease', (48, 60))	('TCC', 'cellular_component', 'GO:0005579', ('161', '164'))	('amplification', 'Var', (79, 92))
144117	28507621	Amplified FGFR3 gene was reported in 85.7% of low-grade tumours with marked staining intensity showing a significant difference compared to the high-grade tumours at p-value < 0.01.	('tumours', 'Disease', (155, 162))	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Disease', (56, 63))	('FGFR3', 'Gene', '2261', (10, 15))	('FGFR', 'molecular_function', 'GO:0005007', ('10', '14'))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('FGFR3', 'Gene', (10, 15))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('tumours', 'Disease', 'MESH:D009369', (155, 162))	('Amplified', 'Var', (0, 9))
144133	28507621	who stated that SCC showed a predisposition to a high level of FGFR3 protein expression and mutation.	('expression', 'MPA', (77, 87))	('FGFR3', 'Gene', '2261', (63, 68))	('mutation', 'Var', (92, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('protein', 'Protein', (69, 76))	('SCC', 'Gene', (16, 19))	('FGFR3', 'Gene', (63, 68))	('SCC', 'Gene', '6317', (16, 19))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))
144137	28507621	who stated that 63% of NMBIC group and 59% were at low-grade show FGFR3 gene amplification.	('FGFR3', 'Gene', (66, 71))	('FGFR3', 'Gene', '2261', (66, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('amplification', 'Var', (77, 90))
144138	28507621	We found positivity for FGFR3gene amplification in almost all bilharziasis associated malignant cases (SCC and TCC).	('FGFR3', 'Gene', '2261', (24, 29))	('bilharziasis', 'Disease', 'MESH:D012552', (62, 74))	('SCC', 'Gene', (103, 106))	('TCC', 'cellular_component', 'GO:0005579', ('111', '114'))	('FGFR3', 'Gene', (24, 29))	('bilharziasis', 'Disease', (62, 74))	('SCC', 'Gene', '6317', (103, 106))	('amplification', 'Var', (34, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))
144142	28507621	FGFR3 point mutations, overexpression of FGFR3 protein has been described.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('overexpression', 'PosReg', (23, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('FGFR3', 'Gene', '2261', (41, 46))	('FGFR3', 'Gene', (0, 5))	('point mutations', 'Var', (6, 21))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('FGFR3', 'Gene', (41, 46))	('FGFR3', 'Gene', '2261', (0, 5))
144143	28507621	Although this overexpression was associated strongly with the presence of FGFR3 mutations (up to 85% of FGFR3-mutated tumours show strong FGFR3 protein expression), FGFR3 overexpression was also found in 40% of tumours with wild-type FGFR3, particularly in those with an invasive phenotype.	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('tumours', 'Disease', 'MESH:D009369', (211, 218))	('overexpression', 'PosReg', (171, 185))	('FGFR3', 'Gene', (165, 170))	('FGFR3', 'Gene', '2261', (104, 109))	('FGFR', 'molecular_function', 'GO:0005007', ('104', '108'))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('FGFR', 'molecular_function', 'GO:0005007', ('138', '142'))	('FGFR3', 'Gene', '2261', (165, 170))	('FGFR', 'molecular_function', 'GO:0005007', ('234', '238'))	('FGFR3', 'Gene', (104, 109))	('mutations', 'Var', (80, 89))	('FGFR3', 'Gene', (234, 239))	('FGFR3', 'Gene', (138, 143))	('expression', 'MPA', (152, 162))	('FGFR3', 'Gene', '2261', (234, 239))	('FGFR3', 'Gene', (74, 79))	('FGFR3', 'Gene', '2261', (138, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('165', '169'))	('tumours', 'Disease', (118, 125))	('FGFR3', 'Gene', '2261', (74, 79))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('tumours', 'Disease', (211, 218))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumours', 'Phenotype', 'HP:0002664', (211, 218))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))
144144	28507621	We detected FGFR3 gene amplification in 88.2% of the TCC cases; about 70% were of low grade, and 80% were in NMIBC group.	('FGFR3', 'Gene', (12, 17))	('NMIBC', 'Chemical', '-', (109, 114))	('amplification', 'Var', (23, 36))	('TCC', 'Disease', (53, 56))	('FGFR3', 'Gene', '2261', (12, 17))	('TCC', 'cellular_component', 'GO:0005579', ('53', '56'))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))
144146	28507621	found in their study all FGFR3amplified samples showed concomitant FGFR3 mutations and FGFR3 protein overexpression.	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('overexpression', 'PosReg', (101, 115))	('FGFR3', 'Gene', (67, 72))	('FGFR3', 'Gene', '2261', (25, 30))	('FGFR3', 'Gene', '2261', (87, 92))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('protein', 'Protein', (93, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('FGFR3', 'Gene', (87, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('FGFR3', 'Gene', (25, 30))	('FGFR3', 'Gene', '2261', (67, 72))	('mutations', 'Var', (73, 82))
144147	28507621	In conclusion, our findings suggest that invasive tumours may develop either from carcinoma in situ or Ta cases having multiple genetic alterations together including gene amplifications in bilharzial associated carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (212, 222))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('carcinomas', 'Disease', 'MESH:D002277', (212, 222))	('develop', 'PosReg', (62, 69))	('carcinomas', 'Disease', (212, 222))	('carcinoma in situ', 'Disease', 'MESH:D002278', (82, 99))	('bilharzial', 'Chemical', '-', (190, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('invasive tumours', 'Disease', (41, 57))	('carcinoma in situ', 'Disease', (82, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('invasive tumours', 'Disease', 'MESH:D009361', (41, 57))	('gene amplifications', 'Var', (167, 186))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (82, 99))
144156	27737647	Five-year relative survival increased annually with 0.004 in men (p = 1.3   10-6) and 0.003 in women (p = 4.5   10-6).	('increased', 'PosReg', (28, 37))	('relative survival', 'MPA', (10, 27))	('men', 'Species', '9606', (97, 100))	('0.004', 'Var', (52, 57))	('women', 'Species', '9606', (95, 100))	('men', 'Species', '9606', (61, 64))
144177	27737647	The majority of these tumors will recur, but the risk of progression to invasive UCB is low (4-7 %) for low-grade Ta tumors and approximately 12-23 % for high-grade Ta tumors.	('UCB', 'Chemical', '-', (81, 84))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('Ta tumors', 'Disease', (114, 123))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('low-grade', 'Var', (104, 113))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumors', 'Disease', (117, 123))	('Ta tumors', 'Disease', 'MESH:D009369', (114, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Ta tumors', 'Disease', (165, 174))	('tumors', 'Disease', (22, 28))	('Ta tumors', 'Disease', 'MESH:D009369', (165, 174))
144368	24901005	However, mitomycin C was seen to own several side effects and in particular after transurethral resection it has been described to delay the healing of the mucosa at resection sites both in animal and human.	('mitomycin', 'Var', (9, 18))	('healing of the mucosa at resection', 'CPA', (141, 175))	('human', 'Species', '9606', (201, 206))	('delay', 'NegReg', (131, 136))	('mitomycin C', 'Chemical', 'MESH:D016685', (9, 20))
144369	24901005	Urologists remained unconvinced that the benefits of MMC (immediate + maintenance), including a 30% relative reduction in the recurrence of a nonlethal disease, outweigh the potential harms, for example, cystitis, which can occasionally be severe and irreversible.	('cystitis', 'Disease', 'MESH:D003556', (204, 212))	('MMC', 'Chemical', 'MESH:D016685', (53, 56))	('reduction', 'NegReg', (109, 118))	('MMC', 'Var', (53, 56))	('recurrence', 'MPA', (126, 136))	('cystitis', 'Disease', (204, 212))
144406	24901005	Furthermore, the knockout of TRPV1 in mice led to intermicturition spotting, suggested by an increase in the frequency of nonvoiding contractions in cystometrograms, but it does not affect normal micturition.	('TRPV1', 'Gene', (29, 34))	('increase', 'PosReg', (93, 101))	('mice', 'Species', '10090', (38, 42))	('frequency', 'MPA', (109, 118))	('intermicturition spotting', 'Disease', (50, 75))	('micturition', 'biological_process', 'GO:0060073', ('196', '207'))	('knockout', 'Var', (17, 25))	('led to', 'Reg', (43, 49))
144427	24901005	On the other hand, attention has to be paid to the Capsaicin property to exhibit tumor-promoting effects, in a receptor-dependent manner, in particular in cancer strain cells lacking TRPV1 receptor, where the transfection with the TRPV1 cDNA leads to an increase in capsaicin-mediated calcium level, growth inhibition, apoptosis, and capsaicin-induced migration regression, suggesting that the TRPV1 plays an inhibitory role in urothelial cancer invasion and metastasis.	('capsaicin', 'Chemical', 'MESH:D002211', (266, 275))	('growth inhibition', 'CPA', (300, 317))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('capsaicin-mediated calcium level', 'MPA', (266, 298))	('cancer', 'Disease', 'MESH:D009369', (439, 445))	('capsaicin-induced migration regression', 'CPA', (334, 372))	('tumor', 'Disease', (81, 86))	('rat', 'Species', '10116', (355, 358))	('capsaicin', 'Chemical', 'MESH:D002211', (334, 343))	('Capsaicin', 'Chemical', 'MESH:D002211', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cancer', 'Disease', (155, 161))	('TRPV1', 'Gene', (231, 236))	('calcium', 'Chemical', 'MESH:D002118', (285, 292))	('urothelial cancer', 'Disease', 'MESH:D014523', (428, 445))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('apoptosis', 'CPA', (319, 328))	('cancer', 'Disease', (439, 445))	('transfection', 'Var', (209, 221))	('apoptosis', 'biological_process', 'GO:0097194', ('319', '328'))	('apoptosis', 'biological_process', 'GO:0006915', ('319', '328'))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('urothelial cancer', 'Disease', (428, 445))	('cancer', 'Phenotype', 'HP:0002664', (439, 445))	('increase', 'PosReg', (254, 262))
144466	24901005	described that curcumin potentiates the apoptotic effects of gemcitabine against human bladder cancer, where curcumin also suppresses the cell survival transcription factor NF-kappaB activated by gemcitabine.	('curcumin', 'Chemical', 'MESH:D003474', (109, 117))	('curcumin', 'Chemical', 'MESH:D003474', (15, 23))	('apoptotic', 'CPA', (40, 49))	('NF-kappaB', 'Gene', (173, 182))	('curcumin', 'Var', (109, 117))	('gemcitabine', 'Chemical', 'MESH:C056507', (196, 207))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('suppresses', 'NegReg', (123, 133))	('transcription', 'biological_process', 'GO:0006351', ('152', '165'))	('transcription factor', 'molecular_function', 'GO:0000981', ('152', '172'))	('bladder cancer', 'Disease', 'MESH:D001749', (87, 101))	('bladder cancer', 'Disease', (87, 101))	('NF-kappaB', 'Gene', '4790', (173, 182))	('human', 'Species', '9606', (81, 86))	('gemcitabine', 'Chemical', 'MESH:C056507', (61, 72))
144472	24901005	At least, curcumin reduced capsaicin-induced currents in a dose-dependent manner in both trigeminal ganglion neurons; thus, the antagonism of TRPV1 may provide a potential mechanism underlying the antihyperalgesic effect of curcumin.	('capsaicin', 'Chemical', 'MESH:D002211', (27, 36))	('curcumin', 'Chemical', 'MESH:D003474', (224, 232))	('curcumin', 'Chemical', 'MESH:D003474', (10, 18))	('reduced', 'NegReg', (19, 26))	('antagonism', 'Var', (128, 138))	('TRPV1', 'Gene', (142, 147))	('capsaicin-induced currents', 'MPA', (27, 53))
144488	22189739	Among the mediators of this effect of smoking is nuclear factor-kappa B. Curcumin suppresses cellular transformation by downregulating the activity of nuclear factor-kappa B. Prima-1 is a compound that induces apoptosis in human tumor cells, restoring the function of mutant p53.	('cellular transformation', 'CPA', (93, 116))	('function', 'MPA', (256, 264))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('Curcumin', 'Chemical', 'MESH:D003474', (73, 81))	('human', 'Species', '9606', (223, 228))	('mutant', 'Var', (268, 274))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('suppresses', 'NegReg', (82, 92))	('restoring', 'PosReg', (242, 251))	('tumor', 'Disease', (229, 234))	('apoptosis', 'biological_process', 'GO:0097194', ('210', '219'))	('apoptosis', 'biological_process', 'GO:0006915', ('210', '219'))	('apoptosis', 'CPA', (210, 219))	('p53', 'Gene', (275, 278))
144508	22189739	Mutations in p53 occur in at least 50% of human tumors, and p53 is characteristically mutated in high-grade, invasive urothelial carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('high-grade', 'Disease', (97, 107))	('human', 'Species', '9606', (42, 47))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (109, 138))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (13, 16))	('invasive urothelial carcinoma', 'Disease', (109, 138))
144509	22189739	Prima-1 is a low-molecular-weight compound able to induce apoptosis in human tumor cells by restoring the transcriptional transactivation function of mutant p53.	('transcriptional transactivation', 'biological_process', 'GO:2000144', ('106', '137'))	('transcriptional transactivation function', 'MPA', (106, 146))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('restoring', 'PosReg', (92, 101))	('apoptosis', 'biological_process', 'GO:0097194', ('58', '67'))	('apoptosis', 'biological_process', 'GO:0006915', ('58', '67'))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('p53', 'Gene', (157, 160))	('mutant', 'Var', (150, 156))	('human', 'Species', '9606', (71, 76))
144535	22189739	The mean percentage of tumor necrosis in mice treated with curcumin was 67%, whereas in the other groups, the mean was only 27% (p<0.001).	('necrosis', 'biological_process', 'GO:0019835', ('29', '37'))	('necrosis', 'biological_process', 'GO:0001906', ('29', '37'))	('necrosis', 'biological_process', 'GO:0008220', ('29', '37'))	('mice', 'Species', '10090', (41, 45))	('tumor necrosis', 'Disease', 'MESH:D009336', (23, 37))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('curcumin', 'Var', (59, 67))	('curcumin', 'Chemical', 'MESH:D003474', (59, 67))	('necrosis', 'biological_process', 'GO:0070265', ('29', '37'))	('tumor necrosis', 'Disease', (23, 37))	('necrosis', 'biological_process', 'GO:0008219', ('29', '37'))
144541	22189739	Because Prima-1 restores the activity of the mutated p53 protein, we expected to find some difference in the expression of p21 among these groups of animals.	('p21', 'Gene', '12575', (123, 126))	('activity', 'MPA', (29, 37))	('mutated', 'Var', (45, 52))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('p53 protein', 'Protein', (53, 64))	('protein', 'Protein', (57, 64))	('p21', 'Gene', (123, 126))
144545	22189739	Although there was no statistically significant difference in tumor size between the different groups, tumors treated with curcumin were smaller, especially when compared with those exposed to saline alone (mean 2.85 mm vs. 6.23 mm).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('smaller', 'NegReg', (137, 144))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('curcumin', 'Chemical', 'MESH:D003474', (123, 131))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (62, 67))	('curcumin', 'Var', (123, 131))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('saline', 'Chemical', 'MESH:D012965', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
144550	22189739	The mean percentage of cyclin D1-positive tumor cells was 23% in animals treated with curcumin and 49% in untreated mice (p<0.01).	('mice', 'Species', '10090', (116, 120))	('cyclin D1', 'Gene', '12443', (23, 32))	('tumor', 'Disease', (42, 47))	('cyclin D1', 'Gene', (23, 32))	('cyclin', 'molecular_function', 'GO:0016538', ('23', '29'))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('curcumin', 'Chemical', 'MESH:D003474', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('curcumin', 'Var', (86, 94))
144638	33912514	Antiplatelet/anticoagulant therapy and bladder V70 > 29% are the factors associated with the need of patients' hospitalization.	('patients', 'Species', '9606', (101, 109))	('bladder', 'Gene', (39, 46))	('> 29%', 'Var', (51, 56))	('associated', 'Reg', (73, 83))
144644	33543020	However, IGF-IR depletion in metastatic bladder cancer cells only partially inhibited anchorage-independent growth.	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('anchorage-independent growth', 'CPA', (86, 114))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('depletion', 'Var', (16, 25))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('IGF-IR', 'Gene', (9, 15))	('inhibited', 'NegReg', (76, 85))	('IGF-IR', 'Gene', '3480', (9, 15))
144663	33543020	It has been recently shown that DDR1 kinase activity is determined by its molecular density, and autophosphorylation of the receptor leads to aggregation into large clusters.	('leads to', 'Reg', (133, 141))	('DDR1', 'Gene', '780', (32, 36))	('autophosphorylation', 'Var', (97, 116))	('DDR1', 'Gene', (32, 36))	('activity', 'MPA', (44, 52))	('aggregation', 'MPA', (142, 153))	('kinase activity', 'molecular_function', 'GO:0016301', ('37', '52'))
144664	33543020	Aberrant receptor signaling is associated with the progression of various human diseases, including fibrosis, arthritis, and cancer, where DDR1 may promote resistance to therapy.	('human', 'Species', '9606', (74, 79))	('arthritis', 'Disease', (110, 119))	('Aberrant', 'Var', (0, 8))	('DDR1', 'Gene', '780', (139, 143))	('resistance', 'MPA', (156, 166))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('DDR1', 'Gene', (139, 143))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('fibrosis', 'Disease', 'MESH:D005355', (100, 108))	('associated', 'Reg', (31, 41))	('receptor', 'Protein', (9, 17))	('fibrosis', 'Disease', (100, 108))	('arthritis', 'Disease', 'MESH:D001168', (110, 119))	('arthritis', 'Phenotype', 'HP:0001369', (110, 119))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('cancer', 'Disease', (125, 131))	('promote', 'PosReg', (148, 155))
144765	33543020	In the present study, we show that: (A) Stable IGF-IR depletion in metastatic bladder cancer cells only partially inhibits motility and anchorage-independent growth.	('depletion', 'Var', (54, 63))	('IGF-IR', 'Gene', (47, 53))	('bladder cancer', 'Phenotype', 'HP:0009725', (78, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('inhibits', 'NegReg', (114, 122))	('IGF-IR', 'Gene', '3480', (47, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (78, 92))	('bladder cancer', 'Disease', (78, 92))	('motility', 'CPA', (123, 131))
144767	33543020	(C) Expression of the collagen receptor DDR1 enhances bladder cancer progression.	('bladder cancer', 'Phenotype', 'HP:0009725', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('DDR1', 'Gene', '780', (40, 44))	('collagen receptor', 'Gene', (22, 39))	('bladder cancer', 'Disease', 'MESH:D001749', (54, 68))	('Expression', 'Var', (4, 14))	('bladder cancer', 'Disease', (54, 68))	('DDR1', 'Gene', (40, 44))	('collagen', 'molecular_function', 'GO:0005202', ('22', '30'))	('enhances', 'PosReg', (45, 53))	('collagen receptor', 'Gene', '3673', (22, 39))
144798	33543020	Based on these observations, we hypothesize that a specific RTK interaction between DDR1 and the IGF-IR/IR would regulate cell migration by controlling actomyosin and focal adhesion dynamics.	('controlling', 'Reg', (140, 151))	('regulate', 'Reg', (113, 121))	('DDR1', 'Gene', '780', (84, 88))	('actomyosin', 'cellular_component', 'GO:0042641', ('152', '162'))	('RTK interaction', 'Var', (60, 75))	('DDR1', 'Gene', (84, 88))	('cell migration', 'biological_process', 'GO:0016477', ('122', '136'))	('IGF-IR/IR', 'Gene', (97, 106))	('cell migration', 'CPA', (122, 136))	('focal adhesion', 'cellular_component', 'GO:0005925', ('167', '181'))	('IGF-IR/IR', 'Gene', '3480;3643', (97, 106))
144841	33391354	A total of eight elements in the ceRNA network were considered as key members and correlated with the prognosis of BLCA, including ELN, SREBF1, DSC2, TTLL7, DIP2C, SATB1, hsa-miR-20a-5p, and hsa-miR-29c-3p.	('miR-29c-3p', 'Chemical', '-', (195, 205))	('hsa-miR-20a', 'Gene', (171, 182))	('hsa-miR-29c-3p', 'Var', (191, 205))	('SATB1', 'Gene', (164, 169))	('SATB1', 'Gene', '6304', (164, 169))	('DIP2C', 'Gene', (157, 162))	('DSC2', 'Gene', '1824', (144, 148))	('DIP2C', 'Gene', '22982', (157, 162))	('hsa-miR-20a', 'Gene', '406982', (171, 182))	('SREBF1', 'Gene', '6720', (136, 142))	('TTLL7', 'Gene', (150, 155))	('TTLL7', 'Gene', '79739', (150, 155))	('SREBF1', 'Gene', (136, 142))	('ELN', 'Gene', (131, 134))	('DSC2', 'Gene', (144, 148))	('ELN', 'Gene', '2006', (131, 134))	('BLCA', 'Disease', (115, 119))
144844	33391354	Our results suggest that the mechanism of hsa-miR-29c-3p regulates the expression of ELN and DSC2, and the infiltration of Tfh and neutrophils might play pivotal roles in the progression of BLCA.	('ELN', 'Gene', (85, 88))	('expression', 'MPA', (71, 81))	('Tfh', 'Chemical', '-', (123, 126))	('regulates', 'Reg', (57, 66))	('DSC2', 'Gene', (93, 97))	('ELN', 'Gene', '2006', (85, 88))	('DSC2', 'Gene', '1824', (93, 97))	('hsa-miR-29c-3p', 'Var', (42, 56))	('miR-29c-3p', 'Chemical', '-', (46, 56))	('BLCA', 'Disease', (190, 194))
144883	33391354	Simultaneously, there was a significantly negative correlation between hsa-miR-29c-3p and neutrophils (Figure 8E), ELN and Tfh (Figure 8F).	('Tfh', 'Chemical', '-', (123, 126))	('hsa-miR-29c-3p', 'Var', (71, 85))	('neutrophils', 'CPA', (90, 101))	('negative', 'NegReg', (42, 50))	('ELN', 'Gene', (115, 118))	('miR-29c-3p', 'Chemical', '-', (75, 85))	('ELN', 'Gene', '2006', (115, 118))
144889	33391354	The results of survival analyses elucidated that the high expression level of ELN was associated with worse overall survival (OS) in BLCA patients, while there was no survival difference of DSC2 (Supplementary Figures 2E,F).	('worse', 'NegReg', (102, 107))	('overall survival', 'MPA', (108, 124))	('patients', 'Species', '9606', (138, 146))	('high', 'Var', (53, 57))	('BLCA', 'Disease', (133, 137))	('ELN', 'Gene', '2006', (78, 81))	('DSC2', 'Gene', (190, 194))	('DSC2', 'Gene', '1824', (190, 194))	('ELN', 'Gene', (78, 81))
144897	33391354	We identified that the high expression levels of ELN and DSC2 were also associated with worse OS in BLCA (Supplementary Figure 6A), which was compatible with the previous results.	('DSC2', 'Gene', '1824', (57, 61))	('expression levels', 'MPA', (28, 45))	('high', 'Var', (23, 27))	('ELN', 'Gene', (49, 52))	('associated', 'Reg', (72, 82))	('DSC2', 'Gene', (57, 61))	('ELN', 'Gene', '2006', (49, 52))	('BLCA', 'Disease', (100, 104))
144900	33391354	Not surprisingly, we found potential binding sites of hsa-miR-29c-3p on ELN (Supplementary Figure 6B) and DSC2 (Supplementary Figure 6C).	('binding', 'molecular_function', 'GO:0005488', ('37', '44'))	('binding', 'Interaction', (37, 44))	('DSC2', 'Gene', '1824', (106, 110))	('miR-29c-3p', 'Chemical', '-', (58, 68))	('hsa-miR-29c-3p', 'Var', (54, 68))	('ELN', 'Gene', (72, 75))	('DSC2', 'Gene', (106, 110))	('ELN', 'Gene', '2006', (72, 75))
144904	33391354	In the ceRNA network, we observed that the expression levels of ELN, SREBF1, DSC2, TTLL7, DIP2C, SATB1, hsa-miR-20a-5p, and hsa-miR-29c-3p were significantly correlated with the OS in patients with BLCA.	('DSC2', 'Gene', '1824', (77, 81))	('SREBF1', 'Gene', (69, 75))	('hsa-miR-20a', 'Gene', (104, 115))	('hsa-miR-20a', 'Gene', '406982', (104, 115))	('TTLL7', 'Gene', (83, 88))	('SATB1', 'Gene', (97, 102))	('DSC2', 'Gene', (77, 81))	('SATB1', 'Gene', '6304', (97, 102))	('DIP2C', 'Gene', (90, 95))	('ELN', 'Gene', (64, 67))	('ELN', 'Gene', '2006', (64, 67))	('correlated', 'Reg', (158, 168))	('TTLL7', 'Gene', '79739', (83, 88))	('patients', 'Species', '9606', (184, 192))	('hsa-miR-29c-3p', 'Var', (124, 138))	('miR-29c-3p', 'Chemical', '-', (128, 138))	('SREBF1', 'Gene', '6720', (69, 75))	('expression', 'MPA', (43, 53))	('DIP2C', 'Gene', '22982', (90, 95))
144906	33391354	Furthermore, we also found that hsa-miR-29c-3p was negatively correlated with neutrophils infiltration, ELN was negatively correlated with Tfh infiltration, and DSC2 was positively correlated with neutrophils infiltration.	('Tfh infiltration', 'CPA', (139, 155))	('neutrophils infiltration', 'CPA', (78, 102))	('hsa-miR-29c-3p', 'Var', (32, 46))	('negatively', 'NegReg', (51, 61))	('DSC2', 'Gene', '1824', (161, 165))	('ELN', 'Gene', (104, 107))	('ELN', 'Gene', '2006', (104, 107))	('negatively', 'NegReg', (112, 122))	('Tfh', 'Chemical', '-', (139, 142))	('neutrophils infiltration', 'CPA', (197, 221))	('miR-29c-3p', 'Chemical', '-', (36, 46))	('DSC2', 'Gene', (161, 165))
144908	33391354	miR-29c-3p, which was reported as a tumor suppressor in the miRNAs family, plays a protective role in various malignancies, such as head and neck cancers, gastrointestinal cancers, hepatobiliary cancers, breast cancer, and BLCA.	('cancers', 'Disease', (146, 153))	('miR-29c-3p', 'Chemical', '-', (0, 10))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (204, 217))	('tumor', 'Disease', (36, 41))	('malignancies', 'Disease', 'MESH:D009369', (110, 122))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('neck', 'cellular_component', 'GO:0044326', ('141', '145'))	('breast cancer', 'Disease', 'MESH:D001943', (204, 217))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('malignancies', 'Disease', (110, 122))	('breast cancer', 'Disease', (204, 217))	('miR-29c-3p', 'Var', (0, 10))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('tumor suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (155, 179))	('cancers', 'Disease', (172, 179))	('head and neck cancers', 'Phenotype', 'HP:0012288', (132, 153))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('head and neck cancers', 'Disease', 'MESH:D006258', (132, 153))	('BLCA', 'Disease', (223, 227))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancers', 'Disease', (195, 202))	('gastrointestinal cancers', 'Disease', (155, 179))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
144925	33391354	Dysregulation in Tfh cell generation has been implicated in various diseases, such as autoimmune diseases, immunodeficiency, cancer, asthma, and other allergic diseases.	('allergic diseases', 'Disease', 'MESH:D004342', (151, 168))	('asthma', 'Phenotype', 'HP:0002099', (133, 139))	('immunodeficiency', 'Phenotype', 'HP:0002721', (107, 123))	('Dysregulation', 'Var', (0, 13))	('implicated', 'Reg', (46, 56))	('Tfh', 'Chemical', '-', (17, 20))	('autoimmune diseases', 'Disease', 'MESH:D001327', (86, 105))	('autoimmune diseases', 'Disease', (86, 105))	('immunodeficiency', 'Disease', 'MESH:D007153', (107, 123))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('immunodeficiency', 'Disease', (107, 123))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (86, 105))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('asthma', 'Disease', 'MESH:D001249', (133, 139))	('allergic diseases', 'Disease', (151, 168))	('asthma', 'Disease', (133, 139))
144930	33391354	Previous studies indicated that the N1 phenotype TIN plays an anti-tumoral role by inducing cytotoxicity, mediating tumor rejection, and anti-tumoral immune memory.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('inducing', 'PosReg', (83, 91))	('tumoral immune memory', 'Disease', (142, 163))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (67, 72))	('tumoral', 'Disease', (142, 149))	('tumoral', 'Disease', 'MESH:D009369', (142, 149))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumoral immune memory', 'Disease', 'MESH:D007154', (142, 163))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('TIN', 'Var', (49, 52))	('TIN', 'Chemical', '-', (49, 52))	('tumoral', 'Disease', (67, 74))	('tumoral', 'Disease', 'MESH:D009369', (67, 74))	('tumor', 'Disease', (142, 147))	('mediating', 'Reg', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('memory', 'biological_process', 'GO:0007613', ('157', '163'))	('cytotoxicity', 'Disease', (92, 104))	('cytotoxicity', 'Disease', 'MESH:D064420', (92, 104))	('tumor', 'Disease', (116, 121))
144935	33391354	We will continue to explore the potential mechanism of how the hsa-miR-29c-3p regulates the expression of ELN and DSC2 and affects the infiltration of the immune cells in BLCA in our future work.	('regulates', 'Reg', (78, 87))	('ELN', 'Gene', (106, 109))	('DSC2', 'Gene', (114, 118))	('affects', 'Reg', (123, 130))	('infiltration of the immune cells', 'CPA', (135, 167))	('ELN', 'Gene', '2006', (106, 109))	('miR-29c-3p', 'Chemical', '-', (67, 77))	('DSC2', 'Gene', '1824', (114, 118))	('expression', 'MPA', (92, 102))	('hsa-miR-29c-3p', 'Var', (63, 77))
144937	33391354	Our study also inferred that the mechanism of hsa-miR-29c-3p regulates the expression of ELN and DSC2, and the infiltration of Tfh and neutrophils might play pivotal roles in the progression of BLCA.	('Tfh', 'Chemical', '-', (127, 130))	('BLCA', 'Disease', (194, 198))	('regulates', 'Reg', (61, 70))	('DSC2', 'Gene', (97, 101))	('ELN', 'Gene', '2006', (89, 92))	('hsa-miR-29c-3p', 'Var', (46, 60))	('miR-29c-3p', 'Chemical', '-', (50, 60))	('DSC2', 'Gene', '1824', (97, 101))	('ELN', 'Gene', (89, 92))	('expression', 'MPA', (75, 85))
144941	33391354	The results suggest that the mechanism of hsa-miR-29c-3p regulates the expression of ELN and DSC2, and the infiltration of Tfh and neutrophils might play pivotal roles in the progression of BLCA.	('ELN', 'Gene', (85, 88))	('expression', 'MPA', (71, 81))	('Tfh', 'Chemical', '-', (123, 126))	('regulates', 'Reg', (57, 66))	('DSC2', 'Gene', (93, 97))	('ELN', 'Gene', '2006', (85, 88))	('DSC2', 'Gene', '1824', (93, 97))	('hsa-miR-29c-3p', 'Var', (42, 56))	('miR-29c-3p', 'Chemical', '-', (46, 56))	('BLCA', 'Disease', (190, 194))
144960	31419984	In straightforward cases of urothelial CIS in which the diagnosis was unequivocal on H&E light microscopy alone, we found AMACR positivity, defined as expression in > 1/3 of the apical urothelial thickness, to have 100% sensitivity.	('H&E', 'Chemical', '-', (85, 88))	('CIS', 'Phenotype', 'HP:0030075', (39, 42))	('urothelial CIS', 'Disease', (28, 42))	('found', 'Gene', (116, 121))	('AMACR', 'Var', (122, 127))
145066	30534426	The cadherins swich respectively E-caderinei - N-cadherin replacement, has been indicated in numerous studies on carcinomas, including those of the urinary bladder.	('N-cadherin', 'Gene', '1000', (47, 57))	('cadherin', 'molecular_function', 'GO:0008014', ('49', '57'))	('E-caderinei', 'Var', (33, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('carcinomas', 'Disease', 'MESH:D002277', (113, 123))	('N-cadherin', 'Gene', (47, 57))	('carcinomas', 'Disease', (113, 123))
145163	29428524	In non-muscle invasive carcinoma patients treated by transurethral resection, high CAIX expression levels were associated with poorer recurrencefree survival and higher risk of progression.	('high', 'Var', (78, 82))	('CAIX', 'Gene', '768', (83, 87))	('patients', 'Species', '9606', (33, 41))	('poorer', 'NegReg', (127, 133))	('invasive carcinoma', 'Disease', (14, 32))	('recurrencefree', 'CPA', (134, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('expression levels', 'MPA', (88, 105))	('invasive carcinoma', 'Disease', 'MESH:D009361', (14, 32))	('CAIX', 'Gene', (83, 87))
145168	29428524	Eligible patients (n = 499) with pT1/T2N0M0 urothelial cancer underwent p53 assessment by immunohistochemistry.	('patients', 'Species', '9606', (9, 17))	('urothelial cancer', 'Disease', (44, 61))	('pT1/T2N0M0', 'Var', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('p53', 'Gene', '7157', (72, 75))	('p53', 'Gene', (72, 75))	('urothelial cancer', 'Disease', 'MESH:D014523', (44, 61))
145175	29428524	According to their findings, DNA ploidy may provide prognostic information on patients with muscle invasive urothelial carcinoma and thus, facilitate patient stratification for postoperative management.	('patient', 'Species', '9606', (150, 157))	('patient', 'Species', '9606', (78, 85))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('patients', 'Species', '9606', (78, 86))	('DNA', 'Var', (29, 32))	('facilitate', 'PosReg', (139, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('muscle invasive urothelial carcinoma', 'Disease', 'MESH:D009217', (92, 128))	('muscle invasive urothelial carcinoma', 'Disease', (92, 128))
145181	29428524	In addition, mutational load emerges as a significant predictive biomarker in metastatic urothelial cancer, since the approval of immunotherapeutic agents.	('urothelial cancer', 'Disease', 'MESH:D014523', (89, 106))	('mutational load', 'Var', (13, 28))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('urothelial cancer', 'Disease', (89, 106))
145182	29428524	It has long been hypothesized that the efficacy of immunotherapy is correlated with the mutational load of the tumor.	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mutational load', 'Var', (88, 103))	('tumor', 'Disease', 'MESH:D009369', (111, 116))
145183	29428524	Recognition of neoantigens is an important component of cancer immunotherapy and despite that immune response may be directed by specific mutations, mutational load remains a surrogate marker of neoantigen formation.	('component of cancer', 'Disease', 'MESH:D009369', (43, 62))	('formation', 'biological_process', 'GO:0009058', ('206', '215'))	('immune response', 'biological_process', 'GO:0006955', ('94', '109'))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutational load', 'Var', (149, 164))	('component of cancer', 'Disease', (43, 62))	('mutations', 'Var', (138, 147))
145184	29428524	ImVigor 210 trial provided confirmatory evidence, since response to anti-PD-L1 antibody Atezolizumab was correlated to the mutational load.	('Atezolizumab', 'Chemical', 'MESH:C000594389', (88, 100))	('antibody', 'cellular_component', 'GO:0042571', ('79', '87'))	('PD-L1', 'Gene', '29126', (73, 78))	('correlated', 'Reg', (105, 115))	('antibody', 'cellular_component', 'GO:0019815', ('79', '87'))	('antibody', 'cellular_component', 'GO:0019814', ('79', '87'))	('antibody', 'molecular_function', 'GO:0003823', ('79', '87'))	('mutational load', 'Var', (123, 138))	('PD-L1', 'Gene', (73, 78))
145189	29428524	When adenomatous polyposis coli (APC) mutations were investigated alongside with beta-catenin expression and molecular interactions with proliferation, apoptosis, and angiogenesis markers in invasive urothelial cancer patients, APC mutations and/or the aberrant expression of beta-catenin were associated with worse clinical outcomes.	('APC', 'Disease', 'MESH:D011125', (33, 36))	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('APC', 'Disease', (33, 36))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('mutations', 'Var', (232, 241))	('APC', 'Phenotype', 'HP:0005227', (228, 231))	('beta-catenin', 'Gene', (81, 93))	('APC', 'Phenotype', 'HP:0005227', (33, 36))	('APC', 'Disease', 'MESH:D011125', (228, 231))	('APC', 'Disease', (228, 231))	('beta-catenin', 'Gene', '1499', (81, 93))	('associated', 'Reg', (294, 304))	('angiogenesis', 'biological_process', 'GO:0001525', ('167', '179'))	('beta-catenin', 'Gene', (276, 288))	('beta-catenin', 'Gene', '1499', (276, 288))	('invasive urothelial cancer', 'Disease', (191, 217))	('aberrant', 'Var', (253, 261))	('patients', 'Species', '9606', (218, 226))	('APC', 'cellular_component', 'GO:0005680', ('33', '36'))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (5, 31))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (5, 31))	('adenomatous polyposis coli', 'Disease', (5, 31))	('APC', 'cellular_component', 'GO:0005680', ('228', '231'))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('invasive urothelial cancer', 'Disease', 'MESH:D009362', (191, 217))
145190	29428524	Fibroblast growth factor receptor-3 (FGFR3) was long thought as a promising urothelial cancer biomarker, as FGFR3 signaling is modified in many urothelial cancer patients and FGF3 mutations are prevalent in 74% of non-invasive papillary tumors.	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('Fibroblast growth factor receptor-3', 'Gene', (0, 35))	('urothelial cancer', 'Disease', 'MESH:D014523', (76, 93))	('FGFR3', 'Gene', (37, 42))	('FGF3', 'Gene', (175, 179))	('FGFR3', 'Gene', '2261', (37, 42))	('urothelial cancer', 'Disease', (76, 93))	('modified', 'Reg', (127, 135))	('FGFR3', 'Gene', (108, 113))	('FGF3', 'Gene', '2248', (175, 179))	('patients', 'Species', '9606', (162, 170))	('mutations', 'Var', (180, 189))	('FGFR3', 'Gene', '2261', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('papillary tumors', 'Phenotype', 'HP:0007482', (227, 243))	('urothelial cancer', 'Disease', 'MESH:D014523', (144, 161))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('Fibroblast growth factor', 'molecular_function', 'GO:0005104', ('0', '24'))	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('papillary tumors', 'Disease', 'MESH:D002291', (227, 243))	('papillary tumors', 'Disease', (227, 243))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('prevalent', 'Reg', (194, 203))	('urothelial cancer', 'Disease', (144, 161))	('Fibroblast growth factor receptor-3', 'Gene', '2261', (0, 35))
145193	29428524	The study of Guancial and coworkers reported that FGFR3 mutations were observed in 2% of primary and 9% of secondary tumors, although FGFR3 immunohistochemistry staining was present in 29% of primary and 49% of secondary tumors, yet, with no effect on overall survival (P = .89, primary tumors; P = .78, metastases).	('FGFR3', 'Gene', (134, 139))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('FGFR3', 'Gene', '2261', (134, 139))	('metastases', 'Disease', 'MESH:D009362', (304, 314))	('tumors', 'Disease', 'MESH:D009369', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutations', 'Var', (56, 65))	('observed', 'Reg', (71, 79))	('primary tumors', 'Disease', (279, 293))	('metastases', 'Disease', (304, 314))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', (221, 227))	('FGFR', 'molecular_function', 'GO:0005007', ('134', '138'))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('primary tumors', 'Disease', 'MESH:D009369', (279, 293))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('FGFR3', 'Gene', (50, 55))	('primary', 'Disease', (89, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('50', '54'))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('FGFR3', 'Gene', '2261', (50, 55))	('tumors', 'Disease', (287, 293))
145197	29428524	HER2 overexpression or amplification in the primary tumor did not predict overall survival in patients with metastatic urothelial carcinoma, when primary tumors from two patient cohorts from Spain and Greece, treated with platinum-based chemotherapy were evaluated.	('tumor', 'Disease', (52, 57))	('urothelial carcinoma', 'Disease', (119, 139))	('primary tumors', 'Disease', (146, 160))	('HER2', 'Gene', '2064', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (154, 159))	('patients', 'Species', '9606', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('patient', 'Species', '9606', (94, 101))	('primary tumors', 'Disease', 'MESH:D009369', (146, 160))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (119, 139))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('platinum', 'Chemical', 'MESH:D010984', (222, 230))	('HER2', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('amplification', 'Var', (23, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('patient', 'Species', '9606', (170, 177))
145210	29428524	Intense efforts also focus on cancer metabolism (in particular, aberrant glucose and choline metabolism), angiogenesis, inflammation, the tumor microenvironment or stromal cell receptors for tumor specific delivery in the context of image-guided targeted molecular medicine.	('choline metabolism', 'biological_process', 'GO:0019695', ('85', '103'))	('choline', 'Chemical', 'MESH:D002794', (85, 92))	('glucose', 'Chemical', 'MESH:D005947', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', (138, 143))	('angiogenesis', 'biological_process', 'GO:0001525', ('106', '118'))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('metabolism', 'biological_process', 'GO:0008152', ('37', '47'))	('inflammation', 'Disease', 'MESH:D007249', (120, 132))	('aberrant', 'Var', (64, 72))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('inflammation', 'biological_process', 'GO:0006954', ('120', '132'))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('inflammation', 'Disease', (120, 132))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
145215	29428524	90Y-rituximab and 131I-tositumomab are examples of radiolabeled antibodies for cancer treatment during radioimmunotherapy, which serve as imaging theranostics.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('131I-tositumomab', 'Chemical', 'MESH:C119496', (18, 34))	('90Y-rituximab', 'Chemical', '-', (0, 13))	('90Y-rituximab', 'Var', (0, 13))	('131I-tositumomab', 'Var', (18, 34))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
145217	29428524	Medium-energy beta-emitters (131I, 177Lu) are more effective against small tumors, whereas isotopes emitting high-energy beta-radiation (90Y) are a better alternative, in the case of larger tumors.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('131I', 'Chemical', 'MESH:C000614965', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (190, 196))	('tumors', 'Disease', (75, 81))	('131I', 'Var', (29, 33))
145243	29343916	On multivariable analysis controlling for age, Charlson comorbidity index, grade, and tumor stage, tumor size >=3.5 cm was independently predictive of worse OS (odds ratio: 1.13 [95% confidence interval: 1.02-1.26], P = 0.023).	('worse OS', 'Disease', (151, 159))	('tumor', 'Disease', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('>=3.5', 'Var', (110, 115))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('OS', 'Chemical', '-', (157, 159))
145276	29343916	The 5-year survival was worse for pN + versus pN0 (14.8% vs. 55.8%, P < 0.0001), high grade tumors versus low grade tumors (48.4% vs. 74.3%, P < 0.0001), and tumor size >= 3.5 cm versus < 3.5 cm (45.9% vs. 58.5%, P < 0.0001).	('high grade', 'Var', (81, 91))	('tumor', 'Disease', (158, 163))	('pN +', 'Var', (34, 38))	('worse', 'NegReg', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumors versus low grade tumors', 'Disease', (92, 122))	('tumors versus low grade tumors', 'Disease', 'MESH:D009369', (92, 122))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
145278	29343916	Multivariable survival analysis demonstrated that increasing age (P < 0.001), increasing comorbidity (P < 0.001), larger tumor size (P = 0.043), high grade tumors (P < 0.001), and increasing pT stage are associated with worse OS outcomes [Table 3].	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('high grade', 'Var', (145, 155))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (156, 161))	('tumors', 'Disease', (156, 162))	('OS', 'Chemical', '-', (226, 228))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
145288	29343916	Our findings suggest that tumor size can be used as a predictor of 5-year survival, with rates of 58.5% for <=3.5 cm versus 45.9% for those larger than 3.5 cm.	('<=3.5 cm', 'Var', (108, 116))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))
145310	29077939	Because the related data, especially mutations in cancers, increased sharply, we updated the lncRNASNP to version 2 (http://bioinfo.life.hust.edu.cn/lncRNASNP2).	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Disease', (50, 57))	('mutations', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
145312	29077939	(i) noncoding variants from COSMIC cancer data (859534) in lncRNAs and their effects on lncRNA structure and function; (ii) TCGA cancer mutations (315234) in lncRNAs and their impacts; (iii) lncRNA expression profiling of 20 cancer types in both tumor and its adjacent samples; (iv) expanded lncRNA-associated diseases; (v) optimized the results about lncRNAs structure change induced by variants; (vi) reduced false positives in miRNA and lncRNA interaction results.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lncRNA-associated diseases', 'Disease', (292, 318))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('lncRNAs structure change', 'MPA', (352, 376))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('false', 'biological_process', 'GO:0071877', ('411', '416'))	('315234', 'Var', (147, 153))	('mutations (315234', 'Var', (136, 153))	('expanded', 'PosReg', (283, 291))	('tumor', 'Disease', (246, 251))	('variants', 'Var', (388, 396))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('cancer', 'Disease', (35, 41))	('false', 'biological_process', 'GO:0071878', ('411', '416'))
145315	29077939	Genome variants including SNPs and mutations contribute to changes of lncRNA structure and function, thus increase the susceptibility to cancers and other diseases.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('susceptibility', 'Reg', (119, 133))	('variants', 'Var', (7, 15))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('SNPs', 'Disease', (26, 30))	('changes', 'Reg', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('lncRNA structure', 'MPA', (70, 86))	('increase', 'PosReg', (106, 114))	('function', 'MPA', (91, 99))	('mutations', 'Var', (35, 44))
145316	29077939	SNPs have been reported to affect the structure, expression, and function of lncRNAs, such as SNP rs920778 in HOTAIR contributes to the risk of gastric cancer and SNP rs11655237 in LINC00673 confers susceptibility to pancreatic cancer by creating a miR-1231 binding site.	('SNP rs11655237', 'Var', (163, 177))	('structure', 'MPA', (38, 47))	('function', 'MPA', (65, 73))	('creating', 'Reg', (238, 246))	('gastric cancer', 'Disease', 'MESH:D013274', (144, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (217, 234))	('rs920778', 'Mutation', 'rs920778', (98, 106))	('SNP rs920778', 'Var', (94, 106))	('rs920778', 'Var', (98, 106))	('binding', 'Interaction', (258, 265))	('expression', 'MPA', (49, 59))	('LINC00673', 'Gene', '100499467', (181, 190))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('affect', 'Reg', (27, 33))	('gastric cancer', 'Phenotype', 'HP:0012126', (144, 158))	('binding', 'molecular_function', 'GO:0005488', ('258', '265'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (217, 234))	('miR-1231', 'Protein', (249, 257))	('susceptibility', 'Reg', (199, 213))	('HOTAIR', 'Gene', '100124700', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('LINC00673', 'Gene', (181, 190))	('HOTAIR', 'Gene', (110, 116))	('pancreatic cancer', 'Disease', (217, 234))	('rs11655237', 'Mutation', 'rs11655237', (167, 177))	('gastric cancer', 'Disease', (144, 158))
145317	29077939	Two high frequency mutations in lncRNA GAS8-AS1 were associated with papillary thyroid carcinoma.	('GAS8', 'Gene', '2622', (39, 43))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (69, 96))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (69, 96))	('AS1', 'Gene', '5729', (44, 47))	('AS1', 'Gene', (44, 47))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (79, 96))	('mutations', 'Var', (19, 28))	('GAS8', 'Gene', (39, 43))	('associated', 'Reg', (53, 63))	('GAS', 'molecular_function', 'GO:0034005', ('39', '42'))	('papillary thyroid carcinoma', 'Disease', (69, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
145318	29077939	A study of whole-genome mutational landscape of liver cancer discovered recurrent mutations in lncRNA NEAT1 and MALAT1.	('NEAT1', 'Gene', (102, 107))	('NEAT1', 'Gene', '283131', (102, 107))	('liver cancer', 'Phenotype', 'HP:0002896', (48, 60))	('liver cancer', 'Disease', 'MESH:D006528', (48, 60))	('mutations', 'Var', (82, 91))	('MALAT1', 'Gene', '378938', (112, 118))	('liver cancer', 'Disease', (48, 60))	('MALAT1', 'Gene', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
145319	29077939	It was reported that mutations in lncRNA NEAT1 were associated with increased expression and unfavorable outcome in papillary renal-cell carcinoma.	('papillary renal-cell carcinoma', 'Phenotype', 'HP:0006766', (116, 146))	('expression', 'MPA', (78, 88))	('renal-cell carcinoma', 'Phenotype', 'HP:0005584', (126, 146))	('associated', 'Reg', (52, 62))	('papillary renal-cell carcinoma', 'Disease', 'MESH:C538614', (116, 146))	('NEAT1', 'Gene', (41, 46))	('NEAT1', 'Gene', '283131', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('papillary renal-cell carcinoma', 'Disease', (116, 146))	('increased', 'PosReg', (68, 77))	('mutations', 'Var', (21, 30))
145320	29077939	These studies indicate that it is very necessary to study the variants on lncRNAs in cancers to identify biomarkers for carcinogenesis and prognosis.	('carcinogenesis', 'Disease', 'MESH:D063646', (120, 134))	('variants', 'Var', (62, 70))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('carcinogenesis', 'Disease', (120, 134))	('lncRNAs', 'Gene', (74, 81))	('cancers', 'Disease', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
145322	29077939	As the increasing of identified lncRNAs and SNPs in human genome, especially mutations in cancers, we updated the lncRNASNP with the latest data and developed new functions to improve it.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('human', 'Species', '9606', (52, 57))	('mutations', 'Var', (77, 86))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
145332	29077939	For example, COSN4621983 (score 0.9955) in genes was reported to provide a potential treatment target for mantle cell lymphoma.	('cell lymphoma', 'Phenotype', 'HP:0012191', (113, 126))	('COSN4621983', 'Chemical', '-', (13, 24))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (106, 126))	('mantle cell lymphoma', 'Disease', (106, 126))	('COSN4621983', 'Var', (13, 24))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))
145334	29077939	Finally, we identified 315 234 mutations in lncRNA transcripts among 34 cancer types.	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lncRNA transcripts', 'Gene', (44, 62))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
145335	29077939	The top three cancer types with the highest mutation numbers in lncRNAs were SKCM (Skin Cutaneous Melanoma), COAD (Colon adenocarcinoma) and STAD (Stomach adenocarcinoma).	('cancer', 'Disease', (14, 20))	('Stomach adenocarcinoma', 'Disease', 'MESH:D013274', (147, 169))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('mutation', 'Var', (44, 52))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (83, 106))	('COAD', 'Disease', 'MESH:D029424', (109, 113))	('Melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('Colon adenocarcinoma', 'Disease', 'MESH:D003110', (115, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('STAD', 'Disease', (141, 145))	('Colon adenocarcinoma', 'Disease', (115, 135))	('Stomach adenocarcinoma', 'Disease', (147, 169))	('COAD', 'Disease', (109, 113))	('Skin Cutaneous Melanoma', 'Disease', (83, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
145336	29077939	Inspired by COSMIC, FATHMM was used to assess mutation impacts on lncRNA transcripts, as the TCGA cancer mutations we collected were filtered by MutSig (http://archive.broadinstitute.org/cancer/cga/mutsig), 78.35% of them tend to be 'Pathogenic'.	('TCGA', 'Gene', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (187, 193))	('cga', 'Gene', '1113', (194, 197))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('mutations', 'Var', (105, 114))	('cancer', 'Disease', (98, 104))	('cga', 'Gene', (194, 197))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	("'Pathogenic", 'PosReg', (233, 244))
145337	29077939	In recent years, the dysregulation of lncRNAs was found related to tumor progression and survival.	('survival', 'CPA', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('dysregulation', 'Var', (21, 34))	('lncRNAs', 'Protein', (38, 45))	('tumor', 'Disease', (67, 72))	('related', 'Reg', (56, 63))
145344	29077939	Among the variants we identified, 80.94% (5 876 208) SNPs, 33.53% (105,683) TCGA cancer mutations and 54.12% (465 178) CosmicNCVs in human were attributed to induce the potential miRNA target sites gain/loss, respectively, and for mouse, the number of SNPs was 79.76% (3 127 650).	('variants', 'Var', (10, 18))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('gain/loss', 'PosReg', (198, 207))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (88, 97))	('cancer', 'Disease', (81, 87))	('gain/loss', 'NegReg', (198, 207))	('mouse', 'Species', '10090', (231, 236))	('human', 'Species', '9606', (133, 138))
145349	29077939	Totally, 1 425 449 (19.63%) and 395 443 (10.08%) SNPs in human and mouse lncRNA transcripts were identified to impact on lncRNA structure, respectively.	('lncRNA structure', 'MPA', (121, 137))	('lncRNA', 'Gene', (73, 79))	('SNPs', 'Var', (49, 53))	('mouse', 'Species', '10090', (67, 72))	('impact', 'Reg', (111, 117))	('human', 'Species', '9606', (57, 62))
145350	29077939	Except for SNPs, we also predicted lncRNA structure changes caused by cancer mutations, and results showed that 16.67% TCGA cancer mutations and 17.3% CosmicNCVs may lead to the change of lncRNA secondary structure.	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (124, 130))	('lncRNA secondary structure', 'MPA', (188, 214))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('change', 'Reg', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lead to', 'Reg', (166, 173))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
145352	29077939	Under the 'Variants in lncRNA' tag, we integrated SNPs, TCGA cancer mutations and CosmicNCVs in lncRNA (Figure 1A).	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('rat', 'Species', '10116', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (68, 77))
145354	29077939	Users can browse mutations on lncRNAs and their effects of the selected cancer.	('effects', 'Reg', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', (72, 78))
145355	29077939	Taking the BLCA (Bladder urothelial carcinoma) as an example, on the page of BLCA mutations in lncRNA, the first line is 'chr1:2189723 C>T on lncRNA NONHSAT000397.2'.	('2189723 C>T', 'Mutation', 'g.2189723C>T', (127, 138))	('Bladder urothelial carcinoma', 'Disease', (17, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('mutations', 'Var', (82, 91))	('Bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (17, 45))
145356	29077939	The content under 'miRNA target gain' tag indicates that the mutation creates a target site of miR-630 and the 'show' button will present the detailed interaction pair (Figure 1B).	('target site', 'MPA', (80, 91))	('mutation', 'Var', (61, 69))	('miR-630', 'Gene', (95, 102))	('miR-630', 'Gene', '693215', (95, 102))
145405	28928814	4, Ki-67, p53 and GATA-3 analysis of LGPUC and IUC tissues revealed significant differences between LGPUC and IUC tissue samples stained with Ki-67 (P<0.0001), p53 (P=0.0191) and GATA-3 (P=0.0087).	('GATA-3', 'Gene', '2625', (179, 185))	('p53', 'Gene', '7157', (10, 13))	('GATA-3', 'Gene', '2625', (18, 24))	('GATA-3', 'Gene', (179, 185))	('GATA-3', 'Gene', (18, 24))	('Ki-67', 'Var', (142, 147))	('p53', 'Gene', (160, 163))	('p53', 'Gene', '7157', (160, 163))	('p53', 'Gene', (10, 13))
145410	28928814	These results suggest that IUC may be distinguished from LGPUC by utilizing Ki-67 and p53, and muscle invasion cases may be identified from non-muscle invasion cases by GATA-3.	('muscle invasion', 'CPA', (95, 110))	('p53', 'Gene', '7157', (86, 89))	('IUC', 'Disease', (27, 30))	('Ki-67', 'Var', (76, 81))	('GATA-3', 'Gene', '2625', (169, 175))	('GATA-3', 'Gene', (169, 175))	('p53', 'Gene', (86, 89))
145411	28928814	The present study aimed to determine the cutoff values of Ki-67, p53 and GATA-3 positive ratios in order to distinguish IUC from LGPUC using Ki-67 and p53 or muscular invasion cases (pT2) from non-muscle invasion cases (pTa plus pT1), using GATA-3 and utilizing ROC curves and Youden index analyses.	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('GATA-3', 'Gene', '2625', (241, 247))	('GATA-3', 'Gene', (241, 247))	('p53', 'Gene', '7157', (151, 154))	('pT1', 'Gene', '58492', (229, 232))	('Ki-67', 'Var', (141, 146))	('muscular invasion', 'Disease', (158, 175))	('GATA-3', 'Gene', '2625', (73, 79))	('GATA-3', 'Gene', (73, 79))	('pT1', 'Gene', (229, 232))	('p53', 'Gene', (151, 154))	('pTa', 'molecular_function', 'GO:0008959', ('220', '223'))
145412	28928814	The AUC for the p53 index (LGPUC vs. IUC) was 0.73587 and the cutoff value was 9.2%.	('p53', 'Gene', '7157', (16, 19))	('p53', 'Gene', (16, 19))	('0.73587', 'Var', (46, 53))
145413	28928814	The AUC for the GATA-3 index (pT2 vs. pTa + pT1) was 0.86420 and the cutoff value was 63.9%.	('pT1', 'Gene', '58492', (44, 47))	('0.86420', 'Var', (53, 60))	('GATA-3', 'Gene', '2625', (16, 22))	('GATA-3', 'Gene', (16, 22))	('pTa', 'molecular_function', 'GO:0008959', ('38', '41'))	('pT1', 'Gene', (44, 47))
145425	28928814	In the present study, the AUC for the p53 index (LGPUC vs. IUC) was 0.73587 (moderate accuracy) and the cutoff value was 9.2%.	('0.73587', 'Var', (68, 75))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))
145440	28099114	Previously we described mtDNA copy number depletion across many solid tumor types (Reznik et al., 2016).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('solid tumor', 'Disease', (64, 75))	('solid tumor', 'Disease', 'MESH:D009369', (64, 75))	('copy number depletion', 'Var', (30, 51))	('mtDNA', 'cellular_component', 'GO:0000262', ('24', '29'))
145460	28099114	In, we observed widespread mtDNA copy number depletion in tumors compared to matched adjacent normal tissue in a number of solid tumor types.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('copy number depletion', 'Var', (33, 54))	('solid tumor', 'Disease', (123, 134))	('solid tumor', 'Disease', 'MESH:D009369', (123, 134))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mtDNA', 'cellular_component', 'GO:0000262', ('27', '32'))	('mtDNA', 'Gene', (27, 32))
145465	28099114	We also observed that LUAD (lung adenocarcinoma), which we found to be the only cancer type with increased mtDNA copy number in, had lower expression of 6/13 mtRNAs, suggesting that any increase in mtDNA copy number in LUAD was compensated for at the transcriptional level.	('mtDNA', 'Gene', (107, 112))	('lung adenocarcinoma', 'Disease', (28, 47))	('mtRNAs', 'Protein', (158, 164))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (28, 47))	('copy number', 'Var', (113, 124))	('mtDNA', 'cellular_component', 'GO:0000262', ('107', '112'))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mtDNA', 'cellular_component', 'GO:0000262', ('198', '203'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('expression', 'MPA', (139, 149))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('lower', 'NegReg', (133, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('LUAD', 'Disease', (22, 26))	('cancer', 'Disease', (80, 86))
145470	28099114	Two recent publications have highlighted the role that mtDNA mutations have in the development of one substype of chromophobes, eosinophilic chromophobe renal cell carcinomas.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (153, 174))	('mtDNA', 'Gene', (55, 60))	('eosinophilic chromophobe renal cell carcinomas', 'Disease', (128, 174))	('mutations', 'Var', (61, 70))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (153, 173))	('eosinophilic chromophobe renal cell carcinomas', 'Disease', 'MESH:C538614', (128, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('mtDNA', 'cellular_component', 'GO:0000262', ('55', '60'))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
145472	28099114	This phenotype arises from two critical dysfunctions: somatic mtDNA mutations that render mitochondrial OXPHOS non-functional, and defective mitophagy that prevents clearance of dysfunctional mitochondria.	('mtDNA', 'Gene', (62, 67))	('mtDNA', 'cellular_component', 'GO:0000262', ('62', '67'))	('mitophagy', 'CPA', (141, 150))	('dysfunctional mitochondria', 'Disease', 'MESH:C564925', (178, 204))	('clearance', 'MPA', (165, 174))	('mitochondrial OXPHOS non-functional', 'MPA', (90, 125))	('mitochondria', 'cellular_component', 'GO:0005739', ('192', '204'))	('mitophagy', 'biological_process', 'GO:0000422', ('141', '150'))	('mutations', 'Var', (68, 77))	('dysfunctional mitochondria', 'Disease', (178, 204))	('OXPHOS', 'biological_process', 'GO:0002082', ('104', '110'))	('mitophagy', 'biological_process', 'GO:0000423', ('141', '150'))	('prevents', 'NegReg', (156, 164))
145479	28099114	Among these, papillary renal cell carcinoma (KIRP), esophageal carcinoma (ESCA), and thyroid cancer (THCA) showed an association between high mtRNA expression and increased age.	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (13, 43))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (13, 43))	('esophageal carcinoma', 'Disease', (52, 72))	('high', 'Var', (137, 141))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (52, 72))	('papillary renal cell carcinoma', 'Disease', (13, 43))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (23, 43))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (52, 72))	('thyroid cancer', 'Disease', (85, 99))	('thyroid cancer', 'Phenotype', 'HP:0002890', (85, 99))	('expression', 'MPA', (148, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('thyroid cancer', 'Disease', 'MESH:D013964', (85, 99))
145488	28099114	Of the seven cancer types with mtDNA depletion in tumors relative to normal tissue, five (all but esophageal and head and neck) showed positive correlation between mtDNA copy number and expression.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('mtDNA', 'cellular_component', 'GO:0000262', ('164', '169'))	('mtDNA', 'Gene', (31, 36))	('positive correlation', 'Reg', (135, 155))	('neck', 'cellular_component', 'GO:0044326', ('122', '126'))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('expression', 'MPA', (186, 196))	('mtDNA', 'cellular_component', 'GO:0000262', ('31', '36'))	('mtDNA', 'Gene', (164, 169))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('copy number', 'Var', (170, 181))
145493	28099114	Upon closer examination of samples from KICH (Figure 4:figure supplement 3), we found that tumor and normal samples had strong but distinct patterns of correlation between mtDNA copy number and mtRNA levels.	('mtRNA levels', 'MPA', (194, 206))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('mtDNA', 'cellular_component', 'GO:0000262', ('172', '177'))	('copy number', 'Var', (178, 189))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('correlation', 'Interaction', (152, 163))	('tumor', 'Disease', (91, 96))	('mtDNA', 'Gene', (172, 177))
145496	28099114	Given that many KICH tumors harbor mtDNA mutations, these observations suggest that compensation for such mitochondrial dysfunction in KICH may be via transcriptional mechanisms, rather than changes to mtDNA ploidy.	('mutations', 'Var', (41, 50))	('mitochondrial dysfunction', 'Disease', (106, 131))	('mtDNA', 'Gene', (35, 40))	('mtDNA', 'cellular_component', 'GO:0000262', ('35', '40'))	('mtDNA', 'cellular_component', 'GO:0000262', ('202', '207'))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (106, 131))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (106, 131))	('KICH tumors', 'Disease', (16, 27))	('KICH tumors', 'Disease', 'MESH:D009369', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
145510	28099114	While changes in mtDNA copy number and mtRNA expression cannot be used as surrogates for changes in respiratory flux, several of the cancer types examined here are driven by genetic changes affecting mitochondrial respiration, suggesting that changes in mtRNA levels may reflect bona fide changes in respiration.	('driven by', 'Reg', (164, 173))	('respiration', 'biological_process', 'GO:0007585', ('214', '225'))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('respiration', 'biological_process', 'GO:0007585', ('300', '311'))	('cancer', 'Disease', (133, 139))	('changes', 'Var', (182, 189))	('mitochondrial respiration', 'MPA', (200, 225))	('mtDNA', 'cellular_component', 'GO:0000262', ('17', '22'))	('respiration', 'biological_process', 'GO:0045333', ('214', '225'))	('affecting', 'Reg', (190, 199))	('respiration', 'biological_process', 'GO:0045333', ('300', '311'))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
145511	28099114	For example, clear-cell renal cell carcinomas are driven by homozygous loss of VHL, which leads to activation of hypoxia inducible factor (HIF), and subsequently increased transcription of glycolytic enzymes.	('VHL', 'Gene', '7428', (79, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (24, 44))	('hypoxia', 'Disease', 'MESH:D000860', (113, 120))	('increased', 'PosReg', (162, 171))	('transcription', 'biological_process', 'GO:0006351', ('172', '185'))	('transcription', 'MPA', (172, 185))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('hypoxia', 'Disease', (113, 120))	('activation', 'PosReg', (99, 109))	('clear-cell renal cell carcinomas', 'Disease', 'MESH:C538614', (13, 45))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (24, 45))	('clear-cell renal cell carcinomas', 'Disease', (13, 45))	('loss', 'Var', (71, 75))	('VHL', 'Gene', (79, 82))	('glycolytic enzymes', 'Enzyme', (189, 207))
145527	28099114	Prior studies of mitochondrial-nuclear (mitonuclear) protein imbalance in C. elegans claimed that it promotes longevity via activation of the mitochondrial unfolded protein response (UPRMT), a transcriptional response preserving mitochondrial function in the face of stress.	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('activation', 'PosReg', (124, 134))	('mitochondrial unfolded protein response', 'MPA', (142, 181))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('imbalance', 'Var', (61, 70))	('longevity', 'CPA', (110, 119))	('mitochondrial unfolded protein response', 'biological_process', 'GO:0034514', ('142', '181'))	('imbalance', 'Phenotype', 'HP:0002172', (61, 70))	('promotes', 'PosReg', (101, 109))	('C. elegans', 'Species', '6239', (74, 84))
145528	28099114	If cancer cells indeed have substantial changes in mtDNA copy number and transcription (and mtDNA mutations), then activation of the mammalian UPR may be critical in supporting their proliferation in the face of increased mitochondrial stress.	('mtDNA', 'Gene', (51, 56))	('changes', 'Reg', (40, 47))	('transcription', 'MPA', (73, 86))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('transcription', 'biological_process', 'GO:0006351', ('73', '86'))	('mutations', 'Var', (98, 107))	('mammalian', 'Species', '9606', (133, 142))	('mtDNA', 'Gene', (92, 97))	('cancer', 'Disease', (3, 9))	('mtDNA', 'cellular_component', 'GO:0000262', ('92', '97'))	('mtDNA', 'cellular_component', 'GO:0000262', ('51', '56'))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
145554	28099114	Several recent studies based on the TCGA specimens have revealed that mitochondria DNAs are altered in cancers, including mtDNA mutations as well as copy number changes.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('copy number changes', 'Var', (149, 168))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (128, 137))	('mitochondria', 'cellular_component', 'GO:0005739', ('70', '82'))	('mitochondria DNAs', 'MPA', (70, 87))	('mtDNA', 'Disease', (122, 127))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('altered', 'Reg', (92, 99))	('mtDNA', 'cellular_component', 'GO:0000262', ('122', '127'))	('cancers', 'Disease', (103, 110))
145579	28099114	We are unable to perform in vivo or in vitro experiments to measure how suppression of mtRNAs affects respiratory flux and proliferation/malignancy.	('malignancy', 'Disease', (137, 147))	('mtRNAs', 'Gene', (87, 93))	('suppression', 'Var', (72, 83))	('affects', 'Reg', (94, 101))	('respiratory flux', 'MPA', (102, 118))	('malignancy', 'Disease', 'MESH:D009369', (137, 147))
145582	28099114	In both of these cancer types, we propose that changes in mtRNA are an adaptive response to "driver" genetic mutations and upstream changes in cell signaling.	('mtRNA', 'Gene', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('changes', 'Var', (47, 54))	('cancer', 'Disease', (17, 23))	('mutations', 'Var', (109, 118))	('signaling', 'biological_process', 'GO:0023052', ('146', '155'))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
145583	28099114	For example, VHL inactivation in KIRC leads to activation of HIF which upregulates glycolytic genes and suppresses OXPHOS gene expression.	('suppresses', 'NegReg', (104, 114))	('inactivation', 'Var', (17, 29))	('glycolytic genes', 'MPA', (83, 99))	('upregulates', 'PosReg', (71, 82))	('activation', 'PosReg', (47, 57))	('OXPHOS', 'biological_process', 'GO:0002082', ('115', '121'))	('gene expression', 'biological_process', 'GO:0010467', ('122', '137'))	('VHL', 'Gene', (13, 16))	('OXPHOS gene expression', 'MPA', (115, 137))	('VHL', 'Gene', '7428', (13, 16))
145646	27683459	This commercially available laboratory test, uCyt+  (formerly ImmunoCyt ) ((Scimedx Corp., Denville, NJ) combines standard urine cytology with immunofluorescence detection of three monoclonal antibodies (M344, LDQ10, and 19A211) which target carcinoembryonic antigen and two tumour associated mucins.	('carcinoembryonic antigen', 'Protein', (242, 266))	('M344', 'Var', (204, 208))	('tumour', 'Phenotype', 'HP:0002664', (275, 281))	('tumour', 'Disease', 'MESH:D009369', (275, 281))	('tumour', 'Disease', (275, 281))
145652	27683459	Mutations in the promoter of TERT can lead to increased expression of telomerase enabling malignant cells to continue to renew telomeres and avoid end replication problems.	('TERT', 'Gene', '7015', (29, 33))	('increased', 'PosReg', (46, 55))	('telomerase', 'Protein', (70, 80))	('expression', 'MPA', (56, 66))	('Mutations', 'Var', (0, 9))	('TERT', 'Gene', (29, 33))
145654	27683459	Alloy et al, screened two different tumour cohorts and found the TERT promoter mutations present in 70% of tumours of all stages and in a second cohort 80% in NMIBC and 79% in MIBC, using a SNapShot  assay (Applied Biosystems ).	('MIBC', 'Chemical', '-', (176, 180))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumours', 'Disease', 'MESH:D009369', (107, 114))	('tumours', 'Disease', (107, 114))	('tumour', 'Disease', (36, 42))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('NMIBC', 'Chemical', '-', (159, 164))	('TERT', 'Gene', (65, 69))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('tumour', 'Disease', (107, 113))	('TERT', 'Gene', '7015', (65, 69))	('MIBC', 'Chemical', '-', (160, 164))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('NMIBC', 'Disease', (159, 164))	('mutations', 'Var', (79, 88))
145656	27683459	It also been shown that the TERT promoter mutations can be detected from urine using PCR amplification and miSEQ.	('TERT', 'Gene', '7015', (28, 32))	('mutations', 'Var', (42, 51))	('TERT', 'Gene', (28, 32))
145657	27683459	In fact using this technique, Kindle et al, found that 8/15 patients with TERT promoter mutations, detected in urine following TURBT (at time of follow up cystoscopy), all 8 (100%) had subsequent recurrence discovered.	('TERT', 'Gene', '7015', (74, 78))	('patients', 'Species', '9606', (60, 68))	('mutations', 'Var', (88, 97))	('TERT', 'Gene', (74, 78))
145659	27683459	Fibroblast growth factor receptor 3 mutation is a frequent genetic event, particularly in low-grade tumours.Van Oers et al, developed and tested a SNapSHot  assay targeting nine FGFR-3 mutations.	('Fibroblast growth factor', 'molecular_function', 'GO:0005104', ('0', '24'))	('tumours', 'Disease', 'MESH:D009369', (100, 107))	('tumours', 'Disease', (100, 107))	('FGFR-3', 'Gene', (178, 184))	('FGFR-3', 'Gene', '2261', (178, 184))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('mutations', 'Var', (185, 194))	('Fibroblast growth factor receptor 3', 'Gene', (0, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('178', '182'))	('Fibroblast growth factor receptor 3', 'Gene', '2261', (0, 35))
145661	27683459	This SNapShot  assay panel was evaluated in the follow up setting of 200 patients known to have low grade NMIBC (67% of tumours were mutant FGFR3), the sensitivity of the assay was found to be 58% for concomitant disease.	('FGFR', 'molecular_function', 'GO:0005007', ('140', '144'))	('FGFR3', 'Gene', (140, 145))	('NMIBC', 'Chemical', '-', (106, 111))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('NMIBC', 'Disease', (106, 111))	('FGFR3', 'Gene', '2261', (140, 145))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (120, 127))	('mutant', 'Var', (133, 139))	('patients', 'Species', '9606', (73, 81))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
145666	27683459	It is very unlikely that FGFR3 will have utility as a urinary biomarker in its own right as tumours with FGFR3 mutation can still progress to MIBC and so cystoscopy could not be obviated in cases of urine positive for FGFR3 mutation.	('FGFR3', 'Gene', (218, 223))	('FGFR3', 'Gene', (105, 110))	('MIBC', 'Disease', (142, 146))	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('FGFR3', 'Gene', '2261', (25, 30))	('progress', 'PosReg', (130, 138))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('tumours', 'Disease', (92, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('218', '222'))	('MIBC', 'Chemical', '-', (142, 146))	('FGFR3', 'Gene', '2261', (218, 223))	('FGFR3', 'Gene', '2261', (105, 110))	('mutation', 'Var', (111, 119))	('FGFR3', 'Gene', (25, 30))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))
145668	27683459	There has been recent interest in this gene as three papers, performing genomic analysis of UBC tumours, all found STAG2 to be frequently mutated (inactivated) or deleted.	('mutated', 'Var', (138, 145))	('STAG2', 'Gene', (115, 120))	('STAG2', 'Gene', '10735', (115, 120))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('deleted', 'Var', (163, 170))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('UBC tumours', 'Disease', (92, 103))	('UBC tumours', 'Disease', 'MESH:D009369', (92, 103))
145669	27683459	The significance of STAG2 mutations has yet to be truly elucidated, with the published papers not agreeing on the prognostic implications or the exact mechanism of action of STAG2.	('STAG2', 'Gene', (20, 25))	('STAG2', 'Gene', '10735', (174, 179))	('mutations', 'Var', (26, 35))	('STAG2', 'Gene', '10735', (20, 25))	('STAG2', 'Gene', (174, 179))
145670	27683459	To date no researcher as provided details of urinary evaluation of STAG2 mutation, but the frequency of mutation may make it an attractive future marker.	('mutation', 'Var', (73, 81))	('STAG2', 'Gene', '10735', (67, 72))	('STAG2', 'Gene', (67, 72))
145680	27683459	In this study miR-126, 182 and 199a were significantly increased in UBC patients urine compared to controls and the ratio of miR126:152 had a sensitivity of 72% for detecting UBC at a set specificity of 82%.	('199a', 'MPA', (31, 35))	('miR126', 'Chemical', '-', (125, 131))	('increased', 'PosReg', (55, 64))	('UBC', 'Disease', (68, 71))	('miR-126', 'Gene', '406913', (14, 21))	('UBC', 'Disease', (175, 178))	('miR126:152', 'Var', (125, 135))	('UBC', 'Chemical', '-', (68, 71))	('miR-126', 'Gene', (14, 21))	('UBC', 'Chemical', '-', (175, 178))	('patients', 'Species', '9606', (72, 80))
145682	27683459	Miah et al, tested 121 urine samples (68 from UBC patients and 53 symptomatic controls attending cystoscopy clinic) for the presence of 15 miRs(using qPCR) known to be differentially expressed or associated with epigenetic hotspots in UBC.	('UBC', 'Disease', (235, 238))	('patients', 'Species', '9606', (50, 58))	('UBC', 'Chemical', '-', (46, 49))	('associated', 'Reg', (196, 206))	('UBC', 'Chemical', '-', (235, 238))	('epigenetic', 'Var', (212, 222))
145683	27683459	As a result of this analysis they found that a combination of miRs-135b/15b/1224-3p could detect bladder cancer with 94.1% sensitivity and 51% specificity.	('detect', 'Reg', (90, 96))	('bladder cancer', 'Disease', 'MESH:D001749', (97, 111))	('bladder cancer', 'Disease', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('miRs-135b/15b/1224-3p', 'Var', (62, 83))
145697	27683459	Scher et al, developed a small urine volume nested methylation-specific PCR assay for the detection of UBC based on methylation of BCL2, CDKN2A, and NID2 with a sensitivity of 80.9% and 86.4%.	('UBC', 'Gene', (103, 106))	('UBC', 'Chemical', '-', (103, 106))	('methylation', 'Var', (116, 127))	('small urine volume', 'Phenotype', 'HP:0011037', (25, 43))	('BCL2', 'Gene', '596', (131, 135))	('NID2', 'Gene', (149, 153))	('BCL2', 'molecular_function', 'GO:0015283', ('131', '135'))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('CDKN2A', 'Gene', (137, 143))	('CDKN2A', 'Gene', '1029', (137, 143))	('methylation', 'biological_process', 'GO:0032259', ('116', '127'))	('BCL2', 'Gene', (131, 135))	('NID2', 'Gene', '22795', (149, 153))
145767	24085110	We observe recurrent fusion events, including human papillomavirus insertions in RAD51B and ERBB2.	('ERBB2', 'Gene', '2064', (92, 97))	('ERBB2', 'Gene', (92, 97))	('human papillomavirus', 'Disease', (46, 66))	('RAD51B', 'Gene', '5890', (81, 87))	('RAD51B', 'Gene', (81, 87))	('insertions', 'Var', (67, 77))	('human papillomavirus', 'Species', '10566', (46, 66))	('papilloma', 'Phenotype', 'HP:0012740', (52, 61))	('RAD', 'biological_process', 'GO:1990116', ('81', '84'))
145774	24085110	Viruses can cause cellular transformation by expression of viral oncogenes, by genomic integration to alter the activity of cellular proto-oncogenes or tumour suppressors, and by inducing inflammation that promotes oncogenesis.	('cellular proto-oncogenes', 'Protein', (124, 148))	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('oncogenesis', 'CPA', (215, 226))	('oncogenesis', 'biological_process', 'GO:0007048', ('215', '226'))	('inducing', 'Reg', (179, 187))	('tumour', 'Disease', (152, 158))	('alter', 'Reg', (102, 107))	('inflammation', 'biological_process', 'GO:0006954', ('188', '200'))	('inflammation', 'Disease', 'MESH:D007249', (188, 200))	('promotes', 'PosReg', (206, 214))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('inflammation', 'Disease', (188, 200))	('Viruses', 'Var', (0, 7))	('activity', 'MPA', (112, 120))	('cause', 'Reg', (12, 17))	('cellular transformation', 'CPA', (18, 41))
145787	24085110	Our observations fall into six main categories: confirmation of established associations, such as high-risk HPV in cervical and head and neck cancer, which validates our methodology and provides reference viral expression levels and patterns in tumours with known viral aetiology; confirmation or rejection of controversial hypotheses, such as HPV18 in colorectal cancer; rare occurrences of known viruses in novel contexts; new viral isolates, including a novel recombinant enterovirus strain; novel recurrent host:virus fusion events, such as HPV insertions in ERBB2 and RAD51B; and patterns of coadaptation between viral and host gene expression.	('colorectal cancer', 'Disease', (353, 370))	('RAD', 'biological_process', 'GO:1990116', ('573', '576'))	('RAD51B', 'Gene', (573, 579))	('ERBB2', 'Gene', (563, 568))	('neck', 'cellular_component', 'GO:0044326', ('137', '141'))	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('insertions', 'Var', (549, 559))	('colorectal cancer', 'Phenotype', 'HP:0003003', (353, 370))	('ERBB2', 'Gene', '2064', (563, 568))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumours', 'Disease', (245, 252))	('head and neck cancer', 'Phenotype', 'HP:0012288', (128, 148))	('neck cancer', 'Disease', 'MESH:D006258', (137, 148))	('neck cancer', 'Disease', (137, 148))	('RAD51B', 'Gene', '5890', (573, 579))	('tumours', 'Phenotype', 'HP:0002664', (245, 252))	('fall', 'Phenotype', 'HP:0002527', (17, 21))	('tumours', 'Disease', 'MESH:D009369', (245, 252))	('gene expression', 'biological_process', 'GO:0010467', ('633', '648'))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('colorectal cancer', 'Disease', 'MESH:D015179', (353, 370))
145798	24085110	Many of these detections could be attributed to cytomegalovirus (CMV/HHV5) and EBV in colon adenocarcinoma (COAD), probably because of lymphocytic infiltration (Fig.	('COAD', 'Disease', 'MESH:D029424', (108, 112))	('colon adenocarcinoma', 'Disease', (86, 106))	('EBV', 'Var', (79, 82))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (86, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('COAD', 'Disease', (108, 112))	('HHV5', 'Species', '10359', (69, 73))	('EBV', 'Species', '10376', (79, 82))
145799	24085110	T-lymphocyte infiltration could also probably explain one case of low-FVR HIV1 in rectal adenocarcinoma (READ).	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('HIV1', 'Species', '11676', (74, 78))	('low-FVR', 'Var', (66, 73))	('rectal adenocarcinoma', 'Disease', (82, 103))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (82, 103))
145807	24085110	HNSC showed 14.1% HPV association, with 83.7% and 14.0% of positive tumours attributed to HPV16 and HPV33, respectively; this is notably different from CESC and compatible with earlier data.	('HPV16', 'Var', (90, 95))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('HPV33', 'Var', (100, 105))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('tumours', 'Disease', (68, 75))	('HPV', 'Disease', (18, 21))	('HPV16', 'Species', '333760', (90, 95))
145850	24085110	HPV genomic integrations are believed to occur as a consequence of HPV oncogene-induced chromosomal instability, and integrations in or near known tumour genes have been described, sometimes in conjunction with local copy-number change and altered expression of targeted genes.	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('integrations', 'Var', (117, 129))	('tumour', 'Disease', (147, 153))	('chromosomal instability', 'Phenotype', 'HP:0040012', (88, 111))
145857	24085110	It is noteworthy that of six genes with recurrent integrations, all were known cancer genes or previously described recurrent targets (Fig.	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Disease', (79, 85))	('integrations', 'Var', (50, 62))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
145863	24085110	Retinoblastoma protein (RB) inhibition increases RAD51B-induced apoptosis and the two proteins interact, suggesting that RAD51B inactivation by HPV integration could act synergistically with the HPV E7 gene, which inactivates RB.	('RAD51B', 'Gene', '5890', (49, 55))	('RAD', 'biological_process', 'GO:1990116', ('49', '52'))	('RAD51B', 'Gene', (49, 55))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (0, 14))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('HPV', 'Gene', (144, 147))	('inhibition', 'Var', (28, 38))	('interact', 'Interaction', (95, 103))	('inactivation', 'NegReg', (128, 140))	('apoptosis', 'biological_process', 'GO:0097194', ('64', '73'))	('apoptosis', 'biological_process', 'GO:0006915', ('64', '73'))	('Retinoblastoma', 'Disease', 'MESH:D012175', (0, 14))	('RAD', 'biological_process', 'GO:1990116', ('121', '124'))	('Retinoblastoma', 'Disease', (0, 14))	('RAD51B', 'Gene', (121, 127))	('RAD51B', 'Gene', '5890', (121, 127))
145865	24085110	Results from LIHC confirmed recurrent HBV fusions with MLL4 and FN1 in tumours and adjacent normal liver, respectively, two of which were found to be in-frame (Supplementary Fig.	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('FN1', 'Gene', (64, 67))	('HBV', 'Gene', (38, 41))	('tumours', 'Disease', (71, 78))	('MLL4', 'Gene', '9757', (55, 59))	('MLL4', 'Gene', (55, 59))	('HBV', 'Species', '10407', (38, 41))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('fusions', 'Var', (42, 49))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
145869	24085110	The PVT1 and LOC727677 lncRNAs, in the MYC region, had significantly higher expression in tumours with integration.	('LOC727677', 'Var', (13, 22))	('MYC', 'Gene', '4609', (39, 42))	('PVT1', 'Gene', (4, 8))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('expression', 'MPA', (76, 86))	('PVT1', 'Gene', '5820', (4, 8))	('MYC', 'Gene', (39, 42))	('higher', 'PosReg', (69, 75))	('tumours', 'Disease', (90, 97))
145870	24085110	RAD51B showed a weak, non-significant, reduction in tumours with HPV integration.	('RAD51B', 'Gene', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('reduction in tumours', 'Disease', (39, 59))	('HPV integration', 'Var', (65, 80))	('reduction in tumours', 'Disease', 'MESH:D009369', (39, 59))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('RAD', 'biological_process', 'GO:1990116', ('0', '3'))	('RAD51B', 'Gene', '5890', (0, 6))
145871	24085110	Consistent with previous data, MLL4 was strongly induced in LIHC samples with HBV integration, whereas FN1 was not significantly altered (Fig.	('induced', 'PosReg', (49, 56))	('HBV', 'Species', '10407', (78, 81))	('HBV integration', 'Var', (78, 93))	('MLL4', 'Gene', '9757', (31, 35))	('MLL4', 'Gene', (31, 35))
145873	24085110	Our results support that the activity of tumour genes can be altered by viral insertions, and nominate ERBB2 and RAD51B as functional targets.	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('activity', 'MPA', (29, 37))	('ERBB2', 'Gene', (103, 108))	('RAD51B', 'Gene', '5890', (113, 119))	('altered', 'Reg', (61, 68))	('ERBB2', 'Gene', '2064', (103, 108))	('RAD', 'biological_process', 'GO:1990116', ('113', '116'))	('RAD51B', 'Gene', (113, 119))	('tumour', 'Disease', (41, 47))	('viral insertions', 'Var', (72, 88))
145891	24085110	No host genes could be associated to the E7 or the E4/E5/E7 sets (q<0.05), showing that neither genomic integration nor E4/E5 expression has a strong impact on host expression.	('E4/E5', 'Var', (120, 125))	('E5/E7', 'Gene', (54, 59))	('impact', 'Reg', (150, 156))	('host expression', 'MPA', (160, 175))	('E5/E7', 'Gene', '22899', (54, 59))
145894	24085110	6d), confirming them as robustly associated with E6-expressing tumours.	('tumours', 'Disease', (63, 70))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('associated', 'Reg', (33, 43))	('E6-expressing', 'Var', (49, 62))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
145903	24085110	Recurrent integrations, as evidenced by host-virus fusions, were typically in known cancer genes, including ERBB2, RAD51B and in the 13q22.1 intergenic region harbouring the LINC00393 lncRNA.	('RAD', 'biological_process', 'GO:1990116', ('115', '118'))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('RAD51B', 'Gene', (115, 121))	('RAD51B', 'Gene', '5890', (115, 121))	('cancer', 'Disease', (84, 90))	('LINC00393', 'Gene', (174, 183))	('LINC00393', 'Gene', '100874156', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('integrations', 'Var', (10, 22))	('ERBB2', 'Gene', '2064', (108, 113))	('ERBB2', 'Gene', (108, 113))
145945	19885323	Immunohistochemical analysis showed positive staining for cytokeratin (CK) 7, CK20, high-molecular-weight cytokeratin (CK34BE12) and p63 (Fig.	('p63', 'Gene', '8626', (133, 136))	('CK34BE12', 'Var', (119, 127))	('CK20', 'Gene', (78, 82))	('CK20', 'Gene', '54474', (78, 82))	('p63', 'Gene', (133, 136))
145964	19885323	A variety of markers such as CK7, CK20, CK34BE12 and p63 have been used as potential urothelial markers.	('CK20', 'Gene', (34, 38))	('CK20', 'Gene', '54474', (34, 38))	('p63', 'Gene', '8626', (53, 56))	('CK34BE12', 'Var', (40, 48))	('CK7', 'Gene', (29, 32))	('CK7', 'Gene', '3855', (29, 32))	('p63', 'Gene', (53, 56))
146013	33287876	Proteins with fold change > 2 and adjusted p value < 0.05 were considered to be cancer-associated proteins.	('fold', 'Var', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Proteins', 'Protein', (0, 8))	('cancer', 'Disease', (80, 86))
146107	33287876	Moreover, we discovered the drugs targeting cyclin-dependent kinases (CDKs), such as CKD2, CKD4 and CKD6, which were overexpressed in several cancer types.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cyclin', 'Gene', '5111', (44, 50))	('CKD6', 'Var', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cyclin', 'Gene', (44, 50))	('CDKs', 'Gene', (70, 74))	('cyclin', 'molecular_function', 'GO:0016538', ('44', '50'))	('CDKs', 'Gene', '1017;1019;1021;51755', (70, 74))	('CKD2', 'Var', (85, 89))	('CKD4', 'Var', (91, 95))	('cancer', 'Disease', (142, 148))
146147	29848605	Efficacy of BGJ398, a fibroblast growth factor receptor 1-3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations BGJ398, a potent and selective pan-fibroblast growth factor receptor (FGFR) antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (116, 136))	('FGFR3', 'Gene', '2261', (142, 147))	('FGFR', 'molecular_function', 'GO:0005007', ('230', '234'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (304, 324))	('BGJ398', 'Chemical', 'MESH:C568950', (12, 18))	('fibroblast growth factor receptor 1-3', 'Gene', '2260;2263;2261', (22, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('22', '46'))	('FGFR', 'molecular_function', 'GO:0005007', ('142', '146'))	('alterations', 'Var', (358, 369))	('patients', 'Species', '9606', (74, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('352', '356'))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('urothelial carcinoma', 'Disease', (116, 136))	('patients', 'Species', '9606', (279, 287))	('FGFR3', 'Gene', (352, 357))	('urothelial carcinoma', 'Disease', (304, 324))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('195', '219'))	('BGJ398', 'Chemical', 'MESH:C568950', (160, 166))	('FGFR3', 'Gene', '2261', (352, 357))	('fibroblast growth factor receptor 1-3', 'Gene', (22, 59))	('FGFR3', 'Gene', (142, 147))
146155	29848605	More recently, inhibitors of programmed death-1 (PD-1) and its ligand (PD-L1) have supplanted cytotoxic therapies in this setting.	('programmed death-1', 'Gene', (29, 47))	('programmed death-1', 'Gene', '5133', (29, 47))	('ligand', 'molecular_function', 'GO:0005488', ('63', '69'))	('PD-1', 'Gene', (49, 53))	('supplanted', 'NegReg', (83, 93))	('PD-L1', 'Gene', (71, 76))	('PD-1', 'Gene', '5133', (49, 53))	('PD-L1', 'Gene', '29126', (71, 76))	('inhibitors', 'Var', (15, 25))
146162	29848605	FGFR3 alterations commonly occur in urothelial carcinoma, and act as an oncogenic driver.	('alterations', 'Var', (6, 17))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('urothelial carcinoma', 'Disease', (36, 56))	('FGFR3', 'Gene', (0, 5))	('occur', 'Reg', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (36, 56))	('FGFR3', 'Gene', '2261', (0, 5))
146163	29848605	Although these alterations are more frequent in non-muscle invasive bladder cancer, they are found in up to 21% of locally advanced or metastatic urothelial tumors.	('urothelial tumors', 'Disease', (146, 163))	('frequent', 'Reg', (36, 44))	('bladder cancer', 'Phenotype', 'HP:0009725', (68, 82))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (48, 75))	('alterations', 'Var', (15, 26))	('invasive bladder cancer', 'Disease', (59, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('invasive bladder', 'Phenotype', 'HP:0100645', (59, 75))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (59, 82))	('urothelial tumors', 'Disease', 'MESH:D001749', (146, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('-muscle invasive bladder cancer', 'Phenotype', 'HP:0006740', (51, 82))	('found', 'Reg', (93, 98))
146164	29848605	BGJ398 is an orally bioavailable, selective, ATP-competitive FGFR1-3 inhibitor with activity against tumor models harboring FGFR alterations.	('BGJ398', 'Chemical', 'MESH:C568950', (0, 6))	('FGFR1', 'Gene', (61, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('124', '128'))	('BGJ398', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('ATP', 'Chemical', 'MESH:D000255', (45, 48))	('FGFR1', 'Gene', '2260', (61, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('61', '65'))	('FGFR', 'Gene', (124, 128))	('activity', 'MPA', (84, 92))	('alterations', 'Var', (129, 140))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
146166	29848605	In a phase I trial of BGJ398, tumor regression was first noted in four of five patients with advanced urothelial carcinoma bearing FGFR3 mutations.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (102, 122))	('FGFR3', 'Gene', '2261', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('131', '135'))	('mutations', 'Var', (137, 146))	('urothelial carcinoma', 'Disease', (102, 122))	('BGJ398', 'Chemical', 'MESH:C568950', (22, 28))	('patients', 'Species', '9606', (79, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('FGFR3', 'Gene', (131, 136))	('tumor', 'Disease', (30, 35))
146173	29848605	Foundation Medicine (FM) next-generation sequencing data were available for 53 patients, and analysis using an FM sequencing panel of common genetic alterations found that the most common alterations outside of FGFR3 were in TERT (68%), CDKN2A (58%), CDKN2B (51%), and KDM6A (45%).	('KDM6A', 'Gene', '7403', (269, 274))	('FGFR3', 'Gene', '2261', (211, 216))	('FGFR3', 'Gene', (211, 216))	('TERT', 'Gene', '7015', (225, 229))	('FGFR', 'molecular_function', 'GO:0005007', ('211', '215'))	('CDKN2B', 'Gene', '1030', (251, 257))	('KDM6A', 'Gene', (269, 274))	('CDKN2B', 'Gene', (251, 257))	('alterations', 'Var', (188, 199))	('patients', 'Species', '9606', (79, 87))	('CDKN2A', 'Gene', (237, 243))	('TERT', 'Gene', (225, 229))	('CDKN2A', 'Gene', '1029', (237, 243))
146184	29848605	Figure 2b outlines the duration of therapy in individual patients, highlights the most commonly observed FGFR3 alterations, and overall survival.	('FGFR3', 'Gene', (105, 110))	('patients', 'Species', '9606', (57, 65))	('alterations', 'Var', (111, 122))	('FGFR3', 'Gene', '2261', (105, 110))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))
146185	29848605	As depicted, the most frequent alterations were mutations in S249C, followed by R248C.	('R248C', 'Var', (80, 85))	('S249C', 'Mutation', 'rs121913483', (61, 66))	('R248C', 'Mutation', 'rs121913482', (80, 85))	('S249C', 'Var', (61, 66))
146200	29848605	Circulating tumor (ct)DNA was identified based upon the detection of mutations reported in COSMIC.	('mutations', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('tumor', 'Disease', (12, 17))
146201	29848605	Of these 50 patients, 34 (68%) showed FGFR3 alterations in cfDNA that matched the screening analysis, 1 patient had FGFR3 Y375C mutation at screening, but Y373C alteration in cfDNA.	('patients', 'Species', '9606', (12, 20))	('FGFR3', 'Gene', '2261', (38, 43))	('FGFR', 'molecular_function', 'GO:0005007', ('116', '120'))	('FGFR3', 'Gene', (116, 121))	('Y375C', 'Mutation', 'rs121913485', (122, 127))	('Y375C', 'Var', (122, 127))	('cfDNA', 'Disease', (59, 64))	('FGFR3', 'Gene', (38, 43))	('Y373C', 'Mutation', 'rs121913485', (155, 160))	('alterations', 'Reg', (44, 55))	('patient', 'Species', '9606', (104, 111))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('Y373C alteration', 'Var', (155, 171))	('patient', 'Species', '9606', (12, 19))	('FGFR3', 'Gene', '2261', (116, 121))
146203	29848605	FM tumor sequencing data were available for two of the four patients who had detectable ctDNA with absent FGFR3 alterations, and confirmed the same FGFR3 mutations reported by screening in these two patients.	('FGFR3', 'Gene', '2261', (106, 111))	('tumor', 'Disease', (3, 8))	('FGFR', 'molecular_function', 'GO:0005007', ('148', '152'))	('ctDNA', 'Disease', (88, 93))	('patients', 'Species', '9606', (60, 68))	('FGFR3', 'Gene', (106, 111))	('FGFR3', 'Gene', '2261', (148, 153))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('absent', 'NegReg', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('patients', 'Species', '9606', (199, 207))	('FGFR3', 'Gene', (148, 153))	('alterations', 'Var', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
146204	29848605	A closer inspection of the tumor sequencing data for these two patients revealed that in one of the patients, JAK2 V617F was the only FM tumor mutation detected in cfDNA.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('JAK', 'molecular_function', 'GO:0004713', ('110', '113'))	('tumor', 'Disease', (137, 142))	('V617F', 'SUBSTITUTION', 'None', (115, 120))	('tumor', 'Disease', (27, 32))	('JAK2', 'Gene', '3717', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (63, 71))	('V617F', 'Var', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('JAK2', 'Gene', (110, 114))
146207	29848605	In the tumor sequencing data from the other patient, all mutations found in the tumor were detected in cfDNA except for FGFR3 G370C.	('G370C', 'Var', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('patient', 'Species', '9606', (44, 51))	('FGFR3', 'Gene', (120, 125))	('tumor', 'Disease', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', (80, 85))	('detected', 'Reg', (91, 99))	('cfDNA', 'Disease', (103, 108))	('FGFR', 'molecular_function', 'GO:0005007', ('120', '124'))	('FGFR3', 'Gene', '2261', (120, 125))	('G370C', 'Mutation', 'rs199740841', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
146209	29848605	FGFR3 resistance mutations, including FGFR3 gatekeeper mutations (V443L, V443M, and L496V), as determined by preclinical studies, were detected in the cfDNA of four patients during treatment (Figure 3a-d).	('V443M', 'Var', (73, 78))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', '2261', (38, 43))	('FGFR3', 'Gene', (0, 5))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('FGFR3', 'Gene', (38, 43))	('L496V', 'Var', (84, 89))	('detected', 'Reg', (135, 143))	('gatekeeper', 'Species', '111938', (44, 54))	('V443L', 'Var', (66, 71))	('V443M', 'Mutation', 'rs1474187970', (73, 78))	('patients', 'Species', '9606', (165, 173))	('V443L', 'Mutation', 'p.V443L', (66, 71))	('L496V', 'Mutation', 'p.L496V', (84, 89))	('FGFR3', 'Gene', '2261', (0, 5))
146211	29848605	Notably, error correction techniques were not applied in our analysis which could have resulted in missed FGFR3 resistance mutations.	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('FGFR3', 'Gene', '2261', (106, 111))	('FGFR3', 'Gene', (106, 111))	('mutations', 'Var', (123, 132))
146212	29848605	A preliminary analysis of the correlation between FGFR3 mutations in cfDNA and disease progression was performed.	('mutations', 'Var', (56, 65))	('FGFR3', 'Gene', (50, 55))	('cfDNA', 'Disease', (69, 74))	('FGFR', 'molecular_function', 'GO:0005007', ('50', '54'))	('FGFR3', 'Gene', '2261', (50, 55))
146214	29848605	A decrease in FGFR3 mutations with BGJ398 treatment appeared to correlate with a longer time on study and a greater percentage decrease in tumor size from baseline (Figure 3f-g).	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('decrease', 'NegReg', (2, 10))	('FGFR3', 'Gene', '2261', (14, 19))	('decrease', 'NegReg', (127, 135))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('BGJ398', 'Chemical', 'MESH:C568950', (35, 41))	('BGJ398', 'Gene', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('FGFR3', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))
146223	29848605	Current preliminary data suggest that tumors that harbor FGFR3 alterations are more likely to be resistant to immune checkpoint blockade, indicating a role for molecularly targeted therapies.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('FGFR3', 'Gene', (57, 62))	('alterations', 'Var', (63, 74))	('tumors', 'Disease', (38, 44))	('resistant', 'MPA', (97, 106))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('FGFR3', 'Gene', '2261', (57, 62))	('FGFR', 'molecular_function', 'GO:0005007', ('57', '61'))
146224	29848605	Recent guidelines from the National Comprehensive Cancer Network (NCCN) support molecular testing in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory for all patients with advanced urothelial carcinoma thereby facilitating this approach.	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('CLIA', 'Disease', 'None', (147, 151))	('urothelial carcinoma', 'Disease', (205, 225))	('CLIA', 'Disease', (147, 151))	('molecular testing', 'Var', (80, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('patients', 'Species', '9606', (182, 190))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (205, 225))
146226	29848605	Although prospective studies are needed to clarify this, the emerging evidence suggests that patients whose cancer bears FGFR3 alterations (and other actionable targets) may have non-T-cell-inflamed tumors.	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('FGFR3', 'Gene', '2261', (121, 126))	('FGFR', 'molecular_function', 'GO:0005007', ('121', '125'))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('FGFR3', 'Gene', (121, 126))	('alterations', 'Var', (127, 138))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
146232	29848605	Preclinical studies have identified FGFR3 resistance mutations, and these were detected in four patients in the current study.	('FGFR3', 'Gene', (36, 41))	('mutations', 'Var', (53, 62))	('patients', 'Species', '9606', (96, 104))	('FGFR3', 'Gene', '2261', (36, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
146233	29848605	Further examination of acquired resistance was carried out by investigating FGFR3 mutations in blood samples from patients who had relapsed following treatment with BGJ398.	('BGJ398', 'Chemical', 'MESH:C568950', (165, 171))	('FGFR3', 'Gene', '2261', (76, 81))	('mutations', 'Var', (82, 91))	('patients', 'Species', '9606', (114, 122))	('FGFR3', 'Gene', (76, 81))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))
146234	29848605	Analysis of FGFR3 mutations in the cfDNA of a patient in this study predicted disease progression ahead of computerized tomography (CT) scans, suggesting a role for the collection and analysis of cfDNA over the course of FGFR3 inhibitor treatment.	('FGFR3', 'Gene', (12, 17))	('patient', 'Species', '9606', (46, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))	('FGFR3', 'Gene', '2261', (221, 226))	('FGFR3', 'Gene', '2261', (12, 17))	('FGFR', 'molecular_function', 'GO:0005007', ('221', '225'))	('disease', 'Disease', (78, 85))	('FGFR3', 'Gene', (221, 226))	('predicted', 'Reg', (68, 77))	('mutations', 'Var', (18, 27))
146235	29848605	Consistent with these findings was the observation that a decrease in allelic fractions of FGFR3 driver mutations in the second cycle of treatment correlated with improved response.	('FGFR3', 'Gene', (91, 96))	('mutations', 'Var', (104, 113))	('improved', 'PosReg', (163, 171))	('decrease', 'NegReg', (58, 66))	('FGFR3', 'Gene', '2261', (91, 96))	('response', 'MPA', (172, 180))	('allelic', 'MPA', (70, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('91', '95'))
146236	29848605	The finding of resistance mutations in the FGFR gene family in response to BGJ398 therapy is not unique; in the setting of intrahepatic cholangiocarcinoma, point mutations in the FGFR2 kinase domain have been identified in cfDNA.	('identified', 'Reg', (209, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('intrahepatic cholangiocarcinoma', 'Disease', (123, 154))	('cfDNA', 'Disease', (223, 228))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (136, 154))	('FGFR', 'molecular_function', 'GO:0005007', ('179', '183'))	('BGJ398', 'Chemical', 'MESH:C568950', (75, 81))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('FGFR2', 'Gene', '2263', (179, 184))	('FGFR2', 'Gene', (179, 184))	('point mutations', 'Var', (156, 171))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 154))
146237	29848605	Notably, distinct alterations in FGFR3 may sensitize to BGJ938 differently.	('alterations', 'Var', (18, 29))	('sensitize', 'Reg', (43, 52))	('FGFR3', 'Gene', '2261', (33, 38))	('FGFR3', 'Gene', (33, 38))	('BGJ938', 'Gene', (56, 62))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))
146238	29848605	For example, the K650E mutation, in the kinase domain, is a known FGFR3 kinase activating mutation that leads to destabilization of the inactive conformation of the kinase domain and stabilization of the active conformation of the activation loop of the kinase domain of the receptor.	('stabilization', 'MPA', (183, 196))	('activation loop of the kinase domain', 'MPA', (231, 267))	('FGFR3', 'Gene', '2261', (66, 71))	('inactive conformation of the kinase domain', 'MPA', (136, 178))	('K650E', 'Mutation', 'rs78311289', (17, 22))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('FGFR3', 'Gene', (66, 71))	('K650E', 'Var', (17, 22))	('destabilization', 'NegReg', (113, 128))
146239	29848605	Even though this residue is not in direct contact with BGJ398, its mutation destabilizes the inactive conformation to which BGJ398 preferentially binds and this explain the lower activity of BGJ398 against K650E mutant FGFR3.	('activity', 'MPA', (179, 187))	('FGFR3', 'Gene', '2261', (219, 224))	('mutation', 'Var', (67, 75))	('inactive conformation', 'MPA', (93, 114))	('preferentially', 'PosReg', (131, 145))	('destabilizes', 'NegReg', (76, 88))	('binds', 'Interaction', (146, 151))	('BGJ398', 'Chemical', 'MESH:C568950', (124, 130))	('BGJ398', 'Chemical', 'MESH:C568950', (55, 61))	('FGFR3', 'Gene', (219, 224))	('BGJ398', 'Chemical', 'MESH:C568950', (191, 197))	('BGJ398', 'Gene', (124, 130))	('lower', 'NegReg', (173, 178))	('K650E', 'Var', (206, 211))	('K650E', 'Mutation', 'rs78311289', (206, 211))	('FGFR', 'molecular_function', 'GO:0005007', ('219', '223'))
146240	29848605	We have data that indeed shows that BGJ398 is 5 - 10 fold less active against this kinase mutant than against a form of the receptor that is kinase wild type.	('active', 'MPA', (63, 69))	('mutant', 'Var', (90, 96))	('BGJ398', 'Chemical', 'MESH:C568950', (36, 42))	('BGJ398', 'Gene', (36, 42))	('less', 'NegReg', (58, 62))
146241	29848605	Analysis of the F386L alteration suggests that it is likely a germline polymorphism as opposed to a somatic mutation, also providing a plausible explanation for primary PD noted in the single patient bearing this mutation.	('F386L', 'Mutation', 'rs17881656', (16, 21))	('patient', 'Species', '9606', (192, 199))	('primary PD', 'Disease', (161, 171))	('F386L', 'Var', (16, 21))
146242	29848605	Other mutations occurring outside the kinase domain are not expected to impact the ability of BGJ398 to bind and inhibit the kinase of FGFR3.	('FGFR', 'molecular_function', 'GO:0005007', ('135', '139'))	('BGJ398', 'Chemical', 'MESH:C568950', (94, 100))	('inhibit', 'NegReg', (113, 120))	('FGFR3', 'Gene', '2261', (135, 140))	('kinase', 'MPA', (125, 131))	('BGJ398', 'Gene', (94, 100))	('FGFR3', 'Gene', (135, 140))	('mutations', 'Var', (6, 15))	('bind', 'Interaction', (104, 108))
146243	29848605	An analysis of clinical outcome limited to patients with documented activating mutations in FGFR3 (S249C, R248C, Y375C and Y373C) yields a confirmed response rate of 28.6% (16 of 56 patients); including unconfirmed responses, the response rate rises further to 42.9% (24 of 56 patients).	('S249C', 'Var', (99, 104))	('R248C', 'Mutation', 'rs121913482', (106, 111))	('FGFR3', 'Gene', (92, 97))	('S249C', 'Mutation', 'rs121913483', (99, 104))	('activating', 'PosReg', (68, 78))	('Y373C', 'Mutation', 'rs121913485', (123, 128))	('Y375C', 'Mutation', 'rs121913485', (113, 118))	('Y375C', 'Var', (113, 118))	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (277, 285))	('patients', 'Species', '9606', (182, 190))	('R248C', 'Var', (106, 111))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('FGFR3', 'Gene', '2261', (92, 97))	('Y373C', 'Var', (123, 128))
146246	29848605	Enriching for patients who carry known activating mutations in FGFR3 appears to increase response rates considerably.	('FGFR3', 'Gene', '2261', (63, 68))	('mutations', 'Var', (50, 59))	('increase', 'PosReg', (80, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('FGFR3', 'Gene', (63, 68))	('response', 'MPA', (89, 97))	('activating', 'PosReg', (39, 49))	('patients', 'Species', '9606', (14, 22))
146247	29848605	The high specificity of BGJ398 for FGFR3 likely accounts for the substantial improvement in activity seen relative to previous FGFR family inhibitors such as dovitinib, which has shown limited benefit in both FGFR3 mutant and wild-type metastatic urothelial carcinoma.	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('BGJ398', 'Gene', (24, 30))	('FGFR3', 'Gene', '2261', (35, 40))	('BGJ398', 'Chemical', 'MESH:C568950', (24, 30))	('FGFR3', 'Gene', (209, 214))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (247, 267))	('urothelial carcinoma', 'Disease', (247, 267))	('improvement', 'PosReg', (77, 88))	('FGFR3', 'Gene', (35, 40))	('dovitinib', 'Chemical', 'MESH:C500007', (158, 167))	('mutant', 'Var', (215, 221))	('FGFR', 'molecular_function', 'GO:0005007', ('209', '213'))	('activity', 'MPA', (92, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('127', '131'))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('FGFR3', 'Gene', '2261', (209, 214))
146253	29848605	Specimens for molecular profiling were mandated; patients had to demonstrate alterations in FGFR3 as defined in the subsequent section.	('FGFR3', 'Gene', (92, 97))	('alterations', 'Var', (77, 88))	('patients', 'Species', '9606', (49, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('FGFR3', 'Gene', '2261', (92, 97))
146259	29848605	Patients were either pre-screened for alterations in FGFR3, or underwent genomic assessment identifying these alterations in the course of routine clinical care.	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('pre', 'molecular_function', 'GO:0003904', ('21', '24'))	('Patients', 'Species', '9606', (0, 8))	('FGFR3', 'Gene', '2261', (53, 58))	('alterations', 'Var', (38, 49))	('FGFR3', 'Gene', (53, 58))
146261	29848605	FGFR3 mutations permitted in the study included mutations in exon 7 (R248C, S249C), exon 10 (G372C, A393E, Y375C), or exon 15 (K652M/T, K652E/Q).	('R248C', 'Var', (69, 74))	('K652E', 'Var', (136, 141))	('G372C', 'Mutation', 'rs121913479', (93, 98))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('K652E', 'SUBSTITUTION', 'None', (136, 141))	('FGFR3', 'Gene', (0, 5))	('K652M', 'SUBSTITUTION', 'None', (127, 132))	('R248C', 'Mutation', 'rs121913482', (69, 74))	('A393E', 'Mutation', 'rs28931615', (100, 105))	('S249C', 'Var', (76, 81))	('Y375C', 'Mutation', 'rs121913485', (107, 112))	('Y375C', 'Var', (107, 112))	('S249C', 'Mutation', 'rs121913483', (76, 81))	('K652M', 'Var', (127, 132))	('A393E', 'Var', (100, 105))	('G372C', 'Var', (93, 98))	('FGFR3', 'Gene', '2261', (0, 5))
146264	29848605	The tumor mutational burden in plasma was calculated using PureCN for all samples with detectable FGFR3 driver mutations.	('tumor', 'Disease', (4, 9))	('mutations', 'Var', (111, 120))	('FGFR3', 'Gene', (98, 103))	('FGFR', 'molecular_function', 'GO:0005007', ('98', '102'))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('FGFR3', 'Gene', '2261', (98, 103))
146266	29848605	Eligible patients with metastatic urothelial carcinoma and pre-specified FGFR3 alterations received oral BGJ398 125 mg/day for 21 days followed by 7 days without treatment, constituting a 28-day cycle.	('patients', 'Species', '9606', (9, 17))	('alterations', 'Var', (79, 90))	('BGJ398', 'Chemical', 'MESH:C568950', (105, 111))	('FGFR', 'molecular_function', 'GO:0005007', ('73', '77'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (34, 54))	('FGFR3', 'Gene', '2261', (73, 78))	('pre', 'molecular_function', 'GO:0003904', ('59', '62'))	('urothelial carcinoma', 'Disease', (34, 54))	('FGFR3', 'Gene', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
146273	29848605	BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('FGFR3', 'Gene', '2261', (49, 54))	('reductions', 'NegReg', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Disease', (88, 93))	('FGFR3', 'Gene', (49, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('alterations', 'Var', (34, 45))
146278	29123257	Strong positivity of EP2/EP4 in non-muscle-invasive tumours or positivity of EP2/EP4 in muscle-invasive tumours strongly correlated with disease progression or disease-specific mortality, respectively.	('muscle-invasive tumours', 'Disease', 'MESH:D009217', (36, 59))	('muscle-invasive tumours', 'Disease', 'MESH:D009217', (88, 111))	('positivity', 'Var', (7, 17))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('EP2/EP4', 'Gene', (21, 28))	('positivity', 'Var', (63, 73))	('correlated with', 'Reg', (121, 136))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('muscle-invasive tumours', 'Disease', (36, 59))	('EP2/EP4', 'Var', (77, 84))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('muscle-invasive tumours', 'Disease', (88, 111))	('disease', 'Disease', (137, 144))
146283	29123257	EP2/EP4 and PTEN were also elevated and reduced, respectively, in cisplatin-resistant BC sublines.	('EP2/EP4', 'Var', (0, 7))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('cisplatin-resistant', 'Disease', (66, 85))	('PTEN', 'Gene', (12, 16))	('reduced', 'NegReg', (40, 47))	('PTEN', 'Gene', '5728', (12, 16))
146292	29123257	Therefore, inhibition of PGE2 is considered a possible anticancer strategy.	('PGE2', 'Chemical', 'MESH:D015232', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('PGE2', 'Gene', (25, 29))	('inhibition', 'Var', (11, 21))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
146293	29123257	Prostaglandin E2 exerts its effects via G-protein-coupled receptors (GPCRs), including PGE2 receptor 2 (EP2), EP3, and EP4.	('EP4', 'Var', (119, 122))	('G-protein-coupled receptors', 'Protein', (40, 67))	('PGE2', 'Chemical', 'MESH:D015232', (87, 91))	('EP3', 'Gene', (110, 113))	('effects', 'MPA', (28, 35))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('Prostaglandin E2', 'Chemical', 'MESH:D015232', (0, 16))	('EP3', 'Gene', '5733', (110, 113))
146294	29123257	EP2 and EP4 are coupled with G protein and increase the intracellular cyclic adenosine monophosphate, whereas EP3 is coupled with an inhibitory G protein and decreases it.	('G protein', 'Protein', (29, 38))	('decreases', 'NegReg', (158, 167))	('EP2', 'Var', (0, 3))	('intracellular', 'cellular_component', 'GO:0005622', ('56', '69'))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('EP3', 'Gene', (110, 113))	('increase', 'PosReg', (43, 51))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('EP4', 'Var', (8, 11))	('intracellular cyclic adenosine monophosphate', 'MPA', (56, 100))	('cyclic adenosine monophosphate', 'Chemical', 'MESH:D000242', (70, 100))	('EP3', 'Gene', '5733', (110, 113))
146299	29123257	AH6809 (EP2 antagonist), butaprost (EP2 agonist), and CAY10598 (EP4 agonist) were purchased from Cayman Chemical (Ann Arbor, MI, USA).	('CAY10598', 'Var', (54, 62))	('butaprost', 'Chemical', 'MESH:C048491', (25, 34))	('AH6809', 'Var', (0, 6))	('CAY10598', 'Chemical', 'MESH:C000598602', (54, 62))	('AH6809', 'Chemical', 'MESH:C053876', (0, 6))
146329	29123257	Immunohistochemistry was performed on the sections (5 mum thick) from the bladder TMAs, using a primary antibody to EP2 (dilution 1 : 200), EP3 (dilution 1 : 200), or EP4 (dilution 1 : 200), and a broad-spectrum secondary antibody (Invitrogen), as described previously.	('antibody', 'molecular_function', 'GO:0003823', ('104', '112'))	('mum', 'Gene', '56925', (54, 57))	('bladder TMAs', 'Disease', 'MESH:D001745', (74, 86))	('antibody', 'cellular_component', 'GO:0019815', ('222', '230'))	('antibody', 'cellular_component', 'GO:0019814', ('222', '230'))	('mum', 'Gene', (54, 57))	('EP4', 'Var', (167, 170))	('antibody', 'molecular_function', 'GO:0003823', ('222', '230'))	('antibody', 'cellular_component', 'GO:0042571', ('104', '112'))	('dilution', 'Var', (145, 153))	('antibody', 'cellular_component', 'GO:0019815', ('104', '112'))	('EP3', 'Gene', '5733', (140, 143))	('bladder TMAs', 'Disease', (74, 86))	('antibody', 'cellular_component', 'GO:0019814', ('104', '112'))	('antibody', 'cellular_component', 'GO:0042571', ('222', '230'))	('EP3', 'Gene', (140, 143))
146331	29123257	We first stained immunohistochemically for EP2, EP3, and EP4 in the bladder TMAs, consisting of 129 urothelial neoplasms and corresponding 87 non-neoplastic bladder tissues.	('EP2', 'Var', (43, 46))	('bladder TMAs', 'Disease', 'MESH:D001745', (68, 80))	('neoplastic bladder', 'Phenotype', 'HP:0009725', (146, 164))	('urothelial neoplasms', 'Disease', (100, 120))	('EP4', 'Var', (57, 60))	('EP3', 'Gene', (48, 51))	('urothelial neoplasms', 'Disease', 'MESH:D014523', (100, 120))	('neoplasm', 'Phenotype', 'HP:0002664', (111, 119))	('neoplasms', 'Phenotype', 'HP:0002664', (111, 120))	('EP3', 'Gene', '5733', (48, 51))	('bladder TMAs', 'Disease', (68, 80))
146334	29123257	In tumours, there were significant associations in the expression of EP2 vs EP4 (CC=0.209, P=0.017) and EP3 vs EP4 (CC=0.488, P<0.001), but not that of EP2 vs EP3 (CC=0.097, P=0.273).	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('EP3', 'Gene', (104, 107))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('EP2', 'Var', (69, 72))	('EP3', 'Gene', (159, 162))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))	('EP4', 'Var', (111, 114))	('EP3', 'Gene', '5733', (159, 162))	('EP3', 'Gene', '5733', (104, 107))
146341	29123257	However, patients with EP2(2+) (P=0.002) or EP4(2+/3+) (P=0.049) non-muscle-invasive tumour had significantly higher risks of disease progression (Figure 1B).	('patients', 'Species', '9606', (9, 17))	('muscle-invasive tumour', 'Disease', (69, 91))	('muscle-invasive tumour', 'Disease', 'MESH:D009217', (69, 91))	('disease progression', 'CPA', (126, 145))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('EP2(2+', 'Var', (23, 29))
146342	29123257	In patients with muscle-invasive tumour, there were significant associations between positivity of EP2 (P=0.035) or EP4 (P=0.027) and lower cancer-specific survival rates (Figure 1C).	('positivity', 'Var', (85, 95))	('lower', 'NegReg', (134, 139))	('muscle-invasive tumour', 'Disease', (17, 39))	('EP4', 'Var', (116, 119))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('muscle-invasive tumour', 'Disease', 'MESH:D009217', (17, 39))	('patients', 'Species', '9606', (3, 11))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('EP2', 'Gene', (99, 102))
146343	29123257	To determine whether EP2 or EP4 expression was an independent prognosticator, multivariate analysis was performed with Cox model (Supplementary Table S1).	('EP2', 'Var', (21, 24))	('EP4 expression', 'Var', (28, 42))	('men', 'Species', '9606', (136, 139))
146344	29123257	In non-muscle-invasive tumours, strong (2+/3+) EP2 or EP4 expression was not significantly (P>0.1) associated with disease progression.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('EP4', 'Var', (54, 57))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('muscle-invasive tumours', 'Disease', 'MESH:D009217', (7, 30))	('muscle-invasive tumours', 'Disease', (7, 30))	('EP2', 'Protein', (47, 50))	('associated', 'Reg', (99, 109))
146345	29123257	In muscle-invasive tumours, however, EP2 positivity (hazard ration (HR)=6.452, P=0.069) and EP4 positivity (HR=5.604, P=0.022) showed a trend towards significance and statistical significance, respectively, for cancer-specific mortality.	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('EP4 positivity', 'Var', (92, 106))	('positivity', 'Var', (41, 51))	('muscle-invasive tumours', 'Disease', 'MESH:D009217', (3, 26))	('cancer', 'Disease', (211, 217))	('EP2 positivity', 'Var', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('muscle-invasive tumours', 'Disease', (3, 26))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
146366	29123257	AH6809 (24-34% decrease), ONO-AE3-208 (19-31% decrease), and celecoxib (20-23% decrease) significantly inhibited wound closure of 647V and 5637 cells 24 h after wound generation (Figure 3B).	('decrease', 'NegReg', (15, 23))	('celecoxib', 'Chemical', 'MESH:D000068579', (61, 70))	('ONO-AE3-208', 'Chemical', 'MESH:C487890', (26, 37))	('wound closure', 'CPA', (113, 126))	('inhibited', 'NegReg', (103, 112))	('AH6809', 'Var', (0, 6))	('AH6809', 'Chemical', 'MESH:C053876', (0, 6))	('decrease', 'NegReg', (46, 54))	('inhibited wound closure', 'Phenotype', 'HP:0001058', (103, 126))
146372	29123257	As expected, the levels of EP2 expression were substantially lower in EP2-siRNA-expressing lines than in a control line (Supplementary Figure S2A).	('EP2-siRNA-expressing', 'Var', (70, 90))	('lower', 'NegReg', (61, 66))	('levels', 'MPA', (17, 23))	('men', 'Species', '9606', (127, 130))	('EP2 expression', 'MPA', (27, 41))
146373	29123257	Moreover, transfection of each EP2-siRNA resulted in the upregulation of PTEN expression.	('PTEN', 'Gene', (73, 77))	('expression', 'MPA', (78, 88))	('PTEN', 'Gene', '5728', (73, 77))	('EP2-siRNA', 'Var', (31, 40))	('upregulation', 'PosReg', (57, 69))
146379	29123257	Compared with respective control sublines, the expression levels of EP2, EP4, YB-1, and its phosphorylated form (p-YB-1) were elevated in 647V-CR and 5637-CR (Supplementary Figure S3).	('men', 'Species', '9606', (165, 168))	('EP2', 'Var', (68, 71))	('647V-CR', 'Var', (138, 145))	('5637-CR', 'Var', (150, 157))	('YB-1', 'Gene', '4904', (115, 119))	('YB-1', 'Gene', (78, 82))	('YB-1', 'Gene', '4904', (78, 82))	('elevated', 'PosReg', (126, 134))	('expression levels', 'MPA', (47, 64))	('YB-1', 'Gene', (115, 119))
146382	29123257	Treatment with EP2 antagonist (Figure 4A), EP4 antagonist (Figure 4B), or celecoxib (Figure 4C) each at 1 muM resulted in considerable increases in CDDP sensitivity.	('EP4 antagonist', 'Var', (43, 57))	('muM', 'Gene', '56925', (106, 109))	('CDDP sensitivity', 'MPA', (148, 164))	('CDDP', 'Chemical', '-', (148, 152))	('muM', 'Gene', (106, 109))	('increases', 'PosReg', (135, 144))	('EP2', 'Protein', (15, 18))	('men', 'Species', '9606', (5, 8))	('celecoxib', 'Chemical', 'MESH:D000068579', (74, 83))
146386	29123257	Finally, we immunohistochemically stained again for EP2 and EP4 in our TMA consisting of muscle-invasive BC specimens from patients who subsequently received CDDP-based neoadjuvant chemotherapy.	('EP4', 'Var', (60, 63))	('TMA', 'Disease', 'MESH:D000783', (71, 74))	('patients', 'Species', '9606', (123, 131))	('EP2', 'Var', (52, 55))	('men', 'Species', '9606', (113, 116))	('TMA', 'Disease', (71, 74))	('CDDP', 'Chemical', '-', (158, 162))
146395	29123257	These observations suggest that EP2 and EP4 contribute to induction of urothelial cancer initiation.	('EP4', 'Var', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('urothelial cancer initiation', 'Disease', (71, 99))	('urothelial cancer initiation', 'Disease', 'MESH:D014523', (71, 99))	('EP2', 'Var', (32, 35))
146400	29123257	Specifically, in non-urothelial cancer cells, EP2 and EP4 could modulate E-cadherin /hypoxia-inducible factor-1alpha, and PI3K-AKT/NF-kappaB, respectively, up- or downregulation of whose expression in urothelial cancer has indeed been linked to the prognosis of the patients.	('non-urothelial cancer', 'Disease', (17, 38))	('urothelial cancer', 'Disease', 'MESH:D014523', (21, 38))	('hypoxia-inducible factor-1alpha', 'Gene', '3091', (85, 116))	('urothelial cancer', 'Disease', 'MESH:D014523', (201, 218))	('patients', 'Species', '9606', (266, 274))	('AKT', 'Gene', '207', (127, 130))	('urothelial cancer', 'Disease', (201, 218))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('downregulation', 'NegReg', (163, 177))	('modulate', 'Reg', (64, 72))	('cadherin', 'molecular_function', 'GO:0008014', ('75', '83'))	('NF-kappaB', 'Gene', (131, 140))	('hypoxia-inducible factor-1alpha', 'Gene', (85, 116))	('EP4', 'Var', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('E-cadherin', 'Gene', (73, 83))	('E-cadherin', 'Gene', '999', (73, 83))	('non-urothelial cancer', 'Disease', 'MESH:D014523', (17, 38))	('NF-kappaB', 'Gene', '4790', (131, 140))	('EP2', 'Var', (46, 49))	('PI3K', 'molecular_function', 'GO:0016303', ('122', '126'))	('up-', 'PosReg', (156, 159))	('AKT', 'Gene', (127, 130))
146405	29123257	These results suggest that EP2 and EP4 promote urothelial cancer progression.	('urothelial cancer', 'Disease', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('promote', 'PosReg', (39, 46))	('EP2', 'Var', (27, 30))	('EP4', 'Var', (35, 38))	('urothelial cancer', 'Disease', 'MESH:D014523', (47, 64))
146407	29123257	Using preclinical models for gastric cancer, celecoxib has also been shown to enhance the cytotoxic effects of CDDP by modulating P-glycoprotein expression.	('enhance', 'PosReg', (78, 85))	('modulating', 'Reg', (119, 129))	('CDDP', 'Chemical', '-', (111, 115))	('gastric cancer', 'Disease', (29, 43))	('gastric cancer', 'Disease', 'MESH:D013274', (29, 43))	('cytotoxic effects', 'CPA', (90, 107))	('celecoxib', 'Chemical', 'MESH:D000068579', (45, 54))	('P-glycoprotein', 'molecular_function', 'GO:0008559', ('130', '144'))	('gastric cancer', 'Phenotype', 'HP:0012126', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('celecoxib', 'Var', (45, 54))	('P-glycoprotein expression', 'MPA', (130, 155))
146409	29123257	We then found increases in the expression levels of EP2 and EP4, along with those of YB-1/p-YB-1 and NF-kappaB/p-NF-kappaB that were known to involve chemoresistance in BC cells, in CDDP-resistant sublines, compared with respective control sublines.	('EP4', 'Var', (60, 63))	('YB-1', 'Gene', (92, 96))	('involve', 'Reg', (142, 149))	('increases', 'PosReg', (14, 23))	('CDDP', 'Chemical', '-', (182, 186))	('NF-kappaB', 'Gene', '4790', (113, 122))	('expression levels', 'MPA', (31, 48))	('YB-1', 'Gene', (85, 89))	('NF-kappaB', 'Gene', (113, 122))	('chemoresistance', 'CPA', (150, 165))	('YB-1', 'Gene', '4904', (92, 96))	('NF-kappaB', 'Gene', '4790', (101, 110))	('YB-1', 'Gene', '4904', (85, 89))	('NF-kappaB', 'Gene', (101, 110))
146413	29123257	PTEN is a tumour suppressor and its mutations are often seen in various types of malignancies, including BC.	('malignancies', 'Disease', 'MESH:D009369', (81, 93))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('malignancies', 'Disease', (81, 93))	('seen', 'Reg', (56, 60))	('mutations', 'Var', (36, 45))	('tumour', 'Disease', 'MESH:D009369', (10, 16))	('tumour', 'Disease', (10, 16))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
146415	29123257	In particular, PTEN inactivation resulted in activation of the mTOR/AKT pathways in BC cells.	('mTOR', 'Gene', (63, 67))	('inactivation', 'Var', (20, 32))	('mTOR', 'Gene', '2475', (63, 67))	('PTEN', 'Gene', (15, 19))	('AKT', 'Gene', '207', (68, 71))	('PTEN', 'Gene', '5728', (15, 19))	('activation', 'PosReg', (45, 55))	('AKT', 'Gene', (68, 71))
146423	29123257	Thus, EP2 and EP4 may downregulate PTEN expression via the NF-kappaB pathway.	('expression', 'MPA', (40, 50))	('EP2', 'Var', (6, 9))	('NF-kappaB', 'Gene', '4790', (59, 68))	('downregulate', 'NegReg', (22, 34))	('PTEN', 'Gene', (35, 39))	('PTEN', 'Gene', '5728', (35, 39))	('EP4', 'Var', (14, 17))	('NF-kappaB', 'Gene', (59, 68))
146424	29123257	It will still need to be determined how EP2/EP4 modulate PTEN signalling in non-neoplastic and neoplastic urothelial cells.	('signalling', 'biological_process', 'GO:0023052', ('62', '72'))	('PTEN', 'Gene', (57, 61))	('PTEN', 'Gene', '5728', (57, 61))	('EP2/EP4', 'Var', (40, 47))	('modulate', 'Reg', (48, 56))
146425	29123257	The levels of EP2/EP4 expression have been shown to be elevated in several types of malignancies, such as colorectal and endometrial carcinomas, compared with corresponding normal tissues.	('malignancies', 'Disease', (84, 96))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (121, 143))	('EP2/EP4', 'Var', (14, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (121, 143))	('colorectal', 'Disease', 'MESH:D015179', (106, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('colorectal', 'Disease', (106, 116))	('endometrial carcinomas', 'Disease', (121, 143))	('elevated', 'PosReg', (55, 63))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))
146429	29123257	However, EP2 expression was shown to correlate (P=0.08) with better outcomes in patients with upper urinary tract urothelial carcinoma, although EP4 expression was strongly (P=0.002) associated with worse prognosis in the same cohort of patients.	('EP4 expression', 'Var', (145, 159))	('better', 'PosReg', (61, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('patients', 'Species', '9606', (80, 88))	('upper urinary tract urothelial carcinoma', 'Disease', 'MESH:D014552', (94, 134))	('upper urinary tract urothelial carcinoma', 'Disease', (94, 134))	('EP2 expression', 'Var', (9, 23))	('associated', 'Reg', (183, 193))	('patients', 'Species', '9606', (237, 245))
146435	29123257	For instance, an EP2 antagonist AH6809 has been shown to function as a weak antagonist for other prostaglandin receptors, such as EP1 and EP3.	('EP3', 'Gene', (138, 141))	('AH6809', 'Var', (32, 38))	('EP1', 'Gene', (130, 133))	('AH6809', 'Chemical', 'MESH:C053876', (32, 38))	('EP1', 'Gene', '5731', (130, 133))	('EP3', 'Gene', '5733', (138, 141))
146437	29123257	In conclusion, our results suggest that EP2 and EP4 have an important role in inducing urothelial tumourigenesis, bladder tumour progression, and chemoresistance in BC cells, presumably via downregulating PTEN expression.	('PTEN', 'Gene', (205, 209))	('chemoresistance', 'CPA', (146, 161))	('PTEN', 'Gene', '5728', (205, 209))	('urothelial tumour', 'Disease', 'MESH:D014523', (87, 104))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('expression', 'MPA', (210, 220))	('urothelial tumour', 'Disease', (87, 104))	('bladder tumour', 'Disease', (114, 128))	('downregulating', 'NegReg', (190, 204))	('inducing', 'PosReg', (78, 86))	('EP4', 'Var', (48, 51))	('bladder tumour', 'Phenotype', 'HP:0009725', (114, 128))	('bladder tumour', 'Disease', 'MESH:D001749', (114, 128))	('EP2', 'Var', (40, 43))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
146438	29123257	Thus, EP2/EP4 inactivation, using available inhibitors, has the potential of being not only a chemopreventive and therapeutic option for urothelial cancer but also a means of chemosensitisation particularly in patients with EP2/EP4-positive tumour.	('EP2/EP4 inactivation', 'Var', (6, 26))	('urothelial cancer', 'Disease', (137, 154))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('urothelial cancer', 'Disease', 'MESH:D014523', (137, 154))	('tumour', 'Disease', 'MESH:D009369', (241, 247))	('patients', 'Species', '9606', (210, 218))	('tumour', 'Disease', (241, 247))
146451	28423646	Another study revealed that blockade of TIM-3 could reverse the impaired phenotype of NK cells in patients with metastatic melanoma, which highlights the potential possibility of TIM-3 targeted therapy.	('patients', 'Species', '9606', (98, 106))	('blockade', 'Var', (28, 36))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('TIM-3', 'Gene', (40, 45))
146461	28423646	As shown by Table 3, TIM-3 expression had no obvious association with patients' age, sex or T stage; however, high TIM-3 expression was significantly associated with advanced TNM stage (3 studies, n=331, III/IV vs. I/II, RR=2.02; 95% CI: 1.45-2.81; p < 0.001) (Figure 3).	('associated', 'Reg', (150, 160))	('patients', 'Species', '9606', (70, 78))	('TNM', 'Gene', '10178', (175, 178))	('TIM-3', 'Gene', (115, 120))	('expression', 'MPA', (121, 131))	('TNM', 'Gene', (175, 178))	('high', 'Var', (110, 114))	('advanced', 'CPA', (166, 174))
146463	28423646	We systematically evaluated survival data for 869 patients and demonstrated a positive relationship between TIM-3 high expression and poor prognosis in cancer patients.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('patients', 'Species', '9606', (50, 58))	('TIM-3', 'Gene', (108, 113))	('poor prognosis', 'CPA', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('patients', 'Species', '9606', (159, 167))	('high expression', 'Var', (114, 129))
146468	28423646	Our lab recently identified that TIM-3+ CD8+ T cell have impaired ability of IFN-gamma production which inhibited the cytotoxic activity of functional T cells.	('cytotoxic activity of functional T cells', 'CPA', (118, 158))	('CD8', 'Gene', '925', (40, 43))	('impaired', 'NegReg', (57, 65))	('TIM-3+', 'Var', (33, 39))	('inhibited', 'NegReg', (104, 113))	('CD8', 'Gene', (40, 43))
146473	28423646	Unfortunately, there are no optimal targets so far, although the PD-1 blockage has shown some encouraging effects and has been implicated in some clinical trials, however, the benefits and improved prognosis for cancer patients remain unsatisfactory.	('blockage', 'Var', (70, 78))	('PD-1', 'Gene', (65, 69))	('PD-1', 'Gene', '5133', (65, 69))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('patients', 'Species', '9606', (219, 227))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
146474	28423646	Our study implies that TIM-3 may be a prognostic marker of patients' survival with solid tumors, and high expression of TIM-3 may correlate with advanced tumor stage.	('solid tumors', 'Disease', 'MESH:D009369', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (154, 159))	('correlate', 'Reg', (130, 139))	('expression', 'MPA', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('solid tumors', 'Disease', (83, 95))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('high', 'Var', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('TIM-3', 'Gene', (120, 125))
146481	28423646	The collected data included the name of first author, publication year, patients' country of origin, tumor type, number of patients, age, sex, cancer stage or grade, detection method for TIM-3 expression, percentage exhibiting high TIM-3 expression and the corresponding cutoff value, median follow-up months, outcome, HR and 95%CI of high TIM-3 expression group versus low.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('patients', 'Species', '9606', (123, 131))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('high', 'Var', (227, 231))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('patients', 'Species', '9606', (72, 80))
146484	26592553	MLN4924 Synergistically Enhances Cisplatin-induced Cytotoxicity via JNK and Bcl-xL Pathways in Human Urothelial Carcinoma Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('MLN4924', 'Var', (0, 7))	('Enhances', 'PosReg', (24, 32))	('Human', 'Species', '9606', (95, 100))	('Cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('Carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (191, 219))	('Bcl-xL', 'Gene', '598', (76, 82))	('Cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('Cytotoxicity', 'Disease', (51, 63))	('JNK', 'Gene', (68, 71))	('JNK', 'molecular_function', 'GO:0004705', ('68', '71'))	('bladder urothelial carcinoma', 'Disease', (191, 219))	('Urothelial Carcinoma', 'Disease', (101, 121))	('Bcl-xL', 'Gene', (76, 82))	('Urothelial Carcinoma', 'Disease', 'MESH:D014526', (101, 121))	('JNK', 'Gene', '5599', (68, 71))	('Cytotoxicity', 'Disease', 'MESH:D064420', (51, 63))
146485	26592553	This study investigated the anti-tumor effect and underlying mechanisms of the combination of cisplatin and the NEDD8-activating enzyme inhibitor MLN4924 in human bladder urothelial carcinoma.	('MLN4924', 'Chemical', 'MESH:C539933', (146, 153))	('NEDD8', 'Gene', '4738', (112, 117))	('NEDD8', 'Gene', (112, 117))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (163, 191))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('MLN4924', 'Var', (146, 153))	('bladder urothelial carcinoma', 'Disease', (163, 191))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('human', 'Species', '9606', (157, 162))
146486	26592553	The combination of cisplatin and MLN4924 exerted synergistic cytotoxicity on two high-grade bladder urothelial carcinoma cell lines, NTUB1 and T24 (combination index <1).	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('cytotoxicity', 'Disease', (61, 73))	('MLN4924', 'Chemical', 'MESH:C539933', (33, 40))	('cytotoxicity', 'Disease', 'MESH:D064420', (61, 73))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (92, 120))	('MLN4924', 'Var', (33, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('bladder urothelial carcinoma', 'Disease', (92, 120))
146487	26592553	MLN4924 also potentiated the cisplatin-induced apoptosis and activation of caspase-3 and -7, phospho-histone H2A.X and PARP.	('MLN4924', 'Var', (0, 7))	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('PARP', 'Gene', (119, 123))	('cisplatin-induced apoptosis', 'CPA', (29, 56))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('activation', 'PosReg', (61, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('potentiated', 'PosReg', (13, 24))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('caspase-3', 'Protein', (75, 84))	('PARP', 'Gene', '1302', (119, 123))
146488	26592553	c-Jun N-terminal kinase (JNK) activation and a down-regulation of B-cell lymphoma-extra large (Bcl-xL) were also observed during cisplatin and MLN4924 treatment.	('c-Jun N-terminal kinase', 'Gene', (0, 23))	('JNK', 'Gene', '5599', (25, 28))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (66, 81))	('Bcl-xL', 'Gene', (95, 101))	('c-Jun N-terminal kinase', 'Gene', '5599', (0, 23))	('regulation', 'biological_process', 'GO:0065007', ('52', '62'))	('JNK', 'molecular_function', 'GO:0004705', ('25', '28'))	('activation', 'PosReg', (30, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('down-regulation', 'NegReg', (47, 62))	('MLN4924', 'Chemical', 'MESH:C539933', (143, 150))	('B-cell lymphoma-extra', 'Disease', (66, 87))	('JNK', 'Gene', (25, 28))	('lymphoma', 'Phenotype', 'HP:0002665', (73, 81))	('MLN4924', 'Var', (143, 150))	('Bcl-xL', 'Gene', '598', (95, 101))
146491	26592553	MLN4924 significantly potentiated cisplatin-induced tumor suppression in urothelial carcinoma xenograft mice.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('MLN4924', 'Var', (0, 7))	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('urothelial carcinoma', 'Disease', (73, 93))	('tumor', 'Disease', (52, 57))	('potentiated', 'PosReg', (22, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('mice', 'Species', '10090', (104, 108))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (73, 93))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('cisplatin-induced', 'MPA', (34, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
146492	26592553	In summary, MLN4924 synergistically enhanced the anti-tumor effect of cisplatin via an increase in DNA damage, JNK activation and down-regulation of Bcl-xL in urothelial carcinoma cells.	('activation', 'PosReg', (115, 125))	('increase', 'PosReg', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('DNA damage', 'MPA', (99, 109))	('JNK', 'molecular_function', 'GO:0004705', ('111', '114'))	('JNK', 'Gene', (111, 114))	('MLN4924', 'Chemical', 'MESH:C539933', (12, 19))	('JNK', 'Gene', '5599', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (159, 179))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('down-regulation', 'NegReg', (130, 145))	('Bcl-xL', 'Gene', (149, 155))	('enhanced', 'PosReg', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('regulation', 'biological_process', 'GO:0065007', ('135', '145'))	('Bcl-xL', 'Gene', '598', (149, 155))	('MLN4924', 'Var', (12, 19))	('tumor', 'Disease', (54, 59))	('urothelial carcinoma', 'Disease', (159, 179))
146506	26592553	The selective NEDD8 activating enzyme inhibitor MLN4924 was identified as a promising anti-cancer drug in 2009, and it was evaluated in several phase I clinical trials.	('MLN4924', 'Var', (48, 55))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('NEDD8', 'Gene', '4738', (14, 19))	('NEDD8', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('MLN4924', 'Chemical', 'MESH:C539933', (48, 55))
146507	26592553	Disruption of neddylation leads to the accumulation of numerous intracellular proteins, which induce DNA damage responses, autophagy, apoptosis and many abnormal cellular responses that contribute to cytotoxicity in tumor cells.	('apoptosis', 'CPA', (134, 143))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))	('cytotoxicity', 'Disease', (200, 212))	('Disruption', 'Var', (0, 10))	('intracellular', 'cellular_component', 'GO:0005622', ('64', '77'))	('tumor', 'Disease', (216, 221))	('cytotoxicity', 'Disease', 'MESH:D064420', (200, 212))	('abnormal cellular responses', 'CPA', (153, 180))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('neddylation', 'Gene', (14, 25))	('autophagy', 'biological_process', 'GO:0016236', ('123', '132'))	('induce', 'Reg', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('apoptosis', 'biological_process', 'GO:0097194', ('134', '143'))	('DNA', 'MPA', (101, 104))	('autophagy', 'CPA', (123, 132))	('accumulation', 'PosReg', (39, 51))	('autophagy', 'biological_process', 'GO:0006914', ('123', '132'))	('apoptosis', 'biological_process', 'GO:0006915', ('134', '143'))	('intracellular proteins', 'Protein', (64, 86))
146509	26592553	Therefore, we hypothesized that a combination of cisplatin and MLN4924 would be a new strategy for the treatment of bladder urothelial carcinoma.	('MLN4924', 'Var', (63, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (116, 144))	('MLN4924', 'Chemical', 'MESH:C539933', (63, 70))	('bladder urothelial carcinoma', 'Disease', (116, 144))
146510	26592553	Our results demonstrated that the combination of cisplatin and MLN4924 synergistically enhanced the cytotoxicity of cisplatin through increased DNA damage and JNK activation and the down-regulation of the anti-apoptotic protein Bcl-xL in vitro and in vivo.	('JNK', 'Gene', (159, 162))	('activation', 'PosReg', (163, 173))	('JNK', 'Gene', '5599', (159, 162))	('regulation', 'biological_process', 'GO:0065007', ('187', '197'))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('down-regulation', 'NegReg', (182, 197))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('enhanced', 'PosReg', (87, 95))	('DNA damage', 'MPA', (144, 154))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('MLN4924', 'Var', (63, 70))	('cytotoxicity', 'Disease', (100, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('cytotoxicity', 'Disease', 'MESH:D064420', (100, 112))	('Bcl-xL', 'Gene', (228, 234))	('JNK', 'molecular_function', 'GO:0004705', ('159', '162'))	('Bcl-xL', 'Gene', '598', (228, 234))	('increased', 'PosReg', (134, 143))	('MLN4924', 'Chemical', 'MESH:C539933', (63, 70))
146511	26592553	Our data suggest that the combination of cisplatin and MLN4924 is a high efficacy regimen for the clinical treatment of bladder urothelial carcinoma.	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('MLN4924', 'Var', (55, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (120, 148))	('bladder urothelial carcinoma', 'Disease', (120, 148))	('MLN4924', 'Chemical', 'MESH:C539933', (55, 62))
146512	26592553	We previously reported that the treatment of human bladder urothelial carcinoma cells with MLN4924 significantly induced anti-tumor effects in vitro and in vivo, and MLN4924 exhibited minimal toxicity on normal urothelial cells.	('MLN4924', 'Chemical', 'MESH:C539933', (166, 173))	('toxicity', 'Disease', 'MESH:D064420', (192, 200))	('bladder urothelial carcinoma', 'Disease', (51, 79))	('toxicity', 'Disease', (192, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('MLN4924', 'Chemical', 'MESH:C539933', (91, 98))	('human', 'Species', '9606', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('MLN4924', 'Var', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (51, 79))	('tumor', 'Disease', (126, 131))
146513	26592553	Therefore, we examined the anti-tumor efficacy of the combination of MLN4924 and cisplatin in this study.	('MLN4924', 'Var', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('tumor', 'Disease', (32, 37))	('MLN4924', 'Chemical', 'MESH:C539933', (69, 76))
146514	26592553	Two high-grade urothelial carcinoma cell lines, NTUB1 and T24, were treated with MLN4924 (250 and 500 nM) and different concentrations of cisplatin (0 to 20 muM) individually or in combination.	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('muM', 'Gene', (157, 160))	('MLN4924 (250 and 500 nM', 'Var', (81, 104))	('MLN4924', 'Chemical', 'MESH:C539933', (81, 88))	('urothelial carcinoma', 'Disease', (15, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (15, 35))	('muM', 'Gene', '56925', (157, 160))
146515	26592553	Figure 1A shows that cisplatin and MLN4924, alone or in combination, suppressed urothelial carcinoma cell viability, and the inhibitory effect was increased when both agents were used in combination.	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('MLN4924', 'Var', (35, 42))	('urothelial carcinoma', 'Disease', (80, 100))	('suppressed', 'NegReg', (69, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (80, 100))	('MLN4924', 'Chemical', 'MESH:C539933', (35, 42))
146519	26592553	We chose 10 muM cisplatin and 250 nM MLN4924 as our working concentrations for the following investigation.	('MLN4924', 'Chemical', 'MESH:C539933', (37, 44))	('muM', 'Gene', '56925', (12, 15))	('MLN4924', 'Var', (37, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (16, 25))	('muM', 'Gene', (12, 15))
146520	26592553	The de-neddylation of cullin-1 in NTUB1 and T24 cells was investigated to ensure that MLN4924-mediated neddylation inhibition was involved in our study (Fig.	('cullin-1', 'Gene', (22, 30))	('MLN4924', 'Chemical', 'MESH:C539933', (86, 93))	('cullin-1', 'Gene', '8454', (22, 30))	('MLN4924-mediated', 'Var', (86, 102))
146521	26592553	The anti-tumor effect of cisplatin is primarily derived from increased apoptosis, Therefore, we investigated whether the combination of cisplatin and MLN4924 treatment increased apoptosis in NTUB1 and T24 cells.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('cisplatin', 'Chemical', 'MESH:D002945', (25, 34))	('MLN4924', 'Chemical', 'MESH:C539933', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('MLN4924', 'Var', (150, 157))	('apoptosis', 'biological_process', 'GO:0097194', ('178', '187'))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('apoptosis', 'biological_process', 'GO:0006915', ('178', '187'))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))
146522	26592553	Figure 2A shows increased protein levels of cleaved caspase-3 and -7 and cleaved PARP, which indicates that cisplatin alone and in combination treatment with MLN4924 induced apoptosis in urothelial carcinoma cells.	('induced', 'Reg', (166, 173))	('urothelial carcinoma', 'Disease', (187, 207))	('apoptosis', 'biological_process', 'GO:0097194', ('174', '183'))	('apoptosis', 'biological_process', 'GO:0006915', ('174', '183'))	('PARP', 'Gene', (81, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('apoptosis', 'CPA', (174, 183))	('protein levels', 'MPA', (26, 40))	('MLN4924', 'Chemical', 'MESH:C539933', (158, 165))	('increased', 'PosReg', (16, 25))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (187, 207))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('MLN4924', 'Var', (158, 165))	('PARP', 'Gene', '1302', (81, 85))
146526	26592553	One study reported that the combination of MLN4924 and cisplatin suppressed DNA damage-induced Chk-1 phosphorylation and inhibited DNA repair.	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('phosphorylation', 'biological_process', 'GO:0016310', ('101', '116'))	('MLN4924', 'Chemical', 'MESH:C539933', (43, 50))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))	('suppressed', 'NegReg', (65, 75))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('DNA damage-induced', 'MPA', (76, 94))	('DNA repair', 'MPA', (131, 141))	('inhibited', 'NegReg', (121, 130))	('DNA repair', 'biological_process', 'GO:0006281', ('131', '141'))	('Chk-1', 'Gene', '1111', (95, 100))	('MLN4924', 'Var', (43, 50))	('Chk-1', 'Gene', (95, 100))
146527	26592553	We observed that phosphorylated protein levels of ATM, Chk1 and BRCA1, which are involved in the DNA damage response, decreased further after cisplatin and MLN4924 co-treatment.	('BRCA1', 'Gene', '672', (64, 69))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('phosphorylated protein levels', 'MPA', (17, 46))	('ATM', 'Gene', (50, 53))	('MLN4924', 'Chemical', 'MESH:C539933', (156, 163))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('BRCA1', 'Gene', (64, 69))	('ATM', 'Gene', '472', (50, 53))	('Chk1', 'Gene', (55, 59))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('MLN4924', 'Var', (156, 163))	('decreased', 'NegReg', (118, 127))	('cisplatin', 'Var', (142, 151))	('Chk1', 'Gene', '1111', (55, 59))	('DNA damage response', 'biological_process', 'GO:0006974', ('97', '116'))
146528	26592553	Consistently, the expression of phospho-histone H2A.X, which is a marker of DNA damage, increased with co-treatment compared with cisplatin treatment alone (Fig.	('co-treatment', 'Var', (103, 115))	('increased', 'PosReg', (88, 97))	('expression', 'MPA', (18, 28))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))
146533	26592553	Our data suggest that combination treatment with cisplatin and MLN4924 significantly induced DNA damage and the subsequent apoptosis.	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('MLN4924', 'Var', (63, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('induced', 'Reg', (85, 92))	('apoptosis', 'CPA', (123, 132))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('DNA damage', 'CPA', (93, 103))	('MLN4924', 'Chemical', 'MESH:C539933', (63, 70))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))
146534	26592553	We investigated the precise molecular mechanisms associated with the apoptosis induced by combination treatment with cisplatin and MLN4924 in urothelial carcinoma cells.	('urothelial carcinoma', 'Disease', (142, 162))	('MLN4924', 'Chemical', 'MESH:C539933', (131, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('MLN4924', 'Var', (131, 138))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (142, 162))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))
146538	26592553	These findings suggest that JNK activation participates in apoptosis induced by combined cisplatin and MLN4924 treatment.	('JNK', 'Gene', (28, 31))	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('JNK', 'Gene', '5599', (28, 31))	('MLN4924 treatment', 'Var', (103, 120))	('activation', 'PosReg', (32, 42))	('apoptosis', 'CPA', (59, 68))	('JNK', 'molecular_function', 'GO:0004705', ('28', '31'))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('MLN4924', 'Chemical', 'MESH:C539933', (103, 110))
146541	26592553	Figure 3B shows that cisplatin and MLN4924 exerted a combined effect only on JNK activation but not ERK1/2 and p38 pathways.	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('ERK1/2', 'Gene', (100, 106))	('MLN4924', 'Var', (35, 42))	('JNK', 'Gene', (77, 80))	('ERK1/2', 'Gene', '5595;5594', (100, 106))	('p38', 'Gene', (111, 114))	('activation', 'PosReg', (81, 91))	('JNK', 'molecular_function', 'GO:0004705', ('77', '80'))	('JNK', 'Gene', '5599', (77, 80))	('ERK1', 'molecular_function', 'GO:0004707', ('100', '104'))	('p38', 'Gene', '5594', (111, 114))	('MLN4924', 'Chemical', 'MESH:C539933', (35, 42))
146543	26592553	The expression of the anti-apoptotic protein Bcl-xL decreased significantly after cisplatin and MLN4924 co-treatment compared to cisplatin alone (Fig.	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('MLN4924', 'Var', (96, 103))	('decreased', 'NegReg', (52, 61))	('Bcl-xL', 'Gene', '598', (45, 51))	('expression', 'MPA', (4, 14))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('Bcl-xL', 'Gene', (45, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('MLN4924', 'Chemical', 'MESH:C539933', (96, 103))
146546	26592553	The JNK inhibitor SP600125 competes with ATP and selectively blocks JNK activation.	('SP600125', 'Var', (18, 26))	('blocks', 'NegReg', (61, 67))	('JNK', 'Gene', '5599', (68, 71))	('ATP', 'Chemical', 'MESH:D000255', (41, 44))	('JNK', 'molecular_function', 'GO:0004705', ('4', '7'))	('JNK', 'Gene', (68, 71))	('JNK', 'Gene', (4, 7))	('JNK', 'molecular_function', 'GO:0004705', ('68', '71'))	('SP600125', 'Chemical', 'MESH:C432165', (18, 26))	('JNK', 'Gene', '5599', (4, 7))
146547	26592553	Figure 4A shows that the addition of SP600125 significantly rescued the decreased cell viability caused by the combination of cisplatin and MLN4924 treatment in NTUB1 and T24 cells.	('cell viability', 'CPA', (82, 96))	('decreased', 'NegReg', (72, 81))	('SP600125', 'Chemical', 'MESH:C432165', (37, 45))	('MLN4924', 'Chemical', 'MESH:C539933', (140, 147))	('SP600125', 'Var', (37, 45))	('MLN4924 treatment', 'Var', (140, 157))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))
146548	26592553	This finding suggests that the combinative cytotoxicity of cisplatin and MLN4924 relies on activation of the JNK pathway.	('cytotoxicity', 'Disease', (43, 55))	('MLN4924', 'Var', (73, 80))	('activation', 'PosReg', (91, 101))	('JNK', 'Gene', (109, 112))	('JNK', 'molecular_function', 'GO:0004705', ('109', '112'))	('cytotoxicity', 'Disease', 'MESH:D064420', (43, 55))	('JNK', 'Gene', '5599', (109, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('MLN4924', 'Chemical', 'MESH:C539933', (73, 80))
146550	26592553	SP600125 treatment significantly decreased apoptosis induced by the combination of cisplatin and MLN4924 (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (97, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('apoptosis', 'CPA', (43, 52))	('MLN4924', 'Var', (97, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('SP600125', 'Chemical', 'MESH:C432165', (0, 8))	('SP600125', 'Var', (0, 8))	('decreased', 'NegReg', (33, 42))
146551	26592553	We also found that SP600125 partially restored the down-regulation of Bcl-xL in NTUB1 and T24 cells after combined cisplatin and MLN4924 treatment (Fig.	('SP600125', 'Chemical', 'MESH:C432165', (19, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('regulation', 'biological_process', 'GO:0065007', ('56', '66'))	('Bcl-xL', 'Gene', '598', (70, 76))	('MLN4924', 'Chemical', 'MESH:C539933', (129, 136))	('SP600125', 'Var', (19, 27))	('MLN4924 treatment', 'Var', (129, 146))	('Bcl-xL', 'Gene', (70, 76))	('down-regulation', 'NegReg', (51, 66))
146552	26592553	We knocked down JNK1 using siRNA to examine the existence of off-target effects of SP600125.	('knocked', 'Reg', (3, 10))	('JNK1', 'Gene', (16, 20))	('JNK1', 'Gene', '5599', (16, 20))	('SP600125', 'Var', (83, 91))	('JNK', 'molecular_function', 'GO:0004705', ('16', '19'))	('SP600125', 'Chemical', 'MESH:C432165', (83, 91))
146553	26592553	JNK1 knockdown significantly rescued cell viability, reduced apoptosis and restored Bcl-xL expression levels in NTUB1 and T24 cells (Supplementary information, Fig.	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('restored', 'PosReg', (75, 83))	('apoptosis', 'CPA', (61, 70))	('knockdown', 'Var', (5, 14))	('JNK', 'molecular_function', 'GO:0004705', ('0', '3'))	('reduced', 'NegReg', (53, 60))	('Bcl-xL', 'Gene', '598', (84, 90))	('JNK1', 'Gene', (0, 4))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('cell viability', 'CPA', (37, 51))	('Bcl-xL', 'Gene', (84, 90))	('JNK1', 'Gene', '5599', (0, 4))	('rescued', 'PosReg', (29, 36))
146554	26592553	These findings confirm our hypothesis that the combination of cisplatin and MLN4924 treatment induces JNK activation and downstream Bcl-xL down-regulation, which leads to apoptosis in urothelial carcinoma cells.	('regulation', 'biological_process', 'GO:0065007', ('144', '154'))	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('171', '180'))	('apoptosis', 'biological_process', 'GO:0006915', ('171', '180'))	('MLN4924', 'Chemical', 'MESH:C539933', (76, 83))	('urothelial carcinoma', 'Disease', (184, 204))	('down-regulation', 'NegReg', (139, 154))	('JNK', 'molecular_function', 'GO:0004705', ('102', '105'))	('leads to', 'Reg', (162, 170))	('MLN4924', 'Var', (76, 83))	('JNK', 'Gene', (102, 105))	('Bcl-xL', 'Gene', '598', (132, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (184, 204))	('JNK', 'Gene', '5599', (102, 105))	('activation', 'PosReg', (106, 116))	('Bcl-xL', 'Gene', (132, 138))
146555	26592553	The above findings revealed that the JNK-Bcl-xL axis plays an important role in the apoptosis induced by combination of cisplatin and MLN4924 treatment.	('apoptosis', 'CPA', (84, 93))	('Bcl-xL', 'Gene', '598', (41, 47))	('MLN4924', 'Chemical', 'MESH:C539933', (134, 141))	('JNK', 'Gene', (37, 40))	('JNK', 'molecular_function', 'GO:0004705', ('37', '40'))	('Bcl-xL', 'Gene', (41, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('MLN4924', 'Var', (134, 141))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('JNK', 'Gene', '5599', (37, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))
146558	26592553	Urothelial carcinoma cells with Bcl-xL overexpression exhibited a restored cell viability after combined cisplatin and MLN4924 treatment compared to the control (vector) group (Fig.	('Bcl-xL', 'Gene', (32, 38))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('Urothelial carcinoma', 'Disease', 'MESH:D014526', (0, 20))	('Urothelial carcinoma', 'Disease', (0, 20))	('MLN4924', 'Chemical', 'MESH:C539933', (119, 126))	('restored', 'PosReg', (66, 74))	('cell viability', 'CPA', (75, 89))	('MLN4924', 'Var', (119, 126))	('Bcl-xL', 'Gene', '598', (32, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
146562	26592553	Taken together, these findings suggest that the JNK-Bcl-xL axis plays an important role in the apoptosis induced by combined cisplatin and MLN4924 treatment.	('JNK', 'Gene', (48, 51))	('JNK', 'Gene', '5599', (48, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (125, 134))	('Bcl-xL', 'Gene', '598', (52, 58))	('MLN4924', 'Chemical', 'MESH:C539933', (139, 146))	('apoptosis', 'CPA', (95, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('Bcl-xL', 'Gene', (52, 58))	('MLN4924', 'Var', (139, 146))	('JNK', 'molecular_function', 'GO:0004705', ('48', '51'))
146563	26592553	The modulation of the JNK-Bcl-xL pathway is likely to further enhance the anti-tumor efficacy of cisplatin in urothelial carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('Bcl-xL', 'Gene', (26, 32))	('JNK', 'Gene', (22, 25))	('tumor', 'Disease', (79, 84))	('modulation', 'Var', (4, 14))	('JNK', 'molecular_function', 'GO:0004705', ('22', '25'))	('enhance', 'PosReg', (62, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (110, 130))	('JNK', 'Gene', '5599', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('Bcl-xL', 'Gene', '598', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('urothelial carcinoma', 'Disease', (110, 130))
146564	26592553	We evaluated the anti-tumor effects of cisplatin and MLN4924 alone or in combination in vivo using a xenograft mouse model.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('mouse', 'Species', '10090', (111, 116))	('MLN4924', 'Chemical', 'MESH:C539933', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('MLN4924', 'Var', (53, 60))	('tumor', 'Disease', (22, 27))
146567	26592553	The combination of cisplatin and MLN4924 exerted the most significant anti-tumor effect on T24 and NTUB1 xenografts compared to cisplatin or MLN4924 alone (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (33, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('MLN4924', 'Var', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('MLN4924', 'Chemical', 'MESH:C539933', (141, 148))	('tumor', 'Disease', (75, 80))
146568	26592553	We examined the expression levels of phospho-JNK and Bcl-xL in xenograft tumor samples from each group to confirm our in vitro findings concerning the associations between JNK activation, Bcl-xL down-regulation and apoptosis induced by combination of cisplatin and MLN4924 treatment.	('Bcl-xL', 'Gene', '598', (188, 194))	('MLN4924', 'Var', (265, 272))	('apoptosis', 'CPA', (215, 224))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('activation', 'PosReg', (176, 186))	('apoptosis', 'biological_process', 'GO:0097194', ('215', '224'))	('JNK', 'molecular_function', 'GO:0004705', ('172', '175'))	('apoptosis', 'biological_process', 'GO:0006915', ('215', '224'))	('MLN4924', 'Chemical', 'MESH:C539933', (265, 272))	('JNK', 'Gene', (172, 175))	('JNK', 'Gene', (45, 48))	('JNK', 'molecular_function', 'GO:0004705', ('45', '48'))	('JNK', 'Gene', '5599', (172, 175))	('JNK', 'Gene', '5599', (45, 48))	('tumor', 'Disease', (73, 78))	('down-regulation', 'NegReg', (195, 210))	('regulation', 'biological_process', 'GO:0065007', ('200', '210'))	('Bcl-xL', 'Gene', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (251, 260))	('Bcl-xL', 'Gene', (188, 194))	('Bcl-xL', 'Gene', '598', (53, 59))
146570	26592553	Figure S3 (Supplementary information) shows that the combination of cisplatin and MLN4924 led to higher JNK activation compared to the single-agent treatment groups.	('higher', 'PosReg', (97, 103))	('JNK', 'Gene', '5599', (104, 107))	('JNK', 'molecular_function', 'GO:0004705', ('104', '107'))	('MLN4924', 'Chemical', 'MESH:C539933', (82, 89))	('MLN4924', 'Var', (82, 89))	('JNK', 'Gene', (104, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
146571	26592553	Consistently, western blots revealed decreased Bcl-xL levels after combined cisplatin and MLN4924 treatment in NTUB1 and T24 tumor tissues (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('Bcl-xL', 'Gene', (47, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('MLN4924 treatment', 'Var', (90, 107))	('tumor', 'Disease', (125, 130))	('decreased', 'NegReg', (37, 46))	('Bcl-xL', 'Gene', '598', (47, 53))
146572	26592553	These findings further support the in vitro findings that cisplatin and MLN4924 work synergistically to suppress urothelial carcinoma growth via JNK activation and Bcl-xL down-regulation.	('JNK', 'Gene', (145, 148))	('suppress', 'NegReg', (104, 112))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (113, 133))	('Bcl-xL', 'Gene', '598', (164, 170))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('MLN4924', 'Var', (72, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('JNK', 'Gene', '5599', (145, 148))	('regulation', 'biological_process', 'GO:0065007', ('176', '186'))	('urothelial carcinoma', 'Disease', (113, 133))	('Bcl-xL', 'Gene', (164, 170))	('down-regulation', 'NegReg', (171, 186))	('MLN4924', 'Chemical', 'MESH:C539933', (72, 79))	('JNK', 'molecular_function', 'GO:0004705', ('145', '148'))	('activation', 'PosReg', (149, 159))
146577	26592553	Our previous study observed that treatment with MLN4924 elicited significant anticancer effects on bladder urothelial carcinoma.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('MLN4924', 'Var', (48, 55))	('cancer', 'Disease', (81, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (99, 127))	('bladder urothelial carcinoma', 'Disease', (99, 127))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('MLN4924', 'Chemical', 'MESH:C539933', (48, 55))
146578	26592553	Therefore, we combined MLN4924 with cisplatin for the treatment of urothelial carcinoma in the current study.	('urothelial carcinoma', 'Disease', (67, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('MLN4924', 'Chemical', 'MESH:C539933', (23, 30))	('MLN4924', 'Var', (23, 30))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (67, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))
146579	26592553	Our results indicated that the combination of cisplatin and MLN4924 was synergistic, which means that the addition of MLN4924 significantly improved the efficacy of cisplatin.	('MLN4924', 'Chemical', 'MESH:C539933', (118, 125))	('improved', 'PosReg', (140, 148))	('efficacy', 'MPA', (153, 161))	('MLN4924', 'Var', (118, 125))	('MLN4924', 'Chemical', 'MESH:C539933', (60, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('MLN4924', 'Var', (60, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (165, 174))
146580	26592553	We also observed a prominent enhancement of apoptosis in bladder urothelial carcinoma cells under combined cisplatin and MLN4924 treatment, and this effect was reproduced in our in vivo model.	('MLN4924', 'Chemical', 'MESH:C539933', (121, 128))	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('apoptosis', 'CPA', (44, 53))	('MLN4924', 'Var', (121, 128))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('enhancement', 'PosReg', (29, 40))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (57, 85))	('bladder urothelial carcinoma', 'Disease', (57, 85))
146583	26592553	The combination treatment with MLN4924 and cisplatin further increased the activation level of JNK.	('MLN4924', 'Var', (31, 38))	('activation level', 'MPA', (75, 91))	('JNK', 'Gene', (95, 98))	('increased', 'PosReg', (61, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('JNK', 'Gene', '5599', (95, 98))	('MLN4924', 'Chemical', 'MESH:C539933', (31, 38))	('JNK', 'molecular_function', 'GO:0004705', ('95', '98'))
146587	26592553	The link between DNA damage and JNK activation led us to investigate the relationship between JNK activation and the combination of cisplatin and MLN4924.	('MLN4924', 'Chemical', 'MESH:C539933', (146, 153))	('JNK', 'Gene', '5599', (94, 97))	('JNK', 'Gene', (32, 35))	('MLN4924', 'Var', (146, 153))	('cisplatin', 'Chemical', 'MESH:D002945', (132, 141))	('JNK', 'molecular_function', 'GO:0004705', ('94', '97'))	('JNK', 'Gene', '5599', (32, 35))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('JNK', 'molecular_function', 'GO:0004705', ('32', '35'))	('JNK', 'Gene', (94, 97))
146588	26592553	The increased expression of the DNA damage marker phospho-histone H2A.X was concurrent with JNK activation during cisplatin treatment alone or in combination with MLN4924, as we anticipated.	('MLN4924', 'Chemical', 'MESH:C539933', (163, 170))	('MLN4924', 'Var', (163, 170))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('expression', 'MPA', (14, 24))	('JNK', 'Gene', (92, 95))	('JNK', 'Gene', '5599', (92, 95))	('JNK', 'molecular_function', 'GO:0004705', ('92', '95'))	('increased', 'PosReg', (4, 13))	('activation', 'PosReg', (96, 106))
146590	26592553	A selective NEDD8 activating enzyme inhibitor that disrupts neddylation, MLN4924, is a prominent anti-cancer agent in several cancer types.	('NEDD8', 'Gene', '4738', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('MLN4924', 'Var', (73, 80))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('disrupts', 'NegReg', (51, 59))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('NEDD8', 'Gene', (12, 17))	('neddylation', 'MPA', (60, 71))	('MLN4924', 'Chemical', 'MESH:C539933', (73, 80))
146591	26592553	The disruption of neddylation leads to the failure of a major subset of ubiquitin E3 ligase CRLs and the subsequent accumulation of numerous CRL substrates.	('accumulation', 'PosReg', (116, 128))	('CRL', 'Gene', (141, 144))	('CRL', 'Gene', '133396', (92, 95))	('failure', 'NegReg', (43, 50))	('disruption', 'Var', (4, 14))	('CRL', 'Gene', '133396', (141, 144))	('ubiquitin', 'molecular_function', 'GO:0031386', ('72', '81'))	('CRL', 'Gene', (92, 95))
146592	26592553	The combination of MLN4924 and DNA damage agents, such as cisplatin or mitomycin C, enhances DNA damage by interfering with the DNA repair system.	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('DNA repair', 'biological_process', 'GO:0006281', ('128', '138'))	('enhances', 'PosReg', (84, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('DNA damage', 'MPA', (93, 103))	('MLN4924', 'Chemical', 'MESH:C539933', (19, 26))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('interfering', 'NegReg', (107, 118))	('DNA', 'Pathway', (128, 131))	('MLN4924', 'Var', (19, 26))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('mitomycin C', 'Chemical', 'MESH:D016685', (71, 82))
146593	26592553	Our study found that cisplatin in combination with MLN4924 suppressed the phosphorylation of ATM, Chk1 and BRCA1 after 24 hours of treatment, and these results were accompanied with a higher expression level of phospho-histone H2A.X.	('phosphorylation', 'MPA', (74, 89))	('BRCA1', 'Gene', '672', (107, 112))	('MLN4924', 'Var', (51, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('expression level', 'MPA', (191, 207))	('ATM', 'Gene', '472', (93, 96))	('Chk1', 'Gene', (98, 102))	('suppressed', 'NegReg', (59, 69))	('Chk1', 'Gene', '1111', (98, 102))	('BRCA1', 'Gene', (107, 112))	('higher', 'PosReg', (184, 190))	('MLN4924', 'Chemical', 'MESH:C539933', (51, 58))	('ATM', 'Gene', (93, 96))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))
146595	26592553	The discrepancy between the 8-hour and 24-hour time points may have occurred because MLN4924 manipulated factors that accounted for increased DNA damage at different time points, in other words, MLN4924 may augment DNA damage caused by cisplatin through affecting a set of proteins in early time points, and at later time points, another set of proteins are interfered so that it sustain and increase DNA damage throughout the entire treatment period, which increases JNK activation.	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('MLN4924', 'Var', (195, 202))	('JNK', 'Gene', '5599', (468, 471))	('JNK', 'molecular_function', 'GO:0004705', ('468', '471'))	('increase', 'PosReg', (392, 400))	('affecting', 'Reg', (254, 263))	('DNA damage', 'MPA', (215, 225))	('MLN4924', 'Chemical', 'MESH:C539933', (85, 92))	('DNA damage', 'MPA', (401, 411))	('augment', 'PosReg', (207, 214))	('MLN4924', 'Chemical', 'MESH:C539933', (195, 202))	('cisplatin', 'Chemical', 'MESH:D002945', (236, 245))	('JNK', 'Gene', (468, 471))	('DNA', 'cellular_component', 'GO:0005574', ('401', '404'))	('DNA', 'cellular_component', 'GO:0005574', ('215', '218'))
146598	26592553	Previous studies demonstrated that Bcl-2, which is an anti-apoptotic protein similar to Bcl-xL, is phosphorylated on Ser87 and Thr56, and the phosphorylation of Bcl-2 decreases its anti-apoptotic activity, possibly via the inhibition of homo/heterodimer formation, which induces the release of cytochrome c. Similar to Bcl-2, Bcl-xL is phosphorylated on Ser62 by JNK, and other studies reported that the phosphorylation of Ser62 dissociates Bcl-xL from Bax, which allows Bax oligomerization and induces intrinsic apoptotic pathways.	('formation', 'biological_process', 'GO:0009058', ('254', '263'))	('Bcl-xL', 'Gene', (441, 447))	('Bax', 'Gene', '581', (471, 474))	('cytochrome c', 'molecular_function', 'GO:0045155', ('294', '306'))	('intrinsic apoptotic pathways', 'Pathway', (503, 531))	('phosphorylation', 'biological_process', 'GO:0016310', ('404', '419'))	('Bcl-xL', 'Gene', '598', (441, 447))	('Bcl-xL', 'Gene', (88, 94))	('cytochrome c', 'Gene', '54205', (294, 306))	('Ser62', 'Chemical', '-', (354, 359))	('Bcl-2', 'molecular_function', 'GO:0015283', ('161', '166'))	('JNK', 'Gene', (363, 366))	('phosphorylation', 'biological_process', 'GO:0016310', ('142', '157'))	('Bcl-xL', 'Gene', '598', (88, 94))	('Bcl-2', 'Gene', (161, 166))	('JNK', 'Gene', '5599', (363, 366))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('Bax', 'Gene', (453, 456))	('Ser62', 'Chemical', '-', (423, 428))	('cytochrome c', 'molecular_function', 'GO:0009461', ('294', '306'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('319', '324'))	('Bcl-2', 'Gene', (35, 40))	('Bcl-xL', 'Gene', (326, 332))	('JNK', 'molecular_function', 'GO:0004705', ('363', '366'))	('Bax', 'Gene', '581', (453, 456))	('induces', 'Reg', (495, 502))	('cytochrome c', 'Gene', (294, 306))	('Ser', 'cellular_component', 'GO:0005790', ('354', '357'))	('Bcl-2', 'Gene', (319, 324))	('Bcl-2', 'molecular_function', 'GO:0015283', ('35', '40'))	('Bcl-2', 'Gene', '596', (161, 166))	('Bcl-xL', 'Gene', '598', (326, 332))	('Bcl-2', 'Gene', '596', (35, 40))	('phosphorylation', 'Var', (404, 419))	('Bax', 'Gene', (471, 474))	('Ser', 'cellular_component', 'GO:0005790', ('117', '120'))	('Bcl-2', 'Gene', '596', (319, 324))	('Ser', 'cellular_component', 'GO:0005790', ('423', '426'))
146605	26592553	Ryutaro and colleagues (2014) reported that the Ser62 phosphorylation of Bcl-xL by JNK led to the ubiquitination of Bcl-xL, which was subsequently sent to proteosomes for degradation.	('JNK', 'molecular_function', 'GO:0004705', ('83', '86'))	('degradation', 'biological_process', 'GO:0009056', ('171', '182'))	('Ser', 'cellular_component', 'GO:0005790', ('48', '51'))	('Bcl-xL', 'Gene', (116, 122))	('JNK', 'Gene', '5599', (83, 86))	('led to', 'Reg', (87, 93))	('Bcl-xL', 'Gene', '598', (116, 122))	('Bcl-xL', 'Gene', '598', (73, 79))	('Ser62', 'Var', (48, 53))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('Ser62', 'Chemical', '-', (48, 53))	('ubiquitination', 'MPA', (98, 112))	('Bcl-xL', 'Gene', (73, 79))	('JNK', 'Gene', (83, 86))
146606	26592553	We found that Bcl-xL expression level was restored when the proteosome inhibitor MG132 was present during cisplatin and MLN4924 treatment (Supplementary information, Fig.	('Bcl-xL', 'Gene', (14, 20))	('restored', 'PosReg', (42, 50))	('Bcl-xL', 'Gene', '598', (14, 20))	('MLN4924', 'Chemical', 'MESH:C539933', (120, 127))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('MLN4924', 'Var', (120, 127))	('MG132', 'Chemical', 'MESH:C072553', (81, 86))
146613	26592553	Bcl-xL overexpression partially reduced the apoptosis caused by the combination of cisplatin and MLN4924.	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('MLN4924', 'Chemical', 'MESH:C539933', (97, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('apoptosis', 'CPA', (44, 53))	('Bcl-xL', 'Gene', '598', (0, 6))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('reduced', 'NegReg', (32, 39))	('MLN4924', 'Var', (97, 104))	('Bcl-xL', 'Gene', (0, 6))
146614	26592553	Our in vivo model also revealed that the higher JNK activation and significant decline in Bcl-xL protein levels after combined cisplatin and MLN4924 treatment corresponded to significant tumor retardation.	('JNK', 'Gene', (48, 51))	('decline', 'NegReg', (79, 86))	('MLN4924', 'Var', (141, 148))	('JNK', 'Gene', '5599', (48, 51))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('Bcl-xL', 'Gene', '598', (90, 96))	('tumor retardation', 'Disease', 'MESH:D009369', (187, 204))	('tumor retardation', 'Disease', (187, 204))	('higher', 'PosReg', (41, 47))	('Bcl-xL', 'Gene', (90, 96))	('MLN4924', 'Chemical', 'MESH:C539933', (141, 148))	('JNK', 'molecular_function', 'GO:0004705', ('48', '51'))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))	('activation', 'PosReg', (52, 62))
146615	26592553	Our results demonstrated that Bcl-xL was a prominent target of the combined cisplatin and MLN4924 treatment.	('MLN4924', 'Chemical', 'MESH:C539933', (90, 97))	('Bcl-xL', 'Gene', (30, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('MLN4924', 'Var', (90, 97))	('Bcl-xL', 'Gene', '598', (30, 36))
146616	26592553	In summary, MLN4924 enhances the cytotoxicity of cisplatin synergistically via increased DNA damage and JNK activation, which represses Bcl-xL expression levels in vitro and in vivo.	('increased', 'PosReg', (79, 88))	('cytotoxicity', 'Disease', (33, 45))	('Bcl-xL', 'Gene', (136, 142))	('JNK', 'Gene', '5599', (104, 107))	('MLN4924', 'Chemical', 'MESH:C539933', (12, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('JNK', 'molecular_function', 'GO:0004705', ('104', '107'))	('MLN4924', 'Var', (12, 19))	('DNA damage', 'MPA', (89, 99))	('enhances', 'PosReg', (20, 28))	('cytotoxicity', 'Disease', 'MESH:D064420', (33, 45))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('JNK', 'Gene', (104, 107))	('Bcl-xL', 'Gene', '598', (136, 142))	('represses', 'NegReg', (126, 135))	('activation', 'PosReg', (108, 118))
146624	26592553	The c-Jun N-terminal kinase (JNK) inhibitor (SP600125) and MG132 were purchased from Merck Millipore (Billerica, MA, USA).	('c-Jun N-terminal kinase', 'Gene', (4, 27))	('MG132', 'Chemical', 'MESH:C072553', (59, 64))	('c-Jun N-terminal kinase', 'Gene', '5599', (4, 27))	('JNK', 'Gene', (29, 32))	('JNK', 'Gene', '5599', (29, 32))	('JNK', 'molecular_function', 'GO:0004705', ('29', '32'))	('SP600125', 'Chemical', 'MESH:C432165', (45, 53))	('SP600125', 'Var', (45, 53))
146641	26592553	After the tumors had grown to approximately 150 mm3, the mice were treated with cisplatin, MLN4924, cisplatin combined with MLN4924, or the control group (n = 6 for each group).	('mice', 'Species', '10090', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('MLN4924', 'Chemical', 'MESH:C539933', (91, 98))	('MLN4924', 'Var', (124, 131))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('MLN4924', 'Var', (91, 98))	('MLN4924', 'Chemical', 'MESH:C539933', (124, 131))
146642	26592553	The cisplatin- and MLN4924-treated groups received intraperitoneal injections of 3 mg/kg cisplatin and 25 mg/kg MLN4924 in normal saline, respectively, three times weekly for four weeks.	('MLN4924', 'Chemical', 'MESH:C539933', (19, 26))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('MLN4924-treated', 'Var', (19, 34))	('MLN4924', 'Chemical', 'MESH:C539933', (112, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('MLN4924', 'Var', (112, 119))
146649	26592553	MLN4924 Synergistically Enhances Cisplatin-induced Cytotoxicity via JNK and Bcl-xL Pathways in Human Urothelial Carcinoma.	('MLN4924', 'Var', (0, 7))	('Enhances', 'PosReg', (24, 32))	('Human', 'Species', '9606', (95, 100))	('Urothelial Carcinoma', 'Disease', 'MESH:D014526', (101, 121))	('Cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('JNK', 'Gene', '5599', (68, 71))	('Carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('Bcl-xL', 'Gene', '598', (76, 82))	('Cytotoxicity', 'Disease', (51, 63))	('JNK', 'Gene', (68, 71))	('JNK', 'molecular_function', 'GO:0004705', ('68', '71'))	('Urothelial Carcinoma', 'Disease', (101, 121))	('Bcl-xL', 'Gene', (76, 82))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('Cisplatin-induced', 'MPA', (33, 50))	('Cytotoxicity', 'Disease', 'MESH:D064420', (51, 63))
146675	24486290	We identified 6,585 patients in the RD who were 40 years of age or older and were diagnosed with a first episode of hematuria between 2004 and 2012 either by urinalysis (>3 RBCs per high power field) or International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes for hematuria (599.7, 599.70, 599.71 or 599.72), at one of Vanderbilt's 19 primary care clinics.	('hematuria', 'Disease', (288, 297))	('hematuria', 'Disease', 'MESH:D006417', (116, 125))	('hematuria', 'Disease', 'MESH:D006417', (288, 297))	('599.7', 'Var', (299, 304))	('patients', 'Species', '9606', (20, 28))	('hematuria', 'Phenotype', 'HP:0000790', (116, 125))	('hematuria', 'Phenotype', 'HP:0000790', (288, 297))	('hematuria', 'Disease', (116, 125))
146810	22491421	First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription.	('guanines', 'Chemical', 'MESH:D006147', (172, 180))	('DNA', 'cellular_component', 'GO:0005574', ('184', '187'))	('Zalypsis', 'Disease', 'None', (108, 116))	('man', 'Species', '9606', (9, 12))	('DNA replication', 'biological_process', 'GO:0006260', ('213', '228'))	('DNA replication', 'MPA', (213, 228))	('solid tumours', 'Disease', 'MESH:D009369', (144, 157))	('DNA', 'cellular_component', 'GO:0005574', ('213', '216'))	('Zalypsis', 'Disease', (108, 116))	('PM00104', 'Var', (158, 165))	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('binds', 'Interaction', (166, 171))	('impacting', 'Reg', (203, 212))	('transcription', 'biological_process', 'GO:0006351', ('233', '246'))	('patients', 'Species', '9606', (121, 129))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('transcription', 'MPA', (233, 246))	('tetrahydroisoquinoline', 'Chemical', 'MESH:C014843', (67, 89))	('solid tumours', 'Disease', (144, 157))
146811	22491421	A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly.	('PKs', 'cellular_component', 'GO:0034081', ('139', '142'))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('toxicities', 'Disease', 'MESH:D064420', (68, 78))	('PM00104', 'Var', (183, 190))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('tumour', 'Disease', (164, 170))	('toxicities', 'Disease', (68, 78))
146812	22491421	Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data.	('solid tumours', 'Disease', 'MESH:D009369', (23, 36))	('Patients', 'Species', '9606', (0, 8))	('solid tumours', 'Disease', (23, 36))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('PM00104', 'Var', (46, 53))	('toxicity', 'Disease', 'MESH:D064420', (95, 103))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))	('toxicity', 'Disease', (95, 103))
146818	22491421	PM00104 is well tolerated, with preliminary evidence of antitumour activity observed.	('PM00104', 'Var', (0, 7))	('tumour', 'Disease', (60, 66))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))
146819	22491421	PM00104 (Zalypsis, PharmaMar, Madrid, Spain) is a novel marine-derived synthetic tetrahydroisoquinoline alkaloid, which is structurally related to jorumycins (isolated from the Pacific nudibranch Jorunna funebris) and renieramycins (from marine sponges; Figure 1).	('PM00104', 'Var', (0, 7))	('jorumycins', 'Chemical', 'MESH:C507297', (147, 157))	('tetrahydroisoquinoline alkaloid', 'Chemical', '-', (81, 112))	('renieramycins', 'Chemical', '-', (218, 231))	('Pacific nudibranch Jorunna funebris', 'Disease', (177, 212))	('Pacific nudibranch Jorunna funebris', 'Disease', 'None', (177, 212))	('Zalypsis', 'Disease', 'None', (9, 17))	('Zalypsis', 'Disease', (9, 17))
146820	22491421	PM00104 showed potent cytotoxic activity against a wide range of human tumour cell lines, with IC50 values in the low nanomolar range.	('PM00104', 'Var', (0, 7))	('human', 'Species', '9606', (65, 70))	('tumour', 'Disease', (71, 77))	('cytotoxic activity', 'CPA', (22, 40))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
146822	22491421	PM00104 exerts its antitumour effects through the covalent modification of guanines in the DNA minor groove, thereby affecting DNA replication and transcription.	('PM00104', 'Var', (0, 7))	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('transcription', 'MPA', (147, 160))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('affecting', 'Reg', (117, 126))	('transcription', 'biological_process', 'GO:0006351', ('147', '160'))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('tumour', 'Disease', (23, 29))	('groove', 'cellular_component', 'GO:0097610', ('101', '107'))	('DNA replication', 'MPA', (127, 142))	('DNA replication', 'biological_process', 'GO:0006260', ('127', '142'))	('guanines', 'Chemical', 'MESH:D006147', (75, 83))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))
146823	22491421	DNA adducts are transformed into DNA double-strand breaks at nanomolar concentrations of PM00104, as detected by an increased proportion of cells with abundant gammaH2AX foci formation in solid tumour and multiple myeloma cell lines.	('tumour', 'Disease', (194, 200))	('formation', 'biological_process', 'GO:0009058', ('175', '184'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('multiple myeloma', 'Phenotype', 'HP:0006775', (205, 221))	('multiple myeloma', 'Disease', 'MESH:D009101', (205, 221))	('multiple myeloma', 'Disease', (205, 221))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('PM00104', 'Var', (89, 96))	('tumour', 'Disease', 'MESH:D009369', (194, 200))
146824	22491421	DNA damage induced by PM00104 results in S-phase cell cycle arrest in various solid tumour cell lines and activates DNA replication checkpoints.	('tumour', 'Disease', (84, 90))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('DNA replication checkpoints', 'MPA', (116, 143))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('49', '66'))	('S-phase', 'biological_process', 'GO:0051320', ('41', '48'))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('DNA replication', 'biological_process', 'GO:0006260', ('116', '131'))	('activates', 'PosReg', (106, 115))	('arrest', 'Disease', 'MESH:D006323', (60, 66))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('PM00104', 'Var', (22, 29))	('arrest', 'Disease', (60, 66))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (49, 66))
146825	22491421	PM00104 caused tumour cells to accumulate in S-phase and induced apoptotic cell death, which was dependent on caspase activity, resulting in cleavage of poly (ADP-ribose) polymerase-1 and cytokeratin 18.	('PM00104', 'Var', (0, 7))	('accumulate', 'PosReg', (31, 41))	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('caspase activity', 'molecular_function', 'GO:0097153', ('110', '126'))	('tumour', 'Disease', (15, 21))	('induced', 'Reg', (57, 64))	('caspase activity', 'molecular_function', 'GO:0030693', ('110', '126'))	('cytokeratin 18', 'Gene', (188, 202))	('caspase activity', 'molecular_function', 'GO:0004197', ('110', '126'))	('S-phase', 'biological_process', 'GO:0051320', ('45', '52'))	('apoptotic cell death', 'CPA', (65, 85))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('65', '85'))	('cytokeratin 18', 'Gene', '3875', (188, 202))	('cleavage', 'MPA', (141, 149))	('S-phase', 'CPA', (45, 52))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('poly (ADP-ribose) polymerase-1', 'Gene', '142', (153, 183))	('poly (ADP-ribose) polymerase-1', 'Gene', (153, 183))
146826	22491421	In preclinical studies, PM00104 given by intravenous injection produced toxicological effects primarily affecting the bone marrow, reticuloendothelial system and gastrointestinal tract in dogs and rats, as well as the liver and injection site.	('gastrointestinal tract', 'Disease', 'MESH:D004067', (162, 184))	('PM00104', 'Var', (24, 31))	('affecting', 'Reg', (104, 113))	('dogs', 'Species', '9615', (188, 192))	('gastrointestinal tract', 'Disease', (162, 184))	('rats', 'Species', '10116', (197, 201))
146830	22491421	The primary objectives were to assess the safety and tolerability of PM00104, determine dose-limiting toxicities (DLTs) and establish the recommended phase II dose (RP2D) for PM00104 as a 1- or 3-h 3-weekly intravenous infusion.	('PM00104', 'Gene', (69, 76))	('toxicities', 'Disease', 'MESH:D064420', (102, 112))	('toxicities', 'Disease', (102, 112))	('PM00104', 'Var', (175, 182))
146838	22491421	A second schedule in which the duration of infusion was increased from 1 to 3 h was also planned a priori as an alternative strategy if toxicity due to PM00104-related maximum plasma concentration (Cmax), or if a more than proportional increase in Cmax was observed during dose escalation with the 1-h schedule.	('toxicity', 'Disease', 'MESH:D064420', (136, 144))	('toxicity', 'Disease', (136, 144))	('PM00104-related', 'Var', (152, 167))	('maximum plasma concentration', 'MPA', (168, 196))
146847	22491421	In the 1-h schedule, the dose of PM00104 was escalated by increments of 100% (50% if grade 2 toxicity occurred, and 25% if grade 3 or 4 toxicity occurred), while in the 3-h schedule, in view of the higher starting dosing, doses were escalated by increments of 25%.	('toxicity', 'Disease', 'MESH:D064420', (136, 144))	('toxicity', 'Disease', (136, 144))	('toxicity', 'Disease', 'MESH:D064420', (93, 101))	('toxicity', 'Disease', (93, 101))	('PM00104', 'Var', (33, 40))
146860	22491421	The patient with the DLT at 1.8 mg m-2 was a patient with metastatic NSCLC, who developed G3 hypotension on day 2 of PM00104.	('hypotension', 'Disease', (93, 104))	('NSCLC', 'Disease', (69, 74))	('PM00104', 'Var', (117, 124))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('patient', 'Species', '9606', (4, 11))	('hypotension', 'Phenotype', 'HP:0002615', (93, 104))	('patient', 'Species', '9606', (45, 52))	('hypotension', 'Disease', 'MESH:D007022', (93, 104))
146861	22491421	The patient developed G2 vomiting after the end of his PM00104 infusion on day 1 and was also on regular antihypertensive medications, which could have contributed to the hypotension.	('hypotension', 'Phenotype', 'HP:0002615', (171, 182))	('vomiting', 'Phenotype', 'HP:0002013', (25, 33))	('PM00104', 'Var', (55, 62))	('hypotension', 'Disease', 'MESH:D007022', (171, 182))	('patient', 'Species', '9606', (4, 11))	('vomiting', 'Disease', (25, 33))	('vomiting', 'Disease', 'MESH:D014839', (25, 33))	('hypotension', 'Disease', (171, 182))
146862	22491421	At this dose of 3.5 mg m-2 of PM00104, in the initial cohort of three patients, one patient with metastatic urothelial carcinoma developed G3 hypotension on day 2 of treatment associated with nausea, vomiting and diarrhoea, which resolved within 1 day.	('nausea', 'Phenotype', 'HP:0002018', (192, 198))	('vomiting', 'Disease', (200, 208))	('diarrhoea', 'Phenotype', 'HP:0002014', (213, 222))	('patients', 'Species', '9606', (70, 78))	('nausea', 'Disease', (192, 198))	('patient', 'Species', '9606', (70, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('urothelial carcinoma', 'Disease', (108, 128))	('hypotension', 'Disease', (142, 153))	('nausea', 'Disease', 'MESH:D009325', (192, 198))	('PM00104', 'Var', (30, 37))	('hypotension', 'Disease', 'MESH:D007022', (142, 153))	('patient', 'Species', '9606', (84, 91))	('diarrhoea', 'Disease', (213, 222))	('vomiting', 'Disease', 'MESH:D014839', (200, 208))	('hypotension', 'Phenotype', 'HP:0002615', (142, 153))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (108, 128))	('diarrhoea', 'Disease', 'MESH:D003967', (213, 222))	('vomiting', 'Phenotype', 'HP:0002013', (200, 208))
146865	22491421	Two of these subsequent three patients experienced DLTs; a patient with metastatic colorectal carcinoma had an asymptomatic and reversible G3 hypotension on day 2 of PM00104.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('patient', 'Species', '9606', (30, 37))	('hypotension', 'Disease', (142, 153))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (83, 103))	('hypotension', 'Phenotype', 'HP:0002615', (142, 153))	('patient', 'Species', '9606', (59, 66))	('PM00104', 'Var', (166, 173))	('patients', 'Species', '9606', (30, 38))	('colorectal carcinoma', 'Disease', (83, 103))	('hypotension', 'Disease', 'MESH:D007022', (142, 153))
146867	22491421	In view of the similar toxicities and the absence of an advantage in the PK exposure of PM00104 with the 3-h infusion, it was concluded that the 3-h infusion did not have any added benefit over the 1-h infusion.	('toxicities', 'Disease', 'MESH:D064420', (23, 33))	('toxicities', 'Disease', (23, 33))	('PM00104', 'Var', (88, 95))
146868	22491421	Most drug-related AEs or laboratory abnormalities (Table 3) experienced by patients receiving PM00104 at the RP2D of 3.0 mg m-2 for the 1-h schedule and 2.8 mg m-2 for the 3-h schedule were mild or moderate.	('laboratory abnormalities', 'Disease', 'MESH:D007757', (25, 49))	('PM00104', 'Var', (94, 101))	('patients', 'Species', '9606', (75, 83))	('laboratory abnormalities', 'Phenotype', 'HP:0001939', (25, 49))	('drug-related AEs', 'Disease', (5, 21))	('laboratory abnormalities', 'Disease', (25, 49))
146869	22491421	The most common AEs related to PM00104 treatment were nausea (n=6), fatigue (n=5) and injection site phlebitis (n=4).	('nausea', 'Phenotype', 'HP:0002018', (54, 60))	('phlebitis', 'Disease', (101, 110))	('nausea', 'Disease', 'MESH:D009325', (54, 60))	('PM00104', 'Var', (31, 38))	('fatigue', 'Disease', 'MESH:D005221', (68, 75))	('phlebitis', 'Disease', 'MESH:D010689', (101, 110))	('fatigue', 'Disease', (68, 75))	('nausea', 'Disease', (54, 60))	('fatigue', 'Phenotype', 'HP:0012378', (68, 75))
146875	22491421	The most common AEs related to PM00104 treatment were constipation, nausea and vomiting (n=3).	('nausea', 'Phenotype', 'HP:0002018', (68, 74))	('nausea', 'Disease', (68, 74))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (68, 87))	('PM00104', 'Var', (31, 38))	('constipation', 'Phenotype', 'HP:0002019', (54, 66))	('nausea', 'Disease', 'MESH:D009325', (68, 74))	('vomiting', 'Phenotype', 'HP:0002013', (79, 87))	('constipation', 'Disease', 'MESH:D003248', (54, 66))	('vomiting', 'Disease', (79, 87))	('vomiting', 'Disease', 'MESH:D014839', (79, 87))	('constipation', 'Disease', (54, 66))
146889	22491421	The analysis of the effect of PM00104 PK exposure on biochemical and haematological parameters (measured as the ratio of the worst level in cycle 1 to the baseline level of each parameter) showed that a longer half-life and increases in AUC and Cmax were related with higher transaminases and bilirubin, and lower counts of neutrophils, platelets and white blood cells, whereas haemoglobin and renal function were not affected.	('lower', 'NegReg', (308, 313))	('increases', 'PosReg', (224, 233))	('Cmax', 'MPA', (245, 249))	('lower counts of neutrophils', 'Phenotype', 'HP:0001875', (308, 335))	('half-life', 'MPA', (210, 219))	('longer', 'PosReg', (203, 209))	('bilirubin', 'MPA', (293, 302))	('bilirubin', 'Chemical', 'MESH:D001663', (293, 302))	('counts of neutrophils', 'MPA', (314, 335))	('AUC', 'MPA', (237, 240))	('PM00104', 'Var', (30, 37))	('transaminases', 'MPA', (275, 288))	('higher', 'PosReg', (268, 274))
146890	22491421	A total of 39 of 47 patients treated with both schedules of PM00104 were evaluable for antitumour efficacy assessments.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('tumour', 'Disease', (91, 97))	('patients', 'Species', '9606', (20, 28))	('PM00104', 'Var', (60, 67))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
146892	22491421	This heavily pretreated patient achieved RECIST tumour shrinkage of 49.0% after two cycles of PM00104 (Figure 3).	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('PM00104', 'Var', (94, 101))	('patient', 'Species', '9606', (24, 31))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (48, 54))
146894	22491421	The patient temporarily discontinued PM00104 to receive whole-brain radiotherapy, but after acquiring appropriate Ethics Committee permission, proceeded to receive further cycles of PM100104.	('PM00104', 'Gene', (37, 44))	('PM100104', 'Var', (182, 190))	('patient', 'Species', '9606', (4, 11))
146898	22491421	Dose-limiting toxicities observed with the 1-h schedule of PM00104 included G3 transaminitis, fatigue, nausea and vomiting and G4 thrombocytopenia (n=1 each).	('toxicities', 'Disease', (14, 24))	('thrombocytopenia', 'Disease', (130, 146))	('fatigue', 'Disease', (94, 101))	('PM00104', 'Var', (59, 66))	('nausea', 'Phenotype', 'HP:0002018', (103, 109))	('G3 transaminitis', 'Disease', (76, 92))	('nausea', 'Disease', (103, 109))	('nausea', 'Disease', 'MESH:D009325', (103, 109))	('fatigue', 'Phenotype', 'HP:0012378', (94, 101))	('vomiting', 'Phenotype', 'HP:0002013', (114, 122))	('toxicities', 'Disease', 'MESH:D064420', (14, 24))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (103, 122))	('thrombocytopenia', 'Disease', 'MESH:D013921', (130, 146))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (130, 146))	('vomiting', 'Disease', (114, 122))	('vomiting', 'Disease', 'MESH:D014839', (114, 122))	('fatigue', 'Disease', 'MESH:D005221', (94, 101))
146899	22491421	Dose-limiting toxicities with the 3-h schedule of PM00104 included G3 hypotension (n=2) and G4 neutropenia >5 days (n=1).	('neutropenia', 'Disease', 'MESH:D009503', (95, 106))	('hypotension', 'Disease', (70, 81))	('toxicities', 'Disease', (14, 24))	('neutropenia', 'Phenotype', 'HP:0001875', (95, 106))	('hypotension', 'Phenotype', 'HP:0002615', (70, 81))	('PM00104', 'Var', (50, 57))	('toxicities', 'Disease', 'MESH:D064420', (14, 24))	('neutropenia', 'Disease', (95, 106))	('hypotension', 'Disease', 'MESH:D007022', (70, 81))
146900	22491421	These findings are consistent with preliminary results from other phase I trials evaluating other schedules of PM00104, in which myelosuppression, nausea and vomiting have also been observed, in keeping with this agent's mechanism of action.	('myelosuppression', 'Disease', 'MESH:D001855', (129, 145))	('nausea', 'Phenotype', 'HP:0002018', (147, 153))	('myelosuppression', 'Disease', (129, 145))	('nausea', 'Disease', (147, 153))	('nausea', 'Disease', 'MESH:D009325', (147, 153))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (147, 166))	('vomiting', 'Phenotype', 'HP:0002013', (158, 166))	('vomiting', 'Disease', (158, 166))	('PM00104', 'Var', (111, 118))	('vomiting', 'Disease', 'MESH:D014839', (158, 166))
146902	22491421	PM00104-related AEs at the RP2D for both schedules were mostly G1-G2, with the most frequently observed toxicities being transient nausea, vomiting and fatigue.	('fatigue', 'Disease', 'MESH:D005221', (152, 159))	('vomiting', 'Disease', (139, 147))	('toxicities', 'Disease', (104, 114))	('vomiting', 'Disease', 'MESH:D014839', (139, 147))	('PM00104-related', 'Var', (0, 15))	('fatigue', 'Disease', (152, 159))	('nausea', 'Phenotype', 'HP:0002018', (131, 137))	('fatigue', 'Phenotype', 'HP:0012378', (152, 159))	('nausea', 'Disease', (131, 137))	('toxicities', 'Disease', 'MESH:D064420', (104, 114))	('nausea', 'Disease', 'MESH:D009325', (131, 137))	('G1-G2', 'Disease', (63, 68))	('vomiting', 'Phenotype', 'HP:0002013', (139, 147))
146905	22491421	The most common G3-G4 haematological abnormalities with both schedules of PM00104 at the respective RP2Ds were transient and comprised neutropenia and leucopenia (1-h), and neutropenia alone (3-h).	('neutropenia', 'Phenotype', 'HP:0001875', (135, 146))	('neutropenia and leucopenia', 'Disease', 'MESH:D009503', (135, 161))	('G3-G4', 'Gene', (16, 21))	('neutropenia', 'Disease', (173, 184))	('haematological abnormalities', 'Phenotype', 'HP:0001871', (22, 50))	('neutropenia', 'Disease', (135, 146))	('neutropenia', 'Phenotype', 'HP:0001875', (173, 184))	('neutropenia', 'Disease', 'MESH:D009503', (173, 184))	('neutropenia', 'Disease', 'MESH:D009503', (135, 146))	('PM00104', 'Var', (74, 81))
146907	22491421	Data from this and other phase I studies of PM00104 suggest that there is no evidence of acute cardiac damage in patients treated with PM00104.	('patients', 'Species', '9606', (113, 121))	('cardiac damage', 'Disease', (95, 109))	('cardiac damage', 'Disease', 'MESH:D006331', (95, 109))	('PM00104', 'Var', (135, 142))
146910	22491421	The long-term effects of such a rise in troponin I levels is currently unknown, but may suggest that elevations in troponin I levels observed in this small subset of patients receiving PM00104 may simply reflect a biochemical finding, rather than clinical sequelae of cardiac damage.	('cardiac damage', 'Disease', 'MESH:D006331', (268, 282))	('PM00104', 'Var', (185, 192))	('elevations', 'PosReg', (101, 111))	('cardiac damage', 'Disease', (268, 282))	('troponin I', 'MPA', (115, 125))	('rise in troponin I levels', 'Phenotype', 'HP:0410173', (32, 57))	('elevations in troponin I levels', 'Phenotype', 'HP:0410173', (101, 132))	('patients', 'Species', '9606', (166, 174))
146916	22491421	Furthermore, a patient with advanced urothelial carcinoma had a RECIST partial response, with tumour shrinkage by 49% after 2 months of treatment, indicating that PM00104 has antitumour activity.	('tumour', 'Disease', (94, 100))	('patient', 'Species', '9606', (15, 22))	('advanced urothelial carcinoma', 'Disease', (28, 57))	('PM00104', 'Var', (163, 170))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('advanced urothelial carcinoma', 'Disease', 'MESH:D020178', (28, 57))	('tumour', 'Disease', 'MESH:D009369', (94, 100))	('tumour', 'Disease', (179, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
146918	22491421	In view of the well-tolerated toxicities, active PK profile and preliminary evidence of antitumour activity observed for PM00104 in this first-in-human study, multiple phase II clinical trials have now been initiated.	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('toxicities', 'Disease', 'MESH:D064420', (30, 40))	('tumour', 'Disease', (92, 98))	('PM00104', 'Var', (121, 128))	('human', 'Species', '9606', (146, 151))	('toxicities', 'Disease', (30, 40))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
146919	22491421	Currently, PM00104 is being assessed in phase II studies undertaken in patients with advanced endometrial cancer, cervical cancer, multiple myeloma, advanced Ewing family of tumours and advanced urothelial cancer (http://www.clinicaltrials.gov).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('PM00104', 'Var', (11, 18))	('patients', 'Species', '9606', (71, 79))	('multiple myeloma', 'Disease', 'MESH:D009101', (131, 147))	('endometrial cancer', 'Disease', (94, 112))	('Ewing family of tumours and advanced urothelial cancer', 'Disease', 'MESH:D009369', (158, 212))	('multiple myeloma', 'Phenotype', 'HP:0006775', (131, 147))	('endometrial cancer', 'Phenotype', 'HP:0012114', (94, 112))	('multiple myeloma', 'Disease', (131, 147))	('endometrial cancer', 'Disease', 'MESH:D016889', (94, 112))	('cervical cancer', 'Disease', (114, 129))	('cervical cancer', 'Disease', 'MESH:D002583', (114, 129))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
146925	33769711	Core driver combinations involving NFE2L2 mutations were identified in four cancer types, supporting the therapeutic potential of NRF2 pathway inhibition.	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('NRF2', 'Gene', '4780', (130, 134))	('NFE2L2', 'Gene', '4780', (35, 41))	('NFE2L2', 'Gene', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('NRF2', 'Gene', (130, 134))	('cancer', 'Disease', (76, 82))	('mutations', 'Var', (42, 51))
146931	33769711	For example, activating mutations in KRAS/NRAS are frequently accompanied by loss of function of CDKN2A/B in melanoma, lung, pancreatic, and other cancers.	('pancreatic', 'Disease', (125, 135))	('loss of function', 'NegReg', (77, 93))	('CDKN2A/B', 'Gene', '1029;1030', (97, 105))	('NRAS', 'Gene', '4893', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('KRAS', 'Gene', '3845', (37, 41))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('CDKN2A/B', 'Gene', (97, 105))	('KRAS', 'Gene', (37, 41))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('activating mutations', 'Var', (13, 33))	('cancers', 'Disease', (147, 154))	('pancreatic', 'Disease', 'MESH:D010195', (125, 135))	('lung', 'Disease', (119, 123))	('NRAS', 'Gene', (42, 46))
146934	33769711	From a biological perspective, co-occurrence of driver alterations clearly does occur (Ulz et al, 2016; Wang et al, 2017; VanderLaan et al, 2017; Kim et al, 2019), and appears to be a requirement for most carcinogenesis events, as evidenced by the insufficiency of BRAF and RAS hotspot mutations to transform benign colon polyps and nevi into invasive carcinoma (Pollock et al, 2003; Juarez et al, 2017).	('benign colon polyps', 'Disease', 'MESH:D003111', (309, 328))	('carcinogenesis', 'Disease', (205, 219))	('insufficiency of BRAF', 'Disease', (248, 269))	('mutations', 'Var', (286, 295))	('nevi', 'Phenotype', 'HP:0003764', (333, 337))	('Pollock', 'Species', '8060', (363, 370))	('carcinoma', 'Phenotype', 'HP:0030731', (352, 361))	('nevi', 'Disease', (333, 337))	('benign colon polyps', 'Disease', (309, 328))	('invasive carcinoma', 'Disease', 'MESH:D009361', (343, 361))	('insufficiency of BRAF', 'Disease', 'MESH:D000309', (248, 269))	('RAS', 'Gene', (274, 277))	('invasive carcinoma', 'Disease', (343, 361))	('carcinogenesis', 'Disease', 'MESH:D063646', (205, 219))
146941	33769711	CRSO seeks to find a collection of rules called a rule set that represents all of the unique minimal combinations that can explain all of the given tumors in the study population, i.e., every sample is required to harbor all of the alterations in at least one of the rules.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('alterations', 'Var', (232, 243))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumors', 'Disease', (148, 154))
146943	33769711	We show that CRSO can identify known and novel combinations of driver alterations in 19 tissue types from The Cancer Genome Atlas (TCGA) (Cancer Genome Atlas Network, 2013; Tomczak et al, 2015) and that some of these combinations correlate with clinical outcomes.	('Cancer', 'Disease', 'MESH:D009369', (138, 144))	('alterations', 'Var', (70, 81))	('Cancer', 'Disease', 'MESH:D009369', (110, 116))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Cancer', 'Disease', (110, 116))	('Cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Cancer', 'Disease', (138, 144))	('correlate with', 'Reg', (230, 244))
146944	33769711	CRSO finds combinations of genomic alterations (referred to as events) that are predicted to cooperate to drive cancer in individual patients.	('genomic alterations', 'Var', (27, 46))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('patients', 'Species', '9606', (133, 141))	('drive', 'PosReg', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
146945	33769711	Three primary event types were considered: coding mutations identified as candidate drivers by dNdScv (Martincorena et al, 2017), as well as copy number amplifications and deletions identified as candidate drivers by GISTIC2 (Mermel et al, 2011).	('deletions', 'Var', (172, 181))	('dNdScv', 'Gene', (95, 101))	('copy number', 'Var', (141, 152))	('dNdScv', 'Chemical', '-', (95, 101))
146946	33769711	However, CRSO models can include additional alteration types, such as gene fusions and aneuploidies.	('aneuploidies', 'Disease', 'MESH:D000782', (87, 99))	('aneuploidies', 'Disease', (87, 99))	('gene fusions', 'Var', (70, 82))
146947	33769711	Similarly, deletion events take values in {Z, WD, SD}, corresponding to wild type, weak deletion (hemizygous), and strong deletion (homozygous), respectively.	('deletion', 'Var', (11, 19))	('deletion', 'Var', (122, 130))	('WD', 'Disease', 'MESH:D006527', (46, 48))
146988	33769711	The union of the melanoma core RS and con-GCRs comprise 11 distinct rules and are dominated by rules that contain either BRAF or NRAS mutations (Table 2).	('BRAF', 'Gene', (121, 125))	('BRAF', 'Gene', '673', (121, 125))	('melanoma core RS', 'Disease', 'MESH:D041441', (17, 33))	('NRAS', 'Gene', (129, 133))	('GCR', 'Gene', (42, 45))	('NRAS', 'Gene', '4893', (129, 133))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('GCR', 'Gene', '2908', (42, 45))	('mutations', 'Var', (134, 143))	('melanoma core RS', 'Disease', (17, 33))	('core', 'cellular_component', 'GO:0019013', ('26', '30'))
146990	33769711	Hotspot mutations in BRAF and NRAS define the two major subtypes of melanoma that are mutually exclusive, with 50% of patients harboring BRAFV600E mutations and 30% of patients harboring NRAS hotspot mutations (Cancer Genome Atlas Network, 2015a).	('mutations', 'Var', (147, 156))	('Cancer', 'Phenotype', 'HP:0002664', (211, 217))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('Cancer', 'Disease', (211, 217))	('NRAS', 'Gene', '4893', (187, 191))	('mutations', 'Var', (8, 17))	('BRAF', 'Gene', '673', (21, 25))	('BRAF', 'Gene', (21, 25))	('NRAS', 'Gene', '4893', (30, 34))	('Cancer', 'Disease', 'MESH:D009369', (211, 217))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('BRAFV600E', 'Mutation', 'rs113488022', (137, 146))	('NRAS', 'Gene', (187, 191))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('NRAS', 'Gene', (30, 34))	('patients', 'Species', '9606', (168, 176))	('patients', 'Species', '9606', (118, 126))
146992	33769711	The first 4 of these rules are instances of co-occurring MAPK3 pathway activation with P53 inactivation:a synergy that is known to promote carcinogenesis (Gen, 2004; Stramucci et al, 2018).	('carcinogenesis', 'Disease', (139, 153))	('MAPK', 'molecular_function', 'GO:0004707', ('57', '61'))	('activation', 'PosReg', (71, 81))	('MAPK3', 'Gene', (57, 62))	('MAPK3', 'Gene', '5595', (57, 62))	('inactivation', 'Var', (91, 103))	('carcinogenesis', 'Disease', 'MESH:D063646', (139, 153))	('P53', 'Gene', (87, 90))	('P53', 'Gene', '7157', (87, 90))	('promote', 'PosReg', (131, 138))
147009	33769711	Mazur et al (2014) showed that SMYD3 methylation of MAP3K2 leads to upregulation of MAP kinase signaling and promotes carcinogenesis in RAS mutated lung and pancreatic cancers.	('RAS mutated lung', 'Disease', (136, 152))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('carcinogenesis', 'Disease', (118, 132))	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('methylation', 'Var', (37, 48))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (157, 175))	('MAP3K2', 'Gene', (52, 58))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('MAP3K', 'molecular_function', 'GO:0004709', ('52', '57'))	('signaling', 'biological_process', 'GO:0023052', ('95', '104'))	('upregulation', 'PosReg', (68, 80))	('MAP kinase signaling', 'MPA', (84, 104))	('pancreatic cancers', 'Disease', (157, 175))	('MAP3K2', 'Gene', '10746', (52, 58))	('pancreatic cancers', 'Disease', 'MESH:D010190', (157, 175))	('MAP', 'molecular_function', 'GO:0004239', ('84', '87'))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))	('promotes', 'PosReg', (109, 117))
147010	33769711	The authors further showed that preventing SMYD3 catalytic activity in mouse models with oncogenic RAS mutations inhibited tumor development (Mazur et al, 2014).	('mutations', 'Var', (103, 112))	('tumor', 'Disease', (123, 128))	('inhibited', 'NegReg', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('mouse', 'Species', '10090', (71, 76))	('SMYD3', 'Gene', (43, 48))	('RAS', 'Gene', (99, 102))	('catalytic activity', 'molecular_function', 'GO:0003824', ('49', '67'))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('catalytic activity', 'MPA', (49, 67))
147011	33769711	This presents a direct biological link between SMYD3 expression and RAS mutations, and nominates SMYD3 as a drug target for RAS-driven cancers.	('RAS', 'Gene', (68, 71))	('mutations', 'Var', (72, 81))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('SMYD3', 'Gene', (47, 52))
147018	33769711	Because TCGA tumors are primary and treatment-naive, this observation suggests that BRAF amplification and BRAFV600E may be a sufficient combination for tumor formation, and a cause of intrinsic resistance to BRAF inhibition.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('ntr', 'Gene', (186, 189))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', (153, 158))	('formation', 'biological_process', 'GO:0009058', ('159', '168'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('BRAF', 'Gene', '673', (84, 88))	('tumors', 'Disease', (13, 19))	('BRAFV600E', 'Mutation', 'rs113488022', (107, 116))	('BRAF', 'Gene', (84, 88))	('ntr', 'Gene', '4923', (186, 189))	('amplification', 'Var', (89, 102))	('BRAF', 'Gene', '673', (107, 111))	('BRAF', 'Gene', (107, 111))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))
147026	33769711	NFE2L2 mutations were identified as part of a con-GCR in 4 cancer types: LUSC, HNSC, ESCA, and BLCA.	('GCR', 'Gene', '2908', (50, 53))	('HNSC', 'Disease', (79, 83))	('LUSC', 'Disease', (73, 77))	('ESCA', 'Disease', (85, 89))	('GCR', 'Gene', (50, 53))	('NFE2L2', 'Gene', '4780', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('BLCA', 'Disease', (95, 99))	('NFE2L2', 'Gene', (0, 6))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('mutations', 'Var', (7, 16))
147030	33769711	However, we now have evidence that constitutive NRF2 activation via mutations in KEAP1 or recurrent NFE2L2 exon 2 deletions can drive tumor proliferation and metastasis (Goldstein et al, 2016; Rojo de la Vega et al, 2018).	('NRF2', 'Gene', '4780', (48, 52))	('KEAP1', 'Gene', (81, 86))	('activation', 'PosReg', (53, 63))	('NRF2', 'Gene', (48, 52))	('drive', 'PosReg', (128, 133))	('tumor', 'Disease', (134, 139))	('NFE2L2', 'Gene', '4780', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('NFE2L2', 'Gene', (100, 106))	('KEAP1', 'Gene', '9817', (81, 86))	('metastasis', 'CPA', (158, 168))	('mutations', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('deletions', 'Var', (114, 123))
147031	33769711	NFE2L2 mutations have recently been shown to define subtypes with differential prognosis in lung and head and neck cancers (Frank et al, 2018; Namani et al, 2018; Xu et al, 2020; Liu et al, 2020b).	('neck', 'cellular_component', 'GO:0044326', ('110', '114'))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('NFE2L2', 'Gene', '4780', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('head and neck cancers', 'Disease', 'MESH:D006258', (101, 122))	('lung', 'Disease', (92, 96))	('NFE2L2', 'Gene', (0, 6))	('head and neck cancers', 'Phenotype', 'HP:0012288', (101, 122))	('mutations', 'Var', (7, 16))
147032	33769711	Several upcoming clinical trials are designed to explore the therapeutic benefit of compounds that inhibit NRF2 in advanced cancer patients harboring mutations in NFE2L2 or KEAP1 (ClinicalTrials.gov, NCT02417701; ClinicalTrials.gov, NCT04267913; ClinicalTrials.gov, NCT03872427).	('patients', 'Species', '9606', (131, 139))	('NRF2', 'Gene', '4780', (107, 111))	('cancer', 'Disease', (124, 130))	('NRF2', 'Gene', (107, 111))	('inhibit', 'NegReg', (99, 106))	('NFE2L2', 'Gene', '4780', (163, 169))	('KEAP1', 'Gene', '9817', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutations', 'Var', (150, 159))	('NFE2L2', 'Gene', (163, 169))	('KEAP1', 'Gene', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
147035	33769711	Patients that have these two mutations and are also wild type for TP53 have been shown to define a biologically distinct subtype characterized by low SCNV burden (Cancer Genome Atlas Network, 2015c).	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('mutations', 'Var', (29, 38))	('Cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Patients', 'Species', '9606', (0, 8))	('Cancer', 'Disease', 'MESH:D009369', (163, 169))	('Cancer', 'Disease', (163, 169))
147037	33769711	Two high confidence GCRs were identified in LIHC involving ALB mutations: ALB-M + CTNNB1-M (conf.	('mutations', 'Var', (63, 72))	('ALB', 'Gene', (59, 62))	('CTNNB1', 'Gene', (82, 88))	('GCR', 'Gene', '2908', (20, 23))	('ALB', 'Gene', '213', (74, 77))	('GCR', 'Gene', (20, 23))	('CTNNB1', 'Gene', '1499', (82, 88))	('ALB', 'Gene', (74, 77))	('ALB', 'Gene', '213', (59, 62))
147040	33769711	Cooperations involving ALB have not been systematically reported, and the two combinations we identified may help inform context-dependent treatments of ALB mutant patients.	('mutant', 'Var', (157, 163))	('ALB', 'Gene', '213', (153, 156))	('ALB', 'Gene', '213', (23, 26))	('ALB', 'Gene', (153, 156))	('ALB', 'Gene', (23, 26))	('patients', 'Species', '9606', (164, 172))
147052	33769711	IDH1 mutations occur in 78% of LGGs and are a biomarker for improved outcome in LGG patients (Cancer Genome Atlas Network, 2015d) (Fig 6A).	('Cancer', 'Phenotype', 'HP:0002664', (94, 100))	('LGGs', 'Disease', (31, 35))	('patients', 'Species', '9606', (84, 92))	('mutations', 'Var', (5, 14))	('LGG', 'Disease', (80, 83))	('Cancer', 'Disease', (94, 100))	('IDH1', 'Gene', (0, 4))	('Cancer', 'Disease', 'MESH:D009369', (94, 100))	('IDH1', 'Gene', '3417', (0, 4))
147053	33769711	Differential outcomes were detected between the event/rule pairings IDH1-M versus IDH1-M + IC-M and IDH1-M versus IDH1-M + PIK3CA-M that could further stratify IDH1 mutant samples (Fig 6).	('IDH1', 'Gene', (114, 118))	('mutant', 'Var', (165, 171))	('IDH1', 'Gene', '3417', (100, 104))	('IDH1', 'Gene', (160, 164))	('PIK3CA', 'Gene', (123, 129))	('IDH1', 'Gene', (68, 72))	('IDH1', 'Gene', (82, 86))	('IDH1', 'Gene', '3417', (160, 164))	('PIK3CA', 'Gene', '5290', (123, 129))	('IDH1', 'Gene', '3417', (114, 118))	('IDH1', 'Gene', '3417', (82, 86))	('IDH1', 'Gene', '3417', (68, 72))	('IDH1', 'Gene', (100, 104))
147056	33769711	Collectively, these results suggest that LGG patients could be stratified into 4 groups: IDH1 wild type, IDH1 mutant + CIC mutant, IDH1 mutant + PIK3CA mutant, and IDH1 mutant + CIC/PIK3CA wild type.	('LGG', 'Disease', (41, 44))	('IDH1', 'Gene', '3417', (131, 135))	('IDH1', 'Gene', '3417', (105, 109))	('patients', 'Species', '9606', (45, 53))	('IDH1', 'Gene', (89, 93))	('CIC', 'Gene', '23152', (119, 122))	('PIK3CA', 'Gene', '5290', (182, 188))	('PIK3CA', 'Gene', (145, 151))	('CIC', 'Gene', (178, 181))	('IDH1', 'Gene', '3417', (89, 93))	('mutant +', 'Var', (136, 144))	('IDH1', 'Gene', (164, 168))	('mutant +', 'Var', (110, 118))	('IDH1', 'Gene', (131, 135))	('IDH1', 'Gene', (105, 109))	('PIK3CA', 'Gene', (182, 188))	('CIC', 'Gene', '23152', (178, 181))	('CIC', 'Gene', (119, 122))	('PIK3CA', 'Gene', '5290', (145, 151))	('mutant', 'Var', (123, 129))	('IDH1', 'Gene', '3417', (164, 168))
147058	33769711	The improved prognosis of IDH1-M + CIC-M relative to other IDH1 mutant LGGs has been previously reported and has been independently characterized by p1/q19 co-deletions, which overlap highly with CIC mutations (Jiao et al, 2012; Brat et al, 2015; Cancer Genome Atlas Network, 2015d).	('CIC', 'Gene', (35, 38))	('IDH1', 'Gene', '3417', (59, 63))	('improved', 'PosReg', (4, 12))	('prognosis', 'MPA', (13, 22))	('Cancer', 'Disease', (247, 253))	('IDH1', 'Gene', (26, 30))	('Cancer', 'Disease', 'MESH:D009369', (247, 253))	('Cancer', 'Phenotype', 'HP:0002664', (247, 253))	('CIC', 'Gene', '23152', (196, 199))	('CIC', 'Gene', '23152', (35, 38))	('IDH1', 'Gene', (59, 63))	('IDH1', 'Gene', '3417', (26, 30))	('mutant', 'Var', (64, 70))	('CIC', 'Gene', (196, 199))
147059	33769711	We did not find literature evidence of the poor prognosis of IDH1 tumors harboring PIK3CA mutations in LGGs.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('IDH1 tumors', 'Disease', 'MESH:D009369', (61, 72))	('mutations', 'Var', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('IDH1 tumors', 'Disease', (61, 72))	('PIK3CA', 'Gene', (83, 89))	('PIK3CA', 'Gene', '5290', (83, 89))
147067	33769711	In our study, CDKN2A deletion and CDKN2A mutations were combined into a single hybrid event, resulting in a simple association between CDKN2A-MD status and poor PFI (Fig 9A).	('mutations', 'Var', (41, 50))	('CDKN2A', 'Gene', (135, 141))	('CDKN2A', 'Gene', '1029', (135, 141))	('CDKN2A', 'Gene', '1029', (14, 20))	('deletion', 'Var', (21, 29))	('CDKN2A', 'Gene', (34, 40))	('CDKN2A', 'Gene', '1029', (34, 40))	('PFI', 'molecular_function', 'GO:0034016', ('161', '164'))	('CDKN2A', 'Gene', (14, 20))
147071	33769711	For each tissue, we compared the total coverage of all statistically co-occurrent pairs identified by SELECT within a curated set of 505 pan-cancer mutations and CNVs (Mina et al, 2017), versus the coverages of the core rule sets identified by CRSO (Table 5).	('mutations', 'Var', (148, 157))	('core', 'cellular_component', 'GO:0019013', ('215', '219'))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('CNVs', 'Gene', (162, 166))
147081	33769711	Many driver alterations are recurrently identified by GISTIC2 and dNdScv in multiple different cancer types.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('alterations', 'Var', (12, 23))	('dNdScv', 'Chemical', '-', (66, 72))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
147102	33769711	We developed CRSO as a stochastic optimization procedure for predicting combinations of alterations that are minimally sufficient to drive cancer in individual patients.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('patients', 'Species', '9606', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('alterations', 'Var', (88, 99))	('cancer', 'Disease', (139, 145))
147119	33769711	However, many other types of alterations were omitted that may contribute to cancer formation, including germline alterations, arm level CNVs, gene fusions, chromosomal translocations, and epigenetic alterations.	('ntr', 'Gene', '4923', (65, 68))	('ntr', 'Gene', (65, 68))	('cancer', 'Disease', (77, 83))	('chromosomal', 'Disease', (157, 168))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('epigenetic alterations', 'Var', (189, 211))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('formation', 'biological_process', 'GO:0009058', ('84', '93'))	('gene fusions', 'Var', (143, 155))
147120	33769711	For example, TMPRSS2-ERG fusions are observed in 40% of prostate cancers (Cancer Genome Atlas Network, 2015b), and p1/q19 chromosomal co-deletions are observed in 30% of lower-grade gliomas (Brat et al, 2015).	('ERG', 'Gene', (21, 24))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('p1/q19', 'Var', (115, 121))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('TMPRSS2', 'Gene', '7113', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))	('ERG', 'Gene', '2078', (21, 24))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('TMPRSS2', 'Gene', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancers', 'Disease', 'MESH:D011471', (56, 72))	('Cancer', 'Disease', (74, 80))	('observed', 'Reg', (37, 45))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('prostate cancers', 'Phenotype', 'HP:0012125', (56, 72))	('gliomas', 'Disease', (182, 189))	('prostate cancers', 'Disease', (56, 72))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('gliomas', 'Disease', 'MESH:D005910', (182, 189))
147141	33769711	Similarly, deletion events take values in {Z, WD, SD}, corresponding to wild type, weak deletion (hemizygous), and strong deletion (homozygous).	('deletion', 'Var', (11, 19))	('deletion', 'Var', (122, 130))	('WD', 'Disease', 'MESH:D006527', (46, 48))
147145	33769711	Some tumors may contain one of many nonsense point mutations within TP53, whereas other tumors may contain a highly recurrent missense mutation, or a splice site mutation that produces an alternative isoform of the TP53 protein.	('tumors', 'Disease', (5, 11))	('missense mutation', 'Var', (126, 143))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('TP53', 'Gene', (215, 219))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', '7157', (215, 219))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('nonsense point mutations', 'Var', (36, 60))	('contain', 'Reg', (16, 23))	('tumors', 'Disease', (88, 94))	('TP53', 'Gene', (68, 72))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('contain', 'Reg', (99, 106))
147146	33769711	Although all of these alterations are TP53 mutations, they occur with very different passenger probabilities, sometimes spanning multiple orders of magnitude.	('TP53', 'Gene', (38, 42))	('alterations', 'Var', (22, 33))	('TP53', 'Gene', '7157', (38, 42))
147147	33769711	Silent mutations and intronic mutations do not lead to amino acid changes and by definition cannot be hotspots.	('ntr', 'Gene', (22, 25))	('Silent mutations', 'Var', (0, 16))	('ntr', 'Gene', '4923', (22, 25))
147153	33769711	Mutation rates for every possible amino acid substitution in each SMG were calculated as described in Cannataro et al (2018).	('SMG', 'Gene', (66, 69))	('SMG', 'Gene', '23034', (66, 69))	('amino acid substitution', 'Var', (34, 57))
147168	33769711	The entries of MG take values in {SD, WD, Z, WA, SA}, corresponding, respectively, to strong deletions (SD), weak deletions (WD), wild type (Z), weak amplifications (WA), and strong amplifications (SA).	('WD', 'Disease', 'MESH:D006527', (38, 40))	('weak deletions', 'Var', (109, 123))	('ntr', 'Gene', '4923', (5, 8))	('WD', 'Disease', 'MESH:D006527', (125, 127))	('ntr', 'Gene', (5, 8))
147242	33769711	For each cancer type, a set of common mutations was identified as the intersection of the SELECT pan-cancer mutations with the cancer-specific mutation events identified by dNdScv that were used in the CRSO analysis.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (108, 117))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('dNdScv', 'Chemical', '-', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
147244	33769711	In these cancers, large coverage discrepancies were observed in duos involving CDKN2A because SELECT encoded CDKN2A mutations as separate events from CDKN2A copy number loss.	('CDKN2A', 'Gene', '1029', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('CDKN2A', 'Gene', (150, 156))	('CDKN2A', 'Gene', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('CDKN2A', 'Gene', '1029', (150, 156))	('CDKN2A', 'Gene', '1029', (109, 115))	('mutations', 'Var', (116, 125))	('CDKN2A', 'Gene', (79, 85))
147270	32102537	Urothelial carcinomas with papillary patterns showed lower parameters of CDK4 and STAT3 expression compared to the non-papillary variant, with significant differences.	('Urothelial carcinomas', 'Disease', (0, 21))	('CDK4', 'Gene', '1019', (73, 77))	('papillary patterns', 'Var', (27, 45))	('papillary patterns', 'Phenotype', 'HP:0007482', (27, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('STAT3', 'Gene', '6774', (82, 87))	('Urothelial carcinomas', 'Disease', 'MESH:D014523', (0, 21))	('CDK', 'molecular_function', 'GO:0004693', ('73', '76'))	('parameters', 'MPA', (59, 69))	('STAT3', 'Gene', (82, 87))	('expression', 'MPA', (88, 98))	('lower', 'NegReg', (53, 58))	('CDK4', 'Gene', (73, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))
147272	32102537	Muscle invasion increases the level of CDK4 and STAT3 expression parameters, compared to non-muscle invasive UC.	('STAT3', 'Gene', (48, 53))	('CDK', 'molecular_function', 'GO:0004693', ('39', '42'))	('level', 'MPA', (30, 35))	('CDK4', 'Gene', '1019', (39, 43))	('CDK4', 'Gene', (39, 43))	('Muscle', 'Var', (0, 6))	('increases', 'PosReg', (16, 25))	('STAT3', 'Gene', '6774', (48, 53))
147320	32102537	Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity.	('represses', 'NegReg', (63, 72))	('SMAD3', 'Gene', (20, 25))	('cell-cycle', 'biological_process', 'GO:0007049', ('31', '41'))	('phosphorylates', 'Var', (5, 19))	('transcriptional activity', 'MPA', (77, 101))	('SMAD3', 'Gene', '4088', (20, 25))
147333	32102537	Muscle invasion increases the level of CDK4 expression parameters, compared to non-muscle invasive UC.	('CDK', 'molecular_function', 'GO:0004693', ('39', '42'))	('CDK4', 'Gene', '1019', (39, 43))	('CDK4', 'Gene', (39, 43))	('Muscle', 'Var', (0, 6))	('increases', 'PosReg', (16, 25))	('level of', 'MPA', (30, 38))
147350	32102537	In our current study we have demonstrated that urothelial carcinomas with papillary patterns showed lower parameters of STAT3 expression compared to the non-papillary variant, with significant differences for STAT3 intensity (p<0.05), percent (p<0.01) and score (p<0.01).	('score', 'MPA', (256, 261))	('differences', 'Reg', (193, 204))	('urothelial carcinomas', 'Disease', (47, 68))	('lower', 'NegReg', (100, 105))	('parameters', 'MPA', (106, 116))	('STAT3', 'Gene', '6774', (209, 214))	('STAT3', 'Gene', '6774', (120, 125))	('percent', 'MPA', (235, 242))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (47, 68))	('papillary patterns', 'Var', (74, 92))	('STAT3', 'Gene', (209, 214))	('STAT3', 'Gene', (120, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('papillary patterns', 'Phenotype', 'HP:0007482', (74, 92))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
147421	28469388	Significant Prognostic Features and Patterns of Somatic TP53 Mutations in Human Cancers TP53 is the most frequently altered gene in human cancers.	('Cancers', 'Disease', 'MESH:D009369', (80, 87))	('TP53', 'Gene', '7157', (56, 60))	('Mutations', 'Var', (61, 70))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('TP53', 'Gene', (56, 60))	('TP53', 'Gene', '7157', (88, 92))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('human', 'Species', '9606', (132, 137))	('Human', 'Species', '9606', (74, 79))	('Cancers', 'Disease', (80, 87))	('TP53', 'Gene', (88, 92))	('cancers', 'Disease', (138, 145))	('Cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
147422	28469388	Numerous retrospective studies have related its mutation and abnormal p53 protein expression to poor patient survival.	('p53', 'Gene', '7157', (70, 73))	('p53', 'Gene', (70, 73))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('mutation', 'Var', (48, 56))	('patient', 'Species', '9606', (101, 108))
147426	28469388	They include the following: (1) similar to previously reported cases in breast cancer, the mutations in exons 1 to 4 of TP53 were more lethal than those in exons 5 to 9 for the patients with lung adenocarcinomas; (2) TP53 mutants tended to be negatively selected in mammalian evolution, but the evolutionary conservation had various clinical implications for different cancers; (3) conserved correlation patterns (ie, consistent co-occurrence or consistent mutual exclusivity) between TP53 mutations and the alterations in several other cancer genes (ie, PIK3CA, PTEN, KRAS, APC, CDKN2A, and ATM) were present in several cancers in which prognosis was associated with TP53 status and/or the mutational characteristics; (4) among TP53-mutated tumors, the total mutation burden in other driver genes was a predictive signature (P < .05, false discovery rate <0.11) for better patient survival outcome in several cancer types, including glioblastoma multiforme.	('TP53', 'Gene', '7157', (217, 221))	('KRAS', 'Gene', '3845', (569, 573))	('cancers', 'Phenotype', 'HP:0002664', (369, 376))	('cancers', 'Disease', (369, 376))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (191, 211))	('TP53', 'Gene', '7157', (668, 672))	('carcinomas', 'Phenotype', 'HP:0030731', (201, 211))	('TP53', 'Gene', (729, 733))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('false', 'biological_process', 'GO:0071878', ('835', '840'))	('cancers', 'Phenotype', 'HP:0002664', (621, 628))	('breast cancer', 'Disease', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (910, 916))	('cancers', 'Disease', (621, 628))	('cancer', 'Disease', (621, 627))	('to 9', 'Species', '1214577', (164, 168))	('TP53', 'Gene', '7157', (120, 124))	('KRAS', 'Gene', (569, 573))	('PTEN', 'Gene', '5728', (563, 567))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('cancer', 'Disease', 'MESH:D009369', (537, 543))	('TP53', 'Gene', '7157', (485, 489))	('glioblastoma', 'Phenotype', 'HP:0012174', (934, 946))	('patient', 'Species', '9606', (874, 881))	('lung adenocarcinomas', 'Disease', (191, 211))	('cancer', 'Phenotype', 'HP:0002664', (621, 627))	('ATM', 'Gene', '472', (592, 595))	('PIK3CA', 'Gene', '5290', (555, 561))	('tumors', 'Phenotype', 'HP:0002664', (742, 748))	('CDKN2A', 'Gene', (580, 586))	('better', 'PosReg', (867, 873))	('glioblastoma multiforme', 'Disease', (934, 957))	('cancer', 'Disease', (79, 85))	('APC', 'cellular_component', 'GO:0005680', ('575', '578'))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (934, 957))	('TP53', 'Gene', (485, 489))	('tumor', 'Phenotype', 'HP:0002664', (742, 747))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('TP53', 'Gene', (217, 221))	('tumors', 'Disease', (742, 748))	('cancers', 'Disease', 'MESH:D009369', (369, 376))	('TP53', 'Gene', '7157', (729, 733))	('CDKN2A', 'Gene', '1029', (580, 586))	('cancers', 'Disease', 'MESH:D009369', (621, 628))	('mammalian', 'Species', '9606', (266, 275))	('TP53', 'Gene', (668, 672))	('cancer', 'Disease', (910, 916))	('cancer', 'Disease', 'MESH:D009369', (621, 627))	('APC', 'Disease', 'MESH:D011125', (575, 578))	('APC', 'Disease', (575, 578))	('PIK3CA', 'Gene', (555, 561))	('TP53', 'Gene', (120, 124))	('false', 'biological_process', 'GO:0071877', ('835', '840'))	('ATM', 'Gene', (592, 595))	('cancer', 'Disease', (369, 375))	('cancer', 'Phenotype', 'HP:0002664', (910, 916))	('cancer', 'Disease', (537, 543))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('patients', 'Species', '9606', (177, 185))	('patient', 'Species', '9606', (177, 184))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (191, 211))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('cancer', 'Phenotype', 'HP:0002664', (537, 543))	('tumors', 'Disease', 'MESH:D009369', (742, 748))	('mutation', 'Var', (760, 768))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('PTEN', 'Gene', (563, 567))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (191, 210))
147427	28469388	Among these findings, the fourth is of special significance as it suggested the potential existence of epistatic interaction effects among the mutations in different cancer driver genes on clinical outcomes.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('mutations', 'Var', (143, 152))
147430	28469388	Loss or disruption of p53 function due to a mutation can lead to uncontrolled cell proliferation and cancer.	('cell proliferation', 'biological_process', 'GO:0008283', ('78', '96'))	('uncontrolled cell proliferation', 'CPA', (65, 96))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('disruption', 'NegReg', (8, 18))	('mutation', 'Var', (44, 52))	('function', 'MPA', (26, 34))	('cancer', 'Disease', (101, 107))	('p53', 'Gene', (22, 25))	('lead to', 'Reg', (57, 64))	('Loss', 'NegReg', (0, 4))	('p53', 'Gene', '7157', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
147431	28469388	Some p53 mutants gain new functions, exhibit oncogenic properties, and exert a dominant negative effect by preventing wild-type (WT) p53 from binding to the promoter of its target genes.	('negative', 'NegReg', (88, 96))	('preventing', 'NegReg', (107, 117))	('oncogenic', 'CPA', (45, 54))	('binding', 'molecular_function', 'GO:0005488', ('142', '149'))	('p53', 'Gene', '7157', (133, 136))	('mutants', 'Var', (9, 16))	('p53', 'Gene', (5, 8))	('binding', 'Interaction', (142, 149))	('p53', 'Gene', '7157', (5, 8))	('functions', 'MPA', (26, 35))	('p53', 'Gene', (133, 136))	('gain', 'PosReg', (17, 21))
147432	28469388	Aberrations in TP53 could cause a burst of somatic mutations in tumor cells, disrupting the age-related accumulation patterns.	('disrupting', 'NegReg', (77, 87))	('cause', 'Reg', (26, 31))	('tumor', 'Disease', (64, 69))	('somatic mutations', 'MPA', (43, 60))	('age-related accumulation patterns', 'MPA', (92, 125))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('Aberrations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
147434	28469388	Most somatic TP53 mutations are single-base substitutions distributed throughout exons 5 to 8.	('TP53', 'Gene', '7157', (13, 17))	('TP53', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
147435	28469388	Notably, about 20% of these mutations alter 1 of 3 codons (175, 248, or 273) of the 393 amino acids in p53 protein.	('p53', 'Gene', '7157', (103, 106))	('p53', 'Gene', (103, 106))	('protein', 'Protein', (107, 114))	('alter', 'Reg', (38, 43))	('mutations', 'Var', (28, 37))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
147437	28469388	Numerous retrospective studies have associated its mutation and abnormal p53 protein expression with poor patient survival.	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('patient', 'Species', '9606', (106, 113))	('mutation', 'Var', (51, 59))
147441	28469388	Beyond the genotypes, more prognostic value of mutations in TP53 may be hidden in their tumor-specific characteristics as well as the interaction with other genomic aberrations.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('mutations', 'Var', (47, 56))	('TP53', 'Gene', '7157', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('TP53', 'Gene', (60, 64))
147442	28469388	Skaug et al and Huang et al showed that for patients with non-small cell lung cancer (NSCLC), mutations in exon 8 of the TP53 gene were more fatal than those in exons 5 and 7.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (58, 84))	('patients', 'Species', '9606', (44, 52))	('NSCLC', 'Disease', (86, 91))	('mutations in exon 8', 'Var', (94, 113))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (58, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('non-small cell lung cancer', 'Disease', (58, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (62, 84))
147443	28469388	Molina-Vila et al found that nondisruptive p53 mutations, including in-frame deletions outside of the L2 and L3 loop domains and missense single-base substitutions, were associated with shorter survival in patients with NSCLC.	('NSCLC', 'Disease', (220, 225))	('deletions', 'Var', (77, 86))	('missense single-base substitutions', 'Var', (129, 163))	('survival', 'MPA', (194, 202))	('mutations', 'Var', (47, 56))	('NSCLC', 'Disease', 'MESH:D002289', (220, 225))	('patients', 'Species', '9606', (206, 214))	('shorter', 'NegReg', (186, 193))	('NSCLC', 'Phenotype', 'HP:0030358', (220, 225))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))
147444	28469388	Contrary to this finding in NSCLC, several studies on head and neck squamous cell carcinomas (HNSCs) showed that tumors containing mutations in the DNA-binding regions (L2, L3, and loop-sheet-helix domains) of TP53 led to a significantly worse prognosis and response to radiotherapy than tumors outside those regions.	('tumors', 'Disease', (113, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('TP53', 'Gene', (210, 214))	('response to radiotherapy', 'CPA', (258, 282))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('HNSCs', 'Phenotype', 'HP:0012288', (94, 99))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (68, 92))	('DNA-binding', 'molecular_function', 'GO:0003677', ('148', '159'))	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('NSCLC', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('neck', 'cellular_component', 'GO:0044326', ('63', '67'))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (54, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('TP53', 'Gene', '7157', (210, 214))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('mutations', 'Var', (131, 140))	('neck squamous cell carcinomas', 'Disease', (63, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (63, 92))	('worse', 'NegReg', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', (288, 294))
147445	28469388	A recent publication reported that the combination of TP53 mutation and loss of chromosome 3p associated with a remarkable decrease in short-period survival rates for patients with HNSC.	('HNSC', 'Disease', (181, 185))	('loss', 'NegReg', (72, 76))	('decrease', 'NegReg', (123, 131))	('short-period survival rates', 'CPA', (135, 162))	('patients', 'Species', '9606', (167, 175))	('chromosome', 'cellular_component', 'GO:0005694', ('80', '90'))	('TP53', 'Gene', '7157', (54, 58))	('mutation', 'Var', (59, 67))	('TP53', 'Gene', (54, 58))
147447	28469388	Our analysis was primarily focused on several less investigated features of the mutation spectra, such as the evolutionary selection of mutant alleles in TP53 during mammalian evolution, with an extension to the pan-cancer patterns of exclusivity and co-occurrence relationships between TP53 mutations and the alterations in other cancer driver genes.	('mutations', 'Var', (292, 301))	('cancer', 'Disease', (331, 337))	('TP53', 'Gene', (154, 158))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('mammalian', 'Species', '9606', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('TP53', 'Gene', '7157', (287, 291))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('mutant', 'Var', (136, 142))	('TP53', 'Gene', '7157', (154, 158))	('TP53', 'Gene', (287, 291))
147454	28469388	The mutational association (or relationship) between TP53 and another gene was measured by the Yule phi coefficient (a Pearson correlation applied to dichotomous data) between the numbered genotypes (1 and 0 were assigned to mutant and WT, respectively).	('mutant', 'Var', (225, 231))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))
147456	28469388	Among the 33 cancer types with clinically annotated multiomic data available at TCGA database by April 24, 2015, 12 were studied in this work by considering the genetic diversity of patients and the prevalence of somatic TP53 mutations in these tumors.	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('TP53', 'Gene', '7157', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('TP53', 'Gene', (221, 225))	('patients', 'Species', '9606', (182, 190))	('mutations', 'Var', (226, 235))	('tumors', 'Disease', (245, 251))
147457	28469388	Each of the selected cancer types had at least 14 patients from a minority population (ie, black American or Asian) besides the dominant white Americans, and the ratio of samples with TP53 nonsynonymous mutations was more than 25% (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('patients', 'Species', '9606', (50, 58))	('nonsynonymous mutations', 'Var', (189, 212))	('TP53', 'Gene', '7157', (184, 188))	('TP53', 'Gene', (184, 188))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
147461	28469388	In the modeling, TP53 (p53) status (ie, WT versus mutant) was treated as the stratification factor of primary interest and the patient age at the initial clinical date was included as a covariate.	('patient', 'Species', '9606', (127, 134))	('mutant', 'Var', (50, 56))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
147462	28469388	The results demonstrated association between TP53 mutation and overall poor patient survival in 4 cancer types, namely, HNSC, LUAD, BRCA, and COAD (Supplementary Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('COAD', 'Disease', 'MESH:D029424', (142, 146))	('LUAD', 'Phenotype', 'HP:0030078', (126, 130))	('LUAD', 'Disease', (126, 130))	('TP53', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (45, 49))	('BRCA', 'Gene', '672', (132, 136))	('poor', 'NegReg', (71, 75))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('BRCA', 'Gene', (132, 136))	('COAD', 'Disease', (142, 146))	('cancer', 'Disease', (98, 104))	('association', 'Reg', (25, 36))	('patient', 'Species', '9606', (76, 83))	('HNSC', 'Disease', (120, 124))	('mutation', 'Var', (50, 58))
147464	28469388	We depicted the physical distributions of TP53 mutations over the coding regions in Supplementary Figure 2.	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))
147466	28469388	Occasionally, mutations also occurred in exons 2, 3, and 9 in these cancer types.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('occurred', 'Reg', (29, 37))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('mutations', 'Var', (14, 23))
147468	28469388	Powell et al found that mutations within exon 4 were particularly associated with poor prognosis in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('associated', 'Reg', (66, 76))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('mutations', 'Var', (24, 33))
147470	28469388	The result showed that for patients with BRCA and LUAD, the mutations in exons 2 to 4 were more lethal than those in other exons (Figure 1).	('BRCA', 'Gene', (41, 45))	('lethal', 'Reg', (96, 102))	('LUAD', 'Disease', (50, 54))	('patients', 'Species', '9606', (27, 35))	('LUAD', 'Phenotype', 'HP:0030078', (50, 54))	('mutations', 'Var', (60, 69))	('BRCA', 'Phenotype', 'HP:0003002', (41, 45))	('BRCA', 'Gene', '672', (41, 45))
147471	28469388	In BRCA, the P values were less than 2 x 10-5 (Benjamini-Hochberg FDR <2 x 10-4) in the comparison of E2-4 vs WT and larger than 0.05 in the comparison of E5-9 vs WT.	('BRCA', 'Gene', '672', (3, 7))	('BRCA', 'Gene', (3, 7))	('E2-4', 'Var', (102, 106))	('E5-9', 'Gene', '22899', (155, 159))	('E5-9', 'Gene', (155, 159))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))
147475	28469388	Therefore, the TP53 mutations observed in human tumors could be subject to the natural selection mechanisms during mammalian evolution.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mammalian', 'Species', '9606', (115, 124))	('human', 'Species', '9606', (42, 47))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))
147477	28469388	We found that cancer-related TP53 variants tended to be negatively selected in the evolution of mammals.	('cancer', 'Disease', (14, 20))	('variants', 'Var', (34, 42))	('negatively', 'NegReg', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
147479	28469388	Second, of the DNA bases in which the somatic mutations arose, those with PhyloP scores more than 1.301 accounted for a large proportion consistently across the 12 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('mutations', 'Var', (46, 55))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))
147480	28469388	The ratio was ~40% higher than that of the entire base set of exons 4 to 9, in which more than 99% of the somatic mutations in tumors were located.	('to 9', 'Species', '1214577', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', (127, 133))	('mutations', 'Var', (114, 123))	('tumors', 'Disease', 'MESH:D009369', (127, 133))
147481	28469388	We were particularly interested in the potential prognostic implications of the evolutionary conservation of somatic TP53 mutants.	('TP53', 'Gene', '7157', (117, 121))	('mutants', 'Var', (122, 129))	('TP53', 'Gene', (117, 121))
147482	28469388	As such, based on the presence or absence of a negatively selected TP53 variant in mammalian evolution, we partitioned the TP53-mutated samples of each cancer type into 2 groups (Con and nCon) and then performed survival analysis with this classification as the stratification factor of primary interest.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('variant', 'Var', (72, 79))	('mammalian', 'Species', '9606', (83, 92))	('TP53', 'Gene', (123, 127))
147490	28469388	We found that there existed a "conserved" pattern (Figure 5) in the mutual-exclusivity and co-occurrence relationships between TP53 mutations and the alterations of these genes.	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('mutations', 'Var', (132, 141))
147491	28469388	That is, the mutational associations for a specific gene pair were always in the same category, co-occurrence or mutual-exclusivity, across the cancer types.	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mutational', 'Var', (13, 23))
147493	28469388	We further noted that these significant relationships were primarily present in several cancers where patient outcome was associated with TP53 status and/or the positional and evolutionary characteristics of the mutations, as shown in Supplementary Figure 1, Figure 1, and Figure 2.	('associated', 'Reg', (122, 132))	('TP53', 'Gene', '7157', (138, 142))	('patient', 'Species', '9606', (102, 109))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('TP53', 'Gene', (138, 142))	('cancers', 'Disease', (88, 95))	('mutations', 'Var', (212, 221))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
147495	28469388	It is well known that most cancers, including those with mutated TP53, are driven by multiple genetic mutations.	('driven by', 'Reg', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('mutated', 'Var', (57, 64))	('cancers', 'Disease', (27, 34))
147496	28469388	Therefore, a general TP53-involved co-occurrence mutation pattern (or model) can be expressed by [Mp53, Mother], where Mp53 is the genotype (ie, mutant and WT) of TP53 gene in a tumor and Mother is the number of mutations on other cancer driver genes.	('TP53', 'Gene', (21, 25))	('tumor', 'Disease', (178, 183))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('p53', 'Gene', '7157', (120, 123))	('mutant', 'Var', (145, 151))	('TP53', 'Gene', '7157', (163, 167))	('cancer', 'Disease', (231, 237))	('TP53', 'Gene', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('p53', 'Gene', '7157', (99, 102))	('p53', 'Gene', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('p53', 'Gene', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('TP53', 'Gene', '7157', (21, 25))
147499	28469388	Notably, this finding indicates that TP53 mutation is also related to the prognosis of OV tumors, whereas the relevance cannot be detected by directly analyzing the association between TP53 genotypes (and other mutational features) and the survival times of patients.	('TP53', 'Gene', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('TP53', 'Gene', '7157', (37, 41))	('OV', 'Phenotype', 'HP:0012887', (87, 89))	('OV tumors', 'Disease', 'MESH:D009369', (87, 96))	('mutation', 'Var', (42, 50))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('patients', 'Species', '9606', (258, 266))	('related', 'Reg', (59, 66))	('TP53', 'Gene', (37, 41))	('OV tumors', 'Disease', (87, 96))	('TP53', 'Gene', '7157', (185, 189))
147501	28469388	In this study, we found that the mutations in exons 2 to 4 of TP53 gene defined a poor prognosis group in BRCA and LUAD.	('BRCA', 'Gene', (106, 110))	('TP53', 'Gene', '7157', (62, 66))	('TP53', 'Gene', (62, 66))	('mutations in', 'Var', (33, 45))	('LUAD', 'Phenotype', 'HP:0030078', (115, 119))	('LUAD', 'Disease', (115, 119))	('BRCA', 'Phenotype', 'HP:0003002', (106, 110))	('BRCA', 'Gene', '672', (106, 110))
147503	28469388	Meanwhile, we noticed that prevalence of mutations in these exon regions was an important characteristic of several cancers, including HNSC, LUAD, LUSC, BRCA, and STAD, where drinking and smoking are 2 common risk factors.	('mutations', 'Var', (41, 50))	('LUAD', 'Phenotype', 'HP:0030078', (141, 145))	('BRCA', 'Phenotype', 'HP:0003002', (153, 157))	('LUSC', 'Phenotype', 'HP:0030359', (147, 151))	('LUAD', 'Disease', (141, 145))	('STAD', 'Disease', (163, 167))	('HNSC', 'Disease', (135, 139))	('BRCA', 'Gene', '672', (153, 157))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('BRCA', 'Gene', (153, 157))	('LUSC', 'Disease', (147, 151))
147504	28469388	Due to this finding, an interesting question worth further study is whether alcohol and/or tobacco is a specific mutagen responsible for the alterations in exons 2 to 4 of TP53 gene.	('tobacco', 'Species', '4097', (91, 98))	('alcohol', 'Chemical', 'MESH:D000438', (76, 83))	('alterations', 'Var', (141, 152))	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (172, 176))
147505	28469388	Our analysis shows that TP53 variants tend to be negatively selected in the evolution of mammals.	('TP53', 'Gene', (24, 28))	('negatively', 'NegReg', (49, 59))	('variants', 'Var', (29, 37))	('TP53', 'Gene', '7157', (24, 28))
147506	28469388	While being consistent with the existing knowledge that recurrent mutations in tumors can be differentiated from single mutations by the evolutionary conservation-based functional impact score, this observation cannot be sufficiently explained by the survival disadvantage that is exerted on the carrier of the mutations (in a specific species) by the increased risk of cancer.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('cancer', 'Disease', (370, 376))	('mutations', 'Var', (311, 320))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('carrier', 'molecular_function', 'GO:0005215', ('296', '303'))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))
147508	28469388	As a result, the survival disadvantage of the individuals with a germline mutation burden in TP53 gene is not equivalent to a lower fitness in evolution.	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('germline mutation burden', 'Var', (65, 89))
147509	28469388	In this regard, the negative selection of TP53 mutants may involve reproduction-related mechanisms that could be interrupted by the loss or disruption of p53 function in DNA repair.	('DNA repair', 'biological_process', 'GO:0006281', ('170', '180'))	('TP53', 'Gene', '7157', (42, 46))	('negative', 'NegReg', (20, 28))	('TP53', 'Gene', (42, 46))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('reproduction', 'biological_process', 'GO:0000003', ('67', '79'))	('mutants', 'Var', (47, 54))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))
147510	28469388	This hypothesis is supported by the varied clinical implications of a TP53 mutation occurred in evolutionarily conserved DNA bases for different cancers (Figure 3).	('cancers', 'Disease', (145, 152))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('TP53', 'Gene', '7157', (70, 74))	('mutation', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('TP53', 'Gene', (70, 74))	('cancers', 'Disease', 'MESH:D009369', (145, 152))
147511	28469388	In particular, the favorable prognosis of the BLCA patients with mutations in conserved sites of TP53 sequence suggests that the lower evolutionary fitness of TP53 mutants cannot be simply attributed to the cancer-caused death.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('TP53', 'Gene', '7157', (97, 101))	('cancer', 'Disease', (207, 213))	('TP53', 'Gene', '7157', (159, 163))	('TP53', 'Gene', (97, 101))	('TP53', 'Gene', (159, 163))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('patients', 'Species', '9606', (51, 59))	('death', 'Disease', 'MESH:D003643', (221, 226))	('evolutionary fitness', 'CPA', (135, 155))	('mutants', 'Var', (164, 171))	('mutations in', 'Var', (65, 77))	('death', 'Disease', (221, 226))
147512	28469388	Mutual exclusivity and co-occurrence of genomic alterations have been heavily studied in the past years.. A proposed naive rule is that mutations in genes functioning in different pathways can occur in the same cancer, whereas those in genes functioning in the same pathway are rarely mutated in the same sample.	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (211, 217))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('occur', 'Reg', (193, 198))
147513	28469388	Our work showed that the rule was systematically violated when the analysis was focused on the specific relationships between TP53 mutations and genetic alterations occurred in several other major cancer driver genes (ie, PIK3CA, PTEN, KRAS, APC, CDKN2A, and ATM).	('PTEN', 'Gene', '5728', (230, 234))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('TP53', 'Gene', (126, 130))	('KRAS', 'Gene', (236, 240))	('APC', 'cellular_component', 'GO:0005680', ('242', '245'))	('PIK3CA', 'Gene', '5290', (222, 228))	('CDKN2A', 'Gene', (247, 253))	('ATM', 'Gene', '472', (259, 262))	('APC', 'Disease', 'MESH:D011125', (242, 245))	('TP53', 'Gene', '7157', (126, 130))	('APC', 'Disease', (242, 245))	('cancer', 'Disease', (197, 203))	('CDKN2A', 'Gene', '1029', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('PTEN', 'Gene', (230, 234))	('PIK3CA', 'Gene', (222, 228))	('mutations', 'Var', (131, 140))	('ATM', 'Gene', (259, 262))	('KRAS', 'Gene', '3845', (236, 240))
147517	28469388	Another example, PIK3CA gene plays roles in the PI3K/ART pathway, which regulates cell proliferation and apoptosis in a different manner from the p53 pathway, but, our results showed that the alterations in PIK3CA and TP53 tended to occur in a mutually exclusive way within 4 cancers (ie, BRCA, STAT, COAD, and HNSC).	('BRCA', 'Phenotype', 'HP:0003002', (289, 293))	('occur', 'Reg', (233, 238))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('p53', 'Gene', (146, 149))	('man', 'Species', '9606', (130, 133))	('PIK3CA', 'Gene', '5290', (17, 23))	('COAD', 'Disease', 'MESH:D029424', (301, 305))	('PI3K', 'molecular_function', 'GO:0016303', ('48', '52'))	('STAT', 'Disease', (295, 299))	('PIK3CA', 'Gene', '5290', (207, 213))	('BRCA', 'Gene', '672', (289, 293))	('apoptosis', 'biological_process', 'GO:0097194', ('105', '114'))	('apoptosis', 'biological_process', 'GO:0006915', ('105', '114'))	('TP53', 'Gene', (218, 222))	('alterations', 'Var', (192, 203))	('COAD', 'Disease', (301, 305))	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('cell proliferation', 'biological_process', 'GO:0008283', ('82', '100'))	('PIK3CA', 'Gene', (17, 23))	('BRCA', 'Gene', (289, 293))	('cancers', 'Disease', (276, 283))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('PIK3CA', 'Gene', (207, 213))	('p53', 'Gene', '7157', (146, 149))	('TP53', 'Gene', '7157', (218, 222))
147519	28469388	Underlying this prognostic stratification are the intrinsic subtypes (within the same cancer) that are approximately determined by the mutations in TP53 and the other driver genes such as PIK3CA.	('PIK3CA', 'Gene', (188, 194))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('mutations', 'Var', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('PIK3CA', 'Gene', '5290', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
147520	28469388	In most cancer types, an average tumor sample contains at least half of hundreds of nonsynonymous somatic alterations, including a few cancer driver mutations that are fixed by conferring the recipient cells' fitness advantage and numerous passenger mutations that are fixed by the Muller ratchet and hitchhiking.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', (8, 14))	('mutations', 'Var', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
147521	28469388	However, a recently emerging theory proposes that some passenger mutations could be deleterious to the host cells and their accumulation may build strength to alter cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('accumulation', 'PosReg', (124, 136))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('alter', 'Reg', (159, 164))	('mutations', 'Var', (65, 74))
147522	28469388	Our previous analyses of TCGA data suggested that some passenger mutations would exert significant impacts on the resistance of cancer cells to the treatments in ovarian carcinomas.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('impacts', 'Reg', (99, 106))	('ovarian carcinomas', 'Disease', (162, 180))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (162, 180))	('resistance', 'CPA', (114, 124))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (162, 180))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('mutations', 'Var', (65, 74))	('cancer', 'Disease', (128, 134))
147524	28469388	Significant interactive effects of cancer driver mutations and passenger mutations on the clinical outcome of patients was implied by another recent publication, which showed that high mutation number forecasted a remarkably favorable outcome in ovarian patients carrying mutations in BRCA1 and BRCA2 genes.	('mutations', 'Var', (272, 281))	('BRCA2', 'Gene', '675', (295, 300))	('ovarian', 'Disease', 'MESH:D010051', (246, 253))	('BRCA1', 'Gene', '672', (285, 290))	('patients', 'Species', '9606', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('BRCA1', 'Gene', (285, 290))	('ovarian', 'Disease', (246, 253))	('BRCA2', 'Gene', (295, 300))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('BRCA', 'Phenotype', 'HP:0003002', (295, 299))	('patients', 'Species', '9606', (254, 262))	('cancer', 'Disease', (35, 41))	('BRCA', 'Phenotype', 'HP:0003002', (285, 289))
147527	28469388	Second, for the first time (to our knowledge), it suggested the potential existence of epistatic effects between the mutations in different cancer driver genes on clinical outcomes.	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutations', 'Var', (117, 126))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))
147529	28469388	In summary, through an integrative analysis of the genomic and clinical data of 12 cancers generated by TCGA, we pinpointed a set of significant prognostic features and patterns of somatic TP53 mutations.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('TP53', 'Gene', '7157', (189, 193))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('TP53', 'Gene', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutations', 'Var', (194, 203))	('TCGA', 'Gene', (104, 108))	('cancers', 'Disease', (83, 90))
147570	27390610	One-fourth of patients had variant component in their histology, comprised of 23 squamous, 7 glandular, 3 micropapillary, and 3 sarcomatoid differentiation.	('sarcomatoid', 'Disease', (128, 139))	('sarcomatoid', 'Disease', 'MESH:C538614', (128, 139))	('variant', 'Var', (27, 34))	('squamous', 'Disease', (81, 89))	('glandular', 'Disease', (93, 102))	('patients', 'Species', '9606', (14, 22))
147578	27390610	Subgroup analysis showed age   60 years (HR: 0.38, 95% CI: 0.12-0.97), PUC (HR: 0.56, 95% CI: 0.34-0.90), >1 metastatic sites (HR: 0.19, 95% CI: 0.08-0.44) and NLR>3 (HR: 0.45, 95% CI: 0.25-0.81) have strong prognostic benefits toward MVAC, while VUC (HR: 0.56, 95% CI: 0.34-0.90) significantly prolongs survival toward GC.	('GC', 'Chemical', '-', (320, 322))	('survival', 'MPA', (304, 312))	('MVAC', 'Chemical', '-', (235, 239))	('prolongs', 'PosReg', (295, 303))	('VUC', 'Var', (247, 250))	('benefits', 'PosReg', (219, 227))	('MVAC', 'Disease', (235, 239))
147587	27390610	Numerous efforts have identified the poor prognostic roles of histologic variant for bladder cancer after radical surgery.	('bladder cancer', 'Phenotype', 'HP:0009725', (85, 99))	('histologic variant', 'Var', (62, 80))	('bladder cancer', 'Disease', 'MESH:D001749', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('bladder cancer', 'Disease', (85, 99))
147607	25042800	High frequency of TERT promoter mutation in small cell carcinoma of bladder, but not in small cell carcinoma of other origins TERT promoter mutations were recently discovered in melanoma by next generation sequencing.	('small cell carcinoma', 'Phenotype', 'HP:0030357', (88, 108))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (44, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('TERT', 'Gene', (126, 130))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('TERT', 'Gene', (18, 22))	('TERT', 'Gene', '7015', (126, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('TERT', 'Gene', '7015', (18, 22))	('mutation', 'Var', (32, 40))	('carcinoma of bladder', 'Disease', 'MESH:D001749', (55, 75))	('carcinoma of bladder', 'Disease', (55, 75))
147608	25042800	Subsequently, several malignancies including urothelial carcinoma were also found to be associated with the same TERT promoter mutations.	('malignancies', 'Disease', 'MESH:D009369', (22, 34))	('TERT', 'Gene', '7015', (113, 117))	('malignancies', 'Disease', (22, 34))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (45, 65))	('associated', 'Reg', (88, 98))	('mutations', 'Var', (127, 136))	('urothelial carcinoma', 'Disease', (45, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('TERT', 'Gene', (113, 117))
147610	25042800	Despite the frequent occurrence of TERT promoter mutations in urothelial carcinoma, the incidence of the mutations in SCC of the urinary bladder is unknown.	('mutations', 'Var', (49, 58))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (62, 82))	('SCC', 'Gene', (118, 121))	('SCC', 'Gene', '6317', (118, 121))	('TERT', 'Gene', (35, 39))	('SCC', 'Phenotype', 'HP:0030357', (118, 121))	('TERT', 'Gene', '7015', (35, 39))	('urothelial carcinoma', 'Disease', (62, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
147618	25042800	All (11/11) SCC of the urinary bladder bear TERT promoter mutation C228T.	('TERT', 'Gene', (44, 48))	('C228T', 'Mutation', 'rs1020833107', (67, 72))	('TERT', 'Gene', '7015', (44, 48))	('SCC', 'Phenotype', 'HP:0030357', (12, 15))	('C228T', 'Var', (67, 72))	('SCC', 'Gene', (12, 15))	('urinary bladder', 'Disease', (23, 38))	('SCC', 'Gene', '6317', (12, 15))
147619	25042800	Neither of SCC from all other origins nor matched non-neoplastic tissue contains the TERT promoter mutations.	('SCC', 'Gene', (11, 14))	('TERT', 'Gene', (85, 89))	('SCC', 'Phenotype', 'HP:0030357', (11, 14))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (54, 71))	('TERT', 'Gene', '7015', (85, 89))	('SCC', 'Gene', '6317', (11, 14))	('mutations', 'Var', (99, 108))
147639	25042800	Recently, two studies reported  a high frequency (approximately 70%) somatic mutation in the TERT promoter in melanoma at positions 1,295,228 (C228T) and 1,295,250 (C250T).	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('C228T', 'Var', (143, 148))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('C250T', 'Var', (165, 170))	('C250T', 'Mutation', 'rs541791751', (165, 170))	('C228T', 'Mutation', 'rs1020833107', (143, 148))	('TERT', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (93, 97))
147640	25042800	These mutations create consensus binding motifs for E-twenty six (ETS)/ternary complex factor (TCF) transcription factors (GGA[A/T] or CCGGAA), leading to increased TERT promoter activity.	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('increased', 'PosReg', (155, 164))	('TERT', 'Gene', (165, 169))	('TERT', 'Gene', '7015', (165, 169))	('transcription', 'biological_process', 'GO:0006351', ('100', '113'))	('TCF', 'Gene', (95, 98))	('TCF', 'Gene', '3172', (95, 98))	('binding', 'Interaction', (33, 40))	('mutations', 'Var', (6, 15))
147641	25042800	Subsequently, theses mutations have been found to be associated with different types of cancer, including urothelial carcinoma, but not in other common carcinoma, such as: lung, prostate, breast and cervical cancers .	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', (208, 214))	('carcinoma', 'Disease', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast and cervical cancers', 'Disease', 'MESH:D001943', (188, 215))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (106, 126))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('associated', 'Reg', (53, 63))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('carcinoma', 'Disease', 'MESH:D002277', (152, 161))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinoma', 'Disease', (117, 126))	('prostate', 'Disease', (178, 186))	('mutations', 'Var', (21, 30))	('lung', 'Disease', (172, 176))	('urothelial carcinoma', 'Disease', (106, 126))	('carcinoma', 'Disease', 'MESH:D002277', (117, 126))
147646	25042800	A fragment of the TERT promoter was amplified by polymerase chain reaction (PCR) using primers 5'-CAGCGCTGCCTGAAACTC-3' (sense) and 5'-GTCCTGCCCCTTCACCTT-3' (antisense), resulting in a PCR product of 163 bp, which contained the sites of C228T and C250T mutations(chr5: 1,295,228; chr5: 1,295,250, respectively; hg19).	("5'-CAGCGCTGCCTGAAACTC-3", 'Chemical', '-', (95, 118))	("5'-GTCCTGCCCCTTCACCTT-3", 'Chemical', '-', (132, 155))	('C250T', 'Var', (247, 252))	('TERT', 'Gene', (18, 22))	('C250T', 'Mutation', 'rs541791751', (247, 252))	('C228T', 'Mutation', 'rs1020833107', (237, 242))	('TERT', 'Gene', '7015', (18, 22))	('C228T', 'Var', (237, 242))
147668	25042800	A case series  in 2001 found TTF-1 positivity in 42% (21 of 50) of extrapulmonary SCC cases, including prostate and urinary bladder (1/3 each) primaries.	('SCC', 'Gene', '6317', (82, 85))	('SCC', 'Phenotype', 'HP:0030357', (82, 85))	('positivity', 'Var', (35, 45))	('TTF-1', 'Gene', (29, 34))	('TTF-1', 'Gene', '7270', (29, 34))	('SCC', 'Gene', (82, 85))	('urinary bladder', 'Disease', (116, 131))	('prostate', 'Disease', (103, 111))
147680	25042800	Identical point mutations of TP53 were found in invasive SCC of the urinary bladder and coexisting UC in situ; further more, no loss of heterozygosity of 9 microsatellite markers and TP53alu was found in either component .	('SCC', 'Gene', '6317', (57, 60))	('TP53', 'Gene', '7157', (183, 187))	('SCC', 'Phenotype', 'HP:0030357', (57, 60))	('found', 'Reg', (39, 44))	('TP53', 'Gene', (183, 187))	('TP53', 'Gene', '7157', (29, 33))	('point mutations', 'Var', (10, 25))	('TP53', 'Gene', (29, 33))	('SCC', 'Gene', (57, 60))
147681	25042800	In prostatic SCC, it has been found that ERG rearrangements in nearly half of SCC of the prostate is a similar rate of the same rearrangements in prostatic acinar carcinomas; and these rearrangements have not been detected in SCC of the urinary bladder or lung .	('ERG', 'Gene', '2078', (41, 44))	('ERG', 'Gene', (41, 44))	('SCC', 'Gene', (226, 229))	('SCC', 'Gene', '6317', (13, 16))	('SCC', 'Phenotype', 'HP:0030357', (78, 81))	('SCC', 'Gene', '6317', (78, 81))	('SCC', 'Phenotype', 'HP:0030357', (13, 16))	('prostatic acinar carcinomas', 'Disease', (146, 173))	('SCC', 'Phenotype', 'HP:0030357', (226, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('rearrangements', 'Var', (45, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('SCC', 'Gene', '6317', (226, 229))	('prostatic acinar carcinomas', 'Disease', 'MESH:D018267', (146, 173))	('SCC', 'Gene', (13, 16))	('SCC', 'Gene', (78, 81))
147683	25042800	Recent reports  also revealed that small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4, and this mutation is very rare in other common tumors.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('mutations', 'Var', (142, 151))	('carcinoma of the ovary', 'Disease', (46, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('SMARCA4', 'Gene', (155, 162))	('SMARCA4', 'Gene', '6597', (155, 162))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (35, 55))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('small cell carcinoma', 'Gene', (35, 55))	('tumors', 'Disease', (211, 217))	('small cell carcinoma', 'Gene', '6317', (35, 55))	('inactivating', 'NegReg', (108, 120))	('carcinoma of the ovary', 'Disease', 'MESH:D010051', (46, 68))
147686	25042800	TERT promoter mutations, originally be discovered in ~70% melanoma, have also been found to be the most common genetic mutations of UC.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('mutations', 'Var', (14, 23))	('melanoma', 'Disease', (58, 66))
147687	25042800	Interestingly, these mutations have very low incidence in other prevalent carcinomas: lung, prostate and colon cancers.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('colon cancers', 'Disease', (105, 118))	('prostate', 'Disease', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('lung', 'Disease', (86, 90))	('colon cancers', 'Phenotype', 'HP:0003003', (105, 118))	('colon cancers', 'Disease', 'MESH:D015179', (105, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('carcinomas', 'Disease', (74, 84))	('carcinomas', 'Disease', 'MESH:D002277', (74, 84))	('mutations', 'Var', (21, 30))
147689	25042800	Our data showed that no TERT promoter mutations were identified in SCC of lung, prostate and other origins, in contrast, all SCC of bladder harbor TERT promoter mutation: C228T.	('TERT', 'Gene', (147, 151))	('TERT', 'Gene', (24, 28))	('C228T', 'Mutation', 'rs1020833107', (171, 176))	('SCC', 'Gene', (125, 128))	('SCC', 'Gene', (67, 70))	('TERT', 'Gene', '7015', (147, 151))	('C228T', 'Var', (171, 176))	('TERT', 'Gene', '7015', (24, 28))	('SCC of bladder', 'Phenotype', 'HP:0100645', (125, 139))	('SCC', 'Phenotype', 'HP:0030357', (67, 70))	('SCC', 'Phenotype', 'HP:0030357', (125, 128))	('SCC', 'Gene', '6317', (125, 128))	('SCC', 'Gene', '6317', (67, 70))
147690	25042800	These incidences of TERT promoter mutations in SCC of different origins are concord with those counterpart usual carcinomas.	('SCC', 'Gene', '6317', (47, 50))	('SCC', 'Phenotype', 'HP:0030357', (47, 50))	('TERT', 'Gene', (20, 24))	('TERT', 'Gene', '7015', (20, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinomas', 'Disease', 'MESH:D002277', (113, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('mutations', 'Var', (34, 43))	('SCC', 'Gene', (47, 50))	('carcinomas', 'Disease', (113, 123))
147691	25042800	Multiple studies [-] including our unpublished results demonstrated that up to 70-80% UC carries the TERT promoter mutations disregarding grade, stage or location.	('TERT', 'Gene', '7015', (101, 105))	('mutations', 'Var', (115, 124))	('TERT', 'Gene', (101, 105))
147692	25042800	This study showed 100% SCC of bladder carry TERT promoter mutation: C228T.	('TERT', 'Gene', (44, 48))	('TERT', 'Gene', '7015', (44, 48))	('SCC', 'Gene', '6317', (23, 26))	('C228T', 'Mutation', 'rs1020833107', (68, 73))	('SCC of bladder carry', 'Phenotype', 'HP:0100645', (23, 43))	('SCC', 'Gene', (23, 26))	('C228T', 'Var', (68, 73))	('SCC of bladder', 'Phenotype', 'HP:0100645', (23, 37))	('SCC', 'Phenotype', 'HP:0030357', (23, 26))
147693	25042800	Additionally, no C250T TERT promoter mutation, the second most common mutation in UC, is identifies in SCC of bladder.	('TERT', 'Gene', (23, 27))	('TERT', 'Gene', '7015', (23, 27))	('SCC', 'Gene', (103, 106))	('C250T', 'Mutation', 'rs541791751', (17, 22))	('C250T', 'Var', (17, 22))	('SCC of bladder', 'Phenotype', 'HP:0100645', (103, 117))	('SCC', 'Gene', '6317', (103, 106))	('SCC', 'Phenotype', 'HP:0030357', (103, 106))
147697	25042800	Since low frequency to none of TERT promoter mutations are in SCC of lung, prostate and other sites, only positive mutation could be suggestive of bladder origin.	('mutations', 'Var', (45, 54))	('SCC', 'Gene', '6317', (62, 65))	('SCC', 'Phenotype', 'HP:0030357', (62, 65))	('prostate', 'Disease', (75, 83))	('TERT', 'Gene', (31, 35))	('TERT', 'Gene', '7015', (31, 35))	('SCC', 'Gene', (62, 65))
147700	25042800	These mutations create consensus binding motifs for E-twenty six (ETS)/ternary complex factor (TCF) transcription factors (GGA[A/T] or CCGGAA) leading to increased TERT promoter activity and subsequently TERT transcriptional upregulation.	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('TERT', 'Gene', '7015', (204, 208))	('upregulation', 'PosReg', (225, 237))	('TERT', 'Gene', (164, 168))	('TERT', 'Gene', '7015', (164, 168))	('transcription', 'biological_process', 'GO:0006351', ('100', '113'))	('TCF', 'Gene', (95, 98))	('TERT', 'Gene', (204, 208))	('TCF', 'Gene', '3172', (95, 98))	('binding', 'Interaction', (33, 40))	('increased', 'PosReg', (154, 163))	('mutations', 'Var', (6, 15))
147702	25042800	However, TERT expression upregulation could not be distinguished between TERT promoter mutations and other molecular mechanisms, such as gene amplification.	('TERT', 'Gene', (73, 77))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (73, 77))	('mutations', 'Var', (87, 96))	('TERT', 'Gene', '7015', (9, 13))
147718	23724131	KRAS transfection of urothelial carcinoma cells led to upregulation of p16INK4a and uPA accompanied by loss of E-cadherin that could be inhibited by application of the kinase-inhibitor Sorafenib.	('transfection', 'Var', (5, 17))	('uPA', 'Gene', (84, 87))	('E-cadherin', 'Gene', '999', (111, 121))	('kinase-inhibitor', 'biological_process', 'GO:0033673', ('168', '184'))	('uPA', 'molecular_function', 'GO:0008243', ('84', '87'))	('p16INK4a', 'Gene', (71, 79))	('uPA', 'Gene', '5328', (84, 87))	('Sorafenib', 'Chemical', 'MESH:D000077157', (185, 194))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (21, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('cadherin', 'molecular_function', 'GO:0008014', ('113', '121'))	('p16INK4a', 'Gene', '1029', (71, 79))	('urothelial carcinoma', 'Disease', (21, 41))	('E-cadherin', 'Gene', (111, 121))	('KRAS', 'Gene', (0, 4))	('upregulation', 'PosReg', (55, 67))	('loss', 'NegReg', (103, 107))	('KRAS', 'Gene', '3845', (0, 4))
147724	23724131	In animal models, it has been shown that UCIS lesions can be induced by exposure to the carcinogene nitrosamine and that they progress to invasive carcinomas upon STAT3 activation, P53 mutations and loss of heterozygosity of chromosome 9.	('STAT3', 'Gene', '6774', (163, 168))	('progress', 'PosReg', (126, 134))	('STAT3', 'Gene', (163, 168))	('loss of heterozygosity', 'Var', (199, 221))	('nitrosamine', 'Chemical', 'MESH:D009602', (100, 111))	('invasive carcinomas', 'Disease', (138, 157))	('invasive carcinomas', 'Disease', 'MESH:D009361', (138, 157))	('mutations', 'Var', (185, 194))	('P53', 'Gene', (181, 184))	('P53', 'Gene', '7157', (181, 184))	('chromosome', 'cellular_component', 'GO:0005694', ('225', '235'))	('UCIS', 'Disease', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))
147754	23724131	Overexpression of KRAS was proven by RAS immunoblotting; insertion of mutated KRAS was proven by KRAS strip assay testing (Fig.	('KRAS', 'Gene', (18, 22))	('KRAS', 'Gene', (97, 101))	('expression', 'Species', '29278', (4, 14))	('KRAS', 'Gene', '3845', (18, 22))	('KRAS', 'Gene', '3845', (97, 101))	('KRAS', 'Gene', (78, 82))	('KRAS', 'Gene', '3845', (78, 82))	('mutated', 'Var', (70, 77))
147776	23724131	After transfection with either wild-type or G12D-mutated (constitutively active) KRAS, we detected stronger signals for p16INK4a, RAS and pERK1/2 while there were no detectable levels of pAKT.	('KRAS', 'Gene', '3845', (81, 85))	('ERK', 'Gene', '5594', (139, 142))	('RAS', 'Protein', (130, 133))	('stronger', 'PosReg', (99, 107))	('ERK', 'Gene', (139, 142))	('p16INK4a', 'Gene', (120, 128))	('G12D-mutated', 'Var', (44, 56))	('G12D', 'Mutation', 'rs121913529', (44, 48))	('KRAS', 'Gene', (81, 85))	('p16INK4a', 'Gene', '1029', (120, 128))
147781	23724131	Secondly, there was a strong increase in urokinase plasminogen activator (uPA) expression after KRAS transfection.	('expression', 'Species', '29278', (79, 89))	('urokinase plasminogen activator', 'Gene', (41, 72))	('KRAS', 'Gene', '3845', (96, 100))	('urokinase plasminogen activator', 'molecular_function', 'GO:0008243', ('41', '72'))	('uPA', 'Gene', (74, 77))	('uPA', 'Gene', '5328', (74, 77))	('increase', 'PosReg', (29, 37))	('urokinase plasminogen activator', 'Gene', '5328', (41, 72))	('transfection', 'Var', (101, 113))	('uPA', 'molecular_function', 'GO:0008243', ('74', '77'))	('KRAS', 'Gene', (96, 100))
147783	23724131	This shows that transfection-induced activation of the RAS/MAPK signaling pathway is sufficient to cause EMT in vitro, and that this effect can be inhibited by Sorafenib.	('transfection-induced', 'Var', (16, 36))	('MAPK signaling', 'biological_process', 'GO:0000165', ('59', '73'))	('activation', 'PosReg', (37, 47))	('Sorafenib', 'Chemical', 'MESH:D000077157', (160, 169))	('signaling pathway', 'biological_process', 'GO:0007165', ('64', '81'))	('MAPK', 'molecular_function', 'GO:0004707', ('59', '63'))	('cause', 'PosReg', (99, 104))	('EMT in vitro', 'CPA', (105, 117))	('EMT', 'biological_process', 'GO:0001837', ('105', '108'))	('RAS/MAPK signaling pathway', 'Pathway', (55, 81))
147801	23724131	The described differences around the world might also be caused by different distribution of risk factors; for example, presence of HPV DNA in bladder cancer might be associated with Schistosomiasis-induced tumourigenesis.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('HPV DNA', 'Gene', (132, 139))	('Schistosomiasis-induced tumourigenesis', 'Disease', 'MESH:D012552', (183, 221))	('Schistosomiasis-induced tumourigenesis', 'Disease', (183, 221))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('bladder cancer', 'Phenotype', 'HP:0009725', (143, 157))	('bladder cancer', 'Disease', (143, 157))	('HPV', 'Species', '10566', (132, 135))	('bladder cancer', 'Disease', 'MESH:D001749', (143, 157))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('presence', 'Var', (120, 128))	('associated', 'Reg', (167, 177))
147830	19628257	Changes in ATP Stimulated ATP Release Suggests an Association between Cytokine and Purinergic Signaling in Bladder Urothelial Cells To determine whether antiproliferative factor (APF) or epidermal growth factor (EGF) can induce changes in purinergic signaling in normal bladder urothelial cells (BUC) and/or whether antagonizing EGF activity or blocking ATP-purinergic receptors can induce changes in purinergic signaling in interstitial cystitis (IC) cells.	('changes', 'Reg', (390, 397))	('interstitial cystitis', 'Disease', (425, 446))	('ATP', 'Chemical', 'MESH:D000255', (354, 357))	('EGF', 'Gene', '1950', (329, 332))	('Signaling', 'biological_process', 'GO:0023052', ('94', '103'))	('changes', 'Reg', (228, 235))	('EGF', 'molecular_function', 'GO:0005154', ('329', '332'))	('purinergic signaling', 'MPA', (239, 259))	('signaling', 'biological_process', 'GO:0023052', ('250', '259'))	('ATP', 'Chemical', 'MESH:D000255', (11, 14))	('EGF', 'Gene', (212, 215))	('EGF', 'molecular_function', 'GO:0005154', ('212', '215'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('187', '210'))	('ATP', 'Chemical', 'MESH:D000255', (26, 29))	('ATP-purinergic receptors', 'Protein', (354, 378))	('EGF', 'Gene', (329, 332))	('interstitial cystitis', 'Disease', 'MESH:D018856', (425, 446))	('antagonizing', 'Var', (316, 328))	('signaling', 'biological_process', 'GO:0023052', ('412', '421'))	('purinergic signaling', 'MPA', (401, 421))	('epidermal growth factor', 'Gene', (187, 210))	('epidermal growth factor', 'Gene', '1950', (187, 210))	('EGF', 'Gene', '1950', (212, 215))
147837	19628257	Conversely, normal BUC treated with EGF or APF resulted in significantly increased ATP release and P2X3 expression, converting normal BUC to an IC phenotype.	('increased', 'PosReg', (73, 82))	('P2X3', 'Enzyme', (99, 103))	('EGF', 'molecular_function', 'GO:0005154', ('36', '39'))	('EGF', 'Gene', '1950', (36, 39))	('ATP release', 'MPA', (83, 94))	('APF', 'Var', (43, 46))	('ATP', 'Chemical', 'MESH:D000255', (83, 86))	('EGF', 'Gene', (36, 39))
147930	31107371	70 year old Asian male who failed his seventh line of intravesical therapy, including three induction courses of intravesical BCG as well as BCG with interferon (IFN), was found to have BCG unresponsive disease, T1NxMx high-grade urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (230, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('T1NxMx', 'Var', (212, 218))	('BCG unresponsive disease', 'Disease', (186, 210))	('urothelial carcinoma', 'Disease', (230, 250))
147935	31107371	Six months later, cystoscopy noted a one centimeter bladder mass, which was completely resected and found to be T2NxMx high-grade urothelial carcinoma (i.e., disease progression).	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (130, 150))	('urothelial carcinoma', 'Disease', (130, 150))	('T2NxMx', 'Var', (112, 118))
147941	31107371	Our goal is to begin describing the genetic alterations identified through molecular testing that may potentially elucidate the mechanism of sensitivity in patients treated with ALT-803 with BCG.	('patients', 'Species', '9606', (156, 164))	('alterations', 'Var', (44, 55))	('elucidate', 'Reg', (114, 123))	('ALT', 'molecular_function', 'GO:0004021', ('178', '181'))
147963	31107371	We highlight the development of CTLA4, CD39 and CCL2-CCR2 axis amplifications as potential mechanisms of acquired resistance in these patients.	('CCL', 'molecular_function', 'GO:0044101', ('48', '51'))	('CCL2', 'Gene', '6347', (48, 52))	('CD39', 'Gene', (39, 43))	('CCR2', 'Gene', (53, 57))	('CD39', 'Gene', '953', (39, 43))	('CCL2', 'Gene', (48, 52))	('CCR', 'molecular_function', 'GO:0043880', ('53', '56'))	('patients', 'Species', '9606', (134, 142))	('amplifications', 'Var', (63, 77))	('CTLA4', 'Gene', '1493', (32, 37))	('CCR2', 'Gene', '729230', (53, 57))	('CTLA4', 'Gene', (32, 37))
147975	30064501	Like SAHA, 19i increased the G2/M-fraction, disturbed mitosis, and elicited apoptosis or in some cells senescence.	('mitosis', 'biological_process', 'GO:0000278', ('54', '61'))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('SAHA', 'Chemical', 'MESH:D000077337', (5, 9))	('mitosis', 'Disease', (54, 61))	('19i', 'Var', (11, 14))	('increased', 'PosReg', (15, 24))	('senescence', 'biological_process', 'GO:0010149', ('103', '113'))	('mitosis', 'Disease', 'None', (54, 61))	('apoptosis', 'CPA', (76, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('G2/M-fraction', 'MPA', (29, 42))	('disturbed', 'Reg', (44, 53))	('19i', 'Chemical', '-', (11, 14))	('elicited', 'Reg', (67, 75))
147996	30064501	For example, homozygous deletion of HDAC4 is a frequent event in malignant melanoma, whereas inhibition of HDAC4 expression by miR-125a-5p was anti-neoplastic in breast cancer cells and HDAC4 promotes proliferation of gastric cancer cell lines.	('anti-neoplastic', 'CPA', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('gastric cancer', 'Phenotype', 'HP:0012126', (218, 232))	('neoplastic in breast', 'Phenotype', 'HP:0100013', (148, 168))	('malignant melanoma', 'Phenotype', 'HP:0002861', (65, 83))	('malignant melanoma', 'Disease', 'MESH:D008545', (65, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('HDAC4', 'Gene', '9759', (107, 112))	('HDAC4', 'Gene', '9759', (186, 191))	('gastric cancer', 'Disease', (218, 232))	('proliferation', 'CPA', (201, 214))	('HDAC4', 'Gene', '9759', (36, 41))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Disease', (162, 175))	('HDAC4', 'Gene', (107, 112))	('HDAC4', 'Gene', (186, 191))	('gastric cancer', 'Disease', 'MESH:D013274', (218, 232))	('HDAC4', 'Gene', (36, 41))	('malignant melanoma', 'Disease', (65, 83))	('inhibition', 'Var', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
147999	30064501	Here, we aimed to address whether inhibiting HDAC4 might contribute to the therapeutic efficacy of HDACi in urothelial carcinoma.	('inhibiting', 'Var', (34, 44))	('urothelial carcinoma', 'Disease', (108, 128))	('HDAC4', 'Gene', (45, 50))	('HDAC', 'Gene', '9734', (99, 103))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (108, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('HDAC', 'Gene', (99, 103))	('HDAC', 'Gene', (45, 49))	('HDAC', 'Gene', '9734', (45, 49))	('HDAC4', 'Gene', '9759', (45, 50))
148030	30064501	In brief, to produce replication-deficient lentiviruses, HEK-293T cells were transfected with helper plasmid expression construct (pCD/NL-BH), envelope vector (pczVSV-G), and the vector plasmids puc2CL12IPwo or puc2CL12IPwo-HDAC4-FLAG.	('envelope', 'cellular_component', 'GO:0031975', ('143', '151'))	('HDAC4', 'Gene', '9759', (224, 229))	('HDAC4', 'Gene', (224, 229))	('puc2CL12IPwo', 'Var', (195, 207))	('HEK-293T', 'CellLine', 'CVCL:0063', (57, 65))	('envelope', 'cellular_component', 'GO:0009274', ('143', '151'))	('pCD', 'biological_process', 'GO:0012501', ('131', '134'))
148065	30064501	As in some UC cells, low doses of 19i increased HBLAK viability (Fig.	('19i', 'Var', (34, 37))	('HBLAK viability', 'CPA', (48, 63))	('increased', 'PosReg', (38, 47))	('19i', 'Chemical', '-', (34, 37))
148073	30064501	These findings indicate that 19i induces proliferation arrest rather than cell death in normal control cells.	('cell death', 'biological_process', 'GO:0008219', ('74', '84'))	('19i', 'Var', (29, 32))	('proliferation arrest', 'Disease', (41, 61))	('proliferation arrest', 'Disease', 'MESH:D006323', (41, 61))	('19i', 'Chemical', '-', (29, 32))
148076	30064501	However, 19i caused a more profound increase in the G2/M fraction.	('increase', 'PosReg', (36, 44))	('G2/M fraction', 'MPA', (52, 65))	('19i', 'Var', (9, 12))	('19i', 'Chemical', '-', (9, 12))
148083	30064501	Expression of p21 protein was more prominently induced by 19i than by SAHA (Additional file 6 Figure S4).	('p21', 'Gene', '1026', (14, 17))	('Expression', 'MPA', (0, 10))	('p21', 'Gene', (14, 17))	('19i', 'Var', (58, 61))	('induced', 'Reg', (47, 54))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('SAHA', 'Chemical', 'MESH:D000077337', (70, 74))	('19i', 'Chemical', '-', (58, 61))
148085	30064501	Global acetylation of histones H3 and H4 was likewise enhanced following 19i treatment (Fig.	('19i treatment', 'Var', (73, 86))	('19i', 'Chemical', '-', (73, 76))	('histones H3', 'Protein', (22, 33))	('acetylation', 'MPA', (7, 18))	('enhanced', 'PosReg', (54, 62))
148086	30064501	Intriguingly, mRNA expression of class IIA HDACs was affected by treatment with 19i as well as SAHA (Fig.	('19i', 'Var', (80, 83))	('affected', 'Reg', (53, 61))	('SAHA', 'Chemical', 'MESH:D000077337', (95, 99))	('19i', 'Chemical', '-', (80, 83))	('HDAC', 'Gene', (43, 47))	('mRNA expression', 'MPA', (14, 29))	('HDAC', 'Gene', '9734', (43, 47))
148103	30064501	Both VM-CUB1-HDAC4 and UM-UC-3-HDAC4 cells formed fewer colonies after treatment with 19i (Fig.	('HDAC4', 'Gene', (31, 36))	('19i', 'Chemical', '-', (86, 89))	('VM-CUB1-HDAC4', 'Gene', (5, 18))	('fewer', 'NegReg', (50, 55))	('colonies', 'CPA', (56, 64))	('19i', 'Var', (86, 89))	('HDAC4', 'Gene', '9759', (13, 18))	('HDAC4', 'Gene', (13, 18))	('VM-CUB1-HDAC4', 'Gene', '9759', (5, 18))	('HDAC4', 'Gene', '9759', (31, 36))
148105	30064501	Upon treatment with 19i, the number of mitoses decreased in VM-CUB1-HDAC4 as well as VM-CUB1-LV, but in contrast to the controls, fewer micronuclei were detectable in VM-CUB1-HDAC4.	('VM-CUB1-HDAC4', 'Gene', '9759', (167, 180))	('19i', 'Chemical', '-', (20, 23))	('decreased', 'NegReg', (47, 56))	('19i', 'Var', (20, 23))	('VM-CUB1-HDAC4', 'Gene', (60, 73))	('VM-CUB1-HDAC4', 'Gene', '9759', (60, 73))	('VM-CUB1-HDAC4', 'Gene', (167, 180))
148106	30064501	In UM-UC-3-HDAC4 treated with 19i, disturbances of mitosis were seen as in the controls with a decreased number of mitoses but increased number of micronuclei (Fig.	('disturbances of mitosis', 'Disease', (35, 58))	('mitoses', 'CPA', (115, 122))	('19i', 'Var', (30, 33))	('disturbances of mitosis', 'Disease', 'MESH:D010468', (35, 58))	('micronuclei', 'CPA', (147, 158))	('HDAC4', 'Gene', '9759', (11, 16))	('19i', 'Chemical', '-', (30, 33))	('HDAC4', 'Gene', (11, 16))	('mitosis', 'biological_process', 'GO:0000278', ('51', '58'))	('increased', 'PosReg', (127, 136))
148118	30064501	As 19i turned out to be a weak inhibitor of HDAC4 and the novel compound TMP269 specifically inhibiting class IIA HDACs has recently become available, we tested its effect on UC cell lines using MTT and high-content analysis-based fluorescent live/dead cell assays (Fig.	('TMP269', 'Chemical', '-', (73, 79))	('TMP269', 'Var', (73, 79))	('HDAC', 'Gene', (114, 118))	('MTT', 'Chemical', 'MESH:C070243', (195, 198))	('tested', 'Reg', (154, 160))	('HDAC', 'Gene', '9734', (114, 118))	('HDAC', 'Gene', (44, 48))	('HDAC4', 'Gene', (44, 49))	('HDAC4', 'Gene', '9759', (44, 49))	('HDAC', 'Gene', '9734', (44, 48))	('inhibiting', 'NegReg', (93, 103))	('19i', 'Chemical', '-', (3, 6))
148125	30064501	The novel hydroxamic acid HDAC inhibitors, 19i (LMK235), 19h (LMK233), and 19e (LMK225), were thought to inhibit HDAC4/5 with in vitro IC50s in the nanomolar range, whereas their in vitro IC50s for HDAC1/2 range between 0.3 and 1.4 muM.	('LMK233', 'Var', (62, 68))	('inhibit', 'NegReg', (105, 112))	('HDAC', 'Gene', (198, 202))	('muM', 'Gene', '56925', (232, 235))	('HDAC', 'Gene', (113, 117))	('HDAC4', 'Gene', (113, 118))	('HDAC', 'Gene', '9734', (198, 202))	('50s', 'Species', '1214577', (190, 193))	('HDAC', 'Gene', '9734', (113, 117))	('HDAC', 'Gene', (26, 30))	('HDAC4', 'Gene', '9759', (113, 118))	('HDAC', 'Gene', '9734', (26, 30))	('19i', 'Chemical', '-', (43, 46))	('muM', 'Gene', (232, 235))	('hydroxamic acid', 'Chemical', 'MESH:D006877', (10, 25))	('50s', 'Species', '1214577', (137, 140))
148127	30064501	Applied to urothelial carcinoma cell lines, 19i consistently yielded the lowest CC50 values and was therefore selected for closer investigation of its mechanism of action.	('19i', 'Var', (44, 47))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (11, 31))	('19i', 'Chemical', '-', (44, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('urothelial carcinoma', 'Disease', (11, 31))	('CC50 values', 'MPA', (80, 91))	('lowest', 'NegReg', (73, 79))
148134	30064501	However, even specific inhibitors or knockdown of HDAC6 exert only limited effects on UC cell lines, and therefore, this inhibitory activity is unlikely to contribute substantially to the anti-neoplastic activity of 19i.	('19i', 'Chemical', '-', (216, 219))	('HDAC6', 'Gene', '10013', (50, 55))	('knockdown', 'Var', (37, 46))	('HDAC6', 'Gene', (50, 55))
148138	30064501	Moreover, 19i increased overall histone acetylation like the more HDAC1/2-specific inhibitors romidepsin and givinostat.	('increased', 'PosReg', (14, 23))	('19i', 'Chemical', '-', (10, 13))	('histone acetylation', 'biological_process', 'GO:0016573', ('32', '51'))	('histone acetylation', 'MPA', (32, 51))	('19i', 'Var', (10, 13))
148145	30064501	Our results implicate that the greatly enhanced activity of the variant might not only result from the additional hydrogen bonding by the mutant tyrosine residue, but also from the restriction of the conformational freedom of the lysine inside the catalytic center.	('restriction', 'NegReg', (181, 192))	('mutant tyrosine', 'Var', (138, 153))	('additional', 'PosReg', (103, 113))	('activity', 'MPA', (48, 56))	('conformational freedom', 'MPA', (200, 222))	('tyrosine', 'Chemical', 'MESH:D014443', (145, 153))	('tyrosine', 'Var', (145, 153))	('hydrogen', 'Chemical', 'MESH:D006859', (114, 122))	('lysine', 'Chemical', 'MESH:D008239', (230, 236))	('hydrogen bonding', 'MPA', (114, 130))	('enhanced', 'PosReg', (39, 47))
148158	30064501	The mechanisms underlying this difference is unknown, but we note that HEK-293 are also more sensitive to a new compound, 4SC-202, which inhibits HDAC1/2 and HDAC3 as well as the histone demethylase LSD1/KDM1A and potentially WNT and hedgehog signaling.	('HDAC3', 'Gene', (158, 163))	('HDAC1/2', 'Enzyme', (146, 153))	('KDM1A', 'Gene', '23028', (204, 209))	('LSD1', 'Gene', '23028', (199, 203))	('4SC-202', 'Var', (122, 129))	('KDM1A', 'Gene', (204, 209))	('HEK-293', 'CellLine', 'CVCL:0045', (71, 78))	('signaling', 'biological_process', 'GO:0023052', ('243', '252'))	('inhibits', 'NegReg', (137, 145))	('HDAC3', 'Gene', '8841', (158, 163))	('LSD1', 'Gene', (199, 203))
148177	27751354	Mutant TP53 disrupts age-related accumulation patterns of somatic mutations in multiple cancer types Most cancers are driven by somatic mutations in proto-oncogenes and tumor suppressor genes.	('accumulation', 'MPA', (33, 45))	('cancer', 'Disease', (88, 94))	('TP53', 'Gene', (7, 11))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancer', 'Disease', (106, 112))	('cancers', 'Disease', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('169', '185'))	('tumor', 'Disease', (169, 174))	('disrupts', 'NegReg', (12, 20))	('tumor suppressor', 'biological_process', 'GO:0051726', ('169', '185'))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('TP53', 'Gene', '7157', (7, 11))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('Mutant', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))
148178	27751354	Genetic changes in a tumor may accumulate in the tissue self-renewal phase prior to neoplasm.	('tissue self-renewal phase', 'CPA', (49, 74))	('accumulate', 'PosReg', (31, 41))	('tumor', 'Disease', (21, 26))	('Genetic changes', 'Var', (0, 15))	('neoplasm', 'Disease', (84, 92))	('neoplasm', 'Phenotype', 'HP:0002664', (84, 92))	('neoplasm', 'Disease', 'MESH:D009369', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
148182	27751354	Hereby, we speculate that mutant TP53 can disrupt the age-related accumulation patterns of somatic mutations in tumors.	('disrupt', 'NegReg', (42, 49))	('accumulation patterns', 'MPA', (66, 87))	('TP53', 'Gene', '7157', (33, 37))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('TP53', 'Gene', (33, 37))	('mutant', 'Var', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
148183	27751354	We found that there was a significant interaction between TP53 genotype (mutant versus wild-type) and patient age at the initial clinical date on somatic mutation burden for five cancers.	('TP53', 'Gene', '7157', (58, 62))	('patient', 'Species', '9606', (102, 109))	('TP53', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mutant', 'Var', (73, 79))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', (179, 186))
148188	27751354	In light of the classical multi-mutation theory of tumorigenesis, which states that cancer is the result of accumulated mutations in a cell's DNA, the age-related pattern of cancer incidences can be explained by several mutually complementary mechanisms.	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cancer', 'Disease', (84, 90))	('tumor', 'Disease', (51, 56))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
148190	27751354	In this regard, a positive association between patient age and the number of accumulated mutations in tumors could exist across a wide spectrum of cancer types.	('patient', 'Species', '9606', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('mutations', 'Var', (89, 98))	('cancer', 'Disease', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
148193	27751354	no age-mutation association was found in chronic myelomonocytic leukemia (CMML) for which <5% of patients have a TP53 mutation, although such a relationship was reported in acute myeloid leukemia (AML).	('chronic myelomonocytic leukemia', 'Disease', (41, 72))	('acute myeloid leukemia', 'Disease', (173, 195))	('leukemia', 'Phenotype', 'HP:0001909', (187, 195))	('TP53', 'Gene', (113, 117))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (41, 72))	('AML', 'Disease', 'MESH:D015470', (197, 200))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (173, 195))	('AML', 'Phenotype', 'HP:0004808', (197, 200))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (179, 195))	('AML', 'Disease', (197, 200))	('mutation', 'Var', (118, 126))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (173, 195))	('patients', 'Species', '9606', (97, 105))	('CMML', 'Disease', 'MESH:D054429', (74, 78))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (41, 72))	('TP53', 'Gene', '7157', (113, 117))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('CMML', 'Disease', (74, 78))	('CMML', 'Phenotype', 'HP:0012325', (74, 78))
148195	27751354	The loss or disruption of p53 function due to a mutation can lead to uncontrolled cell proliferation and eventually cancer.	('function', 'MPA', (30, 38))	('cell proliferation', 'biological_process', 'GO:0008283', ('82', '100'))	('lead to', 'Reg', (61, 68))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('uncontrolled cell proliferation', 'CPA', (69, 100))	('disruption', 'NegReg', (12, 22))	('p53', 'Gene', (26, 29))	('mutation', 'Var', (48, 56))	('p53', 'Gene', '7157', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('loss', 'NegReg', (4, 8))
148196	27751354	Considering the crucial roles of normal p53 in conserving genome stability, we speculate that its aberration can disrupt or reshape age-related accumulation patterns of somatic mutations in tumors.	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('accumulation', 'MPA', (144, 156))	('disrupt', 'Reg', (113, 120))	('p53', 'Gene', (40, 43))	('reshape', 'Reg', (124, 131))	('p53', 'Gene', '7157', (40, 43))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('aberration', 'Var', (98, 108))
148198	27751354	Among the 33 cancer types with clinically-annotated multiomic data (available at TCGA database by April 24, 2015), twelve were studied in this work by considering the genetic diversity of patients and the prevalence of somatic TP53 mutations in these tumors.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('TP53', 'Gene', '7157', (227, 231))	('tumors', 'Disease', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('TP53', 'Gene', (227, 231))	('cancer', 'Disease', (13, 19))	('mutations', 'Var', (232, 241))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('patients', 'Species', '9606', (188, 196))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
148200	27751354	black American or Asian) besides the dominant white Americans, and the ratio of samples with TP53 non-synonymous mutations was over 25%.	('TP53', 'Gene', (93, 97))	('TP53', 'Gene', '7157', (93, 97))	('non-synonymous mutations', 'Var', (98, 122))
148211	27751354	wild-type versus mutant) of a tumor (patient) was indexed by i (i = 1, 2).	('tumor', 'Disease', (30, 35))	('patient', 'Species', '9606', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutant', 'Var', (17, 23))
148212	27751354	(1), yij and xj represented the status-specific mutation burden on the jth tumor sample and the age of the jth patient, respectively.	('yij', 'Var', (5, 8))	('jth tumor', 'Disease', 'MESH:D009369', (71, 80))	('jth tumor', 'Disease', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('patient', 'Species', '9606', (111, 118))
148213	27751354	I was a binary variable with a value of 1 or 0, indicating the mutant or wild-type TP53 tumors.	('TP53', 'Gene', '7157', (83, 87))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('mutant', 'Var', (63, 69))	('TP53', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
148214	27751354	The baseline was denoted by mu and could be considered as the expected mutation burden for a TP53 wild-type tumor carried by a patient aged at x. alpha represented the effect of TP53 mutation on y, i.e.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('TP53', 'Gene', '7157', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patient', 'Species', '9606', (127, 134))	('TP53', 'Gene', (178, 182))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('tumor', 'Disease', (108, 113))	('mutation', 'Var', (183, 191))
148215	27751354	the age-adjusted average increase or decrease (when the value was negative) in mutation burden for a tumor with mutated TP53.	('decrease', 'NegReg', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('increase', 'PosReg', (25, 33))	('mutated', 'Var', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('TP53', 'Gene', '7157', (120, 124))	('mutation burden', 'MPA', (79, 94))	('TP53', 'Gene', (120, 124))
148216	27751354	mu + alpha stood for the expected mutation burden for a mutant TP53 tumor carried by a patient aged at x.	('tumor', 'Disease', (68, 73))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('mutant', 'Var', (56, 62))	('patient', 'Species', '9606', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
148224	27751354	LUAD, in which the slope was negative and significant in the mutant TP53 tumors but not in the wild-type counterparts.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('mutant', 'Var', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('LUAD', 'Phenotype', 'HP:0030078', (0, 4))
148225	27751354	The third group, consisting of BRCA, GBM and HNSC, demonstrated consistent positive association between mutation burden and patient age.	('BRCA', 'Phenotype', 'HP:0003002', (31, 35))	('BRCA', 'Gene', '672', (31, 35))	('positive', 'PosReg', (75, 83))	('mutation burden', 'Var', (104, 119))	('BRCA', 'Gene', (31, 35))	('patient', 'Species', '9606', (124, 131))	('HNSC', 'Phenotype', 'HP:0012288', (45, 49))
148233	27751354	Here, we repeated our linear model analysis on an "alternative" dataset similar to that used in Ref., in which the tumors with more than 200 (or 250) mutations in UCEC (or COAD) were also eliminated.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('COAD', 'Disease', (172, 176))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (150, 159))	('UCEC', 'Gene', (163, 167))	('COAD', 'Disease', 'MESH:D029424', (172, 176))
148234	27751354	As shown in Supplemental Figure S2, this reanalysis confirmed our results that the TP53 genotype-dependent positive association between mutation burden and patient age did exist in UCEC.	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', (83, 87))	('positive association', 'PosReg', (107, 127))	('UCEC', 'Disease', (181, 185))	('mutation burden', 'Var', (136, 151))	('patient', 'Species', '9606', (156, 163))
148236	27751354	was observed in the mutant TP53 tumors, with the p-value being smaller and significant (i.e.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('mutant', 'Var', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
148240	27751354	More importantly, the fact that most of these patterns only appeared in TP53 wild-type tumors confirmed our hypothesis about the interference of TP53 alteration to the mutation accumulation process.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('alteration', 'Var', (150, 160))	('TP53', 'Gene', '7157', (72, 76))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (72, 76))	('TP53', 'Gene', (145, 149))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
148241	27751354	Considering that mutant-TP53 tumors had a heavier mutation burden than TP53 wild-type tumors in ten cancers (alpha in Supplemental Table S3), it is plausible to predict a burst of genetic alterations in cells following the disruption of function of the TP53 gene.	('tumors in ten cancers', 'Disease', (86, 107))	('heavier', 'PosReg', (42, 49))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('TP53', 'Gene', '7157', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mutation burden', 'MPA', (50, 65))	('tumors', 'Disease', (86, 92))	('TP53', 'Gene', '7157', (253, 257))	('TP53', 'Gene', '7157', (71, 75))	('tumors', 'Disease', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('TP53', 'Gene', (24, 28))	('tumors in ten cancers', 'Disease', 'MESH:D009369', (86, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('disruption', 'Var', (223, 233))	('TP53', 'Gene', (71, 75))	('TP53', 'Gene', (253, 257))
148244	27751354	In the case that the altered TP53 is DM-a, many genetic changes from the subsequent mutation burst will be fixed as hitchhikers in forming new clone(s) that get additional fitness advantage from DM-b.	('altered', 'Var', (21, 28))	('DM-a', 'Gene', '3108', (37, 41))	('DM-a', 'Gene', (37, 41))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))
148245	27751354	On the other hand, when the altered TP53 is DM-b or DM-c, the fixation of genetic changes arising from the mutation burst will happen during a time period close to the initial clinical date (or the tumor tissue sampling date).	('altered', 'Var', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('TP53', 'Gene', '7157', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('DM-c', 'Gene', (52, 56))	('DM-b', 'Var', (44, 48))	('DM-c', 'Gene', '284340', (52, 56))	('TP53', 'Gene', (36, 40))	('tumor', 'Disease', (198, 203))
148247	27751354	In COAD, ESCA and LUSC, the TP53 wild-type tumors did not demonstrate the expected age-related accumulation patterns for somatic mutations, suggesting the existence of other "mutators" that, similar to TP53 mutation, could impact the stability of other genes.	('TP53', 'Gene', (202, 206))	('TP53', 'Gene', '7157', (28, 32))	('LUSC', 'Phenotype', 'HP:0030359', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (43, 49))	('stability', 'MPA', (234, 243))	('mutators', 'Var', (175, 183))	('COAD', 'Disease', (3, 7))	('TP53', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('impact', 'Reg', (223, 229))	('ESCA', 'Phenotype', 'HP:0011459', (9, 13))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('COAD', 'Disease', 'MESH:D029424', (3, 7))	('TP53', 'Gene', '7157', (202, 206))
148250	27751354	In this study, we found that mutant TP53 could disrupt or reshape age-related accumulation patterns of somatic mutations present in tumors.	('disrupt', 'NegReg', (47, 54))	('accumulation patterns', 'MPA', (78, 99))	('reshape', 'Reg', (58, 65))	('mutant', 'Var', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('TP53', 'Gene', '7157', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('TP53', 'Gene', (36, 40))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
148264	28430799	Further analysis revealed that tumours with low TUG1 expression are characterized by a basal-squamous-like subtype signature accounting for the association with poor outcome.	('TUG1', 'Gene', '55000', (48, 52))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('low', 'Var', (44, 47))	('TUG1', 'Gene', (48, 52))	('basal-squamous-like', 'Disease', (87, 106))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('expression', 'MPA', (53, 63))	('tumours', 'Disease', 'MESH:D009369', (31, 38))	('tumours', 'Disease', (31, 38))
148311	28430799	In the univariate analysis patients with high UCA1 expression from tissue set 1 (above median) had a considerably better overall survival (HR 0.567; 95% CI, 0.367-0.876; p = 0.011; Table 2), which also remained significant in both multivariate analysis (p = 0.015; Table 3) and Kaplan-Meier survival curve (Fig 2, left).	('UCA1', 'Gene', '652995', (46, 50))	('overall survival', 'MPA', (121, 137))	('UCA1', 'Gene', (46, 50))	('high', 'Var', (41, 45))	('patients', 'Species', '9606', (27, 35))	('set 1', 'Gene', '9739', (74, 79))	('better', 'PosReg', (114, 120))	('set 1', 'Gene', (74, 79))
148338	28430799	To further elucidate the association between low TUG1 expression and poor prognosis in a subgroup of patients, we investigated an extended set of TCGA tumour samples (provisional set, n = 408) that also contains a higher number of non-muscle-invasive cases.	('expression', 'MPA', (54, 64))	('TUG1', 'Gene', '55000', (49, 53))	('patients', 'Species', '9606', (101, 109))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('TUG1', 'Gene', (49, 53))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('tumour', 'Disease', (151, 157))	('low', 'Var', (45, 48))
148343	28430799	Indeed, in the extended TCGA data set most tumours with low TUG1 could be assigned to the BASQ type with significant upregulated KRT5 and KRT14 expression and significantly lower expression of luminal markers FOXA1 and GATA3 (Fig 3C and 3D, Fig 4A).	('tumours', 'Disease', (43, 50))	('KRT14', 'Gene', '3861', (138, 143))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('TUG1', 'Gene', (60, 64))	('KRT14', 'Gene', (138, 143))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('expression', 'MPA', (144, 154))	('KRT5', 'Gene', '3852', (129, 133))	('tumours', 'Disease', 'MESH:D009369', (43, 50))	('GATA3', 'Gene', '2625', (219, 224))	('TUG1', 'Gene', '55000', (60, 64))	('FOXA1', 'Gene', '3169', (209, 214))	('GATA3', 'Gene', (219, 224))	('KRT5', 'Gene', (129, 133))	('FOXA1', 'Gene', (209, 214))	('low', 'Var', (56, 59))	('expression', 'MPA', (179, 189))	('upregulated', 'PosReg', (117, 128))	('lower', 'NegReg', (173, 178))
148347	28430799	To substantiate the association of low TUG1 expression with the BASQ subtype, we included further marker genes reported to define molecular subtypes of UC.	('expression', 'MPA', (44, 54))	('BASQ', 'Disease', (64, 68))	('TUG1', 'Gene', '55000', (39, 43))	('low', 'Var', (35, 38))	('TUG1', 'Gene', (39, 43))
148348	28430799	Hierarchical clustering analysis of the extended TCGA data set for a panel of 30 coding genes distinguishing between subtypes and the lncRNA candidates demonstrated again an association between low TUG1 expression and the basal-like subtype (Fig 4A).	('low', 'Var', (194, 197))	('expression', 'MPA', (203, 213))	('TUG1', 'Gene', '55000', (198, 202))	('TUG1', 'Gene', (198, 202))	('basal-like subtype', 'Disease', (222, 240))
148382	28430799	Concordant with the previous report, high linc-UBC1 expression was associated with worse survival in the TCGA cohort, but neither associated with survival nor lymph node status in the samples analysed by RT-qPCR.	('high', 'Var', (37, 41))	('linc-UBC1', 'Gene', (42, 51))	('worse', 'NegReg', (83, 88))	('linc-UBC1', 'Gene', '101669762', (42, 51))	('expression', 'MPA', (52, 62))
148418	28430799	Strikingly, TUG1 was the only investigated lncRNA candidate that was significantly associated with survival in Kaplan-Meier analyses across both cohorts, but unexpectedly, low rather than high TUG1 expression was significantly correlated with poor overall survival, which remained significant in multivariate analysis.	('overall survival', 'MPA', (248, 264))	('TUG1', 'Gene', '55000', (193, 197))	('TUG1', 'Gene', '55000', (12, 16))	('poor', 'NegReg', (243, 247))	('low', 'Var', (172, 175))	('TUG1', 'Gene', (193, 197))	('expression', 'MPA', (198, 208))	('TUG1', 'Gene', (12, 16))
148420	28430799	In their study, TUG1 knockdown in NSCLC cell lines promoted cellular proliferation, whereas in T24 bladder cancer cells TUG1 overexpression increased cell invasion.	('TUG1', 'Gene', (120, 124))	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('cell invasion', 'CPA', (150, 163))	('NSCLC', 'Disease', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('cellular proliferation', 'CPA', (60, 82))	('promoted', 'PosReg', (51, 59))	('TUG1', 'Gene', '55000', (16, 20))	('bladder cancer', 'Disease', (99, 113))	('TUG1', 'Gene', '55000', (120, 124))	('knockdown', 'Var', (21, 30))	('increased', 'PosReg', (140, 149))	('TUG1', 'Gene', (16, 20))
148421	28430799	A new finding in our study was the association of low TUG1 expression with a particular molecular subtype of muscle-invasive UC, the basal subtype with squamous differentiation patterns (BASQ).	('muscle-invasive UC', 'Disease', (109, 127))	('low', 'Var', (50, 53))	('TUG1', 'Gene', '55000', (54, 58))	('squamous differentiation patterns', 'Disease', (152, 185))	('expression', 'MPA', (59, 69))	('TUG1', 'Gene', (54, 58))
148423	28430799	Among five markers for BASQ, low TUG1 expression significantly correlated with four, i.e.	('correlated', 'Reg', (63, 73))	('expression', 'MPA', (38, 48))	('low', 'Var', (29, 32))	('TUG1', 'Gene', '55000', (33, 37))	('TUG1', 'Gene', (33, 37))
148428	28430799	proposed TUG1 as a direct transcriptional target of p53 and reported that TUG1 was not induced in cell lines depleted of p53 or harbouring common p53 mutations.	('p53', 'Gene', (121, 124))	('p53', 'Gene', (146, 149))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (146, 149))	('p53', 'Gene', '7157', (121, 124))	('p53', 'Gene', '7157', (52, 55))	('TUG1', 'Gene', '55000', (9, 13))	('TUG1', 'Gene', '55000', (74, 78))	('TUG1', 'Gene', (9, 13))	('mutations', 'Var', (150, 159))	('TUG1', 'Gene', (74, 78))
148429	28430799	P53 mutations are common in urothelial carcinomas, especially in the BASQ subtype, and might explain low TUG1 expression in some tumour tissues.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('common', 'Reg', (18, 24))	('urothelial carcinomas', 'Disease', (28, 49))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('TUG1', 'Gene', '55000', (105, 109))	('tumour', 'Disease', (129, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('P53', 'Gene', (0, 3))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (28, 49))	('expression', 'MPA', (110, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('P53', 'Gene', '7157', (0, 3))	('TUG1', 'Gene', (105, 109))	('mutations', 'Var', (4, 13))
148520	16330712	A related finding was made by, who described a sharp boundary between normal-appearing transitional epithelium (K20+, K14-, and K13 basal/intermediate) and squamous epithelium in the human bladder (K20-, K14+, and K13 suprabasal).	('K13', 'Gene', (214, 217))	('K20', 'Gene', (198, 201))	('K20', 'Gene', (112, 115))	('K13', 'Gene', '3860', (214, 217))	('K20', 'Gene', '54474', (198, 201))	('K20', 'Gene', '54474', (112, 115))	('human', 'Species', '9606', (183, 188))	('K13', 'Gene', '3860', (128, 131))	('K13', 'Gene', (128, 131))	('K14+', 'Var', (204, 208))
148527	16330712	It is interesting to note, however, that deficiency in essential fatty acids can cause papillary transitional cell tumors mainly in the renal pelvis and upper portion of the ureter.	('cause', 'Reg', (81, 86))	('renal pelvis', 'Phenotype', 'HP:0000125', (136, 148))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('essential fatty acids', 'Chemical', 'MESH:D005228', (55, 76))	('transitional cell tumors', 'Phenotype', 'HP:0006740', (97, 121))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('deficiency', 'Var', (41, 51))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('essential fatty', 'Protein', (55, 70))
148528	16330712	Moreover, reported that urothelial carcinoma caused by the use of a weight-reducing Chinese herbal medicine that was contaminated by aristolochic acid, a potent carcinogen, occurred almost exclusively in the renal pelvis and ureter.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (24, 44))	('aristolochic acid', 'Chemical', 'MESH:C000228', (133, 150))	('urothelial carcinoma', 'Disease', (24, 44))	('aristolochic acid', 'Var', (133, 150))	('renal pelvis', 'Phenotype', 'HP:0000125', (208, 220))	('herbal medicine', 'Species', '1407750', (92, 107))
148552	33508232	Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity.	('Dinucleotide', 'Chemical', 'MESH:D015226', (0, 12))	('peptide hydrophobicity/immunogenicity', 'MPA', (136, 173))	('enhanced', 'PosReg', (127, 135))	('Dinucleotide variants', 'Var', (0, 21))
148553	33508232	Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance.	('amplification', 'Var', (166, 179))	('CCND1', 'Gene', (160, 165))	('associated', 'Reg', (180, 190))	('TRAF2', 'Gene', '7186', (119, 124))	('TRAF2', 'Gene', (119, 124))	('response', 'Disease', (147, 155))	('resistance', 'Disease', (196, 206))	('loss', 'NegReg', (126, 130))	('CCND1', 'Gene', '595', (160, 165))	('CPI', 'Chemical', '-', (61, 64))
148558	33508232	Furthermore, given that CPIs activate the immune system rather than target cancer-cell-intrinsic pathways, we hypothesized that a systematic pan-tumor analysis could help elucidate the critical features underpinning CPI response and enable appropriately powered biomarker discovery.	('CPI', 'Chemical', '-', (216, 219))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('CPIs', 'Var', (24, 28))	('CPI', 'Chemical', '-', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Disease', (75, 81))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CPIs', 'Chemical', '-', (24, 28))
148563	33508232	The CPI1000+ cohort comprises data from seven tumor types (metastatic urothelial cancer [n = 387], malignant melanoma [n = 353], head and neck cancer [n = 107], non-small cell lung cancer [n = 76], renal cell carcinoma [RCC] [n = 51], colorectal cancer [n = 20], and breast cancer [n = 14]), treated with three classes of CPIs (anti-CTLA-4 [n = 155], anti-PD-1 [n = 432], and anti-PD-L1 [n = 421]) (Table S1).	('malignant melanoma', 'Disease', 'MESH:D008545', (99, 117))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CPI', 'Chemical', '-', (4, 7))	('CPIs', 'Chemical', '-', (322, 326))	('urothelial cancer', 'Disease', (70, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (235, 252))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (267, 280))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('anti-PD-1', 'Var', (351, 360))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('neck', 'cellular_component', 'GO:0044326', ('138', '142'))	('breast cancer', 'Disease', 'MESH:D001943', (267, 280))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (198, 218))	('head and neck cancer', 'Phenotype', 'HP:0012288', (129, 149))	('PD-L1', 'Gene', (381, 386))	('breast cancer', 'Disease', (267, 280))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('neck cancer', 'Disease', 'MESH:D006258', (138, 149))	('neck cancer', 'Disease', (138, 149))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (161, 187))	('malignant melanoma', 'Disease', (99, 117))	('PD-L1', 'Gene', '29126', (381, 386))	('CTLA-4', 'Gene', '1493', (333, 339))	('colorectal cancer', 'Disease', 'MESH:D015179', (235, 252))	('tumor', 'Disease', (46, 51))	('CTLA-4', 'Gene', (333, 339))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('colorectal cancer', 'Disease', (235, 252))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('renal cell carcinoma', 'Disease', (198, 218))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (198, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('malignant melanoma', 'Phenotype', 'HP:0002861', (99, 117))	('CPI', 'Chemical', '-', (322, 325))	('lung cancer', 'Disease', (176, 187))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (165, 187))	('urothelial cancer', 'Disease', 'MESH:D014523', (70, 87))
148570	33508232	The biomarker with strongest effect size across all 12 studies in the CPI1000+ cohort was clonal TMB (i.e., the number of nonsynonymous mutations estimated to be present in every cancer cell) (odds ratio [OR] for "CR/PR" versus "SD/PD" = 1.74; 95% confidence interval [CI], [1.41-2.15], p = 2.9 x 10-7), closely followed by total TMB (OR = 1.70 [1.33-2.17], p = 1.9 x 10-5).	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('CPI', 'Chemical', '-', (70, 73))	('TMB', 'Chemical', '-', (330, 333))	('TMB', 'Chemical', '-', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))	('CPI1000+', 'Var', (70, 78))
148573	33508232	Within the sources of antigen category, other biomarkers such as frameshift insertion/deletion burden (indel TMB) (OR = 1.34 [1.12-1.62], p = 1.6 x 10-3), nonsense-mediated decay (NMD) escaping (NMD-escape) fs-indel burden (OR = 1.38 [1.15-1.66], p = 5.6 x 10-4), proportion of mutations fitting tobacco (OR = 1.39 [1.02-1.88], p = 3.5 x 10-2), UV (OR = 1.34 [1.12-1.60], p = 1.2 x 10-3), and APOBEC (OR = 1.39 [1.09-1.76], p = 8.1 x 10-3) mutation signatures, as well as SERPINB3 mutations (OR = 1.33 [1.12-1.59], p = 1.2 x 10-3), were all significantly associated with CPI response.	('CPI response', 'Disease', (571, 583))	('mutations', 'Var', (278, 287))	('mutations', 'Var', (481, 490))	('APOBEC', 'cellular_component', 'GO:0030895', ('393', '399'))	('SERPINB3', 'Gene', '6317', (472, 480))	('tobacco', 'Species', '4097', (296, 303))	('CPI', 'Chemical', '-', (571, 574))	('SERPINB3', 'Gene', (472, 480))	('APOBEC', 'Gene', (393, 399))	('associated with', 'Reg', (555, 570))	('TMB', 'Chemical', '-', (109, 112))
148574	33508232	Regarding nonsense mediated decay, we note CPI response rates are particularly elevated (~50%-70% CR/PR) in patients with >=5 fs-indel NMD-escaping mutations (Figure S1B).	('mutations', 'Var', (148, 157))	('CPI response rates', 'MPA', (43, 61))	('elevated', 'PosReg', (79, 87))	('patients', 'Species', '9606', (108, 116))	('CPI', 'Chemical', '-', (43, 46))	('NMD-escaping', 'Gene', (135, 147))
148575	33508232	Within the sources of antigen category, DNA damage response pathway mutations were not associated with CPI response (OR = 1.14 [0.95-1.36, p = 0.17]), nor was the differential agretopicity index (OR = 1.03 [0.81-1.32, p = 0.79]), MUC16 neoantigen count (OR = 1.15 [0.98-1.35, p = 0.08]), or AxR neoantigen fitness model (OR = 1.12 [0.95-1.32, p = 0.18]).	('MUC16', 'Gene', '94025', (230, 235))	('CPI', 'Chemical', '-', (103, 106))	('DNA damage response', 'biological_process', 'GO:0006974', ('40', '59'))	('CPI response', 'MPA', (103, 115))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('MUC16', 'Gene', (230, 235))	('mutations', 'Var', (68, 77))
148576	33508232	With regard to drivers of immune escape, we observed no significant association between the level of somatic copy-number alteration (SCNA), measured using the weighted genome instability index (wGII), and CPI response (OR = 1.05 [0.87-1.25], p = 0.62), or copy-number loss burden (OR = 1.09 [0.93-1.28], p = 0.27).	('copy-number alteration', 'Var', (109, 131))	('CPI', 'Chemical', '-', (205, 208))	('copy-number loss burden', 'Var', (256, 279))	('CPI', 'MPA', (205, 208))
148577	33508232	B2M, PTEN, JAK1/JAK2, KRAS, TP53, and receptor tyrosine kinase (RTK) mutations did not reach overall significance, despite showing strong effect sizes in some individual cohorts (see Figure 2A), nor did the ITH Shannon diversity index.	('receptor tyrosine kinase', 'Gene', (38, 62))	('PTEN', 'Gene', (5, 9))	('JAK', 'molecular_function', 'GO:0004713', ('16', '19'))	('KRAS', 'Gene', (22, 26))	('JAK', 'molecular_function', 'GO:0004713', ('11', '14'))	('JAK2', 'Gene', '3717', (16, 20))	('TP53', 'Gene', (28, 32))	('B2M', 'Gene', (0, 3))	('PTEN', 'Gene', '5728', (5, 9))	('RTK', 'Gene', (64, 67))	('JAK1', 'Gene', '3716', (11, 15))	('mutations', 'Var', (69, 78))	('RTK', 'Gene', '5979', (64, 67))	('JAK2', 'Gene', (16, 20))	('B2M', 'Gene', '567', (0, 3))	('TP53', 'Gene', '7157', (28, 32))	('receptor tyrosine kinase', 'Gene', '5979', (38, 62))	('KRAS', 'Gene', '3845', (22, 26))	('JAK1', 'Gene', (11, 15))
148578	33508232	Intriguingly, loss of heterozygosity (LOH) at the human leukocyte antigen (HLA) locus (LOHHLA) had a non-significant OR in the direction of improved chances of CPI response (OR = 1.14, [0.95-1.36, p = 0.16), the opposite of what may be expected, and possibly reflecting the fact that LOHHLA is found at higher frequency later in tumor evolution and is enriched in hot versus cold tumors.	('tumor', 'Disease', (380, 385))	('improved', 'PosReg', (140, 148))	('heterozygosity', 'Var', (22, 36))	('tumors', 'Phenotype', 'HP:0002664', (380, 386))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('tumor', 'Disease', 'MESH:D009369', (380, 385))	('CPI', 'Chemical', '-', (160, 163))	('hot versus cold tumors', 'Disease', (364, 386))	('human', 'Species', '9606', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('CPI response', 'MPA', (160, 172))	('hot versus cold tumors', 'Disease', 'MESH:D019584', (364, 386))	('tumor', 'Disease', (329, 334))	('loss', 'NegReg', (14, 18))
148579	33508232	Regarding host factors, we did not observe a significant association between the level of germline HLA-I evolutionary divergence (OR = 1.01 [0.80-1.28], p = 0.94) in the combined meta-analysis, nor for maximal HLA heterozygosity (OR = 0.97 [0.83-1.14], p = 0.70), HLA B62 supertype (OR = 0.93 [0.78-1.11], p = 0.45), HLA B1501 type (OR = 0.97 [0.81-1.16], p = 0.75), or germline variants in the KIR3DS1 gene (OR = 1.16 [0.99-1.37], p = 0.067).	('variants', 'Var', (379, 387))	('KIR3DS1', 'Gene', '3813', (395, 402))	('KIR3DS1', 'Gene', (395, 402))
148587	33508232	Furthermore, for rarer mutational events, this analysis is underpowered (e.g., B2M mutations/deletions were found only in 1.4% of cases), meaning larger sample sizes are likely required to confirm the role of these events in influencing CPI response.	('CPI', 'Chemical', '-', (237, 240))	('B2M', 'Gene', (79, 82))	('CPI response', 'CPA', (237, 249))	('B2M', 'Gene', '567', (79, 82))	('mutations/deletions', 'Var', (83, 102))
148595	33508232	Third, SERPINB3 mutations were found to have significantly higher effect size in anti-CTLA-4 versus anti-PD-1/L1 cohorts (p = 3.9 x 10-2) (Figure S2A).	('CTLA-4', 'Gene', (86, 92))	('SERPINB3', 'Gene', '6317', (7, 15))	('SERPINB3', 'Gene', (7, 15))	('mutations', 'Var', (16, 25))	('CTLA-4', 'Gene', '1493', (86, 92))	('higher', 'PosReg', (59, 65))	('effect', 'MPA', (66, 72))
148596	33508232	We next assessed the level of correlation between continuous biomarkers, observing a high level of correlation between metrics within each category (e.g., mutational metrics like TMB and clonal TMB were strongly correlated with each other).	('TMB', 'Chemical', '-', (179, 182))	('clonal', 'Var', (187, 193))	('TMB', 'Chemical', '-', (194, 197))	('TMB', 'Disease', (179, 182))	('correlated', 'Reg', (212, 222))
148605	33508232	Hence, a final combined pan-cancer model was trained using all CPI1000+ samples (n = 1,008) based on the set of 11 biomarkers listed above (Figure 3B), with feature importance scores as displayed in (Figure 3C).	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('CPI', 'Chemical', '-', (63, 66))	('CPI1000+', 'Var', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
148619	33508232	For each signature, we tested for association between the proportion of mutations fitting that signature and CPI response.	('mutations', 'Var', (72, 81))	('tested', 'Reg', (23, 29))	('CPI', 'MPA', (109, 112))	('CPI', 'Chemical', '-', (109, 112))
148621	33508232	For example, UV signature mutations were compared within each melanoma cohort (comparing more or less sun damage within melanoma patients), and then study-level results were combined only via meta-analysis.	('melanoma', 'Disease', (62, 70))	('patients', 'Species', '9606', (129, 137))	('mutations', 'Var', (26, 35))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('sun damage', 'Phenotype', 'HP:0000992', (102, 112))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
148626	33508232	Interestingly, we noted a strong association between signature 4 (tobacco)/signature 7 (UV) mutations and dinucleotide variant (DNV) count.	('tobacco', 'Species', '4097', (66, 73))	('dinucleotide', 'Chemical', 'MESH:D015226', (106, 118))	('dinucleotide variant', 'MPA', (106, 126))	('mutations', 'Var', (92, 101))
148627	33508232	DNVs were particularly enriched in melanoma, correlating strongly with signature 7 (UV) mutation proportion (rho = 0.65, p < 2.2 x 10-16, Figure 4B) and significantly associated with CPI response (Figure S2B).	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('UV', 'Gene', (84, 86))	('mutation', 'Var', (88, 96))	('CPI', 'Chemical', '-', (183, 186))	('associated', 'Reg', (167, 177))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))	('CPI response', 'Disease', (183, 195))
148628	33508232	Dinucleotide changes have two unique properties compared to single-nucleotide variants (SNVs): (1) where they straddle two codons, a double amino acid change can occur; and (2) in cases where both nucleotide changes are in the same codon, a more radical change in amino acid properties can result.	('Dinucleotide', 'Chemical', 'MESH:D015226', (0, 12))	('Dinucleotide', 'Var', (0, 12))	('double amino acid change', 'MPA', (133, 157))	('change', 'Reg', (254, 260))	('amino acid properties', 'MPA', (264, 285))
148635	33508232	Hence, loss of 9q34 was associated with sensitization to CPI therapy.	('CPI', 'Chemical', '-', (57, 60))	('associated', 'Reg', (24, 34))	('sensitization', 'MPA', (40, 53))	('loss of', 'Var', (7, 14))	('sensitization', 'biological_process', 'GO:0046960', ('40', '53'))	('9q34', 'Gene', (15, 19))
148641	33508232	In addition, we obtained drug screen data from the "Genomics of Drug Sensitivity in Cancer" database for two TNF pathway compounds that inhibit TRAF2 binding partners, BIRC2/BIRC3 (IAP-5620) and BIRC2 (AZD5582).	('BIRC2', 'Gene', '329', (195, 200))	('BIRC3', 'Gene', '330', (174, 179))	('BIRC2', 'Gene', '329', (168, 173))	('IAP-5620', 'Var', (181, 189))	('Cancer', 'Disease', 'MESH:D009369', (84, 90))	('inhibit', 'NegReg', (136, 143))	('TRAF2', 'Gene', '7186', (144, 149))	('BIRC2', 'Gene', (195, 200))	('BIRC3', 'Gene', (174, 179))	('BIRC2', 'Gene', (168, 173))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (64, 80))	('TNF', 'Gene', (109, 112))	('TRAF2', 'Gene', (144, 149))	('TNF', 'Gene', '7124', (109, 112))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Cancer', 'Disease', (84, 90))	('binding', 'Interaction', (150, 157))
148642	33508232	Cell lines with heterozygous TRAF2 mutation (n = 32) were significantly more sensitive to IAP-5620 treatment than wild-type (n = 685) cell lines (Figure S3A; p = 2.5 x 10-2).	('TRAF2', 'Gene', (29, 34))	('mutation', 'Var', (35, 43))	('more', 'PosReg', (72, 76))	('sensitive to', 'MPA', (77, 89))	('TRAF2', 'Gene', '7186', (29, 34))
148646	33508232	Chromosome 9 contains a number of tumor suppressor genes, with loss of CDKN2A (9p21.3) in particular being under strong positive selection and associated with aggressive tumor growth in multiple tumor types.	('aggressive tumor growth', 'Disease', (159, 182))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', (34, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('loss', 'Var', (63, 67))	('CDKN2A', 'Gene', (71, 77))	('associated with', 'Reg', (143, 158))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('CDKN2A', 'Gene', '1029', (71, 77))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('tumor', 'Disease', (170, 175))	('aggressive tumor growth', 'Disease', 'MESH:D006130', (159, 182))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))
148647	33508232	By contrast, loss of TRAF2 is not documented as a cancer-driver event (e.g., not listed in the Cancer Gene Census; https://cancer.sanger.ac.uk/census), and hence, loss of this gene may be a passenger event.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Cancer', 'Disease', (95, 101))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('TRAF2', 'Gene', '7186', (21, 26))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('TRAF2', 'Gene', (21, 26))	('loss', 'Var', (13, 17))
148649	33508232	Hence, these data suggest an evolutionary model where loss of whole chromosome 9 is selected as a driver event early in tumor evolution (e.g., due to CDKN2A), but then later leads to collateral sensitivity to immunotherapy, possibly due to 9q34 (TRAF2) loss.	('CDKN2A', 'Gene', (150, 156))	('TRAF2', 'Gene', (246, 251))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('collateral sensitivity', 'MPA', (183, 205))	('tumor', 'Disease', (120, 125))	('loss', 'NegReg', (253, 257))	('loss', 'Var', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('CDKN2A', 'Gene', '1029', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('TRAF2', 'Gene', '7186', (246, 251))	('leads to', 'Reg', (174, 182))
148653	33508232	Next, we considered focal (<3 Mb) amplifications (defined as copy number >= 5) and homozygous deletions (copy number = 0) in oncogenes and tumor suppressor genes respectively, to understand if these events are associated with CPI response.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('CPI', 'Chemical', '-', (226, 229))	('amplifications', 'Var', (34, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('139', '155'))	('associated', 'Reg', (210, 220))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('139', '155'))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))
148654	33508232	The most significant association was found to be significantly lower rates of CPI response in tumors with CCND1 amplification (response rate = 16.3%) compared to wild-type (26.6%) (p = 4.8 x 10-2; Figure 6A).	('CPI response', 'MPA', (78, 90))	('lower', 'NegReg', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('amplification', 'Var', (112, 125))	('tumors', 'Disease', (94, 100))	('CCND1', 'Gene', (106, 111))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('CPI', 'Chemical', '-', (78, 81))	('CCND1', 'Gene', '595', (106, 111))
148658	33508232	To validate the effect of CCND1 amplification in an independent cohort, we conducted overall survival analysis in n = 214 urothelial cancer patients treated with CPI in the MSK1600 cohort and observed a strong effect size whereby CCND1 amplification was associated with significantly shorter overall survival (hazard ratio [HR] = 3.6 [1.9-7.0], p = 1.3 x 10-4)(Figure 6D).	('overall survival', 'MPA', (292, 308))	('CCND1', 'Gene', '595', (230, 235))	('urothelial cancer', 'Disease', (122, 139))	('amplification', 'Var', (236, 249))	('CCND1', 'Gene', (26, 31))	('CCND1', 'Gene', (230, 235))	('CPI', 'Chemical', '-', (162, 165))	('urothelial cancer', 'Disease', 'MESH:D014523', (122, 139))	('patients', 'Species', '9606', (140, 148))	('CCND1', 'Gene', '595', (26, 31))	('shorter', 'NegReg', (284, 291))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
148660	33508232	Finally, we assessed the role of CCND1 amplification in a pan-cancer context in MSK1600 and found a significant association with reduced overall survival in CPI-treated patients (HR = 2.0 [1.4-2.9], p = 3.3 x 10-4) (Figure 6F), but not the non-CPI-treated MSK cohort (p = n.s., which is a larger cohort with arguably greater power) (Figure 6G).	('patients', 'Species', '9606', (169, 177))	('CCND1', 'Gene', (33, 38))	('CPI', 'Chemical', '-', (244, 247))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('amplification', 'Var', (39, 52))	('overall survival', 'MPA', (137, 153))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('CCND1', 'Gene', '595', (33, 38))	('reduced', 'NegReg', (129, 136))	('CPI', 'Chemical', '-', (157, 160))
148668	33508232	The gene next most highly expressed in responders was CCR5, a chemokine receptor central to T cell migration within draining lymph nodes and tumor tissues, which was also significantly higher in Mult+ cells (log2 FC = 8.9 versus Mult-, q = 0.002) (Figures 7A-7C).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('CCR', 'molecular_function', 'GO:0043880', ('54', '57'))	('T cell migration', 'biological_process', 'GO:0072678', ('92', '108'))	('CCR5', 'Gene', '1234', (54, 58))	('higher', 'PosReg', (185, 191))	('Mult+ cells', 'Var', (195, 206))	('CCR5', 'Gene', (54, 58))
148690	33508232	To address this gap, we conducted additional discovery analysis, identifying a number of other pan-cancer factors influencing CPI response, namely 9q34.3 (TRAF2) loss, CCND1 amplification, DNV count, and expression of CXCL13.	('CCND1', 'Gene', '595', (168, 173))	('CPI', 'Chemical', '-', (126, 129))	('loss', 'NegReg', (162, 166))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('CXCL13', 'Gene', (218, 224))	('cancer', 'Disease', (99, 105))	('amplification', 'Var', (174, 187))	('CCND1', 'Gene', (168, 173))	('TRAF2', 'Gene', '7186', (155, 160))	('CXCL13', 'Gene', '10563', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TRAF2', 'Gene', (155, 160))
148692	33508232	From a clinical perspective, the observation of CCND1 amplification as a cause of CPI resistance may offer potential therapeutic relevance, either as genetically defined subgroup unlikely to benefit from anti-PD-1/PD-L1 treatment or as a population suitable for combined CPI/anti-CDK4/6 therapy.	('cause', 'Reg', (73, 78))	('CPI', 'Chemical', '-', (271, 274))	('amplification', 'Var', (54, 67))	('CCND1', 'Gene', '595', (48, 53))	('PD-L1', 'Gene', (214, 219))	('CDK4/6', 'Gene', (280, 286))	('CDK', 'molecular_function', 'GO:0004693', ('280', '283'))	('CPI resistance', 'Disease', (82, 96))	('PD-L1', 'Gene', '29126', (214, 219))	('CPI', 'Chemical', '-', (82, 85))	('CCND1', 'Gene', (48, 53))	('CDK4/6', 'Gene', '1019;1021', (280, 286))
148702	33508232	Second, we note that IHC PD-L1 data are only available in a minority of cohorts, and hence, we have estimated expression at the mRNA rather than protein level in the CPI1000+ cohort.	('estimated', 'Reg', (100, 109))	('PD-L1', 'Gene', '29126', (25, 30))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('CPI', 'Chemical', '-', (166, 169))	('expression', 'MPA', (110, 120))	('CPI1000+', 'Var', (166, 174))	('PD-L1', 'Gene', (25, 30))
148703	33508232	Lastly, we note the single-tumor-region nature of the CPI1000+ dataset means that subclonal mutation counts are underestimated, impairing our ability to observe an association (or lack thereof) between subclonal mutation burden and response.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CPI1000+', 'Var', (54, 62))	('tumor', 'Disease', (27, 32))	('impairing', 'NegReg', (128, 137))	('response', 'MPA', (232, 240))	('CPI', 'Chemical', '-', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
148717	33508232	Hellman et al., an unpublished cohort of non-small cell lung cancer samples treated with anti-PD-1.	('anti-PD-1', 'Var', (89, 98))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (45, 67))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (41, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))
148718	33508232	Le et al., a colorectal cancer cohort treated with anti-PD-1 therapy.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('colorectal cancer', 'Disease', (13, 30))	('anti-PD-1', 'Var', (51, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (13, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))
148724	33508232	"all other tumor types" (n = 76) cohort (from KEYNOTE-028 and KEYNOTE-012 studies), treated with anti-PD-1.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('anti-PD-1', 'Var', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
148737	33508232	We have previously identified CD8+ neoantigen reactive T cells (NARTs) targeted against a clonal neoantigen (arising from the mutated MTFR2 gene) in NSCLC tumor regions derived from patient L011.	('CD8', 'Gene', (30, 33))	('CD8', 'Gene', '925', (30, 33))	('NSCLC tumor', 'Disease', 'MESH:D009369', (149, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('NSCLC tumor', 'Disease', (149, 160))	('patient', 'Species', '9606', (182, 189))	('MTFR2', 'Gene', (134, 139))	('MTFR2', 'Gene', '113115', (134, 139))	('mutated', 'Var', (126, 133))
148738	33508232	Briefly, neoantigen-specific CD8 T cells were identified using high throughput MHC multimer screening of candidate mutant peptides generated from patient-specific neoantigens of predicted < 500nM affinity for cognate HLA as previously described.	('CD8', 'Gene', '925', (29, 32))	('patient', 'Species', '9606', (146, 153))	('mutant', 'Var', (115, 121))	('CD8', 'Gene', (29, 32))
148739	33508232	In patient L011, TILs were found to recognize the HLA-B*3501 restricted, MTFR2D326Y-derived mutated sequence FAFQEYDSF (netMHC binding score: 22nM), but not the wild-type sequence FAFQEDDSF (netMHC binding score: 10nM).	('MTFR2', 'Gene', '113115', (73, 78))	('FAFQEYDSF', 'Var', (109, 118))	('patient', 'Species', '9606', (3, 10))	('binding', 'molecular_function', 'GO:0005488', ('198', '205'))	('MTFR2', 'Gene', (73, 78))	('HLA-B', 'Gene', (50, 55))	('binding', 'molecular_function', 'GO:0005488', ('127', '134'))	('HLA-B', 'Gene', '3106', (50, 55))
148754	33508232	VarScan2 somatic (version 2.3.6) used output from SAMtools mpileup to identify somatic variants between tumor and matched germline samples.	('variants', 'Var', (87, 95))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
148760	33508232	In addition, an orthogonal measure of tumor purity was derived based on mutation variant allele fraction, as previously described, and samples with a mismatch in purity between ASCAT and orthogonal measurements of greater than 1 standard deviation were additionally flagged for manual review.	('variant', 'Var', (81, 88))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
148763	33508232	For each sample variant calls were integrated with local allele specific copy number (obtained from ASCAT), tumor purity (also obtained from ASCAT), and variant allele frequency data.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('variant', 'Var', (16, 23))	('tumor', 'Disease', (108, 113))
148764	33508232	This enables mutations to be grouped together based on likely co-occurrence in the same set of cancer cells (clones), from which the founding (truncal) clone can be identified.	('mutations', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (95, 101))
148766	33508232	Binding affinities of mutant and corresponding wild-type peptides, relevant to the corresponding POLYSOLVER-inferred HLA alleles, were predicted using NetMHCpan (v3.0) and NetMHC (v4.0).	('NetMHCpan', 'Chemical', '-', (151, 160))	('NetMHC', 'Chemical', '-', (172, 178))	('mutant', 'Var', (22, 28))	('NetMHC', 'Chemical', '-', (151, 157))	('Binding affinities', 'MPA', (0, 18))
148775	33508232	The following previously published biomarkers were tested for association with response to CPI therapy: tumor mutation burden (TMB) (also split out into Clonal and Subclonal TMB), frameshift insertion/deletion (indel) mutation burden, burden of indels escaping nonsense mediated decay, Tobacco mutation signature, UV signature, APOBEC signature, Differential Agretopicity Index, MUC16 neoantigens, Neoantigen fitness model, SERPINB3/SERPINB4 mutations, DNA damage response pathway mutations, Shannon diversity index for intratumor heterogeneity (SDI-ITH), burden of somatic copy number alterations, burden of somatic copy number losses, HLA-I evolutionary divergence, maximal HLA heterozygosity, HLA B44/B62 supertypes, HLA B1501 type, KIR3DS1 germline variants, loss of heterozygosity at the HLA locus, sex, B2M mutations, JAK1/JAK2 mutations, KRAS and TP53 mutations, PTEN mutations, RTK mutations, STK11 mutations, BAP1 mutations, CD8A, CD274 (PD-L1), CD38, HAVCR2 (TIM3)/LGALS9, MEX3B and CXCL9 expression, as well as the CD8 T cell effector, proliferation, cytolytic, stroma-EMT, TGF beta pan fibroblast, IMPRES, CD8 T effector from the POPLAR trial, 12-cheomokine, HERV-3 family expression and T cell inflamed gene expression signatures.	('KRAS', 'Gene', '3845', (845, 849))	('JAK2', 'Gene', (829, 833))	('KIR3DS1', 'Gene', (736, 743))	('CXCL9', 'Gene', '4283', (993, 998))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('CD38', 'Gene', (955, 959))	('MUC16', 'Gene', (379, 384))	('MEX3B', 'Gene', (983, 988))	('PTEN', 'Gene', (870, 874))	('DNA damage response', 'biological_process', 'GO:0006974', ('453', '472'))	('TP53', 'Gene', (854, 858))	('STK11', 'molecular_function', 'GO:0033868', ('901', '906'))	('Tobacco', 'Species', '4097', (286, 293))	('KRAS', 'Gene', (845, 849))	('CD274', 'Gene', '29126', (940, 945))	('CD8A', 'Gene', '925', (934, 938))	('STK11', 'Gene', (901, 906))	('BAP1', 'Gene', '8314', (918, 922))	('CD8', 'Gene', '925', (1118, 1121))	('CD8', 'Gene', (1026, 1029))	('JAK', 'molecular_function', 'GO:0004713', ('829', '832'))	('APOBEC', 'cellular_component', 'GO:0030895', ('328', '334'))	('PTEN', 'Gene', '5728', (870, 874))	('JAK1', 'Gene', (824, 828))	('CD8', 'Gene', '925', (934, 937))	('SERPINB3', 'Gene', (424, 432))	('B2M', 'Gene', (809, 812))	('KIR3DS1', 'Gene', '3813', (736, 743))	('tumor', 'Disease', (525, 530))	('DNA', 'cellular_component', 'GO:0005574', ('453', '456'))	('JAK', 'molecular_function', 'GO:0004713', ('824', '827'))	('CD8A', 'Gene', (934, 938))	('tumor', 'Disease', (104, 109))	('CD274', 'Gene', (940, 945))	('BAP1', 'Gene', (918, 922))	('SERPINB3', 'Gene', '6317', (424, 432))	('TP53', 'Gene', '7157', (854, 858))	('tumor', 'Disease', 'MESH:D009369', (525, 530))	('EMT', 'biological_process', 'GO:0001837', ('1080', '1083'))	('MUC16', 'Gene', '94025', (379, 384))	('CD38', 'Gene', '952', (955, 959))	('SERPINB4', 'Gene', (433, 441))	('JAK2', 'Gene', '3717', (829, 833))	('B2M', 'Gene', '567', (809, 812))	('TMB', 'Chemical', '-', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('RTK', 'Gene', (886, 889))	('CD8', 'Gene', (1118, 1121))	('TMB', 'Chemical', '-', (127, 130))	('PD-L1', 'Gene', (947, 952))	('mutations', 'Var', (923, 932))	('CXCL9', 'Gene', (993, 998))	('CD8', 'Gene', '925', (1026, 1029))	('RTK', 'Gene', '5979', (886, 889))	('CD8', 'Gene', (934, 937))	('SERPINB4', 'Gene', '6318', (433, 441))	('CPI', 'Chemical', '-', (91, 94))	('PD-L1', 'Gene', '29126', (947, 952))	('tumor', 'Phenotype', 'HP:0002664', (525, 530))	('gene expression', 'biological_process', 'GO:0010467', ('1216', '1231'))	('JAK1', 'Gene', '3716', (824, 828))	('MEX3B', 'Gene', '84206', (983, 988))
148777	33508232	For inactivating pathway mutations (i.e., B2M, PTEN, JAK1/JAK2, DNA damage response) loss of function mutations (i.e., those causing a premature stop codon) and homozygous deletions were included.	('JAK', 'molecular_function', 'GO:0004713', ('53', '56'))	('premature stop codon', 'MPA', (135, 155))	('JAK1', 'Gene', (53, 57))	('loss of function', 'NegReg', (85, 101))	('DNA damage response', 'biological_process', 'GO:0006974', ('64', '83'))	('B2M', 'Gene', '567', (42, 45))	('JAK2', 'Gene', '3717', (58, 62))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('JAK1', 'Gene', '3716', (53, 57))	('mutations', 'Var', (102, 111))	('B2M', 'Gene', (42, 45))	('PTEN', 'Gene', (47, 51))	('PTEN', 'Gene', '5728', (47, 51))	('JAK', 'molecular_function', 'GO:0004713', ('58', '61'))	('JAK2', 'Gene', (58, 62))
148786	33508232	DeconstructSigs was used to derive COSMIC mutational signatures (v2) for each tumor samples with >= 50 somatic mutations (n = 872 patients).	('mutations', 'Var', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patients', 'Species', '9606', (130, 138))	('tumor', 'Disease', (78, 83))	('COSMIC mutational signatures', 'MPA', (35, 63))
148790	33508232	In the analysis we included disruptive events (non-synonymous mutations or copy-number loss defined relative to ploidy) of the following genes: CIITA, IRF1, PSME1, PSME2, PSME3, ERAP1, ERAP2, HSPA, HSPC, TAP1, TAP2, TAPBP, CALR, CNX, PDIA3 and B2M.	('TAPBP', 'Gene', (216, 221))	('ERAP2', 'Gene', (185, 190))	('TAPBP', 'Gene', '6892', (216, 221))	('PSME2', 'Gene', '5721', (164, 169))	('PSME3', 'Gene', (171, 176))	('TAP2', 'Gene', '6891', (210, 214))	('ERAP1', 'Gene', '51752', (178, 183))	('IRF1', 'Gene', (151, 155))	('CIITA', 'Gene', '4261', (144, 149))	('ERAP2', 'Gene', '64167', (185, 190))	('PDIA3', 'Gene', (234, 239))	('HSPC', 'Gene', '5688', (198, 202))	('TAP1', 'Gene', (204, 208))	('HSPC', 'Gene', (198, 202))	('TAP1', 'Gene', '6890', (204, 208))	('HSPA', 'Gene', (192, 196))	('PSME3', 'Gene', '10197', (171, 176))	('PDIA3', 'Gene', '2923', (234, 239))	('IRF1', 'Gene', '3659', (151, 155))	('CIITA', 'Gene', (144, 149))	('CALR', 'Gene', (223, 227))	('B2M', 'Gene', (244, 247))	('ERAP1', 'Gene', (178, 183))	('PSME1', 'Gene', (157, 162))	('copy-number', 'Var', (75, 86))	('CALR', 'Gene', '811', (223, 227))	('loss', 'NegReg', (87, 91))	('PSME2', 'Gene', (164, 169))	('CNX', 'Gene', '821', (229, 232))	('TAP2', 'Gene', (210, 214))	('B2M', 'Gene', '567', (244, 247))	('PSME1', 'Gene', '5720', (157, 162))	('CNX', 'Gene', (229, 232))
148792	33508232	Copy number segment data from ASCAT for all responders and non-responders were utilized to identify tumors with either focal amplification (copy number >= 5 and segment length < 3Mb) or homozygous deletions (copy number = 0 and segment length < 3Mb), in known oncogenes (for amplifications) or tumor suppressor genes (for deep deletions).	('tumor', 'Disease', (294, 299))	('copy', 'Var', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor suppressor', 'biological_process', 'GO:0051726', ('294', '310'))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('294', '310'))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('copy number >= 5', 'Var', (140, 156))
148805	33204153	Phosphorylated mitogen-activated protein kinase 14 (P-MAPK14, Thr180/Tyr182) was highly expressed in bladder cancer tissues and bladder cancer cell lines.	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('Thr180/Tyr182', 'Var', (62, 75))	('bladder cancer', 'Disease', (128, 142))	('bladder cancer', 'Disease', 'MESH:D001749', (128, 142))	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('Tyr182', 'Chemical', '-', (69, 75))	('bladder cancer', 'Disease', (101, 115))	('mitogen-activated protein kinase 14', 'Gene', (15, 50))	('mitogen-activated protein kinase 14', 'Gene', '1432', (15, 50))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Thr180', 'Chemical', '-', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('P-MAPK14', 'Var', (52, 60))
148806	33204153	Accordingly, P-MAPK14 could be combined with RUNX2 and maintain its protein stability and promote the proliferation and migration of bladder cancer cells.	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('MAPK', 'molecular_function', 'GO:0004707', ('15', '19'))	('maintain', 'PosReg', (55, 63))	('migration', 'CPA', (120, 129))	('promote', 'PosReg', (90, 97))	('P-MAPK14', 'Var', (13, 21))	('bladder cancer', 'Disease', (133, 147))	('proliferation', 'CPA', (102, 115))	('bladder cancer', 'Disease', 'MESH:D001749', (133, 147))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('protein stability', 'MPA', (68, 85))
148807	33204153	These results suggest that P-MAPK14 might play an important role in the development of bladder cancer and in the regulation of RUNX2 protein expression.	('protein', 'Protein', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('P-MAPK14', 'Var', (27, 35))	('RUNX2', 'Gene', (127, 132))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('MAPK', 'molecular_function', 'GO:0004707', ('29', '33'))	('expression', 'MPA', (141, 151))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('regulation', 'biological_process', 'GO:0065007', ('113', '123'))	('bladder cancer', 'Disease', 'MESH:D001749', (87, 101))	('bladder cancer', 'Disease', (87, 101))	('play', 'Reg', (42, 46))
148825	33204153	Phosphorylated RUNX2 is tightly related to the metastasis of prostate cancer.	('metastasis of prostate cancer', 'Disease', (47, 76))	('related', 'Reg', (32, 39))	('Phosphorylated', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('metastasis of prostate cancer', 'Disease', 'MESH:D011471', (47, 76))	('prostate cancer', 'Phenotype', 'HP:0012125', (61, 76))	('RUNX2', 'Gene', (15, 20))
148826	33204153	Overexpression of RUNX2 could increase the cancer cell proliferation in mantle cell lymphoma.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('lymphoma', 'Phenotype', 'HP:0002665', (84, 92))	('RUNX2', 'Gene', (18, 23))	('cancer', 'Disease', (43, 49))	('cell lymphoma', 'Phenotype', 'HP:0012191', (79, 92))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (72, 92))	('Overexpression', 'Var', (0, 14))	('increase', 'PosReg', (30, 38))	('mantle cell lymphoma', 'Disease', (72, 92))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
148833	33204153	This study suggested that P-MAPK14 might promote bladder cancer cell proliferation and migration by maintaining the stability of RUNX2 protein.	('migration', 'CPA', (87, 96))	('bladder cancer', 'Disease', (49, 63))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('bladder cancer', 'Phenotype', 'HP:0009725', (49, 63))	('promote', 'PosReg', (41, 48))	('MAPK', 'molecular_function', 'GO:0004707', ('28', '32'))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('P-MAPK14', 'Var', (26, 34))	('bladder cancer', 'Disease', 'MESH:D001749', (49, 63))	('stability', 'MPA', (116, 125))	('RUNX2 protein', 'Protein', (129, 142))
148851	33204153	After blocked by 5% skim milk for 1 hour, the proteins were then tested with the following antibodies: anti-MAPK14 (1:1000, 9218, CST), anti-P-MAPK14 (1:1000, 4511, CST), anti-RUNX2 (1:1000, 12,556, CST), anti-Tubulin (1:1000, 2128S, CST), anti-GAPDH (1:1000, 5174, CST) at 4 C overnight.	('CST', 'Gene', (234, 237))	('CST', 'Gene', '106478911', (199, 202))	('CST', 'Gene', (130, 133))	('GAPDH', 'Gene', '2597', (245, 250))	('1:1000', 'Var', (183, 189))	('CST', 'Gene', '106478911', (165, 168))	('MAPK', 'molecular_function', 'GO:0004707', ('143', '147'))	('1:1000', 'Var', (151, 157))	('CST', 'Gene', (199, 202))	('CST', 'Gene', '106478911', (266, 269))	('1:1000', 'Var', (252, 258))	('1:1000', 'Var', (116, 122))	('CST', 'Gene', '106478911', (234, 237))	('GAPDH', 'Gene', (245, 250))	('1:1000', 'Var', (219, 225))	('CST', 'Gene', (165, 168))	('CST', 'Gene', '106478911', (130, 133))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('tested', 'Reg', (65, 71))	('CST', 'Gene', (266, 269))
148863	33204153	The protein level of MAPK14 in bladder cancer samples was not statistically significant with that in adjacent non-cancerous tissues, while P-MAPK14 in bladder cancer samples was significantly higher than that in adjacent tissues (Figure 1C-F).	('bladder cancer', 'Disease', (151, 165))	('MAPK', 'molecular_function', 'GO:0004707', ('141', '145'))	('cancerous', 'Disease', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('bladder cancer', 'Phenotype', 'HP:0009725', (31, 45))	('P-MAPK14', 'Var', (139, 147))	('bladder cancer', 'Phenotype', 'HP:0009725', (151, 165))	('higher', 'PosReg', (192, 198))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancerous', 'Disease', 'MESH:D009369', (114, 123))	('bladder cancer', 'Disease', 'MESH:D001749', (151, 165))	('MAPK', 'molecular_function', 'GO:0004707', ('21', '25'))	('bladder cancer', 'Disease', 'MESH:D001749', (31, 45))	('bladder cancer', 'Disease', (31, 45))
148864	33204153	Moreover, compared with SV-HUC (immortalized human urothelial cells), high protein expression of P-MAPK14 was also observed in 5637, T24, and UMUC3 cell lines (Figure 1G).	('P-MAPK14', 'Var', (97, 105))	('human', 'Species', '9606', (45, 50))	('SV-HUC', 'CellLine', 'CVCL:3798', (24, 30))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('MAPK', 'molecular_function', 'GO:0004707', ('99', '103'))	('protein expression', 'MPA', (75, 93))
148872	33204153	In order to investigate whether RUNX2 can affect the stability of MAPK14 and P-MAPK14 protein, bladder cancer cell lines overexpressing RUNX2 protein was constructed.	('affect', 'Reg', (42, 48))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('MAPK', 'molecular_function', 'GO:0004707', ('79', '83'))	('bladder cancer', 'Disease', 'MESH:D001749', (95, 109))	('P-MAPK14', 'Var', (77, 85))	('bladder cancer', 'Disease', (95, 109))	('stability', 'MPA', (53, 62))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('MAPK', 'molecular_function', 'GO:0004707', ('66', '70'))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))
148873	33204153	To investigate the regulatory relationship between P-MAPK14 and RUNX2, immunoprecipitation assay was performed in two bladder cancer cell lines T24 and UMUC3, Western blot result showed that P-MAPK14 and RUNX2 might be bind to each other in the two cell lines (Figure 3E).	('bind', 'Interaction', (219, 223))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('MAPK', 'molecular_function', 'GO:0004707', ('193', '197'))	('P-MAPK14', 'Var', (191, 199))	('bladder cancer', 'Disease', 'MESH:D001749', (118, 132))	('bladder cancer', 'Disease', (118, 132))	('MAPK', 'molecular_function', 'GO:0004707', ('53', '57'))	('RUNX2', 'Gene', (204, 209))	('bladder cancer', 'Phenotype', 'HP:0009725', (118, 132))
148879	33204153	These data suggest that P-MAPK14 might promote the progression of bladder cancer partially by stabilizing RUNX2 protein.	('RUNX2 protein', 'Protein', (106, 119))	('bladder cancer', 'Disease', (66, 80))	('stabilizing', 'MPA', (94, 105))	('promote', 'PosReg', (39, 46))	('bladder cancer', 'Phenotype', 'HP:0009725', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('MAPK', 'molecular_function', 'GO:0004707', ('26', '30'))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('bladder cancer', 'Disease', 'MESH:D001749', (66, 80))	('protein', 'Protein', (112, 119))	('P-MAPK14', 'Var', (24, 32))
148882	33204153	As a crucial member of the P38 MAPK family, MAPK14 is highly expressed in a variety of cells and the main form of activation is phosphorylated MAPK14 (P-MAPK14, Thr180/Tyr182).	('activation', 'PosReg', (114, 124))	('Tyr182', 'Chemical', '-', (168, 174))	('P38', 'Gene', (27, 30))	('MAPK14', 'Gene', (44, 50))	('MAPK', 'molecular_function', 'GO:0004707', ('31', '35'))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('P38', 'Gene', '1432', (27, 30))	('MAPK', 'molecular_function', 'GO:0004707', ('153', '157'))	('P-MAPK14', 'Var', (151, 159))	('Thr180', 'Chemical', '-', (161, 167))	('MAPK', 'molecular_function', 'GO:0004707', ('143', '147'))
148883	33204153	Our previous in vivo and in vitro studies have shown that knockdown of MAPK14 can inhibit the proliferation and migration of renal cell clear cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('renal cell clear cell carcinoma', 'Phenotype', 'HP:0006770', (125, 156))	('renal cell clear cell carcinoma', 'Disease', (125, 156))	('inhibit', 'NegReg', (82, 89))	('MAPK', 'molecular_function', 'GO:0004707', ('71', '75'))	('renal cell clear cell carcinoma', 'Disease', 'MESH:C538614', (125, 156))	('MAPK14', 'Gene', (71, 77))	('knockdown', 'Var', (58, 67))
148891	33204153	It could be hypothesized that P-MAPK14 might promote the development of bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('MAPK', 'molecular_function', 'GO:0004707', ('32', '36'))	('P-MAPK14', 'Var', (30, 38))	('promote', 'PosReg', (45, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (72, 86))	('bladder cancer', 'Disease', (72, 86))
148896	33204153	At the same time, it was also found that P-MAPK14 and RUNX2 could be bind to each other, which is consistent with the results of bone formation and bone microenvironment studies in mice.	('bind', 'Interaction', (69, 73))	('RUNX2', 'Gene', (54, 59))	('mice', 'Species', '10090', (181, 185))	('bone formation', 'biological_process', 'GO:0001503', ('129', '143'))	('P-MAPK14', 'Var', (41, 49))	('MAPK', 'molecular_function', 'GO:0004707', ('43', '47'))
148898	33204153	It was found that MG-132 could effectively increase the expression of RUNX2 protein, in addition, the protein level of RUNX2 in the absence of MAPK14 protein could be recovered to some extent.	('MG-132', 'Chemical', 'MESH:C072553', (18, 24))	('MG-132', 'Var', (18, 24))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('RUNX2 protein', 'Protein', (70, 83))	('protein', 'Protein', (76, 83))	('expression', 'MPA', (56, 66))	('increase', 'PosReg', (43, 51))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('MAPK', 'molecular_function', 'GO:0004707', ('143', '147'))
148899	33204153	After bladder cancer cells were incubated with MG-132, there was no significant difference in protein level of MAPK14 as compared with the control group.	('MAPK14', 'Protein', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('bladder cancer', 'Phenotype', 'HP:0009725', (6, 20))	('protein level', 'MPA', (94, 107))	('MG-132', 'Chemical', 'MESH:C072553', (47, 53))	('MG-132', 'Var', (47, 53))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))	('bladder cancer', 'Disease', 'MESH:D001749', (6, 20))	('MAPK', 'molecular_function', 'GO:0004707', ('111', '115'))	('bladder cancer', 'Disease', (6, 20))
148900	33204153	Moreover, cycloheximide tracing experiment showed that the degradation rate of RUNX2 protein was significantly accelerated in the absence of MAPK14 protein.	('accelerated', 'PosReg', (111, 122))	('absence', 'Var', (130, 137))	('RUNX2', 'Gene', (79, 84))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('MAPK', 'molecular_function', 'GO:0004707', ('141', '145'))	('degradation rate', 'MPA', (59, 75))	('degradation', 'biological_process', 'GO:0009056', ('59', '70'))	('protein', 'Protein', (85, 92))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('cycloheximide', 'Chemical', 'MESH:D003513', (10, 23))
148902	33204153	In conclusion, P-MAPK14 is highly expressed in bladder cancer tissues, and P-MAPK14 can promote cell proliferation and migration.	('MAPK', 'molecular_function', 'GO:0004707', ('17', '21'))	('bladder cancer', 'Disease', 'MESH:D001749', (47, 61))	('promote', 'PosReg', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cell proliferation', 'CPA', (96, 114))	('MAPK', 'molecular_function', 'GO:0004707', ('77', '81'))	('bladder cancer', 'Disease', (47, 61))	('P-MAPK14', 'Var', (75, 83))	('cell proliferation', 'biological_process', 'GO:0008283', ('96', '114'))	('bladder cancer', 'Phenotype', 'HP:0009725', (47, 61))
148906	32471161	Inhibition of Heparanase Expression Results in Suppression of Invasion, Migration and Adhesion Abilities of Bladder Cancer Cells Heparan sulfate proteoglycan syndecan-1, CD138, is known to be associated with cell proliferation, adhesion, and migration in malignancies.	('Migration', 'CPA', (72, 81))	('Cancer', 'Disease', (116, 122))	('malignancies', 'Disease', 'MESH:D009369', (255, 267))	('Heparanase', 'Gene', '10855', (14, 24))	('malignancies', 'Disease', (255, 267))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (108, 122))	('Cancer', 'Disease', 'MESH:D009369', (116, 122))	('Adhesion Abilities', 'CPA', (86, 104))	('Suppression', 'NegReg', (47, 58))	('syndecan', 'molecular_function', 'GO:0015023', ('158', '166'))	('CD138', 'Gene', '6382', (170, 175))	('cell proliferation', 'biological_process', 'GO:0008283', ('208', '226'))	('Inhibition', 'Var', (0, 10))	('Heparanase', 'Gene', (14, 24))	('syndecan-1', 'Gene', (158, 168))	('Heparan sulfate', 'Chemical', 'MESH:D006497', (129, 144))	('Cancer', 'Phenotype', 'HP:0002664', (116, 122))	('proteoglycan', 'molecular_function', 'GO:0005203', ('145', '157'))	('CD138', 'Gene', (170, 175))	('Invasion', 'CPA', (62, 70))	('syndecan-1', 'Gene', '6382', (158, 168))
148910	32471161	A bladder cancer development mouse model was treated with RK-682 and the bladder tissues were examined using immunohistochemical analysis for Ki-67, E-cadherin, LC3, and CD31 expressions.	('A bladder cancer', 'Disease', 'MESH:D001749', (0, 16))	('LC3', 'Gene', (161, 164))	('CD31', 'Gene', (170, 174))	('E-cadherin', 'Protein', (149, 159))	('Ki-67', 'Gene', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cadherin', 'molecular_function', 'GO:0008014', ('151', '159'))	('mouse', 'Species', '10090', (29, 34))	('RK-682', 'Var', (58, 64))	('A bladder cancer', 'Disease', (0, 16))	('Ki-67', 'Gene', '17345', (142, 147))	('bladder cancer', 'Phenotype', 'HP:0009725', (2, 16))
148912	32471161	Inhibition of heparanase was found to suppress autophagy.	('autophagy', 'biological_process', 'GO:0006914', ('47', '56'))	('heparanase', 'Gene', '10855', (14, 24))	('autophagy', 'biological_process', 'GO:0016236', ('47', '56'))	('Inhibition', 'Var', (0, 10))	('autophagy', 'CPA', (47, 56))	('suppress', 'NegReg', (38, 46))	('heparanase', 'Gene', (14, 24))
148925	32471161	In vitro experiments showed that knocking down syndecan-1 using siRNA induces cellular apoptosis and decreases the capacity for cellular proliferation.	('syndecan-1', 'Gene', (47, 57))	('capacity for cellular proliferation', 'CPA', (115, 150))	('cellular apoptosis', 'CPA', (78, 96))	('decreases', 'NegReg', (101, 110))	('induces', 'Reg', (70, 77))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('syndecan-1', 'Gene', '6382', (47, 57))	('knocking down', 'Var', (33, 46))	('syndecan', 'molecular_function', 'GO:0015023', ('47', '55'))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))
148933	32471161	Recently, a small molecule inhibitor of heparanase was shown to reduce metastatic characteristics in a hepatocellular carcinoma model.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('reduce', 'NegReg', (64, 70))	('metastatic characteristics in a', 'CPA', (71, 102))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 127))	('inhibitor', 'Var', (27, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('hepatocellular carcinoma', 'Disease', (103, 127))	('heparanase', 'Gene', (40, 50))	('heparanase', 'Gene', '10855', (40, 50))
148948	32471161	We first examined the suppression of heparanase protein expression and mRNA expression by knockdown with Si RNA (Supplementary Figure S2).	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('knockdown', 'Var', (90, 99))	('heparanase', 'Gene', (37, 47))	('mRNA expression', 'MPA', (71, 86))	('suppression', 'NegReg', (22, 33))	('heparanase', 'Gene', '10855', (37, 47))	('RNA', 'cellular_component', 'GO:0005562', ('108', '111'))
148949	32471161	MGH-U3 showed a significant decrease in cell activity due to heparanase knockdown compared to T24.	('heparanase', 'Gene', (61, 71))	('decrease', 'NegReg', (28, 36))	('heparanase', 'Gene', '10855', (61, 71))	('knockdown', 'Var', (72, 81))	('cell activity', 'CPA', (40, 53))
148951	32471161	In the UROtsa cell line, heparanase knockdown suppressed growth activity by 15%.	('heparanase', 'Gene', '10855', (25, 35))	('growth activity', 'CPA', (57, 72))	('knockdown', 'Var', (36, 45))	('heparanase', 'Gene', (25, 35))	('suppressed', 'NegReg', (46, 56))
148952	32471161	Further, heparanase knock-down by siRNA induced apoptosis (Figure 2b).	('heparanase', 'Gene', (9, 19))	('knock-down', 'Var', (20, 30))	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('heparanase', 'Gene', '10855', (9, 19))	('apoptosis', 'CPA', (48, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))
148956	32471161	MGH-U3 and T24 cell lines were treated with RK-682 and examined in a cell viability assay to determine cytotoxicity.	('cytotoxicity', 'Disease', (103, 115))	('RK-682', 'Var', (44, 50))	('cytotoxicity', 'Disease', 'MESH:D064420', (103, 115))
148959	32471161	UROtsa, which has low expression of heparanae, has an IC50 of RK-682 about 2-3 times higher than that of urothelial carcinoma cell line, MGH-U3 cell line and T24 cell line which has high expression of heparanase.	('heparanase', 'Gene', (201, 211))	('urothelial carcinoma', 'Disease', (105, 125))	('higher', 'PosReg', (85, 91))	('heparanae', 'Chemical', '-', (36, 45))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (105, 125))	('IC50', 'MPA', (54, 58))	('heparanase', 'Gene', '10855', (201, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('RK-682', 'Var', (62, 68))
148960	32471161	In the heparanse knockdown experiment with Si RNA, the UROtsa cell line showed almost no inhibition of the cell activity, whereas RK-682 inhibited the cell activity of the UROtsa cell line at a high concentration.	('inhibited', 'NegReg', (137, 146))	('cell activity', 'CPA', (151, 164))	('RK-682', 'Var', (130, 136))	('RNA', 'cellular_component', 'GO:0005562', ('46', '49'))	('heparanse', 'Chemical', '-', (7, 16))
148961	32471161	From this fact, it is considered that RK-682 has an action other than the inhibition of heparanase.	('heparanase', 'Gene', '10855', (88, 98))	('heparanase', 'Gene', (88, 98))	('RK-682', 'Var', (38, 44))
148966	32471161	There was a significant decrease in the bladder weight/body wight, (RK-682 group vs. control group; 0.028 vs. 0.056 p = 0.0051) and ratio of infiltrative bladder cancer (RK-682 group vs. control group; 28.6% vs. 85.7% p = 0.027) in the RK-682 treatment group compared to the control group (Figure 4b).	('bladder weight/body wight', 'CPA', (40, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (154, 168))	('RK-682', 'Var', (236, 242))	('decrease', 'NegReg', (24, 32))	('infiltrative bladder cancer', 'Disease', 'MESH:D001749', (141, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('infiltrative bladder cancer', 'Disease', (141, 168))
148967	32471161	IHC studies of the mouse tissue showed decreased expression of Ki67, LC3, and CD31 markers in the specimens from animals treated with RK-682.	('Ki67', 'Gene', '17345', (63, 67))	('CD31', 'Gene', (78, 82))	('expression', 'MPA', (49, 59))	('LC3', 'Gene', (69, 72))	('RK-682', 'Var', (134, 140))	('Ki67', 'Gene', (63, 67))	('mouse', 'Species', '10090', (19, 24))	('decreased', 'NegReg', (39, 48))
148971	32471161	We have demonstrated that inhibition of heparanase suppresses cell proliferation, epithelial-mesenchymal transition (EMT), autophagy and angiogenesis.	('autophagy', 'CPA', (123, 132))	('epithelial-mesenchymal transition', 'CPA', (82, 115))	('EMT', 'biological_process', 'GO:0001837', ('117', '120'))	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('autophagy', 'biological_process', 'GO:0006914', ('123', '132'))	('inhibition', 'Var', (26, 36))	('cell proliferation', 'CPA', (62, 80))	('heparanase', 'Gene', (40, 50))	('angiogenesis', 'CPA', (137, 149))	('angiogenesis', 'biological_process', 'GO:0001525', ('137', '149'))	('suppresses', 'NegReg', (51, 61))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('82', '115'))	('heparanase', 'Gene', '10855', (40, 50))	('autophagy', 'biological_process', 'GO:0016236', ('123', '132'))
148978	32471161	In this study, inhibition of heparanase activity significantly reduced the ability of cancer cells to migrate and infiltrate.	('reduced', 'NegReg', (63, 70))	('heparanase', 'Gene', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('activity', 'MPA', (40, 48))	('heparanase', 'Gene', '10855', (29, 39))	('heparanase activity', 'molecular_function', 'GO:0030305', ('29', '48'))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('inhibition', 'Var', (15, 25))	('cancer', 'Disease', (86, 92))
148990	32471161	Expression analysis shows that RK-682 does have a heparanase inhibitory effect (Supplementary Figure S3).	('RK-682', 'Var', (31, 37))	('heparanase', 'Gene', (50, 60))	('heparanase', 'Gene', '10855', (50, 60))
149030	31420607	We have found that miR-29b acts as an oncogenic miRNA in Tsc2-deficient cells: inhibition of miR-29b suppressed cell proliferation, anchorage-independent cell growth, cell migration, invasion, and the growth of Tsc2-deficient tumors in vivo.	('miR-29b', 'Gene', (19, 26))	('Tsc2-deficient tumors', 'Disease', (211, 232))	('growth', 'CPA', (201, 207))	('rat', 'Species', '10116', (175, 178))	('cell proliferation', 'biological_process', 'GO:0008283', ('112', '130'))	('miR', 'Gene', (93, 96))	('miR', 'Gene', '220972', (19, 22))	('cell proliferation', 'CPA', (112, 130))	('miR-29b', 'Gene', '407024', (93, 100))	('anchorage-independent cell growth', 'CPA', (132, 165))	('inhibition', 'Var', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('Tsc2-deficient tumors', 'Disease', 'MESH:C566021', (211, 232))	('invasion', 'CPA', (183, 191))	('cell migration', 'CPA', (167, 181))	('rat', 'Species', '10116', (124, 127))	('miR', 'Gene', (19, 22))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('cell growth', 'biological_process', 'GO:0016049', ('154', '165'))	('cell migration', 'biological_process', 'GO:0016477', ('167', '181'))	('miR', 'Gene', '220972', (48, 51))	('miR-29b', 'Gene', '407024', (19, 26))	('miR-29b', 'Gene', (93, 100))	('suppressed', 'NegReg', (101, 111))	('miR', 'Gene', '220972', (93, 96))	('miR', 'Gene', (48, 51))
149035	31420607	miR-29b expression correlated with low RARbeta expression in renal clear cell carcinomas and bladder urothelial carcinomas, tumors associated with TSC gene mutations.	('bladder urothelial carcinomas', 'Disease', 'MESH:D001749', (93, 122))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('renal clear cell carcinomas', 'Disease', 'MESH:D002292', (61, 88))	('mutations', 'Var', (156, 165))	('renal clear cell carcinomas', 'Disease', (61, 88))	('TSC', 'Gene', (147, 150))	('RARbeta', 'Protein', (39, 46))	('TSC', 'Gene', '7248', (147, 150))	('miR-29b', 'Gene', '407024', (0, 7))	('tumors', 'Disease', (124, 130))	('miR-29b', 'Gene', (0, 7))	('bladder urothelial carcinomas', 'Disease', (93, 122))	('low', 'NegReg', (35, 38))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('expression', 'MPA', (47, 57))
149036	31420607	Overexpression of ING4 inhibited the migration and invasion of Tsc2-deficient cells while silencing of ING4 reversed the RARbeta-mediated suppression of cell migration and invasion.	('ING4', 'Gene', (18, 22))	('ING4', 'Gene', (103, 107))	('inhibited', 'NegReg', (23, 32))	('silencing', 'Var', (90, 99))	('cell migration', 'biological_process', 'GO:0016477', ('153', '167'))	('rat', 'Species', '10116', (40, 43))	('rat', 'Species', '10116', (161, 164))
149039	31420607	TSC is caused by germline loss-of-function mutations in one of the two tumor suppressor genes, TSC1 or TSC2.	('tumor suppressor', 'biological_process', 'GO:0051726', ('71', '87'))	('TSC', 'Gene', '7248', (95, 98))	('TSC2', 'Gene', '7249', (103, 107))	('TSC2', 'Gene', (103, 107))	('TSC1', 'Gene', '7248', (95, 99))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('71', '87'))	('TSC', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('TSC1', 'Gene', (95, 99))	('mutations', 'Var', (43, 52))	('TSC', 'Gene', '7248', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('TSC', 'Gene', '7248', (103, 106))	('TSC', 'Gene', (103, 106))	('tumor', 'Disease', (71, 76))	('loss-of-function', 'NegReg', (26, 42))	('TSC', 'Gene', (95, 98))
149042	31420607	Mutational inactivation of TSC1 or TSC2 results in hyperactivation of mTORC1.	('hyperactivation', 'PosReg', (51, 66))	('TSC2', 'Gene', '7249', (35, 39))	('mTORC1', 'Gene', '382056', (70, 76))	('TSC1', 'Gene', '7248', (27, 31))	('Mutational inactivation', 'Var', (0, 23))	('mTORC1', 'cellular_component', 'GO:0031931', ('70', '76'))	('TSC2', 'Gene', (35, 39))	('TSC1', 'Gene', (27, 31))	('mTORC1', 'Gene', (70, 76))
149046	31420607	Through an RNA-induced silencing complex, miRNAs bind to the 3'-untranslated region of their target genes, either by perfect base pairing resulting in mRNA degradation or by imperfect base pairing to block translation.	('bind', 'Interaction', (49, 53))	('imperfect base', 'Var', (174, 188))	('mRNA degradation', 'MPA', (151, 167))	('base pairing', 'MPA', (125, 137))	('base pairing', 'molecular_function', 'GO:0003676', ('184', '196'))	('block', 'NegReg', (200, 205))	('translation', 'biological_process', 'GO:0006412', ('206', '217'))	('mRNA degradation', 'biological_process', 'GO:0006402', ('151', '167'))	('perfect', 'Var', (117, 124))	('miR', 'Gene', '220972', (42, 45))	('miR', 'Gene', (42, 45))	('translation', 'MPA', (206, 217))	('RNA-induced silencing complex', 'cellular_component', 'GO:0016442', ('11', '40'))	('base pairing', 'molecular_function', 'GO:0003676', ('125', '137'))
149047	31420607	Because a single miRNA can bind to several different mRNA transcripts and one mRNA transcript is often targeted by multiple miRNA species, small changes in miRNA levels can have large downstream effects on phenotypes that can include proliferation, cell cycle progression, differentiation, migration, apoptosis, and metabolism.	('apoptosis', 'CPA', (301, 310))	('miR', 'Gene', (124, 127))	('miR', 'Gene', (156, 159))	('rat', 'Species', '10116', (293, 296))	('metabolism', 'biological_process', 'GO:0008152', ('316', '326'))	('miR', 'Gene', '220972', (17, 20))	('cell cycle', 'biological_process', 'GO:0007049', ('249', '259'))	('cell cycle progression', 'CPA', (249, 271))	('changes', 'Var', (145, 152))	('differentiation', 'CPA', (273, 288))	('proliferation', 'CPA', (234, 247))	('metabolism', 'CPA', (316, 326))	('apoptosis', 'biological_process', 'GO:0097194', ('301', '310'))	('miR', 'Gene', (17, 20))	('apoptosis', 'biological_process', 'GO:0006915', ('301', '310'))	('rat', 'Species', '10116', (241, 244))	('migration', 'CPA', (290, 299))	('effects', 'Reg', (195, 202))	('miR', 'Gene', '220972', (124, 127))	('miR', 'Gene', '220972', (156, 159))
149061	31420607	Targeting miR-29b represents a novel therapeutic strategy for TSC and other tumors with mTORC1 hyperactivation.	('miR-29b', 'Gene', '407024', (10, 17))	('mTORC1', 'Gene', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('TSC', 'Gene', (62, 65))	('TSC', 'Gene', '7248', (62, 65))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('miR-29b', 'Gene', (10, 17))	('mTORC1', 'cellular_component', 'GO:0031931', ('88', '94'))	('mTORC1', 'Gene', '382056', (88, 94))	('Targeting', 'Var', (0, 9))	('rat', 'Species', '10116', (51, 54))
149063	31420607	To determine whether rapamycin-induced miR-29b expression is observed in other Tsc2-deficient models, we treated two pairs of Tsc2 wild-type and Tsc2-knockout mouse embryonic fibroblasts (MEFs) (referred to as Tsc2+/+ and Tsc2-/- MEFs; Tsc2 WT and Tsc2 KO MEFs) with rapamycin (20 nM) for 24 h. Using RT-qPCR, we found that miR-29b expression was upregulated by ~2.5-fold (P < 0.001) in Tsc2-/- MEFs (Fig.	('MEFs', 'CellLine', 'CVCL:9115', (188, 192))	('expression', 'MPA', (332, 342))	('miR-29b', 'Gene', (39, 46))	('MEFs', 'CellLine', 'CVCL:9115', (256, 260))	('miR-29b', 'Gene', '407024', (324, 331))	('mouse', 'Species', '10090', (159, 164))	('rapamycin', 'Chemical', 'MESH:D020123', (267, 276))	('MEFs', 'CellLine', 'CVCL:9115', (395, 399))	('MEFs', 'CellLine', 'CVCL:9115', (230, 234))	('upregulated', 'PosReg', (347, 358))	('miR-29b', 'Gene', (324, 331))	('rapamycin', 'Chemical', 'MESH:D020123', (21, 30))	('miR-29b', 'Gene', '407024', (39, 46))	('Tsc2-/- MEFs', 'Var', (387, 399))
149081	31420607	Similarly, miR-29b knockdown with miR-29b-ZIP in Tsc2-/- MEFs further enhanced the inhibition of cell proliferation by the ATP-competitive inhibitors of mTOR, Torin 1 or PP242, compared with vehicle-treated cells (Supplementary Fig.	('MEFs', 'CellLine', 'CVCL:9115', (57, 61))	('PP242', 'Var', (170, 175))	('inhibition', 'NegReg', (83, 93))	('ZIP', 'Gene', '1613', (42, 45))	('miR-29b', 'Gene', '407024', (11, 18))	('miR-29b', 'Gene', '407024', (34, 41))	('ATP', 'Chemical', 'MESH:D000255', (123, 126))	('mTOR', 'Gene', (153, 157))	('ZIP', 'Gene', (42, 45))	('mTOR', 'Gene', '2475', (153, 157))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('83', '115'))	('rat', 'Species', '10116', (109, 112))	('miR-29b', 'Gene', (11, 18))	('miR-29b', 'Gene', (34, 41))	('enhanced', 'PosReg', (70, 78))	('cell proliferation', 'CPA', (97, 115))
149092	31420607	These data demonstrate that miR-29b is a critical regulator of cell proliferation and anchorage-independent growth in Tsc2-deficient cells and suggest that inhibition of miR-29b may enhance the therapeutic effect of rapamycin.	('miR-29b', 'Gene', (170, 177))	('inhibition', 'Var', (156, 166))	('rat', 'Species', '10116', (18, 21))	('enhance', 'PosReg', (182, 189))	('miR-29b', 'Gene', '407024', (28, 35))	('rat', 'Species', '10116', (75, 78))	('therapeutic effect', 'CPA', (194, 212))	('rapamycin', 'Chemical', 'MESH:D020123', (216, 225))	('miR-29b', 'Gene', '407024', (170, 177))	('miR-29b', 'Gene', (28, 35))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))
149094	31420607	miR-29b knockdown decreased cell migration by 55% (P <0.05).	('cell migration', 'biological_process', 'GO:0016477', ('28', '42'))	('cell migration', 'CPA', (28, 42))	('decreased', 'NegReg', (18, 27))	('knockdown', 'Var', (8, 17))	('rat', 'Species', '10116', (36, 39))	('miR-29b', 'Gene', (0, 7))	('miR-29b', 'Gene', '407024', (0, 7))
149097	31420607	Similarly, miR-29b inhibition markedly suppressed the invasive capacity of Tsc2-/- MEFs (45%, P < 0.01), as demonstrated using a Boyden chamber invasion assay, while the combination of miR-29b inhibition and rapamycin treatment further inhibited invasive capacity (73%, P <0.001) (Fig.	('miR-29b', 'Gene', '407024', (185, 192))	('rapamycin', 'Chemical', 'MESH:D020123', (208, 217))	('rat', 'Species', '10116', (115, 118))	('inhibition', 'Var', (19, 29))	('miR-29b', 'Gene', '407024', (11, 18))	('inhibited', 'NegReg', (236, 245))	('inhibition', 'NegReg', (193, 203))	('miR-29b', 'Gene', (185, 192))	('invasive capacity', 'CPA', (54, 71))	('MEFs', 'CellLine', 'CVCL:9115', (83, 87))	('miR-29b', 'Gene', (11, 18))	('invasive capacity', 'CPA', (246, 263))	('suppressed', 'NegReg', (39, 49))
149104	31420607	We then focused on genes whose expression was upregulated by miR-29b inhibition and suppressed by rapamycin, and identified RARbeta, whose expression is downregulated by rapamycin and is restored by miR-29b inhibition (Fig.	('miR-29b', 'Gene', '407024', (199, 206))	('rapamycin', 'Chemical', 'MESH:D020123', (170, 179))	('upregulated', 'PosReg', (46, 57))	('miR-29b', 'Gene', (61, 68))	('rapamycin', 'Chemical', 'MESH:D020123', (98, 107))	('miR-29b', 'Gene', (199, 206))	('expression', 'MPA', (31, 41))	('miR-29b', 'Gene', '407024', (61, 68))	('expression', 'MPA', (139, 149))	('inhibition', 'Var', (69, 79))	('RARbeta', 'Gene', (124, 131))	('downregulated', 'NegReg', (153, 166))
149127	31420607	However, miR-29b inhibition and/or rapamycin treatment did not alter ING4 mRNA levels (Fig.	('miR-29b', 'Gene', (9, 16))	('inhibition', 'Var', (17, 27))	('miR-29b', 'Gene', '407024', (9, 16))	('ING4 mRNA levels', 'MPA', (69, 85))	('rapamycin', 'Chemical', 'MESH:D020123', (35, 44))
149132	31420607	5d-h), we hypothesized that knockdown of ING4 in RARbeta2 overexpressing cells could elevate migratory/invasive phenotypes.	('elevate', 'PosReg', (85, 92))	('knockdown', 'Var', (28, 37))	('RARbeta2', 'Gene', (49, 57))	('rat', 'Species', '10116', (96, 99))	('ING4', 'Gene', (41, 45))	('migratory/invasive phenotypes', 'CPA', (93, 122))
149137	31420607	However, inhibition of miR-29b significantly decreased tumor growth (Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('miR-29b', 'Gene', (23, 30))	('decreased', 'NegReg', (45, 54))	('tumor', 'Disease', (55, 60))	('miR-29b', 'Gene', '407024', (23, 30))	('inhibition', 'Var', (9, 19))
149144	31420607	RT-qPCR analysis of tumor RNA demonstrated that miR-29b knockdown increased RARbeta mRNA levels by fourfold (P < 0.05) in vehicle-treated tumors and by sixfold (P <0.01) in rapamycin-treated tumors (Fig.	('tumor', 'Disease', (138, 143))	('miR-29b', 'Gene', '407024', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumors', 'Disease', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('miR-29b', 'Gene', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('increased', 'PosReg', (66, 75))	('rat', 'Species', '10116', (37, 40))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Disease', (191, 196))	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))	('knockdown', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('rapamycin', 'Chemical', 'MESH:D020123', (173, 182))	('RARbeta mRNA levels', 'MPA', (76, 95))	('tumors', 'Disease', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', (20, 25))
149149	31420607	We focused on these tumors since they can be both associated with TSC gene mutations.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('TSC', 'Gene', (66, 69))	('TSC', 'Gene', '7248', (66, 69))	('mutations', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('associated', 'Reg', (50, 60))
149156	31420607	Given that mTORC1 hyperactivation and miR-29b dysregulation are relevant to many human tumors, the mechanistic insights gained from this study have broad potential implications.	('miR-29b', 'Gene', '407024', (38, 45))	('hyperactivation', 'PosReg', (18, 33))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('dysregulation', 'Var', (46, 59))	('miR-29b', 'Gene', (38, 45))	('mTORC1', 'Gene', '382056', (11, 17))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('mTORC1', 'cellular_component', 'GO:0031931', ('11', '17'))	('mTORC1', 'Gene', (11, 17))	('human', 'Species', '9606', (81, 86))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
149175	31420607	RARbeta expression is upregulated in Tsc2-deficient cells with knockdown of miR-29b and upregulated in cells over-expressing miR-29b; this is the result of targeting of the 3' UTR of the RARbeta transcript by miR-29b.	('upregulated', 'PosReg', (22, 33))	('miR-29b', 'Gene', (76, 83))	('miR-29b', 'Gene', (209, 216))	('upregulated', 'PosReg', (88, 99))	('miR-29b', 'Gene', '407024', (125, 132))	('miR-29b', 'Gene', '407024', (76, 83))	('RARbeta', 'Gene', (0, 7))	('expression', 'MPA', (8, 18))	('miR-29b', 'Gene', '407024', (209, 216))	('knockdown', 'Var', (63, 72))	('RARbeta', 'Gene', (187, 194))	('miR-29b', 'Gene', (125, 132))
149182	31420607	Furthermore, this interaction has functional relevance, as RARbeta2-mediated inhibition of cell migration and invasion was elevated by siRNA knockdown of ING4.	('knockdown', 'Var', (141, 150))	('rat', 'Species', '10116', (99, 102))	('elevated', 'PosReg', (123, 131))	('inhibition', 'NegReg', (77, 87))	('ING4', 'Gene', (154, 158))	('cell migration', 'CPA', (91, 105))	('inhibition of cell migration', 'biological_process', 'GO:0030336', ('77', '105'))
149186	31420607	Of particular relevance to our findings, ING4 suppresses melanoma cell migration and invasion by regulating Kang-Ai 1, a well-known tumor metastasis suppressor in prostate cancer via the regulation of NF-kappaB/p65.	('p65', 'Gene', (211, 214))	('regulating', 'Reg', (97, 107))	('prostate cancer', 'Disease', (163, 178))	('regulation', 'biological_process', 'GO:0065007', ('187', '197'))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('tumor', 'Disease', (132, 137))	('invasion', 'CPA', (85, 93))	('cell migration', 'biological_process', 'GO:0016477', ('66', '80'))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('p65', 'Gene', '5970', (211, 214))	('Kang-Ai 1', 'Gene', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('ING4', 'Var', (41, 45))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('suppresses', 'NegReg', (46, 56))	('rat', 'Species', '10116', (74, 77))	('prostate cancer', 'Disease', 'MESH:D011471', (163, 178))	('prostate cancer', 'Phenotype', 'HP:0012125', (163, 178))
149194	31420607	Inhibition of miR-29b suppresses Tsc2-deficient tumor progression by downregulating cell growth, migration, and invasion via RARbeta, a direct and novel target of miR-29b, and ING4, a tumor suppressor that directly interacts with RARbeta.	('miR-29b', 'Gene', '407024', (14, 21))	('invasion via RARbeta', 'Disease', 'MESH:D009361', (112, 132))	('miR-29b', 'Gene', '407024', (163, 170))	('downregulating', 'NegReg', (69, 83))	('tumor', 'Disease', (184, 189))	('Tsc2-deficient', 'Gene', (33, 47))	('rat', 'Species', '10116', (100, 103))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('184', '200'))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', (48, 53))	('miR-29b', 'Gene', (14, 21))	('invasion via RARbeta', 'Disease', (112, 132))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor suppressor', 'biological_process', 'GO:0051726', ('184', '200'))	('miR-29b', 'Gene', (163, 170))	('suppresses', 'NegReg', (22, 32))	('cell growth', 'biological_process', 'GO:0016049', ('84', '95'))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cell growth', 'CPA', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
149195	31420607	These findings may have clinical relevance for the adults and children with TSC and for the women with LAM, and for sporadic tumors with mTORC1 hyperactivation (estimated to represent 50% of all human malignancies).	('malignancies', 'Disease', (201, 213))	('children', 'Species', '9606', (62, 70))	('human', 'Species', '9606', (195, 200))	('TSC', 'Gene', '7248', (76, 79))	('mTORC1', 'Gene', '382056', (137, 143))	('LAM', 'Phenotype', 'HP:0012798', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('women', 'Species', '9606', (92, 97))	('LAM', 'Chemical', 'MESH:C050016', (103, 106))	('sporadic tumors', 'Disease', 'MESH:D020821', (116, 131))	('mTORC1', 'cellular_component', 'GO:0031931', ('137', '143'))	('LAM', 'Disease', (103, 106))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('sporadic tumors', 'Disease', (116, 131))	('hyperactivation', 'Var', (144, 159))	('mTORC1', 'Gene', (137, 143))	('malignancies', 'Disease', 'MESH:D009369', (201, 213))	('TSC', 'Gene', (76, 79))
149203	31420607	To overexpress RARbeta2 and to knockdown ING4, Tsc2-/- MEFs were cotransfected with 3 mug of pCMV6-RARbeta2-Myc-DDK or 25 nM SMARTpool ING4 siRNA (Dharmacon, USA), respectively.	('overexpress', 'PosReg', (3, 14))	('Myc', 'Gene', '4609', (108, 111))	('mug', 'molecular_function', 'GO:0043739', ('86', '89'))	('MEFs', 'CellLine', 'CVCL:9115', (55, 59))	('DDK', 'cellular_component', 'GO:0031431', ('112', '115'))	('Myc', 'Gene', (108, 111))	('knockdown', 'Var', (31, 40))
149359	31387579	CNV copy number variation TCGA The Cancer Genome Atlas BLCA bladder urothelial carcinoma LGG Brain Lower Grade Glioma PAAD pancreatic adenocarcinoma STAD stomach adenocarcinoma AUC area under the curve ROC receiver operating characteristic HR hazard ratio CI confidence intervals YPZ, XL and YJX conceived and designed the overall study.	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (154, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('BLCA', 'Chemical', '-', (55, 59))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (123, 148))	('Glioma', 'Disease', 'MESH:D005910', (111, 117))	('stomach adenocarcinoma', 'Disease', (154, 176))	('PAAD', 'Chemical', '-', (118, 122))	('Glioma', 'Phenotype', 'HP:0009733', (111, 117))	('bladder urothelial carcinoma', 'Disease', (60, 88))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (123, 148))	('PAAD', 'Phenotype', 'HP:0006725', (118, 122))	('pancreatic adenocarcinoma', 'Disease', (123, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('copy number variation', 'Var', (4, 25))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (60, 88))	('Glioma', 'Disease', (111, 117))	('STAD', 'Chemical', '-', (149, 153))
149373	29379304	Dual inhibition of mTORC1 and mTORC2 by miR-99a-5p was confirmed by the decreased phosphorylation of mTOR (at Ser2448 and Ser2481), phospho-rpS6 and phospho-4EBP1.	('phosphorylation', 'MPA', (82, 97))	('Ser', 'cellular_component', 'GO:0005790', ('110', '113'))	('miR-99a', 'Gene', '407055', (40, 47))	('Ser2448', 'Chemical', '-', (110, 117))	('Ser2481', 'Var', (122, 129))	('mTORC1', 'Gene', (19, 25))	('decreased', 'NegReg', (72, 81))	('Ser', 'cellular_component', 'GO:0005790', ('122', '125'))	('4EBP1', 'Gene', '1978', (157, 162))	('mTORC1', 'Gene', '382056', (19, 25))	('mTORC2', 'Gene', (30, 36))	('Ser2481', 'Chemical', '-', (122, 129))	('inhibition', 'NegReg', (5, 15))	('mTORC1', 'cellular_component', 'GO:0031931', ('19', '25'))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))	('5p', 'Chemical', '-', (48, 50))	('rpS6', 'Gene', (140, 144))	('mTOR', 'Gene', (101, 105))	('miR-99a', 'Gene', (40, 47))	('mTORC2', 'cellular_component', 'GO:0031932', ('30', '36'))	('rpS6', 'Gene', '6194', (140, 144))	('mTORC2', 'Gene', '74343', (30, 36))	('4EBP1', 'Gene', (157, 162))
149374	29379304	The phosphorylation of AKT was significantly inhibited in miR-99a-5p-transfected cells upon RAD001 treatment.	('miR-99a', 'Gene', '407055', (58, 65))	('AKT', 'Gene', '207', (23, 26))	('RAD001', 'Var', (92, 98))	('phosphorylation', 'MPA', (4, 19))	('miR-99a', 'Gene', (58, 65))	('AKT', 'Gene', (23, 26))	('RAD', 'biological_process', 'GO:1990116', ('92', '95'))	('inhibited', 'NegReg', (45, 54))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('5p', 'Chemical', '-', (66, 68))
149390	29379304	An mTORC1 inhibitor RAD001 (everolimus) has been shown to have limited effects on bladder cancer models both in vivo and in vitro.	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('mTORC1', 'Gene', '382056', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('RAD', 'biological_process', 'GO:1990116', ('20', '23'))	('RAD001', 'Var', (20, 26))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))	('mTORC1', 'Gene', (3, 9))	('bladder cancer', 'Disease', (82, 96))	('mTORC1', 'cellular_component', 'GO:0031931', ('3', '9'))	('everolimus', 'Chemical', 'MESH:D000068338', (28, 38))
149392	29379304	It is suggested that RAD001, as an mTOC1 inhibitor, may increase mTORC2 signaling that activates AKT S473 phosphorylation and promotes cancer cell survival.	('AKT', 'Gene', '207', (97, 100))	('RAD001', 'Gene', (21, 27))	('mTORC2', 'Gene', '74343', (65, 71))	('cancer', 'Disease', (135, 141))	('RAD', 'biological_process', 'GO:1990116', ('21', '24'))	('increase', 'PosReg', (56, 64))	('mTOC', 'cellular_component', 'GO:0005815', ('35', '39'))	('phosphorylation', 'biological_process', 'GO:0016310', ('106', '121'))	('mTORC2', 'cellular_component', 'GO:0031932', ('65', '71'))	('S473', 'Var', (101, 105))	('promotes', 'PosReg', (126, 134))	('AKT', 'Gene', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mTORC2', 'Gene', (65, 71))	('activates', 'PosReg', (87, 96))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))
149397	29379304	Dysregulation of miRNAs has been involved in the tumorigenesis of many cancer types, indicating that miRNAs may act as oncogenes or tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('involved', 'Reg', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (71, 77))	('miRNAs', 'Protein', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
149407	29379304	All other chemicals, unless otherwise stated, were from Sigma-Aldrich Co. Antibodies against mTOR, phospho-mTOR (Ser2448), phospho-mTOR (Ser2481), AKT, phospho-AKT (Ser473), rpS6, phospho-rpS6, 4EBP1 and phospho-4EBP1 were purchased from Cell Signaling Technology (Danvers, MA, USA).	('Ser', 'cellular_component', 'GO:0005790', ('165', '168'))	('Ser2481', 'Var', (137, 144))	('AKT', 'Gene', '207', (160, 163))	('4EBP1', 'Gene', (194, 199))	('rpS6', 'Gene', (188, 192))	('4EBP1', 'Gene', '1978', (212, 217))	('rpS6', 'Gene', (174, 178))	('AKT', 'Gene', (147, 150))	('Ser2481', 'Chemical', '-', (137, 144))	('rpS6', 'Gene', '6194', (188, 192))	('Ser', 'cellular_component', 'GO:0005790', ('137', '140'))	('rpS6', 'Gene', '6194', (174, 178))	('Ser', 'cellular_component', 'GO:0005790', ('113', '116'))	('4EBP1', 'Gene', '1978', (194, 199))	('Ser2448', 'Chemical', '-', (113, 120))	('AKT', 'Gene', '207', (147, 150))	('Ser473', 'Var', (165, 171))	('AKT', 'Gene', (160, 163))	('4EBP1', 'Gene', (212, 217))	('Ser473', 'Chemical', '-', (165, 171))	('Signaling', 'biological_process', 'GO:0023052', ('243', '252'))	('Ser2448', 'Var', (113, 120))
149426	29379304	A similar cloning step using oligonucleotides containing three repeats of anti-sense miR-99a-5p was performed to generate another reporter construct designated as pmiR-GLO-99a-PTS (with antisense miR-99a-5p sequence, positive targeting sequence).	('miR-99a', 'Gene', '407055', (85, 92))	('5p', 'Chemical', '-', (204, 206))	('oligonucleotides', 'Chemical', 'MESH:D009841', (29, 45))	('miR-99a', 'Gene', '407055', (196, 203))	('5p', 'Chemical', '-', (93, 95))	('miR-99a', 'Gene', (85, 92))	('miR-99a', 'Gene', (196, 203))	('anti-sense', 'Var', (74, 84))
149432	29379304	Detection of mTOR, phospho-mTOR (Ser2448), rpS6, phospho-rpS6 (Ser235/236), phospho-mTOR (Ser2481), 4EBP1, phospho-4EBP1 (Ser65 and Thr37/46), AKT and phospho-AKT (Ser473) was performed as described.	('Ser', 'cellular_component', 'GO:0005790', ('33', '36'))	('Ser2448', 'Chemical', '-', (33, 40))	('rpS6', 'Gene', '6194', (43, 47))	('Ser2481', 'Var', (90, 97))	('rpS6', 'Gene', (57, 61))	('AKT', 'Gene', '207', (159, 162))	('Ser2448', 'Var', (33, 40))	('rpS6', 'Gene', '6194', (57, 61))	('4EBP1', 'Gene', (100, 105))	('Ser', 'cellular_component', 'GO:0005790', ('164', '167'))	('4EBP1', 'Gene', (115, 120))	('Thr37', 'Chemical', '-', (132, 137))	('Ser', 'cellular_component', 'GO:0005790', ('122', '125'))	('AKT', 'Gene', '207', (143, 146))	('Ser235', 'Chemical', '-', (63, 69))	('Ser2481', 'Chemical', '-', (90, 97))	('Ser', 'cellular_component', 'GO:0005790', ('63', '66'))	('Ser235/236', 'Var', (63, 73))	('Ser', 'cellular_component', 'GO:0005790', ('90', '93'))	('4EBP1', 'Gene', '1978', (100, 105))	('4EBP1', 'Gene', '1978', (115, 120))	('AKT', 'Gene', (159, 162))	('rpS6', 'Gene', (43, 47))	('Ser65', 'Chemical', '-', (122, 127))	('Ser473', 'Chemical', '-', (164, 170))	('AKT', 'Gene', (143, 146))
149464	29379304	As shown in Figure 6A, the phosphorylation of mTOR on residue Ser2448 and Ser2481 was inhibited by the transfection of pSM-99a, while not affected by transfection of pSM-28-5p.	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('Ser', 'cellular_component', 'GO:0005790', ('62', '65'))	('Ser2481', 'Chemical', '-', (74, 81))	('5p', 'Chemical', '-', (173, 175))	('Ser2448', 'Chemical', '-', (62, 69))	('Ser2448', 'Var', (62, 69))	('pSM', 'Gene', '2346', (166, 169))	('phosphorylation', 'MPA', (27, 42))	('mTOR', 'Gene', (46, 50))	('pSM', 'Gene', (166, 169))	('Ser', 'cellular_component', 'GO:0005790', ('74', '77'))	('transfection', 'Var', (103, 115))	('inhibited', 'NegReg', (86, 95))	('pSM', 'Gene', '2346', (119, 122))	('Ser2481', 'Var', (74, 81))	('pSM', 'Gene', (119, 122))
149469	29379304	As shown in Figure 6C, transfection of pSM-99a suppressed the levels of both Raptor and Rictor that co-immunoprecipitated with mTOR.	('suppressed', 'NegReg', (47, 57))	('Raptor', 'Gene', (77, 83))	('transfection', 'Var', (23, 35))	('Raptor', 'Gene', '57521', (77, 83))	('Rictor', 'Gene', '253260', (88, 94))	('Rictor', 'Gene', (88, 94))	('levels of', 'MPA', (62, 71))	('pSM', 'Gene', '2346', (39, 42))	('pSM', 'Gene', (39, 42))
149476	29379304	Our study showed that reactivation of miR-99a-5p, which is downregulated in bladder cancer cells, contributes to the inhibition of bladder cancer growth through dual disruption of mTORC1 and mTORC2 signaling by targeting mTOR.	('signaling', 'biological_process', 'GO:0023052', ('198', '207'))	('5p', 'Chemical', '-', (46, 48))	('mTORC2', 'cellular_component', 'GO:0031932', ('191', '197'))	('miR-99a', 'Gene', (38, 45))	('inhibition', 'NegReg', (117, 127))	('targeting', 'Reg', (211, 220))	('mTORC2', 'Gene', (191, 197))	('reactivation', 'Var', (22, 34))	('mTOR', 'Gene', (221, 225))	('mTORC2', 'Gene', '74343', (191, 197))	('miR-99a', 'Gene', '407055', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (131, 145))	('mTORC1', 'Gene', (180, 186))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))	('bladder cancer', 'Disease', (76, 90))	('bladder cancer', 'Disease', (131, 145))	('disruption', 'NegReg', (166, 176))	('mTORC1', 'cellular_component', 'GO:0031931', ('180', '186'))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('mTORC1', 'Gene', '382056', (180, 186))	('bladder cancer', 'Phenotype', 'HP:0009725', (131, 145))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))
149477	29379304	Recent studies have found that PTEN, the PI3K antagonist, is a target for mutation in bladder cancer, indicating that dysregulation of PI3K signaling may play an important role in bladder tumorigenesis.	('bladder tumor', 'Disease', 'MESH:D001749', (180, 193))	('PTEN', 'Gene', (31, 35))	('mutation', 'Var', (74, 82))	('bladder cancer', 'Disease', (86, 100))	('PTEN', 'Gene', '5728', (31, 35))	('PI3K', 'molecular_function', 'GO:0016303', ('41', '45'))	('bladder tumor', 'Phenotype', 'HP:0009725', (180, 193))	('PI3K signaling', 'biological_process', 'GO:0014065', ('135', '149'))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bladder tumor', 'Disease', (180, 193))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))	('dysregulation', 'Var', (118, 131))
149485	29379304	As described in the Introduction section, one possibility is that inhibition of mTORC1 (rapamycin, CCI-779 and RAD001) activates mTORC2, which triggers the phosphorylation of pro-survival of AKT pathway.	('pro-survival', 'biological_process', 'GO:0043066', ('175', '187'))	('mTORC2', 'cellular_component', 'GO:0031932', ('129', '135'))	('CCI-779', 'Chemical', 'MESH:C401859', (99, 106))	('AKT', 'Gene', '207', (191, 194))	('rapamycin', 'Chemical', 'MESH:D020123', (88, 97))	('phosphorylation', 'biological_process', 'GO:0016310', ('156', '171'))	('mTORC1', 'Gene', '382056', (80, 86))	('mTORC2', 'Gene', (129, 135))	('triggers', 'Reg', (143, 151))	('AKT', 'Gene', (191, 194))	('inhibition', 'Var', (66, 76))	('mTORC1', 'cellular_component', 'GO:0031931', ('80', '86'))	('mTORC2', 'Gene', '74343', (129, 135))	('activates', 'PosReg', (119, 128))	('RAD', 'biological_process', 'GO:1990116', ('111', '114'))	('phosphorylation', 'MPA', (156, 171))	('mTORC1', 'Gene', (80, 86))
149486	29379304	Therefore, researchers had developed several novel molecules inhibiting both mTORC1 and mTORC2, including AZD8055, Torin 1 and PP242.	('inhibiting', 'NegReg', (61, 71))	('mTORC2', 'Gene', (88, 94))	('AZD8055', 'Var', (106, 113))	('AZD8055', 'Chemical', 'MESH:C546624', (106, 113))	('mTORC1', 'Gene', (77, 83))	('mTORC2', 'Gene', '74343', (88, 94))	('mTORC2', 'cellular_component', 'GO:0031932', ('88', '94'))	('mTORC1', 'cellular_component', 'GO:0031931', ('77', '83'))	('PP242', 'Var', (127, 132))	('mTORC1', 'Gene', '382056', (77, 83))
149487	29379304	Recent studies have suggested that dysregulation of miRNAs is a common event in human cancers, including bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (105, 119))	('miRNAs', 'Protein', (52, 58))	('bladder cancer', 'Disease', (105, 119))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('dysregulation', 'Var', (35, 48))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancers', 'Disease', (86, 93))
149495	29379304	We also confirmed the activation of AKT in RAD001-treated 5637 and T24 cells, suggesting the existence of mTORC2 feedback loop.	('RAD', 'biological_process', 'GO:1990116', ('43', '46'))	('mTORC2', 'cellular_component', 'GO:0031932', ('106', '112'))	('AKT', 'Gene', '207', (36, 39))	('activation', 'PosReg', (22, 32))	('mTORC2', 'Gene', (106, 112))	('AKT', 'Gene', (36, 39))	('mTORC2', 'Gene', '74343', (106, 112))	('RAD001-treated', 'Var', (43, 57))
149516	22550998	In acute doses, Cd+2 has been shown to cause damage to the central nervous system, lung, bone, gastrointestinal tract, liver, ovary, testis, placenta, and the developing embryo.	('damage to the central nervous system', 'Disease', 'MESH:D002493', (45, 81))	('Cd+2', 'Var', (16, 20))	('damage to the central nervous system', 'Disease', (45, 81))	('gastrointestinal tract', 'Disease', (95, 117))	('bone', 'CPA', (89, 93))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (95, 117))
149517	22550998	Chronic exposure to low amounts of Cd+2 has been shown to cause renal proximal tubular metabolic acidosis and osteomalacia (renal Fanconi syndrome).	('renal proximal tubular metabolic acidosis and osteomalacia', 'Disease', 'MESH:D000141', (64, 122))	('acidosis', 'Phenotype', 'HP:0001941', (97, 105))	('metabolic acidosis', 'Phenotype', 'HP:0001942', (87, 105))	('renal Fanconi syndrome', 'Disease', (124, 146))	('cause', 'Reg', (58, 63))	('renal Fanconi syndrome', 'Disease', 'MESH:D007674', (124, 146))	('renal Fanconi syndrome', 'Phenotype', 'HP:0001994', (124, 146))	('osteomalacia', 'Phenotype', 'HP:0002749', (110, 122))	('proximal tubular metabolic acidosis', 'Phenotype', 'HP:0002049', (70, 105))	('Cd+2', 'Var', (35, 39))
149518	22550998	Cadmium is also classified as a human "Category 1" carcinogen due to its strong correlation with lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Cadmium', 'Var', (0, 7))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('correlation', 'Interaction', (80, 91))	('human', 'Species', '9606', (32, 37))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('Cadmium', 'Chemical', 'MESH:D002104', (0, 7))
149525	22550998	This laboratory has developed a model of Cd+2 and As+3 induced human urothelial cancer through the direct malignant transformation of the UROtsa cell line, a cell line retaining characteristics of human urothelium.	('human', 'Species', '9606', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('urothelial cancer', 'Disease', (69, 86))	('Cd+2', 'Var', (41, 45))	('urothelial cancer', 'Disease', 'MESH:D014523', (69, 86))	('As+3', 'Chemical', '-', (50, 54))	('human', 'Species', '9606', (197, 202))	('induced', 'Reg', (55, 62))
149531	22550998	Recent studies have shown a relationship between a specific allelic difference in the mouse Slc39a8 gene encoding the ZIP8 transporter and the specific phenotypes of Cd-induced testicular necrosis and acute renal failure.	('necrosis', 'Disease', 'MESH:D009336', (188, 196))	('acute renal failure', 'Phenotype', 'HP:0001919', (201, 220))	('necrosis', 'biological_process', 'GO:0008220', ('188', '196'))	('Cd', 'Chemical', 'MESH:D002104', (166, 168))	('mouse', 'Species', '10090', (86, 91))	('necrosis', 'biological_process', 'GO:0001906', ('188', '196'))	('renal failure', 'Phenotype', 'HP:0000083', (207, 220))	('acute renal failure', 'Disease', (201, 220))	('Slc39a8', 'Gene', (92, 99))	('allelic difference', 'Var', (60, 78))	('necrosis', 'biological_process', 'GO:0070265', ('188', '196'))	('acute renal failure', 'Disease', 'MESH:D058186', (201, 220))	('Slc39a8', 'Gene', '67547', (92, 99))	('necrosis', 'biological_process', 'GO:0008219', ('188', '196'))	('necrosis', 'Disease', (188, 196))	('necrosis', 'biological_process', 'GO:0019835', ('188', '196'))
149578	22550998	The intracellular localization of ZIP8 was similar between the parent (Figure 7A, D, G) and As+3 (Figure 7B, E, F) or Cd+2 (Figure 7C, F, I) transformed UROtsa cell lines although the transformed cells were more likely to have at least some apical localization of ZIP8 in addition to the strong paranuclear localization.	('ZIP8', 'Gene', (264, 268))	('Cd+2', 'Var', (118, 122))	('intracellular', 'cellular_component', 'GO:0005622', ('4', '17'))	('intracellular localization', 'biological_process', 'GO:0051641', ('4', '30'))	('apical localization', 'MPA', (241, 260))	('localization', 'biological_process', 'GO:0051179', ('307', '319'))	('localization', 'biological_process', 'GO:0051179', ('248', '260'))	('As+3', 'Chemical', '-', (92, 96))
149623	22550998	The fact that the one urothelial cancer that did not express the ZIP8 protein was in the high grade invasive group could be important since the loss of ZIP8 could be associated with tumor progression.	('urothelial cancer', 'Disease', (22, 39))	('loss', 'Var', (144, 148))	('tumor', 'Disease', (182, 187))	('ZIP8', 'Gene', (152, 156))	('urothelial cancer', 'Disease', 'MESH:D014523', (22, 39))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('associated', 'Reg', (166, 176))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
149625	22550998	The results showed that both Cd+2 and As+3 transformed UROtsa cells and their tumor transplants expressed higher levels of ZIP8 mRNA and protein compared to the parental cell line.	('N', 'Chemical', 'MESH:D009584', (130, 131))	('As+3', 'Chemical', '-', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('higher', 'PosReg', (106, 112))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('tumor', 'Disease', (78, 83))	('Cd+2', 'Var', (29, 33))
149626	22550998	There was no notable difference in the expression of ZIP8 between the Cd+2 and As+3 transformed cell lines, ruling out a Cd+2 specific alteration in ZIP8 expression that might be associated with the development of urothelial cancer.	('urothelial cancer', 'Disease', (214, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('ZIP8', 'Gene', (149, 153))	('associated with', 'Reg', (179, 194))	('urothelial cancer', 'Disease', 'MESH:D014523', (214, 231))	('As+3', 'Chemical', '-', (79, 83))	('alteration', 'Var', (135, 145))	('men', 'Species', '9606', (206, 209))
149636	22550998	Epigenetics alterations are thus suspected in the case of ZIP8 overexpression in Cd+2- and As+3-transformed cells.	('As+3', 'Chemical', '-', (91, 95))	('ZIP8', 'Gene', (58, 62))	('Epigenetics', 'Var', (0, 11))	('overexpression', 'PosReg', (63, 77))
149641	22550998	The study also shows that the HPT cells should provide an effective human in vitro model system for the study of the role of ZIP8 in proximal tubule damage by Cd+2 and possibly other heavy metals.	('proximal tubule', 'MPA', (133, 148))	('human', 'Species', '9606', (68, 73))	('Cd+2', 'Var', (159, 163))	('metal', 'Chemical', 'MESH:D008670', (189, 194))
149684	22745542	PLZ4 facilitated the uptake of micelles together with the cargo load into the target cells.	('cargo', 'molecular_function', 'GO:0140355', ('58', '63'))	('PLZ4', 'Var', (0, 4))	('facilitated', 'PosReg', (5, 16))	('uptake', 'biological_process', 'GO:0098739', ('21', '27'))	('mice', 'Species', '10090', (31, 35))	('uptake', 'biological_process', 'GO:0098657', ('21', '27'))	('uptake', 'MPA', (21, 27))	('PLZ4', 'Chemical', '-', (0, 4))
149694	22745542	Telodendrimers can self-assemble in an aqueous solution to form micelles that are characterized by their small size, long shelf life, and high efficiency in drug loading.	('drug loading', 'MPA', (157, 169))	('mice', 'Species', '10090', (64, 68))	('Telodendrimers', 'Var', (0, 14))
149704	22745542	In this study, we determined if PLZ4 enhances the tumor targeting of micelles to dog bladder cancer cells.	('bladder cancer', 'Phenotype', 'HP:0009725', (85, 99))	('dog', 'Species', '9615', (81, 84))	('enhances', 'PosReg', (37, 45))	('bladder cancer', 'Disease', 'MESH:D001749', (85, 99))	('PLZ4', 'Chemical', '-', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('mice', 'Species', '10090', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('bladder cancer', 'Disease', (85, 99))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('PLZ4', 'Var', (32, 36))	('tumor', 'Disease', (50, 55))
149761	22745542	This data indicated the ability of dog bladder cancer cells to take up micelles even after a short period of incubation, and PLZ4 on the micelle surface further improved the targeting and cell uptake of micelles.	('PLZ4 on', 'Var', (125, 132))	('targeting', 'CPA', (174, 183))	('mice', 'Species', '10090', (71, 75))	('bladder cancer', 'Disease', 'MESH:D001749', (39, 53))	('bladder cancer', 'Phenotype', 'HP:0009725', (39, 53))	('mice', 'Species', '10090', (203, 207))	('PLZ4', 'Chemical', '-', (125, 129))	('bladder cancer', 'Disease', (39, 53))	('cell uptake', 'CPA', (188, 199))	('uptake', 'biological_process', 'GO:0098657', ('193', '199'))	('uptake', 'biological_process', 'GO:0098739', ('193', '199'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('dog', 'Species', '9615', (35, 38))	('mice', 'Species', '10090', (137, 141))	('improved', 'PosReg', (161, 169))
149767	22745542	These results also support the notion that PLZ4 enhances nanoparticle attachment to the cell surface and subsequent cell uptake.	('PLZ4', 'Var', (43, 47))	('cell surface', 'cellular_component', 'GO:0009986', ('88', '100'))	('nanoparticle attachment to the cell surface', 'CPA', (57, 100))	('cell uptake', 'CPA', (116, 127))	('PLZ4', 'Chemical', '-', (43, 47))	('enhances', 'PosReg', (48, 56))	('uptake', 'biological_process', 'GO:0098739', ('121', '127'))	('uptake', 'biological_process', 'GO:0098657', ('121', '127'))
149770	22745542	DNR killed cancer cells in a dose-dependent manner, regardless of whether in the free form, nontargeting, or targeting micelle formulation.	('DNR', 'Var', (0, 3))	('mice', 'Species', '10090', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('DNR', 'Chemical', 'MESH:D003630', (0, 3))	('cancer', 'Disease', (11, 17))
149812	22745542	However, conjugation of PLZ4 on the surface of micelles not only contributed to the attachment of micelles to target cancer cell surfaces, but also induced the uptake of micelles by cancer cells (Figure 3).	('PLZ4', 'Chemical', '-', (24, 28))	('uptake', 'biological_process', 'GO:0098657', ('160', '166'))	('conjugation', 'biological_process', 'GO:0000746', ('9', '20'))	('uptake', 'biological_process', 'GO:0098739', ('160', '166'))	('cancer', 'Disease', (182, 188))	('attachment', 'CPA', (84, 94))	('mice', 'Species', '10090', (170, 174))	('cancer', 'Disease', (117, 123))	('conjugation', 'Var', (9, 20))	('mice', 'Species', '10090', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('uptake', 'MPA', (160, 166))	('induced', 'Reg', (148, 155))	('contributed', 'Reg', (65, 76))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('PLZ4', 'Gene', (24, 28))	('mice', 'Species', '10090', (47, 51))
149815	22745542	First, micelles can enhance drug delivery to the tumor sites through the EPR effect.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('enhance', 'PosReg', (20, 27))	('drug', 'CPA', (28, 32))	('mice', 'Species', '10090', (7, 11))	('tumor', 'Disease', (49, 54))	('micelles', 'Var', (7, 15))	('EPR', 'CPA', (73, 76))
149826	22745542	We found that small noncoding regulatory microRNA might be involved in the chemoresistance of bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('small noncoding', 'Var', (14, 29))	('chemoresistance', 'CPA', (75, 90))	('involved', 'Reg', (59, 67))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))
149849	22293631	No significant differences in tumor tissue staining between treatment groups was observed for COX-2, Ki-67, activated caspase 3, Akt, p-Akt, MAPK, or p-MAPK.	('COX-2', 'Gene', '4513', (94, 99))	('COX-2', 'Gene', (94, 99))	('p-MAPK', 'Var', (150, 156))	('Akt', 'Gene', '207', (129, 132))	('men', 'Species', '9606', (65, 68))	('MAPK', 'molecular_function', 'GO:0004707', ('141', '145'))	('caspase 3', 'Gene', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('Ki-67', 'Gene', (101, 106))	('Akt', 'Gene', '207', (136, 139))	('MAPK', 'Gene', (141, 145))	('caspase 3', 'Gene', '836', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Akt', 'Gene', (129, 132))	('Akt', 'Gene', (136, 139))	('MAPK', 'molecular_function', 'GO:0004707', ('152', '156'))	('tumor', 'Disease', (30, 35))	('activated', 'PosReg', (108, 117))
149877	22293631	Participants meeting the eligibility criteria were randomized (1:1:1) to one of three arms: G-2535, one capsule taken orally bid, for a dose of 300 mg genistein/day; G-2535, two capsules taken orally bid, for a dose of 600 mg genistein/day; or placebo, one or two capsules taken orally bid for 14-21 days until the day prior to planned TURBT or cystectomy, or up to 30 days if surgery was delayed.	('genistein', 'Chemical', 'MESH:D019833', (226, 235))	('cystectomy', 'Disease', (345, 355))	('G-2535', 'Var', (166, 172))	('capsule', 'cellular_component', 'GO:0042603', ('104', '111'))	('G-2535', 'Var', (92, 98))	('TURBT', 'Disease', (336, 341))	('genistein', 'Chemical', 'MESH:D019833', (151, 160))	('Participants', 'Species', '9606', (0, 12))	('G-2535', 'Chemical', '-', (166, 172))	('G-2535', 'Chemical', '-', (92, 98))
149909	22293631	The other IHC assays for Ki67, activated caspase-3, Akt, MAPK, p-MAPK, COX-2, and survivin were validated using standard antibodies.	('Akt', 'Gene', (52, 55))	('COX-2', 'Gene', '4513', (71, 76))	('MAPK', 'molecular_function', 'GO:0004707', ('57', '61'))	('Ki67', 'Var', (25, 29))	('caspase-3', 'Gene', '836', (41, 50))	('COX-2', 'Gene', (71, 76))	('p-MAPK', 'Var', (63, 69))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('activated', 'PosReg', (31, 40))	('caspase-3', 'Gene', (41, 50))	('Akt', 'Gene', '207', (52, 55))
149919	22293631	Eight (14%) subjects met the criteria for noncompliance (lack of documentation of taking >95% of doses), including five on the placebo arm, and three on the treatment arms (300 mg - 1; 600 mg - 2).	('men', 'Species', '9606', (162, 165))	('men', 'Species', '9606', (69, 72))	('300', 'Var', (173, 176))	('noncompliance', 'Disease', (42, 55))
149958	22293631	The doses of G-2535 chosen for this study, 150 and 300 mg genistein bid, produced plasma concentrations that have been shown to rapidly silence protein tyrosine phosphorylation in peripheral lymphocytes within three to six hours and maintain that effect for over 24 hours in a previous study with a similar isoflavone mixture containing lower concentrations of genistein.	('protein tyrosine phosphorylation', 'MPA', (144, 176))	('isoflavone', 'Chemical', 'MESH:D007529', (307, 317))	('G-2535', 'Chemical', '-', (13, 19))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('tyrosine', 'Chemical', 'MESH:D014443', (152, 160))	('genistein', 'Chemical', 'MESH:D019833', (58, 67))	('genistein', 'Chemical', 'MESH:D019833', (361, 370))	('G-2535', 'Var', (13, 19))	('phosphorylation', 'biological_process', 'GO:0016310', ('161', '176'))	('silence', 'NegReg', (136, 143))
149971	22293631	Evidence from other studies found that genistein can induce a bimodal response, rendering higher doses less effective than lower ones, as do other biologic response modifiers and natural substances.	('bimodal response', 'MPA', (62, 78))	('genistein', 'Var', (39, 48))	('less', 'NegReg', (103, 107))	('genistein', 'Chemical', 'MESH:D019833', (39, 48))
149973	22293631	Whether related to the lack of any observed correlation between EGFR phosphorylation inhibition and dose or genistein concentrations, blood levels of genistein were roughly as high at 300 mg/day as at 600 mg/day.	('blood levels', 'MPA', (134, 146))	('phosphorylation', 'biological_process', 'GO:0016310', ('69', '84'))	('300 mg/day', 'Var', (184, 194))	('genistein', 'Chemical', 'MESH:D019833', (108, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('genistein', 'Chemical', 'MESH:D019833', (150, 159))
150004	22032647	Moreover, silencing of NOX4 by siRNA significantly reduced cancer cell growth in vivo as assessed in an orthotopic mouse model.	('cell growth', 'biological_process', 'GO:0016049', ('66', '77'))	('NOX4', 'Enzyme', (23, 27))	('reduced', 'NegReg', (51, 58))	('mouse', 'Species', '10090', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('siRNA', 'Gene', (31, 36))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('silencing', 'Var', (10, 19))
150019	22032647	Specific variants have a distinct therapeutic strategy in addition to the conventional clinical management of urothelial carcinoma.	('variants', 'Var', (9, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (110, 130))	('urothelial carcinoma', 'Disease', (110, 130))
150048	22032647	For our transfection analyses, 106 cells from each urothelial carcinoma cell line were seeded in 6-cm dish plates and transfected with either 100 nM of control RNA (Santa Cruz) or with the small interfering RNA (siRNA) of NOX4.	('RNA', 'cellular_component', 'GO:0005562', ('160', '163'))	('small interfering RNA', 'Var', (189, 210))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (51, 71))	('C', 'Chemical', 'MESH:D002244', (171, 172))	('RNA', 'cellular_component', 'GO:0005562', ('207', '210'))	('urothelial carcinoma', 'Disease', (51, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
150078	22032647	ROS, including the radical superoxide anion and non-radical hydrogen peroxide, were constitutively generated as examined by fluorescent microscopy or flow cytometry using DHE and CM-DCF-DA, but ROS levels significantly declined following NOX4 siRNA transfection (Figures 1A and 1B).	('radical', 'Chemical', '-', (19, 26))	('DHE', 'Chemical', 'MESH:C067883', (171, 174))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('ROS levels', 'MPA', (194, 204))	('NOX4', 'Var', (238, 242))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (60, 77))	('superoxide anion', 'Chemical', 'MESH:D013481', (27, 43))	('radical', 'Chemical', '-', (52, 59))	('ROS', 'Chemical', 'MESH:D017382', (194, 197))	('declined', 'NegReg', (219, 227))	('CM-DCF-DA', 'Chemical', '-', (179, 188))
150080	22032647	Moreover, NOX4 knockdown by siRNA transfection suppressed cell growth via p16 induction and cell cycle arrest at the G1 phase in the T24 and UMUC6 cell lines (Figure 1C)).	('induction', 'PosReg', (78, 87))	('p16', 'Gene', (74, 77))	('suppressed', 'NegReg', (47, 57))	('knockdown', 'Var', (15, 24))	('cell growth', 'biological_process', 'GO:0016049', ('58', '69'))	('G1 phase', 'biological_process', 'GO:0051318', ('117', '125'))	('cell cycle arrest at the G1 phase', 'CPA', (92, 125))	('NOX4', 'Gene', (10, 14))	('C', 'Chemical', 'MESH:D002244', (167, 168))	('p16', 'Gene', '1029', (74, 77))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (92, 109))	('UMUC6', 'CellLine', 'CVCL:2751', (141, 146))	('C', 'Chemical', 'MESH:D002244', (144, 145))	('cell growth', 'CPA', (58, 69))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('92', '109'))
150082	22032647	Treatment with ROS scavengers, such as N-acetyl-L-cysteine, induced cell cycle arrest as expected and inhibited the rate of cell growth (data not shown).	('cell growth', 'biological_process', 'GO:0016049', ('124', '135'))	('N-acetyl-L-cysteine', 'Var', (39, 58))	('inhibited', 'NegReg', (102, 111))	('N-acetyl-L-cysteine', 'Chemical', 'MESH:D000111', (39, 58))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (68, 85))	('rate of cell growth', 'CPA', (116, 135))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('68', '85'))	('ROS', 'Chemical', 'MESH:D017382', (15, 18))	('cell cycle arrest', 'CPA', (68, 85))
150104	22032647	Thus, ROS labeling together with C-C might improve accuracy by increasing the sensitivity for detecting bladder cancer, especially with low grade, non-invasive phenotypes.	('bladder cancer', 'Disease', (104, 118))	('ROS', 'Var', (6, 9))	('improve', 'PosReg', (43, 50))	('ROS', 'Chemical', 'MESH:D017382', (6, 9))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('C', 'Chemical', 'MESH:D002244', (33, 34))	('accuracy', 'MPA', (51, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('increasing', 'PosReg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (104, 118))
150126	22032647	Moreover, NOX4 silencing reduced ROS generation and suppressed cancer cell growth via p16-dependent cell cycle arrest at the G1 phase, both in vitro and in vivo.	('ROS generation', 'biological_process', 'GO:1903409', ('33', '47'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (100, 117))	('reduced', 'NegReg', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('G1 phase', 'biological_process', 'GO:0051318', ('125', '133'))	('NOX4', 'Gene', (10, 14))	('p16', 'Gene', (86, 89))	('silencing', 'Var', (15, 24))	('suppressed', 'NegReg', (52, 62))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('100', '117'))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('ROS', 'Chemical', 'MESH:D017382', (33, 36))	('ROS generation', 'MPA', (33, 47))	('cell growth', 'biological_process', 'GO:0016049', ('70', '81'))	('cancer', 'Disease', (63, 69))	('p16', 'Gene', '1029', (86, 89))
150137	22032647	NOX4 knockdown was expected to have no significant effects on NOX1 expression but ROS levels were strongly decreased, and the same phenomenon was also observed in a NOX1 knockdown experiment (data not shown).	('NOX1', 'Gene', (62, 66))	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('NOX1', 'Gene', '27035', (62, 66))	('knockdown', 'Var', (5, 14))	('decreased', 'NegReg', (107, 116))	('NOX1', 'Gene', '27035', (165, 169))	('ROS levels', 'MPA', (82, 92))	('NOX1', 'Gene', (165, 169))
150142	22032647	demonstrated inhibition of NOX4 activates apoptosis via the Akt/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells, but apoptosis was not observed in urothelial carcinoma cells by NOX4 knockdown, unlike in NOX1 gene silencing.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (178, 198))	('NOX4', 'Gene', (27, 31))	('PANC-1', 'CellLine', 'CVCL:0480', (130, 136))	('activates', 'PosReg', (32, 41))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('apoptosis signal-regulating kinase 1', 'Gene', (64, 100))	('Akt', 'Gene', (60, 63))	('NOX1', 'Gene', '27035', (234, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('Akt', 'Gene', '207', (60, 63))	('gene silencing', 'biological_process', 'GO:0016458', ('239', '253'))	('apoptosis', 'CPA', (42, 51))	('urothelial carcinoma', 'Disease', (178, 198))	('NOX1', 'Gene', (234, 238))	('apoptosis signal-regulating kinase 1', 'Gene', '4217', (64, 100))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))	('apoptosis', 'biological_process', 'GO:0097194', ('148', '157'))	('apoptosis', 'biological_process', 'GO:0006915', ('148', '157'))	('inhibition', 'Var', (13, 23))	('apoptosis', 'biological_process', 'GO:0097194', ('64', '73'))	('apoptosis', 'biological_process', 'GO:0006915', ('64', '73'))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('pancreatic cancer', 'Disease', (112, 129))
150148	22032647	Our idea was to introduce labeling of ROS produced by urothelial carcinoma cells (but not by non-malignant cells) to conventional cytology: ROS-positive cells are theoretically considered to be malignant cells despite little morphological atypia.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('ROS-positive', 'Var', (140, 152))	('ROS', 'Chemical', 'MESH:D017382', (140, 143))	('ROS', 'Chemical', 'MESH:D017382', (38, 41))	('urothelial carcinoma', 'Disease', (54, 74))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (54, 74))
150157	22032647	Moreover, fluorescence labeling of ROS can bring about accurate pathological and cytological diagnoses of human bladder cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('human', 'Species', '9606', (106, 111))	('bladder cancers', 'Disease', 'MESH:D001749', (112, 127))	('ROS', 'Chemical', 'MESH:D017382', (35, 38))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('ROS', 'Gene', (35, 38))	('bladder cancers', 'Disease', (112, 127))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))	('fluorescence labeling', 'Var', (10, 31))	('bring about', 'Reg', (43, 54))	('bladder cancers', 'Phenotype', 'HP:0009725', (112, 127))
150257	30996566	Smoking can increase the risk of bladder cancer by 2-5 times, and the risk of bladder cancer is also proportional to smoking intensity and length.	('bladder cancer', 'Disease', 'MESH:D001749', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('bladder cancer', 'Phenotype', 'HP:0009725', (78, 92))	('Smoking', 'Var', (0, 7))	('bladder cancer', 'Disease', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (78, 92))	('bladder cancer', 'Disease', (78, 92))	('bladder cancer', 'Phenotype', 'HP:0009725', (33, 47))
150299	30996566	In patients with T1WI bladder cancer, the signal of urine is very low, low to moderate for bladder wall, and high for fat around the bladder.	('low', 'NegReg', (71, 74))	('bladder cancer', 'Disease', 'MESH:D001749', (22, 36))	('bladder cancer', 'Phenotype', 'HP:0009725', (22, 36))	('bladder cancer', 'Disease', (22, 36))	('signal', 'MPA', (42, 48))	('patients', 'Species', '9606', (3, 11))	('T1WI', 'Var', (17, 21))	('low', 'NegReg', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
150357	30996566	However, 14% of high-grade urothelial carcinoma expresses CK34Betae12 instead of CK7 and CK20.	('CK7', 'Gene', (81, 84))	('CK34Betae12', 'Var', (58, 69))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (27, 47))	('CK7', 'Gene', '3855', (81, 84))	('CK20', 'Gene', '54474', (89, 93))	('urothelial carcinoma', 'Disease', (27, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('CK20', 'Gene', (89, 93))
150368	30996566	Patient with bladder cancer in stage T2-T4a, N0M0 may be treated with neoadjuvant chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('T4a', 'Gene', (40, 43))	('N0M0', 'Var', (45, 49))	('bladder cancer', 'Phenotype', 'HP:0009725', (13, 27))	('bladder cancer', 'Disease', 'MESH:D001749', (13, 27))	('bladder cancer', 'Disease', (13, 27))	('T4a', 'Gene', '6317', (40, 43))	('Patient', 'Species', '9606', (0, 7))
150394	30996566	Laser surgery may coagulate and vaporize tumor, and thus the probability of intraoperative hemorrhage and obturator nerve reflex is low.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('intraoperative hemorrhage', 'Disease', 'MESH:D006470', (76, 101))	('intraoperative hemorrhage', 'Disease', (76, 101))	('reflex', 'biological_process', 'GO:0060004', ('122', '128'))	('tumor', 'Disease', (41, 46))	('vaporize', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
150400	30996566	Photosensitizers commonly used for intravesical perfusion include 5-aminolevulinic acid (5-HAL) and aminoketovalerate (HAL).	('HAL', 'Gene', (119, 122))	('HAL', 'Gene', (91, 94))	('HAL', 'Gene', '3034', (91, 94))	('HAL', 'Gene', '3034', (119, 122))	('aminoketovalerate', 'Var', (100, 117))	('5-aminolevulinic acid', 'Chemical', 'MESH:C000614854', (66, 87))	('aminoketovalerate', 'Chemical', '-', (100, 117))
150418	30996566	For T1 stage with medium- and high-grading bladder cancer, the residual rate was 33%-55% after initial electric resection and 41.4% in TaG3 stage.	('bladder cancer', 'Disease', 'MESH:D001749', (43, 57))	('bladder cancer', 'Disease', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('medium-', 'Var', (18, 25))	('bladder cancer', 'Phenotype', 'HP:0009725', (43, 57))
150422	30996566	In a retrospective multicenter study of 2,451 patients with T1G3/HG, re-TURBt reduced the rate of tumor recurrence and progression in patients without muscle in the specimen from initial resection.	('patients', 'Species', '9606', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('progression', 'CPA', (119, 130))	('patients', 'Species', '9606', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('men', 'Species', '9606', (170, 173))	('reduced', 'NegReg', (78, 85))	('tumor', 'Disease', (98, 103))	('T1G3/HG', 'Var', (60, 67))
150498	30996566	Multiple randomized trials and meta-analyses studies have shown that cisplatin-based neoadjuvant chemotherapy can significantly increase the rate of complete tumor response, improve the overall survival and reduce mortality by 10%-13% in MIBC patient.	('reduce', 'NegReg', (207, 213))	('tumor', 'Disease', (158, 163))	('increase', 'PosReg', (128, 136))	('improve', 'PosReg', (174, 181))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('mortality', 'CPA', (214, 223))	('patient', 'Species', '9606', (243, 250))	('complete', 'MPA', (149, 157))	('MIBC', 'Disease', (238, 242))	('overall survival', 'CPA', (186, 202))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('cisplatin-based', 'Var', (69, 84))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('MIBC', 'Chemical', '-', (238, 242))
150563	30996566	In a phase III clinical trial, CMV regimen has been shown to reduce mortality by 16% and increase the 10-year survival by 6%.	('reduce', 'NegReg', (61, 67))	('CMV regimen', 'Var', (31, 42))	('CMV', 'Chemical', 'MESH:C046870', (31, 34))	('mortality', 'CPA', (68, 77))	('men', 'Species', '9606', (39, 42))	('10-year survival', 'CPA', (102, 118))	('increase', 'PosReg', (89, 97))
150632	30736840	High SPAG5 expression was associated with increased lymph node metastasis and high risk of local recurrence.	('increased', 'PosReg', (42, 51))	('SPAG5', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('SPAG5', 'Gene', '10615', (5, 10))	('lymph node metastasis', 'CPA', (52, 73))
150634	30736840	Gene set enrichment analysis of TNBC data from The Cancer Genome Atlas (TCGA) indicated that high SPAG5 expression was significantly associated with cell cycle and the ATR-BRCA pathway.	('SPAG5', 'Gene', (98, 103))	('BRCA', 'Gene', '672', (172, 176))	('cell cycle', 'biological_process', 'GO:0007049', ('149', '159'))	('ATR', 'Gene', '545', (168, 171))	('BRCA', 'Gene', (172, 176))	('ATR', 'Gene', (168, 171))	('SPAG5', 'Gene', '10615', (98, 103))	('cell cycle', 'CPA', (149, 159))	('expression', 'MPA', (104, 114))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (51, 70))	('Cancer Genome Atlas', 'Disease', (51, 70))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))	('high', 'Var', (93, 97))	('associated', 'Reg', (133, 143))
150638	30736840	Collectively, our results indict that SPAG5 is an efficient prognostic factor in TNBC, and that SPAG5 knockdown increases the sensitivity of TNBC to the PARPi olaparib.	('SPAG5', 'Gene', '10615', (96, 101))	('PARP', 'Gene', '142', (153, 157))	('sensitivity', 'MPA', (126, 137))	('knockdown', 'Var', (102, 111))	('olaparib', 'Chemical', 'MESH:C531550', (159, 167))	('SPAG5', 'Gene', (38, 43))	('SPAG5', 'Gene', (96, 101))	('increases', 'PosReg', (112, 121))	('TNBC', 'Disease', (81, 85))	('PARP', 'Gene', (153, 157))	('SPAG5', 'Gene', '10615', (38, 43))
150642	30736840	Notably, compared with other breast cancer subtypes, TNBC shows a higher prevalence of germline breast cancer-associated gene (BRCA) mutations and tumor-infiltrating lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BRCA', 'Gene', '672', (127, 131))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('mutations', 'Var', (133, 142))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('breast cancer-associated gene', 'Gene', (96, 125))	('breast cancer', 'Disease', (29, 42))	('BRCA', 'Gene', (127, 131))	('breast cancer-associated gene', 'Gene', '672', (96, 125))
150652	30736840	To explore the potential functions of SPAG5 in TNBC, we performed a gene set enrichment analysis (GSEA) using mRNA expression data from The Cancer Genome Atlas (TCGA) database, and the results showed that high SPAG5 expression was significantly correlated with cell-cycle-related genes, G2-phase-related genes, and ATR BRCA pathway-related genes.	('SPAG5', 'Gene', '10615', (210, 215))	('correlated', 'Reg', (245, 255))	('BRCA', 'Gene', '672', (319, 323))	('Cancer Genome Atlas', 'Disease', (140, 159))	('BRCA', 'Gene', (319, 323))	('ATR', 'Gene', (315, 318))	('ATR', 'Gene', '545', (315, 318))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (140, 159))	('expression', 'MPA', (216, 226))	('Cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cell-cycle-related', 'CPA', (261, 279))	('cell-cycle', 'biological_process', 'GO:0007049', ('261', '271'))	('SPAG5', 'Gene', (38, 43))	('G2-phase', 'biological_process', 'GO:0051319', ('287', '295'))	('GSEA', 'Chemical', '-', (98, 102))	('SPAG5', 'Gene', (210, 215))	('high', 'Var', (205, 209))	('SPAG5', 'Gene', '10615', (38, 43))
150653	30736840	Previous studies indicated that deficiencies in DNA repair pathways, such as BRCA1 and BRCA2 mutations, can increase PARPi activity in breast and ovarian cancer.	('BRCA1', 'Gene', (77, 82))	('PARP', 'Gene', '142', (117, 121))	('increase', 'PosReg', (108, 116))	('DNA repair pathways', 'Pathway', (48, 67))	('mutations', 'Var', (93, 102))	('BRCA2', 'Gene', '675', (87, 92))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (135, 160))	('deficiencies', 'Var', (32, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (146, 160))	('PARP', 'Gene', (117, 121))	('BRCA1', 'Gene', '672', (77, 82))	('DNA repair', 'biological_process', 'GO:0006281', ('48', '58'))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('BRCA2', 'Gene', (87, 92))
150654	30736840	The PARPi olaparib (Lynparza, AstraZeneca) has recently been approved for the treatment of ovarian cancers with BRCA1/2 mutations.	('ovarian cancers', 'Phenotype', 'HP:0100615', (91, 106))	('ovarian cancers', 'Disease', (91, 106))	('PARP', 'Gene', (4, 8))	('olaparib', 'Chemical', 'MESH:C531550', (10, 18))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('ovarian cancers', 'Disease', 'MESH:D010051', (91, 106))	('BRCA1/2', 'Gene', (112, 119))	('mutations', 'Var', (120, 129))	('PARP', 'Gene', '142', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))	('BRCA1/2', 'Gene', '672;675', (112, 119))
150664	30736840	Taken together, our finds suggested that TNBC patients with high SPAG5 expression have poor prognoses.	('patients', 'Species', '9606', (46, 54))	('high', 'Var', (60, 64))	('SPAG5', 'Gene', (65, 70))	('SPAG5', 'Gene', '10615', (65, 70))	('TNBC', 'Disease', (41, 45))
150675	30736840	The antibodies used for FACS were anti-CD24-PE and anti-ESA-APC (Miltenyi Biotec).	('CD24', 'Gene', '100133941', (39, 43))	('anti-ESA-APC', 'Var', (51, 63))	('CD24', 'Gene', (39, 43))	('APC', 'cellular_component', 'GO:0005680', ('60', '63'))	('Biotec', 'Chemical', '-', (74, 80))
150681	30736840	Antibodies targeting CDC20 (abs135883) and RAD51 (abs137543) were purchased from Absin.	('RAD', 'biological_process', 'GO:1990116', ('43', '46'))	('CDC20', 'Gene', '991', (21, 26))	('abs137543', 'Var', (50, 59))	('abs135883', 'Var', (28, 37))	('CDC20', 'Gene', (21, 26))	('RAD51', 'Gene', (43, 48))	('RAD51', 'Gene', '5888', (43, 48))
150732	30736840	High SPAG5 expression was associated with more CD8+ T cell infiltration in breast cancer (Fig.	('SPAG5', 'Gene', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('High', 'Var', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('CD8', 'Gene', (47, 50))	('SPAG5', 'Gene', '10615', (5, 10))	('CD8', 'Gene', '925', (47, 50))	('more', 'PosReg', (42, 46))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
150734	30736840	In breast cancer, we found that high SPAG5 expression was associated with increased local recurrence (p < 0.001, Additional file 3: Table S2).	('high', 'Var', (32, 36))	('local recurrence', 'CPA', (84, 100))	('SPAG5', 'Gene', (37, 42))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('SPAG5', 'Gene', '10615', (37, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('increased', 'PosReg', (74, 83))	('expression', 'MPA', (43, 53))
150737	30736840	Furthermore, we found that high SPAG5 expression was associated with increased lymph node metastasis (p = 0.040) and increased risk of local recurrence (p = 0.009, Table 1) in TNBC.	('increased', 'PosReg', (69, 78))	('SPAG5', 'Gene', (32, 37))	('expression', 'MPA', (38, 48))	('TNBC', 'Disease', (176, 180))	('high', 'Var', (27, 31))	('SPAG5', 'Gene', '10615', (32, 37))	('lymph node metastasis', 'CPA', (79, 100))	('local recurrence', 'CPA', (135, 151))
150740	30736840	To further explore the potential functions of SPAG5 in TNBC, we performed a gene set enrichment analysis (GSEA) using mRNA expression data from TCGA database, and the results showed that high SPAG5 expression was significantly correlated with cell-cycle-related genes and G2-phase-related genes (Fig.	('SPAG5', 'Gene', '10615', (46, 51))	('cell-cycle', 'biological_process', 'GO:0007049', ('243', '253'))	('cell-cycle-related', 'CPA', (243, 261))	('SPAG5', 'Gene', (192, 197))	('GSEA', 'Chemical', '-', (106, 110))	('SPAG5', 'Gene', '10615', (192, 197))	('SPAG5', 'Gene', (46, 51))	('G2-phase', 'biological_process', 'GO:0051319', ('272', '280'))	('correlated', 'Reg', (227, 237))	('high', 'Var', (187, 191))
150742	30736840	Interestingly, high SPAG5 expression also correlated with ATR-BRCA pathway-related genes (Fig.	('expression', 'MPA', (26, 36))	('high', 'Var', (15, 19))	('BRCA', 'Gene', '672', (62, 66))	('SPAG5', 'Gene', (20, 25))	('ATR', 'Gene', '545', (58, 61))	('ATR', 'Gene', (58, 61))	('BRCA', 'Gene', (62, 66))	('correlated', 'Reg', (42, 52))	('SPAG5', 'Gene', '10615', (20, 25))
150750	30736840	Overexpression of SPAG5 increased the G2-phase cell population and decreased the G1-phase cell population, whereas SPAG5 knockdown induced S to G2 arrest, indicating that SPAG5 promotes the S/G2 transition (Fig.	('promotes', 'PosReg', (177, 185))	('SPAG5', 'Gene', '10615', (115, 120))	('S/G2', 'Var', (190, 194))	('SPAG5', 'Gene', (171, 176))	('G1-phase cell population', 'CPA', (81, 105))	('G1-phase', 'biological_process', 'GO:0051318', ('81', '89'))	('S/G2', 'SUBSTITUTION', 'None', (190, 194))	('SPAG5', 'Gene', (18, 23))	('G2-phase cell population', 'CPA', (38, 62))	('SPAG5', 'Gene', '10615', (171, 176))	('SPAG5', 'Gene', (115, 120))	('G2-phase', 'biological_process', 'GO:0051319', ('38', '46'))	('decreased', 'NegReg', (67, 76))	('SPAG5', 'Gene', '10615', (18, 23))	('increased', 'PosReg', (24, 33))
150751	30736840	Regarding to apoptosis, ectopic SPAG5 expression inhibited apoptosis in MDA-MB-231 and MDA-MB-468 cells, while SPAG5 knockdown induced apoptosis in Hs-578t and BT549 cells (Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('apoptosis', 'biological_process', 'GO:0097194', ('13', '22'))	('SPAG5', 'Gene', '10615', (111, 116))	('SPAG5', 'Gene', (32, 37))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('apoptosis', 'biological_process', 'GO:0006915', ('13', '22'))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (72, 82))	('SPAG5', 'Gene', '10615', (32, 37))	('apoptosis', 'CPA', (59, 68))	('BT549', 'CellLine', 'CVCL:1092', (160, 165))	('ectopic', 'Var', (24, 31))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (87, 97))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('SPAG5', 'Gene', (111, 116))	('inhibited', 'NegReg', (49, 58))
150756	30736840	SPAG5 knockdown Hs-578t and BT549 cells were significantly more sensitive to the PARPi olaparib than the negative control cells (Fig.	('SPAG5', 'Gene', '10615', (0, 5))	('SPAG5', 'Gene', (0, 5))	('PARP', 'Gene', (81, 85))	('more', 'PosReg', (59, 63))	('olaparib', 'Chemical', 'MESH:C531550', (87, 95))	('PARP', 'Gene', '142', (81, 85))	('knockdown', 'Var', (6, 15))	('sensitive to', 'MPA', (64, 76))	('BT549', 'CellLine', 'CVCL:1092', (28, 33))
150758	30736840	CCK8 assays indicated that SPAG5 knockdown promoted the efficacy of olaparib in Hs-578t cells, while SPAG5 overexpression decreased the efficacy of olaparib in MDA-MB-231 cells (Fig.	('efficacy', 'MPA', (56, 64))	('olaparib', 'Chemical', 'MESH:C531550', (68, 76))	('promoted', 'PosReg', (43, 51))	('SPAG5', 'Gene', '10615', (101, 106))	('knockdown', 'Var', (33, 42))	('SPAG5', 'Gene', (27, 32))	('olaparib', 'Chemical', 'MESH:C531550', (148, 156))	('SPAG5', 'Gene', (101, 106))	('SPAG5', 'Gene', '10615', (27, 32))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (160, 170))	('decreased', 'NegReg', (122, 131))
150770	30736840	Importantly, IHC staining in tumors generated from xenografts showed that high SPAG5 expression displayed high MYCBP and Ki67 staining (Fig.	('expression', 'MPA', (85, 95))	('high', 'Var', (74, 78))	('SPAG5', 'Gene', '10615', (79, 84))	('MYCBP', 'Gene', '26292', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('SPAG5', 'Gene', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('MYCBP', 'Gene', (111, 116))	('Ki67 staining', 'MPA', (121, 134))
150775	30736840	Our results showed that the expression of MYCBP protein was increased after dysregulation of SPAG5 in the presence of the proteasome inhibitor MG132 (Fig.	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('SPAG5', 'Gene', '10615', (93, 98))	('MG132', 'Chemical', 'MESH:C072553', (143, 148))	('protein', 'Protein', (48, 55))	('expression', 'MPA', (28, 38))	('proteasome', 'cellular_component', 'GO:0000502', ('122', '132'))	('proteasome', 'molecular_function', 'GO:0004299', ('122', '132'))	('MYCBP', 'Gene', (42, 47))	('dysregulation', 'Var', (76, 89))	('SPAG5', 'Gene', (93, 98))	('increased', 'PosReg', (60, 69))	('MYCBP', 'Gene', '26292', (42, 47))
150778	30736840	Consistent with the GSEA results, upregulation of cell-cycle-related and ATR-BRCA pathway-related genes was confirmed in SPAG5 overexpressing MDA-MB-231 cells compared with their expression in the vector control cells (Fig.	('SPAG5', 'Gene', '10615', (121, 126))	('cell-cycle', 'biological_process', 'GO:0007049', ('50', '60'))	('BRCA', 'Gene', (77, 81))	('overexpressing', 'Var', (127, 141))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (142, 152))	('ATR', 'Gene', '545', (73, 76))	('BRCA', 'Gene', '672', (77, 81))	('SPAG5', 'Gene', (121, 126))	('GSEA', 'Chemical', '-', (20, 24))	('cell-cycle-related', 'Gene', (50, 68))	('ATR', 'Gene', (73, 76))	('upregulation', 'PosReg', (34, 46))
150780	30736840	They were all significantly upregulated by SPAG5 overexpression and downregulated by SPAG5 knockdown in TNBC cells (Fig.	('SPAG5', 'Gene', (43, 48))	('downregulated', 'NegReg', (68, 81))	('SPAG5', 'Gene', (85, 90))	('knockdown', 'Var', (91, 100))	('SPAG5', 'Gene', '10615', (43, 48))	('SPAG5', 'Gene', '10615', (85, 90))	('upregulated', 'PosReg', (28, 39))	('overexpression', 'PosReg', (49, 63))
150781	30736840	It was also confirmed that mRNA expression of the c-MYC targets CDC25C, CDC20, RAD51, BRCA1, and BRCA2 was significantly downregulated by c-MYC knockdown in MDA-MB-231 and MDA-MB-231 cells (Additional file 7: Fig.	('BRCA2', 'Gene', (97, 102))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (157, 167))	('c-MYC', 'Gene', (138, 143))	('CDC25C', 'Gene', (64, 70))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (172, 182))	('CDC25C', 'Gene', '995', (64, 70))	('downregulated', 'NegReg', (121, 134))	('mRNA expression', 'MPA', (27, 42))	('RAD51', 'Gene', (79, 84))	('RAD51', 'Gene', '5888', (79, 84))	('c-MYC', 'Gene', '4609', (50, 55))	('BRCA2', 'Gene', '675', (97, 102))	('c-MYC', 'Gene', (50, 55))	('CDC20', 'Gene', '991', (72, 77))	('knockdown', 'Var', (144, 153))	('CDC20', 'Gene', (72, 77))	('BRCA1', 'Gene', '672', (86, 91))	('RAD', 'biological_process', 'GO:1990116', ('79', '82'))	('BRCA1', 'Gene', (86, 91))	('c-MYC', 'Gene', '4609', (138, 143))
150783	30736840	As shown by qPCR, SPAG5 knockdown in BT549 cells significantly reduced the occupancy of c-MYC on the promoters of CDC20, CDC25C, RAD51, BRCA1, and BRCA2 (Fig.	('BT549', 'CellLine', 'CVCL:1092', (37, 42))	('SPAG5', 'Gene', '10615', (18, 23))	('c-MYC', 'Gene', '4609', (88, 93))	('occupancy', 'MPA', (75, 84))	('BRCA2', 'Gene', '675', (147, 152))	('CDC20', 'Gene', '991', (114, 119))	('c-MYC', 'Gene', (88, 93))	('BRCA1', 'Gene', '672', (136, 141))	('BRCA1', 'Gene', (136, 141))	('reduced', 'NegReg', (63, 70))	('CDC20', 'Gene', (114, 119))	('CDC25C', 'Gene', (121, 127))	('knockdown', 'Var', (24, 33))	('CDC25C', 'Gene', '995', (121, 127))	('SPAG5', 'Gene', (18, 23))	('RAD51', 'Gene', (129, 134))	('RAD51', 'Gene', '5888', (129, 134))	('BRCA2', 'Gene', (147, 152))	('RAD', 'biological_process', 'GO:1990116', ('129', '132'))
150788	30736840	We found that knockdown of MYCBP significantly abolished the positive effects of SPAG5 on cell proliferation (Fig.	('MYCBP', 'Gene', '26292', (27, 32))	('SPAG5', 'Gene', (81, 86))	('cell proliferation', 'CPA', (90, 108))	('MYCBP', 'Gene', (27, 32))	('SPAG5', 'Gene', '10615', (81, 86))	('knockdown', 'Var', (14, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))	('abolished', 'NegReg', (47, 56))
150789	30736840	Cell cycle analysis indicated that knockdown of MYCBP significantly abolished the positive effects of SPAG5 on cell-cycle progression (Fig.	('MYCBP', 'Gene', '26292', (48, 53))	('knockdown', 'Var', (35, 44))	('abolished', 'NegReg', (68, 77))	('SPAG5', 'Gene', (102, 107))	('cell-cycle progression', 'CPA', (111, 133))	('MYCBP', 'Gene', (48, 53))	('SPAG5', 'Gene', '10615', (102, 107))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('cell-cycle', 'biological_process', 'GO:0007049', ('111', '121'))
150792	30736840	The resistance to olaparib induced by SPAG5 overexpressing in MDA-MB-231 and MDA-MB-468 cells was also significantly abolished by MYCBP knockdown (Fig.	('resistance to olaparib', 'MPA', (4, 26))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (77, 87))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (62, 72))	('abolished', 'NegReg', (117, 126))	('MYCBP', 'Gene', (130, 135))	('knockdown', 'Var', (136, 145))	('olaparib', 'Chemical', 'MESH:C531550', (18, 26))	('overexpressing', 'PosReg', (44, 58))	('SPAG5', 'Gene', (38, 43))	('MYCBP', 'Gene', '26292', (130, 135))	('SPAG5', 'Gene', '10615', (38, 43))
150795	30736840	We found that knockdown of c-MYC significantly abolished the positive effects of SPAG5 on cell proliferation (Fig.	('c-MYC', 'Gene', (27, 32))	('SPAG5', 'Gene', (81, 86))	('cell proliferation', 'CPA', (90, 108))	('c-MYC', 'Gene', '4609', (27, 32))	('SPAG5', 'Gene', '10615', (81, 86))	('knockdown', 'Var', (14, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))	('abolished', 'NegReg', (47, 56))
150802	30736840	In addition, SPAG5 knockdown increased the sensitivity to the PARPi olaparib in TNBC cells.	('olaparib', 'Chemical', 'MESH:C531550', (68, 76))	('knockdown', 'Var', (19, 28))	('SPAG5', 'Gene', (13, 18))	('increased', 'PosReg', (29, 38))	('PARP', 'Gene', (62, 66))	('SPAG5', 'Gene', '10615', (13, 18))	('PARP', 'Gene', '142', (62, 66))
150807	30736840	For breast cancer, the analysis of multiple breast cancer cohorts indicated that high SPAG5 transcript expression was associated with decreased survival in all breast cancer subtypes and estrogen receptor-positive subgroups; although, its prognostic value in TNBC was not clear.	('decreased', 'NegReg', (134, 143))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Disease', (44, 57))	('high', 'Var', (81, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('SPAG5', 'Gene', (86, 91))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('survival', 'MPA', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (160, 173))	('SPAG5', 'Gene', '10615', (86, 91))	('transcript expression', 'MPA', (92, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
150808	30736840	Accordingly, our data suggested that high SPAG5 expression is associated with worse patient outcomes, which are consistent with the previous study.	('high', 'Var', (37, 41))	('expression', 'MPA', (48, 58))	('SPAG5', 'Gene', (42, 47))	('SPAG5', 'Gene', '10615', (42, 47))	('patient', 'Species', '9606', (84, 91))
150811	30736840	The GSEA analysis of TNBC suggested that high SPAG5 expression is associated with cell-cycle-related genes (CDC20 and CDC25C) and ATR BRCA pathway-related genes (RAD51, BRCA2, BRCA1).	('BRCA', 'Gene', '672', (134, 138))	('BRCA2', 'Gene', (169, 174))	('CDC20', 'Gene', '991', (108, 113))	('RAD', 'biological_process', 'GO:1990116', ('162', '165'))	('CDC25C', 'Gene', (118, 124))	('SPAG5', 'Gene', (46, 51))	('CDC25C', 'Gene', '995', (118, 124))	('BRCA', 'Gene', (134, 138))	('CDC20', 'Gene', (108, 113))	('BRCA1', 'Gene', '672', (176, 181))	('ATR', 'Gene', '545', (130, 133))	('cell-cycle', 'biological_process', 'GO:0007049', ('82', '92'))	('BRCA1', 'Gene', (176, 181))	('BRCA2', 'Gene', '675', (169, 174))	('SPAG5', 'Gene', '10615', (46, 51))	('BRCA', 'Gene', '672', (176, 180))	('BRCA', 'Gene', '672', (169, 173))	('RAD51', 'Gene', (162, 167))	('associated', 'Reg', (66, 76))	('ATR', 'Gene', (130, 133))	('high', 'Var', (41, 45))	('expression', 'MPA', (52, 62))	('RAD51', 'Gene', '5888', (162, 167))	('BRCA', 'Gene', (176, 180))	('BRCA', 'Gene', (169, 173))	('GSEA', 'Chemical', '-', (4, 8))
150812	30736840	It has been reported that ATR enforces an S/G2 transition to promote genome integrity.	('ATR', 'Gene', '545', (26, 29))	('ATR', 'Gene', (26, 29))	('promote', 'PosReg', (61, 68))	('genome integrity', 'CPA', (69, 85))	('S/G2', 'Var', (42, 46))	('S/G2', 'SUBSTITUTION', 'None', (42, 46))
150813	30736840	The cell cycle analysis in our study also indicated that SPAG5 could promote the S/G2 transition.	('SPAG5', 'Gene', (57, 62))	('promote', 'PosReg', (69, 76))	('cell cycle', 'biological_process', 'GO:0007049', ('4', '14'))	('SPAG5', 'Gene', '10615', (57, 62))	('S/G2', 'Var', (81, 85))	('S/G2', 'SUBSTITUTION', 'None', (81, 85))
150814	30736840	Ectopic SPAG5 expression increased Cyclin B1, Cyclin A2, and CDC20 expression, but decreased P21, P27 expression.	('P27', 'Gene', (98, 101))	('P21', 'Gene', (93, 96))	('P27', 'Gene', '51014', (98, 101))	('Cyclin B1', 'Gene', (35, 44))	('CDC20', 'Gene', (61, 66))	('Cyclin A2', 'Gene', (46, 55))	('expression', 'Var', (14, 24))	('SPAG5', 'Gene', (8, 13))	('Cyclin B1', 'Gene', '891', (35, 44))	('Cyclin', 'molecular_function', 'GO:0016538', ('35', '41'))	('Cyclin', 'molecular_function', 'GO:0016538', ('46', '52'))	('SPAG5', 'Gene', '10615', (8, 13))	('increased', 'PosReg', (25, 34))	('expression', 'MPA', (102, 112))	('Cyclin A2', 'Gene', '890', (46, 55))	('decreased', 'NegReg', (83, 92))	('CDC20', 'Gene', '991', (61, 66))	('P21', 'Gene', '1026', (93, 96))	('expression', 'MPA', (67, 77))
150820	30736840	Our findings showed that SPAG5 overexpression decreased the sensitivity of MDA-MB-231 and MDA-MB-468 cells to olaparib, while SPAG5 knockdown increased the sensitivity to olaparib.	('olaparib', 'Chemical', 'MESH:C531550', (171, 179))	('increased', 'PosReg', (142, 151))	('knockdown', 'Var', (132, 141))	('SPAG5', 'Gene', (126, 131))	('olaparib', 'Chemical', 'MESH:C531550', (110, 118))	('SPAG5', 'Gene', '10615', (126, 131))	('sensitivity', 'MPA', (156, 167))	('SPAG5', 'Gene', (25, 30))	('decreased', 'NegReg', (46, 55))	('SPAG5', 'Gene', '10615', (25, 30))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (75, 85))	('overexpression', 'PosReg', (31, 45))	('sensitivity', 'MPA', (60, 71))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (90, 100))
150823	30736840	In current clinical management, BRCA1/BRCA2 mutations remain the most frequently used biomarkers of HR DNA repair deficiency in TNBC to determine whether patients are suitable for PARPi treatment or not.	('BRCA1', 'Gene', (32, 37))	('DNA repair', 'biological_process', 'GO:0006281', ('103', '113'))	('BRCA2', 'Gene', '675', (38, 43))	('PARP', 'Gene', '142', (180, 184))	('deficiency', 'Disease', (114, 124))	('patients', 'Species', '9606', (154, 162))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('deficiency', 'Disease', 'MESH:D007153', (114, 124))	('mutations', 'Var', (44, 53))	('BRCA1', 'Gene', '672', (32, 37))	('PARP', 'Gene', (180, 184))	('BRCA2', 'Gene', (38, 43))
150824	30736840	However, whether PARPi has potential effects in addition to BRCA1/BRCA2 mutation carriers remains an important question.	('BRCA1', 'Gene', (60, 65))	('BRCA2', 'Gene', (66, 71))	('PARP', 'Gene', (17, 21))	('BRCA2', 'Gene', '675', (66, 71))	('PARP', 'Gene', '142', (17, 21))	('mutation', 'Var', (72, 80))	('BRCA1', 'Gene', '672', (60, 65))
150828	30736840	Thus, the increased S-phase cell population and decreased RAD51 and BRCA1/2 mRNA and protein expression by SPAG5 knockdown is a potential mechanism that explains how reduced SPAG5 expression increases sensitivity to olaparib.	('SPAG5', 'Gene', '10615', (107, 112))	('RAD51', 'Gene', (58, 63))	('RAD51', 'Gene', '5888', (58, 63))	('sensitivity to olaparib', 'MPA', (201, 224))	('olaparib', 'Chemical', 'MESH:C531550', (216, 224))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('BRCA1/2', 'Gene', '672;675', (68, 75))	('SPAG5', 'Gene', (174, 179))	('decreased', 'NegReg', (48, 57))	('increased', 'PosReg', (10, 19))	('RAD', 'biological_process', 'GO:1990116', ('58', '61'))	('expression', 'MPA', (180, 190))	('knockdown', 'Var', (113, 122))	('increases', 'PosReg', (191, 200))	('SPAG5', 'Gene', (107, 112))	('S-phase cell population', 'CPA', (20, 43))	('SPAG5', 'Gene', '10615', (174, 179))	('BRCA1/2', 'Gene', (68, 75))	('reduced', 'Var', (166, 173))	('S-phase', 'biological_process', 'GO:0051320', ('20', '27'))
150832	30736840	We observed that SPAG5 knockdown reduced MYCBP protein but not mRNA expression.	('MYCBP', 'Gene', '26292', (41, 46))	('knockdown', 'Var', (23, 32))	('SPAG5', 'Gene', (17, 22))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('reduced', 'NegReg', (33, 40))	('SPAG5', 'Gene', '10615', (17, 22))	('MYCBP', 'Gene', (41, 46))
150837	30736840	As shown in our results, knockdown of SPAG5 could lead to decreased expression of c-MYC target genes related to cell cycle progression and the ATR BRCA pathway.	('c-MYC', 'Gene', '4609', (82, 87))	('BRCA', 'Gene', (147, 151))	('cell cycle', 'biological_process', 'GO:0007049', ('112', '122'))	('ATR', 'Gene', '545', (143, 146))	('decreased', 'NegReg', (58, 67))	('expression of', 'MPA', (68, 81))	('ATR', 'Gene', (143, 146))	('SPAG5', 'Gene', (38, 43))	('c-MYC', 'Gene', (82, 87))	('SPAG5', 'Gene', '10615', (38, 43))	('knockdown', 'Var', (25, 34))	('BRCA', 'Gene', '672', (147, 151))
150838	30736840	The CHIP-qPCR assay confirmed that SPAG5 knockdown significantly reduces the occupancy of c-MYC on the promoters of CDC20, CDC25C, BRCA1, BRCA2, and RAD51, which supports our speculation that SPAG5 can positively regulate c-MYC transcriptional activity by increasing MYCBP protein expression.	('occupancy', 'MPA', (77, 86))	('BRCA2', 'Gene', '675', (138, 143))	('BRCA1', 'Gene', '672', (131, 136))	('SPAG5', 'Gene', (192, 197))	('regulate', 'Reg', (213, 221))	('CDC20', 'Gene', (116, 121))	('BRCA1', 'Gene', (131, 136))	('c-MYC', 'Gene', '4609', (90, 95))	('SPAG5', 'Gene', '10615', (35, 40))	('c-MYC', 'Gene', (90, 95))	('reduces', 'NegReg', (65, 72))	('SPAG5', 'Gene', '10615', (192, 197))	('c-MYC', 'Gene', '4609', (222, 227))	('CDC25C', 'Gene', (123, 129))	('RAD', 'biological_process', 'GO:1990116', ('149', '152'))	('RAD51', 'Gene', (149, 154))	('c-MYC', 'Gene', (222, 227))	('RAD51', 'Gene', '5888', (149, 154))	('CDC25C', 'Gene', '995', (123, 129))	('BRCA2', 'Gene', (138, 143))	('knockdown', 'Var', (41, 50))	('MYCBP', 'Gene', (267, 272))	('increasing', 'PosReg', (256, 266))	('MYCBP', 'Gene', '26292', (267, 272))	('CDC20', 'Gene', '991', (116, 121))	('SPAG5', 'Gene', (35, 40))	('expression', 'MPA', (281, 291))	('protein', 'cellular_component', 'GO:0003675', ('273', '280'))
150842	30736840	In summary, our study indicated that SPAG5 was upregulated in TNBC tissues and that high SPAG5 expression was associated with high risk of local recurrence and poorer outcomes in TNBC patients.	('SPAG5', 'Gene', (37, 42))	('high', 'Var', (84, 88))	('patients', 'Species', '9606', (184, 192))	('SPAG5', 'Gene', (89, 94))	('TNBC', 'Disease', (62, 66))	('upregulated', 'PosReg', (47, 58))	('SPAG5', 'Gene', '10615', (37, 42))	('associated', 'Reg', (110, 120))	('SPAG5', 'Gene', '10615', (89, 94))	('local recurrence', 'CPA', (139, 155))	('expression', 'MPA', (95, 105))
150844	30736840	Moreover, SPAG5 knockdown increased TNBC cell sensitivity to the PARPi olaparib.	('olaparib', 'Chemical', 'MESH:C531550', (71, 79))	('knockdown', 'Var', (16, 25))	('PARP', 'Gene', (65, 69))	('SPAG5', 'Gene', (10, 15))	('increased', 'PosReg', (26, 35))	('SPAG5', 'Gene', '10615', (10, 15))	('PARP', 'Gene', '142', (65, 69))
150855	29057879	Deletion of 3p13-14 locus spanning FOXP1 to SHQ1 cooperates with PTEN loss in prostate oncogenesis A multigenic locus at 3p13-14, spanning FOXP1 to SHQ1, is commonly deleted in prostate cancer and lost broadly in a range of cancers but has unknown significance to oncogenesis or prognosis.	('FOXP1', 'Gene', (139, 144))	('SHQ1', 'Gene', (44, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (177, 192))	('oncogenesis', 'biological_process', 'GO:0007048', ('87', '98'))	('FOXP1', 'Gene', '108655', (139, 144))	('prostate cancer', 'Phenotype', 'HP:0012125', (177, 192))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancers', 'Disease', (224, 231))	('oncogenesis', 'biological_process', 'GO:0007048', ('264', '275'))	('FOXP1', 'Gene', (35, 40))	('SHQ1', 'Gene', '72171', (148, 152))	('prostate cancer', 'Disease', (177, 192))	('in a', 'Gene', '226180', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('FOXP1', 'Gene', '108655', (35, 40))	('SHQ1', 'Gene', '72171', (44, 48))	('in a', 'Gene', (210, 214))	('Deletion', 'Var', (0, 8))	('lost', 'NegReg', (197, 201))	('PTEN', 'Gene', (65, 69))	('deleted', 'Var', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('PTEN', 'Gene', '19211', (65, 69))	('SHQ1', 'Gene', (148, 152))
150856	29057879	Here, we report that FOXP1-SHQ1 deletion cooperates with PTEN loss to accelerate prostate oncogenesis and that loss of component genes correlates with prostate, breast, and head and neck cancer recurrence.	('loss', 'NegReg', (62, 66))	('breast', 'Disease', (161, 167))	('deletion', 'Var', (32, 40))	('neck', 'cellular_component', 'GO:0044326', ('182', '186'))	('accelerate', 'PosReg', (70, 80))	('recurrence', 'Disease', (194, 204))	('PTEN', 'Gene', (57, 61))	('prostate', 'Disease', (81, 89))	('prostate', 'Disease', (151, 159))	('FOXP1-SHQ1', 'Gene', (21, 31))	('head and neck cancer', 'Phenotype', 'HP:0012288', (173, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('oncogenesis', 'biological_process', 'GO:0007048', ('90', '101'))	('head and neck cancer', 'Disease', 'MESH:D006258', (173, 193))
150857	29057879	We demonstrate that Foxp1-Shq1 deletion accelerates prostate tumorigenesis in mice in combination with Pten loss, consistent with the association of FOXP1-SHQ1 and PTEN loss observed in human cancers.	('accelerates', 'PosReg', (40, 51))	('prostate tumor', 'Phenotype', 'HP:0100787', (52, 66))	('prostate tumor', 'Disease', 'MESH:D011471', (52, 66))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancers', 'Disease', (192, 199))	('deletion', 'Var', (31, 39))	('human', 'Species', '9606', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Foxp1-Shq1', 'Gene', (20, 30))	('prostate tumor', 'Disease', (52, 66))	('mice', 'Species', '10090', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
150858	29057879	Tumors with combined Foxp1-Shq1 and Pten deletion show increased proliferation and anaplastic dedifferentiation, as well as mTORC1 hyperactivation with reduced Akt phosphorylation.	('Pten', 'Gene', (36, 40))	('mTORC1', 'Gene', (124, 130))	('proliferation', 'CPA', (65, 78))	('anaplastic dedifferentiation', 'CPA', (83, 111))	('hyperactivation', 'PosReg', (131, 146))	('increased', 'PosReg', (55, 64))	('mTORC1', 'cellular_component', 'GO:0031931', ('124', '130'))	('reduced', 'NegReg', (152, 159))	('dedifferentiation', 'biological_process', 'GO:0043696', ('94', '111'))	('deletion', 'Var', (41, 49))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('mTORC1', 'Gene', '382056', (124, 130))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Akt', 'Pathway', (160, 163))	('phosphorylation', 'biological_process', 'GO:0016310', ('164', '179'))	('Foxp1-Shq1', 'Gene', (21, 31))
150859	29057879	Foxp1-Shq1 deletion restores expression of AR target genes repressed in tumors with Pten loss, circumventing PI3K-mediated repression of the androgen axis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PI3K', 'molecular_function', 'GO:0016303', ('109', '113'))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('restores', 'PosReg', (20, 28))	('deletion', 'Var', (11, 19))	('expression', 'MPA', (29, 39))	('Foxp1-Shq1', 'Gene', (0, 10))	('loss', 'NegReg', (89, 93))
150860	29057879	Moreover, FOXP1-SHQ1 deletion has prognostic relevance, with cancer recurrence associated with combined loss of PTEN and FOXP1-SHQ1 genes.	('loss', 'NegReg', (104, 108))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('deletion', 'Var', (21, 29))	('PTEN', 'Gene', (112, 116))	('FOXP1-SHQ1', 'Gene', (10, 20))	('FOXP1-SHQ1', 'Gene', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
150862	29057879	Here, the authors, using a PTEN loss-driven prostate cancer mouse model, show that a multigenic FOXP1-SHQ1 deletion is a driver event with prognostic value.	('prostate cancer', 'Disease', (44, 59))	('mouse', 'Species', '10090', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('FOXP1-SHQ1', 'Gene', (96, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (44, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (44, 59))	('deletion', 'Var', (107, 115))
150865	29057879	Prostate cancer, the most common malignancy in men, shows a significant multigenic deletion at 3p13-14 that spans FOXP1, EIF4E3, GPR27, PROK2, RYBP, and SHQ1 .	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('FOXP1', 'Gene', (114, 119))	('SHQ1', 'Gene', (153, 157))	('Prostate cancer', 'Disease', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('men', 'Species', '9606', (47, 50))	('PROK2', 'Gene', (136, 141))	('malignancy', 'Disease', 'MESH:D009369', (33, 43))	('EIF4', 'cellular_component', 'GO:0008304', ('121', '125'))	('malignancy', 'Disease', (33, 43))	('deletion', 'Var', (83, 91))	('EIF4E3', 'Gene', (121, 127))	('Prostate cancer', 'Disease', 'MESH:D011471', (0, 15))	('GPR27', 'Gene', (129, 134))
150866	29057879	It is unknown whether this region has a tumor suppressive function, but more than 12% of primary prostate tumors show copy number loss of the 3p13-14 region from FOXP1 to SHQ1 (termed FOXP1-SHQ1 deletion) and 15% show copy number loss of the individual FOXP1 or SHQ1 genes that bound the deletion.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('prostate tumor', 'Phenotype', 'HP:0100787', (97, 111))	('primary prostate tumors', 'Disease', (89, 112))	('FOXP1', 'Gene', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('SHQ1', 'Gene', (171, 175))	('tumor', 'Disease', (106, 111))	('primary prostate tumors', 'Disease', 'MESH:D011471', (89, 112))	('loss', 'NegReg', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('copy number', 'Var', (118, 129))	('FOXP1', 'Gene', (162, 167))	('SHQ1', 'Gene', (262, 266))	('loss', 'NegReg', (230, 234))
150867	29057879	Deletion of the FOXP1-SHQ1 region is seen in a wide variety of cancers, ranging from 27% of primary breast cancer and stomach cancer to 70% or more in renal clear cell and head and neck cancers, often within larger deletions.	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('neck cancers', 'Disease', (181, 193))	('neck', 'cellular_component', 'GO:0044326', ('181', '185'))	('cancers', 'Disease', (186, 193))	('neck cancers', 'Disease', 'MESH:D006258', (181, 193))	('stomach cancer', 'Disease', 'MESH:D013274', (118, 132))	('head and neck cancer', 'Phenotype', 'HP:0012288', (172, 192))	('stomach cancer', 'Phenotype', 'HP:0012126', (118, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('FOXP1-SHQ1', 'Gene', (16, 26))	('cancers', 'Disease', (63, 70))	('Deletion', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('in a', 'Gene', '226180', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('in a', 'Gene', (42, 46))	('breast cancer', 'Disease', (100, 113))	('head and neck cancer', 'Disease', 'MESH:D006258', (172, 192))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('renal clear cell', 'Disease', (151, 167))	('stomach cancer', 'Disease', (118, 132))	('head and neck cancers', 'Phenotype', 'HP:0012288', (172, 193))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
150869	29057879	SHQ1, an RNP assembly factor required for ribosome and telomerase function, acts as a co-factor to dyskeratosis congenita protein DKC1 mutated in resulting malignancies.	('malignancies', 'Disease', (156, 168))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('dyskeratosis congenita', 'Disease', (99, 121))	('mutated', 'Var', (135, 142))	('ribosome', 'cellular_component', 'GO:0005840', ('42', '50'))	('DKC1', 'Gene', (130, 134))	('malignancies', 'Disease', 'MESH:D009369', (156, 168))	('RNP', 'cellular_component', 'GO:1990904', ('9', '12'))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (99, 121))
150872	29057879	FOXP1 has the highest number of somatic point mutations in prostate cancer, including H515R/Y and the adjacent L519del in the forkhead domain, which are also seen in other cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('L519del', 'Mutation', 'p.519delL', (111, 118))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('prostate cancer', 'Disease', (59, 74))	('FOXP1', 'Gene', (0, 5))	('H515R', 'SUBSTITUTION', 'None', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('H515R', 'Var', (86, 91))	('cancers', 'Disease', (172, 179))	('L519del', 'Var', (111, 118))
150873	29057879	SHQ1, though infrequently mutated, has been found to have a A228T mutation found in other cancer types, as well as additional mutations in the SHQ1-dyskerin interaction domain.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('A228T', 'Var', (60, 65))	('SHQ1', 'Gene', (0, 4))	('SHQ1-dyskerin', 'Gene', (143, 156))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('A228T', 'Mutation', 'rs772128613', (60, 65))
150874	29057879	Thus, deletion of the 3p13-14 FOXP1-SHQ1 region may confer loss of multiple tumor suppressor functions.	('FOXP1-SHQ1', 'Gene', (30, 40))	('multiple tumor', 'Disease', (67, 81))	('multiple tumor', 'Disease', 'MESH:D009369', (67, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('deletion', 'Var', (6, 14))	('tumor suppressor', 'biological_process', 'GO:0051726', ('76', '92'))	('loss', 'NegReg', (59, 63))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('76', '92'))
150875	29057879	Here, we provide conclusive evidence that the 3p13-14 FOXP1-SHQ1 deletion is a driver event in prostate oncogenesis through interaction with other genetic alterations, most notably phosphoinositide 3-kinase (PI3K) pathway activation by PTEN loss.	('FOXP1-SHQ1', 'Gene', (54, 64))	('loss', 'NegReg', (241, 245))	('oncogenesis', 'biological_process', 'GO:0007048', ('104', '115'))	('PI3K', 'molecular_function', 'GO:0016303', ('208', '212'))	('interaction', 'Interaction', (124, 135))	('activation', 'PosReg', (222, 232))	('prostate oncogenesis', 'Disease', (95, 115))	('PTEN', 'Gene', (236, 240))	('deletion', 'Var', (65, 73))	('phosphoinositide', 'Chemical', 'MESH:D010716', (181, 197))
150876	29057879	Furthermore, human tumors with FOXP1-SHQ1 deletion are enriched in PTEN deletion.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('human', 'Species', '9606', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('FOXP1-SHQ1', 'Gene', (31, 41))	('PTEN', 'Gene', (67, 71))	('deletion', 'Var', (42, 50))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('deletion', 'Var', (72, 80))
150879	29057879	To explore the genetic interactions between the 3p13-14 FOXP1-SHQ1 deletion and other major cancer alterations, we assessed whether prostate cancers with this deletion showed significant co-enrichment of other focal copy number alterations.	('men', 'Species', '9606', (196, 199))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('deletion', 'Var', (67, 75))	('prostate cancers', 'Disease', 'MESH:D011471', (132, 148))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('FOXP1-SHQ1', 'Gene', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('deletion', 'Var', (159, 167))	('prostate cancers', 'Phenotype', 'HP:0012125', (132, 148))	('cancer', 'Disease', (141, 147))	('prostate cancers', 'Disease', (132, 148))
150880	29057879	We find that FOXP1-SHQ1 deletion co-occurs more often than expected with loss of PTEN, a common tumor suppressor of the PI3K pathway, in primary prostate adenocarcinoma (Memorial Sloan Kettering cohort, P = 0.008, Fisher's exact test, Supplementary Table 1, Fig.	('loss', 'NegReg', (73, 77))	('men', 'Species', '9606', (241, 244))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('96', '112'))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('primary prostate adenocarcinoma', 'Disease', (137, 168))	('FOXP1-SHQ1', 'Gene', (13, 23))	('PI3K', 'molecular_function', 'GO:0016303', ('120', '124'))	('tumor', 'Disease', (96, 101))	('PTEN', 'Gene', (81, 85))	('deletion', 'Var', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('primary prostate adenocarcinoma', 'Disease', 'MESH:D011471', (137, 168))	('tumor suppressor', 'biological_process', 'GO:0051726', ('96', '112'))
150881	29057879	PTEN loss occurs in 40% of prostate tumors that show FOXP1-SHQ1 deletion, but in only 13% overall.	('deletion', 'Var', (64, 72))	('prostate tumors', 'Disease', (27, 42))	('loss', 'NegReg', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('PTEN', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('prostate tumor', 'Phenotype', 'HP:0100787', (27, 41))	('prostate tumors', 'Disease', 'MESH:D011471', (27, 42))	('FOXP1-SHQ1', 'Gene', (53, 63))
150884	29057879	Moreover, PIK3CB mutation and amplification is significantly enriched in tumors with FOXP1-SHQ1 deletion (P = 0.002, Fisher's exact test) in the TCGA prostate cancer cohort, which has available exome sequencing data (Supplementary Table 1).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('men', 'Species', '9606', (223, 226))	('FOXP1-SHQ1', 'Gene', (85, 95))	('prostate cancer', 'Disease', (150, 165))	('PIK3CB', 'Gene', (10, 16))	('mutation', 'Var', (17, 25))	('cat', 'Gene', (37, 40))	('cat', 'Gene', '12359', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('deletion', 'Var', (96, 104))	('prostate cancer', 'Disease', 'MESH:D011471', (150, 165))	('tumors', 'Disease', (73, 79))	('prostate cancer', 'Phenotype', 'HP:0012125', (150, 165))
150885	29057879	Interestingly, the association between PI3KB mutation and FOXP1-SHQ1 loss primarily occurs in the context of PTEN loss (P = 0.004 in the subset with PTEN loss, NS in the subset without PTEN loss, Fisher's exact test).	('PI3KB', 'Gene', (39, 44))	('PTEN', 'Gene', (149, 153))	('loss', 'NegReg', (114, 118))	('PTEN', 'Gene', (109, 113))	('mutation', 'Var', (45, 53))	('loss', 'NegReg', (154, 158))	('FOXP1-SHQ1 loss', 'Disease', (58, 73))	('FOXP1-SHQ1 loss', 'Disease', 'MESH:D015431', (58, 73))
150886	29057879	Since PTEN deleted tumors are likely dependent on PIK3CB due to feedback inhibition of PIK3CA , activating PIK3CB mutations such as the observed E552K mutation may be a mechanism of enhancing the oncogenicity associated with PTEN deletion.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('E552K', 'Mutation', 'p.E552K', (145, 150))	('PTEN', 'Gene', (225, 229))	('activating', 'PosReg', (96, 106))	('feedback inhibition', 'MPA', (64, 83))	('enhancing', 'PosReg', (182, 191))	('E552K mutation', 'Var', (145, 159))	('PIK3CB', 'Gene', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('oncogenicity', 'CPA', (196, 208))
150888	29057879	Together, these findings suggest that activating PI3K pathway alterations are associated with 3p13-14 FOXP1-SHQ1 deletion in prostate cancer.	('PI3K pathway', 'Pathway', (49, 61))	('activating', 'PosReg', (38, 48))	('FOXP1-SHQ1', 'Gene', (102, 112))	('deletion', 'Var', (113, 121))	('prostate cancer', 'Disease', 'MESH:D011471', (125, 140))	('prostate cancer', 'Phenotype', 'HP:0012125', (125, 140))	('PI3K', 'molecular_function', 'GO:0016303', ('49', '53'))	('prostate cancer', 'Disease', (125, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('alterations', 'Var', (62, 73))
150889	29057879	While we previously found that FOXP1-SHQ1 deletion is co-enriched with ERG fusion in addition to PTEN loss in human prostate cancer, PTEN loss is not co-enriched with ERG fusion within the SHQ1-FOXP1 deleted population (P = 0.24, Fisher's exact test, prostate TCGA cohort).	('in a', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('prostate cancer', 'Disease', (116, 131))	('human', 'Species', '9606', (110, 115))	('FOXP1-SHQ1', 'Gene', (31, 41))	('loss', 'NegReg', (102, 106))	('deletion', 'Var', (42, 50))	('prostate cancer', 'Disease', 'MESH:D011471', (116, 131))	('in a', 'Gene', '226180', (82, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (116, 131))
150890	29057879	ERG fusion and PTEN loss are known to be co-enriched in unselected patients and functionally cooperate in oncogenesis, but we find that their statistical co-enrichment is only seen in human prostate cancer lacking FOXP1-SHQ1 deletion (P < 0.001, Fisher's exact test, prostate TCGA cohort).	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('oncogenesis', 'biological_process', 'GO:0007048', ('106', '117'))	('deletion', 'Var', (225, 233))	('patients', 'Species', '9606', (67, 75))	('prostate cancer', 'Disease', (190, 205))	('men', 'Species', '9606', (163, 166))	('lacking', 'NegReg', (206, 213))	('prostate cancer', 'Disease', 'MESH:D011471', (190, 205))	('human', 'Species', '9606', (184, 189))	('prostate cancer', 'Phenotype', 'HP:0012125', (190, 205))	('FOXP1-SHQ1', 'Gene', (214, 224))
150891	29057879	Conversely, it has been previously reported that FOXP1 deletion is only co-enriched with PTEN deletion in ERG fusion-negative tumors as ascertained by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), though we do not see this association in other genomic cohorts (prostate TCGA, MSKCC, P > 0.1).	('deletion', 'Var', (94, 102))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('deletion', 'Var', (55, 63))	('FOXP1', 'Gene', (49, 54))
150894	29057879	Of 12 published TCGA cohorts showing FOXP1-SHQ1 deletion and PTEN deletion individually in at least 2% of tumors, 7 cancer types showed significantly enriched co-deletion of the two regions (Fig.	('FOXP1-SHQ1', 'Gene', (37, 47))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('in a', 'Gene', (88, 92))	('tumors', 'Disease', (106, 112))	('cancer', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('PTEN', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('in a', 'Gene', '226180', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('deletion', 'Var', (48, 56))	('deletion', 'Var', (66, 74))
150896	29057879	One additional TCGA cohort, bladder urothelial carcinoma, showed a significant association between FOXP1-SHQ1 deletion and PIK3CA mutation or amplification (Supplementary Table 2).	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (28, 56))	('cat', 'Gene', '12359', (149, 152))	('bladder urothelial carcinoma', 'Disease', (28, 56))	('mutation', 'Var', (130, 138))	('FOXP1-SHQ1', 'Gene', (99, 109))	('PIK3CA', 'Gene', (123, 129))	('men', 'Species', '9606', (163, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('cat', 'Gene', (149, 152))	('deletion', 'Var', (110, 118))
150898	29057879	To address the role of FOXP1-SHQ1 deletion in oncogenesis and its potential cooperativity with PTEN loss, we conditionally deleted the syntenic Foxp1-Shq1 region in transgenic mice (Supplementary Fig.	('oncogenesis', 'biological_process', 'GO:0007048', ('46', '57'))	('FOXP1-SHQ1', 'Gene', (23, 33))	('deletion', 'Var', (34, 42))	('Foxp1-Shq1', 'Gene', (144, 154))	('transgenic mice', 'Species', '10090', (165, 180))	('men', 'Species', '9606', (188, 191))	('deleted', 'Var', (123, 130))
150901	29057879	Cre introduction results in conditional deletion of Foxp1 and Shq1 individually through recombination at their respective loxP pairs or deletion of the larger region from Shq1 (exon 2) to Foxp1 (exon 12) through the outer loxP sites (Supplementary Fig.	('Foxp1', 'Gene', (188, 193))	('men', 'Species', '9606', (240, 243))	('deletion', 'Var', (40, 48))	('Foxp1', 'Gene', (52, 57))	('deletion', 'Var', (136, 144))	('Shq1', 'Gene', (171, 175))	('Shq1', 'Gene', (62, 66))
150903	29057879	Foxp1-Shq1 f/f mice show heterogeneous deletion of the full Foxp1-Shq1 locus as well as of the individual Foxp1 and Shq1 genes (Supplementary Fig.	('deletion', 'Var', (39, 47))	('men', 'Species', '9606', (134, 137))	('Foxp1-Shq1', 'Gene', (60, 70))	('Shq1', 'Gene', (116, 120))	('mice', 'Species', '10090', (15, 19))	('Foxp1-Shq1', 'Gene', (0, 10))	('Foxp1', 'Gene', (106, 111))
150904	29057879	To test whether Foxp1-Shq1 deletion cooperates functionally with Pten loss, we compared prostate phenotypes in mice with both Foxp1-Shq1 and Pten deletion (Foxp1-Shq1 f/f ;Pten f/f) to those with only Pten deletion (Pten f/f) or Foxp1-Shq1 deletion (Foxp1-Shq1 f/f).	('Pten', 'Gene', (141, 145))	('deletion', 'Var', (146, 154))	('mice', 'Species', '10090', (111, 115))	(';Pten', 'Gene', '19211', (171, 176))	('Foxp1-Shq1', 'Var', (126, 136))	(';Pten', 'Gene', (171, 176))
150907	29057879	In the setting of Pten loss, eight of nine Foxp1-Shq1 f/f ;Pten f/f tumors tested by genomic PCR showed recombination of the full Foxp1-Shq1 locus, with one showing exclusive Foxp1-Shq1 locus deletion and seven showing a mix of full Foxp1-Shq1 locus deletion and individual Foxp1 and Shq1 deletion (Supplementary Fig.	('tumors', 'Disease', (68, 74))	('recombination', 'Var', (104, 117))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('Foxp1-Shq1', 'Gene', (43, 53))	('men', 'Species', '9606', (305, 308))	('deletion', 'Var', (289, 297))	('Shq1', 'Gene', (284, 288))	('Foxp1-Shq1', 'Gene', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Foxp1', 'Gene', (274, 279))	(';Pten', 'Gene', '19211', (58, 63))	(';Pten', 'Gene', (58, 63))
150910	29057879	2d), similar to human prostate cancers with the deletion.	('human prostate cancers', 'Disease', 'MESH:D011471', (16, 38))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('prostate cancer', 'Phenotype', 'HP:0012125', (22, 37))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('human prostate cancers', 'Disease', (16, 38))	('deletion', 'Var', (48, 56))	('prostate cancers', 'Phenotype', 'HP:0012125', (22, 38))
150911	29057879	2c), possibly because Prok2 exhibits positive feedback activation of its own transcription and heterogeneous deletion of this secreted cytokine may result in greater reduction in its levels in adjacent cells with incomplete locus deletion.	('in a', 'Gene', (190, 194))	('transcription', 'MPA', (77, 90))	('reduction', 'NegReg', (166, 175))	('deletion', 'Var', (109, 117))	('levels', 'MPA', (183, 189))	('in a', 'Gene', '226180', (190, 194))	('transcription', 'biological_process', 'GO:0006351', ('77', '90'))	('activation', 'PosReg', (55, 65))
150912	29057879	Since the human 3p13-14 locus more commonly exhibits mono-allelic loss than bi-allelic deletion in prostate cancer and its component genes show an average 1.5-fold reduction in RNA expression upon mono-allelic loss, the Foxp1-Shq1 f/f ;Pten f/f mouse model exhibits similar level of 3p13-14 gene expression change to that of human disease.	('RNA', 'cellular_component', 'GO:0005562', ('177', '180'))	('loss', 'NegReg', (66, 70))	('human', 'Species', '9606', (10, 15))	('RNA expression', 'MPA', (177, 191))	('gene expression', 'biological_process', 'GO:0010467', ('291', '306'))	(';Pten', 'Gene', '19211', (235, 240))	('prostate cancer', 'Disease', (99, 114))	(';Pten', 'Gene', (235, 240))	('mouse', 'Species', '10090', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mono-allelic', 'Var', (197, 209))	('reduction', 'NegReg', (164, 173))	('prostate cancer', 'Disease', 'MESH:D011471', (99, 114))	('prostate cancer', 'Phenotype', 'HP:0012125', (99, 114))	('human', 'Species', '9606', (325, 330))
150913	29057879	In sum, both DNA and RNA analysis of prostate tissue confirmed deletion of the entire Foxp1-Shq1 locus similar to that seen in human prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (133, 148))	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('RNA', 'cellular_component', 'GO:0005562', ('21', '24'))	('Foxp1-Shq1', 'Gene', (86, 96))	('human', 'Species', '9606', (127, 132))	('prostate cancer', 'Disease', (133, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('deletion', 'Var', (63, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (133, 148))
150917	29057879	Notably, Foxp1-Shq1 deletion did not cooperate with Tmprss2-Erg fusion in transgenic Foxp1-Shq1 f/f ;R26 ERG mice (n = 9 per time point at 6, 9, 12, and 18 months), which we created to test the functional cooperativity between statistically co-enriched FOXP1-SHQ1 deletion and TMPRSS2-ERG fusion.	('transgenic', 'Species', '10090', (74, 84))	('FOXP1-SHQ1', 'Gene', (253, 263))	('mice', 'Species', '10090', (109, 113))	('deletion', 'Var', (264, 272))
150919	29057879	This indicates that SHQ1 loss alone in this system is insufficient to cause the observed cooperative oncogenesis, despite reports that orthotopic SHQ1 shRNA-based knockdown is sufficient to increase metastasis in a Trp53 +/loxP ;PtenloxP/loxP background.	('SHQ1', 'Gene', (146, 150))	('oncogenesis', 'biological_process', 'GO:0007048', ('101', '112'))	('insufficient', 'Disease', (54, 66))	('in a', 'Gene', '226180', (210, 214))	('cat', 'Gene', (9, 12))	('knockdown', 'Var', (163, 172))	('p53', 'Gene', (217, 220))	('increase', 'PosReg', (190, 198))	('cat', 'Gene', '12359', (9, 12))	(';Pten', 'Gene', '19211', (228, 233))	('in a', 'Gene', (210, 214))	(';Pten', 'Gene', (228, 233))	('p53', 'Gene', '22060', (217, 220))	('metastasis', 'CPA', (199, 209))	('insufficient', 'Disease', 'MESH:D000309', (54, 66))
150924	29057879	In Foxp1-Shq1 f/f ;Pten f/f murine tumors, cellular proliferation assayed by Ki67 IHC was significantly increased compared to Pten f/f tumors, which is itself higher than the low proliferation rates seen in Foxp1-Shq1 f/f and wild-type prostates (Supplementary Fig.	(';Pten', 'Gene', '19211', (18, 23))	(';Pten', 'Gene', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('f/f', 'Var', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('increased', 'PosReg', (104, 113))	('cellular proliferation', 'CPA', (43, 65))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('murine', 'Species', '10090', (28, 34))	('men', 'Species', '9606', (253, 256))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('higher', 'PosReg', (159, 165))
150926	29057879	Expression signatures of differentiation were repressed (FDR < 0.01, gene set enrichment analysis (GSEA)) in Foxp1-Shq1 f/f ;Pten f/f prostate tumors, which exhibit distinct gene expression patterns from Pten f/f tumors by unsupervised RNA-seq clustering as well as repression of Foxp factor-derived expression signatures when compared to Pten f/f tumors (Supplementary Fig.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('gene expression', 'biological_process', 'GO:0010467', ('174', '189'))	('Foxp1-Shq1', 'Var', (109, 119))	('tumors', 'Phenotype', 'HP:0002664', (348, 354))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('GSEA', 'Chemical', '-', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', (213, 219))	(';Pten', 'Gene', '19211', (124, 129))	('prostate tumors', 'Disease', (134, 149))	(';Pten', 'Gene', (124, 129))	('tumors', 'Disease', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('prostate tumors', 'Disease', 'MESH:D011471', (134, 149))	('tumors', 'Disease', (348, 354))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('prostate tumor', 'Phenotype', 'HP:0100787', (134, 148))	('RNA', 'cellular_component', 'GO:0005562', ('236', '239'))	('tumors', 'Disease', 'MESH:D009369', (348, 354))	('men', 'Species', '9606', (362, 365))	('men', 'Species', '9606', (84, 87))
150927	29057879	These results indicate that Foxp1-Shq1 deletion cooperates with Pten loss in murine models to promote prostate cancer.	('cat', 'Gene', '12359', (18, 21))	('loss', 'NegReg', (69, 73))	('murine', 'Species', '10090', (77, 83))	('deletion', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('prostate cancer', 'Disease', (102, 117))	('promote', 'PosReg', (94, 101))	('prostate cancer', 'Disease', 'MESH:D011471', (102, 117))	('cat', 'Gene', (18, 21))	('Foxp1-Shq1', 'Gene', (28, 38))	('prostate cancer', 'Phenotype', 'HP:0012125', (102, 117))
150928	29057879	Foxp1-Shq1 f/f ;Pten f/f murine tumors show elevated S6 phosphorylation by IHC compared to Pten f/f tumors by 12 months but reduced Akt phosphorylation, suggesting a high level of mTORC1 activation with feedback inhibition of PI3K (Fig.	('elevated', 'PosReg', (44, 52))	('PI3K', 'molecular_function', 'GO:0016303', ('226', '230'))	('Akt', 'Pathway', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('S6 phosphorylation', 'MPA', (53, 71))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('tumors', 'Disease', (100, 106))	('mTORC1', 'Gene', (180, 186))	('reduced', 'NegReg', (124, 131))	('mTORC1', 'cellular_component', 'GO:0031931', ('180', '186'))	(';Pten', 'Gene', '19211', (15, 20))	('mTORC1', 'Gene', '382056', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	(';Pten', 'Gene', (15, 20))	('phosphorylation', 'biological_process', 'GO:0016310', ('136', '151'))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('murine', 'Species', '10090', (25, 31))	('Foxp1-Shq1', 'Var', (0, 10))
150929	29057879	In support of this conclusion, expression signatures from Foxp1-Shq1 f/f ;Pten f/f tumors were inversely associated with signatures of TORC1 inhibition, compared to Pten f/f tumors (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('inhibition', 'NegReg', (141, 151))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('inversely', 'NegReg', (95, 104))	(';Pten', 'Gene', '19211', (73, 78))	('tumors', 'Disease', (83, 89))	(';Pten', 'Gene', (73, 78))	('TORC1', 'Gene', (135, 140))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('expression', 'MPA', (31, 41))	('TORC1', 'Gene', '382056', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('TORC1', 'cellular_component', 'GO:0031931', ('135', '140'))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('men', 'Species', '9606', (188, 191))	('Foxp1-Shq1', 'Var', (58, 68))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
150931	29057879	Consistent with MEK involvement, genes repressed by MEK activation are under-represented in prostate tumors from Foxp1-Shq1 f/f ;Pten f/f mice relative to Pten f/f mice at 12 months, as assessed by GSEA of RNA-seq expression data (P = 0.004, FDR = 0.05, GSEA, Supplementary Fig.	('prostate tumor', 'Phenotype', 'HP:0100787', (92, 106))	('prostate tumors', 'Disease', (92, 107))	('mice', 'Species', '10090', (164, 168))	(';Pten', 'Gene', '19211', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mice', 'Species', '10090', (138, 142))	('GSEA', 'Chemical', '-', (198, 202))	('MEK', 'Gene', (52, 55))	('under-represented', 'NegReg', (71, 88))	(';Pten', 'Gene', (128, 133))	('men', 'Species', '9606', (266, 269))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('men', 'Species', '9606', (27, 30))	('RNA', 'cellular_component', 'GO:0005562', ('206', '209'))	('prostate tumors', 'Disease', 'MESH:D011471', (92, 107))	('activation', 'PosReg', (56, 66))	('f/f', 'Var', (134, 137))	('GSEA', 'Chemical', '-', (254, 258))
150942	29057879	FOXP1-SHQ1 deletion may therefore be selected in PTEN-null prostate cancers as a mechanism to modulate the inhibitory effects of PI3K pathway activation on androgen signaling.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('prostate cancers', 'Disease', 'MESH:D011471', (59, 75))	('androgen signaling', 'MPA', (156, 174))	('modulate', 'Reg', (94, 102))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('PI3K', 'molecular_function', 'GO:0016303', ('129', '133'))	('PI3K pathway', 'Pathway', (129, 141))	('FOXP1-SHQ1', 'Gene', (0, 10))	('prostate cancers', 'Phenotype', 'HP:0012125', (59, 75))	('signaling', 'biological_process', 'GO:0023052', ('165', '174'))	('prostate cancers', 'Disease', (59, 75))	('deletion', 'Var', (11, 19))
150943	29057879	Since Foxp1-Shq1 deletion and Pten loss cooperate together to promote murine prostate oncogenesis, we next asked whether combined loss of PTEN and FOXP1-SHQ1 locus genes were associated with worse outcome in human cancer.	('associated', 'Reg', (175, 185))	('PTEN', 'Gene', (138, 142))	('cancer', 'Disease', (214, 220))	('loss', 'NegReg', (35, 39))	('Pten', 'Gene', (30, 34))	('FOXP1-SHQ1', 'Gene', (147, 157))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('deletion', 'Var', (17, 25))	('promote', 'PosReg', (62, 69))	('prostate oncogenesis', 'Disease', (77, 97))	('loss', 'NegReg', (130, 134))	('oncogenesis', 'biological_process', 'GO:0007048', ('86', '97'))	('human', 'Species', '9606', (208, 213))	('murine', 'Species', '10090', (70, 76))	('Foxp1-Shq1', 'Gene', (6, 16))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
150956	29057879	In addition to accelerating cancer progression, deletion of the Foxp1-Shq1 locus with Pten loss results in changes in signaling, such as mTORC1 activation and restored nuclear hormone receptor activity, that are mirrored in human prostate cancers with comparable genotypes.	('Pten', 'Gene', (86, 90))	('human prostate cancers', 'Disease', (224, 246))	('restored', 'PosReg', (159, 167))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('deletion', 'Var', (48, 56))	('receptor activity', 'molecular_function', 'GO:0038024', ('184', '201'))	('signaling', 'biological_process', 'GO:0023052', ('118', '127'))	('nuclear hormone receptor activity', 'MPA', (168, 201))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('nuclear hormone receptor', 'molecular_function', 'GO:0004879', ('168', '192'))	('mTORC1', 'cellular_component', 'GO:0031931', ('137', '143'))	('activation', 'PosReg', (144, 154))	('cancer', 'Disease', (239, 245))	('mTORC1', 'Gene', (137, 143))	('loss', 'NegReg', (91, 95))	('human prostate cancers', 'Disease', 'MESH:D011471', (224, 246))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('mTORC1', 'Gene', '382056', (137, 143))	('prostate cancer', 'Phenotype', 'HP:0012125', (230, 245))	('receptor activity', 'molecular_function', 'GO:0038023', ('184', '201'))	('prostate cancers', 'Phenotype', 'HP:0012125', (230, 246))	('signaling', 'MPA', (118, 127))	('cancer', 'Disease', (28, 34))	('accelerating', 'PosReg', (15, 27))	('changes', 'Reg', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('Foxp1-Shq1', 'Gene', (64, 74))
150962	29057879	It is interesting to speculate that functional interactions between FOXP1 and the nuclear hormone receptors AR and ER may play a role in the 3p13-14 deletion's prognostic significance in prostate and breast cancers and potentially others.	('deletion', 'Var', (149, 157))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('3p13-14', 'Gene', (141, 148))	('interactions', 'Interaction', (47, 59))	('breast cancers', 'Phenotype', 'HP:0003002', (200, 214))	('role', 'Reg', (129, 133))	('FOXP1', 'Gene', (68, 73))	('play', 'Reg', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('breast cancers', 'Disease', 'MESH:D001943', (200, 214))	('breast cancers', 'Disease', (200, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('prostate', 'Disease', (187, 195))
150963	29057879	Since we observe co-enrichment of FOXP1-SHQ1 and PTEN deletion in a variety of cancer types, the potential cooperativity of several genes in the FOXP1-SHQ1 locus with PTEN loss could provide multiple mechanisms depending on the cancer type.	('loss', 'NegReg', (172, 176))	('cancer', 'Disease', (228, 234))	('FOXP1-SHQ1', 'Gene', (34, 44))	('in a', 'Gene', '226180', (63, 67))	('deletion', 'Var', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('men', 'Species', '9606', (26, 29))	('in a', 'Gene', (63, 67))	('FOXP1-SHQ1', 'Gene', (145, 155))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('PTEN', 'Gene', (49, 53))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
150964	29057879	Beyond nuclear hormone receptor-based synergy, the PI3K pathway has been shown to positively regulate FOXP1 expression and its downstream transcriptional effects; FOXP1 deletion in the context of PTEN loss therefore allows tumors to circumvent the induction of tumor suppressive FOXP1-mediated transcriptional activity, which would otherwise result from PTEN loss-mediated PI3K activation.	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('PI3K', 'molecular_function', 'GO:0016303', ('373', '377'))	('loss', 'NegReg', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('tumors', 'Disease', (223, 229))	('deletion', 'Var', (169, 177))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('PTEN', 'Gene', (196, 200))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('nuclear hormone receptor', 'molecular_function', 'GO:0004879', ('7', '31'))	('FOXP1', 'Gene', (163, 168))
150965	29057879	Moreover, the other genes in the deletion, EIF4E3, RYBP, PROK2, and GPR27 all mediate activities that intersect with the PI3K pathway in a potentially tumor suppressive manner.	('in a', 'Gene', '226180', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('PI3K pathway', 'Pathway', (121, 133))	('activities', 'MPA', (86, 96))	('EIF4E3', 'Gene', (43, 49))	('mediate', 'Reg', (78, 85))	('EIF4', 'cellular_component', 'GO:0008304', ('43', '47'))	('deletion', 'Var', (33, 41))	('GPR27', 'Gene', (68, 73))	('tumor', 'Disease', (151, 156))	('in a', 'Gene', (134, 138))	('PROK2', 'Gene', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('PI3K', 'molecular_function', 'GO:0016303', ('121', '125'))	('RYBP', 'Gene', (51, 55))
150967	29057879	EIF4E3 is known to antagonize EIF4E1, and its loss has the potential to remove the brakes on TOR pathway-induced growth through S6K-phosporylated 4E-BP1.	('TOR', 'Chemical', 'MESH:D017312', (93, 96))	('loss', 'NegReg', (46, 50))	('EIF4E3', 'Var', (0, 6))	('brakes', 'MPA', (83, 89))	('EIF4', 'cellular_component', 'GO:0008304', ('30', '34'))	('remove', 'NegReg', (72, 78))	('EIF4', 'cellular_component', 'GO:0008304', ('0', '4'))	('TOR pathway-induced', 'Pathway', (93, 112))
150968	29057879	Last, we observed both ERK activation and hyperactivation of S6 beyond that caused by PTEN deletion alone in the tumors with both FOXP1-SHQ1 deletion and PTEN loss.	('FOXP1-SHQ1', 'Gene', (130, 140))	('deletion', 'Var', (141, 149))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('loss', 'NegReg', (159, 163))	('ERK', 'molecular_function', 'GO:0004707', ('23', '26'))	('activation', 'PosReg', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('hyperactivation', 'PosReg', (42, 57))	('PTEN', 'Gene', (154, 158))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
150970	29057879	PROK2 deletion may therefore mediate some level of negative feedback of the ERK activation observed in our transgenic mice and thereby modulate oncogenic stress in tumors with combined PTEN and FOXP1-SHQ1 deletion.	('negative feedback', 'MPA', (51, 68))	('deletion', 'Var', (205, 213))	('modulate', 'Reg', (135, 143))	('ERK', 'molecular_function', 'GO:0004707', ('76', '79'))	('transgenic mice', 'Species', '10090', (107, 122))	('ERK', 'Gene', (76, 79))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('PROK2', 'Gene', (0, 5))	('deletion', 'Var', (6, 14))	('FOXP1-SHQ1', 'Gene', (194, 204))	('oncogenic stress', 'MPA', (144, 160))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('PTEN', 'Gene', (185, 189))	('activation', 'PosReg', (80, 90))
150971	29057879	Interestingly, GPR27, an orphan G-protein-coupled receptor, has also been shown to mediate phosphoinositol-mediated phosphorylation of ERK and Akt; GPR27 deletion may therefore have similar effects to PROK2 loss on ERK signaling.	('Akt', 'Pathway', (143, 146))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('loss', 'NegReg', (207, 211))	('phosphorylation', 'biological_process', 'GO:0016310', ('116', '131'))	('ERK', 'molecular_function', 'GO:0004707', ('215', '218'))	('phosphoinositol', 'Chemical', '-', (91, 106))	('ERK', 'molecular_function', 'GO:0004707', ('135', '138'))	('deletion', 'Var', (154, 162))	('phosphoinositol-mediated phosphorylation', 'MPA', (91, 131))	('GPR27', 'Gene', (148, 153))	('ERK signaling', 'MPA', (215, 228))	('signaling', 'biological_process', 'GO:0023052', ('219', '228'))
150972	29057879	Future work may explore the contributions of these genes and their interplay in PI3K-driven cancer progression and its molecular underpinnings.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('PI3K-driven', 'Var', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('PI3K', 'molecular_function', 'GO:0016303', ('80', '84'))
150973	29057879	First, the loxP sites in Foxp1-Shq1 locus in our model were engineered in a manner that allows conditional deletion of FoxP1 and Shq1 individually or deletion of the entire locus.	('FoxP1', 'Gene', '108655', (119, 124))	('in a', 'Gene', (71, 75))	('Shq1', 'Gene', (129, 133))	('deletion', 'Var', (150, 158))	('in a', 'Gene', '226180', (71, 75))	('FoxP1', 'Gene', (119, 124))
150974	29057879	The fact that all the prostate tumors are enriched for deletion of the entire locus or for deletion of both FoxP1 and Shq1, rather than selective deletion of FoxP1 and/or Shq1 individually, suggests that at least two genes in the interval play a role in restraining tumor progression in this model.	('deletion', 'Var', (91, 99))	('FoxP1', 'Gene', '108655', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', (31, 36))	('FoxP1', 'Gene', (108, 113))	('Shq1', 'Gene', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('prostate tumor', 'Phenotype', 'HP:0100787', (22, 36))	('FoxP1', 'Gene', '108655', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('prostate tumors', 'Disease', 'MESH:D011471', (22, 37))	('deletion', 'Var', (55, 63))	('tumor', 'Disease', (266, 271))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('FoxP1', 'Gene', (158, 163))	('prostate tumors', 'Disease', (22, 37))
150975	29057879	Second, the negative prognostic impact of FOXP1-SHQ1 deletion attributable largely to FOXP1 loss suggests FOXP1 may have tumor suppressor activity, consistent with the known suppressive effects of FOXP1 on hormone receptor signaling.	('signaling', 'biological_process', 'GO:0023052', ('223', '232'))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('121', '137'))	('deletion', 'Var', (53, 61))	('tumor', 'Disease', (121, 126))	('FOXP1-SHQ1', 'Gene', (42, 52))	('FOXP1', 'Gene', (106, 111))	('tumor suppressor', 'biological_process', 'GO:0051726', ('121', '137'))	('loss', 'NegReg', (92, 96))	('FOXP1', 'Gene', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
150978	29057879	The work presented here suggests that multigenic and multi-driver alterations, such as 3p13-14, may functionally cooperate with other major alterations such as PTEN loss to promote cancer.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('3p13-14', 'Var', (87, 94))	('promote', 'PosReg', (173, 180))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))
150984	29057879	Fisher's exact test was similarly used to identify significant co-enrichment of copy number loss between PTEN CN and FOXP1-SHQ1 CN loss in the 12 published TCGA cancer cohorts that had PTEN and FOXP1-SHQ1 loss in >2% of cases (listed above).	('PTEN CN', 'Gene', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('men', 'Species', '9606', (72, 75))	('loss', 'NegReg', (131, 135))	('FOXP1-SHQ1 loss', 'Disease', (194, 209))	('FOXP1-SHQ1 loss', 'Disease', 'MESH:D015431', (194, 209))	('FOXP1-SHQ1', 'Gene', (117, 127))	('loss', 'NegReg', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('copy number', 'Var', (80, 91))	('cancer', 'Disease', (161, 167))	('PTEN', 'Gene', (185, 189))
150985	29057879	For survival analyses, Cox regression was used to test the association between cancer recurrence and the following loss groups: FOXP1-SHQ1 loss alone, PTEN loss alone, combined FOXP1-SHQ1 and PTEN loss, and neither lost.	(', Cox', 'Gene', '12857', (21, 26))	('FOXP1-SHQ1 loss', 'Disease', (128, 143))	('FOXP1-SHQ1', 'Var', (177, 187))	('FOXP1-SHQ1 loss', 'Disease', 'MESH:D015431', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('loss', 'NegReg', (156, 160))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('loss', 'NegReg', (197, 201))	('cancer', 'Disease', (79, 85))	('PTEN', 'Gene', (151, 155))
150992	29057879	Foxp1-Shq1 flox conditional knockout transgenic mice (M. musculus) were generated by targeting the SHQ1 conditional frameshift construct HTGRS0100_A_A12 (EUCOMM, KO first allele reporter-tagged insertion with conditional potential) into Foxp1 f/f ES cells generated from the Foxp1 f/f conditional knockout mice in Feng et al., which were then injected into C57BL/6 blastocysts.	('Foxp1', 'Gene', (275, 280))	('mice', 'Species', '10090', (48, 52))	('M. musculus', 'Species', '10090', (54, 65))	('transgenic mice', 'Species', '10090', (37, 52))	('HTGRS0100_A_A12', 'Var', (137, 152))	('SHQ1', 'Gene', (99, 103))	('mice', 'Species', '10090', (306, 310))
150993	29057879	SHQ1 flox conditional knockout transgenic mice were generated by targeting the same SHQ1 conditional frameshift construct HTGRS0100_A_A12 (EUCOMM) into 129 ES cells and injected into C57BL/6 blastocysts by the Rockefeller University Gene Targeting Facility.	('transgenic mice', 'Species', '10090', (31, 46))	('SHQ1', 'Gene', (84, 88))	('HTGRS0100_A_A12', 'Var', (122, 137))
151031	29057879	Analyses were carried out in R. For GSEA, differentially expressed genes (defined as genes differentially expressed between FOXP1-SHQ1 f/f ;PTEN f/f 12mo murine prostate tumors relative to PTEN f/f 12mo murine prostate tumor with P < 0.05, Wald) were ranked by fold change and analyzed by GSEA (GSEAPreranked, classic scoring scheme, Broad GenePattern, using MSigDB gene sets c2-c7).	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('GSEA', 'Chemical', '-', (289, 293))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('prostate tumors', 'Disease', (161, 176))	('prostate tumor', 'Disease', 'MESH:D011471', (161, 175))	('murine', 'Species', '10090', (154, 160))	('GSEA', 'Chemical', '-', (36, 40))	('prostate tumor', 'Disease', 'MESH:D011471', (210, 224))	('murine', 'Species', '10090', (203, 209))	('GSEA', 'Chemical', '-', (295, 299))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('prostate tumor', 'Disease', (210, 224))	('prostate tumor', 'Phenotype', 'HP:0100787', (161, 175))	('prostate tumor', 'Phenotype', 'HP:0100787', (210, 224))	('FOXP1-SHQ1', 'Var', (124, 134))	('prostate tumors', 'Disease', 'MESH:D011471', (161, 176))
151033	29057879	The significance of the differences in these signatures in the RNA-seq data from Foxp1-Shq1 flox/flox ;Pten flox/flox and Pten flox/flox mouse prostate at 12 months was tested by t-test.	('mouse', 'Species', '10090', (137, 142))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('Foxp1-Shq1', 'Gene', (81, 91))	(';Pten', 'Gene', '19211', (102, 107))	(';Pten', 'Gene', (102, 107))	('flox/flox', 'Var', (108, 117))
151058	23449892	We were concerned that resection would cause significant bleeding and the use of monopolar energy with the Bugbee electrode would cause urethral stricture.	('cause', 'Reg', (39, 44))	('urethral stricture', 'Disease', (136, 154))	('cause', 'Reg', (130, 135))	('use', 'Var', (74, 77))	('bleeding', 'Disease', 'MESH:D006470', (57, 65))	('bleeding', 'Disease', (57, 65))	('urethral stricture', 'Phenotype', 'HP:0012227', (136, 154))	('monopolar energy', 'Var', (81, 97))
151114	28848663	Overall, given the level 1 evidence available for UCB, we advocate that physicians actively enrol patients into existing trials (NCT01993979, NCT01261728, NCT02412670, NCT02876861).	('UCB', 'Phenotype', 'HP:0006740', (50, 53))	('patients', 'Species', '9606', (98, 106))	('NCT02876861', 'Var', (168, 179))	('NCT01993979', 'Var', (129, 140))	('NCT02412670', 'Var', (155, 166))	('NCT01261728', 'Var', (142, 153))	('UCB', 'Chemical', '-', (50, 53))
151120	28848663	In terms of what specific cisplatin-based regimen is recommended, a recent multi-institutional study from Japan found that those who received adjuvant methotrexate, vinblastine, doxorubicin, cisplatin had favourable recurrence-free survival rates compared with those who received gemcitabine and cisplatin (71.4% vs 48.2%, p=0.022).	('cisplatin', 'Chemical', 'MESH:D002945', (296, 305))	('methotrexate', 'Chemical', 'MESH:D008727', (151, 163))	('cisplatin', 'Var', (191, 200))	('recurrence-free survival', 'CPA', (216, 240))	('doxorubicin', 'Chemical', 'MESH:D004317', (178, 189))	('cisplatin', 'Chemical', 'MESH:D002945', (191, 200))	('cisplatin', 'Chemical', 'MESH:D002945', (26, 35))	('vinblastine', 'Chemical', 'MESH:D014747', (165, 176))	('gemcitabine', 'Chemical', 'MESH:C056507', (280, 291))	('doxorubicin', 'Var', (178, 189))	('methotrexate', 'Var', (151, 163))	('vinblastine', 'Var', (165, 176))
151131	28333147	Kaplan-Meier survival curves showed that high SLC12A5 expression was associated with poor survival in patients with BUC.	('expression', 'MPA', (54, 64))	('SLC12A5', 'Gene', (46, 53))	('patients', 'Species', '9606', (102, 110))	('high', 'Var', (41, 45))	('poor', 'NegReg', (85, 89))
151133	28333147	Moreover, we identified that SLC12A5 promoted the migration and invasion of BUC by enhancing MMP-7 expression via NF-kappaB-dependent transcription.	('expression', 'MPA', (99, 109))	('NF-kappaB', 'Gene', (114, 123))	('promoted', 'PosReg', (37, 45))	('SLC12A5', 'Var', (29, 36))	('enhancing', 'PosReg', (83, 92))	('migration', 'CPA', (50, 59))	('MMP-7', 'molecular_function', 'GO:0004235', ('93', '98'))	('MMP-7', 'Gene', (93, 98))	('transcription', 'biological_process', 'GO:0006351', ('134', '147'))	('NF-kappaB', 'Gene', '4790', (114, 123))	('invasion of BUC', 'CPA', (64, 79))	('MMP-7', 'Gene', '4316', (93, 98))
151144	28333147	Recently, two studies showed that mutated SLC12A5 is highly expressed in colorectal cancer at the single-cell level, but exhibited low prevalence at the population level; they then identified that mutant SLC12A5 has a potential oncogenic effect in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('oncogenic effect', 'CPA', (228, 244))	('colorectal cancer', 'Phenotype', 'HP:0003003', (248, 265))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('colorectal cancer', 'Disease', (248, 265))	('colorectal cancer', 'Disease', (73, 90))	('mutant', 'Var', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('SLC12A5', 'Gene', (42, 49))	('colorectal cancer', 'Disease', 'MESH:D015179', (248, 265))	('mutated', 'Var', (34, 41))	('SLC12A5', 'Gene', (204, 211))
151160	28333147	Knocking down SLC12A5 did not alter the cellular growth rate in vitro (Figure 3b) and in vivo (Supplementary Figures 1A and B), suggesting that SLC12A5 does not have a role in controlling cellular growth.	('men', 'Species', '9606', (101, 104))	('cellular growth', 'biological_process', 'GO:0016049', ('40', '55'))	('SLC12A5', 'Gene', (14, 21))	('cellular growth', 'biological_process', 'GO:0016049', ('188', '203'))	('Knocking', 'Var', (0, 8))
151162	28333147	To investigate the in vivo effect of SLC12A5 knockdown on metastasis, we used an experimental metastasis assay in which we injected T24 and BIU87 cells producing the control shRNA and SLC12A5 shRNA into the lateral tail vein of severe combined immunodeficiency (SCID) mice.	('SCID', 'Phenotype', 'HP:0004430', (262, 266))	('immunodeficiency', 'Phenotype', 'HP:0002721', (244, 260))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (235, 260))	('immunodeficiency', 'Disease', (244, 260))	('immunodeficiency', 'Disease', 'MESH:D007153', (244, 260))	('men', 'Species', '9606', (87, 90))	('mice', 'Species', '10090', (268, 272))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (228, 260))	('lateral tail', 'Phenotype', 'HP:0002825', (207, 219))	('SCID', 'Disease', 'MESH:D053632', (262, 266))	('SCID', 'Disease', (262, 266))	('SLC12A5', 'Var', (184, 191))
151163	28333147	In accordance with previous results, the mice injected with T24 and BIU87 cells expressing the SLC12A5 shRNA formed fewer nodes per lung compared with the mice injected with control shRNA-producing cells (3.8+-4.0 versus 16.0+-5.5, P=0.004; 3.8+-3.1 versus 15.3+-6.7, P=0.009 for T24 and BIU87 cells, respectively).	('mice', 'Species', '10090', (41, 45))	('mice', 'Species', '10090', (155, 159))	('SLC12A5', 'Var', (95, 102))	('fewer', 'NegReg', (116, 121))
151166	28333147	The results identified six upregulated and five downregulated genes (by >1.5-fold) in T24-SLC12A54-ShRNA cells compared with those in T24-Control-ShRNA cells (Supplementary Table 3).	('men', 'Species', '9606', (165, 168))	('T24-SLC12A54-ShRNA', 'Var', (86, 104))	('upregulated', 'PosReg', (27, 38))	('downregulated', 'NegReg', (48, 61))
151167	28333147	Subsequently, MMP-7, PTEN, BRMS1, KISS1, CXCR2, FGFR4, FLT4, MMP-3 and MAGT5, which exhibited >2-fold mRNA differences before and after SLC12A5 knockdown (Figure 4a), were selected and analyzed further by western blot.	('BRMS1', 'Gene', (27, 32))	('FLT4', 'Gene', (55, 59))	('FLT4', 'Gene', '2324', (55, 59))	('PTEN', 'Gene', '5728', (21, 25))	('FGFR4', 'Gene', '2264', (48, 53))	('KISS1', 'Gene', '3814', (34, 39))	('MMP-3', 'Gene', (61, 66))	('KISS1', 'Gene', (34, 39))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('MMP-7', 'molecular_function', 'GO:0004235', ('14', '19'))	('FGFR4', 'Gene', (48, 53))	('BRMS1', 'Gene', '25855', (27, 32))	('MMP-3', 'Gene', '4314', (61, 66))	('MMP-7', 'Gene', (14, 19))	('knockdown', 'Var', (144, 153))	('CXCR2', 'Gene', (41, 46))	('CXCR2', 'Gene', '3579', (41, 46))	('MMP-3', 'molecular_function', 'GO:0004248', ('61', '66'))	('MMP-7', 'Gene', '4316', (14, 19))	('PTEN', 'Gene', (21, 25))
151168	28333147	Consistent with that of mRNA expression in real-time PCR array, decreased protein expression of MMP-7 were demonstrated by western blot in T24 cells after SLC12A5 knockdown (Figure 4b).	('knockdown', 'Var', (163, 172))	('MMP-7', 'molecular_function', 'GO:0004235', ('96', '101'))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('MMP-7', 'Gene', (96, 101))	('SLC12A5', 'Gene', (155, 162))	('protein expression', 'MPA', (74, 92))	('MMP-7', 'Gene', '4316', (96, 101))	('decreased', 'NegReg', (64, 73))
151170	28333147	In addition, a significant correlation between the levels of SLC12A5 and MMP-7 were evaluated in our BUC cohort, in which the frequency of cases with low SLC12A5 levels was significantly higher in negative MMP-7 expression cases (42/56 cases, 75.0%) compared with that in positive MMP-7 expression ones (27/92 cases, 29.3% P<0.001, Supplementary Table 4).	('SLC12A5 levels', 'MPA', (154, 168))	('MMP-7', 'Gene', (281, 286))	('MMP-7', 'Gene', '4316', (73, 78))	('MMP-7', 'molecular_function', 'GO:0004235', ('206', '211'))	('MMP-7', 'molecular_function', 'GO:0004235', ('281', '286'))	('men', 'Species', '9606', (338, 341))	('MMP-7', 'molecular_function', 'GO:0004235', ('73', '78'))	('MMP-7', 'Gene', '4316', (281, 286))	('negative', 'Var', (197, 205))	('higher', 'PosReg', (187, 193))	('MMP-7', 'Gene', (206, 211))	('MMP-7', 'Gene', '4316', (206, 211))	('MMP-7', 'Gene', (73, 78))
151174	28333147	Unfortunately, data showed that TIMP-1 expression was unchanged when MMP-7 expression was downregulated in SLC12A5-knockdown T24 and BIU87 cells (Figure 5a).	('SLC12A5-knockdown', 'Gene', (107, 124))	('SLC12A5-knockdown', 'Var', (107, 124))	('MMP-7', 'molecular_function', 'GO:0004235', ('69', '74'))	('TIMP-1', 'Gene', '7076', (32, 38))	('TIMP-1', 'Gene', (32, 38))	('downregulated', 'NegReg', (90, 103))	('MMP-7', 'Gene', (69, 74))	('MMP-7', 'Gene', '4316', (69, 74))	('expression', 'MPA', (75, 85))
151176	28333147	The western blot results showed that the level of MMP-7 protein decreased in BUC cells after SLC12A5 knockdown (Figure 5b).	('MMP-7', 'Gene', (50, 55))	('decreased', 'NegReg', (64, 73))	('MMP-7', 'Gene', '4316', (50, 55))	('level', 'MPA', (41, 46))	('MMP-7', 'molecular_function', 'GO:0004235', ('50', '55'))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('SLC12A5', 'Gene', (93, 100))	('knockdown', 'Var', (101, 110))
151186	28333147	The western blot results showed that the level of p65 protein decreased in BUC cells after SLC12A5 knockdown (Figure 6a).	('p65', 'Gene', (50, 53))	('SLC12A5', 'Gene', (91, 98))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('decreased', 'NegReg', (62, 71))	('p65', 'Gene', '5970', (50, 53))	('level', 'MPA', (41, 46))	('knockdown', 'Var', (99, 108))
151190	28333147	Migration and invasion abilities were decreased in T24-SLC12A5-ShRNA cells and BIU87-SLC12A5-ShRNA cells; however, these effects were rescued by overexpression of NF-kappaB-p65 (Figures 6b and c).	('decreased', 'NegReg', (38, 47))	('invasion abilities', 'CPA', (14, 32))	('T24-SLC12A5-ShRNA', 'Var', (51, 68))	('Migration', 'CPA', (0, 9))	('NF-kappaB-p65', 'Gene', '5970', (163, 176))	('BIU87-SLC12A5-ShRNA', 'Var', (79, 98))	('NF-kappaB-p65', 'Gene', (163, 176))
151200	28333147	In addition, in an experimental in vivo metastasis model using SCID mice, we further showed that the tail vein injection of SLC12A5-ShRNA T24 and BIU87 cells led to a significant decrease in the number of metastatic lesions in the lungs of mice, as compared with those in the lungs of mice injected with control T24 and BIU87 cells.	('mice', 'Species', '10090', (68, 72))	('BIU87 cells', 'Var', (146, 157))	('mice', 'Species', '10090', (240, 244))	('mice', 'Species', '10090', (285, 289))	('decrease', 'NegReg', (179, 187))	('SLC12A5-ShRNA T24', 'Var', (124, 141))	('metastatic lesions', 'CPA', (205, 223))	('SCID', 'Disease', 'MESH:D053632', (63, 67))	('SCID', 'Disease', (63, 67))	('SCID', 'Phenotype', 'HP:0004430', (63, 67))	('men', 'Species', '9606', (25, 28))
151201	28333147	We revealed that the enhanced cell invasion and migration by SLC12A5 were mediated via downregulation of key anti-metastasis genes, including BRMS1, KISS1 and PTEN, and upregulation of important pro-metastasis genes MMP-7, CXCR2, FGFR4, FLT4, MMP-3 and MAGT5 (Supplementary Table 3).	('migration', 'CPA', (48, 57))	('cell invasion', 'CPA', (30, 43))	('KISS1', 'Gene', (149, 154))	('upregulation', 'PosReg', (169, 181))	('PTEN', 'Gene', '5728', (159, 163))	('MMP-7', 'Gene', (216, 221))	('FGFR', 'molecular_function', 'GO:0005007', ('230', '234'))	('FGFR4', 'Gene', '2264', (230, 235))	('MMP-7', 'molecular_function', 'GO:0004235', ('216', '221'))	('BRMS1', 'Gene', (142, 147))	('MMP-7', 'Gene', '4316', (216, 221))	('FLT4', 'Gene', (237, 241))	('FLT4', 'Gene', '2324', (237, 241))	('FGFR4', 'Gene', (230, 235))	('MMP-3', 'molecular_function', 'GO:0004248', ('243', '248'))	('enhanced', 'PosReg', (21, 29))	('SLC12A5', 'Var', (61, 68))	('CXCR2', 'Gene', (223, 228))	('MMP-3', 'Gene', (243, 248))	('CXCR2', 'Gene', '3579', (223, 228))	('PTEN', 'Gene', (159, 163))	('BRMS1', 'Gene', '25855', (142, 147))	('KISS1', 'Gene', '3814', (149, 154))	('downregulation', 'NegReg', (87, 101))	('men', 'Species', '9606', (266, 269))	('MMP-3', 'Gene', '4314', (243, 248))
151202	28333147	Consistent with the mRNA expression in the qRT-PCR array, upregulated PTEN and downregulated MMP-7 in protein levels were observed after SLC12A5 knockdown in T24 cells.	('knockdown', 'Var', (145, 154))	('PTEN', 'Gene', (70, 74))	('PTEN', 'Gene', '5728', (70, 74))	('SLC12A5', 'Gene', (137, 144))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('upregulated', 'PosReg', (58, 69))	('downregulated', 'NegReg', (79, 92))	('MMP-7', 'molecular_function', 'GO:0004235', ('93', '98'))	('MMP-7', 'Gene', (93, 98))	('MMP-7', 'Gene', '4316', (93, 98))
151211	28333147	In BUC, high MMP-7 gene expression proved to be an independent prognostic indicators of metastasis and lymph node metastasis.	('lymph node metastasis', 'CPA', (103, 124))	('high', 'Var', (8, 12))	('MMP-7', 'molecular_function', 'GO:0004235', ('13', '18'))	('metastasis', 'CPA', (88, 98))	('MMP-7', 'Gene', (13, 18))	('MMP-7', 'Gene', '4316', (13, 18))	('gene expression', 'biological_process', 'GO:0010467', ('19', '34'))
151220	28333147	NF-kappaB is present constitutively in cells as a heterodimer, consisting of a p50 DNA-binding subunit and a p65 transactivating subunit.	('NF-kappaB', 'Gene', '4790', (0, 9))	('p65', 'Gene', (109, 112))	('NF-kappaB', 'Gene', (0, 9))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('p65', 'Gene', '5970', (109, 112))	('DNA-binding', 'molecular_function', 'GO:0003677', ('83', '94'))	('p50', 'Var', (79, 82))
151224	28333147	The decreased migration and invasion by SLC12A5 knockdown in BUC cells was also rescued by overexpression of NF-kappaB-p65.	('migration', 'CPA', (14, 23))	('decreased', 'NegReg', (4, 13))	('SLC12A5', 'Gene', (40, 47))	('NF-kappaB-p65', 'Gene', '5970', (109, 122))	('NF-kappaB-p65', 'Gene', (109, 122))	('invasion', 'CPA', (28, 36))	('knockdown', 'Var', (48, 57))
151225	28333147	In conclusion, our study showed that elevated expression of SLC12A5 increased the metastatic potential of BUC cells and that SLC12A5 promoted the migration and invasion of BUC cells through a process involving NF-kappaB-dependent regulation of MMP-7 expression.	('invasion of BUC cells', 'CPA', (160, 181))	('migration', 'CPA', (146, 155))	('SLC12A5', 'Gene', (60, 67))	('NF-kappaB', 'Gene', (210, 219))	('elevated', 'PosReg', (37, 45))	('promoted', 'PosReg', (133, 141))	('regulation', 'biological_process', 'GO:0065007', ('230', '240'))	('MMP-7', 'Gene', (244, 249))	('NF-kappaB', 'Gene', '4790', (210, 219))	('MMP-7', 'molecular_function', 'GO:0004235', ('244', '249'))	('MMP-7', 'Gene', '4316', (244, 249))	('expression', 'MPA', (46, 56))	('metastatic potential of BUC cells', 'CPA', (82, 115))	('increased', 'PosReg', (68, 77))	('SLC12A5', 'Var', (125, 132))
151260	28333147	To produce experimental subcutaneous tumor growth, the BALB/c nude mice were randomly divided into four groups (T24-shSLC12A5 and T24-shCtrl; BIU87-shSLC12A5 and BIU87-shCtrl) consisting of four mice each.	('mice', 'Species', '10090', (195, 199))	('BIU87-shSLC12A5', 'Var', (142, 157))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('BIU87-shCtrl', 'Var', (162, 174))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (24, 42))	('mice', 'Species', '10090', (67, 71))	('nude mice', 'Species', '10090', (62, 71))	('men', 'Species', '9606', (17, 20))
151263	28333147	To produce experimental metastasis, the BALB/c nude mice were randomly divided into four groups (T24-shSLC12A5 and T24-shCtrl; BIU87-shSLC12A5 and BIU87-shCtrl) consisting of six mice each.	('mice', 'Species', '10090', (179, 183))	('mice', 'Species', '10090', (52, 56))	('nude mice', 'Species', '10090', (47, 56))	('BIU87-shCtrl', 'Var', (147, 159))	('BIU87-shSLC12A5', 'Var', (127, 142))	('men', 'Species', '9606', (17, 20))
151318	27099604	reported a correlation between high ADC values and good histopathological features of bladder tumors which is the case for urothelial carcinoma.	('bladder tumors', 'Phenotype', 'HP:0009725', (86, 100))	('bladder tumor', 'Phenotype', 'HP:0009725', (86, 99))	('bladder tumors', 'Disease', (86, 100))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('urothelial carcinoma', 'Disease', (123, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('high', 'Var', (31, 35))	('bladder tumors', 'Disease', 'MESH:D001749', (86, 100))	('ADC values', 'MPA', (36, 46))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (123, 143))
151352	25429526	Patients were also required to have adequate bone marrow, renal, and hepatic function, which was indicated by neutrophils >3000 ul-1, platelets >=100 000 ul-1, and hemoglobin >9 g dl-1, serum creatinine <1.5 mg dl-1 (if values were borderline, the creatinine clearance had to be >=60 ml min-1 by Cockcroft and Gault formula), total bilirubin <=1.5 times the normal limit, and alanine aminotransferase and aspartate aminotransferase <=3 times the upper limit of normal.	('alanine aminotransferase', 'Gene', '2875', (376, 400))	('<=3', 'NegReg', (432, 435))	('min-1', 'Gene', '966', (287, 292))	('>=100 000', 'Var', (144, 153))	('>3000', 'Var', (122, 127))	('total bilirubin', 'MPA', (326, 341))	('Patients', 'Species', '9606', (0, 8))	('aspartate aminotransferase', 'MPA', (405, 431))	('alanine aminotransferase', 'Gene', (376, 400))	('hepatic', 'Disease', (69, 76))	('min-1', 'Gene', (287, 292))
151550	33061595	On MRI, lesions usually show hypointense on T1W images, predominantly hypointense on T2W (8/15, 53.3%) followed by iso/hypointense (5/15, 33.3%) and hyperintense (2/15, 13.3%).	('age', 'Gene', '5973', (50, 53))	('age', 'Gene', (50, 53))	('hypointense', 'Var', (29, 40))	('hypointense', 'Var', (70, 81))
151577	33061595	In addition, our log-rank analysis showed that grade 3 was associated with a lower OS than grade 2 for UC spinal metastasis (p=0.012), which is consistent with the aggressive behavior of WHO classification.	('lower', 'NegReg', (77, 82))	('grade 3', 'Var', (47, 54))	('aggressive behavior', 'Phenotype', 'HP:0000718', (164, 183))	('UC spinal metastasis', 'Disease', 'MESH:D009362', (103, 123))	('aggressive behavior', 'biological_process', 'GO:0002118', ('164', '183'))	('UC spinal metastasis', 'Disease', (103, 123))
151588	33061595	Eleven patients who received cisplatin-based adjuvant chemotherapy in our series achieved significantly longer OS than those who did not (p=0.037), which is consistent with the previous report that chemotherapy is a favorable factor for UC bone metastasis.	('cisplatin-based', 'Var', (29, 44))	('UC bone metastasis', 'Disease', (237, 255))	('UC bone metastasis', 'Disease', 'MESH:D009362', (237, 255))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('longer', 'PosReg', (104, 110))	('patients', 'Species', '9606', (7, 15))
151620	32315283	In bladder cancer, HMGN5 silencing could block the PI3K/Akt signaling pathway, therefore improving the chemical sensitivity of human bladder cancer cells to cisplatin, whereby the viability and invasion of these cells could be inhibited in vitro and in vivo.	('silencing', 'Var', (25, 34))	('Akt signaling', 'biological_process', 'GO:0043491', ('56', '69'))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('Akt', 'Gene', (56, 59))	('inhibited', 'NegReg', (227, 236))	('Akt', 'Gene', '207', (56, 59))	('invasion', 'CPA', (194, 202))	('chemical sensitivity', 'MPA', (103, 123))	('viability', 'CPA', (180, 189))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))	('human', 'Species', '9606', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('improving', 'PosReg', (89, 98))	('bladder cancer', 'Disease', 'MESH:D001749', (133, 147))	('bladder cancer', 'Disease', (133, 147))	('HMGN5', 'Gene', (19, 24))	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('block', 'NegReg', (41, 46))	('signaling pathway', 'biological_process', 'GO:0007165', ('60', '77'))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))
151629	32315283	In prostate cancer, silencing Hsp27 can decrease IL-6-dependent STAT3 phosphorylation, nuclear translocation, and STAT3 targeting of the Twist promoter, indicating that Hsp27 is required for IL-6-mediated EMT via regulation of STAT3/Twist signaling.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('Twist', 'Gene', '7291', (137, 142))	('STAT3', 'Gene', '6774', (114, 119))	('prostate cancer', 'Disease', (3, 18))	('STAT3', 'Gene', (64, 69))	('decrease IL-6', 'Phenotype', 'HP:0030783', (40, 53))	('EMT', 'biological_process', 'GO:0001837', ('205', '208'))	('Twist', 'Gene', (233, 238))	('STAT3', 'Gene', '6774', (64, 69))	('phosphorylation', 'biological_process', 'GO:0016310', ('70', '85'))	('IL-6', 'molecular_function', 'GO:0005138', ('49', '53'))	('silencing', 'Var', (20, 29))	('IL-6', 'Gene', '3569', (49, 53))	('STAT3', 'Gene', (227, 232))	('IL-6', 'Gene', '3569', (191, 195))	('Twist', 'Gene', (137, 142))	('signaling', 'biological_process', 'GO:0023052', ('239', '248'))	('IL-6', 'Gene', (49, 53))	('STAT3', 'Gene', '6774', (227, 232))	('decrease', 'NegReg', (40, 48))	('IL-6', 'Gene', (191, 195))	('Twist', 'Gene', '7291', (233, 238))	('nuclear translocation', 'MPA', (87, 108))	('regulation', 'biological_process', 'GO:0065007', ('213', '223'))	('STAT3', 'Gene', (114, 119))	('Hsp27', 'Protein', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('IL-6', 'molecular_function', 'GO:0005138', ('191', '195'))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
151654	32315283	In contrast to HMGN5 or Hsp27 overexpression, HMGN5 or Hsp27 silencing significantly inhibited bladder cancer cell invasion (Figure 4A) and increased the E-cadherin expression and decreased Vimentin expression (Figure 4B, 4C).	('Vimentin', 'cellular_component', 'GO:0045099', ('190', '198'))	('cadherin', 'molecular_function', 'GO:0008014', ('156', '164'))	('Vimentin', 'Gene', '7431', (190, 198))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('inhibited', 'NegReg', (85, 94))	('expression', 'MPA', (165, 175))	('Vimentin', 'Gene', (190, 198))	('decreased', 'NegReg', (180, 189))	('E-cadherin', 'Gene', (154, 164))	('bladder cancer', 'Disease', (95, 109))	('silencing', 'Var', (61, 70))	('E-cadherin', 'Gene', '999', (154, 164))	('increased', 'PosReg', (140, 149))	('bladder cancer', 'Disease', 'MESH:D001749', (95, 109))	('Vimentin', 'cellular_component', 'GO:0045098', ('190', '198'))	('HMGN5', 'Gene', (46, 51))	('Hsp27', 'Protein', (55, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))
151664	32315283	HMGN5 silencing significantly decreased the phosphorylation of Hsp27 and STAT3 induced by IL-6 stimulation in J82 and T24 cells (Figure 6A).	('IL-6', 'Gene', (90, 94))	('phosphorylation', 'MPA', (44, 59))	('phosphorylation', 'biological_process', 'GO:0016310', ('44', '59'))	('IL-6', 'molecular_function', 'GO:0005138', ('90', '94'))	('IL-6', 'Gene', '3569', (90, 94))	('HMGN5', 'Gene', (0, 5))	('STAT3', 'Gene', (73, 78))	('J82', 'CellLine', 'CVCL:0359', (110, 113))	('Hsp27', 'Protein', (63, 68))	('silencing', 'Var', (6, 15))	('decreased', 'NegReg', (30, 39))	('STAT3', 'Gene', '6774', (73, 78))
151666	32315283	The inducing effects of IL-6 on STAT3 targeting of Twist promoter DNA could be significantly attenuated by HMGN5 silencing but partially rescued by Hsp27 overexpression (Figure 6B).	('STAT3', 'Gene', '6774', (32, 37))	('Twist', 'Gene', '7291', (51, 56))	('HMGN5', 'Protein', (107, 112))	('attenuated', 'NegReg', (93, 103))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('STAT3', 'Gene', (32, 37))	('IL-6', 'Gene', (24, 28))	('silencing', 'Var', (113, 122))	('Twist', 'Gene', (51, 56))	('IL-6', 'molecular_function', 'GO:0005138', ('24', '28'))	('IL-6', 'Gene', '3569', (24, 28))	('Hsp27', 'Protein', (148, 153))
151674	32315283	In contrast, knockdown of Hsp27 or HMGN5 alone clearly decreased restrained the tumor volume and tumor weight, and the inhibitory effect on tumor volume and tumor weight was amplified in the group with combined HMGN5 and Hsp27 silencing (Figure 7D-7F).	('tumor', 'Disease', (157, 162))	('silencing', 'NegReg', (227, 236))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('Hsp27', 'Protein', (26, 31))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (97, 102))	('decreased', 'NegReg', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('knockdown', 'Var', (13, 22))	('Hsp27', 'Protein', (221, 226))
151697	32315283	HMGN5 silencing attenuated IL-6-induced bladder cancer EMT and bladder cancer cell invasion.	('bladder cancer', 'Disease', 'MESH:D001749', (63, 77))	('bladder cancer', 'Disease', (63, 77))	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('HMGN5', 'Gene', (0, 5))	('IL-6', 'molecular_function', 'GO:0005138', ('27', '31'))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('bladder cancer', 'Phenotype', 'HP:0009725', (63, 77))	('IL-6', 'Gene', '3569', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('attenuated', 'NegReg', (16, 26))	('IL-6', 'Gene', (27, 31))	('silencing', 'Var', (6, 15))	('EMT', 'biological_process', 'GO:0001837', ('55', '58'))
151699	32315283	Moreover, IL-6-induced STAT3 targeting of the Twist promoter could also be suppressed by HMGN5 silencing.	('HMGN5', 'Protein', (89, 94))	('suppressed', 'NegReg', (75, 85))	('STAT3', 'Gene', '6774', (23, 28))	('IL-6', 'molecular_function', 'GO:0005138', ('10', '14'))	('STAT3', 'Gene', (23, 28))	('Twist', 'Gene', '7291', (46, 51))	('silencing', 'Var', (95, 104))	('IL-6', 'Gene', (10, 14))	('Twist', 'Gene', (46, 51))	('IL-6', 'Gene', '3569', (10, 14))
151719	32315283	An SDS-PAGE minigel was used for protein separation and the proteins were then transferred onto a PVDF membrane, which was then probed with the following antibodies (dilution 1:1000) : anti-Hsp27 (ab2790, Abcam), anti-p-Hsp27 (ab5594, Abcam), anti-HMGN5 (ab56031, Abcam), anti-E-cadherin (ab1416, Abcam), anti-Vimentin (ab8978, Abcam), anti-STAT3 (ab68153, Abcam), anti-p-STAT3 (ab76315, Tyr705, Abcam), and anti-GAPDH (ab8245, Abcam) at 4 C overnight followed by the incubation with the HRP-conjugated secondary antibody (dilution 1:5000).	('Vimentin', 'cellular_component', 'GO:0045098', ('310', '318'))	('STAT3', 'Gene', (372, 377))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('STAT3', 'Gene', (341, 346))	('SDS', 'Chemical', 'MESH:D012967', (3, 6))	('Vimentin', 'Gene', '7431', (310, 318))	('STAT3', 'Gene', '6774', (372, 377))	('membrane', 'cellular_component', 'GO:0016020', ('103', '111'))	('STAT3', 'Gene', '6774', (341, 346))	('antibody', 'cellular_component', 'GO:0019815', ('513', '521'))	('Vimentin', 'Gene', (310, 318))	('GAPDH', 'Gene', '2597', (413, 418))	('antibody', 'cellular_component', 'GO:0019814', ('513', '521'))	('Vimentin', 'cellular_component', 'GO:0045099', ('310', '318'))	('ab76315', 'Var', (379, 386))	('GAPDH', 'Gene', (413, 418))	('E-cadherin', 'Gene', (277, 287))	('E-cadherin', 'Gene', '999', (277, 287))	('antibody', 'molecular_function', 'GO:0003823', ('513', '521'))	('antibody', 'cellular_component', 'GO:0042571', ('513', '521'))	('cadherin', 'molecular_function', 'GO:0008014', ('279', '287'))
151734	30816443	A recent study demonstrated that ZNF692 is overexpressed in lung adenocarcinoma (LUAD) tissues and that ZNF692 knockdown inhibited LUAD cell proliferation, migration, and invasion both in vitro and in vivo.	('LUAD', 'Phenotype', 'HP:0030078', (81, 85))	('knockdown', 'Var', (111, 120))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (60, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('ZNF692', 'Gene', (33, 39))	('invasion', 'CPA', (171, 179))	('migration', 'CPA', (156, 165))	('LUAD', 'Phenotype', 'HP:0030078', (131, 135))	('lung adenocarcinoma', 'Disease', (60, 79))	('ZNF692', 'Gene', '55657', (104, 110))	('cell proliferation', 'biological_process', 'GO:0008283', ('136', '154'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (60, 79))	('inhibited', 'NegReg', (121, 130))	('LUAD cell proliferation', 'CPA', (131, 154))	('ZNF692', 'Gene', (104, 110))	('ZNF692', 'Gene', '55657', (33, 39))
151736	30816443	The present study revealed that ZNF692 was upregulated in COAD tissues and cells and that high ZNF692 expression was significantly correlated with lymph node metastasis, distant metastasis and tumor stage in COAD patients.	('distant metastasis', 'CPA', (170, 188))	('ZNF692', 'Gene', '55657', (32, 38))	('ZNF692', 'Gene', (32, 38))	('upregulated', 'PosReg', (43, 54))	('correlated', 'Reg', (131, 141))	('ZNF692', 'Gene', '55657', (95, 101))	('ZNF692', 'Gene', (95, 101))	('expression', 'MPA', (102, 112))	('lymph node metastasis', 'CPA', (147, 168))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('COAD', 'Disease', 'MESH:D029424', (208, 212))	('high', 'Var', (90, 94))	('COAD', 'Disease', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('COAD', 'Disease', 'MESH:D029424', (58, 62))	('patients', 'Species', '9606', (213, 221))	('tumor', 'Disease', (193, 198))	('COAD', 'Disease', (208, 212))
151755	30816443	High ZNF692 expression was correlated with lymph node metastasis, distant metastasis and tumor stage in patients with COAD.	('ZNF692', 'Gene', '55657', (5, 11))	('ZNF692', 'Gene', (5, 11))	('High', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('COAD', 'Disease', 'MESH:D029424', (118, 122))	('expression', 'MPA', (12, 22))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('lymph node metastasis', 'CPA', (43, 64))	('distant metastasis', 'CPA', (66, 84))	('COAD', 'Disease', (118, 122))	('correlated', 'Reg', (27, 37))	('patients', 'Species', '9606', (104, 112))	('tumor', 'Disease', (89, 94))
151756	30816443	In addition, ZNF692 knockdown attenuated cell proliferation, migration and invasion in vitro and in vivo; conversely, ZNF692 upregulation produced the opposite effects.	('cell proliferation', 'biological_process', 'GO:0008283', ('41', '59'))	('upregulation', 'PosReg', (125, 137))	('invasion', 'CPA', (75, 83))	('ZNF692', 'Gene', '55657', (13, 19))	('cell proliferation', 'CPA', (41, 59))	('migration', 'CPA', (61, 70))	('ZNF692', 'Gene', (13, 19))	('knockdown', 'Var', (20, 29))	('ZNF692', 'Gene', '55657', (118, 124))	('attenuated', 'NegReg', (30, 40))	('ZNF692', 'Gene', (118, 124))
151757	30816443	Flow cytometric analysis revealed that ZNF692 knockdown induced G1-phase cell cycle arrest in COAD cells, whereas ZNF692 overexpression promoted G1/S phase transition.	('ZNF692', 'Gene', (114, 120))	('G1-phase cell cycle arrest', 'CPA', (64, 90))	('ZNF692', 'Gene', (39, 45))	('knockdown', 'Var', (46, 55))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('73', '90'))	('promoted', 'PosReg', (136, 144))	('G1/S phase transition', 'CPA', (145, 166))	('S phase', 'biological_process', 'GO:0051320', ('148', '155'))	('COAD', 'Disease', (94, 98))	('ZNF692', 'Gene', '55657', (114, 120))	('G1-phase', 'biological_process', 'GO:0051318', ('64', '72'))	('COAD', 'Disease', 'MESH:D029424', (94, 98))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (73, 90))	('ZNF692', 'Gene', '55657', (39, 45))
151759	30816443	The PI3K/AKT inhibitor LY294002 markedly reversed ZNF692-induced cyclin D1 and MMP-9 expression.	('cyclin D1', 'Gene', (65, 74))	('expression', 'MPA', (85, 95))	('MMP-9', 'Gene', (79, 84))	('MMP-9', 'Gene', '4318', (79, 84))	('AKT', 'Gene', '207', (9, 12))	('cyclin', 'molecular_function', 'GO:0016538', ('65', '71'))	('ZNF692', 'Gene', (50, 56))	('MMP-9', 'molecular_function', 'GO:0004229', ('79', '84'))	('LY294002', 'Chemical', 'MESH:C085911', (23, 31))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('LY294002', 'Var', (23, 31))	('AKT', 'Gene', (9, 12))	('cyclin D1', 'Gene', '595', (65, 74))	('ZNF692', 'Gene', '55657', (50, 56))
151846	30816443	The results of these assays demonstrated that ZNF692 knockdown cells displayed reduced viability and colony formation efficiency (P<0.01; Fig.	('ZNF692', 'Gene', '55657', (46, 52))	('ZNF692', 'Gene', (46, 52))	('reduced', 'NegReg', (79, 86))	('knockdown', 'Var', (53, 62))	('viability', 'CPA', (87, 96))	('formation', 'biological_process', 'GO:0009058', ('108', '117'))	('colony formation efficiency', 'CPA', (101, 128))
151848	30816443	2G, ZNF692 silencing resulted in G1 arrest in COAD cells (P<0.05).	('silencing', 'Var', (11, 20))	('COAD', 'Disease', 'MESH:D029424', (46, 50))	('COAD', 'Disease', (46, 50))	('ZNF692', 'Gene', '55657', (4, 10))	('ZNF692', 'Gene', (4, 10))	('G1 arrest', 'CPA', (33, 42))
151850	30816443	The results demonstrated that ZNF692 knockdown decreased the migration of DLD-1 (P<0.05) and LoVo cells (P<0.01) compared with the control group (Fig.	('ZNF692', 'Gene', '55657', (30, 36))	('LoVo', 'CellLine', 'CVCL:0399', (93, 97))	('knockdown', 'Var', (37, 46))	('ZNF692', 'Gene', (30, 36))	('migration', 'CPA', (61, 70))	('decreased', 'NegReg', (47, 56))
151852	30816443	Having confirmed the inhibitory effects of ZNF692 knockdown in COAD cells, HCT116 cells, which exhibit low levels of ZNF692 (Fig.	('ZNF692', 'Gene', '55657', (43, 49))	('HCT116', 'CellLine', 'CVCL:0291', (75, 81))	('ZNF692', 'Gene', (43, 49))	('COAD', 'Disease', (63, 67))	('knockdown', 'Var', (50, 59))	('ZNF692', 'Gene', '55657', (117, 123))	('ZNF692', 'Gene', (117, 123))	('COAD', 'Disease', 'MESH:D029424', (63, 67))
151861	30816443	Quantification of the tumor weights and volumes also demonstrated that the Lv-NC group tumors were significantly larger compared with the sh-ZNF692 #1 group (P<0.01; Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('Lv-NC', 'Var', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('larger', 'PosReg', (113, 119))	('tumor', 'Disease', (22, 27))	('tumors', 'Disease', (87, 93))	('ZNF692', 'Gene', (141, 147))	('ZNF692', 'Gene', '55657', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
151864	30816443	According to IHC analysis, ZNF692 knockdown significantly decreased the expression of the cell proliferation marker Ki-67 (Fig.	('ZNF692', 'Gene', (27, 33))	('decreased', 'NegReg', (58, 67))	('cell proliferation', 'CPA', (90, 108))	('expression', 'MPA', (72, 82))	('ZNF692', 'Gene', '55657', (27, 33))	('knockdown', 'Var', (34, 43))	('Ki-67', 'Protein', (116, 121))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))
151866	30816443	6A-D, ZNF692 knockdown decreased AKT phosphorylation in DLD-1 (P<0.05) and LoVo (P<0.01) cells, but the opposite results were obtained when ZNF692 was upregulated in HCT116 cells (P<0.01).	('ZNF692', 'Gene', '55657', (140, 146))	('HCT116', 'CellLine', 'CVCL:0291', (166, 172))	('AKT', 'Gene', '207', (33, 36))	('ZNF692', 'Gene', (140, 146))	('ZNF692', 'Gene', '55657', (6, 12))	('knockdown', 'Var', (13, 22))	('ZNF692', 'Gene', (6, 12))	('LoVo', 'CellLine', 'CVCL:0399', (75, 79))	('phosphorylation', 'biological_process', 'GO:0016310', ('37', '52'))	('AKT', 'Gene', (33, 36))	('decreased', 'NegReg', (23, 32))
151872	30816443	6E, cyclin D1 and MMP-9 expression induced by ectopic ZNF692 expression was significantly reversed following treatment of HCT116 cells with LY294002 (20 microM).	('HCT116', 'CellLine', 'CVCL:0291', (122, 128))	('MMP-9', 'Gene', '4318', (18, 23))	('ectopic', 'Var', (46, 53))	('ZNF692', 'Gene', '55657', (54, 60))	('MMP-9', 'Gene', (18, 23))	('ZNF692', 'Gene', (54, 60))	('expression', 'Var', (61, 71))	('cyclin', 'molecular_function', 'GO:0016538', ('4', '10'))	('LY294002', 'Chemical', 'MESH:C085911', (140, 148))	('MMP-9', 'molecular_function', 'GO:0004229', ('18', '23'))	('cyclin D1', 'Gene', '595', (4, 13))	('cyclin D1', 'Gene', (4, 13))
151894	30816443	The current western blot results indicated that ZNF692 silencing significantly increased the expression of p27Kip1.	('increased', 'PosReg', (79, 88))	('silencing', 'Var', (55, 64))	('ZNF692', 'Gene', '55657', (48, 54))	('p27Kip1', 'Gene', '1027', (107, 114))	('expression', 'MPA', (93, 103))	('ZNF692', 'Gene', (48, 54))	('p27Kip1', 'Gene', (107, 114))
151898	30816443	PI3K transduces various signals, such as growth factors and cytokines, from the extracellular matrix (ECM) into the intracellular environment, which in turn results in the phosphorylation of AKT.	('extracellular matrix', 'cellular_component', 'GO:0031012', ('80', '100'))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PI3K', 'Var', (0, 4))	('AKT', 'Gene', '207', (191, 194))	('intracellular', 'cellular_component', 'GO:0005622', ('116', '129'))	('phosphorylation', 'MPA', (172, 187))	('phosphorylation', 'biological_process', 'GO:0016310', ('172', '187'))	('AKT', 'Gene', (191, 194))	('results in', 'Reg', (157, 167))
151904	30816443	This hypothesis was also supported by the addition of LY294002, which dramatically reversed the ZNF692-induced cyclin D1 expression.	('cyclin D1', 'Gene', (111, 120))	('LY294002', 'Chemical', 'MESH:C085911', (54, 62))	('expression', 'MPA', (121, 131))	('ZNF692', 'Gene', '55657', (96, 102))	('LY294002', 'Var', (54, 62))	('ZNF692', 'Gene', (96, 102))	('cyclin', 'molecular_function', 'GO:0016538', ('111', '117'))	('cyclin D1', 'Gene', '595', (111, 120))
151913	30816443	To decipher the molecular mechanism through which ZNF692 contributes to cell migration and invasion, the MMP-9 protein expression levels were analyzed by western blotting, in the presence or absence of LY294002.	('LY294002', 'Var', (202, 210))	('contributes', 'Reg', (57, 68))	('ZNF692', 'Gene', (50, 56))	('invasion', 'CPA', (91, 99))	('cell migration', 'CPA', (72, 86))	('cell migration', 'biological_process', 'GO:0016477', ('72', '86'))	('LY294002', 'Chemical', 'MESH:C085911', (202, 210))	('MMP-9', 'molecular_function', 'GO:0004229', ('105', '110'))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('MMP-9', 'Gene', '4318', (105, 110))	('MMP-9', 'Gene', (105, 110))	('ZNF692', 'Gene', '55657', (50, 56))
151917	30816443	In summary, the present findings revealed that ZNF692 expression is significantly upregulated in COAD tissues and cell lines and that high ZNF692 expression is significantly associated with lymph node metastasis, distant metastasis and tumor stage.	('expression', 'MPA', (54, 64))	('ZNF692', 'Gene', (139, 145))	('COAD', 'Disease', 'MESH:D029424', (97, 101))	('associated with', 'Reg', (174, 189))	('ZNF692', 'Gene', '55657', (47, 53))	('ZNF692', 'Gene', (47, 53))	('lymph node metastasis', 'CPA', (190, 211))	('high', 'Var', (134, 138))	('upregulated', 'PosReg', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('COAD', 'Disease', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('distant metastasis', 'CPA', (213, 231))	('ZNF692', 'Gene', '55657', (139, 145))	('expression', 'MPA', (146, 156))	('tumor', 'Disease', (236, 241))
151924	28802887	We retrospectively identified 30 patients with nested variant who, between 1997 and 2012, underwent transurethral resection with T1 tumor stage, followed by restaging transurethral resection within 3 months confirming non-muscle invasive disease.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('patients', 'Species', '9606', (33, 41))	('non-muscle invasive disease', 'Disease', (218, 245))	('variant', 'Var', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('transurethral', 'Disease', (100, 113))
151926	28802887	Nested variant patients had no statistically significant difference in metastasis-free survival (p=0.2) and cancer-specific survival (p=0.2) compared with patients to patients with pure urothelial carcinoma.	('patients', 'Species', '9606', (15, 23))	('urothelial carcinoma', 'Disease', (186, 206))	('pure', 'molecular_function', 'GO:0034023', ('181', '185'))	('patients', 'Species', '9606', (167, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('variant', 'Var', (7, 14))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (186, 206))	('patients', 'Species', '9606', (155, 163))	('metastasis-free survival', 'CPA', (71, 95))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
152029	28218662	It is reported that up to 25% of patients with high-grade Ta lesions will progress to muscle-invasive disease, and under-staging of T1 lesions is reported to occur in ~20% of patients who undergo TURBT restaging.	('patients', 'Species', '9606', (33, 41))	('progress', 'Reg', (74, 82))	('high-grade', 'Var', (47, 57))	('patients', 'Species', '9606', (175, 183))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (86, 109))	('muscle-invasive disease', 'Disease', (86, 109))
152046	28218662	Total RNA from patients was pooled into two groups: (1) TaG3 or T1G3 without clinical progression and (2) TaG3 or T1G3 with progression to >=T2 disease.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('patients', 'Species', '9606', (15, 23))	('T1G3', 'Var', (64, 68))	('TaG3', 'Var', (106, 110))	('T1G3', 'Var', (114, 118))
152062	28218662	The differences observed were statistically significant for five out of the nineteen miRNAs where miR-145-5p was the only significantly up-regulated miRNA while miR-141-3p, -200a-3p, -203a-3p, and miR-205-5p were significantly down-regulated in the progressor group.	('miR-205', 'Gene', (197, 204))	('miR-145-5p', 'Var', (98, 108))	('miR-205', 'Gene', '406988', (197, 204))	('down-regulated', 'NegReg', (227, 241))	('miR-145-5p', 'Chemical', '-', (98, 108))	('miR-141-3p', 'Var', (161, 171))	('up-regulated', 'PosReg', (136, 148))
152077	28218662	When the logistic regression model fit the data with miRNA expression only, miR-412-3p was significant in predicting overall mortality (p = 0.020), and miR-412-3p and miR-32-5p were significant in predicting cancer specific mortality (p = 0.037 and p = 0.049 respectively).	('miR-412-3p', 'Var', (152, 162))	('cancer', 'Disease', (208, 214))	('miR-32', 'Gene', (167, 173))	('miR-32', 'Gene', '407036', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('predicting', 'Reg', (197, 207))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('predicting', 'Reg', (106, 116))	('miR-412-3p', 'Var', (76, 86))	('miRNA', 'MPA', (53, 58))
152086	28218662	Multivariate Cox regression analysis showed miR-412-3p and -224-5p were significantly associated with time to death from cancer (miR-412-3p: hazard ratio (HR), 1.45; p = 0.046; miR-224-5p: HR, 1.32; p = 0.046).	('miR-224-5p', 'Var', (177, 187))	('Cox', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('miR-412-3p', 'Var', (44, 54))	('associated', 'Reg', (86, 96))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('death', 'Disease', 'MESH:D003643', (110, 115))	('death', 'Disease', (110, 115))	('cancer', 'Disease', (121, 127))	('Cox', 'Gene', '1351', (13, 16))
152087	28218662	For each 2-fold increase in miR-412-3p and -224-5p, the probability of survival decreases and the instantaneous risk of death from cancer increases by 45% and 32%, respectively.	('cancer', 'Disease', (131, 137))	('death', 'Disease', 'MESH:D003643', (120, 125))	('increases', 'PosReg', (138, 147))	('death', 'Disease', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('decreases', 'NegReg', (80, 89))	('increase', 'PosReg', (16, 24))	('miR-412-3p', 'Var', (28, 38))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
152094	28218662	The experimental platform for this analysis emanates from the miRNA expression microarray profiling data and for this reason we selected tumor samples with Ta/G3 or T1/G3 lesions in the absence of additional clinical changes e.g., carcinoma in situ.	('T1/G3', 'Gene', (165, 170))	('carcinoma in situ', 'Disease', 'MESH:D002278', (231, 248))	('tumor', 'Disease', (137, 142))	('T1/G3', 'Gene', '921', (165, 170))	('carcinoma in situ', 'Disease', (231, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (231, 248))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('Ta/G3', 'Var', (156, 161))
152105	28218662	The miRs -17-5p, -20a-5p, -30b-5p and -203a-3p were associated with progression, and miRs -19b-3p, -32-5p, -224-5p, and -412-3p were related to cancer-specific survival.	('miRs -17-5p', 'Var', (4, 15))	('miRs -19b-3p', 'Var', (85, 97))	('progression', 'CPA', (68, 79))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('associated', 'Reg', (52, 62))	('related', 'Reg', (133, 140))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
152111	28218662	Of particular note, recently Inamoto et al administered miR-145-5p in an intravesical orthotopic mouse model, and observed a 76% decrease in tumor growth along with increased survival.	('miR-145-5p', 'Chemical', '-', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('decrease', 'NegReg', (129, 137))	('tumor', 'Disease', (141, 146))	('mouse', 'Species', '10090', (97, 102))	('miR-145-5p', 'Var', (56, 66))	('increased', 'PosReg', (165, 174))
152115	28218662	Two miRNAs (miR-412-3p and miR-224-5p) were significantly associated with time to death from UCB.	('UCB', 'Disease', (93, 96))	('death', 'Disease', 'MESH:D003643', (82, 87))	('death', 'Disease', (82, 87))	('associated', 'Reg', (58, 68))	('miR-412-3p', 'Var', (12, 22))	('miR-224-5p', 'Var', (27, 37))	('UCB', 'Phenotype', 'HP:0006740', (93, 96))
152118	31383940	Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression Advanced Bladder Cancer (BLCA) remains a clinical challenge that lacks effective therapeutic measures.	('bladder cancer', 'Disease', (90, 104))	('AOX1', 'Gene', '316', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Cancer', 'Disease', (134, 140))	('Epigenetic loss', 'Var', (0, 15))	('promotes', 'PosReg', (81, 89))	('Cancer', 'Disease', 'MESH:D009369', (134, 140))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('AOX1', 'Gene', (19, 23))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (126, 140))	('metabolic deregulations', 'MPA', (53, 76))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('leads to', 'Reg', (44, 52))	('EZH2', 'Gene', (39, 43))	('EZH2', 'Gene', '2146', (39, 43))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))
152122	31383940	Inhibition of NADP synthesis rescues the metabolic effects of AOX1 KD.	('NADP', 'Chemical', 'MESH:D009249', (14, 18))	('AOX1 KD', 'Var', (62, 69))	('NADP synthesis', 'biological_process', 'GO:0006741', ('14', '28'))	('Inhibition', 'Var', (0, 10))	('metabolic effects', 'MPA', (41, 58))	('NADP', 'Protein', (14, 18))	('rescues', 'PosReg', (29, 36))
152123	31383940	Ectopic AOX1 expression decreases NADP production, PPP flux and nucleotide synthesis, while decreasing invasion in cell line models and suppressing growth in tumor xenografts.	('decreases', 'NegReg', (24, 33))	('suppressing', 'NegReg', (136, 147))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('decreasing', 'NegReg', (92, 102))	('NADP production', 'MPA', (34, 49))	('AOX1', 'Gene', (8, 12))	('expression', 'Var', (13, 23))	('Ectopic', 'Var', (0, 7))	('PPP flux', 'MPA', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('64', '84'))	('nucleotide synthesis', 'MPA', (64, 84))	('invasion', 'CPA', (103, 111))	('NADP', 'Chemical', 'MESH:D009249', (34, 38))
152131	31383940	Molecular studies of non-muscle-invasive urothelial carcinoma of the bladder (NMIBC) have clearly shown the effects of genomic instability, chromosomal alterations, and allelic loss on the development and progression of BLCA.	('men', 'Species', '9606', (196, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('genomic instability', 'Var', (119, 138))	('allelic loss', 'Var', (169, 181))	('invasive urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (32, 76))	('chromosomal alterations', 'Var', (140, 163))	('non-muscle-invasive urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (21, 76))
152135	31383940	Promoter hypermethylation is a common mechanism for transcriptional silencing of tumor suppressor genes, such as RB1 and p16INK4A.	('p16INK4A', 'Gene', '1029', (121, 129))	('tumor suppressor', 'biological_process', 'GO:0051726', ('81', '97'))	('transcriptional', 'MPA', (52, 67))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('81', '97'))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('RB1', 'Gene', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('p16INK4A', 'Gene', (121, 129))	('RB1', 'Gene', '5925', (113, 116))	('tumor', 'Disease', (81, 86))	('Promoter hypermethylation', 'Var', (0, 25))
152138	31383940	In this study, we show that AOX1 is epigenetically silenced by EZH2-mediated chromatin alterations in its promoter.	('silenced', 'NegReg', (51, 59))	('AOX1', 'Gene', (28, 32))	('EZH2', 'Gene', '2146', (63, 67))	('chromatin alterations', 'Var', (77, 98))	('chromatin', 'cellular_component', 'GO:0000785', ('77', '86'))	('EZH2', 'Gene', (63, 67))
152139	31383940	In normal bladder epithelial cells, knockdown of AOX1 led to the activation of the tryptophan-kynurenine pathway.	('AOX1', 'Gene', (49, 53))	('tryptophan-kynurenine pathway', 'Pathway', (83, 112))	('tryptophan', 'Chemical', 'MESH:D014364', (83, 93))	('knockdown', 'Var', (36, 45))	('kynurenine', 'Chemical', 'MESH:D007737', (94, 104))	('activation', 'PosReg', (65, 75))
152141	31383940	Ectopic expression of AOX1 in cancer cells resulted in decreased PPP metabolic flux, cell invasion, and nucleotide synthesis.	('cell invasion', 'CPA', (85, 98))	('nucleotide synthesis', 'MPA', (104, 124))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('Ectopic expression', 'Var', (0, 18))	('PPP metabolic flux', 'MPA', (65, 83))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('104', '124'))	('decreased', 'NegReg', (55, 64))	('AOX1', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
152142	31383940	Also, ectopic AOX1 expression reduced tumor xenograft growth in mice, possibly via a reduction in nucleotide synthesis.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('reduction', 'NegReg', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('ectopic', 'Var', (6, 13))	('reduced', 'NegReg', (30, 37))	('nucleotide synthesis', 'MPA', (98, 118))	('AOX1', 'Gene', (14, 18))	('mice', 'Species', '10090', (64, 68))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('98', '118'))
152166	31383940	Moreover, EZH2 knockdown resulted in a significant increase of AOX1 expression in UMUC3 and T24 cells (Fig.	('AOX1', 'Gene', (63, 67))	('increase', 'PosReg', (51, 59))	('knockdown', 'Var', (15, 24))	('expression', 'MPA', (68, 78))	('EZH2', 'Gene', '2146', (10, 14))	('EZH2', 'Gene', (10, 14))
152167	31383940	EZH2 regulates epigenetic silencing by methylation of histone H3 on lysine 27 (H3K27) at the gene promoter locus or controls DNA methylation.	('regulates', 'Reg', (5, 14))	('H3K27', 'Gene', (79, 84))	('EZH2', 'Gene', '2146', (0, 4))	('methylation', 'Var', (39, 50))	('DNA methylation', 'biological_process', 'GO:0006306', ('125', '140'))	('epigenetic silencing', 'MPA', (15, 35))	('EZH2', 'Gene', (0, 4))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('DNA methylation', 'MPA', (125, 140))	('lysine', 'Chemical', 'MESH:D008239', (68, 74))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))
152170	31383940	We performed ChIP assays to assess enrichment of EZH2 and H3K27me3 at the AOX1 promoter in EZH2 knockdown and GSK126-treated BLCA cells.	('knockdown', 'Var', (96, 105))	('EZH2', 'Gene', (91, 95))	('EZH2', 'Gene', '2146', (91, 95))	('EZH2', 'Gene', '2146', (49, 53))	('EZH2', 'Gene', (49, 53))	('H3K27me3', 'Protein', (58, 66))	('GSK126', 'Chemical', 'MESH:C577920', (110, 116))	('GSK', 'molecular_function', 'GO:0050321', ('110', '113'))	('men', 'Species', '9606', (41, 44))
152172	31383940	EZH2 levels were significantly reduced at the AOX1 promoter locus in EZH2 knockdown cells, but remained unchanged in GSK126-treated cells.	('EZH2', 'Gene', '2146', (0, 4))	('reduced', 'NegReg', (31, 38))	('GSK126', 'Chemical', 'MESH:C577920', (117, 123))	('EZH2', 'Gene', '2146', (69, 73))	('EZH2', 'Gene', (0, 4))	('knockdown', 'Var', (74, 83))	('EZH2', 'Gene', (69, 73))	('GSK', 'molecular_function', 'GO:0050321', ('117', '120'))
152175	31383940	We transfected normal immortalized bladder epithelial cells (SV-HUC-1) with adenovirus constructs expressing wild type EZH2 and a mutant version of EZH2 (DeltaSET) that had a truncated C-terminal SET domain and lacked methyltransferase activity.	('SV-HUC-1', 'CellLine', 'CVCL:3798', (61, 69))	('EZH2', 'Gene', (119, 123))	('methyltransferase activity', 'molecular_function', 'GO:0008168', ('218', '244'))	('EZH2', 'Gene', (148, 152))	('EZH2', 'Gene', '2146', (148, 152))	('mutant', 'Var', (130, 136))	('adenovirus', 'Species', '10508', (76, 86))	('EZH2', 'Gene', '2146', (119, 123))
152180	31383940	AOX1 is one of the key enzymes of tryptophan catabolism and loss of AOX1 may lead to the accumulation of kynurenine and NADP (Fig.	('kynurenine', 'MPA', (105, 115))	('kynurenine', 'Chemical', 'MESH:D007737', (105, 115))	('accumulation', 'PosReg', (89, 101))	('NADP', 'MPA', (120, 124))	('AOX1', 'Gene', (68, 72))	('loss', 'Var', (60, 64))	('tryptophan catabolism', 'biological_process', 'GO:0006569', ('34', '55'))	('tryptophan', 'Chemical', 'MESH:D014364', (34, 44))	('NADP', 'Chemical', 'MESH:D009249', (120, 124))
152181	31383940	AOX1 KD cells showed elevated levels of kynurenine, NADP, and a higher NADP/NADPH ratio compared with control cells (Fig.	('kynurenine', 'Chemical', 'MESH:D007737', (40, 50))	('AOX1 KD', 'Var', (0, 7))	('kynurenine', 'MPA', (40, 50))	('NADP', 'Chemical', 'MESH:D009249', (52, 56))	('higher', 'PosReg', (64, 70))	('NADP', 'Chemical', 'MESH:D009249', (76, 80))	('elevated', 'PosReg', (21, 29))	('NADP', 'MPA', (52, 56))	('NADPH', 'Gene', (76, 81))	('levels', 'MPA', (30, 36))	('NADPH', 'Gene', '1666', (76, 81))	('NADP', 'Chemical', 'MESH:D009249', (71, 75))
152184	31383940	Metabolic flux analysis, using (U)13C glucose demonstrated, enrichment of glucose derived carbon in glucose-6-phosphate (M + 6), fructose 1,6-bisphosphate (M + 6), glyceraldehyde-3-phosphate (M + 3), and lactate (M + 3) in AOX1 KD compared with control (Fig.	('glucose', 'Chemical', 'MESH:D005947', (38, 45))	('men', 'Species', '9606', (66, 69))	('glucose', 'Chemical', 'MESH:D005947', (100, 107))	('lactate', 'Chemical', 'MESH:D019344', (204, 211))	('carbon', 'Chemical', 'MESH:D002244', (90, 96))	('AOX1 KD', 'Var', (223, 230))	('lactate', 'MPA', (204, 211))	('fructose 1,6-bisphosphate', 'Chemical', 'MESH:C029063', (129, 154))	('glucose', 'Chemical', 'MESH:D005947', (74, 81))	('13C', 'Chemical', 'MESH:C000615229', (34, 37))	('glyceraldehyde-3-phosphate', 'Chemical', 'MESH:D005986', (164, 190))	('glucose-6-phosphate', 'MPA', (100, 119))
152185	31383940	PPP metabolites such as 6-phosphogluconate (M + 6), ribulose/xylose 5-phosphate (M + 5), and sedoheptulose 7-phosphate (M + 7) were also significantly increased in AOX1 KD compared with control (Fig.	('increased', 'PosReg', (151, 160))	('ribulose', 'Chemical', 'MESH:C100182', (52, 60))	('PPP metabolites', 'MPA', (0, 15))	('sedoheptulose 7-phosphate', 'MPA', (93, 118))	('6-phosphogluconate', 'MPA', (24, 42))	('xylose 5-phosphate', 'Chemical', '-', (61, 79))	('ribulose/xylose 5-phosphate', 'MPA', (52, 79))	('sedoheptulose 7-phosphate', 'Chemical', 'MESH:C020495', (93, 118))	('6-phosphogluconate', 'Chemical', 'MESH:C008884', (24, 42))	('AOX1 KD', 'Var', (164, 171))
152187	31383940	4i), which indicated reduced flow of glucose into the TCA cycle in AOX1 KD.	('reduced', 'NegReg', (21, 28))	('flow of glucose', 'MPA', (29, 44))	('TCA', 'Chemical', 'MESH:D014233', (54, 57))	('AOX1 KD', 'Var', (67, 74))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('TCA cycle', 'biological_process', 'GO:0006099', ('54', '63'))	('TCA', 'Enzyme', (54, 57))
152188	31383940	Nucleotide flux analysis showed a significant increase in the synthesis of adenosine monophosphate (M + 5), guanosine monophosphate (M + 5) cytidine monophosphate (M + 5), and inosine monophosphate (M + 5) in AOX1 KD (Fig.	('inosine monophosphate', 'Chemical', 'MESH:D007291', (176, 197))	('increase', 'PosReg', (46, 54))	('synthesis', 'MPA', (62, 71))	('cytidine monophosphate', 'Chemical', 'MESH:D003568', (140, 162))	('adenosine', 'Chemical', 'MESH:D000241', (75, 84))	('synthesis', 'biological_process', 'GO:0009058', ('62', '71'))	('guanosine monophosphate', 'Chemical', 'MESH:D006157', (108, 131))	('AOX1 KD', 'Var', (209, 216))	('inosine monophosphate', 'MPA', (176, 197))
152190	31383940	Because levels of kynurenine and NADP were elevated in the absence of AOX1, we tested whether pharmacological inhibition of NADP synthesis altered the metabolic effects caused by the loss of AOX1.	('NADP', 'MPA', (33, 37))	('loss', 'Var', (183, 187))	('NADP', 'Chemical', 'MESH:D009249', (124, 128))	('kynurenine', 'MPA', (18, 28))	('elevated', 'PosReg', (43, 51))	('levels', 'MPA', (8, 14))	('NADP synthesis', 'biological_process', 'GO:0006741', ('124', '138'))	('NADP', 'Chemical', 'MESH:D009249', (33, 37))	('kynurenine', 'Chemical', 'MESH:D007737', (18, 28))	('metabolic effects', 'MPA', (151, 168))	('tested', 'Reg', (79, 85))
152193	31383940	Inhibition of TDO2 resulted in decreased NADP synthesis leading to a reduction in 6-phosphogluconate and ribose/ribulose 5-phosphate in AOX1 KD cells compared with untreated AOX1 KD (Fig.	('6-phosphogluconate', 'Chemical', 'MESH:C008884', (82, 100))	('NADP', 'Chemical', 'MESH:D009249', (41, 45))	('NADP synthesis', 'MPA', (41, 55))	('Inhibition', 'NegReg', (0, 10))	('TDO2', 'Gene', '6999', (14, 18))	('decreased', 'NegReg', (31, 40))	('ribose/ribulose 5-phosphate', 'Chemical', '-', (105, 132))	('AOX1 KD', 'Var', (136, 143))	('reduction', 'NegReg', (69, 78))	('NADP synthesis', 'biological_process', 'GO:0006741', ('41', '55'))	('TDO2', 'Gene', (14, 18))	('TDO', 'molecular_function', 'GO:0004833', ('14', '17'))
152194	31383940	These findings suggest loss of AOX1 in BLCA cells may enable increased NADP production.	('AOX1', 'Gene', (31, 35))	('NADP production', 'MPA', (71, 86))	('increased', 'PosReg', (61, 70))	('loss', 'Var', (23, 27))	('NADP', 'Chemical', 'MESH:D009249', (71, 75))
152197	31383940	Ectopic expression of AOX1 in BLCA cells significantly reduced the levels of kynurenine and NADP, suggesting activation of the regular tryptophan pathway (Fig.	('NADP', 'MPA', (92, 96))	('kynurenine', 'Chemical', 'MESH:D007737', (77, 87))	('regular tryptophan pathway', 'Pathway', (127, 153))	('reduced', 'NegReg', (55, 62))	('tryptophan', 'Chemical', 'MESH:D014364', (135, 145))	('Ectopic expression', 'Var', (0, 18))	('activation', 'PosReg', (109, 119))	('AOX1', 'Gene', (22, 26))	('NADP', 'Chemical', 'MESH:D009249', (92, 96))
152200	31383940	Ectopic AOX1 expression resulted in a decrease in levels of the glycolytic intermediates, glucose-6-phosphate (M + 6) and fructose 1,6-bisphosphate (M + 6) (Fig.	('AOX1', 'Gene', (8, 12))	('decrease', 'NegReg', (38, 46))	('Ectopic', 'Var', (0, 7))	('levels of the glycolytic intermediates', 'MPA', (50, 88))	('fructose 1,6-bisphosphate', 'Chemical', 'MESH:C029063', (122, 147))	('glucose', 'Chemical', 'MESH:D005947', (90, 97))
152208	31383940	In contrast, the knockdown of AOX1 under these conditions significantly increases the abundance of kynuerenine, NADP and PPP pathway metabolites (Fig.	('kynuerenine', 'Chemical', '-', (99, 110))	('abundance', 'MPA', (86, 95))	('increases', 'PosReg', (72, 81))	('PPP pathway', 'Gene', (121, 132))	('kynuerenine', 'MPA', (99, 110))	('knockdown', 'Var', (17, 26))	('NADP', 'Chemical', 'MESH:D009249', (112, 116))	('AOX1', 'Gene', (30, 34))	('NADP', 'Gene', (112, 116))
152210	31383940	Together, these experiments suggest AOX1 plays a pivotal role in central carbon metabolism by rewiring the tryptophan metabolic pathway, which further regulates PPP pathway through NADP.	('AOX1', 'Var', (36, 40))	('tryptophan', 'Chemical', 'MESH:D014364', (107, 117))	('rewiring', 'Reg', (94, 102))	('carbon', 'Chemical', 'MESH:D002244', (73, 79))	('men', 'Species', '9606', (22, 25))	('metabolism', 'biological_process', 'GO:0008152', ('80', '90'))	('central carbon metabolism', 'MPA', (65, 90))	('regulates', 'Reg', (151, 160))	('PPP pathway', 'Pathway', (161, 172))	('tryptophan metabolic pathway', 'Pathway', (107, 135))	('NADP', 'Chemical', 'MESH:D009249', (181, 185))
152214	31383940	AOX1KD cells showed lower levels of E-cadherin and higher levels of vimentin and N-cadherin (Fig.	('E-cadherin', 'MPA', (36, 46))	('cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))	('lower', 'NegReg', (20, 25))	('N-cadherin', 'Gene', '1000', (81, 91))	('vimentin', 'MPA', (68, 76))	('vimentin', 'cellular_component', 'GO:0045099', ('68', '76'))	('levels', 'MPA', (26, 32))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('vimentin', 'cellular_component', 'GO:0045098', ('68', '76'))	('AOX1KD', 'Var', (0, 6))	('higher', 'PosReg', (51, 57))	('N-cadherin', 'Gene', (81, 91))
152225	31383940	GSK126 treated cells were used for AOX1 gain, followed by shAOX1 knockdown for loss of AOX1 in the same setting.	('shAOX1', 'Gene', (58, 64))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('AOX1', 'Gene', (35, 39))	('GSK126', 'Chemical', 'MESH:C577920', (0, 6))	('gain', 'PosReg', (40, 44))	('knockdown', 'Var', (65, 74))
152227	31383940	We found AOX1 expression resulted in a significant reduction in tumor growth while AOX1 knockdown enhanced growth (Fig.	('enhanced', 'PosReg', (98, 106))	('AOX1', 'Gene', (83, 87))	('reduction', 'NegReg', (51, 60))	('tumor', 'Disease', (64, 69))	('AOX1', 'Gene', (9, 13))	('growth', 'CPA', (107, 113))	('knockdown', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
152240	31383940	This result supports a recent study demonstrating loss of tumor suppressor KDM6A (a H3K27 demethylase) amplifies PRC2-regulated transcriptional repression by EZH2 in BLCA.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('EZH2', 'Gene', '2146', (158, 162))	('EZH2', 'Gene', (158, 162))	('KDM6A', 'Gene', '7403', (75, 80))	('amplifies', 'PosReg', (103, 112))	('loss', 'Var', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('KDM6A', 'Gene', (75, 80))	('PRC2-regulated transcriptional repression', 'MPA', (113, 154))	('tumor suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))
152243	31383940	Our results add merit to the emerging mechanisms of epigenetic gene silencing of xenobiotic enzymes during BLCA development.	('xenobiotic enzymes', 'Enzyme', (81, 99))	('men', 'Species', '9606', (119, 122))	('gene silencing', 'biological_process', 'GO:0016458', ('63', '77'))	('epigenetic gene silencing', 'Var', (52, 77))
152244	31383940	Hypermethylated genes have been shown to be promising cancer markers for early detection of BLCA.	('Hypermethylated genes', 'Var', (0, 21))	('BLCA', 'Disease', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
152246	31383940	Muscle invasive bladder cancer (MIBC) shows distinct patterns of CpG island hypermethylation at the AOX1 promoter when compared with NMIBC.	('CpG island hypermethylation', 'Var', (65, 92))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('Muscle invasive bladder cancer', 'Disease', (0, 30))	('hypermethylation', 'Var', (76, 92))	('invasive bladder', 'Phenotype', 'HP:0100645', (7, 23))	('bladder cancer', 'Phenotype', 'HP:0009725', (16, 30))	('Muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (0, 30))
152250	31383940	Loss of AOX1 may disrupt the tryptophan- kynurenine pathway resulting in production of NADP and fueling nucleotide synthesis.	('fueling nucleotide synthesis', 'MPA', (96, 124))	('disrupt', 'NegReg', (17, 24))	('NADP', 'Chemical', 'MESH:D009249', (87, 91))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('104', '124'))	('AOX1', 'Gene', (8, 12))	('tryptophan', 'Chemical', 'MESH:D014364', (29, 39))	('kynurenine', 'Chemical', 'MESH:D007737', (41, 51))	('tryptophan- kynurenine pathway', 'Pathway', (29, 59))	('Loss', 'Var', (0, 4))	('production of NADP', 'MPA', (73, 91))
152254	31383940	Kynurenine may mitigate immune suppressive effects by binding to the aryl hydrocarbon (AhR) receptor there by promoting invasion and metastasis.	('binding', 'molecular_function', 'GO:0005488', ('54', '61'))	('immune suppressive effects', 'CPA', (24, 50))	('Kynurenine', 'Var', (0, 10))	('promoting', 'PosReg', (110, 119))	('mitigate', 'NegReg', (15, 23))	('aryl hydrocarbon (AhR) receptor', 'Gene', '196', (69, 100))	('Kynurenine', 'Chemical', 'MESH:D007737', (0, 10))	('binding', 'Interaction', (54, 61))
152256	31383940	Loss of AOX1 leads to upregulation of metabolic enzymes such as hexokinase 1, phosphofructokinase 1, and glucose-6-phosphate dehydrogenase, which suggest a possible role for increased glucose metabolism in activating the PPP.	('glucose-6-phosphate dehydrogenase', 'Gene', '2539', (105, 138))	('increased glucose', 'Phenotype', 'HP:0003074', (174, 191))	('phosphofructokinase 1', 'Gene', '5214', (78, 99))	('phosphofructokinase 1', 'molecular_function', 'GO:0008662', ('78', '99'))	('hexokinase 1', 'Gene', (64, 76))	('glucose metabolism', 'Disease', 'MESH:D044882', (184, 202))	('glucose metabolism', 'biological_process', 'GO:0006006', ('184', '202'))	('AOX1', 'Gene', (8, 12))	('hexokinase 1', 'Gene', '3098', (64, 76))	('glucose-6-phosphate dehydrogenase', 'Gene', (105, 138))	('upregulation', 'PosReg', (22, 34))	('metabolic enzymes', 'MPA', (38, 55))	('glucose metabolism', 'Disease', (184, 202))	('Loss', 'Var', (0, 4))	('increased', 'PosReg', (174, 183))	('phosphofructokinase 1', 'Gene', (78, 99))
152264	31383940	Pharmacologic inhibition of TDO2 in AOX1KD decreases flux through PPP suggesting a novel therapeutic opportunity to suppress nucleotide biosynthesis at the level of the kynurenine pathway.	('TDO2', 'Gene', (28, 32))	('TDO', 'molecular_function', 'GO:0004833', ('28', '31'))	('TDO2', 'Gene', '6999', (28, 32))	('suppress', 'NegReg', (116, 124))	('nucleotide biosynthesis', 'biological_process', 'GO:0009165', ('125', '148'))	('decreases', 'NegReg', (43, 52))	('kynurenine', 'Chemical', 'MESH:D007737', (169, 179))	('flux through PPP', 'MPA', (53, 69))	('nucleotide biosynthesis', 'MPA', (125, 148))	('AOX1KD', 'Var', (36, 42))
152267	31383940	This is the first study to demonstrate the generation of NADP/NADPH via a previously unrecognized pathway in response to loss of AOX1, thus connecting metabolism and carcinogenesis.	('metabolism', 'biological_process', 'GO:0008152', ('151', '161'))	('NADP', 'Chemical', 'MESH:D009249', (62, 66))	('NADPH', 'Gene', (62, 67))	('loss', 'Var', (121, 125))	('AOX1', 'Gene', (129, 133))	('NADPH', 'Gene', '1666', (62, 67))	('carcinogenesis', 'Disease', 'MESH:D063646', (166, 180))	('NADP', 'Chemical', 'MESH:D009249', (57, 61))	('carcinogenesis', 'Disease', (166, 180))
152332	31383940	After blocking for 1 h in 5% milk/TBST, cells were incubated overnight at 4  C with rabbit anti-vimentin (1:250, Cell Signaling) or mouse anti-E-cadherin (1:250, Cell Signaling) in TBST/5% milk.	('1:250', 'Var', (155, 160))	('vimentin', 'cellular_component', 'GO:0045098', ('96', '104'))	('Signaling', 'biological_process', 'GO:0023052', ('118', '127'))	('Signaling', 'biological_process', 'GO:0023052', ('167', '176'))	('cadherin', 'molecular_function', 'GO:0008014', ('145', '153'))	('1:250', 'Var', (106, 111))	('TBST', 'Chemical', '-', (181, 185))	('TBST', 'Chemical', '-', (34, 38))	('mouse', 'Species', '10090', (132, 137))	('vimentin', 'cellular_component', 'GO:0045099', ('96', '104'))
152420	33401585	Grade 3 or 4 adverse events were less common in the Pembrolizumab group (15%) as compared to 49.4% in the chemotherapy-treated arm.	('Pembrolizumab', 'Chemical', 'MESH:C582435', (52, 65))	('less', 'NegReg', (33, 37))	('Pembrolizumab', 'Var', (52, 65))
152436	33401585	Nevertheless, the reported median OS was greater in PD-L1 positive patients compared to patients whose tumor cells expressed <=1% PD-L1 (11.30 months vs. 5.95 months).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('PD-L1', 'Gene', '29126', (52, 57))	('greater', 'PosReg', (41, 48))	('patients', 'Species', '9606', (67, 75))	('tumor', 'Disease', (103, 108))	('patients', 'Species', '9606', (88, 96))	('PD-L1', 'Gene', (130, 135))	('positive', 'Var', (58, 66))	('PD-L1', 'Gene', '29126', (130, 135))	('PD-L1', 'Gene', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
152442	33401585	Nonetheless, there was a trend toward increased survival after 12 weeks of treatment (primary end-point) in patients with high PD-L1 expressing tumors as compared to patients with low PD-L1 expressing tumors (ORR of 53.8% vs. 9.0%, respectively).	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('survival', 'MPA', (48, 56))	('PD-L1', 'Gene', (184, 189))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('PD-L1', 'Gene', '29126', (184, 189))	('high', 'Var', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('patients', 'Species', '9606', (166, 174))	('PD-L1', 'Gene', (127, 132))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('patients', 'Species', '9606', (108, 116))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('increased', 'PosReg', (38, 47))	('PD-L1', 'Gene', '29126', (127, 132))
152449	33401585	In patients with advanced UC, combinations of Avelumab with radiation (NCT03747419) and KHK2455 (an indoleamine 2,3-dioxygenase inhibitor; NCT03915405) are also being tested.	('advanced UC', 'Disease', (17, 28))	('KHK2455', 'Chemical', '-', (88, 95))	('Avelumab', 'Chemical', 'MESH:C000609138', (46, 54))	('patients', 'Species', '9606', (3, 11))	('NCT03747419', 'Var', (71, 82))
152462	33401585	In fact, trials evaluating Pembrolizumab (NCT02324582, NCT02808143) or Atezolizumab (NCT02792192) in combination with BCG are still recruiting patients.	('BCG', 'Species', '33892', (118, 121))	('NCT02324582', 'Var', (42, 53))	('Atezolizumab', 'Chemical', 'MESH:C000594389', (71, 83))	('NCT02792192', 'Var', (85, 96))	('patients', 'Species', '9606', (143, 151))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (27, 40))	('NCT02808143', 'Var', (55, 66))
152474	33401585	The authors concluded that a synergistic antitumor effect could be seen when chemotherapy is administered to patients that have received previous PD-1 inhibitors, and that the synergistic effect seems to be transitory and therefore of limited clinical value.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Disease', (45, 50))	('PD-1', 'Gene', (146, 150))	('PD-1', 'Gene', '5133', (146, 150))	('inhibitors', 'Var', (151, 161))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
152512	33401585	Reportedly, a durable response to ICI in metastatic bladder cancer is connected to the mutational load or tumor mutation burden (TMB) present in a given tumor as well as the number of related neoantigens.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('mutational', 'Var', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('bladder cancer', 'Disease', (52, 66))	('TMB', 'Chemical', '-', (129, 132))	('tumor', 'Disease', (106, 111))
152517	33401585	On the other side, data from 119 samples in cohort 1 of IMvigor 210, in which TMB was determined, resulted in a positive correlation toward better OS in the highest quartile of TMB (>16 to <62.2 mutations per megabase) compared to quartiles 1 to 3.	('>16 to <62.2 mutations', 'Var', (182, 204))	('TMB', 'Chemical', '-', (177, 180))	('TMB', 'Chemical', '-', (78, 81))	('better', 'PosReg', (140, 146))
152519	33401585	In practical terms, patients having a combination of two biomarkers including high PD-L1 and high TMB might experience durable response following ICI therapy.	('PD-L1', 'Gene', '29126', (83, 88))	('high', 'Var', (78, 82))	('patients', 'Species', '9606', (20, 28))	('PD-L1', 'Gene', (83, 88))	('TMB', 'Gene', (98, 101))	('TMB', 'Chemical', '-', (98, 101))
152534	33401585	Tumors with MSI and with DNA damage repair deleterious mutations have a higher load of insertions/deletions that make these tumors more sensitive to ICI.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('more', 'PosReg', (131, 135))	('mutations', 'Var', (55, 64))	('sensitive to ICI', 'MPA', (136, 152))	('insertions/deletions', 'Var', (87, 107))	('Tumors', 'Disease', (0, 6))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('MSI', 'Disease', (12, 15))
152537	33401585	According to Vidotto et al., the presence of a basal subtype, CD8+ high TILs, and a high expression of PD-1, LAG-3, IDO1, CTLA-4, and PD-L1 was associated with better prognosis and decreased disease recurrence.	('IDO1', 'Gene', (116, 120))	('IDO', 'molecular_function', 'GO:0033754', ('116', '119'))	('CD8', 'Gene', (62, 65))	('PD-L1', 'Gene', (134, 139))	('IDO1', 'Gene', '3620', (116, 120))	('PD-1', 'Gene', (103, 107))	('CD8', 'Gene', '925', (62, 65))	('presence', 'Var', (33, 41))	('PD-1', 'Gene', '5133', (103, 107))	('LAG-3', 'Gene', '3902', (109, 114))	('CTLA-4', 'Gene', '1493', (122, 128))	('LAG-3', 'Gene', (109, 114))	('IDO', 'molecular_function', 'GO:0047719', ('116', '119'))	('PD-L1', 'Gene', '29126', (134, 139))	('decreased disease', 'Disease', (181, 198))	('CTLA-4', 'Gene', (122, 128))	('decreased disease', 'Disease', 'MESH:D002303', (181, 198))
152546	33401585	Reportedly, several types of urologic and non-urologic tumors showing mismatch repair (MMR) defects may be responsive to Pembrolizumab, and this is independent of their tissue of origin; then, assessing MMR status in bladder malignancies might have a role in certain cases.	('bladder malignancies', 'Phenotype', 'HP:0009725', (217, 237))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('bladder malignancies', 'Disease', 'MESH:D001749', (217, 237))	('bladder malignancies', 'Disease', (217, 237))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('mismatch repair', 'biological_process', 'GO:0006298', ('70', '85'))	('tumors', 'Disease', (55, 61))	('defects', 'Var', (92, 99))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('MMR', 'biological_process', 'GO:0006298', ('203', '206'))	('MMR', 'biological_process', 'GO:0006298', ('87', '90'))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (121, 134))	('responsive', 'MPA', (107, 117))
152547	33401585	Unfortunately, the low number of bladder cancer with such alterations precludes a limitation in practice.	('bladder cancer', 'Disease', 'MESH:D001749', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('low number of bladder', 'Phenotype', 'HP:0005343', (19, 40))	('bladder cancer', 'Disease', (33, 47))	('bladder cancer', 'Phenotype', 'HP:0009725', (33, 47))	('alterations', 'Var', (58, 69))
152573	29303511	The four gene expression data sets, which consist of pancreatic adenocarcinoma (PAAD, GSE21501, n=132), lung adenocarcinoma (LUAD, GSE31210, n=246), breast invasive carcinoma (BRCA, GSE20486, n=97), and bladder urothelial carcinoma (BLCA, GSE13507, n=165) samples, were obtained from the NCBI GEO database.	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (149, 174))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (53, 78))	('gene expression', 'biological_process', 'GO:0010467', ('9', '24'))	('BRCA', 'Phenotype', 'HP:0003002', (176, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('breast invasive carcinoma', 'Disease', (149, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('PAAD', 'Phenotype', 'HP:0006725', (80, 84))	('lung adenocarcinoma', 'Disease', (104, 123))	('LUAD', 'Phenotype', 'HP:0030078', (125, 129))	('BRCA', 'Gene', '672', (176, 180))	('GSE21501', 'Var', (86, 94))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (53, 78))	('pancreatic adenocarcinoma', 'Disease', (53, 78))	('bladder urothelial carcinoma', 'Disease', (203, 231))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (104, 123))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (149, 174))	('BRCA', 'Gene', (176, 180))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (104, 123))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (203, 231))
152639	29303511	A recent study suggested that miR-34a directly targets FOXM1 and MYC via binding the 3' untranslated regions in liver cancer cells, which indicates that expression changes in miR-34a might be a critical factor for the diagnosis of HCC patients.	('FOXM1', 'Gene', (55, 60))	('HCC', 'Gene', '619501', (231, 234))	('miR-34a', 'Gene', '407040', (30, 37))	('HCC', 'Phenotype', 'HP:0001402', (231, 234))	('changes', 'Var', (164, 171))	('HCC', 'Gene', (231, 234))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))	('patients', 'Species', '9606', (235, 243))	('MYC', 'Gene', (65, 68))	('liver cancer', 'Disease', 'MESH:D006528', (112, 124))	('FOXM1', 'Gene', '2305', (55, 60))	('binding', 'Interaction', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('MYC', 'Gene', '4609', (65, 68))	('liver cancer', 'Phenotype', 'HP:0002896', (112, 124))	('miR-34a', 'Gene', (175, 182))	('liver cancer', 'Disease', (112, 124))	('miR-34a', 'Gene', (30, 37))	('miR-34a', 'Gene', '407040', (175, 182))
152665	29050329	CEUS patterns were divided into three types: type I, fast wash-in and fast wash-out, 86% (36/42) of low-grade urothelial carcinomas showed quick enhancement in and around the lesions, and regression occurred earlier than in adjacent normal bladder wall (Figure 1); type II, slow wash-in and fast wash-out, 7% (4/54) of high-grade tumors and 5% (2/42) of low-grade tumors showed slow enhancement, and regression occurred earlier than in adjacent normal bladder wall; and type III, fast wash-in and slow wash-out, 85% (46/54) of high-grade urothelial carcinomas were quickly enhanced from the central tumor to its periphery, and regression occurred later than in adjacent normal bladder wall (Figure 2).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('tumors', 'Phenotype', 'HP:0002664', (364, 370))	('tumor', 'Disease', (330, 335))	('tumor', 'Disease', (599, 604))	('carcinoma', 'Phenotype', 'HP:0030731', (549, 558))	('carcinomas', 'Phenotype', 'HP:0030731', (549, 559))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('tumor', 'Disease', 'MESH:D009369', (599, 604))	('tumors', 'Disease', (364, 370))	('enhanced', 'PosReg', (573, 581))	('tumors', 'Phenotype', 'HP:0002664', (330, 336))	('men', 'Species', '9606', (152, 155))	('men', 'Species', '9606', (390, 393))	('urothelial carcinomas', 'Disease', (538, 559))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (538, 559))	('tumors', 'Disease', 'MESH:D009369', (364, 370))	('tumor', 'Phenotype', 'HP:0002664', (599, 604))	('tumors', 'Disease', (330, 336))	('fast wash-in', 'Var', (480, 492))	('urothelial carcinomas', 'Disease', (110, 131))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (110, 131))	('tumor', 'Disease', (364, 369))	('tumors', 'Disease', 'MESH:D009369', (330, 336))	('tumor', 'Disease', 'MESH:D009369', (364, 369))
152695	29050329	Low-grade tumors were associated with low flow rates and straight- and regularly-organized vessels.	('Low-grade', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('low', 'NegReg', (38, 41))
152771	28415608	In the detailed examination of the murine bladder wall, MGH-U3, UM-UC-14, and UM-UC-3 displayed typical nodular, trabecular, and infiltrative growth patterns, respectively (Figure 1B).	('nodular', 'CPA', (104, 111))	('MGH-U3', 'Chemical', '-', (56, 62))	('trabecular', 'CPA', (113, 123))	('infiltrative growth patterns', 'CPA', (129, 157))	('UM-UC-3', 'Var', (78, 85))	('murine', 'Species', '10090', (35, 41))
152783	28415608	To investigate genes whose expression levels were altered by at least 2-fold in UM-UC-14 vs. MGH-U3, in UM-UC-3 vs. MGH-U3, and in UM-UC-3 vs. UM-UC-14, these genes and their corresponding log2 fold-change values were analyzed with IPA software.	('expression levels', 'MPA', (27, 44))	('UM-UC-14', 'Var', (80, 88))	('MGH-U3', 'Chemical', '-', (93, 99))	('altered', 'Reg', (50, 57))	('MGH-U3', 'Chemical', '-', (116, 122))
152784	28415608	The core analysis function in IPA revealed 22 biological networks from our dataset containing 279 differentially expressed genes (161 up- and 118 down-regulated) in UM-UC-3 vs. MGH-U3.	('up-', 'PosReg', (134, 137))	('MGH-U3', 'Chemical', '-', (177, 183))	('core', 'cellular_component', 'GO:0019013', ('4', '8'))	('down-regulated', 'NegReg', (146, 160))	('UM-UC-3', 'Var', (165, 172))
152794	28415608	COL4A1 and COL13A1 expression was notably increased in the trabecular and infiltrative patterns compared with that in the nodular pattern (P = 0.017 and 0.012, respectively; Figure 4B and 4C), implying that the expression of these two collagens increases biological aggressiveness and tumor invasiveness in human UCB.	('increased', 'PosReg', (42, 51))	('expression', 'MPA', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('expression', 'Var', (211, 221))	('aggressiveness', 'Phenotype', 'HP:0000718', (266, 280))	('increases', 'PosReg', (245, 254))	('COL13A1', 'Gene', (11, 18))	('COL4A1', 'Gene', (0, 6))	('aggressiveness and tumor invasiveness', 'Disease', 'MESH:D001523', (266, 303))	('trabecular', 'CPA', (59, 69))	('human', 'Species', '9606', (307, 312))	('UCB', 'Chemical', '-', (313, 316))	('COL4A1', 'Gene', '1282', (0, 6))	('COL13A1', 'Gene', '1305', (11, 18))
152797	28415608	Kaplan-Meier analysis of MIBC patients showed that high expression of COL13A1, but not COL4A1, was significantly associated with poor outcomes after RC (Figure 4D).	('COL13A1', 'Gene', '1305', (70, 77))	('COL13A1', 'Gene', (70, 77))	('COL4A1', 'Gene', '1282', (87, 93))	('MIBC', 'Chemical', '-', (25, 29))	('patients', 'Species', '9606', (30, 38))	('high', 'Var', (51, 55))	('COL4A1', 'Gene', (87, 93))	('associated', 'Reg', (113, 123))
152810	28415608	We examined if the expression levels of the genes encoding integrins alpha2 and beta1 were altered by knockdown of COL4A1 and COL13A1.	('COL4A1', 'Gene', '1282', (115, 121))	('COL13A1', 'Gene', (126, 133))	('knockdown', 'Var', (102, 111))	('altered', 'Reg', (91, 98))	('COL4A1', 'Gene', (115, 121))	('expression levels', 'MPA', (19, 36))	('COL13A1', 'Gene', '1305', (126, 133))
152814	28415608	Collagen knockdown reduced the number of invadopodial structures per cell (Figure 5D and 5E) and the expression of dynamin I/II.	('knockdown', 'Var', (9, 18))	('dynamin I/II', 'Gene', (115, 127))	('dynamin I/II', 'Gene', '1785', (115, 127))	('Collagen', 'molecular_function', 'GO:0005202', ('0', '8'))	('reduced', 'NegReg', (19, 26))	('expression', 'MPA', (101, 111))
152819	28415608	The sizes and weights of resected bladder tumors treated with COLs siRNA were not apparently different from those treated with NC siRNA (data not shown).	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('COLs siRNA', 'Var', (62, 72))	('bladder tumors', 'Disease', 'MESH:D001749', (34, 48))	('bladder tumors', 'Phenotype', 'HP:0009725', (34, 48))	('bladder tumor', 'Phenotype', 'HP:0009725', (34, 47))	('bladder tumors', 'Disease', (34, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
152828	28415608	Along with the knocking down of two collagens, decreased phosphorylated AKT, N-cadherin, and dynamin were observed whereas increased membranous expression of E-cadherin was seen.	('AKT', 'Gene', '207', (72, 75))	('increased', 'PosReg', (123, 132))	('cadherin', 'molecular_function', 'GO:0008014', ('160', '168'))	('cadherin', 'molecular_function', 'GO:0008014', ('79', '87'))	('dynamin', 'Protein', (93, 100))	('N-cadherin', 'Gene', '1000', (77, 87))	('AKT', 'Gene', (72, 75))	('knocking down', 'Var', (15, 28))	('E-cadherin', 'Gene', (158, 168))	('E-cadherin', 'Gene', '999', (158, 168))	('phosphorylated', 'MPA', (57, 71))	('N-cadherin', 'Gene', (77, 87))	('decreased', 'NegReg', (47, 56))
152849	28415608	We first demonstrated that expression of COL13A1 in UCB cells potentially causes a significant increase in invasion capability via the formation of the infiltrative invasion pattern and invadopodia.	('invasion capability', 'CPA', (107, 126))	('formation', 'biological_process', 'GO:0009058', ('135', '144'))	('increase', 'PosReg', (95, 103))	('COL13A1', 'Gene', (41, 48))	('UCB', 'Chemical', '-', (52, 55))	('expression', 'Var', (27, 37))	('COL13A1', 'Gene', '1305', (41, 48))
152971	25937998	Other genes with site specificity were also summarized, such as bladder SmCC with TERT promoter mutations; prostate SmCC with ERG translocations; ovarian SmCC with SMARCA4 mutations; Merkel cell carcinoma (skin) and cervical SmCC with Merkel cell polyomavirus (MCV or MCPyV) and human papillomavirus (HPV).	('SMARCA4', 'Gene', '6597', (164, 171))	('SmCC', 'Phenotype', 'HP:0030357', (72, 76))	('ERG', 'Gene', (126, 129))	('HPV', 'Disease', 'MESH:D030361', (301, 304))	('ovarian SmCC', 'Disease', (146, 158))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (183, 204))	('ERG', 'Gene', '2078', (126, 129))	('mutations', 'Var', (96, 105))	('human papillomavirus', 'Disease', (279, 299))	('Merkel cell polyomavirus', 'Species', '493803', (235, 259))	('SmCC', 'Phenotype', 'HP:0030357', (116, 120))	('Merkel cell carcinoma', 'Disease', (183, 204))	('SMARCA4', 'Gene', (164, 171))	('TERT', 'Gene', (82, 86))	('ovarian SmCC', 'Disease', 'MESH:D010051', (146, 158))	('bladder SmCC', 'Disease', (64, 76))	('SmCC', 'Phenotype', 'HP:0030357', (225, 229))	('TERT', 'Gene', '7015', (82, 86))	('human papillomavirus', 'Species', '10566', (279, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('SmCC', 'Phenotype', 'HP:0030357', (154, 158))	('HPV', 'Disease', (301, 304))	('mutations', 'Var', (172, 181))	('MCV', 'Species', '493803', (261, 264))	('Merkel cell polyomavirus', 'Disease', (235, 259))
152986	25937998	In mice, SCLC is initiated by deletion of two tumor suppressor genes (RB1 and TP53).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('RB1', 'Gene', (70, 73))	('mice', 'Species', '10090', (3, 7))	('tumor', 'Disease', (46, 51))	('tumor suppressor', 'biological_process', 'GO:0051726', ('46', '62'))	('SCLC', 'Gene', '7864', (9, 13))	('SCLC', 'Phenotype', 'HP:0030357', (9, 13))	('SCLC', 'Gene', (9, 13))	('deletion', 'Var', (30, 38))	('TP53', 'Gene', (78, 82))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('46', '62'))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
152987	25937998	Deletion of these two genes produces a model that recapitulates the clinical features of human SCLC.	('human', 'Species', '9606', (89, 94))	('SCLC', 'Gene', '7864', (95, 99))	('SCLC', 'Phenotype', 'HP:0030357', (95, 99))	('SCLC', 'Gene', (95, 99))	('Deletion', 'Var', (0, 8))
152988	25937998	Infrequent activating mutations have also been found in PIK3CA, EGFR and KRAS (all 10% or lower).	('KRAS', 'Gene', (73, 77))	('KRAS', 'Gene', '3845', (73, 77))	('activating', 'PosReg', (11, 21))	('PIK3CA', 'Gene', (56, 62))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('PIK3CA', 'Gene', '5290', (56, 62))
152990	25937998	Mean levels of total PARP1 (a DNA repair protein and E2F1 co-activator) were higher in SCLC cell lines than in NSCLC cell lines, and SCLC growth was inhibited by PARP1 and EZH2 knockdown.	('SCLC', 'Gene', '7864', (87, 91))	('SCLC', 'Gene', (87, 91))	('NSCLC', 'Disease', (111, 116))	('PARP1', 'Gene', (162, 167))	('E2F1', 'Gene', '100036852', (53, 57))	('SCLC', 'Gene', (133, 137))	('SCLC', 'Gene', '7864', (133, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('DNA repair protein', 'molecular_function', 'GO:0003684', ('30', '48'))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('DNA repair', 'biological_process', 'GO:0006281', ('30', '40'))	('higher', 'PosReg', (77, 83))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('knockdown', 'Var', (177, 186))	('E2F1', 'Gene', (53, 57))	('PARP1', 'Gene', '397928', (21, 26))	('DNA repair protein', 'molecular_function', 'GO:0003685', ('30', '48'))	('PARP1', 'Gene', '397928', (162, 167))	('SCLC', 'Phenotype', 'HP:0030357', (112, 116))	('SCLC', 'Phenotype', 'HP:0030357', (87, 91))	('EZH2', 'Gene', '399174', (172, 176))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('EZH2', 'Gene', (172, 176))	('SCLC', 'Gene', (112, 116))	('SCLC', 'Phenotype', 'HP:0030357', (133, 137))	('inhibited', 'NegReg', (149, 158))	('SCLC', 'Gene', '7864', (112, 116))	('PARP1', 'Gene', (21, 26))
153008	25937998	Distingushing SmCC of the prostate and from that of the bladder can be very challenging, if even possible, because of low positivity of GATA3 in SmCC of the bladder and low positivity of PSA and other prostatic markers, such as P501S, in SmCC of the prostate.	('low', 'NegReg', (118, 121))	('SmCC', 'Phenotype', 'HP:0030357', (14, 18))	('P501S', 'Var', (228, 233))	('positivity', 'MPA', (173, 183))	('SmCC', 'Phenotype', 'HP:0030357', (145, 149))	('SmCC', 'Phenotype', 'HP:0030357', (238, 242))	('positivity', 'MPA', (122, 132))	('GATA3', 'Gene', (136, 141))	('P501S', 'Mutation', 'p.P501S', (228, 233))	('GATA3', 'Gene', '2625', (136, 141))
153009	25937998	TERT promoter mutations, originally discovered in ~70% of melanomas, have also been found to be the most common form of genetic mutations in urothelial carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('mutations', 'Var', (128, 137))	('melanomas', 'Disease', 'MESH:D008545', (58, 67))	('TERT', 'Gene', (0, 4))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('TERT', 'Gene', '7015', (0, 4))	('melanomas', 'Disease', (58, 67))	('urothelial carcinomas', 'Disease', (141, 162))	('mutations', 'Var', (14, 23))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (141, 162))
147687	25937998	Interestingly, these mutations have very low incidence in other prevalent carcinomas: lung, prostate and colon cancers.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('colon cancers', 'Disease', (105, 118))	('prostate', 'Disease', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('lung', 'Disease', (86, 90))	('colon cancers', 'Phenotype', 'HP:0003003', (105, 118))	('colon cancers', 'Disease', 'MESH:D015179', (105, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('carcinomas', 'Disease', (74, 84))	('carcinomas', 'Disease', 'MESH:D002277', (74, 84))	('mutations', 'Var', (21, 30))
153011	25937998	Our recent study showed that 100% (10 cases) of SmCC of the urinary bladder carry TERT promoter mutation C228T, yet none of SmCC from all other origins including prostate, lung, cervix, esophagus, and skin (Merkel cell carcinoma) contain the TERT promoter mutations.	('TERT', 'Gene', (242, 246))	('TERT', 'Gene', '7015', (242, 246))	('SmCC', 'Phenotype', 'HP:0030357', (48, 52))	('TERT', 'Gene', (82, 86))	('SmCC', 'Phenotype', 'HP:0030357', (124, 128))	('C228T', 'Mutation', 'c.228C>T', (105, 110))	('TERT', 'Gene', '7015', (82, 86))	('C228T', 'Var', (105, 110))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (207, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('Merkel cell carcinoma', 'Disease', (207, 228))
153018	25937998	PSA and other prostatic markers, such as P501S, are only positive in about 17-25% cases, often focally.	('PSA', 'Disease', (0, 3))	('P501S', 'Mutation', 'p.P501S', (41, 46))	('P501S', 'Var', (41, 46))
153020	25937998	Interestingly, both conventional prostatic adenocarcinoma and SmCC of prostate share ERG gene rearrangement which is absent in SmCC from other body sites.	('SmCC', 'Phenotype', 'HP:0030357', (62, 66))	('men', 'Species', '9606', (103, 106))	('prostatic adenocarcinoma', 'Disease', 'MESH:D011471', (33, 57))	('prostatic adenocarcinoma', 'Disease', (33, 57))	('SmCC', 'Phenotype', 'HP:0030357', (127, 131))	('rearrangement', 'Var', (94, 107))	('ERG', 'Gene', '2078', (85, 88))	('ERG', 'Gene', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
153046	25937998	Recently 3 independent studies reported that SCCOHT is a monogenic disease caused by mutations in the SMARCA4 gene.	('SMARCA4', 'Gene', (102, 109))	('SMARCA4', 'Gene', '6597', (102, 109))	('SCCOHT', 'Disease', (45, 51))	('caused by', 'Reg', (75, 84))	('mutations', 'Var', (85, 94))
153047	25937998	Whole-exome sequencing on DNA obtained from 24 familial or sporadic cases of SCCOHT revealed that 22 of the 24 cases analyzed were due to SMARCA4 mutations; and Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors.	('protein', 'cellular_component', 'GO:0003675', ('282', '289'))	('SMARCA4', 'Gene', '6597', (267, 274))	('BRG1', 'Gene', (276, 280))	('mutations', 'Var', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('loss', 'NegReg', (259, 263))	('SMARCA4', 'Gene', (138, 145))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('SMARCA4', 'Gene', '6597', (138, 145))	('BRG1', 'Gene', '6597', (276, 280))	('protein', 'Protein', (282, 289))	('tumors', 'Disease', (302, 308))	('tumors', 'Disease', 'MESH:D009369', (302, 308))	('due to', 'Reg', (131, 137))	('SMARCA4', 'Gene', (267, 274))
153050	25937998	reported that germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors but in only 0.4% (2/485) of other primary ovarian tumors.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumors', 'Disease', (255, 261))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('SMARCA4', 'Gene', (152, 159))	('tumors', 'Disease', (198, 204))	('SMARCA4', 'Gene', '6597', (99, 106))	('inactivating mutations', 'Var', (35, 57))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('SCCOHT', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('ovarian tumors', 'Disease', (247, 261))	('ovarian tumors', 'Disease', 'MESH:D010051', (247, 261))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('SMARCA4', 'Gene', '6597', (152, 159))	('SMARCA4', 'Gene', (99, 106))	('loss', 'NegReg', (168, 172))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('73', '93'))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('ovarian tumors', 'Phenotype', 'HP:0100615', (247, 261))	('chromatin', 'cellular_component', 'GO:0000785', ('73', '82'))
153051	25937998	These new pieces of evidence demonstrated that alterations in SMARCA4, the major cause of SCCOHT, could lead to improvements in genetic counseling and new treatment approaches.	('cause', 'Reg', (81, 86))	('SMARCA4', 'Gene', (62, 69))	('SMARCA4', 'Gene', '6597', (62, 69))	('SCCOHT', 'Disease', (90, 96))	('men', 'Species', '9606', (160, 163))	('men', 'Species', '9606', (119, 122))	('alterations', 'Var', (47, 58))
153062	25937998	The cell of origin for small cell lung cancer The usage of cell type-restricted Adeno-Cre vectors to distinct cell populations in the lung of adult mouse showed that loss of TP53 and RB1 can efficiently transform neuroendocrine and Surfactant Protein C (SPC)-expressing cells to SCLC, albeit SPC-expressing cells at a lesser efficiency.	('SPC', 'Gene', (254, 257))	('TP53', 'Gene', (174, 178))	('small cell lung cancer', 'Disease', 'MESH:D055752', (23, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('loss', 'Var', (166, 170))	('SPC', 'Gene', '6440', (292, 295))	('SPC', 'Gene', '6440', (254, 257))	('small cell lung cancer', 'Disease', (23, 45))	('SPC', 'molecular_function', 'GO:0009004', ('292', '295'))	('neuroendocrine and', 'MPA', (213, 231))	('mouse', 'Species', '10090', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('SCLC', 'Phenotype', 'HP:0030357', (279, 283))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (23, 45))	('transform', 'Reg', (203, 212))	('SPC', 'molecular_function', 'GO:0009004', ('254', '257'))	('SCLC', 'Gene', '7864', (279, 283))	('SCLC', 'Gene', (279, 283))	('RB1', 'Gene', (183, 186))	('SPC', 'Gene', (292, 295))
153067	25937998	Evidence for this hypothesis comes from an identical pattern of allelic loss in SmCC of urinary bladder mixed with urothelial carcinoma (UC).	('urothelial carcinoma', 'Disease', (115, 135))	('allelic loss', 'Var', (64, 76))	('SmCC', 'Phenotype', 'HP:0030357', (80, 84))	('SmCC', 'Gene', (80, 84))	('urinary bladder', 'Disease', (88, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (115, 135))
153068	25937998	Identical point mutations of TP53 were found in invasive bladder SmCC and coexisting UC in situ; additionally, no loss of heterozygosity of 9 microsatellite markers and TP53 was found in either component.	('invasive bladder SmCC', 'Disease', (48, 69))	('invasive bladder SmCC', 'Disease', 'MESH:D001745', (48, 69))	('SmCC', 'Phenotype', 'HP:0030357', (65, 69))	('found', 'Reg', (39, 44))	('point mutations', 'Var', (10, 25))	('TP53', 'Gene', (29, 33))	('invasive bladder', 'Phenotype', 'HP:0100645', (48, 64))
153074	25937998	There is a high concordance rate of ERG rearrangement between the SmCC of prostate and prostatic acinar components in a given patient; however, the absence of ERG rearrangement in bladder or lung small cell carcinomas supports a common origin for these two subtypes of prostate cancer.	('rearrangement', 'Var', (163, 176))	('ERG', 'Gene', (36, 39))	('men', 'Species', '9606', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (196, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('ERG', 'Gene', '2078', (36, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (207, 217))	('prostate cancer', 'Disease', 'MESH:D011471', (269, 284))	('patient', 'Species', '9606', (126, 133))	('ERG', 'Gene', (159, 162))	('prostate cancer', 'Phenotype', 'HP:0012125', (269, 284))	('prostate cancer', 'Disease', (269, 284))	('men', 'Species', '9606', (172, 175))	('SmCC', 'Phenotype', 'HP:0030357', (66, 70))	('bladder or lung small cell carcinomas', 'Disease', (180, 217))	('bladder or lung small cell carcinomas', 'Disease', 'MESH:D055752', (180, 217))	('ERG', 'Gene', '2078', (159, 162))	('lung small', 'Phenotype', 'HP:0002089', (191, 201))
153078	25937998	Recent reports also revealed that small cell carcinoma of the ovary, hypercalcemic type, display frequent inactivating germline and somatic mutations in SMARCA4, a mutation rare in other common tumors.	('cell carcinoma', 'Disease', (40, 54))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (34, 54))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('SMARCA4', 'Gene', (153, 160))	('carcinoma of the ovary', 'Disease', 'MESH:D010051', (45, 67))	('inactivating', 'NegReg', (106, 118))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('cell carcinoma', 'Disease', 'MESH:C538614', (40, 54))	('mutations', 'Var', (140, 149))	('SMARCA4', 'Gene', '6597', (153, 160))	('tumors', 'Disease', (194, 200))	('carcinoma of the ovary', 'Disease', (45, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
153082	25937998	Loss of RB1 by deletion is a common event in prostatic small cell carcinoma (90, 26/29), but rarely occurs in high-grade acinar tumors (7%, 10/150) and primary acinar carcinomas with neuroendocrine differentiation (11%, 4/35).	('acinar carcinomas', 'Disease', 'MESH:D018267', (160, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('RB1', 'Gene', (8, 11))	('deletion', 'Var', (15, 23))	('acinar tumors', 'Disease', 'MESH:D018267', (121, 134))	('prostatic small', 'Phenotype', 'HP:0008687', (45, 60))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Loss', 'NegReg', (0, 4))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (55, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('acinar carcinomas', 'Disease', (160, 177))	('prostatic small cell carcinoma', 'Disease', 'MESH:D018288', (45, 75))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('acinar tumors', 'Disease', (121, 134))	('prostatic small cell carcinoma', 'Disease', (45, 75))
153083	25937998	General inactivation of the RB1 pathway and deregulation of the cell cycle was a common early event in human cancers, however homozygous deletion of RB1 is a relatively late-stage genomic alteration in acinar prostate cancer progression.	('prostate cancer', 'Phenotype', 'HP:0012125', (209, 224))	('RB1', 'Gene', (149, 152))	('human', 'Species', '9606', (103, 108))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('RB1 pathway', 'Pathway', (28, 39))	('cancers', 'Disease', (109, 116))	('deletion', 'Var', (137, 145))	('inactivation', 'NegReg', (8, 20))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cell cycle', 'biological_process', 'GO:0007049', ('64', '74'))	('acinar prostate cancer', 'Disease', 'MESH:D011471', (202, 224))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('acinar prostate cancer', 'Disease', (202, 224))
153095	24722643	Sparing the prostate apex was potentially associated with a 1.0% risk of leaving significant cancer of the prostate or urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (119, 139))	('cancer of the prostate', 'Disease', 'MESH:D011471', (93, 115))	('apex', 'Gene', (21, 25))	('apex', 'cellular_component', 'GO:0097683', ('21', '25'))	('Sparing', 'Var', (0, 7))	('urothelial carcinoma', 'Disease', (119, 139))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('apex', 'Gene', '328', (21, 25))	('cancer of the prostate', 'Phenotype', 'HP:0012125', (93, 115))	('cancer of the prostate', 'Disease', (93, 115))
153173	24722643	Since the incidence rate of incidental prostate cancer was 6.8% in RCP specimens and the prostate-apex involvement rate was 14.7% (4 apical involvement by incidental prostate cancer and 1 apical involvement by urothelial carcinoma), sparing the prostate apex would be potentially associated with a 1.0% risk of leaving significant cancer of the prostate or urothelial cancer, which was much lower than the estimated risk reported by Gakis et al from a Germany cohort.	('men', 'Species', '9606', (202, 205))	('apex', 'cellular_component', 'GO:0097683', ('98', '102'))	('cancer', 'Phenotype', 'HP:0002664', (368, 374))	('men', 'Species', '9606', (76, 79))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (210, 230))	('urothelial cancer', 'Disease', (357, 374))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('apex', 'Gene', (254, 258))	('sparing', 'Var', (233, 240))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('apex', 'Gene', '328', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('cancer of the prostate', 'Disease', (331, 353))	('men', 'Species', '9606', (110, 113))	('prostate cancer', 'Disease', 'MESH:D011471', (166, 181))	('prostate cancer', 'Phenotype', 'HP:0012125', (166, 181))	('prostate cancer', 'Disease', 'MESH:D011471', (39, 54))	('urothelial carcinoma', 'Disease', (210, 230))	('apex', 'Gene', '328', (254, 258))	('prostate cancer', 'Phenotype', 'HP:0012125', (39, 54))	('prostate cancer', 'Disease', (166, 181))	('cancer of the prostate', 'Disease', 'MESH:D011471', (331, 353))	('apex', 'cellular_component', 'GO:0097683', ('254', '258'))	('prostate cancer', 'Disease', (39, 54))	('urothelial cancer', 'Disease', 'MESH:D014523', (357, 374))	('cancer of the prostate', 'Phenotype', 'HP:0012125', (331, 353))	('apex', 'Gene', (98, 102))	('men', 'Species', '9606', (147, 150))
153183	24722643	Meanwhile, considering the possibility of concomitant invasion of prostate apex by urothelial carcinoma, we believe the inclusion criteria for prostate apex-sparing surgery in Chinese patients should be limited as follows: young age (<60 years) and socially active, normal erectile function, normal DRE, pT2 solitary bladder cancer, no urothelial carcinoma in trigone, in bladder neck or in prostatic urethra and without carcinoma in situ.	('apex', 'Gene', (75, 79))	('neck', 'cellular_component', 'GO:0044326', ('380', '384'))	('carcinoma in situ', 'Disease', 'MESH:D002278', (421, 438))	('normal erectile function', 'Phenotype', 'HP:0000802', (266, 290))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (83, 103))	('apex', 'Gene', (152, 156))	('bladder cancer', 'Disease', 'MESH:D001749', (317, 331))	('bladder cancer', 'Disease', (317, 331))	('pT2', 'Var', (304, 307))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (336, 356))	('bladder cancer', 'Phenotype', 'HP:0009725', (317, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (421, 430))	('apex', 'Gene', '328', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (347, 356))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('apex', 'Gene', '328', (152, 156))	('apex', 'cellular_component', 'GO:0097683', ('152', '156'))	('carcinoma in situ', 'Disease', (421, 438))	('urothelial carcinoma', 'Disease', (83, 103))	('solitary bladder', 'Phenotype', 'HP:0008691', (308, 324))	('patients', 'Species', '9606', (184, 192))	('urothelial carcinoma', 'Disease', (336, 356))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (421, 438))	('apex', 'cellular_component', 'GO:0097683', ('75', '79'))
153205	30999871	Follow-up and analysis of smoking effects, consumption of traditional Chinese medicine containing aristolochic acid, history of bladder cancer, age, sex, presence or absence of diabetes mellitus (DM), metformin use, tumor characteristics (number, location, stage, grade), and open or laparoscopic surgery on the prognosis of UTUCs were performed.	('tumor', 'Disease', (216, 221))	('bladder cancer', 'Disease', 'MESH:D001749', (128, 142))	('bladder cancer', 'Disease', (128, 142))	('absence of diabetes mellitus', 'Disease', 'MESH:D003920', (166, 194))	('DM', 'Disease', 'MESH:D009223', (196, 198))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (177, 194))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('aristolochic', 'Var', (98, 110))	('absence of diabetes mellitus', 'Disease', (166, 194))	('aristolochic acid', 'Chemical', 'MESH:C000228', (98, 115))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('metformin', 'Chemical', 'MESH:D008687', (201, 210))	('absence of diabetes mellitus', 'Phenotype', 'HP:0005978', (166, 194))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
153250	30999871	Eight factors, namely smoking, consumption of Chinese medicine containing aristolochic acid, history of BC, age, tumor stage, tumor grade, tumor size, and LNM, had a significant effect on survival and were identified as prognostic factors (P < 0.05).	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('aristolochic acid', 'Chemical', 'MESH:C000228', (74, 91))	('aristolochic acid', 'Var', (74, 91))	('tumor', 'Disease', (126, 131))
153265	30999871	A significant difference in 5-year survival rate occurred between low tumor staging (T1-T2) and high tumor staging (T3-T4), as well as between different tumor grades (G1-G2 and G3-G4).	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('high tumor', 'Disease', (96, 106))	('low tumor', 'Disease', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('high tumor', 'Disease', 'MESH:D009369', (96, 106))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('G1-G2', 'Var', (167, 172))	('low tumor', 'Disease', 'MESH:D009800', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
153274	30999871	LNM can independently affect tumor recurrence and survival rate; hence, it is an independent risk factor for UTUC prognosis.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('LNM', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('affect', 'Reg', (22, 28))	('tumor', 'Disease', (29, 34))	('survival rate', 'CPA', (50, 63))
153279	30999871	The incidence of urothelial carcinoma in smokers is three times greater than that in nonsmokers, probably owing to a mutation in tumor protein p53, chromosomal changes, immune regulation, etc.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (17, 37))	('p53', 'Gene', '7157', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('regulation', 'biological_process', 'GO:0065007', ('176', '186'))	('urothelial carcinoma', 'Disease', (17, 37))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('mutation', 'Var', (117, 125))	('tumor', 'Disease', (129, 134))	('p53', 'Gene', (143, 146))
153282	30999871	DNA compounds can be formed in vivo under the influence of aristolochic acid, leading to the A-T base-pair proto-oncogene mutation, activation of RAS, and dysfunction of the cancer suppressor gene P53.	('activation', 'PosReg', (132, 142))	('P53', 'Gene', '7157', (197, 200))	('aristolochic acid', 'Chemical', 'MESH:C000228', (59, 76))	('mutation', 'Var', (122, 130))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('dysfunction of the cancer', 'Disease', 'MESH:D009369', (155, 180))	('dysfunction of the cancer', 'Disease', (155, 180))	('RAS', 'Protein', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('P53', 'Gene', (197, 200))
153294	30999871	analyzed the risk factors of BC recurrence after primary UTUC radical resection in 438 cases and found that high-grade ureteral cancer and multiple tumors were high-risk factors of BC recurrence.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('ureteral cancer', 'Disease', (119, 134))	('high-grade', 'Var', (108, 118))	('ureteral cancer', 'Phenotype', 'HP:0100516', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ureteral cancer', 'Disease', 'MESH:D014516', (119, 134))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('multiple tumors', 'Disease', (139, 154))	('multiple tumors', 'Disease', 'MESH:D009369', (139, 154))
153310	30999871	Currently, research has shown that metformin can reduce the risk of cancer by inhibiting the proliferation of tumor cells in vivo and in vitro.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('inhibiting', 'NegReg', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('metformin', 'Var', (35, 44))	('tumor', 'Disease', (110, 115))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('metformin', 'Chemical', 'MESH:D008687', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
153325	30005692	The loss of 5hmC has been identified as a hallmark of most types of cancer and is related to tumorigenesis and progression.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('5hmC', 'Chemical', 'MESH:C011865', (12, 16))	('5hmC', 'Protein', (12, 16))	('related', 'Reg', (82, 89))	('tumor', 'Disease', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('loss', 'Var', (4, 8))
153335	30005692	Alterations in DNA methylation are among the earliest and most common events in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('common', 'Reg', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('DNA methylation', 'Protein', (15, 30))	('Alterations', 'Var', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('tumor', 'Disease', (80, 85))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))
153345	30005692	Loss of 5hmC could be a novel biomarker and treatment target for bladder cancer.	('bladder cancer', 'Disease', (65, 79))	('5hmC', 'Chemical', 'MESH:C011865', (8, 12))	('5hmC', 'Protein', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('bladder cancer', 'Phenotype', 'HP:0009725', (65, 79))	('Loss', 'Var', (0, 4))	('bladder cancer', 'Disease', 'MESH:D001749', (65, 79))
153352	30005692	1e), suggesting that the loss of 5hmC is critical for bladder cancer progression.	('bladder cancer', 'Phenotype', 'HP:0009725', (54, 68))	('loss', 'Var', (25, 29))	('5hmC', 'Chemical', 'MESH:C011865', (33, 37))	('5hmC', 'Protein', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('bladder cancer', 'Disease', 'MESH:D001749', (54, 68))	('bladder cancer', 'Disease', (54, 68))
153378	30005692	In summary, high-dose vitamin C could directly induce growth arrest and apoptosis in bladder cancer cells, unlike low-dose vitamin C, which suppressed cancer cell growth in an H2O2-independent manner that included 5hmC restoration.	('cell growth', 'biological_process', 'GO:0016049', ('158', '169'))	('vitamin C', 'Chemical', 'MESH:D001205', (123, 132))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('5hmC', 'Chemical', 'MESH:C011865', (214, 218))	('growth arrest', 'Phenotype', 'HP:0001510', (54, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('cancer', 'Disease', (151, 157))	('high-dose', 'Var', (12, 21))	('growth arrest', 'Disease', 'MESH:D006323', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('H2O2', 'Chemical', 'MESH:D006861', (176, 180))	('bladder cancer', 'Disease', 'MESH:D001749', (85, 99))	('bladder cancer', 'Disease', (85, 99))	('cancer', 'Disease', (93, 99))	('growth arrest', 'Disease', (54, 67))	('bladder cancer', 'Phenotype', 'HP:0009725', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('apoptosis', 'CPA', (72, 81))	('vitamin C', 'Chemical', 'MESH:D001205', (22, 31))
153411	30005692	Various mechanisms may underlie 5hmC depletion in cancer, such as mutations in TETs and IDHs, which thus decrease the expression of TETs and IDHs.	('mutations', 'Var', (66, 75))	('5hmC', 'Chemical', 'MESH:C011865', (32, 36))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('IDHs', 'Gene', (88, 92))	('TETs', 'Chemical', 'MESH:C010349', (79, 83))	('TETs', 'Chemical', 'MESH:C010349', (132, 136))	('TETs', 'Gene', (132, 136))	('TETs', 'Gene', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('IDHs', 'Gene', (141, 145))	('decrease', 'NegReg', (105, 113))	('expression', 'MPA', (118, 128))
153417	30005692	Other studies recently showed that vitamin C selectively killed KRAS and BRAF mutant colorectal cancer cells by targeting glyceraldehyde-3-phosphate dehydrogenase (GAPDH).	('BRAF', 'Gene', '673', (73, 77))	('GAPDH', 'Gene', '2597', (164, 169))	('GAPDH', 'Gene', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Disease', (85, 102))	('vitamin C', 'Chemical', 'MESH:D001205', (35, 44))	('KRAS', 'Gene', (64, 68))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (122, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('BRAF', 'Gene', (73, 77))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (122, 162))	('mutant', 'Var', (78, 84))	('KRAS', 'Gene', '3845', (64, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
153424	30005692	Vitamin C abrogated cetuximab resistance mediated by mutant KRAS in human colon cancer cells.	('abrogated', 'NegReg', (10, 19))	('colon cancer', 'Phenotype', 'HP:0003003', (74, 86))	('human', 'Species', '9606', (68, 73))	('Vitamin C', 'Chemical', 'MESH:D001205', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('colon cancer', 'Disease', 'MESH:D015179', (74, 86))	('colon cancer', 'Disease', (74, 86))	('KRAS', 'Gene', (60, 64))	('mutant', 'Var', (53, 59))	('KRAS', 'Gene', '3845', (60, 64))	('cetuximab resistance', 'MPA', (20, 40))	('cetuximab', 'Chemical', 'MESH:D000068818', (20, 29))
153427	30005692	Consistent with previous studies, we found that high-dose vitamin C could directly cause selective bladder cancer cell death and apoptosis in an H2O2-dependent manner and that low-dose vitamin C suppressed bladder cancer cell growth in an H2O2-independent manner that included 5hmC restoration.	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('vitamin C suppressed', 'Phenotype', 'HP:0100510', (185, 205))	('cell death', 'biological_process', 'GO:0008219', ('114', '124'))	('vitamin C', 'Chemical', 'MESH:D001205', (185, 194))	('vitamin C', 'Chemical', 'MESH:D001205', (58, 67))	('5hmC', 'Chemical', 'MESH:C011865', (277, 281))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('bladder cancer', 'Disease', 'MESH:D001749', (206, 220))	('bladder cancer', 'Disease', (206, 220))	('apoptosis', 'CPA', (129, 138))	('H2O2', 'Chemical', 'MESH:D006861', (145, 149))	('suppressed', 'NegReg', (195, 205))	('bladder cancer', 'Phenotype', 'HP:0009725', (206, 220))	('bladder cancer cell death', 'Disease', (99, 124))	('cause', 'Reg', (83, 88))	('H2O2', 'Chemical', 'MESH:D006861', (239, 243))	('cell growth', 'biological_process', 'GO:0016049', ('221', '232'))	('bladder cancer cell death', 'Disease', 'MESH:D001749', (99, 124))	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('high-dose', 'Var', (48, 57))
153430	30005692	The mechanisms of how these 5hmC changes alter gene expression and contribute to the decreased malignancy of bladder cancer cells remain unclear and require further examination in the future.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('changes', 'Var', (33, 40))	('decreased malignancy of bladder cancer', 'Disease', (85, 123))	('gene expression', 'MPA', (47, 62))	('gene expression', 'biological_process', 'GO:0010467', ('47', '62'))	('alter', 'Reg', (41, 46))	('5hmC', 'Chemical', 'MESH:C011865', (28, 32))	('decreased malignancy of bladder cancer', 'Disease', 'MESH:D001749', (85, 123))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))
153436	30005692	Our results suggest that the loss of 5hmC is a novel hallmark of bladder cancer with prognostic and outcome significance.	('bladder cancer', 'Disease', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('5hmC', 'Chemical', 'MESH:C011865', (37, 41))	('5hmC', 'Protein', (37, 41))	('bladder cancer', 'Phenotype', 'HP:0009725', (65, 79))	('loss', 'Var', (29, 33))	('bladder cancer', 'Disease', 'MESH:D001749', (65, 79))
153457	30005692	After baking at 80  C for 60 min and being blocked with 5% nonfat milk for 1 h at room temperature, the membrane was incubated in anti-5hmC (Active Motif, 39769) and anti-5mC antibodies (ZYMO RESEARCH, #A3001-200) at 4  C overnight and visualized by chemiluminescence.	('5hmC', 'Chemical', 'MESH:C011865', (135, 139))	('membrane', 'cellular_component', 'GO:0016020', ('104', '112'))	('5mC', 'Chemical', 'MESH:D044503', (171, 174))	('anti-5mC', 'Var', (166, 174))	('anti-5hmC', 'Var', (130, 139))
153470	30005692	After blocking for 1 h with 5% nonfat milk, the membranes were incubated overnight at 4  C with Caspase-3 (Abcam, ab13847), Bcl-2 (Abcam, ab32124), Bcl-xl (Abcam, ab32370), PARP (Abcam, ab191217), and beta-actin (Proteintech, 66009).	('beta-actin', 'Gene', '728378', (201, 211))	('Bcl-xl', 'Gene', (148, 154))	('beta-actin', 'Gene', (201, 211))	('Bcl-2', 'molecular_function', 'GO:0015283', ('124', '129'))	('Bcl-2', 'Gene', (124, 129))	('Caspase-3', 'Gene', (96, 105))	('Bcl-2', 'Gene', '596', (124, 129))	('Caspase-3', 'Gene', '836', (96, 105))	('Bcl-xl', 'Gene', '598', (148, 154))	('PARP', 'Gene', '1302', (173, 177))	('PARP', 'Gene', (173, 177))	('Abcam', 'Var', (179, 184))
153536	33184390	Such alterations would favour both strengthening of TRPV1-dependent afferent limb of micturition reflex and potentiation of local TRPV1-dependent "efferent" functions of bladder afferents, consistent with the promotion of urge incontinence.	('reflex', 'biological_process', 'GO:0060004', ('97', '103'))	('rat', 'Species', '10116', (9, 12))	('TRPV1-dependent', 'Protein', (52, 67))	('micturition', 'biological_process', 'GO:0060073', ('85', '96'))	('potentiation', 'PosReg', (108, 120))	('alterations', 'Var', (5, 16))	('incontinence', 'Disease', (227, 239))	('afferent limb of micturition reflex', 'MPA', (68, 103))	('incontinence', 'Disease', 'MESH:D014549', (227, 239))	('strengthening', 'PosReg', (35, 48))
153546	33184390	5a) GSK1016790A (1 microM) induced two effects: (1) transient enhancement of basal tension (Fig.	('basal', 'MPA', (77, 82))	('GSK1016790A', 'Var', (4, 15))	('men', 'Species', '9606', (69, 72))	('GSK1016790A', 'Chemical', 'MESH:C530602', (4, 15))	('GSK', 'molecular_function', 'GO:0050321', ('4', '7'))	('enhancement', 'PosReg', (62, 73))
153548	33184390	5b) decreased the amplitude of tension enhancement in response to GSK1016790A by about 36% (i.e.	('decreased', 'NegReg', (4, 13))	('amplitude', 'MPA', (18, 27))	('GSK', 'molecular_function', 'GO:0050321', ('66', '69'))	('GSK1016790A', 'Chemical', 'MESH:C530602', (66, 77))	('men', 'Species', '9606', (46, 49))	('tension enhancement', 'MPA', (31, 50))	('GSK1016790A', 'Var', (66, 77))
153549	33184390	5d) and effectively reduced ASC enhancement by GSK1016790A (i.e.	('reduced', 'NegReg', (20, 27))	('ASC', 'Gene', '282817', (28, 31))	('ASC', 'Gene', (28, 31))	('enhancement', 'PosReg', (32, 43))	('men', 'Species', '9606', (39, 42))	('GSK1016790A', 'Var', (47, 58))	('GSK', 'molecular_function', 'GO:0050321', ('47', '50'))	('GSK1016790A', 'Chemical', 'MESH:C530602', (47, 58))
153551	33184390	Exposure of cancer-DSM strips to GSK1016790A (Fig.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('GSK1016790A', 'Var', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('GSK', 'molecular_function', 'GO:0050321', ('33', '36'))	('GSK1016790A', 'Chemical', 'MESH:C530602', (33, 44))
153557	33184390	Figure 6a-d shows that exposure of the control-DSM strip to the non-specific BK-channel inhibitor TEA (3 mM) transiently enhanced basal tension, and strongly increased both ASC and fSC, indicating that BK blockade and associated DSM depolarization brings about global [Ca2+]i rise as well as promotes burst-type electrical activity within the strip, underlying spontaneous contractility, through the increase of the frequency and duration of burst firing.	('fSC', 'MPA', (181, 184))	('depolarization', 'Var', (233, 247))	('global [Ca2+]i', 'MPA', (261, 275))	('basal tension', 'MPA', (130, 143))	('ASC', 'Gene', '282817', (173, 176))	('burst-type electrical activity', 'MPA', (301, 331))	('rise', 'PosReg', (276, 280))	('enhanced', 'PosReg', (121, 129))	('ASC', 'Gene', (173, 176))	('increase', 'PosReg', (400, 408))	('promotes', 'PosReg', (292, 300))	('Ca2+', 'Chemical', 'MESH:D000069285', (269, 273))	('rat', 'Species', '10116', (432, 435))	('burst firing', 'MPA', (442, 454))	('blockade', 'Var', (205, 213))	('increased', 'PosReg', (158, 167))
153569	33184390	ACh and ATP) release and/or clearance, and (3) aberrant mAChR- and P2X-mediated signalling in DSM due to decreased expression of respective receptors or downregulation of signalling pathway(s) linked to their activation.	('aberrant', 'Var', (47, 55))	('clearance', 'CPA', (28, 37))	('ACh', 'Chemical', 'MESH:D000109', (0, 3))	('signalling pathway', 'biological_process', 'GO:0007165', ('171', '189'))	('signalling pathway', 'Pathway', (171, 189))	('expression', 'MPA', (115, 125))	('signalling', 'biological_process', 'GO:0023052', ('80', '90'))	('ATP', 'Chemical', 'MESH:D000255', (8, 11))	('receptors', 'Protein', (140, 149))	('DSM', 'Disease', (94, 97))	('decreased', 'NegReg', (105, 114))	('downregulation', 'NegReg', (153, 167))	('ACh', 'Chemical', 'MESH:D000109', (57, 60))
153574	33184390	In the event of bladder cancer-promoted neuronal TRPV1 expression one would also expect strengthening of TRPV1-dependent afferent limb of micturition reflex.	('neuronal', 'Var', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('strengthening', 'PosReg', (88, 101))	('bladder cancer', 'Disease', 'MESH:D001749', (16, 30))	('bladder cancer', 'Disease', (16, 30))	('reflex', 'biological_process', 'GO:0060004', ('150', '156'))	('micturition', 'biological_process', 'GO:0060073', ('138', '149'))	('expression', 'MPA', (55, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (16, 30))	('TRPV1', 'Gene', (49, 54))
153575	33184390	Altogether, such alterations would favour decreased micturition threshold, increased perception of pain and increased local DSM contractility in response to irritants in bladder cancer, which would be generally consistent with the promotion of urge incontinence.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('decreased', 'NegReg', (42, 51))	('pain', 'Phenotype', 'HP:0012531', (99, 103))	('incontinence', 'Disease', (249, 261))	('incontinence', 'Disease', 'MESH:D014549', (249, 261))	('irritants in bladder', 'Phenotype', 'HP:0000737', (157, 177))	('increased', 'PosReg', (108, 117))	('rat', 'Species', '10116', (21, 24))	('increased', 'PosReg', (75, 84))	('pain', 'Disease', 'MESH:D010146', (99, 103))	('alterations', 'Var', (17, 28))	('micturition threshold', 'MPA', (52, 73))	('local DSM contractility', 'MPA', (118, 141))	('micturition', 'biological_process', 'GO:0060073', ('52', '63'))	('bladder cancer', 'Disease', 'MESH:D001749', (170, 184))	('bladder cancer', 'Disease', (170, 184))	('response to irritants', 'MPA', (145, 166))	('bladder cancer', 'Phenotype', 'HP:0009725', (170, 184))	('pain', 'Disease', (99, 103))
153584	33184390	Intravesical instillation of TRPV4 specific agonist, GSK1016790A, was shown to increase firing of mechanosensitive, CAP-insensitive bladder afferents in rats and to promote bladder overactivity in mice and rats.	('increase', 'PosReg', (79, 87))	('CAP', 'Gene', (116, 119))	('bladder overactivity', 'CPA', (173, 193))	('TRPV4', 'Gene', (29, 34))	('GSK1016790A', 'Var', (53, 64))	('rats', 'Species', '10116', (206, 210))	('bladder overactivity', 'Phenotype', 'HP:0000020', (173, 193))	('GSK', 'molecular_function', 'GO:0050321', ('53', '56'))	('promote', 'PosReg', (165, 172))	('rats', 'Species', '10116', (153, 157))	('GSK1016790A', 'Chemical', 'MESH:C530602', (53, 64))	('mice', 'Species', '10090', (197, 201))	('firing', 'MPA', (88, 94))	('CAP', 'Gene', '686098', (116, 119))
153587	33184390	In our experiments on normal DSM, GSK1016790A caused transient enhancement of basal tension and increased ASC.	('GSK1016790A', 'Chemical', 'MESH:C530602', (34, 45))	('increased', 'PosReg', (96, 105))	('basal tension', 'CPA', (78, 91))	('enhancement', 'PosReg', (63, 74))	('ASC', 'Gene', (106, 109))	('men', 'Species', '9606', (70, 73))	('GSK', 'molecular_function', 'GO:0050321', ('34', '37'))	('GSK1016790A', 'Var', (34, 45))	('men', 'Species', '9606', (13, 16))	('ASC', 'Gene', '282817', (106, 109))
153589	33184390	BBN-induced bladder cancer in rat did not affect the magnitude of GSK1016790A-evoked tension, but reduced the extent of ASC augmentation by GSK1016790A.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('ASC', 'Gene', (120, 123))	('GSK1016790A', 'Chemical', 'MESH:C530602', (140, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (12, 26))	('bladder cancer', 'Disease', (12, 26))	('GSK', 'molecular_function', 'GO:0050321', ('66', '69'))	('GSK1016790A-evoked', 'Var', (66, 84))	('GSK1016790A', 'Chemical', 'MESH:C530602', (66, 77))	('BBN', 'Chemical', 'MESH:D002085', (0, 3))	('rat', 'Species', '10116', (30, 33))	('GSK', 'molecular_function', 'GO:0050321', ('140', '143'))	('GSK1016790A', 'Var', (140, 151))	('reduced', 'NegReg', (98, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (12, 26))	('men', 'Species', '9606', (127, 130))	('ASC', 'Gene', '282817', (120, 123))
153592	33184390	The results of functional studies using GSK1016790A are also divergent: GSK1016790A was reported to induce contraction and ASC increased as well as relaxation and ASC decrease of urothelium-devoid mouse DSM strips.	('GSK1016790A', 'Chemical', 'MESH:C530602', (40, 51))	('urothelium-devoid', 'CPA', (179, 196))	('GSK1016790A', 'Var', (72, 83))	('contraction', 'CPA', (107, 118))	('ASC', 'Gene', '282817', (163, 166))	('GSK', 'molecular_function', 'GO:0050321', ('40', '43'))	('ASC', 'Gene', (163, 166))	('decrease', 'NegReg', (167, 175))	('GSK1016790A', 'Chemical', 'MESH:C530602', (72, 83))	('induce', 'PosReg', (100, 106))	('mouse', 'Species', '10090', (197, 202))	('ASC', 'Gene', '282817', (123, 126))	('relaxation', 'CPA', (148, 158))	('GSK', 'molecular_function', 'GO:0050321', ('72', '75'))	('ASC', 'Gene', (123, 126))	('increased', 'PosReg', (127, 136))
153593	33184390	In guinea-pig bladder TRPV4 was detected in DSM and muscularis mucosae (smooth muscle layer between urothelium and DSM) with GSK1016790A producing sustained contraction and not enhancement, but cessation of spontaneous activity in both tissue types.	('spontaneous activity', 'MPA', (207, 227))	('TRPV4', 'Protein', (22, 27))	('GSK1016790A', 'Var', (125, 136))	('GSK', 'molecular_function', 'GO:0050321', ('125', '128'))	('men', 'Species', '9606', (184, 187))	('GSK1016790A', 'Chemical', 'MESH:C530602', (125, 136))	('cessation', 'NegReg', (194, 203))	('guinea-pig', 'Species', '10141', (3, 13))
153634	31996725	PD-L1 expression in the tumor microenvironment significantly correlated with presence of CD3, CD8 and chronic inflammation.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('inflammation', 'Disease', (110, 122))	('CD3', 'Gene', '12501', (89, 92))	('tumor', 'Disease', (24, 29))	('expression', 'MPA', (6, 16))	('PD-L1', 'Gene', (0, 5))	('correlated', 'Reg', (61, 71))	('CD8', 'Gene', (94, 97))	('presence', 'Var', (77, 85))	('CD8', 'Gene', '925', (94, 97))	('inflammation', 'biological_process', 'GO:0006954', ('110', '122'))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('PD-L1', 'Gene', '29126', (0, 5))	('inflammation', 'Disease', 'MESH:D007249', (110, 122))	('CD3', 'Gene', (89, 92))
153640	31996725	At present, there are five Food and Drug Administration (FDA) approved PD1/PD-L1 inhibitors for advanced urothelial carcinoma (atezolizumab, pembrolizumab, nivolumab, durvalumab, and avelumab).	('urothelial carcinoma', 'Disease', (105, 125))	('inhibitors', 'Var', (81, 91))	('PD-L1', 'Gene', (75, 80))	('PD-L1', 'Gene', '29126', (75, 80))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (105, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))
153665	31996725	Invasive UC is significantly associated with the immune high cluster (Fig.	('immune', 'Var', (49, 55))	('UC', 'Disease', 'MESH:D014523', (9, 11))	('associated', 'Reg', (29, 39))
153667	31996725	Within the invasive UC variants, squamous and sarcomatoid histologies tended to be immune high compared to the other variants, but this was not statistically significant by Chi-square test (Supplementary Fig.	('variants', 'Var', (23, 31))	('UC', 'Disease', 'MESH:D014523', (20, 22))	('sarcomatoid', 'Disease', (46, 57))	('sarcomatoid', 'Disease', 'MESH:D002292', (46, 57))
153702	31996725	The behind mechanisms, for example, whether this molecular subtype is closely related the group of tumors with high tumor mutational burden or its decreased cell adhesion and lack of tissue organization along the tumor-stroma interface, etc, remain unclear and need more studies.	('cell adhesion', 'CPA', (157, 170))	('tumor', 'Disease', (213, 218))	('lack', 'NegReg', (175, 179))	('tumor', 'Disease', (99, 104))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('cell adhesion', 'biological_process', 'GO:0007155', ('157', '170'))	('decreased', 'NegReg', (147, 156))	('mutational burden', 'Var', (122, 139))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (116, 121))	('tumors', 'Disease', (99, 105))
153716	31996725	Primary antibodies for PD1 (Ventana #760-4895) and PD-L1 (Ventana #740-4859) were used after optimization with serial titrations.	('PD-L1', 'Gene', '29126', (51, 56))	('Ventana #760-4895', 'Var', (28, 45))	('Ventana #740-4859', 'Var', (58, 75))	('PD1', 'Gene', (23, 26))	('PD-L1', 'Gene', (51, 56))
153718	31996725	Amplification kit (anti-rabbit HQ (Ventana #760-4815, 8 minutes), anti HQ HRP (Ventana #760-4820, 8 minutes), Disc Amp kit (Ventana, #760-052) and Disc anti-HQ HRP (Ventana, #760-4602)) was used for PD-L1 detection.	('Ventana #760-4820', 'Var', (79, 96))	('PD-L1', 'Gene', (199, 204))	('PD-L1', 'Gene', '29126', (199, 204))	('Ventana #760-4815', 'Var', (35, 52))
153733	30701024	Pan-cancer analysis of intratumor heterogeneity associated with patient prognosis using multidimensional measures Human cancers accumulate various mutations during development and consist of highly heterogeneous cell populations.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (147, 156))	('patient', 'Species', '9606', (64, 71))	('Pan-cancer', 'Disease', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('cancers', 'Disease', (120, 127))	('Human', 'Species', '9606', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
153741	30701024	Cancer is indicated via dysregulated cell growth, proliferation, and cell cycle progression.	('dysregulated', 'Var', (24, 36))	('cell cycle progression', 'CPA', (69, 91))	('cell growth', 'CPA', (37, 48))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cell cycle', 'biological_process', 'GO:0007049', ('69', '79'))	('cell growth', 'biological_process', 'GO:0016049', ('37', '48'))
153742	30701024	Cancer cells often consist of heterogeneous populations with various mutations rather than composed of homogeneous populations.	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (69, 78))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
153743	30701024	Previous studies demonstrated that cancer develops from mutations in certain driver genes and eventually accumulates various genetic mutations through cell growth, leading to intratumor heterogeneity (ITH).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (180, 185))	('leading to', 'Reg', (164, 174))	('mutations', 'Var', (133, 142))	('cell growth', 'biological_process', 'GO:0016049', ('151', '162'))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
153747	30701024	VAFs are able to estimate the fraction of tumor populations containing mutations in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Disease', (42, 47))	('cancer', 'Disease', (84, 90))	('mutations', 'Var', (71, 80))	('VAF', 'Chemical', '-', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
153750	30701024	Moreover, mutant-allele tumor heterogeneity (MATH) scores represent the variance of VAFs, and the entropy-based mutation allele fraction (EMAF) represents uncertainty of somatic mutation patterns.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutant-allele', 'Var', (10, 23))	('VAF', 'Chemical', '-', (84, 87))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
153759	30701024	Since correlation coefficients were -0.44, 0.03, and 0.00, which were observed between m_Peaks vs. m_MATH, m_Peak vs. m_Count, and m_Count vs. m_MATH, respectively, we considered the parameters could be used as independent variables representing the characteristics of VAF distributions.	('VAF', 'Chemical', '-', (269, 272))	('m_Peak', 'Var', (107, 113))	('m_Peaks', 'Var', (87, 94))
153765	30701024	We drew histograms of VAFs assembled from all mutations in samples belonging to each cluster and created trunk-branch models of mutations in tumors (Figure 2A).	('trunk', 'cellular_component', 'GO:0043198', ('105', '110'))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('trunk-branch', 'Disease', (105, 117))	('trunk-branch', 'Disease', 'MESH:D016750', (105, 117))	('VAF', 'Chemical', '-', (22, 25))
153767	30701024	Since the VAF distributions showed that samples in cluster 1 had more MF mutations with higher VAF than lower VAF, while the samples in cluster 2 had more MF mutations with lower VAF than higher VAF, they were predicted to have accumulated clonal mutations in cluster 1 and subclonal mutations in cluster 2, respectively.	('VAF', 'Chemical', '-', (95, 98))	('VAF', 'Chemical', '-', (10, 13))	('VAF', 'Chemical', '-', (195, 198))	('VAF', 'Chemical', '-', (179, 182))	('lower', 'NegReg', (173, 178))	('VAF', 'Chemical', '-', (110, 113))	('mutations', 'Var', (73, 82))
153768	30701024	This observation was consistent with a recent study by McGranahan and colleagues, which indicated that, in some cancer types, including melanoma and lung cancer, mutations accumulated prior to carcinogenesis.	('mutations', 'Var', (162, 171))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('carcinogenesis', 'Disease', (193, 207))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (193, 207))	('melanoma and lung cancer', 'Disease', 'MESH:D008175', (136, 160))
153771	30701024	This trend can be interpreted as MF mutations occurring in the early stages of cancer development and maintained through cancer progression, without further accumulating a large number of MF mutations among samples in cluster 3.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
153772	30701024	In cluster 4, expansion of some subclones with certain MF mutations might occur during cancer progression under strong positive selection.	('cancer', 'Disease', (87, 93))	('mutations', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
153773	30701024	In contrast, samples in cluster 5 had MF mutations that possibly occurred under neutral cancer evolution.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
153774	30701024	To evaluate the clusters' genetic characteristics, we calculated MF mutation frequencies of each gene for 16 cancer types and examined the 10 genes with the highest frequency of mutations in each cluster (Supplementary Figure 2).	('mutation', 'Var', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))
153775	30701024	In BRCA, the frequencies of MF mutation in PIK3CA in clusters 3, 4, and 5 (35.5%, 40.5%, and 32.5%, respectively), in which the m_Count was small, were relatively high.	('PIK3CA', 'Gene', '5290', (43, 49))	('BRCA', 'Gene', '672', (3, 7))	('BRCA', 'Gene', (3, 7))	('mutation', 'Var', (31, 39))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))	('PIK3CA', 'Gene', (43, 49))
153776	30701024	Once mutations in PIK3CA occurred, without a striking increase in the number of other mutations, cells may remain genetically stable.	('PIK3CA', 'Gene', (18, 24))	('PIK3CA', 'Gene', '5290', (18, 24))	('mutations', 'Var', (5, 14))
153778	30701024	This result suggests that liver cancer cells with mutations in the driver gene CTNNB1, which have been generated in the earlier stage of cancer development, occupied in the cancer cell population.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('CTNNB1', 'Gene', '1499', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (173, 179))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (32, 38))	('liver cancer', 'Disease', (26, 38))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CTNNB1', 'Gene', (79, 85))	('liver cancer', 'Phenotype', 'HP:0002896', (26, 38))	('liver cancer', 'Disease', 'MESH:D006528', (26, 38))
153781	30701024	In our study, the samples in cluster 2 was predicted to have the highest ITH level due to a large number of mutations with lower VAF.	('VAF', 'Chemical', '-', (129, 132))	('ITH level', 'MPA', (73, 82))	('lower', 'NegReg', (123, 128))	('mutations', 'Var', (108, 117))
153783	30701024	In melanoma, the frequency of C>T transitions decreases, and the frequency of T>G transversions increases among branch mutations compared to trunk mutations.	('T>G transversions', 'Var', (78, 95))	('increases', 'PosReg', (96, 105))	('C>T transitions', 'Var', (30, 45))	('trunk', 'cellular_component', 'GO:0043198', ('141', '146'))	('decreases', 'NegReg', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
153784	30701024	Therefore, most mutations in samples with fewer mutations were proposed to occur in later, rather than earlier, stages of cancer development.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
153788	30701024	As mentioned above, samples in clusters 1 and 2 supposedly accumulated a large number of MF mutations during cancer development.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (109, 115))	('mutations', 'Var', (92, 101))
153807	30701024	This suggested more mutations are associated with worse prognosis in these cancer types.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (75, 81))	('mutations', 'Var', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
153808	30701024	Cancer cells occupied by a lower number of mutations occurring early in cancer development might be associated with worse prognosis in BLCA and UCEC.	('cancer', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('UCEC', 'Disease', (144, 148))	('mutations', 'Var', (43, 52))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('BLCA', 'Disease', (135, 139))
153809	30701024	Thus, samples were associated with poor prognosis when fewer mutations occurred at carcinogenesis and survived during cancer development.	('cancer', 'Disease', (118, 124))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('carcinogenesis', 'Disease', (83, 97))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
153810	30701024	Since frequencies of MF mutations in IDH1, which is one of the driver genes in LGG, were higher among samples in clusters 3, 4, and 5 (69.5%, 54.5%, and 59.5%, respectively), it was expected that other factors that increase the number of mutations from the early to mid-stage of cancer development may affect patient prognosis.	('affect', 'Reg', (302, 308))	('patient prognosis', 'CPA', (309, 326))	('IDH1', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('patient', 'Species', '9606', (309, 316))	('higher', 'PosReg', (89, 95))	('IDH1', 'Gene', '3417', (37, 41))	('mutations', 'Var', (24, 33))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))
153823	30701024	Previous studies have shown that melanoma is a highly malignant cancer and harbors various mutations in the early stages of cancer development.	('cancer', 'Disease', (124, 130))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
153825	30701024	Our results consistently showed that most samples have a large number of mutations accumulated prior to carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (104, 118))	('carcinogenesis', 'Disease', (104, 118))	('mutations', 'Var', (73, 82))
153826	30701024	Taking the mutation spectrum into consideration, most mutations in the samples with fewer mutations were considered to occur in the later rather than earlier stages of cancer development.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))
153828	30701024	From these results, we proposed the following hypothesis of the genetic evolution of melanoma: melanoma is generated by a large number of genetic mutations, including those in BRAF (clusters 1 and 2), and only those cells with certain mutations are selected under selective pressure.	('mutations', 'Var', (146, 155))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('generated by', 'Reg', (107, 119))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('BRAF', 'Gene', '673', (176, 180))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('BRAF', 'Gene', (176, 180))
153830	30701024	Other mutated genes may be involved in evolutionary process of melanoma because of the low frequency of driver gene mutations in samples with few mutations.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('involved', 'Reg', (27, 35))	('mutations', 'Var', (116, 125))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
153833	30701024	Previous studies showed that high TMB in NSCLC was associated with worse prognosis.	('NSCLC', 'Disease', (41, 46))	('TMB', 'Chemical', '-', (34, 37))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('high TMB', 'Var', (29, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))
153834	30701024	In LUAD, the mutations partially attributable to smoking may gradually accumulate in cells during cancer progression, leading to more aggressive cancer cells.	('cancer', 'Disease', (145, 151))	('more', 'PosReg', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('leading to', 'Reg', (118, 128))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('aggressive cancer', 'Disease', 'MESH:D009369', (134, 151))	('cancer', 'Disease', (98, 104))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('aggressive cancer', 'Disease', (134, 151))
153835	30701024	Conversely, in LUSC, once mutations are occupied in cancer cells under selective pressure (cluster 4), those samples were predicted to have a worse prognosis than cancer cells with a large number of clonal mutations (cluster 1).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('LUSC', 'Phenotype', 'HP:0030359', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
153840	30701024	In this study, we analyzed 16 cancer types using only single nucleotide substitutions in genes.	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('single nucleotide substitutions', 'Var', (54, 85))
153846	30701024	The MF mutations of amino acid substitution may have an impact on protein structures and/or functions, suggesting their possible involvement in cancer development or progression.	('mutations of amino acid substitution', 'Var', (7, 43))	('protein', 'Protein', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('involvement', 'Reg', (129, 140))	('cancer', 'Disease', (144, 150))	('functions', 'MPA', (92, 101))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('impact', 'Reg', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
153901	30349834	GATA-3 is a zinc-finger transcription factor that binds the DNA consensus sequence G-A-T-A.	('GATA-3', 'Gene', '2625', (0, 6))	('GATA-3', 'Gene', (0, 6))	('transcription factor', 'molecular_function', 'GO:0000981', ('24', '44'))	('G-A-T-A', 'Var', (83, 90))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('transcription', 'biological_process', 'GO:0006351', ('24', '37'))
153962	27379325	All tumours exhibited chromosomal alterations similar to those commonly found in urothelial carcinoma in Urovysion fluorescence in situ hybridization (FISH) assays.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (81, 101))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('chromosomal alterations', 'Var', (22, 45))	('exhibited', 'Reg', (12, 21))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('urothelial carcinoma', 'Disease', (81, 101))	('tumours', 'Disease', (4, 11))
153964	27379325	integrated molecular genetic evaluation by means of fluorescent in situ hybridization (FISH) and X-chromosome inactivation with conventional morphologic and immunohistochemical analysis in 12 patients who had clear cell adenocarcinomas in their urinary tract.	('X-chromosome', 'cellular_component', 'GO:0000805', ('97', '109'))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('patients', 'Species', '9606', (192, 200))	('X-chromosome inactivation', 'Var', (97, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (225, 235))	('X-chromosome inactivation', 'biological_process', 'GO:0009048', ('97', '122'))	('clear cell adenocarcinomas', 'Disease', 'MESH:D008649', (209, 235))	('clear cell adenocarcinomas', 'Disease', (209, 235))
154008	27379325	In Urovysion fluorescence in situ hybridization assays, all the tumours displayed chromosomal alterations similar to those commonly found in urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('urothelial carcinoma', 'Disease', (141, 161))	('displayed', 'Reg', (72, 81))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('chromosomal', 'Var', (82, 93))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (141, 161))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
154010	27379325	integrated molecular genetic evaluation by fluorescence in situ hybridization (FISH) and X-chromosome inactivation with conventional morphologic and immunohistochemical analyses in 12 patients, with clear cell adenocarcinomas in the urinary tract.	('patients', 'Species', '9606', (184, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('X-chromosome', 'Var', (89, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (215, 225))	('X-chromosome', 'cellular_component', 'GO:0000805', ('89', '101'))	('X-chromosome inactivation', 'biological_process', 'GO:0009048', ('89', '114'))	('clear cell adenocarcinomas', 'Disease', (199, 225))	('clear cell adenocarcinomas', 'Disease', 'MESH:D008649', (199, 225))
154014	27379325	The muscle layer of the bladder was invaded by tumour cells (T2aN0M0).	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('T2aN0M0', 'Var', (61, 68))	('tumour', 'Disease', (47, 53))
154119	24132290	Mutational landscape and significance across 12 major cancer types The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours.	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('Cancer Genome Atlas', 'Disease', (71, 90))	('TC', 'Chemical', 'MESH:D013667', (92, 94))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (71, 90))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('cancer', 'Disease', (54, 60))	('variants', 'Var', (170, 178))	('CG', 'Chemical', 'MESH:C028505', (93, 95))	('tumours', 'Disease', 'MESH:D009369', (199, 206))	('tumours', 'Disease', (199, 206))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
154120	24132290	Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort.	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('tumour type', 'Disease', (124, 135))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('Cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumours', 'Disease', 'MESH:D009369', (106, 113))	('CG', 'Chemical', 'MESH:C028505', (153, 155))	('tumours', 'Disease', (106, 113))	('point mutations', 'Var', (48, 63))	('small insertions/deletions', 'Var', (68, 94))	('tumour type', 'Disease', 'MESH:D009369', (124, 135))	('TC', 'Chemical', 'MESH:D013667', (152, 154))
154124	24132290	Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types.	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
154131	24132290	We determined interactions among mutations and correlated mutations in BAP1, FBXW7 and TP53 with detrimental phenotypes across several cancer types.	('FBXW7', 'Gene', '55294', (77, 82))	('mutations', 'Var', (58, 67))	('cancer', 'Disease', (135, 141))	('TP53', 'Gene', '7157', (87, 91))	('FBXW7', 'Gene', (77, 82))	('interactions', 'Interaction', (14, 26))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('BAP1', 'Gene', '8314', (71, 75))	('BAP1', 'Gene', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
154132	24132290	The subclonal structure and transcription status of underlying somatic mutations reveal the trajectory of tumour progression in patients with cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('transcription', 'biological_process', 'GO:0006351', ('28', '41'))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutations', 'Var', (71, 80))	('tumour', 'Disease', (106, 112))	('patients', 'Species', '9606', (128, 136))	('reveal', 'Reg', (81, 87))	('cancer', 'Disease', (142, 148))
154139	24132290	Indeed, there is a significant correlation between high mutation frequency and DNA repair pathway genes (for example, PRKDC, TP53 and MSH6) (Supplementary Table 3c).	('MSH6', 'Gene', '2956', (134, 138))	('TP53', 'Gene', '7157', (125, 129))	('DNA', 'Gene', (79, 82))	('high mutation frequency', 'Var', (51, 74))	('PRKDC', 'Gene', '5591', (118, 123))	('TP53', 'Gene', (125, 129))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('PRKDC', 'Gene', (118, 123))	('MSH6', 'Gene', (134, 138))	('DNA repair', 'biological_process', 'GO:0006281', ('79', '89'))
154140	24132290	Notably, PRKDC mutations are associated with high frequency in BLCA, COAD/READ, LUAD and UCEC, whereas TP53 mutations are related with higher frequencies in AML, BLCA, BRCA, HNSC, LUAD, LUSC and UCEC (all P < 0.05).	('PRKDC', 'Gene', '5591', (9, 14))	('BRCA', 'Gene', (168, 172))	('PRKDC', 'Gene', (9, 14))	('COAD', 'Disease', 'MESH:D029424', (69, 73))	('TP53', 'Gene', '7157', (103, 107))	('mutations', 'Var', (15, 24))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('UCEC', 'Disease', (195, 199))	('BLCA', 'Disease', (162, 166))	('BRCA', 'Phenotype', 'HP:0003002', (168, 172))	('COAD', 'Disease', (69, 73))	('LUAD', 'Disease', (80, 84))	('LUSC', 'Disease', (186, 190))	('AML', 'Disease', 'MESH:D015470', (157, 160))	('LUAD', 'Phenotype', 'HP:0030078', (180, 184))	('AML', 'Disease', (157, 160))	('HNSC', 'Disease', (174, 178))	('BRCA', 'Gene', '672', (168, 172))	('LUSC', 'Phenotype', 'HP:0030359', (186, 190))	('TP53', 'Gene', (103, 107))	('LUAD', 'Disease', (180, 184))	('BLCA', 'Disease', (63, 67))	('UCEC', 'Disease', (89, 93))	('HNSC', 'Phenotype', 'HP:0012288', (174, 178))
154141	24132290	Mutations in POLQ and POLE associate with highfrequencies in multiple cancer types; POLE association in UCEC is consistent with previous observations.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Mutations', 'Var', (0, 9))	('UCEC', 'Disease', (104, 108))	('POLQ', 'Gene', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))	('POLQ', 'Gene', '10721', (13, 17))
154142	24132290	The frequency of thymine 1-bp (base pair) upstream of C>G transversions is markedly higher in BLCA, BRCA and HNSC than in other cancer types (Extended Data Fig.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('BLCA', 'Disease', (94, 98))	('BRCA', 'Gene', '672', (100, 104))	('HNSC', 'Phenotype', 'HP:0012288', (109, 113))	('thymine', 'Var', (17, 24))	('C>G transversions', 'Var', (54, 71))	('BRCA', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('HNSC', 'Disease', (109, 113))	('BRCA', 'Phenotype', 'HP:0003002', (100, 104))	('higher', 'PosReg', (84, 90))	('cancer', 'Disease', (128, 134))
154143	24132290	GBM, AML, COAD/READ and UCEC have similar contexts in that the proportions of guanine 1 base downstream of C>T transitions are between 59% and 67%, substantially higher than the approximately 40% in other cancer types.	('C>T transitions', 'Var', (107, 122))	('higher', 'PosReg', (162, 168))	('AML', 'Disease', 'MESH:D015470', (5, 8))	('COAD', 'Disease', (10, 14))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (205, 211))	('guanine 1 base', 'MPA', (78, 92))	('AML', 'Disease', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('guanine', 'Chemical', 'MESH:D006147', (78, 85))	('COAD', 'Disease', 'MESH:D029424', (10, 14))
154144	24132290	Higher frequencies of transition mutations at CpG in gastrointestinal tumours, including colorectal, were previously reported.	('gastrointestinal tumours', 'Disease', 'MESH:D004067', (53, 77))	('CpG', 'Gene', (46, 49))	('gastrointestinal tumours', 'Disease', (53, 77))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('colorectal', 'Disease', (89, 99))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('transition mutations', 'Var', (22, 42))
154145	24132290	We found three additional cancer types (GBM, AML and UCEC) clustered in the C>T mutation at CpG, consistent with previous findings of aberrant DNA methylation in endometrial cancer and glioblastoma.	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('endometrial cancer', 'Disease', (162, 180))	('additional cancer', 'Disease', 'MESH:D009369', (15, 32))	('DNA methylation', 'biological_process', 'GO:0006306', ('143', '158'))	('glioblastoma', 'Disease', (185, 197))	('endometrial cancer', 'Phenotype', 'HP:0012114', (162, 180))	('glioblastoma', 'Disease', 'MESH:D005909', (185, 197))	('endometrial cancer', 'Disease', 'MESH:D016889', (162, 180))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('AML', 'Disease', 'MESH:D015470', (45, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (185, 197))	('additional cancer', 'Disease', (15, 32))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('C>T mutation', 'Var', (76, 88))	('AML', 'Disease', (45, 48))
154153	24132290	Notably, 3,053 out of 3,281 total samples (93%) across the Pan-Cancer collection had at least one non-synonymous mutation in at least one SMG.	('SMG', 'Gene', '23034', (138, 141))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('non-synonymous mutation', 'Var', (98, 121))	('SMG', 'Gene', (138, 141))
154154	24132290	The average number of point mutations and small indels in these genes varies across tumour types, with the highest (~6 mutations per tumour) in UCEC, LUAD and LUSC, and the lowest (~2 mutations per tumour) in AML, BRCA, KIRC and OV.	('tumour', 'Disease', (84, 90))	('point mutations', 'Var', (22, 37))	('tumour type', 'Disease', (84, 95))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('tumour', 'Disease', (133, 139))	('BRCA', 'Gene', (214, 218))	('LUSC', 'Phenotype', 'HP:0030359', (159, 163))	('LUAD', 'Phenotype', 'HP:0030078', (150, 154))	('BRCA', 'Phenotype', 'HP:0003002', (214, 218))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('tumour', 'Disease', 'MESH:D009369', (198, 204))	('tumour', 'Disease', (198, 204))	('tumour type', 'Disease', 'MESH:D009369', (84, 95))	('AML', 'Disease', 'MESH:D015470', (209, 212))	('BRCA', 'Gene', '672', (214, 218))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('AML', 'Disease', (209, 212))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
154157	24132290	Its mutations predominate in serous ovarian (95%) and serous endometrial carcinomas (89%) (Fig.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (61, 82))	('serous endometrial carcinomas', 'Phenotype', 'HP:0012887', (54, 83))	('serous endometrial carcinomas', 'Disease', 'MESH:D016889', (54, 83))	('serous ovarian', 'Disease', 'MESH:D010051', (29, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('serous ovarian', 'Disease', (29, 43))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (61, 83))	('mutations', 'Var', (4, 13))	('serous endometrial carcinomas', 'Disease', (54, 83))
154158	24132290	TP53 mutations are also associated with basal subtype breast tumours.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('associated', 'Reg', (24, 34))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('mutations', 'Var', (5, 14))	('basal subtype breast tumours', 'Disease', 'MESH:D001943', (40, 68))	('basal subtype breast tumours', 'Disease', (40, 68))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
154160	24132290	PIK3CA mutations frequented UCEC (52%) and BRCA (33.6%), being specifically enriched in luminal subtype tumours.	('luminal subtype tumours', 'Disease', 'MESH:C535673', (88, 111))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('PIK3CA', 'Gene', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('PIK3CA', 'Gene', '5290', (0, 6))	('BRCA', 'Phenotype', 'HP:0003002', (43, 47))	('BRCA', 'Gene', '672', (43, 47))	('luminal subtype tumours', 'Disease', (88, 111))	('BRCA', 'Gene', (43, 47))	('mutations', 'Var', (7, 16))
154161	24132290	Tumours lacking PIK3CA mutations often had mutations in PIK3R1, with the highest occurrences in UCEC (31%) and GBM (11%) (Fig.	('PIK3CA', 'Gene', '5290', (16, 22))	('PIK3R1', 'Gene', '5295', (56, 62))	('GBM', 'Disease', (111, 114))	('PIK3R1', 'Gene', (56, 62))	('mutations', 'Var', (43, 52))	('occurrences', 'Reg', (81, 92))	('UCEC', 'Disease', (96, 100))	('PIK3CA', 'Gene', (16, 22))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
154162	24132290	Many cancer types carried mutations in chromatin re-modelling genes.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('carried', 'Reg', (18, 25))	('chromatin', 'cellular_component', 'GO:0000785', ('39', '48'))	('cancer', 'Disease', (5, 11))	('mutations', 'Var', (26, 35))	('chromatin re-modelling genes', 'Gene', (39, 67))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
154164	24132290	Mutations in ARID1A are frequent in BLCA, UCEC, LUAD and LUSC, whereas mutations in ARID5B predominate in UCEC (10%) (Fig.	('ARID5B', 'Gene', '84159', (84, 90))	('BLCA', 'Disease', (36, 40))	('ARID1A', 'Gene', '8289', (13, 19))	('LUAD', 'Phenotype', 'HP:0030078', (48, 52))	('ARID1A', 'Gene', (13, 19))	('LUAD', 'Disease', (48, 52))	('Mutations', 'Var', (0, 9))	('LUSC', 'Disease', (57, 61))	('LUSC', 'Phenotype', 'HP:0030359', (57, 61))	('UCEC', 'Disease', (42, 46))	('frequent', 'Reg', (24, 32))	('ARID5B', 'Gene', (84, 90))
154166	24132290	EGFR mutations are frequent in GBM (27%) and LUAD (11%).	('LUAD', 'Phenotype', 'HP:0030078', (45, 49))	('LUAD', 'Disease', (45, 49))	('EGFR', 'Gene', (0, 4))	('frequent', 'Reg', (19, 27))	('GBM', 'Disease', (31, 34))	('mutations', 'Var', (5, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))
154167	24132290	Recurrent, gain-of-function mutations in IDH1 (Arg 132) and/or IDH2 (Arg 172) typify GBM and AML (Supplementary Table 2 and Fig.	('Arg 172', 'Var', (69, 76))	('IDH2', 'Gene', '3418', (63, 67))	('Arg', 'Chemical', 'MESH:D001120', (69, 72))	('AML', 'Disease', (93, 96))	('Arg', 'Chemical', 'MESH:D001120', (47, 50))	('IDH1', 'Gene', (41, 45))	('GBM', 'Disease', (85, 88))	('IDH2', 'Gene', (63, 67))	('AML', 'Disease', 'MESH:D015470', (93, 96))	('gain-of-function', 'PosReg', (11, 27))	('Arg 132', 'Var', (47, 54))	('mutations', 'Var', (28, 37))	('IDH1', 'Gene', '3417', (41, 45))
154168	24132290	Although KRAS residues Gly 12 and Gly 13 are commonly mutated in LUAD, COAD/READ and UCEC, the proportion of Gly12Cys changes is significantly higher in lung cancer (P < 3.2 x 10-10), resulting from the high C>A transversion rate (Extended Data Fig.	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('Gly', 'Chemical', 'MESH:D005998', (109, 112))	('Gly', 'Chemical', 'MESH:D005998', (23, 26))	('KRAS', 'Gene', (9, 13))	('COAD', 'Disease', 'MESH:D029424', (71, 75))	('LUAD', 'Phenotype', 'HP:0030078', (65, 69))	('Gly12Cys', 'Var', (109, 117))	('Gly', 'Chemical', 'MESH:D005998', (34, 37))	('lung cancer', 'Disease', (153, 164))	('KRAS', 'Gene', '3845', (9, 13))	('Gly12Cys', 'Mutation', 'rs121913530', (109, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('COAD', 'Disease', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
154170	24132290	Mutations to BAP1 (10%) and SETD2 (12%) are also most common in KIRC.	('BAP1', 'Gene', (13, 17))	('KIRC', 'Disease', (64, 68))	('Mutations', 'Var', (0, 9))	('SETD2', 'Gene', '29072', (28, 33))	('common', 'Reg', (54, 60))	('BAP1', 'Gene', '8314', (13, 17))	('SETD2', 'Gene', (28, 33))
154172	24132290	Predominant COAD/READ-specific mutations are those affecting APC (82%) and Wnt/beta-catenin signalling (93% of samples).	('mutations', 'Var', (31, 40))	('APC', 'Disease', 'MESH:D011125', (61, 64))	('COAD', 'Disease', 'MESH:D029424', (12, 16))	('beta-catenin', 'Gene', '1499', (79, 91))	('APC', 'cellular_component', 'GO:0005680', ('61', '64'))	('APC', 'Disease', (61, 64))	('affecting', 'Reg', (51, 60))	('signalling', 'biological_process', 'GO:0023052', ('92', '102'))	('COAD', 'Disease', (12, 16))	('beta-catenin', 'Gene', (79, 91))
154173	24132290	Several mutations occur exclusively in AML, including recurrent mutations in NPM1 (27%) and FLT3 (27%), and rare mutations affecting MIR142 (Fig.	('AML', 'Disease', 'MESH:D015470', (39, 42))	('FLT3', 'Gene', '2322', (92, 96))	('NPM1', 'Gene', (77, 81))	('NPM1', 'Gene', '4869', (77, 81))	('AML', 'Disease', (39, 42))	('MIR142', 'Gene', (133, 139))	('mutations', 'Var', (64, 73))	('FLT3', 'Gene', (92, 96))	('MIR142', 'Gene', '406934', (133, 139))
154174	24132290	Mutations of methylation and chromatin modifiers are also typical in AML, mostly affecting DNMT3A and TET2.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('AML', 'Disease', (69, 72))	('affecting', 'Reg', (81, 90))	('DNMT3A', 'Gene', (91, 97))	('DNMT3A', 'Gene', '1788', (91, 97))	('TET2', 'Gene', '54790', (102, 106))	('chromatin', 'cellular_component', 'GO:0000785', ('29', '38'))	('Mutations', 'Var', (0, 9))	('TET2', 'Gene', (102, 106))	('AML', 'Disease', 'MESH:D015470', (69, 72))
154175	24132290	BRCA-specific mutations include GATA3 and MAP3K1, whereas KEAP1 mutations predominate in lung cancer (LUAD 17%, LUSC 12%).	('KEAP1', 'Gene', '9817', (58, 63))	('MAP3K1', 'Gene', '4214', (42, 48))	('BRCA', 'Gene', (0, 4))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('LUSC', 'Phenotype', 'HP:0030359', (112, 116))	('GATA3', 'Gene', (32, 37))	('KEAP1', 'Gene', (58, 63))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('MAP3K1', 'Gene', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutations', 'Var', (64, 73))	('GATA3', 'Gene', '2625', (32, 37))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('MAP3K', 'molecular_function', 'GO:0004709', ('42', '47'))	('mutations', 'Var', (14, 23))	('LUAD', 'Phenotype', 'HP:0030078', (102, 106))	('BRCA', 'Gene', '672', (0, 4))
154177	24132290	Cluster analysis on mutations in SMGs (Fig.	('SMG', 'Gene', (33, 36))	('mutations', 'Var', (20, 29))	('SMG', 'Gene', '23034', (33, 36))
154180	24132290	Two major endometrial endometroid clusters were found, one having mutations in PIK3CA, PTEN and ARID1A, and the other containing mutations in two additional genes (PIK3R1 and CTNNB1).	('mutations', 'Var', (66, 75))	('PTEN', 'Gene', (87, 91))	('PIK3R1', 'Gene', '5295', (164, 170))	('PTEN', 'Gene', '5728', (87, 91))	('PIK3R1', 'Gene', (164, 170))	('CTNNB1', 'Gene', (175, 181))	('ARID1A', 'Gene', '8289', (96, 102))	('mutations', 'Reg', (129, 138))	('ARID1A', 'Gene', (96, 102))	('PIK3CA', 'Gene', (79, 85))	('CTNNB1', 'Gene', '1499', (175, 181))	('PIK3CA', 'Gene', '5290', (79, 85))
154181	24132290	Five major breast cancer clusters were observed, with mutations in CDH1, GATA3, MAP3K1, PIK3CA and TP53 as drivers for respective clusters.	('breast cancer clusters', 'Disease', (11, 33))	('TP53', 'Gene', (99, 103))	('GATA3', 'Gene', (73, 78))	('PIK3CA', 'Gene', '5290', (88, 94))	('mutations', 'Var', (54, 63))	('GATA3', 'Gene', '2625', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('TP53', 'Gene', '7157', (99, 103))	('MAP3K1', 'Gene', (80, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('MAP3K', 'molecular_function', 'GO:0004709', ('80', '85'))	('CDH1', 'Gene', (67, 71))	('PIK3CA', 'Gene', (88, 94))	('CDH1', 'Gene', '999', (67, 71))	('MAP3K1', 'Gene', '4214', (80, 86))	('breast cancer clusters', 'Disease', 'MESH:D001943', (11, 33))
154183	24132290	The glioblastoma cluster is characterized by mutations in EGFR.	('EGFR', 'Gene', '1956', (58, 62))	('mutations', 'Var', (45, 54))	('glioblastoma cluster', 'Disease', (4, 24))	('EGFR', 'Gene', (58, 62))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('glioblastoma cluster', 'Disease', 'MESH:D005909', (4, 24))	('glioblastoma', 'Phenotype', 'HP:0012174', (4, 16))
154184	24132290	Two kidney clear cell cancer clusters were detected; both have VHL as the common driver and one has additional mutations in PBRM1 and/or BAP1 (refs).	('BAP1', 'Gene', (137, 141))	('mutations', 'Var', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('VHL', 'Disease', 'MESH:D006623', (63, 66))	('VHL', 'Disease', (63, 66))	('PBRM1', 'Gene', (124, 129))	('BAP1', 'Gene', '8314', (137, 141))	('clear cell cancer', 'Phenotype', 'HP:0006770', (11, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('PBRM1', 'Gene', '55193', (124, 129))
154185	24132290	PBRM1 and BAP1 mutations are mutually exclusive in KIRC (P = 0.006), consistent with previous reports.	('BAP1', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('BAP1', 'Gene', '8314', (10, 14))
154186	24132290	AML has three major clusters represented by various combinations of DNMT3A, NPM1 and FLT3 mutations, and one cluster dominated by RUNX1 mutations.	('mutations', 'Var', (90, 99))	('NPM1', 'Gene', '4869', (76, 80))	('DNMT3A', 'Gene', (68, 74))	('DNMT3A', 'Gene', '1788', (68, 74))	('FLT3', 'Gene', '2322', (85, 89))	('RUNX1', 'Gene', (130, 135))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('RUNX1', 'Gene', '861', (130, 135))	('FLT3', 'Gene', (85, 89))	('NPM1', 'Gene', (76, 80))	('AML', 'Disease', (0, 3))
154187	24132290	One cluster having APC and KRAS mutations was almost exclusively detected in COAD/READ.	('APC', 'Disease', 'MESH:D011125', (19, 22))	('KRAS', 'Gene', '3845', (27, 31))	('APC', 'Disease', (19, 22))	('COAD', 'Disease', 'MESH:D029424', (77, 81))	('mutations', 'Var', (32, 41))	('KRAS', 'Gene', (27, 31))	('COAD', 'Disease', (77, 81))	('APC', 'cellular_component', 'GO:0005680', ('19', '22'))
154189	24132290	TP53 and CDH1 are exclusive in BRCA, with mutations enriched in different subtypes, as are TP53 and CTNNB1 in UCEC.	('TP53', 'Gene', (91, 95))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('BRCA', 'Phenotype', 'HP:0003002', (31, 35))	('BRCA', 'Gene', '672', (31, 35))	('BRCA', 'Gene', (31, 35))	('CDH1', 'Gene', (9, 13))	('CTNNB1', 'Gene', (100, 106))	('CDH1', 'Gene', '999', (9, 13))	('TP53', 'Gene', '7157', (91, 95))	('mutations', 'Var', (42, 51))	('CTNNB1', 'Gene', '1499', (100, 106))
154190	24132290	Cohort analysis identified pairs where at least one gene has mutations strongly associated (corrected P < 0.05) to one cancer type, and also identifies TP53 and PIK3CA with significant exclusivity (Extended Data Fig.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('TP53', 'Gene', '7157', (152, 156))	('mutations', 'Var', (61, 70))	('PIK3CA', 'Gene', (161, 167))	('cancer', 'Disease', (119, 125))	('PIK3CA', 'Gene', '5290', (161, 167))	('associated', 'Reg', (80, 90))	('TP53', 'Gene', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
154193	24132290	Not surprisingly, many are associated (P < 0.05) with one cancer type (for example, VHL mutations in KIRC), demonstrating a strong relationship between exclusivity and tissue of origin.	('VHL', 'Disease', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('VHL', 'Disease', 'MESH:D006623', (84, 87))
154200	24132290	Some findings are unsurprising, such as the correlation of TP53 mutations with generally unfavourable indicators, for example in tumour stage (P = 0.01, Fisher's exact test) and elapsed time to death (P = 0.006, Wilcoxon) in HNSC, age (P = 0.002, Wilcoxon rank test) and time to death (P = 0.09, Wilcoxon) in AML, and vital status in OV (P = 0.04, Fisher).	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('AML', 'Disease', (309, 312))	('TP53', 'Gene', (59, 63))	('HNSC', 'Phenotype', 'HP:0012288', (225, 229))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('tumour', 'Disease', (129, 135))	('AML', 'Disease', 'MESH:D015470', (309, 312))	('mutations', 'Var', (64, 73))	('TP53', 'Gene', '7157', (59, 63))
154201	24132290	In UCEC, mutations in several genes are correlated with the endometrioid rather than serous subtype: PTEN, CTNNB1, PIK3R1, KRAS, ARID1A, CTCF, RPL22 and ARID5B (all P < 0.03) (Supplementary Table 9).	('PTEN', 'Gene', (101, 105))	('mutations', 'Var', (9, 18))	('endometrioid', 'Disease', (60, 72))	('PIK3R1', 'Gene', (115, 121))	('CTNNB1', 'Gene', (107, 113))	('KRAS', 'Gene', (123, 127))	('CTCF', 'Gene', (137, 141))	('RPL22', 'Gene', '6146', (143, 148))	('ARID5B', 'Gene', '84159', (153, 159))	('ARID1A', 'Gene', (129, 135))	('PTEN', 'Gene', '5728', (101, 105))	('RPL22', 'Gene', (143, 148))	('ARID5B', 'Gene', (153, 159))	('ARID1A', 'Gene', '8289', (129, 135))	('PIK3R1', 'Gene', '5295', (115, 121))	('correlated', 'Reg', (40, 50))	('CTNNB1', 'Gene', '1499', (107, 113))	('CTCF', 'Gene', '10664', (137, 141))	('KRAS', 'Gene', '3845', (123, 127))
154202	24132290	We examined which genes correlate with survival using the Cox proportional hazards model, first analysing individual cancer types using age and gender as covariates; an average of 2 genes (range: 0-4) with mutation frequency >=2% were significant (P <= 0.05) in each type (Supplementary Table 10a and Extended Data Fig.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('significant', 'Reg', (235, 246))	('mutation', 'Var', (206, 214))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
154203	24132290	KDM6A and ARID1A mutations correlate with better survival in BLCA (P = 0.03, hazard ratio (HR) = 0.36, 95% confidence interval (CI): 0.14-0.92) and UCEC (P = 0.03, HR = 0.11, 95% CI: 0.01-0.84), respectively, but mutations in SETBP1, recently identified with worse prognosis in atypical chronic myeloid leukaemia (aCML), have a significant detrimental effect in HNSC (P = 0.006, HR = 3.21, 95% CI: 1.39-7.44).	('HNSC', 'Phenotype', 'HP:0012288', (362, 366))	('chronic myeloid leukaemia', 'Disease', 'MESH:D015464', (287, 312))	('chronic myeloid leukaemia', 'Phenotype', 'HP:0005506', (287, 312))	('SETBP1', 'Gene', (226, 232))	('HNSC', 'Disease', (362, 366))	('ARID1A', 'Gene', '8289', (10, 16))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (295, 312))	('ARID1A', 'Gene', (10, 16))	('KDM6A', 'Gene', '7403', (0, 5))	('detrimental', 'NegReg', (340, 351))	('chronic myeloid leukaemia', 'Disease', (287, 312))	('mutations', 'Var', (213, 222))	('SETBP1', 'Gene', '26040', (226, 232))	('KDM6A', 'Gene', (0, 5))
154205	24132290	Conversely, BRCA2 mutations (P = 0.02, HR = 0.31, 95% CI: 0.12-0.85) associate with better survival in ovarian cancer, consistent with previous reports; BRCA1 mutations showed positive correlation with better survival, but did not reach significance here.	('mutations', 'Var', (159, 168))	('BRCA2', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('BRCA1', 'Gene', '672', (153, 158))	('BRCA', 'Phenotype', 'HP:0003002', (153, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('BRCA', 'Phenotype', 'HP:0003002', (12, 16))	('ovarian cancer', 'Disease', 'MESH:D010051', (103, 117))	('BRCA2', 'Gene', '675', (12, 17))	('BRCA1', 'Gene', (153, 158))	('better', 'PosReg', (84, 90))	('ovarian cancer', 'Disease', (103, 117))	('mutations', 'Var', (18, 27))
154206	24132290	We extended our survival analysis across cancer types, restricting our attention to the subset of 97 SMGs whose mutations appeared in >=2% of patients having survival data in >=2 tumour types.	('SMG', 'Gene', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('SMG', 'Gene', '23034', (101, 104))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('mutations', 'Var', (112, 121))	('tumour type', 'Disease', (179, 190))	('tumour type', 'Disease', 'MESH:D009369', (179, 190))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('patients', 'Species', '9606', (142, 150))
154208	24132290	In particular, BAP1 was highly significant (P = 0.00013, HR = 2.20, 95% CI: 1.47-3.29, more than 53 mutated tumours out of 888 total), with mutations associating with detrimental outcome in four tumour types and notable associations in KIRC (P = 0.00079), consistent with a recent report, and in UCEC (P = 0.066).	('BAP1', 'Gene', (15, 19))	('associations', 'Interaction', (220, 232))	('tumours', 'Disease', (108, 115))	('KIRC', 'Disease', (236, 240))	('tumour type', 'Disease', (195, 206))	('detrimental', 'Reg', (167, 178))	('BAP1', 'Gene', '8314', (15, 19))	('tumour type', 'Disease', 'MESH:D009369', (195, 206))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('mutations', 'Var', (140, 149))	('tumours', 'Disease', 'MESH:D009369', (108, 115))	('UCEC', 'Disease', (296, 300))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
154209	24132290	Mutations in several other genes are detrimental, including DNMT3A (HR = 1.59), previously identified with poor prognosis in AML, and KDM5C (HR = 1.63), FBXW7 (HR = 1.57) and TP53 (HR = 1.19).	('AML', 'Disease', 'MESH:D015470', (125, 128))	('FBXW7', 'Gene', (153, 158))	('TP53', 'Gene', (175, 179))	('AML', 'Disease', (125, 128))	('KDM5C', 'Gene', (134, 139))	('DNMT3A', 'Gene', (60, 66))	('DNMT3A', 'Gene', '1788', (60, 66))	('KDM5C', 'Gene', '8242', (134, 139))	('Mutations', 'Var', (0, 9))	('FBXW7', 'Gene', '55294', (153, 158))	('TP53', 'Gene', '7157', (175, 179))
154212	24132290	IDH1 mutations are associated with improved prognosis across the Pan-Cancer set (HR = 0.67, P = 0.16) and also in GBM (HR = 0.42, P = 0.09) (Supplementary Table 10a, b), consistent with previous work.	('prognosis', 'MPA', (44, 53))	('improved', 'PosReg', (35, 43))	('mutations', 'Var', (5, 14))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
154213	24132290	To understand the temporal order of somatic events, we analysed the variant allele fraction (VAF) distribution of mutations in SMGs across AML, BRCA and UCEC (Fig.	('BRCA', 'Gene', (144, 148))	('AML', 'Disease', 'MESH:D015470', (139, 142))	('mutations', 'Var', (114, 123))	('SMG', 'Gene', (127, 130))	('AML', 'Disease', (139, 142))	('SMG', 'Gene', '23034', (127, 130))	('BRCA', 'Phenotype', 'HP:0003002', (144, 148))	('BRCA', 'Gene', '672', (144, 148))
154215	24132290	Mutations in TP53 have higher VAFs on average in all three cancer types, suggesting early appearance during tumorigenesis, although it is possible that a later mutation contributing to tumour cell expansion might have a high VAF.	('TP53', 'Gene', (13, 17))	('higher', 'PosReg', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('Mutations', 'Var', (0, 9))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('VAFs', 'CPA', (30, 34))	('cell expansion', 'biological_process', 'GO:0016049', ('192', '206'))	('TP53', 'Gene', '7157', (13, 17))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (185, 191))
154220	24132290	Conversely, KRAS and/or NRAS mutations tend to have lower VAFs in all three tumour types (Fig.	('NRAS', 'Gene', '4893', (24, 28))	('mutations', 'Var', (29, 38))	('lower', 'NegReg', (52, 57))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('KRAS', 'Gene', (12, 16))	('KRAS', 'Gene', '3845', (12, 16))	('tumour type', 'Disease', 'MESH:D009369', (76, 87))	('tumour type', 'Disease', (76, 87))	('NRAS', 'Gene', (24, 28))	('VAFs', 'MPA', (58, 62))
154224	24132290	Using 50 AML WGS cases, sciClone (http://github.com/genome/sciclone) detected DNMT3A mutations in the founding clone for 100% (8 out of 8) of cases and NRAS mutations in the subclone for 75% (3 out of 4) of cases (Extended Data Fig.	('AML', 'Disease', 'MESH:D015470', (9, 12))	('NRAS', 'Gene', (152, 156))	('DNMT3A', 'Gene', (78, 84))	('DNMT3A', 'Gene', '1788', (78, 84))	('AML', 'Disease', (9, 12))	('NRAS', 'Gene', '4893', (152, 156))	('mutations', 'Var', (157, 166))	('mutations', 'Var', (85, 94))
154227	24132290	In BRCA, 95% (62 out of 65) of cases contained PIK3CA mutations in the founding clone, whereas 33% (3 out of 9) of cases had MLL3 mutations in the subclone.	('PIK3CA', 'Gene', (47, 53))	('contained', 'Reg', (37, 46))	('BRCA', 'Gene', (3, 7))	('PIK3CA', 'Gene', '5290', (47, 53))	('BRCA', 'Gene', '672', (3, 7))	('MLL3', 'Gene', '58508', (125, 129))	('mutations', 'Var', (54, 63))	('MLL3', 'Gene', (125, 129))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))
154228	24132290	Similar patterns were found in UCEC tumours, with 96% (65 out of 68) and 95% (62 out of 65) of tumours containing PIK3CA and PTEN mutations, respectively, in the founding clone, and 9% (2 out of 22) of KRAS and 14% (1 out of 7) of NRAS mutations in the subclone (Extended Data Fig.	('PIK3CA', 'Gene', '5290', (114, 120))	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('PTEN', 'Gene', (125, 129))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('UCEC tumours', 'Disease', (31, 43))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('KRAS', 'Gene', (202, 206))	('NRAS', 'Gene', (231, 235))	('PTEN', 'Gene', '5728', (125, 129))	('tumours', 'Disease', (95, 102))	('PIK3CA', 'Gene', (114, 120))	('UCEC tumours', 'Disease', 'MESH:D009369', (31, 43))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('mutations', 'Var', (236, 245))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('tumours', 'Disease', (36, 43))	('NRAS', 'Gene', '4893', (231, 235))	('mutations', 'Var', (130, 139))	('KRAS', 'Gene', '3845', (202, 206))
154231	24132290	Although a common set of driver mutations exists in each cancer type, the combination of drivers within a cancer type and their distribution within the founding clone and subclones varies for individual patients.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('patients', 'Species', '9606', (203, 211))	('mutations', 'Var', (32, 41))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
154238	24132290	Finally, the TCGA disease analysis working groups (AWGs) may optionally perform manual curation of the variant calls, in which false positives are removed and true negatives are recovered.	('false', 'biological_process', 'GO:0071878', ('127', '132'))	('TCGA', 'Disease', (13, 17))	('TC', 'Chemical', 'MESH:D013667', (13, 15))	('CG', 'Chemical', 'MESH:C028505', (14, 16))	('false', 'biological_process', 'GO:0071877', ('127', '132'))	('variant', 'Var', (103, 110))
154240	24132290	Complete standardization of sensitivity could not be attained, as it would have required a uniform variant calling and filtering workflow across all tumour-normal pairs.	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('variant', 'Var', (99, 106))	('tumour', 'Disease', (149, 155))
154247	24132290	We used correlation modules in the mutational significance in cancer (MuSiC) package to identify genes with mutations that are positively correlated with the number of mutations in the tumour sample.	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumour', 'Disease', (185, 191))
154258	24132290	Tumours with zero detected somatic mutations were also excluded, resulting in mutations from 2,611 tumours for downstream clustering analysis.	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('mutations', 'Var', (78, 87))	('tumours', 'Disease', (99, 106))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
154259	24132290	For instance, eight LUAD and two LUSC tumours are in the solid colorectal cluster, largely owing to their KRAS mutations (Fig.	('tumours', 'Disease', (38, 45))	('mutations', 'Var', (111, 120))	('KRAS', 'Gene', '3845', (106, 110))	('LUAD', 'Phenotype', 'HP:0030078', (20, 24))	('solid colorectal cluster', 'Disease', (57, 81))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('LUSC', 'Phenotype', 'HP:0030359', (33, 37))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('KRAS', 'Gene', (106, 110))	('tumours', 'Disease', 'MESH:D009369', (38, 45))	('solid colorectal cluster', 'Disease', 'MESH:D015179', (57, 81))
154260	24132290	Three UCEC, two GBM, one OV and one HSNC samples are in the BRCA cluster courtesy of TP53 and PIK3CA mutations.	('TP53', 'Gene', (85, 89))	('mutations', 'Var', (101, 110))	('PIK3CA', 'Gene', (94, 100))	('BRCA', 'Phenotype', 'HP:0003002', (60, 64))	('BRCA', 'Gene', '672', (60, 64))	('TP53', 'Gene', '7157', (85, 89))	('BRCA', 'Gene', (60, 64))	('PIK3CA', 'Gene', '5290', (94, 100))
154265	24132290	From these 1,000 genes, we discarded the ones with mutations strongly associated (Bonferroni corrected P <= 0.05 by Fisher's exact test) with a cancer type, and this resulted in 600 genes for Dendrix analysis.	('mutations', 'Var', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('associated', 'Reg', (70, 80))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
154281	24132290	Notably, we observed at least a twofold increase of variant allele expressions in 3.9%, 12.9% and 5.9% of mutations from SMGs in AML (for example, TP53, STAG2 and SMC3), BRCA (for example, CDH1, TP53, GATA3 and MLL3), and UCEC (for example, ARID1A and FGFR2), respectively (Supplementary Table 11a).	('CDH1', 'Gene', '999', (189, 193))	('AML', 'Disease', 'MESH:D015470', (129, 132))	('GATA3', 'Gene', (201, 206))	('BRCA', 'Phenotype', 'HP:0003002', (170, 174))	('STAG2', 'Gene', (153, 158))	('ARID1A', 'Gene', (241, 247))	('MLL3', 'Gene', '58508', (211, 215))	('AML', 'Disease', (129, 132))	('FGFR2', 'Gene', '2263', (252, 257))	('SMG', 'Gene', '23034', (121, 124))	('TP53', 'Gene', (147, 151))	('CDH1', 'Gene', (189, 193))	('TP53', 'Gene', (195, 199))	('SMC3', 'Gene', '9126', (163, 167))	('SMC', 'cellular_component', 'GO:0016029', ('163', '166'))	('ARID1A', 'Gene', '8289', (241, 247))	('BRCA', 'Gene', '672', (170, 174))	('MLL3', 'Gene', (211, 215))	('BRCA', 'Gene', (170, 174))	('TP53', 'Gene', '7157', (147, 151))	('TP53', 'Gene', '7157', (195, 199))	('SMG', 'Gene', (121, 124))	('SMC3', 'Gene', (163, 167))	('increase', 'PosReg', (40, 48))	('STAG2', 'Gene', '10735', (153, 158))	('GATA3', 'Gene', '2625', (201, 206))	('mutations', 'Var', (106, 115))	('FGFR2', 'Gene', (252, 257))	('FGFR', 'molecular_function', 'GO:0005007', ('252', '256'))
154282	24132290	We further compared expression level distributions across mutations from SMGs and non-SMGs.	('mutations', 'Var', (58, 67))	('compared', 'Reg', (11, 19))	('SMG', 'Gene', '23034', (73, 76))	('SMG', 'Gene', (86, 89))	('SMG', 'Gene', (73, 76))	('SMG', 'Gene', '23034', (86, 89))	('expression level', 'MPA', (20, 36))
154323	22890301	One such study utilized a mouse model deficient in tumour protein 63 (p63):a p53 family member that is normally localized to the basal cell layer of bladder urothelium:to study urothelial development.	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('p53', 'Gene', (77, 80))	('deficient', 'Var', (38, 47))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('mouse', 'Species', '10090', (26, 31))	('tumour', 'Disease', (51, 57))	('p53', 'Gene', '22060', (77, 80))
154324	22890301	The investigators demonstrated that the urothelia of p63-deficient embryonic mouse bladders were defective and only contained umbrella cells, suggesting that functional p63 is not required for the generation of umbrella cells.	('p63-deficient', 'Var', (53, 66))	('rat', 'Species', '10116', (201, 204))	('urothelia', 'CPA', (40, 49))	('rat', 'Species', '10116', (25, 28))	('mouse', 'Species', '10090', (77, 82))
154325	22890301	By complementing p63-deficient mouse blastocysts with wild-type embryonic stem cells to create chimeric mouse bladders, the study authors revealed that, although both p63- and p63+ cells developed into umbrella cells, p63+ cells only accounted for about 0-15% of umbrella cells.	('blastocysts', 'Disease', (37, 48))	('p63-', 'Var', (167, 171))	('mouse', 'Species', '10090', (31, 36))	('mouse', 'Species', '10090', (104, 109))	('p63+ cells', 'Var', (176, 186))	('blastocysts', 'Disease', 'MESH:D020964', (37, 48))
154346	22890301	The relative tumorigenic potential of these two cell subpopulations was then determined, based on their ability to form tumours in immunocompromised mice devoid of T, B, and NK cells:created by crossing mice deficient in recombination activating gene 2 (RAG2) and common cytokine receptor gamma chain (gammac).	('recombination activating gene 2', 'Gene', '19374', (221, 252))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('common cytokine receptor gamma chain', 'Gene', (264, 300))	('mice', 'Species', '10090', (203, 207))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('RAG2', 'Gene', (254, 258))	('mice', 'Species', '10090', (149, 153))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (120, 127))	('RAG2', 'Gene', '19374', (254, 258))	('common cytokine receptor gamma chain', 'Gene', '3561', (264, 300))	('deficient', 'Var', (208, 217))	('recombination activating gene 2', 'Gene', (221, 252))
154372	22890301	Functional disruption of the ALDH1A1 gene with a small hairpin RNA construct resulted in decreased CSC clonogenic and tumorigenic potential.	('ALDH1A1', 'Gene', '216', (29, 36))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('ALDH', 'molecular_function', 'GO:0004030', ('29', '33'))	('ALDH1A1', 'Gene', (29, 36))	('disruption', 'Var', (11, 21))	('decreased', 'NegReg', (89, 98))
154381	22890301	Pretreatment of human urothelial cell culture with the PPARgamma antagonist GW9662 attenuated the troglitazone-induced differentiation response (Figure 1c).	('PPARgamma', 'Gene', '5468', (55, 64))	('GW9662', 'Var', (76, 82))	('troglitazone-induced differentiation response', 'MPA', (98, 143))	('attenuated', 'NegReg', (83, 93))	('troglitazone', 'Chemical', 'MESH:D000077288', (98, 110))	('GW9662', 'Chemical', 'MESH:C457499', (76, 82))	('human', 'Species', '9606', (16, 21))	('PPARgamma', 'Gene', (55, 64))
154404	22890301	In epithelial tissues, Oct-4 expression leads to proliferation of progenitor cells, dysplastic growth, and block of differentiation.	('dysplastic growth', 'Disease', (84, 101))	('dysplastic growth', 'Disease', 'MESH:D006130', (84, 101))	('expression', 'Var', (29, 39))	('rat', 'Species', '10116', (56, 59))	('Oct-4', 'Gene', (23, 28))	('Oct-4', 'Gene', '5460', (23, 28))	('leads to', 'Reg', (40, 48))	('block of differentiation', 'CPA', (107, 131))	('proliferation of progenitor cells', 'CPA', (49, 82))
154415	22890301	Further analysis revealed CD90 as a corresponding primitive stem cell marker and loss of CD49 as another terminal differentiation marker (Figure 2a).	('loss', 'Var', (81, 85))	('terminal differentiation', 'biological_process', 'GO:0048468', ('105', '129'))	('CD90', 'Gene', '7070', (26, 30))	('CD90', 'Gene', (26, 30))	('CD49', 'Gene', (89, 93))
154419	22890301	Nevertheless, cancer derived from more differentiated urothelial cells can acquire the characteristics of CSCs via genetic and epigenetic alterations.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('CSCs', 'Disease', (106, 110))	('genetic', 'Var', (115, 122))	('epigenetic alterations', 'Var', (127, 149))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('rat', 'Species', '10116', (142, 145))
154424	22890301	In one study of bladder urothelial carcinomas, patients with high expression of the CSC marker ALDH1A1 were over four times more likely to experience tumour progression and decreased cancer-specific and overall survival than patients with low expression of ALDH1A1.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('patients', 'Species', '9606', (47, 55))	('ALDH1A1', 'Gene', '216', (257, 264))	('ALDH1A1', 'Gene', (95, 102))	('ALDH', 'molecular_function', 'GO:0004030', ('257', '261'))	('bladder urothelial carcinomas', 'Disease', (16, 45))	('cancer', 'Disease', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('bladder urothelial carcinomas', 'Disease', 'MESH:D001749', (16, 45))	('patients', 'Species', '9606', (225, 233))	('ALDH1A1', 'Gene', '216', (95, 102))	('experience', 'PosReg', (139, 149))	('decreased', 'NegReg', (173, 182))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('high expression', 'Var', (61, 76))	('ALDH', 'molecular_function', 'GO:0004030', ('95', '99'))	('ALDH1A1', 'Gene', (257, 264))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Disease', (150, 156))
154426	22890301	Earlier studies established that loss of p63 was associated with muscle-invasive bladder urothelial carcinomas and tumour progression.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('muscle-invasive bladder urothelial carcinomas', 'Disease', (65, 110))	('associated', 'Reg', (49, 59))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('muscle-invasive bladder urothelial carcinomas', 'Disease', 'MESH:D001749', (65, 110))	('p63', 'Protein', (41, 44))	('invasive bladder urothelial carcinomas', 'Phenotype', 'HP:0006740', (72, 110))	('loss', 'Var', (33, 37))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('invasive bladder', 'Phenotype', 'HP:0100645', (72, 88))	('tumour', 'Disease', (115, 121))
154427	22890301	However, a later study demonstrated an association between high p63 expression and decreased survival in patients with muscle-invasive bladder urothelial carcinomas.	('survival', 'MPA', (93, 101))	('patients', 'Species', '9606', (105, 113))	('muscle-invasive bladder urothelial carcinomas', 'Disease', 'MESH:D001749', (119, 164))	('expression', 'MPA', (68, 78))	('invasive bladder urothelial carcinomas', 'Phenotype', 'HP:0006740', (126, 164))	('decreased', 'NegReg', (83, 92))	('invasive bladder', 'Phenotype', 'HP:0100645', (126, 142))	('p63', 'Protein', (64, 67))	('rat', 'Species', '10116', (30, 33))	('high', 'Var', (59, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('muscle-invasive bladder urothelial carcinomas', 'Disease', (119, 164))
154433	22890301	These variants, which comprise less than 5-6% of all bladder cancer specimens in the USA, are associated with poor prognosis and aggressive phenotype.	('variants', 'Var', (6, 14))	('bladder cancer', 'Disease', 'MESH:D001749', (53, 67))	('bladder cancer', 'Disease', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('bladder cancer', 'Phenotype', 'HP:0009725', (53, 67))
154436	22890301	Another study analyzed 20 micropapillary variants of urothelial carcinomas and demonstrated that these cancers stained positive for both 343E12 (basal cell marker) and CK20.	('343E12', 'Var', (137, 143))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (53, 74))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('CK20', 'Gene', (168, 172))	('CK20', 'Gene', '54474', (168, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('rat', 'Species', '10116', (86, 89))	('urothelial carcinomas', 'Disease', (53, 74))	('positive', 'Reg', (119, 127))	('cancers', 'Disease', (103, 110))
154440	22890301	Next-generation sequencing of human urothelial carcinomas has revealed mutations in several chromatin-remodelling genes.	('human', 'Species', '9606', (30, 35))	('chromatin-remodelling genes', 'Gene', (92, 119))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (36, 57))	('rat', 'Species', '10116', (9, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('mutations', 'Var', (71, 80))	('revealed', 'Reg', (62, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('chromatin-remodelling', 'biological_process', 'GO:0006338', ('92', '113'))	('urothelial carcinomas', 'Disease', (36, 57))	('chromatin', 'cellular_component', 'GO:0000785', ('92', '101'))
154441	22890301	Mutation frequency of one of the chromatin-remodelling genes, UTX, is significantly associated with early-stage urothelial carcinomas.	('Mutation frequency', 'Var', (0, 18))	('chromatin', 'cellular_component', 'GO:0000785', ('33', '42'))	('UTX', 'Gene', '7403', (62, 65))	('urothelial carcinomas', 'Disease', (112, 133))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (112, 133))	('associated', 'Reg', (84, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('UTX', 'Gene', (62, 65))	('chromatin-remodelling', 'biological_process', 'GO:0006338', ('33', '54'))
154450	22890301	The investigators reported similarities between the gene expression profiles of the 67LR+ highly tumorigenic cells (HTCs) and other aggressive forms of urothelial carcinoma.	('67LR+', 'Var', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('urothelial carcinoma', 'Disease', (152, 172))	('highly tumorigenic cells', 'CPA', (90, 114))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (152, 172))	('gene expression', 'biological_process', 'GO:0010467', ('52', '67'))
154460	22890301	These urothelial carcinomas commonly contain activating mutations of the fibroblast growth factor receptor 3 (FGFR3), Harvey Ras (HRAS) or PI3-kinase (PIK3CA).	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('HRAS', 'Gene', (130, 134))	('mutations', 'Var', (56, 65))	('Harvey Ras', 'Gene', '3265', (118, 128))	('FGFR', 'molecular_function', 'GO:0005007', ('110', '114'))	('PIK3CA', 'Gene', (151, 157))	('urothelial carcinomas', 'Disease', (6, 27))	('fibroblast growth factor receptor 3', 'Gene', (73, 108))	('FGFR3', 'Gene', '2261', (110, 115))	('activating', 'PosReg', (45, 55))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (6, 27))	('HRAS', 'Gene', '3265', (130, 134))	('PIK3CA', 'Gene', '5290', (151, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('73', '97'))	('FGFR3', 'Gene', (110, 115))	('Harvey Ras', 'Gene', (118, 128))	('fibroblast growth factor receptor 3', 'Gene', '2261', (73, 108))
154463	22890301	These urothelial carcinomas are commonly linked to mutations in the tumour suppressor genes P53, RB, and PTEN.	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('linked', 'Reg', (41, 47))	('mutations', 'Var', (51, 60))	('P53', 'Gene', (92, 95))	('urothelial carcinomas', 'Disease', (6, 27))	('PTEN', 'Gene', (105, 109))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('PTEN', 'Gene', '5728', (105, 109))	('P53', 'Gene', '7157', (92, 95))	('tumour', 'Disease', (68, 74))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (6, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))
154470	22890301	Independent of pathology, urothelial carcinomas with high levels of CK14 expression have been associated with reduced progression-free and overall survival.	('reduced', 'NegReg', (110, 117))	('urothelial carcinomas', 'Disease', (26, 47))	('CK14', 'Gene', '3861', (68, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (26, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('CK14', 'Gene', (68, 72))	('overall survival', 'CPA', (139, 155))	('high levels', 'Var', (53, 64))	('progression-free', 'CPA', (118, 134))
154486	22890301	For example, nonmyeloablative chemotherapy results in pancytopenia.	('nonmyeloablative chemotherapy', 'Var', (13, 42))	('pancytopenia', 'Disease', 'MESH:D010198', (54, 66))	('results in', 'Reg', (43, 53))	('pancytopenia', 'Phenotype', 'HP:0001876', (54, 66))	('pancytopenia', 'Disease', (54, 66))
154495	22890301	Ligation of CD47 to SIRPalpha leads to the suppression of immune cell activity and, ultimately, to the blockade of phagocytosis by macrophages.	('phagocytosis', 'biological_process', 'GO:0006909', ('115', '127'))	('Ligation', 'Var', (0, 8))	('immune cell activity', 'CPA', (58, 78))	('SIRPalpha', 'Gene', '140885', (20, 29))	('phagocytosis', 'CPA', (115, 127))	('CD47', 'Gene', '961', (12, 16))	('suppression', 'NegReg', (43, 54))	('CD47', 'Gene', (12, 16))	('SIRPalpha', 'Gene', (20, 29))
154583	19536901	Unlike other epithelial cancers in which EGFR domain mutations are relatively well understood, there is limited data in urothelial cancer, and additional studies using monoclonal antibodies in combination with chemotherapy are planned.	('EGFR', 'Gene', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('urothelial cancer', 'Disease', (120, 137))	('epithelial cancers', 'Disease', 'MESH:D000077216', (13, 31))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('domain mutations', 'Var', (46, 62))	('urothelial cancer', 'Disease', 'MESH:D014523', (120, 137))	('epithelial cancers', 'Disease', (13, 31))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('EGFR', 'Gene', '1956', (41, 45))
154595	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))
154628	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))
154632	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.	('HIF proteins', 'Disease', 'MESH:D018455', (115, 127))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('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))
154634	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))
154635	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))
154641	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))
154654	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.	('von Hippel-Lindau disease', 'Disease', (124, 149))	('prevent', 'NegReg', (68, 75))	('MK-6482', 'Chemical', '-', (56, 63))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (124, 149))	('patients', 'Species', '9606', (110, 118))	('MK-6482', 'Var', (56, 63))
154661	33552650	In this phase II trial, 61 adults with germline VHL variations with measurable, nonmetastatic RCC received MK-6482 at 120 mg daily.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('MK-6482', 'Var', (107, 114))	('RCC', 'Disease', (94, 97))	('VHL', 'Gene', '7428', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('MK-6482', 'Chemical', '-', (107, 114))	('VHL', 'Gene', (48, 51))
154669	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'))
154678	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.	('CTLA-4', 'Gene', (57, 63))	('inhibition', 'Var', (64, 74))	('PD-1', 'Gene', (48, 52))	('patient', 'Species', '9606', (20, 27))	('patients', 'Species', '9606', (20, 28))	('patient', 'Species', '9606', (128, 135))
154693	30840886	We therefore conducted a pan-cancer analysis of secretome gene expression changes to identify candidate diagnostic biomarkers and to investigate the underlying biological function of these changes.	('cancer', 'Disease', (29, 35))	('changes', 'Var', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('gene expression', 'biological_process', 'GO:0010467', ('58', '73'))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
154811	30840886	BLCA yielded the strongest negative correlation between SB score and log2FC, suggesting that expression increases tend to be associated with low-burden SP genes, whereas the opposite was true for CHOL.	('S', 'Chemical', 'MESH:D013455', (56, 57))	('increases', 'PosReg', (104, 113))	('S', 'Chemical', 'MESH:D013455', (152, 153))	('C', 'Chemical', 'MESH:D002244', (74, 75))	('C', 'Chemical', 'MESH:D002244', (2, 3))	('expression', 'MPA', (93, 103))	('low-burden', 'Var', (141, 151))	('SP', 'Chemical', 'MESH:D021382', (152, 154))	('C', 'Chemical', 'MESH:D002244', (196, 197))
154824	30840886	Furthermore, there are many protein biomarkers in use for the diagnosis or monitoring of different cancer types based on their abundance in serum, plasma, or urine, such as PSA, CA-125, CA19-9, and NuMA for prostate, ovarian, pancreatic, and bladder cancer, respectively.	('S', 'Chemical', 'MESH:D013455', (174, 175))	('C', 'Chemical', 'MESH:D002244', (186, 187))	('CA-125', 'Var', (178, 184))	('pancreatic', 'Disease', 'MESH:D010195', (226, 236))	('ovarian', 'Disease', (217, 224))	('C', 'Chemical', 'MESH:D002244', (178, 179))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('CA19-9', 'Var', (186, 192))	('pancreatic', 'Disease', (226, 236))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))	('NuMA', 'Gene', (198, 202))	('PSA', 'Disease', (173, 176))	('bladder cancer', 'Disease', 'MESH:D001749', (242, 256))	('bladder cancer', 'Disease', (242, 256))	('cancer', 'Disease', (250, 256))	('bladder cancer', 'Phenotype', 'HP:0009725', (242, 256))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('NuMA', 'Gene', '4926', (198, 202))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('prostate', 'Disease', (207, 215))
154865	30840886	The total number of somatic mutation events (insertion, deletion, or single nucleotide polymorphism) for each primary tumor sample were summed to yield a total mutation burden for each sample.	('deletion', 'Var', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('single nucleotide polymorphism', 'Var', (69, 99))	('primary tumor', 'Disease', (110, 123))	('primary tumor', 'Disease', 'MESH:D009369', (110, 123))
154888	30840886	In this manner, genes with low p values and a positive FC receive a pdir near zero, whereas genes with low p values but a negative FC have a pdir close to one.	('C', 'Chemical', 'MESH:D002244', (56, 57))	('dir', 'Gene', (142, 145))	('dir', 'Gene', (69, 72))	('p values', 'Var', (31, 39))	('C', 'Chemical', 'MESH:D002244', (132, 133))	('dir', 'Gene', '554', (69, 72))	('dir', 'Gene', '554', (142, 145))
154955	30719393	Neoadjuvant chemotherapy should be even more strongly considered in the setting of high-risk features, which include variant histology, palpable mass under EUA, lymphovascular invasion on pathology, tumor arising from a diverticulum, or presence of hydronephrosis.	('variant histology', 'Var', (117, 134))	('tumor', 'Disease', (199, 204))	('hydronephrosis', 'Phenotype', 'HP:0000126', (249, 263))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('hydronephrosis', 'Disease', 'MESH:D006869', (249, 263))	('hydronephrosis', 'Disease', (249, 263))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('lymphovascular invasion', 'CPA', (161, 184))
155004	30719393	At present, it is estimated that 5% to 15% of patients yield survival benefits from NAC, so being able to identify the tumor subtypes of this cohort has obvious treatment implications.	('benefits', 'PosReg', (70, 78))	('tumor', 'Disease', (119, 124))	('patients', 'Species', '9606', (46, 54))	('survival', 'CPA', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('NAC', 'Var', (84, 87))	('NAC', 'Chemical', '-', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('NAC', 'cellular_component', 'GO:0005854', ('84', '87'))
155008	30719393	Luminal MIBCs tend to have more papillary histopathologic features, are more common in micropapillary MIBC, and often have FGFR3 mutations.	('FGFR3', 'Gene', '2261', (123, 128))	('micropapillary', 'Disease', (87, 101))	('MIBC', 'Chemical', '-', (8, 12))	('mutations', 'Var', (129, 138))	('MIBCs', 'Chemical', '-', (8, 13))	('FGFR3', 'Gene', (123, 128))	('MIBC', 'Chemical', '-', (102, 106))	('papillary histopathologic features', 'Phenotype', 'HP:0007482', (32, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('123', '127'))
155061	29883442	However, further study is required to determine whether functional expression of BLCA-1 interacts with angiogenic factors and subsequently leads to cancer progression and recurrence.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('BLCA-1', 'Gene', (81, 87))	('expression', 'Var', (67, 77))	('recurrence', 'CPA', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('interacts', 'Reg', (88, 97))	('leads to', 'Reg', (139, 147))
155083	28915710	Also, N-nitroso compounds (NOCs) used in chemically preserved food products are associated with risk for bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('N-nitroso', 'Var', (6, 15))	('bladder cancer', 'Disease', 'MESH:D001749', (105, 119))	('bladder cancer', 'Disease', (105, 119))	('associated', 'Reg', (80, 90))	('N-nitroso compounds', 'Chemical', '-', (6, 25))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
155090	28915710	Development of low grade lesions is associated with molecular aberrations in the oncogene RAS, FGFR3, and deletions of 9q.	('FGFR', 'molecular_function', 'GO:0005007', ('95', '99'))	('rat', 'Species', '10116', (66, 69))	('FGFR3', 'Gene', (95, 100))	('deletions of', 'Var', (106, 118))	('low grade lesions', 'CPA', (15, 32))	('molecular aberrations', 'Var', (52, 73))	('FGFR3', 'Gene', '2261', (95, 100))	('associated', 'Reg', (36, 46))	('men', 'Species', '9606', (7, 10))
155094	28915710	Hence, they are referred to as high-grade intra-urothelial neoplasia and are associated with alterations in p53, retinoblastoma (Rb), and PTEN.	('intra-urothelial neoplasia', 'Disease', 'MESH:D009369', (42, 68))	('rat', 'Species', '10116', (97, 100))	('PTEN', 'Gene', (138, 142))	('p53', 'Gene', (108, 111))	('intra-urothelial neoplasia', 'Disease', (42, 68))	('PTEN', 'Gene', '5728', (138, 142))	('Rb', 'Gene', '5925', (129, 131))	('alterations', 'Var', (93, 104))	('Rb', 'Phenotype', 'HP:0009919', (129, 131))	('retinoblastoma', 'Phenotype', 'HP:0009919', (113, 127))	('neoplasia', 'Phenotype', 'HP:0002664', (59, 68))	('retinoblastoma', 'Gene', '5925', (113, 127))	('retinoblastoma', 'Gene', (113, 127))	('associated', 'Reg', (77, 87))
155122	28915710	The major chemical urothelial carcinogens are N-Butyl-N-(4-hydroxybutyl)nitrosamine (BBN), N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT), and N-methyl-N-nitrosourea (MNU).	('N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide', 'Chemical', 'MESH:D005200', (91, 135))	('BBN', 'Chemical', 'MESH:D002085', (85, 88))	('N-methyl-N-nitrosourea', 'Chemical', 'MESH:D008770', (149, 171))	('FANFT', 'Chemical', 'MESH:D005200', (137, 142))	('N-[', 'Var', (91, 94))	('MNU', 'Chemical', 'MESH:D008770', (173, 176))	('N-Butyl-N-(4-hydroxybutyl)nitrosamine', 'Chemical', 'MESH:D002085', (46, 83))	('urothelial carcinogens', 'Disease', (19, 41))	('urothelial carcinogens', 'Disease', 'MESH:D014522', (19, 41))
155133	28915710	BBN-induced rodent tumors, predominantly mouse tumors, have p53 mutations, or mutations in genes related to the p53 pathway, especially in high-grade tumors.	('tumors', 'Disease', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('mouse', 'Species', '10090', (41, 46))	('BBN', 'Chemical', 'MESH:D002085', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('mutations', 'Var', (78, 87))	('rodent tumors', 'Disease', 'MESH:D012376', (12, 25))	('mutations', 'Var', (64, 73))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('rodent tumors', 'Disease', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('p53', 'Gene', (60, 63))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
155139	28915710	This model showed that genetic ablation of SPARC augmented BBN-induced bladder carcinogenesis, progression and metastasis.	('progression', 'CPA', (95, 106))	('genetic ablation', 'Var', (23, 39))	('metastasis', 'CPA', (111, 121))	('bladder carcinogenesis', 'Disease', 'MESH:D063646', (71, 93))	('men', 'Species', '9606', (52, 55))	('bladder carcinogenesis', 'Disease', (71, 93))	('SPARC augmented BBN-induced', 'Gene', (43, 70))	('BBN', 'Chemical', 'MESH:D002085', (59, 62))
155141	28915710	In another study, utilizing Rgs6-/- mice, the role for RGS6 as a tumor suppressor was reported as they displayed accelerated pathological lesions than Rgs6+/+ mice.	('Rgs6', 'Gene', '50779', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('RGS6', 'Var', (55, 59))	('Rgs6', 'Gene', '50779', (28, 32))	('Rgs', 'molecular_function', 'GO:0016299', ('151', '154'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('65', '81'))	('RGS', 'molecular_function', 'GO:0016299', ('55', '58'))	('rat', 'Species', '10116', (119, 122))	('accelerated', 'PosReg', (113, 124))	('Rgs', 'molecular_function', 'GO:0016299', ('28', '31'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('65', '81'))	('pathological lesions', 'CPA', (125, 145))	('mice', 'Species', '10090', (159, 163))	('Rgs6', 'Gene', (151, 155))	('mice', 'Species', '10090', (36, 40))	('Rgs6', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
155145	28915710	The tumor promoting effect of PLCepsilon was demonstrated by a decreased incidence of ensuing urothelial lesions in PLCepsilon knockout mice compared to their wildtypes as well as a significant downregulation of PLCepsilon downstream targets such as VEGF-A and COX-2.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('PLCepsilon', 'Gene', (30, 40))	('PLCepsilon', 'Gene', (116, 126))	('COX-2', 'Gene', (261, 266))	('PLCepsilon', 'Gene', (212, 222))	('decreased', 'NegReg', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('downregulation', 'NegReg', (194, 208))	('PLCepsilon', 'Gene', '74055', (116, 126))	('PLCepsilon', 'Gene', '74055', (30, 40))	('urothelial lesions', 'Disease', 'MESH:D004194', (94, 112))	('PLCepsilon', 'Gene', '74055', (212, 222))	('knockout', 'Var', (127, 135))	('urothelial lesions', 'Disease', (94, 112))	('VEGF-A', 'Gene', '22339', (250, 256))	('rat', 'Species', '10116', (52, 55))	('mice', 'Species', '10090', (136, 140))	('COX-2', 'Gene', '17709', (261, 266))	('VEGF-A', 'Gene', (250, 256))
155148	28915710	BBN model can be also used to study the impact of conditional cell/tissue specific knockout/knockin of genes; for example, the effect of conditional knockout of estrogen receptor alpha and beta as well as androgen receptor.	('androgen receptor', 'Protein', (205, 222))	('conditional knockout', 'Var', (137, 157))	('BBN', 'Chemical', 'MESH:D002085', (0, 3))	('estrogen receptor alpha', 'Gene', '2099', (161, 184))	('estrogen receptor alpha', 'Gene', (161, 184))
155158	28915710	Mice with germ line deletion may not allow investigation of the gene function if knockout leads to premature death or embryonic lethality and do not allow for the clear distinction of the tissue/cell-specific contribution of a given gene in the disease.	('premature death', 'Disease', (99, 114))	('embryonic lethality', 'Disease', 'MESH:D020964', (118, 137))	('deletion', 'Var', (20, 28))	('Mice', 'Species', '10090', (0, 4))	('premature death', 'Disease', 'MESH:D003643', (99, 114))	('embryonic lethality', 'Disease', (118, 137))
155160	28915710	Urothelial-specific Cre system is available and is typically used to selectively achieve gene knockin/knockout in the bladder epithelium.	('Cre', 'Gene', (20, 23))	('Cre', 'Gene', '2777477', (20, 23))	('knockin/knockout', 'Var', (94, 110))
155176	28915710	This study suggested that the RTK/RAS pathway activation along with p53 deficiency can be used as a combinatorial therapeutic marker to indicate urothelial carcinoma progression.	('urothelial carcinoma', 'Disease', (145, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('activation', 'PosReg', (46, 56))	('deficiency', 'Var', (72, 82))	('RTK/RAS pathway', 'Pathway', (30, 45))	('p53', 'Gene', (68, 71))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (145, 165))
155178	28915710	Ahmad et al., developed a model using UpkII promoter to induce expression of mutated Fgfr3 to the mouse urothelium.	('UpkII', 'Gene', '22269', (38, 43))	('Fgfr', 'molecular_function', 'GO:0005007', ('85', '89'))	('UpkII', 'Gene', (38, 43))	('mutated', 'Var', (77, 84))	('expression', 'MPA', (63, 73))	('Fgfr3', 'Gene', (85, 90))	('mouse', 'Species', '10090', (98, 103))
155179	28915710	Mutated Fgfr3 alone was insufficient to induce urothelial tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('insufficient', 'Disease', 'MESH:D000309', (24, 36))	('Fgfr', 'molecular_function', 'GO:0005007', ('8', '12'))	('Fgfr3', 'Gene', (8, 13))	('insufficient', 'Disease', (24, 36))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Mutated', 'Var', (0, 7))	('induce', 'Reg', (40, 46))
155180	28915710	When Fgfr3 mutations were introduced along with overexpression of K-Ras or beta-catenin inactivating mutations, mice developed tumors indicating that Fgfr3 cooperates with other mutations to drive tumorigenesis.	('mutations', 'Var', (11, 20))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('developed', 'Reg', (117, 126))	('K-Ras', 'Gene', (66, 71))	('K-Ras', 'Gene', '16653', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('drive', 'PosReg', (191, 196))	('Fgfr', 'molecular_function', 'GO:0005007', ('5', '9'))	('Fgfr3', 'Gene', (5, 10))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('mice', 'Species', '10090', (112, 116))	('Fgfr', 'molecular_function', 'GO:0005007', ('150', '154'))	('tumor', 'Disease', (127, 132))	('rat', 'Species', '10116', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', (197, 202))
155181	28915710	In addition, mutations and/or deletions in the p53 gene are among the most common genetic alterations found in human bladder cancer.	('rat', 'Species', '10116', (94, 97))	('p53', 'Gene', (47, 50))	('deletions', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (117, 131))	('human', 'Species', '9606', (111, 116))	('bladder cancer', 'Disease', 'MESH:D001749', (117, 131))	('mutations', 'Var', (13, 22))	('bladder cancer', 'Disease', (117, 131))
155182	28915710	Consistently, He and colleagues demonstrated that urothelial-specific deletion of both copies of Rb did not augment urothelial proliferation, but conversely, this deletion fostered activation of the p53 pathway and led to apoptosis.	('deletion', 'Var', (70, 78))	('apoptosis', 'biological_process', 'GO:0006915', ('222', '231'))	('p53 pathway', 'Pathway', (199, 210))	('apoptosis', 'CPA', (222, 231))	('men', 'Species', '9606', (111, 114))	('rat', 'Species', '10116', (39, 42))	('led to', 'Reg', (215, 221))	('apoptosis', 'biological_process', 'GO:0097194', ('222', '231'))	('fostered activation', 'PosReg', (172, 191))	('rat', 'Species', '10116', (134, 137))	('Rb', 'Phenotype', 'HP:0009919', (97, 99))	('Rb', 'Gene', '5925', (97, 99))
155184	28915710	This study suggested that genetic ablation of both p53 and Rb is essential for the progression of UCC, but insufficient to initiate invasive UCC by itself.	('UCC', 'Disease', (98, 101))	('insufficient', 'Disease', 'MESH:D000309', (107, 119))	('Rb', 'Phenotype', 'HP:0009919', (59, 61))	('Rb', 'Gene', '5925', (59, 61))	('insufficient', 'Disease', (107, 119))	('p53', 'Protein', (51, 54))	('genetic ablation', 'Var', (26, 42))
155185	28915710	Allelic loss of Tp53 alone was sufficient to drive tumorigenesis but not invasiveness of urothelial cancer.	('invasiveness of urothelial cancer', 'Disease', (73, 106))	('invasiveness of urothelial cancer', 'Disease', 'MESH:D009362', (73, 106))	('Tp53', 'Gene', '7157', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Allelic loss', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', (51, 56))	('drive', 'PosReg', (45, 50))	('Tp53', 'Gene', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
155186	28915710	The PTEN-PI3K-AKT pathway has been implicated in bladder cancer and reports suggest that deletion of PTEN occurs frequently in invasive UCC.	('PTEN', 'Gene', '5728', (4, 8))	('bladder cancer', 'Disease', (49, 63))	('PTEN', 'Gene', (101, 105))	('PTEN', 'Gene', '5728', (101, 105))	('PI3K', 'molecular_function', 'GO:0016303', ('9', '13'))	('bladder cancer', 'Phenotype', 'HP:0009725', (49, 63))	('deletion', 'Var', (89, 97))	('invasive UCC', 'Disease', (127, 139))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('bladder cancer', 'Disease', 'MESH:D001749', (49, 63))	('PTEN', 'Gene', (4, 8))
155187	28915710	Studies crossing Uroplakin-Cre mice with reported Pten floxed mice revealed the co-operation of activation of beta-catenin and with Pten deletion to drive urothelial carcinogenesis.	('beta-catenin', 'Protein', (110, 122))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (155, 180))	('mice', 'Species', '10090', (62, 66))	('deletion', 'Var', (137, 145))	('mice', 'Species', '10090', (31, 35))	('Cre', 'Gene', '2777477', (27, 30))	('urothelial carcinogenesis', 'Disease', (155, 180))	('drive', 'PosReg', (149, 154))	('rat', 'Species', '10116', (86, 89))	('activation', 'PosReg', (96, 106))	('Cre', 'Gene', (27, 30))	('Pten', 'Gene', (132, 136))
155189	28915710	Targeted deletion of Pten and expression of activated beta-catenin caused papillary UCC that exhibited increased pAKT signaling and were dependent on mammalian target of rapamycin (mTOR).	('increased', 'PosReg', (103, 112))	('deletion', 'Var', (9, 17))	('mammalian target of rapamycin', 'Gene', '2475', (150, 179))	('mammalian target of rapamycin', 'Gene', (150, 179))	('papillary UCC', 'Disease', (74, 87))	('Pten', 'Gene', (21, 25))	('caused', 'Reg', (67, 73))	('pAKT signaling', 'MPA', (113, 127))	('mTOR', 'Gene', '2475', (181, 185))	('signaling', 'biological_process', 'GO:0023052', ('118', '127'))	('mTOR', 'Gene', (181, 185))
155193	28915710	Yoo et al, developed a GEM model by deleting exons 4-5 of the Pten gene using the FabpCre system, in which the expression of Cre recombinase was placed under the control of transcriptional regulatory elements from a fatty acid-binding protein (Fabp) gene.	('Cre', 'Gene', '2777477', (125, 128))	('fatty acid-binding', 'molecular_function', 'GO:0005504', ('216', '234'))	('men', 'Species', '9606', (203, 206))	('Cre', 'Gene', (125, 128))	('fatty acid-binding protein', 'Gene', '2806', (216, 242))	('protein', 'cellular_component', 'GO:0003675', ('235', '242'))	('fatty acid-binding protein', 'Gene', (216, 242))	('Fabp', 'Gene', (82, 86))	('Cre', 'Gene', '2777477', (86, 89))	('Fabp', 'Gene', (244, 248))	('Fabp', 'Gene', '2806', (82, 86))	('Pten', 'Gene', (62, 66))	('Fabp', 'Gene', '2806', (244, 248))	('deleting', 'Var', (36, 44))	('Cre', 'Gene', (86, 89))
155197	28915710	Thus investigators concluded that deletion of Pten induces distinct tissue-specific pathways that influence tumor and progression.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('influence', 'Reg', (98, 107))	('Pten', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('induces', 'Reg', (51, 58))	('tumor', 'Disease', (108, 113))	('deletion', 'Var', (34, 42))
155201	28915710	Of note, Yang and colleagues observed that the simultaneous inactivation of p53 and activation of K-ras induces quick formation of spindle-cell sarcoma in the soft tissues adjacent to the bladder but slow formation of urothelial hyperplasia inside the bladder.	('sarcoma', 'Disease', (144, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('formation', 'biological_process', 'GO:0009058', ('205', '214'))	('p53', 'Gene', (76, 79))	('activation', 'PosReg', (84, 94))	('urothelial hyperplasia', 'Disease', (218, 240))	('formation', 'biological_process', 'GO:0009058', ('118', '127'))	('K-ras', 'Gene', (98, 103))	('K-ras', 'Gene', '3845', (98, 103))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('urothelial hyperplasia', 'Disease', 'MESH:D006965', (218, 240))	('spindle', 'cellular_component', 'GO:0005819', ('131', '138'))	('inactivation', 'Var', (60, 72))
155207	28915710	Important resources with detailed information regarding genetic alterations in cell lines are the Catalog of Somatic Mutations in Cancer (COSMIC) at the Sanger Institute (Cambridge, United Kingdom), the Cancer Genomic Atlas (TCGA) for tumor samples, the Cancer Cell Line Encyclopedia (CCLE), and the Genomics of Drug Sensitivity in Cancer.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Cancer', 'Disease', (203, 209))	('Cancer', 'Disease', (332, 338))	('Cancer', 'Disease', (130, 136))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (254, 283))	('Cancer', 'Phenotype', 'HP:0002664', (254, 260))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('Cancer', 'Disease', 'MESH:D009369', (203, 209))	('Cancer', 'Disease', 'MESH:D009369', (332, 338))	('Cancer', 'Disease', 'MESH:D009369', (130, 136))	('Cancer', 'Disease', (254, 260))	('rat', 'Species', '10116', (68, 71))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (312, 328))	('Cancer Genomic Atlas', 'Disease', 'MESH:D009369', (203, 223))	('Cancer Cell Line Encyclopedia', 'Disease', (254, 283))	('Mutations', 'Var', (117, 126))	('Cancer', 'Phenotype', 'HP:0002664', (332, 338))	('Cancer', 'Phenotype', 'HP:0002664', (203, 209))	('Cancer', 'Disease', 'MESH:D009369', (254, 260))	('Cancer Genomic Atlas', 'Disease', (203, 223))	('tumor', 'Disease', (235, 240))
155232	28915710	Also, the pharmacologic inhibition of ETAR by ZD4054 prior to injection of tumor cells significantly decreased the early inflammatory response as well as the development of lung metastases.	('metastases', 'Disease', 'MESH:D009362', (178, 188))	('men', 'Species', '9606', (165, 168))	('early inflammatory response', 'CPA', (115, 142))	('ZD4054', 'Var', (46, 52))	('ETAR', 'Gene', (38, 42))	('decreased', 'NegReg', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('ETAR', 'Gene', '1909', (38, 42))	('metastases', 'Disease', (178, 188))	('ZD4054', 'Chemical', 'MESH:C511404', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('inflammatory response', 'biological_process', 'GO:0006954', ('121', '142'))
155237	28915710	Additionally, using a syngeneic model of spontaneous metastasis in which SPARC-proficient MB49 cells were injected SC in SP-/- and SP+/+ mice, host-SPARC not only inhibited the in vivo growth, invasiveness, angiogenesis and inflammation of primary tumors, but also mitigated spontaneous lung metastasis through inhibition of the pre-conditioning of the inflammatory pre-metastatic and metastatic lung niche.	('mitigated', 'NegReg', (265, 274))	('inflammation', 'biological_process', 'GO:0006954', ('224', '236'))	('SP', 'Chemical', 'MESH:C000604007', (73, 75))	('tumors', 'Disease', (248, 254))	('host-SPARC', 'Var', (143, 153))	('inhibited', 'NegReg', (163, 172))	('angiogenesis', 'CPA', (207, 219))	('pre', 'molecular_function', 'GO:0003904', ('329', '332'))	('growth', 'CPA', (185, 191))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('inflammation', 'Disease', 'MESH:D007249', (224, 236))	('invasiveness', 'Disease', (193, 205))	('mice', 'Species', '10090', (137, 141))	('angiogenesis', 'biological_process', 'GO:0001525', ('207', '219'))	('SP', 'Chemical', 'MESH:C000604007', (131, 133))	('SP', 'Chemical', 'MESH:C000604007', (148, 150))	('pre', 'molecular_function', 'GO:0003904', ('366', '369'))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('inflammation', 'Disease', (224, 236))	('SP', 'Chemical', 'MESH:C000604007', (121, 123))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('inhibition', 'NegReg', (311, 321))	('spontaneous lung metastasis', 'CPA', (275, 302))	('invasiveness', 'Disease', 'MESH:D009362', (193, 205))	('MB49', 'CellLine', 'CVCL:7076', (90, 94))
155256	28915710	Another study reported the use of RT4 urothelial carcinoma cell line for tissue recombination experiments to identify the implications of p53 alterations and PTEN loss in urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('p53', 'Gene', (138, 141))	('men', 'Species', '9606', (100, 103))	('rat', 'Species', '10116', (146, 149))	('alterations', 'Var', (142, 153))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (171, 191))	('PTEN loss in urothelial carcinoma', 'Disease', 'MESH:D006223', (158, 191))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (38, 58))	('PTEN loss in urothelial carcinoma', 'Disease', (158, 191))	('urothelial carcinoma', 'Disease', (38, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))
155261	28915710	They demonstrated that Sh3gl2 expression significantly declined in early-stage as well as in advanced bladder cancer, and silencing Sh3gl2 increased tumor volume.	('expression', 'MPA', (30, 40))	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('rat', 'Species', '10116', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('increased', 'PosReg', (139, 148))	('Sh3gl2', 'Gene', (132, 138))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('bladder cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Sh3gl2', 'Gene', '6456', (23, 29))	('tumor', 'Disease', (149, 154))	('silencing', 'Var', (122, 131))	('Sh3gl2', 'Gene', (23, 29))	('declined', 'NegReg', (55, 63))	('Sh3gl2', 'Gene', '6456', (132, 138))
155270	28915710	developed a bladder cancer PDX model and were the first to use established genomic analyses techniques such as short tandem repeat genotyping, mutational analysis, and array-CGH along with conventional histologic analysis.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('bladder cancer', 'Disease', 'MESH:D001749', (12, 26))	('bladder cancer', 'Disease', (12, 26))	('short tandem', 'Var', (111, 123))	('bladder cancer', 'Phenotype', 'HP:0009725', (12, 26))
155296	28915710	HIFU ablation leads to coagulative thermal necrosis and cavitation damage due to absorption of ultrasound energy during transmission in tissue.	('necrosis', 'Disease', 'MESH:D009336', (43, 51))	('ablation', 'Var', (5, 13))	('cavitation damage', 'CPA', (56, 73))	('necrosis', 'biological_process', 'GO:0070265', ('43', '51'))	('necrosis', 'biological_process', 'GO:0008219', ('43', '51'))	('necrosis', 'biological_process', 'GO:0019835', ('43', '51'))	('necrosis', 'Disease', (43, 51))	('necrosis', 'biological_process', 'GO:0001906', ('43', '51'))	('necrosis', 'biological_process', 'GO:0008220', ('43', '51'))
155352	26894971	There were instances in which AGR2 staining was not detected in the primary tumor but was detected in the corresponding lymph nodes (e.g., cases B97-05, B00-08, B05-05, Supplementary Table 1).	('B97-05', 'Var', (145, 151))	('B00-08', 'Var', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('AGR2', 'Gene', (30, 34))	('B05-05', 'Var', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
155353	26894971	Many of the primary tumors showing AGR2 staining also showed AGR2-positive lymph nodes.	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('AGR2-positive', 'Gene', (61, 74))	('staining', 'Var', (40, 48))	('primary tumors', 'Disease', (12, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('AGR2', 'Gene', (35, 39))	('primary tumors', 'Disease', 'MESH:D009369', (12, 26))
155354	26894971	McNemar's test with Yates' correction for continuity for this distribution of AGR2 positivity between primary tumors and lymph node metastases was chi2 = 9.24 (P = <0.01).	('AGR2', 'Gene', (78, 82))	('primary tumors', 'Disease', 'MESH:D009369', (102, 116))	('metastases', 'Disease', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('metastases', 'Disease', 'MESH:D009362', (132, 142))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('positivity', 'Var', (83, 93))	('primary tumors', 'Disease', (102, 116))
155482	24466394	In addition, an SEP accelerates the operation without delay due to a positional change, thus providing better coordinated movements for both the surgeon and the assistant.	('men', 'Species', '9606', (126, 129))	('SEP', 'Var', (16, 19))	('coordinated movements', 'MPA', (110, 131))	('better', 'PosReg', (103, 109))	('accelerates', 'PosReg', (20, 31))
155492	23087801	About 90 to 100% nuclear staining was observed with p63, p53, and Ki-67.	('Ki-67', 'Var', (66, 71))	('p63', 'Gene', (52, 55))	('p53', 'Gene', (57, 60))	('p63', 'Gene', '8626', (52, 55))	('p53', 'Gene', '7157', (57, 60))
155518	23087801	The cellular structures within the myxoid stroma exhibited 90 to 100% nuclear staining with p63 (Figure 6), p53 and Ki-67; strong cytoplasmic staining with cytokeratin 20 (CK20), cytokeratin 7 (CK7) and high molecular weight keratin (34BE12) (Figure 7); and no staining with S-100, calponin, Glial fibrillary acidic protein (GFAP), CDX2, prostate specific antigen (PSA), and leukocyte common antigen (LCA).	('CK20', 'Gene', '54474', (172, 176))	('GFAP', 'cellular_component', 'GO:0045101', ('325', '329'))	('CK7', 'Gene', (194, 197))	('cytokeratin 7', 'Gene', '3855', (179, 192))	('cytokeratin 7', 'Gene', (179, 192))	('S-100', 'Gene', (275, 280))	('Glial fibrillary acidic protein', 'cellular_component', 'GO:0045101', ('292', '323'))	('S-100', 'Gene', '6271', (275, 280))	('Glial fibrillary acidic protein', 'cellular_component', 'GO:0045098', ('292', '323'))	('myxoid stroma', 'Disease', (35, 48))	('cytokeratin 20', 'Gene', (156, 170))	('CK7', 'Gene', '3855', (194, 197))	('p53', 'Gene', '7157', (108, 111))	('CDX2', 'Gene', '1045', (332, 336))	('cytokeratin 20', 'Gene', '54474', (156, 170))	('myxoid stroma', 'Disease', 'MESH:D045888', (35, 48))	('Ki-67', 'Var', (116, 121))	('p63', 'Gene', (92, 95))	('CK20', 'Gene', (172, 176))	('p53', 'Gene', (108, 111))	('prostate specific antigen', 'Gene', (338, 363))	('p63', 'Gene', '8626', (92, 95))	('GFAP', 'Gene', (325, 329))	('CDX2', 'Gene', (332, 336))	('Glial fibrillary acidic protein', 'Gene', (292, 323))	('prostate specific antigen', 'Gene', '354', (338, 363))	('Glial fibrillary acidic protein', 'Gene', '2670', (292, 323))	('GFAP', 'Gene', '2670', (325, 329))
155527	23087801	However, other features such as the presence of typical urothelial carcinoma fields; positive staining for 34BE12, p63, p53, CK7 and CK20; and negative staining for S-100, GFAP, and calponin assist in differential diagnosis.	('CK7', 'Gene', (125, 128))	('CK20', 'Gene', '54474', (133, 137))	('urothelial carcinoma', 'Disease', (56, 76))	('GFAP', 'Gene', '2670', (172, 176))	('S-100', 'Gene', (165, 170))	('p53', 'Gene', '7157', (120, 123))	('GFAP', 'cellular_component', 'GO:0045101', ('172', '176'))	('S-100', 'Gene', '6271', (165, 170))	('CK7', 'Gene', '3855', (125, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (56, 76))	('34BE12', 'Var', (107, 113))	('GFAP', 'Gene', (172, 176))	('p63', 'Gene', (115, 118))	('CK20', 'Gene', (133, 137))	('p53', 'Gene', (120, 123))	('p63', 'Gene', '8626', (115, 118))
155559	33324071	Mounting evidence indicates that the deregulation of lncRNA is implicated in the tumorigenesis and progression of various types of cancers, including BC.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('BC', 'Phenotype', 'HP:0009725', (150, 152))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('deregulation', 'Var', (37, 49))	('lncRNA', 'Protein', (53, 59))	('implicated', 'Reg', (63, 73))	('tumor', 'Disease', (81, 86))
155561	33324071	UCA1 overexpression promotes cell-cycle progression, carcinogenesis, and cancer invasion of BC cells through enhancing ERK1/2, MAPK, and PI3K-Akt pathways.	('Akt', 'Gene', (142, 145))	('carcinogenesis', 'Disease', (53, 67))	('PI3K', 'molecular_function', 'GO:0016303', ('137', '141'))	('MAPK', 'Pathway', (127, 131))	('Akt', 'Gene', '207', (142, 145))	('overexpression', 'Var', (5, 19))	('MAPK', 'molecular_function', 'GO:0004707', ('127', '131'))	('carcinogenesis', 'Disease', 'MESH:D063646', (53, 67))	('cancer', 'Disease', (73, 79))	('UCA1', 'Gene', (0, 4))	('promotes', 'PosReg', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cell-cycle', 'biological_process', 'GO:0007049', ('29', '39'))	('ERK1/2', 'Gene', '5595;5594', (119, 125))	('ERK1/2', 'Gene', (119, 125))	('ERK1', 'molecular_function', 'GO:0004707', ('119', '123'))	('enhancing', 'PosReg', (109, 118))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('BC', 'Phenotype', 'HP:0009725', (92, 94))	('UCA1', 'Gene', '652995', (0, 4))	('cell-cycle progression', 'CPA', (29, 51))
155609	33324071	Among the six lncRNAs, positive coefficients indicated that expression of MAFG-AS1, LINC02321, LINC01322, and LINC00922 correlated with longer OS, whereas expression of SNHG12 and ASMTL-AS1 inversely correlated with survival of patients (Table 3).	('MAFG-AS1', 'Gene', '92659', (74, 82))	('LINC01322', 'Gene', '103695433', (95, 104))	('LINC02321', 'Var', (84, 93))	('LINC01322', 'Gene', (95, 104))	('ASMTL-AS1', 'Gene', (180, 189))	('SNHG12', 'Gene', (169, 175))	('patients', 'Species', '9606', (228, 236))	('LINC00922', 'Gene', (110, 119))	('MAFG-AS1', 'Gene', (74, 82))	('SNHG12', 'Gene', '85028', (169, 175))	('LINC00922', 'Gene', '283867', (110, 119))	('ASMTL-AS1', 'Gene', '80161', (180, 189))	('longer OS', 'CPA', (136, 145))
155610	33324071	To assess whether the combination of the identified lncRNAs improved power in predicting OS of BC patients, we established a risk-scoring formula for OS prediction according to expression of the six lncRNAs: risk score=(-0.301151077 x expression value SNHG12) + (0.316595657 x expression value MAFG-AS1) + (0.172517499 x expression value LINC02321) + (0.179091241 x expression value ASMTL-AS1) + (0.158178271 x expression value LINC01322) + (0.124204122 x expression value LINC00922).	('0.316595657 x', 'Var', (263, 276))	('-0.301151077', 'Var', (220, 232))	('0.172517499 x', 'Var', (307, 320))	('SNHG12', 'Gene', (252, 258))	('ASMTL-AS1', 'Gene', (383, 392))	('patients', 'Species', '9606', (98, 106))	('BC', 'Phenotype', 'HP:0009725', (95, 97))	('0.179091241', 'Var', (352, 363))	('MAFG-AS1', 'Gene', (294, 302))	('SNHG12', 'Gene', '85028', (252, 258))	('ASMTL-AS1', 'Gene', '80161', (383, 392))	('MAFG-AS1', 'Gene', '92659', (294, 302))	('LINC01322', 'Gene', '103695433', (428, 437))	('LINC00922', 'Gene', '283867', (473, 482))	('LINC01322', 'Gene', (428, 437))	('LINC00922', 'Gene', (473, 482))
155637	33324071	As GO and KEGG analyses indicated connection of lncRNAs in the SMALLL signature in the ECM network, often implicated in cancer metastasis, and the difference in SNHG12 between cancer and adjacent cancer was not significant.	('lncRNAs', 'Var', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer metastasis', 'Disease', 'MESH:D009362', (120, 137))	('SNHG12', 'Gene', '85028', (161, 167))	('SMALLL signature', 'Gene', (63, 79))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer metastasis', 'Disease', (120, 137))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('SNHG12', 'Gene', (161, 167))
155642	33324071	As shown in Figure 6E-I, knockdown of MAFG-AS1, LINC02321, and LINC00922 significantly inhibited the migration and invasion of UMUC3 and RT4 cells, and knockdown of ASMTL-AS1 significantly promoted the migration and invasion of RT4 cells.	('knockdown', 'Var', (152, 161))	('MAFG-AS1', 'Gene', (38, 46))	('LINC00922', 'Gene', '283867', (63, 72))	('ASMTL-AS1', 'Gene', '80161', (165, 174))	('LINC00922', 'Gene', (63, 72))	('RT4', 'CellLine', 'CVCL:0036', (137, 140))	('MAFG-AS1', 'Gene', '92659', (38, 46))	('promoted', 'PosReg', (189, 197))	('inhibited', 'NegReg', (87, 96))	('invasion', 'CPA', (216, 224))	('ASMTL-AS1', 'Gene', (165, 174))	('LINC02321', 'Var', (48, 57))	('knockdown', 'Var', (25, 34))	('RT4', 'CellLine', 'CVCL:0036', (228, 231))
155649	33324071	Accumulating evidence has indicated that lncRNAs are involved in many physiological processes, and deregulated lncRNAs may contribute to the occurrence, development, and metastasis of cancer.	('cancer', 'Disease', (184, 190))	('deregulated', 'Var', (99, 110))	('metastasis', 'CPA', (170, 180))	('contribute', 'Reg', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('men', 'Species', '9606', (160, 163))	('development', 'CPA', (153, 164))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
155666	33324071	Next, we confirmed through in vitro experiments that knockdown of these lncRNAs significantly affects the invasion and migration of BC cells.	('knockdown', 'Var', (53, 62))	('affects', 'Reg', (94, 101))	('men', 'Species', '9606', (42, 45))	('BC', 'Phenotype', 'HP:0009725', (132, 134))
155676	30820651	We found that T3G3 tumors had increased CD34 density kurtosis and skewness compared to TaG1 tumors.	('tumors', 'Disease', (19, 25))	('T3G3', 'Var', (14, 18))	('kurtosis and skewness', 'Disease', 'MESH:D015835', (53, 74))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('CD34', 'Gene', (40, 44))	('CD34', 'Gene', '947', (40, 44))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('increased', 'PosReg', (30, 39))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('tumors', 'Disease', (92, 98))
155732	30820651	This analysis revealed that the CD34 density kurtosis and skewness were markedly higher in the T3G3 lesions than in the TaG1 tumors (see Table 1).	('CD34', 'Gene', (32, 36))	('kurtosis and skewness', 'Disease', 'MESH:D015835', (45, 66))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('higher', 'PosReg', (81, 87))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('T3G3', 'Var', (95, 99))	('CD34', 'Gene', '947', (32, 36))
155742	30820651	studied genetic aberrations in UTUC and UCB in 300 cancer-associated genes, and those authors concluded that although there are many similarities in gene mutations, there are also many differences between UCB and UTUC.	('UTUC', 'Disease', (31, 35))	('UTUC', 'Disease', 'MESH:D012141', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('UTUC', 'Disease', 'MESH:D012141', (31, 35))	('aberrations', 'Var', (16, 27))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('UTUC', 'Disease', (213, 217))
155758	30447301	Targeted sequencing of plasmacytoid urothelial carcinoma reveals frequent TERT promoter mutations , Activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the most common genetic alterations in urothelial carcinoma (UC) of the bladder and upper urinary tract.	('transcriptase', 'molecular_function', 'GO:0003968', ('163', '176'))	('transcriptase', 'molecular_function', 'GO:0034062', ('163', '176'))	('carcinoma', 'Disease', 'MESH:D002277', (243, 252))	('mutations', 'Var', (88, 97))	('urothelial carcinoma', 'Disease', (232, 252))	('UC', 'Disease', 'MESH:D014523', (254, 256))	('Activating', 'PosReg', (100, 110))	('mutations', 'Var', (111, 120))	('rat', 'Species', '10116', (221, 224))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (36, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinoma', 'Disease', (47, 56))	('TERT', 'Gene', (74, 78))	('transcriptase', 'molecular_function', 'GO:0003899', ('163', '176'))	('telomerase reverse transcriptase', 'Gene', (144, 176))	('urothelial carcinoma', 'Disease', (36, 56))	('TERT', 'Gene', '7015', (74, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('TERT', 'Gene', (178, 182))	('TERT', 'Gene', '7015', (178, 182))	('carcinoma', 'Disease', (243, 252))	('telomerase reverse transcriptase', 'Gene', '7015', (144, 176))	('carcinoma', 'Disease', 'MESH:D002277', (47, 56))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (232, 252))
155762	30447301	Samples were analyzed for TERT promoter mutations with Safe-SeqS, a sequencing error-reduction technology, and sequenced using a targeted panel of the 10 most commonly mutated genes in bladder cancer on the Illumina MiSeq platform.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('bladder cancer', 'Phenotype', 'HP:0009725', (185, 199))	('mutations', 'Var', (40, 49))	('bladder cancer', 'Disease', 'MESH:D001749', (185, 199))	('bladder cancer', 'Disease', (185, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('error-reduction technology', 'Disease', 'MESH:D012030', (79, 105))	('error-reduction technology', 'Disease', (79, 105))
155764	30447301	In heterogeneous tumors with focal variant histology, concordant mutations were found in plasmacytoid and corresponding conventional, glandular, or sarcomatoid areas.	('found', 'Reg', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('sarcoma', 'Disease', (148, 155))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('sarcomatoid', 'Disease', (148, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('plasmacytoid', 'Disease', (89, 101))	('sarcomatoid', 'Disease', 'MESH:D002292', (148, 159))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mutations', 'Var', (65, 74))
155767	30447301	Mutations are most often truncating somatic variants that result in a nonfunctional E-cadherin protein, which prevents tumor suppression and cell adhesion.	('E-cadherin', 'Gene', (84, 94))	('prevents', 'NegReg', (110, 118))	('E-cadherin', 'Gene', '999', (84, 94))	('cell adhesion', 'CPA', (141, 154))	('tumor suppression', 'CPA', (119, 136))	('nonfunctional', 'MPA', (70, 83))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('Mutations', 'Var', (0, 9))	('cell adhesion', 'biological_process', 'GO:0007155', ('141', '154'))	('cadherin', 'molecular_function', 'GO:0008014', ('86', '94'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('result in', 'Reg', (58, 67))	('variants', 'Var', (44, 52))
155769	30447301	Somatic activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene, originally discovered in most melanomas, have been found to be the most common genetic mutations overall in UC of either the bladder or the upper urinary tract.	('melanomas', 'Phenotype', 'HP:0002861', (128, 137))	('transcriptase', 'molecular_function', 'GO:0003968', ('71', '84'))	('transcriptase', 'molecular_function', 'GO:0003899', ('71', '84'))	('melanomas', 'Disease', 'MESH:D008545', (128, 137))	('mutations', 'Var', (19, 28))	('transcriptase', 'molecular_function', 'GO:0034062', ('71', '84'))	('TERT', 'Gene', (86, 90))	('activating', 'PosReg', (8, 18))	('mutations', 'Var', (185, 194))	('melanomas', 'Disease', (128, 137))
155770	30447301	In a study by Kinde et al, 66% of muscle-invasive and 74% of non-muscle-invasive bladder lesions were shown to harbor these alterations.	('bladder lesions', 'Disease', 'MESH:D001745', (81, 96))	('alterations', 'Var', (124, 135))	('muscle-invasive', 'Disease', (34, 49))	('non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (61, 88))	('invasive bladder', 'Phenotype', 'HP:0100645', (72, 88))	('bladder lesions', 'Disease', (81, 96))
155771	30447301	Recently, we and others have also identified TERT promoter mutations in specific lesional subtypes including papillary urothelial neoplasm of unknown malignant potential, small cell carcinomas of the urinary bladder, micropapillary UC, primary squamous cell carcinoma of the bladder, primary adenocarcinoma of the bladder, nested and "large nested" variants of UC, sarcomatoid UC of the upper urinary tract (6/17 cases), and UC of the renal pelvis and the ureter.	('renal pelvis', 'Phenotype', 'HP:0000125', (435, 447))	('squamous cell carcinoma of the bladder', 'Disease', 'MESH:D002294', (244, 282))	('small cell carcinomas', 'Disease', (171, 192))	('papillary urothelial neoplasm', 'Disease', 'MESH:D014523', (109, 138))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (171, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (365, 372))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('squamous cell carcinoma of the bladder', 'Disease', (244, 282))	('carcinomas', 'Phenotype', 'HP:0030731', (182, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (244, 267))	('UC of the upper urinary tract', 'Phenotype', 'HP:0010935', (377, 406))	('neoplasm', 'Phenotype', 'HP:0002664', (130, 138))	('adenocarcinoma of the bladder', 'Disease', 'MESH:D001749', (292, 321))	('papillary urothelial neoplasm', 'Disease', (109, 138))	('sarcomatoid UC of the upper urinary tract', 'Disease', (365, 406))	('micropapillary UC', 'Disease', 'MESH:D014523', (217, 234))	('mutations', 'Var', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('small cell carcinomas', 'Disease', 'MESH:D018288', (171, 192))	('micropapillary UC', 'Disease', (217, 234))	('adenocarcinoma of the bladder', 'Disease', (292, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))
155784	30447301	Interestingly, 2 additional TP53 mutations, p.R248W (VAF 1.4%) and p.R342* (1%), were detected in the areas with conventional/glandular morphology but not in the separately isolated areas with plasmacytoid or sarcomatoid variant morphology in case 8 (Table 3).	('p.R248W', 'Var', (44, 51))	('TP53', 'Gene', (28, 32))	('p.R342*', 'Var', (67, 74))	('p.R248W', 'Mutation', 'rs121912651', (44, 51))	('p.R342*', 'Mutation', 'p.R342*', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))
155785	30447301	Al-Ahmadie et al recently reported that plasmacytoid UC frequently, if not always, have truncating somatic mutations in cadherin 1 (CDH1), similar to signet ring cell gastric carcinoma and lobular carcinoma of the breast.	('mutations', 'Var', (107, 116))	('truncating', 'MPA', (88, 98))	('CDH1', 'Gene', (132, 136))	('cadherin', 'molecular_function', 'GO:0008014', ('120', '128'))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (197, 220))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (189, 206))	('gastric carcinoma', 'Disease', (167, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (167, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('gastric carcinoma', 'Disease', 'MESH:D013274', (167, 184))	('lobular carcinoma of the breast', 'Disease', (189, 220))
155788	30447301	One study of gastric cancers, however, which looked at the entire TERT promoter region, did note that novel mutations were more frequent than hotspot TERT promoter mutations.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('gastric cancers', 'Disease', 'MESH:D013274', (13, 28))	('mutations', 'Var', (108, 117))	('gastric cancers', 'Disease', (13, 28))	('gastric cancers', 'Phenotype', 'HP:0012126', (13, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('frequent', 'Reg', (128, 136))
155789	30447301	The most common TERT promoter mutations (g.1295228C>T and g.1295250C>T) are believed to result in the creation of novel CCGGAA/T general binding motifs for E26 transformation-specific (ETS)/ternary complex factor transcription factors.	('binding', 'Interaction', (137, 144))	('transcription', 'biological_process', 'GO:0006351', ('213', '226'))	('g.1295250C>T', 'Var', (58, 70))	('g.1295228C>T', 'SUBSTITUTION', 'None', (41, 53))	('ETS', 'Chemical', '-', (185, 188))	('binding', 'molecular_function', 'GO:0005488', ('137', '144'))	('g.1295250C>T', 'Mutation', 'g.1295250C>T', (58, 70))	('g.1295228C>T', 'Var', (41, 53))
155790	30447301	We also found concordant TERT promoter mutations in areas of nonplasmacytoid histology in heterogeneous tumors containing components of conventional urothelial, glandular, or sarcomatoid morphologies.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('mutations', 'Var', (39, 48))	('sarcomatoid morphologies', 'Disease', 'MESH:D002292', (175, 199))	('TERT promoter', 'Gene', (25, 38))	('sarcomatoid morphologies', 'Disease', (175, 199))
155800	31024612	Together, modularized perturbation of splicing represents an functionally important and common mechanism across cancer types.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('splicing', 'biological_process', 'GO:0045292', ('38', '46'))	('perturbation', 'Var', (22, 34))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
155801	31024612	Deregulation of AS also contributes to human diseases and various aspects of cancer development (David and Manley,; Scotti and Swanson,).	('Scotti', 'Disease', (116, 122))	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', (77, 83))	('Manley', 'Disease', (107, 113))	('human diseases', 'Disease', (39, 53))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('contributes', 'Reg', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('human', 'Species', '9606', (39, 44))	('Swanson', 'Disease', (127, 134))
155819	31024612	The splicing classes included are exon skipping (ES), retention of introns (RI), alternative donor (AD), alternative acceptor (AA), mutually exclusive exons (ME), alternative terminator (AT).	('AT', 'Disease', 'None', (187, 189))	('retention', 'biological_process', 'GO:0051235', ('54', '63'))	('splicing', 'biological_process', 'GO:0045292', ('4', '12'))	('AD', 'Disease', 'MESH:D000544', (100, 102))	('AD', 'Disease', (100, 102))	('exon skipping', 'Var', (34, 47))	('donor', 'Species', '9606', (93, 98))
155820	31024612	The numbers of quantified events were found in at least 99% of the samples in each cancer type range from 21129 to 43937 across the cancer types.	('21129', 'Var', (106, 111))	('43937', 'Var', (115, 120))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (83, 89))
155845	31024612	This is actually consistent with a recent pan-cancer analysis using multi-platform integrative clustering (Hoadley et al.,), suggesting that splicing events can also be useful for cancer classification and subtyping.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('splicing', 'Var', (141, 149))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('splicing', 'biological_process', 'GO:0045292', ('141', '149'))	('cancer', 'Disease', (180, 186))
155881	30687563	The perioperative PROSPER study is investigating nivolumab given in the neoadjuvant vs adjuvant settings (NCT03055013), and adjuvant studies IMmotion 010 (NCT03024996) and Keynote 564 (NCT03142334) are respectively testing the addition of atezolizumab and pembrolizumab as treatment after nephrectomy.	('men', 'Species', '9606', (278, 281))	('NCT03142334', 'Var', (185, 196))	('NCT03024996', 'Var', (155, 166))	('nivolumab', 'Chemical', 'MESH:D000077594', (49, 58))	('NCT03055013', 'Var', (106, 117))	('pembrolizumab', 'Chemical', 'MESH:C582435', (256, 269))	('atezolizumab', 'Chemical', 'MESH:C000594389', (239, 251))	('OS', 'Gene', '17451', (20, 22))
155899	30687563	Other ongoing trials are exploiting combination immunotherapies for mUC, including importantly the DANUBE trial with durvalumab and tremelimumab (NCT02516241) and early phase trials combining PD-1 therapies with vaccination strategies (NCT02897765), other receptors such as CD122 (NCT02983045) and GITR (NCT03126110), and chemotherapy via novel delivery systems (NCT03518320).	('NCT02897765', 'Var', (236, 247))	('PD-1', 'Gene', (192, 196))	('PD-1', 'Gene', '5133', (192, 196))	('GITR', 'Gene', (298, 302))	('NCT03518320', 'Var', (363, 374))	('durvalumab', 'Chemical', 'MESH:C000613593', (117, 127))	('NCT03126110', 'Var', (304, 315))	('NCT02983045', 'Var', (281, 292))	('tremelimumab', 'Chemical', 'MESH:C520704', (132, 144))	('GITR', 'Gene', '8784', (298, 302))
155910	30687563	Thus, men with mCRPC and greater mutation burdens and neoantigens may have a greater response to ICI.	('mCRPC', 'Disease', (15, 20))	('mutation', 'Var', (33, 41))	('CR', 'Chemical', '-', (16, 18))	('greater', 'PosReg', (77, 84))	('response to ICI', 'MPA', (85, 100))	('men', 'Species', '9606', (6, 9))
155912	30687563	In select populations including patients with microsatellite instability (MSI- high) somatic alterations, PD-1 inhibitors are indicated and have been associated with durable responses, and pembrolizumab is currently recommended in NCCN guidelines based on a large basket study of patients with microsatellite instability-high (MSI-H) tumors across a range of histologic subtypes, including prostate cancer.	('pembrolizumab', 'Chemical', 'MESH:C582435', (189, 202))	('patients', 'Species', '9606', (32, 40))	('PD-1', 'Gene', '5133', (106, 110))	('prostate cancer', 'Disease', (390, 405))	('MSI', 'Gene', (327, 330))	('patients', 'Species', '9606', (280, 288))	('PD-1', 'Gene', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('MSI', 'Gene', '5928', (327, 330))	('MSI', 'Gene', (74, 77))	('men', 'Species', '9606', (221, 224))	('MSI-H) tumors', 'Disease', 'MESH:D009369', (327, 340))	('tumors', 'Phenotype', 'HP:0002664', (334, 340))	('microsatellite', 'Var', (46, 60))	('MSI', 'Gene', '5928', (74, 77))	('prostate cancer', 'Disease', 'MESH:D011471', (390, 405))	('cancer', 'Phenotype', 'HP:0002664', (399, 405))	('prostate cancer', 'Phenotype', 'HP:0012125', (390, 405))
155913	30687563	However, there were very few patients in this study with MSI-high mCRPC, and thus, more studies are needed to understand the relative benefits and durability of responses to PD-1 inhibition in mismatch repair deficient and/or MSI-high prostate cancer.	('patients', 'Species', '9606', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('PD-1', 'Gene', (174, 178))	('PD-1', 'Gene', '5133', (174, 178))	('CR', 'Chemical', '-', (67, 69))	('MSI', 'Gene', (57, 60))	('prostate cancer', 'Phenotype', 'HP:0012125', (235, 250))	('mismatch repair', 'biological_process', 'GO:0006298', ('193', '208'))	('MSI', 'Gene', (226, 229))	('MSI', 'Gene', '5928', (57, 60))	('MSI-high prostate cancer', 'Disease', 'MESH:D011471', (226, 250))	('MSI', 'Gene', '5928', (226, 229))	('mismatch repair deficient', 'Var', (193, 218))	('MSI-high prostate cancer', 'Disease', (226, 250))
155915	30687563	CDK12 loss is present in about 5% of men with mCRPC and is associated with a tandem duplication genotype and a high prevalence of fusion neoantigens, leading to immunogenicity and a higher response to ICIs targeting PD-1.	('loss', 'NegReg', (6, 10))	('PD-1', 'Gene', (216, 220))	('CDK12', 'Gene', '51755', (0, 5))	('PD-1', 'Gene', '5133', (216, 220))	('CDK', 'molecular_function', 'GO:0004693', ('0', '3'))	('tandem duplication', 'Var', (77, 95))	('CDK12', 'Gene', (0, 5))	('associated', 'Reg', (59, 69))	('higher', 'PosReg', (182, 188))	('immunogenicity', 'MPA', (161, 175))	('fusion neoantigens', 'MPA', (130, 148))	('men', 'Species', '9606', (37, 40))	('CR', 'Chemical', '-', (47, 49))	('mCRPC', 'Disease', (46, 51))
155922	30687563	Moreover, treatment-related neuroendocrine prostate cancer (trNEPC) has emerged as a distinct complication of hormonal therapies in prostate cancer, with shortened clinical courses, and DNA repair pathway alterations seem to drive these more aggressive disease courses.	('prostate cancer', 'Disease', (132, 147))	('aggressive disease', 'Disease', 'MESH:D001523', (242, 260))	('DNA repair pathway', 'Pathway', (186, 204))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('DNA repair', 'biological_process', 'GO:0006281', ('186', '196'))	('DNA', 'cellular_component', 'GO:0005574', ('186', '189'))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('alterations', 'Var', (205, 216))	('aggressive disease', 'Disease', (242, 260))	('prostate cancer', 'Disease', 'MESH:D011471', (132, 147))	('men', 'Species', '9606', (15, 18))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('neuroendocrine prostate cancer', 'Disease', (28, 58))	('prostate cancer', 'Disease', 'MESH:D011471', (43, 58))	('prostate cancer', 'Phenotype', 'HP:0012125', (43, 58))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (28, 58))
155941	28851690	NNK has been identified as a potent carcinogen which induces DNA adducts, mutations and promotes tumor growth through receptor-mediated effects.	('promotes', 'PosReg', (88, 96))	('NNK', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('DNA adducts', 'MPA', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', (97, 102))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('NNK', 'Chemical', 'MESH:C016583', (0, 3))	('induces', 'Reg', (53, 60))
155961	28851690	DNA double-stranded breaks (DSBs) are rapidly generated when cells are exposed to smoke or carcinogens, resulting in the phosphorylation of the histone H2A variant H2AX at Ser 139 (gamma-H2AX) and Checkpoint kinase 2 (Chk2) at Thr68, which are considered to be the sensitive markers for DNA damage.	('Checkpoint kinase 2', 'Gene', '11200', (197, 216))	('Chk2', 'Gene', '11200', (218, 222))	('DNA', 'cellular_component', 'GO:0005574', ('287', '290'))	('Ser', 'Chemical', 'MESH:D012694', (172, 175))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('Chk2', 'Gene', (218, 222))	('variant', 'Var', (156, 163))	('Ser', 'cellular_component', 'GO:0005790', ('172', '175'))	('phosphorylation', 'MPA', (121, 136))	('Checkpoint kinase 2', 'Gene', (197, 216))	('H2AX', 'Protein', (164, 168))	('Thr68', 'Chemical', '-', (227, 232))	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))
155979	28851690	Interestingly, the knockdown cells had significantly lower levels of SAH, homocysteine, glutathione and methyl adducts, but had higher levels of methionine and SAM (Supplementary Figure 3D).	('levels', 'MPA', (59, 65))	('SAM', 'Chemical', '-', (160, 163))	('methionine', 'MPA', (145, 155))	('SAH', 'Gene', (69, 72))	('SAH', 'Gene', '6296', (69, 72))	('levels', 'MPA', (135, 141))	('homocysteine', 'MPA', (74, 86))	('knockdown', 'Var', (19, 28))	('homocysteine', 'Chemical', 'MESH:D006710', (74, 86))	('glutathione', 'MPA', (88, 99))	('SAM', 'MPA', (160, 163))	('methyl adducts', 'MPA', (104, 118))	('methionine', 'Chemical', 'MESH:D008715', (145, 155))	('lower', 'NegReg', (53, 58))	('higher', 'PosReg', (128, 134))	('glutathione', 'Chemical', 'MESH:D005978', (88, 99))
155987	28851690	In this study, we found that the BLCA-associated metabolome was enriched with methylated metabolites, PAHs and DNA adducts, which suggests that methylation is a hallmark of BLCA in smokers.	('BLCA', 'Phenotype', 'HP:0009725', (173, 177))	('methylated metabolites', 'MPA', (78, 100))	('methylation', 'Var', (144, 155))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('methylation', 'biological_process', 'GO:0032259', ('144', '155'))	('PAHs', 'Chemical', 'MESH:D011084', (102, 106))	('BLCA', 'Phenotype', 'HP:0009725', (33, 37))
155993	28851690	Our novel findings demonstrated elevated levels of methylated DNA adducts and metabolites in smokers as well as NNK and BaP treated cell lines, which indicates that NNK and BaP induced hyper methylation is not only involved in the epigenetic modification of tumor suppressor genes, but also plays a role in DNA damage and alteration of cellular metabolism.	('role', 'Reg', (299, 303))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('cellular metabolism', 'MPA', (336, 355))	('tumor', 'Disease', (258, 263))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('alteration', 'Reg', (322, 332))	('hyper methylation', 'Var', (185, 202))	('NNK and BaP', 'Gene', '11331', (112, 123))	('methylation', 'biological_process', 'GO:0032259', ('191', '202'))	('DNA', 'cellular_component', 'GO:0005574', ('307', '310'))	('plays', 'Reg', (291, 296))	('cellular metabolism', 'biological_process', 'GO:0044237', ('336', '355'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('258', '274'))	('NNK and BaP', 'Gene', '11331', (165, 176))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('258', '274'))	('involved', 'Reg', (215, 223))
155998	28851690	DNMT1 inhibitors are currently being investigated as epigenetic therapeutics for the treatment of cancer and our findings further supports the investigation of DNMT1 inhibitors as potential therapeutics for smokers with BLCA.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('DNMT1', 'Gene', (160, 165))	('BLCA', 'Phenotype', 'HP:0009725', (220, 224))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('DNMT1', 'Gene', '1786', (160, 165))	('cancer', 'Disease', (98, 104))	('DNMT1', 'Gene', (0, 5))	('BLCA', 'Disease', (220, 224))	('DNMT1', 'Gene', '1786', (0, 5))	('inhibitors', 'Var', (166, 176))
156002	28851690	Moreover, higher levels of methionine, SAM and lower levels of DNA adducts, SAH in DNMT1 knockdown in BLCA cells further strengthens the role of DNMT1 in BLCA development.	('DNMT1', 'Gene', (145, 150))	('DNMT1', 'Gene', '1786', (83, 88))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('SAH', 'Gene', '6296', (76, 79))	('SAM', 'Chemical', '-', (39, 42))	('DNMT1', 'Gene', '1786', (145, 150))	('BLCA', 'Phenotype', 'HP:0009725', (102, 106))	('SAH', 'Gene', (76, 79))	('BLCA', 'Phenotype', 'HP:0009725', (154, 158))	('methionine', 'Chemical', 'MESH:D008715', (27, 37))	('SAM', 'MPA', (39, 42))	('knockdown', 'Var', (89, 98))	('higher', 'PosReg', (10, 16))	('strengthens', 'PosReg', (121, 132))	('methionine', 'MPA', (27, 37))	('DNMT1', 'Gene', (83, 88))
156007	28851690	The relevant findings were that smoking induced methylation by DNMT1, which plays a critical role in the accumulation of methylated metabolites with resultant DNA damage and altered metabolism in BLCA.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('DNA', 'cellular_component', 'GO:0005574', ('159', '162'))	('BLCA', 'Phenotype', 'HP:0009725', (196, 200))	('metabolism', 'biological_process', 'GO:0008152', ('182', '192'))	('DNMT1', 'Gene', '1786', (63, 68))	('methylated metabolites', 'MPA', (121, 143))	('accumulation', 'PosReg', (105, 117))	('DNA', 'MPA', (159, 162))	('DNMT1', 'Gene', (63, 68))	('methylation', 'Var', (48, 59))	('metabolism', 'MPA', (182, 192))	('altered', 'Reg', (174, 181))
156008	28678170	Differential Effects of Histone Acetyltransferase GCN5 or PCAF Knockdown on Urothelial Carcinoma Cells Disturbances in histone acetyltransferases (HATs) are common in cancers.	('GCN5', 'Gene', (50, 54))	('Effects', 'Reg', (13, 20))	('GCN5', 'Gene', '2648', (50, 54))	('PCAF Knockdown on Urothelial Carcinoma', 'Disease', (58, 96))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancers', 'Disease', (167, 174))	('histone acetyltransferases', 'MPA', (119, 145))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('PCAF Knockdown on Urothelial Carcinoma', 'Disease', 'MESH:D014526', (58, 96))	('Disturbances', 'Var', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('Carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
156009	28678170	In urothelial carcinoma (UC), p300 and CBP are often mutated, whereas the GNAT family HATs GCN5 and PCAF (General Control Nonderepressible 5, p300/CBP-Associated Factor) are often upregulated.	('CBP', 'Gene', '1387', (147, 150))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (3, 23))	('PCAF', 'Gene', (100, 104))	('mutated', 'Var', (53, 60))	('GNAT', 'Gene', '92292', (74, 78))	('CBP', 'Gene', (147, 150))	('upregulated', 'PosReg', (180, 191))	('GCN5', 'Gene', (91, 95))	('p300', 'Gene', (142, 146))	('GCN5', 'Gene', '2648', (91, 95))	('GNAT family HATs', 'Phenotype', 'HP:0007616', (74, 90))	('p300', 'Gene', '2033', (142, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('CBP', 'molecular_function', 'GO:0008140', ('147', '150'))	('urothelial carcinoma', 'Disease', (3, 23))	('CBP', 'Gene', '1387', (39, 42))	('CBP', 'molecular_function', 'GO:0008140', ('39', '42'))	('p300', 'Gene', (30, 34))	('p300', 'Gene', '2033', (30, 34))	('CBP', 'Gene', (39, 42))	('GNAT', 'Gene', (74, 78))
156010	28678170	Here, we explored the effects of specific siRNA-mediated knockdown of GCN5, PCAF or both in four UC cell lines (UCCs).	('PCAF', 'Gene', (76, 80))	('GCN5', 'Gene', '2648', (70, 74))	('GCN5', 'Gene', (70, 74))	('knockdown', 'Var', (57, 66))
156014	28678170	PCAF knockdown elicited GCN5 mRNA upregulation.	('knockdown', 'Var', (5, 14))	('PCAF', 'Gene', (0, 4))	('GCN5', 'Gene', (24, 28))	('GCN5', 'Gene', '2648', (24, 28))	('upregulation', 'PosReg', (34, 46))
156017	28678170	GCN5 knockdown impeded growth of specific UCCs, whereas PCAF knockdown elicited minor effects.	('impeded', 'NegReg', (15, 22))	('knockdown', 'Var', (5, 14))	('GCN5', 'Gene', (0, 4))	('GCN5', 'Gene', '2648', (0, 4))	('growth', 'CPA', (23, 29))
156025	28678170	According to the Cancer Genome Atlas Research Network and concurrent reports by others, genes encoding chromatin regulators are more frequently mutated in urothelial carcinoma than in other common cancers.	('urothelial carcinoma', 'Disease', (155, 175))	('mutated', 'Var', (144, 151))	('chromatin', 'cellular_component', 'GO:0000785', ('103', '112'))	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('cancers', 'Disease', (197, 204))	('Cancer Genome Atlas', 'Disease', (17, 36))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (155, 175))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (17, 36))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
156038	28678170	The search moreover revealed that in UC tissues, p300 and CBP are often affected by deletions, missense mutations or truncating mutations, whereas GCN5, PCAF, MYST3 are rather amplified or upregulated, and MYST4 shows the same but fewer alterations.	('CBP', 'Gene', '1387', (58, 61))	('missense mutations', 'Var', (95, 113))	('MYST4', 'Gene', (206, 211))	('MYST4', 'Gene', '23522', (206, 211))	('p300', 'Gene', (49, 53))	('GCN5', 'Gene', (147, 151))	('MYST3', 'Gene', (159, 164))	('p300', 'Gene', '2033', (49, 53))	('MYST3', 'Gene', '7994', (159, 164))	('CBP', 'molecular_function', 'GO:0008140', ('58', '61'))	('upregulated', 'PosReg', (189, 200))	('GCN5', 'Gene', '2648', (147, 151))	('affected', 'Reg', (72, 80))	('CBP', 'Gene', (58, 61))	('truncating', 'MPA', (117, 127))	('deletions', 'Var', (84, 93))
156039	28678170	TRRAP was likewise mutated in some UC tissues (Figure S1).	('TRRAP', 'Gene', (0, 5))	('TRRAP', 'Gene', '8295', (0, 5))	('mutated', 'Var', (19, 26))
156043	28678170	Expression of p300 and CBP mRNA was variable in UCCs and UPs, but p300 mRNA was distinctly decreased in individual cell lines known to harbor inactivating mutations (especially 639-V and 647-V).	('CBP', 'Gene', '1387', (23, 26))	('p300', 'Gene', (14, 18))	('647-V', 'Var', (187, 192))	('p300', 'Gene', (66, 70))	('p300', 'Gene', '2033', (14, 18))	('CBP', 'Gene', (23, 26))	('CBP', 'molecular_function', 'GO:0008140', ('23', '26'))	('p300', 'Gene', '2033', (66, 70))	('decreased', 'NegReg', (91, 100))	('639-V', 'Var', (177, 182))
156054	28678170	Of note, knockdown of GCN5 consistently led to upregulation of PCAF mRNA in UM-UC-3, VM-CUB-1 and BFTC-905 (Figure 3B).	('PCAF mRNA', 'Gene', (63, 72))	('knockdown', 'Var', (9, 18))	('GCN5', 'Gene', (22, 26))	('GCN5', 'Gene', '2648', (22, 26))	('upregulation', 'PosReg', (47, 59))	('BFTC-905', 'Chemical', '-', (98, 106))
156056	28678170	At 72 h after GCN5 knockdown by siRNA transfection, the number of viable cells was strongly diminished in BFTC-905 and UM-UC-3 cells, but not in the two other cell lines (Figure 4A).	('diminished', 'NegReg', (92, 102))	('number of viable cells', 'CPA', (56, 78))	('BFTC-905', 'Chemical', '-', (106, 114))	('knockdown', 'Var', (19, 28))	('transfection', 'Var', (38, 50))	('GCN5', 'Gene', (14, 18))	('GCN5', 'Gene', '2648', (14, 18))
156057	28678170	GCN5 knockdown also inhibited clonogenic growth almost completely in BFTC-905, and less strongly in UM-UC-3 and VM-CUB-1 (Figure 5).	('clonogenic growth', 'CPA', (30, 47))	('BFTC-905', 'Chemical', '-', (69, 77))	('knockdown', 'Var', (5, 14))	('inhibited', 'NegReg', (20, 29))	('GCN5', 'Gene', (0, 4))	('GCN5', 'Gene', '2648', (0, 4))
156059	28678170	Overall, only slight differences were detected by flow cytometry in the cell cycle distribution of cells treated with GCN5 or PCAF siRNAs compared to the irrelevant siRNA.	('PCAF siRNAs', 'Var', (126, 137))	('GCN5', 'Gene', (118, 122))	('GCN5', 'Gene', '2648', (118, 122))	('cell cycle', 'biological_process', 'GO:0007049', ('72', '82'))	('cell cycle', 'CPA', (72, 82))
156063	28678170	However, the more sensitive caspase-3/7 assay revealed slightly increased apoptosis in BFTC-905 and UM-UC-3 following GCN5 knockdown (Figure 4C), in accord with the significant decrease in cell viability.	('apoptosis', 'CPA', (74, 83))	('GCN5', 'Gene', (118, 122))	('GCN5', 'Gene', '2648', (118, 122))	('caspase-3', 'Gene', '836', (28, 37))	('BFTC-905', 'Chemical', '-', (87, 95))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('caspase-3', 'Gene', (28, 37))	('knockdown', 'Var', (123, 132))	('increased', 'PosReg', (64, 73))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))
156064	28678170	Because of the limited effects of single knockdown, and a hint at compensatory upregulation of PCAF following GCN5 knockdown (Figure 3), the four UCCs were double-transfected with siRNAs to downregulate both GNATs.	('PCAF', 'Gene', (95, 99))	('GCN5', 'Gene', '2648', (110, 114))	('GNAT', 'Gene', '92292', (208, 212))	('GNAT', 'Gene', (208, 212))	('GCN5', 'Gene', (110, 114))	('upregulation', 'PosReg', (79, 91))	('downregulate', 'NegReg', (190, 202))	('knockdown', 'Var', (115, 124))
156065	28678170	Nevertheless, at 72 h after siRNA transfection, the number of viable cells was significantly diminished only in BFTC-905, to a lesser degree in UM-UC-3 and, different to GCN5 single knockdown, also in VM-CUB-1 (Figure 7A).	('BFTC-905', 'Var', (112, 120))	('GCN5', 'Gene', (170, 174))	('GCN5', 'Gene', '2648', (170, 174))	('BFTC-905', 'Chemical', '-', (112, 120))	('diminished', 'NegReg', (93, 103))
156076	28678170	Expression of a general c-MYC target gene, nucleophosmin (gene: NPM1) was not significantly affected by GCN5 and PCAF double knockdown (Figure 8C).	('PCAF', 'Gene', (113, 117))	('NPM1', 'Gene', (64, 68))	('Expression', 'MPA', (0, 10))	('nucleophosmin', 'Gene', '4869', (43, 56))	('NPM1', 'Gene', '4869', (64, 68))	('GCN5', 'Gene', (104, 108))	('GCN5', 'Gene', '2648', (104, 108))	('nucleophosmin', 'Gene', (43, 56))	('double knockdown', 'Var', (118, 134))
156078	28678170	In a similar fashion, MDM2 protein was upregulated following GCN5 and PCAF double knockdown in all cell lines, but least so in BFTC-905 (Figure 6 and Figure S4D).	('BFTC-905', 'Chemical', '-', (127, 135))	('protein', 'Protein', (27, 34))	('MDM2', 'Gene', (22, 26))	('upregulated', 'PosReg', (39, 50))	('PCAF double', 'Gene', (70, 81))	('knockdown', 'Var', (82, 91))	('GCN5', 'Gene', (61, 65))	('GCN5', 'Gene', '2648', (61, 65))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))
156079	28678170	Despite the discovery of prevalent mutations in various histone acetyltransferase (HAT) genes in urothelial carcinoma, the function of these enzymes is poorly studied in this cancer type.	('urothelial carcinoma', 'Disease', (97, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('HAT', 'Gene', (83, 86))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (97, 117))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('mutations', 'Var', (35, 44))
156083	28678170	Efficient GCN5 knockdown inhibited short-term and long-term proliferation of specific, albeit not all UCCs.	('inhibited', 'NegReg', (25, 34))	('GCN5', 'Gene', (10, 14))	('GCN5', 'Gene', '2648', (10, 14))	('knockdown', 'Var', (15, 24))
156084	28678170	In the sensitive cell lines, knockdown resulted in G1 cell cycle arrest, albeit not senescence, and moderately increased caspase-3/7 activity indicative of a moderate degree of apoptosis.	('caspase-3', 'Gene', (121, 130))	('increased', 'PosReg', (111, 120))	('knockdown', 'Var', (29, 38))	('caspase-3', 'Gene', '836', (121, 130))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('G1 cell cycle arrest', 'CPA', (51, 71))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('54', '71'))	('senescence', 'biological_process', 'GO:0010149', ('84', '94'))	('activity', 'MPA', (133, 141))	('apoptosis', 'biological_process', 'GO:0097194', ('177', '186'))	('apoptosis', 'biological_process', 'GO:0006915', ('177', '186'))
156085	28678170	The limited impact of the efficient knockdown might partly result from upregulation of PCAF in response to GCN5 knockdown, which may act in a compensatory fashion.	('knockdown', 'Var', (112, 121))	('PCAF', 'Gene', (87, 91))	('upregulation', 'PosReg', (71, 83))	('GCN5', 'Gene', (107, 111))	('GCN5', 'Gene', '2648', (107, 111))
156086	28678170	Interestingly, PCAF knockdown did not elicit an analogous upregulation of GCN5, which was instead slightly downregulated.	('PCAF', 'Gene', (15, 19))	('GCN5', 'Gene', (74, 78))	('GCN5', 'Gene', '2648', (74, 78))	('downregulated', 'NegReg', (107, 120))	('knockdown', 'Var', (20, 29))
156093	28678170	Ultimately, the expression of typical c-MYC target genes remained essentially unchanged, as did the expression of the CDK inhibitor p21, which typically increases as a consequence of treatment with epigenetic inhibitors.	('p21', 'Gene', '1026', (132, 135))	('p21', 'Gene', (132, 135))	('CDK inhibitor', 'molecular_function', 'GO:0004861', ('118', '131'))	('expression', 'MPA', (100, 110))	('increases', 'PosReg', (153, 162))	('men', 'Species', '9606', (188, 191))	('epigenetic inhibitors', 'Var', (198, 219))	('expression', 'MPA', (16, 26))
156096	28678170	The most unexpected finding in our study is the strong selectivity of the anti-proliferative effects of GCN5 knockdown for specific cell lines, which does not accord with the concept of GCN5 as a "supervisor in all-inclusive control of vertebrate cell cycle progression".	('GCN5', 'Gene', (186, 190))	('GCN5', 'Gene', '2648', (186, 190))	('knockdown', 'Var', (109, 118))	('GCN5', 'Gene', (104, 108))	('GCN5', 'Gene', '2648', (104, 108))	('anti-proliferative', 'NegReg', (74, 92))
156099	28678170	Evidently, this constitution sensitizes to GCN5 knockdown, likely by creating a dependency on the paralogous enzyme.	('sensitizes', 'Reg', (29, 39))	('GCN5', 'Gene', (43, 47))	('GCN5', 'Gene', '2648', (43, 47))	('knockdown', 'Var', (48, 57))
156104	28678170	Expression levels of GCN5 and PCAF do not straightforwardly explain, however, why UM-UC-3 was more sensitive to GCN5 knockdown than VM-CUB-1 or 639-V.	('GCN5', 'Gene', (112, 116))	('sensitive', 'MPA', (99, 108))	('GCN5', 'Gene', '2648', (112, 116))	('GCN5', 'Gene', (21, 25))	('GCN5', 'Gene', '2648', (21, 25))	('knockdown', 'Var', (117, 126))
156105	28678170	Inhibitors targeting HATs are considered as potential drugs for cancer therapy.	('HATs', 'Gene', (21, 25))	('cancer', 'Disease', (64, 70))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
156107	28678170	In urothelial carcinoma, CBP/p300 are often affected by inactivating mutations and are likely to act as tumor suppressors.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('affected', 'Reg', (44, 52))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (3, 23))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('inactivating mutations', 'Var', (56, 78))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('urothelial carcinoma', 'Disease', (3, 23))	('CBP/p300', 'Gene', '1387;2033', (25, 33))	('CBP', 'molecular_function', 'GO:0008140', ('25', '28'))	('CBP/p300', 'Gene', (25, 33))
156109	28678170	Intriguingly, however, we find that especially a UC cell line with low GCN5 as well as PCAF was most sensitive to GCN5 knockdown.	('GCN5', 'Gene', (114, 118))	('GCN5', 'Gene', '2648', (114, 118))	('GCN5', 'Gene', (71, 75))	('GCN5', 'Gene', '2648', (71, 75))	('knockdown', 'Var', (119, 128))
156114	28678170	The siRNAs were Silencer  Select validated siRNA (#4390824, GCN5: s5658; PCAF: s16894) or Silencer  Select Negative Control #2 validated siRNA (#4390846).	('Silencer', 'Disease', 'None', (16, 24))	('GCN5', 'Gene', (60, 64))	('Silencer', 'Disease', (90, 98))	('GCN5', 'Gene', '2648', (60, 64))	('Silencer', 'Disease', (16, 24))	('Silencer', 'Disease', 'None', (90, 98))	('#4390824', 'Var', (50, 58))
156166	28421161	Here, the authors review the immune-related side effect profiles of PD-1 and PD-L1 inhibitors in GU malignancies.	('PD-1', 'Gene', '5133', (68, 72))	('GU malignancies', 'Disease', 'MESH:D009369', (97, 112))	('GU malignancies', 'Disease', (97, 112))	('PD-L1', 'Gene', (77, 82))	('GU malignancies', 'Phenotype', 'HP:0007379', (97, 112))	('PD-1', 'Gene', (68, 72))	('inhibitors', 'Var', (83, 93))
156242	28421161	All the reported evidence to date of PD-1 and PD-L1 inhibitors in GU malignancies are based on clinical trials.	('PD-L1', 'Gene', (46, 51))	('PD-1', 'Gene', '5133', (37, 41))	('GU malignancies', 'Phenotype', 'HP:0007379', (66, 81))	('GU malignancies', 'Disease', 'MESH:D009369', (66, 81))	('inhibitors', 'Var', (52, 62))	('as', 'Chemical', 'MESH:D001151', (87, 89))	('PD-1', 'Gene', (37, 41))	('GU malignancies', 'Disease', (66, 81))
156286	26361392	Biochemical and transmission electron microscopy analyses revealed that MCD and OlyA/PlyB induce necrotic cell death in these cancer cells, while viability of NPU cells was not significantly affected by either treatment.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('MCD', 'Var', (72, 75))	('MCD', 'Chemical', 'MESH:C108732', (72, 75))	('necrotic cell death', 'biological_process', 'GO:0070265', ('97', '116'))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('OlyA', 'Chemical', '-', (80, 84))	('men', 'Species', '9606', (215, 218))	('OlyA/PlyB', 'Gene', (80, 89))	('necrotic cell death', 'Disease', (97, 116))	('necrotic cell death', 'Disease', 'MESH:D003643', (97, 116))
156294	26361392	Clinical and experimental evidence suggests that perturbations in cholesterol metabolism can have important roles in cancerogenesis and tumor development (reviewed in).	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('men', 'Species', '9606', (149, 152))	('cholesterol metabolism', 'biological_process', 'GO:0008203', ('66', '88'))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cholesterol', 'Chemical', 'MESH:D002784', (66, 77))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cholesterol metabolism', 'MPA', (66, 88))	('men', 'Species', '9606', (19, 22))	('cancer', 'Disease', (117, 123))	('perturbations', 'Var', (49, 62))	('tumor', 'Disease', (136, 141))	('roles', 'Reg', (108, 113))
156295	26361392	Such perturbations have been demonstrated in several malignancies, and cholesterol metabolites can promote or suppress cancers.	('suppress', 'NegReg', (110, 118))	('malignancies', 'Disease', (53, 65))	('promote', 'PosReg', (99, 106))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('cholesterol', 'Var', (71, 82))	('malignancies', 'Disease', 'MESH:D009369', (53, 65))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cholesterol', 'Chemical', 'MESH:D002784', (71, 82))
156361	26361392	In addition, we could observe that dying, PI positive cells were annexin V negative or positive, whereas a population of single annexin V positive cells was never prominent, which suggests that the cell death is necrotic rather than apoptotic (Fig 2A).	('annexin V', 'Gene', '308', (65, 74))	('negative', 'NegReg', (75, 83))	('cell death', 'biological_process', 'GO:0008219', ('198', '208'))	('necrotic', 'Disease', 'MESH:D009336', (212, 220))	('annexin V', 'Gene', (65, 74))	('annexin V', 'Gene', '308', (128, 137))	('positive', 'Reg', (87, 95))	('annexin V', 'Gene', (128, 137))	('necrotic', 'Disease', (212, 220))	('PI positive', 'Var', (42, 53))
156414	26361392	There was significant reduction in cell viability of T24 cells, which is in agreement with their highest content of cholesterol and which would mean that cholesterol is more available to MCD in this cell type.	('MCD', 'Chemical', 'MESH:C108732', (187, 190))	('cell viability', 'CPA', (35, 49))	('cholesterol', 'Chemical', 'MESH:D002784', (154, 165))	('cholesterol', 'Chemical', 'MESH:D002784', (116, 127))	('reduction', 'NegReg', (22, 31))	('men', 'Species', '9606', (81, 84))	('T24', 'Var', (53, 56))
156528	27047702	As a result, we now know the most commonly mutated genes in dozens of cancers and can use this information to give patients targeted therapeutics.	('patients', 'Species', '9606', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('genes', 'Gene', (51, 56))	('mutated', 'Var', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
156529	27047702	Whereas well established statistical techniques exist for identifying mutations which are drivers instead of simply passengers (mut-drivers), identifying copy number aberrations, methylation changes, or non-coding mutations that alter expression of a gene and result in a growth advantage (epi-drivers) are more difficult to identify and represent a "dark matter" of cancer.	('expression', 'MPA', (235, 245))	('growth advantage', 'CPA', (272, 288))	('mutations', 'Var', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (367, 373))	('copy', 'Var', (154, 158))	('methylation changes', 'Var', (179, 198))	('mutations', 'Var', (214, 223))	('cancer', 'Disease', (367, 373))	('methylation', 'biological_process', 'GO:0032259', ('179', '190'))	('cancer', 'Phenotype', 'HP:0002664', (367, 373))	('alter', 'Reg', (229, 234))
156592	27047702	To date, different cancers have been compared to each other through mRNA levels, miRNA levels, protein levels, networks, copy number alterations, DNA methylation, somatic mutations or some combination of these.	('miRNA levels', 'MPA', (81, 93))	('DNA methylation', 'biological_process', 'GO:0006306', ('146', '161'))	('networks', 'MPA', (111, 119))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('copy number alterations', 'Var', (121, 144))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('protein levels', 'MPA', (95, 109))	('mRNA levels', 'MPA', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('DNA methylation', 'MPA', (146, 161))
156615	27047702	Our results show that patients with high expression of genes utilizing oxygen survive longer, which underscores the importance of a metabolic shift in this cancer.	('high expression', 'Var', (36, 51))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('genes', 'Var', (55, 60))	('oxygen', 'Chemical', 'MESH:D010100', (71, 77))
156631	27047702	For example, currently EGFR inhibitors are recommended for LUAD patients with EGFR mutations, but EGFR mutations are rare in LUSC and patients with mutations do not respond well to tyrosine kinase inhibitors.	('EGFR', 'Gene', (98, 102))	('mutations', 'Var', (83, 92))	('LUAD', 'Phenotype', 'HP:0030078', (59, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('patients', 'Species', '9606', (64, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('23', '27'))	('patients', 'Species', '9606', (134, 142))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'Gene', (78, 82))	('EGFR', 'Gene', (23, 27))
156657	23253220	These former, low-grade and noninvasive tumors, frequently demonstrate constitutive activation of the RAS-MAPK pathway, with activating mutations in HRAS and FGFR3 genes.	('RAS-MAPK pathway', 'Pathway', (102, 118))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('activation', 'PosReg', (84, 94))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('MAPK', 'molecular_function', 'GO:0004707', ('106', '110'))	('HRAS', 'Gene', '3265', (149, 153))	('FGFR', 'molecular_function', 'GO:0005007', ('158', '162'))	('activating', 'PosReg', (125, 135))	('FGFR3', 'Gene', (158, 163))	('HRAS', 'Gene', (149, 153))	('mutations', 'Var', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('FGFR3', 'Gene', '2261', (158, 163))	('tumors', 'Disease', (40, 46))
156659	23253220	Additional mutations, known to play a role in driving growth and progression of other solid tumors, have recently been identified in small subsets of invasive UC including KRAS and PIK3CA mutations.	('KRAS', 'Gene', (172, 176))	('solid tumors', 'Disease', 'MESH:D009369', (86, 98))	('KRAS', 'Gene', '3845', (172, 176))	('PIK3CA', 'Gene', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('solid tumors', 'Disease', (86, 98))	('PIK3CA', 'Gene', '5290', (181, 187))	('mutations', 'Var', (188, 197))	('invasive UC', 'Disease', (150, 161))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
156676	23253220	Patients with 10% nuclear positivity by immunohistochemistry of p53 were randomized to three cycles of adjuvant MVAC, while patients with wild-type p53 were observed.	('nuclear positivity', 'Var', (18, 36))	('p53', 'Gene', (148, 151))	('MVAC', 'Chemical', 'MESH:C044361', (112, 116))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (148, 151))	('Patients', 'Species', '9606', (0, 8))	('p53', 'Gene', '7157', (64, 67))	('patients', 'Species', '9606', (124, 132))
156689	23253220	For enrollment on this trial, patient's tumors were required to have HER-2 overexpression by immunohistochemistry, HER2 gene amplification and/or elevated serum HER-2.	('HER2', 'Gene', (115, 119))	('amplification', 'Var', (125, 138))	('patient', 'Species', '9606', (30, 37))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('overexpression', 'PosReg', (75, 89))	('HER2', 'Gene', '2064', (115, 119))	('gene amplification', 'Var', (120, 138))	('HER-2', 'Gene', '2064', (161, 166))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('HER-2', 'Gene', (69, 74))	('serum', 'MPA', (155, 160))	('HER-2', 'Gene', (161, 166))	('HER-2', 'Gene', '2064', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('elevated', 'PosReg', (146, 154))	('tumors', 'Disease', (40, 46))
156698	23253220	Of the 33 patients with metastatic bladder cancer tested, 12 patients had HER2 amplification by FISH, none of whom achieved an objective response to treatment.	('bladder cancer', 'Disease', (35, 49))	('HER2', 'Gene', (74, 78))	('patients', 'Species', '9606', (61, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (35, 49))	('HER2', 'Gene', '2064', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('patients', 'Species', '9606', (10, 18))	('amplification', 'Var', (79, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (35, 49))
156699	23253220	Activating mutations in FGFR3 are present in a large proportion of noninvasive UC.	('FGFR3', 'Gene', '2261', (24, 29))	('Activating mutations', 'Var', (0, 20))	('FGFR3', 'Gene', (24, 29))	('noninvasive UC', 'Disease', (67, 81))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))
156700	23253220	However, recent studies have demonstrated that FGFR3 mutations are also present in 10-20% of muscle-invasive UC specimens, leading to intense interest in exploring FGFR3 inhibition as a therapeutic strategy in UC, in an effort to recreate the successes achieved with targeting oncogenic mutations in other solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (312, 318))	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('FGFR3', 'Gene', (47, 52))	('solid tumors', 'Disease', 'MESH:D009369', (306, 318))	('FGFR', 'molecular_function', 'GO:0005007', ('164', '168'))	('mutations', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('FGFR3', 'Gene', (164, 169))	('muscle-invasive UC', 'Disease', (93, 111))	('FGFR3', 'Gene', '2261', (47, 52))	('solid tumors', 'Disease', (306, 318))	('FGFR3', 'Gene', '2261', (164, 169))
156701	23253220	Dovitinib is a small molecule inhibitor of several tyrosine kinase receptors, including the VEGF receptor and FGFR3, which has demonstrated inhibition of tumor growth and proliferation in UC models selected for the presence of FGFR3 activating mutations or protein over-expression.	('FGFR3', 'Gene', '2261', (227, 232))	('protein', 'Protein', (257, 264))	('protein', 'cellular_component', 'GO:0003675', ('257', '264'))	('Dovitinib', 'Chemical', 'MESH:C500007', (0, 9))	('activating', 'PosReg', (233, 243))	('over-expression', 'PosReg', (265, 280))	('FGFR', 'molecular_function', 'GO:0005007', ('110', '114'))	('FGFR3', 'Gene', '2261', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('227', '231'))	('inhibition', 'NegReg', (140, 150))	('FGFR3', 'Gene', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mutations', 'Var', (244, 253))	('FGFR3', 'Gene', (110, 115))	('proliferation', 'CPA', (171, 184))	('tumor', 'Disease', (154, 159))
156703	23253220	In this trial, 40 patients will be enrolled into two groups of 20, based on the presence or absence of mutation in the FGFR3 gene.	('FGFR3', 'Gene', (119, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))	('patients', 'Species', '9606', (18, 26))	('mutation', 'Var', (103, 111))	('FGFR3', 'Gene', '2261', (119, 124))
156711	23253220	The median survival was significantly higher in patients with low ERCC1 levels (25.4 vs 15.4 months; p = 0.03).	('ERCC1', 'Gene', '2067', (66, 71))	('ERCC1', 'Gene', (66, 71))	('higher', 'PosReg', (38, 44))	('low', 'Var', (62, 65))	('patients', 'Species', '9606', (48, 56))
156723	23253220	As a result, recent efforts have sought to profile both noninvasive and invasive samples, and samples of varying grades, for a variety of known cancer-related mutations (Table 1).	('mutations', 'Var', (159, 168))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (144, 150))
156725	23253220	This study identified that FGFR3 and PIK3CA mutations were positively associated, and were identified more commonly in noninvasive low-grade tumors.	('PIK3CA', 'Gene', '5290', (37, 43))	('FGFR3', 'Gene', '2261', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('FGFR3', 'Gene', (27, 32))	('associated', 'Interaction', (70, 80))	('mutations', 'Var', (44, 53))	('PIK3CA', 'Gene', (37, 43))
156726	23253220	Furthermore, the potential importance of APC signaling was identified as 6% of the investigated tumors either demonstrated inactivating APC or activating CTNNB1 mutations.	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('CTNNB1', 'Gene', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('activating', 'PosReg', (143, 153))	('APC', 'Disease', 'MESH:D011125', (41, 44))	('APC', 'Disease', 'MESH:D011125', (136, 139))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('APC', 'Disease', (41, 44))	('APC', 'Disease', (136, 139))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('mutations', 'Var', (161, 170))	('CTNNB1', 'Gene', '1499', (154, 160))	('inactivating', 'Var', (123, 135))	('APC', 'cellular_component', 'GO:0005680', ('41', '44'))	('APC', 'cellular_component', 'GO:0005680', ('136', '139'))
156727	23253220	The mTOR regulatory tuberous sclerosis complex genes (TSC1 and TSC2) were found to be mutated at a combined frequency of 15%.	('mutated', 'Var', (86, 93))	('TSC2', 'Gene', '7249', (63, 67))	('TSC1', 'Gene', '7248', (54, 58))	('TSC2', 'Gene', (63, 67))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (20, 38))	('TSC1', 'Gene', (54, 58))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('20', '46'))	('mTOR', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (4, 8))	('tuberous sclerosis', 'Disease', (20, 38))
156729	23253220	recently demonstrated the potential clinical relevance of oncogenic mutations in urothelial cancer.	('mutations', 'Var', (68, 77))	('urothelial cancer', 'Disease', (81, 98))	('urothelial cancer', 'Disease', 'MESH:D014523', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
156731	23253220	Notably, whole-genome sequencing of tumors from patients treated on this study revealed that the presence of TSC1 mutations correlated with response to treatment.	('TSC1', 'Gene', '7248', (109, 113))	('correlated', 'Reg', (124, 134))	('mutations', 'Var', (114, 123))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('TSC1', 'Gene', (109, 113))	('patients', 'Species', '9606', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
156767	25596749	mTORC1 promotes mRNA translation via p70S6K to regulate protein synthesis and cell metabolism.	('protein synthesis', 'MPA', (56, 73))	('mRNA translation', 'MPA', (16, 32))	('mTORC1', 'cellular_component', 'GO:0031931', ('0', '6'))	('regulate', 'Reg', (47, 55))	('mTORC1', 'Gene', '382056', (0, 6))	('metabolism', 'biological_process', 'GO:0008152', ('83', '93'))	('p70S6K', 'Var', (37, 43))	('promotes', 'PosReg', (7, 15))	('cell metabolism', 'CPA', (78, 93))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('mTORC1', 'Gene', (0, 6))	('protein synthesis', 'biological_process', 'GO:0006412', ('56', '73'))	('translation', 'biological_process', 'GO:0006412', ('21', '32'))
156770	25596749	PI3K plays a crucial role in mTORC2 activation.	('mTORC2', 'Gene', '74343', (29, 35))	('PI3K', 'Var', (0, 4))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('mTORC2', 'cellular_component', 'GO:0031932', ('29', '35'))	('mTORC2', 'Gene', (29, 35))
156771	25596749	In an in vitro mTORC2 kinase assay, mTORC2 was directly activated by PI3K-phosphatidylinositol-3, 4, 5-trisphosphate (PIP3) in HEK293T cells.	('mTORC2', 'cellular_component', 'GO:0031932', ('36', '42'))	('PIP3', 'Chemical', '-', (118, 122))	('PI3K', 'molecular_function', 'GO:0016303', ('69', '73'))	('mTORC2', 'cellular_component', 'GO:0031932', ('15', '21'))	('mTORC2', 'Gene', (36, 42))	('mTORC2', 'Gene', (15, 21))	('PI3K-phosphatidylinositol-3', 'Var', (69, 96))	('mTORC2', 'Gene', '74343', (36, 42))	('phosphatidylinositol-3, 4, 5-trisphosphate', 'Chemical', 'MESH:C060974', (74, 116))	('mTORC2', 'Gene', '74343', (15, 21))	('HEK293T', 'CellLine', 'CVCL:0063', (127, 134))	('activated', 'PosReg', (56, 65))
156774	25596749	mTORC1 activates p70S6K to phosphorylate rictor at Thr1135, leading to a reduction in mTORC2 activity.	('p70S6K', 'Var', (17, 23))	('Thr1135', 'Chemical', '-', (51, 58))	('mTORC1', 'cellular_component', 'GO:0031931', ('0', '6'))	('activity', 'MPA', (93, 101))	('mTORC1', 'Gene', '382056', (0, 6))	('mTORC2', 'cellular_component', 'GO:0031932', ('86', '92'))	('mTORC1', 'Gene', (0, 6))	('mTORC2', 'Gene', (86, 92))	('reduction', 'NegReg', (73, 82))	('mTORC2', 'Gene', '74343', (86, 92))
156777	25596749	In addition to phosphorylation of rictor, phosphorylation of sin1 attenuates mTORC2 activity.	('mTORC2', 'cellular_component', 'GO:0031932', ('77', '83'))	('sin1', 'Gene', '79109', (61, 65))	('sin1', 'Gene', (61, 65))	('attenuates', 'NegReg', (66, 76))	('mTORC2', 'Gene', (77, 83))	('mTORC2', 'Gene', '74343', (77, 83))	('phosphorylation', 'Var', (42, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('phosphorylation', 'biological_process', 'GO:0016310', ('15', '30'))
156778	25596749	p70S6K and AKT induce phosphorylation of sin1 on Thr86 and Thr398 to dissociate sin1 from the mTORC2 complex.	('mTORC2', 'cellular_component', 'GO:0031932', ('94', '100'))	('mTORC2', 'Gene', '74343', (94, 100))	('sin1', 'Gene', '79109', (80, 84))	('p70S6K', 'Var', (0, 6))	('sin1', 'Gene', '79109', (41, 45))	('sin1', 'Gene', (41, 45))	('AKT', 'Pathway', (11, 14))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('Thr86', 'Chemical', '-', (49, 54))	('Thr398', 'Chemical', '-', (59, 65))	('sin1', 'Gene', (80, 84))	('phosphorylation', 'MPA', (22, 37))	('mTORC2', 'Gene', (94, 100))
156801	25596749	Not only the mTORC2 activity, the mTORC1 activity (phosphorylation of mTOR at Ser2448 and phosphorylation of p70S6K at Thr389) also significantly increased in both human and rat bladder tissues.	('mTOR', 'Gene', '2475', (70, 74))	('Thr389', 'Chemical', '-', (119, 125))	('rat', 'Species', '10116', (174, 177))	('mTORC1', 'Gene', (34, 40))	('mTOR', 'Gene', (34, 38))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('mTORC1', 'Gene', '382056', (34, 40))	('increased', 'PosReg', (146, 155))	('Ser2448', 'Chemical', '-', (78, 85))	('mTORC2', 'cellular_component', 'GO:0031932', ('13', '19'))	('Ser', 'cellular_component', 'GO:0005790', ('78', '81'))	('mTOR', 'Gene', '2475', (34, 38))	('phosphorylation', 'biological_process', 'GO:0016310', ('90', '105'))	('mTORC2', 'Gene', (13, 19))	('mTOR', 'Gene', (13, 17))	('p70S6K', 'Var', (109, 115))	('mTORC1', 'cellular_component', 'GO:0031931', ('34', '40'))	('activity', 'MPA', (20, 28))	('mTOR', 'Gene', (70, 74))	('human', 'Species', '9606', (164, 169))	('mTOR', 'Gene', '2475', (13, 17))	('phosphorylation', 'MPA', (51, 66))	('phosphorylation', 'MPA', (90, 105))	('mTORC2', 'Gene', '74343', (13, 19))	('activity', 'MPA', (41, 49))
156802	25596749	Furthermore, knockdown of Gab1 inhibited T24 cells colony formation (Figure S1B) and migration (Figure S1C).	('rat', 'Species', '10116', (88, 91))	('formation', 'biological_process', 'GO:0009058', ('58', '67'))	('migration', 'CPA', (85, 94))	('T24 cells colony formation', 'CPA', (41, 67))	('inhibited', 'NegReg', (31, 40))	('knockdown', 'Var', (13, 22))	('Gab1', 'Gene', (26, 30))
156807	25596749	In the current study, we used Gab1 siRNA to knock down endogenous Gab1 in T24 cells, and we found that mTOR and raptor could not translocate to the plasma membrane after EGF stimulation (Figure 2A).	('mTOR', 'Gene', (103, 107))	('Gab1', 'Gene', (66, 70))	('EGF', 'Gene', '1950', (170, 173))	('plasma membrane', 'cellular_component', 'GO:0005886', ('148', '163'))	('raptor', 'Gene', (112, 118))	('knock down', 'Var', (44, 54))	('raptor', 'Gene', '57521', (112, 118))	('mTOR', 'Gene', '2475', (103, 107))	('EGF', 'molecular_function', 'GO:0005154', ('170', '173'))	('translocate', 'MPA', (129, 140))	('EGF', 'Gene', (170, 173))
156810	25596749	In contrast, expression of a Gab1 mutant lacking the PH domain (Gab1DeltaPH) or treatment with the PI3K inhibitor LY294002 suppressed membrane translocation of both proteins after EGF stimulation (Figure 3A).	('PI3K', 'molecular_function', 'GO:0016303', ('99', '103'))	('EGF', 'Gene', '1950', (180, 183))	('suppressed', 'NegReg', (123, 133))	('membrane', 'cellular_component', 'GO:0016020', ('134', '142'))	('EGF', 'molecular_function', 'GO:0005154', ('180', '183'))	('Gab1', 'Gene', (29, 33))	('LY294002', 'Chemical', 'MESH:C085911', (114, 122))	('EGF', 'Gene', (180, 183))	('mutant', 'Var', (34, 40))	('membrane translocation of both proteins', 'MPA', (134, 173))
156815	25596749	First, we knocked down endogenous Gab1 in T24 cells, and we found that the activities of mTORC1 and mTORC2 were inhibited after EGF stimulation.	('mTORC1', 'Gene', '382056', (89, 95))	('mTORC2', 'cellular_component', 'GO:0031932', ('100', '106'))	('EGF', 'Gene', '1950', (128, 131))	('inhibited', 'NegReg', (112, 121))	('Gab1', 'Gene', (34, 38))	('mTORC1', 'cellular_component', 'GO:0031931', ('89', '95'))	('mTORC1', 'Gene', (89, 95))	('activities', 'MPA', (75, 85))	('EGF', 'Gene', (128, 131))	('mTORC2', 'Gene', (100, 106))	('knocked', 'Var', (10, 17))	('EGF', 'molecular_function', 'GO:0005154', ('128', '131'))	('mTORC2', 'Gene', '74343', (100, 106))
156816	25596749	Furthermore, a PI3K inhibitor (LY294002) inhibited the activity of the mTORCs after EGF stimulation (Figure 4A).	('EGF', 'molecular_function', 'GO:0005154', ('84', '87'))	('LY294002', 'Var', (31, 39))	('PI3K', 'molecular_function', 'GO:0016303', ('15', '19'))	('activity', 'MPA', (55, 63))	('EGF', 'Gene', (84, 87))	('EGF', 'Gene', '1950', (84, 87))	('mTOR', 'Gene', '2475', (71, 75))	('LY294002', 'Chemical', 'MESH:C085911', (31, 39))	('mTOR', 'Gene', (71, 75))	('inhibited', 'NegReg', (41, 50))
156817	25596749	We found that overexpression of Gab1 increased the activity of mTORC1 and mTORC2 after EGF stimulation, and LY294002 also inhibited mTORC activities (Figure 4B).	('mTOR', 'Gene', '2475', (132, 136))	('mTORC2', 'cellular_component', 'GO:0031932', ('74', '80'))	('mTORC2', 'Gene', (74, 80))	('mTOR', 'Gene', (74, 78))	('increased', 'PosReg', (37, 46))	('LY294002', 'Chemical', 'MESH:C085911', (108, 116))	('EGF', 'Gene', (87, 90))	('mTORC1', 'cellular_component', 'GO:0031931', ('63', '69'))	('inhibited', 'NegReg', (122, 131))	('mTORC2', 'Gene', '74343', (74, 80))	('mTOR', 'Gene', '2475', (74, 78))	('Gab1', 'Gene', (32, 36))	('EGF', 'molecular_function', 'GO:0005154', ('87', '90'))	('mTOR', 'Gene', (63, 67))	('mTOR', 'Gene', '2475', (63, 67))	('mTORC1', 'Gene', (63, 69))	('EGF', 'Gene', '1950', (87, 90))	('activity', 'MPA', (51, 59))	('LY294002', 'Var', (108, 116))	('mTOR', 'Gene', (132, 136))	('mTORC1', 'Gene', '382056', (63, 69))
156818	25596749	As shown in Figure 4A and 4B, inhibition of PI3K and Gab1 decreased mTORC activity after EGF stimulation.	('PI3K', 'Gene', (44, 48))	('EGF', 'Gene', (89, 92))	('inhibition', 'Var', (30, 40))	('decreased', 'NegReg', (58, 67))	('mTOR', 'Gene', '2475', (68, 72))	('EGF', 'molecular_function', 'GO:0005154', ('89', '92'))	('EGF', 'Gene', '1950', (89, 92))	('mTOR', 'Gene', (68, 72))	('Gab1', 'Gene', (53, 57))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))
156819	25596749	We then overexpressed the Gab1DeltaPH mutant in E6 cells, and we found that overexpression of Gab1DeltaPH decreased mTORC1 and mTORC2 activity after EGF stimulation (Figure 4C).	('decreased', 'NegReg', (106, 115))	('mTORC1', 'cellular_component', 'GO:0031931', ('116', '122'))	('EGF', 'Gene', '1950', (149, 152))	('E6', 'CellLine', 'CVCL:4582', (48, 50))	('mTORC1', 'Gene', (116, 122))	('EGF', 'molecular_function', 'GO:0005154', ('149', '152'))	('mTORC2', 'Gene', (127, 133))	('mTORC2', 'cellular_component', 'GO:0031932', ('127', '133'))	('EGF', 'Gene', (149, 152))	('mTORC2', 'Gene', '74343', (127, 133))	('Gab1DeltaPH', 'Var', (94, 105))	('mTORC1', 'Gene', '382056', (116, 122))
156821	25596749	mTORC1 activity was inhibited by raptor knockdown, and mTORC2 activity was inhibited by rictor knockdown (Figure 4D).	('activity', 'MPA', (7, 15))	('raptor', 'Gene', (33, 39))	('activity', 'MPA', (62, 70))	('mTORC1', 'cellular_component', 'GO:0031931', ('0', '6'))	('mTORC1', 'Gene', '382056', (0, 6))	('inhibited', 'NegReg', (75, 84))	('knockdown', 'Var', (40, 49))	('knockdown', 'Var', (95, 104))	('raptor', 'Gene', '57521', (33, 39))	('inhibited', 'NegReg', (20, 29))	('rictor', 'Gene', (88, 94))	('mTORC2', 'Gene', (55, 61))	('mTORC1', 'Gene', (0, 6))	('mTORC2', 'Gene', '74343', (55, 61))	('mTORC2', 'cellular_component', 'GO:0031932', ('55', '61'))
156830	25596749	We found that knockdown of Gab1 decreased the integrity of mTORCs in T24 cells (Figure 5A and 5B).	('Gab1', 'Gene', (27, 31))	('integrity', 'MPA', (46, 55))	('knockdown', 'Var', (14, 23))	('mTOR', 'Gene', '2475', (59, 63))	('decreased', 'NegReg', (32, 41))	('mTOR', 'Gene', (59, 63))
156831	25596749	Knockdown of raptor or rictor decreased the integrity of mTORCs and also decreased the association of Gab1 with mTORCs (Figure 3A and 3B).	('integrity', 'MPA', (44, 53))	('Knockdown', 'Var', (0, 9))	('decreased', 'NegReg', (73, 82))	('raptor', 'Gene', '57521', (13, 19))	('mTOR', 'Gene', (57, 61))	('association', 'Interaction', (87, 98))	('mTOR', 'Gene', '2475', (112, 116))	('raptor', 'Gene', (13, 19))	('mTOR', 'Gene', '2475', (57, 61))	('mTOR', 'Gene', (112, 116))	('Gab1', 'Gene', (102, 106))	('decreased', 'NegReg', (30, 39))	('rictor', 'Gene', (23, 29))
156849	25596749	(2013) revealed that mTORC1-activated p70S6K phosphorylated rictor at Thr1135 and phosphorylated sin1 at Thr86 and Thr398 to inhibit mTORC2 activity.	('p70S6K', 'Var', (38, 44))	('Thr398', 'Chemical', '-', (115, 121))	('inhibit', 'NegReg', (125, 132))	('Thr86', 'Chemical', '-', (105, 110))	('Thr1135', 'Chemical', '-', (70, 77))	('mTORC1', 'Gene', '382056', (21, 27))	('mTORC1', 'cellular_component', 'GO:0031931', ('21', '27'))	('mTORC2', 'cellular_component', 'GO:0031932', ('133', '139'))	('mTORC2', 'Gene', (133, 139))	('mTORC2', 'Gene', '74343', (133, 139))	('sin1', 'Gene', (97, 101))	('mTORC1', 'Gene', (21, 27))	('sin1', 'Gene', '79109', (97, 101))
156860	25596749	We also revealed that PI3K activates mTORCs via the PH domain of Gab1, which binds to PIP3.	('Gab1', 'Gene', (65, 69))	('PI3K', 'molecular_function', 'GO:0016303', ('22', '26'))	('mTOR', 'Gene', (37, 41))	('mTOR', 'Gene', '2475', (37, 41))	('PIP3', 'Chemical', '-', (86, 90))	('binds', 'Interaction', (77, 82))	('PI3K', 'Var', (22, 26))	('activates', 'PosReg', (27, 36))
156873	25596749	A recent study indicated that the WD40 domain in raptor binds the lipid PI(3,5)P2, suggesting that mTORC1 translocates to the plasma membrane.	('mTORC1', 'Gene', '382056', (99, 105))	('raptor', 'Gene', '57521', (49, 55))	('translocates to the', 'MPA', (106, 125))	('plasma membrane', 'cellular_component', 'GO:0005886', ('126', '141'))	('WD40 domain', 'Var', (34, 45))	('mTORC1', 'Gene', (99, 105))	('lipid', 'Chemical', 'MESH:D008055', (66, 71))	('raptor', 'Gene', (49, 55))	('PI(3,5)P2', 'Chemical', 'MESH:C106336', (72, 81))	('mTORC1', 'cellular_component', 'GO:0031931', ('99', '105'))
156875	25596749	PI(3,5)P2 is generated in lysosomes and at the plasma membrane after stimulation with amino acids and growth factors, and PI(3,5)P2 binding could also contribute to lysosome translocation.	('PI(3,5)P2', 'Var', (122, 131))	('lysosome translocation', 'MPA', (165, 187))	('plasma membrane', 'cellular_component', 'GO:0005886', ('47', '62'))	('PI(3,5)P2', 'Chemical', 'MESH:C106336', (122, 131))	('PI(3,5)P2', 'Chemical', 'MESH:C106336', (0, 9))	('binding', 'molecular_function', 'GO:0005488', ('132', '139'))	('contribute', 'Reg', (151, 161))	('binding', 'Interaction', (132, 139))	('rat', 'Species', '10116', (17, 20))	('lysosome', 'cellular_component', 'GO:0005764', ('165', '173'))
156879	25596749	Furthermore, mTORC1 and mTORC2 colocalized with Rac1 at the plasma membrane after serum treatment, and deletion of Rac1 prevented membrane localization of mTORCs.	('prevented', 'NegReg', (120, 129))	('mTORC2', 'cellular_component', 'GO:0031932', ('24', '30'))	('localization', 'biological_process', 'GO:0051179', ('139', '151'))	('mTORC1', 'Gene', '382056', (13, 19))	('mTOR', 'Gene', (155, 159))	('mTORC2', 'Gene', (24, 30))	('mTORC1', 'cellular_component', 'GO:0031931', ('13', '19'))	('deletion', 'Var', (103, 111))	('membrane localization', 'MPA', (130, 151))	('mTOR', 'Gene', '2475', (155, 159))	('Rac1', 'Gene', '5879', (48, 52))	('mTORC2', 'Gene', '74343', (24, 30))	('mTOR', 'Gene', (24, 28))	('Rac1', 'Gene', (115, 119))	('plasma membrane', 'cellular_component', 'GO:0005886', ('60', '75'))	('membrane', 'cellular_component', 'GO:0016020', ('130', '138'))	('mTOR', 'Gene', (13, 17))	('mTOR', 'Gene', '2475', (24, 28))	('mTORC1', 'Gene', (13, 19))	('mTOR', 'Gene', '2475', (13, 17))	('Rac1', 'Gene', (48, 52))	('Rac1', 'Gene', '5879', (115, 119))
156888	25596749	The grade of these bladder cell line and urothelial carcinoma cell lines: E6 (Normal), RT4 (Grade 1), TSGH8301 (Grade 2) and J82, T24 (Grade 3), respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (41, 61))	('E6', 'CellLine', 'CVCL:4582', (74, 76))	('urothelial carcinoma', 'Disease', (41, 61))	('J82', 'Var', (125, 128))
156891	25596749	The primary antibodies used in this study included the following: mTOR-pS2481, mTOR-pS2448, mTOR, p70S6K-pT389, ERK, ERK-p, Gab1, AKT (Cell Signaling, Boston, MA), mSin1 (Millipore, Billerica, MA), p70S6K, AKT-pS473, c-myc (Santa Cruz Biotechnology Inc., Santa Cruz, CA), rictor, raptor and beta-actin (GeneTex, Hsinchu, Taiwan).	('ERK', 'Gene', (117, 120))	('Signaling', 'biological_process', 'GO:0023052', ('140', '149'))	('beta-actin', 'Gene', (291, 301))	('mTOR', 'Gene', '2475', (92, 96))	('ERK', 'Gene', '2048', (117, 120))	('mTOR', 'Gene', (66, 70))	('c-myc', 'Gene', '4609', (217, 222))	('ERK', 'molecular_function', 'GO:0004707', ('112', '115'))	('raptor', 'Gene', '57521', (280, 286))	('p70S6K-pT389', 'Var', (98, 110))	('mTOR', 'Gene', (79, 83))	('mTOR', 'Gene', '2475', (66, 70))	('beta-actin', 'Gene', '728378', (291, 301))	('mSin1', 'Gene', (164, 169))	('mSin1', 'Gene', '227743', (164, 169))	('ERK', 'Gene', (112, 115))	('mTOR', 'Gene', '2475', (79, 83))	('raptor', 'Gene', (280, 286))	('c-myc', 'Gene', (217, 222))	('mTOR', 'Gene', (92, 96))	('ERK', 'Gene', '2048', (112, 115))	('ERK', 'molecular_function', 'GO:0004707', ('117', '120'))
156892	25596749	EGF (100 ng/ml) and insulin (2 mug/ml) were purchased from PEPROTECH, and LY294002 (20 muM) was purchased from GIBCO .	('EGF', 'molecular_function', 'GO:0005154', ('0', '3'))	('LY294002', 'Chemical', 'MESH:C085911', (74, 82))	('insulin', 'molecular_function', 'GO:0016088', ('20', '27'))	('mug', 'molecular_function', 'GO:0043739', ('31', '34'))	('EGF', 'Gene', (0, 3))	('insulin', 'Gene', (20, 27))	('LY294002', 'Var', (74, 82))	('EGF', 'Gene', '1950', (0, 3))	('insulin', 'Gene', '3630', (20, 27))
156925	32597311	Aberrantly expressed tRFs have the potential to serve as diagnostic biomarkers and therapeutic targets in cancer treatments.	('Aberrantly expressed', 'Var', (0, 20))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('men', 'Species', '9606', (118, 121))	('cancer', 'Disease', (106, 112))	('tRF', 'Gene', (21, 24))	('tRF', 'Gene', '7013', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
156927	32597311	CU1276 was shown to function similar to a miRNA and suppress proliferation in B cell lymphoma.	('CU1276', 'Var', (0, 6))	('suppress', 'NegReg', (52, 60))	('B cell lymphoma', 'Disease', 'MESH:D016393', (78, 93))	('B cell lymphoma', 'Disease', (78, 93))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (78, 93))	('CU1276', 'Chemical', '-', (0, 6))	('lymphoma', 'Phenotype', 'HP:0002665', (85, 93))	('proliferation', 'CPA', (61, 74))
156928	32597311	SHOT-RNAAsp-GUC, SHOT-RNAHis-GUG, and SHOT-RNALys-CUU are sex hormone-dependent tRNA halves that promote cell proliferation in breast and prostate cancers.	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('His', 'Chemical', 'MESH:D006639', (25, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (138, 153))	('SHOT-RNALys-CUU', 'Var', (38, 53))	('tRNA', 'molecular_function', 'GO:0030533', ('80', '84'))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('breast and prostate cancers', 'Disease', 'MESH:D001943', (127, 154))	('prostate cancers', 'Phenotype', 'HP:0012125', (138, 154))	('cell proliferation', 'CPA', (105, 123))	('promote', 'PosReg', (97, 104))
156957	32597311	The 'Alignment & Modification' page provides a visualization of the tRF on the secondary structure of the source tRNA, including possible modifications (Fig.	('men', 'Species', '9606', (10, 13))	('tRF', 'Gene', (68, 71))	('possible', 'Var', (129, 137))	('tRNA', 'molecular_function', 'GO:0030533', ('113', '117'))	('tRF', 'Gene', '7013', (68, 71))
156959	32597311	Such modifications may play a role in the tRF function and biogenesis in cancers.	('cancers', 'Disease', (73, 80))	('tRF', 'Gene', '7013', (42, 45))	('biogenesis', 'CPA', (59, 69))	('play', 'Reg', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('modifications', 'Var', (5, 18))	('role', 'Reg', (30, 34))	('tRF', 'Gene', (42, 45))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
157033	32597311	First, OncotRF provides an integrated view of dysregulated tRFs among cancers.	('OncotRF', 'Disease', 'None', (7, 14))	('OncotRF', 'Disease', (7, 14))	('tRF', 'Gene', '7013', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('dysregulated', 'Var', (46, 58))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('tRF', 'Gene', (11, 14))	('tRF', 'Gene', (59, 62))	('cancers', 'Disease', (70, 77))	('tRF', 'Gene', '7013', (11, 14))
157034	32597311	Users can retrieve the median expression levels in tumour and normal tissue groups, fold changes, p-values, and false discovery rates for differential expression analysis of dysregulated tRFs in each cancer type.	('expression', 'MPA', (30, 40))	('false', 'biological_process', 'GO:0071877', ('112', '117'))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tRF', 'Gene', '7013', (187, 190))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('dysregulated', 'Var', (174, 186))	('tRF', 'Gene', (187, 190))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('false', 'biological_process', 'GO:0071878', ('112', '117'))	('tumour', 'Disease', (51, 57))	('cancer', 'Disease', (200, 206))
157037	32597311	These dysregulated tRFs are relatively stable due to their own chemical modification, and thereby can serve as promising biomarkers for cancer diagnosis and potential new targets for cancer treatment.	('dysregulated', 'Var', (6, 18))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', (183, 189))	('tRF', 'Gene', (19, 22))	('men', 'Species', '9606', (195, 198))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', (136, 142))	('tRF', 'Gene', '7013', (19, 22))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
157039	32597311	Second, OncotRF provides comprehensive functional annotations of dysregulated tRFs among cancers.	('dysregulated', 'Var', (65, 77))	('tRF', 'Gene', (12, 15))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('tRF', 'Gene', (78, 81))	('tRF', 'Gene', '7013', (12, 15))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('OncotRF', 'Disease', 'None', (8, 15))	('OncotRF', 'Disease', (8, 15))	('cancers', 'Disease', (89, 96))	('tRF', 'Gene', '7013', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
157042	32597311	Enrichment analyses of mRNAs co-expressed with dysregulated tRFs can then be performed using multiple annotation categories including GO terms, bio-pathways, and disease associations.	('dysregulated', 'Var', (47, 59))	('tRF', 'Gene', '7013', (60, 63))	('men', 'Species', '9606', (6, 9))	('tRF', 'Gene', (60, 63))
157045	32597311	This resource provides new insights into dysregulated tRFs and helps users to design their experiments and generate testable hypotheses to study the molecular mechanisms of tRFs in cancers.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tRF', 'Gene', (54, 57))	('men', 'Species', '9606', (97, 100))	('tRF', 'Gene', '7013', (173, 176))	('tRF', 'Gene', '7013', (54, 57))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('tRFs in cancers', 'Disease', (173, 188))	('dysregulated', 'Var', (41, 53))	('tRF', 'Gene', (173, 176))	('tRFs in cancers', 'Disease', 'MESH:D009369', (173, 188))
157068	32597311	It provides several prominent features over currently existing databases including information about dysregulated tRFs and their clinical and functional relevance to cancers.	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('tRF', 'Gene', '7013', (114, 117))	('dysregulated', 'Var', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tRF', 'Gene', (114, 117))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
157080	32597311	S8, each class of tRFs in our tRF annotation database starts with a unique class identifier (i.e., 3' U-tRFs start with 3'U-, 5'-tRFs start with 5'-, 3'-tRFs start with 3'- and i-tRFs start with i-).	('tRF', 'Gene', '7013', (104, 107))	('tRF', 'Gene', '7013', (18, 21))	('tRF', 'Gene', (30, 33))	('tRF', 'Gene', (153, 156))	('tRF', 'Gene', '7013', (129, 132))	('tRF', 'Gene', (129, 132))	('tRF', 'Gene', '7013', (153, 156))	('tRF', 'Gene', (179, 182))	('tRF', 'Gene', '7013', (30, 33))	("3'U-", 'Var', (120, 124))	('tRF', 'Gene', (104, 107))	('tRF', 'Gene', (18, 21))	('tRF', 'Gene', '7013', (179, 182))
157139	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))
157151	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', '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', 'MESH:D001749', (319, 323))	('BlCa', 'Disease', (319, 323))	('BlCa', 'Disease', (190, 194))	('suppressing', 'NegReg', (205, 216))	('inhibited', 'NegReg', (180, 189))
157152	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))
157155	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))	('response', 'CPA', (304, 312))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('better', 'PosReg', (297, 303))	('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))	('associated', 'Reg', (281, 291))	('BCG', 'Species', '33892', (316, 319))	('DNA', 'cellular_component', 'GO:0005574', ('230', '233'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
157157	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))
157159	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))	('pneumocystis pneumonia', 'Disease', (105, 127))	('polyamine levels', 'MPA', (45, 61))	('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))
157160	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))
157166	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))
157169	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))
157170	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.	('BlCa', 'Disease', (22, 26))	('stimulation', 'PosReg', (136, 147))	('NK cells signaling', 'MPA', (151, 169))	('KDM6A', 'Gene', (68, 73))	('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))
157171	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))
157172	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))
157174	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'))
157198	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'))
157200	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))
157208	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))
157209	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))
157212	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))	('GSK126', 'Chemical', 'MESH:C577920', (127, 133))	('RCC', 'Disease', 'MESH:D002292', (93, 96))	('epigenetic aberrations', 'Var', (26, 48))	('suppressed', 'NegReg', (141, 151))	('HDAC', 'Gene', (188, 192))	('HDAC', 'Gene', '9734', (188, 192))
157215	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'))
157219	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))
157220	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))
157240	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))
157244	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))
157254	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))
157256	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))
157258	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))	('prostate cancer', 'Disease', 'MESH:D011471', (187, 202))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('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))
157259	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))
157262	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))
157268	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))
157277	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))	('upregulation', 'PosReg', (186, 198))	('MHC1', 'Gene', (181, 185))	('impacts', 'Reg', (109, 116))	('increase', 'PosReg', (254, 262))
157304	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))
157310	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))
157336	31356140	MMAE disrupts microtubule networks, leading to cell-cycle arrest and apoptotic death of Nectin-4-expressing cells.	('Nectin-4', 'Gene', (88, 96))	('MMAE', 'Chemical', 'MESH:C495575', (0, 4))	('microtubule networks', 'MPA', (14, 34))	('cell-cycle arrest', 'CPA', (47, 64))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('47', '64'))	('MMAE', 'Var', (0, 4))	('leading to', 'Reg', (36, 46))	('apoptotic death', 'CPA', (69, 84))	('disrupts', 'NegReg', (5, 13))	('Nectin-4', 'Gene', '81607', (88, 96))	('microtubule', 'cellular_component', 'GO:0005874', ('14', '25'))
157557	27458527	In deer immunized with either BCG or IL-2 rBCG, IL-2 secreting rBCG induces a strong IFN-gamma: IL-4 ratio, which may skew the immune response towards a Th1 response , .	('rBCG', 'Var', (63, 67))	('IL-2', 'Gene', '3558', (48, 52))	('rBCG', 'Chemical', '-', (63, 67))	('IL-4', 'Gene', '16189', (96, 100))	('BCG', 'Species', '33892', (30, 33))	('rBCG', 'Chemical', '-', (42, 46))	('IL-2', 'Gene', (48, 52))	('IL-4', 'molecular_function', 'GO:0005136', ('96', '100'))	('BCG', 'Species', '33892', (43, 46))	('IL-4', 'Gene', (96, 100))	('immune', 'MPA', (127, 133))	('BCG', 'Species', '33892', (64, 67))	('IL-2', 'Gene', '3558', (37, 41))	('IL-2', 'molecular_function', 'GO:0005134', ('48', '52'))	('IL-2', 'molecular_function', 'GO:0005134', ('37', '41'))	('IL-2', 'Gene', (37, 41))	('skew', 'Reg', (118, 122))	('immune response', 'biological_process', 'GO:0006955', ('127', '142'))
157569	27458527	Although no trials to date have studied the efficacy of IFN-alpha as a single agent in humans, in vitro studies have shown rBCG-IFN-alpha to enhance the Th1 IFN-gamma immune response of human peripheral blood mononuclear cells (PBMC).	('humans', 'Species', '9606', (87, 93))	('human', 'Species', '9606', (87, 92))	('enhance', 'PosReg', (141, 148))	('immune response', 'biological_process', 'GO:0006955', ('167', '182'))	('human', 'Species', '9606', (186, 191))	('rBCG-IFN-alpha', 'Var', (123, 137))	('Th1 IFN-gamma immune response', 'MPA', (153, 182))	('rBCG', 'Chemical', '-', (123, 127))
157585	27458527	In vitro data shows PstS1 may be exploited as a potent immunostimulatory antigen, resulting in increased cytotoxicity, IFN-gamma release, and proliferation of PBMCs.	('proliferation', 'CPA', (142, 155))	('cytotoxicity', 'Disease', 'MESH:D064420', (105, 117))	('PstS1', 'Var', (20, 25))	('increased', 'PosReg', (95, 104))	('cytotoxicity', 'Disease', (105, 117))
157617	27458527	MPDL3280A is an anti-PD-L1 monoclonal antibody that inhibits the interaction between PD-1 and PD-L1.	('antibody', 'cellular_component', 'GO:0019815', ('38', '46'))	('PD-1', 'Gene', (85, 89))	('MPDL3280A', 'Var', (0, 9))	('PD-1', 'Gene', '5133', (85, 89))	('antibody', 'cellular_component', 'GO:0019814', ('38', '46'))	('interaction', 'Interaction', (65, 76))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (0, 9))	('inhibits', 'NegReg', (52, 60))	('antibody', 'molecular_function', 'GO:0003823', ('38', '46'))	('antibody', 'cellular_component', 'GO:0042571', ('38', '46'))
157621	27458527	After a 6 week follow up from treatment, objective response rates were 43% in patients with PD-L1 expression on tumor infiltrating immune cells by immunohistochemistry, representing remarkable clinical activity against metastatic bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (230, 244))	('expression', 'Var', (98, 108))	('PD-L1', 'Gene', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('patients', 'Species', '9606', (78, 86))	('bladder cancer', 'Disease', 'MESH:D001749', (230, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('bladder cancer', 'Disease', (230, 244))	('tumor', 'Disease', (112, 117))
157622	27458527	Other check point inhibitors such as B7-H3, B7-H4, LAG3, and TIM3 have been identified in basic studies, of which some are being studied in a clinical setting.	('B7-H4', 'Var', (44, 49))	('LAG3', 'Gene', (51, 55))	('TIM3', 'Gene', (61, 65))	('LAG3', 'Gene', '3902', (51, 55))	('TIM3', 'Gene', '84868', (61, 65))
157627	27458527	A meta-analysis of nine studies found that HER2 expression in patients with bladder cancer was associated with higher histological grade, higher rates of lymph node metastasis, poor survival rates and poor disease free .	('survival rates', 'CPA', (182, 196))	('bladder cancer', 'Disease', (76, 90))	('poor', 'NegReg', (177, 181))	('HER2', 'Gene', (43, 47))	('HER2', 'Gene', '2064', (43, 47))	('patients', 'Species', '9606', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('expression', 'Var', (48, 58))	('higher', 'PosReg', (111, 117))	('lymph node metastasis', 'CPA', (154, 175))	('higher', 'PosReg', (138, 144))	('histological grade', 'CPA', (118, 136))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))
157629	27458527	A recently completed phase 2 trial investigated DN24-02, a form of autologous immunotherapy consisting leukapheresed APCs cultured in recombinant a HER2 antigen (NCT01353222).	('HER2', 'Gene', (148, 152))	('NCT01353222', 'Var', (162, 173))	('HER2', 'Gene', '2064', (148, 152))
157656	27458527	Transduced genes provide antitumor activity against NMIBC by sensitizing the cancer cells to the immune system.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('sensitizing', 'Reg', (61, 72))	('genes', 'Var', (11, 16))	('tumor', 'Disease', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
157669	27458527	In 2003, systemic adenoviral gene therapy of a patient with ornithine transcarbamylase deficiency resulted in a fatal systemic inflammatory response syndrome, raising concerns regarding the safety of viral gene therapy .	('inflammatory response', 'biological_process', 'GO:0006954', ('127', '148'))	('patient', 'Species', '9606', (47, 54))	('deficiency', 'Var', (87, 97))	('resulted in', 'Reg', (98, 109))
157680	27458527	infused autologous T lymphocytes from the metinel node of patients with advanced urothelial carcinoma T2N1 or higher to determine if this form of immunotherapy would be safe and technically feasible.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (81, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('urothelial carcinoma', 'Disease', (81, 101))	('patients', 'Species', '9606', (58, 66))	('T2N1', 'Var', (102, 106))
157682	27458527	However, demonstrating clinical response in patients with bladder cancer presents certain challenges as epithelial cancers contain fewer mutations than melanoma and there is little data on endogenous mutation specific T-cell response .	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('patients', 'Species', '9606', (44, 52))	('fewer', 'NegReg', (131, 136))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('epithelial cancers', 'Disease', 'MESH:D000077216', (104, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (137, 146))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('bladder cancer', 'Disease', (58, 72))	('epithelial cancers', 'Disease', (104, 122))
157704	33072070	Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study Combination therapy with inhibitors of cytotoxic T lymphocyte-associated protein (CTLA)4 and programmed death (PD)-1 has demonstrated efficacy in cancer patients.	('Aberrant', 'Var', (25, 33))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('Cancer', 'Disease', (101, 107))	('death', 'Disease', 'MESH:D003643', (218, 223))	('cytotoxic T lymphocyte-associated protein (CTLA)4', 'Gene', '1493', (153, 202))	('patients', 'Species', '9606', (267, 275))	('PD-1', 'Gene', (34, 38))	('CTLA4', 'Gene', '1493', (43, 48))	('Cancer', 'Disease', 'MESH:D009369', (101, 107))	('Combination', 'Interaction', (114, 125))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('Cancer', 'Disease', (64, 70))	('death', 'Disease', (218, 223))	('CTLA4', 'Gene', (43, 48))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))
157718	33072070	For example, tumor hypoxia-associated multi-omic investigations have shown that some molecular variants are correlated with antitumor drug sensitivity or resistance, which has important implications for cancer treatment.	('tumor', 'Disease', (13, 18))	('correlated', 'Reg', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('variants', 'Var', (95, 103))	('tumor hypoxia', 'Disease', 'MESH:D000860', (13, 26))	('tumor hypoxia', 'Disease', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('resistance', 'MPA', (154, 164))	('cancer', 'Disease', (203, 209))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('tumor', 'Disease', (128, 133))	('drug sensitivity', 'Phenotype', 'HP:0020174', (134, 150))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
157725	33072070	PD-1 is a transmembrane protein that is expressed by immunocytes; blocking PD-1 signaling enhances the anticancer effect of T cells, thereby promoting cancer cell killing.	('PD-1', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('promoting', 'PosReg', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('transmembrane', 'cellular_component', 'GO:0044214', ('10', '23'))	('transmembrane', 'cellular_component', 'GO:0016021', ('10', '23'))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('blocking', 'Var', (66, 74))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('cancer', 'Disease', (107, 113))	('cell killing', 'biological_process', 'GO:0001906', ('158', '170'))	('enhances', 'PosReg', (90, 98))
157727	33072070	Although PD-1 and CTLA4 overexpression, mutations, and gene amplification have been reported in certain cancers, the studies had small sample sizes and used different experimental approaches, making it difficult to compare the findings.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CTLA4', 'Gene', (18, 23))	('gene amplification', 'Var', (55, 73))	('mutations', 'Var', (40, 49))	('overexpression', 'PosReg', (24, 38))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('PD-1', 'Gene', (9, 13))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
157755	33072070	Patients with high MSI (MSI-H) cancers benefit from immunotherapy, and MSI is an index used for cancer detection.	('MSI-H', 'Gene', (24, 29))	('MSI', 'Gene', '5928', (71, 74))	('MSI', 'Gene', (71, 74))	('MSI', 'Gene', (24, 27))	('cancer', 'Disease', (96, 102))	('MSI', 'Gene', '5928', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('high', 'Var', (14, 18))	('MSI-H', 'Gene', '5928', (24, 29))	('Patients', 'Species', '9606', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancers', 'Disease', (31, 38))	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('benefit', 'PosReg', (39, 46))	('MSI', 'Gene', (19, 22))	('immunotherapy', 'CPA', (52, 65))	('MSI', 'Gene', '5928', (19, 22))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancers', 'Disease', 'MESH:D009369', (31, 38))
157757	33072070	Gene mutation frequency may be increased in cancer cells as a result of downregulation of MMR genes or defective MMR.	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('MMR', 'biological_process', 'GO:0006298', ('90', '93'))	('Gene mutation', 'Var', (0, 13))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('MMR', 'Gene', (113, 116))	('MMR', 'biological_process', 'GO:0006298', ('113', '116'))	('downregulation', 'NegReg', (72, 86))	('defective', 'NegReg', (103, 112))	('MMR genes', 'Gene', (90, 99))
157773	33072070	The Kaplan-Meier survival analysis showed that subjects with higher PD-1 levels had shorter OS than those with lower levels in GBM (P = 0.037), KIRP (P = 0.040), LAML (P = 0.002), low-grade glioma (LGG) (P < 0.001), and UVM (P < 0.001).	('glioma', 'Disease', (190, 196))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('levels', 'Var', (73, 79))	('shorter', 'NegReg', (84, 91))	('UVM', 'Phenotype', 'HP:0007716', (220, 223))	('PD-1', 'Gene', (68, 72))
157776	33072070	The Kaplan-Meier survival analysis showed that patients with higher CTLA4 expression had shorter OS than those with lower CTLA4 expression in KIRC (P = 0.008), LGG (P < 0.001), and THYM (P = 0.040).	('THYM', 'Phenotype', 'HP:0100522', (181, 185))	('higher', 'PosReg', (61, 67))	('CTLA4', 'Gene', (68, 73))	('patients', 'Species', '9606', (47, 55))	('expression', 'Var', (74, 84))	('shorter', 'NegReg', (89, 96))
157798	33072070	Our results showed that PD-1 and CTLA4 expression varies across cancer types and that most cancers are characterized by PD-1 and CTLA4 mutations that lead to their abnormal expression, which can serve as a prognostic biomarker.	('PD-1', 'Gene', (120, 124))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('cancer', 'Disease', (91, 97))	('mutations', 'Var', (135, 144))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('expression', 'MPA', (173, 183))	('CTLA4', 'Gene', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
157801	33072070	Identifying aberrantly expressed genes in tumors is important for the development of individualized treatments, which can improve therapeutic outcomes.	('aberrantly expressed', 'Var', (12, 32))	('tumors', 'Disease', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
157807	33072070	Gene mutations are the major cause of cancer development, and specific mutations predict treatment response and prognosis.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('treatment response', 'CPA', (89, 107))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('mutations', 'Var', (71, 80))	('predict', 'Reg', (81, 88))	('cancer', 'Disease', (38, 44))	('cause', 'Reg', (29, 34))
157808	33072070	TMB affects the generation of immunogenic peptides, thereby affecting patients' response to immune checkpoint inhibitor treatment.	('patients', 'Species', '9606', (70, 78))	('affecting', 'Reg', (60, 69))	('TMB', 'Chemical', '-', (0, 3))	('affects', 'Reg', (4, 11))	('TMB', 'Var', (0, 3))	('generation of immunogenic peptides', 'MPA', (16, 50))	('response to immune checkpoint inhibitor treatment', 'MPA', (80, 129))
157817	33072070	However, it remains to be determined whether the combination of PD-1 and CTLA4 inhibitors has greater efficacy than monotherapy in these cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('PD-1', 'Gene', (64, 68))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('inhibitors', 'Var', (79, 89))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('CTLA4', 'Gene', (73, 78))
157818	33072070	Epigenetic modifications modulate gene expression and can be exploited by tumor cells to evade immune surveillance.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('gene expression', 'biological_process', 'GO:0010467', ('34', '49'))	('gene expression', 'MPA', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('modulate', 'Reg', (25, 33))	('Epigenetic modifications', 'Var', (0, 24))
157831	31842801	Among these genes, ZAP70, CD3E, CD3G, CD3D, and CD247 were part of the TCR 'signal-triggering module'; (3) High expression of the PIGs involved in the TCR signaling pathway was associated with improved OS in 5 cancer types (breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), lung adenocarcinoma (LUAD), and sarcoma (SARC)), but was associated with decreased OS in brain lower-grade glioma (LGG).	('BRCA', 'Gene', '672', (251, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (359, 368))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (331, 368))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('TCR', 'Gene', '6962', (151, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('lung adenocarcinoma', 'Disease', (377, 396))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (331, 368))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (224, 249))	('BRCA', 'Gene', (251, 255))	('TCR', 'Gene', (71, 74))	('TCR', 'cellular_component', 'GO:0042101', ('151', '154'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (267, 290))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (258, 322))	('carcinoma', 'Phenotype', 'HP:0030731', (387, 396))	('sarcoma', 'Disease', 'MESH:D012509', (409, 416))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('glioma', 'Disease', (484, 490))	('TCR', 'Gene', (151, 154))	('sarcoma', 'Disease', (409, 416))	('decreased', 'NegReg', (450, 459))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (377, 396))	('glioma', 'Disease', 'MESH:D005910', (484, 490))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (377, 396))	('TCR signaling pathway', 'biological_process', 'GO:0050852', ('151', '172'))	('PIGs', 'Species', '9823', (130, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('glioma', 'Phenotype', 'HP:0009733', (484, 490))	('breast invasive carcinoma', 'Disease', (224, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (409, 416))	('TCR', 'cellular_component', 'GO:0042101', ('71', '74'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (345, 368))	('improved', 'PosReg', (193, 201))	('High expression', 'Var', (107, 122))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (224, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('TCR', 'biological_process', 'GO:0006283', ('71', '74'))	('cancer', 'Disease', (210, 216))	('TCR', 'Gene', '6962', (71, 74))	('neck', 'cellular_component', 'GO:0044326', ('340', '344'))
157843	31842801	In addition, pembrolizumab was associated with a significantly longer OS for platinum-refractory advanced urothelial carcinoma than standard therapy.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('platinum', 'Chemical', 'MESH:D010984', (77, 85))	('urothelial carcinoma', 'Disease', (106, 126))	('pembrolizumab', 'Var', (13, 26))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (106, 126))	('pembrolizumab', 'Chemical', 'MESH:C582435', (13, 26))
157890	31842801	Eleven genes (ZAP70, PTPRC, LCK, ICOS, CD3E, CD3G, CD3D, ITK, CD247, CD40LG, and GRAP2) were identified as participating in the TCR signaling pathway (Fig.	('participating', 'Reg', (107, 120))	('TCR', 'cellular_component', 'GO:0042101', ('128', '131'))	('CD40LG', 'Gene', (69, 75))	('ZAP70', 'Var', (14, 19))	('TCR', 'Gene', (128, 131))	('GRAP2', 'Gene', (81, 86))	('CD3G', 'Gene', (45, 49))	('PTPRC', 'Gene', '100522631', (21, 26))	('ICOS', 'Gene', (33, 37))	('ITK', 'Gene', (57, 60))	('CD3E', 'Gene', (39, 43))	('TCR signaling pathway', 'biological_process', 'GO:0050852', ('128', '149'))	('CD247', 'Var', (62, 67))	('PTPRC', 'Gene', (21, 26))	('GRAP2', 'Gene', '100516438', (81, 86))	('ICOS', 'Gene', '733597', (33, 37))	('TCR', 'Gene', '6962', (128, 131))	('CD40LG', 'Gene', '397231', (69, 75))	('CD3D', 'Gene', (51, 55))	('ITK', 'Gene', '100523474', (57, 60))
157892	31842801	ZAP70, CD3E, CD3G, CD3D, and CD247 were classified into a 'TCR signal triggering module' by Acuto et al., which was crucial to the successful initiation of T cell activation.	('CD3E', 'Var', (7, 11))	('CD3G', 'Var', (13, 17))	('CD3D', 'Var', (19, 23))	('T cell activation', 'biological_process', 'GO:0042110', ('156', '173'))	('TCR', 'cellular_component', 'GO:0042101', ('59', '62'))	('ZAP70', 'Var', (0, 5))	('TCR', 'Gene', '6962', (59, 62))	('CD247', 'Var', (29, 34))	('TCR', 'biological_process', 'GO:0006283', ('59', '62'))	('TCR', 'Gene', (59, 62))
157895	31842801	Second, 6 (LCK, ZAP70, CD3E, CD3G, CD3D, and CD247) out of 11 PIGs played crucial roles in activating T cell activation.	('CD247', 'Var', (45, 50))	('activating T cell activation', 'MPA', (91, 119))	('T cell activation', 'biological_process', 'GO:0042110', ('102', '119'))	('PIGs', 'Species', '9823', (62, 66))
157906	31842801	High-level expression of the PIGs participating in the TCR signaling pathway was associated with improved OS in 5 cancer types (BRCA, CESC, HNSC, LUAD, and SARC), but with decreased OS in LGG.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('HNSC', 'Disease', (140, 144))	('TCR', 'cellular_component', 'GO:0042101', ('55', '58'))	('cancer', 'Disease', (114, 120))	('BRCA', 'Gene', (128, 132))	('LUAD', 'Disease', (146, 150))	('improved', 'PosReg', (97, 105))	('BRCA', 'Gene', '672', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('TCR', 'Gene', '6962', (55, 58))	('CESC', 'Disease', (134, 138))	('PIGs', 'Species', '9823', (29, 33))	('High-level expression', 'Var', (0, 21))	('TCR signaling pathway', 'biological_process', 'GO:0050852', ('55', '76'))	('TCR', 'Gene', (55, 58))
157925	31842801	Eleven PIGs (ZAP70, PTPRC, LCK, ICOS, CD3E, CD3G, CD3D, ITK, CD247, CD40LG, and GRAP2) were mainly shared by the 6 cancer types (BRCA, CESC, HNSC, LUAD, SARC, and LGG) involved in the TCR signaling pathway.	('CD40LG', 'Gene', '397231', (68, 74))	('CD3D', 'Var', (50, 54))	('ITK', 'Gene', '100523474', (56, 59))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('PIGs', 'Species', '9823', (7, 11))	('ZAP70', 'Var', (13, 18))	('CD40LG', 'Gene', (68, 74))	('TCR', 'Gene', (184, 187))	('TCR', 'cellular_component', 'GO:0042101', ('184', '187'))	('PTPRC', 'Gene', '100522631', (20, 25))	('BRCA', 'Gene', '672', (129, 133))	('TCR signaling pathway', 'biological_process', 'GO:0050852', ('184', '205'))	('ICOS', 'Gene', (32, 36))	('GRAP2', 'Gene', (80, 85))	('BRCA', 'Gene', (129, 133))	('CD3G', 'Var', (44, 48))	('PTPRC', 'Gene', (20, 25))	('cancer', 'Disease', (115, 121))	('ITK', 'Gene', (56, 59))	('ICOS', 'Gene', '733597', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('CD247', 'Var', (61, 66))	('GRAP2', 'Gene', '100516438', (80, 85))	('TCR', 'Gene', '6962', (184, 187))
157926	31842801	Six genes (ZAP70, LCK, CD3E, CD3G, CD3D, and CD247) played a key role in triggering the TCR signaling pathway.	('CD3D', 'Gene', (35, 39))	('CD3G', 'Gene', (29, 33))	('LCK', 'Gene', (18, 21))	('CD247', 'Gene', (45, 50))	('TCR', 'Gene', (88, 91))	('ZAP70', 'Var', (11, 16))	('TCR signaling pathway', 'biological_process', 'GO:0050852', ('88', '109'))	('triggering', 'Reg', (73, 83))	('TCR', 'cellular_component', 'GO:0042101', ('88', '91'))	('TCR', 'Gene', '6962', (88, 91))	('CD3E', 'Gene', (23, 27))
157932	31842801	In this study, there was no significant difference between the OS in patients with high expression of CTLA4 and PD1 and that of patients with low expression of CTLA4 and PD1 in most cancer types.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('CTLA4', 'Gene', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('high expression', 'Var', (83, 98))	('cancer', 'Disease', (182, 188))	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (128, 136))	('PD1', 'Gene', (112, 115))
157934	31842801	High expression of 11 PIGs was associated with good prognosis in BRCA, CESC, HNSC, LUAD, and SARC but poor prognosis in LGG.	('High expression', 'Var', (0, 15))	('BRCA', 'Gene', (65, 69))	('LUAD', 'Disease', (83, 87))	('SARC but', 'Disease', (93, 101))	('CESC', 'Disease', (71, 75))	('BRCA', 'Gene', '672', (65, 69))	('PIGs', 'Species', '9823', (22, 26))	('HNSC', 'Disease', (77, 81))
157939	31842801	Among them, CD45 can modulate LCK activation or inactivation by the dephosphorylation of Tyr505 of LCK or the dephosphorylation of Tyr394 of LCK.	('CD45', 'Var', (12, 16))	('Tyr505', 'Var', (89, 95))	('LCK', 'Protein', (141, 144))	('inactivation', 'NegReg', (48, 60))	('Tyr394', 'Chemical', '-', (131, 137))	('dephosphorylation', 'MPA', (110, 127))	('dephosphorylation', 'biological_process', 'GO:0016311', ('68', '85'))	('Tyr505', 'Chemical', '-', (89, 95))	('LCK', 'Protein', (99, 102))	('activation', 'PosReg', (34, 44))	('LCK', 'Protein', (30, 33))	('modulate', 'Reg', (21, 29))	('dephosphorylation', 'biological_process', 'GO:0016311', ('110', '127'))	('dephosphorylation', 'MPA', (68, 85))
157992	31344359	Deviant genes generally appeared with greater frequency in cancer types having large numbers of copy number alterations (LUSC, LUAD, ESCA, SARC, BLCA, OV), whereas fewer disagreements tended to occur within cancer types harboring fewer copy number alterations (THCA, LAML, KIRP, UVM, THYM, KIRC) (Figure 2C).	('ESCA', 'Disease', (133, 137))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('THCA', 'Chemical', '-', (261, 265))	('copy number alterations', 'Var', (96, 119))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('SARC', 'Disease', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('LUAD', 'Disease', (127, 131))
157994	31344359	Almost all (93%; 482/521) of these driver alterations in both marker papers and hg19 GISTIC analyses were matched in the analysis of the hg38 data, meaning they were either found in both hg19 and hg38 or not present in either (Data S2.6).	('hg38', 'Gene', (196, 200))	('hg38', 'Gene', '8549', (196, 200))	('alterations', 'Var', (42, 53))	('S2.6', 'Gene', (232, 236))	('hg38', 'Gene', (137, 141))	('hg38', 'Gene', '8549', (137, 141))	('S2.6', 'Gene', '6231', (232, 236))
157998	31344359	"beta") values was not altered, and thus methylation beta values for individual probes were identical between the hg19 and hg38 versions.	('hg19', 'Var', (114, 118))	('methylation', 'MPA', (41, 52))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('hg38', 'Gene', (123, 127))	('hg38', 'Gene', '8549', (123, 127))
158004	31344359	Some of the new protein coding associations involved alternative promoters of known cancer genes that were not represented in the hg19 version, such as epigenetic regulation of the PAX8 gene in a subset of CHOL tumors (Figure 3D-E).	('PAX8', 'Gene', '7849', (181, 185))	('involved', 'Reg', (44, 52))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('CHOL tumors', 'Disease', (206, 217))	('protein', 'cellular_component', 'GO:0003675', ('16', '23'))	('PAX8', 'Gene', (181, 185))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('regulation', 'biological_process', 'GO:0065007', ('163', '173'))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('CHOL tumors', 'Disease', 'MESH:D009369', (206, 217))	('epigenetic regulation', 'Var', (152, 173))
158009	31344359	These differences:in alignment, quantification, normalization, and references (Figure 4A):are expected to introduce bias between the hg19 and hg38 abundance estimates.	('differences', 'Var', (6, 17))	('hg38', 'Gene', '8549', (142, 146))	('hg38', 'Gene', (142, 146))	('introduce', 'Reg', (106, 115))	('hg19', 'Gene', (133, 137))
158023	31344359	Across 1,902 shared tumor samples, the mutation overlap between GDC and MC3 contained a total of 488,138 public somatic SNV calls from 21,535 genes (Figure 5B).	('mutation', 'Var', (39, 47))	('GDC', 'Gene', (64, 67))	('MC3', 'Gene', '4159', (72, 75))	('MC3', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
158026	31344359	The stringent one-caller mutation removal in MC3 contributed to the majority of the recoverable GDC-unique calls (59.0%).	('MC3', 'Gene', (45, 48))	('MC3', 'Gene', '4159', (45, 48))	('mutation removal', 'Var', (25, 41))
158027	31344359	The gene annotation changes can also alter the exonic definition (at least 2.1% of all recoverable GDC-unique calls), such as genes CCDC168 and EFCAB8 (Figure S4C, D).	('CCDC168', 'Gene', '643677', (132, 139))	('EFCAB8', 'Gene', (144, 150))	('exonic definition', 'MPA', (47, 64))	('alter', 'Reg', (37, 42))	('CCDC168', 'Gene', (132, 139))	('EFCAB8', 'Gene', '388795', (144, 150))	('changes', 'Var', (20, 27))
158028	31344359	The GDC labels a mutation call 'public' when it is also found in the validation sequencing, regardless of the filter status, whereas MC3 calling did not utilize validation status.	('MC3', 'Gene', (133, 136))	('MC3', 'Gene', '4159', (133, 136))	('mutation', 'Var', (17, 25))
158065	31344359	The main differences between the hg19 and hg38 versions of the pipeline involve the versions of some software components, and the reference data files used (Figure 1A).	('hg38', 'Gene', (42, 46))	('hg38', 'Gene', '8549', (42, 46))	('hg19', 'Var', (33, 37))
158085	31344359	As described in the main text, copy number alterations were identified from TCGA Level 3 segmented copy number profiles, generated from the same pipeline for both hg19 and hg38.	('hg38', 'Gene', (172, 176))	('hg38', 'Gene', '8549', (172, 176))	('copy number alterations', 'Var', (31, 54))	('TCGA', 'Gene', (76, 80))
158099	31344359	Similarly, among focal deletions in COAD, only 1519 genes were called in both runs' peaks compared to 938 and 809 genes found only in the hg19-aligned and hg38-aligned GISTIC2.0 deletion peaks, respectively.	('deletions', 'Var', (23, 32))	('COAD', 'Disease', 'MESH:D029424', (36, 40))	('hg38', 'Gene', (155, 159))	('hg38', 'Gene', '8549', (155, 159))	('COAD', 'Disease', (36, 40))
158105	31344359	Forty drivers were absent from both hg19 and hg38 GISTIC2.0 runs and likely stem from multiple causes: the marker papers often used smaller sets of TCGA samples to discover these drivers, utilized manual inspection and rescue of drivers proximal to identified copy number peaks but not explicitly called within these peaks, and used earlier versions of GISTIC running on hg18-aligned copy number data.	('hg38', 'Gene', '8549', (45, 49))	('copy', 'Var', (260, 264))	('hg38', 'Gene', (45, 49))
158115	31344359	In addition, "experiment-specific" probe masking is performed, based on weak signal or high background due to array quality, experimental failure, or genomic deletions in the sample.	('genomic deletions', 'Var', (150, 167))	('experimental failure', 'Disease', (125, 145))	('experimental failure', 'Disease', 'MESH:D006333', (125, 145))
158128	31344359	The vast majority of probes remained validly mapped without mismatches in hg38 (98.0% of HM27 and 98.9% of HM450, Table S4).	('hg38', 'Gene', '8549', (74, 78))	('hg38', 'Gene', (74, 78))	('HM27', 'CellLine', 'CVCL:8807', (89, 93))	('mismatches', 'Var', (60, 70))
158132	31344359	Most probes (64% HM27 and 67% HM450 probes) were completely concordant between hg19 and hg38, meaning that the gene(s) annotated were completely identical between the two releases (Figure S2A,B).	('hg19', 'Gene', (79, 83))	('hg38', 'Gene', (88, 92))	('hg38', 'Gene', '8549', (88, 92))	('HM27', 'Var', (17, 21))	('HM27', 'CellLine', 'CVCL:8807', (17, 21))
158134	31344359	Gene name changes also contributed to these differences: for roughly 25k probes (23,508 HM450 and 1,467 HM27), the probe was associated with the same gene in both hg19 and hg38 releases, but the gene symbol was updated in hg38.	('HM450', 'Var', (88, 93))	('hg38', 'Gene', (172, 176))	('hg38', 'Gene', '8549', (172, 176))	('hg38', 'Gene', (222, 226))	('hg38', 'Gene', '8549', (222, 226))	('HM27', 'CellLine', 'CVCL:8807', (104, 108))
158137	31344359	This approach was commonly used in TCGA to infer epigenetic silencing of genes such as BRCA1 in ovarian cancer.	('epigenetic silencing', 'Var', (49, 69))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (96, 110))	('BRCA1 in ovarian cancer', 'Disease', 'OMIM:604370', (87, 110))	('BRCA1 in ovarian cancer', 'Disease', (87, 110))
158139	31344359	Because the newer gene associations contained more genes and alternative transcripts, and associated CpG probes both upstream and downstream of the TSS (illustrated in Figure 3B), we were able to identify substantially more significant associations in the hg38 methylation data than in its hg19 predecessor (Figure 3C).	('methylation', 'Var', (261, 272))	('hg38', 'Gene', (256, 260))	('hg38', 'Gene', '8549', (256, 260))	('methylation', 'biological_process', 'GO:0032259', ('261', '272'))
158142	31344359	De-methylation of the associated promoter CpG is associated with increased expression in a subset of TCGA-CHOL tumors (Figure 3E).	('CpG', 'Gene', (42, 45))	('increased', 'PosReg', (65, 74))	('De-methylation', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('TCGA-CHOL tumors', 'Disease', (101, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('methylation', 'biological_process', 'GO:0032259', ('3', '14'))	('TCGA-CHOL tumors', 'Disease', 'MESH:D009369', (101, 117))	('expression', 'MPA', (75, 85))
158152	31344359	This explains the small subsets for some data types such as simple nucleotide variation, and data formats such as VCF, FA, and TAR.	('TAR', 'Disease', (127, 130))	('simple nucleotide variation', 'Var', (60, 87))	('TAR', 'Disease', 'MESH:C536940', (127, 130))
158173	31344359	The genomic coordinates of MC3 variant calls were lifted over from hg19 to hg38 using CrossMap v0.2.7 and chain files from University of California, Santa Cruz (UCSC).	('MC3', 'Gene', '4159', (27, 30))	('variant', 'Var', (31, 38))	('MC3', 'Gene', (27, 30))	('hg38', 'Gene', (75, 79))	('hg38', 'Gene', '8549', (75, 79))
158204	31052182	According to the TCGA analysis accessed via cBioPortal in February 2019, only 12 out of 411 invasive UC contained genome alterations in HDAC4, predominantly deep deletions, and seven cases contained alterations in HDAC5, predominantly missense mutations.	('missense mutations', 'Var', (235, 253))	('February 2019', 'Disease', 'MESH:C000657245', (58, 71))	('February 2019', 'Disease', (58, 71))	('HDAC4', 'Gene', '9759', (136, 141))	('HDAC4', 'Gene', (136, 141))	('HDAC5', 'Gene', '10014', (214, 219))	('deep deletions', 'Var', (157, 171))	('HDAC5', 'Gene', (214, 219))	('alterations', 'Reg', (199, 210))
158227	31052182	We next measured cell proliferation by MTT assay at different time points over 96 h. Until 72 h (48 h in the case of UM-UC-3), HDAC5 and vector-only transduced cell lines grew quite similarly, but at 96 h proliferation of HDAC5-expressing RT112, SW1710 and UM-UC-3 cells was clearly diminished (around 40%, 40%, and 70%, respectively) in comparison to their respective vector-only cells (Figure 2).	('HDAC5', 'Gene', '10014', (127, 132))	('MTT', 'Chemical', 'MESH:C070243', (39, 42))	('HDAC5', 'Gene', (127, 132))	('UC-3', 'Species', '947040', (120, 124))	('UC-3', 'Species', '947040', (260, 264))	('RT112', 'Var', (239, 244))	('proliferation', 'CPA', (205, 218))	('cell proliferation', 'biological_process', 'GO:0008283', ('17', '35'))	('SW1710', 'CellLine', 'CVCL:1721', (246, 252))	('SW1710', 'Var', (246, 252))	('HDAC5', 'Gene', '10014', (222, 227))	('HDAC5', 'Gene', (222, 227))	('diminished', 'NegReg', (283, 293))
158233	31052182	Notably, HDAC5 expressing VM-Cub-1 formed loose aggregates, whereas HDAC5 expressing RT112 cells were compact and bigger, but fewer in number (Figure 4).	('HDAC5', 'Gene', (68, 73))	('VM-Cub-1', 'Var', (26, 34))	('HDAC5', 'Gene', '10014', (9, 14))	('HDAC5', 'Gene', (9, 14))	('HDAC5', 'Gene', '10014', (68, 73))
158239	31052182	To characterize the overall changes in the proteome of the UCCs following HDAC5 overexpression, we performed high-throughput proteomics analysis by mass spectrometry.	('HDAC5', 'Gene', '10014', (74, 79))	('HDAC5', 'Gene', (74, 79))	('overexpression', 'Var', (80, 94))	('changes', 'Reg', (28, 35))
158246	31052182	KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis identified metabolic processes, especially "amino sugar and nucleotide sugar metabolism", as well as "proteasome" and "ribosome" as consistently enriched in VM-Cub-1 compared to the other three UC cell lines (Figure 8).	('metabolic processes', 'MPA', (75, 94))	('nucleotide sugar', 'Chemical', '-', (124, 140))	('enriched', 'Reg', (209, 217))	('amino sugar', 'Chemical', 'MESH:D000606', (108, 119))	('VM-Cub-1', 'Var', (221, 229))
158276	31052182	Lentiviral transduction of HDAC5 indeed decreased the short-term proliferation of three of the four UCCs and their ability to form clones.	('Lentiviral', 'Var', (0, 10))	('transduction', 'biological_process', 'GO:0009293', ('11', '23'))	('HDAC5', 'Gene', '10014', (27, 32))	('HDAC5', 'Gene', (27, 32))	('short-term proliferation', 'CPA', (54, 78))	('decreased', 'NegReg', (40, 49))
158283	31052182	It is indeed intriguing that expression of HDAC5 on its own is capable of inducing EMT in certain circumstances, and notably, appears to be more effective than even TGFbeta, which can promote enhanced migration and invasion in some UCCs.	('expression', 'Var', (29, 39))	('invasion', 'CPA', (215, 223))	('EMT', 'CPA', (83, 86))	('migration', 'CPA', (201, 210))	('promote enhanced', 'PosReg', (184, 200))	('TGFbeta', 'Gene', (165, 172))	('inducing', 'PosReg', (74, 82))	('EMT', 'biological_process', 'GO:0001837', ('83', '86'))	('HDAC5', 'Gene', '10014', (43, 48))	('HDAC5', 'Gene', (43, 48))	('TGFbeta', 'Gene', '7040', (165, 172))
158288	31052182	We therefore investigated whether the presence of HDAC5 would change the response of the UC cell lines to the two cytokines.	('presence', 'Var', (38, 46))	('change', 'Reg', (62, 68))	('HDAC5', 'Gene', '10014', (50, 55))	('response', 'MPA', (73, 81))	('HDAC5', 'Gene', (50, 55))
158294	31052182	Accordingly, lentiviral transduction of HDAC5, but not HDAC4 had significant effects on cellular properties.	('HDAC5', 'Gene', (40, 45))	('HDAC4', 'Gene', '9759', (55, 60))	('effects', 'Reg', (77, 84))	('cellular properties', 'CPA', (88, 107))	('lentiviral', 'Var', (13, 23))	('HDAC5', 'Gene', '10014', (40, 45))	('transduction', 'biological_process', 'GO:0009293', ('24', '36'))	('HDAC4', 'Gene', (55, 60))
158308	31052182	Briefly, HEK-293T cells were transfected with helper plasmid expression construct pCD/NL-BH, envelope vector (pczVSV-G) and either the vector plasmids puc2CL12IPwo or puc2CL12IPwo-HDAC5-FLAG.	('HEK-293T', 'CellLine', 'CVCL:0063', (9, 17))	('envelope', 'cellular_component', 'GO:0009274', ('93', '101'))	('puc2CL12IPwo', 'Var', (151, 163))	('HDAC5', 'Gene', '10014', (180, 185))	('HDAC5', 'Gene', (180, 185))	('pCD', 'biological_process', 'GO:0012501', ('82', '85'))	('envelope', 'cellular_component', 'GO:0031975', ('93', '101'))
158338	30926888	Moreover, UCGD and a poor 5 -year overall survival (OS) (P = 0.02) while there was no difference in cancer-specific survival (CSS) (P = 0.062) between two groups.	('overall', 'MPA', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('UCGD', 'Var', (10, 14))	('poor', 'NegReg', (21, 25))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('CSS', 'Chemical', '-', (126, 129))
158374	30926888	reported glandular and squamous differentiation had effect of on oncologic outcomes, they found histologic variant to be an independent predictor for cancer specific survival on multivariate analysis.	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('variant', 'Var', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
158423	28533583	He underwent USG abdomen and was diagnosed with urothelial bladder mass (29x17mm) seen along the left lateral wall with mild adjacent perivesical fat stranding with small bilateral obturator nodes and prostomegaly.	('urothelial bladder mass', 'Disease', 'MESH:D001745', (48, 71))	('urothelial bladder mass', 'Disease', (48, 71))	('29x17mm', 'Var', (73, 80))	('prostomegaly', 'Disease', (201, 213))	('prostomegaly', 'Disease', 'None', (201, 213))
158462	28036280	We thus assume that the destruction of a coordinated regulatory network might result in tumorigenesis and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('result in', 'Reg', (78, 87))	('destruction', 'Var', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (106, 111))
158466	28036280	They proposed that perturbation of these conserved genes was associated with embryonic lethality and cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('perturbation', 'Var', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('associated', 'Reg', (61, 71))	('embryonic lethality', 'Disease', 'MESH:D020964', (77, 96))	('embryonic lethality', 'Disease', (77, 96))
158505	28036280	Meanwhile, gene ontology (GO) analysis of DEGs (244 genes) in at least 12 cancers revealed that they were mainly enriched in the cell cycle (FDR corrected P-value 1.6260E-40, 77 genes), organelle organization (FDR corrected P-value 5.6591E-18, 68 genes), mitosis (FDR corrected P-value 1.3085E-35, 45 genes), etc., which were all closely related to tumor characteristics (Figures 4B, , and 4D).	('mitosis', 'Disease', 'None', (255, 262))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('organelle', 'cellular_component', 'GO:0043226', ('186', '195'))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('related', 'Reg', (338, 345))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cell cycle', 'CPA', (129, 139))	('FDR', 'Var', (210, 213))	('mitosis', 'biological_process', 'GO:0000278', ('255', '262'))	('cell cycle', 'biological_process', 'GO:0007049', ('129', '139'))	('gene ontology', 'biological_process', 'GO:0003673', ('11', '24'))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('FDR', 'Var', (264, 267))	('organelle organization', 'CPA', (186, 208))	('mitosis', 'Disease', (255, 262))	('tumor', 'Disease', (349, 354))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('organelle organization', 'biological_process', 'GO:0006996', ('186', '208'))
158509	28036280	Additionally, they can be significantly separated into two groups (Supplementary Figure 3, logrank test, P < 0.05) based on 3~25 survival-related DEGs in each cancer (Supplementary Table 3).	('cancer', 'Disease', (159, 165))	('DEGs', 'Var', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
158523	28036280	Further identification of shared DEGs between normal and tumor tissues uncovers dysregulation of cell cycle processes, which is one of the hallmarks in cancer.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('dysregulation of cell cycle', 'Phenotype', 'HP:0011018', (80, 107))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cell cycle', 'biological_process', 'GO:0007049', ('97', '107'))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cell cycle processes', 'CPA', (97, 117))	('dysregulation', 'Var', (80, 93))	('tumor', 'Disease', (57, 62))
158529	28036280	It encodes thyroid peroxidase enzyme, which is a thyroid-specific glycosylated hemoprotein, and aberrant regulation of TPO can result in thyroid dyshormonogenesis.	('TPO', 'Gene', (119, 122))	('aberrant regulation', 'Var', (96, 115))	('thyroid dyshormonogenesis', 'Disease', (137, 162))	('result in', 'Reg', (127, 136))	('thyroid dyshormonogenesis', 'Disease', 'MESH:C564766', (137, 162))	('TPO', 'Gene', '7173', (119, 122))	('regulation', 'biological_process', 'GO:0065007', ('105', '115'))
158555	25502898	We identified 9 unique non-synonymous somatic mutations across the six UC samples, including five present in each carcinoma sample, consistent with clonal origin and limited intertumoral heterogeneity.	('non-synonymous somatic mutations', 'Var', (23, 55))	('carcinoma', 'Disease', 'MESH:D002277', (114, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('carcinoma', 'Disease', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
158562	25502898	The field effect theory asserts the entire urothelium in patients with UC may be unstable, due to genetic hits and progressive outgrowth of genetically unstable cells throughout the entire urothelium.	('genetic hits', 'Disease', (98, 110))	('patients', 'Species', '9606', (57, 65))	('genetic hits', 'Disease', 'MESH:D030342', (98, 110))	('genetically unstable', 'Var', (140, 160))	('progressive outgrowth', 'Phenotype', 'HP:0001548', (115, 136))	('outgrowth', 'CPA', (127, 136))
158563	25502898	Findings consistent with possible field effects in multifocal UC include promoter methylation of cancer-associated genes in histologically normal urothelium adjacent to UC, such as E-cadherin promoter methylation in the urothelium of elderly patients, as well as widespread TP53 mutations in the urothelium of patients with high level radiation exposure.	('high level radiation exposure', 'Phenotype', 'HP:0011133', (324, 353))	('patients', 'Species', '9606', (310, 318))	('mutations', 'Var', (279, 288))	('promoter methylation', 'MPA', (73, 93))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('E-cadherin', 'Gene', (181, 191))	('methylation', 'biological_process', 'GO:0032259', ('201', '212'))	('TP53', 'Gene', '7157', (274, 278))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cadherin', 'molecular_function', 'GO:0008014', ('183', '191'))	('methylation', 'biological_process', 'GO:0032259', ('82', '93'))	('E-cadherin', 'Gene', '999', (181, 191))	('TP53', 'Gene', (274, 278))	('patients', 'Species', '9606', (242, 250))
158565	25502898	Evidence for the clonal expansion proposal includes data showing that identical genetic abnormalities are present in spatially distinct UCs from the same patient, such as identified by loss of heterozygosity (LOH) analysis, comparative genome hybridization (CGH), and TP53 mutational work.	('genetic abnormalities', 'Disease', (80, 101))	('TP53', 'Gene', '7157', (268, 272))	('patient', 'Species', '9606', (154, 161))	('loss', 'Var', (185, 189))	('TP53', 'Gene', (268, 272))	('genetic abnormalities', 'Disease', 'MESH:D030342', (80, 101))
158602	25502898	Analysis was performed in Torrent Suite 3.6, with alignment by TMAP (version 3.6.39) using default parameters, and variant calling using the Torrent Suite Variant Caller plugin (version 3.6.63335) using default low-stringency somatic variant settings.	('TMAP', 'Gene', (63, 67))	('variant', 'Var', (115, 122))	('TMAP', 'Gene', '26586', (63, 67))
158603	25502898	For BL193A and BL193B, samples were processed, sequenced and analyzed as just described, but were assessed using a custom Ion Torrent Ampliseq panel that targets ~130 cancer related genes.	('BL193B', 'Var', (15, 21))	('BL193', 'CellLine', 'CVCL:S838', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('BL193B', 'CellLine', 'CVCL:S838', (15, 21))	('cancer', 'Disease', (167, 173))	('BL193A', 'Var', (4, 10))	('BL193', 'CellLine', 'CVCL:S838', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
158607	25502898	To identify somatic variants for each tumor sample from Case 1, called variants were filtered to remove synonymous variants and those without adequate read support by removing variants with: flow corrected read depths (FDP) less than 20, flow corrected variant allele containing reads (FAO) less than 6, variant allele frequencies (FAO/FDP) less than 0.10 and skewed variant read support (>5-fold difference in number of forward (FSAF) vs. reverse (FSAR) reads containing the variant allele [FSAF/FSAR < 0.2 or FSAF/FSAR > 5]).	('variants', 'Var', (71, 79))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('less than', 'Var', (224, 233))
158610	25502898	For Cases 2-4, called variants in each tumor component were filtered to remove synonymous variants and those without adequate read support by removing variants with: FDP<20, FAO<6, FAO/FDP<0.10, indels with FSAF/FSAR <0.2 or FSAF/FSAR>5.	('FAO<6', 'Var', (174, 179))	('FDP<20', 'Var', (166, 172))	('FAO/FDP<0.10', 'Var', (181, 193))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('indels', 'Var', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('variants', 'Var', (22, 30))
158613	25502898	Then, to prioritize potentially driving somatic variants and those informing on the relationship of paired invasive/invasive components, only variants that 1) differed between paired non-invasive/invasive samples, 2) have been reported in COSMIC, or 3) are deleterious variants in tumor suppressors, were retained.	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('variants', 'Var', (142, 150))	('tumor', 'Disease', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (281, 286))
158617	25502898	To identify areas of loss of heterozygosity in Case 1, we identified all presumed heterozygous, adequately supported SNPs called in BL193 (0.40<=FAO/FDP<=0.60 and FAO>5) that were also called in at least one tumor sample (FAO>5).	('BL193', 'Gene', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (208, 213))	('BL193', 'CellLine', 'CVCL:S838', (132, 137))	('0.40<=FAO/FDP<=0.60', 'Var', (139, 158))
158621	25502898	Positions with candidate somatic mutations in at least one tumor sample in Case 1 were subjected to validation through Sanger sequencing of the paired normal tissue (BL193) and all tumor samples.	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', (59, 64))	('mutations', 'Var', (33, 42))	('BL193', 'CellLine', 'CVCL:S838', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
158635	25502898	Tumor cell nuclei were high grade, showing nuclear enlargement, anisonucleosis, and hyperchromasia; mitotic figures were increased.	('hyperchromasia', 'Disease', (84, 98))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('increased', 'PosReg', (121, 130))	('hyperchromasia', 'Disease', 'None', (84, 98))	('anisonucleosis', 'Var', (64, 78))	('nuclear enlargement', 'CPA', (43, 62))	('mitotic figures', 'CPA', (100, 115))
158638	25502898	Across the six tumor components, we identified a total of 36, high confidence, non-synonymous somatic mutations, representing 9 unique genomic positions (Fig 1E and Table S2).	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('mutations', 'Var', (102, 111))	('non-synonymous', 'Var', (79, 93))
158640	25502898	The two failed variants (MYH9 E1115K and E1244K in BL190) were not detected by Sanger sequencing in either the appropriate tumor or normal sample, and were called at low variant allele frequencies (0.14 and 0.17, respectively, Table S2).	('E1244K', 'Mutation', 'rs773790950', (41, 47))	('tumor', 'Disease', (123, 128))	('BL190', 'Gene', (51, 56))	('E1115K', 'Mutation', 'p.E1115K', (30, 36))	('MYH9', 'Gene', (25, 29))	('E1244K', 'Var', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('BL190', 'CellLine', 'CVCL:0671', (51, 56))	('E1115K', 'Var', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('MYH9', 'Gene', '4627', (25, 29))
158641	25502898	Among confirmed non-synonymous somatic mutations, five identical mutations were present in all six UC samples: HRAS (Q61L), FLT4 (Q827X), MLL2 (Q3867fs), NTRK3 (T332M), and PIK3CA (H1047L), consistent with a clonal relationship for all five non-muscle-invasive UCs present at distinct locations and the paired invasive component of one tumor (Fig 1E).	('H1047L', 'Mutation', 'rs121913279', (181, 187))	('Q61L', 'Var', (117, 121))	('tumor', 'Disease', (336, 341))	('T332M', 'Mutation', 'rs145157285', (161, 166))	('T332M', 'Var', (161, 166))	('H1047L', 'Var', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('Q3867fs', 'Var', (144, 151))	('FLT4', 'Gene', '2324', (124, 128))	('FLT4', 'Gene', (124, 128))	('Q827X', 'Var', (130, 135))	('PIK3CA', 'Gene', '5290', (173, 179))	('MLL2', 'Gene', '8085', (138, 142))	('NTRK3', 'Gene', '4916', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('NTRK3', 'Gene', (154, 159))	('Q827X', 'Mutation', 'p.Q827X', (130, 135))	('MLL2', 'Gene', (138, 142))	('Q61L', 'Mutation', 'rs121913233', (117, 121))	('HRAS', 'Gene', '3265', (111, 115))	('HRAS', 'Gene', (111, 115))	('Q3867fs', 'Mutation', 'p.Q3867fsX', (144, 151))	('PIK3CA', 'Gene', (173, 179))
158642	25502898	Compared to the overlying non-invasive tumor (BL196), the paired invasive carcinoma component (BL190) also demonstrated a confirmed mutation in CIC (F1493L).	('CIC', 'Gene', (144, 147))	('BL196', 'CellLine', 'CVCL:1509', (46, 51))	('BL190', 'CellLine', 'CVCL:0671', (95, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('invasive tumor', 'Disease', (30, 44))	('F1493L', 'Var', (149, 155))	('invasive carcinoma component', 'Disease', 'MESH:C562869', (65, 93))	('F1493L', 'Mutation', 'p.F1493L', (149, 155))	('invasive tumor', 'Disease', 'MESH:D009369', (30, 44))	('invasive carcinoma component', 'Disease', (65, 93))
158643	25502898	Three unique mutations were seen in the remaining bladder (BL195) and prostatic urethra (BL194) tumors--ACVR2A W64S in BL195, and DPYD R21X and ATR R989G in BL194:consistent with continued, but very limited, clonal evolution in potential cancer drivers after divergence from the founding clone.	('ACVR2A', 'Gene', (104, 110))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('R989G', 'Mutation', 'p.R989G', (148, 153))	('DPYD R21X', 'Var', (130, 139))	('BL194', 'CellLine', 'CVCL:H961', (157, 162))	('bladder', 'Disease', (50, 57))	('R21X', 'Mutation', 'p.R21X', (135, 139))	('BL194', 'Gene', (89, 94))	('tumors', 'Disease', (96, 102))	('BL194', 'CellLine', 'CVCL:H961', (89, 94))	('ACVR2A', 'Gene', '92', (104, 110))	('W64S', 'SUBSTITUTION', 'None', (111, 115))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('W64S', 'Var', (111, 115))
158647	25502898	Conversely, BL190 harbored a focal homozygous deletion of the CDKN2A locus which was not present in any of the non-invasive components (Fig 2B).	('BL190', 'CellLine', 'CVCL:0671', (12, 17))	('CDKN2A', 'Gene', (62, 68))	('deletion', 'Var', (46, 54))	('CDKN2A', 'Gene', '1029', (62, 68))
158649	25502898	We similarly assessed loss of heterozygosity (LOH) in the tumors, which can be due to copy number alteration or copy number neutral, by comparing variant allele frequencies for heterozygous SNPs between the normal tissue sample (BL193) and each tumor sample.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('variant', 'Var', (146, 153))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('BL193', 'CellLine', 'CVCL:S838', (229, 234))	('tumor', 'Disease', (245, 250))
158651	25502898	We identified 629 well-supported, heterozygous SNPs present in BL193 that were also called in at least one tumor sample.	('BL193', 'CellLine', 'CVCL:S838', (63, 68))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('SNPs', 'Var', (47, 51))	('BL193', 'Gene', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
158652	25502898	As shown in Figure 3A&B, we observed concordant changes in SNP variant allele frequencies across all tumors on chromosome 8, consistent with the broad copy number loss/gain described above.	('number', 'PosReg', (156, 162))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('SNP', 'Var', (59, 62))	('number', 'NegReg', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('chromosome', 'cellular_component', 'GO:0005694', ('111', '121'))	('concordant', 'Reg', (37, 47))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))
158653	25502898	We also identified concordant changes in variant allele frequencies for SNPs in IGF2R (chr 6q25) across all six tumors (Fig 3A&B), with focal low level IGF2R copy loss observed in all six tumors (Fig 3C).	('tumors', 'Disease', (188, 194))	('IGF2R', 'Gene', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('changes', 'Reg', (30, 37))	('IGF2R', 'Gene', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('IGF2R', 'Gene', '3482', (152, 157))	('IGF2R', 'Gene', '3482', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('SNPs', 'Var', (72, 76))	('tumors', 'Disease', (112, 118))
158654	25502898	Likewise, all five non-invasive tumors showed concordant SNP variant allele frequency changes in the area of copy number gain on chromosome 5p, which was not present in BL190 (Fig 3A&B).	('BL190', 'CellLine', 'CVCL:0671', (169, 174))	('invasive tumors', 'Disease', (23, 38))	('gain', 'PosReg', (121, 125))	('variant', 'Var', (61, 68))	('invasive tumors', 'Disease', 'MESH:D009369', (23, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('changes', 'Reg', (86, 93))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('SNP', 'Gene', (57, 60))	('chromosome', 'cellular_component', 'GO:0005694', ('129', '139'))
158656	25502898	We also observed focal concordant copy number neutral LOH in contiguous SNPs extending from HRAS to NUP98 on chromosome 11p15 (rs41258054, rs35404087, rs11029446) in all six tumors (Fig 3C).	('rs35404087', 'Var', (139, 149))	('rs41258054', 'Var', (127, 137))	('tumors', 'Disease', (174, 180))	('rs35404087', 'Mutation', 'rs35404087', (139, 149))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('rs41258054', 'Mutation', 'rs41258054', (127, 137))	('HRAS', 'Gene', '3265', (92, 96))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('NUP98', 'Gene', '4928', (100, 105))	('rs11029446', 'Var', (151, 161))	('rs11029446', 'Mutation', 'rs11029446', (151, 161))	('NUP98', 'Gene', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('HRAS', 'Gene', (92, 96))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
158657	25502898	In addition, we observed broad copy neutral LOH across chromosome 9 in BL190, which was not present in the overlying non-invasive component (BL196) or any of the other non-invasive UCs (Fig 3A-C).	('LOH', 'Var', (44, 47))	('BL196', 'CellLine', 'CVCL:1509', (141, 146))	('BL190', 'CellLine', 'CVCL:0671', (71, 76))	('BL190', 'Gene', (71, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))
158660	25502898	All equally-plausible models demonstrated that BL190 diverged from the clone that gave rise to all five non-invasive components, consistent with the CDKN2A homozygous deletion and chromosome 9 LOH present only in BL190, and the chromosome 5p and X CNAs found exclusively in the five non-invasive lesions (Fig 4D&E).	('CDKN2A', 'Gene', '1029', (149, 155))	('chromosome', 'cellular_component', 'GO:0005694', ('228', '238'))	('BL190', 'CellLine', 'CVCL:0671', (47, 52))	('BL190', 'CellLine', 'CVCL:0671', (213, 218))	('chromosome', 'cellular_component', 'GO:0005694', ('180', '190'))	('deletion', 'Var', (167, 175))	('CDKN2A', 'Gene', (149, 155))
158664	25502898	Hence, we performed careful macrodissection of two sections of histologically normal urothelium (Fig S1), one through the left ureteral orifice, and performed targeted NGS using a custom Ion Torrent Ampliseq panel that targets ~130 cancer related genes, including the observed HRAS and PIK3CA mutations.	('HRAS', 'Gene', (277, 281))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', (232, 238))	('mutations', 'Var', (293, 302))	('HRAS', 'Gene', '3265', (277, 281))	('PIK3CA', 'Gene', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('PIK3CA', 'Gene', '5290', (286, 292))
158665	25502898	At high coverage over the HRAS (375x in BL193A and 381x in BL193B) and PIK3CA mutation positions (381x in BL193A and 459x in BL193B) in these normal urothelial samples, we observed no evidence of the clonal mutations found in all tumor samples (0 mutant allele containing reads), as shown in Fig S1.	('tumor', 'Disease', (230, 235))	('BL193', 'CellLine', 'CVCL:S838', (106, 111))	('PIK3CA', 'Gene', '5290', (71, 77))	('HRAS', 'Gene', (26, 30))	('BL193B', 'CellLine', 'CVCL:S838', (59, 65))	('BL193', 'CellLine', 'CVCL:S838', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('381x', 'Var', (98, 102))	('BL193', 'CellLine', 'CVCL:S838', (125, 130))	('PIK3CA', 'Gene', (71, 77))	('HRAS', 'Gene', '3265', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('BL193B', 'CellLine', 'CVCL:S838', (125, 131))	('BL193', 'CellLine', 'CVCL:S838', (40, 45))	('375x', 'Var', (32, 36))
158668	25502898	Across the paired non-invasive tumor components in Cases 2, 3 and 4, we identified a total of 14, 38 and 13 high confidence, non-synonymous somatic mutations, representing 9, 20 and 8 unique genomic positions, respectively (Fig 5B and Table S2).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mutations', 'Var', (148, 157))	('invasive tumor', 'Disease', 'MESH:D009369', (22, 36))	('invasive tumor', 'Disease', (22, 36))
158669	25502898	In each case, known driving alterations were present in both non-invasive and invasive components, including ARID1A Q1212X, ERBB2 S310F and TP53 Q375X in Case 2, FGFR3 R248C, ARID1A R1463C/S2068L and MLH1 E613X in Case 3, and KMT2D 2451fs, RB1 567X and TP53 V272M in Case 4, consistent with clonality.	('KMT2D', 'Gene', '8085', (226, 231))	('RB1', 'Gene', '5925', (240, 243))	('V272M', 'Mutation', 'rs121912657', (258, 263))	('ARID1A', 'Gene', (175, 181))	('TP53', 'Gene', (140, 144))	('R1463C', 'SUBSTITUTION', 'None', (182, 188))	('E613X', 'Mutation', 'p.E613X', (205, 210))	('TP53', 'Gene', '7157', (253, 257))	('FGFR3', 'Gene', (162, 167))	('R248C', 'Var', (168, 173))	('MLH1', 'Gene', '4292', (200, 204))	('ARID1A', 'Gene', '8289', (175, 181))	('Q1212X', 'Mutation', 'p.Q1212X', (116, 122))	('R248C', 'Mutation', 'rs121913482', (168, 173))	('FGFR3', 'Gene', '2261', (162, 167))	('Q1212X', 'Var', (116, 122))	('KMT2D', 'Gene', (226, 231))	('FGFR', 'molecular_function', 'GO:0005007', ('162', '166'))	('MLH1', 'Gene', (200, 204))	('ERBB2', 'Gene', (124, 129))	('TP53', 'Gene', '7157', (140, 144))	('ARID1A', 'Gene', (109, 115))	('RB1', 'Gene', (240, 243))	('Q375X', 'Var', (145, 150))	('R1463C', 'Var', (182, 188))	('S2068L', 'SUBSTITUTION', 'None', (189, 195))	('Q375X', 'Mutation', 'p.Q375X', (145, 150))	('S310F', 'Mutation', 'rs1057519816', (130, 135))	('ERBB2', 'Gene', '2064', (124, 129))	('S2068L', 'Var', (189, 195))	('ARID1A', 'Gene', '8289', (109, 115))	('TP53', 'Gene', (253, 257))	('E613X', 'Var', (205, 210))
158670	25502898	Case 2 harbored a low variant frequency SYNE1 L4867F mutation exclusively in the invasive component (BL301), but three mutations exclusively in the non-invasive component (BL300, including ARID1A Q581X).	('L4867F', 'Var', (46, 52))	('Q581X', 'Mutation', 'p.Q581X', (196, 201))	('BL301', 'CellLine', 'CVCL:M579', (101, 106))	('Q581X', 'Var', (196, 201))	('ARID1A', 'Gene', '8289', (189, 195))	('ARID1A', 'Gene', (189, 195))	('SYNE1', 'Gene', '23345', (40, 45))	('L4867F', 'Mutation', 'rs1395336092', (46, 52))	('SYNE1', 'Gene', (40, 45))
158671	25502898	Lastly, Case 4 harbored two somatic mutations in the invasive component (BL306, including ARID2 Q1165X) and one low frequency mutation exclusively in the non-invasive component (BL305).	('BL306', 'Gene', (73, 78))	('BL306', 'CellLine', 'CVCL:T042', (73, 78))	('ARID2', 'Gene', (90, 95))	('Q1165X', 'Mutation', 'p.Q1165X', (96, 102))	('Q1165X', 'Var', (96, 102))	('ARID2', 'Gene', '196528', (90, 95))
158672	25502898	Focal, high level CNAs were identified in both components of Cases 2 (DEK amplification) and 4 (TRIM33 amplification and CDH2 deletion).	('CDH2', 'Gene', '1000', (121, 125))	('TRIM33', 'Gene', '51592', (96, 102))	('TRIM33', 'Gene', (96, 102))	('deletion', 'Var', (126, 134))	('CDH2', 'Gene', (121, 125))
158677	25502898	In total, we sequenced three benign macrodissected urothelium samples (BL193A, BL193B and BL303mn), 12 UC samples from Cases 1-4, and two technical replicates with additional amplification cycles during library preparation (BL302b and BL205b).	('BL193A', 'Var', (71, 77))	('BL193B and BL303mn', 'Var', (79, 97))	('BL303mn', 'Var', (90, 97))	('BL302b', 'Var', (224, 230))	('BL193', 'CellLine', 'CVCL:S838', (79, 84))	('BL193B', 'CellLine', 'CVCL:S838', (79, 85))	('BL205b', 'Var', (235, 241))	('BL193', 'CellLine', 'CVCL:S838', (71, 76))
158678	25502898	Normalized target gene expression was highly concordant for biological (BL193A/B) and technical (BL302/b, BL305/b) replicates ( Pearson's r2 = 0.90, 0.97 and 0.89, respectively).	('BL302/b', 'Var', (97, 104))	('BL305/b', 'Var', (106, 113))	('BL193A/B', 'Var', (72, 80))	('BL193', 'CellLine', 'CVCL:S838', (72, 77))	('gene expression', 'biological_process', 'GO:0010467', ('18', '33'))
158680	25502898	Here we used targeted, multiplexed PCR based NGS from routine FFPE tissue to assess clonality, DNA/RNA based alterations in multifocal and paired non-invasive/invasive tumor components in an extreme case of multifocal urothelial cancer (Case 1) and three additional cases of upper tract UC with distinct non-invasive/invasive components (Cases 2-4).	('multifocal urothelial cancer', 'Disease', 'None', (207, 235))	('RNA', 'cellular_component', 'GO:0005562', ('99', '102'))	('invasive tumor', 'Disease', (159, 173))	('multifocal urothelial cancer', 'Disease', (207, 235))	('invasive tumor', 'Disease', 'MESH:D009369', (159, 173))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('alterations', 'Var', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
158682	25502898	The shared HRAS Q61L and PIK3CA H1047L mutations are well described recurrent hotspot mutations in UC, and MLL2 was recently identified as one of the most significantly mutated genes (predominantly inactivating frameshift mutations) in UC by The Cancer Genome Atlas (TCGA) effort.	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (246, 265))	('HRAS', 'Gene', '3265', (11, 15))	('MLL2', 'Gene', (107, 111))	('inactivating', 'NegReg', (198, 210))	('H1047L mutations', 'Var', (32, 48))	('mutations', 'Var', (39, 48))	('HRAS', 'Gene', (11, 15))	('PIK3CA', 'Gene', (25, 31))	('MLL2', 'Gene', '8085', (107, 111))	('PIK3CA', 'Gene', '5290', (25, 31))	('Q61L', 'Mutation', 'rs121913233', (16, 20))	('H1047L', 'Mutation', 'rs121913279', (32, 38))	('Cancer Genome Atlas', 'Disease', (246, 265))	('Cancer', 'Phenotype', 'HP:0002664', (246, 252))
158687	25502898	However, we identified only three private somatic non-synonymous mutations and no private high level CNAs amongst the five tumors, supporting very limited inter-tumoral heterogeneity amongst likely cancer driver genes.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumor', 'Disease', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('non-synonymous mutations', 'Var', (50, 74))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
158689	25502898	BL190 and all non-invasive components shared the same five somatic mutations, chromosome 8 and IGF2R CNAs (supported by LOH analysis), and copy number neutral LOH in HRAS-NUP98.	('IGF2R', 'Gene', '3482', (95, 100))	('NUP98', 'Gene', (171, 176))	('NUP98', 'Gene', '4928', (171, 176))	('chromosome', 'cellular_component', 'GO:0005694', ('78', '88'))	('BL190', 'CellLine', 'CVCL:0671', (0, 5))	('HRAS', 'Gene', '3265', (166, 170))	('HRAS', 'Gene', (166, 170))	('IGF2R', 'Gene', (95, 100))	('copy number neutral LOH', 'Var', (139, 162))
158690	25502898	A validated CIC F1493L somatic mutation, focal homozygous loss of CDKN2A, and chromosome 9 LOH were present exclusively in BL190, while BL190 lacked the chromosome 5p and X chromosome CNAs that were present in all five non-invasive tumors.	('F1493L', 'Mutation', 'p.F1493L', (16, 22))	('loss', 'NegReg', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('chromosome', 'cellular_component', 'GO:0005694', ('78', '88'))	('BL190', 'CellLine', 'CVCL:0671', (136, 141))	('chromosome', 'cellular_component', 'GO:0005694', ('153', '163'))	('CDKN2A', 'Gene', '1029', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('CIC F1493L', 'Var', (12, 22))	('BL190', 'CellLine', 'CVCL:0671', (123, 128))	('X chromosome', 'cellular_component', 'GO:0000805', ('171', '183'))	('invasive tumors', 'Disease', (223, 238))	('CDKN2A', 'Gene', (66, 72))	('invasive tumors', 'Disease', 'MESH:D009369', (223, 238))
158691	25502898	Although loss of CDKN2A is the most common focal somatic event in urothelial cancer and has been shown to be more common in muscularis propria invasive (pT2) vs non-invasive UC (pTa), to our knowledge it has not previously been described as a driver of the invasive phenotype from non-invasive carcinoma.	('common', 'Reg', (114, 120))	('pTa', 'molecular_function', 'GO:0008959', ('178', '181'))	('invasive carcinoma', 'Disease', (285, 303))	('muscularis propria', 'Phenotype', 'HP:0030936', (124, 142))	('loss', 'Var', (9, 13))	('urothelial cancer', 'Disease', (66, 83))	('CDKN2A', 'Gene', (17, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('CDKN2A', 'Gene', '1029', (17, 23))	('urothelial cancer', 'Disease', 'MESH:D014523', (66, 83))	('invasive carcinoma', 'Disease', 'MESH:D009361', (285, 303))	('muscularis propria invasive', 'Disease', (124, 151))
158692	25502898	Likewise, results from sequencing three additional cases with paired non-invasive/invasive components identified an ARID2 Q1165X mutation exclusively in the invasive component of Case 4, nominating another potential mediator of invasion in UC.	('ARID2', 'Gene', (116, 121))	('ARID2', 'Gene', '196528', (116, 121))	('Q1165X', 'Var', (122, 128))	('Q1165X', 'Mutation', 'p.Q1165X', (122, 128))
158695	25502898	similarly showed that while both non-invasive and invasive cancers showed multiple identical mutations, indicating clonal origin, mutational events unique to both non-invasive and invasive tumors were present.	('invasive cancers', 'Disease', (50, 66))	('mutations', 'Var', (93, 102))	('invasive tumors', 'Disease', (180, 195))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('invasive tumors', 'Disease', 'MESH:D009369', (180, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('invasive cancers', 'Disease', 'MESH:D009362', (50, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
158703	25502898	Likewise, known driving alterations, such as DEK amplification and TP53 mutations were identified in each case.	('mutations', 'Var', (72, 81))	('DEK', 'MPA', (45, 48))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))
158704	25502898	Intriguingly, in Cases 2, we identified focal amplification of ERBB2 and a deleterious ARID1A mutation (Q1212X) exclusively in the non-invasive component.	('Q1212X', 'Var', (104, 110))	('ERBB2', 'Gene', '2064', (63, 68))	('ERBB2', 'Gene', (63, 68))	('ARID1A', 'Gene', '8289', (87, 93))	('Q1212X', 'Mutation', 'p.Q1212X', (104, 110))	('ARID1A', 'Gene', (87, 93))
158705	25502898	Of note, a known somatic driving mutation in ERBB2 (S310F) and a second deleterious mutation in ARID1A (Q1212X) were present in both the non-invasive and invasive components from this case.	('Q1212X', 'Var', (104, 110))	('ARID1A', 'Gene', '8289', (96, 102))	('ARID1A', 'Gene', (96, 102))	('S310F', 'Var', (52, 57))	('ERBB2', 'Gene', '2064', (45, 50))	('Q1212X', 'Mutation', 'p.Q1212X', (104, 110))	('ERBB2', 'Gene', (45, 50))	('S310F', 'Mutation', 'rs1057519816', (52, 57))
158706	25502898	Variant frequencies of other somatic alterations in both components of this case (including a homozygous TP53 Q375X mutation) support similar tumor content, yet the ERBB2 S310F variant was present at much lower frequency in the non-invasive vs. invasive component (0.13 vs. 0.37), consistent with amplification of non-mutant ERBB2 allele in the non-invasive component.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('S310F', 'Var', (171, 176))	('ERBB2', 'Gene', '2064', (165, 170))	('tumor', 'Disease', (142, 147))	('ERBB2', 'Gene', (325, 330))	('ERBB2', 'Gene', '2064', (325, 330))	('Q375X', 'Mutation', 'p.Q375X', (110, 115))	('ERBB2', 'Gene', (165, 170))	('S310F', 'Mutation', 'rs1057519816', (171, 176))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
158707	25502898	Together, these results demonstrate heterogeneity in known driving alterations between paired non-invasive/invasive components and support continued selection for somatic alteration of these genes in the non-invasive tumor component after divergence of the invasive clone.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('alteration', 'Var', (171, 181))	('invasive tumor', 'Disease', 'MESH:D009369', (208, 222))	('invasive tumor', 'Disease', (208, 222))
158709	25502898	For example, Case 3 (BL302/303), which showed highly similar mutational and CNA profiles (including FGFR3 R248C mutation), showed highly correlated transcriptional profiles in both components (basalhi/luminallow/p63low/CK20hi/proliferationhi/EMTlow/FGFR3hi).	('FGFR3', 'Gene', (249, 254))	('CK20', 'Gene', (219, 223))	('R248C', 'Mutation', 'rs121913482', (106, 111))	('CK20', 'Gene', '54474', (219, 223))	('R248C mutation', 'Var', (106, 120))	('FGFR3', 'Gene', '2261', (100, 105))	('FGFR3', 'Gene', '2261', (249, 254))	('FGFR3', 'Gene', (100, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('100', '104'))	('transcriptional profiles', 'MPA', (148, 172))	('FGFR', 'molecular_function', 'GO:0005007', ('249', '253'))
158710	25502898	Likewise, Case 4 (BL305/306) showed highly correlated basallow/ luminallow/ p63hi/ CK20low/ proliferationhi/ EMTlow/ FGFR3low transcriptional programs in both components.	('CK20', 'Gene', (83, 87))	('FGFR3', 'Gene', '2261', (117, 122))	('CK20', 'Gene', '54474', (83, 87))	('FGFR3', 'Gene', (117, 122))	('FGFR', 'molecular_function', 'GO:0005007', ('117', '121'))	('basallow/', 'Var', (54, 63))
158715	27308321	We recently reported a high incidence of APOBEC-mediated driver mutations in human papillomavirus-associated cancer, suggesting a key role for these enzymes in the development of such tumors.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('human papillomavirus', 'Species', '10566', (77, 97))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cancer', 'Disease', (109, 115))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('papilloma', 'Phenotype', 'HP:0012740', (83, 92))	('mutations', 'Var', (64, 73))	('APOBEC-mediated', 'Gene', (41, 56))	('APOBEC', 'cellular_component', 'GO:0030895', ('41', '47'))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
158720	27308321	Work by Stratton and colleagues analyzing the nature and sequence context of mutations to identify the mutational processes operating in different cancers uncovered a particular signature of long clusters of the point mutations TC > TT or TC > TG on the same strand, which they called "kataegis," the Greek for thunderstorm.	('TG', 'Chemical', '-', (244, 246))	('TC', 'Chemical', 'MESH:D013667', (239, 241))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('TC > TT', 'Var', (228, 235))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('TC > TG', 'Var', (239, 246))	('TC', 'Chemical', 'MESH:D013667', (228, 230))
158721	27308321	These mutation showers are likely caused by activity of a subset of the A3 enzymes that preferentially target cytosines following a thymine, with the resulting uracil then undergoing transversion to guanine or transition to thymine.	('guanine', 'Chemical', 'MESH:D006147', (199, 206))	('uracil', 'MPA', (160, 166))	('undergoing', 'Reg', (172, 182))	('mutation', 'Var', (6, 14))	('A3', 'Gene', '10312', (72, 74))	('thymine', 'Chemical', 'MESH:D013941', (224, 231))	('transversion', 'MPA', (183, 195))	('uracil', 'Chemical', 'MESH:D014498', (160, 166))	('thymine', 'Chemical', 'MESH:D013941', (132, 139))	('cytosine', 'Chemical', 'MESH:D003596', (110, 118))
158724	27308321	Several cancer types, notably cervical squamous cell carcinoma (CESC), bladder urothelial carcinoma (BLCA), and head and neck squamous cell carcinoma (HNSC), show a particularly strong enrichment for these signature mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('bladder urothelial carcinoma', 'Disease', (71, 99))	('neck squamous cell carcinoma', 'Disease', (121, 149))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (121, 149))	('cancer', 'Disease', (8, 14))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (71, 99))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (39, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('BLCA', 'Chemical', '-', (101, 105))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (112, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('squamous cell carcinoma', 'Disease', (39, 62))	('HNSC', 'Phenotype', 'HP:0012288', (151, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (126, 149))	('neck', 'cellular_component', 'GO:0044326', ('121', '125'))	('mutations', 'Var', (216, 225))
158727	27308321	We used a variety of metrics to compare the extent of A3-mediated mutagenesis in the HPV+ and HPV- HNSC samples, including extraction of mutational signatures and calculating the prevalence of TCW (TpCpA/T) > TTW and TCW > TGW mutations in each sample.	('TC', 'Chemical', 'MESH:D013667', (193, 195))	('TCW', 'Var', (193, 196))	('TCW > TGW', 'Mutation', 'TCW > TGW', (217, 226))	('HPV', 'Species', '10566', (94, 97))	('mutagenesis', 'biological_process', 'GO:0006280', ('66', '77'))	('TC', 'Chemical', 'MESH:D013667', (217, 219))	('HNSC', 'Phenotype', 'HP:0012288', (99, 103))	('HPV', 'Species', '10566', (85, 88))	('TCW', 'Gene', (217, 220))	('A3', 'Gene', '10312', (54, 56))
158728	27308321	Each metric by which we could assess A3-mediated mutation showed enrichment with HPV positivity.	('HPV', 'Disease', (81, 84))	('HPV', 'Species', '10566', (81, 84))	('A3', 'Gene', '10312', (37, 39))	('mutation', 'Var', (49, 57))
158730	27308321	We found that specific hotspot mutations in the PIK3CA proto-oncogene are of the TCW type and that PIK3CA is exclusively mutated at these sites in tumors displaying strong exome-wide enrichment for TCW mutations (HPV+ HNSC, CESC, and BLCA).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('mutations', 'Var', (31, 40))	('BLCA', 'Chemical', '-', (234, 238))	('tumors', 'Disease', (147, 153))	('TC', 'Chemical', 'MESH:D013667', (198, 200))	('TCW', 'Gene', (198, 201))	('PIK3CA', 'Gene', (48, 54))	('mutations', 'Var', (202, 211))	('TC', 'Chemical', 'MESH:D013667', (81, 83))	('mutated', 'Var', (121, 128))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('BLCA', 'Disease', (234, 238))	('HNSC', 'Phenotype', 'HP:0012288', (218, 222))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('CESC', 'Disease', (224, 228))	('HPV', 'Species', '10566', (213, 216))	('PIK3CA', 'Gene', (99, 105))
158735	27308321	One striking feature of TCW mutations that we observed is their close relationship with the number of non-TCW point mutations.	('TCW', 'Gene', (24, 27))	('mutations', 'Var', (28, 37))	('TC', 'Chemical', 'MESH:D013667', (106, 108))	('TC', 'Chemical', 'MESH:D013667', (24, 26))
158736	27308321	Furano and colleagues recently demonstrated that ssDNA that is exposed during repair of mismatches can be mutated by TC-specific A3 enzymes.	('mismatches', 'Var', (88, 98))	('ssDNA', 'Disease', (49, 54))	('TC', 'Chemical', 'MESH:D013667', (117, 119))	('A3', 'Gene', '10312', (129, 131))
158738	27308321	In such cases, repair of mismatches may expose extended stretches of ssDNA to A3 activity, offering a possible explanation for the strong correlation between TCW and other mutations.	('A3', 'Gene', '10312', (78, 80))	('TC', 'Chemical', 'MESH:D013667', (158, 160))	('repair', 'Var', (15, 21))	('mismatches', 'Var', (25, 35))
158740	27308321	Evidence from DNA repair models in yeast suggest that C > G transversions result largely from BER whereas C > T transitions may result from error prone DNA translesion synthesis during replication.	('result', 'Reg', (74, 80))	('DNA repair', 'biological_process', 'GO:0006281', ('14', '24'))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('BER', 'Disease', (94, 97))	('translesion synthesis', 'biological_process', 'GO:0019985', ('156', '177'))	('C > T', 'Var', (106, 111))	('DNA translesion synthesis', 'MPA', (152, 177))	('yeast', 'Species', '4932', (35, 40))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))	('result from', 'Reg', (128, 139))	('C > G transversions', 'Var', (54, 73))	('BER', 'biological_process', 'GO:0006284', ('94', '97'))
158742	27308321	1) the increased fraction of C > T and C > G mutations at vulnerable sites in the HPV+ tumors is clear.	('HPV+ tumors', 'Disease', 'MESH:D030361', (82, 93))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('HPV+ tumors', 'Disease', (82, 93))	('C > T', 'Var', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('C > G mutations', 'Var', (39, 54))
158743	27308321	Furthermore, in the HPV- tumors, TCW mutations are more often of the C > G type, suggesting that BER may be more active in these cells, whereas both HPV+ HNSC and CESC are particularly enriched for transitions, potentially indicating replication across uracil without repair in HPV+ tumors (Fig.	('C >', 'Disease', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('HPV- tumors', 'Disease', (20, 31))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('HPV', 'Species', '10566', (20, 23))	('TCW', 'Gene', (33, 36))	('HPV+ tumors', 'Disease', (278, 289))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('HNSC', 'Phenotype', 'HP:0012288', (154, 158))	('BER', 'biological_process', 'GO:0006284', ('97', '100'))	('mutations', 'Var', (37, 46))	('HPV- tumors', 'Disease', 'MESH:D030361', (20, 31))	('TC', 'Chemical', 'MESH:D013667', (33, 35))	('uracil', 'Chemical', 'MESH:D014498', (253, 259))	('indicating', 'Reg', (223, 233))	('HPV', 'Species', '10566', (149, 152))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('HPV', 'Species', '10566', (278, 281))	('HPV+ tumors', 'Disease', 'MESH:D030361', (278, 289))
158750	26320192	Subsequent assays including treatment with epigenetic depressive agents and in vitro methylation showed ZNF671 methylation to result in its transcriptional repression.	('ZNF671', 'Gene', '79891', (104, 110))	('depressive', 'Disease', 'MESH:D000275', (54, 64))	('methylation', 'biological_process', 'GO:0032259', ('85', '96'))	('transcriptional repression', 'MPA', (140, 166))	('ZNF671', 'Gene', (104, 110))	('depressive', 'Disease', (54, 64))	('methylation', 'biological_process', 'GO:0032259', ('111', '122'))	('result in', 'Reg', (126, 135))	('methylation', 'Var', (111, 122))
158751	26320192	ZNF671 re-expression in UC cell lines, via ectopic expression, inhibited tumor growth and invasion, in possible conjunction with downregulation of cancer stem cell markers (c-KIT, NANOG, OCT4).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('OCT4', 'Gene', '5460', (187, 191))	('ectopic expression', 'Var', (43, 61))	('OCT4', 'Gene', (187, 191))	('ZNF671', 'Gene', (0, 6))	('ZNF671', 'Gene', '79891', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('c-KIT', 'Gene', (173, 178))	('NANOG', 'Gene', '79923', (180, 185))	('inhibited', 'NegReg', (63, 72))	('NANOG', 'Gene', (180, 185))	('cancer', 'Disease', (147, 153))	('c-KIT', 'Gene', '3815', (173, 178))	('re-expression', 'PosReg', (7, 20))	('KIT', 'molecular_function', 'GO:0005020', ('175', '178'))
158752	26320192	Clinically, high ZNF671 methylation in UC tumor tissues (n=96; 63 bladder, 33 upper urinary tract) associated with tumor grade and poor locoregional disease-free survival.	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('high', 'Var', (12, 16))	('poor', 'NegReg', (131, 135))	('ZNF671', 'Gene', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('UC tumor', 'Disease', (39, 47))	('tumor', 'Disease', (115, 120))	('methylation', 'Var', (24, 35))	('ZNF671', 'Gene', '79891', (17, 23))	('UC tumor', 'Disease', 'MESH:D009369', (39, 47))	('locoregional disease-free survival', 'CPA', (136, 170))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('associated', 'Reg', (99, 109))
158755	26320192	In summary, ZNF671, an epigenetically silenced novel tumor suppressor, represents a potential predictor for UC relapse and non-invasive biomarker that could assist in UC clinical decision-making.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('ZNF671', 'Gene', '79891', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('UC relapse', 'Disease', (108, 118))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('ZNF671', 'Gene', (12, 18))	('epigenetically', 'Var', (23, 37))	('assist', 'Reg', (157, 163))	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))
158761	26320192	Accumulation of multiple genetic and epigenetic alternations that lead to the activation of proto-oncogenes and/or inactivation of tumor-suppressor genes (TSGs) is a ubiquitous event in human carcinogensis.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('proto-oncogenes', 'Gene', (92, 107))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('131', '147'))	('tumor', 'Disease', (131, 136))	('inactivation', 'NegReg', (115, 127))	('human', 'Species', '9606', (186, 191))	('activation', 'PosReg', (78, 88))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('131', '147'))	('alternations', 'Var', (48, 60))
158762	26320192	The intimate association of cancer and epigenetic aberrations, such as deviant DNA methylation and histone modifications, is reflective of the indispensability of epigenetics as a gene regulatory mechanism governing multi-/pluripotent cell fate commitment.	('deviant', 'Var', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('DNA', 'Gene', (79, 82))	('cell fate commitment', 'biological_process', 'GO:0045165', ('235', '255'))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('DNA methylation', 'biological_process', 'GO:0006306', ('79', '94'))
158763	26320192	As loss of differentiation is an essential and omnipresent event in carcinogenesis, reversal of dedifferentiating epigenetic aberrations could be highly effective for the therapy of several tumor types.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('carcinogenesis', 'Disease', 'MESH:D063646', (68, 82))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('carcinogenesis', 'Disease', (68, 82))	('tumor', 'Disease', (190, 195))	('epigenetic aberrations', 'Var', (114, 136))
158766	26320192	However, the role of epigenetic alterations in the tumor progression and recurrence of urothelial carcinoma remains little explored.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('tumor', 'Disease', (51, 56))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (87, 107))	('epigenetic alterations', 'Var', (21, 43))	('urothelial carcinoma', 'Disease', (87, 107))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
158767	26320192	Consequently, we herein set forth to identify epigenetically silenced genes involved in UC tumor progression and recurrence, using methylomic screening of primary normal human urothelial cells (HUCs) and bladder UC tissue samples.	('UC tumor', 'Disease', (88, 96))	('UC tumor', 'Disease', 'MESH:D009369', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('epigenetically silenced genes', 'Var', (46, 75))	('human', 'Species', '9606', (170, 175))
158768	26320192	That screening, and other assays, revealed one DNA methylation target, ZNF671, to be epigenetically silenced by promoter methylation in bladder UC.	('methylation', 'biological_process', 'GO:0032259', ('121', '132'))	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('bladder UC', 'Disease', (136, 146))	('DNA methylation', 'biological_process', 'GO:0006306', ('47', '62'))	('ZNF671', 'Gene', '79891', (71, 77))	('ZNF671', 'Gene', (71, 77))	('promoter methylation', 'Var', (112, 132))	('silenced', 'NegReg', (100, 108))
158769	26320192	Our results demonstrate that ZNF671 promoter methylation is frequently found in urothelial carcinoma and thus, represents a promising, non-invasive biomarker for the detection and guided therapy of urothelial carcinoma.	('ZNF671', 'Gene', '79891', (29, 35))	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('urothelial carcinoma', 'Disease', (80, 100))	('urothelial carcinoma', 'Disease', (198, 218))	('found', 'Reg', (71, 76))	('methylation', 'Var', (45, 56))	('ZNF671', 'Gene', (29, 35))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (80, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (198, 218))
158770	26320192	We previously identified several tumor suppressors that are epigenetically silenced by promoter methylation in bladder UC.	('promoter methylation', 'Var', (87, 107))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('methylation', 'biological_process', 'GO:0032259', ('96', '107'))	('bladder UC', 'Disease', (111, 121))
158773	26320192	One identified target, the ZNF671 transcriptional repressor (Figure 1A, arrow head), caught our attention, as ZNF671 was recently found epigenetically silenced by promoter DNA methylation in renal cell and cervical cancers.	('renal cell', 'Disease', (191, 201))	('ZNF671', 'Gene', '79891', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('ZNF671', 'Gene', (27, 33))	('cervical cancers', 'Disease', (206, 222))	('DNA methylation', 'biological_process', 'GO:0006306', ('172', '187'))	('promoter DNA methylation', 'Var', (163, 187))	('ZNF671', 'Gene', (110, 116))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('cervical cancers', 'Disease', 'MESH:D002583', (206, 222))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ZNF671', 'Gene', '79891', (27, 33))
158779	26320192	Those assays showed that ZNF671 promoter methylation was obvious in all bladder UC cell lines but not in normal bladder HUC cells (Supplementary Figure 1A).	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('ZNF671', 'Gene', (25, 31))	('methylation', 'Var', (41, 52))	('bladder UC', 'Disease', (72, 82))	('ZNF671', 'Gene', '79891', (25, 31))
158786	26320192	A 960-bp region (-329/631) containing the ZNF671 promoter was cloned into a pGL3 luciferase reporter plasmid (Figure 2C), showing that in vitro methylation of the ZNF671 promoter significantly (P < 0.05) decreased luciferase activity, as compared to the unmethylated control (Figure 2D).	('ZNF671', 'Gene', '79891', (163, 169))	('luciferase activity', 'molecular_function', 'GO:0047712', ('214', '233'))	('luciferase', 'Enzyme', (214, 224))	('ZNF671', 'Gene', (42, 48))	('pGL', 'molecular_function', 'GO:0004598', ('76', '79'))	('pGL3', 'Gene', (76, 80))	('luciferase activity', 'molecular_function', 'GO:0050397', ('214', '233'))	('methylation', 'Var', (144, 155))	('luciferase activity', 'molecular_function', 'GO:0050248', ('214', '233'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('214', '233'))	('ZNF671', 'Gene', (163, 169))	('activity', 'MPA', (225, 233))	('methylation', 'biological_process', 'GO:0032259', ('144', '155'))	('decreased', 'NegReg', (204, 213))	('pGL3', 'Gene', '6391', (76, 80))	('ZNF671', 'Gene', '79891', (42, 48))	('luciferase activity', 'molecular_function', 'GO:0047077', ('214', '233'))
158789	26320192	COBRA also confirmed that ZNF671 promoter methylation correlated with gene down-regulation in these non-UC cells (Supplementary Figure 1B).	('regulation', 'biological_process', 'GO:0065007', ('80', '90'))	('gene', 'MPA', (70, 74))	('down-regulation', 'NegReg', (75, 90))	('ZNF671', 'Gene', '79891', (26, 32))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('methylation', 'Var', (42, 53))	('ZNF671', 'Gene', (26, 32))
158799	26320192	Interestingly, ZNF671 overexpression significantly decreased the expression of three stem cell markers, c-KIT, NANOG, and OCT4 in UMUC3 (Figure 4A) but only one such marker (c-KIT) in TSGH8301 bladder UC cells (Figure 4B).	('KIT', 'molecular_function', 'GO:0005020', ('176', '179'))	('c-KIT', 'Gene', (174, 179))	('c-KIT', 'Gene', '3815', (174, 179))	('KIT', 'molecular_function', 'GO:0005020', ('106', '109'))	('ZNF671', 'Gene', '79891', (15, 21))	('decreased', 'NegReg', (51, 60))	('c-KIT', 'Gene', (104, 109))	('NANOG', 'Gene', '79923', (111, 116))	('OCT4', 'Gene', '5460', (122, 126))	('expression', 'MPA', (65, 75))	('overexpression', 'Var', (22, 36))	('c-KIT', 'Gene', '3815', (104, 109))	('NANOG', 'Gene', (111, 116))	('ZNF671', 'Gene', (15, 21))	('OCT4', 'Gene', (122, 126))
158802	26320192	The above experiments demonstrate that ZNF671 is likely a tumor suppressor that is transcriptionally suppressed by promoter DNA methylation in bladder UC cell lines.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('ZNF671', 'Gene', '79891', (39, 45))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('DNA methylation', 'biological_process', 'GO:0006306', ('124', '139'))	('promoter DNA methylation', 'Var', (115, 139))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('ZNF671', 'Gene', (39, 45))	('suppressed', 'NegReg', (101, 111))
158807	26320192	To assess possible detection of ZNF671 methylation in various UC subsites, 33 upper urinary tract UC tissue samples originating from the ureter or renal pelvis, were also procured for analysis (Table 1).	('renal pelvis', 'Phenotype', 'HP:0000125', (147, 159))	('methylation', 'Var', (39, 50))	('ureter or renal pelvis', 'Disease', (137, 159))	('ZNF671', 'Gene', '79891', (32, 38))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('ureter or renal pelvis', 'Disease', 'MESH:D014516', (137, 159))	('ZNF671', 'Gene', (32, 38))
158809	26320192	Importantly, there was no significant difference between ZNF671 methylation in UC tissue samples from the bladder vs. upper urinary tract (Figure 5B).	('ZNF671', 'Gene', '79891', (57, 63))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))	('methylation', 'Var', (64, 75))	('ZNF671', 'Gene', (57, 63))
158819	26320192	The correlation between UC tumor tissue ZNF671 hypermethylation and locoregional disease-free survival was also analyzed.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('UC tumor', 'Disease', 'MESH:D009369', (24, 32))	('ZNF671', 'Gene', '79891', (40, 46))	('UC tumor', 'Disease', (24, 32))	('ZNF671', 'Gene', (40, 46))	('hypermethylation', 'Var', (47, 63))
158821	26320192	Multivariate analysis also confirmed that ZNF671 methylation was an independent risk factor for predicting recurrence (HR, 3.742; 95% CI, 1.464 - 9.562; P < 0.01; Table 3).	('ZNF671', 'Gene', (42, 48))	('recurrence', 'Disease', (107, 117))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('methylation', 'Var', (49, 60))	('ZNF671', 'Gene', '79891', (42, 48))
158822	26320192	Having demonstrated that the potential tumor suppressor ZNF671 is epigenetically silenced in UC, and in consideration of other cancer biomarkers found in human urine, we assessed the feasibility of using ZNF671 methylation as a biomarker for non-invasive cancer detection in urine.	('human', 'Species', '9606', (154, 159))	('ZNF671', 'Gene', '79891', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancer', 'Disease', (255, 261))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('39', '55'))	('methylation', 'biological_process', 'GO:0032259', ('211', '222'))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('tumor suppressor', 'biological_process', 'GO:0051726', ('39', '55'))	('cancer', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ZNF671', 'Gene', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('tumor', 'Disease', (39, 44))	('ZNF671', 'Gene', '79891', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('epigenetically', 'Var', (66, 80))	('ZNF671', 'Gene', (204, 210))	('silenced', 'NegReg', (81, 89))
158825	26320192	Based on the cutoff value generated by the area under the receiver operating characteristic curve (ROC, AUC = 0.783, a cutoff value of 5.37%, Figure 6B), we observed methylated ZNF671 to exhibit a sensitivity of 42% and a specificity of 92.8% for UC detection in urine (Table 4).	('methylated', 'Var', (166, 176))	('ZNF671', 'Gene', (177, 183))	('ZNF671', 'Gene', '79891', (177, 183))
158829	26320192	These results suggest that ZNF671 methylation may serve as a non-invasive biomarker for bladder UC detection using urine.	('methylation', 'Var', (34, 45))	('ZNF671', 'Gene', (27, 33))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('bladder UC', 'Disease', (88, 98))	('ZNF671', 'Gene', '79891', (27, 33))
158830	26320192	We therefore examined the sensitivity and specificity of cancer detection in urine by combining methylated ZNF671 with methylation of two other TSGs (IRF8 and sFRP1) using a previously published urine sample cohort (26 UCs and 19 non-cancerous controls).	('combining', 'Reg', (86, 95))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('ZNF671', 'Gene', (107, 113))	('cancer', 'Disease', (57, 63))	('ZNF671', 'Gene', '79891', (107, 113))	('methylated', 'Var', (96, 106))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('IRF8', 'Gene', (150, 154))	('sFRP1', 'Gene', (159, 164))	('sFRP1', 'Gene', '6422', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', (234, 240))	('non-cancer', 'Disease', (230, 240))	('non-cancer', 'Disease', 'MESH:D009369', (230, 240))	('IRF8', 'Gene', '3394', (150, 154))
158831	26320192	While the sensitivity and specificity of cancer detection using ZNF671 methylation alone was 57.7% and 89.5% (Table 5), combining hypermethylation of ZNF671 with that of IRF8 and SFRP1 increased the sensitivity to 96.2% (Table 5).	('IRF8', 'Gene', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('SFRP1', 'Gene', (179, 184))	('SFRP1', 'Gene', '6422', (179, 184))	('IRF8', 'Gene', '3394', (170, 174))	('ZNF671', 'Gene', '79891', (150, 156))	('ZNF671', 'Gene', '79891', (64, 70))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('hypermethylation', 'Var', (130, 146))	('increased', 'PosReg', (185, 194))	('ZNF671', 'Gene', (150, 156))	('ZNF671', 'Gene', (64, 70))
158832	26320192	Taken together, these results imply that combining ZNF671 DNA methylation with other methylated genes could represent a sensitive biomarker panel for non-invasive bladder UC detection using urine.	('ZNF671', 'Gene', '79891', (51, 57))	('invasive bladder', 'Phenotype', 'HP:0100645', (154, 170))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('ZNF671', 'Gene', (51, 57))	('DNA methylation', 'biological_process', 'GO:0006306', ('58', '73'))	('DNA', 'Var', (58, 61))
158835	26320192	In this study, by using various DNA methylation assessments, we identified a novel tumor suppressor gene, ZNF671 that is epigenetically silenced by promoter DNA methylation in UC.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor suppressor', 'biological_process', 'GO:0051726', ('83', '99'))	('ZNF671', 'Gene', (106, 112))	('tumor', 'Disease', (83, 88))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('83', '99'))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('ZNF671', 'Gene', '79891', (106, 112))	('methylation', 'Var', (161, 172))	('DNA methylation', 'biological_process', 'GO:0006306', ('157', '172'))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('DNA methylation', 'biological_process', 'GO:0006306', ('32', '47'))
158837	26320192	Through recruitment of KRAB-associated protein-1 (KAP1) and other co-repressors, KRAB-ZFPs form heterochromatin with HP1, SETDB1, and various histone deacetylases (HDACs) to epigenetically silence their targets.	('SETDB1', 'Gene', (122, 128))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('heterochromatin', 'cellular_component', 'GO:0000792', ('96', '111'))	('KAP1', 'Gene', (50, 54))	('epigenetically', 'Var', (174, 188))	('HP1', 'Gene', '1667', (117, 120))	('SETDB1', 'Gene', '9869', (122, 128))	('KAP1', 'Gene', '10155', (50, 54))	('KRAB-associated protein-1', 'Gene', '10155', (23, 48))	('KRAB-associated protein-1', 'Gene', (23, 48))	('HP1', 'Gene', (117, 120))
158839	26320192	Previous studies demonstrated that some of these ZNF proteins are tumor suppressors that are epigenetically silenced by DNA methylation in multiple human cancers.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('DNA methylation', 'biological_process', 'GO:0006306', ('120', '135'))	('human', 'Species', '9606', (148, 153))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('DNA methylation', 'Var', (120, 135))	('cancers', 'Disease', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('proteins', 'Protein', (53, 61))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('ZNF', 'Gene', (49, 52))
158842	26320192	Although ZNF671 was previously found to be silenced by promoter methylation in renal cell and cervical carcinomas, its role in UC has never been explored.	('promoter methylation', 'Var', (55, 75))	('cervical carcinomas', 'Disease', (94, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('cervical carcinomas', 'Disease', 'MESH:D002575', (94, 113))	('renal cell', 'Disease', (79, 89))	('ZNF671', 'Gene', (9, 15))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('ZNF671', 'Gene', '79891', (9, 15))
158843	26320192	In this study, we found that ZNF671 was epigenetically silenced by promoter hypermethylation in UC cell lines and patient tumor tissue samples.	('ZNF671', 'Gene', '79891', (29, 35))	('promoter hypermethylation', 'Var', (67, 92))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('ZNF671', 'Gene', (29, 35))	('patient', 'Species', '9606', (114, 121))	('tumor', 'Disease', (122, 127))
158846	26320192	We also observed ZNF671 epigenetic repression in patient tumors of the upper urinary tract, which in Taiwan is a more common site for this malignancy, in addition to significant association with high tumor grade and shorter locoregional disease-free survival.	('high tumor', 'Disease', 'MESH:D009369', (195, 205))	('shorter', 'NegReg', (216, 223))	('ZNF671', 'Gene', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors of the upper urinary tract', 'Phenotype', 'HP:0010935', (57, 90))	('high tumor', 'Disease', (195, 205))	('patient', 'Species', '9606', (49, 56))	('epigenetic repression', 'Var', (24, 45))	('ZNF671', 'Gene', '79891', (17, 23))	('malignancy', 'Disease', 'MESH:D009369', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('malignancy', 'Disease', (139, 149))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('locoregional disease-free survival', 'CPA', (224, 258))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
158847	26320192	Thus, a role for ZNF671 methylation as a non-invasive biomarker for this disease deserves further investigation.	('ZNF671', 'Gene', '79891', (17, 23))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('ZNF671', 'Gene', (17, 23))	('methylation', 'Var', (24, 35))
158848	26320192	Our functional studies additionally showed that ZNF671 overexpression inhibits UC invasion and growth both in vitro, and in vivo (in xenograft mouse models).	('ZNF671', 'Gene', (48, 54))	('mouse', 'Species', '10090', (143, 148))	('UC invasion', 'CPA', (79, 90))	('overexpression', 'Var', (55, 69))	('inhibits', 'NegReg', (70, 78))	('ZNF671', 'Gene', '79891', (48, 54))	('growth', 'CPA', (95, 101))
158849	26320192	Furthermore, recent studies showed that the transcriptionally repressive ZNF KRAB domain can recruit KAP1, another transcriptional co-repressor that cooperates in epigenetically silencing KRAB-ZNF targets.	('epigenetically silencing', 'Var', (163, 187))	('KAP1', 'Gene', (101, 105))	('KAP1', 'Gene', '10155', (101, 105))
158850	26320192	demonstrated that ZBRK1, a KRAB-ZFP could suppress tumor invasion by recruiting KAP1 in cervical cancer, as loss of ZBRK1 resulted in KAP1 up-regulation and tumor migration and invasion.	('KAP1', 'Gene', '10155', (134, 138))	('cervical cancer', 'Disease', (88, 103))	('cervical cancer', 'Disease', 'MESH:D002583', (88, 103))	('recruiting', 'PosReg', (69, 79))	('ZBRK1', 'Gene', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('ZBRK1', 'Gene', '59348', (116, 121))	('suppress', 'NegReg', (42, 50))	('loss', 'Var', (108, 112))	('KAP1', 'Gene', (80, 84))	('tumor', 'Disease', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('KAP1', 'Gene', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('ZBRK1', 'Gene', (18, 23))	('invasion', 'CPA', (177, 185))	('ZBRK1', 'Gene', '59348', (18, 23))	('tumor', 'Disease', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('regulation', 'biological_process', 'GO:0065007', ('142', '152'))	('up-regulation', 'PosReg', (139, 152))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('KAP1', 'Gene', '10155', (80, 84))
158852	26320192	Previous reports, including ours, demonstrate that detection of DNA methylation in exfoliated cells from the urine of bladder UC patients represents a useful and sensitive biomarker for cancer detection.	('DNA', 'Gene', (64, 67))	('methylation', 'Var', (68, 79))	('patients', 'Species', '9606', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('DNA methylation', 'biological_process', 'GO:0006306', ('64', '79'))	('bladder UC', 'Disease', (118, 128))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
158855	26320192	In the current study, using qMSP assay, we found that ZNF671 methylation exhibited a sensitivity of around 45% (42%-48%) in detecting bladder UC in urine, and that combining methylated ZNF671, IRF8 and sFRP1 increased the overall sensitivity for cancer detection in urine, to 96.2% (overall disease), 90% (low-grade disease) and remarkably 100% for high-grade tumors (Table 5).	('tumors', 'Disease', 'MESH:D009369', (360, 366))	('ZNF671', 'Gene', '79891', (54, 60))	('methylated', 'Var', (174, 184))	('methylation', 'Var', (61, 72))	('cancer', 'Disease', (246, 252))	('IRF8', 'Gene', '3394', (193, 197))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('detecting', 'Reg', (124, 133))	('tumors', 'Phenotype', 'HP:0002664', (360, 366))	('bladder UC', 'Disease', (134, 144))	('ZNF671', 'Gene', (185, 191))	('increased', 'PosReg', (208, 217))	('ZNF671', 'Gene', '79891', (185, 191))	('UC in urine', 'Phenotype', 'HP:0003149', (142, 153))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('IRF8', 'Gene', (193, 197))	('tumors', 'Disease', (360, 366))	('sFRP1', 'Gene', (202, 207))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('combining', 'Interaction', (164, 173))	('sFRP1', 'Gene', '6422', (202, 207))	('ZNF671', 'Gene', (54, 60))
158860	26320192	Thus, the possible role of ZNF671 methylation as a non-invasive biomarker for all UC sub-types requires further investigation.	('ZNF671', 'Gene', (27, 33))	('ZNF671', 'Gene', '79891', (27, 33))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('methylation', 'Var', (34, 45))
158861	26320192	In conclusion, ZNF671 is a potential tumor suppressor that is epigenetically silenced by promoter methylation in bladder urothelial carcinoma.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('ZNF671', 'Gene', '79891', (15, 21))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (113, 141))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('bladder urothelial carcinoma', 'Disease', (113, 141))	('ZNF671', 'Gene', (15, 21))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))	('promoter methylation', 'Var', (89, 109))
158862	26320192	Methylation of ZNF671 represents a novel epigenetic biomarker candidate for the non-invasive diagnosis of bladder UC.	('Methylation', 'Var', (0, 11))	('bladder UC', 'Disease', (106, 116))	('ZNF671', 'Gene', '79891', (15, 21))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('ZNF671', 'Gene', (15, 21))
158875	26320192	To examine whether ZNF671 methylation could also be detected in UC in the upper urinary tract, 33 UC tissue samples from the ureter or renal pelvis were also procured for analysis.	('methylation', 'Var', (26, 37))	('ZNF671', 'Gene', '79891', (19, 25))	('ureter or renal pelvis', 'Disease', (125, 147))	('detected', 'Reg', (52, 60))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('renal pelvis', 'Phenotype', 'HP:0000125', (135, 147))	('UC in the upper urinary tract', 'Phenotype', 'HP:0010935', (64, 93))	('ureter or renal pelvis', 'Disease', 'MESH:D014516', (125, 147))	('ZNF671', 'Gene', (19, 25))
158890	26320192	For detection of ZNF671 methylation in urine samples, DNA was extracted (see above) and quantitative real-time methylation-specific PCR (qMSP) was performed as previously described.	('ZNF671', 'Gene', (17, 23))	('methylation', 'Var', (24, 35))	('methylation', 'biological_process', 'GO:0032259', ('111', '122'))	('ZNF671', 'Gene', '79891', (17, 23))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))
158891	26320192	In brief, 4 mul of bisulphite converted DNA was subjected to real time MSP within specific promoter ZNF671 regions using distinct primer sets (Supplementary Table 1) in an ABI Step One real time PCR system (ABI).	('MSP', 'Var', (71, 74))	('bisulphite', 'Chemical', 'MESH:C042345', (19, 29))	('ZNF671', 'Gene', (100, 106))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('ZNF671', 'Gene', '79891', (100, 106))
158902	26320192	For the construction of a ZNF671 promoter plasmid, a 960-bp region of the ZNF671 promoter (-329/+631) was amplified by PCR using specific primers (Supplementary Table 1) from genomic DNA of HUC cells.	('-329/+631', 'Var', (91, 100))	('ZNF671', 'Gene', '79891', (26, 32))	('ZNF671', 'Gene', '79891', (74, 80))	('DNA', 'cellular_component', 'GO:0005574', ('183', '186'))	('ZNF671', 'Gene', (26, 32))	('ZNF671', 'Gene', (74, 80))
158933	33334367	In vitro experiments revealed that knockdown of MIR31HG inhibits cell proliferation, colony formation, and migration in bladder cancer.	('knockdown', 'Var', (35, 44))	('MIR31HG', 'Gene', (48, 55))	('migration', 'CPA', (107, 116))	('MIR31HG', 'Gene', '554202', (48, 55))	('formation', 'biological_process', 'GO:0009058', ('92', '101'))	('bladder cancer', 'Disease', 'MESH:D001749', (120, 134))	('inhibits', 'NegReg', (56, 64))	('bladder cancer', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cell proliferation', 'biological_process', 'GO:0008283', ('65', '83'))	('cell proliferation', 'CPA', (65, 83))	('colony formation', 'CPA', (85, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (120, 134))
158948	33334367	Considering that dysregulation of mRNA splicing can trigger cancer signaling pathways and contribute to almost all hallmarks of cancer, the alternative splicing of lncRNAs may also impact cellular processes, which could open new possibilities for biomarker discovery.	('mRNA splicing', 'biological_process', 'GO:0006371', ('34', '47'))	('mRNA splicing', 'biological_process', 'GO:0000394', ('34', '47'))	('lncRNAs', 'Gene', (164, 171))	('alternative splicing', 'Var', (140, 160))	('mRNA splicing', 'biological_process', 'GO:0000374', ('34', '47'))	('cancer', 'Disease', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('trigger', 'Reg', (52, 59))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('contribute', 'Reg', (90, 100))	('mRNA splicing', 'biological_process', 'GO:0000373', ('34', '47'))	('cellular processes', 'CPA', (188, 206))	('mRNA splicing', 'biological_process', 'GO:0000372', ('34', '47'))	('dysregulation', 'Var', (17, 30))	('splicing', 'biological_process', 'GO:0045292', ('152', '160'))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('mRNA splicing', 'biological_process', 'GO:0000398', ('34', '47'))	('cancer', 'Disease', (60, 66))	('mRNA splicing', 'MPA', (34, 47))	('impact', 'Reg', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
158949	33334367	Previously, it was reported that splice variants of osteopontin have prognostic value in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('osteopontin', 'Gene', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('splice variants', 'Var', (33, 48))	('osteopontin', 'Gene', '6696', (52, 63))
158954	33334367	Upon knockdown of MIR31HG, a series of in vitro experiments was performed to investigate the effects of MIR31HG on proliferation, colony formation, and migration of BLCA cells.	('MIR31HG', 'Gene', (18, 25))	('migration', 'CPA', (152, 161))	('knockdown', 'Var', (5, 14))	('formation', 'biological_process', 'GO:0009058', ('137', '146'))	('colony formation', 'CPA', (130, 146))	('MIR31HG', 'Gene', (104, 111))	('MIR31HG', 'Gene', '554202', (104, 111))	('MIR31HG', 'Gene', '554202', (18, 25))
159012	33334367	Putative copy-number alterations including deep/shallow deletion, diploid, gain, and amplification were acquired from the GISTIC (Genomic Identification of Significant Targets in Cancer) algorithm.	('gain', 'PosReg', (75, 79))	('Cancer', 'Phenotype', 'HP:0002664', (179, 185))	('Cancer', 'Disease', (179, 185))	('Cancer', 'Disease', 'MESH:D009369', (179, 185))	('deep/shallow deletion', 'Var', (43, 64))	('diploid', 'Var', (66, 73))
159013	33334367	MIR31HG showed 56.76% of shallow/deep deletion (n = 210), 31.62% of diploid (n = 117), and 11.62% of gain/amplification (n = 43, Fig.	('shallow/deep deletion', 'Var', (25, 46))	('gain/amplification', 'PosReg', (101, 119))	('MIR31HG', 'Gene', '554202', (0, 7))	('diploid', 'Var', (68, 75))	('MIR31HG', 'Gene', (0, 7))
159015	33334367	High expression of MIR31HG was found in the subgroup with deletion and diploid alteration than in gain (n = 47, 20.44% in gain; n = 99, 43.04% in diploid; n = 84, 36.52% in deletion), while low expression was observed in the subgroup with deletion alteration, compared to diploid and gain (n = 15, 8.67% with gain; n = 28, 16.18% with diploid; n = 130, 75.15% with deletion, Fig.	('expression', 'MPA', (5, 15))	('MIR31HG', 'Gene', (19, 26))	('MIR31HG', 'Gene', '554202', (19, 26))	('deletion alteration', 'Var', (239, 258))	('alteration', 'Var', (79, 89))	('deletion', 'Var', (58, 66))
159021	33334367	In the Mannheim cohort, Kaplan-Meier analysis and the log-rank test were used to evaluate the association of the expression of two MIR31HG splice variants with OS and DFS.	('MIR31HG', 'Gene', (131, 138))	('DFS', 'Disease', (167, 170))	('MIR31HG', 'Gene', '554202', (131, 138))	('association', 'Interaction', (94, 105))	('variants', 'Var', (146, 154))
159038	33334367	Cell viability was determined using the MTS assay based on absorbance at 490 nm after 0, 24, 48, and 72 h. T24, UMUC3, and SCaBER cells with MIR31HG knockdown by siRNA showed lower cellular viability at three time points compared to the control group transfected with scramble siRNA (si-NC, Fig.	('MIR31HG', 'Gene', '554202', (141, 148))	('SCaBER', 'CellLine', 'CVCL:3599', (123, 129))	('knockdown', 'Var', (149, 158))	('lower', 'NegReg', (175, 180))	('MIR31HG', 'Gene', (141, 148))	('cellular viability at three time points', 'CPA', (181, 220))
159040	33334367	T24, UMUC3, and SCaBER cells with MIR31HG knockdown showed fewer cell colonies compared to the control group (Fig.	('cell colonies', 'CPA', (65, 78))	('SCaBER', 'CellLine', 'CVCL:3599', (16, 22))	('MIR31HG', 'Gene', (34, 41))	('fewer', 'NegReg', (59, 64))	('MIR31HG', 'Gene', '554202', (34, 41))	('knockdown', 'Var', (42, 51))
159041	33334367	BLCA cells with MIR31HG knockdown showed a reduced formation of colonies compared to the control group (Fig.	('MIR31HG', 'Gene', (16, 23))	('MIR31HG', 'Gene', '554202', (16, 23))	('formation', 'biological_process', 'GO:0009058', ('51', '60'))	('formation of colonies', 'CPA', (51, 72))	('reduced', 'NegReg', (43, 50))	('knockdown', 'Var', (24, 33))
159042	33334367	T24, UMUC3, and SCaBER cells with MIR31HG knockdown showed a larger open wound area compared with the control group after 12 h (Fig.	('open wound area', 'CPA', (68, 83))	('SCaBER', 'CellLine', 'CVCL:3599', (16, 22))	('larger', 'PosReg', (61, 67))	('MIR31HG', 'Gene', (34, 41))	('MIR31HG', 'Gene', '554202', (34, 41))	('knockdown', 'Var', (42, 51))
159043	33334367	BLCA cells with MIR31HG knockdown showed fewer changes in open wound area compared with the control group (Fig.	('open wound area', 'CPA', (58, 73))	('knockdown', 'Var', (24, 33))	('MIR31HG', 'Gene', (16, 23))	('MIR31HG', 'Gene', '554202', (16, 23))
159045	33334367	Cell viability was quantified by MTS assay based on absorbance at 490 nm after 0, 24, 48, and 72 h. T24, UMUC3, and SCaBER cells with MIR31HGDeltaE1 and MIR31HGDeltaE3 knockdown by specific siRNA showed decreased cellular viability with cell specificity (Fig.	('MIR31HG', 'Gene', '554202', (153, 160))	('decreased', 'NegReg', (203, 212))	('cellular viability', 'CPA', (213, 231))	('MIR31HG', 'Gene', (134, 141))	('MIR31HG', 'Gene', '554202', (134, 141))	('knockdown', 'Var', (168, 177))	('SCaBER', 'CellLine', 'CVCL:3599', (116, 122))	('MIR31HG', 'Gene', (153, 160))
159046	33334367	MIR31HGDeltaE1 knockdown showed significantly decreased absorbance in T24 (p = 0.0018, Fig.	('absorbance in T24', 'MPA', (56, 73))	('knockdown', 'Var', (15, 24))	('MIR31HG', 'Gene', '554202', (0, 7))	('decreased', 'NegReg', (46, 55))	('MIR31HG', 'Gene', (0, 7))
159047	33334367	7b) cells after 72 h, and MIR31HGDeltaE3 knockdown resulted in a significant decrease in absorbance in SCaBER (p = 0.0346, Fig.	('absorbance in SCaBER', 'MPA', (89, 109))	('MIR31HG', 'Gene', (26, 33))	('decrease', 'NegReg', (77, 85))	('SCaBER', 'CellLine', 'CVCL:3599', (103, 109))	('MIR31HG', 'Gene', '554202', (26, 33))	('knockdown', 'Var', (41, 50))
159049	33334367	T24, UMUC3, and SCaBER cells with MIR31HGDeltaE1 and MIR31HGDeltaE3 knockdown by specific siRNA showed fewer cell colonies with cell specificity (Fig.	('MIR31HG', 'Gene', (53, 60))	('MIR31HG', 'Gene', '554202', (53, 60))	('SCaBER', 'CellLine', 'CVCL:3599', (16, 22))	('knockdown', 'Var', (68, 77))	('cell colonies', 'CPA', (109, 122))	('MIR31HG', 'Gene', (34, 41))	('MIR31HG', 'Gene', '554202', (34, 41))	('fewer', 'NegReg', (103, 108))
159051	33334367	SCaBER cells with MIR31HGDeltaE3 knockdown showed significantly decreased staining intensity (Fig.	('MIR31HG', 'Gene', (18, 25))	('MIR31HG', 'Gene', '554202', (18, 25))	('knockdown', 'Var', (33, 42))	('SCaBER', 'CellLine', 'CVCL:3599', (0, 6))	('staining intensity', 'MPA', (74, 92))	('decreased', 'NegReg', (64, 73))
159052	33334367	T24, UMUC3, and SCaBER cells with MIR31HGDeltaE1 and MIR31HGDeltaE3 knockdown by specific siRNA showed a larger open wound area compared with cell specificity after 12 h (Fig.	('MIR31HG', 'Gene', (53, 60))	('MIR31HG', 'Gene', '554202', (53, 60))	('SCaBER', 'CellLine', 'CVCL:3599', (16, 22))	('larger', 'PosReg', (105, 111))	('knockdown', 'Var', (68, 77))	('MIR31HG', 'Gene', (34, 41))	('MIR31HG', 'Gene', '554202', (34, 41))	('open wound area', 'CPA', (112, 127))
159054	33334367	SCaBER cells showed fewer changes in the open wound area upon MIR31HGDeltaE3 knockdown (Fig.	('open wound area', 'CPA', (41, 56))	('SCaBER', 'CellLine', 'CVCL:3599', (0, 6))	('knockdown', 'Var', (77, 86))	('MIR31HG', 'Gene', '554202', (62, 69))	('MIR31HG', 'Gene', (62, 69))
159059	33334367	Significantly higher expression of EGFR was observed in SCaBER cells with MIR31HG knockdown compared to the control group (p = 0.0367, Fig.	('knockdown', 'Var', (82, 91))	('expression', 'MPA', (21, 31))	('EGFR', 'Gene', (35, 39))	('MIR31HG', 'Gene', (74, 81))	('EGFR', 'Gene', '1956', (35, 39))	('SCaBER', 'CellLine', 'CVCL:3599', (56, 62))	('MIR31HG', 'Gene', '554202', (74, 81))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))	('higher', 'PosReg', (14, 20))
159060	33334367	No significant difference of expression was observed between T24 (p = 0.4086) and UMUC3 (p = 0.4734) cells with MIR31HG knockdown and control group (Fig.	('MIR31HG', 'Gene', '554202', (112, 119))	('knockdown', 'Var', (120, 129))	('MIR31HG', 'Gene', (112, 119))
159093	33334367	In this study, by knocking down MIR31HG expression using siRNA, diminished cell proliferation, colony formation, and migration were assessed in BLCA cell lines.	('MIR31HG', 'Gene', '554202', (32, 39))	('migration', 'CPA', (117, 126))	('knocking down', 'Var', (18, 31))	('MIR31HG', 'Gene', (32, 39))	('diminished', 'NegReg', (64, 74))	('colony formation', 'CPA', (95, 111))	('formation', 'biological_process', 'GO:0009058', ('102', '111'))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('cell proliferation', 'CPA', (75, 93))
159103	33334367	Similarly, it was shown that silencing of MIR31HG significantly inhibited NSCLC cell migration, invasion, and metastasis by attenuated sponging of miR-214.	('miR-214', 'Gene', '406996', (147, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('silencing', 'Var', (29, 38))	('inhibited', 'NegReg', (64, 73))	('attenuated', 'NegReg', (124, 134))	('miR-214', 'Gene', (147, 154))	('NSCLC', 'Disease', (74, 79))	('invasion', 'CPA', (96, 104))	('cell migration', 'biological_process', 'GO:0016477', ('80', '94'))	('MIR31HG', 'Gene', (42, 49))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('MIR31HG', 'Gene', '554202', (42, 49))
159110	33334367	Furthermore, splice variants in V600E BRAF-mutant-positive malignant melanoma patients were shown to be associated with vemurafenib resistance, indicating that aberrant splicing could be a novel mechanism of acquired resistance.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('vemurafenib resistance', 'MPA', (120, 142))	('V600E', 'Mutation', 'rs113488022', (32, 37))	('malignant melanoma', 'Phenotype', 'HP:0002861', (59, 77))	('splice', 'Var', (13, 19))	('patients', 'Species', '9606', (78, 86))	('BRAF', 'Gene', '673', (38, 42))	('associated', 'Reg', (104, 114))	('splicing', 'biological_process', 'GO:0045292', ('169', '177'))	('V600E', 'Var', (32, 37))	('BRAF', 'Gene', (38, 42))	('vemurafenib', 'Chemical', 'MESH:D000077484', (120, 131))	('melanoma', 'Disease', (69, 77))
159183	28127447	Missing CIS during cystoscopy may result in progression and higher risk of cancer specific death in up to 20-83% of patients.	('death', 'Disease', 'MESH:D003643', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('death', 'Disease', (91, 96))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Disease', (75, 81))	('Missing CIS', 'Var', (0, 11))	('result in', 'Reg', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CIS', 'Phenotype', 'HP:0030075', (8, 11))
159185	28127447	PDD increased the detection rate of CIS in these patients, hence giving a higher accuracy for superficial cancer detection.	('CIS', 'Phenotype', 'HP:0030075', (36, 39))	('higher', 'PosReg', (74, 80))	('CIS', 'Disease', (36, 39))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('detection', 'MPA', (18, 27))	('PDD', 'Var', (0, 3))	('cancer', 'Disease', (106, 112))	('patients', 'Species', '9606', (49, 57))	('increased', 'PosReg', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
159225	24579024	Final pathology revealed T2a N0 urothelial carcinoma of the bladder.	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (32, 67))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (32, 67))	('urothelial carcinoma of the bladder', 'Disease', (32, 67))	('T2a', 'Var', (25, 28))
159292	20046960	Patients with high-grade T1 papillary tumors, multiple tumors, or with associated CIS are at high risk for recurrence and/or progression to muscle invasion.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('papillary tumors', 'Disease', 'MESH:D002291', (28, 44))	('high-grade', 'Var', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('papillary tumors', 'Phenotype', 'HP:0007482', (28, 44))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('CIS', 'Phenotype', 'HP:0030075', (82, 85))	('Patients', 'Species', '9606', (0, 8))	('multiple tumors', 'Disease', (46, 61))	('multiple tumors', 'Disease', 'MESH:D009369', (46, 61))	('papillary tumors', 'Disease', (28, 44))
159334	20046960	The intracellular source of TRAIL appears to be preformed, because neutrophils treated with compounds that inhibit transcription or translation release equal amounts of TRAIL compared with untreated neutrophils when stimulated with BCG.	('inhibit', 'NegReg', (107, 114))	('translation', 'MPA', (132, 143))	('intracellular', 'cellular_component', 'GO:0005622', ('4', '17'))	('TRAIL', 'Gene', '8743', (28, 33))	('compounds', 'Var', (92, 101))	('BCG', 'Species', '33892', (232, 235))	('transcription', 'biological_process', 'GO:0006351', ('115', '128'))	('translation', 'biological_process', 'GO:0006412', ('132', '143'))	('TRAIL', 'Gene', (28, 33))	('TRAIL', 'Gene', '8743', (169, 174))	('transcription', 'MPA', (115, 128))	('TRAIL', 'Gene', (169, 174))
159363	20046960	TLR ligation induces an inflammatory cascade and influx of effector cells to sites of infection.	('inflammatory', 'CPA', (24, 36))	('induces', 'Reg', (13, 20))	('infection', 'Disease', (86, 95))	('infection', 'Disease', 'MESH:D007239', (86, 95))	('ligation', 'Var', (4, 12))	('TLR', 'Gene', (0, 3))	('influx', 'CPA', (49, 55))
159374	20046960	Analysis of several cytokines known to be induced by BCG, including IL-2, -6, -10 and IFN-gamma, showed that SNPs present in IL-10, TGF-beta and IL-4 were associated with progression despite BCG therapy.	('BCG', 'Species', '33892', (191, 194))	('IL-4', 'Gene', (145, 149))	('SNPs', 'Var', (109, 113))	('IL-2', 'molecular_function', 'GO:0005134', ('68', '72'))	('IFN-gamma', 'Gene', '3458', (86, 95))	('IFN-gamma', 'Gene', (86, 95))	('BCG', 'Species', '33892', (53, 56))	('IL-4', 'molecular_function', 'GO:0005136', ('145', '149'))	('TGF-beta', 'Gene', (132, 140))	('IL-10', 'Gene', (125, 130))	('associated with', 'Reg', (155, 170))	('IL-10', 'molecular_function', 'GO:0005141', ('125', '130'))	('IL-2', 'Gene', (68, 72))	('IL-2', 'Gene', '3558', (68, 72))
159375	20046960	A specific polymorphism in the gene NRAMP1, which has been implicated in human and murine responses to mycobacteria among other immune stimuli, was found in 2-3% of normal controls and 12% of patients at high risk of recurrence.	('NRAMP1', 'Gene', (36, 42))	('polymorphism', 'Var', (11, 23))	('patients', 'Species', '9606', (192, 200))	('human', 'Species', '9606', (73, 78))	('NRAMP1', 'Gene', '6556', (36, 42))	('found', 'Reg', (148, 153))	('murine', 'Species', '10090', (83, 89))
159382	20046960	BCG induces a massive influx of cytokines and inflammatory cells into the bladder wall and lumen.	('BCG', 'Species', '33892', (0, 3))	('BCG', 'Var', (0, 3))	('influx of cytokines', 'MPA', (22, 41))
159410	20046960	Molecular approaches have identified specific polymorphisms in cytokine genes, which seem to play a role in the response to BCG.	('polymorphisms', 'Var', (46, 59))	('cytokine genes', 'Gene', (63, 77))	('role', 'Reg', (100, 104))	('BCG', 'Species', '33892', (124, 127))	('play', 'Reg', (93, 97))
159411	33864445	Comprehensive analysis of ferritin subunits expression and positive correlations with tumor-associated macrophages and T regulatory cells infiltration in most solid tumors Ferritin is the most important iron storage form and is known to influence tumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Ferritin', 'Var', (172, 180))	('iron', 'Chemical', 'MESH:D007501', (203, 207))	('tumor', 'Disease', (247, 252))	('tumor', 'Disease', (86, 91))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('storage', 'biological_process', 'GO:0051235', ('208', '215'))	('influence', 'Reg', (237, 246))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (165, 170))
159437	33864445	The results suggested that high FTL (Figure 2B, 2C) or high FTH1 (Figure 2E-2J) mRNA levels were each related to poor OS in several cancer types.	('cancer', 'Disease', (132, 138))	('FTH1', 'Gene', (60, 64))	('mRNA levels', 'MPA', (80, 91))	('FTL', 'Gene', (32, 35))	('related', 'Reg', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('FTH1', 'Gene', '2495', (60, 64))	('high', 'Var', (55, 59))	('FTL', 'Gene', '2512', (32, 35))	('poor OS', 'Disease', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
159440	33864445	FTL expression was significantly associated with PFI in four cancer types (Figure 3A): LGG (HR 1.5, 95% CI 1.26-1.78, P = 3.8 x 10-6), KIRC (HR 1.31, 95% CI 1.06-1.62, P = 1.4 x 10-2), UCEC (HR 1.21, 95% CI 1.00-1.46, P = 4.4 x 10-2), and GBM (HR 1.26, 95% CI 1.02-1.57, P = 3.3 x 10-2).	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('FTL', 'Gene', '2512', (0, 3))	('PFI', 'Disease', (49, 52))	('cancer', 'Disease', (61, 67))	('LGG', 'Disease', (87, 90))	('PFI', 'molecular_function', 'GO:0034016', ('49', '52'))	('associated', 'Reg', (33, 43))	('expression', 'Var', (4, 14))	('UCEC', 'Disease', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('GBM', 'Disease', (239, 242))	('FTL', 'Gene', (0, 3))	('KIRC', 'Disease', (135, 139))
159442	33864445	As was observed for OS, poor PFI was significantly associated with high FTL (Figure 3B, 3C) or high FTH1 (Figure 3E-3J) mRNA levels in some cancers.	('FTH1', 'Gene', '2495', (100, 104))	('FTL', 'Gene', (72, 75))	('high', 'Var', (95, 99))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('PFI', 'molecular_function', 'GO:0034016', ('29', '32'))	('FTH1', 'Gene', (100, 104))	('FTL', 'Gene', '2512', (72, 75))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('mRNA levels', 'MPA', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('PFI', 'MPA', (29, 32))
159463	33864445	Iron is an essential element in supporting cell proliferation and often accumulates in cancer cells; however, excessive levels of Fe2+ can promote the Fenton reaction, production of reactive oxygen species, and cell death through apoptosis and ferroptosis.	('cancer', 'Disease', (87, 93))	('cell death', 'CPA', (211, 221))	('promote', 'PosReg', (139, 146))	('cell proliferation', 'biological_process', 'GO:0008283', ('43', '61'))	('cell death', 'biological_process', 'GO:0008219', ('211', '221'))	('ferroptosis', 'CPA', (244, 255))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('apoptosis', 'CPA', (230, 239))	('apoptosis', 'biological_process', 'GO:0097194', ('230', '239'))	('apoptosis', 'biological_process', 'GO:0006915', ('230', '239'))	('ferroptosis', 'biological_process', 'GO:0097707', ('244', '255'))	('Fe2+', 'Var', (130, 134))	('Fe2+', 'Chemical', '-', (130, 134))	('production of reactive oxygen species', 'MPA', (168, 205))	('Fenton reaction', 'MPA', (151, 166))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('Iron', 'Chemical', 'MESH:D007501', (0, 4))	('oxygen', 'Chemical', 'MESH:D010100', (191, 197))
159473	33864445	We found that high FTH1 expression is positively related to poor prognosis in 11 cancers, including HNSC, which is consistent with our previous study.	('HNSC', 'Disease', (100, 104))	('FTH1', 'Gene', (19, 23))	('expression', 'MPA', (24, 34))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('FTH1', 'Gene', '2495', (19, 23))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('high', 'Var', (14, 18))	('HNSC', 'Phenotype', 'HP:0012288', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
159478	33864445	showed that FTH1 is critical for proper functioning of the antioxidant system in ovarian cancer cells, suggesting that inhibition of FTH1 may improve cisplatin-induced cytotoxicity.	('FTH1', 'Gene', (12, 16))	('cytotoxicity', 'Disease', 'MESH:D064420', (168, 180))	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('ovarian cancer', 'Disease', 'MESH:D010051', (81, 95))	('FTH1', 'Gene', (133, 137))	('inhibition', 'Var', (119, 129))	('ovarian cancer', 'Disease', (81, 95))	('FTH1', 'Gene', '2495', (12, 16))	('FTH1', 'Gene', '2495', (133, 137))	('improve', 'PosReg', (142, 149))	('cytotoxicity', 'Disease', (168, 180))	('cisplatin-induced', 'MPA', (150, 167))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
159499	33864445	However, whether FTL or FTH1 inhibition can induce M2-to-M1 repolarization will need to be investigated in future studies.	('FTH1', 'Gene', '2495', (24, 28))	('FTL', 'Gene', '2512', (17, 20))	('FTH1', 'Gene', (24, 28))	('FTL', 'Gene', (17, 20))	('M2-to-M1 repolarization', 'MPA', (51, 74))	('inhibition', 'Var', (29, 39))
159519	33557266	Pan-Cancer Analysis Shows TP53 Mutations Modulate the Association of NOX4 with Genetic Programs of Cancer Progression and Clinical Outcome Previously, we have shown TGF-beta-induced NOX4 expression is involved in the epithelial-to-mesenchymal transition (EMT), a process critical for cancer metastasis, and that wild-type (WT) and mutant (Mut) p53 have divergent effects on TGF-beta induction of NOX4: WT-p53 suppresses whereas Mut-p53 augments NOX4 mRNA and protein production in several tumor cell models.	('p53', 'Gene', (432, 435))	('p53', 'Gene', (344, 347))	('tumor', 'Disease', 'MESH:D009369', (489, 494))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('TP53', 'Gene', '7157', (26, 30))	('p53', 'Gene', '7157', (405, 408))	('NOX4', 'Gene', '50507', (445, 449))	('tumor', 'Phenotype', 'HP:0002664', (489, 494))	('EMT', 'biological_process', 'GO:0001837', ('255', '258'))	('NOX4', 'Gene', (445, 449))	('p53', 'Gene', (405, 408))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('217', '253'))	('NOX4', 'Gene', '50507', (396, 400))	('cancer metastasis', 'Disease', (284, 301))	('NOX4', 'Gene', (396, 400))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('Mutations', 'Var', (31, 40))	('NOX4', 'Gene', '50507', (182, 186))	('NOX4', 'Gene', '50507', (69, 73))	('TP53', 'Gene', (26, 30))	('p53', 'Gene', '7157', (432, 435))	('NOX4', 'Gene', (182, 186))	('p53', 'Gene', '7157', (344, 347))	('NOX4', 'Gene', (69, 73))	('suppresses', 'NegReg', (409, 419))	('augments', 'PosReg', (436, 444))	('tumor', 'Disease', (489, 494))	('protein', 'cellular_component', 'GO:0003675', ('459', '466'))	('cancer metastasis', 'Disease', 'MESH:D009362', (284, 301))
159524	33557266	Notably, increased NOX4 expression is linked to poorer survival in patients with Mut-TP53, but better survival in patients with WT-TP53.	('Mut-TP53', 'Var', (81, 89))	('patients', 'Species', '9606', (67, 75))	('expression', 'MPA', (24, 34))	('poorer', 'NegReg', (48, 54))	('increased', 'PosReg', (9, 18))	('NOX4', 'Protein', (19, 23))	('patients', 'Species', '9606', (114, 122))
159525	33557266	NOX4 is negatively associated with markers of apoptosis and positively with markers of proliferation in patients with Mut-TP53, consistent with their poorer survival.	('apoptosis', 'CPA', (46, 55))	('NOX4', 'Gene', (0, 4))	('proliferation', 'CPA', (87, 100))	('negatively', 'NegReg', (8, 18))	('Mut-TP53', 'Var', (118, 126))	('positively', 'PosReg', (60, 70))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('patients', 'Species', '9606', (104, 112))
159526	33557266	These findings suggest that TP53 mutations could "switch" NOX4 from being protective and an indicator of good prognosis to deleterious by promoting programs favoring cancer progression.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('TP53', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
159527	33557266	Although critical in normal development and wound healing, aberrant EMT has been linked to cancer metastasis, and over-expression of EMT drivers, such as SNAI1 and SNAI2, are associated with poor clinical prognoses in cancer.	('cancer metastasis', 'Disease', 'MESH:D009362', (91, 108))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('SNAI2', 'Gene', '6591', (164, 169))	('SNAI2', 'Gene', (164, 169))	('cancer', 'Disease', (218, 224))	('aberrant', 'Var', (59, 67))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('SNAI1', 'Gene', '6615', (154, 159))	('SNAI1', 'Gene', (154, 159))	('over-expression', 'PosReg', (114, 129))	('wound healing', 'biological_process', 'GO:0042060', ('44', '57'))	('EMT', 'biological_process', 'GO:0001837', ('68', '71'))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer metastasis', 'Disease', (91, 108))	('linked', 'Reg', (81, 87))	('EMT', 'biological_process', 'GO:0001837', ('133', '136'))
159532	33557266	Our previous work indicated that while wild-type tumor suppressor protein 53 (p53) suppresses TGF-beta-induced NOX4-driven cell migration, mutant forms of p53 support NOX4 induction and cell migration in vitro.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('protein 53', 'Gene', '7157', (66, 76))	('protein 53', 'Gene', (66, 76))	('TGF-beta-induced', 'Gene', (94, 110))	('cell migration', 'CPA', (186, 200))	('cell migration', 'biological_process', 'GO:0016477', ('186', '200'))	('suppresses', 'NegReg', (83, 93))	('cell migration', 'biological_process', 'GO:0016477', ('123', '137'))	('NOX4', 'Enzyme', (167, 171))	('p53', 'Gene', '7157', (78, 81))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('p53', 'Gene', '7157', (155, 158))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('49', '65'))	('tumor', 'Disease', (49, 54))	('p53', 'Gene', (78, 81))	('tumor suppressor', 'biological_process', 'GO:0051726', ('49', '65'))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('p53', 'Gene', (155, 158))	('mutant', 'Var', (139, 145))
159538	33557266	However, there have been no broad-based human primary tumor surveys described to date correlating NOX4 expression patterns with programs of cancer progression specifically in the context of TP53 mutation status.	('NOX4', 'Gene', (98, 102))	('human', 'Species', '9606', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('TP53', 'Gene', (190, 194))	('tumor', 'Disease', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutation status', 'Var', (195, 210))
159544	33557266	The clinical outcome associated with an increase in NOX4 expression is different in patients with WT or Mut-p53, in that increased NOX4 in patients with Mut-TP53 is deleterious, whereas increased NOX4 is protective in those with WT-TP53.	('p53', 'Gene', '7157', (108, 111))	('p53', 'Gene', (108, 111))	('patients', 'Species', '9606', (139, 147))	('patients', 'Species', '9606', (84, 92))	('increased', 'PosReg', (121, 130))	('Mut-TP53', 'Var', (153, 161))	('NOX4', 'MPA', (131, 135))
159545	33557266	Together, we describe gene expression correlates that provide insight into the role of NOX4 in cancer progression, and how TP53 mutation status could be used to modulate NOX4-dependent cancer-related events.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (95, 101))	('modulate', 'Reg', (161, 169))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('gene expression', 'biological_process', 'GO:0010467', ('22', '37'))	('mutation', 'Var', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (185, 191))	('TP53', 'Gene', (123, 127))
159550	33557266	The most common p53 mutations within the DNA-binding domain from residue 101 to 306 were identified using literature reviews and the International Agency for Research on Cancer (IARC) p53 Database R18.	('Cancer', 'Phenotype', 'HP:0002664', (170, 176))	('DNA-binding', 'molecular_function', 'GO:0003677', ('41', '52'))	('p53', 'Gene', (16, 19))	('p53', 'Gene', (184, 187))	('p53', 'Gene', '7157', (184, 187))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('p53', 'Gene', '7157', (16, 19))	('mutations', 'Var', (20, 29))
159552	33557266	From the TCGA database, we downloaded all available gene expression and clinical data, and identified tumor samples with WT-TP53 and those with common TP53 mutations within the DNA-binding domain.	('TP53', 'Gene', (151, 155))	('mutations', 'Var', (156, 165))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('DNA', 'cellular_component', 'GO:0005574', ('177', '180'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('gene expression', 'biological_process', 'GO:0010467', ('52', '67'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('177', '188'))
159553	33557266	We excluded patients with TP53 frameshift mutations, multiple mutations, and patients missing p53 annotation (Figure 1).	('TP53', 'Gene', (26, 30))	('frameshift mutations', 'Var', (31, 51))	('patients', 'Species', '9606', (12, 20))	('p53', 'Gene', '7157', (94, 97))	('p53', 'Gene', (94, 97))	('patients', 'Species', '9606', (77, 85))
159564	33557266	In the Preliminary Pan-Cancer Dataset, we sorted tumor samples as having WT-TP53 or any of the 15 most common hot-spot mutants (Mut-p53) and found that in tumors with Mut-TP53, the level of p53 mRNA positively correlates with NOX4 mRNA (rho = 0.23), whereas WT-TP53 mRNA negatively correlates with NOX4 mRNA (rho = -0.2, Figure 3).	('Mut-TP53', 'Var', (167, 175))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (49, 54))	('p53', 'Gene', (190, 193))	('NOX4 mRNA', 'MPA', (226, 235))	('tumor', 'Disease', (155, 160))	('p53', 'Gene', '7157', (190, 193))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))
159566	33557266	This also suggests that TP53 mutation status may play a critical role in cellular processes previously shown to involve NOX4, such as EMT, cell migration, angiogenesis and other genetic and metabolic programs that promote cancer progression.	('mutation', 'Var', (29, 37))	('EMT', 'biological_process', 'GO:0001837', ('134', '137'))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('angiogenesis', 'biological_process', 'GO:0001525', ('155', '167'))	('TP53', 'Gene', (24, 28))	('cancer', 'Disease', (222, 228))	('cell migration', 'CPA', (139, 153))	('cell migration', 'biological_process', 'GO:0016477', ('139', '153'))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('play', 'Reg', (49, 53))	('angiogenesis', 'CPA', (155, 167))
159572	33557266	Together, these data suggest that NOX4 expression is associated with aggressive cancer phenotypes, such as enhanced cell migration and dissemination, but not in regaining the epithelial phenotype.	('aggressive cancer', 'Disease', (69, 86))	('expression', 'Var', (39, 49))	('NOX4', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cell migration', 'biological_process', 'GO:0016477', ('116', '130'))	('enhanced', 'PosReg', (107, 115))	('cell migration', 'CPA', (116, 130))	('dissemination', 'CPA', (135, 148))	('aggressive cancer', 'Disease', 'MESH:D009369', (69, 86))
159582	33557266	Furthermore, observations with Nox4 knock-out mice indicate the absence of Nox4 results in several proinflammatory phenotypes, including increased macrophage Nox2 expression and enhanced infiltration of proinflammatory macrophages in tumors of an induced fibrosarcoma model.	('Nox2', 'Gene', '13058', (158, 162))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('fibrosarcoma', 'Disease', 'MESH:D005354', (255, 267))	('Nox4', 'Gene', (75, 79))	('Nox4', 'Gene', '50490', (75, 79))	('fibrosarcoma', 'Disease', (255, 267))	('absence', 'Var', (64, 71))	('increased', 'PosReg', (137, 146))	('macrophage', 'MPA', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('increased macrophage', 'Phenotype', 'HP:0004311', (137, 157))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('infiltration', 'CPA', (187, 199))	('enhanced', 'PosReg', (178, 186))	('Nox4', 'Gene', (31, 35))	('Nox2', 'Gene', (158, 162))	('tumors', 'Disease', (234, 240))	('Nox4', 'Gene', '50490', (31, 35))	('mice', 'Species', '10090', (46, 50))	('expression', 'MPA', (163, 173))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (255, 267))
159584	33557266	Since NOX4 is the strongest correlate of genetic programs of cancer progression, we explored factors that could further enhance or alter this association.	('genetic', 'Var', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
159585	33557266	Previously, we showed that WT and several p53 mutants can alter both TGF-beta-dependent and -independent NOX4 expression.	('p53', 'Gene', (42, 45))	('TGF-beta-dependent', 'MPA', (69, 87))	('p53', 'Gene', '7157', (42, 45))	('mutants', 'Var', (46, 53))	('alter', 'Reg', (58, 63))
159586	33557266	Therefore, we sorted the Final Pan-Cancer cohort by many common p53 mutations and determined the rho-values of the indicated EMT signature in relation to NOX4 mRNA levels (Figure 6A).	('p53', 'Gene', '7157', (64, 67))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mutations', 'Var', (68, 77))	('p53', 'Gene', (64, 67))	('EMT', 'biological_process', 'GO:0001837', ('125', '128'))
159588	33557266	Many p53 mutants, such as p53-V157F, R158L, R273L, H193R, G245S, R248W, R273C, R273H, and R248Q, appear to augment the correlation between NOX4 with key EMT markers such as collagens (COL1A2, COL3A1, COL5A2), metalloproteases (MMP2, MMP9) and fibronectin (FN1).	('FN1', 'Gene', (256, 259))	('correlation', 'Interaction', (119, 130))	('fibronectin', 'Gene', '2335', (243, 254))	('MMP2', 'Gene', (227, 231))	('p53', 'Gene', (26, 29))	('COL5A2', 'Gene', (200, 206))	('R248Q', 'Mutation', 'rs11540652', (90, 95))	('V157F', 'Mutation', 'rs121912654', (30, 35))	('COL3A1', 'Gene', (192, 198))	('COL1A2', 'Gene', '1278', (184, 190))	('R273H', 'Var', (79, 84))	('R248Q', 'Var', (90, 95))	('R273C', 'Mutation', 'rs121913343', (72, 77))	('MMP2', 'Gene', '4313', (227, 231))	('MMP9', 'molecular_function', 'GO:0004229', ('233', '237'))	('R248W', 'Mutation', 'rs121912651', (65, 70))	('COL1A2', 'Gene', (184, 190))	('H193R', 'Mutation', 'rs786201838', (51, 56))	('p53', 'Gene', '7157', (5, 8))	('R273L', 'Mutation', 'rs28934576', (44, 49))	('R158L', 'Mutation', 'rs587782144', (37, 42))	('H193R', 'Var', (51, 56))	('R273H', 'Mutation', 'rs28934576', (79, 84))	('fibronectin', 'Gene', (243, 254))	('FN1', 'Gene', '2335', (256, 259))	('R273C', 'Var', (72, 77))	('EMT', 'biological_process', 'GO:0001837', ('153', '156'))	('MMP9', 'Gene', '4318', (233, 237))	('MMP9', 'Gene', (233, 237))	('R248W', 'Var', (65, 70))	('R273L', 'Var', (44, 49))	('MMP2', 'molecular_function', 'GO:0004228', ('227', '231'))	('R158L', 'Var', (37, 42))	('p53', 'Gene', (5, 8))	('G245S', 'Mutation', 'rs28934575', (58, 63))	('COL5A2', 'Gene', '1290', (200, 206))	('augment', 'PosReg', (107, 114))	('p53', 'Gene', '7157', (26, 29))	('COL3A1', 'Gene', '1281', (192, 198))	('G245S', 'Var', (58, 63))
159589	33557266	Further, when we collapsed the p53 mutants we studied into a single group, the increases in rho of NOX4 and several EMT genes were still apparent, e.g., collagens, MMP2/9, and SNAI1/2 transcription factors (Figure 6B).	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('SNAI1/2', 'Gene', '6615;6591', (176, 183))	('MMP2/9', 'Gene', '4313;4318', (164, 170))	('NOX4', 'Gene', (99, 103))	('rho', 'MPA', (92, 95))	('mutants', 'Var', (35, 42))	('EMT genes', 'Gene', (116, 125))	('increases', 'PosReg', (79, 88))	('MMP2/9', 'Gene', (164, 170))	('EMT', 'biological_process', 'GO:0001837', ('116', '119'))	('transcription', 'biological_process', 'GO:0006351', ('184', '197'))	('collagens', 'MPA', (153, 162))	('SNAI1/2', 'Gene', (176, 183))	('MMP2', 'molecular_function', 'GO:0004228', ('164', '168'))
159590	33557266	So far, we have shown the involvement of NOX4 in cancer progression and how TP53 mutations affect NOX4 expression and its correlation with key EMT signatures, but how these factors influence clinical parameters is unknown.	('NOX4', 'Gene', (98, 102))	('EMT', 'biological_process', 'GO:0001837', ('143', '146'))	('correlation', 'Interaction', (122, 133))	('involvement', 'Reg', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('expression', 'MPA', (103, 113))	('affect', 'Reg', (91, 97))	('TP53', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
159592	33557266	We classified patients' tumors as either having WT-TP53 or Mut-TP53 and estimated the patient survival probability in relation to NOX4 levels using Kaplan-Meier plots and calculated the p-value using the non-parametric Log-Rank tests.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('Mut-TP53', 'Var', (59, 67))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('patient', 'Species', '9606', (86, 93))	('patient', 'Species', '9606', (14, 21))	('patients', 'Species', '9606', (14, 22))
159595	33557266	In contrast, in patients with Mut-TP53, the median survival is reversed:about four years longer with low NOX4 expression.	('low', 'NegReg', (101, 104))	('longer', 'PosReg', (89, 95))	('patients', 'Species', '9606', (16, 24))	('NOX4', 'Protein', (105, 109))	('Mut-TP53', 'Var', (30, 38))
159599	33557266	In tumor samples with Mut-TP53, NOX4 overexpression is positively correlated with proliferation markers such as proliferating cell nuclear antigen (PCNA) and cyclin-dependent kinase 1 (CDK1, Figure 8A), and negatively correlated with apoptosis-related markers such as Bcl-associated agonist of cell death (BAD), caspase 9 (CASP9), tyrosine-protein kinase ABL1 (ABL1), and TP53-binding protein 1 (TP53BP1) (Figure 8B).	('PCNA', 'Gene', '5111', (148, 152))	('caspase 9', 'Gene', (312, 321))	('TP53-binding protein 1', 'Gene', '7158', (372, 394))	('correlated', 'Reg', (218, 228))	('ABL1', 'Gene', '25', (361, 365))	('cell death', 'biological_process', 'GO:0008219', ('294', '304'))	('CASP9', 'Gene', '842', (323, 328))	('proliferating cell nuclear antigen', 'Gene', (112, 146))	('cyclin-dependent kinase 1', 'Gene', (158, 183))	('tyrosine-protein kinase ABL1', 'Gene', '25', (331, 359))	('tumor', 'Disease', (3, 8))	('proliferating cell nuclear antigen', 'molecular_function', 'GO:0003892', ('112', '146'))	('caspase 9', 'Gene', '842', (312, 321))	('TP53BP1', 'Gene', '7158', (396, 403))	('binding', 'molecular_function', 'GO:0005488', ('377', '384'))	('CDK1', 'Gene', (185, 189))	('CDK1', 'Gene', '983', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('NOX4', 'Gene', (32, 36))	('TP53BP1', 'Gene', (396, 403))	('ABL1', 'Gene', (355, 359))	('CDK', 'molecular_function', 'GO:0004693', ('185', '188'))	('PCNA', 'molecular_function', 'GO:0003892', ('148', '152'))	('negatively', 'NegReg', (207, 217))	('PCNA', 'Gene', (148, 152))	('TP53-binding protein 1', 'Gene', (372, 394))	('Mut-TP53', 'Var', (22, 30))	('cyclin', 'molecular_function', 'GO:0016538', ('158', '164'))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('protein', 'cellular_component', 'GO:0003675', ('385', '392'))	('proliferating cell nuclear antigen', 'Gene', '5111', (112, 146))	('ABL1', 'Gene', '25', (355, 359))	('protein', 'cellular_component', 'GO:0003675', ('340', '347'))	('tyrosine-protein kinase ABL1', 'Gene', (331, 359))	('apoptosis', 'biological_process', 'GO:0097194', ('234', '243'))	('ABL1', 'Gene', (361, 365))	('apoptosis', 'biological_process', 'GO:0006915', ('234', '243'))	('cyclin-dependent kinase 1', 'Gene', '983', (158, 183))	('CASP9', 'Gene', (323, 328))
159601	33557266	Previously, our lab has demonstrated that TGF-beta-induced NOX4-dependent EMT is modulated by TP53 status; WT-p53 suppresses whereas several mutant forms of p53 augment NOX4 expression and NOX4-dependent cell migration in vitro.	('NOX4', 'Enzyme', (169, 173))	('p53', 'Gene', '7157', (157, 160))	('p53', 'Gene', (110, 113))	('augment', 'PosReg', (161, 168))	('mutant', 'Var', (141, 147))	('expression', 'MPA', (174, 184))	('EMT', 'biological_process', 'GO:0001837', ('74', '77'))	('p53', 'Gene', '7157', (110, 113))	('NOX4-dependent cell migration', 'CPA', (189, 218))	('cell migration', 'biological_process', 'GO:0016477', ('204', '218'))	('p53', 'Gene', (157, 160))	('suppresses', 'NegReg', (114, 124))
159607	33557266	Our preliminary analysis of data in TCGA indicated that NOX4 transcript levels are elevated in human primary breast, pancreatic, and head and neck tumors detected with several common TP53 hotspot mutations.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('human', 'Species', '9606', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('head and neck tumors', 'Phenotype', 'HP:0012288', (133, 153))	('neck', 'cellular_component', 'GO:0044326', ('142', '146'))	('neck tumors', 'Disease', (142, 153))	('NOX4 transcript levels', 'MPA', (56, 78))	('neck tumors', 'Disease', 'MESH:D006258', (142, 153))	('elevated', 'PosReg', (83, 91))	('pancreatic', 'Disease', (117, 127))	('mutations', 'Var', (196, 205))
159616	33557266	We uncovered that most common TP53 hotspot mutations generally strengthen the correlation of NOX4 with the EMT genetic program, and this effect was still seen when gene expression profiles from all tumors with TP53 mutations were merged together and compared as a group vs. WT-TP53 tumors (Figure 6).	('TP53', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('TP53', 'Gene', (210, 214))	('tumors', 'Disease', (282, 288))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('gene expression', 'biological_process', 'GO:0010467', ('164', '179'))	('mutations', 'Var', (215, 224))	('NOX4', 'Gene', (93, 97))	('mutations', 'Var', (43, 52))	('strengthen', 'PosReg', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('correlation', 'MPA', (78, 89))	('EMT', 'biological_process', 'GO:0001837', ('107', '110'))
159617	33557266	More importantly, TP53 mutation status alters survival outcome based on NOX4 expression: increased NOX4 expression is protective in patients with WT-TP53 tumors but deleterious in patients with Mut-TP53 (Figure 7).	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('NOX4', 'Enzyme', (99, 103))	('expression', 'MPA', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('Mut-TP53', 'Var', (194, 202))	('increased', 'PosReg', (89, 98))	('patients', 'Species', '9606', (132, 140))	('patients', 'Species', '9606', (180, 188))
159618	33557266	Together, this suggests the mechanisms and targets of NOX4-generated ROS are dependent on TP53 mutation status.	('ROS', 'Chemical', 'MESH:D017382', (69, 72))	('TP53', 'Gene', (90, 94))	('mutation', 'Var', (95, 103))
159620	33557266	Here, we found that in patients with Mut-TP53, increases in NOX4 expression are directly associated with decreases in key apoptotic markers and increases in proliferation markers, whereas the opposite trends were found in patients with WT-TP53 (Figure 8).	('increases', 'PosReg', (144, 153))	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (222, 230))	('key apoptotic markers', 'MPA', (118, 139))	('expression', 'MPA', (65, 75))	('Mut-TP53', 'Var', (37, 45))	('proliferation markers', 'CPA', (157, 178))	('increases', 'PosReg', (47, 56))	('decreases', 'NegReg', (105, 114))	('NOX4', 'Gene', (60, 64))
159623	33557266	The effects of NOX4 are altered under the influence of WT versus Mut-p53, suggesting mutations in TP53 switch downstream signaling targets to enhance cancer cell dissemination and proliferation via NOX4-generated ROS (Figure 9).	('ROS', 'Chemical', 'MESH:D017382', (213, 216))	('signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('proliferation', 'CPA', (180, 193))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('mutations', 'Var', (85, 94))	('enhance', 'PosReg', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('TP53', 'Gene', (98, 102))
159632	33557266	Later studies using NOX4 silencing or inhibition approaches suggested that fibroblastic NOX4 could limit the accessibility of CD8+ T-cells to the intratumoral microenvironment.	('silencing', 'Var', (25, 34))	('accessibility', 'MPA', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('limit', 'NegReg', (99, 104))	('CD8', 'Gene', (126, 129))	('tumor', 'Disease', (151, 156))	('CD8', 'Gene', '925', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
159636	33557266	In summary, our Pan-Cancer analysis of human tumor data indicates NOX4 can contribute to several gene expression programs that promote cancer progression in many tumor types with common TP53 mutations, and that TP53 mutations could "switch" NOX4 from being protective and an indicator of good prognosis to deleterious outcomes of cancer progression.	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (45, 50))	('TP53', 'Gene', (211, 215))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('cancer', 'Disease', (135, 141))	('promote', 'PosReg', (127, 134))	('mutations', 'Var', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('TP53', 'Gene', (186, 190))	('human', 'Species', '9606', (39, 44))	('gene expression', 'biological_process', 'GO:0010467', ('97', '112'))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Disease', (330, 336))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('Cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (216, 225))
159637	33557266	Therapeutic strategies targeting NOX4 or the ROS it generates should take into consideration TP53 mutation status, as NOX4 may provide patient survival benefits in the presence of WT-p53 but may represent a worthwhile target in advanced cancers with mutated p53.	('patient', 'Species', '9606', (135, 142))	('p53', 'Gene', (258, 261))	('benefits', 'PosReg', (152, 160))	('p53', 'Gene', '7157', (258, 261))	('ROS', 'Chemical', 'MESH:D017382', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('p53', 'Gene', (183, 186))	('p53', 'Gene', '7157', (183, 186))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('mutated', 'Var', (250, 257))	('cancers', 'Disease', (237, 244))	('cancers', 'Disease', 'MESH:D009369', (237, 244))
159679	33613113	Moreover, the results of the receiver operating characteristic curve (ROC) analysis showed that plasma has_circ_0001445 could be used as a more accurate marker to distinguish HCC cases from healthy people, cirrhosis, or hepatitis B patients.	('HCC', 'Gene', (175, 178))	('cirrhosis', 'Disease', (206, 215))	('patients', 'Species', '9606', (232, 240))	('has_circ_0001445', 'Var', (103, 119))	('ROC', 'Chemical', '-', (70, 73))	('people', 'Species', '9606', (198, 204))	('hepatitis B', 'Disease', 'MESH:D006509', (220, 231))	('HCC', 'Gene', '619501', (175, 178))	('cirrhosis', 'Phenotype', 'HP:0001394', (206, 215))	('hepatitis B', 'Disease', (220, 231))	('cirrhosis', 'Disease', 'MESH:D005355', (206, 215))	('hepatitis', 'Phenotype', 'HP:0012115', (220, 229))
159680	33613113	Similar studies also performed by detecting low expression of has_circ_0000190 detected in the serum of gastric cancer by Chen et al.	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('expression', 'MPA', (48, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('has_circ_0000190', 'Var', (62, 78))	('gastric cancer', 'Disease', (104, 118))
159683	33613113	identified that the expression of has_circ_0006848 in plasma was significantly inhibited in patients with early gastric cancer compared with healthy volunteers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('expression', 'MPA', (20, 30))	('gastric cancer', 'Disease', 'MESH:D013274', (112, 126))	('gastric cancer', 'Disease', (112, 126))	('patients', 'Species', '9606', (92, 100))	('inhibited', 'NegReg', (79, 88))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))	('has_circ_0006848', 'Var', (34, 50))
159688	33613113	The differential expression of circRNA had a diagnostic value for oral squamous cell carcinoma, in which the AUC value of has_circ_0001874 was the highest; the diagnostic accuracy of the combined diagnosis of has_circ_0001874 and has_circ_0001971 was additionally enhanced.	('has_circ_0001874', 'Var', (122, 138))	('has_circ_0001874', 'Var', (209, 225))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('oral squamous cell carcinoma', 'Disease', (66, 94))	('enhanced', 'PosReg', (264, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('has_circ_0001971', 'Var', (230, 246))
159712	33613113	Prior to this, studies have reported that in breast cancer epithelial cells, inhibition of IGF-1R increases cell stress, CC motif chemokine ligand 2 (CCL2), IL-10, and IL-6, and reduces TNF-alpha.	('reduces', 'NegReg', (178, 185))	('CCL2', 'Gene', (150, 154))	('CC motif chemokine ligand 2', 'Gene', (121, 148))	('IL-6', 'molecular_function', 'GO:0005138', ('168', '172'))	('IL-10', 'molecular_function', 'GO:0005141', ('157', '162'))	('increases', 'PosReg', (98, 107))	('IL-10', 'Gene', '3586', (157, 162))	('CC motif chemokine ligand 2', 'Gene', '6347', (121, 148))	('IL-10', 'Gene', (157, 162))	('TNF-alpha', 'Gene', '7124', (186, 195))	('TNF-alpha', 'Gene', (186, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('CCL2', 'Gene', '6347', (150, 154))	('stress', 'Disease', 'MESH:D000079225', (113, 119))	('CCL', 'molecular_function', 'GO:0044101', ('150', '153'))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('stress', 'Disease', (113, 119))	('IL-6', 'Gene', '3569', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('inhibition', 'Var', (77, 87))	('ligand', 'molecular_function', 'GO:0005488', ('140', '146'))	('IGF-1R', 'Gene', (91, 97))	('IGF-1R', 'Gene', '3480', (91, 97))	('IL-6', 'Gene', (168, 172))
159715	33613113	Circ-0008433 regulates the expression of matrix metallopeptidase 2 (MMP2) by competitively binding to miR-181c-5p and miR-181b-5p, which further recruits NK cells to attack arterial elastic fibers, remodel blood vessels, and promote the progression of aneurysms (Figure 2C).	('miR-181c', 'Gene', '406957', (102, 110))	('recruits', 'PosReg', (145, 153))	('miR-181b-5p', 'Var', (118, 129))	('MMP2', 'Gene', '4313', (68, 72))	('aneurysms', 'Disease', 'MESH:D000783', (252, 261))	('progression', 'CPA', (237, 248))	('matrix metallopeptidase 2', 'Gene', '4313', (41, 66))	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))	('aneurysms', 'Disease', (252, 261))	('binding', 'Interaction', (91, 98))	('MMP2', 'Gene', (68, 72))	('MMP2', 'molecular_function', 'GO:0004228', ('68', '72'))	('aneurysms', 'Phenotype', 'HP:0002617', (252, 261))	('promote', 'PosReg', (225, 232))	('miR-181c', 'Gene', (102, 110))	('matrix metallopeptidase 2', 'Gene', (41, 66))
159722	33613113	found that knock out circUHRF1 in HCC cells improved the sensitivity of anti-PD-1 treatment and improved the overall survival rate of patients (Figure 2D), suggesting that exosomal circUHRF1 may lead to resistance to anti-PD-1 immunotherapy and provide a potential treatment strategy for patients with HCC.	('improved', 'PosReg', (96, 104))	('HCC', 'Gene', (34, 37))	('patients', 'Species', '9606', (134, 142))	('sensitivity', 'MPA', (57, 68))	('circUHRF1', 'Gene', (21, 30))	('HCC', 'Gene', '619501', (302, 305))	('PD-1', 'Gene', '9825', (222, 226))	('lead to', 'Reg', (195, 202))	('knock out', 'Var', (11, 20))	('HCC', 'Gene', (302, 305))	('PD-1', 'Gene', '9825', (77, 81))	('patients', 'Species', '9606', (288, 296))	('improved', 'PosReg', (44, 52))	('exosomal circUHRF1', 'Var', (172, 190))	('PD-1', 'Gene', (222, 226))	('resistance', 'CPA', (203, 213))	('circUHRF1', 'Var', (181, 190))	('HCC', 'Gene', '619501', (34, 37))	('PD-1', 'Gene', (77, 81))
159731	33613113	found that knock down of lncRNA UCA1 in serum exosomes blocked the mitogen-activated protein kinase (MAPK) signaling pathway, and up-regulated the expression of circHIPK3.	('knock down', 'Var', (11, 21))	('MAPK', 'molecular_function', 'GO:0004707', ('101', '105'))	('UCA1', 'Gene', '652995', (32, 36))	('UCA1', 'Gene', (32, 36))	('expression', 'MPA', (147, 157))	('up-regulated', 'PosReg', (130, 142))	('signaling pathway', 'biological_process', 'GO:0007165', ('107', '124'))	('circHIPK3', 'Gene', (161, 170))	('blocked', 'NegReg', (55, 62))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('101', '116'))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
159735	33613113	Survival analysis showed that the expression of circ-IARS negatively correlated with the survival time of patients with pancreatic cancer, suggesting that circ-IARS in serum exosomes may be a non-invasive biomarker for early diagnosis and prognosis of pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (252, 269))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('circ-IARS', 'Var', (155, 164))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('pancreatic cancer', 'Disease', 'MESH:D010190', (252, 269))	('pancreatic cancer', 'Disease', (252, 269))	('negatively', 'NegReg', (58, 68))	('pancreatic cancer', 'Disease', (120, 137))
159736	33613113	found that the expression of exosomal circPDE8A in plasma was related to the progression and prognosis of PDAC patients, suggesting that exosomal circPDE8A may be an important indicator for early diagnosis and prognosis of PDAC.	('PDAC', 'Disease', (223, 227))	('PDAC', 'Disease', (106, 110))	('related', 'Reg', (62, 69))	('exosomal', 'Var', (137, 145))	('patients', 'Species', '9606', (111, 119))
159739	33613113	found that the expression levels of has_circ_0109046 and has_circ_0002577 in the serum exosomes of patients with endometrial cancer increased dramatically, indicating their potential as blood diagnostic markers for endometrial cancer.	('endometrial cancer', 'Disease', 'MESH:D016889', (215, 233))	('endometrial cancer', 'Phenotype', 'HP:0012114', (113, 131))	('has_circ_0002577', 'Var', (57, 73))	('endometrial cancer', 'Disease', 'MESH:D016889', (113, 131))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('increased', 'PosReg', (132, 141))	('patients', 'Species', '9606', (99, 107))	('expression levels', 'MPA', (15, 32))	('has_circ_0109046', 'Var', (36, 52))	('endometrial cancer', 'Disease', (215, 233))	('endometrial cancer', 'Disease', (113, 131))	('endometrial cancer', 'Phenotype', 'HP:0012114', (215, 233))
159749	33613113	Similar studies have found that has_circ_0010522 can promote white fat browning, and that its expression level in gastric cancer plasma is positively correlated with white fat browning.	('fat browning', 'Phenotype', 'HP:0031622', (172, 184))	('gastric cancer', 'Disease', (114, 128))	('white fat browning', 'MPA', (61, 79))	('has_circ_0010522', 'Var', (32, 48))	('expression level', 'MPA', (94, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('fat browning', 'Phenotype', 'HP:0031622', (67, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('correlated', 'Reg', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('promote', 'PosReg', (53, 60))
159794	31923345	Although these advances resulted in more refined diagnoses and classifications of glioma tumors, integrating histological and molecular information (e.g., IDH1/2 mutations and 1p/19q codeletion) (Louis et al., 2016), significant improvements in therapies that truly impact on patient outcomes are still lacking.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('mutations', 'Var', (162, 171))	('IDH1/2', 'Gene', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('IDH1/2', 'Gene', '3417;3418', (155, 161))	('glioma tumors', 'Disease', (82, 95))	('glioma tumors', 'Disease', 'MESH:D005910', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('patient', 'Species', '9606', (276, 283))
159796	31923345	Functionally, WNT6 expression was associated with increased GBM cell viability, proliferation, invasion, migration, resistance to TMZ, and stemness capacity (Goncalves et al., 2018).	('resistance to TMZ', 'CPA', (116, 133))	('invasion', 'CPA', (95, 103))	('stemness capacity', 'CPA', (139, 156))	('GBM', 'Phenotype', 'HP:0012174', (60, 63))	('proliferation', 'CPA', (80, 93))	('increased', 'PosReg', (50, 59))	('expression', 'Var', (19, 29))	('GBM cell viability', 'CPA', (60, 78))	('migration', 'CPA', (105, 114))	('TMZ', 'Chemical', 'MESH:D000077204', (130, 133))	('WNT6', 'Gene', (14, 18))
159797	31923345	In vivo, WNT6 accelerated GBM-associated death in mice.	('GBM', 'Phenotype', 'HP:0012174', (26, 29))	('WNT6', 'Var', (9, 13))	('death', 'Disease', 'MESH:D003643', (41, 46))	('death', 'Disease', (41, 46))	('mice', 'Species', '10090', (50, 54))	('accelerated', 'PosReg', (14, 25))
159801	31923345	Agilent G4502A 244K data were used for LGG and GBM (WNT6 and HOXA9-high expression was considered when TCGA level 3 value >= 0 [GBM median value] or 3, respectively), while RNAseq data (Illumina HiSeq 2000 Sequencing System) were downloaded for all cancers (WNT6-high expression was considered when TCGA FPKM-UQ value >= 6800 [GBM median value]) (The Cancer Genome Atlas Research Network, 2008).	('G4502A', 'Var', (8, 14))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('GBM', 'Phenotype', 'HP:0012174', (47, 50))	('cancers', 'Disease', (249, 256))	('Cancer', 'Disease', (351, 357))	('G4502A', 'SUBSTITUTION', 'None', (8, 14))	('Cancer', 'Disease', 'MESH:D009369', (351, 357))	('Cancer', 'Phenotype', 'HP:0002664', (351, 357))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('GBM', 'Phenotype', 'HP:0012174', (327, 330))
159836	31923345	For beta-catenin IF (610153; BD Transduction Laboratories, San Jose, CA, USA, 1 : 200), U87-MSCV and U87-HOXA9 cells plated on coverslips were fixed in 95% EtOH and 5% acetic acid (v/v), followed by incubation in 1% BSA in PBS-0.1% Tween for 1 h, and overnight at 4  C with the primary antibody.	('Tween', 'Chemical', 'MESH:D011136', (232, 237))	('antibody', 'cellular_component', 'GO:0019815', ('286', '294'))	('610153;', 'Var', (21, 28))	('Transduction', 'biological_process', 'GO:0009293', ('32', '44'))	('antibody', 'cellular_component', 'GO:0019814', ('286', '294'))	('EtOH', 'Chemical', 'MESH:D000431', (156, 160))	('acetic acid', 'Chemical', 'MESH:D019342', (168, 179))	('antibody', 'molecular_function', 'GO:0003823', ('286', '294'))	('PBS', 'Chemical', 'MESH:D007854', (223, 226))	('MSCV', 'Species', '258023', (92, 96))	('beta-catenin', 'Protein', (4, 16))	('antibody', 'cellular_component', 'GO:0042571', ('286', '294'))
159856	31923345	Together, these results show that high WNT6 expression associates with higher glioma grades independently of IDH mutation and 1p/19q codeletion status.	('higher', 'PosReg', (71, 77))	('IDH', 'Gene', '3417', (109, 112))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('WNT6', 'Gene', (39, 43))	('high', 'Var', (34, 38))	('glioma', 'Disease', (78, 84))	('IDH', 'Gene', (109, 112))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
159857	31923345	To understand the mechanisms responsible for WNT6 overexpression in glioma, we started by investigating copy number alterations of the WNT6 locus in LGG (n = 509) and GBM (n = 565) patients from TCGA (Fig.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('WNT6', 'Gene', (135, 139))	('GBM', 'Phenotype', 'HP:0012174', (167, 170))	('copy number alterations', 'Var', (104, 127))	('patients', 'Species', '9606', (181, 189))	('glioma', 'Disease', (68, 74))
159865	31923345	Interestingly, looking for the 28 DNA methylation sites within the WNT6 locus, in 516 LGG and 141 GBM patients, we identified regions that are consistently hypomethylated (e.g., from the 4th probe [cg16256504] to the 8th probe [cg02175741]) or hypermethylated (e.g., 16th probe [cg05618201]) both in LGG and in GBM (Figs 2A and S2), showing a remarkable homogeneity of DNA methylation levels of these particular regions across very heterogeneous glioma samples of different grades.	('GBM', 'Phenotype', 'HP:0012174', (311, 314))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('patients', 'Species', '9606', (102, 110))	('glioma', 'Disease', 'MESH:D005910', (446, 452))	('glioma', 'Phenotype', 'HP:0009733', (446, 452))	('[cg16256504]', 'Var', (197, 209))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('DNA methylation', 'biological_process', 'GO:0006306', ('369', '384'))	('DNA methylation', 'biological_process', 'GO:0006306', ('34', '49'))	('[cg02175741]', 'Var', (227, 239))	('DNA', 'cellular_component', 'GO:0005574', ('369', '372'))	('glioma', 'Disease', (446, 452))
159869	31923345	MSP analyses showed that five of the seven cell lines presented 5-Aza-mediated demethylation (A172, SNB19, KNS42, SW1783, and Res186; Fig.	('5-Aza', 'Chemical', 'MESH:D000077209', (64, 69))	('demethylation', 'biological_process', 'GO:0070988', ('79', '92'))	('A172', 'Var', (94, 98))	('SW1783', 'CellLine', 'CVCL:1722', (114, 120))	('SNB19', 'Var', (100, 105))	('SW1783', 'Var', (114, 120))	('5-Aza-mediated demethylation', 'MPA', (64, 92))
159870	31923345	Interestingly, 5-Aza treatment successfully increased WNT6 expression in four of these five cell lines (fold changes between 1.7 and 3.15; for KNS42, SW1783, A172, and Res186).	('WNT6 expression', 'MPA', (54, 69))	('increased', 'PosReg', (44, 53))	('5-Aza', 'Chemical', 'MESH:D000077209', (15, 20))	('SW1783', 'CellLine', 'CVCL:1722', (150, 156))	('SW1783', 'Var', (150, 156))
159879	31923345	Interestingly, when performing GSEA to identify transcriptomic signatures reminiscent of WNT6-associated genes in GBM patients (Goncalves et al., 2018), we found that WNT6-negatively correlated genes were enriched for genes upregulated in LAML cells upon HOXA9 knockdown [enrichment score (ES) = -0.26 and false discovery rate, FDR = 0.18; Fig.	('knockdown', 'Var', (261, 270))	('GSEA', 'Chemical', '-', (31, 35))	('false', 'biological_process', 'GO:0071878', ('306', '311'))	('upregulated', 'PosReg', (224, 235))	('false', 'biological_process', 'GO:0071877', ('306', '311'))	('GBM', 'Phenotype', 'HP:0012174', (114, 117))	('patients', 'Species', '9606', (118, 126))
159881	31923345	This association was not only observed in vitro but also in vivo, as U87+/-HOXA9 tumors grown subcutaneously in nude mice also showed significantly higher expression of WNT6 and beta-catenin (mainly in the nucleus) in HOXA9-positive tumors when compared to HOXA9-negative tumors (Fig.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('nude mice', 'Species', '10090', (112, 121))	('WNT6', 'Protein', (169, 173))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('beta-catenin', 'Protein', (178, 190))	('higher', 'PosReg', (148, 154))	('U87+/-HOXA9', 'Var', (69, 80))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('nucleus', 'cellular_component', 'GO:0005634', ('206', '213'))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', (272, 278))	('tumors', 'Disease', (233, 239))	('HOXA9-positive', 'Var', (218, 232))	('expression', 'MPA', (155, 165))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
159882	31923345	In addition, cyclin D1, a known transcriptional target of the canonical WNT/beta-catenin pathway, was also upregulated in HOXA9-positive tumors when compared to negative tumors (Fig.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('cyclin D1', 'Gene', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('HOXA9-positive', 'Var', (122, 136))	('cyclin', 'molecular_function', 'GO:0016538', ('13', '19'))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('cyclin D1', 'Gene', '595', (13, 22))	('upregulated', 'PosReg', (107, 118))	('tumors', 'Disease', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
159886	31923345	Thus, the clinical impact of WNT6 in GBM was evaluated using a multivariable Cox model to adjust to potential confounding effects of other putative prognostic factors, namely patient age, KPS, gender, therapy, IDH mutation status, and HOXA9 expression (Tables 2 and S2).	('GBM', 'Phenotype', 'HP:0012174', (37, 40))	('mutation', 'Var', (214, 222))	('IDH', 'Gene', '3417', (210, 213))	('patient', 'Species', '9606', (175, 182))	('IDH', 'Gene', (210, 213))
159888	31923345	Importantly, IDHwt GBM patients with both WNT6-high and HOXA9-high expression presented a shorter OS (median OS = 290 days) when compared to all other patients (median OS = 425; log-rank P = 0.002; Fig.	('IDH', 'Gene', '3417', (13, 16))	('GBM', 'Phenotype', 'HP:0012174', (19, 22))	('patients', 'Species', '9606', (23, 31))	('shorter', 'NegReg', (90, 97))	('patients', 'Species', '9606', (151, 159))	('HOXA9-high expression', 'Var', (56, 77))	('IDH', 'Gene', (13, 16))
159899	31923345	In contrast, our findings demonstrated that DNA methylation, a critical epigenetic mechanism, associates with WNT6 expression levels in glioma (Figs 2, S2 and S3), similarly to what was observed for other WNT ligands in other cancer types (Carmona et al., 2013; Jung et al., 2015; Kim et al., 2015a; Liu et al., 2016; Xu et al., 2005).	('WNT6', 'Gene', (110, 114))	('DNA', 'MPA', (44, 47))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('cancer', 'Disease', (226, 232))	('glioma', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('methylation', 'Var', (48, 59))	('DNA methylation', 'biological_process', 'GO:0006306', ('44', '59'))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
159901	31923345	Interestingly, most of the CpG sites are more frequently methylated in LGG than GBM patients (19 out of 28; Fig.	('GBM', 'Phenotype', 'HP:0012174', (80, 83))	('LGG', 'Disease', (71, 74))	('methylated', 'Var', (57, 67))	('patients', 'Species', '9606', (84, 92))
159903	31923345	Although DNA methylation was clearly associated with WNT6 expression in glioma, this association was not universal.	('glioma', 'Disease', (72, 78))	('methylation', 'Var', (13, 24))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('WNT6', 'Gene', (53, 57))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('associated', 'Reg', (37, 47))	('DNA', 'MPA', (9, 12))
159913	31923345	Interestingly, WNT6 was also shown to be associated with shorter survival in LGG patients (Dao Trong et al., 2018), where HOXA9 overexpression is not frequent (Pojo et al., 2015).	('patients', 'Species', '9606', (81, 89))	('WNT6', 'Var', (15, 19))	('LGG', 'Disease', (77, 80))	('survival', 'MPA', (65, 73))	('shorter', 'NegReg', (57, 64))
159921	29057889	The numbers of tumor driver mutations are differentiated (p < 0.05) over the racial groups in five cancers, such as lung adenocarcinoma.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (116, 135))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('cancers', 'Disease', (99, 106))	('tumor', 'Disease', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('lung adenocarcinoma', 'Disease', (116, 135))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (116, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('mutations', 'Var', (28, 37))
159922	29057889	By treating a specific cancer type and a racial group as an "experimental unit", driver mutation numbers demonstrate a significant (r = 0.46, p < 0.002) positive correlation with cancer incidence rates, especially when the five cancers with mutational disparities are exclusively focused (r = 0.88, p < 0.00002).	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('mutation', 'Var', (88, 96))	('cancers', 'Disease', (228, 235))	('cancer', 'Disease', (228, 234))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
159930	29057889	reported that racial differences in TP53 mutation, PAM50 basal subtype and triple-negative tumor prevalence influence the magnitude and significance of racial disparity in tumor recurrence of breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (172, 177))	('breast cancer', 'Disease', (192, 205))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('TP53', 'Gene', '7157', (36, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('mutation', 'Var', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TP53', 'Gene', (36, 40))	('influence', 'Reg', (108, 117))
159932	29057889	They further found that a novel deletion of the LSAMP locus, as a prevalent genomic alteration in AA CaP, was associated with rapid disease progression.	('associated with', 'Reg', (110, 125))	('deletion', 'Var', (32, 40))	('LSAMP', 'Gene', (48, 53))	('LSAMP', 'Gene', '4045', (48, 53))
159968	29057889	As shown in Table 2, racial disparities (p < 0.05) are observed in five cancer types regarding the mutations present in the pcDriver genes.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pcDriver', 'Gene', (124, 132))	('mutations', 'Var', (99, 108))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
159971	29057889	On the other hand, white patients suffer more mutations than black patients for UCEC and KIRP.	('mutations', 'Var', (46, 55))	('UCEC', 'Disease', (80, 84))	('patients', 'Species', '9606', (67, 75))	('suffer', 'Reg', (34, 40))	('patients', 'Species', '9606', (25, 33))	('KIRP', 'Disease', (89, 93))
159977	29057889	The association between cancer incidence rate and the number of mutations in the pan-cancer driver (pcDriver) genes or the log2 transformed number of mutations in the HOGO genes is estimated by the Pearson correlation (r).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('pcDriver', 'Gene', (100, 108))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', (85, 91))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
159980	29057889	3) largely confirm the positive association between cancer incidence and mutation burden observed in AS-1.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mutation', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (52, 58))
159987	29057889	In this regard, the number of mutations in pcDriver genes in a tumor should be considered as an estimate (or a representative metric) of its driver mutation burden.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mutations', 'Var', (30, 39))	('pcDriver genes', 'Gene', (43, 57))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
159988	29057889	Of the total 33400 non-synonymous pcDriver gene mutations in all 4839 tumor samples analyzed in this study, 29623 (amounting to 88.7%) are single nucleotide variations (SNVs).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('pcDriver gene', 'Gene', (34, 47))	('tumor', 'Disease', (70, 75))	('29623', 'Var', (108, 113))	('single nucleotide variations', 'Var', (139, 167))	('mutations', 'Var', (48, 57))
159992	29057889	The mutations not occurring in cancer driver genes are typically known as passenger mutations.	('mutations', 'Var', (4, 13))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))
160001	29057889	In this study, we found that the numbers of tumor driver mutations are differentiated (p < 0.05) over the racial groups in five cancers.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mutations', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
160007	29057889	This association seems to deviate from the well-known perception that relates cancer incidence rate to the total number of (driver) mutations that can be accumulated in a tissue during the lifespan of a person.	('mutations', 'Var', (132, 141))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('person', 'Species', '9606', (203, 209))
160009	29057889	A potential explanation for the paradox is that: the requirement for driver mutations to develop cancer in a tissue with a large population of stem cells (and/or being readily subject to mutagens) could be relatively high but the precancerous cells meeting the threshold in such a tissue still outnumber the precancerous cells in a "smaller" (and/or "safe") tissue.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('mutations', 'Var', (76, 85))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
160016	26261759	A total of 51 male patients with cTa-4N0-2M0 bladder cancer were treated with anterior urethra sparing cystoprostatectomy and simultaneous urinary diversion between 2000 and 2013, and underwent follow up for 4 months or more.	('patients', 'Species', '9606', (19, 27))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cTa-4N0-2M0', 'Var', (33, 44))	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('bladder cancer', 'Disease', (45, 59))
160033	26261759	Ultimately, a study population of 51 males with cTa-4N0-2M0 bladder cancer undergoing anterior urethra sparing cystoprostatectomy and simultaneous urinary diversion was eligible for analysis.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('bladder cancer', 'Disease', 'MESH:D001749', (60, 74))	('cTa-4N0-2M0', 'Var', (48, 59))	('bladder cancer', 'Disease', (60, 74))
160106	31929742	Mutations in tumor cells can be transcribed and translated, and may form new antigens can be identified and targeted by the immune system.	('tumor', 'Disease', (13, 18))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
160107	31929742	The more tumor mutations, the more antigens it may form.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', (9, 14))	('antigens', 'MPA', (35, 43))
160120	31929742	C > T transversion is the most common type of SNV in bladder cancer (Figure 1C).	('bladder cancer', 'Disease', 'MESH:D001749', (53, 67))	('bladder cancer', 'Disease', (53, 67))	('C > T transversion', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('bladder cancer', 'Phenotype', 'HP:0009725', (53, 67))
160124	31929742	Kaplan-Meier survival analysis revealed that patients with high TMB had a higher survival rate than those with low TMB (Figure 2A).	('patients', 'Species', '9606', (45, 53))	('high', 'Var', (59, 63))	('survival rate', 'CPA', (81, 94))	('higher', 'PosReg', (74, 80))
160127	31929742	In BP category, "cell chemotaxis", "lymphocyte chemotaxis" and "regulation of ion transmembrane transport" were enriched, which means the DEGs affects the consists of immune cells in tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('affects', 'Reg', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('DEGs', 'Var', (138, 142))
160128	31929742	We also performed KEGG pathway enrichment analysis to determine the pathways most enriched for DEGs, which included "TGF-beta signaling pathway", "chemokine signaling pathway" and "pathways in cancer" (Figure 4B).	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('DEGs', 'Var', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))
160131	31929742	The results showed that high CXCL10 expression samples were mainly enriched in natural killer cell mediated cytotoxicity, antigen processing and presentation, chemokine signaling pathway and T cell receptor signaling pathway (Figure 5B).	('CXCL10', 'Gene', (29, 35))	('T cell receptor signaling pathway', 'Pathway', (191, 224))	('cytotoxicity', 'Disease', 'MESH:D064420', (108, 120))	('natural', 'Pathway', (79, 86))	('natural killer cell mediated cytotoxicity', 'biological_process', 'GO:0042267', ('79', '120'))	('chemokine', 'Pathway', (159, 168))	('T cell receptor signaling pathway', 'biological_process', 'GO:0050852', ('191', '224'))	('antigen processing and presentation', 'biological_process', 'GO:0019882', ('122', '157'))	('high', 'Var', (24, 28))	('signaling pathway', 'biological_process', 'GO:0007165', ('169', '186'))	('cytotoxicity', 'Disease', (108, 120))	('CXCL10', 'Gene', '3627', (29, 35))
160132	31929742	Previous studies have shown that the higher mutation burden in tumors tends to form more new antigens, making tumors to have higher immunogenicity.	('mutation', 'Var', (44, 52))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', (63, 69))	('new antigens', 'MPA', (89, 101))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('immunogenicity', 'MPA', (132, 146))
160137	31929742	Genetic changes in tumors include nonsynonymous mutations, synonymous mutations, insertions or deletions, and copy number gains and losses.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('losses', 'NegReg', (132, 138))	('deletions', 'Var', (95, 104))	('nonsynonymous mutations', 'Var', (34, 57))	('synonymous mutations', 'Var', (59, 79))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('copy number gains', 'Var', (110, 127))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('insertions', 'Var', (81, 91))
160139	31929742	The genetic changes increase the tumors' immunogenic.	('genetic changes', 'Var', (4, 19))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Disease', (33, 39))	('increase', 'PosReg', (20, 28))
160165	31929742	Mast cells in the low TMB group may promote tumor growth and metastasis.	('promote', 'PosReg', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('low TMB', 'Var', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
160166	31929742	High TMB tends to cause the chemotaxis of immune cells in BLCA and the crosstalk between these cells play an important role in the growth of tumors.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('chemotaxis', 'biological_process', 'GO:0006935', ('28', '38'))	('tumors', 'Disease', (141, 147))	('High TMB', 'Var', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('BLCA', 'Disease', 'MESH:D001749', (58, 62))	('cause', 'Reg', (18, 23))	('BLCA', 'Phenotype', 'HP:0009725', (58, 62))	('BLCA', 'Disease', (58, 62))	('chemotaxis', 'CPA', (28, 38))
160167	31929742	In summary, our data implicate that higher-TMB patients could gain a more favorable prognosis in bladder cancer.	('gain', 'PosReg', (62, 66))	('bladder cancer', 'Disease', 'MESH:D001749', (97, 111))	('bladder cancer', 'Disease', (97, 111))	('patients', 'Species', '9606', (47, 55))	('higher-TMB', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))
160201	30711015	UC typically shows positivity for high-molecular-weight CK and p63 with coexpression of CK7 and CK20 in 50 to 80% of cases.	('CK20', 'Gene', (96, 100))	('positivity', 'Var', (19, 29))	('CK20', 'Gene', '54474', (96, 100))	('p63', 'Gene', (63, 66))	('CK7', 'Gene', (88, 91))	('CK7', 'Gene', '3855', (88, 91))	('p63', 'Gene', '8626', (63, 66))	('high-molecular-weight CK', 'Protein', (34, 58))
160216	28007623	Small Cell Lung Cancer Exhibits Frequent Inactivating Mutations in the Histone Methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance) SCLC is a lethal neuroendocrine tumor type that is highly prone to metastasis.	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('KMT2D', 'Gene', '8085', (97, 102))	('neuroendocrine tumor', 'Disease', (150, 170))	('MLL2', 'Gene', '8085', (103, 107))	('MLL2', 'Gene', (103, 107))	('Inactivating Mutations', 'Var', (41, 63))	('SCLC', 'Gene', (133, 137))	('Small Cell Lung Cancer', 'Disease', 'MESH:D055752', (0, 22))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (0, 22))	('Small Cell Lung Cancer', 'Disease', (0, 22))	('SCLC', 'Gene', '7864', (133, 137))	('Lung Cancer', 'Phenotype', 'HP:0100526', (11, 22))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (150, 170))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (150, 170))	('KMT2D', 'Gene', (97, 102))
160217	28007623	There is an urgency to understand the mutated genes that promote SCLC, as there are no approved targeted therapies yet available.	('promote', 'PosReg', (57, 64))	('SCLC', 'Gene', '7864', (65, 69))	('SCLC', 'Gene', (65, 69))	('mutated genes', 'Var', (38, 51))
160221	28007623	We report frequent mutations in the lysine methyltransferase 2D gene (KMT2D) (also known as MLL2), a key regulator of transcriptional enhancer function.	('methyltransferase 2', 'molecular_function', 'GO:0043851', ('43', '62'))	('MLL2', 'Gene', '8085', (92, 96))	('MLL2', 'Gene', (92, 96))	('mutations', 'Var', (19, 28))	('lysine', 'Chemical', 'MESH:D008239', (36, 42))	('KMT2D', 'Gene', (70, 75))
160222	28007623	KMT2D exhibited truncating nonsense/frameshift/splice site mutations in 8% of SCLC tumors and 17% of SCLC cell lines.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('SCLC', 'Gene', '7864', (101, 105))	('SCLC', 'Gene', (101, 105))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('KMT2D', 'Gene', (0, 5))	('SCLC', 'Gene', '7864', (78, 82))	('nonsense/frameshift/splice site mutations', 'Var', (27, 68))	('SCLC', 'Gene', (78, 82))	('SCLC tumors', 'Disease', 'MESH:D018288', (78, 89))	('SCLC tumors', 'Disease', (78, 89))
160223	28007623	We found that KMT2D mutation in human SCLC cell lines was associated with reduced lysine methyltransferase 2D protein levels and reduced monomethylation of histone H3 lysine 4, a mark associated with transcriptional enhancers.	('SCLC', 'Gene', (38, 42))	('lysine 4', 'Chemical', '-', (167, 175))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('lysine methyltransferase 2D protein levels', 'MPA', (82, 124))	('methyltransferase 2', 'molecular_function', 'GO:0043851', ('89', '108'))	('monomethylation', 'MPA', (137, 152))	('mutation', 'Var', (20, 28))	('lysine', 'Chemical', 'MESH:D008239', (167, 173))	('H3', 'Chemical', 'MESH:C012616', (164, 166))	('lysine', 'Chemical', 'MESH:D008239', (82, 88))	('human', 'Species', '9606', (32, 37))	('reduced', 'NegReg', (129, 136))	('reduced', 'NegReg', (74, 81))	('KMT2D', 'Gene', (14, 19))	('SCLC', 'Gene', '7864', (38, 42))
160224	28007623	We also found mutations in other genes associated with transcriptional enhancer control, including CREB binding protein gene (CREBBP), E1A binding protein p300 gene (EP300), and chromodomain helicase DNA binding protein 7 gene (CHD7), and we report mutations in additional chromatin remodeling genes such as polybromo 1 gene (PBRM1).	('p300', 'Gene', '2033', (155, 159))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('273', '293'))	('PBRM1', 'Gene', '55193', (326, 331))	('chromodomain helicase DNA binding protein 7', 'Gene', (178, 221))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('DNA binding', 'molecular_function', 'GO:0003677', ('200', '211'))	('DNA', 'cellular_component', 'GO:0005574', ('200', '203'))	('PBRM1', 'Gene', (326, 331))	('CREB binding protein', 'Gene', (99, 119))	('chromodomain helicase DNA binding protein 7', 'Gene', '55636', (178, 221))	('CHD7', 'Gene', (228, 232))	('CHD7', 'Gene', '55636', (228, 232))	('mutations', 'Var', (14, 23))	('binding', 'molecular_function', 'GO:0005488', ('139', '146'))	('CREB binding', 'molecular_function', 'GO:0008140', ('99', '111'))	('CREBBP', 'Gene', (126, 132))	('CREB binding protein', 'Gene', '1387', (99, 119))	('polybromo 1', 'Gene', '55193', (308, 319))	('EP300', 'Gene', '2033', (166, 171))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('mutations', 'Var', (249, 258))	('chromatin', 'cellular_component', 'GO:0000785', ('273', '282'))	('EP300', 'Gene', (166, 171))	('p300', 'Gene', (155, 159))	('CREBBP', 'Gene', '1387', (126, 132))	('polybromo 1', 'Gene', (308, 319))
160225	28007623	These data indicate that KMT2D is one of the major mutated genes in SCLC, and they point to perturbation of transcriptional enhancer control as potentially contributing to SCLC.	('SCLC', 'Gene', (172, 176))	('SCLC', 'Gene', '7864', (172, 176))	('SCLC', 'Gene', (68, 72))	('perturbation', 'Var', (92, 104))	('contributing', 'Reg', (156, 168))	('SCLC', 'Gene', '7864', (68, 72))	('KMT2D', 'Gene', (25, 30))
160228	28007623	SCLC typically arises in heavy smokers, and the first whole genome sequencing of an SCLC cell line suggested a vast smoking-induced mutational burden.	('SCLC', 'Gene', '7864', (0, 4))	('mutational', 'Var', (132, 142))	('SCLC', 'Gene', (84, 88))	('SCLC', 'Gene', '7864', (84, 88))	('SCLC', 'Gene', (0, 4))
160229	28007623	Additional genomic analyses of SCLC also revealed mutations in the CREB binding protein gene (CREBBP)/E1A binding protein p300 gene (EP300) acetyltransferases, notch 1 gene (NOTCH1), and tumor protein p73 gene (TP73), among other genes, well as amplifications including SRYbox 2 gene (SOX2).	('p300', 'Gene', (122, 126))	('SRYbox 2 gene', 'Gene', (270, 283))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('CREBBP', 'Gene', '1387', (94, 100))	('NOTCH1', 'Gene', (174, 180))	('CREB binding', 'molecular_function', 'GO:0008140', ('67', '79'))	('p300', 'Gene', '2033', (122, 126))	('CREB binding protein', 'Gene', (67, 87))	('notch 1', 'Gene', (160, 167))	('binding', 'molecular_function', 'GO:0005488', ('106', '113'))	('SCLC', 'Gene', '7864', (31, 35))	('SCLC', 'Gene', (31, 35))	('NOTCH1', 'Gene', '4851', (174, 180))	('TP73', 'Gene', '7161', (211, 215))	('SOX2', 'Gene', '6657', (285, 289))	('CREB binding protein', 'Gene', '1387', (67, 87))	('SOX2', 'Gene', (285, 289))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor protein p73', 'Gene', (187, 204))	('TP73', 'Gene', (211, 215))	('SRYbox 2 gene', 'Gene', '6657', (270, 283))	('CREBBP', 'Gene', (94, 100))	('EP300', 'Gene', '2033', (133, 138))	('EP300', 'Gene', (133, 138))	('mutations', 'Var', (50, 59))	('notch 1', 'Gene', '4851', (160, 167))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('tumor protein p73', 'Gene', '7161', (187, 204))	('acetyltransferases', 'Enzyme', (140, 158))
160241	28007623	1 and Supplementary Table 3) included nonsynonymous exonic mutations as well as intronic mutations in essential splice sites that were present in the tumor but not matched normal controls.	('nonsynonymous exonic mutations', 'Var', (38, 68))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('intronic mutations', 'Var', (80, 98))	('tumor', 'Disease', (150, 155))
160254	28007623	The antibodies H3K4me1 (Millipore, Bedford, MA) and H3K4me2 (Abcam, Cambridge, MA) were used to detect histone modifications.	('histone modifications', 'MPA', (103, 124))	('detect', 'Reg', (96, 102))	('H3', 'Chemical', 'MESH:C012616', (15, 17))	('H3K4me1', 'Var', (15, 22))	('H3', 'Chemical', 'MESH:C012616', (52, 54))	('H3K4me2', 'Var', (52, 59))
160255	28007623	Membranes were first probed with antibodies detecting histone modifications, then stripped with Restore Plus Western blot stripping buffer (Fisher Thermo Scientific, Waltham, MA), and finally probed for total H3 (Cell Signaling Technology, Danvers, MA).	('modifications', 'Var', (62, 75))	('histone', 'Protein', (54, 61))	('Signaling', 'biological_process', 'GO:0023052', ('218', '227'))	('H3', 'Chemical', 'MESH:C012616', (209, 211))
160260	28007623	Filtering for variants that were absent in the germline, removing synonymous changes, and removing variants present in the 1000 Genomes database resulted in the detection of a median of 283 protein-altering mutations in cell lines and 224 in tumors (Fig.	('protein-altering', 'NegReg', (190, 206))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('mutations', 'Var', (207, 216))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('tumors', 'Disease', (242, 248))
160262	28007623	We found that C:G>A:T transversions and C:G>T:A transitions were the most prevalent alterations in cell lines and primary tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('C:G>A:T transversions', 'Var', (14, 35))	('prevalent', 'Reg', (74, 83))	('primary tumors', 'Disease', (114, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('C:G>T:A transitions', 'Var', (40, 59))	('primary tumors', 'Disease', 'MESH:D009369', (114, 128))
160263	28007623	These alterations have been associated with carcinogens from tobacco smoke.	('associated', 'Reg', (28, 38))	('alterations', 'Var', (6, 17))	('tobacco', 'Species', '4097', (61, 68))
160264	28007623	The most frequently mutated SCLC genes in the exome analyses were RB1 (18 of 25) and TP53 (21 of 25) (Fig.	('TP53', 'Gene', (85, 89))	('SCLC', 'Gene', (28, 32))	('SCLC', 'Gene', '7864', (28, 32))	('RB1', 'Gene', '5925', (66, 69))	('TP53', 'Gene', '7157', (85, 89))	('mutated', 'Var', (20, 27))	('RB1', 'Gene', (66, 69))
160266	28007623	The RB1 mutations included insertions/deletions, nonsense, and essential splice site mutations.	('insertions/deletions', 'Var', (27, 47))	('nonsense', 'Var', (49, 57))	('RB1', 'Gene', '5925', (4, 7))	('mutations', 'Var', (8, 17))	('RB1', 'Gene', (4, 7))
160267	28007623	In contrast, the TP53 mutations were typically missense mutations (see Fig.	('TP53', 'Gene', '7157', (17, 21))	('missense mutations', 'Var', (47, 65))	('TP53', 'Gene', (17, 21))
160269	28007623	Focusing on genes in our exome data that harbored multiple truncating mutations, a number of known cancer genes were recurrently mutated.	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('truncating mutations', 'Var', (59, 79))
160270	28007623	NOTCH1 exhibited truncating mutations in three of 18 primary SCLCs (R938fs and splice site mutation, both A929fs and Y527X in the same sample, as well as E298X nonsense mutation).	('E298X', 'Mutation', 'p.E298X', (154, 159))	('A929fs', 'Var', (106, 112))	('SCLC', 'Gene', '7864', (61, 65))	('Y527X', 'Mutation', 'p.Y527X', (117, 122))	('R938fs', 'Var', (68, 74))	('splice', 'MPA', (79, 85))	('truncating', 'MPA', (17, 27))	('NOTCH1', 'Gene', (0, 6))	('Y527X', 'Var', (117, 122))	('NOTCH1', 'Gene', '4851', (0, 6))	('A929fs', 'Mutation', 'p.A929fsX', (106, 112))	('SCLC', 'Gene', (61, 65))	('E298X', 'Var', (154, 159))	('R938fs', 'Mutation', 'p.R938fsX', (68, 74))
160271	28007623	Two primary SCLC tumors harbored nonsense mutations in the KMT2D/MLL2 histone methyltransferase (G4779X and both S2590X and Q809fs in the same sample).	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('MLL2', 'Gene', '8085', (65, 69))	('G4779X', 'Mutation', 'p.G4779X', (97, 103))	('Q809fs', 'Var', (124, 130))	('Q809fs', 'Mutation', 'p.Q809fsX', (124, 130))	('SCLC tumors', 'Disease', 'MESH:D018288', (12, 23))	('SCLC tumors', 'Disease', (12, 23))	('G4779X', 'Var', (97, 103))	('MLL2', 'Gene', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('S2590X', 'Mutation', 'p.S2590X', (113, 119))	('S2590X', 'Var', (113, 119))
160272	28007623	Moreover, the cell line NCI-H2171 harbored a homozygous point mutation in exon 51 of KMT2D, leading to an I5430M substitution.	('KMT2D', 'Gene', (85, 90))	('I5430M', 'Mutation', 'p.I5430M', (106, 112))	('NCI-H2171', 'CellLine', 'CVCL:1536', (24, 33))	('I5430M', 'Var', (106, 112))
160273	28007623	Also, we found truncating mutations in polybromo 1 gene (PBRM1), a chromatin-remodeling gene, in a primary tumor (V1011fs), and in the cell line NCI H2195 (K912fs).	('PBRM1', 'Gene', (57, 62))	('truncating mutations', 'Var', (15, 35))	('V1011fs', 'Mutation', 'p.V1011fsX', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('polybromo 1', 'Gene', '55193', (39, 50))	('PBRM1', 'Gene', '55193', (57, 62))	('NCI H2195', 'CellLine', 'CVCL:1538', (145, 154))	('chromatin', 'cellular_component', 'GO:0000785', ('67', '76'))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('67', '87'))	('polybromo 1', 'Gene', (39, 50))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('K912fs', 'Mutation', 'p.K912fsX', (156, 162))
160275	28007623	This gene is located at 3p21, a region of frequent deletion in SCLC.	('SCLC', 'Gene', (63, 67))	('deletion', 'Var', (51, 59))	('SCLC', 'Gene', '7864', (63, 67))
160280	28007623	Again, TP53 and RB1 were the most frequently mutated genes, but we also found a striking rate of mutations in KMT2D and NOTCH1 (Fig.	('mutations', 'Var', (97, 106))	('KMT2D', 'Gene', (110, 115))	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('NOTCH1', 'Gene', '4851', (120, 126))	('NOTCH1', 'Gene', (120, 126))	('RB1', 'Gene', (16, 19))	('RB1', 'Gene', '5925', (16, 19))
160282	28007623	We found examples of expressed nonsense or frameshift KMT2D mutations in two additional lines, NCI-H446 and NCI-H2195, with mutations validated by using Sanger sequencing of genomic DNA (Supplementary Fig.	('NCI-H2195', 'CellLine', 'CVCL:1538', (108, 117))	('frameshift', 'Var', (43, 53))	('KMT2D', 'Gene', (54, 59))	('NCI-H446', 'CellLine', 'CVCL:1562', (95, 103))	('mutations', 'Var', (60, 69))	('DNA', 'cellular_component', 'GO:0005574', ('182', '185'))
160283	28007623	Our resequencing analysis revealed truncating mutations in many chromatin-regulating genes beyond the CREBBP and EP300 acetyltransferases that have already been well described in SCLC (Figs.	('acetyltransferases', 'Enzyme', (119, 137))	('EP300', 'Gene', (113, 118))	('EP300', 'Gene', '2033', (113, 118))	('SCLC', 'Gene', '7864', (179, 183))	('CREBBP', 'Gene', (102, 108))	('chromatin', 'cellular_component', 'GO:0000785', ('64', '73'))	('truncating mutations', 'Var', (35, 55))	('chromatin-regulating genes', 'Gene', (64, 90))	('CREBBP', 'Gene', '1387', (102, 108))	('SCLC', 'Gene', (179, 183))
160284	28007623	For example, we found truncating mutations in lysine demethylase 6A gene (KDM6A)/UTX, a histone demethylase found in the same protein complex as KMT2D (see Figs.	('truncating mutations', 'Var', (22, 42))	('lysine', 'Chemical', 'MESH:D008239', (46, 52))	('UTX', 'Gene', (81, 84))	('UTX', 'Gene', '7403', (81, 84))	('KDM6A', 'Gene', (74, 79))	('protein complex', 'cellular_component', 'GO:0032991', ('126', '141'))	('KDM6A', 'Gene', '7403', (74, 79))
160285	28007623	We found mutations in PBRM1, and other adenosine triphosphate-dependent SWI-SNF complex members, such as AT-rich interaction domain 1 gene (ARID1A) and AT-rich interaction domain 1B gene (ARID1B).	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (39, 61))	('ARID1A', 'Gene', '8289', (140, 146))	('ARID1A', 'Gene', (140, 146))	('PBRM1', 'Gene', '55193', (22, 27))	('mutations', 'Var', (9, 18))	('AT-rich interaction domain 1B', 'Gene', '57492', (152, 181))	('ARID1B', 'Gene', '57492', (188, 194))	('AT-rich interaction domain 1B', 'Gene', (152, 181))	('SWI-SNF complex', 'cellular_component', 'GO:0016514', ('72', '87'))	('ARID1B', 'Gene', (188, 194))	('PBRM1', 'Gene', (22, 27))
160286	28007623	Mutations were also found in chromodomain helicase DNA binding protein 7 gene (CHD7), a gene whose protein product interacts with the PBRM1-containing PBAF complex.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('DNA binding', 'molecular_function', 'GO:0003677', ('51', '62'))	('chromodomain helicase DNA binding protein 7', 'Gene', (29, 72))	('PBRM1', 'Gene', (134, 139))	('CHD7', 'Gene', (79, 83))	('CHD7', 'Gene', '55636', (79, 83))	('PBRM1', 'Gene', '55193', (134, 139))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('Mutations', 'Var', (0, 9))	('chromodomain helicase DNA binding protein 7', 'Gene', '55636', (29, 72))	('PBAF complex', 'cellular_component', 'GO:0016586', ('151', '163'))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))
160288	28007623	As there has been little study of KMT2D mutations in SCLC, we examined KMT2D protein levels in SCLC cell lines with wild-type KMT2D and either hemizygous or homozygous truncating mutations (Fig.	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('SCLC', 'Gene', '7864', (53, 57))	('truncating mutations', 'Var', (168, 188))	('SCLC', 'Gene', (53, 57))	('SCLC', 'Gene', '7864', (95, 99))	('SCLC', 'Gene', (95, 99))
160289	28007623	KMT2D has been reported to confer monomethylation and dimethylation of histone H3 and lysine 4, with monomethylation of H3K4 being a chromatin mark associated with transcriptional enhancers.	('histone H3', 'Protein', (71, 81))	('monomethylation', 'Var', (101, 116))	('H3K4', 'Protein', (120, 124))	('monomethylation', 'MPA', (34, 49))	('H3', 'Chemical', 'MESH:C012616', (120, 122))	('lysine 4', 'Chemical', '-', (86, 94))	('KMT2D', 'Gene', (0, 5))	('dimethylation', 'MPA', (54, 67))	('chromatin', 'cellular_component', 'GO:0000785', ('133', '142'))	('H3', 'Chemical', 'MESH:C012616', (79, 81))
160290	28007623	We next examined whether mutation in KMT2D correlates with histone H3K4 methylation status in SCLC cell lines.	('H3', 'Chemical', 'MESH:C012616', (67, 69))	('KMT2D', 'Gene', (37, 42))	('mutation', 'Var', (25, 33))	('SCLC', 'Gene', '7864', (94, 98))	('SCLC', 'Gene', (94, 98))	('histone H3K4 methylation', 'biological_process', 'GO:0051568', ('59', '83'))	('histone H3K4 methylation status', 'MPA', (59, 90))
160291	28007623	Western blot analysis of extracted histones showed that KMT2D mutation in SCLC cell lines correlated with global reduction in H3K4 monomethylation and with a trend toward reduced H3K4 dimethylation (Fig.	('H3', 'Chemical', 'MESH:C012616', (126, 128))	('H3K4', 'Protein', (126, 130))	('reduction', 'NegReg', (113, 122))	('H3K4', 'Protein', (179, 183))	('SCLC', 'Gene', (74, 78))	('mutation', 'Var', (62, 70))	('SCLC', 'Gene', '7864', (74, 78))	('H3', 'Chemical', 'MESH:C012616', (179, 181))	('monomethylation', 'MPA', (131, 146))	('KMT2D', 'Gene', (56, 61))	('reduced', 'NegReg', (171, 178))
160292	28007623	We report frequent genetic alterations in chromatin regulators in SCLC.	('genetic alterations', 'Var', (19, 38))	('chromatin', 'cellular_component', 'GO:0000785', ('42', '51'))	('SCLC', 'Gene', '7864', (66, 70))	('SCLC', 'Gene', (66, 70))
160293	28007623	Most striking was the high frequency of truncating KMT2D mutations in our data set, which were found in 17% of SCLC cell lines and 8% of SCLC tumors.	('SCLC tumors', 'Disease', (137, 148))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('SCLC', 'Gene', (111, 115))	('truncating', 'MPA', (40, 50))	('SCLC', 'Gene', '7864', (111, 115))	('mutations', 'Var', (57, 66))	('SCLC', 'Gene', '7864', (137, 141))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('SCLC', 'Gene', (137, 141))	('KMT2D', 'Gene', (51, 56))	('SCLC tumors', 'Disease', 'MESH:D018288', (137, 148))
160294	28007623	Although truncating KMT2D mutations were occasionally homozygous, most were hemizygous, suggesting that decreased gene dosage may contribute to SCLC.	('SCLC', 'Gene', (144, 148))	('contribute', 'Reg', (130, 140))	('mutations', 'Var', (26, 35))	('KMT2D', 'Gene', (20, 25))	('SCLC', 'Gene', '7864', (144, 148))
160295	28007623	Although we focused on truncating mutations, some of the missense mutations in KMT2D from our study and other SCLC data sets may also be functionally important, as has been shown with a subset of KMT2D missense mutations found in lymphoma.	('missense mutations', 'Var', (57, 75))	('found', 'Reg', (221, 226))	('SCLC', 'Gene', '7864', (110, 114))	('SCLC', 'Gene', (110, 114))	('lymphoma', 'Disease', (230, 238))	('lymphoma', 'Disease', 'MESH:D008223', (230, 238))	('missense mutations', 'Var', (202, 220))	('lymphoma', 'Phenotype', 'HP:0002665', (230, 238))	('KMT2D', 'Gene', (79, 84))	('KMT2D', 'Gene', (196, 201))
160296	28007623	For example, the SCLC cell line H2171 harbors a homozygous I5430M mutation in the catalytic SET methyltransferase domain that is likely to be functionally important.	('I5430M', 'Var', (59, 65))	('H2171', 'CellLine', 'CVCL:1536', (32, 37))	('I5430M', 'Mutation', 'p.I5430M', (59, 65))	('SCLC', 'Gene', '7864', (17, 21))	('SCLC', 'Gene', (17, 21))
160297	28007623	Inactivating KMT2D mutations have been reported in approximately 90% of follicular lymphomas, approximately 27% of bladder urothelial cancer, medulloblastoma, prostate cancer, and squamous cell lung cancer, among many other cancer types.	('medulloblastoma', 'Disease', 'MESH:D008527', (142, 157))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (199, 205))	('medulloblastoma', 'Phenotype', 'HP:0002885', (142, 157))	('cancer', 'Disease', (224, 230))	('lung cancer', 'Phenotype', 'HP:0100526', (194, 205))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('medulloblastoma', 'Disease', (142, 157))	('lymphomas', 'Phenotype', 'HP:0002665', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('prostate cancer', 'Disease', 'MESH:D011471', (159, 174))	('cancer', 'Disease', (134, 140))	('Inactivating', 'Var', (0, 12))	('prostate cancer', 'Phenotype', 'HP:0012125', (159, 174))	('prostate cancer', 'Disease', (159, 174))	('follicular lymphomas', 'Disease', (72, 92))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (115, 140))	('follicular lymphomas', 'Disease', 'MESH:D008224', (72, 92))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('squamous cell lung cancer', 'Disease', (180, 205))	('KMT2D', 'Gene', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('reported', 'Reg', (39, 47))	('mutations', 'Var', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('lymphoma', 'Phenotype', 'HP:0002665', (83, 91))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (180, 205))	('bladder urothelial cancer', 'Disease', (115, 140))
160298	28007623	Truncating mutations are found at a much lower rate in lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('Truncating mutations', 'Var', (0, 20))	('lung adenocarcinoma', 'Disease', (55, 74))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (55, 74))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))
160299	28007623	Inactivation of Kmt2d in mice accelerates tumorigenesis in sensitized models of B-cell lymphoma, indicating that Kmt2d functions as a bona fide tumor suppressor gene.	('tumor', 'Disease', (144, 149))	('mice', 'Species', '10090', (25, 29))	('Kmt2d', 'Gene', (16, 21))	('tumor', 'Disease', (42, 47))	('accelerates', 'PosReg', (30, 41))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (80, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('144', '160'))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (80, 95))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('B-cell lymphoma', 'Disease', (80, 95))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('Inactivation', 'Var', (0, 12))	('tumor suppressor', 'biological_process', 'GO:0051726', ('144', '160'))
160302	28007623	Genetic loss of function studies have shown that disruption of Kmt2d or its Drosophila homologue (Trr) impairs transcriptional enhancer function.	('transcriptional enhancer function', 'MPA', (111, 144))	('Drosophila', 'Species', '7227', (76, 86))	('Kmt2d', 'Gene', (63, 68))	('disruption', 'Var', (49, 59))	('impairs', 'NegReg', (103, 110))
160304	28007623	We found that SCLC cell lines harboring KMT2D mutation exhibited reduced H3K4 monomethylation, as has been found in other KMT2D mutant cells.	('SCLC', 'Gene', '7864', (14, 18))	('H3', 'Chemical', 'MESH:C012616', (73, 75))	('SCLC', 'Gene', (14, 18))	('reduced', 'NegReg', (65, 72))	('monomethylation', 'MPA', (78, 93))	('KMT2D', 'Gene', (40, 45))	('H3K4', 'Protein', (73, 77))	('mutation', 'Var', (46, 54))
160305	28007623	Impaired enhancer function, as found upon Kmt2d deletion in mice constitutes a potential means through which KMT2D mutation may be cancer promoting.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('mice', 'Species', '10090', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('KMT2D', 'Gene', (109, 114))	('mutation', 'Var', (115, 123))	('enhancer function', 'MPA', (9, 26))	('deletion', 'Var', (48, 56))
160307	28007623	In our exome data set, we found a truncating KDM6A mutation in a primary SCLC and nonsense mutation in an SCLC cell line, NCI-H128 (Supplementary Table 3), which confirms a previously reported result in this line.	('SCLC', 'Gene', '7864', (73, 77))	('SCLC', 'Gene', (73, 77))	('NCI-H128', 'CellLine', 'CVCL:1460', (122, 130))	('KDM6A', 'Gene', (45, 50))	('mutation', 'Var', (51, 59))	('KDM6A', 'Gene', '7403', (45, 50))	('SCLC', 'Gene', '7864', (106, 110))	('SCLC', 'Gene', (106, 110))
160308	28007623	KMT2D undergoes frequent hemizygous inactivating mutations in Kabuki syndrome, and a smaller subset of patients with Kabuki syndrome retain wild-type KMT2D but harbor KDM6A mutation.	('Kabuki syndrome', 'Disease', (117, 132))	('KDM6A', 'Gene', '7403', (167, 172))	('Kabuki syndrome', 'Disease', 'MESH:C537705', (62, 77))	('hemizygous inactivating mutations', 'Var', (25, 58))	('Kabuki syndrome', 'Disease', 'MESH:C537705', (117, 132))	('Kabuki syndrome', 'Disease', (62, 77))	('KDM6A', 'Gene', (167, 172))	('patients', 'Species', '9606', (103, 111))
160309	28007623	In bladder urothelial cancer, KDM6A and KMT2D mutations are both frequent and they occur in a mutually exclusive fashion.	('mutations', 'Var', (46, 55))	('KDM6A', 'Gene', '7403', (30, 35))	('KMT2D', 'Gene', (40, 45))	('bladder urothelial cancer', 'Disease', (3, 28))	('frequent', 'Reg', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (3, 28))	('KDM6A', 'Gene', (30, 35))
160310	28007623	Thus, KMT2D mutations and KDM6A mutations likely perturb a common pathway, with KMT2D mutated in SCLC much more frequently than KDM6A.	('KDM6A', 'Gene', '7403', (128, 133))	('mutated', 'Var', (86, 93))	('SCLC', 'Gene', (97, 101))	('mutations', 'Var', (12, 21))	('KDM6A', 'Gene', '7403', (26, 31))	('perturb', 'Reg', (49, 56))	('SCLC', 'Gene', '7864', (97, 101))	('mutations', 'Var', (32, 41))	('KDM6A', 'Gene', (128, 133))	('KMT2D', 'Gene', (6, 11))	('KDM6A', 'Gene', (26, 31))
160311	28007623	Despite a number of previous sequencing studies having been performed on SCLC samples, including studies also showing significant KMT2D mutation rates, KMT2D is underappreciated as a major SCLC-mutated gene.	('SCLC', 'Gene', '7864', (189, 193))	('SCLC', 'Gene', (189, 193))	('SCLC', 'Gene', '7864', (73, 77))	('SCLC', 'Gene', (73, 77))	('mutation', 'Var', (136, 144))	('KMT2D', 'Gene', (130, 135))
160312	28007623	first reported KMT2D mutation in the NCI-H209 SCLC line, and Rudin et al.	('KMT2D', 'Gene', (15, 20))	('SCLC', 'Gene', '7864', (46, 50))	('SCLC', 'Gene', (46, 50))	('mutation', 'Var', (21, 29))
160313	28007623	However, recent reports describing whole genome sequencing of 110 SCLCs and exome analysis of 99 SCLCs did not highlight the presence of KMT2D/MLL2 mutations.	('mutations', 'Var', (148, 157))	('MLL2', 'Gene', '8085', (143, 147))	('SCLC', 'Gene', '7864', (66, 70))	('SCLC', 'Gene', (66, 70))	('SCLC', 'Gene', (97, 101))	('SCLC', 'Gene', '7864', (97, 101))	('MLL2', 'Gene', (143, 147))
160315	28007623	data set lacking KMT2D mutation instead harbored truncating mutations in KDM6A; thus, 16 of 110 samples (15%) had either a truncating KMT2D or KDM6A mutation.	('truncating', 'NegReg', (123, 133))	('KDM6A', 'Gene', (143, 148))	('KMT2D', 'Gene', (134, 139))	('KDM6A', 'Gene', '7403', (143, 148))	('KDM6A', 'Gene', (73, 78))	('truncating mutations', 'Var', (49, 69))	('mutation', 'Var', (149, 157))	('KDM6A', 'Gene', '7403', (73, 78))
160319	28007623	Bias toward truncating KMT2D mutations in SCLC instead suggests that there is a selective advantage to inactivating this gene.	('KMT2D', 'Gene', (23, 28))	('mutations', 'Var', (29, 38))	('SCLC', 'Gene', '7864', (42, 46))	('SCLC', 'Gene', (42, 46))
160320	28007623	Overall, truncating mutations in KMT2D are very frequent in human SCLC.	('truncating mutations', 'Var', (9, 29))	('KMT2D', 'Gene', (33, 38))	('SCLC', 'Gene', '7864', (66, 70))	('SCLC', 'Gene', (66, 70))	('frequent', 'Reg', (48, 56))	('human', 'Species', '9606', (60, 65))
160321	28007623	Other chromatin-modifying enzymes were also found mutated in our SCLC data set, including PBRM1, encoding BAF-180.	('SCLC', 'Gene', '7864', (65, 69))	('SCLC', 'Gene', (65, 69))	('BAF-180', 'Gene', (106, 113))	('BAF-180', 'Gene', '55193', (106, 113))	('mutated', 'Var', (50, 57))	('PBRM1', 'Gene', (90, 95))	('PBRM1', 'Gene', '55193', (90, 95))	('chromatin', 'cellular_component', 'GO:0000785', ('6', '15'))
160324	28007623	PBRM1 is a candidate 3p21 tumor suppressor frequently mutated in renal cell carcinoma and cholangiocarcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (65, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('cholangiocarcinoma', 'Disease', (90, 108))	('PBRM1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('PBRM1', 'Gene', '55193', (0, 5))	('tumor suppressor', 'biological_process', 'GO:0051726', ('26', '42'))	('mutated', 'Var', (54, 61))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('26', '42'))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('renal cell carcinoma', 'Disease', (65, 85))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (65, 85))
160325	28007623	PBRM1 was previously investigated as a potential target of mutations in SCLC cell lines, but mutations were not found in the subset of SCLC cell lines examined.	('SCLC', 'Gene', (72, 76))	('PBRM1', 'Gene', (0, 5))	('SCLC', 'Gene', (135, 139))	('PBRM1', 'Gene', '55193', (0, 5))	('SCLC', 'Gene', '7864', (72, 76))	('SCLC', 'Gene', '7864', (135, 139))	('mutations', 'Var', (59, 68))
160326	28007623	Given our finding of PBRM1 nonsense and frameshift mutations in SCLC, it will be important to now reexamine PBRM1 as a potential 3p21 driver mutation in SCLC.	('PBRM1', 'Gene', '55193', (108, 113))	('SCLC', 'Gene', '7864', (153, 157))	('PBRM1', 'Gene', (21, 26))	('SCLC', 'Gene', (153, 157))	('frameshift mutations', 'Var', (40, 60))	('PBRM1', 'Gene', '55193', (21, 26))	('SCLC', 'Gene', '7864', (64, 68))	('SCLC', 'Gene', (64, 68))	('PBRM1', 'Gene', (108, 113))	('nonsense', 'Var', (27, 35))
160327	28007623	Notably, mutations in other members of the PBAF SWI/SNF complexes are also mutated in SCLC, such as the catalytic component of the PBAF complex, BRG1 encoded by SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 gene (SMARCA4).	('BRG1', 'Gene', (145, 149))	('SCLC', 'Gene', (86, 90))	('SMARCA4', 'Gene', (265, 272))	('SWI/SNF', 'Gene', (48, 55))	('mutations', 'Var', (9, 18))	('SCLC', 'Gene', '7864', (86, 90))	('BRG1', 'Gene', '6597', (145, 149))	('SMARCA4', 'Gene', '6597', (265, 272))	('mutated', 'Var', (75, 82))	('PBAF complex', 'cellular_component', 'GO:0016586', ('131', '143'))	('PBAF SWI/SNF', 'Gene', (43, 55))	('chromatin', 'cellular_component', 'GO:0000785', ('226', '235'))	('SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4', 'Gene', '6597', (161, 258))
160328	28007623	Moreover, we found CHD7 mutations in SCLC.	('CHD7', 'Gene', '55636', (19, 23))	('SCLC', 'Gene', '7864', (37, 41))	('CHD7', 'Gene', (19, 23))	('SCLC', 'Gene', (37, 41))	('mutations', 'Var', (24, 33))
160330	28007623	Chromodomain helicase DNA binding protein 7 has also been found localized to transcriptional enhancers with enriched DNA binding to sites of H3K4 monomethylation, the mark conferred by KMT2D.	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('DNA binding', 'molecular_function', 'GO:0003677', ('22', '33'))	('Chromodomain helicase DNA binding protein 7', 'Gene', '55636', (0, 43))	('monomethylation', 'Var', (146, 161))	('DNA binding', 'molecular_function', 'GO:0003677', ('117', '128'))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('binding', 'Interaction', (121, 128))	('H3K4', 'Protein', (141, 145))	('Chromodomain helicase DNA binding protein 7', 'Gene', (0, 43))	('H3', 'Chemical', 'MESH:C012616', (141, 143))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))
160333	28007623	For example, truncating KMT2D mutations were more frequent in SCLC cell lines than in tumors (see Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('SCLC', 'Gene', (62, 66))	('frequent', 'Reg', (50, 58))	('truncating', 'Var', (13, 23))	('SCLC', 'Gene', '7864', (62, 66))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (30, 39))	('KMT2D', 'Gene', (24, 29))
160334	28007623	Phosphatase and tensin homolog gene (PTEN)/phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutations were also more frequent in SCLC cell lines than in primary tumors (see Fig.	('PIK3CA', 'Gene', (120, 126))	('primary tumors', 'Disease', (189, 203))	('mutations', 'Var', (128, 137))	('frequent', 'Reg', (153, 161))	('primary tumors', 'Disease', 'MESH:D009369', (189, 203))	('PIK3CA', 'Gene', '5290', (120, 126))	('PTEN', 'Gene', (37, 41))	('PTEN', 'Gene', '5728', (37, 41))	('Phosphatase', 'molecular_function', 'GO:0016791', ('0', '11'))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('Phosphatase and tensin homolog gene', 'Gene', '5728', (0, 35))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('Phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('0', '30'))	('SCLC', 'Gene', '7864', (165, 169))	('SCLC', 'Gene', (165, 169))
160335	28007623	In contrast, truncating NOTCH1 mutations were found more frequently in tumors than in cell lines.	('mutations', 'Var', (31, 40))	('truncating', 'Var', (13, 23))	('NOTCH1', 'Gene', '4851', (24, 30))	('NOTCH1', 'Gene', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
160337	28007623	Thus, it is possible that KMT2D and/or PTEN/PIK3CA pathway mutations may be associated with more advanced SCLC.	('PIK3CA', 'Gene', (44, 50))	('PIK3CA', 'Gene', '5290', (44, 50))	('KMT2D', 'Gene', (26, 31))	('associated', 'Reg', (76, 86))	('PTEN', 'Gene', (39, 43))	('mutations', 'Var', (59, 68))	('PTEN', 'Gene', '5728', (39, 43))	('SCLC', 'Gene', '7864', (106, 110))	('SCLC', 'Gene', (106, 110))
160338	28007623	It is also possible that certain gene mutations may influence the likelihood of cell line establishment from a tumor.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('influence', 'Reg', (52, 61))	('mutations', 'Var', (38, 47))
160339	28007623	Thus, it will be critical for future studies to directly compare mutation profiles in sequentially collected SCLC tumor biopsy samples (or liquid biopsy samples) to determine whether genetic alterations in KMT2D and/or the PTEN/PIK3CA pathway are associated with more advanced and/or chemoresistant SCLC.	('PTEN', 'Gene', (223, 227))	('SCLC', 'Gene', '7864', (299, 303))	('PTEN', 'Gene', '5728', (223, 227))	('associated', 'Reg', (247, 257))	('SCLC', 'Gene', (299, 303))	('genetic alterations', 'Var', (183, 202))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('SCLC tumor', 'Disease', 'MESH:D018288', (109, 119))	('SCLC tumor', 'Disease', (109, 119))	('SCLC', 'Gene', (109, 113))	('SCLC', 'Gene', '7864', (109, 113))	('KMT2D', 'Gene', (206, 211))	('PIK3CA', 'Gene', (228, 234))	('PIK3CA', 'Gene', '5290', (228, 234))
160340	28007623	This study highlights the high frequency of inactivating mutations in KMT2D in SCLC.	('KMT2D', 'Gene', (70, 75))	('SCLC', 'Gene', '7864', (79, 83))	('inactivating mutations', 'Var', (44, 66))	('SCLC', 'Gene', (79, 83))
160341	28007623	We show that mutations in the KMT2D methyltransferase in SCLC cell lines are associated with global reductions in H3K4 monomethylation, a mark associated with transcriptional enhancers (see Fig.	('H3K4', 'Protein', (114, 118))	('H3', 'Chemical', 'MESH:C012616', (114, 116))	('monomethylation', 'MPA', (119, 134))	('mutations', 'Var', (13, 22))	('KMT2D', 'Gene', (30, 35))	('SCLC', 'Gene', '7864', (57, 61))	('SCLC', 'Gene', (57, 61))	('reductions', 'NegReg', (100, 110))
160342	28007623	Notably, other genes associated with the activation of transcriptional enhancers (i.e., the acetyltransferases CREBBP and EP300) are frequently mutated in SCLC (see Fig.	('mutated', 'Var', (144, 151))	('CREBBP', 'Gene', '1387', (111, 117))	('SCLC', 'Gene', (155, 159))	('EP300', 'Gene', (122, 127))	('acetyltransferases', 'Enzyme', (92, 110))	('EP300', 'Gene', '2033', (122, 127))	('SCLC', 'Gene', '7864', (155, 159))	('CREBBP', 'Gene', (111, 117))
160343	28007623	If KMT2D tumor suppressor function is mediated through reduced H3K4 methylation and impaired enhancer function, then therapeutic approaches might be designed to reverse this effect.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('9', '25'))	('impaired enhancer function', 'Disease', (84, 110))	('reduced', 'NegReg', (55, 62))	('impaired enhancer function', 'Disease', 'MESH:D003072', (84, 110))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('tumor', 'Disease', (9, 14))	('H3K4', 'Protein', (63, 67))	('methylation', 'MPA', (68, 79))	('KMT2D', 'Var', (3, 8))	('H3', 'Chemical', 'MESH:C012616', (63, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('9', '25'))
160345	28007623	Whether mutations in KMT2D influence response to inhibitors of H3K4 demethylases will be critical for future studies to determine.	('response to inhibitors', 'MPA', (37, 59))	('H3K4 demethylases', 'Enzyme', (63, 80))	('mutations', 'Var', (8, 17))	('influence', 'Reg', (27, 36))	('KMT2D', 'Gene', (21, 26))	('H3', 'Chemical', 'MESH:C012616', (63, 65))
160351	29050298	Considering the clinicopathological parameters, highly-expressed COL3A1 was closely correlated with local recurrence and BCa stage.	('COL3A1', 'Gene', '1281', (65, 71))	('BCa', 'Phenotype', 'HP:0009725', (121, 124))	('correlated', 'Reg', (84, 94))	('local recurrence', 'CPA', (100, 116))	('COL3A1', 'Gene', (65, 71))	('BCa stage', 'CPA', (121, 130))	('highly-expressed', 'Var', (48, 64))
160361	29050298	As MIBC frequently causes distant metastases, it is urgent to understand the mechanisms that promote cancer progression and find novel molecular markers for the early diagnosis and prognosis.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('causes', 'Reg', (19, 25))	('cancer', 'Disease', (101, 107))	('MIBC', 'Var', (3, 7))	('MIBC', 'Chemical', '-', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('metastases', 'Disease', (34, 44))	('metastases', 'Disease', 'MESH:D009362', (34, 44))
160373	29050298	In addition, we discovered that patients with higher expression of COL3A1 had a significantly shorter overall survival time and disease free survival time (Figure 5G and 5H).	('patients', 'Species', '9606', (32, 40))	('expression', 'Var', (53, 63))	('higher', 'PosReg', (46, 52))	('COL3A1', 'Gene', '1281', (67, 73))	('shorter', 'NegReg', (94, 101))	('overall survival time', 'CPA', (102, 123))	('disease free survival time', 'CPA', (128, 154))	('COL3A1', 'Gene', (67, 73))
160409	29050298	Interestingly, according to the correlations between COL3A1 expression and clinicopathological parameters in bladder cancer, we found that highly expressed COL3A1 could cause the progression of BCa and more local recurrence rate.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('COL3A1', 'Gene', '1281', (156, 162))	('COL3A1', 'Gene', '1281', (53, 59))	('more', 'PosReg', (202, 206))	('highly expressed', 'Var', (139, 155))	('bladder cancer', 'Disease', 'MESH:D001749', (109, 123))	('BCa', 'Disease', (194, 197))	('bladder cancer', 'Disease', (109, 123))	('COL3A1', 'Gene', (53, 59))	('local recurrence rate', 'CPA', (207, 228))	('BCa', 'Phenotype', 'HP:0009725', (194, 197))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))	('COL3A1', 'Gene', (156, 162))	('cause', 'Reg', (169, 174))
160444	27959455	Silencing of B23 by short hairpin RNA inhibited tumor cell growth and colony formation.	('tumor', 'Disease', (48, 53))	('RNA', 'cellular_component', 'GO:0005562', ('34', '37'))	('B23', 'Gene', '4869', (13, 16))	('B23', 'Gene', (13, 16))	('inhibited', 'NegReg', (38, 47))	('short hairpin RNA', 'Gene', (20, 37))	('formation', 'biological_process', 'GO:0009058', ('77', '86'))	('cell growth', 'biological_process', 'GO:0016049', ('54', '65'))	('Silencing', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('colony formation', 'CPA', (70, 86))
160445	27959455	In addition, knockdown of B23 suppressed the phosphorylation of extracellular signal-regulated kinase (ERK), resulting in the inactivation of the ERK signaling pathway.	('ERK', 'Gene', '5594', (146, 149))	('signaling pathway', 'biological_process', 'GO:0007165', ('150', '167'))	('ERK', 'molecular_function', 'GO:0004707', ('146', '149'))	('phosphorylation', 'biological_process', 'GO:0016310', ('45', '60'))	('B23', 'Gene', (26, 29))	('ERK', 'Gene', (103, 106))	('suppressed', 'NegReg', (30, 40))	('ERK', 'Gene', (146, 149))	('B23', 'Gene', '4869', (26, 29))	('ERK', 'molecular_function', 'GO:0004707', ('103', '106'))	('extracellular signal-regulated kinase', 'Gene', '5594', (64, 101))	('phosphorylation', 'MPA', (45, 60))	('extracellular', 'cellular_component', 'GO:0005576', ('64', '77'))	('knockdown', 'Var', (13, 22))	('extracellular signal-regulated kinase', 'Gene', (64, 101))	('ERK', 'Gene', '5594', (103, 106))	('inactivation', 'NegReg', (126, 138))
160510	27959455	Therefore, to investigate whether B23 affected bladder cancer cell growth via the ERK signaling pathway, the present study detected the protein expression levels of p-ERK, and it was observed that the phosphorylation of ERK was inhibited by B23 knockdown; however, the total protein expression levels of ERK remained unaltered (Fig.	('inhibited', 'NegReg', (228, 237))	('ERK', 'Gene', '5594', (304, 307))	('ERK', 'Gene', '5594', (82, 85))	('B23', 'Gene', '4869', (241, 244))	('ERK', 'molecular_function', 'GO:0004707', ('304', '307'))	('B23', 'Gene', (34, 37))	('bladder cancer', 'Disease', 'MESH:D001749', (47, 61))	('ERK', 'Gene', (304, 307))	('ERK', 'Gene', '5594', (167, 170))	('bladder cancer', 'Disease', (47, 61))	('B23', 'Gene', '4869', (34, 37))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('phosphorylation', 'biological_process', 'GO:0016310', ('201', '216'))	('ERK', 'Gene', (82, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (47, 61))	('ERK', 'molecular_function', 'GO:0004707', ('82', '85'))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('signaling pathway', 'biological_process', 'GO:0007165', ('86', '103'))	('ERK', 'Gene', '5594', (220, 223))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('ERK', 'Gene', (167, 170))	('ERK', 'molecular_function', 'GO:0004707', ('167', '170'))	('knockdown', 'Var', (245, 254))	('protein', 'cellular_component', 'GO:0003675', ('275', '282'))	('ERK', 'molecular_function', 'GO:0004707', ('220', '223'))	('B23', 'Gene', (241, 244))	('phosphorylation', 'MPA', (201, 216))	('ERK', 'Gene', (220, 223))
160513	27959455	The effect of B23 on cell growth was suppressed by ERK inhibition via U0126 (Fig.	('ERK', 'Gene', (51, 54))	('U0126', 'Chemical', 'MESH:C113580', (70, 75))	('B23', 'Gene', (14, 17))	('U0126', 'Var', (70, 75))	('ERK', 'molecular_function', 'GO:0004707', ('51', '54'))	('cell growth', 'CPA', (21, 32))	('B23', 'Gene', '4869', (14, 17))	('ERK', 'Gene', '5594', (51, 54))	('cell growth', 'biological_process', 'GO:0016049', ('21', '32'))	('inhibition', 'NegReg', (55, 65))
160516	27959455	Patients with high B23 expression had a markedly lower survival rate compared with patients with low B23 expression (P<0.001).	('B23', 'Gene', '4869', (101, 104))	('B23', 'Gene', '4869', (19, 22))	('B23', 'Gene', (19, 22))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (49, 54))	('survival rate', 'CPA', (55, 68))	('patients', 'Species', '9606', (83, 91))	('B23', 'Gene', (101, 104))
160539	27959455	To determine whether B23 was involved in the activation of the MAPK signaling pathway in bladder cancer, the present study detected the expression of phosphorylation of ERK and revealed that knockdown of B23 inhibited the activation of ERK.	('ERK', 'Gene', '5594', (169, 172))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('MAPK', 'molecular_function', 'GO:0004707', ('63', '67'))	('ERK', 'molecular_function', 'GO:0004707', ('236', '239'))	('phosphorylation', 'MPA', (150, 165))	('expression', 'MPA', (136, 146))	('ERK', 'Gene', (169, 172))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('ERK', 'molecular_function', 'GO:0004707', ('169', '172'))	('MAPK', 'Gene', '5595;5594;5595', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('MAPK signaling', 'biological_process', 'GO:0000165', ('63', '77'))	('signaling pathway', 'biological_process', 'GO:0007165', ('68', '85'))	('ERK', 'Gene', '5594', (236, 239))	('inhibited', 'NegReg', (208, 217))	('MAPK', 'Gene', (63, 67))	('B23', 'Gene', (21, 24))	('phosphorylation', 'biological_process', 'GO:0016310', ('150', '165'))	('B23', 'Gene', (204, 207))	('ERK', 'Gene', (236, 239))	('knockdown', 'Var', (191, 200))	('B23', 'Gene', '4869', (21, 24))	('activation', 'MPA', (222, 232))	('B23', 'Gene', '4869', (204, 207))
160546	27959455	In addition, it was observed that elevated B23 expression accelerated bladder cancer cell growth and tumorigenesis via the MAPK signaling pathway.	('MAPK', 'Gene', '5595;5594;5595', (123, 127))	('MAPK', 'Gene', (123, 127))	('bladder cancer', 'Disease', (70, 84))	('B23', 'Gene', '4869', (43, 46))	('MAPK signaling', 'biological_process', 'GO:0000165', ('123', '137'))	('MAPK', 'molecular_function', 'GO:0004707', ('123', '127'))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('B23', 'Gene', (43, 46))	('signaling pathway', 'biological_process', 'GO:0007165', ('128', '145'))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('accelerated', 'PosReg', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('cell growth', 'biological_process', 'GO:0016049', ('85', '96'))	('expression', 'MPA', (47, 57))	('bladder cancer', 'Disease', 'MESH:D001749', (70, 84))	('elevated', 'Var', (34, 42))
160551	26577765	Metastases showed higher HS than primary invasive UCA (P <= 0.0001), and high HS was associated with a lower pT stage (P <= 0.0001) and a trend toward the absence of lymphovascular invasion (LVI, P = 0.09), but not pN stage (P = 0.35) and surgical margin status (P = 0.81).	('high HS', 'Var', (73, 80))	('lymphovascular invasion', 'CPA', (166, 189))	('pT stage', 'CPA', (109, 117))	('lower', 'NegReg', (103, 108))	('lower pT', 'Phenotype', 'HP:0032198', (103, 111))	('Metastases', 'Disease', (0, 10))	('higher', 'PosReg', (18, 24))	('Metastases', 'Disease', 'MESH:D009362', (0, 10))
160563	26577765	A strong association has been found between RBM3 overexpression and early biochemical prostate cancer recurrence in a large series.	('prostate cancer', 'Disease', 'MESH:D011471', (86, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (86, 101))	('overexpression', 'Var', (49, 63))	('RBM3', 'Gene', '5935', (44, 48))	('prostate cancer', 'Disease', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('RBM3', 'Gene', (44, 48))
160566	26577765	However, conflicting results emerged from many clinical studies which have found high RBM3 expression to be associated with a better prognosis in various cancers including colorectal cancer, melanoma, estrogen-positive breast cancers as well as esophageal and gastric adenocarcinomas.	('breast cancers', 'Disease', 'MESH:D001943', (219, 233))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('breast cancers', 'Disease', (219, 233))	('melanoma', 'Disease', (191, 199))	('high', 'Var', (81, 85))	('RBM3', 'Gene', (86, 90))	('breast cancers', 'Phenotype', 'HP:0003002', (219, 233))	('colorectal cancer', 'Phenotype', 'HP:0003003', (172, 189))	('gastric adenocarcinomas', 'Disease', (260, 283))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (260, 283))	('melanoma', 'Disease', 'MESH:D008545', (191, 199))	('associated', 'Reg', (108, 118))	('colorectal cancer', 'Disease', 'MESH:D015179', (172, 189))	('RBM3', 'Gene', '5935', (86, 90))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('colorectal cancer', 'Disease', (172, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('cancers', 'Disease', (226, 233))	('esophageal', 'Disease', (245, 255))	('cancers', 'Disease', (154, 161))	('carcinomas', 'Phenotype', 'HP:0030731', (273, 283))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
160597	26577765	Down-regulation of RBM3 mRNA and protein by small-interfering RNA (siRNA) reduces cell proliferation and viability in human embryonic kidney cells.	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('embryonic kidney', 'Disease', (124, 140))	('cell proliferation', 'biological_process', 'GO:0008283', ('82', '100'))	('regulation', 'biological_process', 'GO:0065007', ('5', '15'))	('small-interfering', 'Var', (44, 61))	('RBM3', 'Gene', '5935', (19, 23))	('mRNA and', 'MPA', (24, 32))	('Down-regulation', 'NegReg', (0, 15))	('embryonic kidney', 'Disease', 'MESH:D007674', (124, 140))	('RNA', 'cellular_component', 'GO:0005562', ('62', '65'))	('human', 'Species', '9606', (118, 123))	('reduces', 'NegReg', (74, 81))	('protein', 'Protein', (33, 40))	('RBM3', 'Gene', (19, 23))
160604	26577765	It is possible that CIS lesions with a high RBM3 might be more aggressive and become invasive in a shorter time frame for example; however, the testing of this hypothesis would require matched cases of chronologically evolutive lesions:benign, CIS, invasive urothelial carcinoma, and eventually metastasis:which could not be achieved in the current study.	('CIS', 'Disease', (244, 247))	('high', 'Var', (39, 43))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (249, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('benign', 'Disease', (236, 242))	('RBM3', 'Gene', '5935', (44, 48))	('invasive urothelial carcinoma', 'Disease', (249, 278))	('RBM3', 'Gene', (44, 48))
160606	26577765	Other studies that associate high RBM3 expression with a good prognosis in colon, breast, and urothelial cancer purposely highlighted the in vitro data by Sureban et al.	('high', 'Var', (29, 33))	('colon', 'Disease', (75, 80))	('urothelial cancer', 'Disease', 'MESH:D014523', (94, 111))	('RBM3', 'Gene', (34, 38))	('colon', 'Disease', 'MESH:D015179', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('urothelial cancer', 'Disease', (94, 111))	('RBM3', 'Gene', '5935', (34, 38))	('breast', 'Disease', (82, 88))
160615	26577765	Specifically concerning urothelial bladder cancer, the only study currently published on this topic reported loss of RBM3 expression to be associated with clinically more aggressive tumors and to be an independent factor of poor prognosis.	('expression', 'MPA', (122, 132))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('RBM3', 'Gene', '5935', (117, 121))	('aggressive tumors', 'Disease', 'MESH:D001523', (171, 188))	('bladder cancer', 'Phenotype', 'HP:0009725', (35, 49))	('loss', 'Var', (109, 113))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (24, 49))	('RBM3', 'Gene', (117, 121))	('urothelial bladder cancer', 'Disease', (24, 49))	('associated', 'Reg', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('aggressive tumors', 'Disease', (171, 188))	('more', 'PosReg', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
160633	25741387	Instead, we observed distinctive epigenetic alterations at the three regions controlling DLK1 and MEG3 expression, namely the DLK1 promoter; the intergenic (IG) and MEG3 differentially methylated regions (DMRs).	('DLK1', 'Gene', '8788', (126, 130))	('DLK1', 'Gene', '8788', (89, 93))	('epigenetic', 'Var', (33, 43))	('DLK1', 'Gene', (126, 130))	('DMRs', 'Chemical', '-', (205, 209))	('MEG3', 'Gene', (98, 102))	('DLK1', 'Gene', (89, 93))	('MEG3', 'Gene', (165, 169))	('MEG3', 'Gene', '55384', (98, 102))	('MEG3', 'Gene', '55384', (165, 169))
160635	25741387	Our data support the idea that the main cause of the prevalent downregulation of DLK1 and MEG3 in urothelial carcinoma is epigenetic silencing across the 14q32 imprinted gene cluster, resulting in the unusual concomitant inactivation of oppositely expressed and imprinted genes.	('epigenetic silencing', 'Var', (122, 142))	('DLK1', 'Gene', '8788', (81, 85))	('MEG3', 'Gene', (90, 94))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (98, 118))	('DLK1', 'Gene', (81, 85))	('MEG3', 'Gene', '55384', (90, 94))	('inactivation', 'MPA', (221, 233))	('urothelial carcinoma', 'Disease', (98, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('downregulation', 'NegReg', (63, 77))
160638	25741387	Their inactivation in cancers is brought about by deletion of the active allele or by a change of the epigenetic state of the active allele to that of the inactive one, that is, epitype switching.	('inactivation', 'NegReg', (6, 18))	('deletion', 'Var', (50, 58))	('epigenetic state', 'MPA', (102, 118))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('cancers', 'Disease', (22, 29))	('change', 'Reg', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
160639	25741387	A well-studied example is the imprinted tumor suppressor gene CDKN1C, which is inactivated alternatively by genetic or epigenetic mechanisms in several human cancers, including urothelial carcinoma.	('CDKN1C', 'Gene', '1028', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('urothelial carcinoma', 'Disease', (177, 197))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('human', 'Species', '9606', (152, 157))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (177, 197))	('epigenetic', 'Var', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('CDKN1C', 'Gene', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))
160640	25741387	In several cancers, a cluster of imprinted genes at 14q32.2, the DLK1-MEG3 cluster, is affected by allelic losses or epigenetic changes.	('MEG3', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('DLK1', 'Gene', '8788', (65, 69))	('MEG3', 'Gene', '55384', (70, 74))	('allelic loss', 'Disease', 'MESH:C566065', (99, 111))	('DLK1', 'Gene', (65, 69))	('epigenetic changes', 'Var', (117, 135))	('affected', 'Reg', (87, 95))	('allelic loss', 'Disease', (99, 111))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Disease', (11, 18))	('cancers', 'Disease', 'MESH:D009369', (11, 18))
160647	25741387	Loss of imprinting in the 14q32 region due to epimutations at the IG DMR or microdeletions has been implicated in a range of diseases including UPD14mat/pat (uniparental disomy 14) and various cancers.	('uniparental disomy 14', 'Disease', (158, 179))	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('DMR', 'Chemical', '-', (69, 72))	('cancers', 'Disease', (193, 200))	('microdeletions', 'Var', (76, 90))	('IG DMR', 'Gene', (66, 72))	('epimutations', 'Var', (46, 58))	('Loss', 'NegReg', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('uniparental disomy 14', 'Disease', 'MESH:D024182', (158, 179))	('mat', 'molecular_function', 'GO:0004314', ('149', '152'))	('implicated', 'Reg', (100, 110))
160652	25741387	In particular, more than 30% of invasive urothelial cancers, especially high stage cases, have been reported to contain losses at 14q32.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('invasive urothelial cancers', 'Disease', 'MESH:D009362', (32, 59))	('invasive urothelial cancers', 'Disease', (32, 59))	('14q32', 'Protein', (130, 135))	('losses', 'Var', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
160658	25741387	Indeed, upon closer investigation, we found that inactivation of the two genes is associated with the establishment of a novel epigenetic state in the region, which is distinct from that of either parental allele and is independent of copy number changes in most urothelial carcinoma tissues and cell lines.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (263, 283))	('urothelial carcinoma', 'Disease', (263, 283))	('inactivation', 'Var', (49, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))
160659	25741387	Initially, we quantified DLK1 and MEG3 mRNA by qPCR in urothelial cancer tissues (n = 30) and cell lines compared to benign bladder tissue samples (n = 11) and primary cultured normal urothelial cells.	('DLK1', 'Gene', '8788', (25, 29))	('urothelial cancer', 'Disease', 'MESH:D014523', (55, 72))	('DLK1', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('urothelial cancer', 'Disease', (55, 72))	('MEG3', 'Gene', (34, 38))	('qPCR', 'Var', (47, 51))	('MEG3', 'Gene', '55384', (34, 38))
160666	25741387	Similarly, gene copy number changes affected all analyzed genes to the same extent in urothelial cancer cell lines (UC).	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('urothelial cancer', 'Disease', (86, 103))	('urothelial cancer', 'Disease', 'MESH:D014523', (86, 103))	('gene copy number changes', 'Var', (11, 35))
160675	25741387	In contrast, in urothelial cancer cell lines (SW1710, BC61) and urothelial cancer tissues (BT152 and BT186), methylation at the promoter assumed a homogeneous pattern with methylated CpGs at the center of the sequence flanked by unmethylated CpG sites at its margins (Figure 4).	('urothelial cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('methylation', 'Var', (109, 120))	('urothelial cancer', 'Disease', 'MESH:D014523', (16, 33))	('urothelial cancer', 'Disease', 'MESH:D014523', (64, 81))	('methylated', 'Var', (172, 182))	('methylation', 'biological_process', 'GO:0032259', ('109', '120'))	('SW1710', 'CellLine', 'CVCL:1721', (46, 52))	('urothelial cancer', 'Disease', (16, 33))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CpGs', 'Var', (183, 187))
160680	25741387	In contrast, the urothelial cancer cell lines presented a novel methylation pattern in which CpGs 1 to 6 and 10 to 16 were methylated, whereas CpGs 7 to 9 and 17 to 19 were unmethylated, thereby resulting in a 'striped' pattern (Figure 4).	('methylated', 'Var', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('resulting in', 'Reg', (195, 207))	('urothelial cancer', 'Disease', (17, 34))	("'striped' pattern", 'MPA', (210, 227))	('to 9', 'Species', '1214577', (150, 154))	('urothelial cancer', 'Disease', 'MESH:D014523', (17, 34))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))
160693	25741387	We furthermore observed a few cancerous samples with hypomethylation or hypermethylation at all analyzed CpGs compared to benign tissues (Figure 5E), including the cancer tissue BT152 also shown in Figures 3 and 4.	('cancerous', 'Disease', 'MESH:D009369', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('hypermethylation', 'Var', (72, 88))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancerous', 'Disease', (30, 39))	('hypomethylation', 'Var', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
160708	25741387	However, expression was still low suggesting that silencing of the two genes in urothelial cancer cells involves further mechanisms in addition to DNA methylation.	('urothelial cancer', 'Disease', 'MESH:D014523', (80, 97))	('DNA methylation', 'biological_process', 'GO:0006306', ('147', '162'))	('low', 'NegReg', (30, 33))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('silencing', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('urothelial cancer', 'Disease', (80, 97))
160709	25741387	Using chromatin immunoprecipitation (ChIP), we quantified the H3K4me3 histone modification associated with active genes, the H3K9me3 and H3K27me3 modifications associated with repression, and H4K16ac, a marker of transcriptional competence but also of fixed nucleosomes, at the DLK1 promoter, the IG DMR and the MEG3 DMR in normal urothelial cells, HepG2 cells and seven urothelial carcinoma cell lines (Figure 6 and [see Additional file 1: Figure S4]).	('histone modification', 'biological_process', 'GO:0016570', ('70', '90'))	('urothelial carcinoma cell lines', 'Disease', 'MESH:C538614', (371, 402))	('carcinoma', 'Phenotype', 'HP:0030731', (382, 391))	('DMR', 'Chemical', '-', (317, 320))	('DMR', 'Chemical', '-', (300, 303))	('DLK1', 'Gene', '8788', (278, 282))	('MEG3', 'Gene', (312, 316))	('H3K27me3', 'Var', (137, 145))	('H3K4me3', 'Var', (62, 69))	('HepG2', 'CellLine', 'CVCL:0027', (349, 354))	('active genes', 'Gene', (107, 119))	('DLK1', 'Gene', (278, 282))	('MEG3', 'Gene', '55384', (312, 316))	('urothelial carcinoma cell lines', 'Disease', (371, 402))	('H3K9me3', 'Var', (125, 132))	('chromatin', 'cellular_component', 'GO:0000785', ('6', '15'))
160710	25741387	As expected for an imprinted bivalent domain, these normal urothelial cells displayed enrichment of H3K4me3 and H3K9me3 at comparable levels and slightly more enriched H4K16ac at the DLK1 promoter.	('H3K4me3', 'Protein', (100, 107))	('H3K9me3', 'Var', (112, 119))	('DLK1', 'Gene', '8788', (183, 187))	('DLK1', 'Gene', (183, 187))	('H4K16ac', 'Var', (168, 175))
160711	25741387	The IG DMR likewise displayed enrichment of both active and repressive histone modifications, H3K4me3 and H3K9me3, and more strongly H3K27me3.	('H3K4me3', 'Var', (94, 101))	('H3K9me3', 'Var', (106, 113))	('H3K27me3', 'Var', (133, 141))	('DMR', 'Chemical', '-', (7, 10))
160713	25741387	At the MEG3 DMR, in agreement with the high expression in normal bladder, the active histone modification H3K4me3 was enriched, whereas repressive histone modifications (H3K9me3 and H3K27me3) were low.	('histone modification', 'biological_process', 'GO:0016570', ('85', '105'))	('H3K4me3', 'Var', (106, 113))	('DMR', 'Chemical', '-', (12, 15))	('H3K27me3', 'Var', (182, 190))	('MEG3', 'Gene', (7, 11))	('H3K9me3', 'Var', (170, 177))	('MEG3', 'Gene', '55384', (7, 11))
160716	25741387	The active mark H3K4me3 was highly enriched at the IG DMR in HepG2 cells, with higher levels of H3K9me3 compared to H3K27me3, which is the inverse pattern compared to that in normal urothelial cells.	('H3K4me3', 'Var', (16, 23))	('levels', 'MPA', (86, 92))	('HepG2', 'CellLine', 'CVCL:0027', (61, 66))	('DMR', 'Chemical', '-', (54, 57))	('H3K9me3', 'Var', (96, 103))	('higher', 'PosReg', (79, 85))
160718	25741387	In comparison, repressive histone modifications (H3K9me3 and H3K27me3) were generally increased, in particular H3K9me3 at both DMRs, whereas increases in H3K27me3 were more evident at the DLK1 promoter and the MEG3 DMR.	('DMRs', 'Chemical', '-', (127, 131))	('increased', 'PosReg', (86, 95))	('DLK1', 'Gene', (188, 192))	('DMR', 'Chemical', '-', (127, 130))	('H3K27me3', 'Var', (61, 69))	('DMR', 'Chemical', '-', (215, 218))	('H3K9me3', 'Var', (49, 56))	('MEG3', 'Gene', (210, 214))	('repressive histone modifications', 'MPA', (15, 47))	('H3K9me3', 'Var', (111, 118))	('DLK1', 'Gene', '8788', (188, 192))	('MEG3', 'Gene', '55384', (210, 214))
160720	25741387	Interestingly, in contrast to the H3K4me3 mark, the H4K14ac modification was less severely depleted or even retained in some cell lines, with lowered levels especially at the IG DMR.	('levels', 'MPA', (150, 156))	('DMR', 'Chemical', '-', (178, 181))	('lowered', 'NegReg', (142, 149))	('H4K14ac', 'Var', (52, 59))
160721	25741387	In summary, the ChIP analyses revealed the predominance of repressive histone modifications and a nearly complete loss of H3K4me3, with partial retention of H4K16ac, a modification characteristic of fixed nucleosomes, across the entire analyzed region in all urothelial carcinoma cells.	('urothelial carcinoma', 'Disease', (259, 279))	('loss', 'NegReg', (114, 118))	('retention', 'biological_process', 'GO:0051235', ('144', '153'))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('modifications', 'Var', (78, 91))	('histone', 'Protein', (70, 77))	('H4K16ac', 'Var', (157, 164))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (259, 279))	('H3K4me3', 'Protein', (122, 129))
160726	25741387	Indeed, DLK1 is downregulated by epigenetic mechanisms in renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (58, 78))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (58, 78))	('epigenetic', 'Var', (33, 43))	('DLK1', 'Gene', '8788', (8, 12))	('DLK1', 'Gene', (8, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('downregulated', 'NegReg', (16, 29))	('renal cell carcinoma', 'Disease', (58, 78))
160741	25741387	Accordingly, we found a range of copy numbers between one and four in urothelial carcinoma tissues and cell lines indicating that both losses and gains of this region are frequent, accounting for the high frequency of apparent 'loss of heterozygosity' in previous reports.	('gains', 'PosReg', (146, 151))	('urothelial carcinoma', 'Disease', (70, 90))	('copy', 'Var', (33, 37))	('losses', 'NegReg', (135, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (70, 90))
160744	25741387	This type of change is exemplified by the HepG2 cell line, which shows strong DLK1 expression associated with a paternal epigenetic state.	('DLK1', 'Gene', (78, 82))	('HepG2', 'CellLine', 'CVCL:0027', (42, 47))	('expression', 'MPA', (83, 93))	('DLK1', 'Gene', '8788', (78, 82))	('paternal epigenetic state', 'Var', (112, 137))
160747	25741387	Of note, several microRNAs encoded in the DLK1-MEG3 cluster (Figure 1) within RTL1 (for example, miR127, miR136, miR431 and miR433) and between RTL1 and DIO3 (miR376a, miR487b, miR382, miR380-5p and miR412) have also been described to be significantly reduced or silenced by DNA hypermethylation in bladder tumor tissues and the cell lines RT4, RT112 and T24 suggesting that silencing may extend across a large part or the entire imprinted gene cluster at 14q32.	('miR431', 'Gene', '574038', (113, 119))	('bladder tumor', 'Disease', (299, 312))	('miR487b', 'Gene', (168, 175))	('DIO3', 'Gene', '1735', (153, 157))	('bladder tumor', 'Disease', 'MESH:D001749', (299, 312))	('DIO3', 'Gene', (153, 157))	('miR127', 'Gene', '406914', (97, 103))	('miR382', 'Gene', (177, 183))	('DLK1', 'Gene', '8788', (42, 46))	('MEG3', 'Gene', (47, 51))	('DLK1', 'Gene', (42, 46))	('miR376a', 'Var', (159, 166))	('miR380-5p', 'Var', (185, 194))	('RTL1', 'Gene', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('miR412', 'Gene', (199, 205))	('reduced', 'NegReg', (252, 259))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('275', '295'))	('MEG3', 'Gene', '55384', (47, 51))	('DNA', 'cellular_component', 'GO:0005574', ('275', '278'))	('miR431', 'Gene', (113, 119))	('miR433', 'Gene', (124, 130))	('miR136', 'Gene', '406927', (105, 111))	('RTL1', 'Gene', '388015', (144, 148))	('bladder tumor', 'Phenotype', 'HP:0009725', (299, 312))	('RTL1', 'Gene', (78, 82))	('miR433', 'Gene', '574034', (124, 130))	('miR487b', 'Gene', '664616', (168, 175))	('miR136', 'Gene', (105, 111))	('silenced', 'NegReg', (263, 271))	('miR412', 'Gene', '574433', (199, 205))	('miR382', 'Gene', '494331', (177, 183))	('RTL1', 'Gene', '388015', (78, 82))	('miR127', 'Gene', (97, 103))
160748	25741387	Interestingly, a coordinated regional epigenetic change has been reported for another, more centromeric, region at chromosome14q12 in urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (134, 154))	('chromosome', 'cellular_component', 'GO:0005694', ('115', '125'))	('epigenetic', 'Var', (38, 48))	('urothelial carcinoma', 'Disease', (134, 154))
160749	25741387	The repressed state of the DLK1-MEG3 cluster in urothelial carcinoma cell lines is also reflected in the predominance of repressive histone modifications such as H3K9 and H3K27 trimethylation (Figure 6).	('urothelial carcinoma cell lines', 'Disease', 'MESH:C538614', (48, 79))	('MEG3', 'Gene', (32, 36))	('DLK1', 'Gene', '8788', (27, 31))	('MEG3', 'Gene', '55384', (32, 36))	('DLK1', 'Gene', (27, 31))	('H3K9', 'Var', (162, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('urothelial carcinoma cell lines', 'Disease', (48, 79))	('H3K27 trimethylation', 'Var', (171, 191))
160750	25741387	Interestingly, whereas other active modifications were lost, H4K16ac was largely retained, despite the observation that mono-acetylated H4K16 tends to become lost in cancer in general.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('lost', 'NegReg', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('H4K16ac', 'Var', (61, 68))	('H4K16', 'Gene', (136, 141))
160752	25741387	In particular, altered nucleosomal positioning could account for the peculiar patterning of DNA methylation at the MEG3 DMR, where one specific CpG site (#6) became significantly hypomethylated in cancer cells, while methylation of flanking sites rather increased.	('DNA methylation', 'biological_process', 'GO:0006306', ('92', '107'))	('MEG3', 'Gene', (115, 119))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('MEG3', 'Gene', '55384', (115, 119))	('methylation', 'biological_process', 'GO:0032259', ('217', '228'))	('hypomethylated', 'Var', (179, 193))	('altered', 'Reg', (15, 22))	('DMR', 'Chemical', '-', (120, 123))
160760	25741387	One target of these changes is evidently MEG3, which emerges as a tumor suppressor in many different tissues.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('MEG3', 'Gene', '55384', (41, 45))	('tumor suppressor', 'biological_process', 'GO:0051726', ('66', '82'))	('tumor', 'Disease', (66, 71))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('66', '82'))	('MEG3', 'Gene', (41, 45))	('changes', 'Var', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
160763	25741387	However, the inactivation of MEG3 alone could be achieved by conventional mechanisms such as allelic loss or by epitype switching.	('inactivation', 'NegReg', (13, 25))	('allelic loss', 'Disease', 'MESH:C566065', (93, 105))	('epitype switching', 'Var', (112, 129))	('MEG3', 'Gene', (29, 33))	('allelic loss', 'Disease', (93, 105))	('MEG3', 'Gene', '55384', (29, 33))
160767	25741387	The tumor stages and grades according to the current UICC classification were as follows: pT3 G3 in 11 cases, pT4 G3 in 6 cases, pT2 G2 in 6 cases, pT2 G3 in 3 cases and one case each of pT3 G2, pT1 G2, pTa G3 and pTa G2.	('tumor', 'Disease', (4, 9))	('pT2 G3', 'Var', (148, 154))	('pTa', 'molecular_function', 'GO:0008959', ('214', '217'))	('pTa', 'molecular_function', 'GO:0008959', ('203', '206'))	('pT3', 'Disease', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('pT4 G3', 'Var', (110, 116))
160784	25741387	CTCFL was used as a control for a silenced gene with inactive histone modifications (H3K9me3 and H3K27me3), whereas GAPDH was used as control for a highly expressed gene with active histone modifications (H3K4me3, H4K14ac).	('H3K27me3', 'Var', (97, 105))	('H3K9me3', 'Var', (85, 92))	('CTCFL', 'Gene', '140690', (0, 5))	('H4K14ac', 'Var', (214, 221))	('CTCFL', 'Gene', (0, 5))	('GAPDH', 'Gene', '2597', (116, 121))	('GAPDH', 'Gene', (116, 121))	('H3K4me3', 'Var', (205, 212))
160786	25741387	ChIP chromatin immunoprecipitation DMR differentially methylated region ICR imprinting control region IG intergenic UCC urothelial cancer cell UP (normal) urothelial cell culture.	('chromatin', 'cellular_component', 'GO:0000785', ('5', '14'))	('DMR', 'Chemical', '-', (35, 38))	('urothelial cancer', 'Disease', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('urothelial cancer', 'Disease', 'MESH:D014523', (120, 137))	('DMR', 'Var', (35, 38))
160800	29471873	Here, we used the query options in the control panel to enter the TCGA identifiers for adrenocortical carcinoma (ACC) and bladder urothelial carcinoma (BLCA) studies, and the miRBase IDs for has-let-7b and has-let-7c.	('bladder urothelial carcinoma', 'Disease', (122, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('let-7b', 'Gene', '406884', (195, 201))	('has-let-7c', 'Var', (206, 216))	('let-7b', 'Gene', (195, 201))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (87, 111))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (87, 111))	('ACC', 'Phenotype', 'HP:0006744', (113, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (122, 150))	('adrenocortical carcinoma', 'Disease', (87, 111))
160876	29157296	Notably, the anti-PD-1 antibody pembrolizumab demonstrated improved OS relative to chemotherapy in a randomized phase III study for second line treatment of mUC; this level 1 evidence led to approval from the U.S. Food and Drug Administration (FDA).	('antibody', 'cellular_component', 'GO:0042571', ('23', '31'))	('anti-PD-1', 'Var', (13, 22))	('improved', 'PosReg', (59, 67))	('antibody', 'cellular_component', 'GO:0019815', ('23', '31'))	('pembrolizumab', 'Chemical', 'MESH:C582435', (32, 45))	('antibody', 'cellular_component', 'GO:0019814', ('23', '31'))	('antibody', 'molecular_function', 'GO:0003823', ('23', '31'))	('OS', 'Gene', '17451', (68, 70))	('pembrolizumab', 'Gene', (32, 45))
160911	29157296	Conversely, median OS was 11.30 months for patients with >=1% PD-L1 expression in comparison to 5.95 months with <=1% PD-L1 expression.	('PD-L1', 'Gene', (62, 67))	('patients', 'Species', '9606', (43, 51))	('OS', 'Gene', '17451', (19, 21))	('expression', 'Var', (68, 78))
160931	29157296	Response rates for patients with PD-L1 expressing tumor cells were 46.4% in comparison to 22% for PD-L1 negative tumors.	('tumor', 'Disease', (113, 118))	('patients', 'Species', '9606', (19, 27))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('PD-L1 expressing', 'Var', (33, 49))	('tumor', 'Disease', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
160941	29157296	At a primary end-point of 12-weeks there was a trend towards increased survival in high PD-L1 expressing patients, with ORR of 53.8% vs 9.0% in PD-L1 tumor cell high relative to low expressing tumors (cutoff 5%, Dako PD-L1 IHC kit, Dako North America, Carpenteria, CA, USA, Merck 73-10 monoclonal antibody).	('antibody', 'cellular_component', 'GO:0019815', ('297', '305'))	('patients', 'Species', '9606', (105, 113))	('PD-L1', 'Gene', (88, 93))	('antibody', 'cellular_component', 'GO:0019814', ('297', '305'))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('increased', 'PosReg', (61, 70))	('antibody', 'molecular_function', 'GO:0003823', ('297', '305'))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('PD-L1 tumor', 'Disease', (144, 155))	('high', 'Var', (83, 87))	('survival', 'MPA', (71, 79))	('PD-L1 tumor', 'Disease', 'MESH:D010300', (144, 155))	('antibody', 'cellular_component', 'GO:0042571', ('297', '305'))
160951	29157296	A number of on-going trials are evaluating novel targets in combination with PD-1 therapy, including traditional chemotherapy, intra-vesical BCG, IDO inhibitors such as epacadostat, CD27, CD137, OX-40, and CSF1-R (Tables 2 and 3).	('CSF1', 'molecular_function', 'GO:0005011', ('206', '210'))	('IDO', 'molecular_function', 'GO:0033754', ('146', '149'))	('CD27', 'Var', (182, 186))	('IDO', 'molecular_function', 'GO:0047719', ('146', '149'))	('BCG', 'Species', '33892', (141, 144))	('CD137', 'Var', (188, 193))
160954	29157296	Early phase clinical trials evaluating BCG in combination with both pembrolizumab (NCT02324582, NCT02808143) and atezolizumab (NCT02792192) are currently accruing.	('atezolizumab', 'Chemical', 'MESH:C000594389', (113, 125))	('NCT02324582', 'Var', (83, 94))	('NCT02792192', 'Var', (127, 138))	('BCG', 'Species', '33892', (39, 42))	('pembrolizumab', 'Chemical', 'MESH:C582435', (68, 81))
160963	29157296	Another comparison of the 22C3, 28-8, SP26, and SP142 antibodies in 90 NSCLC specimens confirmed that SP-142 detected significantly lower mean PD-L1 TC and IC expression - again illustrating the challenges of comparing PD-L1 expression between assays.	('SP142', 'Chemical', '-', (48, 53))	('SP', 'Chemical', 'MESH:C000604007', (102, 104))	('SP-142', 'Var', (102, 108))	('IC expression -', 'MPA', (156, 171))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))	('lower', 'NegReg', (132, 137))	('NSCLC', 'Disease', (71, 76))	('TC', 'Chemical', '-', (149, 151))	('PD-L1', 'Protein', (143, 148))	('SP', 'Chemical', 'MESH:C000604007', (48, 50))	('SP', 'Chemical', 'MESH:C000604007', (38, 40))
160981	29157296	In both melanoma and NSCLC, mutational load, as well as the number of predicted neoantigens is associated with a greater likelihood of durable responses to immune checkpoint blockade.	('melanoma', 'Disease', 'MESH:D008545', (8, 16))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanoma', 'Disease', (8, 16))	('NSCLC', 'Disease', (21, 26))	('mutational load', 'Var', (28, 43))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))
160982	29157296	In fact, those retrospective data suggest that mutational load may potentially predict response more robustly than PD-L1 IHC, presence of tumor infiltrating lymphocytes, or clinical variables.	('mutational load', 'Var', (47, 62))	('predict', 'Reg', (79, 86))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
160996	29157296	Data in NSCLC using targeted exome sequencing of cancer specific genes identified an association between high mutation burden and durable overall response.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('high mutation burden', 'Var', (105, 125))	('NSCLC', 'Disease', (8, 13))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('NSCLC', 'Disease', 'MESH:D002289', (8, 13))	('cancer', 'Disease', (49, 55))
160997	29157296	A composite score of PD-L1 status >1% and tumor mutation burden above the median correlated with response, with 60% of patients with high PD-L1 and high TMB deriving durable clinical responses.	('tumor', 'Disease', (42, 47))	('patients', 'Species', '9606', (119, 127))	('high PD-L1', 'Var', (133, 143))	('correlated', 'Reg', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('high', 'Var', (148, 152))	('TMB', 'Chemical', '-', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
161005	29157296	tobacco, ultraviolet light, aniline dye), defects in DNA repair mechanisms such as microsatellite instability/mismatch repair defects, and POLE mutations have emerged as potentially useful clinical biomarkers.	('defects', 'Var', (42, 49))	('tobacco', 'Species', '4097', (0, 7))	('aniline', 'Chemical', 'MESH:C023650', (28, 35))	('DNA repair', 'biological_process', 'GO:0006281', ('53', '63'))	('mismatch repair', 'biological_process', 'GO:0006298', ('110', '125'))	('microsatellite instability/mismatch repair', 'MPA', (83, 125))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('mutations', 'Var', (144, 153))
161006	29157296	Based on this notion and data demonstrating an overall response rate of 39.6% with pembrolizumab in microsatellite instability (MSI) high and mismatch repair deficient malignancies, pembrolizumab has been approved for patients with these gene defects solid after progression on prior treatments prompting investigation in a phase III setting.	('microsatellite instability', 'MPA', (100, 126))	('deficient malignancies', 'Disease', (158, 180))	('patients', 'Species', '9606', (218, 226))	('mismatch repair', 'biological_process', 'GO:0006298', ('142', '157'))	('MSI', 'Disease', 'None', (128, 131))	('MSI', 'Disease', (128, 131))	('defects', 'Var', (243, 250))	('deficient malignancies', 'Disease', 'MESH:D009369', (158, 180))	('pembrolizumab', 'Chemical', 'MESH:C582435', (182, 195))	('pembrolizumab', 'Chemical', 'MESH:C582435', (83, 96))
161008	29157296	Interestingly, certain mutational variants may portend a lack of benefit with PD-1 therapy, such as individual mutations in EGFR and STK11 that are associated with a lack of benefit in NSCLC and lung adenocarcinoma.	('mutations', 'Var', (111, 120))	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('STK11', 'Gene', '6794', (133, 138))	('EGFR', 'Gene', '1956', (124, 128))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (195, 214))	('STK11', 'molecular_function', 'GO:0033868', ('133', '138'))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('EGFR', 'Gene', (124, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('lung adenocarcinoma', 'Disease', (195, 214))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (195, 214))	('STK11', 'Gene', (133, 138))	('NSCLC', 'Disease', (185, 190))
161019	29157296	Higher values in the IFN-gamma gene signature were correlated with response to nivolumab relative to low value IFN-gamma expression score (p = 0.0003, CR or PR in 20/59 patients with high IFN-gamma signature relative to CR or PR in 19/118 patients with medium or low IFN-gamma signature).	('patients', 'Species', '9606', (169, 177))	('IFN-gamma', 'Gene', '3458', (111, 120))	('IFN-gamma', 'Gene', (111, 120))	('IFN-gamma', 'Gene', (188, 197))	('patients', 'Species', '9606', (239, 247))	('response to nivolumab', 'MPA', (67, 88))	('IFN-gamma', 'Gene', '3458', (21, 30))	('high', 'Var', (183, 187))	('IFN-gamma', 'Gene', (267, 276))	('nivolumab', 'Chemical', 'MESH:D000077594', (79, 88))	('IFN-gamma', 'Gene', '3458', (267, 276))	('IFN-gamma', 'Gene', '3458', (188, 197))	('IFN-gamma', 'Gene', (21, 30))
161026	29157296	This 18-gene panel has now been validated using tumor specimens from patients across 9 tumor types in 220 patients treated with PD-1 therapy and is currently being evaluated prospectively in 3 ongoing Phase III trials with pembrolizumab (NCT02628067, NCT02559687, and NCT02564263).	('pembrolizumab', 'Chemical', 'MESH:C582435', (223, 236))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (48, 53))	('NCT02564263', 'Var', (268, 279))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('patients', 'Species', '9606', (106, 114))	('NCT02628067', 'Var', (238, 249))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('patients', 'Species', '9606', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('NCT02559687', 'Var', (251, 262))
161093	23497335	The risk of presenting nodal disease (p=0.002, Fisher's exact test) or distant metastasis (p=0.016, Fisher's exact test; Table 1) also increased significantly in patients with a CRP value >5 mg/l.	('patients', 'Species', '9606', (162, 170))	('distant metastasis', 'CPA', (71, 89))	('nodal disease', 'Disease', 'MESH:D013611', (23, 36))	('CRP', 'Gene', (178, 181))	('nodal disease', 'Disease', (23, 36))	('increased', 'PosReg', (135, 144))	('CRP', 'Gene', '1401', (178, 181))	('>5 mg/l', 'Var', (188, 195))
161104	23497335	Furthermore, a high CRP value was associated with poor cancer specific survival in patients undergoing resection for UUT-UC.	('high', 'Var', (15, 19))	('UUT-UC', 'Disease', (117, 123))	('poor', 'NegReg', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('patients', 'Species', '9606', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('CRP', 'Gene', (20, 23))	('cancer', 'Disease', (55, 61))	('CRP', 'Gene', '1401', (20, 23))
161225	21603201	The etiology of increased risk for BUC among transplant recipients is multifactorial, and in addition to common risk factors for BUC such as smoking, also includes risk factors unique to the transplant recipient, such as direct cytotoxic damage from immunosuppressive agents, impaired DNA repair mechanisms in immunocompromised patients, impaired protection against viral oncogenes, and urinary tract infections.	('impaired', 'NegReg', (338, 346))	('BUC', 'Disease', (35, 38))	('urinary tract infections', 'Phenotype', 'HP:0000010', (387, 411))	('urinary tract infections', 'Disease', (387, 411))	('DNA', 'cellular_component', 'GO:0005574', ('285', '288'))	('impaired', 'Var', (276, 284))	('DNA repair', 'biological_process', 'GO:0006281', ('285', '295'))	('urinary tract infections', 'Disease', 'MESH:D014552', (387, 411))
161286	32120859	It shows that the Young's modulus of SW780 (G1) and RT4 (G1) were apparently higher than the other four kinds of cell lines, while the Young's modulus of 253J (G4) was the lowest.	('RT4', 'Var', (52, 55))	('SW780', 'Var', (37, 42))	('SW780', 'CellLine', 'CVCL:1728', (37, 42))	('higher', 'PosReg', (77, 83))
161290	32120859	It shows that the SMC value of SW780 (G1) and RT4 (G1) was significantly lower than the other four types of cell lines.	('SMC', 'cellular_component', 'GO:0016029', ('18', '21'))	('SW780', 'CellLine', 'CVCL:1728', (31, 36))	('RT4', 'Var', (46, 49))	('lower', 'NegReg', (73, 78))	('SMC value', 'MPA', (18, 27))	('SW780', 'Var', (31, 36))
161294	32120859	Based on the combination of two physical properties, the data points fell into three categories: the points of 253J cell lines were mainly contained in the green oval area, which is G4; the points of T24, J82, and 5637 cell lines were mainly contained in the blue oval area, which are G2 and G3; the points of SW780 and RT4 cell lines were mainly contained in the red oval area, which is G1.	('J82', 'Var', (205, 208))	('blue oval area', 'Phenotype', 'HP:0000635', (259, 273))	('J82', 'CellLine', 'CVCL:0359', (205, 208))	('SW780', 'CellLine', 'CVCL:1728', (310, 315))	('T24', 'Var', (200, 203))
161308	21777423	We evaluated the diagnostic utility of a dual immunohistochemical stain comprising p63 and P501S (prostein), applied sequentially on a single slide and visualized by double chromogen reaction, in differentiating these two cancers.	('P501S', 'Mutation', 'p.P501S', (91, 96))	('prostein', 'Gene', '85414', (98, 106))	('P501S', 'Var', (91, 96))	('p63', 'Gene', (83, 86))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('prostein', 'Gene', (98, 106))	('cancers', 'Disease', (222, 229))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('p63', 'Gene', '8626', (83, 86))
161309	21777423	Thus far, there have been no previous studies assessing the diagnostic utility of p63 and P501S combined together as a dual immunostain in distinguishing between these two cancers.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('p63', 'Gene', '8626', (82, 85))	('P501S', 'Mutation', 'p.P501S', (90, 95))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('P501S', 'Var', (90, 95))	('p63', 'Gene', (82, 85))
161310	21777423	p63/P501S dual-color sequential immunohistochemical staining was performed on archival material from 132 patients with high-grade UC and 23 patients with PC, and evaluated for p63 (brown nuclear) and P501S (red cytoplasmic) expression.	('PC', 'Phenotype', 'HP:0012125', (154, 156))	('patients', 'Species', '9606', (105, 113))	('P501S', 'Mutation', 'p.P501S', (4, 9))	('p63', 'Gene', (0, 3))	('p63', 'Gene', '8626', (0, 3))	('P501S', 'Mutation', 'p.P501S', (200, 205))	('p63', 'Gene', (176, 179))	('patients', 'Species', '9606', (140, 148))	('p63', 'Gene', '8626', (176, 179))	('P501S', 'Var', (200, 205))
161313	21777423	P501S was positive in 22/23 of PC and negative in UC.	('P501S', 'Mutation', 'p.P501S', (0, 5))	('positive', 'Reg', (10, 18))	('P501S', 'Var', (0, 5))	('PC', 'Phenotype', 'HP:0012125', (31, 33))
161316	21777423	Our results indicate that double sequential immunohistochemical staining with p63 and P501S is highly specific and can be a useful tool in distinguishing UC from PC especially when there is limited diagnostic tissue as it can be performed on a single slide.	('p63', 'Gene', (78, 81))	('p63', 'Gene', '8626', (78, 81))	('P501S', 'Mutation', 'p.P501S', (86, 91))	('PC', 'Phenotype', 'HP:0012125', (162, 164))	('P501S', 'Var', (86, 91))
161321	21777423	Among the newer markers, prostate-specific membrane antigen (PSMA) and P501S (prostein) have been shown to have excellent specificity in differentiating prostate from urothelial cancers.	('prostate', 'Disease', (153, 161))	('urothelial cancers', 'Disease', 'MESH:D014523', (167, 185))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('prostein', 'Gene', '85414', (78, 86))	('P501S', 'Var', (71, 76))	('urothelial cancers', 'Disease', (167, 185))	('prostein', 'Gene', (78, 86))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('prostate-specific membrane antigen', 'molecular_function', 'GO:0043275', ('25', '59'))	('prostate-specific', 'Protein', (25, 42))	('membrane', 'cellular_component', 'GO:0016020', ('43', '51'))	('PSMA', 'molecular_function', 'GO:0043275', ('61', '65'))	('P501S', 'Mutation', 'p.P501S', (71, 76))
161330	21777423	The aim of this study was to evaluate the diagnostic utility of p63 and P501S in distinguishing between PC and UC using dual-color immunohistochemical staining performed on a single slide by sequentially applying the antibodies.	('p63', 'Gene', (64, 67))	('p63', 'Gene', '8626', (64, 67))	('P501S', 'Mutation', 'p.P501S', (72, 77))	('PC', 'Phenotype', 'HP:0012125', (104, 106))	('P501S', 'Var', (72, 77))
161341	21777423	The remaining 132 urothelial cancer cases and 23 prostate cancer cases [Gleason score 10 (n = 1), Gleason score 9 (n = 6), Gleason score 8 (n = 7), Gleason score 7 (n = 4), Gleason score 6 (n = 5) were included in the final analyses.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (49, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (49, 64))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('urothelial cancer', 'Disease', (18, 35))	('urothelial cancer', 'Disease', 'MESH:D014523', (18, 35))	('prostate cancer', 'Disease', (49, 64))	('Gleason', 'Var', (98, 105))	('Gleason score', 'Var', (123, 136))
161351	21777423	Immunohistochemical staining scores for p63 and P501S were individually compared between urothelial and prostate cancers, and a p-value less than 0.05 was considered statistically significant.	('p63', 'Gene', '8626', (40, 43))	('prostate cancers', 'Disease', 'MESH:D011471', (104, 120))	('P501S', 'Mutation', 'p.P501S', (48, 53))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('urothelial', 'Disease', (89, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (104, 119))	('P501S', 'Var', (48, 53))	('prostate cancers', 'Phenotype', 'HP:0012125', (104, 120))	('prostate cancers', 'Disease', (104, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('p63', 'Gene', (40, 43))
161352	21777423	The sensitivity, specificity, and predictive values for combined p63 and P501S immunostaining was also determined for both tumor types.	('P501S', 'Var', (73, 78))	('tumor', 'Disease', (123, 128))	('p63', 'Gene', (65, 68))	('P501S', 'Mutation', 'p.P501S', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('p63', 'Gene', '8626', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
161353	21777423	Neither UC nor PC was positive for both p63 and p501S.	('PC', 'Phenotype', 'HP:0012125', (15, 17))	('p501S', 'Var', (48, 53))	('p63', 'Gene', (40, 43))	('p63', 'Gene', '8626', (40, 43))
161354	21777423	Statistically significant p-values were observed for p63 and P501S expression, individually, in the distinction of UC from PC.	('PC', 'Phenotype', 'HP:0012125', (123, 125))	('p63', 'Gene', '8626', (53, 56))	('P501S', 'Var', (61, 66))	('p63', 'Gene', (53, 56))	('P501S', 'Mutation', 'p.P501S', (61, 66))
161358	21777423	P501S showed red granular perinuclear cytoplasmic staining of prostate cancer cells.	('P501S', 'Mutation', 'p.P501S', (0, 5))	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('P501S', 'Var', (0, 5))	('prostate cancer', 'Disease', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('prostate cancer', 'Disease', 'MESH:D011471', (62, 77))
161360	21777423	The p63 and P501S combination immunohistochemical profiles in UC and PC are illustrated in Figure 2.	('p63', 'Gene', (4, 7))	('P501S', 'Var', (12, 17))	('p63', 'Gene', '8626', (4, 7))	('PC', 'Phenotype', 'HP:0012125', (69, 71))	('P501S', 'Mutation', 'p.P501S', (12, 17))
161361	21777423	The sensitivity, specificity, and predictive values of p63 and P501S combination immunoprofiles for distinguishing PC from UC are shown in Table 2.	('P501S', 'Mutation', 'p.P501S', (63, 68))	('p63', 'Gene', (55, 58))	('P501S', 'Var', (63, 68))	('p63', 'Gene', '8626', (55, 58))	('PC', 'Phenotype', 'HP:0012125', (115, 117))
161367	21777423	Although the diagnostic utility of p63 and P501S in distinguishing between primary PC and UC have been individually evaluated previously, thus far, there have been no previous studies evaluating these two markers together either as a cocktail or applied sequentially.	('primary PC', 'Disease', (75, 85))	('P501S', 'Var', (43, 48))	('p63', 'Gene', (35, 38))	('PC', 'Phenotype', 'HP:0012125', (83, 85))	('p63', 'Gene', '8626', (35, 38))	('P501S', 'Mutation', 'p.P501S', (43, 48))
161368	21777423	Our results indicate that dual-color immunohistochemistry with p63 and P501S applied sequentially shows excellent specificity for distinguishing UC from PC.	('P501S', 'Var', (71, 76))	('p63', 'Gene', (63, 66))	('PC', 'Phenotype', 'HP:0012125', (153, 155))	('p63', 'Gene', '8626', (63, 66))	('P501S', 'Mutation', 'p.P501S', (71, 76))
161369	21777423	The differential localization (diffuse nuclear for p63 versus granular cytoplasmic for P501S) combined with the double chromogen reaction facilitate easy visualization (brown for p63 and red for P501S) and enable quick and easy interpretation of the markers all in one slide.	('P501S', 'Mutation', 'p.P501S', (195, 200))	('localization', 'biological_process', 'GO:0051179', ('17', '29'))	('p63', 'Gene', (179, 182))	('p63', 'Gene', (51, 54))	('P501S', 'Mutation', 'p.P501S', (87, 92))	('p63', 'Gene', '8626', (179, 182))	('P501S', 'Var', (195, 200))	('p63', 'Gene', '8626', (51, 54))
161384	21777423	These authors also found P501S to have high specificity with only 2/35 (6%) high grade UC showing focal weak positivity.	('P501S', 'Var', (25, 30))	('high grade UC', 'Disease', (76, 89))	('P501S', 'Mutation', 'p.P501S', (25, 30))
161388	21777423	The single P501S negative case in our study was diagnosed as a poorly differentiated prostatic adenocarcinoma (Gleason score 9).	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('P501S', 'Mutation', 'p.P501S', (11, 16))	('P501S', 'Var', (11, 16))	('prostatic adenocarcinoma', 'Disease', 'MESH:D011471', (85, 109))	('prostatic adenocarcinoma', 'Disease', (85, 109))
161406	21777423	Immunohistochemistry using a triple antibody combination of p63, P501S, and S100P or HMWCK or thrombomodulin may increase the sensitivity of the p63/P501S immunostain for detection of UC, and needs to be confirmed in future studies.	('antibody', 'cellular_component', 'GO:0042571', ('36', '44'))	('S100P', 'Gene', '6286', (76, 81))	('P501S', 'Mutation', 'p.P501S', (65, 70))	('p63', 'Gene', '8626', (60, 63))	('thrombomodulin', 'Gene', '7056', (94, 108))	('antibody', 'cellular_component', 'GO:0019815', ('36', '44'))	('sensitivity', 'MPA', (126, 137))	('thrombomodulin', 'Gene', (94, 108))	('S100P', 'Gene', (76, 81))	('p63', 'Gene', (145, 148))	('antibody', 'cellular_component', 'GO:0019814', ('36', '44'))	('P501S', 'Mutation', 'p.P501S', (149, 154))	('P501S', 'Var', (65, 70))	('increase', 'PosReg', (113, 121))	('p63', 'Gene', '8626', (145, 148))	('antibody', 'molecular_function', 'GO:0003823', ('36', '44'))	('p63', 'Gene', (60, 63))
161412	19843858	In contrast, none of the other subtypes of kidney neoplasms (e.g., clear cell renal cell carcinoma) harbored PIK3CA mutations (n = 87; P < 0.001).	('PIK3CA', 'Gene', (109, 115))	('neoplasms', 'Phenotype', 'HP:0002664', (50, 59))	('kidney neoplasms', 'Phenotype', 'HP:0009726', (43, 59))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (67, 98))	('kidney neoplasms', 'Disease', (43, 59))	('kidney neoplasms', 'Disease', 'MESH:D007680', (43, 59))	('clear cell renal cell carcinoma', 'Disease', (67, 98))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (78, 98))	('mutations', 'Var', (116, 125))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (67, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))
161414	19843858	To confirm the role of the PI3K/AKT pathway in urothelial carcinoma, we generated mice containing biallelic inactivation of Pten in the urogenital epithelia.	('mice', 'Species', '10090', (82, 86))	('PI3K', 'molecular_function', 'GO:0016303', ('27', '31'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (47, 67))	('urogenital epithelia', 'Disease', (136, 156))	('biallelic inactivation', 'Var', (98, 120))	('urothelial carcinoma', 'Disease', (47, 67))	('urogenital epithelia', 'Disease', 'MESH:D014564', (136, 156))	('Pten', 'Gene', (124, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
161416	19843858	Laser capture microdissection followed by PCR confirmed the deletion of Pten exons 4 and 5 in the animal tumor cells.	('Pten', 'Gene', (72, 76))	('deletion', 'Var', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
161428	19843858	PI3K-mediated production of PIP3 triggers a signaling cascade which results in the activation of the serine/threonine kinase AKT and some of its downstream targets, including mTOR (mammalian target of rapamycin).	('production', 'Var', (14, 24))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PIP3', 'Var', (28, 32))	('PI3K-mediated', 'Var', (0, 13))	('signaling', 'MPA', (44, 53))	('mammalian target of rapamycin', 'Gene', '2475', (181, 210))	('mammalian target of rapamycin', 'Gene', (181, 210))	('signaling cascade', 'biological_process', 'GO:0007165', ('44', '61'))	('PIP3', 'Chemical', '-', (28, 32))	('serine/threonine kinase AKT', 'Pathway', (101, 128))	('activation', 'PosReg', (83, 93))
161429	19843858	Activated mTOR itself phosphorylates and activates downstream targets, including p70 S6 kinase (S6K).	('S6K', 'Gene', (96, 99))	('p70', 'Var', (81, 84))	('S6K', 'Gene', '72508', (96, 99))	('activates', 'PosReg', (41, 50))
161433	19843858	PTEN is commonly inactivated by mutation and loss of heterozygosity (LOH) in human cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('inactivated', 'NegReg', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('PTEN', 'Gene', (0, 4))	('mutation', 'Var', (32, 40))	('loss', 'Var', (45, 49))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
161439	19843858	The DNA from another 87 kidney tumors of various pathological types (32 clear cell, 15 chromophobe, and 15 papillary RCC, 10 oncocytoma, 6 Wilms' tumor, and 9 unknown kidney tumors) was also extracted for PIK3CA mutation screening.	('PIK3CA', 'Gene', (205, 211))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (139, 151))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('kidney tumor', 'Phenotype', 'HP:0009726', (167, 179))	('kidney tumor', 'Phenotype', 'HP:0009726', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('oncocytoma', 'Disease', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('15 papillary RCC', 'Disease', 'MESH:C538614', (104, 120))	('kidney tumors', 'Disease', (24, 37))	("Wilms' tumor", 'Disease', 'MESH:D009396', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	("Wilms' tumor", 'Disease', (139, 151))	('unknown kidney tumors', 'Disease', (159, 180))	('15 papillary RCC', 'Disease', (104, 120))	('clear cell', 'Disease', (72, 82))	('kidney tumors', 'Disease', 'MESH:D007674', (167, 180))	('oncocytoma', 'Disease', 'MESH:D018249', (125, 135))	('unknown kidney tumors', 'Disease', 'MESH:D009382', (159, 180))	('kidney tumors', 'Phenotype', 'HP:0009726', (167, 180))	('mutation', 'Var', (212, 220))	('kidney tumors', 'Phenotype', 'HP:0009726', (24, 37))	('kidney tumors', 'Disease', 'MESH:D007674', (24, 37))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
161444	19843858	Briefly, sets of genes that were over- or down-expressed by activation of MYC, RAS, E2F, SRC, AKT, synergistic HGF/VEGF, inactivation of VHL, or induction of hypoxia were obtained from the literature.	('RAS', 'Gene', (79, 82))	('AKT', 'Gene', (94, 97))	('SRC', 'Gene', (89, 92))	('activation', 'PosReg', (60, 70))	('E2F', 'Gene', (84, 87))	('MYC', 'Gene', (74, 77))	('SRC', 'Gene', '20779', (89, 92))	('VEGF', 'Gene', (115, 119))	('hypoxia', 'Disease', (158, 165))	('HGF', 'Gene', '15234', (111, 114))	('VEGF', 'Gene', '22339', (115, 119))	('hypoxia', 'Disease', 'MESH:D000860', (158, 165))	('VHL', 'Gene', (137, 140))	('inactivation', 'Var', (121, 133))	('MYC', 'Gene', '17869', (74, 77))	('HGF', 'Gene', (111, 114))	('over-', 'PosReg', (33, 38))	('down-expressed', 'NegReg', (42, 56))	('VHL', 'Gene', '22346', (137, 140))
161446	19843858	For consistent presentation, all "up" and "down" gene lists reflect the gene expression changes in treated/mutant cells versus the nearest approximation of wild-type cells; for example, MYC-transfected cells were compared with mock-transfected cells.	('MYC', 'Gene', (186, 189))	('gene expression', 'biological_process', 'GO:0010467', ('68', '83'))	('MYC', 'Gene', '17869', (186, 189))	('gene expression', 'MPA', (72, 87))	('treated/mutant', 'Var', (99, 113))
161458	19843858	Eight matched samples of renal pelvic urothelial carcinoma tumor tissue and normal tissue were studied using 12 highly polymorphic microsatellite markers from human chromosome 10: D10S1652, D10S537, D10S1686, W1218, D10S1739, W213, D10S1753, D10S564, D10S583, D10S185, D10S192, and D10S597.	('D10S1652', 'Var', (180, 188))	('D10S1739', 'Var', (216, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('D10S597', 'Var', (282, 289))	('D10S537', 'Var', (190, 197))	('W213', 'Var', (226, 230))	('D10S192', 'Var', (269, 276))	('renal pelvic urothelial carcinoma tumor', 'Disease', 'MESH:D007674', (25, 64))	('chromosome', 'cellular_component', 'GO:0005694', ('165', '175'))	('D10S583', 'Var', (251, 258))	('renal pelvic urothelial carcinoma tumor', 'Disease', (25, 64))	('D10S185', 'Var', (260, 267))	('D10S1753', 'Var', (232, 240))	('human', 'Species', '9606', (159, 164))	('D10S1686', 'Var', (199, 207))	('D10S564', 'Var', (242, 249))	('W1218', 'Var', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
161481	19843858	This analysis revealed that a set of genes over-expressed following activation of PI3K/AKT in tissue culture cells was also significantly over-expressed in 10 of 13 urothelial carcinoma samples (76.9%) (Fig.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (165, 185))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('PI3K/AKT', 'Var', (82, 90))	('over-expressed', 'PosReg', (138, 152))	('activation', 'PosReg', (68, 78))	('urothelial carcinoma', 'Disease', (165, 185))	('over-expressed', 'PosReg', (43, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
161482	19843858	Clear cell RCCs, which represent the majority of adult kidney tumors, are associated with biallelic inactivation of the VHL gene.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('biallelic inactivation', 'Var', (90, 112))	('adult kidney tumors', 'Disease', 'MESH:D007690', (49, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('VHL', 'Gene', (120, 123))	('adult kidney tumors', 'Disease', (49, 68))	('VHL', 'Gene', '22346', (120, 123))	('kidney tumor', 'Phenotype', 'HP:0009726', (55, 67))	('kidney tumors', 'Phenotype', 'HP:0009726', (55, 68))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))	('associated', 'Reg', (74, 84))
161483	19843858	Consistent with VHL inactivation, a set of VHL-regulated genes were significantly down-regulated in the clear cell RCC samples (Fig.	('VHL', 'Gene', (16, 19))	('down-regulated', 'NegReg', (82, 96))	('VHL', 'Gene', (43, 46))	('inactivation', 'Var', (20, 32))	('VHL', 'Gene', '22346', (16, 19))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('VHL', 'Gene', '22346', (43, 46))
161484	19843858	The VHL-regulated genes were not significantly deregulated in the urothelial carcinoma samples, suggesting that defects in AKT signaling, but not VHL signaling, are associated with development of urothelial carcinoma of renal pelvis.	('urothelial carcinoma', 'Disease', (66, 86))	('VHL', 'Gene', (146, 149))	('renal pelvis', 'Phenotype', 'HP:0000125', (220, 232))	('urothelial carcinoma of renal pelvis', 'Disease', 'MESH:C538614', (196, 232))	('signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (196, 216))	('VHL', 'Gene', '22346', (146, 149))	('AKT signaling', 'MPA', (123, 136))	('associated', 'Reg', (165, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('carcinoma of renal', 'Phenotype', 'HP:0005584', (207, 225))	('urothelial carcinoma of renal pelvis', 'Disease', (196, 232))	('defects', 'Var', (112, 119))	('VHL', 'Gene', (4, 7))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (66, 86))	('AKT signaling', 'biological_process', 'GO:0043491', ('123', '136'))	('VHL', 'Gene', '22346', (4, 7))
161485	19843858	Activating mutations in the catalytic subunit of PI3K (PIK3CA) are common occurrences in cancer.	('Activating mutations', 'Var', (0, 20))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('PI3K', 'molecular_function', 'GO:0016303', ('49', '53'))	('cancer', 'Disease', (89, 95))	('PIK3CA', 'Gene', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
161486	19843858	To determine if activating mutations in PIK3CA are associated with the predicted frequent activation of the PI3K/AKT pathway in renal pelvic urothelial carcinoma, sequence analysis of PIK3CA was performed on 22 human renal pelvic urothelial carcinomas and 87 cases of other types of renal tumors.	('mutations', 'Var', (27, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('carcinomas', 'Phenotype', 'HP:0030731', (241, 251))	('renal pelvic urothelial carcinomas', 'Disease', (217, 251))	('renal tumors', 'Disease', (283, 295))	('activating', 'PosReg', (16, 26))	('activation', 'PosReg', (90, 100))	('renal tumors', 'Disease', 'MESH:D007674', (283, 295))	('renal pelvic urothelial carcinomas', 'Disease', 'MESH:D007674', (217, 251))	('renal tumors', 'Phenotype', 'HP:0009726', (283, 295))	('renal pelvic urothelial carcinoma', 'Disease', 'MESH:D007674', (217, 250))	('renal pelvic urothelial carcinoma', 'Disease', (128, 161))	('renal pelvic urothelial carcinoma', 'Disease', 'MESH:D007674', (128, 161))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('PIK3CA', 'Gene', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))	('PI3K/AKT pathway', 'Pathway', (108, 124))	('human', 'Species', '9606', (211, 216))
161487	19843858	Mutations of PIK3CA were found in 4 (18.2%) urothelial carcinoma cases (one tumor with K111E mutation in exon 1, two with E545K, and one with E542K in exon 9).	('E542K', 'Var', (142, 147))	('E545K', 'Mutation', 'rs104886003', (122, 127))	('PIK3CA', 'Gene', (13, 19))	('E545K', 'Var', (122, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('K111E', 'Var', (87, 92))	('urothelial carcinoma', 'Disease', (44, 64))	('E542K', 'Mutation', 'rs121913273', (142, 147))	('Mutations', 'Var', (0, 9))	('K111E', 'Mutation', 'rs1057519933', (87, 92))	('found', 'Reg', (25, 30))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (44, 64))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
161488	19843858	Of these, the mutations of E545K and E542K in exon 9 occur in a hotspot of sequence mutation and are known activating mutations.	('E542K', 'Mutation', 'rs121913273', (37, 42))	('E545K', 'Mutation', 'rs104886003', (27, 32))	('E542K', 'Var', (37, 42))	('E545K', 'Var', (27, 32))
161489	19843858	Therefore, at least a 13.6% (3/22) frequency of an activating PI3KCA mutation was found in the urothelial carcinoma samples (Supplemental Table 1).	('PI3KCA', 'Gene', (62, 68))	('urothelial carcinoma', 'Disease', (95, 115))	('mutation', 'Var', (69, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('activating', 'PosReg', (51, 61))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (95, 115))
161490	19843858	In contrast, no mutation was found in the 87 cases of other renal neoplasms; thus, the prevalence of activating mutations in PIK3CA is significantly higher in renal pelvic urothelial carcinoma (P = 0.01).	('renal pelvic urothelial carcinoma', 'Disease', 'MESH:D007674', (159, 192))	('renal pelvic urothelial carcinoma', 'Disease', (159, 192))	('renal neoplasms', 'Disease', (60, 75))	('renal neoplasms', 'Phenotype', 'HP:0009726', (60, 75))	('renal neoplasms', 'Disease', 'MESH:D007680', (60, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('PIK3CA', 'Gene', (125, 131))	('mutations', 'Var', (112, 121))	('activating', 'PosReg', (101, 111))	('higher', 'PosReg', (149, 155))	('neoplasms', 'Phenotype', 'HP:0002664', (66, 75))
161491	19843858	In addition to DNA sequence mutations, LOH of PTEN is a well-known event in many malignancies and serves to activate the PI3K/AKT pathway.	('LOH', 'Var', (39, 42))	('malignancies', 'Disease', 'MESH:D009369', (81, 93))	('PTEN', 'Gene', (46, 50))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('malignancies', 'Disease', (81, 93))	('PI3K/AKT pathway', 'Pathway', (121, 137))	('activate', 'PosReg', (108, 116))	('PI3K', 'molecular_function', 'GO:0016303', ('121', '125'))
161497	19843858	While neither transitional epithelial hyperplasia nor urothelial carcinoma was found in wild-type or monoallelic Pten knock-out (Ksp-Cre/Ptenflox/+) mice, typical urothelial carcinomas of renal pelvis were found in homozygous Pten deletion (Ksp-Cre/Ptenflox/flox) mice (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('deletion', 'Var', (231, 239))	('lox', 'Gene', (254, 257))	('Pten', 'Gene', (226, 230))	('lox', 'Gene', (142, 145))	('mice', 'Species', '10090', (149, 153))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (27, 49))	('renal pelvis', 'Phenotype', 'HP:0000125', (188, 200))	('lox', 'Gene', '16948', (259, 262))	('urothelial carcinoma', 'Disease', (54, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('carcinomas', 'Phenotype', 'HP:0030731', (174, 184))	('urothelial carcinomas of renal pelvis', 'Disease', (163, 200))	('lox', 'Gene', (259, 262))	('mice', 'Species', '10090', (264, 268))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (54, 74))	('urothelial carcinomas of renal pelvis', 'Disease', 'MESH:C538614', (163, 200))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (163, 183))	('epithelial hyperplasia', 'Disease', (27, 49))	('lox', 'Gene', '16948', (254, 257))	('lox', 'Gene', '16948', (142, 145))
161498	19843858	It was common in homozygous Pten deletion mice older than one year that urothelial carcinoma involving the uretero-pelvic junction obstructed urine outflow and caused hydronephrosis (Fig.	('urothelial carcinoma', 'Disease', (72, 92))	('obstructed', 'NegReg', (131, 141))	('urine outflow', 'MPA', (142, 155))	('mice', 'Species', '10090', (42, 46))	('deletion', 'Var', (33, 41))	('hydronephrosis', 'Phenotype', 'HP:0000126', (167, 181))	('pelvic junction obstructed', 'Phenotype', 'HP:0000074', (115, 141))	('caused', 'Reg', (160, 166))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (72, 92))	('hydronephrosis', 'Disease', (167, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('hydronephrosis', 'Disease', 'MESH:D006869', (167, 181))
161501	19843858	The incidence rates of urothelial carcinoma of renal pelvis and precancerous transitional epithelial hyperplasia in homozygous Pten deletion mice increased along with age (Fig.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('carcinoma of renal', 'Phenotype', 'HP:0005584', (34, 52))	('deletion', 'Var', (132, 140))	('cancer', 'Disease', (67, 73))	('increased', 'PosReg', (146, 155))	('Pten', 'Gene', (127, 131))	('urothelial carcinoma of renal pelvis', 'Disease', (23, 59))	('renal pelvis', 'Phenotype', 'HP:0000125', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mice', 'Species', '10090', (141, 145))	('urothelial carcinoma of renal pelvis', 'Disease', 'MESH:C538614', (23, 59))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (90, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('epithelial hyperplasia', 'Disease', (90, 112))
161503	19843858	To confirm the inactivation of Pten in the murine urothelial carcinomas, tissue was isolated using LCM (Fig.	('Pten', 'Gene', (31, 35))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (50, 71))	('murine', 'Species', '10090', (43, 49))	('inactivation', 'Var', (15, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('urothelial carcinomas', 'Disease', (50, 71))
161505	19843858	This analysis confirmed the deletion of Pten exons 4 and 5 in the mouse urothelial carcinoma tissues (Fig.	('urothelial carcinoma', 'Disease', (72, 92))	('Pten', 'Gene', (40, 44))	('mouse', 'Species', '10090', (66, 71))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (72, 92))	('deletion', 'Var', (28, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
161508	19843858	Since the Ksp-cadherin promoter is expressed in the epithelial cells of the kidney as well as the developing genitourinary tract, inactivation of Pten in our animal model also resulted in some structural abnormalities in the renal parenchyma and the genital organs.	('resulted in', 'Reg', (176, 187))	('structural abnormalities in the renal parenchyma', 'Disease', (193, 241))	('structural abnormalities in the renal parenchyma', 'Disease', 'MESH:D007674', (193, 241))	('inactivation', 'Var', (130, 142))	('Ksp-cadherin', 'Gene', (10, 22))	('cadherin', 'molecular_function', 'GO:0008014', ('14', '22'))	('epithelia', 'Disease', 'None', (52, 61))	('epithelia', 'Disease', (52, 61))	('Ksp-cadherin', 'Gene', '12556', (10, 22))	('Pten', 'Gene', (146, 150))
161510	19843858	4D, left panel), occurred in all kidneys of homozygous Pten deletion mice in every age group (Fig.	('deletion', 'Var', (60, 68))	('Pten', 'Gene', (55, 59))	('mice', 'Species', '10090', (69, 73))
161511	19843858	This abnormality was present in 50% or less of the kidneys of heterozygous Pten deletion mice in every age group and increased in frequency as the animals aged.	('mice', 'Species', '10090', (89, 93))	('deletion', 'Var', (80, 88))	('Pten', 'Gene', (75, 79))
161515	19843858	4D, right panel) only occurred in the homozygous Pten deletion mice, and the frequency also increased with age (Fig.	('deletion', 'Var', (54, 62))	('Pten', 'Gene', (49, 53))	('mice', 'Species', '10090', (63, 67))
161518	19843858	Consistent with these findings, endometrial carcinomas and seminal vesicle carcinomas were found in our study in 43.5% of the homozygous Pten deletion mice (Fig.	('endometrial carcinomas and seminal vesicle carcinomas', 'Disease', 'MESH:D016889', (32, 85))	('mice', 'Species', '10090', (151, 155))	('Pten', 'Gene', (137, 141))	('found', 'Reg', (91, 96))	('vesicle', 'cellular_component', 'GO:0031982', ('67', '74'))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (32, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('deletion', 'Var', (142, 150))
161522	19843858	Subsequently, we found 13.6% of these human tumors contained activating somatic PIK3CA mutations and 25% had LOH in and around the PTEN locus.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('human', 'Species', '9606', (38, 43))	('mutations', 'Var', (87, 96))	('PIK3CA', 'Gene', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('activating', 'PosReg', (61, 71))
161525	19843858	Finally, we were able to demonstrate induction of renal pelvic urothelial carcinoma highly similar to that of humans by means of a homozygous tissue-specific Pten deletion and activation of Akt and mTor signaling in a murine model.	('deletion', 'Var', (163, 171))	('mTor', 'Gene', '2475', (198, 202))	('humans', 'Species', '9606', (110, 116))	('murine', 'Species', '10090', (218, 224))	('renal pelvic urothelial carcinoma', 'Disease', (50, 83))	('renal pelvic urothelial carcinoma', 'Disease', 'MESH:D007674', (50, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('signaling', 'biological_process', 'GO:0023052', ('203', '212'))	('mTor', 'Gene', (198, 202))	('Pten', 'Gene', (158, 162))	('activation', 'PosReg', (176, 186))
161533	19843858	HNPCC is caused by germline mutations in the mismatch repair genes.	('germline mutations', 'Var', (19, 37))	('caused by', 'Reg', (9, 18))	('mismatch repair genes', 'Gene', (45, 66))	('HNPCC', 'Disease', 'None', (0, 5))	('HNPCC', 'Disease', (0, 5))	('mismatch repair', 'biological_process', 'GO:0006298', ('45', '60'))
161534	19843858	Mismatch repair deficiency in this setting results in the cellular phenotype known as microsatellite instability, which particularly affects mononucleotide repeat tracts.	('mononucleotide repeat tracts', 'Var', (141, 169))	('results in', 'Reg', (43, 53))	('deficiency', 'NegReg', (16, 26))	('Mismatch repair', 'biological_process', 'GO:0006298', ('0', '15'))	('microsatellite', 'MPA', (86, 100))	('Mismatch repair', 'Protein', (0, 15))	('mononucleotide', 'Chemical', '-', (141, 155))
161535	19843858	In subsets of HNPCC-related colorectal cancers and endometrial cancers, somatic mutations targeting the 6A tracts in exons 7 and 8 of PTEN have been found, resulting in upregulation of the AKT pathway.	('HNPCC', 'Disease', 'None', (14, 19))	('HNPCC', 'Disease', (14, 19))	('mutations', 'Var', (80, 89))	('upregulation', 'PosReg', (169, 181))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('colorectal cancers', 'Disease', 'MESH:D015179', (28, 46))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colorectal cancers', 'Disease', (28, 46))	('endometrial cancers', 'Disease', 'MESH:D016889', (51, 70))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('endometrial cancers', 'Disease', (51, 70))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('PTEN', 'Gene', (134, 138))	('AKT pathway', 'Pathway', (189, 200))
161547	19843858	We found that the AKT pathway was activated in the majority of human renal pelvic urothelial carcinomas, which might be partly due to activating mutations of PIK3CA and the loss of PTEN.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('human', 'Species', '9606', (63, 68))	('renal pelvic urothelial carcinomas', 'Disease', (69, 103))	('PIK3CA', 'Gene', (158, 164))	('mutations', 'Var', (145, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('loss', 'NegReg', (173, 177))	('PTEN', 'Protein', (181, 185))	('activated', 'PosReg', (34, 43))	('renal pelvic urothelial carcinomas', 'Disease', 'MESH:D007674', (69, 103))	('activating', 'PosReg', (134, 144))	('AKT pathway', 'Pathway', (18, 29))
161548	19843858	Conditional knock-out of the Pten gene results in renal pelvic urothelial carcinoma in mice, which confirms the etiological effect of AKT pathway activation in this malignancy.	('Pten', 'Gene', (29, 33))	('malignancy', 'Disease', 'MESH:D009369', (165, 175))	('knock-out', 'Var', (12, 21))	('results in', 'Reg', (39, 49))	('malignancy', 'Disease', (165, 175))	('renal pelvic urothelial carcinoma', 'Disease', (50, 83))	('renal pelvic urothelial carcinoma', 'Disease', 'MESH:D007674', (50, 83))	('mice', 'Species', '10090', (87, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))
161623	33604380	In particular, evaluation of the mutations in immune cells is capable of predicting the outcome of patients with cancerous tumors.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('cancerous tumors', 'Disease', 'MESH:D009369', (113, 129))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (99, 107))	('cancerous tumors', 'Disease', (113, 129))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
161633	33604380	We discovered that the related immune cell infiltration signatures were differently expressed between low and high CDCA3 expression groups.	('CDCA3', 'Gene', (115, 120))	('high', 'Var', (110, 114))	('CDCA3', 'Gene', '83461', (115, 120))
161634	33604380	We also found that the higher proportion of CD8+ T cells, CD4+ T cells, and B cells appeared in the high CDCA3 expression group.	('CD8', 'Gene', (44, 47))	('CD8', 'Gene', '925', (44, 47))	('CD4', 'Gene', '920', (58, 61))	('CDCA3', 'Gene', '83461', (105, 110))	('high', 'Var', (100, 104))	('CDCA3', 'Gene', (105, 110))	('CD4', 'Gene', (58, 61))
161635	33604380	Our data suggested that the high CDCA3 expression promoted the infiltration of T cells and exhausted these cells, and the patients with high CDCA3 expression might have poorer outcomes by analyzing the information of HCC patients obtained from The Cancer Genome Atlas (TCGA) database.	('CDCA3', 'Gene', '83461', (141, 146))	('patients', 'Species', '9606', (221, 229))	('promoted', 'PosReg', (50, 58))	('CDCA3', 'Gene', (141, 146))	('expression', 'Var', (39, 49))	('CDCA3', 'Gene', '83461', (33, 38))	('CDCA3', 'Gene', (33, 38))	('patients', 'Species', '9606', (122, 130))	('Cancer', 'Phenotype', 'HP:0002664', (248, 254))	('Cancer', 'Disease', (248, 254))	('high', 'Var', (28, 32))	('Cancer', 'Disease', 'MESH:D009369', (248, 254))	('HCC', 'Phenotype', 'HP:0001402', (217, 220))	('infiltration of T cells', 'CPA', (63, 86))
161645	33604380	Significance of HR referred to the ratio of risk rate produced by high CDCA3 expression to the risk rate produced by low CDCA3 expression, on the premise that p < 0.05.	('expression', 'MPA', (77, 87))	('CDCA3', 'Gene', (121, 126))	('CDCA3', 'Gene', '83461', (71, 76))	('CDCA3', 'Gene', (71, 76))	('high', 'Var', (66, 70))	('CDCA3', 'Gene', '83461', (121, 126))
161646	33604380	The higher the HR value, the bigger the ratio of risk rate produced by high CDCA3 expression on survival.	('HR value', 'MPA', (15, 23))	('CDCA3', 'Gene', (76, 81))	('CDCA3', 'Gene', '83461', (76, 81))	('high', 'Var', (71, 75))
161657	33604380	Here, we established a standard to describe the association between CDCA3 expression and gene markers of infiltrating immune cells, where 0.00-0.29 was considered weak, 0.30-0.59 was considered moderate, 0.60-0.79 was considered strong, and 0.80-1.00 was considered very strong expression.	('CDCA3', 'Gene', '83461', (68, 73))	('0.30-0.59', 'Var', (169, 178))	('association', 'Interaction', (48, 59))	('CDCA3', 'Gene', (68, 73))
161663	33604380	Here, logrank p < 0.05 was statistically significant, and significance of HR referred to the ratio of risk rate produced by the application of high expression of CDCA3 to the risk rate produced by low expression of CDCA3.	('CDCA3', 'Gene', '83461', (162, 167))	('high expression', 'Var', (143, 158))	('CDCA3', 'Gene', (162, 167))	('CDCA3', 'Gene', (215, 220))	('CDCA3', 'Gene', '83461', (215, 220))
161685	33604380	As revealed by PPS (HR = 0.67, 95%CI = 0.54-0.84, p = 0.00038) (Figure 2(j)), the high CDCA3 expression was associated with the better prognosis in gastric cancer because the HR < 1 and p < 0.05.	('PPS', 'Chemical', '-', (15, 18))	('gastric cancer', 'Disease', (148, 162))	('CDCA3', 'Gene', (87, 92))	('high', 'Var', (82, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('expression', 'MPA', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CDCA3', 'Gene', '83461', (87, 92))
161688	33604380	These results indicated that a high expression of CDCA3 had a strong association with poor outcomes for patients with various cancers, especially in HCC, and the correlation depended on the type of tumor.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('HCC', 'Phenotype', 'HP:0001402', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('CDCA3', 'Gene', '83461', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancers', 'Disease', (126, 133))	('CDCA3', 'Gene', (50, 55))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('tumor', 'Disease', (198, 203))	('HCC', 'Disease', (149, 152))	('patients', 'Species', '9606', (104, 112))	('expression', 'MPA', (36, 46))	('high', 'Var', (31, 35))
161695	33604380	p < 0.05 was statistically significant, and the hazard ratio > 1 represented the higher risk factors produced by high CDCA3 expression affected in the prognosis of patients with different clinicopathologic features.	('high', 'Var', (113, 117))	('CDCA3', 'Gene', '83461', (118, 123))	('CDCA3', 'Gene', (118, 123))	('expression', 'MPA', (124, 134))	('patients', 'Species', '9606', (164, 172))	('affected', 'Reg', (135, 143))
161699	33604380	It was remarkable that the hazard ratio (HR) of CDCA3 expression in univariate analysis equaled to 2.075, the value of HR and the p < 0.001 both indicated that CDCA3 can predict the prognosis in HCC, and the hazard ratio revealed that the patients with high CDCA3 expression had 2.075 times of higher risk in poor OS than the patients with low CDCA3 expression in univariate analysis.	('CDCA3', 'Gene', (258, 263))	('high', 'Var', (253, 257))	('CDCA3', 'Gene', (48, 53))	('CDCA3', 'Gene', '83461', (344, 349))	('poor OS', 'Disease', (309, 316))	('CDCA3', 'Gene', (344, 349))	('patients', 'Species', '9606', (239, 247))	('patients', 'Species', '9606', (326, 334))	('CDCA3', 'Gene', '83461', (160, 165))	('CDCA3', 'Gene', (160, 165))	('HCC', 'Disease', (195, 198))	('HCC', 'Phenotype', 'HP:0001402', (195, 198))	('expression', 'Var', (264, 274))	('CDCA3', 'Gene', '83461', (258, 263))	('CDCA3', 'Gene', '83461', (48, 53))
161701	33604380	The results showed that high expression of CDCA3 was associated with poor outcomes in HCC patients, and it could act as a potential independent predictor of survival (HR = 2.037; 95%CI = 1.484-2.796; p < 0.001; Figure 3(d)) by excluding confounding factors.	('CDCA3', 'Gene', '83461', (43, 48))	('CDCA3', 'Gene', (43, 48))	('high', 'Var', (24, 28))	('HCC', 'Disease', (86, 89))	('patients', 'Species', '9606', (90, 98))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))
161702	33604380	Besides, the value of the hazard ratio revealed that the patients with high CDCA3 expression had 2.037 times of higher risk in poor OS than the patients with low CDCA3 expression.	('poor OS', 'Disease', (127, 134))	('CDCA3', 'Gene', '83461', (162, 167))	('CDCA3', 'Gene', '83461', (76, 81))	('high', 'Var', (71, 75))	('patients', 'Species', '9606', (57, 65))	('CDCA3', 'Gene', (162, 167))	('CDCA3', 'Gene', (76, 81))	('expression', 'Var', (82, 92))	('patients', 'Species', '9606', (144, 152))
161709	33604380	The results showed that high expression of CDCA3 was associated with poor prognosis of patients, high levels of infiltrating immune cells, and tumor purity in HCC and ACC.	('tumor', 'Disease', (143, 148))	('patients', 'Species', '9606', (87, 95))	('CDCA3', 'Gene', '83461', (43, 48))	('CDCA3', 'Gene', (43, 48))	('ACC', 'Phenotype', 'HP:0006744', (167, 170))	('high', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('expression', 'MPA', (29, 39))	('HCC', 'Disease', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))
161712	33604380	The high CDCA3 expression was also correlated with a poorer survival (OS: HR = 2.5, p = 6.4E - 07; DFS: HR = 1.8, p = 0.00026) (Figure S1 ac-ad) but was positively related to the infiltrating levels of B cells (partial cor = 0.252, p = 2.42E - 08), CD4+ T cells (partial cor = 0.222, p = 1.01E - 06), macrophages (partial cor = 0.207, p = 5.93E - 06), neutrophils (partial cor = 0.174, p = 1.35E - 04), and dendritic cells (partial cor = 0.229, p = 4.54E - 07) in LGG (Figure S2 s).	('CDCA3', 'Gene', '83461', (9, 14))	('CDCA3', 'Gene', (9, 14))	('related', 'Reg', (164, 171))	('expression', 'MPA', (15, 25))	('high', 'Var', (4, 8))	('CD4', 'Gene', (249, 252))	('CD4', 'Gene', '920', (249, 252))
161740	33604380	According to the univariate and multivariate analyses, we identified that T stage, M stage, and CDCA3 expression had significant prognostic values for predicting the survival of patients with HCC; in fact, the high expression determined poor OS of patients with HCC and suggested that increased CDCA3 expression deteriorated the state of patients with HCC.	('HCC', 'Phenotype', 'HP:0001402', (262, 265))	('HCC', 'Disease', (352, 355))	('CDCA3', 'Gene', (96, 101))	('increased', 'PosReg', (285, 294))	('HCC', 'Phenotype', 'HP:0001402', (352, 355))	('patients', 'Species', '9606', (178, 186))	('determined', 'Reg', (226, 236))	('HCC', 'Phenotype', 'HP:0001402', (192, 195))	('high', 'Var', (210, 214))	('CDCA3', 'Gene', '83461', (295, 300))	('patients', 'Species', '9606', (338, 346))	('patients', 'Species', '9606', (248, 256))	('HCC', 'Disease', (262, 265))	('CDCA3', 'Gene', (295, 300))	('CDCA3', 'Gene', '83461', (96, 101))
161744	33604380	Thus, CDCA3 expression can potentially influence the immunosuppressive effect in HCC.	('influence', 'Reg', (39, 48))	('HCC', 'Disease', (81, 84))	('expression', 'Var', (12, 22))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('immunosuppressive', 'MPA', (53, 70))	('CDCA3', 'Gene', '83461', (6, 11))	('CDCA3', 'Gene', (6, 11))
161755	33604380	According to the results of the univariate and multivariate analyses, T stage, M stage, and CDCA3 expression were important prognostic factors for the survival of patients with HCC; importantly, high CDCA3 expression had the potential to be an independent predictor for poor outcome for patients with HCC according to the results of multivariate analyses.	('patients', 'Species', '9606', (163, 171))	('HCC', 'Disease', (301, 304))	('CDCA3', 'Gene', '83461', (200, 205))	('expression', 'MPA', (206, 216))	('HCC', 'Phenotype', 'HP:0001402', (177, 180))	('HCC', 'Phenotype', 'HP:0001402', (301, 304))	('patients', 'Species', '9606', (287, 295))	('CDCA3', 'Gene', (200, 205))	('CDCA3', 'Gene', '83461', (92, 97))	('high', 'Var', (195, 199))	('CDCA3', 'Gene', (92, 97))
161819	32328179	Unfortunately, 18F-FDG is not an ideal radiotracer for use in urology due to its urinary elimination.	('18F-FDG', 'Var', (15, 22))	('18F-FDG', 'Chemical', '-', (15, 22))	('urinary', 'MPA', (81, 88))
161831	32328179	We found that when patients had tumor size < 1.1 cm, their probability of being in the negative PET group was 75%.	('patients', 'Species', '9606', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('< 1.1', 'Var', (43, 48))	('tumor', 'Disease', (32, 37))
161859	29556919	In this study, pembrolizumab was associated with significantly longer overall survival (OS) and a lower rate of adverse events (AEs) compared to chemotherapy as the second-line therapy for platinum-refractory advanced UC.	('overall survival', 'MPA', (70, 86))	('pembrolizumab', 'Chemical', 'MESH:C582435', (15, 28))	('pembrolizumab', 'Var', (15, 28))	('longer', 'PosReg', (63, 69))	('AEs', 'Chemical', '-', (128, 131))	('platinum', 'Chemical', 'MESH:D010984', (189, 197))
161862	29556919	In addition, among patients who had high PD-L1 expression (10% or more), the median OS was 8.0 months for those treated with pembrolizumab (95% CI 5.0-12.3 months) as compared to 5.2 months for those treated with chemotherapy (95% CI 4.0-7.4 months, HR, 0.57, 95% CI 0.37-0.88, P = 0.005).	('patients', 'Species', '9606', (19, 27))	('PD-L1', 'Gene', '29126', (41, 46))	('pembrolizumab', 'Chemical', 'MESH:C582435', (125, 138))	('pembrolizumab', 'Var', (125, 138))	('PD-L1', 'Gene', (41, 46))	('expression', 'MPA', (47, 57))
161875	29556919	At a median follow-up of 7 months, median OS was 8.7 months (95% CI 6.1 months to not reached) among all patients, 11.3 months (95% CI 8.7 months to not reached) in patients with high PD-L1 expression (>= 1%), and 5.9 months (95% CI 4.30-8.08 months) in those with low PD-L1 expression (< 1%).	('PD-L1', 'Gene', (269, 274))	('PD-L1', 'Gene', (184, 189))	('patients', 'Species', '9606', (105, 113))	('PD-L1', 'Gene', '29126', (184, 189))	('high', 'Var', (179, 183))	('PD-L1', 'Gene', '29126', (269, 274))	('patients', 'Species', '9606', (165, 173))	('expression', 'MPA', (190, 200))
161888	29556919	In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3-4 treatment-related AEs than did those receiving chemotherapy (20 versus 43%) as well as fewer AEs leading to treatment discontinuation (7 versus 18%).	('atezolizumab', 'Chemical', 'MESH:C000594389', (57, 69))	('atezolizumab', 'Var', (57, 69))	('treatment discontinuation', 'MPA', (198, 223))	('grade 3-4 treatment-related AEs', 'Disease', (80, 111))	('fewer', 'NegReg', (74, 79))	('patients', 'Species', '9606', (38, 46))	('AEs', 'Chemical', '-', (183, 186))	('AEs', 'Chemical', '-', (108, 111))
161900	29556919	It is worth remembering that avelumab causes infusion-related reactions frequently, whereas this is seldom seen in the other checkpoint inhibitors.	('causes', 'Reg', (38, 44))	('avelumab', 'Var', (29, 37))	('infusion-related reactions', 'Disease', (45, 71))	('avelumab', 'Chemical', 'MESH:C000609138', (29, 37))
161939	29556919	This evidence validates the inhibition of VEGFR-2 signaling as a potential new therapeutic treatment option for patients with UC.	('VEGFR-2', 'Gene', '3791', (42, 49))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('patients', 'Species', '9606', (112, 120))	('inhibition', 'Var', (28, 38))	('VEGFR-2', 'Gene', (42, 49))
161950	29556919	In the eligible population (n = 357), the median OS was also significantly longer for vinflunine plus BSC than it was for BSC alone (6.9 versus 4.3 months), with the difference being statistically significant (P = 0.040).	('BSC', 'Gene', (102, 105))	('BSC', 'Gene', '6558', (102, 105))	('BSC', 'Gene', (122, 125))	('BSC', 'Gene', '6558', (122, 125))	('vinflunine', 'Var', (86, 96))	('vinflunine', 'Chemical', 'MESH:C111217', (86, 96))
161953	29556919	Two factors were extracted as independent indicators of poor prognosis: KPS less than 80% and the presence of visceral metastasis.	('KPS', 'Var', (72, 75))	('less', 'NegReg', (76, 80))	('visceral metastasis', 'Disease', (110, 129))	('visceral metastasis', 'Disease', 'MESH:D009362', (110, 129))
161957	29556919	These chemotherapy resistance genes are considered to inhibit the efficacy of cytotoxic chemotherapy for the patients with metastatic UC.	('metastatic UC', 'Disease', (123, 136))	('genes', 'Var', (30, 35))	('inhibit', 'NegReg', (54, 61))	('patients', 'Species', '9606', (109, 117))
162042	24648880	The tumor was evaluated as a urothelial carcinoma metastasis owing to the clinical history of the patient, the existence of other metastases, the morphological similarity of the tumor cells with the primary tumor, and CK 20 positivity in some cases immunohistochemically (Fig.	('tumor', 'Disease', (4, 9))	('patient', 'Species', '9606', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('urothelial carcinoma metastasis', 'Disease', (29, 60))	('metastases', 'Disease', (130, 140))	('CK 20', 'Gene', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', (178, 183))	('CK 20', 'Gene', '54474', (218, 223))	('primary tumor', 'Disease', 'MESH:D009369', (199, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('primary tumor', 'Disease', (199, 212))	('urothelial carcinoma metastasis', 'Disease', 'MESH:D009362', (29, 60))	('tumor', 'Disease', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('positivity', 'Var', (224, 234))	('metastases', 'Disease', 'MESH:D009362', (130, 140))
162084	24359437	The results of western immunoblotting demonstrated that PEE treatment could not only evoke the activation of pro-caspase-3, -8,-9 but also increase Bax/Bcl-2 ratio in T24 cells.	('Bax', 'Gene', (148, 151))	('PEE', 'Var', (56, 59))	('Bcl-2', 'Gene', '596', (152, 157))	('Bcl-2', 'molecular_function', 'GO:0015283', ('152', '157'))	('men', 'Species', '9606', (65, 68))	('Bcl-2', 'Gene', (152, 157))	('activation', 'PosReg', (95, 105))	('PEE', 'Chemical', '-', (56, 59))	('increase', 'PosReg', (139, 147))	('Bax', 'Gene', '581', (148, 151))	('pro-caspase-3, -8,-9', 'Gene', '836', (109, 129))
162093	24359437	In primary lung tumor animal model, PFE also inhibits tumor growth/progression/angiogenesis by the suppression of NF-kappaB, MAP kinase pathway and mTOR signaling pathway .	('PFE', 'Chemical', 'MESH:D000074263', (36, 39))	('NF-kappaB', 'Gene', (114, 123))	('lung tumor', 'Phenotype', 'HP:0100526', (11, 21))	('mTOR', 'Gene', '2475', (148, 152))	('MAP', 'molecular_function', 'GO:0004239', ('125', '128'))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('NF-kappaB', 'Gene', '4790', (114, 123))	('signaling pathway', 'biological_process', 'GO:0007165', ('153', '170'))	('inhibits', 'NegReg', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('PFE', 'Var', (36, 39))	('lung tumor', 'Disease', 'MESH:D008175', (11, 21))	('tumor', 'Disease', (16, 21))	('suppression', 'NegReg', (99, 110))	('mTOR', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('MAP kinase pathway', 'Pathway', (125, 143))	('angiogenesis', 'biological_process', 'GO:0001525', ('79', '91'))	('lung tumor', 'Disease', (11, 21))	('tumor', 'Disease', (54, 59))
162096	24359437	PFE can cause G1-phase arrest of prostate cancer PC3 cell through dwindling the expressions of cyclins D and E and increasing the levels of cyclin-dependent kinase-2, -4 and -6, and thus resulting in an increase in WAF1/p21 as well as KIP1/p27 .	('cyclin', 'molecular_function', 'GO:0016538', ('140', '146'))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('PFE', 'Var', (0, 3))	('dwindling', 'MPA', (66, 75))	('arrest of prostate cancer', 'Disease', 'MESH:D011471', (23, 48))	('WAF1', 'Gene', '1026', (215, 219))	('G1-phase', 'biological_process', 'GO:0051318', ('14', '22'))	('WAF1', 'Gene', (215, 219))	('KIP1', 'Gene', '1027', (235, 239))	('prostate cancer', 'Phenotype', 'HP:0012125', (33, 48))	('increasing', 'PosReg', (115, 125))	('increase', 'PosReg', (203, 211))	('p21', 'Gene', (220, 223))	('arrest of prostate cancer', 'Disease', (23, 48))	('cyclin-dependent kinase-2, -4 and -6', 'Gene', '1017;1019;1021', (140, 176))	('PFE', 'Chemical', 'MESH:D000074263', (0, 3))	('p27', 'Gene', '3429', (240, 243))	('p27', 'Gene', (240, 243))	('expressions', 'MPA', (80, 91))	('PC3', 'CellLine', 'CVCL:0035', (49, 52))	('KIP1', 'Gene', (235, 239))	('p21', 'Gene', '1026', (220, 223))
162109	24359437	Our results showed that PEE could evoke T24 cell apoptosis via mitochondrial pathway, death receptor pathway and endothelium reticulum (ER) stress.	('PEE', 'Var', (24, 27))	('endothelium', 'MPA', (113, 124))	('T24 cell apoptosis', 'CPA', (40, 58))	('PEE', 'Chemical', '-', (24, 27))	('mitochondrial', 'CPA', (63, 76))	('evoke', 'Reg', (34, 39))	('death', 'Disease', 'MESH:D003643', (86, 91))	('death', 'Disease', (86, 91))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))
162110	24359437	Furthermore PEE-evoked ER stress might dys-regulate vasolin-containing protein (VCP) to activate pro-caspase-12, and thus induce the apoptosis in T24 cell.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('apoptosis', 'CPA', (133, 142))	('VCP', 'Gene', (80, 83))	('PEE', 'Chemical', '-', (12, 15))	('dys-regulate', 'Var', (39, 51))	('induce', 'Reg', (122, 128))	('vasolin-containing', 'Protein', (52, 70))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('activate', 'PosReg', (88, 96))	('VCP', 'Gene', '7415', (80, 83))	('pro-caspase-12', 'MPA', (97, 111))
162154	24359437	The observation results suggested that PEE could affect the viability of UBUC cells.	('UBUC', 'Chemical', '-', (73, 77))	('affect', 'Reg', (49, 55))	('viability of UBUC cells', 'CPA', (60, 83))	('PEE', 'Var', (39, 42))	('PEE', 'Chemical', '-', (39, 42))
162158	24359437	However, PEE could impede bladder cancer T24 or J82 cell in a dose-dependent manner.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('bladder cancer', 'Phenotype', 'HP:0009725', (26, 40))	('PEE', 'Var', (9, 12))	('bladder cancer', 'Disease', 'MESH:D001749', (26, 40))	('bladder cancer', 'Disease', (26, 40))	('J82', 'CellLine', 'CVCL:0359', (48, 51))	('impede', 'NegReg', (19, 25))	('PEE', 'Chemical', '-', (9, 12))	('PEE could impede bladder', 'Phenotype', 'HP:0100645', (9, 33))
162166	24359437	According to the above results, PEE could invoke an inhibitory impact on human T24 cell proliferation.	('human T24 cell proliferation', 'CPA', (73, 101))	('PEE', 'Var', (32, 35))	('human', 'Species', '9606', (73, 78))	('PEE', 'Chemical', '-', (32, 35))	('cell proliferation', 'biological_process', 'GO:0008283', ('83', '101'))
162168	24359437	Cell cycle analyses conducted after incubation of human T24 cell with a series of increasing concentration for various durations demonstrated that PEE arrested human T24 cells in S phase in a dose-and-time dependent response (Figure  3A).	('PEE', 'Chemical', '-', (147, 150))	('S phase', 'CPA', (179, 186))	('S phase', 'biological_process', 'GO:0051320', ('179', '186'))	('PEE', 'Var', (147, 150))	('human', 'Species', '9606', (50, 55))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('human', 'Species', '9606', (160, 165))
162171	24359437	The subsequent findings showed that cyclin A level was increased whereas CDK1 level was decreased in PEE-treated human T24 cell (Figure  3), suggesting that PEE evoked S phase arrest in human T24 cell possibly through the dys-regulation of cyclin A and CDK1.	('cyclin A', 'Gene', '890', (36, 44))	('increased', 'PosReg', (55, 64))	('cyclin', 'molecular_function', 'GO:0016538', ('36', '42'))	('cyclin A', 'Gene', (36, 44))	('regulation', 'biological_process', 'GO:0065007', ('226', '236'))	('PEE', 'Chemical', '-', (157, 160))	('human', 'Species', '9606', (113, 118))	('cyclin', 'molecular_function', 'GO:0016538', ('240', '246'))	('S phase', 'biological_process', 'GO:0051320', ('168', '175'))	('PEE', 'Chemical', '-', (101, 104))	('CDK1', 'Gene', '983', (73, 77))	('cyclin A', 'Gene', '890', (240, 248))	('CDK1', 'Gene', (73, 77))	('CDK', 'molecular_function', 'GO:0004693', ('253', '256'))	('phase arrest', 'CPA', (170, 182))	('cyclin A', 'Gene', (240, 248))	('PEE', 'Var', (157, 160))	('CDK1', 'Gene', '983', (253, 257))	('CDK1', 'Gene', (253, 257))	('human', 'Species', '9606', (186, 191))	('CDK', 'molecular_function', 'GO:0004693', ('73', '76'))
162177	24359437	The data of cell cycle analyses indicated that PEE exposure could induce the formation of hypodiploid subG1 peak in a dose-and-time dependent response as compared to those of the control, implicating that PEE could cause the DNA fragmentation in human T24 cells, although the percentage of subG1 population in the cell profile was low (< 2.3%).	('PEE', 'Chemical', '-', (47, 50))	('cause', 'Reg', (215, 220))	('formation', 'MPA', (77, 86))	('DNA fragmentation', 'biological_process', 'GO:0006309', ('225', '242'))	('cell cycle', 'biological_process', 'GO:0007049', ('12', '22'))	('PEE', 'Var', (205, 208))	('hypodiploid', 'Disease', 'None', (90, 101))	('DNA fragmentation', 'CPA', (225, 242))	('PEE', 'Chemical', '-', (205, 208))	('hypodiploid', 'Disease', (90, 101))	('DNA', 'cellular_component', 'GO:0005574', ('225', '228'))	('PEE', 'Var', (47, 50))	('human', 'Species', '9606', (246, 251))	('formation', 'biological_process', 'GO:0009058', ('77', '86'))	('men', 'Species', '9606', (233, 236))
162178	24359437	The results of annexin V/PI staining indicated that after incubation with PEE in a dose-and-time dependent manner it could provoke phosphatidylserine (PS) translocation in the cell membrane, which is an initial sign of apoptosis that leads to the subsequent membrane leakage (late apoptotic cell) and thus increases the percentage of early and late apoptotic cells (Figure  4).	('leads to', 'Reg', (234, 242))	('increases', 'PosReg', (306, 315))	('PEE', 'Var', (74, 77))	('annexin V', 'Gene', '308', (15, 24))	('membrane leakage', 'MPA', (258, 274))	('annexin V', 'Gene', (15, 24))	('apoptosis', 'biological_process', 'GO:0097194', ('219', '228'))	('apoptosis', 'biological_process', 'GO:0006915', ('219', '228'))	('PEE', 'Chemical', '-', (74, 77))	('provoke', 'Reg', (123, 130))	('cell membrane', 'cellular_component', 'GO:0005886', ('176', '189'))	('membrane', 'cellular_component', 'GO:0016020', ('258', '266'))
162179	24359437	Although the aforementioned results showed that PEE might induce the apoptosis in human T24 cell, cytometric analysis cannot decipher whether PEE results in the apoptosis by death receptor signaling, mitochondrial damage pathway or ER stress.	('apoptosis', 'biological_process', 'GO:0097194', ('161', '170'))	('men', 'Species', '9606', (18, 21))	('death', 'Disease', 'MESH:D003643', (174, 179))	('PEE', 'Chemical', '-', (48, 51))	('death', 'Disease', (174, 179))	('apoptosis', 'biological_process', 'GO:0006915', ('161', '170'))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('PEE', 'Chemical', '-', (142, 145))	('human', 'Species', '9606', (82, 87))	('apoptosis', 'CPA', (69, 78))	('signaling', 'biological_process', 'GO:0023052', ('189', '198'))	('PEE', 'Var', (48, 51))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))
162180	24359437	In order to define the molecular mechanism by which PEE invoked the apoptosis, western immunoblotting was conducted to examine the processing and activation of caspase-3 which is considered to play a central role in both mitochondrial damage and death receptor signaling, and can be activated by caspase-8 in death receptor signaling and by caspase-9 in mitochondrial damage.	('PEE', 'Var', (52, 55))	('caspase-9', 'Gene', (341, 350))	('death', 'Disease', 'MESH:D003643', (246, 251))	('death', 'Disease', (246, 251))	('caspase-3', 'Gene', (160, 169))	('signaling', 'biological_process', 'GO:0023052', ('261', '270'))	('death', 'Disease', 'MESH:D003643', (309, 314))	('PEE', 'Chemical', '-', (52, 55))	('death', 'Disease', (309, 314))	('signaling', 'biological_process', 'GO:0023052', ('324', '333'))	('caspase-9', 'Gene', '842', (341, 350))	('caspase-3', 'Gene', '836', (160, 169))	('apoptosis', 'biological_process', 'GO:0097194', ('68', '77'))	('apoptosis', 'biological_process', 'GO:0006915', ('68', '77'))
162183	24359437	Significantly reduced numbers of early apoptotic T24 cells present in inhibitor/PEE treatment of annexin V/PI staining experiments showed that Z-DEVD-FMK could antagonize the apoptotic effects of PEE on human T24 cell as compared to those of sole PEE exposure (Figure  5B).	('reduced', 'NegReg', (14, 21))	('PEE', 'Chemical', '-', (196, 199))	('apoptotic effects', 'CPA', (175, 192))	('annexin V', 'Gene', '308', (97, 106))	('human', 'Species', '9606', (203, 208))	('annexin V', 'Gene', (97, 106))	('antagonize', 'NegReg', (160, 170))	('PEE', 'Chemical', '-', (247, 250))	('men', 'Species', '9606', (125, 128))	('Z-DEVD-FMK', 'Chemical', 'MESH:C110772', (143, 153))	('PEE', 'Chemical', '-', (80, 83))	('men', 'Species', '9606', (89, 92))	('Z-DEVD-FMK', 'Var', (143, 153))
162186	24359437	The results in Figure  5C and 5D demonstrated that the levels of pro-caspase-9 and -8 dwindled temporally in 50 mug/ml and 100 mug/ml PEE-administrated human T24 cells whereas activated caspase-9 amount increased, implying that PEE-induced human T24 cell apoptosis might be attributed to the mitochondrial damage pathway and death receptor signaling.	('PEE-administrated', 'Var', (134, 151))	('apoptosis', 'biological_process', 'GO:0097194', ('255', '264'))	('PEE', 'Chemical', '-', (134, 137))	('caspase-9', 'Gene', (186, 195))	('death', 'Disease', 'MESH:D003643', (325, 330))	('apoptosis', 'biological_process', 'GO:0006915', ('255', '264'))	('human', 'Species', '9606', (240, 245))	('caspase-9', 'Gene', '842', (69, 78))	('death', 'Disease', (325, 330))	('human', 'Species', '9606', (152, 157))	('mug', 'molecular_function', 'GO:0043739', ('112', '115'))	('PEE', 'Chemical', '-', (228, 231))	('mug', 'molecular_function', 'GO:0043739', ('127', '130'))	('signaling', 'biological_process', 'GO:0023052', ('340', '349'))	('caspase-9', 'Gene', '842', (186, 195))	('caspase-9', 'Gene', (69, 78))
162189	24359437	The above findings demonstrated that PEE caused human T24 cell apoptosis possibly via mitochondrial damage and death receptor signaling.	('death', 'Disease', 'MESH:D003643', (111, 116))	('human', 'Species', '9606', (48, 53))	('PEE', 'Var', (37, 40))	('signaling', 'biological_process', 'GO:0023052', ('126', '135'))	('PEE', 'Chemical', '-', (37, 40))	('mitochondrial damage', 'CPA', (86, 106))	('death', 'Disease', (111, 116))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))
162190	24359437	However, it is likely that PEE exposure could also result in ER stress, and thus cell apoptosis in human T24 cell.	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('PEE', 'Chemical', '-', (27, 30))	('ER stress', 'MPA', (61, 70))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('cell apoptosis', 'CPA', (81, 95))	('human', 'Species', '9606', (99, 104))	('PEE', 'Var', (27, 30))	('result in', 'Reg', (51, 60))
162191	24359437	The follow-up discovery showed that pro-caspase-12 level was reduced while cleaved pro-caspase-12 (activated form) amount increased in PEE-exposed T24 cells in a temporal response (Figure  6A), implicating that PEE might provoke an ER stress in human T24 cell.	('pro-caspase-12 level', 'MPA', (36, 56))	('PEE', 'Var', (211, 214))	('PEE', 'Chemical', '-', (135, 138))	('PEE-exposed', 'Var', (135, 146))	('PEE', 'Chemical', '-', (211, 214))	('human', 'Species', '9606', (245, 250))	('increased', 'PosReg', (122, 131))	('reduced', 'NegReg', (61, 68))	('cleaved pro-caspase-12', 'MPA', (75, 97))
162206	24359437	Cell cycle analyses demonstrated that PEE exposure caused S-phase arrest in human T24 cells and de-regulation of cyclin A as well as CDK1, the complex of which is essential for S to G2/M transition.	('PEE', 'Var', (38, 41))	('S-phase arrest', 'CPA', (58, 72))	('cyclin A', 'Gene', (113, 121))	('PEE', 'Chemical', '-', (38, 41))	('CDK1', 'Gene', (133, 137))	('cyclin A', 'Gene', '890', (113, 121))	('CDK1', 'Gene', '983', (133, 137))	('human', 'Species', '9606', (76, 81))	('cyclin', 'molecular_function', 'GO:0016538', ('113', '119'))	('regulation', 'biological_process', 'GO:0065007', ('99', '109'))	('de-regulation', 'NegReg', (96, 109))	('S-phase', 'biological_process', 'GO:0051320', ('58', '65'))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('CDK', 'molecular_function', 'GO:0004693', ('133', '136'))
162208	24359437	Furthermore, BBSKE augments Bax/Bcl-2 ratio, and thus induces apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('BBSKE', 'Chemical', 'MESH:C478160', (13, 18))	('augments', 'PosReg', (19, 27))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('32', '37'))	('Bax', 'Gene', '581', (28, 31))	('Bcl-2', 'Gene', (32, 37))	('Bcl-2', 'Gene', '596', (32, 37))	('apoptosis', 'CPA', (62, 71))	('men', 'Species', '9606', (22, 25))	('Bax', 'Gene', (28, 31))	('induces', 'Reg', (54, 61))	('BBSKE', 'Var', (13, 18))
162209	24359437	In contrast, PFE (acetone extract of pomegranate juice) incubation results in G1 phase arrest in prostate cancer and lung cancer cells .	('G1 phase arrest', 'CPA', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('prostate cancer', 'Disease', 'MESH:D011471', (97, 112))	('lung cancer', 'Disease', (117, 128))	('PFE', 'Chemical', 'MESH:D000074263', (13, 16))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (97, 112))	('acetone', 'Chemical', 'MESH:D000096', (18, 25))	('juice', 'Chemical', '-', (49, 54))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('G1 phase', 'biological_process', 'GO:0051318', ('78', '86'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('pomegranate', 'Species', '22663', (37, 48))	('prostate cancer', 'Disease', (97, 112))	('PFE', 'Var', (13, 16))
162213	24359437	The results of annexin V/PI staining demonstrated that PEE treatment could evoke T24 cell apoptosis in a dose-and-time dependent manner.	('evoke', 'Reg', (75, 80))	('PEE', 'Chemical', '-', (55, 58))	('T24 cell apoptosis', 'CPA', (81, 99))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('annexin V', 'Gene', '308', (15, 24))	('annexin V', 'Gene', (15, 24))	('men', 'Species', '9606', (64, 67))	('PEE treatment', 'Var', (55, 68))
162221	24359437	(2005) found that PFE treatment to prostate cancer and lung cancer cells could induce G1 phase arrest and provoke prostate cancer cell apoptosis by dys-regulation of both cyclins and CDKs and down-regulation of anti-apoptotic Bcl-XL and Bcl-2 .	('Bcl-2', 'Gene', (237, 242))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('prostate cancer', 'Disease', 'MESH:D011471', (35, 50))	('G1 phase arrest', 'CPA', (86, 101))	('prostate cancer', 'Disease', 'MESH:D011471', (114, 129))	('prostate cancer', 'Phenotype', 'HP:0012125', (35, 50))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('CDKs', 'Gene', (183, 187))	('lung cancer', 'Disease', (55, 66))	('dys-regulation', 'Var', (148, 162))	('prostate cancer', 'Disease', (35, 50))	('prostate cancer', 'Disease', (114, 129))	('Bcl-2', 'Gene', '596', (237, 242))	('cyclins', 'Protein', (171, 178))	('CDKs', 'Gene', '983;1017;1019;1021', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Bcl-2', 'molecular_function', 'GO:0015283', ('237', '242'))	('PFE', 'Chemical', 'MESH:D000074263', (18, 21))	('regulation', 'biological_process', 'GO:0065007', ('152', '162'))	('provoke', 'PosReg', (106, 113))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('G1 phase', 'biological_process', 'GO:0051318', ('86', '94'))	('induce', 'PosReg', (79, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('regulation', 'biological_process', 'GO:0065007', ('197', '207'))	('Bcl-XL', 'Gene', '598', (226, 232))	('down-regulation', 'NegReg', (192, 207))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('Bcl-XL', 'Gene', (226, 232))	('men', 'Species', '9606', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
162222	24359437	However, few evidences supported that PFE could induce cell apoptosis in prostate cancer and lung cancer cells.	('prostate cancer', 'Disease', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('PFE', 'Var', (38, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('apoptosis', 'biological_process', 'GO:0006915', ('60', '69'))	('lung cancer', 'Disease', (93, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('60', '69'))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('PFE', 'Chemical', 'MESH:D000074263', (38, 41))	('cell apoptosis', 'CPA', (55, 69))
162223	24359437	This study provided extensive findings which showed that PEE administration could evoke UBUC cell apoptosis.	('evoke', 'Reg', (82, 87))	('UBUC', 'Chemical', '-', (88, 92))	('PEE administration', 'Var', (57, 75))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('UBUC cell apoptosis', 'CPA', (88, 107))	('PEE', 'Chemical', '-', (57, 60))
162225	24359437	More importantly PEE exposure could provoke intensive activation of ER stress which might be the cardinal apoptotic mechanism of PEE-induced inhibition of bladder cancer cell.	('bladder cancer', 'Disease', (155, 169))	('PEE', 'Chemical', '-', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('activation', 'PosReg', (54, 64))	('bladder cancer', 'Phenotype', 'HP:0009725', (155, 169))	('ER stress', 'MPA', (68, 77))	('PEE', 'Var', (17, 20))	('bladder cancer', 'Disease', 'MESH:D001749', (155, 169))	('PEE', 'Chemical', '-', (129, 132))
162290	22099988	Pretreatment and posttreatment peripheral blood mononuclear cell and invasive urothelial carcinoma DNA, respectively, was analyzed for global and gene specific [CDKN2A (p14ARF)] methylation changes.	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('invasive urothelial carcinoma', 'Disease', (69, 98))	('methylation', 'Var', (178, 189))	('CDKN2A', 'Gene', '100271861', (161, 167))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (69, 98))	('CDKN2A', 'Gene', (161, 167))	('p14ARF', 'Gene', '100271861', (169, 175))	('methylation', 'biological_process', 'GO:0032259', ('178', '189'))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('p14ARF', 'Gene', (169, 175))
162311	22099988	Also, the molecular pathogenesis of canine iUC emulates that of human UC with over expression of bFGF, COX1 (PTGS1), COX2 (PTGS2) and mutated TP53.	('PTGS2', 'Gene', (123, 128))	('PTGS', 'biological_process', 'GO:0016441', ('109', '113'))	('pathogenesis', 'biological_process', 'GO:0009405', ('20', '32'))	('canine', 'Species', '9615', (36, 42))	('COX2', 'Gene', (117, 121))	('PTGS1', 'Gene', '5742', (109, 114))	('over expression', 'PosReg', (78, 93))	('TP53', 'Gene', '7157', (142, 146))	('COX1', 'Gene', (103, 107))	('PTGS1', 'Gene', (109, 114))	('bFGF', 'Gene', '2247', (97, 101))	('PTGS', 'biological_process', 'GO:0016441', ('123', '127'))	('COX2', 'Gene', '4513', (117, 121))	('human', 'Species', '9606', (64, 69))	('PTGS2', 'Gene', '5743', (123, 128))	('COX1', 'Gene', '4512', (103, 107))	('bFGF', 'Gene', (97, 101))	('TP53', 'Gene', (142, 146))	('mutated', 'Var', (134, 141))
162359	22099988	Grade 3 or 4 nausea or anorexia developed in 1 dog on 0.3 mg/kg per day in the 28d cohort and in 2 (15.8%, 95% CI 3.3-39.6) in the 14d cohort after more than 2 cycles of therapy, which did not represent DLT events at the 0.1 mg/kg per day dose.	('nausea', 'Phenotype', 'HP:0002018', (13, 19))	('nausea', 'Disease', (13, 19))	('nausea', 'Disease', 'MESH:D009325', (13, 19))	('14d', 'Chemical', '-', (131, 134))	('0.3', 'Var', (54, 57))	('anorexia', 'Disease', 'MESH:D000855', (23, 31))	('dog', 'Species', '9615', (47, 50))	('anorexia', 'Disease', (23, 31))	('anorexia', 'Phenotype', 'HP:0002039', (23, 31))
162402	22099988	Lastly, while using 5-azaC as an epigenetic modifier of tumor suppressor gene function represents an attractive novel anticancer mechanistic approach, the presence of myelosuppression in the absence of consistent gene specific methylation changes may indicate clinical efficacy through a traditional cytotoxic mechanism in our canine model.	('methylation', 'biological_process', 'GO:0032259', ('227', '238'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('56', '72'))	('5-azaC', 'Chemical', 'MESH:D001374', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('methylation changes', 'Var', (227, 246))	('canine', 'Species', '9615', (327, 333))	('myelosuppression', 'Disease', 'MESH:D001855', (167, 183))	('cancer', 'Disease', (122, 128))	('tumor', 'Disease', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('myelosuppression', 'Disease', (167, 183))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor suppressor', 'biological_process', 'GO:0051726', ('56', '72'))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
162413	22099988	After success against human hematological neoplasms azanucleosides are now being extensively investigated in solid tumor clinical trials as monotherapy and combined with other epigenetic or chemotherapeutic agents.	('hematological neoplasms', 'Phenotype', 'HP:0004377', (28, 51))	('azanucleosides', 'Var', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('azanucleosides', 'Chemical', '-', (52, 66))	('hematological neoplasms', 'Disease', 'MESH:D019337', (28, 51))	('neoplasms', 'Phenotype', 'HP:0002664', (42, 51))	('human', 'Species', '9606', (22, 27))	('hematological neoplasms', 'Disease', (28, 51))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
162472	22125429	The molecular mechanism of AA-induced carcinogenesis demonstrated a strong association between DNA adduct formation, mutation pattern, and tumor development.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('carcinogenesis', 'Disease', 'MESH:D063646', (38, 52))	('men', 'Species', '9606', (152, 155))	('tumor', 'Disease', (139, 144))	('carcinogenesis', 'Disease', (38, 52))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('formation', 'biological_process', 'GO:0009058', ('106', '115'))	('mutation', 'Var', (117, 125))
162505	22125429	Immunostaining of the proapoptotic marker Bax was lower in BEN tumors (Figure 1(c) ) with the high grade, high stage, with the presence of necrosis, and without metaplastic differentiation (chi2 = 5.73, P < 0.05; chi2 = 4.84, P < 0.05; chi2 = 4.13, P < 0.05; chi2 = 3.85, P < 0.05, resp.)	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('lower', 'NegReg', (50, 55))	('BEN tumors', 'Disease', (59, 69))	('Bax', 'Gene', '581', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('high grade', 'Var', (94, 104))	('necrosis', 'biological_process', 'GO:0070265', ('139', '147'))	('necrosis', 'biological_process', 'GO:0008219', ('139', '147'))	('necrosis', 'Disease', (139, 147))	('BEN tumors', 'Disease', 'MESH:D009369', (59, 69))	('necrosis', 'biological_process', 'GO:0019835', ('139', '147'))	('necrosis', 'biological_process', 'GO:0008220', ('139', '147'))	('Bax', 'Gene', (42, 45))	('necrosis', 'Disease', 'MESH:D009336', (139, 147))	('necrosis', 'biological_process', 'GO:0001906', ('139', '147'))
162531	22125429	In addition, present study demonstrated that Survivin expression was significantly higher in BEN tumors with high grade and solid growth than in control tumors with the same morphological features.	('expression', 'MPA', (54, 64))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('BEN tumors', 'Disease', (93, 103))	('high grade', 'Var', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (97, 103))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('Survivin', 'Protein', (45, 53))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('higher', 'PosReg', (83, 89))	('BEN tumors', 'Disease', 'MESH:D009369', (93, 103))	('solid growth', 'CPA', (124, 136))
162532	22125429	Although some authors suggested that Survivin expression did not correlate with clinicopathologic findings in UTUC, recent studies of bladder cancer demonstrated that nuclear positive staining correlated strongly with increased grade, stage, and the probability of tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('bladder cancer', 'Disease', 'MESH:D001749', (134, 148))	('tumor', 'Disease', (265, 270))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('increased', 'PosReg', (218, 227))	('bladder cancer', 'Disease', (134, 148))	('grade', 'CPA', (228, 233))	('nuclear positive', 'Var', (167, 183))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('bladder cancer', 'Phenotype', 'HP:0009725', (134, 148))
162534	22125429	Aberrant Bcl-2 staining expressed significant association with tumor grade and tumor invasiveness in the TCC of the bladder.	('tumor', 'Disease', (63, 68))	('TCC', 'Phenotype', 'HP:0006740', (105, 108))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', (79, 84))	('Bcl-2', 'Gene', (9, 14))	('Bcl-2', 'Gene', '596', (9, 14))	('tumor invasiveness', 'Disease', 'MESH:D009369', (79, 97))	('Bcl-2', 'molecular_function', 'GO:0015283', ('9', '14'))	('TCC', 'cellular_component', 'GO:0005579', ('105', '108'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('association', 'Interaction', (46, 57))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor invasiveness', 'Disease', (79, 97))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
162545	22125429	Aberrant Fas expression was observed in 52.3% of BEN UTUC and 36.1% control tumors but without statistically significant difference between these two groups.	('Fas', 'Chemical', 'MESH:C038178', (9, 12))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('BEN UTUC', 'Disease', (49, 57))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
162595	21512138	Cell line identity was assured by use within 6 months of receipt from ATCC or short tandem repeat (STR) confirmation using reference material provided by the contributor (UROtsa cells) or by an online database maintained by the Deutsche Sammlung von Mikroorganismen und Zellkulturen repository.	('von', 'Disease', 'MESH:D014842', (246, 249))	('von', 'Disease', (246, 249))	('short tandem repeat', 'Var', (78, 97))
162599	21512138	Antibodies against human EGFR, beta-actin (#A5316) and GAPDH (#sc-32233) were purchased from Dako (Carpenteria, CA), Sigma, and Santa Cruz Biotechnology (Santa Cruz, CA), respectively.	('#sc-32233', 'Var', (62, 71))	('#A5316', 'Var', (43, 49))	('human', 'Species', '9606', (19, 24))	('beta-actin', 'Gene', '728378', (31, 41))	('PD', 'Disease', 'MESH:D010300', (57, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))	('beta-actin', 'Gene', (31, 41))
162613	21512138	Cells cultured in fresh complete or serum-free media overnight (16 hours) were treated with inhibitors of one of the following targets: PI3K (LY294002), MEK1/2 (U0126), p38 MAPK (PD 169316), EGFR (Erlotinib), or vehicle control (DMSO) in fresh serum-free medium for 2 hours, then EGF (10 ng/ml), or HB-EGF (10 or 50 ng/ml) for an additional 24 hours.	('MAPK', 'molecular_function', 'GO:0004707', ('173', '177'))	('EGF', 'Gene', (302, 305))	('HB-EGF', 'Gene', '1839', (299, 305))	('EGF', 'molecular_function', 'GO:0005154', ('302', '305'))	('EGF', 'molecular_function', 'GO:0005154', ('280', '283'))	('DMSO', 'Chemical', 'MESH:D004121', (229, 233))	('EGF', 'Gene', '1950', (280, 283))	('U0126', 'Chemical', 'MESH:C113580', (161, 166))	('Erlotinib', 'Chemical', 'MESH:D000069347', (197, 206))	('LY294002', 'Var', (142, 150))	('EGF', 'Gene', '1950', (191, 194))	('MEK1/2', 'Gene', '5604;5605', (153, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('136', '140'))	('U0126', 'Var', (161, 166))	('MEK1/2', 'Gene', (153, 159))	('HB-EGF', 'Gene', (299, 305))	('EGF', 'Gene', (280, 283))	('EGF', 'Gene', '1950', (302, 305))	('EGFR', 'molecular_function', 'GO:0005006', ('191', '195'))	('MEK1', 'molecular_function', 'GO:0004708', ('153', '157'))	('PD', 'Disease', 'MESH:D010300', (179, 181))	('LY294002', 'Chemical', 'MESH:C085911', (142, 150))	('EGF', 'Gene', (191, 194))
162652	21512138	In UROtsa cells, treatment with H2O2, NaCl, or ATP-gamma-S (a non-hydrolyzable form of ATP) induced coordinate EGFR phosphorylation and elevated levels of SOX9 (Fig.	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('ATP', 'Chemical', 'MESH:D000255', (47, 50))	('levels', 'MPA', (145, 151))	('phosphorylation', 'MPA', (116, 131))	('ATP-gamma-S', 'Chemical', 'MESH:C022571', (47, 58))	('ATP-gamma-S', 'Var', (47, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('116', '131'))	('EGFR', 'Protein', (111, 115))	('H2O2', 'Var', (32, 36))	('H2O2', 'Chemical', 'MESH:D006861', (32, 36))	('NaCl', 'Chemical', 'MESH:D012965', (38, 42))	('elevated', 'PosReg', (136, 144))	('ATP', 'Chemical', 'MESH:D000255', (87, 90))
162678	21512138	shRNA-mediated knockdown of SOX9 expression in UroCa cells can result in a migration defect without affecting tumor cell growth.	('knockdown', 'Var', (15, 24))	('cell growth', 'biological_process', 'GO:0016049', ('116', '127'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('SOX9', 'Gene', (28, 32))	('migration defect', 'Disease', 'MESH:D014085', (75, 91))	('result in', 'Reg', (63, 72))	('migration defect', 'Disease', (75, 91))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
162697	21512138	Recent evidence indicates that arsenic can also induce EGFR ligands and activate urothelial EGFR and Erk1/2.	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('Erk1/2', 'CPA', (101, 107))	('EGFR ligands', 'Protein', (55, 67))	('induce', 'PosReg', (48, 54))	('arsenic', 'Chemical', 'MESH:D001151', (31, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('arsenic', 'Var', (31, 38))	('activate', 'PosReg', (72, 80))	('Erk1', 'molecular_function', 'GO:0004707', ('101', '105'))	('urothelial EGFR', 'CPA', (81, 96))
162709	34039257	lncRNAs participate in embryogenesis, angiogenesis, and cancer progression by exerting epigenetic changes in many processes, including inactivation of X chromatin, regulation of the function of key metabolic genes, cell cycle control, and cell differentiation (Yao et al.	('X chromatin', 'Protein', (151, 162))	('cell cycle control', 'CPA', (215, 233))	('regulation', 'Reg', (164, 174))	('participate', 'Reg', (8, 19))	('embryogenesis', 'biological_process', 'GO:0009793', ('23', '36'))	('regulation', 'biological_process', 'GO:0065007', ('164', '174'))	('cell cycle control', 'biological_process', 'GO:1901987', ('215', '233'))	('function', 'MPA', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cell differentiation', 'biological_process', 'GO:0030154', ('239', '259'))	('chromatin', 'cellular_component', 'GO:0000785', ('153', '162'))	('cell differentiation', 'CPA', (239, 259))	('inactivation', 'Var', (135, 147))	('embryogenesis', 'biological_process', 'GO:0009792', ('23', '36'))	('angiogenesis', 'biological_process', 'GO:0001525', ('38', '50'))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('embryogenesis', 'biological_process', 'GO:0009790', ('23', '36'))
162741	34039257	The effect of p53-regulated lncRNA TUG1 on the proliferation of non-small cell lung cancer cells was partly exerted through epigenetic regulation of homeobox B7 (HOXB7).	('homeobox B7', 'Gene', (149, 160))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('effect', 'Reg', (4, 10))	('regulation', 'biological_process', 'GO:0065007', ('135', '145'))	('HOXB7', 'Gene', '3217', (162, 167))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('HOXB7', 'Gene', (162, 167))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('exerted', 'Reg', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (64, 90))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (68, 90))	('proliferation', 'CPA', (47, 60))	('homeobox B7', 'Gene', '3217', (149, 160))	('epigenetic regulation', 'Var', (124, 145))
162745	34039257	3. lncRNA TUG1 affected proliferation by regulating wnt/beta-catenin signal pathway, miR-384, miR-498, miR-29c, miR-299-3p, or microRNA-9, in oral squamous cell carcinoma, nasopharyngeal carcinoma,esophageal squamous cell carcinoma, pancreatic cancer, breast cancer, respectively.	('miR-498', 'Gene', '574460', (94, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (233, 250))	('miR-29c', 'Gene', (103, 110))	('affected', 'Reg', (15, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('beta-catenin', 'Gene', (56, 68))	('miR-498', 'Gene', (94, 101))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (172, 196))	('miR-299-3p', 'Var', (112, 122))	('beta-catenin', 'Gene', '1499', (56, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (142, 170))	('microRNA-9', 'Var', (127, 137))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('oral squamous cell carcinoma', 'Disease', (142, 170))	('breast cancer', 'Disease', (252, 265))	('pancreatic cancer', 'Disease', 'MESH:D010190', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('carcinoma,esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (187, 231))	('miR-384', 'Gene', (85, 92))	('pancreatic cancer', 'Disease', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('regulating', 'Reg', (41, 51))	('miR-384', 'Gene', '494333', (85, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('miR-29c', 'Gene', '407026', (103, 110))
162778	34039257	lncRNA TUG1 promoted the proliferation, migration, and invasion of osteosarcoma through competitively sponging of miR-219a-5p, resulting in the up-regulation of phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and the activation of the protein kinase B (AKT) signal pathway (Yang et al.).	('proliferation', 'CPA', (25, 38))	('AKT', 'Gene', (286, 289))	('activation', 'PosReg', (250, 260))	('miR-219a-5p', 'Var', (114, 125))	('protein kinase B', 'Gene', '2185', (268, 284))	('migration', 'CPA', (40, 49))	('up-regulation', 'PosReg', (144, 157))	('protein kinase B', 'Gene', (268, 284))	('phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (161, 232))	('PIK3CA', 'Gene', (234, 240))	('osteosarcoma', 'Disease', (67, 79))	('AKT', 'Gene', '207', (286, 289))	('promoted', 'PosReg', (12, 20))	('osteosarcoma', 'Disease', 'MESH:D012516', (67, 79))	('invasion', 'CPA', (55, 63))	('protein', 'cellular_component', 'GO:0003675', ('268', '275'))	('PIK3CA', 'Gene', '5290', (234, 240))	('regulation', 'biological_process', 'GO:0065007', ('147', '157'))	('osteosarcoma', 'Phenotype', 'HP:0002669', (67, 79))
162780	34039257	To sum up, lncRNA TUG1 promoted invasion and metastasis by some molecule, including miR-143p, miR-9-5p, miR-212-3p, miR-219a-5p, miR-140-5p, miR-212-3p, miR-335-5p, miR-132-3p, SOX4, RUNX2, PFN2, ROCK1,FOXA1, or POU2F1 in osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (222, 234))	('PFN2', 'Gene', (190, 194))	('SOX4', 'Gene', (177, 181))	('miR-212', 'Gene', '406994', (141, 148))	('ROCK1', 'Gene', (196, 201))	('miR-140', 'Gene', (129, 136))	('miR-143p', 'Gene', '406935', (84, 92))	('miR-335', 'Gene', (153, 160))	('promoted', 'PosReg', (23, 31))	('PFN2', 'Gene', '5217', (190, 194))	('miR-140', 'Gene', '406932', (129, 136))	('SOX4', 'Gene', '6659', (177, 181))	('miR-143p', 'Gene', (84, 92))	('miR-132-3p', 'Gene', (165, 175))	('miR-212', 'Gene', (104, 111))	('RUNX2', 'Gene', (183, 188))	('miR-9-5p', 'Gene', '407052', (94, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (222, 234))	('invasion', 'CPA', (32, 40))	('POU2F1', 'Gene', '5451', (212, 218))	('RUNX2', 'Gene', '860', (183, 188))	('ROCK1', 'Gene', '6093', (196, 201))	('FOXA1', 'Gene', '3169', (202, 207))	('miR-212', 'Gene', (141, 148))	('miR-9-5p', 'Gene', (94, 102))	('POU2F1', 'Gene', (212, 218))	('FOXA1', 'Gene', (202, 207))	('miR-212', 'Gene', '406994', (104, 111))	('miR-335', 'Gene', '442904', (153, 160))	('osteosarcoma', 'Disease', (222, 234))	('miR-132-3p', 'Gene', '100302255', (165, 175))	('miR-219a-5p', 'Var', (116, 127))
162788	34039257	lncRNA TUG1 knockout promoted cell growth by promoting cell cycle progression and regulating the expression of cyclinD1 and CDK4 (Fan et al.).	('cell growth', 'biological_process', 'GO:0016049', ('30', '41'))	('lncRNA TUG1', 'Gene', (0, 11))	('cyclinD1', 'Gene', (111, 119))	('knockout', 'Var', (12, 20))	('CDK4', 'Gene', '1019', (124, 128))	('promoting', 'PosReg', (45, 54))	('CDK', 'molecular_function', 'GO:0004693', ('124', '127'))	('cell cycle', 'biological_process', 'GO:0007049', ('55', '65'))	('cell cycle progression', 'CPA', (55, 77))	('regulating', 'Reg', (82, 92))	('cyclinD1', 'Gene', '595', (111, 119))	('promoted', 'PosReg', (21, 29))	('cell growth', 'CPA', (30, 41))	('expression', 'MPA', (97, 107))	('CDK4', 'Gene', (124, 128))
162805	34039257	In tongue squamous cell carcinoma, down-regulation of lncRNA TUG1 inhibited cell proliferation, and silencing of lncRNA TUG1 regulated the progression of the cell cycle (Li et al.).	('tongue squamous cell carcinoma', 'Disease', (3, 33))	('silencing', 'Var', (100, 109))	('regulation', 'biological_process', 'GO:0065007', ('40', '50'))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('progression of the cell cycle', 'CPA', (139, 168))	('cell proliferation', 'CPA', (76, 94))	('cell cycle', 'biological_process', 'GO:0007049', ('158', '168'))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('inhibited', 'NegReg', (66, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (10, 33))	('lncRNA TUG1', 'Gene', (54, 65))	('lncRNA TUG1', 'Gene', (113, 124))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 33))	('down-regulation', 'NegReg', (35, 50))	('regulated', 'Reg', (125, 134))
162806	34039257	TUG1 knockout blocked cell cycle, accelerated apoptosis and inhibitted the proliferation of pancreatic cancer cells (Hui Bingqing and Yetao).	('proliferation', 'CPA', (75, 88))	('apoptosis', 'CPA', (46, 55))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('TUG1', 'Gene', (0, 4))	('knockout', 'Var', (5, 13))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('pancreatic cancer', 'Disease', (92, 109))	('cell cycle', 'biological_process', 'GO:0007049', ('22', '32'))	('accelerated', 'PosReg', (34, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('blocked', 'NegReg', (14, 21))	('cell cycle', 'CPA', (22, 32))	('inhibitted', 'NegReg', (60, 70))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))
162807	34039257	Knocking out the TUG1 reduced that enhancer of zeste homolog 2 (EZH2) binded to the promoter regions of Rho family GTPase 3 (RND3) and metallothionein 2A (MT2A) (Hui Bingqing and Yetao).	('TUG1', 'Gene', (17, 21))	('enhancer of zeste homolog 2', 'Gene', '2146', (35, 62))	('RND3', 'Gene', '390', (125, 129))	('MT2A', 'Gene', '4502', (155, 159))	('metallothionein 2A', 'Gene', (135, 153))	('enhancer of zeste homolog 2', 'Gene', (35, 62))	('MT2A', 'Gene', (155, 159))	('binded', 'Interaction', (70, 76))	('MT2', 'molecular_function', 'GO:0043851', ('155', '158'))	('RND3', 'Gene', (125, 129))	('metallothionein 2A', 'Gene', '4502', (135, 153))	('EZH2', 'Gene', (64, 68))	('Knocking', 'Var', (0, 8))	('EZH2', 'Gene', '2146', (64, 68))
162812	34039257	lncRNA TUG1 knockout inhibited glucose consumption, lactic acid production, and reduced the cell viability of osteosarcoma cells.	('lactic acid production', 'MPA', (52, 74))	('lncRNA TUG1', 'Gene', (0, 11))	('knockout', 'Var', (12, 20))	('glucose', 'CPA', (31, 38))	('osteosarcoma', 'Disease', (110, 122))	('reduced', 'NegReg', (80, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (110, 122))	('osteosarcoma', 'Disease', 'MESH:D012516', (110, 122))	('inhibited', 'NegReg', (21, 30))	('lactic acid', 'Chemical', 'MESH:D019344', (52, 63))	('glucose', 'Chemical', 'MESH:D005947', (31, 38))
162814	34039257	The abnormal expression of lncRNA TUG1 significantly affected the expression of hexokinase-2 (HK2), which might be an important molecule through which lncRNA TUG1 affects glycolysis (Xiufu et al.).	('lncRNA TUG1', 'Gene', (27, 38))	('affected', 'Reg', (53, 61))	('abnormal', 'Var', (4, 12))	('glycolysis', 'MPA', (171, 181))	('expression', 'MPA', (66, 76))	('glycolysis', 'biological_process', 'GO:0006096', ('171', '181'))	('HK2', 'molecular_function', 'GO:0008256', ('94', '97'))	('HK2', 'Gene', '3099', (94, 97))	('affects', 'Reg', (163, 170))	('hexokinase-2', 'Gene', (80, 92))	('HK2', 'Gene', (94, 97))	('hexokinase-2', 'Gene', '3099', (80, 92))
162815	34039257	HK2 gene knockout weakened the effect of lncRNA TUG1 overexpression on glycolysis in osteosarcoma cells (Xiufu et al.).	('HK2', 'Gene', '3099', (0, 3))	('knockout', 'Var', (9, 17))	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('osteosarcoma', 'Disease', (85, 97))	('osteosarcoma', 'Disease', 'MESH:D012516', (85, 97))	('glycolysis', 'biological_process', 'GO:0006096', ('71', '81'))	('glycolysis', 'MPA', (71, 81))	('HK2', 'molecular_function', 'GO:0008256', ('0', '3'))	('HK2', 'Gene', (0, 3))	('weakened', 'NegReg', (18, 26))
162816	34039257	lncRNA TUG1 was up-regulated in AML patients and cells, and its knockout inhibited glycolysis in AML cells by targeting miR-185 (Weide et al.).	('glycolysis', 'MPA', (83, 93))	('lncRNA TUG1', 'Gene', (0, 11))	('AML', 'Disease', 'MESH:D015470', (32, 35))	('miR-185', 'Gene', (120, 127))	('patients', 'Species', '9606', (36, 44))	('knockout', 'Var', (64, 72))	('AML', 'Phenotype', 'HP:0004808', (97, 100))	('AML', 'Disease', (97, 100))	('AML', 'Phenotype', 'HP:0004808', (32, 35))	('up-regulated', 'PosReg', (16, 28))	('AML', 'Disease', (32, 35))	('inhibited', 'NegReg', (73, 82))	('AML', 'Disease', 'MESH:D015470', (97, 100))	('targeting', 'Reg', (110, 119))	('miR-185', 'Gene', '406961', (120, 127))	('glycolysis', 'biological_process', 'GO:0006096', ('83', '93'))
162820	34039257	Knockout of lncRNA TUG1 inhibited angiogenesis in ovarian cancer by regulating LRG1 (Mingjun et al.).	('ovarian cancer', 'Disease', 'MESH:D010051', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('angiogenesis', 'biological_process', 'GO:0001525', ('34', '46'))	('LRG1', 'Gene', (79, 83))	('ovarian cancer', 'Disease', (50, 64))	('inhibited', 'NegReg', (24, 33))	('lncRNA TUG1', 'Gene', (12, 23))	('Knockout', 'Var', (0, 8))	('angiogenesis', 'CPA', (34, 46))	('LRG1', 'Gene', '116844', (79, 83))	('ovarian cancer', 'Phenotype', 'HP:0100615', (50, 64))
162825	34039257	lncRNA TUG1 regulated CCND2, through EZH2-related miR-194-5p silencing, to promote the growth of bladder cancer cells and confer cisplatin resistance (Gan et al.).	('growth', 'MPA', (87, 93))	('cisplatin resistance', 'MPA', (129, 149))	('promote', 'PosReg', (75, 82))	('bladder cancer', 'Disease', 'MESH:D001749', (97, 111))	('CCND2', 'Gene', (22, 27))	('bladder cancer', 'Disease', (97, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('CCND2', 'Gene', '894', (22, 27))	('silencing', 'Var', (61, 70))	('confer', 'Reg', (122, 128))	('miR-194-5p silencing', 'Var', (50, 70))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('EZH2', 'Gene', '2146', (37, 41))	('EZH2', 'Gene', (37, 41))
162828	34039257	lncRNA TUG1 knockout can induce apoptosis by inhibiting MET/Akt signalling, thus reducing the resistance of osteosarcoma cells to cisplatin (Zhou Qiang and Yuan).	('resistance', 'MPA', (94, 104))	('reducing', 'NegReg', (81, 89))	('lncRNA TUG1', 'Gene', (0, 11))	('knockout', 'Var', (12, 20))	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('Akt', 'Gene', '207', (60, 63))	('induce', 'PosReg', (25, 31))	('osteosarcoma', 'Phenotype', 'HP:0002669', (108, 120))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('osteosarcoma', 'Disease', (108, 120))	('osteosarcoma', 'Disease', 'MESH:D012516', (108, 120))	('MET', 'Gene', '79811', (56, 59))	('inhibiting', 'NegReg', (45, 55))	('Akt', 'Gene', (60, 63))	('MET', 'Gene', (56, 59))	('signalling', 'biological_process', 'GO:0023052', ('64', '74'))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))
162832	34039257	lncRNA TUG1 enhanced adriamycin resistance in AML by inhibiting the expression of miR-34a through EZH2 epigenetically (Li et al.).	('EZH2', 'Gene', (98, 102))	('expression', 'MPA', (68, 78))	('AML', 'Phenotype', 'HP:0004808', (46, 49))	('epigenetically', 'Var', (103, 117))	('AML', 'Disease', (46, 49))	('miR-34a', 'Gene', '407040', (82, 89))	('adriamycin', 'Chemical', 'MESH:D004317', (21, 31))	('enhanced', 'PosReg', (12, 20))	('adriamycin resistance', 'MPA', (21, 42))	('AML', 'Disease', 'MESH:D015470', (46, 49))	('miR-34a', 'Gene', (82, 89))	('inhibiting', 'NegReg', (53, 63))	('EZH2', 'Gene', '2146', (98, 102))
162839	34039257	Knockout of lncRNA TUG1 enhanced the radiosensitivity of prostate cancer through the lncRNA TUG1/miR-139-5p/structural maintenance of chromosomes protein 1A (SMC1A) axis (Dianhui et al.).	('prostate cancer', 'Disease', (57, 72))	('SMC', 'cellular_component', 'GO:0016029', ('158', '161'))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('prostate cancer', 'Disease', 'MESH:D011471', (57, 72))	('enhanced', 'PosReg', (24, 32))	('lncRNA TUG1', 'Gene', (12, 23))	('Knockout', 'Var', (0, 8))	('prostate cancer', 'Phenotype', 'HP:0012125', (57, 72))	('radiosensitivity', 'CPA', (37, 53))
162841	34039257	The high expression of lncRNA TUG1 was associated with chemotherapy resistance and poor prognosis in oesophageal squamous cell carcinoma (Lin et al.).	('chemotherapy resistance', 'CPA', (55, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('oesophageal squamous cell carcinoma', 'Disease', (101, 136))	('high', 'Var', (4, 8))	('associated', 'Reg', (39, 49))	('lncRNA TUG1', 'Gene', (23, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 136))
162856	34039257	At present, there are relatively fewer clinical studies on lncRNA TUG1, but existing studies suggest that lncRNA TUG1 may be an effective diagnostic or prognostic cancer biomarker.	('lncRNA', 'Var', (106, 112))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
162869	34039257	Although lncRNA TUG1 could reduce the radiosensitivity of bladder cancer, it could also enhance the radiosensitivity of esophageal cancer.	('cancer', 'Disease', (131, 137))	('radiosensitivity', 'MPA', (38, 54))	('radiosensitivity', 'MPA', (100, 116))	('lncRNA', 'Var', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('reduce', 'NegReg', (27, 33))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('bladder cancer', 'Disease', (58, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', (66, 72))	('enhance', 'PosReg', (88, 95))
162874	34039257	If any of the key proteins in this signalling pathway are mutated, resulting in abnormal signal activation, it may induce the development of cancer (Shuang et al.).	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('induce', 'Reg', (115, 121))	('signalling pathway', 'biological_process', 'GO:0007165', ('35', '53'))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('mutated', 'Var', (58, 65))	('cancer', 'Disease', (141, 147))	('signal activation', 'MPA', (89, 106))
162875	34039257	For example, activating the Wnt/beta-catenin signalling pathway regulated the invasion and proliferation of oesophageal squamous cell carcinoma, cervical cancer, bladder cancer, and colorectal cancer, and induced their epithelial cell transformation (Fu-Bing et al.).	('colorectal cancer', 'Phenotype', 'HP:0003003', (182, 199))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', (193, 199))	('signalling pathway', 'biological_process', 'GO:0007165', ('45', '63'))	('beta-catenin', 'Gene', (32, 44))	('beta-catenin', 'Gene', '1499', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('activating', 'Var', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('epithelial cell transformation', 'CPA', (219, 249))	('colorectal cancer', 'Disease', 'MESH:D015179', (182, 199))	('induced', 'Reg', (205, 212))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('colorectal cancer', 'Disease', (182, 199))	('proliferation', 'CPA', (91, 104))	('bladder cancer', 'Disease', 'MESH:D001749', (162, 176))	('bladder cancer', 'Disease', (162, 176))	('invasion', 'CPA', (78, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (162, 176))	('cancer', 'Disease', (154, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('oesophageal squamous cell carcinoma', 'Disease', (108, 143))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 143))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
162881	34039257	lncRNA TUG1 promoted the proliferation, migration, and invasion of hepatoma cells by activating the JAK2/STAT3 pathway, upregulating the expression of AURKA, interacting with miR-216B-5p and inhibiting apoptosis by activating DLX2, or by down-regulating miR-142-3p to regulate the miR-29c-3p/COL1A1 axis.	('proliferation', 'CPA', (25, 38))	('STAT3', 'Gene', '6774', (105, 110))	('migration', 'CPA', (40, 49))	('miR-142-3p', 'Pathway', (254, 264))	('hepatoma', 'Disease', 'MESH:D006528', (67, 75))	('COL1A1', 'Gene', (292, 298))	('activating', 'PosReg', (215, 225))	('expression', 'MPA', (137, 147))	('apoptosis', 'biological_process', 'GO:0097194', ('202', '211'))	('apoptosis', 'biological_process', 'GO:0006915', ('202', '211'))	('interacting', 'Interaction', (158, 169))	('JAK2', 'Gene', '3717', (100, 104))	('JAK', 'molecular_function', 'GO:0004713', ('100', '103'))	('miR-142-3p', 'Chemical', '-', (254, 264))	('promoted', 'PosReg', (12, 20))	('activating', 'PosReg', (85, 95))	('upregulating', 'PosReg', (120, 132))	('down-regulating', 'NegReg', (238, 253))	('hepatoma', 'Disease', (67, 75))	('miR-29c', 'Gene', '407026', (281, 288))	('miR-216B-5p', 'Var', (175, 186))	('invasion', 'CPA', (55, 63))	('apoptosis', 'CPA', (202, 211))	('DLX2', 'Gene', (226, 230))	('DLX2', 'Gene', '1746', (226, 230))	('JAK2', 'Gene', (100, 104))	('AURKA', 'Gene', '6790', (151, 156))	('inhibiting', 'NegReg', (191, 201))	('AURKA', 'Gene', (151, 156))	('miR-29c', 'Gene', (281, 288))	('STAT3', 'Gene', (105, 110))	('COL1A1', 'Gene', '1277', (292, 298))
162882	34039257	lncRNA TUG1 regulated downstream genes, including miR-143p, miR-9-5p, miR-212-3p, miR-140-5p, microRNA-212-3p, miR-335-5p and miR-219a-5p, to participate in the proliferation and invasion of osteosarcoma cells.	('miR-212', 'Gene', '406994', (70, 77))	('invasion', 'CPA', (179, 187))	('osteosarcoma', 'Phenotype', 'HP:0002669', (191, 203))	('miR-140', 'Gene', (82, 89))	('lncRNA TUG1', 'Gene', (0, 11))	('miR-140', 'Gene', '406932', (82, 89))	('miR-335', 'Gene', '442904', (111, 118))	('miR-143p', 'Gene', '406935', (50, 58))	('miR-9-5p', 'Gene', '407052', (60, 68))	('participate', 'Reg', (142, 153))	('miR-143p', 'Gene', (50, 58))	('osteosarcoma', 'Disease', (191, 203))	('miR-212', 'Gene', (70, 77))	('osteosarcoma', 'Disease', 'MESH:D012516', (191, 203))	('miR-9-5p', 'Gene', (60, 68))	('proliferation', 'CPA', (161, 174))	('miR-219a-5p', 'Var', (126, 137))	('miR-335', 'Gene', (111, 118))	('microRNA-212-3p', 'Var', (94, 109))
162993	30158554	4d, when categorized into four groups based on median EMT and ITA gene expression, patients with ITAhigh EMTlow tumors demonstrated the best OS while patients with ITAlow EMThigh tumors demonstrated the worst OS.	('OS', 'Chemical', '-', (141, 143))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('ITAhigh', 'Var', (97, 104))	('patients', 'Species', '9606', (150, 158))	('low EMT', 'Phenotype', 'HP:0032198', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('OS', 'Chemical', '-', (209, 211))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('patients', 'Species', '9606', (83, 91))	('gene expression', 'biological_process', 'GO:0010467', ('66', '81'))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))	('EMT', 'biological_process', 'GO:0001837', ('54', '57'))	('high EMT', 'Phenotype', 'HP:0008151', (100, 108))
163021	30158554	Patients with high CD8 infiltration and low EMT/Stroma core gene expression had the highest response rates and longest PFS and OS, while patients with high CD8 infiltration but high EMT/Stroma core gene expression had worse outcomes.	('CD8', 'Gene', (19, 22))	('CD8', 'Gene', '925', (19, 22))	('gene expression', 'biological_process', 'GO:0010467', ('198', '213'))	('core', 'cellular_component', 'GO:0019013', ('193', '197'))	('low EMT', 'Phenotype', 'HP:0032198', (40, 47))	('PFS', 'CPA', (119, 122))	('low', 'Var', (40, 43))	('patients', 'Species', '9606', (137, 145))	('high EMT', 'Phenotype', 'HP:0008151', (177, 185))	('Patients', 'Species', '9606', (0, 8))	('gene expression', 'biological_process', 'GO:0010467', ('60', '75'))	('core', 'cellular_component', 'GO:0019013', ('55', '59'))	('EMT', 'biological_process', 'GO:0001837', ('44', '47'))	('response rates', 'CPA', (92, 106))	('OS', 'Chemical', '-', (127, 129))	('CD8', 'Gene', (156, 159))	('EMT', 'biological_process', 'GO:0001837', ('182', '185'))	('CD8', 'Gene', '925', (156, 159))
163099	20012924	Although cancer progression often selects for the acquisition of defects on TGFbeta signaling, in some cases, the mutations appear to selectively inactivate TGFbeta's growth inhibitory effects without interfering with EMT signaling.	('cancer', 'Disease', (9, 15))	('TGFbeta', 'Gene', (76, 83))	('inactivate', 'NegReg', (146, 156))	('signaling', 'biological_process', 'GO:0023052', ('222', '231'))	('mutations', 'Var', (114, 123))	('growth inhibitory effects', 'MPA', (167, 192))	('EMT', 'biological_process', 'GO:0001837', ('218', '221'))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('TGFbeta', 'Gene', (157, 164))	('TGFbeta', 'Gene', '7040', (76, 83))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('TGFbeta', 'Gene', '7040', (157, 164))	('defects', 'Var', (65, 72))
163110	20012924	Studies in preclinical models demonstrated that loss of E-cadherin directly promoted an EMT phenotype and reprogrammed global gene expression.	('reprogrammed global gene expression', 'MPA', (106, 141))	('loss', 'Var', (48, 52))	('cadherin', 'molecular_function', 'GO:0008014', ('58', '66'))	('EMT phenotype', 'CPA', (88, 101))	('EMT', 'biological_process', 'GO:0001837', ('88', '91'))	('gene expression', 'biological_process', 'GO:0010467', ('126', '141'))	('promoted', 'PosReg', (76, 84))	('E-cadherin', 'Gene', (56, 66))	('E-cadherin', 'Gene', '999', (56, 66))
163115	20012924	In addition, E-cadherin is infrequently inactivated by mutation, and under these circumstances, there may or may not be added selective pressure on the miR200 family or the EMT-mediating E-cadherin repressors.	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('E-cadherin', 'Gene', (187, 197))	('E-cadherin', 'Gene', '999', (187, 197))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('mutation', 'Var', (55, 63))	('EMT', 'biological_process', 'GO:0001837', ('173', '176'))	('cadherin', 'molecular_function', 'GO:0008014', ('189', '197'))
163126	20012924	Importantly, overexpression of Zeb-2 in "epithelial" cell lines rendered them resistant to radiation-induced apoptosis, and overexpression of Zeb-2 in radiation-exposed primary tumors was also associated with poor clinical outcome.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('Zeb-2', 'Gene', '9839', (142, 147))	('Zeb-2', 'Gene', '9839', (31, 36))	('overexpression', 'Var', (124, 138))	('primary tumors', 'Disease', (169, 183))	('resistant', 'CPA', (78, 87))	('overexpression', 'PosReg', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('associated with', 'Reg', (193, 208))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('primary tumors', 'Disease', 'MESH:D009369', (169, 183))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('Zeb-2', 'Gene', (142, 147))	('Zeb-2', 'Gene', (31, 36))
163140	20012924	Inhibitors of the epidermal growth factor receptor (EGFR) were among the first targeted agents to be developed for cancer therapy.	('cancer', 'Disease', (115, 121))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('18', '41'))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('epidermal growth factor receptor', 'Gene', (18, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('epidermal growth factor receptor', 'Gene', '1956', (18, 50))
163142	20012924	Preclinical studies provided further support for the idea that EGFR inhibitors might exert unique potency in bladder cancer.	('EGFR', 'Gene', '1956', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('EGFR', 'Gene', (63, 67))	('inhibitors', 'Var', (68, 78))	('bladder cancer', 'Disease', 'MESH:D001749', (109, 123))	('bladder cancer', 'Disease', (109, 123))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))
163143	20012924	For example, work from our group demonstrated that EGFR blockade inhibited the growth and metastasis of orthotopic human 253J B-V bladder xenografts, effects that were linked to inhibition of tumor production of angiogenic factors (VEGF, bFGF, and IL-8), and overexpression of the EGFR promotes tumorigenesis in transgenic mice.	('overexpression', 'PosReg', (259, 273))	('bFGF', 'Gene', (238, 242))	('EGFR', 'Gene', (51, 55))	('IL-8', 'molecular_function', 'GO:0005153', ('248', '252'))	('IL-8', 'Gene', (248, 252))	('EGFR', 'Gene', (281, 285))	('inhibited', 'NegReg', (65, 74))	('tumor', 'Disease', (295, 300))	('EGFR', 'Gene', '1956', (51, 55))	('VEGF', 'Gene', '7422', (232, 236))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('VEGF', 'Gene', (232, 236))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('bFGF', 'Gene', '2247', (238, 242))	('IL-8', 'Gene', '3576', (248, 252))	('blockade', 'Var', (56, 64))	('inhibition', 'NegReg', (178, 188))	('EGFR', 'Gene', '1956', (281, 285))	('human', 'Species', '9606', (115, 120))	('transgenic mice', 'Species', '10090', (312, 327))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('promotes', 'PosReg', (286, 294))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('EGFR', 'molecular_function', 'GO:0005006', ('281', '285'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
163149	20012924	This change has been driven largely by the results of clinical trials with EGFR inhibitors in other solid malignancies.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('malignancies', 'Disease', (106, 118))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', (75, 79))	('inhibitors', 'Var', (80, 90))
163153	20012924	Conversely, the presence of activating Kras mutations renders lung and colon cancers resistant to EGFR-directed therapy.	('EGFR', 'Gene', (98, 102))	('Kras', 'Gene', (39, 43))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('colon cancer', 'Phenotype', 'HP:0003003', (71, 83))	('activating', 'PosReg', (28, 38))	('Kras', 'Gene', '3845', (39, 43))	('colon cancers', 'Phenotype', 'HP:0003003', (71, 84))	('mutations', 'Var', (44, 53))	('lung and colon cancers', 'Disease', 'MESH:D008175', (62, 84))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))
163159	20012924	Importantly, RNAi-mediated knockdown of E-cadherin rendered cells resistant to cetuximab, demonstrating that E-cadherin plays a causal role in maintaining EGFR inhibitor sensitivity.	('knockdown', 'Var', (27, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('155', '159'))	('EGFR', 'Gene', '1956', (155, 159))	('E-cadherin', 'Gene', (40, 50))	('E-cadherin', 'Gene', '999', (40, 50))	('cadherin', 'molecular_function', 'GO:0008014', ('42', '50'))	('EGFR', 'Gene', (155, 159))	('E-cadherin', 'Gene', '999', (109, 119))	('E-cadherin', 'Gene', (109, 119))	('RNAi', 'biological_process', 'GO:0016246', ('13', '17'))	('cadherin', 'molecular_function', 'GO:0008014', ('111', '119'))	('cetuximab', 'Chemical', 'MESH:D000068818', (79, 88))
163161	20012924	Reanalysis of our gene expression profiling data revealed that the levels of FGFR3 were higher in the "epithelial" as compared to the "mesenchymal" cells (W. Choi, unpublished observation), and direct sequencing of FGFR3 demonstrated that four of our cell lines possessed activating FGFR3 mutations (P. Black, manuscript in preparation).	('FGFR3', 'Gene', (77, 82))	('FGFR3', 'Gene', (283, 288))	('FGFR3', 'Gene', (215, 220))	('mutations', 'Var', (289, 298))	('activating', 'PosReg', (272, 282))	('FGFR', 'molecular_function', 'GO:0005007', ('211', '215'))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('levels', 'MPA', (67, 73))	('mes', 'Chemical', 'MESH:C004550', (135, 138))	('FGFR', 'molecular_function', 'GO:0005007', ('279', '283'))	('FGFR3', 'Gene', '2261', (77, 82))	('FGFR3', 'Gene', '2261', (283, 288))	('FGFR3', 'Gene', '2261', (215, 220))	('gene expression', 'biological_process', 'GO:0010467', ('18', '33'))
163162	20012924	As discussed in previous chapters of this volume, activating FGFR3 mutations are very common in superficial tumors, and more recent work has demonstrated that RNAi-mediated knockdown of FGFR3 or exposure to a clinical FGFR3 inhibitor blocked proliferation in these cells.	('knockdown', 'Var', (173, 182))	('RNAi', 'biological_process', 'GO:0016246', ('159', '163'))	('FGFR', 'molecular_function', 'GO:0005007', ('186', '190'))	('FGFR', 'molecular_function', 'GO:0005007', ('218', '222'))	('FGFR3', 'Gene', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('blocked', 'NegReg', (234, 241))	('FGFR3', 'Gene', '2261', (61, 66))	('FGFR3', 'Gene', (186, 191))	('FGFR3', 'Gene', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('FGFR', 'molecular_function', 'GO:0005007', ('61', '65'))	('FGFR3', 'Gene', '2261', (186, 191))	('tumors', 'Disease', (108, 114))	('FGFR3', 'Gene', '2261', (218, 223))	('proliferation', 'CPA', (242, 255))	('mutations', 'Var', (67, 76))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('activating', 'PosReg', (50, 60))
163167	20012924	We also screened our cell lines and a relatively large set of primary human tumors for the presence of EGFR gene amplification, the presence of activating kinase domain mutations (akin to those described in lung cancer), and expression of a variant form of the EGFR (type III) that has been implicated in EGFR dependency in gliomas.	('EGFR', 'Gene', '1956', (103, 107))	('gliomas', 'Disease', 'MESH:D005910', (324, 331))	('activating', 'PosReg', (144, 154))	('EGFR', 'molecular_function', 'GO:0005006', ('305', '309'))	('gliomas', 'Phenotype', 'HP:0009733', (324, 331))	('EGFR', 'Gene', (305, 309))	('EGFR', 'Gene', '1956', (261, 265))	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('kinase', 'MPA', (155, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('EGFR', 'Gene', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('human', 'Species', '9606', (70, 75))	('tumors', 'Disease', (76, 82))	('EGFR', 'Gene', '1956', (305, 309))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('gliomas', 'Disease', (324, 331))	('EGFR', 'Gene', (261, 265))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('261', '265'))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('variant', 'Var', (241, 248))	('lung cancer', 'Disease', (207, 218))
163170	20012924	Therefore, it is not clear to us that activating Ras mutations and activation of the EGFR or FGFR3 play redundant roles in driving the growth of the "epithelial" subset of urothelial cancer cells.	('Ras', 'Gene', (49, 52))	('EGFR', 'Gene', (85, 89))	('activating', 'PosReg', (38, 48))	('FGFR3', 'Gene', '2261', (93, 98))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('mutations', 'Var', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('urothelial cancer', 'Disease', (172, 189))	('FGFR3', 'Gene', (93, 98))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('EGFR', 'Gene', '1956', (85, 89))	('growth', 'MPA', (135, 141))	('urothelial cancer', 'Disease', 'MESH:D014523', (172, 189))
163184	20012924	Conversely, we have found that knockdown of Zeb-1 in "mesenchymal" cell lines inhibits tumor cell invasion and migration, although the effects are highly cell type-dependent.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Zeb-1', 'Gene', '6935', (44, 49))	('tumor', 'Disease', (87, 92))	('Zeb-1', 'Gene', (44, 49))	('mes', 'Chemical', 'MESH:C004550', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('inhibits', 'NegReg', (78, 86))	('knockdown', 'Var', (31, 40))
163185	20012924	For example, in UMUC3 cells, Zeb-1 knockdown results in strong upregulation of E-cadherin mRNA and protein levels and parallel strong inhibition of invasion (A. Das et al, manuscript in preparation).	('knockdown', 'Var', (35, 44))	('cadherin', 'molecular_function', 'GO:0008014', ('81', '89'))	('E-cadherin', 'Gene', (79, 89))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('inhibition', 'NegReg', (134, 144))	('Zeb-1', 'Gene', (29, 34))	('E-cadherin', 'Gene', '999', (79, 89))	('upregulation', 'PosReg', (63, 75))	('Zeb-1', 'Gene', '6935', (29, 34))	('invasion', 'CPA', (148, 156))
163186	20012924	However, in KU7 or T24 cells, Zeb-1 knockdown weakly upregulates E-cadherin mRNA expression and does not appreciably affect protein expression, and as a result, invasion is not attenuated.	('upregulates', 'PosReg', (53, 64))	('Zeb-1', 'Gene', '6935', (30, 35))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('invasion', 'CPA', (161, 169))	('knockdown', 'Var', (36, 45))	('cadherin', 'molecular_function', 'GO:0008014', ('67', '75'))	('E-cadherin', 'Gene', '999', (65, 75))	('E-cadherin', 'Gene', (65, 75))	('Zeb-1', 'Gene', (30, 35))
163190	20012924	By analyzing E-cadherin promoter histone methylation by chromatin immunoprecipitation, we have found that a repressive histone methylation mark (H3K27me3) is present at much higher levels in the KU7 and T24 cells as compared to UMUC3 (A. Das, manuscript in preparation).	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('H3K27me3', 'Var', (145, 153))	('chromatin', 'cellular_component', 'GO:0000785', ('56', '65'))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('histone methylation', 'biological_process', 'GO:0016571', ('33', '52'))	('histone methylation', 'biological_process', 'GO:0016571', ('119', '138'))
163197	20012924	Consistent with this idea, we have shown that miR200c directly targets the mRNA encoding ERRFI-1, an inhibitor of EGFR signaling, and that knockdown of ERRFI-1 in UMUC3 also increases cellular sensitivity to EGFR inhibitors.	('increases', 'PosReg', (174, 183))	('ERRFI-1', 'Gene', (89, 96))	('miR200c', 'Gene', (46, 53))	('ERRFI-1', 'Gene', '54206', (152, 159))	('EGFR', 'molecular_function', 'GO:0005006', ('208', '212'))	('knockdown', 'Var', (139, 148))	('ERRFI-1', 'Gene', '54206', (89, 96))	('EGFR', 'Gene', '1956', (208, 212))	('EGFR', 'Gene', '1956', (114, 118))	('miR200c', 'Gene', '406985', (46, 53))	('EGFR', 'Gene', (208, 212))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))	('ERRFI-1', 'Gene', (152, 159))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))
163213	20012924	Along these lines, recent work has demonstrated that clinical histone deacetylase (HDAC) inhibitors are capable of restoring E-cadherin expression and EGFR inhibitor sensitivity in lung cancer cells, prompting interest in performing clinical trials with EGFR inhibitor/HDAC inhibitor combinations in patients.	('EGFR', 'molecular_function', 'GO:0005006', ('254', '258'))	('E-cadherin', 'Gene', '999', (125, 135))	('expression', 'MPA', (136, 146))	('restoring', 'PosReg', (115, 124))	('EGFR', 'Gene', (254, 258))	('EGFR', 'Gene', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('inhibitors', 'Var', (89, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('cadherin', 'molecular_function', 'GO:0008014', ('127', '135'))	('sensitivity', 'MPA', (166, 177))	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('E-cadherin', 'Gene', (125, 135))	('patients', 'Species', '9606', (300, 308))	('EGFR', 'Gene', '1956', (254, 258))	('EGFR', 'Gene', '1956', (151, 155))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
163215	20012924	The recently published work demonstrating that Zeb-2 expression is associated with poor outcome in patients receiving radiation therapy suggests that EMT might contribute to a more global therapeutic resistance than has been described here, or it may at least suppress DNA damage-induced cell death.	('expression', 'Var', (53, 63))	('DNA damage-induced cell death', 'CPA', (269, 298))	('contribute', 'Reg', (160, 170))	('Zeb-2', 'Gene', (47, 52))	('global therapeutic resistance', 'MPA', (181, 210))	('patients', 'Species', '9606', (99, 107))	('DNA', 'cellular_component', 'GO:0005574', ('269', '272'))	('cell death', 'biological_process', 'GO:0008219', ('288', '298'))	('associated', 'Reg', (67, 77))	('suppress', 'NegReg', (260, 268))	('Zeb-2', 'Gene', '9839', (47, 52))	('EMT', 'biological_process', 'GO:0001837', ('150', '153'))
163219	28719033	Identification of driver copy number alterations in diverse cancer types and application in drug repositioning Results from numerous studies suggest an important role for somatic copy number alterations (SCNAs) in cancer progression.	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('copy number alterations', 'Var', (25, 48))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
163266	28719033	a + b + c + d is the total number of genes in the expression profile, and a + b is the number of census cancer genes in the expression profile.	('a + b + c + d', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('census cancer', 'Disease', (97, 110))	('census cancer', 'Disease', 'MESH:D009369', (97, 110))	('a + b', 'Var', (74, 79))
163279	28719033	Second, alterations, including SCNAs, that affect expression levels of other genes in the cancer genome have been used to identify key events for carcinogenesis (Masica and Karchin, 2011).	('carcinogenesis', 'Disease', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('alterations', 'Var', (8, 19))	('affect', 'Reg', (43, 49))	('expression levels', 'MPA', (50, 67))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))
163298	28719033	The drivers with deletions also significantly overlapped with tumor suppressor genes in the TSGene database in 11 of the 18 cancer types (Fig.	('overlapped', 'Reg', (46, 56))	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('deletions', 'Var', (17, 26))	('tumor', 'Disease', (62, 67))	('tumor suppressor', 'biological_process', 'GO:0051726', ('62', '78'))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('62', '78'))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
163305	28719033	Many studies have reported aberrations in POU5F1B in cancer, such as in gastric and prostate cancer (Hayashi et al., 2015; Kastler et al., 2010).	('cancer', 'Disease', (93, 99))	('gastric and prostate cancer', 'Disease', 'MESH:D013274', (72, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('POU5F1B', 'Gene', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('POU5F1B', 'Gene', '5462', (42, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))	('aberrations', 'Var', (27, 38))
163306	28719033	5C, a total of nine non-coding drivers (hsa-mir-106b, hsa-mir-218-2, hsa-mir-548k, AP006216.10, CAPN10-AS1, RP11-1191J2.4, RP11-191L9.4, RP11-443B7.1 and RP11-794P6.1) were shared by two cancer types, and three non-coding drivers (PVT1, SOX2-OT and hsa-mir-429) by three cancer types.	('AS1', 'Gene', (103, 106))	('RP11', 'Gene', (108, 112))	('RP11', 'Gene', '26121', (154, 158))	('PVT1', 'Gene', '5820', (231, 235))	('RP11', 'Gene', (123, 127))	('cancer', 'Disease', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('RP11', 'Gene', (137, 141))	('RP11', 'Gene', (154, 158))	('SOX2-OT', 'Gene', (237, 244))	('AS1', 'Gene', '5729', (103, 106))	('CAPN10', 'Gene', (96, 102))	('SOX2-OT', 'Gene', '347689', (237, 244))	('RP11', 'Gene', '26121', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('CAPN10', 'Gene', '11132', (96, 102))	('hsa-mir-218-2', 'Gene', '407001', (54, 67))	('RP11', 'Gene', '26121', (123, 127))	('cancer', 'Disease', (187, 193))	('hsa-mir-218-2', 'Gene', (54, 67))	('AP006216.10', 'Var', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('hsa-mir-429', 'Gene', '554210', (249, 260))	('PVT1', 'Gene', (231, 235))	('RP11', 'Gene', '26121', (137, 141))	('hsa-mir-429', 'Gene', (249, 260))
163310	28719033	In total, seven drivers (MYC with amplification, PER2, HDAC4, PTPRG, PIK3R1, RAPGEF1 and PPP5C with deletion) were detected in both BRCA and OV.	('BRCA', 'Gene', '672', (132, 136))	('PIK3R1', 'Gene', (69, 75))	('MYC', 'Gene', (25, 28))	('HDAC4', 'Gene', '9759', (55, 60))	('RAPGEF1', 'Gene', '2889', (77, 84))	('PPP5C', 'Gene', (89, 94))	('PPP5C', 'Gene', '5536', (89, 94))	('BRCA', 'Gene', (132, 136))	('OV', 'Phenotype', 'HP:0100615', (141, 143))	('amplification', 'Var', (34, 47))	('deletion', 'Var', (100, 108))	('HDAC4', 'Gene', (55, 60))	('PIK3R1', 'Gene', '5295', (69, 75))	('MYC', 'Gene', '4609', (25, 28))	('PTPRG', 'Gene', (62, 67))	('PER2', 'Gene', (49, 53))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('RAPGEF1', 'Gene', (77, 84))	('PTPRG', 'Gene', '5793', (62, 67))	('PER2', 'Gene', '8864', (49, 53))
163321	28719033	Copy number alterations of non-coding RNAs play important roles in the progression of diverse types of cancer (Du et al., 2016).	('RNAs', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Copy number alterations', 'Var', (0, 23))	('roles', 'Reg', (58, 63))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
163324	28719033	For example, driver lncRNA GAS5 with amplification in liver hepatocellular carcinoma (LIHC) identified in our work has been reported with oncogenic roles in LIHC by Tao et al.	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (54, 84))	('GAS5', 'Gene', '60674', (27, 31))	('LIHC', 'Disease', (86, 90))	('LIHC', 'Disease', 'None', (86, 90))	('amplification', 'Var', (37, 50))	('GAS5', 'Gene', (27, 31))	('GAS', 'molecular_function', 'GO:0034005', ('27', '30'))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('LIHC', 'Disease', (157, 161))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('LIHC', 'Disease', 'None', (157, 161))	('liver hepatocellular carcinoma', 'Disease', (54, 84))
163325	28719033	Hsa-mir-134, a driver miRNA with a deletion in LUAD, was found to suppress NSCLC progression through down-regulation of CCND1 (Sun et al., 2016).	('LUAD', 'Gene', (47, 51))	('regulation', 'biological_process', 'GO:0065007', ('106', '116'))	('suppress', 'NegReg', (66, 74))	('down-regulation', 'NegReg', (101, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('Hsa-mir-134', 'Gene', '406924', (0, 11))	('CCND1', 'Gene', (120, 125))	('NSCLC', 'Disease', (75, 80))	('deletion', 'Var', (35, 43))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('Hsa-mir-134', 'Gene', (0, 11))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('CCND1', 'Gene', '595', (120, 125))
163349	28719033	Afatinib, another FDA approved drug, is used to treat late stage (metastatic) NSCLC with EGFR mutations (Dungo and Keating, 2013) (Fig.	('EGFR', 'Gene', '1956', (89, 93))	('EGFR', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('NSCLC', 'Disease', (78, 83))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
163350	28719033	LUSC cell lines with amplification of EGFR show marginally significant sensitivity to lapatinib compared with those of LUSC cell lines with wild-type EGFR in the CCLE database (P = 0.049, Wilcoxon rank-sum test, Fig.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('EGFR', 'Gene', (150, 154))	('EGFR', 'Gene', (38, 42))	('lapatinib', 'Chemical', 'MESH:D000077341', (86, 95))	('sensitivity to lapatinib', 'MPA', (71, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('150', '154'))	('CCLE', 'Chemical', '-', (162, 166))	('LUSC', 'Phenotype', 'HP:0030359', (119, 123))	('amplification', 'Var', (21, 34))	('EGFR', 'Gene', '1956', (150, 154))	('LUSC', 'Phenotype', 'HP:0030359', (0, 4))
163351	28719033	LGG cell lines with amplification of EGFR show significant sensitivity to lapatinib compared with those of LGG cell lines with wild-type EGFR in the GDSC database (P = 6.1 x 10-3, Wilcoxon rank-sum test, Fig.	('EGFR', 'Gene', (137, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('sensitivity to lapatinib', 'MPA', (59, 83))	('EGFR', 'Gene', '1956', (37, 41))	('lapatinib', 'Chemical', 'MESH:D000077341', (74, 83))	('EGFR', 'Gene', '1956', (137, 141))	('amplification', 'Var', (20, 33))	('EGFR', 'Gene', (37, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))
163352	28719033	BRCA cell lines with amplification of ERBB2 show significantly lower IC50 levels of afatinib compared with those of BRCA cell lines with wild-type ERBB2 in the GDSC database (P = 6.1 x 10-3, Wilcoxon rank-sum test, Fig.	('IC50 levels of afatinib', 'MPA', (69, 92))	('BRCA', 'Gene', (0, 4))	('lower', 'NegReg', (63, 68))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('ERBB2', 'Gene', (38, 43))	('ERBB2', 'Gene', (147, 152))	('ERBB2', 'Gene', '2064', (38, 43))	('ERBB2', 'Gene', '2064', (147, 152))	('afatinib', 'Chemical', 'MESH:D000077716', (84, 92))	('BRCA', 'Phenotype', 'HP:0003002', (116, 120))	('amplification', 'Var', (21, 34))	('BRCA', 'Gene', (116, 120))	('BRCA', 'Gene', '672', (116, 120))	('BRCA', 'Gene', '672', (0, 4))
163364	28719033	Both CDKN2A and RB1 were reported to have deletions in BRCA and LGG (Bieche and Lidereau, 2000; Debniak et al., 2004).	('BRCA', 'Phenotype', 'HP:0003002', (55, 59))	('BRCA', 'Gene', '672', (55, 59))	('CDKN2A', 'Gene', (5, 11))	('BRCA', 'Gene', (55, 59))	('RB1', 'Gene', (16, 19))	('LGG', 'Gene', (64, 67))	('CDKN2A', 'Gene', '1029', (5, 11))	('deletions', 'Var', (42, 51))	('RB1', 'Gene', '5925', (16, 19))
163366	28719033	Notably, our work investigated the similarity and specificity of different cancer types from copy number alterations, which only represents one kind of molecular feature of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('copy number alterations', 'Var', (93, 116))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
163369	28719033	The drivers with amplifications in BRCA identified by our work significantly overlapped those detected by the Helios method (P = 9.46 x 10-10, hypergeometric test), including CCND1, MYC, ERBB2, ERLIN2, FOXA1, RAD52 and TOMM20.	('TOMM20', 'Gene', '9804', (219, 225))	('amplifications', 'Var', (17, 31))	('RAD', 'biological_process', 'GO:1990116', ('209', '212'))	('CCND1', 'Gene', '595', (175, 180))	('RAD52', 'Gene', '5893', (209, 214))	('BRCA', 'Phenotype', 'HP:0003002', (35, 39))	('CCND1', 'Gene', (175, 180))	('ERLIN2', 'Gene', '11160', (194, 200))	('MYC', 'Gene', (182, 185))	('BRCA', 'Gene', '672', (35, 39))	('FOXA1', 'Gene', '3169', (202, 207))	('ERBB2', 'Gene', (187, 192))	('ERLIN2', 'Gene', (194, 200))	('FOXA1', 'Gene', (202, 207))	('BRCA', 'Gene', (35, 39))	('TOMM20', 'Gene', (219, 225))	('MYC', 'Gene', '4609', (182, 185))	('RAD52', 'Gene', (209, 214))	('ERBB2', 'Gene', '2064', (187, 192))
163371	28719033	(2016) reported that gistic 2.0 tends to call larger deletion regions than amplification regions and identifies more drivers in deleted regions than in amplified regions for breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('deletion', 'Var', (53, 61))
163372	28719033	Generally, our methods identified more drivers with deletions than drivers with amplifications for each cancer type, except for LIHC, which has 77 amplified drivers and 41 deleted drivers (Table S2).	('LIHC', 'Disease', 'None', (128, 132))	('LIHC', 'Disease', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('deletions', 'Var', (52, 61))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
163374	28719033	Some studies have also found that deletions or losses are more common than amplifications or gains in cancer (Cancer Genome Atlas Network, 2012; Schoch et al., 2002), which is an interesting phenomenon that warrants further exploration.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('deletions', 'Var', (34, 43))	('losses', 'NegReg', (47, 53))	('Cancer Genome Atlas', 'Disease', (110, 129))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gains in cancer', 'Disease', (93, 108))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (110, 129))	('gains in cancer', 'Disease', 'MESH:D015430', (93, 108))
163379	28719033	The mutation status of known cancer genes may affect the expression of CDEGs.	('expression', 'MPA', (57, 67))	('cancer', 'Disease', (29, 35))	('CDEGs', 'Gene', (71, 76))	('mutation', 'Var', (4, 12))	('affect', 'Reg', (46, 52))	('CDEGs', 'Chemical', '-', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
163386	27602104	Epigenetic modification suppresses proliferation, migration and invasion of urothelial cancer cell lines Epigenetic approaches offer additional therapeutic options, including apoptosis induction, modification of cell cycle regulating proteins and the re-expression of pharmaceutical targets, such as hormone receptors.	('invasion', 'CPA', (64, 72))	('proliferation', 'CPA', (35, 48))	('modification', 'Var', (196, 208))	('apoptosis', 'CPA', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cell cycle', 'biological_process', 'GO:0007049', ('212', '222'))	('suppresses', 'NegReg', (24, 34))	('urothelial cancer', 'Disease', (76, 93))	('cell', 'Protein', (212, 216))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))	('Epigenetic modification', 'Var', (0, 23))	('urothelial cancer', 'Disease', 'MESH:D014523', (76, 93))
163389	27602104	In conclusion, epigenetic modifications suppressed the motility and invasiveness of three out of four urothelial cancer cell lines.	('suppressed', 'NegReg', (40, 50))	('motility', 'CPA', (55, 63))	('urothelial cancer', 'Disease', 'MESH:D014523', (102, 119))	('invasiveness', 'CPA', (68, 80))	('epigenetic modifications', 'Var', (15, 39))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('urothelial cancer', 'Disease', (102, 119))
163391	27602104	Epigenetic gene expression modulation is an aspect of physiological development, and its dysregulation is involved in carcinogenesis.	('carcinogenesis', 'Disease', (118, 132))	('Epigenetic gene expression modulation', 'Var', (0, 37))	('involved', 'Reg', (106, 114))	('dysregulation', 'Var', (89, 102))	('gene expression', 'biological_process', 'GO:0010467', ('11', '26'))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))
163393	27602104	Epidermal growth factor receptor is downregulated by epigenetic modifications, and the re-expressed receptor after treatment with, for example, hypomethylating agents is a potential therapeutic target leading to cell death.	('hypomethylating', 'Var', (144, 159))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('0', '23'))	('cell death', 'biological_process', 'GO:0008219', ('212', '222'))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('epigenetic modifications', 'Var', (53, 77))	('downregulated', 'NegReg', (36, 49))
163400	27602104	Methylation inhibition of CpG islands of the estrogen receptor leads to its downregulation, and treatment with aza restores estrogen receptor expression.	('downregulation', 'MPA', (76, 90))	('estrogen receptor', 'Gene', (45, 62))	('estrogen receptor', 'Gene', (124, 141))	('estrogen receptor', 'Gene', '2099', (45, 62))	('estrogen receptor', 'Gene', '2099', (124, 141))	('Methylation inhibition', 'Var', (0, 22))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('aza', 'Chemical', 'MESH:D001379', (111, 114))	('expression', 'MPA', (142, 152))
163408	27602104	Epigenetic approaches may offer potential therapeutic options for urothelial cancer.	('urothelial cancer', 'Disease', (66, 83))	('urothelial cancer', 'Disease', 'MESH:D014523', (66, 83))	('Epigenetic approaches', 'Var', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
163429	27602104	With the exception of RT-4 cells (P=0.2083), MMP-14 mRNA expression was significantly suppressed by epigenetic modifier treatment in RT-112 (P<0.0001), VMCUB-1 (P=0.0005) and T-24 (P=0.0003) cell lines.	('MMP-14', 'Gene', (45, 51))	('epigenetic modifier treatment', 'Var', (100, 129))	('suppressed', 'NegReg', (86, 96))	('MMP-14', 'Gene', '4323', (45, 51))	('MMP', 'molecular_function', 'GO:0004235', ('45', '48'))
163442	27602104	MMP-28 mRNA was suppressed by epigenetic modifier treatment in RT-4 and RT-112 cells.	('suppressed', 'NegReg', (16, 26))	('epigenetic modifier treatment', 'Var', (30, 59))	('MMP-28', 'Gene', (0, 6))	('MMP', 'molecular_function', 'GO:0004235', ('0', '3'))	('MMP-28', 'Gene', '79148', (0, 6))
163446	27602104	Treatment with epigenetic modifiers significantly induced the expression of TIMP-4 mRNA in RT-4, VCUMB-1 and T-24 cell lines, whereas in RT-112 cells this appeared to be a statistical trend.	('expression', 'MPA', (62, 72))	('TIMP-4', 'Gene', '7079', (76, 82))	('epigenetic modifiers', 'Var', (15, 35))	('induced', 'PosReg', (50, 57))	('TIMP-4', 'Gene', (76, 82))	('mRNA', 'MPA', (83, 87))
163447	27602104	Epigenetics may offer additional treatment options for solid malignancies.	('solid malignancies', 'Disease', (55, 73))	('solid malignancies', 'Disease', 'MESH:D009369', (55, 73))	('Epigenetics', 'Var', (0, 11))
163452	27602104	The requirement of a combined epigenetic modification, leading to a decreased proliferation in the other cell lines (RT-112, VMCUB-1 and T-24), suggests that there are pre-existing structural gene alterations of cell cycle promoting or controlling proteins, whose effects are affected by combined TSA and aza treatment.	('TSA', 'molecular_function', 'GO:0033984', ('297', '300'))	('epigenetic modification', 'Var', (30, 53))	('decreased', 'NegReg', (68, 77))	('cell cycle', 'CPA', (212, 222))	('alterations', 'Var', (197, 208))	('pre', 'molecular_function', 'GO:0003904', ('168', '171'))	('proliferation', 'CPA', (78, 91))	('aza', 'Chemical', 'MESH:D001379', (305, 308))	('TSA', 'Chemical', 'MESH:C012589', (297, 300))	('cell cycle', 'biological_process', 'GO:0007049', ('212', '222'))
163456	27602104	Shukeir et al identified a decreased MMP 2 expression triggered by gene methylation in highly invasive prostate cancer cell lines.	('MMP 2', 'Gene', '4313', (37, 42))	('gene methylation', 'Var', (67, 83))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('decreased', 'NegReg', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('MMP 2', 'molecular_function', 'GO:0004228', ('37', '42'))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('invasive prostate cancer', 'Disease', (94, 118))	('invasive prostate cancer', 'Disease', 'MESH:D011471', (94, 118))	('expression', 'MPA', (43, 53))	('MMP 2', 'Gene', (37, 42))
163457	27602104	Couillard et al described an increased MMP-3 expression in colon cancer cell lines following demethylating treatment with aza.	('colon cancer', 'Disease', (59, 71))	('aza', 'Chemical', 'MESH:D001379', (122, 125))	('MMP-3', 'Gene', '4314', (39, 44))	('MMP-3', 'molecular_function', 'GO:0004248', ('39', '44'))	('MMP-3', 'Gene', (39, 44))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('increased', 'PosReg', (29, 38))	('expression', 'MPA', (45, 55))	('demethylating', 'Var', (93, 106))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))
163473	27602104	In colorectal cancer and cancer cell lines, MMP-16 promoter hypermethylation was reported to be associated with a decreased mRNA expression.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('MMP', 'molecular_function', 'GO:0004235', ('44', '47'))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('MMP-16', 'Gene', (44, 50))	('promoter hypermethylation', 'Var', (51, 76))	('decreased', 'NegReg', (114, 123))	('colorectal cancer', 'Disease', (3, 20))	('MMP-16', 'Gene', '4325', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Disease', (25, 31))	('mRNA expression', 'MPA', (124, 139))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
163481	27602104	In conclusion, the present study revealed that the epigenetic modifications of aza and TSA suppressed the motility and invasiveness of three out of four urothelial cancer cell lines.	('suppressed', 'NegReg', (91, 101))	('urothelial cancer', 'Disease', 'MESH:D014523', (153, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('aza', 'Chemical', 'MESH:D001379', (79, 82))	('epigenetic modifications', 'Var', (51, 75))	('TSA', 'Gene', (87, 90))	('TSA', 'Chemical', 'MESH:C012589', (87, 90))	('urothelial cancer', 'Disease', (153, 170))	('aza', 'Gene', (79, 82))	('TSA', 'molecular_function', 'GO:0033984', ('87', '90'))
163486	33676485	Level 3c involved renal cell carcinoma >= T2b, high-grade bladder urothelial carcinoma, adrenal mass/cancer > 6 cm, testicular cancer requiring radical orchiectomy, and penile cancer.	('testicular cancer', 'Disease', (116, 133))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (18, 38))	('penile cancer', 'Disease', 'MESH:D010412', (169, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('testicular cancer', 'Phenotype', 'HP:0010788', (116, 133))	('>= T2b', 'Var', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('adrenal mass', 'Disease', 'MESH:C536030', (88, 100))	('penile cancer', 'Disease', (169, 182))	('cancer', 'Disease', (127, 133))	('adrenal mass', 'Disease', (88, 100))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('renal cell carcinoma', 'Disease', (18, 38))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (18, 38))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('testicular cancer', 'Disease', 'MESH:D013736', (116, 133))	('bladder urothelial carcinoma', 'Disease', (58, 86))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (58, 86))	('cancer', 'Disease', (176, 182))
163742	31534952	Tumor mutational burden (TMB) is defined as the total number of somatic missense mutations present in the baseline tumor sample and it has been a biomarker of tumorigenesis and immune response.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('TMB', 'Chemical', '-', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', (159, 164))	('immune response', 'biological_process', 'GO:0006955', ('177', '192'))	('missense mutations', 'Var', (72, 90))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
163757	31534952	Gene Expression Profiling Interactive Analysis (GEPIA, http://gepia.cancer-pku.cn/) is an open website consisting of seven sections: general, differential genes, expression DIY, survival, similar genes, correlation, and PCA.	('gepia.cancer-pku', 'Disease', (62, 78))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('PCA', 'Disease', (220, 223))	('gepia.cancer-pku', 'Disease', 'MESH:C567494', (62, 78))	('Gene Expression', 'biological_process', 'GO:0010467', ('0', '15'))	('differential genes', 'Var', (142, 160))
163763	31534952	The most common mutations in the malignant tumor of urinary bladder are missense mutations.	('malignant tumor', 'Disease', 'MESH:D018198', (33, 48))	('common', 'Reg', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('malignant tumor', 'Disease', (33, 48))	('missense mutations', 'Var', (72, 90))
163764	31534952	At the same time, the top 10 genes with the most mutations in urinary bladder neoplasm were obtained (see Figure 1(a)).	('mutations', 'Var', (49, 58))	('urinary bladder neoplasm', 'Disease', 'MESH:D001749', (62, 86))	('urinary bladder neoplasm', 'Disease', (62, 86))	('bladder neoplasm', 'Phenotype', 'HP:0009725', (70, 86))	('neoplasm', 'Phenotype', 'HP:0002664', (78, 86))
163766	31534952	For example, mutant TP53 and mutant FGFR3 are mutually exclusive (p-value < 0.001).	('mutant', 'Var', (13, 19))	('FGFR3', 'Gene', (36, 41))	('TP53', 'Gene', (20, 24))	('mutant', 'Var', (29, 35))	('FGFR3', 'Gene', '2261', (36, 41))	('TP53', 'Gene', '7157', (20, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
163767	31534952	Mutant TP53 and mutant RB1 coexist (p-value < 0.001).	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('mutant', 'Var', (16, 22))	('RB1', 'Gene', (23, 26))	('Mutant', 'Var', (0, 6))	('RB1', 'Gene', '5925', (23, 26))
163768	31534952	Mutant TTN coexists significantly with mutant ERBB2, OBSCN, FAT4, ATM, MACF1, and MUC16 (p-value < 0.001).	('ATM', 'Gene', '472', (66, 69))	('TTN', 'Gene', (7, 10))	('MACF1', 'Gene', (71, 76))	('MACF1', 'Gene', '23499', (71, 76))	('FAT4', 'Gene', (60, 64))	('MUC16', 'Gene', (82, 87))	('FAT4', 'Gene', '79633', (60, 64))	('MUC16', 'Gene', '94025', (82, 87))	('TTN', 'Gene', '7273', (7, 10))	('OBSCN', 'Gene', '84033', (53, 58))	('ATM', 'Gene', (66, 69))	('mutant', 'Var', (39, 45))	('Mutant', 'Var', (0, 6))	('OBSCN', 'Gene', (53, 58))	('ERBB2', 'Gene', (46, 51))	('ERBB2', 'Gene', '2064', (46, 51))
163771	31534952	It was concluded that the survival rate of the group with high-TMB was significantly higher than that of the group with low-TMB (p-value < 0.006).	('higher', 'PosReg', (85, 91))	('TMB', 'Chemical', '-', (124, 127))	('TMB', 'Chemical', '-', (63, 66))	('survival rate', 'CPA', (26, 39))	('high-TMB', 'Var', (58, 66))
163796	31534952	Angiotensin type 2 dysregulation affects the proliferation and apoptosis of bladder cancer cells.	('dysregulation', 'Var', (19, 32))	('bladder cancer', 'Disease', (76, 90))	('proliferation', 'CPA', (45, 58))	('affects', 'Reg', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('apoptosis', 'CPA', (63, 72))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))
163798	31534952	Finally, the results showed that CD4 and CD8 T cells increased in the high-TMB group of bladder cancer.	('high-TMB', 'Var', (70, 78))	('bladder cancer', 'Disease', 'MESH:D001749', (88, 102))	('bladder cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('CD8', 'Gene', (41, 44))	('T cells increased', 'Phenotype', 'HP:0100828', (45, 62))	('CD8', 'Gene', '925', (41, 44))	('increased', 'PosReg', (53, 62))	('CD4', 'Gene', (33, 36))	('CD4', 'Gene', '920', (33, 36))	('TMB', 'Chemical', '-', (75, 78))	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))
163822	30652029	Chemotherapy regimens are usually based on how groups of people with similar cancers respond to them, but genetic differences can render the drugs more or less effective in individual patients.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('patients', 'Species', '9606', (184, 192))	('genetic differences', 'Var', (106, 125))	('cancers', 'Disease', (77, 84))	('people', 'Species', '9606', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
163842	30652029	A concern with each of these ML approaches is that an insufficient number of samples coupled with a large number of features, i.e., GE changes, in each sample may result in overfitting of the model, affecting its generalizability with other sources of data.	('insufficient', 'Disease', (54, 66))	('result in', 'Reg', (163, 172))	('changes', 'Var', (135, 142))	('affecting', 'Reg', (199, 208))	('overfitting', 'MPA', (173, 184))	('insufficient', 'Disease', 'MESH:D000309', (54, 66))	('generalizability', 'MPA', (213, 229))
163878	30652029	The elimination of ERCC2, POLD1, BARD1, BCL2, PRKCA, and PRKCB consistently significantly increased the misclassification error (average > 16% increase) in moderate threshold cisplatin SVMs (GI50 thresholds: 5.1-5.5).	('BCL2', 'molecular_function', 'GO:0015283', ('40', '44'))	('PRKCB', 'Gene', '5579', (57, 62))	('BARD1', 'Gene', '580', (33, 38))	('PRKCA', 'Gene', (46, 51))	('increased', 'PosReg', (90, 99))	('elimination', 'Var', (4, 15))	('BARD1', 'Gene', (33, 38))	('ERCC2', 'Gene', '2068', (19, 24))	('BCL2', 'Gene', '596', (40, 44))	('moderate threshold cisplatin SVMs', 'MPA', (156, 189))	('POLD1', 'Gene', (26, 31))	('POLD1', 'Gene', '5424', (26, 31))	('PRKCB', 'Gene', (57, 62))	('ERCC2', 'Gene', (19, 24))	('misclassification error', 'MPA', (104, 127))	('BCL2', 'Gene', (40, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('PRKCA', 'Gene', '5578', (46, 51))
163946	30652029	Alterations in the expression of MAP3K1, MAPK3, SLC22A5, and SLC31A2 corrected discordant predictions of patient outcome.	('SLC31A2', 'Gene', (61, 68))	('MAP3K1', 'Gene', (33, 39))	('SLC22A5', 'Gene', '6584', (48, 55))	('MAP3K1', 'Gene', '4214', (33, 39))	('patient', 'Species', '9606', (105, 112))	('MAP3K', 'molecular_function', 'GO:0004709', ('33', '38'))	('Alterations', 'Var', (0, 11))	('SLC31A2', 'Gene', '1318', (61, 68))	('MAPK', 'molecular_function', 'GO:0004707', ('41', '45'))	('MAPK3', 'Gene', (41, 46))	('MAPK3', 'Gene', '5595', (41, 46))	('SLC22A5', 'Gene', (48, 55))
163947	30652029	Alterations in BCL2L1 expression were more likely to correct the discordant predictions of Cis1 (4 of 5) than Cis2 (2 of 4).	('BCL2', 'molecular_function', 'GO:0015283', ('15', '19'))	('BCL2L1', 'Gene', (15, 21))	('Alterations', 'Var', (0, 11))	('BCL2L1', 'Gene', '598', (15, 21))	('Cis2', 'Gene', '8835', (110, 114))	('Cis2', 'Gene', (110, 114))	('Cis1', 'Gene', (91, 95))	('discordant', 'MPA', (65, 75))	('Cis1', 'Gene', '1154', (91, 95))	('expression', 'MPA', (22, 32))
163951	30652029	CpG island methylation is associated with smoking in pack years in a subset of the TCGA patients with bladder urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('methylation', 'biological_process', 'GO:0032259', ('11', '22'))	('CpG island', 'Protein', (0, 10))	('patients', 'Species', '9606', (88, 96))	('smoking', 'Disease', (42, 49))	('methylation', 'Var', (11, 22))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (102, 130))	('associated', 'Reg', (26, 36))	('bladder urothelial carcinoma', 'Disease', (102, 130))
164011	30652029	In summary, we describe GI50 or IC50 threshold-independent ML gene signatures that predict the chemotherapy responses of patients with cancer to platin agents.	('cancer', 'Disease', (135, 141))	('predict', 'Reg', (83, 90))	('GI50', 'Var', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('platin', 'Chemical', 'MESH:D010984', (145, 151))	('IC50', 'Gene', (32, 36))	('patients', 'Species', '9606', (121, 129))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
164104	28438212	Expression of several cytokeratin and especially CK 34betaE12, CK 5/6 and p63 favors sarcomatoid carcinoma.	('CK 5/6', 'Gene', (63, 69))	('CK 5/6', 'Gene', '3852', (63, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('p63', 'Gene', '8626', (74, 77))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (85, 106))	('sarcomatoid carcinoma', 'Disease', (85, 106))	('sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (85, 106))	('CK 34betaE12', 'Var', (49, 61))	('p63', 'Gene', (74, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
164127	28035326	The karyotype was stable, with few chromosomal changes, especially gains of chromosomes 5 and 20 and a chromosome 9p21 deletion resulting in p16INK4A loss.	('chromosome', 'cellular_component', 'GO:0005694', ('103', '113'))	('p16INK4A', 'Gene', '1029', (141, 149))	('deletion', 'Var', (119, 127))	('gains', 'PosReg', (67, 72))	('p21', 'Gene', (115, 118))	('p21', 'Gene', '644914', (115, 118))	('loss', 'NegReg', (150, 154))	('p16INK4A', 'Gene', (141, 149))
164128	28035326	A C228T TERT promoter mutation was present, but no other mutation typical of urothelial carcinoma.	('TERT', 'Gene', (8, 12))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (77, 97))	('TERT', 'Gene', '7015', (8, 12))	('C228T', 'Mutation', 'c.228C>T', (2, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('C228T', 'Var', (2, 7))	('urothelial carcinoma', 'Disease', (77, 97))
164143	28035326	In one protocol, EGFR inhibition and PPARgamma activation were achieved by treatment with 1 muM PD153035 (Merck, Germany) and 1 muM Troglitazone (Cayman, USA) in CnT-Prime Epithelial Culture Medium (ready to use and supplemented with EGF, CELLnTEC) or in KFSM medium without supplemented EGF (Life Technologies, Germany) for seven days, during which the medium was changed twice.	('muM', 'Gene', (92, 95))	('EGF', 'Gene', '1950', (234, 237))	('EGFR', 'Gene', (17, 21))	('inhibition', 'NegReg', (22, 32))	('muM', 'Gene', '56925', (128, 131))	('PPARgamma', 'Gene', '5468', (37, 46))	('EGF', 'Gene', '1950', (288, 291))	('muM', 'Gene', (128, 131))	('EGF', 'Gene', '1950', (17, 20))	('EGF', 'molecular_function', 'GO:0005154', ('288', '291'))	('EGF', 'molecular_function', 'GO:0005154', ('234', '237'))	('activation', 'PosReg', (47, 57))	('EGF', 'Gene', (234, 237))	('EGFR', 'Gene', '1956', (17, 21))	('EGF', 'Gene', (288, 291))	('PD153035', 'Chemical', 'MESH:C088860', (96, 104))	('PPARgamma', 'Gene', (37, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('17', '21'))	('EGF', 'Gene', (17, 20))	('PD153035', 'Var', (96, 104))	('KFSM medium', 'Chemical', '-', (255, 266))	('muM', 'Gene', '56925', (92, 95))	('Troglitazone', 'Chemical', 'MESH:D000077288', (132, 144))
164163	28035326	Mutations in the telomerase reverse transcriptase (TERT) promoter region were detected following PCR amplification.	('telomerase reverse transcriptase', 'Gene', '7015', (17, 49))	('TERT', 'Gene', (51, 55))	('transcriptase', 'molecular_function', 'GO:0003968', ('36', '49'))	('transcriptase', 'molecular_function', 'GO:0003899', ('36', '49'))	('Mutations', 'Var', (0, 9))	('TERT', 'Gene', '7015', (51, 55))	('transcriptase', 'molecular_function', 'GO:0034062', ('36', '49'))	('detected', 'Reg', (78, 86))	('telomerase reverse transcriptase', 'Gene', (17, 49))
164164	28035326	Deletion of p16INK4A was detected by amplification of exon 3 from genomic DNA.	('p16INK4A', 'Gene', '1029', (12, 20))	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('p16INK4A', 'Gene', (12, 20))	('Deletion', 'Var', (0, 8))
164170	28035326	Total protein was extracted by lysing the cells in a buffer containing 150 mM NaCl, 1% Triton X-100, 0.5% deoxycholate, 1% Nonidet P-40, 0.1% SDS, 1 mM EDTA, 50 mM Tris (pH 7.6), protease inhibitor cocktail (P-8340, Sigma-Aldrich) and phosphatase inhibitor cocktail (P-0044, Sigma Aldrich) for 30 min on ice.	('NaCl', 'Chemical', 'MESH:D012965', (78, 82))	('P-40', 'cellular_component', 'GO:0043514', ('131', '135'))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('Tris', 'Chemical', '-', (164, 168))	('P-0044', 'Var', (267, 273))	('P-8340', 'Var', (208, 214))	('EDTA', 'Chemical', 'MESH:D004492', (152, 156))	('Triton X-100', 'Chemical', 'MESH:D017830', (87, 99))	('deoxycholate', 'Chemical', 'MESH:D003840', (106, 118))	('SDS', 'Chemical', 'MESH:D012967', (142, 145))	('P-40', 'cellular_component', 'GO:0070743', ('131', '135'))	('phosphatase', 'molecular_function', 'GO:0016791', ('235', '246'))
164174	28035326	Primary antibodies (p53 Ab-6, 1:1000, OP43-100UG, Oncogene Science, USA; p21 Sx118, 1:1000, 556430, BD Biosciences, Germany) were applied overnight at 4 C. alpha-Tubulin was used as a loading control (1:10000, ab4074, Abcam).	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('p21', 'Gene', (73, 76))	('alpha-Tubulin', 'Gene', (156, 169))	('p21', 'Gene', '644914', (73, 76))	('alpha-Tubulin', 'Gene', '10376', (156, 169))	('OP43-100UG', 'Var', (38, 48))
164186	28035326	In one protocol, simultaneous inhibition of epidermal growth factor receptor (EGFR) signaling with PD153035 and activation of PPARgamma by its cognate agonist Troglitazone led to significant induction of the differentiation markers UPK2 and CK20 after one week (Fig.	('CK20', 'Gene', (241, 245))	('EGFR', 'Gene', '1956', (78, 82))	('PPARgamma', 'Gene', '5468', (126, 135))	('activation', 'PosReg', (112, 122))	('UPK2', 'Gene', (232, 236))	('CK20', 'Gene', '54474', (241, 245))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('44', '67'))	('inhibition', 'NegReg', (30, 40))	('Troglitazone', 'Chemical', 'MESH:D000077288', (159, 171))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('induction', 'PosReg', (191, 200))	('epidermal growth factor receptor', 'Gene', (44, 76))	('epidermal growth factor receptor', 'Gene', '1956', (44, 76))	('PPARgamma', 'Gene', (126, 135))	('EGFR', 'Gene', (78, 82))	('UPK2', 'Gene', '7379', (232, 236))	('PD153035', 'Chemical', 'MESH:C088860', (99, 107))	('PD153035', 'Var', (99, 107))
164192	28035326	In a different low-calcium medium (KFSM), where EGF supplementation is optional, the addition of PD153035 and Troglitazone resulted in a significant induction of CK20 and UPK2 in the absence of EGF (Fig.	('EGF', 'Gene', '1950', (48, 51))	('EGF', 'Gene', (194, 197))	('UPK2', 'Gene', '7379', (171, 175))	('EGF', 'molecular_function', 'GO:0005154', ('48', '51'))	('CK20', 'Gene', (162, 166))	('CK20', 'Gene', '54474', (162, 166))	('calcium', 'Chemical', 'MESH:D002118', (19, 26))	('PD153035', 'Chemical', 'MESH:C088860', (97, 105))	('UPK2', 'Gene', (171, 175))	('EGF', 'Gene', '1950', (194, 197))	('EGF', 'Gene', (48, 51))	('induction', 'PosReg', (149, 158))	('Troglitazone', 'Chemical', 'MESH:D000077288', (110, 122))	('PD153035', 'Var', (97, 105))	('EGF', 'molecular_function', 'GO:0005154', ('194', '197'))
164197	28035326	Standard karyotyping revealed a hyperdiploid karyotype with trisomies of chromosomes 5 and 20 in all metaphases; two subclones were characterized by additional gains of chromosomes 7 or 9, respectively.	('gains', 'PosReg', (160, 165))	('trisomies', 'Var', (60, 69))	('hyperdiploid', 'Disease', (32, 44))	('hyperdiploid', 'Disease', 'MESH:D054198', (32, 44))
164199	28035326	The homozygous deletion at 9p21.3 affected a 60 kb region including part of the CDKN2A locus, the MTAP gene and part of the non-coding RNA ANRIL gene.	('CDKN2A', 'Gene', '1029', (80, 86))	('ANRIL', 'Gene', (139, 144))	('deletion', 'Var', (15, 23))	('p21', 'Gene', (28, 31))	('affected', 'Reg', (34, 42))	('MTAP', 'Gene', (98, 102))	('p21', 'Gene', '644914', (28, 31))	('RNA', 'cellular_component', 'GO:0005562', ('135', '138'))	('ANRIL', 'Gene', '100048912', (139, 144))	('MTAP', 'Gene', '4507', (98, 102))	('CDKN2A', 'Gene', (80, 86))
164200	28035326	Deletion of CDKN2A/p16INK4 was further confirmed by PCR for CDKN2A exon 3 (Fig.	('CDKN2A', 'Gene', (12, 18))	('CDKN2A', 'Gene', '1029', (12, 18))	('CDKN2A', 'Gene', (60, 66))	('CDKN2A', 'Gene', '1029', (60, 66))	('p16INK4', 'Gene', '1029', (19, 26))	('p16INK4', 'Gene', (19, 26))	('Deletion', 'Var', (0, 8))
164204	28035326	Mutations in the TERT promoter region leading to elevated telomerase expression are highly prevalent in urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('TERT', 'Gene', (17, 21))	('TERT', 'Gene', '7015', (17, 21))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (104, 124))	('prevalent', 'Reg', (91, 100))	('Mutations', 'Var', (0, 9))	('telomerase expression', 'MPA', (58, 79))	('elevated', 'PosReg', (49, 57))	('urothelial carcinoma', 'Disease', (104, 124))
164205	28035326	Indeed, sequencing of the TERT promoter region in HBLAK revealed the most common C228T mutation (Fig.	('C228T', 'Var', (81, 86))	('C228T', 'Mutation', 'c.228C>T', (81, 86))	('TERT', 'Gene', (26, 30))	('TERT', 'Gene', '7015', (26, 30))
164206	28035326	TERT mRNA expression was determined by real time qRT-PCR in different passages of HBLAK cells and other cell lines with wildtype (HEK293, 253J) or mutant TERT promoter (VM-CUB1) as well as in TERT-NHUC cells (Fig.	('mutant', 'Var', (147, 153))	('HEK293', 'CellLine', 'CVCL:0045', (130, 136))	('TERT', 'Gene', (192, 196))	('TERT', 'Gene', (154, 158))	('TERT', 'Gene', '7015', (192, 196))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', '7015', (154, 158))	('TERT-NHUC', 'CellLine', 'CVCL:C452', (192, 201))
164210	28035326	Expression of the mRNA encoding full-length p53 was well detectable, but not as strongly as in the UC cell lines J82 and VM-CUB1 with mutant p53 (Fig.	('p53', 'Gene', (141, 144))	('p53', 'Gene', '7157', (141, 144))	('p53', 'Gene', '7157', (44, 47))	('p53', 'Gene', (44, 47))	('J82', 'CellLine', 'CVCL:0359', (113, 116))	('mutant', 'Var', (134, 140))
164213	28035326	Exome sequencing confirmed the deletion of CDKN2A/p16INK4A exon 3 and the lack of p53 mutations.	('p16INK4A', 'Gene', (50, 58))	('CDKN2A', 'Gene', (43, 49))	('CDKN2A', 'Gene', '1029', (43, 49))	('p16INK4A', 'Gene', '1029', (50, 58))	('deletion', 'Var', (31, 39))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))
164227	28035326	Accordingly, treatment with PD153035 and Troglitazone induced the urothelial differentiation marker UPK2 only in medium without EGF.	('EGF', 'Gene', '1950', (128, 131))	('UPK2', 'Gene', '7379', (100, 104))	('PD153035', 'Chemical', 'MESH:C088860', (28, 36))	('Troglitazone', 'Chemical', 'MESH:D000077288', (41, 53))	('UPK2', 'Gene', (100, 104))	('PD153035', 'Var', (28, 36))	('induced', 'PosReg', (54, 61))	('EGF', 'Gene', (128, 131))	('urothelial differentiation', 'CPA', (66, 92))	('EGF', 'molecular_function', 'GO:0005154', ('128', '131'))
164232	28035326	Inactivation of p53 and RB1 is also common in invasive UC and accordingly, in many UC cell lines, but essentially absent in papillary UC.	('RB1', 'Gene', (24, 27))	('RB1', 'Gene', '5925', (24, 27))	('p53', 'Gene', (16, 19))	('invasive UC', 'Disease', (46, 57))	('p53', 'Gene', '7157', (16, 19))	('common', 'Reg', (36, 42))	('Inactivation', 'Var', (0, 12))
164234	28035326	Interestingly, both 20q gain and 20q13.2 amplification have been reported for various cancer types including UC, where amplifications of chromosome 20q generally appear to be associated with immortalization, oncogenic transformation and malignant progression.	('amplifications', 'Var', (119, 133))	('20q13.2', 'Gene', (33, 40))	('associated with', 'Reg', (175, 190))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('immortalization', 'CPA', (191, 206))	('malignant progression', 'CPA', (237, 258))	('chromosome', 'cellular_component', 'GO:0005694', ('137', '147'))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))	('oncogenic transformation', 'CPA', (208, 232))
164235	28035326	Whereas high level amplifications correlated with tumor progression in breast cancer, low-level amplifications appeared to be rather associated with early stage ovarian carcinoma.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('correlated with', 'Reg', (34, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (161, 178))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (161, 178))	('ovarian carcinoma', 'Disease', (161, 178))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('amplifications', 'Var', (19, 33))	('tumor', 'Disease', (50, 55))	('associated', 'Reg', (133, 143))
164237	28035326	In UC, activation of telomerase is a common early event and is typically caused by mutations in the TERT gene promoter.	('mutations', 'Var', (83, 92))	('TERT', 'Gene', (100, 104))	('caused', 'Reg', (73, 79))	('activation', 'PosReg', (7, 17))	('TERT', 'Gene', '7015', (100, 104))	('telomerase', 'Enzyme', (21, 31))
164240	28035326	Moreover, sequencing of the TERT promoter in HBLAK revealed the most common TERT promoter mutation in urothelial carcinoma and TERT mRNA was moderately overexpressed compared to normal urothelial cells, albeit not as strongly as in UC cell lines.	('TERT', 'Gene', '7015', (76, 80))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (102, 122))	('TERT', 'Gene', (127, 131))	('TERT', 'Gene', '7015', (127, 131))	('overexpressed', 'PosReg', (152, 165))	('TERT', 'Gene', (28, 32))	('urothelial carcinoma', 'Disease', (102, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('TERT', 'Gene', (76, 80))	('TERT', 'Gene', '7015', (28, 32))	('mutation', 'Var', (90, 98))
164241	28035326	All deletions detected in HBLAK can also occur in UC, especially in papillary tumors.	('papillary tumors', 'Phenotype', 'HP:0007482', (68, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('occur', 'Reg', (41, 46))	('deletions', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('papillary tumors', 'Disease', 'MESH:D002291', (68, 84))	('HBLAK', 'Gene', (26, 31))	('papillary tumors', 'Disease', (68, 84))
164242	28035326	Loss of chromosome 9 is the most common chromosomal aberration in UC and the most consistently deleted region is 9p21.3 encompassing CDKN2A encoding the cell cycle inhibitor p16INK4.	('p21', 'Gene', (114, 117))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('cell cycle', 'biological_process', 'GO:0007049', ('153', '163'))	('p16INK4', 'Gene', '1029', (174, 181))	('p21', 'Gene', '644914', (114, 117))	('CDKN2A', 'Gene', (133, 139))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (40, 62))	('CDKN2A', 'Gene', '1029', (133, 139))	('Loss', 'Var', (0, 4))	('p16INK4', 'Gene', (174, 181))
164243	28035326	As loss of p16INK4 contributes to senescence bypass, the homozygous deletion at 9p21.3 removing the 3'-end of CDKN2A in HBLAK cells is likely a third factor permitting their immortalization.	('CDKN2A', 'Gene', (110, 116))	("3'-end", 'MPA', (100, 106))	('loss', 'Var', (3, 7))	('p16INK4', 'Gene', '1029', (11, 18))	('p16INK4', 'Gene', (11, 18))	('CDKN2A', 'Gene', '1029', (110, 116))	('senescence bypass', 'MPA', (34, 51))	('deletion', 'Var', (68, 76))	('senescence', 'biological_process', 'GO:0010149', ('34', '44'))	('p21', 'Gene', (81, 84))	('p21', 'Gene', '644914', (81, 84))
164246	28035326	Notably, these studies also demonstrate clearly that cells with this limited extent of genetic changes can retain an otherwise normal epithelial phenotype and do not necessarily undergo transformation towards a malignant phenotype.	('genetic changes', 'Var', (87, 102))	('undergo', 'Reg', (178, 185))	('epithelia', 'Disease', (134, 143))	('epithelia', 'Disease', 'None', (134, 143))
164247	28035326	Cells with such genetic alterations therefore do not necessarily originate from cancer cells, but may be susceptible to transformation by further genetic changes.	('genetic alterations', 'Var', (16, 35))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))
164250	28035326	While MDM2 amplifications do occur in papillary urothelial carcinoma, none was found in HBLAK.	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('amplifications', 'Var', (11, 25))	('MDM2', 'Gene', '4193', (6, 10))	('MDM2', 'Gene', (6, 10))	('papillary urothelial carcinoma', 'Disease', (38, 68))	('occur', 'Reg', (29, 34))	('papillary urothelial carcinoma', 'Disease', 'MESH:D002291', (38, 68))
164253	28035326	Notably, we did not obtain evidence for genetic changes characteristic of invasive UC such as p53 mutation and general chromosomal instability.	('p53', 'Gene', '7157', (94, 97))	('chromosomal instability', 'Phenotype', 'HP:0040012', (119, 142))	('p53', 'Gene', (94, 97))	('mutation', 'Var', (98, 106))	('invasive UC', 'Disease', (74, 85))
164258	28035326	Interestingly, the immortalization of HBLAK cells appears to be brought about by specific genetic alterations that are thought to lead to immortalization during urothelial carcinogenesis.	('urothelial carcinogenesis', 'Disease', (161, 186))	('alterations', 'Var', (98, 109))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (161, 186))	('immortalization', 'CPA', (19, 34))	('brought about', 'Reg', (64, 77))
164259	28035326	However, the cells do not contain genetic alterations typical of invasive UC and not even an FGFR3 mutation, suggesting that they represent a preneoplastic stage of urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (165, 185))	('FGFR3', 'Gene', '2261', (93, 98))	('invasive UC', 'Disease', (65, 76))	('mutation', 'Var', (99, 107))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('FGFR3', 'Gene', (93, 98))	('urothelial carcinoma', 'Disease', (165, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
164327	29654370	Importantly, 91% of CIS cases demonstrated a positivity for at least one of the two predictive markers Her2 and ERbeta, indicating that the analysis of Her2 and ERbeta may help to identify CIS-patient subgroups prone to more efficient targeted treatment strategies.	('Her2', 'Gene', '2064', (103, 107))	('Her2', 'Gene', (152, 156))	('ERbeta', 'Gene', '2100', (112, 118))	('positivity', 'Var', (45, 55))	('Her2', 'Gene', '2064', (152, 156))	('ERbeta', 'Gene', (112, 118))	('ERbeta', 'Gene', '2100', (161, 167))	('men', 'Species', '9606', (249, 252))	('patient', 'Species', '9606', (193, 200))	('CIS', 'Phenotype', 'HP:0030075', (189, 192))	('CIS', 'Phenotype', 'HP:0030075', (20, 23))	('ERbeta', 'Gene', (161, 167))	('Her2', 'Gene', (103, 107))	('CIS', 'Disease', (20, 23))
164333	29654370	Most MIBCs arise from carcinoma in situ (CIS), a flat, high-grade, superficial urothelial lesion that is characterized by TP53 mutations and accounts for approximately 10% of all diagnosed bladder tumors.	('MIBC', 'Chemical', '-', (5, 9))	('TP53', 'Gene', (122, 126))	('urothelial lesion', 'Disease', 'MESH:D004194', (79, 96))	('carcinoma in situ', 'Disease', 'MESH:D002278', (22, 39))	('arise from', 'Reg', (11, 21))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('MIBCs', 'Disease', (5, 10))	('carcinoma in situ', 'Disease', (22, 39))	('bladder tumors', 'Disease', 'MESH:D001749', (189, 203))	('urothelial lesion', 'Disease', (79, 96))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (22, 39))	('bladder tumors', 'Phenotype', 'HP:0009725', (189, 203))	('mutations', 'Var', (127, 136))	('TP53', 'Gene', '7157', (122, 126))	('CIS', 'Phenotype', 'HP:0030075', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('bladder tumors', 'Disease', (189, 203))
164367	29654370	p53 accumulation due to mutation was diagnosed if over 20% of cells showed intense nuclear staining.	('accumulation', 'PosReg', (4, 16))	('p53', 'Gene', '7157', (0, 3))	('mutation', 'Var', (24, 32))	('p53', 'Gene', (0, 3))
164392	29654370	Aberrant p53 expression was seen in 62% (95/156) of CIS cases (Fig.	('CIS', 'Phenotype', 'HP:0030075', (52, 55))	('Aberrant', 'Var', (0, 8))	('CIS', 'Disease', (52, 55))	('expression', 'MPA', (13, 23))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))
164397	29654370	Her2 amplification was detected in 8/126 (6%) cases.	('amplification', 'Var', (5, 18))	('Her2', 'Gene', '2064', (0, 4))	('Her2', 'Gene', (0, 4))
164398	29654370	Her2 protein expression correlated significantly with cases showing polysomy or amplification (Fisher's exact test p = 0.049) (Table 2 and Fig.	('amplification', 'Var', (80, 93))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('Her2', 'Gene', (0, 4))	('polysomy', 'Var', (68, 76))	('Her2', 'Gene', '2064', (0, 4))
164421	29654370	As such, the observed ERbeta positivity in the majority of CIS cases in our cohort warrants further investigation of ERbeta as a potential target in early, flat, high-grade bladder cancer.	('ERbeta', 'Gene', (117, 123))	('bladder cancer', 'Disease', 'MESH:D001749', (173, 187))	('bladder cancer', 'Disease', (173, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('bladder cancer', 'Phenotype', 'HP:0009725', (173, 187))	('ERbeta', 'Gene', (22, 28))	('ERbeta', 'Gene', '2100', (117, 123))	('CIS', 'Phenotype', 'HP:0030075', (59, 62))	('positivity', 'Var', (29, 39))	('ERbeta', 'Gene', '2100', (22, 28))
164425	29654370	A recent investigation of the mechanism of Her2 expression in MIBC showed that Her2 protein overexpression arises from various mechanisms, including gene amplification.	('overexpression', 'PosReg', (92, 106))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('Her2', 'Gene', (43, 47))	('gene amplification', 'Var', (149, 167))	('Her2', 'Gene', '2064', (43, 47))	('MIBC', 'Chemical', '-', (62, 66))	('Her2', 'Gene', (79, 83))	('Her2', 'Gene', '2064', (79, 83))
164429	29654370	We observed a significantly higher Her2 expression in cases with polysomy 17 or Her2 amplification, compared to CIS cases without these alterations.	('expression', 'MPA', (40, 50))	('Her2', 'Gene', (35, 39))	('Her2', 'Gene', (80, 84))	('Her2', 'Gene', '2064', (80, 84))	('Her2', 'Gene', '2064', (35, 39))	('CIS', 'Phenotype', 'HP:0030075', (112, 115))	('polysomy 17', 'Var', (65, 76))	('higher', 'PosReg', (28, 34))	('amplification', 'Var', (85, 98))
164430	29654370	Chromosome 17 polysomy has been previously described as one of the mechanisms driving Her2 expression in breast cancer, especially in tumors with IHC 2+ scores.	('expression', 'MPA', (91, 101))	('tumors', 'Disease', (134, 140))	('polysomy', 'Var', (14, 22))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('Her2', 'Gene', '2064', (86, 90))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancer', 'Disease', (105, 118))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Her2', 'Gene', (86, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
164441	29654370	In summary, positivity for either ERbeta, Her2, or both proteins was observed in 91% (142/156) of CIS cases, while normal urothelium showed significantly lower expression of both markers, highlighting their potential for clinical use.	('CIS', 'Disease', (98, 101))	('Her2', 'Gene', '2064', (42, 46))	('ERbeta', 'Gene', '2100', (34, 40))	('CIS', 'Phenotype', 'HP:0030075', (98, 101))	('ERbeta', 'Gene', (34, 40))	('Her2', 'Gene', (42, 46))	('positivity', 'Var', (12, 22))
164466	28927108	However, previous studies have suggested that the presence of variant histology is usually associated with more aggressive behavior and a worse patient outcome.	('aggressive behavior', 'Disease', (112, 131))	('aggressive behavior', 'Disease', 'MESH:D001523', (112, 131))	('aggressive behavior', 'Phenotype', 'HP:0000718', (112, 131))	('patient', 'Species', '9606', (144, 151))	('aggressive behavior', 'biological_process', 'GO:0002118', ('112', '131'))	('variant', 'Var', (62, 69))	('more', 'PosReg', (107, 111))	('associated', 'Reg', (91, 101))
164518	28927108	However, Scosyrev et al reported that patients with squamous or glandular histological UCB variants exhibited an improved response to neoadjuvant chemotherapy [methotrexate, vinblastine, doxorubicin (Adriamycin) and cisplatin] in a post hoc analysis of a prospective trial.	('UCB', 'Gene', (87, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (216, 225))	('methotrexate', 'Chemical', 'MESH:D008727', (160, 172))	('response', 'MPA', (122, 130))	('variants', 'Var', (91, 99))	('vinblastine', 'Chemical', 'MESH:D014747', (174, 185))	('UCB', 'Chemical', '-', (87, 90))	('patients', 'Species', '9606', (38, 46))	('Adriamycin', 'Chemical', 'MESH:D004317', (200, 210))	('doxorubicin', 'Chemical', 'MESH:D004317', (187, 198))	('improved', 'PosReg', (113, 121))
164522	28927108	Patients with variant UCB histology had a higher risk of disease recurrence and progression, and lower survival rates following TURBT compared with patients with pure UCB.	('patients', 'Species', '9606', (148, 156))	('UCB', 'Chemical', '-', (167, 170))	('UCB', 'Gene', (22, 25))	('Patients', 'Species', '9606', (0, 8))	('pure', 'molecular_function', 'GO:0034023', ('162', '166'))	('lower', 'NegReg', (97, 102))	('disease recurrence', 'CPA', (57, 75))	('variant', 'Var', (14, 21))	('survival rates', 'CPA', (103, 117))	('UCB', 'Chemical', '-', (22, 25))
164524	28927108	In a study by Miller and Epstein, the presence of glandular differentiation in noninvasive UCB was associated with an increased risk of developing to high-grade prognostically poor invasive bladder carcinomas including poorly-differentiated UCB.	('presence', 'Var', (38, 46))	('invasive bladder carcinomas', 'Disease', 'MESH:D001749', (181, 208))	('UCB', 'Chemical', '-', (91, 94))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (190, 208))	('invasive bladder', 'Phenotype', 'HP:0100645', (181, 197))	('glandular differentiation', 'Var', (50, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('poorly-differentiated UCB', 'Disease', (219, 244))	('UCB', 'Chemical', '-', (241, 244))	('carcinomas', 'Phenotype', 'HP:0030731', (198, 208))	('invasive bladder carcinomas', 'Disease', (181, 208))
164535	28927108	As an independent prognostic factor of recurrence, patients with the variant form of NMIUCB present a shorter RFS duration, and should therefore be followed up closely in case of recurrence.	('shorter', 'NegReg', (102, 109))	('variant', 'Var', (69, 76))	('UCB', 'Chemical', '-', (88, 91))	('RFS duration', 'MPA', (110, 122))	('NMIUCB', 'Gene', (85, 91))	('patients', 'Species', '9606', (51, 59))
164692	27123328	Some of the more recent series used the two-piered system and found that low grade was a strong independent prognostic factor for better outcome in patients with UTUC that were treated with RNU.	('low grade', 'Var', (73, 82))	('patients', 'Species', '9606', (148, 156))	('UTUC', 'Disease', (162, 166))	('RNU', 'Chemical', '-', (190, 193))
164711	27123328	LVI was also associated with the male gender, high grading and tumor necrosis (p = 0.017; <0.001 and <0.001 respectively).	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor necrosis', 'Disease', 'MESH:D009336', (63, 77))	('necrosis', 'biological_process', 'GO:0008220', ('69', '77'))	('necrosis', 'biological_process', 'GO:0070265', ('69', '77'))	('necrosis', 'biological_process', 'GO:0008219', ('69', '77'))	('LVI', 'Chemical', '-', (0, 3))	('tumor necrosis', 'Disease', (63, 77))	('necrosis', 'biological_process', 'GO:0019835', ('69', '77'))	('LVI', 'Disease', (0, 3))	('high grading', 'Var', (46, 58))	('necrosis', 'biological_process', 'GO:0001906', ('69', '77'))
164797	26297435	Approximately 80 spheroids derived from 5637 cells or CTOSs were plated in 24-well tissue culture dishes (Corning Inc., Corning, NY) or type I collagen (Cellmatrix)-coated dishes, and cultured with 0.1% dimethyl sulfoxide or the indicated dose of MG132 (Sigma-Aldrich) or SB216763 (Sigma-Aldrich).	('MG132', 'Var', (247, 252))	('MG132', 'Chemical', 'MESH:C072553', (247, 252))	('collagen', 'molecular_function', 'GO:0005202', ('143', '151'))	('CTOSs', 'Chemical', '-', (54, 59))	('SB216763', 'Var', (272, 280))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (203, 221))	('SB216763', 'Chemical', 'MESH:C417521', (272, 280))
164845	26297435	An inhibitor of GSK3, SB216763, suppressed the decrease in   Np63alpha protein levels after attachment (Figure 4D).	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('p63', 'Gene', (62, 65))	('GSK', 'molecular_function', 'GO:0050321', ('16', '19'))	('SB216763', 'Var', (22, 30))	('decrease', 'NegReg', (47, 55))	('SB216763', 'Chemical', 'MESH:C417521', (22, 30))	('p63', 'Gene', '8626', (62, 65))	('suppressed', 'NegReg', (32, 42))
164846	26297435	The same effect was observed in CTOSs from MG132 and SB216763 (Figure 4, C and D).	('SB216763', 'Chemical', 'MESH:C417521', (53, 61))	('CTOSs', 'Chemical', '-', (32, 37))	('SB216763', 'Var', (53, 61))	('MG132', 'Chemical', 'MESH:C072553', (43, 48))	('MG132', 'Var', (43, 48))
164856	26297435	When CTOSs were attached to the matrix, E-cadherin signals decreased markedly in cells within CTOSs (left panels) in parallel with the decline in p63 (right panels) (Figure 5E).	('decreased', 'NegReg', (59, 68))	('CTOSs', 'Chemical', '-', (94, 99))	('E-cadherin', 'Gene', (40, 50))	('E-cadherin', 'Gene', '999', (40, 50))	('cadherin', 'molecular_function', 'GO:0008014', ('42', '50'))	('CTOSs', 'Chemical', '-', (5, 10))	('p63', 'Gene', (146, 149))	('decline', 'NegReg', (135, 142))	('CTOSs', 'Var', (94, 99))	('p63', 'Gene', '8626', (146, 149))
164871	26297435	On the contrary, clearance by the p63 knockdown spheroid cells was enhanced (Figure 6, F and G).	('clearance', 'CPA', (17, 26))	('p63', 'Gene', (34, 37))	('p63', 'Gene', '8626', (34, 37))	('knockdown', 'Var', (38, 47))	('enhanced', 'PosReg', (67, 75))
164879	26297435	Mutations or deletions in TP63 are rarely reported in malignant tumors, including urothelial cancers, whereas gene manipulation of   Np63alpha revealed that suppression of   Np63alpha promotes EMT in human bladder cancer cells.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('EMT', 'biological_process', 'GO:0001837', ('193', '196'))	('TP63', 'Gene', (26, 30))	('deletions', 'Var', (13, 22))	('urothelial cancers', 'Disease', 'MESH:D014523', (82, 100))	('human', 'Species', '9606', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('p63', 'Gene', (175, 178))	('p63', 'Gene', '8626', (175, 178))	('TP63', 'Gene', '8626', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('Mutations', 'Var', (0, 9))	('bladder cancer', 'Disease', 'MESH:D001749', (206, 220))	('bladder cancer', 'Disease', (206, 220))	('p63', 'Gene', (134, 137))	('bladder cancer', 'Phenotype', 'HP:0009725', (206, 220))	('EMT', 'CPA', (193, 196))	('p63', 'Gene', '8626', (134, 137))	('urothelial cancers', 'Disease', (82, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('promotes', 'PosReg', (184, 192))	('malignant tumors', 'Disease', 'MESH:D018198', (54, 70))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('suppression', 'Var', (157, 168))	('malignant tumors', 'Disease', (54, 70))
164918	32917158	As a result, androgen receptor activation may play a role in urothelial tumorigenesis and progression, which makes androgen receptor inactivation a potentially viable urothelial cancer treatment.	('urothelial cancer', 'Disease', (167, 184))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('urothelial', 'Disease', (61, 71))	('androgen receptor', 'Gene', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', (72, 77))	('androgen receptor', 'Gene', '367', (13, 30))	('androgen receptor', 'Gene', (13, 30))	('urothelial cancer', 'Disease', 'MESH:D014523', (167, 184))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('men', 'Species', '9606', (190, 193))	('androgen receptor', 'Gene', '367', (115, 132))	('activation', 'PosReg', (31, 41))	('inactivation', 'Var', (133, 145))
164935	32917158	Surgical procedures were identified by procedure codes 78008C for transurethral resection of the bladder tumor; 78010C for partial cystectomy; 78011B, 78039B, 78040B, 78012B, 78013B, 78014B, 78041B, 78042B, 78043B, 78044B, 78045B, 78046B for Radical cystectomy.	('78010C', 'Var', (112, 118))	('partial cystectomy', 'Disease', (123, 141))	('bladder tumor', 'Disease', 'MESH:D001749', (97, 110))	('78039B', 'Var', (151, 157))	('78045B', 'Var', (223, 229))	('78012B', 'Var', (167, 173))	('78041B', 'Var', (191, 197))	('78011B', 'Var', (143, 149))	('bladder tumor', 'Phenotype', 'HP:0009725', (97, 110))	('78042B', 'Var', (199, 205))	('78014B', 'Var', (183, 189))	('78046B', 'Var', (231, 237))	('78013B', 'Var', (175, 181))	('bladder tumor', 'Disease', (97, 110))	('78044B', 'Var', (215, 221))	('78043B', 'Var', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('78040B', 'Var', (159, 165))
164953	32917158	Some animal studies confirmed that 5a-reductase is also expressed in urothelial cancer cells and dihydrotestosterone may affect the growth of those cells.	('affect', 'Reg', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('urothelial cancer', 'Disease', (69, 86))	('growth', 'CPA', (132, 138))	('dihydrotestosterone', 'Chemical', 'MESH:D013196', (97, 116))	('urothelial cancer', 'Disease', 'MESH:D014523', (69, 86))	('dihydrotestosterone', 'Var', (97, 116))
164988	32695668	In addition, high expression of CORO1C was found to be significantly correlated with tumor-infiltrating neutrophils (TINs), a negative regulatory component that facilitates tumor distant progression and induces poor clinical outcome.	('tumor', 'Disease', (85, 90))	('correlated', 'Reg', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('TINs', 'Chemical', '-', (117, 121))	('CORO1C', 'Gene', (32, 38))	('high', 'Var', (13, 17))	('facilitates', 'PosReg', (161, 172))	('CORO1C', 'Gene', '23603', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('induces', 'Reg', (203, 210))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('expression', 'MPA', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
165041	32695668	The two genes had almost identical mutational rates, both around 2%, but the major genetic changes in CORO1C are mutation and copy number amplification while deep depletion of TMPRSS4 gene is detectable in a small group of patients, which suggests a heterogeneous gene alteration pattern and exclusive molecular function of these two genes (Figures 8E,F).	('TMPRSS4', 'Gene', '56649', (176, 183))	('changes', 'Reg', (91, 98))	('mutation', 'Var', (113, 121))	('copy', 'MPA', (126, 130))	('CORO1C', 'Gene', (102, 108))	('CORO1C', 'Gene', '23603', (102, 108))	('TMPRSS4', 'Gene', (176, 183))	('molecular function', 'molecular_function', 'GO:0003674', ('302', '320'))	('patients', 'Species', '9606', (223, 231))
165054	32695668	In lung squamous cell carcinoma, overexpressed TMPRSS4 is associated with disease recurrence and poor survival by promoting invasion and metastasis.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('TMPRSS4', 'Gene', (47, 54))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('promoting', 'PosReg', (114, 123))	('overexpressed', 'Var', (33, 46))	('TMPRSS4', 'Gene', '56649', (47, 54))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (3, 31))
165059	32695668	In pancreatic carcinoma, TMPRSS4 is identified as a candidate biomarker by affecting the clonability and invasiveness of pancreatic cancer cells, and overexpressed TMPRSS4 predicts poor prognosis.	('affecting', 'Reg', (75, 84))	('TMPRSS4', 'Gene', (164, 171))	('invasiveness of pancreatic cancer', 'Disease', (105, 138))	('clonability', 'CPA', (89, 100))	('TMPRSS4', 'Gene', (25, 32))	('invasiveness of pancreatic cancer', 'Disease', 'MESH:D010190', (105, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('TMPRSS4', 'Gene', '56649', (164, 171))	('pancreatic carcinoma', 'Disease', (3, 23))	('overexpressed', 'Var', (150, 163))	('TMPRSS4', 'Gene', '56649', (25, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (121, 138))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (3, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
165060	32695668	In prostate cancer cells, overexpressed TMPRSS4 promotes migration via the progression of EMT.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('EMT', 'biological_process', 'GO:0001837', ('90', '93'))	('progression of EMT', 'CPA', (75, 93))	('migration', 'CPA', (57, 66))	('TMPRSS4', 'Gene', '56649', (40, 47))	('promotes', 'PosReg', (48, 56))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('overexpressed', 'Var', (26, 39))	('TMPRSS4', 'Gene', (40, 47))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
165061	32695668	Interestingly, in contrast to most cancer types in published research, our study finds that high expression of TMPRSS4 predicts a better clinical outcome in bladder cancer, and this finding has been verified in three data sets (two online and one from our center).	('better', 'PosReg', (130, 136))	('TMPRSS4', 'Gene', (111, 118))	('high', 'Var', (92, 96))	('TMPRSS4', 'Gene', '56649', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('bladder cancer', 'Disease', 'MESH:D001749', (157, 171))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('bladder cancer', 'Disease', (157, 171))	('cancer', 'Disease', (35, 41))
165066	32695668	In lung squamous cell carcinoma, CORO1C was identified as a target of the miR-1/133a cluster, and silencing CORO1C inhibited cancer cell proliferation, migration, and invasion.	('miR-1', 'Gene', '79187', (74, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('inhibited', 'NegReg', (115, 124))	('CORO1C', 'Gene', (108, 114))	('CORO1C', 'Gene', '23603', (108, 114))	('cancer', 'Disease', (125, 131))	('CORO1C', 'Gene', (33, 39))	('CORO1C', 'Gene', '23603', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('miR-1', 'Gene', (74, 79))	('silencing', 'Var', (98, 107))	('invasion', 'CPA', (167, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (3, 31))	('migration', 'CPA', (152, 161))	('cell proliferation', 'biological_process', 'GO:0008283', ('132', '150'))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
165067	32695668	In gastric cancer, overexpressed CORO1C is associated with poor prognosis and could promote metastasis by regulating cyclin D1 and vimentin.	('CORO1C', 'Gene', (33, 39))	('cyclin D1', 'Gene', (117, 126))	('promote', 'PosReg', (84, 91))	('vimentin', 'Gene', '7431', (131, 139))	('CORO1C', 'Gene', '23603', (33, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('metastasis', 'CPA', (92, 102))	('vimentin', 'Gene', (131, 139))	('regulating', 'Reg', (106, 116))	('cyclin', 'molecular_function', 'GO:0016538', ('117', '123'))	('vimentin', 'cellular_component', 'GO:0045099', ('131', '139'))	('overexpressed', 'Var', (19, 32))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('vimentin', 'cellular_component', 'GO:0045098', ('131', '139'))	('cyclin D1', 'Gene', '595', (117, 126))
165068	32695668	In our study, the high expression level of CORO1C also predicted poor survival outcomes in bladder cancer, which is consistent with other cancer types.	('survival outcomes', 'CPA', (70, 87))	('cancer', 'Disease', (138, 144))	('CORO1C', 'Gene', (43, 49))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('CORO1C', 'Gene', '23603', (43, 49))	('bladder cancer', 'Disease', (91, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('expression level', 'MPA', (23, 39))	('high', 'Var', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('poor', 'NegReg', (65, 69))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
165071	32695668	Many studies have shown that TINs promote the adhesion of tumor cells to the epithelial monolayer and, thus, accelerate the metastasis of tumor cells.	('accelerate', 'PosReg', (109, 119))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (138, 143))	('TINs', 'Var', (29, 33))	('adhesion', 'CPA', (46, 54))	('TINs', 'Chemical', '-', (29, 33))	('promote', 'PosReg', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
165072	32695668	In pancreatic ductal adenocarcinoma, TINs promote the EMT process and the invasive growth of tumor cells.	('EMT process', 'CPA', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('invasive growth', 'biological_process', 'GO:0001404', ('74', '89'))	('invasive growth', 'biological_process', 'GO:0036267', ('74', '89'))	('invasive growth', 'biological_process', 'GO:0044412', ('74', '89'))	('TINs', 'Chemical', '-', (37, 41))	('tumor', 'Disease', (93, 98))	('TINs', 'Var', (37, 41))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (3, 35))	('invasive growth', 'biological_process', 'GO:0044409', ('74', '89'))	('promote', 'PosReg', (42, 49))	('pancreatic ductal adenocarcinoma', 'Disease', (3, 35))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (3, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('invasive growth', 'biological_process', 'GO:0051831', ('74', '89'))	('invasive growth', 'biological_process', 'GO:0007125', ('74', '89'))	('EMT', 'biological_process', 'GO:0001837', ('54', '57'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
165145	32509772	Inhibiting coinhibitory checkpoints using ICBT has been regarded as a promising method for controlling tumors, and many studies have demonstrated its efficacy.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('Inhibiting', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))
165155	32509772	Specifically, 101 and 72 pairs of normal and matched cancer samples were obtained from GSE40435 and GSE53757, respectively.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('GSE53757', 'Var', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('GSE40435', 'Var', (87, 95))
165186	32509772	Patients with high HHLA2 expression had a significantly longer survival time than those patients with low expression.	('patients', 'Species', '9606', (88, 96))	('survival time', 'CPA', (63, 76))	('HHLA2', 'Gene', '11148', (19, 24))	('high', 'Var', (14, 18))	('longer', 'PosReg', (56, 62))	('Patients', 'Species', '9606', (0, 8))	('HHLA2', 'Gene', (19, 24))
165198	32509772	Copy number alterations (CNAs) are an important mechanism of oncogene activation in cancer.	('Copy number alterations', 'Var', (0, 23))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (84, 90))
165202	32509772	The proportion of single copy deletions showed the opposite trend, with 41.4 and 11.4% in the HHLA2-low and high groups, respectively (Figures 3A,B).	('HHLA2', 'Gene', (94, 99))	('HHLA2', 'Gene', '11148', (94, 99))	('single copy deletions', 'Var', (18, 39))
165204	32509772	Only seven CpG sites had associated data; among them, five CpG sites, including cg02059214, cg02124498, cg08817540, cg10431989, and cg11326415, showed a negative correlation with HHLA2 expression; the other two sites were positively correlated with HHLA2 (Figure 3C).	('HHLA2', 'Gene', (249, 254))	('expression', 'MPA', (185, 195))	('HHLA2', 'Gene', '11148', (249, 254))	('negative', 'NegReg', (153, 161))	('HHLA2', 'Gene', (179, 184))	('HHLA2', 'Gene', '11148', (179, 184))	('cg10431989', 'Var', (116, 126))	('cg11326415', 'Var', (132, 142))	('cg08817540', 'Var', (104, 114))	('cg02124498', 'Var', (92, 102))	('cg02059214', 'Var', (80, 90))
165265	32509772	Patients with high HHLA2 showed longer survival rates, contradicting previous studies.	('longer', 'PosReg', (32, 38))	('survival rates', 'CPA', (39, 53))	('HHLA2', 'Gene', '11148', (19, 24))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('HHLA2', 'Gene', (19, 24))
165284	32509772	Taking these findings into consideration, immunotherapy based on HHLA2 expression may further improve the prognosis of patients with high HHLA2 expression.	('high', 'Var', (133, 137))	('patients', 'Species', '9606', (119, 127))	('HHLA2', 'Gene', (65, 70))	('HHLA2', 'Gene', (138, 143))	('improve', 'PosReg', (94, 101))	('HHLA2', 'Gene', '11148', (65, 70))	('HHLA2', 'Gene', '11148', (138, 143))
165294	31202631	Here we present CHASMplus, a computational method, that is uniquely capable of identifying driver missense mutations, including those specific to a cancer type, as evidenced by significantly superior performance on diverse benchmarks.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('missense mutations', 'Var', (98, 116))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('CHASMplus', 'Disease', (16, 25))	('CHASMplus', 'Disease', 'None', (16, 25))
165295	31202631	Applied to 8,657 tumor samples across 32 cancer types in The Cancer Genome Atlas, CHASMplus identifies over 4,000 unique driver missense mutations in 240 genes, supporting a prominent role for rare driver mutations.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Cancer', 'Disease', (61, 67))	('tumor', 'Disease', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Cancer', 'Disease', 'MESH:D009369', (61, 67))	('CHASMplus', 'Disease', (82, 91))	('cancer', 'Disease', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('missense mutations', 'Var', (128, 146))	('CHASMplus', 'Disease', 'None', (82, 91))
165298	31202631	Their analysis revealed that most driver mutations occur only in a few patients, presenting a challenge for precision medicine, and several cancer types will benefit from additional sequencing to identify these rare driver mutations.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
165299	31202631	Cancer is a disease of the genome where certain somatic mutations drive the neoplastic process of cancer, while the majority of mutations are benign passengers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (56, 65))	('neoplastic process', 'CPA', (76, 94))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', (98, 104))	('drive', 'PosReg', (66, 71))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
165300	31202631	Missense mutations are the most common protein-coding mutation found in cancer genomes.	('cancer', 'Disease', (72, 78))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('Missense mutations', 'Var', (0, 18))
165301	31202631	However, due to the large number of somatic mutations identified in DNA sequencing of human tumors, it has been logistically impossible to experimentally validate driver mutations at sufficiently large scale.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('human', 'Species', '9606', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mutations', 'Var', (44, 53))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
165302	31202631	The task of identifying putative drivers from cancer sequencing studies has therefore depended on statistical models to identify genes with an excess number of mutations over expectation.	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('mutations', 'Var', (160, 169))
165303	31202631	The rationale is that because driver mutations provide a fitness advantage to cancer cells, they will be observed more often than expected by chance due to their contribution to carcinogenesis and, as such, leave a statistically detectable signal.	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (178, 192))	('mutations', 'Var', (37, 46))	('fitness', 'Disease', (57, 64))	('carcinogenesis', 'Disease', (178, 192))	('fitness', 'Disease', 'MESH:D012640', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
165304	31202631	Based on such gene-level analyses, it has been hypothesized that cancer driver mutations exhibit a long tail phenomenon with few common drivers and many rare drivers, suggesting that numerous rare drivers remain to be discovered.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('long tail', 'Phenotype', 'HP:0002831', (99, 108))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('mutations', 'Var', (79, 88))
165307	31202631	Overall, this highlights the critical importance of new methods that can identify putative driver missense mutations and separate them from passenger mutations even within known cancer genes, which could spur effective experimental validation.	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('missense mutations', 'Var', (98, 116))
165308	31202631	While many computational methods have been developed to predict whether a missense mutation is generally deleterious or pathogenic, there has not previously been a method to score the oncogenic impact of a missense mutation specifically by cancer type.	('missense mutation', 'Var', (206, 223))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('missense mutation', 'Var', (74, 91))	('cancer', 'Disease', (240, 246))
165309	31202631	Although it is well known that missense mutations have different impacts in different cancer types, currently available computational methods either do not take it into consideration or fail at the task of distinguishing the differences.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('missense mutations', 'Var', (31, 49))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('impacts', 'Reg', (65, 72))	('cancer', 'Disease', (86, 92))
165310	31202631	This indicates an unmet need, given the clinical relevance of mutations is increasingly understood to depend both on the particular mutation and cancer type.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('mutations', 'Var', (62, 71))
165311	31202631	In this work, we introduce a machine learning method, CHASMplus, to predict the driver status of missense mutations in a cancer type-specific manner.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('CHASMplus', 'Disease', (54, 63))	('CHASMplus', 'Disease', 'None', (54, 63))	('cancer', 'Disease', (121, 127))	('missense mutations', 'Var', (97, 115))
165313	31202631	We explore the emerging role for rare driver missense mutations in cancer and, when possible, relate predictions to supporting functional evidence.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('missense mutations', 'Var', (45, 63))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
165314	31202631	We provide an interactive resource for exploring driver missense mutations identified from the TCGA (http://karchinlab.github.io/CHASMplus) and a user-friendly tool (http://chasmplus.readthedocs.io/) to predict whether newly observed mutations from further sequencing are likely cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('CHASMplus', 'Disease', (129, 138))	('CHASMplus', 'Disease', 'None', (129, 138))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('mutations', 'Var', (234, 243))
165315	31202631	Lastly, we examine the diversity of driver missense mutations across various types of cancer, which leads to a refined understanding of the likely trajectory of driver missense mutation discovery with further sequencing.	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('missense mutations', 'Var', (43, 61))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (86, 92))
165316	31202631	We have developed a method named CHASMplus that uses machine learning to discriminate somatic missense mutations (referred to hereafter as missense mutations) as either cancer drivers or passengers (Figure 1a, Methods).	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('CHASMplus', 'Disease', (33, 42))	('CHASMplus', 'Disease', 'None', (33, 42))	('missense mutations', 'Var', (94, 112))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
165321	31202631	In contrast, most previous methods provide a single impact score for each missense mutation, regardless of cancer type.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('missense mutation', 'Var', (74, 91))
165324	31202631	First, a cancer type-specific model should accurately predict oncogenic effects of missense mutations in an appropriate cell line.	('missense mutations', 'Var', (83, 101))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
165325	31202631	We therefore compared predictions of breast cancer-specific CHASMplus, CHASM, and CanDrA models in known breast cancer driver genes to a previous large-scale validation of 698 missense mutations in MCF10A (breast epithelium) cells that measured cell viability (Figure 2a, Methods).	('breast cancer', 'Disease', (37, 50))	('CHASM', 'Gene', '219537', (60, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('CHASMplus', 'Disease', 'None', (60, 69))	('MCF10A', 'CellLine', 'CVCL:0598', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('CHASM', 'Gene', (71, 76))	('CHASM', 'Gene', (60, 65))	('MCF10A', 'Gene', (198, 204))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('CHASM', 'Gene', '219537', (71, 76))	('missense mutations', 'Var', (176, 194))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('breast cancer', 'Disease', (105, 118))	('CHASMplus', 'Disease', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
165335	31202631	It has been previously documented that lung adenocarcinoma (LUAD) missense mutations in EGFR appear predominantly in its kinase domain, while GBM missense mutations appear in its extracellular domain.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('extracellular', 'cellular_component', 'GO:0005576', ('179', '192'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('missense mutations', 'Var', (66, 84))	('EGFR', 'Gene', '1956', (88, 92))	('lung adenocarcinoma', 'Disease', (39, 58))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (39, 58))	('EGFR', 'Gene', (88, 92))
165336	31202631	We therefore scored TCGA missense mutations in the gene EGFR from LUAD patients and from GBM patients with CHASMplus, CanDrA, and CHASM (Figure 2c).	('CHASM', 'Gene', (107, 112))	('CHASM', 'Gene', '219537', (130, 135))	('CHASMplus', 'Disease', (107, 116))	('EGFR', 'Gene', '1956', (56, 60))	('patients', 'Species', '9606', (71, 79))	('CHASM', 'Gene', '219537', (107, 112))	('missense mutations', 'Var', (25, 43))	('CHASMplus', 'Disease', 'None', (107, 116))	('EGFR', 'Gene', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('CHASM', 'Gene', (130, 135))	('patients', 'Species', '9606', (93, 101))
165337	31202631	The CHASMplus GBM model correctly scores the missense mutations from GBM patients significantly higher than those from LUAD patients (p=0.004, two-sided t-test), and vice versa for the CHASMplus LUAD model (p=0.003, two-sided t-test).	('CHASMplus', 'Disease', (185, 194))	('CHASMplus', 'Disease', (4, 13))	('GBM', 'Disease', (69, 72))	('CHASMplus LUAD', 'Disease', 'None', (185, 199))	('CHASMplus', 'Disease', 'None', (4, 13))	('CHASMplus', 'Disease', 'None', (185, 194))	('CHASMplus LUAD', 'Disease', (185, 199))	('missense mutations', 'Var', (45, 63))	('higher', 'PosReg', (96, 102))	('patients', 'Species', '9606', (73, 81))	('patients', 'Species', '9606', (124, 132))
165338	31202631	In contrast, the CHASM GBM model and the CHASM LUAD model both score the mutations from LUAD patients higher than those from GBM patients (p=1e-5 and 5e-5, respectively, two-sided t-test).	('CHASM', 'Gene', (41, 46))	('score', 'PosReg', (63, 68))	('patients', 'Species', '9606', (129, 137))	('CHASM', 'Gene', '219537', (17, 22))	('higher', 'PosReg', (102, 108))	('CHASM', 'Gene', '219537', (41, 46))	('patients', 'Species', '9606', (93, 101))	('mutations', 'Var', (73, 82))	('CHASM', 'Gene', (17, 22))
165339	31202631	CanDrA does not have a LUAD model, but its GBM model scores mutations from LUAD patients higher than those from GBM patients (p=0.0002, two-sided t-test), which is significant in the wrong direction.	('mutations', 'Var', (60, 69))	('higher', 'PosReg', (89, 95))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (80, 88))
165340	31202631	In summary, several lines of evidence suggest that CHASMplus, relative to other methods, has a substantial advantage in distinguishing between driver and passenger missense mutations, specifically by cancer type.	('driver', 'Var', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('CHASMplus', 'Disease', (51, 60))	('CHASMplus', 'Disease', 'None', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
165342	31202631	This approach is useful because some cancer driver mutations do occur in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
165343	31202631	The power to detect these mutations, particularly when they occur at low frequency in many cancer types, is increased when many cancer types are aggregated, known as a pan-cancer analysis.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (91, 97))	('increased', 'PosReg', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (128, 134))
165346	31202631	A range of benchmarks was critical because missense mutations with the most established experimental support for a driver role tend to be in a few well-understood cancer driver genes.	('missense mutations', 'Var', (43, 61))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
165348	31202631	These results suggest that CHASMplus improves on previous methods to predict driver missense mutations in a pan-cancer setting, as well as in a cancer type-specific manner.	('driver missense mutations', 'Var', (77, 102))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('CHASMplus', 'Disease', (27, 36))	('CHASMplus', 'Disease', 'None', (27, 36))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
165351	31202631	Using cancer type-specific models, we found a wide range of putative driver missense mutations in various cancer types.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('missense mutations', 'Var', (76, 94))	('cancer', 'Disease', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
165353	31202631	In total, 479 unique driver missense mutations were identified by the cancer type-specific analyses but missed by pan-cancer analysis.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('missense mutations', 'Var', (28, 46))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
165354	31202631	The pan-cancer analysis identified 3,527 unique missense mutations as putative drivers (Table S3) and had substantial overlap with our earlier pan-cancer analysis (p<2.2e-16, one-sided Fisher's exact test).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('missense mutations', 'Var', (48, 66))	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
165355	31202631	Given the substantially different methodology, the overlap suggests the CHASMplus pan-cancer analysis identifies a core set of driver mutations with multiple distinct sources of evidence.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CHASMplus pan-cancer', 'Disease', 'MESH:D009369', (72, 92))	('core', 'cellular_component', 'GO:0019013', ('115', '119'))	('mutations', 'Var', (134, 143))	('CHASMplus pan-cancer', 'Disease', (72, 92))
165357	31202631	Notably, the cancer type-specific analysis identified a substantial number of putative driver mutations not previously characterized in OncoKB (median overlap 53%).	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (94, 103))
165358	31202631	Altogether across the pan-cancer and cancer type-specific analyses, 4,006 unique driver missense mutations were identified by CHASMplus, of which 2,037 were neither found by OncoKB nor our earlier pan-cancer analysis, indicating a potentially expanded landscape of putative driver missense mutations of interest for further examination.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('CHASMplus', 'Disease', (126, 135))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('CHASMplus', 'Disease', 'None', (126, 135))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('missense mutations', 'Var', (88, 106))
165363	31202631	These results suggest that CHASMplus has potential to discriminate driver and passenger mutations in both well-known and putative cancer driver genes, although follow up experiments are required for confirmation.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('CHASMplus', 'Disease', (27, 36))	('mutations', 'Var', (88, 97))	('CHASMplus', 'Disease', 'None', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
165364	31202631	Based on our mutation-level analysis, we observed that the spectrum of rare (<1% of cancer samples), intermediate (1-5%), and common (>5%) frequency driver missense mutations varied substantially among cancer types (Figure 3a).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (202, 208))	('missense mutations', 'Var', (156, 174))
165365	31202631	For example, uveal melanoma was dominated by common driver missense mutations (88%), while head and neck squamous cell carcinoma (HNSC) was dominated by rare driver missense mutations (63%).	('uveal melanoma', 'Disease', (13, 27))	('neck squamous cell carcinoma', 'Disease', (100, 128))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('missense mutations', 'Var', (59, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (100, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('neck', 'cellular_component', 'GO:0044326', ('100', '104'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (13, 27))	('uveal melanoma', 'Disease', 'MESH:C536494', (13, 27))
165366	31202631	However, when we considered all cancer types together (pan-cancer), the overall proportion of rare driver missense mutations considered rare was slightly greater than for common (35.5% and 35.4%, respectively) and 4-fold greater than found by the cancer hotspots method (8%, P<2.2e-16, Fisher's exact test).	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('missense mutations', 'Var', (106, 124))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
165367	31202631	These results suggest that rare driver missense mutations have a greater role in many cancer types than previously suggested, but that this might not be the case for every cancer type.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('missense mutations', 'Var', (39, 57))	('cancer', 'Disease', (86, 92))
165368	31202631	We observed, after adjusting for sample size, that the average tumor mutation burden for a cancer type positively correlated with the prevalence of rare (but not common) driver missense mutations (R=0.63, P=4.7e-5, likelihood ratio test, Figure 3b).	('tumor', 'Disease', (63, 68))	('missense mutations', 'Var', (177, 195))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
165369	31202631	While cancer types appear to have different proportions of rare, intermediate and common driver missense mutations across cancer types, this result could be confounded by differences in subtypes or cell-of-origin.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('missense mutations', 'Var', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (6, 12))
165372	31202631	Fifty-five out of 223 genes (24.7%) contained putative driver missense mutations that were enriched in particular cancer subtypes (q-value<=0.1, chi-squared test, Figure 3c, Table S5, Figure S4).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('missense mutations', 'Var', (62, 80))	('cancer', 'Disease', (114, 120))
165373	31202631	Several genes showed strong specificity, consistent with prior literature, such as NFE2L2 mutations in esophageal cancers of squamous cell-of-origin, TP53 mutations in Human Papillomavirus-negative tumors in head and neck cancer, KIT mutations in testicular seminomas and PIK3CA mutations in the Luminal A subtype of breast cancer.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('TP53', 'Gene', (150, 154))	('mutations', 'Var', (90, 99))	('cancers', 'Disease', (114, 121))	('breast cancer', 'Disease', 'MESH:D001943', (317, 330))	('breast cancer', 'Disease', (317, 330))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('KIT', 'Gene', '3815', (230, 233))	('testicular seminomas', 'Phenotype', 'HP:0100617', (247, 267))	('Papillomavirus-negative tumors', 'Disease', 'MESH:D030361', (174, 204))	('KIT', 'molecular_function', 'GO:0005020', ('230', '233'))	('mutations', 'Var', (279, 288))	('Papillomavirus-negative tumors', 'Disease', (174, 204))	('PIK3CA', 'Gene', (272, 278))	('NFE2L2', 'Gene', '4780', (83, 89))	('neck', 'cellular_component', 'GO:0044326', ('217', '221'))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('neck cancer', 'Disease', 'MESH:D006258', (217, 228))	('TP53', 'Gene', '7157', (150, 154))	('neck cancer', 'Disease', (217, 228))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('seminomas', 'Disease', 'MESH:D018239', (258, 267))	('seminomas', 'Disease', (258, 267))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('head and neck cancer', 'Phenotype', 'HP:0012288', (208, 228))	('NFE2L2', 'Gene', (83, 89))	('mutations', 'Var', (234, 243))	('KIT', 'Gene', (230, 233))	('mutations', 'Var', (155, 164))	('PIK3CA', 'Gene', '5290', (272, 278))	('breast cancer', 'Phenotype', 'HP:0003002', (317, 330))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
165374	31202631	It should be noted that in some cases these differences are confounded by the fact that subtypes were originally defined by mutation status (GBM or LGG with IDH1/IDH2 mutations).	('IDH2', 'Gene', '3418', (162, 166))	('IDH2', 'Gene', (162, 166))	('mutations', 'Var', (167, 176))	('IDH1', 'Gene', (157, 161))	('IDH1', 'Gene', '3417', (157, 161))
165375	31202631	For example, the protein phosphatase PPP2R1A, which has been implicated as a tumor suppressor gene in many tumor types, contained common driver missense mutations in our pan-cancer analysis at residue positions 179 and 183, which is located at the protein interface composing the phosphatase 2A complex (Figure 3d).	('PPP2R1A', 'Gene', '5518', (37, 44))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('77', '93'))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('protein', 'cellular_component', 'GO:0003675', ('248', '255'))	('phosphatase 2A', 'molecular_function', 'GO:0004722', ('280', '294'))	('missense mutations', 'Var', (144, 162))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('phosphatase', 'molecular_function', 'GO:0016791', ('25', '36'))	('PPP2R1A', 'Gene', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (77, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('77', '93'))
165376	31202631	It also had a much broader set of rare driver mutations throughout the protein interface, such as R105Q and R459C.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('R105Q', 'Mutation', 'rs1489963266', (98, 103))	('R105Q', 'Var', (98, 103))	('R459C', 'Var', (108, 113))	('R459C', 'Mutation', 'p.R459C', (108, 113))
165377	31202631	Similarly, CHASMplus identified common driver missense mutations (S310A/F/Y) in the extracellular domain of the well-known oncogene ERBB2, but also finds rare driver missense mutations in both the extracellular and kinase domain (e.g., L313V and R678Q) (Figure 3e).	('R678Q', 'Var', (246, 251))	('ERBB2', 'Gene', (132, 137))	('S310A/F/Y', 'Var', (66, 75))	('S310A/F/Y', 'Mutation', 'rs1057519816', (66, 75))	('L313V', 'Mutation', 'p.L313V', (236, 241))	('extracellular', 'cellular_component', 'GO:0005576', ('197', '210'))	('CHASMplus', 'Disease', (11, 20))	('CHASMplus', 'Disease', 'None', (11, 20))	('L313V', 'Var', (236, 241))	('extracellular', 'cellular_component', 'GO:0005576', ('84', '97'))	('ERBB2', 'Gene', '2064', (132, 137))	('R678Q', 'Mutation', 'rs1057519862', (246, 251))
165378	31202631	This is supportive of previous experimental work implicating rare cancer driver mutations in commonly mutated cancer driver genes.	('cancer', 'Disease', (110, 116))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (66, 72))
165379	31202631	Truncating or likely loss-of-function mutations are typical hallmarks of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('loss-of-function', 'NegReg', (21, 37))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('73', '89'))	('tumor', 'Disease', (73, 78))	('Truncating', 'Var', (0, 10))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('73', '89'))	('mutations', 'Var', (38, 47))
165380	31202631	However, the role of driver missense mutations may be under-characterized in tumor suppressor genes, since these mutations are more diverse and occur over a larger region than in oncogenes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('77', '93'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('missense mutations', 'Var', (28, 46))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('77', '93'))
165381	31202631	As a case in point, the tumor suppressor gene CASP8 contains many truncating variants, while all of the putative driver missense mutations identified by CHASMplus were considered rare (Figure 3f).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('variants', 'Var', (77, 85))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('CHASMplus', 'Disease', (153, 162))	('CASP8', 'Gene', (46, 51))	('CHASMplus', 'Disease', 'None', (153, 162))	('CASP8', 'Gene', '841', (46, 51))	('truncating', 'MPA', (66, 76))
165383	31202631	We explored functional evidence to support whether the rare driver missense mutations in CASP8, predicted by CHASMplus, behaved similarly to truncating variants.	('CHASMplus', 'Disease', 'None', (109, 118))	('CASP8', 'Gene', (89, 94))	('CASP8', 'Gene', '841', (89, 94))	('CHASMplus', 'Disease', (109, 118))	('missense mutations', 'Var', (67, 85))
165385	31202631	For 12 immune-related markers, we compared tumor samples with driver missense mutations or truncating mutations in CASP8 to control samples with no mutations in CASP8.	('CASP8', 'Gene', (161, 166))	('truncating mutations', 'Var', (91, 111))	('CASP8', 'Gene', '841', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('CASP8', 'Gene', (115, 120))	('CASP8', 'Gene', '841', (115, 120))	('missense mutations', 'Var', (69, 87))	('tumor', 'Disease', (43, 48))
165387	31202631	Conventional wisdom has suggested that because rare missense mutations in tumor suppressor genes do not tend to cluster in protein sequence, they are solely passenger events.	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('missense mutations', 'Var', (52, 70))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('tumor', 'Disease', (74, 79))
165388	31202631	However, our work suggests that rare driver missense mutations in CASP8 and perhaps in other tumor suppressor genes may be relevant to tumor immune-related phenotypes.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('missense mutations', 'Var', (44, 62))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (135, 140))	('CASP8', 'Gene', (66, 71))	('CASP8', 'Gene', '841', (66, 71))	('tumor suppressor', 'biological_process', 'GO:0051726', ('93', '109'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('93', '109'))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
165393	31202631	Because PTEN mutations are found in many cancer types, we used CHASMplus pan-cancer predictions.	('CHASMplus pan-cancer', 'Disease', 'MESH:D009369', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('CHASMplus pan-cancer', 'Disease', (63, 83))	('found', 'Reg', (27, 32))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
165397	31202631	Next, we examined the lipid phosphatase activity and protein abundance for the PTEN mutations that we predicted as drivers in the TCGA.	('lipid phosphatase activity', 'molecular_function', 'GO:0042577', ('22', '48'))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('mutations', 'Var', (84, 93))	('PTEN', 'Gene', (79, 83))	('PTEN', 'Gene', '5728', (79, 83))
165398	31202631	We observed that these driver missense mutations, regardless of frequency, had significantly lower lipid phosphatase activity than other missense mutations in PTEN (common: p=0.008; intermediate: p=1.9e-9; rare: p=1.6e-18; Mann-Whitney U test, Figure 5e).	('lipid phosphatase activity', 'molecular_function', 'GO:0042577', ('99', '125'))	('PTEN', 'Gene', (159, 163))	('PTEN', 'Gene', '5728', (159, 163))	('missense mutations', 'Var', (30, 48))	('lipid phosphatase activity', 'MPA', (99, 125))	('lower', 'NegReg', (93, 98))
165399	31202631	A likely explanation is that greater decreases in PTEN lipid phosphatase activity may promote tumor growth and tumor clones with these mutations are positively selected in many patients.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('activity', 'MPA', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('patients', 'Species', '9606', (177, 185))	('mutations', 'Var', (135, 144))	('PTEN', 'Gene', (50, 54))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (111, 116))	('promote', 'PosReg', (86, 93))	('PTEN', 'Gene', '5728', (50, 54))	('lipid phosphatase activity', 'molecular_function', 'GO:0042577', ('55', '81'))	('decreases', 'NegReg', (37, 46))
165407	31202631	Based on our cancer type-specific models from CHASMplus, we found that the diversity and prevalence of driver missense mutations varied considerably across TCGA cancer types (Figure 6a, Methods).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('CHASMplus', 'Disease', (46, 55))	('cancer', 'Disease', (13, 19))	('CHASMplus', 'Disease', 'None', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('missense mutations', 'Var', (110, 128))	('TCGA', 'Disease', (156, 160))
165412	31202631	Are there substantially more cancer driver missense mutations yet to be discovered?	('missense mutations', 'Var', (43, 61))	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))
165415	31202631	Subsampling analysis showed all cancer types had a linear increase in the number of unique driver missense mutations identified (R2 > 0.5) with no evidence of saturation at current sample sizes (Figure S7a).	('S7', 'Gene', '6264', (202, 204))	('increase', 'PosReg', (58, 66))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('missense mutations', 'Var', (98, 116))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
165416	31202631	However, discovery of driver missense mutations, which occur in aggregate at a given prevalence (average number per cancer sample), varied substantially among cancer types (Figure 6b).	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('missense mutations', 'Var', (29, 47))
165418	31202631	This resulted in only marginal increases in the overall prevalence of identified driver missense mutations, consistent with our predicted trajectory based only on TCGA samples (Methods, Table S7, Figure S7b).	('S7', 'Gene', '6264', (203, 205))	('missense mutations', 'Var', (88, 106))	('increases', 'PosReg', (31, 40))	('S7', 'Gene', '6264', (192, 194))
165419	31202631	In contrast, thymoma (THYM), uveal melanoma (UVM), and pancreatic ductal adenocarcinoma (PAAD) contained common driver missense mutations that could be detected based on only a few samples from the cohort, e.g., GTF2I L424H in THYM.	('thymoma', 'Gene', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('GTF2I', 'Gene', (212, 217))	('thymoma', 'Gene', '7063', (13, 20))	('thymoma', 'Phenotype', 'HP:0100522', (13, 20))	('GTF2I', 'Gene', '2969', (212, 217))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (55, 87))	('missense', 'Var', (119, 127))	('L424H', 'Mutation', 'p.L424H', (218, 223))	('pancreatic ductal adenocarcinoma', 'Disease', (55, 87))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (55, 87))
165420	31202631	In contrast, the prevalence of rare driver missense mutations increased substantially with sample size in breast cancer (BRCA), head and neck squamous cell carcinoma (HNSC), and colon adenocarcinoma (COAD).	('missense mutations', 'Var', (43, 61))	('neck', 'cellular_component', 'GO:0044326', ('137', '141'))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (137, 165))	('colon adenocarcinoma', 'Disease', (178, 198))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (178, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('neck squamous cell carcinoma', 'Disease', (137, 165))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
165421	31202631	These results suggest cancer types can be clustered by patterns of driver missense mutation diversity and prevalence (Figure 6a), in addition to well-established approaches to define cancer subtypes, such as by cell-of-origin.	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('driver missense mutation', 'Var', (67, 91))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
165423	31202631	Future insights into cancer evolution and its relevance for clinical care will increasingly rely on the precise interpretation of whether individual mutations are cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
165425	31202631	The long tail hypothesis posits that there are many rare driver mutations in human cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('long tail', 'Phenotype', 'HP:0002831', (4, 13))	('mutations', 'Var', (64, 73))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
165428	31202631	The observed diversity of driver mutations across patients' tumors may be influenced by tumor mutation burden, the type of gene (i.e., tumor suppressor genes), the functional strength of the mutation, and the mutation's subtype specificity.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('135', '151'))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('patients', 'Species', '9606', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('influenced', 'Reg', (74, 84))	('tumor', 'Disease', (135, 140))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor suppressor', 'biological_process', 'GO:0051726', ('135', '151'))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (88, 93))	('tumors', 'Disease', (60, 66))
165429	31202631	The diversity of driver missense mutations supports the critical role of understanding the origins and overall contribution of rare driver mutations -- failure to capture and identify rare driver mutations, which occur in aggregate at reasonable prevalence, may result in crucial missed opportunities for interpreting a patient's cancer.	('missense mutations', 'Var', (24, 42))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('patient', 'Species', '9606', (320, 327))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('cancer', 'Disease', (330, 336))
165431	31202631	We therefore have precomputed the score of every possible missense mutation across the genome, effectively an in silico saturation mutagenesis across all genes to score as of yet unobserved mutations that are potential cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('missense mutation', 'Var', (58, 75))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (219, 225))	('mutagenesis', 'biological_process', 'GO:0006280', ('131', '142'))
165432	31202631	Although missense mutations are the most frequent protein-coding somatic alteration in cancer, CHASMplus only predicts missense mutations; but, in principle, our approach could be extended to other types of alterations.	('cancer', 'Disease', (87, 93))	('CHASMplus', 'Disease', (95, 104))	('CHASMplus', 'Disease', 'None', (95, 104))	('missense mutations', 'Var', (119, 137))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('missense mutations', 'Var', (9, 27))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
165433	31202631	Lastly, while our study leverages the large sized TCGA cohorts to make informed judgements about driver missense mutations, inevitably these tumors may still miss important contexts for understanding cancer.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('missense mutations', 'Var', (104, 122))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
165435	31202631	For example, it is well known EGFR mutations in lung adenocarcinoma are more highly prevalent in Asian compared to Caucasian populations.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (48, 67))	('EGFR', 'Gene', (30, 34))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('prevalent', 'Reg', (84, 93))	('mutations', 'Var', (35, 44))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('EGFR', 'Gene', '1956', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('lung adenocarcinoma', 'Disease', (48, 67))
165437	31202631	We expect that an increasingly complete catalog of driver missense mutations will be generated by a combination of improved computational methods and cumulative growth of available samples from cancer sequencing studies.	('missense mutations', 'Var', (58, 76))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
165438	31202631	However, for some cancer types in some populations, discovery of driver missense mutations may already be effectively saturated.	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('missense mutations', 'Var', (72, 90))
165439	31202631	By analyzing the trajectory of discovery at the level of driver missense mutations, we identified a more complicated pattern which depends on the cancer type.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('missense mutations', 'Var', (64, 82))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
165440	31202631	Future work will further elucidate a broader range of driver mutations, including those within non-coding regions of the genome, at different stages of carcinogenesis, such as in pre-cancerous lesions, and in response to therapeutic treatment.	('carcinogenesis', 'Disease', (152, 166))	('cancerous lesions', 'Disease', 'MESH:D009369', (183, 200))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancerous lesions', 'Disease', (183, 200))	('pre', 'molecular_function', 'GO:0003904', ('179', '182'))	('carcinogenesis', 'Disease', 'MESH:D063646', (152, 166))
165443	31202631	We collected a set of 1,225,917 somatic mutations in 8,657 samples from The Cancer Genome Atlas (TCGA) somatic mutation calls from whole-exome sequencing (v0.2.8, https://synapse.org/MC3).	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('MC3', 'Gene', (183, 186))	('MC3', 'Gene', '4159', (183, 186))	('mutations', 'Var', (40, 49))	('Cancer', 'Disease', (76, 82))	('synapse', 'cellular_component', 'GO:0045202', ('171', '178'))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))
165445	31202631	We identified hypermutated samples as having more mutations than 1.5 times the interquartile range above the third quartile (Tukey's condition) of samples within the same cancer type.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (171, 177))
165448	31202631	Previous machine learning approaches for predicting driver mutations have been trained on a small positive class of bona fide driver missense mutations, which are highly prevalent in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('missense mutations', 'Var', (133, 151))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', (188, 194))
165450	31202631	Driver genes have been labeled but the labels of missense mutations are inferred by cluster assumptions, e.g., driver missense mutations may occur together in known driver genes and in significantly mutated genes for a particular cancer type.	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('occur', 'Reg', (141, 146))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('missense mutations', 'Var', (118, 136))
165451	31202631	Mutations are assigned to the 'positive' class (driver-like) for a cancer type based on these assumptions, and all other mutations are assigned to the 'negative' class (passenger-like).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
165452	31202631	To extend this approach to a pan-cancer prediction, all mutations from the positive class were merged into one group and a single classifier was trained.	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (56, 65))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))
165454	31202631	To test the assumptions of our training procedure, we rigorously evaluated CHASMplus on orthogonally labeled mutations based on in vitro experiments, in vivo experiments, and literature curation.	('CHASMplus', 'Disease', (75, 84))	('CHASMplus', 'Disease', 'None', (75, 84))	('mutations', 'Var', (109, 118))
165457	31202631	The positive class (likely-driver missense mutations) was selected by the following criteria: 1) missense mutations had to occur in a curated set of 125 pan-cancer driver genes; 2) for each of the 32 TCGA cancer types, missense mutations found in that cancer type had to occur in a significantly mutated gene for that cancer type according to MutSigCV v1.4.	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (318, 324))	('v1.4', 'Gene', '28815', (352, 356))	('cancer', 'Disease', (252, 258))	('cancer', 'Disease', (205, 211))	('missense mutations', 'Var', (219, 237))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('v1.4', 'Gene', (352, 356))
165459	31202631	Notably, MutSigCV v1.4 only assess the total number of mutations in a gene, and not any characteristics of those mutations; thus, we avoid making strong assumptions about the properties of a particular driver mutation; 3) missense mutations had to occur in samples with relatively low mutation rate (less than 500 mutations, half the minimum hypermutator threshold as defined above).	('missense mutations', 'Var', (222, 240))	('v1.4', 'Gene', '28815', (18, 22))	('v1.4', 'Gene', (18, 22))
165469	31202631	We used random forests, a machine learning technique, to predict whether a missense mutation is a cancer driver.	('missense mutation', 'Var', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
165471	31202631	Since missense mutations in the same gene may have overlapping feature representations which result in classifier overfitting, we performed prediction using a 10-fold gene hold-out cross-validation procedure for both CHASMplus and 20/20+.	('overfitting', 'PosReg', (114, 125))	('CHASMplus', 'Disease', (217, 226))	('CHASMplus', 'Disease', 'None', (217, 226))	('missense mutations', 'Var', (6, 24))	('result in', 'Reg', (93, 102))
165473	31202631	The CHASMplus score represents the fraction of decision trees which vote for the mutation being a driver.	('CHASMplus', 'Disease', (4, 13))	('mutation', 'Var', (81, 89))	('CHASMplus', 'Disease', 'None', (4, 13))
165478	31202631	Next, each simulated missense mutation and gene was scored with the CHASMplus and 20/20+ models that were previously trained on the observed data.	('missense mutation', 'Var', (21, 38))	('CHASMplus', 'Disease', (68, 77))	('CHASMplus', 'Disease', 'None', (68, 77))
165480	31202631	We compared CHASMplus to 12 other methods that were designed to prioritize likely cancer driver missense mutations or have been used for that purpose (VEST, CADD, FATHMM cancer, SIFT, MutationAssessor, REVEL, MCAP, ParsSNP, CHASM, Polyphen2, transFIC and CanDrA).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MCAP', 'Gene', (209, 213))	('cancer', 'Disease', (170, 176))	('CHASM', 'Gene', (224, 229))	('CHASM', 'Gene', (12, 17))	('CHASM', 'Gene', '219537', (224, 229))	('cancer', 'Disease', (82, 88))	('CADD', 'Disease', (157, 161))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('missense mutations', 'Var', (96, 114))	('CHASMplus', 'Disease', (12, 21))	('CHASMplus', 'Disease', 'None', (12, 21))	('CHASM', 'Gene', '219537', (12, 17))	('MCAP', 'Gene', '23476', (209, 213))
165491	31202631	Mutations were scored using the corresponding cancer type models of CHASMplus, CanDrA, and CHASM, along with two high-performing methods which are not cancer type-specific (ParsSNP and REVEL).	('CHASMplus', 'Disease', (68, 77))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('CHASMplus', 'Disease', 'None', (68, 77))	('CHASM', 'Gene', '219537', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (46, 52))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (151, 157))	('CHASM', 'Gene', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('CHASM', 'Gene', (68, 73))	('CHASM', 'Gene', '219537', (91, 96))
165493	31202631	To assess each method's ability to distinguish breast cancer-specific driver mutations, mutations that increased cell viability in known breast cancer driver genes were labeled as positive class.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Disease', (137, 150))	('increased', 'PosReg', (103, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('mutations', 'Var', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cell viability', 'CPA', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
165494	31202631	Mutations that did not increase cell viability or increased cell viability but were not found in breast cancer-specific genes were labeled as negative class.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))
165496	31202631	Breast cancer-specific genes were labeled based on the Cancer Gene Census (CGC, genes marked as relevant to "breast" cancer and somatic missense mutations, COSMIC v79) or The Cancer Genome Atlas (TCGA).	('Cancer', 'Disease', (175, 181))	('missense mutations', 'Var', (136, 154))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Cancer', 'Disease', 'MESH:D009369', (175, 181))	('Cancer', 'Phenotype', 'HP:0002664', (175, 181))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('Cancer', 'Disease', (55, 61))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Disease', (117, 123))	('Breast cancer', 'Disease', (0, 13))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))
165498	31202631	We obtained all missense mutations from targeted sequencing with the MSK-IMPACT gene panel of 414 cancer-related genes originating from approximately 10,000 patients' tumors.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('missense mutations', 'Var', (16, 34))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('patients', 'Species', '9606', (157, 165))	('cancer', 'Disease', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
165500	31202631	For each cancer type, mutations were labeled as 'positive' class if they occurred in a cancer driver gene implicated for that cancer type and also a tumor of the same type.	('cancer', 'Disease', (87, 93))	('occurred', 'Reg', (73, 81))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (149, 154))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
165507	31202631	We obtained all missense mutations from targeted sequencing with the MSK-IMPACT gene panel of 414 cancer-related genes, originating from approximately 10,000 patients' tumors.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('missense mutations', 'Var', (16, 34))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('patients', 'Species', '9606', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
165509	31202631	The study selected mutations based on their presence in sequenced human tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('human', 'Species', '9606', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('mutations', 'Var', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', (72, 78))
165512	31202631	We assessed each method's ability to distinguish TP53 mutations with low transactivation (positive class) versus all other TP53 mutations (negative class).	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('transactivation', 'MPA', (73, 88))	('mutations', 'Var', (54, 63))	('transactivation', 'biological_process', 'GO:2000144', ('73', '88'))	('low', 'NegReg', (69, 72))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
165513	31202631	We evaluated all missense mutations (n=2,314) for TP53 from the IARC TP53 database.	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('missense mutations', 'Var', (17, 35))	('TP53', 'Gene', '7157', (50, 54))	('TP53', 'Gene', (50, 54))
165514	31202631	Low transactivation was considered as less than 50% wildtype, as indicated by the median of 8 different targets (WAF1, MDM2, BAX, h1433s, AIP1, GADD45, NOXA, and P53R2).	('WAF1', 'Gene', (113, 117))	('transactivation', 'MPA', (4, 19))	('MDM2', 'Gene', '4193', (119, 123))	('GADD45', 'Gene', (144, 150))	('NOXA', 'Gene', (152, 156))	('MDM2', 'Gene', (119, 123))	('h1433s', 'Var', (130, 136))	('AIP1', 'Gene', '23204', (138, 142))	('NOXA', 'Gene', '5366', (152, 156))	('P53R2', 'Gene', '50484', (162, 167))	('BAX', 'Gene', (125, 128))	('transactivation', 'biological_process', 'GO:2000144', ('4', '19'))	('WAF1', 'Gene', '1026', (113, 117))	('BAX', 'Gene', '581', (125, 128))	('GADD45', 'Gene', '1647', (144, 150))	('P53R2', 'Gene', (162, 167))	('AIP1', 'Gene', (138, 142))
165516	31202631	The experiment assumes that mutations that provide a growth advantage to cells with growth factors withdrawn reflect cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('growth', 'MPA', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('mutations', 'Var', (28, 37))
165517	31202631	We compared (pan-cancer) CHASMplus to the cancer hotspots method (v0.6), with respect to its sensitivity to identify driver missense mutations.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('CHASMplus', 'Disease', (25, 34))	('CHASMplus', 'Disease', 'None', (25, 34))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('missense mutations', 'Var', (124, 142))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
165519	31202631	The sensitivity of CHASMplus to detect the OncoKB-labeled mutations was 0.83, which was significantly higher than the hotspot method (0.46, p<2.2e-16, McNemar's test, n=896).	('mutations', 'Var', (58, 67))	('CHASMplus', 'Disease', (19, 28))	('CHASMplus', 'Disease', 'None', (19, 28))	('higher', 'PosReg', (102, 108))
165520	31202631	To minimize potential gene bias, we also repeated the analysis after excluding all 389 TP53 mutations, yielding sensitivity of 0.76 for CHASMplus and 0.49 for hotspot detection, a difference which is still statistically significant (p<2.2e-16, McNemar's test, n=507) (Figure 7b).	('CHASMplus', 'Disease', 'None', (136, 145))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('CHASMplus', 'Disease', (136, 145))
165527	31202631	We performed gene ontology analysis on the set of 75 genes (Table S4) containing at least one driver missense mutation from CHASMplus that did not overlap with previous genes from the Cancer Gene Census (COSMIC v79, annotated with somatic missense) or any driver genes from the TCGA PancanAtlas analysis.	('gene ontology', 'biological_process', 'GO:0003673', ('13', '26'))	('CHASMplus', 'Disease', (124, 133))	('CHASMplus', 'Disease', 'None', (124, 133))	('mutation', 'Var', (110, 118))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Cancer', 'Disease', (184, 190))	('Cancer', 'Disease', 'MESH:D009369', (184, 190))
165528	31202631	Mutation frequency was calculated based on the fraction of cancer samples that contained a driver mutation in a particular cancer type.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutation', 'Var', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
165530	31202631	All mutations within a codon are then classified as rare (<1% of cancer samples), intermediate (1-5%), or common (>5%).	('mutations', 'Var', (4, 13))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
165536	31202631	gwCHASMplus scores were computed for each of these missense mutations.	('missense mutations', 'Var', (51, 69))	('gwCHASMplus', 'Disease', 'None', (0, 11))	('gwCHASMplus', 'Disease', (0, 11))
165539	31202631	We extended our comparison of the PTEN saturation mutagenesis experiment of lipid phosphatase activity to the two "runner-up" methods (CanDrA and ParsSNP), assessed in the five benchmarks in Figure 2d.	('lipid phosphatase activity', 'molecular_function', 'GO:0042577', ('76', '102'))	('activity', 'MPA', (94, 102))	('mutagenesis', 'Var', (50, 61))	('mutagenesis', 'biological_process', 'GO:0006280', ('50', '61'))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))
165540	31202631	CHASMplus, CanDrA and ParsSNP were then compared to each other based on their specificity, sensitivity, precision and F1 score to identify mutations damaging to lipid phosphatase activity in PTEN.	('CHASMplus', 'Disease', (0, 9))	('CHASMplus', 'Disease', 'None', (0, 9))	('lipid phosphatase activity', 'molecular_function', 'GO:0042577', ('161', '187'))	('damaging', 'Reg', (149, 157))	('mutations', 'Var', (139, 148))	('PTEN', 'Gene', (191, 195))	('PTEN', 'Gene', '5728', (191, 195))	('lipid phosphatase activity', 'MPA', (161, 187))
165541	31202631	Most driver missense mutation prediction methods do not report p-values, but CHASMplus does compute a p-value.	('CHASMplus', 'Disease', 'None', (77, 86))	('missense mutation', 'Var', (12, 29))	('CHASMplus', 'Disease', (77, 86))
165544	31202631	We clustered TCGA cancer types according to two features, prevalence (fraction of samples mutated) and normalized diversity (normalized entropy) among predicted missense mutation drivers (q <= 0.01).	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('missense mutation', 'Var', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))
165546	31202631	To evaluate this possibility, we correlated the mean Variant Allele Fraction (VAF) for mutations in tumor samples in each cancer type with a variety of metrics summarizing our results.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutations', 'Var', (87, 96))
165548	31202631	We found no significant correlation between mean VAF for cancer types with: average number of predicted driver mutations per sample (Pearson r=0.26, p=0.14, correlation test), fraction of samples with predicted driver mutations (Pearson r=0.2, p=0.28, correlation test), unique number of significant mutations (Pearson r=0.04, p=0.82, correlation test), and normalized driver diversity (Pearson r=0.33, p=0.07, correlation test).	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (111, 120))
165549	31202631	We performed driver missense mutation predictions on random subsamples of each of 9 representative cancer types (ACC, SARC, PRAD, THYM, UVM, PAAD, BRCA, HNSC, and COAD), using CHASMplus.	('missense mutation', 'Var', (20, 37))	('UVM', 'Disease', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('CHASMplus', 'Disease', (176, 185))	('HNSC', 'Disease', (153, 157))	('cancer', 'Disease', (99, 105))	('PRAD', 'Disease', (124, 128))	('THYM', 'Disease', (130, 134))	('BRCA', 'Disease', (147, 151))	('CHASMplus', 'Disease', 'None', (176, 185))	('ACC', 'Disease', (113, 116))	('SARC', 'Disease', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('PAAD', 'Disease', (141, 145))
165552	31202631	The number of unique driver missense mutations and overall driver prevalence (average number of driver missense mutations per cancer sample) were then calculated based on significant CHASMplus predictions (q<=0.01).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('CHASMplus', 'Disease', (183, 192))	('missense mutations', 'Var', (28, 46))	('CHASMplus', 'Disease', 'None', (183, 192))
165556	31202631	Similar to statistical methods for driver gene detection, hotspot detection identifies an excess number of mutations compared to expectation using a large number of cancer samples.	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', (165, 171))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))
165557	31202631	We assessed the number of samples required to detect driver missense mutations across a range of frequencies (proportion of tumor samples in which a mutation occurs) and somatic background mutation rates.	('missense mutations', 'Var', (60, 78))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
165558	31202631	In Figure 7a, each of the 32 TCGA cancer types is placed according to its sample size and background mutation rate, relative to six curves which represent the required sample size to detect driver missense mutations of a certain frequency, with 90% power, using hotspot detection (see Statistical Power Analysis).	('cancer', 'Disease', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('missense mutations', 'Var', (197, 215))	('cancer', 'Disease', 'MESH:D009369', (34, 40))
165560	31202631	At current TCGA sample sizes, we found codon-based hotspot detection approaches were not well powered to identify driver missense mutations that occurred at less than 1% frequency in most cancer types.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('missense mutations', 'Var', (121, 139))	('cancer', 'Disease', (188, 194))
165563	31202631	For these mutations, pan-cancer analysis using ~10,000 TCGA samples should enable detection of driver mutations at frequency as low as 0.1%.	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (10, 19))
165565	31202631	Interactive portal for exploring driver missense mutations in TCGA: https://karchinlab.github.io/CHASMplus.	('missense mutations', 'Var', (40, 58))	('CHASMplus', 'Disease', (97, 106))	('CHASMplus', 'Disease', 'None', (97, 106))
165566	31202631	Missense mutations are the most frequent type of protein-coding alteration in cancers and the most difficult to interpret.	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Missense mutations', 'Var', (0, 18))
165567	31202631	While many computational methods have been developed to predict whether genes are cancer drivers or whether missense mutations are generally deleterious or pathogenic, there has not previously been a method to score the oncogenic impact of a missense mutation specifically by cancer type, limiting adoption of computational missense mutation predictors in the clinic.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('missense', 'Var', (242, 250))
165570	31202631	We introduce a machine learning method honed for each cancer type, and a resource for fast lookup of the cancer-specific driver propensity of every possible missense mutation in the human exome.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('human', 'Species', '9606', (182, 187))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('missense mutation', 'Var', (157, 174))
165571	31202631	CHASMplus identifies driver missense mutations in a cancer type-specific manner Rare driver mutations are common in cancer when considered as a group In some cancers, further sequencing will yield insight into rare driver mutations Comprehensive resource of driver propensity for all possible missense mutations	('CHASMplus', 'Disease', (0, 9))	('CHASMplus', 'Disease', 'None', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancer', 'Disease', (158, 164))	('cancers', 'Disease', (158, 165))	('missense mutations', 'Var', (28, 46))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
165576	29695918	Univariate analysis showed that high HMGB1 expression was significantly associated with a shortened patients' overall survival (OS) and disease-free survival (DFS; both P<0.001).	('high', 'Var', (32, 36))	('overall survival', 'CPA', (110, 126))	('disease-free survival', 'CPA', (136, 157))	('patients', 'Species', '9606', (100, 108))	('shortened', 'NegReg', (90, 99))	('expression', 'MPA', (43, 53))	('HMGB1', 'Gene', (37, 42))
165590	29695918	In addition, high HMGB1 expression has been detected in many kinds of tumor and predicted a poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('high', 'Var', (13, 17))	('expression', 'MPA', (24, 34))	('HMGB1', 'Gene', (18, 23))	('tumor', 'Disease', (70, 75))	('detected', 'Reg', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
165618	29695918	In subgroup analysis, high expression of HMGB1 was merely associated with adverse OS of pT1 BUC patients without lymph node metastasis (pT1/pN-, n=41, P=0.001; Figure 2).	('pT1', 'Gene', (136, 139))	('associated', 'Reg', (58, 68))	('high', 'Var', (22, 26))	('pT1', 'Gene', '58492', (88, 91))	('HMGB1', 'Gene', (41, 46))	('pT1', 'Gene', '58492', (136, 139))	('patients', 'Species', '9606', (96, 104))	('pT1', 'Gene', (88, 91))
165631	29695918	Overexpression of HMGB1 has been reported in a variety of human cancers, such as prostate cancer, renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), lung cancer, colorectal cancer, and gastric cancer, which may suggest the potential oncogenic role of HMGB1 in various human cancers.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('lung cancer', 'Disease', (158, 169))	('cancers', 'Disease', 'MESH:D009369', (283, 290))	('human', 'Species', '9606', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HCC', 'Phenotype', 'HP:0001402', (152, 155))	('Overexpression', 'Var', (0, 14))	('gastric cancer', 'Phenotype', 'HP:0012126', (194, 208))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (126, 150))	('colorectal cancer', 'Phenotype', 'HP:0003003', (171, 188))	('prostate cancer', 'Disease', (81, 96))	('renal cell carcinoma', 'Disease', (98, 118))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('cancers', 'Disease', (64, 71))	('reported', 'Reg', (33, 41))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('human', 'Species', '9606', (277, 282))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('hepatocellular carcinoma', 'Disease', (126, 150))	('cancers', 'Phenotype', 'HP:0002664', (283, 290))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('gastric cancer', 'Disease', (194, 208))	('cancers', 'Disease', (283, 290))	('HMGB1', 'Gene', (18, 23))	('colorectal cancer', 'Disease', 'MESH:D015179', (171, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('colorectal cancer', 'Disease', (171, 188))	('gastric cancer', 'Disease', 'MESH:D013274', (194, 208))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (126, 150))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (98, 118))
165636	29695918	Univariate and multivariate survival analyses showed that prostate cancer patients who underwent radical prostatectomy (RP) with positive HMGB1 expression had a poorer BCR- free survival rate at 5 years (6.0% vs 54.0%, P<0.001), and HMGB1 expression was an independent prognostic factor for BCR-free survival after RP (HR =2.348, 95% CI =1.373-6.361, P=0.001).	('positive', 'Var', (129, 137))	('prostate cancer', 'Phenotype', 'HP:0012125', (58, 73))	('poorer', 'NegReg', (161, 167))	('HMGB1', 'Gene', (138, 143))	('BCR- free survival rate', 'CPA', (168, 191))	('patients', 'Species', '9606', (74, 82))	('BC', 'Phenotype', 'HP:0009725', (291, 293))	('prostate cancer', 'Disease', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BC', 'Phenotype', 'HP:0009725', (168, 170))	('prostate cancer', 'Disease', 'MESH:D011471', (58, 73))
165639	29695918	In addition, their study also demonstrated that high HMGB1 expression was significantly associated with advanced TNM stage and incomplete tumor encapsulation.	('TNM', 'Gene', (113, 116))	('tumor', 'Disease', (138, 143))	('TNM', 'Gene', '10178', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('expression', 'MPA', (59, 69))	('associated', 'Reg', (88, 98))	('high', 'Var', (48, 52))	('HMGB1', 'Gene', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
165640	29695918	Furthermore, the multivariate analysis revealed that high expression of HMGB1 predicted poorer OS and DFS for patients with HCC after curative hepatectomy.	('HCC', 'Phenotype', 'HP:0001402', (124, 127))	('HMGB1', 'Gene', (72, 77))	('poorer', 'NegReg', (88, 94))	('DFS', 'CPA', (102, 105))	('high expression', 'Var', (53, 68))	('patients', 'Species', '9606', (110, 118))
165642	29695918	Overexpression of HMGB1 has been implicated in all central hallmarks of cancer, including apoptosis, angiogenesis, invasion, metastasis, and inflammatory microenvironment.	('implicated', 'Reg', (33, 43))	('angiogenesis', 'CPA', (101, 113))	('metastasis', 'CPA', (125, 135))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('HMGB1', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('men', 'Species', '9606', (166, 169))	('Overexpression', 'Var', (0, 14))	('angiogenesis', 'biological_process', 'GO:0001525', ('101', '113'))	('apoptosis', 'CPA', (90, 99))	('invasion', 'CPA', (115, 123))	('cancer', 'Disease', (72, 78))
165693	29059045	Although no consensus is available regarding this, most reports refer to tumors with Gleason scores >=7, adverse pathological patterns (such as cribriform), and increased tumor size (>0.5 cm3) to be at risk for progression.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', (73, 78))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('Gleason', 'Var', (85, 92))
165716	29059045	A large prospective study showed that the 4Kscore test had an AUC of 0.82 for detecting cancers with Gleason score >=7, compared to 0.75 using total and free PSA.	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('Gleason score >=7', 'Var', (101, 118))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PSA', 'Gene', '354', (158, 161))	('PSA', 'Gene', (158, 161))
165728	29059045	Although currently standard practice does not include genetic testing for prostate cancer screening, reports of increased prostate cancer risk in men with mutations in BRCA1 and BRCA2 have been published.	('BRCA1', 'Gene', '672', (168, 173))	('prostate cancer', 'Disease', 'MESH:D011471', (122, 137))	('mutations', 'Var', (155, 164))	('increased prostate cancer', 'Disease', 'MESH:D011471', (112, 137))	('prostate cancer', 'Disease', (74, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('BRCA1', 'Gene', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('men', 'Species', '9606', (146, 149))	('increased prostate cancer', 'Disease', (112, 137))	('BRCA2', 'Gene', (178, 183))	('prostate cancer', 'Disease', 'MESH:D011471', (74, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('BRCA2', 'Gene', '675', (178, 183))
165730	29059045	Data suggest poor survival rates in BRCA2 mutation carriers relative to BRCA1 mutation carriers.	('BRCA1', 'Gene', '672', (72, 77))	('BRCA2', 'Gene', (36, 41))	('BRCA1', 'Gene', (72, 77))	('poor', 'NegReg', (13, 17))	('mutation', 'Var', (42, 50))	('BRCA2', 'Gene', '675', (36, 41))
165743	29059045	Additionally, single nucleotide polymorphisms (SNPs) associated with prostate cancer have been evaluated, although the sensitivity is still unclear.	('prostate cancer', 'Disease', 'MESH:D011471', (69, 84))	('single nucleotide polymorphisms', 'Var', (14, 45))	('prostate cancer', 'Phenotype', 'HP:0012125', (69, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('prostate cancer', 'Disease', (69, 84))
165750	29059045	Compared to using a 3 ng/mL PSA threshold for recommending a biopsy, the reported strategy effectively diagnosed all men with Gleason >=7 while decreasing the biopsy rate by 32% (improved area under the curve from 0.56 to 0.74).	('PSA', 'Gene', '354', (28, 31))	('PSA', 'Gene', (28, 31))	('men', 'Species', '9606', (51, 54))	('biopsy', 'MPA', (159, 165))	('men', 'Species', '9606', (117, 120))	('decreasing', 'NegReg', (144, 154))	('Gleason', 'Var', (126, 133))
165755	29059045	For clinically significant cancer, MP-MRI was more sensitive (93%; 95% CI, 88%-96%) than TRUS-guided biopsy (48%; 95% CI, 42%-55%; P<0.01) but had reduced specificity.	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('MP-MRI', 'Var', (35, 41))	('cancer', 'Disease', (27, 33))
165757	29059045	If MP-MRI is performed prior to the first prostate biopsy, it could reduce the number of biopsies by up to one-quarter, leading to decreased diagnosis of clinically insignificant prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('prostate cancer', 'Disease', 'MESH:D011471', (179, 194))	('prostate cancer', 'Phenotype', 'HP:0012125', (179, 194))	('decreased', 'NegReg', (131, 140))	('prostate cancer', 'Disease', (179, 194))	('MP-MRI', 'Var', (3, 9))
165763	29059045	Sporadic urothelial carcinoma has been known to be associated with smoking, as well as aryl amines and other chemical carcinogen exposures.	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('aryl', 'Var', (87, 91))	('Sporadic urothelial carcinoma', 'Disease', 'MESH:C538614', (0, 29))	('associated', 'Reg', (51, 61))	('aryl amines', 'Chemical', 'MESH:C023650', (87, 98))	('Sporadic urothelial carcinoma', 'Disease', (0, 29))
165766	29059045	The estimated risk of urothelial cancer in LS is 5%-20%, with risk increasing in males and MSH2 mutation carriers.	('urothelial cancer', 'Disease', (22, 39))	('MSH2', 'Gene', (91, 95))	('urothelial cancer', 'Disease', 'MESH:D014523', (22, 39))	('MSH2', 'Gene', '4436', (91, 95))	('mutation', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('increasing', 'PosReg', (67, 77))
165778	29059045	In our opinion, they should be studied in selected cohorts of high-risk Lynch syndrome patients like those that carry MSH2 mutations or with a family history of urinary tract cancers.	('Lynch syndrome', 'Disease', (72, 86))	('MSH2', 'Gene', '4436', (118, 122))	('Lynch syndrome', 'Disease', 'MESH:D003123', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (161, 181))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('urinary tract cancers', 'Disease', 'MESH:D014571', (161, 182))	('urinary tract cancers', 'Disease', (161, 182))	('patients', 'Species', '9606', (87, 95))	('mutations', 'Var', (123, 132))	('MSH2', 'Gene', (118, 122))
165779	29059045	During the early 1990s, reports have documented an association of endemic nephropathy as well as upper-tract transitional cell carcinoma (TCC) with aristolochic acid exposure.	('nephropathy', 'Phenotype', 'HP:0000112', (74, 85))	('carcinoma', 'Disease', (127, 136))	('TCC', 'cellular_component', 'GO:0005579', ('138', '141'))	('association', 'Interaction', (51, 62))	('aristolochic acid', 'Chemical', 'MESH:C000228', (148, 165))	('aristolochic acid', 'Var', (148, 165))	('nephropathy', 'Disease', 'MESH:D007674', (74, 85))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (109, 136))	('men', 'Species', '9606', (41, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinoma', 'Disease', 'MESH:D002277', (127, 136))	('TCC', 'Phenotype', 'HP:0006740', (138, 141))	('nephropathy', 'Disease', (74, 85))
165780	29059045	Additional reports have suggested that aristolochic acid may contaminate herbal medicine extracts, especially ones used as slimming pills, causing increased risk of upper-tract TCC.	('TCC', 'Phenotype', 'HP:0006740', (177, 180))	('upper-tract TCC', 'Disease', (165, 180))	('TCC', 'cellular_component', 'GO:0005579', ('177', '180'))	('herbal medicine', 'Species', '1407750', (73, 88))	('aristolochic acid', 'Var', (39, 56))	('aristolochic acid', 'Chemical', 'MESH:C000228', (39, 56))
165807	29059045	Better risk stratification together with incorporating genetic and epigenetic testing and state-of-the-art imaging will probably take a central role in upcoming years, and produce a personalized protocol of screening for prostate cancer.	('prostate cancer', 'Disease', (221, 236))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('prostate cancer', 'Disease', 'MESH:D011471', (221, 236))	('prostate cancer', 'Phenotype', 'HP:0012125', (221, 236))	('epigenetic testing', 'Var', (67, 85))
165813	29059045	BRCA gene breast cancer gene LS Lynch syndrome MMR mismatch repair MP-MRI multi-parametric magnetic resonance imaging PCA3 prostate cancer antigen 3 PHI prostate health index PPV positive predictive value PSA prostate-specific antigen SNP single nucleotide polymorphism TCC transitional cell carcinoma.	('prostate cancer', 'Phenotype', 'HP:0012125', (123, 138))	('BRCA', 'Gene', (0, 4))	('PSA', 'Gene', (205, 208))	('Lynch syndrome', 'Disease', 'MESH:D003123', (32, 46))	('single nucleotide polymorphism', 'Var', (239, 269))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('TCC', 'Phenotype', 'HP:0006740', (270, 273))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (274, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('mismatch repair', 'biological_process', 'GO:0006298', ('51', '66'))	('PCA3', 'Gene', '50652', (118, 122))	('carcinoma', 'Disease', (292, 301))	('breast cancer', 'Phenotype', 'HP:0003002', (10, 23))	('PSA', 'Gene', '354', (205, 208))	('PCA3', 'Gene', (118, 122))	('TCC', 'cellular_component', 'GO:0005579', ('270', '273'))	('MMR', 'biological_process', 'GO:0006298', ('47', '50'))	('BRCA', 'Gene', '672', (0, 4))	('TCC', 'Gene', (270, 273))	('breast cancer', 'Disease', 'MESH:D001943', (10, 23))	('prostate cancer antigen 3', 'Gene', '50652', (123, 148))	('prostate cancer antigen 3', 'Gene', (123, 148))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', (10, 23))	('Lynch syndrome', 'Disease', (32, 46))	('carcinoma', 'Disease', 'MESH:D002277', (292, 301))
165817	25314078	Progression is dramatically reduced by pharmacological activation of BMP pathway activity with low-dose FK506, suggesting an approach to management of human bladder cancer.	('reduced', 'NegReg', (28, 35))	('BMP', 'Gene', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (151, 156))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('bladder cancer', 'Disease', 'MESH:D001749', (157, 171))	('FK506', 'Chemical', 'MESH:D016559', (104, 109))	('activity', 'MPA', (81, 89))	('bladder cancer', 'Disease', (157, 171))	('BMP', 'Gene', '649', (69, 72))	('FK506', 'Var', (104, 109))	('activation', 'PosReg', (55, 65))
165821	25314078	Nitrosamines are potent carcinogens present in cigarette smoke, the most important risk factor in human bladder cancer, and BBN specifically induces advanced bladder cancer in many experimental animals.	('bladder cancer', 'Disease', (104, 118))	('bladder cancer', 'Phenotype', 'HP:0009725', (158, 172))	('Nitrosamines', 'Chemical', 'MESH:D009602', (0, 12))	('induces', 'Reg', (141, 148))	('BBN', 'Var', (124, 127))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (158, 172))	('bladder cancer', 'Disease', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('BBN', 'Chemical', 'MESH:D002085', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('human', 'Species', '9606', (98, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (104, 118))
165826	25314078	One possible explanation for this observation is that loss of Shh expression may somehow promote tumor progression.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Shh', 'Protein', (62, 65))	('promote', 'PosReg', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('loss', 'Var', (54, 58))
165827	25314078	This effect, however, would represent a novel protective role for Hh pathway activity, as mutational activation of the Hh pathway is causative in the primary cells of basal cell carcinoma and medulloblastoma, and ligand-dependent pathway activity in stroma has been thought to promote growth of pancreatic cancer.	('ligand', 'molecular_function', 'GO:0005488', ('213', '219'))	('Hh pathway', 'Pathway', (119, 129))	('medulloblastoma', 'Disease', 'MESH:D008527', (192, 207))	('promote', 'PosReg', (277, 284))	('mutational', 'Var', (90, 100))	('activation', 'PosReg', (101, 111))	('medulloblastoma', 'Phenotype', 'HP:0002885', (192, 207))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (295, 312))	('pancreatic cancer', 'Disease', 'MESH:D010190', (295, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('medulloblastoma', 'Disease', (192, 207))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (167, 187))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (167, 187))	('growth', 'MPA', (285, 291))	('basal cell carcinoma', 'Disease', (167, 187))	('pancreatic cancer', 'Disease', (295, 312))
165835	25314078	Given the consistent absence of SHH expression in invasive urothelial carcinoma, we tested the possibility that loss of Hh signaling may accelerate tumor growth and progression, using exposure of mice to BBN in drinking water as a model of bladder carcinogenesis with a defined course of progression to invasive carcinoma.	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('mice', 'Species', '10090', (196, 200))	('accelerate', 'PosReg', (137, 147))	('bladder carcinogenesis', 'Disease', 'MESH:D063646', (240, 262))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (50, 79))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('absence', 'NegReg', (21, 28))	('SHH', 'Gene', (32, 35))	('bladder carcinogenesis', 'Disease', (240, 262))	('BBN', 'Chemical', 'MESH:D002085', (204, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('progression', 'CPA', (165, 176))	('invasive urothelial carcinoma', 'Disease', (50, 79))	('tumor', 'Disease', (148, 153))	('invasive carcinoma', 'Disease', (303, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('water', 'Chemical', 'MESH:D014867', (220, 225))	('loss', 'Var', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('invasive carcinoma', 'Disease', 'MESH:D009361', (303, 321))
165839	25314078	Ablation of Smo in this manner will block Hh response in stromal cells undergoing Hh response under baseline conditions, prior to BBN exposure.	('Smo', 'Gene', (12, 15))	('Ablation', 'Var', (0, 8))	('BBN', 'Chemical', 'MESH:D002085', (130, 133))	('Hh response', 'CPA', (42, 53))	('block', 'NegReg', (36, 41))
165841	25314078	Furthermore, these mice survived a median of 140 days, as compared to 215 days for Smo heterozygous control animals (Figure 2B), indicating that wild-type Smo function confers a 53% survival benefit.	('function', 'Var', (159, 167))	('mice', 'Species', '10090', (19, 23))	('survival benefit', 'CPA', (182, 198))
165842	25314078	Genetic ablation of Hh response in bladder stroma thus significantly accelerates the progression of BBN-induced bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('bladder stroma', 'Disease', 'MESH:D001745', (35, 49))	('progression', 'CPA', (85, 96))	('bladder stroma', 'Disease', (35, 49))	('bladder cancer', 'Disease', 'MESH:D001749', (112, 126))	('bladder cancer', 'Disease', (112, 126))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))	('Genetic ablation', 'Var', (0, 16))	('BBN', 'Chemical', 'MESH:D002085', (100, 103))	('accelerates', 'PosReg', (69, 80))
165843	25314078	This result suggests a possible basis for the prevalence of invasive carcinomas lacking Shh expression: given that uniform loss of Hh response throughout the stroma accelerates cancer growth, it seems reasonable that loss of Shh expression from a clone of pre-malignant cells in a CIS lesion may confer a local growth advantage by reducing Hh pathway response in neighboring stroma, ultimately leading to preferential expansion of such clones of cells during progression to advanced invasive urothelial carcinomas.	('cancer', 'Disease', (177, 183))	('invasive urothelial carcinomas', 'Disease', (483, 513))	('pre', 'molecular_function', 'GO:0003904', ('256', '259'))	('loss', 'NegReg', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('growth', 'CPA', (311, 317))	('invasive carcinomas', 'Disease', 'MESH:D009361', (60, 79))	('Hh pathway', 'Pathway', (340, 350))	('CIS', 'Phenotype', 'HP:0030075', (281, 284))	('preferential expansion', 'PosReg', (405, 427))	('invasive carcinomas', 'Disease', (60, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (483, 513))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('accelerates', 'PosReg', (165, 176))	('reducing', 'NegReg', (331, 339))	('loss', 'Var', (217, 221))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('Shh', 'Gene', (225, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (503, 512))	('carcinomas', 'Phenotype', 'HP:0030731', (503, 513))
165851	25314078	Supporting this hypothesis, we found that Uroplakin gene expression, which is indicative of urothelial differentiation, is significantly decreased in Smo-ablated mouse bladders (Figure S2E).	('expression', 'MPA', (57, 67))	('Smo-ablated', 'Var', (150, 161))	('mouse', 'Species', '10090', (162, 167))	('Uroplakin gene', 'Gene', (42, 56))	('decreased', 'NegReg', (137, 146))	('gene expression', 'biological_process', 'GO:0010467', ('52', '67'))
165865	25314078	To pharmacologically activate the BMP pathway we selected FK506, a drug that has long been used in transplant patients for its immunopsuppressive effects.	('BMP', 'Gene', (34, 37))	('activate', 'PosReg', (21, 29))	('FK506', 'Var', (58, 63))	('BMP', 'Gene', '649', (34, 37))	('FK506', 'Chemical', 'MESH:D016559', (58, 63))	('patients', 'Species', '9606', (110, 118))
165866	25314078	FK506 binds FKBP12 and inhibits calcineurin, thus preventing activation of NFAT and transcription of cytokines essential for immune response.	('activation', 'MPA', (61, 71))	('FKBP12', 'Gene', '2285', (12, 18))	('calcineurin', 'MPA', (32, 43))	('calcineurin', 'molecular_function', 'GO:0004723', ('32', '43'))	('FK506', 'Var', (0, 5))	('FK506', 'Chemical', 'MESH:D016559', (0, 5))	('immune response', 'biological_process', 'GO:0006955', ('125', '140'))	('NFAT', 'MPA', (75, 79))	('FKBP', 'molecular_function', 'GO:0030051', ('12', '16'))	('preventing', 'NegReg', (50, 60))	('FKBP12', 'Gene', (12, 18))	('transcription', 'biological_process', 'GO:0006351', ('84', '97'))	('transcription of cytokines', 'MPA', (84, 110))	('inhibits', 'NegReg', (23, 31))	('binds', 'Interaction', (6, 11))	('calcineurin', 'molecular_function', 'GO:0004722', ('32', '43'))
165867	25314078	Of particular interest here, we recently showed that FK506 also causes dissociation of FKBP12 from Type 1 BMP receptors, thus activating the BMP pathway; this occurs at concentrations below those required for immunosuppression, and FK506 at these lower doses has proven to be effective upon systemic administration in animal models of pulmonary arterial hypertension, which is causally associated with a deficiency of BMP pathway activity.	('pulmonary arterial hypertension', 'Disease', (335, 366))	('BMP', 'Gene', (141, 144))	('FKBP12', 'Gene', '2285', (87, 93))	('BMP', 'Gene', (418, 421))	('hypertension', 'Phenotype', 'HP:0000822', (354, 366))	('FK506', 'Var', (53, 58))	('activating', 'PosReg', (126, 136))	('FK506', 'Chemical', 'MESH:D016559', (232, 237))	('FKBP', 'molecular_function', 'GO:0030051', ('87', '91'))	('BMP', 'Gene', '649', (106, 109))	('pulmonary arterial hypertension', 'Phenotype', 'HP:0002092', (335, 366))	('FKBP12', 'Gene', (87, 93))	('BMP', 'Gene', '649', (141, 144))	('FK506', 'Var', (232, 237))	('BMP', 'Gene', (106, 109))	('FK506', 'Chemical', 'MESH:D016559', (53, 58))	('pulmonary arterial hypertension', 'Disease', 'MESH:D000081029', (335, 366))	('dissociation', 'MPA', (71, 83))	('BMP', 'Gene', '649', (418, 421))
165868	25314078	The treatment of cultured primary urothelial cells with FK506 induced expression of the BMP target gene ID1; this activation was blocked by combined treatment with FK506 and the potent and specific BMP inhibitor LDN-193189 (Figure 4C), thereby confirming in our system that FK506 acts via BMP pathway activation.	('BMP', 'Gene', '649', (88, 91))	('ID1', 'Gene', (104, 107))	('BMP', 'Gene', '649', (198, 201))	('LDN-193189', 'Chemical', 'MESH:C554430', (212, 222))	('BMP', 'Gene', (289, 292))	('FK506', 'Chemical', 'MESH:D016559', (274, 279))	('FK506', 'Chemical', 'MESH:D016559', (56, 61))	('FK506', 'Chemical', 'MESH:D016559', (164, 169))	('expression', 'MPA', (70, 80))	('BMP', 'Gene', (88, 91))	('BMP', 'Gene', (198, 201))	('FK506', 'Var', (56, 61))	('ID1', 'Gene', '3397', (104, 107))	('BMP', 'Gene', '649', (289, 292))
165869	25314078	Treatment of cultured urothelial cells with FK506 also induced expression of the uroplakin genes UPK1B, UPK2 and UPK3A, indicative of urothelial cell differentiation and consistent with the previously reported role of BMP pathway activity in promoting urothelial differentiation in vivo; again, this differentiation-inducing effect of FK506 treatment was blocked by combined treatment with LDN-193189 (Figures 4D and S3B).	('UPK3A', 'Gene', '7380', (113, 118))	('UPK3A', 'Gene', (113, 118))	('UPK2', 'Gene', '7379', (104, 108))	('FK506', 'Var', (44, 49))	('FK506', 'Chemical', 'MESH:D016559', (44, 49))	('BMP', 'Gene', '649', (218, 221))	('expression', 'MPA', (63, 73))	('urothelial differentiation', 'CPA', (252, 278))	('FK506', 'Chemical', 'MESH:D016559', (335, 340))	('LDN-193189', 'Chemical', 'MESH:C554430', (390, 400))	('UPK1B', 'Gene', '7348', (97, 102))	('cell differentiation', 'biological_process', 'GO:0030154', ('145', '165'))	('UPK2', 'Gene', (104, 108))	('BMP', 'Gene', (218, 221))	('UPK1B', 'Gene', (97, 102))
165877	25314078	For the cohort of 10 mice treated with FK506 during the final month, however, no invasive carcinoma was observed (Figures 5B, 5C and S4D), suggesting that activation of Bmp pathway activity may impede progression if treatment occurs prior to formation of invasive carcinoma.	('Bmp', 'Gene', (169, 172))	('FK506', 'Chemical', 'MESH:D016559', (39, 44))	('invasive carcinoma', 'Disease', (255, 273))	('mice', 'Species', '10090', (21, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('impede', 'NegReg', (194, 200))	('FK506', 'Var', (39, 44))	('progression', 'MPA', (201, 212))	('Bmp', 'Gene', '649', (169, 172))	('formation', 'biological_process', 'GO:0009058', ('242', '251'))	('invasive carcinoma', 'Disease', 'MESH:D009361', (81, 99))	('invasive carcinoma', 'Disease', 'MESH:D009361', (255, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('invasive carcinoma', 'Disease', (81, 99))	('activation', 'PosReg', (155, 165))	('activity', 'MPA', (181, 189))
165899	25314078	Interestingly, the TCGA study revealed that mutations of genes involved in epigenetic regulation were highly enriched in invasive urothelial carcinomas; these findings suggest the possibility that increased epigenetic plasticity may facilitate the loss of SHH expression during urothelial carcinoma progression.	('expression', 'MPA', (260, 270))	('SHH', 'Protein', (256, 259))	('facilitate', 'PosReg', (233, 243))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (130, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('epigenetic plasticity', 'Var', (207, 228))	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (121, 151))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (278, 298))	('mutations', 'Var', (44, 53))	('invasive urothelial carcinomas', 'Disease', (121, 151))	('loss', 'NegReg', (248, 252))	('urothelial carcinoma', 'Disease', (278, 298))
165911	25314078	One possible explanation for the heightened emphasis on differentiation factors is that cells of nascent epithelial cancers may first acquire reduced dependence on extracellular proliferative signals through genetic or epigenetic changes that generate cell-autonomous proliferative drive, while still leaving cells sensitive to the effects of stromal differentiation-inducing factors.	('extracellular', 'cellular_component', 'GO:0005576', ('164', '177'))	('reduced', 'NegReg', (142, 149))	('epithelial cancers', 'Disease', (105, 123))	('epigenetic changes', 'Var', (219, 237))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('dependence on extracellular proliferative signals', 'MPA', (150, 199))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('epithelial cancers', 'Disease', 'MESH:D000077216', (105, 123))	('genetic', 'Var', (208, 215))
165916	25314078	Second, because FK506 treatment produces therapeutic BMP pathway activation at doses that cause minimal immunosuppression, such low-dose FK506 treatment may have utility in treatment of cancers arising from organs in which BMP pathway activity induces cellular differentiation.	('FK506', 'Chemical', 'MESH:D016559', (16, 21))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('BMP', 'Gene', (223, 226))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('FK506', 'Var', (137, 142))	('BMP', 'Gene', '649', (53, 56))	('induces', 'Reg', (244, 251))	('FK506', 'Chemical', 'MESH:D016559', (137, 142))	('BMP', 'Gene', (53, 56))	('cellular differentiation', 'CPA', (252, 276))	('activation', 'PosReg', (65, 75))	('BMP', 'Gene', '649', (223, 226))
165918	25314078	The ability to halt or slow progression by treatment with agents such as FK506 thus could have a significant beneficial impact on the clinical management of bladder cancer.	('FK506', 'Chemical', 'MESH:D016559', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('slow', 'NegReg', (23, 27))	('bladder cancer', 'Disease', 'MESH:D001749', (157, 171))	('FK506', 'Var', (73, 78))	('bladder cancer', 'Disease', (157, 171))
165959	25314078	Aberrant Hedgehog (Hh) pathway activation has been associated with a wide range of cancers, yet clinical trials involving the treatment of solid tumors with Hh pathway inhibitors have yielded disappointing results.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('Aberrant', 'Var', (0, 8))	('solid tumors', 'Disease', 'MESH:D009369', (139, 151))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('associated', 'Reg', (51, 61))	('solid tumors', 'Disease', (139, 151))	('activation', 'PosReg', (31, 41))	('cancers', 'Disease', (83, 90))
165960	25314078	Our findings that loss of human urothelial SHH expression accompanies progression to invasive urothelial carcinoma, and that ablation of Shh response in stromal cells can accelerate progression in mice shows both that stromal signaling has a beneficial role in restraining progression of urothelial carcinoma and that pharmacological blockade of Hh signaling is contra-indicated in this disease.	('carcinoma', 'Phenotype', 'HP:0030731', (299, 308))	('ablation', 'Var', (125, 133))	('signaling', 'biological_process', 'GO:0023052', ('226', '235'))	('invasive urothelial carcinoma', 'Disease', (85, 114))	('loss', 'Var', (18, 22))	('urothelial carcinoma', 'Disease', (288, 308))	('beneficial', 'PosReg', (242, 252))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (94, 114))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (85, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('signaling', 'biological_process', 'GO:0023052', ('349', '358'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (288, 308))	('mice', 'Species', '10090', (197, 201))	('human', 'Species', '9606', (26, 31))
165961	25314078	A favorable effect of BMP pathway activation with low-dose FK506 suggests a clinical approach to control of progression in the 70-80% of patients that present with non-invasive urothelial carcinoma at initial diagnosis.	('BMP', 'Gene', '649', (22, 25))	('low-dose FK506', 'Var', (50, 64))	('invasive urothelial carcinoma', 'Disease', (168, 197))	('FK506', 'Var', (59, 64))	('patients', 'Species', '9606', (137, 145))	('FK506', 'Chemical', 'MESH:D016559', (59, 64))	('BMP', 'Gene', (22, 25))	('activation', 'PosReg', (34, 44))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (168, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))
165962	25314078	SHH expression is absent in human invasive urothelial carcinoma Genetic ablation of stromal Hh response accelerates bladder cancer progression Epithelial Hh elicits stromal expression of differentiation factors BMP4 and BMP5 Pharmacological activation of the BMP pathway impedes tumor progression	('BMP', 'Gene', '649', (211, 214))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('BMP', 'Gene', '649', (259, 262))	('accelerates', 'PosReg', (104, 115))	('BMP', 'Gene', (220, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('impedes', 'NegReg', (271, 278))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (34, 63))	('BMP', 'Gene', (211, 214))	('BMP', 'Gene', (259, 262))	('tumor', 'Disease', (279, 284))	('bladder cancer', 'Disease', 'MESH:D001749', (116, 130))	('bladder cancer', 'Disease', (116, 130))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('invasive urothelial carcinoma', 'Disease', (34, 63))	('ablation', 'Var', (72, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (116, 130))	('human', 'Species', '9606', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BMP', 'Gene', '649', (220, 223))
166044	33027843	7 ,  24  Several reports have shown that cfDNA with cancer-specific mutations (ctDNA) are shorter than cfDNA without the mutation.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (68, 77))	('cfDNA', 'Disease', (41, 46))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
166108	29789781	The mean Cys-C level of patients with plasma fibrinogen levels (PFL) < 2.9 g/L was significantly lower than that of patients with PFL >= 2.9 g/L (P = 0.030).	('fibrinogen', 'Gene', (45, 55))	('fibrinogen', 'cellular_component', 'GO:0005577', ('45', '55'))	('Cys-C', 'Gene', '1471', (9, 14))	('fibrinogen', 'molecular_function', 'GO:0008001', ('45', '55'))	('patients', 'Species', '9606', (116, 124))	('PFL', 'molecular_function', 'GO:0008861', ('130', '133'))	('Cys-C', 'Gene', (9, 14))	('PFL', 'molecular_function', 'GO:0008861', ('64', '67'))	('lower', 'NegReg', (97, 102))	('patients', 'Species', '9606', (24, 32))	('< 2.9', 'Var', (69, 74))	('fibrinogen', 'Gene', '2244', (45, 55))
166150	29354497	Urothelial cancer is a polyclonal disease with a substantial tumor heterogeneity and a high mutational load which may be beneficial as this may trigger a stronger T-cell mediated immune response.	('Urothelial cancer', 'Disease', (0, 17))	('polyclonal disease', 'Disease', (23, 41))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('stronger', 'PosReg', (154, 162))	('T-cell mediated immune response', 'CPA', (163, 194))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mutational load', 'Var', (92, 107))	('cell mediated immune response', 'biological_process', 'GO:0002443', ('165', '194'))	('trigger', 'Reg', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Urothelial cancer', 'Disease', 'MESH:D014523', (0, 17))	('tumor', 'Disease', (61, 66))	('polyclonal disease', 'Disease', 'MESH:C564707', (23, 41))
166157	29354497	The focus of contemporary immunotherapy is the T cell activity which may be modulated by the tumor's immunogenic properties ("foreignness"), general immune status, IC infiltration, absence of checkpoints, absence of soluble inhibitors, absence of inhibitory tumor metabolism and tumor's sensitivity to immune effectors.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('modulated', 'Reg', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('absence', 'Var', (205, 212))	('metabolism', 'biological_process', 'GO:0008152', ('262', '272'))	('tumor', 'Disease', (258, 263))	('tumor', 'Disease', (279, 284))	('tumor', 'Disease', (93, 98))	('soluble inhibitors', 'Protein', (216, 234))	('soluble', 'cellular_component', 'GO:0005625', ('214', '221'))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
166166	29354497	Tumors with a high mutational load can benefit from immunotherapy as they may induce a greater T-cell mediated immune response.	('induce', 'Reg', (78, 84))	('greater', 'PosReg', (87, 94))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('cell mediated immune response', 'biological_process', 'GO:0002443', ('97', '126'))	('high mutational load', 'Var', (14, 34))	('T-cell mediated immune response', 'CPA', (95, 126))
166167	29354497	When arranging tumors in a hierarchical list from highest to lowest mutational load urothelial cancer is fourth on the list suggesting that it is an excellent candidate for Immunotherapy.	('urothelial cancer', 'Disease', 'MESH:D014523', (84, 101))	('lowest', 'NegReg', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('arranging tumors', 'Disease', (5, 21))	('mutational', 'Var', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('arranging tumors', 'Disease', 'MESH:D009369', (5, 21))	('urothelial cancer', 'Disease', (84, 101))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
166169	29354497	In a meta-analysis, the overall response rate to PDL-1 positive tumors was significantly higher than in PDL-1 negative tumors but this difference was not significant for Genitourinary Cancers.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('PDL-1', 'Gene', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('PDL-1', 'Gene', (49, 54))	('tumors', 'Disease', (64, 70))	('response', 'MPA', (32, 40))	('tumors', 'Disease', (119, 125))	('positive', 'Var', (55, 63))	('Genitourinary Cancers', 'Disease', (170, 191))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('PDL-1', 'Gene', '29126', (49, 54))	('PDL-1', 'Gene', '29126', (104, 109))	('higher', 'PosReg', (89, 95))	('Genitourinary Cancers', 'Disease', 'MESH:D014565', (170, 191))	('Cancers', 'Phenotype', 'HP:0002664', (184, 191))
166186	29354497	The Immunoscore is a numeration of CD8 and CD45R0 cells at the center of the tumor and the invasive margin and has been proposed as an adjunct to the AJCC/UICC TNM classification.	('TNM', 'Gene', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('CD8', 'Gene', (35, 38))	('TNM', 'Gene', '10178', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CD8', 'Gene', '925', (35, 38))	('CD45R0', 'Var', (43, 49))	('tumor', 'Disease', (77, 82))
166188	29354497	In a correlative analysis with survival, it was found that patients with a high Immunoscore had improved overall survival with or without adjuvant whole brain radiation therapy.	('high', 'Var', (75, 79))	('improved', 'PosReg', (96, 104))	('patients', 'Species', '9606', (59, 67))	('overall survival', 'MPA', (105, 121))
166189	29354497	Mutational changes within a tumor can result in very different effects in terms of response to Immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('Mutational changes', 'Var', (0, 18))
166207	29354497	In summary, there is currently no evidence supporting the PD-L1 use as a biomarker for selecting patients for ICI therapy in chemotherapy-naive patients, and definitive conclusions will be likely drawn with the results of the ongoing, randomized, phase 3 studies that are currently open in the first-line setting (NCT02853305, NCT02807636, NCT02516241, NCT03036098).	('PD-L1', 'Gene', '29126', (58, 63))	('NCT02807636', 'Var', (327, 338))	('NCT02516241', 'Var', (340, 351))	('patients', 'Species', '9606', (144, 152))	('NCT02853305', 'Var', (314, 325))	('PD-L1', 'Gene', (58, 63))	('NCT03036098', 'Var', (353, 364))	('patients', 'Species', '9606', (97, 105))
166216	29354497	Luminal-I tumors displayed low Teff expression, and may be regarded to as being characterized by an "immune desert" in their microenvironment, according to Rosenberg et al.. Interestingly, this subtype is also enriched of alterations of the fibroblast growth-factor receptors (FGFR) genes, and therefore combination of ICI and pan-FGFR inhibitors might be particularly beneficial for their patients.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('FGFR', 'Gene', (277, 281))	('patients', 'Species', '9606', (390, 398))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('alterations', 'Var', (222, 233))
166219	29354497	Based on the results available to date, PD-L1 expression was associated with improved OS in both arms: in the atezolizumab arm, median OS was 8.6 months in ITT population vs. 11.1 months in IC2/3+ patients.	('expression', 'Var', (46, 56))	('patients', 'Species', '9606', (197, 205))	('PD-L1', 'Gene', (40, 45))	('atezolizumab', 'Chemical', 'MESH:C000594389', (110, 122))	('IC2/3', 'Gene', (190, 195))	('PD-L1', 'Gene', '29126', (40, 45))	('IC2/3', 'Gene', '1781', (190, 195))	('improved', 'PosReg', (77, 85))
166223	29354497	For both durvalumab and avelumab, despite signals of improved responses were reported in PD-L1 positive patients (using Ventana SP263 antibody and Dako 73-10 antibody, respectively, and both evaluating tumor cells and ICs), conditional approval was granted for all comers regardless of PD-L1 expression.	('antibody', 'cellular_component', 'GO:0019815', ('134', '142'))	('antibody', 'cellular_component', 'GO:0019814', ('158', '166'))	('PD-L1', 'Gene', (89, 94))	('PD-L1', 'Gene', '29126', (89, 94))	('PD-L1', 'Gene', (286, 291))	('positive', 'Var', (95, 103))	('antibody', 'cellular_component', 'GO:0019814', ('134', '142'))	('PD-L1', 'Gene', '29126', (286, 291))	('tumor', 'Disease', (202, 207))	('antibody', 'molecular_function', 'GO:0003823', ('158', '166'))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('antibody', 'cellular_component', 'GO:0042571', ('158', '166'))	('durvalumab', 'Chemical', 'MESH:C000613593', (9, 19))	('antibody', 'molecular_function', 'GO:0003823', ('134', '142'))	('avelumab', 'Chemical', 'MESH:C000609138', (24, 32))	('antibody', 'cellular_component', 'GO:0042571', ('134', '142'))	('improved', 'PosReg', (53, 61))	('patients', 'Species', '9606', (104, 112))	('antibody', 'cellular_component', 'GO:0019815', ('158', '166'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('responses', 'MPA', (62, 71))
166257	28690523	The results of the NGS analysis showed the presence of 107 variants including 4 actionable mutations (FANCA S1088F, HIF1A P582S, CSMD3 E1883*, and RB1 S576*).	('P582S', 'Var', (122, 127))	('HIF1A', 'Gene', (116, 121))	('HIF1A', 'Gene', '3091', (116, 121))	('RB1', 'Gene', '5925', (147, 150))	('S576*', 'SUBSTITUTION', 'None', (151, 156))	('P582S', 'Mutation', 'rs11549465', (122, 127))	('FANCA', 'Gene', '2175', (102, 107))	('E1883*', 'Var', (135, 141))	('S1088F', 'Mutation', 'rs17233497', (108, 114))	('CSMD3', 'Gene', (129, 134))	('E1883*', 'SUBSTITUTION', 'None', (135, 141))	('CSMD3', 'Gene', '114788', (129, 134))	('S576*', 'Var', (151, 156))	('FANCA', 'Gene', (102, 107))	('RB1', 'Gene', (147, 150))
166275	28690523	Mutations detected in the molecular analysis of the tumor were relevant for showing the presence of the likely driver of malignancy involving the RB1 gene.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('malignancy', 'Disease', 'MESH:D009369', (121, 131))	('tumor', 'Disease', (52, 57))	('RB1', 'Gene', (146, 149))	('malignancy', 'Disease', (121, 131))	('Mutations', 'Var', (0, 9))	('RB1', 'Gene', '5925', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
166276	28690523	The variant detected (p.S576*) induces a premature stop codon within the pocket domain of the protein required for its binding to the threonine-phosphorylated domain C, thereby not preventing its interaction with heterodimeric E2F/DP transcription factor complexes required for its tumor suppressor activity.	('transcription', 'biological_process', 'GO:0006351', ('234', '247'))	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('interaction', 'Interaction', (196, 207))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('p.S576*', 'Var', (22, 29))	('p.S576*', 'Mutation', 'p.S576*', (22, 29))	('induces', 'Reg', (31, 38))	('tumor', 'Disease', (282, 287))	('tumor suppressor', 'biological_process', 'GO:0051726', ('282', '298'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('282', '298'))	('transcription factor', 'molecular_function', 'GO:0000981', ('234', '254'))	('premature stop codon', 'MPA', (41, 61))	('threonine', 'Chemical', 'MESH:D013912', (134, 143))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
166277	28690523	RB1, a tumor suppressor gene, is a negative regulator of the cell cycle, and its alterations are related to carcinogenesis in several cancers.	('cell cycle', 'biological_process', 'GO:0007049', ('61', '71'))	('related', 'Reg', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('RB1', 'Gene', '5925', (0, 3))	('tumor', 'Disease', (7, 12))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('tumor suppressor', 'biological_process', 'GO:0051726', ('7', '23'))	('cancers', 'Disease', (134, 141))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('7', '23'))	('alterations', 'Var', (81, 92))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('RB1', 'Gene', (0, 3))	('carcinogenesis', 'Disease', (108, 122))
166278	28690523	For muscle-invasive BC, the expression loss of RB1 has been described to be an adverse prognosis biomarker.	('RB1', 'Gene', '5925', (47, 50))	('BC', 'Phenotype', 'HP:0009725', (20, 22))	('expression loss', 'Var', (28, 43))	('RB1', 'Gene', (47, 50))	('muscle-invasive BC', 'Disease', (4, 22))
166279	28690523	In addition, those BCs presenting a mutation of the RB1 gene combined with low FGFR3 levels have been associated with a significantly poor disease-specific survival.	('FGFR3', 'Gene', '2261', (79, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('RB1', 'Gene', (52, 55))	('FGFR3', 'Gene', (79, 84))	('BC', 'Phenotype', 'HP:0009725', (19, 21))	('RB1', 'Gene', '5925', (52, 55))	('poor', 'NegReg', (134, 138))	('disease-specific survival', 'CPA', (139, 164))	('mutation', 'Var', (36, 44))
166433	32047816	To identify potential biomarkers for BLCA, we performed a series of analyses based on high-throughput sequencing data obtained from three data sets, GSE7476, GSE13507, and TCGA BLCA.	('BLCA', 'Disease', 'MESH:D001749', (37, 41))	('BLCA', 'Phenotype', 'HP:0009725', (37, 41))	('BLCA', 'Phenotype', 'HP:0009725', (177, 181))	('BLCA', 'Disease', (177, 181))	('GSE7476', 'Var', (149, 156))	('BLCA', 'Disease', (37, 41))	('GSE13507', 'Var', (158, 166))	('BLCA', 'Disease', 'MESH:D001749', (177, 181))
166454	32047816	Then, the hub genes were identified by four methods: DEGREE, MCC, DMNC, and MNC in cytoHubba.	('MNC', 'Var', (76, 79))	('MCC', 'biological_process', 'GO:0120197', ('61', '64'))	('hub', 'Gene', '1993', (10, 13))	('MCC', 'cellular_component', 'GO:0033597', ('61', '64'))	('hub', 'Gene', (10, 13))
166479	32047816	Then, we identified 14 hub genes based on the DEGREE (Figure 3(b)), MCC (Figure 3(c)), DMNC (Figure 3(d)), and MNC (Figure 3(e)) plugins for the Cytoscape software.	('hub', 'Gene', '1993', (23, 26))	('MCC', 'biological_process', 'GO:0120197', ('68', '71'))	('DMNC', 'Var', (87, 91))	('hub', 'Gene', (23, 26))	('MCC', 'Gene', (68, 71))	('MNC', 'Gene', (111, 114))	('MCC', 'cellular_component', 'GO:0033597', ('68', '71'))
166515	32047816	In this study, we found 291 integrated DEGs in BLCA by a comprehensive analysis of GEO (GSE7476, GSE13507) and TCGA BLCA datasets.	('BLCA', 'Disease', 'MESH:D001749', (116, 120))	('DEGs', 'Gene', '8560', (39, 43))	('BLCA', 'Phenotype', 'HP:0009725', (47, 51))	('GSE13507', 'Var', (97, 105))	('BLCA', 'Disease', (47, 51))	('BLCA', 'Phenotype', 'HP:0009725', (116, 120))	('BLCA', 'Disease', (116, 120))	('GSE7476', 'Var', (88, 95))	('DEGs', 'Gene', (39, 43))	('BLCA', 'Disease', 'MESH:D001749', (47, 51))
166553	32047816	Manipulation of TOX expression is thought to calibrate T cells to maintain their effector function in cell differentiation and ultimately achieve long-lasting therapeutic outcomes.	('TOX', 'Gene', '9760', (16, 19))	('cell differentiation', 'biological_process', 'GO:0030154', ('102', '122'))	('TOX', 'Gene', (16, 19))	('Manipulation', 'Var', (0, 12))	('effector', 'MPA', (81, 89))	('cell differentiation', 'CPA', (102, 122))
166628	30975211	To date, the FDA has approved more than 20 small-molecule inhibitors for clinical use in the treatment of cancer.	('small-molecule', 'Var', (43, 57))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
166633	30975211	These utilize several different mechanisms, some of which include: targeting the immune system, e.g., alemtuzumab (Campath , Sanofi, France), which binds CD52 inducing an immune response; targeting antigens on cancer cells that are involved in cell growth and proliferation, e.g., trastuzumab (Herceptin , Genentech, USA) for HER2; and immune check-point inhibitors, e.g., ipilimumab (Yervoy , Bristol-Myers Squibb, USA) for cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4).	('ipilimumab', 'Chemical', 'MESH:D000074324', (373, 383))	('targeting', 'Var', (67, 76))	('trastuzumab', 'Chemical', 'MESH:D000068878', (281, 292))	('CD52', 'Gene', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('inducing', 'Reg', (159, 167))	('HER2', 'Gene', (326, 330))	('rat', 'Species', '10116', (267, 270))	('immune response', 'MPA', (171, 186))	('HER2', 'Gene', '2064', (326, 330))	('CD52', 'Gene', '1043', (154, 158))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cell growth', 'biological_process', 'GO:0016049', ('244', '255'))	('cancer', 'Disease', (210, 216))	('immune response', 'biological_process', 'GO:0006955', ('171', '186'))
166648	30975211	The EGFR family has been implicated in the development and progression of many cancers, notably NSCLCs, glioblastomas, colorectal cancers (CRCs), breast cancers, and ovarian tumors, through specific driver mutations.	('cancers', 'Disease', (153, 160))	('ovarian tumors', 'Phenotype', 'HP:0100615', (166, 180))	('colorectal cancers', 'Disease', (119, 137))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('glioblastomas', 'Disease', 'MESH:D005909', (104, 117))	('NSCLCs', 'Disease', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('breast cancers', 'Disease', 'MESH:D001943', (146, 160))	('implicated', 'Reg', (25, 35))	('breast cancers', 'Disease', (146, 160))	('ovarian tumors', 'Disease', (166, 180))	('cancers', 'Disease', (79, 86))	('mutations', 'Var', (206, 215))	('colorectal cancers', 'Disease', 'MESH:D015179', (119, 137))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ovarian tumors', 'Disease', 'MESH:D010051', (166, 180))	('NSCLCs', 'Disease', 'MESH:D002289', (96, 102))	('breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('glioblastomas', 'Phenotype', 'HP:0012174', (104, 117))	('EGFR family', 'Gene', (4, 15))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('4', '8'))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('glioblastomas', 'Disease', (104, 117))
166649	30975211	Notably, kinase domain hotspot mutations, which are often found in NSCLC patients of Eastern Asian origin, frequently have the L858R point mutation.	('kinase', 'Gene', (9, 15))	('L858R', 'Var', (127, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('L858R', 'Mutation', 'rs121434568', (127, 132))	('NSCLC', 'Disease', (67, 72))	('patients', 'Species', '9606', (73, 81))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
166651	30975211	Consequently, these mutations tend to confer inappropriate activation of the downstream, anti-apoptotic Ras signaling cascade, leading to uncontrolled cell proliferation.	('rat', 'Species', '10116', (163, 166))	('signaling cascade', 'biological_process', 'GO:0007165', ('108', '125'))	('cell proliferation', 'biological_process', 'GO:0008283', ('151', '169'))	('uncontrolled cell proliferation', 'CPA', (138, 169))	('leading to', 'Reg', (127, 137))	('activation', 'PosReg', (59, 69))	('mutations', 'Var', (20, 29))
166657	30975211	Positive results from pre-clinical studies prompted extensive clinical studies in NSCLC patients, which have demonstrated anti-cancer activity against EGFR mutated cancers.	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('EGFR', 'Gene', (151, 155))	('patients', 'Species', '9606', (88, 96))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('pre', 'molecular_function', 'GO:0003904', ('22', '25'))	('mutated', 'Var', (156, 163))	('cancer', 'Disease', (164, 170))	('cancers', 'Disease', (164, 171))	('rat', 'Species', '10116', (116, 119))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
166659	30975211	Since its initial introduction into the Japanese market in 2002, gefitinib has since been FDA approved as a first-line treatment for metastatic, EGFR-mutated (exon 19 deletions or exon 21 L858R substitutions) NSCLC.	('exon 19 deletions', 'Var', (159, 176))	('NSCLC', 'Disease', 'MESH:D002289', (209, 214))	('gefitinib', 'Chemical', 'MESH:D000077156', (65, 74))	('L858R', 'Mutation', 'rs121434568', (188, 193))	('NSCLC', 'Phenotype', 'HP:0030358', (209, 214))	('EGFR', 'molecular_function', 'GO:0005006', ('145', '149'))	('L858R substitutions', 'Var', (188, 207))	('NSCLC', 'Disease', (209, 214))
166660	30975211	This was based on data from the 'IPASS' clinical trials and the follow-up 'IFUM' studies, in which gefitinib improved median overall survival (OS; 18.6 vs. 17.3 months), median progression-free survival (PFS; 24.9 vs. 6.7%; p < 0.001) and objective response rates (ORR; 43.0 vs. 32.2%; p < 0.001), when compared with standard treatment of carboplatin and paclitaxel (Table 1).	('carboplatin', 'Chemical', 'MESH:D016190', (339, 350))	('paclitaxel', 'Chemical', 'MESH:D017239', (355, 365))	('PF', 'Chemical', 'MESH:C002997', (204, 206))	('overall', 'MPA', (125, 132))	('gefitinib', 'Var', (99, 108))	('OS', 'Chemical', '-', (143, 145))	('improved', 'PosReg', (109, 117))	('progression-free survival', 'CPA', (177, 202))	('rat', 'Species', '10116', (258, 261))	('gefitinib', 'Chemical', 'MESH:D000077156', (99, 108))	('objective response rates', 'CPA', (239, 263))
166665	30975211	These clinical trials have revealed that, in addition to the common side effects of diarrhea and skin reactions, gefitinib can cause more serious adverse effects, including interstitial lung disease, liver damage, gastrointestinal perforation, severe diarrhea and ocular disorders.	('diarrhea', 'Disease', (251, 259))	('lung disease', 'Phenotype', 'HP:0002088', (186, 198))	('ocular disorders', 'Phenotype', 'HP:0000478', (264, 280))	('gefitinib', 'Var', (113, 122))	('liver damage', 'Disease', (200, 212))	('diarrhea', 'Disease', (84, 92))	('gastrointestinal perforation', 'Disease', (214, 242))	('rat', 'Species', '10116', (236, 239))	('diarrhea', 'Disease', 'MESH:D003967', (251, 259))	('diarrhea', 'Disease', 'MESH:D003967', (84, 92))	('liver damage', 'Disease', 'MESH:D056486', (200, 212))	('interstitial lung disease', 'Phenotype', 'HP:0006530', (173, 198))	('interstitial lung disease', 'Disease', 'MESH:D017563', (173, 198))	('ocular disorders', 'Disease', 'MESH:D005128', (264, 280))	('severe diarrhea', 'Phenotype', 'HP:0002028', (244, 259))	('interstitial lung disease', 'Disease', (173, 198))	('skin reactions', 'Phenotype', 'HP:0011123', (97, 111))	('diarrhea', 'Phenotype', 'HP:0002014', (251, 259))	('ocular disorders', 'Disease', (264, 280))	('diarrhea', 'Phenotype', 'HP:0002014', (84, 92))	('gefitinib', 'Chemical', 'MESH:D000077156', (113, 122))
166670	30975211	The 'SATURN' trial showed that erlotinib significantly extended median OS (12.4 vs. 11.0 months; p < 0.01) and PFS (12.3 vs. 11.1 weeks; p < 0.0001) in a broad patient population, including squamous and non-squamous histology, compared with the placebo (Table 1).	('PF', 'Chemical', 'MESH:C002997', (111, 113))	('erlotinib', 'Var', (31, 40))	('OS', 'Chemical', '-', (71, 73))	('PFS', 'MPA', (111, 114))	('extended', 'PosReg', (55, 63))	('patient', 'Species', '9606', (160, 167))	('erlotinib', 'Chemical', 'MESH:D000069347', (31, 40))
166672	30975211	This led to modification of the indication for erlotinib, limiting treatment to metastatic NSCLC that have specific EGFR mutants, and as a maintenance therapy if there is no progression after platinum based first-line treatment.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('mutants', 'Var', (121, 128))	('erlotinib', 'Chemical', 'MESH:D000069347', (47, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('116', '120'))	('platinum', 'Chemical', 'MESH:D010984', (192, 200))	('NSCLC', 'Disease', (91, 96))	('EGFR', 'Gene', (116, 120))
166681	30975211	However, the success of the first generation TKIs has been limited by acquired resistance, developing at around 12-16 months, mediated mostly by a T790 M missense mutation on exon 20 of EGFR.	('EGFR', 'molecular_function', 'GO:0005006', ('186', '190'))	('T790 M', 'Mutation', 'rs121434569', (147, 153))	('EGFR', 'Gene', (186, 190))	('T790 M missense', 'Var', (147, 162))	('rat', 'Species', '10116', (38, 41))
166689	30975211	These treatment benefits were greatest in EGFR-mutant patients.	('patients', 'Species', '9606', (54, 62))	('EGFR-mutant', 'Gene', (42, 53))	('EGFR-mutant', 'Var', (42, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))
166690	30975211	The FDA has approved afatinib as a first-line treatment for metastatic NSCLC EGFR-mutant cancers, as well as for advanced squamous cell carcinoma of the lung following failure of platinum-based chemotherapy.	('afatinib', 'Chemical', 'MESH:D000077716', (21, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('squamous cell carcinoma of the lung', 'Disease', (122, 157))	('EGFR-mutant', 'Var', (77, 88))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (122, 157))	('cancers', 'Disease', (89, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('NSCLC', 'Disease', (71, 76))	('platinum', 'Chemical', 'MESH:D010984', (179, 187))	('EGFR-mutant', 'Gene', (77, 88))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
166691	30975211	Approval was based on the clinical trials, 'LUX-Lung 2', 'LUX-Lung 3', and 'LUX-Lung 6', in NSCLC harboring non-resistant EGFR mutations (S768I, L861Q, and/or G719X) and the 'LUX-Lung 8' in patients with advanced squamous cell carcinomas of the lung (Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinomas', 'Phenotype', 'HP:0030731', (227, 237))	('squamous cell carcinomas of the lung', 'Disease', (213, 249))	('squamous cell carcinomas of the lung', 'Disease', 'MESH:D002294', (213, 249))	('patients', 'Species', '9606', (190, 198))	('L861Q', 'Mutation', 'rs121913444', (145, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('L861Q', 'Var', (145, 150))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('122', '126'))	('S768I', 'Mutation', 'rs121913465', (138, 143))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (213, 237))	('S768I', 'Var', (138, 143))	('NSCLC', 'Disease', (92, 97))	('G719X', 'Mutation', 'p.G719X', (159, 164))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('EGFR', 'Gene', (122, 126))	('G719X', 'Var', (159, 164))
166695	30975211	In vitro studies in HER2-amplified breast cancer cell lines and EGFR mutant NSCLC cell lines have demonstrated the strong anti-proliferative activity of dacomitinib, providing a rational for its progression into clinical testing against HER2 positive and EGFR mutant cancers.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('HER2', 'Gene', (20, 24))	('anti-proliferative activity', 'MPA', (122, 149))	('cancers', 'Disease', 'MESH:D009369', (267, 274))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('dacomitinib', 'Chemical', 'MESH:C525726', (153, 164))	('rat', 'Species', '10116', (134, 137))	('EGFR', 'Gene', (64, 68))	('HER2', 'Gene', '2064', (237, 241))	('NSCLC', 'Disease', (76, 81))	('EGFR', 'molecular_function', 'GO:0005006', ('255', '259'))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('rat', 'Species', '10116', (178, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('HER2', 'Gene', '2064', (20, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('mutant', 'Var', (69, 75))	('rat', 'Species', '10116', (105, 108))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('cancers', 'Disease', (267, 274))	('breast cancer', 'Disease', (35, 48))	('HER2', 'Gene', (237, 241))
166696	30975211	In September 2018, dacomitinib received its first FDA approval as a first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations.	('NSCLC', 'Disease', (117, 122))	('dacomitinib', 'Chemical', 'MESH:C525726', (19, 30))	('EGFR', 'molecular_function', 'GO:0005006', ('128', '132'))	('L858R', 'Mutation', 'rs121434568', (161, 166))	('EGFR', 'Gene', (128, 132))	('patients', 'Species', '9606', (92, 100))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('L858R', 'Var', (161, 166))
166712	30975211	These agents include osimertinib (AZD9291/ Tagrisso ; AstraZeneca; formerly mereletinib), rociletinib (CO-1686; Clovis Oncology, USA), olmutinib (HM61713; Hanmi Pharmaceutical, South Korea), naquotinib (ASP8273; Astellas Pharma Inc., Japan), tesevatinib (XL647/KD019; Kadmon Corporation, USA), nazartinib (Novartis, Switzerland; EGF816), and PF-06747775.	('EGF', 'Gene', (329, 332))	('rociletinib', 'Chemical', 'MESH:C000589977', (90, 101))	('Oncology', 'Phenotype', 'HP:0002664', (119, 127))	('osimertinib', 'Chemical', 'MESH:C000603933', (21, 32))	('rat', 'Species', '10116', (280, 283))	('EGF', 'Gene', '1950', (329, 332))	('PF', 'Chemical', 'MESH:C002997', (342, 344))	('nazartinib', 'Chemical', 'MESH:C000619734', (294, 304))	('olmutinib', 'Chemical', 'MESH:C000617753', (135, 144))	('PF-06747775', 'Var', (342, 353))	('naquotinib', 'Chemical', 'MESH:C000627869', (191, 201))	('EGF', 'molecular_function', 'GO:0005154', ('329', '332'))
166714	30975211	Osimertinib is an irreversible T790 M-EGFR mutant-selective TKI that is also able to bind irreversibly to EGFR that hold a L858R mutation or an exon 19 deletion.	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('L858R', 'Var', (123, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('106', '110'))	('Osimertinib', 'Chemical', 'MESH:C000603933', (0, 11))	('T790 M', 'Mutation', 'rs121434569', (31, 37))	('L858R', 'Mutation', 'rs121434568', (123, 128))	('T790', 'Var', (31, 35))
166715	30975211	More than 50% of NSCLC patients that are EGFR mutation-positive and who have experienced disease progression following EGFR-TKI treatment, have developed a T790 M resistance mutation, for which there has been few treatment options.	('EGFR', 'molecular_function', 'GO:0005006', ('119', '123'))	('T790 M', 'Var', (156, 162))	('NSCLC', 'Disease', (17, 22))	('patients', 'Species', '9606', (23, 31))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))	('T790 M', 'Mutation', 'rs121434569', (156, 162))
166716	30975211	Following the results of the Phase II 'AURA2' and the Phase III 'AURA3' clinical trials, in 2015, the FDA accelerated approval of osimertinib for the treatment of EGFR-T790 M mutant NSCLC patients following EGFR-TKI therapy (Table 1).	('NSCLC', 'Disease', (182, 187))	('EGFR', 'molecular_function', 'GO:0005006', ('207', '211'))	('AURA2', 'Gene', '1326', (39, 44))	('T790 M', 'Mutation', 'rs121434569', (168, 174))	('EGFR-T790 M mutant', 'Var', (163, 181))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('patients', 'Species', '9606', (188, 196))	('rat', 'Species', '10116', (112, 115))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))	('AURA2', 'Gene', (39, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (182, 187))	('osimertinib', 'Chemical', 'MESH:C000603933', (130, 141))
166719	30975211	Rociletinib is also an irreversible mutant-selective inhibitor of commonly mutated forms of EGFR (exon 19 deletion, L858R, and T790 M) that has been assessed in early Phase I-II clinical trials.	('L858R', 'Var', (116, 121))	('Rociletinib', 'Chemical', 'MESH:C000589977', (0, 11))	('L858R', 'Mutation', 'rs121434568', (116, 121))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('T790 M', 'Mutation', 'rs121434569', (127, 133))	('T790 M', 'Var', (127, 133))
166721	30975211	Due to its mutation-specific selectivity, rociletinib did not cause the syndrome of rash, stomatitis, and paronychia that is associated with inhibition of non-mutant EGFR.	('rash', 'Disease', 'MESH:D005076', (84, 88))	('paronychia', 'Phenotype', 'HP:0001818', (106, 116))	('paronychia', 'Disease', (106, 116))	('rash', 'Disease', (84, 88))	('rash', 'Phenotype', 'HP:0000988', (84, 88))	('stomatitis', 'Disease', 'MESH:D013280', (90, 100))	('rociletinib', 'Chemical', 'MESH:C000589977', (42, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('166', '170'))	('EGFR', 'Gene', (166, 170))	('stomatitis', 'Disease', (90, 100))	('stomatitis', 'Phenotype', 'HP:0010280', (90, 100))	('non-mutant', 'Var', (155, 165))
166726	30975211	Naquotinib has also been assessed for activity against NSCLC with EGFR mutations in the phase III 'SOLAR' trial.	('NSCLC', 'Disease', (55, 60))	('EGFR', 'Gene', (66, 70))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('mutations', 'Var', (71, 80))	('Naquotinib', 'Chemical', 'MESH:C000627869', (0, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
166728	30975211	Tesevatinib, nazartinib and PF-06747775 are currently in phase II/III trials to assess their activity against NSCLCs.	('PF', 'Chemical', 'MESH:C002997', (28, 30))	('NSCLCs', 'Disease', (110, 116))	('PF-06747775', 'Var', (28, 39))	('Tesevatinib', 'Chemical', 'MESH:C571826', (0, 11))	('NSCLCs', 'Disease', 'MESH:D002289', (110, 116))	('nazartinib', 'Chemical', 'MESH:C000619734', (13, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
166736	30975211	This was based on data from the 'EXTREME' clinical trial of cetuximab treatment in head and neck cancer patients, where patients receiving the cetuximab combination therapy had a significantly longer median OS (10.1 vs. 7.4 months; p < 0.05) and PFS (5.6 vs. 3.3 months; p < 0.0001) compared to those receiving chemotherapy only (Table 2).	('longer', 'PosReg', (193, 199))	('head and neck cancer', 'Phenotype', 'HP:0012288', (83, 103))	('patients', 'Species', '9606', (104, 112))	('PF', 'Chemical', 'MESH:C002997', (246, 248))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('OS', 'Chemical', '-', (207, 209))	('cetuximab', 'Var', (143, 152))	('patients', 'Species', '9606', (120, 128))	('neck', 'cellular_component', 'GO:0044326', ('92', '96'))	('PFS', 'MPA', (246, 249))	('cetuximab', 'Chemical', 'MESH:D000068818', (60, 69))	('head and neck cancer', 'Disease', 'MESH:D006258', (83, 103))	('cetuximab', 'Chemical', 'MESH:D000068818', (143, 152))
166739	30975211	Cancers may acquire activating mutations in exon 2 of KRAS, thus isolating the signaling pathway from the effect of upstream EGFR2, rendering the EGFR inhibitors ineffective.	('signaling pathway', 'Pathway', (79, 96))	('mutations', 'Var', (31, 40))	('activating', 'PosReg', (20, 30))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('signaling pathway', 'biological_process', 'GO:0007165', ('79', '96'))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('KRAS', 'Gene', (54, 58))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('EGFR', 'molecular_function', 'GO:0005006', ('146', '150'))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))
166740	30975211	Indeed, the mutation status of KRAS in CRCs is predictive of the patient's response to therapy.	('KRAS', 'Gene', (31, 35))	('mutation', 'Var', (12, 20))	('patient', 'Species', '9606', (65, 72))
166747	30975211	Therefore, like cetuximab, panitumumab monotherapy efficacy in mutant CRC is limited to patients with wild-type KRAS tumors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutant', 'Var', (63, 69))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (88, 96))	('panitumumab', 'Chemical', 'MESH:D000077544', (27, 38))	('cetuximab', 'Chemical', 'MESH:D000068818', (16, 25))	('KRAS tumors', 'Disease', 'MESH:D009369', (112, 123))	('KRAS tumors', 'Disease', (112, 123))	('CRC', 'Disease', (70, 73))
166763	30975211	Overexpression of VEGF has been correlated with advanced tumor stages and invasiveness and is, therefore, a target for cancer therapeutics.	('invasiveness', 'Disease', (74, 86))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('VEGF', 'Gene', '7422', (18, 22))	('correlated', 'Reg', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Disease', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Overexpression', 'Var', (0, 14))	('invasiveness', 'Disease', 'MESH:D009361', (74, 86))	('tumor', 'Disease', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('VEGF', 'Gene', (18, 22))
166764	30975211	Mutations in oncogenes, such as ras or p53, and the inhibition of several tumor suppressor genes, such as PTEN or WT1, can result in the up-regulation of VEGF.	('VEGF', 'Gene', '7422', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('regulation', 'biological_process', 'GO:0065007', ('140', '150'))	('ras', 'Gene', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('up-regulation', 'PosReg', (137, 150))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (39, 42))	('PTEN', 'Gene', (106, 110))	('tumor', 'Disease', (74, 79))	('WT1', 'Gene', (114, 117))	('VEGF', 'Gene', (154, 158))	('p53', 'Gene', '7157', (39, 42))	('WT1', 'Gene', '7490', (114, 117))	('PTEN', 'Gene', '5728', (106, 110))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('inhibition', 'NegReg', (52, 62))
166789	30975211	Following its success in clinical trials, bevacizumab is currently approved for the treatment of CRC (NCT01169558), glioblastoma (NCT00345163), ovarian cancer (GOG-0213, OCEANS, NCT01239732), renal cancer (AVOREN), breast cancer (E2100, BEATRICE) and cervical cancer (GOG-240).	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('breast cancer', 'Disease', 'MESH:D001943', (215, 228))	('cancer', 'Disease', (152, 158))	('breast cancer', 'Disease', (215, 228))	('cancer', 'Disease', (198, 204))	('glioblastoma', 'Disease', (116, 128))	('cancer', 'Disease', (222, 228))	('ovarian cancer', 'Disease', 'MESH:D010051', (144, 158))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('renal cancer', 'Disease', (192, 204))	('renal cancer', 'Phenotype', 'HP:0009726', (192, 204))	('CRC', 'Disease', (97, 100))	('cancer', 'Disease', (260, 266))	('ovarian cancer', 'Disease', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('bevacizumab', 'Chemical', 'MESH:D000068258', (42, 53))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('renal cancer', 'Disease', 'MESH:D007680', (192, 204))	('NCT01169558', 'Var', (102, 113))
166848	30975211	T-DM1 is therefore able to bind to HER2-overexpressing cells and is internalized by the cell where the tubulin inhibitor is released (Fig.	('T-DM1', 'Var', (0, 5))	('HER2', 'Gene', (35, 39))	('T-DM1', 'Chemical', 'MESH:C550911', (0, 5))	('HER2', 'Gene', '2064', (35, 39))	('bind', 'Interaction', (27, 31))
166850	30975211	Clinical trials of the drug have shown that T-DM1 has low toxicity and can be used in combination with lapatinib and nab-paclitaxel for significant anti-tumor activity and, is therefore, a promising drug candidate for HER2-overexpressing breast cancer (Table 4).	('paclitaxel', 'Chemical', 'MESH:D017239', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('T-DM1', 'Var', (44, 49))	('lapatinib', 'Chemical', 'MESH:D000077341', (103, 112))	('HER2', 'Gene', (218, 222))	('toxicity', 'Disease', 'MESH:D064420', (58, 66))	('HER2', 'Gene', '2064', (218, 222))	('toxicity', 'Disease', (58, 66))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('breast cancer', 'Disease', 'MESH:D001943', (238, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('breast cancer', 'Disease', (238, 251))	('breast cancer', 'Phenotype', 'HP:0003002', (238, 251))	('T-DM1', 'Chemical', 'MESH:C550911', (44, 49))
166868	30975211	Importantly, trastuzumab, T-DM1, pertuzumab and lapatinib have shown clinical importance in the treatment of HER2 overexpressing breast cancer and the application of these drugs have shown significant improvement in patient outcomes.	('breast cancer', 'Disease', (129, 142))	('T-DM1', 'Var', (26, 31))	('T-DM1', 'Chemical', 'MESH:C550911', (26, 31))	('trastuzumab', 'Chemical', 'MESH:D000068878', (13, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('overexpressing', 'PosReg', (114, 128))	('HER2', 'Gene', (109, 113))	('lapatinib', 'Chemical', 'MESH:D000077341', (48, 57))	('pertuzumab', 'Chemical', 'MESH:C485206', (33, 43))	('HER2', 'Gene', '2064', (109, 113))	('patient', 'Species', '9606', (216, 223))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
166872	30975211	In cancer, translocations involving the ALK gene form nearly 30 different fusion oncogenes.	('ALK', 'Gene', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('ALK', 'Gene', '238', (40, 43))	('translocations', 'Var', (11, 25))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
166874	30975211	ALK alterations have been found in several cancers, such as anaplastic large cell lymphoma, NSCLC, inflammatory myofibroblastic tumor, diffuse large B-cell lymphomas, esophageal squamous cell carcinoma, renal medulla carcinoma, RCC, breast cancer, colon carcinoma, serous ovarian carcinoma, and anaplastic thyroid carcinoma.	('rat', 'Species', '10116', (8, 11))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (149, 164))	('RCC', 'Disease', 'MESH:D002292', (228, 231))	('lymphomas', 'Disease', 'MESH:D008223', (156, 165))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (149, 165))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (82, 90))	('cell lymphoma', 'Phenotype', 'HP:0012191', (151, 164))	('cancers', 'Disease', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('colon carcinoma', 'Disease', (248, 263))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (272, 289))	('lymphoma', 'Disease', (156, 164))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (295, 323))	('lymphomas', 'Phenotype', 'HP:0002665', (156, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('lymphoma', 'Disease', 'MESH:D008223', (156, 164))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('cell lymphoma', 'Phenotype', 'HP:0012191', (77, 90))	('ovarian carcinoma', 'Disease', (272, 289))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (306, 323))	('esophageal squamous cell carcinoma', 'Disease', (167, 201))	('alterations', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('thyroid carcinoma', 'Disease', (306, 323))	('B-cell lymphoma', 'Disease', (149, 164))	('colon carcinoma', 'Disease', 'MESH:D015179', (248, 263))	('found', 'Reg', (26, 31))	('NSCLC', 'Disease', (92, 97))	('renal medulla carcinoma', 'Disease', (203, 226))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (272, 289))	('lymphoma', 'Disease', (82, 90))	('lymphoma', 'Disease', 'MESH:D008223', (82, 90))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (306, 323))	('lymphomas', 'Disease', (156, 165))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('tumor', 'Disease', (128, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('ALK', 'Gene', '238', (0, 3))	('lymphoma', 'Phenotype', 'HP:0002665', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (149, 164))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (112, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('RCC', 'Disease', (228, 231))	('breast cancer', 'Disease', 'MESH:D001943', (233, 246))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (167, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (314, 323))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('breast cancer', 'Disease', (233, 246))	('ALK', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('renal medulla carcinoma', 'Disease', 'MESH:D002292', (203, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
166883	30975211	These include: the first-generation ALK inhibitor, crizotinib (Xalkori , formerly PF-02341066, Pfizer); the second-generation inhibitors, ceritinib (Zykadia , formerly LDK378; Novartis), alectinib (Alcensa , formerly RO5424802/CH5424802, Hoffmann-La Roche, Inc./Genentech, Inc.), and brigatinib (Alunbrig , formerly AP26113, Takeda Pharmaceutical Company, Ltd); and the third-generation inhibitor, lorlatinib (PF-06463922; Pfizer; Fig.	('crizotinib', 'Chemical', 'MESH:D000077547', (51, 61))	('ceritinib', 'Chemical', 'MESH:C586847', (138, 147))	('brigatinib', 'Chemical', 'MESH:C000598580', (284, 294))	('ALK', 'Gene', '238', (36, 39))	('rat', 'Species', '10116', (29, 32))	('rat', 'Species', '10116', (380, 383))	('rat', 'Species', '10116', (119, 122))	('alectinib', 'Chemical', 'MESH:C582670', (187, 196))	('PF-06463922;', 'Var', (410, 422))	('PF', 'Chemical', 'MESH:C002997', (410, 412))	('PF', 'Chemical', 'MESH:C002997', (82, 84))	('lorlatinib', 'Chemical', 'MESH:C000590786', (398, 408))	('ALK', 'Gene', (36, 39))
166887	30975211	Furthermore, the 'PROFILE 1014' trial showed crizotinib to be superior, compared to standard first-line platinum/pemetrexed chemotherapy in patients with untreated, advanced, NSCLC; for which it is now an approved treatment.	('platinum', 'Chemical', 'MESH:D010984', (104, 112))	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('crizotinib', 'Var', (45, 55))	('pemetrexed', 'Chemical', 'MESH:D000068437', (113, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('patients', 'Species', '9606', (140, 148))	('NSCLC', 'Disease', (175, 180))	('crizotinib', 'Chemical', 'MESH:D000077547', (45, 55))
166892	30975211	Secondary resistance has been attributed to point mutations in the ALK gene, gene amplification, and modification of downstream signaling pathways to bypass ALK inhibition.	('downstream signaling pathways', 'Pathway', (117, 146))	('point mutations', 'Var', (44, 59))	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('ALK', 'Gene', '238', (67, 70))	('ALK', 'Gene', (157, 160))	('modification', 'Reg', (101, 113))	('ALK', 'Gene', '238', (157, 160))	('ALK', 'Gene', (67, 70))
166905	30975211	Only 12% of patients treated with alectinib developed CNS progression, compared with 45% of those treated with crizotinib.	('CNS progression', 'CPA', (54, 69))	('patients', 'Species', '9606', (12, 20))	('alectinib', 'Var', (34, 43))	('crizotinib', 'Chemical', 'MESH:D000077547', (111, 121))	('alectinib', 'Chemical', 'MESH:C582670', (34, 43))
166910	30975211	Lorlatinib, a third generation ALK-inhibitor, was designed to inhibit ALK resistant mutants and penetrate the blood brain barrier (BBB).	('ALK', 'Gene', '238', (31, 34))	('rat', 'Species', '10116', (101, 104))	('ALK', 'Gene', '238', (70, 73))	('Lorlatinib', 'Chemical', 'MESH:C000590786', (0, 10))	('mutants', 'Var', (84, 91))	('ALK', 'Gene', (31, 34))	('inhibit', 'NegReg', (62, 69))	('rat', 'Species', '10116', (24, 27))	('ALK', 'Gene', (70, 73))
166924	30975211	BRAF mutations have been extensively reported in numerous cancers, including melanomas (50-66%), papillary thyroid tumors (45-50%), CRCs (10%), prostate tumors (10%), and NSCLCs (3%).	('NSCLCs', 'Disease', 'MESH:D002289', (171, 177))	('prostate tumors', 'Disease', (144, 159))	('melanomas', 'Disease', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('CRCs', 'Disease', (132, 136))	('BRAF', 'Gene', '673', (0, 4))	('prostate tumors', 'Disease', 'MESH:D011471', (144, 159))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('NSCLCs', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('papillary thyroid tumors', 'Disease', 'MESH:C536915', (97, 121))	('papillary thyroid tumors', 'Phenotype', 'HP:0002895', (97, 121))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('papillary thyroid tumors', 'Disease', (97, 121))	('cancers', 'Disease', (58, 65))	('reported', 'Reg', (37, 45))
166925	30975211	Studies have reported a V600E hotspot mutation in malignant melanomas and CRCs which increases BRAF kinase activity.	('V600E', 'Var', (24, 29))	('BRAF', 'Gene', '673', (95, 99))	('malignant melanomas', 'Phenotype', 'HP:0002861', (50, 69))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('kinase activity', 'molecular_function', 'GO:0016301', ('100', '115'))	('BRAF', 'Gene', (95, 99))	('malignant melanomas', 'Disease', 'MESH:D008545', (50, 69))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('V600E', 'Mutation', 'rs113488022', (24, 29))	('malignant melanomas', 'Disease', (50, 69))	('increases', 'PosReg', (85, 94))
166926	30975211	This mutation represents about 70-90% of all BRAF mutations.	('mutations', 'Var', (50, 59))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))
166927	30975211	Moreover, activating mutations of the BRAF oncogene are reported in approximately 5-10% of all human malignancies, leading to constitutive activation of the MAPK pathway.	('constitutive', 'MPA', (126, 138))	('malignancies', 'Disease', (101, 113))	('human', 'Species', '9606', (95, 100))	('MAPK', 'Gene', (157, 161))	('MAPK', 'molecular_function', 'GO:0004707', ('157', '161'))	('activation', 'PosReg', (139, 149))	('activating', 'PosReg', (10, 20))	('BRAF', 'Gene', '673', (38, 42))	('BRAF', 'Gene', (38, 42))	('malignancies', 'Disease', 'MESH:D009369', (101, 113))	('MAPK', 'Gene', '5594', (157, 161))	('mutations', 'Var', (21, 30))
166928	30975211	These BRAF mutant cancers have been associated with poor patient prognosis.	('mutant', 'Var', (11, 17))	('cancers', 'Disease', (18, 25))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('patient', 'Species', '9606', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('BRAF', 'Gene', '673', (6, 10))	('BRAF', 'Gene', (6, 10))	('cancers', 'Disease', 'MESH:D009369', (18, 25))
166933	30975211	Sorafenib was the first RAF inhibitor to enter clinical trials, which occurred prior to the discovery of BRAF mutations in cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('BRAF', 'Gene', '673', (105, 109))	('mutations', 'Var', (110, 119))	('RAF', 'Gene', '22882', (24, 27))	('RAF', 'Gene', (24, 27))	('BRAF', 'Gene', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('RAF', 'Gene', '22882', (106, 109))	('RAF', 'Gene', (106, 109))
166934	30975211	Molecular characterization studies of NSCLC and HCC lesions has since revealed a BRAF exon 11 mutation (G469 V) that may be responsible in part for some of the observed sensitivity to sorafenib.	('NSCLC and HCC lesions', 'Disease', 'MESH:D006528', (38, 59))	('HCC', 'Phenotype', 'HP:0001402', (48, 51))	('G469 V', 'Mutation', 'rs121913355', (104, 110))	('BRAF', 'Gene', '673', (81, 85))	('sorafenib', 'Chemical', 'MESH:D000077157', (184, 193))	('BRAF', 'Gene', (81, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('G469 V', 'Var', (104, 110))
166936	30975211	However, when sorafenib was studied in Phase II trials for the treatment of melanoma, no relationship between V600E BRAF status and disease stability was observed (Table 6).	('melanoma', 'Disease', (76, 84))	('V600E', 'Mutation', 'rs113488022', (110, 115))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('BRAF', 'Gene', '673', (116, 120))	('V600E', 'Var', (110, 115))	('BRAF', 'Gene', (116, 120))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('sorafenib', 'Chemical', 'MESH:D000077157', (14, 23))
166942	30975211	Vemurafenib is a potent small-molecule inhibitor of BRAF V600E among other BRAF mutations.	('V600E', 'Mutation', 'rs113488022', (57, 62))	('BRAF', 'Gene', '673', (75, 79))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('BRAF', 'Gene', (75, 79))	('V600E', 'Var', (57, 62))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (52, 56))
166943	30975211	The FDA approved vemurafenib for the treatment of patients with mutant-V600E BRAF metastatic melanomas in 2011.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('patients', 'Species', '9606', (50, 58))	('mutant-V600E', 'Var', (64, 76))	('BRAF', 'Gene', '673', (77, 81))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('melanomas', 'Disease', 'MESH:D008545', (93, 102))	('BRAF', 'Gene', (77, 81))	('melanomas', 'Disease', (93, 102))	('vemurafenib', 'Chemical', 'MESH:D000077484', (17, 28))
166945	30975211	In these studies, melanoma patients bearing mutant-V600E BRAF had partial or complete response rates to vemurafenib between 48 and 81% with the median PFS extending beyond 7 months.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('BRAF', 'Gene', '673', (57, 61))	('rat', 'Species', '10116', (95, 98))	('vemurafenib', 'Chemical', 'MESH:D000077484', (104, 115))	('BRAF', 'Gene', (57, 61))	('patients', 'Species', '9606', (27, 35))	('mutant-V600E', 'Var', (44, 56))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('V600E', 'Mutation', 'rs113488022', (51, 56))	('PF', 'Chemical', 'MESH:C002997', (151, 153))	('melanoma', 'Disease', (18, 26))
166948	30975211	Dabrafenib is also an extremely potent inhibitor of V600E-mutated BRAF, which has shown efficacy in melanoma and CRC both in vitro and in vivo.	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('efficacy', 'PosReg', (88, 96))	('CRC', 'Disease', (113, 116))	('BRAF', 'Gene', '673', (66, 70))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('V600E-mutated', 'Var', (52, 65))	('melanoma', 'Disease', (100, 108))	('BRAF', 'Gene', (66, 70))	('V600E', 'Mutation', 'rs113488022', (52, 57))
166949	30975211	In addition to V600E, dabrafenib also has demonstrated activity against V600D+ and V600R+ cancers.	('cancers', 'Disease', (90, 97))	('activity', 'MPA', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('dabrafenib', 'Chemical', 'MESH:C561627', (22, 32))	('V600E', 'Mutation', 'rs113488022', (15, 20))	('V600R', 'Mutation', 'rs121913227', (83, 88))	('V600R+', 'Var', (83, 89))	('V600D', 'Mutation', 'rs121913377', (72, 77))	('V600E', 'Var', (15, 20))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('V600D+', 'Var', (72, 78))	('rat', 'Species', '10116', (49, 52))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
166950	30975211	In Phase I and II clinical trials, dabrafenib demonstrated a 53-78% partial or complete response rate in melanoma patients bearing mutant V600E BRAF.	('dabrafenib', 'Chemical', 'MESH:C561627', (35, 45))	('rat', 'Species', '10116', (97, 100))	('V600E', 'Var', (138, 143))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('BRAF', 'Gene', '673', (144, 148))	('rat', 'Species', '10116', (53, 56))	('BRAF', 'Gene', (144, 148))	('V600E', 'Mutation', 'rs113488022', (138, 143))	('patients', 'Species', '9606', (114, 122))	('partial', 'NegReg', (68, 75))
166953	30975211	Following the success of the Phase II clinical trials, dabrafenib has been approved for the treatment of V600E mutant-BRAF NSCLC (NCT01336634) and BRAF+ anaplastic thyroid cancers (NCT01723202).	('BRAF', 'Gene', '673', (118, 122))	('dabrafenib', 'Chemical', 'MESH:C561627', (55, 65))	('thyroid cancers', 'Disease', (164, 179))	('NSCLC', 'Disease', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('BRAF', 'Gene', (118, 122))	('thyroid cancers', 'Disease', 'MESH:D013964', (164, 179))	('V600E', 'Mutation', 'rs113488022', (105, 110))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('V600E', 'Var', (105, 110))	('thyroid cancer', 'Phenotype', 'HP:0002890', (164, 178))	('anaplastic thyroid cancers', 'Phenotype', 'HP:0011779', (153, 179))
166956	30975211	Regorafenib is a multi-kinase inhibitor, which has been shown to inhibit both wild-type and mutant V600E BRAF in vitro.	('BRAF', 'Gene', '673', (105, 109))	('Regorafenib', 'Chemical', 'MESH:C559147', (0, 11))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('23', '39'))	('BRAF', 'Gene', (105, 109))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('inhibit', 'NegReg', (65, 72))	('V600E', 'Var', (99, 104))	('mutant V600E', 'Var', (92, 104))
166961	30975211	In this trial, patients receiving regorafenib had a significantly longer median PFS longer than patients given the placebo (4.8 vs. 0.9 months; p < 0.000001, Table 6).	('patients', 'Species', '9606', (15, 23))	('regorafenib', 'Chemical', 'MESH:C559147', (34, 45))	('PF', 'Chemical', 'MESH:C002997', (80, 82))	('regorafenib', 'Var', (34, 45))	('longer', 'PosReg', (66, 72))	('patients', 'Species', '9606', (96, 104))	('PFS', 'MPA', (80, 83))
166965	30975211	A number of other small molecule inhibitors targeting BRAF have also been evaluated in vitro and are currently in clinical development for their anti-tumor activity against V600E mutant cancers.	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('BRAF', 'Gene', '673', (54, 58))	('BRAF', 'Gene', (54, 58))	('V600E', 'Mutation', 'rs113488022', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('V600E mutant', 'Var', (173, 185))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
166966	30975211	These include encorafenib (LGX818), XL281 (BMS-908662), ARQ736, PLX4720, PLX3603 (RO5212054), SB-590885, GDC-0879 and RAF265.	('SB-590885', 'Chemical', 'MESH:C508204', (94, 103))	('RO5212054', 'Var', (82, 91))	('RAF', 'Gene', '22882', (118, 121))	('RAF', 'Gene', (118, 121))	('GDC-0879', 'Chemical', 'MESH:C540167', (105, 113))	('encorafenib', 'Chemical', 'MESH:C000601108', (14, 25))
166970	30975211	Cobimetinib was FDA approved in 2015 for the use in combination with vemurafenib for the treatment of advanced melanomas with BRAF V600E or V600K mutations.	('V600E', 'Mutation', 'rs113488022', (131, 136))	('V600K', 'Mutation', 'rs121913227', (140, 145))	('melanomas', 'Disease', 'MESH:D008545', (111, 120))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('vemurafenib', 'Chemical', 'MESH:D000077484', (69, 80))	('melanomas', 'Disease', (111, 120))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('V600K', 'Var', (140, 145))	('Cobimetinib', 'Chemical', 'MESH:C574276', (0, 11))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))
166972	30975211	Similarly, trametinib prolonged the survival of melanoma patients in the Phase III clinical trials 'COMBI-AD', and was FDA approved in 2018 for use in combination with dabrafenib for patients with melanomas with BRAF V600E or V600K mutations (Table 6).	('dabrafenib', 'Chemical', 'MESH:C561627', (168, 178))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanoma', 'Disease', (48, 56))	('V600K', 'Mutation', 'rs121913227', (226, 231))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanomas', 'Phenotype', 'HP:0002861', (197, 206))	('melanoma', 'Disease', (197, 205))	('BRAF', 'Gene', '673', (212, 216))	('COMBI-AD', 'Chemical', '-', (100, 108))	('BRAF', 'Gene', (212, 216))	('V600E', 'Mutation', 'rs113488022', (217, 222))	('survival', 'CPA', (36, 44))	('prolonged', 'PosReg', (22, 31))	('trametinib', 'Chemical', 'MESH:C560077', (11, 21))	('V600K', 'Var', (226, 231))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('patients', 'Species', '9606', (183, 191))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('patients', 'Species', '9606', (57, 65))	('melanomas', 'Disease', 'MESH:D008545', (197, 206))	('melanomas', 'Disease', (197, 206))
166985	30975211	Therefore, inhibition of CTLA-4 can shift this balance towards T-cell activation, resulting in destruction of the antigens expressed on tumor cells.	('destruction', 'NegReg', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('inhibition', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('T-cell activation', 'biological_process', 'GO:0042110', ('63', '80'))	('tumor', 'Disease', (136, 141))	('CTLA-4', 'Gene', (25, 31))
166987	30975211	Preclinical and clinical data has shown that the inhibition of CTLA-4 directly activates CD4+ and CD8+ effector T-cells.	('CD4', 'Gene', '920', (89, 92))	('CD8', 'Gene', (98, 101))	('CTLA-4', 'Gene', (63, 69))	('CD8', 'Gene', '925', (98, 101))	('inhibition', 'Var', (49, 59))	('CD4', 'Gene', (89, 92))	('activates', 'PosReg', (79, 88))
167003	30975211	Despite this, ipilimumab has since been approved for BRAF V600 wild-type melanomas, melanomas after surgery (NCT00636168), unresectable or metastatic melanomas (CHECKMATE-067/ NCT01696045), intermediate or poor-risk advanced RCCs (CHECKMATE-214), and metastatic CRC (CHECKMATE-142) (Table 7).	('melanomas', 'Disease', (84, 93))	('melanomas', 'Phenotype', 'HP:0002861', (150, 159))	('melanomas', 'Disease', 'MESH:D008545', (73, 82))	('RCC', 'Disease', (225, 228))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('melanomas', 'Disease', (73, 82))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('NCT00636168', 'Var', (109, 120))	('RCC', 'Disease', 'MESH:D002292', (225, 228))	('melanomas', 'Disease', 'MESH:D008545', (150, 159))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('melanomas', 'Disease', (150, 159))	('ipilimumab', 'Chemical', 'MESH:D000074324', (14, 24))	('melanomas', 'Disease', 'MESH:D008545', (84, 93))	('metastatic CRC', 'Disease', (251, 265))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
167021	30975211	In 2015, pembrolizumab received an expanded first-line indication to include previously untreated advanced melanomas regardless of their BRAF mutation status, following the results of the 'KEYNOTE-006' clinical trial (Table 7).	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('melanomas regardless', 'Disease', (107, 127))	('pembrolizumab', 'Chemical', 'MESH:C582435', (9, 22))	('melanomas regardless', 'Disease', 'MESH:D008545', (107, 127))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('mutation', 'Var', (142, 150))
167022	30975211	One-year OS and ORR rates were significantly improved in patients receiving pembrolizumab compared to ipilimumab.	('ipilimumab', 'Chemical', 'MESH:D000074324', (102, 112))	('pembrolizumab', 'Var', (76, 89))	('improved', 'PosReg', (45, 53))	('pembrolizumab', 'Chemical', 'MESH:C582435', (76, 89))	('patients', 'Species', '9606', (57, 65))	('OS', 'Chemical', '-', (9, 11))	('ORR rates', 'CPA', (16, 25))	('rat', 'Species', '10116', (20, 23))
167025	30975211	Since 2015, the FDA has approved pembrolizumab for the treatment of advanced/metastatic NSCLC (KEYNOTE-001), recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-012), high PD-1 expressing metastatic NSCLC (KEYNOTE-024), classical Hodgkin lymphoma (KEYNOTE-087), first-line metastatic non-squamous NSCLC irrespective of PD-L1 expression (KEYNOTE-021), locally advanced/metastatic urothelial carcinoma (KEYNOTE-052), unresectable or metastatic solid tumors with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors (KEYNOTE-016, - 164, - 012, - 028, and - 158), advanced/metastatic gastric or gastroesophageal junction cancers expressing PD-L1 (KEYNOTE-059), metastatic cervical cancers expressing PD-L1 (KEYNOTE-158), refractory or relapsed primary mediastinal large B-Cell lymphomas (PMBCL; KEYNOTE-170), and metastatic non-squamous NSCLCs with no EGFR or ALK mutations (KEYNOTE-189; Table 7).	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('cancers', 'Disease', 'MESH:D009369', (696, 703))	('cancer', 'Phenotype', 'HP:0002664', (756, 762))	('carcinoma', 'Phenotype', 'HP:0030731', (406, 415))	('neck', 'cellular_component', 'GO:0044326', ('139', '143'))	('solid tumors', 'Disease', 'MESH:D009369', (579, 591))	('tumors', 'Phenotype', 'HP:0002664', (585, 591))	('lymphoma', 'Phenotype', 'HP:0002665', (852, 860))	('B-Cell lymphomas', 'Disease', (845, 861))	('mismatch repair deficient (dMMR) solid tumors', 'Disease', 'MESH:C536928', (546, 591))	('pembrolizumab', 'Chemical', 'MESH:C582435', (33, 46))	('NSCLC', 'Disease', (215, 220))	('EGFR', 'molecular_function', 'GO:0005006', ('927', '931'))	('NSCLC', 'Disease', (912, 917))	('gastroesophageal junction cancers', 'Disease', 'MESH:D009369', (670, 703))	('B-Cell lymphomas', 'Disease', 'MESH:D016393', (845, 861))	('solid tumors', 'Disease', (458, 470))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (246, 262))	('PD-L1', 'Gene', (715, 720))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (246, 262))	('non-squamous NSCLC', 'Disease', (300, 318))	('tumor', 'Phenotype', 'HP:0002664', (585, 590))	('NSCLC', 'Phenotype', 'HP:0030358', (215, 220))	('gastroesophageal junction cancers', 'Disease', (670, 703))	('NSCLC', 'Disease', 'MESH:D002289', (313, 318))	('NSCLC', 'Phenotype', 'HP:0030358', (912, 917))	('NSCLCs', 'Disease', (912, 918))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (899, 917))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('cancers', 'Disease', 'MESH:D009369', (756, 763))	('tumor', 'Phenotype', 'HP:0002664', (464, 469))	('lymphoma', 'Phenotype', 'HP:0002665', (254, 262))	('gastric or gastroesophageal junction cancer', 'Disease', 'MESH:D013274', (659, 702))	('B-Cell lymphomas', 'Phenotype', 'HP:0012191', (845, 861))	('NSCLC', 'Disease', (313, 318))	('cancers', 'Phenotype', 'HP:0002664', (696, 703))	('gastric or gastroesophageal junction cancer', 'Disease', (659, 702))	('lymphomas', 'Phenotype', 'HP:0002665', (852, 861))	('cancers', 'Disease', (696, 703))	('solid tumors', 'Disease', 'MESH:D009369', (458, 470))	('tumors', 'Phenotype', 'HP:0002664', (464, 470))	('PD-L1', 'Var', (775, 780))	('cancer', 'Phenotype', 'HP:0002664', (696, 702))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (313, 318))	('NSCLCs', 'Disease', 'MESH:D002289', (912, 918))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (300, 318))	('solid tumors', 'Disease', (579, 591))	('PD-1', 'Gene', '5133', (188, 192))	('PD-1', 'Gene', (188, 192))	('ALK', 'Gene', '238', (935, 938))	('ALK', 'Gene', (935, 938))	('cancers', 'Phenotype', 'HP:0002664', (756, 763))	('NSCLC', 'Disease', (88, 93))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (139, 167))	('neck squamous cell carcinoma', 'Disease', (139, 167))	('metastatic urothelial carcinoma', 'Disease', 'MESH:C538445', (384, 415))	('Hodgkin lymphoma', 'Disease', (246, 262))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('non-squamous NSCLC', 'Disease', (899, 917))	('mismatch repair', 'biological_process', 'GO:0006298', ('546', '561'))	('cancers', 'Disease', (756, 763))	('NSCLC', 'Disease', 'MESH:D002289', (215, 220))	('metastatic urothelial carcinoma', 'Disease', (384, 415))	('NSCLC', 'Disease', 'MESH:D002289', (912, 917))
167035	30975211	Later in 2015, nivolumab was also approved for the treatment of advanced non-squamous NSCLC, as patients treated with nivolumab in the 'CHECKMATE-057' trials lived an average of 12.2 months compared to 9.4 months in those treated with docetaxel.	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (73, 91))	('nivolumab', 'Chemical', 'MESH:D000077594', (15, 24))	('nivolumab', 'Chemical', 'MESH:D000077594', (118, 127))	('non-squamous NSCLC', 'Disease', (73, 91))	('nivolumab', 'Var', (118, 127))	('docetaxel', 'Chemical', 'MESH:D000077143', (235, 244))	('to 9', 'Species', '1214577', (199, 203))	('patients', 'Species', '9606', (96, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))
167046	30975211	In patients with positive PD-L1 expression, 26% experienced a tumor response, compared with 9.5% in those that were PD-L1 negative (Table 7).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('positive', 'Var', (17, 25))	('expression', 'Var', (32, 42))	('PD-L1', 'Gene', (26, 31))	('tumor', 'Disease', (62, 67))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
167053	30975211	The ORR of this study was 26.3% in patients with highly PD-L1 expressing tumors, compared with 17.0% in all evaluable patients regardless of their PD-L1 status.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('highly', 'Var', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('patients', 'Species', '9606', (35, 43))	('patients', 'Species', '9606', (118, 126))	('PD-L1', 'Gene', (56, 61))
167056	30975211	Early in 2018, durvalumab was also approved for the treatment of stage III unresectable NSCLC following the success of the 'PACIFIC' Phase III trials, which showed a median PFS for patients taking durvalumab of 16.8 months compared to 5.6 months for patients receiving the placebo (Table 7).	('durvalumab', 'Chemical', 'MESH:C000613593', (15, 25))	('durvalumab', 'Chemical', 'MESH:C000613593', (197, 207))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('durvalumab', 'Var', (197, 207))	('patients', 'Species', '9606', (250, 258))	('PF', 'Chemical', 'MESH:C002997', (173, 175))	('NSCLC', 'Disease', (88, 93))	('patients', 'Species', '9606', (181, 189))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))
167100	33923108	Interestingly, ROS overproduction may induce the production of proinflammatory cytokines, which finally activated angiogenesis.	('overproduction', 'Var', (19, 33))	('production of proinflammatory cytokines', 'MPA', (49, 88))	('induce', 'PosReg', (38, 44))	('ROS', 'Chemical', 'MESH:D017382', (15, 18))	('angiogenesis', 'biological_process', 'GO:0001525', ('114', '126'))	('ROS', 'Protein', (15, 18))	('activated', 'PosReg', (104, 113))	('angiogenesis', 'CPA', (114, 126))
167111	33923108	Tobacco is a strong carcinogenic agent because it is a rich source of polycyclic aromatic hydrocarbons, aromatic amines and N-nitroso compounds, which cause DNA damage via adduct formation, single- and double-strand DNA breaks and modifications of the base.	('age', 'Gene', (33, 36))	('formation', 'biological_process', 'GO:0009058', ('179', '188'))	('age', 'Gene', (164, 167))	('carcinogenic', 'Disease', 'MESH:D063646', (20, 32))	('DNA', 'cellular_component', 'GO:0005574', ('216', '219'))	('carcinogenic', 'Disease', (20, 32))	('modifications', 'Var', (231, 244))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('age', 'Gene', '5973', (33, 36))	('Tobacco', 'Species', '4097', (0, 7))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (70, 102))	('age', 'Gene', '5973', (164, 167))	('N-nitroso compounds', 'Chemical', '-', (124, 143))	('adduct', 'MPA', (172, 178))	('aromatic amines', 'Chemical', '-', (104, 119))
167133	33923108	Previous studies confirmed that single nucleotide polymorphisms (SNPs) might modulate the risk of bladder cancer development.	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('modulate', 'Reg', (77, 85))	('single nucleotide polymorphisms', 'Var', (32, 63))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('men', 'Species', '9606', (120, 123))
167139	33923108	In consequence, the changes of NAT genes might be associated with the risk of bladder cancer.	('NAT', 'Gene', '6046', (31, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (78, 92))	('NAT', 'Gene', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (78, 92))	('bladder cancer', 'Disease', (78, 92))	('changes', 'Var', (20, 27))	('associated', 'Reg', (50, 60))
167140	33923108	The previous meta-analysis confirmed that the NAT2 slow acetylator genotype was associated with a 40% increased risk of bladder cancer development.	('men', 'Species', '9606', (142, 145))	('NAT2', 'Gene', (46, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (120, 134))	('slow', 'Var', (51, 55))	('NAT2', 'Gene', '10', (46, 50))	('bladder cancer', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('bladder cancer', 'Phenotype', 'HP:0009725', (120, 134))
167141	33923108	(2010) confirmed that polymorphism in the NAT2 gene may modulate BC risk.	('modulate', 'Reg', (56, 64))	('polymorphism', 'Var', (22, 34))	('NAT2', 'Gene', (42, 46))	('NAT2', 'Gene', '10', (42, 46))
167142	33923108	The G allele of NAT2 polymorphism (rs1495741) decreased the risk of BC occurrence, while the A/A genotype associated with slow acetylation increased the risk by about 15%.	('slow acetylation', 'MPA', (122, 138))	('rs1495741', 'Var', (35, 44))	('BC occurrence', 'Disease', (68, 81))	('NAT2', 'Gene', '10', (16, 20))	('NAT2', 'Gene', (16, 20))	('decreased', 'NegReg', (46, 55))	('rs1495741', 'Mutation', 'rs1495741', (35, 44))
167145	33923108	The previous meta-analysis showed that GSTM1-null genotypes increased BC risk by about 50%.	('genotypes', 'Var', (50, 59))	('GSTM1', 'Gene', '2944', (39, 44))	('GSTM1', 'Gene', (39, 44))	('increased', 'PosReg', (60, 69))
167148	33923108	Previous studies confirmed that the mutations localised in FGFR3, RB1, HARS, TP53 and TSC1 genes might be associated with BC.	('FGFR3', 'Gene', '2261', (59, 64))	('TSC1', 'Gene', (86, 90))	('TSC1', 'Gene', '7248', (86, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('HARS', 'Gene', (71, 75))	('associated', 'Reg', (106, 116))	('RB1', 'Gene', '5925', (66, 69))	('FGFR3', 'Gene', (59, 64))	('mutations', 'Var', (36, 45))	('HARS', 'Gene', '3035', (71, 75))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('RB1', 'Gene', (66, 69))
167149	33923108	Moreover, mutations of TP53 may be associated with the invasive character of bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('associated', 'Reg', (35, 45))	('bladder cancer', 'Disease', (77, 91))	('invasive', 'Disease', (55, 63))	('mutations', 'Var', (10, 19))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
167150	33923108	Besides, TERT gene mutations have been confirmed in 70% of patients with BC.	('mutations', 'Var', (19, 28))	('patients', 'Species', '9606', (59, 67))	('TERT', 'Gene', (9, 13))	('confirmed', 'Reg', (39, 48))	('TERT', 'Gene', '7015', (9, 13))
167155	33923108	The missense mutation of HRAS, causing the replacement of the glycine with the valine at position 12, is also associated with BC.	('missense mutation', 'Var', (4, 21))	('HRAS', 'Gene', (25, 29))	('glycine with the valine at position 12', 'Mutation', 'rs104894230', (62, 100))	('replacement', 'MPA', (43, 54))	('glycine with', 'MPA', (62, 74))	('associated', 'Reg', (110, 120))	('men', 'Species', '9606', (50, 53))	('HRAS', 'Gene', '3265', (25, 29))
167156	33923108	In consequence of mutations, the protein is activated and then causes growth of the cells and divides in the absence of outside signals, which leads to uncontrolled cell division and the formation of a tumour in the bladder.	('leads to', 'Reg', (143, 151))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('cell division', 'biological_process', 'GO:0051301', ('165', '178'))	('formation', 'biological_process', 'GO:0009058', ('187', '196'))	('growth', 'CPA', (70, 76))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('uncontrolled cell division', 'CPA', (152, 178))	('activated', 'PosReg', (44, 53))	('causes', 'Reg', (63, 69))	('tumour', 'Disease', (202, 208))	('tumour in the bladder', 'Phenotype', 'HP:0009725', (202, 223))	('mutations', 'Var', (18, 27))
167157	33923108	Moreover, the mutations of HRAS may be associated with the cancer progression and may also increase the risk of tumour recurrence after the anti-cancer treatment.	('cancer', 'Disease', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('HRAS', 'Gene', (27, 31))	('tumour', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('associated', 'Reg', (39, 49))	('men', 'Species', '9606', (157, 160))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('HRAS', 'Gene', '3265', (27, 31))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('mutations', 'Var', (14, 23))	('increase', 'Reg', (91, 99))
167159	33923108	The mutations of STAG2 were observed in about 36% of patients with papillary non-invasive urothelial carcinomas and in 16% of invasive urothelial carcinomas of the bladder.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('STAG2', 'Gene', (17, 22))	('STAG2', 'Gene', '10735', (17, 22))	('patients', 'Species', '9606', (53, 61))	('papillary non-invasive urothelial carcinomas', 'Disease', (67, 111))	('invasive urothelial carcinomas of the bladder', 'Phenotype', 'HP:0006740', (126, 171))	('invasive urothelial carcinomas of the bladder', 'Disease', 'MESH:D001749', (126, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('invasive urothelial carcinomas of the bladder', 'Disease', (126, 171))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('mutations', 'Var', (4, 13))	('papillary non-invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (67, 111))	('observed', 'Reg', (28, 36))
167166	33923108	ROS may damage proteins, nucleic acids and lipids.	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('age', 'Gene', (11, 14))	('lipids', 'Chemical', 'MESH:D008055', (43, 49))	('proteins', 'Protein', (15, 23))	('age', 'Gene', '5973', (11, 14))
167176	33923108	The adhesion may activate the xanthine-oxidase and cause enhanced hydrogen peroxide production in a vicious circle.	('vicious circle', 'CPA', (100, 114))	('activate', 'PosReg', (17, 25))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (66, 83))	('enhanced hydrogen peroxide production', 'Phenotype', 'HP:0025464', (57, 94))	('adhesion', 'Var', (4, 12))	('hydrogen peroxide production', 'MPA', (66, 94))	('xanthine-oxidase', 'Enzyme', (30, 46))	('enhanced', 'PosReg', (57, 65))
167184	33923108	Thus, disorders of NOX-4 may play a crucial role in the molecular mechanisms involved in urothelial carcinogenesis's early steps.	('disorders', 'Var', (6, 15))	('urothelial carcinogenesis', 'Disease', (89, 114))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (89, 114))	('NOX-4', 'Gene', (19, 24))	('NOX-4', 'Gene', '50507', (19, 24))
167196	33923108	Moreover, the Ala9Val polymorphism of SOD2 may modulate the risk of BC development.	('SOD2', 'Gene', (38, 42))	('modulate', 'Reg', (47, 55))	('SOD2', 'molecular_function', 'GO:0004784', ('38', '42'))	('men', 'Species', '9606', (78, 81))	('Ala9Val', 'Mutation', 'rs4880', (14, 21))	('SOD2', 'Gene', '6648', (38, 42))	('polymorphism', 'Var', (22, 34))
167198	33923108	The Val/Val genotype of the SNP was associated with nearly double the risk of BC.	('Val', 'Chemical', 'MESH:D014633', (8, 11))	('Val', 'Chemical', 'MESH:D014633', (4, 7))	('Val/Val', 'Var', (4, 11))	('SNP', 'Gene', (28, 31))
167224	33923108	Molecular analysis showed that the MMP-9 5'-proximal promoter region consists of putative binding sites for AP-1 (-79 and -533), NF-kappaB (-600), Sp1 (-558) and PEA3 (-540).	('AP-1', 'cellular_component', 'GO:0005907', ('108', '112'))	('NF-kappaB', 'Gene', '4790', (129, 138))	('-79 and -533', 'Var', (114, 126))	('binding', 'molecular_function', 'GO:0005488', ('90', '97'))	('NF-kappaB', 'Gene', (129, 138))	('PEA3', 'Gene', '2118', (162, 166))	('-600', 'Var', (140, 144))	('MMP-9', 'Gene', '4318', (35, 40))	('AP-1', 'Gene', '2353', (108, 112))	('binding', 'Interaction', (90, 97))	('PEA3', 'Gene', (162, 166))	('MMP-9', 'Gene', (35, 40))	('MMP-9', 'molecular_function', 'GO:0004229', ('35', '40'))	('AP-1', 'Gene', (108, 112))	('-558', 'Var', (152, 156))
167231	33923108	In the case of patients with recurrence after 1 year from transurethral resection, the activity of GPx1 in erythrocytes and GPx3 in plasma was lower than these patients at the moment of diagnosis.	('patients', 'Species', '9606', (15, 23))	('patients', 'Species', '9606', (160, 168))	('GPx1', 'Gene', '2876', (99, 103))	('activity', 'MPA', (87, 95))	('lower', 'NegReg', (143, 148))	('GPx3', 'Gene', (124, 128))	('transurethral', 'Var', (58, 71))	('GPx1', 'Gene', (99, 103))	('men', 'Species', '9606', (178, 181))	('GPx3', 'Gene', '2878', (124, 128))
167232	33923108	(2004) found that the SNP of GPx1, which caused the substitutes Pro to Leu at codon 198 (Pro198Leu), may modulate BC risk.	('Pro198Leu', 'Var', (89, 98))	('modulate', 'Reg', (105, 113))	('GPx1', 'Gene', (29, 33))	('Pro to Leu at codon 198', 'Mutation', 'rs1050450', (64, 87))	('SNP', 'Var', (22, 25))	('Pro198Leu', 'SUBSTITUTION', 'None', (89, 98))	('GPx1', 'Gene', '2876', (29, 33))
167233	33923108	The frequency of the Pro/Leu genotype of the GPx1 gene was higher in patients with BC than in the control group, and additionally, the Pro/Leu genotype was associated with the advanced tumour stage (significantly more common in cases of T2-T4 tumours than T1 tumours).	('tumour', 'Disease', (259, 265))	('tumours', 'Phenotype', 'HP:0002664', (259, 266))	('tumours', 'Phenotype', 'HP:0002664', (243, 250))	('tumours', 'Disease', 'MESH:D009369', (259, 266))	('GPx1', 'Gene', '2876', (45, 49))	('tumours', 'Disease', 'MESH:D009369', (243, 250))	('patients', 'Species', '9606', (69, 77))	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('tumour', 'Disease', 'MESH:D009369', (243, 249))	('tumour', 'Disease', (243, 249))	('age', 'Gene', (194, 197))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('higher', 'PosReg', (59, 65))	('tumour', 'Disease', (185, 191))	('GPx1', 'Gene', (45, 49))	('Pro/Leu', 'Var', (135, 142))	('age', 'Gene', '5973', (194, 197))	('tumours', 'Disease', (259, 266))	('tumours', 'Disease', (243, 250))	('tumour', 'Phenotype', 'HP:0002664', (259, 265))	('associated with', 'Reg', (156, 171))	('tumour', 'Disease', 'MESH:D009369', (259, 265))
167234	33923108	Thus, patients with the Pro/Leu genotype were characterised by an increased risk of advanced disease (T2-T4) compared with patients with the Pro/Pro genotype.	('patients', 'Species', '9606', (123, 131))	('Pro/Leu', 'Var', (24, 31))	('patients', 'Species', '9606', (6, 14))	('advanced disease', 'Disease', (84, 100))
167235	33923108	The next study confirmed that the Pro198Leu polymorphism may also be associated with bladder cancer recurrence risk.	('bladder cancer', 'Phenotype', 'HP:0009725', (85, 99))	('associated', 'Reg', (69, 79))	('bladder cancer', 'Disease', 'MESH:D001749', (85, 99))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (85, 110))	('Pro198Leu', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('bladder cancer', 'Disease', (85, 99))	('Pro198Leu', 'SUBSTITUTION', 'None', (34, 43))
167236	33923108	(2005) found that the patients with superficial bladder cancer with Pro/Pro genotype of GPx1 were characterised by longer overall recurrence-free survival but only in individuals younger than 64 years and in women.	('bladder cancer', 'Disease', (48, 62))	('women', 'Species', '9606', (208, 213))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('Pro/Pro genotype', 'Var', (68, 84))	('GPx1', 'Gene', (88, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))	('longer', 'PosReg', (115, 121))	('GPx1', 'Gene', '2876', (88, 92))
167242	33923108	The Q/Q genotype frequency was lower in the patient group than controls, while the R/R genotype was more common in BC patients.	('patient', 'Species', '9606', (44, 51))	('lower', 'NegReg', (31, 36))	('patient', 'Species', '9606', (118, 125))	('Q/Q', 'Var', (4, 7))	('R/R', 'Var', (83, 86))	('patients', 'Species', '9606', (118, 126))
167255	33923108	Previous studies confirmed that Ras mutation was identified in about 30% of BC patients, whereas the p53 mutation is associated with over 50% of BC patients.	('patients', 'Species', '9606', (148, 156))	('associated', 'Reg', (117, 127))	('identified', 'Reg', (49, 59))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('patients', 'Species', '9606', (79, 87))	('Ras', 'Disease', (32, 35))	('mutation', 'Var', (36, 44))
167256	33923108	Moreover, ROS may modulate the methylation status of the promoter region of genes associated with carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (98, 112))	('methylation status of the promoter region', 'MPA', (31, 72))	('ROS', 'Var', (10, 13))	('carcinogenesis', 'Disease', (98, 112))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('modulate', 'Reg', (18, 26))
167257	33923108	ROS expositions can cause hypermethylation of tumour suppressors and hypomethylation of oncogenes, which are involved in cancer initiation.	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('cause', 'Reg', (20, 25))	('hypermethylation', 'MPA', (26, 42))	('oncogenes', 'Gene', (88, 97))	('tumour', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('hypomethylation', 'MPA', (69, 84))	('ROS expositions', 'Var', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (121, 127))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
167262	33923108	On the other hand, a moderate ROS level may initiate the process involved in cancer transformations.	('ROS level', 'MPA', (30, 39))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('moderate', 'Var', (21, 29))	('initiate', 'Reg', (44, 52))	('rat', 'Species', '10116', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ROS', 'Chemical', 'MESH:D017382', (30, 33))
167266	33923108	Peroxynitrate is a mutagenic compound reacting with DNA and may lead to DNA mutations of proliferating cells, including bladder epithelial cells.	('mutations', 'Var', (76, 85))	('rat', 'Species', '10116', (9, 12))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('age', 'Gene', '5973', (22, 25))	('lead to', 'Reg', (64, 71))	('Peroxynitrate', 'Chemical', '-', (0, 13))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('DNA', 'Gene', (72, 75))	('rat', 'Species', '10116', (96, 99))	('age', 'Gene', (22, 25))
167275	33923108	JAKs are signalling proteins involved in transducing signals due to tyrosine phosphorylation of STAT-3.	('signalling', 'biological_process', 'GO:0023052', ('9', '19'))	('tyrosine', 'Chemical', 'MESH:D014443', (68, 76))	('STAT-3', 'Gene', '6774', (96, 102))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('STAT-3', 'Gene', (96, 102))	('tyrosine', 'Var', (68, 76))
167291	33923108	Therefore, the inhibition of NF-kappaB by mutated IkappaB-alpha with substitutions at the serine 32 and serine 36 residues led to the reduced expression of IL-8, in resulting in a decreased angiogenesis, invasion, and metastasis in human ovarian and prostate cancer models.	('inhibition', 'NegReg', (15, 25))	('invasion', 'CPA', (204, 212))	('IL-8', 'molecular_function', 'GO:0005153', ('156', '160'))	('IkappaB-alpha', 'Gene', (50, 63))	('human', 'Species', '9606', (232, 237))	('IkappaB-alpha', 'Gene', '4792', (50, 63))	('IL-8', 'Gene', '3576', (156, 160))	('substitutions', 'Var', (69, 82))	('angiogenesis', 'biological_process', 'GO:0001525', ('190', '202'))	('serine', 'Chemical', 'MESH:D012694', (90, 96))	('reduced', 'NegReg', (134, 141))	('ovarian and prostate cancer', 'Disease', 'MESH:D011472', (238, 265))	('NF-kappaB', 'Gene', (29, 38))	('angiogenesis', 'CPA', (190, 202))	('metastasis', 'CPA', (218, 228))	('serine', 'Chemical', 'MESH:D012694', (104, 110))	('decreased', 'NegReg', (180, 189))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('expression', 'MPA', (142, 152))	('NF-kappaB', 'Gene', '4790', (29, 38))	('IL-8', 'Gene', (156, 160))	('mutated', 'Var', (42, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (250, 265))
167292	33923108	The -251 T/A polymorphism in the promoter region of IL-8 may modulate its expression and risk BC development.	('expression', 'MPA', (74, 84))	('men', 'Species', '9606', (104, 107))	('-251 T/A', 'Mutation', 'rs4073', (4, 12))	('The -251 T/A', 'Var', (0, 12))	('risk', 'Reg', (89, 93))	('IL-8', 'Gene', '3576', (52, 56))	('modulate', 'Reg', (61, 69))	('IL-8', 'Gene', (52, 56))	('IL-8', 'molecular_function', 'GO:0005153', ('52', '56'))
167318	33923108	Therefore, the study suggests that the tested polymorphism may involve angiogenesis regulation, which is essential for the invasion and metastasis of cancer.	('angiogenesis', 'biological_process', 'GO:0001525', ('71', '83'))	('regulation', 'biological_process', 'GO:0065007', ('84', '94'))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('polymorphism', 'Var', (46, 58))	('cancer', 'Disease', (150, 156))	('angiogenesis regulation', 'MPA', (71, 94))	('involve', 'Reg', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
167319	33923108	Additionally, smokers or people who had ever smoked and carried the A/A genotype of TNF-alpha -308 and the T/T genotype of IL-8 -251 polymorphism were characterised by a higher risk of BC than non-smokers.	('people', 'Species', '9606', (25, 31))	('IL-8', 'Gene', '3576', (123, 127))	('IL-8', 'Gene', (123, 127))	('IL-8', 'molecular_function', 'GO:0005153', ('123', '127'))	('polymorphism', 'Var', (133, 145))	('A/A', 'Var', (68, 71))	('TNF-alpha -308', 'Gene', (84, 98))
167324	33923108	Furthermore, the C/A+A/A genotype variant of the studied polymorphism was more common in patients with grade I (44.6%) than grade III (29.8%).	('common', 'Reg', (79, 85))	('died', 'Disease', (52, 56))	('died', 'Disease', 'MESH:D003643', (52, 56))	('patients', 'Species', '9606', (89, 97))	('C/A+A/A', 'Var', (17, 24))
167327	33923108	Previous studies showed that MMP-2 and MMP9 are associated with a high stage and grade of bladder cancer.	('bladder cancer', 'Disease', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('age', 'Gene', '5973', (73, 76))	('associated', 'Reg', (48, 58))	('MMP9', 'molecular_function', 'GO:0004229', ('39', '43'))	('MMP-2', 'Var', (29, 34))	('MMP-2', 'molecular_function', 'GO:0004228', ('29', '34'))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('MMP9', 'Gene', (39, 43))	('age', 'Gene', (73, 76))	('MMP9', 'Gene', '4318', (39, 43))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))
167340	33923108	In turn, blocking IL-6 resulted in a reduction of BC tumour growth and invasive ability due to a decrease in cell proliferation, lower epithelial-mesenchymal transition, reduced DNA methyltransferase 1 expression and attenuated angiogenesis.	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('135', '168'))	('attenuated', 'NegReg', (217, 227))	('reduction', 'NegReg', (37, 46))	('expression', 'MPA', (202, 212))	('reduced', 'NegReg', (170, 177))	('cell proliferation', 'biological_process', 'GO:0008283', ('109', '127'))	('IL-6', 'molecular_function', 'GO:0005138', ('18', '22'))	('angiogenesis', 'biological_process', 'GO:0001525', ('228', '240'))	('lower', 'NegReg', (129, 134))	('BC tumour growth', 'Disease', 'MESH:D006130', (50, 66))	('IL-6', 'Gene', '3569', (18, 22))	('BC tumour growth', 'Disease', (50, 66))	('decrease', 'NegReg', (97, 105))	('IL-6', 'Gene', (18, 22))	('epithelial-mesenchymal transition', 'CPA', (135, 168))	('DNA methyltransferase 1', 'Gene', (178, 201))	('cell proliferation', 'CPA', (109, 127))	('DNA methyltransferase 1', 'Gene', '1786', (178, 201))	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('angiogenesis', 'CPA', (228, 240))	('invasive ability', 'CPA', (71, 87))	('methyltransferase 1', 'molecular_function', 'GO:0047152', ('182', '201'))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('blocking', 'Var', (9, 17))	('rat', 'Species', '10116', (121, 124))
167346	33923108	(2008) showed that IL-6 inhibition decreased STAT3 activity and, as a result, led to increased E-cadherin and decreased VEGF and MMP-9 expressions.	('VEGF', 'Gene', '7422', (120, 124))	('IL-6', 'Gene', (19, 23))	('STAT3', 'Gene', (45, 50))	('E-cadherin', 'Gene', (95, 105))	('cadherin', 'molecular_function', 'GO:0008014', ('97', '105'))	('MMP-9', 'molecular_function', 'GO:0004229', ('129', '134'))	('decreased', 'NegReg', (110, 119))	('decreased', 'NegReg', (35, 44))	('IL-6', 'Gene', '3569', (19, 23))	('inhibition', 'Var', (24, 34))	('E-cadherin', 'Gene', '999', (95, 105))	('MMP-9', 'Gene', (129, 134))	('MMP-9', 'Gene', '4318', (129, 134))	('increased', 'PosReg', (85, 94))	('VEGF', 'Gene', (120, 124))	('IL-6', 'molecular_function', 'GO:0005138', ('19', '23'))	('STAT3', 'Gene', '6774', (45, 50))
167357	33923108	Moreover, the C/C genotype of -174 G>C polymorphism localised in the IL-6 gene was associated with the increased risk of BC in ever smokers and not in never smokers with the highest BC risk occurring current smokers.	('IL-6', 'Gene', '3569', (69, 73))	('IL-6', 'molecular_function', 'GO:0005138', ('69', '73'))	('-174 G>C', 'Mutation', 'rs1800795', (30, 38))	('IL-6', 'Gene', (69, 73))	('C/C', 'Var', (14, 17))
167359	33923108	Moreover, gender analysis showed that the C/C genotype of the -174G>C polymorphism was associated with the risk of BC occurrence in the men group but not in women.	('men', 'Species', '9606', (159, 162))	('women', 'Species', '9606', (157, 162))	('BC occurrence', 'Disease', (115, 128))	('-174G>C', 'Mutation', 'rs1800795', (62, 69))	('C/C', 'Var', (42, 45))	('men', 'Species', '9606', (136, 139))
167360	33923108	Interestingly, the G/C and C/C genotypes of the SNP were correlated with the near twice-increased progression risk in patients with non-muscle-invasive BC.	('C/C', 'Var', (27, 30))	('SNP', 'Gene', (48, 51))	('patients', 'Species', '9606', (118, 126))	('G/C', 'Var', (19, 22))
167361	33923108	Therefore, the -174G>C polymorphism of the IL-6 may play a crucial role in bladder cancer development.	('IL-6', 'Gene', (43, 47))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('men', 'Species', '9606', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('-174G>C', 'Mutation', 'rs1800795', (15, 22))	('the -174G>C', 'Var', (11, 22))	('role', 'Reg', (67, 71))	('IL-6', 'Gene', '3569', (43, 47))	('IL-6', 'molecular_function', 'GO:0005138', ('43', '47'))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))	('play', 'Reg', (52, 56))
167362	33923108	The change from G to C at position 174 of IL-6 gene leads to creating a potential binding site for the transcription factor NF-1.	('transcription', 'biological_process', 'GO:0006351', ('103', '116'))	('binding', 'molecular_function', 'GO:0005488', ('82', '89'))	('NF-1', 'Gene', '4763', (124, 128))	('change', 'Var', (4, 10))	('G to C at position 174', 'Mutation', 'rs1800795', (16, 38))	('NF-1', 'Gene', (124, 128))	('transcription factor', 'molecular_function', 'GO:0000981', ('103', '123'))	('IL-6', 'Gene', (42, 46))	('binding', 'Interaction', (82, 89))	('IL-6', 'Gene', '3569', (42, 46))	('IL-6', 'molecular_function', 'GO:0005138', ('42', '46'))
167365	33923108	Thus, the C/C genotype of the SNP may favour an increase of the inflammation and, consequently, development of the BC.	('men', 'Species', '9606', (103, 106))	('inflammation', 'Disease', 'MESH:D007249', (64, 76))	('inflammation', 'Disease', (64, 76))	('inflammation', 'biological_process', 'GO:0006954', ('64', '76'))	('SNP', 'Gene', (30, 33))	('increase', 'PosReg', (48, 56))	('C/C genotype', 'Var', (10, 22))
167366	33923108	On the other hand, the G/C+C/C variant of the IL-6 improved a 5-year overall and disease-specific survival in patients with invasive BC.	('IL-6', 'Gene', (46, 50))	('disease-specific survival', 'CPA', (81, 106))	('improved', 'PosReg', (51, 59))	('IL-6', 'molecular_function', 'GO:0005138', ('46', '50'))	('IL-6', 'Gene', '3569', (46, 50))	('G/C+C/C', 'Var', (23, 30))	('invasive BC', 'Disease', (124, 135))	('patients', 'Species', '9606', (110, 118))
167367	33923108	Moreover, in the Indian population, the G/C+C/C variant genotypes were more common in patients with grade I than grade III tumours.	('common', 'Reg', (76, 82))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('G/C+C/C', 'Var', (40, 47))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('tumours', 'Disease', (123, 130))	('patients', 'Species', '9606', (86, 94))
167376	33923108	Interestingly, an in vitro study showed that MB49 cells with knockout IL-17 (-/-) were characterised by reduced growth.	('reduced', 'NegReg', (104, 111))	('growth', 'MPA', (112, 118))	('IL-17', 'Gene', (70, 75))	('MB49', 'CellLine', 'CVCL:7076', (45, 49))	('knockout', 'Var', (61, 69))	('IL-17', 'molecular_function', 'GO:0030367', ('70', '75'))
167377	33923108	In addition, the TT genotype and T allele of rs763780 and A/A genotype and A allele of rs2275913 polymorphism localised in IL-17 gene were associated with an increased risk of BC occurrence in a Chinese Han population.	('IL-17', 'Gene', (123, 128))	('rs763780', 'Var', (45, 53))	('rs763780', 'Mutation', 'rs763780', (45, 53))	('IL-17', 'molecular_function', 'GO:0030367', ('123', '128'))	('rs2275913', 'Var', (87, 96))	('rs2275913', 'Mutation', 'rs2275913', (87, 96))
167379	33923108	However, only rs763780 polymorphism was associated with invasion of bladder cancer.	('rs763780', 'Var', (14, 22))	('bladder cancer', 'Phenotype', 'HP:0009725', (68, 82))	('rs763780', 'Mutation', 'rs763780', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('bladder cancer', 'Disease', 'MESH:D001749', (68, 82))	('bladder cancer', 'Disease', (68, 82))	('associated', 'Reg', (40, 50))
167406	33923108	(2006) found that the genetic deletion or blockade of IL-23 in mice caused an increased infiltration of cytotoxic T cells with protective effects against cancer.	('rat', 'Species', '10116', (94, 97))	('IL-23', 'Gene', (54, 59))	('IL-23', 'molecular_function', 'GO:0045519', ('54', '59'))	('blockade', 'NegReg', (42, 50))	('cancer', 'Disease', (154, 160))	('mice', 'Species', '10090', (63, 67))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('increased', 'PosReg', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('genetic deletion', 'Var', (22, 38))	('infiltration of cytotoxic T cells', 'CPA', (88, 121))
167410	33923108	A meta-analysis showed that the IL-4 haplotypes, IL4-589T and IL4-33T, were associated with the patients higher survival rate with the haplotype IL-4-589C-33C.	('IL4', 'Gene', '3565', (62, 65))	('IL4', 'Gene', (62, 65))	('IL4', 'Gene', '3565', (49, 52))	('IL4', 'Gene', (49, 52))	('higher', 'PosReg', (105, 111))	('IL-4-589C-33C', 'Var', (145, 158))	('IL-4', 'Gene', (32, 36))	('IL-4', 'molecular_function', 'GO:0005136', ('145', '149'))	('IL4', 'molecular_function', 'GO:0005136', ('62', '65'))	('IL4', 'molecular_function', 'GO:0005136', ('49', '52'))	('IL-4', 'molecular_function', 'GO:0005136', ('32', '36'))	('patients', 'Species', '9606', (96, 104))	('survival rate', 'CPA', (112, 125))	('rat', 'Species', '10116', (121, 124))
167411	33923108	The T/T genotype of IL-4 polymorphism (rs2243250) was associated with an increased risk of developing multiple BCs.	('IL-4', 'molecular_function', 'GO:0005136', ('20', '24'))	('T/T', 'Var', (4, 7))	('rs2243250', 'Var', (39, 48))	('multiple BCs', 'Disease', (102, 114))	('IL-4', 'Gene', (20, 24))	('rs2243250', 'Mutation', 'rs2243250', (39, 48))
167436	33923108	Interestingly, the risk of recurrence in patients with high-grade T1 tumours receiving BCG therapy may be modulated by tumour size, age and presence of carcinoma in situ, peripheral blood neutrophil-to-lymphocyte ratio (NLR), high-grade T1 on re-transurethral resection of bladder tumour (TURBT), obesity, as well as lymph-vascular invasion.	('BCG', 'Species', '33892', (87, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('obesity', 'Disease', (297, 304))	('modulated', 'Reg', (106, 115))	('carcinoma', 'Disease', (152, 161))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('rat', 'Species', '10116', (213, 216))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('bladder tumour', 'Disease', (273, 287))	('age', 'Gene', (132, 135))	('lymph-vascular invasion', 'CPA', (317, 340))	('tumour', 'Phenotype', 'HP:0002664', (281, 287))	('tumour', 'Disease', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (281, 287))	('obesity', 'Disease', 'MESH:D009765', (297, 304))	('tumour', 'Disease', (281, 287))	('carcinoma', 'Disease', 'MESH:D009369', (152, 161))	('bladder tumour', 'Phenotype', 'HP:0009725', (273, 287))	('age', 'Gene', '5973', (132, 135))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (152, 169))	('patients', 'Species', '9606', (41, 49))	('obesity', 'Phenotype', 'HP:0001513', (297, 304))	('high-grade', 'Var', (226, 236))	('tumours', 'Disease', (69, 76))	('bladder tumour', 'Disease', 'MESH:D001749', (273, 287))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('tumour', 'Disease', (119, 125))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
167452	33923108	Thus, a high SII level was correlated with low cancer-specific survival (CSS) in MIBC patients after radical cystectomy.	('high', 'Var', (8, 12))	('low', 'NegReg', (43, 46))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('MIBC', 'Chemical', '-', (81, 85))	('cancer', 'Disease', (47, 53))	('MIBC', 'Disease', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('SII level', 'MPA', (13, 22))	('patients', 'Species', '9606', (86, 94))
167458	33923108	The median recurrence-free survival time for BCG-treated NIMBC patients with high baseline IL-8 levels was shorter than those with low IL-8 levels (7.9 vs. >78.4 months, respectively).	('IL-8', 'Gene', (135, 139))	('IL-8', 'Gene', '3576', (91, 95))	('high', 'Var', (77, 81))	('NIMBC', 'Gene', (57, 62))	('recurrence-free survival time', 'CPA', (11, 40))	('IL-8', 'Gene', (91, 95))	('IL-8', 'molecular_function', 'GO:0005153', ('91', '95'))	('IL-8', 'molecular_function', 'GO:0005153', ('135', '139'))	('shorter', 'NegReg', (107, 114))	('patients', 'Species', '9606', (63, 71))	('BCG', 'Species', '33892', (45, 48))	('IL-8', 'Gene', '3576', (135, 139))
167466	33923108	Genetic analysis indicated that polymorphisms localised in genes associated with inflammation may be also used as a potential biomarker of recurrence risk of NIMBC.	('polymorphisms', 'Var', (32, 45))	('NIMBC', 'Disease', (158, 163))	('inflammation', 'biological_process', 'GO:0006954', ('81', '93'))	('inflammation', 'Disease', 'MESH:D007249', (81, 93))	('inflammation', 'Disease', (81, 93))
167467	33923108	The C/C genotype of IL-6 (-174 G>C) polymorphism was associated with decreased recurrence risk in the BCG-treated group.	('recurrence', 'Disease', (79, 89))	('IL-6', 'molecular_function', 'GO:0005138', ('20', '24'))	('decreased', 'NegReg', (69, 78))	('-174 G>C', 'Var', (26, 34))	('BCG', 'Species', '33892', (102, 105))	('-174 G>C', 'Mutation', 'rs1800795', (26, 34))	('IL-6', 'Gene', (20, 24))	('C/C', 'Var', (4, 7))	('IL-6', 'Gene', '3569', (20, 24))
167468	33923108	In the case of polymorphism localised in the TNF-alpha gene (rs1799964), the C/C homozygote decreased the recurrence risk after BCG immunotherapy.	('TNF-alpha', 'Gene', (45, 54))	('recurrence', 'CPA', (106, 116))	('rs1799964', 'Mutation', 'rs1799964', (61, 70))	('rs1799964', 'Var', (61, 70))	('decreased', 'NegReg', (92, 101))	('BCG', 'Species', '33892', (128, 131))
167470	33923108	In northern India, the A/A genotype of -251 T > A IL-8 polymorphism was associated with a reduced recurrence risk after BCG immunotherapy.	('IL-8', 'Gene', (50, 54))	('reduced', 'NegReg', (90, 97))	('IL-8', 'molecular_function', 'GO:0005153', ('50', '54'))	('BCG', 'Species', '33892', (120, 123))	('-251 T > A', 'Mutation', 'rs4073', (39, 49))	('of -251 T > A', 'Var', (36, 49))	('IL-8', 'Gene', '3576', (50, 54))
167482	33923108	Thus, abnormal VEGFs expression can be used as a prognostic marker in bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('abnormal', 'Var', (6, 14))	('VEGF', 'Gene', (15, 19))	('expression', 'MPA', (21, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('VEGF', 'Gene', '7422', (15, 19))	('bladder cancer', 'Disease', 'MESH:D001749', (70, 84))	('bladder cancer', 'Disease', (70, 84))
167485	33923108	(2009) showed that the VEGF transcript level was higher in patients with pT2-T4 than in pTa and pT1 urothelial tumours.	('urothelial tumours', 'Disease', (100, 118))	('pT1', 'Gene', (96, 99))	('pTa', 'molecular_function', 'GO:0008959', ('88', '91'))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('VEGF', 'Gene', (23, 27))	('patients', 'Species', '9606', (59, 67))	('pT1', 'Gene', '58492', (96, 99))	('pTa', 'Gene', (88, 91))	('pT2-T4', 'Var', (73, 79))	('urothelial tumours', 'Disease', 'MESH:D014523', (100, 118))	('higher', 'PosReg', (49, 55))	('pTa', 'Gene', '171558', (88, 91))	('VEGF', 'Gene', '7422', (23, 27))
167486	33923108	Additionally, BC patients with higher mRNA level of VEGF-A were characterised by shorter survival without progression than those with a lower level.	('VEGF-A', 'Gene', '7422', (52, 58))	('mRNA level', 'Var', (38, 48))	('VEGF-A', 'Gene', (52, 58))	('patients', 'Species', '9606', (17, 25))	('higher', 'PosReg', (31, 37))	('survival', 'MPA', (89, 97))	('shorter', 'NegReg', (81, 88))
167506	33923108	The comprehensive analysis of polymorphisms localised in the VEGF gene showed that the A/A genotype of -15648A>C (rs833052) polymorphism, T/T genotype of -9228G>T (rs1109324) polymorphism, the T/T genotype of -8339A>T (rs1547651) and the T/T genotype of Ex1-73C>T (5'UTR) (rs25648) polymorphism were associated with increased risk of BC.	('VEGF', 'Gene', '7422', (61, 65))	('-15648A>C', 'Mutation', 'rs833052', (103, 112))	('rs25648', 'Mutation', 'rs25648', (273, 280))	('-73C>T', 'Mutation', 'c.-73C>T', (257, 263))	('-8339A>T', 'Mutation', 'rs1547651', (209, 217))	('-9228G>T', 'Mutation', 'rs1109324', (154, 162))	('VEGF', 'Gene', (61, 65))	('rs1547651', 'Var', (219, 228))	('rs833052', 'Mutation', 'rs833052', (114, 122))	('rs1109324', 'Mutation', 'rs1109324', (164, 173))	('rs25648', 'Var', (273, 280))	('rs1547651', 'Mutation', 'rs1547651', (219, 228))	('of -15648A>C (rs833052', 'Var', (100, 122))
167507	33923108	On the other hand, in the case of IV42 +1378C>T polymorphism localised in the second intron of VEGF gene (rs3024994), the heterozygote decreased the risk.	('rs3024994', 'Mutation', 'rs3024994', (106, 115))	('VEGF', 'Gene', '7422', (95, 99))	('IV42 +1378C>T', 'Var', (34, 47))	('+1378C>T', 'Mutation', 'c.+1378C>T', (39, 47))	('VEGF', 'Gene', (95, 99))	('decreased', 'NegReg', (135, 144))	('rs3024994', 'Var', (106, 115))
167508	33923108	An Asian population subgroup study showed that the C/T genotype of rs3025039 SNP and the C/A genotype of rs833052 SNP were more common in patients with BC than homozygote variants.	('rs833052', 'Mutation', 'rs833052', (105, 113))	('rs3025039 SNP', 'Var', (67, 80))	('common', 'Reg', (128, 134))	('rs833052 SNP', 'Var', (105, 117))	('rs3025039', 'Mutation', 'rs3025039', (67, 76))	('patients', 'Species', '9606', (138, 146))
167515	33923108	Theodoropoulos's team confirmed that the high expression of HIF-1 was associated with the development of high-grade superficial urothelial carcinomas.	('urothelial carcinomas', 'Disease', 'MESH:D014523', (128, 149))	('men', 'Species', '9606', (97, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('high expression', 'Var', (41, 56))	('HIF-1', 'Gene', '3091', (60, 65))	('associated with', 'Reg', (70, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('urothelial carcinomas', 'Disease', (128, 149))	('HIF-1', 'Gene', (60, 65))
167519	33923108	Interestingly, the previous analysis showed that P582S and A588T polymorphism in the HIF-1alpha gene causes an increase in transcriptional activity compared to the wild type.	('increase', 'PosReg', (111, 119))	('transcriptional activity', 'MPA', (123, 147))	('HIF-1alpha', 'Gene', '3091', (85, 95))	('P582S', 'Var', (49, 54))	('P582S', 'Mutation', 'rs11549465', (49, 54))	('HIF-1alpha', 'Gene', (85, 95))	('A588T', 'Mutation', 'rs11549467', (59, 64))	('A588T', 'Var', (59, 64))
167520	33923108	Although the study showed that genotypes of studied HIF-1alpha polymorphism did not influence the incidence of transitional cell carcinoma, among patients who underwent radical cystectomy, those with a variant allele (T allele for P582S and A allele for A588T) had significantly worse disease-free survival and disease-specific survival than those without a variant allele.	('disease-specific survival', 'CPA', (311, 336))	('HIF-1alpha', 'Gene', (52, 62))	('transitional cell carcinoma', 'Disease', (111, 138))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (111, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('disease-free survival', 'CPA', (285, 306))	('worse', 'NegReg', (279, 284))	('died', 'Disease', (47, 51))	('HIF-1alpha', 'Gene', '3091', (52, 62))	('P582S', 'Var', (231, 236))	('died', 'Disease', 'MESH:D003643', (47, 51))	('transitional cell carcinoma', 'Disease', 'MESH:D002295', (111, 138))	('patients', 'Species', '9606', (146, 154))	('P582S', 'Mutation', 'rs11549465', (231, 236))	('A588T', 'Mutation', 'rs11549467', (254, 259))
167536	33923108	The G/G genotype of -181A/G polymorphism (rs11568818) localised in MMP7 was more common in the BC patients than the control group, but the polymorphism was not correlated with the tumour grade or stage.	('rs11568818', 'Var', (42, 52))	('age', 'Gene', (198, 201))	('MMP7', 'Gene', (67, 71))	('MMP7', 'molecular_function', 'GO:0004235', ('67', '71'))	('MMP7', 'Gene', '4316', (67, 71))	('-181A/G', 'Mutation', 'rs11568818', (20, 27))	('patients', 'Species', '9606', (98, 106))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('age', 'Gene', '5973', (198, 201))	('rs11568818', 'Mutation', 'rs11568818', (42, 52))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('common', 'Reg', (81, 87))	('tumour', 'Disease', (180, 186))
167537	33923108	The 2G/1G+1G/1G genotype of MMP1 polymorphism (rs1799750) reduced BC risk.	('MMP1', 'molecular_function', 'GO:0004232', ('28', '32'))	('MMP1', 'Gene', '4312', (28, 32))	('rs1799750', 'Mutation', 'rs1799750', (47, 56))	('reduced', 'NegReg', (58, 65))	('rs1799750', 'Var', (47, 56))	('MMP1', 'Gene', (28, 32))
167541	33923108	The G/G genotype -181A/G polymorphism localised in MMP-7 gene was associated with a 1.56-fold increased risk of BC compared to the A/A genotype in a Chinese Han population.	('polymorphism', 'Var', (25, 37))	('-181A/G', 'Mutation', 'rs11568818', (17, 24))	('MMP-7', 'molecular_function', 'GO:0004235', ('51', '56'))	('MMP-7', 'Gene', (51, 56))	('G/G genotype -181A/G polymorphism', 'Var', (4, 37))	('MMP-7', 'Gene', '4316', (51, 56))
167543	33923108	Moreover, the A/G or G/G genotype of the studied polymorphism was associated with BC risk in the groups of tumour size >= 3 cm.	('G/G', 'Var', (21, 24))	('A/G', 'Var', (14, 17))	('associated', 'Reg', (66, 76))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('died', 'Disease', (44, 48))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('died', 'Disease', 'MESH:D003643', (44, 48))	('tumour', 'Disease', (107, 113))
167553	33923108	The analysis of -696C/T (rs2664139) polymorphism of TSP-1 showed that the C/C genotype increased the risk of BC as compared to the C/T and T/T genotypes in the Chinese population.	('increased', 'PosReg', (87, 96))	('TSP-1', 'molecular_function', 'GO:0004277', ('52', '57'))	('C/C', 'Var', (74, 77))	('TSP-1', 'Gene', (52, 57))	('TSP-1', 'Gene', '7057', (52, 57))	('-696C/T', 'Mutation', 'rs2664139', (16, 23))	('rs2664139', 'Mutation', 'rs2664139', (25, 34))
167555	33923108	Moreover, the analysis of BC clinical features showed that the studied polymorphism was associated with a higher risk of developing grade III, multiple-tumour and large-BC.	('large-BC', 'Disease', (163, 171))	('died', 'Disease', 'MESH:D003643', (66, 70))	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('died', 'Disease', (66, 70))	('tumour', 'Disease', (152, 158))	('grade III', 'Disease', (132, 141))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('polymorphism', 'Var', (71, 83))
167556	33923108	On the other hand, in the case of -1223A/G (rs2169830) polymorphism localised in TSP-1 gene, no significant differences were detected in the genotype frequencies of controls and BC patients in the Chinese population.	('TSP-1', 'Gene', '7057', (81, 86))	('TSP-1', 'molecular_function', 'GO:0004277', ('81', '86'))	('-1223A/G', 'Mutation', 'rs2169830', (34, 42))	('rs2169830) polymorphism', 'Var', (44, 67))	('patients', 'Species', '9606', (181, 189))	('rs2169830', 'Mutation', 'rs2169830', (44, 53))	('TSP-1', 'Gene', (81, 86))
167557	33923108	However, the mRNA expression of the gene in bladder cancer tissues was lower in patients with the A/G genotype than those in those with an A/A genotype, while patients with the G/G genotype were characterised by the lowest expression.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (44, 58))	('patients', 'Species', '9606', (80, 88))	('mRNA expression', 'MPA', (13, 28))	('bladder cancer', 'Disease', 'MESH:D001749', (44, 58))	('bladder cancer', 'Disease', (44, 58))	('patients', 'Species', '9606', (159, 167))	('A/G', 'Var', (98, 101))	('lower', 'NegReg', (71, 76))
167569	33923108	The most frequent somatic FGFR3 mutations are localised in exons 7 (codon 248/249), exon 10, (codon 372) and exon 15 (codon 652); moreover, the mutations were associated with the development of tumours with favourable prognosis (including low-grade non-invasive papillary urothelial cancer and papillary urothelial neoplasms of low malignant potential).	('tumours', 'Phenotype', 'HP:0002664', (194, 201))	('papillary urothelial neoplasms', 'Disease', 'MESH:D014523', (294, 324))	('FGFR3', 'Gene', (26, 31))	('codon', 'Var', (94, 99))	('tumours', 'Disease', 'MESH:D009369', (194, 201))	('neoplasms', 'Phenotype', 'HP:0002664', (315, 324))	('tumours', 'Disease', (194, 201))	('associated with', 'Reg', (159, 174))	('men', 'Species', '9606', (186, 189))	('invasive papillary urothelial cancer', 'Disease', 'MESH:D002291', (253, 289))	('mutations', 'Var', (32, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('FGFR3', 'Gene', '2261', (26, 31))	('papillary urothelial neoplasms', 'Disease', (294, 324))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('mutations', 'Var', (144, 153))	('invasive papillary urothelial cancer', 'Disease', (253, 289))
167572	33923108	On the one hand, ROS overproduction may induce activity of proinflammatory cytokines, including IL-6 and TNF-alpha.	('IL-6', 'Gene', '3569', (96, 100))	('ROS', 'Chemical', 'MESH:D017382', (17, 20))	('TNF-alpha', 'MPA', (105, 114))	('ROS', 'Protein', (17, 20))	('proinflammatory cytokines', 'MPA', (59, 84))	('overproduction', 'Var', (21, 35))	('IL-6', 'Gene', (96, 100))	('IL-6', 'molecular_function', 'GO:0005138', ('96', '100'))	('activity', 'MPA', (47, 55))	('induce', 'PosReg', (40, 46))
167580	32370101	In this study, we demonstrate that cells expressing cancer-associated activating FGFR3 mutants and the FGFR3-TACC3 fusion showed primary resistance to infigratinib in long-term colony formation assays in both NIH-3T3 and urothelial carcinoma models.	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('NIH-3T3', 'CellLine', 'CVCL:0594', (209, 216))	('urothelial carcinoma', 'Disease', (221, 241))	('FGFR3', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('103', '107'))	('infigratinib', 'Chemical', 'MESH:C568950', (151, 163))	('activating', 'PosReg', (70, 80))	('mutants', 'Var', (87, 94))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (221, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('formation', 'biological_process', 'GO:0009058', ('184', '193'))	('resistance', 'MPA', (137, 147))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
167581	32370101	We find that expression of these FGFR3 molecular alterations resulted in elevated constitutive Src activation compared to wildtype FGFR3 and that cells co-opted this pathway as a means to achieve intrinsic resistance to infigratinib.	('alterations', 'Var', (49, 60))	('infigratinib', 'Chemical', 'MESH:C568950', (220, 232))	('FGFR', 'molecular_function', 'GO:0005007', ('131', '135'))	('activation', 'PosReg', (99, 109))	('intrinsic', 'MPA', (196, 205))	('elevated', 'PosReg', (73, 81))	('FGFR3', 'Gene', (33, 38))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('constitutive Src', 'MPA', (82, 98))
167582	32370101	Targeting the Src pathway with low doses of the kinase inhibitor dasatinib synergistically sensitized multiple urothelial carcinoma lines harbouring endogenous FGFR3 alterations to infigratinib.	('FGFR3', 'Gene', (160, 165))	('urothelial carcinoma', 'Disease', (111, 131))	('infigratinib', 'Chemical', 'MESH:C568950', (181, 193))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (111, 131))	('alterations', 'Var', (166, 177))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('48', '64'))	('dasatinib', 'Chemical', 'MESH:D000069439', (65, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('FGFR', 'molecular_function', 'GO:0005007', ('160', '164'))	('Src pathway', 'Pathway', (14, 25))
167583	32370101	Our data provide preclinical rationale that supports the use of dasatinib in combination with selective FGFR inhibitors as a means to overcome intrinsic drug resistance in the salvage therapy setting in urothelial cancer patients with FGFR3 molecular alterations Activating molecular alterations in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene have been identified through large-scale next generation genomic sequencing efforts across a range of tumour types including urothelial carcinoma, lung squamous cell carcinoma, glioblastoma and myeloma.	('alterations', 'Var', (251, 262))	('patients', 'Species', '9606', (221, 229))	('Fibroblast Growth Factor Receptor 3', 'Gene', '2261', (303, 338))	('drug resistance', 'biological_process', 'GO:0042493', ('153', '168'))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (477, 497))	('FGFR3', 'Gene', (340, 345))	('FGFR', 'molecular_function', 'GO:0005007', ('235', '239'))	('FGFR', 'molecular_function', 'GO:0005007', ('104', '108'))	('Fibroblast Growth Factor Receptor 3', 'Gene', (303, 338))	('urothelial cancer', 'Disease', 'MESH:D014523', (203, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (518, 527))	('urothelial carcinoma', 'Disease', (477, 497))	('glioblastoma', 'Phenotype', 'HP:0012174', (529, 541))	('FGFR3', 'Gene', (235, 240))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (499, 527))	('dasatinib', 'Chemical', 'MESH:D000069439', (64, 73))	('urothelial cancer', 'Disease', (203, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('drug resistance', 'Phenotype', 'HP:0020174', (153, 168))	('glioblastoma and myeloma', 'Disease', 'MESH:D005909', (529, 553))	('tumour', 'Phenotype', 'HP:0002664', (454, 460))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (499, 527))	('tumour', 'Disease', 'MESH:D009369', (454, 460))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (504, 527))	('lung squamous cell carcinoma', 'Disease', (499, 527))	('tumour', 'Disease', (454, 460))	('carcinoma', 'Phenotype', 'HP:0030731', (488, 497))	('FGFR', 'molecular_function', 'GO:0005007', ('340', '344'))	('Fibroblast Growth Factor', 'molecular_function', 'GO:0005104', ('303', '327'))	('drug resistance', 'biological_process', 'GO:0009315', ('153', '168'))
167584	32370101	These molecular alterations primarily comprise of point mutations that span across the gene (e.g., S249C, R248C and K652E) and gene fusions (e.g., FGFR3-TACC3 fusion).	('K652E', 'Var', (116, 121))	('R248C', 'Mutation', 'rs121913482', (106, 111))	('K652E', 'Mutation', 'rs78311289', (116, 121))	('S249C', 'Mutation', 'rs121913483', (99, 104))	('FGFR', 'molecular_function', 'GO:0005007', ('147', '151'))	('R248C', 'Var', (106, 111))
167585	32370101	The cancer type with the highest proportion of FGFR3 alterations is urothelial carcinoma with a frequency of 60-80% in the non-muscle-invasive form and 15-20% in the muscle-invasive form harbouring these molecular aberrations.	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('FGFR3', 'Gene', (47, 52))	('non-muscle-invasive', 'Disease', (123, 142))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('alterations', 'Var', (53, 64))	('urothelial carcinoma', 'Disease', (68, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (68, 88))	('cancer', 'Disease', (4, 10))
167586	32370101	The most common FGFR3 point mutation found across cancer types is S249C in which the extracellular domain cysteine substitution leads to the formation of a disulphide bond between receptor monomers resulting in ligand-independent constitutive dimerization and activation.	('formation', 'Reg', (141, 150))	('FGFR3', 'Gene', (16, 21))	('disulphide bond', 'MPA', (156, 171))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('disulphide', 'Chemical', '-', (156, 166))	('S249C', 'Var', (66, 71))	('formation', 'biological_process', 'GO:0009058', ('141', '150'))	('leads to', 'Reg', (128, 136))	('activation', 'PosReg', (260, 270))	('S249C', 'Mutation', 'rs121913483', (66, 71))	('extracellular', 'cellular_component', 'GO:0005576', ('85', '98'))	('ligand', 'molecular_function', 'GO:0005488', ('211', '217'))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('ligand-independent constitutive dimerization', 'MPA', (211, 255))	('point mutation', 'Var', (22, 36))	('cysteine', 'Chemical', 'MESH:D003545', (106, 114))
167587	32370101	In contrast, the FGFR3-TACC3 fusion has been described at low frequencies (2-8%) in urothelial cancers and glioblastoma and mediates it oncogenic activity through constitutive dimerization of FGFR3 driven by TACC3.	('urothelial cancers', 'Disease', 'MESH:D014523', (84, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('FGFR3-TACC3', 'Gene', (17, 28))	('urothelial cancers', 'Disease', (84, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('FGFR3', 'Gene', (192, 197))	('constitutive', 'MPA', (163, 175))	('glioblastoma', 'Phenotype', 'HP:0012174', (107, 119))	('glioblastoma', 'Disease', (107, 119))	('oncogenic activity', 'CPA', (136, 154))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('fusion', 'Var', (29, 35))	('glioblastoma', 'Disease', 'MESH:D005909', (107, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('192', '196'))
167590	32370101	Pal et al., reported response rates of 25.4% in the evaluation of infigratinib in 67 patients with previously treated advanced urothelial carcinoma with FGFR3 alterations.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('Pal', 'molecular_function', 'GO:0004598', ('0', '3'))	('FGFR', 'molecular_function', 'GO:0005007', ('153', '157'))	('alterations', 'Var', (159, 170))	('infigratinib', 'Chemical', 'MESH:C568950', (66, 78))	('patients', 'Species', '9606', (85, 93))	('urothelial carcinoma', 'Disease', (127, 147))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (127, 147))	('FGFR3', 'Gene', (153, 158))
167592	32370101	This result has led to the accelerated approval of erdafitinib in 2019 by the US Food and Drug Administration (FDA) for locally advanced or metastatic urothelial carcinomas with FGFR2 and FGFR3 alterations.	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('FGFR', 'molecular_function', 'GO:0005007', ('188', '192'))	('urothelial carcinomas', 'Disease', (151, 172))	('FGFR3', 'Gene', (188, 193))	('alterations', 'Var', (194, 205))	('erdafitinib', 'Chemical', 'MESH:C000604580', (51, 62))	('FGFR2', 'Gene', '2263', (178, 183))	('locally advanced', 'Disease', (120, 136))	('FGFR', 'molecular_function', 'GO:0005007', ('178', '182'))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (151, 172))	('FGFR2', 'Gene', (178, 183))
167593	32370101	Despite these promising results, the BLC2001 trial showed that only 49% and 16% of patients with FGFR point mutations and fusions, respectively, achieved disease response with erdafitinib.	('point mutations', 'Var', (102, 117))	('FGFR', 'molecular_function', 'GO:0005007', ('97', '101'))	('disease response', 'MPA', (154, 170))	('fusions', 'Var', (122, 129))	('FGFR', 'Gene', (97, 101))	('erdafitinib', 'Chemical', 'MESH:C000604580', (176, 187))	('patients', 'Species', '9606', (83, 91))
167594	32370101	Similarly, Pal et al., reported that only 42.9% of patients with documented FGFR3 activating point mutations responded to infigratinib.	('responded', 'Reg', (109, 118))	('infigratinib', 'Chemical', 'MESH:C568950', (122, 134))	('activating', 'PosReg', (82, 92))	('patients', 'Species', '9606', (51, 59))	('point mutations', 'Var', (93, 108))	('FGFR3', 'Gene', (76, 81))	('Pal', 'molecular_function', 'GO:0004598', ('11', '14'))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))
167597	32370101	We further demonstrate that expression of these FGFR3 mutants and FGFR3-TACC3 results in elevated constitutive Src activation levels compared to wildtype (WT) FGFR3, which can be exploited for therapy with the multi-target TKI dasatinib.	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('FGFR3-TACC3', 'Gene', (66, 77))	('constitutive Src activation levels', 'MPA', (98, 132))	('dasatinib', 'Chemical', 'MESH:D000069439', (227, 236))	('mutants', 'Var', (54, 61))	('FGFR3', 'Gene', (48, 53))	('elevated', 'PosReg', (89, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))
167598	32370101	We find that targeting the Src pathway with low dose dasatinib sensitizes urothelial carcinoma cell lines harbouring endogenous FGFR3 molecular alterations to selective FGFR TKIs including infigratinib.	('dasatinib', 'Chemical', 'MESH:D000069439', (53, 62))	('FGFR', 'molecular_function', 'GO:0005007', ('169', '173'))	('infigratinib', 'Chemical', 'MESH:C568950', (189, 201))	('urothelial carcinoma', 'Disease', (74, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('128', '132'))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (74, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('alterations', 'Var', (144, 155))	('sensitizes', 'Reg', (63, 73))	('FGFR3', 'Gene', (128, 133))
167599	32370101	Our preclinical data suggest that patients with FGFR3 molecular alterations may benefit from treatment with FGFR and Src inhibitors in combination, which can overcome intrinsic resistance associated with selective FGFR TKI monotherapy.	('FGFR', 'molecular_function', 'GO:0005007', ('214', '218'))	('benefit', 'PosReg', (80, 87))	('FGFR3', 'Gene', (48, 53))	('patients', 'Species', '9606', (34, 42))	('alterations', 'Var', (64, 75))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))
167600	32370101	We first evaluated the effects of infigratinib in NIH-3T3 cells expressing a selection of the most prevalent activating FGFR3 molecular alterations in cancer.	('FGFR3', 'Gene', (120, 125))	('infigratinib', 'Chemical', 'MESH:C568950', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('alterations', 'Var', (136, 147))	('FGFR', 'molecular_function', 'GO:0005007', ('120', '124'))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('NIH-3T3', 'CellLine', 'CVCL:0594', (50, 57))	('activating', 'PosReg', (109, 119))
167601	32370101	These included the most common FGFR3 fusion (FGFR3-TACC3) and extracellular domain (S249C) and kinase domain (K652E) point mutations.	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('S249C', 'Var', (84, 89))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('K652E', 'Var', (110, 115))	('extracellular', 'cellular_component', 'GO:0005576', ('62', '75'))	('K652E', 'Mutation', 'rs78311289', (110, 115))	('FGFR3', 'Gene', (31, 36))	('S249C', 'Mutation', 'rs121913483', (84, 89))
167602	32370101	In addition, we examined N542K, which has previously been described as a congenital mutation in hypochondroplasia, due to its reported high kinase activity in in vitro assays.	('kinase activity', 'molecular_function', 'GO:0016301', ('140', '155'))	('N542K', 'Var', (25, 30))	('high kinase activity', 'MPA', (135, 155))	('N542K', 'Mutation', 'rs28933068', (25, 30))	('hypochondroplasia', 'Disease', (96, 113))	('hypochondroplasia', 'Disease', 'MESH:C562937', (96, 113))
167603	32370101	Expression of the FGFR3-TACC3 gene fusion and FGFR3 mutations S249C, N542K and K652E led to constitutive phosphorylation of Src when compared to the WT FGFR3 control with no differences observed in Erk1/2 and AKT phosphorylation levels (Figure 1A).	('N542K', 'Var', (69, 74))	('S249C', 'Var', (62, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('Src', 'MPA', (124, 127))	('K652E', 'Mutation', 'rs78311289', (79, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('152', '156'))	('S249C', 'Mutation', 'rs121913483', (62, 67))	('FGFR3-TACC3', 'Gene', (18, 29))	('Erk1', 'molecular_function', 'GO:0004707', ('198', '202'))	('constitutive', 'MPA', (92, 104))	('phosphorylation', 'biological_process', 'GO:0016310', ('213', '228'))	('AKT', 'Gene', (209, 212))	('led to', 'Reg', (85, 91))	('N542K', 'Mutation', 'rs28933068', (69, 74))	('K652E', 'Var', (79, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('AKT', 'Gene', '207', (209, 212))	('FGFR3', 'Gene', (46, 51))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))
167604	32370101	Short-term (72 h) cell viability experiments found that as previously shown, cells expressing FGFR3-TACC3 and the three FGFR3 mutants were sensitive to treatment with infigratinib with IC50 values in the nanomolar range (Figure 1D,E).	('sensitive', 'MPA', (139, 148))	('IC50', 'MPA', (185, 189))	('FGFR3', 'Gene', (120, 125))	('FGFR3-TACC3', 'Gene', (94, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('120', '124'))	('FGFR', 'molecular_function', 'GO:0005007', ('94', '98'))	('mutants', 'Var', (126, 133))	('infigratinib', 'Chemical', 'MESH:C568950', (167, 179))
167605	32370101	We show that unlike the WT FGFR3 cells, treatment with infigratinib decreased phosphoErk1/2 levels in the three mutant FGFR3 lines and abolished Erk1/2 phosphorylation in a dose-dependent manner in the FGFR3-TACC3 cells, confirming that this pathway is a direct downstream target of the FGFR3 mutants and FGFR3-TACC3 fusion (Figure 1F).	('FGFR', 'molecular_function', 'GO:0005007', ('287', '291'))	('decreased', 'NegReg', (68, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('phosphoErk1/2 levels', 'MPA', (78, 98))	('FGFR3', 'Gene', (119, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('305', '309'))	('infigratinib', 'Chemical', 'MESH:C568950', (55, 67))	('Erk1/2 phosphorylation', 'MPA', (145, 167))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))	('abolished', 'NegReg', (135, 144))	('Erk1', 'molecular_function', 'GO:0004707', ('145', '149'))	('mutant', 'Var', (112, 118))	('FGFR', 'molecular_function', 'GO:0005007', ('202', '206'))	('phosphorylation', 'biological_process', 'GO:0016310', ('152', '167'))
167606	32370101	Interestingly, although constitutive activation of Src was associated with the expression of the FGFR3 mutants and FGFR3-TACC3 fusion in the NIH-3T3 cells (Figure 1A), the phosphorylation levels of Src were not downregulated upon FGFR3 kinase inhibition by infigratinib (Figure 1F).	('infigratinib', 'Chemical', 'MESH:C568950', (257, 269))	('FGFR', 'molecular_function', 'GO:0005007', ('115', '119'))	('mutants', 'Var', (103, 110))	('activation', 'PosReg', (37, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('97', '101'))	('phosphorylation', 'biological_process', 'GO:0016310', ('172', '187'))	('phosphorylation levels', 'MPA', (172, 194))	('NIH-3T3', 'CellLine', 'CVCL:0594', (141, 148))	('FGFR', 'molecular_function', 'GO:0005007', ('230', '234'))	('FGFR3', 'Gene', (97, 102))	('Src', 'MPA', (51, 54))
167607	32370101	Further assessment of the efficacy of infigratinib in long-term (2 weeks) colony formation assays finds that despite the potent effects of this drug in the FGFR3 mutant and fusion expressing cells in short-term cell viability assays, there was an unexpected observation of a high number of resistant colonies persisting after 2 weeks of drug treatment (Figure 1G,H).	('formation', 'biological_process', 'GO:0009058', ('81', '90'))	('FGFR3', 'Gene', (156, 161))	('infigratinib', 'Chemical', 'MESH:C568950', (38, 50))	('mutant', 'Var', (162, 168))	('FGFR', 'molecular_function', 'GO:0005007', ('156', '160'))
167610	32370101	These inhibitors include broad-spectrum kinase inhibitors such as imatinib, dasatinib and foretinib as well as selective kinase inhibitors such as infigratinib (FGFR), binimetinib (MEK), AZD5363 (AKT), BEZ235 (PI3K/mTOR) and MK8776 (CHK1).	('MK8776', 'Chemical', 'MESH:C559815', (225, 231))	('CHK1', 'Gene', (233, 237))	('MEK', 'Gene', '5609', (181, 184))	('FGFR', 'molecular_function', 'GO:0005007', ('161', '165'))	('infigratinib', 'Chemical', 'MESH:C568950', (147, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('210', '214'))	('AKT', 'Gene', (196, 199))	('AZD5363', 'Chemical', 'MESH:C575618', (187, 194))	('BEZ235', 'Var', (202, 208))	('foretinib', 'Chemical', 'MESH:C544831', (90, 99))	('MEK', 'Gene', (181, 184))	('mTOR', 'Gene', (215, 219))	('CHK1', 'Gene', '1111', (233, 237))	('mTOR', 'Gene', '2475', (215, 219))	('dasatinib', 'Chemical', 'MESH:D000069439', (76, 85))	('AKT', 'Gene', '207', (196, 199))	('MK8776', 'Var', (225, 231))	('imatinib', 'Chemical', 'MESH:D000068877', (66, 74))	('BEZ235', 'Chemical', 'MESH:C531198', (202, 208))	('AZD5363', 'Var', (187, 194))	('binimetinib', 'Chemical', 'MESH:C581313', (168, 179))
167611	32370101	The screen also has a small number of non-kinase inhibitors including NVP-AUY922 (HSP90), GSK126 (enhancer of zeste homolog 2 (EZH2)) and JQ1 (bromodomain and extra-terminal (BET)) (See Table S1 for list of compounds used in the screen and key targets).	('GSK', 'molecular_function', 'GO:0050321', ('90', '93'))	('EZH2', 'Gene', (127, 131))	('EZH2', 'Gene', '2146', (127, 131))	('enhancer of zeste homolog 2', 'Gene', (98, 125))	('NVP-AUY922', 'Gene', (70, 80))	('GSK126', 'Gene', (90, 96))	('enhancer of zeste homolog 2', 'Gene', '2146', (98, 125))	('JQ1', 'Var', (138, 141))
167612	32370101	As a positive control for the assay, we show that as expected, FGFR3 point mutant and fusion expressing cells were sensitive to both multi-target (ponatinib, foretinib, lenvatinib, cediranib) and selective (infigratinib and AZD4546) FGFR TKIs (Figure 2A).	('AZD4546', 'Var', (224, 231))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('FGFR3', 'Gene', (63, 68))	('sensitive', 'Reg', (115, 124))	('infigratinib', 'Chemical', 'MESH:C568950', (207, 219))	('FGFR', 'molecular_function', 'GO:0005007', ('233', '237'))	('ponatinib', 'Chemical', 'MESH:C545373', (147, 156))	('cediranib', 'Chemical', 'MESH:C500926', (181, 190))	('AZD4546', 'Chemical', '-', (224, 231))	('foretinib', 'Chemical', 'MESH:C544831', (158, 167))	('lenvatinib', 'Chemical', 'MESH:C531958', (169, 179))
167613	32370101	These included BEZ235 (N542K and K652E), JQ1 (FGFR-TACC3, S249C and K652E), MK8776 (S249C) and dasatinib (FGFR3-TACC3 and S249C).	('K652E', 'Mutation', 'rs78311289', (33, 38))	('S249C', 'Var', (122, 127))	('MK8776 (S249C', 'Var', (76, 89))	('K652E', 'Var', (68, 73))	('S249C', 'Mutation', 'rs121913483', (122, 127))	('dasatinib', 'Chemical', 'MESH:D000069439', (95, 104))	('S249C', 'Var', (58, 63))	('K652E', 'Mutation', 'rs78311289', (68, 73))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('S249C', 'Mutation', 'rs121913483', (58, 63))	('N542K', 'Var', (23, 28))	('N542K', 'Mutation', 'rs28933068', (23, 28))	('K652E', 'Var', (33, 38))	('MK8776', 'Chemical', 'MESH:C559815', (76, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('S249C', 'Var', (84, 89))	('S249C', 'Mutation', 'rs121913483', (84, 89))	('BEZ235', 'Chemical', 'MESH:C531198', (15, 21))
167614	32370101	Given that the expression of FGFR3 molecular alterations led to the constitutive activation of Src (Figure 1A), dasatinib, a broad-spectrum TKI that potently inhibits Src as one of its targets, was taken forward for further investigation.	('alterations', 'Var', (45, 56))	('Src', 'Gene', (95, 98))	('FGFR3', 'Gene', (29, 34))	('dasatinib', 'Chemical', 'MESH:D000069439', (112, 121))	('FGFR', 'molecular_function', 'GO:0005007', ('29', '33'))	('activation', 'PosReg', (81, 91))	('constitutive', 'MPA', (68, 80))
167615	32370101	Full dose response assessment of dasatinib in short-term viability assays showed that FGFR3-TACC3 and S249C conferred resistance to this drug with an IC50 of 3-4 microM compared to the WT FGFR3 and the N542K and K652E mutations (<1 microM) (Figure 2B,C).	('N542K', 'Var', (202, 207))	('FGFR3-TACC3', 'Var', (86, 97))	('S249C', 'Var', (102, 107))	('resistance', 'MPA', (118, 128))	('K652E', 'Var', (212, 217))	('S249C', 'Mutation', 'rs121913483', (102, 107))	('FGFR', 'molecular_function', 'GO:0005007', ('188', '192'))	('conferred', 'Reg', (108, 117))	('K652E', 'Mutation', 'rs78311289', (212, 217))	('N542K', 'Mutation', 'rs28933068', (202, 207))	('dasatinib', 'Chemical', 'MESH:D000069439', (33, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('86', '90'))	('and S249C', 'Var', (98, 107))
167619	32370101	Since disruption of the FGFR3-TACC3 fusion through genetic means is non-trivial, we focused our efforts on the S249C point mutation.	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))	('S249C', 'Var', (111, 116))	('FGFR3-TACC3', 'Gene', (24, 35))	('S249C', 'Mutation', 'rs121913483', (111, 116))
167620	32370101	It has previously been demonstrated that the cysteine substitution in S249 within the extracellular domain of FGFR3 leads to constitutive receptor dimerization and activation through the formation of an intermolecular disulphide bond.	('formation', 'biological_process', 'GO:0009058', ('187', '196'))	('constitutive receptor dimerization', 'MPA', (125, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('110', '114'))	('disulphide', 'Chemical', '-', (218, 228))	('extracellular', 'cellular_component', 'GO:0005576', ('86', '99'))	('cysteine', 'Var', (45, 53))	('activation', 'PosReg', (164, 174))	('FGFR3', 'Gene', (110, 115))	('cysteine', 'Chemical', 'MESH:D003545', (45, 53))	('leads to', 'Reg', (116, 124))
167621	32370101	To investigate the role of this cysteine residue in driving resistance to dasatinib, we engineered NIH-3T3 cell lines expressing an FGFR3 mutant where the cysteine has been substituted to an alanine residue (S249A).	('NIH-3T3', 'CellLine', 'CVCL:0594', (99, 106))	('FGFR3', 'Gene', (132, 137))	('cysteine', 'Chemical', 'MESH:D003545', (155, 163))	('S249A', 'Mutation', 'p.S249A', (208, 213))	('FGFR', 'molecular_function', 'GO:0005007', ('132', '136'))	('cysteine', 'Chemical', 'MESH:D003545', (32, 40))	('S249A', 'Var', (208, 213))	('alanine', 'Chemical', 'MESH:D000409', (191, 198))	('dasatinib', 'Chemical', 'MESH:D000069439', (74, 83))
167622	32370101	Evaluation in non-reducing PAGE showed that the alanine substitution led to the loss of constitutive FGFR3 dimers both in the presence and absence of infigratinib (Figure S1A).	('alanine substitution', 'Var', (48, 68))	('loss', 'NegReg', (80, 84))	('alanine', 'Chemical', 'MESH:D000409', (48, 55))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))	('FGFR3', 'Gene', (101, 106))	('dimers', 'MPA', (107, 113))	('constitutive', 'MPA', (88, 100))	('infigratinib', 'Chemical', 'MESH:C568950', (150, 162))
167623	32370101	While cells expressing S249C were resistant to dasatinib in both short-term viability assays and long-term colony formation assays, the substitution to alanine resulted in pronounced sensitivity to this drug with levels comparable to WT FGFR3 expressing cells (Figure S1B-D).	('alanine', 'Chemical', 'MESH:D000409', (152, 159))	('sensitivity', 'MPA', (183, 194))	('FGFR', 'molecular_function', 'GO:0005007', ('237', '241'))	('S249C', 'Var', (23, 28))	('formation', 'biological_process', 'GO:0009058', ('114', '123'))	('S249C', 'Mutation', 'rs121913483', (23, 28))	('dasatinib', 'Chemical', 'MESH:D000069439', (47, 56))
167624	32370101	Similar results were seen in cells engineered to express another common FGFR3 cysteine mutant found in urothelial carcinoma (R248C) and its glycine substituted mutant (R248G) (Figure S1E,F).	('urothelial carcinoma', 'Disease', (103, 123))	('cysteine', 'Chemical', 'MESH:D003545', (78, 86))	('R248C', 'Var', (125, 130))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (103, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('R248C', 'Mutation', 'rs121913482', (125, 130))	('R248G', 'Mutation', 'p.R248G', (168, 173))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('R248G', 'Var', (168, 173))	('FGFR3', 'Gene', (72, 77))	('glycine', 'Chemical', 'MESH:D005998', (140, 147))
167625	32370101	Taken together, our data demonstrate that while treatment with dasatinib resulted in a decrease in Src phosphorylation levels in all FGFR3 expressing cell lines examined, the expression of FGFR3-TACC3 and S249C unexpectedly confers resistance to this drug.	('S249C', 'Mutation', 'rs121913483', (205, 210))	('FGFR3', 'Gene', (133, 138))	('FGFR', 'molecular_function', 'GO:0005007', ('189', '193'))	('Src phosphorylation levels', 'MPA', (99, 125))	('resistance', 'MPA', (232, 242))	('dasatinib', 'Chemical', 'MESH:D000069439', (63, 72))	('FGFR3-TACC3', 'Gene', (189, 200))	('decrease', 'NegReg', (87, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('133', '137'))	('phosphorylation', 'biological_process', 'GO:0016310', ('103', '118'))	('S249C', 'Var', (205, 210))
167626	32370101	Furthermore, we show that in two of the most common FGFR3 extracellular cysteine mutants in urothelial carcinoma (S249C and R248C), the constitutive receptor dimerization mediated by the cysteine residue is necessary for driving dasatinib resistance.	('extracellular', 'cellular_component', 'GO:0005576', ('58', '71'))	('cysteine', 'Chemical', 'MESH:D003545', (72, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('cysteine', 'Chemical', 'MESH:D003545', (187, 195))	('R248C', 'Var', (124, 129))	('urothelial carcinoma', 'Disease', (92, 112))	('S249C', 'Var', (114, 119))	('R248C', 'Mutation', 'rs121913482', (124, 129))	('S249C', 'Mutation', 'rs121913483', (114, 119))	('FGFR3', 'Gene', (52, 57))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (92, 112))	('dasatinib', 'Chemical', 'MESH:D000069439', (229, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
167630	32370101	This result was recapitulated in the short-term cell viability assays with the FGFR3-TACC3 and S249C expressing cells having a more pronounced sensitivity to the combination than WT FGFR3 expressing cells (Figure 3C).	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('S249C', 'Mutation', 'rs121913483', (95, 100))	('FGFR3-TACC3', 'Gene', (79, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('182', '186'))	('S249C', 'Var', (95, 100))
167632	32370101	As expected, cells bearing FGFR3-TACC3, S294C, N542K and K652E showed a decrease in the phosphorylation levels of both Src and Erk1/2 upon treatment with the combination, which is the result of the independent effects of dasatinib and infigratinib on these pathways respectively as single agents (Figure 3D).	('FGFR3-TACC3', 'Var', (27, 38))	('phosphorylation', 'biological_process', 'GO:0016310', ('88', '103'))	('N542K', 'Mutation', 'rs28933068', (47, 52))	('K652E', 'Mutation', 'rs78311289', (57, 62))	('phosphorylation levels', 'MPA', (88, 110))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('Erk1', 'molecular_function', 'GO:0004707', ('127', '131'))	('S294C', 'Mutation', 'p.S294C', (40, 45))	('Src', 'MPA', (119, 122))	('Erk1/2', 'MPA', (127, 133))	('dasatinib', 'Chemical', 'MESH:D000069439', (221, 230))	('N542K', 'Var', (47, 52))	('decrease', 'NegReg', (72, 80))	('K652E', 'Var', (57, 62))	('S294C', 'Var', (40, 45))	('infigratinib', 'Chemical', 'MESH:C568950', (235, 247))
167633	32370101	In the S249C and K652E expressing cells, there was a more potent inhibition of phosphoErk1/2 in the drug combination compared to single agent treatment with infigratinib alone (Figure 1F), suggesting that in a subset of FGFR3 mutants, dasatinib may enhance the effects of infigratinib by increased suppression of the Erk1/2 pathway.	('infigratinib', 'Chemical', 'MESH:C568950', (157, 169))	('Erk1/2 pathway', 'Pathway', (317, 331))	('S249C', 'Var', (7, 12))	('infigratinib', 'Chemical', 'MESH:C568950', (272, 284))	('K652E', 'Var', (17, 22))	('S249C', 'Mutation', 'rs121913483', (7, 12))	('effects', 'MPA', (261, 268))	('K652E', 'Mutation', 'rs78311289', (17, 22))	('Erk1', 'molecular_function', 'GO:0004707', ('317', '321'))	('FGFR3', 'Gene', (220, 225))	('FGFR', 'molecular_function', 'GO:0005007', ('220', '224'))	('dasatinib', 'Chemical', 'MESH:D000069439', (235, 244))	('suppression', 'NegReg', (298, 309))	('increased', 'PosReg', (288, 297))	('mutants', 'Var', (226, 233))	('enhance', 'PosReg', (249, 256))
167635	32370101	To that end, we evaluated the effects of two structurally unrelated selective FGFR inhibitors (infigratinib and PD173074) and dasatinib as single agents or in combination in a panel of urothelial cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('FGFR', 'Gene', (78, 82))	('PD173074', 'Var', (112, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('78', '82'))	('PD173074', 'Chemical', 'MESH:C115711', (112, 120))	('dasatinib', 'Chemical', 'MESH:D000069439', (126, 135))	('urothelial cancer', 'Disease', (185, 202))	('urothelial cancer', 'Disease', 'MESH:D014523', (185, 202))	('infigratinib', 'Chemical', 'MESH:C568950', (95, 107))
167637	32370101	Long-term colony formation assays show that in line with previous reports, RT112M was partially sensitive to infigratinib and PD173074 as single agents compared to BFTC905 and 639V (Figure 4A).	('RT112M', 'Var', (75, 81))	('PD173074', 'Var', (126, 134))	('PD173074', 'Chemical', 'MESH:C115711', (126, 134))	('formation', 'biological_process', 'GO:0009058', ('17', '26'))	('infigratinib', 'Chemical', 'MESH:C568950', (109, 121))
167639	32370101	The addition of dasatinib at low dose enhanced the efficacy of both selective FGFR inhibitors in the RT112M and 639V cells resulting in a decrease in colony formation in the combination arm compared to single agent FGFR inhibitor treatment (Figure 4A,B).	('FGFR', 'molecular_function', 'GO:0005007', ('215', '219'))	('FGFR', 'Gene', (78, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('78', '82'))	('enhanced', 'PosReg', (38, 46))	('colony formation', 'CPA', (150, 166))	('efficacy', 'MPA', (51, 59))	('decrease', 'NegReg', (138, 146))	('formation', 'biological_process', 'GO:0009058', ('157', '166'))	('dasatinib', 'Chemical', 'MESH:D000069439', (16, 25))	('inhibitors', 'Var', (83, 93))
167641	32370101	Assessment of the combination index (CI) showed that the combination of dasatinib and infigratinib led to a synergistic decrease in the cell viability (CI < 1) in the RT112M and 639V cells across all drug doses tested up to 1 microM (Figure 4D).	('infigratinib', 'Gene', (86, 98))	('combination', 'Interaction', (57, 68))	('RT112M', 'Var', (167, 173))	('infigratinib', 'Chemical', 'MESH:C568950', (86, 98))	('decrease', 'NegReg', (120, 128))	('dasatinib', 'Chemical', 'MESH:D000069439', (72, 81))	('dasatinib', 'Gene', (72, 81))	('cell viability', 'CPA', (136, 150))
167643	32370101	Infigratinib and PD173074 treatment did not affect phosphoErk1/2 levels in the BFTC905 and 639V cells but abolished phosphoErk1/2 levels in the RT112M cell line (Figure 4E).	('Infigratinib', 'Chemical', 'MESH:C568950', (0, 12))	('PD173074', 'Var', (17, 25))	('phosphoErk1/2 levels', 'MPA', (116, 136))	('PD173074', 'Chemical', 'MESH:C115711', (17, 25))	('abolished', 'NegReg', (106, 115))
167645	32370101	As observed in the NIH-3T3 cells, the combination of a selective FGFR inhibitor with dasatinib led to a reduction in the phosphorylation levels of both Erk1/2 and Src in the two cell lines harbouring FGFR3 molecular alterations, RT112M and 639V.	('Src', 'MPA', (163, 166))	('reduction', 'NegReg', (104, 113))	('NIH-3T3', 'CellLine', 'CVCL:0594', (19, 26))	('dasatinib', 'Chemical', 'MESH:D000069439', (85, 94))	('Erk1/2', 'MPA', (152, 158))	('FGFR', 'molecular_function', 'GO:0005007', ('200', '204'))	('inhibitor', 'NegReg', (70, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('RT112M', 'Var', (229, 235))	('Erk1', 'molecular_function', 'GO:0004707', ('152', '156'))	('combination', 'Interaction', (38, 49))	('FGFR', 'Gene', (65, 69))	('phosphorylation levels', 'MPA', (121, 143))	('FGFR3', 'Gene', (200, 205))	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))
167646	32370101	The Epidermal Growth Factor Receptor (EGFR) has previously been shown to be a compensatory bypass mechanism which confers intrinsic resistance to PD173074 treatment in the RT112M cell line.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('Epidermal Growth Factor', 'molecular_function', 'GO:0005154', ('4', '27'))	('Epidermal Growth Factor Receptor', 'Gene', (4, 36))	('EGFR', 'Gene', (38, 42))	('PD173074', 'Var', (146, 154))	('PD173074', 'Chemical', 'MESH:C115711', (146, 154))	('intrinsic resistance', 'MPA', (122, 142))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (4, 36))
167650	32370101	Specifically, we evaluated the ability of the gatekeeper mutation in the avian Src gene (T338I), which blocks dasatinib binding to its kinase domain, to rescue the phenotypic effects of dasatinib.	('dasatinib', 'MPA', (110, 119))	('binding', 'molecular_function', 'GO:0005488', ('120', '127'))	('gatekeeper', 'Species', '111938', (46, 56))	('binding', 'Interaction', (120, 127))	('T338I', 'Mutation', 'p.T338I', (89, 94))	('blocks', 'NegReg', (103, 109))	('T338I', 'Var', (89, 94))	('dasatinib', 'Chemical', 'MESH:D000069439', (110, 119))	('dasatinib', 'Chemical', 'MESH:D000069439', (186, 195))
167651	32370101	Engineered urothelial cancer cell lines expressing each of the Src variants or the EV control were subjected to long-term colony formation assays in the presence of infigratinib and dasatinib as single agents or in combination.	('infigratinib', 'Chemical', 'MESH:C568950', (165, 177))	('formation', 'biological_process', 'GO:0009058', ('129', '138'))	('Engineered urothelial cancer', 'Disease', 'MESH:D014523', (0, 28))	('dasatinib', 'Chemical', 'MESH:D000069439', (182, 191))	('Engineered urothelial cancer', 'Disease', (0, 28))	('Src', 'Gene', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('variants', 'Var', (67, 75))
167652	32370101	Expression of the gatekeeper mutant rescued the effects of dasatinib, conferring robust resistance to this drug in all three cell lines when compared to the WT Src and EV cells (Figure S2B).	('gatekeeper', 'Species', '111938', (18, 28))	('dasatinib', 'Chemical', 'MESH:D000069439', (59, 68))	('mutant', 'Var', (29, 35))	('effects', 'MPA', (48, 55))	('resistance to', 'MPA', (88, 101))
167654	32370101	Despite some clinical success with selective FGFR inhibitors in cancers with FGFR3 molecular alterations, these therapies are not curative and there remains a substantial patient population that harbour intrinsic resistance to these drugs.	('FGFR3', 'Gene', (77, 82))	('patient', 'Species', '9606', (171, 178))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('alterations', 'Var', (93, 104))	('FGFR', 'Gene', (45, 49))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('cancers', 'Disease', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
167656	32370101	In this study, we use a combination of NIH-3T3 and urothelial cancer cells to demonstrate that cells expressing a subset of FGFR3 molecular alterations co-opt the Src pathway to promote intrinsic resistance to selective FGFR inhibitors.	('NIH-3T3', 'CellLine', 'CVCL:0594', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('124', '128'))	('promote', 'PosReg', (178, 185))	('alterations', 'Var', (140, 151))	('urothelial cancer', 'Disease', (51, 68))	('intrinsic resistance to selective', 'MPA', (186, 219))	('FGFR3', 'Gene', (124, 129))	('Src pathway', 'Pathway', (163, 174))	('FGFR', 'molecular_function', 'GO:0005007', ('220', '224'))	('urothelial cancer', 'Disease', 'MESH:D014523', (51, 68))
167657	32370101	While cells expressing the FGFR3-TACC3 fusion and extracellular domain cysteine mutants were resistant to the Src inhibitor dasatinib and selective FGFR inhibitor infigratinib as single agents, the addition of low dose dasatinib profoundly sensitized these cells to selective FGFR inhibitors.	('extracellular', 'cellular_component', 'GO:0005576', ('50', '63'))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('dasatinib', 'Chemical', 'MESH:D000069439', (219, 228))	('FGFR', 'molecular_function', 'GO:0005007', ('276', '280'))	('FGFR3-TACC3', 'Gene', (27, 38))	('mutants', 'Var', (80, 87))	('infigratinib', 'Chemical', 'MESH:C568950', (163, 175))	('cysteine', 'Chemical', 'MESH:D003545', (71, 79))	('dasatinib', 'Chemical', 'MESH:D000069439', (124, 133))	('FGFR', 'molecular_function', 'GO:0005007', ('148', '152'))
167659	32370101	While on-target resistance mutations in the FGFR2 kinase domain (N649H/K, V564F, E656A, L617V, K641R and K659M) have been detected in circulating tumour DNA in the context of FGFR2 translocations in cholangiocarcinoma patients who have received infigratinib, such mutations have yet to be identified in cancers with FGFR3 molecular alterations.	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('FGFR', 'molecular_function', 'GO:0005007', ('175', '179'))	('L617V', 'Mutation', 'p.L617V', (88, 93))	('FGFR2', 'Gene', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (303, 310))	('cancers', 'Disease', (303, 310))	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('V564F', 'Mutation', 'p.V564F', (74, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('N649H', 'SUBSTITUTION', 'None', (65, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (199, 217))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('L617V', 'Var', (88, 93))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('FGFR2', 'Gene', (175, 180))	('FGFR2', 'Gene', '2263', (44, 49))	('FGFR', 'molecular_function', 'GO:0005007', ('316', '320'))	('V564F', 'Var', (74, 79))	('tumour', 'Disease', 'MESH:D009369', (146, 152))	('cholangiocarcinoma', 'Disease', (199, 217))	('tumour', 'Disease', (146, 152))	('patients', 'Species', '9606', (218, 226))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (199, 217))	('K641R', 'Mutation', 'rs1057519047', (95, 100))	('E656A', 'Mutation', 'p.E656A', (81, 86))	('K659M', 'Var', (105, 110))	('FGFR2', 'Gene', '2263', (175, 180))	('cancers', 'Disease', 'MESH:D009369', (303, 310))	('K641R', 'Var', (95, 100))	('N649H', 'Var', (65, 70))	('E656A', 'Var', (81, 86))	('K659M', 'Mutation', 'p.K659M', (105, 110))	('infigratinib', 'Chemical', 'MESH:C568950', (245, 257))
167661	32370101	In the paradigm of intrinsic resistance, Herrera-Abreu et al., has shown that EGFR activation is an escape mechanism to PD173074 treatment and that a combination of gefitinib and PD173074 could overcome drug resistance in urothelial cancer lines harbouring FGFR3 molecular alterations.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('PD173074', 'Var', (120, 128))	('EGFR', 'Gene', '1956', (78, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('257', '261'))	('drug resistance', 'MPA', (203, 218))	('gefitinib', 'Chemical', 'MESH:D000077156', (165, 174))	('drug resistance', 'biological_process', 'GO:0009315', ('203', '218'))	('activation', 'PosReg', (83, 93))	('drug resistance', 'biological_process', 'GO:0042493', ('203', '218'))	('drug resistance', 'Phenotype', 'HP:0020174', (203, 218))	('PD173074', 'Chemical', 'MESH:C115711', (179, 187))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('PD173074', 'Var', (179, 187))	('FGFR3', 'Gene', (257, 262))	('EGFR', 'Gene', (78, 82))	('urothelial cancer', 'Disease', 'MESH:D014523', (222, 239))	('Herrera', 'CellLine', 'None', (41, 48))	('PD173074', 'Chemical', 'MESH:C115711', (120, 128))	('urothelial cancer', 'Disease', (222, 239))
167667	32370101	Interestingly, it has been shown in another study that genetic silencing of Src in RT4 cells promotes cancer cell migration and invasion.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cell migration', 'biological_process', 'GO:0016477', ('109', '123'))	('Src', 'Gene', (76, 79))	('RT4', 'CellLine', 'CVCL:0036', (83, 86))	('promotes', 'PosReg', (93, 101))	('invasion', 'CPA', (128, 136))	('genetic silencing', 'Var', (55, 72))
167670	32370101	Our data show that expression of FGFR3-TACC3 and S249C results in a paradoxical resistance to dasatinib despite the constitutive activation of the Src pathway, reinforcing the idea that this drug as a monotherapy is likely to be ineffective in cancers with these FGFR3 molecular alterations.	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('FGFR', 'molecular_function', 'GO:0005007', ('263', '267'))	('resistance to dasatinib', 'MPA', (80, 103))	('S249C', 'Var', (49, 54))	('activation', 'PosReg', (129, 139))	('S249C', 'Mutation', 'rs121913483', (49, 54))	('cancers', 'Disease', 'MESH:D009369', (244, 251))	('Src pathway', 'Pathway', (147, 158))	('FGFR3-TACC3', 'Gene', (33, 44))	('cancers', 'Disease', (244, 251))	('dasatinib', 'Chemical', 'MESH:D000069439', (94, 103))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))
167671	32370101	We find that co-targeting FGFR3 and Src with low nanomolar concentrations of infigratinib and dasatinib respectively is highly effective in reducing cell viability in urothelial cancer cell lines.	('urothelial cancer', 'Disease', (167, 184))	('co-targeting', 'Var', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('FGFR3', 'Gene', (26, 31))	('reducing', 'NegReg', (140, 148))	('urothelial cancer', 'Disease', 'MESH:D014523', (167, 184))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('dasatinib', 'Chemical', 'MESH:D000069439', (94, 103))	('infigratinib', 'Chemical', 'MESH:C568950', (77, 89))
167672	32370101	The use of Src inhibitors such as dasatinib to overcome resistance to kinase inhibitors has previously been investigated in the context of mutant EGFR lung cancer.	('EGFR', 'Gene', '1956', (146, 150))	('dasatinib', 'Chemical', 'MESH:D000069439', (34, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('EGFR', 'Gene', (146, 150))	('mutant', 'Var', (139, 145))	('lung cancer', 'Disease', (151, 162))	('EGFR', 'molecular_function', 'GO:0005006', ('146', '150'))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))
167675	32370101	Since expression of the FGFR3-TACC3 fusion and the substitution of extracellular domain cysteines in FGFR3 confers resistance to dasatinib as a single agent, it is tempting to speculate a mechanism whereby dasatinib treatment alone has no therapeutic effect, while the addition of a selective FGFR inhibitor induces a new dependency to the Src pathway leading to vulnerability to co-treatment with dasatinib.	('induces', 'Reg', (308, 315))	('cysteines', 'Chemical', 'MESH:D003545', (88, 97))	('leading', 'Reg', (352, 359))	('dasatinib', 'Chemical', 'MESH:D000069439', (129, 138))	('FGFR3-TACC3', 'Gene', (24, 35))	('dasatinib', 'Chemical', 'MESH:D000069439', (398, 407))	('dasatinib', 'Chemical', 'MESH:D000069439', (206, 215))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))	('extracellular', 'cellular_component', 'GO:0005576', ('67', '80'))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))	('substitution', 'Var', (51, 63))	('FGFR3', 'Gene', (101, 106))	('Src pathway', 'Pathway', (340, 351))	('FGFR', 'molecular_function', 'GO:0005007', ('293', '297'))	('dependency', 'Reg', (322, 332))
167677	32370101	Furthermore, it remains unclear why some FGFR3 aberrations (FGFR3-TACC3 and cysteine mutants) induce resistance to single agent dasatinib while others (N542K and K652E) do not.	('cysteine', 'MPA', (76, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('N542K', 'Var', (152, 157))	('K652E', 'Var', (162, 167))	('cysteine', 'Chemical', 'MESH:D003545', (76, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('induce', 'Reg', (94, 100))	('FGFR3', 'Gene', (41, 46))	('N542K', 'Mutation', 'rs28933068', (152, 157))	('K652E', 'Mutation', 'rs78311289', (162, 167))	('dasatinib', 'Chemical', 'MESH:D000069439', (128, 137))	('resistance to single agent dasatinib', 'MPA', (101, 137))
167681	32370101	This study provides proof-of-principle evidence that supports co-targeting Src and FGFR3 as a therapeutic approach to tackle drug resistance in the treatment of urothelial cancers with FGFR3 molecular alterations.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('FGFR', 'molecular_function', 'GO:0005007', ('185', '189'))	('drug resistance', 'Phenotype', 'HP:0020174', (125, 140))	('FGFR', 'molecular_function', 'GO:0005007', ('83', '87'))	('FGFR3', 'Gene', (185, 190))	('FGFR3', 'Gene', (83, 88))	('urothelial cancers', 'Disease', 'MESH:D014523', (161, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('drug resistance', 'biological_process', 'GO:0009315', ('125', '140'))	('co-targeting', 'Var', (62, 74))	('urothelial cancers', 'Disease', (161, 179))	('drug resistance', 'MPA', (125, 140))	('drug resistance', 'biological_process', 'GO:0042493', ('125', '140'))
167682	32370101	NIH-3T3 cells stably expressing WT FGFR3, FGFR3-TACC3, S249C, N542K and K652E) have previously been described.	('N542K', 'Var', (62, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('NIH-3T3', 'CellLine', 'CVCL:0594', (0, 7))	('FGFR3-TACC3', 'Gene', (42, 53))	('S249C', 'Var', (55, 60))	('K652E', 'Var', (72, 77))	('N542K', 'Mutation', 'rs28933068', (62, 67))	('K652E', 'Mutation', 'rs78311289', (72, 77))	('FGFR3', 'Gene', (35, 40))	('S249C', 'Mutation', 'rs121913483', (55, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))
167684	32370101	The remaining NIH-3T3 FGFR3 mutant expressing cell lines were generated in-house.	('NIH-3T3', 'CellLine', 'CVCL:0594', (14, 21))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('mutant', 'Var', (28, 34))	('NIH-3T3 FGFR3', 'Gene', (14, 27))
167688	32370101	FGFR3 point mutations (S249C, S249A, R248C and R248G) were generated using a retroviral expression vector containing full-length human FGFR3 by site-directed mutagenesis (SDM).	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('R248C', 'Mutation', 'rs121913482', (37, 42))	('R248G', 'Mutation', 'p.R248G', (47, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('135', '139'))	('FGFR3', 'Gene', (0, 5))	('S249A', 'Mutation', 'p.S249A', (30, 35))	('R248G', 'Var', (47, 52))	('mutagenesis', 'biological_process', 'GO:0006280', ('158', '169'))	('R248C', 'Var', (37, 42))	('S249A', 'Var', (30, 35))	('human', 'Species', '9606', (129, 134))	('S249C', 'Var', (23, 28))	('S249C', 'Mutation', 'rs121913483', (23, 28))
167714	31968685	Our findings suggested that DAB2 expression was associated with poor prognosis through increased oncogenic properties including tumor proliferation, migration, invasion, and enhancement of EMT in human UCB.	('increased', 'PosReg', (87, 96))	('DAB2', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('invasion', 'CPA', (160, 168))	('expression', 'Var', (33, 43))	('migration', 'CPA', (149, 158))	('human', 'Species', '9606', (196, 201))	('oncogenic properties', 'CPA', (97, 117))	('UCB', 'Phenotype', 'HP:0006740', (202, 205))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('UCB', 'Chemical', '-', (202, 205))	('EMT', 'biological_process', 'GO:0001837', ('189', '192'))	('enhancement', 'PosReg', (174, 185))	('tumor', 'Disease', (128, 133))
167730	31968685	Alterations in chromosome 5p13 have been recognized in bladder cancer specimens.	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('bladder cancer', 'Disease', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Alterations', 'Var', (0, 11))	('chromosome', 'cellular_component', 'GO:0005694', ('15', '25'))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))
167747	31968685	Dual immunofluorescent staining was performed using antibodies specific to DAB2 (rabbit monoclonal) or alphaSMA (A2547; mouse monoclonal, Sigma-Aldrich, St Louis, MO, USA).	('DAB2', 'Gene', (75, 79))	('A2547;', 'Var', (113, 119))	('mouse', 'Species', '10090', (120, 125))
167779	31968685	The pathological characteristics, including clinical T stage, tumor grade, the presence of carcinoma in situ, histological variants and tumor infiltrative patterns, were significantly different between patients with low and high DAB2 expression.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('expression', 'MPA', (234, 244))	('carcinoma', 'Disease', 'MESH:D009369', (91, 100))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('DAB2', 'Gene', (229, 233))	('patients', 'Species', '9606', (202, 210))	('different', 'Reg', (184, 193))	('high', 'Var', (224, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('low', 'Var', (216, 219))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (91, 108))	('tumor', 'Disease', (136, 141))	('carcinoma', 'Disease', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
167787	31968685	In MIBC, high expression of DAB2, in both cancer and stromal cells, was associated with a shorter over-all and cancer-specific survival (p = 0.026, Figure 2B; p = 0.028, Figure S1B; p = 0.008, Figure 2C; p = 0.007, Figure S1C, respectively).	('DAB2', 'Gene', (28, 32))	('high expression', 'Var', (9, 24))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('shorter', 'NegReg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('MIBC', 'Chemical', '-', (3, 7))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('MIBC', 'Disease', (3, 7))
167802	31968685	Tumor weights were significantly lower in mice treated with DAB2 siRNA compared to "no treatment" and negative control siRNA groups.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (42, 46))	('Tumor weights', 'CPA', (0, 13))	('lower', 'NegReg', (33, 38))	('DAB2 siRNA', 'Var', (60, 70))
167803	31968685	However, in the xenograft model of MGH-U-3, there were no significant changes in tumor weight and tumor growth compared with the 'no treatment' and non-target siRNA groups (Figure 6C).	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('MGH-U-3', 'Var', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (81, 86))
167813	31968685	reported that there are different functions between p96-DAB2 and p67 DAB2 in the process of oncogenesis on lung cancers.	('p96-DAB2', 'Var', (52, 60))	('p67', 'Gene', (65, 68))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('lung cancers', 'Disease', (107, 119))	('p67', 'Gene', '6812', (65, 68))	('oncogenesis', 'biological_process', 'GO:0007048', ('92', '103'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung cancers', 'Disease', 'MESH:D008175', (107, 119))	('lung cancers', 'Phenotype', 'HP:0100526', (107, 119))
167814	31968685	UC cell lines in this study expressed mainly p96-DAB2 but depending on cancer types and cell lines, DAB2 expression isoforms and the location of expression differ, which is presumed to result in the difference of tumor promotion or suppression.	('p96-DAB2', 'Var', (45, 53))	('promotion', 'PosReg', (219, 228))	('DAB2', 'Gene', (100, 104))	('tumor', 'Disease', (213, 218))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('suppression', 'NegReg', (232, 243))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))
167819	31968685	This in vitro research showed evidence that DAB2 knock-down can inhibit cancer migration in UM-UC-3 cells and T24, and cancer invasion in J82 and T24 (Figure 4B,C).	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', (119, 125))	('knock-down', 'Var', (49, 59))	('DAB2', 'Gene', (44, 48))	('inhibit', 'NegReg', (64, 71))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', (72, 78))
167838	31968685	The role of DAB2 is that expression in CAFs promotes EMT of tumor cells, and induces tumor migration and invasion, resulting in the accumulation of cancer cells that are beneficial to the tumor microenvironment.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', (85, 90))	('EMT', 'biological_process', 'GO:0001837', ('53', '56'))	('DAB2', 'Gene', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Disease', (60, 65))	('CAFs', 'Gene', (39, 43))	('invasion', 'CPA', (105, 113))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('promotes', 'PosReg', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('induces', 'PosReg', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('expression', 'Var', (25, 35))	('cancer', 'Disease', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('accumulation', 'PosReg', (132, 144))
167840	31968685	Inhibiting this pathway may be an alternative approach to existing UCB treatment, and may contribute to improving cancer prognosis.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('improving', 'PosReg', (104, 113))	('Inhibiting', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('UCB', 'Chemical', '-', (67, 70))	('UCB', 'Phenotype', 'HP:0006740', (67, 70))	('cancer', 'Disease', (114, 120))
167866	32280307	Accumulating evidences have showed that aberrant expression of lncRNA could drive tumor phenotypes, including initiation, invasion, and metastasis, via interacting with other cellular macromolecules.	('aberrant expression', 'Var', (40, 59))	('interacting', 'Interaction', (152, 163))	('lncRNA', 'Gene', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('invasion', 'CPA', (122, 130))	('metastasis', 'CPA', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('initiation', 'CPA', (110, 120))	('drive', 'PosReg', (76, 81))	('tumor', 'Disease', (82, 87))
167908	32280307	Increasing evidences have established a strong relationship between dysfunction of lncRNAs and cell fate determination as well as disease pathogenesis, such as aging, arthritis, and cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cell fate determination', 'CPA', (95, 118))	('aging', 'biological_process', 'GO:0007568', ('160', '165'))	('arthritis', 'Disease', (167, 176))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('pathogenesis', 'biological_process', 'GO:0009405', ('138', '150'))	('cancer', 'Disease', (182, 188))	('arthritis', 'Disease', 'MESH:D001168', (167, 176))	('cell fate determination', 'biological_process', 'GO:0001709', ('95', '118'))	('arthritis', 'Phenotype', 'HP:0001369', (167, 176))	('dysfunction', 'Var', (68, 79))
167914	32280307	Notably, MIR31HG expression was even higher in gefitinib-resistant NSCLC cells, and knockdown of MIR31HG could promote cell apoptosis and cell cycle arrest, and subsequently induce gefitinib sensitivity.	('MIR31HG', 'Gene', (97, 104))	('MIR31HG', 'Gene', (9, 16))	('MIR31HG', 'Gene', '554202', (97, 104))	('MIR31HG', 'Gene', '554202', (9, 16))	('knockdown', 'Var', (84, 93))	('arrest', 'Disease', (149, 155))	('gefitinib', 'Chemical', 'MESH:D000077156', (47, 56))	('gefitinib sensitivity', 'MPA', (181, 202))	('gefitinib', 'Chemical', 'MESH:D000077156', (181, 190))	('higher', 'PosReg', (37, 43))	('expression', 'MPA', (17, 27))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('138', '155'))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('promote', 'PosReg', (111, 118))	('induce', 'Reg', (174, 180))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('arrest', 'Disease', 'MESH:D006323', (149, 155))	('cell apoptosis', 'CPA', (119, 133))	('NSCLC', 'Disease', (67, 72))
167920	32280307	The pooled results of subgroup analysis as per the tumor types demonstrated that high MIR31HG expression predicted unfavorable OS in patients with lung cancer and other cancers, and poor RFS in all selected studies, respectively.	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cancers', 'Disease', (169, 176))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('high', 'Var', (81, 85))	('lung cancer', 'Disease', (147, 158))	('tumor', 'Disease', (51, 56))	('patients', 'Species', '9606', (133, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('MIR31HG', 'Gene', (86, 93))	('predicted', 'Reg', (105, 114))	('unfavorable', 'Disease', (115, 126))	('MIR31HG', 'Gene', '554202', (86, 93))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
167932	32280307	In OSCC, MIR31HG knockdown impaired the HIF-1alpha transactivation, sphere-forming ability, metabolic shift and metastatic cascade both in vitro and in vivo.	('metastatic cascade', 'CPA', (112, 130))	('metabolic shift', 'CPA', (92, 107))	('HIF-1alpha', 'Gene', '3091', (40, 50))	('MIR31HG', 'Gene', (9, 16))	('MIR31HG', 'Gene', '554202', (9, 16))	('HIF-1alpha', 'Gene', (40, 50))	('impaired', 'NegReg', (27, 35))	('knockdown', 'Var', (17, 26))	('transactivation', 'biological_process', 'GO:2000144', ('51', '66'))	('sphere-forming ability', 'CPA', (68, 90))
167950	32280307	81902745), Natural Science Foundation of Hunan Province, China (2018JJ3716, 2018JJ3762), China Scholarship Council (201806375067, 201806375068), and the Fundamental Research Funds for the Central Universities of Central South University (2017zzts231).	('2018JJ3762', 'Var', (76, 86))	('2018JJ3716', 'Var', (64, 74))	('JJ3716', 'CellLine', 'CVCL:8Z96', (68, 74))	('201806375067', 'Var', (116, 128))	('2018JJ3762', 'CellLine', 'CVCL:6553', (76, 86))	('201806375068', 'Var', (130, 142))
167991	31333338	The K-M survival curve revealed that high TPST1 or P3H4 expression conferred worse overall survival (Fig.	('overall survival', 'MPA', (83, 99))	('high', 'Var', (37, 41))	('TPST1', 'Gene', '8460', (42, 47))	('P3H4', 'Gene', '10609', (51, 55))	('P3H4', 'Gene', (51, 55))	('worse', 'NegReg', (77, 82))	('P3H', 'molecular_function', 'GO:0033763', ('51', '54'))	('TPST1', 'Gene', (42, 47))
167995	31333338	As expected, the K-M survival curve revealed that patients with high risk score were correlated with worse overall survival (Fig.	('high risk', 'Var', (64, 73))	('worse', 'NegReg', (101, 106))	('patients', 'Species', '9606', (50, 58))	('overall survival', 'MPA', (107, 123))
168017	30038717	CAD/POLD2 gene expression is associated with poor overall survival and chemoresistance in bladder urothelial carcinoma Somatic mutations in DNA repair genes have been clinically associated with chemosensitivity, although few studies have interrogated the nucleotide synthesis pathways that supply DNA repair processes.	('DNA', 'cellular_component', 'GO:0005574', ('297', '300'))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (90, 118))	('associated', 'Reg', (178, 188))	('gene expression', 'biological_process', 'GO:0010467', ('10', '25'))	('CAD', 'Gene', '730249', (0, 3))	('bladder urothelial carcinoma', 'Disease', (90, 118))	('DNA repair', 'biological_process', 'GO:0006281', ('140', '150'))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('POLD2', 'Gene', '5425', (4, 9))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('DNA repair', 'biological_process', 'GO:0006281', ('297', '307'))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('255', '275'))	('mutations', 'Var', (127, 136))	('CAD', 'Gene', (0, 3))	('POLD2', 'Gene', (4, 9))	('DNA repair', 'Gene', (140, 150))
168018	30038717	Previous work suggests that bladder urothelial carcinoma is uniquely enriched for mutations in nucleotide excision repair genes, and that these mutations are associated with response to platinum-based therapy and favorable survival.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (28, 56))	('associated with', 'Reg', (158, 173))	('nucleotide excision repair genes', 'Gene', (95, 127))	('bladder urothelial carcinoma', 'Disease', (28, 56))	('platinum', 'Chemical', 'MESH:D010984', (186, 194))	('response to platinum', 'biological_process', 'GO:0070541', ('174', '194'))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('95', '121'))	('mutations', 'Var', (82, 91))	('mutations', 'Var', (144, 153))
168026	30038717	The implications of DNA repair gene alterations have recently emerged to help better stratify urothelial cancer patients by predicted response to systemic chemotherapy.	('urothelial cancer', 'Disease', 'MESH:D014523', (94, 111))	('alterations', 'Var', (36, 47))	('patients', 'Species', '9606', (112, 120))	('DNA repair gene', 'Gene', (20, 35))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('urothelial cancer', 'Disease', (94, 111))	('DNA repair', 'biological_process', 'GO:0006281', ('20', '30'))
168028	30038717	While mutations in the genes of these repair pathways have been implicated in patient prognosis and response to platinum-based chemotherapy, the complementary analysis of DNA repair and nucleotide supply remains relatively unexplored in urothelial carcinoma.	('patient', 'Species', '9606', (78, 85))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (237, 257))	('response to platinum', 'biological_process', 'GO:0070541', ('100', '120'))	('platinum', 'Chemical', 'MESH:D010984', (112, 120))	('implicated', 'Reg', (64, 74))	('DNA', 'cellular_component', 'GO:0005574', ('171', '174'))	('urothelial carcinoma', 'Disease', (237, 257))	('mutations', 'Var', (6, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))	('DNA repair', 'biological_process', 'GO:0006281', ('171', '181'))
168032	30038717	A recent study examining DNA repair alterations across 21 TCGA cancer cohorts, showed that BLCA was significantly associated with DNA repair alterations via the mechanism of nucleotide excision repair (NER).	('alterations', 'Var', (141, 152))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('174', '200'))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('DNA repair', 'biological_process', 'GO:0006281', ('25', '35'))	('BLCA', 'Disease', (91, 95))	('NER', 'biological_process', 'GO:0006289', ('202', '205'))	('associated', 'Reg', (114, 124))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('DNA repair', 'biological_process', 'GO:0006281', ('130', '140'))	('DNA repair', 'Gene', (130, 140))	('BLCA', 'Chemical', '-', (91, 95))	('cancer', 'Disease', (63, 69))
168052	30038717	We also fit a multivariate model and showed that patients that possessed both high CAD and high POLD2 expression together exhibited the worst overall survival (Logrank P = 0.0019; Figure 4E, Supplementary Table 3).	('overall survival', 'MPA', (142, 158))	('CAD', 'Gene', (83, 86))	('expression', 'MPA', (102, 112))	('high', 'Var', (91, 95))	('POLD2', 'Gene', (96, 101))	('CAD', 'Gene', '730249', (83, 86))	('patients', 'Species', '9606', (49, 57))	('POLD2', 'Gene', '5425', (96, 101))	('worst', 'NegReg', (136, 141))
168063	30038717	Our prognostic observations of CAD are also in line with its amplification as a marker of genomic instability in tumorigenic liver cells, its association with mutant TP53 status, and its implication in cancer cell viability in BLCA and TNBC.	('tumor', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('CAD', 'Gene', (31, 34))	('BLCA', 'Chemical', '-', (227, 231))	('mutant', 'Var', (159, 165))	('CAD', 'Gene', '730249', (31, 34))	('TP53', 'Gene', '7157', (166, 170))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('association', 'Interaction', (142, 153))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('TP53', 'Gene', (166, 170))	('cancer', 'Disease', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
168068	30038717	Of note, we found that ERCC2 alterations (which are recurrently found in bladder cancer) co-occur significantly with POLD2 expression (P = 0.010; data not shown), but not with CAD expression, suggesting POLD2 as putative gene of interest in future studies examining ERCC2.	('expression', 'MPA', (123, 133))	('bladder cancer', 'Disease', (73, 87))	('POLD2', 'Gene', (117, 122))	('POLD2', 'Gene', (203, 208))	('CAD', 'Gene', (176, 179))	('ERCC2', 'Gene', '2068', (23, 28))	('alterations', 'Var', (29, 40))	('ERCC2', 'Gene', '2068', (266, 271))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('ERCC2', 'Gene', (23, 28))	('POLD2', 'Gene', '5425', (203, 208))	('POLD2', 'Gene', '5425', (117, 122))	('CAD', 'Gene', '730249', (176, 179))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ERCC2', 'Gene', (266, 271))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))
168075	30038717	This may therefore suggest that the detrimental effect of high CAD/POLD2 co-expression is pronounced early in the course of the disease when patients are generally more aggressively treated with systemic chemotherapy regimens such as cisplatin-based therapy.	('cisplatin', 'Chemical', 'MESH:D002945', (234, 243))	('POLD2', 'Gene', '5425', (67, 72))	('aggressively', 'Disease', (169, 181))	('CAD', 'Gene', '730249', (63, 66))	('POLD2', 'Gene', (67, 72))	('high', 'Var', (58, 62))	('aggressively', 'Disease', 'MESH:D001523', (169, 181))	('patients', 'Species', '9606', (141, 149))	('CAD', 'Gene', (63, 66))
168076	30038717	Therefore, an interesting hypothesis to pose for future studies is the possibility that the unfavorable prognostic effect of CAD/POLD2 co-expression is driven by the ability to suppress the pro-apoptotic effects of chemotherapy.	('POLD2', 'Gene', '5425', (129, 134))	('CAD', 'Gene', (125, 128))	('suppress', 'NegReg', (177, 185))	('CAD', 'Gene', '730249', (125, 128))	('POLD2', 'Gene', (129, 134))	('co-expression', 'Var', (135, 148))	('pro-apoptotic effects of chemotherapy', 'MPA', (190, 227))
168077	30038717	It is also worth considering these results in light of neoantigen burden and immunogenicity, as recent work has shown that inactivating DNA repair processes can increase the amount of neoantigens and impair tumor growth in colorectal cancer, breast adenocarcinoma, and pancreatic ductal carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('pancreatic ductal carcinoma', 'Disease', 'MESH:D021441', (269, 296))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (242, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('colorectal cancer', 'Disease', 'MESH:D015179', (223, 240))	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('breast adenocarcinoma', 'Disease', (242, 263))	('colorectal cancer', 'Disease', (223, 240))	('amount', 'MPA', (174, 180))	('DNA repair', 'Gene', (136, 146))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (242, 263))	('neoantigens', 'MPA', (184, 195))	('DNA repair', 'biological_process', 'GO:0006281', ('136', '146'))	('impair', 'NegReg', (200, 206))	('increase', 'PosReg', (161, 169))	('tumor', 'Disease', (207, 212))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (280, 296))	('pancreatic ductal carcinoma', 'Disease', (269, 296))	('colorectal cancer', 'Phenotype', 'HP:0003003', (223, 240))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('inactivating', 'Var', (123, 135))
168160	24121487	TERT Promoter Mutations Occur Early in Urothelial Neoplasia and are Biomarkers of Early Disease and Disease Recurrence in Urine Activating mutations occur in the promoter of the telomerase reverse transcriptase (TERT) gene in 66% of muscle-invasive urothelial carcinomas.	('Urothelial Neoplasia', 'Disease', (39, 59))	('TERT', 'Gene', (212, 216))	('TERT', 'Gene', '7015', (212, 216))	('transcriptase', 'molecular_function', 'GO:0003899', ('197', '210'))	('Neoplasia', 'Phenotype', 'HP:0002664', (50, 59))	('telomerase reverse transcriptase', 'Gene', '7015', (178, 210))	('muscle-invasive urothelial carcinomas', 'Disease', (233, 270))	('Recurrence in Urine', 'Phenotype', 'HP:0000010', (108, 127))	('Urothelial Neoplasia', 'Disease', 'MESH:D009369', (39, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('carcinomas', 'Phenotype', 'HP:0030731', (260, 270))	('transcriptase', 'molecular_function', 'GO:0003968', ('197', '210'))	('transcriptase', 'molecular_function', 'GO:0034062', ('197', '210'))	('Activating', 'PosReg', (128, 138))	('mutations', 'Var', (139, 148))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('muscle-invasive urothelial carcinomas', 'Disease', 'MESH:D009217', (233, 270))	('telomerase reverse transcriptase', 'Gene', (178, 210))
168163	24121487	A high rate of TERT promoter mutation was observed in both papillary and flat lesions, as well as in low- and high-grade noninvasive urothelial neoplasms (mean: 74%).	('TERT', 'Gene', '7015', (15, 19))	('mutation', 'Var', (29, 37))	('urothelial neoplasms', 'Disease', 'MESH:D014523', (133, 153))	('TERT', 'Gene', (15, 19))	('flat lesions', 'Disease', (73, 85))	('papillary and flat lesions', 'Phenotype', 'HP:0007482', (59, 85))	('neoplasms', 'Phenotype', 'HP:0002664', (144, 153))	('urothelial neoplasms', 'Disease', (133, 153))	('low- and', 'Disease', (101, 109))	('papillary', 'Disease', (59, 68))
168171	24121487	Activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene lead to increased telomerase expression and, in doing so, allow some neoplasms to overcome the end-replication problem and avoid senescence.	('mutations', 'Var', (11, 20))	('TERT', 'Gene', (78, 82))	('TERT', 'Gene', '7015', (78, 82))	('increased', 'PosReg', (97, 106))	('transcriptase', 'molecular_function', 'GO:0003968', ('63', '76'))	('senescence', 'CPA', (218, 228))	('end-replication', 'MPA', (184, 199))	('senescence', 'biological_process', 'GO:0010149', ('218', '228'))	('transcriptase', 'molecular_function', 'GO:0034062', ('63', '76'))	('transcriptase', 'molecular_function', 'GO:0003899', ('63', '76'))	('neoplasms', 'Phenotype', 'HP:0002664', (158, 167))	('telomerase reverse transcriptase', 'Gene', (44, 76))	('telomerase reverse transcriptase', 'Gene', '7015', (44, 76))	('telomerase expression', 'MPA', (107, 128))	('neoplasms', 'Disease', 'MESH:D009369', (158, 167))	('neoplasms', 'Disease', (158, 167))
168172	24121487	TERT promoter mutations were initially described in melanoma and have subsequently been described in a discrete spectrum of cancer types, including 66% of muscle-invasive urothelial carcinomas of the bladder.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('cancer', 'Disease', (124, 130))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('TERT', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('TERT', 'Gene', '7015', (0, 4))	('invasive urothelial carcinomas of the bladder', 'Phenotype', 'HP:0006740', (162, 207))	('described', 'Reg', (88, 97))	('muscle-invasive urothelial carcinomas of the bladder', 'Disease', 'MESH:D001749', (155, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('carcinomas', 'Phenotype', 'HP:0030731', (182, 192))	('mutations', 'Var', (14, 23))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
168173	24121487	TERT is therefore the most frequently mutated gene in advanced forms of this disease, and the localization of these mutations to a small gene region in the TERT promoter provides an extraordinary opportunity for biomarker development.	('localization', 'biological_process', 'GO:0051179', ('94', '106'))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('mutations', 'Var', (116, 125))	('TERT', 'Gene', (156, 160))	('TERT', 'Gene', '7015', (156, 160))
168174	24121487	For TERT promoter mutations to be a useful marker of early, curable disease, these mutations should be present in pre-invasive bladder tumors and shed into the urine.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('TERT', 'Gene', (4, 8))	('bladder tumors', 'Disease', 'MESH:D001749', (127, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('TERT', 'Gene', '7015', (4, 8))	('bladder tumors', 'Phenotype', 'HP:0009725', (127, 141))	('pre-invasive', 'Disease', (114, 126))	('pre', 'molecular_function', 'GO:0003904', ('114', '117'))	('invasive bladder', 'Phenotype', 'HP:0100645', (118, 134))	('bladder tumors', 'Disease', (127, 141))	('mutations', 'Var', (18, 27))
168176	24121487	We also determined the sequence of the TERT promoter in a separate group of superficial bladder cancers and corresponding follow-up urine samples to establish the feasibility of detecting TERT mutations in urine and their potential utility in predicting recurrence.	('TERT', 'Gene', (39, 43))	('bladder cancers', 'Disease', 'MESH:D001749', (88, 103))	('TERT', 'Gene', (188, 192))	('TERT', 'Gene', '7015', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('TERT', 'Gene', '7015', (39, 43))	('bladder cancers', 'Disease', (88, 103))	('mutations', 'Var', (193, 202))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('bladder cancers', 'Phenotype', 'HP:0009725', (88, 103))	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))
168185	24121487	To better discriminate genuine TERT promoter mutations from artifactual sequencing variants introduced during the sequencing process, we used Safe-SeqS, a sequencing error-reduction technology described previously.	('mutations', 'Var', (45, 54))	('error-reduction', 'Disease', (166, 181))	('error-reduction', 'Disease', 'MESH:D012030', (166, 181))	('TERT', 'Gene', (31, 35))	('TERT', 'Gene', '7015', (31, 35))
168186	24121487	1, Safe-SeqS amplification primers were designed to amplify a 126-bp segment containing the region of the TERT promoter previously shown to harbor mutations in melanomas and other tumors.	('mutations', 'Var', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('melanomas', 'Disease', 'MESH:D008545', (160, 169))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('TERT', 'Gene', (106, 110))	('melanomas', 'Phenotype', 'HP:0002861', (160, 169))	('TERT', 'Gene', '7015', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumors', 'Disease', (180, 186))	('harbor', 'Reg', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('melanomas', 'Disease', (160, 169))
168190	24121487	Urine samples were considered positive when the frequency of mutation exceeded 0.1% of alleles (a frequency at least 10x higher than found in control DNA templates from urine samples of patients without TERT mutations in their primary tumors).	('mutation', 'Var', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumors', 'Disease', (235, 241))	('TERT', 'Gene', (203, 207))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('DNA', 'cellular_component', 'GO:0005574', ('150', '153'))	('TERT', 'Gene', '7015', (203, 207))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('patients', 'Species', '9606', (186, 194))
168191	24121487	We used a massively parallel sequencing technology to determine the presence and representation of mutant TERT promoter alleles in urothelial cancers.	('urothelial cancers', 'Disease', 'MESH:D014523', (131, 149))	('urothelial cancers', 'Disease', (131, 149))	('TERT', 'Gene', (106, 110))	('TERT', 'Gene', '7015', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutant', 'Var', (99, 105))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))
168195	24121487	TERT promoter mutations were identified in 56/76 (74%) of these urothelial carcinomas (Table 2).	('urothelial carcinomas', 'Disease', 'MESH:D014526', (64, 85))	('TERT', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('TERT', 'Gene', '7015', (0, 4))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('mutations', 'Var', (14, 23))	('urothelial carcinomas', 'Disease', (64, 85))
168196	24121487	In contrast, none of the eight samples of adjacent normal urothelium harbored TERT promoter mutations.	('TERT', 'Gene', (78, 82))	('TERT', 'Gene', '7015', (78, 82))	('mutations', 'Var', (92, 101))
168198	24121487	Twelve of the blood samples and five of the normal urothelial samples were from patients whose tumors harbored TERT promoter mutations.	('mutations', 'Var', (125, 134))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('patients', 'Species', '9606', (80, 88))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('TERT', 'Gene', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('TERT', 'Gene', '7015', (111, 115))
168199	24121487	These data demonstrate that the TERT promoter mutations in these patients were unequivocally somatic and limited to the neoplastic urothelium in the bladder.	('patients', 'Species', '9606', (65, 73))	('TERT', 'Gene', '7015', (32, 36))	('mutations', 'Var', (46, 55))	('TERT', 'Gene', (32, 36))
168200	24121487	The predominant alterations were g.1295228C>T (minus strand of chromosome 5, hg19 assembly) and g.1295250C>T mutations, which accounted for 75% and 20% of the total alterations, respectively.	('g.1295250C>T', 'Var', (96, 108))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('g.1295228C>T', 'Mutation', 'g.1295228C>T', (33, 45))	('g.1295228C>T', 'Var', (33, 45))	('g.1295250C>T', 'Mutation', 'g.1295250C>T', (96, 108))
168201	24121487	In addition, we identified one g.1295228C>A mutation and two g.1295242C>T mutations not previously reported (Table S1).	('g.1295242C>T', 'Mutation', 'g.1295242C>T', (61, 73))	('g.1295228C>A', 'Var', (31, 43))	('g.1295242C>T', 'Var', (61, 73))	('g.1295228C>A', 'Mutation', 'g.1295228C>A', (31, 43))
168202	24121487	The mutations were found in all types and grades of these early cancers: in 76% of papillary lesions and 65% of flat lesions; in 86% of low-grade and in 68% of high-grade lesions (Table 2).	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('papillary lesions', 'Phenotype', 'HP:0007482', (83, 100))	('cancers', 'Disease', (64, 71))	('papillary lesions', 'Disease', 'MESH:D007681', (83, 100))	('mutations', 'Var', (4, 13))	('papillary lesions', 'Disease', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
168209	24121487	All of the mutations in the second cohort were at either g.1295228C>T or g.1295250C>T (Table 5).	('g.1295250C>T', 'Mutation', 'g.1295250C>T', (73, 85))	('g.1295228C>T', 'Mutation', 'g.1295228C>T', (57, 69))	('g.1295250C>T', 'Var', (73, 85))	('g.1295228C>T', 'Var', (57, 69))
168214	24121487	Of the 11 patients in whom a TERT mutation was present in the tumor, seven patients were observed to have a mutation in the DNA isolated from their urine cell pellets; in each case, the mutation was identical to that observed in the primary tumor removed via TURB (Table 5).	('TERT', 'Gene', '7015', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', (62, 67))	('patients', 'Species', '9606', (75, 83))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('patients', 'Species', '9606', (10, 18))	('mutation', 'Var', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('TERT', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
168218	24121487	In contrast, no TERT mutations were evident in the urine samples of four patients whose original tumors contained a TERT promoter mutation: the tumors of three of these patients never recurred while the fourth developed a recurrence 3.5 months after the urine sample was collected (Table 5).	('TERT', 'Gene', (16, 20))	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('original tumors', 'Disease', (88, 103))	('patients', 'Species', '9606', (169, 177))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('TERT', 'Gene', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('TERT', 'Gene', '7015', (116, 120))	('mutation', 'Var', (130, 138))	('TERT', 'Gene', '7015', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('patients', 'Species', '9606', (73, 81))	('original tumors', 'Disease', 'MESH:D009369', (88, 103))
168219	24121487	As shown in Table 6, the presence of detectable TERT promoter mutations in the urine was strongly associated with recurrence of urothelial carcinoma (P <0.001; Pearson's correlation coefficient =0.87).	('associated with', 'Reg', (98, 113))	('urothelial carcinoma', 'Disease', (128, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('TERT', 'Gene', (48, 52))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (128, 148))	('TERT', 'Gene', '7015', (48, 52))	('presence', 'Var', (25, 33))
168220	24121487	TERT promoter mutations are detectable in urine, and their presence in urine is strongly associated with bladder cancer recurrence.	('associated with', 'Reg', (89, 104))	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (105, 130))	('bladder cancer', 'Disease', 'MESH:D001749', (105, 119))	('bladder cancer', 'Disease', (105, 119))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('mutations', 'Var', (14, 23))
168224	24121487	We also show that these mutations can be detected in the urine of patients with bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (80, 94))	('bladder cancer', 'Disease', (80, 94))	('bladder cancer', 'Phenotype', 'HP:0009725', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (24, 33))	('patients', 'Species', '9606', (66, 74))
168226	24121487	Given the high prevalence of TERT promoter mutations in early bladder neoplasia, their presence or absence in tumors is of limited prognostic value.	('TERT', 'Gene', '7015', (29, 33))	('bladder neoplasia', 'Phenotype', 'HP:0009725', (62, 79))	('bladder neoplasia', 'Disease', (62, 79))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('neoplasia', 'Phenotype', 'HP:0002664', (70, 79))	('tumors', 'Disease', (110, 116))	('mutations', 'Var', (43, 52))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('TERT', 'Gene', (29, 33))	('bladder neoplasia', 'Disease', 'MESH:D009369', (62, 79))
168229	24121487	Among patients with TERT mutations in their primary tumors, there was a highly significant correlation between the presence of mutations in subsequent urine collections and recurrence (Table 6).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('TERT', 'Gene', (20, 24))	('TERT', 'Gene', '7015', (20, 24))	('patients', 'Species', '9606', (6, 14))	('mutations', 'Var', (127, 136))
168230	24121487	Our results therefore suggest two potential avenues for application of TERT promoter mutations in the clinic: early detection in high-risk patients and monitoring of patients with bladder cancer, both through the analysis of urine specimens.	('bladder cancer', 'Disease', 'MESH:D001749', (180, 194))	('bladder cancer', 'Disease', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('TERT', 'Gene', (71, 75))	('patients', 'Species', '9606', (139, 147))	('TERT', 'Gene', '7015', (71, 75))	('bladder cancer', 'Phenotype', 'HP:0009725', (180, 194))	('mutations', 'Var', (85, 94))	('patients', 'Species', '9606', (166, 174))
168231	24121487	For example, we have not yet shown that bladder cancer patients have detectable mutations in urine prior to tumor diagnosis; all of our urine samples were taken at follow-up visits after surgery.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('tumor', 'Disease', (108, 113))	('patients', 'Species', '9606', (55, 63))
168233	24121487	Still, our study provides a strong proof-of-principle: TERT promoter mutations occur early, are specific for neoplasia, and can be identified in the urine with currently available technologies.	('mutations', 'Var', (69, 78))	('neoplasia', 'Disease', (109, 118))	('TERT', 'Gene', (55, 59))	('TERT', 'Gene', '7015', (55, 59))	('neoplasia', 'Phenotype', 'HP:0002664', (109, 118))	('neoplasia', 'Disease', 'MESH:D009369', (109, 118))
168251	22216392	HER-2/neu protein overexpression and HER-2/neu gene amplification were correlated with higher histologic tumor grade and primary bladder cancer invasiveness in several studies; however, these reports used immunohistochemistry, fluorescent in situ hybridization, or polymerase chain reaction.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('HER-2/neu', 'Gene', '2064', (37, 46))	('HER-2/neu', 'Gene', (0, 9))	('protein', 'Protein', (10, 17))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('HER-2/neu', 'Gene', '2064', (0, 9))	('bladder cancer invasiveness', 'Disease', 'MESH:D001749', (129, 156))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('bladder cancer invasiveness', 'Disease', (129, 156))	('HER-2/neu', 'Gene', (37, 46))	('amplification', 'Var', (52, 65))	('overexpression', 'PosReg', (18, 32))	('higher', 'PosReg', (87, 93))
168274	22216392	The clinical significance of serum HER-2/neu has already been evaluated in prostate, colorectal, and stomach cancers; patients with elevated serum HER-2/neu demonstrate poor survival compared with patients with lower HER-2/neu.	('elevated', 'PosReg', (132, 140))	('patients', 'Species', '9606', (197, 205))	('serum', 'Var', (141, 146))	('colorectal', 'Disease', 'MESH:D015179', (85, 95))	('stomach cancers', 'Disease', (101, 116))	('stomach cancers', 'Phenotype', 'HP:0012126', (101, 116))	('HER-2/neu', 'Gene', '2064', (147, 156))	('HER-2/neu', 'Gene', '2064', (217, 226))	('HER-2/neu', 'Gene', '2064', (35, 44))	('poor', 'NegReg', (169, 173))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('colorectal', 'Disease', (85, 95))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('HER-2/neu', 'Gene', (147, 156))	('HER-2/neu', 'Gene', (217, 226))	('stomach cancers', 'Disease', 'MESH:D013274', (101, 116))	('HER-2/neu', 'Gene', (35, 44))	('prostate', 'Disease', (75, 83))	('patients', 'Species', '9606', (118, 126))
168294	31844177	Prevalence of pathogenic germline cancer risk variants in high-risk urothelial carcinoma To date, there has not been a large, systematic evaluation of the prevalence of germline risk variants in urothelial carcinoma (UC).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (195, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('urothelial carcinoma', 'Disease', (68, 88))	('variants', 'Var', (46, 54))	('cancer', 'Disease', (34, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (68, 88))	('urothelial carcinoma', 'Disease', (195, 215))
168296	31844177	Case-control enrichment analysis was performed to screen for pathogenic variant enrichment in 17 DNA repair genes in 1038 UC patients relative to cancer-free individuals.	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('men', 'Species', '9606', (86, 89))	('DNA repair', 'biological_process', 'GO:0006281', ('97', '107'))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('DNA repair genes', 'Gene', (97, 113))	('men', 'Species', '9606', (19, 22))	('variant enrichment', 'Var', (72, 90))	('patients', 'Species', '9606', (125, 133))
168299	31844177	Compared to the cancer-free cohort, UC patients had significant variant enrichment in MSH2 (odds ratio [OR]: 15.4, 95% confidence interval [CI]: 7.1-32.7, p < 0.0001), MLH1 (OR: 15.9, 95% CI: 4.4-67.7, p < 0.0001), BRCA2 (OR: 5.7, 95% CI: 3.2-9.6, p < 0.0001), and ATM (OR: 3.8, 95% CI: 1.8-8.3, p = 0.02).	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('patients', 'Species', '9606', (39, 47))	('ATM', 'Gene', '472', (265, 268))	('cancer', 'Disease', (16, 22))	('variant', 'Var', (64, 71))	('BRCA2', 'Gene', (215, 220))	('MLH1', 'Gene', '4292', (168, 172))	('MLH1', 'Gene', (168, 172))	('MSH2', 'Gene', (86, 90))	('MSH2', 'Gene', '4436', (86, 90))	('men', 'Species', '9606', (78, 81))	('ATM', 'Gene', (265, 268))	('BRCA2', 'Gene', '675', (215, 220))
168300	31844177	In this study, 24% of UC patients harbored pathogenic germline variants and 18.6% had clinically actionable variants.	('pathogenic', 'Reg', (43, 53))	('germline variants', 'Var', (54, 71))	('patients', 'Species', '9606', (25, 33))
168306	31844177	UCs are known component cancers of Lynch syndrome, which is caused by pathogenic variants in mismatch repair genes (including MLH1, MSH2, MSH6, and PMS2).	('cancers of Lynch syndrome', 'Disease', 'MESH:D009369', (24, 49))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('MSH6', 'Gene', (138, 142))	('mismatch repair', 'biological_process', 'GO:0006298', ('93', '108'))	('MLH1', 'Gene', '4292', (126, 130))	('MSH6', 'Gene', '2956', (138, 142))	('PMS2', 'Gene', (148, 152))	('MSH2', 'Gene', (132, 136))	('cancers of Lynch syndrome', 'Disease', (24, 49))	('caused by', 'Reg', (60, 69))	('MLH1', 'Gene', (126, 130))	('PMS2', 'Gene', '5395', (148, 152))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('MSH2', 'Gene', '4436', (132, 136))	('variants', 'Var', (81, 89))
168308	31844177	In addition, a recent study of 98 Chinese patients with bladder cancer reported germline DNA damage repair gene (DRG) variants in 10.2% of cases.	('variants', 'Var', (118, 126))	('DRG', 'Gene', (113, 116))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('patients', 'Species', '9606', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('bladder cancer', 'Disease', (56, 70))
168311	31844177	Herein, we describe the prevalence of germline cancer risk variants among a large cohort of high-risk UC patients completing genetic testing.	('patients', 'Species', '9606', (105, 113))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('variants', 'Var', (59, 67))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
168312	31844177	This study is the largest to date to examine germline cancer risk variants and identify associated clinical factors in patients with UC.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('patients', 'Species', '9606', (119, 127))	('variants', 'Var', (66, 74))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
168327	31844177	As an example, the East Asian ExAC population has the highest reported frequency of MSH2 germline variants among all ancestries (0.23%).	('MSH2', 'Gene', (84, 88))	('variants', 'Var', (98, 106))	('MSH2', 'Gene', '4436', (84, 88))
168328	31844177	As such, the East Asian ExAC population was used as the control group when comparing the prevalence of pathogenic MSH2 variants with our UC cohort.	('MSH2', 'Gene', (114, 118))	('variants', 'Var', (119, 127))	('MSH2', 'Gene', '4436', (114, 118))
168329	31844177	For the enrichment analysis, we included all pathogenic variant calls from our cohort except for genomic alterations not included in ExAC data release that was used for the analysis (deletions [n = 15] or duplications [n = 1] spanning entire exons) or intronic regions without adequate coverage (n = 1).	('duplications [', 'Var', (205, 219))	('deletions', 'Var', (183, 192))	('men', 'Species', '9606', (14, 17))
168330	31844177	Of note, loss-of-function (LOF) variants in CHEK2 and low penetrance CHEK2 p.Ile157Thr variants were analyzed separately as they exhibit distinctive functional and clinical features.	('CHEK2', 'Gene', '11200', (69, 74))	('variants', 'Var', (87, 95))	('CHEK2', 'Gene', (69, 74))	('p.Ile157Thr', 'Mutation', 'rs17879961', (75, 86))	('variants', 'Var', (32, 40))	('CHEK2', 'Gene', '11200', (44, 49))	('loss-of-function', 'NegReg', (9, 25))	('CHEK2', 'Gene', (44, 49))
168339	31844177	The cumulative frequency of patients with pathogenic germline variants in all examined genes was 24%.	('pathogenic', 'Reg', (42, 52))	('patients', 'Species', '9606', (28, 36))	('germline variants', 'Var', (53, 70))
168340	31844177	Overall, the highest frequency of pathogenic germline variants was in MSH2 (34/969, 3.5%, 95% CI = 2.5-4.9%), BRCA1 (20/867, 2.3%, 95% CI = 1.5-3.5%), BRCA2 (18/867, 2.1%, 95% CI = 1.3-3.3%), heterozygous MUTYH (15/754, 2.0%, 95% CI = 1.2-3.3%), and ATM (13/827, 1.6%, 95% CI = 0.9-2.7%) as shown in Tables 2 and S1.3.	('MSH2', 'Gene', '4436', (70, 74))	('MUTYH', 'Gene', (205, 210))	('MUTYH', 'Gene', '4595', (205, 210))	('BRCA2', 'Gene', '675', (151, 156))	('BRCA1', 'Gene', '672', (110, 115))	('ATM', 'Gene', (250, 253))	('ATM', 'Gene', '472', (250, 253))	('BRCA1', 'Gene', (110, 115))	('pathogenic', 'Reg', (34, 44))	('MSH2', 'Gene', (70, 74))	('variants', 'Var', (54, 62))	('BRCA2', 'Gene', (151, 156))
168341	31844177	Loss-of-function and low penetrance CHEK2 variants were each identified in 1.4% (12/862, 95% CI = 0.8-2.4%) of patients.	('CHEK2', 'Gene', (36, 41))	('Loss-of-function', 'NegReg', (0, 16))	('variants', 'Var', (42, 50))	('low', 'NegReg', (21, 24))	('CHEK2', 'Gene', '11200', (36, 41))	('patients', 'Species', '9606', (111, 119))
168343	31844177	Of note, fumarate hydratase (FH) pathogenic germline variants were found in 1.3% (5/390, 95% CI = 0.5-3.0%) while germline variants in the melanocyte inducing transcription factor (MITF) were detected in 1.2% (4/339, 95% CI = 0.5-3.0%, Table S1.3).	('fumarate hydratase', 'Gene', (9, 27))	('transcription factor', 'molecular_function', 'GO:0000981', ('159', '179'))	('melanocyte inducing transcription factor', 'Gene', '4286', (139, 179))	('transcription', 'biological_process', 'GO:0006351', ('159', '172'))	('pathogenic', 'Reg', (33, 43))	('MITF', 'Gene', '4286', (181, 185))	('MITF', 'Gene', (181, 185))	('FH', 'Gene', '2271', (29, 31))	('melanocyte inducing transcription factor', 'Gene', (139, 179))	('fumarate hydratase', 'Gene', '2271', (9, 27))	('variants', 'Var', (53, 61))
168345	31844177	Of the four MITF p.E318K carriers, only one patient had a personal history of an MITF-associated malignancy (melanoma) (Table S1.1).	('MITF', 'Gene', '4286', (12, 16))	('MITF', 'Gene', (12, 16))	('patient', 'Species', '9606', (44, 51))	('S1.1', 'Gene', '6267', (126, 130))	('S1.1', 'Gene', (126, 130))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('MITF', 'Gene', '4286', (81, 85))	('MITF', 'Gene', (81, 85))	('malignancy', 'Disease', 'MESH:D009369', (97, 107))	('p.E318K', 'Var', (17, 24))	('p.E318K', 'Mutation', 'rs149617956', (17, 24))	('malignancy', 'Disease', (97, 107))
168348	31844177	Among the 1038 patients, 20% harbored pathogenic germline variants in one of the DRGs.	('germline variants', 'Var', (49, 66))	('patients', 'Species', '9606', (15, 23))	('pathogenic', 'Reg', (38, 48))
168350	31844177	Pathogenic variants in the homologous recombination (HR) pathway were the most prevalent, occurring at a cumulative frequency of 11.1% (Table S1.4, Fig.	('S1.4', 'Gene', (142, 146))	('S1.4', 'Gene', '6208', (142, 146))	('variants', 'Var', (11, 19))	('Pathogenic', 'Reg', (0, 10))	('homologous recombination', 'biological_process', 'GO:0035825', ('27', '51'))
168351	31844177	Among the HR pathway genes, a total of 20 pathogenic variants were identified in BRCA1 and another 18 pathogenic variants were found in BRCA2.	('BRCA1', 'Gene', (81, 86))	('BRCA2', 'Gene', (136, 141))	('pathogenic', 'Reg', (42, 52))	('BRCA1', 'Gene', '672', (81, 86))	('variants', 'Var', (53, 61))	('BRCA2', 'Gene', '675', (136, 141))
168353	31844177	Additionally, our analysis identified 13 pathogenic variants in ATM.	('ATM', 'Gene', '472', (64, 67))	('ATM', 'Gene', (64, 67))	('pathogenic', 'Reg', (41, 51))	('variants', 'Var', (52, 60))
168356	31844177	Pathogenic germline variants in these genes were detected in 5.9% of patients and represented a quarter of the total germline variants detected in DRGs.	('patients', 'Species', '9606', (69, 77))	('Pathogenic', 'Reg', (0, 10))	('variants', 'Var', (20, 28))
168358	31844177	All MSH2 pathogenic variants (n = 34) were predicted to cause LOF with 11 (32%, CI = 19-49%) MSH2 pathogenic calls involving exonic deletions.	('variants', 'Var', (20, 28))	('MSH2', 'Gene', (4, 8))	('MSH2', 'Gene', '4436', (4, 8))	('MSH2', 'Gene', (93, 97))	('LOF', 'NegReg', (62, 65))	('exonic deletions', 'Var', (125, 141))	('MSH2', 'Gene', '4436', (93, 97))
168359	31844177	Six of 10 (60%, CI = 31-83%) pathogenic variants in MLH1 led to protein truncation.	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('led to', 'Reg', (57, 63))	('MLH1', 'Gene', (52, 56))	('protein truncation', 'MPA', (64, 82))	('MLH1', 'Gene', '4292', (52, 56))	('variants', 'Var', (40, 48))
168360	31844177	One variant p.Gly67Arg affected the histidine kinase-, DNA gyrase B, and HSP90-like ATPase (HATPase_c_3).	('p.Gly67Arg', 'Var', (12, 22))	('HSP90-like ATPase', 'Protein', (73, 90))	('DNA', 'Protein', (55, 58))	('affected', 'Reg', (23, 31))	('p.Gly67Arg', 'Mutation', 'rs63750206', (12, 22))	('histidine', 'Protein', (36, 45))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))
168361	31844177	Among the eight germline variants in MSH6, six (75%, CI = 41-96%) were truncating.	('MSH6', 'Gene', '2956', (37, 41))	('MSH6', 'Gene', (37, 41))	('variants', 'Var', (25, 33))
168362	31844177	Both pathogenic germline variants in PMS2 were missense and involved either the HATPase- or MutL-C terminal domains (Fig.	('missense', 'Var', (47, 55))	('variants', 'Var', (25, 33))	('PMS2', 'Gene', '5395', (37, 41))	('pathogenic', 'Reg', (5, 15))	('HATPase-', 'Protein', (80, 88))	('PMS2', 'Gene', (37, 41))	('MutL-C terminal domains', 'MPA', (92, 115))	('involved', 'Reg', (60, 68))
168363	31844177	Based on data from prior studies suggesting higher frequency of germline defects in the MMR pathway in UC, we performed enrichment analysis on an expanded set of 17 DRGs (see "Materials and Methods").	('MMR pathway', 'Pathway', (88, 99))	('MMR', 'biological_process', 'GO:0006298', ('88', '91'))	('men', 'Species', '9606', (126, 129))	('germline defects', 'Var', (64, 80))
168365	31844177	Using a p value of less than 0.05 for significant associations (correcting for the number of conducted tests), we showed a significant pathogenic variant enrichment of ATM, BRCA2, MLH1, and MSH2 in our cohort relative to cancer-free cohorts (Fig.	('MSH2', 'Gene', '4436', (190, 194))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('pathogenic', 'Reg', (135, 145))	('variant', 'Var', (146, 153))	('cancer', 'Disease', (221, 227))	('BRCA2', 'Gene', (173, 178))	('ATM', 'Gene', (168, 171))	('ATM', 'Gene', '472', (168, 171))	('BRCA2', 'Gene', '675', (173, 178))	('men', 'Species', '9606', (160, 163))	('MSH2', 'Gene', (190, 194))	('MLH1', 'Gene', '4292', (180, 184))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('MLH1', 'Gene', (180, 184))
168366	31844177	Our enrichment analysis findings showed that patients with germline alterations in MLH1 and MSH2 were roughly 15 times more likely to develop UC compared with cancer-free controls (OR = 15.9, 95% CI = 4.4-67.7, adjusted p < 0.0001 and OR = 15.4, 95% CI = 7.1-32.7, adjusted p < 0.0001, respectively).	('cancer', 'Disease', (159, 165))	('MSH2', 'Gene', (92, 96))	('men', 'Species', '9606', (10, 13))	('MSH2', 'Gene', '4436', (92, 96))	('germline alterations', 'Var', (59, 79))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('MLH1', 'Gene', '4292', (83, 87))	('patients', 'Species', '9606', (45, 53))	('MLH1', 'Gene', (83, 87))	('develop', 'PosReg', (134, 141))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
168367	31844177	Of note, 7 of 10 (70%, CI = 40-89%) pathogenic variants in MLH1 led to LOF.	('MLH1', 'Gene', (59, 63))	('LOF', 'NegReg', (71, 74))	('variants', 'Var', (47, 55))	('MLH1', 'Gene', '4292', (59, 63))
168369	31844177	Compared with cancer-free individuals, patients with UC were roughly six times more likely to carry pathogenic variants in BRCA2 (OR = 5.7, 95% CI = 3.2-9.6, p < 0.0001).	('cancer', 'Disease', (14, 20))	('BRCA2', 'Gene', '675', (123, 128))	('pathogenic', 'CPA', (100, 110))	('patients', 'Species', '9606', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('variants', 'Var', (111, 119))	('BRCA2', 'Gene', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
168370	31844177	Our enrichment analysis also demonstrated that germline pathogenic variants in ATM were approximately four times more frequent in the UC patients compared with the ExAC cohort (OR = 3.8, 95% CI = 1.8-8.3, adjusted p = 0.02).	('ATM', 'Gene', '472', (79, 82))	('men', 'Species', '9606', (10, 13))	('patients', 'Species', '9606', (137, 145))	('ATM', 'Gene', (79, 82))	('variants', 'Var', (67, 75))
168372	31844177	Lynch syndrome gene variants represented 5.9% of the total 18.6% (Table 3).	('variants', 'Var', (20, 28))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('Lynch syndrome', 'Disease', (0, 14))
168373	31844177	Highly penetrant cancer risk variants were as follows: BRCA1 or BRCA2 (38/867, 4.4%, 95% CI = 3.2-5.9%), MSH2 (34/969, 3.5%, 95% CI = 2.5-4.9%), MLH1 (10/957, 1%, 95% CI = 0.6-1.9%), and TP53 (2/929, 0.2%, 95% CI = 0.04-0.8%).	('MSH2', 'Gene', (105, 109))	('BRCA2', 'Gene', '675', (64, 69))	('MSH2', 'Gene', '4436', (105, 109))	('TP53', 'Gene', '7157', (187, 191))	('BRCA1', 'Gene', '672', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('variants', 'Var', (29, 37))	('cancer', 'Disease', (17, 23))	('TP53', 'Gene', (187, 191))	('BRCA1', 'Gene', (55, 60))	('BRCA2', 'Gene', (64, 69))	('MLH1', 'Gene', '4292', (145, 149))	('MLH1', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
168374	31844177	The most common moderately penetrant actionable pathogenic variants were CHEK2 (12/862, 1.4%, 95% CI = 0.8-2.4%), MSH6 (8/959, 0.8%, 95% CI = 0.4-1.6%), and PMS2 (5/956, 0.5%, 95% CI = 0.2-1.2%).	('PMS2', 'Gene', (157, 161))	('variants', 'Var', (59, 67))	('PMS2', 'Gene', '5395', (157, 161))	('CHEK2', 'Gene', '11200', (73, 78))	('MSH6', 'Gene', (114, 118))	('CHEK2', 'Gene', (73, 78))	('MSH6', 'Gene', '2956', (114, 118))	('moderately penetrant actionable pathogenic', 'CPA', (16, 58))
168375	31844177	Low penetrance variants were most frequent as follows: CHEK2, p.I157T variant (12/862, 1.4%, 95% CI = 0.8-2.4%) and heterozygous MUTYH (15/754, 2%, 95% CI = 1.2-3.3%, Tables 3 and S1.7).	('MUTYH', 'Gene', '4595', (129, 134))	('S1.7', 'Gene', (180, 184))	('CHEK2', 'Gene', '11200', (55, 60))	('p.I157T', 'Mutation', 'rs17879961', (62, 69))	('S1.7', 'Gene', '6218', (180, 184))	('CHEK2', 'Gene', (55, 60))	('Low penetrance', 'MPA', (0, 14))	('p.I157T', 'Var', (62, 69))	('MUTYH', 'Gene', (129, 134))
168376	31844177	Four genes (MSH2, BRCA1, BRCA2, and MUTYH) met criteria for this analysis as they had over 100 requisitions and pathogenic variants were present in >=2% of UC patients.	('MSH2', 'Gene', '4436', (12, 16))	('BRCA2', 'Gene', (25, 30))	('MUTYH', 'Gene', (36, 41))	('BRCA1', 'Gene', '672', (18, 23))	('MUTYH', 'Gene', '4595', (36, 41))	('BRCA1', 'Gene', (18, 23))	('BRCA2', 'Gene', '675', (25, 30))	('patients', 'Species', '9606', (159, 167))	('MSH2', 'Gene', (12, 16))	('variants', 'Var', (123, 131))
168378	31844177	Patients with upper tract urothelial carcinoma (UTUC) were more likely to have MSH2 pathogenic variants compared with those with bladder tumors only (9/67, 13% versus 22/856, 3%; OR = 5.9; 95% CI = 2.6-13.4; p < 0.001).	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('pathogenic', 'Reg', (84, 94))	('bladder tumors', 'Disease', 'MESH:D001749', (129, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('bladder tumors', 'Phenotype', 'HP:0009725', (129, 143))	('MSH2', 'Gene', (79, 83))	('upper tract urothelial carcinoma', 'Disease', (14, 46))	('Patients', 'Species', '9606', (0, 8))	('bladder tumors', 'Disease', (129, 143))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (14, 46))	('MSH2', 'Gene', '4436', (79, 83))	('variants', 'Var', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
168379	31844177	BRCA1, BRCA2, and MUTYH pathogenic variants did not correlate with age at diagnosis, gender, family history of any cancer, or site of UC.	('cancer', 'Disease', (115, 121))	('BRCA1', 'Gene', (0, 5))	('BRCA2', 'Gene', '675', (7, 12))	('variants', 'Var', (35, 43))	('MUTYH', 'Gene', (18, 23))	('MUTYH', 'Gene', '4595', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('BRCA2', 'Gene', (7, 12))	('BRCA1', 'Gene', '672', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
168383	31844177	Similarly, female patients with a personal history of breast cancer were not significantly more likely to harbor BRCA1 pathogenic variants compared with females who did not have a diagnosis of breast cancer (OR = 1.3, 95% CI = 0.4-4.2, p = 0.76).	('breast cancer', 'Disease', (193, 206))	('variants', 'Var', (130, 138))	('breast cancer', 'Disease', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('BRCA1', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('patients', 'Species', '9606', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('BRCA1', 'Gene', '672', (113, 118))
168386	31844177	Herein, our analysis of 1038 patients with cancer of the bladder or upper tract revealed a prevalence of germline variants in 24% of patients with the majority (20%) harboring variants in DRGs.	('patients', 'Species', '9606', (29, 37))	('DRGs', 'Gene', (188, 192))	('cancer of the bladder', 'Disease', (43, 64))	('patients', 'Species', '9606', (133, 141))	('variants', 'Var', (114, 122))	('variants', 'Var', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer of the bladder', 'Disease', 'MESH:D001749', (43, 64))
168388	31844177	One study of East Asian bladder cancer patients (n = 98) found pathogenic and likely pathogenic variants in DRGs occurred in 10.2%.	('patients', 'Species', '9606', (39, 47))	('variants', 'Var', (96, 104))	('bladder cancer', 'Phenotype', 'HP:0009725', (24, 38))	('bladder cancer', 'Disease', 'MESH:D001749', (24, 38))	('bladder cancer', 'Disease', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('DRGs', 'Gene', (108, 112))
168391	31844177	In this cohort, we reported significantly higher rates of germline pathogenic variants in ATM, BRCA2, MLH1, and MSH2 relative to cancer-free control individuals.	('BRCA2', 'Gene', '675', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('MSH2', 'Gene', (112, 116))	('MSH2', 'Gene', '4436', (112, 116))	('ATM', 'Gene', '472', (90, 93))	('MLH1', 'Gene', '4292', (102, 106))	('MLH1', 'Gene', (102, 106))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('higher', 'PosReg', (42, 48))	('BRCA2', 'Gene', (95, 100))	('ATM', 'Gene', (90, 93))	('variants', 'Var', (78, 86))
168395	31844177	In response to double-strand breaks in DNA, ATM phosphorylates downstream cellular processes that ultimately regulate DNA-end resection.	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('ATM', 'Gene', (44, 47))	('ATM', 'Gene', '472', (44, 47))	('double-strand breaks', 'Var', (15, 35))
168396	31844177	Prior studies have focused on ATM's pivotal role in cancer development and associated heterozygous carriers of ATM variants with increased risks of breast cancer, colorectal cancer, and potentially pancreatic cancer.	('men', 'Species', '9606', (66, 69))	('ATM', 'Gene', '472', (111, 114))	('variants', 'Var', (115, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('ATM', 'Gene', '472', (30, 33))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('pancreatic cancer', 'Disease', (198, 215))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (174, 180))	('breast cancer', 'Disease', (148, 161))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('pancreatic cancer', 'Disease', 'MESH:D010190', (198, 215))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('ATM', 'Gene', (111, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (198, 215))	('ATM', 'Gene', (30, 33))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('colorectal cancer', 'Disease', 'MESH:D015179', (163, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', (209, 215))	('colorectal cancer', 'Disease', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
168398	31844177	Although prior studies clearly linked pathogenic ATM and BRCA2 variants to the development of several cancers, none have associated such variants with an increased risk of UC.	('ATM', 'Gene', '472', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('men', 'Species', '9606', (86, 89))	('variants', 'Var', (63, 71))	('BRCA2', 'Gene', (57, 62))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('ATM', 'Gene', (49, 52))	('BRCA2', 'Gene', '675', (57, 62))	('cancers', 'Disease', (102, 109))
168400	31844177	Germline variants in DRGs were found in 20% of patients, among which HR pathway genes contributed to almost half of the DRG variants.	('HR pathway genes', 'Gene', (69, 85))	('DRGs', 'Gene', (21, 25))	('variants', 'Var', (124, 132))	('patients', 'Species', '9606', (47, 55))
168402	31844177	The same group also showed that variants in HR and MMR pathway genes occur in 11/101 (11%) and 8/101 (8%) patients, respectively.	('MMR pathway genes', 'Gene', (51, 68))	('occur', 'Reg', (69, 74))	('variants', 'Var', (32, 40))	('patients', 'Species', '9606', (106, 114))	('MMR', 'biological_process', 'GO:0006298', ('51', '54'))
168404	31844177	In a separate study of 98 East Asian patients with UC with all stages of disease who were referred for multi-DRG germline testing (n = 54 DRGs), 10.2% harbored pathogenic DRG variants, 1% had a pathogenic variant in an MMR gene, while 4 (4%) had variants in HR pathway genes.	('variants', 'Var', (175, 183))	('HR pathway', 'Pathway', (258, 268))	('pathogenic', 'Reg', (194, 204))	('patients', 'Species', '9606', (37, 45))	('MMR gene', 'Gene', (219, 227))	('pathogenic', 'Reg', (160, 170))	('MMR', 'biological_process', 'GO:0006298', ('219', '222'))	('DRG', 'Gene', (171, 174))
168407	31844177	Collectively, 5% of the UC patients in our study carried a variant in BRCA1, BRCA2, or PALB2, which are core components of the HR pathway.	('core', 'cellular_component', 'GO:0019013', ('104', '108'))	('BRCA1', 'Gene', '672', (70, 75))	('BRCA2', 'Gene', (77, 82))	('BRCA1', 'Gene', (70, 75))	('patients', 'Species', '9606', (27, 35))	('PALB2', 'Gene', '79728', (87, 92))	('variant', 'Var', (59, 66))	('BRCA2', 'Gene', '675', (77, 82))	('PALB2', 'Gene', (87, 92))
168408	31844177	Additionally, our study found 5.9% of patients with germline MMR variants.	('MMR', 'Gene', (61, 64))	('variants', 'Var', (65, 73))	('MMR', 'biological_process', 'GO:0006298', ('61', '64'))	('patients', 'Species', '9606', (38, 46))
168411	31844177	In addition to the therapeutic utility, variants in these genes significantly increase a patient's lifetime risk of developing other malignancies, some of which have readily available and effective screening options.	('patient', 'Species', '9606', (89, 96))	('malignancies', 'Disease', (133, 145))	('increase', 'PosReg', (78, 86))	('variants', 'Var', (40, 48))	('malignancies', 'Disease', 'MESH:D009369', (133, 145))
168413	31844177	We also found pathogenic germline variants in FH and MITF in 1.3% and 1.2% respectively.	('pathogenic', 'Reg', (14, 24))	('variants', 'Var', (34, 42))	('MITF', 'Gene', '4286', (53, 57))	('MITF', 'Gene', (53, 57))	('FH', 'Gene', '2271', (46, 48))
168416	31844177	The MITF p.E318K variant has been associated with both melanoma and renal cell carcinoma.	('associated', 'Reg', (34, 44))	('p.E318K', 'Mutation', 'rs149617956', (9, 16))	('MITF', 'Gene', '4286', (4, 8))	('MITF', 'Gene', (4, 8))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (68, 88))	('melanoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (55, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('p.E318K', 'Var', (9, 16))
168417	31844177	Future studies focused on screening genetically enriched patients may be a powerful strategy to determine whether this variant or the FH variants confer an increased risk of urothelial carcinoma.	('patients', 'Species', '9606', (57, 65))	('variant', 'Var', (119, 126))	('urothelial carcinoma', 'Disease', (174, 194))	('FH', 'Gene', '2271', (134, 136))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (174, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('variants', 'Var', (137, 145))
168419	31844177	In our analysis, germline pathogenic variants in Lynch syndrome genes explained the higher risk of UC in only 6% of highly selected UC patients, leaving much of the missing heritability unexplained.	('variants', 'Var', (37, 45))	('patients', 'Species', '9606', (135, 143))	('Lynch syndrome', 'Disease', 'MESH:D003123', (49, 63))	('Lynch syndrome', 'Disease', (49, 63))
168420	31844177	First, our patients were selected for genetic testing based on a suspicion of heritable pathogenic variants: history of >=1 other nonurothelial cancers, young age, or family history of cancer or cancer predisposition syndrome.	('variants', 'Var', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (195, 201))	('nonurothelial cancers', 'Disease', (130, 151))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', (144, 150))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('nonurothelial cancers', 'Disease', 'MESH:D009369', (130, 151))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('patients', 'Species', '9606', (11, 19))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
168425	31844177	In this large study evaluating 1038 UC patients, 24% of patients carried pathogenic cancer predisposition variants with 20% harboring variants in DNA damage repair genes.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('patients', 'Species', '9606', (56, 64))	('variants', 'Var', (106, 114))	('patients', 'Species', '9606', (39, 47))	('cancer', 'Disease', (84, 90))	('pathogenic', 'Reg', (73, 83))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
168427	31844177	While 11% of tested UC patients were found to have germline variants for which targeted therapeutics may be considered, actionable germline variants that have gene-specific NCCN cancer management recommendations were identified in 19% of UC patients.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('patients', 'Species', '9606', (23, 31))	('men', 'Species', '9606', (201, 204))	('men', 'Species', '9606', (191, 194))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('variants', 'Var', (60, 68))	('patients', 'Species', '9606', (241, 249))
168458	31867214	It was agreed uniformly that based on the clinical, radiological, cystocopic, laparoscopic and pathological findings all taken into consideration, the most possible and confident diagnosis for our patient's presentation was extravesical, extraperitoneal metastasis of bladder tumour due to microperforation during TURP.	('microperforation', 'Var', (290, 306))	('bladder tumour', 'Disease', (268, 282))	('bladder tumour', 'Phenotype', 'HP:0009725', (268, 282))	('bladder tumour', 'Disease', 'MESH:D001749', (268, 282))	('tumour', 'Phenotype', 'HP:0002664', (276, 282))	('patient', 'Species', '9606', (197, 204))
168468	31569404	Moreover, overexpression of a dominant-negative p53 mutant downregulated miR-34a, but upregulated c-Myc and CD44, in UC cell lines.	('CD44', 'Gene', (108, 112))	('p53', 'Gene', (48, 51))	('miR-34a', 'Protein', (73, 80))	('mutant', 'Var', (52, 58))	('p53', 'Gene', '7157', (48, 51))	('expression', 'Species', '29278', (14, 24))	('c-Myc', 'Gene', '4609', (98, 103))	('downregulated', 'NegReg', (59, 72))	('upregulated', 'PosReg', (86, 97))	('UC', 'Disease', 'MESH:D014523', (117, 119))	('CD44', 'Gene', '960', (108, 112))	('c-Myc', 'Gene', (98, 103))
168469	31569404	Functionally, the ectopic expression of miR-34a was shown to significantly suppress CD44 expression, and subsequently, suppression of cell growth and invasion capability, while also reducing chemoresistance.	('CD44', 'Gene', '960', (84, 88))	('expression', 'MPA', (89, 99))	('ectopic expression', 'Var', (18, 36))	('cell growth', 'biological_process', 'GO:0016049', ('134', '145'))	('CD44', 'Gene', (84, 88))	('reducing', 'NegReg', (182, 190))	('chemoresistance', 'CPA', (191, 206))	('miR-34a', 'Gene', (40, 47))	('suppress', 'NegReg', (75, 83))	('invasion capability', 'CPA', (150, 169))	('suppression', 'NegReg', (119, 130))	('expression', 'Species', '29278', (26, 36))	('expression', 'Species', '29278', (89, 99))
168470	31569404	In conclusion, it appears that aberrant promoter methylation, and c-Myc-mediated ceRNA mechanisms, may attenuate the function of miR-34a, in UC.	('c-Myc', 'Gene', '4609', (66, 71))	('attenuate', 'NegReg', (103, 112))	('aberrant', 'Var', (31, 39))	('c-Myc', 'Gene', (66, 71))	('function', 'MPA', (117, 125))	('promoter', 'MPA', (40, 48))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('miR-34a', 'Gene', (129, 136))	('UC', 'Disease', 'MESH:D014523', (141, 143))
168480	31569404	Epigenetic modification is considered a hallmark of cancer, due to its roles in cellular carcinogenesis and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('roles', 'Reg', (71, 76))	('carcinogenesis', 'Disease', (89, 103))	('tumor', 'Disease', (108, 113))	('hallmark of cancer', 'Disease', (40, 58))	('hallmark of cancer', 'Disease', 'MESH:D009369', (40, 58))	('Epigenetic modification', 'Var', (0, 23))
168483	31569404	In this ceRNA mechanism, the 3'UTR of the mRNA could act in trans to modulate gene expression, epigenetically.	('epigenetically', 'Var', (95, 109))	('gene expression', 'MPA', (78, 93))	('expression', 'Species', '29278', (83, 93))	('gene expression', 'biological_process', 'GO:0010467', ('78', '93'))	('modulate', 'Reg', (69, 77))
168490	31569404	Researchers also have yet to determine the role of epigenetic modification in the expression of miR-34a.	('expression', 'Species', '29278', (82, 92))	('epigenetic modification', 'Var', (51, 74))	('miR-34a', 'Gene', (96, 103))
168491	31569404	Consequently, our objective in this study was to determine the role of epigenetic modification in the expression of miR-34a, and its target genes, in UC.	('expression', 'Species', '29278', (102, 112))	('UC', 'Disease', 'MESH:D014523', (150, 152))	('miR-34a', 'Gene', (116, 123))	('epigenetic modification', 'Var', (71, 94))
168495	31569404	Previous studies have demonstrated that dysregulation of miRNA, through promoter CpG island methylation, is an important mechanism in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (134, 148))	('miR', 'Gene', '220972', (57, 60))	('methylation', 'Var', (92, 103))	('miR', 'Gene', (57, 60))	('dysregulation', 'Var', (40, 53))	('carcinogenesis', 'Disease', (134, 148))	('methylation', 'biological_process', 'GO:0032259', ('92', '103'))
168511	31569404	As expected, transfection of miR-34a reduced mRNA and protein levels of c-Myc in UMUC3 cells (Figure 2B).	('c-Myc', 'Gene', '4609', (72, 77))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('transfection', 'Var', (13, 25))	('UMUC3', 'CellLine', 'CVCL:1783', (81, 86))	('c-Myc', 'Gene', (72, 77))	('miR-34a', 'Var', (29, 36))	('reduced', 'NegReg', (37, 44))
168513	31569404	Indeed, overexpression of miR-34a was shown to reduce both mRNA and protein of CD44 in UMUC3 cells (Figure 2C).	('overexpression', 'PosReg', (8, 22))	('reduce', 'NegReg', (47, 53))	('protein', 'MPA', (68, 75))	('CD44', 'Gene', '960', (79, 83))	('miR-34a', 'Var', (26, 33))	('expression', 'Species', '29278', (12, 22))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('UMUC3', 'CellLine', 'CVCL:1783', (87, 92))	('CD44', 'Gene', (79, 83))
168521	31569404	To determine whether c-Myc acts as a ceRNA of CD44 through miR-34a, we disrupted miRNA biogenesis via knockdown of the double-strand RNA endoribonuclease, Dicer, in TCCSUP and TSGH8301 cells.	('miR', 'Gene', '220972', (81, 84))	('miR', 'Gene', (81, 84))	('CD44', 'Gene', (46, 50))	('Dicer', 'Gene', (155, 160))	('disrupted', 'NegReg', (71, 80))	('Dicer', 'Gene', '23405', (155, 160))	('c-Myc', 'Gene', (21, 26))	('miRNA biogenesis', 'biological_process', 'GO:0035196', ('81', '97'))	('knockdown', 'Var', (102, 111))	('miR', 'Gene', '220972', (59, 62))	('RNA', 'cellular_component', 'GO:0005562', ('133', '136'))	('miR', 'Gene', (59, 62))	('c-Myc', 'Gene', '4609', (21, 26))	('CD44', 'Gene', '960', (46, 50))
168525	31569404	It is also noteworthy that TSGH8301 cells (with lower Dicer knockdown efficiency), had increased c-Myc and CD44 expression levels, following overexpression of either 3'UTR, in poorly knocked down Dicer cells (Figure 5D-F).	('increased', 'PosReg', (87, 96))	('CD44', 'Gene', (107, 111))	('c-Myc', 'Gene', '4609', (97, 102))	('expression', 'Species', '29278', (145, 155))	('TSGH8301', 'Var', (27, 35))	('Dicer', 'Gene', '23405', (54, 59))	('Dicer', 'Gene', (54, 59))	('c-Myc', 'Gene', (97, 102))	('CD44', 'Gene', '960', (107, 111))	('expression levels', 'MPA', (112, 129))	('expression', 'Species', '29278', (112, 122))	('Dicer', 'Gene', '23405', (196, 201))	('Dicer', 'Gene', (196, 201))
168526	31569404	Taken together, these results confirm that c-Myc and CD44 act as ceRNAs, through miR-34a, in UC.	('UC', 'Disease', 'MESH:D014523', (93, 95))	('CD44', 'Gene', '960', (53, 57))	('c-Myc', 'Gene', '4609', (43, 48))	('CD44', 'Gene', (53, 57))	('miR-34a', 'Var', (81, 88))	('c-Myc', 'Gene', (43, 48))
168539	31569404	Compared to the control, overexpression of the p53 mutant downregulated miR-34a expression, while upregulating CD44 and c-Myc (Figure 7).	('upregulating', 'PosReg', (98, 110))	('CD44', 'Gene', (111, 115))	('c-Myc', 'Gene', (120, 125))	('miR-34a', 'Gene', (72, 79))	('mutant', 'Var', (51, 57))	('expression', 'Species', '29278', (80, 90))	('downregulated', 'NegReg', (58, 71))	('c-Myc', 'Gene', '4609', (120, 125))	('expression', 'Species', '29278', (29, 39))	('expression', 'MPA', (80, 90))	('CD44', 'Gene', '960', (111, 115))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))
168549	31569404	Epigenetic silencing of miR-34a has also been addressed in several previous studies of human cancer; however, the mechanism underlying miR-34a downregulation, in UC, has yet to be elucidated.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('human', 'Species', '9606', (87, 92))	('downregulation', 'NegReg', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Epigenetic', 'Var', (0, 10))	('miR-34a', 'Gene', (135, 142))	('UC', 'Disease', 'MESH:D014523', (162, 164))
168551	31569404	Clinical analyses also found that most UC patient samples were devoid of promoter miR-34a hypermethylation.	('UC', 'Disease', 'MESH:D014523', (39, 41))	('Clinical', 'Species', '191496', (0, 8))	('hypermethylation', 'Var', (90, 106))	('patient', 'Species', '9606', (42, 49))	('devoid', 'NegReg', (63, 69))
168557	31569404	In the current study, we demonstrated that overexpression of the c-Myc 3'UTR could upregulate CD44 through miR-34a.	('CD44', 'Gene', (94, 98))	('upregulate', 'PosReg', (83, 93))	('expression', 'Species', '29278', (47, 57))	('c-Myc', 'Gene', (65, 70))	('overexpression', 'PosReg', (43, 57))	('miR-34a', 'Var', (107, 114))	('CD44', 'Gene', '960', (94, 98))	('c-Myc', 'Gene', '4609', (65, 70))
168561	31569404	In another study, lnc015192 was shown to sponge miR-34a to upregulate Adam12 expression in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('expression', 'MPA', (77, 87))	('breast cancer', 'Disease', (91, 104))	('Adam12', 'Gene', (70, 76))	('lnc015192', 'Var', (18, 27))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('expression', 'Species', '29278', (77, 87))	('upregulate', 'PosReg', (59, 69))	('lnc015192', 'Chemical', 'None', (18, 27))
168564	31569404	Note that the genomic amplification of chromosome 8q (where c-Myc resides), commonly associated with UC, provides an additional driving force for the overexpression of CD44.	('expression', 'Species', '29278', (154, 164))	('genomic amplification', 'Var', (14, 35))	('UC', 'Disease', 'MESH:D014523', (101, 103))	('overexpression', 'PosReg', (150, 164))	('CD44', 'Gene', '960', (168, 172))	('c-Myc', 'Gene', '4609', (60, 65))	('CD44', 'Gene', (168, 172))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('c-Myc', 'Gene', (60, 65))
168567	31569404	In the future, it may be possible to implement epigenetic interventions to restore miR-34a expression, and inhibit cancer stemness, in a subset of UC patients with epigenetic silencing of this micro-RNA.	('inhibit', 'NegReg', (107, 114))	('expression', 'MPA', (91, 101))	('RNA', 'cellular_component', 'GO:0005562', ('199', '202'))	('miR-34a', 'Gene', (83, 90))	('cancer stemness', 'Disease', (115, 130))	('epigenetic silencing', 'Var', (164, 184))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (150, 158))	('UC', 'Disease', 'MESH:D014523', (147, 149))	('restore', 'PosReg', (75, 82))	('cancer stemness', 'Disease', 'MESH:D009369', (115, 130))	('expression', 'Species', '29278', (91, 101))
168569	31569404	In this regard, overexpression of a dominant-negative p53 mutant resulted in miR-34a downregulation, and the subsequent upregulation of CD44 and c-Myc, in UC cells with wild-type p53.	('mutant', 'Var', (58, 64))	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (179, 182))	('c-Myc', 'Gene', '4609', (145, 150))	('overexpression', 'PosReg', (16, 30))	('downregulation', 'NegReg', (85, 99))	('CD44', 'Gene', '960', (136, 140))	('c-Myc', 'Gene', (145, 150))	('CD44', 'Gene', (136, 140))	('p53', 'Gene', (54, 57))	('miR-34a', 'Gene', (77, 84))	('p53', 'Gene', '7157', (54, 57))	('upregulation', 'PosReg', (120, 132))	('UC', 'Disease', 'MESH:D014523', (155, 157))	('expression', 'Species', '29278', (20, 30))
168598	31569404	In conclusion, miR-34a was epigenetically silenced only in a subset of UC cell lines and patient samples.	('patient', 'Species', '9606', (89, 96))	('miR-34a', 'Gene', (15, 22))	('epigenetically silenced', 'Var', (27, 50))	('UC', 'Disease', 'MESH:D014523', (71, 73))
168599	31569404	Moreover, overexpression of c-Myc was shown to upregulate CD44, via a miR-34a-mediated ceRNA mechanism, in UC cell lines and clinical samples.	('c-Myc', 'Gene', '4609', (28, 33))	('clinical samples', 'Species', '191496', (125, 141))	('c-Myc', 'Gene', (28, 33))	('upregulate', 'PosReg', (47, 57))	('miR-34a-mediated', 'Var', (70, 86))	('expression', 'Species', '29278', (14, 24))	('CD44', 'Gene', '960', (58, 62))	('overexpression', 'PosReg', (10, 24))	('CD44', 'Gene', (58, 62))	('UC', 'Disease', 'MESH:D014523', (107, 109))
168600	31569404	The overexpression of miR-34a was also shown to suppress tumor growth and invasive capability, while reducing drug resistance.	('suppress', 'NegReg', (48, 56))	('overexpression', 'PosReg', (4, 18))	('drug resistance', 'biological_process', 'GO:0042493', ('110', '125'))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('drug resistance', 'CPA', (110, 125))	('invasive capability', 'CPA', (74, 93))	('expression', 'Species', '29278', (8, 18))	('drug resistance', 'Phenotype', 'HP:0020174', (110, 125))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('reducing', 'NegReg', (101, 109))	('miR-34a', 'Var', (22, 29))	('tumor', 'Disease', (57, 62))	('drug resistance', 'biological_process', 'GO:0009315', ('110', '125'))
168601	31569404	Thus, amplification of c-Myc is an important mechanism in controlling cancer stemness, through ceRNA mechanisms, in UC.	('cancer stemness', 'Disease', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('UC', 'Disease', 'MESH:D014523', (116, 118))	('c-Myc', 'Gene', '4609', (23, 28))	('cancer stemness', 'Disease', 'MESH:D009369', (70, 85))	('controlling', 'Reg', (58, 69))	('c-Myc', 'Gene', (23, 28))	('amplification', 'Var', (6, 19))
168603	31569404	This research was funded by the Ministry of Science and Technology, Taiwan (MOST 104-2320-B-194-001-MY3, 106-2923-B-194-001-MY3, 108-2314-B-194-003-MY2), Ditmanson Medical Foundation Chiayi Christian Hospital, Taiwan (grant no.	('108-2314-B-194-003', 'Chemical', 'MESH:C087337', (129, 147))	('108-2314-B-194-003-MY2', 'Var', (129, 151))	('104-2320-B-194', 'Chemical', 'MESH:C572498', (81, 95))	('Chia', 'Gene', (183, 187))	('106-2923-B-194', 'Chemical', 'MESH:C572498', (105, 119))	('Chia', 'Gene', '27159', (183, 187))
168621	29518027	In surgical specimens, we also demonstrated that ELK1 or phospho-ELK1 (p-ELK1) expression was up-regulated in bladder cancer, compared with non-neoplastic urothelium, and that positivity of p-ELK1, but not ELK1, was associated with the risk of recurrence of non-muscle-invasive tumors (hazard ratio (HR) = 2.829; P = 0.056) or cancer-specific mortality in patients with muscle-invasive tumor (HR = 2.693; P = 0.021) in a multivariate setting.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (262, 284))	('muscle-invasive tumors', 'Disease', (262, 284))	('patients', 'Species', '9606', (356, 364))	('ELK1', 'Gene', (192, 196))	('muscle-invasive tumor', 'Disease', 'MESH:D009217', (262, 283))	('ELK1', 'Gene', (65, 69))	('ELK1', 'Gene', (49, 53))	('cancer', 'Disease', (327, 333))	('ELK1', 'Gene', (73, 77))	('expression', 'MPA', (79, 89))	('up-regulated', 'PosReg', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('ELK1', 'Gene', (206, 210))	('bladder cancer', 'Disease', 'MESH:D001749', (110, 124))	('bladder cancer', 'Disease', (110, 124))	('cancer', 'Disease', (118, 124))	('muscle-invasive tumor', 'Disease', 'MESH:D009217', (370, 391))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('positivity', 'Var', (176, 186))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('bladder cancer', 'Phenotype', 'HP:0009725', (110, 124))	('ELK1', 'Gene', '2002', (192, 196))	('muscle-invasive tumor', 'Disease', (370, 391))	('ELK1', 'Gene', '2002', (49, 53))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('ELK1', 'Gene', '2002', (73, 77))	('ELK1', 'Gene', '2002', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('ELK1', 'Gene', '2002', (206, 210))
168628	29518027	Thus, the rate of p-ELK1 positivity was significantly higher in tumors than in benign tissues (P = 0.002).	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('higher', 'PosReg', (54, 60))	('positivity', 'Var', (25, 35))	('ELK1', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('ELK1', 'Gene', '2002', (20, 24))
168634	29518027	The rates of p-ELK1 positivity in the renal pelvic tumors, ureteral tumors, and bladder tumors were 40.0% (18 of 45), 56.0% (28 of 50), and 65.9% (85 of 129; shown in our previous study), respectively (renal pelvis vs. bladder: P = 0.003; ureter vs. bladder: P = 0.231).	('bladder tumors', 'Disease', (80, 94))	('ELK1', 'Gene', '2002', (15, 19))	('renal pelvis', 'Disease', (202, 214))	('ureteral tumors', 'Phenotype', 'HP:0100516', (59, 74))	('ureteral tumors', 'Disease', 'MESH:D014516', (59, 74))	('bladder tumors', 'Phenotype', 'HP:0009725', (80, 94))	('positivity', 'Var', (20, 30))	('ureteral tumors', 'Disease', (59, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('renal pelvis', 'Phenotype', 'HP:0000125', (202, 214))	('ELK1', 'Gene', (15, 19))	('bladder tumor', 'Phenotype', 'HP:0009725', (80, 93))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('bladder tumors', 'Disease', 'MESH:D001749', (80, 94))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('renal pelvic tumors', 'Disease', 'MESH:D007674', (38, 57))	('renal pelvis', 'Disease', 'MESH:D010386', (202, 214))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('renal pelvic tumors', 'Disease', (38, 57))
168644	29518027	By contrast, moderate p-ELK1 expression was marginally or significantly associated with lower progression-free survival (PFS) (0/1+ vs. 2+, P = 0.055; Figure 2a,b), overall survival (OS) (0/1+ vs. 2+, P = 0.020; figure not shown), and cancer-specific survival (CSS) (0/1+ vs. 2+, P = 0.008; Figure 2c,d) rates.	('overall survival', 'CPA', (165, 181))	('ELK1', 'Gene', '2002', (24, 28))	('expression', 'Var', (29, 39))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('moderate', 'Var', (13, 21))	('progression-free survival', 'CPA', (94, 119))	('ELK1', 'Gene', (24, 28))	('lower', 'NegReg', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('CSS', 'Chemical', '-', (261, 264))
168662	29518027	In addition, although p-ELK1 positivity in non-muscle-invasive bladder tumors was shown to predict the risk of their recurrence, we failed to show an association between p-ELK1 overexpression in UUTUCs and their recurrence in the bladder.	('non-muscle-invasive', 'Disease', (43, 62))	('ELK1', 'Gene', '2002', (24, 28))	('bladder tumors', 'Disease', (63, 77))	('ELK1', 'Gene', '2002', (172, 176))	('overexpression', 'PosReg', (177, 191))	('bladder tumors', 'Phenotype', 'HP:0009725', (63, 77))	('bladder tumor', 'Phenotype', 'HP:0009725', (63, 76))	('non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (43, 70))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('ELK1', 'Gene', (24, 28))	('bladder tumors', 'Disease', 'MESH:D001749', (63, 77))	('positivity', 'Var', (29, 39))	('invasive bladder', 'Phenotype', 'HP:0100645', (54, 70))	('ELK1', 'Gene', (172, 176))
168665	29518027	Moreover, ELK1 inactivation resulted in strong inhibition of the growth of bladder (and prostate) cancer cells only in the presence of an activated AR.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ELK1', 'Gene', '2002', (10, 14))	('AR', 'Gene', '367', (148, 150))	('growth', 'CPA', (65, 71))	('inhibition', 'NegReg', (47, 57))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('inactivation', 'Var', (15, 27))	('ELK1', 'Gene', (10, 14))
168696	27562343	These data provide statistical evidence that inactivation of cell fate-specifying transcription factors in cancer is an important step in carcinogenesis and that it occurs predominantly through a mechanism associated with promoter hypermethylation.	('inactivation', 'NegReg', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('promoter hypermethylation', 'Var', (222, 247))	('transcription', 'biological_process', 'GO:0006351', ('82', '95'))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('carcinogenesis', 'Disease', 'MESH:D063646', (138, 152))	('cancer', 'Disease', (107, 113))	('carcinogenesis', 'Disease', (138, 152))
168697	27562343	Biological evidence for this model has recently come from studies showing how genetic mutations in epigenetic regulators such as isocitrate dehydrogenases can result in the inactivation of key transcription factors, promoting cancer.	('result in', 'Reg', (159, 168))	('inactivation', 'MPA', (173, 185))	('genetic mutations', 'Var', (78, 95))	('isocitrate dehydrogenases', 'Gene', (129, 154))	('cancer', 'Disease', (226, 232))	('key', 'Protein', (189, 192))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('transcription', 'biological_process', 'GO:0006351', ('193', '206'))	('promoting', 'PosReg', (216, 225))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
168701	27562343	Moreover, inactivation of key transcription factors has been associated with other epigenetic alterations such as histone remodelling, raising further questions as to the role of the observed DNA hypermethylation in cancer.	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('inactivation', 'Var', (10, 22))	('histone', 'MPA', (114, 121))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('192', '212'))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('transcription', 'biological_process', 'GO:0006351', ('30', '43'))	('associated', 'Reg', (61, 71))	('DNA', 'cellular_component', 'GO:0005574', ('192', '195'))
168702	27562343	For instance, epigenetic silencing of HNF4A (a key liver-specifying TF) in liver cancer has been linked to loss of promoter H3K4me3 without changes in promoter methylation.	('HNF4A', 'Gene', (38, 43))	('liver cancer', 'Disease', (75, 87))	('loss', 'NegReg', (107, 111))	('epigenetic silencing', 'Var', (14, 34))	('methylation', 'biological_process', 'GO:0032259', ('160', '171'))	('promoter H3K4me3', 'Protein', (115, 131))	('liver cancer', 'Phenotype', 'HP:0002896', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('HNF4A', 'Gene', '3172', (38, 43))	('liver cancer', 'Disease', 'MESH:D006528', (75, 87))
168703	27562343	Given the large-scale availability of mutational, copy number variation (CNV) and DNA methylation data in primary cancer material, no study has yet systematically explored which mechanism, i.e.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('DNA methylation', 'biological_process', 'GO:0006306', ('82', '97'))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('copy number variation', 'Var', (50, 71))	('cancer', 'Disease', (114, 120))
168704	27562343	mutation, CNV loss, or promoter hypermethylation, is predominantly associated with in-cis silencing of transcription factors in cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('CNV loss', 'Disease', 'MESH:D015431', (10, 18))	('CNV loss', 'Disease', (10, 18))	('transcription', 'biological_process', 'GO:0006351', ('103', '116'))	('in-cis', 'MPA', (83, 89))	('mutation', 'Var', (0, 8))	('promoter hypermethylation', 'Var', (23, 48))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
168711	27562343	This resulted in an expression data set of 17,967 uniquely annotated Entrez gene IDs and 239 samples, including 107 hESC lines, 52 induced pluripotent stem cells and 32 somatic differentiated tissue samples, with the rest of the samples representing human cell lines.	('Entrez gene', 'Gene', (69, 80))	('human', 'Species', '9606', (250, 255))	('IDs', 'Var', (81, 84))
168713	27562343	However, the stomach samples were not considered further because the top principal component of variation in the corresponding stomach adenocarcinoma (STAD) TCGA data set correlated with an unknown confounding factor, most likely representing cellular heterogeneity.	('variation', 'Var', (96, 105))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (127, 149))	('correlated', 'Reg', (171, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('stomach adenocarcinoma', 'Disease', (127, 149))
168732	27562343	We hypothesized that TFs which are important for differentiation of a tissue type, and which are, therefore, expressed in that tissue type, may be under selection pressure to undergo silencing in the corresponding cancer type.	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('silencing', 'Var', (183, 192))	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
168737	27562343	As a concrete example, FOXA1 (HNF4A) is a transcription factor important for the specification of the intestine and stomach as well as liver and silencing of HNF4A leads to liver cancer.	('liver cancer', 'Disease', (173, 185))	('HNF4A', 'Gene', (158, 163))	('FOXA1', 'Gene', '3169', (23, 28))	('leads to', 'Reg', (164, 172))	('silencing', 'Var', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('transcription', 'biological_process', 'GO:0006351', ('42', '55'))	('transcription factor', 'molecular_function', 'GO:0000981', ('42', '62'))	('HNF4A', 'Gene', '3172', (30, 35))	('FOXA1', 'Gene', (23, 28))	('liver cancer', 'Disease', 'MESH:D006528', (173, 185))	('liver cancer', 'Phenotype', 'HP:0002896', (173, 185))	('HNF4A', 'Gene', '3172', (158, 163))	('HNF4A', 'Gene', (30, 35))
168744	27562343	In the case of colon cancer, silenced TFs included well known intestinal differentiation factors such as CDX1, CDX2 and NEUROD1.	('colon cancer', 'Phenotype', 'HP:0003003', (15, 27))	('colon cancer', 'Disease', 'MESH:D015179', (15, 27))	('CDX1', 'Gene', '1044', (105, 109))	('CDX2', 'Gene', '1045', (111, 115))	('NEUROD1', 'Gene', '4760', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('NEUROD1', 'Gene', (120, 127))	('colon cancer', 'Disease', (15, 27))	('CDX1', 'Gene', (105, 109))	('silenced', 'Var', (29, 37))	('included', 'Reg', (42, 50))	('CDX2', 'Gene', (111, 115))
168750	27562343	In order to assess the statistical and biological significance of these observations, we next compared the degree of molecular alteration of the silenced TFs with that of all genes underexpressed in the given cancer type, as well as to a randomly chosen set of genes, a procedure which adjusts for the differential sensitivity of the different molecular assays.	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('silenced', 'Var', (145, 153))	('cancer', 'Disease', (209, 215))	('TFs', 'Gene', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
168751	27562343	Likewise, the average frequency of inactivating mutations of these TFs across cancers was generally not higher compared with underexpressed genes or randomly selected genes (Fig.	('inactivating mutations', 'Var', (35, 57))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
168752	27562343	In general, for each cancer type there were more TFs and tumours with significant positive differential methylation statistics than the corresponding expected number had the genes been drawn from the set of all cancer underexpressed genes (Additional file 1: Figure S12).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (211, 217))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumours', 'Disease', (57, 64))	('methylation', 'Var', (104, 115))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('methylation', 'biological_process', 'GO:0032259', ('104', '115'))
168754	27562343	Using a meta-analysis over all cancer types, it was only for the case of promoter hypermethylation that we observed a significantly higher level of alteration at the silenced TFs compared with all underexpressed genes (Table 1; P < 10-8 for promoter hypermethylation, P = 0.98 for CNV loss and P = 0.47 for mutation, combined Fisher test).	('higher', 'PosReg', (132, 138))	('alteration', 'MPA', (148, 158))	('promoter hypermethylation', 'Var', (73, 98))	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('CNV loss', 'Disease', (281, 289))	('mutation', 'Var', (307, 315))	('CNV loss', 'Disease', 'MESH:D015431', (281, 289))	('TFs', 'Gene', (175, 178))
168755	27562343	We note that if we compared all underexpressed genes in a given cancer type to a randomly selected set of genes, then all molecular categories were significant, consistent with the view that all molecular events, be it promoter hypermethylation, CNV loss or inactivating mutation, are associated with underexpression in cancer (Additional file 1: Figure S14).	('inactivating mutation', 'Var', (258, 279))	('underexpression', 'MPA', (301, 316))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('CNV loss', 'Disease', (246, 254))	('CNV loss', 'Disease', 'MESH:D015431', (246, 254))	('promoter hypermethylation', 'Var', (219, 244))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (320, 326))
168756	27562343	4 and Table 1 suggest that promoter hypermethylation is the more likely mechanism associated with in-cis TF silencing in cancer.	('silencing', 'NegReg', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('promoter hypermethylation', 'Var', (27, 52))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
168759	27562343	For each TF and across all tumours exhibiting underexpression of this TF, we then counted the fraction of tumours exhibiting genomic loss of the TF, as well as the fraction of tumours exhibiting hypermethylation of the TF's promoter ("Methods").	('tumours', 'Disease', 'MESH:D009369', (176, 183))	('tumours', 'Disease', (176, 183))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('loss', 'NegReg', (133, 137))	('tumours', 'Disease', 'MESH:D009369', (106, 113))	('tumours', 'Disease', (106, 113))	('tumours', 'Phenotype', 'HP:0002664', (176, 183))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('tumours', 'Disease', (27, 34))	('hypermethylation', 'Var', (195, 211))
168760	27562343	In general, this revealed that promoter hypermethylation events could account for a higher fraction of cancers exhibiting underexpression of the corresponding TF compared with genomic loss (Fig.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('promoter hypermethylation', 'Var', (31, 56))	('cancers', 'Disease', (103, 110))
168766	27562343	Indeed, broadly speaking, there were three types of silenced TFs in each cancer type (Fig.	('TFs', 'Gene', (61, 64))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('silenced', 'Var', (52, 60))
168775	27562343	Next, we asked if the mechanism associated with silenced TFs is similar between cancer types.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('silenced', 'Var', (48, 56))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('TFs', 'Gene', (57, 60))	('cancer', 'Disease', (80, 86))
168781	27562343	Although impairment of differentiation is a well known cancer hallmark, only a few concrete examples of TF inactivation have been shown to block differentiation and predispose to epithelial cancer.	('predispose', 'Reg', (165, 175))	('differentiation', 'CPA', (145, 160))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('epithelial cancer', 'Disease', 'MESH:D000077216', (179, 196))	('inactivation', 'Var', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('block', 'NegReg', (139, 144))	('epithelial cancer', 'Phenotype', 'HP:0031492', (179, 196))	('cancer hallmark', 'Disease', (55, 70))	('epithelial cancer', 'Disease', (179, 196))	('cancer hallmark', 'Disease', 'MESH:D009369', (55, 70))
168786	27562343	Indeed, whereas CNV loss and inactivation mutations are known to affect tumour suppressors, the frequencies of these events across tumours of a given cancer type are generally quite low, making it difficult to identify novel cancer driver genes.	('tumours', 'Disease', (131, 138))	('cancer', 'Disease', (225, 231))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('CNV loss', 'Disease', (16, 24))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('tumour', 'Disease', (131, 137))	('low', 'NegReg', (182, 185))	('cancer', 'Disease', (150, 156))	('CNV loss', 'Disease', 'MESH:D015431', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('inactivation mutations', 'Var', (29, 51))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))	('affect', 'Reg', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutations', 'Var', (42, 51))
168791	27562343	Also, the important role of DNAm alterations at super-enhancers and associated DNAm and mRNA expression changes at linked gene promoters in cancer has recently been noted.	('DNAm', 'MPA', (79, 83))	('mRNA expression', 'MPA', (88, 103))	('DNAm', 'MPA', (28, 32))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('alterations', 'Var', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
168792	27562343	Thus, our data can't distinguish between a causative model, in which promoter hypermethylation causes the observed underexpression of the TFs, from an effects model, in which the observed hypermethylation and silencing is the consequence of an upstream TF inactivation event, be this a CNV loss, inactivating mutation, promoter methylation or increased methylation at an enhancer.	('promoter', 'MPA', (319, 327))	('methylation', 'MPA', (353, 364))	('silencing', 'MPA', (209, 218))	('underexpression', 'MPA', (115, 130))	('CNV loss', 'Disease', 'MESH:D015431', (286, 294))	('hypermethylation', 'MPA', (188, 204))	('CNV loss', 'Disease', (286, 294))	('inactivating mutation', 'Var', (296, 317))	('methylation', 'biological_process', 'GO:0032259', ('328', '339'))	('methylation', 'biological_process', 'GO:0032259', ('353', '364'))	('increased', 'PosReg', (343, 352))	('inactivation', 'NegReg', (256, 268))
168795	27562343	Moreover, it has recently been noted that bivalently marked miRNA promoters are also frequently hypermethylated in cancer, with many of these also exhibiting underexpression.	('cancer', 'Disease', (115, 121))	('bivalently marked', 'Var', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('miRNA', 'Protein', (60, 65))	('hypermethylated', 'Var', (96, 111))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
168799	27562343	This normal-adjacent tissue may already contain age-associated epigenetic field defects, which may reduce the sensitivity to detect silencing events in cancer.	('silencing events', 'MPA', (132, 148))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('reduce', 'NegReg', (99, 105))	('sensitivity', 'MPA', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('epigenetic field defects', 'Var', (63, 87))
168806	27562343	For instance, as remarked earlier, HNF4A is a TF which is needed for liver specification, silencing of it leading to liver cancer, yet it is also expressed in other tissue types such as kidney and stomach.	('HNF4A', 'Gene', '3172', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('liver cancer', 'Phenotype', 'HP:0002896', (117, 129))	('silencing', 'Var', (90, 99))	('HNF4A', 'Gene', (35, 40))	('liver cancer', 'Disease', 'MESH:D006528', (117, 129))	('liver cancer', 'Disease', (117, 129))	('leading to', 'Reg', (106, 116))
168813	27562343	This suggests that putative differentiation blocks arising as a result of their inactivation are strongly selected for during carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('inactivation', 'Var', (80, 92))	('carcinogenesis', 'Disease', (126, 140))
168814	27562343	Importantly, our data suggest that the silencing of these TFs in cancer is predominantly associated with promoter hypermethylation.	('associated', 'Reg', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('promoter', 'MPA', (105, 113))	('silencing', 'Var', (39, 48))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('TFs', 'Gene', (58, 61))
168824	27052470	Cell line study also proved that knock down of ERbeta cause less UTUC proliferation and migration.	('ERbeta', 'Gene', '2100', (47, 53))	('less', 'NegReg', (60, 64))	('UTUC proliferation', 'CPA', (65, 83))	('knock down', 'Var', (33, 43))	('ERbeta', 'Gene', (47, 53))
168862	27052470	The result of cell line validation showed that knock down of ERbeta cause aggressive UTUC cancer cell proliferation behavior by wound healing assay (Fig.	('aggressive UTUC cancer', 'Disease', (74, 96))	('wound healing', 'biological_process', 'GO:0042060', ('128', '141'))	('cell proliferation', 'biological_process', 'GO:0008283', ('97', '115'))	('ERbeta', 'Gene', '2100', (61, 67))	('wound healing assay', 'CPA', (128, 147))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cause', 'Reg', (68, 73))	('aggressive UTUC cancer', 'Disease', 'MESH:D009369', (74, 96))	('knock down', 'Var', (47, 57))	('ERbeta', 'Gene', (61, 67))
168888	27052470	In our cell line study, knock down of ERbeta does cause aggressive UTUC cancer cell behavior.	('cause', 'Reg', (50, 55))	('aggressive UTUC cancer', 'Disease', 'MESH:D009369', (56, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ERbeta', 'Gene', '2100', (38, 44))	('aggressive UTUC cancer', 'Disease', (56, 78))	('ERbeta', 'Gene', (38, 44))	('knock down', 'Var', (24, 34))
168889	27052470	In addition, agonist activation of ERbeta has been shown to be associated with cell sensitization to cisplatin cytotoxicity, which is compatible with our cell line study.	('cell sensitization', 'CPA', (79, 97))	('sensitization', 'biological_process', 'GO:0046960', ('84', '97'))	('agonist', 'Var', (13, 20))	('ERbeta', 'Gene', (35, 41))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('cytotoxicity', 'Disease', 'MESH:D064420', (111, 123))	('ERbeta', 'Gene', '2100', (35, 41))	('cytotoxicity', 'Disease', (111, 123))
168952	26251520	Kaplan-Meier analyses for PFS and RFS depicted in figures 2A, B, respectively, show that patients with strong Cx43 immunoreactivity have a significantly shorter PFS and RFS than patients with weak or negative staining for Cx43.	('PFS', 'MPA', (161, 164))	('RFS', 'MPA', (169, 172))	('patients', 'Species', '9606', (178, 186))	('shorter', 'NegReg', (153, 160))	('Cx43', 'Var', (110, 114))	('patients', 'Species', '9606', (89, 97))
168971	26251520	Our findings suggest that the overexpression of Cx43 in BC facilitates tumour cell survival and progression by enhanced gap junction activity, which has previously been shown to induce tumour growth and tumour cell survival.	('gap junction activity', 'molecular_function', 'GO:0022829', ('120', '141'))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('induce', 'PosReg', (178, 184))	('overexpression', 'PosReg', (30, 44))	('tumour', 'Disease', 'MESH:D009369', (203, 209))	('progression', 'CPA', (96, 107))	('tumour', 'Disease', (203, 209))	('BC', 'Phenotype', 'HP:0009725', (56, 58))	('facilitates', 'PosReg', (59, 70))	('Cx43', 'Var', (48, 52))	('enhanced', 'PosReg', (111, 119))	('tumour growth', 'Disease', 'MESH:D006130', (185, 198))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('gap junction', 'cellular_component', 'GO:0005921', ('120', '132'))	('tumour', 'Disease', (185, 191))	('tumour', 'Disease', 'MESH:D009369', (71, 77))	('tumour growth', 'Disease', (185, 198))	('tumour', 'Disease', (71, 77))	('gap junction activity', 'MPA', (120, 141))
168974	24856830	Cohesin gene mutations in tumorigenesis: from discovery to clinical significance Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells.	('protein complex', 'cellular_component', 'GO:0032991', ('100', '115'))	('enabling', 'PosReg', (321, 329))	('RAD21', 'Gene', '5885', (161, 166))	('SMC3', 'Gene', '9126', (155, 159))	('core', 'cellular_component', 'GO:0019013', ('133', '137'))	('mitosis', 'Disease', (305, 312))	('mitosis', 'biological_process', 'GO:0000278', ('305', '312'))	('STAG2', 'Gene', '10735', (188, 193))	('mitosis', 'Disease', 'None', (305, 312))	('SMC1A', 'Gene', (148, 153))	('SMC', 'cellular_component', 'GO:0016029', ('148', '151'))	('SMC', 'cellular_component', 'GO:0016029', ('155', '158'))	('mutations', 'Var', (13, 22))	('DNA', 'cellular_component', 'GO:0005574', ('263', '266'))	('STAG2', 'Gene', (188, 193))	('SMC3', 'Gene', (155, 159))	('SMC1A', 'Gene', '8243', (148, 153))	('RAD21', 'Gene', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('DNA replication', 'biological_process', 'GO:0006260', ('263', '278'))	('RAD', 'biological_process', 'GO:1990116', ('161', '164'))
168977	24856830	Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations.	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('cancers', 'Disease', (183, 190))	('cohesin', 'Gene', (201, 208))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('inactivation', 'NegReg', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('mutations', 'Var', (209, 218))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cohesin', 'Protein', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
168987	24856830	ESPL1 cleaves the RAD21 subunit of the remaining chromatin-bound cohesin thereby enabling segregation of the sister chromatids.	('enabling', 'PosReg', (81, 89))	('ESPL1', 'Gene', '9700', (0, 5))	('ESPL1', 'Gene', (0, 5))	('RAD', 'biological_process', 'GO:1990116', ('18', '21'))	('cleaves', 'Var', (6, 13))	('segregation', 'CPA', (90, 101))	('chromatin', 'cellular_component', 'GO:0000785', ('49', '58'))	('RAD21', 'Gene', (18, 23))	('cohesin', 'Protein', (65, 72))	('RAD21', 'Gene', '5885', (18, 23))
168993	24856830	In 2004 mutations in the cohesin regulatory factor NIPBL were discovered to cause Cornelia de Lange (CdL) syndrome (OMIM 122470 and 300590), a rare autosomal dominant disorder characterized by facial dysmorphism, growth delay, mental retardation, and limb abnormalities.	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (148, 175))	('mental retardation', 'Disease', 'MESH:D008607', (227, 245))	('growth delay', 'Disease', (213, 225))	('limb abnormalities', 'Disease', (251, 269))	('limb abnormalities', 'Phenotype', 'HP:0002813', (251, 269))	('limb abnormalities', 'Disease', 'MESH:D017880', (251, 269))	('growth delay', 'Phenotype', 'HP:0001510', (213, 225))	('mutations', 'Var', (8, 17))	('facial dysmorphism', 'Disease', 'None', (193, 211))	('NIPBL', 'Gene', (51, 56))	('autosomal dominant disorder', 'Disease', (148, 175))	('facial dysmorphism', 'Phenotype', 'HP:0001999', (193, 211))	('cause', 'Reg', (76, 81))	('Cornelia de Lange (CdL) syndrome', 'Disease', 'MESH:D003635', (82, 114))	('facial dysmorphism', 'Disease', (193, 211))	('mental retardation', 'Disease', (227, 245))	('mental retardation', 'Phenotype', 'HP:0001249', (227, 245))
168994	24856830	Subsequently, mutations in cohesin core subunits SMC1A, SMC3, and RAD21 have been found in the subset of CdL patients without NIPBL mutations.	('SMC3', 'Gene', (56, 60))	('SMC1A', 'Gene', '8243', (49, 54))	('RAD21', 'Gene', '5885', (66, 71))	('RAD', 'biological_process', 'GO:1990116', ('66', '69'))	('SMC3', 'Gene', '9126', (56, 60))	('patients', 'Species', '9606', (109, 117))	('found', 'Reg', (82, 87))	('core', 'cellular_component', 'GO:0019013', ('35', '39'))	('CdL', 'Disease', (105, 108))	('SMC1A', 'Gene', (49, 54))	('SMC', 'cellular_component', 'GO:0016029', ('56', '59'))	('mutations', 'Var', (14, 23))	('SMC', 'cellular_component', 'GO:0016029', ('49', '52'))	('RAD21', 'Gene', (66, 71))
168996	24856830	However, subsequent studies have not observed similar defects in sister chromatid cohesion, calling into question the functional consequence of cohesin mutations in CdL patients.	('cohesin', 'Gene', (144, 151))	('CdL', 'Disease', (165, 168))	('patients', 'Species', '9606', (169, 177))	('mutations', 'Var', (152, 161))	('chromatid', 'cellular_component', 'GO:0005695', ('72', '81'))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('65', '90'))	('chromatid', 'cellular_component', 'GO:0005694', ('72', '81'))
168997	24856830	Genome-wide transcriptional profiling in cells derived from CdL patients with NIPBL or SMC1A mutations versus normal subjects found a conserved pattern of transcriptional dysregulation, identifying a group of 339 genes with recurrently altered expression amongst the CdL patients and a significant correlation between the degree of transcriptional alteration and phenotypic disease severity.	('mutations', 'Var', (93, 102))	('patients', 'Species', '9606', (64, 72))	('SMC1A', 'Gene', (87, 92))	('altered', 'Reg', (236, 243))	('expression', 'MPA', (244, 254))	('patients', 'Species', '9606', (271, 279))	('SMC', 'cellular_component', 'GO:0016029', ('87', '90'))	('NIPBL', 'Gene', (78, 83))	('SMC1A', 'Gene', '8243', (87, 92))
169004	24856830	These studies demonstrate that cohesin inactivation both alters gene expression leading to developmental defects and sister chromatid cohesion leading to aneuploidy and increased tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('117', '142'))	('gene expression', 'MPA', (64, 79))	('aneuploidy', 'Disease', 'MESH:D000782', (154, 164))	('chromatid', 'cellular_component', 'GO:0005695', ('124', '133'))	('gene expression', 'biological_process', 'GO:0010467', ('64', '79'))	('increased', 'PosReg', (169, 178))	('sister chromatid cohesion', 'CPA', (117, 142))	('tumor', 'Disease', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('aneuploidy', 'Disease', (154, 164))	('cohesin', 'Protein', (31, 38))	('developmental defects', 'Disease', (91, 112))	('developmental defects', 'Disease', 'MESH:D003147', (91, 112))	('inactivation', 'Var', (39, 51))	('chromatid', 'cellular_component', 'GO:0005694', ('124', '133'))	('alters', 'Reg', (57, 63))	('leading to', 'Reg', (80, 90))
169006	24856830	Most recently, an inactivating mutation of the meiosis-specific cohesin subunit STAG3 was found in a large consanguineous family with premature ovarian failure and was present in each of six affected family members.	('found', 'Reg', (90, 95))	('premature ovarian failure', 'Disease', (134, 159))	('premature ovarian failure', 'Disease', 'MESH:D016649', (134, 159))	('STAG3', 'Gene', (80, 85))	('inactivating mutation', 'Var', (18, 39))	('premature ovarian failure', 'Phenotype', 'HP:0008209', (134, 159))	('meiosis', 'biological_process', 'GO:0051321', ('47', '54'))
169010	24856830	Given its function in controlling faithful sister chromatid segregation, dysregulation of the cohesin complex was hypothesized to contribute to the development of aneuploidy during tumorigenesis since its isolation and characterization in the late 1990's.	('chromatid', 'cellular_component', 'GO:0005694', ('50', '59'))	('tumor', 'Disease', (181, 186))	('sister chromatid segregation', 'biological_process', 'GO:0000819', ('43', '71'))	('aneuploidy', 'Disease', (163, 173))	('contribute', 'Reg', (130, 140))	('cohesin complex', 'cellular_component', 'GO:0008278', ('94', '109'))	('chromatid', 'cellular_component', 'GO:0005695', ('50', '59'))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('dysregulation', 'Var', (73, 86))	('aneuploidy', 'Disease', 'MESH:D000782', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
169011	24856830	The first report of cohesin gene alterations in human tumors was in 2008 wherein Barber et al.	('cohesin', 'Gene', (20, 27))	('human', 'Species', '9606', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('alterations', 'Var', (33, 44))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
169012	24856830	found somatic mutations of SMC1A, SMC3, and NIPBL in 9 out of 132 colorectal adenocarcinomas (see Table 1 for summary of cohesin gene mutations identified in human tumors), wherein they suggested that chromatid cohesion defects may underlie the chromosomal instability present in the vast majority of colorectal cancers.	('colorectal cancers', 'Disease', (301, 319))	('SMC', 'cellular_component', 'GO:0016029', ('34', '37'))	('SMC1A', 'Gene', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (312, 319))	('SMC1A', 'Gene', '8243', (27, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('chromatid', 'cellular_component', 'GO:0005694', ('201', '210'))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (66, 92))	('SMC3', 'Gene', '9126', (34, 38))	('colorectal cancers', 'Disease', 'MESH:D015179', (301, 319))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('mutations', 'Var', (14, 23))	('NIPBL', 'Gene', (44, 49))	('chromosomal instability', 'Phenotype', 'HP:0040012', (245, 268))	('human', 'Species', '9606', (158, 163))	('tumors', 'Disease', (164, 170))	('chromatid', 'cellular_component', 'GO:0005695', ('201', '210'))	('SMC', 'cellular_component', 'GO:0016029', ('27', '30'))	('colorectal adenocarcinomas', 'Disease', (66, 92))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('SMC3', 'Gene', (34, 38))
169013	24856830	Then in 2010 an array comparative genomic hybridization study of 167 myeloid disease samples identified a chronic myelomonocytic leukemia with a deletion of RAD21 (additionally harboring an NPM1 exon 12 mutation) and a de novo acute myeloid leukemia with a deletion of STAG2 (additionally harboring an IDH1-R132C mutation).	('RAD', 'biological_process', 'GO:1990116', ('157', '160'))	('IDH1', 'Gene', (302, 306))	('NPM1', 'Gene', (190, 194))	('myeloid disease', 'Disease', (69, 84))	('STAG2', 'Gene', '10735', (269, 274))	('RAD21', 'Gene', (157, 162))	('acute myeloid leukemia', 'Disease', (227, 249))	('myelomonocytic leukemia', 'Disease', 'MESH:D054429', (114, 137))	('IDH1', 'Gene', '3417', (302, 306))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (233, 249))	('STAG2', 'Gene', (269, 274))	('myeloid disease', 'Disease', 'MESH:D007951', (69, 84))	('RAD21', 'Gene', '5885', (157, 162))	('R132C', 'Mutation', 'rs121913499', (307, 312))	('leukemia', 'Phenotype', 'HP:0001909', (129, 137))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (227, 249))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (106, 137))	('NPM1', 'Gene', '4869', (190, 194))	('leukemia', 'Phenotype', 'HP:0001909', (241, 249))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (227, 249))	('myelomonocytic leukemia', 'Disease', (114, 137))	('deletion', 'Var', (145, 153))
169014	24856830	These first studies provided tantalizing evidence that the cohesin complex is a frequent target of genetic alterations during tumorigenesis.	('alterations', 'Var', (107, 118))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cohesin complex', 'cellular_component', 'GO:0008278', ('59', '74'))	('genetic alterations', 'Var', (99, 118))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
169016	24856830	In a screen of 155 unique human cancer cell lines, complete loss of STAG2 expression was identified in 3/21 glioblastoma, 5/9 Ewing sarcoma, 1/10 melanoma, 1/6 cervical carcinoma, and 2/20 hematologic cancer cell lines and found truncating mutations or deletions in 10/12 of these samples with STAG2 loss (see Table 2 for summary of cohesin gene mutations identified in human cancer cell lines).	('loss', 'NegReg', (300, 304))	('cancer', 'Disease', (376, 382))	('cancer', 'Disease', (201, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('loss', 'NegReg', (60, 64))	('carcinoma', 'Disease', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('glioblastoma', 'Disease', (108, 120))	('STAG2', 'Gene', '10735', (294, 299))	('human', 'Species', '9606', (26, 31))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))	('hematologic cancer', 'Phenotype', 'HP:0004377', (189, 207))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (126, 139))	('STAG2', 'Gene', (294, 299))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (126, 139))	('cancer', 'Disease', 'MESH:D009369', (376, 382))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('carcinoma', 'Disease', 'MESH:D002277', (169, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('STAG2', 'Gene', '10735', (68, 73))	('human', 'Species', '9606', (370, 375))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('truncating mutations', 'Var', (229, 249))	('melanoma', 'Disease', (146, 154))	('deletions', 'Var', (253, 262))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('Ewing sarcoma', 'Disease', (126, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (108, 120))	('STAG2', 'Gene', (68, 73))
169017	24856830	Analysis of primary tumor samples found somatic STAG2 mutations in 4/68 glioblastoma, 1/24 Ewing sarcoma, and 1/48 melanoma samples (see Fig.	('Ewing sarcoma', 'Disease', (91, 104))	('STAG2', 'Gene', '10735', (48, 53))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('mutations', 'Var', (54, 63))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (91, 104))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('glioblastoma', 'Disease', (72, 84))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))	('STAG2', 'Gene', (48, 53))	('tumor', 'Disease', (20, 25))
169018	24856830	2 for diagram of STAG2 mutations reported in human tumors to date).	('STAG2', 'Gene', (17, 22))	('STAG2', 'Gene', '10735', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('human', 'Species', '9606', (45, 50))	('mutations', 'Var', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Disease', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))
169021	24856830	Somatic cell gene targeting was used to correct the endogenous inactivating STAG2 mutations in two aneuploid glioblastoma cell lines (H4 and 42MGBA cells) via homologous recombination and to knockout STAG2 in a near-diploid, chromosomally stable colorectal carcinoma cell line (HCT116 cells).	('colorectal carcinoma', 'Disease', (246, 266))	('aneuploid glioblastoma', 'Disease', (99, 121))	('STAG2', 'Gene', (76, 81))	('STAG2', 'Gene', '10735', (76, 81))	('STAG2', 'Gene', (200, 205))	('STAG2', 'Gene', '10735', (200, 205))	('HCT116', 'CellLine', 'CVCL:0291', (278, 284))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('mutations', 'Var', (82, 91))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (246, 266))	('homologous recombination', 'biological_process', 'GO:0035825', ('159', '183'))	('aneuploid glioblastoma', 'Disease', 'MESH:D005909', (99, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
169022	24856830	Repair of the STAG2 gene led to restoration of the sister chromatid cohesion defect, a decrease in abnormal mitotic figures, and a reduction in chromosomal instability in the two aneuploid glioblastoma cell lines.	('reduction', 'NegReg', (131, 140))	('STAG2', 'Gene', (14, 19))	('Repair', 'Var', (0, 6))	('STAG2', 'Gene', '10735', (14, 19))	('chromosomal instability', 'Phenotype', 'HP:0040012', (144, 167))	('chromatid', 'cellular_component', 'GO:0005695', ('58', '67'))	('aneuploid glioblastoma', 'Disease', (179, 201))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('51', '76'))	('chromatid', 'cellular_component', 'GO:0005694', ('58', '67'))	('chromosomal instability', 'CPA', (144, 167))	('abnormal mitotic figures', 'CPA', (99, 123))	('decrease', 'NegReg', (87, 95))	('aneuploid glioblastoma', 'Disease', 'MESH:D005909', (179, 201))	('glioblastoma', 'Phenotype', 'HP:0012174', (189, 201))	('defect', 'NegReg', (77, 83))	('sister', 'MPA', (51, 57))
169023	24856830	In contrast, STAG2 knockout in HCT116 cells led to precocious sister chromatid separation and aneuploidy including trisomies, monosomies, and de novo translocations.	('monosomies', 'CPA', (126, 136))	('STAG2', 'Gene', '10735', (13, 18))	('knockout', 'Var', (19, 27))	('aneuploidy', 'Disease', (94, 104))	('HCT116', 'CellLine', 'CVCL:0291', (31, 37))	('trisomies', 'Disease', (115, 124))	('aneuploidy', 'Disease', 'MESH:D000782', (94, 104))	('chromatid', 'cellular_component', 'GO:0005695', ('69', '78'))	('STAG2', 'Gene', (13, 18))	('chromatid', 'cellular_component', 'GO:0005694', ('69', '78'))
169024	24856830	No significant difference in transcriptional profile was observed in these paired STAG2 mutant and wild-type glioblastoma and colorectal carcinoma cell lines, suggesting that the major tumor suppressive function of STAG2 is due to its canonical role in sister chromatid cohesin and not transcriptional regulation.	('tumor', 'Disease', (185, 190))	('glioblastoma', 'Disease', (109, 121))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (126, 146))	('glioblastoma', 'Disease', 'MESH:D005909', (109, 121))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('STAG2', 'Gene', (215, 220))	('regulation', 'biological_process', 'GO:0065007', ('302', '312'))	('STAG2', 'Gene', (82, 87))	('STAG2', 'Gene', '10735', (82, 87))	('mutant', 'Var', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('STAG2', 'Gene', '10735', (215, 220))	('chromatid', 'cellular_component', 'GO:0005695', ('260', '269'))	('colorectal carcinoma', 'Disease', (126, 146))	('chromatid', 'cellular_component', 'GO:0005694', ('260', '269'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
169026	24856830	However, the complete spectrum of tumors harboring cohesin mutations and the precise functional significance of cohesin mutations in the pathogenesis of specific tumor types remained undefined.	('tumors', 'Disease', (34, 40))	('cohesin', 'Gene', (51, 58))	('tumor', 'Disease', (34, 39))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (162, 167))	('pathogenesis', 'biological_process', 'GO:0009405', ('137', '149'))	('mutations', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
169027	24856830	Whole exome sequencing of 8 acute myeloid leukemia (AML) genomes reported in 2012 identified one AML (type M1 arising in an adult female) with an SMC3 missense mutation also harboring DNMT3A, NPM1, and FLT3 mutations.	('AML', 'Phenotype', 'HP:0004808', (52, 55))	('SMC', 'cellular_component', 'GO:0016029', ('146', '149'))	('AML', 'Disease', (52, 55))	('AML', 'Disease', 'MESH:D015470', (97, 100))	('FLT3', 'Gene', (202, 206))	('SMC3', 'Gene', '9126', (146, 150))	('AML', 'Phenotype', 'HP:0004808', (97, 100))	('AML', 'Disease', (97, 100))	('FLT3', 'Gene', '2322', (202, 206))	('acute myeloid leukemia', 'Disease', (28, 50))	('NPM1', 'Gene', '4869', (192, 196))	('DNMT3A', 'Gene', (184, 190))	('missense mutation', 'Var', (151, 168))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (28, 50))	('SMC3', 'Gene', (146, 150))	('NPM1', 'Gene', (192, 196))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (34, 50))	('leukemia', 'Phenotype', 'HP:0001909', (42, 50))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (28, 50))	('DNMT3A', 'Gene', '1788', (184, 190))	('AML', 'Disease', 'MESH:D015470', (52, 55))
169028	24856830	This AML at initial presentation had normal diploid karyotype, and upon relapse harbored a single chromosomal aberration (t(10;12) translocation) along with new ETV6 and MYO18B mutations.	('AML', 'Disease', 'MESH:D015470', (5, 8))	('ETV6', 'Gene', '2120', (161, 165))	('mutations', 'Var', (177, 186))	('AML', 'Disease', (5, 8))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (98, 120))	('AML', 'Phenotype', 'HP:0004808', (5, 8))	('MYO18B', 'Gene', '84700', (170, 176))	('MYO18B', 'Gene', (170, 176))	('ETV6', 'Gene', (161, 165))
169029	24856830	A subsequent whole exome sequencing study of 7 secondary AMLs arising in patients with antecedent myelodysplastic syndrome (MDS) found two AMLs with cohesin mutations, one with a truncating mutation in STAG2 and one with a truncating mutation in SMC3.	('cohesin', 'Gene', (149, 156))	('MDS', 'Disease', (124, 127))	('AML', 'Disease', 'MESH:D015470', (139, 142))	('AML', 'Phenotype', 'HP:0004808', (139, 142))	('AML', 'Disease', (139, 142))	('AML', 'Disease', 'MESH:D015470', (57, 60))	('SMC3', 'Gene', (246, 250))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (98, 122))	('mutations', 'Var', (157, 166))	('AML', 'Disease', (57, 60))	('AML', 'Phenotype', 'HP:0004808', (57, 60))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (98, 122))	('MDS', 'Phenotype', 'HP:0002863', (124, 127))	('patients', 'Species', '9606', (73, 81))	('STAG2', 'Gene', '10735', (202, 207))	('SMC', 'cellular_component', 'GO:0016029', ('246', '249'))	('MDS', 'Disease', 'MESH:D009190', (124, 127))	('SMC3', 'Gene', '9126', (246, 250))	('myelodysplastic syndrome', 'Disease', (98, 122))	('STAG2', 'Gene', (202, 207))
169030	24856830	The STAG2 mutation was present in both the antecedent MDS and the secondary AML with additional PTPN11 and RUNX1 mutations arising de novo in the secondary AML that had normal cytogenetics.	('AML', 'Disease', 'MESH:D015470', (156, 159))	('AML', 'Disease', (76, 79))	('RUNX1', 'Gene', '861', (107, 112))	('PTPN11', 'Gene', '5781', (96, 102))	('AML', 'Phenotype', 'HP:0004808', (156, 159))	('AML', 'Phenotype', 'HP:0004808', (76, 79))	('AML', 'Disease', (156, 159))	('PTPN11', 'Gene', (96, 102))	('STAG2', 'Gene', '10735', (4, 9))	('mutations', 'Var', (113, 122))	('MDS', 'Disease', (54, 57))	('MDS', 'Disease', 'MESH:D009190', (54, 57))	('MDS', 'Phenotype', 'HP:0002863', (54, 57))	('STAG2', 'Gene', (4, 9))	('AML', 'Disease', 'MESH:D015470', (76, 79))	('RUNX1', 'Gene', (107, 112))
169031	24856830	The SMC3 mutation was present at low frequency in the antecedent MDS and at high frequency in the secondary AML that also harbored NPM1 mutation and had normal cytogenetics.	('NPM1', 'Gene', (131, 135))	('AML', 'Disease', (108, 111))	('AML', 'Phenotype', 'HP:0004808', (108, 111))	('mutation', 'Var', (136, 144))	('NPM1', 'Gene', '4869', (131, 135))	('SMC3', 'Gene', '9126', (4, 8))	('SMC', 'cellular_component', 'GO:0016029', ('4', '7'))	('SMC3', 'Gene', (4, 8))	('MDS', 'Phenotype', 'HP:0002863', (65, 68))	('AML', 'Disease', 'MESH:D015470', (108, 111))	('MDS', 'Disease', (65, 68))	('MDS', 'Disease', 'MESH:D009190', (65, 68))
169033	24856830	This study found cohesin mutations in 7/65 type M1 AMLs (11%) but no cohesin gene mutations in the 43 type M3 AMLs (0%).	('AML', 'Disease', (51, 54))	('mutations', 'Var', (25, 34))	('AML', 'Phenotype', 'HP:0004808', (51, 54))	('AML', 'Phenotype', 'HP:0004808', (110, 113))	('AML', 'Disease', (110, 113))	('AML', 'Disease', 'MESH:D015470', (51, 54))	('AML', 'Disease', 'MESH:D015470', (110, 113))
169035	24856830	All seven of these AMLs with cohesin mutations had fewer than three cytogenetic abnormalities, while 6/7 of these AMLs also harbored FLT3 mutations, 3/7 also harbored NPM1 mutations, 2/7 also harbored DNMT3A mutations, and 2/7 also harbored TET2 mutations.	('AML', 'Disease', (114, 117))	('NPM1', 'Gene', (167, 171))	('AML', 'Disease', 'MESH:D015470', (19, 22))	('AML', 'Phenotype', 'HP:0004808', (114, 117))	('mutations', 'Var', (208, 217))	('FLT3', 'Gene', '2322', (133, 137))	('AML', 'Disease', (19, 22))	('AML', 'Phenotype', 'HP:0004808', (19, 22))	('cohesin', 'Gene', (29, 36))	('DNMT3A', 'Gene', (201, 207))	('TET2', 'Gene', (241, 245))	('harbored', 'Reg', (124, 132))	('mutations', 'Var', (37, 46))	('NPM1', 'Gene', '4869', (167, 171))	('mutations', 'Var', (138, 147))	('mutations', 'Var', (172, 181))	('FLT3', 'Gene', (133, 137))	('AML', 'Disease', 'MESH:D015470', (114, 117))	('TET2', 'Gene', '54790', (241, 245))	('DNMT3A', 'Gene', '1788', (201, 207))
169036	24856830	Given the near-diploid karyotype of all AMLs with identified cohesin mutations, the authors speculated that cohesin mutations may be selected for during leukemogenesis not due to loss of sister chromatid cohesion and induction of aneuploidy, but rather other loss of function mechanisms such as transcriptional deregulation.	('mutations', 'Var', (69, 78))	('aneuploidy', 'Disease', (230, 240))	('AML', 'Disease', 'MESH:D015470', (40, 43))	('cohesin', 'Gene', (108, 115))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('187', '212'))	('aneuploidy', 'Disease', 'MESH:D000782', (230, 240))	('chromatid', 'cellular_component', 'GO:0005695', ('194', '203'))	('AML', 'Phenotype', 'HP:0004808', (40, 43))	('leukemogenesis', 'Disease', (153, 167))	('mutations', 'Var', (116, 125))	('AML', 'Disease', (40, 43))	('sister', 'Protein', (187, 193))	('chromatid', 'cellular_component', 'GO:0005694', ('194', '203'))	('loss', 'NegReg', (179, 183))	('cohesin', 'Gene', (61, 68))
169038	24856830	They found cohesin mutations in 26 of these AMLs (13%) including 7 with STAG2 mutations (all truncating), 7 with SMC3 mutations (5/7 missense), 7 with SMC1A mutations (6/7 missense), and 5 with RAD21 mutations (all truncating).	('cohesin', 'Gene', (11, 18))	('RAD21', 'Gene', (194, 199))	('SMC3', 'Gene', '9126', (113, 117))	('STAG2', 'Gene', (72, 77))	('STAG2', 'Gene', '10735', (72, 77))	('SMC3', 'Gene', (113, 117))	('AML', 'Disease', 'MESH:D015470', (44, 47))	('mutations', 'Var', (118, 127))	('RAD21', 'Gene', '5885', (194, 199))	('mutations', 'Var', (19, 28))	('mutations', 'Var', (78, 87))	('AML', 'Disease', (44, 47))	('SMC1A', 'Gene', (151, 156))	('AML', 'Phenotype', 'HP:0004808', (44, 47))	('RAD', 'biological_process', 'GO:1990116', ('194', '197'))	('SMC', 'cellular_component', 'GO:0016029', ('151', '154'))	('SMC', 'cellular_component', 'GO:0016029', ('113', '116'))	('SMC1A', 'Gene', '8243', (151, 156))
169039	24856830	no AML had multiple cohesin gene mutations) demonstrating that genetic inactivation of a single cohesin subunit is likely sufficient to disrupt the tumor suppressive function of cohesin in myeloid leukemogenesis.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('myeloid leukemogenesis', 'Disease', 'MESH:D007951', (189, 211))	('myeloid leukemogenesis', 'Phenotype', 'HP:0012324', (189, 211))	('myeloid leukemogenesis', 'Disease', (189, 211))	('cohesin', 'Protein', (178, 185))	('genetic inactivation', 'Var', (63, 83))	('disrupt', 'NegReg', (136, 143))	('AML', 'Phenotype', 'HP:0004808', (3, 6))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('AML', 'Disease', (3, 6))
169042	24856830	Given the frequent mutations of cohesin genes in AML, Kon et al.	('AML', 'Disease', (49, 52))	('cohesin genes', 'Gene', (32, 45))	('mutations', 'Var', (19, 28))	('AML', 'Disease', 'MESH:D015470', (49, 52))	('AML', 'Phenotype', 'HP:0004808', (49, 52))
169044	24856830	In accordance with previous studies, cohesin mutations were identified in 16/120 de novo AMLs (13%).	('mutations', 'Var', (45, 54))	('AML', 'Disease', 'MESH:D015470', (89, 92))	('cohesin', 'Protein', (37, 44))	('AML', 'Phenotype', 'HP:0004808', (89, 92))	('identified', 'Reg', (60, 70))	('AML', 'Disease', (89, 92))
169045	24856830	Additionally, cohesin mutations were found in 19/224 myelodysplastic syndromes (8%), 3/37 secondary AMLs (8%), 4/64 chronic myelogenous leukemias (6%), 10/88 chronic myelomonocytic leukemias (11%), and 1/77 myeloproliferative neoplasms (1%).	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (158, 189))	('myelomonocytic leukemias', 'Disease', 'MESH:D054429', (166, 190))	('chronic myelomonocytic leukemias', 'Phenotype', 'HP:0012325', (158, 190))	('leukemia', 'Phenotype', 'HP:0001909', (136, 144))	('myelomonocytic leukemias', 'Disease', (166, 190))	('neoplasms', 'Phenotype', 'HP:0002664', (226, 235))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (53, 77))	('leukemias', 'Phenotype', 'HP:0001909', (181, 190))	('myelogenous leukemias', 'Disease', (124, 145))	('cohesin', 'Gene', (14, 21))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (53, 78))	('leukemia', 'Phenotype', 'HP:0001909', (181, 189))	('myelodysplastic syndromes', 'Disease', (53, 78))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (207, 235))	('neoplasms', 'Disease', 'MESH:D009369', (226, 235))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (53, 78))	('AML', 'Disease', 'MESH:D015470', (100, 103))	('mutations', 'Var', (22, 31))	('chronic myelogenous leukemias', 'Phenotype', 'HP:0005506', (116, 145))	('neoplasms', 'Disease', (226, 235))	('AML', 'Disease', (100, 103))	('AML', 'Phenotype', 'HP:0004808', (100, 103))	('found', 'Reg', (37, 42))	('myelogenous leukemias', 'Disease', 'MESH:D007951', (124, 145))	('leukemias', 'Phenotype', 'HP:0001909', (136, 145))	('myelogenous leukemias', 'Phenotype', 'HP:0012324', (124, 145))
169046	24856830	Cohesin mutated leukemia cells had reduced levels of chromatin-bound cohesin components, and the growth of cohesin mutated leukemia cells was suppressed by forced over-expression of the respective wild-type cohesin subunit, thereby leading the authors to speculate that cohesin mutations participate in leukemogenesis through the deregulated expression of genes involved in myeloid development and differentiation.	('leukemia', 'Disease', 'MESH:D007938', (16, 24))	('expression', 'MPA', (342, 352))	('mutations', 'Var', (278, 287))	('leukemia', 'Disease', (123, 131))	('leukemia', 'Disease', (16, 24))	('leukemia', 'Disease', 'MESH:D007938', (123, 131))	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('reduced', 'NegReg', (35, 42))	('leukemia', 'Phenotype', 'HP:0001909', (16, 24))	('cohesin', 'Gene', (270, 277))	('participate', 'Reg', (288, 299))	('leukemogenesis', 'Disease', (303, 317))	('chromatin', 'cellular_component', 'GO:0000785', ('53', '62'))	('suppressed', 'NegReg', (142, 152))	('deregulated', 'Reg', (330, 341))	('levels of', 'MPA', (43, 52))
169047	24856830	In order to explore the clinical significance of cohesin mutations in AML, Thol et al.	('AML', 'Disease', (70, 73))	('AML', 'Phenotype', 'HP:0004808', (70, 73))	('mutations', 'Var', (57, 66))	('cohesin', 'Protein', (49, 56))	('AML', 'Disease', 'MESH:D015470', (70, 73))
169049	24856830	Mutations were identified in 22 patients (6%), all of which were mutually exclusive and were strongly associated with the co-occurrence of NPM1 mutations.	('NPM1', 'Gene', (139, 143))	('patients', 'Species', '9606', (32, 40))	('associated', 'Reg', (102, 112))	('NPM1', 'Gene', '4869', (139, 143))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (144, 153))
169050	24856830	Up to 10% of patients with constitutional trisomy 21 (Down syndrome) experience transient abnormal myelopoiesis (TAM) during infancy, an abnormal myeloproliferative disorder that morphologically resembles acute megakaryoblastic leukemia (AMKL) but is usually self-limiting and spontaneously resolves within 3-4 months after birth.	('abnormal myeloproliferative disorder', 'Disease', (137, 173))	('TAM', 'Gene', (113, 116))	('acute megakaryoblastic leukemia', 'Disease', 'MESH:D007947', (205, 236))	('TAM', 'Gene', '8205', (113, 116))	('patients', 'Species', '9606', (13, 21))	('abnormal myelopoiesis', 'Disease', 'MESH:C563551', (90, 111))	('TAM', 'Phenotype', 'HP:0005534', (113, 116))	('AMKL', 'Phenotype', 'HP:0006733', (238, 242))	('myeloproliferative disorder', 'Phenotype', 'HP:0005547', (146, 173))	('abnormal myeloproliferative disorder', 'Disease', 'MESH:D009196', (137, 173))	('acute megakaryoblastic leukemia', 'Phenotype', 'HP:0006733', (205, 236))	('abnormal myelopoiesis', 'Disease', (90, 111))	('acute megakaryoblastic leukemia', 'Disease', (205, 236))	('transient abnormal myelopoiesis', 'Phenotype', 'HP:0005534', (80, 111))	('constitutional trisomy 21', 'Var', (27, 52))	('leukemia', 'Phenotype', 'HP:0001909', (228, 236))
169052	24856830	It was discovered in 2002 that all TAM samples harbor truncating mutations in the 5' coding exons of the GATA1 gene, an essential hematopoietic transcription factor, resulting in downstream re-initiation and production of a shorter GATA1 variant lacking the N-terminal activation domain.	('GATA1', 'Gene', '2623', (232, 237))	('truncating mutations', 'Var', (54, 74))	('GATA1', 'Gene', '2623', (105, 110))	('transcription factor', 'molecular_function', 'GO:0000981', ('144', '164'))	('transcription', 'biological_process', 'GO:0006351', ('144', '157'))	('TAM', 'Gene', (35, 38))	('GATA1', 'Gene', (232, 237))	('TAM', 'Gene', '8205', (35, 38))	('re-initiation', 'PosReg', (190, 203))	('GATA1', 'Gene', (105, 110))	('lacking', 'NegReg', (246, 253))	('N-terminal activation domain', 'MPA', (258, 286))	('TAM', 'Phenotype', 'HP:0005534', (35, 38))
169053	24856830	While the combination of GATA1 mutation and trisomy 21 are sufficient for the induction of TAM, it is unclear what the driving third genetic hit is that results in AMKL in Down syndrome patients.	('TAM', 'Gene', '8205', (91, 94))	('Down syndrome', 'Disease', (172, 185))	('GATA1', 'Gene', (25, 30))	('AMKL', 'Phenotype', 'HP:0006733', (164, 168))	('TAM', 'Phenotype', 'HP:0005534', (91, 94))	('mutation', 'Var', (31, 39))	('trisomy 21', 'Var', (44, 54))	('GATA1', 'Gene', '2623', (25, 30))	('TAM', 'Gene', (91, 94))	('patients', 'Species', '9606', (186, 194))
169054	24856830	An exome sequencing study found that cohesin mutations were present in 23/49 (47%) of Down syndrome-associated AMKL cases (predominantly STAG2 and RAD21 mutations and occasional cases with mutations in cohesin regulatory genes, all of which were mutually exclusive) while cohesin mutations were less commonly found in sporadic AMKL (2/19 cases, 11%) and were never present in TAM (0/41 cases).	('mutations', 'Var', (45, 54))	('Down syndrome-associated AMKL', 'Disease', (86, 115))	('TAM', 'Phenotype', 'HP:0005534', (376, 379))	('mutations', 'Var', (153, 162))	('TAM', 'Gene', (376, 379))	('AMKL', 'Phenotype', 'HP:0006733', (327, 331))	('STAG2', 'Gene', '10735', (137, 142))	('AMKL', 'Phenotype', 'HP:0006733', (111, 115))	('cohesin', 'Gene', (37, 44))	('present', 'Reg', (60, 67))	('RAD21', 'Gene', (147, 152))	('RAD21', 'Gene', '5885', (147, 152))	('RAD', 'biological_process', 'GO:1990116', ('147', '150'))	('STAG2', 'Gene', (137, 142))	('TAM', 'Gene', '8205', (376, 379))
169055	24856830	The majority of cohesin mutated AMKLs had two or fewer chromosomal aberrations other than trisomy 21, again supporting a non-aneuploidy driven mechanism for cohesin inactivation in myeloid leukemogenesis.	('mutated', 'Var', (24, 31))	('aneuploidy', 'Disease', (125, 135))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (55, 77))	('myeloid leukemogenesis', 'Disease', 'MESH:D007951', (181, 203))	('myeloid leukemogenesis', 'Phenotype', 'HP:0012324', (181, 203))	('AMKL', 'Phenotype', 'HP:0006733', (32, 36))	('myeloid leukemogenesis', 'Disease', (181, 203))	('cohesin', 'Gene', (16, 23))	('aneuploidy', 'Disease', 'MESH:D000782', (125, 135))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (55, 78))
169057	24856830	In order to explore the complete tumor spectrum harboring STAG2 inactivation, Solomon et al.	('STAG2', 'Gene', (58, 63))	('inactivation', 'Var', (64, 76))	('STAG2', 'Gene', '10735', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))
169060	24856830	No STAG2 loss was found in 18 bladder adenocarcinomas or 15 bladder squamous cell carcinomas, suggesting a specific role for STAG2 inactivation in urothelial carcinoma of the bladder (also referred to as transitional cell carcinoma).	('STAG2', 'Gene', (3, 8))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (204, 231))	('15 bladder squamous cell carcinomas', 'Disease', 'MESH:D002294', (57, 92))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (147, 182))	('bladder adenocarcinomas', 'Disease', (30, 53))	('bladder adenocarcinomas', 'Disease', 'MESH:D001749', (30, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('STAG2', 'Gene', '10735', (125, 130))	('urothelial carcinoma of the bladder', 'Disease', (147, 182))	('carcinoma', 'Disease', 'MESH:D002277', (82, 91))	('carcinoma', 'Disease', 'MESH:D002277', (43, 52))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (68, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('inactivation', 'Var', (131, 143))	('carcinoma', 'Disease', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Disease', (222, 231))	('carcinoma', 'Disease', (158, 167))	('STAG2', 'Gene', (125, 130))	('loss', 'NegReg', (9, 13))	('STAG2', 'Gene', '10735', (3, 8))	('15 bladder squamous cell carcinomas', 'Disease', (57, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinoma', 'Disease', 'MESH:D002277', (222, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('carcinoma', 'Disease', 'MESH:D002277', (158, 167))	('carcinoma', 'Disease', (43, 52))
169061	24856830	Sequencing of STAG2 in an independent cohort of urothelial bladder carcinomas identified mutations in 9/25 papillary non-invasive carcinomas (36%), 6/22 superficially invasive carcinomas (27%), and 8/64 muscle invasive carcinomas (13%).	('invasive carcinomas', 'Disease', (167, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('mutations', 'Var', (89, 98))	('urothelial bladder carcinomas', 'Disease', (48, 77))	('urothelial bladder carcinomas', 'Disease', 'MESH:D001749', (48, 77))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (59, 77))	('STAG2', 'Gene', '10735', (14, 19))	('invasive carcinomas', 'Disease', 'MESH:D009361', (210, 229))	('invasive carcinomas', 'Disease', 'MESH:D009361', (121, 140))	('papillary non-invasive carcinomas', 'Disease', 'MESH:D002291', (107, 140))	('STAG2', 'Gene', (14, 19))	('muscle invasive carcinomas', 'Disease', 'MESH:D009217', (203, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (59, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (219, 229))	('invasive carcinomas', 'Disease', 'MESH:D009361', (167, 186))	('papillary non-invasive carcinomas', 'Disease', (107, 140))	('muscle invasive carcinomas', 'Disease', (203, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
169062	24856830	21/25 of the identified mutations were truncating causing loss of STAG2 expression as seen by immunohistochemistry.	('loss', 'NegReg', (58, 62))	('STAG2', 'Gene', '10735', (66, 71))	('STAG2', 'Gene', (66, 71))	('expression', 'MPA', (72, 82))	('mutations', 'Var', (24, 33))
169064	24856830	These findings highlight the clonal heterogeneity of urothelial bladder carcinoma and suggest that while STAG2 inactivation occurs an early event in most bladder tumors with uniform STAG2 loss throughout, STAG2 mutations are also selected for during the clonal progression in occasional tumors.	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (53, 81))	('urothelial bladder carcinoma', 'Disease', (53, 81))	('STAG2', 'Gene', (105, 110))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (64, 81))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (287, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('STAG2', 'Gene', '10735', (182, 187))	('bladder tumors', 'Disease', 'MESH:D001749', (154, 168))	('STAG2', 'Gene', '10735', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('STAG2', 'Gene', (182, 187))	('inactivation', 'NegReg', (111, 123))	('STAG2', 'Gene', (205, 210))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('bladder tumors', 'Disease', (154, 168))	('mutations', 'Var', (211, 220))	('bladder tumors', 'Phenotype', 'HP:0009725', (154, 168))	('STAG2', 'Gene', '10735', (105, 110))	('loss', 'NegReg', (188, 192))	('tumors', 'Disease', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumors', 'Disease', (287, 293))
169065	24856830	Truncating mutations of STAG2 were also identified in 5/32 urothelial carcinoma cell lines (16%).	('Truncating mutations', 'Var', (0, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (59, 79))	('identified', 'Reg', (40, 50))	('STAG2', 'Gene', '10735', (24, 29))	('urothelial carcinoma', 'Disease', (59, 79))	('STAG2', 'Gene', (24, 29))
169069	24856830	Copy number analysis of 12 STAG2 mutant urothelial bladder carcinomas demonstrated multiple chromosomal aberrations in each of 9 tumors and no aberrations in the other 3 tumors, whereas 10/12 STAG2 wild-type urothelial bladder carcinomas contained detectable chromosomal aberrations.	('urothelial bladder carcinomas', 'Disease', 'MESH:D001749', (208, 237))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (51, 68))	('tumors', 'Disease', (129, 135))	('urothelial bladder carcinomas', 'Disease', (40, 69))	('urothelial bladder carcinomas', 'Disease', 'MESH:D001749', (40, 69))	('STAG2', 'Gene', (27, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (92, 115))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (92, 114))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (259, 281))	('mutant', 'Var', (33, 39))	('STAG2', 'Gene', (192, 197))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (51, 69))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (219, 237))	('multiple chromosomal aberrations', 'Phenotype', 'HP:0040012', (83, 115))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (259, 282))	('STAG2', 'Gene', '10735', (27, 32))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (219, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinomas', 'Phenotype', 'HP:0030731', (227, 237))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('STAG2', 'Gene', '10735', (192, 197))	('tumors', 'Disease', (170, 176))	('urothelial bladder carcinomas', 'Disease', (208, 237))
169070	24856830	Re-expression of wild-type STAG2 in three urothelial carcinoma cell lines with truncating STAG2 mutations did not affect cellular proliferation in vitro, tumor growth in vivo, or mean chromosome count per cell.	('tumor', 'Disease', (154, 159))	('STAG2', 'Gene', (90, 95))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (42, 62))	('STAG2', 'Gene', '10735', (90, 95))	('STAG2', 'Gene', '10735', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('chromosome', 'cellular_component', 'GO:0005694', ('184', '194'))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cellular proliferation', 'CPA', (121, 143))	('urothelial carcinoma', 'Disease', (42, 62))	('mutations', 'Var', (96, 105))	('STAG2', 'Gene', (27, 32))
169071	24856830	shRNA knockdown of STAG2 in a urothelial carcinoma cell line with wild-type STAG2 led to a modest alteration in chromosome count per cell.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('STAG2', 'Gene', (76, 81))	('STAG2', 'Gene', '10735', (76, 81))	('STAG2', 'Gene', (19, 24))	('urothelial carcinoma', 'Disease', (30, 50))	('STAG2', 'Gene', '10735', (19, 24))	('alteration', 'Reg', (98, 108))	('knockdown', 'Var', (6, 15))	('chromosome count per cell', 'CPA', (112, 137))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (30, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('112', '122'))
169073	24856830	Simultaneous to the publication of this study, two additional whole-exome sequencing studies of urothelial bladder carcinoma identifying frequent mutations of cohesin genes were also published.	('cohesin genes', 'Gene', (159, 172))	('mutations', 'Var', (146, 155))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (107, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (96, 124))	('urothelial bladder carcinoma', 'Disease', (96, 124))
169074	24856830	In the first of these other two studies, cohesin mutations were found in 10/33 papillary non-invasive tumors (30%), 3/32 superficially invasive tumors (9%), and 2/9 muscle invasive tumors (22%).	('cohesin', 'Gene', (41, 48))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('invasive tumors', 'Disease', 'MESH:D009369', (172, 187))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('invasive tumors', 'Disease', (135, 150))	('mutations', 'Var', (49, 58))	('invasive tumors', 'Disease', 'MESH:D009369', (93, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('invasive tumors', 'Disease', 'MESH:D009369', (135, 150))	('papillary non-invasive tumors', 'Disease', 'MESH:D002291', (79, 108))	('found', 'Reg', (64, 69))	('muscle invasive tumors', 'Disease', 'MESH:D009217', (165, 187))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('papillary non-invasive tumors', 'Disease', (79, 108))	('muscle invasive tumors', 'Disease', (165, 187))
169075	24856830	These were predominantly truncating mutations of STAG2, with occasional tumors harboring mutations in other core cohesin genes as well as cohesin regulatory genes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('STAG2', 'Gene', '10735', (49, 54))	('STAG2', 'Gene', (49, 54))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('truncating', 'Var', (25, 35))	('core', 'cellular_component', 'GO:0019013', ('108', '112'))
169076	24856830	In the second of these other two studies, cohesin mutations were found in 10/32 superficially invasive tumors (31%) and 6/61 muscle invasive tumors (10%), with an additional 9 muscle invasive tumors harboring mutations in cohesin regulatory genes, predominantly ESPL1 which encodes the enzyme Separase that cleaves Rad21 at the metaphase to anaphase transition to enable sister chromatid segregation.	('invasive tumors', 'Disease', (94, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('invasive tumors', 'Disease', 'MESH:D009369', (94, 109))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('ESPL1', 'Gene', '9700', (262, 267))	('Rad21', 'Gene', '5885', (315, 320))	('found', 'Reg', (65, 70))	('Separase', 'Gene', (293, 301))	('muscle invasive tumors', 'Disease', (176, 198))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('chromatid', 'cellular_component', 'GO:0005694', ('378', '387'))	('invasive tumors', 'Disease', 'MESH:D009369', (132, 147))	('ESPL1', 'Gene', (262, 267))	('enable', 'Reg', (364, 370))	('muscle invasive tumors', 'Disease', 'MESH:D009217', (125, 147))	('anaphase', 'biological_process', 'GO:0051322', ('341', '349'))	('chromatid', 'cellular_component', 'GO:0005695', ('378', '387'))	('Rad', 'biological_process', 'GO:1990116', ('315', '318'))	('sister chromatid segregation', 'biological_process', 'GO:0000819', ('371', '399'))	('sister chromatid segregation', 'CPA', (371, 399))	('muscle invasive tumors', 'Disease', (125, 147))	('cohesin', 'Gene', (42, 49))	('mutations', 'Var', (50, 59))	('invasive tumors', 'Disease', 'MESH:D009369', (183, 198))	('Separase', 'Gene', '9700', (293, 301))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('Rad21', 'Gene', (315, 320))	('muscle invasive tumors', 'Disease', 'MESH:D009217', (176, 198))	('mutations', 'Var', (209, 218))	('metaphase', 'biological_process', 'GO:0051323', ('328', '337'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
169077	24856830	In the first study, STAG2 mutation in non-muscle invasive tumors was associated with co-occurrence of FGFR3 mutations and absence of p53 overexpression.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('mutation', 'Var', (26, 34))	('mutations', 'Var', (108, 117))	('FGFR3', 'Gene', (102, 107))	('p53', 'Gene', '7157', (133, 136))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('associated', 'Reg', (69, 79))	('muscle invasive tumors', 'Disease', 'MESH:D009217', (42, 64))	('STAG2', 'Gene', (20, 25))	('p53', 'Gene', (133, 136))	('STAG2', 'Gene', '10735', (20, 25))	('muscle invasive tumors', 'Disease', (42, 64))	('FGFR3', 'Gene', '2261', (102, 107))
169082	24856830	shRNA knockdown of STAG2 in urothelial carcinoma cell lines with wild-type STAG2 was not found to significantly alter the mean chromosome count per cell, and re-expression of wild-type STAG2 in cell lines with inactivating STAG2 mutations led to reduced colony formation in vitro .	('STAG2', 'Gene', (223, 228))	('STAG2', 'Gene', '10735', (223, 228))	('formation', 'biological_process', 'GO:0009058', ('261', '270'))	('mutations', 'Var', (229, 238))	('colony formation in vitro', 'CPA', (254, 279))	('STAG2', 'Gene', (19, 24))	('STAG2', 'Gene', '10735', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('reduced', 'NegReg', (246, 253))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (28, 48))	('STAG2', 'Gene', (75, 80))	('STAG2', 'Gene', '10735', (75, 80))	('chromosome', 'cellular_component', 'GO:0005694', ('127', '137'))	('STAG2', 'Gene', '10735', (185, 190))	('urothelial carcinoma', 'Disease', (28, 48))	('STAG2', 'Gene', (185, 190))
169083	24856830	In the second study, invasive urothelial carcinomas with STAG2 mutations were significantly more aneuploid than invasive urothelial carcinomas without any alterations in core cohesin or cohesin regulatory genes.	('mutations', 'Var', (63, 72))	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (112, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('core', 'cellular_component', 'GO:0019013', ('170', '174'))	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (21, 51))	('invasive urothelial carcinomas', 'Disease', (112, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('STAG2', 'Gene', (57, 62))	('STAG2', 'Gene', '10735', (57, 62))	('invasive urothelial carcinomas', 'Disease', (21, 51))
169084	24856830	Additionally, patients with either superficially invasive or muscle invasive urothelial carcinomas harboring STAG2 mutations were associated with reduced overall survival compared to patients with wild-type tumors.	('mutations', 'Var', (115, 124))	('muscle invasive urothelial carcinomas', 'Disease', 'MESH:D009217', (61, 98))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('reduced', 'NegReg', (146, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('superficially invasive', 'Disease', (35, 57))	('STAG2', 'Gene', (109, 114))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('overall survival', 'MPA', (154, 170))	('STAG2', 'Gene', '10735', (109, 114))	('muscle invasive urothelial carcinomas', 'Disease', (61, 98))	('patients', 'Species', '9606', (183, 191))	('patients', 'Species', '9606', (14, 22))
169086	24856830	In a subsequent in-depth study of STAG2 inactivation in urothelial bladder carcinoma, STAG2 mutations were identified in 46/138 papillary non-invasive tumors (33%), 16/76 superficially invasive tumors (21%), and 10/80 muscle invasive tumors (13%).	('muscle invasive tumors', 'Disease', (218, 240))	('invasive tumors', 'Disease', 'MESH:D009369', (142, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('STAG2', 'Gene', '10735', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('papillary non-invasive tumors', 'Disease', (128, 157))	('STAG2', 'Gene', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('mutations', 'Var', (92, 101))	('invasive tumors', 'Disease', 'MESH:D009369', (225, 240))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (56, 84))	('invasive tumors', 'Disease', (185, 200))	('STAG2', 'Gene', '10735', (34, 39))	('invasive tumors', 'Disease', 'MESH:D009369', (185, 200))	('urothelial bladder carcinoma', 'Disease', (56, 84))	('muscle invasive tumors', 'Disease', 'MESH:D009217', (218, 240))	('identified', 'Reg', (107, 117))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (67, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('papillary non-invasive tumors', 'Disease', 'MESH:D002291', (128, 157))	('STAG2', 'Gene', (34, 39))
169087	24856830	STAG2 mutations were significantly associated with lower tumor grade, lower tumor stage, co-occurrence of FGRF3 and PIK3CA mutations, and wild-type TP53 status.	('PIK3CA', 'Gene', (116, 122))	('STAG2', 'Gene', '10735', (0, 5))	('FGRF3', 'Gene', (106, 111))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('PIK3CA', 'Gene', '5290', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('lower', 'NegReg', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('STAG2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
169088	24856830	No significant association of STAG2 mutation with disease recurrence in either papillary non-invasive carcinomas or invasive carcinomas was found.	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('papillary non-invasive carcinomas', 'Disease', 'MESH:D002291', (79, 112))	('invasive carcinomas', 'Disease', 'MESH:D009361', (93, 112))	('STAG2', 'Gene', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('STAG2', 'Gene', '10735', (30, 35))	('papillary non-invasive carcinomas', 'Disease', (79, 112))	('invasive carcinomas', 'Disease', (116, 135))	('invasive carcinomas', 'Disease', 'MESH:D009361', (116, 135))	('mutation', 'Var', (36, 44))
169091	24856830	Copy number analysis of 220 urothelial bladder carcinomas found that STAG2 mutation was inversely related with chromosomal copy number alterations.	('STAG2', 'Gene', (69, 74))	('STAG2', 'Gene', '10735', (69, 74))	('mutation', 'Var', (75, 83))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (39, 57))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (39, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('urothelial bladder carcinomas', 'Disease', (28, 57))	('urothelial bladder carcinomas', 'Disease', 'MESH:D001749', (28, 57))	('chromosomal', 'MPA', (111, 122))
169093	24856830	In total they identified cohesin mutations in 22/131 muscle invasive carcinomas (17%), including 14 tumors (11%) with STAG2 mutations and 8 tumors with mutations in other core cohesin genes.	('core', 'cellular_component', 'GO:0019013', ('171', '175'))	('mutations', 'Var', (33, 42))	('14 tumors', 'Disease', (97, 106))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('STAG2', 'Gene', '10735', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('muscle invasive carcinomas', 'Disease', 'MESH:D009217', (53, 79))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', (140, 146))	('14 tumors', 'Disease', 'MESH:C567448', (97, 106))	('tumors', 'Disease', (100, 106))	('STAG2', 'Gene', (118, 123))	('muscle invasive carcinomas', 'Disease', (53, 79))	('cohesin', 'Gene', (25, 32))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('mutations', 'Var', (124, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('identified', 'Reg', (14, 24))	('tumors', 'Disease', 'MESH:D009369', (100, 106))
169094	24856830	Additionally, 17/131 tumors (13%) harbored mutations in cohesin regulatory genes including CDCA5, ESPL1, and NIPBL.	('ESPL1', 'Gene', (98, 103))	('NIPBL', 'Gene', (109, 114))	('ESPL1', 'Gene', '9700', (98, 103))	('harbored', 'Reg', (34, 42))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('CDCA5', 'Gene', '113130', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (43, 52))	('cohesin regulatory genes', 'Gene', (56, 80))	('CDCA5', 'Gene', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
169095	24856830	Clustering of the 131 tumors based on mutations and copy number alterations identified three distinct groups, and 11/14 of the tumors with STAG2 mutations belonged to Group B enriched in tumors harboring CDKN2A deletions, FGFR3 mutations, and papillary histology.	('FGFR3', 'Gene', (222, 227))	('CDKN2A', 'Gene', '1029', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (145, 154))	('FGFR3', 'Gene', '2261', (222, 227))	('papillary histology', 'Phenotype', 'HP:0007482', (243, 262))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('deletions', 'Var', (211, 220))	('tumors', 'Disease', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('tumors', 'Disease', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('mutations', 'Var', (228, 237))	('STAG2', 'Gene', '10735', (139, 144))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('FGFR', 'molecular_function', 'GO:0005007', ('222', '226'))	('CDKN2A', 'Gene', (204, 210))	('STAG2', 'Gene', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (187, 193))
169096	24856830	Why STAG2 mutations occur at higher frequency in particular molecular subgroups of urothelial carcinomas remains undefined.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('STAG2', 'Gene', (4, 9))	('urothelial carcinomas', 'Disease', (83, 104))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (83, 104))	('mutations', 'Var', (10, 19))	('STAG2', 'Gene', '10735', (4, 9))
169097	24856830	Not only have cohesin gene mutations been identified in urothelial carcinomas arising in the bladder, exome sequencing of urothelial carcinomas arising in the upper urothelial tract (e.g.	('identified', 'Reg', (42, 52))	('mutations', 'Var', (27, 36))	('cohesin', 'Gene', (14, 21))	('urothelial carcinomas', 'Disease', (122, 143))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (122, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('urothelial carcinomas', 'Disease', (56, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (56, 77))
169098	24856830	ureter and renal pelvis) have found cohesin mutations in 2/5 papillary non-invasive (40%) and 7/21 invasive urothelial carcinomas (33%) of the upper urothelial tract.	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (99, 129))	('ureter and renal pelvis', 'Disease', 'MESH:D014516', (0, 23))	('renal pelvis', 'Phenotype', 'HP:0000125', (11, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('cohesin', 'Gene', (36, 43))	('invasive urothelial carcinomas', 'Disease', (99, 129))	('mutations', 'Var', (44, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('papillary non-invasive', 'Disease', (61, 83))
169100	24856830	As the genomes of additional tumor types are revealed by next generation sequencing, the cohesin complex is emerging as a target of frequent of somatic alterations in a diverse range of tumors.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cohesin complex', 'cellular_component', 'GO:0008278', ('89', '104'))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('alterations', 'Var', (152, 163))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))
169101	24856830	Comprehensive genomic characterization of 291 glioblastomas by The Cancer Genome Atlas identified cohesin gene mutations in 23 tumors (8%), including 12 tumors with mutations in STAG2 (one of the most commonly mutated genes identified), as well as 15 additional tumors (5%) with mutations in cohesin regulatory genes.	('15 additional tumors', 'Disease', 'MESH:C567447', (248, 268))	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('glioblastomas', 'Disease', (46, 59))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('Cancer', 'Disease', (67, 73))	('glioblastomas', 'Disease', 'MESH:D005909', (46, 59))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutations', 'Var', (111, 120))	('tumors', 'Disease', (127, 133))	('tumors', 'Disease', (262, 268))	('mutations', 'Var', (165, 174))	('Cancer', 'Disease', 'MESH:D009369', (67, 73))	('cohesin gene', 'Gene', (98, 110))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('glioblastomas', 'Phenotype', 'HP:0012174', (46, 59))	('STAG2', 'Gene', '10735', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('STAG2', 'Gene', (178, 183))	('15 additional tumors', 'Disease', (248, 268))
169102	24856830	In addition to glioblastomas, whole-exome sequencing of medulloblastoma, a primitive neuroectodermal tumor arising in the cerebellum and posterior fossa of the brain of pediatric and young adults, found cohesin mutations in 3/125 cases.	('cohesin', 'Gene', (203, 210))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (85, 106))	('medulloblastoma', 'Disease', (56, 71))	('glioblastomas', 'Disease', (15, 28))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (85, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (15, 27))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (75, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('found', 'Reg', (197, 202))	('mutations', 'Var', (211, 220))	('neuroectodermal tumor', 'Disease', (85, 106))	('medulloblastoma', 'Disease', 'MESH:D008527', (56, 71))	('medulloblastoma', 'Phenotype', 'HP:0002885', (56, 71))	('glioblastomas', 'Phenotype', 'HP:0012174', (15, 28))	('glioblastomas', 'Disease', 'MESH:D005909', (15, 28))
169103	24856830	Whole-exome sequencing of 100 invasive breast adenocarcinomas identified 3 tumors with cohesin gene mutations and 7 tumors with mutations in cohesin regulatory genes.	('tumors', 'Disease', (116, 122))	('mutations', 'Var', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('breast adenocarcinomas', 'Disease', 'MESH:D000230', (39, 61))	('cohesin gene', 'Gene', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('breast adenocarcinomas', 'Disease', (39, 61))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumors', 'Disease', (75, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
169104	24856830	Whether cohesin mutations in breast carcinomas are associated with a specific histologic subtype (e.g.	('breast carcinomas', 'Phenotype', 'HP:0003002', (29, 46))	('mutations', 'Var', (16, 25))	('cohesin', 'Gene', (8, 15))	('associated', 'Reg', (51, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('breast carcinomas', 'Disease', 'MESH:D001943', (29, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))	('breast carcinomas', 'Disease', (29, 46))
169105	24856830	A recent investigation into the genomes of 50 pancreatic ductal adenocarcinomas found two tumors with STAG2 alterations, one with gene deletion and one with missense mutation.	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('alterations', 'Var', (108, 119))	('STAG2', 'Gene', '10735', (102, 107))	('pancreatic ductal adenocarcinomas', 'Disease', (46, 79))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (46, 79))	('STAG2', 'Gene', (102, 107))	('gene deletion', 'Var', (130, 143))	('missense mutation', 'Var', (157, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
169107	24856830	An investigation of microsatellite-unstable gastric and colorectal adenocarcinomas found frequent frameshift mutations in the cohesin regulatory genes PDS5B and SGOL1 which harbor long mononucleotide repeats within their coding sequences.	('SGOL1', 'Gene', (161, 166))	('colorectal adenocarcinomas', 'Disease', (56, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('PDS5B', 'Gene', (151, 156))	('PDS5B', 'Gene', '23047', (151, 156))	('SGOL1', 'Gene', '151648', (161, 166))	('mononucleotide', 'Chemical', '-', (185, 199))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (56, 82))	('frameshift mutations', 'Var', (98, 118))
169108	24856830	In addition to the frequent truncating mutations of STAG2 in Ewing sarcoma cell lines reported by Solomon et al., ongoing as yet unpublished sequencing studies have also identified frequent cohesin mutations (predominantly of the STAG2 subunit) in Ewing sarcoma primary tumors samples as well.	('STAG2', 'Gene', '10735', (230, 235))	('Ewing sarcoma', 'Disease', (61, 74))	('STAG2', 'Gene', (52, 57))	('STAG2', 'Gene', '10735', (52, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (254, 261))	('cohesin', 'Protein', (190, 197))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (61, 74))	('mutations', 'Var', (198, 207))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (61, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('Ewing sarcoma primary tumors', 'Disease', (248, 276))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (248, 261))	('STAG2', 'Gene', (230, 235))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (248, 261))	('Ewing sarcoma primary tumors', 'Disease', 'MESH:C563168', (248, 276))
169109	24856830	The clinical significance of cohesin mutations and the precise mechanism of tumor suppressive function in the pathogenesis of many of these specific tumor types currently remain undefined.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cohesin', 'Protein', (29, 36))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', (149, 154))	('pathogenesis', 'biological_process', 'GO:0009405', ('110', '122'))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
169110	24856830	Given the high frequency of inactivation in particular cancer types, mechanisms of selectively targeting cancer cells harboring cohesin mutations is of significant clinical interest.	('cohesin', 'Gene', (128, 135))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('inactivation', 'Var', (28, 40))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
169111	24856830	The RAD21 gene was originally isolated in the fission yeast S. pombe as a mutant that caused radiation sensitivity and was also found to be essential for mitosis.	('caused', 'Reg', (86, 92))	('RAD21', 'Gene', '5885', (4, 9))	('radiation sensitivity', 'Disease', (93, 114))	('mitosis', 'Disease', (154, 161))	('RAD', 'biological_process', 'GO:1990116', ('4', '7'))	('RAD21', 'Gene', (4, 9))	('fission yeast', 'Species', '4896', (46, 59))	('mitosis', 'biological_process', 'GO:0000278', ('154', '161'))	('S. pombe', 'Species', '4896', (60, 68))	('mitosis', 'Disease', 'None', (154, 161))	('mutant', 'Var', (74, 80))
169112	24856830	Of note, SMC1A mutant cells from a CdL patient have shown increased sensitivity to ionizing radiation and interstrand DNA crosslinking agents compared to normal controls, although this sensitivity was to a lesser extent than cells from patients with ataxia telangiectasia or Fanconi anemia syndromes.	('SMC1A', 'Gene', (9, 14))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (250, 271))	('ataxia', 'Phenotype', 'HP:0001251', (250, 256))	('increased sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (58, 101))	('SMC1A', 'Gene', '8243', (9, 14))	('patients', 'Species', '9606', (236, 244))	('anemia', 'Phenotype', 'HP:0001903', (283, 289))	('patient', 'Species', '9606', (236, 243))	('SMC', 'cellular_component', 'GO:0016029', ('9', '12'))	('patient', 'Species', '9606', (39, 46))	('increased', 'PosReg', (58, 67))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('mutant', 'Var', (15, 21))	('ataxia telangiectasia', 'Disease', (250, 271))	('Fanconi anemia syndromes', 'Disease', (275, 299))	('Fanconi anemia syndromes', 'Disease', 'MESH:D005199', (275, 299))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (275, 289))	('telangiectasia', 'Phenotype', 'HP:0001009', (257, 271))	('sensitivity', 'MPA', (68, 79))
169113	24856830	These findings suggest that tumors harboring cohesin mutations might have increased sensitivity to ionizing radiation and/or specific DNA damaging chemotherapeutic agents.	('cohesin', 'Gene', (45, 52))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('increased sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (74, 117))	('mutations', 'Var', (53, 62))	('increased', 'PosReg', (74, 83))	('sensitivity to', 'MPA', (84, 98))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))
169114	24856830	One study has shown that knockdown of STAG2 in a pancreatic adenocarcinoma cell line led to increased sensitivity to platinum-based chemotherapy agents including cisplatin.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('platinum', 'Chemical', 'MESH:D010984', (117, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (49, 74))	('pancreatic adenocarcinoma', 'Disease', (49, 74))	('sensitivity to platinum-based chemotherapy agents', 'MPA', (102, 151))	('increased', 'PosReg', (92, 101))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (49, 74))	('STAG2', 'Gene', '10735', (38, 43))	('cisplatin', 'MPA', (162, 171))	('knockdown', 'Var', (25, 34))	('STAG2', 'Gene', (38, 43))
169115	24856830	Considering the potential for rational targeted therapies, inhibitors of poly(ADP-ribose) polymerase (PARP) such as olaparib have shown promise in ovarian cancers deficient in DNA repair due to mutations in BRCA1 and BRCA2.	('DNA', 'cellular_component', 'GO:0005574', ('176', '179'))	('PARP', 'Gene', (102, 106))	('BRCA2', 'Gene', '675', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ovarian cancers', 'Phenotype', 'HP:0100615', (147, 162))	('mutations', 'Var', (194, 203))	('DNA repair', 'biological_process', 'GO:0006281', ('176', '186'))	('PARP', 'Gene', '142', (102, 106))	('poly(ADP-ribose) polymerase', 'Gene', '142', (73, 100))	('BRCA1', 'Gene', '672', (207, 212))	('ovarian cancers deficient', 'Disease', 'MESH:D010051', (147, 172))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('BRCA2', 'Gene', (217, 222))	('poly(ADP-ribose) polymerase', 'Gene', (73, 100))	('ovarian cancers deficient', 'Disease', (147, 172))	('olaparib', 'Chemical', 'MESH:C531550', (116, 124))	('BRCA1', 'Gene', (207, 212))
169116	24856830	Similarly, glioblastoma cell lines harboring truncating STAG2 mutations were recently shown to have increased sensitivity to multiple unique small molecule inhibitors of PARP, leading to arrest in G2 phase of the cell cycle, more frequent micronuclei, and increased atypical mitotic figures.	('STAG2', 'Gene', (56, 61))	('atypical mitotic figures', 'CPA', (266, 290))	('STAG2', 'Gene', '10735', (56, 61))	('increased', 'PosReg', (100, 109))	('mutations', 'Var', (62, 71))	('micronuclei', 'CPA', (239, 250))	('PARP', 'Gene', '142', (170, 174))	('glioblastoma', 'Disease', (11, 23))	('truncating', 'Var', (45, 55))	('G2 phase', 'biological_process', 'GO:0051319', ('197', '205'))	('G2 phase of the cell cycle', 'CPA', (197, 223))	('glioblastoma', 'Disease', 'MESH:D005909', (11, 23))	('increased', 'PosReg', (256, 265))	('cell cycle', 'biological_process', 'GO:0007049', ('213', '223'))	('PARP', 'Gene', (170, 174))	('more', 'PosReg', (225, 229))	('glioblastoma', 'Phenotype', 'HP:0012174', (11, 23))
169118	24856830	Together, these studies demonstrate that tumors harboring cohesin mutations might have specific sensitivities that can be rationally targeted to provide clinical benefit for the many patients with such cohesin altered cancers.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('altered cancers', 'Disease', 'MESH:D009369', (210, 225))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('altered cancers', 'Disease', (210, 225))	('cohesin', 'Gene', (58, 65))	('patients', 'Species', '9606', (183, 191))
169121	24856830	Emerging cancer genomics studies have now documented that cohesin genes are a frequent target of somatic alterations in a number of tumor types including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia.	('urothelial carcinoma', 'Disease', (183, 203))	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (132, 137))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (168, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (168, 181))	('acute myeloid leukemia', 'Disease', (205, 227))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('alterations', 'Var', (105, 116))	('acute megakaryoblastic leukemia', 'Disease', 'MESH:D007947', (233, 264))	('glioblastoma', 'Disease', 'MESH:D005909', (154, 166))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (183, 203))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (211, 227))	('acute megakaryoblastic leukemia', 'Phenotype', 'HP:0006733', (233, 264))	('acute megakaryoblastic leukemia', 'Disease', (233, 264))	('leukemia', 'Phenotype', 'HP:0001909', (219, 227))	('glioblastoma', 'Disease', (154, 166))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Ewing sarcoma', 'Disease', (168, 181))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (205, 227))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (205, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('cohesin genes', 'Gene', (58, 71))	('leukemia', 'Phenotype', 'HP:0001909', (256, 264))
169122	24856830	Initial studies demonstrated that cohesin mutations may be a source of chromosomal instability and aneuploidy in tumors, while subsequent studies in other cancer types have found normal karyotypes in tumors harboring cohesin mutations, leading to speculation that cohesin inactivation may be causing dysregulation of other pathways during tumorigenesis, particularly altered gene expression profiles.	('tumor', 'Disease', (339, 344))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (339, 344))	('gene expression', 'biological_process', 'GO:0010467', ('375', '390'))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('chromosomal instability', 'Phenotype', 'HP:0040012', (71, 94))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('aneuploidy in tumors', 'Disease', 'MESH:D000782', (99, 119))	('tumor', 'Disease', (200, 205))	('aneuploidy in tumors', 'Disease', (99, 119))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('cohesin', 'Protein', (264, 271))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('inactivation', 'Var', (272, 284))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('gene expression profiles', 'MPA', (375, 399))	('dysregulation', 'MPA', (300, 313))	('cancer', 'Disease', (155, 161))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('cohesin', 'Gene', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutations', 'Var', (42, 51))	('altered', 'Reg', (367, 374))
169123	24856830	Recent studies have begun to demonstrate that cohesin mutant tumors might have increased sensitivity to select DNA damaging agents and PARP inhibitors.	('increased', 'PosReg', (79, 88))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('cohesin', 'Protein', (46, 53))	('PARP', 'Gene', '142', (135, 139))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('PARP', 'Gene', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutant', 'Var', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('sensitivity to', 'MPA', (89, 103))
169124	24856830	Continued investigation will be necessary to define the precise mechanism(s) by which cohesin inactivation contributes to tumorigenesis and methods to effectively target cancers harboring cohesin mutations.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('inactivation', 'NegReg', (94, 106))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cohesin', 'Gene', (188, 195))	('cohesin', 'Protein', (86, 93))	('tumor', 'Disease', (122, 127))	('mutations', 'Var', (196, 205))
169164	24023933	The human transitional cell carcinoma cell line T24 (G3, p53 mutant type) was obtained from American Type Culture Collection (Rockville, MD) and the normal human urothelial cell line E6 was obtained from the laboratory of Dr. Hong-Chen Chen (Department of life science, National Chung-Hsing University, Taichung, Taiwan) and Dr. Hsiao-Sheng Liu (Department of Microbiology & Immunology, National Cheng Kung University, Tainan, Taiwan).	('human', 'Species', '9606', (4, 9))	('E6', 'CellLine', 'CVCL:4582', (183, 185))	('carcinoma', 'Disease', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('mutant', 'Var', (61, 67))	('p53', 'Gene', (57, 60))	('rat', 'Species', '10116', (212, 215))	('carcinoma', 'Disease', 'MESH:D002277', (28, 37))	('human', 'Species', '9606', (156, 161))	('p53', 'Gene', '7157', (57, 60))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (10, 37))
169167	24023933	The T24 cells and E6 cells were stimulated with EGF (100ng/ml) and T24 cells and E6 cells were also treated with LY294002 (20microM) (GIBCO) and PD184352 (10microM) (BioVision) to inhibit mTORC2-AKT and ERK pathway.	('EGF', 'Gene', '1950', (48, 51))	('PD184352', 'Var', (145, 153))	('PD184352', 'Chemical', 'MESH:C120227', (145, 153))	('LY294002', 'Chemical', 'MESH:C085911', (113, 121))	('EGF', 'molecular_function', 'GO:0005154', ('48', '51'))	('inhibit', 'NegReg', (180, 187))	('mTORC2', 'cellular_component', 'GO:0031932', ('188', '194'))	('E6', 'CellLine', 'CVCL:4582', (18, 20))	('mTORC2', 'Gene', (188, 194))	('ERK', 'molecular_function', 'GO:0004707', ('203', '206'))	('EGF', 'Gene', (48, 51))	('E6', 'CellLine', 'CVCL:4582', (81, 83))	('ERK', 'Gene', '5594', (203, 206))	('LY294002', 'Var', (113, 121))	('mTORC2', 'Gene', '74343', (188, 194))	('ERK', 'Gene', (203, 206))
169199	24023933	Compared with the hydronephrotic urine treatment after 2 weeks of UUO, the same treatment after 3 weeks UUO induced more phosphorylation of AKT-Ser473, mTOR-Ser2481 and ERK in the T24 cells and E6 cells (Figure 4C).	('ERK', 'Gene', '5594', (169, 172))	('Ser2481', 'Chemical', '-', (157, 164))	('mTOR-Ser2481', 'Var', (152, 164))	('hydronephrotic urine', 'Disease', 'MESH:D014555', (18, 38))	('E6', 'CellLine', 'CVCL:4582', (194, 196))	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))	('ERK', 'Gene', (169, 172))	('ERK', 'molecular_function', 'GO:0004707', ('169', '172'))	('UUO', 'Chemical', '-', (66, 69))	('Ser473', 'Chemical', '-', (144, 150))	('hydronephrotic urine', 'Disease', (18, 38))	('UUO', 'Phenotype', 'HP:0006000', (66, 69))	('UUO', 'Chemical', '-', (104, 107))	('Ser', 'cellular_component', 'GO:0005790', ('144', '147'))	('hydronephrotic urine', 'Phenotype', 'HP:0000126', (18, 38))	('UUO', 'Phenotype', 'HP:0006000', (104, 107))	('Ser', 'cellular_component', 'GO:0005790', ('157', '160'))	('AKT-Ser473', 'Protein', (140, 150))	('more', 'PosReg', (116, 120))	('phosphorylation', 'MPA', (121, 136))
169203	24023933	PI3K has been reported to be a critical upstream regulator of mTORC2-AKT signaling pathway.	('mTORC2', 'cellular_component', 'GO:0031932', ('62', '68'))	('AKT signaling', 'biological_process', 'GO:0043491', ('69', '82'))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PI3K', 'Var', (0, 4))	('mTORC2', 'Gene', (62, 68))	('signaling pathway', 'biological_process', 'GO:0007165', ('73', '90'))	('mTORC2', 'Gene', '74343', (62, 68))
169204	24023933	In figure 6A, LY294002 and PD184352 inhibit the phosphorylation of mTOR2481, AKTSer473 and ERK induced by the treatment of hydronephrotic urine in T24 and E6 cells (Figure 6A).	('Ser473', 'Chemical', '-', (80, 86))	('ERK', 'molecular_function', 'GO:0004707', ('91', '94'))	('E6', 'CellLine', 'CVCL:4582', (155, 157))	('mTOR2481', 'Gene', (67, 75))	('LY294002', 'Var', (14, 22))	('ERK', 'Gene', '5594', (91, 94))	('inhibit', 'NegReg', (36, 43))	('hydronephrotic urine', 'Disease', (123, 143))	('AKTSer473', 'Gene', (77, 86))	('hydronephrotic urine', 'Phenotype', 'HP:0000126', (123, 143))	('ERK', 'Gene', (91, 94))	('phosphorylation', 'MPA', (48, 63))	('PD184352', 'Var', (27, 35))	('LY294002', 'Chemical', 'MESH:C085911', (14, 22))	('PD184352', 'Chemical', 'MESH:C120227', (27, 35))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))	('hydronephrotic urine', 'Disease', 'MESH:D014555', (123, 143))
169215	24023933	In this study, EGF really induced mTOR2481, AKTSer473 and ERK phosphorylation (Figure 8A, B).	('EGF', 'Gene', (15, 18))	('ERK', 'molecular_function', 'GO:0004707', ('58', '61'))	('EGF', 'molecular_function', 'GO:0005154', ('15', '18'))	('induced', 'Reg', (26, 33))	('mTOR2481', 'Var', (34, 42))	('AKTSer473', 'Gene', (44, 53))	('EGF', 'Gene', '1950', (15, 18))	('ERK', 'Gene', '5594', (58, 61))	('ERK', 'Gene', (58, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))
169251	32225123	Clinical parameter data and tumor specimens were collected from 86 patients with pT3N0M0 UTUC who had undergone radical nephroureterectomy.	('tumor', 'Disease', (28, 33))	('patients', 'Species', '9606', (67, 75))	('pT3N0M0', 'Var', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
169256	32225123	Univariate analysis revealed that high GAL1 expression was significantly associated with poor recurrence-free survival (RFS; p = 0.028) and low cancer-specific survival (CSS; p = 0.025).	('expression', 'MPA', (44, 54))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('low', 'NegReg', (140, 143))	('high', 'Var', (34, 38))	('poor', 'NegReg', (89, 93))	('GAL1', 'Gene', (39, 43))	('recurrence-free survival', 'CPA', (94, 118))	('GAL1', 'Gene', '3956', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
169258	32225123	In vitro studies revealed that GAL1 knockdown significantly reduced migration and invasiveness in UTUC (BFTC-909) and bladder cancer cells (T24).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('GAL1', 'Gene', (31, 35))	('bladder cancer', 'Disease', 'MESH:D001749', (118, 132))	('bladder cancer', 'Disease', (118, 132))	('GAL1', 'Gene', '3956', (31, 35))	('knockdown', 'Var', (36, 45))	('invasiveness', 'CPA', (82, 94))	('reduced', 'NegReg', (60, 67))	('bladder cancer', 'Phenotype', 'HP:0009725', (118, 132))	('BFTC-909', 'Chemical', '-', (104, 112))	('migration', 'CPA', (68, 77))
169259	32225123	GAL1 knockdown significantly reduced protein levels of matrix metalloproteinase-2 (MMP-2) and MMP-9, which increased tissue inhibitor of metalloproteinase-1 (TIMP-1) and promoted epithelial-mesenchymal transition (EMT).	('matrix metalloproteinase-2', 'Gene', '4313', (55, 81))	('GAL1', 'Gene', '3956', (0, 4))	('epithelial-mesenchymal transition', 'CPA', (179, 212))	('knockdown', 'Var', (5, 14))	('MMP-9', 'Gene', '4318', (94, 99))	('MMP-9', 'Gene', (94, 99))	('TIMP-1', 'Gene', '7076', (158, 164))	('tissue inhibitor of metalloproteinase-1', 'Gene', (117, 156))	('GAL1', 'Gene', (0, 4))	('TIMP-1', 'Gene', (158, 164))	('MMP-2', 'Gene', '4313', (83, 88))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('increased', 'PosReg', (107, 116))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('179', '212'))	('protein levels', 'MPA', (37, 51))	('EMT', 'biological_process', 'GO:0001837', ('214', '217'))	('matrix metalloproteinase-2', 'Gene', (55, 81))	('MMP-2', 'molecular_function', 'GO:0004228', ('83', '88'))	('MMP-2', 'Gene', (83, 88))	('promoted', 'PosReg', (170, 178))	('tissue inhibitor of metalloproteinase-1', 'Gene', '7076', (117, 156))	('reduced', 'NegReg', (29, 36))	('MMP-9', 'molecular_function', 'GO:0004229', ('94', '99'))	('metalloproteinase-1', 'molecular_function', 'GO:0051405', ('137', '156'))
169267	32225123	However, several comprehensive genomic studies have argued that UTUC and UCB are distinct and that the disease can be characterized by a unique fingerprint mutation signature; this signature takes the form of A:T to T:A transversions induced by aristolochic acid.	('aristolochic acid', 'Chemical', 'MESH:C000228', (245, 262))	('UCB', 'Phenotype', 'HP:0006740', (73, 76))	('transversions', 'Var', (220, 233))	('aristolochic acid', 'Var', (245, 262))
169275	32225123	In terms of prognostic effect, several anecdotal studies have demonstrated a consistent relationship between high GAL1 expression and poor survival in patients with cancers of the lung, uterine cervix, and bladder.	('expression', 'MPA', (119, 129))	('uterine cervix', 'Phenotype', 'HP:0030160', (186, 200))	('high', 'Var', (109, 113))	('poor survival', 'CPA', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('GAL1', 'Gene', (114, 118))	('patients', 'Species', '9606', (151, 159))	('GAL1', 'Gene', '3956', (114, 118))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('uterine cervix', 'Disease', (186, 200))
169277	32225123	In the lung cancer model, downregulation of GAL1 reduced tumor invasion and migration via the p38 MAPK-ERK and cyclooxygenase-2 (COX2) pathways.	('COX2', 'Gene', '5743', (129, 133))	('cyclooxygenase-2', 'Gene', '5743', (111, 127))	('lung cancer', 'Disease', (7, 18))	('downregulation', 'Var', (26, 40))	('cyclooxygenase-2', 'Gene', (111, 127))	('reduced', 'NegReg', (49, 56))	('GAL1', 'Gene', '3956', (44, 48))	('tumor', 'Disease', (57, 62))	('lung cancer', 'Disease', 'MESH:D008175', (7, 18))	('ERK', 'Gene', '5594', (103, 106))	('COX2', 'Gene', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (7, 18))	('GAL1', 'Gene', (44, 48))	('MAPK', 'molecular_function', 'GO:0004707', ('98', '102'))	('ERK', 'Gene', (103, 106))	('ERK', 'molecular_function', 'GO:0004707', ('103', '106'))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
169329	32225123	The overall survival of patients with tumors with high GAL1 expression was significantly poorer than that of patients with tumors with low GAL1 expression in the TCGA (p = 0.01) and GSE32894 cohorts (p = 0.0011; Figure 2A,B).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('GAL1', 'Gene', (55, 59))	('poorer', 'NegReg', (89, 95))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', (38, 44))	('patients', 'Species', '9606', (109, 117))	('GAL1', 'Gene', '3956', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('GAL1', 'Gene', (139, 143))	('expression', 'Var', (60, 70))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('GAL1', 'Gene', '3956', (139, 143))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('patients', 'Species', '9606', (24, 32))	('high', 'Var', (50, 54))
169335	32225123	High GAL1 expression was significantly associated with a poor recurrence-free survival (RFS; p = 0.028; Figure 2G) and cancer-specific survival (CSS; p = 0.025; Figure 2H); hence, RFS and CSS were lower in the GAL-high group than in the GAL1-low group.	('lower', 'NegReg', (197, 202))	('High', 'Var', (0, 4))	('GAL1', 'Gene', '3956', (237, 241))	('poor', 'NegReg', (57, 61))	('GAL1', 'Gene', (5, 9))	('RFS', 'MPA', (180, 183))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('expression', 'MPA', (10, 20))	('cancer', 'Disease', (119, 125))	('recurrence-free survival', 'CPA', (62, 86))	('GAL1', 'Gene', '3956', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('GAL1', 'Gene', (237, 241))	('CSS', 'CPA', (188, 191))
169341	32225123	As shown in Figure 3C,D, the levels of GAL1 protein and mRNA were significantly reduced in the sh-GAL1-T24 and sh-GAL1-BFTC-909 cells, indicating the efficiency of silencing LGALS1 gene function.	('mRNA', 'MPA', (56, 60))	('levels', 'MPA', (29, 35))	('GAL1', 'Gene', (114, 118))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('reduced', 'NegReg', (80, 87))	('GAL1', 'Gene', (39, 43))	('GAL1', 'Gene', (98, 102))	('BFTC-909', 'Chemical', '-', (119, 127))	('GAL1', 'Gene', '3956', (39, 43))	('GAL1', 'Gene', '3956', (114, 118))	('LGALS1', 'Gene', (174, 180))	('silencing', 'Var', (164, 173))	('LGALS1', 'Gene', '3956', (174, 180))	('GAL1', 'Gene', '3956', (98, 102))
169354	32225123	The results showed downregulation of N-cadherin, vimentin, beta-catenin, and snail and upregulation of E-cadherin and ZO-1 after knockdown GAL1 in the BFTC-909 and T24 cells.	('N-cadherin', 'Gene', '1000', (37, 47))	('BFTC-909', 'Chemical', '-', (151, 159))	('vimentin', 'Gene', '7431', (49, 57))	('upregulation', 'PosReg', (87, 99))	('cadherin', 'molecular_function', 'GO:0008014', ('105', '113'))	('vimentin', 'Gene', (49, 57))	('vimentin', 'cellular_component', 'GO:0045099', ('49', '57'))	('knockdown', 'Var', (129, 138))	('downregulation', 'NegReg', (19, 33))	('cadherin', 'molecular_function', 'GO:0008014', ('39', '47'))	('ZO-1', 'Gene', '7082', (118, 122))	('GAL1', 'Gene', '3956', (139, 143))	('E-cadherin', 'Gene', (103, 113))	('E-cadherin', 'Gene', '999', (103, 113))	('beta-catenin', 'Gene', (59, 71))	('ZO-1', 'Gene', (118, 122))	('beta-catenin', 'Gene', '1499', (59, 71))	('GAL1', 'Gene', (139, 143))	('vimentin', 'cellular_component', 'GO:0045098', ('49', '57'))	('N-cadherin', 'Gene', (37, 47))
169361	32225123	The results showed that, in the GAL1 knockdown BFTC-909 and T24 cells, the phosphorylation of FAK, PI3K, AKT, and mTOR decreased.	('decreased', 'NegReg', (119, 128))	('AKT', 'Gene', '207', (105, 108))	('GAL1', 'Gene', (32, 36))	('PI3K', 'molecular_function', 'GO:0016303', ('99', '103'))	('knockdown', 'Var', (37, 46))	('mTOR', 'Gene', '2475', (114, 118))	('PI3K', 'Pathway', (99, 103))	('mTOR', 'Gene', (114, 118))	('AKT', 'Gene', (105, 108))	('GAL1', 'Gene', '3956', (32, 36))	('BFTC-909', 'Chemical', '-', (47, 55))	('FAK', 'Gene', '5747', (94, 97))	('FAK', 'molecular_function', 'GO:0004717', ('94', '97'))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('phosphorylation', 'MPA', (75, 90))	('FAK', 'Gene', (94, 97))
169362	32225123	Moreover, in the J82 cells with GAL1 overexpression, the phosphorylation of FAK, PI3K, AKT, and mTOR increased.	('FAK', 'Gene', (76, 79))	('mTOR', 'Gene', (96, 100))	('FAK', 'Gene', '5747', (76, 79))	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('J82', 'CellLine', 'CVCL:0359', (17, 20))	('GAL1', 'Gene', (32, 36))	('AKT', 'Gene', (87, 90))	('increased', 'PosReg', (101, 110))	('FAK', 'molecular_function', 'GO:0004717', ('76', '79'))	('AKT', 'Gene', '207', (87, 90))	('GAL1', 'Gene', '3956', (32, 36))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('PI3K', 'Pathway', (81, 85))	('overexpression', 'Var', (37, 51))	('phosphorylation', 'MPA', (57, 72))	('mTOR', 'Gene', '2475', (96, 100))
169363	32225123	The protein expression of PI3K, AKT, and mTOR did not change after GAL1 knockdown or overexpression (Figure 6D).	('knockdown', 'Var', (72, 81))	('AKT', 'Gene', '207', (32, 35))	('overexpression', 'PosReg', (85, 99))	('PI3K', 'molecular_function', 'GO:0016303', ('26', '30'))	('AKT', 'Gene', (32, 35))	('GAL1', 'Gene', (67, 71))	('GAL1', 'Gene', '3956', (67, 71))	('mTOR', 'Gene', (41, 45))	('mTOR', 'Gene', '2475', (41, 45))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
169382	32225123	showed that deregulated proteins are involved in several biological pathways, including lipid, amino acid, and energy metabolism; cell proliferation and apoptosis; cytoskeleton functions; cell-cell interaction; metastasis; and protein degradation.	('deregulated', 'Var', (12, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('130', '148'))	('amino acid', 'MPA', (95, 105))	('apoptosis', 'biological_process', 'GO:0097194', ('153', '162'))	('metabolism', 'biological_process', 'GO:0008152', ('118', '128'))	('protein degradation', 'biological_process', 'GO:0030163', ('227', '246'))	('apoptosis', 'biological_process', 'GO:0006915', ('153', '162'))	('protein', 'cellular_component', 'GO:0003675', ('227', '234'))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('164', '176'))	('lipid', 'Chemical', 'MESH:D008055', (88, 93))	('cell-cell interaction', 'CPA', (188, 209))	('biological', 'CPA', (57, 67))	('cytoskeleton functions', 'CPA', (164, 186))	('metastasis', 'CPA', (211, 221))	('protein degradation', 'CPA', (227, 246))	('involved', 'Reg', (37, 45))	('apoptosis', 'CPA', (153, 162))	('proteins', 'Protein', (24, 32))	('energy', 'CPA', (111, 117))	('cell proliferation', 'CPA', (130, 148))	('lipid', 'MPA', (88, 93))
169385	32225123	We could successfully knockdown GAL1 expression in the BFTC-909 and T24 cell lines by using the shRNA and lentivirus methods, resulting in significant inhibition of tumor invasion and migration.	('GAL1', 'Gene', (32, 36))	('knockdown', 'Var', (22, 31))	('GAL1', 'Gene', '3956', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('inhibition', 'NegReg', (151, 161))	('BFTC-909', 'Chemical', '-', (55, 63))	('tumor', 'Disease', (165, 170))
169390	32225123	Through gene microarray analysis of parental and knockdown GAL1 cells, multiple crucial signaling pathways are involved in alteration of GAL1 expression, including the p53, FOXO, cell cycle, and PI3K/AKT pathways.	('cell cycle', 'CPA', (179, 189))	('GAL1', 'Gene', '3956', (59, 63))	('GAL1', 'Gene', '3956', (137, 141))	('AKT', 'Gene', '207', (200, 203))	('signaling', 'biological_process', 'GO:0023052', ('88', '97'))	('FOXO', 'Pathway', (173, 177))	('alteration', 'Var', (123, 133))	('p53', 'Gene', '7157', (168, 171))	('PI3K', 'molecular_function', 'GO:0016303', ('195', '199'))	('GAL1', 'Gene', (137, 141))	('AKT', 'Gene', (200, 203))	('involved', 'Reg', (111, 119))	('cell cycle', 'biological_process', 'GO:0007049', ('179', '189'))	('expression', 'MPA', (142, 152))	('GAL1', 'Gene', (59, 63))	('p53', 'Gene', (168, 171))
169408	29540229	Although cisplatin is a key drug for the treatment of patients with advanced UC, a significant nephrotoxicity associated with cisplatin therapy restricts its use to patients with appropriate kidney function.	('restricts', 'NegReg', (144, 153))	('patients', 'Species', '9606', (54, 62))	('cisplatin', 'Var', (126, 135))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('C', 'Chemical', 'MESH:D002244', (78, 79))	('nephrotoxicity', 'Disease', (95, 109))	('patients', 'Species', '9606', (165, 173))	('nephrotoxicity', 'Disease', 'MESH:D007674', (95, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))
169416	29540229	recently showed that renal cell carcinoma patients with surgically-induced CKD (CKD-S) have a relatively low risk of progressive renal function decline, whereas those with medically-induced CKD (CKD-M) have an increased risk.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (21, 41))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (21, 41))	('C', 'Chemical', 'MESH:D002244', (80, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('C', 'Chemical', 'MESH:D002244', (190, 191))	('CKD', 'Var', (75, 78))	('progressive renal function decline', 'Phenotype', 'HP:0012622', (117, 151))	('C', 'Chemical', 'MESH:D002244', (75, 76))	('renal cell carcinoma', 'Disease', (21, 41))	('C', 'Chemical', 'MESH:D002244', (195, 196))	('patients', 'Species', '9606', (42, 50))
169451	29540229	No significant differences were observed in the proportion of medical comorbidities between bilateral and solitary-functioning kidney patients with pretreatment eGFR >=60 or < 60 mL/min/1.73 m2.	('min/1', 'Gene', (182, 187))	('eGFR', 'MPA', (161, 165))	('>=60', 'Var', (166, 170))	('-functioning kidney', 'Phenotype', 'HP:0000083', (114, 133))	('patients', 'Species', '9606', (134, 142))	('< 60', 'Var', (174, 178))	('min/1', 'Gene', '966', (182, 187))	('eGFR', 'molecular_function', 'GO:0005006', ('161', '165'))
169459	29540229	The prevalence of impaired eGFR of > 20% from baseline in the post-third and fourth courses in patients with pretreatment eGFR >=60 mL/min/1.73 m2 was significantly higher than those in patients with pretreatment eGFR < 60 mL/min/1.73 m2 (p = 0.015 and p = 0.028; Table 4).	('impaired eGFR', 'MPA', (18, 31))	('eGFR', 'molecular_function', 'GO:0005006', ('122', '126'))	('patients', 'Species', '9606', (95, 103))	('min/1', 'Gene', (135, 140))	('eGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('min/1', 'Gene', '966', (226, 231))	('higher', 'PosReg', (165, 171))	('>=60', 'Var', (127, 131))	('eGFR', 'molecular_function', 'GO:0005006', ('213', '217'))	('min/1', 'Gene', '966', (135, 140))	('min/1', 'Gene', (226, 231))	('patients', 'Species', '9606', (186, 194))
169460	29540229	Furthermore, the prevalence of impaired eGFR of > 30% from baseline at the post-fourth course in patients with pretreatment eGFR >=60 mL/min/1.73 m2 was significantly higher than that of patients with pretreatment eGFR < 60 mL/min/1.73 m2 (p = 0.012; Table 4).	('patients', 'Species', '9606', (187, 195))	('higher', 'PosReg', (167, 173))	('min/1', 'Gene', (137, 142))	('min/1', 'Gene', (227, 232))	('eGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('eGFR', 'molecular_function', 'GO:0005006', ('214', '218'))	('eGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('>=60', 'Var', (129, 133))	('eGFR', 'Gene', (40, 44))	('min/1', 'Gene', '966', (137, 142))	('min/1', 'Gene', '966', (227, 232))	('patients', 'Species', '9606', (97, 105))
169468	29540229	Moreover, the mean kidney function between patients with bilateral- and solitary-functioning kidneys did not significantly differ in both patients with pretreatment eGFR >=60 and < 60 mL/min/1.73 m2.	('min/1', 'Gene', '966', (187, 192))	('-functioning kidneys', 'Phenotype', 'HP:0000083', (80, 100))	('>=60', 'Var', (170, 174))	('patients', 'Species', '9606', (43, 51))	('eGFR', 'molecular_function', 'GO:0005006', ('165', '169'))	('min/1', 'Gene', (187, 192))	('-functioning kidney', 'Phenotype', 'HP:0000083', (80, 99))	('patients', 'Species', '9606', (138, 146))
169474	29540229	Although the difference was not significant, comorbidities were more frequently observed in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney.	('-functioning kidney', 'Phenotype', 'HP:0000083', (165, 184))	('observed', 'Reg', (80, 88))	('patients', 'Species', '9606', (92, 100))	('-functioning kidney', 'Phenotype', 'HP:0000083', (115, 134))	('bilateral-functioning', 'Var', (106, 127))	('-functioning kidneys', 'Phenotype', 'HP:0000083', (115, 135))
169477	29540229	Another finding in this retrospective study was that patients with impaired kidney function were more frequently observed in patients with pretreatment eGFR >=60 than in < 60 mL/min/1.73 m2, probably because of the frequent dose reductions in patients with pretreatment eGFR < 60 mL/min/1.73 m2.	('min/1', 'Gene', (178, 183))	('min/1', 'Gene', '966', (283, 288))	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (243, 251))	('impaired kidney function', 'Disease', 'MESH:D007674', (67, 91))	('impaired kidney function', 'Disease', (67, 91))	('eGFR', 'Var', (152, 156))	('min/1', 'Gene', (283, 288))	('min/1', 'Gene', '966', (178, 183))	('>=60', 'Var', (157, 161))	('eGFR', 'molecular_function', 'GO:0005006', ('270', '274'))	('eGFR', 'molecular_function', 'GO:0005006', ('152', '156'))	('patients', 'Species', '9606', (125, 133))
169479	29540229	However, the prevalence was not increased in patients with pretreatment eGFR < 60 mL/min/1.73 m2 with a 33.6% reduction in the dose of cisplatin.	('reduction', 'NegReg', (110, 119))	('< 60', 'Var', (77, 81))	('eGFR', 'Gene', (72, 76))	('min/1', 'Gene', '966', (85, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('patients', 'Species', '9606', (45, 53))	('dose', 'MPA', (127, 131))	('eGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('min/1', 'Gene', (85, 90))
169484	29540229	From the current study results, cisplatin-based chemotherapies could be recommended at least in CKD-S patients with marginal kidney function, such as around 10% of patients who are categorized in pretreatment 24hCCr > 60 mL/min, as well as eGFR < 60 mL/min/1.73 m2, as shown in Fig.	('C', 'Chemical', 'MESH:D002244', (212, 213))	('C', 'Chemical', 'MESH:D002244', (96, 97))	('min/1', 'Gene', '966', (253, 258))	('patients', 'Species', '9606', (102, 110))	('> 60', 'Var', (216, 220))	('min/1', 'Gene', (253, 258))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('eGFR', 'molecular_function', 'GO:0005006', ('240', '244'))	('patients', 'Species', '9606', (164, 172))	('C', 'Chemical', 'MESH:D002244', (213, 214))	('24hCCr', 'Chemical', '-', (209, 215))
169575	23462915	Aristolochic acid exposure is significantly associated with an increased risk of UUC, and there is a dose-dependent relationship between cumulative AA exposure and end stage renal disease risk.	('associated', 'Reg', (44, 54))	('Aristolochic acid', 'Chemical', 'MESH:C000228', (0, 17))	('Aristolochic acid', 'Var', (0, 17))	('UUC', 'Disease', (81, 84))	('end stage renal disease', 'Disease', (164, 187))	('renal disease', 'Phenotype', 'HP:0000112', (174, 187))	('end stage renal disease', 'Phenotype', 'HP:0003774', (164, 187))	('end stage renal disease', 'Disease', 'MESH:D007676', (164, 187))	('UUC', 'Chemical', '-', (81, 84))
169582	23462915	In the 1990s, aristolochic acid was identified as the agent causing severe renal diseases in Belgian women who had consumed weight-loss supplements containing Aristolochia fangchi.	('aristolochic', 'Var', (14, 26))	('renal diseases', 'Disease', (75, 89))	('Aristolochia fangchi', 'Species', '425107', (159, 179))	('aristolochic acid', 'Chemical', 'MESH:C000228', (14, 31))	('renal disease', 'Phenotype', 'HP:0000112', (75, 88))	('renal diseases', 'Disease', 'MESH:D007674', (75, 89))	('weight-loss', 'Disease', 'MESH:D015431', (124, 135))	('weight-loss', 'Disease', (124, 135))	('causing', 'Reg', (60, 67))	('weight-loss', 'Phenotype', 'HP:0001824', (124, 135))	('women', 'Species', '9606', (101, 106))	('Aristolochia', 'Var', (159, 171))
169588	23462915	All herbal medicines suspected to contain aristolochic acid are listed in IARC Monograph 100A.	('aristolochic', 'Var', (42, 54))	('aristolochic acid', 'Chemical', 'MESH:C000228', (42, 59))	('herbal medicine', 'Species', '1407750', (4, 19))	('IARC', 'Disease', 'None', (74, 78))	('IARC', 'Disease', (74, 78))
169589	23462915	IARC has classified plants containing aristolochic acid as a Group 1 human carcinogen.	('IARC', 'Disease', (0, 4))	('aristolochic acid', 'Var', (38, 55))	('aristolochic acid', 'Chemical', 'MESH:C000228', (38, 55))	('human', 'Species', '9606', (69, 74))	('IARC', 'Disease', 'None', (0, 4))
169600	23462915	Search terms used without restriction included combinations of: (aristolochic acid), (guang fangchi/fangji), (guan mutong/mu tong), (end stage renal disease), (Balkan Endemic Nephropathy), (Chinese herb[s] nephropathy), (urothelial carcinoma), (transitional cell carcinoma), and (dose response).	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('aristolochic acid', 'Chemical', 'MESH:C000228', (65, 82))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (245, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('carcinoma', 'Disease', (263, 272))	('end stage renal disease', 'Phenotype', 'HP:0003774', (133, 156))	('carcinoma', 'Disease', (232, 241))	('end stage renal disease', 'Disease', 'MESH:D007676', (133, 156))	('Nephropathy', 'Phenotype', 'HP:0000112', (175, 186))	('urothelial carcinoma', 'Disease', (221, 241))	('mutong', 'Species', '13331', (115, 121))	('Balkan Endemic Nephropathy', 'Disease', 'MESH:D007674', (160, 186))	('nephropathy', 'Disease', (206, 217))	('renal disease', 'Phenotype', 'HP:0000112', (143, 156))	('nephropathy', 'Disease', 'MESH:D007674', (206, 217))	('carcinoma', 'Disease', 'MESH:D002277', (263, 272))	('mu tong', 'Species', '13331', (122, 129))	('carcinoma', 'Disease', 'MESH:D002277', (232, 241))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (221, 241))	('Balkan Endemic Nephropathy', 'Disease', (160, 186))	('aristolochic acid', 'Var', (65, 82))	('nephropathy', 'Phenotype', 'HP:0000112', (206, 217))	('end stage renal disease', 'Disease', (133, 156))
169609	23462915	Ten studies were found in which human exposure to aristolochic acid was associated with adverse health effects.	('aristolochic acid', 'Chemical', 'MESH:C000228', (50, 67))	('aristolochic acid', 'Var', (50, 67))	('associated', 'Reg', (72, 82))	('human', 'Species', '9606', (32, 37))
169612	23462915	One of the case-control studies investigated the risk of UUC at two AA exposure levels (151-250 mg; >250 mg).	('UUC', 'Chemical', '-', (57, 60))	('151-250 mg', 'Var', (88, 98))	('UUC', 'Disease', (57, 60))
169624	23462915	AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3 or HRAS oncogenes.	('mutations', 'Var', (83, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('TP53', 'Gene', (96, 100))	('HRAS', 'Gene', '3265', (111, 115))	('FGFR3', 'Gene', (102, 107))	('HRAS', 'Gene', (111, 115))	('AL', 'Chemical', 'MESH:D000535', (0, 2))	('patients', 'Species', '9606', (58, 66))	('DNA', 'cellular_component', 'GO:0005574', ('3', '6'))	('FGFR3', 'Gene', '2261', (102, 107))	('TP53', 'Gene', '7157', (96, 100))
169627	23462915	ORs were also estimated using, as measures of exposure, the presence of AL-DNA adducts and the presence of both TP53 A T transversions and AL-DNA adducts.	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('AL', 'Chemical', 'MESH:D000535', (139, 141))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('AL-DNA', 'Var', (139, 145))	('AL', 'Chemical', 'MESH:D000535', (72, 74))	('TP53', 'Gene', '7157', (112, 116))	('TP53', 'Gene', (112, 116))
169654	23462915	The review of the epidemiological literature indicates that aristolochic acid exposure is causally related to urothelial carcinoma and end-stage renal disease in humans, in a dose-dependent manner.	('end-stage renal disease', 'Phenotype', 'HP:0003774', (135, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('related', 'Reg', (99, 106))	('humans', 'Species', '9606', (162, 168))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (110, 130))	('aristolochic acid', 'Chemical', 'MESH:C000228', (60, 77))	('aristolochic acid', 'Var', (60, 77))	('end-stage renal disease', 'Disease', (135, 158))	('end-stage renal disease', 'Disease', 'MESH:D007676', (135, 158))	('renal disease', 'Phenotype', 'HP:0000112', (145, 158))	('urothelial carcinoma', 'Disease', (110, 130))
169679	23462915	On the other hand, two other very recent studies identified a particular genotype - a polymorphism located at the T allele of rs9642880 on chromosome 8q24 - that appears to confer susceptibility to urothelial carcinomas of the upper urinary tract.	('rs9642880', 'Var', (126, 135))	('rs9642880', 'Mutation', 'rs9642880', (126, 135))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (198, 219))	('chromosome', 'cellular_component', 'GO:0005694', ('139', '149'))	('susceptibility', 'Reg', (180, 194))	('carcinomas', 'Phenotype', 'HP:0030731', (209, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('urothelial carcinomas', 'Disease', (198, 219))
169683	23462915	Fortunately, many regulatory bodies worldwide have in the last decade taken measures to reduce the sales of herbal medicines containing Aristolochia.	('sales', 'MPA', (99, 104))	('herbal medicine', 'Species', '1407750', (108, 123))	('Aristolochia', 'Var', (136, 148))	('Aristolochia', 'Species', '158538', (136, 148))	('reduce', 'NegReg', (88, 94))
169689	20334706	Loss of specific tumour suppressor genes as well as gain-of-function mutations in proteins within defined cellular signalling pathways have been implicated in NMIUC aetiology.	('mutations', 'Var', (69, 78))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('Loss', 'NegReg', (0, 4))	('signalling', 'biological_process', 'GO:0023052', ('115', '125'))	('tumour', 'Disease', (17, 23))	('gain-of-function', 'PosReg', (52, 68))	('MIUC', 'Chemical', '-', (160, 164))
169690	20334706	The regions of chromosome 9 that harbour CDKN2A, CDKN2B, TSC1, PTCH1 and DBC1 are frequently mutated in NMIUC, resulting in functional loss; in addition, HRAS and FGFR3, which are both proto-oncogenes encoding components of the Ras-MAPK signalling pathway, have been found to harbour activating mutations in a large number of NMIUCs.	('FGFR', 'molecular_function', 'GO:0005007', ('163', '167'))	('chromosome', 'cellular_component', 'GO:0005694', ('15', '25'))	('PTCH1', 'Gene', (63, 68))	('signalling pathway', 'biological_process', 'GO:0007165', ('237', '255'))	('MIUC', 'Chemical', '-', (105, 109))	('mutated', 'Var', (93, 100))	('MIUC', 'Chemical', '-', (327, 331))	('CDKN2A', 'Gene', (41, 47))	('DBC1', 'Gene', '1620', (73, 77))	('FGFR3', 'Gene', (163, 168))	('MAPK', 'molecular_function', 'GO:0004707', ('232', '236'))	('HRAS', 'Gene', (154, 158))	('TSC1', 'Gene', (57, 61))	('PTCH1', 'Gene', '5727', (63, 68))	('CDKN2A', 'Gene', '1029', (41, 47))	('TSC1', 'Gene', '7248', (57, 61))	('loss', 'NegReg', (135, 139))	('DBC1', 'Gene', (73, 77))	('functional', 'MPA', (124, 134))	('MAPK signalling', 'biological_process', 'GO:0000165', ('232', '247'))	('CDKN2B', 'Gene', (49, 55))
169711	20334706	One of the first studies noting this phenomenon identified that a large number of human bladder cancer specimens contained allelic loss of chromosome 9q independent of tumour grade (Ref.).	('allelic loss', 'Var', (123, 135))	('bladder cancer', 'Disease', 'MESH:D001749', (88, 102))	('bladder cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('chromosome', 'cellular_component', 'GO:0005694', ('139', '149'))	('tumour', 'Disease', (168, 174))	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))	('human', 'Species', '9606', (82, 87))
169712	20334706	After analysing 252 bladder specimens, one group identified that 50% of Ta tumours contained LOH on either 9p or 9q and speculated that these regions were important in early UC development and likely to harbour tumour suppressor gene loci (Ref.).	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('tumour', 'Disease', (211, 217))	('Ta tumours', 'Disease', (72, 82))	('tumour', 'Disease', (75, 81))	('LOH on', 'Var', (93, 99))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('Ta tumours', 'Disease', 'MESH:D009369', (72, 82))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
169720	20334706	A comparative multiplex polymerase chain reaction (PCR) approach revealed homozygous deletions and sequence mutations in CDKN2A in SCC that were present at three times the frequency seen in UC (Ref.).	('CDKN2A', 'Gene', '1029', (121, 127))	('mutations', 'Var', (108, 117))	('deletions', 'Var', (85, 94))	('SCC', 'Gene', (131, 134))	('SCC', 'Phenotype', 'HP:0002860', (131, 134))	('CDKN2A', 'Gene', (121, 127))	('SCC', 'Gene', '6317', (131, 134))
169721	20334706	In addition, hemizygous and homozygous deletions were shown to be present in 92% of SCCs on chromosome 9p but in only 39% of UCs, and deletions in 9p without concomitant mutation in 9q were found at a rate of 92%, compared with only 10% of UCs having this pattern.	('SCC', 'Gene', '6317', (84, 87))	('deletions', 'Var', (134, 143))	('deletions', 'Var', (39, 48))	('chromosome', 'cellular_component', 'GO:0005694', ('92', '102'))	('SCC', 'Gene', (84, 87))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))
169723	20334706	In addition, statistically significant frequencies of homozygous and hemizygous deletions in both CDKN2A and CDKN2B were reported for a cohort of patients with UC (Ref.).	('CDKN2B', 'Gene', (109, 115))	('CDKN2A', 'Gene', (98, 104))	('deletions', 'Var', (80, 89))	('CDKN2A', 'Gene', '1029', (98, 104))	('patients', 'Species', '9606', (146, 154))
169725	20334706	Finally, CDKN2B was found to have decreased mRNA expression levels in NMIUC (Ref.).	('MIUC', 'Chemical', '-', (71, 75))	('CDKN2B', 'Var', (9, 15))	('decreased', 'NegReg', (34, 43))	('expression', 'Species', '29278', (49, 59))	('mRNA expression levels', 'MPA', (44, 66))
169729	20334706	It was later shown using single-strand conformation polymorphism analysis (SSCP) that there are multiple nonsense and missense mutations in 9q34, a region that encompasses the TSC1 (tuberous sclerosis 1) gene and is frequently deleted (Ref.).	('TSC1', 'Gene', (176, 180))	('tuberous sclerosis 1', 'Gene', (182, 202))	('tuberous sclerosis 1', 'Gene', '7248', (182, 202))	('9q34', 'Gene', (140, 144))	('missense mutations', 'Var', (118, 136))	('TSC1', 'Gene', '7248', (176, 180))
169731	20334706	When the mutations found on chromosome 9q were analysed, 90% were found to be novel and specific to bladder cancer in that they were not found in previous germline tuberous sclerosis cases (Ref.).	('bladder cancer', 'Disease', (100, 114))	('chromosome', 'cellular_component', 'GO:0005694', ('28', '38'))	('mutations', 'Var', (9, 18))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (164, 182))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (100, 114))	('tuberous sclerosis', 'Disease', (164, 182))	('bladder cancer', 'Disease', 'MESH:D001749', (100, 114))
169732	20334706	It was later shown that missense mutations in the TSC1 gene induced mislocalisation of the TCS1 protein in bladder cancer cells (Ref.).	('bladder cancer', 'Disease', 'MESH:D001749', (107, 121))	('bladder cancer', 'Disease', (107, 121))	('TCS1', 'Gene', '6949', (91, 95))	('protein', 'Protein', (96, 103))	('induced', 'Reg', (60, 67))	('missense mutations', 'Var', (24, 42))	('TSC1', 'Gene', (50, 54))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('TCS1', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (107, 121))	('mislocalisation', 'MPA', (68, 83))	('TSC1', 'Gene', '7248', (50, 54))
169733	20334706	This study also identified that when these same missense mutations were present in tuberous sclerosis, which was infrequent, they played no role in causation of tuberous sclerosis.	('tuberous sclerosis', 'Disease', (161, 179))	('present', 'Reg', (72, 79))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (83, 101))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (161, 179))	('missense mutations', 'Var', (48, 66))	('tuberous sclerosis', 'Disease', (83, 101))
169734	20334706	LOH at chromosome 9q34 was associated with decreased expression of P27, a CDK inhibitor protein encoded by CDKN1B, in a cohort of four tumours, suggesting that there might be a relationship between loss-of-function mutations in TSC1 and CDKN1B in UC (Ref.).	('loss-of-function', 'NegReg', (198, 214))	('P27', 'MPA', (67, 70))	('TSC1', 'Gene', '7248', (228, 232))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('CDKN1B', 'Gene', (237, 243))	('TSC1', 'Gene', (228, 232))	('CDKN1B', 'Gene', (107, 113))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('chromosome', 'cellular_component', 'GO:0005694', ('7', '17'))	('tumours', 'Disease', (135, 142))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (215, 224))	('expression', 'Species', '29278', (53, 63))	('CDK inhibitor', 'molecular_function', 'GO:0004861', ('74', '87'))	('expression', 'MPA', (53, 63))	('decreased', 'NegReg', (43, 52))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))
169738	20334706	It was also found that the DBC1 gene is a frequent target for hypermethylation, suggesting that hypermethylation at this locus could be important in the early development of bladder tumour formation even in cases where deletion does not occur (Ref.).	('DBC1', 'Gene', (27, 31))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('bladder tumour', 'Disease', 'MESH:D001749', (174, 188))	('hypermethylation', 'Var', (96, 112))	('formation', 'biological_process', 'GO:0009058', ('189', '198'))	('DBC1', 'Gene', '1620', (27, 31))	('important', 'Reg', (136, 145))	('bladder tumour', 'Phenotype', 'HP:0009725', (174, 188))	('bladder tumour', 'Disease', (174, 188))
169739	20334706	Specifically, the 9q22.3 locus was found to harbour deletions in the region encompassing PTCH1 (patched homologue 1) and MSSE (multiple self-healing squamous epithelioma) genes, both of which are known to play important roles in diseases characterised by the development of skin tumours.	('skin tumours', 'Disease', 'MESH:D012878', (274, 286))	('squamous epithelioma', 'Phenotype', 'HP:0002860', (149, 169))	('PTCH1', 'Gene', (89, 94))	('skin tumours', 'Disease', (274, 286))	('MSSE', 'Gene', (121, 125))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('squamous epithelioma', 'Disease', 'MESH:D002277', (149, 169))	('tumours', 'Phenotype', 'HP:0002664', (279, 286))	('deletions', 'Var', (52, 61))	('PTCH1', 'Gene', '5727', (89, 94))	('squamous epithelioma', 'Disease', (149, 169))
169742	20334706	A significant association between risk of recurrence and LOH at the region encompassing TSC1 was noted, whereas LOH at CDKN2A or DBC1 did not show any significant relation to tumour recurrence.	('LOH', 'Var', (57, 60))	('recurrence', 'Disease', (42, 52))	('DBC1', 'Gene', '1620', (129, 133))	('TSC1', 'Gene', '7248', (88, 92))	('tumour', 'Disease', 'MESH:D009369', (175, 181))	('TSC1', 'Gene', (88, 92))	('tumour', 'Disease', (175, 181))	('CDKN2A', 'Gene', (119, 125))	('CDKN2A', 'Gene', '1029', (119, 125))	('DBC1', 'Gene', (129, 133))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))
169743	20334706	In addition, a later study showed that LOH of the region of chromosome 9p21 encompassing CDKN2A was not significantly associated with recurrence-free interval in NMIUC (Ref.).	('LOH', 'Var', (39, 42))	('CDKN2A', 'Gene', (89, 95))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('CDKN2A', 'Gene', '1029', (89, 95))	('MIUC', 'Chemical', '-', (163, 167))
169746	20334706	Additional support for the positive correlation between LOH of chromosome 9 and tumour recurrence included a recent study that showed LOH at the DCB1 locus (9q32-q33) was correlated positively with tumour recurrence of NMIUC only if the LOH was located in the normal urothelium adjacent to the tumour and not in the tumour itself.	('tumour', 'Disease', (80, 86))	('tumour', 'Disease', (198, 204))	('tumour', 'Disease', 'MESH:D009369', (294, 300))	('LOH', 'Var', (134, 137))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('tumour', 'Disease', (294, 300))	('MIUC', 'Chemical', '-', (220, 224))	('tumour', 'Phenotype', 'HP:0002664', (316, 322))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (316, 322))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('tumour', 'Disease', (316, 322))	('DCB1', 'Gene', (145, 149))	('tumour', 'Phenotype', 'HP:0002664', (294, 300))	('tumour', 'Disease', 'MESH:D009369', (198, 204))	('9q32-q33', 'Var', (157, 165))
169747	20334706	This suggests that when LOH occurs at the DBC1 locus in the NMIUC itself the recurrence of that tumour is less likely (Ref.).	('MIUC', 'Chemical', '-', (61, 65))	('DBC1', 'Gene', (42, 46))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('LOH occurs', 'Var', (24, 34))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('DBC1', 'Gene', '1620', (42, 46))	('tumour', 'Disease', (96, 102))
169748	20334706	In this study, it was shown that histologically normal urothelium with LOH at the DCB1 locus was associated with larger tumours than in cases without this anomaly.	('anomaly', 'Disease', (155, 162))	('DCB1', 'Gene', (82, 86))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('anomaly', 'Disease', 'MESH:D000014', (155, 162))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (120, 127))	('LOH', 'Var', (71, 74))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
169751	20334706	FGFR3 first became relevant to human disease when specific point mutations in different domains of the FGFR3 gene were discovered in various autosomal dominant human skeletal diseases including achondroplasia, hypochondroplasia, thanatophoric dysplasia I and II, and severe achondroplaisa with developmental delay and acanthosis nigrans (SADDAN) (Refs).	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'molecular_function', 'GO:0005007', ('103', '107'))	('skeletal diseases', 'Disease', (166, 183))	('developmental delay', 'Phenotype', 'HP:0001263', (294, 313))	('hypochondroplasia', 'Disease', (210, 227))	('acanthosis', 'Phenotype', 'HP:0025092', (318, 328))	('skeletal diseases', 'Disease', 'MESH:C538496', (166, 183))	('achondroplasia', 'Disease', 'MESH:D000130', (194, 208))	('point mutations', 'Var', (59, 74))	('achondroplaisa', 'Disease', 'None', (274, 288))	('thanatophoric dysplasia I', 'Disease', 'MESH:C566844', (229, 254))	('skeletal disease', 'Phenotype', 'HP:0000924', (166, 182))	('human', 'Species', '9606', (160, 165))	('hypochondroplasia', 'Disease', 'MESH:C562937', (210, 227))	('thanatophoric dysplasia I', 'Disease', (229, 254))	('human', 'Species', '9606', (31, 36))	('developmental delay and acanthosis nigrans', 'Disease', 'MESH:D000130', (294, 336))	('achondroplaisa', 'Disease', (274, 288))	('discovered', 'Reg', (119, 129))	('achondroplasia', 'Disease', (194, 208))	('FGFR3', 'Gene', (103, 108))
169752	20334706	Interestingly, the mutations found to be responsible for the aforementioned debilitating autosomal dominant human skeletal diseases were found to be prevalent in human bladder cancer.	('skeletal diseases', 'Disease', (114, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (168, 182))	('skeletal diseases', 'Disease', 'MESH:C538496', (114, 131))	('prevalent', 'Reg', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('mutations', 'Var', (19, 28))	('human', 'Species', '9606', (162, 167))	('skeletal disease', 'Phenotype', 'HP:0000924', (114, 130))	('human', 'Species', '9606', (108, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (168, 182))	('bladder cancer', 'Disease', (168, 182))
169753	20334706	In 1999, somatic missense mutations (R248C, S249C, G370/372C, K650/652E) were reported in 35% (9 of 26) of UCs and 25% (3 of 12) of cervical carcinomas examined (Ref.).	('S249C', 'Mutation', 'rs121913483', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('K650/652E', 'Var', (62, 71))	('UCs', 'Disease', (107, 110))	('cervical carcinomas', 'Disease', (132, 151))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('G370/372C', 'Var', (51, 60))	('R248C', 'Var', (37, 42))	('cervical carcinomas', 'Disease', 'MESH:D002575', (132, 151))	('R248C', 'Mutation', 'rs121913482', (37, 42))	('S249C', 'Var', (44, 49))	('G370/372C', 'Mutation', 'c.370,372G>C', (51, 60))
169755	20334706	It was later shown that the mutations in FGFR3 that correspond to the mutations in the autosomal dominant human skeletal diseases occur at a much higher rate in UCs than in cervical carcinomas and multiple myeloma and are virtually nonexistent in carcinomas of the upper aerodigestive tract, oesophagus, stomach, lung, rectum, colon, prostate, ovarian, breast, brain or kidneys (Refs).	('human', 'Species', '9606', (106, 111))	('carcinomas', 'Disease', (182, 192))	('cervical carcinomas', 'Disease', (173, 192))	('multiple myeloma', 'Disease', 'MESH:D009101', (197, 213))	('skeletal diseases', 'Disease', 'MESH:C538496', (112, 129))	('UCs', 'Disease', (161, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('carcinomas', 'Phenotype', 'HP:0030731', (247, 257))	('skeletal disease', 'Phenotype', 'HP:0000924', (112, 128))	('carcinomas', 'Disease', 'MESH:D002277', (247, 257))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('multiple myeloma', 'Disease', (197, 213))	('stomach', 'Disease', (304, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('carcinomas', 'Phenotype', 'HP:0030731', (182, 192))	('carcinomas', 'Disease', 'MESH:D002277', (182, 192))	('mutations', 'Var', (70, 79))	('colon, prostate, ovarian, breast, brain or kidneys', 'Disease', 'MESH:D061325', (327, 377))	('cervical carcinomas', 'Disease', 'MESH:D002575', (173, 192))	('mutations', 'Var', (28, 37))	('lung', 'Disease', (313, 317))	('carcinomas', 'Disease', (247, 257))	('multiple myeloma', 'Phenotype', 'HP:0006775', (197, 213))	('skeletal diseases', 'Disease', (112, 129))	('FGFR3', 'Gene', (41, 46))	('oesophagus', 'Disease', (292, 302))
169756	20334706	Interestingly, the R248C and K650/652E mutations had previously been implicated in constitutive activation of FGFR3 (Refs), thus hinting at a mechanism of the oncogenic role these mutations might play in bladder cancer.	('bladder cancer', 'Disease', (204, 218))	('FGFR', 'molecular_function', 'GO:0005007', ('110', '114'))	('R248C', 'Var', (19, 24))	('R248C', 'Mutation', 'rs121913482', (19, 24))	('K650/652E', 'Var', (29, 38))	('bladder cancer', 'Phenotype', 'HP:0009725', (204, 218))	('FGFR3', 'Gene', (110, 115))	('activation', 'PosReg', (96, 106))	('bladder cancer', 'Disease', 'MESH:D001749', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
169757	20334706	The R248C mutation has been shown to constitutively activate FGFR3 through exposure of a cysteine residue that can participate in an intermolecular disulfide bond, resulting in ligand-independent dimerisation of the receptor (Ref.).	('FGFR3', 'Gene', (61, 66))	('ligand-independent dimerisation', 'MPA', (177, 208))	('R248C', 'Mutation', 'rs121913482', (4, 9))	('disulfide', 'Chemical', 'MESH:D004220', (148, 157))	('FGFR', 'molecular_function', 'GO:0005007', ('61', '65'))	('activate', 'PosReg', (52, 60))	('ligand', 'molecular_function', 'GO:0005488', ('177', '183'))	('R248C', 'Var', (4, 9))	('cysteine', 'Chemical', 'MESH:D003545', (89, 97))
169758	20334706	It was later shown that the oncogenic role of mutated FGFR3 might be working through the Ras-MAPK/ERK (mitogen-activated protein kinase or extracellular-signal-regulated kinase) pathway.	('FGFR', 'molecular_function', 'GO:0005007', ('54', '58'))	('FGFR3', 'Gene', (54, 59))	('ERK', 'molecular_function', 'GO:0004707', ('98', '101'))	('extracellular', 'cellular_component', 'GO:0005576', ('139', '152'))	('ERK', 'Gene', '5594', (98, 101))	('mutated', 'Var', (46, 53))	('ERK', 'Gene', (98, 101))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('MAPK', 'molecular_function', 'GO:0004707', ('93', '97'))
169761	20334706	In fact, a recent report also indirectly hinted at the importance of the Ras pathway downstream of FGFR3 by finding that Ras mutations, also common in NMIUC (see section below), and mutations in FGFR3 are mutually exclusive in this tumour type, suggestive of functional equivalence (Ref.).	('mutations', 'Var', (125, 134))	('Ras', 'Gene', (121, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('tumour', 'Disease', (232, 238))	('FGFR3', 'Gene', (195, 200))	('FGFR', 'molecular_function', 'GO:0005007', ('195', '199'))	('tumour', 'Disease', 'MESH:D009369', (232, 238))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('MIUC', 'Chemical', '-', (152, 156))	('mutations', 'Var', (182, 191))
169762	20334706	The discovery of somatic missense mutations in the FGFR3 gene in human bladder cancer spawned the question of where in the pathogenesis of UC were these mutations relevant.	('human', 'Species', '9606', (65, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('bladder cancer', 'Disease', (71, 85))	('pathogenesis', 'biological_process', 'GO:0009405', ('123', '135'))	('missense mutations', 'Var', (25, 43))	('FGFR3', 'Gene', (51, 56))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))
169763	20334706	One study found that 34 of 53 TaG1-2 bladder cancer samples had somatic missense mutations leading to amino acid changes that were identical to those found in the autosomal dominant skeletal diseases (Ref.).	('amino acid changes', 'MPA', (102, 120))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('skeletal disease', 'Phenotype', 'HP:0000924', (182, 198))	('bladder cancer', 'Disease', 'MESH:D001749', (37, 51))	('TaG1', 'Gene', (30, 34))	('bladder cancer', 'Disease', (37, 51))	('autosomal dominant skeletal diseases', 'Disease', 'MESH:D030342', (163, 199))	('autosomal dominant skeletal diseases', 'Disease', (163, 199))	('TaG1', 'Gene', '6900', (30, 34))	('missense mutations', 'Var', (72, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (37, 51))
169764	20334706	Furthermore, none of the 19 higher-stage tumours had such mutations.	('mutations', 'Var', (58, 67))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('tumours', 'Disease', (41, 48))
169765	20334706	Another study found that the frequency of mutations was significantly higher in Ta tumours (74%; 37 of 50) than Tis (0%; 0 of 20), T1 (21%; 4 of 19) and T2-4 (16%; 7 of 43) (Ref.).	('Ta tumours', 'Disease', 'MESH:D009369', (80, 90))	('higher', 'Reg', (70, 76))	('Ta tumours', 'Disease', (80, 90))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('mutations', 'Var', (42, 51))
169766	20334706	Furthermore, when stratifying by grade, FGFR3 mutations were more prevalent in G1 (84%; 27 of 32) tumours than G2 (55%; 16 of 29) or G3 (7%; 5 of 71) tumours.	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('mutations', 'Var', (46, 55))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('FGFR3', 'Gene', (40, 45))	('tumours', 'Disease', 'MESH:D009369', (150, 157))	('tumours', 'Disease', (150, 157))	('tumours', 'Disease', 'MESH:D009369', (98, 105))	('tumours', 'Disease', (98, 105))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('prevalent', 'Reg', (66, 75))
169767	20334706	These differences in expression of mutant FGFR3 highlight an important point concerning NMIUCs.	('expression', 'Species', '29278', (21, 31))	('MIUC', 'Chemical', '-', (89, 93))	('mutant', 'Var', (35, 41))	('expression', 'MPA', (21, 31))	('FGFR3', 'Gene', (42, 47))	('differences', 'Reg', (6, 17))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))
169771	20334706	Similar to the previous study that showed a higher frequency of FGFR3 mutation in noninvasive tumours, another group showed that in a cohort of 81 patients there was an inverse correlation between FGFR3 mutations and grade/stage of bladder cancer (Ref.).	('FGFR3', 'Gene', (197, 202))	('bladder cancer', 'Disease', 'MESH:D001749', (232, 246))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('invasive tumours', 'Disease', (85, 101))	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('bladder cancer', 'Disease', (232, 246))	('FGFR', 'molecular_function', 'GO:0005007', ('197', '201'))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('patients', 'Species', '9606', (147, 155))	('invasive tumours', 'Disease', 'MESH:D009361', (85, 101))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (232, 246))	('mutations', 'Var', (203, 212))	('inverse', 'NegReg', (169, 176))
169772	20334706	A study that looked at FGFR3 mutations in urothelial papillomas, considered the least aggressive of urothelial tumours, found that 75% (9 of 12) of urothelial papillomas evaluated harboured FGFR3 mutations (Ref.).	('FGFR3', 'Gene', (23, 28))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('urothelial papillomas', 'Disease', (42, 63))	('urothelial tumours', 'Disease', (100, 118))	('urothelial papillomas', 'Disease', 'MESH:D010212', (148, 169))	('urothelial papillomas', 'Disease', 'MESH:D010212', (42, 63))	('FGFR3', 'Gene', (190, 195))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('urothelial papillomas', 'Disease', (148, 169))	('FGFR', 'molecular_function', 'GO:0005007', ('190', '194'))	('papillomas', 'Phenotype', 'HP:0012740', (159, 169))	('papillomas', 'Phenotype', 'HP:0012740', (53, 63))	('harboured', 'Reg', (180, 189))	('urothelial tumours', 'Disease', 'MESH:D014523', (100, 118))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('mutations', 'Var', (196, 205))
169773	20334706	This frequency was similar to the frequency of FGFR3 mutations in papillary urothelial neoplasms of low malignant potential (85%) and low-grade papillary UCs (88%).	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('FGFR3', 'Gene', (47, 52))	('neoplasm', 'Phenotype', 'HP:0002664', (87, 95))	('mutations', 'Var', (53, 62))	('neoplasms', 'Phenotype', 'HP:0002664', (87, 96))	('papillary urothelial neoplasms', 'Disease', 'MESH:D002291', (66, 96))	('papillary urothelial neoplasms', 'Disease', (66, 96))
169774	20334706	Thus, several studies validate that the FGFR3 mutation is important in the pathogenesis NMIUC, but also suggest that the FGFR3 mutation is not essential or is possibly inversely associated with progression to high-stage/grade bladder cancer.	('ral', 'Gene', (10, 13))	('ral', 'Gene', '5898', (10, 13))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('associated with', 'Reg', (178, 193))	('FGFR3', 'Gene', (40, 45))	('FGFR', 'molecular_function', 'GO:0005007', ('121', '125'))	('mutation', 'Var', (127, 135))	('MIUC', 'Chemical', '-', (89, 93))	('pathogenesis', 'biological_process', 'GO:0009405', ('75', '87'))	('bladder cancer', 'Disease', 'MESH:D001749', (226, 240))	('bladder cancer', 'Disease', (226, 240))	('FGFR3', 'Gene', (121, 126))	('mutation', 'Var', (46, 54))	('bladder cancer', 'Phenotype', 'HP:0009725', (226, 240))
169775	20334706	As FGFR3 somatic mutations are the most common somatic mutation in NMIUC while TP53 and RB1 mutations were noted to be frequent in MIUC (Refs), the idea of a dual-track pathway implicating alterations in FGFR3 in NMIUC versus TP53 in MIUC arose (Ref.).	('MIUC', 'Chemical', '-', (214, 218))	('MIUC', 'Chemical', '-', (68, 72))	('MIUC', 'Chemical', '-', (234, 238))	('RB1', 'Gene', (88, 91))	('FGFR3', 'Gene', (3, 8))	('FGFR', 'molecular_function', 'GO:0005007', ('3', '7'))	('FGFR', 'molecular_function', 'GO:0005007', ('204', '208'))	('MIUC', 'Chemical', '-', (131, 135))	('FGFR3', 'Gene', (204, 209))	('MIUC', 'Disease', (131, 135))	('mutations', 'Var', (17, 26))	('RB1', 'Gene', '5925', (88, 91))	('alterations', 'Var', (189, 200))
169776	20334706	When the mutational status of FGFR3 and TP53 in a cohort of 81 newly diagnosed UCs was evaluated, a strong association of FGFR3 mutations with low-stage/grade cancers was found while mutation in TP53 was almost exclusively associated with high-stage/grade bladder cancer (Ref.).	('cancers', 'Disease', (159, 166))	('associated', 'Reg', (223, 233))	('mutations', 'Var', (128, 137))	('FGFR3', 'Gene', (122, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (256, 270))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('bladder cancer', 'Disease', (256, 270))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('FGFR', 'molecular_function', 'GO:0005007', ('122', '126'))	('bladder cancer', 'Phenotype', 'HP:0009725', (256, 270))
169777	20334706	In a separate study that examined DNA from 260 UC tissue samples, only 5.7% had concomitant mutations in FGFR3 and overexpression of TP53 (which is generally presumed to reflect missense mutation of the TP53 gene conferring supraphysiological protein stability), while 72.7% of the samples were positive for either FGFR3 or TP53 individually (Ref.).	('FGFR3', 'Gene', (105, 110))	('ral', 'Gene', (152, 155))	('protein', 'cellular_component', 'GO:0003675', ('243', '250'))	('expression', 'Species', '29278', (119, 129))	('ral', 'Gene', '5898', (152, 155))	('FGFR', 'molecular_function', 'GO:0005007', ('315', '319'))	('mutations', 'Var', (92, 101))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('TP53', 'Gene', (133, 137))	('overexpression', 'PosReg', (115, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))
169778	20334706	Furthermore, mutations in FGFR3 and TP53 overexpression were found to be dependent on stage and grade.	('FGFR3', 'Gene', (26, 31))	('expression', 'Species', '29278', (45, 55))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('TP53', 'Gene', (36, 40))	('mutations', 'Var', (13, 22))	('overexpression', 'PosReg', (41, 55))
169779	20334706	Mutations in FGFR3 were present in 77% of Ta, 31% of T1, and 15% of >=T2 tumours; in relation to grade, mutations were found in 85% of urothelial neoplasia of low malignant potential, and in 71% of low-grade and 26% of high-grade cases.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('tumours', 'Disease', (73, 80))	('mutations', 'Var', (104, 113))	('neoplasia', 'Phenotype', 'HP:0002664', (146, 155))	('tumours', 'Disease', 'MESH:D009369', (73, 80))	('FGFR3', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('found', 'Reg', (119, 124))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('urothelial neoplasia', 'Disease', (135, 155))	('urothelial neoplasia', 'Disease', 'MESH:D009369', (135, 155))
169781	20334706	Other work has also found an inverse relationship between mutations in FGFR3 and bladder tumour stage/grade, and a positive correlation between mutations in TP53 and bladder tumour stage/grade (Ref.).	('TP53', 'Gene', (157, 161))	('FGFR3', 'Gene', (71, 76))	('inverse', 'NegReg', (29, 36))	('mutations', 'Var', (58, 67))	('bladder tumour', 'Disease', 'MESH:D001749', (81, 95))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('bladder tumour', 'Phenotype', 'HP:0009725', (81, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('bladder tumour', 'Phenotype', 'HP:0009725', (166, 180))	('bladder tumour', 'Disease', (166, 180))	('bladder tumour', 'Disease', (81, 95))	('bladder tumour', 'Disease', 'MESH:D001749', (166, 180))	('mutations', 'Var', (144, 153))
169783	20334706	In addition, FGFR3+/TP53- tumours had a slower recurrence rate than the other tumours studied (FGFR3+/TP53+, FGFR3-/TP53- and FGFR3-/TP53+).	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('95', '99'))	('FGFR3+/TP53-', 'Var', (13, 25))	('slower', 'NegReg', (40, 46))	('recurrence rate', 'CPA', (47, 62))	('tumours', 'Disease', (26, 33))	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('FGFR', 'molecular_function', 'GO:0005007', ('109', '113'))	('tumours', 'Disease', (78, 85))	('FGFR', 'molecular_function', 'GO:0005007', ('126', '130'))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))
169784	20334706	Furthermore, FGFR3 mutations were found in 45% (9/20) of examined inverted papillomas (which are usually benign) while there were no TP53 mutations in this cohort (Ref.).	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('papillomas', 'Disease', 'MESH:D010212', (75, 85))	('mutations', 'Var', (19, 28))	('FGFR3', 'Gene', (13, 18))	('papillomas', 'Disease', (75, 85))	('found', 'Reg', (34, 39))	('papillomas', 'Phenotype', 'HP:0012740', (75, 85))
169786	20334706	The inverse correlation between the presence of FGFR3 mutations and UC grade and stage that was established by various independent studies raised an intriguing question: can the mutational status of FGFR3 predict disease recurrence or progression in patients with low-stage/grade bladder cancer?	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('bladder cancer', 'Phenotype', 'HP:0009725', (280, 294))	('mutational status', 'Var', (178, 195))	('mutations', 'Var', (54, 63))	('predict', 'Reg', (205, 212))	('patients', 'Species', '9606', (250, 258))	('FGFR3', 'Gene', (199, 204))	('bladder cancer', 'Disease', (280, 294))	('bladder cancer', 'Disease', 'MESH:D001749', (280, 294))	('FGFR3', 'Gene', (48, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('199', '203'))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('disease', 'Disease', (213, 220))
169788	20334706	It was noted that 14 of 23 patients with wild-type FGFR3 developed recurrent tumours within a year while only 7 of 34 patients with mutant FGFR3 developed recurrent tumours.	('developed', 'Reg', (57, 66))	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('recurrent tumours', 'Disease', 'MESH:D009369', (155, 172))	('recurrent tumours', 'Disease', (155, 172))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('mutant', 'Var', (132, 138))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('recurrent tumours', 'Disease', 'MESH:D009369', (67, 84))	('recurrent tumours', 'Disease', (67, 84))	('patients', 'Species', '9606', (27, 35))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('FGFR3', 'Gene', (51, 56))	('patients', 'Species', '9606', (118, 126))	('FGFR', 'molecular_function', 'GO:0005007', ('139', '143'))	('FGFR3', 'Gene', (139, 144))
169789	20334706	The mean recurrence rates per year for tumours harbouring wild-type FGFR3 and mutant FGFR3 were 1.12 and 0.24, respectively.	('tumours', 'Phenotype', 'HP:0002664', (39, 46))	('FGFR3', 'Gene', (85, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('68', '72'))	('tumours', 'Disease', 'MESH:D009369', (39, 46))	('FGFR3', 'Gene', (68, 73))	('tumours', 'Disease', (39, 46))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('mutant', 'Var', (78, 84))
169790	20334706	In 2003, this same group found that evaluation of FGFR3 mutational status is a better and more reproducible predictor than pathological grade of tumour recurrence rate, progression, and disease-specific survival (Ref.).	('tumour', 'Disease', (145, 151))	('FGFR3', 'Gene', (50, 55))	('mutational status', 'Var', (56, 73))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('FGFR', 'molecular_function', 'GO:0005007', ('50', '54'))	('tumour', 'Disease', 'MESH:D009369', (145, 151))
169791	20334706	A later study showed that in a cohort of 772 patients having NMIUCs (including TaG1, TaG2, TaG3 and T1G3 tumours) those tumours with mutations of FGFR3 trended towards reduced rates of progression but increased rates of recurrence when compared with tumours expressing wild-type FGFR3 (Ref.	('tumours', 'Phenotype', 'HP:0002664', (250, 257))	('tumours', 'Disease', 'MESH:D009369', (250, 257))	('tumours', 'Disease', (105, 112))	('patients', 'Species', '9606', (45, 53))	('tumour', 'Phenotype', 'HP:0002664', (250, 256))	('reduced', 'NegReg', (168, 175))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('TaG1', 'Gene', (79, 83))	('mutations', 'Var', (133, 142))	('FGFR3', 'Gene', (146, 151))	('tumours', 'Disease', (120, 127))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('FGFR', 'molecular_function', 'GO:0005007', ('146', '150'))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('progression', 'MPA', (185, 196))	('tumours', 'Disease', (250, 257))	('FGFR', 'molecular_function', 'GO:0005007', ('279', '283'))	('MIUC', 'Chemical', '-', (62, 66))	('TaG1', 'Gene', '6900', (79, 83))
169792	20334706	Another study showed that while the mutational status of FGFR3 was generally not reliable in predicting disease recurrence in a cohort of 221 patients, in a particular subset of these patients (high-grade NMIUC) mutant FGFR3 corresponded with decreased progression when compared with high-grade NMIUC cases with wild-type FGFR3 (P = 0.009) (Ref.).	('mutant', 'Var', (212, 218))	('patients', 'Species', '9606', (184, 192))	('progression', 'MPA', (253, 264))	('MIUC', 'Chemical', '-', (206, 210))	('ral', 'Gene', (71, 74))	('FGFR3', 'Gene', (219, 224))	('ral', 'Gene', '5898', (71, 74))	('MIUC', 'Chemical', '-', (296, 300))	('FGFR', 'molecular_function', 'GO:0005007', ('57', '61'))	('FGFR', 'molecular_function', 'GO:0005007', ('219', '223'))	('patients', 'Species', '9606', (142, 150))	('FGFR', 'molecular_function', 'GO:0005007', ('322', '326'))	('decreased', 'NegReg', (243, 252))
169794	20334706	Interestingly, no correlation between mutational status of FGFR3 and ability to predict disease recurrence and survival was found in T1G3 tumours, leading to the suggestion that T1G3 tumours are at a crossroads between the FGFR3 and p53 oncogenic pathway and that the role of FGFR3 in this subset of tumours is diminished and less significant (Ref.).	('tumours', 'Disease', (300, 307))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('tumours', 'Disease', (183, 190))	('tumour', 'Phenotype', 'HP:0002664', (300, 306))	('FGFR', 'molecular_function', 'GO:0005007', ('223', '227'))	('FGFR', 'molecular_function', 'GO:0005007', ('276', '280'))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('T1G3', 'Var', (178, 182))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('tumours', 'Disease', 'MESH:D009369', (183, 190))	('p53', 'Gene', '7157', (233, 236))	('tumours', 'Phenotype', 'HP:0002664', (300, 307))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('tumours', 'Disease', 'MESH:D009369', (300, 307))	('tumours', 'Phenotype', 'HP:0002664', (183, 190))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('p53', 'Gene', (233, 236))	('tumours', 'Disease', (138, 145))
169795	20334706	In summary, the preponderance of data suggests that FGFR3 mutation status might serve as a predictor of reduced progression of NMIUCs, although large, prospective interinstitutional studies will be necessary to resolve this conundrum definitively.	('reduced', 'NegReg', (104, 111))	('progression', 'MPA', (112, 123))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('NMIUCs', 'Disease', (127, 133))	('mutation', 'Var', (58, 66))	('MIUC', 'Chemical', '-', (128, 132))	('FGFR3', 'Gene', (52, 57))
169796	20334706	There has been no study to date that has definitively developed a relationship between mutant FGFR3 and tumour recurrence.	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('mutant', 'Var', (87, 93))	('FGFR3', 'Gene', (94, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('94', '98'))	('tumour', 'Disease', (104, 110))
169798	20334706	), mutational status might correlate to exquisite sensitivity of the tumour to pharmacological inhibition of the receptor, through a process that has been termed oncogene addiction (Ref.).	('tumour', 'Disease', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('sensitivity', 'MPA', (50, 61))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('mutational', 'Var', (3, 13))	('correlate to', 'Reg', (27, 39))
169799	20334706	In such a scenario, even though a mutant-FGFR3-harbouring tumour carries a relatively favourable prognosis, it could be treated and exhibit dramatic responses to a noninvasive, targeted modality like a small-molecule kinase inhibitor.	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('mutant-FGFR3-harbouring', 'Var', (34, 57))	('tumour', 'Disease', (58, 64))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('217', '233'))
169800	20334706	However, given the positive prognostic associations between FGFR3 mutation and nonprogression, one could also imagine a scenario where tumours that harbour FGFR3-activating mutations might be contraindicated for FGFR3-targeted therapy, and where such therapy could paradoxically induce tumour aggression.	('aggression', 'biological_process', 'GO:0002118', ('293', '303'))	('FGFR3', 'Gene', (60, 65))	('tumour', 'Phenotype', 'HP:0002664', (286, 292))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('tumours', 'Disease', (135, 142))	('induce', 'Reg', (279, 285))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (173, 182))	('tumour aggression', 'Disease', 'MESH:D001523', (286, 303))	('nonprogression', 'Disease', (79, 93))	('FGFR', 'molecular_function', 'GO:0005007', ('212', '216'))	('tumour aggression', 'Disease', (286, 303))	('mutation', 'Var', (66, 74))	('FGFR', 'molecular_function', 'GO:0005007', ('156', '160'))	('FGFR3-activating', 'Gene', (156, 172))	('aggression', 'Phenotype', 'HP:0000718', (293, 303))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))
169803	20334706	There have been several in vitro studies using small-molecule inhibitors designed against FGFR3 (SU5402, SU6668, CHIR-258, PD173074) that have shown strong in vitro inhibition (Refs) (Table 1).	('SU5402', 'Var', (97, 103))	('PD173074', 'Var', (123, 131))	('PD173074', 'Chemical', 'MESH:C115711', (123, 131))	('SU6668', 'Chemical', 'MESH:C412603', (105, 111))	('SU6668', 'Var', (105, 111))	('ral', 'Gene', '5898', (20, 23))	('SU5402', 'Chemical', 'MESH:C105686', (97, 103))	('FGFR3', 'Gene', (90, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))	('ral', 'Gene', (20, 23))
169804	20334706	Many of these studies have used multiple myeloma cell lines as they have been shown to harbour activating FGFR3 mutations, although these mutations are different from those generally in NMIUC.	('ral', 'Gene', (177, 180))	('FGFR3', 'Gene', (106, 111))	('ral', 'Gene', '5898', (177, 180))	('multiple myeloma', 'Disease', 'MESH:D009101', (32, 48))	('mutations', 'Var', (112, 121))	('multiple myeloma', 'Phenotype', 'HP:0006775', (32, 48))	('multiple myeloma', 'Disease', (32, 48))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('MIUC', 'Chemical', '-', (187, 191))	('activating', 'PosReg', (95, 105))
169807	20334706	A recent study using antibodies that were generated from hybridoma clones recognised bacterially expressed fragments of FGFR3 corresponding to loops II-III of the extracellular domain (region that encompasses the S249C oncogenic mutation) (Ref.).	('S249C', 'Var', (213, 218))	('FGFR3', 'Gene', (120, 125))	('S249C', 'Mutation', 'rs121913483', (213, 218))	('extracellular', 'cellular_component', 'GO:0005576', ('163', '176'))	('FGFR', 'molecular_function', 'GO:0005007', ('120', '124'))
169808	20334706	These antibodies could detect bacterially expressed wild-type FGFR3 and the mutant S249C FGFR3, implying a use for this methodology in detection or therapeutics in bladder cancer.	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('bladder cancer', 'Phenotype', 'HP:0009725', (164, 178))	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('S249C', 'Var', (83, 88))	('FGFR3', 'Gene', (89, 94))	('S249C', 'Mutation', 'rs121913483', (83, 88))	('FGFR3', 'Gene', (62, 67))	('bladder cancer', 'Disease', 'MESH:D001749', (164, 178))	('bladder cancer', 'Disease', (164, 178))
169809	20334706	); furthermore, the R3Mab was shown to have significant antitumour activity through interruption of FGFR3 signalling and antibody-dependent cell-mediated cytotoxicty (ADCC).	('FGFR', 'molecular_function', 'GO:0005007', ('100', '104'))	('antibody', 'cellular_component', 'GO:0019814', ('121', '129'))	('antibody', 'cellular_component', 'GO:0042571', ('121', '129'))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('ADCC', 'biological_process', 'GO:0001788', ('167', '171'))	('tumour', 'Disease', (60, 66))	('FGFR3', 'Protein', (100, 105))	('antibody', 'molecular_function', 'GO:0003823', ('121', '129'))	('signalling', 'biological_process', 'GO:0023052', ('106', '116'))	('interruption', 'NegReg', (84, 96))	('antibody-dependent cell-mediated cytotoxicty', 'CPA', (121, 165))	('R3Mab', 'Var', (20, 25))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('antibody', 'cellular_component', 'GO:0019815', ('121', '129'))
169811	20334706	Although these studies are preliminary, the use of antibodies directed against FGFR3 in order to treat NMIUC might prove beneficial for the prevention of recurrence.	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('FGFR3', 'Gene', (79, 84))	('MIUC', 'Chemical', '-', (104, 108))	('NMIUC', 'Disease', (103, 108))	('antibodies', 'Var', (51, 61))
169813	20334706	When Ras family members become activated, through physiological stimuli or through mutation, they signal to key pathways involved in cell growth, survival, differentiation and migration, including the RAF-MAPK (Ref.	('RAF', 'Gene', '22882', (201, 204))	('RAF', 'Gene', (201, 204))	('MAPK', 'molecular_function', 'GO:0004707', ('205', '209'))	('signal to', 'Reg', (98, 107))	('mutation', 'Var', (83, 91))	('cell growth', 'biological_process', 'GO:0016049', ('133', '144'))	('Ras', 'Gene', (5, 8))	('activated', 'PosReg', (31, 40))
169816	20334706	Several point mutations have been identified in the HRAS oncogene in UC, with the most frequent mutations occurring at codons 12, 13 and 61 (Refs), causing an inability to hydrolyse GTP to GDP (Refs).	('inability', 'NegReg', (159, 168))	('hydrolyse GTP', 'MPA', (172, 185))	('GTP', 'Chemical', 'MESH:D006160', (182, 185))	('GDP', 'MPA', (189, 192))	('ral', 'Gene', '5898', (4, 7))	('GDP', 'Chemical', 'MESH:D006153', (189, 192))	('HRAS', 'Gene', (52, 56))	('mutations', 'Var', (96, 105))	('ral', 'Gene', (4, 7))
169818	20334706	Historically, characterisation of the exact role of HRAS mutation in UC, both in terms of epidemiology of the mutation in tumours and its functional phenotypic consequence, has proven complex, despite the early isolation of the mutant HRAS oncogene from the classic UC cell line model T24 (Ref.).	('mutation', 'Var', (57, 65))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('HRAS', 'Gene', (52, 56))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('HRAS', 'Gene', (235, 239))	('tumours', 'Disease', (122, 129))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
169820	20334706	One early study of HRAS in UC showed that by transforming a NMIUC cell line (RT4) with either normal or mutated HRAS and then orthotopically inoculating nude mice transurethrally, one could cause RT4 cells to acquire a phenotype that was more similar to cell lines derived from tumours of high grade or stage (Ref.).	('tumours', 'Disease', (278, 285))	('nude mice', 'Species', '10090', (153, 162))	('RT4', 'CellLine', 'CVCL:0036', (77, 80))	('MIUC', 'Chemical', '-', (61, 65))	('mutated', 'Var', (104, 111))	('ral', 'Gene', (173, 176))	('ral', 'Gene', '5898', (173, 176))	('tumour', 'Phenotype', 'HP:0002664', (278, 284))	('RT4', 'CellLine', 'CVCL:0036', (196, 199))	('acquire', 'PosReg', (209, 216))	('tumours', 'Phenotype', 'HP:0002664', (278, 285))	('cause', 'Reg', (190, 195))	('tumours', 'Disease', 'MESH:D009369', (278, 285))
169821	20334706	It was argued that either deregulation of HRAS expression (overexpression in this case) or expression of a mutant form of HRAS manifested as a 'second hit' in a two-hit pathway could lead to invasive cancer.	('deregulation', 'Var', (26, 38))	('HRAS', 'Gene', (122, 126))	('HRAS', 'Protein', (42, 46))	('mutant', 'Var', (107, 113))	('expression', 'Species', '29278', (63, 73))	('invasive cancer', 'Disease', 'MESH:D009362', (191, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('expression', 'Species', '29278', (47, 57))	('lead to', 'Reg', (183, 190))	('invasive cancer', 'Disease', (191, 206))	('expression', 'MPA', (47, 57))	('expression', 'Species', '29278', (91, 101))
169822	20334706	A combination of PCR amplification and computerised analysis later identified the point mutation G to T at codon 12 in 30 of 67 tumour samples examined (Ref.	('tumour', 'Disease', (128, 134))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('G to T at codon 12', 'Mutation', 'c.12G>T', (97, 115))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('G to T', 'Var', (97, 103))
169823	20334706	), and when these tumour samples were stratified by grade, the overwhelming majority of HRAS mutations were found in higher-grade tumours.	('found', 'Reg', (108, 113))	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('mutations', 'Var', (93, 102))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('tumour', 'Disease', (130, 136))	('tumours', 'Disease', (130, 137))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('HRAS', 'Gene', (88, 92))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('tumour', 'Disease', (18, 24))
169825	20334706	In contrast, evaluation of 152 bladder tumours of varying grade or stage showed that the presence of HRAS mutations had no statistically significant correlation as verified by chi-squared analysis to either grade or stage of the UC studied (Ref.).	('bladder tumours', 'Disease', (31, 46))	('tumours', 'Phenotype', 'HP:0002664', (39, 46))	('bladder tumour', 'Phenotype', 'HP:0009725', (31, 45))	('bladder tumours', 'Disease', 'MESH:D001749', (31, 46))	('HRAS', 'Gene', (101, 105))	('mutations', 'Var', (106, 115))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))
169826	20334706	Interestingly, another study that evaluated DNA fragments present in urine for the most common HRAS mutations in UC found that HRAS mutation status was better able to identify low-grade lesions (47%) than cytology alone (16%) in a cohort of 100 patients (Ref.).	('mutations', 'Var', (100, 109))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('HRAS', 'Gene', (95, 99))	('patients', 'Species', '9606', (245, 253))
169827	20334706	One of the first studies to clearly define the role of HRAS in human UC evaluated the development of bladder tumours in transgenic mice expressing mutant HRAS under the regulation of the urothelial-specific uroplakin promoter (Ref.).	('mutant', 'Var', (147, 153))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('HRAS', 'Gene', (154, 158))	('human', 'Species', '9606', (63, 68))	('regulation', 'biological_process', 'GO:0065007', ('169', '179'))	('bladder tumours', 'Disease', (101, 116))	('bladder tumour', 'Phenotype', 'HP:0009725', (101, 115))	('bladder tumours', 'Disease', 'MESH:D001749', (101, 116))	('development', 'CPA', (86, 97))	('transgenic mice', 'Species', '10090', (120, 135))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
169828	20334706	The study showed that mice with low copy numbers of chromosomally integrated, mutant, uroplakin-driven rabbit HRAS developed urothelial hyperplasia followed by the onset of superficial papillary tumours.	('urothelial hyperplasia', 'Disease', (125, 147))	('uroplakin-driven rabbit HRAS', 'Disease', 'MESH:D001480', (86, 114))	('mice', 'Species', '10090', (22, 26))	('superficial papillary tumours', 'Disease', 'MESH:D000077273', (173, 202))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('urothelial hyperplasia', 'Disease', 'MESH:D006965', (125, 147))	('superficial papillary tumours', 'Disease', (173, 202))	('papillary tumours', 'Phenotype', 'HP:0007482', (185, 202))	('uroplakin-driven rabbit HRAS', 'Disease', (86, 114))	('mutant', 'Var', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
169829	20334706	In addition, mice that had high copy numbers of mutated HRAS also exhibited urotheilal hyperplasia with accelerated-onset superficial papillary tumours.	('mice', 'Species', '10090', (13, 17))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('mutated', 'Var', (48, 55))	('exhibited', 'Reg', (66, 75))	('papillary tumours', 'Phenotype', 'HP:0007482', (134, 151))	('superficial papillary tumours', 'Disease', (122, 151))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('HRAS', 'Gene', (56, 60))	('superficial papillary tumours', 'Disease', 'MESH:D000077273', (122, 151))	('urotheilal hyperplasia', 'Disease', 'MESH:D006965', (76, 98))	('urotheilal hyperplasia', 'Disease', (76, 98))
169831	20334706	Interestingly, this same group later found that mice harbouring mutant HRAS formed these superficial papillary tumours independent of the loss of function of TP53, a tumour suppressor that is frequently mutated or deleted in a large proportion of MIUCs (see above section) (Ref.).	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('papillary tumours', 'Phenotype', 'HP:0007482', (101, 118))	('tumour', 'Disease', (166, 172))	('superficial papillary tumours', 'Disease', 'MESH:D000077273', (89, 118))	('MIUC', 'Chemical', '-', (247, 251))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('mice', 'Species', '10090', (48, 52))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('HRAS', 'Gene', (71, 75))	('tumour', 'Disease', (111, 117))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('mutant', 'Var', (64, 70))	('superficial papillary tumours', 'Disease', (89, 118))
169832	20334706	In this study, the group crossed mice that harboured mutant TP53 (dominant-negative mutant, driven by the mouse uroplakin II gene promoter, that lacks the DNA-binding domain but retains the tetramerisation domain, interfering with the function of the normal TP53 protein) with mice expressing activated HRAS.	('mice', 'Species', '10090', (277, 281))	('function', 'MPA', (235, 243))	('uroplakin II', 'Gene', '22269', (112, 124))	('DNA-binding', 'molecular_function', 'GO:0003677', ('155', '166'))	('DNA', 'cellular_component', 'GO:0005574', ('155', '158'))	('protein', 'cellular_component', 'GO:0003675', ('263', '270'))	('lacks', 'NegReg', (145, 150))	('mice', 'Species', '10090', (33, 37))	('mutant', 'Var', (53, 59))	('tetramerisation', 'MPA', (190, 205))	('interfering', 'NegReg', (214, 225))	('TP53', 'Gene', (60, 64))	('uroplakin II', 'Gene', (112, 124))	('mouse', 'Species', '10090', (106, 111))
169834	20334706	In contrast, when the mice expressing HRAS-activating mutations were crossed with TP53-knockout mice, the progeny went on to develop either low- or high-grade superficial papillary tumours, suggesting that complete loss of TP53, rather than reduction of expression or function, is requisite to synergise with mutant HRAS.	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('mice', 'Species', '10090', (96, 100))	('expression', 'Species', '29278', (254, 264))	('mutant', 'Var', (309, 315))	('superficial papillary tumours', 'Disease', 'MESH:D000077273', (159, 188))	('TP53', 'Gene', (223, 227))	('mutations', 'Var', (54, 63))	('loss', 'NegReg', (215, 219))	('develop', 'PosReg', (125, 132))	('superficial papillary tumours', 'Disease', (159, 188))	('tumours', 'Phenotype', 'HP:0002664', (181, 188))	('papillary tumours', 'Phenotype', 'HP:0007482', (171, 188))	('HRAS', 'Gene', (316, 320))	('low-', 'CPA', (140, 144))	('mice', 'Species', '10090', (22, 26))
169835	20334706	Another group found that progression to papillary tumours of the bladder with regards to mutant HRAS expression was dose dependent (Ref.	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('HRAS', 'Gene', (96, 100))	('papillary tumours of the bladder', 'Disease', 'MESH:D001749', (40, 72))	('papillary tumours of the bladder', 'Disease', (40, 72))	('papillary tumours', 'Phenotype', 'HP:0007482', (40, 57))	('expression', 'Species', '29278', (101, 111))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('mutant', 'Var', (89, 95))
169836	20334706	): mice that were homozygous for the activated HRAS mutation were able to develop early-onset superficial papillary tumours, while mice that were heterozygous for the activating HRAS mutant were not able to develop superficial papillary tumours, regardless of mutational status of potential tumour suppressor genes on chromosome 9.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('tumour', 'Disease', 'MESH:D009369', (291, 297))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('superficial papillary tumours', 'Disease', 'MESH:D000077273', (215, 244))	('tumour', 'Disease', (291, 297))	('tumour', 'Disease', (116, 122))	('chromosome', 'cellular_component', 'GO:0005694', ('318', '328'))	('mutation', 'Var', (52, 60))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('superficial papillary tumours', 'Disease', (215, 244))	('mice', 'Species', '10090', (131, 135))	('superficial papillary tumours', 'Disease', 'MESH:D000077273', (94, 123))	('tumours', 'Phenotype', 'HP:0002664', (237, 244))	('mice', 'Species', '10090', (3, 7))	('papillary tumours', 'Phenotype', 'HP:0007482', (227, 244))	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('papillary tumours', 'Phenotype', 'HP:0007482', (106, 123))	('tumour', 'Disease', 'MESH:D009369', (237, 243))	('superficial papillary tumours', 'Disease', (94, 123))	('tumour', 'Disease', (237, 243))	('develop', 'PosReg', (74, 81))	('tumour', 'Phenotype', 'HP:0002664', (291, 297))	('HRAS', 'Gene', (47, 51))
169844	20334706	A later study by the same group showed that the potential mechanism for apoptotic cell death in mutant HRAS transgenic J82 cells is an increase in reactive oxygen species, which induces both intrinsic and extrinsic caspase pathways (Ref.).	('induces', 'Reg', (178, 185))	('mutant', 'Var', (96, 102))	('extrinsic caspase pathways', 'Pathway', (205, 231))	('increase', 'PosReg', (135, 143))	('HRAS', 'Gene', (103, 107))	('reactive oxygen species', 'MPA', (147, 170))	('J82', 'CellLine', 'CVCL:0359', (119, 122))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('72', '92'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (147, 170))	('apoptotic cell death', 'CPA', (72, 92))
169846	20334706	Taken together, these data show that HDACIs might potentially play an important role in stopping the growth of bladder tumours that harbour activating HRAS mutations.	('growth', 'MPA', (101, 107))	('stopping', 'NegReg', (88, 96))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('HRAS', 'Gene', (151, 155))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('mutations', 'Var', (156, 165))	('bladder tumour', 'Phenotype', 'HP:0009725', (111, 125))	('bladder tumours', 'Disease', (111, 126))	('bladder tumours', 'Disease', 'MESH:D001749', (111, 126))	('activating', 'PosReg', (140, 150))
169849	20334706	In cells with mutant KRAS2, inhibition of PLK1 (polo-like kinase 1) and depletion of STK33 (serine/threonine kinase 33) result in a robust induction of cell death that does not occur in normal cells (Refs).	('serine/threonine kinase 33', 'Gene', (92, 118))	('PLK1', 'Gene', '5347', (42, 46))	('mutant', 'Var', (14, 20))	('KRAS2', 'Gene', (21, 26))	('polo-like kinase 1', 'Gene', '5347', (48, 66))	('inhibition', 'NegReg', (28, 38))	('KRAS2', 'Gene', '3845', (21, 26))	('STK33', 'Gene', '65975', (85, 90))	('serine/threonine kinase 33', 'Gene', '65975', (92, 118))	('STK33', 'Gene', (85, 90))	('cell death', 'biological_process', 'GO:0008219', ('152', '162'))	('polo-like kinase 1', 'Gene', (48, 66))	('STK', 'molecular_function', 'GO:0050359', ('85', '88'))	('cell death', 'CPA', (152, 162))	('PLK1', 'Gene', (42, 46))	('depletion', 'MPA', (72, 81))
169850	20334706	Such synthetic lethal screens suggest that targeting this class of genes could provide an exquisitely specific way to target mutant tumour cells with minimal toxicity to wild-type cells.	('tumour', 'Disease', (132, 138))	('toxicity', 'Disease', 'MESH:D064420', (158, 166))	('mutant', 'Var', (125, 131))	('toxicity', 'Disease', (158, 166))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))
169854	20334706	Despite the poor results in clinical trials, in an animal model of urothelial tumours with mutationally active HRAS, treatment with FTIs significantly sensitised the tumours to radiation (Ref.).	('urothelial tumours', 'Disease', 'MESH:D014523', (67, 85))	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('tumours', 'Disease', (166, 173))	('mutationally active', 'Var', (91, 110))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('tumours', 'Disease', (78, 85))	('HRAS', 'Gene', (111, 115))	('urothelial tumours', 'Disease', (67, 85))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('sensitised', 'Reg', (151, 161))	('tumours', 'Phenotype', 'HP:0002664', (166, 173))	('tumours', 'Disease', 'MESH:D009369', (166, 173))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
169859	20334706	The cancers in which BRAF mutations are prevalent (i.e.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('BRAF', 'Gene', '673', (21, 25))	('mutations', 'Var', (26, 35))	('BRAF', 'Gene', (21, 25))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (4, 11))
169862	20334706	For example, CI-1040 showed great promise in inhibition of colon carcinomas in vivo and was demonstrated to have a negative impact on the growth, survival, invasion and angiogenesis profiles of cancer cells (Refs).	('inhibition', 'NegReg', (45, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('cancer', 'Disease', (194, 200))	('colon carcinomas', 'Disease', 'MESH:D015179', (59, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('colon carcinomas', 'Disease', (59, 75))	('growth', 'CPA', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('angiogenesis', 'biological_process', 'GO:0001525', ('169', '181'))	('negative', 'NegReg', (115, 123))	('CI-1040', 'Var', (13, 20))	('angiogenesis profiles', 'CPA', (169, 190))	('survival', 'CPA', (146, 154))	('CI-1040', 'Chemical', 'MESH:C120227', (13, 20))	('invasion', 'CPA', (156, 164))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
169864	20334706	This result prompted development of the MEK inhibitor ARRY-142886, which is much more specific than CI-1040 (Refs).	('ARRY-142886', 'Var', (54, 65))	('CI-1040', 'Chemical', 'MESH:C120227', (100, 107))	('MEK', 'Gene', '5609', (40, 43))	('MEK', 'Gene', (40, 43))
169868	20334706	Loss of heterozygosity of chromosome 9, activating mutations in FGFR3, and activating mutations in the oncogene HRAS have all been shown to be prevalent and important in NMIUC, with the latter two alterations being infrequent or absent in the invasive subtype of UC.	('activating', 'PosReg', (40, 50))	('mutations', 'Var', (86, 95))	('MIUC', 'Chemical', '-', (171, 175))	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('FGFR3', 'Gene', (64, 69))	('Loss', 'NegReg', (0, 4))	('HRAS', 'Gene', (112, 116))
169896	30166228	The interaction between PD-1 and PD-L1 or PD-L2 normally allows evasion of the cellular immune response, whereas disruption of the signaling might restore antitumor activity.	('PD-L1', 'Gene', (33, 38))	('interaction', 'Interaction', (4, 15))	('restore', 'PosReg', (147, 154))	('cellular immune response', 'biological_process', 'GO:0002449', ('79', '103'))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PD-1', 'Gene', (24, 28))	('disruption', 'Var', (113, 123))	('evasion', 'MPA', (64, 71))	('tumor', 'Disease', (159, 164))	('cellular immune response', 'MPA', (79, 103))	('PD-L2', 'Gene', (42, 47))	('cellular immune response', 'biological_process', 'GO:0002443', ('79', '103'))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('cellular immune response', 'biological_process', 'GO:0002456', ('79', '103'))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
169961	30166228	Whereas MPS counts tumor cells and tumor-associated immune cells reactive to PD-L1, immune cells in the adjacent tissue or stroma reactive to PD-L1 are excluded.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', (35, 40))	('PD-L1', 'Var', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))
169967	30166228	In addition, large studies are evaluating the combination of immune checkpoint inhibition with platinum-based chemotherapy in treatment-naive patients (NCT02853305, NCT03036098).	('platinum', 'Chemical', 'MESH:D010984', (95, 103))	('NCT02853305', 'Var', (152, 163))	('NCT03036098', 'Chemical', 'MESH:C079985', (165, 176))	('patients', 'Species', '9606', (142, 150))	('NCT03036098', 'Var', (165, 176))
169983	30107644	The results showed that recurrent mutations in MUC genes were significantly associated with better survival prognosis.	('better', 'PosReg', (92, 98))	('MUC', 'Gene', '100508689', (47, 50))	('MUC', 'Gene', (47, 50))	('associated', 'Reg', (76, 86))	('mutations', 'Var', (34, 43))
169984	30107644	Only a small part of RMGs was differentially expressed due to their own mutations and most of them were downregulated.	('RMGs', 'Chemical', '-', (21, 25))	('mutations', 'Var', (72, 81))	('RMGs', 'Gene', (21, 25))	('downregulated', 'NegReg', (104, 117))
169990	30107644	The accumulation of necessary somatic mutations is a leading cause of cancer initiation and development (Vogelstein & Kinzler, 1993).	('cause', 'Reg', (61, 66))	('development', 'CPA', (92, 103))	('cancer initiation', 'Disease', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer initiation', 'Disease', 'MESH:D009369', (70, 87))	('mutations', 'Var', (38, 47))
169991	30107644	Mutations in cancer genome can influence molecular function of genes and signaling pathways, leading to cell differentiation, proliferation, and survival (Hanahan & Weinberg Robert, 2011; Watson, Takahashi, Futreal, & Chin, 2013).	('genes', 'Pathway', (63, 68))	('proliferation', 'CPA', (126, 139))	('leading to', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cell differentiation', 'CPA', (104, 124))	('cell differentiation', 'biological_process', 'GO:0030154', ('104', '124'))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('Mutations', 'Var', (0, 9))	('molecular function', 'molecular_function', 'GO:0003674', ('41', '59'))	('signaling pathways', 'Pathway', (73, 91))	('survival', 'CPA', (145, 153))	('influence', 'Reg', (31, 40))	('molecular function', 'MPA', (41, 59))
169995	30107644	TP53 (OMIM *191170) was reported as the most frequently mutated gene in diverse cancers, and patients with TP53 mutation tend to have worse prognosis (Wang & Sun, 2017).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (112, 120))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('TP53', 'Gene', '7157', (107, 111))	('cancers', 'Disease', (80, 87))	('TP53', 'Gene', (107, 111))	('patients', 'Species', '9606', (93, 101))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
169996	30107644	investigated 127 significantly mutated genes in 12 cancers and categorized them into 20 cellular processes, including Wnt/beta-catenin, MAPK, and PI3K signaling pathways (Kandoth et al., 2013).	('PI3K', 'molecular_function', 'GO:0016303', ('146', '150'))	('PI3K signaling pathways', 'Pathway', (146, 169))	('cancers', 'Disease', (51, 58))	('beta-catenin', 'Gene', '1499', (122, 134))	('PI3K signaling', 'biological_process', 'GO:0014065', ('146', '160'))	('MAPK', 'molecular_function', 'GO:0004707', ('136', '140'))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('beta-catenin', 'Gene', (122, 134))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('mutated', 'Var', (31, 38))
169998	30107644	For instance, 10 RMGs including KRAS (* 190070), TP53, CDKN2A (* 600160), and RREB1 (* 602209) were identified in Pancreatic Ductal Adenocarcinoma (PDAC), and it was revealed that the frequent disruptions in RAS-MAPK pathway played a pivotal role in this cancer (Network, 2014).	('CDKN2A', 'Gene', '1029', (55, 61))	('TP53', 'Gene', '7157', (49, 53))	('RMGs', 'Chemical', '-', (17, 21))	('cancer', 'Disease', (255, 261))	('* 600160', 'Var', (63, 71))	('PDAC', 'Phenotype', 'HP:0006725', (148, 152))	('disruptions', 'Reg', (193, 204))	('Pancreatic Ductal Adenocarcinoma', 'Disease', (114, 146))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('KRAS', 'Gene', '3845', (32, 36))	('Pancreatic Ductal Adenocarcinoma', 'Phenotype', 'HP:0006725', (114, 146))	('MAPK', 'molecular_function', 'GO:0004707', ('212', '216'))	('TP53', 'Gene', (49, 53))	('KRAS', 'Gene', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('RREB1', 'Gene', '6239', (78, 83))	('Pancreatic Ductal Adenocarcinoma', 'Disease', 'MESH:D021441', (114, 146))	('CDKN2A', 'Gene', (55, 61))	('RAS-MAPK pathway', 'Pathway', (208, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('RREB1', 'Gene', (78, 83))	('* 602209', 'Var', (85, 93))
169999	30107644	Besides, dozens of significantly mutated genes in various canonical signaling pathways were identified in Muscle-Invasive Bladder Cancer (BLCA), which highlighted the importance of these pathways in the disease (Robertson et al., 2017).	('Muscle-Invasive Bladder Cancer', 'Disease', 'MESH:D001749', (106, 136))	('Invasive Bladder', 'Phenotype', 'HP:0100645', (113, 129))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (122, 136))	('mutated', 'Var', (33, 40))	('Muscle-Invasive Bladder Cancer', 'Disease', (106, 136))	('BLCA', 'Phenotype', 'HP:0009725', (138, 142))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))
170002	30107644	Besides, it was reported that the mutations of six RMGs including TP53, KDR (* 191306), PIK3CA (* 171834), ATM (* 607585), AKT1 (* 164730), and KIT (* 164920) were associated with a poor prognosis in sporadic triple negative breast cancer (Pop et al., 2018).	('PIK3CA', 'Gene', '5290', (88, 94))	('TP53', 'Gene', '7157', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('* 191306', 'Var', (77, 85))	('AKT1', 'Gene', '207', (123, 127))	('KDR', 'Gene', '3791', (72, 75))	('* 164730', 'Var', (129, 137))	('* 171834', 'Var', (96, 104))	('PIK3CA', 'Gene', (88, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('AKT1', 'Gene', (123, 127))	('* 164920', 'Var', (149, 157))	('ATM', 'Gene', '472', (107, 110))	('TP53', 'Gene', (66, 70))	('* 607585', 'Var', (112, 120))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('KIT', 'molecular_function', 'GO:0005020', ('144', '147'))	('breast cancer', 'Disease', (225, 238))	('KIT', 'Gene', (144, 147))	('KDR', 'Gene', (72, 75))	('RMGs', 'Chemical', '-', (51, 55))	('ATM', 'Gene', (107, 110))
170003	30107644	The diagnostic and prognostic impacts of RMGs (e.g., EZH2 (* 601573), ELP3 (* 612722), and IDH2 (* 147650)) in lymphoma were surveyed for better clinical decision making (Rosenquist et al., 2016).	('* 601573', 'Var', (59, 67))	('* 147650', 'Var', (97, 105))	('ELP3', 'Gene', '55140', (70, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (111, 119))	('IDH2', 'Gene', (91, 95))	('lymphoma', 'Disease', 'MESH:D008223', (111, 119))	('lymphoma', 'Disease', (111, 119))	('RMGs', 'Chemical', '-', (41, 45))	('IDH2', 'Gene', '3418', (91, 95))	('ELP3', 'Gene', (70, 74))	('* 612722', 'Var', (76, 84))	('EZH2', 'Gene', (53, 57))	('EZH2', 'Gene', '2146', (53, 57))
170004	30107644	Moreover, RMGs (e.g., TET2 (* 612839), DNMT3A (* 602769), BAP1 (* 603089), and ASXL1 (* 612990)) involved in histone modification, chromatin remodeling and DNA methylation were associated with adverse outcome in thymic carcinoma (Wang et al., 2014).	('BAP1', 'Gene', (58, 62))	('* 602769', 'Var', (47, 55))	('RMGs', 'Chemical', '-', (10, 14))	('TET2', 'Gene', (22, 26))	('ASXL1', 'Gene', (79, 84))	('DNMT3A', 'Gene', '1788', (39, 45))	('chromatin', 'cellular_component', 'GO:0000785', ('131', '140'))	('thymic carcinoma', 'Disease', (212, 228))	('* 603089', 'Var', (64, 72))	('DNA methylation', 'biological_process', 'GO:0006306', ('156', '171'))	('* 612839', 'Var', (28, 36))	('TET2', 'Gene', '54790', (22, 26))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('ASXL1', 'Gene', '171023', (79, 84))	('thymic carcinoma', 'Disease', 'MESH:D013945', (212, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('BAP1', 'Gene', '8314', (58, 62))	('DNMT3A', 'Gene', (39, 45))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('131', '151'))	('associated', 'Reg', (177, 187))	('histone modification', 'biological_process', 'GO:0016570', ('109', '129'))	('* 612990', 'Var', (86, 94))
170020	30107644	The differences of overall survival time between RMG-mutation, RMG-MS or RMG-NS patients and RMG wild-type patients were shown by KM survival curves (log-rank test).	('RMG-NS', 'Disease', (73, 79))	('patients', 'Species', '9606', (80, 88))	('RMG-mutation', 'Var', (49, 61))	('RMG-NS', 'Disease', 'MESH:D009404', (73, 79))	('RMG-MS', 'Disease', (63, 69))	('patients', 'Species', '9606', (107, 115))
170023	30107644	As a result, we identified 897 unique RMGs across 31 cancer types (Supporting Information Table S1).	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('RMGs', 'Var', (38, 42))	('RMGs', 'Chemical', '-', (38, 42))
170025	30107644	There were more than 100 RMGs in SKCM, STAD, LUSC, LUAD, ACC, and DLBC (see the abbreviations of cancer types in method section), indicating that these cancers were closely related to gene recurrent mutations.	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('cancer', 'Disease', (152, 158))	('cancers', 'Disease', (152, 159))	('cancer', 'Disease', (97, 103))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('LUSC', 'Phenotype', 'HP:0030359', (45, 49))	('ACC', 'Phenotype', 'HP:0006744', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('RMGs', 'Chemical', '-', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mutations', 'Var', (199, 208))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
170038	30107644	In addition, we identified 624 specifically mutated RMGs (smRMGs) that were only in a single cancer type (Figure 1d and Supporting Information Table S2).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('RMGs', 'Chemical', '-', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mutated', 'Var', (44, 51))	('RMGs', 'Chemical', '-', (52, 56))
170042	30107644	We also detected another five smRMGs that mutated in nearly half of the samples in corresponding cancers, including PCDHAC2 in SKCM (53%), ZFPM1 in ACC (52%), VHL in KIRC (49%), GNAQ in UVM (49%), and ADAM6 in LUSC (45%).	('PCDHAC2', 'Gene', '56134', (116, 123))	('UVM', 'Phenotype', 'HP:0007716', (186, 189))	('ADAM6', 'Gene', '8755', (201, 206))	('PCDHAC2', 'Gene', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('RMGs', 'Chemical', '-', (32, 36))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('VHL', 'Disease', (159, 162))	('GNAQ', 'Gene', '2776', (178, 182))	('GNAQ', 'Gene', (178, 182))	('ZFPM1', 'Gene', '161882', (139, 144))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('LUSC', 'Phenotype', 'HP:0030359', (210, 214))	('ACC', 'Phenotype', 'HP:0006744', (148, 151))	('mutated', 'Var', (42, 49))	('ADAM6', 'Gene', (201, 206))	('VHL', 'Disease', 'MESH:D006623', (159, 162))	('ZFPM1', 'Gene', (139, 144))
170045	30107644	PI3K-Akt signaling pathway had the most number of RMGs (n = 47) and were disrupted in 23 cancer types.	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('Akt', 'Gene', '207', (5, 8))	('RMGs', 'Var', (50, 54))	('RMGs', 'Chemical', '-', (50, 54))	('signaling pathway', 'biological_process', 'GO:0007165', ('9', '26'))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('Akt signaling', 'biological_process', 'GO:0043491', ('5', '18'))	('cancer', 'Disease', (89, 95))	('Akt', 'Gene', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
170049	30107644	It was also shown that BLCA had the greatest proportion of RMGs in cell cycle.	('BLCA', 'Phenotype', 'HP:0009725', (23, 27))	('cell cycle', 'biological_process', 'GO:0007049', ('67', '77'))	('RMGs', 'Var', (59, 63))	('RMGs', 'Chemical', '-', (59, 63))	('cell cycle', 'CPA', (67, 77))
170055	30107644	For most cRMGs, missense mutation accounts for the largest proportion (>50%), especially for PIK3CA.	('PIK3CA', 'Gene', (93, 99))	('PIK3CA', 'Gene', '5290', (93, 99))	('RMGs', 'Chemical', '-', (10, 14))	('missense mutation', 'Var', (16, 33))
170056	30107644	Specially, KMT2C in LUSC and CHOL as well as DNAH5 in CHOL were more frequently disrupted by nonsense mutation.	('DNAH5', 'Gene', (45, 50))	('DNAH5', 'Gene', '1767', (45, 50))	('disrupted', 'Reg', (80, 89))	('CHOL', 'Phenotype', 'HP:0030153', (29, 33))	('KMT2C', 'Gene', (11, 16))	('nonsense mutation', 'Var', (93, 110))	('KMT2C', 'Gene', '58508', (11, 16))	('CHOL', 'Phenotype', 'HP:0030153', (54, 58))	('LUSC', 'Phenotype', 'HP:0030359', (20, 24))
170057	30107644	In addition, frame shift insertion was also found to be a key mutation for MUC5B in KICH, which occupied a relatively large proportion.	('MUC5B', 'Gene', '727897', (75, 80))	('frame shift insertion', 'Var', (13, 34))	('MUC5B', 'Gene', (75, 80))
170058	30107644	To analyze the functional effects of mutations, we identified differentially expressed genes (DEGs) potentially affected by each cRMG, whereas these DEGs showed a relatively low overlap across different cancer types, except for the DEGs affected by TP53 mutations.	('affected', 'Reg', (112, 120))	('differentially expressed genes', 'MPA', (62, 92))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (203, 209))	('TP53', 'Gene', (249, 253))	('TP53', 'Gene', '7157', (249, 253))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
170060	30107644	It was observed that TP53 was more frequently disrupted by nonsense mutations, frame-shift indels and splice site mutations compared with other cRMGs (Figure 3a), which results in the initiation and progression of cancers (Payne & Kemp, 2005; Wojnarowicz et al., 2012).	('TP53', 'Gene', (21, 25))	('RMGs', 'Chemical', '-', (145, 149))	('frame-shift indels', 'Var', (79, 97))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('splice site mutations', 'Var', (102, 123))	('results in', 'Reg', (169, 179))	('nonsense mutations', 'Var', (59, 77))	('cancers', 'Disease', (214, 221))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('progression', 'PosReg', (199, 210))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('disrupted', 'Reg', (46, 55))	('TP53', 'Gene', '7157', (21, 25))
170062	30107644	To assess the functional impacts of TP53 mutations, we identified 87 DEGs shared by more than one-quarter of the 21 cancer types.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('TP53', 'Gene', '7157', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TP53', 'Gene', (36, 40))
170068	30107644	Surprisingly, patients with MUC3A, MUC4, MUC5B, MUC6, and MUC16 mutations had significantly better OS prognoses compared with those without mutations in several cancer types (Figure 4a).	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('MUC6', 'Gene', (48, 52))	('better', 'PosReg', (92, 98))	('MUC4', 'Gene', '4585', (35, 39))	('patients', 'Species', '9606', (14, 22))	('MUC16', 'Gene', '94025', (58, 63))	('MUC4', 'Gene', (35, 39))	('MUC6', 'Gene', '4588', (48, 52))	('MUC5B', 'Gene', '727897', (41, 46))	('mutations', 'Var', (64, 73))	('MUC5B', 'Gene', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('MUC3A', 'Gene', '4584', (28, 33))	('MUC3A', 'Gene', (28, 33))	('OS prognoses', 'CPA', (99, 111))	('MUC16', 'Gene', (58, 63))
170070	30107644	Results showed that there was a greater proportion of in-frame deletion of MUC4 in KIPAN and KIRC (Figure 3a), where the mutations of MUC4 were significantly associated with prognosis.	('MUC4', 'Gene', (75, 79))	('MUC4', 'Gene', (134, 138))	('mutations', 'Var', (121, 130))	('associated with', 'Reg', (158, 173))	('MUC4', 'Gene', '4585', (134, 138))	('in-frame deletion', 'Var', (54, 71))	('MUC4', 'Gene', '4585', (75, 79))
170071	30107644	Similarly, we found a greater proportion of frame-shift deletion of MUC5B in STAD and STES.	('STES', 'Chemical', '-', (86, 90))	('MUC5B', 'Gene', '727897', (68, 73))	('MUC5B', 'Gene', (68, 73))	('STAD', 'Disease', (77, 81))	('frame-shift deletion', 'Var', (44, 64))	('STES', 'Disease', (86, 90))
170075	30107644	There were more recurrently mutated MUC family genes in SKCM, DLBC, CHOL, ACC, ESCA, KICH, and STAD compared with other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('STAD', 'Disease', (95, 99))	('KICH', 'Disease', (85, 89))	('mutated', 'Var', (28, 35))	('SKCM', 'Disease', (56, 60))	('CHOL', 'Disease', (68, 72))	('ESCA', 'Phenotype', 'HP:0011459', (79, 83))	('DLBC', 'Disease', (62, 66))	('ESCA', 'Disease', (79, 83))	('ACC', 'Phenotype', 'HP:0006744', (74, 77))	('cancer', 'Disease', (120, 126))	('ACC', 'Disease', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('MUC', 'Gene', '100508689', (36, 39))	('CHOL', 'Phenotype', 'HP:0030153', (68, 72))	('MUC', 'Gene', (36, 39))
170077	30107644	As a result, the better OS prognosis were observed in SKCM and STAD (Supporting Information Figure S3), which further suggested that mutations of MUC family genes were frequently associated with better survival prognosis in cancers.	('associated', 'Reg', (179, 189))	('better', 'PosReg', (195, 201))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancers', 'Disease', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('mutations', 'Var', (133, 142))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('MUC', 'Gene', '100508689', (146, 149))	('MUC', 'Gene', (146, 149))
170078	30107644	To explore the impacts of mutation types on gene expression, we firstly identified 37 RMGs which were differentially expressed caused by their own mutations (Supporting Information Table S3).	('RMGs', 'Chemical', '-', (86, 90))	('mutations', 'Var', (147, 156))	('gene expression', 'biological_process', 'GO:0010467', ('44', '59'))	('caused', 'Reg', (127, 133))
170081	30107644	We further categorized the mutations into two groups: MS (including missense and in-frame mutations) and NS (including nonsense, frame-shift, and splice site mutations).	('NS', 'Disease', 'MESH:D009404', (105, 107))	('frame-shift', 'Var', (129, 140))	('nonsense', 'Var', (119, 127))	('splice site mutations', 'Var', (146, 167))	('missense', 'Var', (68, 76))
170084	30107644	When comparing RMG-NS cancers to RMG wild-type cancers, we found all the 20 differentially expressed RMGs are downregulated (Supporting Information Figure S4), which may mainly due to nonsense-mediated mRNA decay (Noensie & Dietz, 2001).	('RMGs', 'Chemical', '-', (101, 105))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('RMG-NS cancers', 'Disease', 'MESH:D009369', (15, 29))	('downregulated', 'NegReg', (110, 123))	('cancers', 'Disease', (22, 29))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('RMG-NS cancers', 'Disease', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('nonsense-mediated mRNA decay', 'Var', (184, 212))	('nonsense-mediated mRNA decay', 'biological_process', 'GO:0000184', ('184', '212'))	('RMGs', 'Gene', (101, 105))
170089	30107644	Similarly, to study the influences of mutation types on prognosis, we identified 13 cRMGs that mutated in sufficient samples (n >= 5) in each respective group (MS and NS) excluding TP53 that have been widely explored (Freed-Pastor & Prives, 2012).	('NS', 'Disease', 'MESH:D009404', (167, 169))	('TP53', 'Gene', (181, 185))	('mutated', 'Var', (95, 102))	('RMGs', 'Chemical', '-', (85, 89))	('TP53', 'Gene', '7157', (181, 185))
170091	30107644	The results showed that six cRMGs including OBSCN, CDKN2A, CSMD3, DMD, DNAH5, and KMT2Cwith MS or NS mutations have significant associations with prognosis in several cancer types (Figure 5c).	('CDKN2A', 'Gene', '1029', (51, 57))	('DMD', 'Gene', '1756', (66, 69))	('NS', 'Disease', 'MESH:D009404', (98, 100))	('mutations', 'Var', (101, 110))	('RMGs', 'Chemical', '-', (29, 33))	('OBSCN', 'Gene', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('OBSCN', 'Gene', '84033', (44, 49))	('cancer', 'Disease', (167, 173))	('KMT2C', 'Gene', (82, 87))	('KMT2C', 'Gene', '58508', (82, 87))	('DNAH5', 'Gene', '1767', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('DNAH5', 'Gene', (71, 76))	('DMD', 'Gene', (66, 69))	('CDKN2A', 'Gene', (51, 57))	('CSMD3', 'Gene', (59, 64))	('CSMD3', 'Gene', '114788', (59, 64))
170092	30107644	Patients with NS mutations in CDKN2A (PAAD), CSMD3 (STAD), and DMD (STAD and STES) had worse survival.	('CSMD3', 'Gene', (45, 50))	('CSMD3', 'Gene', '114788', (45, 50))	('DMD', 'Gene', '1756', (63, 66))	('CDKN2A', 'Gene', (30, 36))	('NS', 'Disease', 'MESH:D009404', (14, 16))	('CDKN2A', 'Gene', '1029', (30, 36))	('Patients', 'Species', '9606', (0, 8))	('PAAD', 'Phenotype', 'HP:0006725', (38, 42))	('STES', 'Chemical', '-', (77, 81))	('DMD', 'Gene', (63, 66))	('mutations', 'Var', (17, 26))
170095	30107644	The NS mutations downregulated its mRNA expression, therefore, dysregulated transcription, chromatin architecture or cellular differentiation.	('chromatin', 'cellular_component', 'GO:0000785', ('91', '100'))	('downregulated', 'NegReg', (17, 30))	('cellular differentiation', 'CPA', (117, 141))	('transcription', 'biological_process', 'GO:0006351', ('76', '89'))	('NS', 'Disease', 'MESH:D009404', (4, 6))	('transcription', 'MPA', (76, 89))	('mRNA expression', 'MPA', (35, 50))	('dysregulated', 'Reg', (63, 75))	('chromatin architecture', 'CPA', (91, 113))	('mutations', 'Var', (7, 16))
170096	30107644	Whereas, both OBSCN (in STAD) and DNAH5 (in SKCM) with MS mutations had better survival.	('OBSCN', 'Gene', '84033', (14, 19))	('mutations', 'Var', (58, 67))	('DNAH5', 'Gene', '1767', (34, 39))	('OBSCN', 'Gene', (14, 19))	('better', 'PosReg', (72, 78))	('DNAH5', 'Gene', (34, 39))
170101	30107644	Of which, mutations in ARID1A and PIK3CA were co-occurred (p-value < 0.01), which was consistent with the previous study (Liang et al., 2012).	('PIK3CA', 'Gene', (34, 40))	('ARID1A', 'Gene', '8289', (23, 29))	('ARID1A', 'Gene', (23, 29))	('PIK3CA', 'Gene', '5290', (34, 40))	('mutations', 'Var', (10, 19))
170104	30107644	Mutations in ARID1A could activate the PI3K pathway activity, and the concordance of mutations in ARID1A and PI3K pathway contributed to tumorigenesis (Liang et al., 2012).	('ARID1A', 'Gene', '8289', (98, 104))	('PI3K', 'molecular_function', 'GO:0016303', ('39', '43'))	('tumor', 'Disease', (137, 142))	('ARID1A', 'Gene', (98, 104))	('activate', 'PosReg', (26, 34))	('ARID1A', 'Gene', '8289', (13, 19))	('ARID1A', 'Gene', (13, 19))	('activity', 'MPA', (52, 60))	('PI3K', 'molecular_function', 'GO:0016303', ('109', '113'))	('PI3K pathway', 'Pathway', (39, 51))	('PI3K pathway', 'Pathway', (109, 121))	('mutations', 'Var', (85, 94))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('contributed', 'Reg', (122, 133))
170107	30107644	The co-occurred mutations in RNF43 and FAT3/FAT4 disrupted the Wnt signaling and thus promoted the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('RNF43', 'Gene', (29, 34))	('FAT3', 'Gene', (39, 43))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('RNF43', 'Gene', '54894', (29, 34))	('FAT3', 'Gene', '120114', (39, 43))	('mutations', 'Var', (16, 25))	('FAT4', 'Gene', (44, 48))	('Wnt signaling', 'Pathway', (63, 76))	('FAT4', 'Gene', '79633', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('disrupted', 'NegReg', (49, 58))	('promoted', 'PosReg', (86, 94))	('cancer', 'Disease', (114, 120))
170112	30107644	Moreover, we found MUC family genes were enriched in RMGs, and mutations of five MUC family genes were associated with better OS prognosis.	('MUC', 'Gene', (81, 84))	('mutations', 'Var', (63, 72))	('MUC', 'Gene', '100508689', (19, 22))	('MUC', 'Gene', '100508689', (81, 84))	('MUC', 'Gene', (19, 22))	('associated', 'Reg', (103, 113))	('RMGs', 'Chemical', '-', (53, 57))	('RMGs', 'Disease', (53, 57))
170113	30107644	In addition, we assessed the impacts of mutations in RMGs on gene expression and survival, as well as the pairwise mutation patterns among RMGs.	('gene expression', 'MPA', (61, 76))	('RMGs', 'Chemical', '-', (139, 143))	('RMGs', 'Chemical', '-', (53, 57))	('mutations', 'Var', (40, 49))	('gene expression', 'biological_process', 'GO:0010467', ('61', '76'))
170114	30107644	In this study, we showed that the RMGs with mutation rates greater than 25% were enriched in hydrolases.	('mutation', 'Var', (44, 52))	('RMGs', 'Chemical', '-', (34, 38))	('hydrolases', 'Enzyme', (93, 103))
170115	30107644	Among these genes, PTEN was a tumor suppressor gene encoding a phosphatase and its mutation may lead to decreased sensitivity to apoptosis stimulating thus promote tumorigenesis (Farrow & Mark Evers, 2003; Stambolic et al., 1998; Zhong et al., 2000).	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('tumor', 'Disease', (164, 169))	('phosphatase', 'molecular_function', 'GO:0016791', ('63', '74'))	('sensitivity to apoptosis stimulating', 'MPA', (114, 150))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('PTEN', 'Gene', (19, 23))	('decreased', 'NegReg', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('mutation', 'Var', (83, 91))	('PTEN', 'Gene', '5728', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (30, 35))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))	('promote', 'PosReg', (156, 163))
170117	30107644	Mutations in PTPRD abrogated its function to regulate STAT3 and promoted cancer progression (Funato, Yamazumi, Oda, & Akiyama, 2011; Zhao et al., 2010).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('PTPRD', 'Gene', '5789', (13, 18))	('promoted', 'PosReg', (64, 72))	('PTPRD', 'Gene', (13, 18))	('STAT3', 'Gene', '6774', (54, 59))	('abrogated', 'NegReg', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Mutations', 'Var', (0, 9))	('STAT3', 'Gene', (54, 59))	('function', 'MPA', (33, 41))
170118	30107644	In addition, the alterations in cathepsins may disrupt lysosomal trafficking and autophagy, thus led to tumor invasion (Dielschneider, Henson, & Gibson, 2017; White, Mehnert, & Chan, 2015).	('disrupt', 'NegReg', (47, 54))	('autophagy', 'biological_process', 'GO:0016236', ('81', '90'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('led to', 'Reg', (97, 103))	('cathepsins', 'Protein', (32, 42))	('tumor', 'Disease', (104, 109))	('autophagy', 'CPA', (81, 90))	('autophagy', 'biological_process', 'GO:0006914', ('81', '90'))	('lysosomal trafficking', 'CPA', (55, 76))	('alterations', 'Var', (17, 28))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
170119	30107644	Recurrent mutations in hydrolases may cause uncontrolled proliferation, differentiation and metastasis, so target tumor cell hydrolases is a good way to treat cancer.	('cancer', 'Disease', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('differentiation', 'CPA', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cause', 'Reg', (38, 43))	('metastasis', 'CPA', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', (114, 119))	('uncontrolled', 'MPA', (44, 56))	('hydrolases', 'Gene', (23, 33))	('mutations', 'Var', (10, 19))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
170123	30107644	The recurrent mutations of MUC4 were detected only in ESCA (16%), whereas not in STAD.	('MUC4', 'Gene', (27, 31))	('detected', 'Reg', (37, 45))	('ESCA', 'Phenotype', 'HP:0011459', (54, 58))	('ESCA', 'Disease', (54, 58))	('MUC4', 'Gene', '4585', (27, 31))	('mutations', 'Var', (14, 23))
170126	30107644	Our results suggested recurrent mutations of MUC family genes are closely associated with survival in diverse cancers, so the mutations of MUC4 may cause the increase in mRNA expression and further protect epithelial surfaces in ESCA and STAD.	('ESCA', 'Disease', (229, 233))	('cancers', 'Disease', (110, 117))	('MUC', 'Gene', '100508689', (139, 142))	('MUC4', 'Gene', '4585', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('MUC', 'Gene', '100508689', (45, 48))	('MUC', 'Gene', (45, 48))	('MUC4', 'Gene', (139, 143))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('mutations', 'Var', (126, 135))	('protect', 'PosReg', (198, 205))	('ESCA', 'Phenotype', 'HP:0011459', (229, 233))	('increase', 'PosReg', (158, 166))	('mRNA expression', 'MPA', (170, 185))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('MUC', 'Gene', (139, 142))
170127	30107644	Similarly, PTEN was frequently mutated in GBM and the combined data, GBMLGG, which could also indicate the mutated PTEN lost its cancer suppressing property thus promote tumorigenesis in GBM.	('PTEN', 'Gene', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lost', 'NegReg', (120, 124))	('PTEN', 'Gene', '5728', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('PTEN', 'Gene', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('PTEN', 'Gene', '5728', (115, 119))	('mutated', 'Var', (107, 114))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', (170, 175))	('promote', 'PosReg', (162, 169))
170129	30107644	Mutant p53 protein encoded by TP53 with MS mutations could inactivate p53-related proteins and acquire new oncogenic functions (Freed-Pastor & Prives, 2012), so the upregulation of TP53 helped the tumor cells evade apoptosis and senescence.	('TP53', 'Gene', (181, 185))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('the', 'PosReg', (161, 164))	('p53', 'Gene', '7157', (7, 10))	('apoptosis', 'biological_process', 'GO:0097194', ('215', '224'))	('oncogenic functions', 'CPA', (107, 126))	('TP53', 'Gene', (30, 34))	('apoptosis', 'biological_process', 'GO:0006915', ('215', '224'))	('cells evade apoptosis and', 'CPA', (203, 228))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('TP53', 'Gene', '7157', (181, 185))	('inactivate', 'NegReg', (59, 69))	('p53', 'Gene', (7, 10))	('p53', 'Gene', '7157', (70, 73))	('Mutant', 'Var', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('11', '18'))	('TP53', 'Gene', '7157', (30, 34))	('senescence', 'biological_process', 'GO:0010149', ('229', '239'))	('p53', 'Gene', (70, 73))	('protein', 'Protein', (11, 18))	('mutations', 'Var', (43, 52))	('tumor', 'Disease', (197, 202))
170131	30107644	The mutated CDKN2A proteins failed to bind to cdk4, which promoted the development of cancer (Lilischkis, Sarcevic, Kennedy, Warlters, & Sutherland, 1996; Liu et al., 1995; Ranade et al., 1995).	('mutated', 'Var', (4, 11))	('CDKN2A', 'Gene', (12, 18))	('cdk4', 'Gene', '1019', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CDKN2A', 'Gene', '1029', (12, 18))	('cdk', 'molecular_function', 'GO:0004693', ('46', '49'))	('cdk4', 'Gene', (46, 50))	('promoted', 'PosReg', (58, 66))	('proteins', 'Protein', (19, 27))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
170134	30107644	Whereas NS mutations could only downregulate gene expression (Supporting Information Figure S4).	('downregulate', 'NegReg', (32, 44))	('gene expression', 'biological_process', 'GO:0010467', ('45', '60'))	('mutations', 'Var', (11, 20))	('gene expression', 'MPA', (45, 60))	('NS', 'Disease', 'MESH:D009404', (8, 10))
170140	30107644	Strong correlation between recurrently mutated MUC family genes and human survival were revealed.	('human survival', 'CPA', (68, 82))	('human', 'Species', '9606', (68, 73))	('MUC', 'Gene', '100508689', (47, 50))	('MUC', 'Gene', (47, 50))	('mutated', 'Var', (39, 46))
170150	30002656	A high mutational load, particularly when accompanied by neoantigens, seems to facilitate immune response and correlates with patient survival for all entities treated by use of ICI.	('high mutational load', 'Var', (2, 22))	('patient', 'Species', '9606', (126, 133))	('immune response', 'CPA', (90, 105))	('immune response', 'biological_process', 'GO:0006955', ('90', '105'))	('ICI', 'Chemical', '-', (178, 181))	('facilitate', 'PosReg', (79, 89))
170161	30002656	In 2017 the FDA also announced a biomarker-based approval for pembrolizumab for patients with unresectable or metastatic solid tumors, and for colorectal carcinoma (CRC) with high microsatellite instability or mismatch repair deficiency (dMMR).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('pembrolizumab', 'Chemical', 'MESH:C582435', (62, 75))	('patients', 'Species', '9606', (80, 88))	('solid tumors', 'Disease', 'MESH:D009369', (121, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('mismatch repair', 'biological_process', 'GO:0006298', ('210', '225'))	('colorectal carcinoma', 'Disease', (143, 163))	('high microsatellite instability', 'Var', (175, 206))	('mismatch repair deficiency', 'Disease', (210, 236))	('solid tumors', 'Disease', (121, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('CRC', 'Phenotype', 'HP:0030731', (165, 168))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (143, 163))
170177	30002656	A good clinical condition expressed by the ECOG (Eastern Cooperative Oncology Group) performance status (ECOG PS 0) is associated with prolonged OS for patients receiving PD1ab treatment, as well as for patients receiving other melanoma treatments such as BRAF inhibitors.	('PD1ab', 'Var', (171, 176))	('BRAF', 'Gene', '673', (256, 260))	('OS', 'Chemical', '-', (145, 147))	('melanoma', 'Disease', 'MESH:D008545', (228, 236))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('BRAF', 'Gene', (256, 260))	('melanoma', 'Disease', (228, 236))	('patients', 'Species', '9606', (203, 211))	('Oncology', 'Phenotype', 'HP:0002664', (69, 77))	('patients', 'Species', '9606', (152, 160))
170227	30002656	High PD-L1 expression on peripheral T cells (CD4+ and CD8+) has been shown to be associated with worse PFS and OS for CTLA4ab treatment of melanoma.	('CD8', 'Gene', '925', (54, 57))	('PFS', 'Disease', (103, 106))	('High', 'Var', (0, 4))	('CD4', 'Gene', (45, 48))	('PD-L1', 'Gene', (5, 10))	('CD4', 'Gene', '920', (45, 48))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('OS', 'Chemical', '-', (111, 113))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('associated', 'Reg', (81, 91))	('CD8', 'Gene', (54, 57))
170228	30002656	For an NSCLC cohort treated mainly by chemotherapy, high PD-1/PD-L1/PD-L2 expression on peripheral blood T cells was associated with shorter OS.	('NSCLC', 'Disease', (7, 12))	('OS', 'Chemical', '-', (141, 143))	('NSCLC', 'Disease', 'MESH:D002289', (7, 12))	('PD-L2', 'Gene', (68, 73))	('PD-L2', 'Gene', '80380', (68, 73))	('high', 'Var', (52, 56))	('shorter OS', 'Disease', (133, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (7, 12))
170234	30002656	Furthermore, HLA-B44 supertype was linked to prolonged OS, whereas the HLA-B62 supertype or somatic loss of heterozygosity at HLA-I were associated with worse OS for melanoma.	('linked to', 'Reg', (35, 44))	('prolonged OS', 'Disease', (45, 57))	('loss', 'Var', (100, 104))	('melanoma', 'Disease', (166, 174))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('OS', 'Chemical', '-', (55, 57))	('OS', 'Chemical', '-', (159, 161))	('HLA-I', 'Gene', (126, 131))
170235	30002656	Nevertheless, this investigation indicates that diversity in antigen presentation might improve tumor defense.	('antigen presentation', 'biological_process', 'GO:0019882', ('61', '81'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('improve', 'PosReg', (88, 95))	('diversity', 'Var', (48, 57))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
170246	30002656	A study found that higher incidence of Vdelta2+ cells (versus Vdelta1+ cells) was linked to longer OS in melanoma patients, and suggested that Vdelta2+ cells potentially have tumor-killing capability.	('Vdelta2+', 'Var', (143, 151))	('Vdelta2+ cells', 'Var', (39, 53))	('tumor', 'Disease', (175, 180))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('longer', 'Disease', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('patients', 'Species', '9606', (114, 122))	('OS', 'Chemical', '-', (99, 101))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
170266	30002656	Elevated CXCL11 in blood has been linked to poorer outcome for ipilimumab-treated melanoma.	('CXCL11', 'Gene', '6373', (9, 15))	('ipilimumab', 'Chemical', 'MESH:D000074324', (63, 73))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('Elevated', 'Var', (0, 8))	('CXCL11', 'Gene', (9, 15))
170271	30002656	An association between treatment response and a decrease in CTCs and ctDNA has been found for targeted therapy, but not for ICI.	('ICI', 'Chemical', '-', (124, 127))	('CTCs', 'MPA', (60, 64))	('targeted therapy', 'Var', (94, 110))	('decrease', 'NegReg', (48, 56))	('ctDNA', 'Disease', (69, 74))
170279	30002656	Furthermore, an association was found between high hypermutated ctDNA levels and response, PFS, and OS for diverse malignancies treated by use of ICI.	('high', 'Var', (46, 50))	('OS', 'Chemical', '-', (100, 102))	('PFS', 'Disease', (91, 94))	('ICI', 'Chemical', '-', (146, 149))	('response', 'Disease', (81, 89))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))	('malignancies', 'Disease', (115, 127))
170288	30002656	Enrichment with Faecalibacterium and other Firmucutes was associated with improved response and with development of colitis, whereas a higher representation of Bacteroidetes was related to poorer response to CTLA4ab therapy.	('colitis', 'Disease', (116, 123))	('Faecalibacterium', 'Species', '853', (16, 32))	('colitis', 'Phenotype', 'HP:0002583', (116, 123))	('Faecalibacterium', 'Var', (16, 32))	('improved', 'PosReg', (74, 82))	('response', 'MPA', (83, 91))	('colitis', 'Disease', 'MESH:D003092', (116, 123))
170289	30002656	For melanoma patients receiving PD1ab therapy, enrichment of Ruminococcaceae and Clostridiales was found in responders whereas Bacteriodales were enriched in non-responders.	('patients', 'Species', '9606', (13, 21))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))	('PD1ab', 'Var', (32, 37))
170303	30002656	It is worth mentioning that in a retrospective analysis of metastatic melanoma patients, PD-L1 expression was linked to improved OS irrespective of treatment type; this raises the possibility of a prognostic rather than a predictive value for ICI.	('melanoma', 'Disease', (70, 78))	('improved', 'PosReg', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('expression', 'Var', (95, 105))	('PD-L1', 'Gene', (89, 94))	('patients', 'Species', '9606', (79, 87))	('OS', 'Chemical', '-', (129, 131))	('ICI', 'Chemical', '-', (243, 246))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
170315	30002656	The presence of TILs has prognostic potential for different tumor entities regardless of tumor stage.	('tumor entities regardless of tumor', 'Disease', 'MESH:D009369', (60, 94))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('presence', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor entities regardless of tumor', 'Disease', (60, 94))
170316	30002656	For patients with metastatic melanoma, TILs were associated with a better outcome for primary melanoma and metastatic disease, irrespective of treatment type.	('primary melanoma', 'Disease', (86, 102))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('TILs', 'Var', (39, 43))	('patients', 'Species', '9606', (4, 12))	('metastatic disease', 'Disease', (107, 125))	('primary melanoma', 'Disease', 'MESH:D008545', (86, 102))
170322	30002656	Preliminary investigations on TCR clonality of TILs in melanoma metastases revealed higher clonal expansion of TCR for PD1ab-responders compared with non-responders.	('TCR', 'Gene', '6962', (30, 33))	('TCR', 'biological_process', 'GO:0006283', ('111', '114'))	('TCR', 'Gene', (111, 114))	('TCR', 'cellular_component', 'GO:0042101', ('111', '114'))	('PD1ab-responders', 'Var', (119, 135))	('TCR', 'cellular_component', 'GO:0042101', ('30', '33'))	('melanoma metastases', 'Disease', (55, 74))	('TCR', 'Gene', (30, 33))	('clonal', 'MPA', (91, 97))	('TCR', 'Gene', '6962', (111, 114))	('TCR', 'biological_process', 'GO:0006283', ('30', '33'))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma metastases', 'Disease', 'MESH:D009362', (55, 74))	('higher', 'PosReg', (84, 90))
170326	30002656	A significantly longer PFS and OS were observed for patients with high IFN-gamma expression.	('OS', 'Chemical', '-', (31, 33))	('IFN-gamma', 'Gene', '3458', (71, 80))	('IFN-gamma', 'Gene', (71, 80))	('patients', 'Species', '9606', (52, 60))	('high', 'Var', (66, 70))	('longer', 'PosReg', (16, 22))	('PFS', 'MPA', (23, 26))
170328	30002656	Primary mutations in IFN-gamma signaling pathways (e.g., JAK1 and JAK2 mutations) have been described for several tumor entities.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('JAK', 'molecular_function', 'GO:0004713', ('57', '60'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('JAK1', 'Gene', (57, 61))	('JAK1', 'Gene', '3716', (57, 61))	('JAK2', 'Gene', '3717', (66, 70))	('tumor', 'Disease', (114, 119))	('mutations', 'Var', (71, 80))	('IFN-gamma', 'Gene', '3458', (21, 30))	('JAK', 'molecular_function', 'GO:0004713', ('66', '69'))	('JAK2', 'Gene', (66, 70))	('IFN-gamma', 'Gene', (21, 30))
170329	30002656	For cutaneous melanomas, JAK1/2 mutations were detected before treatment in 21% of tissue specimens.	('JAK1/2', 'Gene', '3716;3717', (25, 31))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (4, 23))	('JAK', 'molecular_function', 'GO:0004713', ('25', '28'))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (4, 23))	('cutaneous melanomas', 'Disease', (4, 23))	('JAK1/2', 'Gene', (25, 31))	('mutations', 'Var', (32, 41))	('melanomas', 'Phenotype', 'HP:0002861', (14, 23))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
170330	30002656	Interestingly, patients with resistance to ICI were found to harbor JAK mutations with consecutive loss of IFN-gamma pathways.	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (15, 23))	('IFN-gamma', 'Gene', '3458', (107, 116))	('IFN-gamma', 'Gene', (107, 116))	('JAK', 'molecular_function', 'GO:0004713', ('68', '71'))	('loss', 'NegReg', (99, 103))	('ICI', 'Chemical', '-', (43, 46))
170332	30002656	The first notion that mutational changes might affect tumor response came with the observation that melanoma patients with a high mutation rate benefitted more from ipilimumab treatment than patients with a low one, resulting in longer OS.	('patients', 'Species', '9606', (191, 199))	('ipilimumab', 'Chemical', 'MESH:D000074324', (165, 175))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('benefitted', 'PosReg', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('longer OS', 'MPA', (229, 238))	('affect', 'Reg', (47, 53))	('OS', 'Chemical', '-', (236, 238))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('tumor', 'Disease', (54, 59))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('mutation rate', 'Var', (130, 143))
170335	30002656	Stratification according to mismatch repair deficiency and mismatch-repair proficiency revealed a 40% response for patients with mismatch-repair deficiency (MSI high, dMMR), whereas mismatch-repair proficient patients did not respond at all.	('patients', 'Species', '9606', (115, 123))	('MSI', 'Disease', 'None', (157, 160))	('mismatch-repair', 'biological_process', 'GO:0006298', ('59', '74'))	('mismatch-repair', 'biological_process', 'GO:0006298', ('129', '144'))	('MSI', 'Disease', (157, 160))	('patients', 'Species', '9606', (209, 217))	('mismatch-repair deficiency', 'Var', (129, 155))	('mismatch-repair', 'biological_process', 'GO:0006298', ('182', '197'))	('mismatch repair', 'biological_process', 'GO:0006298', ('28', '43'))
170336	30002656	Whereas mismatch-repair deficiency can be found in gastrointestinal and genitourinary tumors, it is of minor significance for melanoma.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mismatch-repair deficiency', 'Var', (8, 34))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('gastrointestinal and genitourinary tumors', 'Disease', 'MESH:D014565', (51, 92))	('found', 'Reg', (42, 47))	('genitourinary tumors', 'Phenotype', 'HP:0007379', (72, 92))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('mismatch-repair', 'biological_process', 'GO:0006298', ('8', '23'))
170338	30002656	Here, a high mutational load seems to result in prolonged OS in particular, whereas no correlation with response to PD1ab was observed.	('result', 'Reg', (38, 44))	('prolonged', 'Disease', (48, 57))	('high mutational load', 'Var', (8, 28))	('OS', 'Chemical', '-', (58, 60))
170339	30002656	This is in agreement with the observation that melanoma patients treated with PD1ab survive longer even when not responding to the treatment.	('patients', 'Species', '9606', (56, 64))	('PD1ab', 'Var', (78, 83))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))
170342	30002656	Clonal neoantigens in particular might significantly affect ICI outcome.	('ICI', 'Disease', (60, 63))	('affect', 'Reg', (53, 59))	('ICI', 'Chemical', '-', (60, 63))	('Clonal', 'Var', (0, 6))
170344	30002656	Specific types of mutations might be more frequent, e.g., the frameshift insertion and deletion count was found to be associated with ICI response for melanoma.	('frameshift insertion', 'Var', (62, 82))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('associated', 'Reg', (118, 128))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('ICI response', 'Disease', (134, 146))	('deletion count', 'Var', (87, 101))	('ICI', 'Chemical', '-', (134, 137))
170346	30002656	Tumor antigen presentation is essential for the immune defense of cancer, and mutations affecting pathways important for antigen presentation, e.g., beta-2-microglobuline (B2M) loss, might result in ICI resistance.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor antigen', 'molecular_function', 'GO:0008222', ('0', '13'))	('antigen presentation', 'biological_process', 'GO:0019882', ('6', '26'))	('ICI', 'Chemical', '-', (199, 202))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('B2M', 'Gene', (172, 175))	('antigen presentation', 'biological_process', 'GO:0019882', ('121', '141'))	('B2M', 'Gene', '567', (172, 175))	('loss', 'NegReg', (177, 181))	('mutations', 'Var', (78, 87))	('result in', 'Reg', (189, 198))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('ICI resistance', 'Disease', (199, 213))	('cancer', 'Disease', (66, 72))
170347	30002656	B2M mutations are more frequent for melanoma, bladder, gastric, and lung cancer in particular, with 27-50% found for these cancers in The Cancer Genome Atlas dataset compared with 1.8% across all tumor types.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('bladder', 'Disease', (46, 53))	('tumor', 'Disease', (196, 201))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('Cancer', 'Phenotype', 'HP:0002664', (138, 144))	('B2M', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('Cancer', 'Disease', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('lung cancer', 'Disease', (68, 79))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('frequent', 'Reg', (23, 31))	('gastric', 'Disease', (55, 62))	('B2M', 'Gene', '567', (0, 3))	('mutations', 'Var', (4, 13))	('Cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))
170351	30002656	In a retrospective analysis from the pre-ICI era, NRAS mutations, which are seen in up to 20% of melanomas, were found to be associated with worse OS.	('OS', 'Chemical', '-', (147, 149))	('ICI', 'Chemical', '-', (41, 44))	('melanomas', 'Disease', 'MESH:D008545', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanomas', 'Phenotype', 'HP:0002861', (97, 106))	('mutations', 'Var', (55, 64))	('NRAS', 'Gene', (50, 54))	('pre', 'molecular_function', 'GO:0003904', ('37', '40'))	('associated', 'Reg', (125, 135))	('NRAS', 'Gene', '4893', (50, 54))	('worse OS', 'Disease', (141, 149))	('melanomas', 'Disease', (97, 106))
170354	30002656	The NF-1 mutation, which is associated with UV damage and high mutational load, was linked to higher incidence of response and prolonged survival for PD1ab-treated patients.	('mutation', 'Var', (9, 17))	('response', 'MPA', (114, 122))	('NF-1', 'Gene', '4763', (4, 8))	('NF-1', 'Gene', (4, 8))	('UV damage', 'Disease', 'MESH:C563466', (44, 53))	('patients', 'Species', '9606', (164, 172))	('higher', 'PosReg', (94, 100))	('UV damage', 'Disease', (44, 53))
170355	30002656	A more favorable response to PD1ab therapy was observed for desmoplastic melanomas which are characterized by a high mutational load and frequent NF-1 mutations; it should be mentioned that this observation was also made from retrospective assessment.	('NF-1', 'Gene', '4763', (146, 150))	('desmoplastic melanomas', 'Disease', 'MESH:D008545', (60, 82))	('NF-1', 'Gene', (146, 150))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('desmoplastic melanomas', 'Disease', (60, 82))	('mutations', 'Var', (151, 160))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
170356	30002656	For NSCLC, single-gene mutation analysis showed that the presence of an EGFR-mutation seems to be a negative predictor for PD1ab response.	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('negative', 'NegReg', (100, 108))	('EGFR', 'Gene', '1956', (72, 76))	('EGFR', 'Gene', (72, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (4, 9))	('presence', 'Var', (57, 65))	('NSCLC', 'Disease', (4, 9))
170391	30002656	developed the anti-PD-1 tracers 89Zr-keytruda and 64Cu-keytruda; these were evaluated in a humanized NOD-scid mouse model, and uptake in tumors and lymphoid tissue was observed for human melanoma tumors.	('human', 'Species', '9606', (181, 186))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('melanoma tumors', 'Disease', (187, 202))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('64Cu-keytruda', 'Var', (50, 63))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('mouse', 'Species', '10090', (110, 115))	('uptake', 'biological_process', 'GO:0098657', ('127', '133'))	('melanoma tumors', 'Disease', 'MESH:D008545', (187, 202))	('uptake', 'biological_process', 'GO:0098739', ('127', '133'))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('human', 'Species', '9606', (91, 96))
170399	30002656	Several factors might affect response to ICI treatment, including mutational load, tumor microenvironment, and stool microbiome.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('ICI', 'Chemical', '-', (41, 44))	('mutational load', 'Var', (66, 81))	('response', 'MPA', (29, 37))	('tumor', 'Disease', (83, 88))	('affect', 'Reg', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
170424	26778300	Several studies have shown a correlation between genomic alterations in DNA damage pathways and response to platinum therapy in mUC, though none have been prospectively validated[.	('platinum', 'Chemical', 'MESH:D010984', (108, 116))	('DNA damage pathways', 'Pathway', (72, 91))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('genomic alterations', 'Var', (49, 68))	('response to platinum', 'biological_process', 'GO:0070541', ('96', '116'))
170432	26778300	Genomic alterations of BRCA1, BRCA2, and RAD51 are associated with poor prognosis in multiple cancers.	('multiple cancers', 'Disease', 'MESH:D009369', (85, 101))	('RAD', 'biological_process', 'GO:1990116', ('41', '44'))	('RAD51', 'Gene', (41, 46))	('RAD51', 'Gene', '5888', (41, 46))	('BRCA2', 'Gene', '675', (30, 35))	('associated', 'Reg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('BRCA2', 'Gene', (30, 35))	('Genomic alterations', 'Var', (0, 19))	('BRCA1', 'Gene', '672', (23, 28))	('multiple cancers', 'Disease', (85, 101))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('BRCA1', 'Gene', (23, 28))
170433	26778300	Conversely, alterations in these genes also correlate with increased response rates (RR) to platinum chemotherapy as they may enhance chemotherapy-induced DNA damage.	('enhance', 'PosReg', (126, 133))	('DNA', 'cellular_component', 'GO:0005574', ('155', '158'))	('alterations', 'Var', (12, 23))	('response rates', 'MPA', (69, 83))	('chemotherapy-induced DNA damage', 'MPA', (134, 165))	('platinum', 'Chemical', 'MESH:D010984', (92, 100))	('increased', 'PosReg', (59, 68))
170439	26778300	The aim of our study was to assess the value of variant expression of ERCC1, RAD51, BRCA1/2, PAR, and PARP-1, with OS through multispectral image analysis.	('PAR', 'Gene', '10899', (102, 105))	('PAR', 'Gene', (93, 96))	('ERCC1', 'Gene', (70, 75))	('OS', 'Chemical', '-', (115, 117))	('ERCC1', 'Gene', '2067', (70, 75))	('BRCA1/2', 'Gene', (84, 91))	('RAD', 'biological_process', 'GO:1990116', ('77', '80'))	('PAR', 'Gene', (102, 105))	('RAD51', 'Gene', (77, 82))	('PAR', 'Gene', '10899', (93, 96))	('PARP-1', 'Gene', '142', (102, 108))	('BRCA1/2', 'Gene', '672;675', (84, 91))	('PARP-1', 'Gene', (102, 108))	('variant', 'Var', (48, 55))	('RAD51', 'Gene', '5888', (77, 82))
170467	26778300	Patients with less than 79% of nuclei staining had a significantly longer OS on multivariate analysis [HR=2.7 (1.5, 4.9), p=0.0007] (Figure 2).	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (74, 76))	('less than 79%', 'Var', (14, 27))	('longer', 'PosReg', (67, 73))
170471	26778300	Less than 50% nuclear staining was significantly associated with a longer OS on multivariate analysis [HR=5.6 (1.7, 18.3), p=0.005] (Figure 4).	('OS', 'Chemical', '-', (74, 76))	('Less than 50%', 'Var', (0, 13))	('longer', 'Disease', (67, 73))
170483	26778300	It is hypothesized that dysfunction of these pathways, through mutations or reduced protein expression, results in an increased RR to platinum chemotherapy in mUC.	('mutations', 'Var', (63, 72))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('dysfunction', 'Var', (24, 35))	('increased', 'PosReg', (118, 127))	('RR to platinum chemotherapy', 'MPA', (128, 155))	('reduced', 'NegReg', (76, 83))	('protein', 'Protein', (84, 91))	('platinum', 'Chemical', 'MESH:D010984', (134, 142))
170518	26778300	Synthetic lethality occurs when one alteration to a gene promotes cell viability, while alteration of two genes leads to cell death.	('alteration', 'Var', (36, 46))	('death', 'Disease', 'MESH:D003643', (126, 131))	('cell viability', 'CPA', (66, 80))	('death', 'Disease', (126, 131))	('cell death', 'biological_process', 'GO:0008219', ('121', '131'))	('alteration', 'Var', (88, 98))	('promotes', 'PosReg', (57, 65))
170521	26778300	It may also be possible that combined expression or mutation of multiple DNA repair markers, including RAD51 and ERCC1 may have stronger prediction power than individual markers.	('RAD51', 'Gene', (103, 108))	('ERCC1', 'Gene', '2067', (113, 118))	('RAD', 'biological_process', 'GO:1990116', ('103', '106'))	('RAD51', 'Gene', '5888', (103, 108))	('mutation', 'Var', (52, 60))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('ERCC1', 'Gene', (113, 118))	('DNA repair', 'biological_process', 'GO:0006281', ('73', '83'))
170522	26778300	This hypothesis also supports the potential clinical efficacy of PARP-1 inhibitors combined with chemotherapy in mUC.	('PARP-1', 'Gene', (65, 71))	('inhibitors', 'Var', (72, 82))	('PARP-1', 'Gene', '142', (65, 71))	('mUC', 'Disease', (113, 116))
170544	27339696	Further, recurrent HBV integration at the KMT2B locus is present in three liver tumors, but absent in their matched adjacent normal samples, indicating that viral integration induced host driver genetic alterations are required on top of viral oncogene expression for initiation and progression of liver hepatocellular carcinoma.	('liver tumors', 'Disease', (74, 86))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (298, 328))	('liver hepatocellular carcinoma', 'Disease', (298, 328))	('KMT2B', 'Gene', '9757', (42, 47))	('liver tumors', 'Phenotype', 'HP:0002896', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('integration', 'Var', (23, 34))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (304, 328))	('KMT2B', 'Gene', (42, 47))	('liver tumors', 'Disease', 'MESH:D008113', (74, 86))	('HBV', 'Gene', (19, 22))
170545	27339696	Notably, viral integrations were found in many genes, including novel recurrent HPV integrations at PTPN13 in cervical cancer.	('cervical cancer', 'Disease', (110, 125))	('found', 'Reg', (33, 38))	('HPV', 'Species', '10566', (80, 83))	('PTPN13', 'Gene', '5783', (100, 106))	('HPV integrations', 'Var', (80, 96))	('PTPN13', 'Gene', (100, 106))	('cervical cancer', 'Disease', 'MESH:D002583', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
170546	27339696	Finally, we observed a set of HHV4 and HBV variants strongly associated with ethnic groups, likely due to viral sequence evolution under environmental influences.	('HBV', 'Gene', (39, 42))	('HHV4', 'Species', '10376', (30, 34))	('HHV4', 'Gene', (30, 34))	('variants', 'Var', (43, 51))	('associated', 'Reg', (61, 71))
170549	27339696	The Cancer Genome Atlas (TCGA) Pan-Cancer project has discovered numerous somatic mutations in key cancer genes.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('mutations', 'Var', (82, 91))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Disease', (35, 41))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Cancer Genome Atlas', 'Disease', (4, 23))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('Cancer', 'Disease', 'MESH:D009369', (35, 41))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
170561	27339696	Three important issues are explicitly addressed in the present study: 1) differential viral expression and integration patterns between tumors and adjacent normal samples, 2) the discovery and implications of novel rare viral insertions and 3) differences among ethnicities that may point to environmental influences on viral sequence evolution.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('viral', 'MPA', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('insertions', 'Var', (226, 236))	('integration', 'MPA', (107, 118))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('differences', 'Reg', (244, 255))
170581	27339696	However, we did observe some exceptional cases that were positive for two different viruses, for example, one STAD case having HHV4 and HHV5, one LIHC case having HBV and HPV16 (Fig.	('HHV5', 'Var', (136, 140))	('HPV16', 'Species', '333760', (171, 176))	('HHV4', 'Species', '10376', (127, 131))	('HHV5', 'Species', '10359', (136, 140))	('HHV4', 'Var', (127, 131))
170582	27339696	S3A) and one BLCA with having HPV6 and HPV11 (Fig.	('HPV11', 'Var', (39, 44))	('HPV6', 'Var', (30, 34))	('HPV11', 'Species', '10580', (39, 44))	('HPV', 'Species', '10566', (30, 33))	('HPV', 'Species', '10566', (39, 42))
170588	27339696	The clinical-pathological information shows that patient DD-A1EH with only HBV in adjacent normal has a family history of cancer, and sample DD-A11A with HBV in tumor has no family history of cancer, which may indicate different cancer etiologies, i.e., inherited mutations and HBV infection, respectively.	('DD-A1EH', 'Var', (57, 64))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('patient', 'Species', '9606', (49, 56))	('HBV infection', 'Disease', (278, 291))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('HBV infection', 'Disease', 'MESH:D006509', (278, 291))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
170606	27339696	Importantly, in these six tumors, we found three samples with HBV virus integration in KMT2B (MLL4), suggesting the integration sites in this gene are important for the development of liver cancer, consistent with other studies.	('important', 'Reg', (151, 160))	('integration', 'Var', (72, 83))	('KMT2B', 'Gene', '9757', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('liver cancer', 'Phenotype', 'HP:0002896', (184, 196))	('MLL4', 'Gene', '9757', (94, 98))	('MLL4', 'Gene', (94, 98))	('liver cancer', 'Disease', 'MESH:D006528', (184, 196))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('KMT2B', 'Gene', (87, 92))	('liver cancer', 'Disease', (184, 196))	('tumors', 'Disease', (26, 32))
170617	27339696	For instance, we found that EBER-1 is highly expressed in BR-8676.	('EBER-1', 'Gene', (28, 34))	('BR-8676', 'Var', (58, 65))	('BR', 'Chemical', 'MESH:D001966', (58, 60))
170621	27339696	Because disruption of apoptosis can lead to tumor initiation, progression, or metastasis, RNA2.7 can be regarded as a viral oncogene.	('disruption', 'Var', (8, 18))	('lead to', 'Reg', (36, 43))	('apoptosis', 'biological_process', 'GO:0006915', ('22', '31'))	('progression', 'CPA', (62, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('22', '31'))	('tumor initiation', 'Disease', 'MESH:D009369', (44, 60))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('RNA', 'cellular_component', 'GO:0005562', ('90', '93'))	('metastasis', 'CPA', (78, 88))	('apoptosis', 'Protein', (22, 31))	('tumor initiation', 'Disease', (44, 60))
170627	27339696	E6/E7 were involved in binding and degrading p53/Rb proteins and their expression suggests that HPV16 may also play a role in the tumorgenesis in these LGG samples.	('tumor', 'Disease', (130, 135))	('expression', 'MPA', (71, 81))	('E6/E7', 'Var', (0, 5))	('p53', 'Gene', (45, 48))	('play', 'Reg', (111, 115))	('p53', 'Gene', '7157', (45, 48))	('HPV16', 'Species', '333760', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('binding', 'molecular_function', 'GO:0005488', ('23', '30'))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('LGG', 'Disease', (152, 155))	('HPV16', 'Gene', (96, 101))	('binding', 'Interaction', (23, 30))	('degrading', 'NegReg', (35, 44))
170628	27339696	Discordant read pair analysis using Pindel (see Methods) revealed a battery of genes having recurrent HPV integrations in several cancers (Fig.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('integrations', 'Var', (106, 118))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('HPV', 'Species', '10566', (102, 105))
170636	27339696	The second hotpot of recurrent virus integration is at the RAD51B locus in 8 CESC samples, which include 3 samples with HPV16, 2 samples with HPV39, one with HPV18 and one with HPV45; interestingly, two HNSC tumors also harbor HPV16 integration at RAD51B.	('RAD51B', 'Gene', (59, 65))	('RAD51B', 'Gene', '5890', (248, 254))	('RAD51B', 'Gene', '5890', (59, 65))	('HNSC tumors', 'Disease', (203, 214))	('RAD51B', 'Gene', (248, 254))	('HPV', 'Species', '10566', (227, 230))	('HPV16', 'Species', '333760', (120, 125))	('HPV', 'Species', '10566', (142, 145))	('RAD', 'biological_process', 'GO:1990116', ('248', '251'))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('HPV', 'Species', '10566', (177, 180))	('HPV16 integration', 'Var', (227, 244))	('HPV16', 'Species', '333760', (227, 232))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('HNSC tumors', 'Disease', 'MESH:D009369', (203, 214))	('RAD', 'biological_process', 'GO:1990116', ('59', '62'))	('HPV', 'Species', '10566', (158, 161))	('HPV', 'Species', '10566', (120, 123))
170637	27339696	Whole-genome sequencing analysis reveals that HPV integration amplifies the somatic copy number of this region.	('HPV', 'Species', '10566', (46, 49))	('integration', 'Var', (50, 61))	('amplifies', 'PosReg', (62, 71))	('HPV', 'Gene', (46, 49))
170642	27339696	Three samples (C5-A1M9, DS-A7WF, LP-A5U3) with viral integration at ERBB2 locus showed significantly increased expression across all exons (P-value < 0.05) (Fig.	('increased', 'PosReg', (101, 110))	('viral integration', 'Var', (47, 64))	('ERBB2', 'Gene', '2064', (68, 73))	('ERBB2', 'Gene', (68, 73))	('expression', 'MPA', (111, 121))
170651	27339696	4C, HPV18 integrates at intron 1 of PTPN13 in sample EK-A2PK, while HPV16 integrates at exons 2 and 14 for samples WL-A834 and VS-A8QC, respectively.	('HPV', 'Species', '10566', (4, 7))	('integrates', 'Reg', (10, 20))	('PTPN13', 'Gene', (36, 42))	('HPV16', 'Species', '333760', (68, 73))	('VS-A8QC', 'Var', (127, 134))	('HPV18', 'Gene', (4, 9))	('integrates', 'Reg', (74, 84))	('HPV16', 'Gene', (68, 73))	('HPV', 'Species', '10566', (68, 71))	('PTPN13', 'Gene', '5783', (36, 42))
170652	27339696	The distinct virus integration sites and the consistent increase of the expression of the integrated or nearby exons provide strong evidence of novel recurrent HPV integrations within PTPN13.	('increase', 'PosReg', (56, 64))	('integrations', 'Var', (164, 176))	('expression', 'MPA', (72, 82))	('PTPN13', 'Gene', '5783', (184, 190))	('HPV', 'Species', '10566', (160, 163))	('HPV', 'Gene', (160, 163))	('PTPN13', 'Gene', (184, 190))
170657	27339696	For example, TERT was recently implicated by somatic events or viral integration in hepatocarcinogensis.	('TERT', 'Gene', (13, 17))	('hepatocarcinogensis', 'Disease', (84, 103))	('TERT', 'Gene', '7015', (13, 17))	('hepatocarcinogensis', 'Disease', 'None', (84, 103))	('viral integration', 'Var', (63, 80))
170658	27339696	Figure 4D and Table S2 show that the integration sites on KMT2B are between exon 3 and exon 8 and integrations often lead to increased expression of exons following these sites; this holds true for TERT, as well (Fig.	('increased', 'PosReg', (125, 134))	('KMT2B', 'Gene', '9757', (58, 63))	('TERT', 'Gene', '7015', (198, 202))	('integrations', 'Var', (98, 110))	('KMT2B', 'Gene', (58, 63))	('TERT', 'Gene', (198, 202))	('expression of exons', 'MPA', (135, 154))
170662	27339696	The average number of variants for HHV4, HBV and HPV16 are 121, 52 and 22, respectively.	('HBV', 'Gene', (41, 44))	('HHV4', 'Species', '10376', (35, 39))	('HHV4', 'Gene', (35, 39))	('HPV16', 'Gene', (49, 54))	('variants', 'Var', (22, 30))	('HPV16', 'Species', '333760', (49, 54))
170664	27339696	Using RPHM >= 1000 and sites with coverage >10X, we selected 50 variant sites for HBV across 50 HBV-positive LIHC samples, 101 variants across 24 HHV4-positive STAD samples, 17 variants across 60 HPV16-postive HNSC samples and 22 variants across 142 HPV16-positive CESC samples.	('variants', 'Var', (127, 135))	('HBV', 'Gene', (82, 85))	('HPV16', 'Species', '333760', (250, 255))	('HHV4', 'Species', '10376', (146, 150))	('variant', 'Var', (64, 71))	('HPV16', 'Species', '333760', (196, 201))
170665	27339696	Figure 5A shows the unsupervised clustering results for HHV4 variants across HHV4-positive samples with Caucasian and Asian cohorts separated in distinct groups.	('HHV4', 'Species', '10376', (56, 60))	('HHV4', 'Gene', (56, 60))	('HHV4-positive', 'Gene', (77, 90))	('HHV4', 'Species', '10376', (77, 81))	('variants', 'Var', (61, 69))
170666	27339696	Three variants, C   T at sites 343 and 454 and G   A at site 633, result in amino acid substitutions, L418F and P455S in HBV polymerase protein and R160K in S protein, respectively.	('S protein', 'Protein', (157, 166))	('R160K', 'Mutation', 'rs1222267645', (148, 153))	('R160K', 'Var', (148, 153))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('P455S', 'Var', (112, 117))	('HBV', 'Gene', (121, 124))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('P455S', 'Mutation', 'p.P455S', (112, 117))	('L418F', 'Mutation', 'p.L418F', (102, 107))	('L418F', 'Var', (102, 107))
170667	27339696	Variants C   T at sites 505 and 586 and A   G at site 616 are missense mutations, which lead to the respective amino acid substitutions H472Y, R499W and I509 V in HBV polymerase.	('R499W', 'Var', (143, 148))	('I509 V', 'Mutation', 'p.I509V', (153, 159))	('R499W', 'Mutation', 'rs199530208', (143, 148))	('H472Y', 'Mutation', 'p.H472Y', (136, 141))	('I509 V', 'Var', (153, 159))	('H472Y', 'Var', (136, 141))	('HBV polymerase', 'Enzyme', (163, 177))
170668	27339696	Finally, the tumor and adjacent normal pairs have the same variants for the sites observed in Fig.	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', (13, 18))	('variants', 'Var', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
170669	27339696	5B, except for sample DD-A116, in which HBV found in the tumor has an additional variant (A   G) at site 1034, leading to an amino acid substitution Q648R in the HBV polymerase.	('Q648R', 'Var', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Q648R', 'Mutation', 'rs1057519862', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('HBV polymerase', 'Enzyme', (162, 176))	('tumor', 'Disease', (57, 62))
170670	27339696	We also examined viral variation by cancer type by comparing HPV16 variants between CESC and HNSC samples.	('comparing', 'Reg', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('HPV16', 'Gene', (61, 66))	('HPV16', 'Species', '333760', (61, 66))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('examined', 'Reg', (8, 16))	('variants', 'Var', (67, 75))
170672	27339696	Most HPV16 variants overlap between the two cancer types, which suggests they reflect population diversity rather than tissue origin.	('HPV16', 'Gene', (5, 10))	('HPV16', 'Species', '333760', (5, 10))	('variants', 'Var', (11, 19))	('overlap', 'Reg', (20, 27))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
170675	27339696	We did not observe any strong correlation between HPV16 variants and ethnic group.	('HPV16', 'Species', '333760', (50, 55))	('HPV16', 'Gene', (50, 55))	('variants', 'Var', (56, 64))
170678	27339696	HPV subtypes in BLCA are HPV45, HPV51, HPV56 and HPV6 and virus abundance in four samples is especially high (RPHM > 104).	('HPV45', 'Var', (25, 30))	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Species', '10566', (25, 28))	('HPV', 'Species', '10566', (49, 52))	('HPV51', 'Var', (32, 37))	('HPV6', 'Var', (49, 53))	('HPV', 'Species', '10566', (32, 35))	('HPV', 'Species', '10566', (39, 42))	('HPV56', 'Var', (39, 44))
170688	27339696	For instance, recurrent HBV integrations in the KMT2B (MLL4) were observed in tumors, but none in adjacent normal samples.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('KMT2B', 'Gene', '9757', (48, 53))	('HBV', 'Gene', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MLL4', 'Gene', '9757', (55, 59))	('MLL4', 'Gene', (55, 59))	('integrations', 'Var', (28, 40))	('KMT2B', 'Gene', (48, 53))
170696	27339696	In addition, the analyses of virus variants in tumor samples reveal the association of virus variants and ethnicity groups for HBV in LIHC and HHV4 in STAD.	('HBV', 'Gene', (127, 130))	('HHV4', 'Gene', (143, 147))	('association', 'Interaction', (72, 83))	('variants', 'Var', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('LIHC', 'Disease', (134, 138))	('tumor', 'Disease', (47, 52))	('HHV4', 'Species', '10376', (143, 147))
170716	27339696	We used the contml tool from the PHYLIP toolkit (http://evolution.genetics.washington.edu/phylip.html) to construct phylogenetic trees based on variant allele fraction for HBV and HHV4.	('HHV4', 'Gene', (180, 184))	('variant', 'Var', (144, 151))	('HBV', 'Gene', (172, 175))	('HHV4', 'Species', '10376', (180, 184))
170729	26797093	However, RNU increases the risk of renal function decline and cardiovascular events and affects the eligibility for adjuvant chemotherapy.	('renal function decline', 'Disease', (35, 57))	('RNU', 'Var', (9, 12))	('affects', 'Reg', (88, 95))	('RNU', 'Chemical', '-', (9, 12))	('cardiovascular events', 'Phenotype', 'HP:0001626', (62, 83))	('cardiovascular events', 'CPA', (62, 83))	('renal function decline', 'Disease', 'MESH:D007674', (35, 57))
170806	32398651	It has been proposed that ACSS3 acts as an important prognosis biomarker in gastric cancer and ACSS3 serves as a biomarker to stratify subtypes of hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', (147, 171))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (147, 171))	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('ACSS3', 'Var', (95, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (147, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('gastric cancer', 'Disease', (76, 90))
170849	32398651	Then block the membrane with 5% non-fat milk, incubated with primary antibodies at 4  C overnight and followed by secondary antibody for 1 h. The primary antibodies used were as follows: anti-ACSS1 (Invitrogen, PA5-59392), anti-ACSS2 (Cell Signaling Technology, 3568 S), anti-ACSS3 (Invitrogen, PA5-80305), anti-Tubulin (Proteintech, 66031-1), anti-acetyl-histone H4 (Millipore, 06-598), anti-histone H3 (CST, 4499), anti-acetyl-histone H3 (Millipore, 06-599), and anti-histone H4 (CST, 13919).	('antibody', 'molecular_function', 'GO:0003823', ('124', '132'))	('histone H4', 'Gene', (356, 366))	('anti-acetyl-histone', 'Var', (417, 436))	('ACSS2', 'Gene', (228, 233))	('acetyl-histone', 'Chemical', '-', (349, 363))	('acetyl-histone', 'Chemical', '-', (422, 436))	('ACSS2', 'Gene', '55902', (228, 233))	('ACSS1', 'Gene', '84532', (192, 197))	('antibody', 'cellular_component', 'GO:0042571', ('124', '132'))	('histone H4', 'Gene', (470, 480))	('histone H4', 'Gene', '8361', (356, 366))	('antibody', 'cellular_component', 'GO:0019814', ('124', '132'))	('antibody', 'cellular_component', 'GO:0019815', ('124', '132'))	('ACSS1', 'Gene', (192, 197))	('Signaling', 'biological_process', 'GO:0023052', ('240', '249'))	('histone H4', 'Gene', '8361', (470, 480))	('membrane', 'cellular_component', 'GO:0016020', ('15', '23'))
170861	32398651	Although the growth of BLCA cells (UMUC3 and T24) was not affected by C75 treatment in full serum, we observed that the growth of BLCA cells cultured in low serum was significantly inhibited by C75 administration (Fig.	('BLCA', 'Phenotype', 'HP:0009725', (23, 27))	('BLCA', 'Phenotype', 'HP:0009725', (130, 134))	('inhibited', 'NegReg', (181, 190))	('BLCA', 'Chemical', '-', (130, 134))	('C75', 'Var', (194, 197))	('BLCA', 'Chemical', '-', (23, 27))	('growth', 'CPA', (120, 126))
170874	32398651	Meanwhile, the protein level of ACSS1 and ACSS2 were not changed when ACSS3 was knocked down by siRNA (Fig.	('ACSS1', 'Gene', '84532', (32, 37))	('knocked', 'Var', (80, 87))	('ACSS3', 'Gene', (70, 75))	('ACSS1', 'Gene', (32, 37))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('ACSS2', 'Gene', (42, 47))	('ACSS2', 'Gene', '55902', (42, 47))
170876	32398651	Cell number counting revealed that ACSS3 knockdown significantly inhibited cell proliferation in both normoxia and hypoxia conditions (Fig.	('hypoxia', 'Disease', 'MESH:D000860', (115, 122))	('ACSS3', 'Gene', (35, 40))	('inhibited', 'NegReg', (65, 74))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('knockdown', 'Var', (41, 50))	('hypoxia', 'Disease', (115, 122))	('cell proliferation', 'CPA', (75, 93))
170878	32398651	Importantly, a significant reduction was found in the lipogenic AcCoA from 13C-acetate (Fig.	('lipogenic AcCoA', 'MPA', (54, 69))	('AcCoA', 'Chemical', 'MESH:D000105', (64, 69))	('13C-acetate', 'Chemical', '-', (75, 86))	('13C-acetate', 'Var', (75, 86))	('reduction', 'NegReg', (27, 36))
170884	32398651	Our results showed that ACSS3 knockdown attenuated acetate consumption from the medium (Fig.	('acetate', 'Chemical', 'MESH:D000085', (51, 58))	('acetate consumption', 'MPA', (51, 70))	('knockdown', 'Var', (30, 39))	('ACSS3', 'Gene', (24, 29))	('attenuated', 'NegReg', (40, 50))
170887	32398651	We next calculated the ratio of acetate release and consumption in BLCA cells transfected with control siRNA or ACSS3 siRNA and found that this ratio was markedly increased in BLCA cells transfected with ACSS3 siRNA (Fig.	('increased', 'PosReg', (163, 172))	('consumption', 'MPA', (52, 63))	('BLCA', 'Chemical', '-', (176, 180))	('BLCA', 'Chemical', '-', (67, 71))	('acetate release', 'MPA', (32, 47))	('BLCA', 'Phenotype', 'HP:0009725', (176, 180))	('ACSS3', 'Var', (204, 209))	('acetate', 'Chemical', 'MESH:D000085', (32, 39))	('BLCA', 'Phenotype', 'HP:0009725', (67, 71))
170888	32398651	3b), further suggesting that ACSS3 facilitated acetate metabolism in cancer cells.	('acetate metabolism', 'biological_process', 'GO:0006083', ('47', '65'))	('ACSS3', 'Var', (29, 34))	('acetate', 'Chemical', 'MESH:D000085', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('facilitated', 'PosReg', (35, 46))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('acetate metabolism', 'MPA', (47, 65))	('cancer', 'Disease', (69, 75))
170898	32398651	The tumor growth of the xenografts formed by BLCA cells expressing ACSS3 shRNA was significantly inhibited in comparison with xenografts formed by BLCA cells expressing control shRNA or xenografts formed by BLCA cells without doxycycline treatment (Fig.	('tumor', 'Disease', (4, 9))	('BLCA', 'Chemical', '-', (147, 151))	('BLCA', 'Chemical', '-', (45, 49))	('ACSS3 shRNA', 'Var', (67, 78))	('BLCA', 'Phenotype', 'HP:0009725', (147, 151))	('BLCA', 'Chemical', '-', (207, 211))	('BLCA', 'Phenotype', 'HP:0009725', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('inhibited', 'NegReg', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('doxycycline', 'Chemical', 'MESH:D004318', (226, 237))	('BLCA', 'Phenotype', 'HP:0009725', (207, 211))
170903	32398651	Taken together, our analysis illustrated that the expression of ACSS3 was statistically elevated in BLCA patients and high ACSS3 level predicted poor outcome of BCLA prognosis.	('high', 'Var', (118, 122))	('BLCA', 'Chemical', '-', (100, 104))	('patients', 'Species', '9606', (105, 113))	('elevated', 'PosReg', (88, 96))	('BLCA', 'Phenotype', 'HP:0009725', (100, 104))	('BLCA', 'Disease', (100, 104))	('ACSS3', 'Gene', (64, 69))	('expression', 'MPA', (50, 60))
170918	32398651	It is of special significance to further determine the role of methylated ACSS3 in the progression of BLCA.	('BLCA', 'Phenotype', 'HP:0009725', (102, 106))	('ACSS3', 'Gene', (74, 79))	('BLCA', 'Disease', (102, 106))	('methylated', 'Var', (63, 73))	('BLCA', 'Chemical', '-', (102, 106))
170924	32398651	In addition to the data illustrating that inhibition of ACSS3 suppressed xenograft formation in mice, we also analyzed clinical samples and found that the expression of ACSS3 was significantly increased in BLCA samples compared with adjacent normal tissues.	('ACSS3', 'Gene', (56, 61))	('BLCA', 'Chemical', '-', (206, 210))	('mice', 'Species', '10090', (96, 100))	('xenograft formation in mice', 'CPA', (73, 100))	('formation', 'biological_process', 'GO:0009058', ('83', '92'))	('ACSS3', 'Gene', (169, 174))	('BLCA', 'Phenotype', 'HP:0009725', (206, 210))	('expression', 'MPA', (155, 165))	('inhibition', 'Var', (42, 52))	('suppressed', 'NegReg', (62, 72))	('increased', 'PosReg', (193, 202))
170929	32398651	More importantly, ACSS3 facilitates the acetate utilization and histone acetylation in metabolic stressed BLCA cells and promotes BLCA cell growth.	('acetate', 'Chemical', 'MESH:D000085', (40, 47))	('BLCA', 'Phenotype', 'HP:0009725', (130, 134))	('BLCA', 'Phenotype', 'HP:0009725', (106, 110))	('facilitates', 'PosReg', (24, 35))	('acetate utilization', 'MPA', (40, 59))	('ACSS3', 'Var', (18, 23))	('BLCA cell growth', 'CPA', (130, 146))	('promotes', 'PosReg', (121, 129))	('stress', 'Disease', (97, 103))	('histone acetylation', 'MPA', (64, 83))	('stress', 'Disease', 'MESH:D000079225', (97, 103))	('histone acetylation', 'biological_process', 'GO:0016573', ('64', '83'))	('cell growth', 'biological_process', 'GO:0016049', ('135', '146'))	('acetate utilization', 'biological_process', 'GO:0019427', ('40', '59'))	('BLCA', 'Chemical', '-', (130, 134))	('BLCA', 'Chemical', '-', (106, 110))
170978	32099387	3195T, 5741T, 13116T, 9116T, 12231T, 8685T, 8828s, 5023T, 3498T and 9964T, respectively; 1: 1000 dilution for each; Cell Signaling Technology).	('9964T', 'Var', (68, 73))	('5741T', 'Var', (7, 12))	('5023T', 'Var', (51, 56))	('3498T', 'CellLine', 'CVCL:F114', (58, 63))	('13116T', 'Var', (14, 20))	('9116T', 'Var', (22, 27))	('12231T', 'Var', (29, 35))	('Signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('9116T', 'CellLine', 'CVCL:3174', (22, 27))	('3498T', 'Var', (58, 63))	('3195T', 'Var', (0, 5))	('8828s', 'Var', (44, 49))	('8685T', 'Var', (37, 42))
170997	32099387	Subsequently, a PrognoScan online analysis demonstrated that patients with high NUSAP1 expression had shorter 5-year metastasis-free survival rates than those with low NUSAP1 expression (Figure 1G).	('shorter', 'NegReg', (102, 109))	('expression', 'Var', (87, 97))	('5-year metastasis-free survival rates', 'CPA', (110, 147))	('NUSAP1', 'Gene', '51203', (168, 174))	('high', 'Var', (75, 79))	('NUSAP1', 'Gene', (168, 174))	('patients', 'Species', '9606', (61, 69))	('NUSAP1', 'Gene', '51203', (80, 86))	('NUSAP1', 'Gene', (80, 86))
170999	32099387	Therefore, these results indicate that NUSAP1 expression is significantly upregulated in BLCA and that high NUSAP1 expression predicts a poor prognosis in BLCA patients.	('patients', 'Species', '9606', (160, 168))	('upregulated', 'PosReg', (74, 85))	('NUSAP1', 'Gene', '51203', (108, 114))	('BLCA', 'Disease', 'MESH:D001749', (89, 93))	('BLCA', 'Phenotype', 'HP:0009725', (89, 93))	('BLCA', 'Disease', (89, 93))	('expression', 'MPA', (115, 125))	('NUSAP1', 'Gene', (108, 114))	('BLCA', 'Disease', 'MESH:D001749', (155, 159))	('high', 'Var', (103, 107))	('NUSAP1', 'Gene', '51203', (39, 45))	('BLCA', 'Disease', (155, 159))	('expression', 'MPA', (46, 56))	('BLCA', 'Phenotype', 'HP:0009725', (155, 159))	('NUSAP1', 'Gene', (39, 45))
171001	32099387	The results revealed that NUSAP1 expression was significantly lower in 5637 cells in the siRNA3 group than in the normal control and other siRNA groups (Figure 2A and B).	('siRNA3', 'Var', (89, 95))	('lower', 'NegReg', (62, 67))	('expression', 'MPA', (33, 43))	('NUSAP1', 'Gene', '51203', (26, 32))	('NUSAP1', 'Gene', (26, 32))
171007	32099387	These results indicated that high NUSAP1 expression significantly enhanced the proliferative capacity of BLCA cells.	('high', 'Var', (29, 33))	('NUSAP1', 'Gene', (34, 40))	('NUSAP1', 'Gene', '51203', (34, 40))	('BLCA', 'Disease', (105, 109))	('expression', 'MPA', (41, 51))	('enhanced', 'PosReg', (66, 74))	('BLCA', 'Disease', 'MESH:D001749', (105, 109))	('BLCA', 'Phenotype', 'HP:0009725', (105, 109))
171022	32099387	We found that the cell migration and invasion abilities were markedly increased in the 5637-NC and T24-NUSAP1 groups, while those abilities were apparently decreased in the 5637-siNUSAP1 and T24-NC groups (Figure 4B-E).	('increased', 'PosReg', (70, 79))	('NUSAP1', 'Gene', '51203', (103, 109))	('cell migration', 'CPA', (18, 32))	('NUSAP1', 'Gene', '51203', (180, 186))	('NUSAP1', 'Gene', (103, 109))	('NUSAP1', 'Gene', (180, 186))	('invasion abilities', 'CPA', (37, 55))	('5637-NC', 'Var', (87, 94))	('cell migration', 'biological_process', 'GO:0016477', ('18', '32'))
171031	32099387	In addition, silencing NUSAP1 in 5637 cells resulted in decreases in TGFBR1, p-Smad2/3, vimentin, and N-cadherin but an increase in E-cadherin; however, NUSAP1 overexpression in T24 cells resulted in increases in TGFBR1, p-Smad2/3, vimentin and N-cadherin and a decrease in E-cadherin (Figure 5D).	('vimentin', 'cellular_component', 'GO:0045099', ('88', '96'))	('E-cadherin', 'MPA', (274, 284))	('NUSAP1', 'Gene', (23, 29))	('cadherin', 'molecular_function', 'GO:0008014', ('134', '142'))	('Smad2', 'Gene', '4087', (223, 228))	('Smad2', 'Gene', '4087', (79, 84))	('TGFBR1', 'Gene', '7046', (213, 219))	('TGFBR1', 'Gene', (213, 219))	('in T', 'Gene', (210, 214))	('N-cadherin', 'MPA', (245, 255))	('vimentin', 'Gene', '7431', (88, 96))	('vimentin', 'cellular_component', 'GO:0045098', ('232', '240'))	('vimentin', 'Gene', '7431', (232, 240))	('increases', 'PosReg', (200, 209))	('Smad2', 'Gene', (79, 84))	('vimentin', 'Gene', (232, 240))	('NUSAP1', 'Gene', (153, 159))	('vimentin', 'Gene', (88, 96))	('Smad2', 'Gene', (223, 228))	('in T', 'Gene', '27152', (210, 214))	('silencing', 'Var', (13, 22))	('TGFBR1', 'Gene', '7046', (69, 75))	('NUSAP1', 'Gene', '51203', (23, 29))	('TGFBR1', 'Gene', (69, 75))	('vimentin', 'cellular_component', 'GO:0045098', ('88', '96'))	('cadherin', 'molecular_function', 'GO:0008014', ('247', '255'))	('in T', 'Gene', (66, 70))	('N-cadherin', 'MPA', (102, 112))	('cadherin', 'molecular_function', 'GO:0008014', ('104', '112'))	('in T', 'Gene', (175, 179))	('cadherin', 'molecular_function', 'GO:0008014', ('276', '284'))	('in T', 'Gene', '27152', (66, 70))	('overexpression', 'PosReg', (160, 174))	('vimentin', 'cellular_component', 'GO:0045099', ('232', '240'))	('decreases', 'NegReg', (56, 65))	('2/3, vimentin,', 'Gene', '7431', (83, 97))	('decrease', 'NegReg', (262, 270))	('in T', 'Gene', '27152', (175, 179))	('increase', 'PosReg', (120, 128))	('NUSAP1', 'Gene', '51203', (153, 159))	('E-cadherin', 'MPA', (132, 142))
171032	32099387	SB525334 inhibited TGFBR1 in NUSAP1-overexpressing T24 cells, and cell invasion and metastasis abilities were also significantly suppressed (Figure 5E-H); p-Smad2/3 and vimentin expression was also reduced following treatment (Figure 5I).	('inhibited', 'NegReg', (9, 18))	('suppressed', 'NegReg', (129, 139))	('Smad2', 'Gene', '4087', (157, 162))	('vimentin', 'cellular_component', 'GO:0045099', ('169', '177'))	('SB525334', 'Var', (0, 8))	('SB525334', 'Chemical', 'MESH:C521813', (0, 8))	('TGFBR1', 'Gene', '7046', (19, 25))	('Smad2', 'Gene', (157, 162))	('vimentin', 'Gene', '7431', (169, 177))	('TGFBR1', 'Gene', (19, 25))	('metastasis abilities', 'Disease', 'MESH:D009362', (84, 104))	('vimentin', 'Gene', (169, 177))	('NUSAP1', 'Gene', '51203', (29, 35))	('reduced', 'NegReg', (198, 205))	('NUSAP1', 'Gene', (29, 35))	('metastasis abilities', 'Disease', (84, 104))	('vimentin', 'cellular_component', 'GO:0045098', ('169', '177'))
171038	32099387	Similarly, high NUSAP1 expression levels promoted astrocytoma progression through the Hedgehog signaling pathway.	('Hedgehog signaling pathway', 'biological_process', 'GO:0007224', ('86', '112'))	('promoted', 'PosReg', (41, 49))	('astrocytoma', 'Disease', 'MESH:D001254', (50, 61))	('astrocytoma', 'Phenotype', 'HP:0009592', (50, 61))	('high', 'Var', (11, 15))	('expression levels', 'MPA', (23, 40))	('astrocytoma', 'Disease', (50, 61))	('NUSAP1', 'Gene', (16, 22))	('NUSAP1', 'Gene', '51203', (16, 22))	('Hedgehog signaling pathway', 'Pathway', (86, 112))
171040	32099387	In colorectal cancer, NUSAP1 knockdown induced apoptosis and inhibited tumor cell migration, invasion, cell proliferation and EMT by inhibiting the expression of DNA methyltransferase 1 (DNMT1), indicating that NUSAP1 can be used as an independent prognostic biomarker.	('(DNMT1', 'Gene', '1786', (186, 192))	('inhibited', 'NegReg', (61, 70))	('knockdown', 'Var', (29, 38))	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('inhibiting', 'NegReg', (133, 143))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('apoptosis', 'CPA', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('colorectal cancer', 'Disease', (3, 20))	('EMT', 'CPA', (126, 129))	('NUSAP1', 'Gene', (211, 217))	('invasion', 'CPA', (93, 101))	('cell proliferation', 'CPA', (103, 121))	('cell migration', 'biological_process', 'GO:0016477', ('77', '91'))	('NUSAP1', 'Gene', '51203', (22, 28))	('DNMT1', 'Gene', (187, 192))	('induced', 'Reg', (39, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('methyltransferase 1', 'molecular_function', 'GO:0047152', ('166', '185'))	('DNA', 'cellular_component', 'GO:0005574', ('162', '165'))	('EMT', 'biological_process', 'GO:0001837', ('126', '129'))	('tumor', 'Disease', (71, 76))	('NUSAP1', 'Gene', '51203', (211, 217))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('expression', 'MPA', (148, 158))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('NUSAP1', 'Gene', (22, 28))
171041	32099387	In prostate cancer, high NUSAP1 expression promoted prostate cancer cell proliferation and invasion with the loss of RB1 via the RB1/E2F1 axis.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('RB1', 'Gene', (117, 120))	('invasion', 'CPA', (91, 99))	('NUSAP1', 'Gene', (25, 31))	('promoted', 'PosReg', (43, 51))	('NUSAP1', 'Gene', '51203', (25, 31))	('loss', 'NegReg', (109, 113))	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('high', 'Var', (20, 24))	('prostate cancer', 'Disease', (3, 18))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))	('prostate cancer', 'Disease', (52, 67))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
171045	32099387	Moreover, the GSE13507 database revealed that patients with high NUSAP1 expression had shorter 5-year metastasis-free survival rates.	('patients', 'Species', '9606', (46, 54))	('high', 'Var', (60, 64))	('5-year metastasis-free survival rates', 'CPA', (95, 132))	('expression', 'MPA', (72, 82))	('shorter', 'NegReg', (87, 94))	('NUSAP1', 'Gene', (65, 71))	('NUSAP1', 'Gene', '51203', (65, 71))
171052	32099387	Similarly, a previous report illustrated that SHOX2 acts as a transcription factor to upregulate TGFBR1 expression, and the TGFBR1 inhibitor LY364497 abolishes EMT induction by ectopic SHOX2 expression, suggesting that TGF-beta signaling is essential for SHOX2-induced EMT.	('TGFBR1', 'Gene', '7046', (124, 130))	('TGFBR1', 'Gene', '7046', (97, 103))	('TGFBR1', 'Gene', (124, 130))	('TGFBR1', 'Gene', (97, 103))	('SHOX2', 'Gene', (185, 190))	('abolishes', 'NegReg', (150, 159))	('signaling', 'biological_process', 'GO:0023052', ('228', '237'))	('LY364497', 'Chemical', '-', (141, 149))	('LY364497', 'Var', (141, 149))	('expression', 'MPA', (104, 114))	('transcription', 'biological_process', 'GO:0006351', ('62', '75'))	('EMT', 'biological_process', 'GO:0001837', ('269', '272'))	('EMT', 'biological_process', 'GO:0001837', ('160', '163'))	('EMT induction', 'CPA', (160, 173))	('upregulate', 'PosReg', (86, 96))	('transcription factor', 'molecular_function', 'GO:0000981', ('62', '82'))
171057	32099387	As expected, we found that silencing NUSAP1 in cells caused TGFBR1, Smad2/3, vimentin and N-cadherin downregulation and E-cadherin upregulation.	('downregulation', 'NegReg', (101, 115))	('E-cadherin', 'Protein', (120, 130))	('cadherin', 'molecular_function', 'GO:0008014', ('122', '130'))	('upregulation', 'PosReg', (131, 143))	('silencing', 'Var', (27, 36))	('vimentin', 'cellular_component', 'GO:0045099', ('77', '85'))	('vimentin', 'cellular_component', 'GO:0045098', ('77', '85'))	('vimentin', 'Gene', '7431', (77, 85))	('cadherin', 'molecular_function', 'GO:0008014', ('92', '100'))	('TGFBR1', 'Gene', (60, 66))	('NUSAP1', 'Gene', (37, 43))	('Smad2/3', 'Protein', (68, 75))	('NUSAP1', 'Gene', '51203', (37, 43))	('N-cadherin', 'Protein', (90, 100))	('vimentin', 'Gene', (77, 85))
171059	32099387	Next, SB525334 inhibited TGFBR1 in NUSAP1-overexpressing T24 cells, and cell invasion and metastasis were significantly suppressed; p-Smad2/3 and EMT-associated protein expression levels were also decreased.	('inhibited', 'NegReg', (15, 24))	('suppressed', 'NegReg', (120, 130))	('SB525334', 'Var', (6, 14))	('SB525334', 'Chemical', 'MESH:C521813', (6, 14))	('Smad2', 'Gene', '4087', (134, 139))	('NUSAP1', 'Gene', '51203', (35, 41))	('EMT', 'biological_process', 'GO:0001837', ('146', '149'))	('Smad2', 'Gene', (134, 139))	('2/3 and EMT-', 'Gene', '3702', (138, 150))	('NUSAP1', 'Gene', (35, 41))	('decreased', 'NegReg', (197, 206))	('TGFBR1', 'Gene', '7046', (25, 31))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('TGFBR1', 'Gene', (25, 31))
171135	31398895	Similar results were found regarding the Recurrence Free Survival (RFS) for pT2 or higher tumors as shown in Abe et al., where RFS was significantly higher in pN0 patients compared to pNx patients.	('patients', 'Species', '9606', (163, 171))	('pN0', 'Var', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('patients', 'Species', '9606', (188, 196))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('RFS', 'MPA', (127, 130))	('higher', 'PosReg', (149, 155))
171147	31398895	Indeed, investigators proved in a subgroup multivariate analysis limited to patients with locally advanced disease that pN0 patients' diseases have a significantly lower risk of recurrence (HR: 0.3; p < 0.001) and death (HR: 0.3; p < 0.001) when compared with pNx.	('pN0', 'Var', (120, 123))	('death', 'Disease', (214, 219))	('recurrence', 'MPA', (178, 188))	('patients', 'Species', '9606', (76, 84))	('lower', 'NegReg', (164, 169))	('patients', 'Species', '9606', (124, 132))	('death', 'Disease', 'MESH:D003643', (214, 219))
171176	31398895	They showed that a Lymph node Density >=30% was associated with a greater five-year recurrence rate (25% vs. 38%; HR: 1,8; p = 0.021) and a greater five-year cancer-specific mortality rate (30% vs. 48%; HR: 1.7; p = 0.032).	('>=30', 'Var', (38, 42))	('greater', 'PosReg', (140, 147))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('recurrence', 'CPA', (84, 94))
171192	31398895	This study also shows a probable therapeutic role of lymph node dissection with an interest in the survival of pN0 patients compared to pNx subgroup (treatment of subclinical metastases) and interest in pN+ patients (treatment of lymph node invasion).	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (207, 215))	('metastases', 'Disease', (175, 185))	('pN0', 'Var', (111, 114))	('metastases', 'Disease', 'MESH:D009362', (175, 185))
171197	31261684	AA is believed to cause its carcinogenicity through forming DNA adducts of deoxyadenosine-aristolactam, as well as A:T   T:A transversions in the TP53 tumor suppressor gene.	('tumor suppressor', 'biological_process', 'GO:0051726', ('151', '167'))	('TP53', 'Gene', '7157', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('deoxyadenosine-aristolactam', 'Chemical', '-', (75, 102))	('tumor', 'Disease', (151, 156))	('TP53', 'Gene', (146, 150))	('carcinogenic', 'Disease', 'MESH:D063646', (28, 40))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('151', '167'))	('carcinogenic', 'Disease', (28, 40))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('transversions', 'Var', (125, 138))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
171203	31261684	Although UTUC and UCB shared tobacco exposure as one of their main risk factors, the consumption of aristolochic acid (AA), which had been a common component of Chinese medicines and certain weight-losing medications, was identified as a depictive environmental factor associated more with UTUC rather than UCB.	('tobacco', 'Species', '4097', (29, 36))	('weight-losing', 'Phenotype', 'HP:0001824', (191, 204))	('aristolochic acid', 'Chemical', 'MESH:C000228', (100, 117))	('aristolochic acid', 'Var', (100, 117))	('UTUC', 'Disease', (290, 294))	('UCB', 'Phenotype', 'HP:0006740', (18, 21))	('UCB', 'Chemical', '-', (18, 21))	('UCB', 'Phenotype', 'HP:0006740', (307, 310))	('UCB', 'Chemical', '-', (307, 310))
171216	31261684	Within patients diagnosed with UTUC, only those from AA-endemic regions were found with AA-derived DNA adducts, accompanied by high frequencies of mutations of A:T pairs of the TP53 gene.	('mutations', 'Var', (147, 156))	('TP53', 'Gene', '7157', (177, 181))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('TP53', 'Gene', (177, 181))	('patients', 'Species', '9606', (7, 15))
171218	31261684	In addition, mutations in the TP53 gene were identified in 40% of patients from AA-endemic areas, with over half of these mutations being an A:T   T:A transversion mutation.	('TP53', 'Gene', (30, 34))	('mutations', 'Var', (122, 131))	('mutations', 'Var', (13, 22))	('TP53', 'Gene', '7157', (30, 34))	('patients', 'Species', '9606', (66, 74))
171223	31261684	Besides, UTUC cases were further found with more microsatellite instability and hypermethylation compared with UCB, while their frequencies of certain genomic alterations, such as alternations in the TP53 and CDKN2A genes, also diverge.	('microsatellite instability', 'MPA', (49, 75))	('hypermethylation', 'MPA', (80, 96))	('alternations', 'Var', (180, 192))	('TP53', 'Gene', '7157', (200, 204))	('TP53', 'Gene', (200, 204))	('CDKN2A', 'Gene', (209, 215))	('CDKN2A', 'Gene', '1029', (209, 215))	('UCB', 'Phenotype', 'HP:0006740', (111, 114))	('UCB', 'Chemical', '-', (111, 114))
171225	31261684	Besides their distinct etiologies and the resultant difference in mutations, UTUC may further differ from UCB in terms of clinical modality.	('mutations', 'Var', (66, 75))	('UTUC', 'Disease', (77, 81))	('UCB', 'Phenotype', 'HP:0006740', (106, 109))	('UCB', 'Chemical', '-', (106, 109))
171234	31261684	For instance, it was reported that in 388 patients who underwent RNU, their postoperative mean estimated glomerular filtration rate was 24% lower than their preoperative one, and this further excluded about one-third of eligible candidates for postoperative chemotherapy.	('RNU', 'Chemical', '-', (65, 68))	('lower', 'NegReg', (140, 145))	('estimated glomerular filtration rate', 'MPA', (95, 131))	('glomerular filtration', 'biological_process', 'GO:0003094', ('105', '126'))	('excluded', 'NegReg', (192, 200))	('RNU', 'Var', (65, 68))	('patients', 'Species', '9606', (42, 50))
171249	31261684	Other biomarkers that predict the outcome of ICI therapies include higher mutation load, gene expression profiling linked to interferon gamma signaling, as well as densities and subtypes of tumor-infiltrating cytotoxic T lymphocytes.	('gene expression', 'biological_process', 'GO:0010467', ('89', '104'))	('mutation', 'Var', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('signaling', 'biological_process', 'GO:0023052', ('142', '151'))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('interferon gamma', 'molecular_function', 'GO:0005133', ('125', '141'))	('tumor', 'Disease', (190, 195))
171253	31261684	Interestingly, it has been known that genes representing luminal subtype are highly expressed in UTUC, which were also found to be associated with an elevated incidence of mutations in TP53 signaling, a greater genomic instability, and in non-smokers.	('mutations', 'Var', (172, 181))	('signaling', 'biological_process', 'GO:0023052', ('190', '199'))	('TP53', 'Gene', (185, 189))	('associated', 'Reg', (131, 141))	('genomic instability', 'CPA', (211, 230))	('TP53', 'Gene', '7157', (185, 189))
171264	31261684	The response rate was also higher in the pembrolizumab arm, accounting for 21.1% versus 11.0% in the chemotherapy arm.	('higher', 'PosReg', (27, 33))	('pembrolizumab', 'Chemical', 'MESH:C582435', (41, 54))	('pembrolizumab', 'Var', (41, 54))	('response', 'MPA', (4, 12))
171293	31261684	Importantly, this study also found that patients within the highest quartile of mutation load showed significantly longer survival compared to the other quartiles; whether this may be a hint for the better response in the UTUC subgroup requires further confirmation.	('survival', 'MPA', (122, 130))	('longer', 'PosReg', (115, 121))	('patients', 'Species', '9606', (40, 48))	('mutation load', 'Var', (80, 93))
171296	31261684	Moreover, despite the promising results in these early phase clinical trials, it is important to point out that early reviews of their following clinical trials, which were KEYNOTE-361 and IMvigor-130, found that patients eligible for platinum-containing chemotherapy randomized into the ICI-monotherapy arms with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.	('decreased', 'NegReg', (335, 344))	('PD-L1', 'Gene', (314, 319))	('survival', 'MPA', (345, 353))	('carboplatin', 'Chemical', 'MESH:D016190', (402, 413))	('PD-L1', 'Gene', '29126', (314, 319))	('platinum', 'Chemical', 'MESH:D010984', (235, 243))	('patients', 'Species', '9606', (366, 374))	('low status', 'Var', (320, 330))	('patients', 'Species', '9606', (213, 221))	('cisplatin', 'Chemical', 'MESH:D002945', (388, 397))
171299	31261684	Intriguingly, patients with deleterious somatic DNA damage response mutations had a higher response rate.	('response', 'MPA', (91, 99))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('DNA damage response', 'biological_process', 'GO:0006974', ('48', '67'))	('mutations', 'Var', (68, 77))	('patients', 'Species', '9606', (14, 22))	('higher', 'PosReg', (84, 90))
171301	31261684	So far, the presence of AA-derived DNA adducts and an aberrantly high percentage of A:T   T:A mutations are the most widely-accepted hallmarks to indicate AA-associated UTUC and UCB, as introduced in the previous sections.	('mutations', 'Var', (94, 103))	('UCB', 'Phenotype', 'HP:0006740', (178, 181))	('UCB', 'Chemical', '-', (178, 181))	('UCB', 'Disease', (178, 181))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))
171304	31261684	Although high-grade UTUC was the least frequent subgroup to have a KDM6A mutation, the frequency was still around 20%; whereas the frequency of mutated CREBBP accounted for 16% of all the UC cases.	('CREBBP', 'Gene', (152, 158))	('KDM6A', 'Gene', '7403', (67, 72))	('CREBBP', 'Gene', '1387', (152, 158))	('KDM6A', 'Gene', (67, 72))	('mutation', 'Var', (73, 81))
171306	31261684	found a strong association between mutations of KDM6A and FGFR3 in UCB.	('UCB', 'Disease', (67, 70))	('FGFR3', 'Gene', '2261', (58, 63))	('KDM6A', 'Gene', (48, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('FGFR3', 'Gene', (58, 63))	('KDM6A', 'Gene', '7403', (48, 53))	('UCB', 'Chemical', '-', (67, 70))	('UCB', 'Phenotype', 'HP:0006740', (67, 70))	('mutations', 'Var', (35, 44))
171307	31261684	Although the luminal-papillary subtype of UCB is characterized by FGFR3 mutations and it was reported that the majority of UTUC in the non-endemic area also resembled this subtype of UCB, FGFR3 mutations were noted in only 0-8% of AA-associated UC.	('mutations', 'Var', (72, 81))	('FGFR3', 'Gene', '2261', (188, 193))	('FGFR', 'molecular_function', 'GO:0005007', ('188', '192'))	('FGFR3', 'Gene', '2261', (66, 71))	('FGFR3', 'Gene', (188, 193))	('AA-associated', 'Disease', (231, 244))	('UCB', 'Chemical', '-', (42, 45))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('FGFR3', 'Gene', (66, 71))	('UCB', 'Chemical', '-', (183, 186))	('UCB', 'Phenotype', 'HP:0006740', (42, 45))	('UCB', 'Phenotype', 'HP:0006740', (183, 186))
171308	31261684	Recalling the distinct etiology and biology of UTUC, careful interpretations are needed when drawing an analogy between intrinsic types of UCB to corresponding mutations in UTUC, and further genetic and epigenetic examinations focusing on UTUC and AA-associated UC are warranted.	('UCB', 'Phenotype', 'HP:0006740', (139, 142))	('mutations', 'Var', (160, 169))	('UTUC', 'Gene', (173, 177))	('UCB', 'Disease', (139, 142))	('Recalling', 'Disease', 'MESH:D008569', (0, 9))	('Recalling', 'Disease', (0, 9))	('UCB', 'Chemical', '-', (139, 142))
171309	31261684	Although mutations in certain genes are more common in AA-associated UTUC, current knowledge shows that it is insufficient for them to stand for this etiology specifically, and therefore, they may not serve as good biomarkers to select AA-associated cancers.	('UTUC', 'Disease', (69, 73))	('common', 'Reg', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (250, 257))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('mutations', 'Var', (9, 18))	('cancers', 'Disease', (250, 257))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('AA-associated UTUC', 'Disease', (55, 73))
171311	31261684	Based on the rationale of being effective against tumors with high mutation load, ICIs have generally proven themselves to be safe and at least non-inferior compared to traditional chemotherapy for advanced or metastatic UC.	('high mutation load', 'Var', (62, 80))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
171340	28424325	Based on the preliminary clinical evidence showing a confirmed response rate of 50% (95% CI: 29.3%, 70.7%) in 20 patients with high PD-L1 expression as determined by the prototype assay, atezolizumab received a Breakthrough Therapy designation in May 2014 for the treatment of patients with advanced urothelial carcinoma who have received prior platinum-containing chemotherapy.	('urothelial carcinoma', 'Disease', (300, 320))	('PD-L1', 'Gene', (132, 137))	('high', 'Var', (127, 131))	('patients', 'Species', '9606', (113, 121))	('platinum', 'Chemical', 'MESH:D010984', (345, 353))	('patients', 'Species', '9606', (277, 285))	('PD-L1', 'Gene', '29126', (132, 137))	('atezolizumab', 'Chemical', 'MESH:C000594389', (187, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (300, 320))
171364	28424325	There were 5 CRs (2.4%) in patients with PD-L1 expression of <5% and 12 CRs (12%) in those with PD-L1 expression of >=5%, suggesting that the PD-L1 expression increased the possibility of a CR but did not preclude the development of a CR.	('expression', 'Var', (148, 158))	('PD-L1', 'Gene', '29126', (96, 101))	('CRs', 'Chemical', 'MESH:D002857', (72, 75))	('PD-L1', 'Gene', '29126', (41, 46))	('CR', 'Chemical', 'MESH:D002857', (190, 192))	('PD-L1', 'Gene', '29126', (142, 147))	('CR', 'Chemical', 'MESH:D002857', (13, 15))	('CR', 'Chemical', 'MESH:D002857', (72, 74))	('increased', 'PosReg', (159, 168))	('patients', 'Species', '9606', (27, 35))	('CR', 'Chemical', 'MESH:D002857', (235, 237))	('CRs', 'Chemical', 'MESH:D002857', (13, 16))	('PD-L1', 'Gene', (96, 101))	('PD-L1', 'Gene', (41, 46))	('PD-L1', 'Gene', (142, 147))
171396	28424325	Although the response rate in patients with PD-L1 expression of >=5% in ICs was modestly higher than that in those with PD-L1 expression of <5% in ICs, there were CRs in those with PD-L1 expression of <5%.	('ICs', 'Disease', (72, 75))	('CRs', 'Chemical', 'MESH:D002857', (163, 166))	('expression', 'Var', (50, 60))	('PD-L1', 'Gene', (44, 49))	('PD-L1', 'Gene', (181, 186))	('response', 'MPA', (13, 21))	('higher', 'PosReg', (89, 95))	('PD-L1', 'Gene', (120, 125))	('patients', 'Species', '9606', (30, 38))	('PD-L1', 'Gene', '29126', (120, 125))	('PD-L1', 'Gene', '29126', (44, 49))	('PD-L1', 'Gene', '29126', (181, 186))
171444	33907145	Immunohistochemistry showed positive Ki67 staining, mostly in the basal layer, while p53 staining was rarely positive.	('p53', 'Gene', '7157', (85, 88))	('Ki67', 'Var', (37, 41))	('p53', 'Gene', (85, 88))
171447	33907145	All epithelial tissue layers were ki67 positive, and the p53 positive rate was higher than that in the LG samples.	('ki67', 'Var', (34, 38))	('ki67', 'Chemical', '-', (34, 38))	('p53', 'Gene', (57, 60))	('higher', 'PosReg', (79, 85))	('p53', 'Gene', '7157', (57, 60))
171473	33907145	Immunohistochemical staining for ki67 was positive in all epithelial layers, and its positive rate was higher than that in LG areas.	('positive', 'MPA', (85, 93))	('ki67', 'Chemical', '-', (33, 37))	('ki67', 'Var', (33, 37))	('higher', 'PosReg', (103, 109))
171492	33907145	In bladder cancer, TP53 mutations mostly occur in poorly differentiated tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('occur', 'Reg', (41, 46))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('mutations', 'Var', (24, 33))
171527	30769831	Presence or variations in expression of those molecules could be linked to bladder cancer.	('expression', 'MPA', (26, 36))	('linked', 'Reg', (65, 71))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('variations', 'Var', (12, 22))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))
171545	30769831	These are further examined for chromosomal aberrations observed in bladder cancer: aneuploidy of chromosomes 3, 7, and 17, and a loss of locus 9p21.	('aneuploidy', 'Var', (83, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (31, 54))	('9p21', 'Gene', (143, 147))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('loss of locus', 'NegReg', (129, 142))
171560	30769831	Overexpression of certain cytokeratins is associated with bladder cancer.	('associated', 'Reg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('Overexpression', 'Var', (0, 14))	('bladder cancer', 'Disease', (58, 72))	('cytokeratins', 'Protein', (26, 38))
171579	30769831	As examples of genetic biomarkers for bladder cancer, mutations in the fibroblast growth factor receptor 3 (FGFR3) oncogene are frequent in low-grade non-muscle invasive bladder cancer (NMIBC) tumors.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('71', '95'))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('fibroblast growth factor receptor 3', 'Gene', (71, 106))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('frequent', 'Reg', (128, 136))	('mutations', 'Var', (54, 63))	('invasive bladder', 'Phenotype', 'HP:0100645', (161, 177))	('bladder cancer', 'Disease', 'MESH:D001749', (38, 52))	('bladder cancer', 'Disease', (38, 52))	('MIBC', 'Chemical', '-', (187, 191))	('FGFR3', 'Gene', (108, 113))	('fibroblast growth factor receptor 3', 'Gene', '2261', (71, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (38, 52))	('muscle invasive bladder cancer', 'Disease', (154, 184))	('FGFR3', 'Gene', '2261', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (154, 184))	('bladder cancer', 'Disease', 'MESH:D001749', (170, 184))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('bladder cancer', 'Phenotype', 'HP:0009725', (170, 184))	('tumors', 'Disease', (193, 199))
171580	30769831	Mutations in RAS (Rat sarcoma) oncogenes occur in 13% of all bladder tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('bladder tumors', 'Disease', 'MESH:D001749', (61, 75))	('bladder tumors', 'Phenotype', 'HP:0009725', (61, 75))	('sarcoma', 'Disease', 'MESH:D012509', (22, 29))	('occur', 'Reg', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('Rat', 'Species', '10116', (18, 21))	('bladder tumors', 'Disease', (61, 75))	('Mutations', 'Var', (0, 9))	('sarcoma', 'Disease', (22, 29))	('bladder tumor', 'Phenotype', 'HP:0009725', (61, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('RAS', 'Gene', (13, 16))
171581	30769831	The sensitivity for detecting bladder cancer by FGFR3 mutation analysis was 58% in a study undertaken by Zuiverloon et al.	('mutation analysis', 'Var', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('FGFR3', 'Gene', '2261', (48, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (30, 44))	('bladder cancer', 'Disease', (30, 44))	('FGFR3', 'Gene', (48, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))
171582	30769831	Mutations in p53 genes are seen more often in high-grade NMIBC.	('p53', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('MIBC', 'Chemical', '-', (58, 62))	('high-grade NMIBC', 'Disease', (46, 62))	('p53', 'Gene', '7157', (13, 16))	('seen', 'Reg', (27, 31))
171583	30769831	Mutations in these genes are a strong indicator for bladder cancer.	('bladder cancer', 'Disease', (52, 66))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('Mutations', 'Var', (0, 9))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
171590	30769831	Epigenetic factors also play an important role in the development of bladder cancer and can be also used as biomarkers.	('Epigenetic factors', 'Var', (0, 18))	('bladder cancer', 'Disease', (69, 83))	('bladder cancer', 'Disease', 'MESH:D001749', (69, 83))	('bladder cancer', 'Phenotype', 'HP:0009725', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('men', 'Species', '9606', (61, 64))
171591	30769831	One of those factors are alterations in DNA methylation which may change the gene expression and can ultimately lead to the development and progression of urinary bladder cancer.	('alterations', 'Var', (25, 36))	('gene expression', 'MPA', (77, 92))	('DNA', 'Gene', (40, 43))	('lead to', 'Reg', (112, 119))	('change', 'Reg', (66, 72))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (155, 177))	('men', 'Species', '9606', (131, 134))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('bladder cancer', 'Phenotype', 'HP:0009725', (163, 177))	('gene expression', 'biological_process', 'GO:0010467', ('77', '92'))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('urinary bladder cancer', 'Disease', (155, 177))	('DNA methylation', 'biological_process', 'GO:0006306', ('40', '55'))
171622	30769831	(2015), for example, showed that urothelial cells undergo epithelial-to-mesenchymal transition after exposure to EVs of MIBC.	('MIBC', 'Chemical', '-', (120, 124))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('58', '94'))	('urothelial cells', 'CPA', (33, 49))	('EVs', 'Var', (113, 116))	('epithelial-to-mesenchymal transition', 'CPA', (58, 94))	('undergo', 'Reg', (50, 57))	('MIBC', 'Gene', (120, 124))
171640	30769831	This resulted in the identification of elevated levels of CD36, CD44, 5T4, basigin, and CD73 in bladder cancer.	('levels', 'MPA', (48, 54))	('bladder cancer', 'Disease', 'MESH:D001749', (96, 110))	('CD36', 'MPA', (58, 62))	('CD44', 'Gene', '960', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CD36', 'Species', '42374', (58, 62))	('elevated', 'PosReg', (39, 47))	('CD44', 'Gene', (64, 68))	('bladder cancer', 'Phenotype', 'HP:0009725', (96, 110))	('CD73', 'Var', (88, 92))	('bladder cancer', 'Disease', (96, 110))	('5T4', 'MPA', (70, 73))
171641	30769831	(2014) found that EVs isolated from high-grade bladder cancer cell lines as well as the urine of patients with high-grade bladder cancer promoted angiogenesis and migration of bladder cancer cells and endothelial cells and thus tumor progression.	('bladder cancer', 'Phenotype', 'HP:0009725', (122, 136))	('high-grade', 'Var', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('angiogenesis', 'biological_process', 'GO:0001525', ('146', '158'))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('bladder cancer', 'Phenotype', 'HP:0009725', (176, 190))	('bladder cancer', 'Disease', 'MESH:D001749', (47, 61))	('angiogenesis', 'CPA', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('bladder cancer', 'Disease', (47, 61))	('bladder cancer', 'Phenotype', 'HP:0009725', (47, 61))	('migration', 'CPA', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('patients', 'Species', '9606', (97, 105))	('promoted', 'PosReg', (137, 145))	('bladder cancer', 'Disease', 'MESH:D001749', (122, 136))	('bladder cancer', 'Disease', (122, 136))	('tumor', 'Disease', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('bladder cancer', 'Disease', 'MESH:D001749', (176, 190))	('bladder cancer', 'Disease', (176, 190))
171654	30769831	One of them is HOX transcript antisense RNA (HOTAIR), that facilitates tumor initiation and progression.	('HOTAIR', 'Gene', '100124700', (45, 51))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('facilitates', 'PosReg', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('antisense', 'Var', (30, 39))	('HOTAIR', 'Gene', (45, 51))	('tumor', 'Disease', (71, 76))	('antisense RNA', 'molecular_function', 'GO:0009388', ('30', '43'))
171657	30769831	(2015) identified a number of miRNAs upregulated in urinary EVs from bladder cancer patients, for example, miR-4454, miR-720, miR-21, miR-205-5p, and miR-200c-3p.	('miR-21', 'Gene', (126, 132))	('bladder cancer', 'Disease', 'MESH:D001749', (69, 83))	('bladder cancer', 'Disease', (69, 83))	('upregulated', 'PosReg', (37, 48))	('patients', 'Species', '9606', (84, 92))	('miR-4454', 'Gene', (107, 115))	('miR-205', 'Gene', (134, 141))	('miR-4454', 'Gene', '100616234', (107, 115))	('miR-21', 'Gene', '406991', (126, 132))	('bladder cancer', 'Phenotype', 'HP:0009725', (69, 83))	('miR-205', 'Gene', '406988', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('miRNAs', 'MPA', (30, 36))	('miR-720', 'Var', (117, 124))	('miR-200c-3p', 'Var', (150, 161))
171703	30257981	Each line was treated, in triplicate, with respective agents (cisplatin, obatoclax, 17-AAG, and alisertib) starting at 33 muM followed by 1:10 serial dilutions (3.3 muM, 0.33 muM, 0.033 muM) and DMSO-only control.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('muM', 'Gene', '56925', (165, 168))	('alisertib', 'Chemical', 'MESH:C550258', (96, 105))	('muM', 'Gene', '56925', (122, 125))	('muM', 'Gene', (175, 178))	('muM', 'Gene', (122, 125))	('3.3', 'Var', (161, 164))	('muM', 'Gene', (165, 168))	('DMSO', 'Chemical', 'MESH:D004121', (195, 199))	('muM', 'Gene', '56925', (186, 189))	('17-AAG', 'Chemical', 'MESH:C112765', (84, 90))	('muM', 'Gene', (186, 189))	('muM', 'Gene', '56925', (175, 178))
171704	30257981	In the case of metastatic non-small cell lung cancer (NSCLC) with exon 19 deletions or L858R mutation in EGFR, SOC therapy includes tyrosine-kinase inhibitors (TKIs) such as erlotinib, gefitinib or afatinib, which provide high initial response rates (RR) but to which resistance almost inevitably develops.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (26, 52))	('L858R', 'Var', (87, 92))	('EGFR', 'Gene', (105, 109))	('exon 19 deletions', 'Var', (66, 83))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('deletions', 'Var', (74, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('non-small cell lung cancer', 'Disease', (26, 52))	('SOC', 'biological_process', 'GO:0031578', ('111', '114'))	('NSCLC', 'Disease', (54, 59))	('afatinib', 'Chemical', 'MESH:C522924', (198, 206))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('EGFR', 'Gene', '1956', (105, 109))	('L858R', 'Mutation', 'rs121434568', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (26, 52))	('erlotinib', 'Chemical', 'MESH:C400278', (174, 183))	('SCLC', 'Phenotype', 'HP:0030357', (55, 59))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (30, 52))	('gefitinib', 'Chemical', 'MESH:C419708', (185, 194))	('tyrosine', 'Chemical', 'None', (132, 140))
171705	30257981	In approximately 50% of patient tumors, this resistance is due to the acquisition of a second EGFR mutation, T790M.	('EGFR', 'molecular_function', 'GO:0005006', ('94', '98'))	('EGFR', 'Gene', '1956', (94, 98))	('patient', 'Species', '9606', (24, 31))	('T790M', 'Mutation', 'rs121434569', (109, 114))	('EGFR', 'Gene', (94, 98))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('T790M', 'Var', (109, 114))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
171707	30257981	Specifically, 40% of erlotinib-resistant NSCLC cell lines (IC50 values > ~160 nanomolar (nM)) were sensitive to osimertinib (IC50 values < ~160 nM) and these were the cell lines with T790M EGFR mutations.	('EGFR', 'Gene', '1956', (189, 193))	('T790M', 'Var', (183, 188))	('erlotinib', 'Chemical', 'MESH:C400278', (21, 30))	('NSCLC', 'Disease', (41, 46))	('SCLC', 'Phenotype', 'HP:0030357', (42, 46))	('sensitive', 'MPA', (99, 108))	('EGFR', 'Gene', (189, 193))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('osimertinib', 'Chemical', 'None', (112, 123))	('EGFR', 'molecular_function', 'GO:0005006', ('189', '193'))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('T790M', 'Mutation', 'rs121434569', (183, 188))
171709	30257981	For patients whose leukemia develops resistance to these agents, often via a T315I mutation in BRC-ABL, ponatinib was identified by DISARM as an attractive candidate (Fig.	('T315I', 'Mutation', 'rs121913459', (77, 82))	('T315I', 'Var', (77, 82))	('ponatinib', 'Chemical', 'MESH:C545373', (104, 113))	('leukemia', 'Phenotype', 'HP:0001909', (19, 27))	('patients', 'Species', '9606', (4, 12))	('leukemia', 'Disease', 'MESH:D007938', (19, 27))	('BRC-ABL', 'Gene', (95, 102))	('leukemia', 'Disease', (19, 27))
171717	30257981	The top 31 drugs share numerous targets, including six drugs which target PI3K or mTOR, and multiple drugs targeting AURKA, BCL-2 family proteins, proteasomes and cyclin-dependent kinases.	('BCL-2', 'molecular_function', 'GO:0015283', ('124', '129'))	('BCL-2', 'Gene', '596', (124, 129))	('AURKA', 'Protein', (117, 122))	('cyclin', 'molecular_function', 'GO:0016538', ('163', '169'))	('mTOR', 'Gene', (82, 86))	('mTOR', 'Gene', '2475', (82, 86))	('PI3K', 'molecular_function', 'GO:0016303', ('74', '78'))	('BCL-2', 'Gene', (124, 129))	('PI3K', 'Var', (74, 78))
171724	30257981	Of the cell lines that are sensitive to none of the PI3K/mTOR inhibitors, all five (H2029, H1417, H128, H2330, COR-L88) are sensitive to both agents targeting the BCL-2 pathway.	('BCL-2', 'molecular_function', 'GO:0015283', ('163', '168'))	('H2029', 'Var', (84, 89))	('H128', 'Var', (98, 102))	('PI3K', 'molecular_function', 'GO:0016303', ('52', '56'))	('H2330', 'Chemical', 'MESH:C049902', (104, 109))	('mTOR', 'Gene', (57, 61))	('sensitive', 'Reg', (124, 133))	('BCL-2', 'Gene', '596', (163, 168))	('mTOR', 'Gene', '2475', (57, 61))	('H2330', 'Var', (104, 109))	('H128', 'Chemical', 'MESH:C555346', (98, 102))	('BCL-2', 'Gene', (163, 168))
171767	30257981	Meanwhile, bryostatin-1, a protein kinase-C (PKC) inhibitor, has a superior mean IC50 value in six different malignancies, consistent with previous data suggesting that depletion of PKC can restore cisplatin sensitivity.	('malignancies', 'Disease', 'MESH:D009369', (109, 121))	('depletion', 'Var', (169, 178))	('bryostatin', 'Chemical', 'MESH:D054713', (11, 21))	('PKC', 'molecular_function', 'GO:0004697', ('45', '48'))	('malignancies', 'Disease', (109, 121))	('IC50 value', 'MPA', (81, 91))	('PKC', 'molecular_function', 'GO:0004697', ('182', '185'))	('cisplatin', 'Chemical', 'MESH:D002945', (198, 207))	('cisplatin sensitivity', 'MPA', (198, 219))	('restore', 'PosReg', (190, 197))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))
171768	30257981	DISARM's analyses also revealed several targeted therapies with potentially novel utility across platinum-resistant malignancies including multiple inhibitors of PI3K, mTOR, BCL-2, HSP90, and MEK (Fig.	('mTOR', 'Gene', (168, 172))	('MEK', 'Gene', (192, 195))	('inhibitors', 'Var', (148, 158))	('BCL-2', 'Gene', '596', (174, 179))	('mTOR', 'Gene', '2475', (168, 172))	('MEK', 'Gene', '5609', (192, 195))	('HSP90', 'Gene', (181, 186))	('malignancies', 'Disease', 'MESH:D009369', (116, 128))	('platinum', 'Chemical', 'MESH:D010984', (97, 105))	('malignancies', 'Disease', (116, 128))	('BCL-2', 'Gene', (174, 179))	('BCL-2', 'molecular_function', 'GO:0015283', ('174', '179'))	('HSP90', 'Gene', '3320', (181, 186))	('PI3K', 'molecular_function', 'GO:0016303', ('162', '166'))	('PI3K', 'Gene', (162, 166))
171774	30257981	Specifically, high expression of pS217 MEK1/2 (p=0.01), pT202_Y204 MAPK (p=0.008), pT180 p38 (p=0.003), and p90RSK (p=0.03) (Supplementary Fig.	('p90RSK', 'Gene', '6195', (108, 114))	('p90RSK', 'Gene', (108, 114))	('p38', 'Gene', '1432', (89, 92))	('MEK1', 'molecular_function', 'GO:0004708', ('39', '43'))	('MAPK', 'molecular_function', 'GO:0004707', ('67', '71'))	('pT202_Y204 MAPK', 'Var', (56, 71))	('MEK1/2', 'Gene', '5604;5605', (39, 45))	('p38', 'Gene', (89, 92))	('MEK1/2', 'Gene', (39, 45))
171785	30257981	For 17-AAG, we again selected two cell lines predicted to have cisplatin resistance (H1436 and H2227) that did not appear in our prior GDSC 17-AAG analysis and similarly found that these cell lines were sensitive to 17-AAG but resistant to cisplatin per DISARM (Supplementary Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (240, 249))	('17-AAG', 'Chemical', 'MESH:C112765', (216, 222))	('H2227', 'Chemical', 'MESH:C041320', (95, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('H1436', 'Var', (85, 90))	('17-AAG', 'Chemical', 'MESH:C112765', (4, 10))	('17-AAG', 'Chemical', 'MESH:C112765', (140, 146))	('H2227', 'Var', (95, 100))
171792	30257981	While we confirmed that both models are cisplatin-resistant, we find that NJH29 is alisertib sensitive, while H2227 is alisertib resistant, as predicted by our biomarker analysis (Fig.	('alisertib', 'Chemical', 'MESH:C550258', (119, 128))	('alisertib', 'Chemical', 'MESH:C550258', (83, 92))	('H2227', 'Var', (110, 115))	('H2227', 'Chemical', 'MESH:C041320', (110, 115))	('NJH29', 'Var', (74, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))
171801	30257981	MEK inhibitors are an especially intriguing result from this analysis as targeting MEK has a well-characterized role in overcoming treatment resistance in the case of BRAF inhibitors in BRAF mutant melanoma and lung cancer, ultimately leading to FDA approval of trametinib (melanoma; NSCLC) and cobimetinib (melanoma) for these indications.	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('MEK', 'Gene', (0, 3))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('melanoma', 'Disease', 'MESH:D008545', (274, 282))	('NSCLC', 'Disease', 'MESH:D002289', (284, 289))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (308, 316))	('MEK', 'Gene', '5609', (83, 86))	('melanoma', 'Disease', (308, 316))	('mutant', 'Var', (191, 197))	('NSCLC', 'Disease', (284, 289))	('melanoma and lung cancer', 'Disease', 'MESH:D008175', (198, 222))	('overcoming', 'PosReg', (120, 130))	('treatment resistance', 'MPA', (131, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (284, 289))	('MEK', 'Gene', (83, 86))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('melanoma', 'Disease', (274, 282))	('cobimetinib', 'Chemical', 'MESH:C574276', (295, 306))	('BRAF', 'Gene', '673', (186, 190))	('BRAF', 'Gene', (186, 190))	('SCLC', 'Phenotype', 'HP:0030357', (285, 289))	('trametinib', 'Chemical', 'MESH:C560077', (262, 272))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('MEK', 'Gene', '5609', (0, 3))	('melanoma', 'Disease', 'MESH:D008545', (308, 316))
171807	30257981	For example, DISARM's analysis suggests the use of PI3K and AURKA inhibitors specifically in TTF-1 negative SCLC.	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('PI3K', 'Var', (51, 55))	('SCLC', 'Gene', '7864', (108, 112))	('SCLC', 'Phenotype', 'HP:0030357', (108, 112))	('SCLC', 'Gene', (108, 112))	('TTF-1', 'Gene', (93, 98))	('TTF-1', 'Gene', '7270', (93, 98))	('AURKA', 'Gene', (60, 65))
171823	29617662	Driver Fusions and Their Implications in the Development and Treatment of Human Cancers Gene fusions represent an important class of somatic alterations in cancer.	('Gene fusions', 'Var', (88, 100))	('Human Cancers', 'Disease', (74, 87))	('Human Cancers', 'Disease', 'MESH:D009369', (74, 87))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Cancers', 'Phenotype', 'HP:0002664', (80, 87))
171825	29617662	Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect.	('oncogenes', 'Gene', (104, 113))	('gene expression', 'biological_process', 'GO:0010467', ('15', '30'))	('tumor', 'Disease', (178, 183))	('expression', 'MPA', (140, 150))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('increased', 'PosReg', (130, 139))	('fusions', 'Var', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
171831	29617662	To date, many studies have focused on determining the landscape of SNPs, insertions, deletions, and copy number alterations in cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('deletions', 'Var', (85, 94))	('copy number alterations', 'Var', (100, 123))	('SNPs', 'Var', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('insertions', 'Var', (73, 83))	('cancer', 'Disease', (127, 133))
171832	29617662	Although such genomic alterations make up a large fraction of the typical tumor mutation burden, gene fusions also play a critical role in oncogenesis.	('oncogenesis', 'CPA', (139, 150))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('alterations', 'Var', (22, 33))	('tumor', 'Disease', (74, 79))	('oncogenesis', 'biological_process', 'GO:0007048', ('139', '150'))
171834	29617662	Gene fusions function as diagnostic markers for specific cancer types.	('cancer', 'Disease', (57, 63))	('Gene fusions', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))
171835	29617662	For example, a frequent translocation between chromosomes 11 and 22 creates a fusion between EWSR1 and FLI1 in Ewing's sarcoma.	('fusion', 'Var', (78, 84))	('translocation', 'Var', (24, 37))	('FLI1', 'Gene', (103, 107))	('EWSR1', 'Gene', (93, 98))	('FLI1', 'Gene', '2313', (103, 107))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (111, 126))	('EWSR1', 'Gene', '2130', (93, 98))	("Ewing's sarcoma", 'Disease', (111, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (111, 126))
171842	29617662	performed breakpoint analysis on exon microarrays across 974 cancer samples and identified 198 candidate fusions in annotated cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('fusions', 'Var', (105, 112))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
171844	29617662	Some studies focus on important classes of genes, such as kinase fusions, which may have particular structural properties that are selected for during oncogenesis and cancer progression.	('oncogenesis', 'biological_process', 'GO:0007048', ('151', '162'))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('kinase fusions', 'Var', (58, 72))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
171858	29617662	Fusion events may be associated with altered expression of one or both of the fusion gene partners, a well-known example being multiple myeloma tumors in which translocation t(4;14) fuses the highly expressed IGH locus with the tyrosine protein kinase FGFR3.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('protein', 'cellular_component', 'GO:0003675', ('237', '244'))	('FGFR3', 'Gene', (252, 257))	('myeloma tumors', 'Disease', 'MESH:D009101', (136, 150))	('IGH', 'Gene', '3492', (209, 212))	('FGFR', 'molecular_function', 'GO:0005007', ('252', '256'))	('IGH', 'Gene', (209, 212))	('myeloma tumors', 'Disease', (136, 150))	('multiple myeloma', 'Phenotype', 'HP:0006775', (127, 143))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('FGFR3', 'Gene', '2261', (252, 257))	('translocation t', 'Var', (160, 175))
171860	29617662	Figure 2A shows that between 6% (mesothelioma [MESO]) and 28% (KIRP) of kinase fusions displayed outlier overexpression of the kinase partner.	('fusions', 'Var', (79, 86))	('mesothelioma', 'Disease', 'MESH:D008654', (33, 45))	('overexpression', 'PosReg', (105, 119))	('mesothelioma', 'Disease', (33, 45))
171861	29617662	Oncogenes tended to show higher likelihoods of overexpression, whereas TSGs displayed lower likelihoods.	('Oncogenes', 'Var', (0, 9))	('TSG', 'Gene', '57045', (71, 74))	('overexpression', 'MPA', (47, 61))	('TSG', 'Gene', (71, 74))
171862	29617662	Between 3% (breast invasive carcinoma [BRCA]) and 38% (PCPG) of TSG fusions showed outlier underexpression, generally higher than both oncogenes and kinases.	('BRCA', 'Gene', (39, 43))	('fusions', 'Var', (68, 75))	('TSG', 'Gene', (64, 67))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (12, 37))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (12, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('breast invasive carcinoma', 'Disease', (12, 37))	('BRCA', 'Gene', '672', (39, 43))	('underexpression', 'NegReg', (91, 106))	('TSG', 'Gene', '57045', (64, 67))
171864	29617662	Samples with fusions involving oncogenes, such as EGFR, ERBB2, and RET, showed increased expression of those genes relative to samples without fusions across cancer types.	('increased', 'PosReg', (79, 88))	('expression', 'MPA', (89, 99))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('RET', 'Gene', '5979', (67, 70))	('EGFR', 'Gene', '1956', (50, 54))	('fusions', 'Var', (13, 20))	('cancer', 'Disease', (158, 164))	('ERBB2', 'Gene', '2064', (56, 61))	('EGFR', 'Gene', (50, 54))	('ERBB2', 'Gene', (56, 61))	('RET', 'Gene', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
171868	29617662	For example, TP53 is affected by mutations rather than fusions in most cancer types.	('TP53', 'Gene', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('mutations', 'Var', (33, 42))	('affected', 'Reg', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('TP53', 'Gene', '7157', (13, 17))
171869	29617662	However, in sarcoma (SARC), both fusions and mutations affecting TP53 were detected.	('mutations', 'Var', (45, 54))	('TP53', 'Gene', '7157', (65, 69))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('TP53', 'Gene', (65, 69))	('sarcoma', 'Disease', (12, 19))	('fusions', 'Var', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('detected', 'Reg', (75, 83))
171870	29617662	In acute myeloid leukemia (LAML), several CBFB fusions but no mutations were observed, yet other cancer types also exhibited CBFB mutations (Table S3; Figure S2).	('CBFB', 'Gene', '865', (125, 129))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('cancer', 'Disease', (97, 103))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))	('CBFB', 'Gene', (42, 46))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('exhibited', 'Reg', (115, 124))	('CBFB', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (130, 139))	('fusions', 'Var', (47, 54))	('acute myeloid leukemia', 'Disease', (3, 25))	('CBFB', 'Gene', '865', (42, 46))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
171874	29617662	Recurrent CBFB-MYH11 fusions in LAML are significantly associated with decreased expression of the tumor suppressor CBFB, which functions as a transcriptional regulator (Figure 2D).	('tumor', 'Disease', (99, 104))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('99', '115'))	('CBFB', 'Gene', (10, 14))	('MYH11', 'Gene', '4629', (15, 20))	('MYH11', 'Gene', (15, 20))	('tumor suppressor', 'biological_process', 'GO:0051726', ('99', '115'))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('CBFB', 'Gene', '865', (116, 120))	('fusions', 'Var', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('CBFB', 'Gene', '865', (10, 14))	('decreased', 'NegReg', (71, 80))	('expression', 'MPA', (81, 91))	('CBFB', 'Gene', (116, 120))
171875	29617662	In breast cancer, copy number amplification is a well-known mechanism of ERBB2 overexpression, and treatment of these HER2+ patients with trastuzumab is an established and effective targeted therapy.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('copy number amplification', 'Var', (18, 43))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('HER2', 'Gene', (118, 122))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('HER2', 'Gene', '2064', (118, 122))	('trastuzumab', 'Chemical', 'MESH:D000068878', (138, 149))	('overexpression', 'PosReg', (79, 93))	('ERBB2', 'Gene', (73, 78))	('ERBB2', 'Gene', '2064', (73, 78))	('patients', 'Species', '9606', (124, 132))
171876	29617662	Interestingly, three of four samples with ERBB2 fusions and two samples without a called fusion showed HPV integration within 1 Mb of ERBB2.	('fusions', 'Var', (48, 55))	('ERBB2', 'Gene', '2064', (134, 139))	('ERBB2', 'Gene', (134, 139))	('ERBB2', 'Gene', '2064', (42, 47))	('ERBB2', 'Gene', (42, 47))	('HPV integration', 'CPA', (103, 118))
171879	29617662	Comparison of kinase fusions across different cancer types indicated that kinase fusions are significantly enriched in THCA (35.6%, Fisher's exact test, p < 2.2e-16) (Figure 3B).	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('THCA', 'Disease', (119, 123))	('kinase fusions', 'Var', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
171883	29617662	For example, there are more TK fusions in THCA and GBM, more CK1 fusions in uterine corpus endometrial carcinoma (UCEC), colon adenocarcinoma (COAD), and esophageal carcinoma (ESCA) and more AGC fusions in liver hepatocellular carcinoma (LIHC).	('colon adenocarcinoma', 'Disease', (121, 141))	('TK fusions', 'Var', (28, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (154, 174))	('COAD', 'Disease', (143, 147))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (206, 236))	('CK1', 'Gene', (61, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('esophageal carcinoma', 'Disease', (154, 174))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (91, 112))	('LIHC', 'Disease', (238, 242))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (121, 141))	('corpus endometrial carcinoma', 'Disease', (84, 112))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (84, 112))	('fusions', 'Var', (65, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('CK1', 'Species', '2498238', (61, 64))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (154, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('liver hepatocellular carcinoma', 'Disease', (206, 236))	('LIHC', 'Disease', 'None', (238, 242))	('COAD', 'Disease', 'MESH:D029424', (143, 147))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (212, 236))
171884	29617662	Across different cancer types, we found an enrichment of TK and TKL kinase fusions for 3'-kinases but no strong preference for 5'-kinases (Figure S3).	('TKL', 'Gene', (64, 67))	('fusions', 'Var', (75, 82))	("3'-kinases", 'MPA', (87, 97))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('TKL', 'Gene', '7294', (64, 67))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
171886	29617662	As expected, fusions in the FGFR kinase family (FGFR2 and FGFR3) are the most frequent 5'-kinase fusions, given their high recurrence in individual cancer types (Figure 3C).	('cancer', 'Disease', (148, 154))	('FGFR2', 'Gene', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('FGFR2', 'Gene', '2263', (48, 53))	('FGFR3', 'Gene', '2261', (58, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('FGFR3', 'Gene', (58, 63))	('fusions', 'Var', (13, 20))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))
171896	29617662	For example, we found a TRABD-DDR2 fusion in one head and neck squamous cell carcinoma (HNSC) sample, which fused the stronger TRABD promoter with DDR2, resulting in its overexpression (Figure 4D).	('neck squamous cell carcinoma', 'Disease', (58, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('DDR2', 'Gene', (147, 151))	('DDR2', 'Gene', '4921', (147, 151))	('DDR2', 'Gene', '4921', (30, 34))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (58, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('fusion', 'Var', (35, 41))	('neck', 'cellular_component', 'GO:0044326', ('58', '62'))	('DDR2', 'Gene', (30, 34))	('overexpression', 'PosReg', (170, 184))
171898	29617662	DDR2 fusions were also detected in another nine samples from five different cancer types, which could be treated similarly given sufficient DDR2 overexpression (Table S1).	('fusions', 'Var', (5, 12))	('DDR2', 'Gene', '4921', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('DDR2', 'Gene', '4921', (140, 144))	('DDR2', 'Gene', (140, 144))	('cancer', 'Disease', (76, 82))	('DDR2', 'Gene', (0, 4))	('overexpression', 'PosReg', (145, 159))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
171899	29617662	Although mutations in oncogenes or TSGs may lead to tumorigenesis, fusions involving those genes are also an important class of cancer driver events.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('lead to', 'Reg', (44, 51))	('tumor', 'Disease', (52, 57))	('TSG', 'Gene', '57045', (35, 38))	('mutations', 'Var', (9, 18))	('oncogenes', 'Gene', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('TSG', 'Gene', (35, 38))	('cancer', 'Disease', (128, 134))
171901	29617662	We characterized patients as having a driver mutation, a mutation in a driver gene, and/or a driver fusion (fusion involving a driver gene).	('mutation', 'Var', (57, 65))	('driver fusion', 'Disease', (93, 106))	('driver gene', 'Gene', (71, 82))	('driver', 'Disease', (38, 44))	('patients', 'Species', '9606', (17, 25))
171902	29617662	Although the majority of cancer cases have known driver mutations (48.6%, mean 6.8 mutations) or mutations in driver genes (28.1%, mean 4.2 mutations), we found that 8.3% have both driver mutations and driver fusion events (mean 5.5 mutations and 1.2 fusions), 6.4% have both mutations and fusions in driver genes (mean 4.2 mutations and 1.3 fusions), and 1.8% have driver fusions only (mean 1.1 fusions) (Figure 5A).	('mutations', 'Var', (97, 106))	('mutations', 'Var', (56, 65))	('mutations', 'Var', (324, 333))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (276, 285))	('fusions', 'Var', (290, 297))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))
171904	29617662	The significant decrease in the numbers of mutations (Mann-Whitney U test, p < 2.2e-16) reflects the functionality of fusions across multiple cancer types.	('multiple cancer', 'Disease', (133, 148))	('decrease', 'NegReg', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutations', 'Var', (43, 52))	('multiple cancer', 'Disease', 'MESH:D009369', (133, 148))
171905	29617662	Moreover, within cancer types, we observed a range of 0.2% (HNSC) to 14.0% (LAML) of tumors with fusions but no driver gene mutations.	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('fusions', 'Var', (97, 104))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
171914	29617662	Several Food and Drug Administration (FDA)-approved drugs exist to target ALK fusions in lung and other cancer types.	('ALK', 'Gene', (74, 77))	('lung', 'Disease', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('fusions', 'Var', (78, 85))	('ALK', 'Gene', '238', (74, 77))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
171916	29617662	In most cases, fusion status corresponded to copy number neutral overexpression of ALK (Figure 6D).	('ALK', 'Gene', '238', (83, 86))	('copy number neutral', 'Var', (45, 64))	('corresponded', 'Reg', (29, 41))	('overexpression', 'PosReg', (65, 79))	('ALK', 'Gene', (83, 86))
171919	29617662	We detected ESR1 fusions in 16 samples from five different cancer types (9 samples from BRCA).	('ESR1', 'Gene', '2099', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('fusions', 'Var', (17, 24))	('BRCA', 'Gene', '672', (88, 92))	('ESR1', 'Gene', (12, 16))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('BRCA', 'Gene', (88, 92))	('detected', 'Reg', (3, 11))
171921	29617662	We observed strict mutual exclusivity between ESR1 mutations and fusions (Figure 5C).	('ESR1', 'Gene', (46, 50))	('mutations', 'Var', (51, 60))	('ESR1', 'Gene', '2099', (46, 50))
171926	29617662	Similarly, ESR1 expression is higher when ESR1 is mutated in BRCA, CESC, and UCEC, which are all hormone receptor-related cancer types.	('ESR1', 'Gene', '2099', (11, 15))	('higher', 'PosReg', (30, 36))	('ESR1', 'Gene', (42, 46))	('cancer', 'Disease', (122, 128))	('UCEC', 'Disease', (77, 81))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('CESC', 'Disease', (67, 71))	('hormone receptor', 'Gene', (97, 113))	('ESR1', 'Gene', (11, 15))	('mutated', 'Var', (50, 57))	('hormone receptor', 'Gene', '3164', (97, 113))	('ESR1', 'Gene', '2099', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('BRCA', 'Gene', '672', (61, 65))	('expression', 'MPA', (16, 26))	('BRCA', 'Gene', (61, 65))
171927	29617662	Further functional study to determine the mechanism of ESR1 fusions could suggest drug development directions.	('ESR1', 'Gene', (55, 59))	('ESR1', 'Gene', '2099', (55, 59))	('fusions', 'Var', (60, 67))
171930	29617662	However, patients with known driver fusions may be poor candidates for immunotherapy because of their reduced mutational burden, especially without clear evidence of immune cell infiltration and overall immunogenicity.	('patients', 'Species', '9606', (9, 17))	('reduced', 'NegReg', (102, 109))	('mutational burden', 'MPA', (110, 127))	('fusions', 'Var', (36, 43))
171938	29617662	When comparing fusion events with the remainder of the cancer cohort, fusions involving oncogenes such as EGFR, ERBB2, and RET had increased expression.	('ERBB2', 'Gene', '2064', (112, 117))	('increased', 'PosReg', (131, 140))	('ERBB2', 'Gene', (112, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('106', '110'))	('RET', 'Gene', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('expression', 'MPA', (141, 151))	('RET', 'Gene', '5979', (123, 126))	('EGFR', 'Gene', '1956', (106, 110))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('fusions', 'Var', (70, 77))	('cancer', 'Disease', (55, 61))	('EGFR', 'Gene', (106, 110))
171940	29617662	In addition to well-known recurrent fusions such as FGFR3-TACC3, we also detected 245 kinases with recurrent fusions to different partner genes, which may ultimately prove to be successful drug targets.	('TACC3', 'Gene', '10460', (58, 63))	('FGFR3', 'Gene', '2261', (52, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('TACC3', 'Gene', (58, 63))	('fusions', 'Var', (109, 116))	('FGFR3', 'Gene', (52, 57))
171941	29617662	We showed that a meaningful percentage of patients (1.8%) harbor fusions involving cancer driver genes but have no driver gene mutations.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('patients', 'Species', '9606', (42, 50))	('fusions', 'Var', (65, 72))	('cancer', 'Disease', (83, 89))
171944	29617662	The significant decrease in mutational burden observed in patients with fusions in driver genes points toward a reduced efficacy of immunotherapy in these patients, despite fusion peptides themselves potentially being good immunogenic targets.	('decrease', 'NegReg', (16, 24))	('efficacy of immunotherapy', 'CPA', (120, 145))	('patients', 'Species', '9606', (155, 163))	('mutational burden', 'MPA', (28, 45))	('reduced', 'NegReg', (112, 119))	('patients', 'Species', '9606', (58, 66))	('fusions', 'Var', (72, 79))
171946	29617662	We sought to prioritize fusions relevant to cancer by highlighting their associations with gene expression, potential for targeted therapy, and roles in cancer hallmark pathways.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('gene expression', 'MPA', (91, 106))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('associations', 'Interaction', (73, 85))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('gene expression', 'biological_process', 'GO:0010467', ('91', '106'))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('fusions', 'Var', (24, 31))
171948	29617662	Fusions play an increasingly appreciated role in tumorigenesis and progression and represent an important source of improved treatment options.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('progression', 'CPA', (67, 78))	('Fusions', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))
171963	29617662	The percentage of kinase genes in each group across different cancer types was defined as the number of kinase genes with fusions in each group divided by their sum, denoted as pg.	('fusions', 'Var', (122, 129))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))
171968	29617662	For TCGA tumor samples where both MC3 (Key Resources Table) mutation calls and gene fusion calls were available, we obtained the genetic alteration events, including fusion, inframe deletion, inframe insertion, missense mutation, nonsense mutation, nonstop mutation, splice site mutation, and translation start site mutation in 299 driver genes.	('nonstop', 'Disease', (249, 256))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('nonsense mutation', 'Var', (230, 247))	('translation', 'biological_process', 'GO:0006412', ('293', '304'))	('missense mutation', 'Var', (211, 228))	('tumor', 'Disease', (9, 14))	('inframe insertion', 'Var', (192, 209))	('splice', 'MPA', (267, 273))	('MC3', 'Gene', (34, 37))	('fusion', 'Var', (166, 172))	('MC3', 'Gene', '4159', (34, 37))
171970	29617662	Highly recurrent fusions were found in prostate, bladder, breast, and lung cancers Expression increased in oncogene fusions but decreased in tumor suppressor genes Thyroid carcinoma showed significantly higher rates of kinase fusions Tumors with fusion events tend to have lower mutational burden	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor suppressor', 'biological_process', 'GO:0051726', ('141', '157'))	('increased', 'PosReg', (94, 103))	('Tumors', 'Disease', 'MESH:D009369', (234, 240))	('Expression', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('prostate', 'Disease', (39, 47))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (164, 181))	('fusions', 'Var', (116, 123))	('decreased', 'NegReg', (128, 137))	('breast', 'Disease', (58, 64))	('oncogene', 'Gene', (107, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('Tumors', 'Phenotype', 'HP:0002664', (234, 240))	('lung cancers', 'Disease', 'MESH:D008175', (70, 82))	('bladder', 'Disease', (49, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('141', '157'))	('lung cancers', 'Disease', (70, 82))	('tumor', 'Disease', (141, 146))	('Tumors', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lung cancers', 'Phenotype', 'HP:0100526', (70, 82))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (164, 181))	('Thyroid carcinoma', 'Disease', (164, 181))
171980	27213592	For example, in advanced lung cancer, smoking status is linked to higher mutational burden, higher rates of C > A transversion mutations, and increased frequency of EGFR alterations, the latter having subsequent impact on selection of EGFR-directed therapies.	('EGFR', 'Gene', (165, 169))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('lung cancer', 'Disease', (25, 36))	('alterations', 'Var', (170, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('C > A', 'Gene', (108, 113))	('EGFR', 'Gene', '1956', (235, 239))	('impact', 'Reg', (212, 218))	('EGFR', 'Gene', (235, 239))	('higher', 'PosReg', (66, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('165', '169'))	('higher rates', 'PosReg', (92, 104))	('mutational burden', 'MPA', (73, 90))	('EGFR', 'molecular_function', 'GO:0005006', ('235', '239'))	('EGFR', 'Gene', '1956', (165, 169))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))
171986	27213592	We have previously reported CGP in 69 patients with UC of bladder where PIK3CA mutation appeared to be more frequent in non-smokers when compared to current and ex-smokers (43% vs. 11%, p = 0.1760).	('PIK3CA', 'Gene', '5290', (72, 78))	('mutation', 'Var', (79, 87))	('PIK3CA', 'Gene', (72, 78))	('patients', 'Species', '9606', (38, 46))
172002	27213592	TGFBR2 alterations were also more frequent in non-smokers and current smokers (11% in both groups) as compared to ex-smokers (0%; P = 0.04).	('frequent', 'Reg', (34, 42))	('TGFBR2', 'Gene', (0, 6))	('alterations', 'Var', (7, 18))	('TGFBR2', 'Gene', '7048', (0, 6))
172011	27213592	Beyond these approaches, there has been much enthusiasm surrounding use of novel immunotherapeutic strategies such as programmed death-1 (PD-1) inhibition or PD-L1 inhibition.	('PD-L1', 'Gene', '29126', (158, 163))	('programmed death-1', 'Gene', (118, 136))	('programmed death-1', 'Gene', '5133', (118, 136))	('inhibition', 'Var', (164, 174))	('PD-1', 'Gene', (138, 142))	('PD-1', 'Gene', '5133', (138, 142))	('PD-L1', 'Gene', (158, 163))	('inhibition', 'NegReg', (144, 154))
172013	27213592	Luminal cluster II molecular subtype and mutational load (but not smoking status) were shown to be recently associated with higher response rate to anti-PD-L1 agent in patients with platinum-refractory advanced UC.	('platinum', 'Chemical', 'MESH:D010984', (182, 190))	('PD-L1', 'Gene', (153, 158))	('response', 'MPA', (131, 139))	('mutational load', 'Var', (41, 56))	('PD-L1', 'Gene', '29126', (153, 158))	('associated', 'Reg', (108, 118))	('patients', 'Species', '9606', (168, 176))	('higher', 'PosReg', (124, 130))
172016	27213592	In urothelial cancer, several studies and case reports have shown benefit with everolimus when applied in patients with TSC1 specific alterations, found more commonly altered, among non-smokers in our series.	('benefit', 'PosReg', (66, 73))	('TSC1', 'Gene', '7248', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('urothelial cancer', 'Disease', (3, 20))	('TSC1', 'Gene', (120, 124))	('alterations', 'Var', (134, 145))	('patients', 'Species', '9606', (106, 114))	('urothelial cancer', 'Disease', 'MESH:D014523', (3, 20))	('everolimus', 'Chemical', 'MESH:D000068338', (79, 89))
172019	27213592	Perhaps the most compelling finding from this study is the identification of a high frequency of NSD1 alteration in current smokers, although the results should be interpreted with caution given small number of patients.	('NSD1', 'Gene', '64324', (97, 101))	('alteration', 'Var', (102, 112))	('patients', 'Species', '9606', (211, 219))	('NSD1', 'Gene', (97, 101))
172020	27213592	NSD1 alterations have been associated with Sotos syndrome, a syndrome of childhood overgrowth.	('NSD1', 'Gene', (0, 4))	('a syndrome', 'Disease', 'MESH:D013577', (59, 69))	('Sotos syndrome', 'Disease', 'MESH:D058495', (43, 57))	('a syndrome', 'Disease', (59, 69))	('associated', 'Reg', (27, 37))	('Sotos syndrome', 'Disease', (43, 57))	('alterations', 'Var', (5, 16))	('NSD1', 'Gene', '64324', (0, 4))	('overgrowth', 'Phenotype', 'HP:0001548', (83, 93))
172021	27213592	In the context of malignancy, translocations involving NSD1 have been identified in pediatric leukemias.	('leukemias', 'Phenotype', 'HP:0001909', (94, 103))	('identified', 'Reg', (70, 80))	('NSD1', 'Gene', (55, 59))	('leukemias', 'Disease', (94, 103))	('malignancy', 'Disease', 'MESH:D009369', (18, 28))	('translocations', 'Var', (30, 44))	('malignancy', 'Disease', (18, 28))	('leukemias', 'Disease', 'MESH:D007938', (94, 103))	('NSD1', 'Gene', '64324', (55, 59))
172024	27213592	A more marginal association was found between smoking status and TGFBR2 alteration, with higher rates in both current smokers and non-smokers as compared to ex-smokers.	('TGFBR2', 'Gene', '7048', (65, 71))	('TGFBR2', 'Gene', (65, 71))	('alteration', 'Var', (72, 82))	('higher rates', 'PosReg', (89, 101))
172026	27213592	The idea that a molecular signature or single gene mutation in urothelial carcinomas would differ between smoking-associated and smoking-independent cancers is supported by prior observations in other tumor types.	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('urothelial carcinomas', 'Disease', (63, 84))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('differ', 'Reg', (91, 97))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (63, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('tumor', 'Disease', (201, 206))	('single gene mutation', 'Var', (39, 59))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
172028	27213592	A larger analysis is required to rigourously interrogate genetic alterations in NSD1 as possibly differing amongst smoking groups.	('NSD1', 'Gene', '64324', (80, 84))	('NSD1', 'Gene', (80, 84))	('genetic alterations', 'Var', (57, 76))
172033	27213592	The data from the present study suggest that CS status portends worse OS in patients with advanced urothelial cancer.	('CS status', 'Var', (45, 54))	('patients', 'Species', '9606', (76, 84))	('OS', 'Chemical', '-', (70, 72))	('urothelial cancer', 'Disease', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('urothelial cancer', 'Disease', 'MESH:D014523', (99, 116))
172034	27213592	Despite these limitations, mutations in NSD1 were identified more frequently in current smokers compared to other smoking groups.	('NSD1', 'Gene', (40, 44))	('identified', 'Reg', (50, 60))	('NSD1', 'Gene', '64324', (40, 44))	('mutations', 'Var', (27, 36))
172047	26927070	The number of CD4+, CD8+, CD25+, FoxP3+ and CD20+ TILs was analyzed in association with clinico-pathomorphological features.	('CD25+', 'Var', (26, 31))	('TIL', 'Gene', (50, 53))	('CD20+', 'Var', (44, 49))	('CD4+', 'Var', (14, 18))	('FoxP3', 'Gene', '50943', (33, 38))	('CD8', 'Gene', (20, 23))	('CD8', 'Gene', '925', (20, 23))	('FoxP3', 'Gene', (33, 38))	('TIL', 'Gene', '7096', (50, 53))
172051	26927070	The changes in TILs, as well as of local and systemic Tregs, were accompanied by changes in the histological phenotype of urothelial carcinoma regarding pT stage, NDs, TIT, and clinical outcomes.	('TIL', 'Gene', (15, 18))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (122, 142))	('changes', 'Reg', (81, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('ND', 'Disease', 'MESH:C537849', (163, 165))	('urothelial carcinoma', 'Disease', (122, 142))	('clinical', 'Species', '191496', (177, 185))	('TIL', 'Gene', '7096', (15, 18))	('changes', 'Var', (4, 11))
172053	26927070	Moreover, a significant reduction in the number of CD4+ and CD8+ TILs with the development of NDs in more advanced tumors may be associated with lower tumor immunogenicity, resulting in immune tolerance towards tumor tissue.	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('TIL', 'Gene', '7096', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('lower', 'NegReg', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CD8', 'Gene', '925', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('TIL', 'Gene', (65, 68))	('reduction', 'NegReg', (24, 33))	('advanced tumors', 'Disease', 'MESH:D020178', (106, 121))	('CD4+', 'Var', (51, 55))	('immune tolerance', 'CPA', (186, 202))	('tumor', 'Disease', (151, 156))	('advanced tumors', 'Disease', (106, 121))	('ND', 'Disease', 'MESH:C537849', (94, 96))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('CD8', 'Gene', (60, 63))
172058	26927070	Specifically, tumors at pT2-pT4 exhibit a more aggressive tissue invasion type (TIT) compared with pT1 tumors), which are limited to the mucosa and the submucosa of the urinary bladder wall.	('pT1', 'Gene', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('pT2-pT4', 'Var', (24, 31))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('pT1', 'Gene', '58492', (99, 102))	('tumors', 'Disease', (14, 20))	('tissue invasion type', 'CPA', (58, 78))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tissue invasion', 'biological_process', 'GO:0001404', ('58', '73'))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
172067	26927070	We have expected that changes of these variables in combination with selected pathomorphological features may be a predictive of changes in urothelial bladder cancer immunogenicity.	('changes', 'Reg', (129, 136))	('changes', 'Var', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('bladder cancer', 'Phenotype', 'HP:0009725', (151, 165))	('urothelial bladder cancer', 'Disease', (140, 165))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (140, 165))
172068	26927070	To evaluate correlations between the advancement stage and the immunogenicity status of tumors, the number of CD4+, CD8+, CD25+, FoxP3+ and CD20+ TILs in invasive tumors was analyzed in relation to the phase of tumor development, as indicated by pT stage.	('CD8', 'Gene', (116, 119))	('CD20+', 'Var', (140, 145))	('TIL', 'Gene', '7096', (146, 149))	('FoxP3', 'Gene', '50943', (129, 134))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', (211, 216))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('invasive tumors', 'Disease', (154, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('invasive tumors', 'Disease', 'MESH:D009369', (154, 169))	('tumor', 'Disease', (88, 93))	('TIL', 'Gene', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CD8', 'Gene', '925', (116, 119))	('tumors', 'Disease', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('FoxP3', 'Gene', (129, 134))
172069	26927070	The number of CD4+, CD8+, CD25+, FoxP3+ and CD20+ TILs in the late phase of tumor development (pT3-pT4) was significantly lower compared to that observed for less advanced tumors (pT1-pT2) (Figure 1A-E).	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', (76, 81))	('CD8', 'Gene', (20, 23))	('FoxP3', 'Gene', (33, 38))	('TIL', 'Gene', '7096', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('CD25+', 'Var', (26, 31))	('lower', 'NegReg', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('CD20+', 'Var', (44, 49))	('FoxP3', 'Gene', '50943', (33, 38))	('advanced tumors', 'Disease', 'MESH:D020178', (163, 178))	('advanced tumors', 'Disease', (163, 178))	('pT3', 'Gene', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('TIL', 'Gene', (50, 53))	('CD4+', 'Var', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('CD8', 'Gene', '925', (20, 23))	('pT1-pT2', 'Gene', (180, 187))	('pT1-pT2', 'Gene', '58492', (180, 187))	('pT3', 'Gene', '7694', (95, 98))
172075	26927070	There was no significant correlation between NDN and the presence of CD20+, CD25+ and FoxP3+ TILs (data not shown).	('FoxP3', 'Gene', '50943', (86, 91))	('TIL', 'Gene', '7096', (93, 96))	('ND', 'Disease', 'MESH:C537849', (45, 47))	('FoxP3', 'Gene', (86, 91))	('CD25+', 'Var', (76, 81))	('CD20+', 'Var', (69, 74))	('TIL', 'Gene', (93, 96))
172079	26927070	To assess a correlation between the presence of TILs and the metastatic potential, the number of CD4+, CD8+, CD25+, FoxP3+, and CD20+ TILs in non-metastasizing and metastasizing tumors was evaluated.	('metastasizing tumors', 'Disease', (164, 184))	('CD20+', 'Var', (128, 133))	('FoxP3', 'Gene', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('TIL', 'Gene', (134, 137))	('TIL', 'Gene', '7096', (48, 51))	('metastasizing tumors', 'Disease', 'MESH:D009362', (164, 184))	('TIL', 'Gene', (48, 51))	('CD8', 'Gene', (103, 106))	('CD8', 'Gene', '925', (103, 106))	('FoxP3', 'Gene', '50943', (116, 121))	('CD25+', 'Var', (109, 114))	('TIL', 'Gene', '7096', (134, 137))
172083	26927070	There was no significant correlation between patient death and the presence of CD8+, CD20+, CD25+ and FoxP3+ TILs (not shown).	('death', 'Disease', 'MESH:D003643', (53, 58))	('death', 'Disease', (53, 58))	('FoxP3', 'Gene', (102, 107))	('TIL', 'Gene', (109, 112))	('CD20+', 'Var', (85, 90))	('CD8', 'Gene', (79, 82))	('patient', 'Species', '9606', (45, 52))	('CD8', 'Gene', '925', (79, 82))	('CD25+', 'Var', (92, 97))	('TIL', 'Gene', '7096', (109, 112))	('FoxP3', 'Gene', '50943', (102, 107))
172084	26927070	However the detailed analysis using the Kaplan-Meier method with experimentally-determined cut-off points showed that the lower number of analyzed TILs (CD4+, CD8+, CD20+, CD25+ and FoxP3+) was related to shorter overall survival (Figure 7B-F).	('TIL', 'Gene', '7096', (147, 150))	('FoxP3', 'Gene', '50943', (182, 187))	('CD25+', 'Var', (172, 177))	('CD20+', 'Var', (165, 170))	('FoxP3', 'Gene', (182, 187))	('CD8', 'Gene', (159, 162))	('TIL', 'Gene', (147, 150))	('shorter', 'NegReg', (205, 212))	('CD4+', 'Var', (153, 157))	('CD8', 'Gene', '925', (159, 162))	('overall', 'MPA', (213, 220))
172085	26927070	In the present study, we analyzed a correlation between CD4+, CD8+, CD25+, FoxP3+, and CD20+ TILs and pathomorphological features (pT advancement, NDN, and the type of tissue invasion) as well as clinical outcomes (metastasis and patients' death).	('CD25+', 'Var', (68, 73))	('CD8', 'Gene', (62, 65))	('CD8', 'Gene', '925', (62, 65))	('ND', 'Disease', 'MESH:C537849', (147, 149))	('TIL', 'Gene', '7096', (93, 96))	('death', 'Disease', (240, 245))	('death', 'Disease', 'MESH:D003643', (240, 245))	('metastasis', 'Disease', (215, 225))	('CD4+', 'Var', (56, 60))	('metastasis', 'Disease', 'MESH:D009362', (215, 225))	('patients', 'Species', '9606', (230, 238))	('FoxP3', 'Gene', '50943', (75, 80))	('tissue invasion', 'biological_process', 'GO:0001404', ('168', '183'))	('CD20+', 'Var', (87, 92))	('clinical', 'Species', '191496', (196, 204))	('TIL', 'Gene', (93, 96))	('FoxP3', 'Gene', (75, 80))
172089	26927070	Furthermore, more advanced (pT3-pT4) tumors were characterized by a lower number of CD20+ B-cell TILs (Figure 1E) and TILs with a Treg phenotype, CD25+ and FoxP3+ (Figure 1C,D).	('FoxP3', 'Gene', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('lower', 'NegReg', (68, 73))	('CD25+', 'Var', (146, 151))	('pT3', 'Gene', '7694', (28, 31))	('TIL', 'Gene', '7096', (118, 121))	('pT3', 'Gene', (28, 31))	('TIL', 'Gene', '7096', (97, 100))	('lower number of CD20+ B-', 'Phenotype', 'HP:0030378', (68, 92))	('FoxP3', 'Gene', '50943', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('TIL', 'Gene', (97, 100))	('TIL', 'Gene', (118, 121))	('CD20+', 'Var', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
172091	26927070	Moreover, CD8+, CD20+, CD25+, and FoxP3+ TILs were seen less frequently in aggressive invasive tumors (NE/ST/DI) (Figure 5).	('aggressive invasive tumors', 'Disease', (75, 101))	('CD20+', 'Var', (16, 21))	('TIL', 'Gene', '7096', (41, 44))	('FoxP3', 'Gene', (34, 39))	('CD8', 'Gene', (10, 13))	('CD8', 'Gene', '925', (10, 13))	('TIL', 'Gene', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('aggressive invasive tumors', 'Disease', 'MESH:D001523', (75, 101))	('CD25+', 'Var', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('FoxP3', 'Gene', '50943', (34, 39))
172092	26927070	Correspondingly, a reduced number of CD4+, CD8+, CD20+, CD25+, and FoxP3+ TILs was found in metastasizing tumors (Figure 6).	('FoxP3', 'Gene', (67, 72))	('CD4+', 'Var', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('TIL', 'Gene', (74, 77))	('CD8', 'Gene', (43, 46))	('metastasizing tumors', 'Disease', 'MESH:D009362', (92, 112))	('CD8', 'Gene', '925', (43, 46))	('CD25+', 'Var', (56, 61))	('metastasizing tumors', 'Disease', (92, 112))	('reduced', 'NegReg', (19, 26))	('TIL', 'Gene', '7096', (74, 77))	('FoxP3', 'Gene', '50943', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('CD20+', 'Var', (49, 54))
172096	26927070	The differences in the presence of CD4+, CD8+, and CD20+ TILs in pT1-pT2 vs. pT3-pT4 tumors suggest that the immune response depends on the stage of tumor development, being less effective in more advanced tumors.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('advanced tumors', 'Disease', 'MESH:D020178', (197, 212))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('CD4+', 'Var', (35, 39))	('immune response', 'biological_process', 'GO:0006955', ('109', '124'))	('pT3', 'Gene', '7694', (77, 80))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('pT1-pT2', 'Gene', '58492', (65, 72))	('advanced tumors', 'Disease', (197, 212))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('pT1-pT2', 'Gene', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('CD8', 'Gene', (41, 44))	('tumors', 'Disease', (206, 212))	('CD20+', 'Var', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('TIL', 'Gene', '7096', (57, 60))	('tumors', 'Disease', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('pT3', 'Gene', (77, 80))	('TIL', 'Gene', (57, 60))	('tumor', 'Disease', (206, 211))	('CD8', 'Gene', '925', (41, 44))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
172098	26927070	We observed a lower representation of CD25+ and FoxP3+ TILs in advanced cancers and a reduction of blood Treg frequency after the excision of pT3-pT4 tumors.	('TIL', 'Gene', (55, 58))	('reduction', 'NegReg', (86, 95))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('blood Treg frequency', 'CPA', (99, 119))	('CD25+', 'Var', (38, 43))	('lower', 'NegReg', (14, 19))	('TIL', 'Gene', '7096', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pT3', 'Gene', '7694', (142, 145))	('FoxP3', 'Gene', (48, 53))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('pT3', 'Gene', (142, 145))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('FoxP3', 'Gene', '50943', (48, 53))
172102	26927070	The lower number of TILs (CD4+, CD8+, CD25+, FoxP3+ and CD20+) observed in more advanced pT3-pT4 tumors compared to pT1-pT2 tumors (Figure 1 and Figure 2) may also reflect the lower immunogenicity of advanced lesions and the development of immune tolerance rather than the progression of biological malignancy with the appearance of new invasive cells.	('CD8', 'Gene', '925', (32, 35))	('FoxP3', 'Gene', '50943', (45, 50))	('TIL', 'Gene', '7096', (20, 23))	('pT1-pT2', 'Gene', (116, 123))	('tumors', 'Disease', (97, 103))	('CD4+', 'Var', (26, 30))	('pT3', 'Gene', (89, 92))	('malignancy', 'Disease', 'MESH:D009369', (299, 309))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('TIL', 'Gene', (20, 23))	('CD8', 'Gene', (32, 35))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('CD25+', 'Var', (38, 43))	('tumors', 'Disease', (124, 130))	('malignancy', 'Disease', (299, 309))	('CD20+', 'Var', (56, 61))	('pT3', 'Gene', '7694', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('FoxP3', 'Gene', (45, 50))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('pT1-pT2', 'Gene', '58492', (116, 123))
172121	26927070	For immunohistochemical analysis, 4 mum-thick sections were cut from archival paraffin-embedded blocks and stained with anti-CD4, anti-CD8, anti-CD20, anti-CD25, and anti-FoxP3 antibodies, as summarized in Table 2.	('anti-CD20', 'Var', (140, 149))	('FoxP3', 'Gene', (171, 176))	('CD8', 'Gene', '925', (135, 138))	('anti-CD25', 'Var', (151, 160))	('anti-CD4', 'Var', (120, 128))	('paraffin', 'Chemical', 'MESH:D010232', (78, 86))	('CD8', 'Gene', (135, 138))	('FoxP3', 'Gene', '50943', (171, 176))
172124	26927070	For each group of lymphocytes that infiltrated the tumor mass and/or localized in the vicinity of 2 HPF from the tumor, the mean number of CD4+, CD8+, CD20+, CD25+ and FoxP3+ cells within 20 HPF was evaluated.	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('FoxP3', 'Gene', (168, 173))	('tumor', 'Disease', (51, 56))	('CD8', 'Gene', (145, 148))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('CD4+', 'Var', (139, 143))	('CD20+', 'Var', (151, 156))	('CD8', 'Gene', '925', (145, 148))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('FoxP3', 'Gene', '50943', (168, 173))
172134	26927070	We found that the number of CD4+, CD8+, CD25+, FoxP3+ and CD20+ TILs and the frequency of blood Tregs changed with the progression of the urinary bladder cancer.	('CD25+', 'Var', (40, 45))	('TIL', 'Gene', '7096', (64, 67))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (138, 160))	('CD8', 'Gene', (34, 37))	('CD4+', 'Var', (28, 32))	('TIL', 'Gene', (64, 67))	('CD20+', 'Var', (58, 63))	('CD8', 'Gene', '925', (34, 37))	('bladder cancer', 'Phenotype', 'HP:0009725', (146, 160))	('FoxP3', 'Gene', '50943', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('changed', 'Reg', (102, 109))	('urinary bladder cancer', 'Disease', (138, 160))	('FoxP3', 'Gene', (47, 52))
172138	26927070	Moreover, this study indicates that the number of CD4+ and CD8+ TILs decreases with the development of new histological patterns, i.e., non-classic differentiations in more advanced tumors (pT3-pT4), which can be associated with lower tumor immunogenicity, resulting in stronger immune tolerance to cancer.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('decreases', 'NegReg', (69, 78))	('advanced tumors', 'Disease', 'MESH:D020178', (173, 188))	('CD8', 'Gene', (59, 62))	('pT3', 'Gene', '7694', (190, 193))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('advanced tumors', 'Disease', (173, 188))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('stronger', 'PosReg', (270, 278))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('TIL', 'Gene', '7096', (64, 67))	('CD8', 'Gene', '925', (59, 62))	('cancer', 'Disease', (299, 305))	('pT3', 'Gene', (190, 193))	('tumor', 'Disease', (182, 187))	('TIL', 'Gene', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('tumor', 'Disease', (235, 240))	('CD4+', 'Var', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
172146	24795386	However, treatment of transgenic mice with licofelone led to a significant, dose-dependent inhibition of the urothelial tumor growth (by 68.6 - 80.2%, p<0.0001 in males; by 36.9 - 55.3%, p<0.0001 in females) compared with the control group.	('men', 'Species', '9606', (14, 17))	('transgenic mice', 'Species', '10090', (22, 37))	('inhibition', 'NegReg', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('urothelial tumor', 'Disease', 'MESH:D001749', (109, 125))	('licofelone', 'Var', (43, 53))	('licofelone', 'Chemical', 'MESH:C088092', (43, 53))	('urothelial tumor', 'Disease', (109, 125))
172150	24795386	These results suggest that licofelone can serve as potential chemopreventive for bladder TCC.	('licofelone', 'Var', (27, 37))	('bladder TCC', 'Disease', (81, 92))	('licofelone', 'Chemical', 'MESH:C088092', (27, 37))	('TCC', 'cellular_component', 'GO:0005579', ('89', '92'))
172161	24795386	Clinically, aberrant expression of the COX-2 and 5-LOX enzymes has been observed in urothelial tumors and found to be associated with poor prognosis.	('observed', 'Reg', (72, 80))	('urothelial tumors', 'Disease', (84, 101))	('associated', 'Reg', (118, 128))	('COX-2 and 5', 'Gene', '17709', (39, 50))	('expression', 'MPA', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('aberrant', 'Var', (12, 20))	('5-LOX', 'Gene', (49, 54))	('urothelial tumors', 'Disease', 'MESH:D001749', (84, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('5-LOX', 'Gene', '11689', (49, 54))
172172	24795386	Transgenic mice (UPII-SV40T) expressing a Simian Virus 40 large T antigen (SV40T) specifically in urothelial cells under the control of the Uroplakin II (UPII) promoter and reproducibly developing high-grade carcinoma in situ (CIS) and invasive tumors throughout the urothelium were used.	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('carcinoma in situ', 'Disease', 'MESH:D002278', (208, 225))	('invasive tumors', 'Disease', (236, 251))	('SV40T', 'Var', (75, 80))	('UPII', 'Gene', (154, 158))	('UPII', 'Gene', (17, 21))	('carcinoma in situ', 'Disease', (208, 225))	('Uroplakin II', 'Gene', '22269', (140, 152))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (208, 225))	('invasive tumors', 'Disease', 'MESH:D009369', (236, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('UPII', 'Gene', '22269', (17, 21))	('UPII', 'Gene', '22269', (154, 158))	('Uroplakin II', 'Gene', (140, 152))	('Transgenic mice', 'Species', '10090', (0, 15))	('Simian Virus 40', 'Species', '1891767', (42, 57))
172212	24795386	All of the transgenic and wild type mice fed control and licofelone-containing modified AIN76A diets were weighed weekly and monitored throughout the study.	('licofelone', 'Chemical', 'MESH:C088092', (57, 67))	('modified AIN76A', 'Var', (79, 94))	('AIN76A', 'Var', (88, 94))	('mice', 'Species', '10090', (36, 40))	('transgenic', 'Species', '10090', (11, 21))
172230	24795386	Urothelial tumors of the transgenic mice were found to have significant over-expression of the proliferation and angiogenesis markers PCNA and VEGF (Fig 1D) compared with those in the normal urothelium of bladders from wild type mice.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('angiogenesis', 'biological_process', 'GO:0001525', ('113', '125'))	('Urothelial tumors', 'Disease', 'MESH:D001749', (0, 17))	('mice', 'Species', '10090', (229, 233))	('over-expression', 'PosReg', (72, 87))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('PCNA', 'Gene', (134, 138))	('angiogenesis', 'CPA', (113, 125))	('PCNA', 'molecular_function', 'GO:0003892', ('134', '138'))	('VEGF', 'Gene', (143, 147))	('mice', 'Species', '10090', (36, 40))	('transgenic mice', 'Species', '10090', (25, 40))	('Urothelial tumors', 'Disease', (0, 17))	('proliferation', 'CPA', (95, 108))	('transgenic', 'Var', (25, 35))	('PCNA', 'Gene', '18538', (134, 138))
172233	24795386	The tumor suppressor p16 (Fig 3A) was induced in the licofelone group while Cyclin E protein (Fig 3B) was significantly inhibited.	('tumor', 'Disease', (4, 9))	('licofelone', 'Chemical', 'MESH:C088092', (53, 63))	('induced', 'PosReg', (38, 45))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('4', '20'))	('inhibited', 'NegReg', (120, 129))	('p16', 'Gene', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor suppressor', 'biological_process', 'GO:0051726', ('4', '20'))	('licofelone', 'Var', (53, 63))	('p16', 'Gene', '12578', (21, 24))	('Cyclin', 'molecular_function', 'GO:0016538', ('76', '82'))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('Cyclin E protein', 'MPA', (76, 92))
172235	24795386	Real time PCR analysis of the mRNA showed a significant increase in the levels of the tumor suppressor protein p53 in tumors from licofelone-fed mice (Fig.	('increase', 'PosReg', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('86', '102'))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('licofelone', 'Chemical', 'MESH:C088092', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('licofelone-fed', 'Var', (130, 144))	('tumors', 'Disease', (118, 124))	('tumor suppressor', 'biological_process', 'GO:0051726', ('86', '102'))	('p53', 'Gene', (111, 114))	('levels of', 'MPA', (72, 81))	('mice', 'Species', '10090', (145, 149))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('p53', 'Gene', '22060', (111, 114))	('tumor', 'Disease', (86, 91))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
172239	24795386	3A and 3B) also were induced by the licofelone treatment, suggesting that licofelone may lead to inhibition of tumor growth by inducing apoptosis.	('licofelone', 'Var', (74, 84))	('licofelone', 'Chemical', 'MESH:C088092', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('licofelone', 'Chemical', 'MESH:C088092', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('apoptosis', 'CPA', (136, 145))	('men', 'Species', '9606', (52, 55))	('inhibition', 'NegReg', (97, 107))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('tumor', 'Disease', (111, 116))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))	('inducing', 'PosReg', (127, 135))
172257	24795386	did not observe a clinical benefit of celecoxib in preventing recurrence of non-muscle-invasive bladder cancer in a randomized controlled trial, although, celecoxib had a marginally significant effect on reducing metachronous recurrences compared with placebo.	('celecoxib', 'Chemical', 'MESH:D000068579', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (96, 110))	('metachronous recurrences', 'MPA', (213, 237))	('invasive bladder', 'Phenotype', 'HP:0100645', (87, 103))	('celecoxib', 'Chemical', 'MESH:D000068579', (155, 164))	('celecoxib', 'Var', (155, 164))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (80, 110))	('muscle-invasive bladder cancer', 'Disease', (80, 110))
172259	24795386	Similarly, targeting 5-LOX using the specific inhibitor AA861 caused a dose-dependent inhibition of bladder cancer cell growth.	('AA861', 'Var', (56, 61))	('bladder cancer', 'Disease', (100, 114))	('5-LOX', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (100, 114))	('cell growth', 'biological_process', 'GO:0016049', ('115', '126'))	('5-LOX', 'Gene', '11689', (21, 26))	('bladder cancer', 'Disease', 'MESH:D001749', (100, 114))	('inhibition', 'NegReg', (86, 96))
172271	24795386	Here we demonstrate that suppression of inflammatory pathways by licofelone is associated with prevention of this progression of urothelial tumors to invasive disease and modulation of genes that affect cell proliferation and apoptosis.	('suppression', 'NegReg', (25, 36))	('urothelial tumors to invasive disease', 'Disease', 'MESH:D014522', (129, 166))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('cell proliferation', 'CPA', (203, 221))	('apoptosis', 'biological_process', 'GO:0006915', ('226', '235'))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('licofelone', 'Gene', (65, 75))	('urothelial tumors to invasive disease', 'Disease', (129, 166))	('licofelone', 'Chemical', 'MESH:C088092', (65, 75))	('cell proliferation', 'biological_process', 'GO:0008283', ('203', '221'))	('inflammatory pathways', 'Pathway', (40, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('226', '235'))	('modulation', 'Var', (171, 181))
172273	24795386	Licofelone inhibited colonic tumors in a mouse colon cancer model by 72-100%, caused a significant reduction in small intestinal polyps, and provided better efficacy that did celecoxib in suppressing tumor growth.	('intestinal polyps', 'Disease', (118, 135))	('colonic tumors', 'Disease', 'MESH:D015179', (21, 35))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mouse', 'Species', '10090', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('Licofelone', 'Var', (0, 10))	('intestinal polyps', 'Disease', 'MESH:D007417', (118, 135))	('colon cancer', 'Disease', (47, 59))	('colonic tumors', 'Disease', (21, 35))	('intestinal polyps', 'Phenotype', 'HP:0005266', (118, 135))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (200, 205))	('reduction', 'NegReg', (99, 108))	('inhibited', 'NegReg', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('colon cancer', 'Phenotype', 'HP:0003003', (47, 59))	('celecoxib', 'Chemical', 'MESH:D000068579', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('small intestinal polyps', 'Phenotype', 'HP:0012737', (112, 135))	('colon cancer', 'Disease', 'MESH:D015179', (47, 59))	('tumor', 'Disease', (29, 34))	('Licofelone', 'Chemical', 'MESH:C088092', (0, 10))
172274	24795386	In a benzo(a)pyrene-induced lung cancer model, licofelone inhibited tumor multiplicity by 26% with a significant decrease in tumor incidence.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('decrease', 'NegReg', (113, 121))	('licofelone', 'Chemical', 'MESH:C088092', (47, 57))	('lung cancer', 'Disease', 'MESH:D008175', (28, 39))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('lung cancer', 'Disease', (28, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))	('inhibited', 'NegReg', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('pyrene', 'Chemical', 'MESH:C030984', (13, 19))	('licofelone', 'Var', (47, 57))
172281	24795386	The tumor suppressor protein p16 is most frequently deleted or inactivated by hypermethylation in bladder cancers.	('p16', 'Gene', (29, 32))	('tumor', 'Disease', (4, 9))	('bladder cancers', 'Disease', 'MESH:D001749', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('4', '20'))	('inactivated', 'NegReg', (63, 74))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('p16', 'Gene', '12578', (29, 32))	('bladder cancers', 'Disease', (98, 113))	('tumor suppressor', 'biological_process', 'GO:0051726', ('4', '20'))	('hypermethylation', 'Var', (78, 94))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('bladder cancers', 'Phenotype', 'HP:0009725', (98, 113))
172295	24795386	In the present study we have shown that licofelone, a dual COX/LOX inhibitor, inhibits urothelial tumor growth and prevents invasion in vivo.	('prevents', 'NegReg', (115, 123))	('licofelone', 'Var', (40, 50))	('licofelone', 'Chemical', 'MESH:C088092', (40, 50))	('invasion', 'CPA', (124, 132))	('urothelial tumor', 'Disease', 'MESH:D001749', (87, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('urothelial tumor', 'Disease', (87, 103))	('inhibits', 'NegReg', (78, 86))
172304	25013169	Network analysis of aberrantly methylated lincRNAs in cancers showed that lincRNAs with aberrant methylation patterns might be involved in cancer development and progression.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('lincRNA', 'Chemical', '-', (42, 49))	('methylation patterns', 'Var', (97, 117))	('involved', 'Reg', (127, 135))	('cancers', 'Disease', (54, 61))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (54, 60))	('methylation', 'biological_process', 'GO:0032259', ('97', '108'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('lincRNA', 'Chemical', '-', (74, 81))	('cancer', 'Disease', (139, 145))
172305	25013169	The methylated and demethylated lincRNAs identified in this study provide novel insights for developing cancer biomarkers and potential therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lincRNA', 'Chemical', '-', (32, 39))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('demethylated', 'Var', (19, 31))
172321	25013169	Some lincRNAs with aberrant methylation patterns in cancers might involve in cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('lincRNA', 'Chemical', '-', (5, 12))	('progression', 'CPA', (100, 111))	('involve', 'Reg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('aberrant methylation patterns', 'Var', (19, 48))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
172322	25013169	Early detection of hypermethylated or hypomethylated lincRNAs could serve as cancer biomarkers for diagnosis or treatment.	('lincRNAs', 'Gene', (53, 61))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('hypermethylated', 'Var', (19, 34))	('lincRNA', 'Chemical', '-', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('hypomethylated', 'Var', (38, 52))
172334	25013169	LincRNAs with methylated promoters in more than 20% of all tumor samples were defined as PM lincRNAs.	('tumor', 'Disease', (59, 64))	('methylated', 'Var', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('lincRNA', 'Chemical', '-', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
172351	25013169	Tumors were separated according to the median methylation of each lincRNA.	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('methylation', 'Var', (46, 57))	('lincRNA', 'Chemical', '-', (66, 73))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
172357	25013169	We identified lincRNAs with prognosis-associated (PA) methylation patterns in cancers with tumor sample size available for both clinical and methylation data >= 200 and a censoring (alive sample) rate <= 0.9; or the tumor sample size < 200 and a censoring rate <= 0.8 for an effective survival analysis (Supplementary Table S1).	('tumor', 'Disease', (216, 221))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('methylation', 'Var', (54, 65))	('methylation', 'biological_process', 'GO:0032259', ('141', '152'))	('lincRNA', 'Chemical', '-', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', (91, 96))
172369	25013169	Compared with the other three regions, hypermethylation of promoters was more tightly linked to transcriptional silencing of lincRNAs (Supplementary Figure S4).	('transcriptional', 'MPA', (96, 111))	('linked', 'Reg', (86, 92))	('silencing', 'NegReg', (112, 121))	('lincRNA', 'Chemical', '-', (125, 132))	('hypermethylation', 'Var', (39, 55))	('lincRNAs', 'Gene', (125, 133))
172373	25013169	Since disrupting DNA methyltransferases may promote chromosome instability and tumor progression, cancer cells are usually less methylated at individual CpG dinucleotides than healthy cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('chromosome', 'cellular_component', 'GO:0005694', ('52', '62'))	('promote', 'PosReg', (44, 51))	('chromosome instability', 'CPA', (52, 74))	('tumor', 'Disease', (79, 84))	('disrupting', 'Var', (6, 16))	('less', 'NegReg', (123, 127))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('chromosome instability', 'Phenotype', 'HP:0040012', (52, 74))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
172375	25013169	In contrast, hypermethylation of lincRNAs might be involved in DNA repair, tumor cell invasion, cell cycle regulation and other events in which silencing might induce metastasis.	('DNA repair', 'biological_process', 'GO:0006281', ('63', '73'))	('lincRNAs', 'Gene', (33, 41))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('cell cycle', 'CPA', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('involved', 'Reg', (51, 59))	('metastasis', 'CPA', (167, 177))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('induce', 'Reg', (160, 166))	('lincRNA', 'Chemical', '-', (33, 40))	('silencing', 'Var', (144, 153))	('hypermethylation', 'Var', (13, 29))	('tumor', 'Disease', (75, 80))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('96', '117'))
172376	25013169	Aberrant promoter methylation was frequently observed in cancer samples and might have contributed to tumor progression by silencing tumor suppressor genes or activating oncogenes.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('Aberrant', 'Var', (0, 8))	('contributed', 'Reg', (87, 98))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancer', 'Disease', (57, 63))	('tumor suppressor', 'biological_process', 'GO:0051726', ('133', '149'))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('133', '149'))	('promoter', 'MPA', (9, 17))	('activating', 'PosReg', (159, 169))	('tumor', 'Disease', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('silencing', 'NegReg', (123, 132))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('oncogenes', 'Gene', (170, 179))
172378	25013169	We obtained three representative cancer type-specific methylation patterns for 20 cancer types, and examples were shown in bladder urothelial cancer (BLCA), head and neck squamous cell cancer (HNSC) and LGG (Supplementary Figure S5).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('neck', 'cellular_component', 'GO:0044326', ('166', '170'))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', (82, 88))	('neck squamous cell cancer', 'Disease', (166, 191))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('HNSC', 'Phenotype', 'HP:0012288', (193, 197))	('methylation', 'Var', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (123, 148))	('cancer', 'Disease', (142, 148))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('neck squamous cell cancer', 'Disease', 'MESH:D002294', (166, 191))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('head and neck squamous cell cancer', 'Phenotype', 'HP:0012288', (157, 191))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (171, 191))	('bladder urothelial cancer', 'Disease', (123, 148))	('LGG', 'Disease', (203, 206))
172399	25013169	RE insertion close to a lincRNA promoter or RE hypermethylation might interrupt the transcription factors or other regulatory elements binding to lincRNA promoters, which could contribute to lincRNAs tissue-specific expression.	('contribute', 'Reg', (177, 187))	('transcription', 'Protein', (84, 97))	('lincRNA', 'Chemical', '-', (24, 31))	('lincRNA', 'Chemical', '-', (146, 153))	('binding', 'molecular_function', 'GO:0005488', ('135', '142'))	('binding', 'Interaction', (135, 142))	('interrupt', 'NegReg', (70, 79))	('lincRNA', 'Chemical', '-', (191, 198))	('transcription', 'biological_process', 'GO:0006351', ('84', '97'))	('hypermethylation', 'Var', (47, 63))
172411	25013169	Since aberrant promoter methylation silences tumor suppressor genes and activates oncogenes, we analyzed the different methylation patterns of lincRNA promoters between tumors and corresponding normal tissue samples.	('activates', 'PosReg', (72, 81))	('oncogenes', 'Gene', (82, 91))	('tumor', 'Disease', (45, 50))	('promoter', 'MPA', (15, 23))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('45', '61'))	('tumor', 'Disease', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor suppressor', 'biological_process', 'GO:0051726', ('45', '61'))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('aberrant', 'Var', (6, 14))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('silences', 'NegReg', (36, 44))	('lincRNA', 'Chemical', '-', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('tumors', 'Disease', (169, 175))
172414	25013169	The hypomethylated CM lincRNAs in BRCA or LUSC showed a more common methylation pattern in normal samples than in tumors.	('BRCA', 'Gene', '672', (34, 38))	('LUSC', 'Phenotype', 'HP:0030359', (42, 46))	('BRCA', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('methylation pattern', 'MPA', (68, 87))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('lincRNA', 'Chemical', '-', (22, 29))	('hypomethylated', 'Var', (4, 18))
172416	25013169	We identified the lincRNAs with subtype-specific methylation patterns in BRCA and LUSC (Figure 4E and F and Supplementary Table S6).	('methylation patterns', 'Var', (49, 69))	('BRCA', 'Gene', '672', (73, 77))	('BRCA', 'Gene', (73, 77))	('lincRNA', 'Chemical', '-', (18, 25))	('LUSC', 'Phenotype', 'HP:0030359', (82, 86))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))
172424	25013169	We combined the lincRNA methylation profiles with clinical annotations and identified a subset of lincRNAs with methylation values showing a trend associated with OS in BRCA, LUSC and UCEC.	('UCEC', 'Disease', (184, 188))	('methylation', 'biological_process', 'GO:0032259', ('112', '123'))	('associated', 'Reg', (147, 157))	('methylation', 'Var', (112, 123))	('BRCA', 'Gene', '672', (169, 173))	('lincRNA', 'Chemical', '-', (16, 23))	('LUSC', 'Phenotype', 'HP:0030359', (175, 179))	('BRCA', 'Gene', (169, 173))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('lincRNA', 'Chemical', '-', (98, 105))	('LUSC', 'Disease', (175, 179))
172428	25013169	For example, BRCA patients with lower methylation level of lincRNA XLOC_009284 had better prognosis (Figure 5A).	('methylation level', 'MPA', (38, 55))	('XLOC_009284', 'Var', (67, 78))	('lincRNA', 'Chemical', '-', (59, 66))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))	('BRCA', 'Gene', '672', (13, 17))	('patients', 'Species', '9606', (18, 26))	('BRCA', 'Gene', (13, 17))	('lower', 'NegReg', (32, 37))
172429	25013169	LUSC patients with relatively lower methylation level of lincRNA XLOC_009367 showed poorer prognosis (Figure 5B).	('lower', 'NegReg', (30, 35))	('patients', 'Species', '9606', (5, 13))	('XLOC_009367', 'Var', (65, 76))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('methylation level', 'MPA', (36, 53))	('lincRNA', 'Gene', (57, 64))	('lincRNA', 'Chemical', '-', (57, 64))	('LUSC', 'Phenotype', 'HP:0030359', (0, 4))
172430	25013169	For UCEC, patients with the highest methylation level of lincRNA XLOC_007617 had a better prognosis than patients with lower methylation level (Figure 5C).	('XLOC_007617', 'Var', (65, 76))	('methylation', 'biological_process', 'GO:0032259', ('125', '136'))	('patients', 'Species', '9606', (105, 113))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('methylation', 'MPA', (36, 47))	('UCEC', 'Disease', (4, 8))	('patients', 'Species', '9606', (10, 18))	('lincRNA', 'Gene', (57, 64))	('lincRNA', 'Chemical', '-', (57, 64))
172437	25013169	XLOC_007617 was a lincRNA that showed positive correlation between its methylation and drug-free survival in UCEC (log-rank P = 0.013; Supplementary Figure S8).	('methylation', 'Var', (71, 82))	('lincRNA', 'Chemical', '-', (18, 25))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('positive', 'PosReg', (38, 46))	('drug-free survival', 'CPA', (87, 105))	('XLOC_007617', 'Var', (0, 11))
172446	25013169	Using the AM lincRNAs between tumors and corresponding normal samples identified from 14 types of cancers with at least seven normal samples, we constructed an AM lincRNA-cancer network (AMCN; Supplementary Figure S10A).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('lincRNA', 'Chemical', '-', (13, 20))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('S10A', 'SUBSTITUTION', 'None', (214, 218))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('AMCN', 'Chemical', '-', (187, 191))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (171, 177))	('lincRNA', 'Chemical', '-', (163, 170))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancer', 'Disease', (98, 104))	('cancers', 'Disease', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('S10A', 'Var', (214, 218))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
172449	25013169	The AMCN illustrated that most lincRNAs were aberrantly methylated in a single cancer and a few lincRNAs were aberrantly methylated in multiple cancers (Supplementary Figure S10B).	('S10B', 'SUBSTITUTION', 'None', (174, 178))	('AMCN', 'Chemical', '-', (4, 8))	('lincRNA', 'Chemical', '-', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lincRNA', 'Chemical', '-', (96, 103))	('multiple cancers', 'Disease', (135, 151))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('methylated', 'Var', (56, 66))	('cancer', 'Disease', (144, 150))	('S10B', 'Var', (174, 178))	('aberrantly methylated', 'Var', (45, 66))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('multiple cancers', 'Disease', 'MESH:D009369', (135, 151))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
172450	25013169	A total of 196 lincRNAs were aberrantly methylated in more than one cancer out of all 434 AM lincRNAs in the AMCN.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('aberrantly methylated', 'Var', (29, 50))	('lincRNA', 'Chemical', '-', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('AMCN', 'Chemical', '-', (109, 113))	('cancer', 'Disease', (68, 74))	('lincRNA', 'Chemical', '-', (15, 22))
172452	25013169	The lincRNA XLOC_013592, located in chromosome 20, co-occurred with other AM lincRNAs in six types of cancer.	('XLOC_013592', 'Var', (12, 23))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lincRNA', 'Chemical', '-', (4, 11))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('lincRNA', 'Chemical', '-', (77, 84))	('chromosome', 'cellular_component', 'GO:0005694', ('36', '46'))
172458	25013169	Furthermore, 191 AM lincRNAs showed consistent hypermethylated or hypomethylated status in diverse cancers.	('lincRNA', 'Chemical', '-', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('hypermethylated', 'Var', (47, 62))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('hypomethylated', 'Var', (66, 80))
172464	25013169	In UCEC, XLOC_013045 and XLOC_013050 were found to be adjacent to zinc-finger protein genes (ZNF181, ZNF30, ZNF404, ZNF45).	('ZNF30', 'Gene', '90075', (101, 106))	('ZNF181', 'Gene', (93, 99))	('XLOC_013050', 'Var', (25, 36))	('ZNF30', 'Gene', (101, 106))	('ZNF404', 'Gene', '342908', (108, 114))	('ZNF45', 'Gene', '7596', (116, 121))	('ZNF404', 'Gene', (108, 114))	('ZNF181', 'Gene', '339318', (93, 99))	('ZNF45', 'Gene', (116, 121))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('XLOC_013045', 'Var', (9, 20))
172465	25013169	The expression level of XLOC_013350 was negatively correlated with its methylation level (Pearson's correlation coefficient, PCC = -0.63, P < 0.05) and positively correlated with the expression of ZNF404 (PCC = 0.26, P < 0.05).	('expression level', 'MPA', (4, 20))	('PCC', 'cellular_component', 'GO:0120205', ('125', '128'))	('XLOC_013350', 'Var', (24, 35))	('PCC', 'Gene', '1421', (125, 128))	('PCC', 'cellular_component', 'GO:0120205', ('205', '208'))	('PCC', 'Gene', '1421', (205, 208))	('correlated', 'Interaction', (163, 173))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('negatively', 'NegReg', (40, 50))	('ZNF404', 'Gene', '342908', (197, 203))	('PCC', 'Gene', (125, 128))	('ZNF404', 'Gene', (197, 203))	('methylation level', 'MPA', (71, 88))	('PCC', 'Gene', (205, 208))
172466	25013169	We also observed a positive correlation between the expression of XLOC_013045 and ZNF181 (PCC = 0.18, P < 0.05), indicating that these two lincRNAs may be involved in cell growth and apoptosis.	('ZNF181', 'Gene', (82, 88))	('ZNF181', 'Gene', '339318', (82, 88))	('PCC', 'Gene', '1421', (90, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('183', '192'))	('XLOC_013045', 'Var', (66, 77))	('cell growth', 'CPA', (167, 178))	('involved', 'Reg', (155, 163))	('PCC', 'Gene', (90, 93))	('lincRNA', 'Chemical', '-', (139, 146))	('PCC', 'cellular_component', 'GO:0120205', ('90', '93'))	('apoptosis', 'CPA', (183, 192))	('apoptosis', 'biological_process', 'GO:0006915', ('183', '192'))	('cell growth', 'biological_process', 'GO:0016049', ('167', '178'))
172467	25013169	In PRAD, lincRNA XLOC_002726 was significantly hypermethylated in tumors and showed a negative correlation between its expression and methylation (PCC = -0.26, P < 0.05), which was a newly found susceptibility locus for prostate cancer in genome-wide association studies.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('expression', 'MPA', (119, 129))	('prostate cancer', 'Disease', 'MESH:D011471', (220, 235))	('XLOC_002726', 'Var', (17, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (220, 235))	('PCC', 'Gene', (147, 150))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('lincRNA', 'Chemical', '-', (9, 16))	('methylation', 'biological_process', 'GO:0032259', ('134', '145'))	('negative', 'NegReg', (86, 94))	('prostate cancer', 'Disease', (220, 235))	('PRAD', 'Gene', (3, 7))	('PCC', 'cellular_component', 'GO:0120205', ('147', '150'))	('methylation', 'MPA', (134, 145))	('PCC', 'Gene', '1421', (147, 150))
172470	25013169	Therefore, lincRNAs with aberrant methylation patterns in cancers might be involved in cancer development and progression.	('aberrant methylation patterns', 'Var', (25, 54))	('cancer', 'Disease', (87, 93))	('involved', 'Reg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lincRNA', 'Chemical', '-', (11, 18))	('cancer', 'Disease', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
172471	25013169	Early detection of hypermethylation or hypomethylation of lincRNAs might serve as biomarkers for cancer diagnosis or treatment.	('lincRNA', 'Chemical', '-', (58, 65))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('hypermethylation', 'Var', (19, 35))	('lincRNAs', 'Gene', (58, 66))	('hypomethylation', 'Var', (39, 54))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
172473	25013169	For example, DNA methylation disrupted a long non-coding RNA activity by affecting expression in a lethal lung developmental disorder.	('disrupted', 'NegReg', (29, 38))	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('lung developmental disorder', 'Disease', 'MESH:D008171', (106, 133))	('expression in a lethal', 'MPA', (83, 105))	('methylation', 'Var', (17, 28))	('lung developmental disorder', 'Disease', (106, 133))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('DNA methylation', 'biological_process', 'GO:0006306', ('13', '28'))	('affecting', 'Reg', (73, 82))	('DNA', 'Var', (13, 16))	('developmental disorder', 'Phenotype', 'HP:0001263', (111, 133))
172528	34030643	Unselected enrollment of patients would also facilitate feasible accrual of patients with DDR gene alterations that are uncommon in UC, while allowing the study to be a priori powered to assess the efficacy of rucaparib in patients with HRD-positive tumors.	('patients', 'Species', '9606', (76, 84))	('DDR gene', 'Gene', (90, 98))	('alterations', 'Var', (99, 110))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('patients', 'Species', '9606', (25, 33))	('rucaparib', 'Chemical', 'MESH:C531549', (210, 219))	('HRD-positive tumors', 'Disease', 'MESH:D009369', (237, 256))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('HRD-positive tumors', 'Disease', (237, 256))	('patients', 'Species', '9606', (223, 231))
172545	34030643	Tumor HRD status and DDR gene alterations were identified using the DX1 next-generation sequencing (NGS) assay from Foundation Medicine, Inc. (Cambridge, MA, USA).	('Tumor HRD', 'Disease', (0, 9))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor HRD', 'Disease', 'MESH:D009369', (0, 9))	('alterations', 'Var', (30, 41))	('DDR gene', 'Gene', (21, 29))
172549	34030643	In patients with genomic LOH >=10%, platinum-based chemotherapy showed a statistically significant survival benefit compared to patients with genomic LOH < 10%.	('>=10%', 'Var', (29, 34))	('platinum', 'Chemical', 'MESH:D010984', (36, 44))	('benefit', 'PosReg', (108, 115))	('survival', 'CPA', (99, 107))	('patients', 'Species', '9606', (3, 11))	('platinum-based chemotherapy', 'CPA', (36, 63))	('patients', 'Species', '9606', (128, 136))
172602	34030643	The most common genes with deleterious alterations within this patient population included the TERT promoter (75%), CDKN2A (52%), TP53 (52%), CDKN2B (50%), MTAP (38%), KDM6A (31%), CCND1 (19%), FGF19 (19%), FGFR3 (19%), MLL2 (19%), and RB1 (19%) (Fig.	('FGFR3', 'Gene', (207, 212))	('TERT', 'Gene', (95, 99))	('TERT', 'Gene', '7015', (95, 99))	('RB1', 'Gene', (236, 239))	('CDKN2A', 'Gene', '1029', (116, 122))	('FGFR3', 'Gene', '2261', (207, 212))	('FGFR', 'molecular_function', 'GO:0005007', ('207', '211'))	('KDM6A', 'Gene', (168, 173))	('CDKN2B', 'Gene', (142, 148))	('MLL2', 'Gene', '8085', (220, 224))	('FGF19', 'Gene', '9965', (194, 199))	('patient', 'Species', '9606', (63, 70))	('RB1', 'Gene', '5925', (236, 239))	('MLL2', 'Gene', (220, 224))	('FGF19', 'Gene', (194, 199))	('TP53', 'Gene', (130, 134))	('CCND1', 'Gene', '595', (181, 186))	('CDKN2B', 'Gene', '1030', (142, 148))	('CCND1', 'Gene', (181, 186))	('CDKN2A', 'Gene', (116, 122))	('MTAP', 'Gene', (156, 160))	('KDM6A', 'Gene', '7403', (168, 173))	('MTAP', 'Gene', '4507', (156, 160))	('alterations', 'Var', (39, 50))	('TP53', 'Gene', '7157', (130, 134))
172606	34030643	Alterations in these DDR genes were not associated with the antitumor activity of rucaparib for these patients.	('tumor', 'Disease', (64, 69))	('rucaparib', 'Chemical', 'MESH:C531549', (82, 91))	('Alterations', 'Var', (0, 11))	('DDR genes', 'Gene', (21, 30))	('patients', 'Species', '9606', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
172617	34030643	Deleterious alterations in DDR genes associated with increased sensitivity to PARP inhibitors in other tumor types (e.g.	('PARP', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('alterations', 'Var', (12, 23))	('tumor', 'Disease', (103, 108))	('sensitivity to', 'MPA', (63, 77))	('PARP', 'Gene', '142', (78, 82))	('DDR genes', 'Gene', (27, 36))	('increased', 'PosReg', (53, 62))	('associated', 'Reg', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
172620	34030643	In clinical studies, rucaparib has shown antitumor activity in ovarian and prostate carcinomas with a deleterious germline or somatic BRCA mutation.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutation', 'Var', (139, 147))	('BRCA', 'Gene', (134, 138))	('ovarian and prostate carcinomas', 'Disease', 'MESH:D010051', (63, 94))	('tumor', 'Disease', (45, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('rucaparib', 'Chemical', 'MESH:C531549', (21, 30))	('BRCA', 'Gene', '675', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
172625	34030643	Unfortunately, the significance of inactivating homozygous DDR gene alterations in metastatic UC for sensitivity to PARP inhibitor remains unclear because the majority of DDR gene alterations characterized in this study were heterozygous or the zygosity was unknown/not reported.	('DDR gene', 'Gene', (59, 67))	('metastatic UC', 'Disease', (83, 96))	('PARP', 'Gene', (116, 120))	('alterations', 'Var', (180, 191))	('PARP', 'Gene', '142', (116, 120))	('alterations', 'Var', (68, 79))	('DDR gene', 'Gene', (171, 179))
172626	34030643	The effect of rucaparib in multiple tumor types (including UC) with selected DDR gene alterations shown to be sensitive to PARP inhibition is being further evaluated in the LODESTAR trial (NCT04171700).	('PARP', 'Gene', (123, 127))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('rucaparib', 'Chemical', 'MESH:C531549', (14, 23))	('PARP', 'Gene', '142', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('DDR gene', 'Gene', (77, 85))	('tumor', 'Disease', (36, 41))	('alterations', 'Var', (86, 97))
172627	34030643	Additionally, the effect of the PARP inhibitor olaparib for patients with metastatic UC with DNA-repair gene defects is being investigated in a phase 2 trial (NCT03375307).	('olaparib', 'Chemical', 'MESH:C531550', (47, 55))	('metastatic UC', 'Disease', (74, 87))	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('patients', 'Species', '9606', (60, 68))	('DN', 'Chemical', 'MESH:C022306', (93, 95))	('PARP', 'Gene', '142', (32, 36))	('defects', 'Var', (109, 116))	('DNA-repair', 'biological_process', 'GO:0006281', ('93', '103'))	('PARP', 'Gene', (32, 36))
172628	34030643	Alterations in genes mapping to the cell cycle, RTK, TP53, PI3K, metabolic, and chromatin remodeling pathways were commonly seen in ATLAS patient samples, at frequencies similar to that in prior reports.	('cell cycle', 'biological_process', 'GO:0007049', ('36', '46'))	('AS', 'Chemical', 'MESH:D001151', (135, 137))	('chromatin', 'cellular_component', 'GO:0000785', ('80', '89'))	('Alterations', 'Var', (0, 11))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('80', '100'))	('PI3K', 'Gene', (59, 63))	('patient', 'Species', '9606', (138, 145))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))	('PI3K', 'molecular_function', 'GO:0016303', ('59', '63'))
172630	34030643	Alterations in cell cycle regulatory genes were also detected in the tumor DNA of patients enrolled in the phase Ib BISCAY trial, in which 15% of patients with UC carried an amplification in RICTOR or a deleterious alteration in TSC1/TSC2.	('TSC2', 'Gene', '7249', (234, 238))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('TSC2', 'Gene', (234, 238))	('RICTOR', 'Gene', (191, 197))	('tumor', 'Disease', (69, 74))	('patients', 'Species', '9606', (82, 90))	('TSC1', 'Gene', (229, 233))	('cell cycle', 'biological_process', 'GO:0007049', ('15', '25'))	('DN', 'Chemical', 'MESH:C022306', (75, 77))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('RICTOR', 'Gene', '253260', (191, 197))	('amplification', 'Var', (174, 187))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('patients', 'Species', '9606', (146, 154))	('TSC1', 'Gene', '7248', (229, 233))
172637	34030643	Responses have been observed in studies evaluating olaparib with durvalumab in patients with advanced UC: a response rate of 35.7% was observed among patients with DDR gene alterations in the BISCAY trial, and a pathologic complete response rate of 44.5% was seen in a single-arm phase 2 neoadjuvant trial.	('olaparib', 'Chemical', 'MESH:C531550', (51, 59))	('alterations', 'Var', (173, 184))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (79, 87))	('durvalumab', 'Chemical', 'MESH:C000613593', (65, 75))	('DDR gene', 'Gene', (164, 172))
172639	34030643	Evaluation of PARP inhibitor monotherapy and combination treatment for patients with UC is ongoing in other trials (NCT03459846, NCT03534492, NCT02546661, and EudraCT 2015-003249-25).	('NCT03534492', 'Var', (129, 140))	('patients', 'Species', '9606', (71, 79))	('PARP', 'Gene', (14, 18))	('NCT03459846', 'Var', (116, 127))	('NCT02546661', 'Var', (142, 153))	('PARP', 'Gene', '142', (14, 18))
172644	34030643	It should also be noted that patients were not selected based on genomic characteristics that may have differential sensitivities to treatment with a PARP inhibitor, such as tumor HRD status, alterations in DDR pathway genes, zygosity status of specific alterations, or germline alterations.	('alterations', 'Var', (254, 265))	('tumor HRD status', 'Disease', 'MESH:D013226', (174, 190))	('patients', 'Species', '9606', (29, 37))	('PARP', 'Gene', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('PARP', 'Gene', '142', (150, 154))	('germline alterations', 'Var', (270, 290))	('alterations', 'Var', (192, 203))	('DDR', 'Gene', (207, 210))	('zygosity status', 'Var', (226, 241))	('tumor HRD status', 'Disease', (174, 190))
172652	34030643	Future studies should evaluate potential synergy of PARP inhibitors in combination with other therapies such as ICI, particularly in patients with metastatic UC associated with a DDR alteration.	('metastatic UC', 'Disease', (147, 160))	('PARP', 'Gene', '142', (52, 56))	('associated', 'Reg', (161, 171))	('patients', 'Species', '9606', (133, 141))	('PARP', 'Gene', (52, 56))	('alteration', 'Var', (183, 193))
172664	32320410	Impact of cancer-associated mutations in Hsh155/SF3b1 HEAT repeats 9-12 on pre-mRNA splicing in Saccharomyces cerevisiae Mutations in the splicing machinery have been implicated in a number of human diseases.	('splicing', 'biological_process', 'GO:0045292', ('138', '146'))	('pre', 'molecular_function', 'GO:0003904', ('75', '78'))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('implicated', 'Reg', (167, 177))	('SF3b1', 'Gene', (48, 53))	('Hsh155', 'Gene', '855332', (41, 47))	('SF3b1', 'Gene', '23451', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('pre-mRNA splicing', 'MPA', (75, 92))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('75', '92'))	('mutations', 'Var', (28, 37))	('cancer', 'Disease', (10, 16))	('human', 'Species', '9606', (193, 198))	('Hsh155', 'Gene', (41, 47))
172665	32320410	Most notably, the U2 small nuclear ribonucleoprotein (snRNP) component SF3b1 has been found to be frequently mutated in blood cancers such as myelodysplastic syndromes (MDS).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('SF3b1', 'Gene', (71, 76))	('blood cancers', 'Phenotype', 'HP:0001909', (120, 133))	('snRNP', 'Gene', (54, 59))	('snRNP', 'molecular_function', 'GO:0003734', ('54', '59'))	('blood cancers', 'Disease', (120, 133))	('SF3b1', 'Gene', '23451', (71, 76))	('small nuclear ribonucleoprotein', 'molecular_function', 'GO:0003734', ('21', '52'))	('snRNP', 'Gene', '57819', (54, 59))	('small nuclear ribonucleoprotein', 'cellular_component', 'GO:0030532', ('21', '52'))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('mutated', 'Var', (109, 116))	('blood cancer', 'Phenotype', 'HP:0001909', (120, 132))	('blood cancers', 'Disease', 'MESH:D007022', (120, 133))	('snRNP', 'cellular_component', 'GO:0030532', ('54', '59'))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (142, 167))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (142, 167))	('myelodysplastic syndromes', 'Disease', (142, 167))
172666	32320410	SF3b1 is a highly conserved HEAT repeat (HR)-containing protein and most of these blood cancer mutations cluster in a hot spot located in HR4-8.	('blood cancer', 'Disease', 'MESH:D007022', (82, 94))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('SF3b1', 'Gene', '23451', (0, 5))	('SF3b1', 'Gene', (0, 5))	('blood cancer', 'Phenotype', 'HP:0001909', (82, 94))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('blood cancer', 'Disease', (82, 94))
172668	32320410	The consequences of these mutations on SF3b1 functions during splicing have not yet been tested.	('mutations', 'Var', (26, 35))	('SF3b1', 'Gene', '23451', (39, 44))	('splicing', 'biological_process', 'GO:0045292', ('62', '70'))	('SF3b1', 'Gene', (39, 44))
172669	32320410	We incorporated the corresponding mutations into the yeast homolog of SF3b1 and tested their impact on splicing.	('yeast', 'Species', '4932', (53, 58))	('SF3b1', 'Gene', (70, 75))	('SF3b1', 'Gene', '23451', (70, 75))	('tested', 'Reg', (80, 86))	('splicing', 'MPA', (103, 111))	('mutations', 'Var', (34, 43))	('splicing', 'biological_process', 'GO:0045292', ('103', '111'))
172670	32320410	We find that all of these HR9-12 mutations can support splicing in yeast, and this suggests that none of them are loss of function alleles in humans.	('support', 'Reg', (47, 54))	('HR9-12', 'CellLine', 'CVCL:2676', (26, 32))	('yeast', 'Species', '4932', (67, 72))	('mutations', 'Var', (33, 42))	('HR9-12', 'Gene', (26, 32))	('splicing', 'MPA', (55, 63))	('splicing', 'biological_process', 'GO:0045292', ('55', '63'))	('humans', 'Species', '9606', (142, 148))
172671	32320410	The Hsh155V502F mutation alters splicing of several pre-mRNA reporters containing weak branch sites as well as a genetic interaction with Prp2 and physical interactions with Prp5 and Prp3.	('Prp2', 'Protein', (138, 142))	('Prp5', 'Protein', (174, 178))	('interaction', 'Interaction', (121, 132))	('V502F', 'Mutation', 'p.V502F', (10, 15))	('pre', 'molecular_function', 'GO:0003904', ('52', '55'))	('Hsh155V502F', 'Var', (4, 15))	('alters', 'Reg', (25, 31))	('splicing', 'biological_process', 'GO:0045292', ('32', '40'))	('interactions', 'Interaction', (156, 168))	('splicing', 'MPA', (32, 40))
172685	32320410	Aberrant BS recognition by U2 snRNP may lead to production and accumulation of altered spliced products and cancer.	('lead to', 'Reg', (40, 47))	('Aberrant', 'Var', (0, 8))	('snRNP', 'Gene', (30, 35))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('27', '35'))	('production', 'MPA', (48, 58))	('accumulation', 'MPA', (63, 75))	('snRNP', 'Gene', '57819', (30, 35))	('altered spliced products', 'MPA', (79, 103))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('snRNP', 'molecular_function', 'GO:0003734', ('30', '35'))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
172687	32320410	Recent experiments have shown that MDS-related mutations in SF3b1 promote usage of alternative BS within introns.	('SF3b1', 'Gene', (60, 65))	('SF3b1', 'Gene', '23451', (60, 65))	('mutations', 'Var', (47, 56))	('promote', 'PosReg', (66, 73))	('usage of alternative BS within introns', 'MPA', (74, 112))
172688	32320410	MDS mutations cluster in SF3b1 HR 4-7 and overlap with a region of the protein proposed to directly interact with the spliceosomal ATPase Prp5 (HEAT repeats 1-12; Fig 1A).	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('MDS', 'Gene', (0, 3))	('SF3b1', 'Gene', (25, 30))	('SF3b1', 'Gene', '23451', (25, 30))	('mutations', 'Var', (4, 13))
172689	32320410	MDS mutations in HR 4-7 alter this interaction when monitored with a yeast two-hybrid assay or by pull-down.	('MDS', 'Gene', (0, 3))	('interaction', 'Interaction', (35, 46))	('HR 4-7', 'Gene', (17, 23))	('yeast', 'Species', '4932', (69, 74))	('alter', 'Reg', (24, 29))	('mutations', 'Var', (4, 13))
172690	32320410	Multiple mechanisms have been proposed to describe how MDS mutations in SF3b1 ultimately lead to selection of alternative BS.	('SF3b1', 'Gene', (72, 77))	('lead to', 'Reg', (89, 96))	('SF3b1', 'Gene', '23451', (72, 77))	('mutations', 'Var', (59, 68))
172691	32320410	These mutations may influence splicing by altering interactions with Prp5 or the human splicing factor SUGP1, disrupting SF3b1 conformational change, or by perturbing the direct interactions between the intronic pre-mRNA and SF3b1 itself.	('direct', 'MPA', (171, 177))	('interactions', 'Interaction', (178, 190))	('splicing', 'MPA', (30, 38))	('interactions', 'Interaction', (51, 63))	('splicing', 'biological_process', 'GO:0045292', ('30', '38'))	('SF3b1', 'Gene', (121, 126))	('SUGP1', 'Gene', (103, 108))	('human', 'Species', '9606', (81, 86))	('conformational change', 'MPA', (127, 148))	('splicing factor', 'Gene', (87, 102))	('disrupting', 'NegReg', (110, 120))	('SF3b1', 'Gene', '23451', (225, 230))	('mutations', 'Var', (6, 15))	('perturbing', 'NegReg', (156, 166))	('pre', 'molecular_function', 'GO:0003904', ('212', '215'))	('altering', 'Reg', (42, 50))	('Prp5', 'Protein', (69, 73))	('influence', 'Reg', (20, 29))	('splicing factor', 'Gene', '10569', (87, 102))	('SF3b1', 'Gene', '23451', (121, 126))	('SUGP1', 'Gene', '57794', (103, 108))	('splicing', 'biological_process', 'GO:0045292', ('87', '95'))	('SF3b1', 'Gene', (225, 230))
172692	32320410	A meta-analysis of splicing factor genes from 33 different tumor types across >10,000 samples uncovered a second site of frequent mutation in SF3b1.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('splicing factor', 'Gene', '10569', (19, 34))	('mutation', 'Var', (130, 138))	('splicing', 'biological_process', 'GO:0045292', ('19', '27'))	('SF3b1', 'Gene', (142, 147))	('splicing factor', 'Gene', (19, 34))	('SF3b1', 'Gene', '23451', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
172693	32320410	HR9-12 contain hotspots that are enriched in acute myeloid leukemia (LAML; 3 HR9-12 mutations found in 201 samples), bladder urothelial carcinoma (BLCA; 11 HR9-12 mutations found in 438 samples), and uterine corpus endometrial carcinoma (UCEC; 13 HR9-12 mutations found in 564 samples) cancer cells.	('HR9-12', 'CellLine', 'CVCL:2676', (0, 6))	('HR9-12', 'Gene', (77, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('cancer', 'Disease', (286, 292))	('HR9-12', 'CellLine', 'CVCL:2676', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('endometrial carcinoma', 'Disease', (215, 236))	('acute myeloid leukemia', 'Disease', (45, 67))	('HR9-12', 'CellLine', 'CVCL:2676', (156, 162))	('bladder urothelial carcinoma', 'Disease', (117, 145))	('leukemia', 'Phenotype', 'HP:0001909', (59, 67))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (51, 67))	('mutations', 'Var', (84, 93))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('AML', 'Disease', 'MESH:D015470', (70, 73))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (117, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (215, 236))	('AML', 'Disease', (70, 73))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (45, 67))	('HR9-12', 'CellLine', 'CVCL:2676', (247, 253))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (45, 67))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (215, 236))
172694	32320410	While some amino acids in HR9-12 such as E862 were mutated in multiple cancers, others were only observed in a single cohort (e.g., all 3 HR9-12 mutations observed in LAML are L833F).	('HR9-12', 'CellLine', 'CVCL:2676', (26, 32))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('L833F', 'Var', (176, 181))	('L833F', 'Mutation', 'rs780559382', (176, 181))	('cancers', 'Disease', (71, 78))	('HR9-12', 'Gene', (138, 144))	('mutated', 'Reg', (51, 58))	('AML', 'Disease', 'MESH:D015470', (168, 171))	('HR9-12', 'Gene', (26, 32))	('HR9-12', 'CellLine', 'CVCL:2676', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('AML', 'Disease', (168, 171))	('E862', 'Var', (41, 45))
172697	32320410	Bioinformatic analyses of the splicing phenotypes of LBU cancer cells revealed that LBU mutations conferred a phenotype more similar to wild-type (WT) SF3b1 than do MDS mutations.	('LBU', 'Chemical', '-', (53, 56))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('mutations', 'Var', (88, 97))	('LBU', 'Gene', (84, 87))	('SF3b1', 'Gene', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('splicing', 'biological_process', 'GO:0045292', ('30', '38'))	('SF3b1', 'Gene', '23451', (151, 156))	('LBU', 'Chemical', '-', (84, 87))
172698	32320410	A detailed RNA-Seq analysis of BLCA tumor cells harboring the most prevalent LBU mutation (E902K) showed only a small number of significantly altered splice junctions; however, these aberrant isoforms showed preferential use of downstream 3'SS rather than the upstream sites observed in MDS.	('BLCA tumor', 'Disease', 'MESH:D009369', (31, 41))	('E902K', 'Mutation', 'p.E902K', (91, 96))	('E902K', 'Var', (91, 96))	('LBU', 'Gene', (77, 80))	('preferential', 'PosReg', (208, 220))	('BLCA tumor', 'Disease', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('LBU', 'Chemical', '-', (77, 80))	('RNA', 'cellular_component', 'GO:0005562', ('11', '14'))
172699	32320410	Taken together these data suggest that mutations in the MDS and LBU sites may perturb the function of the spliceosome in different ways.	('LBU', 'Chemical', '-', (64, 67))	('function of the spliceosome', 'MPA', (90, 117))	('perturb', 'Reg', (78, 85))	('spliceosome', 'cellular_component', 'GO:0005681', ('106', '117'))	('MDS', 'Gene', (56, 59))	('mutations', 'Var', (39, 48))	('LBU', 'Gene', (64, 67))
172700	32320410	Here, we explore the effect of LBU disease-related mutations in Hsh155 on splicing in yeast.	('splicing', 'biological_process', 'GO:0045292', ('74', '82'))	('mutations', 'Var', (51, 60))	('LBU', 'Chemical', '-', (31, 34))	('Hsh155', 'Gene', (64, 70))	('yeast', 'Species', '4932', (86, 91))	('LBU disease-related', 'Disease', (31, 50))
172701	32320410	Using a reporter transcript in vivo, we show that the hotspot mutation V502F alters splicing of introns containing non-consensus BS in yeast as well as a genetic interaction between the spliceosomal ATPase Prp2 and Hsh155.	('alters', 'Reg', (77, 83))	('yeast', 'Species', '4932', (135, 140))	('splicing of introns containing', 'MPA', (84, 114))	('V502F', 'Var', (71, 76))	('Hsh155', 'Gene', (215, 221))	('splicing', 'biological_process', 'GO:0045292', ('84', '92'))	('V502F', 'Mutation', 'p.V502F', (71, 76))
172702	32320410	Other LBU mutants in Hsh155 showed less pronounced phenotypes.	('LBU', 'Chemical', '-', (6, 9))	('Hsh155', 'Gene', (21, 27))	('mutants', 'Var', (10, 17))
172703	32320410	Consistent with recent cryo-EM data, we also identify a new yeast two-hybrid interaction between Hsh155 and Prp3 that is disrupted by the V502F mutation.	('yeast two-hybrid interaction', 'Interaction', (60, 88))	('yeast', 'Species', '4932', (60, 65))	('V502F', 'Mutation', 'p.V502F', (138, 143))	('Hsh155', 'Gene', (97, 103))	('Prp3', 'Gene', (108, 112))	('disrupted', 'NegReg', (121, 130))	('V502F', 'Var', (138, 143))
172704	32320410	Combined these data indicate that cancer hotspot mutations in Hsh155 have the potential to impact multiple interactions between splicing factors.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (49, 58))	('splicing factor', 'Gene', (128, 143))	('impact', 'Reg', (91, 97))	('interactions', 'Interaction', (107, 119))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('splicing factor', 'Gene', '10569', (128, 143))	('splicing', 'biological_process', 'GO:0045292', ('128', '136'))	('Hsh155', 'Gene', (62, 68))
172706	32320410	However, L833 in human SF3b1 corresponds to a smaller hydrophobic amino acid in yeast Hsh155 (V502) and R957 in human SF3b1 is not conserved in yeast (I626 at the corresponding position).	('SF3b1', 'Gene', '23451', (118, 123))	('SF3b1', 'Gene', (23, 28))	('human', 'Species', '9606', (17, 22))	('yeast', 'Species', '4932', (144, 149))	('V502', 'Chemical', '-', (94, 98))	('L833', 'Var', (9, 13))	('human', 'Species', '9606', (112, 117))	('R957', 'Var', (104, 108))	('yeast', 'Species', '4932', (80, 85))	('SF3b1', 'Gene', (118, 123))	('smaller', 'NegReg', (46, 53))	('hydrophobic amino acid', 'MPA', (54, 76))	('SF3b1', 'Gene', '23451', (23, 28))
172711	32320410	Next, we transformed the TRP1/CEN6-containing plasmids containing the above mutant alleles into this yeast strain and then carried out 5-FOA selection of the resulting transformants.	('TRP1', 'molecular_function', 'GO:0004167', ('25', '29'))	('TRP1', 'Gene', '851570', (25, 29))	('mutant', 'Var', (76, 82))	('TRP1', 'Gene', (25, 29))	('yeast', 'Species', '4932', (101, 106))
172713	32320410	We next tested each LBU-mutant yeast strain for growth defects on solid media.	('tested', 'Reg', (8, 14))	('LBU', 'Chemical', '-', (20, 23))	('LBU-mutant', 'Var', (20, 30))	('growth', 'MPA', (48, 54))	('yeast', 'Species', '4932', (31, 36))
172714	32320410	The growth of each strain was assayed at four different temperatures ranging from 16 C to 37 C. All of the mutant yeast strains were viable at all temperatures when expressing LBU-mutant Hsh155.	('Hsh155', 'Gene', (187, 193))	('yeast', 'Species', '4932', (114, 119))	('LBU', 'Chemical', '-', (176, 179))	('LBU-mutant', 'Var', (176, 186))
172716	32320410	We have previously shown that MDS-mutant Hsh155 yeast strains containing substitutions in HR4-7 do not significantly perturb yeast proliferation.	('substitutions', 'Var', (73, 86))	('yeast proliferation', 'CPA', (125, 144))	('perturb', 'Reg', (117, 124))	('yeast', 'Species', '4932', (48, 53))	('yeast', 'Species', '4932', (125, 130))	('Hsh155', 'Gene', (41, 47))	('HR4-7', 'Gene', (90, 95))
172717	32320410	To test if the LBU-mutants also impact splicing despite the lack of a growth phenotype, we used the ACT1-CUP1 reporter transcript to assay splicing in vivo.	('impact', 'Reg', (32, 38))	('splicing', 'biological_process', 'GO:0045292', ('39', '47'))	('LBU-mutants', 'Gene', (15, 26))	('LBU-mutants', 'Var', (15, 26))	('splicing', 'MPA', (39, 47))	('ACT1', 'Gene', '850504', (100, 104))	('splicing', 'biological_process', 'GO:0045292', ('139', '147'))	('CUP1', 'Gene', '856450', (105, 109))	('LBU', 'Chemical', '-', (15, 18))	('ACT1', 'Gene', (100, 104))	('CUP1', 'Gene', (105, 109))
172722	32320410	However, in the presence of ACT1-CUP1 reporters harboring a non-consensus, weak BS (A258U) both the Hsh155V502F and Hsh155D563G mutants showed lower Cu2+ resistance (Fig 2D).	('Hsh155D563G', 'Var', (116, 127))	('lower', 'NegReg', (143, 148))	('ACT1', 'Gene', '850504', (28, 32))	('CUP1', 'Gene', '856450', (33, 37))	('D563G', 'Mutation', 'p.D563G', (122, 127))	('Hsh155V502F', 'Var', (100, 111))	('Cu2+ resistance', 'MPA', (149, 164))	('Cu2+', 'Chemical', '-', (149, 153))	('ACT1', 'Gene', (28, 32))	('CUP1', 'Gene', (33, 37))
172723	32320410	Hsh155V502F additionally showed lower Cu2+ resistance with the non-consensus U257C ACT1-CUP1 reporter (Fig 2E).	('CUP1', 'Gene', (88, 92))	('Cu2+', 'Chemical', '-', (38, 42))	('Cu2+ resistance', 'MPA', (38, 53))	('ACT1', 'Gene', '850504', (83, 87))	('Hsh155V502F', 'Var', (0, 11))	('CUP1', 'Gene', '856450', (88, 92))	('ACT1', 'Gene', (83, 87))	('lower', 'NegReg', (32, 37))
172725	32320410	We performed primer extension using RNA isolated from strains expressing the WT or Hsh155V502F Hsh155D563G LBU-mutants in the presence of WT, A258U, or U257C ACT1-CUP1 reporters.	('ACT1', 'Gene', '850504', (158, 162))	('RNA', 'cellular_component', 'GO:0005562', ('36', '39'))	('CUP1', 'Gene', '856450', (163, 167))	('LBU', 'Chemical', '-', (107, 110))	('Hsh155V502F Hsh155D563G', 'Var', (83, 106))	('ACT1', 'Gene', (158, 162))	('CUP1', 'Gene', (163, 167))	('U257C', 'Var', (152, 157))	('A258U', 'Var', (142, 147))	('Hsh155D563G', 'Var', (95, 106))
172726	32320410	The Hsh155V502F LBU-mutant strain was defective in splicing the A258U and U257C reporters, while only a small decrease in splicing of the A258U reporter was observed with the Hsh155D563G mutant (Fig 3B and 3C).	('U257C', 'Var', (74, 79))	('Hsh155V502F LBU-mutant', 'Var', (4, 26))	('Hsh155D563G', 'Var', (175, 186))	('V502F', 'Mutation', 'p.V502F', (10, 15))	('defective', 'NegReg', (38, 47))	('D563G', 'Mutation', 'p.D563G', (181, 186))	('LBU', 'Chemical', '-', (16, 19))	('splicing', 'biological_process', 'GO:0045292', ('51', '59'))	('splicing', 'MPA', (51, 59))	('splicing', 'biological_process', 'GO:0045292', ('122', '130'))	('A258U', 'Protein', (64, 69))
172728	32320410	Only a subset of the mutants (Hsh155V502F and Hsh155D563G) show changes in splicing of reporter pre-mRNAs harboring non-consensus BS.	('Hsh155D563G', 'Var', (46, 57))	('Hsh155V502F', 'Var', (30, 41))	('splicing', 'MPA', (75, 83))	('changes', 'Reg', (64, 71))	('pre', 'molecular_function', 'GO:0003904', ('96', '99'))	('splicing', 'biological_process', 'GO:0045292', ('75', '83'))	('D563G', 'Mutation', 'p.D563G', (52, 57))
172729	32320410	We combined the V502F mutation with two previously characterized MDS-mutant alleles: H331D and D450G.	('H331D', 'Var', (85, 90))	('D450G', 'Var', (95, 100))	('D450G', 'Mutation', 'p.D450G', (95, 100))	('V502F', 'Var', (16, 21))	('V502F', 'Mutation', 'p.V502F', (16, 21))	('H331D', 'Mutation', 'rs755893837', (85, 90))
172730	32320410	These two MDS alleles have opposing effects on splicing of pre-mRNAs with non-consensus BS: H331D inhibits while D450G promotes their splicing.	('promotes', 'PosReg', (119, 127))	('D450G', 'Var', (113, 118))	('D450G', 'Mutation', 'p.D450G', (113, 118))	('splicing', 'biological_process', 'GO:0045292', ('134', '142'))	('splicing', 'MPA', (47, 55))	('splicing', 'MPA', (134, 142))	('splicing', 'biological_process', 'GO:0045292', ('47', '55'))	('H331D', 'Var', (92, 97))	('H331D', 'Mutation', 'rs755893837', (92, 97))	('pre', 'molecular_function', 'GO:0003904', ('59', '62'))	('inhibits', 'NegReg', (98, 106))
172732	32320410	The H331D or D450G mutations still decreased or increased Cu2+ tolerance; however, the addition of the V502F mutation lowered the degree of Cu2+ tolerance overall.	('H331D', 'Mutation', 'rs755893837', (4, 9))	('increased', 'PosReg', (48, 57))	('Cu2+', 'Chemical', '-', (140, 144))	('D450G', 'Var', (13, 18))	('D450G', 'Mutation', 'p.D450G', (13, 18))	('Cu2+ tolerance', 'MPA', (140, 154))	('V502F', 'Mutation', 'p.V502F', (103, 108))	('Cu2+ tolerance', 'MPA', (58, 72))	('decreased', 'NegReg', (35, 44))	('Cu2+', 'Chemical', '-', (58, 62))	('lowered', 'NegReg', (118, 125))	('V502F', 'Var', (103, 108))	('H331D', 'Var', (4, 9))
172733	32320410	The K740R and N747A mutations in HR15 also decrease or increase Cu2+ tolerance in yeast (respectively) when using non-consensus BS reporters.	('decrease', 'NegReg', (43, 51))	('increase', 'PosReg', (55, 63))	('N747A', 'Var', (14, 19))	('yeast', 'Species', '4932', (82, 87))	('N747A', 'Mutation', 'p.N747A', (14, 19))	('Cu2+ tolerance in yeast', 'MPA', (64, 87))	('HR15', 'Gene', (33, 37))	('K740R', 'Mutation', 'p.K740R', (4, 9))	('K740R', 'Var', (4, 9))	('Cu2+', 'Chemical', '-', (64, 68))
172734	32320410	The K740R and N747A mutations in HR15 have not been previously studied in combination with those located in distal HR.	('N747A', 'Var', (14, 19))	('N747A', 'Mutation', 'p.N747A', (14, 19))	('HR15', 'Gene', (33, 37))	('K740R', 'Mutation', 'p.K740R', (4, 9))	('K740R', 'Var', (4, 9))
172735	32320410	Therefore, we combined the N747A or K740R mutations in HR15 with the V502F mutation in HR9.	('HR15', 'Gene', (55, 59))	('N747A', 'Var', (27, 32))	('N747A', 'Mutation', 'p.N747A', (27, 32))	('V502F', 'Mutation', 'p.V502F', (69, 74))	('K740R', 'Var', (36, 41))	('K740R', 'Mutation', 'p.K740R', (36, 41))	('V502F', 'Var', (69, 74))
172736	32320410	The results were similar those observed with the H331D and D450G MDS-mutants in HR5 and HR8 (Fig 4B-4D).	('H331D', 'Mutation', 'rs755893837', (49, 54))	('D450G', 'Var', (59, 64))	('H331D', 'Var', (49, 54))	('D450G', 'Mutation', 'p.D450G', (59, 64))	('HR8', 'Gene', (88, 91))	('HR5', 'Gene', (80, 83))
172737	32320410	The addition of the V502F mutation lowers the degree of Cu2+ tolerance in an additive manner in combination with effects from HR15 mutation.	('V502F', 'Mutation', 'p.V502F', (20, 25))	('lowers', 'NegReg', (35, 41))	('Cu2+', 'Chemical', '-', (56, 60))	('Cu2+ tolerance', 'MPA', (56, 70))	('V502F', 'Var', (20, 25))
172740	32320410	However, Hsh155V502F exacerbated the cs phenotype of Prp2Q548N.	('cs', 'Chemical', '-', (37, 39))	('Prp2Q548N', 'Var', (53, 62))	('V502F', 'Mutation', 'p.V502F', (15, 20))	('Hsh155V502F', 'Var', (9, 20))	('exacerbated', 'PosReg', (21, 32))
172741	32320410	At 23 C, yeast strains containing both Hsh155V502F and Prp2Q548N exhibited a severe defect in growth (Fig 5B).	('Prp2Q548N', 'Var', (55, 64))	('yeast', 'Species', '4932', (9, 14))	('growth', 'MPA', (94, 100))	('Hsh155V502F', 'Var', (39, 50))
172742	32320410	Other LBU-mutants showed little to no change in growth at either 23 C or 16 C (not shown) in the presence of Prp2Q548N.	('LBU', 'Chemical', '-', (6, 9))	('Prp2Q548N', 'Var', (109, 118))	('growth', 'MPA', (48, 54))
172743	32320410	The splicing phenotype displayed by the Hsh155V502F mutant could also arise due to changes in interactions with splicing factors in addition to Prp2.	('splicing factor', 'Gene', '10569', (112, 127))	('splicing', 'biological_process', 'GO:0045292', ('112', '120'))	('splicing', 'MPA', (4, 12))	('V502F', 'Mutation', 'p.V502F', (46, 51))	('interactions', 'Interaction', (94, 106))	('splicing factor', 'Gene', (112, 127))	('arise', 'Reg', (70, 75))	('Hsh155V502F', 'Var', (40, 51))	('changes', 'Reg', (83, 90))	('splicing', 'biological_process', 'GO:0045292', ('4', '12'))
172744	32320410	Tang and coworkers recently defined the Prp5-interacting region of Hsh155 to include HR1-6 and HR9-12 which contains the site of the V502F substitution.	('V502F', 'Mutation', 'p.V502F', (133, 138))	('HR9-12', 'CellLine', 'CVCL:2676', (95, 101))	('Hsh155', 'Gene', (67, 73))	('V502F', 'Var', (133, 138))
172746	32320410	Other tested LBU-mutants with no or weaker splicing phenotypes (Hsh155D563G, E571K) did not significantly alter the two-hybrid interaction.	('LBU', 'Chemical', '-', (13, 16))	('Hsh155D563G', 'Var', (64, 75))	('E571K', 'Var', (77, 82))	('splicing', 'biological_process', 'GO:0045292', ('43', '51'))	('D563G', 'Mutation', 'p.D563G', (70, 75))	('E571K', 'Mutation', 'p.E571K', (77, 82))
172749	32320410	Intriguingly, this interaction is also disrupted by the Hsh155V502F allele but not by LBU-mutants located closer to the observed Hsh155/Prp3 interface (Hsh155D563G, E571K; Fig 1A and Fig 6B).	('Hsh155V502F', 'Var', (56, 67))	('LBU', 'Chemical', '-', (86, 89))	('V502F', 'Mutation', 'p.V502F', (62, 67))	('E571K', 'Var', (165, 170))	('interaction', 'Interaction', (19, 30))	('disrupted', 'Reg', (39, 48))	('Hsh155D563G', 'Var', (152, 163))	('E571K', 'Mutation', 'p.E571K', (165, 170))
172750	32320410	Together, this data suggests that V502F mutation may be causing conformational changes in the Hsh155 structure, disrupting the intermolecular interactions with both Prp3 and Prp5 splicing partners as well as the genetic interaction with Prp2.	('conformational', 'MPA', (64, 78))	('Prp2', 'Protein', (237, 241))	('Prp5', 'Protein', (174, 178))	('Hsh155', 'Gene', (94, 100))	('interaction', 'Interaction', (220, 231))	('V502F', 'Mutation', 'p.V502F', (34, 39))	('intermolecular interactions', 'MPA', (127, 154))	('V502F mutation', 'Var', (34, 48))	('Prp3', 'Protein', (165, 169))	('splicing', 'biological_process', 'GO:0045292', ('179', '187'))	('disrupting', 'NegReg', (112, 122))
172751	32320410	The impact of Hsh155V502F on splicing is likely complex since it potentially interferes with complexes forming at different stages in the splicing reaction.	('splicing', 'biological_process', 'GO:0045292', ('138', '146'))	('V502F', 'Mutation', 'p.V502F', (20, 25))	('Hsh155V502F', 'Var', (14, 25))	('splicing', 'biological_process', 'GO:0045292', ('29', '37'))	('interferes', 'NegReg', (77, 87))	('complexes', 'MPA', (93, 102))
172752	32320410	In this work, we tested the impact of the SF3b1 mutations associated with LBU cancers on splicing in yeast.	('associated', 'Reg', (58, 68))	('LBU cancers', 'Disease', (74, 85))	('LBU cancers', 'Disease', 'MESH:D009369', (74, 85))	('SF3b1', 'Gene', (42, 47))	('tested', 'Reg', (17, 23))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('SF3b1', 'Gene', '23451', (42, 47))	('splicing', 'biological_process', 'GO:0045292', ('89', '97'))	('yeast', 'Species', '4932', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (48, 57))
172754	32320410	Given the high conservation of the splicing machinery between yeast and humans, this suggests that these mutations are not loss of function in humans but alter splicing in more subtle ways.	('splicing', 'MPA', (160, 168))	('alter', 'Reg', (154, 159))	('mutations', 'Var', (105, 114))	('splicing', 'biological_process', 'GO:0045292', ('35', '43'))	('humans', 'Species', '9606', (143, 149))	('yeast', 'Species', '4932', (62, 67))	('splicing', 'biological_process', 'GO:0045292', ('160', '168'))	('humans', 'Species', '9606', (72, 78))
172755	32320410	In support of this, the Hsh155V502F and Hsh155D563G mutants decrease Cu2+-tolerance of yeast in the presence of ACT1-CUP1 reporter pre-mRNAs harboring non-consensus BS.	('ACT1', 'Gene', '850504', (112, 116))	('CUP1', 'Gene', '856450', (117, 121))	('decrease', 'NegReg', (60, 68))	('Hsh155D563G mutants', 'Var', (40, 59))	('ACT1', 'Gene', (112, 116))	('Hsh155V502F', 'Var', (24, 35))	('CUP1', 'Gene', (117, 121))	('Cu2+', 'Chemical', '-', (69, 73))	('pre', 'molecular_function', 'GO:0003904', ('131', '134'))	('yeast', 'Species', '4932', (87, 92))	('Cu2+-tolerance', 'MPA', (69, 83))
172756	32320410	It has previously been noted that cancer-associated mutations in SF3b1 tend to follow a periodicity of 40 amino acids (approximately the size of one HR) and that the mutations tend to cluster along an edge of the protein.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('SF3b1', 'Gene', (65, 70))	('protein', 'cellular_component', 'GO:0003675', ('213', '220'))	('SF3b1', 'Gene', '23451', (65, 70))	('cancer', 'Disease', (34, 40))
172757	32320410	Cretu and co-workers speculated that some cancer-associated mutations in SF3b1 may result in structural perturbations of the HEAT repeat superhelix.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('structural', 'MPA', (93, 103))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('result', 'Reg', (83, 89))	('mutations', 'Var', (60, 69))	('SF3b1', 'Gene', (73, 78))	('SF3b1', 'Gene', '23451', (73, 78))
172760	32320410	SF3b1/Hsh155 is no exception, and cryo-EM analysis of yeast and human spliceosome structures have revealed a number of splicing factors which interact with the SF3b1/Hsh155 HR domain Many of these interactions are transient and likely occur consecutively in an ordered fashion: the HR binds to and then releases Prp5 during spliceosome assembly the HR then interacts with Prp3 in B complex spliceosomes before activation and release of the U4 snRNP (including Prp3), and finally Prp2 docks onto the HR to release U2 proteins including SF3b1/Hsh155 prior to splicing catalysis The ability of the Hsh155V502F mutation studied here as well as other MDS-mutations in Hsh155 to change yeast two-hybrid and genetic interactions with these splicing factors suggests that SF3b1 mutations can perturb splicing at multiple stages.	('SF3b1', 'Gene', '23451', (160, 165))	('SF3b1', 'Gene', (764, 769))	('splicing factor', 'Gene', (119, 134))	('interactions', 'Interaction', (709, 721))	('spliceosome', 'cellular_component', 'GO:0005681', ('324', '335'))	('splicing factor', 'Gene', (733, 748))	('mutations', 'Var', (770, 779))	('splicing', 'biological_process', 'GO:0045292', ('792', '800'))	('splicing factor', 'Gene', '10569', (733, 748))	('SF3b1', 'Gene', (0, 5))	('spliceosome', 'cellular_component', 'GO:0005681', ('70', '81'))	('splicing at multiple stages', 'MPA', (792, 819))	('splicing', 'biological_process', 'GO:0045292', ('119', '127'))	('splicing', 'biological_process', 'GO:0045292', ('557', '565'))	('spliceosome assembly', 'biological_process', 'GO:0000245', ('324', '344'))	('snRNP', 'molecular_function', 'GO:0003734', ('443', '448'))	('human', 'Species', '9606', (64, 69))	('SF3b1', 'Gene', (160, 165))	('SF3b1', 'Gene', '23451', (535, 540))	('splicing factor', 'Gene', '10569', (119, 134))	('yeast', 'Species', '4932', (54, 59))	('splicing', 'biological_process', 'GO:0045292', ('733', '741'))	('yeast', 'Species', '4932', (680, 685))	('SF3b1', 'Gene', '23451', (764, 769))	('U4 snRNP', 'cellular_component', 'GO:0005687', ('440', '448'))	('V502F', 'Mutation', 'p.V502F', (601, 606))	('SF3b1', 'Gene', '23451', (0, 5))	('snRNP', 'Gene', (443, 448))	('perturb', 'Reg', (784, 791))	('snRNP', 'Gene', '57819', (443, 448))	('SF3b1', 'Gene', (535, 540))
172761	32320410	While most models for SF3b1 dysfunction in cancer have focused on steps involved in BS recognition and U2 loading, it is possible that some degree of splicing dysregulation occurs through disruption of later steps.	('SF3b1', 'Gene', '23451', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('splicing dysregulation', 'MPA', (150, 172))	('cancer', 'Disease', (43, 49))	('splicing', 'biological_process', 'GO:0045292', ('150', '158'))	('dysfunction', 'Var', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('SF3b1', 'Gene', (22, 27))
172762	32320410	For example, some alternative BS may be used due to their ability to assemble spliceosomes that can be successfully activated through altered interactions between SF3b1 and the human homologs of Prp2 and/or Prp3.	('SF3b1', 'Gene', '23451', (163, 168))	('interactions', 'Interaction', (142, 154))	('Prp3', 'Gene', (207, 211))	('human', 'Species', '9606', (177, 182))	('altered', 'Var', (134, 141))	('Prp2', 'Protein', (195, 199))	('SF3b1', 'Gene', (163, 168))
172764	32320410	Understanding how mutant alleles of SF3b1 give rise to particular RNA isoforms and lead to disease may therefore require detailed investigations into the entire splicing pathway from start to finish.	('RNA', 'cellular_component', 'GO:0005562', ('66', '69'))	('SF3b1', 'Gene', (36, 41))	('splicing', 'biological_process', 'GO:0045292', ('161', '169'))	('SF3b1', 'Gene', '23451', (36, 41))	('RNA isoforms', 'MPA', (66, 78))	('mutant', 'Var', (18, 24))	('disease', 'Disease', (91, 98))	('lead to', 'Reg', (83, 90))	('give rise', 'Reg', (42, 51))
172769	32320410	Yeast strains expressing WT or mutant proteins were grown to mid-log phase at 30 C in YPD liquid media.	('proteins', 'Protein', (38, 46))	('mutant', 'Var', (31, 37))	('Yeast', 'Species', '4932', (0, 5))
172771	32320410	Copper resistant growth assays were performed using yeast strains expressing WT Hsh155 or mutant Hsh155 alleles and ACT1-CUP1 reporters.	('ACT1', 'Gene', '850504', (116, 120))	('CUP1', 'Gene', '856450', (121, 125))	('mutant', 'Var', (90, 96))	('Copper', 'Chemical', 'MESH:D003300', (0, 6))	('Hsh155', 'Gene', (97, 103))	('ACT1', 'Gene', (116, 120))	('CUP1', 'Gene', (121, 125))	('yeast', 'Species', '4932', (52, 57))
172775	32320410	LBU-mutants of Hsh155 (V502F, D563G, and E571K) were derived from a plasmid (pAAH0499), which generates a GAL4 activation domain fused with Hsh155 The open reading frames of Prp5 and Prp3 were fused to the C-terminus of the GAL4-DNA binding domain in plasmid pGBKT7 Each pair of the plasmids was transformed into the S. cerevisiae strain Y2H GOLD (Takara Biosciences; Mountain View, CA).	('D563G', 'Var', (30, 35))	('S. cerevisiae', 'Species', '4932', (317, 330))	('E571K', 'Mutation', 'p.E571K', (41, 46))	('LBU', 'Chemical', '-', (0, 3))	('GAL4', 'Gene', (106, 110))	('D563G', 'Mutation', 'p.D563G', (30, 35))	('GAL4', 'Gene', '855828', (224, 228))	('V502F', 'Var', (23, 28))	('Hsh155', 'Gene', (15, 21))	('GAL4', 'Gene', (224, 228))	('DNA', 'cellular_component', 'GO:0005574', ('229', '232'))	('DNA binding', 'molecular_function', 'GO:0003677', ('229', '240'))	('E571K', 'Var', (41, 46))	('V502F', 'Mutation', 'p.V502F', (23, 28))	('GAL4', 'Gene', '855828', (106, 110))	('Hsh155 The', 'Mutation', 'c.155HSH>THE', (140, 150))
172778	32320410	26 Feb 2020  PONE-D-20-02992 Impact of Cancer-Associated Mutations in Hsh155/SF3b1 HEAT Repeats 9-12 on pre-mRNA Splicing in Saccharomyces cerevisiae PLOS ONE Dear Dr hoskins, Thank you for submitting your manuscript to PLOS ONE.	('SF3b1', 'Gene', (77, 82))	('Cancer', 'Disease', 'MESH:D009369', (39, 45))	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Mutations', 'Var', (57, 66))	('SF3b1', 'Gene', '23451', (77, 82))	('Saccharomyces cerevisiae', 'Species', '4932', (125, 149))	('pre-mRNA Splicing', 'biological_process', 'GO:0000398', ('104', '121'))	('PONE-D-20-02992', 'Chemical', '-', (13, 28))	('pre', 'molecular_function', 'GO:0003904', ('104', '107'))	('Cancer', 'Disease', (39, 45))
172781	32320410	(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Aaron Hoskins and co-authors use yeast genetic systems to investigate the functional consequences of a subset of cancer-associated mutations in the pre-mRNA splicing factor SF3B1 (called Hsh155 in yeast).	('mutations', 'Var', (221, 230))	('SF3B1', 'Gene', '23451', (263, 268))	('yeast', 'Species', '4932', (287, 292))	('splicing factor', 'Gene', '10569', (247, 262))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('238', '255'))	('yeast', 'Species', '4932', (123, 128))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('pre', 'molecular_function', 'GO:0003904', ('238', '241'))	('SF3B1', 'Gene', (263, 268))	('splicing factor', 'Gene', (247, 262))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
172782	32320410	They focus on a subset of mutations concentrated in HR9-12 and associated with AML, bladder and uterine cancers.	('AML', 'Disease', (79, 82))	('HR9-12', 'Gene', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('uterine cancers', 'Phenotype', 'HP:0010784', (96, 111))	('bladder', 'Disease', (84, 91))	('associated', 'Reg', (63, 73))	('HR9-12', 'CellLine', 'CVCL:2676', (52, 58))	('mutations', 'Var', (26, 35))	('AML', 'Disease', 'MESH:D015470', (79, 82))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
172783	32320410	Incorporation of the mutants in the yeast homologue has no detectable effect on cell proliferation or temperature sensitivity.	('mutants', 'Var', (21, 28))	('cell proliferation', 'CPA', (80, 98))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('yeast', 'Species', '4932', (36, 41))
172784	32320410	Likewise, most mutations had little effect on splicing of an ACT1-CUP1 reporter.	('CUP1', 'Gene', '856450', (66, 70))	('ACT1', 'Gene', '850504', (61, 65))	('mutations', 'Var', (15, 24))	('CUP1', 'Gene', (66, 70))	('splicing', 'biological_process', 'GO:0045292', ('46', '54'))	('ACT1', 'Gene', (61, 65))	('splicing', 'MPA', (46, 54))
172785	32320410	In particular, Hsh155V502F was defective in splicing ACT1-CUP1 when the BPS was degenerate.	('CUP1', 'Gene', '856450', (58, 62))	('splicing', 'MPA', (44, 52))	('ACT1', 'Gene', (53, 57))	('CUP1', 'Gene', (58, 62))	('defective', 'NegReg', (31, 40))	('Hsh155V502F', 'Var', (15, 26))	('splicing', 'biological_process', 'GO:0045292', ('44', '52'))	('ACT1', 'Gene', '850504', (53, 57))
172786	32320410	Hsh155V502F reduced genetic/two-hybrid interactions with Prp2 and Prp5 helicases or Prp3 U4/U6 subunit compared to WT Hsh155.	('V502F', 'Mutation', 'p.V502F', (6, 11))	('genetic/two-hybrid', 'CPA', (20, 38))	('Prp5 helicases', 'Protein', (66, 80))	('reduced', 'NegReg', (12, 19))	('Hsh155V502F', 'Var', (0, 11))	('Prp2', 'Protein', (57, 61))
172787	32320410	These results provide new insights to the field, since few studies of mutations in SF3B1 HR9-12 are available compared to the well-characterized, MDS-associated mutations of HR4-8.	('mutations', 'Var', (70, 79))	('HR9-12', 'CellLine', 'CVCL:2676', (89, 95))	('SF3B1', 'Gene', (83, 88))	('MDS-associated', 'Disease', (146, 160))	('SF3B1', 'Gene', '23451', (83, 88))	('HR9-12', 'Gene', (89, 95))
172793	32320410	5) Only one of the mutations studied, V502F, has a significant effect on splicing.	('splicing', 'biological_process', 'GO:0045292', ('73', '81'))	('V502F', 'Var', (38, 43))	('V502F', 'Mutation', 'p.V502F', (38, 43))	('splicing', 'MPA', (73, 81))
172794	32320410	6) The mutations are shown mapped on the HSH155 structure, but the structure has not been related to the consequences of the mutations in the text.	('HSH155', 'Gene', '855332', (41, 47))	('HSH155', 'Gene', (41, 47))	('mutations', 'Var', (7, 16))
172796	32320410	For example, the Cretu SF3B1 structure Mol Cell (2016) discuss the likely unfolding or partial unfolding of HEAT repeats by the MDS-associated SF3B1 mutations.	('mutations', 'Var', (149, 158))	('unfolding', 'MPA', (74, 83))	('SF3B1', 'Gene', '23451', (23, 28))	('SF3B1', 'Gene', (143, 148))	('MDS-associated', 'Disease', (128, 142))	('SF3B1', 'Gene', '23451', (143, 148))	('SF3B1', 'Gene', (23, 28))
172797	32320410	It is hard to see in the figures, but it appears that V502 is partially buried between HEAT repeats, such that a mutation to bulky F could locally unfold this region.	('mutation', 'Var', (113, 121))	('V502', 'Chemical', '-', (54, 58))	('V502', 'Var', (54, 58))
172798	32320410	7) Since V502 is Leucine in humans, would the authors expect the effects of an L502F mutation to be as severe as in yeast?	('L502F', 'Var', (79, 84))	('V502', 'Var', (9, 13))	('Leucine', 'Chemical', 'MESH:D007930', (17, 24))	('yeast', 'Species', '4932', (116, 121))	('L502F', 'Mutation', 'p.L502F', (79, 84))	('humans', 'Species', '9606', (28, 34))	('V502', 'Chemical', '-', (9, 13))
172799	32320410	Reviewer #2: In the manuscript "Impact of Cancer-Associated Mutations in Hsh155/SF3b1 HEAT Repeats 9-12 on Pre-mRNA Splicing in Saccharomyces cerevisiae," Hoskins and colleagues analyze the effect of incorporating several cancer-relevant mutations into the yeast homolog of SF3b1, Hsh155.	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('SF3b1', 'Gene', '23451', (274, 279))	('Saccharomyces cerevisiae', 'Species', '4932', (128, 152))	('SF3b1', 'Gene', (274, 279))	('cancer', 'Disease', (222, 228))	('Mutations', 'Var', (60, 69))	('Cancer', 'Disease', 'MESH:D009369', (42, 48))	('Cancer', 'Disease', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('Cancer', 'Phenotype', 'HP:0002664', (42, 48))	('yeast', 'Species', '4932', (257, 262))	('SF3b1', 'Gene', (80, 85))	('SF3b1', 'Gene', '23451', (80, 85))
172800	32320410	The authors find that the hotspot mutation V502F affects splicing of introns with non-consensus branch site (BS) sequences and shows genetic interactions and altered physical interactions with several splicing factors.	('interactions', 'Interaction', (175, 187))	('splicing', 'biological_process', 'GO:0045292', ('201', '209'))	('splicing factor', 'Gene', (201, 216))	('V502F', 'Var', (43, 48))	('splicing', 'biological_process', 'GO:0045292', ('57', '65'))	('splicing of introns', 'MPA', (57, 76))	('affects', 'Reg', (49, 56))	('interactions', 'Interaction', (141, 153))	('altered', 'Reg', (158, 165))	('splicing factor', 'Gene', '10569', (201, 216))	('V502F', 'Mutation', 'p.V502F', (43, 48))
172802	32320410	It is interesting that of the mutations tested, mutation of the BP adenosine (A259G) has the least sensitivity to copper when compared to the other mutations?	('least', 'NegReg', (93, 98))	('copper', 'Chemical', 'MESH:D003300', (114, 120))	('sensitivity to copper', 'MPA', (99, 120))	('adenosine', 'Chemical', 'MESH:D000241', (67, 76))	('mutation', 'Var', (48, 56))	('A259G', 'Mutation', 'rs138172773', (78, 83))
172803	32320410	10.1371/journal.pone.0229315.r002  19 Mar 2020  Reviewer #1: Aaron Hoskins and co-authors use yeast genetic systems to investigate the functional consequences of a subset of cancer-associated mutations in the pre-mRNA splicing factor SF3B1 (called Hsh155 in yeast).	('yeast', 'Species', '4932', (94, 99))	('splicing factor', 'Gene', '10569', (218, 233))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('209', '226'))	('SF3B1', 'Gene', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('yeast', 'Species', '4932', (258, 263))	('SF3B1', 'Gene', '23451', (234, 239))	('splicing factor', 'Gene', (218, 233))	('mutations', 'Var', (192, 201))	('pre', 'molecular_function', 'GO:0003904', ('209', '212'))
172804	32320410	with respect to the diseases mentioned in the introduction and have included the number of mutations observed in HR9-12 along with the number of samples studied and more detailed information on SF3b1L833F/Hsh155V502F (pg 5, Lines 85-90).	('V502F', 'Mutation', 'p.V502F', (211, 216))	('HR9-12', 'CellLine', 'CVCL:2676', (113, 119))	('HR9-12', 'Gene', (113, 119))	('SF3b1L833F/Hsh155V502F', 'Var', (194, 216))
172806	32320410	Reviewer comments 5-7 all address interpretation of the V502F mutation.	('address', 'Reg', (26, 33))	('V502F', 'Var', (56, 61))	('V502F', 'Mutation', 'p.V502F', (56, 61))
172807	32320410	We predict that the packing of the alpha helices is disrupted by this mutation (in agreement with hypotheses made by Cretu) and it is likely this disruption also occurs with humans.	('packing', 'MPA', (20, 27))	('mutation', 'Var', (70, 78))	('disrupted', 'NegReg', (52, 61))	('humans', 'Species', '9606', (174, 180))
172810	32320410	Importantly, regardless of its identity our interpretation of the data remain valid: the Hsh155V502F and Hsh155D563G mutants produce less of the correct mRNA product than WT and this is consistent with ACT1-CUP1 growth data.	('ACT1', 'Gene', '850504', (202, 206))	('Hsh155D563G', 'Var', (105, 116))	('Hsh155V502F', 'Var', (89, 100))	('mRNA product', 'MPA', (153, 165))	('CUP1', 'Gene', '856450', (207, 211))	('less', 'NegReg', (133, 137))	('ACT1', 'Gene', (202, 206))	('CUP1', 'Gene', (207, 211))
172811	32320410	We have previously observed this phenomenon with other SF3b1/Hsh155 mutations (see studies by Carrocci and Hoskins).	('mutations', 'Var', (68, 77))	('SF3b1', 'Gene', '23451', (55, 60))	('SF3b1', 'Gene', (55, 60))
172813	32320410	23 Mar 2020  Impact of Cancer-Associated Mutations in Hsh155/SF3b1 HEAT Repeats 9-12 on pre-mRNA Splicing in Saccharomyces cerevisiae PONE-D-20-02992R1 Dear Dr. hoskins, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.	('SF3b1', 'Gene', '23451', (61, 66))	('SF3b1', 'Gene', (61, 66))	('Cancer', 'Disease', (23, 29))	('pre', 'molecular_function', 'GO:0003904', ('88', '91'))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('PONE-D-20-02992', 'Chemical', '-', (134, 149))	('Saccharomyces cerevisiae', 'Species', '4932', (109, 133))	('pre-mRNA Splicing', 'biological_process', 'GO:0000398', ('88', '105'))	('Mutations', 'Var', (41, 50))
172814	32320410	24 Mar 2020  PONE-D-20-02992R1  Impact of Cancer-Associated Mutations in Hsh155/SF3b1 HEAT Repeats 9-12 on pre-mRNA Splicing in Saccharomyces cerevisiae  Dear Dr. Hoskins: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE.	('Saccharomyces cerevisiae', 'Species', '4932', (128, 152))	('pre', 'molecular_function', 'GO:0003904', ('107', '110'))	('Mutations', 'Var', (60, 69))	('Cancer', 'Disease', 'MESH:D009369', (42, 48))	('Cancer', 'Disease', (42, 48))	('Cancer', 'Phenotype', 'HP:0002664', (42, 48))	('pre-mRNA Splicing', 'biological_process', 'GO:0000398', ('107', '124'))	('PONE-D-20-02992', 'Chemical', '-', (13, 28))	('SF3b1', 'Gene', (80, 85))	('SF3b1', 'Gene', '23451', (80, 85))
172826	31576137	Previous studies have shown that infiltrating immune cells, especially lymphocytes, play an important role in anti-tumor immunity and the presence of tumor-infiltrating lymphocytes (TILs) has been associated with favorable prognosis in several neoplasms.	('presence', 'Var', (138, 146))	('neoplasms', 'Disease', 'MESH:D009369', (244, 253))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('neoplasms', 'Disease', (244, 253))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('neoplasms', 'Phenotype', 'HP:0002664', (244, 253))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
172832	31576137	In prostate cancer, relevant studies have identified genomic defects in DNA repair in 20-30% of advanced castration-resistant prostate cancer cases, BRCA2 gene alterations are particularly prevalent and are correlated with poor prognosis as well as poor responses to systemic therapy for castration-resistant prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('DNA repair', 'biological_process', 'GO:0006281', ('72', '82'))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('prevalent', 'Reg', (189, 198))	('prostate cancer', 'Disease', 'MESH:D011471', (309, 324))	('BRCA2', 'Gene', (149, 154))	('DNA repair', 'Gene', (72, 82))	('prostate cancer', 'Phenotype', 'HP:0012125', (309, 324))	('alterations', 'Var', (160, 171))	('prostate cancer', 'Disease', (309, 324))	('prostate cancer', 'Disease', 'MESH:D011471', (126, 141))	('prostate cancer', 'Phenotype', 'HP:0012125', (126, 141))	('BRCA2', 'Gene', '675', (149, 154))	('prostate cancer', 'Disease', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
172833	31576137	Teo's study claimed that DDR alterations are independently associated with response to PD-1/PD-L1 blockade and platinum-based treatments in patients with advanced urothelial carcinoma.	('platinum', 'Chemical', 'MESH:D010984', (111, 119))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (163, 183))	('PD-L1', 'Gene', (92, 97))	('DDR', 'Gene', (25, 28))	('associated', 'Reg', (59, 69))	('alterations', 'Var', (29, 40))	('PD-1', 'Gene', (87, 91))	('PD-1', 'Gene', '5133', (87, 91))	('patients', 'Species', '9606', (140, 148))	('PD-L1', 'Gene', '29126', (92, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('urothelial carcinoma', 'Disease', (163, 183))
172865	31576137	Kaplan-Meier analysis and log-rank tests demonstrated that low expression of IRF3 (p=0.0091) CD4 (p=0.0075), CD8 (p=0.0086) and high expression of polbeta (p=0.0471) were associated with shorter DFS (Figure 1); high expression of APE1 (p=0.026), polbeta (p=0.001), and low expression of CD4 (p=0.0042), CD8 (p=0.0009), IRF3 (p=0.0266) were correlated with poor OS (Figure 2).	('poor OS', 'Disease', (356, 363))	('CD4', 'Gene', '920', (93, 96))	('shorter', 'NegReg', (187, 194))	('IRF3', 'Gene', '3661', (77, 81))	('CD8', 'Gene', '925', (109, 112))	('polbeta', 'Gene', '5423', (246, 253))	('CD4', 'Gene', (93, 96))	('polbeta', 'Gene', (147, 154))	('CD8', 'Gene', (303, 306))	('low', 'NegReg', (269, 272))	('high expression', 'Var', (128, 143))	('IRF3', 'Gene', (319, 323))	('p=0.0471', 'Var', (156, 164))	('p=0.0086', 'Var', (114, 122))	('DFS', 'MPA', (195, 198))	('APE1', 'Gene', '328', (230, 234))	('CD4', 'Gene', '920', (287, 290))	('CD8', 'Gene', (109, 112))	('IRF3', 'Gene', '3661', (319, 323))	('polbeta', 'Gene', (246, 253))	('low', 'NegReg', (59, 62))	('polbeta', 'Gene', '5423', (147, 154))	('CD8', 'Gene', '925', (303, 306))	('IRF3', 'Gene', (77, 81))	('CD4', 'Gene', (287, 290))	('APE1', 'Gene', (230, 234))
172874	31576137	Genome instability and mutation is the hallmark of cancer.	('mutation', 'Var', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Genome instability', 'CPA', (0, 18))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
172876	31576137	On the other hand, a large number of recent basic studies have found that genome instability can further activate innate and adaptive immunity by releasing dangerous signals such as dsDNA and being recognized by pattern recognition receptors such as cGAS-STING pathway.	('genome instability', 'Var', (74, 92))	('releasing', 'PosReg', (146, 155))	('cGAS', 'Gene', (250, 254))	('dsDNA', 'Disease', (182, 187))	('activate', 'PosReg', (105, 113))	('cGAS', 'Gene', '115004', (250, 254))
172878	31576137	The main findings are: high expression of IRF3 is associated with better prognosis, regardless of DFS or OS.	('IRF3', 'Gene', (42, 46))	('IRF3', 'Gene', '3661', (42, 46))	('high expression', 'Var', (23, 38))
172879	31576137	In addition, high expression of APE1, polbeta is associated with poor prognosis.	('high', 'Var', (13, 17))	('APE1', 'Gene', (32, 36))	('APE1', 'Gene', '328', (32, 36))	('polbeta', 'Gene', '5423', (38, 45))	('polbeta', 'Gene', (38, 45))
172886	31576137	Consistent with previous studies, our study found that high expression of APE1 was associated with adverse OS; however, the relationship between APE1 and DFS was not found, nor was the difference between APE1 in low-grade and high-grade urothelial cancer, muscle invasion and non-muscle invasion found.	('adverse OS', 'Disease', (99, 109))	('APE1', 'Gene', (145, 149))	('urothelial cancer', 'Disease', 'MESH:D014523', (237, 254))	('APE1', 'Gene', '328', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('APE1', 'Gene', (204, 208))	('urothelial cancer', 'Disease', (237, 254))	('APE1', 'Gene', (74, 78))	('muscle invasion', 'Disease', (280, 295))	('high expression', 'Var', (55, 70))	('associated', 'Reg', (83, 93))	('muscle invasion', 'Disease', (256, 271))	('APE1', 'Gene', '328', (204, 208))	('APE1', 'Gene', '328', (74, 78))	('muscle invasion', 'Disease', 'MESH:D019042', (280, 295))	('muscle invasion', 'Disease', 'MESH:D019042', (256, 271))
172889	31576137	polbeta is responsible for inserting the correct bases into the DNA backbone of the APE1-cut DNA in the BER pathway and restoring the correct base pairing of the DNA strand.	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('base pairing', 'MPA', (142, 154))	('DNA', 'cellular_component', 'GO:0005574', ('162', '165'))	('APE1', 'Gene', (84, 88))	('base pairing', 'molecular_function', 'GO:0003676', ('142', '154'))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('polbeta', 'Gene', '5423', (0, 7))	('APE1', 'Gene', '328', (84, 88))	('polbeta', 'Gene', (0, 7))	('restoring', 'PosReg', (120, 129))	('BER', 'biological_process', 'GO:0006284', ('104', '107'))	('inserting', 'Var', (27, 36))
172890	31576137	A large number of studies have found that mutations in polbeta at some key sites are associated with susceptibility to cancer, and some somatic mutations are associated with resistance to platinum treatment.	('polbeta', 'Gene', (55, 62))	('associated with', 'Reg', (158, 173))	('resistance', 'CPA', (174, 184))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('platinum', 'Chemical', 'MESH:D010984', (188, 196))	('polbeta', 'Gene', '5423', (55, 62))	('mutations', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('associated', 'Reg', (85, 95))
172892	31576137	In this study, polbeta was found to have worse prognosis in patients with high expression of UTUC in terms of protein expression, and it was found to be negatively correlated with tumor-infiltrating CD8+ T lymphocytes, the mechanism of which remains to be further studied.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('high expression', 'Var', (74, 89))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('polbeta', 'Gene', '5423', (15, 22))	('polbeta', 'Gene', (15, 22))	('negatively', 'NegReg', (153, 163))	('CD8', 'Gene', (199, 202))	('patients', 'Species', '9606', (60, 68))	('tumor', 'Disease', (180, 185))	('protein expression', 'MPA', (110, 128))	('CD8', 'Gene', '925', (199, 202))	('UTUC', 'Gene', (93, 97))
172908	31576137	In this study, univariate analysis showed that CD4 and CD8 are prognostic factors of DFS and OS, but only CD8 function as an independent prognostic factor after multivariate analysis, and high expression CD8 was associated with good prognosis.	('CD8', 'Gene', '925', (204, 207))	('CD4', 'Gene', '920', (47, 50))	('DFS', 'Disease', (85, 88))	('CD8', 'Gene', (106, 109))	('high expression', 'Var', (188, 203))	('CD8', 'Gene', '925', (106, 109))	('CD8', 'Gene', (55, 58))	('CD8', 'Gene', '925', (55, 58))	('CD8', 'Gene', (204, 207))	('CD4', 'Gene', (47, 50))
172914	30987376	Contingencies of UTX/KDM6A Action in Urothelial Carcinoma The histone demethylase Ubiquitously Transcribed Tetratricopeptide Repeat Protein X-Linked (UTX/KDM6A) demethylates H3K27me2/3 at genes and enhancers and is often inactivated by mutations in urothelial carcinoma (UC).	('KDM6A', 'Gene', (154, 159))	('UTX', 'Gene', '7403', (17, 20))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (249, 269))	('demethylates', 'Var', (161, 173))	('KDM6A', 'Gene', (21, 26))	('KDM6A', 'Gene', '7403', (154, 159))	('urothelial carcinoma', 'Disease', (249, 269))	('H3K27me2/3', 'Var', (174, 184))	('KDM6A', 'Gene', '7403', (21, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('mutations', 'Var', (236, 245))	('UTX', 'Gene', (150, 153))	('Carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('Urothelial Carcinoma', 'Disease', (37, 57))	('UTX', 'Gene', '7403', (150, 153))	('UTX', 'Gene', (17, 20))	('Urothelial Carcinoma', 'Disease', 'MESH:D014526', (37, 57))
172915	30987376	We have investigated the consequences of moderate UTX overexpression across a range of UC cell lines with or without mutations in KDM6A or its interaction partners and in a normal control cell line.	('mutations', 'Var', (117, 126))	('interaction', 'Interaction', (143, 154))	('overexpression', 'PosReg', (54, 68))	('KDM6A', 'Gene', '7403', (130, 135))	('UTX', 'Gene', (50, 53))	('UTX', 'Gene', '7403', (50, 53))	('KDM6A', 'Gene', (130, 135))
172919	30987376	The histone demethylase Ubiquitously Transcribed Tetratricopeptide Repeat Protein X-Linked (UTX, also known as Lysine demethylase 6A, gene name KDM6A) demethylates K27me2/3 on histone 3 (H3), which is usually associated with gene activation.	('Lysine demethylase 6A', 'Gene', '7403', (111, 132))	('KDM6A', 'Gene', (144, 149))	('Lysine demethylase 6A', 'Gene', (111, 132))	('KDM6A', 'Gene', '7403', (144, 149))	('demethylates K27me2/3', 'Var', (151, 172))	('K27me2/3', 'Var', (164, 172))	('UTX', 'Gene', (92, 95))	('histone 3 (H3', 'Gene', '126961', (176, 189))	('UTX', 'Gene', '7403', (92, 95))
172925	30987376	In other cancer types, UTX function is compromised or abolished by deleterious mutations in the KDM6A gene.	('cancer', 'Disease', (9, 15))	('KDM6A', 'Gene', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('UTX', 'Gene', (23, 26))	('abolished', 'NegReg', (54, 63))	('KDM6A', 'Gene', '7403', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('UTX', 'Gene', '7403', (23, 26))	('mutations', 'Var', (79, 88))
172926	30987376	While the consequences of UTX inactivation are not fully understood, studies on hematological malignancies and pancreatic carcinoma, among others, suggest that it leads to a general increase in H3K27 trimethylation, a redistribution of H3K4 methylation, altered activity of enhancers, and ultimately gene transcription patterns.	('hematological malignancies', 'Disease', (80, 106))	('redistribution', 'Reg', (218, 232))	('increase', 'PosReg', (182, 190))	('activity', 'MPA', (262, 270))	('methylation', 'MPA', (241, 252))	('altered', 'Reg', (254, 261))	('inactivation', 'Var', (30, 42))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (111, 131))	('pancreatic carcinoma', 'Disease', (111, 131))	('H3K4', 'Protein', (236, 240))	('H3K27', 'Protein', (194, 199))	('transcription', 'biological_process', 'GO:0006351', ('305', '318'))	('UTX', 'Gene', (26, 29))	('UTX', 'Gene', '7403', (26, 29))	('hematological malignancies', 'Disease', 'MESH:D019337', (80, 106))	('enhancers', 'MPA', (274, 283))	('trimethylation', 'MPA', (200, 214))	('transcription', 'MPA', (305, 318))	('hematological malignancies', 'Phenotype', 'HP:0004377', (80, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('methylation', 'biological_process', 'GO:0032259', ('241', '252'))
172929	30987376	Among all cancer types, deleterious KDM6A mutations are most frequent in urothelial carcinoma (UC), the most common histological type of urinary bladder cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('bladder cancer', 'Disease', 'MESH:D001749', (145, 159))	('urothelial carcinoma', 'Disease', (73, 93))	('cancer', 'Disease', (153, 159))	('KDM6A', 'Gene', '7403', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('frequent', 'Reg', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (73, 93))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('KDM6A', 'Gene', (36, 41))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (10, 16))	('bladder cancer', 'Disease', (145, 159))
172932	30987376	While KDM6A mutations are found across all UC stages and subtypes, their frequency varies and is particularly high in non-muscle-invasive low-grade papillary tumors, with up to 70% in female patients, whereas the frequency is around 25% in muscle-invasive tumors.	('KDM6A', 'Gene', (6, 11))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('patients', 'Species', '9606', (191, 199))	('papillary tumors', 'Disease', (148, 164))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (240, 262))	('papillary tumors', 'Disease', 'MESH:D002291', (148, 164))	('mutations', 'Var', (12, 21))	('muscle-invasive tumors', 'Disease', (240, 262))	('KDM6A', 'Gene', '7403', (6, 11))	('papillary tumors', 'Phenotype', 'HP:0007482', (148, 164))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('high', 'Reg', (110, 114))
172934	30987376	observed no differences in monolayer growth of T-24-T cells with a homozygous KDM6A nonsense mutation following transfection of a UTX expression plasmid.	('T-24-T', 'CellLine', 'CVCL:M892', (47, 53))	('nonsense mutation', 'Var', (84, 101))	('KDM6A', 'Gene', '7403', (78, 83))	('KDM6A', 'Gene', (78, 83))	('UTX', 'Gene', (130, 133))	('monolayer growth', 'CPA', (27, 43))	('UTX', 'Gene', '7403', (130, 133))
172936	30987376	found an increase in cell proliferation over nine days following KDM6A knockout in two UC cell lines (HT-1197 and UM-UC-3).	('cell proliferation', 'biological_process', 'GO:0008283', ('21', '39'))	('KDM6A', 'Gene', (65, 70))	('cell proliferation', 'CPA', (21, 39))	('knockout', 'Var', (71, 79))	('increase', 'PosReg', (9, 17))	('KDM6A', 'Gene', '7403', (65, 70))	('HT-1197', 'CellLine', 'CVCL:1291', (102, 109))
172937	30987376	observed a slight increase in proliferation following KDM6A knockout in the papillary UC cell line RT-4, whereas restoration of KDM6A in the Ku-19-19 cell line, which has a homozygous KDM6A mutation, did not appear to affect the basal proliferative activity of this cell line.	('mutation', 'Var', (190, 198))	('increase', 'PosReg', (18, 26))	('basal proliferative activity', 'CPA', (229, 257))	('KDM6A', 'Gene', '7403', (128, 133))	('knockout', 'Var', (60, 68))	('KDM6A', 'Gene', '7403', (54, 59))	('RT-4', 'CellLine', 'CVCL:0036', (99, 103))	('KDM6A', 'Gene', (128, 133))	('KDM6A', 'Gene', (184, 189))	('KDM6A', 'Gene', (54, 59))	('KDM6A', 'Gene', '7403', (184, 189))	('proliferation', 'CPA', (30, 43))
172938	30987376	Interestingly, UC cell lines with constitutive or engineered KDM6A inactivation were more sensitive to inhibitors of the H3K27 methyltransferase EZH2, the UTX antagonist.	('inactivation', 'Var', (67, 79))	('engineered', 'Var', (50, 60))	('KDM6A', 'Gene', '7403', (61, 66))	('UTX', 'Gene', '7403', (155, 158))	('EZH2', 'Gene', '2146', (145, 149))	('H3K27 methyltransferase', 'Enzyme', (121, 144))	('EZH2', 'Gene', (145, 149))	('KDM6A', 'Gene', (61, 66))	('inhibitors', 'MPA', (103, 113))	('sensitive', 'MPA', (90, 99))	('UTX', 'Gene', (155, 158))
172939	30987376	In preliminary work, we had observed quite variable responses of UC cell lines to plasmid-based overexpression or knockdown of UTX, especially with respect to long-term clonogenicity.	('UTX', 'Gene', (127, 130))	('knockdown', 'Var', (114, 123))	('UTX', 'Gene', '7403', (127, 130))	('overexpression', 'PosReg', (96, 110))
172941	30987376	To this end, we used a lentiviral vector to transduce UTX fused C-terminally to TagGFP2 or TagGFP2 only into various UC cell lines (UCCs) with different endogenous KDM6A status, as well as into a newly engineered UC KDM6A knockout cell line and into a non-transformed immortalized urothelial cell line.	('KDM6A', 'Gene', (216, 221))	('KDM6A', 'Gene', (164, 169))	('KDM6A', 'Gene', '7403', (216, 221))	('KDM6A', 'Gene', '7403', (164, 169))	('UTX', 'Gene', (54, 57))	('TagGFP2', 'Var', (80, 87))	('UTX', 'Gene', '7403', (54, 57))	('TagGFP2', 'Var', (91, 98))
172946	30987376	RT112 from a female patient contains a frame-shift mutation in one allele, but expresses UTX from the other one.	('frame-shift mutation', 'Var', (39, 59))	('patient', 'Species', '9606', (20, 27))	('UTX', 'Gene', (89, 92))	('UTX', 'Gene', '7403', (89, 92))	('RT112', 'Gene', (0, 5))
172947	30987376	VM-CUB-1 contains a homozygous, relatively conservative missense mutation (I237N) in one of the UTX TPR repeats.	('UTX', 'Gene', '7403', (96, 99))	('I237N', 'Var', (75, 80))	('I237N', 'Mutation', 'p.I237N', (75, 80))	('VM-CUB-1', 'Gene', (0, 8))	('UTX', 'Gene', (96, 99))
172948	30987376	In addition, we investigated 639-V, a cell line wild-type for KDM6A, but containing mutations in two important COMPASS genes (KMT2C and KMT2D), as well as two cell lines lacking functional UTX, namely Ku-19-19, which is homozygous for a KDM6A nonsense mutation (Q683*) and T-24, which contains two truncating KDM6A mutations (E895*/E902*).	('Q683*', 'Var', (262, 267))	('UTX', 'Gene', (189, 192))	('E902*', 'Var', (332, 337))	('KDM6A', 'Gene', '7403', (62, 67))	('KDM6A', 'Gene', (309, 314))	('KDM6A', 'Gene', (237, 242))	('KDM6A', 'Gene', (62, 67))	('UTX', 'Gene', '7403', (189, 192))	('E895*', 'SUBSTITUTION', 'None', (326, 331))	('KDM6A', 'Gene', '7403', (309, 314))	('KMT2C', 'Gene', '58508', (126, 131))	('KMT2C', 'Gene', (126, 131))	('KMT2D', 'Gene', (136, 141))	('E902*', 'SUBSTITUTION', 'None', (332, 337))	('Q683*', 'SUBSTITUTION', 'None', (262, 267))	('KDM6A', 'Gene', '7403', (237, 242))	('KMT2D', 'Gene', '8085', (136, 141))	('E895*', 'Var', (326, 331))
172950	30987376	This knockout cell line was then transduced with UTX-TagGFP2 or TagGFP2.	('UTX', 'Gene', '7403', (49, 52))	('TagGFP2', 'Var', (64, 71))	('UTX', 'Gene', (49, 52))
172954	30987376	Interestingly VM-CUB-1, with its homozygous missense mutation, expressed only low levels of the UTX protein.	('UTX', 'Gene', '7403', (96, 99))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('missense mutation', 'Var', (44, 61))	('VM-CUB-1', 'Gene', (14, 22))	('UTX', 'Gene', (96, 99))
172956	30987376	Likewise, neither overall levels of WDR5, a component of the COMPASS complex nor of EZH2, the H3K27 methyltransferase, were affected by UTX-TagGFP2 expression.	('WDR5', 'Gene', (36, 40))	('expression', 'Var', (148, 158))	('UTX', 'Gene', '7403', (136, 139))	('COMPASS complex', 'cellular_component', 'GO:0048188', ('61', '76'))	('WDR5', 'Gene', '11091', (36, 40))	('EZH2', 'Gene', '2146', (84, 88))	('UTX', 'Gene', (136, 139))	('EZH2', 'Gene', (84, 88))
172958	30987376	Whereas the larger 70 kDa isoform was unaffected, the smaller 55 kDa isoform disappeared upon re-expression of UTX-TagGFP2 in the two cell lines with homozygous KDM6A nonsense mutations (T-24 and Ku-19-19) as well as in SW1710 cells following UTX knockout and reintroduction.	('SW1710', 'CellLine', 'CVCL:1721', (220, 226))	('KDM6A', 'Gene', '7403', (161, 166))	('UTX', 'Gene', (111, 114))	('UTX', 'Gene', (243, 246))	('UTX', 'Gene', '7403', (111, 114))	('nonsense mutations', 'Var', (167, 185))	('UTX', 'Gene', '7403', (243, 246))	('KDM6A', 'Gene', (161, 166))
172961	30987376	KDM6A knockout in SW1710 cells rather diminished colony numbers, and this effect was reversed by UTX reintroduction.	('UTX', 'Gene', (97, 100))	('diminished', 'NegReg', (38, 48))	('UTX', 'Gene', '7403', (97, 100))	('KDM6A', 'Gene', '7403', (0, 5))	('SW1710', 'CellLine', 'CVCL:1721', (18, 24))	('colony numbers', 'CPA', (49, 63))	('knockout', 'Var', (6, 14))	('KDM6A', 'Gene', (0, 5))
172962	30987376	Notably, while Ku-19-19 and T-24 cells both contain homozygous KDM6A nonsense mutations, the two cell lines responded differently to UTX reintroduction.	('KDM6A', 'Gene', (63, 68))	('nonsense mutations', 'Var', (69, 87))	('responded', 'Reg', (108, 117))	('UTX', 'Gene', (133, 136))	('KDM6A', 'Gene', '7403', (63, 68))	('UTX', 'Gene', '7403', (133, 136))
172965	30987376	In keeping with the 2D clone formation assays, RT112 and VM-CUB-1 transduced with UTX-TagGFP2 formed visibly smaller colonies, whereas colonies from 639-V and T-24 cells transduced with UTX-TagGFP2 were substantially or slightly larger, respectively, than those expressing only TagGFP2.	('smaller', 'NegReg', (109, 116))	('UTX', 'Gene', (186, 189))	('colonies', 'CPA', (117, 125))	('transduced', 'Var', (66, 76))	('UTX', 'Gene', '7403', (186, 189))	('RT112', 'Gene', (47, 52))	('UTX', 'Gene', (82, 85))	('formation', 'biological_process', 'GO:0009058', ('29', '38'))	('UTX', 'Gene', '7403', (82, 85))
172969	30987376	In addition, RNA expression profiles were obtained from SW1710 KDM6A knockout cells transduced with UTX-TagGFP2 or TagGFP2 only.	('UTX', 'Gene', (100, 103))	('KDM6A', 'Gene', (63, 68))	('UTX', 'Gene', '7403', (100, 103))	('SW1710', 'CellLine', 'CVCL:1721', (56, 62))	('SW1710', 'Var', (56, 62))	('KDM6A', 'Gene', '7403', (63, 68))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))
172971	30987376	Between SW1710 KDM6A knockout cells transduced with UTX-TagGFP2 or TagGFP2 only 49 genes were differentially expressed (19 up and 30 down) at least 1.5-fold.	('KDM6A', 'Gene', '7403', (15, 20))	('UTX', 'Gene', (52, 55))	('UTX', 'Gene', '7403', (52, 55))	('SW1710', 'CellLine', 'CVCL:1721', (8, 14))	('KDM6A', 'Gene', (15, 20))	('TagGFP2', 'Var', (67, 74))
172981	30987376	In RT112, but not in VM-CUB1, further HOX genes were differentially regulated, namely HOXA1, HOXA2, HOXA3, HOXA13 and HOXB3.	('HOXA1', 'Gene', (86, 91))	('HOXA3', 'Gene', (100, 105))	('HOXA1', 'Gene', (107, 112))	('RT112', 'Var', (3, 8))	('HOXA13', 'Gene', (107, 113))	('HOXA2', 'Gene', (93, 98))	('HOXA1', 'Gene', '3198', (86, 91))	('HOXA3', 'Gene', '3200', (100, 105))	('HOXA1', 'Gene', '3198', (107, 112))	('HOXA13', 'Gene', '3209', (107, 113))	('HOXA2', 'Gene', '3199', (93, 98))	('HOX genes', 'Gene', (38, 47))	('HOXB3', 'Gene', '3213', (118, 123))	('HOXB3', 'Gene', (118, 123))
172998	30987376	In contrast, a substantial fraction of UTX protein remained in the cytoplasm after concomitant knockdown of both genes, KMT2C and KMT2D (Figure 9c,d).	('KMT2D', 'Gene', '8085', (130, 135))	('KMT2C', 'Gene', '58508', (120, 125))	('KMT2C', 'Gene', (120, 125))	('knockdown', 'Var', (95, 104))	('KMT2D', 'Gene', (130, 135))	('cytoplasm', 'cellular_component', 'GO:0005737', ('67', '76'))	('UTX', 'Gene', (39, 42))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('UTX', 'Gene', '7403', (39, 42))
173000	30987376	Accordingly, in 639-V cells, which contain a homozygous nonsense mutation in KMT2D and a heterozygous nonsense mutation in KMT2C, UTX localized much more strongly in the cytoplasm than in the nucleus (Figure 9e).	('localized', 'MPA', (134, 143))	('KMT2D', 'Gene', (77, 82))	('KMT2D', 'Gene', '8085', (77, 82))	('mutation', 'Var', (65, 73))	('cytoplasm', 'cellular_component', 'GO:0005737', ('170', '179'))	('KMT2C', 'Gene', '58508', (123, 128))	('KMT2C', 'Gene', (123, 128))	('UTX', 'Gene', (130, 133))	('strongly', 'PosReg', (154, 162))	('nucleus', 'cellular_component', 'GO:0005634', ('192', '199'))	('UTX', 'Gene', '7403', (130, 133))
173001	30987376	The high prevalence of evidently deleterious KDM6A mutations throughout all stages and molecular subtypes of UC suggests an important tumor-suppressive function of UTX.	('UTX', 'Gene', '7403', (164, 167))	('mutations', 'Var', (51, 60))	('KDM6A', 'Gene', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('KDM6A', 'Gene', '7403', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('UTX', 'Gene', (164, 167))	('tumor', 'Disease', (134, 139))
173005	30987376	First, as one might expect, the effects of exogenous UTX appeared to depend on the status of its endogenous counterpart.	('UTX', 'Gene', '7403', (53, 56))	('UTX', 'Gene', (53, 56))	('exogenous', 'Var', (43, 52))
173008	30987376	reported a decreased long-term growth ability of T24-T cells, a T-24 subclone with the same homozygous KDM6A nonsense mutation, following transient transfection with a UTX-expression plasmid.	('nonsense mutation', 'Var', (109, 126))	('UTX', 'Gene', '7403', (168, 171))	('KDM6A', 'Gene', (103, 108))	('decreased', 'NegReg', (11, 20))	('KDM6A', 'Gene', '7403', (103, 108))	('UTX', 'Gene', (168, 171))	('long-term growth ability', 'CPA', (21, 45))
173011	30987376	In UC, mutations in either of these genes are almost mutually exclusive with those in KDM6A.	('KDM6A', 'Gene', '7403', (86, 91))	('KDM6A', 'Gene', (86, 91))	('mutations', 'Var', (7, 16))
173014	30987376	This situation is exemplified by the 639-V cell line, which has deleterious mutations in three out of four KMT2C and KMT2D alleles, but is wild-type for UTX.	('mutations', 'Var', (76, 85))	('UTX', 'Gene', (153, 156))	('KMT2D', 'Gene', (117, 122))	('UTX', 'Gene', '7403', (153, 156))	('KMT2D', 'Gene', '8085', (117, 122))	('KMT2C', 'Gene', '58508', (107, 112))	('KMT2C', 'Gene', (107, 112))
173024	30987376	In particular, knockdown of both factors, combined, but not individually, diminished the fraction of UTX in the nucleus and increased its amount in the cytoplasm.	('diminished', 'NegReg', (74, 84))	('knockdown', 'Var', (15, 24))	('increased', 'PosReg', (124, 133))	('UTX', 'Gene', (101, 104))	('cytoplasm', 'cellular_component', 'GO:0005737', ('152', '161'))	('amount', 'MPA', (138, 144))	('UTX', 'Gene', '7403', (101, 104))	('nucleus', 'cellular_component', 'GO:0005634', ('112', '119'))	('fraction', 'MPA', (89, 97))
173039	30987376	reported decreased invasion and migration following transfection of UTX into T24-T cells.	('invasion', 'CPA', (19, 27))	('decreased', 'NegReg', (9, 18))	('transfection', 'Var', (52, 64))	('UTX', 'Gene', (68, 71))	('UTX', 'Gene', '7403', (68, 71))
173054	30987376	have provided evidence that KDM6A mutations are predictive for a response of UC to inhibitors of EZH2.	('UC to inhibitors', 'MPA', (77, 93))	('KDM6A', 'Gene', (28, 33))	('KDM6A', 'Gene', '7403', (28, 33))	('predictive', 'Reg', (48, 58))	('EZH2', 'Gene', '2146', (97, 101))	('EZH2', 'Gene', (97, 101))	('response', 'MPA', (65, 73))	('mutations', 'Var', (34, 43))
173055	30987376	For most experiments, six different UCCs overexpressing TagGFP2 or UTX-TagGFP2 (VM-CUB1, RT112, SW1710, T24, 639-V and KU-19-19) were used.	('UTX', 'Gene', (67, 70))	('SW1710', 'CellLine', 'CVCL:1721', (96, 102))	('KU-19-19', 'Disease', 'MESH:C567026', (119, 127))	('T24', 'Var', (104, 107))	('UTX', 'Gene', '7403', (67, 70))	('KU-19-19', 'Disease', (119, 127))
173061	30987376	In brief, to produce replication-deficient lentiviruses HEK-293T cells were transfected with helper plasmid expression construct (pCD/NL-BH), envelope vector (pczVSV-G) and the vector plasmids puc2CL12IPwo-TagGFP2 or puc2CL12IPwo-KDM6A-TagGFP2.	('puc2CL12IPwo-TagGFP2', 'Var', (193, 213))	('envelope', 'cellular_component', 'GO:0009274', ('142', '150'))	('KDM6A', 'Gene', '7403', (230, 235))	('pCD', 'biological_process', 'GO:0012501', ('130', '133'))	('envelope', 'cellular_component', 'GO:0031975', ('142', '150'))	('HEK-293T', 'CellLine', 'CVCL:0063', (56, 64))	('KDM6A', 'Gene', (230, 235))
173069	30987376	Viability of cells was measured after 24 h, 48 h and 72 h of seeding by 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye reduction assay (MTT, M2128-G, Sigma Aldrich, St. Louis, MO, USA).	('MTT', 'Chemical', 'MESH:C070243', (153, 156))	('3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide', 'Chemical', '-', (72, 131))	('M2128-G', 'Var', (158, 165))	('MTT', 'Var', (153, 156))	('M2128-G', 'Mutation', 'p.M2128G', (158, 165))
173079	30987376	The datasets generated by RNA-Seq were split into two based on up- and downregulated genes upon UTX-TagGFP2 overexpression compared to TagGFP2 overexpression and were statistically significant for multiple testing by FDR.	('downregulated', 'NegReg', (71, 84))	('UTX', 'Gene', '7403', (96, 99))	('up-', 'PosReg', (63, 66))	('overexpression', 'Var', (108, 122))	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))	('UTX', 'Gene', (96, 99))
173089	30987376	Although mutations of the epigenetic regulator UTX/KDM6A occur at a similar frequency as those in p53 in urothelial carcinoma, their consequences are poorly understood.	('UTX', 'Gene', '7403', (47, 50))	('urothelial carcinoma', 'Disease', (105, 125))	('mutations', 'Var', (9, 18))	('KDM6A', 'Gene', (51, 56))	('UTX', 'Gene', (47, 50))	('p53', 'Gene', (98, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('KDM6A', 'Gene', '7403', (51, 56))	('p53', 'Gene', '7157', (98, 101))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (105, 125))
173091	30987376	In cell lines with KDM6A deficiencies, introduction of functional UTX generally diminished long-term, but not short-term growth.	('UTX', 'Gene', (66, 69))	('KDM6A', 'Gene', '7403', (19, 24))	('UTX', 'Gene', '7403', (66, 69))	('deficiencies', 'Var', (25, 37))	('KDM6A', 'Gene', (19, 24))	('diminished', 'NegReg', (80, 90))	('long-term', 'CPA', (91, 100))
173094	30987376	Our study thus suggests a new level of regulation of UTX activity and moreover, that the activity of wild-type UTX may be substantially compromised by mutations in KMT2C and KMT2D in UC and likely other cancers.	('activity', 'MPA', (89, 97))	('UTX', 'Gene', (111, 114))	('regulation', 'biological_process', 'GO:0065007', ('39', '49'))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('UTX', 'Gene', '7403', (111, 114))	('UTX', 'Gene', (53, 56))	('KMT2C', 'Gene', (164, 169))	('KMT2D', 'Gene', (174, 179))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('KMT2C', 'Gene', '58508', (164, 169))	('compromised', 'NegReg', (136, 147))	('UTX', 'Gene', '7403', (53, 56))	('KMT2D', 'Gene', '8085', (174, 179))	('mutations', 'Var', (151, 160))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
173097	30079348	Therefore, we conducted a meta-analysis to determine whether PINX1 expression is associated with overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), recurrence-free survival (RFS), and clinicopathological characteristics in patients with malignant tumors.	('tumors', 'Disease', (281, 287))	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('expression', 'Var', (67, 77))	('OS', 'Chemical', '-', (115, 117))	('patient', 'Species', '9606', (257, 264))	('overall', 'MPA', (97, 104))	('malignant tumors', 'Disease', (271, 287))	('DSS', 'Gene', (147, 150))	('PINX1', 'Gene', (61, 66))	('recurrence-free', 'Disease', (182, 197))	('patients', 'Species', '9606', (257, 265))	('disease-free', 'Disease', (153, 165))	('malignant tumors', 'Disease', 'MESH:D018198', (271, 287))	('DSS', 'Gene', '5376', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('associated', 'Reg', (81, 91))
173109	30079348	The association between PINX1 dysregulation and carcinogenesis has been described in several reports.	('carcinogenesis', 'Disease', (48, 62))	('carcinogenesis', 'Disease', 'MESH:D063646', (48, 62))	('PINX1', 'Gene', (24, 29))	('dysregulation', 'Var', (30, 43))
173128	27376132	In particular, the PI3K/AKT/mTOR pathway has been shown in multiple studies to be altered in up to 40% of urothelial carcinomas, either through PIK3CA mutation, PTEN deletion, AKT1 mutation, or TSC1/TSC2 mutation.	('mutation', 'Var', (204, 212))	('urothelial carcinomas', 'Disease', (106, 127))	('TSC2', 'Gene', (199, 203))	('AKT', 'Gene', (24, 27))	('mTOR', 'Gene', (28, 32))	('PIK3CA', 'Gene', '5290', (144, 150))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (106, 127))	('mTOR', 'Gene', '2475', (28, 32))	('AKT', 'Gene', '207', (176, 179))	('deletion', 'Var', (166, 174))	('TSC1', 'Gene', (194, 198))	('PI3K', 'molecular_function', 'GO:0016303', ('19', '23'))	('AKT', 'Gene', '207', (24, 27))	('PTEN', 'Gene', (161, 165))	('TSC1', 'Gene', '7248', (194, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('PIK3CA', 'Gene', (144, 150))	('mutation', 'Var', (151, 159))	('AKT1', 'Gene', '207', (176, 180))	('PTEN', 'Gene', '5728', (161, 165))	('TSC2', 'Gene', '7249', (199, 203))	('AKT', 'Gene', (176, 179))	('mutation', 'Var', (181, 189))	('AKT1', 'Gene', (176, 180))	('altered', 'Reg', (82, 89))
173130	27376132	Both studies identified few partial responses and several cases with minor tumor regression, with one patient whose tumor harbored a TSC1 mutation displaying an exceptional response to the drug.	('TSC1', 'Gene', '7248', (133, 137))	('patient', 'Species', '9606', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('TSC1', 'Gene', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutation', 'Var', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (75, 80))
173262	29871649	Notably, the gene regulatory networks orchestrated by enhancer methylation across different cancer types are seen to converge on a common architecture.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('methylation', 'Var', (63, 74))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
173264	29871649	Some genes have been verified to be regulated by aberrant promoter methylation with a causal effect on tumorigenesis, including CDKN2B, CDKN2A, RB, APC, BRCA1, and MLH1.	('CDKN2B', 'Gene', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('regulated', 'Reg', (36, 45))	('APC', 'cellular_component', 'GO:0005680', ('148', '151'))	('effect', 'Reg', (93, 99))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('CDKN2B', 'Gene', '1030', (128, 134))	('BRCA1', 'Gene', '672', (153, 158))	('BRCA', 'Phenotype', 'HP:0003002', (153, 157))	('MLH1', 'Gene', (164, 168))	('CDKN2A', 'Gene', (136, 142))	('BRCA1', 'Gene', (153, 158))	('APC', 'Disease', 'MESH:D011125', (148, 151))	('APC', 'Disease', (148, 151))	('aberrant promoter methylation', 'Var', (49, 78))	('tumor', 'Disease', (103, 108))	('MLH1', 'Gene', '4292', (164, 168))	('CDKN2A', 'Gene', '1029', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
173269	29871649	To identify the subset that are causal, we need solutions that enable us to: (1) genome-wide identify causal DNA methylation of enhancers and its gene targets in pan-cancers in an unbiased manner; and (2) directly validate a specific methylation event on the putative enhancer by experimentation.	('cancers', 'Disease', (166, 173))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('methylation', 'Var', (113, 124))	('methylation', 'biological_process', 'GO:0032259', ('234', '245'))	('DNA methylation', 'biological_process', 'GO:0006306', ('109', '124'))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
173271	29871649	In this study, we designed a set of tools for identifying genome-wide DNA methylation of distal regulatory sites that result in a causal effect on tumorigenesis.	('DNA methylation', 'Var', (70, 85))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('DNA methylation', 'biological_process', 'GO:0006306', ('70', '85'))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('effect', 'Reg', (137, 143))
173274	29871649	Our strategy recovered many known enhancers and unannotated regulatory sites from different cancer types, differential methylation of which regulated known or novel tumor-suppressor/oncogene with causal effect on cell malignancy and patient survival.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('patient', 'Species', '9606', (233, 240))	('methylation', 'Var', (119, 130))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('malignancy', 'Disease', 'MESH:D009369', (218, 228))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('165', '181'))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('malignancy', 'Disease', (218, 228))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('165', '181'))	('tumor', 'Disease', (165, 170))
173285	29871649	We then compared both negatively and positively correlated DREs for the enrichment of active chromatin marks (H3K27ac, H3K4me1, p300, and DNase I hypersensitivity) and repressive marks (H3K9me3 and H3K27me3).	('hypersensitivity)', 'Disease', 'MESH:D004342', (146, 163))	('H3K9me3', 'Var', (186, 193))	('H3K27me3', 'Var', (198, 206))	('hypersensitivity', 'biological_process', 'GO:0002524', ('146', '162'))	('H3K27ac', 'Var', (110, 117))	('p300', 'Gene', (128, 132))	('DNase I', 'molecular_function', 'GO:0004530', ('138', '145'))	('H3K4me1', 'Var', (119, 126))	('p300', 'Gene', '2033', (128, 132))	('chromatin', 'cellular_component', 'GO:0000785', ('93', '102'))
173291	29871649	Remarkably, targeting DNMT3A-3 L to the region near cg02935351 downregulated WNT5B, while targeting TET1 to this region produced similar results to treatment with the global DNA methylation inhibitor, 5-AZA, and upregulated WNT5B (Fig.	('WNT5B', 'Gene', '81029', (77, 82))	('DNA methylation', 'biological_process', 'GO:0006306', ('174', '189'))	('WNT5B', 'Gene', (77, 82))	('DNMT3A', 'Gene', (22, 28))	('DNMT3A', 'Gene', '1788', (22, 28))	('TET1', 'Gene', '80312', (100, 104))	('upregulated', 'PosReg', (212, 223))	('downregulated', 'NegReg', (63, 76))	('WNT5B', 'Gene', '81029', (224, 229))	('cg02935351', 'Var', (52, 62))	('WNT5B', 'Gene', (224, 229))	('DNA', 'cellular_component', 'GO:0005574', ('174', '177'))	('5-AZA', 'Chemical', 'MESH:D001374', (201, 206))	('TET1', 'Gene', (100, 104))
173296	29871649	In addition, we verified several other genes, including MLEC, LLGL2, CDCA5, MEN1, CLDN7, SOX9, and FGFR1 by epigenetic modulation of distal DREs followed by quantitative polymerase chain reaction (qPCR), migration assay, and luciferase reporter assay (Fig.	('CLDN7', 'Gene', '1366', (82, 87))	('LLGL2', 'Gene', '3993', (62, 67))	('epigenetic modulation', 'Var', (108, 129))	('SOX9', 'Gene', (89, 93))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('FGFR1', 'Gene', (99, 104))	('CDCA5', 'Gene', (69, 74))	('MLEC', 'Gene', '9761', (56, 60))	('MEN1', 'Gene', (76, 80))	('SOX9', 'Gene', '6662', (89, 93))	('MEN1', 'Gene', '4221', (76, 80))	('FGFR1', 'Gene', '2260', (99, 104))	('CLDN7', 'Gene', (82, 87))	('LLGL2', 'Gene', (62, 67))	('CDCA5', 'Gene', '113130', (69, 74))	('MLEC', 'Gene', (56, 60))
173298	29871649	1, MICMIC predicted a distal DRE for CDCA5, cg02933228, which is > 240 kb away from the TSS of CDCA5 (Fig.	('CDCA5', 'Gene', (95, 100))	('CDCA5', 'Gene', '113130', (37, 42))	('cg02933228', 'Chemical', '-', (44, 54))	('CDCA5', 'Gene', '113130', (95, 100))	('cg02933228', 'Var', (44, 54))	('CDCA5', 'Gene', (37, 42))
173299	29871649	This same distal DRE, cg02933228, was also predicted to control the gene MEN1, which we were also able to experimentally confirm.	('cg02933228', 'Chemical', '-', (22, 32))	('MEN1', 'Gene', (73, 77))	('MEN1', 'Gene', '4221', (73, 77))	('cg02933228', 'Var', (22, 32))	('control', 'Reg', (56, 63))
173304	29871649	As expected, targeted methylation with DNMT3A-3 L to the cg03190578 region decreased HDAC11 expression, while targeted demethylation with TET1 dramatically increased HDAC11 expression (Fig.	('DNMT3A', 'Gene', (39, 45))	('TET1', 'Gene', (138, 142))	('DNMT3A', 'Gene', '1788', (39, 45))	('HDAC11', 'Gene', '79885', (85, 91))	('cg03190578', 'Chemical', '-', (57, 67))	('increased', 'PosReg', (156, 165))	('HDAC11', 'Gene', (166, 172))	('methylation', 'Var', (22, 33))	('methylation', 'biological_process', 'GO:0032259', ('22', '33'))	('HDAC11', 'Gene', (85, 91))	('TET1', 'Gene', '80312', (138, 142))	('demethylation', 'biological_process', 'GO:0070988', ('119', '132'))	('expression', 'MPA', (173, 183))	('HDAC11', 'Gene', '79885', (166, 172))	('expression', 'MPA', (92, 102))	('decreased', 'NegReg', (75, 84))
173305	29871649	Consequently, we found that modulation of DNA methylation on the distal DRE, cg03190578, by dcas9-DNMT3A-3 L significantly decreased cancer cell migration suggesting an oncogenic function for HDAC11 in liver cancer, which was confirmed by increased cell migration upon overexpression of HDAC11 (Fig.	('cancer', 'Disease', (208, 214))	('modulation', 'Var', (28, 38))	('liver cancer', 'Disease', 'MESH:D006528', (202, 214))	('decreased', 'NegReg', (123, 132))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('DNMT3A', 'Gene', '1788', (98, 104))	('cell migration', 'CPA', (249, 263))	('HDAC11', 'Gene', '79885', (287, 293))	('liver cancer', 'Phenotype', 'HP:0002896', (202, 214))	('DNA methylation', 'biological_process', 'GO:0006306', ('42', '57'))	('HDAC11', 'Gene', '79885', (192, 198))	('liver cancer', 'Disease', (202, 214))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('cell migration', 'biological_process', 'GO:0016477', ('249', '263'))	('DNMT3A', 'Gene', (98, 104))	('HDAC11', 'Gene', (287, 293))	('cancer', 'Disease', (133, 139))	('increased', 'PosReg', (239, 248))	('cell migration', 'biological_process', 'GO:0016477', ('140', '154'))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('HDAC11', 'Gene', (192, 198))	('cg03190578', 'Chemical', '-', (77, 87))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))
173308	29871649	APOA1 shared cg23193059 with APOC3 and CDT1 shared cg20283771 with CBFA2T3.	('APOA1', 'Gene', (0, 5))	('cg20283771', 'Chemical', '-', (51, 61))	('CBFA2T3', 'Gene', '863', (67, 74))	('APOC3', 'Gene', '345', (29, 34))	('CDT1', 'Gene', '81620', (39, 43))	('APOC3', 'Gene', (29, 34))	('APOA1', 'Gene', '335', (0, 5))	('CBFA2T3', 'Gene', (67, 74))	('cg20283771', 'Var', (51, 61))	('CDT1', 'Gene', (39, 43))	('cg23193059', 'Var', (13, 23))
173310	29871649	Both genes were verified to be causally regulated by methylation of cg20283771 with combined effect on cancer cell migration after dCas9-DNMT3A-3 L targeting (Fig.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cg20283771', 'Gene', (68, 78))	('effect', 'Reg', (93, 99))	('DNMT3A', 'Gene', '1788', (137, 143))	('DNMT3A', 'Gene', (137, 143))	('cell migration', 'biological_process', 'GO:0016477', ('110', '124'))	('cg20283771', 'Chemical', '-', (68, 78))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))	('methylation', 'Var', (53, 64))
173317	29871649	5a inset), suggesting that hypermethylated distal DREs from the negative-down group in conjunction with the decreased expression of the cognate tissue-specific TFs, lead to downregulation of its distal gene targets in cancer.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (218, 224))	('hypermethylated', 'Var', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('downregulation', 'NegReg', (173, 187))
173319	29871649	For distal DREs positively correlated with its targets, we found significant enrichment of TFs with repressor activity (p value = 8e-7), suggesting that DNA methylation may affect the binding of TF repressors with implications in tumorigenesis (Additional file 1: Figure S14).	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('tumor', 'Disease', (230, 235))	('binding', 'molecular_function', 'GO:0005488', ('184', '191'))	('affect', 'Reg', (173, 179))	('DNA', 'Var', (153, 156))	('methylation', 'Var', (157, 168))	('DNA methylation', 'biological_process', 'GO:0006306', ('153', '168'))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('implications', 'Reg', (214, 226))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('binding', 'Interaction', (184, 191))
173321	29871649	We identified 1081 DRE methylation correlated with patient survival (q-value < 0.1, FDR by BH procedure) in bladder cancer (BLCA), breast cancer (BRCA), head and neck carcinoma (HNSC), liver cancer (LIHC), lung cancer (LUAD), and uterine corpus endometrial cancer (UCEC).	('BRCA', 'Phenotype', 'HP:0003002', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('lung cancer', 'Disease', (206, 217))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('correlated', 'Reg', (35, 45))	('methylation', 'Var', (23, 34))	('BRCA', 'Gene', '672', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('LIHC', 'Disease', (199, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('neck carcinoma (HNSC), liver cancer', 'Disease', 'MESH:D006528', (162, 197))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))	('liver cancer', 'Phenotype', 'HP:0002896', (185, 197))	('BRCA', 'Gene', (146, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', (131, 144))	('LIHC', 'Disease', 'None', (199, 203))	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('bladder cancer', 'Disease', (108, 122))	('LUAD', 'Phenotype', 'HP:0030078', (219, 223))	('1081', 'Var', (14, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('endometrial cancer', 'Phenotype', 'HP:0012114', (245, 263))	('patient', 'Species', '9606', (51, 58))	('neck', 'cellular_component', 'GO:0044326', ('162', '166'))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('BLCA', 'Phenotype', 'HP:0009725', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('corpus endometrial cancer', 'Disease', 'MESH:D016889', (238, 263))	('corpus endometrial cancer', 'Disease', (238, 263))
173322	29871649	We then calculated the number of master cancer genes (via MRA) that are regulated by DNA methylation of the promoter or distal DREs and used the density distribution to quantify the effect that methylation of those DREs have on tumorigenesis (Fig.	('methylation', 'Var', (194, 205))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('methylation', 'biological_process', 'GO:0032259', ('194', '205'))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('master cancer', 'Disease', (33, 46))	('tumor', 'Disease', (228, 233))	('DNA methylation', 'biological_process', 'GO:0006306', ('85', '100'))	('master cancer', 'Disease', 'MESH:D009369', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
173323	29871649	The results indicated that the methylation of distal DREs compared to proximal DREs had more of an impact on the regulation of both oncogenes and tumor suppressors at the initiation and progression stage of tumorigenesis.	('methylation', 'MPA', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('oncogenes', 'Protein', (132, 141))	('impact', 'Reg', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', (146, 151))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('regulation', 'MPA', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('distal DREs', 'Var', (46, 57))	('regulation', 'biological_process', 'GO:0065007', ('113', '123'))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
173339	29871649	In this study, we aimed to identify DNA methylation of distal regulatory regions with causal effects on tumorigenesis.	('methylation', 'Var', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('effects', 'Reg', (93, 100))	('tumor', 'Disease', (104, 109))	('DNA methylation', 'biological_process', 'GO:0006306', ('36', '51'))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
173346	29871649	For instance, we can increase or decrease the DNA methylation level of the same DRE site in AGS cell line by dCas9 targeting, and consequentially change the gene expression level in both directions, upregulation or downregulation.	('gene expression level', 'MPA', (157, 178))	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('decrease', 'NegReg', (33, 41))	('downregulation', 'NegReg', (215, 229))	('gene expression', 'biological_process', 'GO:0010467', ('157', '172'))	('AGS', 'Disease', (92, 95))	('AGS', 'Disease', 'MESH:C535607', (92, 95))	('DNA methylation level', 'MPA', (46, 67))	('upregulation', 'PosReg', (199, 211))	('change', 'Reg', (146, 152))	('targeting', 'Var', (115, 124))	('DNA methylation', 'biological_process', 'GO:0006306', ('46', '61'))	('dCas9', 'Gene', (109, 114))	('increase', 'PosReg', (21, 29))
173347	29871649	As shown above, both oncogene CDCA5 and tumor-suppressor MEN1 were verified to be regulated by the same distal DRE cg02933228.	('cg02933228', 'Var', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('CDCA5', 'Gene', '113130', (30, 35))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('40', '56'))	('MEN1', 'Gene', (57, 61))	('cg02933228', 'Chemical', '-', (115, 125))	('MEN1', 'Gene', '4221', (57, 61))	('tumor', 'Disease', (40, 45))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('CDCA5', 'Gene', (30, 35))
173348	29871649	However, the decreased cell migration phenotype after dCas9-DNMT3A-3 L targeting of cg02933228 was only consistent with CDCA5's function prediction.	('CDCA5', 'Gene', (120, 125))	('decreased', 'NegReg', (13, 22))	('cell migration', 'biological_process', 'GO:0016477', ('23', '37'))	('cell migration phenotype', 'CPA', (23, 47))	('cg02933228', 'Var', (84, 94))	('DNMT3A', 'Gene', (60, 66))	('DNMT3A', 'Gene', '1788', (60, 66))	('CDCA5', 'Gene', '113130', (120, 125))	('cg02933228', 'Chemical', '-', (84, 94))
173351	29871649	Furthermore, we showed that the network topology of GRN derived from DNA methylation of distal DREs may have the same architecture across different cancer types, enriched for network motifs like "feed forwards loop," "regulated mutual," and "regulating mutual."	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('regulated mutual', 'MPA', (218, 234))	('regulating mutual', 'MPA', (242, 259))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('methylation', 'Var', (73, 84))	('DNA methylation', 'biological_process', 'GO:0006306', ('69', '84'))
173354	29871649	Our study reveals the prevalent regulation of genome-wide putative enhancers by DNA-methylation with causal effect on cellular malignancy and patient survival.	('malignancy', 'Disease', 'MESH:D009369', (127, 137))	('DNA-methylation', 'Var', (80, 95))	('malignancy', 'Disease', (127, 137))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('patient', 'Species', '9606', (142, 149))	('DNA-methylation', 'biological_process', 'GO:0006306', ('80', '95'))	('regulation', 'biological_process', 'GO:0065007', ('32', '42'))	('enhancers', 'PosReg', (67, 76))
173367	29871649	We downloaded chromatin marks including histone modifications of H3K4me1, H3K4me3, H3K9me3, H3K27me3, H3K27ac, and p300 ChIP-seq signals to evaluate the enhancer activity of distal DREs, from breast cancer cells (MCF-7), colon cancer cells (HCT116), cervical cancer cells (HeLa-S3), liver cancer cells (HepG2), and lung cancer cells (A549).	('A549', 'CellLine', 'CVCL:0023', (334, 338))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('p300', 'Gene', '2033', (115, 119))	('colon cancer', 'Disease', (221, 233))	('breast cancer', 'Disease', (192, 205))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('HCT116', 'CellLine', 'CVCL:0291', (241, 247))	('HeLa', 'CellLine', 'CVCL:0030', (273, 277))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('liver cancer', 'Phenotype', 'HP:0002896', (283, 295))	('liver cancer', 'Disease', (283, 295))	('lung cancer', 'Disease', (315, 326))	('HepG2', 'CellLine', 'CVCL:0027', (303, 308))	('MCF-7', 'CellLine', 'CVCL:0031', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('colon cancer', 'Phenotype', 'HP:0003003', (221, 233))	('cervical cancer', 'Disease', 'MESH:D002583', (250, 265))	('cervical cancer', 'Disease', (250, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('lung cancer', 'Disease', 'MESH:D008175', (315, 326))	('colon cancer', 'Disease', 'MESH:D015179', (221, 233))	('lung cancer', 'Phenotype', 'HP:0100526', (315, 326))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('chromatin', 'cellular_component', 'GO:0000785', ('14', '23'))	('p300', 'Gene', (115, 119))	('liver cancer', 'Disease', 'MESH:D006528', (283, 295))	('H3K27ac', 'Var', (102, 109))
173391	29871649	For dCas9-TET1 targeting, we used these plasmids: pCAG-dCas9-5xPlat2AflD and pCAG-scFvGCN4sfGFPTET1CD (Addgene plasmid #82560 and #82561, gifts from Izuho Hatada).	('scFv', 'Gene', (82, 86))	('TET1', 'Gene', '80312', (95, 99))	('TET1', 'Gene', '80312', (10, 14))	('#82561', 'Var', (130, 136))	('TET1', 'Gene', (95, 99))	('TET1', 'Gene', (10, 14))	('scFv', 'Gene', '652070', (82, 86))
173392	29871649	We generated catalytically inactive TET1 with H1671Y and D1673A mutations with primers: Tet1-muH1671-Forward, TCC CTA CAG GGC CAT TCA CAA CAT GAA TAA TGG AAG CAC TG; and Tet1-muH1671-Reverse, AAT GGC CCT GTA GGG ATG AGC ACA GAA GTC CAG, with sequencing confirmation.	('Tet1', 'Gene', '80312', (170, 174))	('CAT', 'molecular_function', 'GO:0004096', ('138', '141'))	('Tet1', 'Gene', (170, 174))	('D1673A', 'Mutation', 'p.D1673A', (57, 63))	('H1671Y', 'Mutation', 'p.H1671Y', (46, 52))	('TET1', 'Gene', (36, 40))	('Tet1', 'Gene', '80312', (88, 92))	('CAT', 'molecular_function', 'GO:0004096', ('126', '129'))	('Tet1', 'Gene', (88, 92))	('H1671Y', 'Var', (46, 52))	('TCC', 'cellular_component', 'GO:0005579', ('110', '113'))	('TET1', 'Gene', '80312', (36, 40))	('AAT', 'molecular_function', 'GO:0004069', ('192', '195'))	('D1673A', 'Var', (57, 63))
173401	29871649	For these "untargeted," catalytically active DNMT3A-3 L/TET1 was overexpressed but targeted to nowhere due to the deletion of "linker" domain.	('TET1', 'Gene', (56, 60))	('DNMT3A', 'Gene', (45, 51))	('DNMT3A', 'Gene', '1788', (45, 51))	('TET1', 'Gene', '80312', (56, 60))	('deletion', 'Var', (114, 122))
173410	29871649	We searched the AmiGO database with the key words "transcription repressor" and "negative regulation" to obtain a list of genes related to the transcriptional repression process and collected the repressor information from GO:0017053, GO:0090571, GO:0001206, GO:0001227, GO:0001191, GO:0000900, GO:0070491, GO:0070176, GO:0003714,GO:0032785, GO:2000143, GO:1903507, and GO:0001078.	('GO:2000143', 'Var', (342, 352))	('GO:0000900', 'Var', (283, 293))	('GO:0017053', 'Var', (223, 233))	('GO:0001206', 'Var', (247, 257))	('GO:0001191', 'Var', (271, 281))	('GO:0070176', 'Var', (307, 317))	('transcription', 'biological_process', 'GO:0006351', ('50', '63'))	('GO:1903507', 'Var', (354, 364))	('GO:0001078', 'Var', (370, 380))	('AmiGO', 'Gene', '57463', (16, 21))	('GO:0090571', 'Var', (235, 245))	('GO:0070491', 'Var', (295, 305))	('GO:0001227', 'Var', (259, 269))	('GO:0003714', 'Var', (319, 329))	('AmiGO', 'Gene', (16, 21))	('GO:0032785', 'Var', (330, 340))
173419	28049532	Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine More effective chemotherapies are urgently needed for bladder cancer, a major cause of morbidity and mortality worldwide.	('urothelial carcinoma', 'Disease', (56, 76))	('bladder cancer', 'Disease', 'MESH:D001749', (152, 166))	('bladder cancer', 'Disease', (152, 166))	('sensitises', 'Reg', (45, 55))	('gemcitabine', 'Chemical', 'MESH:C056507', (86, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (56, 76))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('bladder cancer', 'Phenotype', 'HP:0009725', (152, 166))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('11', '27'))	('AZD7762', 'Var', (28, 35))	('AZD7762', 'Chemical', 'MESH:C532363', (28, 35))
173424	28049532	Combined use of gemcitabine and AZD7762 synergistically reduced urothelial carcinoma cell viability and colony formation relative to either single treatment.	('urothelial carcinoma cell viability', 'Disease', 'MESH:C538614', (64, 99))	('AZD7762', 'Var', (32, 39))	('AZD7762', 'Chemical', 'MESH:C532363', (32, 39))	('gemcitabine', 'Chemical', 'MESH:C056507', (16, 27))	('reduced', 'NegReg', (56, 63))	('formation', 'biological_process', 'GO:0009058', ('111', '120'))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('colony formation', 'CPA', (104, 120))	('urothelial carcinoma cell viability', 'Disease', (64, 99))
173425	28049532	Gemcitabine plus AZD7762 inhibited cell cycle progression causing cell accumulation in S-phase.	('Gemcitabine', 'Chemical', 'MESH:C056507', (0, 11))	('cell accumulation', 'CPA', (66, 83))	('S-phase', 'biological_process', 'GO:0051320', ('87', '94'))	('cell cycle progression', 'CPA', (35, 57))	('AZD7762', 'Chemical', 'MESH:C532363', (17, 24))	('cell cycle', 'biological_process', 'GO:0007049', ('35', '45'))	('AZD7762', 'Var', (17, 24))	('inhibited', 'NegReg', (25, 34))
173427	28049532	Mechanistic investigations showed that AZD7762 treatment inhibited the repair of gemcitabine-induced double strand breaks by interference with CHK1, since siRNA-mediated depletion of CHK1 but not of CHK2 mimicked the effects of AZD7762.	('CHK1', 'Gene', (143, 147))	('AZD7762', 'Chemical', 'MESH:C532363', (228, 235))	('depletion', 'MPA', (170, 179))	('inhibited', 'NegReg', (57, 66))	('AZD7762', 'Chemical', 'MESH:C532363', (39, 46))	('CHK1', 'Gene', (183, 187))	('AZD7762', 'Var', (39, 46))	('CHK1', 'Gene', '1111', (143, 147))	('repair of gemcitabine-induced double strand breaks', 'MPA', (71, 121))	('CHK2', 'Gene', (199, 203))	('CHK2', 'Gene', '11200', (199, 203))	('CHK1', 'Gene', '1111', (183, 187))	('interference', 'NegReg', (125, 137))	('gemcitabine', 'Chemical', 'MESH:C056507', (81, 92))
173428	28049532	AZD7762 enhanced sensitivity of urothelial carcinoma cells to gemcitabine by inhibiting DNA repair and disturbing checkpoints.	('inhibiting', 'NegReg', (77, 87))	('sensitivity', 'MPA', (17, 28))	('gemcitabine', 'Chemical', 'MESH:C056507', (62, 73))	('urothelial carcinoma', 'Disease', (32, 52))	('disturbing', 'Reg', (103, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('enhanced', 'PosReg', (8, 16))	('DNA repair', 'biological_process', 'GO:0006281', ('88', '98'))	('checkpoints', 'MPA', (114, 125))	('AZD7762', 'Var', (0, 7))	('AZD7762', 'Chemical', 'MESH:C532363', (0, 7))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (32, 52))	('DNA repair', 'MPA', (88, 98))
173444	28049532	Inhibition of checkpoint kinases abrogates DNA damage-induced cell cycle arrest allowing cells to enter mitosis despite the presence of DNA damage, which can lead to cell death.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('mitosis', 'Disease', 'None', (104, 111))	('abrogates', 'NegReg', (33, 42))	('lead to', 'Reg', (158, 165))	('cell cycle arrest', 'CPA', (62, 79))	('mitosis', 'biological_process', 'GO:0000278', ('104', '111'))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('Inhibition', 'Var', (0, 10))	('cell', 'CPA', (166, 170))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('62', '79'))	('mitosis', 'Disease', (104, 111))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (62, 79))	('cell death', 'biological_process', 'GO:0008219', ('166', '176'))
173445	28049532	Accordingly, AZD7762, a potent CHK1/CHK2 inhibitor, possesses chemosensitizing activity in vitro and in vivo.	('CHK2', 'Gene', (36, 40))	('CHK2', 'Gene', '11200', (36, 40))	('CHK1', 'Gene', (31, 35))	('AZD7762', 'Var', (13, 20))	('AZD7762', 'Chemical', 'MESH:C532363', (13, 20))	('CHK1', 'Gene', '1111', (31, 35))	('chemosensitizing activity', 'MPA', (62, 87))
173446	28049532	However, it remains unknown to which extent AZD7762 may promote chemotherapy-induced tumour cell death in urothelial cancer cell lines (UCCs).	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('AZD7762', 'Chemical', 'MESH:C532363', (44, 51))	('tumour cell death in urothelial cancer', 'Disease', (85, 123))	('AZD7762', 'Var', (44, 51))	('promote', 'PosReg', (56, 63))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('tumour cell death in urothelial cancer', 'Disease', 'MESH:D009369', (85, 123))	('cell death', 'biological_process', 'GO:0008219', ('92', '102'))
173449	28049532	In the current study we investigated whether AZD7762 co-administration is capable of enhancing the toxicity of gemcitabine in UCCs and investigated the underlying mechanisms.	('enhancing', 'PosReg', (85, 94))	('toxicity', 'Disease', 'MESH:D064420', (99, 107))	('toxicity', 'Disease', (99, 107))	('gemcitabine', 'Chemical', 'MESH:C056507', (111, 122))	('AZD7762', 'Chemical', 'MESH:C532363', (45, 52))	('AZD7762', 'Var', (45, 52))
173453	28049532	The gemcitabine resistant T24 cell line variant T24rGEMCI20 was derived from the Resistant Cancer Cell Line (RCCL) collection (www.kent.ac.uk/stms/cmp/RCCL/RCCLabout.html).	('Cancer', 'Disease', (91, 97))	('RCCL', 'Disease', (109, 113))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('RCCL', 'Disease', 'None', (156, 160))	('gemcitabine', 'Chemical', 'MESH:C056507', (4, 15))	('variant T', 'CellLine', 'CVCL:7204', (40, 49))	('RCCL', 'Disease', 'None', (109, 113))	('RCCL', 'Disease', (151, 155))	('RCCL', 'Disease', 'None', (151, 155))	('RCCL', 'Disease', (156, 160))	('T24rGEMCI20', 'Var', (48, 59))
173465	28049532	After treatment with different concentrations of gemcitabine and/or AZD7762, cells were grown for 24 or 48 h and viability was measured by transferring cell aliquots into 96-well plates using CellTiter-Glo Reagent.	('gemcitabine', 'Chemical', 'MESH:C056507', (49, 60))	('AZD7762', 'Chemical', 'MESH:C532363', (68, 75))	('AZD7762', 'Var', (68, 75))	('transferrin', 'Gene', (139, 150))	('transferrin', 'Gene', '280705', (139, 150))	('to 9', 'Species', '1214577', (168, 172))
173480	28049532	In MTT assays, up to 40 nM AZD7762 had little effect of its own, but enhanced the effects of gemcitabine on the viability of four different urothelial carcinoma cell lines.	('effects', 'MPA', (82, 89))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (140, 160))	('enhanced', 'PosReg', (69, 77))	('MTT', 'Chemical', 'MESH:C070243', (3, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('gemcitabine', 'Chemical', 'MESH:C056507', (93, 104))	('urothelial carcinoma', 'Disease', (140, 160))	('AZD7762', 'Var', (27, 34))	('AZD7762', 'Chemical', 'MESH:C532363', (27, 34))	('viability', 'CPA', (112, 121))
173482	28049532	We then investigated whether the combination of gemcitabine and AZD7762 also affects the clonogenicity of urothelial carcinoma cells.	('affects', 'Reg', (77, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (106, 126))	('clonogenicity', 'CPA', (89, 102))	('AZD7762', 'Var', (64, 71))	('gemcitabine', 'Chemical', 'MESH:C056507', (48, 59))	('AZD7762', 'Chemical', 'MESH:C532363', (64, 71))	('urothelial carcinoma', 'Disease', (106, 126))
173484	28049532	Thus, the combination of gemcitabine with AZD7762 efficiently inhibited long-term growth of urothelial carcinoma cells in vitro.	('gemcitabine', 'Chemical', 'MESH:C056507', (25, 36))	('urothelial carcinoma', 'Disease', (92, 112))	('inhibited', 'NegReg', (62, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('combination', 'Interaction', (10, 21))	('AZD7762', 'Var', (42, 49))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (92, 112))	('AZD7762', 'Chemical', 'MESH:C532363', (42, 49))
173485	28049532	Light microscopic examinations revealed characteristic morphological changes in UCCs treated with gemcitabine and AZD7762.	('UCCs', 'Disease', (80, 84))	('AZD7762', 'Var', (114, 121))	('gemcitabine', 'Chemical', 'MESH:C056507', (98, 109))	('AZD7762', 'Chemical', 'MESH:C532363', (114, 121))
173488	28049532	To compare the response of UCCs to sequential vs. simultaneous treatment, UCCs were pretreated with AZD7762 for 24 h and then incubated with gemcitabine for 48 h. Pretreatment with AZD7762 still enhanced the cytotoxic effect of gemcitabine, but not as strongly as simultaneous treatment (Additional file 1: Figure S1).	('enhanced', 'PosReg', (195, 203))	('gemcitabine', 'Chemical', 'MESH:C056507', (141, 152))	('gemcitabine', 'Chemical', 'MESH:C056507', (228, 239))	('AZD7762', 'Var', (181, 188))	('AZD7762', 'Chemical', 'MESH:C532363', (181, 188))	('AZD7762', 'Chemical', 'MESH:C532363', (100, 107))	('cytotoxic effect', 'CPA', (208, 224))
173489	28049532	MTT assays were also employed to investigate whether AZD7762 likewise enhanced the activity of cisplatin and the class I HDAC-specific inhibitors, romidepsin and givinostat, three agents highly toxic to UC cells.	('activity', 'MPA', (83, 91))	('AZD7762', 'Var', (53, 60))	('AZD7762', 'Chemical', 'MESH:C532363', (53, 60))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('enhanced', 'PosReg', (70, 78))	('givinostat', 'Chemical', 'MESH:C575255', (162, 172))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('romidepsin', 'Chemical', 'MESH:C087123', (147, 157))
173491	28049532	Pharmacologic inhibition of HDAC1 and HDAC2 by romidepsin or givinostat severely disrupts cell cycle progression and likewise induces DNA damage.	('givinostat', 'Chemical', 'MESH:C575255', (61, 71))	('induces', 'Reg', (126, 133))	('cell cycle progression', 'CPA', (90, 112))	('disrupts', 'NegReg', (81, 89))	('cell cycle', 'biological_process', 'GO:0007049', ('90', '100'))	('HDAC2', 'Gene', '3066', (38, 43))	('romidepsin', 'Chemical', 'MESH:C087123', (47, 57))	('HDAC2', 'Gene', (38, 43))	('DNA damage', 'MPA', (134, 144))	('HDAC1', 'Gene', (28, 33))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))	('inhibition', 'Var', (14, 24))	('HDAC1', 'Gene', '3065', (28, 33))
173496	28049532	Additional depletion of CHK2 increased the sensitisation induced by CHK1 depletion.	('CHK1', 'Gene', (68, 72))	('sensitisation', 'MPA', (43, 56))	('CHK1', 'Gene', '1111', (68, 72))	('increased', 'PosReg', (29, 38))	('depletion', 'Var', (73, 82))	('CHK2', 'Gene', (24, 28))	('depletion', 'Var', (11, 20))	('CHK2', 'Gene', '11200', (24, 28))
173497	28049532	These data suggest that sensitisation to gemcitabine by AZD7762 is mainly mediated by CHK1 inhibition and CHK2 inhibition has a supplementary role.	('CHK1', 'Gene', '1111', (86, 90))	('AZD7762', 'Var', (56, 63))	('sensitisation to gemcitabine', 'MPA', (24, 52))	('gemcitabine', 'Chemical', 'MESH:C056507', (41, 52))	('CHK2', 'Gene', (106, 110))	('inhibition', 'NegReg', (91, 101))	('CHK1', 'Gene', (86, 90))	('CHK2', 'Gene', '11200', (106, 110))	('AZD7762', 'Chemical', 'MESH:C532363', (56, 63))
173499	28049532	To further investigate the mechanisms by which AZD7762 increases the effects of gemcitabine, we analysed cell cycle distribution and apoptosis induction in response to treatment.	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('gemcitabine', 'Chemical', 'MESH:C056507', (80, 91))	('analysed', 'Reg', (96, 104))	('AZD7762', 'Var', (47, 54))	('AZD7762', 'Chemical', 'MESH:C532363', (47, 54))	('cell cycle', 'biological_process', 'GO:0007049', ('105', '115'))	('effects', 'MPA', (69, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))
173502	28049532	In contrast, cells treated with gemcitabine and AZD7762 remained accumulated in S phase or underwent apoptosis, as indicated by a significant increase in the fraction of sub-G1 cells in all cell lines after 48 h combined treatment, compared with untreated controls or each single treatment.	('AZD7762', 'Chemical', 'MESH:C532363', (48, 55))	('increase', 'PosReg', (142, 150))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('gemcitabine', 'Chemical', 'MESH:C056507', (32, 43))	('S phase', 'biological_process', 'GO:0051320', ('80', '87'))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('S phase', 'CPA', (80, 87))	('AZD7762', 'Var', (48, 55))
173504	28049532	However, when gemcitabine was combined with AZD7762, its expression remained elevated after 48 h in VM-CUB1, RT-112, and T24 cells.	('expression', 'MPA', (57, 67))	('gemcitabine', 'Chemical', 'MESH:C056507', (14, 25))	('AZD7762', 'Chemical', 'MESH:C532363', (44, 51))	('AZD7762', 'Var', (44, 51))	('elevated', 'PosReg', (77, 85))
173509	28049532	Thus, the combination of gemcitabine and AZD7762 efficiently induced apoptosis in all UCCs, albeit with somewhat different time courses.	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('gemcitabine', 'Chemical', 'MESH:C056507', (25, 36))	('induced', 'Reg', (61, 68))	('combination', 'Interaction', (10, 21))	('apoptosis', 'CPA', (69, 78))	('AZD7762', 'Var', (41, 48))	('AZD7762', 'Chemical', 'MESH:C532363', (41, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))
173516	28049532	The ATR-mediated phosphorylation of CHK1 (Ser345 CHK1) was increased only at the higher concentration of gemcitabine and likewise sustained after 48 h of treatment (Fig.	('CHK1', 'Gene', '1111', (49, 53))	('Ser345', 'Chemical', '-', (42, 48))	('CHK1', 'Gene', '1111', (36, 40))	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('Ser345', 'Var', (42, 48))	('CHK1', 'Gene', (49, 53))	('ATR', 'Gene', '545', (4, 7))	('ATR', 'Gene', (4, 7))	('CHK1', 'Gene', (36, 40))	('Ser', 'cellular_component', 'GO:0005790', ('42', '45'))	('increased', 'PosReg', (59, 68))	('gemcitabine', 'Chemical', 'MESH:C056507', (105, 116))
173517	28049532	To confirm that AZD7762 inhibits CHK1/CHK2 in UCCs, CHK1/CHK2 signalling was investigated.	('AZD7762', 'Chemical', 'MESH:C532363', (16, 23))	('CHK2', 'Gene', (57, 61))	('AZD7762', 'Var', (16, 23))	('CHK1', 'Gene', '1111', (33, 37))	('inhibits', 'NegReg', (24, 32))	('signalling', 'biological_process', 'GO:0023052', ('62', '72'))	('CHK1', 'Gene', (52, 56))	('CHK2', 'Gene', '11200', (57, 61))	('CHK2', 'Gene', (38, 42))	('CHK1', 'Gene', (33, 37))	('CHK1', 'Gene', '1111', (52, 56))	('CHK2', 'Gene', '11200', (38, 42))
173519	28049532	Ser345 CHK1 was transiently phosphorylated after 24 h of gemcitabine treatment returning to near control levels after 48 h. Ser345 CHK1 phosphorylation was further enhanced when UCCs were co-treated with AZD7762.	('CHK1', 'Gene', '1111', (7, 11))	('phosphorylation', 'MPA', (136, 151))	('CHK1', 'Gene', '1111', (131, 135))	('Ser', 'cellular_component', 'GO:0005790', ('124', '127'))	('AZD7762', 'Chemical', 'MESH:C532363', (204, 211))	('Ser345', 'Chemical', '-', (0, 6))	('enhanced', 'PosReg', (164, 172))	('CHK1', 'Gene', (7, 11))	('Ser345', 'Chemical', '-', (124, 130))	('Ser345', 'Var', (124, 130))	('phosphorylation', 'biological_process', 'GO:0016310', ('136', '151'))	('CHK1', 'Gene', (131, 135))	('gemcitabine', 'Chemical', 'MESH:C056507', (57, 68))	('Ser', 'cellular_component', 'GO:0005790', ('0', '3'))
173524	28049532	In The Cancer Genome Atlas (TCGA) dataset, 14% of invasive bladder cancers have mutations in CDKN1A encoding the cyclin-dependent kinase inhibitor p21CIP1.	('CDKN1A', 'Gene', '1026', (93, 99))	('bladder cancers', 'Phenotype', 'HP:0009725', (59, 74))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('113', '146'))	('p21CIP1', 'Gene', (147, 154))	('bladder cancer', 'Phenotype', 'HP:0009725', (59, 73))	('p21CIP1', 'Gene', '1026', (147, 154))	('cyclin', 'Gene', (113, 119))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (7, 26))	('invasive bladder', 'Phenotype', 'HP:0100645', (50, 66))	('mutations', 'Var', (80, 89))	('Cancer Genome Atlas', 'Disease', (7, 26))	('invasive bladder cancers', 'Disease', (50, 74))	('Cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cyclin', 'Gene', '5111', (113, 119))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('130', '146'))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (50, 74))	('CDKN1A', 'Gene', (93, 99))
173525	28049532	It was previously reported that double mutant p53/p21-deficient bladder cancers were more sensitive to combined treatment with gemcitabine and a CHK inhibitor.	('CHK', 'Gene', (145, 148))	('gemcitabine', 'Chemical', 'MESH:C056507', (127, 138))	('p21-deficient bladder cancers', 'Disease', (50, 79))	('CHK', 'Gene', '1119', (145, 148))	('bladder cancer', 'Phenotype', 'HP:0009725', (64, 78))	('p53', 'Gene', (46, 49))	('double mutant', 'Var', (32, 45))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('p53', 'Gene', '7157', (46, 49))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('p21-deficient bladder cancers', 'Disease', 'MESH:D001749', (50, 79))	('bladder cancers', 'Phenotype', 'HP:0009725', (64, 79))	('deficient bladder', 'Phenotype', 'HP:0005343', (54, 71))	('sensitive', 'MPA', (90, 99))
173527	28049532	As mentioned above, in our hands, AZD7762 sensitised all four UCCs including RT-112 to gemcitabine in a synergistic fashion, although checkpoint activation by gemcitabine alone was more pronounced in RT-112.	('gemcitabine', 'Chemical', 'MESH:C056507', (159, 170))	('gemcitabine', 'Chemical', 'MESH:C056507', (87, 98))	('sensitised', 'Reg', (42, 52))	('AZD7762', 'Chemical', 'MESH:C532363', (34, 41))	('AZD7762', 'Var', (34, 41))
173531	28049532	In the present study, we showed that AZD7762, an ATP competitive inhibitor of checkpoint kinases, can strongly sensitise UCCs to the ribonucleotide reductase inhibitor gemcitabine.	('gemcitabine', 'Chemical', 'MESH:C056507', (168, 179))	('sensitise', 'Reg', (111, 120))	('ATP', 'Chemical', 'MESH:D000255', (49, 52))	('AZD7762', 'Var', (37, 44))	('AZD7762', 'Chemical', 'MESH:C532363', (37, 44))
173532	28049532	The effect of AZD7762 is associated with abrogation of the G2 checkpoint activation induced by gemcitabine and especially with persistence of unrepaired DNA damage, as indicated by our findings that AZD7762 increased ATR-mediated CHK1 phosphorylation (Ser345 CHK1) and that it inhibited the repair of gemcitabine-induced double strand breaks as evidenced by sustained expression of gammaH2A.X and 53-BP1.	('CHK1', 'Gene', '1111', (259, 263))	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('phosphorylation', 'biological_process', 'GO:0016310', ('235', '250'))	('Ser', 'cellular_component', 'GO:0005790', ('252', '255'))	('CHK1', 'Gene', (230, 234))	('repair', 'MPA', (291, 297))	('ATR', 'Gene', '545', (217, 220))	('gemcitabine', 'Chemical', 'MESH:C056507', (301, 312))	('AZD7762', 'Chemical', 'MESH:C532363', (199, 206))	('gemcitabine', 'Chemical', 'MESH:C056507', (95, 106))	('gammaH2A.X and 53-BP1', 'Gene', '474256', (382, 403))	('CHK1', 'Gene', '1111', (230, 234))	('CHK1', 'Gene', (259, 263))	('AZD7762', 'Var', (199, 206))	('AZD7762', 'Chemical', 'MESH:C532363', (14, 21))	('inhibited', 'NegReg', (277, 286))	('increased', 'PosReg', (207, 216))	('ATR', 'Gene', (217, 220))	('Ser345', 'Chemical', '-', (252, 258))	('AZD7762', 'Var', (14, 21))
173533	28049532	There are likely several reasons why AZD7762 leads to persistence of double strand breaks, including its inhibitory effects on Rad51 focus formation and homologous recombination DNA repair and on the function of CHK1 in the maintenance of replication forks.	('CHK1', 'Gene', (212, 216))	('Rad51', 'Gene', '5888', (127, 132))	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('formation', 'biological_process', 'GO:0009058', ('139', '148'))	('CHK1', 'Gene', '1111', (212, 216))	('AZD7762', 'Var', (37, 44))	('Rad', 'biological_process', 'GO:1990116', ('127', '130'))	('double strand breaks', 'MPA', (69, 89))	('AZD7762', 'Chemical', 'MESH:C532363', (37, 44))	('homologous recombination', 'biological_process', 'GO:0035825', ('153', '177'))	('Rad51', 'Gene', (127, 132))	('DNA repair', 'biological_process', 'GO:0006281', ('178', '188'))	('persistence', 'MPA', (54, 65))
173534	28049532	The enhancement of cytotoxicity by AZD7762 was relatively specific to gemcitabine, as the combination effect was weaker with other compounds causing DNA strand-breaks, like cisplatin or HDAC1/2 inhibitors (Additional file 2: Figure S2a).	('enhancement', 'PosReg', (4, 15))	('HDAC1/2', 'Gene', '3065;3066', (186, 193))	('cytotoxicity', 'Disease', (19, 31))	('gemcitabine', 'Chemical', 'MESH:C056507', (70, 81))	('cytotoxicity', 'Disease', 'MESH:D064420', (19, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (173, 182))	('AZD7762', 'Var', (35, 42))	('DNA', 'cellular_component', 'GO:0005574', ('149', '152'))	('AZD7762', 'Chemical', 'MESH:C532363', (35, 42))	('HDAC1/2', 'Gene', (186, 193))
173535	28049532	As AZD7762 is an equally potent inhibitor of both CHK1 and CHK2, a priori, inhibition of both kinases might contribute to its enhancement of gemcitabine activity on UCCs.	('enhancement', 'PosReg', (126, 137))	('CHK1', 'Gene', '1111', (50, 54))	('inhibition', 'NegReg', (75, 85))	('gemcitabine', 'Chemical', 'MESH:C056507', (141, 152))	('CHK2', 'Gene', (59, 63))	('CHK2', 'Gene', '11200', (59, 63))	('gemcitabine activity', 'MPA', (141, 161))	('AZD7762', 'Var', (3, 10))	('CHK1', 'Gene', (50, 54))	('AZD7762', 'Chemical', 'MESH:C532363', (3, 10))
173537	28049532	However, siRNA depletion experiments showed that interference with CHK1 results in a much more pronounced UCC sensitisation to gemcitabine compared to interference with CHK2, but that depletion of both kinases was most efficient.	('gemcitabine', 'Chemical', 'MESH:C056507', (127, 138))	('CHK2', 'Gene', (169, 173))	('CHK2', 'Gene', '11200', (169, 173))	('CHK1', 'Gene', '1111', (67, 71))	('UCC sensitisation to gemcitabine', 'MPA', (106, 138))	('interference', 'Var', (49, 61))	('CHK1', 'Gene', (67, 71))
173539	28049532	In concordance, pharmacological inhibition of CHK1 by the CHK1-specific inhibitor Go6976 also efficiently sensitised UCCs to gemcitabine.	('CHK1', 'Gene', '1111', (46, 50))	('pharmacological inhibition', 'Var', (16, 42))	('CHK1', 'Gene', (58, 62))	('Go6976', 'Chemical', 'MESH:C081021', (82, 88))	('CHK1', 'Gene', (46, 50))	('sensitised', 'Reg', (106, 116))	('gemcitabine', 'Chemical', 'MESH:C056507', (125, 136))	('CHK1', 'Gene', '1111', (58, 62))
173540	28049532	However, the effects of CHK1 depletion are further enhanced by additional inhibition of CHK2 activity.	('depletion', 'Var', (29, 38))	('CHK2', 'Gene', (88, 92))	('activity', 'MPA', (93, 101))	('CHK1', 'Gene', (24, 28))	('CHK2', 'Gene', '11200', (88, 92))	('enhanced', 'PosReg', (51, 59))	('inhibition', 'NegReg', (74, 84))	('CHK1', 'Gene', '1111', (24, 28))
173541	28049532	Notably, although CHK1 gene knock-out is lethal in embryos and induces apoptosis in embryonic stem cells, the depletion of CHK1 by siRNA in somatic cells on its own has been reported to cause little cytotoxicity and enhance the efficacy of DNA-damaging drugs in p53-deficient cancer cell lines.	('CHK1', 'Gene', (123, 127))	('enhance', 'PosReg', (216, 223))	('apoptosis', 'CPA', (71, 80))	('p53-deficient cancer', 'Disease', 'MESH:D009369', (262, 282))	('efficacy', 'MPA', (228, 236))	('knock-out', 'Var', (28, 37))	('DNA', 'cellular_component', 'GO:0005574', ('240', '243'))	('CHK1', 'Gene', (18, 22))	('induces', 'Reg', (63, 70))	('cytotoxicity', 'Disease', (199, 211))	('CHK1', 'Gene', '1111', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('p53-deficient cancer', 'Disease', (262, 282))	('depletion', 'Var', (110, 119))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('cytotoxicity', 'Disease', 'MESH:D064420', (199, 211))	('CHK1', 'Gene', '1111', (18, 22))
173542	28049532	In accordance, we did not find AZD7762 to sensitise non-cancerous cells to gemcitabine.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('AZD7762', 'Chemical', 'MESH:C532363', (31, 38))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('gemcitabine', 'Chemical', 'MESH:C056507', (75, 86))	('AZD7762', 'Var', (31, 38))
173545	28049532	Tumour cells harbouring defects in p53 function lack an efficient G1 checkpoint and thus have to rely on the S or G2 checkpoints for DNA repair, in which CHK1/2 have crucial functions.	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('lack', 'NegReg', (48, 52))	('defects', 'Var', (24, 31))	('CHK1/2', 'Gene', '1111;11200', (154, 160))	('G1 checkpoint', 'MPA', (66, 79))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('DNA repair', 'biological_process', 'GO:0006281', ('133', '143'))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('CHK1/2', 'Gene', (154, 160))
173546	28049532	Checkpoint abrogation can therefore promote DNA-damage-induced mitotic catastrophe and cell death in p53-defective tumour cells, whereas normal cells may tolerate DNA damage stress by activating the G1 checkpoint through normal p53 function.	('mitotic catastrophe', 'Disease', (63, 82))	('promote', 'PosReg', (36, 43))	('mitotic catastrophe', 'Disease', 'MESH:D002388', (63, 82))	('p53', 'Gene', (228, 231))	('activating', 'Reg', (184, 194))	('p53', 'Gene', '7157', (228, 231))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('Checkpoint', 'Gene', (0, 10))	('cell death', 'biological_process', 'GO:0008219', ('87', '97'))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('63', '82'))	('abrogation', 'Var', (11, 21))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('cell death', 'CPA', (87, 97))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('tumour', 'Disease', (115, 121))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))
173549	28049532	Accordingly, in a phase I trial conducted in patients with solid tumours - other than UC - only gemcitabine-naive patients responded to the combination of AZD7762 and gemcitabine.	('gemcitabine', 'Chemical', 'MESH:C056507', (167, 178))	('responded', 'Reg', (123, 132))	('gemcitabine', 'Chemical', 'MESH:C056507', (96, 107))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('patients', 'Species', '9606', (45, 53))	('solid tumours', 'Disease', 'MESH:D009369', (59, 72))	('patients', 'Species', '9606', (114, 122))	('AZD7762', 'Var', (155, 162))	('AZD7762', 'Chemical', 'MESH:C532363', (155, 162))	('solid tumours', 'Disease', (59, 72))
173553	28049532	Indeed, in the RT-112 cell line, which has an inactivating mutation in p21CIP1, gemcitabine-induced double strand breaks persisted longer (Fig.	('gemcitabine-induced double strand breaks', 'MPA', (80, 120))	('p21CIP1', 'Gene', (71, 78))	('p21CIP1', 'Gene', '1026', (71, 78))	('gemcitabine', 'Chemical', 'MESH:C056507', (80, 91))	('inactivating mutation', 'Var', (46, 67))
173554	28049532	6) and the sensitisation to gemcitabine by AZD7762 appeared to be quantitatively stronger (Fig.	('sensitisation to gemcitabine', 'MPA', (11, 39))	('stronger', 'PosReg', (81, 89))	('gemcitabine', 'Chemical', 'MESH:C056507', (28, 39))	('AZD7762', 'Var', (43, 50))	('AZD7762', 'Chemical', 'MESH:C532363', (43, 50))
173556	28049532	In the current study, however, CHK1 inhibition by AZD7762 sensitised UCCs to gemcitabine regardless of their p21CIP1 status and in the T24 cell line AZD7762 abrogated DNA repair of gemcitabine-induced DNA double strand breaks (Fig.	('AZD7762', 'Chemical', 'MESH:C532363', (149, 156))	('DNA repair', 'MPA', (167, 177))	('p21CIP1', 'Gene', (109, 116))	('DNA', 'cellular_component', 'GO:0005574', ('201', '204'))	('AZD7762', 'Var', (50, 57))	('gemcitabine', 'Chemical', 'MESH:C056507', (181, 192))	('inhibition', 'NegReg', (36, 46))	('p21CIP1', 'Gene', '1026', (109, 116))	('AZD7762', 'Chemical', 'MESH:C532363', (50, 57))	('abrogated', 'NegReg', (157, 166))	('DNA', 'cellular_component', 'GO:0005574', ('167', '170'))	('CHK1', 'Gene', (31, 35))	('DNA repair', 'biological_process', 'GO:0006281', ('167', '177'))	('gemcitabine', 'Chemical', 'MESH:C056507', (77, 88))	('CHK1', 'Gene', '1111', (31, 35))
173557	28049532	These observations may mean that AZD7762 overcomes the influence of p21CIP1 on the DNA repair process.	('DNA repair', 'biological_process', 'GO:0006281', ('83', '93'))	('p21CIP1', 'Gene', (68, 75))	('AZD7762', 'Chemical', 'MESH:C532363', (33, 40))	('p21CIP1', 'Gene', '1026', (68, 75))	('AZD7762', 'Var', (33, 40))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))
173561	28049532	The CHK1/2 inhibitor AZD7762 enhanced gemcitabine activity in gemcitabine-sensitive UCCs through inhibition of the gemcitabine-induced DNA damage response, which is predominantly mediated through CHK1 inhibition.	('gemcitabine', 'Chemical', 'MESH:C056507', (38, 49))	('gemcitabine', 'Chemical', 'MESH:C056507', (62, 73))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('CHK1/2', 'Gene', (4, 10))	('gemcitabine-induced DNA damage response', 'MPA', (115, 154))	('CHK1', 'Gene', (196, 200))	('gemcitabine activity', 'MPA', (38, 58))	('CHK1', 'Gene', (4, 8))	('inhibition', 'NegReg', (97, 107))	('CHK1', 'Gene', '1111', (196, 200))	('AZD7762', 'Var', (21, 28))	('AZD7762', 'Chemical', 'MESH:C532363', (21, 28))	('gemcitabine', 'Chemical', 'MESH:C056507', (115, 126))	('CHK1', 'Gene', '1111', (4, 8))	('DNA damage response', 'biological_process', 'GO:0006974', ('135', '154'))	('enhanced', 'PosReg', (29, 37))	('CHK1/2', 'Gene', '1111;11200', (4, 10))
173563	28049532	Notably, potentiation of gemcitabine effects by AZD7762 in xenografts from several other cancer types has been already reported.	('AZD7762', 'Chemical', 'MESH:C532363', (48, 55))	('gemcitabine effects', 'MPA', (25, 44))	('gemcitabine', 'Chemical', 'MESH:C056507', (25, 36))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('potentiation', 'PosReg', (9, 21))	('AZD7762', 'Var', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
173565	28049532	ATM Ataxia telangiectasia mutated ATR Ataxia telangiectasia and RAD3-related CDK Cyclin dependent kinase CHK Checkpoint kinase DSB Double strand break MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrayolium bromide UCC Urothelial carcinoma cell line	('telangiectasia', 'Phenotype', 'HP:0001009', (11, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrayolium bromide', 'Chemical', '-', (155, 215))	('CHK', 'Gene', '1119', (105, 108))	('Cyclin', 'Gene', '5111', (81, 87))	('CDK', 'molecular_function', 'GO:0004693', ('77', '80'))	('CHK', 'Gene', (105, 108))	('MTT', 'Chemical', 'MESH:C070243', (151, 154))	('ATR', 'Gene', '545', (34, 37))	('ATM', 'Gene', (0, 3))	('Ataxia', 'Phenotype', 'HP:0001251', (38, 44))	('Cyclin', 'molecular_function', 'GO:0016538', ('81', '87'))	('Ataxia telangiectasia', 'Disease', (38, 59))	('Ataxia telangiectasia', 'Disease', 'MESH:D001260', (38, 59))	('mutated', 'Var', (26, 33))	('Ataxia telangiectasia', 'Disease', (4, 25))	('RAD', 'biological_process', 'GO:1990116', ('64', '67'))	('telangiectasia', 'Phenotype', 'HP:0001009', (45, 59))	('Ataxia telangiectasia', 'Disease', 'MESH:D001260', (4, 25))	('Urothelial carcinoma', 'Disease', 'MESH:D014526', (220, 240))	('Cyclin', 'Gene', (81, 87))	('Urothelial carcinoma', 'Disease', (220, 240))	('ATR', 'Gene', (34, 37))	('Ataxia', 'Phenotype', 'HP:0001251', (4, 10))	('ATM', 'Gene', '472', (0, 3))
173583	31412811	Dysregulation of lncRNA expression has been reported for different cancer types and may contribute to tumor development and progression.	('lncRNA expression', 'Protein', (17, 34))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('contribute', 'Reg', (88, 98))	('cancer', 'Disease', (67, 73))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('progression', 'CPA', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
173618	31412811	The HNSCC cell line panel consisted of UM (University of Michigan) -SCC 10A/ B, -11B, -14A/ B, -17A/ B, - 47, - 104 and UT (University of Turku) -SCC -14, - 24A/ B, - 33, as well as UD (University of Duesseldorf) -SCC 1, - 2, - 3, - 5, - 6, -7A, - 8, and FaDu.	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('SCC', 'Gene', '6317', (68, 71))	('SCC', 'Gene', (6, 9))	('HNSCC', 'Phenotype', 'HP:0012288', (4, 9))	('SCC', 'Gene', '6317', (214, 217))	('SCC', 'Phenotype', 'HP:0002860', (6, 9))	('10A/ B', 'Var', (72, 78))	('SCC', 'Gene', (146, 149))	('SCC', 'Gene', '6317', (6, 9))	('24A/ B', 'SUBSTITUTION', 'None', (157, 163))	('SCC', 'Phenotype', 'HP:0002860', (146, 149))	('SCC', 'Gene', '6317', (146, 149))	('24A/ B', 'Var', (157, 163))	('SCC', 'Gene', (68, 71))	('SCC', 'Gene', (214, 217))	('SCC', 'Phenotype', 'HP:0002860', (214, 217))	('10A/ B', 'SUBSTITUTION', 'None', (72, 78))
173663	31412811	Patients with high expression of either CASC9 (p = 0.002) or HOTAIR (p < 0.001) experienced poor overall survival (Fig.	('overall survival', 'MPA', (97, 113))	('HOTAIR', 'Gene', (61, 67))	('poor', 'NegReg', (92, 96))	('Patients', 'Species', '9606', (0, 8))	('HOTAIR', 'Gene', '100124700', (61, 67))	('high expression', 'Var', (14, 29))	('CASC9', 'Gene', (40, 45))	('CASC9', 'Gene', '101805492', (40, 45))
173679	31412811	Finally, overexpressed CASC9 has been reported in recent publications to influence proliferation, migration and invasion of tumor cell lines from cancers of esophagus, lung, stomach, and liver.	('liver', 'Disease', (187, 192))	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('lung', 'Disease', (168, 172))	('proliferation', 'CPA', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('invasion', 'CPA', (112, 120))	('stomach', 'Disease', (174, 181))	('tumor', 'Disease', (124, 129))	('overexpressed', 'Var', (9, 22))	('CASC9', 'Gene', (23, 28))	('CASC9', 'Gene', '101805492', (23, 28))	('migration', 'CPA', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('influence', 'Reg', (73, 82))	('esophagus', 'Disease', (157, 166))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
173700	31412811	CASC9 expression had excellent tumor specificity according to ROC curve analysis, comparable to results reported in ESCC, and high CASC9 expression was significantly associated with high AJCC stage and extracapsular spread, indicating further diagnostic power.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('expression', 'MPA', (137, 147))	('CASC9', 'Gene', (131, 136))	('CASC9', 'Gene', '101805492', (131, 136))	('SCC', 'Gene', (117, 120))	('tumor', 'Disease', (31, 36))	('CASC9', 'Gene', '101805492', (0, 5))	('high', 'Var', (126, 130))	('high AJCC', 'Disease', (182, 191))	('SCC', 'Gene', '6317', (117, 120))	('extracapsular spread', 'CPA', (202, 222))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('associated', 'Reg', (166, 176))	('CASC9', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
173715	31412811	Since previous studies with cell lines from other cancer types reported stimulating effects of CASC9 expression on proliferation, migration and invasion or inhibitory effects on apoptosis, we modulated CASC9 expression by either stable overexpression or shRNA-mediated knock down in suitable HNSCC cell lines and in the benign HaCaT cell line.	('cancer', 'Disease', (50, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('178', '187'))	('apoptosis', 'biological_process', 'GO:0006915', ('178', '187'))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('HaCaT', 'CellLine', 'CVCL:0038', (327, 332))	('CASC9', 'Gene', '101805492', (95, 100))	('SCC', 'Phenotype', 'HP:0002860', (294, 297))	('CASC9', 'Gene', (202, 207))	('knock down', 'Var', (269, 279))	('modulated', 'Reg', (192, 201))	('SCC', 'Gene', '6317', (294, 297))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('invasion', 'CPA', (144, 152))	('proliferation', 'CPA', (115, 128))	('migration', 'CPA', (130, 139))	('SCC', 'Gene', (294, 297))	('CASC9', 'Gene', (95, 100))	('CASC9', 'Gene', '101805492', (202, 207))	('HNSCC', 'Phenotype', 'HP:0012288', (292, 297))
173753	30881506	Alterations in the expression levels of lncRNAs have been demonstrated to be associated with a number of important cellular functions, and may promote the migration and invasion of cancer cells.	('migration', 'CPA', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('invasion', 'CPA', (169, 177))	('lncRNAs', 'Protein', (40, 47))	('Alterations', 'Var', (0, 11))	('promote', 'PosReg', (143, 150))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('expression levels', 'MPA', (19, 36))	('cancer', 'Disease', (181, 187))	('associated', 'Reg', (77, 87))
173754	30881506	Non-coding RNAs have attracted increasing attention in previous years regarding their role in bladder cancer, with the number of studies on this topic increasing considerably.	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('bladder cancer', 'Disease', (94, 108))	('Non-coding RNAs', 'Var', (0, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))
173755	30881506	The combination of traditional methods of treatment with the use of non-coding RNAs may provide improved therapy for patients.	('non-coding RNAs', 'Var', (68, 83))	('patients', 'Species', '9606', (117, 125))	('therapy', 'MPA', (105, 112))	('men', 'Species', '9606', (47, 50))
173768	30881506	Therefore, the effects of aberrant LINC00460 expression on the biological behavior of 5637 and T24 cells were additionally investigated.	('LINC00460', 'Gene', '728192', (35, 44))	('LINC00460', 'Gene', (35, 44))	('aberrant', 'Var', (26, 34))
173781	30881506	The sh-LINC00460 sequences were as follows: sh-1, 5'-GCTAAGACCTAATAGCCAATA-3'; sh-2, 5'-GCCATCCACTTCAAAGTATTC-3'; and sh-3, 5'-ACCTTGGTCAAACGTTTAACC-3'.	('LINC00460', 'Gene', '728192', (7, 16))	('LINC00460', 'Gene', (7, 16))	('sh-2', 'Var', (79, 83))
173810	30881506	The wound-healing assay revealed that the knockdown of LINC00460 decreased the migration distance of cells (Fig.	('decreased', 'NegReg', (65, 74))	('migration distance of cells', 'CPA', (79, 106))	('wound-healing', 'biological_process', 'GO:0042060', ('4', '17'))	('LINC00460', 'Gene', (55, 64))	('LINC00460', 'Gene', '728192', (55, 64))	('knockdown', 'Var', (42, 51))
173811	30881506	Overall, the results demonstrated that the silencing of LINC00460 may inhibit the proliferation and migration abilities of 5637 and T24 cells.	('silencing', 'Var', (43, 52))	('inhibit', 'NegReg', (70, 77))	('LINC00460', 'Gene', '728192', (56, 65))	('LINC00460', 'Gene', (56, 65))
173919	30823924	According to OncoLnc (www.oncolnc.org; a TCGA data portal), high levels of FSCN1 indicated poor prognosis (Fig.	('high levels', 'Var', (60, 71))	('FSCN1', 'Gene', (75, 80))	('FSCN1', 'Gene', '6624', (75, 80))
173920	30823924	1a); conversely, high miR-200b expression indicated good prognosis (Fig.	('miR-200b', 'Gene', '406984', (22, 30))	('expression', 'MPA', (31, 41))	('miR-200b', 'Gene', (22, 30))	('high', 'Var', (17, 21))
173930	30823924	We found that miR-200b significantly reduced the luciferase activity of the cells (T24, RT4 or 293 T) transfected with the construct containing the wild-type FSCN1 sequence; however, miR200b did not have any effect on the construct with the mutated FSCN1 sequence (Fig.	('luciferase activity', 'molecular_function', 'GO:0045289', ('49', '68'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('49', '68'))	('FSCN1', 'Gene', (158, 163))	('RT4', 'CellLine', 'CVCL:0036', (88, 91))	('luciferase activity', 'molecular_function', 'GO:0050397', ('49', '68'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('49', '68'))	('FSCN1', 'Gene', (249, 254))	('miR-200b', 'Gene', (14, 22))	('mutated', 'Var', (241, 248))	('FSCN1', 'Gene', '6624', (158, 163))	('activity', 'MPA', (60, 68))	('miR200b', 'Gene', '406984', (183, 190))	('293 T', 'CellLine', 'CVCL:0063', (95, 100))	('miR-200b', 'Gene', '406984', (14, 22))	('luciferase activity', 'molecular_function', 'GO:0047077', ('49', '68'))	('miR200b', 'Gene', (183, 190))	('reduced', 'NegReg', (37, 44))	('FSCN1', 'Gene', '6624', (249, 254))	('luciferase', 'Enzyme', (49, 59))
173938	30823924	Flow cytometry assays showed that the percentage of cells in G0/G1 phase significantly increased upon miR-200b overexpression and decreased upon miR-200b knockdown (Additional file 2: Figure S1B).	('increased', 'PosReg', (87, 96))	('miR-200b', 'Gene', '406984', (102, 110))	('miR-200b', 'Gene', (102, 110))	('knockdown', 'Var', (154, 163))	('G0/G1 phase', 'CPA', (61, 72))	('G1 phase', 'biological_process', 'GO:0051318', ('64', '72'))	('overexpression', 'PosReg', (111, 125))	('miR-200b', 'Gene', '406984', (145, 153))	('decreased', 'NegReg', (130, 139))	('miR-200b', 'Gene', (145, 153))
173967	30823924	The tumors derived from ZEB1-AS1 overexpressing cells grew faster than control cells (Fig.	('overexpressing', 'Var', (33, 47))	('faster', 'PosReg', (59, 65))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('grew', 'CPA', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
173969	30823924	These results suggest that ZEB1-AS1 inhibits apoptosis and enhances tumor growth both in vitro and in vivo.	('tumor', 'Disease', (68, 73))	('inhibits', 'NegReg', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('ZEB1-AS1', 'Var', (27, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('enhances', 'PosReg', (59, 67))	('apoptosis', 'CPA', (45, 54))
173974	30823924	Western blot assays showed that ZEB1-AS1 silencing reversed the upregulation of FSCN1 induced by TGF-beta1 treatment in T24 cells (Fig.	('silencing', 'Var', (41, 50))	('TGF-beta1', 'Gene', '7040', (97, 106))	('TGF-beta1', 'Gene', (97, 106))	('upregulation', 'PosReg', (64, 76))	('FSCN1', 'Gene', (80, 85))	('FSCN1', 'Gene', '6624', (80, 85))
173993	30823924	Therefore, ZEB1-AS1 might promote tumor progression by increasing the recurrence of BLCA.	('BLCA', 'Phenotype', 'HP:0009725', (84, 88))	('promote', 'PosReg', (26, 33))	('BLCA', 'Disease', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('increasing', 'PosReg', (55, 65))	('recurrence', 'CPA', (70, 80))	('ZEB1-AS1', 'Var', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
173995	30823924	Furthermore, in functional experiments, we found that ZEB1-AS1 decreased cell apoptosis and G0/G1 arrest and induced BLCA cell proliferation, migration, and invasion, thereby exerting a tumor promoting role via the miR-200b/FSCN1 axis.	('miR-200b', 'Gene', (215, 223))	('migration', 'CPA', (142, 151))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('decreased', 'NegReg', (63, 72))	('cell proliferation', 'biological_process', 'GO:0008283', ('122', '140'))	('FSCN1', 'Gene', '6624', (224, 229))	('miR-200b', 'Gene', '406984', (215, 223))	('induced', 'PosReg', (109, 116))	('cell apoptosis', 'CPA', (73, 87))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('BLCA cell proliferation', 'CPA', (117, 140))	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('invasion', 'CPA', (157, 165))	('ZEB1-AS1', 'Var', (54, 62))	('G0/G1 arrest', 'CPA', (92, 104))	('FSCN1', 'Gene', (224, 229))	('BLCA', 'Phenotype', 'HP:0009725', (117, 121))
174015	27994658	Results: High expression of HSD17B2 was significantly associated with better clinicopathological parameters, including the following parameters in urothelial carcinoma of upper urinary tracts: Ta (non-invasive papillary carcinoma) and T1 (invaded subepithelial connective tissue) disease, without nodal metastasis, without vascular invasion, without perineal invasion and with a low histological grade, and the following parameters specifically in urothelial carcinoma of the urinary bladder: Ta (noninvasive papillary carcinoma) and T1 (invaded into the lamina propria but not into the muscularis propria) disease, without nodal metastasis (all P<0.05).	('urothelial carcinoma of the urinary bladder', 'Disease', 'MESH:D001749', (448, 491))	('papillary carcinoma', 'Disease', (210, 229))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (448, 468))	('papillary carcinoma', 'Disease', (509, 528))	('muscularis propria', 'Phenotype', 'HP:0030936', (587, 605))	('carcinoma', 'Phenotype', 'HP:0030731', (519, 528))	('papillary carcinoma', 'Disease', 'MESH:D002291', (509, 528))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (147, 167))	('carcinoma of upper urinary tracts', 'Phenotype', 'HP:0010935', (158, 191))	('HSD17B2', 'Gene', '3294', (28, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (459, 468))	('urothelial carcinoma of the urinary bladder', 'Disease', (448, 491))	('papillary carcinoma', 'Disease', 'MESH:D002291', (210, 229))	('urothelial carcinoma', 'Disease', (147, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('High expression', 'Var', (9, 24))	('HSD17B2', 'Gene', (28, 35))
174016	27994658	Additionally, HSD17B2 high expression predicted a better prognosis, including improved disease-specific survival and metastasis-free survival in urothelial carcinomas of the urinary tract system.	('high expression', 'Var', (22, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('HSD17B2', 'Gene', '3294', (14, 21))	('HSD17B2', 'Gene', (14, 21))	('metastasis-free survival', 'CPA', (117, 141))	('carcinomas of the urinary tract', 'Phenotype', 'HP:0010786', (156, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (156, 166))	('disease-specific survival', 'CPA', (87, 112))	('urothelial carcinomas', 'Disease', (145, 166))	('improved', 'PosReg', (78, 86))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (145, 166))
174017	27994658	Conclusions: High expression of HSD17B2 is associated with a better prognosis and is therefore a prognostic biomarker that can be used to predict favorable survival in patients with urothelial carcinoma of the urinary tract system.	('HSD17B2', 'Gene', (32, 39))	('High', 'Var', (13, 17))	('carcinoma of the urinary tract', 'Phenotype', 'HP:0010786', (193, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('expression', 'MPA', (18, 28))	('patients', 'Species', '9606', (168, 176))	('HSD17B2', 'Gene', '3294', (32, 39))	('urothelial carcinoma of the urinary tract system', 'Disease', (182, 230))	('urothelial carcinoma of the urinary tract system', 'Disease', 'MESH:D014552', (182, 230))
174054	27994658	Among the genes identified in this analysis, HSD17B2 was the most significantly associated, in that its expression was lower in T2-4 than in Ta-T1 lesions and had a log2 ratio during progression between these stages of -3.1569 (Figure 1 and Table 1, P<0.0001).	('HSD17B2', 'Gene', '3294', (45, 52))	('lower', 'NegReg', (119, 124))	('T2-4', 'Var', (128, 132))	('expression', 'MPA', (104, 114))	('HSD17B2', 'Gene', (45, 52))
174075	27994658	Moreover, of the clinicopathological parameters that affected outcomes in urothelial carcinoma, a high expression level of HSD17B2 was associated with better outcomes in upper urinary tract urothelial carcinoma.	('HSD17B2', 'Gene', '3294', (123, 130))	('expression level', 'MPA', (103, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('better', 'PosReg', (151, 157))	('urothelial carcinoma', 'Disease', (74, 94))	('high', 'Var', (98, 102))	('upper urinary tract urothelial carcinoma', 'Disease', 'MESH:D014552', (170, 210))	('upper urinary tract urothelial carcinoma', 'Disease', (170, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('HSD17B2', 'Gene', (123, 130))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (190, 210))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (74, 94))
174079	27994658	In addition to these clinicopathological parameters, a high level of HSD17B2 expression was associated with better outcomes in urinary bladder urothelial carcinoma.	('expression', 'MPA', (77, 87))	('high level', 'Var', (55, 65))	('urinary bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (127, 163))	('HSD17B2', 'Gene', '3294', (69, 76))	('urinary bladder urothelial carcinoma', 'Disease', (127, 163))	('better', 'PosReg', (108, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('HSD17B2', 'Gene', (69, 76))
174080	27994658	In Figure 3, the results of log-rank tests show that that a high level of expression of HSD17B2 was a novel predictive marker of a better prognosis, including disease-specific survival and metastasis-free survival, in urothelial carcinoma of the urinary system.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (218, 238))	('expression', 'MPA', (74, 84))	('high', 'Var', (60, 64))	('metastasis-free', 'CPA', (189, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('HSD17B2', 'Gene', (88, 95))	('urothelial carcinoma', 'Disease', (218, 238))	('better', 'PosReg', (131, 137))	('HSD17B2', 'Gene', '3294', (88, 95))
174094	27994658	In contrast to colon cancer, our study demonstrated that a high level of expression of HSD17B2 is a favorable prognostic indicator in urothelial carcinoma and that this relationship was not associated with gender.	('HSD17B2', 'Gene', (87, 94))	('colon cancer', 'Disease', 'MESH:D015179', (15, 27))	('colon cancer', 'Phenotype', 'HP:0003003', (15, 27))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (134, 154))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('HSD17B2', 'Gene', '3294', (87, 94))	('colon cancer', 'Disease', (15, 27))	('high', 'Var', (59, 63))	('expression', 'MPA', (73, 83))	('urothelial carcinoma', 'Disease', (134, 154))
174107	27994658	In addition to estrogen receptor-positive breast cancer, our study also revealed a trend toward improved overall survival in urothelial carcinoma patients with high expression levels of HSD17B2.	('improved', 'PosReg', (96, 104))	('high expression levels', 'Var', (160, 182))	('HSD17B2', 'Gene', (186, 193))	('HSD17B2', 'Gene', '3294', (186, 193))	('urothelial carcinoma', 'Disease', (125, 145))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('overall survival', 'MPA', (105, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('estrogen receptor', 'Gene', (15, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (125, 145))	('estrogen receptor', 'Gene', '2099', (15, 32))	('patients', 'Species', '9606', (146, 154))
174114	27994658	High expression of HSD17B2 was associated with better clinicopathological parameters and was also an independent prognostic indicator.	('HSD17B2', 'Gene', '3294', (19, 26))	('HSD17B2', 'Gene', (19, 26))	('High', 'Var', (0, 4))
174154	26844468	In the case presented here, the use of single-agent cyclophosphamide was associated with a confirmed radiological response and prolonged progression-free survival with minimal toxicity and excellent compliance in an elderly patient who had been pretreated with 2 lines of chemotherapy for metastatic disease.	('cyclophosphamide', 'Chemical', 'MESH:D003520', (52, 68))	('prolonged', 'PosReg', (127, 136))	('patient', 'Species', '9606', (224, 231))	('toxicity', 'Disease', 'MESH:D064420', (176, 184))	('toxicity', 'Disease', (176, 184))	('single-agent cyclophosphamide', 'Var', (39, 68))	('progression-free survival', 'CPA', (137, 162))
174156	26844468	Paclitaxel, which is accepted as a standard second-line treatment option, was preferred to vinflunine as vinflunine was associated with grade 3-4 constipation in 16.1% of patients enrolled in the phase III trial on vinflunine versus best supportive care.	('vinflunine', 'Chemical', 'MESH:C111217', (215, 225))	('constipation', 'Phenotype', 'HP:0002019', (146, 158))	('vinflunine', 'Chemical', 'MESH:C111217', (91, 101))	('associated with', 'Reg', (120, 135))	('constipation', 'Disease', 'MESH:D003248', (146, 158))	('vinflunine', 'Chemical', 'MESH:C111217', (105, 115))	('Paclitaxel', 'Chemical', 'MESH:D017239', (0, 10))	('patients', 'Species', '9606', (171, 179))	('constipation', 'Disease', (146, 158))	('vinflunine', 'Var', (105, 115))
174171	26844468	In mice randomly assigned to either placebo or 12.5 mg/kg quercetin or 25 mg/kg quercetin and undergoing a treadmill performance run to fatigue, quercetin increased markers of mitochondrial biogenesis (PGC-1alpha, cytochrome c) and improved both maximal endurance capacity and voluntary wheel-running activity.	('quercetin', 'Chemical', 'MESH:D011794', (145, 154))	('fatigue', 'Phenotype', 'HP:0012378', (136, 143))	('quercetin', 'Var', (145, 154))	('maximal endurance capacity', 'CPA', (246, 272))	('voluntary wheel-running activity', 'CPA', (277, 309))	('increased', 'PosReg', (155, 164))	('PGC-1alpha', 'Gene', '19017', (202, 212))	('mice', 'Species', '10090', (3, 7))	('cytochrome c', 'molecular_function', 'GO:0009461', ('214', '226'))	('cytochrome c', 'molecular_function', 'GO:0045155', ('214', '226'))	('PGC-1alpha', 'Gene', (202, 212))	('fatigue', 'Disease', 'MESH:D005221', (136, 143))	('mitochondrial biogenesis', 'MPA', (176, 200))	('fatigue', 'Disease', (136, 143))	('quercetin', 'Chemical', 'MESH:D011794', (58, 67))	('quercetin', 'Chemical', 'MESH:D011794', (80, 89))	('improved', 'PosReg', (232, 240))
174172	26844468	These results paralleled those obtained in clinical trials, with 1 meta-analysis showing that quercetin supplementation was associated with increased endurance performance.	('endurance performance', 'CPA', (150, 171))	('quercetin', 'Chemical', 'MESH:D011794', (94, 103))	('increased endurance performance', 'Phenotype', 'HP:0003546', (140, 171))	('increased', 'PosReg', (140, 149))	('supplementation', 'Var', (104, 119))
174174	26844468	Similarly, the use of pegylated liposomal doxorubicin as a third-line chemotherapy was associated with a median progression-free survival and overall survival of 4.1 and 6.3 months in 23 patients with advanced urothelial carcinoma, whereas median time to progression and overall survival were 2 and 7.3 months, respectively, in 13 patients treated with third-line gemcitabine.	('patients', 'Species', '9606', (187, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('gemcitabine', 'Chemical', 'MESH:C056507', (364, 375))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (210, 230))	('doxorubicin', 'Chemical', 'MESH:D004317', (42, 53))	('urothelial carcinoma', 'Disease', (210, 230))	('pegylated liposomal', 'Var', (22, 41))	('patients', 'Species', '9606', (331, 339))
174183	32292720	We identified the overlapped differentially expressed genes (DEGs) by combining GSE68020 and The Cancer Genome Atlas (TCGA) datasets.	('Cancer', 'Disease', 'MESH:D009369', (97, 103))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('GSE68020', 'Var', (80, 88))	('Cancer', 'Disease', (97, 103))
174301	32292720	The present study indicated that ECM1 is as an independent prognostic indicator for HGBC and high ECM1 expression can also predict lymph node metastasis.	('lymph node metastasis', 'CPA', (131, 152))	('ECM1', 'Gene', (98, 102))	('ECM1', 'Gene', '1893', (33, 37))	('expression', 'MPA', (103, 113))	('ECM1', 'Gene', '1893', (98, 102))	('ECM1', 'Gene', (33, 37))	('high', 'Var', (93, 97))	('HGBC', 'Disease', (84, 88))	('predict', 'Reg', (123, 130))
174305	32292720	Hypermethylation of the GPX3 promoter reduces GPX3 expression.	('reduces', 'NegReg', (38, 45))	('GPX3', 'Gene', '2878', (24, 28))	('Hypermethylation', 'Var', (0, 16))	('GPX3', 'Gene', (24, 28))	('expression', 'MPA', (51, 61))	('GPX3', 'Gene', (46, 50))	('GPX3', 'Gene', '2878', (46, 50))
174338	32218698	These differences may affect the development of the bladder cancer, the sensitivity to treatment as well as the prognosis.	('bladder cancer', 'Disease', (52, 66))	('differences', 'Var', (6, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('affect', 'Reg', (22, 28))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
174357	32218698	High TMB leads to the formation of more new antigens, making tumors more immunogenic and more sensitive to immunotherapy.	('formation', 'biological_process', 'GO:0009058', ('22', '31'))	('High TMB', 'Var', (0, 8))	('making tumors more immunogenic', 'Disease', (54, 84))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('making tumors more immunogenic', 'Disease', 'MESH:C537705', (54, 84))	('TMB', 'Chemical', '-', (5, 8))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
174378	32218698	The tumor suppressor gene TP53 has been reported to be mutated in more than 50% of human malignancies, and thus, promote the development and progression of cancer.	('TP53', 'Gene', (26, 30))	('tumor', 'Disease', (4, 9))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('malignancies', 'Disease', 'MESH:D009369', (89, 101))	('mutated', 'Var', (55, 62))	('promote', 'PosReg', (113, 120))	('human', 'Species', '9606', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('malignancies', 'Disease', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor suppressor', 'biological_process', 'GO:0051726', ('4', '20'))	('TP53', 'Gene', '7157', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('development', 'CPA', (125, 136))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('4', '20'))
174382	32218698	Additionally, we found that the mutation in TP53 in case of cluster 4 is significantly lower than that in case of the other clusters.	('lower', 'NegReg', (87, 92))	('mutation', 'Var', (32, 40))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))
174383	32218698	TP53 mutations often result in unstable tumor genomes and impaired DNA repair capacity, therefore; TP53 mutant tumors may be more sensitive to DNA damage factors.	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('DNA repair', 'biological_process', 'GO:0006281', ('67', '77'))	('TP53', 'Gene', '7157', (0, 4))	('mutant', 'Var', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('unstable tumor', 'Disease', 'MESH:D000789', (31, 45))	('impaired', 'NegReg', (58, 66))	('TP53', 'Gene', (99, 103))	('mutations', 'Var', (5, 14))	('result', 'Reg', (21, 27))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('TP53', 'Gene', (0, 4))	('DNA repair capacity', 'MPA', (67, 86))	('unstable tumor', 'Disease', (31, 45))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('TP53', 'Gene', '7157', (99, 103))
174392	32218698	These differences may affect the development of the tumors and the sensitivity towards the treatment.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('differences', 'Var', (6, 17))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('affect', 'Reg', (22, 28))
174399	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))
174400	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))
174467	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))
174485	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))
174497	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))
174509	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))
174511	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))	('FGFR3', 'Gene', (13, 18))	('luminal-papillary', 'Disease', (133, 150))	('luminal-papillary bladder cancer', 'Disease', (72, 104))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('luminal-papillary bladder cancer', 'Disease', 'MESH:D001749', (72, 104))	('FGFR3', 'Gene', '2261', (13, 18))
174512	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))
174514	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', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('alterations', 'Var', (53, 64))
174523	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))
174531	32111252	Interestingly, all were enriched for CDKN2A deletions (Fig.	('deletions', 'Var', (44, 53))	('CDKN2A', 'Gene', '1029', (37, 43))	('CDKN2A', 'Gene', (37, 43))
174532	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))
174533	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', '-', (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))	('GSE', 'Chemical', '-', (136, 139))	('GSE3538', 'Chemical', '-', (145, 152))
174570	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))
174572	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', (138, 144))	('cancer', 'Disease', (152, 158))	('CDKN2A', 'Gene', (92, 98))	('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))
174599	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))	('GSE', 'Chemical', '-', (139, 142))	('GSE3538', 'Chemical', '-', (130, 137))	('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))
174616	31307554	A few potential biomarkers have been identified up to now, such as PD-L1 gene expression, microsatellite instability (MSI), mismatch repair deficiency (dMMR), POLE or JAK1/2 mutations, immune cell infiltration, IFNgamma expression, tumor mutational burden (TMB) or neoantigen burden.	('microsatellite instability', 'MPA', (90, 116))	('TMB', 'Chemical', '-', (257, 260))	('IFNgamma', 'Gene', (211, 219))	('IFNgamma', 'Gene', '3458', (211, 219))	('mismatch repair', 'biological_process', 'GO:0006298', ('124', '139'))	('mutations', 'Var', (174, 183))	('tumor', 'Disease', (232, 237))	('JAK', 'molecular_function', 'GO:0004713', ('167', '170'))	('immune cell', 'CPA', (185, 196))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('POLE', 'Gene', (159, 163))	('JAK1/2', 'Gene', '3716;3717', (167, 173))	('gene expression', 'biological_process', 'GO:0010467', ('73', '88'))	('JAK1/2', 'Gene', (167, 173))	('PD-L1', 'Gene', (67, 72))	('expression', 'MPA', (220, 230))	('MSI', 'Disease', 'None', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('PD-L1', 'Gene', '29126', (67, 72))	('MSI', 'Disease', (118, 121))
174619	31307554	Its pattern and distribution is highly variable across different cancer types, with over 1000-fold difference between cancer types with the lowest mutational burden and those with the highest mutational burden, such as those associated with DNA environmental damage, i.e.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('DNA', 'cellular_component', 'GO:0005574', ('241', '244'))	('mutational', 'Var', (147, 157))
174621	31307554	Increased TMB was also observed in tumors with defects in DNA mismatch repair and DNA replication or in tumors characterized by microsatellite instability, as in colorectal cancer.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('mismatch repair', 'biological_process', 'GO:0006298', ('62', '77'))	('DNA', 'Var', (58, 61))	('TMB', 'MPA', (10, 13))	('DNA replication', 'Gene', (82, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (162, 179))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('defects', 'NegReg', (47, 54))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('DNA replication', 'biological_process', 'GO:0006260', ('82', '97'))	('TMB', 'Chemical', '-', (10, 13))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('microsatellite', 'Var', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('colorectal cancer', 'Disease', 'MESH:D015179', (162, 179))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (35, 41))	('colorectal cancer', 'Disease', (162, 179))
174622	31307554	Highly mutated tumors are more likely to produce abundance of tumor-specific mutant epitopes, which may function as neoantigens recognized as non-self by the immune system.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (62, 67))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', (15, 20))	('mutant', 'Var', (77, 83))	('tumors', 'Disease', (15, 21))
174625	31307554	Peptides containing selected mutations are then identified in silico and the efficiency of their presentation to the immune system may be evaluated by mass spectrometry or by algorithms that consider their predicted affinity to the MHC class I complex and patient-specific HLA class I alleles.	('MHC', 'Gene', '3107', (232, 235))	('MHC', 'Gene', (232, 235))	('patient', 'Species', '9606', (256, 263))	('mutations', 'Var', (29, 38))
174627	31307554	Although not all mutations can give rise to tumor immunogenic peptides, their number influences the amount of neoantigens potentially produced.	('influences', 'Reg', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutations', 'Var', (17, 26))	('amount of neoantigens', 'MPA', (100, 121))	('tumor', 'Disease', (44, 49))
174628	31307554	High TMB correlates with long-term clinical benefit from immune checkpoint inhibitors in patients with melanoma, NSCLC and urothelial carcinoma.	('clinical', 'Species', '191496', (35, 43))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('benefit', 'PosReg', (44, 51))	('High', 'Var', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (123, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('urothelial carcinoma', 'Disease', (123, 143))	('TMB', 'MPA', (5, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('patients', 'Species', '9606', (89, 97))	('NSCLC', 'Disease', (113, 118))	('TMB', 'Chemical', '-', (5, 8))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
174632	31307554	In BRCA-1/2 mutated ovarian cancers, TMB correlates with improved overall survival.	('overall survival', 'MPA', (66, 82))	('ovarian cancers', 'Disease', 'MESH:D010051', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('BRCA-1/2', 'Gene', (3, 11))	('mutated', 'Var', (12, 19))	('ovarian cancers', 'Phenotype', 'HP:0100615', (20, 35))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('improved', 'PosReg', (57, 65))	('ovarian cancers', 'Disease', (20, 35))	('BRCA-1/2', 'Gene', '672;675', (3, 11))	('TMB', 'Chemical', '-', (37, 40))
174661	31307554	the variant calling algorithm and the method to remove germline variants) can significantly affect the number of called somatic mutations and have a similar impact on both panel-based and WES-based TMB quantification.	('variant', 'Var', (4, 11))	('mutations', 'Var', (128, 137))	('affect', 'Reg', (92, 98))	('TMB', 'Chemical', '-', (198, 201))
174663	31307554	Indeed, since only somatic mutations can potentially produce tumor neoantigens recognized as non-self by the immune system, it is important to remove germline variants in TMB quantification.	('mutations', 'Var', (27, 36))	('TMB', 'Chemical', '-', (171, 174))	('produce', 'Reg', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
174668	31307554	Extrapolation methods may differ for various choices in variant filtering, such as removal of known cancer mutations or synonymous mutations (Fig.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('synonymous mutations', 'Var', (120, 140))
174669	31307554	Standard gene panels are commonly enriched in known cancer genes, which are more likely to be mutated in a tumor and expectedly enriched in mutations.	('mutated', 'Var', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
174670	31307554	Therefore, it was proposed to remove known cancer variants of targeted genes when performing TMB quantification, to avoid overestimation of TMB when extrapolating it across the whole genome.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('TMB', 'Chemical', '-', (140, 143))	('cancer', 'Disease', (43, 49))	('TMB', 'Chemical', '-', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('variants', 'Var', (50, 58))
174671	31307554	Buchhalter et al., showed that removal of cancer mutational hotspots slightly decreases the number of high TMB tumors identified but does not change the general picture.	('mutational', 'Var', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('TMB', 'Chemical', '-', (107, 110))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('decreases', 'NegReg', (78, 87))
174674	31307554	Indeed, several works compared TMB quantification with or without synonymous variants and observed that, when including synonymous variants, panel-based TMB shows increased correlation with WES-based TMB values and stronger association with clinical response.	('clinical', 'Species', '191496', (241, 249))	('association', 'Interaction', (224, 235))	('increased', 'PosReg', (163, 172))	('TMB', 'Chemical', '-', (31, 34))	('variants', 'Var', (131, 139))	('TMB', 'Chemical', '-', (200, 203))	('correlation', 'Interaction', (173, 184))	('TMB', 'Chemical', '-', (153, 156))
174680	31307554	Moreover, we still need to standardize the conversion of the reference WES-based TMB values to panel-based TMB, since the lower sequencing coverage and higher sequencing depth of gene panels, as compared to WES, may lead to decreased accuracy of TMB values and increased sensitivity in variant calling.	('variant', 'Var', (286, 293))	('lower', 'NegReg', (122, 127))	('increased', 'PosReg', (261, 270))	('decreased', 'NegReg', (224, 233))	('sensitivity', 'MPA', (271, 282))	('accuracy', 'MPA', (234, 242))	('TMB', 'Chemical', '-', (107, 110))	('TMB', 'Chemical', '-', (246, 249))	('TMB', 'Chemical', '-', (81, 84))	('TMB values', 'MPA', (246, 256))
174699	31307554	A few studies previously investigated the feasibility of WES on ctDNA and highlighted some inherent limitations, such as the low amount of available ctDNA, which reduces sensitivity, or ctDNA being more associated with metastases rather than with primary tumors.	('primary tumors', 'Disease', (247, 261))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('associated', 'Reg', (203, 213))	('primary tumors', 'Disease', 'MESH:D009369', (247, 261))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('reduces', 'NegReg', (162, 169))	('sensitivity', 'MPA', (170, 181))	('metastases', 'Disease', (219, 229))	('metastases', 'Disease', 'MESH:D009362', (219, 229))	('ctDNA', 'Var', (186, 191))
174701	31307554	Performance of variant detection was dependent on the fraction of tumor DNA within the analyzed cfDNA, as previously described.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('tumor', 'Disease', (66, 71))	('variant', 'Var', (15, 22))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
174734	31307554	TMB is used as an approximation of neoantigen burden, upon the assumption that the higher the mutational burden, the higher the probability for immunogenic peptides to be generated, which leads to stronger immune response upon inhibition of immune checkpoints.	('stronger', 'PosReg', (197, 205))	('mutational', 'Var', (94, 104))	('TMB', 'Chemical', '-', (0, 3))	('immune response', 'MPA', (206, 221))	('immune response', 'biological_process', 'GO:0006955', ('206', '221'))	('higher', 'PosReg', (117, 123))
174739	31307554	On the other hand, enrichment in subclonal neoantigens may activate T cells against only a subset of tumor cells, leading to less effective tumor control.	('subclonal neoantigens', 'Var', (33, 54))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('activate', 'PosReg', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('T cells against', 'CPA', (68, 83))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('neoantigens', 'Var', (43, 54))	('less', 'NegReg', (125, 129))	('tumor', 'Disease', (140, 145))
174740	31307554	variant allele frequency) improves the predictive power of TMB.	('improves', 'PosReg', (26, 34))	('TMB', 'Disease', (59, 62))	('TMB', 'Chemical', '-', (59, 62))	('variant', 'Var', (0, 7))
174742	31307554	Mutational signatures associated with smoking were also found to be significantly associated with high tumor mutational burden and with response to immunotherapy.	('Mutational', 'Var', (0, 10))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
174743	31307554	Therefore, although the extraction of mutational signatures from gene panels may be hampered by the small number of sampled mutations, these observations suggest that they may prove helpful to infer neoantigen clonality and enhance TMB predictive value.	('mutations', 'Var', (124, 133))	('infer', 'Reg', (193, 198))	('enhance', 'PosReg', (224, 231))	('TMB predictive value', 'CPA', (232, 252))	('neoantigen', 'Protein', (199, 209))	('TMB', 'Chemical', '-', (232, 235))
174745	31307554	For example, TMB, defects in DNA mismatch-repair pathway and the MSI status all are measures of genomic instability that can provide indirect assessment of tumor antigenicity, whereas PD-L1 expression, immune cell infiltration and inflammatory signatures represent biomarkers of the T cell-inflamed tumor microenvironment.	('PD-L1', 'Gene', (184, 189))	('defects', 'Var', (18, 25))	('tumor', 'Disease', (299, 304))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('PD-L1', 'Gene', '29126', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('MSI', 'Disease', 'None', (65, 68))	('mismatch-repair', 'biological_process', 'GO:0006298', ('33', '48'))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('TMB', 'Disease', (13, 16))	('MSI', 'Disease', (65, 68))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('DNA mismatch-repair pathway', 'Pathway', (29, 56))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('TMB', 'Chemical', '-', (13, 16))
174751	31307554	Thus, TMB and T cell-inflamed GEP were jointly used to identify immunotherapy responders: patients with both high TMB and high T cell-inflamed GEP were those with the highest objective response rates on tumors from four KEYNOTE clinical trials across 22 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('high', 'Var', (109, 113))	('tumors', 'Disease', (203, 209))	('TMB', 'Chemical', '-', (6, 9))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('TMB', 'Chemical', '-', (114, 117))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', (254, 260))	('clinical', 'Species', '191496', (228, 236))	('patients', 'Species', '9606', (90, 98))
174763	30838648	Oncogenic mutations in FGFR3, HRAS and the TERT promoter have been reported in these entities but no comprehensive molecular analysis has been performed.	('FGFR3', 'Gene', (23, 28))	('HRAS', 'Gene', (30, 34))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('TERT', 'Gene', (43, 47))	('TERT', 'Gene', '7015', (43, 47))	('FGFR3', 'Gene', '2261', (23, 28))	('mutations', 'Var', (10, 19))	('HRAS', 'Gene', '3265', (30, 34))
174764	30838648	In IUP, 10 of 11 tumors harbored oncogenic hotspot mutations in HRAS and the remaining tumor had an oncogenic KRAS mutation.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('mutations', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Disease', (17, 23))	('KRAS', 'Gene', '3845', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', (87, 92))	('HRAS', 'Gene', '3265', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('HRAS', 'Gene', (64, 68))	('KRAS', 'Gene', (110, 114))
174765	30838648	None of the IUP tumors harbored TERT promoter or FGFR3 mutations.	('TERT', 'Gene', '7015', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('mutations', 'Var', (55, 64))	('FGFR3', 'Gene', '2261', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('FGFR3', 'Gene', (49, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('tumors', 'Disease', (16, 22))	('TERT', 'Gene', (32, 36))
174766	30838648	In UP, 8 of 11 tumors had oncogenic KRAS mutations and 2 had oncogenic HRAS mutations.	('mutations', 'Var', (41, 50))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('KRAS', 'Gene', (36, 40))	('HRAS', 'Gene', '3265', (71, 75))	('KRAS', 'Gene', '3845', (36, 40))	('HRAS', 'Gene', (71, 75))	('tumors', 'Disease', (15, 21))
174767	30838648	One UP tumor had oncogenic mutations in FGFR3, PIK3CA and the TERT promoter and arose in a patient with recurrent non-invasive papillary urothelial carcinomas.	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', (47, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('PIK3CA', 'Gene', '5290', (47, 53))	('FGFR3', 'Gene', (40, 45))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('TERT', 'Gene', (62, 66))	('patient', 'Species', '9606', (91, 98))	('invasive papillary urothelial carcinomas', 'Disease', (118, 158))	('invasive papillary urothelial carcinomas', 'Disease', 'MESH:D009361', (118, 158))	('TERT', 'Gene', '7015', (62, 66))	('FGFR3', 'Gene', '2261', (40, 45))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (127, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
174773	30838648	Prior studies of IUP and UP using single gene assays reported FGFR3 and TERT promoter mutations at various rates.	('mutations', 'Var', (86, 95))	('FGFR3', 'Gene', '2261', (62, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('FGFR3', 'Gene', (62, 67))	('TERT', 'Gene', (72, 76))	('TERT', 'Gene', '7015', (72, 76))
174774	30838648	One prior study of 5 IUP tumors using a targeted next generation sequencing panel reported activating HRAS mutations in 3 tumors and an oncogenic FGFR3 mutation in one.	('FGFR', 'molecular_function', 'GO:0005007', ('146', '150'))	('tumors', 'Disease', (122, 128))	('HRAS', 'Gene', (102, 106))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mutations', 'Var', (107, 116))	('tumors', 'Disease', (25, 31))	('FGFR3', 'Gene', '2261', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('FGFR3', 'Gene', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('HRAS', 'Gene', '3265', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('activating', 'PosReg', (91, 101))
174782	30838648	Oncogenic hotspot mutations in HRAS were identified in all 3 IUPs and oncogenic hotspot KRAS mutations were present in 2 of the 3 UPs (Figure 1C).	('HRAS', 'Gene', '3265', (31, 35))	('HRAS', 'Gene', (31, 35))	('KRAS', 'Gene', (88, 92))	('KRAS', 'Gene', '3845', (88, 92))	('mutations', 'Var', (18, 27))
174783	30838648	The third UP had an oncogenic BRAF mutation (T599dup).	('BRAF', 'Gene', (30, 34))	('T599dup', 'Mutation', 'c.599dupT', (45, 52))	('T599dup', 'Var', (45, 52))	('BRAF', 'Gene', '673', (30, 34))
174789	30838648	Ten of 11 UP tumors also had oncogenic mutations in the RAS/ERK signaling pathway (8 KRAS, 2 HRAS and 1 BRAF mutations).	('HRAS', 'Gene', '3265', (93, 97))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('signaling pathway', 'biological_process', 'GO:0007165', ('64', '81'))	('ERK', 'molecular_function', 'GO:0004707', ('60', '63'))	('mutations', 'Var', (39, 48))	('RAS/ERK signaling pathway', 'Pathway', (56, 81))	('HRAS', 'Gene', (93, 97))	('BRAF', 'Gene', '673', (104, 108))	('KRAS', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('BRAF', 'Gene', (104, 108))	('KRAS', 'Gene', '3845', (85, 89))
174790	30838648	Notably, one of the UP tumors had both KRAS and HRAS mutations (with similar allele frequencies of 0.39 and 0.35).	('HRAS', 'Gene', '3265', (48, 52))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('HRAS', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('KRAS', 'Gene', (39, 43))	('KRAS', 'Gene', '3845', (39, 43))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
174791	30838648	Only one of the cases, a UP, harbored oncogenic FGFR3 or TERT promoter mutations.	('TERT', 'Gene', (57, 61))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('FGFR3', 'Gene', '2261', (48, 53))	('TERT', 'Gene', '7015', (57, 61))	('mutations', 'Var', (71, 80))	('FGFR3', 'Gene', (48, 53))	('oncogenic', 'Reg', (38, 47))
174792	30838648	This tumor, which also had oncogenic PIK3CA, KMT2D, and CDKN1A mutations, had a mutational profile common to that observed in urothelial carcinoma.	('mutations', 'Var', (63, 72))	('PIK3CA', 'Gene', '5290', (37, 43))	('KMT2D', 'Gene', '8085', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('CDKN1A', 'Gene', '1026', (56, 62))	('tumor', 'Disease', (5, 10))	('urothelial carcinoma', 'Disease', (126, 146))	('CDKN1A', 'Gene', (56, 62))	('KMT2D', 'Gene', (45, 50))	('PIK3CA', 'Gene', (37, 43))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (126, 146))
174798	30838648	With the exception of the case outlined above and contrasting prior reports in the literature, none of the other IUP or UP tumors had TERT promoter or activating FGFR3 mutations.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('TERT', 'Gene', (134, 138))	('activating', 'PosReg', (151, 161))	('FGFR3', 'Gene', '2261', (162, 167))	('FGFR', 'molecular_function', 'GO:0005007', ('162', '166'))	('TERT', 'Gene', '7015', (134, 138))	('FGFR3', 'Gene', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('mutations', 'Var', (168, 177))
174808	30838648	HRAS mutations were much more common in IUP, whereas KRAS mutations were more prevalent in UP.	('HRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('common', 'Reg', (30, 36))	('KRAS', 'Gene', (53, 57))	('KRAS', 'Gene', '3845', (53, 57))	('HRAS', 'Gene', '3265', (0, 4))	('IUP', 'Disease', (40, 43))
174809	30838648	Mutations in both KRAS and HRAS were present at the highest allele frequencies and, therefore, are likely to be early events in these tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('KRAS', 'Gene', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('HRAS', 'Gene', (27, 31))	('KRAS', 'Gene', '3845', (18, 22))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('HRAS', 'Gene', '3265', (27, 31))
174810	30838648	The average VAF of KRAS and HRAS mutations was 41%.	('HRAS', 'Gene', '3265', (28, 32))	('HRAS', 'Gene', (28, 32))	('KRAS', 'Gene', (19, 23))	('mutations', 'Var', (33, 42))	('KRAS', 'Gene', '3845', (19, 23))	('VAF', 'CPA', (12, 15))
174811	30838648	In addition, the median tumor cell fractions associated with KRAS and HRAS mutations in the 6 WES samples were mostly 100%, supporting that these are clonal and initiating alterations.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('HRAS', 'Gene', '3265', (70, 74))	('HRAS', 'Gene', (70, 74))	('KRAS', 'Gene', (61, 65))	('mutations', 'Var', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('KRAS', 'Gene', '3845', (61, 65))
174812	30838648	Beyond these specific alterations, these tumors were typically genetically silent with very low TMB.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('TMB', 'Chemical', '-', (96, 99))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('alterations', 'Var', (22, 33))	('TMB', 'MPA', (96, 99))
174814	30838648	Our findings contrast with prior reports of activating FGFR3 and TERT promoter mutations in IUP and UP.	('IUP', 'Disease', (92, 95))	('activating', 'PosReg', (44, 54))	('FGFR3', 'Gene', '2261', (55, 60))	('TERT', 'Gene', (65, 69))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('TERT', 'Gene', '7015', (65, 69))	('FGFR3', 'Gene', (55, 60))	('mutations', 'Var', (79, 88))
174815	30838648	It is important to note that a small subset of urothelial carcinomas harbor hotspot mutations in HRAS and KRAS.	('KRAS', 'Gene', '3845', (106, 110))	('urothelial carcinomas', 'Disease', (47, 68))	('HRAS', 'Gene', '3265', (97, 101))	('HRAS', 'Gene', (97, 101))	('mutations', 'Var', (84, 93))	('KRAS', 'Gene', (106, 110))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (47, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
174816	30838648	These RAS mutant urothelial carcinomas, however, display considerable morphologic atypia, do not exhibit exclusive inverted growth pattern and have other genomic alterations, which distinguish them from IUP and UP (Figure 3C).	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('growth pattern', 'biological_process', 'GO:0007150', ('124', '138'))	('mutant', 'Var', (10, 16))	('urothelial carcinomas', 'Disease', (17, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('RAS mutant', 'Var', (6, 16))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (17, 38))	('growth pattern', 'biological_process', 'GO:0040007', ('124', '138'))
174817	30838648	While the oncogenic RAS mutations observed in IUP and UP are occasionally found in invasive urothelial carcinomas and are also common in several other highly aggressive solid tumors, the fact that none of the papillomas in this study progressed to frank urothelial carcinoma suggests that the co-mutational background or epigenetic differences in the cell of origin may dictate the likelihood that a RAS mutant cell will progress to carcinoma.	('papillomas', 'Phenotype', 'HP:0012740', (209, 219))	('solid tumors', 'Disease', 'MESH:D009369', (169, 181))	('epigenetic', 'Var', (321, 331))	('carcinoma', 'Disease', (265, 274))	('carcinoma', 'Disease', 'MESH:D009369', (433, 442))	('frank urothelial carcinoma', 'Disease', (248, 274))	('mutations', 'Var', (24, 33))	('papillomas', 'Disease', (209, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('carcinoma', 'Disease', (103, 112))	('invasive urothelial carcinomas', 'Disease', (83, 113))	('carcinoma', 'Disease', 'MESH:D009369', (265, 274))	('frank urothelial carcinoma', 'Disease', 'MESH:D014523', (248, 274))	('dictate', 'Reg', (370, 377))	('papilloma', 'Phenotype', 'HP:0012740', (209, 218))	('carcinoma', 'Disease', 'MESH:D009369', (103, 112))	('RAS', 'Gene', (400, 403))	('mutant', 'Var', (404, 410))	('progress', 'PosReg', (421, 429))	('carcinoma', 'Phenotype', 'HP:0030731', (433, 442))	('solid tumors', 'Disease', (169, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('carcinoma', 'Disease', (433, 442))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (83, 113))	('papillomas', 'Disease', 'MESH:D010212', (209, 219))	('progressed', 'Reg', (234, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))
174818	30838648	Lacking a specific co-mutational background, RAS mutations in urothelial cells may induce oncogene-induced senescence and thus result in a benign lesion incapable of further progression to carcinoma.	('RAS', 'Gene', (45, 48))	('carcinoma', 'Disease', (189, 198))	('benign lesion', 'MPA', (139, 152))	('mutations', 'Var', (49, 58))	('induce', 'Reg', (83, 89))	('carcinoma', 'Disease', 'MESH:D009369', (189, 198))	('result in', 'Reg', (127, 136))	('oncogene-induced senescence', 'MPA', (90, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('senescence', 'biological_process', 'GO:0010149', ('107', '117'))
174827	31137727	In particular, H3K14ac showed a cell-cycle independent decrease in all the seven tumor/tumor subtype models tested and could represent a novel epigenetic hallmark of cancer.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cell-cycle', 'biological_process', 'GO:0007049', ('32', '42'))	('K14ac', 'Chemical', '-', (17, 22))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('decrease', 'NegReg', (55, 63))	('H3K14ac', 'Var', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
174828	31137727	Traditionally, cancer has been considered as the result of the accumulation of genetic defects, such as mutations and copy number changes.	('mutations', 'Var', (104, 113))	('copy number changes', 'Var', (118, 137))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('genetic defects', 'Disease', 'MESH:D030342', (79, 94))	('genetic defects', 'Disease', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
174829	31137727	However, striking evidence has now shown how epigenetic changes also contribute to cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('epigenetic changes', 'Var', (45, 63))	('contribute', 'Reg', (69, 79))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
174831	31137727	For instance, active promoters are enriched in histone H3 (H3) K4me3, inactive promoter regions are enriched in H3K9me3 or H3K27me3, and active enhancers are marked by H3K27ac (Hawkins et al., 2011; Hon et al., 2009; Mills, 2010), just to name a few of the most characterized histone PTMs.	('K27', 'Gene', '342574', (170, 173))	('H3K9me3', 'Var', (112, 119))	('K27', 'Gene', (170, 173))	('histone H3', 'Gene', '260423', (47, 57))	('K9me3', 'Chemical', '-', (114, 119))	('enhancers', 'PosReg', (144, 153))	('histone H3', 'Gene', (47, 57))	('active', 'MPA', (14, 20))	('K27', 'Gene', '342574', (125, 128))	('K27', 'Gene', (125, 128))
174833	31137727	Aberrations in the expression and localization of HMEs, as well as mutations in their sequences, have been linked with different types of cancer.	('localization', 'MPA', (34, 46))	('expression', 'MPA', (19, 29))	('cancer', 'Disease', (138, 144))	('HMEs', 'Protein', (50, 54))	('linked', 'Reg', (107, 113))	('localization', 'biological_process', 'GO:0051179', ('34', '46'))	('HMEs', 'Chemical', '-', (50, 54))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Aberrations', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
174835	31137727	Besides epigenetic changes occurring in specific tumors, epigenetic features have been recognized as general hallmarks of cancer, including genome-wide hypomethylation, site-specific hypermethylation of CpG island promoters, and histone PTM changes.	('hallmarks of cancer', 'Disease', 'MESH:D009369', (109, 128))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('hypermethylation', 'Var', (183, 199))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('PTM', 'biological_process', 'GO:0043687', ('237', '240'))	('hallmarks of cancer', 'Disease', (109, 128))	('tumors', 'Disease', (49, 55))	('hypomethylation', 'Var', (152, 167))	('changes', 'Reg', (241, 248))	('CpG', 'Protein', (203, 206))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('hypermethylation of CpG island', 'biological_process', 'GO:0044027', ('183', '213'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
174839	31137727	By demonstrating that alterations in histone PTMs can be associated with cancer, this study represented an important proof of concept for the use of MS-based approaches to study the epigenetic profile of cancer cells.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('histone PTMs', 'Protein', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('alterations', 'Var', (22, 33))	('associated', 'Reg', (57, 67))
174858	31137727	Most of the changes observed in luminal A-like samples were also present in triple negative breast cancer samples, where additional changes could be observed (these included an increase of H3K9me3, H3K36me1, and H3K79ac, and a decrease of H3K27me3-containing peptides and H3K79me1/me2).	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('K27', 'Gene', '342574', (241, 244))	('K36', 'Gene', (200, 203))	('increase', 'PosReg', (177, 185))	('K27', 'Gene', (241, 244))	('H3K9me3', 'Protein', (189, 196))	('H3K79ac', 'Var', (212, 219))	('K9me3', 'Chemical', '-', (191, 196))	('H3K79me1/me2', 'Var', (272, 284))	('decrease', 'NegReg', (227, 235))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('K36', 'Gene', '8689', (200, 203))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
174864	31137727	We found a decrease of at least one peptide containing H3K14ac in all the tumor types tested (highlighted in blue in Figure 1A), which was paralleled by an increase of the non-acetylated forms of the 9-17 peptide.	('K14ac', 'Chemical', '-', (57, 62))	('non-acetylated forms', 'MPA', (172, 192))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('H3K14ac', 'Var', (55, 62))	('increase', 'PosReg', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('peptide', 'MPA', (36, 43))	('decrease', 'NegReg', (11, 19))	('tumor', 'Disease', (74, 79))
174867	31137727	When comparing the average total levels of H3K14ac (given by the sum of H3K14ac, H3K9me1/K14ac, H3K9me2/K14ac, H3K9me3/K14ac, and H3K9ac/K14ac) in the normal-tumor pairs for all the tumor types tested, we found a highly significant decrease in tumor samples, with a paired t-test p-value of 0.00013 (Figure 1E).	('K14ac', 'Chemical', '-', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('K14ac', 'Chemical', '-', (45, 50))	('H3K9me2/K14ac', 'Var', (96, 109))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('K14ac', 'Chemical', '-', (74, 79))	('H3K9ac/K14ac', 'Var', (130, 142))	('K9me3', 'Chemical', '-', (113, 118))	('decrease', 'NegReg', (232, 240))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (244, 249))	('K14ac', 'Chemical', '-', (89, 94))	('K14ac', 'Chemical', '-', (137, 142))	('H3K9me1/K14ac', 'Var', (81, 94))	('H3K14ac', 'Var', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('K14ac', 'Chemical', '-', (104, 109))	('H3K9me3/K14ac', 'Var', (111, 124))
174868	31137727	Of note, we did not observe a decrease of total H3K14ac in mouse glioblastoma, but only of H3K14ac in combination with H3K9ac.	('K14ac', 'Chemical', '-', (50, 55))	('mouse', 'Species', '10090', (59, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('H3K14ac', 'Var', (91, 98))	('glioblastoma', 'Disease', (65, 77))	('K14ac', 'Chemical', '-', (93, 98))	('glioblastoma', 'Disease', 'MESH:D005909', (65, 77))	('H3K14ac', 'Protein', (48, 55))
174869	31137727	In three out of the seven tumor types tested, we also observed an increase of total H3K9me3 (given by the sum of H3K9me3 and H3K9me3K14ac, Figure 1E).	('K9me3', 'Chemical', '-', (127, 132))	('increase', 'PosReg', (66, 74))	('H3K9me3K14ac', 'Var', (125, 137))	('K9me3', 'Chemical', '-', (86, 91))	('K9me3', 'Chemical', '-', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('K14ac', 'Chemical', '-', (132, 137))	('H3K9me3', 'Protein', (84, 91))
174870	31137727	Taken together, these results suggest that H3K14ac may represent a novel general hallmark of cancer, while other histone PTM changes may represent more specific epigenetic aberrations found in distinct tumor types.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('K14ac', 'Chemical', '-', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('H3K14ac', 'Var', (43, 50))	('PTM', 'biological_process', 'GO:0043687', ('121', '124'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
174873	31137727	Previously, we found a significant/close to significant correlation between the proliferation index Ki67 and H3K36me1/me2 and H3K27me3 in luminal breast cancer and glioblastoma tissues, suggesting that these marks may be influenced by the cell cycle.	('glioblastoma', 'Phenotype', 'HP:0012174', (164, 176))	('K36', 'Gene', (111, 114))	('luminal breast cancer', 'Disease', (138, 159))	('Ki67', 'Var', (100, 104))	('cell cycle', 'biological_process', 'GO:0007049', ('239', '249'))	('glioblastoma', 'Disease', (164, 176))	('glioblastoma', 'Disease', 'MESH:D005909', (164, 176))	('luminal breast cancer', 'Disease', 'MESH:D001943', (138, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('K27', 'Gene', '342574', (128, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('K27', 'Gene', (128, 131))	('K36', 'Gene', '8689', (111, 114))
174875	31137727	K14ac did not show any correlation, while K9me3 showed a positive correlation with the Ki-67 index.	('K9me3', 'Var', (42, 47))	('K14ac', 'Chemical', '-', (0, 5))	('Ki-67 index', 'CPA', (87, 98))	('K14ac', 'Var', (0, 5))	('K9me3', 'Chemical', '-', (42, 47))
174877	31137727	These results would suggest that the differences observed in tumors compared with normal tissues for K27, K36, and K9 methylation, but not K14 acetylation, may be due to the increased tumor proliferation rates.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('K9 methylation', 'Var', (115, 129))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('K36', 'Gene', (106, 109))	('methylation', 'Var', (118, 129))	('K27', 'Gene', (101, 104))	('methylation', 'biological_process', 'GO:0032259', ('118', '129'))	('tumor', 'Disease', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Disease', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('K14', 'Gene', (139, 142))	('K14', 'Gene', '3861', (139, 142))	('tumor', 'Disease', (61, 66))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('K36', 'Gene', '8689', (106, 109))	('increased', 'PosReg', (174, 183))	('K27', 'Gene', '342574', (101, 104))
174880	31137727	The H3K14ac mark decreased in the G2-M phase in MDA-MB-231 cells, but remained constant in MCF7 and even increased in MCF10A cells, suggesting that the decrease that we have observed in tumors is not a mere consequence of different proliferation rates (Figure 2B-D).	('H3K14ac', 'Var', (4, 11))	('decreased', 'NegReg', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (48, 58))	('MCF10A', 'CellLine', 'CVCL:0598', (118, 124))	('K14ac', 'Chemical', '-', (6, 11))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('M phase', 'biological_process', 'GO:0000279', ('37', '44'))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumors', 'Disease', (186, 192))	('increased', 'PosReg', (105, 114))	('MCF7', 'CellLine', 'CVCL:0031', (91, 95))
174884	31137727	Because it is known that that H3K27 methylation antagonizes H3K36 methylation, and vice-versa, it is possible that the increase of K36 methylation may be a secondary long-term effect of the decrease of K27me3.	('decrease', 'NegReg', (190, 198))	('K27', 'Gene', (32, 35))	('antagonizes', 'NegReg', (48, 59))	('K36', 'Gene', (131, 134))	('K27', 'Gene', '342574', (32, 35))	('K27', 'Gene', '342574', (202, 205))	('methylation', 'biological_process', 'GO:0032259', ('66', '77'))	('K36', 'Gene', '8689', (62, 65))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('methylation', 'MPA', (135, 146))	('K36', 'Gene', (62, 65))	('K27', 'Gene', (202, 205))	('increase', 'PosReg', (119, 127))	('methylation', 'biological_process', 'GO:0032259', ('135', '146'))	('methylation', 'Var', (36, 47))	('K36', 'Gene', '8689', (131, 134))
174887	31137727	Based on our novel findings, it appears like the different levels of the K27me3 mark in different breast cancer subtypes could be at least partially due to different proliferation rates, while H3K9me3 is confirmed as an interesting marker for breast cancer patient stratification, as it does not merely depend on proliferation.	('breast cancer', 'Disease', (243, 256))	('H3K9me3', 'Var', (193, 200))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('patient', 'Species', '9606', (257, 264))	('K27', 'Gene', '342574', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('K27', 'Gene', (73, 76))	('K9me3', 'Chemical', '-', (195, 200))
174888	31137727	Alterations in histone PTM levels are often a consequence of the anomalous expression, mislocalization, or mutation of the HMEs responsible for their deposition and removal.	('histone PTM levels', 'MPA', (15, 33))	('Alterations', 'Reg', (0, 11))	('HMEs', 'Protein', (123, 127))	('HMEs', 'Chemical', '-', (123, 127))	('mislocalization', 'MPA', (87, 102))	('PTM', 'biological_process', 'GO:0043687', ('23', '26'))	('anomalous', 'Var', (65, 74))	('mutation', 'Var', (107, 115))	('expression', 'MPA', (75, 85))
174916	31137727	In addition, mutations can affect, positively or negatively, the activity of HMEs.	('activity', 'MPA', (65, 73))	('HMEs', 'Protein', (77, 81))	('HMEs', 'Chemical', '-', (77, 81))	('mutations', 'Var', (13, 22))	('affect', 'Reg', (27, 33))
174918	31137727	Accordingly, the mutational analysis of the patient samples present in the TCGA pan-cancer Atlas study shows that 20%-90% of each tumor type presents at least one mutation in one of the HMEs, catalyzing the deposition and removal of methylations or acetylations (Figure 5A).	('methylations', 'MPA', (233, 245))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('patient', 'Species', '9606', (44, 51))	('cancer', 'Disease', (84, 90))	('HMEs', 'Chemical', '-', (186, 190))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('deposition', 'MPA', (207, 217))	('mutation', 'Var', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('acetylations', 'MPA', (249, 261))	('tumor', 'Disease', (130, 135))
174919	31137727	The tumor types containing the highest number of mutations in HMEs are bladder cancer (BLCA), esophageal cancer (ESCA), and melanoma (SKCM), where at least 80% of the patients contain at least one mutation (which include missense mutations, deep deletions, and amplifications) and 35%-55% contain multiple mutations.	('HMEs', 'Gene', (62, 66))	('tumor', 'Disease', (4, 9))	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('amplifications', 'MPA', (261, 275))	('esophageal cancer', 'Disease', (94, 111))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('deep deletions', 'Var', (241, 255))	('mutations', 'Var', (49, 58))	('bladder cancer', 'Disease', 'MESH:D001749', (71, 85))	('bladder cancer', 'Disease', (71, 85))	('contain', 'Reg', (176, 183))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))	('missense mutations', 'Var', (221, 239))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('HMEs', 'Chemical', '-', (62, 66))	('melanoma', 'Disease', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (167, 175))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))
174920	31137727	While in most of the cases, both amplifications and deletions of the same enzymes can occur in different tumors, or even in the same tumor type, some enzymes show a clear predominance of amplifications (e.g., SIRT2, SETDB1, KDM2A; KDM5A; KAT7) or deletions (e.g., ELP3; HDAC2; HDAC4; HDAC10, SIRT3; SETDB2) in all/most of the tumor types analyzed, suggesting a possible general oncogenic or tumor suppressor role, respectively.	('tumors', 'Disease', (105, 111))	('SETDB1', 'Gene', '9869', (216, 222))	('HDAC2', 'Gene', (270, 275))	('HDAC2', 'Gene', '3066', (270, 275))	('KAT', 'molecular_function', 'GO:0003988', ('238', '241'))	('HDAC10', 'Gene', (284, 290))	('HDAC4', 'Gene', '9759', (277, 282))	('SETDB2', 'Gene', '83852', (299, 305))	('KDM5A', 'Gene', '5927', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('KDM2A', 'Gene', (224, 229))	('tumor', 'Disease', (391, 396))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('391', '407'))	('KDM5A', 'Gene', (231, 236))	('SETDB2', 'Gene', (299, 305))	('amplifications', 'MPA', (187, 201))	('HDAC4', 'Gene', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (391, 396))	('tumor', 'Disease', (326, 331))	('ELP3', 'Gene', (264, 268))	('tumor', 'Disease', (105, 110))	('tumor suppressor', 'biological_process', 'GO:0051726', ('391', '407'))	('ELP3', 'Gene', '55140', (264, 268))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('HDAC10', 'Gene', '83933', (284, 290))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('deletions', 'Var', (247, 256))	('KDM2A', 'Gene', '22992', (224, 229))	('SIRT2', 'Gene', (209, 214))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('SIRT3', 'Gene', (292, 297))	('SIRT2', 'Gene', '22933', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('SIRT3', 'Gene', '23410', (292, 297))	('KAT7', 'Gene', '11143', (238, 242))	('SETDB1', 'Gene', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('KAT7', 'Gene', (238, 242))
174922	31137727	Interestingly, in some instances, enzymes with similar functions, such as SETDB1 and SETDB2 (methyltransferases acting on H3K9), showed diverging mutation types (amplifications for SETDB1 and deletions for SETDB2) (Figure 5B).	('SETDB2', 'Gene', (206, 212))	('SETDB1', 'Gene', (181, 187))	('SETDB2', 'Gene', '83852', (206, 212))	('deletions', 'Var', (192, 201))	('SETDB1', 'Gene', '9869', (74, 80))	('SETDB2', 'Gene', (85, 91))	('SETDB1', 'Gene', '9869', (181, 187))	('SETDB2', 'Gene', '83852', (85, 91))	('SETDB1', 'Gene', (74, 80))
174928	31137727	These examples show how a mutational analysis can provide clues on the role of HMEs in cancer.	('cancer', 'Disease', (87, 93))	('HMEs', 'Chemical', '-', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutational', 'Var', (26, 36))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
174929	31137727	Among them, one acetyltransferase specific for H3K14-ELP3 contains almost exclusively deletions.	('H3K14-ELP3', 'Gene', '55140', (47, 57))	('H3K14-ELP3', 'Gene', (47, 57))	('deletions', 'Var', (86, 95))
174931	31137727	When testing the significance of mutation enrichment in each cancer type, we found a total of 19 unique and significantly mutated HMEs (MutSig2CV adjusted p-value < 0.01) in 18 TCGA cancer types (Figure 5C).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (182, 188))	('HMEs', 'Chemical', '-', (130, 134))	('mutated', 'Var', (122, 129))
174934	31137727	The single most recurrent mutated enzyme is NSD1 in head and neck cancer, where loss-of-function mutations in a subset of patients have been reported to promote a favorable response to chemotherapy.	('mutations', 'Var', (97, 106))	('neck', 'cellular_component', 'GO:0044326', ('61', '65'))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('neck cancer', 'Disease', 'MESH:D006258', (61, 72))	('head and neck cancer', 'Phenotype', 'HP:0012288', (52, 72))	('NSD1', 'Gene', '64324', (44, 48))	('patients', 'Species', '9606', (122, 130))	('neck cancer', 'Disease', (61, 72))	('loss-of-function', 'NegReg', (80, 96))	('NSD1', 'Gene', (44, 48))
174943	31137727	No change was detected at the levels of H3K27me3 or H3K36me1/me2, possibly because the cancer cell lines do not have a proliferation rate higher than the normal cells (the doubling times for MCF7, MDA-MB-231, and MCF10A are 41, 43, and 24 hours, respectively).	('cancer', 'Disease', (87, 93))	('K36', 'Gene', '8689', (54, 57))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (197, 207))	('MCF7', 'CellLine', 'CVCL:0031', (191, 195))	('MCF10A', 'Var', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('K36', 'Gene', (54, 57))	('K27', 'Gene', '342574', (42, 45))	('MCF10A', 'CellLine', 'CVCL:0598', (213, 219))	('K27', 'Gene', (42, 45))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
174949	31137727	Compared with the differences found in mouse glioblastoma and normal tissues, the increase in H3K9me3/K14ac was maintained in culture (but the total K9me3 decreased in tumor cell lines), while the marked decrease of H3K9ac/K14ac was lost, possibly because acetylations on the 9-17 histone H3 peptide are highly affected by culture conditions.	('H3K9me3/K14ac', 'Var', (94, 107))	('K9me3', 'Chemical', '-', (96, 101))	('tumor', 'Disease', (168, 173))	('histone H3', 'Gene', '260423', (281, 291))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('K14ac', 'Chemical', '-', (102, 107))	('histone H3', 'Gene', (281, 291))	('K9me3', 'Chemical', '-', (149, 154))	('glioblastoma', 'Disease', (45, 57))	('K14ac', 'Chemical', '-', (223, 228))	('glioblastoma', 'Disease', 'MESH:D005909', (45, 57))	('mouse', 'Species', '10090', (39, 44))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
174950	31137727	Taken together, these results highlight once more how cell lines retain some, but not all, of the features of the tissue samples they derive from and suggest that some of the cancer-induced epigenetic changes are lost/reduced in culture conditions, although an analysis comparing matched tissues and derived cell lines would be required for a definitive conclusion.	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('lost/reduced', 'NegReg', (213, 225))	('epigenetic changes', 'Var', (190, 208))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
174998	31137727	Variable modifications for in-gel digestions included lysine D6-acetylation (+45.0294 Da), lysine monomethylation (+59.0454, corresponding to the sum of D6-acetylation (+45.0294) and monomethylation (+14.016 Da), dimethylation (+28.031 Da), trimethylation (+42.046 Da), and lysine acetylation (+42.010 Da).	('+14.016 Da', 'Var', (200, 210))	('dimethylation', 'MPA', (213, 226))	('+45.0294 Da', 'Var', (77, 88))	('+45.0294', 'Var', (169, 177))	('+28.031 Da', 'Var', (228, 238))	('lysine acetylation', 'MPA', (274, 292))	('lysine', 'Chemical', 'MESH:D008239', (91, 97))	('+42.046 Da', 'Var', (257, 267))	('trimethylation', 'MPA', (241, 255))	('lysine', 'Chemical', 'MESH:D008239', (54, 60))	('lysine', 'Chemical', 'MESH:D008239', (274, 280))	('+42.010', 'Var', (294, 301))	('monomethylation', 'MPA', (183, 198))	('+59.0454', 'Var', (115, 123))
174999	31137727	Variable modifications for in-solution Arg-C digestions were lysine monomethylation (+14.016 Da), dimethylation (+28.031 Da), trimethylation (+42.046 Da), and acetylation (+42.010 Da).	('+42.046 Da', 'Var', (142, 152))	('trimethylation', 'MPA', (126, 140))	('lysine', 'Chemical', 'MESH:D008239', (61, 67))	('+14.016 Da', 'Var', (85, 95))	('Arg', 'Chemical', 'MESH:D001120', (39, 42))	('lysine monomethylation', 'MPA', (61, 83))	('+28.031 Da', 'Var', (113, 123))	('dimethylation', 'MPA', (98, 111))	('acetylation', 'MPA', (159, 170))	('+42.010 Da', 'Var', (172, 182))
175016	31137727	This indicates that the aberrant histone PTM levels may be the result of multiple mechanisms, which include the aberrant levels of HMEs, as well as their mutation and aberrant turnover rates, the altered function of multi-subunit complexes of which HMEs are part, and the increased proliferation rate of tumor cells.	('aberrant', 'Var', (167, 175))	('levels', 'MPA', (121, 127))	('aberrant', 'Var', (112, 120))	('altered', 'Reg', (196, 203))	('proliferation rate', 'CPA', (282, 300))	('HMEs', 'Gene', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('turnover', 'MPA', (176, 184))	('aberrant', 'Var', (24, 32))	('mutation', 'Var', (154, 162))	('HMEs', 'Chemical', '-', (131, 135))	('histone PTM levels', 'MPA', (33, 51))	('HMEs', 'Chemical', '-', (249, 253))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('PTM', 'biological_process', 'GO:0043687', ('41', '44'))	('tumor', 'Disease', (304, 309))	('function', 'MPA', (204, 212))
175019	31137727	Excel files:Dataset S1: AUC values for the normal/tumor samples analyzed; Dataset S2: AUC values for cells synchronized in different phases of the cell cycle; Dataset S3: mutation analysis of HMEs.	('cell cycle', 'biological_process', 'GO:0007049', ('147', '157'))	('mutation', 'Var', (171, 179))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('HMEs', 'Gene', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('HMEs', 'Chemical', '-', (192, 196))	('tumor', 'Disease', (50, 55))
175066	30323625	CTLA-4 ligation causes lymphocyte anergy, which reduces the synthesis of IFNgamma, IL-2, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF), and increases the production of transforming growth factor beta (TGFbeta).	('IL-3', 'molecular_function', 'GO:0005135', ('89', '93'))	('synthesis of IFNgamma', 'MPA', (60, 81))	('increases', 'PosReg', (162, 171))	('transforming growth factor beta', 'Gene', '7040', (190, 221))	('granulocyte-macrophage colony-stimulating factor', 'Gene', '1437', (99, 147))	('GM-CSF', 'Gene', (149, 155))	('TGFbeta', 'Gene', (223, 230))	('granulocyte-macrophage colony-stimulating factor', 'molecular_function', 'GO:0005129', ('99', '147'))	('lymphocyte anergy', 'Disease', (23, 40))	('TGFbeta', 'Gene', '7040', (223, 230))	('IL-2', 'molecular_function', 'GO:0005134', ('83', '87'))	('GM-CSF', 'Gene', '1437', (149, 155))	('IL-3', 'Gene', '3562', (89, 93))	('reduces', 'NegReg', (48, 55))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('190', '221'))	('transforming growth factor beta', 'Gene', (190, 221))	('granulocyte-macrophage colony-stimulating factor', 'Gene', (99, 147))	('CTLA-4', 'Gene', (0, 6))	('synthesis', 'biological_process', 'GO:0009058', ('60', '69'))	('production', 'MPA', (176, 186))	('ligation', 'Var', (7, 15))	('IL-3', 'Gene', (89, 93))	('lymphocyte anergy', 'biological_process', 'GO:0002249', ('23', '40'))
175107	30323625	Thus, tumor cells can protect themselves from lymphocytes by expressing PD-L1, which inhibits lymphocyte activation and considerably reduces their efficacy.	('reduces', 'NegReg', (133, 140))	('inhibits', 'NegReg', (85, 93))	('lymphocyte activation', 'biological_process', 'GO:0046649', ('94', '115'))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('efficacy', 'MPA', (147, 155))	('lymphocyte activation', 'CPA', (94, 115))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('PD-L1', 'Var', (72, 77))	('tumor', 'Disease', (6, 11))
175124	30323625	BMS-936559 - an anti-PD-L1 mAb - caused an objective and durable response in patients with melanoma, lung cancer, kidney cancer, and ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (133, 147))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('melanoma', 'Disease', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('ovarian cancer', 'Disease', 'MESH:D010051', (133, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('kidney cancer', 'Phenotype', 'HP:0009726', (114, 127))	('BMS-936559', 'Var', (0, 10))	('patients', 'Species', '9606', (77, 85))	('ovarian cancer', 'Disease', (133, 147))	('kidney cancer', 'Disease', 'MESH:D007680', (114, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('lung cancer', 'Disease', (101, 112))	('kidney cancer', 'Disease', (114, 127))
175125	30323625	MPDL3280A (atezolizumab), another anti-PD-L1 mAb, proved effective in patients with metastatic urinary bladder cancer.	('patients', 'Species', '9606', (70, 78))	('MPDL3280A', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('bladder cancer', 'Phenotype', 'HP:0009725', (103, 117))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (0, 9))	('atezolizumab', 'Chemical', 'MESH:C000594389', (11, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (103, 117))	('bladder cancer', 'Disease', (103, 117))
175133	30323625	In mice with immunogenic colorectal cancer, treatment with anti-CTLA-4 mAbs before the transfer of tumor cells prevented disease development, mostly due to the activation of CD8+ T cells.	('tumor', 'Disease', (99, 104))	('CD8', 'Gene', (174, 177))	('colorectal cancer', 'Phenotype', 'HP:0003003', (25, 42))	('activation', 'PosReg', (160, 170))	('mice', 'Species', '10090', (3, 7))	('anti-CTLA-4', 'Var', (59, 70))	('immunogenic colorectal cancer', 'Disease', 'MESH:D015179', (13, 42))	('CD8', 'Gene', '925', (174, 177))	('disease development', 'CPA', (121, 140))	('prevented', 'NegReg', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('immunogenic colorectal cancer', 'Disease', (13, 42))	('anti-CTLA-4', 'Gene', (59, 70))
175134	30323625	Moreover, anti-CTLA-4 mAbs caused cancer regression in mice with developed tumors, including weakly immunogenic tumors.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('immunogenic tumors', 'Disease', (100, 118))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('anti-CTLA-4', 'Var', (10, 21))	('mice', 'Species', '10090', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Disease', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('immunogenic tumors', 'Disease', 'MESH:D009369', (100, 118))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (75, 81))	('tumors', 'Disease', (112, 118))
175149	30323625	The effectiveness of IMP321 was shown in phase I clinical trials in patients with breast cancer, renal cell carcinoma, and pancreatic cancer.	('breast cancer', 'Disease', (82, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('pancreatic cancer', 'Disease', (123, 140))	('IMP', 'molecular_function', 'GO:0004244', ('21', '24'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (123, 140))	('patients', 'Species', '9606', (68, 76))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (97, 117))	('IMP', 'cellular_component', 'GO:0042720', ('21', '24'))	('IMP321', 'Var', (21, 27))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('renal cell carcinoma', 'Disease', (97, 117))
175155	30323625	In a mouse model of hepatitis B, TIM-3 blockade was associated with increased production of IFNgamma by CD8+ cells.	('blockade', 'Var', (39, 47))	('production of IFNgamma', 'MPA', (78, 100))	('hepatitis B', 'Disease', 'MESH:D006509', (20, 31))	('TIM-3', 'Gene', (33, 38))	('CD8', 'Gene', (104, 107))	('mouse', 'Species', '10090', (5, 10))	('hepatitis B', 'Disease', (20, 31))	('CD8', 'Gene', '925', (104, 107))	('increased', 'PosReg', (68, 77))	('hepatitis', 'Phenotype', 'HP:0012115', (20, 29))
175156	30323625	Anti-TIM-3 antibodies slowed tumor growth in mice, which was associated with a decreased percentage of exhausted TIM-3+ lymphocytes.	('mice', 'Species', '10090', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('decreased', 'NegReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('antibodies', 'Var', (11, 21))	('tumor', 'Disease', (29, 34))	('Anti-TIM-3', 'Var', (0, 10))	('slowed', 'NegReg', (22, 28))
175157	30323625	A more potent anticancer response was observed when anti-TIM-3 mAbs were given in combination with anti-PD-1 or anti-CTLA-4 mAbs, when compared with the individual effects of these antibodies.	('anti-TIM-3', 'Var', (52, 62))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))
175160	30323625	Currently, anti-TIM-3 mAbs (MBG453, Sym023, TSR-022, and LY3321367) are being investigated in phase I and II clinical trials in patients with advanced malignancies, including leukemia; these treatments will be investigated in patients with solid tumors and lymphomas from June 2018 (six clinical trials).	('LY3321367', 'Var', (57, 66))	('lymphomas', 'Disease', (257, 266))	('leukemia', 'Disease', (175, 183))	('lymphomas', 'Disease', 'MESH:D008223', (257, 266))	('leukemia', 'Disease', 'MESH:D007938', (175, 183))	('malignancies', 'Disease', 'MESH:D009369', (151, 163))	('leukemia', 'Phenotype', 'HP:0001909', (175, 183))	('lymphomas', 'Phenotype', 'HP:0002665', (257, 266))	('TSR', 'molecular_function', 'GO:0047362', ('44', '47'))	('solid tumors', 'Disease', (240, 252))	('MBG453', 'Var', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('patients', 'Species', '9606', (226, 234))	('malignancies', 'Disease', (151, 163))	('lymphoma', 'Phenotype', 'HP:0002665', (257, 265))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('patients', 'Species', '9606', (128, 136))	('solid tumors', 'Disease', 'MESH:D009369', (240, 252))
175176	30323625	For example, immunogenic tumors - that is, those characterized by a high mutational load and, thus, a high neoantigen load - respond well to immune-checkpoint inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mutational', 'Var', (73, 83))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('immunogenic tumors', 'Disease', 'MESH:D009369', (13, 31))	('neoantigen load', 'MPA', (107, 122))	('immunogenic tumors', 'Disease', (13, 31))
175180	30323625	For example, a recent study showed that patients with melanoma who responded to anti-PD-1 immunotherapy had different gut microbiome than did non-responders.	('patients', 'Species', '9606', (40, 48))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('gut microbiome', 'Species', '749906', (118, 132))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('anti-PD-1', 'Var', (80, 89))
175192	29544183	To evaluate miRNAs as putative disease markers for bladder urothelial carcinoma, this study develops a process to identify dysregulated miRNAs in cancer patients and potentially stratify patients based on the association of their microRNAome phenotype to genomic alterations.	('patients', 'Species', '9606', (187, 195))	('cancer', 'Disease', (146, 152))	('bladder urothelial carcinoma', 'Disease', (51, 79))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('patients', 'Species', '9606', (153, 161))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('dysregulated', 'Var', (123, 135))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (51, 79))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', (12, 15))
175209	29544183	The dysregulation of miRNA and other classes of noncoding RNAs, such as long noncoding RNAs, is implicated in the carcinogenesis of a variety of cancers, including bladder urothelial carcinoma, and can act as either tumor suppressors or oncogenes.	('carcinogenesis', 'Disease', (114, 128))	('cancers', 'Disease', (145, 152))	('tumor', 'Disease', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('dysregulation', 'Var', (4, 17))	('miR', 'Gene', '220972', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('miR', 'Gene', (21, 24))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (164, 192))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('carcinogenesis', 'Disease', 'MESH:D063646', (114, 128))	('bladder urothelial carcinoma', 'Disease', (164, 192))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('implicated', 'Reg', (96, 106))
175265	29544183	Multivariate Cox regression analysis revealed that the association of miR-30e downregulation and miR-33a, miR-33b, and miR-483 upregulation with poor patient outcome was largely independent of clinical prognostic factors such as smoking history, gender, clinical stages, and lymphovascular invasion (P<.05; Supp.	('patient', 'Species', '9606', (150, 157))	('miR-33a', 'Var', (97, 104))	('Cox', 'Gene', (13, 16))	('downregulation', 'NegReg', (78, 92))	('miR-483', 'Gene', '619552', (119, 126))	('miR-33b', 'Gene', (106, 113))	('miR-33b', 'Gene', '693120', (106, 113))	('upregulation', 'PosReg', (127, 139))	('miR-483', 'Gene', (119, 126))	('lymphovascular', 'Disease', (275, 289))	('miR-30e', 'Gene', (70, 77))	('Cox', 'Gene', '1351', (13, 16))
175266	29544183	The potential function of the survival-correlated miRNAs could be elucidated by associating their expression levels to changes in the genome that can drive the pathogenesis and progression of bladder urothelial carcinoma, such as CNV or mutational changes.	('bladder urothelial carcinoma', 'Disease', (192, 220))	('miR', 'Gene', '220972', (50, 53))	('mutational changes', 'Var', (237, 255))	('miR', 'Gene', (50, 53))	('pathogenesis', 'biological_process', 'GO:0009405', ('160', '172'))	('CNV', 'Disease', (230, 233))	('drive', 'PosReg', (150, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (192, 220))
175269	29544183	CNVs in 32 unique loci correlated with miRNA expression levels, with the most significant correlations caused by the deletion of 2q22.1 and 3p14.2, which correlated with dysregulation of miR-33a, miR-33b, and miR-30e (Figure 4, A-C).	('miR-33b', 'Gene', '693120', (196, 203))	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('dysregulation', 'MPA', (170, 183))	('miR', 'Gene', '220972', (209, 212))	('miR', 'Gene', (209, 212))	('miR', 'Gene', '220972', (196, 199))	('miR', 'Gene', (196, 199))	('correlated', 'Reg', (154, 164))	('miR-33b', 'Gene', (196, 203))	('correlated', 'Reg', (23, 33))	('miR', 'Gene', (187, 190))	('2q22.1', 'Gene', (129, 135))	('miR', 'Gene', '220972', (187, 190))	('3p14.2', 'Gene', (140, 146))	('deletion', 'Var', (117, 125))
175271	29544183	A number of mutations have shown to be actively involved in the pathogenesis of bladder cancer, although the underlying molecular mechanism of cancer-related pathways is poorly understood and thought to be more complex than previously conceived.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('bladder cancer', 'Disease', 'MESH:D001749', (80, 94))	('cancer', 'Disease', (88, 94))	('bladder cancer', 'Disease', (80, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('mutations', 'Var', (12, 21))	('involved', 'Reg', (48, 56))	('bladder cancer', 'Phenotype', 'HP:0009725', (80, 94))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('pathogenesis', 'biological_process', 'GO:0009405', ('64', '76'))
175272	29544183	The most common mutations associated with bladder urothelial carcinoma, including mutations of TP53, MLL2, FGFR3, and 23 other genes, were the focus of our analysis.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (42, 70))	('MLL2', 'Gene', (101, 105))	('bladder urothelial carcinoma', 'Disease', (42, 70))	('FGFR3', 'Gene', '2261', (107, 112))	('mutations', 'Var', (16, 25))	('MLL2', 'Gene', '8085', (101, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('mutations', 'Var', (82, 91))	('FGFR3', 'Gene', (107, 112))	('TP53', 'Gene', '7157', (95, 99))	('associated', 'Reg', (26, 36))	('TP53', 'Gene', (95, 99))
175273	29544183	Using the Wilcoxon rank sum test (P<.05), we found that the downregulation of miR-30e and miR-378c, the two miRNAs found to be downregulated in bladder cancer tissues in our analysis, correlated with the presence of TP53 mutation (Figure 5, A and C).	('mutation', 'Var', (221, 229))	('TP53', 'Gene', (216, 220))	('bladder cancer', 'Phenotype', 'HP:0009725', (144, 158))	('downregulation', 'NegReg', (60, 74))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('downregulated', 'NegReg', (127, 140))	('miR-378c', 'Gene', (90, 98))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', (108, 111))	('bladder cancer', 'Disease', (144, 158))	('miR', 'Gene', '220972', (90, 93))	('TP53', 'Gene', '7157', (216, 220))	('miR', 'Gene', (90, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('miR-378c', 'Gene', '100422867', (90, 98))
175275	29544183	Additionally, the presence of mutations in RHOA was associated with elevated expression of miR-30e and lowered expression of miR-33b, while presence of mutations in FGFR3 was associated with elevated expressions of miR-30e and miR-378c (Figure 5).	('miR-378c', 'Gene', '100422867', (227, 235))	('FGFR3', 'Gene', '2261', (165, 170))	('expression', 'MPA', (77, 87))	('FGFR', 'molecular_function', 'GO:0005007', ('165', '169'))	('elevated', 'PosReg', (191, 199))	('mutations', 'Var', (152, 161))	('miR-378c', 'Gene', (227, 235))	('FGFR3', 'Gene', (165, 170))	('RHOA', 'Gene', '387', (43, 47))	('elevated', 'PosReg', (68, 76))	('miR-33b', 'Gene', '693120', (125, 132))	('mutations', 'Var', (30, 39))	('lowered', 'NegReg', (103, 110))	('miR-30e', 'Protein', (91, 98))	('RHOA', 'Gene', (43, 47))	('miR-33b', 'Gene', (125, 132))
175284	29544183	This exhaustive process aims to identify genomic alternations that are functionally responsible for the range of miRNA expression values in the patient samples, as opposed to associations with the general potential driving processes of bladder cancer that we performed in a previous analysis.	('miR', 'Gene', '220972', (113, 116))	('miR', 'Gene', (113, 116))	('bladder cancer', 'Disease', 'MESH:D001749', (236, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('patient', 'Species', '9606', (144, 151))	('bladder cancer', 'Disease', (236, 250))	('alternations', 'Var', (49, 61))	('bladder cancer', 'Phenotype', 'HP:0009725', (236, 250))
175286	29544183	Noncoding RNAs, including miRNAs, are known to be involved in cancer pathogenesis pathways.	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('pathogenesis', 'biological_process', 'GO:0009405', ('69', '81'))	('involved', 'Reg', (50, 58))	('Noncoding', 'Var', (0, 9))
175295	29544183	The correlation between expression and poor prognosis was independent of the above variables for miR-30e, miR-33a, miR-33b, and miR-483.	('miR-30e', 'Var', (97, 104))	('expression', 'MPA', (24, 34))	('miR-483', 'Gene', (128, 135))	('miR-33b', 'Gene', '693120', (115, 122))	('miR-33a', 'Var', (106, 113))	('miR-483', 'Gene', '619552', (128, 135))	('miR-33b', 'Gene', (115, 122))
175297	29544183	CNV of locus 2q22.1, the site of LRP1B and frequently deleted in bladder cancer, was strongly implicated with the upregulation of miR-33a, miR-33b, and miR-30e (P<.003, Wilcoxon rank sum).	('LRP1B', 'Gene', (33, 38))	('miR-30e', 'Var', (152, 159))	('bladder cancer', 'Disease', (65, 79))	('miR-33b', 'Gene', (139, 146))	('upregulation', 'PosReg', (114, 126))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('bladder cancer', 'Phenotype', 'HP:0009725', (65, 79))	('miR-33a', 'Gene', (130, 137))	('miR-33b', 'Gene', '693120', (139, 146))	('bladder cancer', 'Disease', 'MESH:D001749', (65, 79))
175299	29544183	LRP1B was found to be a target of miR-30e in broiler chickens, but no association between LRP1B and miR-33a, miR-33b, or miR-30e has been find in humans.	('LRP1B', 'Gene', (0, 5))	('humans', 'Species', '9606', (146, 152))	('miR-33b', 'Gene', (109, 116))	('chickens', 'Species', '9031', (53, 61))	('miR-30e', 'Var', (34, 41))	('miR-33b', 'Gene', '693120', (109, 116))
175302	29544183	The expression levels of the six survival-related miRNAs were associated with presence of mutations in the genes TP53, RHOA, and FGFR3.	('FGFR3', 'Gene', (129, 134))	('expression levels', 'MPA', (4, 21))	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('mutations', 'Var', (90, 99))	('associated', 'Reg', (62, 72))	('RHOA', 'Gene', '387', (119, 123))	('FGFR', 'molecular_function', 'GO:0005007', ('129', '133'))	('TP53', 'Gene', '7157', (113, 117))	('FGFR3', 'Gene', '2261', (129, 134))	('presence', 'Var', (78, 86))	('RHOA', 'Gene', (119, 123))	('TP53', 'Gene', (113, 117))
175303	29544183	Forty-nine percent of bladder urothelial carcinoma patients have a mutation in TP53 , a well-studied tumor suppressor gene that is known to have a complex interaction with miRNAs and is both a regulator of miRNA expression and target of miRNAs.	('miR', 'Gene', (172, 175))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('101', '117'))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('TP53', 'Gene', '7157', (79, 83))	('interaction', 'Interaction', (155, 166))	('mutation', 'Var', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor suppressor', 'biological_process', 'GO:0051726', ('101', '117'))	('bladder urothelial carcinoma', 'Disease', (22, 50))	('patients', 'Species', '9606', (51, 59))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (22, 50))	('miR', 'Gene', '220972', (206, 209))	('miR', 'Gene', '220972', (237, 240))	('TP53', 'Gene', (79, 83))	('tumor', 'Disease', (101, 106))	('miR', 'Gene', '220972', (172, 175))	('miR', 'Gene', (206, 209))	('miR', 'Gene', (237, 240))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
175304	29544183	The presence of mutation in TP53 correlated with the downregulation of miR-30e and miR-378c, both of which are expected to have tumor suppressive roles in bladder cancer from our differential expression analysis data.	('bladder cancer', 'Disease', (155, 169))	('mutation', 'Var', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('downregulation', 'NegReg', (53, 67))	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('miR-30e', 'Gene', (71, 78))	('miR-378c', 'Gene', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('bladder cancer', 'Phenotype', 'HP:0009725', (155, 169))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('miR-378c', 'Gene', '100422867', (83, 91))	('tumor', 'Disease', (128, 133))	('presence', 'Var', (4, 12))	('bladder cancer', 'Disease', 'MESH:D001749', (155, 169))
175305	29544183	Studies in colon carcinoma have suggested that miR-30e increases the expression of the tumor suppressor protein p21 that is downstream of TP53.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('TP53', 'Gene', '7157', (138, 142))	('colon carcinoma', 'Disease', 'MESH:D015179', (11, 26))	('colon carcinoma', 'Disease', (11, 26))	('tumor', 'Disease', (87, 92))	('TP53', 'Gene', (138, 142))	('expression', 'MPA', (69, 79))	('miR-30e', 'Var', (47, 54))	('increases', 'PosReg', (55, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('87', '103'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('87', '103'))	('p21', 'Gene', '1026', (112, 115))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('p21', 'Gene', (112, 115))
175307	29544183	The presence of mutation in RHOA correlated with the upregulation of miR-30e and the downregulation of miR-33b.	('RHOA', 'Gene', (28, 32))	('mutation', 'Var', (16, 24))	('downregulation', 'NegReg', (85, 99))	('miR-30e', 'Protein', (69, 76))	('miR-33b', 'Gene', '693120', (103, 110))	('upregulation', 'PosReg', (53, 65))	('RHOA', 'Gene', '387', (28, 32))	('miR-33b', 'Gene', (103, 110))
175308	29544183	RHOA appears to have an oncogenic role in bladder urothelial carcinoma, and the expression of miR-33b was reported to activate RHOA in melanoma cells.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (42, 70))	('RHOA', 'Gene', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('bladder urothelial carcinoma', 'Disease', (42, 70))	('melanoma', 'Disease', (135, 143))	('miR-33b', 'Gene', '693120', (94, 101))	('RHOA', 'Gene', '387', (127, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('activate', 'PosReg', (118, 126))	('RHOA', 'Gene', '387', (0, 4))	('RHOA', 'Gene', (127, 131))	('miR-33b', 'Gene', (94, 101))	('expression', 'Var', (80, 90))
175309	29544183	FGFR3 is also frequently reported to be mutated in bladder cancer, with 12% of a sample of over 400 patients possessing a mutation of this gene.	('bladder cancer', 'Disease', (51, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('mutation', 'Var', (122, 130))	('FGFR3', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('patients', 'Species', '9606', (100, 108))	('bladder cancer', 'Disease', 'MESH:D001749', (51, 65))	('FGFR3', 'Gene', '2261', (0, 5))
175310	29544183	Mutation in FGFR3 was correlated with the upregulation of miR-30e, miR-378c, and miR-483 in our analysis, but no studies have linked these miRNAs to FGFR3.	('miR', 'Gene', '220972', (58, 61))	('miR-483', 'Gene', (81, 88))	('miR-378c', 'Gene', (67, 75))	('FGFR3', 'Gene', (149, 154))	('miR', 'Gene', (67, 70))	('miR', 'Gene', '220972', (139, 142))	('miR', 'Gene', '220972', (81, 84))	('miR-378c', 'Gene', '100422867', (67, 75))	('miR-483', 'Gene', '619552', (81, 88))	('miR', 'Gene', (58, 61))	('FGFR3', 'Gene', '2261', (149, 154))	('FGFR3', 'Gene', (12, 17))	('miR', 'Gene', (139, 142))	('miR', 'Gene', (81, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('149', '153'))	('FGFR3', 'Gene', '2261', (12, 17))	('Mutation', 'Var', (0, 8))	('miR', 'Gene', '220972', (67, 70))	('upregulation', 'PosReg', (42, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))
175320	29544183	The landscape of CNVs and mutations revealed to have significant association with miRNA expression by REVEALER is very different from the associations observed from correlations using the Wilcoxon rank sum test.	('mutations', 'Var', (26, 35))	('miR', 'Gene', '220972', (82, 85))	('miR', 'Gene', (82, 85))	('association', 'Interaction', (65, 76))
175321	29544183	With the exception of FGFR3 mutation, no mutations neared the threshold of 0.30 for significant correlation, and many fewer CNVs exhibiting significant correlation with each miRNA expression were observed with REVEALER compared to that observed with the Wilcoxon test.	('FGFR3', 'Gene', (22, 27))	('miR', 'Gene', '220972', (174, 177))	('miR', 'Gene', (174, 177))	('mutation', 'Var', (28, 36))	('FGFR3', 'Gene', '2261', (22, 27))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))
175322	29544183	For example, FGFR3 mutation is less strongly associated with the dysregulation of miR-483 than the dysregulation of miR-30e and miR-378c according to the Wilcoxon P value, but FGFR3 mutation is more significantly associated with miR-483 dysregulation according to the REVEALER conditional information coefficient, while association of FGFR3 mutation with miR-30e and miR-378c dysregulation was not near the significant threshold of 0.30.	('FGFR3', 'Gene', '2261', (335, 340))	('miR-483', 'Gene', (82, 89))	('FGFR', 'molecular_function', 'GO:0005007', ('335', '339'))	('miR-378c', 'Gene', (367, 375))	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('associated', 'Reg', (213, 223))	('miR-378c', 'Gene', '100422867', (367, 375))	('miR-483', 'Gene', '619552', (82, 89))	('miR-378c', 'Gene', (128, 136))	('FGFR3', 'Gene', (13, 18))	('miR-378c', 'Gene', '100422867', (128, 136))	('FGFR3', 'Gene', '2261', (13, 18))	('FGFR', 'molecular_function', 'GO:0005007', ('176', '180'))	('miR-483', 'Gene', (229, 236))	('FGFR3', 'Gene', (176, 181))	('miR-483', 'Gene', '619552', (229, 236))	('FGFR3', 'Gene', '2261', (176, 181))	('FGFR3', 'Gene', (335, 340))	('mutation', 'Var', (182, 190))
175327	29544183	Mutations and somatic CNVs are genomic alterations critical to the mechanism of cancer development, and we hope the dissection of their heterogeneity within cancers may lead to informative stratifications of patients.	('lead', 'Reg', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('patients', 'Species', '9606', (208, 216))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('CNVs', 'Gene', (22, 26))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('cancer', 'Disease', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
175328	29544183	Great advancements have been made in developing methods to determine which CNVs and mutations are functionally relevant in the initiation and progression of cancers, but the use of biomarkers to stratify patients based on these critical CNVs and mutations was less well studied.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('patients', 'Species', '9606', (204, 212))	('mutations', 'Var', (84, 93))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))
175333	29544183	Our study demonstrates a workflow that allows for the specific identification of potentially valuable miRNAs for use as biomarkers and the specific CNVs and mutations they may be able to detect.	('mutations', 'Var', (157, 166))	('miR', 'Gene', '220972', (102, 105))	('miR', 'Gene', (102, 105))
175345	26757906	Losses in 9q are present in 50% of cases and high level amplifications are often detected at 1q21~q25, 6p22~p23, 8q21~q22, 8q22~q24.1, 11q13, and 12q14~q21.	('p23', 'Gene', '6237', (108, 111))	('p23', 'Gene', (108, 111))	('1q21~q25', 'Var', (93, 101))	('8q21~q22', 'Var', (113, 121))	('8q22~q24.1', 'Var', (123, 133))
175346	26757906	One study utilized array-based comparative genomic hybridization to detect frequent copy number gains on chromosomal regions 8p23.1 and 20q13.12, and frequent copy number losses on chromosomal regions 13q21.1, 17p13.1, 6q16.3, and 17p11.2.	('gains', 'PosReg', (96, 101))	('copy number', 'Var', (84, 95))	('p23', 'Gene', (126, 129))	('copy number', 'Var', (159, 170))	('p23', 'Gene', '6237', (126, 129))
175347	26757906	DNA copy number aberrations occurred more frequently in tumors with lymphovascular invasion (LVI) than in those without LVI.	('copy number aberrations', 'Var', (4, 27))	('occurred', 'Reg', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('DNA', 'Gene', (0, 3))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('lymphovascular invasion', 'Disease', (68, 91))
175350	26757906	ERBB2 gene amplification was correlated with HER2 protein overexpression and high-grade histology.	('correlated', 'Reg', (29, 39))	('ERBB2', 'Gene', '2064', (0, 5))	('ERBB2', 'Gene', (0, 5))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('overexpression', 'PosReg', (58, 72))	('HER2', 'Gene', (45, 49))	('HER2', 'Gene', '2064', (45, 49))	('high-grade histology', 'CPA', (77, 97))	('amplification', 'Var', (11, 24))
175351	26757906	HER2 positivity was found to be an independent predictive marker for early intravesical recurrence of urothelial carcinoma.	('early intravesical recurrence', 'Disease', (69, 98))	('positivity', 'Var', (5, 15))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (102, 122))	('urothelial carcinoma', 'Disease', (102, 122))	('HER2', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('HER2', 'Gene', '2064', (0, 4))
175357	26757906	LS patients with MSH2 mutations are at an increased risk for not only UTUC, but also UCB.	('MSH2', 'Gene', (17, 21))	('UCB', 'Phenotype', 'HP:0006740', (85, 88))	('UTUC', 'Disease', (70, 74))	('MSH2', 'Gene', '4436', (17, 21))	('UCB', 'Disease', (85, 88))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (22, 31))
175359	26757906	Defective MMR function leads to replication errors and frame shift mutations, which may result in aberrations in major cancer gene pathways.	('MMR', 'biological_process', 'GO:0006298', ('10', '13'))	('frame shift mutations', 'Var', (55, 76))	('MMR', 'Gene', (10, 13))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('replication errors', 'CPA', (32, 50))	('cancer', 'Disease', (119, 125))	('Defective', 'Var', (0, 9))	('result', 'Reg', (88, 94))	('leads to', 'Reg', (23, 31))
175361	26757906	MSI is a hallmark feature seen in approximately 85% of LS-associated tumors in mutation carriers.	('MSI', 'Disease', 'None', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('MSI', 'Disease', (0, 3))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('mutation', 'Var', (79, 87))
175364	26757906	MSI may arise from inactivating germline mutations, MLH1 promoter hypermethylation (10% of sporadic cases of UTUC), or overexpression of upstream miR-155.	('MSI', 'Disease', 'None', (0, 3))	('miR-155', 'Gene', '406947', (146, 153))	('overexpression', 'PosReg', (119, 133))	('inactivating', 'Var', (19, 31))	('promoter hypermethylation', 'Var', (57, 82))	('MSI', 'Disease', (0, 3))	('MLH1', 'Gene', (52, 56))	('miR-155', 'Gene', (146, 153))	('arise from', 'Reg', (8, 18))	('MLH1', 'Gene', '4292', (52, 56))
175365	26757906	recently found that the inactivation of PMS2 or MLH1 occurs in a quarter of sporadic UTUC cases and is an independent marker of good prognosis.	('inactivation', 'Var', (24, 36))	('PMS2', 'Gene', (40, 44))	('MLH1', 'Gene', '4292', (48, 52))	('MLH1', 'Gene', (48, 52))	('UTUC', 'Disease', (85, 89))	('PMS2', 'Gene', '5395', (40, 44))
175367	26757906	Pembrolizumab was administered intravenously in patients with mismatch repair-deficient colorectal cancers and in patients with mismatch repair-proficient colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('patients', 'Species', '9606', (114, 122))	('mismatch repair', 'biological_process', 'GO:0006298', ('128', '143'))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('mismatch', 'Var', (62, 70))	('deficient colorectal cancers', 'Disease', (78, 106))	('colorectal cancers', 'Disease', 'MESH:D015179', (155, 173))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('mismatch repair', 'biological_process', 'GO:0006298', ('62', '77'))	('colorectal cancers', 'Disease', (155, 173))	('colorectal cancers', 'Disease', 'MESH:D015179', (88, 106))	('patients', 'Species', '9606', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('deficient colorectal cancers', 'Disease', 'MESH:D015179', (78, 106))
175371	26757906	The most frequently mutated genes in UTUC tumors included those commonly altered in previous studies of urothelial carcinoma of the bladder (UCB), including FGFR3 (54%), KMT2D (35%), KDM6A (34%), STAG2 (22%), CDKN2A (21%), TP53 (18%), PIK3CA (16%) and TSC1 (16%) (Figure 1).	('KDM6A', 'Gene', '7403', (183, 188))	('FGFR3', 'Gene', (157, 162))	('TSC1', 'Gene', (252, 256))	('CDKN2A', 'Gene', (209, 215))	('UTUC tumors', 'Disease', (37, 48))	('FGFR3', 'Gene', '2261', (157, 162))	('PIK3CA', 'Gene', (235, 241))	('KMT2D', 'Gene', '8085', (170, 175))	('TP53', 'Gene', '7157', (223, 227))	('TSC1', 'Gene', '7248', (252, 256))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (104, 139))	('KDM6A', 'Gene', (183, 188))	('UCB', 'Phenotype', 'HP:0006740', (141, 144))	('CDKN2A', 'Gene', '1029', (209, 215))	('mutated', 'Var', (20, 27))	('STAG2', 'Gene', '10735', (196, 201))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('UTUC tumors', 'Disease', 'MESH:D009369', (37, 48))	('urothelial carcinoma of the bladder', 'Disease', (104, 139))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('STAG2', 'Gene', (196, 201))	('FGFR', 'molecular_function', 'GO:0005007', ('157', '161'))	('KMT2D', 'Gene', (170, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('PIK3CA', 'Gene', '5290', (235, 241))	('TP53', 'Gene', (223, 227))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (104, 139))
175375	26757906	Mutations of p53 have been identified in approximately 50% of all human cancers.	('identified', 'Reg', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('p53', 'Gene', (13, 16))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('p53', 'Gene', '7157', (13, 16))
175379	26757906	Expression of mutant p53 has been found approximately 30-60% of UTUC.	('mutant', 'Var', (14, 20))	('p53', 'Gene', '7157', (21, 24))	('p53', 'Gene', (21, 24))
175387	26757906	The most recent IHC study examined p53 expression in 112 UTUC patients and found high p53 expression was an independent predictor of poor progression-free (hazard ratio [HR] =3.74, p=0.025) and cancer-specific (HR=5.87, p=0.030) survival.	('cancer', 'Disease', (194, 200))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('p53', 'Gene', '7157', (86, 89))	('poor', 'NegReg', (133, 137))	('high', 'Var', (81, 85))	('patients', 'Species', '9606', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('expression', 'MPA', (90, 100))	('progression-free', 'CPA', (138, 154))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('p53', 'Gene', (86, 89))
175389	26757906	The first sequencing study of TP53 point mutations in exons 4 through 9 in UTUC demonstrated TP53 mutations in 7 of 26 cases, 6 of which were also positive for p53 expression.	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('mutations', 'Var', (98, 107))	('p53', 'Gene', (160, 163))	('p53', 'Gene', '7157', (160, 163))	('point mutations', 'Var', (35, 50))	('TP53', 'Gene', '7157', (30, 34))
175390	26757906	Overexpressed p53 was frequently detected in invasive and high-grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Overexpressed', 'Var', (0, 13))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('detected', 'Reg', (33, 41))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))
175391	26757906	Another study identified p53 point mutations in 6 of 21 cases, 5 of which were positive for p53 protein expression.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('p53', 'Gene', (92, 95))	('p53', 'Gene', '7157', (92, 95))	('point mutations', 'Var', (29, 44))
175395	26757906	Mutation of FGFR3 in bladder cancer is strongly associated with low tumor grade and stage.	('low tumor', 'Disease', (64, 73))	('FGFR3', 'Gene', (12, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (21, 35))	('associated', 'Reg', (48, 58))	('Mutation', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('stage', 'CPA', (84, 89))	('bladder cancer', 'Disease', 'MESH:D001749', (21, 35))	('FGFR3', 'Gene', '2261', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('low tumor', 'Disease', 'MESH:D009800', (64, 73))	('bladder cancer', 'Disease', (21, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))
175396	26757906	examined FGFR3 mutations using the SNaPshot method.	('FGFR3', 'Gene', (9, 14))	('mutations', 'Var', (15, 24))	('FGFR3', 'Gene', '2261', (9, 14))	('FGFR', 'molecular_function', 'GO:0005007', ('9', '13'))
175397	26757906	They found that FGFR3 mutations occurred with the same frequency in bladder (48%) and UTUC (46%).	('FGFR3', 'Gene', (16, 21))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('UTUC', 'Disease', (86, 90))	('occurred', 'Reg', (32, 40))	('bladder', 'Disease', (68, 75))	('mutations', 'Var', (22, 31))	('FGFR3', 'Gene', '2261', (16, 21))
175398	26757906	FGFR3 mutations were associated with low-stage tumors and a milder disease course in UTUC and invasive UTUCs with FGFR3 mutations have a more favorable prognosis.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (0, 5))	('associated', 'Reg', (21, 31))	('FGFR3', 'Gene', '2261', (114, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('114', '118'))	('low-stage tumors', 'Disease', 'MESH:D009800', (37, 53))	('low-stage tumors', 'Disease', (37, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutations', 'Var', (120, 129))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', (114, 119))	('FGFR3', 'Gene', '2261', (0, 5))
175399	26757906	identified FGFR3 mutations in 40% of UTUC tumors using real-time polymerase chain reaction.	('FGFR3', 'Gene', '2261', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('UTUC tumors', 'Disease', 'MESH:D009369', (37, 48))	('FGFR3', 'Gene', (11, 16))	('FGFR', 'molecular_function', 'GO:0005007', ('11', '15'))	('UTUC tumors', 'Disease', (37, 48))	('mutations', 'Var', (17, 26))
175400	26757906	FGFR3 mutations were predominantly associated with non-invasive tumors and overall better survival compared with tumors with wild-type FGFR3.	('invasive tumors', 'Disease', 'MESH:D009369', (55, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('tumors', 'Disease', (113, 119))	('invasive tumors', 'Disease', (55, 70))	('FGFR3', 'Gene', '2261', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('better', 'PosReg', (83, 89))	('mutations', 'Var', (6, 15))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('FGFR3', 'Gene', (0, 5))	('associated', 'Reg', (35, 45))	('survival', 'CPA', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('FGFR3', 'Gene', (135, 140))	('FGFR', 'molecular_function', 'GO:0005007', ('135', '139'))	('FGFR3', 'Gene', '2261', (0, 5))
175401	26757906	In our genomic landscape study of UTUC, fifteen patients (18.3%) had TP53 mutations, 6 (7.3%) had mutually exclusive MDM2 amplifications, and 43 (52.4%) had FGFR3 mutations.	('mutations', 'Reg', (163, 172))	('FGFR3', 'Gene', (157, 162))	('TP53', 'Gene', (69, 73))	('TP53', 'Gene', '7157', (69, 73))	('mutations', 'Var', (74, 83))	('patients', 'Species', '9606', (48, 56))	('MDM2', 'Gene', '4193', (117, 121))	('MDM2', 'Gene', (117, 121))	('FGFR', 'molecular_function', 'GO:0005007', ('157', '161'))	('FGFR3', 'Gene', '2261', (157, 162))
175402	26757906	Mutation in TP53 (HR 3.13, 95% CI 1.44-6.80, p=0.002), TP53/MDM2 alteration (HR 3.66, 95% CI 1.77-7.57, p<0.001), CCND1 (HR 5.19, 95% CI 2.04-13.22, p<0.001), and ERBB3 (HR 3.93, 95% CI 1.18-13.10, p=0.016) significantly increased the risk of distant recurrence after RNU whereas mutation in FGFR3 (HR 0.15, 95% CI 0.06-0.37, p<0.001), RTK/Ras/MAPK pathway (HR 0.39, 95% CI 0.19-0.79, p=0.006), KMT2C (HR 0.29, 95% CI 0.09-0.94, p=0.029), and STAG2 (HR 0.22, 95% CI 0.05-0.92, p=0.022) significantly decreased the risk for distant recurrence (Table 1).TP53/MDM2 alterations were associated with adverse clinicopathologic outcomes whereas FGFR3 mutations were associated with favorable outcomes.	('MDM2', 'Gene', (60, 64))	('RNU', 'Chemical', '-', (268, 271))	('FGFR3', 'Gene', (292, 297))	('CCND1', 'Gene', '595', (114, 119))	('TP53', 'Gene', (552, 556))	('MDM2', 'Gene', '4193', (60, 64))	('STAG2', 'Gene', '10735', (443, 448))	('FGFR3', 'Gene', '2261', (292, 297))	('CCND1', 'Gene', (114, 119))	('TP53', 'Gene', '7157', (55, 59))	('ERBB3', 'Gene', '2065', (163, 168))	('TP53', 'Gene', (12, 16))	('FGFR', 'molecular_function', 'GO:0005007', ('638', '642'))	('MDM2', 'Gene', (557, 561))	('STAG2', 'Gene', (443, 448))	('FGFR3', 'Gene', (638, 643))	('FGFR', 'molecular_function', 'GO:0005007', ('292', '296'))	('KMT2C', 'Gene', '58508', (395, 400))	('KMT2C', 'Gene', (395, 400))	('MAPK', 'molecular_function', 'GO:0004707', ('344', '348'))	('MDM2', 'Gene', '4193', (557, 561))	('TP53', 'Gene', '7157', (552, 556))	('FGFR3', 'Gene', '2261', (638, 643))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (12, 16))	('alterations', 'Var', (562, 573))	('ERBB3', 'Gene', (163, 168))
175404	26757906	The risk score was assigned as follows: 0=normal TP53/MDM2 and altered FGFR3, 1=normal TP53/MDM2 and normal FGFR3, 2=altered TP53/MDM2 and normal FGFR3.	('FGFR3', 'Gene', (71, 76))	('MDM2', 'Gene', '4193', (54, 58))	('TP53', 'Gene', '7157', (49, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('MDM2', 'Gene', (92, 96))	('TP53', 'Gene', (125, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('FGFR3', 'Gene', '2261', (71, 76))	('TP53', 'Gene', '7157', (87, 91))	('MDM2', 'Gene', '4193', (92, 96))	('MDM2', 'Gene', (130, 134))	('FGFR3', 'Gene', (146, 151))	('FGFR3', 'Gene', (108, 113))	('FGFR', 'molecular_function', 'GO:0005007', ('146', '150'))	('TP53', 'Gene', '7157', (125, 129))	('TP53', 'Gene', (49, 53))	('FGFR3', 'Gene', '2261', (146, 151))	('MDM2', 'Gene', '4193', (130, 134))	('FGFR3', 'Gene', '2261', (108, 113))	('2=altered', 'Var', (115, 124))	('MDM2', 'Gene', (54, 58))	('TP53', 'Gene', (87, 91))
175410	26757906	They found that C allele of the cell cycle regulator CCND1 C1722G polymorphism may be a potential predictive and prognostic biomarker for advanced UTUC.	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('32', '52'))	('advanced UTUC', 'Disease', (138, 151))	('C1722G', 'Mutation', 'rs678653', (59, 65))	('CCND1', 'Gene', (53, 58))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('32', '52'))	('CCND1', 'Gene', '595', (53, 58))	('C1722G polymorphism', 'Var', (59, 78))
175411	26757906	examined six CAV1 polymorphic genotypes, C521A (rs1997623), G14713A (rs3807987), G21985A (rs12672038), T28608A (rs3757733), T29107A (rs7804372), and G32124A (rs3807992) in 218 UTUC patients and 580 healthy controls using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP).	('rs3807992', 'Mutation', 'rs3807992', (158, 167))	('rs3807987', 'Mutation', 'rs3807987', (69, 78))	('rs3757733', 'Mutation', 'rs3757733', (112, 121))	('rs3807987', 'Var', (69, 78))	('rs12672038', 'Var', (90, 100))	('T28608A (rs3757733', 'Var', (103, 121))	('rs7804372', 'Var', (133, 142))	('patients', 'Species', '9606', (181, 189))	('rs3807992', 'Var', (158, 167))	('T29107A', 'Mutation', 'rs7804372', (124, 131))	('G21985A (rs12672038', 'Var', (81, 100))	('G32124A (rs3807992', 'Var', (149, 167))	('C521A', 'Mutation', 'rs1997623', (41, 46))	('CAV1', 'Gene', (13, 17))	('rs7804372', 'Mutation', 'rs7804372', (133, 142))	('G14713A (rs3807987', 'Var', (60, 78))	('rs3757733', 'Var', (112, 121))	('C521A', 'Var', (41, 46))	('T28608A', 'Mutation', 'rs3757733', (103, 110))	('rs1997623', 'Var', (48, 57))	('G21985A', 'Mutation', 'rs12672038', (81, 88))	('T29107A (rs7804372', 'Var', (124, 142))	('rs12672038', 'Mutation', 'rs12672038', (90, 100))	('G32124A', 'Mutation', 'rs3807992', (149, 156))	('rs1997623', 'Mutation', 'rs1997623', (48, 57))	('CAV1', 'Gene', '857', (13, 17))	('G14713A', 'Mutation', 'rs3807987', (60, 67))
175412	26757906	The haplotype analysis showed the A allele of CAV1 rs3807987 and T allele of CAV1 rs7804372 might become potential biomarkers for the early screening and risk prediction of UUTC.	('CAV1', 'Gene', (77, 81))	('CAV1', 'Gene', '857', (46, 50))	('UUTC', 'Disease', (173, 177))	('rs7804372', 'Var', (82, 91))	('CAV1', 'Gene', '857', (77, 81))	('rs3807987', 'Mutation', 'rs3807987', (51, 60))	('rs3807987', 'Var', (51, 60))	('rs7804372', 'Mutation', 'rs7804372', (82, 91))	('CAV1', 'Gene', (46, 50))
175413	26757906	Another group from France demonstrated an association between a T/T rs9642880 genotype on chromosome 8q24 and aggressive UTUC tumors.	('rs9642880', 'Mutation', 'rs9642880', (68, 77))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('aggressive UTUC tumors', 'Disease', (110, 132))	('chromosome', 'cellular_component', 'GO:0005694', ('90', '100'))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('aggressive UTUC tumors', 'Disease', 'MESH:D001523', (110, 132))	('T/T rs9642880', 'Var', (64, 77))
175414	26757906	Recently, the G allele of COX2 G-765C and A allele of COX2 intron 5 were found to be genomic risk factors predictive biomarkers for UTUC in Taiwan.	('UTUC', 'Disease', (132, 136))	('COX2', 'Gene', (26, 30))	('COX2', 'Gene', (54, 58))	('COX2', 'Gene', '4513', (26, 30))	('COX2', 'Gene', '4513', (54, 58))	('G-765C', 'Mutation', 'rs20417', (31, 37))	('G-765C', 'Var', (31, 37))
175416	26757906	In our cohort of UTUC tumors profiled with next-generation sequencing, mutations in chromatin-modifying genes (CMGs) were highly prevalent in UTUC (KDM6A 34%, ARID1A 12%, KMT2D 35%, CREBBP 16%) (Figure 1).	('CREBBP', 'Gene', '1387', (182, 188))	('chromatin', 'cellular_component', 'GO:0000785', ('84', '93'))	('KDM6A', 'Gene', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('KMT2D', 'Gene', (171, 176))	('prevalent', 'Reg', (129, 138))	('UTUC tumors', 'Disease', 'MESH:D009369', (17, 28))	('mutations', 'Var', (71, 80))	('ARID1A', 'Gene', (159, 165))	('CMGs', 'Gene', (111, 115))	('CREBBP', 'Gene', (182, 188))	('KMT2D', 'Gene', '8085', (171, 176))	('ARID1A', 'Gene', '8289', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('KDM6A', 'Gene', '7403', (148, 153))	('UTUC tumors', 'Disease', (17, 28))
175417	26757906	Promoter methylation of tumor suppressors is a frequent and early event in tumor development.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Promoter methylation', 'Var', (0, 20))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (75, 80))
175420	26757906	Methylation was associated with advanced tumor stage and higher tumor progression and mortality rates, when compared with tumors without methylation.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('mortality rates', 'CPA', (86, 101))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('higher', 'PosReg', (57, 63))	('tumor', 'Disease', (41, 46))	('Methylation', 'Var', (0, 11))	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (122, 127))
175421	26757906	Methylation at the RASSF1A and DAPK loci, in addition to tumor stage and grade, was associated with disease progression.	('associated with', 'Reg', (84, 99))	('RASSF1A', 'Gene', '11186', (19, 26))	('disease progression', 'CPA', (100, 119))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('DAPK', 'Gene', (31, 35))	('DAPK', 'Gene', '1612', (31, 35))	('tumor', 'Disease', (57, 62))	('RASSF1A', 'Gene', (19, 26))
175426	26757906	Among ten genes, only methylated TMEFF2 promoter and BRCA1 promoter were significantly associated with CSS.	('TMEFF2', 'Gene', (33, 39))	('CSS', 'Gene', '55907', (103, 106))	('CSS', 'Gene', (103, 106))	('TMEFF2', 'Gene', '23671', (33, 39))	('associated', 'Reg', (87, 97))	('BRCA1', 'Gene', '672', (53, 58))	('methylated', 'Var', (22, 32))	('BRCA1', 'Gene', (53, 58))
175431	26757906	Further IHC study showed that low protein expression of ALDH2 and high CCNE1/SMAD3 were associated with lower overall survival in a cohort of 103 patients.	('protein expression', 'MPA', (34, 52))	('overall survival', 'MPA', (110, 126))	('CCNE1', 'Gene', '898', (71, 76))	('CCNE1', 'Gene', (71, 76))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('ALDH', 'molecular_function', 'GO:0004030', ('56', '60'))	('low', 'NegReg', (30, 33))	('ALDH2', 'Gene', '217', (56, 61))	('lower', 'NegReg', (104, 109))	('high', 'Var', (66, 70))	('SMAD3', 'Gene', '4088', (77, 82))	('ALDH2', 'Gene', (56, 61))	('patients', 'Species', '9606', (146, 154))	('SMAD3', 'Gene', (77, 82))
175435	26757906	Our recent genomic study not only revealed the molecular landscape of UTUC, but also identified several currently targetable genetic changes in oncogenic pathways of UTUC, such as FGFR3 (54% mutated), CDKN2B (21% altered), TSC1 (16% altered), and PIK3CA (15% altered).	('CDKN2B', 'Gene', (201, 207))	('PIK3CA', 'Gene', (247, 253))	('FGFR3', 'Gene', '2261', (180, 185))	('oncogenic pathways', 'Pathway', (144, 162))	('CDKN2B', 'Gene', '1030', (201, 207))	('mutated', 'Var', (191, 198))	('changes', 'Var', (133, 140))	('TSC1', 'Gene', '7248', (223, 227))	('PIK3CA', 'Gene', '5290', (247, 253))	('FGFR', 'molecular_function', 'GO:0005007', ('180', '184'))	('FGFR3', 'Gene', (180, 185))	('altered', 'Reg', (213, 220))	('TSC1', 'Gene', (223, 227))	('altered', 'Reg', (233, 240))
175438	26757906	MATCH-UP (Molecular Allocation Trial to CHoose therapy for metastatic Urothelial carcinoma following Platinum-based chemo-therapy) is a phase II trial designed to prospectively screen tumor tissues for specific molecular mutations, including FGFR3 fusion/mutation/amplification, RB1 mutation, PI3K mutation, AKT1 mutation/amplification, mTOR mutation, TSC1 deletion/mutation, PTEN deletion/mutation, ERBB2 mutation/fusion/amplification, EGFR amplification, and histone acetyltransferase mutation.	('mutation', 'Var', (283, 291))	('mTOR', 'Gene', (337, 341))	('mutation', 'Var', (298, 306))	('FGFR', 'molecular_function', 'GO:0005007', ('242', '246'))	('deletion/mutation', 'Var', (381, 398))	('RB1', 'Gene', '5925', (279, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('AKT1', 'Gene', (308, 312))	('mTOR', 'Gene', '2475', (337, 341))	('PTEN', 'Gene', (376, 380))	('histone acetyltransferase', 'Enzyme', (461, 486))	('tumor', 'Disease', (184, 189))	('EGFR', 'Gene', (437, 441))	('deletion/mutation', 'Var', (357, 374))	('mutation/fusion/amplification', 'Var', (406, 435))	('PI3K', 'Gene', (293, 297))	('FGFR3', 'Gene', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('fusion/mutation/amplification', 'Var', (248, 277))	('mutation', 'Var', (342, 350))	('PTEN', 'Gene', '5728', (376, 380))	('TSC1', 'Gene', (352, 356))	('FGFR3', 'Gene', '2261', (242, 247))	('mutation/amplification', 'Var', (313, 335))	('ERBB2', 'Gene', (400, 405))	('RB1', 'Gene', (279, 282))	('EGFR', 'molecular_function', 'GO:0005006', ('437', '441'))	('TSC1', 'Gene', '7248', (352, 356))	('EGFR', 'Gene', '1956', (437, 441))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('Urothelial carcinoma', 'Disease', (70, 90))	('Urothelial carcinoma', 'Disease', 'MESH:D014526', (70, 90))	('ERBB2', 'Gene', '2064', (400, 405))	('AKT1', 'Gene', '207', (308, 312))	('PI3K', 'molecular_function', 'GO:0016303', ('293', '297'))
175454	26312564	In addition, CCDC34 knockdown suppressed bladder tumor growth in nude mice.	('bladder tumor', 'Disease', (41, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('suppressed', 'NegReg', (30, 40))	('nude mice', 'Species', '10090', (65, 74))	('bladder tumor', 'Disease', 'MESH:D001749', (41, 54))	('knockdown', 'Var', (20, 29))	('CCDC34', 'Gene', (13, 19))	('bladder tumor', 'Phenotype', 'HP:0009725', (41, 54))
175455	26312564	Moreover, CCDC34 silencing decreased the phosphorylation of MEK, ERK1/2, JNK, p38 and Akt, and the expressions of c-Raf and c-Jun, indicating MAPK and AKT pathways (ERK/MAPK, p38/MAPK, JNK/MAPK and PI3K/Akt) might be involved in CCDC34 regulation of bladder cancer cell proliferation and migration.	('Akt', 'Gene', (86, 89))	('AKT', 'Gene', (151, 154))	('JNK', 'Gene', (73, 76))	('JNK', 'Gene', '5599', (185, 188))	('c-Raf', 'Gene', (114, 119))	('decreased', 'NegReg', (27, 36))	('JNK', 'Gene', '5599', (73, 76))	('p38', 'Gene', '1432', (175, 178))	('phosphorylation', 'MPA', (41, 56))	('ERK', 'molecular_function', 'GO:0004707', ('165', '168'))	('Akt', 'Gene', '207', (86, 89))	('PI3K', 'molecular_function', 'GO:0016303', ('198', '202'))	('ERK', 'Gene', '5594', (65, 68))	('MEK', 'Gene', '5609', (60, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('41', '56'))	('p38', 'Gene', '1432', (78, 81))	('ERK1/2', 'Gene', (65, 71))	('ERK1/2', 'Gene', '5595;5594', (65, 71))	('cell proliferation', 'biological_process', 'GO:0008283', ('265', '283'))	('MAPK', 'molecular_function', 'GO:0004707', ('142', '146'))	('AKT', 'Gene', '207', (151, 154))	('MEK', 'Gene', (60, 63))	('Akt', 'Gene', (203, 206))	('CCDC34', 'Gene', (10, 16))	('ERK', 'Gene', (65, 68))	('ERK1', 'molecular_function', 'GO:0004707', ('65', '69'))	('Akt', 'Gene', '207', (203, 206))	('p38', 'Gene', (175, 178))	('ERK', 'Gene', '5594', (165, 168))	('c-Jun', 'Gene', '3725', (124, 129))	('regulation', 'biological_process', 'GO:0065007', ('236', '246'))	('MAPK', 'molecular_function', 'GO:0004707', ('179', '183'))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('c-Raf', 'Gene', '5894', (114, 119))	('c-Jun', 'Gene', (124, 129))	('bladder cancer', 'Disease', 'MESH:D001749', (250, 264))	('JNK', 'molecular_function', 'GO:0004705', ('73', '76'))	('MAPK', 'molecular_function', 'GO:0004707', ('169', '173'))	('MAPK', 'molecular_function', 'GO:0004707', ('189', '193'))	('JNK', 'molecular_function', 'GO:0004705', ('185', '188'))	('bladder cancer', 'Disease', (250, 264))	('p38', 'Gene', (78, 81))	('migration', 'CPA', (288, 297))	('silencing', 'Var', (17, 26))	('ERK', 'Gene', (165, 168))	('JNK', 'Gene', (185, 188))	('bladder cancer', 'Phenotype', 'HP:0009725', (250, 264))
175476	26312564	We also explored intratumor delivery of CCDC34 siRNA on xenograft tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('CCDC34', 'Var', (40, 46))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
175487	26312564	The lentivirus infection efficiency is above 85% for both CCDC34-siRNA lentivirus and Negative Control lentivirus, so that we can ensure the synchronization of all the following experiments (Supplemental Fig 1).	('lentivirus infection efficiency', 'Disease', 'MESH:D016180', (4, 35))	('CCDC34-siRNA', 'Var', (58, 70))	('men', 'Species', '9606', (197, 200))	('men', 'Species', '9606', (184, 187))	('lentivirus infection efficiency', 'Disease', (4, 35))
175488	26312564	Furthermore, we assayed the colony formation to determine CCDC34 knockdown in bladder cancer cell tumorigenesis in vitro.	('bladder cancer', 'Phenotype', 'HP:0009725', (78, 92))	('formation', 'biological_process', 'GO:0009058', ('35', '44'))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (78, 92))	('bladder cancer', 'Disease', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('knockdown', 'Var', (65, 74))	('CCDC34', 'Gene', (58, 64))
175490	26312564	The T24 xenograft tumor taken rate in nude mice is 100%, and then the nude mice were randomly selected and treated with CCDC34 siRNA (siCCDC34) or control siRNA (siCtrl) twice a week for 4 weeks by intratumor injection.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('nude mice', 'Species', '10090', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('CCDC34', 'Var', (120, 126))	('nude mice', 'Species', '10090', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
175496	26312564	To further explore these mechanisms, we examined the cell cycle by PI/FACS and detected apoptosis by Annexin V/FACS.	('PI/FACS', 'Var', (67, 74))	('apoptosis', 'CPA', (88, 97))	('examined', 'Reg', (40, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('Annexin V', 'Gene', '308', (101, 110))	('Annexin V', 'Gene', (101, 110))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))	('cell cycle', 'CPA', (53, 63))	('cell cycle', 'biological_process', 'GO:0007049', ('53', '63'))
175498	26312564	The abnormal expression of the coiled-coil domain containing proteins has a direct link with the phenotype of tumor cell migration, invasion and metastasis, for example CCDC134 is down-regulated in gastric cancer and its silencing promotes the migration and invasion of both the normal gastric epithelial cell line GES-1 and gastric cancer cell line AGS via the MAPK pathway.	('gastric cancer', 'Disease', (198, 212))	('silencing', 'Var', (221, 230))	('cell migration', 'biological_process', 'GO:0016477', ('116', '130'))	('gastric cancer', 'Disease', (325, 339))	('invasion', 'CPA', (258, 266))	('AGS', 'Disease', 'MESH:C535607', (350, 353))	('migration', 'CPA', (244, 253))	('gastric cancer', 'Disease', 'MESH:D013274', (198, 212))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (325, 339))	('down-regulated', 'NegReg', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('CCDC134', 'Gene', (169, 176))	('MAPK', 'molecular_function', 'GO:0004707', ('362', '366'))	('gastric cancer', 'Phenotype', 'HP:0012126', (198, 212))	('CCDC134', 'Gene', '79879', (169, 176))	('gastric cancer', 'Phenotype', 'HP:0012126', (325, 339))	('promotes', 'PosReg', (231, 239))	('MAPK pathway', 'Pathway', (362, 374))	('AGS', 'Disease', (350, 353))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
175501	26312564	Western blot results showed that phosphorylation of MEK, ERK1/2, JNK, p38 and AKT were reduced in T24 cells with CCDC34 knockdown; the decreased expression of c-Raf and c-Jun was also observed in the cells (Fig.	('c-Raf', 'Gene', '5894', (159, 164))	('JNK', 'Gene', '5599', (65, 68))	('p38', 'Gene', (70, 73))	('c-Jun', 'Gene', (169, 174))	('ERK1/2', 'Gene', (57, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('ERK1/2', 'Gene', '5595;5594', (57, 63))	('AKT', 'Gene', (78, 81))	('phosphorylation', 'MPA', (33, 48))	('c-Raf', 'Gene', (159, 164))	('ERK1', 'molecular_function', 'GO:0004707', ('57', '61'))	('MEK', 'Gene', '5609', (52, 55))	('decreased', 'NegReg', (135, 144))	('p38', 'Gene', '1432', (70, 73))	('CCDC34', 'Gene', (113, 119))	('JNK', 'molecular_function', 'GO:0004705', ('65', '68'))	('reduced', 'NegReg', (87, 94))	('AKT', 'Gene', '207', (78, 81))	('knockdown', 'Var', (120, 129))	('MEK', 'Gene', (52, 55))	('JNK', 'Gene', (65, 68))	('c-Jun', 'Gene', '3725', (169, 174))
175509	26312564	In our study, Lentivirus-mediated CCDC34 knockdown markedly inhibited bladder cancer cell proliferation and migration in vitro.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cell proliferation', 'biological_process', 'GO:0008283', ('85', '103'))	('inhibited', 'NegReg', (60, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('CCDC34', 'Gene', (34, 40))	('knockdown', 'Var', (41, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (70, 84))	('bladder cancer', 'Disease', (70, 84))
175510	26312564	Mouse models bearing T24 cell-derived xenografts were injected with chemically modified CCDC34 siRNA for in vivo tumorigenesis assay, and the results showed siCCDC34 treatment retarded tumor growth significantly compared with the siCtrl treatment.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', (113, 118))	('retarded tumor', 'Disease', 'MESH:D009369', (176, 190))	('siCCDC34', 'Var', (157, 165))	('CCDC34', 'Gene', (88, 94))	('retarded tumor', 'Disease', (176, 190))	('men', 'Species', '9606', (242, 245))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('Mouse', 'Species', '10090', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('men', 'Species', '9606', (171, 174))
175520	26312564	Meanwhile, another important signal transduction factor AKT was found to be down-regulated with CCDC34 knockdown.	('CCDC34', 'Gene', (96, 102))	('AKT', 'Gene', '207', (56, 59))	('signal transduction', 'biological_process', 'GO:0007165', ('29', '48'))	('AKT', 'Gene', (56, 59))	('down-regulated', 'NegReg', (76, 90))	('knockdown', 'Var', (103, 112))
175524	26312564	So our findings preliminarily declared that CCDC34 silencing may suppress bladder cancer proliferation and migration through inactivation of RAF-ERK1/2-MAPK, p38/MAPK, JNK/MAPK and PI3K/Akt signaling pathways.	('MAPK', 'molecular_function', 'GO:0004707', ('172', '176'))	('p38', 'Gene', '1432', (158, 161))	('ERK1/2', 'Gene', (145, 151))	('ERK1/2', 'Gene', '5595;5594', (145, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (74, 88))	('bladder cancer', 'Disease', (74, 88))	('CCDC34', 'Gene', (44, 50))	('suppress', 'NegReg', (65, 73))	('MAPK', 'molecular_function', 'GO:0004707', ('152', '156'))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (74, 88))	('RAF', 'Gene', '22882', (141, 144))	('JNK', 'molecular_function', 'GO:0004705', ('168', '171'))	('ERK1', 'molecular_function', 'GO:0004707', ('145', '149'))	('MAPK', 'molecular_function', 'GO:0004707', ('162', '166'))	('migration', 'CPA', (107, 116))	('RAF', 'Gene', (141, 144))	('Akt', 'Gene', (186, 189))	('PI3K', 'molecular_function', 'GO:0016303', ('181', '185'))	('p38', 'Gene', (158, 161))	('silencing', 'Var', (51, 60))	('Akt', 'Gene', '207', (186, 189))	('inactivation', 'NegReg', (125, 137))	('JNK', 'Gene', (168, 171))	('Akt signaling', 'biological_process', 'GO:0043491', ('186', '199'))	('JNK', 'Gene', '5599', (168, 171))
175526	26312564	the effect of CCDC34 knockdown plus blocking the MAPK or AKT pathway on bladder cancer cells proliferation, apoptosis and migration; and how CCDC34 regulates the phosphorylation and gene expressions.	('CCDC34', 'Gene', (14, 20))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('knockdown', 'Var', (21, 30))	('phosphorylation', 'biological_process', 'GO:0016310', ('162', '177'))	('bladder cancer', 'Disease', 'MESH:D001749', (72, 86))	('bladder cancer', 'Disease', (72, 86))	('gene expressions', 'MPA', (182, 198))	('MAPK', 'molecular_function', 'GO:0004707', ('49', '53'))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('AKT', 'Gene', '207', (57, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('apoptosis', 'CPA', (108, 117))	('migration', 'CPA', (122, 131))	('CCDC34', 'Gene', (141, 147))	('blocking', 'NegReg', (36, 44))	('regulates', 'Reg', (148, 157))	('phosphorylation', 'MPA', (162, 177))	('AKT', 'Gene', (57, 60))	('MAPK', 'Pathway', (49, 53))
175542	26312564	The bladder cancer cell lines were obtained from the institute of Urology, Peking University; with T24, 5637, BIU-87 and EJ cultured in RPMI-1640 medium (Hyclone), and J82 in high glucose DMEM medium (Hyclone).	('bladder cancer', 'Disease', (4, 18))	('glucose', 'Chemical', 'MESH:D005947', (180, 187))	('J82', 'Var', (168, 171))	('RPMI-1640', 'Chemical', '-', (136, 145))	('bladder cancer', 'Phenotype', 'HP:0009725', (4, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('DMEM medium', 'Chemical', '-', (188, 199))	('bladder cancer', 'Disease', 'MESH:D001749', (4, 18))	('EJ', 'CellLine', 'CVCL:7039', (121, 123))	('high glucose', 'Phenotype', 'HP:0003074', (175, 187))
175550	26312564	Endogenous peroxidase activity was blocked (0.35% H2O2 in PBS buffer), antigens were retrieved by microwaving (350 W), and nonspecific binding was blocked by 1% bovine serum albumin in PBS buffer.	('peroxidase activity', 'molecular_function', 'GO:0004601', ('11', '30'))	('bovine', 'Species', '9913', (161, 167))	('H2O2', 'Chemical', 'MESH:D006861', (50, 54))	('binding', 'molecular_function', 'GO:0005488', ('135', '142'))	('Endogenous', 'Enzyme', (0, 10))	('PBS', 'Chemical', '-', (58, 61))	('0.35', 'Var', (44, 48))	('activity', 'MPA', (22, 30))	('PBS', 'Chemical', '-', (185, 188))	('blocked', 'NegReg', (35, 42))
175574	24622401	Among these genes, we filtered 24 cancer-associated alternative splicing genes with differential exon usage.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('splicing', 'biological_process', 'GO:0045292', ('64', '72'))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('alternative splicing', 'Var', (52, 72))
175584	24622401	Prior studies of genomic alterations have revealed that somatic changes, including point mutations, DNA rearrangements (reviewed in) and copy number variations  , can result in mutations that drive the development of UCB.	('DNA', 'Gene', (100, 103))	('drive', 'PosReg', (192, 197))	('mutations', 'Var', (177, 186))	('rat', 'Species', '10116', (29, 32))	('rearrangements', 'Var', (104, 118))	('result in', 'Reg', (167, 176))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('point mutations', 'Var', (83, 98))	('men', 'Species', '9606', (113, 116))	('copy number variations', 'Var', (137, 159))	('men', 'Species', '9606', (209, 212))	('UCB', 'Disease', (217, 220))
175586	24622401	Studying the cancer transcriptome not only enables us to fill in the gap between driver mutations and cancer cell behavior, but also allows us to identify additional candidate cancer-related mutations and the molecular basis of gene regulation.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('regulation', 'biological_process', 'GO:0065007', ('233', '243'))	('mutations', 'Var', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
175588	24622401	The cancer-specific splice variants may potentially be used as diagnostic, prognostic, and predictive biomarkers as well as therapeutic targets.	('cancer', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('splice variants', 'Var', (20, 35))	('cancer', 'Disease', 'MESH:D009369', (4, 10))
175619	24622401	The ratio of junction-reads number for the exon inclusion versus the exon exclusion was obviously higher in the cancer tissue than that in the non-tumor tissue for both of the two genes.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('junction-reads', 'MPA', (13, 27))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('non-tumor', 'Disease', 'MESH:D009369', (143, 152))	('non-tumor', 'Disease', (143, 152))	('higher', 'PosReg', (98, 104))	('rat', 'Species', '10116', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('exon', 'Var', (43, 47))
175625	24622401	The result showed that CD44 (36%, 4/11), PDGFA (64%, 7/11), NUMB (64%, 7/11) and LPHN2 (73%, 8/11) showed exon increased exon inclusion in considerable number of UCB patients, but few patients showed the increased exon exclusion in gene NIN (18%, 2/11) and 9% (1/11).	('exon', 'Var', (106, 110))	('exon exclusion', 'MPA', (214, 228))	('exon inclusion', 'MPA', (121, 135))	('UCB', 'Disease', (162, 165))	('increased', 'PosReg', (111, 120))	('CD44', 'Gene', '960', (23, 27))	('patients', 'Species', '9606', (184, 192))	('LPHN2', 'Gene', '23266', (81, 86))	('CD44', 'Gene', (23, 27))	('NUMB', 'Gene', (60, 64))	('NUMB', 'Gene', '8650', (60, 64))	('patients', 'Species', '9606', (166, 174))	('LPHN2', 'Gene', (81, 86))
175631	24622401	We identified the levels of differentially expressed genes and alternative splicing patterns associated with cancer.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('splicing', 'biological_process', 'GO:0045292', ('75', '83'))	('alternative splicing', 'Var', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
175642	24622401	In addition, several known driver factors that are frequently mutated in UCB, including ARPC5 (p16) and FGF2, showed no change in expression in this study, suggesting that the genetic heterogeneity of UCB or the mutated products might be deleterious even if the expression level is unaffected.	('expression', 'MPA', (130, 140))	('UCB', 'Gene', (73, 76))	('FGF2', 'Gene', (104, 108))	('p16', 'Gene', '1029', (95, 98))	('ARPC5', 'Gene', '10092', (88, 93))	('ARPC5', 'Gene', (88, 93))	('FGF2', 'Gene', '2247', (104, 108))	('p16', 'Gene', (95, 98))	('mutated', 'Var', (62, 69))
175648	24622401	Aberration of the CAMs pathway and ECM receptors enables cancer cells to escape their primary tumor masses, invade adjacent tissues and colonize elsewhere.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Disease', (57, 63))	('tumor', 'Disease', (94, 99))	('ECM receptors', 'Protein', (35, 48))	('invade', 'CPA', (108, 114))	('CAMs pathway', 'Pathway', (18, 30))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('escape', 'CPA', (73, 79))	('rat', 'Species', '10116', (4, 7))	('Aberration', 'Var', (0, 10))
175653	24622401	Some splicing events have been reported to be related to bladder cancer using exon arrays, including CD44, CLSTN1 and CTNND1.	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))	('CTNND1', 'Gene', '1500', (118, 124))	('CD44', 'Gene', (101, 105))	('CLSTN1', 'Gene', (107, 113))	('related', 'Reg', (46, 53))	('CTNND1', 'Gene', (118, 124))	('bladder cancer', 'Disease', 'MESH:D001749', (57, 71))	('bladder cancer', 'Disease', (57, 71))	('splicing', 'Var', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('splicing', 'biological_process', 'GO:0045292', ('5', '13'))	('CLSTN1', 'Gene', '22883', (107, 113))	('CD44', 'Gene', '960', (101, 105))
175656	24622401	In our study, the variant exon v8, v9 and v10 expressed in the UCB tissue, but not in the non-tumor tissue (Fig.	('variant exon v8', 'Var', (18, 33))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('non-tumor', 'Disease', (90, 99))	('v10', 'Var', (42, 45))	('non-tumor', 'Disease', 'MESH:D009369', (90, 99))	('UCB', 'Disease', (63, 66))
175671	24622401	Based on this, the increased inclusion of the alternative exon in MACF1 transcripts was proposed to contribute to altered Wnt signaling in the lung and colon cancers, and our result expands this supposition to the bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('inclusion', 'Var', (29, 38))	('colon cancers', 'Disease', (152, 165))	('bladder cancer', 'Disease', 'MESH:D001749', (214, 228))	('bladder cancer', 'Disease', (214, 228))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('altered', 'Reg', (114, 121))	('colon cancers', 'Disease', 'MESH:D015179', (152, 165))	('colon cancers', 'Phenotype', 'HP:0003003', (152, 165))	('MACF1', 'Gene', '23499', (66, 71))	('increased', 'PosReg', (19, 28))	('bladder cancer', 'Phenotype', 'HP:0009725', (214, 228))	('signaling', 'biological_process', 'GO:0023052', ('126', '135'))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('MACF1', 'Gene', (66, 71))	('colon cancer', 'Phenotype', 'HP:0003003', (152, 164))	('Wnt signaling', 'MPA', (122, 135))	('lung', 'Disease', (143, 147))
175673	24622401	reported that the long isoform of ADD3 with inclusion of exon number 15 was specifically expressed in the non-small cell lung cancer, but the cancer-special function of the isoform is unclear.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (106, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (110, 132))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (106, 132))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('inclusion', 'Var', (44, 53))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('non-small cell lung cancer', 'Disease', (106, 132))	('ADD3', 'Gene', '120', (34, 38))	('ADD3', 'Gene', (34, 38))	('expressed', 'Reg', (89, 98))	('cancer', 'Disease', (142, 148))
175680	24622401	In our study using RNA-Seq, the inclusion exon 9 of NUMB was also significantly increased in the UCB tissue (Fig.	('NUMB', 'Gene', (52, 56))	('increased', 'PosReg', (80, 89))	('NUMB', 'Gene', '8650', (52, 56))	('RNA', 'cellular_component', 'GO:0005562', ('19', '22'))	('inclusion exon', 'Var', (32, 46))
175683	24622401	There are also some differential splicing events which have not been reported to be associated with tumors, such as UCB increased exon inclusion of LPHN2 (chr1:82452585-82452713), EIF4A2 (chr3:186505197-186505373), FAT1 (chr4:187511522-187511557), exon exclusion of CD151 (chr11:834458-834591), and so on.	('FAT1', 'Gene', '2195', (215, 219))	('chr4:187511522-187511557', 'Var', (221, 245))	('EIF4A2', 'Gene', (180, 186))	('chr1', 'Gene', '250280', (155, 159))	('EIF4A2', 'Gene', '1974', (180, 186))	('chr1', 'Gene', '250280', (273, 277))	('CD151', 'Gene', '977', (266, 271))	('LPHN2', 'Gene', (148, 153))	('exon', 'MPA', (248, 252))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('splicing', 'biological_process', 'GO:0045292', ('33', '41'))	('chr1', 'Gene', (155, 159))	('chr1', 'Gene', (273, 277))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('FAT1', 'Gene', (215, 219))	('tumors', 'Disease', (100, 106))	('CD151', 'Gene', (266, 271))	('chr3:186505197-186505373', 'Var', (188, 212))	('increased', 'PosReg', (120, 129))	('EIF4', 'cellular_component', 'GO:0008304', ('180', '184'))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('exon inclusion', 'MPA', (130, 144))	('LPHN2', 'Gene', '23266', (148, 153))
175685	24622401	The splicing events might be a novel alternative splicing changes associated with bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('splicing', 'biological_process', 'GO:0045292', ('49', '57'))	('splicing events', 'Var', (4, 19))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('associated', 'Reg', (66, 76))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))	('bladder cancer', 'Disease', (82, 96))	('splicing', 'biological_process', 'GO:0045292', ('4', '12'))
175730	32585775	The effectiveness of chemotherapy for patients with pT3N0M0 renal pelvic urothelial carcinomas: An inverse probability of treatment weighting comparison using Surveillance, Epidemiology, and End Results data Unlike the established evidence to use chemotherapy for urothelial carcinoma of the bladder, presently there are insufficient data to inform a recommendation on upper urinary tract urothelial carcinoma treatment.	('urothelial carcinoma', 'Disease', (389, 409))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (389, 409))	('urothelial carcinoma of the bladder', 'Disease', (264, 299))	('pT3N0M0', 'Var', (52, 59))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (264, 284))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (73, 93))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (264, 299))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (264, 299))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (400, 409))	('patients', 'Species', '9606', (38, 46))	('renal pelvic urothelial carcinomas', 'Disease', 'MESH:D010386', (60, 94))	('renal pelvic urothelial carcinomas', 'Disease', (60, 94))
175737	32585775	In the IPTW-adjusted Cox proportional hazards regression model, chemotherapy was associated with favorable survival benefits compared with observation (hazard ratio [HR] 0.71, 95% CI 0.52-0.92, P = .031), and this was maintained after bootstrapping (HR 0.72, 95% CI 0.49-0.93).	('benefits', 'PosReg', (116, 124))	('survival', 'CPA', (107, 115))	('IPTW', 'Chemical', '-', (7, 11))	('chemotherapy', 'Var', (64, 76))
175749	32585775	10  However, in the real world, a study based on National Cancer Data Base (NCDB) showed that patients with lymph node metastases and tumors located in the ureter had a higher possibility of receiving adjuvant chemotherapy than patients with negative lymph nodes and tumors located in the renal pelvis.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('renal pelvis', 'Disease', (289, 301))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('tumors', 'Disease', (134, 140))	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (228, 236))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('Cancer', 'Disease', (58, 64))	('tumors', 'Disease', (267, 273))	('metastases', 'Disease', 'MESH:D009362', (119, 129))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('renal pelvis', 'Disease', 'MESH:D007680', (289, 301))	('renal pelvis', 'Phenotype', 'HP:0000125', (289, 301))	('lymph', 'Var', (108, 113))	('metastases', 'Disease', (119, 129))	('Cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (267, 273))
175779	32585775	In the IPTW-adjusted Cox proportional hazards regression model, chemotherapy was associated with favorable survival benefits compared with observation (HR = 0.71, 95% CI 0.52-0.92, P = .031), and this was maintained after bootstrapping (HR = 0.72, 95% CI 0.49-0.93).	('benefits', 'PosReg', (116, 124))	('survival', 'CPA', (107, 115))	('IPTW', 'Chemical', '-', (7, 11))	('chemotherapy', 'Var', (64, 76))
175802	32585775	3 ,  4  The outcomes of the POUT clinical trial validate the survival benefits in patients with pN0, and whether the use of more extensive lymph node dissection would offer additional benefits is uncertain.	('patients', 'Species', '9606', (82, 90))	('survival', 'CPA', (61, 69))	('pN0', 'Var', (96, 99))	('benefits', 'PosReg', (70, 78))
175812	32585775	30  Recently, a pan-FGFR inhibitor was also established for advanced urothelial carcinomas with FGFR alterations, including UTUC.	('urothelial carcinomas', 'Disease', 'MESH:D014523', (69, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('UTUC', 'Disease', (124, 128))	('alterations', 'Var', (101, 112))	('FGFR', 'Gene', (96, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('urothelial carcinomas', 'Disease', (69, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('20', '24'))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))
175816	32585775	32  Some retrospective studies suggested that tumors with PFI may be more likely to metastasize and contain more adverse features than tumors with RPI.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PFI', 'molecular_function', 'GO:0034016', ('58', '61'))	('PFI', 'Var', (58, 61))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Disease', (135, 141))	('metastasize', 'CPA', (84, 95))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
175975	32508060	As a result, the researchers discovered different sizes of mutant HPV-11 genomes in the laryngeal and lung tumor CRCs, respectively, and vorinostat was identified as an effective agent.	('HPV-11', 'Gene', (66, 72))	('vorinostat', 'Chemical', 'MESH:D000077337', (137, 147))	('HPV-11', 'Species', '10580', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('mutant', 'Var', (59, 65))	('lung tumor CRCs', 'Disease', (102, 117))	('lung tumor', 'Phenotype', 'HP:0100526', (102, 112))	('lung tumor CRCs', 'Disease', 'MESH:D008175', (102, 117))
175987	32508060	The results demonstrated that the CRCs retained many cancer-specific copy number alterations and somatic mutations found in the original tumor tissues.	('tumor', 'Disease', (137, 142))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('copy number alterations', 'Var', (69, 92))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('CR', 'Chemical', '-', (34, 36))
176000	32508060	Additionally, Ringer et al found that VMY-1-103 (VMY), a CDK inhibitor, could exert its cytotoxic effect on PCa CRCs through p53-dependent autophagy, which provided implications for the clinical study of VMY.	('PCa CRCs', 'Disease', 'None', (108, 116))	('VMY-1-103', 'Chemical', 'MESH:C557984', (38, 47))	('VMY-1-103', 'Var', (38, 47))	('p53', 'Gene', (125, 128))	('CDK', 'Gene', '12567;12571', (57, 60))	('p53', 'Gene', '7157', (125, 128))	('CDK inhibitor', 'molecular_function', 'GO:0004861', ('57', '70'))	('CDK', 'Gene', (57, 60))	('autophagy', 'biological_process', 'GO:0016236', ('139', '148'))	('PCa', 'Phenotype', 'HP:0012125', (108, 111))	('PCa CRCs', 'Disease', (108, 116))	('autophagy', 'biological_process', 'GO:0006914', ('139', '148'))	('cytotoxic effect', 'CPA', (88, 104))
176044	32508060	146  Moreover, the use of specific agents may improve the selectivity of cancer cells, such as Nutlin-3a, an MDM2 inhibitor that can select for cells harboring TP53 mutations (which occur in half of all human tumors).	('cancer', 'Disease', (73, 79))	('MDM2', 'Gene', (109, 113))	('tumors', 'Disease', (209, 215))	('selectivity', 'MPA', (58, 69))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('human', 'Species', '9606', (203, 208))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('TP53', 'Gene', '7157', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TP53', 'Gene', (160, 164))	('mutations', 'Var', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('MDM2', 'Gene', '4193', (109, 113))
176047	32508060	149  In lung cancer, the tumor CRCs also lacked genetic mutations, which were reported to completely disappear at passage 4 in all samples.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor CRCs', 'Disease', 'MESH:D009369', (25, 35))	('lung cancer', 'Disease', 'MESH:D008175', (8, 19))	('lung cancer', 'Disease', (8, 19))	('tumor CRCs', 'Disease', (25, 35))	('genetic mutations', 'Var', (48, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (8, 19))
176054	32508060	In addition, the use of the ROCK inhibitor Y-27632 may interfere with tumor cell migration and invasion behavior in vitro, as it alters the actin cytoskeleton.	('Y-27632', 'Chemical', 'MESH:C108830', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('actin cytoskeleton', 'MPA', (140, 158))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('140', '158'))	('alters', 'Reg', (129, 135))	('tumor', 'Disease', (70, 75))	('cell migration', 'biological_process', 'GO:0016477', ('76', '90'))	('Y-27632', 'Var', (43, 50))	('invasion behavior', 'CPA', (95, 112))	('interfere', 'NegReg', (55, 64))
176077	24476821	There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell cycle regulation, chromatin regulation, and kinase signaling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer.	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('signaling', 'biological_process', 'GO:0023052', ('163', '172'))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('107', '128'))	('mutations', 'Var', (47, 56))	('chromatin', 'cellular_component', 'GO:0000785', ('130', '139'))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('regulation', 'biological_process', 'GO:0065007', ('140', '150'))	('significant', 'Reg', (25, 36))	('cancer', 'Disease', (258, 264))
176078	24476821	Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation.	('TACC3', 'Gene', '10460', (79, 84))	('in-frame', 'Reg', (53, 61))	('TACC3', 'Gene', (79, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('73', '77'))	('RNA', 'cellular_component', 'GO:0005562', ('17', '20'))	('activating', 'PosReg', (62, 72))	('FGFR3', 'Gene', '2261', (73, 78))	('fusions', 'Var', (85, 92))	('FGFR3', 'Gene', (73, 78))	('HPV16', 'Species', '333760', (153, 158))
176080	24476821	Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any common cancer studied to date, suggesting the future possibility of targeted therapy for chromatin abnormalities.	('mutated', 'Var', (48, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('Chromatin', 'cellular_component', 'GO:0000785', ('0', '9'))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (59, 79))	('cancer', 'Disease', (99, 105))	('Chromatin regulatory genes', 'Gene', (0, 26))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('urothelial carcinoma', 'Disease', (59, 79))	('chromatin', 'cellular_component', 'GO:0000785', ('181', '190'))
176082	24476821	Previous studies have identified multiple regions of somatic copy number alteration, including amplification of PPARG, E2F3, EGFR, CCND1 and MDM2, as well as loss of CDKN2A and RB1.	('CDKN2A', 'Gene', (166, 172))	('CCND1', 'Gene', (131, 136))	('EGFR', 'Gene', '1956', (125, 129))	('CDKN2A', 'Gene', '1029', (166, 172))	('RB1', 'Gene', (177, 180))	('CCND1', 'Gene', '595', (131, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('PPARG', 'Gene', '5468', (112, 117))	('PPARG', 'Gene', (112, 117))	('amplification', 'Var', (95, 108))	('EGFR', 'Gene', (125, 129))	('E2F3', 'Gene', (119, 123))	('RB1', 'Gene', '5925', (177, 180))	('E2F3', 'Gene', '1871', (119, 123))	('MDM2', 'Gene', '4193', (141, 145))	('loss', 'NegReg', (158, 162))	('MDM2', 'Gene', (141, 145))
176083	24476821	Sequencing of candidate pathways has identified recurrent mutations in TP53, FGFR3, PIK3CA, TSC1, RB1 and HRAS.	('mutations', 'Var', (58, 67))	('FGFR3', 'Gene', (77, 82))	('RB1', 'Gene', '5925', (98, 101))	('HRAS', 'Gene', (106, 110))	('TSC1', 'Gene', '7248', (92, 96))	('PIK3CA', 'Gene', '5290', (84, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('TSC1', 'Gene', (92, 96))	('RB1', 'Gene', (98, 101))	('PIK3CA', 'Gene', (84, 90))	('HRAS', 'Gene', '3265', (106, 110))	('TP53', 'Gene', '7157', (71, 75))	('FGFR3', 'Gene', '2261', (77, 82))	('TP53', 'Gene', (71, 75))
176084	24476821	More recently, a candidate gene study identified mutations at >10% frequency in several chromatin remodeling genes: KDM6A, CREBBP, EP300, and ARID1A.	('mutations', 'Var', (49, 58))	('CREBBP', 'Gene', (123, 129))	('KDM6A', 'Gene', '7403', (116, 121))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('88', '108'))	('EP300', 'Gene', (131, 136))	('ARID1A', 'Gene', '8289', (142, 148))	('EP300', 'Gene', '2033', (131, 136))	('chromatin', 'cellular_component', 'GO:0000785', ('88', '97'))	('ARID1A', 'Gene', (142, 148))	('CREBBP', 'Gene', '1387', (123, 129))	('KDM6A', 'Gene', (116, 121))
176085	24476821	Focused molecular analyses have delineated tumour subtypes and identified kinase-activating FGFR3 gene fusions.	('fusions', 'Var', (103, 110))	('FGFR3', 'Gene', (92, 97))	('delineated tumour subtypes', 'Disease', 'MESH:C535673', (32, 58))	('delineated tumour subtypes', 'Disease', (32, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('FGFR3', 'Gene', '2261', (92, 97))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('kinase-activating', 'PosReg', (74, 91))
176088	24476821	This study identifies a number of mutations and regions of copy number variation that involve genes not previously reported as altered in a significant fraction of bladder cancers.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('bladder cancer', 'Phenotype', 'HP:0009725', (164, 178))	('bladder cancers', 'Disease', 'MESH:D001749', (164, 179))	('copy number variation', 'Var', (59, 80))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('bladder cancers', 'Disease', (164, 179))	('bladder cancers', 'Phenotype', 'HP:0009725', (164, 179))
176092	24476821	The tumours displayed a large number of DNA alterations, slightly fewer than in lung cancer and melanoma, but more than in other adult malignancies studied by TCGA (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('melanoma', 'Disease', (96, 104))	('alterations', 'Var', (44, 55))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('malignancies', 'Disease', 'MESH:D009369', (135, 147))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('malignancies', 'Disease', (135, 147))	('tumours', 'Disease', (4, 11))
176096	24476821	Other focal deletions containing <10 genes appeared to target PDE4D, RB1, FHIT, CREBBP, IKZF2, FOXQ1, FAM190A, LRP1B and WWOX.	('WWOX', 'Gene', (121, 125))	('FOXQ1', 'Gene', (95, 100))	('PDE', 'molecular_function', 'GO:0004114', ('62', '65'))	('RB1', 'Gene', (69, 72))	('deletions', 'Var', (12, 21))	('FOXQ1', 'Gene', '94234', (95, 100))	('LRP1B', 'Gene', '53353', (111, 116))	('PDE4D', 'Gene', '5144', (62, 67))	('WWOX', 'Gene', '51741', (121, 125))	('CREBBP', 'Gene', (80, 86))	('FHIT', 'Gene', (74, 78))	('IKZF2', 'Gene', '22807', (88, 93))	('IKZF2', 'Gene', (88, 93))	('RB1', 'Gene', '5925', (69, 72))	('PDE4D', 'Gene', (62, 67))	('FAM190A', 'Gene', (102, 109))	('CREBBP', 'Gene', '1387', (80, 86))	('FHIT', 'Gene', '2272', (74, 78))	('LRP1B', 'Gene', (111, 116))	('FAM190A', 'Gene', '401145', (102, 109))
176099	24476821	We validated the mutation findings in three ways: targeted re-sequencing of all SMG mutations, comparison with RNA-Seq data for 123 samples and comparison with whole genome sequence data for 18 samples.	('mutations', 'Var', (84, 93))	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('SMG', 'Gene', '23034', (80, 83))	('SMG', 'Gene', (80, 83))
176100	24476821	Nearly half (49%) of the samples had TP53 mutations (Fig.	('TP53', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('TP53', 'Gene', '7157', (37, 41))
176102	24476821	Most RB1 mutations were inactivating, were associated with significantly reduced mRNA level (Supplementary Fig.	('mutations', 'Var', (9, 18))	('reduced', 'NegReg', (73, 80))	('RB1', 'Gene', '5925', (5, 8))	('RB1', 'Gene', (5, 8))	('mRNA level', 'MPA', (81, 91))	('inactivating', 'Var', (24, 36))
176103	24476821	S2.7) and were mutually exclusive with CDKN2A deletions (Supplementary Fig.	('deletions', 'Var', (46, 55))	('CDKN2A', 'Gene', (39, 45))	('CDKN2A', 'Gene', '1029', (39, 45))
176104	24476821	FGFR3 mutations (12%) typically affected known kinase-activating sites.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (0, 5))	('kinase-activating sites', 'MPA', (47, 70))	('affected', 'Reg', (32, 40))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
176105	24476821	PIK3CA mutations were relatively common (20%), clustering in the helical domain near E545 (Supplementary Fig.	('PIK3CA', 'Gene', '5290', (0, 6))	('E545', 'Var', (85, 89))	('mutations', 'Var', (7, 16))	('PIK3CA', 'Gene', (0, 6))
176106	24476821	Most TSC1 mutations (8%) were truncating, and six were homozygous (allele fraction > 0.5).	('TSC1', 'Gene', (5, 9))	('mutations', 'Var', (10, 19))	('truncating', 'MPA', (30, 40))	('TSC1', 'Gene', '7248', (5, 9))
176110	24476821	Fifteen of 16 mutations in ERCC2, a nucleotide excision repair gene, were deleterious missense mutations, suggesting dominant negative effects.	('ERCC2', 'Gene', (27, 32))	('mutations', 'Var', (14, 23))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('36', '62'))	('ERCC2', 'Gene', '2068', (27, 32))
176111	24476821	ERCC2-mutant tumours also had significantly fewer C>G mutations than did ERCC2-wild type tumours (Supplementary Figs.	('type tumours', 'Disease', 'MESH:D009369', (84, 96))	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('ERCC2', 'Gene', '2068', (73, 78))	('type tumours', 'Disease', (84, 96))	('tumours', 'Disease', 'MESH:D009369', (89, 96))	('tumours', 'Disease', (89, 96))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumours', 'Disease', (13, 20))	('ERCC2', 'Gene', (73, 78))	('C>G mutations', 'Var', (50, 63))	('ERCC2', 'Gene', '2068', (0, 5))	('fewer', 'NegReg', (44, 49))	('ERCC2', 'Gene', (0, 5))
176112	24476821	Seven of 12 mutations in RXRA (retinoid x nuclear receptor alpha) occurred at the same amino acid (five S427F; two S427Y) in the ligand-binding domain.	('S427Y', 'Var', (115, 120))	('S427F', 'Var', (104, 109))	('retinoid x nuclear receptor alpha', 'Gene', (31, 64))	('S427Y', 'Mutation', 'rs1057519958', (115, 120))	('RXRA', 'Gene', '6256', (25, 29))	('binding', 'molecular_function', 'GO:0005488', ('136', '143'))	('RXRA', 'Gene', (25, 29))	('retinoid x nuclear receptor alpha', 'Gene', '6256', (31, 64))	('ligand', 'molecular_function', 'GO:0005488', ('129', '135'))	('S427F', 'Mutation', 'rs1057519958', (104, 109))
176114	24476821	Eleven tumours (8%) had deleterious missense mutations in the Neh2 domain of NFE2L2, a transcription factor that regulates the anti-oxidant program in response to oxidative stress.	('NFE2L2', 'Gene', (77, 83))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))	('tumours', 'Disease', (7, 14))	('tumours', 'Phenotype', 'HP:0002664', (7, 14))	('response to oxidative stress', 'biological_process', 'GO:0006979', ('151', '179'))	('tumours', 'Disease', 'MESH:D009369', (7, 14))	('oxidative stress', 'Phenotype', 'HP:0025464', (163, 179))	('transcription factor', 'molecular_function', 'GO:0000981', ('87', '107'))	('missense mutations in', 'Var', (36, 57))	('NFE2L2', 'Gene', '4780', (77, 83))
176116	24476821	Furthermore, nine samples had mutations in redox regulator TXNIP (5 of them inactivating) and were mutually exclusive of samples with NFE2L2 mutations, providing another mechanism for dysregulation of redox metabolism.	('NFE2L2', 'Gene', '4780', (134, 140))	('metabolism', 'biological_process', 'GO:0008152', ('207', '217'))	('NFE2L2', 'Gene', (134, 140))	('mutations', 'Var', (30, 39))	('TXNIP', 'Gene', '10628', (59, 64))	('TXNIP', 'Gene', (59, 64))
176118	24476821	Group A (red), labeled as 'focally-amplified', is highly enriched in focal SCNAs in several genes, as well as mutations in MLL2 (Fig.	('MLL2', 'Gene', '8085', (123, 127))	('focal SCNAs', 'Disease', (69, 80))	('MLL2', 'Gene', (123, 127))	('mutations', 'Var', (110, 119))
176121	24476821	Group C (green), labeled as 'TP53/cell-cycle-mutant', shows TP53 mutations in nearly all samples, as well as enrichment with RB1 mutations and amplifications of E2F3 and CCNE1 (Fig.	('E2F3', 'Gene', '1871', (161, 165))	('amplifications', 'Var', (143, 157))	('mutations', 'Var', (129, 138))	('RB1', 'Gene', (125, 128))	('cell-cycle', 'biological_process', 'GO:0007049', ('34', '44'))	('TP53', 'Gene', '7157', (29, 33))	('RB1', 'Gene', '5925', (125, 128))	('TP53', 'Gene', (29, 33))	('TP53', 'Gene', '7157', (60, 64))	('E2F3', 'Gene', (161, 165))	('CCNE1', 'Gene', '898', (170, 175))	('CCNE1', 'Gene', (170, 175))	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
176128	24476821	Three of them had previously been identified as mutated in urothelial cancers, but mutation of MLL2, which encodes a histone H3 lysine 4 (H3K4) methyltransferase, is a novel finding.	('MLL2', 'Gene', '8085', (95, 99))	('urothelial cancers', 'Disease', (59, 77))	('lysine', 'Chemical', 'MESH:D008239', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutation', 'Var', (83, 91))	('MLL2', 'Gene', (95, 99))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('urothelial cancers', 'Disease', 'MESH:D014523', (59, 77))
176130	24476821	Non-silent mutations in chromatin regulatory genes overall were significantly enriched in bladder cancer in comparison with the entire exome, in contrast with all other epithelial cancers studied to date in the TCGA project (Supplementary Table S2.10).	('bladder cancer', 'Disease', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('epithelial cancers', 'Disease', (169, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('Non-silent mutations', 'Var', (0, 20))	('chromatin', 'cellular_component', 'GO:0000785', ('24', '33'))	('chromatin regulatory genes', 'Gene', (24, 50))	('epithelial cancers', 'Disease', 'MESH:D000077216', (169, 187))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))
176131	24476821	Mutations in MLL2 and KDM6A (the latter encoding a histone H3 lysine 27 (H3K27) demethylase) were mutually exclusive (Supplementary Fig.	('KDM6A', 'Gene', '7403', (22, 27))	('MLL2', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('KDM6A', 'Gene', (22, 27))	('lysine', 'Chemical', 'MESH:D008239', (62, 68))	('MLL2', 'Gene', '8085', (13, 17))
176132	24476821	S2.8 and Table S2.8.1), suggesting that mutations in the two genes have redundant downstream effects on carcinogenesis or that the combined loss is synthetically lethal.	('mutations', 'Var', (40, 49))	('effects', 'Reg', (93, 100))	('carcinogenesis', 'Disease', (104, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (104, 118))
176138	24476821	FGFR3-TACC3 fusion, which was recently described in both glioblastoma and bladder cancer, represents a promising therapeutic target.	('fusion', 'Var', (12, 18))	('TACC3', 'Gene', '10460', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (74, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('TACC3', 'Gene', (6, 11))	('glioblastoma and bladder cancer', 'Disease', 'MESH:D001749', (57, 88))	('FGFR3', 'Gene', (0, 5))	('glioblastoma', 'Phenotype', 'HP:0012174', (57, 69))	('FGFR3', 'Gene', '2261', (0, 5))
176139	24476821	The ERBB2 gene was also involved in translocations in four tumours, all with different fusion partners and all confirmed by DNA sequencing, RNA-Seq or both.	('involved in', 'Reg', (24, 35))	('RNA', 'cellular_component', 'GO:0005562', ('140', '143'))	('ERBB2', 'Gene', '2064', (4, 9))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('ERBB2', 'Gene', (4, 9))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('translocations', 'Var', (36, 50))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('tumours', 'Disease', (59, 66))
176150	24476821	Cluster I ('papillary-like') is enriched in tumours with papillary morphology (p=0.0002), FGFR3 mutations (p=0.0007, q=0.02), FGFR3 copy number gain (p=0.04, q=0.1) and elevated FGFR3 expression (p<0.0001) (Fig.	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('FGFR3', 'Gene', (126, 131))	("'papillary-", 'Phenotype', 'HP:0007482', (11, 22))	('expression', 'MPA', (184, 194))	('FGFR3', 'Gene', '2261', (126, 131))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('mutations', 'Var', (96, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('126', '130'))	('gain', 'PosReg', (144, 148))	('elevated', 'PosReg', (169, 177))	('FGFR3', 'Gene', (178, 183))	('papillary morphology', 'Phenotype', 'HP:0007482', (57, 77))	('FGFR3', 'Gene', (90, 95))	('copy number', 'Var', (132, 143))	('FGFR3', 'Gene', '2261', (178, 183))	('tumours', 'Disease', (44, 51))	('FGFR3', 'Gene', '2261', (90, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('178', '182'))
176151	24476821	It includes all three samples with FGFR3-TACC3 fusions.	('TACC3', 'Gene', '10460', (41, 46))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR3', 'Gene', '2261', (35, 40))	('TACC3', 'Gene', (41, 46))	('fusions', 'Var', (47, 54))	('FGFR3', 'Gene', (35, 40))
176153	24476821	They also show lower expression of miR-145 and miR-125b, which have been reported as frequently downregulated in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('miR-125b', 'Var', (47, 55))	('bladder cancer', 'Disease', 'MESH:D001749', (113, 127))	('expression', 'MPA', (21, 31))	('bladder cancer', 'Disease', (113, 127))	('lower', 'NegReg', (15, 20))	('miR-145', 'Gene', (35, 42))	('miR-145', 'Gene', '406937', (35, 42))
176154	24476821	Tumours with FGFR3 alterations, and perhaps other tumours that share the Cluster I expression profile, may respond to inhibitors of FGFR or its downstream targets.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('perhaps other tumours', 'Disease', 'MESH:D009369', (36, 57))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('FGFR', 'molecular_function', 'GO:0005007', ('132', '136'))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('FGFR3', 'Gene', (13, 18))	('alterations', 'Var', (19, 30))	('respond', 'Reg', (107, 114))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('FGFR3', 'Gene', '2261', (13, 18))	('perhaps other tumours', 'Disease', (36, 57))
176166	24476821	When we analyzed the RNA-seq data for transcript splice variation using SpliceSeq (Supplemental Material S11), one finding of interest was an average of 3% PKM1 and 97% PKM2 transcripts in the tumour samples.	('RNA', 'cellular_component', 'GO:0005562', ('21', '24'))	('tumour', 'Disease', (193, 199))	('PKM1', 'Var', (156, 160))	('PKM2', 'Gene', (169, 173))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('tumour', 'Disease', 'MESH:D009369', (193, 199))	('PKM2', 'Gene', '5315', (169, 173))
176169	24476821	Integrated analysis of the mutation and copy-number data revealed three main pathways as frequently dysregulated in bladder cancer: cell cycle regulation (altered in 93% of cases); kinase and PI3K signaling (72%); chromatin remodeling, including mutations/SCNAs in histone modifying genes (89%); and components of the SWI/SNF nucleosome remodeling complex (64%) (Fig.	('chromatin', 'MPA', (214, 223))	('bladder cancer', 'Phenotype', 'HP:0009725', (116, 130))	('altered', 'Reg', (155, 162))	('chromatin', 'cellular_component', 'GO:0000785', ('214', '223'))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('132', '153'))	('bladder cancer', 'Disease', 'MESH:D001749', (116, 130))	('bladder cancer', 'Disease', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('dysregulated', 'Reg', (100, 112))	('nucleosome remodeling complex', 'cellular_component', 'GO:0016585', ('326', '355'))	('PI3K', 'molecular_function', 'GO:0016303', ('192', '196'))	('cell cycle regulation', 'CPA', (132, 153))	('kinase', 'MPA', (181, 187))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('214', '234'))	('mutations/SCNAs', 'Var', (246, 261))	('PI3K signaling', 'biological_process', 'GO:0014065', ('192', '206'))
176171	24476821	Both MYC and MAX showed similar levels of pathway activity, independent of mutations in chromatin genes, suggesting that mutations in histone-modifying genes provide just one mechanism for disruption of the MYC/MAX hub.	('MYC', 'Gene', '4609', (207, 210))	('mutations', 'Var', (121, 130))	('MYC', 'Gene', '4609', (5, 8))	('MYC', 'Gene', (207, 210))	('chromatin', 'cellular_component', 'GO:0000785', ('88', '97'))	('MYC', 'Gene', (5, 8))
176172	24476821	In contrast, tumours with chromatin-related mutations showed differential activity of transcription factors FOXA2 and SP1, implicating de-differentiation processes as a result of the mutations.	('de-differentiation processes', 'CPA', (135, 163))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('FOXA2', 'Gene', '3170', (108, 113))	('chromatin', 'cellular_component', 'GO:0000785', ('26', '35'))	('mutations', 'Var', (183, 192))	('SP1', 'Gene', (118, 121))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('transcription', 'biological_process', 'GO:0006351', ('86', '99'))	('FOXA2', 'Gene', (108, 113))	('activity', 'MPA', (74, 82))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumours', 'Disease', (13, 20))	('mutations', 'Var', (44, 53))
176173	24476821	Our network analysis also identified HSP90AA1 as a critical signaling hub, suggesting that inhibitors of HSP90 may have therapeutic value in urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('inhibitors', 'Var', (91, 101))	('urothelial carcinoma', 'Disease', (141, 161))	('HSP90AA1', 'Gene', (37, 45))	('HSP90AA1', 'Gene', '3320', (37, 45))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (141, 161))	('HSP90', 'Protein', (105, 110))	('signaling', 'biological_process', 'GO:0023052', ('60', '69'))
176174	24476821	Integrated analysis also identified mutations, copy number alterations or RNA expression changes affecting the PI3-kinase/AKT/mTOR pathway in 42% of the tumours (Fig.5a).	('tumours', 'Disease', 'MESH:D009369', (153, 160))	('tumours', 'Disease', (153, 160))	('copy number alterations', 'Var', (47, 70))	('mutations', 'Var', (36, 45))	('RNA', 'cellular_component', 'GO:0005562', ('74', '77'))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('AKT', 'Gene', '207', (122, 125))	('RNA expression', 'Gene', (74, 88))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('affecting', 'Reg', (97, 106))	('mTOR', 'Gene', (126, 130))	('mTOR', 'Gene', '2475', (126, 130))	('AKT', 'Gene', (122, 125))
176175	24476821	Included were activating point mutations in PIK3CA (17%; potentially responsive to PI3K inhibitors), mutation or deletion of TSC1 or TSC2 (9%; potentially responsive to mTOR inhibitors) and overexpression of AKT3 (10%; potentially responsive to AKT inhibitors).	('TSC1', 'Gene', (125, 129))	('AKT', 'Gene', (245, 248))	('TSC2', 'Gene', (133, 137))	('TSC1', 'Gene', '7248', (125, 129))	('PIK3CA', 'Gene', (44, 50))	('AKT', 'Gene', '207', (208, 211))	('mTOR', 'Gene', (169, 173))	('AKT', 'Gene', '207', (245, 248))	('mTOR', 'Gene', '2475', (169, 173))	('point mutations', 'Var', (25, 40))	('activating', 'PosReg', (14, 24))	('AKT3', 'Gene', '10000', (208, 212))	('overexpression', 'PosReg', (190, 204))	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('deletion', 'Var', (113, 121))	('PIK3CA', 'Gene', '5290', (44, 50))	('AKT3', 'Gene', (208, 212))	('AKT', 'Gene', (208, 211))	('TSC2', 'Gene', '7249', (133, 137))	('mutation', 'Var', (101, 109))
176176	24476821	We also observed mutations, genomic amplifications or gene fusions that affect the RTK/RAS pathway in 44% of the tumours (Fig.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('affect', 'Reg', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('RTK/RAS pathway', 'Pathway', (83, 98))	('tumours', 'Disease', 'MESH:D009369', (113, 120))	('genomic amplifications', 'Var', (28, 50))	('tumours', 'Disease', (113, 120))	('gene fusions', 'Var', (54, 66))
176177	24476821	Included were events that can activate FGFR3 (17%; potentially responsive to FGFR inhibitors or antibodies), amplification of EGFR (9%; potentially responsive to EGFR antibodies or inhibitors), mutations of ERBB3 (6%; potentially sensitive to ERBB kinase inhibitors) and mutation or amplification of ERBB2 (9%; potentially sensitive to ERBB2 kinase inhibitors or antibodies).	('ERBB2', 'Gene', '2064', (336, 341))	('EGFR', 'Gene', (162, 166))	('amplification', 'Var', (283, 296))	('amplification', 'Var', (109, 122))	('FGFR3', 'Gene', '2261', (39, 44))	('EGFR', 'Gene', '1956', (126, 130))	('activate', 'PosReg', (30, 38))	('FGFR', 'molecular_function', 'GO:0005007', ('39', '43'))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('mutation', 'Var', (271, 279))	('ERBB2', 'Gene', (300, 305))	('ERBB3', 'Gene', (207, 212))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'molecular_function', 'GO:0005006', ('162', '166'))	('ERBB2', 'Gene', '2064', (300, 305))	('EGFR', 'Gene', (126, 130))	('ERBB2', 'Gene', (336, 341))	('mutations', 'Var', (194, 203))	('ERBB3', 'Gene', '2065', (207, 212))	('FGFR3', 'Gene', (39, 44))
176178	24476821	ERBB3 mutations in bladder cancer have been noted previously, but statistically significant mutation of ERBB2 in bladder cancer has not been reported.	('bladder cancer', 'Disease', 'MESH:D001749', (19, 33))	('ERBB3', 'Gene', (0, 5))	('ERBB3', 'Gene', '2065', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('bladder cancer', 'Disease', (19, 33))	('bladder cancer', 'Disease', 'MESH:D001749', (113, 127))	('bladder cancer', 'Disease', (113, 127))	('ERBB2', 'Gene', '2064', (104, 109))	('bladder cancer', 'Phenotype', 'HP:0009725', (19, 33))	('ERBB2', 'Gene', (104, 109))	('mutations', 'Var', (6, 15))
176179	24476821	Interestingly, ERBB2 alterations were approximately as frequent in this study as in TCGA breast cancers, but with fewer amplifications and more mutations (Fig.	('ERBB2', 'Gene', (15, 20))	('breast cancers', 'Disease', 'MESH:D001943', (89, 103))	('A breast cancer', 'Disease', 'MESH:D001943', (87, 102))	('breast cancers', 'Disease', (89, 103))	('ERBB2', 'Gene', '2064', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('A breast cancer', 'Disease', (87, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('amplifications', 'MPA', (120, 134))	('mutations', 'Reg', (144, 153))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('alterations', 'Var', (21, 32))	('breast cancers', 'Phenotype', 'HP:0003002', (89, 103))
176185	24476821	FGFR3 mutation is a common feature of low-grade non-invasive papillary urothelial bladder cancer, but it occurs at a much lower frequency in high-grade invasive bladder cancer.	('invasive bladder cancer', 'Disease', (152, 175))	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (152, 175))	('papillary urothelial bladder cancer', 'Disease', 'MESH:D001749', (61, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('bladder cancer', 'Phenotype', 'HP:0009725', (161, 175))	('FGFR3', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('papillary urothelial bladder cancer', 'Disease', (61, 96))	('invasive bladder', 'Phenotype', 'HP:0100645', (152, 168))	('FGFR3', 'Gene', '2261', (0, 5))
176193	24476821	Overall, the bladder cancers showed a mutational spectrum highly enriched with mutations in chromatin regulatory genes (Supplementary Table S2.10).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('chromatin regulatory genes', 'Gene', (92, 118))	('bladder cancers', 'Disease', 'MESH:D001749', (13, 28))	('bladder cancer', 'Phenotype', 'HP:0009725', (13, 27))	('bladder cancers', 'Disease', (13, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('bladder cancers', 'Phenotype', 'HP:0009725', (13, 28))	('mutations', 'Var', (79, 88))	('chromatin', 'cellular_component', 'GO:0000785', ('92', '101'))
176194	24476821	Further, integrated network analyses revealed a profound impact of those mutations on the activity levels of various transcription factors and pathways implicated in cancer.	('impact', 'Reg', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', (166, 172))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('activity levels', 'MPA', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('mutations', 'Var', (73, 82))
176195	24476821	Recent development of drugs that bind competitively to acetyl-lysine recognition motifs (i.e., bromodomains) might prove useful for treatment of the subset of bladder tumours that have abnormalities in chromatin-modifyingenzymes.	('bladder tumours', 'Disease', (159, 174))	('acetyl-lysine', 'Chemical', '-', (55, 68))	('bladder tumours', 'Disease', 'MESH:D001749', (159, 174))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('chromatin', 'cellular_component', 'GO:0000785', ('202', '211'))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('abnormalities', 'Var', (185, 198))
176208	23084634	Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been linked to oncogenesis in conventional bladder cancer.	('conventional bladder cancer', 'Disease', (100, 127))	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('oncogenesis', 'biological_process', 'GO:0007048', ('85', '96'))	('oncogenesis', 'Disease', (85, 96))	('linked', 'Reg', (75, 81))
176213	23084634	We found dysregulation of mTOR pathway members in urinary bladder plasmacytoid urothelial carcinoma, suggesting that the use of mTOR pathway inhibitors might be beneficial for patients with this aggressive tumor.	('patients', 'Species', '9606', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('mTOR pathway', 'Pathway', (26, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('patient', 'Species', '9606', (176, 183))	('dysregulation', 'Var', (9, 22))	('urinary bladder plasmacytoid urothelial carcinoma', 'Disease', (50, 99))
176217	23084634	Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been linked to oncogenesis in several malignancies, including conventional bladder cancer.	('Dysregulation', 'Var', (0, 13))	('oncogenesis', 'biological_process', 'GO:0007048', ('85', '96'))	('malignancies', 'Disease', 'MESH:D009369', (108, 120))	('conventional bladder cancer', 'Disease', (132, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('linked', 'Reg', (75, 81))	('malignancies', 'Disease', (108, 120))
176232	23084634	found TP53 mutations in 9 of 31 plasmacytoid urothelial carcinomas (29%) but illustrated lack of FGFR3 and PI3KCA mutations in plasmacytoid urothelial carcinoma.	('mutations', 'Var', (11, 20))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('urothelial carcinomas', 'Disease', (45, 66))	('FGFR3', 'Gene', '2261', (97, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('97', '101'))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (45, 66))	('FGFR3', 'Gene', (97, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
176264	33643901	One explanation may be that tumor cells physically absorb and neutralize ENO1 antibodies expressed and secreted on the surface to reduce circulating levels.	('reduce', 'NegReg', (130, 136))	('tumor', 'Disease', (28, 33))	('circulating levels', 'MPA', (137, 155))	('neutralize', 'Var', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('antibodies', 'Protein', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('ENO1', 'Gene', (73, 77))	('ENO1', 'Gene', '2023', (73, 77))
176275	33643901	In this study, the cBio Cancer Genomics Portal (; accessed by April 30, 2020), which is a web tool for mutation analysis and visualization through TCGA cancer genomics profiles, was used for mutation analysis of ENO1.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Cancer', 'Disease', (24, 30))	('Cancer', 'Disease', 'MESH:D009369', (24, 30))	('Cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ENO1', 'Gene', (212, 216))	('ENO1', 'Gene', '2023', (212, 216))	('mutation', 'Var', (191, 199))
176290	33643901	The highest ENO1 expression was found in EBV-transformed lymphocytes, whereas the lowest was observed in the left ventricle of the heart.	('EBV-transformed', 'Var', (41, 56))	('ENO1', 'Gene', (12, 16))	('expression', 'MPA', (17, 27))	('ENO1', 'Gene', '2023', (12, 16))	('highest', 'PosReg', (4, 11))
176297	33643901	The expression of ENO1 was significantly associated with the prognosis of eight types of cancers, including HNSC (HR = 1.32, P = 0.04), CESC (HR = 1.47, P = 0.04), BLCA (HR = 1.23, P = 0.04), LUAD (HR = 1.36, P = 0.01), SARC (HR = 1.36, P = 0.00), PAAD (HR = 1.65, P = 0.00), KICH (HR = 4.60, P = 0.00), and LIHC (HR = 1.63, P = 0.00), suggesting that high ENO1 expression might be an independent risk factor for these cancers (all HR > 1.00, P < 0.05).	('associated', 'Reg', (41, 51))	('high', 'Var', (352, 356))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', (89, 96))	('KICH', 'Disease', (276, 280))	('LUAD', 'Disease', (192, 196))	('cancers', 'Disease', 'MESH:D009369', (419, 426))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('CESC', 'Disease', (136, 140))	('BLCA', 'Disease', (164, 168))	('ENO1', 'Gene', (18, 22))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Phenotype', 'HP:0002664', (419, 426))	('ENO1', 'Gene', (357, 361))	('cancers', 'Disease', (419, 426))	('ENO1', 'Gene', '2023', (18, 22))	('KICH', 'Disease', 'None', (276, 280))	('HNSC', 'Disease', (108, 112))	('SARC', 'Disease', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (419, 425))	('ENO1', 'Gene', '2023', (357, 361))	('LUAD', 'Phenotype', 'HP:0030078', (192, 196))
176299	33643901	High ENO1 expression was significantly associated with worse OS in CESC (log-rank P = 0.04), BLCA (log-rank P = 0.03), KICH (log-rank P = 0.01), LIHC (log-rank P = 0.00), and SARC (log-rank P = 0.04), and worse DFS in KICH (log-rank P = 0.03) and SARC (log-rank P = 0.07).	('SARC', 'Disease', (175, 179))	('LIHC', 'Disease', (145, 149))	('KICH', 'Disease', 'None', (218, 222))	('High', 'Var', (0, 4))	('ENO1', 'Gene', '2023', (5, 9))	('CESC', 'Disease', (67, 71))	('ENO1', 'Gene', (5, 9))	('expression', 'MPA', (10, 20))	('KICH', 'Disease', 'None', (119, 123))	('KICH', 'Disease', (218, 222))	('SARC', 'Disease', (247, 251))	('KICH', 'Disease', (119, 123))	('BLCA', 'Disease', (93, 97))
176304	33643901	Evidently, 195 samples in the altered group and 10,772 samples in the unaltered group were included for ENO1 mutation analysis.	('ENO1', 'Gene', '2023', (104, 108))	('ENO1', 'Gene', (104, 108))	('mutation', 'Var', (109, 117))
176305	33643901	The results demonstrated that ENO1 was altered in 1.8% of all the included samples, including inframe mutation, missense mutation, truncating mutation, fusion, amplification, and deep deletion ( Figure 6 ).	('truncating', 'MPA', (131, 141))	('amplification', 'Var', (160, 173))	('ENO1', 'Gene', (30, 34))	('deep deletion', 'Var', (179, 192))	('ENO1', 'Gene', '2023', (30, 34))	('altered', 'Reg', (39, 46))	('fusion', 'Var', (152, 158))	('missense mutation', 'Var', (112, 129))
176306	33643901	Furthermore, the prognostic significance of ENO1 mutation was estimated via Kaplan-Meier method.	('ENO1', 'Gene', '2023', (44, 48))	('mutation', 'Var', (49, 57))	('ENO1', 'Gene', (44, 48))
176338	33643901	These findings are consistent with a previous study showing that high ENO1 expression is significantly correlated with DNA replication and cell cycle in hepatocellular carcinoma.	('DNA replication', 'CPA', (119, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('DNA replication', 'biological_process', 'GO:0006260', ('119', '134'))	('ENO1', 'Gene', (70, 74))	('ENO1', 'Gene', '2023', (70, 74))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (153, 177))	('cell cycle', 'CPA', (139, 149))	('high', 'Var', (65, 69))	('hepatocellular carcinoma', 'Disease', (153, 177))	('correlated', 'Reg', (103, 113))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (153, 177))	('cell cycle', 'biological_process', 'GO:0007049', ('139', '149'))	('expression', 'MPA', (75, 85))
176346	33643901	Furthermore, the knockdown of ENO1 has been shown to promote apoptosis and induce the arrest of cell cycle in gastric cancer cells.	('gastric cancer', 'Disease', (110, 124))	('cell cycle', 'biological_process', 'GO:0007049', ('96', '106'))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('apoptosis', 'CPA', (61, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('arrest', 'Disease', (86, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ENO1', 'Gene', (30, 34))	('ENO1', 'Gene', '2023', (30, 34))	('knockdown', 'Var', (17, 26))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('induce', 'Reg', (75, 81))	('promote', 'PosReg', (53, 60))
176351	33643901	Additionally, mutation of ENO1 was analysis, for it was proved that mutation could affect tumor progression; however, ENO1 mutation (1.8%) did not impact on prognosis in this study.	('affect', 'Reg', (83, 89))	('mutation', 'Var', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ENO1', 'Gene', (118, 122))	('tumor', 'Disease', (90, 95))	('ENO1', 'Gene', '2023', (118, 122))	('ENO1', 'Gene', (26, 30))	('ENO1', 'Gene', '2023', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
176355	33643901	In consonance with our results, ENO1 expression was higher in late stages (stages III and IV), particularly that in KICH ( Figure 5E ), meanwhile, high ENO1 expression was significantly associated with worse OS in KICH ( Figure 4I ).	('worse OS', 'Disease', (202, 210))	('expression', 'MPA', (157, 167))	('ENO1', 'Gene', (152, 156))	('ENO1', 'Gene', '2023', (32, 36))	('ENO1', 'Gene', '2023', (152, 156))	('KICH', 'Disease', 'None', (214, 218))	('ENO1', 'Gene', (32, 36))	('KICH', 'Disease', 'None', (116, 120))	('high', 'Var', (147, 151))	('associated', 'Reg', (186, 196))	('higher', 'PosReg', (52, 58))	('KICH', 'Disease', (214, 218))	('expression', 'MPA', (37, 47))	('KICH', 'Disease', (116, 120))
176380	32790011	Fibroblast Growth Factor Receptor (FGFR) Inhibitors in Urothelial Cancer Dysregulated fibroblast growth factor receptor (FGFR) signaling is associated with several cancers, including urothelial carcinoma.	('urothelial carcinoma', 'Disease', (183, 203))	('associated', 'Reg', (140, 150))	('Dysregulated', 'Var', (73, 85))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR', 'molecular_function', 'GO:0005007', ('121', '125'))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (183, 203))	('Fibroblast Growth Factor', 'molecular_function', 'GO:0005104', ('0', '24'))	('cancers', 'Disease', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('Cancer', 'Disease', (66, 72))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('86', '110'))	('Cancer', 'Disease', 'MESH:D009369', (66, 72))
176381	32790011	Preclinical studies with FGFR inhibitors have shown significant antitumor activity, which has led to clinical evaluation of multiple FGFR inhibitors.	('tumor', 'Disease', (68, 73))	('FGFR', 'Gene', (25, 29))	('inhibitors', 'Var', (30, 40))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('FGFR', 'molecular_function', 'GO:0005007', ('133', '137'))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
176382	32790011	Recently, erdafitinib was approved by the U.S. Food and Drug Administration for advanced urothelial carcinoma with FGFR gene alterations as the first molecularly targeted therapy.	('FGFR', 'molecular_function', 'GO:0005007', ('115', '119'))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (89, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('FGFR gene', 'Gene', (115, 124))	('erdafitinib', 'Chemical', 'MESH:C000604580', (10, 21))	('alterations', 'Var', (125, 136))	('urothelial carcinoma', 'Disease', (89, 109))
176383	32790011	Dysregulated fibroblast growth factor receptor (FGFR) signaling is associated with several cancers, including urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (110, 130))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('FGFR', 'Gene', (48, 52))	('associated', 'Reg', (67, 77))	('Dysregulated', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('13', '37'))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('urothelial carcinoma', 'Disease', (110, 130))
176384	32790011	Most recently, erdafitinib was approved by the U.S. Food and Drug Administration for advanced urothelial carcinoma with FGFR gene alterations as the first molecularly targeted therapy.	('urothelial carcinoma', 'Disease', (94, 114))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (94, 114))	('FGFR gene', 'Gene', (120, 129))	('alterations', 'Var', (130, 141))	('FGFR', 'molecular_function', 'GO:0005007', ('120', '124'))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('erdafitinib', 'Chemical', 'MESH:C000604580', (15, 26))
176385	32790011	Focusing on urothelial malignancies, this review summarizes the oncogenic signaling of FGFR alterations, clinical trials of FGFR inhibitors, and resistance patterns.	('FGFR', 'molecular_function', 'GO:0005007', ('124', '128'))	('urothelial malignancies', 'Disease', 'MESH:D009369', (12, 35))	('FGFR', 'Gene', (87, 91))	('alterations', 'Var', (92, 103))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('urothelial malignancies', 'Disease', (12, 35))	('signaling', 'biological_process', 'GO:0023052', ('74', '83'))
176397	32790011	The common genomic alterations leading to FGFR activation include point mutations, gene amplification, gene rearrangements, and fusions [9].	('fusions', 'Var', (128, 135))	('gene amplification', 'Var', (83, 101))	('men', 'Species', '9606', (117, 120))	('activation', 'PosReg', (47, 57))	('FGFR', 'Gene', (42, 46))	('gene rearrangements', 'Var', (103, 122))	('point mutations', 'Var', (66, 81))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))
176398	32790011	In urothelial carcinoma, FGFR3 alterations have been documented in nearly 60% of low-grade noninvasive papillary urothelial carcinoma of the bladder [11] and 26.7% of overall urothelial carcinoma [12].	('papillary urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (103, 148))	('alterations', 'Var', (31, 42))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (113, 148))	('papillary urothelial carcinoma of the bladder', 'Disease', (103, 148))	('FGFR3', 'Gene', '2261', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (103, 133))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('urothelial carcinoma', 'Disease', (3, 23))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (175, 195))	('urothelial carcinoma', 'Disease', (175, 195))	('FGFR3', 'Gene', (25, 30))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (113, 133))	('men', 'Species', '9606', (57, 60))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (3, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
176400	32790011	Of the FGFR3 alterations seen in patients with urothelial cancer, base substitutions are most common (84%) [14].	('urothelial cancer', 'Disease', (47, 64))	('FGFR3', 'Gene', '2261', (7, 12))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('patients', 'Species', '9606', (33, 41))	('common', 'Reg', (94, 100))	('FGFR3', 'Gene', (7, 12))	('urothelial cancer', 'Disease', 'MESH:D014523', (47, 64))	('alterations', 'Var', (13, 24))	('base substitutions', 'Var', (66, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('7', '11'))
176401	32790011	S249C, the most common mutation in bladder urothelial cancer, affects the extracellular domain, stabilizing receptor dimerization, and eventually leads to downstream signal transduction [11, 15].	('stabilizing receptor dimerization', 'MPA', (96, 129))	('S249C', 'Var', (0, 5))	('S249C', 'SUBSTITUTION', 'None', (0, 5))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (35, 60))	('signal transduction', 'biological_process', 'GO:0007165', ('166', '185'))	('leads to', 'Reg', (146, 154))	('affects', 'Reg', (62, 69))	('extracellular', 'cellular_component', 'GO:0005576', ('74', '87'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('bladder urothelial cancer', 'Disease', (35, 60))	('extracellular domain', 'MPA', (74, 94))
176402	32790011	Other notable mutations commonly observed are R248C, Y375C, G372C, and N542S [16, 17, 18].	('Y375C', 'Var', (53, 58))	('R248C', 'Var', (46, 51))	('N542S', 'Var', (71, 76))	('G372C', 'Var', (60, 65))	('Y375C', 'SUBSTITUTION', 'None', (53, 58))	('R248C', 'SUBSTITUTION', 'None', (46, 51))	('G372C', 'SUBSTITUTION', 'None', (60, 65))	('N542S', 'SUBSTITUTION', 'None', (71, 76))
176407	32790011	The presence of these carcinogenic, activating gene alterations provide a novel therapeutic opportunity for the evaluation of selective FGFR inhibitors in urothelial malignancies (Table 1).	('alterations', 'Var', (52, 63))	('urothelial malignancies', 'Disease', 'MESH:D009369', (155, 178))	('FGFR', 'Gene', (136, 140))	('carcinogenic', 'Disease', 'MESH:D063646', (22, 34))	('carcinogenic', 'Disease', (22, 34))	('FGFR', 'molecular_function', 'GO:0005007', ('136', '140'))	('urothelial malignancies', 'Disease', (155, 178))	('activating', 'PosReg', (36, 46))
176410	32790011	In the dose-expansion phase of the study, patients were selected based on FGFR gene alterations, of whom 9.1% had urothelial cancer.	('urothelial cancer', 'Disease', 'MESH:D014523', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('alterations', 'Var', (84, 95))	('urothelial cancer', 'Disease', (114, 131))	('patients', 'Species', '9606', (42, 50))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))	('FGFR', 'Gene', (74, 78))
176413	32790011	Based on the phase I trial, Pal and coworkers studied infigratinib in 67 patients with metastatic urothelial carcinoma (UC) and prespecified FGFR3 alterations [20].	('FGFR3', 'Gene', '2261', (141, 146))	('urothelial carcinoma', 'Disease', (98, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('FGFR3', 'Gene', (141, 146))	('infigratinib', 'Chemical', 'MESH:C568950', (54, 66))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (98, 118))	('Pal', 'molecular_function', 'GO:0004598', ('28', '31'))	('FGFR', 'molecular_function', 'GO:0005007', ('141', '145'))	('patients', 'Species', '9606', (73, 81))	('alterations', 'Var', (147, 158))
176417	32790011	With the caveat of a small cohort, this differential response was attributed to a different FGFR mutation pattern compared with bladder UC.	('FGFR', 'Gene', (92, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('bladder UC', 'Disease', 'MESH:D001745', (128, 138))	('mutation', 'Var', (97, 105))	('bladder UC', 'Disease', (128, 138))
176419	32790011	Cell-free DNA testing for FGFR gene alterations on therapy revealed four patients developed FGFR3 gatekeeper resistance mutations, such as V443L, V443M, and L496V.	('FGFR3', 'Gene', (92, 97))	('V443M', 'Var', (146, 151))	('L496V', 'SUBSTITUTION', 'None', (157, 162))	('gatekeeper', 'Species', '111938', (98, 108))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('patients', 'Species', '9606', (73, 81))	('V443M', 'SUBSTITUTION', 'None', (146, 151))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('V443L', 'SUBSTITUTION', 'None', (139, 144))	('FGFR3', 'Gene', '2261', (92, 97))	('V443L', 'Var', (139, 144))	('L496V', 'Var', (157, 162))
176425	32790011	The antitumor activity of erdafitinib was evaluated in a phase II clinical trial in patients with unresectable or metastatic urothelial cancer harboring a prespecified FGFR3 mutation or FGFR2/3 fusion [22].	('FGFR3', 'Gene', '2261', (168, 173))	('urothelial cancer', 'Disease', 'MESH:D014523', (125, 142))	('patients', 'Species', '9606', (84, 92))	('mutation', 'Var', (174, 182))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('FGFR2', 'Gene', (186, 191))	('FGFR2', 'Gene', '2263', (186, 191))	('FGFR3', 'Gene', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('FGFR', 'molecular_function', 'GO:0005007', ('168', '172'))	('urothelial cancer', 'Disease', (125, 142))	('tumor', 'Disease', (8, 13))	('erdafitinib', 'Chemical', 'MESH:C000604580', (26, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('186', '190'))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
176429	32790011	Thirty-six (49%) of 74 patients with FGFR3 mutations had a response, and 4 patients (16%) of 25 with FGFR 2/3 fusion had a response.	('FGFR3', 'Gene', (37, 42))	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (75, 83))	('mutations', 'Var', (43, 52))	('FGFR3', 'Gene', '2261', (37, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))
176435	32790011	Based on this efficacy data, the U.S. FDA granted accelerated approval for erdafitinib in adult patients with metastatic UC with susceptible FGFR3 or FGFR2 genetic alterations [24].	('FGFR3', 'Gene', '2261', (141, 146))	('FGFR2', 'Gene', '2263', (150, 155))	('metastatic UC', 'Disease', (110, 123))	('genetic alterations', 'Var', (156, 175))	('FGFR3', 'Gene', (141, 146))	('patients', 'Species', '9606', (96, 104))	('FGFR2', 'Gene', (150, 155))	('FGFR', 'molecular_function', 'GO:0005007', ('141', '145'))	('erdafitinib', 'Chemical', 'MESH:C000604580', (75, 86))	('FGFR', 'molecular_function', 'GO:0005007', ('150', '154'))
176436	32790011	In a phase Ib/II clinical trial (NORSE study), the safety and antitumor activity of erdafitinib in combination with cetrelimab (an IgG4 anti-programmed cell death protein 1 [PD-1] inhibitor) was evaluated in patients with metastatic urothelial harboring susceptible FGFR2/3 alternations [25].	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('patients', 'Species', '9606', (208, 216))	('tumor', 'Disease', (66, 71))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('PD-1', 'Gene', (174, 178))	('alternations', 'Var', (274, 286))	('PD-1', 'Gene', '5133', (174, 178))	('cetrelimab', 'Chemical', '-', (116, 126))	('programmed cell death protein 1', 'Gene', '5133', (141, 172))	('IgG4', 'cellular_component', 'GO:0071735', ('131', '135'))	('programmed cell death', 'biological_process', 'GO:0012501', ('141', '162'))	('FGFR', 'molecular_function', 'GO:0005007', ('266', '270'))	('FGFR2', 'Gene', (266, 271))	('FGFR2', 'Gene', '2263', (266, 271))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('erdafitinib', 'Chemical', 'MESH:C000604580', (84, 95))	('programmed cell death protein 1', 'Gene', (141, 172))
176445	32790011	Sixty-four patients with FGFR3 mutation or fusion were assigned to cohort A, and 36 patients with other FGF/FGFR genetic mutations were assigned to cohort B and received pemigatinib.	('FGFR3', 'Gene', '2261', (25, 30))	('pemigatinib', 'Chemical', '-', (170, 181))	('patients', 'Species', '9606', (84, 92))	('mutation', 'Var', (31, 39))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('FGFR3', 'Gene', (25, 30))	('patients', 'Species', '9606', (11, 19))	('fusion', 'Var', (43, 49))
176451	32790011	Preclinical studies showed response to rogaratinib correlated with high FGFR mRNA expression in tumors [27].	('high', 'Var', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('mRNA', 'Protein', (77, 81))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('FGFR', 'Gene', (72, 76))
176460	32790011	Patients were selected based on either FGFR1,3 mRNA overexpression and/or FGFR-3-activating mutations or translocations.	('FGFR1', 'Gene', (39, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('39', '43'))	('FGFR1', 'Gene', '2260', (39, 44))	('mutations', 'Var', (92, 101))	('Patients', 'Species', '9606', (0, 8))	('translocations', 'Var', (105, 119))	('FGFR-3', 'Gene', (74, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))	('FGFR-3', 'Gene', '2261', (74, 80))
176462	32790011	On exploratory analysis in patients with FGFR3 mutations or fusion, ORR was 52.4% for rogaratinib, and with chemotherapy it was 26.7%.	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('FGFR3', 'Gene', '2261', (41, 46))	('mutations', 'Var', (47, 56))	('patients', 'Species', '9606', (27, 35))	('FGFR3', 'Gene', (41, 46))
176468	32790011	FIDES-02 clinical trial is currently evaluating the safety and antitumor activity of single-agent derazantinib or in combination with atezolizumab in patients with urothelial cancer and FGFR aberrations [35].	('atezolizumab', 'Chemical', 'MESH:C000594389', (134, 146))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('aberrations', 'Var', (191, 202))	('urothelial cancer', 'Disease', (164, 181))	('derazantinib', 'Chemical', 'MESH:C000621805', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('patients', 'Species', '9606', (150, 158))	('urothelial cancer', 'Disease', 'MESH:D014523', (164, 181))	('tumor', 'Disease', (67, 72))	('FGFR', 'molecular_function', 'GO:0005007', ('186', '190'))	('FGFR', 'Gene', (186, 190))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
176470	32790011	Meric-Bernstam and colleagues presented preliminary results of an ongoing phase I study in patients with solid tumors and FGFR aberrations [37].	('patients', 'Species', '9606', (91, 99))	('solid tumors', 'Disease', 'MESH:D009369', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('solid tumors', 'Disease', (105, 117))	('aberrations', 'Var', (127, 138))	('FGFR', 'molecular_function', 'GO:0005007', ('122', '126'))
176477	32790011	FGFR1 amplification was most common (40%), followed by FGFR fusion (21%), FGFR2 mutation (12%), and FGFR3 mutation (17%).	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', '2261', (100, 105))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('FGFR2', 'Gene', (74, 79))	('FGFR2', 'Gene', '2263', (74, 79))	('FGFR fusion', 'Gene', (55, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('FGFR3', 'Gene', (100, 105))	('amplification', 'Var', (6, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('100', '104'))	('mutation', 'Var', (80, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))
176485	32790011	Several mechanisms are involved in resistance to FGFR inhibitors and can be classified into three main categories: activation of bypass signaling pathways, alternative or secondary FGFR mutations, and intratumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('activation', 'PosReg', (115, 125))	('bypass signaling pathways', 'Pathway', (129, 154))	('mutations', 'Var', (186, 195))	('FGFR', 'Gene', (181, 185))	('tumor', 'Disease', (206, 211))	('FGFR', 'molecular_function', 'GO:0005007', ('181', '185'))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('signaling', 'biological_process', 'GO:0023052', ('136', '145'))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
176488	32790011	In a study by Herra and colleagues on urothelial tumor cells harboring FGFR3 S249C mutation, cells showed upregulation of EGFR signaling and downregulation of FGFR3 after exposure to PD173074 and gefitinib [34].	('FGFR3', 'Gene', (71, 76))	('S249C', 'SUBSTITUTION', 'None', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('EGFR', 'molecular_function', 'GO:0005006', ('122', '126'))	('FGFR3', 'Gene', '2261', (159, 164))	('downregulation', 'NegReg', (141, 155))	('FGFR3', 'Gene', '2261', (71, 76))	('S249C', 'Var', (77, 82))	('EGFR', 'Gene', (122, 126))	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('upregulation', 'PosReg', (106, 118))	('gefitinib', 'Chemical', 'MESH:D000077156', (196, 205))	('urothelial tumor', 'Disease', 'MESH:D001749', (38, 54))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('urothelial tumor', 'Disease', (38, 54))	('PD173074', 'Chemical', 'MESH:C115711', (183, 191))	('EGFR', 'Gene', '1956', (122, 126))	('FGFR3', 'Gene', (159, 164))
176489	32790011	Additionally, cells with FGFR3-TACC3 fusions acquire resistance by activating EGFR/HER3-dependent PI3K-AKT signaling pathways [41, 42].	('FGFR3', 'Gene', (25, 30))	('AKT', 'Gene', '207', (103, 106))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('HER3', 'Gene', (83, 87))	('FGFR3', 'Gene', '2261', (25, 30))	('TACC3', 'Gene', '10460', (31, 36))	('PI3K', 'molecular_function', 'GO:0016303', ('98', '102'))	('HER3', 'Gene', '2065', (83, 87))	('AKT', 'Gene', (103, 106))	('TACC3', 'Gene', (31, 36))	('fusions', 'Var', (37, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('EGFR', 'Gene', '1956', (78, 82))	('activating', 'PosReg', (67, 77))	('EGFR', 'Gene', (78, 82))	('AKT signaling', 'biological_process', 'GO:0043491', ('103', '116'))
176490	32790011	Other mechanisms by which tumor cells develop resistance is by acquiring different mutations that can alter drug binding sites (gatekeeper mutations).	('mutations', 'Var', (83, 92))	('gatekeeper', 'Species', '111938', (128, 138))	('develop', 'PosReg', (38, 45))	('alter', 'Reg', (102, 107))	('drug binding sites', 'MPA', (108, 126))	('resistance', 'MPA', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('drug binding', 'molecular_function', 'GO:0008144', ('108', '120'))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
176491	32790011	FGFR1 V561M, FGFR2 V564F/I, FGFR3 V555M, and FGFR4 V550E/L are all documented mutations that arise de novo or become predominant during treatment [41, 43].	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR4', 'Gene', (45, 50))	('FGFR1', 'Gene', (0, 5))	('V561M', 'SUBSTITUTION', 'None', (6, 11))	('FGFR2', 'Gene', '2263', (13, 18))	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('V564F', 'SUBSTITUTION', 'None', (19, 24))	('men', 'Species', '9606', (71, 74))	('FGFR3', 'Gene', (28, 33))	('V564F', 'Var', (19, 24))	('men', 'Species', '9606', (141, 144))	('FGFR3', 'Gene', '2261', (28, 33))	('V561M', 'Var', (6, 11))	('FGFR1', 'Gene', '2260', (0, 5))	('V555M', 'SUBSTITUTION', 'None', (34, 39))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('V550E', 'SUBSTITUTION', 'None', (51, 56))	('FGFR4', 'Gene', '2264', (45, 50))	('V550E', 'Var', (51, 56))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('FGFR2', 'Gene', (13, 18))	('V555M', 'Var', (34, 39))
176495	32790011	Clinical responses have been most notable with FGFR3 alterations versus FGFR1/2 alterations.	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('FGFR3', 'Gene', (47, 52))	('alterations', 'Var', (53, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('FGFR3', 'Gene', '2261', (47, 52))	('FGFR1', 'Gene', (72, 77))	('FGFR1', 'Gene', '2260', (72, 77))
176500	32790011	The common trend of adverse effects due to the class effect of FGFR inhibitors include hyperphosphatemia, ocular disorders such as dry eye, blurry vision, lacrimation, conjunctivitis, and central serous retinopathy.	('ocular disorders', 'Phenotype', 'HP:0000478', (106, 122))	('FGFR', 'Gene', (63, 67))	('hyperphosphatemia', 'Disease', (87, 104))	('conjunctivitis', 'Disease', 'MESH:D003231', (168, 182))	('vision', 'biological_process', 'GO:0007601', ('147', '153'))	('hyperphosphatemia', 'Phenotype', 'HP:0002905', (87, 104))	('dry eye', 'Disease', (131, 138))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('central serous retinopathy', 'Phenotype', 'HP:0025567', (188, 214))	('blurry vision', 'Phenotype', 'HP:0000622', (140, 153))	('lacrimation', 'Disease', (155, 166))	('conjunctivitis', 'Phenotype', 'HP:0000509', (168, 182))	('blurry vision', 'Disease', (140, 153))	('serous retinopathy', 'Disease', 'MESH:D056833', (196, 214))	('ocular disorders', 'Disease', 'MESH:D005128', (106, 122))	('dry eye', 'Disease', 'MESH:D015352', (131, 138))	('hyperphosphatemia', 'Disease', 'MESH:D054559', (87, 104))	('retinopathy', 'Phenotype', 'HP:0000488', (203, 214))	('conjunctivitis', 'Disease', (168, 182))	('ocular disorders', 'Disease', (106, 122))	('blurry vision', 'Disease', 'MESH:D015354', (140, 153))	('dry eye', 'Phenotype', 'HP:0001097', (131, 138))	('inhibitors', 'Var', (68, 78))	('serous retinopathy', 'Disease', (196, 214))
176501	32790011	Additionally, gastrointestinal side effects such as diarrhea, stomatitis, dry mouth, and so on and nail changes such as onycholysis, nail dystrophy, and paronychia seem to be commonly associated with FGFR inhibitors.	('stomatitis', 'Disease', 'MESH:D013280', (62, 72))	('dry mouth', 'Disease', 'MESH:D014987', (74, 83))	('stomatitis', 'Disease', (62, 72))	('paronychia', 'Disease', (153, 163))	('dry mouth', 'Disease', (74, 83))	('paronychia', 'Phenotype', 'HP:0001818', (153, 163))	('diarrhea', 'Phenotype', 'HP:0002014', (52, 60))	('FGFR', 'Gene', (200, 204))	('stomatitis', 'Phenotype', 'HP:0010280', (62, 72))	('diarrhea', 'Disease', (52, 60))	('nail dystrophy', 'Phenotype', 'HP:0008404', (133, 147))	('inhibitors', 'Var', (205, 215))	('dry mouth', 'Phenotype', 'HP:0000217', (74, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('200', '204'))	('dystrophy', 'Disease', (138, 147))	('diarrhea', 'Disease', 'MESH:D003967', (52, 60))	('onycholysis', 'Phenotype', 'HP:0001806', (120, 131))	('dystrophy', 'Disease', 'MESH:D008268', (138, 147))	('associated', 'Reg', (184, 194))	('gastrointestinal', 'Disease', (14, 30))	('onycholysis', 'Disease', (120, 131))
176510	32790011	There are conflicting reports about the presence of FGFR alterations and response to checkpoint inhibitors (CPI).	('alterations', 'Var', (57, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('FGFR', 'Gene', (52, 56))	('CPI', 'Chemical', '-', (108, 111))
176511	32790011	It is postulated that FGFR3 alterations, which are enriched in luminal type UC, are associated with lower T-cell infiltration and predict poor response to CPI [50].	('FGFR3', 'Gene', (22, 27))	('alterations', 'Var', (28, 39))	('CPI', 'Chemical', '-', (155, 158))	('T-cell', 'CPA', (106, 112))	('lower', 'NegReg', (100, 105))	('luminal type UC', 'Disease', 'MESH:D003093', (63, 78))	('FGFR3', 'Gene', '2261', (22, 27))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('luminal type UC', 'Disease', (63, 78))
176512	32790011	This effect was demonstrated in a small cohort of patients treated with erdafitinib, where the responses were poor with CPI in patients harboring FGFR2/3 alterations [22].	('FGFR', 'molecular_function', 'GO:0005007', ('146', '150'))	('CPI', 'Chemical', '-', (120, 123))	('patients', 'Species', '9606', (50, 58))	('FGFR2', 'Gene', (146, 151))	('FGFR2', 'Gene', '2263', (146, 151))	('erdafitinib', 'Chemical', 'MESH:C000604580', (72, 83))	('patients', 'Species', '9606', (127, 135))	('alterations', 'Var', (154, 165))
176513	32790011	However, in another study of patients with urothelial cancer treated with CPI, the FGFR3 mutant or wild type status did not alter response [51].	('patients', 'Species', '9606', (29, 37))	('FGFR3', 'Gene', '2261', (83, 88))	('urothelial cancer', 'Disease', (43, 60))	('urothelial cancer', 'Disease', 'MESH:D014523', (43, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('83', '87'))	('FGFR3', 'Gene', (83, 88))	('CPI', 'Chemical', '-', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutant', 'Var', (89, 95))
176541	32635260	A1R and A3R are mainly coupled to the Gi/o subunit and thus inhibit AC and cAMP production; A2AR and A2BR are mainly coupled to the Gs subunit and stimulate cAMP synthesis through AC activation.	('cAMP', 'Gene', (75, 79))	('inhibit', 'NegReg', (60, 67))	('A2BR', 'Chemical', '-', (101, 105))	('cAMP', 'Gene', (157, 161))	('cAMP', 'Gene', '820', (157, 161))	('cAMP', 'Gene', '820', (75, 79))	('stimulate', 'PosReg', (147, 156))	('A2BR', 'Var', (101, 105))	('A2AR', 'Var', (92, 96))	('cAMP synthesis', 'biological_process', 'GO:0006171', ('157', '171'))
176598	32635260	In PANC-1 cells, UTP increased the phosphorylation level of AKT through PKC, PI3K, SRC and Ca2+-calmodulin-dependent protein kinase II.	('SRC', 'Gene', (83, 86))	('PANC-1', 'CellLine', 'CVCL:0480', (3, 9))	('UTP', 'Var', (17, 20))	('increased', 'PosReg', (21, 30))	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('AKT', 'Gene', '207', (60, 63))	('PKC', 'Gene', (72, 75))	('PKC', 'Gene', '112476', (72, 75))	('UTP', 'Chemical', 'MESH:D014544', (17, 20))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('PI3K', 'Enzyme', (77, 81))	('Ca2+-calmodulin-dependent', 'MPA', (91, 116))	('phosphorylation level', 'MPA', (35, 56))	('AKT', 'Gene', (60, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('PKC', 'molecular_function', 'GO:0004697', ('72', '75'))	('SRC', 'Gene', '6714', (83, 86))	('Ca2+', 'Chemical', 'MESH:D000069285', (91, 95))
176602	32635260	Although the purinergic system has mainly been associated with the positive regulation of cell proliferation, diverse evidence supports that it is not a rule; for example, pharmacological activation of purinergic receptors induced apoptosis in cancerous cells.	('apoptosis', 'CPA', (231, 240))	('apoptosis', 'biological_process', 'GO:0097194', ('231', '240'))	('cancerous', 'Disease', 'MESH:D009369', (244, 253))	('apoptosis', 'biological_process', 'GO:0006915', ('231', '240'))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('purine', 'Chemical', 'MESH:C030985', (202, 208))	('purinergic', 'Protein', (202, 212))	('positive regulation of cell proliferation', 'biological_process', 'GO:0008284', ('67', '108'))	('rat', 'Species', '10116', (102, 105))	('purine', 'Chemical', 'MESH:C030985', (13, 19))	('induced', 'Reg', (223, 230))	('cancerous', 'Disease', (244, 253))	('pharmacological activation', 'Var', (172, 198))
176611	32635260	To further support the role of A2BR in cancer progression, studies have shown that pharmacological or genetic inhibition of this receptor decreases cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('148', '166'))	('cancer', 'Disease', (39, 45))	('decreases', 'NegReg', (138, 147))	('rat', 'Species', '10116', (160, 163))	('A2BR', 'Chemical', '-', (31, 35))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('A2BR', 'Gene', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cell proliferation', 'CPA', (148, 166))	('inhibition', 'Var', (110, 120))
176613	32635260	In all these systems, A2BR functioned as a cell proliferation promoter.	('cell proliferation', 'biological_process', 'GO:0008283', ('43', '61'))	('A2BR', 'Chemical', '-', (22, 26))	('rat', 'Species', '10116', (55, 58))	('cell proliferation', 'CPA', (43, 61))	('A2BR', 'Var', (22, 26))
176614	32635260	Moreover, inhibition of A2BR expression in EJ and T24 cell lines, derived from bladder urothelial carcinoma, inhibited cell proliferation and arrested the cells in the G1 phase of the cell cycle.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (79, 107))	('rat', 'Species', '10116', (131, 134))	('cell proliferation', 'CPA', (119, 137))	('G1 phase', 'biological_process', 'GO:0051318', ('168', '176'))	('A2BR', 'Gene', (24, 28))	('bladder urothelial carcinoma', 'Disease', (79, 107))	('EJ', 'CellLine', 'CVCL:7039', (43, 45))	('inhibited', 'NegReg', (109, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('cell proliferation', 'biological_process', 'GO:0008283', ('119', '137'))	('arrested', 'NegReg', (142, 150))	('cell cycle', 'biological_process', 'GO:0007049', ('184', '194'))	('inhibition', 'Var', (10, 20))	('A2BR', 'Chemical', '-', (24, 28))
176630	32635260	In the PC9 human lung cancer cell line, which has a mutated EGFR, P2X7R was constitutively activated, promoting cell migration, even in the absence of TGF-beta1.	('PC9', 'Gene', (7, 10))	('human', 'Species', '9606', (11, 16))	('rat', 'Species', '10116', (120, 123))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('cell migration', 'biological_process', 'GO:0016477', ('112', '126'))	('EGFR', 'Gene', '1956', (60, 64))	('cell migration', 'CPA', (112, 126))	('P2X7R', 'Gene', (66, 71))	('TGF-beta1', 'Gene', (151, 160))	('mutated', 'Var', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('PC9', 'Gene', '255738', (7, 10))	('TGF-beta1', 'Gene', '7040', (151, 160))	('EGFR', 'Gene', (60, 64))	('lung cancer', 'Disease', (17, 28))	('P2X7R', 'Gene', '18439', (66, 71))	('promoting', 'PosReg', (102, 111))	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))
176647	32635260	For instance, ATP in prostate cancer cells promotes Cdc42 and Rac1 activation and MMP expression through P2YR activation.	('prostate cancer', 'Disease', 'MESH:D011471', (21, 36))	('MMP', 'molecular_function', 'GO:0004235', ('82', '85'))	('P2YR', 'Var', (105, 109))	('prostate cancer', 'Phenotype', 'HP:0012125', (21, 36))	('promotes', 'PosReg', (43, 51))	('activation', 'PosReg', (67, 77))	('Cdc42', 'Gene', (52, 57))	('MMP expression', 'Gene', (82, 96))	('ATP', 'Chemical', 'MESH:D000255', (14, 17))	('prostate cancer', 'Disease', (21, 36))	('Rac1', 'Gene', '5879', (62, 66))	('Cdc42', 'Gene', '998', (52, 57))	('Rac1', 'Gene', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
176659	32635260	This finding correlated with in vitro experiments, in which, after CD73 knock-down, cancer cell migration and expression of EMT-genes were reduced and A3R activation promoted HNSCC cell migration and presumably involving the EGFR signaling pathway.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cell migration', 'biological_process', 'GO:0016477', ('91', '105'))	('reduced', 'NegReg', (139, 146))	('EGFR', 'Gene', (225, 229))	('EGFR signaling pathway', 'biological_process', 'GO:0007173', ('225', '247'))	('EMT-genes', 'Gene', (124, 133))	('EMT', 'biological_process', 'GO:0001837', ('124', '127'))	('rat', 'Species', '10116', (189, 192))	('cancer', 'Disease', (84, 90))	('rat', 'Species', '10116', (99, 102))	('EGFR', 'Gene', '1956', (225, 229))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('expression', 'MPA', (110, 120))	('CD73', 'Gene', '4907', (67, 71))	('activation promoted', 'PosReg', (155, 174))	('EGFR', 'molecular_function', 'GO:0005006', ('225', '229'))	('CD73', 'Gene', (67, 71))	('knock-down', 'Var', (72, 82))	('cell migration', 'biological_process', 'GO:0016477', ('181', '195'))	('A3R', 'Gene', (151, 154))	('HNSCC cell migration', 'CPA', (175, 195))
176663	32635260	A2AR activation could restore the effect of knocking down CD73.	('CD73', 'Gene', '4907', (58, 62))	('CD73', 'Gene', (58, 62))	('knocking down', 'Var', (44, 57))
176666	32635260	in 2014 demonstrated that ADO at low microM inhibited cell migration and invasion in prostate and breast cancer cell lines.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('ADO', 'Chemical', 'MESH:D000241', (26, 29))	('breast cancer', 'Disease', (98, 111))	('rat', 'Species', '10116', (15, 18))	('inhibited', 'NegReg', (44, 53))	('ADO', 'Var', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rat', 'Species', '10116', (62, 65))	('cell migration', 'biological_process', 'GO:0016477', ('54', '68'))
176667	32635260	However, the inhibitory effect of ADO in cell migration and invasion has also been proven in human cervical and ovarian cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('invasion', 'CPA', (60, 68))	('cell migration', 'CPA', (41, 55))	('human', 'Species', '9606', (93, 98))	('inhibitory effect', 'NegReg', (13, 30))	('cervical and ovarian cancer', 'Disease', 'MESH:D002575', (99, 126))	('ADO', 'Chemical', 'MESH:D000241', (34, 37))	('cell migration', 'biological_process', 'GO:0016477', ('41', '55'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (112, 126))	('rat', 'Species', '10116', (49, 52))	('ADO', 'Var', (34, 37))
176670	32635260	On the contrary, gastric cancer cell incubation with ADO enhances the expression of stemness and EMT genes, which is attributed to A2AR activation and the AKT-mTor pathway.	('AKT', 'Gene', (155, 158))	('gastric cancer', 'Phenotype', 'HP:0012126', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('EMT', 'biological_process', 'GO:0001837', ('97', '100'))	('ADO', 'Chemical', 'MESH:D000241', (53, 56))	('mTor', 'Gene', (159, 163))	('enhances', 'PosReg', (57, 65))	('ADO', 'Var', (53, 56))	('expression', 'MPA', (70, 80))	('activation', 'PosReg', (136, 146))	('mTor', 'Gene', '2475', (159, 163))	('stemness', 'Gene', (84, 92))	('gastric cancer', 'Disease', (17, 31))	('AKT', 'Gene', '207', (155, 158))	('gastric cancer', 'Disease', 'MESH:D013274', (17, 31))	('EMT genes', 'Gene', (97, 106))
176674	32635260	In agreement, in MDAMB231 cancer cells, ADO increased cells migration through the A2BR/AC/PKA/cAMP axis and A2BR pharmacological inhibition decreased cell migration in human epithelial lung cancer cells and renal cancer cell lines.	('A2BR', 'Chemical', '-', (108, 112))	('cancer', 'Disease', (26, 32))	('ADO', 'Var', (40, 43))	('rat', 'Species', '10116', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cAMP', 'Gene', (94, 98))	('rat', 'Species', '10116', (63, 66))	('cancer', 'Disease', (190, 196))	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('human', 'Species', '9606', (168, 173))	('PKA', 'cellular_component', 'GO:0005952', ('90', '93'))	('cells migration', 'CPA', (54, 69))	('A2BR', 'Gene', (108, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('A2BR', 'Chemical', '-', (82, 86))	('cancer', 'Disease', (213, 219))	('increased', 'PosReg', (44, 53))	('PKA', 'molecular_function', 'GO:0004691', ('90', '93'))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('ADO', 'Chemical', 'MESH:D000241', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cell migration', 'biological_process', 'GO:0016477', ('150', '164'))	('renal cancer', 'Disease', (207, 219))	('renal cancer', 'Phenotype', 'HP:0009726', (207, 219))	('cAMP', 'Gene', '820', (94, 98))	('cell migration', 'CPA', (150, 164))	('decreased', 'NegReg', (140, 149))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('lung cancer', 'Disease', (185, 196))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('MDAMB231', 'CellLine', 'CVCL:0062', (17, 25))	('renal cancer', 'Disease', 'MESH:D007680', (207, 219))
176737	32635260	For example, in non-small cell cancer tissues and cancer-associated fibroblast, antagonists for A2AR (ZM241385 and SCH5826) inhibited cellular proliferation and the human tumor xenograft in mice.	('antagonists', 'Var', (80, 91))	('cancer', 'Disease', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('A2AR', 'Gene', (96, 100))	('cellular proliferation', 'CPA', (134, 156))	('rat', 'Species', '10116', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('ZM241385', 'Var', (102, 110))	('inhibited', 'NegReg', (124, 133))	('ZM241385', 'Chemical', 'MESH:C097270', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('cancer', 'Disease', (31, 37))	('SCH5826', 'Chemical', '-', (115, 122))	('human', 'Species', '9606', (165, 170))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('small cell cancer', 'Phenotype', 'HP:0030357', (20, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('mice', 'Species', '10090', (190, 194))	('tumor', 'Disease', (171, 176))
176739	32635260	Upon pharmacological inhibition of these receptors, Jurkat, THP-1, U-937 and HL-60 cells decrease mitochondrial activity, calcium signaling and cell proliferation.	('rat', 'Species', '10116', (156, 159))	('mitochondrial activity', 'MPA', (98, 120))	('cell proliferation', 'CPA', (144, 162))	('Jurkat', 'CellLine', 'CVCL:0065', (52, 58))	('calcium signaling', 'MPA', (122, 139))	('calcium signaling', 'biological_process', 'GO:0019722', ('122', '139'))	('decrease', 'NegReg', (89, 97))	('HL-60', 'CellLine', 'CVCL:0002', (77, 82))	('inhibition', 'Var', (21, 31))	('U-937', 'CellLine', 'CVCL:0007', (67, 72))	('calcium', 'Chemical', 'MESH:D002118', (122, 129))	('cell proliferation', 'biological_process', 'GO:0008283', ('144', '162'))	('THP-1', 'Gene', '2736', (60, 65))	('THP-1', 'Gene', (60, 65))	('decrease mitochondrial activity', 'Phenotype', 'HP:0040013', (89, 120))
176752	32635260	Tumor growth was accelerated in the p2rx7-/- background.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('rat', 'Species', '10116', (23, 26))	('p2rx7-/- background', 'Var', (36, 55))	('accelerated', 'PosReg', (17, 28))	('Tumor growth', 'CPA', (0, 12))
176753	32635260	The cells infiltrated in tumor-bearing p2rx7-/- contained an immunosuppressive microenvironment, compared to those growing in the wtAT background, with fewer effector T cells (Teff) (CD8+ and CD4+), increased Treg cells (CD4+, CD25+, Foxp3+) and a decline in cytotoxic effector CD8+ T cells (Tcyt).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Foxp3', 'Gene', (234, 239))	('rat', 'Species', '10116', (16, 19))	('decline', 'NegReg', (248, 255))	('CD4', 'Gene', (221, 224))	('CD25', 'Gene', (227, 231))	('CD8', 'Gene', '925', (278, 281))	('Foxp3', 'Gene', '50943', (234, 239))	('Treg cells', 'CPA', (209, 219))	('CD8', 'Gene', (183, 186))	('CD4', 'Gene', '920', (192, 195))	('fewer', 'NegReg', (152, 157))	('CD25', 'Gene', '3559', (227, 231))	('p2rx7-/-', 'Var', (39, 47))	('tumor', 'Disease', (25, 30))	('CD8', 'Gene', (278, 281))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('increased', 'PosReg', (199, 208))	('CD4', 'Gene', (192, 195))	('CD4', 'Gene', '920', (221, 224))	('CD8', 'Gene', '925', (183, 186))
176756	32635260	These changes in CD39/CD73 expression produced a reduction in exATP levels in the TME and an increment in ADO production, causing a general immunosuppressive effect.	('ADO production', 'MPA', (106, 120))	('reduction', 'NegReg', (49, 58))	('CD39', 'Gene', (17, 21))	('CD73', 'Gene', (22, 26))	('changes', 'Var', (6, 13))	('ADO', 'Chemical', 'MESH:D000241', (106, 109))	('CD39', 'Gene', '953', (17, 21))	('increment', 'PosReg', (93, 102))	('exATP', 'Chemical', '-', (62, 67))	('exATP levels in the TME', 'MPA', (62, 85))	('CD73', 'Gene', '4907', (22, 26))
176758	32635260	These results showed that P2X7R expression in the host tissue contributed with an anti-tumor immune response, and confirmed that the deficiency of host P2X7R induces immune failure, suggesting that P2X7R plays a relevant role in the establishment of the immune response in the TME, thus integrating tumor-host interaction.	('contributed', 'Reg', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('P2X7R', 'Gene', '18439', (198, 203))	('rat', 'Species', '10116', (292, 295))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('immune response', 'biological_process', 'GO:0006955', ('93', '108'))	('deficiency', 'Var', (133, 143))	('immune failure', 'CPA', (166, 180))	('P2X7R', 'Gene', (152, 157))	('tumor', 'Disease', (87, 92))	('immune failure', 'Phenotype', 'HP:0002721', (166, 180))	('P2X7R', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (299, 304))	('P2X7R', 'Gene', '18439', (152, 157))	('P2X7R', 'Gene', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('immune response', 'biological_process', 'GO:0006955', ('254', '269'))	('P2X7R', 'Gene', '18439', (26, 31))
176759	32635260	In contrast, it has been suggested that exATP contributes to immunosuppression in the TME.	('exATP', 'Chemical', '-', (40, 45))	('immunosuppression', 'MPA', (61, 78))	('exATP', 'Var', (40, 45))
176765	32635260	ADO inhibits T cell arrival in the tumor through the activation of its receptors, thus preventing these cells from producing their cytotoxic activity against cancer cells.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('inhibits', 'NegReg', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('activation', 'PosReg', (53, 63))	('preventing', 'NegReg', (87, 97))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Disease', (35, 40))	('cytotoxic activity', 'MPA', (131, 149))	('cancer', 'Disease', (158, 164))	('ADO', 'Chemical', 'MESH:D000241', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('ADO', 'Var', (0, 3))
176770	32635260	In a pharmacological intervention assay, the efficiency of reverting the immunosuppression of induced tumors with PD-1 antibodies (responsible for the immunological checkpoint) improved, if an A2AR antagonist was co-administrated.	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('antibodies', 'Var', (119, 129))	('improved', 'PosReg', (177, 185))	('rat', 'Species', '10116', (224, 227))	('PD-1', 'Gene', (114, 118))	('PD-1', 'Gene', '5133', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
176771	32635260	Another approach has consisted in evaluating the effect of A2AR deletion in cultured-activated tumor-draining lymph node (TDLN) T cells.	('A2AR', 'Gene', (59, 63))	('deletion', 'Var', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
176773	32635260	Additionally, the ablation of ADO signaling promoted natural killer cell (NK) maturation and reduced tumor growth.	('promoted', 'PosReg', (44, 52))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('ADO', 'Chemical', 'MESH:D000241', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('ADO signaling', 'Gene', (30, 43))	('reduced', 'NegReg', (93, 100))	('rat', 'Species', '10116', (82, 85))	('ablation', 'Var', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
176774	32635260	It has also been demonstrated in colorectal cancer cells that A2BR working synergically with A2AR, expressed in tumor-associated fibroblast, participated in the immune checkpoint dependent on NT5E/ADO to establish the immunosuppressive response characteristic of tumor cells.	('A2BR', 'Chemical', '-', (62, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (33, 50))	('NT5E', 'Gene', (192, 196))	('rat', 'Species', '10116', (24, 27))	('colorectal cancer', 'Disease', (33, 50))	('immunosuppressive', 'CPA', (218, 235))	('A2BR', 'Var', (62, 66))	('tumor', 'Disease', (263, 268))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('immune', 'MPA', (161, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (33, 50))	('ADO', 'Chemical', 'MESH:D000241', (197, 200))	('NT5E', 'Gene', '4907', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('participated in', 'Reg', (141, 156))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
176775	32635260	Recently, it was reported that A1R deletion suppressed melanoma-derived cell growth and induced the inhibition of T cells in co-culture, antagonizing the anti-tumor immune response depending on another A2AR receptor, through a pathway involving overexpression of PD-L1 driven by the transcription factor ATF3.	('ATF3', 'Gene', '467', (304, 308))	('PD-L1', 'Gene', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PD-L1', 'Gene', '29126', (263, 268))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))	('transcription', 'biological_process', 'GO:0006351', ('283', '296'))	('transcription factor', 'molecular_function', 'GO:0000981', ('283', '303'))	('ATF3', 'Gene', (304, 308))	('inhibition', 'NegReg', (100, 110))	('immune response', 'biological_process', 'GO:0006955', ('165', '180'))	('tumor', 'Disease', (159, 164))	('deletion', 'Var', (35, 43))	('T cells in co-culture', 'CPA', (114, 135))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('suppressed', 'NegReg', (44, 54))	('A1R', 'Gene', (31, 34))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('antagonizing', 'NegReg', (137, 149))	('cell growth', 'biological_process', 'GO:0016049', ('72', '83'))
176779	32635260	In general, the actions of ADO inhibiting the anti-tumor immune response have been demonstrated in a broad group of host immune cells in the TME.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('immune response', 'biological_process', 'GO:0006955', ('57', '72'))	('inhibiting', 'NegReg', (31, 41))	('ADO', 'Chemical', 'MESH:D000241', (27, 30))	('ADO', 'Var', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('rat', 'Species', '10116', (90, 93))
176801	32635260	Moreover, the processing of RNAs coding for NT5E is regulated by a miRNA group, the presence of this miRNA contributes to the role of CD73 in cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('NT5E', 'Gene', '4907', (44, 48))	('CD73', 'Gene', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('NT5E', 'Gene', (44, 48))	('presence', 'Var', (84, 92))	('processing', 'MPA', (14, 24))	('CD73', 'Gene', '4907', (134, 138))	('cancer', 'Disease', (142, 148))
176812	32300588	In particular, SLK was more likely to be cancer-related due to its high missense mutation rate and associated with cell adhesion.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cell adhesion', 'biological_process', 'GO:0007155', ('115', '128'))	('missense mutation', 'Var', (72, 89))	('SLK', 'Gene', '9748', (15, 18))	('SLK', 'Gene', (15, 18))	('cell adhesion', 'CPA', (115, 128))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('associated', 'Reg', (99, 109))
176823	32300588	developed a prognostic 3-miRNA classifier (miR-106b-5p, miR-148a-3p, and miR-338-3p) in early-stage mycosis fungoides.	('miR-338-3p', 'Var', (73, 83))	('miR-148a-3p', 'Var', (56, 67))	('miR-106b', 'Gene', '406900', (43, 51))	('early-stage mycosis fungoides', 'Disease', (88, 117))	('miR-106b', 'Gene', (43, 51))
176855	32300588	Univariate Cox proportional hazards regression model was used to identify candidate survival-related genes from each omics data through the formula: where the explanatory variable X was the omics data (DM, GE, copy number variation, or miRNA expression) of a gene, and the response variable t was the survival time.	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('DM', 'Disease', 'MESH:D009223', (202, 204))	('copy number variation', 'Var', (210, 231))	('survival-related', 'Gene', (84, 100))	('survival-related', 'Gene', '54897', (84, 100))
176913	32300588	We found that SLK had an unconservative exon region, which containing four missense variants (Figure 7A).	('missense', 'Var', (75, 83))	('SLK', 'Gene', '9748', (14, 17))	('SLK', 'Gene', (14, 17))
176914	32300588	In order to further verify the close relationship of SLK and cancer, we checked the mutation of SLK in the COSMIC database, and found that missense substitution occurred in 36.93% of the samples (Figure 7B).	('missense substitution', 'Var', (139, 160))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('SLK', 'Gene', '9748', (53, 56))	('SLK', 'Gene', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('SLK', 'Gene', '9748', (96, 99))	('occurred', 'Reg', (161, 169))	('SLK', 'Gene', (96, 99))
176924	32300588	Based on the COSMIC database, we found extensive mutations occurred in EPRS, and 70% of them were missense mutation.	('EPRS', 'Gene', (71, 75))	('missense mutation', 'Var', (98, 115))	('EPRS', 'Gene', '2058', (71, 75))	('mutations', 'Var', (49, 58))
176931	32300588	These locations were the peak regions of copy number alternation, suggesting a relationship between these genes and cancer.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('relationship', 'Reg', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('copy number', 'Var', (41, 52))
176956	32300588	Cell adhesion plays an important role in the maintenance of tissue structure, whose abnormality results in tumor invasion and metastasis.	('Cell adhesion', 'biological_process', 'GO:0007155', ('0', '13'))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('metastasis', 'CPA', (126, 136))	('results in', 'Reg', (96, 106))	('abnormality', 'Var', (84, 95))
177038	31805718	In osteosarcoma cells, knockdown of NMNAT2 reduced p53-mediated cell death upon DNA damage.	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('NMNAT2', 'Gene', '23057', (36, 42))	('osteosarcoma', 'Disease', (3, 15))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('knockdown', 'Var', (23, 32))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('NMNAT2', 'Gene', (36, 42))	('reduced', 'NegReg', (43, 50))	('cell death', 'biological_process', 'GO:0008219', ('64', '74'))
177040	31805718	In addition, reduced NAD level also activates signaling pathways promoting epithelial to mesenchymal transition (EMT), facilitating tumor progression.	('promoting', 'PosReg', (65, 74))	('NAD', 'Chemical', 'MESH:D009243', (21, 24))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('75', '111'))	('epithelial to mesenchymal transition', 'CPA', (75, 111))	('reduced', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('EMT', 'biological_process', 'GO:0001837', ('113', '116'))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('NAD level', 'MPA', (21, 30))	('activates', 'Reg', (36, 45))	('signaling pathways', 'Pathway', (46, 64))
177043	31805718	NQO1, one of the major quinone reductases highly inducible under cellular stress, modulate NAD/NADH redox balance, and specific polymorphism of NQO1 is associated with cancer risk in urinary system.	('NADH', 'Chemical', 'MESH:D009243', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('NQO1', 'molecular_function', 'GO:0003955', ('0', '4'))	('NAD/NADH redox balance', 'MPA', (91, 113))	('polymorphism', 'Var', (128, 140))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('modulate', 'Reg', (82, 90))	('NQO1', 'Gene', (144, 148))	('NQO1', 'Gene', (0, 4))	('urinary system', 'Disease', (183, 197))	('cancer', 'Disease', (168, 174))	('NAD', 'Chemical', 'MESH:D009243', (91, 94))	('associated with', 'Reg', (152, 167))	('NAD', 'Chemical', 'MESH:D009243', (95, 98))	('NQO1', 'molecular_function', 'GO:0003955', ('144', '148'))	('NQO1', 'Gene', '1728', (144, 148))	('NQO1', 'Gene', '1728', (0, 4))	('quinone', 'Chemical', 'MESH:D011809', (23, 30))
177047	31805718	NAD is also involved in the regulation of oxidative stress, and report showed ascorbate induced cell death of neuroblastoma cells through NAD depletion and ROS-induced DNA damage, which suggested that NAD and ROS production are partially responsible for the cancer cell cytotoxicity.	('neuroblastoma', 'Disease', 'MESH:D009447', (110, 123))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('NAD', 'Chemical', 'MESH:D009243', (0, 3))	('neuroblastoma', 'Disease', (110, 123))	('NAD', 'Chemical', 'MESH:D009243', (138, 141))	('cell death', 'biological_process', 'GO:0008219', ('96', '106'))	('NAD', 'Chemical', 'MESH:D009243', (201, 204))	('cytotoxicity', 'Disease', 'MESH:D064420', (270, 282))	('cancer', 'Disease', (258, 264))	('neuroblastoma', 'Phenotype', 'HP:0003006', (110, 123))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('ascorbate', 'Chemical', 'MESH:D001205', (78, 87))	('regulation', 'biological_process', 'GO:0065007', ('28', '38'))	('cell death', 'CPA', (96, 106))	('oxidative stress', 'Phenotype', 'HP:0025464', (42, 58))	('depletion', 'Var', (142, 151))	('DNA', 'cellular_component', 'GO:0005574', ('168', '171'))	('cytotoxicity', 'Disease', (270, 282))
177051	31805718	The link between inflammation and development of bladder cancer has also been reported, and the oncogenic changes may potentiate inflammatory microenvironment that leads to angiogenesis and invasion of bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('bladder cancer', 'Phenotype', 'HP:0009725', (202, 216))	('invasion of bladder cancer', 'Disease', (190, 216))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('bladder cancer', 'Disease', 'MESH:D001749', (49, 63))	('men', 'Species', '9606', (41, 44))	('bladder cancer', 'Disease', (49, 63))	('bladder cancer', 'Phenotype', 'HP:0009725', (49, 63))	('inflammation', 'Disease', 'MESH:D007249', (17, 29))	('changes', 'Var', (106, 113))	('angiogenesis', 'biological_process', 'GO:0001525', ('173', '185'))	('potentiate', 'PosReg', (118, 128))	('inflammation', 'Disease', (17, 29))	('leads to', 'Reg', (164, 172))	('angiogenesis', 'CPA', (173, 185))	('inflammation', 'biological_process', 'GO:0006954', ('17', '29'))	('men', 'Species', '9606', (154, 157))	('invasion of bladder cancer', 'Disease', 'MESH:D001749', (190, 216))	('bladder cancer', 'Disease', 'MESH:D001749', (202, 216))
177056	31805718	recently reported increased ARRB1 expression in bladder cancer cells, and ARRB1 gene knockout reversed the aggressive phenotype of bladder cancer cell lines.	('reversed', 'NegReg', (94, 102))	('bladder cancer', 'Disease', (48, 62))	('increased', 'PosReg', (18, 27))	('expression', 'MPA', (34, 44))	('bladder cancer', 'Disease', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ARRB1', 'Gene', (28, 33))	('ARRB1', 'Gene', '408', (28, 33))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('knockout', 'Var', (85, 93))	('bladder cancer', 'Phenotype', 'HP:0009725', (131, 145))	('ARRB1', 'Gene', (74, 79))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))	('aggressive phenotype of', 'CPA', (107, 130))	('bladder cancer', 'Disease', 'MESH:D001749', (131, 145))	('ARRB1', 'Gene', '408', (74, 79))
177057	31805718	MiR-185-3p is a potential oncosuppressor miRNA evident in nasopharyngeal carcinoma (NPC), and the inhibition of miR-185-3p promoted invasion and metastasis of NPC cells.	('inhibition', 'Var', (98, 108))	('NPC', 'Phenotype', 'HP:0100630', (84, 87))	('NPC', 'Disease', 'MESH:C538339', (84, 87))	('NPC', 'Disease', (84, 87))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (58, 82))	('MiR', 'Gene', '220972', (0, 3))	('nasopharyngeal carcinoma', 'Disease', 'MESH:C538339', (58, 82))	('miR', 'Gene', '220972', (41, 44))	('NPC', 'cellular_component', 'GO:0005643', ('159', '162'))	('MiR', 'Gene', (0, 3))	('NPC', 'Disease', 'MESH:C538339', (159, 162))	('NPC', 'Phenotype', 'HP:0100630', (159, 162))	('miR', 'Gene', '220972', (112, 115))	('promoted', 'PosReg', (123, 131))	('NPC', 'Disease', (159, 162))	('miR', 'Gene', (41, 44))	('NPC', 'cellular_component', 'GO:0005643', ('84', '87'))	('nasopharyngeal carcinoma', 'Disease', (58, 82))	('miR', 'Gene', (112, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
177077	31805718	This study was supported in part by research grants from the Ministry of Science and Technology (MOST 107-2320-B-037-011-MY3; MOST 107-2314-B-037-092; MOST 107-2635-B-037-001; MOST 108-2314-B-037-027; MOST 108-2628-B-037-003), Kaohsiung Medical University Hospital (KMUH106-6R53; KMUH107-7R56), the Kaohsiung Medical University Research Center Grant (KMU-TC108A04), and the Kaohsiung Medical University (KMU-DK108003).	('107-2635-B-037', 'Chemical', 'MESH:C544608', (156, 170))	('107-2320-B-037-011', 'Chemical', 'MESH:C079769', (102, 120))	('KMUH107-7R56', 'Var', (280, 292))	('108-2314-B-037-027', 'Chemical', 'MESH:C569749', (181, 199))	('KMU-DK108003', 'Chemical', 'MESH:C095602', (404, 416))	('107-2314-B-037-092', 'Chemical', 'MESH:C079769', (131, 149))	('108-2628-B-037-003', 'Chemical', 'MESH:C087337', (206, 224))	('KMUH106-6R53; KMUH107-7R56', 'Var', (266, 292))
177078	31324166	Absence of an embryonic stem cell DNA methylation signature in human cancer Differentiated cells that arise from stem cells in early development contain DNA methylation features that provide a memory trace of their fetal cell origin (FCO).	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('human', 'Species', '9606', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('FCO', 'Chemical', '-', (234, 237))	('methylation', 'Var', (157, 168))	('DNA methylation', 'biological_process', 'GO:0006306', ('153', '168'))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('DNA methylation', 'biological_process', 'GO:0006306', ('34', '49'))	('memory', 'biological_process', 'GO:0007613', ('193', '199'))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
177099	31324166	Programming the cancer stem cell phenotypes are genetic alterations and epigenetic changes in chromatin structure and DNA methylation.	('chromatin structure', 'Protein', (94, 113))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('DNA methylation', 'biological_process', 'GO:0006306', ('118', '133'))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('epigenetic changes', 'Var', (72, 90))	('DNA methylation', 'MPA', (118, 133))	('chromatin', 'cellular_component', 'GO:0000785', ('94', '103'))	('genetic alterations', 'Var', (48, 67))
177100	31324166	The consequence of cancer stem cell epigenetic alterations is to unleash cellular plasticity that favors oncogenic cellular reprogramming.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('cellular plasticity', 'CPA', (73, 92))	('epigenetic alterations', 'Var', (36, 58))	('oncogenic cellular reprogramming', 'CPA', (105, 137))	('favors', 'PosReg', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
177112	31324166	We were able to add nontumor normal samples of cervix, brain, adrenal gland and stomach from GEO data sets GSE46306, GSE80970, GSE77871 and GSE103186 to cervical squamous cell carcinoma and endocervical adenocarcinoma, glioblastoma multiforme, pheochromocytoma and stomach adenocarcinoma projects on TCGA.	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (162, 185))	('endocervical adenocarcinoma', 'Disease', (190, 217))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (265, 287))	('GSE46306', 'Var', (107, 115))	('pheochromocytoma', 'Disease', (244, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (244, 260))	('squamous cell carcinoma', 'Disease', (162, 185))	('glioblastoma multiforme', 'Disease', (219, 242))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (219, 242))	('cervical', 'Disease', (153, 161))	('GSE77871', 'Var', (127, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('GSE80970', 'Var', (117, 125))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (190, 217))	('tumor', 'Disease', (23, 28))	('stomach adenocarcinoma', 'Disease', (265, 287))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('GSE103186', 'Var', (140, 149))	('pheochromocytoma', 'Disease', 'MESH:D010673', (244, 260))
177163	31324166	We applied the FCO algorithm to GEO data sets GSE80241, representing 6 pancreatic ductal adenocarcinoma stem cell samples, and GSE92462, including 22 glioma stem cell samples.	('pancreatic ductal adenocarcinoma', 'Disease', (71, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (71, 103))	('FCO', 'Chemical', '-', (15, 18))	('GSE80241', 'Var', (46, 54))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (71, 103))	('glioma', 'Disease', (150, 156))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
177165	31324166	Further, among 27 FCO CpGs, 3 (cg10338787, cg17310258 and cg16154155) are associated with EZH2.	('EZH2', 'Gene', (90, 94))	('cg17310258', 'Chemical', '-', (43, 53))	('cg17310258', 'Var', (43, 53))	('EZH2', 'Gene', '2146', (90, 94))	('cg10338787', 'Chemical', '-', (31, 41))	('cg16154155', 'Var', (58, 68))	('cg16154155', 'Chemical', '-', (58, 68))	('FCO', 'Chemical', '-', (18, 21))	('associated', 'Reg', (74, 84))	('cg10338787', 'Var', (31, 41))
177166	31324166	We plotted the methylation beta values of these three loci in pancreatic carcinoma samples, normal pancreatic tissue samples and pancreatic cancer stem cell samples from GEO data sets GSE53051 and GSE80241.	('pancreatic carcinoma', 'Disease', (62, 82))	('GSE53051', 'Var', (184, 192))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('GSE80241', 'Var', (197, 205))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (62, 82))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('pancreatic cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
177187	31324166	The former model is supported by recent research indicating that heterogeneous tumor cells develop over time as cancer stem cells differentiate via genetic and epigenetic alterations.	('tumor', 'Disease', (79, 84))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('epigenetic alterations', 'Var', (160, 182))	('genetic', 'Var', (148, 155))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
177191	31324166	Further, our observation of a diminished FCO in tumors is seemingly at odds with reports that DNA hypermethylation in cancer preferentially targets the subset of polycomb repressor loci in cancer stem cells that are developmental regulators.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('cancer', 'Disease', (118, 124))	('FCO', 'MPA', (41, 44))	('diminished', 'NegReg', (30, 40))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('94', '114'))	('FCO', 'Chemical', '-', (41, 44))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('hypermethylation', 'Var', (98, 114))	('cancer', 'Disease', (189, 195))
177230	31324166	DCK was supported by the Kansas IDeA Network of Biomedical Research Excellence (K-INBRE) Bioinformatics Core, supported in part by the National Institute of General Medical Science award P20GM103418, and NIH grant P30CA168524.	('P20GM103418', 'Var', (187, 198))	('DCK', 'Gene', (0, 3))	('DCK', 'Gene', '1633', (0, 3))
177231	31324166	The datasets analyzed during the current study are available on The Cancer Genome Atlas (TCGA) https://portal.gdc.cancer.gov and the Gene Expression Omnibus data repository https://www.ncbi.nlm.nih.gov/geo/ (Accession numbers: GSE49656, GSE53051, GSE52068, GSE52826, GSE52955, GSE54503, GSE56044, GSE75546, GSE77871, GSE85845, GSE76938, GSE112047, GSE101961, GSE72245, GSE106600, GSE80241, GSE92462).	('GSE85845', 'Var', (317, 325))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Gene Expression', 'biological_process', 'GO:0010467', ('133', '148'))	('GSE112047', 'Var', (337, 346))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('GSE76938', 'Var', (327, 335))	('GSE56044', 'Var', (287, 295))	('GSE52955', 'Var', (267, 275))	('GSE72245', 'Var', (359, 367))	('GSE80241', 'Var', (380, 388))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (68, 87))	('GSE101961', 'Var', (348, 357))	('GSE53051', 'Var', (237, 245))	('GSE75546', 'Var', (297, 305))	('GSE106600', 'Var', (369, 378))	('Cancer Genome Atlas', 'Disease', (68, 87))	('GSE92462', 'Var', (390, 398))	('GSE77871', 'Var', (307, 315))	('cancer', 'Disease', (114, 120))
177250	27692813	Molecular analysis of a 50-gene panel using a Clinical Laboratory Improvement Amendments (CLIA) - certified next generation sequencing platform (Table 1) revealed only a single mutation in the codon 271, exon 8 (GAG to AAG) of the TP53 gene that changed the encoded amino acid from Glutamate to Lysine (c.811G>A p.E271K).	('Glutamate', 'Chemical', 'MESH:D018698', (282, 291))	('Lysine', 'Chemical', 'MESH:D008239', (295, 301))	('TP53', 'Gene', '7157', (231, 235))	('8 (GAG to AAG', 'Mutation', 'c.8GAG>AAG', (209, 222))	('c.811G>A', 'Mutation', 'rs1060501191', (303, 311))	('changed', 'Reg', (246, 253))	('CLIA', 'Disease', 'None', (90, 94))	('TP53', 'Gene', (231, 235))	('p.E271K', 'Mutation', 'rs1060501191', (312, 319))	('CLIA', 'Disease', (90, 94))	('c.811G>A p.E271K', 'Var', (303, 319))
177251	27692813	A relatively common germline polymorphism was also noted in codon 541, exon 10 (ATG to CTG) of the KIT gene that would change the encoded amino acid from Methionine to Leucine (c.1621A>C p.M541L).	('Methionine', 'Chemical', 'MESH:D008715', (154, 164))	('change', 'Reg', (119, 125))	('Leucine', 'Chemical', 'MESH:D007930', (168, 175))	('c.1621A>C', 'Mutation', 'rs3822214', (177, 186))	('KIT', 'Gene', (99, 102))	('p.M541L', 'Mutation', 'rs3822214', (187, 194))	('KIT', 'molecular_function', 'GO:0005020', ('99', '102'))	('c.1621A>C p.M541L', 'Var', (177, 194))
177258	27692813	The patient's beta-hCG on 8/6/13 increased to 17171 mIU/mL presumably due to tumor cell death.	('cell death', 'biological_process', 'GO:0008219', ('83', '93'))	('hCG', 'Gene', '93659', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('patient', 'Species', '9606', (4, 11))	('hCG', 'Gene', (19, 22))	('increased', 'PosReg', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('17171 mIU/mL', 'Var', (46, 58))
177310	33902536	At one end of the spectrum, low-grade BLCA would have a low progression rate and a threat to the patient; at the other extreme, high-grade BLCA has a high malignant potential associated with significant progression and cancer death rates.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('progression', 'CPA', (60, 71))	('cancer death', 'Disease', 'MESH:D009369', (219, 231))	('high-grade', 'Var', (128, 138))	('BLCA', 'Phenotype', 'HP:0009725', (38, 42))	('progression', 'CPA', (203, 214))	('patient', 'Species', '9606', (97, 104))	('cancer death', 'Disease', (219, 231))	('low', 'NegReg', (56, 59))	('BLCA', 'Phenotype', 'HP:0009725', (139, 143))
177348	33902536	Notably, the number of surviving decreased, and cancer-related death increased with increasing risk scores, thus the group with high EPDR1 expression seemed as having a shorter OS compared to the low or medium expression-group (Fig.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('EPDR1', 'Gene', '54749', (133, 138))	('death', 'Disease', 'MESH:D003643', (63, 68))	('death', 'Disease', (63, 68))	('EPDR1', 'Gene', (133, 138))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('high', 'Var', (128, 132))	('decreased', 'NegReg', (33, 42))	('expression', 'MPA', (139, 149))
177359	33902536	These results revealed that EPDR1 expression could have a widespread impact on the global transcriptome of BLCA tissues.	('global transcriptome', 'MPA', (83, 103))	('EPDR1', 'Gene', (28, 33))	('expression', 'Var', (34, 44))	('EPDR1', 'Gene', '54749', (28, 33))	('BLCA', 'Phenotype', 'HP:0009725', (107, 111))	('impact', 'Reg', (69, 75))
177368	33902536	In present studies, we explored the expression level of EPDR1 in BLCA, and consequently, we found that the BLCA patients with high EPDR1 expression are more likely to accompany with an advanced grade, stage, metastasis, and poor prognosis than those with low EPDR1 expression.	('EPDR1', 'Gene', '54749', (259, 264))	('EPDR1', 'Gene', (56, 61))	('metastasis', 'CPA', (208, 218))	('accompany', 'Reg', (167, 176))	('patients', 'Species', '9606', (112, 120))	('EPDR1', 'Gene', (131, 136))	('EPDR1', 'Gene', '54749', (131, 136))	('advanced grade', 'CPA', (185, 199))	('high', 'Var', (126, 130))	('EPDR1', 'Gene', (259, 264))	('BLCA', 'Phenotype', 'HP:0009725', (107, 111))	('stage', 'CPA', (201, 206))	('BLCA', 'Phenotype', 'HP:0009725', (65, 69))	('EPDR1', 'Gene', '54749', (56, 61))	('BLCA', 'Disease', (107, 111))
177369	33902536	To assess the prognostic value of EPDR1, we conducted an analysis of the OS rate for patients grouping different expressions of EPDR1 with the risk score, and interestingly, found that the P-value in all of the groups above was statistically significant.	('EPDR1', 'Gene', (34, 39))	('EPDR1', 'Gene', '54749', (128, 133))	('expressions', 'Var', (113, 124))	('patients', 'Species', '9606', (85, 93))	('EPDR1', 'Gene', '54749', (34, 39))	('EPDR1', 'Gene', (128, 133))
177434	30238401	Early reviews have found that patients in the monotherapy (pembrolizumab or atezolizumab) arms of both trials with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.	('low status', 'Var', (121, 131))	('survival', 'MPA', (146, 154))	('PD-L1', 'Gene', (115, 120))	('PD-L1', 'Gene', '29126', (115, 120))	('patients', 'Species', '9606', (167, 175))	('carboplatin', 'Chemical', 'MESH:D016190', (203, 214))	('patients', 'Species', '9606', (30, 38))	('atezolizumab', 'Chemical', 'MESH:C000594389', (76, 88))	('pembrolizumab', 'Chemical', 'MESH:C582435', (59, 72))	('decreased', 'NegReg', (136, 145))	('cisplatin', 'Chemical', 'MESH:D002945', (189, 198))
177471	30238401	Biomarker-positive patients (SP263-positive in immune and tumor cells) had better outcomes.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('patients', 'Species', '9606', (19, 27))	('SP263-positive', 'Var', (29, 43))	('SP263', 'Chemical', '-', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
177488	30238401	In another analysis of only the eligible patient population (n = 357), the median survival was significantly longer for vinflunine + BSC compared to BSC alone (6.9 vs. 4.3 months, p = 0.04).	('longer', 'PosReg', (109, 115))	('BSC', 'Chemical', '-', (149, 152))	('vinflunine', 'Chemical', 'MESH:C111217', (120, 130))	('patient', 'Species', '9606', (41, 48))	('survival', 'MPA', (82, 90))	('BSC', 'Chemical', '-', (133, 136))	('vinflunine', 'Var', (120, 130))
177509	30238401	An analysis of individual patient level data from eight phase 2 trials of single-agent taxane vs. taxane containing combination chemotherapy in 370 patients demonstrated that combination chemotherapy was independently and significantly associated with improved OS (HR: 0.60; 95% CI, 0.45-0.82; p = 0.001).	('patient', 'Species', '9606', (26, 33))	('patients', 'Species', '9606', (148, 156))	('combination', 'Var', (175, 186))	('taxane', 'Chemical', 'MESH:C080625', (87, 93))	('taxane', 'Chemical', 'MESH:C080625', (98, 104))	('patient', 'Species', '9606', (148, 155))	('improved', 'PosReg', (252, 260))
177643	25002073	UCB is a heterogeneous disease, ranging from low-grade cancer that does not recur after initial resection, to high-grade variants that progress to metastatic, lethal disease.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('variants', 'Var', (121, 129))	('UCB', 'Chemical', '-', (0, 3))	('UCB', 'Phenotype', 'HP:0006740', (0, 3))	('metastatic', 'Disease', (147, 157))	('UCB', 'Disease', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('progress', 'PosReg', (135, 143))	('cancer', 'Disease', (55, 61))
177744	24311914	He was known case of UC for which he underwent transurethral resection for bladder tumor (TURBT) (the size was 7 cm, left wall, UC, G2 > G1, pTa) in April 2005.	('bladder tumor', 'Disease', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('pTa', 'molecular_function', 'GO:0008959', ('141', '144'))	('G2 > G1', 'Var', (132, 139))	('pTa', 'Gene', (141, 144))	('bladder tumor', 'Disease', 'MESH:D001749', (75, 88))	('pTa', 'Gene', '171558', (141, 144))	('bladder tumor', 'Phenotype', 'HP:0009725', (75, 88))
177746	24311914	The entire mucosa of the ureter and renal-pelvis were replaced by papillary tumor [Figure 1] and histological examination showed UC, G2>>G3, pT2, ly0, and v0.	('G2>>G3', 'Var', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('ly0', 'Var', (146, 149))	('pT2', 'Var', (141, 144))	('papillary tumor', 'Disease', (66, 81))	('papillary tumor', 'Disease', 'MESH:D002291', (66, 81))
177790	21624607	This laboratory employs the UROtsa cell line to model urothelial cell transformation as a consequence of exposure to As+3 and Cd+2.	('Cd+2', 'Var', (126, 130))	('As+3', 'Chemical', '-', (117, 121))	('urothelial cell transformation', 'CPA', (54, 84))
57588	21624607	This cell line has been used to show that both Cd+2 and As+3 can cause the malignant transformation of human urothelial cells.	('Cd+2', 'Var', (47, 51))	('human', 'Species', '9606', (103, 108))	('cause', 'Reg', (65, 70))	('As+3', 'Chemical', '-', (56, 60))	('malignant transformation of human urothelial cells', 'CPA', (75, 125))	('As+3', 'Var', (56, 60))
177843	21624607	In addition to its name Kindlin-2, it is also reported in the literature as MIG2, KIND2, mig-2, UNC112, PLEKHC1, UNC112B, FLJ34213, FLJ44462, DKFZp686G11125 and FERMT2.	('DKFZp686G11125', 'Var', (142, 156))	('FLJ34213', 'Var', (122, 130))	('mig-2', 'Gene', (89, 94))	('UNC112B', 'Gene', '10979', (113, 120))	('MIG2', 'Gene', '10979', (76, 80))	('KIND2', 'Gene', (82, 87))	('UNC112', 'Gene', '10979', (113, 119))	('FERMT2', 'Gene', '10979', (161, 167))	('UNC112', 'Gene', '10979', (96, 102))	('PLEKHC1', 'Gene', (104, 111))	('MIG2', 'Gene', (76, 80))	('UNC112B', 'Gene', (113, 120))	('PLEKHC1', 'Gene', '10979', (104, 111))	('FLJ44462', 'Var', (132, 140))	('mig-2', 'Gene', '10979', (89, 94))	('UNC112', 'Gene', (113, 119))	('UNC112', 'Gene', (96, 102))	('KIND2', 'Gene', '10979', (82, 87))	('FERMT2', 'Gene', (161, 167))
177854	21624607	In the present study, the microarray screen showed that the 3 cell lines repressed in the expression of Kindlin-2 mRNA were those cell lines able to establish peritoneal tumors when injected into the peritoneal cavity.	('Kindlin-2', 'Gene', (104, 113))	('mRNA', 'Var', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('peritoneal tumors', 'Disease', (159, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('peritoneal tumors', 'Disease', 'MESH:D010534', (159, 176))	('expression', 'Var', (90, 100))
177886	33923166	KLF5 Is Activated by Gene Amplification in Gastric Cancer and Is Essential for Gastric Cell Proliferation Gastric cancer is the third leading cause of cancer death worldwide.	('Gene Amplification', 'Var', (21, 39))	('Gastric cancer', 'Disease', (106, 120))	('KLF5', 'Gene', (0, 4))	('KLF5', 'Gene', '688', (0, 4))	('Gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('Activated', 'PosReg', (8, 17))	('Gastric Cancer', 'Disease', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (43, 57))	('Gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('Cell Proliferation', 'biological_process', 'GO:0008283', ('87', '105'))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Gastric Cancer', 'Disease', 'MESH:D013274', (43, 57))	('cancer death', 'Disease', (151, 163))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer death', 'Disease', 'MESH:D009369', (151, 163))
177890	33923166	We found that KLF5 amplification mainly occurred in the chromosome instable tumors (CIN) and was significantly associated with TP53 mutation.	('mutation', 'Var', (132, 140))	('CIN', 'Disease', 'MESH:D007674', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('associated', 'Reg', (111, 121))	('KLF5', 'MPA', (14, 18))	('occurred', 'Reg', (40, 48))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('chromosome', 'cellular_component', 'GO:0005694', ('56', '66'))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('CIN', 'Disease', (84, 87))
177899	33923166	Gene amplification is a key mechanism applied by cancer to activate oncogenes.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('activate', 'PosReg', (59, 67))	('Gene amplification', 'Var', (0, 18))	('oncogenes', 'Gene', (68, 77))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
177901	33923166	Drugs such as trastuzumab that targeting HER2 had been developed and showed good effects in selected gastric cancer patients with HER2 amplification.	('gastric cancer', 'Disease', (101, 115))	('amplification', 'Var', (135, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('patients', 'Species', '9606', (116, 124))	('trastuzumab', 'Chemical', 'MESH:D000068878', (14, 25))	('HER2', 'Gene', (41, 45))	('HER2', 'Gene', (130, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('HER2', 'Gene', '2064', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('HER2', 'Gene', '2064', (41, 45))
177924	33923166	All four datasets are whole transcriptome profiling studies comparing Klf5 knockout versus wild-type mouse tissues.	('Klf5', 'Gene', (70, 74))	('knockout', 'Var', (75, 83))	('mouse', 'Species', '10090', (101, 106))
177931	33923166	Western blot was probed with antibodies against GAPDH (bsm-0978M, Bioss, Beijing, China) or KLF5 (ab24331, Abcam, Cambridge, UK).	('bsm-0978M', 'Var', (55, 64))	('GAPDH', 'Gene', '2597', (48, 53))	('GAPDH', 'Gene', (48, 53))
177935	33923166	Copy number variation (CNV) of KLF5 is prevalent in different tumor types, according to a previous study.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Copy number variation', 'Var', (0, 21))	('KLF5', 'Gene', (31, 35))	('tumor', 'Disease', (62, 67))	('prevalent', 'Reg', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
177937	33923166	In pan-cancer of 33 tumor types, the KLF5 gene showed both amplifications and deletions in different tumor types.	('deletions', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('KLF5 gene', 'Gene', (37, 46))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', (20, 25))
177938	33923166	The rates of KLF5 variation ranged from 3.6% (acute myeloid leukemia, LAML) to 76.8% (uterine carcinosarcoma, UCS).	('acute myeloid leukemia', 'Disease', (46, 68))	('carcinosarcoma', 'Disease', 'MESH:D002296', (94, 108))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (46, 68))	('variation', 'Var', (18, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (86, 108))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (52, 68))	('carcinosarcoma', 'Disease', (94, 108))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (46, 68))	('leukemia', 'Phenotype', 'HP:0001909', (60, 68))
177940	33923166	Interestingly, both amplification and deletion of KLF5 could be found at a similar rate in some cancer types, such as uterine carcinosarcoma (UCS) and bladder cancer (BLCA).	('cancer', 'Disease', (159, 165))	('bladder cancer', 'Disease', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('carcinosarcoma', 'Disease', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('bladder cancer', 'Phenotype', 'HP:0009725', (151, 165))	('KLF5', 'Gene', (50, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('found', 'Reg', (64, 69))	('deletion', 'Var', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('amplification', 'Var', (20, 33))	('carcinosarcoma', 'Disease', 'MESH:D002296', (126, 140))	('bladder cancer', 'Disease', 'MESH:D001749', (151, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (96, 102))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (118, 140))
177943	33923166	In gastric cancer and a subset of bladder cancer, there were duplications of chromosome 13q as well as regional amplification of a region close to KLF5 (Figure 1B,C).	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('duplications', 'Var', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('chromosome', 'cellular_component', 'GO:0005694', ('77', '87'))	('bladder cancer', 'Disease', 'MESH:D001749', (34, 48))	('gastric cancer', 'Disease', (3, 17))	('bladder cancer', 'Disease', (34, 48))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
177944	33923166	In prostate cancer or another subset of bladder cancer, long segment deletion of chromosome 13q accounted for the loss of KLF5 (Figure 1B).	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('loss', 'NegReg', (114, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('long segment deletion', 'Var', (56, 77))	('KLF5', 'Protein', (122, 126))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
177945	33923166	In gastrointestinal tumors with predominantly KLF5 amplification, including gastric cancer (STAD), colon cancer (COAD), and rectum cancer (READ), an increase in KLF5 transcripts could be observed (Figure 2, top 3).	('READ', 'Disease', (139, 143))	('gastrointestinal tumors', 'Disease', (3, 26))	('colon cancer', 'Disease', 'MESH:D015179', (99, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (3, 26))	('rectum cancer', 'Disease', 'MESH:D012004', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('KLF5 transcripts', 'MPA', (161, 177))	('increase', 'PosReg', (149, 157))	('colon cancer', 'Disease', (99, 111))	('READ', 'Disease', 'None', (139, 143))	('rectum cancer', 'Disease', (124, 137))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('gastric cancer', 'Disease', (76, 90))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (3, 26))	('COAD', 'Disease', 'MESH:D029424', (113, 117))	('KLF5 amplification', 'Var', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rectum cancer', 'Phenotype', 'HP:0100743', (124, 137))	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('colon cancer', 'Phenotype', 'HP:0003003', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('COAD', 'Disease', (113, 117))
177946	33923166	For prostate cancer (PRAD), kidney chromophobe (KICH), and testicular germ cell tumors (TGCT), KLF5 deletion was predominant, and a decrease in KLF5 transcription could be observed (Figure 2, middle 3).	('prostate cancer', 'Disease', 'MESH:D011471', (4, 19))	('KLF5 transcription', 'MPA', (144, 162))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('prostate cancer', 'Phenotype', 'HP:0012125', (4, 19))	('kidney chromophobe', 'Disease', (28, 46))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('KICH', 'Disease', (48, 52))	('kidney chromophobe', 'Disease', 'MESH:D000238', (28, 46))	('prostate cancer', 'Disease', (4, 19))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('KICH', 'Disease', 'None', (48, 52))	('deletion', 'Var', (100, 108))	('germ cell tumors', 'Phenotype', 'HP:0100728', (70, 86))	('transcription', 'biological_process', 'GO:0006351', ('149', '162'))	('decrease', 'NegReg', (132, 140))	('KLF5', 'Gene', (95, 99))
177947	33923166	For other tumor types such as esophageal carcinoma (ESCA), bladder urothelial carcinoma (BLCA) and uterine corpus endometrial carcinoma (UCEC), which had comparable rates of KLF5 amplification and deletion, KLF5 expression changed in accordance to its copy number (Figure 2, bottom 3).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (114, 135))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (30, 50))	('bladder urothelial carcinoma', 'Disease', (59, 87))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (30, 50))	('changed', 'Reg', (223, 230))	('deletion', 'Var', (197, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (114, 135))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (59, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('endometrial carcinoma', 'Disease', (114, 135))	('esophageal carcinoma', 'Disease', (30, 50))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
177956	33923166	This result suggested CNV of KLF5 was related to the overall chromosomal instability of gastric cancer.	('CNV', 'Var', (22, 25))	('gastric cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('KLF5', 'Gene', (29, 33))	('related', 'Reg', (38, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('chromosomal instability', 'Phenotype', 'HP:0040012', (61, 84))
177962	33923166	KLF5 high expression tumors were less represented in the diffused type of gastric cancer (odds ratio = 0.3, p = 4.0 x 10-5) and TP53 mutated samples (odds ratio = 0.56, p = 0.03) (Figure 5).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('KLF5', 'Gene', (0, 4))	('less', 'NegReg', (33, 37))	('diffused', 'Disease', (57, 65))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('tumors', 'Disease', (21, 27))	('gastric cancer', 'Disease', (74, 88))	('high expression', 'PosReg', (5, 20))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('gastric cancer', 'Disease', 'MESH:D013274', (74, 88))	('mutated', 'Var', (133, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
177963	33923166	In multivariate logistic regression analysis, the diffused type of Lauren classification, TP53 mutation, and the MSI subtype of molecular classification were independent predictors of KLF5 expression (Supplementary Table S3).	('KLF5 expression', 'MPA', (184, 199))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (90, 94))	('mutation', 'Var', (95, 103))
177974	33923166	All five studies profiled whole transcriptome of Klf5 knockout transgenic mice.	('Klf5', 'Gene', (49, 53))	('transgenic mice', 'Species', '10090', (63, 78))	('knockout', 'Var', (54, 62))
177975	33923166	Of the 84 genes, Cdkn1c (cyclin-dependent kinase inhibitor 1C) was among the few genes that were upregulated after the knockout of Klf5 (Supplementary Table S5).	('Cdkn1c', 'Gene', '1028', (17, 23))	('cyclin-dependent kinase inhibitor 1C', 'Gene', (25, 61))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('25', '58'))	('cyclin-dependent kinase inhibitor 1C', 'Gene', '1028', (25, 61))	('knockout', 'Var', (119, 127))	('Cdkn1c', 'Gene', (17, 23))	('upregulated', 'PosReg', (97, 108))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('42', '58'))
177988	33923166	After the silencing of KLF5, GPRC5A expression was significantly downregulated (Figure 7B).	('downregulated', 'NegReg', (65, 78))	('KLF5', 'Gene', (23, 27))	('GPRC5A', 'Gene', (29, 35))	('expression', 'MPA', (36, 46))	('silencing', 'Var', (10, 19))	('GPRC5A', 'Gene', '9052', (29, 35))
178002	33923166	In addition, KLF5 was inactivated by the hemizygous deletion in prostate cancer, and re-expression of KLF5 inhibits cell growth in vitro.	('cell growth in vitro', 'CPA', (116, 136))	('prostate cancer', 'Disease', (64, 79))	('cell growth', 'biological_process', 'GO:0016049', ('116', '127'))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('inhibits', 'NegReg', (107, 115))	('re-expression', 'Var', (85, 98))	('prostate cancer', 'Disease', 'MESH:D011471', (64, 79))	('KLF5', 'Gene', (102, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (64, 79))
178008	33923166	In most other tumor types, both KLF5 amplification and deletion were observed.	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('deletion', 'Var', (55, 63))
178012	33923166	More importantly, in ApcMin/KRAS V12 double transgenic mice that had a great tendency to develop small intestine tumors, deleting one allele of Klf5 led to a 92% reduction in tumor burden.	('tumor', 'Disease', (113, 118))	('KRAS', 'Gene', (28, 32))	('reduction', 'NegReg', (162, 171))	('tumor', 'Disease', (175, 180))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('transgenic mice', 'Species', '10090', (44, 59))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('deleting', 'Var', (121, 129))	('Klf5', 'Gene', (144, 148))	('KRAS', 'Gene', '16653', (28, 32))	('small intestine tumors', 'Phenotype', 'HP:0100833', (97, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
178019	33923166	However, a later study revealed that the nuclear staining of KLF5 was associated with more advanced cancer and poorer survival.	('nuclear staining', 'Var', (41, 57))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('associated', 'Reg', (70, 80))	('poorer', 'NegReg', (111, 117))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('KLF5', 'Gene', (61, 65))
178030	33923166	In addition, we also observed decreased clone formation ability of gastric cancer cells when KLF5 was silenced.	('gastric cancer', 'Disease', (67, 81))	('KLF5', 'Gene', (93, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('clone formation ability', 'CPA', (40, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('formation', 'biological_process', 'GO:0009058', ('46', '55'))	('silenced', 'Var', (102, 110))	('decreased', 'NegReg', (30, 39))
178037	33923166	In summary, this study revealed that KLF5 underwent amplification or deletion in different tumor types, which led to up- or downregulation of KLF5 mRNA expression accordingly.	('tumor', 'Disease', (91, 96))	('KLF5', 'Gene', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('downregulation', 'NegReg', (124, 138))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('up-', 'PosReg', (117, 120))	('deletion', 'Var', (69, 77))	('KLF5', 'Gene', (37, 41))	('amplification', 'Var', (52, 65))
178039	33923166	KLF5 amplification was significantly associated with genome-unstable tumors and TP53 mutation.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('TP53', 'Gene', '7157', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mutation', 'Var', (85, 93))	('TP53', 'Gene', (80, 84))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('associated', 'Reg', (37, 47))	('KLF5 amplification', 'Var', (0, 18))
178048	31219487	Overexpression of SIRT1 in urothelial carcinoma of the urinary bladder is associated with local recurrence and poor survival To investigate the relationship of Silent mating type information regulation 2 homolog-1 (SIRT1) immunostaining to urothelial carcinoma of the urinary bladder (UCB) clinicopathological parameters.	('SIRT1', 'Gene', '23411', (215, 220))	('mating', 'biological_process', 'GO:1990277', ('167', '173'))	('SIRT1', 'Gene', (215, 220))	('SIRT1', 'Gene', '23411', (18, 23))	('urothelial carcinoma of the urinary bladder', 'Disease', 'MESH:D001749', (240, 283))	('mating', 'biological_process', 'GO:0007618', ('167', '173'))	('urothelial carcinoma of the urinary bladder', 'Disease', 'MESH:D001749', (27, 70))	('mating', 'biological_process', 'GO:0000747', ('167', '173'))	('Overexpression', 'Var', (0, 14))	('regulation', 'biological_process', 'GO:0065007', ('191', '201'))	('urothelial carcinoma of the urinary bladder', 'Disease', (27, 70))	('SIRT1', 'Gene', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('urothelial carcinoma of the urinary bladder', 'Disease', (240, 283))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))
178053	31219487	High SIRT1 immunostaining was associated with local disease recurrence (p=0.017).	('SIRT1', 'Gene', (5, 10))	('SIRT1', 'Gene', '23411', (5, 10))	('High', 'Var', (0, 4))	('local disease', 'Disease', (46, 59))
178055	31219487	High SIRT1 immunostaining was associated with lower overall survival (log rank [Mantel-Cox]=6.478, and p=0.011) and disease-free survival (log rank [Mantel-Cox])=4.281, and p=0.039).	('disease-free survival', 'CPA', (116, 137))	('SIRT1', 'Gene', '23411', (5, 10))	('High', 'Var', (0, 4))	('SIRT1', 'Gene', (5, 10))	('overall survival', 'CPA', (52, 68))	('Cox', 'Gene', '1351', (87, 90))	('lower', 'NegReg', (46, 51))	('Cox', 'Gene', '1351', (156, 159))	('Cox', 'Gene', (87, 90))	('Cox', 'Gene', (156, 159))
178088	31219487	High SIRT1 immunostaining was associated with local disease recurrence (p=0.002).	('associated', 'Reg', (30, 40))	('SIRT1', 'Gene', '23411', (5, 10))	('High', 'Var', (0, 4))	('SIRT1', 'Gene', (5, 10))	('local disease recurrence', 'Disease', (46, 70))
178089	31219487	Regression analysis revealed that high SIRT1 immunostaining is an independent predictor of local disease (p=0.002, Exp B=0.250, 95% CI: [0.103-0607]).	('Exp', 'Gene', (115, 118))	('SIRT1', 'Gene', (39, 44))	('high', 'Var', (34, 38))	('local disease', 'Disease', (91, 104))	('Exp', 'Gene', '4154', (115, 118))	('SIRT1', 'Gene', '23411', (39, 44))
178090	31219487	In UCB, high SIRT1 immunostaining was associated with lower overall survival (log rank [Mantel-Cox]=6.478 and p=0.011) and disease-free survival (log rank [Mantel-Cox]=4.281 and p=0.039) Figures 2&3.	('high', 'Var', (8, 12))	('disease-free survival', 'CPA', (123, 144))	('SIRT1', 'Gene', '23411', (13, 18))	('UCB', 'Disease', (3, 6))	('Cox', 'Gene', '1351', (163, 166))	('Cox', 'Gene', (163, 166))	('SIRT1', 'Gene', (13, 18))	('overall survival', 'CPA', (60, 76))	('Cox', 'Gene', '1351', (95, 98))	('Cox', 'Gene', (95, 98))	('lower', 'NegReg', (54, 59))
178102	31219487	In this study, it was demonstrated that high SIRT1 immunostaining is associated with local disease recurrence, and regression analysis showed that high SIRT1 immunostaining is an independent predictor of local disease recurrence.	('high', 'Var', (40, 44))	('SIRT1', 'Gene', (152, 157))	('local disease recurrence', 'Disease', (85, 109))	('associated', 'Reg', (69, 79))	('high', 'Var', (147, 151))	('SIRT1', 'Gene', '23411', (152, 157))	('SIRT1', 'Gene', '23411', (45, 50))	('SIRT1', 'Gene', (45, 50))
178104	31219487	It was also demonstrated in this study that high SIRT1 immunostaining was associated with lower overall and disease-free survivals in UCB patients.	('SIRT1', 'Gene', (49, 54))	('high', 'Var', (44, 48))	('lower', 'NegReg', (90, 95))	('UCB', 'Disease', (134, 137))	('immunostaining', 'Var', (55, 69))	('overall', 'CPA', (96, 103))	('SIRT1', 'Gene', '23411', (49, 54))	('disease-free survivals', 'CPA', (108, 130))	('patients', 'Species', '9606', (138, 146))
178107	31219487	By establishing a SIRT-1 knockdown UBC model, Hu et al, concluded that proliferation and viability were suppressed with SIRT1 deficiency in UCB cells.	('SIRT-1', 'Gene', '23411', (18, 24))	('viability', 'CPA', (89, 98))	('deficiency', 'Var', (126, 136))	('SIRT1', 'Gene', '23411', (120, 125))	('SIRT-1', 'Gene', (18, 24))	('SIRT1', 'Gene', (120, 125))	('proliferation', 'CPA', (71, 84))	('suppressed', 'NegReg', (104, 114))	('UBC', 'Gene', '7316', (35, 38))	('UBC', 'Gene', (35, 38))
178116	31219487	It has been demonstrated that high HDACs expression is present in UCBs and it has been found that HDACs were significantly associated with higher tumor grade and patient survival.	('associated', 'Reg', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('exp', 'Gene', (41, 44))	('tumor', 'Disease', (146, 151))	('patient survival', 'CPA', (162, 178))	('HDACs', 'Var', (98, 103))	('patient', 'Species', '9606', (162, 169))	('exp', 'Gene', '4154', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
178117	31219487	In conclusion, the current study demonstrated that high SIRT1 immunoexpression is an independent predictor of local disease recurrence.	('exp', 'Gene', (68, 71))	('local disease recurrence', 'Disease', (110, 134))	('exp', 'Gene', '4154', (68, 71))	('high', 'Var', (51, 55))	('SIRT1', 'Gene', '23411', (56, 61))	('SIRT1', 'Gene', (56, 61))
178118	31219487	High SIRT1 immunostaining is associated with lower overall survival and disease-free survival.	('overall survival', 'CPA', (51, 67))	('SIRT1', 'Gene', '23411', (5, 10))	('High', 'Var', (0, 4))	('SIRT1', 'Gene', (5, 10))	('disease-free survival', 'CPA', (72, 93))	('lower', 'NegReg', (45, 50))
178151	29416316	Further research has described how immune-impenetrable phenotypes and robust tumor microenvironments as well as mutations disrupting MHC-T-cell interaction and interferon-gamma signaling may contribute to tumor escape.	('signaling', 'biological_process', 'GO:0023052', ('177', '186'))	('contribute', 'Reg', (191, 201))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('disrupting', 'NegReg', (122, 132))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('160', '176'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('interferon-gamma', 'Gene', (160, 176))	('mutations', 'Var', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('MHC', 'Gene', (133, 136))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('MHC', 'Gene', '3107', (133, 136))	('tumor', 'Disease', (77, 82))	('interferon-gamma', 'Gene', '3458', (160, 176))
178218	29416316	The main inclusion criteria are high-grade carcinoma in situ (CIS) at 6 months after BCG treatment, progression at 3 months after induction BCG, recurrence of high-grade CIS, or persistent CIS noted in the bladder biopsies within 3 months of completing at least two induction treatments with BCG.	('CIS', 'Phenotype', 'HP:0030075', (170, 173))	('carcinoma in situ', 'Disease', 'MESH:D002278', (43, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('BCG', 'Species', '33892', (85, 88))	('carcinoma in situ', 'Disease', (43, 60))	('CIS', 'Phenotype', 'HP:0030075', (62, 65))	('BCG', 'Species', '33892', (140, 143))	('CIS', 'Phenotype', 'HP:0030075', (189, 192))	('BCG', 'Species', '33892', (292, 295))	('CIS', 'Var', (189, 192))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (43, 60))
178222	29416316	Human leukocyte antigen heterogeneity, mutational load, TCR clonality, and T-cell tumor penetration are all active areas of interest.	('TCR', 'biological_process', 'GO:0006283', ('56', '59'))	('Human', 'Species', '9606', (0, 5))	('T-cell tumor', 'Disease', 'MESH:D016399', (75, 87))	('TCR', 'Gene', (56, 59))	('mutational', 'Var', (39, 49))	('T-cell tumor', 'Disease', (75, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('TCR', 'Gene', '6962', (56, 59))	('TCR', 'cellular_component', 'GO:0042101', ('56', '59'))
178227	28880866	Here we combined whole genome data from >700 tumors and paired normal tissues to provide a portrait of rDNA variation in human tissues and cancers of diverse mutational signatures, including stomach and lung adenocarcinomas, ovarian cancers, and others of the TCGA panel.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancers', 'Disease', (139, 146))	('human', 'Species', '9606', (121, 126))	('ovarian cancers', 'Phenotype', 'HP:0100615', (225, 240))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('variation', 'Var', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (203, 223))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('tumors', 'Disease', (45, 51))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (203, 222))	('ovarian cancers', 'Disease', (225, 240))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (203, 223))	('ovarian cancers', 'Disease', 'MESH:D010051', (225, 240))	('rDNA', 'Gene', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancers', 'Disease', (233, 240))	('lung adenocarcinomas', 'Disease', (203, 223))
178229	28880866	These somatic changes in rDNA CN occur in a background of over 10-fold naturally occurring rDNA CN variation across individuals and cCNV of 5S-45S arrays in some but not all tissues.	('5S', 'Chemical', '-', (140, 142))	('variation', 'Var', (99, 108))	('5S', 'Chemical', '-', (144, 146))	('rDNA CN', 'Gene', (91, 98))
178230	28880866	Analysis of genetic context revealed associations between cancer rDNA CN amplification or loss and the presence of specific somatic alterations, including somatic SNPs and copy number gain/losses in protein coding genes across the cancer genome.	('protein', 'Protein', (199, 206))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('loss', 'NegReg', (90, 94))	('cancer', 'Disease', (231, 237))	('rDNA CN', 'Gene', (65, 72))	('protein', 'cellular_component', 'GO:0003675', ('199', '206'))	('copy number', 'Var', (172, 183))	('gain/losses', 'PosReg', (184, 195))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('amplification', 'Var', (73, 86))
178231	28880866	For instance, somatic inactivation of the tumor suppressor gene TP53 emerged with a strong association with coupled 5S expansion / 45S loss in several cancers.	('tumor', 'Disease', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('loss', 'NegReg', (135, 139))	('tumor suppressor', 'biological_process', 'GO:0051726', ('42', '58'))	('5S expansion / 45S', 'Var', (116, 134))	('5S', 'Chemical', '-', (132, 134))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancers', 'Disease', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('5S', 'Chemical', '-', (116, 118))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('42', '58'))
178233	28880866	We suggest that 5S rDNA amplification facilitates increased proliferation, nucleolar activity, and ribosomal synthesis in cancer, whereas 45S rDNA loss emerges as a byproduct of transcription-replication conflict in rapidly replicating tumor cells.	('facilitates', 'PosReg', (38, 49))	('synthesis', 'biological_process', 'GO:0009058', ('109', '118'))	('cancer', 'Disease', (122, 128))	('increased', 'PosReg', (50, 59))	('5S', 'Chemical', '-', (16, 18))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('transcription', 'biological_process', 'GO:0006351', ('178', '191'))	('5S', 'Chemical', '-', (139, 141))	('nucleolar activity', 'MPA', (75, 93))	('amplification', 'Var', (24, 37))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('proliferation', 'CPA', (60, 73))	('ribosomal synthesis', 'MPA', (99, 118))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (236, 241))
178238	28880866	The coupled 5S amplification and 45S loss is associated with the presence of certain somatic genetic alterations, as well as increased estimates of cancerous cell proliferation rate and nucleolar activity.	('5S', 'Chemical', '-', (34, 36))	('increased', 'PosReg', (125, 134))	('cell proliferation', 'biological_process', 'GO:0008283', ('158', '176'))	('nucleolar activity', 'CPA', (186, 204))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancerous', 'Disease', 'MESH:D009369', (148, 157))	('loss', 'NegReg', (37, 41))	('5S', 'Chemical', '-', (12, 14))	('5S amplification', 'Var', (12, 28))	('cancerous', 'Disease', (148, 157))
178246	28880866	It is thus not surprising that altered ribosomal biogenesis and rRNA regulation has been linked to a variety of human diseases.	('altered', 'Var', (31, 38))	('regulation', 'biological_process', 'GO:0065007', ('69', '79'))	('rRNA regulation', 'MPA', (64, 79))	('ribosomal biogenesis', 'MPA', (39, 59))	('human', 'Species', '9606', (112, 117))	('linked', 'Reg', (89, 95))
178247	28880866	The dysregulation of cRP genes (cRPGs) can destabilize rRNAs and/or disturb their synthesis, or alternatively participate in tumorigenesis through TP53-related pathways.	('rRNAs', 'MPA', (55, 60))	('TP53', 'Gene', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('dysregulation', 'Var', (4, 17))	('disturb', 'NegReg', (68, 75))	('destabilize', 'NegReg', (43, 54))	('synthesis', 'biological_process', 'GO:0009058', ('82', '91'))	('tumor', 'Disease', (125, 130))	('cRP genes (cRPGs', 'Gene', (21, 37))	('cRPGs', 'Gene', (32, 37))	('synthesis', 'MPA', (82, 91))	('TP53', 'Gene', '7157', (147, 151))	('participate', 'Reg', (110, 121))
178259	28880866	We applied new methods and corrections for aneuploidy and sequencing batch to provide a comprehensive portrait of rDNA variation in cancer and normal tissues.	('cancer', 'Disease', (132, 138))	('variation', 'Var', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('aneuploidy', 'Disease', (43, 53))	('rDNA', 'Gene', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('aneuploidy', 'Disease', 'MESH:D000782', (43, 53))
178266	28880866	Hence, we accounted for ploidy variation in tumors using estimates of per gene copy number amplification/loss from the FireBrowse portal, which were ascertained by the GISTIC 2.0 pipeline using the genome-wide SNP array data.	('tumors', 'Disease', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('copy number amplification/loss', 'Var', (79, 109))
178279	28880866	We compared paired tumor and adjacent tissue within an individual to obtain estimates of rDNA fold-change amplification and loss in cancer lineages.	('cancer', 'Disease', (132, 138))	('loss', 'NegReg', (124, 128))	('rDNA', 'Gene', (89, 93))	('fold-change amplification', 'Var', (94, 119))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('amplification', 'Var', (106, 119))	('tumor', 'Disease', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
178290	28880866	Multiple mutations are involved in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mutations', 'Var', (9, 18))	('involved', 'Reg', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
178294	28880866	Reassuringly, the strongest association for 5S is its positive correlation with 1q42.3 amplification in STAD (Fig 4A).	('STAD', 'Disease', (104, 108))	('1q42.3 amplification', 'Var', (80, 100))	('5S', 'Chemical', '-', (44, 46))
178296	28880866	Besides 1q42 amplification, most other significant rDNA-associated SCNAs are physically unlinked to either the 45S or the 5S rDNA array.	('5S', 'Chemical', '-', (112, 114))	('rDNA-associated', 'Disease', (51, 66))	('1q42', 'Var', (8, 12))	('5S', 'Chemical', '-', (122, 124))
178297	28880866	For example, 9q34.3 amplification is significantly associated with the accumulation of 5S (Fig 4A, linear regression's coefficient = 31.15 and P = 5.23e-6), whereas 15q11.2 deletion is associated with 45S loss in STAD (Fig 4A, coefficient = -91.86 and P = 0.00022).	('STAD', 'Disease', (213, 217))	('15q11.2 deletion', 'Var', (165, 181))	('loss', 'NegReg', (205, 209))	('5S', 'Chemical', '-', (202, 204))	('5S', 'Chemical', '-', (87, 89))	('9q34.3', 'Gene', (13, 19))
178300	28880866	Specifically, 9/14 amplification events and 23/25 deletion events resulted in greater 45S rDNA loss (binomial test for total, P = 7.025e-05).	('5S', 'Chemical', '-', (87, 89))	('amplification events', 'Var', (19, 39))	('deletion events', 'Var', (50, 65))	('45S rDNA', 'CPA', (86, 94))	('loss', 'NegReg', (95, 99))
178302	28880866	Specifically, 15/19 amplification events and 11/19 deletion events resulted in greater 5S amplification (P = 0.034 for total).	('deletion events', 'Var', (51, 66))	('greater', 'PosReg', (79, 86))	('5S', 'Chemical', '-', (87, 89))	('5S amplification', 'MPA', (87, 103))	('amplification', 'Var', (20, 33))
178306	28880866	First, we observed significant positive correlations between estimates of 1q42.13 ploidy and 5S rDNA CN in LUAD, LUSC and STAD (Fig 5).	('ploidy', 'Var', (82, 88))	('LUAD', 'Phenotype', 'HP:0030078', (107, 111))	('LUSC', 'Phenotype', 'HP:0030359', (113, 117))	('5S', 'Chemical', '-', (93, 95))	('1q42.13 ploidy', 'Var', (74, 88))
178308	28880866	This suggests that amplification of the 1q42 segment is a common and recurrent mechanism causing increased 5S CN across distinct cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('increased', 'PosReg', (97, 106))	('amplification', 'Var', (19, 32))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('5S', 'Chemical', '-', (107, 109))	('5S CN', 'Disease', (107, 112))
178314	28880866	We next examined somatic mutations associated with rDNA CN amplification or loss in each cancer type.	('loss', 'NegReg', (76, 80))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('rDNA CN', 'Gene', (51, 58))	('cancer', 'Disease', (89, 95))	('amplification', 'Var', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
178316	28880866	We examined a total of 17,035 genes containing somatic mutations with 1,481 of which being present in ten to a few hundred individuals in at least one cancer type.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('mutations', 'Var', (55, 64))
178317	28880866	Strikingly, we found that TP53 mutations are negatively associated with 45S CN in STAD, HNSC (P < 0.005, Wilcoxon rank sum test) and LUAD (P = 0.012, Wilcoxon rank sum test) (Fig 4C and S4 Table).	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('negatively', 'NegReg', (45, 55))	('45S CN', 'Disease', (72, 78))	('LUAD', 'Phenotype', 'HP:0030078', (133, 137))	('HNSC', 'Phenotype', 'HP:0012288', (88, 92))	('5S', 'Chemical', '-', (73, 75))	('TP53', 'Gene', '7157', (26, 30))
178318	28880866	On the other hand, most LUSC tumors show TP53 mutations while most KIRC tumors do not show TP53 mutations, leading to low statistical power for TP53-rDNA association in both cases.	('low', 'NegReg', (118, 121))	('association', 'Interaction', (154, 165))	('TP53', 'Gene', (41, 45))	('TP53', 'Gene', (144, 148))	('TP53', 'Gene', (91, 95))	('mutations', 'Var', (46, 55))	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', '7157', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('TP53', 'Gene', '7157', (91, 95))	('LUSC', 'Phenotype', 'HP:0030359', (24, 28))
178322	28880866	Overall, the associations between mutation presence and rDNA CN are particularly apparent in LUAD, the cancer with the largest sample size.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('LUAD', 'Disease', (93, 97))	('mutation', 'Var', (34, 42))	('LUAD', 'Phenotype', 'HP:0030078', (93, 97))	('rDNA CN', 'Disease', (56, 63))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
178323	28880866	In this case, the associations between mutation presence and 45S rDNA CN are predominantly negative (Fig 4D, 49/50, binomial test P = 9.059e-14), whereas the association between mutation presence and 5S CN are predominantly positive (19/20, P = 4.005e-5).	('mutation', 'Var', (39, 47))	('associations', 'Interaction', (18, 30))	('5S', 'Chemical', '-', (62, 64))	('45S rDNA CN', 'Disease', (61, 72))	('5S', 'Chemical', '-', (200, 202))	('negative', 'NegReg', (91, 99))
178330	28880866	In this analysis TP53 mutations emerged again as one of the top candidates associated with significantly lower 45S (P = 0.0015), as well as significantly higher 5S / 45S ratio (P = 5.24e-9).	('lower', 'NegReg', (105, 110))	('5S', 'Chemical', '-', (161, 163))	('5S / 45S ratio', 'MPA', (161, 175))	('higher', 'PosReg', (154, 160))	('mutations', 'Var', (22, 31))	('45S', 'MPA', (111, 114))	('5S', 'Chemical', '-', (167, 169))	('5S', 'Chemical', '-', (112, 114))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
178331	28880866	Among genes associated with the 5S we find that 89.5% (128/143) of them displayed positive associations, indicating higher 5S rDNA CN in the presence of the mutation.	('5S', 'Chemical', '-', (123, 125))	('higher', 'PosReg', (116, 122))	('mutation', 'Var', (157, 165))	('5S', 'Chemical', '-', (32, 34))	('5S rDNA CN', 'Disease', (123, 133))
178332	28880866	In this pan-cancer analysis, >95% of all significant associations between the presence of the somatic mutation and the 5S / 45S ratio are positive.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('5S', 'Chemical', '-', (119, 121))	('cancer', 'Disease', (12, 18))	('5S', 'Chemical', '-', (125, 127))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('presence', 'Var', (78, 86))
178334	28880866	We then asked if rDNA CN variation is associated with specific TP53 mutations.	('associated', 'Reg', (38, 48))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('rDNA CN', 'Disease', (17, 24))	('mutations', 'Var', (68, 77))
178335	28880866	To address this, we did a pan-cancer analysis for TP53 mutations that recurred in at least 5 patients.	('mutations', 'Var', (55, 64))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('TP53', 'Gene', '7157', (50, 54))	('TP53', 'Gene', (50, 54))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
178337	28880866	All these mutations are missense and all of them are associated with increased 5S / 45S ratio, as expected from our previous analysis with every TP53 mutation merged.	('5S / 45S ratio', 'MPA', (79, 93))	('increased', 'PosReg', (69, 78))	('missense', 'Var', (24, 32))	('5S', 'Chemical', '-', (79, 81))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('mutations', 'Var', (10, 19))	('5S', 'Chemical', '-', (85, 87))
178338	28880866	We hypothesize that contrasting rDNA CN variation may reflect increased nucleolar activity as well as rapid tumor cell proliferation.	('variation', 'Var', (40, 49))	('increased', 'PosReg', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('cell proliferation', 'biological_process', 'GO:0008283', ('114', '132'))	('nucleolar activity', 'MPA', (72, 90))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))
178344	28880866	Notably, higher PRI is associated with lower survival probability (S7A and S7B Fig, also in), as well as more advanced tumor stages (S7C and S7D Fig).	('tumor', 'Disease', (119, 124))	('PRI', 'MPA', (16, 19))	('S7B', 'Var', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('lower', 'NegReg', (39, 44))	('survival probability', 'CPA', (45, 65))
178356	28880866	Finally, the negative correlation of TP53 mutation with 45S, and positive correlations of TP53 mutation and PRI with 5S / 45S ratio remain significant even when they were analyzed together in a multivariate model (S8 Table).	('negative', 'NegReg', (13, 21))	('5S', 'Chemical', '-', (123, 125))	('5S', 'Chemical', '-', (117, 119))	('TP53', 'Gene', '7157', (90, 94))	('mutation', 'Var', (42, 50))	('TP53', 'Gene', (90, 94))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('5S', 'Chemical', '-', (57, 59))
178360	28880866	For instance, coupled 5S gain / 45S loss are particularly salient in lineages with TP53 inactivation from stomach and lung adenocarcinomas, but can also be observed in head and neck squamous cell carcinoma.	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (118, 138))	('loss', 'NegReg', (36, 40))	('5S', 'Chemical', '-', (33, 35))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (182, 205))	('gain', 'PosReg', (25, 29))	('TP53', 'Gene', (83, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (118, 138))	('stomach', 'Disease', (106, 113))	('lung adenocarcinomas', 'Disease', (118, 138))	('neck', 'cellular_component', 'GO:0044326', ('177', '181'))	('5S', 'Chemical', '-', (22, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (168, 205))	('inactivation', 'Var', (88, 100))	('TP53', 'Gene', '7157', (83, 87))	('neck squamous cell carcinoma', 'Disease', (177, 205))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (177, 205))
178366	28880866	The naturally occurring "normal" variation also indicates that excess 45S rDNA CN does not limit cell viability, and argues against a model in which lower 45S rDNA CN facilitates tumorigenesis.	('facilitates', 'PosReg', (167, 178))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('5S', 'Chemical', '-', (71, 73))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('5S', 'Chemical', '-', (156, 158))	('lower 45S rDNA CN', 'Var', (149, 166))	('tumor', 'Disease', (179, 184))
178370	28880866	For instance, our analyses indicated that mutation in TP53 is among the strongest determinants of coupled 5S gain and 45S loss in cancer lineages.	('45S', 'CPA', (118, 121))	('5S', 'Chemical', '-', (119, 121))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('5S', 'Chemical', '-', (106, 108))	('cancer', 'Disease', (130, 136))	('TP53', 'Gene', '7157', (54, 58))	('mutation', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('loss', 'NegReg', (122, 126))	('gain', 'PosReg', (109, 113))	('TP53', 'Gene', (54, 58))
178376	28880866	This is because excess of rDNA copies has been suggested to promote global genome stability, and epigenetic regulation of the 45S rDNA could compensate for the loss of 45S rDNA alleles.	('epigenetic regulation', 'Var', (97, 118))	('promote', 'PosReg', (60, 67))	('5S', 'Chemical', '-', (127, 129))	('5S', 'Chemical', '-', (169, 171))	('regulation', 'biological_process', 'GO:0065007', ('108', '118'))	('global genome stability', 'CPA', (68, 91))
178397	28880866	Note that cancer genomes suffer from large-scale structural variation, with frequent gain or loss of whole genes, partial segments as well as large-scale chromosomal duplications/losses.	('chromosomal duplications/losses', 'Var', (154, 185))	('gain', 'PosReg', (85, 89))	('loss', 'NegReg', (93, 97))	('whole genes', 'Protein', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
178400	28880866	In this pipeline, genomic regions that undergo focal or arm-level amplification or deletion in tumors were identified by using the software GISTIC2 from the human SNP array 6.0 datasets.	('amplification', 'Var', (66, 79))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('deletion', 'Var', (83, 91))	('tumors', 'Disease', (95, 101))	('human', 'Species', '9606', (157, 162))
178432	26980028	Mutations tend to occur in certain "hot spots," most notably g.1295228C>T and g.1295250C>T.	('g.1295228C>T', 'Var', (61, 73))	('g.1295250C>T', 'Mutation', 'g.1295250C>T', (78, 90))	('g.1295228C>T', 'Mutation', 'g.1295228C>T', (61, 73))	('g.1295250C>T', 'Var', (78, 90))
178433	26980028	These mutations have been found in both noninvasive and invasive urothelial carcinomas and have been detected in urine specimens from patients with urothelial carcinoma, making them attractive candidates for early detection and disease surveillance.	('noninvasive', 'Disease', (40, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('patients', 'Species', '9606', (134, 142))	('found', 'Reg', (26, 31))	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (56, 86))	('mutations', 'Var', (6, 15))	('patient', 'Species', '9606', (134, 141))	('invasive urothelial carcinomas', 'Disease', (56, 86))
178436	26980028	Safe-SeqS amplification primers were designed to amplify segments containing the region of the TERT promoter previously shown to harbor mutations in melanomas and other tumors (Fig.	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanomas', 'Disease', 'MESH:D008545', (149, 158))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('harbor', 'Reg', (129, 135))	('mutations', 'Var', (136, 145))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('melanomas', 'Disease', (149, 158))
178441	26980028	Overall, TERT-mut were identified in 4 (28.5%) of 14 cases of primary bladder adenocarcinoma with all showing an identical mutation type (g.1295228C>T) (Table 2).	('g.1295228C>T', 'Var', (138, 150))	('g.1295228C>T', 'SUBSTITUTION', 'None', (138, 150))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (70, 92))	('bladder adenocarcinoma', 'Disease', (70, 92))	('bladder adenocarcinoma', 'Disease', 'MESH:D001749', (70, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
178444	26980028	Subsequently, our group and others demonstrated the presence of similar mutations in a wide spectrum of solid cancers, including urothelial carcinoma, gliomas, and hepatocellular carcinoma, among others.	('solid cancers', 'Disease', 'MESH:D009369', (104, 117))	('hepatocellular carcinoma', 'Disease', (164, 188))	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('presence', 'Reg', (52, 60))	('urothelial carcinoma', 'Disease', (129, 149))	('gliomas', 'Disease', (151, 158))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (164, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('solid cancers', 'Disease', (104, 117))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (164, 188))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
13755	26980028	High rates of TERT-mut have been conspicuously absent in colorectal and lung carcinomas.	('colorectal and lung carcinomas', 'Disease', 'MESH:D015179', (57, 87))	('TERT-mut', 'Var', (14, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('absent', 'NegReg', (47, 53))
178446	26980028	Here, we demonstrate, for the first time, the presence of TERT-mut in a significant subset (57%) of primary adenocarcinomas of the urinary bladder with nonenteric morphology.	('adenocarcinomas of the urinary bladder', 'Disease', 'MESH:D001749', (108, 146))	('TERT-mut', 'Var', (58, 66))	('adenocarcinomas of the urinary bladder', 'Disease', (108, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('presence', 'Reg', (46, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))
178447	26980028	All of the adenocarcinomas with TERT-mut had the same C to T mutation (g.1295228C>T).	('g.1295228C>T', 'SUBSTITUTION', 'None', (71, 83))	('adenocarcinomas', 'Disease', (11, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (16, 26))	('g.1295228C>T', 'Var', (71, 83))
178457	26980028	In summary, the present study illustrates the presence of TERT-mut in a significant proportion of primary bladder adenocarcinomas of nonenteric morphology, albeit at a slightly lower rate compared to that reported for urothelial carcinoma.	('primary bladder adenocarcinomas', 'Disease', (98, 129))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (106, 128))	('TERT-mut', 'Var', (58, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('presence', 'Var', (46, 54))	('primary bladder adenocarcinomas', 'Disease', 'MESH:D001749', (98, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))
178459	26980028	Briefly, TERT-mut were consistently detected in the urine of 74% of patients with non-invasive urothelial carcinomas and, on follow-up, were predictive of disease recurrence.	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('non-invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (82, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('TERT-mut', 'Var', (9, 17))	('non-invasive urothelial carcinomas', 'Disease', (82, 116))
178460	27111033	Somatic ERCC2 Mutations Are Associated with a Distinct Genomic Signature in Urothelial Tumors Alterations in DNA repair pathways are common in tumors and can result in characteristic mutational signatures; however, a specific mutational signature associated with somatic alterations in the nucleotide excision repair (NER) pathway has not yet been identified.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('Tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Disease', (143, 149))	('result', 'Reg', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('ERCC2', 'Gene', '2068', (8, 13))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('290', '316'))	('Urothelial Tumors', 'Disease', (76, 93))	('DNA repair', 'biological_process', 'GO:0006281', ('109', '119'))	('NER', 'biological_process', 'GO:0006289', ('318', '321'))	('Urothelial Tumors', 'Disease', 'MESH:D001749', (76, 93))	('mutational', 'MPA', (183, 193))	('DNA repair pathways', 'Pathway', (109, 128))	('ERCC2', 'Gene', (8, 13))	('Mutations', 'Var', (14, 23))	('Tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
178462	27111033	Analysis of three independent urothelial tumor cohorts reveals a strong association between somatic ERCC2 mutations and activity of a mutational signature characterized by a broad spectrum of base changes.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('urothelial tumor', 'Disease', 'MESH:D001749', (30, 46))	('urothelial tumor', 'Disease', (30, 46))	('ERCC2', 'Gene', (100, 105))	('mutations', 'Var', (106, 115))	('activity', 'MPA', (120, 128))	('ERCC2', 'Gene', '2068', (100, 105))	('mutational signature', 'MPA', (134, 154))
178464	27111033	Together, these analyses identify the first NER-related mutational signature and highlight the related roles of DNA damage and subsequent DNA repair in shaping the tumor mutational landscape.	('mutational', 'Var', (56, 66))	('tumor', 'Disease', (164, 169))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('NER', 'biological_process', 'GO:0006289', ('44', '47'))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('DNA repair', 'biological_process', 'GO:0006281', ('138', '148'))
178466	27111033	The somatic mutational landscape of tumor cells reflects the cumulative activity of discrete mutational processes operating across the lifetime of the cell, and loss of DNA repair fidelity can augment the effect of these processes and lead to increased somatic mutation rates.	('DNA repair fidelity', 'Protein', (169, 188))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('somatic mutation rates', 'CPA', (253, 275))	('DNA repair', 'biological_process', 'GO:0006281', ('169', '179'))	('increased', 'PosReg', (243, 252))	('augment', 'PosReg', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('DNA', 'cellular_component', 'GO:0005574', ('169', '172'))	('loss', 'Var', (161, 165))	('tumor', 'Disease', (36, 41))
178471	27111033	Recurrent somatic ERCC2 mutations have been identified in 6-18% of urothelial tumors in studies published by The Cancer Genome Atlas (TCGA) and others.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('Cancer Genome Atlas', 'Disease', (113, 132))	('Cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (113, 132))	('ERCC2', 'Gene', (18, 23))	('urothelial tumors', 'Disease', (67, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('identified', 'Reg', (44, 54))	('mutations', 'Var', (24, 33))	('ERCC2', 'Gene', '2068', (18, 23))	('urothelial tumors', 'Disease', 'MESH:D001749', (67, 84))
178473	27111033	Many of these carcinogens are known to damage DNA through formation of bulky intrastrand adducts, and several studies have demonstrated an increased risk of bladder cancer in individuals with polymorphisms in ERCC2 or other NER pathway genes.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('polymorphisms', 'Var', (192, 205))	('bladder cancer', 'Disease', 'MESH:D001749', (157, 171))	('ERCC2', 'Gene', '2068', (209, 214))	('formation', 'biological_process', 'GO:0009058', ('58', '67'))	('bladder cancer', 'Disease', (157, 171))	('NER', 'biological_process', 'GO:0006289', ('224', '227'))	('ERCC2', 'Gene', (209, 214))
178475	27111033	ERCC2 mutated urothelial tumors have a higher overall mutation burden than tumors with wildtype (WT) ERCC2 but a lower fraction of C>G mutations.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('ERCC2', 'Gene', '2068', (101, 106))	('higher', 'PosReg', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('urothelial tumors', 'Disease', 'MESH:D001749', (14, 31))	('ERCC2', 'Gene', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('mutation burden', 'MPA', (54, 69))	('ERCC2', 'Gene', '2068', (0, 5))	('C>G mutations', 'Var', (131, 144))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('urothelial tumors', 'Disease', (14, 31))	('tumors', 'Disease', (75, 81))	('mutated', 'Var', (6, 13))	('ERCC2', 'Gene', (0, 5))
178484	27111033	A third signature, characterized by C>T transitions at CpG dinucleotides, is found in all tumor types and is thought to result from age-related accumulation of 5-methyl-cytosine deamination events (C>T CpG in Figure 1b; COSMIC signature 1).	('5-methyl-cytosine deamination events', 'MPA', (160, 196))	('dinucleotides', 'Chemical', 'MESH:D015226', (59, 72))	('result', 'Reg', (120, 126))	('accumulation', 'PosReg', (144, 156))	('C>T CpG', 'Var', (198, 205))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('C>T', 'Var', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
178486	27111033	For each of the 283 genes that had a non-silent mutation in >5% of samples across the TCGA-130 cohort, we compared the activity of signature 5* in tumors which carried a non-silent mutation in the gene versus those that did not.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('non-silent mutation', 'Var', (170, 189))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('activity', 'MPA', (119, 127))
178488	27111033	Overall, 16 of 130 tumors had a non-silent ERCC2 mutation, and these tumors had an increase of 95 mutations (135 vs 40) in the median activity of signature 5* (Figure 3a).	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('increase', 'PosReg', (83, 91))	('signature 5*', 'MPA', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mutation', 'Var', (49, 57))	('mutations', 'Var', (98, 107))	('ERCC2', 'Gene', '2068', (43, 48))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('activity', 'MPA', (134, 142))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('ERCC2', 'Gene', (43, 48))
178494	27111033	This signature is most similar to COSMIC signature 22 (cosine similarity 0.96) and has been linked to exposure to aristolochic acid (AA), an ingredient in some food supplements that are most commonly used in Asian countries.	('linked', 'Reg', (92, 98))	('aristolochic acid', 'Chemical', 'MESH:C000228', (114, 131))	('aristolochic', 'Var', (114, 126))
178496	27111033	As in the other cohorts, tumors with a non-silent mutation in ERCC2 had increased activity of the fourth signature, which includes signature 5* (10 tumors with a non-silent ERCC2 mutation and a median increase of 55 mutations per sample; Q=0.012, P=2.5x10-4; Figure 2; Supplementary Figures 2, 4).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('increased', 'PosReg', (72, 81))	('ERCC2', 'Gene', (62, 67))	('tumors', 'Disease', (25, 31))	('ERCC2', 'Gene', '2068', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('mutation', 'Var', (179, 187))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('ERCC2', 'Gene', (173, 178))	('activity', 'MPA', (82, 90))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('ERCC2', 'Gene', '2068', (62, 67))
178498	27111033	Among the 35 tumors with a non-silent ERCC2 mutation, the median signature 5* activity was increased by 91 mutations compared to WT ERCC2 tumors (124 vs 33), providing the strongest statistical evidence for the association between ERCC2 and signature 5* activity (Q=1.6x10-3, P=1.0x10-5; Fig 2; Supplementary Figure 2, 4).	('mutation', 'Var', (44, 52))	('ERCC2', 'Gene', '2068', (132, 137))	('ERCC2', 'Gene', (231, 236))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('WT ERCC2 tumors', 'Disease', 'MESH:C536751', (129, 144))	('ERCC2', 'Gene', '2068', (231, 236))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('increased', 'PosReg', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('ERCC2', 'Gene', (38, 43))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('signature 5* activity', 'MPA', (65, 86))	('ERCC2', 'Gene', '2068', (38, 43))	('mutations', 'Var', (107, 116))	('WT ERCC2 tumors', 'Disease', (129, 144))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (138, 144))	('ERCC2', 'Gene', (132, 137))
178499	27111033	Together, these data strongly suggest that although signature 5* activity is present in both WT and mutant ERCC2 tumors, somatic ERCC2 mutations are associated with a significant increase in signature 5* activity.	('ERCC2 tumors', 'Disease', 'MESH:D009369', (107, 119))	('mutant', 'Var', (100, 106))	('ERCC2', 'Gene', (107, 112))	('signature 5* activity', 'MPA', (191, 212))	('mutations', 'Var', (135, 144))	('ERCC2', 'Gene', '2068', (129, 134))	('ERCC2 tumors', 'Disease', (107, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('increase', 'PosReg', (179, 187))	('ERCC2', 'Gene', (129, 134))	('ERCC2', 'Gene', '2068', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
178501	27111033	The combined cohort (COMB-279) segregated into two clusters of 222 and 57 tumors, with 25 of the 35 ERCC2 mutated tumors in the second cluster (P=1.7x10-12, Fisher's exact test; Supplementary Figure 6a).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('ERCC2', 'Gene', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('mutated', 'Var', (106, 113))	('ERCC2', 'Gene', '2068', (100, 105))
178502	27111033	Repeating the analysis using the 242 muscle-invasive tumors across cohorts (COMB-MI-242) yielded a more significant association between clusters and ERCC2 mutations (P=4.4x10-14, Supplementary Fig 6b).	('mutations', 'Var', (155, 164))	('ERCC2', 'Gene', '2068', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('ERCC2', 'Gene', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
178503	27111033	Although ERCC2 mutations are associated with higher overall mutation burden, segregation was not driven by it, as ERCC2 mutated tumors segregated less strongly when clustering was performed using the total number of SNVs (PCOMB-279=0.1, PCOMB-MI-242=0.008; Supplementary Figure 6c, d).	('ERCC2', 'Gene', '2068', (9, 14))	('ERCC2', 'Gene', '2068', (114, 119))	('mutations', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('ERCC2', 'Gene', (114, 119))	('mutation burden', 'MPA', (60, 75))	('ERCC2', 'Gene', (9, 14))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
178504	27111033	All but one of the 35 non-silent ERCC2 mutations across cohorts were missense mutations, and most (25 of 34) were located within or adjacent to (+-10 amino acids) the conserved helicase motifs, suggesting that the mutations may have an impact on ERCC2 protein function (Supplementary Figure 7a).	('protein', 'Protein', (252, 259))	('impact', 'Reg', (236, 242))	('function', 'MPA', (260, 268))	('ERCC2', 'Gene', '2068', (246, 251))	('ERCC2', 'Gene', '2068', (33, 38))	('mutations', 'Var', (214, 223))	('mutations', 'Var', (39, 48))	('protein', 'cellular_component', 'GO:0003675', ('252', '259'))	('ERCC2', 'Gene', (246, 251))	('ERCC2', 'Gene', (33, 38))
178505	27111033	To assess the spatial relationship of the mutations, we utilized CLUMPS, a novel algorithm for assessing spatial clustering of mutations within 3D protein structures, and found that the ERCC2 mutations were significantly clustered (p=0.0026), further suggesting a functional role (Supplementary Figure 7b; Methods).	('ERCC2', 'Gene', (186, 191))	('mutations', 'Var', (192, 201))	('ERCC2', 'Gene', '2068', (186, 191))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))
178506	27111033	For each of the three cohorts analyzed here, ERCC2 mutated tumors have been shown to have an increase in overall mutation burden compared to WT ERCC2 tumors.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('ERCC2', 'Gene', '2068', (45, 50))	('ERCC2', 'Gene', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('increase', 'PosReg', (93, 101))	('WT ERCC2 tumors', 'Disease', 'MESH:C536751', (141, 156))	('ERCC2', 'Gene', (45, 50))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('mutation burden', 'MPA', (113, 128))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('WT ERCC2 tumors', 'Disease', (141, 156))	('ERCC2', 'Gene', '2068', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mutated', 'Var', (51, 58))
178507	27111033	Indeed, activity of the APOBEC2 signature was also increased in ERCC2 mutated tumors compared to WT ERCC2 tumors in the TCGA-130 cohort (39 vs 12, P=0.004; Figure 3b); however, unlike the association between ERCC2 and signature 5*, the association of ERCC2 with the APOBEC2 signature was not significant after correcting for multiple testing (Q=0.54).	('tumors', 'Disease', (106, 112))	('activity', 'MPA', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ERCC2', 'Gene', (208, 213))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('APOBEC2', 'Gene', '10930', (266, 273))	('APOBEC', 'cellular_component', 'GO:0030895', ('24', '30'))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('WT ERCC2 tumors', 'Disease', 'MESH:C536751', (97, 112))	('ERCC2', 'Gene', '2068', (208, 213))	('APOBEC2', 'Gene', (24, 31))	('ERCC2', 'Gene', (64, 69))	('tumors', 'Disease', (78, 84))	('increased', 'PosReg', (51, 60))	('ERCC2', 'Gene', '2068', (64, 69))	('APOBEC', 'cellular_component', 'GO:0030895', ('266', '272'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('ERCC2', 'Gene', (251, 256))	('APOBEC2', 'Gene', (266, 273))	('ERCC2', 'Gene', (100, 105))	('WT ERCC2 tumors', 'Disease', (97, 112))	('APOBEC2', 'Gene', '10930', (24, 31))	('ERCC2', 'Gene', '2068', (251, 256))	('mutated', 'Var', (70, 77))	('ERCC2', 'Gene', '2068', (100, 105))
178509	27111033	There was no increase in activity of the APOBEC1 (78 vs 103 in TCGA-130, P=0.99) or C>T CpG (0 vs 13, P=0.91) signatures in mutant vs WT ERCC2 tumors in any of the cohorts (Fig 3b; Supplementary Figure 8).	('APOBEC1', 'Gene', '339', (41, 48))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('WT ERCC2 tumors', 'Disease', (134, 149))	('mutant', 'Var', (124, 130))	('APOBEC1', 'Gene', (41, 48))	('APOBEC', 'cellular_component', 'GO:0030895', ('41', '47'))	('WT ERCC2 tumors', 'Disease', 'MESH:C536751', (134, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('activity', 'MPA', (25, 33))
178510	27111033	These results demonstrate that the increase in overall mutation burden in ERCC2 mutated tumors is due primarily to increased activity of signature 5*, with an additional smaller contribution from the APOBEC2 signature.	('mutation burden', 'MPA', (55, 70))	('increase', 'PosReg', (35, 43))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('APOBEC2', 'Gene', (200, 207))	('increased', 'PosReg', (115, 124))	('ERCC2', 'Gene', '2068', (74, 79))	('activity', 'MPA', (125, 133))	('APOBEC', 'cellular_component', 'GO:0030895', ('200', '206'))	('mutated', 'Var', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('ERCC2', 'Gene', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('APOBEC2', 'Gene', '10930', (200, 207))
178511	27111033	Despite the strong association between signature 5* activity and ERCC2 mutational status, several tumors with high signature 5* activity lacked a somatic ERCC2 mutation.	('ERCC2', 'Gene', (154, 159))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('ERCC2', 'Gene', (65, 70))	('lacked', 'NegReg', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('mutational', 'Var', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ERCC2', 'Gene', '2068', (154, 159))	('ERCC2', 'Gene', '2068', (65, 70))	('association', 'Interaction', (19, 30))
178512	27111033	Somatic mutations in other NER pathway genes are less common in urothelial tumors, and there was no statistically significant association between signature 5* and mutations in any individual NER gene or the pathway as a whole (when ERCC2 is excluded)(Figure 4; Supplementary Figure 10).	('NER', 'Gene', (27, 30))	('mutations', 'Var', (163, 172))	('NER', 'biological_process', 'GO:0006289', ('27', '30'))	('urothelial tumors', 'Disease', (64, 81))	('NER', 'Gene', (191, 194))	('ERCC2', 'Gene', '2068', (232, 237))	('NER', 'biological_process', 'GO:0006289', ('191', '194'))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('ERCC2', 'Gene', (232, 237))	('urothelial tumors', 'Disease', 'MESH:D001749', (64, 81))
178513	27111033	However, anecdotally, among the 20 WT ERCC2 tumors with the highest signature 5* activity, six had a mutation in a different gene in the NER pathway.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('NER', 'biological_process', 'GO:0006289', ('137', '140'))	('WT ERCC2 tumors', 'Disease', 'MESH:C536751', (35, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('WT ERCC2 tumors', 'Disease', (35, 50))	('NER pathway', 'Pathway', (137, 148))	('activity', 'MPA', (81, 89))	('mutation', 'Var', (101, 109))
178514	27111033	In addition, germline data was available for the TCGA-130 and DFCI/MSK-50 cohorts, and there was a trend towards an association between rare (<2% frequency in the cohorts) NER germline variants and signature 5* activity in WT ERCC2 cases (19 of the 32 WT ERCC2 tumors with highest signature 5* activity had a NER germline variant versus only 54 of the remaining 123 WT ERCC2 tumors, p=0.086; Methods; Supplementary Figure 11a).	('WT ERCC2 tumors', 'Disease', (366, 381))	('ERCC2', 'Gene', (226, 231))	('NER', 'biological_process', 'GO:0006289', ('309', '312'))	('NER', 'biological_process', 'GO:0006289', ('172', '175'))	('variants', 'Var', (185, 193))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('ERCC2', 'Gene', (255, 260))	('ERCC2', 'Gene', '2068', (369, 374))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (375, 381))	('ERCC2', 'Gene', '2068', (226, 231))	('WT ERCC2 tumors', 'Disease', 'MESH:C536751', (252, 267))	('ERCC2', 'Gene', (369, 374))	('WT ERCC2 tumors', 'Disease', (252, 267))	('WT ERCC2 tumors', 'Disease', 'MESH:C536751', (366, 381))	('ERCC2', 'Gene', '2068', (255, 260))
178519	27111033	However, activity of signature 5* was significantly higher in smokers than non-smokers (median number of signature 5* mutations: 49 vs 33, p= 0.009; Figure 5b), although the effect size is modest compared to that of an ERCC2 mutation (Figure 5c).	('ERCC2', 'Gene', (219, 224))	('mutations', 'Var', (118, 127))	('activity', 'MPA', (9, 17))	('signature 5*', 'Gene', (105, 117))	('higher', 'PosReg', (52, 58))	('ERCC2', 'Gene', '2068', (219, 224))
178520	27111033	There were no differences in signature 5* activity between current and former smokers; however, there was a correlation between smoking intensity (pack-years) and signature 5* activity in ERCC2 mutated cases (P=0.01; Supplementary Fig 12).	('correlation', 'Interaction', (108, 119))	('ERCC2', 'Gene', (188, 193))	('mutated', 'Var', (194, 201))	('ERCC2', 'Gene', '2068', (188, 193))
178521	27111033	Although an association between smoking and COSMIC signature 5 has previously been noted in lung adenocarcinoma, a different and more common smoking-related signature characterized by frequent C>A transversions (COSMIC signature 4) was not identified in any of the urothelial cohorts analyzed here.	('C>A transversions', 'Var', (193, 210))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (92, 111))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (92, 111))	('lung adenocarcinoma', 'Disease', (92, 111))
178522	27111033	In addition, a bias for C>A transversions on the transcribed strand (similar to COSMIC signature 4) was also observed and may arise from decreased repair of tobacco-induced guanine damage on the non-transcribed strand.	('guanine', 'Chemical', 'MESH:D006147', (173, 180))	('tobacco', 'Species', '4097', (157, 164))	('C>A transversions', 'Var', (24, 41))	('decreased', 'NegReg', (137, 146))	('repair', 'MPA', (147, 153))
178525	27111033	Similarly, on multivariate regression analysis, ERCC2 mutational status (P=3.5x10-14) and smoking (P=0.038) were significantly associated with signature 5* activity, while age (P=0.60) and gender (P=0.48) were not.	('associated', 'Reg', (127, 137))	('ERCC2', 'Gene', (48, 53))	('signature 5* activity', 'MPA', (143, 164))	('mutational status', 'Var', (54, 71))	('ERCC2', 'Gene', '2068', (48, 53))
178526	27111033	To further investigate the factors influencing signature 5* activity, we used ABSOLUTE to estimate the cancer cell fraction (CCF) of each mutation in the 126 tumors from the TCGA-130 cohort for which allelic copy-number data were available (Methods).	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cell fraction', 'cellular_component', 'GO:0000267', ('110', '123'))	('mutation', 'Var', (138, 146))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
178527	27111033	Sixteen of the 126 tumors (13%) had a somatic ERCC2 mutation and all 16 mutations were heterozygous.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('ERCC2', 'Gene', '2068', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('ERCC2', 'Gene', (46, 51))	('mutation', 'Var', (52, 60))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
178528	27111033	We reasoned that if ERCC2 mutations are responsible for increasing the number of signature 5* mutations (rather than just being associated with higher signature 5* activity), then tumors with clonal ERCC2 mutations would have a higher ratio of clonal to subclonal signature 5* mutations than tumors with subclonal ERCC2 mutations.	('ERCC2', 'Gene', '2068', (314, 319))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('mutations', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('ERCC2', 'Gene', (199, 204))	('higher', 'PosReg', (228, 234))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Disease', (292, 298))	('tumors', 'Disease', (180, 186))	('ERCC2', 'Gene', '2068', (199, 204))	('mutations', 'Var', (94, 103))	('mutations', 'Var', (205, 214))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('ERCC2', 'Gene', (20, 25))	('ERCC2', 'Gene', (314, 319))	('increasing', 'PosReg', (56, 66))	('ERCC2', 'Gene', '2068', (20, 25))	('signature 5*', 'Gene', (81, 93))
178529	27111033	Supporting this hypothesis, we found that clonal signature 5* mutations were enriched in tumors with clonal mutations of ERCC2 (clonal:subclonal ratio~5, P=0.0098; pairwise Mann-Whitney test) but not in tumors with subclonal ERCC2 mutations (clonal:subclonal ratio~1.1, P=0.81) or with WT ERCC2 (clonal:subclonal ratio~1.9, P=0.49; Figure 6, Supplementary Figure 17).	('tumors', 'Disease', (89, 95))	('ERCC2', 'Gene', '2068', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('ERCC2', 'Gene', '2068', (225, 230))	('ERCC2', 'Gene', '2068', (289, 294))	('mutations', 'Var', (108, 117))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('ERCC2', 'Gene', (121, 126))	('ERCC2', 'Gene', (225, 230))	('ERCC2', 'Gene', (289, 294))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mutations', 'Var', (62, 71))
178530	27111033	Overall, these data suggest that somatic ERCC2 mutations are often early events in tumorigenesis and drive signature 5* activity.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('ERCC2', 'Gene', (41, 46))	('mutations', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('ERCC2', 'Gene', '2068', (41, 46))
178532	27111033	We recently showed that ERCC2 mutations are enriched in urothelial tumors responsive to cisplatin-based chemotherapy, and other studies have identified additional genetic alterations that characterize cisplatin-responsive tumors.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('ERCC2', 'Gene', (24, 29))	('responsive to cisplatin-based chemotherapy', 'MPA', (74, 116))	('cisplatin', 'Chemical', 'MESH:D002945', (201, 210))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('urothelial tumors', 'Disease', 'MESH:D001749', (56, 73))	('mutations', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('ERCC2', 'Gene', '2068', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (222, 228))	('tumors', 'Disease', (67, 73))	('urothelial tumors', 'Disease', (56, 73))
178535	27111033	Here, we identify and validate an association between somatic non-silent mutations in ERCC2 and activity of a specific mutational signature in three independent urothelial tumor cohorts.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('activity', 'MPA', (96, 104))	('urothelial tumor', 'Disease', 'MESH:D001749', (161, 177))	('urothelial tumor', 'Disease', (161, 177))	('ERCC2', 'Gene', (86, 91))	('non-silent mutations', 'Var', (62, 82))	('ERCC2', 'Gene', '2068', (86, 91))
178536	27111033	Urothelial cancer is unique in that it is the only known tumor type in which the core NER gene ERCC2 is significantly mutated.	('Urothelial cancer', 'Disease', (0, 17))	('ERCC2', 'Gene', (95, 100))	('NER', 'biological_process', 'GO:0006289', ('86', '89'))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('mutated', 'Var', (118, 125))	('core', 'cellular_component', 'GO:0019013', ('81', '85'))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('ERCC2', 'Gene', '2068', (95, 100))	('Urothelial cancer', 'Disease', 'MESH:D014523', (0, 17))	('tumor', 'Disease', (57, 62))
178538	27111033	Therefore, it is unlikely that ERCC2 mutations are solely responsible for signature 5* activity across tumor types.	('ERCC2', 'Gene', '2068', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('ERCC2', 'Gene', (31, 36))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
178539	27111033	In urothelial cancer, somatic ERCC2 mutations appear to be the most common genetic event driving upregulation of lower-fidelity repair pathways and signature 5* activity, whereas in other tumor types, signature 5* activity may result from other genetic or environmental factors that result in increased activity of lower-fidelity repair pathways.	('tumor', 'Disease', (188, 193))	('signature 5* activity', 'MPA', (148, 169))	('upregulation', 'PosReg', (97, 109))	('activity', 'MPA', (303, 311))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('urothelial cancer', 'Disease', (3, 20))	('mutations', 'Var', (36, 45))	('lower-fidelity repair pathways', 'Pathway', (113, 143))	('ERCC2', 'Gene', '2068', (30, 35))	('lower-fidelity', 'Pathway', (315, 329))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('urothelial cancer', 'Disease', 'MESH:D014523', (3, 20))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('ERCC2', 'Gene', (30, 35))
178540	27111033	Given that recurrent ERCC2 mutations appear to be unique to urothelial cancer and are often early events in tumorigenesis, additional efforts to understand the role of ERCC2 in bladder tumor biology may provide important insights.	('mutations', 'Var', (27, 36))	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('urothelial cancer', 'Disease', 'MESH:D014523', (60, 77))	('ERCC2', 'Gene', (168, 173))	('ERCC2', 'Gene', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('bladder tumor', 'Disease', 'MESH:D001749', (177, 190))	('bladder tumor', 'Phenotype', 'HP:0009725', (177, 190))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('ERCC2', 'Gene', '2068', (168, 173))	('ERCC2', 'Gene', '2068', (21, 26))	('urothelial cancer', 'Disease', (60, 77))	('bladder tumor', 'Disease', (177, 190))
178544	27111033	Together, our data suggest that the genomic imprint of signature 5* depends on both the extent of DNA damage (from tobacco or others mutagens) as well as the relative activity of high- and low-fidelity DNA repair pathways, which is altered in the setting of an ERCC2 mutation.	('mutation', 'Var', (267, 275))	('DNA repair pathways', 'Pathway', (202, 221))	('DNA', 'cellular_component', 'GO:0005574', ('202', '205'))	('ERCC2', 'Gene', (261, 266))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('DNA repair', 'biological_process', 'GO:0006281', ('202', '212'))	('tobacco', 'Species', '4097', (115, 122))	('ERCC2', 'Gene', '2068', (261, 266))
178545	27111033	Further studies will be needed to characterize the mechanisms underlying signature 5* activity in tumors that lack an ERCC2 mutation and to explore potential relationships between signature 5* activity and clinically relevant endpoints such as treatment response.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('ERCC2', 'Gene', '2068', (118, 123))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('activity', 'MPA', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutation', 'Var', (124, 132))	('ERCC2', 'Gene', (118, 123))
178549	27111033	Since a collection of somatic mutations in a cancer genome is an outcome of multiple mutagenic processes operating over the lifetime of a patient, the mutation load xij is a superposition of signature-driven mutation burdens  derived from the latent (unobserved) K mutagenic processes.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('mutation', 'Var', (151, 159))	('patient', 'Species', '9606', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('mutations', 'Var', (30, 39))	('cancer', 'Disease', (45, 51))
178556	27111033	Once ERCC2 was identified as the gene with mutation status most significantly associated with signature 5* activity, we utilized the Wilcoxon rank-sum test in assessing downstream associations between smoking status (in ERCC2 mutant or wildtype samples) and overall mutation burden (Figure 5a) or signature 5* activity (Figures 5b, 5c; Supplementary Figures 12, 13).	('ERCC2', 'Gene', '2068', (220, 225))	('associated', 'Reg', (78, 88))	('mutant', 'Var', (226, 232))	('signature', 'MPA', (94, 103))	('activity', 'MPA', (107, 115))	('ERCC2', 'Gene', (220, 225))	('ERCC2', 'Gene', '2068', (5, 10))	('activity', 'MPA', (310, 318))	('ERCC2', 'Gene', (5, 10))
178558	27111033	ERCC2 mutations were mapped to the bacterial protein based on a global sequence alignment of the two proteins using the Uniprot alignment tool with default parameters.	('ERCC2', 'Gene', '2068', (0, 5))	('mutations', 'Var', (6, 15))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('ERCC2', 'Gene', (0, 5))
178561	27111033	We identified all germline variants in 28 manually curated nucleotide excision repair (NER) genes: ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, ERCC8, DDB1, DDB2, GTF2H1, GTF2H2, GTF2H3, GTF2H4, GTF2H5, LIG1, RAD23A, RAD23B, XPA, XPC, CETN2, CUL4B, CUL4A, CDK7, MNAT1, UVSSA, MMS19, ERCC6-PGBD3, and BIVM-ERCC5.	('ERCC2', 'Gene', (106, 111))	('GTF2H1', 'Gene', (160, 166))	('variants', 'Var', (27, 35))	('ERCC6', 'Gene', '2074', (280, 285))	('ERCC1', 'Gene', '2067', (99, 104))	('UVSSA', 'Gene', (266, 271))	('ERCC5', 'Gene', '2073', (302, 307))	('RAD23B', 'Gene', (214, 220))	('ERCC6', 'Gene', (280, 285))	('CUL4B', 'Gene', (239, 244))	('DDB1', 'Gene', (148, 152))	('RAD23A', 'Gene', (206, 212))	('NER', 'biological_process', 'GO:0006289', ('87', '90'))	('CUL4B', 'Gene', '8450', (239, 244))	('ERCC2', 'Gene', '2068', (106, 111))	('MNAT1', 'Gene', '4331', (259, 264))	('RAD', 'biological_process', 'GO:1990116', ('206', '209'))	('BIVM-ERCC5', 'Gene', (297, 307))	('ERCC1', 'Gene', (99, 104))	('GTF2H5', 'Gene', (192, 198))	('ERCC5', 'Gene', (302, 307))	('ERCC5', 'Gene', '2073', (127, 132))	('UVSSA', 'Gene', '57654', (266, 271))	('ERCC6', 'Gene', '2074', (134, 139))	('XPC', 'Gene', '7508', (227, 230))	('ERCC6', 'Gene', (134, 139))	('CDK7', 'Gene', (253, 257))	('LIG1', 'Gene', (200, 204))	('RAD', 'biological_process', 'GO:1990116', ('214', '217'))	('XPA', 'Gene', (222, 225))	('LIG1', 'Gene', '3978', (200, 204))	('CETN2', 'Gene', (232, 237))	('CUL4A', 'Gene', '8451', (246, 251))	('ERCC5', 'Gene', (127, 132))	('GTF2H4', 'Gene', (184, 190))	('CDK7', 'Gene', '1022', (253, 257))	('XPA', 'Gene', '7507', (222, 225))	('MNAT1', 'Gene', (259, 264))	('XPC', 'Gene', (227, 230))	('CDK', 'molecular_function', 'GO:0004693', ('253', '256'))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('59', '85'))	('ERCC3', 'Gene', (113, 118))	('CETN2', 'Gene', '1069', (232, 237))	('ERCC6-PGBD3', 'Gene', '2074;267004', (280, 291))	('GTF2H2', 'Gene', (168, 174))	('CUL4A', 'Gene', (246, 251))	('GTF2H1', 'Gene', '2965', (160, 166))	('MMS19', 'Gene', (273, 278))	('GTF2H3', 'Gene', '2967', (176, 182))	('BIVM-ERCC5', 'Gene', '100533467;54841;2073', (297, 307))	('ERCC4', 'Gene', (120, 125))	('ERCC8', 'Gene', '1161', (141, 146))	('DDB2', 'Gene', '1643', (154, 158))	('ERCC4', 'Gene', '2072', (120, 125))	('RAD23A', 'Gene', '5886', (206, 212))	('GTF2H2', 'Gene', '2966', (168, 174))	('DDB2', 'Gene', (154, 158))	('ERCC8', 'Gene', (141, 146))	('ERCC6-PGBD3', 'Gene', (280, 291))	('DDB1', 'Gene', '1642', (148, 152))	('GTF2H4', 'Gene', '2968', (184, 190))	('MMS19', 'Gene', '64210', (273, 278))	('GTF2H5', 'Gene', '404672', (192, 198))	('GTF2H3', 'Gene', (176, 182))	('ERCC3', 'Gene', '2071', (113, 118))	('RAD23B', 'Gene', '5887', (214, 220))
178562	27111033	To identify an overall enrichment of NER germline variants in samples with a high signature 5* activity, we first computed the running enrichment score (ES) for somatic ERCC2 mutations, which quantifies the degree to which somatic ERCC2 mutations are over-represented in samples with high signature 5* activity (Supplementary Figure 11a).	('ERCC2', 'Gene', '2068', (231, 236))	('ERCC2', 'Gene', '2068', (169, 174))	('NER', 'biological_process', 'GO:0006289', ('37', '40'))	('ERCC2', 'Gene', (231, 236))	('mutations', 'Var', (175, 184))	('variants', 'Var', (50, 58))	('ERCC2', 'Gene', (169, 174))	('over-represented', 'PosReg', (251, 267))	('mutations', 'Var', (237, 246))
178563	27111033	The overall enrichment of NER pathway germline variants was assessed using a one-tailed Fisher's exact test with 2 x 2 contingency table for ERCC2 mutation status and the sample grouping.	('ERCC2', 'Gene', '2068', (141, 146))	('mutation', 'Var', (147, 155))	('ERCC2', 'Gene', (141, 146))	('NER pathway', 'Pathway', (26, 37))	('NER', 'biological_process', 'GO:0006289', ('26', '29'))
178564	27111033	We also repeated the same statistical test after removing samples with somatic ERCC2 mutations in order to examine enrichment of NER germline variants in WT ERCC2 samples.	('ERCC2', 'Gene', (79, 84))	('ERCC2', 'Gene', '2068', (157, 162))	('mutations', 'Var', (85, 94))	('ERCC2', 'Gene', '2068', (79, 84))	('NER', 'biological_process', 'GO:0006289', ('129', '132'))	('ERCC2', 'Gene', (157, 162))
178565	27111033	To eliminate the contribution of ERCC2 somatic mutations on the signature enrichment, the analysis was restricted to WT ERCC2 samples, which identified several germline variants that were associated with signature 5* activity (Supplementary Figure 11b).	('ERCC2', 'Gene', (120, 125))	('signature 5* activity', 'MPA', (204, 225))	('associated', 'Reg', (188, 198))	('ERCC2', 'Gene', '2068', (33, 38))	('ERCC2', 'Gene', '2068', (120, 125))	('ERCC2', 'Gene', (33, 38))	('variants', 'Var', (169, 177))
178566	27111033	ABSOLUTE also estimates local copy-number in the cancer cells and the cancer cell fraction (CCF) of each mutation (i.e., the fraction of cancer cells harboring the mutation).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutation', 'Var', (105, 113))	('cell fraction', 'cellular_component', 'GO:0000267', ('77', '90'))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (49, 55))
178567	27111033	The enrichment analysis of clonal signature 5* mutations in samples with clonal ERCC2 mutations (Figure 6 and Supplementary Figure 17) was performed by pair-wise comparisons of the number of clonal versus subclonal mutations attributed to signature 5* in samples with clonal ERCC2 mutations using the two-tailed pairwise Mann-Whitney test.	('mutations', 'Var', (86, 95))	('ERCC2', 'Gene', '2068', (80, 85))	('ERCC2', 'Gene', (275, 280))	('mutations', 'Var', (47, 56))	('ERCC2', 'Gene', (80, 85))	('mutations', 'Var', (281, 290))	('ERCC2', 'Gene', '2068', (275, 280))
178568	27111033	The age, gender, smoking status, and ERCC2 mutation status were considered as regression variables to explain the activity of signature 5* as a response variable in a multivariate linear regression model.	('mutation', 'Var', (43, 51))	('ERCC2', 'Gene', (37, 42))	('ERCC2', 'Gene', '2068', (37, 42))
178590	23299537	Numerous genetic and epigenetic alterations are found in urothelial bladder cancers.	('urothelial bladder cancers', 'Disease', (57, 83))	('bladder cancers', 'Phenotype', 'HP:0009725', (68, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('bladder cancer', 'Phenotype', 'HP:0009725', (68, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('urothelial bladder cancers', 'Disease', 'MESH:D001749', (57, 83))	('found', 'Reg', (48, 53))	('epigenetic alterations', 'Var', (21, 43))	('genetic', 'Var', (9, 16))
178592	23299537	Inactivating somatic alterations of the retinoblastoma tumour-suppressor gene, RB1, are also prevalent in urothelial carcinomas and have been associated with more invasive tumour variants.	('retinoblastoma', 'Phenotype', 'HP:0009919', (40, 54))	('invasive tumour', 'Disease', (163, 178))	('prevalent', 'Reg', (93, 102))	('urothelial carcinomas', 'Disease', (106, 127))	('RB1', 'Gene', (79, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('RB1', 'Gene', '5925', (79, 82))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (106, 127))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('retinoblastoma tumour', 'Disease', 'MESH:D012175', (40, 61))	('associated with', 'Reg', (142, 157))	('Inactivating somatic alterations', 'Var', (0, 32))	('retinoblastoma tumour', 'Disease', (40, 61))	('invasive tumour', 'Disease', 'MESH:D009361', (163, 178))
178593	23299537	Furthermore, a large proportion of urothelial cancers exhibit aberrant activation of mitogenic signalling pathways linked to the Ras oncoprotein, for example, via somatic ras gene mutations that occur in 30-40% of all urothelial bladder cancers or via missense mutations of the FGFR3 receptor tyrosine kinase gene that acts as an upstream regulator of HRas.	('FGFR3', 'Gene', '2261', (278, 283))	('urothelial bladder cancers', 'Disease', 'MESH:D001749', (218, 244))	('signalling', 'biological_process', 'GO:0023052', ('95', '105'))	('urothelial bladder cancers', 'Disease', (218, 244))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('urothelial cancers', 'Disease', (35, 53))	('missense mutations', 'Var', (252, 270))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('mutations', 'Var', (180, 189))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('activation', 'PosReg', (71, 81))	('bladder cancers', 'Phenotype', 'HP:0009725', (229, 244))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('ras', 'Gene', (171, 174))	('mitogenic signalling pathways', 'Pathway', (85, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (229, 243))	('FGFR', 'molecular_function', 'GO:0005007', ('278', '282'))	('FGFR3', 'Gene', (278, 283))	('urothelial cancers', 'Disease', 'MESH:D014523', (35, 53))
178595	23299537	To address this issue, we (1) analysed BTG2 expression in bladder cancer cells in vitro, (2) tested phenotypic alterations of bladder cancer cells upon silencing of endogenous BTG2 expression by RNA interference (RNAi), (3) investigated BTG2 protein expression in bladder cancer cystectomy specimens by immunohistochemistry, and (4) examined a possible correlation between BTG2 expression levels in the tumours and the clinical prognosis of bladder cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (264, 278))	('BTG2', 'Gene', '7832', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (449, 455))	('BTG2', 'Gene', '7832', (237, 241))	('bladder cancer', 'Disease', 'MESH:D001749', (126, 140))	('bladder cancer', 'Disease', (126, 140))	('patients', 'Species', '9606', (456, 464))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (126, 140))	('BTG2', 'Gene', (176, 180))	('protein', 'cellular_component', 'GO:0003675', ('242', '249'))	('tumours', 'Disease', (403, 410))	('BTG2', 'Gene', (373, 377))	('RNA', 'cellular_component', 'GO:0005562', ('195', '198'))	('tumours', 'Phenotype', 'HP:0002664', (403, 410))	('silencing', 'Var', (152, 161))	('tumours', 'Disease', 'MESH:D009369', (403, 410))	('BTG2', 'Gene', (39, 43))	('investigated', 'Reg', (224, 236))	('bladder cancer', 'Disease', 'MESH:D001749', (441, 455))	('examined', 'Reg', (333, 341))	('BTG2', 'Gene', '7832', (176, 180))	('RNAi', 'biological_process', 'GO:0016246', ('213', '217'))	('bladder cancer', 'Disease', (441, 455))	('BTG2', 'Gene', '7832', (373, 377))	('RNA interference', 'biological_process', 'GO:0016246', ('195', '211'))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('bladder cancer', 'Disease', (58, 72))	('tumour', 'Phenotype', 'HP:0002664', (403, 409))	('BTG2', 'Gene', (237, 241))	('bladder cancer', 'Disease', 'MESH:D001749', (264, 278))	('bladder cancer', 'Disease', (264, 278))	('bladder cancer', 'Phenotype', 'HP:0009725', (441, 455))
178667	23299537	Taken together, these results show that silencing of endogenous BTG2 expression markedly reduces the motility of bladder cancer cells and thus indicate that BTG2 substantially contributes to their migratory activity.	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('migratory activity', 'CPA', (197, 215))	('BTG2', 'Gene', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (113, 127))	('motility', 'CPA', (101, 109))	('BTG2', 'Gene', (157, 161))	('BTG2', 'Gene', '7832', (64, 68))	('BTG2', 'Gene', '7832', (157, 161))	('bladder cancer', 'Disease', (113, 127))	('silencing', 'Var', (40, 49))	('contributes', 'Reg', (176, 187))	('reduces', 'NegReg', (89, 96))
178684	23299537	As shown in Figure 6A, Kaplan-Meier cancer-specific survival curves of the whole cohort of patients (all histologies) revealed a significantly worse prognosis in patients with high BTG2 levels compared with low and moderate BTG2 levels (P=0.02).	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (91, 99))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('BTG2', 'Gene', (181, 185))	('BTG2', 'Gene', (224, 228))	('BTG2', 'Gene', '7832', (181, 185))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('BTG2', 'Gene', '7832', (224, 228))	('high', 'Var', (176, 180))
178685	23299537	In subgroup analyses of patients with urothelial carcinoma or SCC of the bladder, high levels of BTG2 showed a strong tendency towards being an independent predictor of poor cancer-specific survival (P=0.05 and P=0.12, respectively; Figure 6B and C).	('high levels', 'Var', (82, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('BTG2', 'Gene', '7832', (97, 101))	('poor', 'NegReg', (169, 173))	('SCC', 'Gene', '6317', (62, 65))	('SCC', 'Gene', (62, 65))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (38, 58))	('patients', 'Species', '9606', (24, 32))	('urothelial carcinoma', 'Disease', (38, 58))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('BTG2', 'Gene', (97, 101))
178686	23299537	On univariate survival analyses, the risk of death from bladder cancer for patients showing high BTG2 levels in the tumour was significantly enhanced above that for bladder cancer patients who exhibited low BTG2 levels (Supplementary Table S3, HR 2.01, P=0.007).	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('tumour', 'Disease', (116, 122))	('death', 'Disease', 'MESH:D003643', (45, 50))	('patients', 'Species', '9606', (180, 188))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('bladder cancer', 'Disease', (56, 70))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('BTG2', 'Gene', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('BTG2', 'Gene', (207, 211))	('high', 'Var', (92, 96))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('enhanced', 'PosReg', (141, 149))	('death', 'Disease', (45, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (165, 179))	('bladder cancer', 'Disease', (165, 179))	('BTG2', 'Gene', '7832', (97, 101))	('BTG2', 'Gene', '7832', (207, 211))	('bladder cancer', 'Phenotype', 'HP:0009725', (165, 179))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
178688	23299537	In subgroup analyses of urothelial carcinoma, the risk of death for patients with high BTG2 levels in the tumour was also clearly enhanced above that for patients who have low BTG2 levels (Supplementary Table S4, HR=2.4, P=0.02).	('BTG2', 'Gene', (176, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('enhanced', 'PosReg', (130, 138))	('BTG2', 'Gene', '7832', (176, 180))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('high', 'Var', (82, 86))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (24, 44))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('death', 'Disease', 'MESH:D003643', (58, 63))	('death', 'Disease', (58, 63))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (68, 76))	('tumour', 'Disease', (106, 112))	('urothelial carcinoma', 'Disease', (24, 44))	('BTG2', 'Gene', (87, 91))	('BTG2', 'Gene', '7832', (87, 91))
178692	23299537	These analyses revealed that high BTG2 expression displays a strong tendency to be an independent prognostic marker of cancer-specific survival (Supplementary Table S3, HR=2.31, P=0.09).	('high', 'Var', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('BTG2', 'Gene', (34, 38))	('BTG2', 'Gene', '7832', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
178704	23299537	Both assays yielded consistent results, showing a profound reduction of bladder cancer cell migration upon BTG2 suppression.	('reduction of bladder cancer', 'Disease', (59, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cell migration', 'biological_process', 'GO:0016477', ('87', '101'))	('reduction of bladder cancer', 'Disease', 'MESH:D001749', (59, 86))	('suppression', 'Var', (112, 123))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('BTG2', 'Gene', (107, 111))	('BTG2', 'Gene', '7832', (107, 111))
178714	23299537	In contrast, we observed a strongly increased risk of death from urinary bladder cancer for patients exhibiting high BTG2 levels in the tumour tissue when compared with patients with low BTG2 levels (Figure 6A).	('BTG2', 'Gene', (187, 191))	('urinary bladder cancer', 'Disease', (65, 87))	('death', 'Disease', 'MESH:D003643', (54, 59))	('death', 'Disease', (54, 59))	('patients', 'Species', '9606', (169, 177))	('BTG2', 'Gene', '7832', (117, 121))	('BTG2', 'Gene', '7832', (187, 191))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (65, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('high', 'Var', (112, 116))	('tumour', 'Disease', (136, 142))	('patients', 'Species', '9606', (92, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('BTG2', 'Gene', (117, 121))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
178717	23299537	In subgroup analyses of urothelial carcinoma, univariate Cox regression analyses again demonstrated increased levels of BTG2 as a significant risk factor for cancer-specific death (Supplementary Table S4, P=0.02).	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('increased', 'PosReg', (100, 109))	('Cox', 'Gene', (57, 60))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (24, 44))	('death', 'Disease', 'MESH:D003643', (174, 179))	('death', 'Disease', (174, 179))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('BTG2', 'Gene', (120, 124))	('BTG2', 'Gene', '7832', (120, 124))	('levels', 'Var', (110, 116))	('cancer', 'Disease', (158, 164))	('urothelial carcinoma', 'Disease', (24, 44))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('Cox', 'Gene', '1351', (57, 60))
178724	23299537	In conclusion, our study shows that inhibition of endogenous BTG2 expression substantially reduced the motility of bladder cancer cells.	('bladder cancer', 'Disease', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('inhibition', 'Var', (36, 46))	('BTG2', 'Gene', (61, 65))	('motility of', 'CPA', (103, 114))	('reduced', 'NegReg', (91, 98))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('BTG2', 'Gene', '7832', (61, 65))	('bladder cancer', 'Disease', 'MESH:D001749', (115, 129))
178730	29456764	Integrative analysis of the epigenetic basis of muscle-invasive urothelial carcinoma Elucidation of epigenetic alterations in bladder cancer will lead to further understanding of the biology of the disease and hopefully improved therapies.	('bladder cancer', 'Phenotype', 'HP:0009725', (126, 140))	('epigenetic alterations', 'Var', (100, 122))	('rat', 'Species', '10116', (115, 118))	('muscle-invasive urothelial carcinoma', 'Disease', 'MESH:D009217', (48, 84))	('rat', 'Species', '10116', (5, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('bladder cancer', 'Disease', 'MESH:D001749', (126, 140))	('bladder cancer', 'Disease', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('muscle-invasive urothelial carcinoma', 'Disease', (48, 84))
178738	29456764	Genes involved in estrogen metabolism were also hypermethylated while genes involved in the EGFR pathway were found to be hypomethylated.	('estrogen metabolism', 'biological_process', 'GO:0008210', ('18', '37'))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('estrogen', 'MPA', (18, 26))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('hypermethylated', 'Var', (48, 63))
178740	29456764	In patients with invasive urothelial carcinoma, we found differential methylation in patients with better and worse prognosis after cystectomy.	('invasive urothelial carcinoma', 'Disease', (17, 46))	('methylation', 'biological_process', 'GO:0032259', ('70', '81'))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('patients', 'Species', '9606', (85, 93))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (17, 46))	('methylation', 'Var', (70, 81))	('patients', 'Species', '9606', (3, 11))
178741	29456764	Differentially methylated genes are involved in many relevant oncologic pathways, including EGFR and antioxidant pathways, that may be a target for therapy or chemoprevention.	('oncologic pathways', 'Pathway', (62, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('Differentially methylated genes', 'Var', (0, 31))	('antioxidant pathways', 'Pathway', (101, 121))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('involved', 'Reg', (36, 44))
178748	29456764	The Cancer Genome Atlas (TCGA) project demonstrated impressive diversity in both genetic and epigenetic alterations within patients who have muscle-invasive urothelial carcinoma of the bladder.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('rat', 'Species', '10116', (108, 111))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (157, 192))	('rat', 'Species', '10116', (46, 49))	('muscle-invasive urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (141, 192))	('patients', 'Species', '9606', (123, 131))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('invasive urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (148, 192))	('Cancer Genome Atlas', 'Disease', (4, 23))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('epigenetic alterations', 'Var', (93, 115))
178783	29456764	There was a slightly higher proportion of genes hypermethylated in patients in the worse prognosis group (survive < 2 years) when compared with the group with better prognosis (survive > 2 years), but this difference was not statistically significant (p = 0.18).	('genes', 'Gene', (42, 47))	('hypermethylated', 'Var', (48, 63))	('patients', 'Species', '9606', (67, 75))
178786	29456764	Of the 24 genes unique to patients who died within 2 years of surgery, 19 had been described as being candidate tumor suppressor genes or hypermethylated in various cancer types, including urothelial carcinoma (Table 2).	('tumor suppressor', 'molecular_function', 'GO:0008181', ('112', '128'))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (189, 209))	('patients', 'Species', '9606', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('tumor', 'Disease', (112, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('112', '128'))	('urothelial carcinoma', 'Disease', (189, 209))	('hypermethylated', 'Var', (138, 153))
178793	29456764	This heatmap demonstrates patients who survive less than 2 years may have hypermethylation of multiple genes associated with hypermethylation in various cancer types and/or poor prognosis.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('associated', 'Reg', (109, 119))	('cancer', 'Disease', (153, 159))	('hypermethylation', 'Var', (125, 141))	('hypermethylation', 'MPA', (74, 90))	('patients', 'Species', '9606', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('rat', 'Species', '10116', (20, 23))
178795	29456764	For hypermethylated genes, pathways involved in management of free radicals were found to be significant:both the glutathione and NRF2 pathways are key antioxidant pathways.	('glutathione', 'Chemical', 'MESH:D005978', (114, 125))	('men', 'Species', '9606', (54, 57))	('NRF2 pathways', 'Pathway', (130, 143))	('hypermethylated', 'Var', (4, 19))	('free radicals', 'Chemical', 'MESH:D005609', (62, 75))
178803	29456764	Epigenetic changes and modifications are an important part of carcinogenesis and subsequent tumor progression.	('carcinogenesis', 'Disease', (62, 76))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('carcinogenesis', 'Disease', 'MESH:D063646', (62, 76))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('modifications', 'Var', (23, 36))	('tumor', 'Disease', (92, 97))	('Epigenetic changes', 'Var', (0, 18))
178804	29456764	Of the various epigenetic mechanisms, DNA methylation has been most studied and is classically associated with gene silencing via hypermethylation of CpG islands located in promoter regions of tumor suppressor genes.	('gene', 'MPA', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor suppressor', 'biological_process', 'GO:0051726', ('193', '209'))	('gene silencing', 'biological_process', 'GO:0016458', ('111', '125'))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('193', '209'))	('DNA methylation', 'biological_process', 'GO:0006306', ('38', '53'))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('DNA methylation', 'Var', (38, 53))	('tumor', 'Disease', (193, 198))	('hypermethylation', 'Var', (130, 146))
178806	29456764	Alterations in DNA methylation may be involved in the development of urothelial carcinoma of the bladder, with abnormalities identified in the normal urothelium of those who later develop frank cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('methylation', 'Var', (19, 30))	('cancer', 'Disease', (194, 200))	('Alterations', 'Var', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('involved', 'Reg', (38, 46))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (69, 104))	('urothelial carcinoma of the bladder', 'Disease', (69, 104))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (69, 104))	('DNA', 'Protein', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))	('men', 'Species', '9606', (61, 64))	('rat', 'Species', '10116', (4, 7))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
178807	29456764	However, the methylation status of specific genes has been shown to be associated with worse prognosis, indicating that epigenetic changes may also be involved in tumor progression.	('methylation', 'MPA', (13, 24))	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('epigenetic changes', 'Var', (120, 138))	('involved', 'Reg', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('associated', 'Reg', (71, 81))
178810	29456764	In addition to hypermethylation of specific genes, there was also evidence of an association between hypermethylation of multiple genes (characterized by a methylation index) and increased cancer aggressiveness.	('cancer aggressiveness', 'Disease', (189, 210))	('hypermethylation', 'Var', (101, 117))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('aggressiveness', 'Phenotype', 'HP:0000718', (196, 210))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (189, 210))	('increased', 'PosReg', (179, 188))	('methylation', 'biological_process', 'GO:0032259', ('156', '167'))
178813	29456764	Although the TCGA has revealed the remarkable diversity of genetic alterations in bladder cancer, with only lung cancer harboring more mutations per megabase, it is clear that not all identified abnormalities contribute to the development of urothelial cancer, as many events deemed abnormal using high-throughput screening may have no biologic effect.	('urothelial cancer', 'Disease', (242, 259))	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('only lung cancer', 'Disease', 'MESH:D008175', (103, 119))	('rat', 'Species', '10116', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('urothelial cancer', 'Disease', 'MESH:D014523', (242, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('alterations', 'Var', (67, 78))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))	('bladder cancer', 'Disease', (82, 96))	('only lung cancer', 'Disease', (103, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('men', 'Species', '9606', (234, 237))
178815	29456764	demonstrated only 8% of methylated genes had an effect on gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('58', '73'))	('rat', 'Species', '10116', (7, 10))	('methylated', 'Var', (24, 34))	('gene expression', 'MPA', (58, 73))
178823	29456764	As a proof of principle, we show that many patients had hypermethylation of multiple poor-prognosis genes, suggesting that there may be many combinations of hypermethylation events that can lead to poor prognosis.	('patients', 'Species', '9606', (43, 51))	('hypermethylation', 'Var', (56, 72))	('poor-prognosis genes', 'Gene', (85, 105))
178830	29456764	In mice, knockout of the NRF2 gene increased susceptibility to formation of invasive bladder tumors in response to administration of a carcinogen.	('invasive bladder tumors', 'Disease', (76, 99))	('formation', 'biological_process', 'GO:0009058', ('63', '72'))	('knockout', 'Var', (9, 17))	('response to administration of a carcinogen', 'MPA', (103, 145))	('NRF2', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('susceptibility', 'MPA', (45, 59))	('mice', 'Species', '10090', (3, 7))	('invasive bladder tumors', 'Disease', 'MESH:D001749', (76, 99))	('rat', 'Species', '10116', (123, 126))	('bladder tumors', 'Phenotype', 'HP:0009725', (85, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('invasive bladder', 'Phenotype', 'HP:0100645', (76, 92))
178834	29456764	A second interesting observation was enrichment of hypomethylated genes associated with the epidermal growth factor receptor (EGFR) pathway.	('EGFR', 'Gene', (126, 130))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('associated', 'Reg', (72, 82))	('hypomethylated genes', 'Var', (51, 71))	('epidermal growth factor receptor', 'Gene', '1956', (92, 124))	('men', 'Species', '9606', (43, 46))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('92', '115'))	('EGFR', 'Gene', '1956', (126, 130))	('epidermal growth factor receptor', 'Gene', (92, 124))
178838	29456764	In this study, our integrative approach supports the findings of others showing that hypermethylation of specific genes is associated with aggressive urothelial carcinoma.	('hypermethylation', 'Var', (85, 101))	('associated', 'Reg', (123, 133))	('aggressive urothelial carcinoma', 'Disease', 'MESH:D001523', (139, 170))	('aggressive urothelial carcinoma', 'Disease', (139, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('rat', 'Species', '10116', (24, 27))
178841	29456764	Genes involved in oncologically relevant pathways including EGFR were found to be hypomethylated.	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', (60, 64))	('hypomethylated', 'Var', (82, 96))
178861	29348878	Different cancers usually share common hallmarks, such as evading growth suppressors, resisting cell death and inducing angiogenesis.	('growth suppressors', 'CPA', (66, 84))	('angiogenesis', 'biological_process', 'GO:0001525', ('120', '132'))	('resisting cell death', 'CPA', (86, 106))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cell death', 'biological_process', 'GO:0008219', ('96', '106'))	('evading', 'Var', (58, 65))	('inducing', 'Reg', (111, 119))	('angiogenesis', 'CPA', (120, 132))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('cancers', 'Disease', (10, 17))
178912	29348878	The BPs in the M7 are associated with the negative regulation of extracellular matrix disassembly and endothelial cell migration.	('endothelial cell migration', 'CPA', (102, 128))	('BPs', 'Var', (4, 7))	('extracellular matrix disassembly', 'CPA', (65, 97))	('negative', 'NegReg', (42, 50))	('endothelial cell migration', 'biological_process', 'GO:0043542', ('102', '128'))	('rat', 'Species', '10116', (122, 125))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('65', '85'))	('negative regulation of extracellular matrix disassembly', 'biological_process', 'GO:0010716', ('42', '97'))
178915	29348878	It has been reported that alterations in glycosylation impacted cell cycle and may support neoplastic progression.	('cell cycle', 'CPA', (64, 74))	('impacted', 'Reg', (55, 63))	('glycosylation', 'biological_process', 'GO:0070085', ('41', '54'))	('neoplastic progression', 'CPA', (91, 113))	('glycosylation', 'MPA', (41, 54))	('alterations', 'Var', (26, 37))	('rat', 'Species', '10116', (30, 33))	('cell cycle', 'biological_process', 'GO:0007049', ('64', '74'))	('support', 'PosReg', (83, 90))
179210	18588456	Furthermore, false-positive tests have been shown to portend a four- to tenfold increase in the risk of recurrence of bladder cancer.	('recurrence of bladder cancer', 'Phenotype', 'HP:0012786', (104, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('bladder cancer', 'Disease', 'MESH:D001749', (118, 132))	('bladder cancer', 'Disease', (118, 132))	('false', 'biological_process', 'GO:0071878', ('13', '18'))	('false-positive tests', 'Var', (13, 33))	('bladder cancer', 'Phenotype', 'HP:0009725', (118, 132))	('false', 'biological_process', 'GO:0071877', ('13', '18'))
179242	18588456	sFas blocks Fas-Fas-L interaction and, hence, inhibits apoptosis.	('sFas', 'Var', (0, 4))	('blocks', 'NegReg', (5, 11))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('Fas-L', 'Gene', '356', (16, 21))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('inhibits', 'NegReg', (46, 54))	('Fas-L', 'Gene', (16, 21))	('apoptosis', 'CPA', (55, 64))
179278	18588456	A multitude of different locations of microsatellite alterations have been identified in bladder cancer, including chromosomes 4p, 8p, 9p and q, and 11p.	('microsatellite alterations', 'Var', (38, 64))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))
179279	18588456	Over a large number of studies, microsatellite DNA analysis is shown to have a sensitivity of 72-100%, and a specificity of greater than 80% in detecting both primary and recurrent tumors.	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('microsatellite DNA', 'Var', (32, 50))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
179284	18588456	However, these authors pointed out that microsatellite alterations are reflections of a urothelium with changes that may make tumor development more likely, as opposed to predicting clear tumor formation.	('tumor', 'Disease', (188, 193))	('formation', 'biological_process', 'GO:0009058', ('194', '203'))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('changes', 'Var', (104, 111))	('microsatellite alterations', 'Var', (40, 66))	('tumor', 'Disease', (126, 131))
179297	18588456	These include presence of mutated oncogenes and methylation of promoters of tumor suppressor genes.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('76', '92'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('presence', 'Reg', (14, 22))	('mutated', 'Var', (26, 33))	('tumor suppressor', 'biological_process', 'GO:0051726', ('76', '92'))	('methylation', 'Var', (48, 59))	('oncogenes', 'Protein', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
179298	18588456	Nonetheless, very recent studies have linked hypermethylation of known tumor suppressor genes, such as the retinoblastoma gene and p14/ARF, with the presence of urothelial malignancy.	('tumor suppressor', 'biological_process', 'GO:0051726', ('71', '87'))	('urothelial malignancy', 'Disease', 'MESH:D009369', (161, 182))	('hypermethylation', 'Var', (45, 61))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('71', '87'))	('retinoblastoma', 'Gene', '5925', (107, 121))	('ARF', 'Disease', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('retinoblastoma', 'Gene', (107, 121))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('retinoblastoma', 'Phenotype', 'HP:0009919', (107, 121))	('p14', 'Gene', (131, 134))	('tumor', 'Disease', (71, 76))	('ARF', 'Disease', 'MESH:D058186', (135, 138))	('p14', 'Gene', '1029', (131, 134))	('urothelial malignancy', 'Disease', (161, 182))
179302	18588456	As mentioned earlier, mutations in the genes that regulate the cell cycle are frequently seen in bladder carcinoma.	('bladder carcinoma', 'Phenotype', 'HP:0002862', (97, 114))	('cell cycle', 'biological_process', 'GO:0007049', ('63', '73'))	('bladder carcinoma', 'Disease', 'MESH:D001749', (97, 114))	('mutations', 'Var', (22, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('bladder carcinoma', 'Disease', (97, 114))	('seen', 'Reg', (89, 93))
179304	18588456	p53 has been the most studied regulatory target, with authors linking genetic alterations to recurrence and progression in a number of studies.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('recurrence', 'Disease', (93, 103))	('genetic alterations', 'Var', (70, 89))
179305	18588456	Some recent data also suggest that a higher proportion of deranged p53 correlates with increasingly invasive tumors.	('invasive tumors', 'Disease', 'MESH:D009369', (100, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('p53', 'Gene', '7157', (67, 70))	('p53', 'Gene', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('deranged', 'Var', (58, 66))	('invasive tumors', 'Disease', (100, 115))
179332	18588456	Future tumor marker trends include molecular markers, including genetic mutations in pathways leading to or precluding malignant transformation.	('tumor', 'Disease', (7, 12))	('pathways', 'Pathway', (85, 93))	('genetic mutations', 'Var', (64, 81))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
179351	24307907	The final pathology showed a pT2aG3 urothelial carcinoma and multiple sites of urothelial in situ carcinoma.	('pT2aG3', 'Var', (29, 35))	('urothelial carcinoma', 'Disease', (36, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('situ carcinoma', 'Disease', 'MESH:D002278', (93, 107))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (36, 56))	('situ carcinoma', 'Disease', (93, 107))
179355	24307907	Final pathologic report revealed a pT2 g3 urothelial carcinoma with no involvement of any lymph nodes, while all surgical margins were clear.	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('pT2 g3', 'Var', (35, 41))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (42, 62))	('urothelial carcinoma', 'Disease', (42, 62))
179374	23483488	Moreover, blockade of tumor-derived IgG by either antihuman IgG antibody or antisense oligonucleotides increased cell apoptosis and inhibited cell growth in bladder cancer cell lines in vitro, and antihuman IgG antibody could suppress the growth of xenotransplant tumor in vivo.	('IgG', 'Gene', (60, 63))	('IgG antibody', 'Phenotype', 'HP:0003237', (207, 219))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('IgG', 'Gene', '16059', (207, 210))	('apoptosis', 'biological_process', 'GO:0097194', ('118', '127'))	('apoptosis', 'biological_process', 'GO:0006915', ('118', '127'))	('human', 'Species', '9606', (201, 206))	('cell growth', 'biological_process', 'GO:0016049', ('142', '153'))	('inhibited', 'NegReg', (132, 141))	('IgG antibody', 'cellular_component', 'GO:0071736', ('207', '219'))	('cell apoptosis', 'CPA', (113, 127))	('tumor', 'Disease', (264, 269))	('antihuman', 'Var', (197, 206))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('IgG antibody', 'cellular_component', 'GO:0071736', ('60', '72'))	('IgG', 'Gene', (207, 210))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('IgG antibody', 'Phenotype', 'HP:0003237', (60, 72))	('IgG', 'Gene', '16059', (36, 39))	('bladder cancer', 'Disease', 'MESH:D001749', (157, 171))	('IgG', 'Gene', '16059', (60, 63))	('oligonucleotides', 'Chemical', 'MESH:D009841', (86, 102))	('bladder cancer', 'Disease', (157, 171))	('human', 'Species', '9606', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('antibody', 'molecular_function', 'GO:0003823', ('64', '72'))	('increased', 'PosReg', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('antibody', 'molecular_function', 'GO:0003823', ('211', '219'))	('IgG', 'Gene', (36, 39))	('tumor', 'Disease', (22, 27))	('suppress', 'NegReg', (226, 234))
179375	23483488	In addition, either antihuman IgG antibody or antisense oligonucleotides enhanced the sensitivity to mitomycin C in bladder cancer cell line T24.	('mitomycin C', 'Chemical', 'MESH:D016685', (101, 112))	('oligonucleotides', 'Chemical', 'MESH:D009841', (56, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (116, 130))	('human', 'Species', '9606', (24, 29))	('IgG antibody', 'cellular_component', 'GO:0071736', ('30', '42'))	('bladder cancer', 'Disease', 'MESH:D001749', (116, 130))	('bladder cancer', 'Disease', (116, 130))	('IgG', 'Gene', '16059', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('enhanced', 'PosReg', (73, 81))	('sensitivity to mitomycin C', 'MPA', (86, 112))	('antisense oligonucleotides', 'Var', (46, 72))	('IgG antibody', 'Phenotype', 'HP:0003237', (30, 42))	('antibody', 'molecular_function', 'GO:0003823', ('34', '42'))	('IgG', 'Gene', (30, 33))
179376	23483488	Furthermore, blockade of IgG in bladder cancer cell T24 resulted in upregulation of cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase.	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('bladder cancer', 'Disease', (32, 46))	('blockade', 'Var', (13, 21))	('IgG', 'Gene', (25, 28))	('caspase-3', 'Gene', (92, 101))	('poly(ADP-ribose) polymerase', 'Gene', '142', (114, 141))	('upregulation', 'PosReg', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('poly(ADP-ribose) polymerase', 'Gene', (114, 141))	('caspase-3', 'Gene', '836', (92, 101))	('IgG', 'Gene', '16059', (25, 28))
179377	23483488	Our results indicated that bladder cancer cells were capable of expressing IgG, and blockade of IgG expression induced cell apoptosis through activation of caspase-dependent pathway.	('bladder cancer', 'Disease', (27, 41))	('IgG', 'Gene', '16059', (96, 99))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('activation', 'PosReg', (142, 152))	('cell apoptosis', 'CPA', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('IgG', 'Gene', (96, 99))	('bladder cancer', 'Phenotype', 'HP:0009725', (27, 41))	('IgG', 'Gene', '16059', (75, 78))	('bladder cancer', 'Disease', 'MESH:D001749', (27, 41))	('IgG', 'Gene', (75, 78))	('blockade', 'Var', (84, 92))	('caspase-dependent pathway', 'Pathway', (156, 181))
179397	23483488	The immunohistochemistry results were evaluated and classified as - (positive cell under 10 %), + (positive cells 10-30 %), ++ (positive cell under 30-50 %), +++ (positive cells 50-70 %), and ++++ (positive cells 70-100 %) by one senior pathologist without knowledge of the clinicopathological outcomes of the patients.	('patients', 'Species', '9606', (310, 318))	('++++', 'Var', (192, 196))	('+++', 'Var', (158, 161))
179404	23483488	The primers were IgG (184 bp) (forward, ACT ACA AGA CCA CGC CTC C and reverse, CGT CGC ACT CAT TTA CCC), beta-actin (569 bp) (forward, ACT ACC TCA TGA AGA TCC TC and reverse, CTA AAG ATT GCG TGG CGA GG).	('569', 'Var', (117, 120))	('IgG', 'Gene', (17, 20))	('TCC', 'cellular_component', 'GO:0005579', ('155', '158'))	('CGT', 'molecular_function', 'GO:0047801', ('79', '82'))	('beta-actin', 'Gene', (105, 115))	('GCG', 'Gene', (187, 190))	('beta-actin', 'Gene', '728378', (105, 115))	('CAT', 'molecular_function', 'GO:0004096', ('91', '94'))	('CCC', 'cellular_component', 'GO:0030896', ('99', '102'))	('GCG', 'Gene', '2641', (187, 190))	('IgG', 'Gene', '16059', (17, 20))
179407	23483488	Antibodies used for immunoblot analysis were against human IgG (IR512, Dako, Denmark), Caspase-3 (1:500 dilution, sc-7272, Santa Cruz, USA), poly(ADP-ribose) polymerase (PARP) (1:1,000 dilution, sc-1562, Santa Cruz, USA), GAPDH (1:3,000 dilution, sc-32233, Santa Cruz, USA).	('poly(ADP-ribose) polymerase (PARP)', 'Gene', '142', (141, 175))	('Caspase-3', 'Gene', (87, 96))	('IgG', 'Gene', (59, 62))	('Caspase-3', 'Gene', '836', (87, 96))	('poly(ADP-ribose) polymerase (PARP', 'Gene', (141, 174))	('sc-32233', 'Var', (247, 255))	('human', 'Species', '9606', (53, 58))	('GAPDH', 'Gene', (222, 227))	('IgG', 'Gene', '16059', (59, 62))
179446	23483488	Flow cytometry (FCM) shows the percentages of apoptotic cells in T24 cells treated with PBS (Fig.	('PBS', 'Var', (88, 91))	('apoptotic cells', 'CPA', (46, 61))	('PBS', 'Chemical', '-', (88, 91))
179479	23483488	In order to explore the biological effects of tumor-derived IgG in human bladder cancer, we blocked the expression of tumor-derived IgG by either anti-human IgG antibody or antisense oligonucleotides in vitro.	('IgG', 'Gene', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('antisense', 'Var', (173, 182))	('IgG antibody', 'cellular_component', 'GO:0071736', ('157', '169'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))	('antibody', 'molecular_function', 'GO:0003823', ('161', '169'))	('bladder cancer', 'Disease', (73, 87))	('blocked', 'NegReg', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('IgG antibody', 'Phenotype', 'HP:0003237', (157, 169))	('IgG', 'Gene', '16059', (157, 160))	('oligonucleotides', 'Chemical', 'MESH:D009841', (183, 199))	('human', 'Species', '9606', (151, 156))	('tumor', 'Disease', (46, 51))	('IgG', 'Gene', '16059', (132, 135))	('IgG', 'Gene', '16059', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('IgG', 'Gene', (157, 160))	('IgG', 'Gene', (132, 135))	('tumor', 'Disease', (118, 123))	('human', 'Species', '9606', (67, 72))
179480	23483488	Functional studies showed that after blockage of IgG in bladder cancer, the cell growth was inhibited and cell apoptosis was increased.	('IgG', 'Gene', '16059', (49, 52))	('increased', 'PosReg', (125, 134))	('inhibited', 'NegReg', (92, 101))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('cell growth', 'biological_process', 'GO:0016049', ('76', '87'))	('cell apoptosis', 'CPA', (106, 120))	('IgG', 'Gene', (49, 52))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('blockage', 'Var', (37, 45))	('cell growth', 'CPA', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('bladder cancer', 'Disease', (56, 70))
179482	23483488	In addition, combined antihuman IgG antibody or antisense oligonucleotides with mitomycin C could enhance its sensitivity to mitomycin C in bladder cancer cell T24.	('enhance', 'PosReg', (98, 105))	('antisense oligonucleotides', 'Var', (48, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (140, 154))	('IgG antibody', 'Phenotype', 'HP:0003237', (32, 44))	('IgG antibody', 'cellular_component', 'GO:0071736', ('32', '44'))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('mitomycin C', 'Chemical', 'MESH:D016685', (125, 136))	('IgG', 'Gene', '16059', (32, 35))	('mitomycin C', 'Chemical', 'MESH:D016685', (80, 91))	('bladder cancer', 'Disease', 'MESH:D001749', (140, 154))	('bladder cancer', 'Disease', (140, 154))	('oligonucleotides', 'Chemical', 'MESH:D009841', (58, 74))	('antibody', 'molecular_function', 'GO:0003823', ('36', '44'))	('combined', 'Interaction', (13, 21))	('IgG', 'Gene', (32, 35))	('human', 'Species', '9606', (26, 31))	('sensitivity to mitomycin C', 'MPA', (110, 136))
179487	23483488	Further study confirmed that antibodies may enhance tumor cell proliferation by immune complex binding and crosslinking of Fc-receptors expressed either on tumor cells or immune effect cells augmenting tumor growth and a metastatic phenotype during transition to malignancy.	('tumor', 'Disease', (52, 57))	('men', 'Species', '9606', (194, 197))	('augmenting', 'NegReg', (191, 201))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('enhance', 'PosReg', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('crosslinking', 'Var', (107, 119))	('malignancy', 'Disease', 'MESH:D009369', (263, 273))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Fc-receptors', 'Gene', (123, 135))	('immune complex binding', 'Interaction', (80, 102))	('cell proliferation', 'biological_process', 'GO:0008283', ('58', '76'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('antibodies', 'Var', (29, 39))	('metastatic phenotype', 'CPA', (221, 241))	('malignancy', 'Disease', (263, 273))
179489	23483488	In this study, we also investigated the mechanism that blockade of tumor-derived IgG by either antihuman IgG antibody or antisense oligonucleotides increased cell apoptosis and inhibited cell growth.	('increased', 'PosReg', (148, 157))	('antisense oligonucleotides', 'Var', (121, 147))	('tumor', 'Disease', (67, 72))	('IgG antibody', 'cellular_component', 'GO:0071736', ('105', '117'))	('IgG', 'Gene', (105, 108))	('IgG', 'Gene', (81, 84))	('oligonucleotides', 'Chemical', 'MESH:D009841', (131, 147))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('antibody', 'molecular_function', 'GO:0003823', ('109', '117'))	('apoptosis', 'biological_process', 'GO:0097194', ('163', '172'))	('apoptosis', 'biological_process', 'GO:0006915', ('163', '172'))	('inhibited', 'NegReg', (177, 186))	('cell growth', 'biological_process', 'GO:0016049', ('187', '198'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cell apoptosis', 'CPA', (158, 172))	('cell growth', 'CPA', (187, 198))	('IgG antibody', 'Phenotype', 'HP:0003237', (105, 117))	('IgG', 'Gene', '16059', (105, 108))	('IgG', 'Gene', '16059', (81, 84))	('human', 'Species', '9606', (99, 104))
179490	23483488	Our finding suggested that antihuman IgG antibody or antisense oligonucleotides might regulate cell apoptosis through caspase-dependent pathways.	('IgG antibody', 'cellular_component', 'GO:0071736', ('37', '49'))	('caspase-dependent pathways', 'Pathway', (118, 144))	('antibody', 'molecular_function', 'GO:0003823', ('41', '49'))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('cell apoptosis', 'CPA', (95, 109))	('IgG antibody', 'Phenotype', 'HP:0003237', (37, 49))	('human', 'Species', '9606', (31, 36))	('antisense oligonucleotides', 'Var', (53, 79))	('IgG', 'Gene', '16059', (37, 40))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('oligonucleotides', 'Chemical', 'MESH:D009841', (63, 79))	('regulate', 'Reg', (86, 94))	('IgG', 'Gene', (37, 40))
179491	23483488	Although the exact mechanism of IgG expression in malignant epithelial cells remains unclear, several possible hypotheses may explain rearranged immunoglobulin variable (VH) region gene transcripts in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('145', '159'))	('rearranged', 'Var', (134, 144))	('IgG', 'Gene', '16059', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('VH', 'Gene', (170, 172))	('IgG', 'Gene', (32, 35))
179546	21716884	Deep resection may result in significant hemorrhage.	('hemorrhage', 'Disease', (41, 51))	('Deep', 'Var', (0, 4))	('hemorrhage', 'Disease', 'MESH:D006470', (41, 51))	('result', 'Reg', (19, 25))
179549	21716884	Reviews of series of patients treated with antegrade percutaneous resection reveal that this procedure can be performed with reasonable safety and good long-term outcomes for low-grade UTUCC [Table 2], but nonetheless is also associated with certain risks, namely recurrence, hemorrhage, and seeding of the percutaneous tract.	('seeding', 'CPA', (292, 299))	('patients', 'Species', '9606', (21, 29))	('hemorrhage', 'Disease', (276, 286))	('low-grade', 'Var', (175, 184))	('hemorrhage', 'Disease', 'MESH:D006470', (276, 286))
179558	21716884	Recurrence and survival rates for low-grade/stage distal tumors do not differ regardless of the therapeutic approach.	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('low-grade/stage', 'Var', (34, 49))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
179693	33368857	Furthermore, multivariate analysis revealed pT2 or lower-stage (HR 1.25, P = .029), ureteral cancer (HR 2.08, P < .001), and tumor multifocality (HR 1.25, P = .025) to be independent risk factors for IVR development after RNU.	('ureteral cancer', 'Disease', (84, 99))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('pT2', 'Var', (44, 47))	('ureteral cancer', 'Phenotype', 'HP:0100516', (84, 99))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('ureteral cancer', 'Disease', 'MESH:D014516', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', (125, 130))	('age', 'Gene', (59, 62))	('RNU', 'Chemical', '-', (222, 225))	('IVR development', 'Disease', (200, 215))	('age', 'Gene', '5973', (59, 62))
179724	33368857	As shown in Figure S1, no significant differences were found between high and low FGFR3 expression regarding RFS (P = .508), but patients with high FGFR3 expression had a more favorable CSS than their counterparts (P = .130).	('FGFR3', 'Gene', (82, 87))	('CSS', 'Gene', '55907', (186, 189))	('patients', 'Species', '9606', (129, 137))	('CSS', 'Gene', (186, 189))	('high', 'Var', (143, 147))	('FGFR3', 'Gene', '2261', (148, 153))	('RFS', 'Gene', '65211', (109, 112))	('FGFR', 'molecular_function', 'GO:0005007', ('82', '86'))	('FGFR3', 'Gene', '2261', (82, 87))	('RFS', 'Gene', (109, 112))	('FGFR', 'molecular_function', 'GO:0005007', ('148', '152'))	('FGFR3', 'Gene', (148, 153))
179725	33368857	Conversely, regarding p53 expression, patients with high p53 expression had a slightly lower RFS and CSS than their counterparts (P = .170 and P = .034, respectively) (Figure S2).	('CSS', 'Gene', '55907', (101, 104))	('RFS', 'Gene', '65211', (93, 96))	('RFS', 'Gene', (93, 96))	('CSS', 'Gene', (101, 104))	('lower', 'NegReg', (87, 92))	('p53', 'Gene', (22, 25))	('p53', 'Gene', '7157', (22, 25))	('high', 'Var', (52, 56))	('p53', 'Gene', (57, 60))	('patients', 'Species', '9606', (38, 46))	('p53', 'Gene', '7157', (57, 60))
179758	33368857	27  As previous studies have indicated, altered expression of TP53 and RB1 is more frequent in bladder MIBC, which plays an important role in urothelial carcinoma proliferation or poor prognosis.	('urothelial carcinoma proliferation', 'Disease', (142, 176))	('TP53', 'Gene', '7157', (62, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('TP53', 'Gene', (62, 66))	('expression', 'MPA', (48, 58))	('RB1', 'Gene', (71, 74))	('frequent', 'Reg', (83, 91))	('altered', 'Var', (40, 47))	('MIBC', 'Chemical', '-', (103, 107))	('urothelial carcinoma proliferation', 'Disease', 'MESH:D014523', (142, 176))	('RB1', 'Gene', '5925', (71, 74))	('bladder MIBC', 'Disease', (95, 107))
179759	33368857	28  In contrast, FGFR3 mutations, which are associated with favorable outcomes in patients with urothelial carcinoma, are reported to be more frequent in UTUC and are related to longer survival.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('FGFR3', 'Gene', '2261', (17, 22))	('patients', 'Species', '9606', (82, 90))	('longer', 'PosReg', (178, 184))	('mutations', 'Var', (23, 32))	('FGFR3', 'Gene', (17, 22))	('UTUC', 'Chemical', '-', (154, 158))	('urothelial carcinoma', 'Disease', (96, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (96, 116))
179853	32194779	retrospective analysis of 325 patients with bladder cancer confirmed that the 5-year recurrence-free survival rate of patients with low expression of tumor tissue BLCA-4 was 89.8%.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (44, 58))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('bladder cancer', 'Disease', 'MESH:D001749', (44, 58))	('bladder cancer', 'Disease', (44, 58))	('patients', 'Species', '9606', (30, 38))	('BLCA', 'Chemical', '-', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('low expression', 'Var', (132, 146))	('tumor', 'Disease', (150, 155))	('patients', 'Species', '9606', (118, 126))
179882	31827401	With regards to bladder cancer, several studies have suggested that lncRNAs may function as oncogenes or tumor suppressors and may affect overall patient survival and mortality.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mortality', 'Disease', 'MESH:D003643', (167, 176))	('affect', 'Reg', (131, 137))	('bladder cancer', 'Disease', 'MESH:D001749', (16, 30))	('bladder cancer', 'Disease', (16, 30))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('patient survival', 'CPA', (146, 162))	('mortality', 'Disease', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('lncRNAs', 'Var', (68, 75))	('bladder cancer', 'Phenotype', 'HP:0009725', (16, 30))	('patient', 'Species', '9606', (146, 153))	('tumor', 'Disease', (105, 110))
179908	31827401	Five DElncRNAs were significantly related to OS, of which, four DElncRNAs (HCG22, ADAMTS9-AS1, ADAMTS9-AS2, and AC112721.1) were negatively related to OS (Fig.	('AS1', 'Gene', '5729', (90, 93))	('ADAMTS9', 'Gene', '56999', (95, 102))	('ADAMTS9', 'Gene', '56999', (82, 89))	('ADAMTS9', 'Gene', (95, 102))	('HCG22', 'Gene', '285834', (75, 80))	('ADAMTS9', 'Gene', (82, 89))	('HCG22', 'Gene', (75, 80))	('AC112721.1', 'Var', (112, 122))	('related', 'Reg', (34, 41))	('negatively', 'NegReg', (129, 139))	('AS1', 'Gene', (90, 93))
179933	31827401	Low ADAMTS9-AS2 levels were found to be a significant independent predictor of poor survival in glioma patients.	('Low', 'Var', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('ADAMTS9', 'Gene', '56999', (4, 11))	('patients', 'Species', '9606', (103, 111))	('glioma', 'Disease', (96, 102))	('ADAMTS9', 'Gene', (4, 11))
179936	31827401	However, to date, no studies have been performed to determine the role of AC078778.1 and AC112721.1 in cancer.	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('AC112721.1', 'Var', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))
179943	31827401	miR-145 has been frequently observed to be down-regulated in cancers and restoration of miR-145 levels suppressed cancer cell invasion by reversing the EMT phenotype.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('miR-145', 'Gene', (88, 95))	('suppressed', 'NegReg', (103, 113))	('reversing', 'NegReg', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('miR-145', 'Gene', (0, 7))	('EMT phenotype', 'CPA', (152, 165))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('restoration', 'Var', (73, 84))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('down-regulated', 'NegReg', (43, 57))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('miR-145', 'Gene', '406937', (88, 95))	('cancers', 'Disease', (61, 68))	('EMT', 'biological_process', 'GO:0001837', ('152', '155'))	('miR-145', 'Gene', '406937', (0, 7))	('cancer', 'Disease', (114, 120))
179970	31827401	In addition, the majority of PLB4 hotspot mutations are gain-of function mutations that have been demonstrated to be involved in uveal melanoma tumorigenesis by activating the same signaling pathway.	('tumor', 'Disease', (144, 149))	('activating', 'Reg', (161, 171))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('PLB4', 'Gene', (29, 33))	('signaling pathway', 'biological_process', 'GO:0007165', ('181', '198'))	('gain-of function', 'PosReg', (56, 72))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('mutations', 'Var', (42, 51))
179972	31827401	Several studies have demonstrated that knocking down ezrin and P65 expression induces tumor metastasis in different cancers.	('ezrin', 'Gene', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('induces', 'Reg', (78, 85))	('P65', 'Gene', '5970', (63, 66))	('P65', 'Gene', (63, 66))	('tumor metastasis', 'Disease', 'MESH:D009362', (86, 102))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('tumor metastasis', 'Disease', (86, 102))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('knocking down', 'Var', (39, 52))	('ezrin', 'Gene', '7430', (53, 58))
180068	29354490	The UroVysion Kit (Abbott) is test based on FISH that detects aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus of the P16 tumor-suppressor gene in urine specimens from patients with hematuria.	('aneuploidy', 'Disease', (62, 72))	('hematuria', 'Disease', 'MESH:D006417', (197, 206))	('tumor', 'Disease', (137, 142))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('137', '153'))	('loss', 'Var', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('hematuria', 'Phenotype', 'HP:0000790', (197, 206))	('aneuploidy', 'Disease', 'MESH:D000782', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('137', '153'))	('hematuria', 'Disease', (197, 206))	('patients', 'Species', '9606', (183, 191))
180104	29354490	Several new targets, such as Nuclear factor kappa-B (NF-kappaB), miR-138-5p or Human HLA-F adjacent transcript 10 (FAT10), directly or indirectly linked to survivin expression are yet to be explored.	('NF-kappaB', 'Gene', '4790', (53, 62))	('miR-138-5p', 'Var', (65, 75))	('NF-kappaB', 'Gene', (53, 62))	('Nuclear factor kappa-B', 'Gene', (29, 51))	('Human', 'Species', '9606', (79, 84))	('linked', 'Reg', (146, 152))	('Nuclear factor kappa-B', 'Gene', '4790', (29, 51))
180112	29354490	Cyfra21-1 refers to a proteolytic region of cytokeratin-19.	('cytokeratin-19', 'Gene', (44, 58))	('Cyfra21-1', 'Var', (0, 9))	('cytokeratin-19', 'Gene', '3880', (44, 58))
180175	29221154	Moreover, the GD2+ UMUC3 cells proliferated more rapidly than the GD2- UMUC3 cells (Figure 1F).	('proliferated', 'CPA', (31, 43))	('GD2', 'Chemical', '-', (14, 17))	('GD2', 'Chemical', '-', (66, 69))	('GD2+', 'Var', (14, 18))
180180	29221154	The analysis showed the alterations in the important lipid classes and identified 161 individual lipid species were altered between GD2+ and GD2- in both cell lines (Figure 3A).	('individual lipid species', 'MPA', (86, 110))	('altered', 'Reg', (116, 123))	('GD2', 'Chemical', '-', (141, 144))	('lipid', 'Chemical', 'MESH:D008055', (97, 102))	('GD2', 'Chemical', '-', (132, 135))	('lipid', 'Chemical', 'MESH:D008055', (53, 58))	('GD2+', 'Var', (132, 136))	('GD2-', 'Var', (141, 145))	('important lipid classes', 'MPA', (43, 66))	('alterations', 'Reg', (24, 35))
180181	29221154	We have identified that GD2+ cells have lower levels of phosphatidylserine (PS), plasmenyl-phosphatidylethanolamines (pPE), plasmenyl-phosphocholines (pPC), sphingomyelins (SM) tricylglycerols (TGs) and higher levels of Phosphatidylinositol (PI), Phosphatidic acid (PA), and Cardiolipin (CL) (Figure 3B).	('phosphatidylserine', 'Chemical', 'MESH:D010718', (56, 74))	('Phosphatidylinositol', 'Chemical', 'MESH:D010716', (220, 240))	('phosphatidylserine', 'MPA', (56, 74))	('Cardiolipin', 'Chemical', 'MESH:D002308', (275, 286))	('Phosphatidic acid', 'Chemical', 'MESH:D010712', (247, 264))	('plasmenyl-phosphocholines', 'MPA', (124, 149))	('SM', 'Chemical', 'MESH:D013109', (173, 175))	('GD2', 'Chemical', '-', (24, 27))	('levels', 'MPA', (46, 52))	('higher', 'PosReg', (203, 209))	('GD2+', 'Var', (24, 28))	('Phosphatidic acid', 'MPA', (247, 264))	('pPE', 'Chemical', '-', (118, 121))	('PA', 'Chemical', 'MESH:D010712', (266, 268))	('plasmenyl-phosphocholines', 'Chemical', '-', (124, 149))	('tricylglycerols', 'Chemical', '-', (177, 192))	('pPC', 'Chemical', '-', (151, 154))	('lower', 'NegReg', (40, 45))	('PS', 'Chemical', 'MESH:D010718', (76, 78))	('TGs', 'biological_process', 'GO:0006342', ('194', '197'))	('sphingomyelins', 'Chemical', 'MESH:D013109', (157, 171))	('levels of Phosphatidylinositol', 'MPA', (210, 240))	('sphingomyelins', 'MPA', (157, 171))	('TGs', 'Chemical', 'MESH:D014280', (194, 197))	('plasmenyl-phosphatidylethanolamines', 'MPA', (81, 116))	('plasmenyl-phosphatidylethanolamines', 'Chemical', '-', (81, 116))	('Cardiolipin', 'MPA', (275, 286))
180189	29221154	We further checked the GD3 synthase, a major regulatory enzyme for the synthesis of GD2 in UMUC3 BLCA cells and found it to be inhibited by PDMP (Figure 5C).	('GD3', 'Gene', '117189', (23, 26))	('synthesis', 'biological_process', 'GO:0009058', ('71', '80'))	('GD3', 'Gene', (23, 26))	('inhibited', 'NegReg', (127, 136))	('GD2', 'Chemical', '-', (84, 87))	('BLCA', 'Phenotype', 'HP:0009725', (97, 101))	('GD2', 'Gene', (84, 87))	('PDMP', 'Var', (140, 144))
180196	29221154	Specifically, GD2+ cells displayed stem cell properties similar to those of the CD44hiCD24lo population.	('stem cell properties', 'CPA', (35, 55))	('CD44', 'Gene', (80, 84))	('GD2', 'Chemical', '-', (14, 17))	('GD2+', 'Var', (14, 18))	('CD44', 'Gene', '960', (80, 84))	('CD24', 'Gene', '100133941', (86, 90))	('CD24', 'Gene', (86, 90))
180201	29221154	Several studies have evidenced that GD2-specific antibodies inhibit tumor growth without the involvement of the immune system.	('tumor', 'Disease', (68, 73))	('inhibit', 'NegReg', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('antibodies', 'Var', (49, 59))	('GD2', 'Chemical', '-', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('GD2-specific', 'Protein', (36, 48))
180216	29221154	Many evidences show that PLD has a role in cell migration which is key to cell invasion and metastasis and active PLD enhances lymphoma cell metastasis, where as the inactivation of PLD inhibited the metastasis, MMP-2 expression in glioma cell invasion.	('PLD', 'Gene', '2822', (25, 28))	('PLD', 'Gene', (25, 28))	('inhibited', 'NegReg', (186, 195))	('PLD', 'Gene', '2822', (182, 185))	('MMP-2', 'Gene', (212, 217))	('PLD', 'Gene', (182, 185))	('glioma', 'Disease', (232, 238))	('lymphoma', 'Phenotype', 'HP:0002665', (127, 135))	('glioma', 'Disease', 'MESH:D005910', (232, 238))	('enhances', 'PosReg', (118, 126))	('cell migration', 'biological_process', 'GO:0016477', ('43', '57'))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))	('MMP-2', 'molecular_function', 'GO:0004228', ('212', '217'))	('lymphoma', 'Disease', (127, 135))	('metastasis', 'CPA', (200, 210))	('lymphoma', 'Disease', 'MESH:D008223', (127, 135))	('PLD', 'Gene', '2822', (114, 117))	('MMP-2', 'Gene', '4313', (212, 217))	('PLD', 'Gene', (114, 117))	('inactivation', 'Var', (166, 178))	('expression', 'MPA', (218, 228))
180219	29221154	An abnormal increase of cardiolipin in GD2+ needs to be further investigated for its role in cancer progression.	('GD2+', 'Var', (39, 43))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('increase', 'PosReg', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cardiolipin', 'Protein', (24, 35))	('GD2', 'Chemical', '-', (39, 42))
180222	29221154	This is supported by several recent reports that gangliosides including GD1a, GD1b, GD3, and GM3 help tumors evade the immune attack by inducing apoptosis in immune cells, including T and NK cells.	('inducing', 'Reg', (136, 144))	('GD3', 'Gene', '117189', (84, 87))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('GD3', 'Gene', (84, 87))	('GM3', 'Chemical', '-', (93, 96))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('gangliosides', 'Chemical', 'MESH:D005732', (49, 61))	('GM3', 'Var', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('apoptosis', 'CPA', (145, 154))
180229	29221154	In addition, we have ascertained that GD2+ cells promote rapid BLCA growth and display cancer stem cell properties.	('cancer', 'Disease', (87, 93))	('GD2+', 'Var', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rapid BLCA growth', 'CPA', (57, 74))	('GD2', 'Chemical', '-', (38, 41))	('BLCA', 'Phenotype', 'HP:0009725', (63, 67))	('promote', 'PosReg', (49, 56))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
180246	29221154	Cells were detached with trypsin, washed twice in PBS, then stained with anti GD2-APC, anti-CD24-FITC and anti-CD44-PE (Biolegend Antibodies) using 5 mul of antibody per 106 cells, and incubated in ice for 15 min.	('CD44', 'Gene', (111, 115))	('PC', 'Chemical', '-', (83, 85))	('CD24', 'Gene', '100133941', (92, 96))	('antibody', 'cellular_component', 'GO:0019814', ('157', '165'))	('APC', 'cellular_component', 'GO:0005680', ('82', '85'))	('CD24', 'Gene', (92, 96))	('antibody', 'molecular_function', 'GO:0003823', ('157', '165'))	('CD44', 'Gene', '960', (111, 115))	('antibody', 'cellular_component', 'GO:0042571', ('157', '165'))	('anti GD2-APC', 'Var', (73, 85))	('GD2', 'Chemical', '-', (78, 81))	('antibody', 'cellular_component', 'GO:0019815', ('157', '165'))
180259	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))
180261	29088295	High levels of LRP10 mRNA were associated with decreased patient survival in hepatocellular carcinoma, lung adenocarcinoma, and pancreatic adenocarcinoma.	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (128, 153))	('High levels', 'Var', (0, 11))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (103, 122))	('pancreatic adenocarcinoma', 'Disease', (128, 153))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (77, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))	('patient', 'Species', '9606', (57, 64))	('hepatocellular carcinoma', 'Disease', (77, 101))	('LRP10', 'Gene', (15, 20))	('patient survival', 'CPA', (57, 73))	('decreased', 'NegReg', (47, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mRNA', 'MPA', (21, 25))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (128, 153))	('LRP10', 'Gene', '26020', (15, 20))	('lung adenocarcinoma', 'Disease', (103, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (77, 101))
180262	29088295	LRP2 was the only LRP for which high levels of mRNA expression correlated with improved patient survival.	('high', 'Var', (32, 36))	('patient', 'Species', '9606', (88, 95))	('LRP', 'Gene', '4035', (18, 21))	('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))
180293	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))
180317	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))
180320	29088295	This is the only cancer in which we detected a correlation between high levels of expression of an LRP and increased patient survival.	('high levels of', 'Var', (67, 81))	('LRP', 'Gene', (99, 102))	('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))
180325	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))
180328	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))
180335	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))
180341	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))	('associated', 'Reg', (48, 58))	('gastric cancer', 'Disease', (167, 181))	('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))
180347	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))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('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))
180357	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))
180425	27765044	Previous studies have suggested that patients whose tumors harbor heterologous elements may have a worse prognosis compared to those without them.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('patients', 'Species', '9606', (37, 45))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('heterologous elements', 'Var', (66, 87))
180430	27765044	They suggested a common clonal origin of the phenotypically different tumor components, and that TP53 mutations probably occurred early in the common tumorigenesis of these morphologically distinct tumor components.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TP53', 'Gene', '7157', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('TP53', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('mutations', 'Var', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
180479	26364859	The TNM clinical staging system was defined as follows: stage I (T1N0M0), tumors invaded the subepithelial connective tissue; II (T2N0M0), tumors invaded the urachal or bladder muscularis propria; III (T3M0N0 or T4aM0N0), tumors invaded the perivesical soft tissue, prostate, uterus, or vagina; and IV (T4b and any T with N1-3 or M1), tumors invaded the abdominal wall and metastasized to the lymph nodes or other distant sites.	('tumors', 'Disease', (335, 341))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('invaded', 'Reg', (229, 236))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Disease', (222, 228))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (335, 341))	('TNM', 'Gene', '10178', (4, 7))	('invaded', 'Reg', (146, 153))	('TNM', 'Gene', (4, 7))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('muscularis propria', 'Phenotype', 'HP:0030936', (177, 195))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('invaded', 'Reg', (342, 349))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (335, 341))	('T4aM0N0', 'Var', (212, 219))	('bladder muscularis propria', 'Disease', 'MESH:D001745', (169, 195))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('metastasized', 'CPA', (373, 385))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('bladder muscularis propria', 'Disease', (169, 195))	('tumors', 'Disease', (74, 80))
180631	21473752	Low grade papillary urothelial carcinomas have a high risk of progression, with figures varying from 15% to 40%, and of association with invasive disease at the time of diagnosis 3.	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('papillary urothelial carcinomas', 'Disease', (10, 41))	('Low grade', 'Var', (0, 9))	('papillary urothelial carcinomas', 'Disease', 'MESH:D002291', (10, 41))	('invasive disease', 'Disease', (137, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
180718	33762601	The corresponding genes for PSA, PSAP, P501S, PSMA, NKX3.1, AR and AMACR are KLK3, ACPP, SLC45A3, FOLH1, NKX3-1, AR and AMACR, respectively.	('SLC45A3', 'Gene', (89, 96))	('PSA', 'Gene', '354', (28, 31))	('FOLH1', 'Gene', (98, 103))	('NKX3-1', 'Gene', (105, 111))	('ACPP', 'Gene', '55', (83, 87))	('AMACR', 'Gene', (67, 72))	('AR', 'Gene', '367', (60, 62))	('SLC45A3', 'Gene', '85414', (89, 96))	('FOLH1', 'Gene', '2346', (98, 103))	('AR', 'Gene', '367', (113, 115))	('NKX3-1', 'Gene', '4824', (105, 111))	('AMACR', 'Gene', '23600', (67, 72))	('AMACR', 'Gene', (120, 125))	('PSA', 'Gene', '354', (33, 36))	('PSMA', 'molecular_function', 'GO:0043275', ('46', '50'))	('ACPP', 'Gene', (83, 87))	('P501S', 'Var', (39, 44))	('PSA', 'Gene', (28, 31))	('PSMA', 'Gene', '2346', (46, 50))	('P501S', 'Mutation', 'p.P501S', (39, 44))	('AMACR', 'Gene', '23600', (120, 125))	('KLK3', 'Gene', (77, 81))	('PSMA', 'Gene', (46, 50))	('KLK3', 'Gene', '354', (77, 81))	('NKX3.1', 'Gene', '4824', (52, 58))	('PSA', 'Gene', (33, 36))	('NKX3.1', 'Gene', (52, 58))
180744	33762601	On the other hand, recommended prostate lineage markers are PSA, PSAP, P501S, PSMA, NKX3.1, AR, and AMACR.	('AMACR', 'Gene', '23600', (100, 105))	('AMACR', 'Gene', (100, 105))	('NKX3.1', 'Gene', '4824', (84, 90))	('PSA', 'Gene', '354', (65, 68))	('PSA', 'Gene', (65, 68))	('P501S', 'Var', (71, 76))	('PSMA', 'Gene', (78, 82))	('AR', 'Gene', '367', (92, 94))	('NKX3.1', 'Gene', (84, 90))	('PSMA', 'Gene', '2346', (78, 82))	('PSA', 'Gene', '354', (60, 63))	('PSA', 'Gene', (60, 63))	('PSMA', 'molecular_function', 'GO:0043275', ('78', '82'))	('P501S', 'Mutation', 'p.P501S', (71, 76))
180747	33762601	NKX3-1, KLK3, ACPP, SLC45A3 and FOLH1, corresponding to NKX3.1, PSA, PSAP, P501S, and PSMA respectively.	('SLC45A3', 'Gene', '85414', (20, 27))	('P501S', 'Var', (75, 80))	('P501S', 'Mutation', 'p.P501S', (75, 80))	('ACPP', 'Gene', (14, 18))	('PSA', 'Gene', (69, 72))	('NKX3.1', 'Gene', '4824', (56, 62))	('NKX3-1', 'Gene', (0, 6))	('KLK3', 'Gene', (8, 12))	('PSA', 'Gene', '354', (64, 67))	('KLK3', 'Gene', '354', (8, 12))	('NKX3.1', 'Gene', (56, 62))	('FOLH1', 'Gene', (32, 37))	('FOLH1', 'Gene', '2346', (32, 37))	('NKX3-1', 'Gene', '4824', (0, 6))	('SLC45A3', 'Gene', (20, 27))	('PSA', 'Gene', '354', (69, 72))	('PSMA', 'Gene', '2346', (86, 90))	('PSMA', 'molecular_function', 'GO:0043275', ('86', '90'))	('ACPP', 'Gene', '55', (14, 18))	('PSA', 'Gene', (64, 67))	('PSMA', 'Gene', (86, 90))
180752	33762601	NKX3.1 and P501S are relatively newer prostate lineage markers.	('NKX3.1', 'Gene', '4824', (0, 6))	('NKX3.1', 'Gene', (0, 6))	('P501S', 'Var', (11, 16))	('P501S', 'Mutation', 'p.P501S', (11, 16))
180753	33762601	Sensitivities and specificities for NKX3.1 were 69-100% and 99-100%, and for P501S were 94-100% and 99-100%, respectively.	('P501S', 'Mutation', 'p.P501S', (77, 82))	('P501S', 'Var', (77, 82))	('NKX3.1', 'Gene', (36, 42))	('NKX3.1', 'Gene', '4824', (36, 42))
180764	33762601	In descending order of importance, genes for NKX3.1, PSA, PSAP, P501S and PSMA are the most important prostate lineage markers.	('NKX3.1', 'Gene', (45, 51))	('P501S', 'Mutation', 'p.P501S', (64, 69))	('PSMA', 'Gene', (74, 78))	('PSMA', 'molecular_function', 'GO:0043275', ('74', '78'))	('PSMA', 'Gene', '2346', (74, 78))	('P501S', 'Var', (64, 69))	('NKX3.1', 'Gene', '4824', (45, 51))	('PSA', 'Gene', '354', (53, 56))	('PSA', 'Gene', (53, 56))	('PSA', 'Gene', '354', (58, 61))	('PSA', 'Gene', (58, 61))
180802	32523078	Blocking was done using 3% skimmed milk/PBS for 1 h. Subsequently, cells were treated with the primary antibodies (CK5; 1:200, CK7;1:50, CK20;1:200, and UPK3A;1:200) and kept at 4  C overnight.	('CK5; 1:200', 'Var', (115, 125))	('CK20;1:200', 'Var', (137, 147))	('PBS', 'Chemical', '-', (40, 43))	('CK7;1:50', 'Var', (127, 135))
180815	32523078	Our established BC 3D organoids expressed urothelial markers (CK7, CK20, and UPK3A), showed the response to anti-cancer drugs, and exhibited tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('CK20', 'Var', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('UPK3A', 'Gene', (77, 82))	('exhibited', 'Reg', (131, 140))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('BC', 'Phenotype', 'HP:0009725', (16, 18))	('tumor', 'Disease', (141, 146))	('cancer', 'Disease', (113, 119))	('response', 'MPA', (96, 104))	('CK7', 'Var', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
180830	32523078	To characterize the cellular components of the isolated tumor tissues, immunofluorescence staining was carried out and expression of CK7, CK20, and UPK3A was observed in the tumor tissues (Fig.	('tumor', 'Disease', (174, 179))	('UPK3A', 'Gene', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('CK7', 'Var', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('CK20', 'Var', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
180853	32523078	Characterization of the normal and neoplastic epithelium of the urinary bladder has been performed mainly using cytokeratins (especially CK7 and CK20) and UPK3A antibodies in human and dogs.	('human', 'Species', '9606', (175, 180))	('rat', 'Species', '10116', (118, 121))	('neoplastic epithelium', 'Phenotype', 'HP:0031492', (35, 56))	('dogs', 'Species', '9615', (185, 189))	('CK7', 'Var', (137, 140))	('UPK3A', 'Protein', (155, 160))	('CK20', 'Var', (145, 149))
180858	32523078	confirmed the expression of CK7, CK20, and UPK3A in normal dog urinary bladder and 72 dog BC and found that UPK3A is a highly specific and sensitive marker for dog BC, detecting 91% of the examined cases.	('BC', 'Phenotype', 'HP:0009725', (90, 92))	('UPK3A', 'Gene', (43, 48))	('dog', 'Species', '9615', (160, 163))	('CK20', 'Gene', (33, 37))	('BC', 'Phenotype', 'HP:0009725', (164, 166))	('dog', 'Species', '9615', (86, 89))	('CK7', 'Var', (28, 31))	('dog', 'Species', '9615', (59, 62))
180868	32523078	showed that 40% of more than 300 BC samples contained CD44+ cells and were able to form tumors in vivo 10-200 times than CD44- cells in mice.	('CD44+ cells', 'Var', (54, 65))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('mice', 'Species', '10090', (136, 140))	('BC', 'Phenotype', 'HP:0009725', (33, 35))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
180869	32523078	On the contrary, the CD44+/CD24- cells were associated with a better prognosis, indicating that this phenotype is not suitable for detecting CSCs in dog mammary carcinomas.	('dog', 'Species', '9615', (149, 152))	('carcinomas', 'Disease', 'MESH:D009369', (161, 171))	('CD44+/CD24-', 'Var', (21, 32))	('carcinomas', 'Disease', (161, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))
180960	26238022	Impact of reduced levels of APE1 transcripts on the survival of patients with urothelial carcinoma of the bladder Molecular evidence indicates that alterations in genes involved in the maintenance of genome stability may be related to susceptibility to bladder carcinoma.	('APE1', 'Gene', (28, 32))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (78, 113))	('urothelial carcinoma of the bladder', 'Disease', (78, 113))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (78, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('patients', 'Species', '9606', (64, 72))	('alterations', 'Var', (148, 159))	('APE1', 'Gene', '328', (28, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (253, 270))	('bladder carcinoma', 'Disease', 'MESH:D001749', (253, 270))	('related', 'Reg', (224, 231))	('bladder carcinoma', 'Disease', (253, 270))
180965	26238022	Furthermore, the variant genotype (TG/GG) of the APE1 T1349G polymorphism was observed in 75% of a subset of patients who concomitantly experienced reduced levels of the APE1 transcript and death and/or recurrence events.	('T1349G', 'Var', (54, 60))	('APE1', 'Gene', '328', (49, 53))	('TG', 'Disease', 'None', (35, 37))	('APE1', 'Gene', (170, 174))	('patients', 'Species', '9606', (109, 117))	('T1349G', 'Mutation', 'rs1130409', (54, 60))	('reduced', 'NegReg', (148, 155))	('levels', 'MPA', (156, 162))	('APE1', 'Gene', '328', (170, 174))	('death', 'Disease', (190, 195))	('death', 'Disease', 'MESH:D003643', (190, 195))	('APE1', 'Gene', (49, 53))
180974	26238022	A BER malfunction could thus lead to accumulation of DNA lesions with a direct impact on the risk of tumorigenesis, including UCB.	('lead to', 'Reg', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('UCB', 'Phenotype', 'HP:0006740', (126, 129))	('UCB', 'Disease', (126, 129))	('BER', 'biological_process', 'GO:0006284', ('2', '5'))	('accumulation', 'PosReg', (37, 49))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('malfunction', 'Var', (6, 17))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
180981	26238022	The aim of the present study was to investigate whether variations in the levels of transcripts APE1, XRCC1 and POLB could influence the clinical outcomes of patients diagnosed with primary UCB.	('APE1', 'Gene', '328', (96, 100))	('primary UCB', 'Disease', (182, 193))	('XRCC1', 'Gene', (102, 107))	('POLB', 'Gene', (112, 116))	('variations', 'Var', (56, 66))	('influence', 'Reg', (123, 132))	('POLB', 'Gene', '5423', (112, 116))	('XRCC1', 'Gene', '7515', (102, 107))	('patients', 'Species', '9606', (158, 166))	('APE1', 'Gene', (96, 100))	('UCB', 'Phenotype', 'HP:0006740', (190, 193))
180999	26238022	Genotyping assays to evaluate the APE1 T1349G polymorphism were performed by sequencing cDNA samples.	('APE1', 'Gene', '328', (34, 38))	('T1349G', 'Var', (39, 45))	('APE1', 'Gene', (34, 38))	('T1349G', 'Mutation', 'rs1130409', (39, 45))
181022	26238022	Genotyping assays to evaluate the APE1 T1349G polymorphism were performed by preferentially sequencing the cDNA samples from a subset of patients who concomitantly presented reduced levels of APE1 transcripts and death and/or recurrence events (Fig.	('APE1', 'Gene', '328', (34, 38))	('T1349G', 'Mutation', 'rs1130409', (39, 45))	('death', 'Disease', 'MESH:D003643', (213, 218))	('death', 'Disease', (213, 218))	('patients', 'Species', '9606', (137, 145))	('APE1', 'Gene', (192, 196))	('APE1', 'Gene', (34, 38))	('APE1', 'Gene', '328', (192, 196))	('reduced', 'NegReg', (174, 181))	('T1349G', 'Var', (39, 45))	('levels', 'MPA', (182, 188))
181027	26238022	DNA repair mechanisms act as a barrier to prevent genetic instability and cancer susceptibility.	('genetic', 'Var', (50, 57))	('DNA repair', 'biological_process', 'GO:0006281', ('0', '10'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
181030	26238022	Notwithstanding its core interplay in BER, a recent meta-analysis did not associate a dysfunctional XRCC1 polymorphism to UCB risk.	('XRCC1', 'Gene', '7515', (100, 105))	('core', 'cellular_component', 'GO:0019013', ('20', '24'))	('UCB', 'Phenotype', 'HP:0006740', (122, 125))	('XRCC1', 'Gene', (100, 105))	('UCB', 'Disease', (122, 125))	('BER', 'biological_process', 'GO:0006284', ('38', '41'))	('polymorphism', 'Var', (106, 118))
181036	26238022	Approximately 30% of all human tumors express variant Pol beta.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('variant', 'Var', (46, 53))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('human', 'Species', '9606', (25, 30))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('Pol beta', 'Gene', (54, 62))	('Pol beta', 'Gene', '5423', (54, 62))
181040	26238022	Our results revealed that the POLB transcripts had increased levels in ~77% of high-grade tumors, suggesting a strong correlation of POLB dysregulation with tumorigenesis and progression events.	('tumor', 'Disease', (157, 162))	('POLB', 'Gene', (133, 137))	('increased', 'PosReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('POLB', 'Gene', (30, 34))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('levels', 'MPA', (61, 67))	('dysregulation', 'Var', (138, 151))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('POLB', 'Gene', '5423', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('POLB', 'Gene', '5423', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
181042	26238022	APE1 participates in the initial steps of BER by recognizing and nicking potentially genotoxic and mutagenic abasic (AP) sites in different substrates, such as double-strand DNA, hybrid DNA/RNA and RNA molecule.	('BER', 'biological_process', 'GO:0006284', ('42', '45'))	('RNA', 'cellular_component', 'GO:0005562', ('190', '193'))	('DNA', 'cellular_component', 'GO:0005574', ('174', '177'))	('APE1', 'Gene', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('186', '189'))	('nicking', 'Var', (65, 72))	('RNA', 'cellular_component', 'GO:0005562', ('198', '201'))	('APE1', 'Gene', '328', (0, 4))
181044	26238022	In general, its increased levels provide resistance to chemotherapeutic drugs and ionizing radiation and, as expected, marked cisplatin sensitivity was observed to occur in vitro in tumor cells knocked out for APE1.	('APE1', 'Gene', '328', (210, 214))	('tumor', 'Disease', (182, 187))	('occur', 'Reg', (164, 169))	('cisplatin sensitivity', 'MPA', (126, 147))	('levels', 'MPA', (26, 32))	('knocked out', 'Var', (194, 205))	('increased', 'PosReg', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('resistance', 'MPA', (41, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('APE1', 'Gene', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
181054	26238022	In carcinogenesis events, the most extensively studied polymorphism in the APE1 gene is the T to G transversion (T1349G, also known as Asp148Glu, rs3136820).	('Asp148Glu', 'Var', (135, 144))	('rs3136820', 'Mutation', 'rs3136820', (146, 155))	('T1349G', 'Var', (113, 119))	('carcinogenesis', 'Disease', 'MESH:D063646', (3, 17))	('rs3136820', 'Var', (146, 155))	('T1349G', 'Mutation', 'rs1130409', (113, 119))	('APE1', 'Gene', (75, 79))	('Asp148Glu', 'SUBSTITUTION', 'None', (135, 144))	('carcinogenesis', 'Disease', (3, 17))	('APE1', 'Gene', '328', (75, 79))
181057	26238022	In this context, we performed an additional analysis to investigate the presence of the APE1 T1349G polymorphism from this group of patients.	('T1349G', 'Mutation', 'rs1130409', (93, 99))	('APE1', 'Gene', (88, 92))	('APE1', 'Gene', '328', (88, 92))	('T1349G', 'Var', (93, 99))	('patients', 'Species', '9606', (132, 140))
181061	26238022	However, a meta-analysis study performed in 2013 suggested that the APE1 T1349G polymorphism was not associated with bladder cancer risk among Asians or non-Asians.	('T1349G', 'Mutation', 'rs1130409', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (117, 131))	('APE1', 'Gene', (68, 72))	('APE1', 'Gene', '328', (68, 72))	('T1349G', 'Var', (73, 79))	('bladder cancer', 'Disease', 'MESH:D001749', (117, 131))	('bladder cancer', 'Disease', (117, 131))
181062	26238022	Consistent with these observations, our data suggest that besides interfering with APE1 enzymatic activity, as shown in other studies, the G allele may also modify the APE1 transcriptional levels and result in worse clinical outcome for bladder cancer patients.	('APE1', 'Gene', '328', (168, 172))	('interfering', 'NegReg', (66, 77))	('transcriptional levels', 'MPA', (173, 195))	('APE1', 'Gene', '328', (83, 87))	('patients', 'Species', '9606', (252, 260))	('bladder cancer', 'Phenotype', 'HP:0009725', (237, 251))	('bladder cancer', 'Disease', (237, 251))	('modify', 'Reg', (157, 163))	('G allele', 'Var', (139, 147))	('bladder cancer', 'Disease', 'MESH:D001749', (237, 251))	('result', 'Reg', (200, 206))	('APE1', 'Gene', (168, 172))	('APE1', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))
181070	26238022	Despite this, evidence suggests that dysregulated BER transcription may promote bladder carcinogenesis.	('transcription', 'biological_process', 'GO:0006351', ('54', '67'))	('bladder carcinogenesis', 'Disease', (80, 102))	('BER', 'biological_process', 'GO:0006284', ('50', '53'))	('promote', 'PosReg', (72, 79))	('dysregulated', 'Var', (37, 49))	('BER transcription', 'Gene', (50, 67))	('bladder carcinogenesis', 'Disease', 'MESH:D063646', (80, 102))
181071	25108634	New facial papules in a sixty-six year-old woman with bladder cancer Muir-Torre Syndrome (MTS) is an autosomal dominant cancer syndrome that results from a mutation in mismatch repair genes.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('bladder cancer', 'Phenotype', 'HP:0009725', (54, 68))	('mismatch repair', 'biological_process', 'GO:0006298', ('168', '183'))	('woman', 'Species', '9606', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Muir-Torre Syndrome', 'Disease', (69, 88))	('facial papules', 'Disease', (4, 18))	('autosomal dominant cancer syndrome', 'Disease', 'MESH:D009386', (101, 135))	('bladder cancer', 'Disease', 'MESH:D001749', (54, 68))	('bladder cancer', 'Disease', (54, 68))	('facial papule', 'Phenotype', 'HP:0040167', (4, 17))	('papules', 'Phenotype', 'HP:0200034', (11, 18))	('papule', 'Phenotype', 'HP:0200034', (11, 17))	('autosomal dominant cancer syndrome', 'Disease', (101, 135))	('results from', 'Reg', (141, 153))	('mutation', 'Var', (156, 164))
181073	25108634	Mismatch repair immunohistochemistry and microsatellite instability testing of sebaceous neoplasms is available to confirm a diagnosis of MTS.	('neoplasm', 'Phenotype', 'HP:0002664', (89, 97))	('microsatellite', 'Var', (41, 55))	('Mismatch repair', 'biological_process', 'GO:0006298', ('0', '15'))	('neoplasms', 'Phenotype', 'HP:0002664', (89, 98))	('sebaceous neoplasms', 'Disease', 'MESH:D012626', (79, 98))	('sebaceous neoplasms', 'Disease', (79, 98))
181092	25108634	Tumor microsatellite instability was detected in markers BAT-25, BAT-26, MONO-27, and NR-21, demonstrating a high-frequency MSI phenotype, MSI-H. Muir-Torre syndrome with sebaceous epithelioma and associated bladder and endometrial carcinoma.	('MSI-H', 'Disease', (139, 144))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (220, 241))	('MSI', 'Disease', (139, 142))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('sebaceous epithelioma', 'Disease', 'MESH:D002277', (171, 192))	('MSI', 'Disease', 'None', (124, 127))	('endometrial carcinoma', 'Disease', (220, 241))	('Muir-Torre syndrome', 'Disease', (146, 165))	('MSI-H', 'Disease', 'MESH:D000848', (139, 144))	('bladder', 'Disease', (208, 215))	('sebaceous epithelioma', 'Disease', (171, 192))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (220, 241))	('MSI', 'Disease', (124, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('Muir-Torre syndrome', 'Disease', 'MESH:D055653', (146, 165))	('MSI', 'Disease', 'None', (139, 142))	('microsatellite instability', 'Var', (6, 32))	('MONO', 'Chemical', 'MESH:C106553', (73, 77))
181093	25108634	The patient was referred for genetic counseling, germ line testing for MSH2 mutations, and malignancy screening, including upper endoscopy, colonoscopy, and mammography.	('mutations', 'Var', (76, 85))	('MSH2', 'Gene', '4436', (71, 75))	('mammography', 'Disease', (157, 168))	('patient', 'Species', '9606', (4, 11))	('colonoscopy', 'Disease', (140, 151))	('malignancy', 'Disease', 'MESH:D009369', (91, 101))	('upper endoscopy', 'Disease', (123, 138))	('malignancy', 'Disease', (91, 101))	('MSH2', 'Gene', (71, 75))
181098	25108634	MTS is inherited in an autosomal dominant pattern with high penetrance, but variable expressivity, and is associated with mutations in DNA mismatch repair (MMR) genes, including MSH2, MLH1, and MSH6.	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('associated', 'Reg', (106, 116))	('MSH6', 'Gene', (194, 198))	('MSH2', 'Gene', (178, 182))	('MSH2', 'Gene', '4436', (178, 182))	('MMR', 'biological_process', 'GO:0006298', ('156', '159'))	('mutations', 'Var', (122, 131))	('MLH1', 'Gene', '4292', (184, 188))	('MSH6', 'Gene', '2956', (194, 198))	('mismatch repair', 'biological_process', 'GO:0006298', ('139', '154'))	('MTS', 'Disease', (0, 3))	('MLH1', 'Gene', (184, 188))
181099	25108634	MSH2 mutations appear to predominate in the MTS phenotype and are common in patients who develop urothelial carcinoma.	('urothelial carcinoma', 'Disease', (97, 117))	('patients', 'Species', '9606', (76, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('common', 'Reg', (66, 72))	('MSH2', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('MSH2', 'Gene', '4436', (0, 4))	('MTS', 'Disease', (44, 47))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (97, 117))
181100	25108634	Patients with MTS are at highest risk of colorectal cancer (56%), followed by genitourinary (22%), breast, and other neoplasms.	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('genitourinary', 'Disease', (78, 91))	('colorectal cancer', 'Disease', (41, 58))	('neoplasm', 'Phenotype', 'HP:0002664', (117, 125))	('neoplasms', 'Disease', 'MESH:D009369', (117, 126))	('MTS', 'Var', (14, 17))	('neoplasms', 'Disease', (117, 126))	('Patients', 'Species', '9606', (0, 8))	('colorectal cancer', 'Disease', 'MESH:D015179', (41, 58))	('breast', 'Disease', (99, 105))	('neoplasms', 'Phenotype', 'HP:0002664', (117, 126))
181119	25108634	This pattern is more likely with germline mutations in MSH2 rather than MSH6.	('germline mutations', 'Var', (33, 51))	('likely', 'Reg', (21, 27))	('MSH6', 'Gene', (72, 76))	('MSH2', 'Gene', (55, 59))	('MSH2', 'Gene', '4436', (55, 59))	('MSH6', 'Gene', '2956', (72, 76))
181120	25108634	MSH2 and MSH6 mutations portend a higher risk of multiple cancers, particularly endometrial cancer.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('endometrial cancer', 'Disease', (80, 98))	('MSH2', 'Gene', (0, 4))	('multiple cancers', 'Disease', 'MESH:D009369', (49, 65))	('MSH6', 'Gene', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('endometrial cancer', 'Phenotype', 'HP:0012114', (80, 98))	('MSH2', 'Gene', '4436', (0, 4))	('endometrial cancer', 'Disease', 'MESH:D016889', (80, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('MSH6', 'Gene', '2956', (9, 13))	('mutations', 'Var', (14, 23))	('multiple cancers', 'Disease', (49, 65))
181121	25108634	A germline mutation in MSH2 or MSH6 is likely in our patient, given her personal and family history of Lynch-related cancers; however MMR and MSI studies do not distinguish between somatic and germline mutations.	('MSH6', 'Gene', (31, 35))	('MSH2', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('person', 'Species', '9606', (72, 78))	('MSH2', 'Gene', '4436', (23, 27))	('germline mutation', 'Var', (2, 19))	('MSI', 'Disease', 'None', (142, 145))	('MMR', 'biological_process', 'GO:0006298', ('134', '137'))	('MSH6', 'Gene', '2956', (31, 35))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('MSI', 'Disease', (142, 145))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('patient', 'Species', '9606', (53, 60))	('cancers', 'Disease', (117, 124))
181122	25108634	Mutations in tumor specimens may differ from mutations found by germline testing.	('tumor', 'Disease', (13, 18))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
181123	25108634	Given the cost of genetic testing and similar screening guidelines for individuals with a known mutation and those at risk without a confirmed mutation, directly proceeding to malignancy screening in family members is also reasonable.	('malignancy', 'Disease', (176, 186))	('malignancy', 'Disease', 'MESH:D009369', (176, 186))	('mutation', 'Var', (96, 104))
181125	31762797	Measurement of methylated metabolites using Liquid Chromatography-Mass Spectrometry and its biological application Methylation aberrations play an important role in many metabolic disorders including cancer.	('Methylation', 'biological_process', 'GO:0032259', ('115', '126'))	('Methylation aberrations', 'Var', (115, 138))	('metabolic disorders', 'Disease', (170, 189))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('role', 'Reg', (157, 161))	('metabolic disorders', 'Disease', 'MESH:D008659', (170, 189))	('cancer', 'Disease', (200, 206))
181134	31762797	One of these modifications is methylation of nucleotides such as cytosine, adenine and amino acids present on histones particularly lysine and arginine .	('lysine', 'Chemical', 'MESH:C114808', (132, 138))	('cytosine', 'MPA', (65, 73))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('arginine', 'Chemical', 'MESH:D001127', (143, 151))	('methyl', 'Chemical', 'MESH:C031105', (30, 36))	('adenine', 'Chemical', 'MESH:D000225', (75, 82))	('adenine', 'MPA', (75, 82))	('cytosine', 'Chemical', 'MESH:D003596', (65, 73))	('methylation', 'MPA', (30, 41))	('arginine', 'Var', (143, 151))
181135	31762797	Abnormal methylation is one of the hallmarks of cancer development .	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('methyl', 'Chemical', 'MESH:C031105', (9, 15))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (35, 54))	('Abnormal', 'Var', (0, 8))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('methylation', 'MPA', (9, 20))	('hallmarks of cancer', 'Disease', (35, 54))
181173	31762797	The CID of methyl chloroformate [M+H]+ ion (m/z 95), resulted in the major fragment ion of m/z 58 corresponding to loss of HCl.	('methyl chloroformate', 'Chemical', 'MESH:C014667', (11, 31))	('HCl', 'Chemical', 'MESH:C014843', (123, 126))	('loss', 'NegReg', (115, 119))	('m/z 58', 'Var', (91, 97))	('HCl', 'MPA', (123, 126))
181174	31762797	The CID of methyl phosphonic acid [M+H]+ ion (m/z 97), yielded the major fragment ion of m/z 79 corresponding to loss of H2O.	('m/z 79', 'Var', (89, 95))	('H2O', 'Protein', (121, 124))	('methyl phosphonic acid', 'Chemical', 'MESH:C570063', (11, 33))	('loss', 'NegReg', (113, 117))	('H2O', 'Chemical', 'MESH:D014867', (121, 124))
181175	31762797	The CID of methyl-4-amino benzoate [M+H]+ ion (m/z 152), resulted in the major fragment ion of m/z 93 corresponding to loss of CH3O.	('CH3O', 'Chemical', 'MESH:C523063', (127, 131))	('CH3O', 'MPA', (127, 131))	('m/z 93', 'Var', (95, 101))	('methyl-4-amino benzoate', 'Chemical', 'MESH:C044605', (11, 34))	('loss', 'NegReg', (119, 123))
181176	31762797	The CID of methyl-4-hydroxy benzoate [M+H]+ ion (m/z 153), resulted in the major fragment ion of m/z of 120 which resulted in the loss of CH3O.	('CH3O', 'Chemical', 'MESH:C523063', (138, 142))	('CH3O', 'MPA', (138, 142))	('loss', 'NegReg', (130, 134))	('m/z of 120', 'Var', (97, 107))	('methyl-4-hydroxy benzoate', 'Chemical', 'MESH:C044605', (11, 36))
181177	31762797	The CID of methyl malonic acid [M-H]- ion (m/z 117), produced the major fragment ion of m/z 73 corresponding to loss of CO2.	('CO2', 'Chemical', 'MESH:D002245', (120, 123))	('CO2', 'Protein', (120, 123))	('loss', 'NegReg', (112, 116))	('m/z 73', 'Var', (88, 94))	('M-H', 'Chemical', 'MESH:C063476', (32, 35))	('methyl malonic acid', 'Chemical', 'MESH:C030290', (11, 30))
181180	31762797	The CID of N-methyl alanine [M+H] + ion (m/z 104), produced the major fragment ion of m/z 58 corresponding to loss of HCOOH.	('loss', 'NegReg', (110, 114))	('HCOOH', 'Chemical', 'None', (118, 123))	('HCOOH', 'Protein', (118, 123))	('m/z 58', 'Var', (86, 92))	('N-methyl alanine', 'Chemical', 'MESH:C523951', (11, 27))
181181	31762797	The CID of 1-methyl histidine [M+H]+ ion (m/z 170), resulted in the major fragment ion of m/z 124 corresponding to loss of HCOOH.	('loss', 'NegReg', (115, 119))	('HCOOH', 'Protein', (123, 128))	('m/z 124', 'Var', (90, 97))	('HCOOH', 'Chemical', 'None', (123, 128))	('1-methyl histidine', 'Chemical', 'MESH:C115717', (11, 29))
181182	31762797	The CID of 1-methyl-D-tryptophan (m/z 219), [M+H]+ ion produced the major fragment ion of m/z 173 corresponding to loss of HCOOH.	('HCOOH', 'MPA', (123, 128))	('loss', 'NegReg', (115, 119))	('1-methyl-D-tryptophan', 'Chemical', 'None', (11, 32))	('HCOOH', 'Chemical', 'None', (123, 128))	('m/z 173', 'Var', (90, 97))
181183	31762797	The CID of S-(5'-adenosyl)- L-methionine [M+H]+ ion (m/z 399), produced the major fragment ion of m/z 136 corresponding to loss of C10H17NSO5.	('C10H17NSO5', 'Var', (131, 141))	('m/z 136', 'Var', (98, 105))	('loss', 'NegReg', (123, 127))	("S-(5'-adenosyl)- L-methionine", 'Chemical', 'MESH:C468227', (11, 40))
181184	31762797	The CID of 2-methyl glutaric acid (m/z 145), [M-H]- ion yielded a major fragment ion of m/z 101 corresponding to loss of CO2.	('m/z 101', 'Var', (88, 95))	('M-H', 'Chemical', 'MESH:C063476', (46, 49))	('loss', 'NegReg', (113, 117))	('CO2', 'Chemical', 'MESH:D002245', (121, 124))	('CO2', 'MPA', (121, 124))	('2-methyl glutaric acid', 'Chemical', 'MESH:C035736', (11, 33))
181185	31762797	The CID of 3-hydroxy-3-methyl-glutaric acid (m/z 160), [M-H]- ion produced the major fragment ion of m/z 57 corresponding to loss of C3H5O4.	('3-hydroxy-3-methyl-glutaric acid', 'Chemical', 'MESH:C035736', (11, 43))	('C3H5O4', 'Chemical', 'MESH:D014867', (133, 139))	('loss', 'NegReg', (125, 129))	('m/z 57', 'Var', (101, 107))	('M-H', 'Chemical', 'MESH:C063476', (56, 59))	('C3H5O4', 'Var', (133, 139))
181186	31762797	The CID of 5-methoxy-3-indole acetic acid (m/z 204), [M-H]- ion produced the major fragment ion of m/z 160 corresponding to loss of CO2.	('CO2', 'Protein', (132, 135))	('loss', 'NegReg', (124, 128))	('m/z 160', 'Var', (99, 106))	('5-methoxy-3-indole acetic acid', 'Chemical', 'MESH:C030737', (11, 41))	('CO2', 'Chemical', 'MESH:D002245', (132, 135))	('M-H', 'Chemical', 'MESH:C063476', (54, 57))
181188	31762797	The CID of 5-methyl cytosine [M+H]+ ion (m/z 125), produced the major fragment ion of (m/z 109) corresponding to loss of NH3.	('NH3', 'Chemical', 'MESH:D000641', (121, 124))	('loss', 'NegReg', (113, 117))	('m/z 109', 'Var', (87, 94))	('5-methyl cytosine', 'Chemical', 'MESH:D003596', (11, 28))	('NH3', 'Protein', (121, 124))
181189	31762797	The CID of 1-methyl nicotinamide [M+H] + ion (m/z 138), yielded the major fragment ion of m/z 78 corresponding to loss of CH3COOH.	('CH3COOH', 'Chemical', 'MESH:C526539', (122, 129))	('loss', 'NegReg', (114, 118))	('CH3COOH', 'MPA', (122, 129))	('1-methyl nicotinamide', 'Chemical', 'MESH:D009536', (11, 32))	('m/z 78', 'Var', (90, 96))
181190	31762797	The CID of 6-O-methyl guanine [M+H]+ (m/z 166), produced the major fragment ion of m/z 149 with the loss of NH3.	('NH3', 'Chemical', 'MESH:D000641', (108, 111))	('m/z 149', 'Var', (83, 90))	('6-O-methyl guanine', 'Chemical', 'MESH:D006147', (11, 29))	('NH3', 'Protein', (108, 111))
181191	31762797	The CID of 2-amino-6-methyl mercaptopurine [M+H]+ ion (m/z 182), produced the major fragment ion of m/z 134 corresponding to loss of CH3SH.	('2-amino-6-methyl mercaptopurine', 'Chemical', 'MESH:C520946', (11, 42))	('loss', 'NegReg', (125, 129))	('CH3SH', 'Chemical', 'MESH:C014393', (133, 138))	('m/z 134', 'Var', (100, 107))	('CH3SH', 'MPA', (133, 138))
181192	31762797	The CID spectra of 5-methyl cytidine [M+H]+ ion (m/z 258), resulted in the major fragment ion of m/z 126 corresponding to loss of C5H8O4.	('5-methyl cytidine', 'Chemical', 'MESH:D003562', (19, 36))	('m/z 126', 'Var', (97, 104))	('C5H8O4', 'Chemical', 'MESH:C515417', (130, 136))	('loss', 'NegReg', (122, 126))	('C5H8O4', 'Var', (130, 136))
181193	31762797	The CID of 7-methylguanosine [M+H]+ ion (m/z 299), yielded the major fragment ions of m/z 167 corresponding to loss of C5H8O4.	('C5H8O4', 'Var', (119, 125))	('loss', 'NegReg', (111, 115))	('7-methylguanosine', 'Chemical', 'MESH:C016578', (11, 28))	('m/z 167', 'Var', (86, 93))	('C5H8O4', 'Chemical', 'MESH:C515417', (119, 125))
181194	31762797	The CID of 6-methyl-2-thiouracil [M-H]- ion (m/z 141), produced the major fragment ion of m/z 58 corresponding to loss of NCS.	('m/z 58', 'Var', (90, 96))	('M-H', 'Chemical', 'MESH:C063476', (34, 37))	('loss', 'NegReg', (114, 118))	('6-methyl-2-thiouracil', 'Chemical', 'MESH:D008779', (11, 32))	('NCS', 'MPA', (122, 125))
181195	31762797	The CID of 5'-deoxy-5'-methyl thioadenosine [M-H]- ion (m/z 296), produced the major fragment ion of m/z 134 corresponding to loss of C6H9SO3.	('m/z 134', 'Var', (101, 108))	("5'-deoxy-5'-methyl thioadenosine", 'Chemical', 'MESH:C063476', (11, 43))	('C6H9SO3', 'Var', (134, 141))	('M-H', 'Chemical', 'MESH:C063476', (45, 48))	('loss', 'NegReg', (126, 130))
181200	31762797	Epigenetic alterations such as DNA and histone methylations influence the chromatin states and impact gene expression during cancer progression .	('Epigenetic alterations', 'Var', (0, 22))	('gene expression', 'biological_process', 'GO:0010467', ('102', '117'))	('gene expression', 'MPA', (102, 117))	('impact', 'Reg', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('influence', 'Reg', (60, 69))	('chromatin', 'cellular_component', 'GO:0000785', ('74', '83'))	('histone methylations', 'Var', (39, 59))	('methyl', 'Chemical', 'MESH:C031105', (47, 53))	('chromatin states', 'MPA', (74, 90))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))
181218	31400748	However, GGCT deficiency is compatible with normal mouse development, suggesting that GGCT can be a cancer-specific therapeutic target.	('GGCT', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mouse', 'Species', '10090', (51, 56))	('deficiency', 'Var', (14, 24))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
181220	31400748	GGCT is a target of Ras and is required for Ras-induced cancer formation GGCT deletion is compatible with normal mouse development and tissue function GGCT genomic locus is amplified in multiple human cancer types GGCT could alleviate oncogenic stress by regulating GSH-ROS metabolism Biological Sciences; Cell Biology; Cancer Oncogenic transformation in primary somatic cells always leads to cellular stresses, which function as a fail-safe mechanism to prevent cancer formation.	('cancer', 'Phenotype', 'HP:0002664', (463, 469))	('leads to', 'Reg', (384, 392))	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('Cancer', 'Phenotype', 'HP:0002664', (320, 326))	('cancer', 'Disease', (56, 62))	('formation', 'biological_process', 'GO:0009058', ('63', '72'))	('deletion', 'Var', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cellular stresses', 'MPA', (393, 410))	('cancer', 'Disease', 'MESH:D009369', (463, 469))	('GSH-ROS', 'Chemical', '-', (266, 273))	('Cancer', 'Disease', (320, 326))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('Cancer', 'Disease', 'MESH:D009369', (320, 326))	('human', 'Species', '9606', (195, 200))	('metabolism', 'biological_process', 'GO:0008152', ('274', '284'))	('cancer', 'Disease', (463, 469))	('formation', 'biological_process', 'GO:0009058', ('470', '479'))	('mouse', 'Species', '10090', (113, 118))
181221	31400748	Activating Ras mutations are frequently observed in various cancers; however, these Ras mutants are known to be "undruggable" targets.	('Activating', 'PosReg', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('mutations', 'Var', (15, 24))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Ras', 'Gene', (11, 14))
181235	31400748	The selective accumulation of genetic alterations favoring GGCT up-regulation in cancer, but not normal control tissues, can serve as important cancer genomic evidence supporting the cancer-driving (or oncogenic) function of GGCT.	('regulation', 'biological_process', 'GO:0065007', ('67', '77'))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (81, 87))	('genetic alterations', 'Var', (30, 49))	('up-regulation', 'PosReg', (64, 77))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('alterations', 'Var', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('GGCT', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
181236	31400748	Here we systematically studied human cancer genome and identified significant GGCT gene amplification in human lung adenocarcinoma (LUAD).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (111, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('amplification', 'Var', (88, 101))	('cancer', 'Disease', (37, 43))	('lung adenocarcinoma', 'Disease', (111, 130))	('LUAD', 'Phenotype', 'HP:0030078', (132, 136))	('GGCT', 'Gene', (78, 82))	('human', 'Species', '9606', (31, 36))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (111, 130))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('human', 'Species', '9606', (105, 110))
181237	31400748	GGCT genomic locus amplification can directly lead to GGCT mRNA up-regulation, suggesting a cancer-driving function of GGCT in human cancer.	('human', 'Species', '9606', (127, 132))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('amplification', 'Var', (19, 32))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('up-regulation', 'PosReg', (64, 77))	('GGCT', 'Gene', (54, 58))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mRNA', 'MPA', (59, 63))	('GGCT', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('regulation', 'biological_process', 'GO:0065007', ('67', '77'))
181239	31400748	Genetic alterations including point mutations and copy number variations in somatic cells are the driving forces for human cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('point mutations', 'Var', (30, 45))	('human', 'Species', '9606', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('copy number variations', 'Var', (50, 72))	('cancer', 'Disease', (123, 129))
181249	31400748	GGCT gene was originally identified when we compared the differentially expressed genes between KrasG12D-expressing and control primary mouse embryonic fibroblasts (MEFs) (Figure 1A).	('KrasG12D-expressing', 'Var', (96, 115))	('GGCT', 'Gene', (0, 4))	('mouse', 'Species', '10090', (136, 141))	('MEFs', 'CellLine', 'CVCL:9115', (165, 169))
181259	31400748	Results confirmed GGCT copy number variation (CNV) amplification in multiple human cancers including LUAD (Figure 2B).	('copy number variation', 'Var', (23, 44))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))	('LUAD', 'Disease', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('LUAD', 'Phenotype', 'HP:0030078', (101, 105))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('GGCT', 'Gene', (18, 22))	('amplification', 'Var', (51, 64))
181269	31400748	Interestingly, in early-stage (TNM stage I) LUAD, patients with amplified GGCT CNV show significantly decreased overall survival (Figure S4A), whereas in late-stage LUAD GGCT CNV amplification does not lead to significantly poor prognosis (Figure S4B).	('GGCT CNV', 'Gene', (74, 82))	('LUAD', 'Phenotype', 'HP:0030078', (165, 169))	('patients', 'Species', '9606', (50, 58))	('decreased', 'NegReg', (102, 111))	('LUAD', 'Phenotype', 'HP:0030078', (44, 48))	('overall survival', 'MPA', (112, 128))	('amplified', 'Var', (64, 73))
181279	31400748	This indicates that GGCT deficiency is compatible with normal mouse development (Figure 3E).	('GGCT', 'Gene', (20, 24))	('mouse', 'Species', '10090', (62, 67))	('deficiency', 'Var', (25, 35))
181282	31400748	GGCT deletion also completely blocked the in vitro proliferation of KRASG12D-expressing MEFs (Figure 4A).	('MEFs', 'CellLine', 'CVCL:9115', (88, 92))	('deletion', 'Var', (5, 13))	('blocked', 'NegReg', (30, 37))	('in vitro proliferation', 'CPA', (42, 64))	('GGCT', 'Gene', (0, 4))
181285	31400748	In large T antigen-expressing situation, both GGCT-/- and GGCT+/+ MEFs do not show apparent senescent phenotype and can proliferate at similar speed (Figure 4).	('GGCT+/+', 'Var', (58, 65))	('GGCT-/-', 'Gene', (46, 53))	('GGCT-/-', 'Gene', '79017', (46, 53))	('MEFs', 'CellLine', 'CVCL:9115', (66, 70))	('proliferate', 'CPA', (120, 131))
181291	31400748	In both primary and KrasG12D-expressing situations, cell cycle gene signature, specifically Rb-E2F gene signature, is the top different gene signature when comparing GGCT-/- and GGCT+/+ MEFs (Table S3 and Figure S6), whereas in large T antigen-transformed situation, this Rb-E2F signature does not appear (Table S3), and this observation is in line with the fact that large T antigen is able to block Rb tumor suppressor pathway.	('block Rb tumor', 'Disease', 'MESH:D006327', (395, 409))	('GGCT+/+ MEFs', 'Var', (178, 190))	('block Rb tumor', 'Disease', (395, 409))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('404', '420'))	('GGCT-/-', 'Gene', (166, 173))	('tumor', 'Phenotype', 'HP:0002664', (404, 409))	('cell cycle', 'biological_process', 'GO:0007049', ('52', '62'))	('GGCT-/-', 'Gene', '79017', (166, 173))	('cell', 'MPA', (52, 56))	('G12D', 'Mutation', 'rs121913529', (24, 28))	('MEFs', 'CellLine', 'CVCL:9115', (186, 190))	('tumor suppressor', 'biological_process', 'GO:0051726', ('404', '420'))
181292	31400748	GGCT deficiency has no apparent effect on mouse embryonic development and tissue function (Figure 3).	('mouse', 'Species', '10090', (42, 47))	('GGCT', 'Gene', (0, 4))	('deficiency', 'Var', (5, 15))
181304	31400748	In summary, our comprehensive cancer genomic and mouse model studies indicate that both oncogenic signal (Ras activation) and chromosomal 7p amplification lead to GGCT expression up-regulation in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('expression', 'MPA', (168, 178))	('regulation', 'biological_process', 'GO:0065007', ('182', '192'))	('chromosomal 7p amplification', 'Var', (126, 154))	('human', 'Species', '9606', (196, 201))	('cancer', 'Disease', (30, 36))	('GGCT', 'Gene', (163, 167))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('mouse', 'Species', '10090', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancer', 'Disease', (202, 208))	('cancers', 'Disease', (202, 209))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('up-regulation', 'PosReg', (179, 192))
181315	31400748	Based on our experimental data, GGCT deficiency also leads to decreased intracellular L-cysteine and consequently GSH down-regulation.	('down-regulation', 'NegReg', (118, 133))	('decreased', 'NegReg', (62, 71))	('GSH', 'Chemical', 'MESH:D005978', (114, 117))	('GGCT', 'Gene', (32, 36))	('intracellular L-cysteine', 'MPA', (72, 96))	('regulation', 'biological_process', 'GO:0065007', ('123', '133'))	('GSH', 'MPA', (114, 117))	('intracellular', 'cellular_component', 'GO:0005622', ('72', '85'))	('deficiency', 'Var', (37, 47))	('L-cysteine', 'Chemical', 'MESH:D003545', (86, 96))
181321	31400748	Bona fide cancer-driving oncogenes are often selected to be amplified through genetic alterations.	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('genetic alterations', 'Var', (78, 97))
181330	31400748	GGCT deficiency is compatible with normal mouse development and tissue function, but it is required for primary MEFs' in vitro growth and transformation.	('mouse', 'Species', '10090', (42, 47))	('GGCT', 'Gene', (0, 4))	('deficiency', 'Var', (5, 15))	('MEFs', 'CellLine', 'CVCL:9115', (112, 116))
181332	31400748	More importantly, using a LSL-Kras G12D lung cancer mouse model, we demonstrated a critical role of GGCT in oncogenic Ras-induced in vivo tumorigenesis.	('GGCT', 'Protein', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', (138, 143))	('mouse', 'Species', '10090', (52, 57))	('G12D', 'SUBSTITUTION', 'None', (35, 39))	('oncogenic', 'Var', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('G12D', 'Var', (35, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
181342	31382962	Aberration of miRNA expressions could affect their targeting mRNAs involved in cancer-related signaling pathways.	('targeting mRNAs', 'MPA', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('miRNA expressions', 'Protein', (14, 31))	('signaling', 'biological_process', 'GO:0023052', ('94', '103'))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('affect', 'Reg', (38, 44))	('Aberration', 'Var', (0, 10))
181350	31382962	Cancer is a genetic disease caused by alterations of genes that control the cell behavior, like cell growth and division.	('cell growth', 'biological_process', 'GO:0016049', ('96', '107'))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('caused by', 'Reg', (28, 37))	('genetic disease', 'Disease', (12, 27))	('genetic disease', 'Disease', 'MESH:D030342', (12, 27))	('alterations', 'Var', (38, 49))
181354	31382962	TCGA data has been used to characterize key genomic changes, find novel mutations, define intrinsic tumor types, discover similarities and differences across cancer types, reveal therapy resistance mechanisms, and collect tumor evolution evidence.	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
181357	31382962	The aberration of miRNA expression could affect a large number of mRNAs and cancer-related signaling pathways.	('aberration', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('miRNA expression', 'Protein', (18, 34))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('mRNAs', 'Pathway', (66, 71))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('affect', 'Reg', (41, 47))
181387	31382962	Intuitively, the arithmetic mean of absolute values (ie., T_CC and N_CC) is an option to quantify the inversion of their expressional correlation coefficient, namely, inversion of N_CC to T_CC for a miRNA-mRNA pair as shown in Fig.	('inversion', 'Var', (167, 176))	('N_CC', 'Gene', (67, 71))	('N_CC', 'Gene', '6559', (180, 184))	('T_CC', 'Gene', (58, 62))	('T_CC', 'Gene', '94081', (58, 62))	('N_CC', 'Gene', '6559', (67, 71))	('T_CC', 'Gene', (188, 192))	('T_CC', 'Gene', '94081', (188, 192))	('N_CC', 'Gene', (180, 184))
181436	31382962	Biologically, the MWMM approach yields clusters that has relatively higher intra-cluster and relatively lower inter-cluster average GO term similarity distance scores compared to other six clustering algorithms in most of cancer types that are tested.	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('GO term similarity distance scores', 'MPA', (132, 166))	('cancer', 'Disease', (222, 228))	('higher', 'PosReg', (68, 74))	('lower', 'NegReg', (104, 109))	('MWMM', 'Var', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))
181447	29151933	Furthermore, high expression of ARID1B was an independent indicator of poor OS (P=0.022).	('OS', 'Chemical', '-', (76, 78))	('high expression', 'Var', (13, 28))	('ARID1B', 'Gene', (32, 38))	('poor OS', 'Disease', (71, 78))
181448	29151933	Most importantly, the benefit of adjuvant chemotherapy observed in patients with low ARID1B expression was superior to that observed in patients with high ARID1B expression.	('low', 'NegReg', (81, 84))	('patients', 'Species', '9606', (67, 75))	('expression', 'Var', (92, 102))	('adjuvant', 'CPA', (33, 41))	('patients', 'Species', '9606', (136, 144))	('ARID1B', 'Gene', (85, 91))
181461	29151933	Mutations in the ARID1B gene, which shares approximately 60% similarities in amino acid sequence with ARID1A, play an important role in causing Coffin-Siris syndrome.	('ARID1A', 'Gene', '8289', (102, 108))	('ARID1A', 'Gene', (102, 108))	('Mutations', 'Var', (0, 9))	('Siris syndrome', 'Disease', 'MESH:C536436', (151, 165))	('causing', 'Reg', (136, 143))	('Siris syndrome', 'Disease', (151, 165))	('ARID1B', 'Gene', (17, 23))
181463	29151933	More importantly, recent studies have identified mutant alleles of ARID1B by whole-genome or whole-exome surveys in human cancers, such as colorectal, pancreatic, and breast cancer, and neuroblastoma.	('neuroblastoma', 'Disease', (186, 199))	('breast cancer', 'Disease', (167, 180))	('mutant', 'Var', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('colorectal', 'Disease', (139, 149))	('neuroblastoma', 'Phenotype', 'HP:0003006', (186, 199))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('ARID1B', 'Gene', (67, 73))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('pancreatic', 'Disease', 'MESH:D010195', (151, 161))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('neuroblastoma', 'Disease', 'MESH:D009447', (186, 199))	('colorectal', 'Disease', 'MESH:D015179', (139, 149))	('pancreatic', 'Disease', (151, 161))	('human', 'Species', '9606', (116, 121))
181487	29151933	We also found that patients with T4 diseases had a higher rate of high ARID1B expression than did patients with other stages of disease.	('expression', 'MPA', (78, 88))	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (98, 106))	('high', 'Var', (66, 70))	('ARID1B', 'Protein', (71, 77))	('T4 diseases', 'Disease', (33, 44))
181489	29151933	Kaplan-Meier curves showed that patients with high ARID1B expression had a significantly poorer OS (P<0.001, Figure 2) and PFS (P=0.043) than those with low ARID1B expression.	('high', 'Var', (46, 50))	('patients', 'Species', '9606', (32, 40))	('poorer', 'NegReg', (89, 95))	('PFS', 'CPA', (123, 126))	('ARID1B', 'Gene', (51, 57))	('OS', 'Chemical', '-', (96, 98))
181491	29151933	Tumor grade (HR=2.929, 95% CI: 1.052-8.149, P=0.040), high ARID1B expression (HR=2.813, 95% CI: 1.594-4.964, P<0.001), adjuvant chemotherapy (HR=1.865, 95% CI: 1.042-3.336, P=0.036), T stage (per increase in stage: HR=2.197, 95% CI: 1.558-3.099, P<0.001), lymph node status (HR=2.995, 95% CI: 1.691-5.305, P<0.001), and TNM stage (per increase in stage: HR=1.926, 95% CI: 1.466-2.564, P<0.001) were risk factors in univariate analysis (Table 2).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ARID1B', 'Gene', (59, 65))	('high', 'Var', (54, 58))	('TNM', 'Gene', '10178', (320, 323))	('TNM', 'Gene', (320, 323))
181501	29151933	However, treatment with adjuvant chemotherapy was strongly associated with a higher rate of 5-year OS in the low ARID1B expression group (P=0.030), but not in the high ARID1B expression group (P=0.398).	('OS', 'Chemical', '-', (99, 101))	('men', 'Species', '9606', (14, 17))	('5-year OS', 'CPA', (92, 101))	('low', 'Var', (109, 112))
181502	29151933	A test for the interaction between the biomarker and treatment showed that the benefit observed in the low ARID1B group was superior to that observed in the high ARID1B expression group (P for interaction=0.027; Figure 3).	('ARID1B', 'Gene', (107, 113))	('low', 'Var', (103, 106))	('men', 'Species', '9606', (58, 61))
181505	29151933	To the best of our knowledge, we showed for the first time that high ARID1B expression was positively associated with tumor size, T stage, lymph node status, TNM stage, and an increased risk of death, as well as disease progression, in these patients.	('death', 'Disease', (194, 199))	('T stage', 'CPA', (130, 137))	('high', 'Var', (64, 68))	('associated', 'Reg', (102, 112))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('patients', 'Species', '9606', (242, 250))	('ARID1B', 'Gene', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('TNM', 'Gene', (158, 161))	('tumor', 'Disease', (118, 123))	('expression', 'MPA', (76, 86))	('death', 'Disease', 'MESH:D003643', (194, 199))	('disease', 'CPA', (212, 219))	('TNM', 'Gene', '10178', (158, 161))	('lymph node status', 'CPA', (139, 156))
181507	29151933	Most importantly, we demonstrated that patients with low ARID1B expression might benefit from adjuvant chemotherapy.	('expression', 'MPA', (64, 74))	('patients', 'Species', '9606', (39, 47))	('adjuvant chemotherapy', 'CPA', (94, 115))	('low', 'Var', (53, 56))	('ARID1B', 'Gene', (57, 63))	('benefit', 'PosReg', (81, 88))
181508	29151933	We also showed that the knockdown of ARID1B caused significantly decreased cell proliferation, migration and invasion ability in T24 cells, which correlated with the possible role of ARID1B as an oncogene in bladder cancer.	('invasion ability', 'CPA', (109, 125))	('decreased', 'NegReg', (65, 74))	('bladder cancer', 'Disease', (208, 222))	('bladder cancer', 'Disease', 'MESH:D001749', (208, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('ARID1B', 'Gene', (37, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('bladder cancer', 'Phenotype', 'HP:0009725', (208, 222))	('migration', 'CPA', (95, 104))	('knockdown', 'Var', (24, 33))	('cell proliferation', 'CPA', (75, 93))
181515	29151933	This may be an explanation for our finding that patients with low ARID1B expression benefited more from adjuvant chemotherapy.	('adjuvant chemotherapy', 'CPA', (104, 125))	('benefited', 'PosReg', (84, 93))	('ARID1B', 'Protein', (66, 72))	('expression', 'MPA', (73, 83))	('low', 'Var', (62, 65))	('patients', 'Species', '9606', (48, 56))
181521	29151933	Recent studies have suggested that SWI/SNF factors, especially ARID1A and ARID1B, might encode products involved in carcinogenesis by identifying the inactivating mutant alleles in different cancers and primary cancer cells.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('carcinogenesis', 'Disease', 'MESH:D063646', (116, 130))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Disease', (191, 198))	('cancer', 'Disease', (211, 217))	('mutant', 'Var', (163, 169))	('carcinogenesis', 'Disease', (116, 130))	('ARID1A', 'Gene', '8289', (63, 69))	('ARID1A', 'Gene', (63, 69))	('inactivating', 'Reg', (150, 162))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
181522	29151933	suggested that ARID1B confers a specific vulnerability in ARID1A-mutant cancers, and the loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation.	('cancers', 'Disease', (72, 79))	('loss', 'Var', (89, 93))	('SWI/SNF', 'CPA', (149, 156))	('ARID1A', 'Gene', '8289', (58, 64))	('ARID1A', 'Gene', (58, 64))	('ARID1A', 'Gene', '8289', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ARID1A', 'Gene', (107, 113))	('ARID1B', 'Gene', (97, 103))	('proliferation', 'CPA', (169, 182))	('impairs', 'NegReg', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('destabilizes', 'NegReg', (136, 148))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
181529	29151933	Consistent with this previous study, we showed that high ARID1B expression predicted poor OS in patients with bladder urothelial carcinoma.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (110, 138))	('expression', 'MPA', (64, 74))	('OS', 'Chemical', '-', (90, 92))	('bladder urothelial carcinoma', 'Disease', (110, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('high', 'Var', (52, 56))	('ARID1B', 'Gene', (57, 63))	('patients', 'Species', '9606', (96, 104))	('poor OS', 'Disease', (85, 92))
181532	29151933	Additionally, we demonstrated that ARID1B plays an important role in adjuvant chemotherapy and the inhibition of ARID1B caused significant suppression in cell proliferation, migration and invasion in bladder cancer cells.	('cell proliferation', 'CPA', (154, 172))	('bladder cancer', 'Disease', 'MESH:D001749', (200, 214))	('bladder cancer', 'Disease', (200, 214))	('inhibition', 'Var', (99, 109))	('invasion', 'CPA', (188, 196))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('bladder cancer', 'Phenotype', 'HP:0009725', (200, 214))	('suppression', 'NegReg', (139, 150))	('migration', 'CPA', (174, 183))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))	('ARID1B', 'Gene', (113, 119))
181534	26901439	Mitochondrial DNA copy number variation across human cancers Mutations, deletions, and changes in copy number of mitochondrial DNA (mtDNA), are observed throughout cancers.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('113', '130'))	('mtDNA', 'cellular_component', 'GO:0000262', ('132', '137'))	('Mutations', 'Var', (61, 70))	('Mitochondrial DNA', 'cellular_component', 'GO:0000262', ('0', '17'))	('Mitochondrial DNA', 'Gene', (0, 17))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('copy number', 'MPA', (98, 109))	('cancers', 'Disease', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('deletions', 'Var', (72, 81))	('changes', 'Reg', (87, 94))	('human', 'Species', '9606', (47, 52))	('mitochondrial DNA', 'Gene', (113, 130))
181537	26901439	Analysis of genetic context reveals an association between incidence of several somatic alterations, including IDH1 mutations in gliomas, and mtDNA content.	('mtDNA', 'cellular_component', 'GO:0000262', ('142', '147'))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('IDH1', 'Gene', '3417', (111, 115))	('gliomas', 'Disease', (129, 136))	('gliomas', 'Disease', 'MESH:D005910', (129, 136))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('mutations', 'Var', (116, 125))	('IDH1', 'Gene', (111, 115))
181540	26901439	Our results highlight the extent of mtDNA copy number variation in tumors and point to related therapeutic opportunities.	('mtDNA', 'cellular_component', 'GO:0000262', ('36', '41'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mtDNA', 'Gene', (36, 41))	('copy number variation', 'Var', (42, 63))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
181541	26901439	However, in the mutant cells that form cancerous tumors, these roles can be subverted and altered.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cancerous tumors', 'Disease', 'MESH:D009369', (39, 55))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutant', 'Var', (16, 22))	('cancerous tumors', 'Disease', (39, 55))
181545	26901439	also found that the number of copies of mitochondrial DNA in certain tumor types is related to the incidence of key 'driver' mutations that cause cells to become cancerous.	('mitochondrial DNA', 'Gene', (40, 57))	('mutations', 'Var', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('40', '57'))	('tumor', 'Disease', (69, 74))	('cancerous', 'Disease', 'MESH:D009369', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('cancerous', 'Disease', (162, 171))
181548	26901439	Alterations of mitochondrial DNA (mtDNA), via inactivating genetic mutations or depletion of the number of copies of mtDNA in a cell, can impair mitochondrial respiration and contribute to pathologies as diverse as encephelopathies and neuropathies, and the process of aging.	('encephelopathies and neuropathies', 'Disease', 'MESH:D009422', (215, 248))	('inactivating genetic mutations', 'Var', (46, 76))	('aging', 'biological_process', 'GO:0007568', ('269', '274'))	('neuropathies', 'Phenotype', 'HP:0009830', (236, 248))	('mtDNA', 'cellular_component', 'GO:0000262', ('117', '122'))	('Alterations', 'Var', (0, 11))	('respiration', 'biological_process', 'GO:0045333', ('159', '170'))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('15', '32'))	('contribute to', 'Reg', (175, 188))	('impair', 'NegReg', (138, 144))	('mitochondrial respiration', 'MPA', (145, 170))	('depletion', 'Var', (80, 89))	('mtDNA', 'cellular_component', 'GO:0000262', ('34', '39'))	('respiration', 'biological_process', 'GO:0007585', ('159', '170'))	('mtDNA', 'Gene', (117, 122))
181549	26901439	In cancer, a number of studies have examined the role of mtDNA mutations in carcinogenesis.	('mutations', 'Var', (63, 72))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mtDNA', 'Gene', (57, 62))	('cancer', 'Disease', (3, 9))	('mtDNA', 'cellular_component', 'GO:0000262', ('57', '62'))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
181557	26901439	Second, mitochondria are susceptible to mutations in nuclear- and mitochondrially-encoded genes, and a subset of tumors are known to be caused by mutations of the mitochondrial enzymes FH, SDH, and IDH.	('SDH', 'Gene', '6390', (189, 192))	('mutations', 'Var', (146, 155))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('mitochondria', 'cellular_component', 'GO:0005739', ('8', '20'))	('caused by', 'Reg', (136, 145))	('SDH', 'Gene', (189, 192))	('mutations', 'Var', (40, 49))	('IDH', 'Gene', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('IDH', 'Gene', '3417', (198, 201))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
181558	26901439	Furthermore, mtDNA dysfunction affecting the electron transport chain can lead to generation of excess reactive oxygen species (ROS), contributing to tumor cell metastasis.	('contributing to', 'Reg', (134, 149))	('lead to', 'Reg', (74, 81))	('ROS', 'Chemical', 'MESH:D017382', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('mtDNA', 'cellular_component', 'GO:0000262', ('13', '18'))	('electron transport chain', 'MPA', (45, 69))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('electron transport chain', 'biological_process', 'GO:0022900', ('45', '69'))	('dysfunction', 'Var', (19, 30))	('tumor', 'Disease', (150, 155))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (103, 126))
181563	26901439	Finally, we ask whether gross variations of mtDNA copy number are linked to the incidence of somatic alterations (including mutations and copy number alterations) across cancer types.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('linked', 'Reg', (66, 72))	('mtDNA', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('mtDNA', 'cellular_component', 'GO:0000262', ('44', '49'))	('copy number alterations', 'Var', (138, 161))
181564	26901439	Altogether, our results shed light on the contribution of aberrant mitochondrial function, through changes in mtDNA content, to cancer.	('mitochondrial function', 'MPA', (67, 89))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('changes', 'Reg', (99, 106))	('mtDNA', 'cellular_component', 'GO:0000262', ('110', '115'))	('aberrant', 'Var', (58, 66))	('aberrant mitochondrial function', 'Phenotype', 'HP:0003287', (58, 89))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mtDNA content', 'MPA', (110, 123))	('cancer', 'Disease', (128, 134))
181568	26901439	Because tumor cells can exhibit large-scale genomic amplifications and deletions, and may be infiltrated by stromal and immune cells, we applied a ploidy/purity correction (''), described in detail in the Materials and methods.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('deletions', 'Var', (71, 80))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))
181570	26901439	We confirmed that across all combinations of cancer types and sequencing centers, WXS and WGS offer significantly correlated estimates of mtDNA copy number (Figure 2:figure supplement 1).	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('copy number', 'Var', (144, 155))	('mtDNA', 'cellular_component', 'GO:0000262', ('138', '143'))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('mtDNA', 'Gene', (138, 143))
181593	26901439	That mtDNA copy number correlates with better or worse survival, depending on cancer type, suggests that other confounding factors strongly tied to survival, such as the presence of somatic mutations, may influence mtDNA levels.	('influence', 'Reg', (205, 214))	('mtDNA', 'cellular_component', 'GO:0000262', ('215', '220'))	('mtDNA', 'Gene', (5, 10))	('cancer', 'Disease', (78, 84))	('mtDNA levels', 'MPA', (215, 227))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mtDNA', 'cellular_component', 'GO:0000262', ('5', '10'))	('copy number', 'Var', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
181602	26901439	Of particular interest is a recent report by West and colleagues, demonstrating that mtDNA stress induced by depletion of TFAM triggered the innate immune response via interferon-stimulated genes and anti-viral signaling.	('TFAM', 'Gene', '7019', (122, 126))	('TFAM', 'Gene', (122, 126))	('depletion', 'Var', (109, 118))	('innate immune response', 'MPA', (141, 163))	('signaling', 'biological_process', 'GO:0023052', ('211', '220'))	('mtDNA', 'cellular_component', 'GO:0000262', ('85', '90'))	('triggered', 'PosReg', (127, 136))	('innate immune response', 'biological_process', 'GO:0045087', ('141', '163'))
181604	26901439	A subset of tumor types did not show strong positive correlation between mtDNA copy number and expression of mitochondrial metabolic genes.	('mtDNA', 'Gene', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mtDNA', 'cellular_component', 'GO:0000262', ('73', '78'))	('tumor', 'Disease', (12, 17))	('copy number', 'Var', (79, 90))
181613	26901439	TP53 mutations are enriched in the serous-like subtype, and these mutations also showed statistically significant association with mtDNA abundance (BH-corrected p-value 0.012).	('mutations', 'Var', (66, 75))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mtDNA abundance', 'Disease', (131, 146))	('serous', 'Chemical', '-', (35, 41))	('mtDNA', 'cellular_component', 'GO:0000262', ('131', '136'))	('mutations', 'Var', (5, 14))	('association', 'Interaction', (114, 125))	('significant', 'Reg', (102, 113))
181615	26901439	Both IDH1 and IDH2 activating mutations induce production of the so-called 'onco-metabolite' 2-hydroxyglutarate, which competitively inhibits -ketoglutarate-dependent histone demethylases and 5-methylcytosine hydroxylases, inducing a hypermethylation phenotype.	('hypermethylation phenotype', 'MPA', (234, 260))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (93, 111))	('inducing', 'Reg', (223, 231))	('IDH1', 'Gene', (5, 9))	('IDH2', 'Gene', '3418', (14, 18))	('IDH1', 'Gene', '3417', (5, 9))	('5-methylcytosine hydroxylases', 'Enzyme', (192, 221))	('mutations', 'Var', (30, 39))	('IDH2', 'Gene', (14, 18))	('inhibits', 'NegReg', (133, 141))
181616	26901439	Surprisingly, IDH2 mutations showed no statistically significant change in mtDNA abundance, suggesting that the effect is specific to the cytosolic isoform IDH1.	('IDH1', 'Gene', (156, 160))	('IDH1', 'Gene', '3417', (156, 160))	('mutations', 'Var', (19, 28))	('mtDNA abundance', 'MPA', (75, 90))	('IDH2', 'Gene', (14, 18))	('mtDNA', 'cellular_component', 'GO:0000262', ('75', '80'))	('IDH2', 'Gene', '3418', (14, 18))
181617	26901439	Notably, mutations in PTEN were associated with a significant decrease in mtDNA abundance (BH-corrected p-value 0.033).	('mtDNA', 'cellular_component', 'GO:0000262', ('74', '79'))	('mutations', 'Var', (9, 18))	('PTEN', 'Gene', (22, 26))	('decrease', 'NegReg', (62, 70))	('mtDNA abundance', 'MPA', (74, 89))	('PTEN', 'Gene', '5728', (22, 26))
181618	26901439	These results echo a complementary finding by Navis and colleagues, who reported that a mutant IDH1 R132H oligodendroglioma xenograft model displayed high densities of mitochondria and increased levels of mitochondrial metabolic activity.	('IDH1', 'Gene', '3417', (95, 99))	('oligodendroglioma', 'Disease', 'MESH:D009837', (106, 123))	('R132H', 'Var', (100, 105))	('mitochondria', 'cellular_component', 'GO:0005739', ('168', '180'))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('R132H', 'Mutation', 'rs121913500', (100, 105))	('mitochondrial metabolic activity', 'MPA', (205, 237))	('IDH1', 'Gene', (95, 99))	('mutant', 'Var', (88, 94))	('mitochondria', 'MPA', (168, 180))	('oligodendroglioma', 'Disease', (106, 123))	('levels', 'MPA', (195, 201))	('densities', 'MPA', (155, 164))	('increased', 'PosReg', (185, 194))
181619	26901439	They proposed that an increase in mitochondrial mass would increase activity of mitochondrial IDH2 and compensate for loss of activity introduced by mutant IDH1.	('mitochondrial mass', 'MPA', (34, 52))	('IDH1', 'Gene', (156, 160))	('increase', 'PosReg', (59, 67))	('IDH2', 'Gene', '3418', (94, 98))	('mutant', 'Var', (149, 155))	('IDH1', 'Gene', '3417', (156, 160))	('increase', 'PosReg', (22, 30))	('activity', 'MPA', (68, 76))	('activity', 'MPA', (126, 134))	('IDH2', 'Gene', (94, 98))
181620	26901439	Finally, prompted by a recent report implicating mutations in mtDNA itself with the pathology of kidney chromophobe carcinomas (KICH), we investigated the connection between mtDNA copy number and mtDNA mutations in KICH.	('mtDNA', 'cellular_component', 'GO:0000262', ('62', '67'))	('mtDNA', 'cellular_component', 'GO:0000262', ('196', '201'))	('mutations', 'Var', (49, 58))	('kidney chromophobe carcinomas', 'Disease', (97, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('kidney chromophobe carcinomas', 'Disease', 'MESH:C538614', (97, 126))	('mtDNA', 'cellular_component', 'GO:0000262', ('174', '179'))	('mtDNA', 'Gene', (174, 179))
181634	26901439	Orthogonal measurements of transcription levels (via RNA-Seq) and mitochondrial protein levels (via IHC) in a subset of these samples linked this variation to downregulation of mitochondrially-localized metabolic pathways, in some but not all tumor types.	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('RNA', 'cellular_component', 'GO:0005562', ('53', '56'))	('transcription', 'biological_process', 'GO:0006351', ('27', '40'))	('mitochondrially-localized metabolic pathways', 'Pathway', (177, 221))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('variation', 'Var', (146, 155))	('transcription levels', 'MPA', (27, 47))	('downregulation', 'NegReg', (159, 173))	('mitochondrial protein levels', 'MPA', (66, 94))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
181647	26901439	While mtDNA depletion or accumulation may typify certain cancer types, we further identified that subsets of patient samples, characterized by the presence of particular somatic mutations/copy number alterations, were enriched/depleted in mtDNA.	('mtDNA', 'cellular_component', 'GO:0000262', ('6', '11'))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('patient', 'Species', '9606', (109, 116))	('mtDNA', 'Disease', (239, 244))	('cancer', 'Disease', (57, 63))	('mtDNA', 'cellular_component', 'GO:0000262', ('239', '244'))	('mutations/copy', 'Var', (178, 192))	('mutations/copy number alterations', 'Var', (178, 211))	('enriched/depleted', 'NegReg', (218, 235))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
181648	26901439	The presence of activating IDH1 mutations (in low grade gliomas) or a large number of copy number alterations (in serous-like endometrial carcinomas) is strongly correlated to high tumor mtDNA content.	('high tumor', 'Disease', (176, 186))	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('gliomas', 'Disease', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (126, 148))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (126, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('serous', 'Chemical', '-', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('high tumor', 'Disease', 'MESH:D009369', (176, 186))	('endometrial carcinomas', 'Disease', (126, 148))	('mutations', 'Var', (32, 41))	('IDH1', 'Gene', (27, 31))	('mtDNA', 'cellular_component', 'GO:0000262', ('187', '192'))	('activating', 'PosReg', (16, 26))	('IDH1', 'Gene', '3417', (27, 31))
181665	26901439	We observed a statistically significant positive linear correlation (Pearson p-value <0.1 ) between  and  in 17/19 cancer types profiled with WXS, but in 0/7 cancer types profiled with WGS (analysis restricted to studies with adequate numbers of samples, defined as at least 3 different TCGA plate IDs with at least 3 blood and 3 tissue samples).	('cancer', 'Disease', (115, 121))	('WXS', 'Var', (142, 145))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
181670	26901439	Survival analysis was performed with univariate Cox proportional hazards regression models where the independent and dependent variables were the log10-transformed corrected mtDNA copy number and the overall survival respectively.	('copy number', 'Var', (180, 191))	('Cox', 'Gene', '1351', (48, 51))	('Cox', 'Gene', (48, 51))	('mtDNA', 'cellular_component', 'GO:0000262', ('174', '179'))	('mtDNA', 'Gene', (174, 179))
181673	26901439	For mutations, we obtained the MAF file from the output of MutSig.	('mutations', 'Var', (4, 13))	('MAF', 'Gene', (31, 34))	('MAF', 'Gene', '4094', (31, 34))
181674	26901439	For each gene, we calculated the number of patients in which this gene exhibited a nonsynonymous, coding mutation (i.e., missense, non-sense, frameshift, in-frame insertion/deletions, and splice-site mutations), excluding those with greater than 600 non-synonnymous coding mutations).	('frameshift', 'Var', (142, 152))	('patients', 'Species', '9606', (43, 51))	('missense', 'Var', (121, 129))	('in-frame insertion/deletions', 'Var', (154, 182))	('splice-site mutations', 'Var', (188, 209))	('non-sense', 'Var', (131, 140))
181675	26901439	We then retained any genes which were mutated in greater than 4% of patients.Non-parametric Mann-Whitney U-tests were used to evaluate whether tumors bearing a particular somatic alteration contained significantly higher/lower amounts of mtDNA in tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('mtDNA', 'cellular_component', 'GO:0000262', ('238', '243'))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', (247, 252))	('alteration', 'Var', (179, 189))	('higher/lower', 'PosReg', (214, 226))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('higher/lower', 'NegReg', (214, 226))	('patients', 'Species', '9606', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
181685	26901439	Informatic analyses also reveal that mtDNA content correlates with specific changes such as IDH1 mutation.	('mtDNA', 'cellular_component', 'GO:0000262', ('37', '42'))	('IDH1', 'Gene', '3417', (92, 96))	('IDH1', 'Gene', (92, 96))	('mutation', 'Var', (97, 105))
181687	26901439	This may lead to false positive results regarding mtDNA copy number in the tumors and need to be subtracted from the analysis.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('false', 'biological_process', 'GO:0071877', ('17', '22'))	('false', 'biological_process', 'GO:0071878', ('17', '22'))	('mtDNA', 'Gene', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('mtDNA', 'cellular_component', 'GO:0000262', ('50', '55'))	('copy number', 'Var', (56, 67))
181696	26901439	This may lead to a false positive results regarding mtDNA copy number in the tumors and need to be subtracted from the analysis.	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Disease', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('mtDNA', 'cellular_component', 'GO:0000262', ('52', '57'))	('mtDNA', 'Gene', (52, 57))	('false', 'biological_process', 'GO:0071877', ('19', '24'))	('copy number', 'Var', (58, 69))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('false', 'biological_process', 'GO:0071878', ('19', '24'))	('lead', 'Reg', (9, 13))
181709	26901439	As of October 8, 2015, cbioportal.org reported only a handful of TFAM missense/nonsense mutations across all studies in the TCGA.	('TFAM', 'Gene', '7019', (65, 69))	('TFAM', 'Gene', (65, 69))	('missense/nonsense', 'Var', (70, 87))
181710	26901439	Rather than try to tease apart the contribution of these rare mutations to mtDNA copy number, we instead focused on the association of changes in TFAM gene expression and mtDNA copy number.	('mtDNA', 'cellular_component', 'GO:0000262', ('75', '80'))	('gene expression', 'biological_process', 'GO:0010467', ('151', '166'))	('changes', 'Var', (135, 142))	('mtDNA', 'cellular_component', 'GO:0000262', ('171', '176'))	('TFAM', 'Gene', (146, 150))	('TFAM', 'Gene', '7019', (146, 150))	('mtDNA', 'Gene', (171, 176))	('expression', 'MPA', (156, 166))
181713	26901439	Of the 29 cases tested, 13 of them (~45%) showed statistically significant positive correlation between mtDNA copy number and TFAM expression (Spearman rho p-value <0.05).	('mtDNA', 'Gene', (104, 109))	('mtDNA', 'cellular_component', 'GO:0000262', ('104', '109'))	('positive', 'PosReg', (75, 83))	('TFAM', 'Gene', (126, 130))	('TFAM', 'Gene', '7019', (126, 130))	('expression', 'MPA', (131, 141))	('copy number', 'Var', (110, 121))
181717	26901439	In other words, in these tumor types, the interferon signaling pathway was most highly expressed in samples with the lowest mtDNA copy number.	('lowest', 'Var', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('signaling pathway', 'biological_process', 'GO:0007165', ('53', '70'))	('mtDNA', 'Gene', (124, 129))	('tumor', 'Disease', (25, 30))	('mtDNA', 'cellular_component', 'GO:0000262', ('124', '129'))	('interferon signaling pathway', 'Pathway', (42, 70))	('highly', 'PosReg', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('expressed', 'MPA', (87, 96))
181729	26901439	the p-value for the association between IDH1 mutations in gliomas and mtDNA content is now larger/less significant than in prior versions).	('mutations', 'Var', (45, 54))	('IDH1', 'Gene', (40, 44))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('IDH1', 'Gene', '3417', (40, 44))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('mtDNA', 'cellular_component', 'GO:0000262', ('70', '75'))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))
181730	26901439	NF1 mutations are no longer statistically significantly associated with lower mtDNA content because of multiple hypothesis correction (un-corrected p-value 0.006), but we still feature the alteration in Figure 6.	('mtDNA content', 'MPA', (78, 91))	('lower', 'NegReg', (72, 77))	('mtDNA', 'cellular_component', 'GO:0000262', ('78', '83'))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('NF1', 'Gene', '4763', (0, 3))
181787	30887605	Diagnostic potential of TERT promoter and FGFR3 mutations in urinary cell-free DNA in upper tract urothelial carcinoma Most upper tract urothelial carcinomas (UTUC) are muscle invasive at the time of diagnosis.	('FGFR3', 'Gene', '2261', (42, 47))	('TERT', 'Gene', (24, 28))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (86, 118))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (124, 156))	('upper tract urothelial carcinomas', 'Disease', (124, 157))	('FGFR3', 'Gene', (42, 47))	('upper tract urothelial carcinoma', 'Disease', (86, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('TERT', 'Gene', '7015', (24, 28))	('upper tract urothelial carcinomas', 'Disease', 'MESH:D012141', (124, 157))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('mutations', 'Var', (48, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))
181790	30887605	We studied urinary cfDNA from 153 individuals, including 56 patients with localized UTUC, and carried out droplet digital PCR assay for TERT promoter and FGFR3 hotspot mutations.	('FGFR3', 'Gene', (154, 159))	('TERT', 'Gene', (136, 140))	('TERT', 'Gene', '7015', (136, 140))	('patients', 'Species', '9606', (60, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('154', '158'))	('FGFR3', 'Gene', '2261', (154, 159))	('mutations', 'Var', (168, 177))
181791	30887605	We could detect mutations of TERT C228T in 22/56 (39.3%), TERT C250T in 4/56 (7.1%), and FGFR3 S249C in 9/56 (16.1%) patients.	('TERT', 'Gene', '7015', (29, 33))	('S249C', 'Mutation', 'rs121913483', (95, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('C250T', 'SUBSTITUTION', 'None', (63, 68))	('FGFR3', 'Gene', (89, 94))	('C250T', 'Var', (63, 68))	('C228T', 'Mutation', 'c.228C>T', (34, 39))	('TERT', 'Gene', (58, 62))	('TERT', 'Gene', '7015', (58, 62))	('patients', 'Species', '9606', (117, 125))	('TERT', 'Gene', (29, 33))	('FGFR3', 'Gene', '2261', (89, 94))
181792	30887605	FGFR3 mutation was detected only in <=pT1 tumors (positive predictive value: 100.0%).	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('FGFR3', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('pT1', 'Gene', (38, 41))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('pT1', 'Gene', '58492', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('FGFR3', 'Gene', '2261', (0, 5))
181793	30887605	Although these data need to be validated in a larger-scale cohort, mutation analysis of TERT promoter and FGFR3 in urinary cfDNA has the potential to be a non-invasive diagnostic marker and reliable factor for tumor staging.	('urinary', 'Disease', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('mutation analysis', 'Var', (67, 84))	('TERT', 'Gene', '7015', (88, 92))	('FGFR3', 'Gene', (106, 111))	('tumor', 'Disease', (210, 215))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('FGFR3', 'Gene', '2261', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('TERT', 'Gene', (88, 92))
181797	30887605	Next-generation sequencing has shown genomic alterations and transcriptional subtypes in UTUC and UBC tissue.13, 14, 15, 16 Hotspot mutations of TERT promoter and FGFR3 (S249C) are frequently identified in UTUC specimens.	('FGFR', 'molecular_function', 'GO:0005007', ('163', '167'))	('FGFR3', 'Gene', '2261', (163, 168))	('S249C', 'Var', (170, 175))	('UBC', 'Chemical', '-', (98, 101))	('S249C', 'Mutation', 'rs121913483', (170, 175))	('FGFR3', 'Gene', (163, 168))	('TERT', 'Gene', (145, 149))	('TERT', 'Gene', '7015', (145, 149))
181798	30887605	Mutations in the upstream promoter of the TERT gene predominantly affect two hotspots, g.1295228 C>T and g.1295250 C>T,17, 18 hereafter referred to as C228T and C250T, respectively.	('C250T', 'Mutation', 'c.250C>T', (161, 166))	('affect', 'Reg', (66, 72))	('C250T', 'Var', (161, 166))	('g.1295228 C>T', 'Var', (87, 100))	('g.1295228 C>T', 'Mutation', 'g.1295228C>T', (87, 100))	('g.1295250 C>T', 'Mutation', 'g.1295250C>T', (105, 118))	('TERT', 'Gene', (42, 46))	('TERT', 'Gene', '7015', (42, 46))	('C228T', 'Mutation', 'c.228C>T', (151, 156))
181799	30887605	The mutant TERT promoter allele alters the binding site, recruits transcription factor GABPA, and engages in long-range chromatin interactions, subsequently stimulating increased TERT promoter activity and enabling tumors to overcome the end-replication problem and avoid senescence.19, 20, 21 Springer et al16 reported the clinical potential of mutant DNA derived from urinary cells (pellets) by targeted sequencing in patients with UBC or UTUC for cancer detection and surveillance.	('patients', 'Species', '9606', (420, 428))	('transcription', 'biological_process', 'GO:0006351', ('66', '79'))	('senescence', 'biological_process', 'GO:0010149', ('272', '282'))	('transcription factor', 'molecular_function', 'GO:0000981', ('66', '86'))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('cancer', 'Disease', 'MESH:D009369', (450, 456))	('binding', 'molecular_function', 'GO:0005488', ('43', '50'))	('tumors', 'Disease', (215, 221))	('chromatin', 'cellular_component', 'GO:0000785', ('120', '129'))	('TERT', 'Gene', (179, 183))	('TERT', 'Gene', '7015', (179, 183))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('GABPA', 'Gene', '2551', (87, 92))	('DNA', 'cellular_component', 'GO:0005574', ('353', '356'))	('TERT', 'Gene', (11, 15))	('cancer', 'Disease', (450, 456))	('TERT', 'Gene', '7015', (11, 15))	('mutant', 'Var', (346, 352))	('UBC', 'Disease', (434, 437))	('UBC', 'Chemical', '-', (434, 437))	('cancer', 'Phenotype', 'HP:0002664', (450, 456))	('GABPA', 'Gene', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
181801	30887605	In the present study, we developed ddPCR assays for the detection of hotspot mutations of the TERT promoter region and FGFR3 and analyzed the diagnostic potential of urine supernatant cfDNA collected from patients with localized UTUC.	('patients', 'Species', '9606', (205, 213))	('FGFR3', 'Gene', (119, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))	('mutations', 'Var', (77, 86))	('localized', 'Disease', (219, 228))	('TERT', 'Gene', (94, 98))	('TERT', 'Gene', '7015', (94, 98))	('FGFR3', 'Gene', '2261', (119, 124))
181810	30887605	For mutation detection, we used the ddPCR platform QX100 Droplet Digital PCR System (Bio-Rad Laboratories, Hercules, CA, USA), including primers and probes (FAM, mutant type; HEX, wild type), and ddPCR Supermix for Probes (No dUTP) according to the manufacturer's protocol.	('HEX', 'Gene', '3087', (175, 178))	('mutant', 'Var', (162, 168))	('Rad', 'biological_process', 'GO:1990116', ('89', '92'))	('dUTP', 'Chemical', 'MESH:C027078', (226, 230))	('HEX', 'Gene', (175, 178))
181811	30887605	Primers and probes for ddPCR were TERT promoters C228T/C250T, FGFR3 S249C, and PIK3CA E545K (S1).	('FGFR3', 'Gene', '2261', (62, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('TERT', 'Gene', (34, 38))	('C228T', 'Var', (49, 54))	('S249C', 'Mutation', 'rs121913483', (68, 73))	('PIK3CA', 'Gene', (79, 85))	('E545K', 'Mutation', 'rs104886003', (86, 91))	('FGFR3', 'Gene', (62, 67))	('TERT', 'Gene', '7015', (34, 38))	('C250T', 'Mutation', 'c.250C>T', (55, 60))	('C228T', 'SUBSTITUTION', 'None', (49, 54))	('PIK3CA', 'Gene', '5290', (79, 85))
181820	30887605	Fractions of UTUC patients harboring a mutation were 22/56 (39.3%) for TERT C228T, 4/56 (7.1%) for TERT C250T, 9/56 (16.1%) for FGFR3 S249C, 5/56 (8.9%) for PIK3CA E545K, and 32/56 (57.1%) for any mutation (Table 2, Figure 2).	('C228T', 'Mutation', 'c.228C>T', (76, 81))	('S249C', 'Mutation', 'rs121913483', (134, 139))	('TERT', 'Gene', (71, 75))	('TERT', 'Gene', (99, 103))	('TERT', 'Gene', '7015', (71, 75))	('C250T', 'SUBSTITUTION', 'None', (104, 109))	('PIK3CA', 'Gene', (157, 163))	('E545K', 'Mutation', 'rs104886003', (164, 169))	('E545K', 'Var', (164, 169))	('TERT', 'Gene', '7015', (99, 103))	('FGFR', 'molecular_function', 'GO:0005007', ('128', '132'))	('FGFR3', 'Gene', '2261', (128, 133))	('C250T', 'Var', (104, 109))	('PIK3CA', 'Gene', '5290', (157, 163))	('patients', 'Species', '9606', (18, 26))	('FGFR3', 'Gene', (128, 133))
181821	30887605	Because the detection rate of mutant PIK3CA was very low and overlapped with other mutations, hereafter, we focus on the analysis of FGFR3 and TERT promoters (C228T and C250T).	('PIK3CA', 'Gene', '5290', (37, 43))	('FGFR3', 'Gene', (133, 138))	('TERT', 'Gene', (143, 147))	('C228T', 'Var', (159, 164))	('C228T', 'Mutation', 'c.228C>T', (159, 164))	('TERT', 'Gene', '7015', (143, 147))	('C250T', 'Mutation', 'c.250C>T', (169, 174))	('FGFR', 'molecular_function', 'GO:0005007', ('133', '137'))	('FGFR3', 'Gene', '2261', (133, 138))	('C250T', 'Var', (169, 174))	('mutant', 'Var', (30, 36))	('PIK3CA', 'Gene', (37, 43))
181823	30887605	Multivariate logistic regression analysis showed that after adjustment for age, gender and urine cytology, both mutation of TERT promoter and FGFR3 were significant predictors of the presence of UTUC (TERT promoter: OR 23.24, 95% CI 5.66-134.43, P-value <0.0001; FGFR3: OR 1.06E+9, 95% CI 2.77-infinity, P-value = 0.006).	('FGFR3', 'Gene', (263, 268))	('FGFR', 'molecular_function', 'GO:0005007', ('142', '146'))	('mutation', 'Var', (112, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('263', '267'))	('FGFR3', 'Gene', '2261', (142, 147))	('TERT', 'Gene', (124, 128))	('FGFR3', 'Gene', '2261', (263, 268))	('TERT', 'Gene', (201, 205))	('FGFR3', 'Gene', (142, 147))	('UTUC', 'MPA', (195, 199))	('TERT', 'Gene', '7015', (124, 128))	('TERT', 'Gene', '7015', (201, 205))
181830	30887605	Of the 26 individuals in the HC cohort, only one person was determined to be positive for a TERT C250T mutation.	('TERT', 'Gene', (92, 96))	('C250T', 'Var', (97, 102))	('person', 'Species', '9606', (49, 55))	('C250T', 'SUBSTITUTION', 'None', (97, 102))
181833	30887605	An FGFR3 S249C mutation was detected in 29.4% (5/17) of pTa or Tis tumors and in 36.4% (4/11) of pT1 tumors, but it was not detected in any of the muscle-invasive tumors (>=pT2) (0/28) (Table 2).	('FGFR', 'molecular_function', 'GO:0005007', ('3', '7'))	('detected', 'Reg', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Tis tumors', 'Disease', 'MESH:D000072676', (63, 73))	('Tis tumors', 'Disease', (63, 73))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('pT1', 'Gene', '58492', (97, 100))	('pTa', 'Disease', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('pT1', 'Gene', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Disease', (163, 169))	('S249C', 'Var', (9, 14))	('FGFR3', 'Gene', (3, 8))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', (101, 107))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (147, 169))	('FGFR3', 'Gene', '2261', (3, 8))	('pTa', 'molecular_function', 'GO:0008959', ('56', '59'))	('muscle-invasive tumors', 'Disease', (147, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('S249C', 'Mutation', 'rs121913483', (9, 14))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
181834	30887605	Sensitivity and PPV for detecting <=T1 tumor by FGFR3 S249C were 32.1% and 100.0%, respectively.	('S249C', 'Var', (54, 59))	('S249C', 'Mutation', 'rs121913483', (54, 59))	('FGFR3', 'Gene', '2261', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('FGFR3', 'Gene', (48, 53))	('tumor', 'Disease', (39, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))
181842	30887605	In this proof-of-concept study, we showed the diagnostic potential of the TERT promoter and FGFR3 mutations detected by ddPCR of cfDNA extracted from urine supernatant of patients with localized UTUC.	('FGFR3', 'Gene', (92, 97))	('TERT', 'Gene', '7015', (74, 78))	('patients', 'Species', '9606', (171, 179))	('mutations', 'Var', (98, 107))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('FGFR3', 'Gene', '2261', (92, 97))	('TERT', 'Gene', (74, 78))
181844	30887605	Various mutations could be detected in urinary pellet DNA,25, 26, 27 and in urinary cfDNA12, 22 from UBC.	('UBC', 'Chemical', '-', (101, 104))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('detected', 'Reg', (27, 35))	('mutations', 'Var', (8, 17))
181848	30887605	"28 Urinary cfDNA may have the potential to allow observation of the sequential genetic change of UC, from detecting the disease at an early stage to monitoring the response of systemic therapy, even if there is no evidence of disease in the urinary tract.10  Springer et al16 reported that mutant DNA in urinary pellets from UTUC patients in Taiwan could be detected by NGS at rates of 25.0% (TERT C228T), 7.1% (TERT C250T), 10.7% (FGFR3 S249C), and 5.4% (PIK3CA E545K).	('TERT', 'Gene', '7015', (413, 417))	('DNA', 'Gene', (298, 301))	('FGFR3', 'Gene', '2261', (433, 438))	('C228T', 'Mutation', 'c.228C>T', (399, 404))	('S249C', 'Mutation', 'rs121913483', (439, 444))	('C250T', 'Var', (418, 423))	('E545K', 'Mutation', 'rs104886003', (464, 469))	('FGFR3', 'Gene', (433, 438))	('PIK3CA', 'Gene', (457, 463))	('TERT', 'Gene', (394, 398))	('TERT', 'Gene', '7015', (394, 398))	('PIK3CA', 'Gene', '5290', (457, 463))	('TERT', 'Gene', (413, 417))	('mutant', 'Var', (291, 297))	('C250T', 'SUBSTITUTION', 'None', (418, 423))	('patients', 'Species', '9606', (331, 339))
181849	30887605	In the current study, we could detect mutations at rates of 39.3% (TERT C228T), 7.1% (TERT C250T), 16.1% (FGFR3 S249C), and 8.9% (PIK3CA E545K) in urinary cfDNA in Japanese patients.	('PIK3CA', 'Gene', (130, 136))	('FGFR3', 'Gene', '2261', (106, 111))	('TERT', 'Gene', (67, 71))	('S249C', 'Mutation', 'rs121913483', (112, 117))	('PIK3CA', 'Gene', '5290', (130, 136))	('TERT', 'Gene', '7015', (67, 71))	('E545K', 'Mutation', 'rs104886003', (137, 142))	('patients', 'Species', '9606', (173, 181))	('FGFR3', 'Gene', (106, 111))	('C250T', 'SUBSTITUTION', 'None', (91, 96))	('urinary cfDNA', 'Disease', (147, 160))	('TERT', 'Gene', (86, 90))	('TERT', 'Gene', '7015', (86, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('mutations', 'Var', (38, 47))	('C228T', 'Mutation', 'c.228C>T', (72, 77))	('C250T', 'Var', (91, 96))
181850	30887605	The difference in detection rates may be due to differences of the cohorts investigated because as Springer et al reported, the Taiwanese cohort was highly exposed to aristolochic acid, a known carcinogenic and nephrotoxic agent in Aristolochia herbs, whereas our Japanese cohorts were not.	('aristolochic acid', 'Chemical', 'MESH:C000228', (167, 184))	('aristolochic', 'Var', (167, 179))	('carcinogenic and nephrotoxic', 'Disease', 'MESH:D007674', (194, 222))	('exposed', 'Reg', (156, 163))
181854	30887605	However, its sensitivity for diagnosis is relatively low, 16%-84% in UBC29 and 40% in UTUC.8 In the present study, we could detect the three targeted gene mutations (TERT C228T, TERT C250T, and FGFR3 S249C) in 55.4% of urine samples from UTUC patients.	('UBC', 'Chemical', '-', (69, 72))	('patients', 'Species', '9606', (243, 251))	('C250T', 'SUBSTITUTION', 'None', (183, 188))	('C228T', 'Mutation', 'c.228C>T', (171, 176))	('TERT', 'Gene', (178, 182))	('FGFR3', 'Gene', '2261', (194, 199))	('S249C', 'Mutation', 'rs121913483', (200, 205))	('FGFR', 'molecular_function', 'GO:0005007', ('194', '198'))	('TERT', 'Gene', '7015', (178, 182))	('C250T', 'Var', (183, 188))	('TERT', 'Gene', (166, 170))	('TERT', 'Gene', '7015', (166, 170))	('FGFR3', 'Gene', (194, 199))
181858	30887605	Moreover, several researchers reported that TERT promoter mutation is associated with bladder recurrence and survival in UBC.36, 37, 38 Isharwal et al reported that the TERT promoter mutation was associated with overall survival (HR: 2.31, 95% CI: 1.46-3.65), disease-specific survival (HR: 2.23, 95% CI: 1.41-3.53), and metastasis-free survival (HR 1.63, 95% CI: 1.05-2.53).38 Christensen et al12 showed a significant association between ctDNA level and tumor grade and also that the amount of ctDNA from patients whose DNA extracted from bladder tumor tissue was mutation positive was significantly associated with progression-free survival or recurrence-free survival.	('progression-free survival', 'CPA', (617, 642))	('bladder tumor', 'Disease', 'MESH:D001749', (540, 553))	('tumor', 'Disease', (455, 460))	('patients', 'Species', '9606', (506, 514))	('UBC', 'Chemical', '-', (121, 124))	('ctDNA', 'MPA', (439, 444))	('TERT', 'Gene', (44, 48))	('TERT', 'Gene', '7015', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (455, 460))	('recurrence-free survival', 'CPA', (646, 670))	('tumor', 'Disease', (548, 553))	('mutation', 'Var', (565, 573))	('bladder tumor', 'Phenotype', 'HP:0009725', (540, 553))	('tumor', 'Phenotype', 'HP:0002664', (455, 460))	('tumor', 'Disease', 'MESH:D009369', (548, 553))	('TERT', 'Gene', (169, 173))	('TERT', 'Gene', '7015', (169, 173))	('associated with', 'Reg', (601, 616))	('DNA', 'cellular_component', 'GO:0005574', ('521', '524'))	('bladder tumor', 'Disease', (540, 553))	('tumor', 'Phenotype', 'HP:0002664', (548, 553))
181860	30887605	Besides TERT promoter mutation, we selected FGFR3 mutation as an additional biomarker candidate.	('TERT', 'Gene', (8, 12))	('TERT', 'Gene', '7015', (8, 12))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('FGFR3', 'Gene', (44, 49))	('FGFR3', 'Gene', '2261', (44, 49))	('mutation', 'Var', (50, 58))
181861	30887605	Sfakianos et al reported that 30.4% of tissue from UTUC harbors a FGFR3 S249C hotspot mutation, and most of the FGFR3 mutations were detected in non-muscle-invasive UTUC.15 Consistent with a previous report, in the present study, all FGFR3 S249C mutations were detected at the early stage (at most pT1) of UTUC.	('FGFR3', 'Gene', (112, 117))	('S249C', 'Mutation', 'rs121913483', (240, 245))	('FGFR3', 'Gene', (234, 239))	('FGFR3', 'Gene', '2261', (66, 71))	('pT1', 'Gene', '58492', (298, 301))	('FGFR', 'molecular_function', 'GO:0005007', ('112', '116'))	('mutations', 'Var', (246, 255))	('S249C', 'Mutation', 'rs121913483', (72, 77))	('FGFR3', 'Gene', (66, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('S249C mutations', 'Var', (240, 255))	('FGFR3', 'Gene', '2261', (112, 117))	('pT1', 'Gene', (298, 301))	('FGFR', 'molecular_function', 'GO:0005007', ('234', '238'))	('FGFR3', 'Gene', '2261', (234, 239))
181864	30887605	In this study, the sensitivity and PPV for detecting <=T1 tumor by FGFR3 S249C were 32.1% and 100.0%, respectively.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('FGFR3', 'Gene', (67, 72))	('S249C', 'Var', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('S249C', 'Mutation', 'rs121913483', (73, 78))	('FGFR3', 'Gene', '2261', (67, 72))
181865	30887605	Although the sensitivity is relatively low, a positive result of an FGFR3 mutation in urinary cfDNA could help to predict a low-stage tumor as a liquid biopsy not requiring tissue examination.	('mutation', 'Var', (74, 82))	('FGFR3', 'Gene', '2261', (68, 73))	('low-stage tumor', 'Disease', (124, 139))	('FGFR', 'molecular_function', 'GO:0005007', ('68', '72'))	('FGFR3', 'Gene', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('low-stage tumor', 'Disease', 'MESH:D009800', (124, 139))
181866	30887605	This assay for FGFR3 mutation may have the potential to become an alternative for ureteroscopy and a reliable factor for deciding whether to carry out ureteroscopic nephron-sparing surgery.	('FGFR3', 'Gene', (15, 20))	('FGFR3', 'Gene', '2261', (15, 20))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('mutation', 'Var', (21, 29))
181868	30887605	Because there was an association between age and the prevalence of mutation in the UTUC cohort, the difference in age between the UTUC and hematuria cohorts could have influenced the positive rate of detecting mutant cfDNA.	('mutation', 'Var', (67, 75))	('association', 'Interaction', (21, 32))	('hematuria', 'Phenotype', 'HP:0000790', (139, 148))	('cfDNA', 'Disease', (217, 222))	('hematuria cohort', 'Disease', 'MESH:D006417', (139, 155))	('influenced', 'Reg', (168, 178))	('hematuria cohort', 'Disease', (139, 155))
181872	30887605	In conclusion, we could detect TERT promoter and FGFR3 hotspot mutations in urinary cfDNA from UTUC patients.	('mutations', 'Var', (63, 72))	('FGFR3', 'Gene', '2261', (49, 54))	('patients', 'Species', '9606', (100, 108))	('FGFR3', 'Gene', (49, 54))	('TERT', 'Gene', (31, 35))	('TERT', 'Gene', '7015', (31, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('urinary cfDNA', 'Disease', (76, 89))
181873	30887605	Liquid biopsy analysis of TERT promoter and FGFR3 mutations in urinary cfDNA could be a novel diagnostic biomarker and a reliable factor for staging UTUC.	('TERT', 'Gene', (26, 30))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('mutations', 'Var', (50, 59))	('FGFR3', 'Gene', (44, 49))	('TERT', 'Gene', '7015', (26, 30))	('FGFR3', 'Gene', '2261', (44, 49))	('urinary cfDNA', 'Disease', (63, 76))
181917	28988653	Among the 523 metastasectomies, thirty-day mortality after metastasectomy was 10% (n=53) and was largely driven by mortality associated with resections of brain lesions, which were associated with a 15% risk of death in the first 30 days following surgery.	('death', 'Disease', (211, 216))	('resections', 'Var', (141, 151))	('brain lesions', 'Disease', (155, 168))	('brain lesions', 'Disease', 'MESH:D001927', (155, 168))	('death', 'Disease', 'MESH:D003643', (211, 216))
181956	28988653	A recently published propensity score-weighted analysis of patients with metastatic urothelial carcinoma from the National Cancer Data Base showed a significant higher overall survival benefit for patients receiving intensive local therapy defined as the receipt of radical cystectomy or >= 50 Gy of radiation therapy delivered to the bladder compared to patients who received no local therapy, transurethral resection of the bladder tumor alone, or < 50 Gy of radiation therapy.	('patients', 'Species', '9606', (355, 363))	('patients', 'Species', '9606', (197, 205))	('tumor', 'Phenotype', 'HP:0002664', (434, 439))	('>= 50 Gy', 'Var', (288, 296))	('urothelial carcinoma', 'Disease', (84, 104))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Cancer', 'Disease', (123, 129))	('bladder tumor', 'Disease', (426, 439))	('Cancer', 'Disease', 'MESH:D009369', (123, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('patients', 'Species', '9606', (59, 67))	('higher', 'PosReg', (161, 167))	('bladder tumor', 'Disease', 'MESH:D001749', (426, 439))	('bladder tumor', 'Phenotype', 'HP:0009725', (426, 439))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (84, 104))
181959	28988653	Surgical excision of tumors from patients with metastatic disease potentially reduces the tumor burden by removing tumors that may harbor unique mutations from the genetic pool Additionally, metastasectomy allows for the collection of metastatic tumor tissues for genomic profiling which carries potential therapeutic implications for precision medicine.	('tumor', 'Disease', (21, 26))	('mutations', 'Var', (145, 154))	('tumor', 'Disease', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Disease', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', (115, 121))	('tumor', 'Disease', (246, 251))	('reduces', 'NegReg', (78, 85))	('patients', 'Species', '9606', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (115, 121))
181969	28423602	Promoter hypermethylation of LGALS4 correlates with poor prognosis in patients with urothelial carcinoma Galectine-4 (gal-4), encoded by the LGALS4 gene, was recently shown to exhibit a tumor suppressive effect in colorectal carcinoma and pancreatic adenocarcinoma, although how the expression of this gene is regulated remains unknown.	('colorectal carcinoma', 'Disease', (214, 234))	('tumor', 'Disease', (186, 191))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (214, 234))	('nt', 'Chemical', 'MESH:D009711', (75, 77))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (239, 264))	('Promoter hypermethylation', 'Var', (0, 25))	('pancreatic adenocarcinoma', 'Disease', (239, 264))	('patients', 'Species', '9606', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('nt', 'Chemical', 'MESH:D009711', (162, 164))	('LGALS4', 'Gene', (141, 147))	('LGALS4', 'Gene', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('urothelial carcinoma', 'Disease', (84, 104))	('LGALS4', 'Gene', '3960', (141, 147))	('LGALS4', 'Gene', '3960', (29, 35))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (239, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('gal-4', 'Chemical', '-', (118, 123))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (84, 104))
181972	28423602	LGALS4 methylation was initially identified as a progression biomarker for UC patients through genome-wide DNA methylation profiling of 16 tumor samples.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('DNA methylation', 'biological_process', 'GO:0006306', ('107', '122'))	('LGALS4', 'Gene', '3960', (0, 6))	('patients', 'Species', '9606', (78, 86))	('methylation', 'Var', (7, 18))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('nt', 'Chemical', 'MESH:D009711', (83, 85))	('nt', 'Chemical', 'MESH:D009711', (36, 38))	('LGALS4', 'Gene', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('methylation', 'biological_process', 'GO:0032259', ('7', '18'))
181978	28423602	In addition, LGALS4 hypermethylation was an independent predictor of inferior survival in UC patients (P<0.05).	('nt', 'Chemical', 'MESH:D009711', (98, 100))	('hypermethylation', 'Var', (20, 36))	('LGALS4', 'Gene', '3960', (13, 19))	('inferior', 'NegReg', (69, 77))	('LGALS4', 'Gene', (13, 19))	('nt', 'Chemical', 'MESH:D009711', (53, 55))	('patients', 'Species', '9606', (93, 101))
181981	28423602	Our findings provide evidence that methylation-mediated LGALS4 gene repression may be involved in urothelial tumor progression.	('urothelial tumor', 'Disease', (98, 114))	('methylation-mediated', 'Var', (35, 55))	('repression', 'NegReg', (68, 78))	('involved', 'Reg', (86, 94))	('LGALS4', 'Gene', '3960', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('LGALS4', 'Gene', (56, 62))	('urothelial tumor', 'Disease', 'MESH:D001749', (98, 114))
181987	28423602	DNA-based biomarkers, including markers of genetic alterations and epigenetic changes, have been developed for cancer detection.	('epigenetic changes', 'Var', (67, 85))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('genetic alterations', 'Var', (43, 62))
181989	28423602	Promoter hypermethylation alone or in combination with repressive histone modification is a mechanism that is frequently associated with transcriptional gene silencing, which contributes to tumor initiation, invasion, and metastasis in several types of cancer.	('invasion', 'CPA', (208, 216))	('nt', 'Chemical', 'MESH:D009711', (177, 179))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('contributes', 'Reg', (175, 186))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('tumor initiation', 'Disease', 'MESH:D009369', (190, 206))	('metastasis', 'CPA', (222, 232))	('cancer', 'Disease', (253, 259))	('transcriptional gene silencing', 'biological_process', 'GO:0006342', ('137', '167'))	('histone modification', 'biological_process', 'GO:0016570', ('66', '86'))	('nt', 'Chemical', 'MESH:D009711', (116, 118))	('tumor initiation', 'Disease', (190, 206))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('Promoter hypermethylation', 'Var', (0, 25))
181991	28423602	Many biomarkers of methylation status correlate with UC, but the functional relationships with tumor development and progression or their clinical relevance to patient survival are largely unknown.	('methylation', 'Var', (19, 30))	('nt', 'Chemical', 'MESH:D009711', (165, 167))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('nt', 'Chemical', 'MESH:D009711', (110, 112))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('patient', 'Species', '9606', (160, 167))	('tumor', 'Disease', (95, 100))
182005	28423602	The present study systematically identified potential methylation markers associated with UC progression using the Infinium Methylation 27K BeadChip assay.	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('Methylation', 'biological_process', 'GO:0032259', ('124', '135'))	('methylation', 'Var', (54, 65))	('nt', 'Chemical', 'MESH:D009711', (48, 50))	('nt', 'Chemical', 'MESH:D009711', (36, 38))	('nt', 'Chemical', 'MESH:D009711', (9, 11))	('associated', 'Reg', (74, 84))
182008	28423602	We performed in vitro experiments and examined biological function alterations in UC cell lines with ectopic expression of gal-4 to support its association with cancer progression.	('nt', 'Chemical', 'MESH:D009711', (30, 32))	('gal-4', 'Chemical', '-', (123, 128))	('association', 'Interaction', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ectopic expression', 'Var', (101, 119))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('gal-4', 'Gene', (123, 128))
182009	28423602	This study is the first report to provide direct evidence that methylation-mediated LGALS4 gene repression may be involved in UC progression.	('LGALS4', 'Gene', (84, 90))	('methylation-mediated', 'Var', (63, 83))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('involved', 'Reg', (114, 122))	('repression', 'NegReg', (96, 106))	('LGALS4', 'Gene', '3960', (84, 90))
182022	28423602	The proportion of the samples that exhibited hypermethylation, determined using the qMSP analysis, was consistent with the expression levels of gal-4 from the IHC analyses.	('nt', 'Chemical', 'MESH:D009711', (111, 113))	('gal-4', 'Chemical', '-', (144, 149))	('hypermethylation', 'Var', (45, 61))	('exhibited', 'Reg', (35, 44))
182027	28423602	We next examined the association of LGALS4 methylation with overall survival or (distant) metastasis-free survival.	('LGALS4', 'Gene', (36, 42))	('methylation', 'Var', (43, 54))	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('nt', 'Chemical', 'MESH:D009711', (86, 88))	('examined', 'Reg', (8, 16))	('LGALS4', 'Gene', '3960', (36, 42))
182028	28423602	The Kaplan-Meier analyses revealed that the overall survival rate was significantly lower in the high LGALS4 methylation group than in the low methylation group (P=0.002, Figure 4A).	('methylation', 'Var', (109, 120))	('LGALS4', 'Gene', '3960', (102, 108))	('methylation', 'biological_process', 'GO:0032259', ('109', '120'))	('methylation', 'biological_process', 'GO:0032259', ('143', '154'))	('nt', 'Chemical', 'MESH:D009711', (79, 81))	('LGALS4', 'Gene', (102, 108))	('lower', 'NegReg', (84, 89))	('high', 'Var', (97, 101))
182029	28423602	Although not statistically significant (P=0.172), patients with high LGALS4 methylation levels showed a trend towards a lower probability of metastasis-free survival (Figure 4B).	('LGALS4', 'Gene', (69, 75))	('lower', 'NegReg', (120, 125))	('high', 'Var', (64, 68))	('patients', 'Species', '9606', (50, 58))	('metastasis-free survival', 'CPA', (141, 165))	('LGALS4', 'Gene', '3960', (69, 75))	('methylation levels', 'Var', (76, 94))	('nt', 'Chemical', 'MESH:D009711', (55, 57))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('nt', 'Chemical', 'MESH:D009711', (36, 38))
182031	28423602	Cox proportional hazard regression analysis revealed that the UC group with high LGALS4 methylation levels had a 7.36-fold increased risk of mortality compared to the low methylation group (Table 2, Model I).	('LGALS4', 'Gene', '3960', (81, 87))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('LGALS4', 'Gene', (81, 87))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('high', 'Var', (76, 80))	('methylation levels', 'Var', (88, 106))	('methylation', 'biological_process', 'GO:0032259', ('171', '182'))
182032	28423602	The multivariate Cox analyses further demonstrated that a high methylation level remained a significant prognostic factor for a decreased survival rate, independent of the histological grade (P=0.033), tumor T category (P=0.044), or LN metastasis (P=0.018) (Table 2, Model II, III, and IV, respectively).	('Cox', 'Gene', '1351', (17, 20))	('methylation', 'MPA', (63, 74))	('tumor', 'Disease', (202, 207))	('Cox', 'Gene', (17, 20))	('survival rate', 'CPA', (138, 151))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('decreased', 'NegReg', (128, 137))	('nt', 'Chemical', 'MESH:D009711', (162, 164))	('high', 'Var', (58, 62))	('nt', 'Chemical', 'MESH:D009711', (101, 103))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
182035	28423602	Therefore, we conducted in vitro studies using human urothelial cell lines to evaluate whether epigenetic silencing contributed to the decrease in LGALS4 expression.	('LGALS4', 'Gene', '3960', (147, 153))	('LGALS4', 'Gene', (147, 153))	('epigenetic silencing', 'Var', (95, 115))	('nt', 'Chemical', 'MESH:D009711', (118, 120))	('human', 'Species', '9606', (47, 52))	('decrease', 'NegReg', (135, 143))	('expression', 'MPA', (154, 164))
182048	28423602	There was also a significant decrease in the colony formation of T24 cells expressing gal-4 compared to the control cells without gal-4 (Figure 6C).	('gal-4', 'Chemical', '-', (130, 135))	('formation', 'biological_process', 'GO:0009058', ('52', '61'))	('gal-4', 'Chemical', '-', (86, 91))	('nt', 'Chemical', 'MESH:D009711', (110, 112))	('gal-4', 'Var', (86, 91))	('colony formation', 'CPA', (45, 61))	('decrease', 'NegReg', (29, 37))	('nt', 'Chemical', 'MESH:D009711', (26, 28))
182051	28423602	Cells expressing gal-4 were also less invasive over filters than were cells without the gal-4 insert, with an approximate reduction of 70% (Figure 6E).	('less', 'NegReg', (33, 37))	('gal-4', 'Chemical', '-', (17, 22))	('gal-4', 'Var', (17, 22))	('gal-4', 'Chemical', '-', (88, 93))	('invasive', 'MPA', (38, 46))
182062	28423602	A previous genomic analysis by Selamat et al found hypermethylation of LGALS4 in lung adenocarcinoma in smokers, and their studies further indicated an inverse association between promoter hypermethylation and expression of LGALS4 transcripts.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('hypermethylation', 'Var', (51, 67))	('LGALS4', 'Gene', (71, 77))	('expression', 'MPA', (210, 220))	('LGALS4', 'Gene', '3960', (224, 230))	('lung adenocarcinoma', 'Disease', (81, 100))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('LGALS4', 'Gene', '3960', (71, 77))	('inverse', 'NegReg', (152, 159))	('LGALS4', 'Gene', (224, 230))
182081	28423602	In conclusion, we identified a high level of LGALS4 promoter methylation in high-grade and high-T-category UC and observed an association with reduced gal-4 expression in tumor tissues.	('methylation', 'Var', (61, 72))	('expression', 'MPA', (157, 167))	('gal-4', 'Protein', (151, 156))	('gal-4', 'Chemical', '-', (151, 156))	('nt', 'Chemical', 'MESH:D009711', (21, 23))	('LGALS4', 'Gene', '3960', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('LGALS4', 'Gene', (45, 51))	('reduced', 'NegReg', (143, 150))
182084	28423602	Furthermore, the results of our gal-4 overexpression analyses suggest that reactivation may suppress UC cell migration and invasion.	('gal-4', 'Chemical', '-', (32, 37))	('reactivation', 'Var', (75, 87))	('cell migration', 'biological_process', 'GO:0016477', ('104', '118'))	('suppress', 'NegReg', (92, 100))
182154	28423602	A wound healing scratch assay was used to assess the migratory capability of the T24 and TSGH-8301 cells bearing pCMV6-AC-GFP/gal-4 or the empty vector.	('migratory capability', 'CPA', (53, 73))	('pCMV6-AC-GFP/gal-4', 'Var', (113, 131))	('gal-4', 'Chemical', '-', (126, 131))	('wound healing', 'biological_process', 'GO:0042060', ('2', '15'))
182164	28423602	We used multivariate Cox proportional hazards regression models to estimate the hazard ratios (HR) for the high methylation group compared to the low methylation group to further evaluate the significance of LGALS4 methylation as a prognostic factor for the survival probability independent of covariates,.	('methylation', 'Var', (215, 226))	('nt', 'Chemical', 'MESH:D009711', (288, 290))	('Cox', 'Gene', '1351', (21, 24))	('LGALS4', 'Gene', (208, 214))	('Cox', 'Gene', (21, 24))	('LGALS4', 'Gene', '3960', (208, 214))	('methylation', 'biological_process', 'GO:0032259', ('112', '123'))	('methylation', 'biological_process', 'GO:0032259', ('150', '161'))	('methylation', 'biological_process', 'GO:0032259', ('215', '226'))
182175	26172456	Integration of the BK-polyomavirus results in a number of discrete alterations in viral gene expression, including: (a) disruption of VP1 protein expression and robust expression of large T-antigen; (b) preclusion of viral replication; and (c) deletions in the non-coding control region (NCCR), with presumed alterations in promoter feedback loops.	('BK-polyomavirus', 'Gene', (19, 34))	('alterations', 'Reg', (309, 320))	('VP1', 'Gene', (134, 137))	('VP1', 'Gene', '29031008', (134, 137))	('large T-antigen', 'Protein', (182, 197))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('expression', 'MPA', (168, 178))	('viral replication', 'biological_process', 'GO:0019058', ('217', '234'))	('viral replication', 'biological_process', 'GO:0008166', ('217', '234'))	('viral replication', 'biological_process', 'GO:0019079', ('217', '234'))	('BK-polyomavirus', 'Species', '1891762', (19, 34))	('alterations', 'Reg', (67, 78))	('deletions', 'Var', (244, 253))	('viral gene expression', 'biological_process', 'GO:0019080', ('82', '103'))	('disruption', 'NegReg', (120, 130))	('expression', 'MPA', (146, 156))	('viral gene', 'Gene', (82, 92))
182189	26172456	Primary infection with polyomaviruses is likely via the respiratory route, often leading to dissemination and establishment of a latent infection in the urinary tract, especially renal tubular cells and urothelium.	('polyomaviruses', 'Species', '36362', (23, 37))	('infection', 'Disease', (136, 145))	('infection', 'Disease', 'MESH:D007239', (136, 145))	('leading to', 'Reg', (81, 91))	('dissemination', 'MPA', (92, 105))	('Primary infection', 'Disease', (0, 17))	('infection', 'Disease', (8, 17))	('Primary infection', 'Disease', 'MESH:D009378', (0, 17))	('infection', 'Disease', 'MESH:D007239', (8, 17))	('polyomaviruses', 'Var', (23, 37))
182193	26172456	In contrast, neoplasms associated with polyomaviruses, in both immunocompetent and immunosuppressed patients, are exceptionally rare.	('polyomaviruses', 'Species', '36362', (39, 53))	('neoplasms', 'Disease', 'MESH:D009369', (13, 22))	('neoplasm', 'Phenotype', 'HP:0002664', (13, 21))	('neoplasms', 'Disease', (13, 22))	('patients', 'Species', '9606', (100, 108))	('neoplasms', 'Phenotype', 'HP:0002664', (13, 22))	('polyomaviruses', 'Var', (39, 53))
182259	26172456	Diffuse and strong staining limited to the nuclei of invasive and in situ tumour cells was only noted with the SV40 large T-antigen incubation (Figure 2C), indicating high levels of large T-antigen expression in tumour nuclei.	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('SV40', 'Var', (111, 115))	('tumour', 'Disease', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('situ tumour', 'Disease', 'MESH:D002278', (69, 80))	('tumour', 'Disease', (212, 218))	('situ tumour', 'Disease', (69, 80))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
182281	26172456	The insertion resulted in fusion of the VP1 coding sequences with MYBPC1 exonic sequences, predicting a fusion protein consisting of the first 309 codons of VP1, followed by six out-of-frame codons in MYBPC1 exon 26, followed by a stop codon.	('VP1', 'Gene', '29031008', (157, 160))	('MYBPC1', 'Gene', (201, 207))	('MYBPC1', 'Gene', '4604', (201, 207))	('insertion', 'Var', (4, 13))	('VP1', 'Gene', '29031008', (40, 43))	('resulted in', 'Reg', (14, 25))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('VP1', 'Gene', (40, 43))	('VP1', 'Gene', (157, 160))	('MYBPC1', 'Gene', (66, 72))	('MYBPC1', 'Gene', '4604', (66, 72))
182283	26172456	The non-coding control region (NCCR) of the integrated BK-polyomavirus demonstrated deletions of sequence blocks, as compared to archetypal BK-polyomavirus sequences (annotated in GenBank sequence of the BK-polyomavirus CH-1, Accession No.	('BK-polyomavirus', 'Species', '1891762', (204, 219))	('BK-polyomavirus', 'Gene', (55, 70))	('BK-polyomavirus', 'Species', '1891762', (140, 155))	('archetypal BK-polyomavirus', 'Disease', (129, 155))	('BK-polyomavirus CH-1', 'Disease', 'MESH:D027601', (204, 224))	('archetypal BK-polyomavirus', 'Disease', 'MESH:D027601', (129, 155))	('BK-polyomavirus CH-1', 'Disease', (204, 224))	('BK-polyomavirus', 'Species', '1891762', (55, 70))	('deletions', 'Var', (84, 93))
182284	26172456	As compared to the canonical so-called 'OPQRS' NCCR architecture (where each letter refers to a short DNA sequence motif that binds cellular proteins regulating viral gene expression and replication), the tumour variant BK-virus displayed an OPS block architecture with deletion of the Q and R blocks.	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('tumour', 'Disease', (205, 211))	('deletion', 'Var', (270, 278))	('viral gene expression', 'biological_process', 'GO:0019080', ('161', '182'))	('BK-virus', 'Species', '1891762', (220, 228))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
182290	26172456	Our study shows for the first time that a high-grade urothelial tumour arising in a renal allograft is associated with BK-polyomavirus fully integrated into the tumour genome at a single location.	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', (64, 70))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('BK-polyomavirus', 'Species', '1891762', (119, 134))	('tumour', 'Disease', (161, 167))	('urothelial tumour', 'Disease', 'MESH:D014523', (53, 70))	('BK-polyomavirus', 'Var', (119, 134))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('urothelial tumour', 'Disease', (53, 70))
182292	26172456	Linearization and integration of CH-1 disrupts the late viral gene encoding the major capsid protein VP1, while the viral gene for large T-antigen remains intact, with elevated protein expression.	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('integration', 'Var', (18, 29))	('CH-1 disrupts the late viral', 'Disease', 'MESH:D019958', (33, 61))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('VP1', 'Gene', (101, 104))	('protein expression', 'MPA', (177, 195))	('elevated', 'PosReg', (168, 176))	('VP1', 'Gene', '29031008', (101, 104))	('CH-1 disrupts the late viral', 'Disease', (33, 61))
182298	26172456	Only a minority of Merkel cell polyomavirus genome integration breakpoints occurred in the VP1 gene 27.	('VP1', 'Gene', (91, 94))	('breakpoints', 'Var', (63, 74))	('occurred', 'Reg', (75, 83))	('Merkel cell polyomavirus', 'Species', '493803', (19, 43))	('VP1', 'Gene', '29031008', (91, 94))
182302	26172456	In the case reported here, insertional inactivation at the integration site could be caused by disruption of MYBPC1 sequences.	('disruption', 'Var', (95, 105))	('insertional inactivation', 'Var', (27, 51))	('MYBPC1', 'Gene', (109, 115))	('MYBPC1', 'Gene', '4604', (109, 115))
182304	26172456	Its deletion or mutation is associated with disorders of muscle contraction, including distal arthrogryposis and lethal congenital contracture syndrome 32.	('congenital contracture syndrome', 'Disease', (120, 151))	('contracture', 'Phenotype', 'HP:0001371', (131, 142))	('mutation', 'Var', (16, 24))	('arthrogryposis', 'Phenotype', 'HP:0002804', (94, 108))	('distal arthrogryposis', 'Phenotype', 'HP:0005684', (87, 108))	('associated', 'Reg', (28, 38))	('arthrogryposis', 'Disease', (94, 108))	('congenital contracture syndrome', 'Disease', 'MESH:D003286', (120, 151))	('arthrogryposis', 'Disease', 'MESH:D001176', (94, 108))	('deletion', 'Var', (4, 12))	('muscle contraction', 'biological_process', 'GO:0006936', ('57', '75'))	('congenital contracture', 'Phenotype', 'HP:0002803', (120, 142))
182310	26172456	Creation of a novel fusion protein is possible, given the fusion of DNA sequences of VP1 and 'nonsense' out-of-frame sequences from an exon of MYBPC1.	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('DNA sequences', 'Var', (68, 81))	('MYBPC1', 'Gene', (143, 149))	('MYBPC1', 'Gene', '4604', (143, 149))	('VP1', 'Gene', (85, 88))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))	('VP1', 'Gene', '29031008', (85, 88))
182317	26172456	Our data suggest that viral integration impedes viral replication within the tumour.	('viral replication', 'biological_process', 'GO:0019058', ('48', '65'))	('impedes', 'NegReg', (40, 47))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('viral replication', 'biological_process', 'GO:0019079', ('48', '65'))	('viral integration', 'Var', (22, 39))	('viral replication', 'CPA', (48, 65))	('tumour', 'Disease', (77, 83))	('viral replication', 'biological_process', 'GO:0008166', ('48', '65'))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
182324	26172456	In the case of Merkel cell carcinoma, integration of the MC polyomavirus has been described as a 'biological accident' 5, in some cases with dire consequences.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('Merkel cell carcinoma', 'Disease', (15, 36))	('MC polyomavirus', 'Gene', (57, 72))	('integration', 'Var', (38, 49))	('polyomavirus', 'Species', '36362', (60, 72))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (15, 36))
182327	26172456	Given the prevalence of BK-polyomavirus in the genitourinary system, especially in the transplant setting, rare biological accidents of viral DNA integration may account for oncogenesis in kidney transplant recipients.	('account', 'Reg', (162, 169))	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('BK-polyomavirus', 'Var', (24, 39))	('DNA integration', 'biological_process', 'GO:0015074', ('142', '157'))	('oncogenesis', 'biological_process', 'GO:0007048', ('174', '185'))	('BK-polyomavirus', 'Species', '1891762', (24, 39))	('genitourinary system', 'Phenotype', 'HP:0000119', (47, 67))
182328	22406363	High epidermal growth factor receptor immunohistochemical expression in urothelial carcinoma of the bladder is not associated with EGFR mutations in exons 19 and 21: a study using formalin-fixed, paraffin-embedded archival tissues Epidermal growth factor receptor (EGFR) is a member of the erbB tyrosine kinase family reported to be overexpressed in a variety of solid malignancies.	('EGFR', 'Gene', (131, 135))	('mutations', 'Var', (136, 145))	('Epidermal growth factor receptor', 'Gene', (231, 263))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (72, 107))	('EGFR', 'molecular_function', 'GO:0005006', ('131', '135'))	('EGFR', 'Gene', (265, 269))	('solid malignancies', 'Disease', 'MESH:D009369', (363, 381))	('erbB', 'Gene', (290, 294))	('epidermal growth factor receptor', 'Gene', (5, 37))	('solid malignancies', 'Disease', (363, 381))	('epidermal growth factor receptor', 'Gene', '1956', (5, 37))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('231', '254'))	('urothelial carcinoma of the bladder', 'Disease', (72, 107))	('EGFR', 'Gene', '1956', (131, 135))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('5', '28'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (72, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('formalin', 'Chemical', 'MESH:D005557', (180, 188))	('Epidermal growth factor receptor', 'Gene', '1956', (231, 263))	('EGFR', 'molecular_function', 'GO:0005006', ('265', '269'))	('EGFR', 'Gene', '1956', (265, 269))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (72, 107))	('erbB', 'Gene', '1956;2064;2065;2066', (290, 294))	('tyrosine', 'Chemical', 'MESH:D014443', (295, 303))	('paraffin', 'Chemical', 'MESH:D010232', (196, 204))
182329	22406363	Mutations in exons 19 to 21 of the tyrosine kinase domain have been detected in a subset of these tumors and its presence associated with a better response to EGFR inhibitors.	('associated', 'Reg', (122, 132))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('better', 'PosReg', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('EGFR', 'molecular_function', 'GO:0005006', ('159', '163'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Mutations in', 'Var', (0, 12))	('detected', 'Reg', (68, 76))	('tumor', 'Disease', (98, 103))
182331	22406363	The current study assesses EGFR immunohistochemical expression and the presence of mutations in exons 19 and 21 by polymerase chain reaction in 19 bladder urothelial carcinomas from formalin-fixed, paraffin-embedded tissues.	('mutations', 'Var', (83, 92))	('EGFR', 'Gene', (27, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('bladder urothelial carcinomas', 'Disease', (147, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (166, 176))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('bladder urothelial carcinomas', 'Disease', 'MESH:D001749', (147, 176))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (155, 176))
182338	22406363	In gliomas, the most common mechanism involves a deletion of exons 2 to 7 of the EGFR extracellular domain, yielding a mutant form (EGFRvIII) that is constitutively active.	('extracellular', 'cellular_component', 'GO:0005576', ('86', '99'))	('to 7', 'Species', '1214577', (69, 73))	('EGFR', 'molecular_function', 'GO:0005006', ('81', '85'))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('deletion', 'Var', (49, 57))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('gliomas', 'Disease', (3, 10))	('EGFR', 'Gene', (81, 85))
182340	22406363	Mutations of EGFR in exons 19 to 21 have been reported in several solid malignancies, mainly, non-small cell lung carcinomas, in which the detection rate approaches 40% of all cases.	('non-small cell lung carcinomas', 'Disease', (94, 124))	('solid malignancies', 'Disease', (66, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (98, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (94, 124))	('Mutations', 'Var', (0, 9))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('reported', 'Reg', (46, 54))	('EGFR', 'Gene', (13, 17))	('non-small cell lung carcinomas', 'Disease', 'MESH:D002289', (94, 124))
182341	22406363	EGFR mutations involving exons 18 to 21 have been reported in a variety of tumors including colorectal, head and neck, bile duct and gallbladder, prostate, esophageal, pancreatic, and non-small cell lung carcinomas.	('gallbladder', 'Disease', (133, 144))	('non-small cell lung carcinomas', 'Disease', (184, 214))	('reported', 'Reg', (50, 58))	('bile duct', 'Disease', (119, 128))	('pancreatic', 'Disease', 'MESH:D010195', (168, 178))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal', 'Disease', (156, 166))	('EGFR', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('colorectal', 'Disease', (92, 102))	('mutations', 'Var', (5, 14))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (184, 214))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (188, 214))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('pancreatic', 'Disease', (168, 178))	('neck', 'cellular_component', 'GO:0044326', ('113', '117'))	('prostate', 'Disease', (146, 154))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))
182342	22406363	Particularly, a point mutation in exon 21 (L858R) and a deletion mutation in exon 19 (del E746-T751) offer a predictive marker for improved therapeutics with gefitinib or erlotinib.	('del E746-T751', 'Var', (86, 99))	('L858R', 'Mutation', 'rs121434568', (43, 48))	('erlotinib', 'Chemical', 'MESH:D000069347', (171, 180))	('del E746-T751', 'Mutation', 'c.746,751delE,T', (86, 99))	('L858R', 'Var', (43, 48))	('gefitinib', 'Chemical', 'MESH:D000077156', (158, 167))
182349	22406363	Two cell lines were used as controls for EGFR mutation status, NCI-H1650, which has a deletion of amino acids 749 to 750, and NCI-H1975, which has 2 point mutations, L858R and T790M.	('T790M', 'Var', (176, 181))	('L858R', 'SUBSTITUTION', 'None', (166, 171))	('L858R', 'Var', (166, 171))	('NCI-H1975', 'CellLine', 'CVCL:1511', (126, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('T790M', 'Mutation', 'rs121434569', (176, 181))	('NCI-H1650', 'CellLine', 'CVCL:1483', (63, 72))
182356	22406363	No deletions at exon 19 or L858R substitutions at exon 21 of EGFR were found in any of the 19 informative cases.	('L858R', 'Var', (27, 32))	('L858R', 'SUBSTITUTION', 'None', (27, 32))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('EGFR', 'Gene', (61, 65))
182363	22406363	These mechanisms include EGFR gene amplification, increased coexpression of receptor ligands (eg, transforming growth factor alpha and amphiregulin), heterodimerization and cross-talk with HER2 or other members of the erbB family, and interactions with heterologous receptor systems.	('amplification', 'Var', (35, 48))	('coexpression', 'MPA', (60, 72))	('HER2', 'Protein', (189, 193))	('EGFR', 'Gene', (25, 29))	('amphiregulin', 'Gene', (135, 147))	('transforming growth factor alpha', 'molecular_function', 'GO:0005154', ('98', '130'))	('increased', 'PosReg', (50, 59))	('heterodimerization', 'MPA', (150, 168))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))	('amphiregulin', 'Gene', '374', (135, 147))	('interactions', 'Interaction', (235, 247))	('cross-talk', 'Interaction', (173, 183))
182365	33907694	Rapidly Progressing Urothelial Carcinoma Due to a Rare TP53 (p.Arg110Pro) Mutation: A Case Report and Review of the Literature We present a case of a 69-year-old male patient diagnosed with high grade (T1 HG) urothelial carcinoma of the bladder who progressed rapidly towards muscle invasive disease and eventually death despite neoadjuvant chemotherapy and radical cystectomy.	('Urothelial Carcinoma', 'Disease', 'MESH:D014523', (20, 40))	('urothelial carcinoma of the bladder', 'Disease', (209, 244))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (209, 244))	('Urothelial Carcinoma', 'Disease', (20, 40))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (209, 244))	('death', 'Disease', 'MESH:D003643', (315, 320))	('TP53', 'Gene', '7157', (55, 59))	('death', 'Disease', (315, 320))	('TP53', 'Gene', (55, 59))	('muscle invasive disease', 'Disease', (276, 299))	('patient', 'Species', '9606', (167, 174))	('p.Arg110Pro', 'Mutation', 'rs11540654', (61, 72))	('Carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('muscle invasive disease', 'Disease', 'MESH:D009362', (276, 299))	('p.Arg110Pro', 'Var', (61, 72))
182366	33907694	Molecular pathologic data obtained on the initial, non-muscle invasive tumor and the final cystectomy specimen, revealed the same TP53 mutation (p.Arg110Pro) in both specimens with a variant allele frequency of 44%.	('p.Arg110Pro', 'Mutation', 'rs11540654', (145, 156))	('invasive tumor', 'Disease', (62, 76))	('p.Arg110Pro', 'Var', (145, 156))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('invasive tumor', 'Disease', 'MESH:D009361', (62, 76))
182367	33907694	The tumor was tested for 50 common gene mutations in urothelial carcinoma and no other identifiable DNA repair mutations were found, suggesting that this specific TP53 aberration, one that has never been reported in the bladder cancer literature, could be particularly deleterious.	('tumor', 'Disease', (4, 9))	('aberration', 'Var', (168, 178))	('TP53', 'Gene', '7157', (163, 167))	('bladder cancer', 'Phenotype', 'HP:0009725', (220, 234))	('urothelial carcinoma', 'Disease', (53, 73))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('TP53', 'Gene', (163, 167))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (53, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('DNA repair', 'biological_process', 'GO:0006281', ('100', '110'))	('bladder cancer', 'Disease', 'MESH:D001749', (220, 234))	('bladder cancer', 'Disease', (220, 234))
182408	33907694	Rapid tumor progression in the presence of a solitary TP53 gene mutation warrants further investigation as to the deleterious nature of this particular gene.	('mutation', 'Var', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('TP53', 'Gene', '7157', (54, 58))	('TP53', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
182491	31433789	Increasing evidence has demonstrated that dysregulated lncRNAs may contribute to cancer initiation, progression and metastasis.	('cancer initiation', 'Disease', 'MESH:D009369', (81, 98))	('dysregulated', 'Var', (42, 54))	('cancer initiation', 'Disease', (81, 98))	('progression', 'CPA', (100, 111))	('metastasis', 'CPA', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('lncRNAs', 'Protein', (55, 62))	('contribute', 'Reg', (67, 77))
182501	31433789	It does so by competing for miR-339-5p and miR-147b, thus exerting its oncogenic function in non-small- cell carcinoma and colorectal cancer.	('carcinoma', 'Disease', (109, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (123, 140))	('small- cell carcinoma', 'Phenotype', 'HP:0030357', (97, 118))	('colorectal cancer', 'Disease', (123, 140))	('miR-147b', 'Gene', '100126311', (43, 51))	('carcinoma', 'Disease', 'MESH:D002277', (109, 118))	('miR-147b', 'Gene', (43, 51))	('non-small- cell carcinoma', 'Phenotype', 'HP:0030358', (93, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('miR-339-5p', 'Var', (28, 38))	('colorectal cancer', 'Disease', 'MESH:D015179', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
182517	29587736	Hypermethylated gene promoters were significantly more prevalent in renal pelvic tumors (p < 0.001), specifically for TMEFF2, GDF15, RASSF1A, SALL3 and ABCC6 (all p < 0.05).	('SALL3', 'Gene', (142, 147))	('TMEFF2', 'Gene', (118, 124))	('RASSF1A', 'Gene', (133, 140))	('renal pelvic tumors', 'Disease', 'MESH:D007674', (68, 87))	('prevalent', 'Reg', (55, 64))	('TMEFF2', 'Gene', '23671', (118, 124))	('GDF15', 'Gene', (126, 131))	('RASSF1A', 'Gene', '11186', (133, 140))	('Hypermethylated', 'Var', (0, 15))	('ABCC6', 'Gene', '368', (152, 157))	('GDF15', 'Gene', '9518', (126, 131))	('SALL3', 'Gene', '27164', (142, 147))	('pelvic tumor', 'Phenotype', 'HP:0031501', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('renal pelvic tumors', 'Disease', (68, 87))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('ABCC6', 'Gene', (152, 157))
182525	29587736	Microsatellite instability and hypermethylation have been proposed as key genetic differences between bladder cancer and UTUC, and we recently found gene promoter methylation status to hold biologic and prognostic significance in UTUC.	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('hypermethylation', 'Var', (31, 47))	('UTUC', 'Disease', (121, 125))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('bladder cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Microsatellite instability', 'Disease', (0, 26))	('methylation', 'biological_process', 'GO:0032259', ('163', '174'))
182558	29587736	Methylation was present significantly more frequently in renal pelvic tumors (Table 2), particularly with a higher rate of methylated TMEFF2, GDF15, RASSF1A, SALL3 and ABCC6 (all p < 0.05) (Fig.	('methylated', 'Var', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TMEFF2', 'Gene', (134, 140))	('RASSF1A', 'Gene', (149, 156))	('SALL3', 'Gene', '27164', (158, 163))	('ABCC6', 'Gene', '368', (168, 173))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('TMEFF2', 'Gene', '23671', (134, 140))	('renal pelvic tumors', 'Disease', (57, 76))	('ABCC6', 'Gene', (168, 173))	('GDF15', 'Gene', (142, 147))	('SALL3', 'Gene', (158, 163))	('pelvic tumor', 'Phenotype', 'HP:0031501', (63, 75))	('RASSF1A', 'Gene', '11186', (149, 156))	('higher', 'PosReg', (108, 114))	('renal pelvic tumors', 'Disease', 'MESH:D007674', (57, 76))	('GDF15', 'Gene', '9518', (142, 147))
182566	29587736	Other factors, including tumor stage, presence of hydronephrosis, and the methylation status of several genes were proved to be important predictive factors for survival.	('methylation', 'Var', (74, 85))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('hydronephrosis', 'Phenotype', 'HP:0000126', (50, 64))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))	('hydronephrosis', 'Disease', (50, 64))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('hydronephrosis', 'Disease', 'MESH:D006869', (50, 64))
182568	29587736	Though not statistically significant, a trend to higher risk for bladder recurrence in patients with less number of methylated genes (p = 0.081, Fig.	('bladder recurrence', 'Disease', (65, 83))	('patients', 'Species', '9606', (87, 95))	('methylated genes', 'Var', (116, 132))
182569	29587736	Besides the number of methylated genes (as continuous) was found to affect CSS (HR = 1.348, p = 0.003) and bladder recurrence (HR = 0.787, p = 0.026) in univariate analysis (Table 3 and 4).	('bladder recurrence', 'CPA', (107, 125))	('methylated genes', 'Var', (22, 38))	('CSS', 'Chemical', '-', (75, 78))	('CSS', 'CPA', (75, 78))	('affect', 'Reg', (68, 74))
182579	29587736	Hypermethylation is a mechanism for repression of gene transcription in cancer.	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('transcription', 'biological_process', 'GO:0006351', ('55', '68'))	('cancer', 'Disease', (72, 78))
182580	29587736	Prior studies on bladder cancer demonstrated aberrant methylation status of some specific gene promoter as a sign of higher aggressiveness and worse prognosis.	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (17, 31))	('aggressiveness', 'Disease', 'MESH:D001523', (124, 138))	('aggressiveness', 'Disease', (124, 138))	('higher', 'PosReg', (117, 123))	('bladder cancer', 'Disease', (17, 31))	('bladder cancer', 'Disease', 'MESH:D001749', (17, 31))	('aggressiveness', 'Phenotype', 'HP:0000718', (124, 138))	('aberrant methylation status', 'Var', (45, 72))
182581	29587736	We similarly found that increased number of methylated genes appeared to correlate with worse CSS.	('CSS', 'Disease', (94, 97))	('methylated genes', 'Var', (44, 60))	('CSS', 'Chemical', '-', (94, 97))
182583	29587736	It's interesting that the rate of hypermethylation was much more higher in renal pelvis tumors than in the ureter, but the ureteral tumors exhibited higher aggressiveness and relatively worse prognosis.	('aggressiveness', 'Disease', (156, 170))	('ureteral tumor', 'Phenotype', 'HP:0100516', (123, 137))	('hypermethylation', 'Var', (34, 50))	('higher', 'PosReg', (65, 71))	('ureteral tumors', 'Phenotype', 'HP:0100516', (123, 138))	('aggressiveness', 'Phenotype', 'HP:0000718', (156, 170))	('renal pelvis tumors', 'Disease', 'MESH:D010386', (75, 94))	('ureteral tumors', 'Disease', 'MESH:D014516', (123, 138))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('renal pelvis tumors', 'Disease', (75, 94))	('aggressiveness', 'Disease', 'MESH:D001523', (156, 170))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('ureteral tumors', 'Disease', (123, 138))	('higher', 'PosReg', (149, 155))	('renal pelvis', 'Phenotype', 'HP:0000125', (75, 87))
182655	26140262	No significant differences were observed in postoperative or length of stay; however, patients undergoing RALNU were less likely to experience complications compared to patients undergoing laparoscopic nephroureterectomy (p = 0.04).	('less', 'NegReg', (117, 121))	('patients', 'Species', '9606', (169, 177))	('RALNU', 'Var', (106, 111))	('RALNU', 'Chemical', '-', (106, 111))	('patients', 'Species', '9606', (86, 94))
182696	22583918	Additionally, histopathological examination of the prostate revealed a bilateral, multi-centric adenocarcinoma, Gleason 4 + 4 (Figure 2) with perineural and lymphatic/vascular invasion.	('multi-centric adenocarcinoma', 'Disease', (82, 110))	('Gleason', 'Var', (112, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('multi-centric adenocarcinoma', 'Disease', 'MESH:C537372', (82, 110))
182733	22583918	The focus of metastatic urothelial carcinoma was positive for CK7 and pan-CK, and negative for PSA and CK20, while the prostatic carcinoma was positive for PSA and pan-CK and negative for CK7 and CK20.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('pan-CK', 'Var', (70, 76))	('urothelial carcinoma', 'Disease', (24, 44))	('prostatic carcinoma', 'Disease', 'MESH:D011472', (119, 138))	('CK20', 'Gene', (103, 107))	('prostatic carcinoma', 'Phenotype', 'HP:0012125', (119, 138))	('positive', 'Reg', (49, 57))	('PSA', 'Gene', (156, 159))	('CK7', 'Gene', (62, 65))	('PSA', 'Gene', '354', (95, 98))	('CK20', 'Gene', (196, 200))	('CK20', 'Gene', '54474', (103, 107))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (24, 44))	('CK7', 'Gene', (188, 191))	('CK20', 'Gene', '54474', (196, 200))	('CK7', 'Gene', '3855', (62, 65))	('prostatic carcinoma', 'Disease', (119, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('PSA', 'Gene', '354', (156, 159))	('PSA', 'Gene', (95, 98))	('CK7', 'Gene', '3855', (188, 191))
182749	32911596	The assessment of epigenetic alterations, such as DNA methylation, represents a promising cancer biomarker.	('DNA', 'MPA', (50, 53))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('DNA methylation', 'biological_process', 'GO:0006306', ('50', '65'))	('epigenetic alterations', 'Var', (18, 40))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
182750	32911596	Several studies have highlighted the presence of methylated loci in the context of bladder cancer, indicating its potential application as a diagnostic and prognostic biomarker.	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('methylated loci', 'Var', (49, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('bladder cancer', 'Disease', (83, 97))
182758	32911596	One of the novel assays based on a DNA methylation profile, the Bladder EpiCheck (BE), analyzes DNA from spontaneous urine, thereby detecting disease-specific DNA methylation patterns in bladder cancer patients.	('DNA', 'cellular_component', 'GO:0005574', ('159', '162'))	('detecting', 'Reg', (132, 141))	('bladder cancer', 'Disease', 'MESH:D001749', (187, 201))	('BE', 'Chemical', '-', (82, 84))	('DNA methylation', 'biological_process', 'GO:0006306', ('35', '50'))	('bladder cancer', 'Disease', (187, 201))	('patients', 'Species', '9606', (202, 210))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('methylation', 'Var', (163, 174))	('bladder cancer', 'Phenotype', 'HP:0009725', (187, 201))	('DNA methylation', 'biological_process', 'GO:0006306', ('159', '174'))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
182811	32911596	Using multivariable logistic regression analysis, a positive BE result was independently associated with the presence of any-grade (odds ratio, OR = 18.1, 95% CI 8.66-40.2; p < 0.001) and high-grade NMIBC (OR = 78.3, 95% CI 19.2-547; p < 0.001).	('BE', 'Chemical', '-', (61, 63))	('any-grade', 'CPA', (121, 130))	('high-grade', 'Var', (188, 198))
182822	32911596	The test showed an overall sensitivity of 64% (66% for the Xpert Bladder Cancer Monitor test), which increased to 79% in high-grade NMIBCs (57% for low-grade NMIBCs).	('high-grade', 'Var', (121, 131))	('Cancer', 'Disease', 'MESH:D009369', (73, 79))	('Cancer', 'Disease', (73, 79))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (65, 79))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))
182832	32911596	Particularly, the cytology sensitivity was markedly low in low-grade NMIBCs (0-13% across studies), and increased, while remaining lower than BE sensitivity, in high-grade NMIBCs (50-67% across studies).	('low-grade NMIBCs', 'Var', (59, 75))	('cytology sensitivity', 'CPA', (18, 38))	('lower', 'NegReg', (131, 136))	('low', 'NegReg', (52, 55))	('BE', 'Chemical', '-', (142, 144))
182848	32911596	BE could reduce the number of unnecessary cystoscopies and cytologies, without missing any cancer, in patients with a risk of recurrence >10% for any-grade NMIBCs and > 5% for high-grade NMIBCs.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('patients', 'Species', '9606', (102, 110))	('BE', 'Chemical', '-', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('reduce', 'NegReg', (9, 15))	('any-grade', 'Var', (146, 155))
182860	32911596	BE negative cases, on the other hand, could represent a population of high-risk bladder cancers with a more stable methylation pattern, which could present an inferior risk of progression.	('methylation', 'Var', (115, 126))	('bladder cancers', 'Disease', (80, 95))	('bladder cancers', 'Phenotype', 'HP:0009725', (80, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('BE', 'Chemical', '-', (0, 2))	('bladder cancer', 'Phenotype', 'HP:0009725', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('bladder cancers', 'Disease', 'MESH:D001749', (80, 95))	('methylation', 'biological_process', 'GO:0032259', ('115', '126'))
182901	32096345	The overall survival (OS) of the high-infiltrating group was compared with that of the low-infiltrating group, and we found that patients with a high immune-infiltrating TME lived longer than patients with a low immune-infiltrating TME (Figure 1C,F; Figure S2C).	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (192, 200))	('TME', 'Chemical', '-', (170, 173))	('TME', 'Chemical', '-', (232, 235))	('high immune-infiltrating', 'Var', (145, 169))	('longer', 'PosReg', (180, 186))
182902	32096345	Finally, a fixed effects model was employed to pool the HRs of the four cohorts, and the result also validated that patients with a high-infiltrating TME had longer OS times than patients with a low-infiltrating TME (HR = 0.61, 95% CI = 0.47-0.79; I2 = 0%, P = .97) (Figure 1G).	('OS times', 'MPA', (165, 173))	('longer', 'PosReg', (158, 164))	('patients', 'Species', '9606', (116, 124))	('high-infiltrating', 'Var', (132, 149))	('TME', 'Chemical', '-', (150, 153))	('patients', 'Species', '9606', (179, 187))	('TME', 'Chemical', '-', (212, 215))
182905	32096345	Among the six lncRNAs, the expression levels of AC092580.4, USP30-AS1, CTA-384D8.35, and AC002331.1 were the highest in the high-infiltrating group, followed by the median-infiltrating group, and lowest in the low-infiltrating group.	('highest', 'Reg', (109, 116))	('USP30', 'Gene', '84749', (60, 65))	('high-infiltrating', 'Disease', (124, 141))	('expression levels', 'MPA', (27, 44))	('USP', 'molecular_function', 'GO:0051748', ('60', '63'))	('USP30', 'Gene', (60, 65))	('AC092580.4', 'Var', (48, 58))	('AC002331.1', 'Var', (89, 99))	('AS1', 'Gene', (66, 69))	('CTA-384D8.35', 'Var', (71, 83))	('AS1', 'Gene', '5729', (66, 69))
182906	32096345	The expression levels of GATA3-AS1 and AC019117.1 were the highest in the high-infiltrating group, followed by the median-infiltrating group, and lowest in the low-infiltrating group.	('expression levels', 'MPA', (4, 21))	('GATA3', 'Gene', (25, 30))	('AC019117.1', 'Var', (39, 49))	('GATA3', 'Gene', '2625', (25, 30))	('highest', 'Reg', (59, 66))	('AS1', 'Gene', '5729', (31, 34))	('AS1', 'Gene', (31, 34))
182908	32096345	Among the six lncRNAs, the expression levels of AC092580.4, USP30-AS1, CTA-384D8.35, and AC002331.1 were positively correlated with the abundance of most immune cells and the remaining lncRNAs were negatively correlated with the abundance of most immune cells (Figure S4A).	('USP30', 'Gene', '84749', (60, 65))	('USP', 'molecular_function', 'GO:0051748', ('60', '63'))	('expression', 'MPA', (27, 37))	('negatively', 'NegReg', (198, 208))	('correlated', 'Reg', (116, 126))	('USP30', 'Gene', (60, 65))	('AC002331.1', 'Var', (89, 99))	('AS1', 'Gene', (66, 69))	('AC092580.4', 'Var', (48, 58))	('CTA-384D8.35', 'Var', (71, 83))	('AS1', 'Gene', '5729', (66, 69))
182913	32096345	Interestingly, we found that the frequencies of CNVs were lower in patients with a high-infiltrating TME than in patients with a low-infiltrating TME (Kruskal-Wallis test, P < .001) (Figure 2C,D).	('patients', 'Species', '9606', (67, 75))	('lower', 'NegReg', (58, 63))	('high-infiltrating', 'Var', (83, 100))	('patients', 'Species', '9606', (113, 121))	('TME', 'Chemical', '-', (146, 149))	('TME', 'Chemical', '-', (101, 104))
182920	32096345	Then, OS differences between patients with high TIM risk scores and patients with low TIM risk scores were compared using Kaplan-Meier curves followed by the log-rank test, and we found that patients with high TIM risk scores had a worse prognosis than patients with low TIM risk scores (Figure 4C).	('patients', 'Species', '9606', (29, 37))	('patients', 'Species', '9606', (191, 199))	('TIM', 'Gene', (271, 274))	('TIM', 'Gene', (210, 213))	('TIM', 'Gene', (86, 89))	('TIM', 'Gene', (48, 51))	('patients', 'Species', '9606', (253, 261))	('TIM', 'Gene', '26762', (271, 274))	('patients', 'Species', '9606', (68, 76))	('TIM', 'Gene', '26762', (86, 89))	('TIM', 'Gene', '26762', (48, 51))	('TIM', 'Gene', '26762', (210, 213))	('high', 'Var', (205, 209))
182924	32096345	To further validate the stability of the TIM signature in the prognostic prediction of MIBC patients, we pooled the HRs and 95% CIs of the four cohorts using the meta R package, and the result validated that a high TIM risk score was associated with worse prognosis and a low TIM risk score was associated with a better prognosis (HR = 2.11, 95% CI = 1.29-3.43) (Figure 4G).	('TIM', 'Gene', '26762', (276, 279))	('TIM', 'Gene', '26762', (215, 218))	('TIM', 'Gene', (41, 44))	('patients', 'Species', '9606', (92, 100))	('BC', 'Phenotype', 'HP:0009725', (89, 91))	('TIM', 'Gene', '26762', (41, 44))	('high', 'Var', (210, 214))	('MIBC', 'Chemical', '-', (87, 91))	('TIM', 'Gene', (276, 279))	('TIM', 'Gene', (215, 218))
182926	32096345	Although there was heterogeneity among the HRs of different tumors, the result validated that the TIM risk score could predict that cancer patients with high-risk scores were associated with a worse prognosis and that cancer patients with low-risk scores were associated with a better prognosis (HR = 1.43, 95% CI = 1.12-1.82) (Figure 4H).	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('patients', 'Species', '9606', (225, 233))	('patients', 'Species', '9606', (139, 147))	('cancer', 'Disease', (218, 224))	('high-risk', 'Var', (153, 162))	('TIM', 'Gene', '26762', (98, 101))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('TIM', 'Gene', (98, 101))
182932	32096345	We found that the genes of patients with a high TIM score were enriched in protumor-associated pathways, including angiogenesis, apical junction, epithelial-mesenchymal transition, mitotic spindle, and myogenesis (Figure 5D), and the genes of patients with a low TIM score were enriched in immune-associated pathways, including interferon alpha response and interferon gamma response (Figure 5E).	('angiogenesis', 'CPA', (115, 127))	('apical junction', 'cellular_component', 'GO:0043296', ('129', '144'))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('angiogenesis', 'biological_process', 'GO:0001525', ('115', '127'))	('enriched', 'Reg', (63, 71))	('epithelial-mesenchymal transition', 'CPA', (146, 179))	('TIM', 'Gene', (263, 266))	('patients', 'Species', '9606', (243, 251))	('TIM', 'Gene', (48, 51))	('patients', 'Species', '9606', (27, 35))	('apical junction', 'Phenotype', 'HP:0032176', (129, 144))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('146', '179'))	('TIM', 'Gene', '26762', (263, 266))	('interferon gamma', 'molecular_function', 'GO:0005133', ('358', '374'))	('TIM', 'Gene', '26762', (48, 51))	('tumor', 'Disease', (78, 83))	('myogenesis', 'biological_process', 'GO:0007519', ('202', '212'))	('apical junction', 'CPA', (129, 144))	('myogenesis', 'biological_process', 'GO:0042692', ('202', '212'))	('mitotic spindle', 'CPA', (181, 196))	('high', 'Var', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('myogenesis', 'CPA', (202, 212))	('myogenesis', 'biological_process', 'GO:0048740', ('202', '212'))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('181', '196'))
182935	32096345	The TIDE web program was used to infer the immunotherapeutic response of TCGA-BLCA patients, and we excitedly found that patients with a low TIM score had a higher response rate than patients with a high-risk score (Chi-square test, P < .001) (Figure 6A).	('TIM', 'Gene', (141, 144))	('low', 'Var', (137, 140))	('higher', 'PosReg', (157, 163))	('TIM', 'Gene', '26762', (141, 144))	('patients', 'Species', '9606', (83, 91))	('response', 'MPA', (164, 172))	('patients', 'Species', '9606', (121, 129))	('patients', 'Species', '9606', (183, 191))
182954	32096345	We also observed that the expression levels of PD-L1 in the high-infiltrating TME groups were higher than those of the low-infiltrating TME groups, and we inferred that high PD-L1 expression might help tumor cells of high-infiltrating TMEs to tolerate the antitumor activities of immune cells.	('tumor', 'Disease', (260, 265))	('high', 'Var', (169, 173))	('tumor', 'Disease', (202, 207))	('PD-L1', 'Gene', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('help', 'PosReg', (197, 201))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('PD-L1', 'Gene', (174, 179))	('TME', 'Chemical', '-', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('TME', 'Chemical', '-', (235, 238))	('expression levels', 'MPA', (26, 43))	('TME', 'Chemical', '-', (136, 139))	('higher', 'PosReg', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
182968	32096345	But the frequencies of mutations in MIBC patients are overall high, it is not surprising that the differences were not obvious among patients with different infiltrating TMEs.	('MIBC', 'Chemical', '-', (36, 40))	('MIBC', 'Disease', (36, 40))	('patients', 'Species', '9606', (133, 141))	('TME', 'Chemical', '-', (170, 173))	('patients', 'Species', '9606', (41, 49))	('mutations', 'Var', (23, 32))	('BC', 'Phenotype', 'HP:0009725', (38, 40))
183017	32154169	Advanced or mUC was defined according to the appropriate International Classification of Disease (ICD)-10 codes (C65-C68) and tumor, nodes and metastasis (TNM) staging (T4b, N0, M0, or Tany, N1-3, M0, or Tany, Nany, M1).	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('UC', 'Disease', 'MESH:D014523', (13, 15))	('T4b', 'Var', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
183074	32154169	The probability of survival remained higher for the cisplatin sub-cohort up to the 5 years for which OS was estimated (Figure 2).	('OS', 'Gene', '17451', (101, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('higher', 'PosReg', (37, 43))	('cisplatin', 'Var', (52, 61))
183075	32154169	A Cox PH model was constructed to estimate comparative overall survival for the two platinum groups adjusted for binary categorical variables age (<70 years, 70+yrs), sex (male, female), confirmed metastasis (TNM0, TNM1) and performance score (PS < 2, PS = 2+).	('platinum', 'Chemical', 'MESH:D010984', (84, 92))	('TNM1', 'Gene', (215, 219))	('confirmed metastasis', 'CPA', (187, 207))	('TNM1', 'Gene', '10178', (215, 219))	('TNM0', 'Var', (209, 213))	('Cox', 'Gene', '1351', (2, 5))	('Cox', 'Gene', (2, 5))
183127	31754222	Numerous studies have shown cancer genesis is accompanied by an accumulation of harmful mutations, potentiating the identification of cancer based on genomic information.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (88, 97))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (28, 34))
183128	31754222	We analyzed 6,083 samples' WES (Whole Exon Sequencing) mutations files from 12 cancer types obtained from the TCGA (The Cancer Genome Atlas) and 1,991 healthy samples' WES data from the 1000 Genomes project.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (55, 64))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
183135	31754222	It is known that cancer is mainly caused by harmful mutations in proto-oncogenes, tumor suppressor genes and cell cycle regulator genes.	('mutations', 'Var', (52, 61))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('109', '129'))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('tumor suppressor', 'biological_process', 'GO:0051726', ('82', '98'))	('proto-oncogenes', 'Gene', (65, 80))	('cancer', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('82', '98'))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('109', '129'))	('tumor', 'Disease', (82, 87))	('caused', 'Reg', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
183137	31754222	In breast cancer, high penetrance mutations in BRCA1 and BRCA2 cause a loss of tumor suppressive function which correlates with an increased risk of breast cancer.	('BRCA1', 'Gene', (47, 52))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('loss of tumor', 'Disease', 'MESH:D009369', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('BRCA2', 'Gene', (57, 62))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('loss of tumor', 'Disease', (71, 84))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('BRCA2', 'Gene', '675', (57, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('BRCA1', 'Gene', '672', (47, 52))	('breast cancer', 'Disease', (149, 162))	('mutations', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
183139	31754222	There are published reports that stomach cancer may be caused by the accumulation PBLB2 and ATM mutations.	('caused by', 'Reg', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('stomach cancer', 'Disease', 'MESH:D013274', (33, 47))	('ATM', 'Gene', (92, 95))	('stomach cancer', 'Phenotype', 'HP:0012126', (33, 47))	('PBLB2', 'Gene', (82, 87))	('accumulation', 'PosReg', (69, 81))	('stomach cancer', 'Disease', (33, 47))	('ATM', 'Gene', '472', (92, 95))	('mutations', 'Var', (96, 105))
183141	31754222	TCGA researchers have identified many mutated genes that are involved in the cell cycle, DNA repair and chromatin modifications in BLCA.	('mutated', 'Var', (38, 45))	('BLCA', 'Disease', (131, 135))	('cell cycle', 'biological_process', 'GO:0007049', ('77', '87'))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('DNA repair', 'biological_process', 'GO:0006281', ('89', '99'))	('BLCA', 'Disease', 'MESH:D001749', (131, 135))	('chromatin', 'cellular_component', 'GO:0000785', ('104', '113'))
183148	31754222	Kun-Hsing identified thousands of objective features from the images, built and evaluated machine learning classifiers to predict the survival outcomes of lung cancer patient.A deep learning model using non-invasive CT images was used to predict EGFR mutation status for patients with lung adenocarcinoma.	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))	('lung adenocarcinoma', 'Disease', (285, 304))	('patient', 'Species', '9606', (167, 174))	('predict', 'Reg', (238, 245))	('mutation', 'Var', (251, 259))	('patient', 'Species', '9606', (271, 278))	('A deep learning', 'Disease', (175, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (295, 304))	('lung cancer', 'Disease', (155, 166))	('EGFR', 'molecular_function', 'GO:0005006', ('246', '250'))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('patients', 'Species', '9606', (271, 279))	('A deep learning', 'Disease', 'MESH:D007859', (175, 190))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('EGFR', 'Gene', '1956', (246, 250))	('EGFR', 'Gene', (246, 250))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (285, 304))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (285, 304))
183152	31754222	Even though GWAS is used to identify associations between single nucleotide variations and cancer, GWAS is based on linkage analysis to find the diseased genes and requires more intimate segregate sites.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('single nucleotide variations', 'Var', (58, 86))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associations', 'Interaction', (37, 49))
183158	31754222	If the harmful mutations occur in the oncogene or tumor suppressor genes, the normal cells will become cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor suppressor', 'biological_process', 'GO:0051726', ('50', '66'))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('50', '66'))	('tumor', 'Disease', (50, 55))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('oncogene', 'Gene', (38, 46))
183159	31754222	Changes in multiple genes are required to transform a normal cell into a cancer cell.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Changes', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
183165	31754222	To reduce the learning pressure brought about by highly redundant dimensions and to reduce the learning difficulty without affecting the accuracy of the model, we selected point mutations closely related to cancer from the TCGA as the dimension for the model.	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('point mutations', 'Var', (172, 187))
183167	31754222	The accumulation of harmful mutations is the root cause of cancer.	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('mutations', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))
183169	31754222	The first part is the accumulation of mutations that occur that lead to the cancer, and the second part is the accumulation of mutations that occur after the cancer develops, which is the cause of tumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('lead to', 'Reg', (64, 71))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (76, 82))	('tumor', 'Disease', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
183170	31754222	Our goal was to determine the rules that gene mutations follow in converting healthy tissues to cancer, which is reflected in the effect of the mutations on the pathways involved.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
183171	31754222	The difference in genetic mutations between patients with the same type of cancer is large because the effect on different pathways is similar.	('patients', 'Species', '9606', (44, 52))	('type of cancer', 'Disease', 'MESH:D009369', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('type of cancer', 'Disease', (67, 81))	('genetic mutations', 'Var', (18, 35))
183175	31754222	Furthermore, variant sites from healthy people and cancer patients were assigned a score ("0" indicates different from Mutation Collection and "1" indicates the same as Mutation Collection) compared to the Mutation Collection.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('variant', 'Var', (13, 20))	('people', 'Species', '9606', (40, 46))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
183213	31754222	It was further demonstrated that although cancer tissues vary in form, there are large common genomic variations at the molecular level that lead to lower accuracy in the mixture model than in the specific model.	('variations', 'Var', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('accuracy', 'MPA', (155, 163))	('lower', 'NegReg', (149, 154))
183224	31754222	With the implementation of large genome sequencing projects, more and more cancer associated variations especially the ones at low frequency will be identified so that our model will evolve rapidly and become more and more powerful.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('variations', 'Var', (93, 103))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
183229	31754222	With the development of biology and deep learning, mass high reliability variants and algorithm will create a better model for cancer risk identification.	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('variants', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (127, 133))
183245	31444293	Although an inherited form of MMR deficiency (Lynch syndrome) accounts for ~3% of colorectal cancers (CRCs), MMR deficiency accounts for ~15% of all CRCs via somatic mutation [1].	('CRC', 'Phenotype', 'HP:0003003', (102, 105))	('CRCs', 'Disease', 'MESH:D015179', (149, 153))	('deficiency', 'Var', (113, 123))	('colorectal cancers', 'Disease', 'MESH:D015179', (82, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('CRCs', 'Disease', 'MESH:D015179', (102, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('colorectal cancers', 'Disease', (82, 100))	('MMR', 'biological_process', 'GO:0006298', ('30', '33'))	('MMR', 'Gene', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('CRC', 'Phenotype', 'HP:0003003', (149, 152))	('Lynch syndrome', 'Disease', (46, 60))	('MMR', 'Gene', (30, 33))	('CRCs', 'Disease', (149, 153))	('Lynch syndrome', 'Disease', 'MESH:D003123', (46, 60))	('CRCs', 'Disease', (102, 106))	('MMR', 'biological_process', 'GO:0006298', ('109', '112'))
183252	31444293	We present a case of a patient treated effectively with sequential PD-1/PDL-1 inhibitors as well as dual checkpoint inhibition beyond progression with good disease control.	('PD-1', 'Gene', (67, 71))	('PD-1', 'Gene', '5133', (67, 71))	('inhibitors', 'Var', (78, 88))	('PDL-1', 'Gene', '29126', (72, 77))	('PDL-1', 'Gene', (72, 77))	('patient', 'Species', '9606', (23, 30))
183260	31444293	Given the MMR deficiency evident in his colon tumors, we performed germline testing, which revealed an MSH-2 mutation (IVS1 + 2T > G) in some but not all of his cells confirming the diagnosis of a mosaic attenuated Lynch syndrome, consistent with his later age of presentation.	('revealed', 'Reg', (91, 99))	('MSH-2', 'Gene', '4436', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('MMR', 'biological_process', 'GO:0006298', ('10', '13'))	('IVS1 + 2T > G', 'Mutation', 'c.IVS1+2T>G', (119, 132))	('colon tumors', 'Phenotype', 'HP:0100273', (40, 52))	('IVS1', 'Var', (119, 123))	('2T > G', 'Var', (126, 132))	('mosaic attenuated Lynch syndrome', 'Disease', (197, 229))	('2T > G', 'SUBSTITUTION', 'None', (126, 132))	('colon tumors', 'Disease', 'MESH:D015179', (40, 52))	('colon tumors', 'Disease', (40, 52))	('mosaic attenuated Lynch syndrome', 'Disease', 'MESH:D003123', (197, 229))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('MSH-2', 'Gene', (103, 108))
183283	31444293	Our patient with Lynch syndrome was treated with sequential PD-1/PDL-1 inhibitors with response, followed by the combination of a CTLA-4 and PD-1 inhibitor at the time of progression with significant disease control.	('PD-1', 'Gene', '5133', (60, 64))	('Lynch syndrome', 'Disease', 'MESH:D003123', (17, 31))	('inhibitors', 'Var', (71, 81))	('CTLA-4', 'Gene', '1493', (130, 136))	('PDL-1', 'Gene', '29126', (65, 70))	('patient', 'Species', '9606', (4, 11))	('PD-1', 'Gene', (141, 145))	('PDL-1', 'Gene', (65, 70))	('PD-1', 'Gene', '5133', (141, 145))	('CTLA-4', 'Gene', (130, 136))	('Lynch syndrome', 'Disease', (17, 31))	('PD-1', 'Gene', (60, 64))
183299	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))
183301	30072739	Somatic mutations in oncogenes and tumor suppressors represent the most classic biomarkers as they are the main direct drivers of cancer progression .	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancer', 'Disease', (130, 136))	('tumor', 'Disease', (35, 40))	('oncogenes', 'Gene', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Somatic mutations', 'Var', (0, 17))
183304	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))
183314	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'))
183328	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))
183333	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))
183343	30072739	The sdRNA transcriptome exhibited a wide dynamic range of expression across all cancers (Figure S5a), such that 300.13 +- 4.21 (mean +- s.e.m.)	('300.13 +- 4.21', 'Var', (112, 126))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('sdRNA', 'Gene', (4, 9))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
183425	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))
183426	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))	('sarcoma', 'Disease', 'MESH:D012509', (153, 160))	('sarcoma', 'Disease', (153, 160))	('SNORD145', 'Var', (47, 55))	('kidney clear cell carcinoma', 'Disease', (117, 144))	('sdRNAs', 'MPA', (35, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('D snoRNA', 'Phenotype', 'HP:0025267', (60, 68))	('survival times', 'CPA', (99, 113))	('snoRNA', 'Gene', '85390', (62, 68))
183427	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))
183445	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))
183456	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'))
183483	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))
183485	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))	('GSE33858', 'Var', (52, 60))	('EBI', 'Gene', '6907', (150, 153))	('MTAB', 'molecular_function', 'GO:0047152', ('74', '78'))	('ebi', 'Gene', '6907', (167, 170))	('ebi', 'Gene', (167, 170))
183511	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 .	('snoRNA', 'Gene', (197, 203))	('snoRNA', 'cellular_component', 'GO:0005733', ('197', '203'))	('deletion', 'Var', (85, 93))	('snoRNA', 'Gene', '85390', (197, 203))
183512	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))
183515	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))
183521	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))
183526	27520411	High prevalence of TERT promoter mutations in micropapillary urothelial carcinoma Somatic activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the most common genetic alterations in urothelial carcinoma (UC) of the bladder and upper urinary tract.	('transcriptase', 'molecular_function', 'GO:0003899', ('153', '166'))	('TERT', 'Gene', (19, 23))	('TERT', 'Gene', '7015', (19, 23))	('mutations', 'Var', (101, 110))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (222, 242))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('transcriptase', 'molecular_function', 'GO:0003968', ('153', '166'))	('micropapillary urothelial carcinoma', 'Disease', (46, 81))	('urothelial carcinoma', 'Disease', (222, 242))	('mutations', 'Var', (33, 42))	('transcriptase', 'molecular_function', 'GO:0034062', ('153', '166'))	('TERT', 'Gene', (168, 172))	('TERT', 'Gene', '7015', (168, 172))	('micropapillary urothelial carcinoma', 'Disease', 'MESH:D014526', (46, 81))	('telomerase reverse transcriptase', 'Gene', (134, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('telomerase reverse transcriptase', 'Gene', '7015', (134, 166))
183532	27520411	TERT promoter mutations were detected in all specimens with pure MPC (18 of 18) and UC with focal micropapillary features (15 of 15).	('pure', 'molecular_function', 'GO:0034023', ('60', '64'))	('detected', 'Reg', (29, 37))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('mutations', 'Var', (14, 23))
183534	27520411	In heterogeneous tumors with focal variant histology, intratumoral concordant mutations were found in variant (MPC and non-MPC) and corresponding conventional UC.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', (59, 64))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (78, 87))	('variant', 'Var', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('found', 'Reg', (93, 98))
183536	27520411	Our finding of concordant intratumoral mutational alterations in cases with focal variant histology lends support to the common oncogenesis origin of UC and its variant histology.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('variant', 'Var', (82, 89))	('oncogenesis', 'biological_process', 'GO:0007048', ('128', '139'))	('mutational alterations', 'Var', (39, 61))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
183537	27520411	Somatic activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene, originally discovered in the majority of melanomas, have been found to be the most common genetic mutations in urothelial (transitional cell) carcinoma (UC) of either the bladder or upper urinary tract.	('melanomas', 'Phenotype', 'HP:0002861', (139, 148))	('transcriptase', 'molecular_function', 'GO:0003968', ('71', '84'))	('transcriptase', 'molecular_function', 'GO:0003899', ('71', '84'))	('carcinoma', 'Disease', (240, 249))	('telomerase reverse transcriptase', 'Gene', (52, 84))	('melanomas', 'Disease', 'MESH:D008545', (139, 148))	('telomerase reverse transcriptase', 'Gene', '7015', (52, 84))	('mutations', 'Var', (19, 28))	('transcriptase', 'molecular_function', 'GO:0034062', ('71', '84'))	('TERT', 'Gene', (86, 90))	('activating', 'PosReg', (8, 18))	('carcinoma', 'Disease', 'MESH:D002277', (240, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('melanomas', 'Disease', (139, 148))	('TERT', 'Gene', '7015', (86, 90))	('mutations', 'Var', (196, 205))
183538	27520411	In a study by Kinde et al., 66 % of muscle invasive (i.e., invading muscularis propria) and 74 % of non-muscle invasive bladder lesions were shown to harbor these alterations (UC).	('invasive bladder lesions', 'Disease', 'MESH:D001745', (111, 135))	('alterations', 'Var', (163, 174))	('muscularis propria', 'Phenotype', 'HP:0030936', (68, 86))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (100, 127))	('invasive bladder', 'Phenotype', 'HP:0100645', (111, 127))	('muscle invasive', 'Disease', (36, 51))	('invasive bladder lesions', 'Disease', (111, 135))
183555	27520411	We used Safe-SeqS, a sequencing error reduction technology described previously, to discriminate genuine TERT promoter mutations from artifactual sequencing variants introduced during the sequencing process.	('TERT', 'Gene', (105, 109))	('TERT', 'Gene', '7015', (105, 109))	('error reduction technology', 'Disease', 'MESH:D012030', (32, 58))	('error reduction technology', 'Disease', (32, 58))	('mutations', 'Var', (119, 128))
183557	27520411	1) to harbor mutations in melanomas and other tumors.	('melanomas', 'Disease', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('melanomas', 'Phenotype', 'HP:0002861', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('melanomas', 'Disease', 'MESH:D008545', (26, 35))	('tumors', 'Disease', (46, 52))	('mutations', 'Var', (13, 22))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
183565	27520411	The predominant mutation identified was g.1295228C > T (28 of 33) followed by g.1295250C > T (4 of 33) and g.1295243C > T (1 of 33).	('g.1295250C > T', 'Mutation', 'g.1295250C>T', (78, 92))	('g.1295243C > T', 'Var', (107, 121))	('g.1295228C > T', 'Mutation', 'g.1295228C>T', (40, 54))	('g.1295250C > T', 'Var', (78, 92))	('g.1295243C > T', 'Mutation', 'g.1295243C>T', (107, 121))	('g.1295228C > T', 'Var', (40, 54))
183572	27520411	Our analysis of this tumor cohort expands upon previous reports identifying frequent TERT promoter mutations in urothelial carcinomas.	('TERT', 'Gene', (85, 89))	('urothelial carcinomas', 'Disease', (112, 133))	('tumor', 'Disease', (21, 26))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (112, 133))	('TERT', 'Gene', '7015', (85, 89))	('mutations', 'Var', (99, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
183574	27520411	The findings make micropapillary UC the solid tumor type with the highest rate of TERT promoter mutations.	('micropapillary UC', 'Disease', (18, 35))	('TERT', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('TERT', 'Gene', '7015', (82, 86))	('mutations', 'Var', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
183576	27520411	These mutations were also present in areas of non-micropapillary histology in heterogeneous tumors con taining a component of urothelial, glandular, papillary or squamous differentiation in addition to MPC.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('urothelial', 'Disease', (126, 136))	('papillary', 'Disease', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('squamous differentiation', 'Disease', (162, 186))	('tumors', 'Disease', (92, 98))	('mutations', 'Var', (6, 15))
183577	27520411	Interestingly, all cancer-associated TERT promoter mutations discovered thus far generate novel binding sites for the ETS (E26 transformation-specific) family of transcription factors located near the translational start site of TERT.	('mutations', 'Var', (51, 60))	('TERT', 'Gene', (37, 41))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('TERT', 'Gene', '7015', (37, 41))	('binding', 'molecular_function', 'GO:0005488', ('96', '103'))	('binding', 'Interaction', (96, 103))	('cancer', 'Disease', (19, 25))	('transcription', 'biological_process', 'GO:0006351', ('162', '175'))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('ETS', 'Chemical', '-', (118, 121))	('TERT', 'Gene', (229, 233))	('TERT', 'Gene', '7015', (229, 233))
183578	27520411	The cellular or microenvironmental factors that select for cells with the TERT promoter mutations remain unclear.	('TERT', 'Gene', '7015', (74, 78))	('mutations', 'Var', (88, 97))	('TERT', 'Gene', (74, 78))
183579	27520411	However, it has been suggested that TERT promoter mutations preferentially promote tumor progression in differentiated cells which normally have absent to low telomerase and relatively low rates of self-renewal.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TERT', 'Gene', '7015', (36, 40))	('promote', 'PosReg', (75, 82))	('mutations', 'Var', (50, 59))	('tumor', 'Disease', (83, 88))	('TERT', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
183580	27520411	Chiba and colleagues have proposed that tumor-initiating cells in these specialized tissue types acquire somatic TERT promoter mutations at the point of telomere crisis in the course of cellular transformation in response to chronic injury, thus overcoming this telomere-dependent proliferative barrier early in their progression.	('telomere', 'cellular_component', 'GO:0005696', ('262', '270'))	('TERT', 'Gene', '7015', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('telomere', 'cellular_component', 'GO:0000781', ('153', '161'))	('chronic injury', 'Disease', (225, 239))	('telomere', 'cellular_component', 'GO:0005696', ('153', '161'))	('chronic injury', 'Disease', 'MESH:D020208', (225, 239))	('tumor', 'Disease', (40, 45))	('mutations', 'Var', (127, 136))	('telomere', 'cellular_component', 'GO:0000781', ('262', '270'))	('overcoming', 'NegReg', (246, 256))	('TERT', 'Gene', (113, 117))
183581	27520411	Similar findings have been demonstrated in human gastric cancer cells in which bile acids, under acidic conditions, were found to be associated with an increase in TERT expression, perhaps through the activation of c-myc transcription.	('bile acids', 'Chemical', 'MESH:D001647', (79, 89))	('increase', 'PosReg', (152, 160))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('human', 'Species', '9606', (43, 48))	('TERT', 'Gene', (164, 168))	('TERT', 'Gene', '7015', (164, 168))	('c-myc', 'Gene', '4609', (215, 220))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('bile acids', 'Var', (79, 89))	('transcription', 'biological_process', 'GO:0006351', ('221', '234'))	('gastric cancer', 'Disease', (49, 63))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))	('c-myc', 'Gene', (215, 220))
183582	27520411	The most common TERT promoter mutations (C228T and C250T) are believed to result in the creation of novel CCGG AA/T general binding motifs for E26 transformation-specific (ETS)/ternary complex factor (TCF) transcription factors.	('TERT', 'Gene', (16, 20))	('transcription', 'biological_process', 'GO:0006351', ('206', '219'))	('C228T', 'Var', (41, 46))	('binding', 'molecular_function', 'GO:0005488', ('124', '131'))	('TERT', 'Gene', '7015', (16, 20))	('C250T', 'Mutation', 'c.250C>T', (51, 56))	('ETS', 'Chemical', '-', (172, 175))	('C250T', 'Var', (51, 56))	('C228T', 'Mutation', 'c.228C>T', (41, 46))
183583	27520411	The somatic mutations at both positions result in a C > T base change and ETS binding sites that differ from pre-existing ETS binding sites (GGAA/T) within the promoter region.	('ETS', 'Chemical', '-', (74, 77))	('pre', 'molecular_function', 'GO:0003904', ('109', '112'))	('mutations', 'Var', (12, 21))	('ETS', 'Chemical', '-', (122, 125))	('result in', 'Reg', (40, 49))	('binding', 'molecular_function', 'GO:0005488', ('78', '85'))	('ETS', 'MPA', (74, 77))	('binding', 'molecular_function', 'GO:0005488', ('126', '133'))
183587	27520411	suggests that the novel ETS binding sites created by TERT promoter mutations are specifically and directly bound by GA-binding protein (GABP), a ubiquitously expressed transcription factor has been implicated in the regulation of re-entry into S phase of the cell cycle in quiescent cells.	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('bound', 'Interaction', (107, 112))	('mutations', 'Var', (67, 76))	('transcription', 'biological_process', 'GO:0006351', ('168', '181'))	('regulation', 'biological_process', 'GO:0065007', ('216', '226'))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('cell cycle', 'biological_process', 'GO:0007049', ('259', '269'))	('S phase', 'biological_process', 'GO:0051320', ('244', '251'))	('transcription factor', 'molecular_function', 'GO:0000981', ('168', '188'))	('ETS', 'Chemical', '-', (24, 27))	('binding', 'molecular_function', 'GO:0005488', ('28', '35'))
183590	27520411	In fact, the presence of TERT promoter mutations within areas of both focal and pure micropapillary histology reinforces the morphologic plasticity of UC.	('TERT', 'Gene', (25, 29))	('TERT', 'Gene', '7015', (25, 29))	('pure', 'molecular_function', 'GO:0034023', ('80', '84'))	('mutations', 'Var', (39, 48))
183591	27520411	Furthermore, the concordant findings of TERT promoter mutations in areas of typical UC and divergent differentiation point to a putative stem cell originating urothelial carcinoma capable of generating neoplastic TERT-driven populations with different phenotypes.	('TERT', 'Gene', '7015', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('TERT', 'Gene', (213, 217))	('mutations', 'Var', (54, 63))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (159, 179))	('TERT', 'Gene', '7015', (213, 217))	('urothelial carcinoma', 'Disease', (159, 179))	('TERT', 'Gene', (40, 44))
183593	27932416	A PHASE II TRIAL OF DOVITINIB IN BCG-UNRESPONSIVE UROTHELIAL CARCINOMA WITH FGFR3 MUTATIONS OR OVER-EXPRESSION: HOOSIER CANCER RESEARCH NETWORK TRIAL HCRN 12-157 To assess the clinical and pharmacodynamic activity of dovitinib in a treatment resistant, molecularly enriched NMIUC population.	('HCRN', 'Gene', (150, 154))	('BCG', 'Species', '33892', (33, 36))	('FGFR3', 'Gene', '2261', (76, 81))	('CARCINOMA', 'Phenotype', 'HP:0030731', (61, 70))	('HCRN', 'Gene', '51340', (150, 154))	('dovitinib', 'Chemical', 'MESH:C500007', (217, 226))	('MUTATIONS', 'Var', (82, 91))	('CANCER', 'Phenotype', 'HP:0002664', (120, 126))	('FGFR3', 'Gene', (76, 81))	('DOVITINIB', 'Chemical', 'MESH:C500007', (20, 29))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))
183594	27932416	Key eligibility criteria included: BCG unresponsive NMIUC (>= 2 prior intravesical regimens) with increased phosphorylated FGFR3 (pFGFR3) expression by centrally analyzed immunohistochemistry (IHC+) or FGFR3 mutations (Mut+) assessed in a CLIA-licensed laboratory.	('FGFR3', 'Gene', '2261', (123, 128))	('FGFR3', 'Gene', '2261', (202, 207))	('FGFR3', 'Gene', (123, 128))	('mutations', 'Var', (208, 217))	('FGFR3', 'Gene', '2261', (131, 136))	('FGFR', 'molecular_function', 'GO:0005007', ('202', '206'))	('increased', 'PosReg', (98, 107))	('FGFR3', 'Gene', (202, 207))	('FGFR3', 'Gene', (131, 136))	('FGFR', 'molecular_function', 'GO:0005007', ('123', '127'))	('BCG', 'Species', '33892', (35, 38))
183624	27932416	FGFR3 mutations or over-expression promote FGFR dimerization and constitutive activation of downstream signaling pathways in the absence of ligand in up to 80% of low-grade NMIUC tumors.	('dimerization', 'MPA', (48, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'Gene', (43, 47))	('FGFR3', 'Gene', '2261', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('FGFR3', 'Gene', (0, 5))	('ligand', 'molecular_function', 'GO:0005488', ('140', '146'))	('downstream signaling pathways', 'Pathway', (92, 121))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('activation', 'PosReg', (78, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('over-expression promote', 'PosReg', (19, 42))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('UC tumors', 'Disease', (176, 185))	('UC tumors', 'Disease', 'MESH:D009369', (176, 185))	('mutations', 'Var', (6, 15))
183625	27932416	These mutations result in a hyperplastic phenotype dominated by frequent tumor recurrences with infrequent progression to muscle-invasive stages.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('result in', 'Reg', (16, 25))	('tumor', 'Disease', (73, 78))	('mutations', 'Var', (6, 15))
183626	27932416	While FGFR3 mutations are highly associated with low-grade NMIUC, over-expression of FGFR3 has been observed in up to 42% of high-grade muscle-invasive UC tumors.	('FGFR3', 'Gene', '2261', (6, 11))	('over-expression', 'PosReg', (66, 81))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('FGFR3', 'Gene', (85, 90))	('mutations', 'Var', (12, 21))	('FGFR3', 'Gene', (6, 11))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('associated', 'Reg', (33, 43))	('observed', 'Reg', (100, 108))	('low-grade NMIUC', 'Disease', (49, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('6', '10'))	('muscle-invasive UC tumors', 'Disease', 'MESH:D009217', (136, 161))	('muscle-invasive UC tumors', 'Disease', (136, 161))	('FGFR3', 'Gene', '2261', (85, 90))
183627	27932416	Furthermore, either an FGFR3 mutation or over-expression of the FGFR3 protein in the absence of mutation has been observed in 54% of muscle-invasive UC tumors.	('FGFR3', 'Gene', (23, 28))	('mutation', 'Var', (29, 37))	('protein', 'Protein', (70, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('over-expression', 'PosReg', (41, 56))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('FGFR3', 'Gene', (64, 69))	('muscle-invasive UC tumors', 'Disease', 'MESH:D009217', (133, 158))	('muscle-invasive UC tumors', 'Disease', (133, 158))	('FGFR3', 'Gene', '2261', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('observed', 'Reg', (114, 122))	('FGFR3', 'Gene', '2261', (64, 69))
183628	27932416	Thus, while FGFR3 mutations likely are an early event in the tumorigenesis of low-grade non-invasive UC tumors, alterations of FGFR3 may still play a role in the continued proliferation of high-grade UC.	('FGFR3', 'Gene', (12, 17))	('FGFR3', 'Gene', '2261', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('UC tumors', 'Disease', 'MESH:D009369', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('FGFR3', 'Gene', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('FGFR3', 'Gene', '2261', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('127', '131'))	('alterations', 'Var', (112, 123))	('tumor', 'Disease', (61, 66))	('UC tumors', 'Disease', (101, 110))	('mutations', 'Var', (18, 27))
183631	27932416	In preclinical tumor models, blockade of the FGF pathway has proven to be an effective method of overcoming resistance to VEGFR inhibitors.	('blockade', 'Var', (29, 37))	('resistance', 'MPA', (108, 118))	('VEGFR', 'Gene', '3791', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('VEGFR', 'Gene', (122, 127))	('tumor', 'Disease', (15, 20))	('overcoming', 'PosReg', (97, 107))	('FGF pathway', 'Pathway', (45, 56))
183632	27932416	Given the previously described importance of VEGF in UC progression and the frequent FGFR3 aberrations in NMIUC, we conducted a multi-site pilot trial in BCG-unresponsive NMIUC patients harboring FGFR3 gene alterations to evaluate the clinical and biological outcomes of oral dovitinib therapy.	('dovitinib', 'Chemical', 'MESH:C500007', (276, 285))	('FGFR3', 'Gene', (85, 90))	('FGFR3', 'Gene', '2261', (196, 201))	('patients', 'Species', '9606', (177, 185))	('VEGF', 'Gene', '7422', (45, 49))	('BCG', 'Species', '33892', (154, 157))	('aberrations', 'Var', (91, 102))	('FGFR3', 'Gene', (196, 201))	('FGFR', 'molecular_function', 'GO:0005007', ('196', '200'))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('FGFR3', 'Gene', '2261', (85, 90))	('VEGF', 'Gene', (45, 49))
183635	27932416	Key eligibility criteria included: histologically confirmed Ta, T1, or Tis stage NMIUC assessed by TURBT performed within 42 days of registration; somatic tumor mutations in FGFR3 exons 7, 10, or 15 (S373C, G372C, Y375C, G382R, K652E, K652Q, K652T, K652M, A393E, S249C, and R248C) or tumor over-expression of phosphorylated (pFGFR3) by immunohistochemistry (IHC) defined as 1+ or greater tumor pFGFR3 staining; recurrent NMIUC despite at least 2 prior intravesical treatment regimens (no limit), one of which must have been BCG; patients medically unfit for or refusing cystectomy; age >= 18 years; ECOG performance status 0-2; adequate hematologic and liver function; creatinine clearance > 30 ml/min by modified Cockcroft-Gault equation; and documented, written informed consent.	('FGFR3', 'Gene', (395, 400))	('K652M', 'Var', (249, 254))	('G372C', 'Var', (207, 212))	('tumor', 'Disease', (155, 160))	('FGFR3', 'Gene', (174, 179))	('S373C', 'Var', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('K652E', 'Var', (228, 233))	('R248C', 'Var', (274, 279))	('patients', 'Species', '9606', (529, 537))	('G382R', 'Mutation', 'rs28931614', (221, 226))	('R248C', 'Mutation', 'rs121913482', (274, 279))	('FGFR3', 'Gene', '2261', (395, 400))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (388, 393))	('FGFR3', 'Gene', '2261', (174, 179))	('S373C', 'Mutation', 'rs121913484', (200, 205))	('Y375C', 'Mutation', 'rs121913485', (214, 219))	('A393E', 'Mutation', 'rs28931615', (256, 261))	('A393E', 'Var', (256, 261))	('G372C', 'Mutation', 'rs121913479', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('K652T', 'Var', (242, 247))	('FGFR', 'molecular_function', 'GO:0005007', ('174', '178'))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('G382R', 'Var', (221, 226))	('tumor', 'Disease', (388, 393))	('Y375C', 'Var', (214, 219))	('K652E', 'Mutation', 'rs78311289', (228, 233))	('FGFR3', 'Gene', (326, 331))	('BCG', 'Species', '33892', (524, 527))	('K652M', 'Mutation', 'rs121913105', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (388, 393))	('creatinine clearance', 'MPA', (669, 689))	('mutations', 'Var', (161, 170))	('K652Q', 'Var', (235, 240))	('K652T', 'Mutation', 'rs121913105', (242, 247))	('FGFR3', 'Gene', '2261', (326, 331))	('K652Q', 'Mutation', 'rs78311289', (235, 240))	('tumor', 'Disease', (284, 289))	('S249C', 'Mutation', 'rs121913483', (263, 268))
183655	27932416	FGFR3 mutational status was determined using a custom designed SNaPshot assay (ThermoFisher Scientific, Waltham, MA) for all common mutations in FGFR3 coding exons including exons 7, 10, and 15.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'molecular_function', 'GO:0005007', ('145', '149'))	('FGFR3', 'Gene', (0, 5))	('FGFR3', 'Gene', '2261', (145, 150))	('mutations', 'Var', (132, 141))	('FGFR3', 'Gene', (145, 150))	('FGFR3', 'Gene', '2261', (0, 5))
183656	27932416	The presence or absence of specific FGFR3 mutations (S373C, G372C, Y375C, G382R, K652E, K652Q, K652T, K652M, A393E, S249C, and R248C) was communicated to HCRN within 14 days of specimen receipt.	('HCRN', 'Gene', (154, 158))	('G382R', 'Var', (74, 79))	('Y375C', 'Var', (67, 72))	('K652E', 'Mutation', 'rs78311289', (81, 86))	('S249C', 'Var', (116, 121))	('K652Q', 'Var', (88, 93))	('HCRN', 'Gene', '51340', (154, 158))	('K652Q', 'Mutation', 'rs78311289', (88, 93))	('K652M', 'Mutation', 'rs121913105', (102, 107))	('K652T', 'Mutation', 'rs121913105', (95, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))	('FGFR3', 'Gene', (36, 41))	('S249C', 'Mutation', 'rs121913483', (116, 121))	('G372C', 'Var', (60, 65))	('K652M', 'Var', (102, 107))	('S373C', 'Var', (53, 58))	('FGFR3', 'Gene', '2261', (36, 41))	('G382R', 'Mutation', 'rs28931614', (74, 79))	('K652E', 'Var', (81, 86))	('R248C', 'Var', (127, 132))	('R248C', 'Mutation', 'rs121913482', (127, 132))	('A393E', 'Mutation', 'rs28931615', (109, 114))	('Y375C', 'Mutation', 'rs121913485', (67, 72))	('S373C', 'Mutation', 'rs121913484', (53, 58))	('A393E', 'Var', (109, 114))	('G372C', 'Mutation', 'rs121913479', (60, 65))	('K652T', 'Var', (95, 100))
183671	27932416	An algorithm was designed based on pattern recognition that quantified tumor cells within pFGFR3 positive areas (tumor) and pFGFR3 negative areas (invasive margin).	('tumor', 'Disease', (113, 118))	('FGFR3', 'Gene', (91, 96))	('FGFR3', 'Gene', '2261', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('positive areas', 'Var', (97, 111))	('FGFR3', 'Gene', '2261', (91, 96))	('FGFR3', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (71, 76))
183681	27932416	With an estimated FGFR3 mutation or over-expression present in 40% of BCG-unresponsive tumors, screening of 50 patients' tumors was estimated in order to enroll the required 20 patients on dovitinib therapy.	('FGFR3', 'Gene', '2261', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('patients', 'Species', '9606', (177, 185))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('FGFR3', 'Gene', (18, 23))	('patients', 'Species', '9606', (111, 119))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('over-expression', 'PosReg', (36, 51))	('dovitinib', 'Chemical', 'MESH:C500007', (189, 198))	('mutation', 'Var', (24, 32))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('BCG', 'Species', '33892', (70, 73))
183687	27932416	Fifteen patients (88%) had sufficient tumor tissue for FGFR3 mutation testing.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('FGFR3', 'Gene', '2261', (55, 60))	('mutation', 'Var', (61, 69))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('FGFR3', 'Gene', (55, 60))	('patients', 'Species', '9606', (8, 16))
183688	27932416	Two patients with tumors demonstrating no FGFR3 mutations were considered screen-failures after the study amendment capping the enrollment of FGFR3 mutation negative patients was in place.	('FGFR', 'molecular_function', 'GO:0005007', ('142', '146'))	('FGFR3', 'Gene', '2261', (42, 47))	('FGFR3', 'Gene', '2261', (142, 147))	('patients', 'Species', '9606', (166, 174))	('FGFR3', 'Gene', (42, 47))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('patients', 'Species', '9606', (4, 12))	('FGFR3', 'Gene', (142, 147))	('mutations', 'Var', (48, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
183693	27932416	Tumor FGFR3 mutations were detected in 3 patients (18% of screened patients) with a concordant urine FGFR3 mutation detected in 1 of the 3 patients.	('FGFR3', 'Gene', '2261', (6, 11))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('patients', 'Species', '9606', (139, 147))	('patients', 'Species', '9606', (67, 75))	('mutations', 'Var', (12, 21))	('FGFR3', 'Gene', (6, 11))	('FGFR3', 'Gene', '2261', (101, 106))	('patients', 'Species', '9606', (41, 49))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))	('FGFR', 'molecular_function', 'GO:0005007', ('6', '10'))	('FGFR3', 'Gene', (101, 106))	('detected', 'Reg', (27, 35))
183709	27932416	The single complete response patient did harbor an FGFR3 S249C mutation.	('patient', 'Species', '9606', (29, 36))	('FGFR3', 'Gene', '2261', (51, 56))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('FGFR3', 'Gene', (51, 56))	('S249C', 'Var', (57, 62))	('S249C', 'Mutation', 'rs121913483', (57, 62))
183710	27932416	Thus, the pathologic complete response rate amongst FGFR3 mut+ patients was 33% (1 of 3) as summarized in Table 3.	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('FGFR3', 'Gene', '2261', (52, 57))	('mut+', 'Var', (58, 62))	('FGFR3', 'Gene', (52, 57))	('patients', 'Species', '9606', (63, 71))
183712	27932416	Eight patients (62%) underwent cystectomy per the discretion of their physician at any time point following completion of study therapy with a wide variety of pathologic stages ranging from pT0N0 to pN+ disease (Supplementary Table S2).	('cystectomy', 'Disease', (31, 41))	('patients', 'Species', '9606', (6, 14))	('pT0N0', 'Var', (190, 195))	('pN+', 'Disease', (199, 202))
183716	27932416	Staining intensities according to the use of the sc-33041 and ab155960 pFGFR3 antibodies showed significant heterogeneity (Supplemental Table S3).	('sc-33041', 'Chemical', '-', (49, 57))	('FGFR3', 'Gene', '2261', (72, 77))	('FGFR3', 'Gene', (72, 77))	('sc-33041', 'Var', (49, 57))	('ab155960', 'Var', (62, 70))
183724	27932416	Given the established relevance of VEGFR in UC cancer invasion and metastases and the striking frequency of FGFR3 aberrations in low-grade NMIUC, we postulated that an FGFR3/VEGFR2 directed approach with dovitinib would prove both feasible and beneficial in BCG-unresponsive NMIUC patients with tumors harboring FGFR3 alterations.	('FGFR3', 'Gene', '2261', (168, 173))	('tumors', 'Disease', (295, 301))	('VEGFR', 'Gene', '3791', (174, 179))	('metastases', 'Disease', (67, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('168', '172'))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('VEGFR', 'Gene', (174, 179))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('FGFR', 'molecular_function', 'GO:0005007', ('312', '316'))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('BCG-unresponsive NMIUC', 'Disease', (258, 280))	('BCG', 'Species', '33892', (258, 261))	('FGFR3', 'Gene', (108, 113))	('dovitinib', 'Chemical', 'MESH:C500007', (204, 213))	('FGFR3', 'Gene', (312, 317))	('VEGFR2', 'Gene', (174, 180))	('FGFR3', 'Gene', '2261', (108, 113))	('patients', 'Species', '9606', (281, 289))	('VEGFR', 'Gene', '3791', (35, 40))	('alterations', 'Var', (318, 329))	('FGFR3', 'Gene', '2261', (312, 317))	('VEGFR', 'Gene', (35, 40))	('VEGFR2', 'Gene', '3791', (174, 180))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('aberrations', 'Var', (114, 125))	('FGFR3', 'Gene', (168, 173))	('metastases', 'Disease', 'MESH:D009362', (67, 77))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))
183727	27932416	At the time the study was designed, the relative importance of FGFR3 mutations vs. gene fusions vs. over-expression was unknown.	('mutations', 'Var', (69, 78))	('FGFR3', 'Gene', '2261', (63, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('FGFR3', 'Gene', (63, 68))
183733	27932416	In recent trial reports of other FGFR3 inhibitors (JNJ-42756493, BGJ398, AZD4547) in metastatic UC patients, it now appears clear that activating FGFR3 mutations or fusions are required for tumor responses.	('FGFR', 'molecular_function', 'GO:0005007', ('146', '150'))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mutations', 'Var', (152, 161))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('FGFR3', 'Gene', '2261', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('AZD4547', 'Chemical', 'MESH:C572463', (73, 80))	('patients', 'Species', '9606', (99, 107))	('FGFR3', 'Gene', '2261', (33, 38))	('tumor', 'Disease', (190, 195))	('FGFR3', 'Gene', (146, 151))	('FGFR3', 'Gene', (33, 38))	('metastatic UC', 'Disease', (85, 98))
183734	27932416	In trials of these agents mandating either FGFR3 mutation or fusions, reduction of tumor size was observed in 50-60% of metastatic UC patients.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('metastatic UC', 'Disease', (120, 133))	('reduction', 'NegReg', (70, 79))	('FGFR3', 'Gene', (43, 48))	('tumor', 'Disease', (83, 88))	('patients', 'Species', '9606', (134, 142))	('mutation', 'Var', (49, 57))	('fusions', 'Var', (61, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('FGFR3', 'Gene', '2261', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
183735	27932416	Interestingly, in a prior report of dovitinib in metastatic UC patients, no responses were observed amongst 12 patients with FGFR3 mutations.	('mutations', 'Var', (131, 140))	('FGFR3', 'Gene', '2261', (125, 130))	('FGFR', 'molecular_function', 'GO:0005007', ('125', '129'))	('dovitinib', 'Chemical', 'MESH:C500007', (36, 45))	('patients', 'Species', '9606', (63, 71))	('FGFR3', 'Gene', (125, 130))	('metastatic', 'Disease', (49, 59))	('patients', 'Species', '9606', (111, 119))
183740	27932416	Furthermore, a strong trend in decreased post-treatment pFGFR3 staining was observed regardless of FGFR3 mutation status.	('FGFR3', 'Gene', (57, 62))	('mutation', 'Var', (105, 113))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('FGFR3', 'Gene', (99, 104))	('decreased', 'NegReg', (31, 40))	('FGFR3', 'Gene', '2261', (57, 62))	('FGFR3', 'Gene', '2261', (99, 104))
183741	27932416	In addition to patient selection limitations, the high rate of treatment related toxicity led to frequent dose reductions including 2 of the 3 FGFR3 Mut+ patients discontinuing dovitinib early.	('discontinuing', 'NegReg', (163, 176))	('FGFR3', 'Gene', '2261', (143, 148))	('patient', 'Species', '9606', (15, 22))	('toxicity', 'Disease', 'MESH:D064420', (81, 89))	('toxicity', 'Disease', (81, 89))	('Mut+', 'Var', (149, 153))	('patient', 'Species', '9606', (154, 161))	('dovitinib', 'Chemical', 'MESH:C500007', (177, 186))	('FGFR3', 'Gene', (143, 148))	('patients', 'Species', '9606', (154, 162))	('dose', 'MPA', (106, 110))	('FGFR', 'molecular_function', 'GO:0005007', ('143', '147'))
183747	27932416	In fact, of the 17 patients screened, 15 (88%) had sufficient tumor available for FGFR3 mutation testing.	('FGFR3', 'Gene', (82, 87))	('mutation', 'Var', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('patients', 'Species', '9606', (19, 27))	('tumor', 'Disease', (62, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('82', '86'))	('FGFR3', 'Gene', '2261', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
183751	27932416	In addition, our results establish the frequency of FGFR3 mutations in the BCG-unresponsive NMIUC population at 18% (3 of 17 patients), a previously unknown benchmark.	('mutations', 'Var', (58, 67))	('FGFR3', 'Gene', '2261', (52, 57))	('BCG', 'Species', '33892', (75, 78))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('FGFR3', 'Gene', (52, 57))	('patients', 'Species', '9606', (125, 133))
183752	27932416	Our a priori design assumption that the FGFR3 mutation rate in BCG-unresponsive NMIUC patients would fall somewhere between the reported rates in low-grade NMIUC (65%) and muscle-invasive UC (15%) patients proved incorrect.	('BCG-unresponsive NMIUC', 'Disease', (63, 85))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('patients', 'Species', '9606', (197, 205))	('FGFR3', 'Gene', (40, 45))	('fall', 'NegReg', (101, 105))	('mutation', 'Var', (46, 54))	('fall', 'Phenotype', 'HP:0002527', (101, 105))	('FGFR3', 'Gene', '2261', (40, 45))	('BCG', 'Species', '33892', (63, 66))	('patients', 'Species', '9606', (86, 94))
183754	27932416	The lower rate of FGFR3 mutations observed in the BCG-unresponsive NMIUC population has implications on future sample size considerations of FGFR3 targeting trials in this population.	('FGFR3', 'Gene', '2261', (18, 23))	('FGFR3', 'Gene', '2261', (141, 146))	('BCG', 'Species', '33892', (50, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('FGFR3', 'Gene', (18, 23))	('FGFR3', 'Gene', (141, 146))	('BCG-unresponsive', 'Disease', (50, 66))	('mutations', 'Var', (24, 33))	('FGFR', 'molecular_function', 'GO:0005007', ('141', '145'))
183765	27932416	This trial reports the toxicity, pharmacodynamics, and clinical efficacy profiles of the oral FGFR1-3 and VEGFR1-3 multi-targeted tyrosine kinase inhibitor, dovitinib, in a pilot phase II investigation in patients with BCG-unresponsive non-muscle invasive urothelial carcinoma of the bladder (NMIUC) with tumors harboring FGFR3 alterations.	('FGFR1', 'Gene', '2260', (94, 99))	('VEGFR1', 'Gene', (106, 112))	('patients', 'Species', '9606', (205, 213))	('invasive urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (247, 291))	('toxicity', 'Disease', 'MESH:D064420', (23, 31))	('FGFR3', 'Gene', (322, 327))	('dovitinib', 'Chemical', 'MESH:C500007', (157, 166))	('BCG', 'Species', '33892', (219, 222))	('FGFR3', 'Gene', '2261', (322, 327))	('alterations', 'Var', (328, 339))	('FGFR1', 'Gene', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (305, 311))	('toxicity', 'Disease', (23, 31))	('invasive urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (247, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('invasive urothelial carcinoma of the bladder', 'Disease', (247, 291))	('FGFR', 'molecular_function', 'GO:0005007', ('94', '98'))	('tumors', 'Disease', (305, 311))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('139', '155'))	('FGFR', 'molecular_function', 'GO:0005007', ('322', '326'))	('VEGFR1', 'Gene', '2321', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (305, 311))
183767	27932416	Lack of clinical efficacy was hampered by frequent drug toxicity and a paucity of patients harboring FGFR3 mutations.	('drug toxicity', 'Disease', 'MESH:D064420', (51, 64))	('mutations', 'Var', (107, 116))	('patients', 'Species', '9606', (82, 90))	('FGFR3', 'Gene', '2261', (101, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))	('FGFR3', 'Gene', (101, 106))	('drug toxicity', 'Disease', (51, 64))
183773	27150640	Nine germline single nucleotide polymorphisms (SNPs) potentially conferring platinum sensitivity were tested for association with complete pathologic response to neoadjuvant chemotherapy (pT0) or elimination of muscle-invasive cancer (<pT2).	('pT0', 'Chemical', 'MESH:D010984', (188, 191))	('association', 'Interaction', (113, 124))	('platinum', 'Chemical', 'MESH:D010984', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('single nucleotide polymorphisms', 'Var', (14, 45))	('muscle-invasive cancer', 'Disease', 'MESH:D009217', (211, 233))	('muscle-invasive cancer', 'Disease', (211, 233))
183776	27150640	Using a multivariate recessive genetic model, rs244898 in RARS (odds ratio [OR]=6.8 [95% CI 1.8-28.9], P=0.006) and rs7937567 in GALNTL4 (OR=4.8 [95% CI 1.1-22.6], P=0.04) were associated with pT0 in the discovery set.	('rs7937567', 'Mutation', 'rs7937567', (116, 125))	('GALNTL4', 'Gene', (129, 136))	('pT0', 'Disease', (193, 196))	('RARS', 'Gene', '5917', (58, 62))	('rs7937567', 'Var', (116, 125))	('rs244898', 'Mutation', 'rs244898', (46, 54))	('pT0', 'Chemical', 'MESH:D010984', (193, 196))	('GALNTL4', 'Gene', '374378', (129, 136))	('associated', 'Reg', (177, 187))	('rs244898', 'Var', (46, 54))	('RARS', 'Gene', (58, 62))
183778	27150640	A third SNP, rs10964552, was associated with <pT2 in the discovery set, but also failed to replicate.	('rs10964552', 'Var', (13, 23))	('<pT2', 'Disease', (45, 49))	('rs10964552', 'Mutation', 'rs10964552', (13, 23))
183791	27150640	Our project sought to apply rapidly-evolving genomic knowledge to this question, with the hypothesis that germline genetic polymorphisms are potentially important predictors of cisplatin response in urothelial cancer.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('predictors', 'Reg', (163, 173))	('urothelial cancer', 'Disease', (199, 216))	('polymorphisms', 'Var', (123, 136))	('cisplatin', 'Chemical', 'MESH:D002945', (177, 186))	('urothelial cancer', 'Disease', 'MESH:D014523', (199, 216))
183793	27150640	Yet the importance of germline polymorphisms in governing drug levels/disposition, toxicity, and response has long been recognized in oncology (TPMT polymorphisms with 6-mercaptopurine and UGT1A1 polymorphisms with irinotecan are salient examples).	('TPMT', 'Gene', (144, 148))	('6-mercaptopurine', 'Chemical', 'MESH:D015122', (168, 184))	('irinotecan', 'Chemical', 'MESH:D000077146', (215, 225))	('UGT1A1', 'Gene', '54658', (189, 195))	('6-mercaptopurine', 'MPA', (168, 184))	('oncology', 'Phenotype', 'HP:0002664', (134, 142))	('polymorphisms', 'Var', (196, 209))	('toxicity', 'Disease', 'MESH:D064420', (83, 91))	('UGT1A1', 'Gene', (189, 195))	('toxicity', 'Disease', (83, 91))	('TPMT', 'Gene', '7172', (144, 148))	('TPMT', 'molecular_function', 'GO:0008119', ('144', '148'))	('polymorphisms', 'Var', (149, 162))
183794	27150640	In bladder cancer, we previously examined a large list of germline polymorphisms from candidate genes hypothesized to have effects on cisplatin sensitivity and tested these in a heterogeneous population of platinum-treated patients.	('patients', 'Species', '9606', (223, 231))	('tested', 'Reg', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('cisplatin sensitivity', 'MPA', (134, 155))	('platinum', 'Chemical', 'MESH:D010984', (206, 214))	('germline polymorphisms', 'Var', (58, 80))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('effects', 'Reg', (123, 130))
183805	27150640	We therefore intended to apply a different approach to the question by using genome-wide methods to select SNPs for testing - thus not confining analysis to the supposition that important platinum sensitivity SNPs are located in 'traditional' candidate genes.	('SNPs', 'Var', (209, 213))	('platinum', 'Chemical', 'MESH:D010984', (188, 196))	('platinum sensitivity', 'Disease', (188, 208))
183810	27150640	Five of these (rs2191934, rs9527419, rs244903, rs7210837, rs3893319) were strongly associated in a large cell-based genome-wide meta-analysis of n=608 human germline DNA samples treated with platinum compounds to determine sensitivities.	('rs9527419', 'Var', (26, 35))	('DNA', 'cellular_component', 'GO:0005574', ('166', '169'))	('rs2191934', 'Var', (15, 24))	('rs3893319', 'Mutation', 'rs3893319', (58, 67))	('rs7210837', 'Var', (47, 56))	('human', 'Species', '9606', (151, 156))	('platinum', 'Chemical', 'MESH:D010984', (191, 199))	('rs2191934', 'Mutation', 'rs2191934', (15, 24))	('rs244903', 'Mutation', 'rs244903', (37, 45))	('rs244903', 'Var', (37, 45))	('associated', 'Reg', (83, 93))	('rs7210837', 'Mutation', 'rs7210837', (47, 56))	('rs9527419', 'Mutation', 'rs9527419', (26, 35))	('rs3893319', 'Var', (58, 67))
183811	27150640	All five were among the top statistical signals, with rs2191934 (meta P= 8.3 x 10-5) and rs9527419 (meta P=5.8 x 10-6) specifically found to (distantly) regulate the expression of GSTT1, ERCC6, and ERCC2, respectively, although the SNPs themselves were not located in any of these genes which is potentially why they were missed by traditional candidate gene analyses.	('ERCC6', 'Gene', (187, 192))	('rs9527419', 'Mutation', 'rs9527419', (89, 98))	('regulate', 'Reg', (153, 161))	('rs9527419', 'Var', (89, 98))	('rs2191934', 'Mutation', 'rs2191934', (54, 63))	('ERCC2', 'Gene', '2068', (198, 203))	('GSTT1', 'Gene', '2952', (180, 185))	('GSTT1', 'Gene', (180, 185))	('ERCC2', 'Gene', (198, 203))	('rs2191934', 'Var', (54, 63))	('ERCC6', 'Gene', '2074', (187, 192))
183812	27150640	Separately, rs7937567 was identified and replicated in a prior cell-based genome-wide study, and is located in an intron of GALNTL4 which was implicated twice in separate cell-based platinum sensitivity studies, the latter of which also implicated rs2136241 (CDCA1 promoter SNP) and rs1649942 (intron of NRG3) both of which we selected.	('rs1649942', 'Var', (283, 292))	('CDCA1', 'Gene', (259, 264))	('NRG3', 'Gene', (304, 308))	('platinum', 'Chemical', 'MESH:D010984', (182, 190))	('GALNTL4', 'Gene', '374378', (124, 131))	('rs7937567', 'Var', (12, 21))	('NRG3', 'Gene', '10718', (304, 308))	('CDCA1', 'Gene', '83540', (259, 264))	('rs7937567', 'Mutation', 'rs7937567', (12, 21))	('GALNTL4', 'Gene', (124, 131))	('rs2136241', 'Var', (248, 257))	('rs1649942', 'Mutation', 'rs1649942', (283, 292))	('rs2136241', 'Mutation', 'rs2136241', (248, 257))
183813	27150640	rs1649942 was also shown to be significantly associated with survival in a clinical cohort of carboplatin-treated ovarian cancer patients.	('rs1649942', 'Mutation', 'rs1649942', (0, 9))	('ovarian cancer', 'Disease', (114, 128))	('patients', 'Species', '9606', (129, 137))	('rs1649942', 'Var', (0, 9))	('associated', 'Reg', (45, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('carboplatin', 'Chemical', 'MESH:D016190', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('ovarian cancer', 'Disease', 'MESH:D010051', (114, 128))
183814	27150640	rs10964552, located in MLLT3, was selected as it was found as a top signal in a prior cell-based genome-wide study and was shown to regulate expression of HIST1H3A, a histone component, with higher HIST1H3A levels associated with platinum resistance.	('higher', 'PosReg', (191, 197))	('rs10964552', 'Var', (0, 10))	('rs10964552', 'Mutation', 'rs10964552', (0, 10))	('HIST1H3A', 'Gene', (198, 206))	('HIST1H3A', 'Gene', '8350', (155, 163))	('platinum', 'Chemical', 'MESH:D010984', (230, 238))	('platinum resistance', 'Disease', (230, 249))	('expression', 'MPA', (141, 151))	('MLLT3', 'Gene', '4300', (23, 28))	('HIST1H3A', 'Gene', '8350', (198, 206))	('MLLT3', 'Gene', (23, 28))	('regulate', 'Reg', (132, 140))	('associated', 'Reg', (214, 224))	('HIST1H3A', 'Gene', (155, 163))
183815	27150640	Finally, rs6870861 was associated with platinum sensitivity in both a large cell-based genome-wide study and a cohort of head and neck cancer patients, and SNPs in linkage disequilibrium were shown to trans-regulate SLC22A5 which is a member of the organic cation transporter family intensively studied in platinum handling.	('platinum', 'Chemical', 'MESH:D010984', (306, 314))	('rs6870861', 'Var', (9, 18))	('neck', 'cellular_component', 'GO:0044326', ('130', '134'))	('neck cancer', 'Disease', 'MESH:D006258', (130, 141))	('trans-regulate', 'PosReg', (201, 215))	('head and neck cancer', 'Phenotype', 'HP:0012288', (121, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('neck cancer', 'Disease', (130, 141))	('platinum', 'Chemical', 'MESH:D010984', (39, 47))	('associated', 'Reg', (23, 33))	('SLC22A5', 'Gene', '6584', (216, 223))	('patients', 'Species', '9606', (142, 150))	('SLC22A5', 'Gene', (216, 223))	('platinum sensitivity', 'Disease', (39, 59))	('rs6870861', 'Mutation', 'rs6870861', (9, 18))
183816	27150640	For rs244903, a SNP in complete linkage disequilibrium in Caucasians (rs244898) was genotyped as the proxy due to design limitations with rs244903.	('rs244898', 'Var', (70, 78))	('rs244898', 'Mutation', 'rs244898', (70, 78))	('rs244903', 'Var', (4, 12))	('rs244903', 'Mutation', 'rs244903', (138, 146))	('rs244903', 'Mutation', 'rs244903', (4, 12))	('rs244903', 'Var', (138, 146))
183817	27150640	One SNP (rs7210837) was unable to be successfully genotyped because of primer failure, leaving 9 SNPs tested in all patients.	('primer failure', 'Disease', (71, 85))	('primer failure', 'Disease', 'MESH:D017093', (71, 85))	('patients', 'Species', '9606', (116, 124))	('rs7210837', 'Mutation', 'rs7210837', (9, 18))	('rs7210837', 'Var', (9, 18))
183829	27150640	Using a recessive genetic model, rs244898 in RARS (odds ratio [OR] 6.8 [95% CI 1.8-28.9], univariate P=0.006) and rs7937567 in GALNTL4 (OR 4.8 [95% CI 1.1-22.6], univariate P=0.04) were associated with likelihood of achieving pT0.	('GALNTL4', 'Gene', '374378', (127, 134))	('rs244898', 'Var', (33, 41))	('rs7937567', 'Var', (114, 123))	('pT0', 'Chemical', 'MESH:D010984', (226, 229))	('RARS', 'Gene', '5917', (45, 49))	('GALNTL4', 'Gene', (127, 134))	('rs7937567', 'Mutation', 'rs7937567', (114, 123))	('rs244898', 'Mutation', 'rs244898', (33, 41))	('RARS', 'Gene', (45, 49))
183833	27150640	For analysis of the secondary endpoint (<pT2), one SNP was significantly associated with down-staging at time of cystectomy (using an additive genetic model): rs10964552 (in MLLT3) with OR 5.0 (95% CI 1.4-20.5), univariate P=0.02.	('rs10964552', 'Mutation', 'rs10964552', (159, 169))	('MLLT3', 'Gene', '4300', (174, 179))	('MLLT3', 'Gene', (174, 179))	('rs10964552', 'Var', (159, 169))	('down-staging', 'Disease', (89, 101))
183834	27150640	Expressed another way, the likelihood of non-response to cisplatin-based neoadjuvant therapy was significantly higher in patients carrying the A allele for rs10964552 (Figure 2).	('rs10964552', 'Var', (156, 166))	('rs10964552', 'Mutation', 'rs10964552', (156, 166))	('response to cisplatin', 'biological_process', 'GO:0072718', ('45', '66'))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('higher', 'PosReg', (111, 117))	('non-response', 'MPA', (41, 53))	('patients', 'Species', '9606', (121, 129))
183838	27150640	For analysis of the primary endpoint in the replication population, regression was performed on pT0 based on whether patients carried the favorable genotypes:TT for rs244898 and GG for rs7937567.	('rs244898', 'Mutation', 'rs244898', (165, 173))	('pT0', 'Chemical', 'MESH:D010984', (96, 99))	('rs244898', 'Var', (165, 173))	('rs7937567', 'Var', (185, 194))	('patients', 'Species', '9606', (117, 125))	('rs7937567', 'Mutation', 'rs7937567', (185, 194))
183839	27150640	Though each SNP had an odds ratio of effect of approximately 5 on pT0 in the discovery set, neither was associated with achievement of pT0 in the replication set (rs244898 replication cohort OR=1.1, P=0.79; rs7937567 replication cohort OR=0.6, P=0.42).	('pT0', 'Chemical', 'MESH:D010984', (66, 69))	('pT0', 'Gene', (66, 69))	('rs7937567', 'Var', (207, 216))	('rs7937567', 'Mutation', 'rs7937567', (207, 216))	('rs244898', 'Mutation', 'rs244898', (163, 171))	('pT0', 'Chemical', 'MESH:D010984', (135, 138))	('rs244898', 'Var', (163, 171))
183840	27150640	The two SNPs combined (rs244898 and rs7937567 in one model) were also not significant.	('rs244898', 'Mutation', 'rs244898', (23, 31))	('rs7937567', 'Var', (36, 45))	('rs7937567', 'Mutation', 'rs7937567', (36, 45))	('rs244898', 'Var', (23, 31))
183841	27150640	The third SNP (rs10964552) which was associated with pathologic down-staging to <pT2 in the discovery set, also failed to replicate (replication cohort OR=0.9, P=0.69).	('rs10964552', 'Mutation', 'rs10964552', (15, 25))	('rs10964552', 'Var', (15, 25))	('down-staging', 'NegReg', (64, 76))
183843	27150640	Genotype frequencies were not significantly different between the discovery and replication cohorts: rs244898 discovery/replication CC=0.39/0.26, CT=0.41/0.54, TT=0.20/0.20; rs7937567 AA=0.40/0.36, AG=0.44/0.50, GG=0.16/0.14; and rs10964552 CC=0.74/0.72, CA=0.26/0.26, AA=0.00/0.02.	('rs10964552', 'Var', (230, 240))	('rs10964552', 'Mutation', 'rs10964552', (230, 240))	('rs244898', 'Mutation', 'rs244898', (101, 109))	('rs7937567', 'Var', (174, 183))	('rs244898', 'Var', (101, 109))	('rs7937567', 'Mutation', 'rs7937567', (174, 183))
183875	25109877	For example, patterns of copy number change varied across tissue types, and subtyping of the tumors based on copy number alterations revealed a significant correlation with tissue (p < 6x10-6, Chi-square test).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('copy', 'Var', (25, 29))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))
183883	25109877	Of the 11 COCA-integrated subtypes, five show simple, near one-to-one relationships with tissue site of origin: C5-KIRC, C6-UCEC, C9-OV, C10-GBM and C13-LAML (Figure 1A).	('AML', 'Disease', 'MESH:D015470', (154, 157))	('C5-KIRC', 'Var', (112, 119))	('COCA', 'Species', '289672', (10, 14))	('AML', 'Disease', (154, 157))	('C9-OV', 'Var', (130, 135))	('C10-GBM', 'Var', (137, 144))
183888	25109877	That difficulty poses an important clinical challenge since histology is used to guide the selection of chemotherapy and to select patients for further mutational analysis (e.g., EGFR mutation and ALK fusion testing in non-squamous NSCLC).	('EGFR', 'Gene', (179, 183))	('patients', 'Species', '9606', (131, 139))	('EGFR', 'molecular_function', 'GO:0005006', ('179', '183'))	('ALK', 'Gene', (197, 200))	('NSCLC', 'Disease', (232, 237))	('ALK', 'Gene', '238', (197, 200))	('NSCLC', 'Disease', 'MESH:D002289', (232, 237))	('EGFR', 'Gene', '1956', (179, 183))	('mutation', 'Var', (184, 192))
183912	25109877	We next identified the major genomic determinants of the COCA subtypes, including somatic mutations and DNA copy number changes.	('COCA', 'Species', '289672', (57, 61))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('mutations', 'Var', (90, 99))	('COCA', 'Disease', (57, 61))
183916	25109877	KEAP1 and STK11 are preferentially mutated in C1-LUAD-enriched tumors, whereas CDKN2A, NOTCH1, MLL2 and NFE2L2, among others, are preferentially mutated in C2-Squamous-like (Figure 2A).	('mutated', 'Var', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('STK11', 'molecular_function', 'GO:0033868', ('10', '15'))	('STK11', 'Gene', (10, 15))	('C1-LUAD-enriched tumors', 'Disease', 'MESH:C565170', (46, 69))	('C2-Squamous-like', 'Disease', (156, 172))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('C1-LUAD-enriched tumors', 'Disease', (46, 69))	('CDKN2A', 'Gene', (79, 85))
183919	25109877	A protein-protein interaction network analysis of mutations associated with the COCA subtypes obtained using a new version of the HotNet algorithm provides an overview of the genomic determinants of the COCA subtypes (Figure S4E).	('mutations', 'Var', (50, 59))	('protein', 'cellular_component', 'GO:0003675', ('2', '9'))	('COCA', 'Disease', (203, 207))	('COCA', 'Species', '289672', (203, 207))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('COCA', 'Species', '289672', (80, 84))
183920	25109877	The C9-OV, C4-BRCA/Basal and C1-LUAD-enriched subtypes showed the most marked genomic instability, as assessed by average number of copy number segments per subtype (Figure 2C), whereas AML and UCEC showed the least.	('AML', 'Disease', 'MESH:D015470', (186, 189))	('C4-BRCA/Basal', 'Var', (11, 24))	('AML', 'Disease', (186, 189))	('genomic instability', 'CPA', (78, 97))	('C9-OV', 'Var', (4, 9))
183921	25109877	Numerous COCA subtype-associated alterations implicated specific regions, arm-level copy number changes (Figure S4A) and/or focal regions of copy number alteration (Figure S4B).	('COCA', 'Species', '289672', (9, 13))	('alterations', 'Var', (33, 44))	('COCA', 'Disease', (9, 13))
183922	25109877	Of note were a number of previously described tissue type-specific and subtype-specific alterations, including Chr7 gain and Chr10 loss in GBM, 3p loss and 5q gain in kidney, 4q and 5q loss in Breast Basal-like cancers and 3p loss and 3q gain in Lung Squamous tumors.	('kidney', 'Disease', (167, 173))	('Chr10', 'Gene', (125, 130))	('loss', 'NegReg', (147, 151))	('loss', 'NegReg', (226, 230))	('4q and', 'Var', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('Basal-like cancers', 'Phenotype', 'HP:0002671', (200, 218))	('loss', 'NegReg', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('loss', 'NegReg', (185, 189))	('Chr7', 'Gene', (111, 115))	('gain in Lung Squamous tumors', 'Disease', 'MESH:D015430', (238, 266))	('gain in Lung Squamous tumors', 'Disease', (238, 266))	('gain', 'PosReg', (159, 163))	('Breast Basal-like cancers', 'Disease', 'MESH:D001943', (193, 218))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('Breast Basal-like cancers', 'Disease', (193, 218))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('gain', 'PosReg', (116, 120))
183929	25109877	Intriguingly, GP7, along with fatty acid oxidation (GP10), tumor suppressing miRNA targets (GP3) and the PTEN/MTOR signaling program, were found to be significantly associated with patient outcome in kidney cancer using a Cox proportional hazards survival analysis (Figure S5D; Table S4F).	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('MTOR', 'Gene', '2475', (110, 114))	('patient', 'Species', '9606', (181, 188))	('PTEN', 'Gene', (105, 109))	('PTEN', 'Gene', '5728', (105, 109))	('associated with', 'Reg', (165, 180))	('GP7', 'Var', (14, 17))	('kidney cancer', 'Disease', 'MESH:D007680', (200, 213))	('kidney cancer', 'Phenotype', 'HP:0009726', (200, 213))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('fatty acid', 'Chemical', 'MESH:D005227', (30, 40))	('kidney cancer', 'Disease', (200, 213))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('30', '50'))	('MTOR', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
183943	25109877	The identified discriminating features of the COCA subtypes confirm several expectations: 1) C3-BRCA/Luminal was defined by protein and gene signatures for ER and GATA3 determined by the Elastic Net model as well as by PIK3CA-related signaling revealed by copy number variation-based and mutation-based GSEA, 2) C5-KIRC was defined by multiple features of hypoxia found by mutation- and mRNA-Seq-based GSEA as well as predictive Elastic Net features, and 3) C7-COAD/READ was in part defined by APC mutations.	('C7-COAD/READ', 'Disease', 'MESH:C566443', (458, 470))	('mutations', 'Var', (498, 507))	('APC', 'cellular_component', 'GO:0005680', ('494', '497'))	('C7-COAD/READ', 'Disease', (458, 470))	('APC', 'Disease', 'MESH:D011125', (494, 497))	('APC', 'Disease', (494, 497))	('hypoxia', 'Disease', 'MESH:D000860', (356, 363))	('mutation-', 'Var', (373, 382))	('hypoxia', 'Disease', (356, 363))	('COCA', 'Species', '289672', (46, 50))	('signaling', 'biological_process', 'GO:0023052', ('234', '243'))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))
183947	25109877	TP53 mutation is frequent (72%), followed by a dramatic drop-off in mutation frequency to MLL2 (20%), PIK3CA (19%), CDKN2A (18%), NOTCH1 (16%), NFE2L2 (10%) and MALAT1 (6%), the only other genes mutated at >=10% frequency (Table S2A).	('MLL2', 'Gene', (90, 94))	('mutation frequency', 'MPA', (68, 86))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('PIK3CA', 'Gene', (102, 108))	('NOTCH1', 'Gene', (130, 136))	('CDKN2A', 'Gene', (116, 122))	('MALAT1', 'Gene', (161, 167))	('NFE2L2', 'Gene', (144, 150))	('mutation', 'Var', (5, 13))	('drop-off', 'NegReg', (56, 64))
183948	25109877	Of potential interest in the C2-Squamous-like group, tumors without TP53 mutations show a higher density of PIK3CA mutations (Figure 1), consistent with recent evidence linking PI3K activation and wild-type TP53 inactivation in HNSC.	('mutations', 'Var', (115, 124))	('TP53', 'Gene', '7157', (207, 211))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TP53', 'Gene', (207, 211))	('PIK3CA', 'Gene', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('PI3K', 'molecular_function', 'GO:0016303', ('177', '181'))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('tumors', 'Disease', (53, 59))	('mutations', 'Var', (73, 82))
183949	25109877	Putative driver analysis identified several genes (PIK3CA, MLL3 and KEAP1) frequently mutated in the C2-Squamous-like group but also in other COCA subtypes (Figure 4B).	('mutated', 'Var', (86, 93))	('KEAP1', 'Gene', (68, 73))	('C2-Squamous-like', 'Disease', (101, 117))	('MLL3', 'Gene', (59, 63))	('PIK3CA', 'Gene', (51, 57))	('COCA', 'Species', '289672', (142, 146))	('COCA', 'Disease', (142, 146))
183950	25109877	Putative driver analysis also revealed a number of genes with higher mutation frequencies in the C2-Squamous-like subtype than in any other subtype: TP53, SYNE1, MLL2, CDKN2A, NOTCH1, NFE2L2 and EP300, among others (Figure 4C; Figure S7A).	('MLL2', 'Gene', (162, 166))	('C2-Squamous-like subtype', 'Disease', (97, 121))	('TP53', 'Gene', '7157', (149, 153))	('mutation', 'Var', (69, 77))	('higher', 'PosReg', (62, 68))	('CDKN2A', 'Gene', (168, 174))	('TP53', 'Gene', (149, 153))	('EP300', 'Var', (195, 200))	('NFE2L2', 'Gene', (184, 190))	('NOTCH1', 'Gene', (176, 182))
183954	25109877	The C9-OV (94%), C4-BRCA/Basal (80%) and C2-Squamous-like (72%) subtypes have the highest frequencies of TP53 mutation.	('TP53', 'Gene', '7157', (105, 109))	('mutation', 'Var', (110, 118))	('TP53', 'Gene', (105, 109))
183957	25109877	All six of those subtypes show TP53 mutation and large-scale copy number changes.	('TP53', 'Gene', '7157', (31, 35))	('copy', 'MPA', (61, 65))	('TP53', 'Gene', (31, 35))	('mutation', 'Var', (36, 44))
183961	25109877	In addition, both subtypes show up-regulation of the proliferation/DNA synthesis gene program (GP1), as well as signatures of TP53 mutation, MYC targets/TERT, VEGF signaling and activation of the PD1 and CTLA4 immune co-stimulatory pathways (Table S4A, Figure 3).	('CTLA4 immune co-stimulatory pathways', 'Pathway', (204, 240))	('mutation', 'Var', (131, 139))	('TP53', 'Gene', (126, 130))	('regulation', 'biological_process', 'GO:0065007', ('35', '45'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('67', '80'))	('VEGF signaling', 'biological_process', 'GO:0038084', ('159', '173'))	('activation', 'PosReg', (178, 188))	('up-regulation', 'PosReg', (32, 45))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('GP1', 'Gene', (95, 98))	('TP53', 'Gene', '7157', (126, 130))	('MYC targets/TERT', 'MPA', (141, 157))
183967	25109877	High TP53 mutation rates characterize several tumor types including those represented by the COCA subtypes C4-BRCA/Basal, C9-OV, and C2-Squamous-like (Table S2A).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('C9-OV', 'Disease', (122, 127))	('tumor', 'Disease', (46, 51))	('mutation', 'Var', (10, 18))	('C4-BRCA/Basal', 'Disease', (107, 120))	('TP53', 'Gene', '7157', (5, 9))	('COCA', 'Species', '289672', (93, 97))	('C2-Squamous-like', 'Disease', (133, 149))	('TP53', 'Gene', (5, 9))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
183971	25109877	The apparent higher TP53-pathway activity in C2-Squamous-like tumors may be related to the expression of isoforms of related family members TP63 and/or TP73 (Figure 5B), which may compensate for TP53 mutation in the C2-Squamous-like tumors as revealed by PARADIGM-Shift analysis (Figure 5C), and as supported by functional experimental data in HNSC lines and tumors.	('C2-Squamous-like tumors', 'Disease', 'OMIM:217000', (216, 239))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('activity', 'MPA', (33, 41))	('TP53', 'Gene', (195, 199))	('TP53', 'Gene', (20, 24))	('TP73', 'Var', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('higher', 'PosReg', (13, 19))	('C2-Squamous-like tumors', 'Disease', (216, 239))	('mutation', 'Var', (200, 208))	('Squamous-like tumors', 'Phenotype', 'HP:0002860', (48, 68))	('C2-Squamous-like tumors', 'Disease', 'OMIM:217000', (45, 68))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (359, 365))	('HNSC lines and tumors', 'Disease', 'MESH:D009369', (344, 365))	('TP63', 'Var', (140, 144))	('TP53', 'Gene', '7157', (195, 199))	('TP53', 'Gene', '7157', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('RA', 'Disease', 'MESH:D001172', (257, 259))	('C2-Squamous-like tumors', 'Disease', (45, 68))	('Squamous-like tumors', 'Phenotype', 'HP:0002860', (219, 239))
183972	25109877	Third, the transcriptional targets of TP53 shared with TP63/73 appear to be more highly expressed in the C2-Squamous-like subtype than in the C9-OV or C4-BRCA/Basal subtype (Figure S7D).	('highly expressed', 'PosReg', (81, 97))	('TP53', 'Gene', (38, 42))	('C2-Squamous-like', 'Disease', (105, 121))	('TP63/73', 'Var', (55, 62))	('TP53', 'Gene', '7157', (38, 42))
183977	25109877	These studies show the potential for p63/73 compensatory function for mutated or suppressed p53 in HNSCC and breast cancer, which has potential implications for targeted and standard therapy across these malignancies.	('malignancies', 'Disease', (204, 216))	('suppressed', 'NegReg', (81, 91))	('HNSCC', 'Disease', 'MESH:D000077195', (99, 104))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))	('p53', 'Gene', (92, 95))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('HNSCC', 'Disease', (99, 104))	('mutated', 'Var', (70, 77))	('p63/73', 'Var', (37, 43))
183986	25109877	There are significant differences in copy number (Figure S4A), protein expression (Figure 6B), mutations (Figure 6C), gene programs (Figure 6D) and PARADIGM pathway networks (Figure 6E; Figure S8A).	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('copy', 'Var', (37, 41))	('gene programs', 'CPA', (118, 131))	('protein', 'Protein', (63, 70))	('RA', 'Disease', 'MESH:D001172', (150, 152))	('mutations', 'Var', (95, 104))
183987	25109877	There is also a significant difference in 3p arm-level events; the C2-Squamous-like subset shows the characteristic squamous-like pattern of 3p loss, whereas the C8-BLCA subtype does not (Figure 2B).	('squamous-like pattern', 'Phenotype', 'HP:0002860', (116, 137))	('C8-BLCA', 'Chemical', '-', (162, 169))	('loss', 'NegReg', (144, 148))	('C2-Squamous-like', 'Var', (67, 83))
183989	25109877	Conversely, markers of epithelial-to-mesenchymal transition (EMT) such as low E-cadherin, high fibronectin, and high N-cadherin expression are apparent in the C2-Squamous-like bladder cancers (Figure 6B).	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('C2-Squamous-like bladder cancers', 'Disease', (159, 191))	('low', 'NegReg', (74, 77))	('C2-Squamous-like bladder cancers', 'Disease', 'OMIM:217000', (159, 191))	('high', 'Var', (112, 116))	('high', 'Var', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('bladder cancer', 'Phenotype', 'HP:0009725', (176, 190))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))	('epithelial-to-mesenchymal transition', 'CPA', (23, 59))	('bladder cancers', 'Phenotype', 'HP:0009725', (176, 191))	('N-cadherin', 'Protein', (117, 127))	('EMT', 'biological_process', 'GO:0001837', ('61', '64'))	('cadherin', 'molecular_function', 'GO:0008014', ('119', '127'))	('E-cadherin', 'Protein', (78, 88))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('23', '59'))	('expression', 'MPA', (128, 138))
183994	25109877	With respect to its therapeutic relevance, this proportion of potentially misclassified tumors is comparable to the rate of EGFR mutations in unselected non-small cell lung cancers and ERBB2 amplifications among all breast cancers.	('small cell lung cancers', 'Phenotype', 'HP:0030357', (157, 180))	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('EGFR', 'Gene', '1956', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('breast cancers', 'Disease', 'MESH:D001943', (216, 230))	('breast cancers', 'Disease', (216, 230))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (153, 180))	('cell lung cancers', 'Disease', 'MESH:D008175', (163, 180))	('lung cancers', 'Phenotype', 'HP:0100526', (168, 180))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('cell lung cancers', 'Disease', (163, 180))	('breast cancers', 'Phenotype', 'HP:0003002', (216, 230))	('mutations', 'Var', (129, 138))	('ERBB2', 'Gene', (185, 190))	('EGFR', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))
184003	25109877	oral cavity, lungs, and bladder); and malignancies from this cellular subtype possess a characteristic set of dysregulated genomic features, including SOX2 and DeltaNp63 high expression (by 3q26-29 amplification) with TP53 mutation.	('malignancies', 'Disease', 'MESH:D009369', (38, 50))	('TP53', 'Gene', '7157', (218, 222))	('mutation', 'Var', (223, 231))	('malignancies', 'Disease', (38, 50))	('TP53', 'Gene', (218, 222))
184006	25109877	While all three COCA subtypes exhibit comparably high TP53 mutation frequencies and expression of the GP17_Basal signaling gene program, the C2-Squamous-like cancers are distinguished from all others by their significantly higher TP63 and TP73 expression, both short (DeltaNp63, DeltaNp73) and long (TAp63, TAp73) isoforms, which may partially compensate TP53 mutation in this COCA subtype.	('C2-Squamous-like cancers', 'Disease', 'OMIM:217000', (141, 165))	('COCA', 'Species', '289672', (16, 20))	('COCA', 'Species', '289672', (377, 381))	('TP53', 'Gene', '7157', (355, 359))	('C2-Squamous-like cancers', 'Disease', (141, 165))	('TP53', 'Gene', (355, 359))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('TP73', 'Protein', (239, 243))	('Basal signaling', 'biological_process', 'GO:0038034', ('107', '122'))	('TP53', 'Gene', '7157', (54, 58))	('TP63', 'Protein', (230, 234))	('DeltaNp73', 'Var', (279, 288))	('mutation', 'Var', (59, 67))	('expression', 'MPA', (244, 254))	('higher', 'PosReg', (223, 229))	('TP53', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
184037	33604385	Kaplan-Meier survival analysis reveals that patients with a high expression of VCAN have poor prognosis than those patients with a low expression of VCAN.	('patients', 'Species', '9606', (115, 123))	('VCAN', 'Protein', (79, 83))	('patient', 'Species', '9606', (44, 51))	('patients', 'Species', '9606', (44, 52))	('high expression', 'Var', (60, 75))	('patient', 'Species', '9606', (115, 122))
184127	32784716	Life expectancy is increased in 40% of NAC-treated patients, which can be attributed to the reduction of tumor size prior to surgery, the treatment of micrometastases and the prevention of metastasis formation.	('NAC', 'cellular_component', 'GO:0005854', ('39', '42'))	('metastases', 'Disease', (156, 166))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('reduction', 'NegReg', (92, 101))	('formation', 'biological_process', 'GO:0009058', ('200', '209'))	('NAC-treated', 'Var', (39, 50))	('increased', 'PosReg', (19, 28))	('Life expectancy', 'CPA', (0, 15))	('metastases', 'Disease', 'MESH:D009362', (156, 166))	('patients', 'Species', '9606', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('NAC', 'Chemical', '-', (39, 42))	('men', 'Species', '9606', (143, 146))	('tumor', 'Disease', (105, 110))	('metastasis', 'CPA', (189, 199))
184133	32784716	Erdafitinib, an inhibitor of the tyrosine-kinase activity of fibroblast growth factor receptor (FGFR), is approved for patients with FGFR3 or FGFR2 alterations.	('Erdafitinib', 'Chemical', 'MESH:C000604580', (0, 11))	('FGFR3', 'Gene', (133, 138))	('FGFR', 'molecular_function', 'GO:0005007', ('142', '146'))	('FGFR2', 'Gene', (142, 147))	('alterations', 'Var', (148, 159))	('FGFR2', 'Gene', '2263', (142, 147))	('patients', 'Species', '9606', (119, 127))	('FGFR', 'molecular_function', 'GO:0005007', ('133', '137'))	('FGFR3', 'Gene', '2261', (133, 138))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('61', '85'))	('kinase activity', 'molecular_function', 'GO:0016301', ('42', '57'))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))
184154	32784716	Several clinical trials have shown that NAC improves overall survival in only 30-40% of patients.	('NAC', 'cellular_component', 'GO:0005854', ('40', '43'))	('improves', 'PosReg', (44, 52))	('patients', 'Species', '9606', (88, 96))	('overall survival', 'MPA', (53, 69))	('NAC', 'Var', (40, 43))	('NAC', 'Chemical', '-', (40, 43))
184181	32784716	FGFR3-activating mutations are present in almost all the Ta tumors but absent in CIS and less frequent in high-grade T1 NMIBC (30%) and MIBC (10%).	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('MIBC', 'Chemical', '-', (136, 140))	('NMIBC', 'Chemical', '-', (120, 125))	('FGFR3', 'Gene', (0, 5))	('Ta tumors', 'Disease', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MIBC', 'Disease', (136, 140))	('absent', 'NegReg', (71, 77))	('MIBC', 'Chemical', '-', (121, 125))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('Ta tumors', 'Disease', 'MESH:D009369', (57, 66))	('mutations', 'Var', (17, 26))	('FGFR3', 'Gene', '2261', (0, 5))
184183	32784716	Activating FGFR3 mutations are associated with good prognosis and low recurrence rate.	('Activating', 'PosReg', (0, 10))	('FGFR3', 'Gene', '2261', (11, 16))	('FGFR3', 'Gene', (11, 16))	('FGFR', 'molecular_function', 'GO:0005007', ('11', '15'))	('mutations', 'Var', (17, 26))
184184	32784716	Mutations in the telomerase reverse transcriptase (TERT) gene promoter, an early genomic alteration associated with predisposition to develop BLCa, are present in the majority of tumors carrying FGFR3 mutations.	('mutations', 'Var', (201, 210))	('TERT', 'Gene', (51, 55))	('FGFR3', 'Gene', (195, 200))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('BLCa', 'Phenotype', 'HP:0009725', (142, 146))	('transcriptase', 'molecular_function', 'GO:0003899', ('36', '49'))	('transcriptase', 'molecular_function', 'GO:0003968', ('36', '49'))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('Mutations', 'Var', (0, 9))	('TERT', 'Gene', '7015', (51, 55))	('FGFR', 'molecular_function', 'GO:0005007', ('195', '199'))	('transcriptase', 'molecular_function', 'GO:0034062', ('36', '49'))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('FGFR3', 'Gene', '2261', (195, 200))
184185	32784716	TERT re-activation may prevent senescence in FGFR3 mutant hyperproliferative tumors and protect genomic integrity.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('hyperproliferative tumors', 'Disease', 'MESH:D009369', (58, 83))	('hyperproliferative tumors', 'Disease', (58, 83))	('genomic integrity', 'CPA', (96, 113))	('prevent', 'NegReg', (23, 30))	('FGFR3', 'Gene', '2261', (45, 50))	('senescence', 'MPA', (31, 41))	('mutant', 'Var', (51, 57))	('TERT', 'Gene', (0, 4))	('senescence', 'biological_process', 'GO:0010149', ('31', '41'))	('TERT', 'Gene', '7015', (0, 4))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('FGFR3', 'Gene', (45, 50))
184189	32784716	Conversely, concerning the PI3K/Akt/mTOR pathway, activating mutations in PI3KCA are enriched in FGFR3 mutant tumors and present in 25% NMIBC and in 20% MIBC.	('MIBC', 'Chemical', '-', (153, 157))	('Akt', 'Gene', '207', (32, 35))	('mTOR', 'Gene', '2475', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mutant', 'Var', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('PI3KCA', 'Gene', (74, 80))	('NMIBC', 'Chemical', '-', (136, 141))	('mutations', 'Var', (61, 70))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('FGFR3', 'Gene', (97, 102))	('PI3K', 'molecular_function', 'GO:0016303', ('27', '31'))	('MIBC', 'Chemical', '-', (137, 141))	('mTOR', 'Gene', (36, 40))	('Akt', 'Gene', (32, 35))	('FGFR3', 'Gene', '2261', (97, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('97', '101'))	('activating', 'PosReg', (50, 60))
184190	32784716	However, PIK3CA mutations are associated with low risk of progression.	('PIK3CA', 'Gene', '5290', (9, 15))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (9, 15))
184193	32784716	Moreover, truncating mutations in the STAG2 gene, which encodes a component of the cohesin complex, are highly frequent in low-grade Ta tumors and associated with low risk of progression and recurrence.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('cohesin complex', 'cellular_component', 'GO:0008278', ('83', '98'))	('truncating mutations', 'Var', (10, 30))	('Ta tumors', 'Disease', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('STAG2', 'Gene', '10735', (38, 43))	('Ta tumors', 'Disease', 'MESH:D009369', (133, 142))	('frequent', 'Reg', (111, 119))	('STAG2', 'Gene', (38, 43))
184194	32784716	The most common copy number alteration (CNA) in Ta tumors is loss of heterozygosity (LOH) of 9q and 9p.	('loss of heterozygosity', 'Var', (61, 83))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Ta tumors', 'Disease', 'MESH:D009369', (48, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('Ta tumors', 'Disease', (48, 57))
184195	32784716	LOH 9 leads to deletions of several tumor suppressors genes, such as CDKN2A (9q), TSC1 (9p) and PTCH1 (9p).	('CDKN2A', 'Gene', '1029', (69, 75))	('TSC1', 'Gene', '7248', (82, 86))	('leads to', 'Reg', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('PTCH1', 'Gene', (96, 101))	('TSC1', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('deletions', 'Var', (15, 24))	('CDKN2A', 'Gene', (69, 75))	('tumor', 'Disease', (36, 41))	('PTCH1', 'Gene', '5727', (96, 101))
184198	32784716	In BLCa, CDKN2A deletion promotes proliferation and is mutually exclusive with TP53 and RB1 loss.	('proliferation', 'CPA', (34, 47))	('BLCa', 'Phenotype', 'HP:0009725', (3, 7))	('CDKN2A', 'Gene', '1029', (9, 15))	('promotes', 'PosReg', (25, 33))	('deletion', 'Var', (16, 24))	('CDKN2A', 'Gene', (9, 15))
184202	32784716	They share some characteristic mutations, CNA and chromosomal abnormalities resulting from defects in DNA replication/repair machinery genes and mutations in tumor suppressors genes.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('defects', 'NegReg', (91, 98))	('mutations', 'Var', (145, 154))	('DNA replication/repair machinery genes', 'Gene', (102, 140))	('DNA replication', 'biological_process', 'GO:0006260', ('102', '117'))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('chromosomal abnormalities', 'Disease', (50, 75))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (50, 75))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
184203	32784716	Tumors with high genomic instability are associated with advanced stage and poor survival.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('advanced stage', 'CPA', (57, 71))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('high genomic instability', 'Var', (12, 36))
184205	32784716	Mutations in tumor suppressor genes such as TP53, RB1 and PTEN are frequent in MIBC.	('tumor', 'Disease', (13, 18))	('PTEN', 'Gene', (58, 62))	('PTEN', 'Gene', '5728', (58, 62))	('frequent', 'Reg', (67, 75))	('MIBC', 'Chemical', '-', (79, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('13', '29'))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('RB1', 'Gene', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('TP53', 'Gene', (44, 48))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('13', '29'))	('MIBC', 'Disease', (79, 83))
184206	32784716	TP53 mutations are thought to have a central role in the non-papillary pathway and they are present in 50% of MIBC and 10-20% of high-grade T1 tumors.	('MIBC', 'Disease', (110, 114))	('TP53', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('non-papillary pathway', 'Pathway', (57, 78))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('mutations', 'Var', (5, 14))	('MIBC', 'Chemical', '-', (110, 114))	('present', 'Reg', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
184209	32784716	The level of Rb1 is known to be inversely correlated to p16 (CDKN2A) level, and alterations in the Rb1/p16 tumor suppressor checkpoint pathway are associated with MIBC and increased risk of progression.	('Rb1', 'Gene', '5925', (13, 16))	('associated with', 'Reg', (147, 162))	('tumor', 'Disease', (107, 112))	('CDKN2A', 'Gene', '1029', (61, 67))	('tumor suppressor', 'biological_process', 'GO:0051726', ('107', '123'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('Rb1', 'Gene', '5925', (99, 102))	('Rb1', 'Gene', (13, 16))	('alterations', 'Var', (80, 91))	('MIBC', 'Disease', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Rb1', 'Gene', (99, 102))	('p16', 'Gene', (103, 106))	('p16', 'Gene', (56, 59))	('MIBC', 'Chemical', '-', (163, 167))	('p16', 'Gene', '1029', (103, 106))	('p16', 'Gene', '1029', (56, 59))	('CDKN2A', 'Gene', (61, 67))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('107', '123'))
184213	32784716	Defects in DNA damage response genes are present in around 30% of MIBC and high-grade NMIBC, whereas they are absent in most of low-grade NMIBCs.	('MIBC', 'Disease', (66, 70))	('MIBC', 'Chemical', '-', (139, 143))	('MIBCs', 'Chemical', '-', (139, 144))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('Defects', 'Var', (0, 7))	('DNA damage response genes', 'Gene', (11, 36))	('NMIBC', 'Chemical', '-', (138, 143))	('MIBC', 'Chemical', '-', (66, 70))	('NMIBC', 'Chemical', '-', (86, 91))	('DNA damage response', 'biological_process', 'GO:0006974', ('11', '30'))	('MIBC', 'Chemical', '-', (87, 91))
184216	32784716	Interestingly, mutations in NER pathway genes can occur in different types of cancer, but recurrent mutations are rare:ERCC2 in BLCa is an exception.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('ERCC2', 'Gene', (119, 124))	('mutations', 'Var', (15, 24))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('BLCa', 'Phenotype', 'HP:0009725', (128, 132))	('NER', 'biological_process', 'GO:0006289', ('28', '31'))	('ERCC2', 'Gene', '2068', (119, 124))	('BLCa', 'Disease', (128, 132))	('NER pathway genes', 'Gene', (28, 45))	('occur', 'Reg', (50, 55))
184223	32784716	HER2 amplification is expressed higher in lymph node metastases than in primary tumors and both HER2 and EGFR overexpression are associated with a higher risk of recurrence and progression to invasive disease.	('associated', 'Reg', (129, 139))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('amplification', 'Var', (5, 18))	('tumors', 'Disease', (80, 86))	('EGFR', 'Gene', (105, 109))	('HER2', 'Gene', '2064', (0, 4))	('recurrence', 'CPA', (162, 172))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('HER2', 'Gene', (96, 100))	('invasive disease', 'Disease', (192, 208))	('EGFR', 'Gene', '1956', (105, 109))	('HER2', 'Gene', (0, 4))	('metastases', 'Disease', 'MESH:D009362', (53, 63))	('metastases', 'Disease', (53, 63))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('invasive disease', 'Disease', 'MESH:D009361', (192, 208))	('HER2', 'Gene', '2064', (96, 100))	('overexpression', 'PosReg', (110, 124))
184227	32784716	MIBC frequently harbor mutations in PTEN, whereas Ta and T1 tumors retain WT PTEN.	('harbor', 'Reg', (16, 22))	('tumors retain WT PTEN', 'Disease', (60, 81))	('PTEN', 'Gene', (36, 40))	('MIBC', 'Chemical', '-', (0, 4))	('tumors retain WT PTEN', 'Disease', 'MESH:D006223', (60, 81))	('mutations', 'Var', (23, 32))	('PTEN', 'Gene', (77, 81))	('PTEN', 'Gene', '5728', (36, 40))	('PTEN', 'Gene', '5728', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
184228	32784716	Loss of PTEN is associated with aggressive MIBC and metastasis.	('metastasis', 'CPA', (52, 62))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('aggressive MIBC', 'Disease', 'MESH:D001523', (32, 47))	('associated', 'Reg', (16, 26))	('Loss', 'Var', (0, 4))	('aggressive MIBC', 'Disease', (32, 47))
184234	32784716	Mutations affecting DNA replication/repair machinery genes and tumor suppressors genes are shared among high-grade papillary tumors (Ta/T1) and MIBC developing via the non-papillary pathway.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('papillary tumors', 'Disease', (115, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('papillary tumors', 'Disease', 'MESH:D002291', (115, 131))	('MIBC', 'Chemical', '-', (144, 148))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', (125, 130))	('DNA replication', 'biological_process', 'GO:0006260', ('20', '35'))	('DNA replication/repair machinery genes', 'Gene', (20, 58))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('papillary tumors', 'Phenotype', 'HP:0007482', (115, 131))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))
184235	32784716	These alterations lead to the acquisition of the invasion potential in high-grade papillary tumors and can be the intersection between the two distinct carcinogenic pathways.	('alterations', 'Var', (6, 17))	('papillary tumors', 'Phenotype', 'HP:0007482', (82, 98))	('invasion potential', 'CPA', (49, 67))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('papillary tumors', 'Disease', (82, 98))	('papillary tumors', 'Disease', 'MESH:D002291', (82, 98))	('carcinogenic', 'Disease', 'MESH:D063646', (152, 164))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('carcinogenic', 'Disease', (152, 164))
184240	32784716	Class I, with luminal-like features, associated with a good prognosis, is characterized by elevated expressions of early cell cycle regulators (CCDN1) and FGFR3 mutations.	('elevated', 'PosReg', (91, 99))	('luminal', 'Chemical', 'MESH:D010634', (14, 21))	('FGFR3', 'Gene', '2261', (155, 160))	('cell cycle', 'biological_process', 'GO:0007049', ('121', '131'))	('CCDN1', 'Gene', (144, 149))	('expressions', 'MPA', (100, 111))	('FGFR', 'molecular_function', 'GO:0005007', ('155', '159'))	('mutations', 'Var', (161, 170))	('FGFR3', 'Gene', (155, 160))
184244	32784716	Class III, with basal-like features, associated with shorter overall survival, represents a dormant tumor state of NMIBC which shifted towards a basal phenotype with FGFR3 mutations.	('mutations', 'Var', (172, 181))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('166', '170'))	('tumor', 'Disease', (100, 105))	('FGFR3', 'Gene', '2261', (166, 171))	('FGFR3', 'Gene', (166, 171))	('NMIBC', 'Chemical', '-', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
184249	32784716	Therefore, given the fact that Class III tumors have a basal phenotype and FGFR3 mutations, it is not correct to associate the papillary pathway exclusively to luminal-like tumors.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('FGFR3', 'Gene', (75, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('luminal', 'Chemical', 'MESH:D010634', (160, 167))	('mutations', 'Var', (81, 90))	('tumors', 'Disease', (173, 179))	('FGFR3', 'Gene', '2261', (75, 80))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))
184262	32784716	In 25% of Ba/Sq tumors, RB1 was mutated and TP53 and RB1 mutations co-occurred in 14% of Ba/Sq tumors, suggesting an interaction between the two cell cycle regulators.	('cell cycle', 'biological_process', 'GO:0007049', ('145', '155'))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('RB1', 'Gene', (24, 27))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('interaction', 'Interaction', (117, 128))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('mutated', 'Var', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('mutations', 'Var', (57, 66))	('RB1', 'Gene', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (16, 22))	('Ba/Sq', 'Disease', (10, 15))	('tumors', 'Disease', (95, 101))	('TP53', 'Gene', (44, 48))
184264	32784716	Therefore, given the prevalence of TP53 and RB1 mutations, Ba/Sq tumors originate from the non-papillary pathway, however other mutations sustain the invasion potential (Figure 1).	('invasion potential', 'CPA', (150, 168))	('TP53', 'Gene', (35, 39))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('RB1', 'Gene', (44, 47))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
184281	32784716	In BLCa, it was shown that DeltaNp63alpha induces the expression of miR205, which inhibits EMT.	('expression', 'MPA', (54, 64))	('BLCa', 'Phenotype', 'HP:0009725', (3, 7))	('miR205', 'Gene', '406988', (68, 74))	('EMT', 'CPA', (91, 94))	('induces', 'Reg', (42, 49))	('EMT', 'biological_process', 'GO:0001837', ('91', '94'))	('miR205', 'Gene', (68, 74))	('inhibits', 'NegReg', (82, 90))	('DeltaNp63alpha', 'Chemical', '-', (27, 41))	('DeltaNp63alpha', 'Var', (27, 41))
184283	32784716	However, high levels of DeltaNp63alpha were associated with a lethal group of MIBC.	('associated', 'Reg', (44, 54))	('MIBC', 'Chemical', '-', (78, 82))	('MIBC', 'Disease', (78, 82))	('DeltaNp63alpha', 'Chemical', '-', (24, 38))	('DeltaNp63alpha', 'Var', (24, 38))
184285	32784716	The role of DeltaNp63alpha in MIBC is not clear but it is probably involved in cell proliferation rather than in invasion.	('involved', 'Reg', (67, 75))	('DeltaNp63alpha', 'Chemical', '-', (12, 26))	('DeltaNp63alpha', 'Var', (12, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('79', '97'))	('MIBC', 'Chemical', '-', (30, 34))	('MIBC', 'Disease', (30, 34))
184288	32784716	Luminal-like tumors (LumP, LumU and LumNS) presented a papillary morphology enriched in luminal markers such as low molecular weight KRT20 and uroplakins such as UPK1A and UPK2, normally expressed in terminally urothelial cells.	('UPK1A', 'Gene', (162, 167))	('papillary morphology', 'Phenotype', 'HP:0007482', (55, 75))	('KRT20', 'Gene', (133, 138))	('UPK1A', 'Gene', '11045', (162, 167))	('tumors', 'Disease', (13, 19))	('Luminal', 'Chemical', 'MESH:D010634', (0, 7))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('UPK2', 'Gene', '7379', (172, 176))	('low molecular weight', 'Var', (112, 132))	('KRT20', 'Gene', '54474', (133, 138))	('UPK2', 'Gene', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('luminal', 'Chemical', 'MESH:D010634', (88, 95))
184294	32784716	LumP tumors were strongly associated with high FGFR3 activity caused by gene fusion, mutation or amplification.	('amplification', 'Var', (97, 110))	('FGFR3', 'Gene', (47, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mutation', 'Var', (85, 93))	('gene fusion', 'Var', (72, 83))	('activity', 'MPA', (53, 61))	('FGFR3', 'Gene', '2261', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('LumP tumors', 'Disease', (0, 11))	('LumP tumors', 'Disease', 'MESH:C536531', (0, 11))
184295	32784716	FGFR3-activating mutations and overexpression are predominantly associated with low-grade Ta tumors developing via the papillary pathway, which have a favorable outcome in most cases.	('Ta tumors', 'Disease', (90, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('Ta tumors', 'Disease', 'MESH:D009369', (90, 99))	('FGFR3', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('mutations', 'Var', (17, 26))	('overexpression', 'PosReg', (31, 45))	('FGFR3', 'Gene', '2261', (0, 5))
184300	32784716	Given the elevated expression of FGFR3 and the homozygous CDKN2A deletions in 33% of LumP tumors, we can assume that LumP tumors represent the fraction of luminal FGFR3-mutant tumors that originated from Class I tumors and progressed through the papillary pathway (Figure 1).	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('FGFR', 'molecular_function', 'GO:0005007', ('163', '167'))	('luminal', 'Chemical', 'MESH:D010634', (155, 162))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('CDKN2A', 'Gene', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('papillary pathway', 'Pathway', (246, 263))	('expression', 'MPA', (19, 29))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('deletions', 'Var', (65, 74))	('elevated', 'PosReg', (10, 18))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('FGFR3', 'Gene', (163, 168))	('CDKN2A', 'Gene', '1029', (58, 64))	('tumors', 'Disease', (212, 218))	('FGFR3', 'Gene', '2261', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('LumP tumors', 'Disease', (117, 128))	('FGFR3', 'Gene', (33, 38))	('LumP tumors', 'Disease', 'MESH:C536531', (117, 128))	('tumors', 'Disease', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', (90, 96))	('FGFR3', 'Gene', '2261', (33, 38))	('LumP tumors', 'Disease', (85, 96))	('LumP tumors', 'Disease', 'MESH:C536531', (85, 96))
184305	32784716	In the analysis conducted by The Cancer Genome Atlas (TCGA) Consortium, it was shown that MDM2 amplification or overexpression was predicted to inactivate p53 in 76% of MIBC.	('Cancer', 'Disease', 'MESH:D009369', (33, 39))	('Cancer', 'Phenotype', 'HP:0002664', (33, 39))	('p53', 'Gene', (155, 158))	('CGA', 'Gene', (55, 58))	('MIBC', 'Disease', (169, 173))	('overexpression', 'PosReg', (112, 126))	('amplification', 'Var', (95, 108))	('inactivate', 'NegReg', (144, 154))	('MDM2', 'Gene', '4193', (90, 94))	('CGA', 'Gene', '1113', (55, 58))	('Cancer', 'Disease', (33, 39))	('MDM2', 'Gene', (90, 94))	('MIBC', 'Chemical', '-', (169, 173))
184308	32784716	It is the most genomic unstable subtype among luminal subtypes and harbors the highest load of apoliprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC)-induced mutations.	('APOBEC', 'cellular_component', 'GO:0030895', ('158', '164'))	('apoliprotein B mRNA-editing', 'Protein', (95, 122))	('luminal', 'Chemical', 'MESH:D010634', (46, 53))	('mutations', 'Var', (174, 183))	('mRNA-editing', 'biological_process', 'GO:0016556', ('110', '122'))
184309	32784716	LumU had higher cell cycle activity than other subtypes and it was enriched in ERCC2 and TP53 mutations.	('TP53', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('ERCC2', 'Gene', (79, 84))	('ERCC2', 'Gene', '2068', (79, 84))	('cell cycle', 'biological_process', 'GO:0007049', ('16', '26'))	('cell cycle activity', 'CPA', (16, 35))	('higher', 'PosReg', (9, 15))
184310	32784716	The majority of NMIBC (85%) with mutated p53 are of high grade, indicating that p53 inactivation occurred in the majority of NMIBC that have the potential to invade.	('NMIBC', 'Chemical', '-', (16, 21))	('p53', 'Gene', (80, 83))	('mutated', 'Var', (33, 40))	('inactivation', 'NegReg', (84, 96))	('NMIBC', 'Chemical', '-', (125, 130))
184312	32784716	According to the fact that LumU tumors are enriched in mutations characteristic of the non-papillary pathway, we can assume that LumU/GU tumors originated from Class II NMIBCs through the non-papillary pathway (Figure 1).	('NMIBC', 'Chemical', '-', (169, 174))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('MIBCs', 'Chemical', '-', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (55, 64))	('non-papillary', 'Pathway', (188, 201))	('LumU tumors', 'Disease', (27, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('LumU tumors', 'Disease', 'MESH:D009369', (27, 38))	('GU tumors', 'Phenotype', 'HP:0007379', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
184315	32784716	It is enriched in mutations effecting regulatory factors such as ELF3 and PPARG.	('ELF3', 'Gene', (65, 69))	('ELF3', 'Gene', '1999', (65, 69))	('PPARG', 'Gene', '5468', (74, 79))	('PPARG', 'Gene', (74, 79))	('effecting', 'Reg', (28, 37))	('mutations', 'Var', (18, 27))
184323	32784716	Patients with tumors carrying alterations in both TP53 and RB1 have a high risk of BLCa progression and worse clinical outcome than patients with only one of these gene alterations.	('RB1', 'Gene', (59, 62))	('TP53', 'Gene', (50, 54))	('BLCa', 'Phenotype', 'HP:0009725', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('alterations', 'Var', (30, 41))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('BLCa', 'Disease', (83, 87))	('patients', 'Species', '9606', (132, 140))
184346	32784716	Currently, afatinib, a second-generation of tyrosine-kinase inhibitor of ERBB2 and EGFR, is being tested in a clinical trial phase II for metastatic, chemotherapy refractory BLCa patients with HER2/ERBB3 mutations and HER2/EGFR amplification.	('BLCa', 'Phenotype', 'HP:0009725', (174, 178))	('EGFR', 'Gene', '1956', (223, 227))	('amplification', 'Var', (228, 241))	('EGFR', 'Gene', (83, 87))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('53', '69'))	('ERBB2', 'Gene', (73, 78))	('HER2', 'Gene', (193, 197))	('ERBB3', 'Gene', '2065', (198, 203))	('HER2', 'Gene', (218, 222))	('EGFR', 'molecular_function', 'GO:0005006', ('223', '227'))	('patients', 'Species', '9606', (179, 187))	('ERBB2', 'Gene', '2064', (73, 78))	('ERBB3', 'Gene', (198, 203))	('EGFR', 'Gene', '1956', (83, 87))	('mutations', 'Var', (204, 213))	('EGFR', 'Gene', (223, 227))	('HER2', 'Gene', '2064', (193, 197))	('afatinib', 'Chemical', 'MESH:D000077716', (11, 19))	('HER2', 'Gene', '2064', (218, 222))	('EGFR', 'molecular_function', 'GO:0005006', ('83', '87'))
184347	32784716	In the case of EGFR, it was shown in colon cancer that RAS mutations (KRAS and HRAS) can inhibit the response to EGFR-targeted therapy.	('colon cancer', 'Phenotype', 'HP:0003003', (37, 49))	('KRAS', 'Gene', (70, 74))	('colon cancer', 'Disease', 'MESH:D015179', (37, 49))	('HRAS', 'Gene', (79, 83))	('colon cancer', 'Disease', (37, 49))	('KRAS', 'Gene', '3845', (70, 74))	('inhibit', 'NegReg', (89, 96))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (15, 19))	('EGFR', 'Gene', (113, 117))	('mutations', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('113', '117'))	('EGFR', 'molecular_function', 'GO:0005006', ('15', '19'))	('HRAS', 'Gene', '3265', (79, 83))
184356	32784716	Erdafitinib, an inhibitor of the tyrosine kinase activity of FGFR, was recently approved as a treatment for patients with chemo-resistant locally advanced or metastatic BLCa carrying FGFR3 or FGFR2 alteration.	('alteration', 'Var', (198, 208))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (0, 11))	('metastatic BLCa', 'Disease', (158, 173))	('FGFR', 'Gene', (61, 65))	('locally advanced', 'Disease', (138, 154))	('FGFR', 'molecular_function', 'GO:0005007', ('61', '65'))	('FGFR3', 'Gene', '2261', (183, 188))	('FGFR', 'molecular_function', 'GO:0005007', ('183', '187'))	('FGFR2', 'Gene', '2263', (192, 197))	('men', 'Species', '9606', (99, 102))	('BLCa', 'Phenotype', 'HP:0009725', (169, 173))	('patients', 'Species', '9606', (108, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('192', '196'))	('kinase activity', 'molecular_function', 'GO:0016301', ('42', '57'))	('FGFR3', 'Gene', (183, 188))	('FGFR2', 'Gene', (192, 197))
184388	29732391	On multivariate analysis, advancing age, pT4 stage, positive N stage, positive margins, and lower socioeconomic status were associated with worse OS.	('pT4 stage', 'Var', (41, 50))	('positive', 'Var', (70, 78))	('OS', 'Chemical', '-', (146, 148))	('positive', 'Var', (52, 60))
184397	29732391	More recent data suggests that the rate of locoregional recurrence for patients undergoing cystectomy can be as high as 58%, with local failure rates of up to 72% for patients with pT4pN1 disease.	('pT4pN1', 'Var', (181, 187))	('local failure', 'Disease', (130, 143))	('locoregional recurrence', 'CPA', (43, 66))	('patients', 'Species', '9606', (71, 79))	('patients', 'Species', '9606', (167, 175))	('local failure', 'Disease', 'MESH:D012594', (130, 143))
184426	29732391	On multivariate analysis (Table 3), advancing age, pT4 stage, positive N stage, positive surgical margins,receipt of treatment at a non-academic facility, and lower socioeconomic status were associated with worse OS.	('OS', 'Chemical', '-', (213, 215))	('pT4', 'Var', (51, 54))	('positive', 'Var', (62, 70))	('positive', 'Var', (80, 88))
184427	29732391	Multivariate analysis amongst patients specifically with positive margins confirmed (supplemental Table 1) that adjuvant RT was associated with improved OS when accounting for confounding variables (Hazard ratio = 0.474, 95% confidence interval 0.281-0.801, p = 0.005).	('OS', 'Chemical', '-', (153, 155))	('patients', 'Species', '9606', (30, 38))	('adjuvant', 'Var', (112, 120))	('improved', 'PosReg', (144, 152))
184450	29732391	Another possible explanation for the lack of survival benefit seen in our study for patients with pN2-3 disease or T4 disease may be inadequate RT coverage of regions most at risk for recurrence.	('patients', 'Species', '9606', (84, 92))	('pN2', 'Gene', (98, 101))	('T4 disease', 'Var', (115, 125))	('pN2', 'Gene', '351', (98, 101))
184550	29071385	CRT0066101, an inhibitor of PKD, has antitumor activity in multiple types of carcinomas.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('CRT0066101', 'Chemical', 'MESH:C551536', (0, 10))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('tumor', 'Disease', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('carcinomas', 'Disease', 'MESH:D009369', (77, 87))	('CRT0066101', 'Var', (0, 10))	('carcinomas', 'Disease', (77, 87))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
184552	29071385	In the present study, we show that CRT0066101 suppressed the proliferation and migration of four bladder cancer cell lines in vitro.	('migration', 'CPA', (79, 88))	('bladder cancer', 'Disease', 'MESH:D001749', (97, 111))	('bladder cancer', 'Disease', (97, 111))	('CRT0066101', 'Chemical', 'MESH:C551536', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('proliferation', 'CPA', (61, 74))	('CRT0066101', 'Var', (35, 45))	('suppressed', 'NegReg', (46, 56))
184554	29071385	To further assess the role of PKD in bladder carcinoma, we examined the three PKD isoforms and found that PKD2 was highly expressed in eight bladder cancer cell lines and in urothelial carcinoma tissues from the TCGA database, and that short hairpin RNA (shRNA)-mediated knockdown of PKD2 dramatically reduced bladder cancer growth and invasion in vitro and in vivo, suggesting that the effect of the compound in bladder cancer is mediated through inhibition of PKD2.	('urothelial carcinoma', 'Disease', (174, 194))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('reduced bladder', 'Phenotype', 'HP:0005343', (302, 317))	('bladder cancer', 'Disease', 'MESH:D001749', (310, 324))	('bladder cancer', 'Disease', (310, 324))	('bladder cancer', 'Disease', 'MESH:D001749', (413, 427))	('reduced', 'NegReg', (302, 309))	('bladder cancer', 'Disease', (413, 427))	('invasion', 'CPA', (336, 344))	('cancer', 'Phenotype', 'HP:0002664', (421, 427))	('bladder cancer', 'Phenotype', 'HP:0009725', (310, 324))	('bladder cancer', 'Phenotype', 'HP:0009725', (413, 427))	('bladder cancer', 'Disease', 'MESH:D001749', (141, 155))	('bladder cancer', 'Disease', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (37, 54))	('bladder cancer', 'Phenotype', 'HP:0009725', (141, 155))	('PKD2', 'Gene', (284, 288))	('bladder carcinoma', 'Disease', 'MESH:D001749', (37, 54))	('bladder carcinoma', 'Disease', (37, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('knockdown', 'Var', (271, 280))	('RNA', 'cellular_component', 'GO:0005562', ('250', '253'))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (174, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
184555	29071385	This notion was corroborated by demonstrating that the levels of phospho-PKD2 were markedly decreased in CRT0066101-treated bladder tumor explants.	('bladder tumor', 'Disease', 'MESH:D001749', (124, 137))	('bladder tumor', 'Phenotype', 'HP:0009725', (124, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('bladder tumor', 'Disease', (124, 137))	('CRT0066101-treated', 'Var', (105, 123))	('decreased', 'NegReg', (92, 101))	('CRT0066101', 'Chemical', 'MESH:C551536', (105, 115))	('levels of', 'MPA', (55, 64))
184557	29071385	Moreover, CRT0066101 downregulated the expression of Cdc25C, which dephosphorylates/activates CDK1, but enhanced the activity of the checkpoint kinase Chk1, which inhibits CDK1 by phosphorylating/inactivating Cdc25C.	('CRT0066101', 'Chemical', 'MESH:C551536', (10, 20))	('enhanced', 'PosReg', (104, 112))	('CDK1', 'Gene', (172, 176))	('CDK1', 'Gene', '983', (172, 176))	('CRT0066101', 'Var', (10, 20))	('CDK', 'molecular_function', 'GO:0004693', ('94', '97'))	('Cdc25C', 'Gene', '995', (53, 59))	('CDK', 'molecular_function', 'GO:0004693', ('172', '175'))	('expression', 'MPA', (39, 49))	('phosphorylating/inactivating', 'NegReg', (180, 208))	('dephosphorylates/activates', 'PosReg', (67, 93))	('activity', 'MPA', (117, 125))	('Cdc25C', 'Gene', (53, 59))	('Cdc25C', 'Gene', '995', (209, 215))	('downregulated', 'NegReg', (21, 34))	('Chk1', 'Gene', (151, 155))	('Cdc25C', 'Gene', (209, 215))	('Chk1', 'Gene', '1111', (151, 155))	('CDK1', 'Gene', (94, 98))	('CDK1', 'Gene', '983', (94, 98))
184558	29071385	Finally, CRT0066101 was found to elevate the levels of Myt1, Wee1, phospho-Cdc25C (Ser216), Gadd45alpha, and 14-3-3 proteins, all of which reduce the CDK1-cyclin B1 complex activity.	('cyclin', 'molecular_function', 'GO:0016538', ('155', '161'))	('Gadd45alpha', 'Gene', (92, 103))	('Myt1', 'Gene', (55, 59))	('Gadd45alpha', 'Gene', '1647', (92, 103))	('Wee1', 'Gene', '7465', (61, 65))	('Ser', 'cellular_component', 'GO:0005790', ('83', '86'))	('cyclin B1', 'Gene', '891', (155, 164))	('cyclin B1', 'Gene', (155, 164))	('Myt1', 'Gene', '4661', (55, 59))	('elevate', 'PosReg', (33, 40))	('reduce', 'NegReg', (139, 145))	('14-3-3', 'Gene', (109, 115))	('activity', 'MPA', (173, 181))	('Cdc25C', 'Gene', '995', (75, 81))	('CRT0066101', 'Chemical', 'MESH:C551536', (9, 19))	('Cdc25C', 'Gene', (75, 81))	('CDK1', 'Gene', (150, 154))	('CDK1', 'Gene', '983', (150, 154))	('CDK', 'molecular_function', 'GO:0004693', ('150', '153'))	('Ser216', 'Chemical', '-', (83, 89))	('Wee1', 'Gene', (61, 65))	('14-3-3', 'Gene', '10971', (109, 115))	('CRT0066101', 'Var', (9, 19))
184559	29071385	These novel findings suggest that CRT0066101 suppresses bladder cancer growth by inhibiting PKD2 through induction of G2/M cell cycle arrest, leading to the blockade of cell cycle progression.	('arrest', 'Disease', (134, 140))	('inhibiting', 'NegReg', (81, 91))	('G2/M', 'MPA', (118, 122))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (123, 140))	('CRT0066101', 'Var', (34, 44))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('123', '140'))	('cell cycle progression', 'CPA', (169, 191))	('arrest', 'Disease', 'MESH:D006323', (134, 140))	('bladder cancer', 'Disease', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('suppresses', 'NegReg', (45, 55))	('cell cycle', 'biological_process', 'GO:0007049', ('169', '179'))	('CRT0066101', 'Chemical', 'MESH:C551536', (34, 44))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('PKD2', 'Gene', (92, 96))
184570	29071385	When used as a single agent, CRT0066101 has been demonstrated to block tumor growth in animal models of several types of carcinomas including breast, colorectal, and pancreatic cancer.	('CRT0066101', 'Var', (29, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinomas', 'Disease', 'MESH:D009369', (121, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('block', 'NegReg', (65, 70))	('carcinomas', 'Disease', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('pancreatic cancer', 'Disease', (166, 183))	('colorectal', 'Disease', (150, 160))	('breast', 'Disease', (142, 148))	('CRT0066101', 'Chemical', 'MESH:C551536', (29, 39))	('pancreatic cancer', 'Disease', 'MESH:D010190', (166, 183))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', (71, 76))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (166, 183))
184572	29071385	Additionally, in a combination treatment study, CRT0066101 has synergistic antitumor activity with regorafenib, a multi-kinase inhibitor, in human colorectal cancer cells.	('regorafenib', 'Chemical', 'MESH:C559147', (99, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (147, 164))	('colorectal cancer', 'Disease', (147, 164))	('CRT0066101', 'Chemical', 'MESH:C551536', (48, 58))	('tumor', 'Disease', (79, 84))	('human', 'Species', '9606', (141, 146))	('CRT0066101', 'Var', (48, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (147, 164))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('120', '136'))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
184574	29071385	Previous studies have shown that CRT0066101 triggers apoptosis in pancreatic and colorectal cancer, and the apoptosis induced by CRT0066101 is associated with increase in expression of cleaved poly ADP ribose polymerase (PARP) and activated caspase-3 in colorectal cancer and abrogating expression of NF-kappaB-dependent prosurvival proteins such as survivin and cellular inhibitor of apoptosis protein-1 (cIAP-1) in pancreatic cancer.	('caspase-3', 'Gene', (241, 250))	('CRT0066101', 'Var', (33, 43))	('abrogating', 'NegReg', (276, 286))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (417, 434))	('CRT0066101', 'Var', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('poly ADP ribose polymerase', 'Gene', (193, 219))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('pancreatic and colorectal cancer', 'Disease', 'MESH:D015179', (66, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (254, 271))	('expression', 'MPA', (287, 297))	('apoptosis', 'biological_process', 'GO:0097194', ('385', '394'))	('apoptosis', 'biological_process', 'GO:0006915', ('385', '394'))	('NF-kappaB', 'Gene', (301, 310))	('colorectal cancer', 'Disease', (81, 98))	('colorectal cancer', 'Disease', (254, 271))	('cancer', 'Phenotype', 'HP:0002664', (428, 434))	('pancreatic cancer', 'Disease', 'MESH:D010190', (417, 434))	('CRT0066101', 'Chemical', 'MESH:C551536', (129, 139))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('NF-kappaB', 'Gene', '4790', (301, 310))	('cIAP-1', 'Gene', (406, 412))	('activated', 'PosReg', (231, 240))	('poly ADP ribose polymerase', 'Gene', '142', (193, 219))	('pancreatic cancer', 'Disease', (417, 434))	('cellular inhibitor of apoptosis protein-1', 'Gene', (363, 404))	('cIAP-1', 'Gene', '329', (406, 412))	('cellular inhibitor of apoptosis protein-1', 'Gene', '329', (363, 404))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('increase', 'PosReg', (159, 167))	('expression', 'MPA', (171, 181))	('colorectal cancer', 'Phenotype', 'HP:0003003', (254, 271))	('PARP', 'Gene', '142', (221, 225))	('caspase-3', 'Gene', '836', (241, 250))	('protein', 'cellular_component', 'GO:0003675', ('395', '402'))	('CRT0066101', 'Chemical', 'MESH:C551536', (33, 43))	('PARP', 'Gene', (221, 225))	('cleaved', 'MPA', (185, 192))	('survivin', 'Protein', (350, 358))
184575	29071385	In addition, a recent study on CRT0066101 shows that the induction of cell cycle arrest may account for its mechanism of action in colorectal cancer; however, the molecular basis for cell cycle arrest by CRT0066101 remains undefined.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (70, 87))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (183, 200))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('arrest', 'Disease', 'MESH:D006323', (194, 200))	('CRT0066101', 'Chemical', 'MESH:C551536', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('183', '200'))	('CRT0066101', 'Chemical', 'MESH:C551536', (204, 214))	('arrest', 'Disease', 'MESH:D006323', (81, 87))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('70', '87'))	('arrest', 'Disease', (194, 200))	('colorectal cancer', 'Disease', (131, 148))	('arrest', 'Disease', (81, 87))	('CRT0066101', 'Var', (204, 214))
184584	29071385	Not surprisingly, the loss or deactivation of either component of the CDK1-cyclin B1 complex will block cellular progression out of G2.	('CDK', 'molecular_function', 'GO:0004693', ('70', '73'))	('deactivation', 'Var', (30, 42))	('loss', 'NegReg', (22, 26))	('block', 'NegReg', (98, 103))	('cellular progression out of G2', 'CPA', (104, 134))	('cyclin B1', 'Gene', (75, 84))	('CDK1', 'Gene', '983', (70, 74))	('cyclin', 'molecular_function', 'GO:0016538', ('75', '81'))	('cyclin B1', 'Gene', '891', (75, 84))	('CDK1', 'Gene', (70, 74))
184589	29071385	CRT0066101 also had differential effects on cell survival between urothelial bladder carcinoma cells and human uroepithelial cells.	('cell survival', 'CPA', (44, 57))	('CRT0066101', 'Chemical', 'MESH:C551536', (0, 10))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (66, 94))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (77, 94))	('effects', 'Reg', (33, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('CRT0066101', 'Var', (0, 10))	('human', 'Species', '9606', (105, 110))	('urothelial bladder carcinoma', 'Disease', (66, 94))
184590	29071385	Furthermore, we show that the effect of CRT0066101 on growth suppression of bladder carcinoma was associated with cell cycle arrest at the G2/M phase, as well as alterations in the expression and activation of key regulators of the G2/M transition, suggesting that the inhibitory activity of CRT0066101 on the growth and proliferation of bladder cancer cells is mediated, at least in part, through modulation of the cell cycle G2/M checkpoint leading to the blockade of cell cycle progression.	('suppression of bladder carcinoma', 'Disease', (61, 93))	('arrest', 'Disease', (125, 131))	('CRT0066101', 'Chemical', 'MESH:C551536', (40, 50))	('cell cycle', 'biological_process', 'GO:0007049', ('470', '480'))	('CRT0066101', 'Chemical', 'MESH:C551536', (292, 302))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (114, 131))	('CRT0066101', 'Var', (292, 302))	('blockade', 'NegReg', (458, 466))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('427', '442'))	('cell cycle progression', 'CPA', (470, 492))	('arrest', 'Disease', 'MESH:D006323', (125, 131))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('114', '131'))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('M phase', 'biological_process', 'GO:0000279', ('142', '149'))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('bladder cancer', 'Disease', 'MESH:D001749', (338, 352))	('bladder cancer', 'Disease', (338, 352))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (76, 93))	('cell cycle', 'biological_process', 'GO:0007049', ('416', '426'))	('suppression of bladder carcinoma', 'Disease', 'MESH:D001749', (61, 93))	('modulation', 'Reg', (398, 408))	('bladder cancer', 'Phenotype', 'HP:0009725', (338, 352))	('cell cycle G2/M checkpoint', 'Pathway', (416, 442))
184605	29071385	Proliferation rates were calculated from the optical densities of CRT0066101-treated cells relative to the optical density of untreated control cells with no CRT0066101 exposure (control value, 100%).	('CRT0066101', 'Chemical', 'MESH:C551536', (66, 76))	('CRT0066101', 'Chemical', 'MESH:C551536', (158, 168))	('Proliferation', 'CPA', (0, 13))	('CRT0066101-treated', 'Var', (66, 84))
184615	29071385	Bladder carcinoma cells were first treated with CRT0066101 at the indicated concentrations (0, 1, 2, and 3 muM), and then 2 x 105 cells were resuspended in the inner chamber in 200 mul of fresh MEM medium containing 1% FBS.	('CRT0066101', 'Chemical', 'MESH:C551536', (48, 58))	('Bladder carcinoma', 'Disease', (0, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('Bladder carcinoma', 'Phenotype', 'HP:0002862', (0, 17))	('MEM medium', 'Chemical', '-', (194, 204))	('CRT0066101', 'Var', (48, 58))	('Bladder carcinoma', 'Disease', 'MESH:D001749', (0, 17))
184650	29071385	For transduction of the cell using lentivirus with shRNA targeting PKD2 and the control, bladder cancer cells were plated on two 10 cm dishes and grown to 50-75% confluence in complete medium.	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('transduction', 'biological_process', 'GO:0009293', ('4', '16'))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('PKD2', 'Var', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))
184665	29071385	2b, the half-maximal inhibitory concentration (IC50) values of CRT0066101 at day 4 were 0.3333, 0.4782, 0.4796, and 1.4300 muM for T24T, T24, UMUC1, and TCCSUP, respectively.	('0.3333', 'Var', (88, 94))	('TCC', 'Phenotype', 'HP:0006740', (153, 156))	('0.4782', 'Var', (96, 102))	('CRT0066101', 'Chemical', 'MESH:C551536', (63, 73))	('T24T', 'Var', (131, 135))	('CRT0066101', 'Gene', (63, 73))	('0.4796', 'Var', (104, 110))
184672	29071385	2c), which was 2.23-, 1.79-, 4.41-, and 7.78-fold higher than those for the bladder cancer cell lines T24, T24T, TCCSUP, and UMUC1, respectively (P < 0.01), indicating a differential effect of CRT0066101 on cell viability between the human epithelial bladder carcinoma cell lines and the human uroepithelial cell line SV-HUC.	('bladder cancer', 'Disease', (76, 90))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (251, 268))	('human', 'Species', '9606', (288, 293))	('CRT0066101', 'Var', (193, 203))	('SV-HUC', 'CellLine', 'CVCL:3798', (318, 324))	('human', 'Species', '9606', (234, 239))	('TCC', 'Phenotype', 'HP:0006740', (113, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('bladder carcinoma', 'Disease', (251, 268))	('bladder carcinoma', 'Disease', 'MESH:D001749', (251, 268))	('cell viability', 'CPA', (207, 221))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('CRT0066101', 'Chemical', 'MESH:C551536', (193, 203))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))
184674	29071385	Our data showed that CRT0066101 was effective in inhibition of cell growth in low attachment conditions, with the concentrations of 2.5 and 5 muM effective in all four bladder cancer cell lines (Fig.	('CRT0066101', 'Chemical', 'MESH:C551536', (21, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (168, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('CRT0066101', 'Var', (21, 31))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('49', '74'))	('bladder cancer', 'Disease', 'MESH:D001749', (168, 182))	('bladder cancer', 'Disease', (168, 182))	('inhibition', 'NegReg', (49, 59))	('cell growth', 'CPA', (63, 74))
184677	29071385	2e, f, treatment with CRT0066101 profoundly inhibited in vitro invasion of TCCSUP and UMUC1 cells in a concentration-dependent manner.	('inhibited', 'NegReg', (44, 53))	('CRT0066101', 'Var', (22, 32))	('TCC', 'Phenotype', 'HP:0006740', (75, 78))	('CRT0066101', 'Chemical', 'MESH:C551536', (22, 32))
184678	29071385	The number of migrating cells was markedly decreased in CRT0066101-treated TCCSUP and UMUC1 cells as compared with those of the untreated control cells (Fig.	('CRT0066101', 'Chemical', 'MESH:C551536', (56, 66))	('decreased', 'NegReg', (43, 52))	('TCC', 'Phenotype', 'HP:0006740', (75, 78))	('CRT0066101-treated', 'Var', (56, 74))
184679	29071385	2e, f), suggesting that CRT0066101 reduces the invasive ability of bladder cancer cells.	('CRT0066101', 'Chemical', 'MESH:C551536', (24, 34))	('reduces', 'NegReg', (35, 42))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('CRT0066101', 'Var', (24, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
184680	29071385	Given that cell survival and proliferation were reduced in bladder carcinoma cells in vitro following treatment with CRT0066101 (Fig.	('bladder carcinoma', 'Disease', 'MESH:D001749', (59, 76))	('cell survival', 'CPA', (11, 24))	('CRT0066101', 'Chemical', 'MESH:C551536', (117, 127))	('reduced', 'NegReg', (48, 55))	('bladder carcinoma', 'Disease', (59, 76))	('proliferation', 'CPA', (29, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('CRT0066101', 'Var', (117, 127))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (59, 76))
184683	29071385	There was a substantial difference in tumor size between the CRT0066101-treated group and the vehicle-treated control group even on day 18 of the therapy; at the termination of the study (day 25 post-treatment), the difference in tumor volume between the CRT0066101 group and the control group was significant (P < 0.0001).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', (230, 235))	('CRT0066101', 'Chemical', 'MESH:C551536', (255, 265))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('CRT0066101', 'Var', (255, 265))	('CRT0066101', 'Chemical', 'MESH:C551536', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
184684	29071385	The average tumor volumes for bladder cancer on day 25 of the treatment were 835.83 and 1943.08 mm3 in the CRT0066101-treated group and the vehicle-treated control group, respectively (Fig.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('CRT0066101', 'Chemical', 'MESH:C551536', (107, 117))	('CRT0066101-treated', 'Var', (107, 125))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('bladder cancer', 'Disease', 'MESH:D001749', (30, 44))	('bladder cancer', 'Disease', (30, 44))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))
184688	29071385	We found that PKD2 protein was highly expressed in all bladder cancer cell lines except for SCaBER, which presented with slightly lower PKD2 expression levels (Fig.	('lower', 'NegReg', (130, 135))	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('bladder cancer', 'Disease', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('PKD2 protein', 'Var', (14, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('PKD2 expression levels', 'MPA', (136, 158))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))
184692	29071385	The levels of PKD1, PKD2, and PKD3 expression in our bladder cancer cell lines were similar to those detected in human colorectal cancer cell lines.	('PKD2', 'Var', (20, 24))	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('PKD3', 'Gene', '5312', (30, 34))	('colorectal cancer', 'Disease', (119, 136))	('bladder cancer', 'Disease', (53, 67))	('PKD1', 'Gene', (14, 18))	('bladder cancer', 'Disease', 'MESH:D001749', (53, 67))	('PKD3', 'Gene', (30, 34))	('PKD1', 'Gene', '5310', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))	('human', 'Species', '9606', (113, 118))	('bladder cancer', 'Phenotype', 'HP:0009725', (53, 67))
184704	29071385	Thus, we generated stable derivatives of 6 bladder carcinoma cell lines (T24, T24T, TCCSUP, UMUC1, UMUC3, and UMUC5) under-expressing PKD2 (shPKD2#1 and shPKD2#2) and their corresponding controls (shNTC).	('bladder carcinoma', 'Disease', (43, 60))	('bladder carcinoma', 'Disease', 'MESH:D001749', (43, 60))	('TCC', 'Phenotype', 'HP:0006740', (84, 87))	('under-expressing', 'NegReg', (117, 133))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (43, 60))	('PKD2', 'Var', (134, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
184705	29071385	To validate the PKD2 depletion efficiency, we treated shPKD2#1 of UMUC1 with PMA, a known activator of the protein kinase C/PKD pathway, and found that PMA markedly increased PKD2 (Ser876) phosphorylation without affecting PKD2 protein expression (Fig.	('PMA', 'Chemical', 'MESH:D013755', (152, 155))	('protein', 'cellular_component', 'GO:0003675', ('228', '235'))	('Ser876', 'Chemical', '-', (181, 187))	('PMA', 'Chemical', 'MESH:D013755', (77, 80))	('Ser', 'cellular_component', 'GO:0005790', ('181', '184'))	('PMA', 'Var', (152, 155))	('phosphorylation', 'biological_process', 'GO:0016310', ('189', '204'))	('increased', 'PosReg', (165, 174))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
184708	29071385	UMUC1 shNTC and shPKD2#1 were incubated with 200 nM of PMA for 30 min, and we showed that c-Jun (Ser63) phosphorylation was significantly increased in shNTC cells, but remained unaltered in shPKD2#1 cells (data not shown), indicating a decent PKD2 silencing efficiency in UMUC1 cells.	('increased', 'PosReg', (138, 147))	('c-Jun', 'Gene', (90, 95))	('phosphorylation', 'biological_process', 'GO:0016310', ('104', '119'))	('shNTC', 'Var', (151, 156))	('Ser63', 'Chemical', '-', (97, 102))	('Ser', 'cellular_component', 'GO:0005790', ('97', '100'))	('c-Jun', 'Gene', '3725', (90, 95))	('PMA', 'Chemical', 'MESH:D013755', (55, 58))
184710	29071385	Interestingly, cellular proliferation of shPKD2#1 and shPKD2#2 was significantly reduced in all six bladder tumor cell lines as compared with those of shNTC in proliferation assays (P < 0.01; Fig.	('bladder tumor', 'Disease', 'MESH:D001749', (100, 113))	('bladder tumor', 'Phenotype', 'HP:0009725', (100, 113))	('cellular proliferation', 'CPA', (15, 37))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('shPKD2#', 'Var', (41, 48))	('shPKD2', 'Var', (54, 60))	('bladder tumor', 'Disease', (100, 113))	('reduced', 'NegReg', (81, 88))
184711	29071385	We also determined the ability of the bladder carcinoma T24T and UMUC1 cells under-expressing PKD2 for growth in low attachment.	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('bladder carcinoma', 'Disease', (38, 55))	('bladder carcinoma', 'Disease', 'MESH:D001749', (38, 55))	('PKD2', 'Var', (94, 98))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (38, 55))
184713	29071385	Taken together, the findings from both bladder carcinoma cell lines and bladder tumor tissues suggest that PKD2 isoform may play an essential role in the growth, invasion, and proliferation of bladder cancer cells and may be a promising therapeutic target.	('bladder tumor', 'Disease', 'MESH:D001749', (72, 85))	('bladder tumor', 'Phenotype', 'HP:0009725', (72, 85))	('bladder cancer', 'Disease', 'MESH:D001749', (193, 207))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PKD2', 'Var', (107, 111))	('bladder cancer', 'Disease', (193, 207))	('proliferation', 'CPA', (176, 189))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (39, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('bladder tumor', 'Disease', (72, 85))	('bladder carcinoma', 'Disease', 'MESH:D001749', (39, 56))	('bladder cancer', 'Phenotype', 'HP:0009725', (193, 207))	('growth', 'CPA', (154, 160))	('invasion', 'CPA', (162, 170))	('bladder carcinoma', 'Disease', (39, 56))
184717	29071385	There was a substantial difference in tumor mass between the shPKD2 group and the shNTC group as early as day 7 of the study; at the termination of the study (day 14), the difference in tumor weight between the shPKD2 group and the shNTC control group was significant (P = 0.0194; Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('shPKD2', 'Var', (211, 217))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
184718	29071385	Together, these data suggest that PKD2 plays a pivotal role in the growth, proliferation, migration, and invasion of bladder carcinoma cells in vitro and culminating in significantly slower growth rate in vivo.	('invasion', 'CPA', (105, 113))	('PKD2', 'Var', (34, 38))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (117, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('migration', 'CPA', (90, 99))	('bladder carcinoma', 'Disease', 'MESH:D001749', (117, 134))	('bladder carcinoma', 'Disease', (117, 134))	('growth rate', 'CPA', (190, 201))	('proliferation', 'CPA', (75, 88))	('slower', 'NegReg', (183, 189))
184719	29071385	We showed that PKD2 plays an essential role in bladder cancer cell growth and proliferation (Figs.	('bladder cancer', 'Disease', 'MESH:D001749', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('PKD2', 'Var', (15, 19))	('bladder cancer', 'Disease', (47, 61))	('proliferation', 'CPA', (78, 91))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('bladder cancer', 'Phenotype', 'HP:0009725', (47, 61))
184721	29071385	2, 3), suggesting that CRT0066101 may exert its anticancer activity in bladder carcinoma through inhibition of PKD2.	('bladder carcinoma', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('inhibition', 'NegReg', (97, 107))	('CRT0066101', 'Var', (23, 33))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (71, 88))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('bladder carcinoma', 'Disease', 'MESH:D001749', (71, 88))	('CRT0066101', 'Chemical', 'MESH:C551536', (23, 33))	('PKD2', 'Enzyme', (111, 115))
184722	29071385	To verify this notion, we performed western blot analysis of PKD2 protein in cell lysates from the UMUC1 tumor explants treated with CRT0066101 or with vehicle (5% dextrose) as the control.	('dextrose', 'Chemical', 'MESH:D005947', (164, 172))	('PKD2', 'Gene', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('CRT0066101', 'Var', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('CRT0066101', 'Chemical', 'MESH:C551536', (133, 143))	('tumor', 'Disease', (105, 110))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
184723	29071385	Our data showed that CRT0066101 dramatically decreased phosphorylation on Ser706/710, Ser876, and Ser916 of PKD2 protein without affecting PKD2 protein expression in the tumor cells as compared with the vehicle-treated control cells (Fig.	('Ser876', 'Var', (86, 92))	('PKD2', 'Var', (108, 112))	('Ser706/710', 'Var', (74, 84))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('Ser', 'cellular_component', 'GO:0005790', ('98', '101'))	('tumor', 'Disease', (170, 175))	('Ser706', 'Chemical', '-', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('Ser', 'cellular_component', 'GO:0005790', ('74', '77'))	('phosphorylation', 'MPA', (55, 70))	('Ser916', 'Chemical', '-', (98, 104))	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('CRT0066101', 'Chemical', 'MESH:C551536', (21, 31))	('Ser876', 'Chemical', '-', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('Ser916', 'Var', (98, 104))	('CRT0066101', 'Var', (21, 31))	('decreased', 'NegReg', (45, 54))	('Ser', 'cellular_component', 'GO:0005790', ('86', '89'))
184724	29071385	Since c-Jun is a substrate of PKD2, it is instructive to assess whether inhibition of PKD2 results in the inhibition of its direct target in our bladder cancer cells, we analyzed c-Jun and phospho-c-Jun (Ser63) in the same model system, and found that the levels of phospho-c-Jun (Ser63) were strikingly reduced in CRT0066101-treated UMUC1 cells, while c-Jun protein levels remained unchanged as compared with the vehicle-treated tumor cells (Fig.	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('reduced', 'NegReg', (304, 311))	('Ser63', 'Chemical', '-', (204, 209))	('bladder cancer', 'Disease', (145, 159))	('Ser', 'cellular_component', 'GO:0005790', ('204', '207'))	('c-Jun', 'Gene', '3725', (6, 11))	('CRT0066101-treated', 'Var', (315, 333))	('c-Jun', 'Gene', (6, 11))	('CRT0066101', 'Chemical', 'MESH:C551536', (315, 325))	('Ser63', 'Chemical', '-', (281, 286))	('c-Jun', 'Gene', '3725', (197, 202))	('tumor', 'Disease', (430, 435))	('tumor', 'Phenotype', 'HP:0002664', (430, 435))	('c-Jun', 'Gene', '3725', (179, 184))	('c-Jun', 'Gene', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (430, 435))	('c-Jun', 'Gene', (179, 184))	('Ser', 'cellular_component', 'GO:0005790', ('281', '284'))	('protein', 'cellular_component', 'GO:0003675', ('359', '366'))	('c-Jun', 'Gene', '3725', (274, 279))	('c-Jun', 'Gene', '3725', (353, 358))	('levels', 'MPA', (256, 262))	('c-Jun', 'Gene', (274, 279))	('bladder cancer', 'Disease', 'MESH:D001749', (145, 159))	('c-Jun', 'Gene', (353, 358))
184726	29071385	It is well-established that uncontrolled cell proliferation is a hallmark of cancer, and CRT0066101 was shown to effectively inhibit bladder carcinoma cell growth in vitro and in vivo (Figs.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('inhibit', 'NegReg', (125, 132))	('CRT0066101', 'Chemical', 'MESH:C551536', (89, 99))	('cancer', 'Disease', (77, 83))	('CRT0066101', 'Var', (89, 99))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (133, 150))	('cell growth', 'biological_process', 'GO:0016049', ('151', '162'))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cell proliferation', 'biological_process', 'GO:0008283', ('41', '59'))	('bladder carcinoma', 'Disease', (133, 150))	('bladder carcinoma', 'Disease', 'MESH:D001749', (133, 150))
184730	29071385	Figure 11a shows that CRT0066101 arrested UMUC1 cells at the G2/M phase in a dose-dependent manner with all the concentrations examined.	('CRT0066101', 'Var', (22, 32))	('arrest', 'Disease', 'MESH:D006323', (33, 39))	('CRT0066101', 'Chemical', 'MESH:C551536', (22, 32))	('arrest', 'Disease', (33, 39))	('M phase', 'biological_process', 'GO:0000279', ('64', '71'))
184731	29071385	These results indicate that CRT0066101 suppresses the growth and proliferation of bladder tumor cells by controlling the G2/M checkpoint and inducing a specific block in cell cycle progression.	('controlling', 'Reg', (105, 116))	('suppresses', 'NegReg', (39, 49))	('CRT0066101', 'Chemical', 'MESH:C551536', (28, 38))	('G2/M checkpoint', 'MPA', (121, 136))	('cell cycle', 'biological_process', 'GO:0007049', ('170', '180'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('cell cycle progression', 'CPA', (170, 192))	('CRT0066101', 'Var', (28, 38))	('bladder tumor', 'Disease', 'MESH:D001749', (82, 95))	('inducing', 'Reg', (141, 149))	('bladder tumor', 'Phenotype', 'HP:0009725', (82, 95))	('growth', 'CPA', (54, 60))	('block', 'NegReg', (161, 166))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('121', '136'))	('bladder tumor', 'Disease', (82, 95))
184734	29071385	12a, b, there were substantial increases in the fraction of cells in the G2/M phase in PKD2-knockdown UMUC1 cells, but not in PKD3-knockdown UMUC1 cells.	('M phase', 'biological_process', 'GO:0000279', ('76', '83'))	('increases', 'PosReg', (31, 40))	('PKD3', 'Gene', (126, 130))	('PKD2-knockdown', 'Var', (87, 101))	('PKD3', 'Gene', '5312', (126, 130))
184735	29071385	These data suggest that the effect of CRT0066101 on G2/M phase arrest is specifically mediated through inhibition of PKD2 in our bladder cancer cells.	('CRT0066101', 'Chemical', 'MESH:C551536', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('bladder cancer', 'Disease', 'MESH:D001749', (129, 143))	('M phase', 'biological_process', 'GO:0000279', ('55', '62'))	('CRT0066101', 'Var', (38, 48))	('arrest', 'Disease', (63, 69))	('PKD2', 'Gene', (117, 121))	('bladder cancer', 'Disease', (129, 143))	('inhibition', 'NegReg', (103, 113))
184737	29071385	CRT0066101 was found to block cell cycle progression and arrest UMUC1 and T24T cells at the G2/M phase (Fig.	('cell cycle progression', 'CPA', (30, 52))	('CRT0066101', 'Chemical', 'MESH:C551536', (0, 10))	('M phase', 'biological_process', 'GO:0000279', ('95', '102'))	('block', 'NegReg', (24, 29))	('arrest', 'Disease', 'MESH:D006323', (57, 63))	('cell cycle', 'biological_process', 'GO:0007049', ('30', '40'))	('arrest', 'Disease', (57, 63))	('CRT0066101', 'Var', (0, 10))
184739	29071385	To analyze the expression of intracellular proteins regulating cell cycle progression at the G2/M boundary, we first assessed the effect of CRT0066101 on cyclin B1, CDK1, and p27kip1 expression in UMUC1 tumor explants.	('p27kip1', 'Gene', '1027', (175, 182))	('cyclin B1', 'Gene', (154, 163))	('cyclin B1', 'Gene', '891', (154, 163))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('cell cycle', 'biological_process', 'GO:0007049', ('63', '73'))	('CRT0066101', 'Var', (140, 150))	('intracellular', 'cellular_component', 'GO:0005622', ('29', '42'))	('CDK1', 'Gene', '983', (165, 169))	('CDK1', 'Gene', (165, 169))	('p27kip1', 'Gene', (175, 182))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cyclin', 'molecular_function', 'GO:0016538', ('154', '160'))	('CDK', 'molecular_function', 'GO:0004693', ('165', '168'))	('CRT0066101', 'Chemical', 'MESH:C551536', (140, 150))
184740	29071385	13a, the levels of cyclin B1 and CDK1 were decreased but the levels of p27kip1 were increased following treatment of UMUC1 cells with CRT0066101.	('CDK1', 'Gene', (33, 37))	('CDK', 'molecular_function', 'GO:0004693', ('33', '36'))	('CDK1', 'Gene', '983', (33, 37))	('p27kip1', 'Gene', (71, 78))	('levels', 'MPA', (9, 15))	('CRT0066101', 'Var', (134, 144))	('cyclin B1', 'Gene', '891', (19, 28))	('cyclin B1', 'Gene', (19, 28))	('levels', 'MPA', (61, 67))	('p27kip1', 'Gene', '1027', (71, 78))	('increased', 'PosReg', (84, 93))	('decreased', 'NegReg', (43, 52))	('CRT0066101', 'Chemical', 'MESH:C551536', (134, 144))	('cyclin', 'molecular_function', 'GO:0016538', ('19', '25'))
184742	29071385	These data suggest that reduced CDK1-cyclin B1 activity is responsible for CRT0066101-induced G2/M arrest in our model system.	('CDK1', 'Gene', (32, 36))	('cyclin', 'molecular_function', 'GO:0016538', ('37', '43'))	('CDK1', 'Gene', '983', (32, 36))	('CDK', 'molecular_function', 'GO:0004693', ('32', '35'))	('reduced', 'NegReg', (24, 31))	('M arrest', 'Disease', (97, 105))	('CRT0066101-induced', 'Var', (75, 93))	('cyclin B1', 'Gene', '891', (37, 46))	('cyclin B1', 'Gene', (37, 46))	('CRT0066101', 'Chemical', 'MESH:C551536', (75, 85))	('activity', 'MPA', (47, 55))	('M arrest', 'Disease', 'MESH:D006323', (97, 105))
184744	29071385	Conversely, the protein phosphatase Cdc25C activates CDK1 by dephosphorylation of the residues Thr14 and Tyr15.	('Tyr15', 'Var', (105, 110))	('CDK', 'molecular_function', 'GO:0004693', ('53', '56'))	('Cdc25C', 'Gene', (36, 42))	('CDK1', 'Gene', '983', (53, 57))	('protein', 'cellular_component', 'GO:0003675', ('16', '23'))	('Thr14', 'Var', (95, 100))	('CDK1', 'Gene', (53, 57))	('Cdc25C', 'Gene', '995', (36, 42))	('activates', 'PosReg', (43, 52))	('phosphatase', 'molecular_function', 'GO:0016791', ('24', '35'))	('Thr14', 'Chemical', '-', (95, 100))	('dephosphorylation', 'MPA', (61, 78))	('Tyr15', 'Chemical', '-', (105, 110))	('dephosphorylation', 'biological_process', 'GO:0016311', ('61', '78'))
184745	29071385	Since CDK1 phosphorylation at Thr14 and Tyr15 was enhanced by CRT0066101 treatment, we examined the effect of the compound on Cdc25C, Myt1, and Wee1 expression by western blotting.	('CRT0066101', 'Chemical', 'MESH:C551536', (62, 72))	('Wee1', 'Gene', '7465', (144, 148))	('Tyr15', 'Chemical', '-', (40, 45))	('Myt1', 'Gene', '4661', (134, 138))	('Cdc25C', 'Gene', (126, 132))	('phosphorylation', 'MPA', (11, 26))	('CDK1', 'Gene', (6, 10))	('Myt1', 'Gene', (134, 138))	('Cdc25C', 'Gene', '995', (126, 132))	('CDK1', 'Gene', '983', (6, 10))	('CDK', 'molecular_function', 'GO:0004693', ('6', '9'))	('Thr14', 'Chemical', '-', (30, 35))	('phosphorylation', 'biological_process', 'GO:0016310', ('11', '26'))	('enhanced', 'PosReg', (50, 58))	('CRT0066101', 'Var', (62, 72))	('Wee1', 'Gene', (144, 148))
184746	29071385	13b, the administration of the bladder tumor with CRT0066101 markedly reduced Cdc25C protein levels but elevated the Myt1 and Wee1 protein levels.	('Wee1', 'Gene', (126, 130))	('reduced', 'NegReg', (70, 77))	('bladder tumor', 'Phenotype', 'HP:0009725', (31, 44))	('Wee1', 'Gene', '7465', (126, 130))	('CRT0066101', 'Var', (50, 60))	('Cdc25C', 'Gene', (78, 84))	('bladder tumor', 'Disease', (31, 44))	('Myt1', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('CRT0066101', 'Chemical', 'MESH:C551536', (50, 60))	('bladder tumor', 'Disease', 'MESH:D001749', (31, 44))	('Myt1', 'Gene', '4661', (117, 121))	('Cdc25C', 'Gene', '995', (78, 84))	('elevated', 'PosReg', (104, 112))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
184748	29071385	Therefore, we tested the activity of Chk1 and Cdc25C and found that the levels of phospho-Chk1 (Ser317) and phospho-Chk1 (Ser345) as well as Cdc25C phosphorylation at Ser216 were all increased in CRT0066101-treated UMUC1 tumor cells, indicating that enhanced Cdc25C phosphorylation at Ser216 is attributable to the increased Chk1 activity (Fig.	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('Chk1', 'Gene', (325, 329))	('Chk1', 'Gene', '1111', (325, 329))	('phosphorylation', 'biological_process', 'GO:0016310', ('148', '163'))	('Ser345', 'Chemical', '-', (122, 128))	('Chk1', 'Gene', (37, 41))	('Chk1', 'Gene', (116, 120))	('Ser', 'cellular_component', 'GO:0005790', ('285', '288'))	('Cdc25C', 'Gene', '995', (141, 147))	('Cdc25C', 'Gene', '995', (259, 265))	('Chk1', 'Gene', '1111', (37, 41))	('Chk1', 'Gene', '1111', (116, 120))	('Ser', 'cellular_component', 'GO:0005790', ('122', '125'))	('Ser216', 'Chemical', '-', (285, 291))	('Cdc25C', 'Gene', '995', (46, 52))	('Cdc25C', 'Gene', (141, 147))	('Cdc25C', 'Gene', (259, 265))	('CRT0066101-treated', 'Var', (196, 214))	('activity', 'MPA', (330, 338))	('CRT0066101', 'Chemical', 'MESH:C551536', (196, 206))	('Cdc25C', 'Gene', (46, 52))	('tumor', 'Disease', (221, 226))	('Chk1', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('phosphorylation', 'biological_process', 'GO:0016310', ('266', '281'))	('Ser', 'cellular_component', 'GO:0005790', ('167', '170'))	('Chk1', 'Gene', '1111', (90, 94))	('Ser317', 'Chemical', '-', (96, 102))	('Ser', 'cellular_component', 'GO:0005790', ('96', '99'))	('increased', 'PosReg', (183, 192))	('Ser216', 'Chemical', '-', (167, 173))	('enhanced', 'PosReg', (250, 258))	('Ser216', 'Var', (285, 291))
184749	29071385	Since there was an upregulation of Myt1 and Wee1 expression following CRT0066101 treatment (Fig.	('Myt1', 'Gene', (35, 39))	('Wee1', 'Gene', '7465', (44, 48))	('CRT0066101', 'Chemical', 'MESH:C551536', (70, 80))	('expression', 'MPA', (49, 59))	('upregulation', 'PosReg', (19, 31))	('CRT0066101', 'Var', (70, 80))	('Wee1', 'Gene', (44, 48))	('Myt1', 'Gene', '4661', (35, 39))
184757	29071385	Our western blot analysis of extracts from UMUC1 tumor explants after 25-day treatment with CRT0066101 showed increases in Gadd45alpha, 14-3-3epsilon, 14-3-3sigma, and pan-14-3-3 protein levels (Fig.	('14-3-3', 'Gene', '10971', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('14-3-3sigma', 'Gene', (151, 162))	('14-3-3', 'Gene', (136, 142))	('14-3-3sigma', 'Gene', '2810', (151, 162))	('Gadd45alpha', 'Gene', '1647', (123, 134))	('Gadd45alpha', 'Gene', (123, 134))	('14-3-3epsilon', 'Gene', '7531', (136, 149))	('CRT0066101', 'Chemical', 'MESH:C551536', (92, 102))	('14-3-3', 'Gene', (151, 157))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('14-3-3', 'Gene', '10971', (136, 142))	('CRT0066101', 'Var', (92, 102))	('tumor', 'Disease', (49, 54))	('14-3-3', 'Gene', (172, 178))	('14-3-3epsilon', 'Gene', (136, 149))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('14-3-3', 'Gene', '10971', (151, 157))	('increases', 'PosReg', (110, 119))
184758	29071385	These results suggest that the increased expression of Gadd45alpha, 14-3-3epsilon, 14-3-3sigma, and other isoforms of 14-3-3 proteins by CRT0066101 may account for a large part of the reduction in CDK1-cyclin B1 activity and the control of the G2/M checkpoint in bladder cancer cells.	('cyclin', 'molecular_function', 'GO:0016538', ('202', '208'))	('CRT0066101', 'Chemical', 'MESH:C551536', (137, 147))	('CDK1', 'Gene', '983', (197, 201))	('bladder cancer', 'Disease', 'MESH:D001749', (263, 277))	('bladder cancer', 'Disease', (263, 277))	('increased', 'PosReg', (31, 40))	('CDK1', 'Gene', (197, 201))	('G2/M', 'CPA', (244, 248))	('CRT0066101', 'Var', (137, 147))	('bladder cancer', 'Phenotype', 'HP:0009725', (263, 277))	('14-3-3epsilon', 'Gene', '7531', (68, 81))	('14-3-3', 'Gene', '10971', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('expression', 'MPA', (41, 51))	('CDK', 'molecular_function', 'GO:0004693', ('197', '200'))	('14-3-3', 'Gene', '10971', (83, 89))	('activity', 'MPA', (212, 220))	('14-3-3epsilon', 'Gene', (68, 81))	('14-3-3', 'Gene', (118, 124))	('reduction', 'NegReg', (184, 193))	('cyclin B1', 'Gene', (202, 211))	('cyclin B1', 'Gene', '891', (202, 211))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('244', '259'))	('14-3-3sigma', 'Gene', (83, 94))	('14-3-3sigma', 'Gene', '2810', (83, 94))	('Gadd45alpha', 'Gene', '1647', (55, 66))	('Gadd45alpha', 'Gene', (55, 66))	('14-3-3', 'Gene', '10971', (118, 124))	('14-3-3', 'Gene', (68, 74))	('14-3-3', 'Gene', (83, 89))
184760	29071385	Aberrant expression of PKD isoforms has been reported in multiple types of carcinomas, making it a promising target in the development of novel therapies for human cancers.	('reported', 'Reg', (45, 53))	('Aberrant', 'Var', (0, 8))	('human', 'Species', '9606', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('cancers', 'Disease', (164, 171))	('expression', 'MPA', (9, 19))	('carcinomas', 'Disease', 'MESH:D009369', (75, 85))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('carcinomas', 'Disease', (75, 85))
184763	29071385	Furthermore, we found that shRNA-mediated knockdown of PKD2 expression compromised bladder carcinoma growth and migration in vitro and in vivo, suggesting that the antitumor activity of CRT0066101 is mediated through inhibition of PKD2 in bladder cancer.	('bladder carcinoma growth', 'Disease', (83, 107))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('PKD2', 'Gene', (55, 59))	('CRT0066101', 'Chemical', 'MESH:C551536', (186, 196))	('bladder carcinoma growth', 'Disease', 'MESH:D001749', (83, 107))	('bladder cancer', 'Disease', (239, 253))	('bladder cancer', 'Disease', 'MESH:D001749', (239, 253))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('compromised', 'NegReg', (71, 82))	('CRT0066101', 'Var', (186, 196))	('bladder cancer', 'Phenotype', 'HP:0009725', (239, 253))	('knockdown', 'Var', (42, 51))
184764	29071385	This notion was verified through the demonstration that the activity of PKD2 was dramatically reduced in CRT0066101-treated bladder tumor explants.	('bladder tumor', 'Disease', 'MESH:D001749', (124, 137))	('bladder tumor', 'Phenotype', 'HP:0009725', (124, 137))	('reduced', 'NegReg', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('bladder tumor', 'Disease', (124, 137))	('activity', 'MPA', (60, 68))	('CRT0066101-treated', 'Var', (105, 123))	('CRT0066101', 'Chemical', 'MESH:C551536', (105, 115))	('PKD2', 'Enzyme', (72, 76))
184766	29071385	In addition, our cell cycle analysis revealed that CRT0066101 treatment induced bladder carcinoma cell cycle arrest at the G2/M phase.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('98', '115'))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (80, 97))	('cell cycle', 'biological_process', 'GO:0007049', ('17', '27'))	('CRT0066101', 'Chemical', 'MESH:C551536', (51, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (98, 115))	('M phase', 'biological_process', 'GO:0000279', ('126', '133'))	('arrest', 'Disease', 'MESH:D006323', (109, 115))	('bladder carcinoma', 'Disease', (80, 97))	('bladder carcinoma', 'Disease', 'MESH:D001749', (80, 97))	('CRT0066101', 'Var', (51, 61))	('arrest', 'Disease', (109, 115))
184767	29071385	Further experiments showed that depletion of PKD2 also caused cell cycle G2/M phase arrest in the same tumor cell model.	('PKD2', 'Var', (45, 49))	('M phase', 'biological_process', 'GO:0000279', ('76', '83'))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cell cycle', 'biological_process', 'GO:0007049', ('62', '72'))	('tumor', 'Disease', (103, 108))	('arrest', 'Disease', 'MESH:D006323', (84, 90))	('depletion', 'MPA', (32, 41))	('arrest', 'Disease', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
184768	29071385	Taken together, these results indicate that CRT0066101-blocked bladder cancer growth is through induction of G2/M phase arrest of the cell cycle, and that the effect of the compound on cell cycle arrest is mediated through inhibition of PKD2 in bladder urothelial cell carcinoma.	('CRT0066101-blocked', 'Var', (44, 62))	('arrest', 'Disease', 'MESH:D006323', (120, 126))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (185, 202))	('cell cycle', 'biological_process', 'GO:0007049', ('134', '144'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('185', '202'))	('arrest', 'Disease', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('bladder urothelial cell carcinoma', 'Disease', (245, 278))	('bladder cancer', 'Disease', 'MESH:D001749', (63, 77))	('bladder cancer', 'Disease', (63, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('M phase', 'biological_process', 'GO:0000279', ('112', '119'))	('bladder cancer', 'Phenotype', 'HP:0009725', (63, 77))	('bladder urothelial cell carcinoma', 'Disease', 'MESH:D001749', (245, 278))	('arrest', 'Disease', 'MESH:D006323', (196, 202))	('PKD2', 'Enzyme', (237, 241))	('CRT0066101', 'Chemical', 'MESH:C551536', (44, 54))	('arrest', 'Disease', (120, 126))	('inhibition', 'NegReg', (223, 233))
184769	29071385	Recently, several small molecule inhibitors targeting PKD2 including CRT0066101 have been identified, and the latter is currently under intensive investigation for preclinical development as an anticancer agent.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('CRT0066101', 'Chemical', 'MESH:C551536', (69, 79))	('cancer', 'Disease', (198, 204))	('PKD2', 'Var', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('CRT0066101', 'Var', (69, 79))
184770	29071385	Harikumar and colleagues first show that CRT0066101 given orally (80 mg/kg/day) for 24 and 21 days abrogate pancreatic cancer growth in vivo in xenograft model and orthotopic model, respectively.	('CRT0066101', 'Chemical', 'MESH:C551536', (41, 51))	('pancreatic cancer', 'Disease', (108, 125))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('CRT0066101', 'Var', (41, 51))	('abrogate', 'NegReg', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))
184772	29071385	Consistently, we show in this study that CRT0066101 at 120 mg/kg/day orally for 25 days (3 days/week) in UMUC1 subcutaneous xenograft model potently blocked bladder cancer growth in vivo (Fig.	('blocked', 'NegReg', (149, 156))	('CRT0066101', 'Chemical', 'MESH:C551536', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('bladder cancer', 'Disease', 'MESH:D001749', (157, 171))	('CRT0066101', 'Var', (41, 51))	('bladder cancer', 'Disease', (157, 171))
184774	29071385	Although we have all shown that CRT0066101 is an effective drug in our own tumor models, the focus of our studies on the mechanisms of the compound differs from each other.	('CRT0066101', 'Var', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('CRT0066101', 'Chemical', 'MESH:C551536', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
184775	29071385	demonstrate that CRT0066101 increases apoptosis in pancreatic cancer cells, and that the effect of the drug on apoptosis is mediated through abrogating the expression of NF-kappaB-dependent proliferative and prosurvival proteins including cyclin D1, survivin, and cIAP-1.	('cyclin', 'molecular_function', 'GO:0016538', ('239', '245'))	('CRT0066101', 'Chemical', 'MESH:C551536', (17, 27))	('increases', 'PosReg', (28, 37))	('cyclin D1', 'Gene', (239, 248))	('apoptosis', 'CPA', (38, 47))	('CRT0066101', 'Var', (17, 27))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (51, 68))	('cyclin D1', 'Gene', '595', (239, 248))	('apoptosis', 'biological_process', 'GO:0097194', ('38', '47'))	('apoptosis', 'biological_process', 'GO:0006915', ('38', '47'))	('cIAP-1', 'Gene', (264, 270))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cIAP-1', 'Gene', '329', (264, 270))	('pancreatic cancer', 'Disease', 'MESH:D010190', (51, 68))	('survivin', 'Protein', (250, 258))	('NF-kappaB', 'Gene', (170, 179))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('pancreatic cancer', 'Disease', (51, 68))	('NF-kappaB', 'Gene', '4790', (170, 179))	('expression', 'MPA', (156, 166))	('abrogating', 'NegReg', (141, 151))
184776	29071385	In Wei and coworkers' investigation, they find that in addition to induction of apoptosis in human colorectal cancer cells, CRT0066101 also induces G2/M phase arrest in their tumor models.	('tumor', 'Disease', (175, 180))	('arrest', 'Disease', 'MESH:D006323', (159, 165))	('induces', 'Reg', (140, 147))	('colorectal cancer', 'Disease', (99, 116))	('human', 'Species', '9606', (93, 98))	('M phase', 'biological_process', 'GO:0000279', ('151', '158'))	('CRT0066101', 'Chemical', 'MESH:C551536', (124, 134))	('arrest', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('67', '89'))	('CRT0066101', 'Var', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))
184778	29071385	Whereas our group show that CRT0066101 had similar effect on G2/M phase accumulation in bladder cancer cells, and we take a step further to elucidate the molecular mechanisms underlying the effect of the compound on G2/M cell cycle arrest in our bladder tumor model system (Figs.	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))	('CRT0066101', 'Chemical', 'MESH:C551536', (28, 38))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (221, 238))	('bladder cancer', 'Disease', 'MESH:D001749', (88, 102))	('bladder cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('bladder tumor', 'Disease', 'MESH:D001749', (246, 259))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('221', '238'))	('arrest', 'Disease', 'MESH:D006323', (232, 238))	('M phase', 'biological_process', 'GO:0000279', ('64', '71'))	('CRT0066101', 'Var', (28, 38))	('G2/M', 'MPA', (61, 65))	('bladder tumor', 'Phenotype', 'HP:0009725', (246, 259))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('arrest', 'Disease', (232, 238))	('bladder tumor', 'Disease', (246, 259))
184786	29071385	In this study, we found that, in the CRT0066101-treated UMUC1 bladder tumor, the levels of CDK1, phospho-CDK1 (Thr161), and cyclin B1 were decreased, whereas the levels of phospho-CDK1 (Thr14) and phospho-CDK1 (Tyr15) were increased, all these leading to reduced activity of the CDK1-cyclin B1 complex.	('CDK1', 'Gene', (180, 184))	('Thr161', 'Chemical', '-', (111, 117))	('CDK', 'molecular_function', 'GO:0004693', ('91', '94'))	('bladder tumor', 'Disease', (62, 75))	('CDK', 'molecular_function', 'GO:0004693', ('279', '282'))	('CDK', 'molecular_function', 'GO:0004693', ('180', '183'))	('activity', 'MPA', (263, 271))	('bladder tumor', 'Disease', 'MESH:D001749', (62, 75))	('reduced', 'NegReg', (255, 262))	('CDK1', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CDK1', 'Gene', '983', (105, 109))	('cyclin', 'molecular_function', 'GO:0016538', ('284', '290'))	('Thr14', 'Chemical', '-', (186, 191))	('CDK1', 'Gene', '983', (91, 95))	('CDK1', 'Gene', (91, 95))	('cyclin B1', 'Gene', (124, 133))	('cyclin B1', 'Gene', '891', (124, 133))	('CRT0066101', 'Chemical', 'MESH:C551536', (37, 47))	('CDK', 'molecular_function', 'GO:0004693', ('105', '108'))	('CRT0066101-treated', 'Var', (37, 55))	('CDK1', 'Gene', '983', (279, 283))	('Tyr15', 'Chemical', '-', (211, 216))	('cyclin', 'molecular_function', 'GO:0016538', ('124', '130'))	('CDK1', 'Gene', (279, 283))	('CDK1', 'Gene', '983', (205, 209))	('CDK', 'molecular_function', 'GO:0004693', ('205', '208'))	('bladder tumor', 'Phenotype', 'HP:0009725', (62, 75))	('CDK1', 'Gene', (205, 209))	('cyclin B1', 'Gene', '891', (284, 293))	('cyclin B1', 'Gene', (284, 293))	('levels', 'MPA', (81, 87))	('decreased', 'NegReg', (139, 148))	('CDK1', 'Gene', '983', (180, 184))
184787	29071385	These data suggest that the G2/M arrest by CRT0066101 in our tumor model is due to a decrease in CDK1 phosphorylation on Thr161 by CDK-activating kinase (CAK), an increase in CDK1 phosphorylation on Thr14 and Tyr15 by Myt1 and Wee1, and a reduction in CDK1 and cyclin B1 protein levels.	('CAK', 'Gene', (154, 157))	('protein', 'cellular_component', 'GO:0003675', ('271', '278'))	('cyclin B1', 'Gene', '891', (261, 270))	('cyclin B1', 'Gene', (261, 270))	('Wee1', 'Gene', (227, 231))	('CDK1', 'Gene', '983', (252, 256))	('CDK1', 'Gene', (252, 256))	('CDK', 'molecular_function', 'GO:0004693', ('252', '255'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CDK', 'molecular_function', 'GO:0004693', ('131', '134'))	('M arrest', 'Disease', 'MESH:D006323', (31, 39))	('cyclin', 'molecular_function', 'GO:0016538', ('261', '267'))	('CDK', 'molecular_function', 'GO:0004693', ('97', '100'))	('CDK-activating kinase', 'Gene', '1022', (131, 152))	('decrease', 'NegReg', (85, 93))	('Wee1', 'Gene', '7465', (227, 231))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CDK', 'molecular_function', 'GO:0004693', ('175', '178'))	('CAK', 'molecular_function', 'GO:0019912', ('154', '157'))	('phosphorylation', 'biological_process', 'GO:0016310', ('180', '195'))	('M arrest', 'Disease', (31, 39))	('CDK1', 'Gene', (97, 101))	('CDK1', 'Gene', '983', (97, 101))	('Tyr15', 'Chemical', '-', (209, 214))	('reduction', 'NegReg', (239, 248))	('increase', 'PosReg', (163, 171))	('CDK-activating kinase', 'Gene', (131, 152))	('CDK1', 'Gene', '983', (175, 179))	('CDK1', 'Gene', (175, 179))	('CRT0066101', 'Chemical', 'MESH:C551536', (43, 53))	('Thr14', 'Chemical', '-', (199, 204))	('phosphorylation', 'MPA', (180, 195))	('phosphorylation', 'biological_process', 'GO:0016310', ('102', '117'))	('CRT0066101', 'Var', (43, 53))	('Myt1', 'Gene', (218, 222))	('Thr161', 'Chemical', '-', (121, 127))	('CAK', 'Gene', '1022', (154, 157))	('tumor', 'Disease', (61, 66))	('Myt1', 'Gene', '4661', (218, 222))
184788	29071385	Additionally, we showed that CRT0066101 downregulated the expression of Cdc25C, which dephosphorylates/activates CDK1, but increased the activity of the cell cycle checkpoint kinase Chk1, which phosphorylates/inactivates Cdc25C and leads to enhanced Cdc25C phosphorylation at the Ser216 residue in our model system.	('Ser216', 'Chemical', '-', (280, 286))	('expression', 'MPA', (58, 68))	('Cdc25C', 'Gene', '995', (72, 78))	('enhanced', 'PosReg', (241, 249))	('Chk1', 'Gene', (182, 186))	('Chk1', 'Gene', '1111', (182, 186))	('Cdc25C', 'Gene', (72, 78))	('CDK1', 'Gene', '983', (113, 117))	('CDK1', 'Gene', (113, 117))	('Cdc25C', 'Gene', '995', (221, 227))	('phosphorylation', 'biological_process', 'GO:0016310', ('257', '272'))	('CRT0066101', 'Chemical', 'MESH:C551536', (29, 39))	('CRT0066101', 'Var', (29, 39))	('increased', 'PosReg', (123, 132))	('Cdc25C', 'Gene', (221, 227))	('CDK', 'molecular_function', 'GO:0004693', ('113', '116'))	('downregulated', 'NegReg', (40, 53))	('Ser', 'cellular_component', 'GO:0005790', ('280', '283'))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('153', '174'))	('Cdc25C', 'Gene', '995', (250, 256))	('phosphorylates/inactivates', 'NegReg', (194, 220))	('Cdc25C', 'Gene', (250, 256))	('activity', 'MPA', (137, 145))
184790	29071385	For instance, G2/M cell cycle-blocking agents have been shown to inhibit Cdc25C activity through phosphorylation of the Ser216 by upstream Chk1 kinase.	('Chk1', 'Gene', (139, 143))	('Cdc25C', 'Gene', (73, 79))	('Ser216', 'Chemical', '-', (120, 126))	('Chk1', 'Gene', '1111', (139, 143))	('Cdc25C', 'Gene', '995', (73, 79))	('Ser', 'cellular_component', 'GO:0005790', ('120', '123'))	('Ser216', 'Var', (120, 126))	('cell cycle', 'biological_process', 'GO:0007049', ('19', '29'))	('phosphorylation', 'MPA', (97, 112))	('inhibit', 'NegReg', (65, 72))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))
184791	29071385	Therefore, the effect of CRT0066101 on G2/M arrest in UMUC1 cells may be mediated by Chk1 activation through a p53-independent Chk1/Cdc25C/CDK1 signaling pathway.	('CRT0066101', 'Chemical', 'MESH:C551536', (25, 35))	('CDK1', 'Gene', (139, 143))	('Cdc25C', 'Gene', (132, 138))	('Chk1', 'Gene', (127, 131))	('activation', 'PosReg', (90, 100))	('signaling pathway', 'biological_process', 'GO:0007165', ('144', '161'))	('Chk1', 'Gene', (85, 89))	('p53', 'Gene', (111, 114))	('Cdc25C', 'Gene', '995', (132, 138))	('p53', 'Gene', '7157', (111, 114))	('Chk1', 'Gene', '1111', (127, 131))	('CRT0066101', 'Var', (25, 35))	('Chk1', 'Gene', '1111', (85, 89))	('CDK', 'molecular_function', 'GO:0004693', ('139', '142'))	('M arrest', 'Disease', 'MESH:D006323', (42, 50))	('M arrest', 'Disease', (42, 50))	('CDK1', 'Gene', '983', (139, 143))
184792	29071385	Finally, we demonstrate that CRT0066101 induced increases in the levels of p27kip1, Gadd45alpha, 14-3-3epsilon, 14-3-3sigma, and other isoforms of 14-3-3 proteins in UMUC1 bladder cancer cells.	('levels', 'MPA', (65, 71))	('14-3-3sigma', 'Gene', (112, 123))	('14-3-3', 'Gene', (112, 118))	('14-3-3sigma', 'Gene', '2810', (112, 123))	('Gadd45alpha', 'Gene', '1647', (84, 95))	('Gadd45alpha', 'Gene', (84, 95))	('14-3-3epsilon', 'Gene', '7531', (97, 110))	('14-3-3', 'Gene', (97, 103))	('14-3-3', 'Gene', '10971', (147, 153))	('CRT0066101', 'Chemical', 'MESH:C551536', (29, 39))	('14-3-3', 'Gene', '10971', (112, 118))	('CRT0066101', 'Var', (29, 39))	('14-3-3epsilon', 'Gene', (97, 110))	('increases', 'PosReg', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('14-3-3', 'Gene', '10971', (97, 103))	('p27kip1', 'Gene', '1027', (75, 82))	('bladder cancer', 'Disease', 'MESH:D001749', (172, 186))	('bladder cancer', 'Disease', (172, 186))	('p27kip1', 'Gene', (75, 82))	('bladder cancer', 'Phenotype', 'HP:0009725', (172, 186))	('14-3-3', 'Gene', (147, 153))
184803	29071385	Although CRT0066101 can modulate the activation and expression of several G2/M transition regulators in our bladder tumor model, the ability of CRT0066101 to upregulate 14-3-3sigma in UMUC1 cells was unexpected, because 14-3-3sigma has been demonstrated to be a transcriptional target of p53, and we show by DNA sequencing that UMUC1 cells express a mutated form of p53 (data not given).	('14-3-3sigma', 'Gene', '2810', (169, 180))	('CRT0066101', 'Chemical', 'MESH:C551536', (144, 154))	('p53', 'Gene', '7157', (366, 369))	('bladder tumor', 'Disease', 'MESH:D001749', (108, 121))	('bladder tumor', 'Phenotype', 'HP:0009725', (108, 121))	('CRT0066101', 'Chemical', 'MESH:C551536', (9, 19))	('p53', 'Gene', (288, 291))	('14-3-3sigma', 'Gene', (220, 231))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('14-3-3sigma', 'Gene', (169, 180))	('14-3-3sigma', 'Gene', '2810', (220, 231))	('p53', 'Gene', '7157', (288, 291))	('DNA', 'cellular_component', 'GO:0005574', ('308', '311'))	('bladder tumor', 'Disease', (108, 121))	('mutated', 'Var', (350, 357))	('p53', 'Gene', (366, 369))
184805	29071385	Our data are consistent with the literature reporting upregulation of 14-3-3sigma in several pancreatic carcinoma cell lines with mutated p53 phenotype is controlled by an alternative p53-independent mechanism.	('p53', 'Gene', (138, 141))	('pancreatic carcinoma', 'Disease', (93, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('p53', 'Gene', '7157', (138, 141))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (93, 113))	('p53', 'Gene', (184, 187))	('upregulation', 'PosReg', (54, 66))	('p53', 'Gene', '7157', (184, 187))	('14-3-3sigma', 'Gene', (70, 81))	('mutated', 'Var', (130, 137))	('14-3-3sigma', 'Gene', '2810', (70, 81))
184807	29071385	In this model, PKD2 inhibition by CRT0066101 treatment regulates the G2/M transition via modulation of the cyclin dependent kinase CDK1, which is essential for entry into mitosis.	('CDK1', 'Gene', '983', (131, 135))	('CDK1', 'Gene', (131, 135))	('cyclin', 'molecular_function', 'GO:0016538', ('107', '113'))	('CRT0066101', 'Var', (34, 44))	('G2/M transition', 'CPA', (69, 84))	('modulation', 'Reg', (89, 99))	('CDK', 'molecular_function', 'GO:0004693', ('131', '134'))	('regulates', 'Reg', (55, 64))	('cyclin', 'Gene', '891', (107, 113))	('cyclin', 'Gene', (107, 113))	('CRT0066101', 'Chemical', 'MESH:C551536', (34, 44))	('entry into mitosis', 'biological_process', 'GO:0051727', ('160', '178'))
184809	29071385	Following treatment of bladder tumor cells with CRT0066101, the activity of Chk1 kinase is increased, which activates the inhibitory kinases Myt1 and Wee1, which then phosphorylate CDK1 at Thr14 and Tyr15, keeping the CDK1-cyclin B1 complex inactive during G2.	('CRT0066101', 'Chemical', 'MESH:C551536', (48, 58))	('Wee1', 'Gene', '7465', (150, 154))	('bladder tumor', 'Disease', 'MESH:D001749', (23, 36))	('activity', 'MPA', (64, 72))	('CRT0066101', 'Var', (48, 58))	('CDK', 'molecular_function', 'GO:0004693', ('181', '184'))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('CDK', 'molecular_function', 'GO:0004693', ('218', '221'))	('CDK1', 'Gene', (218, 222))	('CDK1', 'Gene', '983', (218, 222))	('increased', 'PosReg', (91, 100))	('Chk1', 'Gene', (76, 80))	('Myt1', 'Gene', (141, 145))	('Chk1', 'Gene', '1111', (76, 80))	('activates', 'PosReg', (108, 117))	('Myt1', 'Gene', '4661', (141, 145))	('bladder tumor', 'Phenotype', 'HP:0009725', (23, 36))	('Tyr15', 'Chemical', '-', (199, 204))	('Wee1', 'Gene', (150, 154))	('cyclin B1', 'Gene', '891', (223, 232))	('cyclin B1', 'Gene', (223, 232))	('bladder tumor', 'Disease', (23, 36))	('CDK1', 'Gene', '983', (181, 185))	('CDK1', 'Gene', (181, 185))	('Thr14', 'Chemical', '-', (189, 194))	('cyclin', 'molecular_function', 'GO:0016538', ('223', '229'))
184810	29071385	At the onset of mitosis, both of these residues (Thr14/Tyr15) are dephosphorylated by the activating phosphatase Cdc25C.	('phosphatase', 'molecular_function', 'GO:0016791', ('101', '112'))	('mitosis', 'biological_process', 'GO:0000278', ('16', '23'))	('Thr14', 'Chemical', '-', (49, 54))	('Thr14/Tyr15', 'Var', (49, 60))	('Tyr15', 'Chemical', '-', (55, 60))	('Cdc25C', 'Gene', (113, 119))	('Cdc25C', 'Gene', '995', (113, 119))	('dephosphorylated', 'MPA', (66, 82))
184817	29071385	Lastly, we show in this study a significant reduction in migration and invasion of bladder cancer cells in response to silencing and pharmacological inhibition of PKD2.	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('invasion', 'CPA', (71, 79))	('migration', 'CPA', (57, 66))	('reduction', 'NegReg', (44, 53))	('PKD2', 'Gene', (163, 167))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('silencing', 'Var', (119, 128))	('bladder cancer', 'Disease', (83, 97))
184818	29071385	The mechanisms accounting for the reduced invasive ability of bladder tumor cells by CRT0066101 treatment or PKD2 depletion are not clear.	('CRT0066101', 'Chemical', 'MESH:C551536', (85, 95))	('invasive ability', 'CPA', (42, 58))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('reduced', 'NegReg', (34, 41))	('CRT0066101', 'Var', (85, 95))	('bladder tumor', 'Disease', (62, 75))	('bladder tumor', 'Disease', 'MESH:D001749', (62, 75))	('bladder tumor', 'Phenotype', 'HP:0009725', (62, 75))
184821	29071385	Recent evidence shows that CRT0066101 treatment or PKD2 silencing markedly decreases tumor cell migration and invasion, prevents PKD2 and c-Jun phosphorylation, and inhibits downstream activation of p44/42 MAPK, p54/46 JNK, p38 MAPK, and NF-kappaB signaling.	('silencing', 'Var', (56, 65))	('tumor', 'Disease', (85, 90))	('PKD2', 'Gene', (51, 55))	('cell migration', 'biological_process', 'GO:0016477', ('91', '105'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('MAPK', 'molecular_function', 'GO:0004707', ('228', '232'))	('NF-kappaB', 'Gene', (238, 247))	('inhibits', 'NegReg', (165, 173))	('p38 MAPK', 'Pathway', (224, 232))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('NF-kappaB', 'Gene', '4790', (238, 247))	('decreases', 'NegReg', (75, 84))	('signaling', 'biological_process', 'GO:0023052', ('248', '257'))	('c-Jun', 'Gene', '3725', (138, 143))	('JNK', 'Gene', (219, 222))	('MAPK', 'molecular_function', 'GO:0004707', ('206', '210'))	('c-Jun', 'Gene', (138, 143))	('p44/42 MAPK', 'Pathway', (199, 210))	('JNK', 'Gene', '5599', (219, 222))	('CRT0066101', 'Chemical', 'MESH:C551536', (27, 37))	('JNK', 'molecular_function', 'GO:0004705', ('219', '222'))	('prevents', 'NegReg', (120, 128))	('Jun phosphorylation', 'biological_process', 'GO:0007258', ('140', '159'))
184822	29071385	Silencing of PKD2 also downregulates the expression of integrin alpha2/4, uPA, uPAR, and MMP1, but increases plasminogen activator inhibitor-2 (PAI-2) expression in cancer cells.	('integrin alpha2/4', 'Gene', (55, 72))	('uPAR', 'Gene', (79, 83))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('uPA', 'Gene', (79, 82))	('Silencing', 'Var', (0, 9))	('increases', 'PosReg', (99, 108))	('uPA', 'Gene', '5328', (79, 82))	('expression', 'MPA', (41, 51))	('MMP1', 'Gene', '4312', (89, 93))	('MMP1', 'Gene', (89, 93))	('uPAR', 'Gene', '5329', (79, 83))	('PAI-2', 'Gene', (144, 149))	('MMP1', 'molecular_function', 'GO:0004232', ('89', '93'))	('increases plasminogen', 'Phenotype', 'HP:0040228', (99, 120))	('expression', 'MPA', (151, 161))	('uPAR', 'molecular_function', 'GO:0030377', ('79', '83'))	('cancer', 'Disease', (165, 171))	('downregulates', 'NegReg', (23, 36))	('PKD2', 'Gene', (13, 17))	('PAI-2', 'Gene', '5055', (144, 149))	('uPA', 'Gene', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('uPA', 'Gene', '5328', (74, 77))	('plasminogen activator inhibitor-2', 'Gene', '5055', (109, 142))	('uPA', 'molecular_function', 'GO:0008243', ('74', '77'))	('integrin alpha2/4', 'Gene', '3673;3676', (55, 72))	('plasminogen activator inhibitor-2', 'Gene', (109, 142))
184823	29071385	Further, PKD2 is found to enhance the activity of uPA and MMP9, whereas depletion of PKD2 significantly impairs uPA and MMP9 activity in prostate carcinoma cells.	('uPA', 'Gene', (112, 115))	('uPA', 'Gene', '5328', (112, 115))	('PKD2', 'Var', (85, 89))	('MMP9', 'molecular_function', 'GO:0004229', ('120', '124'))	('uPA', 'molecular_function', 'GO:0008243', ('50', '53'))	('MMP9', 'molecular_function', 'GO:0004229', ('58', '62'))	('prostate carcinoma', 'Disease', 'MESH:D011471', (137, 155))	('depletion', 'MPA', (72, 81))	('activity', 'MPA', (38, 46))	('activity', 'MPA', (125, 133))	('PKD2', 'Var', (9, 13))	('impairs', 'NegReg', (104, 111))	('uPA', 'molecular_function', 'GO:0008243', ('112', '115'))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (137, 155))	('enhance', 'PosReg', (26, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('MMP9', 'Gene', '4318', (58, 62))	('MMP9', 'Gene', (58, 62))	('uPA', 'Gene', '5328', (50, 53))	('uPA', 'Gene', (50, 53))	('MMP9', 'Gene', '4318', (120, 124))	('prostate carcinoma', 'Disease', (137, 155))	('MMP9', 'Gene', (120, 124))
184824	29071385	These findings suggest that the distinct reduction in tumor cell migration and invasion by pharmacologic inhibition and silencing of PKD2 is mediated via regulating expression of the genes involved in invasion and metastasis in the uPA-uPAR and MMP pathways.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cell migration', 'biological_process', 'GO:0016477', ('60', '74'))	('uPA', 'Gene', (236, 239))	('uPA', 'Gene', '5328', (236, 239))	('MMP', 'molecular_function', 'GO:0004235', ('245', '248'))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('uPAR', 'molecular_function', 'GO:0030377', ('236', '240'))	('uPAR', 'Gene', (236, 240))	('regulating', 'Reg', (154, 164))	('MMP', 'Gene', '4312;4318', (245, 248))	('invasion', 'CPA', (79, 87))	('PKD2', 'Gene', (133, 137))	('reduction', 'NegReg', (41, 50))	('uPA', 'Gene', '5328', (232, 235))	('uPA', 'Gene', (232, 235))	('expression', 'MPA', (165, 175))	('uPA', 'molecular_function', 'GO:0008243', ('232', '235'))	('uPAR', 'Gene', '5329', (236, 240))	('silencing', 'Var', (120, 129))	('MMP', 'Gene', (245, 248))	('tumor', 'Disease', (54, 59))
184826	29071385	However, the mechanism for how CRT0066101 reduces bladder carcinoma cell migration and invasion via inhibition of PKD2 remains experimentally determined.	('bladder carcinoma', 'Disease', 'MESH:D001749', (50, 67))	('cell migration', 'biological_process', 'GO:0016477', ('68', '82'))	('reduces', 'NegReg', (42, 49))	('CRT0066101', 'Chemical', 'MESH:C551536', (31, 41))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (50, 67))	('reduces bladder', 'Phenotype', 'HP:0005343', (42, 57))	('bladder carcinoma', 'Disease', (50, 67))	('invasion', 'CPA', (87, 95))	('CRT0066101', 'Var', (31, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
184828	29071385	Moreover, CRT0066101 had differential effects on cell survival between human urothelial bladder cancer cells and nontumorigenic human uroepithelial cells.	('effects', 'Reg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cell survival', 'CPA', (49, 62))	('CRT0066101', 'Var', (10, 20))	('urothelial bladder cancer', 'Disease', (77, 102))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('CRT0066101', 'Chemical', 'MESH:C551536', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('human', 'Species', '9606', (128, 133))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (77, 102))	('tumor', 'Disease', (116, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))	('human', 'Species', '9606', (71, 76))
184830	29071385	However, further investigation is required to examine whether CRT0066101-induced G2/M arrest links to apoptosis, delineate the p53-dependent signaling pathway by which CRT0066101 triggers cell cycle arrest, as well as elucidate the mechanism underlying the inhibitory effect of CRT0066101 on cancer cell migration and metastatic progression.	('CRT0066101', 'Chemical', 'MESH:C551536', (278, 288))	('CRT0066101', 'Chemical', 'MESH:C551536', (168, 178))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('arrest', 'Disease', (86, 92))	('CRT0066101', 'Var', (168, 178))	('signaling pathway', 'biological_process', 'GO:0007165', ('141', '158'))	('arrest', 'Disease', 'MESH:D006323', (199, 205))	('p53', 'Gene', '7157', (127, 130))	('CRT0066101', 'Chemical', 'MESH:C551536', (62, 72))	('metastatic', 'CPA', (318, 328))	('cancer', 'Disease', (292, 298))	('CRT0066101-induced', 'Var', (62, 80))	('p53', 'Gene', (127, 130))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('M arrest', 'Disease', 'MESH:D006323', (84, 92))	('cell migration', 'biological_process', 'GO:0016477', ('299', '313'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (188, 205))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('188', '205'))	('cell cycle', 'CPA', (188, 198))	('arrest', 'Disease', (199, 205))	('M arrest', 'Disease', (84, 92))	('cancer', 'Disease', 'MESH:D009369', (292, 298))
184832	29071385	These findings also provide a scientific basis for developing the use of CRT0066101 as a novel intravesical agent or a combinatorial treatment for use with other drugs (e.g., cell cycle checkpoint inhibitors, histone deacetylase inhibitors, and heat shock protein 90 inhibitors) as a potentially more effective chemotherapeutic regimen for treatment of bladder tumors, and suggest that further clinical study on PKD inhibition-mediated therapy in patients with bladder cancer is warranted.	('bladder cancer', 'Disease', (461, 475))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('175', '196'))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('shock', 'Phenotype', 'HP:0031273', (250, 255))	('bladder cancer', 'Phenotype', 'HP:0009725', (461, 475))	('CRT0066101', 'Chemical', 'MESH:C551536', (73, 83))	('bladder tumors', 'Disease', 'MESH:D001749', (353, 367))	('tumors', 'Phenotype', 'HP:0002664', (361, 367))	('bladder tumors', 'Phenotype', 'HP:0009725', (353, 367))	('patients', 'Species', '9606', (447, 455))	('bladder tumors', 'Disease', (353, 367))	('protein', 'cellular_component', 'GO:0003675', ('256', '263'))	('bladder cancer', 'Disease', 'MESH:D001749', (461, 475))	('cancer', 'Phenotype', 'HP:0002664', (469, 475))	('bladder tumor', 'Phenotype', 'HP:0009725', (353, 366))	('CRT0066101', 'Var', (73, 83))
184857	33677681	Patients with a TPS >= 1% had an increased ORR compared to those < 1%, with the highest benefit in the patients with >= 50% TPS.	('Patients', 'Species', '9606', (0, 8))	('ORR', 'MPA', (43, 46))	('>= 1%', 'Var', (20, 25))	('patients', 'Species', '9606', (103, 111))
184858	33677681	The indication for metastatic NSCLC was expanded in 2016, to include patients with TPS >= 1% with disease progression on or after platinum-containing chemotherapy and metastatic NSCLC with high PD-L1 expression (TPS >= 50%) with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment.	('PD-L1', 'Gene', (194, 199))	('NSCLC', 'Disease', (178, 183))	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('EGFR', 'molecular_function', 'GO:0005006', ('232', '236'))	('tumor aberrations', 'Disease', (252, 269))	('ALK', 'Gene', '238', (240, 243))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('patients', 'Species', '9606', (69, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('high', 'Var', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('ALK', 'Gene', (240, 243))	('NSCLC', 'Phenotype', 'HP:0030358', (178, 183))	('platinum', 'Chemical', 'MESH:D010984', (130, 138))	('EGFR', 'Gene', '1956', (232, 236))	('EGFR', 'Gene', (232, 236))	('NSCLC', 'Disease', (30, 35))	('tumor aberrations', 'Disease', 'MESH:D002869', (252, 269))
184859	33677681	An improved overall survival rate was seen in patients with high PD-L1 expression.	('patients', 'Species', '9606', (46, 54))	('overall survival', 'MPA', (12, 28))	('improved', 'PosReg', (3, 11))	('high', 'Var', (60, 64))	('PD-L1', 'Gene', (65, 70))
184865	33677681	Patients with a positive PD-L1 expression (CPS > 1) derived benefit, and those patients who expressed a CPS > 20 were found to have the most benefit, with an increase in OS when treated with pembrolizumab with chemotherapy compared to cetuximab with chemotherapy.	('CPS', 'Chemical', '-', (104, 107))	('cetuximab', 'Chemical', 'MESH:D000068818', (235, 244))	('pembrolizumab', 'Chemical', 'MESH:C582435', (191, 204))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (79, 87))	('CPS', 'Chemical', '-', (43, 46))	('expression', 'Var', (31, 41))	('PD-L1', 'Gene', (25, 30))
184871	33677681	Mutations in the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) can lead to MSI due to errors in the DNA microsatellites.	('MSH6', 'Gene', (52, 56))	('errors', 'Reg', (91, 97))	('MSI', 'Gene', (80, 83))	('PMS2', 'Gene', (62, 66))	('MSI', 'Gene', '5928', (80, 83))	('PMS2', 'Gene', '5395', (62, 66))	('MSH6', 'Gene', '2956', (52, 56))	('Mutations', 'Var', (0, 9))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('lead to', 'Reg', (72, 79))	('MSH2', 'Gene', (46, 50))	('mismatch repair', 'biological_process', 'GO:0006298', ('17', '32'))	('MSH2', 'Gene', '4436', (46, 50))	('MLH1', 'Gene', '4292', (40, 44))	('MLH1', 'Gene', (40, 44))
184872	33677681	Tumors with high levels of mismatch repair mutations are commonly associated with higher levels of neoantigen production, rendering the tumors susceptible to the ICI therapy.	('mismatch repair', 'biological_process', 'GO:0006298', ('27', '42'))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('mismatch repair', 'Protein', (27, 42))	('higher', 'PosReg', (82, 88))	('Tumors', 'Disease', (0, 6))	('mutations', 'Var', (43, 52))	('levels of neoantigen production', 'MPA', (89, 120))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
184875	33677681	Within the Keynote-158 (NCT02628067) clinical trial, retrospective analysis was performed on tumor samples and the TMB of >= 10 or >= 13 mutations (mut) per Mb was analyzed by the Foundation One CDx.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('mutations', 'Var', (137, 146))	('TMB', 'Chemical', '-', (115, 118))	('CDx', 'Chemical', '-', (195, 198))
184877	33677681	The higher mutational burden within a tumor is expected to correspond to a higher level of immunogenic neopeptides that would drive T cell-mediated anti-tumor immunity.	('mutational', 'Var', (11, 21))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('higher', 'PosReg', (75, 81))	('drive', 'PosReg', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('level of immunogenic neopeptides', 'MPA', (82, 114))
184882	33677681	In the CheckMate 057 and CheckMate 063, similar retrospective stratification was performed, which demonstrated that PD-L1 expression was predictive of benefit to treatment with nivolumab.	('benefit', 'PosReg', (151, 158))	('nivolumab', 'Chemical', 'MESH:D000077594', (177, 186))	('expression', 'Var', (122, 132))	('PD-L1', 'Gene', (116, 121))
184887	33677681	TMB stratification was divided into three groups, with low < 85, medium 85-169, and high >= 170 missense somatic mutations per tumor.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('low < 85', 'Var', (55, 63))	('tumor', 'Disease', (127, 132))	('TMB', 'Chemical', '-', (0, 3))	('high >= 170 missense somatic', 'Var', (84, 112))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
184891	33677681	Recurrence-free survival was higher in patients with a higher PD-L1 expression, though all patients experienced greater benefit when treated with nivolumab compared to ipilimumab.	('higher', 'PosReg', (29, 35))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (39, 47))	('higher', 'Var', (55, 61))	('expression', 'MPA', (68, 78))	('nivolumab', 'Chemical', 'MESH:D000077594', (146, 155))	('Recurrence-free survival', 'CPA', (0, 24))	('PD-L1', 'Gene', (62, 67))	('ipilimumab', 'Chemical', 'MESH:D000074324', (168, 178))
184916	33677681	Tumor specimens were prospectively evaluated using the Ventana PD-L1 (SP142) assay and patients with high levels of PD-L1 expression had improved PR, CR, and ORR.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ORR', 'MPA', (158, 161))	('patients', 'Species', '9606', (87, 95))	('PD-L1', 'Gene', (116, 121))	('high levels', 'Var', (101, 112))	('improved', 'PosReg', (137, 145))
184920	33677681	PD-L1 positivity correlated with improved OS, PFS, and ORR when treated with atezolizumab as a single agent.	('atezolizumab', 'Chemical', 'MESH:C000594389', (77, 89))	('positivity', 'Var', (6, 16))	('PFS', 'Disease', (46, 49))	('PD-L1', 'Gene', (0, 5))	('improved', 'PosReg', (33, 41))	('ORR', 'Disease', (55, 58))
184921	33677681	In May 2020, following the IMpower110 (NCT02409342) clinical trial, the inclusion criteria of high PD-L1 expression >= 50% of tumor cells or >= 10% of tumor-infiltrating immune cells as defined by an FDA-approved device were approved for the treatment of adult metastatic NSCLC with no EGFR or ALK genomic aberrations.	('NSCLC', 'Disease', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('NSCLC', 'Disease', 'MESH:D002289', (272, 277))	('EGFR', 'Gene', '1956', (286, 290))	('ALK', 'Gene', (294, 297))	('EGFR', 'molecular_function', 'GO:0005006', ('286', '290'))	('tumor', 'Disease', (151, 156))	('PD-L1', 'Gene', (99, 104))	('EGFR', 'Gene', (286, 290))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (272, 277))	('ALK', 'Gene', '238', (294, 297))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('high', 'Var', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Disease', (126, 131))
184930	33677681	In the urothelial carcinoma cohort, the PD-L1 high patients experienced an improved disease control rate but patients treated with durvalumab experienced response regardless of PD-L1 status.	('improved', 'PosReg', (75, 83))	('high', 'Var', (46, 50))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (7, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('patients', 'Species', '9606', (109, 117))	('PD-L1', 'Gene', (40, 45))	('patients', 'Species', '9606', (51, 59))	('urothelial carcinoma', 'Disease', (7, 27))	('disease control', 'CPA', (84, 99))	('durvalumab', 'Chemical', 'MESH:C000613593', (131, 141))
184950	33677681	As PD-L1 positivity is still being evaluated as a predictive biomarker in clinical trials, in which patients with negative or non-evaluable tumor samples have also demonstrated a response, additional biomarkers are being assessed to determine their correlation with response rates and to better identify those patients who will respond.	('patients', 'Species', '9606', (310, 318))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('positivity', 'Var', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('patients', 'Species', '9606', (100, 108))	('PD-L1', 'Gene', (3, 8))	('tumor', 'Disease', (140, 145))
184958	33677681	The cancer immunity cycle is initiated when the accumulation of genetic mutations within cancer cell results in the production of neoantigens, which are able to bind to major histocompatibility complex (MHC) molecules on the cancer cell plasma membrane.	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('169', '201'))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('plasma membrane', 'cellular_component', 'GO:0005886', ('237', '252'))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (225, 231))	('genetic mutations', 'Var', (64, 81))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('bind', 'Interaction', (161, 165))	('cancer', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
184964	33677681	Various clinical trials are studying the sequential treatment of ICIs either prior to or following chemotherapies, to determine if this treatment can turn "cold" non-immunogenic tumor to a "hot" tumor, which would respond to ICI treatment (NCT00527735, NCT02499367).	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('NCT00527735', 'Var', (240, 251))
184965	33677681	The goal of these combinations is to modulate the immune suppressive microenvironment and initiate tumor cell death, recruiting effector T cells to the tumor and increasing the efficacy of the ICIs.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('ICIs', 'CPA', (193, 197))	('combinations', 'Var', (18, 30))	('recruiting', 'PosReg', (117, 127))	('tumor', 'Disease', (152, 157))	('tumor cell death', 'Disease', (99, 115))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cell death', 'biological_process', 'GO:0008219', ('105', '115'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('increasing', 'PosReg', (162, 172))	('tumor cell death', 'Disease', 'MESH:D003643', (99, 115))
185092	30815848	In addition to these proteins, other co-stimulatory and co-inhibitory receptors are being targeted in clinical trials, such as GITR, OX40, 4-1BB, LAG-3 and TIM-3.	('OX40', 'Var', (133, 137))	('4-1BB', 'Gene', '3604', (139, 144))	('TIM-3', 'Gene', (156, 161))	('LAG-3', 'Gene', (146, 151))	('LAG-3', 'Gene', '3902', (146, 151))	('4-1BB', 'Gene', (139, 144))	('TIM-3', 'Gene', '84868', (156, 161))
185096	30815848	Consequently, the PK and inter- and intrapatient variability with ICIs can be mediated through the synthesis of anti-mAb, tumor burden effects, changes in proteolytic function and genetic polymorphisms affecting the neonatal Fc receptor (FcRn).	('FcRn', 'Gene', (238, 242))	('mediated', 'Reg', (78, 86))	('FcRn', 'Gene', '2217', (238, 242))	('synthesis', 'biological_process', 'GO:0009058', ('99', '108'))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('proteolytic function', 'MPA', (155, 175))	('patient', 'Species', '9606', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('changes', 'Reg', (144, 151))	('tumor', 'Disease', (122, 127))	('genetic polymorphisms', 'Var', (180, 201))
185110	30815848	Three studies investigated the effect between ipilimumab exposure and clinical outcomes for melanoma (NCT00135408, NCT00289627, and NCT00289640) (Table 3).	('NCT00289640', 'Var', (132, 143))	('NCT00289627', 'Var', (115, 126))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('ipilimumab', 'Chemical', 'MESH:D000074324', (46, 56))	('melanoma', 'Disease', (92, 100))	('NCT00135408', 'Var', (102, 113))
185156	30815848	An exposure-safety analysis for avelumab was performed on pooled data (n = 1629 patients) of the JAVELIN Solid Tumor, Solid Tumor JPN, and Merkel 200 studies (NCT01772004, NCT01943461, and NCT02155647) (Table 4).	('patients', 'Species', '9606', (80, 88))	('NCT02155647', 'Var', (189, 200))	('NCT01943461', 'Var', (172, 183))	('Tumor', 'Phenotype', 'HP:0002664', (111, 116))	('NCT01772004', 'Var', (159, 170))	('Tumor', 'Phenotype', 'HP:0002664', (124, 129))	('avelumab', 'Chemical', 'MESH:C000609138', (32, 40))
185196	30815848	Pembrolizumab exposure-response analysis was performed for melanoma (n = 1366) and NSCLC (n = 496) [NCT01295827, NCT01704287 and NCT01866319) (Table 3).	('NCT01866319', 'Var', (129, 140))	('NCT01704287', 'Var', (113, 124))	('NSCLC', 'Disease', (83, 88))	('[NCT01295827', 'Var', (99, 111))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
185205	30815848	Binding to the FcRn rescues mAbs from lysosomal degradation and is considered the driving mechanism behind the extended half-lives of ICIs (t1/2 6-27 days) (Fig.	('FcRn', 'Gene', (15, 19))	('degradation', 'biological_process', 'GO:0009056', ('48', '59'))	('lysosomal degradation', 'MPA', (38, 59))	('rescues', 'PosReg', (20, 27))	('FcRn', 'Gene', '2217', (15, 19))	('Binding', 'Var', (0, 7))
185264	30815848	Blockage of the PD-1 receptor is therefore considered capable of antagonizing the interaction with both ligands, while PD-L1 blockade allows binding of PD-L2 to PD-1.	('PD-L2', 'Gene', (152, 157))	('Blockage', 'Var', (0, 8))	('PD-1', 'Gene', '5133', (16, 20))	('PD-L2', 'Gene', '80380', (152, 157))	('PD-1', 'Gene', (161, 165))	('PD-1', 'Gene', '5133', (161, 165))	('binding', 'Interaction', (141, 148))	('antagonizing', 'NegReg', (65, 77))	('binding', 'molecular_function', 'GO:0005488', ('141', '148'))	('interaction', 'Interaction', (82, 93))	('PD-1', 'Gene', (16, 20))
185265	30815848	Based on this assumption, it seems reasonable to believe that PD-1 blockage generates more antitumor and autoimmune responses in comparison to PD-L1.	('blockage', 'Var', (67, 75))	('PD-1', 'Gene', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('PD-1', 'Gene', '5133', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('more', 'PosReg', (86, 90))	('tumor', 'Disease', (95, 100))
185286	30815848	Studies with melanoma, NSCLC, renal cancer, SCCHN, and urothelial carcinoma found that intratumoral PD-L1 expression prior to treatment provides a higher likelihood for treatment response, even though absence of PD-L1 expression does not rule out treatment response in all patients.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('NSCLC', 'Disease', (23, 28))	('urothelial carcinoma', 'Disease', (55, 75))	('renal cancer', 'Disease', (30, 42))	('renal cancer', 'Phenotype', 'HP:0009726', (30, 42))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('melanoma', 'Disease', (13, 21))	('treatment response', 'CPA', (169, 187))	('patients', 'Species', '9606', (273, 281))	('renal cancer', 'Disease', 'MESH:D007680', (30, 42))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (55, 75))	('expression', 'Var', (106, 116))	('higher', 'PosReg', (147, 153))	('PD-L1', 'Gene', (100, 105))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
185290	30815848	Nevertheless, the application of PD-L1 testing contains many pitfalls, including deviations in PD-L1 expression in time and location, concomitant PD-L1 expression in the tumor cytoplasm or microenvironment, and inaccuracies of needle biopsies and histological strategies, not to mention discrepancies between diagnostic kits.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('fall', 'Phenotype', 'HP:0002527', (64, 68))	('cytoplasm', 'cellular_component', 'GO:0005737', ('176', '185'))	('deviations', 'Var', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('PD-L1', 'Gene', (95, 100))	('PD-L1', 'Gene', (146, 151))
185292	30815848	However, since not all mutations give rise to immune-stimulating neoepitopes, this approach requires algorithms that can predict the immunogenicity of mutational profiles.	('mutations', 'Var', (23, 32))	('algorithms', 'Disease', 'None', (101, 111))	('algorithms', 'Disease', (101, 111))
185313	30815848	Because PD-1 and PD-L1 govern immune resistance further down the inflammatory cascade, PD-1/PD-L1 inhibitors give rise to relatively less irAEs than CTLA-4 blockers.	('inhibitors', 'Var', (98, 108))	('PD-1', 'Gene', (87, 91))	('less', 'NegReg', (133, 137))	('PD-1', 'Gene', '5133', (87, 91))	('PD-1', 'Gene', (8, 12))	('PD-1', 'Gene', '5133', (8, 12))	('irAEs', 'Disease', (138, 143))	('immune resistance', 'MPA', (30, 47))
185319	30815848	Further comparison of the PD-1 blockers suggests that pembrolizumab induces more irAEs compared with nivolumab; however, the interpretation here should be cautious as the comparison was made between studies.	('induces', 'Reg', (68, 75))	('PD-1', 'Gene', (26, 30))	('PD-1', 'Gene', '5133', (26, 30))	('pembrolizumab', 'Var', (54, 67))	('irAEs', 'Disease', (81, 86))	('pembrolizumab', 'Chemical', 'MESH:C582435', (54, 67))	('nivolumab', 'Chemical', 'MESH:D000077594', (101, 110))
185339	28678605	Furthermore, the large genomic regions affected by these patterns of hypomethylation encompass genes involved in pathways related to epithelial-mesenchymal transition, immune response, and inflammation.	('inflammation', 'Disease', (189, 201))	('inflammation', 'biological_process', 'GO:0006954', ('189', '201'))	('hypomethylation', 'Var', (69, 84))	('immune response', 'biological_process', 'GO:0006955', ('168', '183'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('133', '166'))	('inflammation', 'Disease', 'MESH:D007249', (189, 201))
185346	28678605	Studies on DNA methylation in cancer cells and placental cells have highlighted similarities in their epigenetic landscapes, which are characterized by a widespread hypomethylation throughout the genome and focal hypermethylation at CpG islands, including at promoters of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor suppressor', 'biological_process', 'GO:0051726', ('272', '288'))	('tumor', 'Disease', (272, 277))	('DNA methylation', 'biological_process', 'GO:0006306', ('11', '26'))	('cancer', 'Disease', (30, 36))	('hypomethylation', 'Var', (165, 180))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('272', '288'))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('placental', 'Species', '9347', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
185347	28678605	A recent study also linked the observation of genes specifically expressed in both the placenta and various tumors to hypomethylation.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('hypomethylation', 'Var', (118, 133))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
185349	28678605	We hypothesized that there may be parallels between the patterns of methylation that distinguish the early pregnancy placenta from the late pregnancy placenta and those that distinguish tumors from corresponding normal tissues, and that such similar epigenetic patterns may contribute to the regulation of shared cancer/placenta phenotypes.	('late pregnancy', 'Phenotype', 'HP:0001622', (135, 149))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('contribute', 'Reg', (274, 284))	('methylation', 'Var', (68, 79))	('regulation', 'biological_process', 'GO:0065007', ('292', '302'))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('early pregnancy', 'Phenotype', 'HP:0001622', (101, 116))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumors', 'Disease', (186, 192))	('cancer', 'Disease', (313, 319))	('cancer', 'Disease', 'MESH:D009369', (313, 319))
185350	28678605	Therefore, we conducted a genome-wide comparison of DNA methylation changes in placental tissues during pregnancy and in 13 types of tumor tissues during neoplastic transformation.	('placental', 'Species', '9347', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('DNA methylation', 'biological_process', 'GO:0006306', ('52', '67'))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('DNA', 'Gene', (52, 55))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('tumor', 'Disease', (133, 138))	('methylation', 'Var', (56, 67))
185362	28678605	Given the similarities between the patterns of hypomethylation in first trimester placental chorionic villi and cancers, we sought to further characterize the genomic regions involved.	('hypomethylation', 'Var', (47, 62))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('placental', 'Species', '9347', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
185363	28678605	Methylomes of solid tumors have been shown to display hypomethylated blocks, defined as large regions within which the average methylation is reduced compared with normal tissues.	('methylation', 'MPA', (127, 138))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('reduced', 'NegReg', (142, 149))	('solid tumors', 'Disease', (14, 26))	('hypomethylated', 'Var', (54, 68))	('methylation', 'biological_process', 'GO:0032259', ('127', '138'))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('solid tumors', 'Disease', 'MESH:D009369', (14, 26))
185371	28678605	Taken together, these observations reveal that the patterns of hypomethylation that distinguish first from third trimester placental tissues are similar in structure, size and location to those that distinguish tumors from matched normal tissues.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('placental', 'Species', '9347', (123, 132))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('hypomethylation', 'Var', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))
185383	28678605	More recently, independent studies in cancer biology and placenta biology have suggested similarities between epigenetic patterns in placental and cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('epigenetic patterns', 'Var', (110, 129))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (38, 44))	('cancer', 'Disease', (147, 153))	('placental', 'Species', '9347', (133, 142))
185385	28678605	We report here that epigenetic similarities between cancer and placenta are most striking in early pregnancy placenta, and that the similarities are partially erased as pregnancy progresses.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('epigenetic similarities', 'Var', (20, 43))	('early pregnancy', 'Phenotype', 'HP:0001622', (93, 108))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
185386	28678605	We also find that these shared epigenetic patterns relate to pivotal genes in both placentogenesis and carcinogenesis.	('placentogenesis', 'Disease', (83, 98))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('relate', 'Reg', (51, 57))	('carcinogenesis', 'Disease', (103, 117))	('epigenetic', 'Var', (31, 41))
185392	28678605	Hypomethylated blocks have initially been described in cancers using whole-genome bisulfite sequencing.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('bisulfite', 'Chemical', 'MESH:C042345', (82, 91))	('Hypomethylated', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))
185395	28678605	These studies have thus established hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('human', 'Species', '9606', (107, 112))	('solid tumors', 'Disease', 'MESH:D009369', (113, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('hypomethylated blocks', 'Var', (36, 57))	('solid tumors', 'Disease', (113, 125))
185396	28678605	Using TCGA data for 13 cancer types, we also observed hypomethylated blocks in breast, colon, lung, pancreas and thyroid cancers, as well as described such hypomethylation patterns for the first time in liver, head and neck, bladder, uterus, esophageal and prostate cancers.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast', 'Disease', (79, 85))	('prostate cancers', 'Phenotype', 'HP:0012125', (257, 273))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('pancreas and thyroid cancers', 'Disease', 'MESH:D010190', (100, 128))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('uterus', 'Disease', (234, 240))	('hypomethylated', 'Var', (54, 68))	('neck', 'cellular_component', 'GO:0044326', ('219', '223'))	('liver', 'Disease', (203, 208))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('bladder', 'Disease', (225, 232))	('lung', 'Disease', (94, 98))	('cancer', 'Disease', (23, 29))	('colon', 'Disease', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('cancer', 'Disease', (266, 272))	('thyroid cancer', 'Phenotype', 'HP:0002890', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Disease', (121, 127))	('esophageal and prostate cancers', 'Disease', 'MESH:D011471', (242, 273))
185400	28678605	Moreover, we also observed that hypomethylated blocks distinguish villous cytotrophoblasts before and after they first come into contact with maternal blood (weeks 10-12), providing the first non-cancer evidence of large-scale hypomethylated blocks in a purified cell type.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('hypomethylated', 'Var', (32, 46))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (196, 202))
185413	28678605	Further analyses of these patterns could eventually lead to the identification of critical epigenetic switches that prevent healthy placentas from degenerating into tumors, and whose failure allows tumor development.	('epigenetic switches', 'Var', (91, 110))	('failure allows tumor', 'Disease', 'MESH:D009369', (183, 203))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('failure allows tumor', 'Disease', (183, 203))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('lead to', 'Reg', (52, 59))
185454	27233780	CTU limitations leading to unclear findings might include flat lesions or focal wall thickening or sub-centimeter lesions for which attenuation measurements are difficult to characterize the lesion, or may be nonspecific findings.	('focal wall thickening', 'CPA', (74, 95))	('flat', 'Disease', (58, 62))	('CTU', 'Chemical', '-', (0, 3))	('sub-centimeter', 'Var', (99, 113))
185475	27233780	UroVysion showed abnormalities in 91% of CIS and all invasive cancers and about 30% of nonneoplastic lesions in patients with concomitant urothelial carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('invasive cancers', 'Disease', (53, 69))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (138, 158))	('CIS', 'Disease', (41, 44))	('patients', 'Species', '9606', (112, 120))	('nonneoplastic lesions', 'Disease', 'MESH:D004194', (87, 108))	('nonneoplastic lesions', 'Disease', (87, 108))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('abnormalities', 'Var', (17, 30))	('invasive cancers', 'Disease', 'MESH:D009362', (53, 69))	('urothelial carcinoma', 'Disease', (138, 158))
185492	27233780	The risk of IVR is even greater in patients managed with KPP, and such patients might logically benefit from the adjuvant intravesical instillation of chemotherapy.	('KPP', 'Var', (57, 60))	('patients', 'Species', '9606', (71, 79))	('patients', 'Species', '9606', (35, 43))	('KPP', 'Chemical', '-', (57, 60))	('IVR', 'Disease', (12, 15))
185520	28382144	Our results suggest that the overexpression of B7-H3 promotes the migration and invasion of human bladder cancer cells through the PI3K/Akt/STAT3 signaling pathway.	('invasion', 'CPA', (80, 88))	('promotes', 'PosReg', (53, 61))	('overexpression', 'PosReg', (29, 43))	('migration', 'CPA', (66, 75))	('PI3K', 'molecular_function', 'GO:0016303', ('131', '135'))	('PI3', 'Gene', (131, 134))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('PI3', 'Gene', '5266', (131, 134))	('B7-H3', 'Var', (47, 52))	('signaling pathway', 'biological_process', 'GO:0007165', ('146', '163'))	('human', 'Species', '9606', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
185525	28382144	These treatment modalities include monoclonal antibodies, cancer vaccines and cytokine therapies.	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('monoclonal', 'Var', (35, 45))
185527	28382144	Members of the B7 superfamily, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1), represent negative co-stimulators that inhibit T cell function, and inhibitors of these factors hold promise in the treatment of bladder cancer.	('PD-1', 'Gene', '5133', (118, 122))	('cytotoxic T-lymphocyte-associated antigen 4', 'Gene', '397286', (39, 82))	('cytotoxic T-lymphocyte-associated antigen 4', 'Gene', (39, 82))	('bladder cancer', 'Phenotype', 'HP:0009725', (297, 311))	('inhibitors', 'Var', (236, 246))	('inhibit', 'NegReg', (207, 214))	('bladder cancer', 'Disease', 'MESH:D001749', (297, 311))	('programmed cell death', 'biological_process', 'GO:0012501', ('128', '149'))	('T cell function', 'CPA', (215, 230))	('programmed cell death', 'biological_process', 'GO:0012501', ('93', '114'))	('CTLA-4', 'Gene', '397286', (84, 90))	('CTLA-4', 'Gene', (84, 90))	('bladder cancer', 'Disease', (297, 311))	('ligand', 'molecular_function', 'GO:0005488', ('150', '156'))	('programmed cell death ligand 1', 'Gene', '574058', (128, 158))	('programmed cell death ligand 1', 'Gene', (128, 158))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('PD-1', 'Gene', (118, 122))
185528	28382144	However, objective response rates have been higher for patients with high expression of PD-L1 /PD-1 than for those with low expression of these factors.	('PD-1', 'Gene', '5133', (95, 99))	('PD-1', 'Gene', (95, 99))	('higher', 'PosReg', (44, 50))	('high expression', 'Var', (69, 84))	('objective response rates', 'CPA', (9, 33))	('patients', 'Species', '9606', (55, 63))
185538	28382144	It was reported that the expression of B7-H3 was potentially increased in urothelial cell carcinoma samples compared with non-tumor urothelial samples and that MGA271, the engineered anti-B7-H3 mAb, exhibited potent in vivo antitumor activity against bladder cell carcinoma xenografts.	('B7-H3', 'Gene', (39, 44))	('bladder cell carcinoma xenografts', 'Disease', (251, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('expression', 'MPA', (25, 35))	('urothelial cell carcinoma', 'Disease', (74, 99))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('anti-B7-H3', 'Var', (183, 193))	('increased', 'PosReg', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', (228, 233))	('urothelial cell carcinoma', 'Disease', 'MESH:C538614', (74, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('bladder cell carcinoma xenografts', 'Disease', 'MESH:D001749', (251, 284))	('tumor', 'Disease', (126, 131))
185550	28382144	The primary antibodies included antibodies against B7-H3, PI3K, p-PI3K, Akt, p-Akt, STAT3, p-STAT3 (Cell Signaling Technology, USA), Ki67 (Santa Cruz biotechnology, USA), matrix metalloproteinase (MMP) 2, and MMP9 (GeneTex, USA), GAPDH.	('B7-H3', 'Protein', (51, 56))	('matrix metalloproteinase (MMP) 2', 'Gene', '4313', (171, 203))	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('GAPDH', 'Gene', (230, 235))	('MMP9', 'molecular_function', 'GO:0004229', ('209', '213'))	('Signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('p-STAT3', 'Var', (91, 98))	('Ki67', 'Gene', (133, 137))	('PI3', 'Gene', '5266', (58, 61))	('MMP) 2', 'molecular_function', 'GO:0004228', ('197', '203'))	('PI3K', 'molecular_function', 'GO:0016303', ('66', '70'))	('PI3', 'Gene', '5266', (66, 69))	('PI3', 'Gene', (58, 61))	('GAPDH', 'Gene', '2597', (230, 235))	('PI3', 'Gene', (66, 69))	('MMP9', 'Gene', (209, 213))	('Ki67', 'Gene', '17345', (133, 137))
185559	28382144	Immunohistochemical staining revealed a significantly greater percentage of bladder urothelial carcinoma samples expressing B7-H3 than adjacent normal tissue samples (P<0.001, Table 3), the intensity of B7-H3 expression was markedly increased in malignant tissue compared to normal tissue, and B7-H3 expression was localized to the entire urothelium (Fig.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (76, 104))	('bladder urothelial carcinoma', 'Disease', (76, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('B7-H3', 'Var', (124, 129))	('increased', 'PosReg', (233, 242))
185572	28382144	Thus, MMP2 and MMP9 are regarded as important markers of cancer cell invasion.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('MMP2', 'molecular_function', 'GO:0004228', ('6', '10'))	('MMP9', 'molecular_function', 'GO:0004229', ('15', '19'))	('MMP9', 'Var', (15, 19))	('MMP2', 'Var', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
185573	28382144	Previous studies have shown that B7-H3 stimulates invasion of hepatocellular carcinoma and melanoma cells via the JAK2/STAT3/Slug or STAT3 signaling pathways, respectively.	('invasion', 'CPA', (50, 58))	('stimulates', 'PosReg', (39, 49))	('hepatocellular carcinoma', 'Disease', (62, 86))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (62, 86))	('JAK2', 'Gene', (114, 118))	('JAK', 'molecular_function', 'GO:0004713', ('114', '117'))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('Slug', 'Gene', '6591', (125, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('STAT3 signaling pathways', 'Pathway', (133, 157))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('Slug', 'Gene', (125, 129))	('B7-H3', 'Var', (33, 38))	('JAK2', 'Gene', '3717', (114, 118))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (62, 86))
185574	28382144	We also found that siB7-H3 transfection decreased the expression level of p-STAT3 in bladder cancer cells (Fig.	('bladder cancer', 'Phenotype', 'HP:0009725', (85, 99))	('expression level', 'MPA', (54, 70))	('siB7-H3 transfection', 'Var', (19, 39))	('transfection', 'Var', (27, 39))	('bladder cancer', 'Disease', 'MESH:D001749', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('bladder cancer', 'Disease', (85, 99))	('decreased', 'NegReg', (40, 49))
185578	28382144	To explore whether there was cross-talk between the STAT3 and PI3K/Akt pathways, we performed experiments using the PI3K inhibitor LY294002 and the STAT3 inhibitor WP1066.	('PI3K', 'molecular_function', 'GO:0016303', ('62', '66'))	('LY294002', 'Chemical', 'MESH:C085911', (131, 139))	('PI3', 'Gene', '5266', (62, 65))	('PI3', 'Gene', '5266', (116, 119))	('LY294002', 'Var', (131, 139))	('PI3', 'Gene', (62, 65))	('PI3', 'Gene', (116, 119))	('PI3K', 'molecular_function', 'GO:0016303', ('116', '120'))
185579	28382144	We observed that the expression of both p-Akt and p-STAT3 was effectively suppressed upon addition of LY294002.	('suppressed', 'NegReg', (74, 84))	('LY294002', 'Chemical', 'MESH:C085911', (102, 110))	('expression', 'MPA', (21, 31))	('p-STAT3', 'Gene', (50, 57))	('p-Akt', 'Pathway', (40, 45))	('LY294002', 'Var', (102, 110))
185582	28382144	Furthermore, siB7-H3 transfection significantly decreased the expression of MMP2 and MMP9 cooperated with LY294002 or WP1066 (Fig.	('LY294002', 'Var', (106, 114))	('MMP9', 'molecular_function', 'GO:0004229', ('85', '89'))	('expression', 'MPA', (62, 72))	('decreased', 'NegReg', (48, 57))	('LY294002', 'Chemical', 'MESH:C085911', (106, 114))	('MMP2', 'molecular_function', 'GO:0004228', ('76', '80'))	('MMP2', 'Gene', (76, 80))	('MMP9', 'Gene', (85, 89))
185586	28382144	A correlation was observed between overexpression of B7-H3 and tumor stages (invading depth), for the expression level of B7-H3 was higher in T2-T4 tumors than in Ta-T1 tumors, then analysis of B7-H3 expression may be necessary for the prediction of bladder cancer prognosis.	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('B7-H3', 'Var', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('Ta-T1 tumors', 'Disease', (163, 175))	('Ta-T1 tumors', 'Disease', 'MESH:D009369', (163, 175))	('tumor', 'Disease', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('bladder cancer', 'Phenotype', 'HP:0009725', (250, 264))	('T2-T4', 'Var', (142, 147))	('higher', 'PosReg', (132, 138))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('expression', 'MPA', (102, 112))	('bladder cancer', 'Disease', 'MESH:D001749', (250, 264))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('bladder cancer', 'Disease', (250, 264))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumors', 'Disease', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
185592	28382144	Post-transcriptional mechanisms are central to the control of MMP activity because MMPs are secreted in inactive zymogens and are activated by cleavage of their N-terminal prodomain.	('cleavage', 'Var', (143, 151))	('MMPs', 'Gene', '4313;17390;4318;17395', (83, 87))	('activated', 'PosReg', (130, 139))	('MMPs', 'Gene', (83, 87))	('MMP', 'molecular_function', 'GO:0004235', ('62', '65'))
185596	28382144	It was reported that 42% of all bladder cancer patients harbor mutations in the PI3K/Akt/mTOR pathway and that the PI3K/Akt pathway can regulate bladder cancer cell invasion.	('patients', 'Species', '9606', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('mutations', 'Var', (63, 72))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('bladder cancer', 'Disease', (32, 46))	('PI3', 'Gene', (115, 118))	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('PI3', 'Gene', '5266', (80, 83))	('PI3K', 'molecular_function', 'GO:0016303', ('80', '84'))	('mTOR', 'Gene', (89, 93))	('PI3K', 'molecular_function', 'GO:0016303', ('115', '119'))	('mTOR', 'Gene', '2475', (89, 93))	('PI3', 'Gene', (80, 83))	('regulate', 'Reg', (136, 144))	('PI3', 'Gene', '5266', (115, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (145, 159))	('bladder cancer', 'Disease', (145, 159))
185600	28382144	In summary, we found that B7-H3 is significantly upregulated in human bladder cancer tissues compared with adjacent normal tissues, overexpression of B7-H3 promoted cell migration and invasion but not proliferation and apoptosis, and knockdown B7-H3 suppressed the expression of MMP2 and MMP9 via the PI3K/Akt/STAT3 signaling pathway (Fig.	('cell migration', 'CPA', (165, 179))	('MMP9', 'molecular_function', 'GO:0004229', ('288', '292'))	('expression', 'MPA', (265, 275))	('knockdown', 'Var', (234, 243))	('PI3K', 'molecular_function', 'GO:0016303', ('301', '305'))	('PI3', 'Gene', '5266', (301, 304))	('MMP2', 'molecular_function', 'GO:0004228', ('279', '283'))	('MMP2', 'Gene', (279, 283))	('apoptosis', 'biological_process', 'GO:0097194', ('219', '228'))	('apoptosis', 'biological_process', 'GO:0006915', ('219', '228'))	('bladder cancer', 'Disease', 'MESH:D001749', (70, 84))	('promoted', 'PosReg', (156, 164))	('bladder cancer', 'Disease', (70, 84))	('human', 'Species', '9606', (64, 69))	('invasion', 'CPA', (184, 192))	('PI3', 'Gene', (301, 304))	('proliferation', 'CPA', (201, 214))	('upregulated', 'PosReg', (49, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('MMP9', 'Gene', (288, 292))	('suppressed', 'NegReg', (250, 260))	('cell migration', 'biological_process', 'GO:0016477', ('165', '179'))	('signaling pathway', 'biological_process', 'GO:0007165', ('316', '333'))
185627	26308952	ICD-O codes used included C67.0 (trigone of bladder), C67.1 (dome of bladder), C67.2 (lateral wall of bladder), C67.3 (anterior wall of bladder), C67.4 (posterior wall of bladder), C67.5 (bladder neck), C67.6 (ureteric orifice), C67.7 (urachus), C67.8 (overlapping lesion of bladder), and C67.9 (bladder NOS).	('C67.2', 'Var', (79, 84))	('C67.0', 'Var', (26, 31))	('C67.6', 'Var', (203, 208))	('C67.9', 'Var', (289, 294))	('neck', 'cellular_component', 'GO:0044326', ('196', '200'))	('C67.3', 'Var', (112, 117))	('C67.1', 'Var', (54, 59))	('C67.5', 'Var', (181, 186))	('OS', 'Chemical', '-', (305, 307))	('ICD', 'Disease', 'OMIM:252500', (0, 3))	('C67.8', 'Var', (246, 251))	('C67.4', 'Var', (146, 151))	('C67.7', 'Var', (229, 234))	('lesion of bladder', 'Phenotype', 'HP:0009725', (265, 282))	('ICD', 'Disease', (0, 3))
185684	26308952	Furthermore, these data establish benchmarks for novel therapies such as programmed death-1 (PD-1) inhibitors.	('programmed death-1', 'Gene', (73, 91))	('programmed death-1', 'Gene', '5133', (73, 91))	('inhibitors', 'Var', (99, 109))	('PD-1', 'Gene', (93, 97))	('PD-1', 'Gene', '5133', (93, 97))
185736	25125901	Ionizing radiation is thought to promote tumorigenesis via genetic alteration, including mutations of TP53 and retinoblastoma tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('TP53', 'Gene', (102, 106))	('promote', 'PosReg', (33, 40))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('126', '142'))	('tumor', 'Disease', (41, 46))	('Ionizing radiation', 'Disease', 'MESH:D004194', (0, 18))	('Ionizing radiation', 'Disease', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('mutations', 'Var', (89, 98))	('tumor suppressor', 'biological_process', 'GO:0051726', ('126', '142'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (111, 125))	('TP53', 'Gene', '7157', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('retinoblastoma tumor', 'Disease', 'MESH:D012175', (111, 131))	('retinoblastoma tumor', 'Disease', (111, 131))	('tumor', 'Disease', (126, 131))
185821	33299884	Another study revealed that high body mass index (BMI) was positively associated with the incidence of several types of cancer, while patients with high BMI at the time of initial diagnosis had higher two/five-year survival rates than those with low BMI.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('higher', 'PosReg', (194, 200))	('high BMI', 'Var', (148, 156))	('low BMI', 'Phenotype', 'HP:0045082', (246, 253))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('associated', 'Reg', (70, 80))	('patients', 'Species', '9606', (134, 142))	('high body mass index', 'Phenotype', 'HP:0031418', (28, 48))	('two/five-year survival rates', 'CPA', (201, 229))
185835	33299884	The patients were divided into four groups based on BMI: normal weight (18 kg/m2 <= BMI < 25 kg/m2), high weight (25 kg/m2 <= BMI < 30 kg/m2), obese (30 kg/m2 <= BMI<40 kg/m2), and extremely obese (BMI >= 40 kg/m2).	('obese', 'Disease', 'MESH:D009765', (191, 196))	('25 kg/m2 <=', 'Var', (114, 125))	('obese', 'Disease', 'MESH:D009765', (143, 148))	('obese', 'Disease', (191, 196))	('patients', 'Species', '9606', (4, 12))	('30 kg/m2 <=', 'Var', (150, 161))	('obese', 'Disease', (143, 148))
185845	33299884	Mutations, copy number variations (CNVs), and controlling expression levels of obesity-related genes were downloaded from TCGA.	('obesity', 'Phenotype', 'HP:0001513', (79, 86))	('Mutations', 'Var', (0, 9))	('obesity', 'Disease', 'MESH:D009765', (79, 86))	('obesity', 'Disease', (79, 86))	('copy number variations', 'Var', (11, 33))
185872	33299884	As displayed in Figure 2(c), for each of the five obesity-related genes (LEPR, MTCH2, MC4R, LEP, and KCTD15), the patients in a high-expression group had a greater cancer survival rate than those in the low/medium-expression groups (P < 0.05).	('KCTD15', 'Gene', '79047', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('LEP', 'Gene', '3952', (92, 95))	('KCTD15', 'Gene', (101, 107))	('obesity', 'Disease', (50, 57))	('greater', 'PosReg', (156, 163))	('patients', 'Species', '9606', (114, 122))	('LEP', 'Gene', (92, 95))	('obesity', 'Disease', 'MESH:D009765', (50, 57))	('LEPR', 'Gene', '3953', (73, 77))	('cancer', 'Disease', (164, 170))	('LEP', 'Gene', '3952', (73, 76))	('LEPR', 'Gene', (73, 77))	('MC4R', 'Gene', (86, 90))	('high-expression', 'Var', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('MTCH2', 'Gene', '23788', (79, 84))	('LEP', 'Gene', (73, 76))	('obesity', 'Phenotype', 'HP:0001513', (50, 57))	('MC4R', 'Gene', '4160', (86, 90))	('MTCH2', 'Gene', (79, 84))
185875	33299884	For patients with six types of cancer (KIRC, LUAD, LGG, GBM, UCEC, and BLCA), those in the PCSK1 low/medium-expression group had higher survival probability than those in the high-expression group.	('LUAD', 'Phenotype', 'HP:0030078', (45, 49))	('LUAD', 'Disease', (45, 49))	('LGG', 'Disease', (51, 54))	('PCSK1', 'Gene', '5122', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('survival', 'CPA', (136, 144))	('higher', 'PosReg', (129, 135))	('GBM', 'Disease', (56, 59))	('UCEC', 'Disease', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('patients', 'Species', '9606', (4, 12))	('PCSK1', 'Gene', (91, 96))	('cancer', 'Disease', (31, 37))	('low/medium-expression', 'Var', (97, 118))
185876	33299884	However, for patients with SKCM, patients with high expression level of PCSK1 may benefit from a superior survival probability than those with low/medium expression level.	('patients', 'Species', '9606', (33, 41))	('PCSK1', 'Gene', (72, 77))	('survival', 'CPA', (106, 114))	('patients', 'Species', '9606', (13, 21))	('high expression level', 'Var', (47, 68))	('PCSK1', 'Gene', '5122', (72, 77))	('benefit', 'PosReg', (82, 89))
185886	33299884	However, the mutation rates of five obesity-related genes in few cancer tissues were >0.05 (i.e., LEPR in SKCM (0.11), UCEC (0.07), and LUSC (0.07) and PCSK1 in SKCM (0.09) and UCEC (0.06)).	('obesity', 'Disease', 'MESH:D009765', (36, 43))	('obesity', 'Phenotype', 'HP:0001513', (36, 43))	('mutation', 'Var', (13, 21))	('LEPR', 'Gene', (98, 102))	('PCSK1', 'Gene', (152, 157))	('obesity', 'Disease', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('PCSK1', 'Gene', '5122', (152, 157))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('LEPR', 'Gene', '3953', (98, 102))
185891	33299884	Then, for each of the 33 types of cancer, the expression levels of the 13 obesity-related genes were divided into different groups based on the seven factors as follows: (1) patients' gender (male or female), (2) patients' race (African-American, Caucasian, and Asian), (3) menopausal status (premenopause, perimenopause, and postmenopause), (4) history of smoking (smoker, nonsmoker, reformed smoker #1 (<=15 years), and reformed smoker #2 (>15 years)), (5) tumor grade (grade 1, grade 2, grade 3, and grade 4), (6) BMI (normal weight (18 kg/m2 <= BMI < 25 kg/m2), high weight (25 kg/m2 <= BMI < 30 kg/m2), obese (30 kg/m2 <= BMI < 40 kg/m2), and extremely obese (BMI >= 40 kg/m2)), and (7) history of drinking (occasional drinker, social drinker, daily drinker, weekly drinker, and nondrinker).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('menopausal status', 'Phenotype', 'HP:0008209', (274, 291))	('tumor', 'Phenotype', 'HP:0002664', (459, 464))	('patients', 'Species', '9606', (213, 221))	('obese', 'Disease', (658, 663))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('obesity', 'Disease', (74, 81))	('obese', 'Disease', 'MESH:D009765', (658, 663))	('30 kg/m2 <= BMI < 40 kg/m2', 'Var', (615, 641))	('obesity', 'Disease', 'MESH:D009765', (74, 81))	('tumor', 'Disease', (459, 464))	('obese', 'Disease', (608, 613))	('25 kg/m2 <= BMI < 30 kg/m2', 'Var', (579, 605))	('tumor', 'Disease', 'MESH:D009369', (459, 464))	('3 obesity', 'Phenotype', 'HP:0025501', (72, 81))	('obese', 'Disease', 'MESH:D009765', (608, 613))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Disease', (34, 40))	('obesity', 'Phenotype', 'HP:0001513', (74, 81))
185938	33299884	For the majority of obesity-related genes, cancer patients who were in low/medium-expression level group had a superior prognosis than those in the high-expression level group.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Disease', (43, 49))	('obesity', 'Phenotype', 'HP:0001513', (20, 27))	('low/medium-expression level', 'Var', (71, 98))	('obesity', 'Disease', 'MESH:D009765', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('obesity', 'Disease', (20, 27))
185941	33299884	However, for three types of cancer (SKCM, ACC, and LUAD), patients in the high-expression group for GPR120 gene could benefit from a greater prognosis as compared to those in the low/medium-expression level group.	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('high-expression', 'Var', (74, 89))	('benefit', 'PosReg', (118, 125))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('GPR120', 'Gene', '338557', (100, 106))	('GPR120', 'Gene', (100, 106))	('cancer', 'Disease', (28, 34))
185942	33299884	Moreover, for four types of cancer (KIRP, UVM, CESC, and LUSC), patients in the high-expression level group for SH2B1 gene experienced a better prognosis than those in the low/medium-expression level group.	('SH2B1', 'Gene', (112, 117))	('better', 'PosReg', (137, 143))	('high-expression level', 'Var', (80, 101))	('patients', 'Species', '9606', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('UVM', 'Disease', (42, 45))	('CESC', 'Disease', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('SH2B1', 'Gene', '25970', (112, 117))
185947	33299884	According to the Kaplan-Meier survival curves, patients with kidney cancer in the low/medium-expression level group for each of LEPR and NEGR1 genes had a long-time life expectancy in comparison to those in the high-expression level group.	('NEGR1', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('kidney cancer', 'Disease', (61, 74))	('LEPR', 'Gene', '3953', (128, 132))	('patients', 'Species', '9606', (47, 55))	('low/medium-expression level', 'Var', (82, 109))	('kidney cancer', 'Disease', 'MESH:D007680', (61, 74))	('kidney cancer', 'Phenotype', 'HP:0009726', (61, 74))	('LEPR', 'Gene', (128, 132))	('NEGR1', 'Gene', '257194', (137, 142))
185948	33299884	However, patients with kidney cancer in the high-expression level group for each of TMEM18 and SH2B1 genes had a long life expectancy than those who in the low/medium-expression level group.	('kidney cancer', 'Disease', (23, 36))	('SH2B1', 'Gene', '25970', (95, 100))	('TMEM18', 'Gene', '129787', (84, 90))	('patients', 'Species', '9606', (9, 17))	('SH2B1', 'Gene', (95, 100))	('TMEM18', 'Gene', (84, 90))	('high-expression level', 'Var', (44, 65))	('kidney cancer', 'Disease', 'MESH:D007680', (23, 36))	('kidney cancer', 'Phenotype', 'HP:0009726', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
185955	33299884	Once mutations or modify alterations occur for obesity gene, microenvironment probably impacts behavior and adaptive evolution of cancer cells.	('behavior', 'CPA', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('obesity', 'Disease', 'MESH:D009765', (47, 54))	('mutations', 'Var', (5, 14))	('obesity', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('impacts', 'Reg', (87, 94))	('obesity', 'Phenotype', 'HP:0001513', (47, 54))
185985	31293963	Predictors contained in the individualized prediction nomogram included the LNM signature and MLL2 mutation status.	('MLL2', 'Gene', '8085', (94, 98))	('MLL2', 'Gene', (94, 98))	('mutation status', 'Var', (99, 114))
185999	31293963	Therefore, this study aims to develop and validate a pre-operative nomogram that incorporates a LN-metastasis signature and genomic mutations for individualized pre-operative prediction of LN metastasis in patients with bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (220, 234))	('pre', 'molecular_function', 'GO:0003904', ('161', '164'))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('patients', 'Species', '9606', (206, 214))	('genomic mutations', 'Var', (124, 141))	('pre', 'molecular_function', 'GO:0003904', ('53', '56'))	('bladder cancer', 'Disease', 'MESH:D001749', (220, 234))	('bladder cancer', 'Disease', (220, 234))
186001	31293963	Two independent cohorts were gathered for validation including one obtained from Gene Expression Omnibus (https://www/ncbi.nlm.nih.gov/geo/) (GEO cohort) by using R package "GEOquery" with a query of GSE106534 and another that is publicly available through the Memorial Sloan-Kettering Cancer Center (MSKCC cohort) cBioPortal for Cancer Genomics.	('GSE106534', 'Var', (200, 209))	('Gene Expression', 'biological_process', 'GO:0010467', ('81', '96'))	('Cancer', 'Phenotype', 'HP:0002664', (330, 336))	('Cancer', 'Disease', (330, 336))	('Cancer', 'Phenotype', 'HP:0002664', (286, 292))	('Cancer', 'Disease', (286, 292))	('Cancer', 'Disease', 'MESH:D009369', (330, 336))	('Cancer', 'Disease', 'MESH:D009369', (286, 292))
186012	31293963	As expected, tumors with LN+ demonstrated poorer prognosis than LN- (p = 0.002, HR = 1.95, 95% CI = [1.18-3.23], Figure 1A) and a tendency could be observed where LN+ tumors presented a higher recurrence rate (p = 0.083, HR = 1.58, 95% CI = [0.88-2.82], Figure 1B).	('tumors', 'Disease', (13, 19))	('recurrence', 'CPA', (193, 203))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('poorer', 'NegReg', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('LN+', 'Var', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
186015	31293963	After filtering out non-silent mutation, tumors with LN+ exhibited a significant lower burden of mutation load as compared to LN- tumors (p = 0.008) (Figure 2C).	('tumors', 'Disease', (130, 136))	('LN- tumors', 'Disease', (126, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('lower', 'NegReg', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('LN+', 'Var', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('LN- tumors', 'Disease', 'MESH:D009369', (126, 136))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mutation load', 'MPA', (97, 110))
186018	31293963	By intersecting with SMGs, mutation of MLL2 (also known as KMT2D) and PSIP1 were identified for constructing a predictive model.	('PSIP1', 'Gene', (70, 75))	('MLL2', 'Gene', (39, 43))	('mutation', 'Var', (27, 35))	('PSIP1', 'Gene', '11168', (70, 75))	('KMT2D', 'Gene', (59, 64))	('KMT2D', 'Gene', '8085', (59, 64))	('MLL2', 'Gene', '8085', (39, 43))
186022	31293963	Logistic regression analysis identified the pre-operative features of LNM signature and MLL2 mutation as independent predictors (Table 3).	('MLL2', 'Gene', (88, 92))	('mutation', 'Var', (93, 101))	('pre', 'molecular_function', 'GO:0003904', ('44', '47'))	('MLL2', 'Gene', '8085', (88, 92))
186033	31293963	The nomogram offers an easy-to-use tool for pre-operative individualized prediction of LN metastasis and incorporates only two pre-operative items, LNM signature which stratifies patients by their risk of LN metastasis, and mutation status of MLL2.	('pre', 'molecular_function', 'GO:0003904', ('127', '130'))	('pre', 'molecular_function', 'GO:0003904', ('44', '47'))	('mutation', 'Var', (224, 232))	('MLL2', 'Gene', (243, 247))	('patients', 'Species', '9606', (179, 187))	('MLL2', 'Gene', '8085', (243, 247))
186038	31293963	Note that mutation of MLL2, which was differentially mutated between LN+ and LN- tumors (7:46, p = 0.0166), was also a significant variable in the predictive model (p = 0.012).	('MLL2', 'Gene', '8085', (22, 26))	('LN- tumors', 'Disease', 'MESH:D009369', (77, 87))	('LN+', 'Disease', (69, 72))	('mutation', 'Var', (10, 18))	('MLL2', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('LN- tumors', 'Disease', (77, 87))
186039	31293963	MLL2, also known as KMT2D (Lysine Methyltransferase 2D), of which mutation is a driver in numerous different cancer types resulting in transcription stress and genome instability, and a recent study demonstrated that MLL2 could sustain prostate carcinogenesis and metastasis.	('resulting in', 'Reg', (122, 134))	('MLL2', 'Gene', '8085', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('Methyltransferase 2', 'molecular_function', 'GO:0043851', ('34', '53'))	('KMT2D', 'Gene', '8085', (20, 25))	('MLL2', 'Gene', (0, 4))	('prostate carcinogenesis', 'Disease', (236, 259))	('transcription stress', 'MPA', (135, 155))	('mutation', 'Var', (66, 74))	('cancer', 'Disease', (109, 115))	('KMT2D', 'Gene', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('metastasis', 'CPA', (264, 274))	('transcription', 'biological_process', 'GO:0006351', ('135', '148'))	('MLL2', 'Gene', '8085', (217, 221))	('prostate carcinogenesis', 'Disease', 'MESH:D063646', (236, 259))	('Lysine Methyltransferase 2D', 'Gene', (27, 54))	('sustain', 'PosReg', (228, 235))	('Lysine Methyltransferase 2D', 'Gene', '8085', (27, 54))	('MLL2', 'Gene', (217, 221))
186040	31293963	Because the LNM signature and the mutation of MLL2 are available pre-operatively, our nomogram which generates individual probability by integrating the two factors provides clinicians and patients with a pre-operative individualized prediction of the LN metastasis risk, which is in line with the current trend toward personalized medicine.	('MLL2', 'Gene', (46, 50))	('mutation', 'Var', (34, 42))	('pre', 'molecular_function', 'GO:0003904', ('65', '68'))	('MLL2', 'Gene', '8085', (46, 50))	('patients', 'Species', '9606', (189, 197))	('pre', 'molecular_function', 'GO:0003904', ('205', '208'))
186060	29016672	Second, arsenic dosages without bladder carcinogenicity (10 ppm) or with slight carcinogenicity (100 ppm) promote BBN-induced mice bladder cancer progression.	('carcinogenic', 'Disease', (40, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (131, 145))	('bladder cancer', 'Disease', (131, 145))	('bladder carcinogenicity', 'Disease', (32, 55))	('100', 'Var', (97, 100))	('mice', 'Species', '10090', (126, 130))	('bladder carcinogenicity', 'Disease', 'MESH:D001745', (32, 55))	('promote', 'PosReg', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('bladder cancer', 'Phenotype', 'HP:0009725', (131, 145))	('arsenic', 'Chemical', 'MESH:D001151', (8, 15))	('carcinogenic', 'Disease', 'MESH:D063646', (40, 52))	('carcinogenic', 'Disease', 'MESH:D063646', (80, 92))	('BBN', 'Chemical', 'MESH:D002085', (114, 117))	('carcinogenic', 'Disease', (80, 92))
186069	29016672	A previous study including 8102 residents in the arseniasis-endemic area of Taiwan indicates that the relative risks of urothelial carcinoma are 1.9-, 8.2-, and 15.3-fold for well water arsenic concentrations of 10.1-50.0, 50.1-100, and >100 mug/liter, respectively, in comparison with those less than 10.0 mug/liter.	('rat', 'Species', '10116', (201, 204))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (120, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('arseniasis', 'Disease', 'None', (49, 59))	('arseniasis', 'Disease', (49, 59))	('mug', 'molecular_function', 'GO:0043739', ('307', '310'))	('arsenic', 'Chemical', 'MESH:D001151', (186, 193))	('50.1-100', 'Var', (223, 231))	('>100 mug/liter', 'Var', (237, 251))	('urothelial carcinoma', 'Disease', (120, 140))	('mug', 'molecular_function', 'GO:0043739', ('242', '245'))	('water', 'Chemical', 'MESH:D014867', (180, 185))
186072	29016672	Unlike BBN, some evidence has indicated that arsenic alone induces bladder tumors in rats, but not in wide-type mice.	('bladder tumors', 'Disease', 'MESH:D001749', (67, 81))	('rats', 'Species', '10116', (85, 89))	('bladder tumors', 'Phenotype', 'HP:0009725', (67, 81))	('arsenic', 'Chemical', 'MESH:D001151', (45, 52))	('bladder tumors', 'Disease', (67, 81))	('induces', 'Reg', (59, 66))	('arsenic', 'Var', (45, 52))	('BBN', 'Chemical', 'MESH:D002085', (7, 10))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('mice', 'Species', '10090', (112, 116))
186073	29016672	Further, in addition to bladder tissue, arsenic induces tumors in other regions of the body in mice and rats; therefore, it may not be an ideal carcinogen specific to bladder cancer in rodent models.	('arsenic', 'Var', (40, 47))	('mice', 'Species', '10090', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('bladder cancer', 'Phenotype', 'HP:0009725', (167, 181))	('bladder cancer', 'Disease', 'MESH:D001749', (167, 181))	('rats', 'Species', '10116', (104, 108))	('tumors', 'Disease', (56, 62))	('bladder cancer', 'Disease', (167, 181))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('induces', 'Reg', (48, 55))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('arsenic', 'Chemical', 'MESH:D001151', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
186074	29016672	Nevertheless, dimethylarsenic acid (DMA) promotes BBN-induced bladder carcinogenesis in a rat study, indicating that arsenic plays a promoting role.	('DMA', 'Chemical', 'MESH:D002101', (36, 39))	('BBN', 'Chemical', 'MESH:D002085', (50, 53))	('promotes', 'PosReg', (41, 49))	('arsenic', 'Chemical', 'MESH:D001151', (117, 124))	('bladder carcinogenesis', 'Disease', 'MESH:D063646', (62, 84))	('dimethylarsenic', 'Var', (14, 29))	('dimethylarsenic acid', 'Chemical', 'MESH:D002101', (14, 34))	('bladder carcinogenesis', 'Disease', (62, 84))	('arsenic', 'Chemical', 'MESH:D001151', (22, 29))	('rat', 'Species', '10116', (90, 93))
186100	29016672	Anti-GSTO1 (15124-1-AP) was purchased from Proteintech (Chicago, IL, USA).	('GSTO1', 'Gene', '14873', (5, 10))	('GSTO1', 'Gene', (5, 10))	('15124-1-AP', 'Var', (12, 22))
186133	29016672	Furthermore, one hundred ppm arsenic had a higher pontential to induce dysplasia than 10 ppm arsenic did (from 10% to 40%).	('dysplasia', 'Disease', (71, 80))	('arsenic', 'Chemical', 'MESH:D001151', (93, 100))	('arsenic', 'Chemical', 'MESH:D001151', (29, 36))	('one hundred ppm', 'Var', (13, 28))	('dysplasia', 'Disease', 'MESH:D004476', (71, 80))
186141	29016672	In contrast, arsenic induces tumor formation in other body parts, rather than the urinary bladder of mice.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('formation', 'biological_process', 'GO:0009058', ('35', '44'))	('induces', 'Reg', (21, 28))	('arsenic', 'Var', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mice', 'Species', '10090', (101, 105))	('tumor', 'Disease', (29, 34))	('rat', 'Species', '10116', (66, 69))	('arsenic', 'Chemical', 'MESH:D001151', (13, 20))
186149	29016672	For example, a report in Taiwan indicates that the higher the arsenic concentration (0.01-0.05 ppm, 0.05-0.1 ppm, more than 0.1 ppm) in drinking water is, the greater the relative risk of developing bladder cancer in humans.	('bladder cancer', 'Phenotype', 'HP:0009725', (199, 213))	('arsenic', 'Chemical', 'MESH:D001151', (62, 69))	('drinking water', 'Chemical', 'MESH:D060766', (136, 150))	('rat', 'Species', '10116', (77, 80))	('humans', 'Species', '9606', (217, 223))	('bladder cancer', 'Disease', 'MESH:D001749', (199, 213))	('bladder cancer', 'Disease', (199, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('0.05-0.1 ppm', 'Var', (100, 112))	('arsenic', 'MPA', (62, 69))
186152	29016672	In the same concept, an epidemiologic study in Taiwan reported a significantly increased risk of urothelial carcinoma in subjects with high urinary smoking metabolites and total arsenic.	('urothelial carcinoma', 'Disease', (97, 117))	('arsenic', 'Chemical', 'MESH:D001151', (178, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (97, 117))	('high urinary', 'Var', (135, 147))
186155	29016672	For example, some studies have proven that arsenic induces oxidative stress and DNA damage.	('arsenic', 'Var', (43, 50))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('induces', 'Reg', (51, 58))	('oxidative stress', 'Phenotype', 'HP:0025464', (59, 75))	('DNA damage', 'CPA', (80, 90))	('oxidative stress', 'MPA', (59, 75))	('arsenic', 'Chemical', 'MESH:D001151', (43, 50))
186156	29016672	Arsenic increases DNA 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in mouse urothelium as well as enhances oxidative stress and 8-OHdG levels in the mitochondria DNA of keratinocytes.	('8-OHdG', 'Chemical', 'MESH:C067134', (51, 57))	('8-OHdG levels', 'MPA', (127, 140))	('Arsenic', 'Chemical', 'MESH:D001151', (0, 7))	('rat', 'Species', '10116', (170, 173))	("8-hydroxy-2'-deoxyguanosine", 'Chemical', 'MESH:C067134', (22, 49))	('mouse', 'Species', '10090', (69, 74))	('oxidative stress', 'Phenotype', 'HP:0025464', (106, 122))	('Arsenic', 'Var', (0, 7))	('increases', 'PosReg', (8, 17))	('8-OHdG', 'Chemical', 'MESH:C067134', (127, 133))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('oxidative stress', 'MPA', (106, 122))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('enhances', 'PosReg', (97, 105))	('mitochondria', 'cellular_component', 'GO:0005739', ('148', '160'))
186160	29016672	Two other reports suggest that arsenic reduces whole DNA 5-methylcytosine methylation levels in the bladders.	('arsenic', 'Chemical', 'MESH:D001151', (31, 38))	('arsenic', 'Var', (31, 38))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (57, 73))	('whole DNA 5-methylcytosine methylation levels', 'MPA', (47, 92))	('reduces', 'NegReg', (39, 46))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))
186174	29016672	Future work would be necessary to elucidate the underlying mechanisms, particularly the carcinogenic effect related to GSTM1 and p21.	('GSTM1', 'Gene', '14862', (119, 124))	('carcinogenic', 'Disease', (88, 100))	('p21', 'Var', (129, 132))	('GSTM1', 'Gene', (119, 124))	('carcinogenic', 'Disease', 'MESH:D063646', (88, 100))
186221	27777772	Additional chromosomal aberrations included amplification of regions of 1q, 6p, and 10p and loss of 8p, findings that are consistent with the diagnosis of urothelial cancer.	('urothelial cancer', 'Disease', 'MESH:D014523', (155, 172))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (11, 34))	('amplification', 'Var', (44, 57))	('urothelial cancer', 'Disease', (155, 172))	('loss', 'NegReg', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
186240	27777772	When it reactivates, it can cause hemorrhagic cystitis, ureteric stenosis and nephritis.	('hemorrhagic cystitis', 'Disease', (34, 54))	('hemorrhagic cystitis', 'Disease', 'MESH:D003556', (34, 54))	('nephritis', 'Phenotype', 'HP:0000123', (78, 87))	('ureteric stenosis and nephritis', 'Disease', 'MESH:D009393', (56, 87))	('cause', 'Reg', (28, 33))	('ureteric stenosis', 'Phenotype', 'HP:0000071', (56, 73))	('reactivates', 'Var', (8, 19))
186288	26358638	Rearrangements and copy number gain of the ALK gene were not detected by FISH (Fig.	('ALK', 'Gene', (43, 46))	('copy number', 'Var', (19, 30))	('ALK', 'Gene', '238', (43, 46))
186296	26358638	Moreover, recent studies have shown that the majority of IMT express ALK protein, and FISH analysis has identified ALK gene alterations within myofibroblastic spindle cells of IMT, suggesting an etiology of a low-grade mesenchymal neoplasm other than primary inflammatory reaction.	('ALK', 'Gene', (115, 118))	('ALK', 'Gene', '238', (69, 72))	('IMT', 'biological_process', 'GO:1990953', ('57', '60'))	('IMT', 'biological_process', 'GO:1990953', ('176', '179'))	('alterations', 'Var', (124, 135))	('ALK', 'Gene', '238', (115, 118))	('mesenchymal neoplasm', 'Disease', 'MESH:C535700', (219, 239))	('neoplasm', 'Phenotype', 'HP:0002664', (231, 239))	('mesenchymal neoplasm', 'Disease', (219, 239))	('ALK', 'Gene', (69, 72))	('spindle', 'cellular_component', 'GO:0005819', ('159', '166'))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))
186312	24121789	Frequent truncating mutations of STAG2 in bladder cancer Here we report the discovery of truncating mutations of the gene encoding the cohesin subunit STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary non-invasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder.	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('174', '199'))	('urothelial carcinomas of the bladder', 'Phenotype', 'HP:0006740', (292, 328))	('STAG2', 'Gene', (33, 38))	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (241, 271))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('chromatid', 'cellular_component', 'GO:0005694', ('181', '190'))	('STAG2', 'Gene', '10735', (151, 156))	('invasive urothelial carcinomas of the bladder', 'Disease', (283, 328))	('carcinomas', 'Phenotype', 'HP:0030731', (303, 313))	('invasive urothelial carcinomas of the bladder', 'Phenotype', 'HP:0006740', (283, 328))	('chromatid', 'cellular_component', 'GO:0005695', ('181', '190'))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('STAG2', 'Gene', (151, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (261, 271))	('truncating mutations', 'Var', (89, 109))	('invasive urothelial carcinomas', 'Disease', (241, 271))	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (283, 313))	('invasive urothelial carcinomas of the bladder', 'Disease', 'MESH:D001749', (283, 328))	('STAG2', 'Gene', '10735', (33, 38))	('bladder cancer', 'Disease', 'MESH:D001749', (42, 56))	('bladder cancer', 'Disease', (42, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))
186315	24121789	Inactivating mutations of the cohesin complex gene STAG2 have recently been identified in human cancer and were demonstrated to cause chromosome segregation defects and aneuploidy.	('STAG2', 'Gene', (51, 56))	('chromosome segregation', 'biological_process', 'GO:0007059', ('134', '156'))	('cohesin complex', 'cellular_component', 'GO:0008278', ('30', '45'))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('aneuploidy', 'Disease', (169, 179))	('Inactivating mutations', 'Var', (0, 22))	('human', 'Species', '9606', (90, 95))	('aneuploidy', 'Disease', 'MESH:D000782', (169, 179))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('134', '144'))	('chromosome segregation defects', 'CPA', (134, 164))	('cause', 'Reg', (128, 133))	('cancer', 'Disease', (96, 102))
186316	24121789	To identify additional tumor types with inactivation of the STAG2 gene, we screened 2,214 human tumors by immunohistochemistry (IHC) using a STAG2 monoclonal antibody that binds at the carboxyl terminus of the protein.	('antibody', 'cellular_component', 'GO:0019815', ('158', '166'))	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('antibody', 'cellular_component', 'GO:0019814', ('158', '166'))	('tumors', 'Disease', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('antibody', 'molecular_function', 'GO:0003823', ('158', '166'))	('human', 'Species', '9606', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('STAG2', 'Gene', (60, 65))	('tumor', 'Disease', (23, 28))	('antibody', 'cellular_component', 'GO:0042571', ('158', '166'))	('inactivation', 'Var', (40, 52))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
186317	24121789	Virtually all tumor-derived STAG2 mutations discovered to date are truncating (e.g.	('tumor', 'Disease', (14, 19))	('truncating', 'MPA', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('STAG2', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (34, 43))
186318	24121789	nonsense, frameshift, splice-site) which lead to absence of the carboxyl-terminal epitope and therefore loss of expression via IHC with this antibody.	('frameshift', 'Var', (10, 20))	('loss', 'NegReg', (104, 108))	('antibody', 'molecular_function', 'GO:0003823', ('141', '149'))	('antibody', 'cellular_component', 'GO:0042571', ('141', '149'))	('antibody', 'cellular_component', 'GO:0019815', ('141', '149'))	('carboxyl-terminal epitope', 'MPA', (64, 89))	('absence', 'NegReg', (49, 56))	('antibody', 'cellular_component', 'GO:0019814', ('141', '149'))	('expression', 'Species', '29278', (112, 122))	('expression', 'MPA', (112, 122))
186324	24121789	In the vast majority of cases, all tumor cells were negative for STAG2 expression; however, in a small number of cases (2/52), there was evidence of mosaicisim (i.e.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('mosaicisim', 'Var', (149, 159))	('expression', 'Species', '29278', (71, 81))
186328	24121789	Mutations were identified in 9/25 (36%) of pTa non-invasive papillary carcinomas, 6/22 (27%) of pT1 superficially invasive carcinomas, and 8/64 (13%) of pT2-T4 muscle invasive carcinomas.	('papillary carcinomas', 'Disease', 'MESH:D002291', (60, 80))	('muscle invasive carcinomas', 'Disease', 'MESH:D009217', (160, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('pT1', 'Gene', (96, 99))	('invasive carcinomas', 'Disease', 'MESH:D009361', (167, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('invasive carcinomas', 'Disease', 'MESH:D009361', (114, 133))	('invasive carcinomas', 'Disease', (114, 133))	('Mutations', 'Var', (0, 9))	('pTa', 'molecular_function', 'GO:0008959', ('43', '46'))	('pT1', 'Gene', '58492', (96, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('muscle invasive carcinomas', 'Disease', (160, 186))	('papillary carcinomas', 'Disease', (60, 80))
186329	24121789	Tumors with truncating STAG2 mutations were negative for STAG2 expression via IHC (examples in Figure 1B and Supplementary Figure 10).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('expression', 'Species', '29278', (63, 73))	('mutations', 'Var', (29, 38))	('STAG2', 'Gene', (23, 28))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('truncating', 'Reg', (12, 22))
186330	24121789	Tumors with missense mutations retained expression of STAG2 by IHC, demonstrating that IHC fails to identify the ~15% of STAG2-mutant tumors with missense mutations of the gene (Supplementary Figure 11).	('missense mutations', 'Var', (12, 30))	('missense mutations', 'Var', (146, 164))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('STAG2-mutant', 'Gene', (121, 133))	('expression', 'Species', '29278', (40, 50))
186331	24121789	Truncating mutations were also observed in 5/32 urothelial carcinoma cell lines (Supplementary Figure 12).	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('Truncating mutations', 'Var', (0, 20))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (48, 68))	('urothelial carcinoma', 'Disease', (48, 68))
186332	24121789	Tumors and cell lines with STAG2 mutation frequently had concurrent p53 overexpression or mutation (Supplementary Figure 13 and Supplementary Table 3).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutation', 'MPA', (90, 98))	('mutation', 'Var', (33, 41))	('expression', 'Species', '29278', (76, 86))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('overexpression', 'PosReg', (72, 86))	('STAG2', 'Gene', (27, 32))
186333	24121789	Next we performed molecular cytogenetic analysis on 12 primary urothelial carcinomas with STAG2 mutations and 12 stage-matched tumors with wild-type STAG2.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('STAG2', 'Gene', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('urothelial carcinomas', 'Disease', (63, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (63, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('mutations', 'Var', (96, 105))
186335	24121789	9/12 STAG2 mutant tumors studied were overtly aneuploid with up to 35 clonal chromosomal aberrations in a single tumor, whereas 3 tumors with STAG2 mutations did not contain detectable chromosomal aberrations.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('mutant', 'Var', (11, 17))	('tumors', 'Disease', (18, 24))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (185, 208))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', (113, 118))	('STAG2', 'Gene', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (77, 100))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumors', 'Disease', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
186336	24121789	10/12 tumors with wild-type STAG2 also contained chromosomal copy number aberrations, demonstrating that there are other pathways whose perturbation also leads to aneuploidy in bladder cancer.	('leads to', 'Reg', (154, 162))	('contained', 'Reg', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('aneuploidy in bladder cancer', 'Disease', (163, 191))	('tumors', 'Disease', (6, 12))	('chromosomal', 'MPA', (49, 60))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('perturbation', 'Var', (136, 148))	('aneuploidy in bladder cancer', 'Disease', 'MESH:D001749', (163, 191))	('bladder cancer', 'Phenotype', 'HP:0009725', (177, 191))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
186337	24121789	We then constructed a STAG2-expressing lentivirus and infected UM-UC-3, UM-UC-14, and VM-CUB-3 cells, three urothelial carcinoma cell lines with truncating mutations of STAG2 (Figure 2A and Supplementary Figure 16).	('truncating mutations', 'Var', (145, 165))	('urothelial carcinoma', 'Disease', (108, 128))	('STAG2', 'Gene', (169, 174))	('UM-UC-3', 'CellLine', 'CVCL:1783', (63, 70))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (108, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))
186338	24121789	Ectopic re-expression of STAG2 had no adverse effect on cellular proliferation or in vivo growth as subcutaneous xenografts (Figure 2B and Supplementary Figure 16).	('Ectopic re-expression', 'Var', (0, 21))	('expression', 'Species', '29278', (11, 21))	('STAG2', 'Gene', (25, 30))	('cellular proliferation', 'CPA', (56, 78))
186340	24121789	In contrast, depletion of wild-type STAG2 via lentiviral shRNA led to a distinct alteration in the modal chromosome number of RT4 urothelial carcinoma cells (Figure 2C-D and Supplementary Figure 18).	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (130, 150))	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('RT4', 'CellLine', 'CVCL:0036', (126, 129))	('alteration', 'Reg', (81, 91))	('lentiviral', 'Var', (46, 56))	('urothelial carcinoma', 'Disease', (130, 150))	('depletion', 'MPA', (13, 22))	('shRNA', 'Gene', (57, 62))	('modal', 'MPA', (99, 104))
186353	24121789	It is notable that STAG2 mutations occur and are most common in early stage bladder cancers including non-invasive papillary carcinomas.	('mutations', 'Var', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('bladder cancers', 'Phenotype', 'HP:0009725', (76, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('STAG2', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancers', 'Disease', 'MESH:D001749', (76, 91))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('papillary carcinomas', 'Disease', (115, 135))	('common', 'Reg', (54, 60))	('papillary carcinomas', 'Disease', 'MESH:D002291', (115, 135))	('bladder cancers', 'Disease', (76, 91))
186354	24121789	As such, we conclude that STAG2 mutation is an early event in bladder tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('STAG2', 'Gene', (26, 31))	('mutation', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
186355	24121789	Furthermore, we find that the major mechanism for STAG2 inactivation in bladder cancer is somatic nonsense (~85%) and missense (~15%) mutations (rather than homozygous deletion or promoter hypermethylation), since all STAG2-deficient cell lines and primary tumors studied harbor truncating mutations in the gene.	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('inactivation', 'NegReg', (56, 68))	('missense', 'Var', (118, 126))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('STAG2', 'Gene', (50, 55))	('primary tumors', 'Disease', (249, 263))	('mutations', 'Var', (134, 143))	('primary tumors', 'Disease', 'MESH:D009369', (249, 263))	('bladder cancer', 'Disease', 'MESH:D001749', (72, 86))	('truncating', 'MPA', (279, 289))	('bladder cancer', 'Disease', (72, 86))
186356	24121789	Whether mutations in STAG2 are a direct cause of aneuploidy in human cancer is currently a source of controversy because a subset of STAG2-deficient acute myeloid leukemias and urothelial carcinomas appear to be diploid (refs.	('leukemias', 'Phenotype', 'HP:0001909', (163, 172))	('aneuploidy', 'Disease', (49, 59))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (149, 172))	('human', 'Species', '9606', (63, 68))	('STAG2', 'Gene', (21, 26))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (8, 17))	('STAG2-deficient acute myeloid leukemias and urothelial carcinomas', 'Disease', 'MESH:D015470', (133, 198))	('aneuploidy', 'Disease', 'MESH:D000782', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('cancer', 'Disease', (69, 75))
186357	24121789	Despite these surprising observations, there are several lines of evidence supporting a direct role for STAG2 inactivation as a cause of aneuploidy in cancer.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('STAG2', 'Gene', (104, 109))	('aneuploidy in cancer', 'Disease', (137, 157))	('inactivation', 'Var', (110, 122))	('cause', 'Reg', (128, 133))	('aneuploidy in cancer', 'Disease', 'MESH:D000782', (137, 157))
186358	24121789	In yeast, mutation of cohesin complex genes causes aberrant chromosome segregation and aneuploidy.	('causes', 'Reg', (44, 50))	('aneuploidy', 'Disease', (87, 97))	('aberrant chromosome segregation', 'CPA', (51, 82))	('aberrant chromosome segregation', 'Phenotype', 'HP:0002916', (51, 82))	('mutation', 'Var', (10, 18))	('chromosome segregation', 'biological_process', 'GO:0007059', ('60', '82'))	('cohesin complex genes', 'Gene', (22, 43))	('yeast', 'Species', '4932', (3, 8))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('aneuploidy', 'Disease', 'MESH:D000782', (87, 97))	('cohesin complex', 'cellular_component', 'GO:0008278', ('22', '37'))
186360	24121789	Targeted inactivation of STAG2 in HCT116 colon cancer cells and depletion of STAG2 in RT4 bladder cancer cells leads to alterations in modal chromosome number (ref.	('bladder cancer', 'Disease', (90, 104))	('STAG2', 'Gene', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('HCT116', 'CellLine', 'CVCL:0291', (34, 40))	('chromosome', 'cellular_component', 'GO:0005694', ('141', '151'))	('RT4', 'CellLine', 'CVCL:0036', (86, 89))	('colon cancer', 'Phenotype', 'HP:0003003', (41, 53))	('STAG2', 'Gene', (77, 82))	('depletion', 'MPA', (64, 73))	('colon cancer', 'Disease', 'MESH:D015179', (41, 53))	('inactivation', 'Var', (9, 21))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('modal chromosome number', 'CPA', (135, 158))	('alterations', 'Reg', (120, 131))	('colon cancer', 'Disease', (41, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))
186361	24121789	Also, ectopic expression of STAG2 has no adverse effect on cellular proliferation or in vivo growth (Figure 2B and Supplementary Figure 16), and targeted correction of endogenous mutant STAG2 in two cancer cell lines resulted in no significant change in global gene expression profiles, arguing against a role for STAG2 in controlling signaling pathways, cellular proliferation, apoptosis, or other transformation-associated processes.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('mutant', 'Var', (179, 185))	('apoptosis', 'biological_process', 'GO:0097194', ('379', '388'))	('signaling', 'biological_process', 'GO:0023052', ('335', '344'))	('apoptosis', 'biological_process', 'GO:0006915', ('379', '388'))	('signaling pathways', 'Pathway', (335, 353))	('expression', 'Species', '29278', (14, 24))	('STAG2', 'Gene', (186, 191))	('expression', 'Species', '29278', (266, 276))	('apoptosis', 'CPA', (379, 388))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('gene expression', 'biological_process', 'GO:0010467', ('261', '276'))	('ectopic expression', 'Var', (6, 24))	('cancer', 'Disease', (199, 205))	('global gene expression profiles', 'MPA', (254, 285))	('STAG2', 'Gene', (28, 33))	('cellular proliferation', 'CPA', (59, 81))	('cellular proliferation', 'CPA', (355, 377))
186363	24121789	Here we report that STAG2 is mutationally inactivated in greater than one third of papillary non-invasive bladder tumors, and that these tumors with STAG2 loss rarely recur or progress, perhaps explaining the difference in the frequencies of STAG2 inactivation in non-invasive urothelial carcinomas (36%) compared to that in invasive urothelial carcinomas (16%).	('tumors', 'Disease', (137, 143))	('invasive urothelial carcinomas', 'Disease', (325, 355))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (288, 298))	('invasive urothelial carcinomas', 'Disease', (268, 298))	('loss', 'NegReg', (155, 159))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('bladder tumors', 'Disease', 'MESH:D001749', (106, 120))	('inactivated', 'NegReg', (42, 53))	('invasive bladder', 'Phenotype', 'HP:0100645', (97, 113))	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (325, 355))	('STAG2', 'Gene', (149, 154))	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (268, 298))	('mutationally', 'Var', (29, 41))	('bladder tumors', 'Disease', (106, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('STAG2', 'Gene', (20, 25))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (345, 354))	('carcinomas', 'Phenotype', 'HP:0030731', (345, 355))	('bladder tumors', 'Phenotype', 'HP:0009725', (106, 120))	('tumors', 'Disease', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
186382	24121789	Traces with putative mutations were re-amplified and sequenced from both tumor and matched normal DNA from blood when available.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('tumor', 'Disease', (73, 78))	('mutations', 'Var', (21, 30))
186390	24121789	Proliferation of pooled clones of STAG2 mutant urothelial cancer cells infected with lentiviral-vector or lentiviral-STAG2 was performed using CellTiter-Glo Luminescent Cell Proliferation Assay according to the manufacturer's instructions (Promega).	('urothelial cancer', 'Disease', (47, 64))	('lentiviral-STAG2', 'Var', (106, 122))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Cell Proliferation', 'biological_process', 'GO:0008283', ('169', '187'))	('urothelial cancer', 'Disease', 'MESH:D014523', (47, 64))	('mutant', 'Var', (40, 46))	('STAG2', 'Gene', (34, 39))
186404	33403043	After stable transfection with either short hairpin RNA to knock down DTX3 expression or full-length complementary DNA to upregulate DTX3 expression, changes of malignant phenotypes in two PTC cell lines K1 and TPC-1 were observed using cell viability, flow cytometry, wound healing and transwell assays.	('TPC-1', 'Gene', (211, 216))	('wound healing', 'biological_process', 'GO:0042060', ('269', '282'))	('TPC-1', 'Gene', '53373', (211, 216))	('PTC', 'Gene', '8030', (189, 192))	('upregulate', 'PosReg', (122, 132))	('knock', 'Var', (59, 64))	('DTX3', 'Gene', (70, 74))	('DTX3', 'Gene', '196403', (70, 74))	('DTX3', 'Gene', '196403', (133, 137))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('expression', 'MPA', (138, 148))	('PTC', 'Gene', (189, 192))	('PTC', 'Phenotype', 'HP:0002895', (189, 192))	('DTX3', 'Gene', (133, 137))	('expression', 'MPA', (75, 85))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))
186409	33403043	Moreover, knockdown of DTX3 led to opposite changes (P<0.05).	('knockdown', 'Var', (10, 19))	('DTX3', 'Gene', '196403', (23, 27))	('DTX3', 'Gene', (23, 27))
186444	33403043	For stable transfection, PTC cells with G418 resistance were selected (0.5 mg/mL for K1 and 0.6 mg/mL for TPC-1).	('G418', 'Var', (40, 44))	('TPC-1', 'Gene', (106, 111))	('PTC', 'Gene', '8030', (25, 28))	('PTC', 'Gene', (25, 28))	('TPC-1', 'Gene', '53373', (106, 111))	('PTC', 'Phenotype', 'HP:0002895', (25, 28))	('G418', 'Chemical', 'MESH:C010680', (40, 44))
186497	33403043	The results of qRT-PCR and WB proved that the relative mRNA and protein expressions of DTX3 in PTC tissues were 0.501 +- 0.267 and 0.551 +- 0.277, which were markedly lower as compared to those in the paired paracancerous normal tissues (1.026 +- 0.094 and 1.008 +- 0.084, P<0.05) (Figures 2B and 2C).	('lower', 'NegReg', (167, 172))	('PTC', 'Gene', (95, 98))	('PTC', 'Gene', '8030', (95, 98))	('0.551 +- 0.277', 'Var', (131, 145))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('DTX3', 'Gene', (87, 91))	('0.501 +- 0.267', 'Var', (112, 126))	('PTC', 'Phenotype', 'HP:0002895', (95, 98))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('DTX3', 'Gene', '196403', (87, 91))	('mRNA', 'MPA', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
186499	33403043	As showed in Table 1, relative mRNA and protein expressions of DTX3 in group with cervical lymph node metastasis were 0.444 +- 0.254 and 0.490 +- 0.255, which were prominently lower than those in no cervical lymph node metastasis group (0.607 +- 0.261 and 0.663 +- 0.282, P<0.05).	('cervical lymph node metastasis', 'Var', (82, 112))	('DTX3', 'Gene', (63, 67))	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (82, 112))	('0.444 +- 0.254', 'Var', (118, 132))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('lower', 'NegReg', (176, 181))	('0.490 +- 0.255', 'Var', (137, 151))	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (199, 229))	('DTX3', 'Gene', '196403', (63, 67))
186508	33403043	In K1 DTX3-shRNA group, the relative mRNA and protein expressions of DTX3 were 0.213 +- 0.023 and 0.346 +- 0.064, which were both significantly reduced, compared with control groups (0.928 +- 0.057 and 0.981 +- 0.109, P<0.05).	('reduced', 'NegReg', (144, 151))	('0.346 +- 0.064', 'Var', (98, 112))	('DTX3', 'Gene', (6, 10))	('DTX3', 'Gene', (69, 73))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('0.213 +- 0.023', 'Var', (79, 93))	('DTX3', 'Gene', '196403', (6, 10))	('DTX3', 'Gene', '196403', (69, 73))
186509	33403043	In TPC-1 DTX3-shRNA cells, the relative mRNA and protein expressions of DTX3 were 0.301 +- 0.035 and 0.368 +- 0.078, which were both obviously lower than those in control groups (0.911 +- 0.050 and 0.985 +- 0.126, P<0.05).	('DTX3', 'Gene', '196403', (72, 76))	('DTX3', 'Gene', '196403', (9, 13))	('lower', 'NegReg', (143, 148))	('DTX3', 'Gene', (72, 76))	('0.301 +- 0.035', 'Var', (82, 96))	('0.368 +- 0.078', 'Var', (101, 115))	('TPC-1', 'Gene', (3, 8))	('DTX3', 'Gene', (9, 13))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('TPC-1', 'Gene', '53373', (3, 8))
186520	33403043	In K1 and TPC-1 DTX3-cDNA cells, the relative protein expressions of Vimentin were 0.620 +- 0.113 and 0.643 +- 0.129, which were lower than those in control groups (0.992 +- 0.122 and 0.989 +- 0.088, P<0.05).	('Vimentin', 'Gene', (69, 77))	('Vimentin', 'cellular_component', 'GO:0045098', ('69', '77'))	('Vimentin', 'Gene', '7431', (69, 77))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('DTX3', 'Gene', '196403', (16, 20))	('TPC-1', 'Gene', (10, 15))	('Vimentin', 'cellular_component', 'GO:0045099', ('69', '77'))	('0.620 +- 0.113', 'Var', (83, 97))	('protein expressions', 'MPA', (46, 65))	('0.643 +- 0.129', 'Var', (102, 116))	('DTX3', 'Gene', (16, 20))	('TPC-1', 'Gene', '53373', (10, 15))	('lower', 'NegReg', (129, 134))
186523	33403043	In K1 and TPC-1 DTX3-shRNA groups, E-cadherin relative expressions were 0.394 +- 0.096 and 0.547 +- 0.066, which were much lower than those in control groups (1.077 +- 0.195 and 0.942 +- 0.134, P<0.05).	('E-cadherin', 'Gene', '999', (35, 45))	('0.547 +- 0.066', 'Var', (91, 105))	('lower', 'NegReg', (123, 128))	('DTX3', 'Gene', '196403', (16, 20))	('TPC-1', 'Gene', (10, 15))	('cadherin', 'molecular_function', 'GO:0008014', ('37', '45'))	('0.394 +- 0.096', 'Var', (72, 86))	('DTX3', 'Gene', (16, 20))	('TPC-1', 'Gene', '53373', (10, 15))	('E-cadherin', 'Gene', (35, 45))
186528	33403043	In K1 and TPC-1 DTX3-cDNA cells, the relative protein expressions of p-AKT were 0.549 +- 0.124 and 0.518 +- 0.099, which were lower than those in control groups (0.982 +- 0.129 and 0.995 +- 0.168, P<0.05).	('lower', 'NegReg', (126, 131))	('AKT', 'Gene', '207', (71, 74))	('0.518 +- 0.099', 'Var', (99, 113))	('0.549 +- 0.124', 'Var', (80, 94))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('DTX3', 'Gene', '196403', (16, 20))	('TPC-1', 'Gene', (10, 15))	('protein expressions', 'MPA', (46, 65))	('AKT', 'Gene', (71, 74))	('DTX3', 'Gene', (16, 20))	('TPC-1', 'Gene', '53373', (10, 15))
186546	33403043	With MG-132, the relative protein expressions of XRCC5 were higher than those in cells without MG-132 added (P<0.05) (Figure 6B).	('higher', 'PosReg', (60, 66))	('XRCC5', 'Gene', '7520', (49, 54))	('MG-132', 'Chemical', 'MESH:C072553', (5, 11))	('MG-132', 'Var', (5, 11))	('MG-132', 'Chemical', 'MESH:C072553', (95, 101))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('protein expressions', 'MPA', (26, 45))	('XRCC5', 'Gene', (49, 54))
186552	33403043	The migration and invasion of Glioblastoma (GBM) cells were positively associated with expressions of DTX1.	('expressions', 'Var', (87, 98))	('Glioblastoma', 'Disease', (30, 42))	('associated', 'Interaction', (71, 81))	('GBM', 'Phenotype', 'HP:0012174', (44, 47))	('Glioblastoma', 'Disease', 'MESH:D005909', (30, 42))	('positively', 'PosReg', (60, 70))	('DTX1', 'Gene', '1840', (102, 106))	('Glioblastoma', 'Phenotype', 'HP:0012174', (30, 42))	('migration', 'CPA', (4, 13))	('DTX1', 'Gene', (102, 106))
186554	33403043	In diffuse large B-cell lymphoma (DLBCL), mutations in DTX1 gene could be discovered to impair its original effects, nearly 65% of which were found in the WWE1-domain.	('B-cell lymphoma', 'Disease', (17, 32))	('original effects', 'MPA', (99, 115))	('DTX1', 'Gene', (55, 59))	('impair', 'NegReg', (88, 94))	('lymphoma', 'Phenotype', 'HP:0002665', (24, 32))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (17, 32))	('mutations', 'Var', (42, 51))	('DTX1', 'Gene', '1840', (55, 59))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (17, 32))
186562	33403043	Gene amplification of DTX3 was also proved to have impacts on overall survival of luminal subtype breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('overall', 'MPA', (62, 69))	('breast cancer', 'Disease', (98, 111))	('DTX3', 'Gene', '196403', (22, 26))	('Gene amplification', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('impacts', 'Reg', (51, 58))	('DTX3', 'Gene', (22, 26))
186571	33403043	In our study, the diminution of DTX3 led to markedly decline of E-cadherin expression, while obviously elaborated Vimentin expression.	('cadherin', 'molecular_function', 'GO:0008014', ('66', '74'))	('Vimentin', 'Gene', (114, 122))	('expression', 'MPA', (123, 133))	('DTX3', 'Gene', '196403', (32, 36))	('elaborated', 'PosReg', (103, 113))	('E-cadherin', 'Gene', (64, 74))	('decline', 'NegReg', (53, 60))	('Vimentin', 'Gene', '7431', (114, 122))	('Vimentin', 'cellular_component', 'GO:0045098', ('114', '122'))	('DTX3', 'Gene', (32, 36))	('E-cadherin', 'Gene', '999', (64, 74))	('Vimentin', 'cellular_component', 'GO:0045099', ('114', '122'))	('diminution', 'Var', (18, 28))	('expression', 'MPA', (75, 85))
186575	33403043	In our study, the increased phosphorylated AKT was observed after DTX3 expression was knocked down.	('expression', 'MPA', (71, 81))	('phosphorylated', 'MPA', (28, 42))	('increased', 'PosReg', (18, 27))	('AKT', 'Gene', '207', (43, 46))	('DTX3', 'Gene', (66, 70))	('knocked', 'Var', (86, 93))	('AKT', 'Gene', (43, 46))	('DTX3', 'Gene', '196403', (66, 70))
186587	33403043	Knocking down XRCC5 decreased the malignancy and inactivated the AKT signal pathway in PTC cells.	('PTC', 'Phenotype', 'HP:0002895', (87, 90))	('malignancy', 'Disease', (34, 44))	('XRCC5', 'Gene', '7520', (14, 19))	('Knocking', 'Var', (0, 8))	('decreased', 'NegReg', (20, 29))	('AKT', 'Gene', (65, 68))	('inactivated', 'NegReg', (49, 60))	('XRCC5', 'Gene', (14, 19))	('PTC', 'Gene', '8030', (87, 90))	('AKT', 'Gene', '207', (65, 68))	('malignancy', 'Disease', 'MESH:D009369', (34, 44))	('PTC', 'Gene', (87, 90))
186595	33403043	Mutations in NDUFAF5 were found to be related to cavitating leukoencephalopathies, lactic acidosis, classic Leigh syndrome, hyponatremia and some lethal neonatal mitochondrial diseases.	('leukoencephalopathies', 'Disease', (60, 81))	('hyponatremia', 'Disease', 'MESH:D007010', (124, 136))	('classic Leigh syndrome', 'Disease', (100, 122))	('acidosis', 'Phenotype', 'HP:0001941', (90, 98))	('hyponatremia', 'Disease', (124, 136))	('neonatal mitochondrial diseases', 'Disease', 'MESH:D028361', (153, 184))	('NDUFAF5', 'Gene', '79133', (13, 20))	('neonatal mitochondrial diseases', 'Disease', (153, 184))	('lactic acidosis', 'Phenotype', 'HP:0003128', (83, 98))	('NDUFAF5', 'Gene', (13, 20))	('hyponatremia', 'Phenotype', 'HP:0002902', (124, 136))	('lactic acidosis', 'Disease', (83, 98))	('Mutations', 'Var', (0, 9))	('related', 'Reg', (38, 45))	('classic Leigh syndrome', 'Disease', 'MESH:D007888', (100, 122))	('lactic acidosis', 'Disease', 'MESH:D000140', (83, 98))	('leukoencephalopathies', 'Disease', 'MESH:D056784', (60, 81))
186602	32067422	Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan-cancer analysis Human epidermal growth factor receptor (EGFR) is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('118', '141'))	('EGFR', 'molecular_function', 'GO:0005006', ('243', '247'))	('mutations', 'Var', (248, 257))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('lung cancer', 'Disease', (226, 237))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epidermal growth factor receptor', 'Gene', '1956', (118, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('cancer', 'Disease', (231, 237))	('Human', 'Species', '9606', (112, 117))	('epidermal growth factor receptor', 'Gene', (118, 150))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('lung cancer', 'Disease', 'MESH:D008175', (226, 237))	('EGFR', 'Gene', (243, 247))	('cancer', 'Disease', (96, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('152', '156'))
186603	32067422	Although there are many reports for some individual cancers, comprehensive profiling of EGFR mutations, overexpression, amplification, DNA methylation, and their clinical associations across many different cancers simultaneously was not available.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('mutations', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('DNA methylation', 'biological_process', 'GO:0006306', ('135', '150'))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', (206, 213))	('EGFR', 'Gene', (88, 92))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
186605	32067422	The Cancer Genome Atlas (TCGA) datasets for 32 cancer types involving 11,314 patients were analyzed for alterations (mutations and amplification/deletion), abnormal expression and DNA methylation in EGFR gene.	('mutations', 'Var', (117, 126))	('rat', 'Species', '10116', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('199', '203'))	('EGFR', 'Gene', (199, 203))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('DNA methylation', 'Var', (180, 195))	('DNA methylation', 'biological_process', 'GO:0006306', ('180', '195'))	('cancer', 'Disease', (47, 53))	('expression', 'MPA', (165, 175))	('amplification/deletion', 'Var', (131, 153))	('patients', 'Species', '9606', (77, 85))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('DNA', 'cellular_component', 'GO:0005574', ('180', '183'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('abnormal', 'Reg', (156, 164))
186607	32067422	EGFR alteration frequency, mutation sites across functional domains, amplification, overexpression, and DNA methylation patterns differed greatly among different cancer types.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('rat', 'Species', '10116', (9, 12))	('EGFR', 'Gene', (0, 4))	('alteration', 'Var', (5, 15))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('DNA methylation', 'biological_process', 'GO:0006306', ('104', '119'))
186609	32067422	Targetable mutations, mainly in lung cancer, were primarily found in the Pkinase_Tyr domain.	('mutations', 'Var', (11, 20))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
186610	32067422	Glioblastoma multiforme had the highest rate of alterations, but it was dominated by gene amplification and most mutations were in the Furin-like domain where targeted therapy was less effective.	('rat', 'Species', '10116', (52, 55))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('rat', 'Species', '10116', (40, 43))	('Glioblastoma multiforme', 'Disease', (0, 23))	('mutations', 'Var', (113, 122))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('Furin', 'Gene', '5045', (135, 140))	('Furin', 'Gene', (135, 140))
186611	32067422	Low-grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome.	('gene amplification', 'Var', (27, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('increased', 'PosReg', (50, 59))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('expression', 'MPA', (65, 75))	('EGFR', 'Gene', (60, 64))	('glioma', 'Disease', (10, 16))
186612	32067422	Colon and pancreatic adenocarcinoma had very few EGFR mutations; however, high EGFR expression was significantly associated with short patient survival.	('patient', 'Species', '9606', (135, 142))	('Colon and pancreatic adenocarcinoma', 'Disease', 'MESH:D003110', (0, 35))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('short', 'NegReg', (129, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (10, 35))	('expression', 'MPA', (84, 94))	('associated', 'Reg', (113, 123))
186614	32067422	DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers.	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('expression', 'MPA', (48, 58))	('associated', 'Reg', (27, 37))	('methylation', 'Var', (4, 15))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('patient', 'Species', '9606', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('EGFR', 'Gene', (43, 47))
186616	32067422	While mutations in the Pkinase_Tyr domain are more important for treatment selection, increased expression from amplification or deregulation affects more tumor types and leads to worse outcome, which calls for new treatment strategies for these EGFR-driven tumors.	('rat', 'Species', '10116', (227, 230))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('leads to', 'Reg', (171, 179))	('increased', 'PosReg', (86, 95))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('deregulation', 'MPA', (129, 141))	('expression', 'MPA', (96, 106))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('EGFR', 'molecular_function', 'GO:0005006', ('246', '250'))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('affects', 'Reg', (142, 149))	('mutations', 'Var', (6, 15))
186618	32067422	Five functional domains are characterized for EGFR according to the database of protein families (Pfam, http://pfam.xfam.org/protein/P00533): Recep_L (57-168aa), Furin-like (177-338aa), Recep_L (361-481aa), GF_recep_IV (505-637aa), and Pkinase_Tyr domains (712-968aa).	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('177-338aa', 'Var', (174, 183))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('712-968aa', 'Var', (257, 266))	('Furin', 'Gene', (162, 167))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('Furin', 'Gene', '5045', (162, 167))	('505-637aa', 'Var', (220, 229))
186620	32067422	Upon stimulation by its ligands, dimerization (both homodimerization and heterodimerization) of EGFR results in its intracellular tyrosine kinase activation and autophosphorylation at multiple tyrosine residues, which activates a number of downstream signaling cascades that not only promote proliferation, growth, and survival of normal cells but also contribute to processes that are crucial to cancer progression, including angiogenesis, metastasis, and apoptosis [4, 5].	('angiogenesis', 'biological_process', 'GO:0001525', ('427', '439'))	('survival', 'CPA', (319, 327))	('intracellular tyrosine kinase', 'MPA', (116, 145))	('cancer', 'Disease', (397, 403))	('activation', 'PosReg', (146, 156))	('proliferation', 'CPA', (292, 305))	('EGFR', 'Gene', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('contribute', 'Reg', (353, 363))	('autophosphorylation', 'MPA', (161, 180))	('rat', 'Species', '10116', (299, 302))	('promote', 'PosReg', (284, 291))	('tyrosine', 'Chemical', 'MESH:D014443', (193, 201))	('apoptosis', 'biological_process', 'GO:0097194', ('457', '466'))	('intracellular', 'cellular_component', 'GO:0005622', ('116', '129'))	('dimerization', 'Var', (33, 45))	('metastasis', 'CPA', (441, 451))	('activates', 'PosReg', (218, 227))	('apoptosis', 'biological_process', 'GO:0006915', ('457', '466'))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('tyrosine', 'Chemical', 'MESH:D014443', (130, 138))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('growth', 'CPA', (307, 313))	('signaling', 'biological_process', 'GO:0023052', ('251', '260'))
186622	32067422	It is frequently activated by gene mutation, amplification, or overexpression through abnormal regulation in human cancers.	('human', 'Species', '9606', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('regulation', 'biological_process', 'GO:0065007', ('95', '105'))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gene mutation', 'Var', (30, 43))	('activated', 'PosReg', (17, 26))	('amplification', 'Var', (45, 58))	('overexpression', 'PosReg', (63, 77))
186624	32067422	In cancers like non-small-cell lung cancer (NSCLC) [13] and colon adenocarcinoma (COAD) [14], EGFR mutation status is considered as a poor prognostic factor, which is often associated with a more aggressive behavior and decreased patient survival.	('COAD', 'Disease', (82, 86))	('lung cancer', 'Disease', (31, 42))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (60, 80))	('aggressive behavior', 'Phenotype', 'HP:0000718', (196, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('patient', 'Species', '9606', (230, 237))	('mutation', 'Var', (99, 107))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('94', '98'))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('aggressive behavior', 'biological_process', 'GO:0002118', ('196', '215'))	('colon adenocarcinoma', 'Disease', (60, 80))	('NSCLC', 'Disease', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('EGFR', 'Gene', (94, 98))	('cancers', 'Disease', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (16, 42))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
186627	32067422	Such treatments are very effective and provide significantly improved patient outcomes, particularly for lung adenocarcinoma (LUAD) patients with EGFR mutations [20, 21].	('improved', 'PosReg', (61, 69))	('LUAD', 'Phenotype', 'HP:0030078', (126, 130))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('patient', 'Species', '9606', (70, 77))	('EGFR', 'Gene', (146, 150))	('lung adenocarcinoma', 'Disease', (105, 124))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('146', '150'))	('patient', 'Species', '9606', (132, 139))	('patients', 'Species', '9606', (132, 140))	('mutations', 'Var', (151, 160))
186629	32067422	Although many literature reports are available on EGFR mutation, overexpression, or amplification for particular cancer types [12, 13, 14, 23, 24], a simultaneous comprehensive profiling over multiple cancer types to explore their similarity and difference is not available.	('rat', 'Species', '10116', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutation', 'Var', (55, 63))	('EGFR', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
186632	32067422	We first examined the patterns of EGFR mutations, including single nucleotide variant (SNV) and short insertion/deletion (indel), across tumors and their implications for targeted therapies.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('single nucleotide variant', 'Var', (60, 85))	('EGFR', 'Gene', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('short insertion/deletion', 'Var', (96, 120))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
186636	32067422	The mutation data included SNVs, indels, and CNVs (defined by GISTIC 2.0 as following for log ratio value: -2/-1 = deletion; 0 = diploid; 1 = gain; 2 = amplification).	('deletion', 'Var', (115, 123))	('rat', 'Species', '10116', (94, 97))	('gain', 'PosReg', (142, 146))	('indels', 'Var', (33, 39))
186646	32067422	The prognostic values of EGFR alterations and its CpG methylation were analyzed with Cox proportional hazard model.	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('EGFR', 'Gene', (25, 29))	('alterations', 'Var', (30, 41))	('rat', 'Species', '10116', (34, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
186647	32067422	The overall EGFR mutation frequency was 2.8% (320/11,410) for all tumor samples and 2.4% (268/11,314) for all patients across the 32 tumor types.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (66, 71))	('mutation', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('EGFR', 'Gene', (12, 16))	('patients', 'Species', '9606', (110, 118))
186648	32067422	The most common tumors with EGFR mutations were glioblastoma multiforme (GBM, 26.8%), LUAD (14.4%), diffuse large B-cell lymphoma (DLBC, 8.3%), and skin cutaneous melanoma (SKCM, 6.5%).	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('EGFR', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', (16, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (121, 129))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (114, 129))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (114, 129))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (148, 171))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))	('skin cutaneous melanoma', 'Disease', (148, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('B-cell lymphoma', 'Disease', (114, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (153, 171))	('LUAD', 'Disease', (86, 90))	('glioblastoma multiforme', 'Disease', (48, 71))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (48, 71))
186649	32067422	On the contrary, kidney chromophobe cell carcinoma (KICH), mesothelioma (MESO), pheochromocytoma and paraganglioma (PCPG), thymoma (THYM), thyroid carcinoma (THCA), uterine carcinosarcoma (UCS), and uveal melanoma (UVM) showed almost no EGFR mutations (Figure 1A).	('mesothelioma', 'Disease', (59, 71))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('THCA', 'Phenotype', 'HP:0002890', (158, 162))	('thymoma', 'Disease', (123, 130))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('carcinosarcoma', 'Disease', 'MESH:D002296', (173, 187))	('thymoma', 'Phenotype', 'HP:0100522', (123, 130))	('UCS', 'Phenotype', 'HP:0002891', (189, 192))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (139, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('UVM', 'Phenotype', 'HP:0007716', (215, 218))	('melanoma', 'Disease', (205, 213))	('thyroid carcinoma', 'Disease', (139, 156))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (101, 114))	('kidney chromophobe cell carcinoma', 'Disease', (17, 50))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (80, 114))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (139, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('kidney chromophobe cell carcinoma', 'Disease', 'MESH:C538614', (17, 50))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (165, 187))	('uveal melanoma', 'Phenotype', 'HP:0007716', (199, 213))	('thymoma', 'Disease', 'MESH:D013945', (123, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('EGFR', 'molecular_function', 'GO:0005006', ('237', '241'))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('mutations', 'Var', (242, 251))	('THYM', 'Phenotype', 'HP:0100522', (132, 136))	('carcinosarcoma', 'Disease', (173, 187))
186651	32067422	The 320 EGFR somatic mutations (from 268 tumor samples) were observed across all cancer types and were widely distributed along different functional domains of EGFR gene.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('8', '12'))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', (41, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('160', '164'))	('cancer', 'Disease', (81, 87))	('observed', 'Reg', (61, 69))	('EGFR', 'Gene', (160, 164))	('EGFR', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mutations', 'Var', (21, 30))
186653	32067422	The location distribution of these EGFR mutations was dramatically different among different cancers (Figure 1B, Supplementary Table S2).	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('EGFR', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))	('different', 'Reg', (67, 76))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
186654	32067422	Mutations in GBM and brain lower-grade glioma (LGG) were most commonly located in the Furin-like domain, about 5 times more than the mutations located in the Pkinase_Tyr domain.	('glioma', 'Disease', (39, 45))	('GBM', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('Furin', 'Gene', (86, 91))	('located', 'Reg', (71, 78))	('Furin', 'Gene', '5045', (86, 91))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
186655	32067422	On the contrary, mutations in NSCLC were primarily in the Pkinase_Tyr domain, especially for LUAD, which amounted to four fifths of all mutations.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('LUAD', 'Phenotype', 'HP:0030078', (93, 97))	('NSCLC', 'Disease', (30, 35))	('mutations', 'Var', (17, 26))
186656	32067422	Mutations in stomach adenocarcinoma (STAD), head and neck squamous cell carcinoma (HNSC), and SKCM were mostly in other domains whose functions were less known.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (53, 81))	('neck', 'cellular_component', 'GO:0044326', ('53', '57'))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma', 'Disease', (21, 35))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (44, 81))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('adenocarcinoma', 'Disease', 'MESH:D000230', (21, 35))	('HNSC', 'Phenotype', 'HP:0012288', (83, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('neck squamous cell carcinoma', 'Disease', (53, 81))
186657	32067422	The 289aa in the Furin-like domain was the most frequently mutated position, which was observed in 27 samples (3 samples with A289D, 1 with A289I, 1 with A289N, 6 with A289T, 15 with A289V, and 1 with A289Rfs*9).	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (201, 210))	('A289V', 'Var', (183, 188))	('A289D', 'Mutation', 'p.A289D', (126, 131))	('A289I', 'Mutation', 'p.A289I', (140, 145))	('Furin', 'Gene', (17, 22))	('A289N', 'Mutation', 'p.A289N', (154, 159))	('A289I', 'Var', (140, 145))	('Furin', 'Gene', '5045', (17, 22))	('A289N', 'Var', (154, 159))	('A289T', 'Mutation', 'rs769696078', (168, 173))	('A289V', 'Mutation', 'p.A289V', (183, 188))	('A289D', 'Var', (126, 131))	('A289T', 'Var', (168, 173))
186658	32067422	A289V is known to be oncogenic, while other mutation types (A289D/T/N/I) are likely oncogenic.	('A289V', 'Mutation', 'p.A289V', (0, 5))	('A289V', 'Var', (0, 5))	('A289D/T/N/I', 'Var', (60, 71))	('A289D', 'Mutation', 'p.A289D', (60, 65))
186659	32067422	The only other tumor with mutations at this position was HNSC (1 sample with A289T and 1 with A289Rfs*9), and their importance was little known to this cancer.	('A289Rfs*', 'Var', (94, 102))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('HNSC', 'Phenotype', 'HP:0012288', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('A289T', 'Mutation', 'rs769696078', (77, 82))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('A289T', 'Var', (77, 82))	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (94, 103))
186660	32067422	The second most mutated position was 598aa in the GF_recep_IV domain: 16 GBMs had G598V, 2 GBMs had G598A, and 1 esophageal squamous cell carcinoma (ESCC) had G598E.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('G598V', 'Mutation', 'rs139236063', (82, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('G598A', 'Mutation', 'rs139236063', (100, 105))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))	('G598E', 'Mutation', 'p.G598E', (159, 164))	('G598E', 'Var', (159, 164))	('G598A', 'Var', (100, 105))	('G598V', 'Var', (82, 87))
186661	32067422	Most mutations in LUAD (35 of 45 mutations) were located in the Pkinase_Tyr domain, especially at the positions of 858aa (8 samples with L858R) and 746-750aa (6 with E746_A750del, 2 with L747_E749del, and 1 with L747_T751del) (Figure 1E).	('E746_A750del', 'Var', (166, 178))	('L747_T751del', 'Var', (212, 224))	('L747_T751del', 'Mutation', 'p.747,751delT', (212, 224))	('L747_E749del', 'Var', (187, 199))	('LUAD', 'Phenotype', 'HP:0030078', (18, 22))	('L858R', 'Mutation', 'rs121434568', (137, 142))	('LUAD', 'Gene', (18, 22))	('E746_A750del', 'Mutation', 'p.746,750delA', (166, 178))	('L747_E749del', 'Mutation', 'p.747,749delE', (187, 199))
186663	32067422	All Level 1 mutations were found in NSCLC (28 in LUAD and 2 in lung squamous cell carcinoma [LUSC]), and these mutations were concentrated in exons 19-21, which included L858R, L861Q, G719A, S768I, L833F, E796_A750del, L747_E749del, E709_T710delinsD, L747_T751del, and T751_E758del (Figure 3).	('S768I', 'Var', (191, 196))	('LUAD', 'Phenotype', 'HP:0030078', (49, 53))	('L747_T751del', 'Var', (251, 263))	('E709_T710delinsD', 'Mutation', 'p.709,710delinsT,D', (233, 249))	('L833F', 'Mutation', 'p.L833F', (198, 203))	('L858R', 'Mutation', 'rs121434568', (170, 175))	('T751_E758del', 'Mutation', 'p.751,758delE', (269, 281))	('E709_T710delinsD', 'Var', (233, 249))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (63, 91))	('S768I', 'Mutation', 'rs121913465', (191, 196))	('rat', 'Species', '10116', (133, 136))	('L833F', 'Var', (198, 203))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('L747_T751del', 'Mutation', 'p.747,751delT', (251, 263))	('G719A', 'Mutation', 'rs121913428', (184, 189))	('L747_E749del', 'Mutation', 'p.747,749delE', (219, 231))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 91))	('lung squamous cell carcinoma', 'Disease', (63, 91))	('L858R', 'Var', (170, 175))	('NSCLC', 'Disease', (36, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('L747_E749del', 'Var', (219, 231))	('E796_A750del', 'Var', (205, 217))	('L861Q', 'Mutation', 'rs121913444', (177, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('G719A', 'Var', (184, 189))	('E796_A750del', 'Mutation', 'p.796,750delA', (205, 217))	('L861Q', 'Var', (177, 182))	('T751_E758del', 'Var', (269, 281))
186667	32067422	The combined EGFR mutation and CNV frequency in all tumors was about 7.0% (746 of 11,314 patients, 748 of 11,410 samples).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('patients', 'Species', '9606', (89, 97))	('mutation', 'Var', (18, 26))	('EGFR', 'Gene', (13, 17))
186669	32067422	Other cancers with dominantEGFR amplification but at much lower amplification rate included ESCA (13.0%), HNSC (9.4%), STAD (5.2%), LGG (5.4%), LUSC (6.4%), and BLCA (4.4%).	('LUSC', 'Disease', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('dominantEGFR', 'Var', (19, 31))	('amplification', 'Var', (32, 45))	('BLCA', 'Disease', (161, 165))	('HNSC', 'Disease', (106, 110))	('rat', 'Species', '10116', (78, 81))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('LGG', 'Disease', (132, 135))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('ESCA', 'Disease', (92, 96))	('STAD', 'Disease', (119, 123))
186671	32067422	Over half of the mutations (47 of 82 mutations) in the Furin-like domain were accompanied by EGFR amplification, while nearly half of mutations (40 of 85 mutations) in the Pkinase_Tyr domain had copy gain.	('copy', 'MPA', (195, 199))	('amplification', 'MPA', (98, 111))	('EGFR', 'molecular_function', 'GO:0005006', ('93', '97'))	('EGFR', 'Gene', (93, 97))	('mutations', 'Var', (37, 46))	('Furin', 'Gene', (55, 60))	('mutations', 'Var', (17, 26))	('Furin', 'Gene', '5045', (55, 60))
186672	32067422	In order to evaluate the clinical significance of EGFR alterations, we analyzed patient survival for pan-cancer and for each cancer type separately by alteration status (mutations and CNVs alone or in combination).	('rat', 'Species', '10116', (155, 158))	('alterations', 'Var', (55, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rat', 'Species', '10116', (59, 62))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('rat', 'Species', '10116', (141, 144))	('patient', 'Species', '9606', (80, 87))
186673	32067422	When all tumors were analyzed together, patients with any EGFR alteration had significantly shorter median OS and DFS than those without EGFR alteration (both P < 0.001, Supplementary Figure S1).	('rat', 'Species', '10116', (67, 70))	('rat', 'Species', '10116', (146, 149))	('patients', 'Species', '9606', (40, 48))	('EGFR', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('tumors', 'Disease', (9, 15))	('alteration', 'Var', (63, 73))	('DFS', 'MPA', (114, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('shorter', 'NegReg', (92, 99))	('median OS', 'MPA', (100, 109))
186674	32067422	When analysis was performed for CNV and mutation separately, the presence of either aberration was associated with shortened patients' OS and DFS (all P < 0.001, Supplementary Figure S2 and S3).	('DFS', 'CPA', (142, 145))	('presence', 'Var', (65, 73))	('rat', 'Species', '10116', (88, 91))	('rat', 'Species', '10116', (53, 56))	('patients', 'Species', '9606', (125, 133))
186675	32067422	For survival association in individual cancer types, only those cancer types with at least 10 tumor samples containing either EGFR mutations or CNVs were included in the analysis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (39, 45))	('EGFR', 'Gene', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
186676	32067422	Among patients with HNSC, LGG, or LUAD, EGFR amplification was associated with short survival (Figure 6A).	('LUAD', 'Phenotype', 'HP:0030078', (34, 38))	('HNSC', 'Disease', (20, 24))	('LUAD', 'Disease', (34, 38))	('short survival', 'MPA', (79, 93))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('EGFR', 'Gene', (40, 44))	('patients', 'Species', '9606', (6, 14))	('HNSC', 'Phenotype', 'HP:0012288', (20, 24))	('LGG', 'Disease', (26, 29))	('amplification', 'Var', (45, 58))
186678	32067422	Not surprisingly, EGFR-amplified tumors had significantly higher EGFR expression than those without EGFR amplification in all 9 cancers types (all P < 0.001, Figure 6C); however, there was no much EGFR expression difference between tumors with or without EGFR mutations except that EGFR mutation status was associated with significantly increased EGFR expression in GBM (P = 0.024) and LUAD (P = 0.001, Figure 6D).	('EGFR', 'molecular_function', 'GO:0005006', ('18', '22'))	('EGFR', 'Gene', (282, 286))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('increased', 'PosReg', (337, 346))	('cancers', 'Disease', (128, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('EGFR', 'molecular_function', 'GO:0005006', ('197', '201'))	('mutation', 'Var', (287, 295))	('EGFR', 'molecular_function', 'GO:0005006', ('282', '286'))	('LUAD', 'Phenotype', 'HP:0030078', (386, 390))	('EGFR', 'molecular_function', 'GO:0005006', ('255', '259'))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('EGFR expression', 'MPA', (347, 362))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('347', '351'))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))	('tumors', 'Disease', (33, 39))	('tumors', 'Disease', (232, 238))
186698	32067422	In individual cancer type analysis, most tumor types had the similar patterns of methylation association with gene expression in promoter and gene body, but a few others had predominant hypomethylation in both regions, such as GBM, LUSC, PRAD, THYM, KIRC, and KICH (Supplementary Figure S5).	('cancer', 'Disease', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('methylation', 'biological_process', 'GO:0032259', ('81', '92'))	('methylation', 'Var', (81, 92))	('tumor', 'Disease', (41, 46))	('THYM', 'Phenotype', 'HP:0100522', (244, 248))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('hypomethylation', 'Var', (186, 201))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('gene expression', 'MPA', (110, 125))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))
186699	32067422	Survival analysis for all tumors with tumor type as a covariate only found 2 CpG sites (cg07311521 and cg16751451) significantly associated with OS, and both were in the promoter region (TSS1500).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('associated with', 'Reg', (129, 144))	('cg16751451', 'Var', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('cg07311521', 'Var', (88, 98))	('tumor', 'Disease', (26, 31))	('tumors', 'Disease', (26, 32))
186704	32067422	GBM had the highest rate of EGFR alterations, and amplification was the primary alteration.	('rat', 'Species', '10116', (84, 87))	('rat', 'Species', '10116', (37, 40))	('alterations', 'Var', (33, 44))	('EGFR', 'MPA', (28, 32))	('rat', 'Species', '10116', (20, 23))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))
186706	32067422	Paradoxically, although EGFR expression in GBM was significantly increased, either by gene amplification or DNA methylation change, the expression level was not associated with patient OS.	('increased', 'PosReg', (65, 74))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('DNA methylation', 'biological_process', 'GO:0006306', ('108', '123'))	('EGFR', 'Gene', (24, 28))	('gene amplification', 'Var', (86, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('expression', 'MPA', (29, 39))	('patient', 'Species', '9606', (177, 184))
186707	32067422	Other common tumor types with EGFR alterations include ESCA, HNSC, LGG, LUSC, and BLCA, all with similar characteristics: alteration frequency of about 5.0% and amplification as a dominant type.	('tumor', 'Disease', (13, 18))	('alterations', 'Var', (35, 46))	('EGFR', 'Gene', (30, 34))	('alteration', 'Var', (122, 132))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('LUSC', 'Disease', (72, 76))	('BLCA', 'Disease', (82, 86))	('HNSC', 'Phenotype', 'HP:0012288', (61, 65))	('ESCA', 'Disease', (55, 59))	('LGG', 'Disease', (67, 70))	('rat', 'Species', '10116', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('rat', 'Species', '10116', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('HNSC', 'Disease', (61, 65))
186709	32067422	On the other side of the spectrum, tumors such as DLBC and SKCM mainly had SNV mutations but rarely CNV; tumors including KIRC, MESO, THCA, THYM, UCS and UVM almost had no EGFR alterations.	('tumors', 'Disease', (105, 111))	('THCA', 'Phenotype', 'HP:0002890', (134, 138))	('THYM', 'Phenotype', 'HP:0100522', (140, 144))	('EGFR', 'molecular_function', 'GO:0005006', ('172', '176'))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('mutations', 'Var', (79, 88))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('THYM', 'Disease', (140, 144))	('rat', 'Species', '10116', (181, 184))	('UCS', 'Phenotype', 'HP:0002891', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('THCA', 'Disease', (134, 138))	('UVM', 'Phenotype', 'HP:0007716', (154, 157))	('tumors', 'Disease', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('UCS', 'Disease', (146, 149))	('SNV', 'Gene', (75, 78))	('MESO', 'Disease', (128, 132))
186710	32067422	Mutations in the Furin-like and Pkinase_Tyr domains accounted for most of EGFR single nucleotide or indel mutations.	('single nucleotide', 'Var', (79, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('Furin', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('Furin', 'Gene', '5045', (17, 22))	('EGFR', 'Gene', (74, 78))
186711	32067422	However, the Pkinase_Tyr domain was far more important in terms of targeted therapy with TKIs as 90% EGFR mutations in LUAD occurred in this region, particularly the exon 19 deletion and the L858R point mutation in exon 21.	('L858R', 'Mutation', 'rs121434568', (191, 196))	('L858R point', 'Var', (191, 202))	('LUAD', 'Gene', (119, 123))	('EGFR', 'molecular_function', 'GO:0005006', ('101', '105'))	('mutations', 'Var', (106, 115))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('exon 19 deletion', 'Var', (166, 182))
186712	32067422	Mutations in these regions are proven predictive markers for effective TKI therapy for NSCLC in clinical practice [7, 33, 34, 35], with significantly prolonged survival as compared with traditional combination chemotherapy [21, 36, 37].	('NSCLC', 'Disease', (87, 92))	('prolonged', 'PosReg', (150, 159))	('survival', 'MPA', (160, 168))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))
186714	32067422	For other uncommon EGFR mutations in NSCLC, targeted therapy generated inconsistent results [34, 40, 41, 42].	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('EGFR', 'Gene', (19, 23))	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('NSCLC', 'Disease', (37, 42))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('mutations', 'Var', (24, 33))	('rat', 'Species', '10116', (65, 68))
186715	32067422	In this large TCGA dataset, the combined alteration rate (amplification, deletion, or mutation) reached 67.3% in GBM.	('rat', 'Species', '10116', (52, 55))	('deletion', 'Var', (73, 81))	('rat', 'Species', '10116', (45, 48))	('mutation', 'Var', (86, 94))
186717	32067422	Compared with LUAD, most EGFR mutations in GBM were located in extracellular domain or single-span transmembrane segment, which was known to be associated with tumorigenesis but not responsiveness to TKIs.	('associated with', 'Reg', (144, 159))	('EGFR', 'Gene', (25, 29))	('LUAD', 'Phenotype', 'HP:0030078', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('GBM', 'Gene', (43, 46))	('extracellular', 'cellular_component', 'GO:0005576', ('63', '76'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('transmembrane', 'cellular_component', 'GO:0016021', ('99', '112'))	('mutations', 'Var', (30, 39))	('transmembrane', 'cellular_component', 'GO:0044214', ('99', '112'))	('tumor', 'Disease', (160, 165))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
186718	32067422	Although EGFR amplification was a predictor of poor prognosis for several cancer types, it was not significantly associated with GBM, consistent with the paradox phenomenon reported in the literature [46].	('rat', 'Species', '10116', (193, 196))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('EGFR', 'Gene', (9, 13))	('GBM', 'Disease', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('amplification', 'Var', (14, 27))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
186719	32067422	Both amplification and high expression of EGFR were correlated with short patient survival in this dataset as reported previously [49, 50].	('patient', 'Species', '9606', (74, 81))	('amplification', 'Var', (5, 18))	('EGFR', 'Gene', (42, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('short patient survival', 'CPA', (68, 90))
186720	32067422	More interestingly, we found that LGG had the highest number of CpGs whose methylation level was associated with patient survival (i.e., hypermethylation of CpGs in the gene body with better survival), which has not been reported before.	('patient', 'Species', '9606', (113, 120))	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('methylation', 'MPA', (75, 86))	('hypermethylation', 'Var', (137, 153))	('patient survival', 'CPA', (113, 129))	('associated', 'Reg', (97, 107))
186721	32067422	COAD and PAAD had very few EGFR mutations in this TCGA dataset.	('PAAD', 'Phenotype', 'HP:0006725', (9, 13))	('COAD', 'Disease', (0, 4))	('EGFR', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('COAD', 'Disease', 'MESH:D029424', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))
186722	32067422	However, high EGFR expression was significantly associated with short patient survival.	('expression', 'MPA', (19, 29))	('EGFR', 'Gene', (14, 18))	('patient', 'Species', '9606', (70, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('high', 'Var', (9, 13))
186724	32067422	Squamous cell carcinomas in the head and neck (HNSC), lung (LUSC), and esophagus (ESCA) have some commonalities: significantly increased EGFR expression, high frequency of EGFR amplification, and low rate of SNV/indel mutations.	('EGFR', 'Gene', (137, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('amplification', 'Var', (177, 190))	('rat', 'Species', '10116', (200, 203))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('EGFR', 'Gene', (172, 176))	('Squamous cell carcinomas', 'Phenotype', 'HP:0002860', (0, 24))	('HNSC', 'Phenotype', 'HP:0012288', (47, 51))	('EGFR', 'molecular_function', 'GO:0005006', ('172', '176'))	('Squamous cell carcinomas', 'Disease', 'MESH:D002294', (0, 24))	('Squamous cell carcinomas', 'Disease', (0, 24))	('esophagus', 'Disease', (71, 80))	('expression', 'MPA', (142, 152))	('lung', 'Disease', (54, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))	('neck', 'cellular_component', 'GO:0044326', ('41', '45'))	('increased', 'PosReg', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
186729	32067422	Our analysis provides a comprehensive view of EGFR mutation, abnormal expression, DNA methylation, and their interplay and clinical implications for 32 cancer types covering over ten thousand tumor samples.	('tumor', 'Disease', (192, 197))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('DNA methylation', 'biological_process', 'GO:0006306', ('82', '97'))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('mutation', 'Var', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('EGFR', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
186730	32067422	While some alternations are involved more in tumorigenesis, others are more therapeutic.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('involved', 'Reg', (28, 36))	('alternations', 'Var', (11, 23))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
186731	32067422	Some cancer types have a higher frequency of EGFR alternations where mutation, amplification, or abnormal expression is associated with outcome or indicated for clinical action.	('associated', 'Reg', (120, 130))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('EGFR', 'Gene', (45, 49))	('alternations', 'Var', (50, 62))	('cancer', 'Disease', (5, 11))	('abnormal expression', 'MPA', (97, 116))	('mutation', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('amplification', 'Var', (79, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))
186743	27512385	This precursor protein was identical to a growth-promoting factor later purified by Dr. Baserga's group from the conditioned media of BRL-3A rat liver cells, which was able to induce cell proliferation of R- cells, derived from mice with a targeted deletion of the insulin-like growth factor receptor (IGF-IR) gene.	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('265', '291'))	('deletion', 'Var', (249, 257))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('IGF-IR', 'Gene', (302, 308))	('cell proliferation', 'biological_process', 'GO:0008283', ('183', '201'))	('rat', 'Species', '10116', (195, 198))	('cell proliferation', 'CPA', (183, 201))	('rat', 'Species', '10116', (141, 144))	('mice', 'Species', '10090', (228, 232))	('IGF-IR', 'Gene', '3480', (302, 308))
186758	27512385	demonstrated that SLPI overexpression protected progranulin from elastase-mediated degradation and increased OC growth and survival, both in vitro and in vivo.	('survival', 'CPA', (123, 131))	('progranulin', 'Gene', '2896', (48, 59))	('OC', 'Phenotype', 'HP:0100615', (109, 111))	('OC growth', 'CPA', (109, 118))	('overexpression', 'Var', (23, 37))	('progranulin', 'Gene', (48, 59))	('rat', 'Species', '10116', (7, 10))	('degradation', 'biological_process', 'GO:0009056', ('83', '94'))	('SLPI', 'Gene', (18, 22))	('increased', 'PosReg', (99, 108))	('SLPI', 'Gene', '6590', (18, 22))
186766	27512385	The risk factors are related to an increase in circulating estrogens secondary to obesity, chronic anovulation and nulliparity estrogen replacement therapy, and tamoxifen use.	('obesity', 'Phenotype', 'HP:0001513', (82, 89))	('increase', 'PosReg', (35, 43))	('obesity', 'Disease', 'MESH:D009765', (82, 89))	('tamoxifen', 'Chemical', 'MESH:D013629', (161, 170))	('obesity', 'Disease', (82, 89))	('circulating estrogens', 'MPA', (47, 68))	('nulliparity', 'Var', (115, 126))	('men', 'Species', '9606', (143, 146))
186768	27512385	Similar to cervical cancer, inhibition of progranulin with shRNAs resulted in decreased endometrial cancer cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('progranulin', 'Gene', '2896', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('decreased endometrial cancer', 'Disease', (78, 106))	('inhibition', 'Var', (28, 38))	('shRNAs', 'Gene', (59, 65))	('progranulin', 'Gene', (42, 53))	('rat', 'Species', '10116', (119, 122))	('cervical cancer', 'Disease', 'MESH:D002583', (11, 26))	('decreased endometrial cancer', 'Disease', 'MESH:D016889', (78, 106))	('endometrial cancer', 'Phenotype', 'HP:0012114', (88, 106))	('cervical cancer', 'Disease', (11, 26))
186797	27512385	Progranulin depletion significantly enhanced cisplatin-dependent cell death as compared to control bladder cancer cells, suggesting that progranulin targeting in combination with cisplatin could enhance the therapeutic efficacy of cisplatin-based therapy in invasive bladder tumors.	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (231, 240))	('Progranulin', 'Gene', '2896', (0, 11))	('invasive bladder', 'Phenotype', 'HP:0100645', (258, 274))	('depletion', 'Var', (12, 21))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('invasive bladder tumors', 'Disease', 'MESH:D001749', (258, 281))	('Progranulin', 'Gene', (0, 11))	('progranulin', 'Gene', '2896', (137, 148))	('invasive bladder tumors', 'Disease', (258, 281))	('progranulin', 'Gene', (137, 148))	('bladder tumors', 'Phenotype', 'HP:0009725', (267, 281))	('enhance', 'PosReg', (195, 202))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('cell death', 'biological_process', 'GO:0008219', ('65', '75'))	('cisplatin-dependent cell death', 'CPA', (45, 75))	('enhanced', 'PosReg', (36, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))	('therapeutic efficacy', 'CPA', (207, 227))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('bladder tumor', 'Phenotype', 'HP:0009725', (267, 280))	('bladder cancer', 'Disease', (99, 113))
186866	32759680	In the androgen deprivation cohort for which tissue specimens were available (n = 72), AR expression in de novo bladder tumors, as an independent prognosticator, was further associated with successful prevention of tumor recurrence (hazard ratio (HR) = 0.27, p = 0.005).	('AR expression', 'Var', (87, 100))	('bladder tumors', 'Disease', 'MESH:D001749', (112, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('bladder tumors', 'Phenotype', 'HP:0009725', (112, 126))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('bladder tumors', 'Disease', (112, 126))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('bladder tumor', 'Phenotype', 'HP:0009725', (112, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (215, 220))	('men', 'Species', '9606', (57, 60))	('tumor', 'Disease', (120, 125))
186878	32759680	Alternations within the AR gene have also been documented in bladder cancer.	('Alternations', 'Var', (0, 12))	('men', 'Species', '9606', (51, 54))	('bladder cancer', 'Disease', 'MESH:D001749', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('documented', 'Reg', (47, 57))	('bladder cancer', 'Disease', (61, 75))	('bladder cancer', 'Phenotype', 'HP:0009725', (61, 75))
186879	32759680	The number of polyglutamine (CAG) repeats within exon 1 of the AR gene, which is usually associated inversely with its transcriptional activity, was found to be shorter in bladder tumors or patients with bladder cancer than in respective controls.	('CAG', 'Chemical', '-', (29, 32))	('bladder tumor', 'Phenotype', 'HP:0009725', (172, 185))	('bladder cancer', 'Disease', (204, 218))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('shorter', 'NegReg', (161, 168))	('patients', 'Species', '9606', (190, 198))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('AR gene', 'Gene', (63, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (204, 218))	('bladder tumors', 'Disease', 'MESH:D001749', (172, 186))	('polyglutamine', 'Var', (14, 27))	('bladder cancer', 'Phenotype', 'HP:0009725', (204, 218))	('bladder tumors', 'Phenotype', 'HP:0009725', (172, 186))	('polyglutamine', 'Chemical', 'MESH:C097188', (14, 27))	('bladder tumors', 'Disease', (172, 186))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
186880	32759680	Shorter CAG repeats have also been associated with a significantly enhanced risk of bladder cancer (odds ratios (ORs) 2.09 in men and 4.94 in women).	('men', 'Species', '9606', (126, 129))	('bladder cancer', 'Phenotype', 'HP:0009725', (84, 98))	('men', 'Species', '9606', (144, 147))	('bladder cancer', 'Disease', 'MESH:D001749', (84, 98))	('bladder cancer', 'Disease', (84, 98))	('Shorter', 'Var', (0, 7))	('CAG', 'Chemical', '-', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('women', 'Species', '9606', (142, 147))
186882	32759680	In addition, analysis of molecular profiling data has suggested somatic mutations in the AR gene in a subset (e.g., 4-6.1%) of urothelial cancers.	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('urothelial cancers', 'Disease', 'MESH:D014523', (127, 145))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('urothelial cancers', 'Disease', (127, 145))
186910	32759680	In a study showing the methylation status of 21 genes in bladder specimens, 44% of tumors vs. 20% of non-tumors were found to have ESR methylation (p = 0.622).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('methylation', 'Var', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('ESR', 'Gene', (131, 134))	('men', 'Species', '9606', (70, 73))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('ESR', 'Gene', '109755', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('methylation', 'biological_process', 'GO:0032259', ('135', '146'))
186918	32759680	Interestingly, ERalpha was immunohistologically detected in bladder tissues from none of the control mice without BBN exposure but 74% of BBN-treated mice, indicating a possible role of ERalpha in inducing urothelial carcinogenesis, while ERbeta was expressed in all these animals with or without BBN.	('mice', 'Species', '10090', (150, 154))	('urothelial carcinogenesis', 'Disease', (206, 231))	('mice', 'Species', '10090', (101, 105))	('urothelial carcinogenesis', 'Disease', 'MESH:D063646', (206, 231))	('inducing', 'Reg', (197, 205))	('BBN', 'Chemical', '-', (138, 141))	('BBN', 'Chemical', '-', (114, 117))	('ERalpha', 'Var', (186, 193))	('BBN', 'Chemical', '-', (297, 300))
186921	32759680	By contrast, deletion of the unique C-terminal amino acids in GRbeta prevents it from binding glucocorticoids or activating glucocorticoid-responsive promoters.	('activating', 'PosReg', (113, 123))	('GR', 'Gene', '14815', (62, 64))	('binding', 'Interaction', (86, 93))	('deletion', 'Var', (13, 21))	('glucocorticoid-responsive promoters', 'MPA', (124, 159))	('prevents', 'NegReg', (69, 77))	('binding', 'molecular_function', 'GO:0005488', ('86', '93'))	('glucocorticoids', 'Protein', (94, 109))
186928	32759680	Our recent studies using the in vitro transformation system described above demonstrated that GR knockdown in SVHUC cells resulted in the significant prevention of MCA-induced neoplastic transformation of urothelial cells.	('knockdown', 'Var', (97, 106))	('MCA-induced', 'Disease', (164, 175))	('GR', 'Gene', '14815', (94, 96))	('MCA', 'Chemical', 'MESH:D008748', (164, 167))	('prevention', 'NegReg', (150, 160))
186930	32759680	Moreover, the preventive effects of prednisone on the neoplastic transformation of GR-positive control SVHUC cells were considerably diminished by a GR antagonist RU486, while prednisone failed to significantly affect the neoplastic transformation of GR knockdown cells.	('diminished', 'NegReg', (133, 143))	('prednisone', 'Chemical', 'MESH:D011241', (176, 186))	('GR', 'Gene', '14815', (251, 253))	('neoplastic transformation', 'CPA', (54, 79))	('GR', 'Gene', '14815', (83, 85))	('RU486', 'Var', (163, 168))	('GR', 'Gene', '14815', (149, 151))	('RU486', 'Chemical', 'MESH:D015735', (163, 168))	('prednisone', 'Chemical', 'MESH:D011241', (36, 46))
186935	32759680	We have additionally demonstrated that CpdA induces only GR transrepression in SVHUC cells and bladder cancer lines.	('CpdA', 'Chemical', '-', (39, 43))	('CpdA', 'Var', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('bladder cancer', 'Disease', 'MESH:D001749', (95, 109))	('bladder cancer', 'Disease', (95, 109))	('GR', 'Gene', '14815', (57, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))
186936	32759680	In SVHUC-AR cells expressing both GR and AR upon carcinogen challenge, CpdA inhibited their neoplastic transformation and its effect was stronger than prednisone or hydroxyflutamide.	('GR', 'Gene', '14815', (34, 36))	('CpdA', 'Chemical', '-', (71, 75))	('prednisone', 'Chemical', 'MESH:D011241', (151, 161))	('CpdA', 'Var', (71, 75))	('hydroxyflutamide', 'Chemical', 'MESH:C014290', (165, 181))	('neoplastic transformation', 'CPA', (92, 117))	('inhibited', 'NegReg', (76, 85))
186946	32759680	A case-control study involving 130 bladder cancer patients versus 346 normal individuals also showed significant differences in the genotype (OR for "FF" = 2.042) or allelic frequency (OR for "F" = 1.489) of VDR (Fok-l) polymorphism, suggesting the association between reduced VDR activity and elevated bladder cancer risk.	('VDR (Fok-l', 'Gene', (208, 218))	('polymorphism', 'Var', (220, 232))	('bladder cancer', 'Disease', (35, 49))	('bladder cancer', 'Disease', (303, 317))	('bladder cancer', 'Disease', 'MESH:D001749', (303, 317))	('patients', 'Species', '9606', (50, 58))	('reduced', 'NegReg', (269, 276))	('VDR', 'Enzyme', (277, 280))	('differences', 'Reg', (113, 124))	('bladder cancer', 'Phenotype', 'HP:0009725', (35, 49))	('bladder cancer', 'Phenotype', 'HP:0009725', (303, 317))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('activity', 'MPA', (281, 289))	('bladder cancer', 'Disease', 'MESH:D001749', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
186962	32759680	In SVHUC-AR cells, DHT considerably reduced the expression levels of UGT1A subtypes as well as UGT1A protein.	('expression levels', 'MPA', (48, 65))	('DHT', 'Var', (19, 22))	('UGT1A', 'Gene', (95, 100))	('DHT', 'Chemical', 'MESH:D013196', (19, 22))	('reduced', 'NegReg', (36, 43))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('UGT1A', 'Gene', (69, 74))
186967	32759680	Meanwhile, in the in vitro transformation system with MCA exposure, UGT1A expression was significantly down-regulated and up-regulated by GR knockdown and hydroxyflutamide/prednisone/CpdA treatment, respectively.	('expression', 'MPA', (74, 84))	('knockdown', 'Var', (141, 150))	('prednisone', 'Chemical', 'MESH:D011241', (172, 182))	('MCA', 'Chemical', 'MESH:D008748', (54, 57))	('men', 'Species', '9606', (193, 196))	('down-regulated', 'NegReg', (103, 117))	('hydroxyflutamide', 'Chemical', 'MESH:C014290', (155, 171))	('CpdA', 'Chemical', '-', (183, 187))	('GR', 'Gene', '14815', (138, 140))	('UGT1A', 'Gene', (68, 73))	('up-regulated', 'PosReg', (122, 134))
186971	32759680	In SVHUC cells subsequently exposed to MCA, GATA3 knockdown resulted in the promotion of neoplastic transformation, along with down-regulation of the expression of tumor suppressor genes (e.g., p53, p21, PTEN) and up-regulation of that of oncogenes (e.g., c-myc, cyclins, FGFR3), suggesting its function as a suppressor of urothelial tumor.	('tumor', 'Disease', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('PTEN', 'Gene', (204, 208))	('p53', 'Gene', (194, 197))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('down-regulation', 'NegReg', (127, 142))	('p53', 'Gene', '22060', (194, 197))	('p21', 'Gene', (199, 202))	('knockdown', 'Var', (50, 59))	('up-regulation', 'PosReg', (214, 227))	('regulation', 'biological_process', 'GO:0065007', ('217', '227'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('164', '180'))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('expression', 'MPA', (150, 160))	('PTEN', 'Gene', '19211', (204, 208))	('tumor suppressor', 'biological_process', 'GO:0051726', ('164', '180'))	('FGFR3', 'Gene', (272, 277))	('tumor', 'Disease', (334, 339))	('GATA3', 'Gene', '14462', (44, 49))	('urothelial tumor', 'Disease', 'MESH:D001749', (323, 339))	('FGFR', 'molecular_function', 'GO:0005007', ('272', '276'))	('urothelial tumor', 'Disease', (323, 339))	('c-myc', 'Protein', (256, 261))	('FGFR3', 'Gene', '14184', (272, 277))	('neoplastic transformation', 'CPA', (89, 114))	('cyclins', 'Protein', (263, 270))	('tumor', 'Disease', 'MESH:D009369', (334, 339))	('p21', 'Gene', '12575', (199, 202))	('MCA', 'Chemical', 'MESH:D008748', (39, 42))	('promotion', 'PosReg', (76, 85))	('regulation', 'biological_process', 'GO:0065007', ('132', '142'))	('GATA3', 'Gene', (44, 49))
186980	32759680	As suggested in several other types of malignancies, we recently demonstrated that FOXO1 knockdown or inhibitor treatment prevented the MCA-mediated neoplastic transformation of SVHUC cells, indicating its function as a suppressor for urothelial cancer.	('prevented', 'NegReg', (122, 131))	('malignancies', 'Disease', (39, 51))	('urothelial cancer', 'Disease', 'MESH:D014523', (235, 252))	('men', 'Species', '9606', (117, 120))	('MCA-mediated neoplastic transformation', 'CPA', (136, 174))	('FOXO1', 'Gene', (83, 88))	('MCA', 'Chemical', 'MESH:D008748', (136, 139))	('FOXO1', 'Gene', '56458', (83, 88))	('knockdown', 'Var', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('malignancies', 'Disease', 'MESH:D009369', (39, 51))	('urothelial cancer', 'Disease', (235, 252))
186984	32759680	Similarly, ERbeta knockdown induced the levels of FOXO1 mRNA/protein expression or transcription and reduced those of p-FOXO1 expression in SVHUC cells, while E2 treatment showed opposite effects.	('knockdown', 'Var', (18, 27))	('ERbeta', 'Gene', (11, 17))	('expression', 'MPA', (126, 136))	('transcription', 'biological_process', 'GO:0006351', ('83', '96'))	('FOXO1', 'Gene', (50, 55))	('FOXO1', 'Gene', (120, 125))	('transcription', 'MPA', (83, 96))	('induced', 'PosReg', (28, 35))	('FOXO1', 'Gene', '56458', (50, 55))	('FOXO1', 'Gene', '56458', (120, 125))	('reduced', 'NegReg', (101, 108))	('E2', 'Chemical', 'MESH:D004958', (159, 161))	('levels', 'MPA', (40, 46))	('mRNA/protein expression', 'MPA', (56, 79))	('men', 'Species', '9606', (167, 170))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
186999	32759680	Indeed, genetic alterations, aberrant expression, and/or activation of beta-catenin as well as Myc in bladder cancer have been documented.	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('expression', 'MPA', (38, 48))	('genetic alterations', 'Var', (8, 27))	('activation', 'PosReg', (57, 67))	('men', 'Species', '9606', (131, 134))	('beta-catenin', 'Gene', '12387', (71, 83))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('bladder cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('aberrant', 'Var', (29, 37))	('beta-catenin', 'Gene', (71, 83))	('Myc', 'Gene', (95, 98))	('Myc', 'Gene', '17869', (95, 98))
187003	32759680	We demonstrated, using SVHUC cells with carcinogen challenge, that knockdown of ELK1 or treatment with a selective alpha1-blocker silodosin, which could inactivate ELK1, prevented the MCA-induced neoplastic formation of SVHUC-AR cells, indicating the oncogenic role of ELK1 in urothelial cancer.	('MCA', 'Chemical', 'MESH:D008748', (184, 187))	('ELK1', 'Gene', (269, 273))	('ELK1', 'Gene', (80, 84))	('urothelial cancer', 'Disease', (277, 294))	('men', 'Species', '9606', (93, 96))	('ELK1', 'Gene', '13712', (80, 84))	('silodosin', 'Chemical', 'MESH:C095285', (130, 139))	('MCA-induced neoplastic formation', 'CPA', (184, 216))	('knockdown', 'Var', (67, 76))	('formation', 'biological_process', 'GO:0009058', ('207', '216'))	('urothelial cancer', 'Disease', 'MESH:D014523', (277, 294))	('ELK1', 'Gene', '13712', (269, 273))	('prevented', 'NegReg', (170, 179))	('inactivate', 'Var', (153, 163))	('ELK1', 'Gene', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('ELK1', 'Gene', '13712', (164, 168))
187005	32759680	In addition, phospho-ELK1 positivity in non-muscle-invasive bladder tumors was associated with a significantly higher risk of disease recurrence.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('bladder tumor', 'Phenotype', 'HP:0009725', (60, 73))	('invasive bladder', 'Phenotype', 'HP:0100645', (51, 67))	('bladder tumors', 'Phenotype', 'HP:0009725', (60, 74))	('muscle-invasive bladder tumors', 'Disease', 'MESH:D001749', (44, 74))	('ELK1', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('ELK1', 'Gene', '13712', (21, 25))	('muscle-invasive bladder tumors', 'Disease', (44, 74))	('non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (40, 67))	('positivity', 'Var', (26, 36))
187007	32759680	Interestingly, ELK1 inactivation via its knockdown or silodosin treatment failed to significantly affect the neoplastic transformation of urothelial cells lacking a functional AR.	('men', 'Species', '9606', (69, 72))	('inactivation', 'Var', (20, 32))	('ELK1', 'Gene', (15, 19))	('lacking', 'NegReg', (155, 162))	('ELK1', 'Gene', '13712', (15, 19))	('silodosin', 'Chemical', 'MESH:C095285', (54, 63))	('neoplastic transformation of urothelial cells', 'CPA', (109, 154))
187013	32759680	Similar to the findings in ELK1, we demonstrated prevention of the neoplastic transformation of MCA-SVHUC-AR cells by ATF2 knockdown.	('ELK1', 'Gene', '13712', (27, 31))	('prevention', 'NegReg', (49, 59))	('ELK1', 'Gene', (27, 31))	('ATF2', 'Gene', (118, 122))	('neoplastic transformation', 'CPA', (67, 92))	('knockdown', 'Var', (123, 132))	('MCA', 'Chemical', 'MESH:D008748', (96, 99))	('ATF2', 'Gene', '11909', (118, 122))
187020	32759680	We recently showed that the expression of p65 and phospho-p65 was significantly elevated in bladder tumors, compared with corresponding benign urothelial tissues, and that the activity of NF-kappaB modulated by its activator or inhibitor was associated with urothelial tumorigenesis, using carcinogen-induced models (e.g., MCA in SVHUC cells, BBN in mice).	('bladder tumors', 'Disease', 'MESH:D001749', (92, 106))	('BBN', 'Chemical', '-', (343, 346))	('p65', 'Gene', (58, 61))	('activity', 'MPA', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('bladder tumors', 'Disease', (92, 106))	('modulated', 'Var', (198, 207))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('p65', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('bladder tumors', 'Phenotype', 'HP:0009725', (92, 106))	('NF-kappaB', 'Gene', (188, 197))	('p65', 'Gene', '19697', (58, 61))	('associated', 'Reg', (242, 252))	('elevated', 'PosReg', (80, 88))	('urothelial tumor', 'Disease', 'MESH:D001749', (258, 274))	('mice', 'Species', '10090', (350, 354))	('expression', 'MPA', (28, 38))	('bladder tumor', 'Phenotype', 'HP:0009725', (92, 105))	('urothelial tumor', 'Disease', (258, 274))	('p65', 'Gene', '19697', (42, 45))	('MCA', 'Chemical', 'MESH:D008748', (323, 326))	('NF-kappaB', 'Gene', '18033', (188, 197))
187023	32759680	Similarly, in bladder cancer cells, DHT enhanced NF-kappaB transactivation, which was blocked by hydroxyflutamide.	('transactivation', 'MPA', (59, 74))	('transactivation', 'biological_process', 'GO:2000144', ('59', '74'))	('NF-kappaB', 'Gene', '18033', (49, 58))	('DHT', 'Chemical', 'MESH:D013196', (36, 39))	('bladder cancer', 'Phenotype', 'HP:0009725', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('hydroxyflutamide', 'Chemical', 'MESH:C014290', (97, 113))	('enhanced', 'PosReg', (40, 48))	('NF-kappaB', 'Gene', (49, 58))	('bladder cancer', 'Disease', 'MESH:D001749', (14, 28))	('bladder cancer', 'Disease', (14, 28))	('DHT', 'Var', (36, 39))
187045	32467720	We apply our algorithms to 381 TCGA samples from 4 cancer types and show that many more TSVs can be identified under a diploid assumption compared to a haploid assumption.	('TSVs', 'Gene', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('diploid', 'Var', (119, 126))	('any', 'Chemical', '-', (79, 82))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
187091	32467720	3c) and find similar fractions between HCC1395 and HCC1954, which indicates that the extent of heterogeneity in two samples are similar.	('HCC1395', 'Var', (39, 46))	('HCC1954', 'Var', (51, 58))	('HCC1954', 'CellLine', 'CVCL:1259', (51, 58))	('HCC1395', 'CellLine', 'CVCL:1249', (39, 46))
187093	32467720	As predicted by D-SQUID, this TSV involves an insertion of the sixth and the seventh exons of FERMT2 between the sixth and seventh exons of ERO1A.	('FERMT2', 'Gene', (94, 100))	('ERO1A', 'Gene', (140, 145))	('FERMT2', 'Gene', '10979', (94, 100))	('insertion', 'Var', (46, 55))	('ERO1A', 'Gene', '30001', (140, 145))
187095	32467720	4b involves an insertion of the 3' untranslated region (UTR) of CLPSL1 and the entire CLPS gene between the first and second exons of CLPSL1.	('insertion', 'Var', (15, 24))	('CLPS', 'Gene', '1208', (64, 68))	('CLPS', 'Gene', (86, 90))	('CLPSL1', 'Gene', '340204', (134, 140))	('CLPS', 'Gene', '1208', (134, 138))	('CLPS', 'Gene', (64, 68))	('CLPSL1', 'Gene', '340204', (64, 70))	('CLPS', 'Gene', (134, 138))	('CLPSL1', 'Gene', (64, 70))	('CLPSL1', 'Gene', (134, 140))	('CLPS', 'Gene', '1208', (86, 90))
187113	32138216	Multiple T cell checkpoint molecules have been described, and the blockade of either of of these two inhibitory proteins, cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1), has resulted in clinical benefit in several tumor types.	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('CTLA4', 'Gene', (156, 161))	('tumor', 'Disease', (251, 256))	('programmed cell death protein 1', 'Gene', (167, 198))	('benefit', 'PosReg', (232, 239))	('programmed cell death', 'biological_process', 'GO:0012501', ('167', '188'))	('blockade', 'Var', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('lymphocyte antigen', 'molecular_function', 'GO:0005557', ('134', '152'))	('cytotoxic T-lymphocyte antigen 4', 'Gene', '1493', (122, 154))	('CTLA4', 'Gene', '1493', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('cytotoxic T-lymphocyte antigen 4', 'Gene', (122, 154))	('programmed cell death protein 1', 'Gene', '5133', (167, 198))
187115	32138216	In preclinical studies, the blockade of CTLA4 led to a 1.5- to two-fold increase in the proliferation of T cells, a six-fold increase in the production of interleukin-2 and the depletion of T regulatory lymphocytes in the tumor microenvironment through a macrophage-dependent process.	('interleukin-2', 'Gene', '3558', (155, 168))	('increase', 'PosReg', (72, 80))	('CTLA4', 'Gene', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('increase', 'PosReg', (125, 133))	('depletion', 'MPA', (177, 186))	('interleukin-2', 'Gene', (155, 168))	('blockade', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('proliferation', 'CPA', (88, 101))	('depletion of T regulatory lymphocytes', 'Phenotype', 'HP:0005419', (177, 214))	('T regulatory', 'CPA', (190, 202))	('CTLA4', 'Gene', '1493', (40, 45))
187131	32138216	Several animal studies have shown that VEGF factors are overexpressed in most solid cancers and that the inhibition of the VEGF signaling pathway can suppress tumor growth.	('VEGF', 'Gene', '7422', (123, 127))	('inhibition', 'Var', (105, 115))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cancers', 'Disease', (84, 91))	('VEGF', 'Gene', (39, 43))	('VEGF', 'Gene', (123, 127))	('tumor', 'Disease', (159, 164))	('VEGF signaling', 'biological_process', 'GO:0038084', ('123', '137'))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('suppress', 'NegReg', (150, 158))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('VEGF', 'Gene', '7422', (39, 43))	('signaling pathway', 'biological_process', 'GO:0007165', ('128', '145'))
187133	32138216	In 1993, a monoclonal neutralizing antibody against VEGFA was reported to inhibit tumor growth in a xenograft model.	('antibody', 'cellular_component', 'GO:0042571', ('35', '43'))	('VEGFA', 'Gene', (52, 57))	('antibody', 'cellular_component', 'GO:0019815', ('35', '43'))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('inhibit', 'NegReg', (74, 81))	('antibody', 'cellular_component', 'GO:0019814', ('35', '43'))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('antibody', 'molecular_function', 'GO:0003823', ('35', '43'))	('VEGFA', 'Gene', '7422', (52, 57))	('monoclonal', 'Var', (11, 21))	('tumor', 'Disease', (82, 87))
187147	32138216	Earlier studies have suggested that anti-angiogenic therapy can elicit or enhance tumor immunity response, whereas reciprocally the immune system can support angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('elicit', 'PosReg', (64, 70))	('angiogenesis', 'biological_process', 'GO:0001525', ('158', '170'))	('anti-angiogenic', 'Var', (36, 51))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('enhance', 'PosReg', (74, 81))
187181	32138216	Vascular normalization can convert the immunosuppressive TME into an immune-stimulatory one by promoting the accumulation, penetration, and antitumor activity of immune effector cells, and by reducing hypoxia and function of suppressive cells (Figure 1).	('reducing', 'NegReg', (192, 200))	('hypoxia', 'Disease', (201, 208))	('accumulation', 'CPA', (109, 121))	('tumor', 'Disease', (144, 149))	('function', 'CPA', (213, 221))	('penetration', 'CPA', (123, 134))	('normalization', 'Var', (9, 22))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('promoting', 'PosReg', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('hypoxia', 'Disease', 'MESH:D000860', (201, 208))
187183	32138216	Several studies have shown that treatment of xenograft cancer models with inhibitors of VEGF-A or VEGFRs increases T cell recruitment and infiltration into tumors and can exert a synergistic antitumor effect with anti-PD1 therapy.	('tumor', 'Disease', (195, 200))	('inhibitors', 'Var', (74, 84))	('PD1', 'Gene', '5133', (218, 221))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('VEGF-A', 'Gene', (88, 94))	('T cell recruitment', 'CPA', (115, 133))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('increases', 'PosReg', (105, 114))	('VEGFR', 'Gene', '3791', (98, 103))	('cancer', 'Disease', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('VEGFR', 'Gene', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('VEGF-A', 'Gene', '7422', (88, 94))	('PD1', 'Gene', (218, 221))	('tumors', 'Disease', (156, 162))	('increases T cell', 'Phenotype', 'HP:0100828', (105, 121))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
187201	32138216	As for renal cancer, it has been shown that the TKI sunitinib reverses type-1 immune suppression and decreases Treg in RCC patients.	('Treg', 'CPA', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('renal cancer', 'Disease', (7, 19))	('type-1 immune suppression', 'MPA', (71, 96))	('reverses', 'NegReg', (62, 70))	('decreases', 'NegReg', (101, 110))	('sunitinib', 'Chemical', 'MESH:D000077210', (52, 61))	('patients', 'Species', '9606', (123, 131))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('renal cancer', 'Disease', 'MESH:D007680', (7, 19))	('renal cancer', 'Phenotype', 'HP:0009726', (7, 19))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('TKI', 'Var', (48, 51))	('Treg', 'Chemical', '-', (111, 115))
187203	32138216	Lastly, the use of anti-PD-1 antibodies in combination with anti-VEGFR antibodies in the CT26 mouse model of CRC resulted in improved antitumor effects, with an average of an approximate 75% reduction in tumor growth compared with control treatment.	('antibodies', 'Var', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Disease', (138, 143))	('anti-PD-1 antibodies', 'Var', (19, 39))	('VEGFR', 'Gene', '3791', (65, 70))	('reduction', 'NegReg', (191, 200))	('CRC', 'Disease', (109, 112))	('CT26', 'CellLine', 'CVCL:7254', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('mouse', 'Species', '10090', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', (204, 209))	('improved', 'PosReg', (125, 133))	('VEGFR', 'Gene', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('CRC', 'Phenotype', 'HP:0003003', (109, 112))	('CRC', 'Disease', 'MESH:D015179', (109, 112))
187204	32138216	Similarly, in mice with tumors derived from injection of mouse colon cancer C26 cells, treatment with a combination of anti-VEGFR2 and anti-PD-1 monoclonal antibodies led to enhanced inhibition of tumor growth compared with either treatment alone.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('inhibition', 'NegReg', (183, 193))	('tumors', 'Disease', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('mice', 'Species', '10090', (14, 18))	('enhanced', 'PosReg', (174, 182))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('colon cancer', 'Phenotype', 'HP:0003003', (63, 75))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('colon cancer', 'Disease', (63, 75))	('tumor', 'Disease', (24, 29))	('C26', 'CellLine', 'CVCL:0240', (76, 79))	('colon cancer', 'Disease', 'MESH:D015179', (63, 75))	('anti-PD-1', 'Var', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mouse', 'Species', '10090', (57, 62))	('tumor', 'Disease', (197, 202))	('anti-VEGFR2', 'Var', (119, 130))
187215	32138216	The rationale is to restore the patient's natural tumor-specific T cell-mediated immune responses by neutralizing any inhibitory signaling.	('patient', 'Species', '9606', (32, 39))	('restore', 'PosReg', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('neutralizing', 'Var', (101, 113))	('T cell-mediated', 'CPA', (65, 80))	('inhibitory signaling', 'MPA', (118, 138))	('tumor', 'Disease', (50, 55))
187220	32138216	Clinically, PDL1 expression is associated with poorer prognosis in a variety of solid tumors, such as melanoma, renal cancer, and lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('renal cancer', 'Disease', 'MESH:D007680', (112, 124))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('solid tumors', 'Disease', 'MESH:D009369', (80, 92))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('melanoma', 'Disease', (102, 110))	('lung cancer', 'Disease', (130, 141))	('PDL1', 'Gene', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'Var', (17, 27))	('PDL1', 'Gene', '29126', (12, 16))	('renal cancer', 'Disease', (112, 124))	('poorer', 'NegReg', (47, 53))	('renal cancer', 'Phenotype', 'HP:0009726', (112, 124))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('solid tumors', 'Disease', (80, 92))
187232	32138216	Any degree of PD-L1 expression was seen in 36% of patients and was associated with increased infiltration with TAMs, compared with lower expression.	('increased', 'PosReg', (83, 92))	('patients', 'Species', '9606', (50, 58))	('TAMs', 'Chemical', 'MESH:D013629', (111, 115))	('expression', 'Var', (20, 30))	('PD-L1', 'Gene', (14, 19))	('infiltration', 'MPA', (93, 105))
187234	32138216	Conversely, a study conducted by Shin and colleagues demonstrated that PD-L1 expression was independently associated with shorter survival in patients with metastatic RCC after VEGF-TKI treatment and significantly related to lack of VEGF-TKI responsiveness (p = 0.012).	('VEGF', 'Gene', '7422', (177, 181))	('shorter', 'NegReg', (122, 129))	('expression', 'Var', (77, 87))	('VEGF', 'Gene', (177, 181))	('PD-L1', 'Gene', (71, 76))	('VEGF', 'Gene', '7422', (233, 237))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('survival', 'MPA', (130, 138))	('VEGF', 'Gene', (233, 237))	('patients', 'Species', '9606', (142, 150))
187236	32138216	Notably, for patients without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) variations, ABCP group had prolonged recurrence-free survival (RFS) (HR = 0.77, p < 0.05, in PD-L1- patients) and OS (HR = 0.78, p = 0.02, in PD-L1- and PD-L1+ patients) regardless of PD-L1 status in comparison with BCP group.	('patients', 'Species', '9606', (13, 21))	('ALK', 'Gene', '238', (101, 104))	('BCP', 'Chemical', '-', (322, 325))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('30', '53'))	('prolonged', 'PosReg', (133, 142))	('epidermal growth factor receptor', 'Gene', (30, 62))	('ALK', 'Gene', (101, 104))	('RFS', 'Disease', 'MESH:D005198', (169, 172))	('patients', 'Species', '9606', (266, 274))	('OS', 'Gene', '17451', (220, 222))	('variations', 'Var', (106, 116))	('epidermal growth factor receptor', 'Gene', '1956', (30, 62))	('EGFR', 'Gene', (64, 68))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (73, 92))	('BCP', 'Chemical', '-', (119, 122))	('anaplastic lymphoma kinase', 'Gene', '238', (73, 99))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('RFS', 'Disease', (169, 172))	('anaplastic lymphoma kinase', 'Gene', (73, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (84, 92))	('recurrence-free survival', 'CPA', (143, 167))	('patients', 'Species', '9606', (206, 214))	('EGFR', 'Gene', '1956', (64, 68))
187281	32138216	Enrolled patients could have any PD-L1 status Patients with EGFR mutations (exon 19 deletion or L858R mutation) as well as ALK translocation have been included in the trial after progression to at least one prior TKI therapy.	('patients', 'Species', '9606', (9, 17))	('Patients', 'Species', '9606', (46, 54))	('ALK', 'Gene', (123, 126))	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('L858R mutation', 'Var', (96, 110))	('L858R', 'Mutation', 'rs121434568', (96, 101))	('EGFR', 'Gene', '1956', (60, 64))	('exon 19 deletion', 'Var', (76, 92))	('ALK', 'Gene', '238', (123, 126))	('EGFR', 'Gene', (60, 64))
187287	32138216	Interestingly, adding atezolizumab to BCP regimen resulted in an advantage in terms of PFS across all subgroups, including those with EGFR or ALK genetic alteration, among patients with low or high PD-L1 expression, those with low Teff gene-signature expression, and those with liver metastases.	('PD-L1', 'Gene', (198, 203))	('ALK', 'Gene', '238', (142, 145))	('EGFR', 'Gene', (134, 138))	('atezolizumab', 'Chemical', 'MESH:C000594389', (22, 34))	('EGFR', 'molecular_function', 'GO:0005006', ('134', '138'))	('metastases', 'Disease', (284, 294))	('PFS', 'MPA', (87, 90))	('advantage', 'PosReg', (65, 74))	('patients', 'Species', '9606', (172, 180))	('ALK', 'Gene', (142, 145))	('metastases', 'Disease', 'MESH:D009362', (284, 294))	('BCP', 'Chemical', '-', (38, 41))	('EGFR', 'Gene', '1956', (134, 138))	('genetic alteration', 'Var', (146, 164))
187289	32138216	ABCP is also approved for EGFR mutant or ALK translocated patients, after failure to appropriate targeted therapies.	('EGFR', 'Gene', (26, 30))	('mutant', 'Var', (31, 37))	('patients', 'Species', '9606', (58, 66))	('BCP', 'Chemical', '-', (1, 4))	('ALK', 'Gene', (41, 44))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))	('EGFR', 'Gene', '1956', (26, 30))	('ALK', 'Gene', '238', (41, 44))
187318	32138216	In this trial, people with untreated metastatic CRC and d-MMR are randomized to receive mFOLFOX6 + atezolizumab + bevacizumab, mFOLFOX6 + bevacizumab or atezolizumab alone.	('CRC', 'Disease', (48, 51))	('bevacizumab', 'Chemical', 'MESH:D000068258', (138, 149))	('atezolizumab', 'Chemical', 'MESH:C000594389', (99, 111))	('bevacizumab', 'Chemical', 'MESH:D000068258', (114, 125))	('MMR', 'biological_process', 'GO:0006298', ('58', '61'))	('mFOLFOX6', 'Chemical', '-', (127, 135))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('CRC', 'Disease', 'MESH:D015179', (48, 51))	('mFOLFOX6', 'Var', (88, 96))	('people', 'Species', '9606', (15, 21))	('mFOLFOX6', 'Var', (127, 135))	('mFOLFOX6', 'Chemical', '-', (88, 96))	('atezolizumab', 'Chemical', 'MESH:C000594389', (153, 165))
187323	32138216	Recently, the FDA also approved pembrolizumab in subsequent lines of therapy, both as third line therapy in case of highly PD-L1 expressing tumors, and for second line therapy for d-MMRI patients with no other treatment options.	('patients', 'Species', '9606', (187, 195))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Disease', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('pembrolizumab', 'Chemical', 'MESH:C582435', (32, 45))	('PD-L1', 'Gene', (123, 128))	('highly', 'Var', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
187594	28807024	The objective response proportion in cohort 2 was 15% and was greater (26%) in patients with high expression of PD-L1 on immune cells (IC2/3).	('PD-L1', 'Gene', (112, 117))	('IC2/3', 'Gene', (135, 140))	('patients', 'Species', '9606', (79, 87))	('PD-L1', 'Gene', '29126', (112, 117))	('high expression', 'Var', (93, 108))	('IC2/3', 'Gene', '1781', (135, 140))
187595	28807024	However, the median overall survival was 11.4 months in the high PD-L1 group (IC2/3), and 7.9 months in the overall cohort.	('high', 'Var', (60, 64))	('PD-L1', 'Gene', (65, 70))	('IC2/3', 'Gene', (78, 83))	('PD-L1', 'Gene', '29126', (65, 70))	('IC2/3', 'Gene', '1781', (78, 83))
187660	33624190	We have shown that the inclusion of the synthetic variables based on the RNA expression levels and copy number alterations can lead to improved quality of prognostic tests.	('quality of prognostic tests', 'MPA', (144, 171))	('synthetic', 'Species', '2086595', (40, 49))	('RNA', 'cellular_component', 'GO:0005562', ('73', '76'))	('improved', 'PosReg', (135, 143))	('copy number alterations', 'Var', (99, 122))	('RNA expression', 'MPA', (73, 87))
187661	33624190	The cancer pathophysiology is related to both genetic and epigenetic changes that are described by various types of biological data.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('epigenetic changes', 'Var', (58, 76))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (4, 10))
187668	33624190	showed that data integration improved prognostic performance in 7 out of 14 of cancer types examined, when compared with the use of clinical variables alone.	('prognostic performance', 'MPA', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('data', 'Var', (12, 16))	('improved', 'PosReg', (29, 37))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
187676	33624190	Three types of descriptors were available for breast cancer patients: clinical data (CD), gene expression profiles (GE) obtained with Illumina Human HT-12 v3 microarray, and copy-number alterations data (CNA) obtained with Affymetrix SNP 6.0.	('copy-number alterations', 'Var', (174, 197))	('gene expression', 'biological_process', 'GO:0010467', ('90', '105'))	('Human', 'Species', '9606', (143, 148))	('patients', 'Species', '9606', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('CD', 'Chemical', '-', (85, 87))	('breast cancer', 'Disease', (46, 59))
187686	33624190	After integrating clinical and molecular data sets, the final BLCA data contained records of 320 patients (149 survivors and 171 deceased) in four subsets containing 21 clinical descriptors (CD), 19006 mRNA gene expression profiles (RNA), 15628 DNA methylation profiles (METH), and 219 reverse-phase protein profiles (RPPA).	('15628 DNA', 'Var', (239, 248))	('protein', 'cellular_component', 'GO:0003675', ('300', '307'))	('reverse-phase protein profiles', 'MPA', (286, 316))	('CD', 'Chemical', '-', (191, 193))	('methylation profiles', 'MPA', (249, 269))	('DNA methylation', 'biological_process', 'GO:0006306', ('245', '260'))	('METH', 'molecular_function', 'GO:0008705', ('271', '275'))	('DNA', 'cellular_component', 'GO:0005574', ('245', '248'))	('mRNA', 'MPA', (202, 206))	('19006', 'Var', (196, 201))	('gene expression', 'biological_process', 'GO:0010467', ('207', '222'))	('RNA', 'cellular_component', 'GO:0005562', ('233', '236'))	('patients', 'Species', '9606', (97, 105))
187707	33624190	The alteration of the number of copies of genes results in modified expression patterns in cells, that in turn can lead to the development of lethal forms of cancer.	('modified', 'Reg', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('alteration', 'Var', (4, 14))	('cancer', 'Disease', (158, 164))	('expression patterns', 'MPA', (68, 87))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lead to', 'Reg', (115, 122))
187735	33624190	The inclusion of the synthetic variables based on the RNA expression levels and copy number alterations can lead to an improved quality of prognostic tests.	('RNA', 'cellular_component', 'GO:0005562', ('54', '57'))	('copy number alterations', 'Var', (80, 103))	('RNA', 'MPA', (54, 57))	('synthetic', 'Species', '2086595', (21, 30))	('improved', 'PosReg', (119, 127))	('quality of prognostic tests', 'MPA', (128, 155))
187737	32886446	Impact of radiotherapy to the primary tumor on the efficacy of pembrolizumab for patients with advanced urothelial cancer: A preliminary study Radiotherapy plus immune checkpoint inhibitors can potentially induce synergistic antitumor immune responses.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('induce', 'Reg', (206, 212))	('Radiotherapy', 'Var', (143, 155))	('patients', 'Species', '9606', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('urothelial cancer', 'Disease', (104, 121))	('pembrolizumab', 'Chemical', 'MESH:C582435', (63, 76))	('urothelial cancer', 'Disease', 'MESH:D014523', (104, 121))
187742	32886446	From multivariate analysis, radiotherapy to the primary tumor was an independent predictor for longer overall survival (hazard ratio, 0.31; P = .032) along with Eastern Cooperative Oncology Group performance status <=1 and the absence of visceral metastasis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('longer', 'PosReg', (95, 101))	('tumor', 'Disease', (56, 61))	('Oncology', 'Phenotype', 'HP:0002664', (181, 189))	('overall survival', 'MPA', (102, 118))	('radiotherapy', 'Var', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
187784	32886446	The primary site was in the bladder in a significantly higher proportion of the Radiotherapy group compared with the Non-radiotherapy group (94% vs 51%; P < .001), reflecting the fact that radiotherapy-based treatment to the primary tumor is established in muscle-invasive bladder cancer including bladder preservation therapy.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('invasive bladder', 'Phenotype', 'HP:0100645', (264, 280))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (257, 287))	('muscle-invasive bladder cancer', 'Disease', (257, 287))	('Radiotherapy', 'Var', (80, 92))	('bladder cancer', 'Phenotype', 'HP:0009725', (273, 287))
187788	32886446	From multivariate logistic regression analysis, radiotherapy to the primary tumor (odds ratio, 8.34; 95% confidence interval, 2.67-28.75; P < .001) was independently associated with objective response (Table 2).	('objective', 'Disease', (182, 191))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('radiotherapy', 'Var', (48, 60))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
187790	32886446	From multivariate analysis, radiotherapy to the primary tumor was an independent predictor for longer OS (hazard ratio, 0.31; 95% confidence interval, 0.07-0.91; P = .032), along with ECOG PS <= 1 (P < .001) and the absence of visceral metastasis (P = .017; Table 3).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('longer OS', 'Disease', (95, 104))	('radiotherapy', 'Var', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
187820	32886446	M2019-059 (Tokyo Medical and Dental University), 2019-1143 (Cancer Institute Hospital), 997 (Saitama Cancer Center), and 2019-205 (National Cancer Center Hospital East).	('Saitama Cancer', 'Disease', (93, 107))	('M2019-059', 'Var', (0, 9))	('Cancer', 'Disease', (140, 146))	('Cancer', 'Disease', 'MESH:D009369', (101, 107))	('Cancer', 'Disease', (60, 66))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', 'MESH:D009369', (140, 146))	('Cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('Saitama Cancer', 'Disease', 'MESH:D009369', (93, 107))	('997', 'Var', (88, 91))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Cancer', 'Disease', (101, 107))
187845	32217756	Eleven laboratories used WES data from The Cancer Genome Atlas Multi-Center Mutation calling in Multiple Cancers (MC3) samples and calculated TMB from the subset of the exome restricted to the genes covered by their targeted panel using their own bioinformatics pipeline (panel TMB).	('Cancer', 'Disease', (43, 49))	('Cancer', 'Disease', (105, 111))	('Cancers', 'Disease', 'MESH:D009369', (105, 112))	('Cancers', 'Phenotype', 'HP:0002664', (105, 112))	('Cancer', 'Disease', 'MESH:D009369', (43, 49))	('Cancer', 'Disease', 'MESH:D009369', (105, 111))	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))	('TMB', 'Chemical', '-', (278, 281))	('TMB', 'Chemical', '-', (142, 145))	('Mutation', 'Var', (76, 84))	('Cancers', 'Disease', (105, 112))
187859	32217756	Tumor mutational burden (TMB), which measures the number of somatic mutations per megabase (Mb) of the interrogated genomic sequence of a tumor, has been most recently identified as a biomarker of response to ICIs in several cancer types.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('tumor', 'Disease', (138, 143))	('TMB', 'Chemical', '-', (25, 28))	('cancer', 'Disease', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('mutations', 'Var', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
187860	32217756	High TMB is associated with improved outcomes in patients with melanoma treated with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade and PD-1/PD-L1 blockade across several cancer types, including melanoma, non-small-cell lung carcinoma, bladder cancer, microsatellite instability cancers and pan-tumor cohorts.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('CTLA-4', 'Gene', '1493', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (224, 249))	('CTLA-4', 'Gene', (130, 136))	('PD-1/PD-L1 blockade', 'Disease', 'MESH:D010300', (151, 170))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('TMB', 'Chemical', '-', (5, 8))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('High', 'Var', (0, 4))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (85, 128))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (220, 249))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('PD-1/PD-L1 blockade', 'Disease', (151, 170))	('lung carcinoma', 'Disease', (235, 249))	('cancer', 'Disease', (294, 300))	('microsatellite instability cancers', 'Disease', (267, 301))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('cancer', 'Disease', (259, 265))	('outcomes', 'MPA', (37, 45))	('microsatellite instability cancers', 'Disease', 'MESH:D053842', (267, 301))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (85, 128))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('tumor', 'Disease', (310, 315))	('bladder cancer', 'Disease', 'MESH:D001749', (251, 265))	('bladder cancer', 'Disease', (251, 265))	('patients', 'Species', '9606', (49, 57))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('melanoma', 'Disease', (210, 218))	('cancer', 'Disease', (186, 192))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('bladder cancer', 'Phenotype', 'HP:0009725', (251, 265))	('improved', 'PosReg', (28, 36))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung carcinoma', 'Disease', 'MESH:D008175', (235, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))
187861	32217756	High TMB has also been associated with improved outcomes in patients treated with a combination of PD-1/PD-L1 and CTLA-4 inhibitors.	('PD-1/PD-L1', 'Disease', (99, 109))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (60, 68))	('CTLA-4', 'Gene', (114, 120))	('outcomes', 'MPA', (48, 56))	('improved', 'PosReg', (39, 47))	('TMB', 'Chemical', '-', (5, 8))	('CTLA-4', 'Gene', '1493', (114, 120))	('PD-1/PD-L1', 'Disease', 'MESH:D010300', (99, 109))
187885	32217756	The remaining cases (n=8291) were randomly assigned to training (n=4157) and validation (n=4134) datasets with similar median candidate mutations and cancer types (online supplementary figure 2).	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
187906	32217756	The uniform method for analysis of WES TMB included minimum thresholds for median target coverage (median 300X as this was identified as the point where sensitivity for the lower allele frequency variants drops drastically) (see online supplementary figure 4), variant allele frequency (>=0.05), read depth (>=25) and variant count (>=3), and synonymous variants were excluded.	('TMB', 'Chemical', '-', (39, 42))	('drops', 'NegReg', (205, 210))	('variants', 'Var', (196, 204))
187916	32217756	A limitation of analyzing all cancer types together is the variable distribution of TMB across different cancer types, with some cancer types displaying large dynamic ranges of TMB values up to several hundred mutations per Mb and others with very limited distributions with very few samples reaching 20 mutations per Mb (see online supplementary figure 3).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (210, 219))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('TMB', 'Chemical', '-', (177, 180))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TMB', 'Chemical', '-', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
187957	32217756	This would be consistent with a recent report that found that in patients who received ICI, those who had high TMB had longer survival than those who had low TMB, but TMB-high cut-offs were cancer-type dependent.	('TMB', 'Chemical', '-', (158, 161))	('cancer', 'Disease', (190, 196))	('TMB', 'Chemical', '-', (167, 170))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('longer', 'PosReg', (119, 125))	('high', 'Var', (106, 110))	('survival', 'CPA', (126, 134))	('TMB', 'Chemical', '-', (111, 114))	('patients', 'Species', '9606', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))
188035	27785429	Non-pure urothelial carcinoma with the presence of variant histology is another marker of aggressive disease that can sometimes be assessed on ureteroscopically-obtained biopsies.	('aggressive disease', 'Disease', (90, 108))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (9, 29))	('pure', 'molecular_function', 'GO:0034023', ('4', '8'))	('urothelial carcinoma', 'Disease', (9, 29))	('variant', 'Var', (51, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('aggressive disease', 'Disease', 'MESH:D001523', (90, 108))
188036	27785429	A large retrospective study compared survival of patients presenting variant histology versus pure urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (99, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('urothelial carcinoma', 'Disease', (99, 119))	('pure', 'molecular_function', 'GO:0034023', ('94', '98'))	('patients', 'Species', '9606', (49, 57))	('variant histology', 'Var', (69, 86))
188037	27785429	At 5-year, patients with variant histology had a 30% lower CSS compared to patients with pure urothelial carcinoma.	('urothelial carcinoma', 'Disease', (94, 114))	('CSS', 'Chemical', '-', (59, 62))	('pure', 'molecular_function', 'GO:0034023', ('89', '93'))	('patients', 'Species', '9606', (75, 83))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (94, 114))	('CSS', 'MPA', (59, 62))	('variant', 'Var', (25, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('patients', 'Species', '9606', (11, 19))	('lower', 'NegReg', (53, 58))
188099	33200223	Among the 12 prognostic genes, MIT-domain containing protein 1 (MITD1) transfection was demonstrated to inhibit T24 cell migration to a certain degree.	('T24 cell migration', 'CPA', (112, 130))	('transfection', 'Var', (71, 83))	('MIT-domain containing protein 1', 'Gene', (31, 62))	('cell migration', 'biological_process', 'GO:0016477', ('116', '130'))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('MIT-domain containing protein 1', 'Gene', '129531', (31, 62))	('MITD1', 'Gene', '129531', (64, 69))	('inhibit', 'NegReg', (104, 111))	('MITD1', 'Gene', (64, 69))
188100	33200223	Experiments performed with a 7-gene siRNA library demonstrated that MITD1 knockdown markedly upregulated cell migratory abilities.	('knockdown', 'Var', (74, 83))	('MITD1', 'Gene', (68, 73))	('upregulated', 'PosReg', (93, 104))	('MITD1', 'Gene', '129531', (68, 73))	('cell migratory abilities', 'CPA', (105, 129))	('men', 'Species', '9606', (6, 9))
188166	33200223	DEGs between the control and MITD1 knockdown groups were uploaded onto DAVID.	('knockdown', 'Var', (35, 44))	('MITD1', 'Gene', (29, 34))	('MITD1', 'Gene', '129531', (29, 34))
188171	33200223	The present study selected the top 18 genes significantly associated with survival in patients with urothelial cancer in the Pathology Atlas project, which met the following criteria: i) The prognostic P<1x10-6 (best cut-off); ii) the prognostic P<1x10-2 (median expression cut-off) and iii) has rarely been reported to be associated with cancer progression.	('P<1x10-6', 'Var', (202, 210))	('associated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (339, 345))	('cancer', 'Disease', 'MESH:D009369', (339, 345))	('urothelial cancer', 'Disease', (100, 117))	('expression', 'Species', '29278', (263, 273))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('urothelial cancer', 'Disease', 'MESH:D014523', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('patients', 'Species', '9606', (86, 94))
188179	33200223	MITD1 knockdown markedly increased cell migration (Fig.	('increased', 'PosReg', (25, 34))	('cell migration', 'CPA', (35, 49))	('cell migration', 'biological_process', 'GO:0016477', ('35', '49'))	('MITD1', 'Gene', (0, 5))	('MITD1', 'Gene', '129531', (0, 5))	('knockdown', 'Var', (6, 15))
188180	33200223	The wound healing assay was performed to validate the role of MITD1 on cell migration and the results demonstrated that MITD1 knockdown significantly promoted cell migration (Fig.	('MITD1', 'Gene', (62, 67))	('cell migration', 'biological_process', 'GO:0016477', ('159', '173'))	('promoted', 'PosReg', (150, 158))	('cell migration', 'CPA', (159, 173))	('cell migration', 'biological_process', 'GO:0016477', ('71', '85'))	('MITD1', 'Gene', (120, 125))	('MITD1', 'Gene', '129531', (120, 125))	('knockdown', 'Var', (126, 135))	('wound healing', 'biological_process', 'GO:0042060', ('4', '17'))	('MITD1', 'Gene', '129531', (62, 67))
188182	33200223	T24 cells were transfected with MITD1 siRNAs or NC oligonucleotide, while the untreated cells were cultured as the BLANK group.	('MITD1', 'Gene', (32, 37))	('oligonucleotide', 'Chemical', 'MESH:D009841', (51, 66))	('NC oligonucleotide', 'Var', (48, 66))	('MITD1', 'Gene', '129531', (32, 37))
188193	33200223	When exogenous recombined MITD1 was transfected into T24 cells, the cell migratory ability was downregulated, while knockdown of MITD1 promoted cell migration.	('promoted', 'PosReg', (135, 143))	('cell migration', 'CPA', (144, 158))	('downregulated', 'NegReg', (95, 108))	('cell migratory ability', 'CPA', (68, 90))	('knockdown', 'Var', (116, 125))	('MITD1', 'Gene', (26, 31))	('MITD1', 'Gene', (129, 134))	('MITD1', 'Gene', '129531', (129, 134))	('MITD1', 'Gene', '129531', (26, 31))	('cell migration', 'biological_process', 'GO:0016477', ('144', '158'))
188201	33200223	The results demonstrated that several potential downstream molecules (KISS1, SPANXB1, SPINT1, PIWIL2, SNAI1, APLN, EDN1 and CTHRC1), which have been reported to be associated with cell metastasis, were dysregulated following MITD1 knockdown.	('EDN1', 'Gene', (115, 119))	('associated', 'Reg', (164, 174))	('MITD1', 'Gene', (225, 230))	('knockdown', 'Var', (231, 240))	('MITD1', 'Gene', '129531', (225, 230))	('cell metastasis', 'CPA', (180, 195))	('dysregulated', 'Reg', (202, 214))
188207	33200223	These results suggest that the genes may influence tumor development independent of altering the cell proliferation rate.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cell proliferation', 'biological_process', 'GO:0008283', ('97', '115'))	('tumor', 'Disease', (51, 56))	('influence', 'Reg', (41, 50))	('men', 'Species', '9606', (64, 67))	('genes', 'Var', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
188212	33200223	There were three possible reasons for this: i) The majority of the prognostic genes identified by the Pathology Atlas project may act as a 'passenger' for tumor development, not the 'driver'; ii) the in vitro experiments may not completely mimic the authentic in vivo context and iii) the prognostic genes may promote cancer progress by altering other characteristics, such as invasion, immune escape and angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('promote', 'PosReg', (310, 317))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('angiogenesis', 'biological_process', 'GO:0001525', ('405', '417'))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Disease', (318, 324))	('tumor', 'Disease', (155, 160))	('altering', 'Reg', (337, 345))	('invasion', 'CPA', (377, 385))	('angiogenesis', 'CPA', (405, 417))	('men', 'Species', '9606', (215, 218))	('immune escape', 'CPA', (387, 400))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('genes', 'Var', (300, 305))	('men', 'Species', '9606', (168, 171))
188222	29344681	Transfusion at any time, patient comorbidity, high grade, advanced stage, positive surgical margins, low preoperative hemoglobin, longer operative duration, and increased blood loss were significantly associated with cancer-specific survival (DSS) on univariable analysis (HR 1.85, 95% CI 1.20-2.85, p<0.005).	('blood loss', 'Disease', 'MESH:D006473', (171, 181))	('cancer', 'Disease', (217, 223))	('patient', 'Species', '9606', (25, 32))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('associated', 'Reg', (201, 211))	('blood loss', 'Disease', (171, 181))	('high grade', 'Var', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('low', 'NegReg', (101, 104))
188244	29344681	Patients receiving transfusion were more likely to be have received open surgery(p=0.010), and had longer operative duration, higher estimated blood loss (EBL), received more intravenous fluids, and had longer length of stay (all p<.001).	('longer', 'PosReg', (99, 105))	('transfusion', 'Var', (19, 30))	('blood loss', 'Disease', (143, 153))	('open', 'Disease', (68, 72))	('higher', 'PosReg', (126, 132))	('Patients', 'Species', '9606', (0, 8))	('blood loss', 'Disease', 'MESH:D006473', (143, 153))
188246	29344681	Notably, receiving transfusion (Figure 1a), higher ASA score, receiving preoperative chemotherapy, high grade, >=stage pT3, and N+ disease, were individually associated with worse OS (Table 2a).	('high grade', 'Var', (99, 109))	('>=stage pT3', 'Var', (111, 122))	('higher', 'PosReg', (44, 50))	('N+ disease', 'Var', (128, 138))	('ASA', 'Chemical', '-', (51, 54))	('ASA', 'Gene', (51, 54))
188255	29344681	Like our study, the authors identified transfusion to be associated with advanced T stage and worse recurrence-free, cancer-specific, and overall survival on univariable analyses but not multivariable analyses.	('transfusion', 'Var', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('recurrence-free', 'CPA', (100, 115))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('worse', 'NegReg', (94, 99))	('cancer', 'Disease', (117, 123))
188268	29344681	Transfusions are associated with a variety of adverse pathologic features such as advanced stage, grade, and positive surgical margins that are easily captured but also lead to hard to quantitate measures of cancer biology such as increased neovascularity and obliteration of natural tissue planes that lead to more challenging surgery.	('Transfusions', 'Var', (0, 12))	('cancer', 'Disease', (208, 214))	('neovascularity', 'CPA', (241, 255))	('obliteration', 'CPA', (260, 272))	('increased', 'PosReg', (231, 240))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
188281	32923402	In several types of squamous cell carcinoma (SCC), the mutations that drive aggressive SCC have been found in RIPK4.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (20, 43))	('squamous cell carcinoma', 'Disease', (20, 43))	('mutations', 'Var', (55, 64))	('RIPK4', 'Gene', (110, 115))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 43))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))
188296	32923402	The observed differences between epidermal-specific RIPK4 knockout mice and RIPK4 full knockout mice may be due to the timing of RIPK4 ablation.	('mice', 'Species', '10090', (96, 100))	('RIPK4', 'Gene', (76, 81))	('ablation', 'Var', (135, 143))	('differences', 'Reg', (13, 24))	('RIPK4', 'Gene', (129, 134))	('mice', 'Species', '10090', (67, 71))
188297	32923402	Furthermore, RIPK4 knockout leads to perinatal lethality in mice, which was most likely due to the suffocation caused by abnormal epidermal differentiation.	('abnormal epidermal differentiation', 'Phenotype', 'HP:0011124', (121, 155))	('knockout', 'Var', (19, 27))	('mice', 'Species', '10090', (60, 64))	('RIPK4', 'Gene', (13, 18))	('perinatal lethality', 'CPA', (37, 56))
188298	32923402	RIPK4 mutations have been linked to Bartsocas-Papas syndrome (BPS) in human, which is typically characterized by aberrant skin, craniofacial and genital development, and early death.	('genital development', 'biological_process', 'GO:0007484', ('145', '164'))	('Bartsocas-Papas syndrome', 'Disease', (36, 60))	('human', 'Species', '9606', (70, 75))	('genital development', 'biological_process', 'GO:0048806', ('145', '164'))	('linked', 'Reg', (26, 32))	('death', 'Disease', 'MESH:D003643', (176, 181))	('death', 'Disease', (176, 181))	('RIPK4', 'Gene', (0, 5))	('aberrant skin', 'Phenotype', 'HP:0011121', (113, 126))	('mutations', 'Var', (6, 15))
188299	32923402	RIPK4 mutations are also associated with CHAND syndrome, and the acronym summarizes the main features: curly hair, ankyloblepharon (fused eyelids), and nail dysplasia.	('CHAND syndrome', 'Disease', (41, 55))	('nail dysplasia', 'Phenotype', 'HP:0002164', (152, 166))	('associated', 'Reg', (25, 35))	('ankyloblepharon', 'Phenotype', 'HP:0009755', (115, 130))	('ankyloblepharon', 'Disease', (115, 130))	('dysplasia', 'Disease', 'MESH:C536170', (157, 166))	('CHAND syndrome', 'Disease', 'MESH:C538074', (41, 55))	('curly hair', 'Disease', (103, 113))	('dysplasia', 'Disease', (157, 166))	('curly hair', 'Phenotype', 'HP:0002212', (103, 113))	('RIPK4', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
188304	32923402	This was in accordance with the finding that RIPK4 knockdown in normal keratinocytes hampered the expression of differentiation markers upon PKC activation.	('hampered', 'NegReg', (85, 93))	('RIPK4', 'Gene', (45, 50))	('PKC', 'Gene', (141, 144))	('expression of differentiation markers', 'MPA', (98, 135))	('PKC', 'Gene', '112476', (141, 144))	('PKC', 'molecular_function', 'GO:0004697', ('141', '144'))	('PKC activation', 'biological_process', 'GO:1990051', ('141', '155'))	('knockdown', 'Var', (51, 60))
188310	32923402	Inhibition of RIPK4 expression can enhance IkappaB level in cultured keratinocytes, indicating the reduced activation of NF-kappaB and the enhancement of keratinocyte differentiation.	('IkappaB level', 'MPA', (43, 56))	('enhancement', 'PosReg', (139, 150))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('107', '130'))	('enhance', 'PosReg', (35, 42))	('NF-kappaB', 'Gene', '4790', (121, 130))	('keratinocyte differentiation', 'CPA', (154, 182))	('keratinocyte differentiation', 'biological_process', 'GO:0030216', ('154', '182'))	('Inhibition', 'Var', (0, 10))	('reduced', 'NegReg', (99, 106))	('NF-kappaB', 'Gene', (121, 130))	('activation', 'PosReg', (107, 117))	('RIPK4', 'Gene', (14, 19))
188311	32923402	Inhibition of PMA-induced NF-kappaB activation by a dominant negative mutant of RIPK4 can be reverted by the co-expression of PKC isoform, PKCbetaI, suggesting that RIPK4 may act as a functional link between PKCbetaI and NF-kappaB activation.	('PMA', 'Chemical', 'MESH:D013755', (14, 17))	('PKC', 'Gene', (126, 129))	('NF-kappaB', 'Gene', (26, 35))	('activation', 'PosReg', (36, 46))	('PKC', 'Gene', '112476', (139, 142))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('26', '46'))	('PKCbetaI', 'Disease', (139, 147))	('NF-kappaB', 'Gene', (221, 230))	('NF-kappaB', 'Gene', '4790', (26, 35))	('PKCbetaI', 'Disease', 'None', (139, 147))	('PKC', 'Gene', (139, 142))	('NF-kappaB', 'Gene', '4790', (221, 230))	('PKC', 'Gene', '112476', (208, 211))	('PKCbetaI', 'Disease', (208, 216))	('mutant', 'Var', (70, 76))	('PKCbetaI', 'Disease', 'None', (208, 216))	('PKC', 'Gene', (208, 211))	('PKC', 'Gene', '112476', (126, 129))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('221', '241'))	('PKC', 'molecular_function', 'GO:0004697', ('126', '129'))	('RIPK4', 'Gene', (80, 85))
188312	32923402	The mechanism by which the PKCbetaI expression reverts the dominant negative effect of the RIPK4 mutant is still unclear.	('dominant negative effect', 'MPA', (59, 83))	('PKCbetaI', 'Disease', (27, 35))	('mutant', 'Var', (97, 103))	('RIPK4', 'Gene', (91, 96))	('PKCbetaI', 'Disease', 'None', (27, 35))
188314	32923402	Moreover, though the intact kinase properties of RIPK4 are required for NF-kappaB activation, catalytically inactive RIPK4 mutants can unexpectedly enhance MEKK2- and MEKK3-induced activation of NF-kappaB.	('NF-kappaB', 'Gene', '4790', (195, 204))	('MEKK2', 'Gene', '10746', (156, 161))	('MEKK3', 'Gene', '4215', (167, 172))	('MEKK2', 'Gene', (156, 161))	('MEKK3', 'Gene', (167, 172))	('MEKK3', 'molecular_function', 'GO:0004709', ('167', '172'))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('181', '204'))	('NF-kappaB', 'Gene', (195, 204))	('NF-kappaB', 'Gene', '4790', (72, 81))	('activation', 'PosReg', (181, 191))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('72', '92'))	('enhance', 'PosReg', (148, 155))	('NF-kappaB', 'Gene', (72, 81))	('MEKK2', 'molecular_function', 'GO:0004709', ('156', '161'))	('RIPK4', 'Gene', (117, 122))	('mutants', 'Var', (123, 130))
188320	32923402	Phosphorylation of DVL2 at Ser298 and Ser480 by RIPK4 favors canonical Wnt signaling.	('RIPK4', 'Gene', (48, 53))	('Wnt', 'Gene', (71, 74))	('Wnt', 'Gene', '89780;7474', (71, 74))	('Ser', 'cellular_component', 'GO:0005790', ('38', '41'))	('Ser298', 'Var', (27, 33))	('Ser480', 'Var', (38, 44))	('DVL2', 'Gene', (19, 23))	('Phosphorylation', 'MPA', (0, 15))	('favors', 'PosReg', (54, 60))	('Ser', 'cellular_component', 'GO:0005790', ('27', '30'))	('canonical', 'MPA', (61, 70))	('Ser480', 'Chemical', '-', (38, 44))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('DVL2', 'Gene', '1856', (19, 23))	('Ser298', 'Chemical', '-', (27, 33))
188322	32923402	The disruption of Wnt signaling can lead to cleft lip/palate.	('lead to', 'Reg', (36, 43))	('cleft lip/palate', 'Phenotype', 'HP:0000202', (44, 60))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('cleft lip/palate', 'Disease', (44, 60))	('cleft lip/palate', 'Disease', 'MESH:D002971', (44, 60))	('cleft lip', 'Phenotype', 'HP:0410030', (44, 53))	('disruption', 'Var', (4, 14))	('Wnt', 'Gene', (18, 21))	('Wnt', 'Gene', '89780;7474', (18, 21))
188324	32923402	RIPK4 promotes keratinocyte differentiation, at least in part by inducing IRF6 transactivator function through the phosphorylation of Ser413 and Ser424 in the C-terminal domain of IRF6.	('phosphorylation', 'MPA', (115, 130))	('Ser413', 'Var', (134, 140))	('Ser424', 'Var', (145, 151))	('keratinocyte differentiation', 'CPA', (15, 43))	('IRF6', 'Gene', (74, 78))	('inducing', 'Reg', (65, 73))	('promotes', 'PosReg', (6, 14))	('Ser', 'cellular_component', 'GO:0005790', ('134', '137'))	('phosphorylation', 'biological_process', 'GO:0016310', ('115', '130'))	('Ser424', 'Chemical', '-', (145, 151))	('keratinocyte differentiation', 'biological_process', 'GO:0030216', ('15', '43'))	('transactivator function', 'MPA', (79, 102))	('Ser413', 'Chemical', '-', (134, 140))	('RIPK4', 'Gene', (0, 5))	('Ser', 'cellular_component', 'GO:0005790', ('145', '148'))
188333	32923402	Mutations in human IRF6 give rise to Van der Woude syndrome (VWS), a developmental condition, and popliteal pterygium syndrome (PPS), which is a less severe form of BPS.	('IRF6', 'Gene', (19, 23))	('VWS', 'Disease', 'None', (61, 64))	('human', 'Species', '9606', (13, 18))	('PPS', 'Disease', (128, 131))	('popliteal pterygium', 'Phenotype', 'HP:0009756', (98, 117))	('give rise to', 'Reg', (24, 36))	('PPS', 'Disease', 'MESH:C562509', (128, 131))	('VWS', 'Disease', (61, 64))	('Van der Woude syndrome', 'Disease', 'MESH:C536528', (37, 59))	('developmental condition', 'Phenotype', 'HP:0001263', (69, 92))	('Van der Woude syndrome', 'Disease', (37, 59))	('Mutations', 'Var', (0, 9))	('popliteal pterygium syndrome', 'Disease', (98, 126))	('pterygium', 'Phenotype', 'HP:0001059', (108, 117))
188336	32923402	Mice harboring loss-of-function mutations of RIPK4 and IRF6 have close phenotypic similarities.	('RIPK4', 'Gene', (45, 50))	('mutations', 'Var', (32, 41))	('Mice', 'Species', '10090', (0, 4))	('IRF6', 'Gene', (55, 59))	('loss-of-function', 'NegReg', (15, 31))
188343	32923402	In addition, the RIPK4 p.Ile121Asn missense mutation, which has been identified in Bartsocas-Papas syndrome, inhibits the kinase activity of RIPK4, thereby abolishing RIPK4-mediated IRF6 and NF-kappaB activation.	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('191', '211'))	('p.Ile121Asn missense', 'Var', (23, 43))	('activation', 'PosReg', (201, 211))	('p.Ile121Asn', 'Mutation', 'rs387906923', (23, 34))	('RIPK4-mediated IRF6', 'Pathway', (167, 186))	('NF-kappaB', 'Gene', (191, 200))	('RIPK4', 'Protein', (141, 146))	('inhibits', 'NegReg', (109, 117))	('kinase activity', 'MPA', (122, 137))	('kinase activity', 'molecular_function', 'GO:0016301', ('122', '137'))	('NF-kappaB', 'Gene', '4790', (191, 200))	('abolishing', 'NegReg', (156, 166))	('RIPK4', 'Gene', (17, 22))
188344	32923402	The mutation also compromises RIPK4-mediated beta-catenin stabilization.	('RIPK4-mediated', 'Protein', (30, 44))	('beta-catenin', 'Gene', '1499', (45, 57))	('mutation', 'Var', (4, 12))	('beta-catenin', 'Gene', (45, 57))	('compromises', 'NegReg', (18, 29))
188345	32923402	Therefore, the severe manifestation of the RIPK4 p.Ile121Asn missense mutation is likely due to impaired signaling by the RIPK4-IRF6 axis, as well as the NF-kappaB and Wnt pathways.	('signaling', 'MPA', (105, 114))	('p.Ile121Asn', 'Var', (49, 60))	('NF-kappaB', 'Gene', '4790', (154, 163))	('NF-kappaB', 'Gene', (154, 163))	('Wnt', 'Gene', (168, 171))	('Wnt', 'Gene', '89780;7474', (168, 171))	('p.Ile121Asn', 'Mutation', 'rs387906923', (49, 60))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('RIPK4', 'Gene', (43, 48))	('impaired', 'NegReg', (96, 104))
188346	32923402	Another BPS-associated mutation, RIPK4 p.Ser376X nonsense mutation, can impair the IRF6 activation and inhibit its stabilization of beta-catenin, while the ability of RIPK4 to activate NF-kappaB and JNK is unaffected.	('p.Ser376X', 'Mutation', 'rs387906921', (39, 48))	('JNK', 'Gene', '5599', (199, 202))	('Ser', 'cellular_component', 'GO:0005790', ('41', '44'))	('NF-kappaB', 'Gene', '4790', (185, 194))	('RIPK4', 'Gene', (33, 38))	('beta-catenin', 'Gene', (132, 144))	('NF-kappaB', 'Gene', (185, 194))	('impair', 'NegReg', (72, 78))	('IRF6', 'Protein', (83, 87))	('beta-catenin', 'Gene', '1499', (132, 144))	('activation', 'MPA', (88, 98))	('p.Ser376X', 'Var', (39, 48))	('JNK', 'Gene', (199, 202))	('inhibit', 'NegReg', (103, 110))	('JNK', 'molecular_function', 'GO:0004705', ('199', '202'))
188347	32923402	These findings not only suggest molecular bases for how RIPK4 mutations cause epidermal disorders but also provide important mechanistic insights into the regulation of keratinocyte differentiation by a RIPK4-related complex signaling network.	('RIPK4', 'Gene', (56, 61))	('signaling', 'biological_process', 'GO:0023052', ('225', '234'))	('regulation of keratinocyte differentiation', 'biological_process', 'GO:0045616', ('155', '197'))	('cause', 'Reg', (72, 77))	('epidermal disorders', 'Disease', 'MESH:D004814', (78, 97))	('mutations', 'Var', (62, 71))	('epidermal disorders', 'Disease', (78, 97))
188348	32923402	The cutaneous SCC (cSCC) data deposited in The Cancer Genome Atlas (TCGA) and the analysis of metastatic cSCC reported a similar high rate of RIPK4 mutagenesis, with mutations clustering within the kinase and ankyrin repeat domains.	('mutagenesis', 'biological_process', 'GO:0006280', ('148', '159'))	('Cancer', 'Disease', (47, 53))	('RIPK4', 'Gene', (142, 147))	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('SCC', 'Phenotype', 'HP:0002860', (20, 23))	('Cancer', 'Disease', 'MESH:D009369', (47, 53))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('SCC', 'Phenotype', 'HP:0002860', (14, 17))	('mutagenesis', 'Var', (148, 159))
188349	32923402	It was strongly implied that the mutations were non-random, thus supporting the hypothesis that RIPK4 is a putative tumor suppressor for cSCC.	('RIPK4', 'Gene', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('mutations', 'Var', (33, 42))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('tumor suppressor', 'biological_process', 'GO:0051726', ('116', '132'))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('116', '132'))	('cSCC', 'Disease', (137, 141))	('tumor', 'Disease', (116, 121))
188350	32923402	The RIPK4 mutations have also been identified in human head and neck SCC (HNSCC) through large-scale sequencing, implicating its critical function in squamous epithelial differentiation and carcinogenesis.	('carcinogenesis', 'Disease', (190, 204))	('carcinogenesis', 'Disease', 'MESH:D063646', (190, 204))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('human', 'Species', '9606', (49, 54))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('neck', 'cellular_component', 'GO:0044326', ('64', '68'))	('mutations', 'Var', (10, 19))	('RIPK4', 'Gene', (4, 9))	('squamous epithelial', 'Disease', (150, 169))
188351	32923402	In addition, RIPK4 point mutation was observed in esophageal SCC and RIPK4 was thus considered as the driver gene for this malignancy.	('malignancy', 'Disease', (123, 133))	('SCC', 'Phenotype', 'HP:0002860', (61, 64))	('esophageal SCC', 'Disease', (50, 64))	('point mutation', 'Var', (19, 33))	('observed', 'Reg', (38, 46))	('RIPK4', 'Gene', (13, 18))	('malignancy', 'Disease', 'MESH:D009369', (123, 133))
188356	32923402	In a novel RIPK4 conditional knockout mouse model, the loss of keratinocyte RIPK4 promoted SCC formation during chemically induced carcinogenesis.	('carcinogenesis', 'Disease', (131, 145))	('mouse', 'Species', '10090', (38, 43))	('RIPK4', 'Gene', (76, 81))	('loss', 'Var', (55, 59))	('promoted', 'PosReg', (82, 90))	('SCC formation', 'CPA', (91, 104))	('formation', 'biological_process', 'GO:0009058', ('95', '104'))	('carcinogenesis', 'Disease', 'MESH:D063646', (131, 145))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))
188359	32923402	RIPK4 knockdown enhanced migration and invasion capabilities of tongue cancer cells, thus implying that RIPK4 might be a tumor suppressor.	('invasion capabilities', 'CPA', (39, 60))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('121', '137'))	('cancer', 'Disease', (71, 77))	('tumor', 'Disease', (121, 126))	('tumor suppressor', 'biological_process', 'GO:0051726', ('121', '137'))	('knockdown', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('RIPK4', 'Gene', (0, 5))	('enhanced', 'PosReg', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
188367	32923402	Quite strikingly, RIPK4 knockdown leading to lung cancer dedifferentiation was NF-kappaB independent and the potential of RIPK4 in reducing lung cancer cells metastases was kinase-independent.	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('lung cancer', 'Disease', (140, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('dedifferentiation', 'biological_process', 'GO:0043696', ('57', '74'))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung cancer', 'Disease', (45, 56))	('leading to', 'Reg', (34, 44))	('NF-kappaB', 'Gene', '4790', (79, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('metastases', 'Disease', (158, 168))	('reducing', 'NegReg', (131, 139))	('NF-kappaB', 'Gene', (79, 88))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('RIPK4', 'Gene', (18, 23))	('knockdown', 'Var', (24, 33))	('metastases', 'Disease', 'MESH:D009362', (158, 168))
188368	32923402	The loss of RIPK4 enhanced the STAT3 pathway in lung cancer cells and promoted the expression of extracellular matrix (ECM) remodeling genes.	('STAT3', 'Gene', (31, 36))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('RIPK4', 'Gene', (12, 17))	('STAT3', 'Gene', '6774', (31, 36))	('enhanced', 'PosReg', (18, 26))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('97', '117'))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('expression', 'MPA', (83, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('promoted', 'PosReg', (70, 78))	('loss', 'Var', (4, 8))
188369	32923402	RIPK4 knockdown in A2780 and COV434 ovarian cancer cells could inhibit beta-catenin accumulation and RIPK4 overexpression could promote ovarian cancer in a xenograft tumor model.	('ovarian cancer', 'Disease', 'MESH:D010051', (36, 50))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('RIPK4', 'Gene', (101, 106))	('overexpression', 'PosReg', (107, 121))	('promote', 'PosReg', (128, 135))	('inhibit', 'NegReg', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('ovarian cancer', 'Disease', 'MESH:D010051', (136, 150))	('ovarian cancer', 'Disease', (36, 50))	('beta-catenin', 'Gene', (71, 83))	('ovarian cancer', 'Phenotype', 'HP:0100615', (36, 50))	('beta-catenin', 'Gene', '1499', (71, 83))	('ovarian cancer', 'Disease', (136, 150))	('tumor', 'Disease', (166, 171))	('RIPK4', 'Gene', (0, 5))	('ovarian cancer', 'Phenotype', 'HP:0100615', (136, 150))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('knockdown', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
188370	32923402	In addition, RIPK4 was significantly upregulated in osteosarcoma and RIPK4 knockdown suppressed EMT by inactivating Wnt/beta-catenin signaling.	('beta-catenin', 'Gene', '1499', (120, 132))	('EMT', 'CPA', (96, 99))	('upregulated', 'PosReg', (37, 48))	('suppressed', 'NegReg', (85, 95))	('signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('osteosarcoma', 'Disease', (52, 64))	('inactivating', 'NegReg', (103, 115))	('Wnt', 'Gene', (116, 119))	('knockdown', 'Var', (75, 84))	('osteosarcoma', 'Phenotype', 'HP:0002669', (52, 64))	('Wnt', 'Gene', '89780;7474', (116, 119))	('osteosarcoma', 'Disease', 'MESH:D012516', (52, 64))	('RIPK4', 'Gene', (69, 74))	('EMT', 'biological_process', 'GO:0001837', ('96', '99'))	('RIPK4', 'Gene', (13, 18))	('beta-catenin', 'Gene', (120, 132))
188372	32923402	However, RIPK4 might only act as an oncogene in Wnt-dependent tumors, since RIPK4 knockdown had no effect on Wnt3a-induced beta-catenin accumulation in pancreatic PANC1 cells, kidney 786-O cells, and breast HCC38 or HS578T cells.	('Wnt', 'Gene', (109, 112))	('HCC', 'Phenotype', 'HP:0001402', (207, 210))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('Wnt', 'Gene', '89780;7474', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('RIPK4', 'Gene', (76, 81))	('tumors', 'Disease', (62, 68))	('knockdown', 'Var', (82, 91))	('Wnt', 'Gene', '89780;7474', (109, 112))	('HS578T', 'CellLine', 'CVCL:0332', (216, 222))	('PANC1', 'CellLine', 'CVCL:0480', (163, 168))	('pancreatic', 'Disease', 'MESH:D010195', (152, 162))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('Wnt3a', 'Gene', '89780', (109, 114))	('beta-catenin', 'Gene', (123, 135))	('beta-catenin', 'Gene', '1499', (123, 135))	('Wnt3a', 'Gene', (109, 114))	('pancreatic', 'Disease', (152, 162))	('Wnt', 'Gene', (48, 51))
188378	32923402	Consistent with previous studies in bladder urothelial carcinoma, the oncogenic activity of RIPK4 depended on the activation of NF-kappaB, leading to increased vascular endothelial growth factor A (VEGF-A) levels, which ultimately mediated the RIPK4-induced EMT and promoted bladder urothelial carcinoma cell aggressiveness.	('EMT', 'biological_process', 'GO:0001837', ('258', '261'))	('RIPK4-induced', 'Var', (244, 257))	('vascular endothelial growth factor A', 'Gene', '7422', (160, 196))	('RIPK4', 'Gene', (92, 97))	('increased', 'PosReg', (150, 159))	('NF-kappaB', 'Gene', (128, 137))	('aggressiveness', 'Phenotype', 'HP:0000718', (309, 323))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('vascular endothelial growth factor A', 'Gene', (160, 196))	('VEGF-A', 'Gene', (198, 204))	('NF-kappaB', 'Gene', '4790', (128, 137))	('promoted', 'PosReg', (266, 274))	('EMT', 'CPA', (258, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('bladder urothelial carcinoma cell aggressiveness', 'Disease', (275, 323))	('bladder urothelial carcinoma', 'Disease', (36, 64))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (275, 303))	('increased vascular endothelial growth', 'Phenotype', 'HP:0031052', (150, 187))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('114', '137'))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (36, 64))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('160', '194'))	('VEGF-A', 'Gene', '7422', (198, 204))	('bladder urothelial carcinoma cell aggressiveness', 'Disease', 'MESH:D001749', (275, 323))
188384	32923402	Notably, as a downstream signaling molecule of PKCdelta, RIPK4 overexpression promoted pancreatic cancer cell migration and invasion via the proteasome-mediated PEBP1 degradation-induced activation of the RAF1/MEK/ERK signaling pathway.	('pancreatic cancer', 'Disease', (87, 104))	('activation', 'PosReg', (187, 197))	('ERK', 'molecular_function', 'GO:0004707', ('214', '217'))	('proteasome', 'molecular_function', 'GO:0004299', ('141', '151'))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('promoted', 'PosReg', (78, 86))	('degradation', 'biological_process', 'GO:0009056', ('167', '178'))	('MEK', 'Gene', '5609', (210, 213))	('proteasome', 'cellular_component', 'GO:0000502', ('141', '151'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('PEBP1', 'Gene', (161, 166))	('ERK', 'Gene', '5594', (214, 217))	('MEK', 'Gene', (210, 213))	('signaling pathway', 'biological_process', 'GO:0007165', ('218', '235'))	('RIPK4', 'Gene', (57, 62))	('cell migration', 'biological_process', 'GO:0016477', ('105', '119'))	('RAF1', 'Gene', '5894', (205, 209))	('signaling molecule', 'molecular_function', 'GO:0048018', ('25', '43'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('overexpression', 'Var', (63, 77))	('PEBP1', 'Gene', '5037', (161, 166))	('ERK', 'Gene', (214, 217))	('PKCdelta', 'Gene', '5580', (47, 55))	('invasion', 'CPA', (124, 132))	('PKCdelta', 'molecular_function', 'GO:0004697', ('47', '55'))	('PKCdelta', 'Gene', (47, 55))	('RAF1', 'Gene', (205, 209))
188391	32923402	As mentioned above, RIPK4 expression is positively associated with favorable prognosis in tongue SCC and lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('expression', 'Var', (26, 36))	('tongue SCC', 'Disease', (90, 100))	('lung adenocarcinoma', 'Disease', (105, 124))	('associated', 'Reg', (51, 61))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('RIPK4', 'Gene', (20, 25))
188441	32326232	A further 3D invasion assay showed concordant findings that MSN knockdown T24 and J82 BUC cells exhibited a remarkable reduction in cell invasion (Figure 4B,C).	('MSN', 'Gene', '4478', (60, 63))	('MSN', 'Gene', (60, 63))	('cell invasion', 'CPA', (132, 145))	('knockdown', 'Var', (64, 73))	('reduction', 'NegReg', (119, 128))	('J82 BUC', 'CellLine', 'CVCL:G691', (82, 89))
188456	32326232	For BUC cell lines, a proteomic analysis was performed after eight BUC cell lines, namely, T24, J82, 253J-BV, 253J, 5637, RT4, HT1376, and HT1197 (ATCC; Manassas, VA, USA), were categorized as IBUC_CL and NIBUC_CL based on their invasion and migration capacities.	('253J', 'Var', (110, 114))	('invasion', 'CPA', (229, 237))	('HT1197', 'CellLine', 'CVCL:1291', (139, 145))	('CL', 'Disease', 'None', (211, 213))	('HT1376', 'CellLine', 'CVCL:1292', (127, 133))	('CL', 'Disease', 'None', (198, 200))	('J82', 'Var', (96, 99))	('HT1376', 'Var', (127, 133))	('253J-BV', 'Var', (101, 108))	('J-BV', 'CellLine', 'CVCL:0182', (104, 108))
188464	32326232	(B) gene ontology results between two groups from BUC LBC samples (left, SIBUC and NIBUC; right, MIBUC and SIBUC), Figure S3: Functional validation of invasive role of LLGL2, NCAM2, and VAPA with small interfering RNA (siRNA) using two-dimensional (2D) and three-dimensional (3D) invasion assays.	('VAPA', 'Gene', '9218', (186, 190))	('small interfering', 'Var', (196, 213))	('VAPA', 'Gene', (186, 190))	('NCAM2', 'Gene', (175, 180))	('RNA', 'cellular_component', 'GO:0005562', ('214', '217'))	('LLGL2', 'Gene', (168, 173))	('NCAM2', 'Gene', '4685', (175, 180))	('gene ontology', 'biological_process', 'GO:0003673', ('4', '17'))	('LLGL2', 'Gene', '3993', (168, 173))
188480	29977169	Mutations in the retinoblastoma gene, phosphatase and tensin homolog (PTEN) gene and Lynch syndrome are also associated with bladder cancer.	('associated', 'Reg', (109, 119))	('retinoblastoma', 'Gene', (17, 31))	('PTEN', 'Gene', (70, 74))	('retinoblastoma', 'Gene', '5925', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('PTEN', 'Gene', '5728', (70, 74))	('retinoblastoma', 'Phenotype', 'HP:0009919', (17, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('Mutations', 'Var', (0, 9))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('38', '68'))	('phosphatase', 'molecular_function', 'GO:0016791', ('38', '49'))	('Lynch syndrome', 'Disease', (85, 99))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))	('Lynch syndrome', 'Disease', 'MESH:D003123', (85, 99))
188507	29977169	The ORR was higher in patients with PD-L1 expression >10 %, but responses were also observed in those with PD-L1 expression <10 %.	('PD-L1', 'Gene', '29126', (107, 112))	('higher', 'PosReg', (12, 18))	('expression >10 %', 'Var', (42, 58))	('ORR', 'MPA', (4, 7))	('PD-L1', 'Gene', (36, 41))	('patients', 'Species', '9606', (22, 30))	('PD-L1', 'Gene', '29126', (36, 41))	('PD-L1', 'Gene', (107, 112))
188525	29977169	For patients with high PD-L1 expression on infiltrating immune cells (IC2/3), a median OS and 12 months of OS were 11.9 months and 50%, respectively, as compared to 6.7 months and 31% in patients with IC 0/1.	('patients', 'Species', '9606', (187, 195))	('OS', 'Chemical', 'MESH:D009992', (107, 109))	('PD-L1', 'Gene', (23, 28))	('OS', 'Chemical', 'MESH:D009992', (87, 89))	('IC2/3', 'Gene', '1781', (70, 75))	('IC2/3', 'Gene', (70, 75))	('PD-L1', 'Gene', '29126', (23, 28))	('high', 'Var', (18, 22))	('patients', 'Species', '9606', (4, 12))
188529	29977169	This study failed to meet the primary endpoint of improving OS in patients with high PD-L1 expression.	('improving', 'PosReg', (50, 59))	('PD-L1', 'Gene', (85, 90))	('OS', 'Chemical', 'MESH:D009992', (60, 62))	('PD-L1', 'Gene', '29126', (85, 90))	('high', 'Var', (80, 84))	('patients', 'Species', '9606', (66, 74))
188541	29977169	Median OS was 8.74 months overall (5.95 months in patients with PD-L1 <1% and 11.3 months in patients with PD-L1 expression of 1%).	('PD-L1', 'Gene', '29126', (107, 112))	('patients', 'Species', '9606', (50, 58))	('<1%', 'Var', (70, 73))	('PD-L1', 'Gene', (64, 69))	('PD-L1', 'Gene', (107, 112))	('PD-L1', 'Gene', '29126', (64, 69))	('patients', 'Species', '9606', (93, 101))	('OS', 'Chemical', 'MESH:D009992', (7, 9))
188551	29977169	The disease control rate, which includes those with ORR and stable disease at 12 weeks, was 57.1% in the PD-L1 positive subgroup and 28.6% in the PD-L1 negative subgroup.	('PD-L1', 'Gene', '29126', (146, 151))	('PD-L1', 'Gene', (105, 110))	('disease control', 'CPA', (4, 19))	('PD-L1', 'Gene', '29126', (105, 110))	('positive', 'Var', (111, 119))	('PD-L1', 'Gene', (146, 151))
188564	29977169	Molecular analysis and subtyping have identified numerous genetic and epigenetic alterations in UCs; examples include mutations in some receptor tyrosine kinases (RTKs) RAS/RAF, PI3K, AKT, and mammalian target of rapamycin (mTOR) pathways.	('mTOR', 'Gene', (224, 228))	('mTOR', 'Gene', '2475', (224, 228))	('AKT', 'Gene', '207', (184, 187))	('mutations', 'Var', (118, 127))	('RAF', 'Gene', (173, 176))	('RAF', 'Gene', '22882', (173, 176))	('PI3K', 'molecular_function', 'GO:0016303', ('178', '182'))	('AKT', 'Gene', (184, 187))	('PI3K', 'Pathway', (178, 182))	('mammalian target of rapamycin', 'Gene', '2475', (193, 222))	('mammalian target of rapamycin', 'Gene', (193, 222))	('UCs', 'Disease', (96, 99))
188565	29977169	Other mutations also identified are TP53, RB1, FGFR3, CCND1, MDM2, PTEN deletions, FGFR 1 amplifications, and aberrations of the chromatin remodeling genes.	('FGFR3', 'Gene', (47, 52))	('RB1', 'Gene', '5925', (42, 45))	('MDM2', 'Gene', (61, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('83', '87'))	('TP53', 'Gene', (36, 40))	('FGFR3', 'Gene', '2261', (47, 52))	('FGFR 1', 'Gene', (83, 89))	('aberrations', 'Var', (110, 121))	('chromatin remodeling genes', 'Gene', (129, 155))	('MDM2', 'Gene', '4193', (61, 65))	('PTEN', 'Gene', (67, 71))	('chromatin', 'cellular_component', 'GO:0000785', ('129', '138'))	('FGFR 1', 'Gene', '2260', (83, 89))	('TP53', 'Gene', '7157', (36, 40))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('129', '149'))	('deletions', 'Var', (72, 81))	('PTEN', 'Gene', '5728', (67, 71))	('CCND1', 'Gene', '595', (54, 59))	('RB1', 'Gene', (42, 45))	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('CCND1', 'Gene', (54, 59))	('amplifications', 'Var', (90, 104))
188567	29977169	An ongoing phase 2 clinical trial, NCI-MATCH (ClinicalTrials.gov Identifier NCT02465060), is currently evaluating 19 likely actionable somatic mutations in advanced refractory solid tumors, lymphomas, or multiple myeloma.	('solid tumors', 'Disease', 'MESH:D009369', (176, 188))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('lymphomas', 'Disease', (190, 199))	('lymphomas', 'Disease', 'MESH:D008223', (190, 199))	('multiple myeloma', 'Phenotype', 'HP:0006775', (204, 220))	('lymphomas', 'Phenotype', 'HP:0002665', (190, 199))	('multiple myeloma', 'Disease', 'MESH:D009101', (204, 220))	('solid tumors', 'Disease', (176, 188))	('multiple myeloma', 'Disease', (204, 220))	('mutations', 'Var', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
188582	29977169	The results confirmed that alterations involving RB1 and NFE2L2 were enriched in basal cancers, whereas alterations involving FGFR3 and KDM6A were enriched in luminal tumors.	('FGFR', 'molecular_function', 'GO:0005007', ('126', '130'))	('RB1', 'Gene', (49, 52))	('NFE2L2', 'Gene', (57, 63))	('FGFR3', 'Gene', (126, 131))	('RB1', 'Gene', '5925', (49, 52))	('luminal tumors', 'Disease', 'MESH:D009369', (159, 173))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('KDM6A', 'Gene', '7403', (136, 141))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('NFE2L2', 'Gene', '4780', (57, 63))	('basal cancers', 'Disease', 'MESH:D002280', (81, 94))	('KDM6A', 'Gene', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('FGFR3', 'Gene', '2261', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('luminal tumors', 'Disease', (159, 173))	('alterations', 'Var', (27, 38))	('basal cancers', 'Disease', (81, 94))
188594	29977169	The enrichment for FGFR3 mutations in the luminal 1 subtype suggests the potential for FGFR3 inhibitors as a future treatment in these immunologically cold tumors.	('mutations', 'Var', (25, 34))	('men', 'Species', '9606', (10, 13))	('men', 'Species', '9606', (121, 124))	('FGFR3', 'Gene', '2261', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('FGFR3', 'Gene', '2261', (19, 24))	('FGFR3', 'Gene', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('tumors', 'Disease', (156, 162))	('FGFR3', 'Gene', (19, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))
188597	29977169	Pairing CTLA-4 blockade along with PD-1/PD-L1 blockade has been effective in other tumor types to enhance the immune response and is being further explored in UCs in multiple ongoing clinical trials.	('blockade', 'Var', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('enhance', 'PosReg', (98, 105))	('tumor', 'Disease', (83, 88))	('CTLA-4', 'Gene', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('PD-L1', 'Gene', (40, 45))	('immune response', 'biological_process', 'GO:0006955', ('110', '125'))	('PD-L1', 'Gene', '29126', (40, 45))	('PD-1', 'Gene', (35, 39))	('PD-1', 'Gene', '5133', (35, 39))	('immune response', 'CPA', (110, 125))	('CTLA-4', 'Gene', '1493', (8, 14))
188721	26988609	It is important to mention that the p53 gene signature and chemo-resistance were not related to p53 mutations.	('mutations', 'Var', (100, 109))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('men', 'Species', '9606', (19, 22))
188737	26988609	Specifically miRNA-296-5p modulation was shown to be associated with altered viability of cell lines exposed to cisplatin.	('miRNA-296-5p modulation', 'Var', (13, 36))	('modulation', 'Var', (26, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))
188742	29445424	Promoter methylation of DNA damage repair (DDR) genes in human tumor entities: RBBP8/CtIP is almost exclusively methylated in bladder cancer Genome-wide studies identified pan-cancer genes and shared biological networks affected by epigenetic dysregulation among diverse tumor entities.	('DDR', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('human', 'Species', '9606', (57, 62))	('RBBP8', 'Gene', '5932', (79, 84))	('cancer', 'Disease', (134, 140))	('epigenetic', 'Var', (232, 242))	('bladder cancer', 'Disease', 'MESH:D001749', (126, 140))	('bladder cancer', 'Disease', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('CtIP', 'Gene', '5932', (85, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (126, 140))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (271, 276))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('CtIP', 'Gene', (85, 89))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('RBBP8', 'Gene', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancer', 'Disease', (176, 182))
188743	29445424	Here, we systematically screened for hypermethylation of DNA damage repair (DDR) genes in a comprehensive candidate-approach and exemplarily identify and validate candidate DDR genes as targets of epigenetic inactivation unique to bladder cancer (BLCA), which may serve as non-invasive biomarkers.	('bladder cancer', 'Disease', 'MESH:D001749', (231, 245))	('bladder cancer', 'Phenotype', 'HP:0009725', (231, 245))	('bladder cancer', 'Disease', (231, 245))	('epigenetic inactivation', 'Var', (197, 220))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('BLCA', 'Chemical', '-', (247, 251))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
188751	29445424	RBBP8 hypermethylation predicted longer overall survival (OS) and was found in 2/4 bladder cancer cell lines but not in any of 33 cancer cell lines from entities with another origin like prostate.	('OS', 'Chemical', '-', (58, 60))	('hypermethylation', 'Var', (6, 22))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', (130, 136))	('overall survival', 'MPA', (40, 56))	('RBBP8', 'Gene', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('bladder cancer', 'Disease', (83, 97))	('longer', 'PosReg', (33, 39))
188752	29445424	RBBP8 methylation was associated with histological grade in primary BLCA and urine samples.	('RBBP8', 'Gene', (0, 5))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('methylation', 'Var', (6, 17))	('primary BLCA', 'Disease', (60, 72))	('BLCA', 'Chemical', '-', (68, 72))	('associated', 'Reg', (22, 32))
188753	29445424	RBBP8 methylation was detectable in urine samples of bladder cancer patients achieving a sensitivity of 52%, at 91% specificity.	('RBBP8', 'Gene', (0, 5))	('bladder cancer', 'Disease', 'MESH:D001749', (53, 67))	('bladder cancer', 'Disease', (53, 67))	('patients', 'Species', '9606', (68, 76))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('methylation', 'Var', (6, 17))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('bladder cancer', 'Phenotype', 'HP:0009725', (53, 67))
188756	29445424	Since RBBP8 methylation was detectable in urines, it may be a complementary marker of high specificity in urine for BLCA detection.	('methylation', 'Var', (12, 23))	('RBBP8', 'Gene', (6, 11))	('methylation', 'biological_process', 'GO:0032259', ('12', '23'))	('BLCA', 'Chemical', '-', (116, 120))
188759	29445424	Genome-wide studies have recently identified pan-cancer DNA methylation (DNAm) patterns among diverse tumor entities, e.g., affected by genetic alterations in epigenetic regulators like DNMT3 (reviewed in Witte et al.).	('DNMT', 'Gene', '1786', (186, 190))	('affected by', 'Reg', (124, 135))	('DNMT', 'Gene', (186, 190))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('genetic alterations', 'Var', (136, 155))	('DNA methylation', 'biological_process', 'GO:0006306', ('56', '71'))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('cancer', 'Disease', (49, 55))
188760	29445424	Still, the co-existence of unique DNAm patterns indicates that also entity-specific and subtype-specific targets of epigenetic deregulation could lead to the development of distinct methylation phenotypes contributing to tumorigenesis.	('epigenetic deregulation', 'Var', (116, 139))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('contributing', 'Reg', (205, 217))	('methylation', 'biological_process', 'GO:0032259', ('182', '193'))	('lead to', 'Reg', (146, 153))	('methylation', 'MPA', (182, 193))
188761	29445424	So far, DNA methylation is proposed as a molecular biomarker for cancer detection but also as a biomarker for prediction and stratification of patients with risk of distinct clinical outcome and response to therapies.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('patients', 'Species', '9606', (143, 151))	('DNA', 'Gene', (8, 11))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('methylation', 'Var', (12, 23))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('DNA methylation', 'biological_process', 'GO:0006306', ('8', '23'))
188765	29445424	Since there is, to our knowledge, no systematic screen for hypermethylation of DNA repair genes, we performed a comprehensive candidate approach comprising 177 DDR genes as targets of epigenetic deregulation in 32 tumor entities.	('epigenetic', 'Var', (184, 194))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('tumor', 'Disease', (214, 219))	('DDR genes', 'Gene', (160, 169))	('DNA repair', 'biological_process', 'GO:0006281', ('79', '89'))
188769	29445424	Our first aim was to identify novel DNA repair genes as targets of epigenetic inactivation unique to human cancer types, which may finally be used as a non-invasive methylation biomarker.	('methylation', 'biological_process', 'GO:0032259', ('165', '176'))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('DNA repair', 'biological_process', 'GO:0006281', ('36', '46'))	('human', 'Species', '9606', (101, 106))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('epigenetic inactivation', 'Var', (67, 90))	('cancer', 'Disease', (107, 113))	('DNA repair genes', 'Gene', (36, 52))
188771	29445424	This includes known epigenetic silenced DDR genes with a therapeutic impact like BRCA1, MGMT, and ERCC1 (Additional file 2).	('BRCA1', 'Gene', (81, 86))	('DDR genes', 'Gene', (40, 49))	('MGMT', 'molecular_function', 'GO:0003908', ('88', '92'))	('MGMT', 'Gene', (88, 92))	('epigenetic silenced', 'Var', (20, 39))	('MGMT', 'Gene', '4255', (88, 92))	('ERCC1', 'Gene', '2067', (98, 103))	('ERCC1', 'Gene', (98, 103))
188775	29445424	The list of genes with stringently tumor-specific hypermethylation includes, for instance, ERCC1, MGMT, POLD1, and RBBP8/CtiP.	('POLD1', 'Gene', '5424', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('MGMT', 'molecular_function', 'GO:0003908', ('98', '102'))	('POLD1', 'Gene', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('hypermethylation', 'Var', (50, 66))	('MGMT', 'Gene', '4255', (98, 102))	('MGMT', 'Gene', (98, 102))	('ERCC1', 'Gene', (91, 96))	('CtiP', 'Gene', '5932', (121, 125))	('CtiP', 'Gene', (121, 125))	('ERCC1', 'Gene', '2067', (91, 96))
188782	29445424	Interestingly, RBBP8 was almost exclusively methylated in bladder cancer (Fig.	('methylated', 'Var', (44, 54))	('RBBP8', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('bladder cancer', 'Disease', (58, 72))
188783	29445424	Overall, 137 out of 368 (37%) analyzed bladder tumors exhibited a tumor-specific RBBP8 promoter methylation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('bladder tumors', 'Disease', 'MESH:D001749', (39, 53))	('RBBP8', 'Gene', (81, 86))	('tumor', 'Disease', (66, 71))	('bladder tumors', 'Phenotype', 'HP:0009725', (39, 53))	('bladder tumors', 'Disease', (39, 53))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('bladder tumor', 'Phenotype', 'HP:0009725', (39, 52))	('methylation', 'Var', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('methylation', 'biological_process', 'GO:0032259', ('96', '107'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (47, 52))
188786	29445424	In all other analyzed cancer types, RBBP8 methylation frequency was lower than 1.0%.	('RBBP8', 'Gene', (36, 41))	('lower', 'NegReg', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('methylation', 'Var', (42, 53))
188790	29445424	Given entity-specific methylation of RBBP8 in BLCA, we aimed to provide a first insight on whether this epigenetic modification may provide a clinical impact in this entity.	('methylation', 'biological_process', 'GO:0032259', ('22', '33'))	('BLCA', 'Chemical', '-', (46, 50))	('methylation', 'Var', (22, 33))	('RBBP8', 'Gene', (37, 42))
188791	29445424	We divided the dataset (overall n = 405, for cohort characteristics see Additional file 5) into low methylated (RBBP8 beta values (beta <= 0.4)) and highly methylated (beta > 0.4) tumor samples and found that a prevalent loss of RBBP8 mRNA expression was only present in tumors with high RBBP8 promoter methylation compared to normal bladder tissue (Fig.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('mRNA expression', 'MPA', (235, 250))	('loss', 'NegReg', (221, 225))	('high', 'Var', (283, 287))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Disease', (271, 277))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('tumor', 'Disease', (271, 276))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('tumor', 'Disease', (180, 185))	('methylation', 'biological_process', 'GO:0032259', ('303', '314'))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('RBBP8', 'Gene', (229, 234))
188792	29445424	Further associations of RBBP8 methylation with clinicopathological characteristics were evaluated as well (Table 2), which showed a significant association of RBBP8 methylation with higher histological tumor grade (p = 0.041).	('methylation', 'biological_process', 'GO:0032259', ('165', '176'))	('tumor', 'Disease', (202, 207))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('methylation', 'Var', (165, 176))	('RBBP8', 'Gene', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
188794	29445424	As dysregulation of DDR repair is known to be associated with patients' outcome, we examined overall survival (OS) as an indicator of potential clinical impact.	('DDR repair', 'Gene', (20, 30))	('dysregulation', 'Var', (3, 16))	('OS', 'Chemical', '-', (111, 113))	('associated', 'Reg', (46, 56))	('patients', 'Species', '9606', (62, 70))
188795	29445424	By Kaplan-Meier analysis, we found that patients with high RBBP8 methylation have a longer overall survival (mean OS 3197.4 days +- 310.3; 95% CI 2589.3 to 3805.5 days) compared to low RBBP8 methylation (mean OS 1800.6 days +- 161.4; 95% CI 1484.1 to 2117.0 days) (Fig.	('high', 'Var', (54, 58))	('OS', 'Chemical', '-', (114, 116))	('patients', 'Species', '9606', (40, 48))	('RBBP8', 'Gene', (59, 64))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('methylation', 'Var', (65, 76))	('overall survival', 'CPA', (91, 107))	('OS', 'Chemical', '-', (209, 211))	('methylation', 'biological_process', 'GO:0032259', ('191', '202'))	('longer', 'PosReg', (84, 90))
188800	29445424	Strong RBBP8 promoter methylation in RT4 (median methylation level 90.5%) and RT112 bladder cancer cells (median methylation level: 28.5%) was confirmed by using bisulfite-pyrosequencing covering the MSP product sequence (Fig.	('bladder cancer', 'Phenotype', 'HP:0009725', (84, 98))	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('bladder cancer', 'Disease', 'MESH:D001749', (84, 98))	('bladder cancer', 'Disease', (84, 98))	('methylation', 'biological_process', 'GO:0032259', ('22', '33'))	('RBBP8', 'Gene', (7, 12))	('bisulfite', 'Chemical', 'MESH:C042345', (162, 171))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('methylation', 'Var', (22, 33))
188807	29445424	RBBP8 methylation frequency was increased to 39.1% (9/23) in primary bladder tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('bladder tumors', 'Phenotype', 'HP:0009725', (69, 83))	('bladder tumor', 'Phenotype', 'HP:0009725', (69, 82))	('primary bladder tumors', 'Disease', (61, 83))	('RBBP8', 'Gene', (0, 5))	('primary bladder tumors', 'Disease', 'MESH:D001749', (61, 83))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('methylation', 'Var', (6, 17))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('increased', 'PosReg', (32, 41))
188808	29445424	None of the papillary low-grade tumors (n = 9) showed RBBP8 methylation, whereas 9 out of 14 invasive BLCAs were methylated for the RBBP8 locus.	('RBBP8', 'Gene', (54, 59))	('methylation', 'Var', (60, 71))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('tumors', 'Disease', (32, 38))	('BLCA', 'Chemical', '-', (102, 106))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
188826	29445424	In line, a statistically inverse correlation between nuclear RBBP8 protein level and RBBP8 promoter methylation was confirmed (Table 4), supporting a contribution of epigenetic RBBP8 alterations to its protein loss in primary bladder tumors.	('RBBP8', 'Gene', (177, 182))	('primary bladder tumors', 'Disease', (218, 240))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('epigenetic', 'Var', (166, 176))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('alterations', 'Var', (183, 194))	('primary bladder tumors', 'Disease', 'MESH:D001749', (218, 240))	('bladder tumors', 'Phenotype', 'HP:0009725', (226, 240))	('protein', 'MPA', (202, 209))	('bladder tumor', 'Phenotype', 'HP:0009725', (226, 239))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('loss', 'NegReg', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('methylation', 'biological_process', 'GO:0032259', ('100', '111'))
188828	29445424	Therefore, urine sediments from bladder cancer patients (n = 22) and healthy controls (n = 10) were initially assessed for RBBP8 methylation by MSP (for cohort characteristics see Additional file 10).	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('methylation', 'Var', (129, 140))	('bladder cancer', 'Disease', (32, 46))	('patients', 'Species', '9606', (47, 55))	('RBBP8', 'Gene', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('methylation', 'biological_process', 'GO:0032259', ('129', '140'))
188838	29445424	ROC curve statistics were performed based on the two CpG sites with the strongest discrimination impact; the methylation ratio between cancerous BLCA urines and both the benign and malignant control set revealed strongest differences for CpG number #7 and #8 (see Fig.	('CpG number #7', 'Var', (238, 251))	('differences', 'Reg', (222, 233))	('methylation', 'biological_process', 'GO:0032259', ('109', '120'))	('cancerous BLCA urines', 'Disease', (135, 156))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('methylation', 'MPA', (109, 120))	('cancerous BLCA urines', 'Disease', 'MESH:D014555', (135, 156))
188840	29445424	Accordingly, RBBP8 methylation significantly discriminates between bladder cancer patients and non-malignant patients with a sensitivity of 51.9% and a specificity of 90.9% (AUC 0.730, 95% CI 0.616-0.844) (Fig.	('methylation', 'Var', (19, 30))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (82, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('RBBP8', 'Gene', (13, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('discriminates', 'Reg', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
188845	29445424	Dysfunction of DNA damage repair (DDR) genes in human cancer is common and, so far, mostly considered to be triggered by genetic alterations.	('Dysfunction', 'Var', (0, 11))	('human', 'Species', '9606', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('cancer', 'Disease', (54, 60))	('DNA', 'Gene', (15, 18))	('DDR) genes', 'Gene', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
188846	29445424	proposed a notable clinical value of epigenetic alterations in distinct DDR genes in human cancer.	('cancer', 'Disease', (91, 97))	('epigenetic alterations', 'Var', (37, 59))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('DDR genes', 'Gene', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('human', 'Species', '9606', (85, 90))
188848	29445424	In the presented study, tumor-specific epigenetic deregulation of DDR genes was found to be a common event in human cancer.	('epigenetic deregulation', 'Var', (39, 62))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('human', 'Species', '9606', (110, 115))	('DDR genes', 'Gene', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
188850	29445424	Most tumor entities were characterized by hypermethylation of distinct DDR genes.	('hypermethylation', 'Var', (42, 58))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('DDR genes', 'Gene', (71, 80))
188851	29445424	Among others, polymerase delta (POLD1) methylation was enriched in 24 out of 32 different tumor types, implying an essential role in DNA repair or tumor suppression independent of tumor entity.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('methylation', 'Var', (39, 50))	('polymerase delta', 'Gene', '5424', (14, 30))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('POLD1', 'Gene', (32, 37))	('tumor', 'Disease', (180, 185))	('POLD1', 'Gene', '5424', (32, 37))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('DNA repair', 'biological_process', 'GO:0006281', ('133', '143'))	('polymerase delta', 'Gene', (14, 30))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
188853	29445424	Unrepaired DNA damage is a major source of potential mutagenic lesions driving tumorigenesis, and loss of DNA repair pathways is thought to accelerate the accumulation rate of additional mutations by 100 to 1000 times.	('accelerate', 'PosReg', (140, 150))	('tumor', 'Disease', (79, 84))	('DNA', 'Gene', (106, 109))	('DNA repair', 'biological_process', 'GO:0006281', ('106', '116'))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('mutations', 'Var', (187, 196))	('loss', 'Var', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
188856	29445424	previously revealed a close association between the CpG island methylator phenotype (CIMP), microsatellite instability, and increased BRAF mutation in COAD.	('mutation', 'Var', (139, 147))	('COAD', 'Disease', (151, 155))	('increased', 'PosReg', (124, 133))	('BRAF', 'Gene', '673', (134, 138))	('BRAF', 'Gene', (134, 138))	('CIMP', 'Chemical', '-', (85, 89))	('microsatellite instability', 'MPA', (92, 118))	('COAD', 'Disease', 'MESH:D029424', (151, 155))
188857	29445424	Moreover, sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated MLH1 methylation, a DNA repair gene involved in MMR and microsatellite instability, whose hypermethylation close to the TSS was confirmed for COAD in the presented study.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('methylation', 'biological_process', 'GO:0032259', ('121', '132'))	('MLH1', 'Gene', (116, 120))	('deficiency', 'NegReg', (44, 54))	('mismatch', 'Var', (28, 36))	('MLH1', 'Gene', '4292', (116, 120))	('MMR', 'biological_process', 'GO:0006298', ('164', '167'))	('COAD', 'Disease', (258, 262))	('DNA repair', 'biological_process', 'GO:0006281', ('136', '146'))	('methylation', 'Var', (121, 132))	('COAD', 'Disease', 'MESH:D029424', (258, 262))	('CIMP', 'Chemical', '-', (100, 104))	('mismatch repair', 'biological_process', 'GO:0006298', ('28', '43'))
188858	29445424	Beyond, our findings may provide novel implications for therapies, as DNA damage repair dysregulation sensitizes cancer cells for DNA damaging agents.	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('sensitizes', 'Reg', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('dysregulation', 'Var', (88, 101))
188864	29445424	Furthermore, the excision repair cross-complementing group 1 (ERCC1) gene, encoding for a known key enzyme of the nucleotide excision repair (NER) pathway, was found frequently methylated in BLCA, up to 17%.	('ERCC1', 'Gene', (62, 67))	('NER', 'biological_process', 'GO:0006289', ('142', '145'))	('BLCA', 'Chemical', '-', (191, 195))	('ERCC1', 'Gene', '2067', (62, 67))	('excision repair cross-complementing group 1', 'Gene', '2067', (17, 60))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('114', '140'))	('methylated', 'Var', (177, 187))	('excision repair cross-complementing group 1', 'Gene', (17, 60))
188869	29445424	RBBP8/CtiP has a proven role in homologous recombination-mediated DNA double-strand break repair (HR and NHEJ pathway), impairment of which reduces DNA repair fidelity and may promote genome instability also in urothelial carcinomas.	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('reduces', 'NegReg', (140, 147))	('NHEJ', 'biological_process', 'GO:0006303', ('105', '109'))	('genome instability', 'MPA', (184, 202))	('homologous recombination', 'biological_process', 'GO:0035825', ('32', '56'))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('DNA repair', 'biological_process', 'GO:0006281', ('148', '158'))	('CtiP', 'Gene', '5932', (6, 10))	('carcinomas', 'Phenotype', 'HP:0030731', (222, 232))	('double-strand break repair', 'biological_process', 'GO:0006302', ('70', '96'))	('CtiP', 'Gene', (6, 10))	('urothelial carcinomas', 'Disease', (211, 232))	('DNA repair fidelity', 'MPA', (148, 167))	('promote', 'PosReg', (176, 183))	('impairment', 'Var', (120, 130))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (211, 232))
188872	29445424	RBBP8 methylation was confirmed to be tumor-specific in up to 45% of analyzed BLCA patients.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('BLCA', 'Disease', (78, 82))	('RBBP8', 'Gene', (0, 5))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('methylation', 'Var', (6, 17))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('BLCA', 'Chemical', '-', (78, 82))	('patients', 'Species', '9606', (83, 91))
188873	29445424	A close association between RBBP8 methylation and its gene expression in primary tumors as well as after demethylation treatment in vitro indicate that RBBP8 methylation could be responsible for its gene inactivation.	('methylation', 'biological_process', 'GO:0032259', ('158', '169'))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('methylation', 'Var', (34, 45))	('gene expression', 'MPA', (54, 69))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('RBBP8', 'Gene', (28, 33))	('demethylation', 'biological_process', 'GO:0070988', ('105', '118'))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('gene expression', 'biological_process', 'GO:0010467', ('54', '69'))	('RBBP8', 'Gene', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
188875	29445424	Interestingly, RBBP8 methylation correlates with a favorable prognosis in the BLCA TCGA dataset.	('RBBP8', 'Gene', (15, 20))	('BLCA', 'Chemical', '-', (78, 82))	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('methylation', 'Var', (21, 32))
188878	29445424	For example, BRCA1 methylation has been revealed to predict significantly higher response rates to cisplatin treatment in breast and ovarian cancer patients, which is also traditionally used as the first-line agent in bladder cancer disease management.	('response rates', 'MPA', (81, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))	('patients', 'Species', '9606', (148, 156))	('methylation', 'Var', (19, 30))	('ovarian cancer', 'Phenotype', 'HP:0100615', (133, 147))	('bladder cancer disease', 'Disease', (218, 240))	('BRCA1', 'Gene', (13, 18))	('higher', 'PosReg', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (122, 147))	('bladder cancer', 'Phenotype', 'HP:0009725', (218, 232))	('bladder cancer disease', 'Disease', 'MESH:D001749', (218, 240))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
188879	29445424	Cisplatin-induced inter-strand adducts can lead to DNA lesions (double-strand breaks) which are regularly removed by the machinery of HR.	('lead', 'Reg', (43, 47))	('inter-strand adducts', 'Var', (18, 38))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('DNA', 'MPA', (51, 54))
188880	29445424	Unrepaired inter-strand crosslinks as consequence of reduced RBBP8 function may thereof sensitize tumor cells to chemotherapy treatment as well.	('RBBP8', 'Gene', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('sensitize', 'Reg', (88, 97))	('reduced', 'NegReg', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('crosslinks', 'Var', (24, 34))	('function', 'MPA', (67, 75))
188881	29445424	Considering that a high RBBP8 methylation frequency correlates with increased survival of BLCA patients, RBBP8 methylation might be a potential biomarker for better therapy response in such subsets of patients; however, further investigation is necessary to validate this hypothetical notion.	('patients', 'Species', '9606', (201, 209))	('methylation', 'Var', (30, 41))	('patients', 'Species', '9606', (95, 103))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('BLCA', 'Chemical', '-', (90, 94))	('RBBP8', 'Gene', (24, 29))	('methylation', 'biological_process', 'GO:0032259', ('111', '122'))	('survival', 'MPA', (78, 86))	('increased', 'PosReg', (68, 77))	('BLCA', 'Disease', (90, 94))
188882	29445424	Nevertheless, accumulating studies already functionally demonstrated the involvement of RBBP8 on sensitizing breast and ovarian cancer cells for PARP inhibitor treatment in a similar way as BRCA1 mutations, thus unveiling novel therapeutic options for a significant subset of patients which may benefit from such approach.	('patients', 'Species', '9606', (276, 284))	('involvement', 'Reg', (73, 84))	('RBBP8', 'Gene', (88, 93))	('sensitizing', 'Reg', (97, 108))	('PARP', 'Gene', '142', (145, 149))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (109, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('BRCA1', 'Gene', (190, 195))	('PARP', 'Gene', (145, 149))	('mutations', 'Var', (196, 205))	('ovarian cancer', 'Phenotype', 'HP:0100615', (120, 134))
188889	29445424	Urine-based tests assessing aberrant DNA methylation are emerging as a potential tool for cancer detection , and various studies described the identification of novel DNA methylation-based biomarkers.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('DNA methylation', 'biological_process', 'GO:0006306', ('167', '182'))	('DNA methylation', 'biological_process', 'GO:0006306', ('37', '52'))	('aberrant', 'Var', (28, 36))	('DNA', 'cellular_component', 'GO:0005574', ('167', '170'))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
188895	29445424	In the current study, we systemically screened for epigenetic configuration of DNA repair genes involved in the DNA damage response (DDR) across 32 human cancer entities and identified 39 methylated DDR genes which may be important targets for novel therapeutic strategies.	('epigenetic', 'Var', (51, 61))	('methylated', 'Var', (188, 198))	('DNA repair', 'biological_process', 'GO:0006281', ('79', '89'))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('human', 'Species', '9606', (148, 153))	('DNA damage response', 'biological_process', 'GO:0006974', ('112', '131'))	('DNA repair genes', 'Gene', (79, 95))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))
188896	29445424	This includes known epigenetic silenced repair genes like MGMT, MLH1, and ERCC1 but also novel targets of epigenetic dysregulation like RBBP8/CtiP, which has a proven role in homologous recombination-mediated DNA double-strand break repair and is further known to sensitize cancer cells for PARP1 inhibitors.	('CtiP', 'Gene', (142, 146))	('homologous recombination', 'biological_process', 'GO:0035825', ('175', '199'))	('MGMT', 'Gene', '4255', (58, 62))	('MLH1', 'Gene', (64, 68))	('MGMT', 'Gene', (58, 62))	('MLH1', 'Gene', '4292', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cancer', 'Disease', (274, 280))	('double-strand break repair', 'biological_process', 'GO:0006302', ('213', '239'))	('epigenetic', 'Var', (106, 116))	('ERCC1', 'Gene', '2067', (74, 79))	('ERCC1', 'Gene', (74, 79))	('CtiP', 'Gene', '5932', (142, 146))	('MGMT', 'molecular_function', 'GO:0003908', ('58', '62'))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('DNA', 'cellular_component', 'GO:0005574', ('209', '212'))
188897	29445424	RBBP8 was almost exclusively hypermethylated in bladder cancers and was detectable by a non-invasive approach in urines from bladder cancer patients.	('bladder cancers', 'Disease', (48, 63))	('hypermethylated', 'Var', (29, 44))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('RBBP8', 'Gene', (0, 5))	('bladder cancers', 'Phenotype', 'HP:0009725', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('bladder cancers', 'Disease', 'MESH:D001749', (48, 63))	('patients', 'Species', '9606', (140, 148))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))
188912	29445424	An exploratory data analysis was performed to identify genomic regions with tumor-specific methylation, i.e., showing unmethylated CpGs in available normal tissue samples.	('methylation', 'Var', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
188915	29445424	With respect to known characteristics of used tumor samples (i.e., the contamination with stromal cells (e.g., fibroblasts) in up to 40% of TCGA specimens; the copy number variations or whole genome duplications (e.g.,); and lastly, the prevalence of subclones) which could affect tumor-associated allele frequencies, a stepwise prioritization strategy with adjusted beta value thresholds was conducted.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('copy number variations', 'Var', (160, 182))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Disease', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
188939	28427185	The dysregulation of these genes is likely to be associated with poor clinical outcomes in cancer.	('dysregulation', 'Var', (4, 17))	('associated', 'Reg', (49, 59))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
188951	28427185	Lawrence et al analyzed 27 cancer types and found that the median frequency of non-synonymous mutations varied by more than 1,000-fold across different cancer types.	('cancer', 'Disease', (152, 158))	('non-synonymous mutations', 'Var', (79, 103))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
188953	28427185	Zack et al analyzed the copy number profiles of 4,934 primary cancer specimens across 11 cancer types and found that the mean rate of somatic copy number alterations (SCNAs) varied across different cancer types with ovarian, cervix, breast and bladder cancers having a large number of SCNAs while leukemia and kidney cancers very few SCNAs.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', (89, 95))	('breast and bladder cancers', 'Disease', 'MESH:D001749', (233, 259))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', (198, 204))	('kidney cancers', 'Disease', (310, 324))	('cervix', 'Disease', (225, 231))	('kidney cancers', 'Disease', 'MESH:D007680', (310, 324))	('cancer', 'Disease', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (317, 323))	('cancers', 'Phenotype', 'HP:0002664', (317, 324))	('copy number', 'Var', (142, 153))	('cancer', 'Disease', (317, 323))	('ovarian', 'Disease', (216, 223))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('ovarian', 'Disease', 'MESH:D010051', (216, 223))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('kidney cancers', 'Phenotype', 'HP:0009726', (310, 324))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('kidney cancer', 'Phenotype', 'HP:0009726', (310, 323))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('leukemia', 'Phenotype', 'HP:0001909', (297, 305))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('bladder cancers', 'Phenotype', 'HP:0009725', (244, 259))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('leukemia', 'Disease', (297, 305))	('leukemia', 'Disease', 'MESH:D007938', (297, 305))
189072	28427185	Likewise, we found a number of genes whose expression follows this pattern: late-stage cancers < early-stage cancers < normal tissue (Figure 7C), such as ADHFE1, LOC653501, NT5DC1, RSBN1, SOCS2 and TAPT1 in five cancer types.	('RSBN1', 'Gene', '54665', (181, 186))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('LOC653501', 'Var', (162, 171))	('late-stage cancers', 'Disease', 'MESH:D009369', (76, 94))	('ADHFE1', 'Gene', '137872', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('RSBN1', 'Gene', (181, 186))	('NT5DC1', 'Gene', '221294', (173, 179))	('NT5DC1', 'Gene', (173, 179))	('SOCS2', 'Gene', '8835', (188, 193))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('SOCS2', 'Gene', (188, 193))	('cancers', 'Disease', (87, 94))	('cancer', 'Disease', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Disease', (109, 115))	('cancers', 'Disease', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('late-stage cancers', 'Disease', (76, 94))	('cancer', 'Disease', (212, 218))	('TAPT1', 'Gene', '202018', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('TAPT1', 'Gene', (198, 203))	('ADHFE1', 'Gene', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
189094	28427185	These results demonstrate that there exist common genes and pathways whose dysregulations lead to the development of different types of cancer.	('dysregulations', 'Var', (75, 89))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('lead to', 'Reg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
189125	28427185	In addition, many upstream factors may affect expression of mRNAs (genes) in cancers such as gene mutations, DNA copy number alterations, DNA methylation, microRNA expression, and expression change of regulators.	('microRNA', 'MPA', (155, 163))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('cancers', 'Disease', (77, 84))	('DNA methylation', 'biological_process', 'GO:0006306', ('138', '153'))	('affect', 'Reg', (39, 45))	('expression', 'MPA', (180, 190))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('methylation', 'Var', (142, 153))	('expression', 'MPA', (46, 56))	('copy number alterations', 'Var', (113, 136))
189140	27793038	In vitro study revealed knockdown of DDR2 resulted in a depletion of cellular viability, migratory, and invasive ability, supporting the oncogenic function of DDR2.	('DDR2', 'Gene', '4921', (37, 41))	('DDR2', 'Gene', (159, 163))	('depletion of cellular viability', 'MPA', (56, 87))	('DDR2', 'Gene', (37, 41))	('migratory', 'CPA', (89, 98))	('DDR2', 'Gene', '4921', (159, 163))	('knockdown', 'Var', (24, 33))	('invasive ability', 'CPA', (104, 120))
189150	27793038	Reanalysis of the transcriptomic profile from GSE31684 with special attention to those associated with transmembrane receptor protein tyrosine kinase activity (GO:0004714), three transcripts were identified to have significant differential expression (Figure 1).	('transmembrane receptor', 'Gene', '8829', (103, 125))	('transmembrane', 'cellular_component', 'GO:0044214', ('103', '116'))	('transmembrane', 'cellular_component', 'GO:0016021', ('103', '116'))	('transmembrane receptor protein tyrosine kinase activity', 'molecular_function', 'GO:0004714', ('103', '158'))	('transmembrane receptor', 'Gene', (103, 125))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('GSE31684', 'Var', (46, 54))
189167	27793038	More than half of the tumor shows infiltrative and trabecular invasion pattern in both UTUC and UBUC groups, significantly corresponding to high DDR2 expression (UTUC and UBUC, P < 0.001).	('UBUC', 'Chemical', '-', (96, 100))	('expression', 'MPA', (150, 160))	('DDR2', 'Gene', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('high', 'Var', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('DDR2', 'Gene', '4921', (145, 149))	('UBUC', 'Chemical', '-', (171, 175))
189175	27793038	As shown in Tables 3 and 4, in univariate and multivariate analyses, both the UTUC and UBUC group with high DDR2 expression had significantly dismal DSS and MeFS (P < 0.01 for all).	('UBUC', 'Chemical', '-', (87, 91))	('DSS', 'Gene', '5376', (149, 152))	('MeFS', 'CPA', (157, 161))	('high', 'Var', (103, 107))	('DDR2', 'Gene', '4921', (108, 112))	('DSS', 'Gene', (149, 152))	('DDR2', 'Gene', (108, 112))
189181	27793038	The altered RTKs in UC have been reported and associated with tumor cell proliferation and survival, including FGFR3 activation, EGFR amplification, ERBB3 mutation, and ERBB2 mutation or amplification.	('FGFR3', 'Gene', (111, 116))	('FGFR3', 'Gene', '2261', (111, 116))	('ERBB3', 'Gene', '2065', (149, 154))	('EGFR', 'Gene', (129, 133))	('ERBB2', 'Gene', '2064', (169, 174))	('EGFR', 'molecular_function', 'GO:0005006', ('129', '133'))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('amplification', 'Var', (187, 200))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('associated', 'Reg', (46, 56))	('survival', 'CPA', (91, 99))	('mutation', 'Var', (175, 183))	('EGFR', 'Gene', '1956', (129, 133))	('ERBB3', 'Gene', (149, 154))	('activation', 'PosReg', (117, 127))	('RTK', 'Gene', (12, 15))	('tumor', 'Disease', (62, 67))	('amplification', 'Var', (134, 147))	('mutation', 'Var', (155, 163))	('RTK', 'Gene', '5979', (12, 15))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))	('ERBB2', 'Gene', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
189197	27793038	DDR2 was mutated in 3-4% of squamous cell cancers of the lung, amplified in 10.4% and mutated in 2.2% adenocarcinomas of lung, amplified in 29% of neuroendocrine prostatic cancers, advanced prostatic adenocarcinomas, advanced hepatocellular carcinomas, nasopharyngeal cancers, amplified in 12.6% and mutated in 0.7% of invasive carcinomas of breast, and amplified in 10.1% of pancreatic adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('hepatocellular carcinomas', 'Disease', (226, 251))	('mutated', 'Var', (300, 307))	('mutated', 'Var', (86, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (241, 251))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (376, 402))	('adenocarcinomas of lung', 'Disease', 'MESH:D000077192', (102, 125))	('DDR2', 'Gene', '4921', (0, 4))	('neuroendocrine prostatic cancers', 'Disease', 'MESH:D011471', (147, 179))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('squamous cell cancers of the lung', 'Disease', 'MESH:D002294', (28, 61))	('prostatic adenocarcinomas', 'Disease', (190, 215))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (226, 250))	('prostatic cancers', 'Phenotype', 'HP:0012125', (162, 179))	('neuroendocrine prostatic cancers', 'Disease', (147, 179))	('DDR2', 'Gene', (0, 4))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (28, 49))	('squamous cell cancers of the lung', 'Disease', (28, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (205, 215))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (376, 402))	('invasive carcinomas of breast', 'Disease', (319, 348))	('invasive carcinomas of breast', 'Disease', 'MESH:D018270', (319, 348))	('adenocarcinomas of lung', 'Disease', (102, 125))	('prostatic adenocarcinomas', 'Disease', 'MESH:D011471', (190, 215))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))	('nasopharyngeal cancers', 'Disease', (253, 275))	('squamous cell cancers of the lung', 'Phenotype', 'HP:0030359', (28, 61))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (226, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('amplified', 'Var', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (392, 401))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (392, 402))	('mutated', 'Var', (9, 16))	('pancreatic adenocarcinomas', 'Disease', (376, 402))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('carcinomas', 'Phenotype', 'HP:0030731', (328, 338))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (226, 251))	('nasopharyngeal cancers', 'Disease', 'MESH:D009303', (253, 275))
189199	27793038	Upregulation and mutations (R105S, H136H and N456S) of DDR2 in non-small cell lung cancer and mutations (G531V, S131C, T681I) of DDR2 in squamous cell carcinoma (SCC) of the lung have been reported.	('S131C', 'Var', (112, 117))	('G531V', 'Var', (105, 110))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (67, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('N456S', 'Mutation', 'rs1374888421', (45, 50))	('H136H', 'Mutation', 'rs2271305', (35, 40))	('DDR2', 'Gene', (129, 133))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (63, 89))	('DDR2', 'Gene', '4921', (55, 59))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (137, 160))	('R105S', 'Mutation', 'p.R105S', (28, 33))	('G531V', 'Mutation', 'p.G531V', (105, 110))	('non-small cell lung cancer', 'Disease', (63, 89))	('S131C', 'Mutation', 'p.S131C', (112, 117))	('H136H', 'Var', (35, 40))	('DDR2', 'Gene', (55, 59))	('squamous cell carcinoma', 'Disease', (137, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('T681I', 'Mutation', 'rs201701502', (119, 124))	('N456S', 'Var', (45, 50))	('Upregulation', 'PosReg', (0, 12))	('DDR2', 'Gene', '4921', (129, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('T681I', 'Var', (119, 124))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (63, 89))	('SCC', 'Phenotype', 'HP:0002860', (162, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))
189200	27793038	The mutation of S131C induces matrix metalloproteinases 2 and reduces E-cadherin expression of the lung SCC cells, promoting migration, invasion, plasticity, and EMT.	('reduces', 'NegReg', (62, 69))	('migration', 'CPA', (125, 134))	('E-cadherin', 'Gene', '999', (70, 80))	('promoting', 'PosReg', (115, 124))	('matrix metalloproteinases 2', 'Enzyme', (30, 57))	('EMT', 'biological_process', 'GO:0001837', ('162', '165'))	('EMT', 'CPA', (162, 165))	('mutation', 'Var', (4, 12))	('invasion', 'CPA', (136, 144))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('induces', 'PosReg', (22, 29))	('plasticity', 'CPA', (146, 156))	('cadherin', 'molecular_function', 'GO:0008014', ('72', '80'))	('S131C', 'Mutation', 'p.S131C', (16, 21))	('E-cadherin', 'Gene', (70, 80))	('S131C', 'Gene', (16, 21))
189202	27793038	In an invasive carcinoma of breast cancer, high DDR2 expression is significantly associated with a high tumor grade and triple-negative subtype and worse survival.	('DDR2', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('high', 'Var', (43, 47))	('carcinoma of breast cancer', 'Disease', (15, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (104, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('triple-negative subtype', 'CPA', (120, 143))	('DDR2', 'Gene', '4921', (48, 52))	('expression', 'MPA', (53, 63))	('associated', 'Reg', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('carcinoma of breast cancer', 'Disease', 'MESH:D001943', (15, 41))
189203	27793038	In a xenograft model of gastric cancer, DDR2 overexpression is mediated by demethylation of a DNA promotor and knockdown of DDR2 suppressed peritoneal metastasis.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('gastric cancer', 'Phenotype', 'HP:0012126', (24, 38))	('knockdown', 'Var', (111, 120))	('DDR2', 'Gene', (124, 128))	('suppressed', 'NegReg', (129, 139))	('demethylation', 'Var', (75, 88))	('DDR2', 'Gene', (40, 44))	('gastric cancer', 'Disease', 'MESH:D013274', (24, 38))	('peritoneal metastasis', 'CPA', (140, 161))	('gastric cancer', 'Disease', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('DDR2', 'Gene', '4921', (124, 128))	('DDR2', 'Gene', '4921', (40, 44))	('overexpression', 'PosReg', (45, 59))	('demethylation', 'biological_process', 'GO:0070988', ('75', '88'))
189212	27793038	The trial for Nilotinib (NCT02029001) is recruiting patients with malignant solid neoplasms with mutations, amplification, or translocation of ABL1, KIT, PDGFRA, DDR1, DDR2, etc.	('mutations', 'Var', (97, 106))	('translocation', 'Var', (126, 139))	('amplification', 'Var', (108, 121))	('DDR1', 'Gene', '780', (162, 166))	('KIT', 'Gene', (149, 152))	('DDR1', 'Gene', (162, 166))	('neoplasms', 'Phenotype', 'HP:0002664', (82, 91))	('malignant solid neoplasms', 'Disease', (66, 91))	('malignant solid neoplasms', 'Disease', 'MESH:D009369', (66, 91))	('Nilotinib', 'Chemical', 'MESH:C498826', (14, 23))	('DDR2', 'Gene', '4921', (168, 172))	('ABL1', 'Gene', '25', (143, 147))	('PDGFRA', 'Gene', '5156', (154, 160))	('PDGFRA', 'Gene', (154, 160))	('KIT', 'molecular_function', 'GO:0005020', ('149', '152'))	('DDR2', 'Gene', (168, 172))	('ABL1', 'Gene', (143, 147))	('patients', 'Species', '9606', (52, 60))
189220	27793038	As in our previous work using pre-designed TaqMan assay reagents (Applied Biosystems), we measured the mRNA abundance of DDR2 (Hs01025953_m1) with the ABI StepOnePlus  System.	('pre', 'molecular_function', 'GO:0003904', ('30', '33'))	('Hs01025953_m1', 'Var', (127, 140))	('DDR2', 'Gene', (121, 125))	('DDR2', 'Gene', '4921', (121, 125))	('mRNA abundance', 'MPA', (103, 117))
189234	27793038	The shRNA sequences used in the vectors were: pLKO.1-shLacZ (TRCN000 0072223: 5'-TGTTCGCATTATCCGAACCAT-3'), pLKO.1-shDDR2#1 (TRCN0000001418: 5'-GCC AGATTTGTCCGGTTCATT-3'; TRCN0000001419: 5'-GCCAAGTGATTCTAGCATGTT-3').	('DDR2', 'Gene', (117, 121))	('TRCN0000001419', 'Disease', (171, 185))	('TRCN000', 'Var', (61, 68))	('DDR2', 'Gene', '4921', (117, 121))	('TRCN0000001419', 'Disease', 'None', (171, 185))
189279	25648269	The risk of post-transplant UC is higher among patients with aristolochic acid nephropathy (AAN) (also called Chinese-herb nephropathy) and those among patients with analgesic nephropathy (AN) because of prior analgesic abuse.	('nephropathy', 'Disease', (123, 134))	('aristolochic acid', 'Chemical', 'MESH:C000228', (61, 78))	('AAN', 'Chemical', '-', (92, 95))	('analgesic nephropathy', 'Disease', (166, 187))	('nephropathy', 'Disease', 'MESH:D007674', (176, 187))	('nephropathy', 'Phenotype', 'HP:0000112', (123, 134))	('post-transplant UC', 'Disease', (12, 30))	('patients', 'Species', '9606', (47, 55))	('nephropathy', 'Phenotype', 'HP:0000112', (79, 90))	('nephropathy', 'Disease', (79, 90))	('analgesic nephropathy', 'Disease', 'MESH:D007674', (166, 187))	('aristolochic', 'Var', (61, 73))	('nephropathy', 'Disease', (176, 187))	('nephropathy', 'Disease', 'MESH:D007674', (123, 134))	('acid nephropathy', 'Phenotype', 'HP:0001947', (74, 90))	('nephropathy', 'Phenotype', 'HP:0000112', (176, 187))	('nephropathy', 'Disease', 'MESH:D007674', (79, 90))	('patients', 'Species', '9606', (152, 160))
189295	25648269	The survival rate of metastatic bladder cancer patients treated with either GC or PCG is significantly higher among patients with low ERCC1 levels.	('ERCC1', 'Gene', '2067', (134, 139))	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('GC', 'Chemical', '-', (76, 78))	('bladder cancer', 'Disease', (32, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('PCG', 'Chemical', '-', (82, 85))	('patients', 'Species', '9606', (116, 124))	('survival', 'CPA', (4, 12))	('patients', 'Species', '9606', (47, 55))	('low', 'Var', (130, 133))	('higher', 'PosReg', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ERCC1', 'Gene', (134, 139))
189297	25648269	RRM1 has also been identified as a significant indicator of survival in patients receiving GC, with low expression levels correlating with greater survival benefit.	('RRM1', 'Gene', '6240', (0, 4))	('RRM1', 'Gene', (0, 4))	('expression levels', 'MPA', (104, 121))	('GC', 'Chemical', '-', (91, 93))	('greater', 'PosReg', (139, 146))	('low', 'Var', (100, 103))	('patients', 'Species', '9606', (72, 80))
189301	25648269	With these modifications, the plasma level of free cisplatin available for anti-tumor activity is almost the same as in patients with normal renal function.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('modifications', 'Var', (11, 24))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('tumor', 'Disease', (80, 85))	('patients', 'Species', '9606', (120, 128))
189311	23159581	31 patients were identified (median age:63.5yrs; 83.3% male; TNM stage:cT1N0,n=4;cT2N0,n=7;cT3b-4aN0,n=5; cT4b, N+ or M+ n = 15).	('TNM', 'Gene', (61, 64))	('cT1N0', 'Var', (71, 76))	('cT3b-4aN0', 'Var', (91, 100))	('patients', 'Species', '9606', (3, 11))	('cT2N0', 'Var', (81, 86))	('TNM', 'Gene', '10178', (61, 64))
189314	23159581	Despite pathologic downstaging in 80% of patients treated with neo-adjuvant chemotherapy, relapses were common and there was no difference in survival between patients treated with neo-adjuvant chemotherapy compared to initial surgery, even though adjuvant chemotherapy was given in 7 patients.	('relapses', 'CPA', (90, 98))	('neo-adjuvant', 'Var', (63, 75))	('patients', 'Species', '9606', (41, 49))	('patients', 'Species', '9606', (285, 293))	('downstaging', 'NegReg', (19, 30))	('patients', 'Species', '9606', (159, 167))
189444	33740735	Immunotherapy, particularly the blockade of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis, has been established as a standard treatment for locally advanced or metastatic urothelial carcinoma (mUC).	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('programmed cell death', 'biological_process', 'GO:0012501', ('48', '69'))	('death', 'Disease', 'MESH:D003643', (64, 69))	('locally advanced', 'Disease', (168, 184))	('ligand', 'molecular_function', 'GO:0005488', ('96', '102'))	('death', 'Disease', (64, 69))	('PD-1', 'Gene', (73, 77))	('PD-L1', 'Gene', (106, 111))	('PD-1', 'Gene', '5133', (73, 77))	('death', 'Disease', 'MESH:D003643', (90, 95))	('death', 'Disease', (90, 95))	('urothelial carcinoma', 'Disease', (199, 219))	('blockade', 'Var', (32, 40))	('PD-L1', 'Gene', '29126', (106, 111))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (199, 219))
189533	33740735	Similarly, in our study, the use of PPI was associated not only with worse OS and PFS but also with lower DCR and ORR.	('PPI', 'Var', (36, 39))	('worse OS', 'Disease', (69, 77))	('lower', 'NegReg', (100, 105))	('PPI', 'biological_process', 'GO:0060134', ('36', '39'))	('DCR', 'Chemical', '-', (106, 109))	('ORR', 'MPA', (114, 117))	('PFS', 'Disease', (82, 85))	('DCR', 'MPA', (106, 109))
189539	33740735	On the other hand, there is available evidence suggesting the role of PPI in altering the functionality of the immune system through gut microbiome modulation.	('altering', 'Reg', (77, 85))	('PPI', 'biological_process', 'GO:0060134', ('70', '73'))	('PPI', 'Var', (70, 73))	('gut microbiome', 'Species', '749906', (133, 147))	('functionality', 'MPA', (90, 103))
189556	31638990	Molecular interrogation confirmed a mutation in CDH1 exon 12 leading to early truncation of the CDH1 protein in the tumor cells.	('CDH1', 'Gene', (96, 100))	('CDH1', 'Gene', (48, 52))	('CDH1', 'Gene', '999', (96, 100))	('early truncation', 'MPA', (72, 88))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('protein', 'Protein', (101, 108))	('CDH1', 'Gene', '999', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('tumor', 'Disease', (116, 121))	('mutation', 'Var', (36, 44))
189560	31638990	The majority of rapid autopsies previously reported in the literature by our group have been for primary prostatic adenocarcinoma, with one case report of metastatic renal cell carcinoma from a patient with a germline fumarate hydratase mutation.	('renal cell carcinoma', 'Disease', 'MESH:D002292', (166, 186))	('patient', 'Species', '9606', (194, 201))	('renal cell carcinoma', 'Disease', (166, 186))	('fumarate hydratase', 'Gene', (218, 236))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (166, 186))	('prostatic adenocarcinoma', 'Disease', 'MESH:D011471', (105, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('prostatic adenocarcinoma', 'Disease', (105, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('mutation', 'Var', (237, 245))	('fumarate hydratase', 'Gene', '2271', (218, 236))
189565	31638990	Chromatin regulatory genes are also more frequently mutated in urothelial carcinoma than in other common cancer types, suggesting a possible therapeutic role for histone deacetylase inhibitors.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (63, 83))	('mutated', 'Var', (52, 59))	('Chromatin', 'cellular_component', 'GO:0000785', ('0', '9'))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('Chromatin regulatory genes', 'Gene', (0, 26))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('urothelial carcinoma', 'Disease', (63, 83))
189566	31638990	The four mutation/focal copy number clusters were characterized by TP53 and RB1 mutations, SOX4/E2F3 amplification, mutations in chromatin-modifying genes, and FGFR3, KDM6A, and STAG2 mutations.	('FGFR3', 'Gene', (160, 165))	('mutations', 'Var', (184, 193))	('amplification', 'PosReg', (101, 114))	('SOX4', 'Gene', '6659', (91, 95))	('FGFR3', 'Gene', '2261', (160, 165))	('KDM6A', 'Gene', (167, 172))	('E2F3', 'Gene', (96, 100))	('mutations', 'Var', (80, 89))	('TP53', 'Gene', (67, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('160', '164'))	('chromatin', 'cellular_component', 'GO:0000785', ('129', '138'))	('E2F3', 'Gene', '1871', (96, 100))	('RB1', 'Gene', (76, 79))	('mutations', 'Var', (116, 125))	('STAG2', 'Gene', '10735', (178, 183))	('KDM6A', 'Gene', '7403', (167, 172))	('SOX4', 'Gene', (91, 95))	('TP53', 'Gene', '7157', (67, 71))	('RB1', 'Gene', '5925', (76, 79))	('STAG2', 'Gene', (178, 183))
189574	31638990	A previous study by some of our co-authors demonstrated pathogenic CDH1 mutations in the majority of PUC.	('mutations', 'Var', (72, 81))	('pathogenic', 'Reg', (56, 66))	('PUC', 'Disease', (101, 104))	('CDH1', 'Gene', (67, 71))	('CDH1', 'Gene', '999', (67, 71))
189575	31638990	Deletions of chromosome 9p21 have been reported to play an important role and TP53 mutations are present in a minority of PUC.	('mutations', 'Var', (83, 92))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('chromosome', 'cellular_component', 'GO:0005694', ('13', '23'))	('Deletions', 'Var', (0, 9))
189576	31638990	FGFR3 mutations have been detected in approximately 60% of cases.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
189629	31638990	3c), patchy expression of CD138, CK903, and p53, and focal expression of PAX-8.	('PAX-8', 'Gene', '7849', (73, 78))	('CD138', 'Gene', '6382', (26, 31))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('PAX-8', 'Gene', (73, 78))	('CK903', 'Var', (33, 38))	('CD138', 'Gene', (26, 31))
189632	31638990	Molecular analysis performed on the index tumor demonstrated a deleterious mutation in CDH1 exon 12 leading to early truncation of the CDH1 protein in the index tumor sample which was absent from the adjacent benign tissue (Fig.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('protein', 'Protein', (140, 147))	('tumor', 'Disease', (42, 47))	('CDH1', 'Gene', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('CDH1', 'Gene', '999', (87, 91))	('mutation', 'Var', (75, 83))	('CDH1', 'Gene', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('truncation', 'MPA', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('CDH1', 'Gene', '999', (135, 139))	('tumor', 'Disease', (161, 166))
189648	31638990	Additionally, the electron microscopic features of our case are similar to those described in microvillus inclusion disease, an autosomal condition causing congenital diarrhea and failure to thrive that results from mutations in the MY05B, which encodes a cytoskeleton motor protein.	('diarrhea', 'Phenotype', 'HP:0002014', (167, 175))	('microvillus', 'cellular_component', 'GO:0005902', ('94', '105'))	('congenital diarrhea and failure', 'Disease', 'MESH:D003967', (156, 187))	('MY05B', 'Gene', (233, 238))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('256', '268'))	('protein', 'cellular_component', 'GO:0003675', ('275', '282'))	('microvillus inclusion disease', 'Disease', 'MESH:C537470', (94, 123))	('results from', 'Reg', (203, 215))	('microvillus inclusion disease', 'Disease', (94, 123))	('mutations', 'Var', (216, 225))	('failure to thrive', 'Phenotype', 'HP:0001508', (180, 197))
189660	31638990	Finally, our patient's tumor demonstrated a deleterious mutation in CDH1 exon 12 leading to early truncation of the CDH1 protein, similar to the findings of our previous study.	('CDH1', 'Gene', '999', (116, 120))	('truncation', 'MPA', (98, 108))	('patient', 'Species', '9606', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('protein', 'Protein', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutation', 'Var', (56, 64))	('CDH1', 'Gene', (68, 72))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('tumor', 'Disease', (23, 28))	('CDH1', 'Gene', (116, 120))	('CDH1', 'Gene', '999', (68, 72))
189688	29354488	In univariable Kaplan-Meier analyses, no difference regarding DFS was found in p53 positive vs. negative (P=0.8) or Ki-67 labeling index >40% vs. <=40% (P=0.078) patients.	('p53', 'Gene', '7157', (79, 82))	('>40', 'Var', (137, 140))	('p53', 'Gene', (79, 82))	('patients', 'Species', '9606', (162, 170))
189698	29354488	Consequently, molecular defects in human cancer cells have been linked to pathway irregularities with inactivated p53 leading to an increased half-life of the protein and prolonged detectability via immunohistochemistry.	('prolonged', 'PosReg', (171, 180))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('molecular defects', 'Disease', 'MESH:C567116', (14, 31))	('p53', 'Gene', (114, 117))	('half-life', 'MPA', (142, 151))	('p53', 'Gene', '7157', (114, 117))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('human', 'Species', '9606', (35, 40))	('detectability', 'MPA', (181, 194))	('inactivated', 'Var', (102, 113))	('increased', 'PosReg', (132, 141))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('molecular defects', 'Disease', (14, 31))
189726	29354488	In the p53 cohort, patients with a positive p53 expression status harbored concomitant carcinoma in situ more often (50.0% vs. 27.6%; P=0.032), and presented with WHO grade 3 more frequently (97.7% vs. 69.0%; P=0.001), as compared to their p53 negative counterparts.	('p53', 'Gene', (240, 243))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (87, 104))	('patients', 'Species', '9606', (19, 27))	('carcinoma', 'Disease', (87, 96))	('p53', 'Gene', '7157', (240, 243))	('p53', 'Gene', '7157', (7, 10))	('positive', 'Var', (35, 43))	('WHO grade', 'CPA', (163, 172))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('harbored', 'Reg', (66, 74))	('p53', 'Gene', (7, 10))	('carcinoma', 'Disease', 'MESH:D002277', (87, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
189735	29354488	However, in multivariable analyses, adjusting for lymphovascular invasion and p53 expression status, Ki-67 positivity was significantly associated with adverse DFS (HR, 2.66; 95% CI, 1.02-6.95; P=0.046).	('positivity', 'Var', (107, 117))	('Ki-67', 'Gene', (101, 106))	('p53', 'Gene', (78, 81))	('p53', 'Gene', '7157', (78, 81))	('adverse DFS', 'Disease', (152, 163))	('associated with', 'Reg', (136, 151))
189744	29354488	First, we found that patients with p53 or Ki-67 positivity presented with higher WHO grade at diagnosis and concomitant carcinoma in situ was found more often in patients with p53 positive tumors.	('carcinoma', 'Disease', (120, 129))	('Ki-67', 'Gene', (42, 47))	('patients', 'Species', '9606', (162, 170))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('p53', 'Gene', (176, 179))	('higher', 'PosReg', (74, 80))	('positivity', 'Var', (48, 58))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('carcinoma', 'Disease', 'MESH:D002277', (120, 129))	('patients', 'Species', '9606', (21, 29))	('p53', 'Gene', '7157', (176, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('WHO grade', 'CPA', (81, 90))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (120, 137))
189746	29354488	Ki-67 is directly associated to cell proliferation and a mutated TP53 gene results in higher levels of p53 protein expression due to a prolonged half-life of the protein.	('cell proliferation', 'biological_process', 'GO:0008283', ('32', '50'))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('p53', 'Gene', (103, 106))	('levels', 'MPA', (93, 99))	('p53', 'Gene', '7157', (103, 106))	('half-life', 'MPA', (145, 154))	('higher', 'PosReg', (86, 92))	('mutated', 'Var', (57, 64))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
189756	29354488	Similarly, another Spanish group found an association of Ki-67 positivity and disease-free, progression-free, and overall survival in 51 patients with pT1 G3 bladder cancer in univariable analyses, which, however, did not hold true in multivariable models.	('bladder cancer', 'Phenotype', 'HP:0009725', (158, 172))	('pT1', 'Gene', (151, 154))	('progression-free', 'CPA', (92, 108))	('overall survival', 'CPA', (114, 130))	('association', 'Interaction', (42, 53))	('positivity', 'Var', (63, 73))	('patients', 'Species', '9606', (137, 145))	('bladder cancer', 'Disease', 'MESH:D001749', (158, 172))	('bladder cancer', 'Disease', (158, 172))	('Ki-67', 'Gene', (57, 62))	('pT1', 'Gene', '58492', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('disease-free', 'CPA', (78, 90))
189765	29354488	showed the predictive benefit of a combination of altered biomarkers (p53, p27, and Ki-67) over solitary biomarker positivity in 80 patients with pT1 bladder cancer.	('p27', 'Gene', (75, 78))	('bladder cancer', 'Phenotype', 'HP:0009725', (150, 164))	('pT1', 'Gene', '58492', (146, 149))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (150, 164))	('bladder cancer', 'Disease', (150, 164))	('pT1', 'Gene', (146, 149))	('Ki-67', 'Var', (84, 89))	('p27', 'Gene', '3429', (75, 78))	('patients', 'Species', '9606', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
189766	29354488	validated the European Organization for Research and Treatment of Cancer (EORTC) risk scores as adopted in the EAU guidelines in a cohort of 230 patients with primary NMIBC and determined its relation to molecular grade based on fibroblast growth factor receptor 3 (FGFR3) gene mutation status and Ki-67 expression.	('patients', 'Species', '9606', (145, 153))	('FGFR3', 'Gene', (266, 271))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('229', '253'))	('fibroblast growth factor receptor 3', 'Gene', '2261', (229, 264))	('FGFR', 'molecular_function', 'GO:0005007', ('266', '270'))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Cancer', 'Disease', (66, 72))	('mutation', 'Var', (278, 286))	('fibroblast growth factor receptor 3', 'Gene', (229, 264))	('FGFR3', 'Gene', '2261', (266, 271))	('men', 'Species', '9606', (58, 61))	('Cancer', 'Disease', 'MESH:D009369', (66, 72))
189899	28501331	The phosphorylation of ERK1/2 was also decreased in the presence of U0126 (Fig.	('phosphorylation', 'MPA', (4, 19))	('U0126', 'Var', (68, 73))	('ERK1/2', 'Protein', (23, 29))	('ERK1', 'molecular_function', 'GO:0004707', ('23', '27'))	('decreased', 'NegReg', (39, 48))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('U0126', 'Chemical', 'MESH:C113580', (68, 73))
189923	28501331	It was shown that the addition of EGF resulted in the phosphorylation of EGFR and the activation of the principle members of the mitogen-activated protein kinase (MAPK) family; ERK1/2 (p-ERK1/2) and JNK1/2 (p-JNK1/2).	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))	('ERK1/2', 'Var', (177, 183))	('EGFR', 'Gene', '1956', (73, 77))	('EGF', 'Gene', '1950', (73, 76))	('ERK1', 'molecular_function', 'GO:0004707', ('187', '191'))	('EGF', 'molecular_function', 'GO:0005154', ('34', '37'))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('EGFR', 'Gene', (73, 77))	('JNK', 'molecular_function', 'GO:0004705', ('209', '212'))	('ERK1', 'molecular_function', 'GO:0004707', ('177', '181'))	('EGF', 'Gene', (34, 37))	('MAPK', 'molecular_function', 'GO:0004707', ('163', '167'))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('activation', 'PosReg', (86, 96))	('EGF', 'Gene', (73, 76))	('EGF', 'Gene', '1950', (34, 37))	('JNK', 'molecular_function', 'GO:0004705', ('199', '202'))	('phosphorylation', 'MPA', (54, 69))
189943	28501331	This is because As+3 exposure, in addition to causing acute toxicity to the bladder, has a well-established strong association for the development of human urothelial carcinoma with chronic exposure.	('human', 'Species', '9606', (150, 155))	('urothelial carcinoma', 'Disease', (156, 176))	('toxicity', 'Disease', (60, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (156, 176))	('toxicity', 'Disease', 'MESH:D064420', (60, 68))	('As+3', 'Chemical', '-', (16, 20))	('As+3', 'Var', (16, 20))
189952	28501331	The MEK inhibitor U0126 was chosen for this study as it has been shown to attenuate the activity of the transcription factor AP-1 which has been implicated in the upregulation of KRT6 expression.	('upregulation', 'PosReg', (163, 175))	('U0126', 'Chemical', 'MESH:C113580', (18, 23))	('transcription factor', 'molecular_function', 'GO:0000981', ('104', '124'))	('AP-1', 'cellular_component', 'GO:0005907', ('125', '129'))	('MEK', 'Gene', (4, 7))	('MEK', 'Gene', '5609', (4, 7))	('KRT6', 'Gene', (179, 183))	('activity', 'MPA', (88, 96))	('KRT6', 'Gene', '140807', (179, 183))	('U0126', 'Var', (18, 23))	('attenuate', 'NegReg', (74, 83))	('AP-1', 'Gene', '3725', (125, 129))	('AP-1', 'Gene', (125, 129))	('transcription', 'biological_process', 'GO:0006351', ('104', '117'))
189994	31660264	have demonstrated the dysregulation of KLK13 in bladder tumors through clinical studies, and emphasized that KLK13 is a promising marker for improving the prognosis of bladder urothelial carcinoma (BLCA) patients.	('dysregulation', 'Var', (22, 35))	('KLK13', 'Gene', (39, 44))	('bladder tumors', 'Disease', (48, 62))	('BLCA', 'Disease', (198, 202))	('KLK13', 'Gene', '26085', (109, 114))	('patients', 'Species', '9606', (204, 212))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('KLK13', 'Gene', (109, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (168, 196))	('bladder tumors', 'Disease', 'MESH:D001749', (48, 62))	('KLK13', 'Gene', '26085', (39, 44))	('BLCA', 'Disease', 'MESH:D001749', (198, 202))	('bladder tumors', 'Phenotype', 'HP:0009725', (48, 62))	('improving', 'PosReg', (141, 150))	('bladder urothelial carcinoma', 'Disease', (168, 196))
190023	31660264	As shown in the model, the expression level of ENSG00000100285 and ENSG00000140093 were negatively correlated with BLCA patient survival time, while the expression level of other mRNA were positively correlated with the BLCA patient survival time.	('ENSG00000100285', 'Var', (47, 62))	('BLCA', 'Disease', 'MESH:D001749', (220, 224))	('patient', 'Species', '9606', (120, 127))	('expression', 'MPA', (27, 37))	('negatively', 'NegReg', (88, 98))	('patient', 'Species', '9606', (225, 232))	('BLCA', 'Disease', (220, 224))	('BLCA', 'Disease', 'MESH:D001749', (115, 119))	('ENSG00000140093', 'Var', (67, 82))	('BLCA', 'Disease', (115, 119))
190064	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))	('tumor', 'Disease', (146, 151))	('immune checkpoint blockade', 'Disease', (54, 80))	('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))
190093	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))	('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))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (216, 243))	('PDO', 'Chemical', 'MESH:C541246', (79, 82))	('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))	('BRAFV600E', 'Mutation', 'rs113488022', (311, 320))	('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))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (115, 140))
190109	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))	('tumor', 'Disease', (69, 74))	('tumors', 'Disease', (31, 37))	('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))
190136	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))
190138	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))	('increased', 'PosReg', (39, 48))	('CD8', 'Gene', (49, 52))	('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))
190140	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))	('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))
190141	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))	('tumor epithelia', 'Disease', (34, 49))	('Annexin-V', 'Gene', '308', (110, 119))	('increased', 'PosReg', (100, 109))	('S6A', 'Chemical', 'MESH:C012008', (267, 270))	('tumor epithelia', 'Disease', 'MESH:D009369', (34, 49))	('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))	('Annexin-V', 'Gene', (110, 119))	('cell killing', 'biological_process', 'GO:0001906', ('51', '63'))
190144	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))
190175	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))	('CD8', 'Gene', (86, 89))	('proliferation', 'CPA', (229, 242))	('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))
190176	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))
190183	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'))	('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))
190219	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))
190228	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))
190230	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))
190231	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', 'Phenotype', 'HP:0002664', (56, 61))	('SNVs/Indels', 'Var', (128, 139))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))
190234	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))	('EMD', 'Disease', 'None', (215, 218))	('CD3e', 'Gene', '12501', (90, 94))	('CD8a', 'Gene', '12525', (54, 58))	('mouse', 'Species', '10090', (84, 89))	('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))
190238	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))
190251	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'))
190262	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))
190270	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))
190301	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))
190306	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))
190325	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))
190392	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))
190393	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))
190394	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).	('corpus endometrial carcinoma', 'Disease', (176, 204))	('TTN', 'Gene', (13, 16))	('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))
190395	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'))	('corpus endometrial carcinoma', 'Disease', (101, 129))	('tumor suppressor', 'Gene', (23, 39))	('PTEN', 'Gene', (40, 44))	('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))
190397	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))
190399	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))
190400	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))
190402	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))
190403	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))	('PCDHA1', 'Gene', (144, 150))	('survival rates', 'MPA', (166, 180))	('PCDHA1', 'Gene', (12, 18))	('corpus endometrial carcinoma', 'Disease', (74, 102))	('PCDHA1', 'Gene', (252, 258))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (74, 102))	('patients', 'Species', '9606', (120, 128))	('mutant', 'Var', (245, 251))	('prolonged', 'PosReg', (200, 209))	('lowest', 'NegReg', (159, 165))	('PCDHA1', 'Gene', '56147', (12, 18))	('PCDHA1', 'Gene', '56147', (252, 258))
190404	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))
190405	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))
190406	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))
190407	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))
190408	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))
190410	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))
190413	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))	('patients', 'Species', '9606', (88, 96))	('hypoxic tumors', 'Disease', (130, 144))	('hypoxia', 'Disease', 'MESH:D000860', (57, 64))	('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))
190427	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.	('cell cycle regulation', 'CPA', (153, 174))	('activate', 'PosReg', (81, 89))	('oxygen', 'Chemical', 'MESH:D010100', (38, 44))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cell polarity', 'CPA', (135, 148))	('influenced', 'Reg', (195, 205))	('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'))	('patients', 'Species', '9606', (227, 235))	('dysregulated', 'Var', (25, 37))
190430	31036064	In colorectal cancer, high KDM6B expression predicted good prognosis, and knock-down of KDM6B was associated with augmented cell proliferation and inhibited apoptosis.	('KDM6B', 'Gene', '23135', (27, 32))	('knock-down', 'Var', (74, 84))	('apoptosis', 'CPA', (157, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('high', 'Var', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('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'))	('cell proliferation', 'CPA', (124, 142))	('inhibited', 'NegReg', (147, 156))	('expression', 'MPA', (33, 43))	('apoptosis', 'biological_process', 'GO:0006915', ('157', '166'))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('KDM6B', 'Gene', (88, 93))
190437	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))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('mutations', 'Var', (161, 170))	('dropped', 'NegReg', (32, 39))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('bladder cancer', 'Disease', (52, 66))	('PCDHA1', 'Gene', (154, 160))	('KDM8', 'Gene', (145, 149))
190438	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))
190444	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))
190454	32235944	Heterogeneity resulting from clonal expansion of individual mutations, genomic alterations and variability of gene expression between tumour regions and, in patients with metastasis, between the primary tumour and metastases, forms the basis of the complexity of cancer.	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Disease', (263, 269))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('metastases', 'Disease', (214, 224))	('tumour', 'Disease', (134, 140))	('tumour', 'Disease', 'MESH:D009369', (203, 209))	('patients', 'Species', '9606', (157, 165))	('metastases', 'Disease', 'MESH:D009362', (214, 224))	('genomic alterations', 'Var', (71, 90))	('tumour', 'Disease', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mutations', 'Var', (60, 69))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
190461	32235944	For example, in lung cancer, driver mutations in TP53, MET, EGFR and BRAF were often clonal, whereas alterations in PIK3CA, NF1 and DNA damage repair and chromatin-regulatory genes were more heterogeneous and occurred as later alterations.	('PIK3CA', 'Gene', (116, 122))	('TP53', 'Gene', '7157', (49, 53))	('NF1', 'Gene', '4763', (124, 127))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('MET', 'Gene', (55, 58))	('EGFR', 'Gene', '1956', (60, 64))	('BRAF', 'Gene', '673', (69, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('BRAF', 'Gene', (69, 73))	('NF1', 'Gene', (124, 127))	('TP53', 'Gene', (49, 53))	('PIK3CA', 'Gene', '5290', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('EGFR', 'Gene', (60, 64))	('MET', 'Gene', '79811', (55, 58))	('mutations', 'Var', (36, 45))	('chromatin', 'cellular_component', 'GO:0000785', ('154', '163'))	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('lung cancer', 'Disease', (16, 27))
190471	32235944	We then describe current knowledge of genomic heterogeneity at the DNA level and the expression level, resulting in different tumour subtypes and the morphological heterogeneity seen in variant bladder cancer histology.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('variant', 'Var', (186, 193))	('bladder cancer', 'Disease', 'MESH:D001749', (194, 208))	('bladder cancer', 'Disease', (194, 208))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('bladder cancer', 'Phenotype', 'HP:0009725', (194, 208))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))
190485	32235944	The identification of a new or different mutation in a metastasis might indicate the need to change therapy, add additional therapy or treat a rogue metastatic lesion with local therapy if it is believed to be an isolated event in a patient with otherwise adequate systemic disease control.	('mutation', 'Var', (41, 49))	('patient', 'Species', '9606', (233, 240))	('change', 'Reg', (93, 99))
190495	32235944	This high mutation rate is believed to fuel tumour heterogeneity and tumour evolution (FIG.	('tumour', 'Disease', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Disease', (44, 50))	('mutation', 'Var', (10, 18))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('fuel', 'PosReg', (39, 43))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
190497	32235944	Mutational analyses of early-late tumour pairs identified the existence of a single ancestral origin within each assessed patient demonstrated by identical mutations at a high cellular prevalence in the primary and invasive tumour pairs.	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('mutations', 'Var', (156, 165))	('invasive tumour', 'Disease', 'MESH:D009361', (215, 230))	('patient', 'Species', '9606', (122, 129))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('invasive tumour', 'Disease', (215, 230))	('tumour', 'Disease', (34, 40))	('tumour', 'Disease', 'MESH:D009369', (224, 230))	('tumour', 'Disease', (224, 230))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
190503	32235944	Tumours from patients with progressive disease had a higher variation in the intrapatient mutational spectrum and a higher frequency of APOBEC-related mutations than those from patients with non-progressive disease.	('patient', 'Species', '9606', (82, 89))	('patient', 'Species', '9606', (13, 20))	('APOBEC-related', 'Gene', (136, 150))	('patients', 'Species', '9606', (177, 185))	('patients', 'Species', '9606', (13, 21))	('APOBEC', 'cellular_component', 'GO:0030895', ('136', '142'))	('intrapatient mutational spectrum', 'MPA', (77, 109))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('variation', 'MPA', (60, 69))	('patient', 'Species', '9606', (177, 184))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('mutations', 'Var', (151, 160))
190506	32235944	Fibroblast growth factor (FGF) signalling was enriched in ancestral clones of early invasive urothelial carcinoma with PIK3CA mutations, whereas DNA damage checkpoint regulation signalling was enriched in progressing subpopulations.	('Fibroblast growth factor', 'molecular_function', 'GO:0005104', ('0', '24'))	('signalling', 'biological_process', 'GO:0023052', ('178', '188'))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (84, 113))	('signalling', 'biological_process', 'GO:0023052', ('31', '41'))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('PIK3CA', 'Gene', (119, 125))	('DNA', 'cellular_component', 'GO:0005574', ('145', '148'))	('PIK3CA', 'Gene', '5290', (119, 125))	('regulation', 'biological_process', 'GO:0065007', ('167', '177'))	('DNA damage checkpoint', 'biological_process', 'GO:0000077', ('145', '166'))	('invasive urothelial carcinoma', 'Disease', (84, 113))	('mutations', 'Var', (126, 135))
190513	32235944	The observed increase in the clonality of mutations found in post-chemotherapy tumours suggested that chemotherapy restricted the mutational landscape of the tumour.	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('tumours', 'Disease', (79, 86))	('tumours', 'Disease', 'MESH:D009369', (79, 86))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('tumour', 'Disease', (158, 164))	('mutational landscape', 'MPA', (130, 150))	('increase', 'PosReg', (13, 21))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('mutations', 'Var', (42, 51))	('tumour', 'Disease', (79, 85))	('clonality', 'MPA', (29, 38))
190517	32235944	The cisplatin mutation signature is enriched in T>A and C>A mutations compared with other mutational signatures, such as the APOBEC (C>T) and mutation signature 5 (comparatively flat signature with minimal signature peaks).	('C>A', 'Gene', (56, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('T>A', 'Disease', (48, 51))	('mutations', 'Var', (60, 69))	('APOBEC', 'cellular_component', 'GO:0030895', ('125', '131'))	('cisplatin', 'Gene', (4, 13))
190520	32235944	Compared with other solid tumours, the high mutational burden in urothelial carcinoma might be partly driven by enzymatic activity.	('tumours', 'Phenotype', 'HP:0002664', (26, 33))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (65, 85))	('solid tumour', 'Disease', (20, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('tumours', 'Disease', (26, 33))	('mutational', 'Var', (44, 54))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('solid tumour', 'Disease', 'MESH:D009369', (20, 32))	('urothelial carcinoma', 'Disease', (65, 85))
190527	32235944	APOBEC3-induced mutational signatures are prevalent in bladder, cervical, breast, head and neck, and lung cancers.	('prevalent', 'Reg', (42, 51))	('bladder', 'Disease', (55, 62))	('lung cancers', 'Disease', 'MESH:D008175', (101, 113))	('lung cancers', 'Phenotype', 'HP:0100526', (101, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('lung cancers', 'Disease', (101, 113))	('neck', 'cellular_component', 'GO:0044326', ('91', '95'))	('APOBEC3', 'Gene', '80287', (0, 7))	('APOBEC3', 'Gene', (0, 7))	('breast', 'Disease', (74, 80))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('mutational signatures', 'Var', (16, 37))	('cervical', 'Disease', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
190528	32235944	Analysis of gene expression data and mutation patterns, distributions and loads of 19 different cancer types showed that APOBEC3B-catalysed genomic uracil lesions are responsible for a large proportion of mutations in urothelial carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutations', 'Var', (205, 214))	('uracil lesions', 'Phenotype', 'HP:0012127', (148, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('APOBEC', 'cellular_component', 'GO:0030895', ('121', '127'))	('responsible', 'Reg', (167, 178))	('urothelial carcinoma', 'Disease', (218, 238))	('uracil', 'Chemical', 'MESH:D014498', (148, 154))	('APOBEC3B', 'Gene', (121, 129))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (218, 238))	('gene expression', 'biological_process', 'GO:0010467', ('12', '27'))	('cancer', 'Disease', (96, 102))	('APOBEC3B', 'Gene', '9582', (121, 129))
190529	32235944	The frequency of APOBEC mutational signatures found at all stages of bladder cancer provides evidence for a role of APOBEC in this disease.	('bladder cancer', 'Disease', 'MESH:D001749', (69, 83))	('bladder cancer', 'Disease', (69, 83))	('mutational signatures', 'Var', (24, 45))	('APOBEC', 'Gene', (17, 23))	('bladder cancer', 'Phenotype', 'HP:0009725', (69, 83))	('APOBEC', 'cellular_component', 'GO:0030895', ('17', '23'))	('APOBEC', 'cellular_component', 'GO:0030895', ('116', '122'))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
190532	32235944	Analysis of the mutational signatures from The Cancer Genome Atlas (TCGA) muscle-invasive urothelial carcinoma patient cohort show that both APOBEC3A and APOBEC3B signatures accounted for 67% of single nucleotide variations.	('accounted', 'Reg', (174, 183))	('APOBEC', 'cellular_component', 'GO:0030895', ('141', '147'))	('Cancer', 'Disease', (47, 53))	('APOBEC', 'cellular_component', 'GO:0030895', ('154', '160'))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('APOBEC3A', 'Gene', (141, 149))	('muscle-invasive urothelial carcinoma', 'Disease', (74, 110))	('single nucleotide variations', 'Var', (195, 223))	('Cancer', 'Disease', 'MESH:D009369', (47, 53))	('muscle-invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (74, 110))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('APOBEC3B', 'Gene', (154, 162))	('APOBEC3B', 'Gene', '9582', (154, 162))	('APOBEC3A', 'Gene', '200315', (141, 149))	('patient', 'Species', '9606', (111, 118))
190534	32235944	APOBEC3A and APOBEC3B expression levels also correlate with APOBEC3-associated mutational load.	('APOBEC3', 'Gene', '80287', (60, 67))	('APOBEC3A', 'Gene', '200315', (0, 8))	('APOBEC3B', 'Gene', (13, 21))	('mutational load', 'Var', (79, 94))	('APOBEC3', 'Gene', (0, 7))	('APOBEC3', 'Gene', (60, 67))	('APOBEC3B', 'Gene', '9582', (13, 21))	('APOBEC', 'cellular_component', 'GO:0030895', ('60', '66'))	('APOBEC', 'cellular_component', 'GO:0030895', ('13', '19'))	('APOBEC3', 'Gene', '80287', (13, 20))	('APOBEC3', 'Gene', (13, 20))	('APOBEC3', 'Gene', '80287', (0, 7))	('APOBEC3A', 'Gene', (0, 8))	('correlate', 'Reg', (45, 54))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('expression', 'MPA', (22, 32))
190535	32235944	Several studies suggest that APOBEC3-associated mutations have a role in shaping urothelial carcinoma evolution.	('APOBEC3', 'Gene', '80287', (29, 36))	('mutations', 'Var', (48, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('APOBEC3', 'Gene', (29, 36))	('APOBEC', 'cellular_component', 'GO:0030895', ('29', '35'))	('urothelial carcinoma', 'Disease', (81, 101))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (81, 101))
190537	32235944	In urothelial carcinoma, 62% and 75% of mutations associated with APOBEC3A and APOBEC3B are clonal, respectively, suggesting that the majority of APOBEC3 signature mutations occur early in urothelial carcinoma evolution.	('APOBEC3', 'Gene', (79, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (189, 209))	('APOBEC', 'cellular_component', 'GO:0030895', ('66', '72'))	('APOBEC3B', 'Gene', (79, 87))	('mutations', 'Var', (40, 49))	('APOBEC3', 'Gene', '80287', (66, 73))	('urothelial carcinoma', 'Disease', (189, 209))	('APOBEC3', 'Gene', (66, 73))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (3, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('APOBEC3', 'Gene', '80287', (146, 153))	('APOBEC', 'cellular_component', 'GO:0030895', ('146', '152'))	('APOBEC3A', 'Gene', (66, 74))	('APOBEC3', 'Gene', (146, 153))	('urothelial carcinoma', 'Disease', (3, 23))	('APOBEC3A', 'Gene', '200315', (66, 74))	('mutations', 'Var', (164, 173))	('APOBEC', 'cellular_component', 'GO:0030895', ('79', '85'))	('APOBEC3B', 'Gene', '9582', (79, 87))	('APOBEC3', 'Gene', '80287', (79, 86))
190539	32235944	APOBEC3 activity is enriched in lagging DNA strands in early-replicating, gene-dense and active chromatin regions and it is plausible that conditions that increase the abundance of single-strand DNA, such as chemotherapy, could increase the substrate availability for APOBEC3-induced mutagenesis.	('mutagenesis', 'biological_process', 'GO:0006280', ('284', '295'))	('APOBEC3', 'Gene', (268, 275))	('DNA', 'cellular_component', 'GO:0005574', ('195', '198'))	('APOBEC', 'cellular_component', 'GO:0030895', ('268', '274'))	('increase', 'PosReg', (228, 236))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('chromatin', 'cellular_component', 'GO:0000785', ('96', '105'))	('APOBEC3', 'Gene', '80287', (0, 7))	('APOBEC3', 'Gene', (0, 7))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('substrate availability', 'MPA', (241, 263))	('mutagenesis', 'MPA', (284, 295))	('single-strand', 'Var', (181, 194))	('APOBEC3', 'Gene', '80287', (268, 275))
190540	32235944	These data suggest a potential interaction between chemotherapy and APOBEC3-induced mutagenesis in shaping the evolutionary landscape of urothelial carcinoma.	('APOBEC3', 'Gene', '80287', (68, 75))	('urothelial carcinoma', 'Disease', (137, 157))	('APOBEC', 'cellular_component', 'GO:0030895', ('68', '74'))	('APOBEC3', 'Gene', (68, 75))	('mutagenesis', 'Var', (84, 95))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (137, 157))	('mutagenesis', 'biological_process', 'GO:0006280', ('84', '95'))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
190546	32235944	Interpatient heterogeneity is likely to be caused by a range of underlying DNA changes (mutations, rearrangements, insertions or deletions, long non-coding RNAs and methylations) accumulated during the evolution of each cancer, but observed differences might also be a product of varying cell-type compositions in the analysed tissue sample.	('deletions', 'Var', (129, 138))	('patient', 'Species', '9606', (5, 12))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('insertions', 'Var', (115, 125))	('cancer', 'Disease', (220, 226))	('rearrangements', 'Var', (99, 113))
190563	32235944	Overall, the gene expression differences mirrored genomic alterations in tumour biopsy samples, suggesting that gene expression patterns might be founded in DNA alterations.	('gene expression', 'biological_process', 'GO:0010467', ('112', '127'))	('tumour', 'Disease', (73, 79))	('gene expression', 'biological_process', 'GO:0010467', ('13', '28'))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('differences', 'Var', (29, 40))
190564	32235944	In TCGA MIBC data set, associations of mutation patterns specifically with a tumour subtype were limited, although luminal papillary tumours were enriched in FGFR3 alterations.	('MIBC', 'Chemical', '-', (8, 12))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('FGFR', 'molecular_function', 'GO:0005007', ('158', '162'))	('tumour', 'Disease', (77, 83))	('luminal papillary tumours', 'Disease', (115, 140))	('FGFR3', 'Gene', (158, 163))	('papillary tumours', 'Phenotype', 'HP:0007482', (123, 140))	('tumour', 'Disease', (133, 139))	('luminal papillary tumours', 'Disease', 'MESH:D009369', (115, 140))	('alterations', 'Var', (164, 175))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('FGFR3', 'Gene', '2261', (158, 163))
190565	32235944	Histone regulation might have a role in subtype development, as luminal tumours have an increased frequency of KDM6A mutations, which are also found in low-grade (papillary) tumours.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('mutations', 'Var', (117, 126))	('luminal tumours', 'Disease', 'MESH:D009369', (64, 79))	('KDM6A', 'Gene', '7403', (111, 116))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('regulation', 'biological_process', 'GO:0065007', ('8', '18'))	('luminal tumours', 'Disease', (64, 79))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('KDM6A', 'Gene', (111, 116))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('tumours', 'Disease', 'MESH:D009369', (174, 181))	('tumours', 'Disease', (174, 181))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumours', 'Disease', (72, 79))
190587	32235944	One analysis of the molecular features of glandular differentiation in urothelial carcinoma has revealed high rates of hotspot mutations in the TERT promoter region, similar to urothelial carcinoma ithout glandular differentiation.	('urothelial carcinoma', 'Disease', (177, 197))	('urothelial carcinoma', 'Disease', (71, 91))	('TERT', 'Gene', (144, 148))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (177, 197))	('TERT', 'Gene', '7015', (144, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (71, 91))	('mutations', 'Var', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))
190591	32235944	To date, a high rate of TERT promoter mutations, which was not found in benign mimickers, was the only molecular finding in this tumour type, suggesting that it has molecular alterations similar to those of urothelial carcinoma in general.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('urothelial carcinoma', 'Disease', (207, 227))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('TERT', 'Gene', (24, 28))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (207, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('tumour', 'Disease', (129, 135))	('TERT', 'Gene', '7015', (24, 28))	('mutations', 'Var', (38, 47))
190596	32235944	It frequently expresses markers of urothelial differentiation, such as CK7, p63, GATA3 and uroplakins, and generally has genetic alterations similar to those of urothelial carcinoma, such as mutations in TP53, RB1, KMT2D and ARID1A.	('GATA3', 'Gene', (81, 86))	('TP53', 'Gene', (204, 208))	('ARID1A', 'Gene', (225, 231))	('CK7', 'Gene', (71, 74))	('mutations', 'Var', (191, 200))	('KMT2D', 'Gene', (215, 220))	('ARID1A', 'Gene', '8289', (225, 231))	('RB1', 'Gene', (210, 213))	('TP53', 'Gene', '7157', (204, 208))	('CK7', 'Gene', '3855', (71, 74))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (161, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('KMT2D', 'Gene', '8085', (215, 220))	('RB1', 'Gene', '5925', (210, 213))	('p63', 'Gene', (76, 79))	('urothelial carcinoma', 'Disease', (161, 181))	('GATA3', 'Gene', '2625', (81, 86))	('urothelial differentiation', 'CPA', (35, 61))	('p63', 'Gene', '8626', (76, 79))
190597	32235944	However, in contrast to urothelial carcinoma, loss-of-function mutations in CDH1, and less commonly promoter hypermethylation of CDH1, drive the development of this variant and contribute to its aggressive biology.	('mutations', 'Var', (63, 72))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (24, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('aggressive biology', 'CPA', (195, 213))	('CDH1', 'Gene', (76, 80))	('CDH1', 'Gene', '999', (76, 80))	('CDH1', 'Gene', (129, 133))	('development', 'CPA', (145, 156))	('urothelial carcinoma', 'Disease', (24, 44))	('loss-of-function', 'NegReg', (46, 62))	('CDH1', 'Gene', '999', (129, 133))
190598	32235944	Targeted next-generation sequencing of macrodissected areas of plasmacytoid and urothelial histologies from the same tumour revealed shared mutations, suggesting that both arose from the same origin, but CDH1 mutation was limited to the plasmacytoid component, supporting the role of CDH1 loss in the development of this variant histology.	('loss', 'NegReg', (289, 293))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('CDH1', 'Gene', (284, 288))	('mutation', 'Var', (209, 217))	('CDH1', 'Gene', (204, 208))	('CDH1', 'Gene', '999', (204, 208))	('tumour', 'Disease', (117, 123))	('CDH1', 'Gene', '999', (284, 288))
190600	32235944	This tumour type is generally associated with high rates of ERBB2 alterations, mostly amplification and less commonly mutations.	('tumour', 'Disease', 'MESH:D009369', (5, 11))	('amplification', 'Var', (86, 99))	('ERBB2', 'Gene', '2064', (60, 65))	('ERBB2', 'Gene', (60, 65))	('mutations', 'Var', (118, 127))	('tumour', 'Disease', (5, 11))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))
190602	32235944	In addition, intratumoural heterogeneity of ERBB2 amplification is common.	('amplification', 'Var', (50, 63))	('ERBB2', 'Gene', '2064', (44, 49))	('ERBB2', 'Gene', (44, 49))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('tumour', 'Disease', (18, 24))
190603	32235944	In tumours with mixed micropapillary and NOS urothelial carcinoma, ERBB2 amplification was more common in micropapillary than NOS urothelial carcinoma components.	('ERBB2', 'Gene', '2064', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('common', 'Reg', (96, 102))	('NOS urothelial carcinoma component', 'Disease', 'MESH:D014523', (126, 160))	('ERBB2', 'Gene', (67, 72))	('NOS urothelial carcinoma', 'Disease', (41, 65))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('NOS urothelial carcinoma', 'Disease', 'MESH:D014523', (126, 150))	('NOS urothelial carcinoma component', 'Disease', (126, 160))	('NOS urothelial carcinoma', 'Disease', 'MESH:D014523', (41, 65))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('amplification', 'Var', (73, 86))
190604	32235944	Additionally, the rate of ERBB2 amplification in the NOS urothelial carcinoma component associated with micropapillary components was much higher than that in NOS urothelial carcinoma not mixed with micropapillary components.	('NOS urothelial carcinoma component', 'Disease', (53, 87))	('NOS urothelial carcinoma', 'Disease', 'MESH:D014523', (53, 77))	('ERBB2', 'Gene', (26, 31))	('ERBB2', 'Gene', '2064', (26, 31))	('amplification', 'Var', (32, 45))	('NOS urothelial carcinoma', 'Disease', (159, 183))	('NOS urothelial carcinoma', 'Disease', 'MESH:D014523', (159, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('NOS urothelial carcinoma component', 'Disease', 'MESH:D014523', (53, 87))	('associated', 'Reg', (88, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('higher', 'PosReg', (139, 145))
190609	32235944	A comprehensive study of sarcomatoid urothelial carcinoma showed that this tumour type is enriched with mutations in TP53, RB1 and PIK3CA and is associated with dysregulation of the epithelial-mesenchymal transition pathway and overexpression of epithelial-mesenchymal transition markers.	('sarcomatoid urothelial carcinoma', 'Disease', 'MESH:C538614', (25, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('overexpression', 'PosReg', (228, 242))	('TP53', 'Gene', (117, 121))	('PIK3CA', 'Gene', (131, 137))	('sarcomatoid urothelial carcinoma', 'Disease', (25, 57))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('mutations', 'Var', (104, 113))	('dysregulation', 'Var', (161, 174))	('tumour', 'Disease', (75, 81))	('RB1', 'Gene', (123, 126))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('246', '279'))	('TP53', 'Gene', '7157', (117, 121))	('PIK3CA', 'Gene', '5290', (131, 137))	('RB1', 'Gene', '5925', (123, 126))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('182', '215'))	('associated', 'Reg', (145, 155))	('epithelial-mesenchymal transition pathway', 'Pathway', (182, 223))
190611	32235944	Its morphological appearance is similar to small-cell carcinomas of other organs; similarly, it commonly harbours co-alterations in both TP53 and RB1 (REFS).	('small-cell carcinomas', 'Disease', 'MESH:D018288', (43, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('RB1', 'Gene', (146, 149))	('small-cell carcinomas', 'Disease', (43, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (54, 64))	('TP53', 'Gene', '7157', (137, 141))	('RB1', 'Gene', '5925', (146, 149))	('co-alterations', 'Var', (114, 128))	('TP53', 'Gene', (137, 141))
190612	32235944	However, TP53 and RB1 mutations are insufficient to explain development of small-cell carcinomas of the bladder, as these genetic alterations also often occur in urothelial carcinoma that does not exhibit features of small-cell or neuroendocrine differentiation.	('urothelial carcinoma', 'Disease', (162, 182))	('RB1', 'Gene', (18, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (162, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('TP53', 'Gene', '7157', (9, 13))	('RB1', 'Gene', '5925', (18, 21))	('TP53', 'Gene', (9, 13))	('small-cell carcinomas of the bladder', 'Disease', 'MESH:D001749', (75, 111))	('mutations', 'Var', (22, 31))	('occur', 'Reg', (153, 158))	('small-cell carcinomas of the bladder', 'Disease', (75, 111))
190615	32235944	A high level of chromosomal instability is observed in bladder small-cell carcinoma, including whole genome duplication in 72% of tumours.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('whole genome duplication', 'Var', (95, 119))	('bladder small-cell carcinoma', 'Disease', (55, 83))	('bladder small-cell carcinoma', 'Disease', 'MESH:D001749', (55, 83))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('tumours', 'Disease', (130, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('bladder small', 'Phenotype', 'HP:0005343', (55, 68))	('chromosomal instability', 'Phenotype', 'HP:0040012', (16, 39))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))
190625	32235944	Genetically, adenocarcinomas are different from urothelial carcinoma, as they generally lack mutations in chromatin-modifying genes and the TERT promoter region and resemble a subset of colorectal adenocarcinoma that is enriched in mutations in TP53, KRAS and SMAD4, as well as a small subset with EGFR and ERBB2 amplification.	('adenocarcinomas', 'Disease', 'MESH:D000230', (13, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('adenocarcinomas', 'Disease', (13, 28))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (48, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('298', '302'))	('mutations', 'Var', (232, 241))	('mutations', 'MPA', (93, 102))	('urothelial carcinoma', 'Disease', (48, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('TERT', 'Gene', (140, 144))	('TP53', 'Gene', '7157', (245, 249))	('SMAD4', 'Gene', (260, 265))	('TERT', 'Gene', '7015', (140, 144))	('EGFR', 'Gene', '1956', (298, 302))	('lack', 'NegReg', (88, 92))	('colorectal adenocarcinoma', 'Disease', (186, 211))	('chromatin', 'cellular_component', 'GO:0000785', ('106', '115'))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('SMAD4', 'Gene', '4089', (260, 265))	('KRAS', 'Gene', '3845', (251, 255))	('ERBB2', 'Gene', (307, 312))	('ERBB2', 'Gene', '2064', (307, 312))	('TP53', 'Gene', (245, 249))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (186, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('KRAS', 'Gene', (251, 255))	('EGFR', 'Gene', (298, 302))
190639	32235944	BLC2001, a phase II dose-escalation study of the FGFR3-targeted agent erdafitinib in 99 patients, demonstrated an overall response rate of 34% and a median duration of response of 5.5 months in patients with metastatic urothelial cancer that harbours FGFR3 mutations and overexpression.	('mutations', 'Var', (257, 266))	('patients', 'Species', '9606', (194, 202))	('FGFR3', 'Gene', '2261', (251, 256))	('erdafitinib', 'Chemical', 'MESH:C000604580', (70, 81))	('patients', 'Species', '9606', (88, 96))	('urothelial cancer', 'Disease', (219, 236))	('FGFR3', 'Gene', '2261', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('FGFR3', 'Gene', (251, 256))	('FGFR3', 'Gene', (49, 54))	('overexpression', 'PosReg', (271, 285))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('FGFR', 'molecular_function', 'GO:0005007', ('251', '255'))	('urothelial cancer', 'Disease', 'MESH:D014523', (219, 236))
190640	32235944	On the basis of these results, erdafitinib was approved by the FDA in 2019 for the treatment of patients with locally advanced or metastatic bladder cancer with FGFR3 or FGFR2 alterations and has progressed following platinum-containing chemotherapy.	('locally advanced', 'Disease', (110, 126))	('bladder cancer', 'Disease', (141, 155))	('erdafitinib', 'Chemical', 'MESH:C000604580', (31, 42))	('FGFR3', 'Gene', (161, 166))	('platinum', 'Chemical', 'MESH:D010984', (217, 225))	('FGFR2', 'Gene', (170, 175))	('alterations', 'Var', (176, 187))	('FGFR2', 'Gene', '2263', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (141, 155))	('FGFR', 'molecular_function', 'GO:0005007', ('161', '165'))	('patients', 'Species', '9606', (96, 104))	('FGFR', 'molecular_function', 'GO:0005007', ('170', '174'))	('bladder cancer', 'Disease', 'MESH:D001749', (141, 155))	('FGFR3', 'Gene', '2261', (161, 166))
190641	32235944	In addition, in a phase II trial, the pan-FGFR inhibitor infigratinib demonstrated a 25.4% response rate and a 38.8% disease stabilization rate in patients with metastatic urothelial carcinoma and FGFR alterations.	('FGFR', 'Gene', (197, 201))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (172, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('FGFR', 'molecular_function', 'GO:0005007', ('197', '201'))	('patients', 'Species', '9606', (147, 155))	('disease stabilization', 'CPA', (117, 138))	('infigratinib', 'Gene', (57, 69))	('urothelial carcinoma', 'Disease', (172, 192))	('infigratinib', 'Chemical', 'MESH:C568950', (57, 69))	('alterations', 'Var', (202, 213))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))
190642	32235944	Response to small molecular therapies targeting mutations or activation of FGFR might depend on intratumoural heterogeneity.	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('FGFR', 'Gene', (75, 79))	('tumour', 'Disease', (101, 107))	('activation', 'PosReg', (61, 71))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (48, 57))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
190665	32235944	For example, the currently limited genomic evaluation of Ta and T1 tumours suggests that FGFR3 alterations are a dominant driver, but the clonality of this mutation during selective intravesical treatment remains unclear.	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('tumours', 'Disease', (67, 74))	('FGFR3', 'Gene', (89, 94))	('alterations', 'Var', (95, 106))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('FGFR3', 'Gene', '2261', (89, 94))
190682	32677159	As a result, moderate to high MUC1-C expression was independently associated with poor survival in UC patients.	('patients', 'Species', '9606', (102, 110))	('associated', 'Reg', (66, 76))	('moderate', 'Var', (13, 21))	('poor', 'NegReg', (82, 86))	('MUC1', 'Gene', (30, 34))	('MUC1', 'Gene', '4582', (30, 34))	('expression', 'MPA', (37, 47))
190701	32677159	10 ,  11  We reported previously that CD44 variant isoforms stabilized xCT in a UC cell line, which enhanced intracellular GSH synthesis through the uptake of cystine, and contributed to the suppression of ROS production.	('GSH', 'Chemical', '-', (123, 126))	('xCT', 'Gene', '23657', (71, 74))	('ROS', 'Chemical', 'MESH:D017382', (206, 209))	('enhanced', 'PosReg', (100, 108))	('cystine', 'Chemical', 'MESH:D003553', (159, 166))	('intracellular GSH synthesis', 'MPA', (109, 136))	('synthesis', 'biological_process', 'GO:0009058', ('127', '136'))	('ROS production', 'MPA', (206, 220))	('suppression', 'NegReg', (191, 202))	('variant', 'Var', (43, 50))	('CD44', 'Gene', '960', (38, 42))	('intracellular', 'cellular_component', 'GO:0005622', ('109', '122'))	('uptake', 'biological_process', 'GO:0098657', ('149', '155'))	('uptake', 'biological_process', 'GO:0098739', ('149', '155'))	('xCT', 'Gene', (71, 74))	('CD44', 'Gene', (38, 42))	('uptake of cystine', 'MPA', (149, 166))
190702	32677159	12 ,  13  Thus, the stabilization of xCT may reinforce defenses against oxidative stress, resulting in CDDP resistance.	('xCT', 'Gene', '23657', (37, 40))	('CDDP resistance', 'MPA', (103, 118))	('stabilization', 'Var', (20, 33))	('oxidative stress', 'Phenotype', 'HP:0025464', (72, 88))	('reinforce', 'PosReg', (45, 54))	('xCT', 'Gene', (37, 40))	('defenses against oxidative stress', 'MPA', (55, 88))	('CDDP', 'Chemical', '-', (103, 107))
190734	32677159	These cells were passaged within 1 mo of drug exposure to confirm the persistence of CDDP resistance (Figure 2A, upper panel).	('CDDP', 'Gene', (85, 89))	('resistance', 'Var', (90, 100))	('CDDP', 'Chemical', '-', (85, 89))
190738	32677159	The primers used for reverse transcription and amplification were as follows: MUC1-C (Hs00159357_m1), ABCB1 (Hs00184500_m1), and beta-actin (Hs01060665_g1).	('reverse transcription', 'biological_process', 'GO:0001171', ('21', '42'))	('ABCB1', 'Gene', (102, 107))	('ABCB1', 'Gene', '5243', (102, 107))	('MUC1', 'Gene', (78, 82))	('Hs00159357_m1', 'Var', (86, 99))	('MUC1', 'Gene', '4582', (78, 82))	('Hs00184500_m1', 'Var', (109, 122))	('Hs01060665_g1', 'Var', (141, 154))
190741	32677159	The membrane was blocked at 4 C overnight in TBS containing 5% Phospho Blocker Blocking Reagent and 0.2% Tween-20, and then incubated at 4 C overnight with the primary Abs for MUC1-C (1:500 dilution), t-AKT (1:1000 dilution, Cell Signaling, Beverly, MA, USA), p-AKT (1:1000 dilution, Cell Signaling), t-mTOR (1:1000 dilution, Cell Signaling), p-mTOR (1:1000 dilution, Cell Signaling), t-S6K1 (1:1000 dilution, Cell Signaling), p-S6K1 (1:1000 dilution, Cell Signaling), xCT (1:500 dilution, Abcam), and MDR1 (1:250, dilution, Thermo Scientific).	('AKT', 'Gene', (262, 265))	('Signaling', 'biological_process', 'GO:0023052', ('457', '466'))	('S6K1', 'Gene', '6198', (387, 391))	('mTOR', 'Gene', (345, 349))	('xCT', 'Gene', (469, 472))	('mTOR', 'Gene', (303, 307))	('mTOR', 'Gene', '2475', (345, 349))	('Signaling', 'biological_process', 'GO:0023052', ('289', '298'))	('MDR1', 'Gene', (502, 506))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))	('AKT', 'Gene', '207', (262, 265))	('1:500 dilution', 'Var', (474, 488))	('mTOR', 'Gene', '2475', (303, 307))	('AKT', 'Gene', (203, 206))	('Signaling', 'biological_process', 'GO:0023052', ('415', '424'))	('MDR', 'molecular_function', 'GO:0004745', ('502', '505'))	('S6K1', 'Gene', (429, 433))	('Signaling', 'biological_process', 'GO:0023052', ('331', '340'))	('S6K1', 'Gene', (387, 391))	('MUC1', 'Gene', (176, 180))	('xCT', 'Gene', '23657', (469, 472))	('MUC1', 'Gene', '4582', (176, 180))	('S6K1', 'Gene', '6198', (429, 433))	('Signaling', 'biological_process', 'GO:0023052', ('230', '239'))	('AKT', 'Gene', '207', (203, 206))	('Signaling', 'biological_process', 'GO:0023052', ('373', '382'))
190766	32677159	Based on multivariate Cox regression analysis, moderate to high MUC1-C expression was one of the independent prognostic factors for both disease recurrence and cancer-specific death (hazard ratio (HR) = 2.22, P = .042 and HR = 3.04, P = .006, respectively) (Table 2).	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('MUC1', 'Gene', (64, 68))	('MUC1', 'Gene', '4582', (64, 68))	('moderate', 'Var', (47, 55))	('death', 'Disease', 'MESH:D003643', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('death', 'Disease', (176, 181))
190771	32677159	Multivariate analysis revealed that moderate to high MUC1-C expression remained as an independent risk factor for both disease recurrence and cancer-specific death (HR = 2.62, P = .007 and HR = 4.09, P = .001, respectively) (Table S1).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('moderate', 'Var', (36, 44))	('MUC1', 'Gene', (53, 57))	('MUC1', 'Gene', '4582', (53, 57))	('death', 'Disease', (158, 163))	('death', 'Disease', 'MESH:D003643', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('disease', 'Disease', (119, 126))	('cancer', 'Disease', (142, 148))
190775	32677159	To confirm the chemoresistance of the T24CR cells and UMUC3CR cell lines (Figure 2A upper panel), we compared the cell viabilities of WT and CR cells with various concentrations of CDDP for 48 h. The IC50 value was 3.8-fold higher in T24CR cells than in T24WT cells (17.1 mumol/L vs 4.5 mumol/L; Figure 2A middle panel).	('IC50', 'MPA', (200, 204))	('higher', 'PosReg', (224, 230))	('T24CR', 'Var', (234, 239))	('CDDP', 'Chemical', '-', (181, 185))
190777	32677159	According to the RT-PCR analysis, MUC1-C mRNA levels were higher in T24CR cells than in T24WT cells (the mRNA level in T24CR cells was 1.75 +- 0.15 relative to that of T24WT cells, P = .040, Figure 2B, upper panel) and in UMUC3CR cells than in UMUC3WT cells (the mRNA level in UMUC3CR cells was 1.83 +- 0.11 relative to that of UMUC3WT, P = .018; Figure 2B, lower panel).	('MUC1', 'Gene', (34, 38))	('MUC1', 'Gene', '4582', (34, 38))	('T24CR', 'Var', (68, 73))	('higher', 'PosReg', (58, 64))
190778	32677159	Furthermore, the western blot analysis indicated that MUC1-C protein levels were higher in both T24CR (Figure 2C, upper panel) and UMUC3CR (Figure 2C, lower panel) cells than in WT cells.	('higher', 'PosReg', (81, 87))	('UMUC3CR', 'Var', (131, 138))	('MUC1', 'Gene', (54, 58))	('MUC1', 'Gene', '4582', (54, 58))	('T24CR', 'Var', (96, 101))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
190779	32677159	We confirmed that the mRNA level of ABCB1 was higher in T24CR (Figure 2D, upper panel) and UMUC3CR (Figure 2D, lower panel) cells than in WT cells.	('ABCB1', 'Gene', (36, 41))	('ABCB1', 'Gene', '5243', (36, 41))	('higher', 'PosReg', (46, 52))	('T24CR', 'Var', (56, 61))	('mRNA level', 'MPA', (22, 32))
190787	32677159	By transfecting siRNA for MUC1, the relative mRNA level of MUC1-C was significantly down-regulated (Figure 3A; T24CR, upper panel; UMUC3CR, lower panel).	('MUC1', 'Gene', '4582', (59, 63))	('mRNA level', 'MPA', (45, 55))	('transfecting', 'Var', (3, 15))	('MUC1', 'Gene', (26, 30))	('MUC1', 'Gene', '4582', (26, 30))	('down-regulated', 'NegReg', (84, 98))	('MUC1', 'Gene', (59, 63))	('T24CR', 'Var', (111, 116))
190788	32677159	Western blot analysis indicated that the protein expression of MUC1-C was weaker in both CR cell lines transfected with both siMUC1#1 and siMUC1#2 than in those transfected with an NTC (Figure 3B: T24CR, upper panel; UMUC3CR, lower panel).	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('T24CR', 'Var', (197, 202))	('weaker', 'NegReg', (74, 80))	('protein expression', 'MPA', (41, 59))	('MUC1', 'Gene', (127, 131))	('MUC1', 'Gene', '4582', (127, 131))	('MUC1', 'Gene', (140, 144))	('MUC1', 'Gene', '4582', (140, 144))	('NTC', 'cellular_component', 'GO:0000974', ('181', '184'))	('MUC1', 'Gene', (63, 67))	('MUC1', 'Gene', '4582', (63, 67))
190792	32677159	To clarify whether ABCB1/MDR1 was responsible for resistance to CDDP, we silenced ABCB1 in CR cell lines and also used NVP-BEZ235 to confirm whether the PI3K-AKT-mTOR pathway was responsible for MDR1 expression (Figure S1).	('ABCB1', 'Gene', '5243', (82, 87))	('ABCB1', 'Gene', (19, 24))	('mTOR', 'Gene', (162, 166))	('ABCB1', 'Gene', (82, 87))	('mTOR', 'Gene', '2475', (162, 166))	('PI3K', 'molecular_function', 'GO:0016303', ('153', '157'))	('silenced', 'Var', (73, 81))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (119, 129))	('AKT', 'Gene', '207', (158, 161))	('CDDP', 'Chemical', '-', (64, 68))	('MDR', 'molecular_function', 'GO:0004745', ('25', '28'))	('MDR', 'molecular_function', 'GO:0004745', ('195', '198'))	('ABCB1', 'Gene', '5243', (19, 24))	('AKT', 'Gene', (158, 161))
190793	32677159	Silencing of ABCB1 in T24CR and UMUC3CR cells markedly increased the sensitivity to CDDP.	('sensitivity to CDDP', 'MPA', (69, 88))	('increased', 'PosReg', (55, 64))	('CDDP', 'Chemical', '-', (84, 88))	('ABCB1', 'Gene', (13, 18))	('ABCB1', 'Gene', '5243', (13, 18))	('Silencing', 'Var', (0, 9))
190794	32677159	Following the addition of NVP-BEZ235, the relative mRNA level of ABCB1 was significantly inhibited and the western blot analysis also revealed that protein expression of p-AKT and MDR1 were reduced by NVP-BEZ235 in a dose-dependent manner.	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (26, 36))	('AKT', 'Gene', (172, 175))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('ABCB1', 'Gene', (65, 70))	('inhibited', 'NegReg', (89, 98))	('NVP-BEZ235', 'Var', (201, 211))	('ABCB1', 'Gene', '5243', (65, 70))	('reduced', 'NegReg', (190, 197))	('MDR', 'molecular_function', 'GO:0004745', ('180', '183'))	('protein expression', 'MPA', (148, 166))	('AKT', 'Gene', '207', (172, 175))	('NVP-BEZ235', 'Var', (26, 36))	('MDR1', 'Gene', (180, 184))	('relative mRNA level', 'MPA', (42, 61))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (201, 211))
190796	32677159	In the western blot analysis, the protein expression of xCT was significantly higher in T24CR cells than in T24WT cells (Figure 4A).	('protein expression', 'MPA', (34, 52))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('T24CR', 'Var', (88, 93))	('higher', 'PosReg', (78, 84))	('xCT', 'Gene', (56, 59))	('xCT', 'Gene', '23657', (56, 59))
190799	32677159	Intracellular GSH levels in T24CR cells treated with 1 or 10 mumol/L CDDP were 2.53-fold and 2.00-fold higher than those in T24WT cells (P < .001, P = .001, respectively).	('GSH', 'Chemical', '-', (14, 17))	('Intracellular GSH levels', 'MPA', (0, 24))	('Intracellular', 'cellular_component', 'GO:0005622', ('0', '13'))	('CDDP', 'Var', (69, 73))	('higher', 'PosReg', (103, 109))	('CDDP', 'Chemical', '-', (69, 73))
190801	32677159	As shown in Figure 4C, the amount of intracellular ROS induced by CDDP in T24WT cells was significantly higher than that in T24WT cells treated with vehicle control (4.4-fold increase in cells with 10 micromol/L CDDP than those without in WT cells).	('amount', 'MPA', (27, 33))	('intracellular', 'cellular_component', 'GO:0005622', ('37', '50'))	('CDDP', 'Chemical', '-', (66, 70))	('T24WT', 'Var', (74, 79))	('ROS', 'Chemical', 'MESH:D017382', (51, 54))	('CDDP', 'Var', (66, 70))	('increase', 'PosReg', (175, 183))	('higher', 'PosReg', (104, 110))	('CDDP', 'Chemical', '-', (212, 216))
190805	32677159	As a result, after the transfection with siMUC1, the amount of intracellular ROS in T24CR cells treated with 10 muM CDDP was significantly higher than that in T24CR cells treated with vehicle control (Figure 4F).	('transfection', 'Var', (23, 35))	('CDDP', 'Var', (116, 120))	('amount of intracellular', 'MPA', (53, 76))	('ROS', 'Chemical', 'MESH:D017382', (77, 80))	('MUC1', 'Gene', (43, 47))	('MUC1', 'Gene', '4582', (43, 47))	('CDDP', 'Chemical', '-', (116, 120))	('ROS', 'Protein', (77, 80))	('higher', 'PosReg', (139, 145))	('intracellular', 'cellular_component', 'GO:0005622', ('63', '76'))
190815	32677159	On day 25 after the start of treatment, the mean +- SD of tumor volume in mice treated with GO-203 alone was 480.4 +- 93.2 mm3, which was significantly lower than that in mice treated with vehicle control (936.3 +- 134.1 mm3, P = .012).	('mice', 'Species', '10090', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mice', 'Species', '10090', (171, 175))	('GO-203', 'Chemical', 'MESH:C582521', (92, 98))	('lower', 'NegReg', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('GO-203', 'Var', (92, 98))
190816	32677159	Furthermore, the mean +- SD of tumor volume in mice treated with the combination of CDDP and GO-203 was 89.8 +- 65.5 mm3, which was significantly lower than that in mice treated with GO-203 alone (P = .044) and CDDP alone (847.9 +- 144.0 mm3, P < .001; Figure 5D).	('GO-203', 'Chemical', 'MESH:C582521', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('GO-203', 'Chemical', 'MESH:C582521', (183, 189))	('mice', 'Species', '10090', (165, 169))	('tumor', 'Disease', (31, 36))	('CDDP', 'Chemical', '-', (211, 215))	('CDDP', 'Chemical', '-', (84, 88))	('CDDP', 'Gene', (84, 88))	('lower', 'NegReg', (146, 151))	('GO-203', 'Var', (93, 99))	('mice', 'Species', '10090', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
190826	32677159	These results suggested that targeting ABCB1 may recover CDDP sensitivity in UC cells even under a CR environment.	('CDDP sensitivity', 'MPA', (57, 73))	('CDDP', 'Chemical', '-', (57, 61))	('recover', 'PosReg', (49, 56))	('ABCB1', 'Gene', (39, 44))	('ABCB1', 'Gene', '5243', (39, 44))	('targeting', 'Var', (29, 38))
190833	32677159	The addition of the AKT-mTOR inhibitor, NVP-BEZ235, clearly resulted in the inhibition of MDR1 protein expression and recovered certain cytotoxic effects of CDDP in CR cells.	('AKT', 'Gene', (20, 23))	('inhibition', 'NegReg', (76, 86))	('MDR1 protein', 'Protein', (90, 102))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (40, 50))	('recovered', 'PosReg', (118, 127))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('mTOR', 'Gene', '2475', (24, 28))	('NVP-BEZ235', 'Var', (40, 50))	('AKT', 'Gene', '207', (20, 23))	('mTOR', 'Gene', (24, 28))	('CDDP', 'Chemical', '-', (157, 161))	('cytotoxic effects', 'CPA', (136, 153))	('MDR', 'molecular_function', 'GO:0004745', ('90', '93'))
190835	32677159	Thus, we found that knockdown of MUC1 recovered CDDP sensitivity in CR cells by suppressing MDR1 expression.	('CDDP', 'Chemical', '-', (48, 52))	('MDR1', 'Gene', (92, 96))	('CDDP sensitivity', 'MPA', (48, 64))	('MDR', 'molecular_function', 'GO:0004745', ('92', '95'))	('MUC1', 'Gene', (33, 37))	('MUC1', 'Gene', '4582', (33, 37))	('suppressing', 'NegReg', (80, 91))	('knockdown', 'Var', (20, 29))	('expression', 'MPA', (97, 107))
190839	32677159	29  Moreover, we recently found that MUC1-C stabilized xCT by creating a link with a CD44v9 variant at the cell membrane and, thus, enhanced cysteine uptake for GSH synthesis in breast cancer.	('link', 'Interaction', (73, 77))	('uptake', 'biological_process', 'GO:0098657', ('150', '156'))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('xCT', 'Gene', (55, 58))	('MUC1', 'Gene', (37, 41))	('MUC1', 'Gene', '4582', (37, 41))	('uptake', 'biological_process', 'GO:0098739', ('150', '156'))	('cysteine', 'Chemical', 'MESH:D003545', (141, 149))	('cell membrane', 'cellular_component', 'GO:0005886', ('107', '120'))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('enhanced', 'PosReg', (132, 140))	('synthesis', 'biological_process', 'GO:0009058', ('165', '174'))	('GSH', 'Chemical', '-', (161, 164))	('CD44', 'Gene', '960', (85, 89))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('variant', 'Var', (92, 99))	('breast cancer', 'Disease', (178, 191))	('CD44', 'Gene', (85, 89))	('cysteine uptake for GSH synthesis', 'MPA', (141, 174))	('xCT', 'Gene', '23657', (55, 58))
190846	32677159	31 ,  32 ,  33 ,  34  The present study demonstrated that the targeting of MUC1-C with GO-203 inhibited p-AKT in UC cells, which suppressed the downstream target, MDR1.	('AKT', 'Gene', (106, 109))	('GO-203', 'Chemical', 'MESH:C582521', (87, 93))	('suppressed', 'NegReg', (129, 139))	('MDR1', 'MPA', (163, 167))	('MUC1', 'Gene', (75, 79))	('MUC1', 'Gene', '4582', (75, 79))	('GO-203', 'Gene', (87, 93))	('AKT', 'Gene', '207', (106, 109))	('targeting', 'Var', (62, 71))	('MDR', 'molecular_function', 'GO:0004745', ('163', '166'))	('inhibited', 'NegReg', (94, 103))
190847	32677159	Furthermore, GO-203 also destabilized the xCT-MUC1-C link by directly inhibiting MUC1-C homodimerization.	('GO-203', 'Var', (13, 19))	('MUC1', 'Gene', (46, 50))	('MUC1', 'Gene', '4582', (46, 50))	('xCT', 'Gene', (42, 45))	('GO-203', 'Chemical', 'MESH:C582521', (13, 19))	('inhibiting', 'NegReg', (70, 80))	('MUC1', 'Gene', (81, 85))	('MUC1', 'Gene', '4582', (81, 85))	('destabilized', 'NegReg', (25, 37))	('xCT', 'Gene', '23657', (42, 45))
190850	32677159	Notably, while UMUC3CR tumors did not respond to CDDP alone because of acquired chemoresistance, the combination of GO-203 with CDDP revealed significant tumor regression.	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('CDDP', 'Chemical', '-', (128, 132))	('GO-203', 'Chemical', 'MESH:C582521', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('combination', 'Interaction', (101, 112))	('CDDP', 'Chemical', '-', (49, 53))	('GO-203', 'Var', (116, 122))	('tumor', 'Disease', (154, 159))
190867	32245016	Blockade of the PD-1 /PDL-1 pathway can enhance anti-tumor T cell reactivity and promotes immune control over the cancerous cells.	('PD-1', 'Gene', '5133', (16, 20))	('PDL-1', 'Gene', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancerous', 'Disease', (114, 123))	('promotes', 'PosReg', (81, 89))	('Blockade', 'Var', (0, 8))	('PDL-1', 'Gene', '29126', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('immune control over the', 'CPA', (90, 113))	('tumor', 'Disease', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancerous', 'Disease', 'MESH:D009369', (114, 123))	('enhance', 'PosReg', (40, 47))	('PD-1', 'Gene', (16, 20))
190897	32245016	As such, blockade of the PD-1 pathway can enhance T cell anti-tumor activity and thereby immune control and killing on the cancerous cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('immune control', 'CPA', (89, 103))	('cancerous', 'Disease', 'MESH:D009369', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('PD-1', 'Gene', (25, 29))	('enhance', 'PosReg', (42, 49))	('enhance T cell', 'Phenotype', 'HP:0100828', (42, 56))	('PD-1', 'Gene', '5133', (25, 29))	('tumor', 'Disease', (62, 67))	('cancerous', 'Disease', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('blockade', 'Var', (9, 17))
190909	32245016	This trial showed that ORR improved with fewer toxic effects with nivolumab against standard-of-care chemotherapy among patients with advanced, unresectable/metastatic melanoma who progressed following ipilimumab treatment, or a BRAF inhibitor if BRAF mutation positive (Category 1).	('ORR', 'MPA', (23, 26))	('BRAF', 'Gene', (229, 233))	('ipilimumab', 'Chemical', 'MESH:D000074324', (202, 212))	('BRAF', 'Gene', '673', (247, 251))	('BRAF', 'Gene', (247, 251))	('patients', 'Species', '9606', (120, 128))	('BRAF', 'Gene', '673', (229, 233))	('nivolumab', 'Chemical', 'MESH:D000077594', (66, 75))	('mutation positive', 'Var', (252, 269))	('melanoma', 'Disease', (168, 176))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
190911	32245016	The FDA again expanded the indication of this combination regimen to metastatic melanoma across BRAF mutation status on 23 January 2016 based on the improved progression-free survival (PFS) rate noted in the CheckMate-067 trial (Category 1).	('progression-free survival', 'CPA', (158, 183))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('improved', 'PosReg', (149, 157))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('mutation', 'Var', (101, 109))
190915	32245016	On 10 October 2015, the FDA further expanded its use in metastatic non-squamous NSCLC patients who progressed on first-line platinum-based chemotherapy in a similar setting; this study included patients with actionable mutations such as EGFR and ALK mutation who progressed after appropriate target therapy, per the CheckMate-057 trial, which resulted in increased survival and decreased immunotherapy-related toxicity (Category 1).	('toxicity', 'Disease', (410, 418))	('ALK', 'Gene', (246, 249))	('platinum', 'Chemical', 'MESH:D010984', (124, 132))	('mutation', 'Var', (250, 258))	('decreased', 'NegReg', (378, 387))	('patients', 'Species', '9606', (194, 202))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (67, 85))	('EGFR', 'Gene', '1956', (237, 241))	('EGFR', 'molecular_function', 'GO:0005006', ('237', '241'))	('increased', 'PosReg', (355, 364))	('nab', 'Chemical', '-', (213, 216))	('EGFR', 'Gene', (237, 241))	('ALK', 'Gene', '238', (246, 249))	('non-squamous NSCLC', 'Disease', (67, 85))	('toxicity', 'Disease', 'MESH:D064420', (410, 418))	('mutations', 'Var', (219, 228))	('patients', 'Species', '9606', (86, 94))
190926	32245016	Nivolumab was studied for metastatic colorectal cancer (mCRC) with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) that had progressed on a combination of fluoropyrimidine, oxaliplatin, and irinotecan.	('colorectal cancer', 'Disease', (37, 54))	('fluoropyrimidine', 'Chemical', '-', (183, 199))	('dMMR', 'Chemical', '-', (137, 141))	('irinotecan', 'Chemical', 'MESH:D000077146', (218, 228))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (37, 54))	('Nivolumab', 'Chemical', 'MESH:D000077594', (0, 9))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (201, 212))	('mismatch', 'Var', (110, 118))	('mismatch repair', 'biological_process', 'GO:0006298', ('110', '125'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (37, 54))
190934	32245016	The FDA further expanded its approval for previously untreated advanced melanoma regardless of BRAF mutation status on 18 December 2015 (Category 2A), based on the Keynote-006 trial, a phase 3 randomized trial comparing pembrolizumab against ipilimumab (then standard therapy), which resulted in a prolonged OS and PFS with less toxicity than ipilimumab.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('toxicity', 'Disease', 'MESH:D064420', (329, 337))	('PFS', 'MPA', (315, 318))	('melanoma', 'Disease', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('BRAF', 'Gene', '673', (95, 99))	('toxicity', 'Disease', (329, 337))	('ipilimumab', 'Chemical', 'MESH:D000074324', (242, 252))	('mutation', 'Var', (100, 108))	('BRAF', 'Gene', (95, 99))	('ipilimumab', 'Chemical', 'MESH:D000074324', (343, 353))	('pembrolizumab', 'Chemical', 'MESH:C582435', (220, 233))
190948	32245016	On 11 April 2019, the FDA further expanded its approval of pembrolizumab in NSCLC as a first-line monotherapy for patients with stage 3 NSCLC who cannot undergo surgical resection as well as chemoradiation or metastatic NSCLC with PDL-1 expression >=1% and no EGFR or ALK mutation.	('EGFR', 'Gene', (260, 264))	('NSCLC', 'Disease', (220, 225))	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('>=1%', 'Var', (248, 252))	('ALK', 'Gene', '238', (268, 271))	('NSCLC', 'Disease', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (220, 225))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('EGFR', 'molecular_function', 'GO:0005006', ('260', '264'))	('pembrolizumab', 'Chemical', 'MESH:C582435', (59, 72))	('EGFR', 'Gene', '1956', (260, 264))	('PDL-1', 'Gene', '29126', (231, 236))	('ALK', 'Gene', (268, 271))	('NSCLC', 'Disease', (136, 141))	('PDL-1', 'Gene', (231, 236))	('patients', 'Species', '9606', (114, 122))
191001	29190997	On the other, the oncogenic changes may induce a chronically inflammatory microenvironment which has many tumor-promoting effects on the cell proliferation, angiogenesis, invasion and metastasis of bladder cancer.	('metastasis of bladder cancer', 'Disease', 'MESH:D009362', (184, 212))	('metastasis of bladder cancer', 'Disease', (184, 212))	('men', 'Species', '9606', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cell proliferation', 'CPA', (137, 155))	('invasion', 'CPA', (171, 179))	('angiogenesis', 'biological_process', 'GO:0001525', ('157', '169'))	('oncogenic changes', 'Var', (18, 35))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cell proliferation', 'biological_process', 'GO:0008283', ('137', '155'))	('angiogenesis', 'CPA', (157, 169))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (198, 212))	('induce', 'Reg', (40, 46))	('tumor', 'Disease', (106, 111))
191008	29190997	The majority of these studies show UTI not only increases the risk of BCa but also is associated with worse BCa outcomes, in both men and women.	('men', 'Species', '9606', (140, 143))	('BCa', 'Phenotype', 'HP:0009725', (108, 111))	('BCa', 'Disease', (108, 111))	('increases', 'PosReg', (48, 57))	('BCa', 'Phenotype', 'HP:0009725', (70, 73))	('BCa', 'Disease', (70, 73))	('UTI', 'Var', (35, 38))	('women', 'Species', '9606', (138, 143))	('men', 'Species', '9606', (130, 133))
191024	29190997	Currently, the molecular subtypes of BCa have been identified and HPV infection may have a role in the development of a small percentage of urothelial carcinoma patients with amplified and overexpressed BCL2L1.	('overexpressed', 'PosReg', (189, 202))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (140, 160))	('HPV infection', 'Disease', 'MESH:D030361', (66, 79))	('men', 'Species', '9606', (110, 113))	('BCL2L1', 'Gene', (203, 209))	('patients', 'Species', '9606', (161, 169))	('BCa', 'Phenotype', 'HP:0009725', (37, 40))	('HPV infection', 'Disease', (66, 79))	('urothelial carcinoma', 'Disease', (140, 160))	('BCL2L1', 'Gene', '598', (203, 209))	('BCL2', 'molecular_function', 'GO:0015283', ('203', '207'))	('amplified', 'Var', (175, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
191048	29190997	Accumulating evidence shows that induction of MDSCs is an important immune-evading strategy for cancer cells, which is linked to their immunosuppressive activity and the capacity to impair T cell function.	('impair', 'NegReg', (182, 188))	('impair T cell function', 'Phenotype', 'HP:0005435', (182, 204))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MDSCs', 'Var', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('T cell function', 'CPA', (189, 204))	('cancer', 'Disease', (96, 102))
191066	29190997	The number of MCs within and around the tumor may be a useful prognostic indicator in patients with bladder carcinomas and MCs density is significantly higher in high-grade BTCC than low-grade BTCC.	('bladder carcinoma', 'Phenotype', 'HP:0002862', (100, 117))	('higher', 'PosReg', (152, 158))	('BTCC', 'Phenotype', 'HP:0006740', (193, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (100, 118))	('bladder carcinomas', 'Disease', (100, 118))	('high-grade', 'Var', (162, 172))	('MCs', 'cellular_component', 'GO:0044232', ('14', '17'))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('BTCC', 'Phenotype', 'HP:0006740', (173, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('bladder carcinomas', 'Disease', 'MESH:D001749', (100, 118))	('MCs', 'cellular_component', 'GO:0044232', ('123', '126'))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('patients', 'Species', '9606', (86, 94))
191081	29190997	Low levels of IL-1alpha mRNA expression are associated with an increased risk for BCa-specific death (Table 1).	('IL-1', 'molecular_function', 'GO:0005149', ('14', '18'))	('IL-1alpha', 'Gene', '3552', (14, 23))	('BCa', 'Phenotype', 'HP:0009725', (82, 85))	('Low levels', 'Var', (0, 10))	('BCa-specific death', 'Disease', (82, 100))	('IL-1alpha', 'Gene', (14, 23))
191110	29190997	JAKs mediate intracellular signaling cascades principally through creating STAT docking sites via phosphorylation of tyrosine residue.	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('phosphorylation', 'biological_process', 'GO:0016310', ('98', '113'))	('tyrosine', 'Chemical', 'MESH:D014443', (117, 125))	('JAKs', 'Gene', '3716;3717;3718;7297', (0, 4))	('STAT docking sites', 'MPA', (75, 93))	('JAKs', 'Gene', (0, 4))	('phosphorylation', 'Var', (98, 113))	('intracellular', 'cellular_component', 'GO:0005622', ('13', '26'))	('mediate', 'Reg', (5, 12))
191112	29190997	STAT3 is a member of STAT family and its phosphorylation at Tyr705 or Ser727 is widely mediated in a variety of cellular contexts, especially JAK2.	('JAK2', 'Gene', (142, 146))	('Ser', 'cellular_component', 'GO:0005790', ('70', '73'))	('phosphorylation', 'biological_process', 'GO:0016310', ('41', '56'))	('JAK', 'molecular_function', 'GO:0004713', ('142', '145'))	('Ser727', 'Var', (70, 76))	('Ser727', 'Chemical', '-', (70, 76))	('phosphorylation', 'MPA', (41, 56))	('JAK2', 'Gene', '3717', (142, 146))	('STAT3', 'Gene', '6774', (0, 5))	('mediated', 'Reg', (87, 95))	('STAT3', 'Gene', (0, 5))	('Tyr705', 'Chemical', '-', (60, 66))
191115	29190997	By contrast, the silencing of STAT3 significantly suppresses proliferation of T24 BC cells both in vitro and in vivo.	('suppresses', 'NegReg', (50, 60))	('STAT3', 'Gene', '6774', (30, 35))	('STAT3', 'Gene', (30, 35))	('proliferation', 'CPA', (61, 74))	('silencing', 'Var', (17, 26))
191116	29190997	Therefore, inhibition of JAK-STAT3 signaling pathway provides us a potential therapeutic approach for BCa.	('JAK', 'molecular_function', 'GO:0004713', ('25', '28'))	('STAT3', 'Gene', '6774', (29, 34))	('STAT3', 'Gene', (29, 34))	('inhibition', 'Var', (11, 21))	('signaling pathway', 'biological_process', 'GO:0007165', ('35', '52'))	('BCa', 'Phenotype', 'HP:0009725', (102, 105))	('BCa', 'Disease', (102, 105))
191125	29190997	The non-canonical pathway (also known as alternative pathway) does not require the trimeric IKK complex and depends on the inducible processing of p100, a molecule functioning as both the precursor of p52 and a RelB-specific inhibitor.	('p100', 'Var', (147, 151))	('p52', 'Gene', (201, 204))	('RelB', 'Gene', (211, 215))	('p52', 'Gene', '4791', (201, 204))	('RelB', 'Gene', '5971', (211, 215))	('trimeric IKK complex', 'cellular_component', 'GO:0008385', ('83', '103'))	('non-canonical pathway', 'Pathway', (4, 25))	('IKK', 'molecular_function', 'GO:0008384', ('92', '95'))
191135	29190997	And then, AKT phosphorylation disrupts the interaction between tuberous sclerosis protein complex 1 (TSC1) and TSC2, and further inhibits the activation of Rheb that is a suppressor of mTOR function.	('phosphorylation', 'Var', (14, 29))	('TSC1', 'Gene', (101, 105))	('TSC2', 'Gene', (111, 115))	('TSC1', 'Gene', '7248', (101, 105))	('AKT', 'Gene', '207', (10, 13))	('activation', 'MPA', (142, 152))	('mTOR', 'Gene', (185, 189))	('tuberous sclerosis protein complex 1', 'Gene', (63, 99))	('Rheb', 'Gene', '6009', (156, 160))	('mTOR', 'Gene', '2475', (185, 189))	('disrupts', 'NegReg', (30, 38))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('inhibits', 'NegReg', (129, 137))	('tuberous sclerosis protein complex 1', 'Gene', '7248', (63, 99))	('interaction', 'Interaction', (43, 54))	('Rheb', 'Gene', (156, 160))	('protein complex', 'cellular_component', 'GO:0032991', ('82', '97'))	('AKT', 'Gene', (10, 13))	('TSC2', 'Gene', '7249', (111, 115))
191141	29190997	evaluated 231 single-nucleotide polymorphisms (SNPs) in 19 genes in the PI3K-AKT-mTOR signaling pathway and they found four SNPs in raptor that were significantly associated with increased risk of BCa.	('single-nucleotide polymorphisms', 'Var', (14, 45))	('mTOR', 'Gene', '2475', (81, 85))	('AKT', 'Gene', '207', (77, 80))	('signaling pathway', 'biological_process', 'GO:0007165', ('86', '103'))	('BCa', 'Phenotype', 'HP:0009725', (197, 200))	('associated', 'Reg', (163, 173))	('BCa', 'Disease', (197, 200))	('PI3K', 'molecular_function', 'GO:0016303', ('72', '76'))	('mTOR', 'Gene', (81, 85))	('AKT', 'Gene', (77, 80))	('SNPs', 'Var', (124, 128))
191143	29190997	Nicotine could induce acquired chemoresistance and increase tumor growth through activation of the PI3K-AKT-mTOR pathway in BCa.	('mTOR', 'Gene', (108, 112))	('mTOR', 'Gene', '2475', (108, 112))	('increase tumor', 'Disease', 'MESH:D009369', (51, 65))	('PI3K', 'molecular_function', 'GO:0016303', ('99', '103'))	('BCa', 'Phenotype', 'HP:0009725', (124, 127))	('AKT', 'Gene', (104, 107))	('BCa', 'Disease', (124, 127))	('Nicotine', 'Var', (0, 8))	('Nicotine', 'Chemical', 'MESH:D009538', (0, 8))	('activation', 'PosReg', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('increase tumor', 'Disease', (51, 65))	('acquired chemoresistance', 'CPA', (22, 46))	('AKT', 'Gene', '207', (104, 107))	('induce', 'PosReg', (15, 21))
191146	29190997	miRNA dysregulation exhibits great regulatory potential during organismal development, cell proliferation and death, immunity, and inflammation.	('cell proliferation', 'biological_process', 'GO:0008283', ('87', '105'))	('inflammation', 'Disease', 'MESH:D007249', (131, 143))	('inflammation', 'Disease', (131, 143))	('dysregulation', 'Var', (6, 19))	('men', 'Species', '9606', (81, 84))	('inflammation', 'biological_process', 'GO:0006954', ('131', '143'))	('miRNA', 'Gene', (0, 5))
191149	29190997	MiRNA-221 silencing promoted cell apoptosis induced by TRAIL in T24 cells.	('cell apoptosis', 'CPA', (29, 43))	('apoptosis', 'biological_process', 'GO:0006915', ('34', '43'))	('MiRNA-221', 'Gene', '407006', (0, 9))	('MiRNA-221', 'Gene', (0, 9))	('TRAIL', 'Gene', '8743', (55, 60))	('promoted', 'PosReg', (20, 28))	('TRAIL', 'Gene', (55, 60))	('apoptosis', 'biological_process', 'GO:0097194', ('34', '43'))	('silencing', 'Var', (10, 19))
191171	29190997	IL-15 gene therapy inhibits cell survival in an orthotopic BCa model through inducing tumor-specific cytotoxic T lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cell survival in an orthotopic', 'CPA', (28, 58))	('IL-15', 'Gene', (0, 5))	('gene therapy', 'Var', (6, 18))	('tumor', 'Disease', (86, 91))	('IL-15', 'molecular_function', 'GO:0016170', ('0', '5'))	('IL-15', 'Gene', '3600', (0, 5))	('inducing', 'PosReg', (77, 85))	('inhibits', 'NegReg', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('BCa', 'Phenotype', 'HP:0009725', (59, 62))
191185	29190997	To assess the efficacy of the combination of pembrolizumab with conventional chemotherapeutics, several clinical trials (NCT02335424, NCT02351739 and NCT022456436) have been launched.	('pembrolizumab', 'Chemical', 'MESH:C582435', (45, 58))	('NCT022456436', 'Var', (150, 162))	('NCT02335424', 'Var', (121, 132))	('NCT02351739', 'Var', (134, 145))
191226	28241422	Androgen supplementation in castrated male rats also re-augmented the thickness of urothelium, the quantity of smooth muscle fibers, and the number of vessels in their bladders.	('supplementation', 'Var', (9, 24))	('rats', 'Species', '10116', (43, 47))	('rat', 'Species', '10116', (32, 35))	('rat', 'Species', '10116', (43, 46))	('men', 'Species', '9606', (15, 18))	('re-augmented', 'PosReg', (53, 65))	('thickness of urothelium', 'CPA', (70, 93))	('men', 'Species', '9606', (59, 62))
191246	28241422	Two studies indicated a correlation between AR positivity and a lower risk of tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('AR positivity', 'Var', (44, 57))	('tumor', 'Disease', (78, 83))
191251	28241422	In addition to the differential expression of AR protein, genetic alterations involving the AR gene have been documented in bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (124, 138))	('bladder cancer', 'Disease', (124, 138))	('documented', 'Reg', (110, 120))	('rat', 'Species', '10116', (70, 73))	('men', 'Species', '9606', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (124, 138))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('genetic alterations', 'Var', (58, 77))	('AR gene', 'Gene', (92, 99))
191254	28241422	Men and women who had 23 (odds ratio = 2.09) and 44 (cumulative; odds ratio = 4.95) CAG repeats were found to have a significantly elevated risk of urothelial carcinoma, compared to those with longer CAG.	('urothelial carcinoma', 'Disease', (148, 168))	('rat', 'Species', '10116', (70, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('CAG', 'Chemical', '-', (84, 87))	('women', 'Species', '9606', (8, 13))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (148, 168))	('CAG', 'Chemical', '-', (200, 203))	('CAG repeats', 'Var', (84, 95))	('rat', 'Species', '10116', (31, 34))	('Men', 'Species', '9606', (0, 3))
191256	28241422	Moreover, there appeared to be a link between shorter CAG repeat length and more aggressive features of bladder cancer in a relatively small number of cases.	('bladder cancer', 'Disease', (104, 118))	('CAG', 'Protein', (54, 57))	('CAG', 'Chemical', '-', (54, 57))	('shorter', 'Var', (46, 53))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (104, 118))
191270	28241422	Otherwise, because only DBD in exon 2 of the AR gene was disrupted in the ARKO mice, the androgen effect on bladder tumorigenesis might be mediated through the truncated AR protein that is unable to bind to DNA.	('mediated', 'Reg', (139, 147))	('bladder tumor', 'Disease', 'MESH:D001749', (108, 121))	('bladder tumor', 'Phenotype', 'HP:0009725', (108, 121))	('DNA', 'cellular_component', 'GO:0005574', ('207', '210'))	('mice', 'Species', '10090', (79, 83))	('truncated', 'Var', (160, 169))	('ARKO', 'Gene', '13075', (74, 78))	('bladder tumor', 'Disease', (108, 121))	('AR protein', 'Protein', (170, 180))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('protein', 'cellular_component', 'GO:0003675', ('173', '180'))	('ARKO', 'Gene', (74, 78))
191273	28241422	In addition, castration inhibited the development of bladder tumors in another transgenic mouse model in which constitutive active beta-catenin in the urothelial basal cells spontaneously induced high-grade urothelial cancer.	('urothelial cancer', 'Disease', 'MESH:D014523', (207, 224))	('men', 'Species', '9606', (45, 48))	('bladder tumors', 'Disease', 'MESH:D001749', (53, 67))	('bladder tumors', 'Phenotype', 'HP:0009725', (53, 67))	('induced', 'Reg', (188, 195))	('mouse', 'Species', '10090', (90, 95))	('inhibited', 'NegReg', (24, 33))	('bladder tumor', 'Phenotype', 'HP:0009725', (53, 66))	('bladder tumors', 'Disease', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('urothelial cancer', 'Disease', (207, 224))	('rat', 'Species', '10116', (17, 20))	('constitutive', 'Var', (111, 123))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
191278	28241422	These enzymes include cytochrome P450 (e.g., CYP4B1) and UDP-glucuronosyltransferase (e.g., UGT1A subtypes) that are known to involve the activation and detoxification, respectively, of bladder carcinogens, such as aromatic amines.	('aromatic amines', 'Chemical', '-', (215, 230))	('detoxification', 'biological_process', 'GO:0098754', ('153', '167'))	('UGT1A', 'Gene', (92, 97))	('CYP4B1', 'Var', (45, 51))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('22', '37'))	('detoxification', 'MPA', (153, 167))	('bladder carcinogens', 'Disease', 'MESH:D001745', (186, 205))	('cytochrome P450', 'molecular_function', 'GO:0019825', ('22', '37'))	('bladder carcinogens', 'Disease', (186, 205))	('cytochrome P450', 'Enzyme', (22, 37))	('UGT1A', 'Gene', '7361', (92, 97))	('UDP-glucuronosyltransferase', 'Enzyme', (57, 84))
191282	28241422	Meanwhile, in SVHUC human normal urothelial cells stably expressing wild-type full-length AR, DHT treatment resulted in considerable decreases in the expression of all UGT1A subtypes, and an anti-androgen hydroxyflutamide blocked the DHT effects.	('human', 'Species', '9606', (20, 25))	('expression', 'MPA', (150, 160))	('DHT', 'Chemical', 'MESH:D013196', (94, 97))	('men', 'Species', '9606', (103, 106))	('UGT1A', 'Gene', '7361', (168, 173))	('DHT', 'Var', (94, 97))	('DHT', 'Chemical', 'MESH:D013196', (234, 237))	('UGT1A', 'Gene', (168, 173))	('decreases', 'NegReg', (133, 142))	('hydroxyflutamide', 'Chemical', 'MESH:C014290', (205, 221))
191292	28241422	Accordingly, AR knockdown as well as treatment with AR antagonists inhibited the cell proliferation of bladder cancer lines cultured with androgens.	('men', 'Species', '9606', (42, 45))	('inhibited', 'NegReg', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('bladder cancer', 'Phenotype', 'HP:0009725', (103, 117))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('knockdown', 'Var', (16, 25))	('bladder cancer', 'Disease', 'MESH:D001749', (103, 117))	('bladder cancer', 'Disease', (103, 117))	('rat', 'Species', '10116', (93, 96))
191295	28241422	In a transgenic mouse model expressing SV40 large T antigen specifically in urothelium (via uroplakin II) and spontaneously developing bladder cancer, castration after tumor formation retarded its growth, which was restored by DHT supplement.	('retarded', 'Disease', 'MESH:D008607', (184, 192))	('bladder cancer', 'Disease', 'MESH:D001749', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('DHT', 'Chemical', 'MESH:D013196', (227, 230))	('SV40 large T', 'Var', (39, 51))	('tumor', 'Disease', (168, 173))	('bladder cancer', 'Disease', (135, 149))	('formation', 'biological_process', 'GO:0009058', ('174', '183'))	('bladder cancer', 'Phenotype', 'HP:0009725', (135, 149))	('retarded', 'Disease', (184, 192))	('mouse', 'Species', '10090', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('rat', 'Species', '10116', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('men', 'Species', '9606', (237, 240))
191297	28241422	Then, AR knockdown or anti-androgen treatment was shown to inhibit them.	('inhibit', 'NegReg', (59, 66))	('men', 'Species', '9606', (41, 44))	('knockdown', 'Var', (9, 18))
191309	28241422	Furthermore, androgen or anti-androgen treatment resulted in a decrease or an increase, respectively, in sensitivity to cisplatin in AR-positive bladder cancer cells, presumably via modulating the activity of a key factor of cisplatin resistance NF-kappaB.	('anti-androgen', 'Var', (25, 38))	('positive bladder', 'Phenotype', 'HP:0100645', (136, 152))	('men', 'Species', '9606', (44, 47))	('modulating', 'Reg', (182, 192))	('cisplatin', 'Chemical', 'MESH:D002945', (225, 234))	('activity', 'MPA', (197, 205))	('increase', 'PosReg', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('sensitivity to cisplatin', 'MPA', (105, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('bladder cancer', 'Disease', 'MESH:D001749', (145, 159))	('bladder cancer', 'Disease', (145, 159))
191312	28241422	In addition, enzalutamide treatment or AR knockdown was shown to inhibit the growth of gemcitabine-resistant bladder cancer cells, while whether it could increase chemosensitivity was not tested.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('men', 'Species', '9606', (31, 34))	('growth', 'MPA', (77, 83))	('gemcitabine', 'Chemical', 'MESH:C056507', (87, 98))	('bladder cancer', 'Disease', (109, 123))	('bladder cancer', 'Disease', 'MESH:D001749', (109, 123))	('inhibit', 'NegReg', (65, 72))	('enzalutamide', 'Chemical', 'MESH:C540278', (13, 25))	('knockdown', 'Var', (42, 51))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))
191319	28241422	Meanwhile, knockdown of each co-activator led to significant reduction in cell proliferation of AR-positive bladder cancer lines, although, inconsistent with the findings in prostate cancer cells, androgen treatment failed to up-regulate the expression levels of these co-activators in these cells.	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('bladder cancer', 'Disease', (108, 122))	('cell proliferation', 'CPA', (74, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (174, 189))	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))	('positive bladder', 'Phenotype', 'HP:0100645', (99, 115))	('reduction', 'NegReg', (61, 70))	('prostate cancer', 'Disease', (174, 189))	('men', 'Species', '9606', (211, 214))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('prostate cancer', 'Disease', 'MESH:D011471', (174, 189))	('rat', 'Species', '10116', (86, 89))	('knockdown', 'Var', (11, 20))
191323	28241422	Loss of JMJD2A was also associated with lymphovascular invasion or worse overall survival, but not cancer-specific mortality.	('JMJD2A', 'Gene', '9682', (8, 14))	('associated', 'Reg', (24, 34))	('overall survival', 'CPA', (73, 89))	('JMJD2A', 'Gene', (8, 14))	('lymphovascular invasion', 'CPA', (40, 63))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Loss', 'Var', (0, 4))	('worse', 'NegReg', (67, 72))
191324	28241422	Remarkably, pharmacological inhibition of LSD1 resulted in significant decreases in the growth and androgen-induced AR transcription in bladder cancer cells.	('LSD1', 'Gene', (42, 46))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('LSD1', 'Gene', '23028', (42, 46))	('inhibition', 'Var', (28, 38))	('bladder cancer', 'Disease', 'MESH:D001749', (136, 150))	('bladder cancer', 'Disease', (136, 150))	('growth', 'CPA', (88, 94))	('transcription', 'biological_process', 'GO:0006351', ('119', '132'))	('decreases', 'NegReg', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
191325	28241422	Altered expression of beta-catenin is well known to correlate with the progression of bladder cancer and poor patient outcomes.	('bladder cancer', 'Disease', (86, 100))	('Altered', 'Var', (0, 7))	('beta-catenin', 'Protein', (22, 34))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('patient', 'Species', '9606', (110, 117))	('expression', 'MPA', (8, 18))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))
191355	27123355	The genetic analyses revealed a MSH2 gene mutation (c.293_296dup (p.Val100X) heterozygous duplication).	('c.293_296dup', 'Var', (52, 64))	('p.Val100X', 'Mutation', 'p.V100X', (66, 75))	('revealed', 'Reg', (21, 29))	('MSH2', 'Gene', (32, 36))	('MSH2', 'Gene', '4436', (32, 36))	('c.293_296dup', 'Mutation', 'c.293_296dup', (52, 64))
191398	24684735	Knockdown of DAB2IP could promote cell proliferation, migration, and invasion.	('promote', 'PosReg', (26, 33))	('Knockdown', 'Var', (0, 9))	('cell proliferation', 'CPA', (34, 52))	('migration', 'CPA', (54, 63))	('DAB2IP', 'Gene', (13, 19))	('invasion', 'CPA', (69, 77))	('DAB2IP', 'Gene', '153090', (13, 19))	('cell proliferation', 'biological_process', 'GO:0008283', ('34', '52'))
191399	24684735	Downregulation of DAB2IP could activate the ERK and Akt pathways and was correlated with the expression of epithelial-mesenchymal transition markers, such as E-cadherin and vimentin.	('DAB2IP', 'Gene', (18, 24))	('cadherin', 'molecular_function', 'GO:0008014', ('160', '168'))	('activate', 'PosReg', (31, 39))	('Akt', 'Gene', (52, 55))	('DAB2IP', 'Gene', '153090', (18, 24))	('ERK', 'Gene', '5594', (44, 47))	('vimentin', 'cellular_component', 'GO:0045099', ('173', '181'))	('Downregulation', 'Var', (0, 14))	('vimentin', 'Gene', '7431', (173, 181))	('ERK', 'molecular_function', 'GO:0004707', ('44', '47'))	('ERK', 'Gene', (44, 47))	('E-cadherin', 'Gene', (158, 168))	('vimentin', 'Gene', (173, 181))	('E-cadherin', 'Gene', '999', (158, 168))	('vimentin', 'cellular_component', 'GO:0045098', ('173', '181'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('107', '140'))	('Akt', 'Gene', '207', (52, 55))
191409	24684735	Due to the altered epigenetic regulation, such as DNA methylation and histone modification in the DAB2IP promoter region, downregulation of DAB2IP was found in different human malignancies including prostate cancer, breast cancer, lung cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tumor, and medulloblastoma.	('lung cancer', 'Disease', (231, 242))	('pancreatic cancer', 'Disease', 'MESH:D010190', (270, 287))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (244, 268))	('malignancies', 'Disease', 'MESH:D009369', (176, 188))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('medulloblastoma', 'Disease', 'MESH:D008527', (317, 332))	('medulloblastoma', 'Phenotype', 'HP:0002885', (317, 332))	('histone modification', 'biological_process', 'GO:0016570', ('70', '90'))	('malignancies', 'Disease', (176, 188))	('pancreatic cancer', 'Disease', (270, 287))	('epigenetic regulation', 'MPA', (19, 40))	('medulloblastoma', 'Disease', (317, 332))	('regulation', 'biological_process', 'GO:0065007', ('30', '40'))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (244, 268))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('DAB2IP', 'Gene', (98, 104))	('lung cancer', 'Disease', 'MESH:D008175', (231, 242))	('gastrointestinal tumor', 'Phenotype', 'HP:0007378', (289, 311))	('DAB2IP', 'Gene', '153090', (140, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (231, 242))	('hepatocellular carcinoma', 'Disease', (244, 268))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('prostate cancer', 'Disease', 'MESH:D011471', (199, 214))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('downregulation', 'NegReg', (122, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('prostate cancer', 'Phenotype', 'HP:0012125', (199, 214))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (270, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('prostate cancer', 'Disease', (199, 214))	('gastrointestinal tumor', 'Disease', 'MESH:D004067', (289, 311))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('histone', 'Reg', (70, 77))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('altered', 'Reg', (11, 18))	('breast cancer', 'Disease', (216, 229))	('modification', 'Var', (78, 90))	('DNA methylation', 'biological_process', 'GO:0006306', ('50', '65'))	('DAB2IP', 'Gene', (140, 146))	('human', 'Species', '9606', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('gastrointestinal tumor', 'Disease', (289, 311))	('DAB2IP', 'Gene', '153090', (98, 104))
191414	24684735	Second, we determined the effect of DAB2IP knockdown on cell proliferation, cell cycle distribution, cell migration, and invasion in vitro.	('cell cycle distribution', 'CPA', (76, 99))	('DAB2IP', 'Gene', (36, 42))	('knockdown', 'Var', (43, 52))	('DAB2IP', 'Gene', '153090', (36, 42))	('cell migration', 'CPA', (101, 115))	('cell cycle', 'biological_process', 'GO:0007049', ('76', '86'))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))	('cell migration', 'biological_process', 'GO:0016477', ('101', '115'))
191437	24684735	Hsieh), phospho-ERK1/2 (T202/Y204), phospho-AKT (Ser473), total ERK1/2, total AKT, and actin antibody (all from Cell Signaling Technologies, Beverly, MA, USA), followed by secondary antibodies.	('ERK1', 'molecular_function', 'GO:0004707', ('16', '20'))	('actin', 'Protein', (87, 92))	('Ser', 'cellular_component', 'GO:0005790', ('49', '52'))	('antibody', 'cellular_component', 'GO:0019815', ('93', '101'))	('Signaling', 'biological_process', 'GO:0023052', ('117', '126'))	('antibody', 'cellular_component', 'GO:0019814', ('93', '101'))	('AKT', 'Gene', '207', (44, 47))	('AKT', 'Gene', '207', (78, 81))	('antibody', 'molecular_function', 'GO:0003823', ('93', '101'))	('T202/Y204', 'Var', (24, 33))	('antibody', 'cellular_component', 'GO:0042571', ('93', '101'))	('AKT', 'Gene', (44, 47))	('AKT', 'Gene', (78, 81))	('ERK1', 'molecular_function', 'GO:0004707', ('64', '68'))
191457	24684735	The Kaplan-Meier analysis and the log-rank test showed that the expression of DAB2IP was associated with an increased risk of disease recurrence (P < 0.001) and cancer-specific mortality (P < 0.001) in UCB patients who underwent RC plus bilateral lymphadenectomy (Fig.2).	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('disease recurrence', 'CPA', (126, 144))	('UCB', 'Phenotype', 'HP:0006740', (202, 205))	('DAB2IP', 'Gene', (78, 84))	('UCB', 'Chemical', '-', (202, 205))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('patients', 'Species', '9606', (206, 214))	('UCB', 'Disease', (202, 205))	('expression', 'Var', (64, 74))	('DAB2IP', 'Gene', '153090', (78, 84))	('cancer', 'Disease', (161, 167))
191458	24684735	Univariate Cox proportional hazards analysis of RFS and CSS showed that DAB2IP and other established prognostic factors including age, tumor stage, grade, size, lymph node invasion, histological variants, lymphovascular invasion, receipt of adjuvant chemotherapy, and expression of Tp53 and Ki67 were all significant risk factors for recurrence and death due to UCB (Table3).	('DAB2IP', 'Gene', '153090', (72, 78))	('variants', 'Var', (195, 203))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('CSS', 'Gene', (56, 59))	('recurrence', 'Disease', (334, 344))	('Tp53', 'Gene', '7157', (282, 286))	('UCB', 'Disease', (362, 365))	('RFS', 'Gene', (48, 51))	('Cox', 'Gene', '1351', (11, 14))	('death', 'Disease', (349, 354))	('DAB2IP', 'Gene', (72, 78))	('Cox', 'Gene', (11, 14))	('tumor', 'Disease', (135, 140))	('UCB', 'Chemical', '-', (362, 365))	('RFS', 'Gene', '65211', (48, 51))	('UCB', 'Phenotype', 'HP:0006740', (362, 365))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('Ki67', 'Var', (291, 295))	('Ki67', 'Chemical', '-', (291, 295))	('death', 'Disease', 'MESH:D003643', (349, 354))	('Tp53', 'Gene', (282, 286))	('CSS', 'Gene', '55907', (56, 59))
191459	24684735	In multivariate analyses, when controlling for the effects of standard clinicopathologic features and molecular markers, the expression of DAB2IP was an independent predictor of RFS (HR, 2.67, P = 0.034; Table3) and CSS (HR, 2.79, P = 0.038; Table4), respectively.	('expression', 'Var', (125, 135))	('DAB2IP', 'Gene', (139, 145))	('DAB2IP', 'Gene', '153090', (139, 145))	('CSS', 'Gene', (216, 219))	('CSS', 'Gene', '55907', (216, 219))	('RFS', 'Gene', '65211', (178, 181))	('RFS', 'Gene', (178, 181))
191491	24684735	As a result, we found that knockdown of DAB2IP led to a dramatic increase of the proliferation, migration, and invasion ability both in T24 and 5637 cell lines.	('increase', 'PosReg', (65, 73))	('migration', 'CPA', (96, 105))	('knockdown', 'Var', (27, 36))	('DAB2IP', 'Gene', (40, 46))	('DAB2IP', 'Gene', '153090', (40, 46))	('invasion ability', 'CPA', (111, 127))	('proliferation', 'CPA', (81, 94))
191494	24684735	In the present study, we showed that knockdown of DAB2IP could activate the ERK or Akt pathways in vitro.	('ERK', 'molecular_function', 'GO:0004707', ('76', '79'))	('Akt', 'Gene', (83, 86))	('ERK', 'Gene', (76, 79))	('DAB2IP', 'Gene', (50, 56))	('activate', 'PosReg', (63, 71))	('knockdown', 'Var', (37, 46))	('DAB2IP', 'Gene', '153090', (50, 56))	('Akt', 'Gene', '207', (83, 86))	('ERK', 'Gene', '5594', (76, 79))
191506	24684735	CON-siRNA control siRNA CSS cancer-specific survival DAB2IP DOC-2/DAB2 interactive protein DAB2IP-siRNA DAB2IP-knockdown EMT epithelial-mesenchymal transition IHC immunohistochemistry MIBC muscle-invasive bladder cancer RC radical cystectomy RFS recurrence-free survival Tp53 tumor protein p53 UCB urothelial carcinoma of the bladder	('Tp53', 'Gene', (271, 275))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (298, 333))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('125', '158'))	('DAB2IP', 'Gene', '153090', (104, 110))	('EMT', 'biological_process', 'GO:0001837', ('121', '124'))	('p53', 'Var', (290, 293))	('RFS', 'Gene', '65211', (242, 245))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('DOC-2/DAB2 interactive protein', 'Gene', (60, 90))	('DAB2IP', 'Gene', (91, 97))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (196, 219))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (309, 318))	('DAB2IP-', 'Gene', '153090', (91, 98))	('protein', 'cellular_component', 'GO:0003675', ('282', '289'))	('urothelial carcinoma of the bladder', 'Disease', (298, 333))	('UCB', 'Phenotype', 'HP:0006740', (294, 297))	('UCB', 'Chemical', '-', (294, 297))	('Tp53', 'Gene', '7157', (271, 275))	('DAB2IP-', 'Gene', (91, 98))	('DAB2IP', 'Gene', '153090', (53, 59))	('invasive bladder cancer', 'Disease', (196, 219))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('cancer', 'Disease', (213, 219))	('DAB2IP', 'Gene', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (298, 333))	('DOC-2/DAB2 interactive protein', 'Gene', '153090;1601', (60, 90))	('RFS', 'Gene', (242, 245))	('tumor', 'Disease', (276, 281))	('DAB2IP', 'Gene', '153090', (91, 97))	('DAB2IP-', 'Gene', '153090', (104, 111))	('cancer', 'Disease', (28, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (205, 219))	('DAB2IP-', 'Gene', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('DAB2IP', 'Gene', (53, 59))	('invasive bladder', 'Phenotype', 'HP:0100645', (196, 212))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('CSS', 'Gene', '55907', (24, 27))	('MIBC', 'Chemical', '-', (184, 188))	('CSS', 'Gene', (24, 27))
191530	33672684	It has been demonstrated that disruption of angiogenesis enhances the efficacy of immune based cancer therapies including vaccines and adoptive cell therapy.	('disruption', 'Var', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('angiogenesis', 'CPA', (44, 56))	('enhances', 'PosReg', (57, 65))	('cancer', 'Disease', (95, 101))	('angiogenesis', 'biological_process', 'GO:0001525', ('44', '56'))	('efficacy', 'CPA', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
191536	33672684	They function by targeting several mRNAs affecting a multitude of transcripts to control cellular metabolisms; therefore, their dysregulation influences numerous cancer-relevant processes such as proliferation, differentiation, apoptosis, and metastasis.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('proliferation', 'CPA', (196, 209))	('apoptosis', 'CPA', (228, 237))	('cancer', 'Disease', (162, 168))	('apoptosis', 'biological_process', 'GO:0097194', ('228', '237'))	('differentiation', 'CPA', (211, 226))	('metastasis', 'CPA', (243, 253))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('apoptosis', 'biological_process', 'GO:0006915', ('228', '237'))	('influences', 'Reg', (142, 152))	('cellular metabolisms', 'MPA', (89, 109))	('dysregulation', 'Var', (128, 141))
191537	33672684	Owing to the genomic events including mutations, deletions amplifications, or transcriptional changes, miRNAs are dysregulated in several diseases including cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('deletions amplifications', 'Var', (49, 73))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('transcriptional changes', 'CPA', (78, 101))	('mutations', 'Var', (38, 47))
191544	33672684	Reactivation of EMT during cancer progression enhances the metastatic phenotype.	('enhances', 'PosReg', (46, 54))	('metastatic phenotype', 'CPA', (59, 79))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('EMT', 'biological_process', 'GO:0001837', ('16', '19'))	('EMT', 'Gene', (16, 19))	('Reactivation', 'Var', (0, 12))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
191549	33672684	Other oncogenic pathways include STAT3, PIK3/Akt, ZEB, oncogenic miRNAs, and long non-coding RNAs (lncRNAs).	('PIK3', 'Gene', '5294', (40, 44))	('Akt', 'Gene', (45, 48))	('STAT3', 'Gene', '6774', (33, 38))	('PIK3', 'Gene', (40, 44))	('long non-coding RNAs', 'Var', (77, 97))	('STAT3', 'Gene', (33, 38))	('Akt', 'Gene', '207', (45, 48))
191574	33672684	Abrogating TGFbeta signaling in tumor cells or its expression in platelets is enough to hinder metastasis and EMT, since platelets are an important source of bioavailable TGFbeta for tumor cells during circulation and extravasation.	('TGFbeta', 'Gene', '7039', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('EMT', 'CPA', (110, 113))	('Abrogating', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('TGFbeta', 'Gene', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('metastasis', 'CPA', (95, 105))	('TGFbeta', 'Gene', (11, 18))	('tumor', 'Disease', (183, 188))	('EMT', 'biological_process', 'GO:0001837', ('110', '113'))	('tumor', 'Disease', (32, 37))	('hinder', 'NegReg', (88, 94))	('TGFbeta', 'Gene', '7039', (171, 178))
191580	33672684	In the course of EMT, E-cadherin cleavage destabilizes the adherens junction, releasing beta-catenin, which functions as a transcriptional activator for cell proliferation.	('adherens junction', 'CPA', (59, 76))	('E-cadherin', 'Protein', (22, 32))	('releasing', 'Reg', (78, 87))	('beta-catenin', 'Gene', (88, 100))	('cadherin', 'molecular_function', 'GO:0008014', ('24', '32'))	('cleavage', 'Var', (33, 41))	('EMT', 'biological_process', 'GO:0001837', ('17', '20'))	('destabilizes', 'NegReg', (42, 54))	('adherens junction', 'cellular_component', 'GO:0005912', ('59', '76'))	('cell proliferation', 'biological_process', 'GO:0008283', ('153', '171'))	('beta-catenin', 'Gene', '1499', (88, 100))
191595	33672684	In EJ and 5637 cells, E-cadherin knockout induces stronger proliferation ability and cell motility, playing a vital role in the miR-373 suppressed EMT signaling pathway, while its deletion associates with tumor recurrence, metastasis, and poor survival of BLCA patients.	('miR-373', 'Gene', (128, 135))	('metastasis', 'CPA', (223, 233))	('stronger', 'PosReg', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('proliferation ability', 'CPA', (59, 80))	('suppressed', 'NegReg', (136, 146))	('miR-373', 'Gene', '442918', (128, 135))	('cell motility', 'biological_process', 'GO:0048870', ('85', '98'))	('cell motility', 'CPA', (85, 98))	('signaling pathway', 'biological_process', 'GO:0007165', ('151', '168'))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('EJ', 'CellLine', 'CVCL:7039', (3, 5))	('deletion', 'Var', (180, 188))	('BLCA', 'Phenotype', 'HP:0009725', (256, 260))	('EMT', 'biological_process', 'GO:0001837', ('147', '150'))	('cadherin', 'molecular_function', 'GO:0008014', ('24', '32'))	('BLCA', 'Disease', (256, 260))	('EMT signaling pathway', 'Pathway', (147, 168))	('associates with', 'Reg', (189, 204))	('tumor', 'Disease', (205, 210))	('patients', 'Species', '9606', (261, 269))
191607	33672684	In CRL1749, E-cadherin expression levels significantly increased after miRNA-141 and miRNA-200b were overexpressed, whereas the expression of the mesenchymal markers vimentin and N-cadherin was downregulated.	('miRNA-200b', 'Var', (85, 95))	('vimentin', 'Gene', '7431', (166, 174))	('cadherin', 'molecular_function', 'GO:0008014', ('14', '22'))	('N-cadherin', 'Gene', (179, 189))	('E-cadherin expression levels', 'MPA', (12, 40))	('vimentin', 'Gene', (166, 174))	('increased', 'PosReg', (55, 64))	('miRNA-141', 'Var', (71, 80))	('overexpressed', 'PosReg', (101, 114))	('N-cadherin', 'Gene', '1000', (179, 189))	('cadherin', 'molecular_function', 'GO:0008014', ('181', '189'))	('vimentin', 'cellular_component', 'GO:0045099', ('166', '174'))	('expression', 'MPA', (128, 138))	('vimentin', 'cellular_component', 'GO:0045098', ('166', '174'))	('downregulated', 'NegReg', (194, 207))
191609	33672684	Together this suggests that modulation of these miRNAs leads to different changes in invasive ability, which is associated with the EMT phenotype of these BLCA cell lines, HTB9 cells being a grade II carcinoma and CRL1749 being a transitional cell carcinoma.	('II carcinoma', 'Disease', 'MESH:D009369', (197, 209))	('modulation', 'Var', (28, 38))	('changes', 'Reg', (74, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('carcinoma', 'Disease', (248, 257))	('EMT', 'biological_process', 'GO:0001837', ('132', '135'))	('carcinoma', 'Disease', (200, 209))	('carcinoma', 'Disease', 'MESH:D009369', (248, 257))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (230, 257))	('HTB9', 'CellLine', 'CVCL:1R14', (172, 176))	('BLCA', 'Phenotype', 'HP:0009725', (155, 159))	('invasive ability', 'CPA', (85, 101))	('II carcinoma', 'Disease', (197, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))	('carcinoma', 'Disease', 'MESH:D009369', (200, 209))
191614	33672684	Following EMT induction and targeting GSk3beta via the Wnt/beta-catenin signaling pathway, miR-135a then accelerated EMT, invasion, and migration of BLCA cells.	('EMT', 'biological_process', 'GO:0001837', ('117', '120'))	('EMT', 'CPA', (117, 120))	('BLCA', 'Phenotype', 'HP:0009725', (149, 153))	('accelerated', 'PosReg', (105, 116))	('beta-catenin', 'Gene', '1499', (59, 71))	('GSk3beta', 'Gene', '2931', (38, 46))	('signaling pathway', 'biological_process', 'GO:0007165', ('72', '89'))	('invasion', 'CPA', (122, 130))	('GSk', 'molecular_function', 'GO:0050321', ('38', '41'))	('EMT', 'biological_process', 'GO:0001837', ('10', '13'))	('migration of BLCA cells', 'CPA', (136, 159))	('miR-135a', 'Var', (91, 99))	('GSk3beta', 'Gene', (38, 46))	('miR-135a', 'Chemical', '-', (91, 99))	('beta-catenin', 'Gene', (59, 71))
191617	33672684	They are downregulated in human cancers due to the aberrant epigenetic gene silencing.	('epigenetic gene silencing', 'Var', (60, 85))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('gene silencing', 'biological_process', 'GO:0016458', ('71', '85'))	('cancers', 'Disease', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('downregulated', 'NegReg', (9, 22))	('human', 'Species', '9606', (26, 31))
191631	33672684	Several studies reported that integrins participate in tumor progression; others have reported their role in the development of resistance to chemotherapy in BLCA with alterations of integrin expression modifying adhesive and invasive behavior of BLCA cells.	('modifying', 'Reg', (203, 212))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('integrin', 'Protein', (183, 191))	('BLCA', 'Phenotype', 'HP:0009725', (247, 251))	('BLCA', 'Phenotype', 'HP:0009725', (158, 162))	('tumor', 'Disease', (55, 60))	('alterations', 'Var', (168, 179))
191655	33672684	Methylation of miR-124-3p contributes to its downregulation and that of several signaling pathways it modulates involved in cell migration and invasion.	('modulates', 'Reg', (102, 111))	('cell migration', 'biological_process', 'GO:0016477', ('124', '138'))	('Methylation', 'Var', (0, 11))	('miR-124-3p', 'Gene', '406909', (15, 25))	('invasion', 'CPA', (143, 151))	('cell migration', 'CPA', (124, 138))	('miR-124-3p', 'Gene', (15, 25))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('signaling pathways', 'Pathway', (80, 98))	('downregulation', 'NegReg', (45, 59))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))
191658	33672684	In addition, overexpression of miR-124-3p and knockdown of ITGA3 resulted in upregulation of E-cadherin and downregulation of N-cadherin.	('N-cadherin', 'Gene', (126, 136))	('miR-124-3p', 'Gene', '406909', (31, 41))	('E-cadherin', 'Protein', (93, 103))	('knockdown', 'Var', (46, 55))	('miR-124-3p', 'Gene', (31, 41))	('ITGA3', 'Gene', '3675', (59, 64))	('N-cadherin', 'Gene', '1000', (126, 136))	('overexpression', 'PosReg', (13, 27))	('upregulation', 'PosReg', (77, 89))	('downregulation', 'NegReg', (108, 122))	('cadherin', 'molecular_function', 'GO:0008014', ('128', '136'))	('cadherin', 'molecular_function', 'GO:0008014', ('95', '103'))	('ITGA3', 'Gene', (59, 64))
191659	33672684	Further silencing of ITGA3 enhances apoptosis reducing viability, proliferation, migration, and invasion.	('ITGA3', 'Gene', (21, 26))	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('apoptosis', 'CPA', (36, 45))	('proliferation', 'CPA', (66, 79))	('silencing', 'Var', (8, 17))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('ITGA3', 'Gene', '3675', (21, 26))	('invasion', 'CPA', (96, 104))	('enhances', 'PosReg', (27, 35))	('viability', 'CPA', (55, 64))	('reducing', 'NegReg', (46, 54))	('migration', 'CPA', (81, 90))
191663	33672684	CD44v6 has the ability to interact with receptor tyrosine kinase, c-Met, in parallel with EpCAM expression, giving cancer cells growth factor microenvironment susceptibility.	('cancer', 'Disease', (115, 121))	('c-Met', 'Gene', (66, 71))	('EpCAM', 'Gene', (90, 95))	('c-Met', 'Gene', '4233', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('EpCAM', 'Gene', '4072', (90, 95))	('CD44v6', 'Var', (0, 6))	('interact', 'Interaction', (26, 34))
191665	33672684	A recent study reported that in MIBC staining of CD44 was significantly associated with clinical lymph node involvement and locoregional recurrence, correlating with lower disease-free survival (DFS) for all MIBC patients.	('clinical lymph node involvement', 'CPA', (88, 119))	('lower disease-free', 'Disease', 'MESH:D008569', (166, 184))	('associated', 'Reg', (72, 82))	('lower disease-free', 'Disease', (166, 184))	('MIBC', 'Disease', (208, 212))	('staining', 'Var', (37, 45))	('patients', 'Species', '9606', (213, 221))	('CD44', 'Gene', (49, 53))	('locoregional recurrence', 'CPA', (124, 147))	('MIBC', 'Chemical', '-', (32, 36))	('MIBC', 'Chemical', '-', (208, 212))
191667	33672684	Increased levels of IL-6 have been observed with BLCA patients, and an activated cytokine IL-6 signaling provides a suitable microenvironment for CD44 induction where in immunocompetent mouse models blockade of IL-6 decreased CD44 expression attenuating tumor aggressiveness.	('decreased', 'NegReg', (216, 225))	('IL-6', 'Gene', (211, 215))	('IL-6 decreased', 'Phenotype', 'HP:0030783', (211, 225))	('IL-6', 'molecular_function', 'GO:0005138', ('211', '215'))	('tumor aggressiveness', 'Disease', (254, 274))	('attenuating', 'NegReg', (242, 253))	('CD44', 'Protein', (226, 230))	('patients', 'Species', '9606', (54, 62))	('aggressiveness', 'Phenotype', 'HP:0000718', (260, 274))	('blockade', 'Var', (199, 207))	('mouse', 'Species', '10090', (186, 191))	('BLCA', 'Phenotype', 'HP:0009725', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('signaling', 'biological_process', 'GO:0023052', ('95', '104'))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (254, 274))	('IL-6', 'molecular_function', 'GO:0005138', ('90', '94'))	('expression', 'MPA', (231, 241))	('IL-6', 'molecular_function', 'GO:0005138', ('20', '24'))
191673	33672684	In in vivo and in vitro studies in BLCA xenograft tumors, transfection by miR-34a reduced VEGF and CD44 levels, subsequently reducing angiogenesis.	('VEGF', 'Gene', (90, 94))	('BLCA xenograft tumors', 'Disease', (35, 56))	('CD44 levels', 'MPA', (99, 110))	('transfection', 'Var', (58, 70))	('angiogenesis', 'CPA', (134, 146))	('VEGF', 'Gene', '7422', (90, 94))	('miR-34a', 'Gene', '407040', (74, 81))	('reducing', 'NegReg', (125, 133))	('angiogenesis', 'biological_process', 'GO:0001525', ('134', '146'))	('BLCA xenograft tumors', 'Disease', 'MESH:D009369', (35, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('reduced', 'NegReg', (82, 89))	('miR-34a', 'Gene', (74, 81))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('BLCA', 'Phenotype', 'HP:0009725', (35, 39))
191674	33672684	Hence, there miR-34a suppresses angiogenesis via directly targeting CD44 in BLCA, and restoration of CD44 could rescue anti-tumor effects of miR-34a.	('miR-34a', 'Gene', '407040', (13, 20))	('restoration', 'Var', (86, 97))	('angiogenesis', 'biological_process', 'GO:0001525', ('32', '44'))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('CD44', 'Protein', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('miR-34a', 'Gene', (141, 148))	('tumor', 'Disease', (124, 129))	('suppresses', 'NegReg', (21, 31))	('CD44', 'Var', (101, 105))	('miR-34a', 'Gene', (13, 20))	('BLCA', 'Phenotype', 'HP:0009725', (76, 80))	('miR-34a', 'Gene', '407040', (141, 148))	('angiogenesis', 'CPA', (32, 44))
191677	33672684	It has been suggested that miRNA biogenesis at both the transcriptional and post-transcriptional level can be affected by ECM via the Drosha- and/or Dicer-mediated interaction.	('Dicer', 'Gene', '23405', (149, 154))	('Dicer', 'Gene', (149, 154))	('Drosha', 'Gene', (134, 140))	('miRNA biogenesis', 'MPA', (27, 43))	('miRNA biogenesis', 'biological_process', 'GO:0035196', ('27', '43'))	('affected', 'Reg', (110, 118))	('ECM', 'Var', (122, 125))	('Drosha', 'Gene', '29102', (134, 140))
191685	33672684	Experimental evidence seems to suggest that ADAM9 might mediate cell-cell communication for cell survival, as it inhibited cell migration and increased apoptotic cell death.	('cell migration', 'CPA', (123, 137))	('increased', 'PosReg', (142, 151))	('death', 'Disease', 'MESH:D003643', (167, 172))	('death', 'Disease', (167, 172))	('inhibited', 'NegReg', (113, 122))	('ADAM9', 'Var', (44, 49))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('152', '172'))	('cell communication', 'biological_process', 'GO:0007154', ('69', '87'))	('cell migration', 'biological_process', 'GO:0016477', ('123', '137'))
191694	33672684	In UBC 5637 cell lines, miR-370-3p directly repressed Wnt7a expression, suppressing invasion.	('expression', 'MPA', (60, 70))	('invasion', 'CPA', (84, 92))	('miR-370-3p', 'Chemical', '-', (24, 34))	('repressed', 'NegReg', (44, 53))	('miR-370-3p', 'Var', (24, 34))	('suppressing', 'NegReg', (72, 83))	('UBC', 'Chemical', '-', (3, 6))	('Wnt7a', 'Gene', (54, 59))	('Wnt7a', 'Gene', '7476', (54, 59))
191696	33672684	MMP11 was also identified to be the direct target of miR-139-5p and miR-139-3p.	('MMP11', 'Gene', '4320', (0, 5))	('miR-139-5p', 'Var', (53, 63))	('miR-139-3p', 'Gene', '406931', (68, 78))	('MMP11', 'molecular_function', 'GO:0004249', ('0', '5'))	('MMP11', 'Gene', (0, 5))	('miR-139-3p', 'Gene', (68, 78))
191697	33672684	In breast cancer, high MMP11 expression correlated with poor prognosis, and in colorectal cancer, it was a predictive survival marker.	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('MMP11', 'Gene', (23, 28))	('colorectal cancer', 'Disease', (79, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('high', 'Var', (18, 22))	('MMP11', 'molecular_function', 'GO:0004249', ('23', '28'))	('expression', 'MPA', (29, 39))	('MMP11', 'Gene', '4320', (23, 28))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))
191704	33672684	In T24 and J82 cell lines, silencing UHRF1 suppresses migration and hinders invasion, thus having an oncogenic role in BLCA, with a role in angiogenesis.	('UHRF1', 'Gene', (37, 42))	('silencing', 'Var', (27, 36))	('UHRF1', 'Gene', '29128', (37, 42))	('suppresses', 'NegReg', (43, 53))	('BLCA', 'Phenotype', 'HP:0009725', (119, 123))	('angiogenesis', 'biological_process', 'GO:0001525', ('140', '152'))	('migration', 'CPA', (54, 63))	('hinders', 'NegReg', (68, 75))	('invasion', 'CPA', (76, 84))
191705	33672684	By regulating UHRF1, the pre-miR-145 and guide strand miR-145-5p and passenger strand miR-145-3p act as anti-tumor miRNA in BLCA, thus indicating that both the guide and passenger strands of miRNA have a biological role through the regulation of several genes in BLCA.	('BLCA', 'Phenotype', 'HP:0009725', (263, 267))	('tumor', 'Disease', (109, 114))	('UHRF1', 'Gene', '29128', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('UHRF1', 'Gene', (14, 19))	('regulation', 'biological_process', 'GO:0065007', ('232', '242'))	('BLCA', 'Phenotype', 'HP:0009725', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('pre', 'molecular_function', 'GO:0003904', ('25', '28'))	('miR-145-3p', 'Var', (86, 96))
191706	33672684	miR-328-3p is found to be downregulated in BLCA predicting poor prognosis.	('downregulated', 'NegReg', (26, 39))	('BLCA', 'Phenotype', 'HP:0009725', (43, 47))	('miR-328-3p', 'Chemical', '-', (0, 10))	('miR-328-3p', 'Var', (0, 10))	('BLCA', 'Disease', (43, 47))
191709	33672684	B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is a direct target of miR-15 and via regulating BMI1 through PI3K/Akt pathway, miR-15 inhibited in vivo BLCA cell progression and tumor growth.	('leukemia', 'Phenotype', 'HP:0001909', (31, 39))	('BMI1', 'Gene', (120, 124))	('miR-15', 'Chemical', '-', (151, 157))	('tumor', 'Disease', (202, 207))	('regulating', 'Reg', (109, 119))	('BLCA cell progression', 'CPA', (176, 197))	('BMI1', 'Gene', '648', (66, 70))	('miR-15', 'Chemical', '-', (94, 100))	('Moloney murine leukemia virus', 'Species', '11801', (16, 45))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('BLCA', 'Phenotype', 'HP:0009725', (176, 180))	('BMI1', 'Gene', '648', (120, 124))	('PI3', 'Gene', '5266', (133, 136))	('Akt', 'Gene', (138, 141))	('miR-15', 'Var', (151, 157))	('Akt', 'Gene', '207', (138, 141))	('miR-15', 'Gene', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('inhibited', 'NegReg', (158, 167))	('PI3', 'Gene', (133, 136))	('PI3K', 'molecular_function', 'GO:0016303', ('133', '137'))	('BMI1', 'Gene', (66, 70))
191725	33672684	Overexpression of MAPK1 correlated with poor survival and induced the transcriptional activity of Slug, upregulating vimentin expression, whereas overexpression of miR-22 reversed MAPK or Snail-induced migration and invasion, thus playing an important role in EMT progression and the MAPK1/Slug/vimentin feedback loop.	('MAPK1', 'Gene', '5594', (18, 23))	('miR-22', 'Gene', (164, 170))	('vimentin', 'cellular_component', 'GO:0045098', ('117', '125'))	('Snail', 'Gene', (188, 193))	('transcriptional activity', 'MPA', (70, 94))	('Overexpression', 'Var', (0, 14))	('vimentin', 'cellular_component', 'GO:0045098', ('295', '303'))	('Slug', 'Gene', '6591', (98, 102))	('EMT', 'biological_process', 'GO:0001837', ('260', '263'))	('MAPK', 'molecular_function', 'GO:0004707', ('18', '22'))	('upregulating', 'PosReg', (104, 116))	('MAPK1', 'Gene', (18, 23))	('survival', 'CPA', (45, 53))	('vimentin', 'Gene', '7431', (295, 303))	('vimentin', 'Gene', (295, 303))	('Slug', 'Gene', (290, 294))	('poor', 'NegReg', (40, 44))	('vimentin', 'cellular_component', 'GO:0045099', ('117', '125'))	('expression', 'MPA', (126, 136))	('Snail', 'Gene', '6615', (188, 193))	('vimentin', 'cellular_component', 'GO:0045099', ('295', '303'))	('MAPK1', 'Gene', '5594', (284, 289))	('induced', 'PosReg', (58, 65))	('vimentin', 'Gene', '7431', (117, 125))	('vimentin', 'Gene', (117, 125))	('Slug', 'Gene', (98, 102))	('MAPK', 'molecular_function', 'GO:0004707', ('180', '184'))	('Slug', 'Gene', '6591', (290, 294))	('miR-22', 'Gene', '407004', (164, 170))	('MAPK', 'molecular_function', 'GO:0004707', ('284', '288'))	('MAPK1', 'Gene', (284, 289))
191726	33672684	Additionally, knockdown of MAPK1 suppressed Slug and vimentin expression, indicating that Slug possibly acts as a scaffold in MAPK1-induced vimentin expression in BLCA cells.	('MAPK1', 'Gene', '5594', (27, 32))	('BLCA', 'Phenotype', 'HP:0009725', (163, 167))	('MAPK', 'molecular_function', 'GO:0004707', ('126', '130'))	('MAPK1', 'Gene', (27, 32))	('Slug', 'Gene', '6591', (90, 94))	('vimentin', 'cellular_component', 'GO:0045098', ('140', '148'))	('MAPK1', 'Gene', '5594', (126, 131))	('vimentin', 'cellular_component', 'GO:0045098', ('53', '61'))	('Slug', 'Gene', (44, 48))	('suppressed', 'NegReg', (33, 43))	('MAPK1', 'Gene', (126, 131))	('vimentin', 'Gene', '7431', (53, 61))	('vimentin', 'cellular_component', 'GO:0045099', ('140', '148'))	('MAPK', 'molecular_function', 'GO:0004707', ('27', '31'))	('vimentin', 'cellular_component', 'GO:0045099', ('53', '61'))	('vimentin', 'Gene', (53, 61))	('Slug', 'Gene', (90, 94))	('vimentin', 'Gene', '7431', (140, 148))	('knockdown', 'Var', (14, 23))	('vimentin', 'Gene', (140, 148))	('Slug', 'Gene', '6591', (44, 48))
191727	33672684	They also performed western blot (WB) assay to reveal the effect of silencing vimentin and found that it suppressed ERK2 phosphorylation, implying that vimentin can activate MAPK1, forming a MAPK1/Slug/vimentin feedback loop in BLCA cells.	('suppressed', 'NegReg', (105, 115))	('ERK2', 'Gene', (116, 120))	('vimentin', 'cellular_component', 'GO:0045098', ('152', '160'))	('ERK2', 'molecular_function', 'GO:0004707', ('116', '120'))	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))	('vimentin', 'Gene', '7431', (152, 160))	('MAPK', 'molecular_function', 'GO:0004707', ('174', '178'))	('vimentin', 'Gene', (152, 160))	('MAPK1', 'Gene', '5594', (191, 196))	('vimentin', 'cellular_component', 'GO:0045099', ('202', '210'))	('vimentin', 'cellular_component', 'GO:0045099', ('78', '86'))	('MAPK1', 'Gene', '5594', (174, 179))	('vimentin', 'cellular_component', 'GO:0045099', ('152', '160'))	('Slug', 'Gene', (197, 201))	('vimentin', 'Gene', '7431', (78, 86))	('silencing', 'Var', (68, 77))	('vimentin', 'Gene', (78, 86))	('MAPK1', 'Gene', (191, 196))	('MAPK', 'molecular_function', 'GO:0004707', ('191', '195'))	('MAPK1', 'Gene', (174, 179))	('vimentin', 'cellular_component', 'GO:0045098', ('202', '210'))	('vimentin', 'Gene', '7431', (202, 210))	('vimentin', 'cellular_component', 'GO:0045098', ('78', '86'))	('ERK2', 'Gene', '5594', (116, 120))	('Slug', 'Gene', '6591', (197, 201))	('vimentin', 'Gene', (202, 210))	('BLCA', 'Phenotype', 'HP:0009725', (228, 232))
191736	33672684	In colorectal cancer, miR-135a activates the downstream Wnt pathway by suppressing the tumor suppressor gene adenomatous polyposis coli (APC).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('colorectal cancer', 'Disease', (3, 20))	('APC', 'cellular_component', 'GO:0005680', ('137', '140'))	('activates', 'PosReg', (31, 40))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (109, 135))	('downstream Wnt pathway', 'Pathway', (45, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('tumor', 'Disease', (87, 92))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('87', '103'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('adenomatous polyposis coli', 'Gene', (109, 135))	('suppressing', 'NegReg', (71, 82))	('APC', 'Phenotype', 'HP:0005227', (137, 140))	('APC', 'Disease', 'MESH:D011125', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('APC', 'Disease', (137, 140))	('tumor suppressor', 'biological_process', 'GO:0051726', ('87', '103'))	('adenomatous polyposis coli', 'Gene', '324', (109, 135))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('miR-135a', 'Chemical', '-', (22, 30))	('miR-135a', 'Var', (22, 30))
191773	33672684	In vitro and in vivo assessment of miR-153 expression on BLCA induced HUVEC angiogenesis, and showed that miR-153 suppressed IDO1, a rate limiting enzyme in tryptophan metabolism, which plays a role in tumor cell escape.	('miR-153', 'Gene', (35, 42))	('IDO1', 'Gene', '3620', (125, 129))	('tryptophan', 'Chemical', 'MESH:D014364', (157, 167))	('BLCA', 'Phenotype', 'HP:0009725', (57, 61))	('angiogenesis', 'biological_process', 'GO:0001525', ('76', '88'))	('tumor', 'Disease', (202, 207))	('tryptophan metabolism', 'biological_process', 'GO:0006568', ('157', '178'))	('HUVEC angiogenesis', 'CPA', (70, 88))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('IDO1', 'Gene', (125, 129))	('IDO', 'molecular_function', 'GO:0033754', ('125', '128'))	('suppressed', 'NegReg', (114, 124))	('miR-153', 'Chemical', '-', (106, 113))	('miR-153', 'Var', (106, 113))	('miR-153', 'Chemical', '-', (35, 42))	('IDO', 'molecular_function', 'GO:0047719', ('125', '128'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
191789	33672684	The expression of the following miRNAs was significant (p < 0.05): miR-30a-3p, miR-99a-5p, and miR-137-3p were up-regulated, and two were down-regulated, miR-141-3p and miR-205-5p.	('miR-205', 'Gene', '406988', (169, 176))	('miR-141', 'Gene', (154, 161))	('up-regulated', 'PosReg', (111, 123))	('miR-99a', 'Gene', '407055', (79, 86))	('down-regulated', 'NegReg', (138, 152))	('miR-137-3p', 'Var', (95, 105))	('miR-141', 'Gene', '406933', (154, 161))	('miR-30a-3p', 'Gene', (67, 77))	('miR-205', 'Gene', (169, 176))	('miR-99a', 'Gene', (79, 86))
191790	33672684	In vivo analysis from patient samples revealed the cellular expression of miR-141-3p, miR-200a-3p, and miR-205-5p was significantly down-regulated in MIBC tumors (p < 0.05) compared to NMIBC.	('miR-205', 'Gene', '406988', (103, 110))	('MIBC tumors', 'Disease', 'MESH:D009369', (150, 161))	('cellular expression', 'MPA', (51, 70))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('MIBC tumors', 'Disease', (150, 161))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('MIBC', 'Chemical', '-', (150, 154))	('miR-141', 'Gene', (74, 81))	('MIBC', 'Chemical', '-', (186, 190))	('miR-200a-3p', 'Var', (86, 97))	('down-regulated', 'NegReg', (132, 146))	('miR-141', 'Gene', '406933', (74, 81))	('miR-205', 'Gene', (103, 110))	('patient', 'Species', '9606', (22, 29))
191805	33672684	Therefore, identifying aberrant miRNA expression and the oncogenic or tumor-suppressive targets is inevitable for the clinical development of novel cancer therapeutics.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('aberrant', 'Var', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('miRNA expression', 'MPA', (32, 48))	('tumor', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
191806	32644978	Metastatic Plasmacytoid Bladder Cancer Harboring a CDH-1 Mutation and Producing High Levels of CA 19-9.	('Cancer', 'Disease', (32, 38))	('Mutation', 'Var', (57, 65))	('Cancer', 'Disease', 'MESH:D009369', (32, 38))	('CDH-1', 'Gene', (51, 56))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (24, 38))	('CDH-1', 'Gene', '999', (51, 56))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))
191808	32644978	Herein, we report a patient with CDH-1 mutated PUC who presented with disseminated peritoneal metastasis and high levels of CA 19-9.	('CDH-1', 'Gene', '999', (33, 38))	('mutated', 'Var', (39, 46))	('patient', 'Species', '9606', (20, 27))	('CDH-1', 'Gene', (33, 38))	('presented', 'Reg', (55, 64))
191812	32644978	A targeted exome next-generation sequencing (NGS) revealed pathogenic mutations in TP53, CDH-1, RB1, and ARIDA1A.	('TP53', 'Gene', '7157', (83, 87))	('CDH-1', 'Gene', (89, 94))	('pathogenic', 'Reg', (59, 69))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', (83, 87))	('RB1', 'Gene', '5925', (96, 99))	('ARIDA1A', 'Gene', (105, 112))	('CDH-1', 'Gene', '999', (89, 94))	('RB1', 'Gene', (96, 99))
191820	32644978	In one report, most cases of PUC harbor pathognomonic somatic alterations in the cadherin-1 (CDH-1) gene.	('cadherin', 'molecular_function', 'GO:0008014', ('81', '89'))	('CDH-1', 'Gene', (93, 98))	('PUC', 'Disease', (29, 32))	('cadherin-1', 'Gene', '999', (81, 91))	('alterations', 'Var', (62, 73))	('cadherin-1', 'Gene', (81, 91))	('CDH-1', 'Gene', '999', (93, 98))
191822	32644978	Herein, we report a patient with CDH-1 mutated PUC who presented with disseminated peritoneal metastasis and had high levels of CA 19-9.	('CDH-1', 'Gene', '999', (33, 38))	('mutated', 'Var', (39, 46))	('patient', 'Species', '9606', (20, 27))	('CDH-1', 'Gene', (33, 38))	('presented', 'Reg', (55, 64))
191844	32644978	NGS showed pathogenic mutations in TP53, CDH-1, RB1, and ARIDA1A (Table 1).	('CDH-1', 'Gene', '999', (41, 46))	('RB1', 'Gene', (48, 51))	('CDH-1', 'Gene', (41, 46))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('RB1', 'Gene', '5925', (48, 51))	('ARIDA1A', 'Gene', (57, 64))	('mutations', 'Var', (22, 31))	('pathogenic', 'Reg', (11, 21))
191851	32644978	In one report, up to 80% of PUC cases harbored pathognomonic somatic alterations in the CDH-1 gene.	('PUC', 'Disease', (28, 31))	('alterations', 'Var', (69, 80))	('CDH-1', 'Gene', '999', (88, 93))	('harbored', 'Reg', (38, 46))	('CDH-1', 'Gene', (88, 93))	('pathognomonic', 'Reg', (47, 60))
191852	32644978	Our patient presented with disseminated peritoneal metastatic PUC that harbored a CDH-1 mutation at an allele frequency of 43.0%.	('mutation', 'Var', (88, 96))	('disseminated peritoneal metastatic PUC', 'Disease', (27, 65))	('CDH-1', 'Gene', '999', (82, 87))	('patient', 'Species', '9606', (4, 11))	('CDH-1', 'Gene', (82, 87))
191875	32644978	The tumor cells showed high proliferative activity with high Ki-67.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('proliferative activity', 'CPA', (28, 50))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Ki-67', 'Var', (61, 66))
191876	32644978	At the molecular level, CDH-1 alterations seem to be characteristic.	('CDH-1', 'Gene', '999', (24, 29))	('alterations', 'Var', (30, 41))	('CDH-1', 'Gene', (24, 29))
191877	32644978	This is supported by the fact that loss of E-cadherin protein is a hallmark for this tumor, in addition to the previous observations which show that alterations in the CDH-1 gene are found in most of the reported cases.	('tumor', 'Disease', (85, 90))	('alterations', 'Var', (149, 160))	('CDH-1', 'Gene', (168, 173))	('E-cadherin', 'Gene', (43, 53))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('loss', 'NegReg', (35, 39))	('E-cadherin', 'Gene', '999', (43, 53))	('cadherin', 'molecular_function', 'GO:0008014', ('45', '53'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('CDH-1', 'Gene', '999', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
191879	32644978	Germline mutations in CDH-1 are associated with hereditary diffuse gastric cancer (HDGC) and increased risk of lobular breast adenocarcinoma.	('hereditary diffuse gastric cancer', 'Disease', (48, 81))	('Germline mutations', 'Var', (0, 18))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (48, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('HDGC', 'Disease', 'MESH:D013274', (83, 87))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (119, 140))	('HDGC', 'Disease', (83, 87))	('CDH-1', 'Gene', '999', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('breast adenocarcinoma', 'Disease', (119, 140))	('associated with', 'Reg', (32, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('CDH-1', 'Gene', (22, 27))	('breast adenocarcinoma', 'Disease', 'MESH:D001943', (119, 140))
191882	32644978	Aside from CDH-1 mutation, the genetic alterations in PUC were similar to that of urothelial carcinoma, with mutations in TP53, RB1, ARID1A, ERBB2, PIK3CA, and TERT promotor, and others.	('ARID1A', 'Gene', '8289', (133, 139))	('PIK3CA', 'Gene', '5290', (148, 154))	('TERT', 'Gene', '7015', (160, 164))	('TP53', 'Gene', (122, 126))	('ARID1A', 'Gene', (133, 139))	('ERBB2', 'Gene', '2064', (141, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('RB1', 'Gene', (128, 131))	('CDH-1', 'Gene', (11, 16))	('urothelial carcinoma', 'Disease', (82, 102))	('RB1', 'Gene', '5925', (128, 131))	('mutations', 'Var', (109, 118))	('PIK3CA', 'Gene', (148, 154))	('TERT', 'Gene', (160, 164))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (82, 102))	('TP53', 'Gene', '7157', (122, 126))	('CDH-1', 'Gene', '999', (11, 16))	('ERBB2', 'Gene', (141, 146))
191883	32644978	Our patient had a somatic nonsense mutation in the CDH-1 gene c.1003C>T with amino acid change p.R335* with allele frequency (AF) of 43%.	('AF', 'Disease', 'MESH:D001281', (126, 128))	('CDH-1', 'Gene', (51, 56))	('p.R335*', 'Var', (95, 102))	('c.1003C>T', 'Mutation', 'rs587780784', (62, 71))	('patient', 'Species', '9606', (4, 11))	('c.1003C>T', 'Var', (62, 71))	('p.R335*', 'Mutation', 'p.R335*', (95, 102))	('CDH-1', 'Gene', '999', (51, 56))
191885	32644978	Our patient tumor also had pathogenic mutations in other genes that are common to urothelial carcinoma and not characteristic to PUC (Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('patient', 'Species', '9606', (4, 11))	('mutations', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('urothelial carcinoma', 'Disease', (82, 102))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (82, 102))	('pathogenic', 'Reg', (27, 37))
191892	32644978	At the molecular level, somatic alterations in CDH-1 seems to be characteristic.	('alterations', 'Var', (32, 43))	('CDH-1', 'Gene', (47, 52))	('CDH-1', 'Gene', '999', (47, 52))
191905	30627543	Table 1 listed mostly frequent DEMs and DEGs across 11 types of cancer, including genes like ADGRB3, ASF1B, CDKN2A, CDT1, DPT, E2F1, E2F7, MYBL2, TCEAL2 and miRNAs like miR-183, miR-96, miR-1, miR-1258, miR-133a, miR-135b, miR-144, miR-182, miR-195, miR-21.	('E2F7', 'Gene', (133, 137))	('miR-183', 'Gene', '406959', (169, 176))	('DPT', 'Gene', (122, 125))	('ASF1B', 'Gene', '55723', (101, 106))	('miR-195', 'Gene', '406971', (241, 248))	('miR-21', 'Gene', '406991', (250, 256))	('CDT1', 'Gene', '81620', (116, 120))	('MYBL2', 'Gene', '4605', (139, 144))	('miR-135b', 'Gene', (213, 221))	('miR-133a', 'Var', (203, 211))	('miR-1258', 'Gene', (193, 201))	('E2F1', 'Gene', (127, 131))	('CDT1', 'Gene', (116, 120))	('miR-96', 'Gene', '407053', (178, 184))	('CDKN2A', 'Gene', '1029', (108, 114))	('miR-183', 'Gene', (169, 176))	('miR-195', 'Gene', (241, 248))	('TCEAL2', 'Gene', '140597', (146, 152))	('E2F1', 'Gene', '1869', (127, 131))	('ADGRB3', 'Gene', (93, 99))	('miR-144', 'Gene', '406936', (223, 230))	('miR-21', 'Gene', (250, 256))	('E2F7', 'Gene', '144455', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('TCEAL2', 'Gene', (146, 152))	('DPT', 'Gene', '1805', (122, 125))	('miR-1', 'Var', (186, 191))	('miR-1258', 'Gene', '100302172', (193, 201))	('ADGRB3', 'Gene', '577', (93, 99))	('miR-144', 'Gene', (223, 230))	('miR-182', 'Var', (232, 239))	('MYBL2', 'Gene', (139, 144))	('ASF1B', 'Gene', (101, 106))	('miR-96', 'Gene', (178, 184))	('CDKN2A', 'Gene', (108, 114))	('miR-135b', 'Gene', '442891', (213, 221))
191906	30627543	For example, MYBL2 which was targeted by miR-143-3p could regulate breast cancer cell proliferation and apoptosis; CDT1 was a critical regulator for normal genome replication, knockdown of TGFBR3 in T24 cells could result in decreased cell growth, motility and invasion, and miRNAs like miR-182, miR-183, miR-21, miR-195 and miR-96 were all associated with tumorigenesis.	('motility', 'CPA', (248, 256))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('associated', 'Reg', (341, 351))	('tumorigenesis', 'CPA', (357, 370))	('apoptosis', 'biological_process', 'GO:0097194', ('104', '113'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('miR-182', 'Var', (287, 294))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('apoptosis', 'biological_process', 'GO:0006915', ('104', '113'))	('miR-183', 'Var', (296, 303))	('miR-96', 'Var', (325, 331))	('CDT1', 'Gene', (115, 119))	('TGFBR3', 'Gene', '7049', (189, 195))	('miR-21', 'Var', (305, 311))	('knockdown', 'Var', (176, 185))	('miR-195', 'Var', (313, 320))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('TGFBR3', 'Gene', (189, 195))	('invasion', 'CPA', (261, 269))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('breast cancer', 'Disease', (67, 80))	('cell growth', 'CPA', (235, 246))	('decreased', 'NegReg', (225, 234))	('cell growth', 'biological_process', 'GO:0016049', ('235', '246'))
191910	30627543	Thus, dysregulated miRNA-target gene pairs involved in these genes like miR-21/GNE, miR-369/TRIM2, and miR-203a/PDE7A might promote the migration of cancer cells.	('miR-369', 'Gene', '442914', (84, 91))	('miR-21/GNE', 'Var', (72, 82))	('PDE', 'molecular_function', 'GO:0004114', ('112', '115'))	('miR-369', 'Gene', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('migration of cancer cells', 'CPA', (136, 161))	('miR-203a', 'Gene', (103, 111))	('miR-203a', 'Gene', '406986', (103, 111))	('promote', 'PosReg', (124, 131))
191912	30627543	These included known cancer-related pathways, such as Pathways in cancer (p = 3.78E-07, Bonferroni correction, BLCA), cell cycle pathway (p = 1.20E-05, Bonferroni correction, BRCA), p53 signaling pathway (p = 8.83E-06, Bonferroni correction, HNSC), and AMPK signaling pathway (p = 3.60E-04, Bonferroni correction, KIRC).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('p53', 'Gene', '7157', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('AMPK', 'molecular_function', 'GO:0047322', ('253', '257'))	('p53 signaling pathway', 'biological_process', 'GO:0030330', ('182', '203'))	('signaling pathway', 'biological_process', 'GO:0007165', ('258', '275'))	('AMPK signaling pathway', 'Pathway', (253, 275))	('cell cycle', 'biological_process', 'GO:0007049', ('118', '128'))	('AMPK', 'molecular_function', 'GO:0004691', ('253', '257'))	('AMPK', 'molecular_function', 'GO:0050405', ('253', '257'))	('cell cycle pathway', 'Pathway', (118, 136))	('p53', 'Gene', (182, 185))	('Bonferroni correction', 'Var', (152, 173))
191914	30627543	And these correlation reduced critical pairs were mostly participant in tumorigeneses and tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('participant', 'Reg', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('participant', 'Species', '9606', (57, 68))	('tumor progression', 'CPA', (90, 107))	('critical pairs', 'CPA', (30, 44))	('tumorigeneses', 'CPA', (72, 85))	('reduced', 'NegReg', (22, 29))	('correlation', 'Var', (10, 21))
191917	21547910	Somatic mutation of Fibroblast Growth Factor Receptor-3 (FGFR3) defines a distinct morphologic subtype of high-grade urothelial carcinoma FGFR3 mutations are common in low grade urothelial carcinoma and represent a potential therapeutic target in this disease.	('FGFR3', 'Gene', (57, 62))	('urothelial carcinoma', 'Disease', (117, 137))	('FGFR3', 'Gene', '2261', (138, 143))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (178, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('Fibroblast Growth Factor', 'molecular_function', 'GO:0005104', ('20', '44'))	('FGFR3', 'Gene', (138, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('138', '142'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (117, 137))	('Fibroblast Growth Factor Receptor-3', 'Gene', '2261', (20, 55))	('Fibroblast Growth Factor Receptor-3', 'Gene', (20, 55))	('urothelial carcinoma', 'Disease', (178, 198))	('FGFR3', 'Gene', '2261', (57, 62))	('FGFR', 'molecular_function', 'GO:0005007', ('57', '61'))	('common', 'Reg', (158, 164))	('mutations', 'Var', (144, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))
191919	21547910	We developed a mass spectrometry based genotyping assay to define the incidence of FGFR3 mutations in a large clinically annotated set of urothelial carcinomas.	('FGFR3', 'Gene', '2261', (83, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('83', '87'))	('FGFR3', 'Gene', (83, 88))	('urothelial carcinomas', 'Disease', (138, 159))	('mutations', 'Var', (89, 98))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (138, 159))
191920	21547910	FGFR3 mutations were found in 17% of HGUC versus 84% of low-grade lesions.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (0, 5))	('HGUC', 'Disease', (37, 41))	('found', 'Reg', (21, 26))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
191921	21547910	Retrospective pathologic review of the class of FGFR3 mutant HGUC revealed unique histologic features characterized by a bulky, exophytic component with branching papillary architecture as well as irregular nuclei with a koilocytoid appearance.	('mutant', 'Var', (54, 60))	('FGFR3', 'Gene', (48, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('FGFR3', 'Gene', '2261', (48, 53))
191922	21547910	Prospective histologic review was able to correctly predict for the presence of an FGFR3 mutation in 13 of 24 HGUC specimens that exhibited the distinct morphology (54%).	('FGFR3', 'Gene', '2261', (83, 88))	('abl', 'Chemical', 'MESH:C030358', (34, 37))	('mutation', 'Var', (89, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('83', '87'))	('FGFR3', 'Gene', (83, 88))	('men', 'Species', '9606', (120, 123))
191924	21547910	Macrodissection of individual tumors confirmed the presence of the FGFR3 mutant allele in non-invasive and invasive, low and high-grade regions of individual tumors and in the lymph node metastases of patients whose tumors possessed the characteristic morphologic signature, suggesting that FGFR3 mutations are not restricted to the more clinically indolent regions of HGUCs.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('metastases', 'Disease', (187, 197))	('tumors', 'Disease', (216, 222))	('FGFR', 'molecular_function', 'GO:0005007', ('291', '295'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('FGFR3', 'Gene', (291, 296))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('mutant', 'Var', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('FGFR3', 'Gene', '2261', (291, 296))	('tumors', 'Disease', (30, 36))	('patients', 'Species', '9606', (201, 209))	('FGFR3', 'Gene', (67, 72))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('FGFR3', 'Gene', '2261', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('metastases', 'Disease', 'MESH:D009362', (187, 197))
191926	21547910	Histologic review could thus aid in the development of targeted inhibitors of FGFR3 by facilitating the identification of the subset of patients most likely to harbor activating mutations in the FGFR3 gene.	('FGFR3', 'Gene', (78, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('78', '82'))	('FGFR3', 'Gene', (195, 200))	('FGFR', 'molecular_function', 'GO:0005007', ('195', '199'))	('patients', 'Species', '9606', (136, 144))	('men', 'Species', '9606', (47, 50))	('FGFR3', 'Gene', '2261', (78, 83))	('mutations', 'Var', (178, 187))	('activating', 'PosReg', (167, 177))	('FGFR3', 'Gene', '2261', (195, 200))
191938	21547910	In UC, FGFR3 is activated through point mutations that are largely found within exons 7, 10 and 15.	('FGFR3', 'Gene', '2261', (7, 12))	('point mutations', 'Var', (34, 49))	('activated', 'PosReg', (16, 25))	('FGFR3', 'Gene', (7, 12))	('FGFR', 'molecular_function', 'GO:0005007', ('7', '11'))
191939	21547910	Prior studies have reported that the majority of low-grade UC harbor activating mutations in FGFR3 whereas the incidence and prognostic relevance of FGFR3 mutations in HGUC lesions remains poorly defined.	('low-grade UC', 'Disease', (49, 61))	('FGFR', 'molecular_function', 'GO:0005007', ('149', '153'))	('FGFR3', 'Gene', '2261', (93, 98))	('FGFR3', 'Gene', '2261', (149, 154))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('FGFR3', 'Gene', (93, 98))	('FGFR3', 'Gene', (149, 154))	('activating mutations', 'Var', (69, 89))
191940	21547910	We examined a large cohort of clinically annotated bladder tumors with the goal of defining the frequency and morphologic features of FGFR3 mutations in patients with high-grade disease.	('bladder tumors', 'Disease', (51, 65))	('FGFR3', 'Gene', (134, 139))	('patients', 'Species', '9606', (153, 161))	('bladder tumor', 'Phenotype', 'HP:0009725', (51, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('bladder tumors', 'Disease', 'MESH:D001749', (51, 65))	('mutations', 'Var', (140, 149))	('FGFR3', 'Gene', '2261', (134, 139))	('bladder tumors', 'Phenotype', 'HP:0009725', (51, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('134', '138'))
191941	21547910	Our results indicate that although FGFR3 mutations occur with lower frequency in high-grade tumors as compared to those with low-grade disease, FGFR3 mutation status defines a distinct morphologic subtype of HGUC.	('mutations', 'Var', (41, 50))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('FGFR3', 'Gene', '2261', (144, 149))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR3', 'Gene', '2261', (35, 40))	('mutation', 'Var', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('FGFR3', 'Gene', (144, 149))	('HGUC', 'Disease', (208, 212))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('FGFR3', 'Gene', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))
191942	21547910	Furthermore, in contrast to the high prevalence of FGFR3 mutations in patients with favorable outcome, low-grade tumors, patients with HGUC whose tumors harbor a mutant FGFR3 allele have a similar risk of post-surgical recurrence and disease-specific mortality as those whose tumors are FGFR3 wild-type.	('FGFR', 'molecular_function', 'GO:0005007', ('169', '173'))	('tumors', 'Disease', (113, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('mutant', 'Var', (162, 168))	('post-surgical recurrence', 'CPA', (205, 229))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('patients', 'Species', '9606', (70, 78))	('abl', 'Chemical', 'MESH:C030358', (89, 92))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (276, 282))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('FGFR3', 'Gene', (51, 56))	('tumors', 'Disease', 'MESH:D009369', (276, 282))	('FGFR3', 'Gene', (169, 174))	('patients', 'Species', '9606', (121, 129))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('287', '291'))	('FGFR3', 'Gene', (287, 292))	('FGFR3', 'Gene', '2261', (51, 56))	('FGFR3', 'Gene', '2261', (169, 174))	('tumors', 'Disease', (146, 152))	('FGFR3', 'Gene', '2261', (287, 292))
191944	21547910	Furthermore, the association of FGFR3 mutations with a distinct papillary morphology suggests that histological examination may aid efforts to enrich clinical trials of agents targeting oncogenic FGFR3.	('FGFR3', 'Gene', (32, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('association', 'Interaction', (17, 28))	('FGFR3', 'Gene', '2261', (196, 201))	('FGFR3', 'Gene', (196, 201))	('FGFR3', 'Gene', '2261', (32, 37))	('papillary morphology', 'Phenotype', 'HP:0007482', (64, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('196', '200'))	('mutations', 'Var', (38, 47))
191950	21547910	In those samples harboring FGFR3 mutations, invasive and non-invasive, high and low-grade components were macro-dissected from corresponding formalin-fixed paraffin-embedded (FFPE) sections when available and sequenced for hotspot mutations in FGFR3.	('formalin', 'Chemical', 'MESH:D005557', (141, 149))	('FGFR3', 'Gene', '2261', (244, 249))	('FGFR3', 'Gene', '2261', (27, 32))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('FGFR', 'molecular_function', 'GO:0005007', ('244', '248'))	('mutations', 'Var', (33, 42))	('FGFR3', 'Gene', (244, 249))	('paraffin', 'Chemical', 'MESH:D010232', (156, 164))	('FGFR3', 'Gene', (27, 32))	('abl', 'Chemical', 'MESH:C030358', (200, 203))
191951	21547910	Additionally, matched normal tissue from each tumor, taken from the bladder wall in an area without evidence of gross morphologic abnormalities, was sequenced for all cases with FGFR3 mutations.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mutations', 'Var', (184, 193))	('tumor', 'Disease', (46, 51))	('FGFR3', 'Gene', (178, 183))	('FGFR', 'molecular_function', 'GO:0005007', ('178', '182'))	('FGFR3', 'Gene', '2261', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
191954	21547910	Detailed histopathologic examination of all hematoxylin & eosin (H&E) slides of the 133 samples was initially performed by a single genitourinary pathologist (HAA) and the morphologic characteristics of tumors with confirmed FGFR3 mutations, including tumor grade and stage, pattern of growth, the presence of a non-invasive component, and cellular and nuclear features, were confirmed with six pathologists, five of whom with expertise in genitourinary pathology (VER, SKT, OL, SWF, AG, YC).	('tumor', 'Disease', (203, 208))	('confirmed', 'Var', (215, 224))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('genitourinary pathology', 'Phenotype', 'HP:0000119', (440, 463))	('hematoxylin', 'Chemical', 'MESH:D006416', (44, 55))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('H&E', 'Chemical', '-', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('FGFR3', 'Gene', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('FGFR3', 'Gene', '2261', (225, 230))	('HAA', 'cellular_component', 'GO:0032117', ('159', '162'))	('eosin', 'Chemical', 'MESH:D004801', (58, 63))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('with', 'Gene', (210, 214))	('FGFR', 'molecular_function', 'GO:0005007', ('225', '229'))	('tumor', 'Disease', (252, 257))
191956	21547910	We later applied these morphologic characteristics to a separate, prospective cohort to determine whether their presence predicted for FGFR3 mutation status (described below).	('mutation status', 'Var', (141, 156))	('predicted', 'Reg', (121, 130))	('FGFR3', 'Gene', '2261', (135, 140))	('FGFR3', 'Gene', (135, 140))	('FGFR', 'molecular_function', 'GO:0005007', ('135', '139'))
191959	21547910	Tumors were screened for FGFR3 hotspot mutations using an iPLEX assay developed specifically for this purpose (Sequenom, Inc., San Diego, CA).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('FGFR3', 'Gene', '2261', (25, 30))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('mutations', 'Var', (39, 48))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('FGFR3', 'Gene', (25, 30))
191960	21547910	To determine the prevalence of FGFR3 mutations in HGUC, we sequenced all coding exons of FGFR3 for 133 frozen tumors, all of which exhibited high-grade morphology.	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('FGFR3', 'Gene', '2261', (31, 36))	('FGFR3', 'Gene', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('mutations', 'Var', (37, 46))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('FGFR3', 'Gene', (31, 36))	('FGFR3', 'Gene', '2261', (89, 94))
191961	21547910	Eighteen samples (13%) harbored FGFR3 mutations.	('harbored', 'Reg', (23, 31))	('FGFR3', 'Gene', (32, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('FGFR3', 'Gene', '2261', (32, 37))	('mutations', 'Var', (38, 47))
191962	21547910	Two samples contained non-hotspot mutations (D468N and S131L) and one of these samples (with the S131L mutation) also harbored a second S249C mutation.	('S131L', 'Mutation', 'rs766911583', (55, 60))	('S131L', 'Mutation', 'rs766911583', (97, 102))	('S249C', 'Mutation', 'rs121913483', (136, 141))	('D468N', 'Var', (45, 50))	('S131L', 'Var', (55, 60))	('D468N', 'Mutation', 'rs761196249', (45, 50))	('S249C', 'Var', (136, 141))
191963	21547910	To facilitate rapid screening for FGFR3 mutations within our sample set, we developed a MALDI-TOF MS Sequenom assay (described above) to detect hotspot mutations within FGFR3, including both the more commonly reported R248C, S249C, and Y375C mutations as well as the less frequent G370C and S371C alterations.	('FGFR3', 'Gene', '2261', (34, 39))	('Y375C', 'Mutation', 'rs121913485', (236, 241))	('Y375C', 'Var', (236, 241))	('S371C', 'Mutation', 'rs121913484', (291, 296))	('FGFR', 'molecular_function', 'GO:0005007', ('169', '173'))	('FGFR3', 'Gene', (34, 39))	('S371C', 'Var', (291, 296))	('S249C', 'Var', (225, 230))	('FGFR3', 'Gene', '2261', (169, 174))	('R248C', 'Var', (218, 223))	('G370C', 'Mutation', 'rs199740841', (281, 286))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('S249C', 'Mutation', 'rs121913483', (225, 230))	('FGFR3', 'Gene', (169, 174))	('R248C', 'Mutation', 'rs121913482', (218, 223))	('G370C', 'Var', (281, 286))
191964	21547910	Representative MS and corresponding Sanger traces for tumors with the S249C and Y375C FGFR3 mutations are shown in Figure 1.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('FGFR3', 'Gene', '2261', (86, 91))	('S249C', 'Var', (70, 75))	('S249C', 'Mutation', 'rs121913483', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('FGFR3', 'Gene', (86, 91))	('Y375C', 'Var', (80, 85))	('FGFR', 'molecular_function', 'GO:0005007', ('86', '90'))	('Y375C', 'Mutation', 'rs121913485', (80, 85))	('tumors', 'Disease', (54, 60))
191965	21547910	The morphologic characteristics of the eighteen tumors harboring FGFR3 mutations were reviewed and compared to the cohort of tumors wild-type for FGFR3.	('FGFR', 'molecular_function', 'GO:0005007', ('146', '150'))	('FGFR3', 'Gene', '2261', (65, 70))	('FGFR3', 'Gene', '2261', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('FGFR3', 'Gene', (65, 70))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('mutations', 'Var', (71, 80))	('FGFR3', 'Gene', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
191966	21547910	All eighteen FGFR3 mutant tumors were noted to be bulky and polypoid, with protrusion of the tumor mass into the lumen of the urinary bladder.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (93, 98))	('men', 'Species', '9606', (115, 118))	('FGFR3', 'Gene', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('mutant', 'Var', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('FGFR3', 'Gene', '2261', (13, 18))	('tumors', 'Disease', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
191973	21547910	While all cases were high-grade carcinomas, in ten of eighteen FGFR3 mutant cases a component of low-grade cytomorphology was also detected.	('FGFR3', 'Gene', '2261', (63, 68))	('mutant', 'Var', (69, 75))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('FGFR3', 'Gene', (63, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (32, 42))	('carcinomas', 'Disease', 'MESH:D002277', (32, 42))	('carcinomas', 'Disease', (32, 42))
191977	21547910	By histopathologic examination the following features were noted in the FGFR3 mutant tumors (Figure 2):  To determine whether the presence of these morphologic features were predictive of FGFR3 mutation status in a prospective cohort, we identified 24 additional tumors that possessed morphologic characteristics similar to the samples identified as FGFR3 mutant from 161 consecutive patients (15%).	('FGFR3', 'Gene', '2261', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('FGFR3', 'Gene', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Disease', (85, 91))	('FGFR3', 'Gene', '2261', (188, 193))	('patients', 'Species', '9606', (384, 392))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('mutant', 'Var', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('FGFR', 'molecular_function', 'GO:0005007', ('188', '192'))	('FGFR3', 'Gene', (350, 355))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('FGFR', 'molecular_function', 'GO:0005007', ('350', '354'))	('FGFR3', 'Gene', (72, 77))	('tumors', 'Disease', (263, 269))	('FGFR3', 'Gene', '2261', (350, 355))
191981	21547910	For comparison, we selected from the same consecutive cohort of 161 patients, 25 additional HGUC tumors, not otherwise specified, that specifically lacked the morphologic features identified in the FGFR3 mutated group (Figure 3).	('FGFR', 'molecular_function', 'GO:0005007', ('198', '202'))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutated', 'Var', (204, 211))	('patients', 'Species', '9606', (68, 76))	('FGFR3', 'Gene', '2261', (198, 203))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('FGFR3', 'Gene', (198, 203))
191982	21547910	The 49 samples were then profiled for FGFR3 hotspot mutations utilizing the Sequenom assay and putative mutations were subsequently confirmed by Sanger sequencing.	('mutations', 'Var', (52, 61))	('FGFR3', 'Gene', '2261', (38, 43))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('FGFR3', 'Gene', (38, 43))
191984	21547910	In summary, thirteen of the 24 tumors that exhibited the distinctive morphology identified previously harbored FGFR3 mutations, resulting in a positive predictive value of 54%, whereas all 25 tumors lacking the distinctive morphology were FGFR3 wild-type (negative predictive value of 100%).	('mutations', 'Var', (117, 126))	('harbored', 'Reg', (102, 110))	('FGFR3', 'Gene', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('FGFR', 'molecular_function', 'GO:0005007', ('239', '243'))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('FGFR3', 'Gene', '2261', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('FGFR3', 'Gene', '2261', (239, 244))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('FGFR3', 'Gene', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
191985	21547910	Notably, the identical FGFR3 mutations found in the primary tumor were also present in the metastatic component of the corresponding lymph node pairs.	('FGFR3', 'Gene', (23, 28))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('abl', 'Chemical', 'MESH:C030358', (3, 6))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('FGFR3', 'Gene', '2261', (23, 28))	('present', 'Reg', (76, 83))	('tumor', 'Disease', (60, 65))
191986	21547910	(Figure 3) Because a prominent feature of the above-described FGFR3 mutation-associated morphology was the presence of a large exophytic, noninvasive component, and as FGFR3 mutations are commonly found in low grade, superficial bladder tumors, we isolated the invasive and non-invasive components of eight FGFR3 mutant tumors from FFPE sections by macro-dissection and genotyped DNA extracted from each component.	('FGFR3', 'Gene', '2261', (168, 173))	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('bladder tumors', 'Disease', 'MESH:D001749', (229, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('mutant', 'Var', (313, 319))	('tumors', 'Disease', 'MESH:D009369', (320, 326))	('FGFR', 'molecular_function', 'GO:0005007', ('168', '172'))	('FGFR3', 'Gene', (62, 67))	('DNA', 'cellular_component', 'GO:0005574', ('380', '383'))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('FGFR', 'molecular_function', 'GO:0005007', ('307', '311'))	('FGFR3', 'Gene', '2261', (62, 67))	('tumors', 'Disease', (237, 243))	('bladder tumors', 'Disease', (229, 243))	('FGFR3', 'Gene', (307, 312))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('bladder tumors', 'Phenotype', 'HP:0009725', (229, 243))	('bladder tumor', 'Phenotype', 'HP:0009725', (229, 242))	('FGFR3', 'Gene', '2261', (307, 312))	('tumors', 'Phenotype', 'HP:0002664', (320, 326))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('FGFR3', 'Gene', (168, 173))	('tumors', 'Disease', (320, 326))
191987	21547910	In six of eight samples (75%), the FGFR3 mutation was detected in both the invasive and non-invasive components.	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR3', 'Gene', '2261', (35, 40))	('detected', 'Reg', (54, 62))	('mutation', 'Var', (41, 49))	('FGFR3', 'Gene', (35, 40))
191988	21547910	Of the two remaining samples, one contained an R248C mutation in only the invasive section while the other possessed an S249C mutation only in a high-grade noninvasive region (Table 1).	('R248C', 'Mutation', 'rs121913482', (47, 52))	('S249C', 'Mutation', 'rs121913483', (120, 125))	('R248C', 'Var', (47, 52))	('abl', 'Chemical', 'MESH:C030358', (177, 180))	('S249C', 'Var', (120, 125))
191989	21547910	In all three cases, FGFR3 mutations were detected in both the low and high-grade components.	('FGFR3', 'Gene', '2261', (20, 25))	('FGFR3', 'Gene', (20, 25))	('mutations', 'Var', (26, 35))	('detected', 'Reg', (41, 49))	('FGFR', 'molecular_function', 'GO:0005007', ('20', '24'))
191990	21547910	We compared the frequency and allele specificity of FGFR3 mutations in our 133 HGUC samples with sixty-three paraffin-embedded low-grade samples.	('mutations', 'Var', (58, 67))	('FGFR3', 'Gene', '2261', (52, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('paraffin', 'Chemical', 'MESH:D010232', (109, 117))	('FGFR3', 'Gene', (52, 57))
191991	21547910	As depicted in Figure 4A, 84% of the low-grade samples harbored an FGFR3 mutation, a rate consistent with that previously reported.	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('FGFR3', 'Gene', (67, 72))	('harbored', 'Reg', (55, 63))	('FGFR3', 'Gene', '2261', (67, 72))	('mutation', 'Var', (73, 81))
191992	21547910	Notably, despite the association of FGFR3 mutations with a favorable prognosis in low grade UC, no statistically significant difference in outcome was observed in the high-grade cohort as a function of FGFR3 mutant status (Figure 4C).	('low grade UC', 'Disease', (82, 94))	('abl', 'Chemical', 'MESH:C030358', (64, 67))	('FGFR3', 'Gene', (36, 41))	('association', 'Interaction', (21, 32))	('FGFR3', 'Gene', '2261', (202, 207))	('abl', 'Chemical', 'MESH:C030358', (3, 6))	('FGFR', 'molecular_function', 'GO:0005007', ('202', '206'))	('FGFR3', 'Gene', (202, 207))	('FGFR3', 'Gene', '2261', (36, 41))	('mutations', 'Var', (42, 51))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
191993	21547910	The clinical characteristics and disease outcomes of all 30 unique FGFR3 mutant high-grade cases identified in both the retrospective and prospective cohorts are depicted in Table 2.	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('FGFR3', 'Gene', (67, 72))	('abl', 'Chemical', 'MESH:C030358', (175, 178))	('mutant', 'Var', (73, 79))	('FGFR3', 'Gene', '2261', (67, 72))
191995	21547910	A comparison of the clinical characteristics between the FGFR3 mutant and wild type cohorts is provided in Table 3.	('FGFR3', 'Gene', (57, 62))	('mutant', 'Var', (63, 69))	('FGFR3', 'Gene', '2261', (57, 62))	('abl', 'Chemical', 'MESH:C030358', (108, 111))	('FGFR', 'molecular_function', 'GO:0005007', ('57', '61'))
191998	21547910	Examples include imatinib in patients with chronic myelogenous leukemia (abl) and gastro-intestinal stromal tumor (c-kit), erlotinib in non-small cell lung cancer (EGFR) and most recently PLX4032 in melanoma (BRAF).	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (43, 71))	('EGFR', 'Gene', (164, 168))	('leukemia', 'Phenotype', 'HP:0001909', (63, 71))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (136, 162))	('PLX4032', 'Var', (188, 195))	('c-kit', 'Gene', (115, 120))	('erlotinib', 'Chemical', 'MESH:D000069347', (123, 132))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('melanoma', 'Disease', (199, 207))	('gastro-intestinal stromal tumor', 'Disease', 'MESH:D046152', (82, 113))	('patients', 'Species', '9606', (29, 37))	('gastro-intestinal stromal tumor', 'Phenotype', 'HP:0100723', (82, 113))	('abl', 'Chemical', 'MESH:C030358', (73, 76))	('non-small cell lung cancer', 'Disease', (136, 162))	('gastro-intestinal stromal tumor', 'Disease', (82, 113))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (43, 71))	('EGFR', 'Gene', '1956', (164, 168))	('chronic myelogenous leukemia', 'Disease', (43, 71))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (51, 71))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('c-kit', 'Gene', '3815', (115, 120))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('imatinib', 'Chemical', 'MESH:D000068877', (17, 25))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (136, 162))	('EGFR', 'molecular_function', 'GO:0005006', ('164', '168'))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (140, 162))
191999	21547910	In the case of imatinib, abl translocations are pathognomonic for chronic myelogenous leukemia and thus pre-treatment patient selection beyond classical cytological characterization is not required in order to identify the population of patients most likely to respond.	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (66, 94))	('pathognomonic', 'Reg', (48, 61))	('chronic myelogenous leukemia', 'Disease', (66, 94))	('abl', 'Gene', (25, 28))	('translocations', 'Var', (29, 43))	('abl', 'Chemical', 'MESH:C030358', (25, 28))	('imatinib', 'Chemical', 'MESH:D000068877', (15, 23))	('patient', 'Species', '9606', (237, 244))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (66, 94))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('men', 'Species', '9606', (113, 116))	('pre', 'molecular_function', 'GO:0003904', ('104', '107'))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (74, 94))	('patient', 'Species', '9606', (118, 125))	('patients', 'Species', '9606', (237, 245))
192000	21547910	In contrast, it is now apparent that solid tumors as traditionally classified by tissue of origin harbor a diversity of mutations that confer overlapping selective advantage.	('solid tumors', 'Disease', 'MESH:D009369', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutations', 'Var', (120, 129))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('solid tumors', 'Disease', (37, 49))
192001	21547910	For example, EGFR, KRAS and BRAF mutations are all non-overlapping in non-small cell lung cancer.	('BRAF', 'Gene', '673', (28, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (74, 96))	('KRAS', 'Gene', (19, 23))	('mutations', 'Var', (33, 42))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (70, 96))	('KRAS', 'Gene', '3845', (19, 23))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (70, 96))	('BRAF', 'Gene', (28, 32))	('EGFR', 'Gene', '1956', (13, 17))	('non-small cell lung cancer', 'Disease', (70, 96))	('EGFR', 'Gene', (13, 17))
192002	21547910	Such observations suggest that the response of patients to targeted kinase inhibitors will depend strongly upon the complement of mutations within an individual patient's tumor and that such predictors (both positive and negative) can be identified.	('patient', 'Species', '9606', (47, 54))	('patient', 'Species', '9606', (161, 168))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('patients', 'Species', '9606', (47, 55))	('mutations', 'Var', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('men', 'Species', '9606', (122, 125))
192003	21547910	The experience with EGFR targeted inhibitors in lung cancer further suggests that it is preferable to know the tumor genotype of patients prospectively in order to use this information to select the appropriate patients for trial.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('patients', 'Species', '9606', (211, 219))	('EGFR', 'Gene', (20, 24))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('patients', 'Species', '9606', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('20', '24'))	('inhibitors', 'Var', (34, 44))	('tumor', 'Disease', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('abl', 'Chemical', 'MESH:C030358', (94, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('EGFR', 'Gene', '1956', (20, 24))
192008	21547910	Most of these FGFR3 mutations occur in the extracellular domain of FGFR-3 and promote constitutive receptor dimerization and activation.	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('promote', 'PosReg', (78, 85))	('FGFR3', 'Gene', '2261', (14, 19))	('constitutive receptor dimerization', 'MPA', (86, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('FGFR-3', 'Gene', (67, 73))	('FGFR3', 'Gene', (14, 19))	('activation', 'MPA', (125, 135))	('FGFR-3', 'Gene', '2261', (67, 73))	('extracellular', 'cellular_component', 'GO:0005576', ('43', '56'))	('mutations', 'Var', (20, 29))
192009	21547910	These findings along with additional preclinical studies using human cancer cell lines expressing mutant FGFR3 suggest that tumors expressing an activating FGFR3 mutant allele may be selectively sensitive to inhibitors of this kinase.	('FGFR3', 'Gene', (105, 110))	('FGFR3', 'Gene', (156, 161))	('human', 'Species', '9606', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutant', 'Var', (162, 168))	('activating', 'PosReg', (145, 155))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('FGFR3', 'Gene', '2261', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('FGFR3', 'Gene', '2261', (156, 161))	('FGFR', 'molecular_function', 'GO:0005007', ('156', '160'))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))	('mutant', 'Var', (98, 104))	('cancer', 'Disease', (69, 75))
192010	21547910	As the bulk of the morbidity and mortality of bladder cancer is attributable to the development of muscularis propria-invasive high-grade disease, we sought to determine the frequency of FGFR3 mutations in high-grade bladder cancer and their prognostic relevance in this population.	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('bladder cancer', 'Phenotype', 'HP:0009725', (217, 231))	('bladder cancer', 'Disease', 'MESH:D001749', (46, 60))	('bladder cancer', 'Disease', (46, 60))	('men', 'Species', '9606', (91, 94))	('mutations', 'Var', (193, 202))	('FGFR3', 'Gene', '2261', (187, 192))	('abl', 'Chemical', 'MESH:C030358', (72, 75))	('bladder cancer', 'Disease', 'MESH:D001749', (217, 231))	('bladder cancer', 'Disease', (217, 231))	('bladder cancer', 'Phenotype', 'HP:0009725', (46, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('187', '191'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('muscularis propria', 'Phenotype', 'HP:0030936', (99, 117))	('FGFR3', 'Gene', (187, 192))
192011	21547910	Although the frequency of FGFR3 mutation was lower in high grade (17%) versus low-grade (84%) urothelial cancers, in patients with HGUC, FGFR3 mutation was associated with an equally aggressive disease course as that of wild type tumors, with a high rate of recurrence and progression to muscularis propria-invasive disease.	('FGFR3', 'Gene', '2261', (137, 142))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('urothelial cancers', 'Disease', (94, 112))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('lower', 'NegReg', (45, 50))	('type tumors', 'Disease', 'MESH:D009369', (225, 236))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (117, 125))	('FGFR', 'molecular_function', 'GO:0005007', ('137', '141'))	('mutation', 'Var', (32, 40))	('muscularis propria', 'Phenotype', 'HP:0030936', (288, 306))	('urothelial cancers', 'Disease', 'MESH:D014523', (94, 112))	('muscularis propria-invasive disease', 'Disease', (288, 323))	('aggressive disease', 'Disease', (183, 201))	('mutation', 'Var', (143, 151))	('type tumors', 'Disease', (225, 236))	('aggressive disease', 'Disease', 'MESH:D001523', (183, 201))	('muscularis propria-invasive disease', 'Disease', 'MESH:D009362', (288, 323))	('FGFR3', 'Gene', (26, 31))	('FGFR3', 'Gene', (137, 142))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('FGFR3', 'Gene', '2261', (26, 31))
192012	21547910	The poor outcome overall of patients with FGFR3 mutant HGUC justifies the testing of selective inhibitors of this kinase in patients with this disease.	('mutant', 'Var', (48, 54))	('FGFR3', 'Gene', '2261', (42, 47))	('FGFR3', 'Gene', (42, 47))	('patients', 'Species', '9606', (28, 36))	('patients', 'Species', '9606', (124, 132))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))
192013	21547910	The high prevalence of FGFR3 mutations in low grade UC may, likewise, represent and attractive target for inhibition in this patient group.	('FGFR3', 'Gene', (23, 28))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('low grade UC', 'Disease', (42, 54))	('mutations', 'Var', (29, 38))	('FGFR3', 'Gene', '2261', (23, 28))	('patient', 'Species', '9606', (125, 132))
192014	21547910	The low frequency of FGFR3 mutation in the high-grade cohort, however, raises a number of logistical hurdles to the accrual of sufficient patients with advanced bladder cancer to trials of selective FGFR-3 inhibitors.	('FGFR3', 'Gene', '2261', (21, 26))	('patients', 'Species', '9606', (138, 146))	('FGFR-3', 'Gene', '2261', (199, 205))	('bladder cancer', 'Phenotype', 'HP:0009725', (161, 175))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('FGFR3', 'Gene', (21, 26))	('mutation', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('bladder cancer', 'Disease', 'MESH:D001749', (161, 175))	('FGFR', 'molecular_function', 'GO:0005007', ('199', '203'))	('bladder cancer', 'Disease', (161, 175))	('FGFR-3', 'Gene', (199, 205))
192015	21547910	With the goal of facilitating the identification of high-grade tumors harboring FGFR3 mutations, we compared in detail the morphologic appearance of FGFR3 mutant and wild-type tumors.	('mutations', 'Var', (86, 95))	('type tumors', 'Disease', (171, 182))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('FGFR', 'molecular_function', 'GO:0005007', ('149', '153'))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('mutant', 'Var', (155, 161))	('FGFR3', 'Gene', '2261', (149, 154))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('FGFR3', 'Gene', '2261', (80, 85))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('FGFR3', 'Gene', (149, 154))	('FGFR3', 'Gene', (80, 85))	('type tumors', 'Disease', 'MESH:D009369', (171, 182))
192016	21547910	Our retrospective review of 133 high-grade tumors found that FGFR3 mutation was associated with specific, easily recognizable histopathologic features that were characterized by the presence of a prominent exophytic, papillary component lined with polygonal cells possessing koilocytoid nuclei.	('FGFR3', 'Gene', (61, 66))	('mutation', 'Var', (67, 75))	('FGFR', 'molecular_function', 'GO:0005007', ('61', '65'))	('FGFR3', 'Gene', '2261', (61, 66))	('abl', 'Chemical', 'MESH:C030358', (121, 124))	('associated', 'Reg', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
192017	21547910	Our prospectively identified case control test set of 24 tumors exhibiting the predictive morphologic features and the 25 tumors lacking these features, further supports the importance of careful histopathologic review, as FGFR3 mutations were identified in 54% of the cases in the former group whereas all 25 control cases of the latter group were FGFR3 wild type.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('FGFR3', 'Gene', '2261', (223, 228))	('mutations', 'Var', (229, 238))	('identified', 'Reg', (244, 254))	('FGFR', 'molecular_function', 'GO:0005007', ('349', '353'))	('FGFR3', 'Gene', (349, 354))	('FGFR3', 'Gene', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('FGFR3', 'Gene', '2261', (349, 354))	('FGFR', 'molecular_function', 'GO:0005007', ('223', '227'))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
192018	21547910	These results suggest that detailed histological evaluation of HGUC can aid in the identification of patients with FGFR3 mutations and thus facilitate the recruitment of such patients to trials of selective FGFR-3 inhibitors.	('FGFR', 'molecular_function', 'GO:0005007', ('115', '119'))	('patients', 'Species', '9606', (101, 109))	('mutations', 'Var', (121, 130))	('men', 'Species', '9606', (162, 165))	('FGFR3', 'Gene', '2261', (115, 120))	('FGFR-3', 'Gene', (207, 213))	('patients', 'Species', '9606', (175, 183))	('FGFR', 'molecular_function', 'GO:0005007', ('207', '211'))	('FGFR-3', 'Gene', '2261', (207, 213))	('FGFR3', 'Gene', (115, 120))
192019	21547910	Interestingly, the suggestive morphology of FGFR3 mutation accurately predicted the presence of such mutations in primary tumors of the upper tract, including renal pelvis and ureter, in addition to urinary bladder tumors.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('bladder tumors', 'Disease', (207, 221))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('renal pelvis', 'Disease', 'MESH:D010386', (159, 171))	('tumors', 'Disease', (215, 221))	('mutation', 'Var', (50, 58))	('bladder tumor', 'Phenotype', 'HP:0009725', (207, 220))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('bladder tumors', 'Phenotype', 'HP:0009725', (207, 221))	('renal pelvis', 'Disease', (159, 171))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('mutations', 'Var', (101, 110))	('FGFR3', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('FGFR3', 'Gene', '2261', (44, 49))	('ureter', 'Disease', (176, 182))	('tumors', 'Disease', (122, 128))	('bladder tumors', 'Disease', 'MESH:D001749', (207, 221))	('renal pelvis', 'Phenotype', 'HP:0000125', (159, 171))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
192021	21547910	Notably, 11 of 24 (46%) of the tumors in the prospective set that displayed some or all the features that predict for the presence of FGFR3 mutations were wild-type for the hotspot mutations included with our Sequenom assay.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('FGFR3', 'Gene', (134, 139))	('tumors', 'Disease', (31, 37))	('abl', 'Chemical', 'MESH:C030358', (3, 6))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('mutations', 'Var', (140, 149))	('FGFR3', 'Gene', '2261', (134, 139))	('FGFR', 'molecular_function', 'GO:0005007', ('134', '138'))
192022	21547910	As the prospective set consisted entirely of FFPE samples, it is possible that in some of these cases, our failure to detect FGFR3 mutations may have been attributable to the lower sensitivity of this assay in FFPE as compared to frozen tissue.	('mutations', 'Var', (131, 140))	('FGFR3', 'Gene', '2261', (125, 130))	('FGFR', 'molecular_function', 'GO:0005007', ('125', '129'))	('abl', 'Chemical', 'MESH:C030358', (163, 166))	('FGFR3', 'Gene', (125, 130))
192023	21547910	Alternatively, such cases may have harbored non-hotspot FGFR3 mutants not included within our Sequenom panel or genomic alterations that phenocopy FGFR3 mutation such as receptor amplification or FGF ligand overexpression.	('receptor', 'Reg', (170, 178))	('overexpression', 'PosReg', (207, 221))	('FGFR3', 'Gene', '2261', (147, 152))	('mutants', 'Var', (62, 69))	('FGFR3', 'Gene', '2261', (56, 61))	('FGFR', 'molecular_function', 'GO:0005007', ('56', '60'))	('FGFR3', 'Gene', (147, 152))	('FGFR3', 'Gene', (56, 61))	('ligand', 'molecular_function', 'GO:0005488', ('200', '206'))	('FGFR', 'molecular_function', 'GO:0005007', ('147', '151'))	('FGF', 'Protein', (196, 199))	('mutation', 'Var', (153, 161))
192024	21547910	In support of this latter possibility, two FGFR3 mutant tumors from the 133 frozen samples in which all FGFR3 coding exons were sequenced contained non-hotspot mutations (D468N and S131L), which have not been reported in the Catalogue of Somatic Mutations in Human Cancer but similarly possessed an extensive exophytic papillary component indistinguishable from the tumors harboring the commonly recurrent hotspot mutations.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (366, 372))	('FGFR3', 'Gene', '2261', (104, 109))	('FGFR', 'molecular_function', 'GO:0005007', ('104', '108'))	('tumors', 'Disease', (56, 62))	('Cancer', 'Phenotype', 'HP:0002664', (265, 271))	('D468N', 'Var', (171, 176))	('abl', 'Chemical', 'MESH:C030358', (352, 355))	('S131L', 'Mutation', 'rs766911583', (181, 186))	('tumors', 'Disease', 'MESH:D009369', (366, 372))	('mutant', 'Var', (49, 55))	('S131L', 'Var', (181, 186))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('Cancer', 'Disease', (265, 271))	('Human', 'Species', '9606', (259, 264))	('FGFR3', 'Gene', (43, 48))	('exophytic papillary', 'Phenotype', 'HP:0007482', (309, 328))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('FGFR3', 'Gene', '2261', (43, 48))	('Cancer', 'Disease', 'MESH:D009369', (265, 271))	('tumors', 'Phenotype', 'HP:0002664', (366, 372))	('D468N', 'Mutation', 'rs761196249', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('FGFR3', 'Gene', (104, 109))
192025	21547910	The presence of an FGFR3 mutation in HGUC does not ensure that these tumors remain dependent upon this kinase.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mutation', 'Var', (25, 33))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('FGFR3', 'Gene', '2261', (19, 24))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('FGFR3', 'Gene', (19, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))
192027	21547910	It is possible that FGFR3 mutations are key drivers of tumor growth and survival in low-grade tumors but that additional genetic events relegate FGFR3 mutations to passenger status in the high-grade tumors in which they are found.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumors', 'Disease', (199, 205))	('mutations', 'Var', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('FGFR3', 'Gene', (20, 25))	('tumors', 'Disease', (94, 100))	('mutations', 'Var', (151, 160))	('tumor', 'Disease', (199, 204))	('FGFR3', 'Gene', '2261', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('FGFR3', 'Gene', (145, 150))	('FGFR', 'molecular_function', 'GO:0005007', ('20', '24'))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('FGFR3', 'Gene', '2261', (145, 150))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('FGFR', 'molecular_function', 'GO:0005007', ('145', '149'))
192028	21547910	Twenty of the 31 FGFR3 mutant high-grade tumors in our series exhibited evidence of a low-grade component.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('FGFR3', 'Gene', '2261', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('low-grade', 'CPA', (86, 95))	('FGFR3', 'Gene', (17, 22))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('mutant', 'Var', (23, 29))
192029	21547910	Careful dissection and genetic analysis of the high- and low-grade components from three such tumors clearly demonstrated that the FGFR3 mutation was present in the high-grade component and confirmed that our finding of FGFR3 mutations in such tumors was not artifactual due to the presence and intermixing of a second low-grade component.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('FGFR3', 'Gene', '2261', (220, 225))	('mutation', 'Var', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('FGFR3', 'Gene', '2261', (131, 136))	('FGFR', 'molecular_function', 'GO:0005007', ('131', '135'))	('FGFR3', 'Gene', (220, 225))	('tumors', 'Disease', (244, 250))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('mutations', 'Var', (226, 235))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('FGFR3', 'Gene', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('220', '224'))
192030	21547910	Furthermore, given the concordance of the mutant alleles between high and low-grade components, our data suggest that in such tumors, the low-grade disease was in fact a precursor to the high-grade disease.	('mutant', 'Var', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
192033	21547910	Finally, as FGFR3 mutations are predominantly found in superficial low grade UC, it was possible that the detected mutations within our high-grade set may have been present only in the exophytic, non-invasive regions of the tumors whereas the invasive component may have been FGFR3 wild-type.	('FGFR3', 'Gene', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('FGFR3', 'Gene', '2261', (276, 281))	('superficial low grade UC', 'Disease', (55, 79))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('FGFR', 'molecular_function', 'GO:0005007', ('276', '280'))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))	('FGFR3', 'Gene', '2261', (12, 17))	('FGFR3', 'Gene', (276, 281))	('mutations', 'Var', (18, 27))
192034	21547910	Using the Sequenom assay on FFPE material consisting of only the invasive component, however, we were able to confirm the presence of an FGFR3 mutation in the invasive component for all but one of the tumors for which sufficient tissue was available for analysis (Table 1).	('FGFR3', 'Gene', '2261', (137, 142))	('presence', 'Reg', (122, 130))	('abl', 'Chemical', 'MESH:C030358', (102, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('137', '141'))	('FGFR3', 'Gene', (137, 142))	('mutation', 'Var', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('abl', 'Chemical', 'MESH:C030358', (265, 268))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('abl', 'Chemical', 'MESH:C030358', (245, 248))
192035	21547910	Moreover, in both FGFR3 mutant cases for which metastatic material from pelvic lymph nodes was available, the identifiable FGFR3 mutant was detectable in both the primary and metastatic lesion.	('mutant', 'Var', (24, 30))	('FGFR3', 'Gene', '2261', (123, 128))	('FGFR3', 'Gene', '2261', (18, 23))	('abl', 'Chemical', 'MESH:C030358', (146, 149))	('FGFR3', 'Gene', (123, 128))	('FGFR3', 'Gene', (18, 23))	('abl', 'Chemical', 'MESH:C030358', (100, 103))	('FGFR', 'molecular_function', 'GO:0005007', ('123', '127'))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('abl', 'Chemical', 'MESH:C030358', (118, 121))
192036	21547910	These data provide further support to the contention that FGFR3 mutations are present in a subset of high-grade metastatic urothelial cancers.	('FGFR3', 'Gene', '2261', (58, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('urothelial cancers', 'Disease', 'MESH:D014523', (123, 141))	('FGFR3', 'Gene', (58, 63))	('mutations', 'Var', (64, 73))	('urothelial cancers', 'Disease', (123, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('present', 'Reg', (78, 85))
192037	21547910	Future studies will be needed, however, to confirm that mutant FGFR3 remains biologically relevant in this context and thus represents a rational therapeutic target.	('mutant', 'Var', (56, 62))	('FGFR3', 'Gene', '2261', (63, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('FGFR3', 'Gene', (63, 68))
192108	21344025	In the current study, the sensitivity of MDCTU was increased with increasing distended bladder volume, and true-positive patients had an acceptable bladder volume (227 ml).	('increased', 'PosReg', (51, 60))	('MDCTU', 'Var', (41, 46))	('distended bladder', 'Phenotype', 'HP:0003270', (77, 94))	('distended bladder volume', 'MPA', (77, 101))	('patients', 'Species', '9606', (121, 129))	('sensitivity', 'MPA', (26, 37))	('MDCTU', 'Chemical', '-', (41, 46))
192179	30214686	On the other hand, urine cytology and BTA assays were able to detect bladder cancer under the same settings only with AUC 0.50 to 0.59 and AUC 0.51 to 0.53, respectively.	('AUC 0.51', 'Var', (139, 147))	('bladder cancer', 'Disease', (69, 83))	('detect', 'Reg', (62, 68))	('bladder cancer', 'Disease', 'MESH:D001749', (69, 83))	('AUC 0.50 to 0.59', 'Var', (118, 134))	('bladder cancer', 'Phenotype', 'HP:0009725', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('BTA', 'Chemical', '-', (38, 41))
192187	30214686	To investigate the practical values of these genes, the diagnostic performance of these genes was also evaluated under hypothetical clinical settings, suggesting these genes may be supplementary to urine cytology as these genes can detect bladder cancer even in the patient population whose cytology results are negative or suspicious.	('patient', 'Species', '9606', (266, 273))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('genes', 'Var', (222, 227))	('bladder cancer', 'Disease', 'MESH:D001749', (239, 253))	('bladder cancer', 'Disease', (239, 253))	('detect', 'Reg', (232, 238))	('bladder cancer', 'Phenotype', 'HP:0009725', (239, 253))
192205	30214686	recently reported that FGFR3 and PIK3CA mutation in urinary cell free DNA allows detection of non-muscle invasive bladder cancer including risks of progression and recurrence.	('FGFR3', 'Gene', (23, 28))	('mutation', 'Var', (40, 48))	('invasive bladder', 'Phenotype', 'HP:0100645', (105, 121))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('-muscle invasive bladder cancer', 'Phenotype', 'HP:0006740', (97, 128))	('PIK3CA', 'Gene', '5290', (33, 39))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (94, 121))	('non-muscle invasive bladder cancer', 'Disease', (94, 128))	('non-muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (94, 128))	('FGFR3', 'Gene', '2261', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('bladder cancer', 'Phenotype', 'HP:0009725', (114, 128))	('PIK3CA', 'Gene', (33, 39))
192231	29228614	CM-transfer increased pro-apoptotic caspase-3 activity, increased cleaved caspase-3 and cleaved PARP expression and reduced survival protein XIAP expression.	('cleaved caspase-3', 'MPA', (66, 83))	('increased', 'PosReg', (56, 65))	('PARP', 'Gene', (96, 100))	('XIAP', 'Gene', (141, 145))	('cleaved', 'MPA', (88, 95))	('increased', 'PosReg', (12, 21))	('XIAP', 'Gene', '331', (141, 145))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('36', '54'))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('36', '54'))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('pro-apoptotic', 'CPA', (22, 35))	('reduced', 'NegReg', (116, 123))	('CM-transfer', 'Var', (0, 11))	('PARP', 'Gene', '142', (96, 100))
192242	29228614	Therefore, the cellular radiation response incorporates both direct effects and indirect bystander effects leading to genetic instability, diminished survival, apoptosis and necrosis.	('apoptosis', 'CPA', (160, 169))	('necrosis', 'biological_process', 'GO:0008220', ('174', '182'))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('necrosis', 'Disease', 'MESH:D009336', (174, 182))	('necrosis', 'biological_process', 'GO:0001906', ('174', '182'))	('survival', 'CPA', (150, 158))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('genetic', 'Var', (118, 125))	('necrosis', 'biological_process', 'GO:0070265', ('174', '182'))	('diminished', 'NegReg', (139, 149))	('necrosis', 'biological_process', 'GO:0008219', ('174', '182'))	('necrosis', 'Disease', (174, 182))	('necrosis', 'biological_process', 'GO:0019835', ('174', '182'))
192243	29228614	Radiation bystander effects have been described in normal bladder explants correlated with aberrant urothelial outgrowth which may be a protective response to urothelial loss that occurs during RT, associated with irritative radiation cystitis.	('irritative radiation cystitis', 'Disease', (214, 243))	('irritative radiation cystitis', 'Disease', 'MESH:D004194', (214, 243))	('urothelial loss', 'Disease', 'MESH:D014522', (159, 174))	('aberrant', 'Var', (91, 99))	('urothelial loss', 'Disease', (159, 174))
192250	29228614	HT1376 urothelial carcinoma cells, had the expected increased foci in uniformly-irradiated vs non-irradiated flasks (Figure 1C), however, similar numbers of foci per nucleus in shielded regions vs non-irradiated cells were observed (p>0.05) indicating absence of a bystander response.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('increased', 'PosReg', (52, 61))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (7, 27))	('nucleus', 'cellular_component', 'GO:0005634', ('166', '173'))	('HT1376', 'CellLine', 'CVCL:1292', (0, 6))	('HT1376', 'Var', (0, 6))	('urothelial carcinoma', 'Disease', (7, 27))	('foci', 'MPA', (62, 66))
192254	29228614	Summary data of the surviving fractions (Figure 3A) demonstrates HT1376 cells to be more radioresistant and normal SV-HUC and T24 to be more radiosensitive.	('HT1376', 'Var', (65, 71))	('radioresistant', 'CPA', (89, 103))	('SV-HUC', 'Disease', (115, 121))	('HT1376', 'CellLine', 'CVCL:1292', (65, 71))	('SV-HUC', 'Disease', 'None', (115, 121))
192264	29228614	In both conditions, cells expressed increased pro-apoptotic proteins; cleaved caspase-3, cleaved PARP and reduced XIAP (inhibitor of apoptosis proteins).	('PARP', 'Gene', '142', (97, 101))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('XIAP', 'Gene', (114, 118))	('pro-apoptotic', 'MPA', (46, 59))	('increased', 'PosReg', (36, 45))	('caspase-3', 'Protein', (78, 87))	('PARP', 'Gene', (97, 101))	('XIAP', 'Gene', '331', (114, 118))	('cleaved', 'Var', (89, 96))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('reduced', 'NegReg', (106, 113))	('cleaved', 'Var', (70, 77))
192269	29228614	The ATP diphosphohydrolase, apyrase (breaks down ATP, 10U/ml) decreased the surviving fraction to 0.83+-0.05 (p<0.05, Figure 5A), confirmed by the presence of cleaved caspase-3 and cleaved PARP, consistent with activation of apoptosis (Figure 5B).	('breaks down', 'Phenotype', 'HP:0001061', (37, 48))	('ATP', 'Gene', '51761', (4, 7))	('decreased', 'NegReg', (62, 71))	('ATP', 'Gene', (4, 7))	('ATP', 'Gene', (49, 52))	('PARP', 'Gene', (189, 193))	('ATP', 'Gene', '51761', (49, 52))	('ATP diphosphohydrolase', 'molecular_function', 'GO:0047693', ('4', '26'))	('surviving fraction', 'CPA', (76, 94))	('activation of apoptosis', 'biological_process', 'GO:0043065', ('211', '234'))	('caspase-3', 'Protein', (167, 176))	('PARP', 'Gene', '142', (189, 193))	('cleaved', 'MPA', (159, 166))	('cleaved', 'Var', (181, 188))	('activation of apoptosis', 'biological_process', 'GO:0006915', ('211', '234'))
192283	29228614	Both 0Gy CM and 8Gy CM evoked Ca2+ transients in recipient cells, consistent with the finding that ATP is released from non-irradiated cells and at a larger concentration from irradiated cells (see above).	('ATP', 'Gene', (99, 102))	('Ca2+ transients', 'MPA', (30, 45))	('ATP', 'Gene', '51761', (99, 102))	('0Gy CM', 'Var', (5, 11))	('evoked', 'Reg', (23, 29))	('Ca2+', 'Chemical', 'MESH:D000069285', (30, 34))
192294	29228614	HT1376 (doubling time 36h vs 19h T24), there is also increased resistance in early G1.	('early', 'Protein', (77, 82))	('HT1376', 'CellLine', 'CVCL:1292', (0, 6))	('increased', 'PosReg', (53, 62))	('resistance', 'MPA', (63, 73))	('HT1376', 'Var', (0, 6))
192308	29228614	T24 rely on basal ATP for survival as promotion or prevention of ATP breakdown by apyrase or ARL67156 respectively reduced survival, indicative of ATP homeostasis.	('promotion', 'PosReg', (38, 47))	('ATP', 'Gene', (147, 150))	('ARL67156', 'Var', (93, 101))	('reduced', 'NegReg', (115, 122))	('ATP', 'Gene', (65, 68))	('ATP', 'Gene', (18, 21))	('ATP', 'Gene', '51761', (18, 21))	('ATP', 'Gene', '51761', (147, 150))	('ATP', 'Gene', '51761', (65, 68))	('ATP breakdown', 'biological_process', 'GO:0006200', ('65', '78'))	('homeostasis', 'biological_process', 'GO:0042592', ('151', '162'))	('survival', 'MPA', (123, 131))	('ARL67156', 'Chemical', 'MESH:C092431', (93, 101))
192311	29228614	Reduction of xenograft urothelial or prostate tumour growth by daily intraperitoneal injections of ATP (mM) has been reported, moreover, inhibition of purinergic receptors also decreases tumour growth.	('ATP', 'Gene', (99, 102))	('tumour growth', 'Disease', 'MESH:D006130', (187, 200))	('ATP', 'Gene', '51761', (99, 102))	('xenograft urothelial or prostate tumour', 'Disease', 'MESH:D011471', (13, 52))	('purinergic receptors', 'Protein', (151, 171))	('inhibition', 'Var', (137, 147))	('tumour growth', 'Disease', (46, 59))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('xenograft urothelial or prostate tumour', 'Disease', (13, 52))	('decreases', 'NegReg', (177, 186))	('tumour growth', 'Disease', (187, 200))	('Reduction', 'NegReg', (0, 9))	('prostate tumour', 'Phenotype', 'HP:0100787', (37, 52))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour growth', 'Disease', 'MESH:D006130', (46, 59))
192316	29228614	HT1376 cells express (P2X4,5,7 and P2Y1,2,4,6,11)), however as they did not exhibit bystander responses in the present study, they were not studied further.	('P2Y', 'molecular_function', 'GO:0045028', ('35', '38'))	('HT1376', 'CellLine', 'CVCL:1292', (0, 6))	('P2Y1', 'Gene', (35, 39))	('P2Y1', 'Gene', '5028', (35, 39))	('P2X4,5,7', 'Var', (22, 30))
192320	29228614	Activation of the pro-apoptotic signaling pathway including executioner cleaved caspase 3 and cleaved PARP is consistent with the CM-evoked Ca2+-responses as both caspase 3 and PARP are known to be Ca2+-dependent.	('pro-apoptotic signaling pathway', 'Pathway', (18, 49))	('Ca2+', 'Chemical', 'MESH:D000069285', (140, 144))	('PARP', 'Gene', (102, 106))	('caspase 3', 'Gene', (80, 89))	('cleaved', 'Var', (94, 101))	('caspase 3', 'Gene', (163, 172))	('caspase 3', 'Gene', '836', (163, 172))	('PARP', 'Gene', '142', (177, 181))	('caspase 3', 'Gene', '836', (80, 89))	('PARP', 'Gene', '142', (102, 106))	('apoptotic signaling pathway', 'biological_process', 'GO:0097190', ('22', '49'))	('Ca2+', 'Chemical', 'MESH:D000069285', (198, 202))	('PARP', 'Gene', (177, 181))
192323	29228614	Urothelial carcinoma cells T24 (McCoy's 5A), HT1376 MEM), immortalised normal urothelial cells SV-HUC (F12K), were purchased from ATCC; primary normal HUC (Urothelial Cell Medium) were obtained from ScienCell Research Laboratories.	('Urothelial carcinoma', 'Disease', 'MESH:D014526', (0, 20))	('HUC', 'Gene', '1995', (98, 101))	('F12K', 'SUBSTITUTION', 'None', (103, 107))	('F12K', 'Var', (103, 107))	('Urothelial carcinoma', 'Disease', (0, 20))	('HUC', 'Gene', '1995', (151, 154))	('urothelial cells SV-HUC', 'Disease', 'MESH:D014522', (78, 101))	('HT1376', 'CellLine', 'CVCL:1292', (45, 51))	('HUC', 'Gene', (98, 101))	('urothelial cells SV-HUC', 'Disease', (78, 101))	('HUC', 'Gene', (151, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
192332	29228614	T24 cells (2 x 106) in T25 flasks were treated with 50muM ARL67156 (Tocris), an ecto-ATPase inhibitor to prevent ATP hydrolysis, before irradiation at 0, 0.5, 2 and 8 Gy as described above (X-Rad 225).	('muM', 'Gene', (54, 57))	('ATP', 'Gene', (85, 88))	('ATP', 'Gene', '51761', (85, 88))	('ATP', 'Gene', (113, 116))	('ATP', 'Gene', '51761', (113, 116))	('ARL67156', 'Var', (58, 66))	('ARL67156', 'Chemical', 'MESH:C092431', (58, 66))	('ATP hydrolysis', 'biological_process', 'GO:0006200', ('113', '127'))	('muM', 'Gene', '56925', (54, 57))	('Rad', 'biological_process', 'GO:1990116', ('192', '195'))
192398	26881187	PSA, PSAP, AMACR/P504S, EMA, cytokeratins AE1/AE3, 7, 8, and 20.	('EMA', 'Disease', (24, 27))	('PSAP', 'Disease', (5, 9))	('P504S', 'Var', (17, 22))	('PSA', 'Disease', (0, 3))	('P504S', 'SUBSTITUTION', 'None', (17, 22))
192405	26881187	reported an 81-year-old man who underwent transurethral resection of bladder tumour and also received a total of 60 Gy of external beam radiotherapy for a T3N1M0 lymphoepithelioma-like variant of urothelial carcinoma who did not develop any recurrence at regular cystoscopies and on assessment of follow-up computed tomography scans but died of other causes 48 months later.	('bladder tumour', 'Disease', (69, 83))	('bladder tumour', 'Phenotype', 'HP:0009725', (69, 83))	('T3N1M0', 'Var', (155, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('bladder tumour', 'Disease', 'MESH:D001749', (69, 83))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
192419	26881187	The frequent presence of UroVysion FISH abnormalities, urothelial carcinoma in situ, and p53 positivity on immunohistochemical studies in cases of urinary tract lymphoepithelioma-like carcinoma would suggest a similar pathogenesis to high-grade invasive urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (245, 274))	('urinary tract lymphoepithelioma-like carcinoma', 'Disease', 'MESH:D014552', (147, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('urinary tract lymphoepithelioma-like carcinoma', 'Disease', (147, 193))	('FISH abnormalities', 'Disease', 'MESH:D000014', (35, 53))	('FISH abnormalities', 'Disease', (35, 53))	('pathogenesis', 'biological_process', 'GO:0009405', ('218', '230'))	('positivity', 'Var', (93, 103))	('p53', 'Gene', (89, 92))	('invasive urothelial carcinoma', 'Disease', (245, 274))	('urothelial', 'Disease', (55, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))
192421	26881187	The features of lymphoepithelioma-like carcinoma they examined included light microscopy; immunohistochemistry for cytokeratin 7 (CK7), CK20, 34betaE12, p53, alpha-methylacyl-CoA racemase, thyroid transcription factor-1, Epstein-Barr virus latent membrane protein-1, and CD30; in situ hybridization for human papillomavirus; and UroVysion fluorescence in situ hybridization.	('transcription factor', 'molecular_function', 'GO:0000981', ('197', '217'))	('thyroid transcription factor-1', 'Gene', '7080', (189, 219))	('membrane', 'cellular_component', 'GO:0016020', ('247', '255'))	('CK20', 'Var', (136, 140))	('transcription', 'biological_process', 'GO:0006351', ('197', '210'))	('lymphoepithelioma-like carcinoma', 'Disease', (16, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('CK7', 'Gene', (130, 133))	('thyroid transcription factor-1', 'Gene', (189, 219))	('human papillomavirus', 'Species', '10566', (303, 323))	('CD30', 'Gene', '943', (271, 275))	('protein', 'cellular_component', 'GO:0003675', ('256', '263'))	('CK7', 'Gene', '3855', (130, 133))	('CD30', 'Gene', (271, 275))
192428	25246945	We uncover the existence of an underlying gene network that at least partially controls cancer 'survivalness', with mutations that are significantly correlated with patient survival, yet independent of tumour origin and type.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('controls', 'Reg', (79, 87))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('patient', 'Species', '9606', (165, 172))	('mutations', 'Var', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Disease', (202, 208))
192432	25246945	Cancer is also a genomic disease in which genetic/epigenetic mutations contribute to tumour progression and heterogeneity.	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('contribute', 'Reg', (71, 81))	('genetic/epigenetic mutations', 'Var', (42, 70))	('tumour', 'Disease', (85, 91))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
192449	25246945	TCGA mutation and survival data were obtained from the supplemental tables published in, retaining for analysis only cancer patients with survival information available.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (124, 132))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('TCGA', 'Gene', (0, 4))	('cancer', 'Disease', (117, 123))	('mutation', 'Var', (5, 13))
192450	25246945	This results in somatic mutational profiles for 3,096 patients with mutations in 19,171 genes (mapped to the Entrez Genes).	('mutations', 'Var', (68, 77))	('patients', 'Species', '9606', (54, 62))	('results', 'Reg', (5, 12))
192453	25246945	Survival analysis was applied to TCGA mutation and survival data based on the Cox proportional hazards model.	('TCGA', 'Gene', (33, 37))	('Cox', 'Gene', '1351', (78, 81))	('Cox', 'Gene', (78, 81))	('mutation', 'Var', (38, 46))
192457	25246945	The calculated Cox HR and P value are indicative of prognostic value: the extent to which mutation status for a gene correlates with patient survival advantage (after adjusting for age, gender and tumour type).	('tumour type', 'Disease', (197, 208))	('tumour type', 'Disease', 'MESH:D009369', (197, 208))	('patient survival advantage', 'CPA', (133, 159))	('patient', 'Species', '9606', (133, 140))	('Cox', 'Gene', '1351', (15, 18))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))	('mutation status', 'Var', (90, 105))	('Cox', 'Gene', (15, 18))
192485	25246945	In addition, dGSEA is also applied to look at the tendency of these survival genes to be at the top of the gene list pre-ranked according to: cross-tumour mutation ubiquity, mutation frequency within a single tumour type, and mutation numbers in each individual patient.	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('mutation', 'Var', (174, 182))	('tumour type', 'Disease', (209, 220))	('cross-tumour', 'Disease', (142, 154))	('tumour type', 'Disease', 'MESH:D009369', (209, 220))	('cross-tumour', 'Disease', 'MESH:C537866', (142, 154))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('patient', 'Species', '9606', (262, 269))	('pre', 'molecular_function', 'GO:0003904', ('117', '120'))	('GSEA', 'Chemical', '-', (14, 18))
192496	25246945	By analysing the 'TCGA' mutation and clinical data of patients covering multiple tumour types, we uncovered a core gene network indicative of cross-tumour patient survival (Figure 3; also see Additional file 1).	('patient', 'Species', '9606', (54, 61))	('tumour type', 'Disease', (81, 92))	('multiple tumour', 'Disease', 'MESH:D009369', (72, 87))	('patients', 'Species', '9606', (54, 62))	("'TCGA'", 'Gene', (17, 23))	('tumour type', 'Disease', 'MESH:D009369', (81, 92))	('cross-tumour', 'Disease', (142, 154))	('patient', 'Species', '9606', (155, 162))	('multiple tumour', 'Disease', (72, 87))	('cross-tumour', 'Disease', 'MESH:C537866', (142, 154))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('core', 'cellular_component', 'GO:0019013', ('110', '114'))	('mutation', 'Var', (24, 32))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
192505	25246945	For example, two tumour types of lung tissue of origins (LUAD and LUSC) locate at the bottom, with the highest proportion of survival genes frequently mutated.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('survival genes', 'Gene', (125, 139))	('tumour type', 'Disease', (17, 28))	('tumour type', 'Disease', 'MESH:D009369', (17, 28))	('mutated', 'Var', (151, 158))
192527	25246945	Prognostic power is seen when compared to the naive use (chosen at random); an average of 10-fold increases in Cox HR will be expected using genes in the survival network.	('Cox', 'Gene', '1351', (111, 114))	('increases', 'PosReg', (98, 107))	('Cox', 'Gene', (111, 114))	('genes', 'Var', (141, 146))
192537	25246945	Viewing genes in the survival network as a signature, we conducted gene set enrichment analysis (GSEA) to look at the extent to which these genes are enriched in terms of cross-tumour mutation ubiquity, mutation frequency within a single tumour type, and mutation numbers for each individual patient (Figure 7).	('cross-tumour', 'Disease', (171, 183))	('cross-tumour', 'Disease', 'MESH:C537866', (171, 183))	('GSEA', 'Chemical', '-', (97, 101))	('patient', 'Species', '9606', (292, 299))	('mutation', 'Var', (203, 211))	('tumour type', 'Disease', 'MESH:D009369', (238, 249))	('tumour', 'Phenotype', 'HP:0002664', (238, 244))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('tumour type', 'Disease', (238, 249))
192547	25246945	When simultaneously displaying the mutation frequency matrix and their first-created ancestors for survival genes (Figure 8), we notice a tendency for Deuterostomia-originated genes to mutate ubiquitously across tumour types.	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('Deuterostomia', 'Disease', 'None', (151, 164))	('tumour type', 'Disease', 'MESH:D009369', (212, 223))	('tumour type', 'Disease', (212, 223))	('mutate', 'Var', (185, 191))	('Deuterostomia', 'Disease', (151, 164))
192561	25246945	Applying dnet in analysing all of the 'TCGA' mutation and clinical data of >3,000 patients covering multiple tumour types (Figure 1), we uncovered a network of genes (Figure 3) for which most of their mutations are significantly correlated with patient survival.	('tumour type', 'Disease', (109, 120))	('mutations', 'Var', (201, 210))	('patient', 'Species', '9606', (82, 89))	('multiple tumour', 'Disease', (100, 115))	('patients', 'Species', '9606', (82, 90))	('tumour type', 'Disease', 'MESH:D009369', (109, 120))	('multiple tumour', 'Disease', 'MESH:D009369', (100, 115))	("'TCGA'", 'Gene', (38, 44))	('correlated', 'Reg', (229, 239))	('mutation', 'Var', (45, 53))	('patient survival', 'CPA', (245, 261))	('patient', 'Species', '9606', (245, 252))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
192572	22873290	Urothelial carcinoma of the upper urinary tract diagnosed via FGFR3 mutation detection in urine: a case report Upper urinary tract cancer is typically diagnosed with urine cytology and imaging techniques.	('cancer', 'Disease', (131, 137))	('Urothelial carcinoma of the upper urinary', 'Phenotype', 'HP:0010935', (0, 41))	('FGFR3', 'Gene', '2261', (62, 67))	('mutation', 'Var', (68, 76))	('Urothelial carcinoma', 'Disease', 'MESH:D014526', (0, 20))	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('Upper urinary tract cancer', 'Phenotype', 'HP:0010935', (111, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Urothelial carcinoma', 'Disease', (0, 20))	('FGFR3', 'Gene', (62, 67))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (117, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
192576	22873290	This assay evaluates the presence of mutations in fibroblast growth factor receptor 3 (FGFR3).	('FGFR3', 'Gene', '2261', (87, 92))	('fibroblast growth factor receptor 3', 'Gene', '2261', (50, 85))	('mutations', 'Var', (37, 46))	('FGFR3', 'Gene', (87, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('fibroblast growth factor receptor 3', 'Gene', (50, 85))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('50', '74'))
192577	22873290	Mutations in FGFR3 are known to be associated with urothelial carcinoma and have a positive predictive value of 95% when detected in patients with no history of TCC.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('patients', 'Species', '9606', (133, 141))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (51, 71))	('TCC', 'cellular_component', 'GO:0005579', ('161', '164'))	('FGFR3', 'Gene', (13, 18))	('associated with', 'Reg', (35, 50))	('Mutations', 'Var', (0, 9))	('FGFR3', 'Gene', '2261', (13, 18))	('urothelial carcinoma', 'Disease', (51, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
192578	22873290	A mutation in exon 10 (Y375C) of FGFR3 was identified.	('Y375C', 'Mutation', 'rs121913485', (23, 28))	('Y375C', 'Var', (23, 28))	('FGFR3', 'Gene', '2261', (33, 38))	('FGFR3', 'Gene', (33, 38))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))
192580	22873290	In addition, PCR analysis on isolated tumor tissue indicated the tumor carried the same FGFR3 mutation as that of the DNA isolated from urine, consistent with the tumor being the origin of the mutant DNA.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('FGFR3', 'Gene', (88, 93))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', (163, 168))	('FGFR3', 'Gene', '2261', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('DNA', 'cellular_component', 'GO:0005574', ('200', '203'))	('FGFR', 'molecular_function', 'GO:0005007', ('88', '92'))	('mutation', 'Var', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
192586	22873290	Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) occur in >50% of low-grade and low-stage bladder tumors (about 64-85% of pTa tumors carry FGFR3 mutations).	('pTa tumors', 'Disease', (145, 155))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('pTa tumors', 'Disease', 'MESH:D009369', (145, 155))	('bladder tumors', 'Phenotype', 'HP:0009725', (113, 127))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('mutations', 'Var', (168, 177))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('FGFR3', 'Gene', (162, 167))	('bladder tumor', 'Phenotype', 'HP:0009725', (113, 126))	('fibroblast growth factor receptor 3', 'Gene', (28, 63))	('pTa', 'molecular_function', 'GO:0008959', ('145', '148'))	('bladder tumors', 'Disease', 'MESH:D001749', (113, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('FGFR3', 'Gene', (65, 70))	('FGFR3', 'Gene', '2261', (162, 167))	('FGFR', 'molecular_function', 'GO:0005007', ('162', '166'))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('28', '52'))	('FGFR3', 'Gene', '2261', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('bladder tumors', 'Disease', (113, 127))	('fibroblast growth factor receptor 3', 'Gene', '2261', (28, 63))
192587	22873290	Eight common FGFR3 mutations in 3 exons (exons 7, 10, and 15) are associated with >90% of all known mutant FGFR3 positive bladder cancers.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('bladder cancers', 'Phenotype', 'HP:0009725', (122, 137))	('bladder cancer', 'Phenotype', 'HP:0009725', (122, 136))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('mutant', 'Var', (100, 106))	('FGFR3', 'Gene', '2261', (107, 112))	('bladder cancers', 'Disease', 'MESH:D001749', (122, 137))	('associated with', 'Reg', (66, 81))	('mutations', 'Var', (19, 28))	('FGFR3', 'Gene', (13, 18))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('FGFR3', 'Gene', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('bladder cancers', 'Disease', (122, 137))	('positive bladder', 'Phenotype', 'HP:0100645', (113, 129))	('FGFR3', 'Gene', '2261', (13, 18))
192588	22873290	Several urine-based genetic assays have been developed to detect FGFR3 mutations in patients with bladder cancer with sensitivity ranging from 58-92%.	('FGFR3', 'Gene', '2261', (65, 70))	('patients', 'Species', '9606', (84, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('FGFR3', 'Gene', (65, 70))	('mutations', 'Var', (71, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
192598	22873290	Prior to initiating more invasive diagnostic methods, a real-time PCR-based genetic assay was used to determine if the patient's urine contained DNA that carried FGFR3 mutations in exons 7, 10, or 15.	('patient', 'Species', '9606', (119, 126))	('DNA', 'cellular_component', 'GO:0005574', ('145', '148'))	('FGFR3', 'Gene', '2261', (162, 167))	('FGFR', 'molecular_function', 'GO:0005007', ('162', '166'))	('FGFR3', 'Gene', (162, 167))	('mutations in', 'Var', (168, 180))
192600	22873290	A mutation was detected in exon 10 (Y375C) of FGFR3, indicating a high probability (94.7% PPV) that the patient had urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (116, 136))	('Y375C', 'Mutation', 'rs121913485', (36, 41))	('Y375C', 'Var', (36, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('FGFR3', 'Gene', '2261', (46, 51))	('urothelial carcinoma', 'Disease', (116, 136))	('patient', 'Species', '9606', (104, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('FGFR3', 'Gene', (46, 51))
192607	22873290	Tumor tissue obtained from the archival paraffin block was found, using quantitative PCR, to have an exon 10 (Y375C) mutation, which is consistent with the tumor being the source of the mutant DNA found in the urine.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('DNA', 'cellular_component', 'GO:0005574', ('193', '196'))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('paraffin', 'Chemical', 'MESH:D010232', (40, 48))	('tumor', 'Disease', (156, 161))	('Y375C', 'Mutation', 'rs121913485', (110, 115))	('Y375C', 'Var', (110, 115))
192609	22873290	We performed a postoperative CertNDx test in March 2012, 7 months after the nephroureterectomy, which was negative for the presence of FGFR3 mutant DNA.	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('mutant', 'Var', (141, 147))	('FGFR3', 'Gene', '2261', (135, 140))	('FGFR3', 'Gene', (135, 140))	('FGFR', 'molecular_function', 'GO:0005007', ('135', '139'))
192612	22873290	We describe a case in which the urine based CertNDx  Bladder Cancer Assay, for mutations in FGFR3, played a pivotal role in diagnosing urothelial cancer in the urinary tract of a patient.	('urothelial cancer', 'Disease', 'MESH:D014523', (135, 152))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('FGFR3', 'Gene', (92, 97))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (53, 67))	('patient', 'Species', '9606', (179, 186))	('cancer in the urinary tract', 'Phenotype', 'HP:0010786', (146, 173))	('diagnosing', 'Reg', (124, 134))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('urothelial cancer', 'Disease', (135, 152))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('FGFR3', 'Gene', '2261', (92, 97))	('mutations', 'Var', (79, 88))
192617	22873290	Analysis of mutations in the FGFR3 gene, using the urine based CertNDx  Bladder Cancer Assay, detected cancer indicating that the tumor was malignant; which was subsequently confirmed by pathology.	('FGFR3', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (12, 21))	('detected', 'Reg', (94, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('29', '33'))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('FGFR3', 'Gene', '2261', (29, 34))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (72, 86))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', (130, 135))
192620	22873290	In a prior clinical trial of 200 patients with low-grade non-muscle-invasive bladder tumors, analysis of FGFR3 mutations identified 3 patients with upper urinary tract recurrent cancer that were not detected by cystoscopy.	('mutations', 'Var', (111, 120))	('FGFR3', 'Gene', (105, 110))	('bladder tumors', 'Disease', 'MESH:D001749', (77, 91))	('patients', 'Species', '9606', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('urinary tract recurrent', 'Phenotype', 'HP:0000010', (154, 177))	('invasive bladder', 'Phenotype', 'HP:0100645', (68, 84))	('upper urinary tract recurrent', 'Phenotype', 'HP:0002788', (148, 177))	('bladder tumors', 'Phenotype', 'HP:0009725', (77, 91))	('patients', 'Species', '9606', (134, 142))	('bladder tumors', 'Disease', (77, 91))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('bladder tumor', 'Phenotype', 'HP:0009725', (77, 90))	('FGFR3', 'Gene', '2261', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
192635	33576304	More intriguingly, CD155 expression had a significant interaction with immune function in several tumors by analyzing Tumor mutational burden and microsatellite in stability, immune score and stromal score.	('tumors', 'Disease', (98, 104))	('CD155', 'Gene', '5817', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('microsatellite', 'Var', (146, 160))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('CD155', 'Gene', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Tumor', 'Phenotype', 'HP:0002664', (118, 123))	('interaction', 'Reg', (54, 65))
192697	33576304	There is also evidence that CD155/CD226 interaction can attenuate the generation of CD8+ T cells by regulating NK T-cell differentiation.	('CD8', 'Gene', '925', (84, 87))	('attenuate', 'NegReg', (56, 65))	('CD226', 'Gene', '10666', (34, 39))	('CD155', 'Gene', '5817', (28, 33))	('interaction', 'Var', (40, 51))	('regulating', 'Reg', (100, 110))	('NK T-cell differentiation', 'CPA', (111, 136))	('CD155', 'Gene', (28, 33))	('CD8', 'Gene', (84, 87))	('NK T-cell differentiation', 'biological_process', 'GO:0001865', ('111', '136'))	('CD226', 'Gene', (34, 39))
192708	33576304	ACC Adrenocortical carcinoma BLCA Bladder Urothelial Carcinoma BRCA Breast invasive carcinoma CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma CHOL Cholangio carcinoma COAD Colon adenocarcinoma DLBC Lymphoid Neoplasm Diffuse Large B-cell Lymphoma ESCA Esophageal carcinoma GBM Glioblastoma multiforme HNSC Head and Neck squamous cell carcinoma KICH Kidney Chromophobe KIRC Kidney renal clear cell carcinoma KIRP Kidney renal papillary cell carcinoma LAML Acute Myeloid Leukemia LGG Brain Lower Grade Glioma LIHC Liver hepatocellular carcinoma LUAD Lung adenocarcinoma TME tumor microenvironment OS overall survival DSS Disease-specific survival LUSC Lung squamous cell carcinoma MESO Mesothelioma OV Ovarian serous cystadenocarcinoma PAAD Pancreatic adenocarcinoma PCPG Pheochromocytoma and Paraganglioma PRAD Prostate adenocarcinoma READ Rectum adenocarcinoma SARC Sarcoma SKCM Skin Cutaneous Melanoma STAD Stomach adenocarcinoma TGCT Testicular Germ Cell Tumors THCA Thyroid carcinoma THYM Thymoma UCEC Uterine Corpus Endometrial Carcinoma UCS Uterine Carcinosarcoma UVM Uveal Melanoma TMB Tumor mutational burden MSI microsatellite in stability DFI Disease-free interval PFI Progression-free interval	('Tumor', 'Phenotype', 'HP:0002664', (978, 983))	('carcinoma', 'Disease', 'MESH:D009369', (179, 188))	('carcinoma', 'Disease', (845, 854))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (394, 427))	('Kidney renal papillary cell carcinoma', 'Disease', (433, 470))	('KICH', 'Disease', (365, 369))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (990, 1007))	('tumor', 'Phenotype', 'HP:0002664', (593, 598))	('Adrenocortical carcinoma', 'Disease', (4, 28))	('Sarcoma', 'Disease', (887, 894))	('Kidney Chromophobe', 'Disease', (370, 388))	('serous cystadenocarcinoma', 'Disease', (729, 754))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (1034, 1062))	('Breast invasive carcinoma', 'Disease', 'MESH:D001943', (68, 93))	('Paraganglioma', 'Phenotype', 'HP:0002668', (812, 825))	('carcinoma', 'Disease', (998, 1007))	('carcinoma', 'Disease', (776, 785))	('carcinoma', 'Disease', (579, 588))	('CHOL', 'Disease', 'None', (164, 168))	('Breast invasive carcinoma', 'Phenotype', 'HP:0003002', (68, 93))	('Urothelial Carcinoma', 'Disease', (42, 62))	('Neck squamous cell carcinoma', 'Disease', (336, 364))	('Acute Myeloid Leukemia', 'Disease', (476, 498))	('carcinoma', 'Disease', (554, 563))	('Melanoma', 'Disease', 'MESH:D008545', (915, 923))	('carcinoma', 'Disease', 'MESH:D009369', (461, 470))	('Pheochromocytoma and Paraganglioma', 'Disease', 'MESH:D010673', (791, 825))	('Melanoma', 'Disease', (1100, 1108))	('Pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (760, 785))	('carcinoma', 'Disease', 'MESH:D009369', (284, 293))	('carcinoma', 'Disease', (179, 188))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (990, 1007))	('Cholangio carcinoma', 'Phenotype', 'HP:0030153', (169, 188))	('Pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (760, 785))	('Pancreatic adenocarcinoma', 'Disease', (760, 785))	('Colon adenocarcinoma', 'Disease', 'MESH:D003110', (194, 214))	('Rectum adenocarcinoma', 'Disease', 'MESH:D012004', (860, 881))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (831, 854))	('CHOL', 'Disease', (164, 168))	('carcinoma', 'Disease', 'MESH:D009369', (872, 881))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinoma', 'Disease', 'MESH:D009369', (418, 427))	('Melanoma', 'Phenotype', 'HP:0002861', (915, 923))	('Head and Neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (327, 364))	('squamous cell carcinoma', 'Disease', (108, 131))	('Cholangio carcinoma', 'Disease', (169, 188))	('Lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (671, 699))	('Carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('Breast invasive carcinoma', 'Disease', (68, 93))	('Kidney Chromophobe', 'Disease', 'MESH:D000238', (370, 388))	('carcinoma', 'Disease', (461, 470))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (136, 163))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (569, 588))	('Myeloid Leukemia', 'Phenotype', 'HP:0012324', (482, 498))	('carcinoma', 'Disease', (872, 881))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('Mesothelioma', 'Disease', (705, 717))	('Kidney renal clear cell carcinoma', 'Disease', (394, 427))	('Thymoma', 'Disease', (1013, 1020))	('Corpus Endometrial Carcinoma', 'Disease', (1034, 1062))	('ACC', 'Gene', '31', (0, 3))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (539, 563))	('Liver hepatocellular carcinoma', 'Disease', (533, 563))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (533, 563))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('Rectum adenocarcinoma', 'Disease', (860, 881))	('tumor', 'Disease', (593, 598))	('Neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (336, 364))	('carcinoma', 'Disease', (418, 427))	('KICH', 'Disease', 'None', (365, 369))	('TME', 'Chemical', '-', (589, 592))	('Stomach adenocarcinoma', 'Disease', (929, 951))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('DSS', 'Gene', '5376', (636, 639))	('tumor', 'Disease', 'MESH:D009369', (593, 598))	('clear cell carcinoma KIRP Kidney', 'Phenotype', 'HP:0006770', (407, 439))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (4, 28))	('Prostate adenocarcinoma', 'Disease', (831, 854))	('Lymphoma', 'Phenotype', 'HP:0002665', (259, 267))	('Skin Cutaneous Melanoma', 'Disease', (900, 923))	('carcinoma', 'Disease', 'MESH:D009369', (942, 951))	('carcinoma', 'Disease', 'MESH:D009369', (355, 364))	('carcinoma', 'Disease', 'MESH:D009369', (690, 699))	('serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (729, 754))	('Thymoma', 'Disease', 'MESH:D013945', (1013, 1020))	('Leukemia', 'Phenotype', 'HP:0001909', (490, 498))	('carcinoma', 'Disease', 'MESH:D009369', (745, 754))	('carcinoma', 'Disease', 'MESH:D009369', (84, 93))	('TMB', 'Chemical', '-', (1109, 1112))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (791, 807))	('Stomach adenocarcinoma', 'Disease', 'MESH:D000230', (929, 951))	('carcinoma', 'Disease', (19, 28))	('Carcinoma', 'Phenotype', 'HP:0030731', (1053, 1062))	('COAD', 'Disease', 'MESH:D029424', (189, 193))	('carcinoma', 'Disease', 'MESH:D009369', (19, 28))	('Glioma', 'Disease', (521, 527))	('MESO Mesothelioma', 'Phenotype', 'HP:0100001', (700, 717))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (341, 364))	('B-cell Lymphoma', 'Phenotype', 'HP:0012191', (252, 267))	('Tumors', 'Disease', 'MESH:D009369', (978, 984))	('carcinoma', 'Disease', 'MESH:D009369', (154, 163))	('Cholangio carcinoma', 'Disease', 'MESH:D009369', (169, 188))	('Glioblastoma', 'Phenotype', 'HP:0012174', (298, 310))	('Melanoma', 'Disease', 'MESH:D008545', (1100, 1108))	('Lung squamous cell carcinoma', 'Disease', (671, 699))	('carcinoma', 'Disease', (284, 293))	('Ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (721, 754))	('Acute Myeloid Leukemia', 'Disease', 'MESH:D015470', (476, 498))	('DSS', 'Gene', (636, 639))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (900, 923))	('carcinoma', 'Disease', (942, 951))	('Carcinosarcoma', 'Disease', 'MESH:D002296', (1075, 1089))	('PFI', 'molecular_function', 'GO:0034016', ('1195', '1198'))	('carcinoma', 'Disease', (745, 754))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (341, 364))	('Colon adenocarcinoma', 'Disease', (194, 214))	('Uterine Carcinosarcoma', 'Phenotype', 'HP:0002891', (1067, 1089))	('Neoplasm', 'Phenotype', 'HP:0002664', (229, 237))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (298, 321))	('carcinoma', 'Disease', 'MESH:D009369', (998, 1007))	('ACC', 'Gene', (0, 3))	('Tumors', 'Phenotype', 'HP:0002664', (978, 984))	('Thyroid carcinoma', 'Disease', (990, 1007))	('Melanoma', 'Phenotype', 'HP:0002861', (1100, 1108))	('Germ Cell Tumors', 'Phenotype', 'HP:0100728', (968, 984))	('carcinoma', 'Disease', 'MESH:D009369', (554, 563))	('THCA', 'Chemical', '-', (985, 989))	('Melanoma', 'Disease', (915, 923))	('endocervical adenocarcinoma', 'Disease', (136, 163))	('Lymphoid Neoplasm Diffuse Large B-cell Lymphoma', 'Disease', 'MESH:D016403', (220, 267))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (676, 699))	('carcinoma', 'Disease', (154, 163))	('Glioma', 'Phenotype', 'HP:0009733', (521, 527))	('carcinoma', 'Disease', 'MESH:D009369', (205, 214))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (905, 923))	('BRCA', 'Gene', (63, 67))	('Tumors', 'Disease', (978, 984))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (1041, 1062))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (273, 293))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (676, 699))	('Thymoma', 'Phenotype', 'HP:0100522', (1013, 1020))	('carcinoma', 'Disease', 'MESH:D009369', (122, 131))	('Sarcoma', 'Phenotype', 'HP:0100242', (887, 894))	('Glioblastoma multiforme', 'Disease', (298, 321))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (569, 588))	('mutational', 'Var', (1119, 1129))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (433, 470))	('carcinoma', 'Disease', 'MESH:D009369', (845, 854))	('Urothelial Carcinoma', 'Disease', 'MESH:D014523', (42, 62))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (1094, 1108))	('Mesothelioma', 'Disease', 'MESH:D008654', (705, 717))	('COAD', 'Disease', (189, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (4, 28))	('carcinoma', 'Disease', (355, 364))	('Acute Myeloid Leukemia', 'Phenotype', 'HP:0004808', (476, 498))	('carcinoma', 'Disease', (690, 699))	('carcinoma', 'Disease', (205, 214))	('carcinoma', 'Disease', (84, 93))	('Glioma', 'Disease', 'MESH:D005910', (521, 527))	('UCEC Uterine Corpus', 'Phenotype', 'HP:0000139', (1021, 1040))	('BRCA', 'Gene', '672', (63, 67))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (671, 699))	('Tumor', 'Phenotype', 'HP:0002664', (1113, 1118))	('Lymphoid Neoplasm Diffuse Large B-cell Lymphoma', 'Disease', (220, 267))	('carcinoma', 'Disease', 'MESH:D009369', (776, 785))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (440, 470))	('carcinoma', 'Disease', 'MESH:D009369', (579, 588))	('Lung adenocarcinoma', 'Disease', (569, 588))	('Carcinosarcoma', 'Disease', (1075, 1089))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinoma', 'Disease', (122, 131))	('Sarcoma', 'Disease', 'MESH:D012509', (887, 894))
192719	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))
192725	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))
192726	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))
192728	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))
192729	32688345	We also analyzed the CNVs in the FRGs among the 32 cancer types and found heterozygous mutations in TP53 and ALOX15B and heterozygous amplifications in RPL8 and PTGS2 (Supplementary Figure 1C).	('RPL8', 'Gene', (152, 156))	('TP53', 'Gene', '7157', (100, 104))	('RPL8', 'Gene', '6132', (152, 156))	('PTGS2', 'Gene', '5743', (161, 166))	('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))
192762	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))
192817	31886014	These protective factors include muscle pH, muscle contractility, alterations in oxygenation, and lactic acid accumulation that may reduce risk of metastatic tumour development.	('muscle contractility', 'CPA', (44, 64))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('lactic acid', 'Chemical', 'MESH:D019344', (98, 109))	('muscle pH', 'CPA', (33, 42))	('lactic acid', 'MPA', (98, 109))	('oxygenation', 'MPA', (81, 92))	('tumour', 'Disease', (158, 164))	('lactic acid accumulation', 'Phenotype', 'HP:0003128', (98, 122))	('alterations', 'Var', (66, 77))
192832	31886014	Heterogenous iso-signal intensity in T1-weighted sequences and heterogenous hyperintense signal in T2-weighted sequences with or without adjacent bone invasion with localised swelling and pain have been identified as features of SMM on MRI imaging.	('swelling', 'Disease', 'MESH:D004487', (175, 183))	('swelling', 'Disease', (175, 183))	('Heterogenous', 'Var', (0, 12))	('pain', 'Phenotype', 'HP:0012531', (188, 192))	('heterogenous hyperintense signal', 'MPA', (63, 95))	('pain', 'Disease', 'MESH:D010146', (188, 192))	('pain', 'Disease', (188, 192))	('SMM', 'Disease', (229, 232))
192862	28410618	Tumors release DNA fragments into circulation that contain tumor-specific alterations including point mutations, copy number variation and DNA methylation (Fig.	('copy number variation', 'Var', (113, 134))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('DNA', 'MPA', (139, 142))	('tumor', 'Disease', (59, 64))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('Tumors', 'Disease', (0, 6))	('point mutations', 'Var', (96, 111))	('men', 'Species', '9606', (23, 26))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('DNA methylation', 'biological_process', 'GO:0006306', ('139', '154'))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
192868	28410618	In addition, tumor-specific mutations can represent as low as 0.01% of total cfDNA, which can make the detection of rare variants challenging.	('tumor', 'Disease', (13, 18))	('cfDNA', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('mutations', 'Var', (28, 37))
192892	28410618	An important epigenetic change in cancer is methylation changes of tumor-related genes, which can significantly affect the initiation and progression of the disease.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Disease', (34, 40))	('affect', 'Reg', (112, 118))	('tumor', 'Disease', (67, 72))	('methylation', 'biological_process', 'GO:0032259', ('44', '55'))	('methylation changes', 'Var', (44, 63))
192895	28410618	CpG island hypermethylation of serum cfDNA was more frequently observed in patients with RCC relative to controls and was able to diagnose RCC with 63% sensitivity and 87% specificity.	('diagnose', 'Reg', (130, 138))	('hypermethylation', 'Var', (11, 27))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('patients', 'Species', '9606', (75, 83))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('cfDNA', 'Gene', (37, 42))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('observed', 'Reg', (63, 71))
192897	28410618	Methylation status of TWIST1 and NID2 in urine could differentiate bladder cancer patients from controls with a combined sensitivity of 90% and combined specificity of 93%.	('NID2', 'Gene', '22795', (33, 37))	('Methylation status', 'Var', (0, 18))	('patients', 'Species', '9606', (82, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('NID2', 'Gene', (33, 37))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('differentiate', 'Reg', (53, 66))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('TWIST1', 'Gene', (22, 28))	('TWIST1', 'Gene', '7291', (22, 28))
192900	28410618	Elevated plasma cfDNA methylation of SRD5A2 and CYP11A1 was seen in prostate cancer patients with biochemical recurrence following radical prostatectomy, indicating that aberrant cfDNA methylation can serve as an early predictor for disease recurrence.	('CYP11A1', 'Gene', (48, 55))	('SRD5A2', 'Gene', '6716', (37, 43))	('patients', 'Species', '9606', (84, 92))	('methylation', 'biological_process', 'GO:0032259', ('185', '196'))	('prostate cancer', 'Disease', (68, 83))	('Elevated', 'PosReg', (0, 8))	('methylation', 'biological_process', 'GO:0032259', ('22', '33'))	('plasma', 'MPA', (9, 15))	('CYP11A1', 'Gene', '1583', (48, 55))	('aberrant', 'Var', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('CYP11A1', 'molecular_function', 'GO:0008386', ('48', '55'))	('prostate cancer', 'Disease', 'MESH:D011471', (68, 83))	('SRD5A2', 'Gene', (37, 43))	('prostate cancer', 'Phenotype', 'HP:0012125', (68, 83))
192901	28410618	Cancer initiation and progression are triggered by the acquisition of somatic DNA mutations and chromosomal aberrations.	('triggered', 'Reg', (38, 47))	('chromosomal aberrations', 'Var', (96, 119))	('Cancer initiation', 'Disease', 'MESH:D009369', (0, 17))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (96, 119))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('Cancer initiation', 'Disease', (0, 17))
192902	28410618	The finding that tumor-derived DNA is released into circulation and that mutations in cfDNA can be detected in various biological fluids has prompted investigations into their use as non-invasive cancer biomarkers.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', (17, 22))	('cfDNA', 'Gene', (86, 91))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mutations', 'Var', (73, 82))
192903	28410618	An early study was able to identify chromosome 3p microsatellite alterations in plasma DNA from patients with ccRCC relative to healthy controls, indicating potential diagnostic value.	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('patients', 'Species', '9606', (96, 104))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('microsatellite alterations', 'Var', (50, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('36', '46'))
192904	28410618	Microsatellite alterations have also been detected in the circulating DNA of bladder cancer patients.	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('patients', 'Species', '9606', (92, 100))	('bladder cancer', 'Disease', (77, 91))	('Microsatellite alterations', 'Var', (0, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('detected', 'Reg', (42, 50))
192905	28410618	Urinary TERT promoter mutations were found to correlate with bladder cancer recurrence.	('TERT', 'Gene', (8, 12))	('TERT', 'Gene', '7015', (8, 12))	('bladder cancer', 'Disease', 'MESH:D001749', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('bladder cancer', 'Disease', (61, 75))	('mutations', 'Var', (22, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (61, 75))
192907	28410618	A panel of chromosomal variations detected in serum could discriminate prostate cancer from controls with a diagnostic accuracy of 83%.	('discriminate', 'Reg', (58, 70))	('prostate cancer', 'Disease', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('prostate cancer', 'Disease', 'MESH:D011471', (71, 86))	('chromosomal variations', 'Var', (11, 33))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))
192911	28410618	High-level copy number gains in the AR locus were detected in the plasma of castration resistant prostate cancer (CRPC) patients but not in castration sensitive prostate cancer (CSPC) patients, suggesting that AR copy number gain can serve as a prognostic marker.	('patients', 'Species', '9606', (184, 192))	('prostate cancer', 'Phenotype', 'HP:0012125', (161, 176))	('copy number gains', 'Var', (11, 28))	('prostate cancer', 'Disease', 'MESH:D011471', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('AR', 'Gene', '367', (36, 38))	('prostate cancer', 'Disease', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('patients', 'Species', '9606', (120, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (97, 112))	('prostate cancer', 'Disease', 'MESH:D011471', (161, 176))	('copy number gain', 'Var', (213, 229))	('AR', 'Gene', '367', (210, 212))	('prostate cancer', 'Disease', (97, 112))
192912	28410618	Plasma androgen receptor (AR) mutations were detected in enzalutamide-resistant and abiraterone-resistant patients with metastatic CRPC.	('detected', 'Reg', (45, 53))	('androgen receptor', 'Gene', (7, 24))	('metastatic CRPC', 'Disease', (120, 135))	('AR', 'Gene', '367', (26, 28))	('androgen receptor', 'Gene', '367', (7, 24))	('mutations', 'Var', (30, 39))	('patients', 'Species', '9606', (106, 114))	('enzalutamide', 'Chemical', 'MESH:C540278', (57, 69))	('abiraterone', 'Chemical', 'MESH:C089740', (84, 95))
192917	28410618	This is in part due to the fact that tumor-specific mutations can represent as low as 0.01% of total cfDNA.	('mutations', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('cfDNA', 'Disease', (101, 106))
192962	28410618	Hypermethylation of the lncRNA H19 in peripheral blood could distinguish prostate cancer from controls.	('prostate cancer', 'Disease', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Hypermethylation', 'Var', (0, 16))	('distinguish', 'Reg', (61, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('lncRNA H19', 'Protein', (24, 34))
193033	28410618	Circulating cell-free DNA levels, integrity, methylation and mutational status have promising clinical applications in the field of urological cancer biomarker discovery.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('methylation', 'Var', (45, 56))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))
193043	25493074	After miR-100 transfection, there was a significant reduction in the mRNA of mTOR (p = 0.006), SMARCA5 (p = 0.007) and BAZ2A (p = 0.029) in RT4, mTOR (p = 0.023) and SMARCA5 (p = 0.015) in T24.	('BAZ2A', 'Gene', (119, 124))	('miR-100', 'Gene', (6, 13))	('SMARCA5', 'Gene', (95, 102))	('BAZ2A', 'Gene', '11176', (119, 124))	('mTOR', 'Gene', (145, 149))	('mTOR', 'Gene', '2475', (145, 149))	('SMARCA5', 'Gene', '8467', (166, 173))	('transfection', 'Var', (14, 26))	('mTOR', 'Gene', '2475', (77, 81))	('miR-100', 'Gene', '406892', (6, 13))	('mTOR', 'Gene', (77, 81))	('SMARCA5', 'Gene', '8467', (95, 102))	('SMARCA5', 'Gene', (166, 173))	('reduction', 'NegReg', (52, 61))
193044	25493074	In T24 miR-100 promoted an increase in cell proliferation and anti-miR 100 promoted apoptosis characterizing miR-100 as an oncomiR in this cell line representative of a high-grade urothelial carcinoma.	('miR', 'Gene', (109, 112))	('miR-100', 'Gene', '406892', (109, 116))	('miR', 'Gene', (67, 70))	('miR 100', 'Gene', '406892', (67, 74))	('apoptosis', 'CPA', (84, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('cell proliferation', 'CPA', (39, 57))	('miR 100', 'Gene', (67, 74))	('increase', 'PosReg', (27, 35))	('miR-100', 'Gene', (7, 14))	('urothelial carcinoma', 'Disease', (180, 200))	('miR', 'Gene', '220972', (7, 10))	('miR', 'Gene', '220972', (127, 130))	('miR-100', 'Gene', (109, 116))	('miR', 'Gene', '220972', (109, 112))	('T24', 'Var', (3, 6))	('promoted', 'PosReg', (75, 83))	('miR', 'Gene', (7, 10))	('miR', 'Gene', (127, 130))	('miR-100', 'Gene', '406892', (7, 14))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (180, 200))	('miR', 'Gene', '220972', (67, 70))
193045	25493074	miR-100 transfection reduces expression of BAZ2A, mTOR and SMARCA5 mRNA and protein in BC cell lines.	('BAZ2A', 'Gene', (43, 48))	('SMARCA5', 'Gene', '8467', (59, 66))	('BAZ2A', 'Gene', '11176', (43, 48))	('mTOR', 'Gene', (50, 54))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('mTOR', 'Gene', '2475', (50, 54))	('miR-100', 'Gene', '406892', (0, 7))	('SMARCA5', 'Gene', (59, 66))	('expression', 'MPA', (29, 39))	('transfection', 'Var', (8, 20))	('miR-100', 'Gene', (0, 7))	('reduces', 'NegReg', (21, 28))
193050	25493074	Aberrant expression patterns and functional abnormalities of miRNAs are implicated in several human diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Aberrant', 'Var', (0, 8))	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', (61, 64))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('expression', 'MPA', (9, 19))	('human', 'Species', '9606', (94, 99))	('functional', 'MPA', (33, 43))	('implicated', 'Reg', (72, 82))
193082	25493074	Although this difference was not statistically different (p = 0.37), there was an increase of 8.5% in cell proliferation after miR-100 transfection.	('miR-100', 'Gene', '406892', (127, 134))	('cell proliferation', 'biological_process', 'GO:0008283', ('102', '120'))	('increase', 'PosReg', (82, 90))	('transfection', 'Var', (135, 147))	('miR-100', 'Gene', (127, 134))	('cell proliferation', 'CPA', (102, 120))
193083	25493074	There was no differences in the number of cells in apoptosis in both cell lines after miR-100 transfection.	('miR-100', 'Gene', (86, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('miR-100', 'Gene', '406892', (86, 93))	('transfection', 'Var', (94, 106))
193088	25493074	After miR-100 transfection, we observed a reduction in mRNA expression of the genes of interest, but the reduction was significant only for mTOR, BAZ2A and SMARCA5.	('miR-100', 'Gene', (6, 13))	('BAZ2A', 'Gene', (146, 151))	('transfection', 'Var', (14, 26))	('mTOR', 'Gene', '2475', (140, 144))	('miR-100', 'Gene', '406892', (6, 13))	('mRNA expression', 'MPA', (55, 70))	('BAZ2A', 'Gene', '11176', (146, 151))	('SMARCA5', 'Gene', '8467', (156, 163))	('mTOR', 'Gene', (140, 144))	('reduction', 'NegReg', (42, 51))	('SMARCA5', 'Gene', (156, 163))
193096	25493074	FGFR3 mutation is the most common phenomenon in low-grade non-invasive urothelial carcinomas, described in 70% of the cases and identified as a molecular marker of non-aggressive disease.	('urothelial carcinomas', 'Disease', (71, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', '2261', (0, 5))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (71, 92))	('non-aggressive disease', 'Disease', (164, 186))	('FGFR3', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('non-aggressive disease', 'Disease', 'MESH:D001523', (164, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('common', 'Reg', (27, 33))
193099	25493074	The most affected genes in both types of cells after miR-100 transfection were SMARCA5 and mTOR.	('affected', 'Reg', (9, 17))	('miR-100', 'Gene', '406892', (53, 60))	('transfection', 'Var', (61, 73))	('SMARCA5', 'Gene', '8467', (79, 86))	('miR-100', 'Gene', (53, 60))	('SMARCA5', 'Gene', (79, 86))	('mTOR', 'Gene', (91, 95))	('mTOR', 'Gene', '2475', (91, 95))
193100	25493074	mTOR (mammalian target of rapamycin) is a serine-threonine protein kinase, which acts with PI3K, AKT and the tumor suppressor gene PTEN to form a signaling pathway involved in the regulation of protein synthesis, cell growth, proliferation, survival, apoptosis, and angiogenesis.	('mammalian target of rapamycin', 'Gene', '2475', (6, 35))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('AKT', 'Gene', '207', (97, 100))	('PI3K', 'Var', (91, 95))	('PTEN', 'Gene', (131, 135))	('mammalian target of rapamycin', 'Gene', (6, 35))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('signaling pathway', 'biological_process', 'GO:0007165', ('146', '163'))	('mTOR', 'Gene', (0, 4))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('109', '125'))	('PTEN', 'Gene', '5728', (131, 135))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('mTOR', 'Gene', '2475', (0, 4))	('tumor suppressor', 'biological_process', 'GO:0051726', ('109', '125'))	('regulation of protein synthesis', 'biological_process', 'GO:0006417', ('180', '211'))	('AKT', 'Gene', (97, 100))	('angiogenesis', 'biological_process', 'GO:0001525', ('266', '278'))	('apoptosis', 'biological_process', 'GO:0097194', ('251', '260'))	('apoptosis', 'biological_process', 'GO:0006915', ('251', '260'))	('PI3K', 'molecular_function', 'GO:0016303', ('91', '95'))	('cell growth', 'biological_process', 'GO:0016049', ('213', '224'))	('tumor', 'Disease', (109, 114))
193101	25493074	Deregulation of the mTOR pathway has been related to oncogenesis in several malignancies, including bladder cancer.	('oncogenesis', 'biological_process', 'GO:0007048', ('53', '64'))	('malignancies', 'Disease', (76, 88))	('bladder cancer', 'Disease', (100, 114))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (100, 114))	('malignancies', 'Disease', 'MESH:D009369', (76, 88))	('related', 'Reg', (42, 49))	('mTOR', 'Gene', '2475', (20, 24))	('bladder cancer', 'Disease', 'MESH:D001749', (100, 114))	('mTOR', 'Gene', (20, 24))
193129	21050361	Mouse xenografts of UMUC3 cells revealed that rapamycin significantly prolonged survival and enhanced the therapeutic efficacy of cisplatin.	('rapamycin', 'Chemical', 'MESH:D020123', (46, 55))	('rapamycin', 'Var', (46, 55))	('therapeutic efficacy', 'CPA', (106, 126))	('prolonged', 'PosReg', (70, 79))	('enhanced', 'PosReg', (93, 101))	('Mouse', 'Species', '10090', (0, 5))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('survival', 'CPA', (80, 88))
193131	21050361	mTOR blockade inhibits urothelial carcinoma cell proliferation and enhances the effectiveness of cisplatin.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (23, 43))	('blockade', 'Var', (5, 13))	('inhibits', 'NegReg', (14, 22))	('enhances', 'PosReg', (67, 75))	('urothelial carcinoma', 'Disease', (23, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))	('mTOR', 'Gene', (0, 4))	('effectiveness', 'MPA', (80, 93))
193138	21050361	As a result, survival for patients with advanced tumours has not significantly improved over time, such that the 5-year survival for pT3 UC was 33% before 1985, and has been noted to be 35% since 1985.	('advanced tumours', 'Disease', (40, 56))	('patients', 'Species', '9606', (26, 34))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('pT3', 'Var', (133, 136))	('advanced tumours', 'Disease', 'MESH:D006223', (40, 56))
193143	21050361	Interestingly, mTOR inhibition has been found to sensitize certain cancer cells to cisplatin therapy.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('cancer', 'Disease', (67, 73))	('mTOR', 'Protein', (15, 19))	('inhibition', 'Var', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('sensitize', 'Reg', (49, 58))
193178	21050361	We found that the addition of rapamycin (5 nM) to relatively low-dose cisplatin (5 microM) was associated with a significant reduction in the number of viable cells compared with treatment with either of the agents alone in both UC cell lines (P< 0.001 for both; Fig.	('reduction', 'NegReg', (125, 134))	('5 nM', 'Var', (41, 45))	('rapamycin', 'Gene', (30, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('rapamycin', 'Chemical', 'MESH:D020123', (30, 39))	('number of viable cells', 'CPA', (142, 164))
193181	21050361	On the other hand, 5 microM cisplatin treatment was associated with a decrease in the proportion of cells in G0/G1 and a marked increase in the number of cells in G2/M, consistent with the described mechanism of G2 cell-cycle arrest for cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (237, 246))	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('increase', 'PosReg', (128, 136))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('215', '232'))	('cisplatin', 'Var', (28, 37))	('decrease', 'NegReg', (70, 78))
193188	21050361	4, treatment with 5 nM rapamycin for 48 h decreased expression of both p-mTOR and p-S6K.	('p-S6K', 'Var', (82, 87))	('decreased', 'NegReg', (42, 51))	('p-mTOR', 'Protein', (71, 77))	('rapamycin', 'Chemical', 'MESH:D020123', (23, 32))	('expression', 'MPA', (52, 62))
193192	21050361	5, we found that rapamycin treatment was associated with an improvement in overall survival of the xenografts, such that the median survival in mice treated with rapamycin was 42 days, vs. 30 days in the control animals (P=0.05).	('mice', 'Species', '10090', (144, 148))	('rapamycin', 'Var', (162, 171))	('improvement', 'PosReg', (60, 71))	('rapamycin', 'Chemical', 'MESH:D020123', (162, 171))	('rapamycin', 'Chemical', 'MESH:D020123', (17, 26))
193196	21050361	Interestingly, we also noted that treatment with rapamycin and cisplatin was associated with a significantly decreased expression of Ki-67 compared with treatment with rapamycin alone (P=0.03) or cisplatin alone (P=0.03).	('decreased', 'NegReg', (109, 118))	('expression', 'MPA', (119, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (196, 205))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('rapamycin', 'Chemical', 'MESH:D020123', (49, 58))	('Ki-67', 'Gene', '17345', (133, 138))	('rapamycin', 'Var', (49, 58))	('cisplatin', 'Var', (63, 72))	('Ki-67', 'Gene', (133, 138))	('rapamycin', 'Chemical', 'MESH:D020123', (168, 177))
193210	21050361	The efficacy of rapamycin for inhibiting mTOR signalling in vitro and in vivo was evident from the marked decrease in expression of p-S6K in treated cells relative to controls.	('inhibiting', 'NegReg', (30, 40))	('rapamycin', 'Chemical', 'MESH:D020123', (16, 25))	('decrease', 'NegReg', (106, 114))	('signalling', 'biological_process', 'GO:0023052', ('46', '56'))	('mTOR signalling', 'MPA', (41, 56))	('expression', 'MPA', (118, 128))	('p-S6K', 'Var', (132, 137))
193217	21050361	With regard to bladder cancer, mTOR inhibition has been found to decrease the development of chemically and genetically induced bladder tumours in mice, and may be effective when delivered intravesically.	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('mice', 'Species', '10090', (147, 151))	('mTOR', 'Gene', (31, 35))	('bladder cancer', 'Disease', 'MESH:D001749', (15, 29))	('inhibition', 'Var', (36, 46))	('bladder tumours', 'Disease', (128, 143))	('bladder cancer', 'Disease', (15, 29))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('bladder tumours', 'Disease', 'MESH:D001749', (128, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (15, 29))	('decrease', 'NegReg', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('development of chemically', 'CPA', (78, 103))
193220	21050361	Our results support data from other cell systems which have shown that inhibition of mTOR increases the susceptibility of cancer cells to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('inhibition', 'Var', (71, 81))	('cancer', 'Disease', (122, 128))	('susceptibility', 'MPA', (104, 118))	('increases', 'PosReg', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('mTOR', 'Gene', (85, 89))
193228	21050361	Moreover, we provide evidence to suggest the potential for mTOR inhibitors to enhance the current cisplatin-based chemotherapy regimens.	('enhance', 'PosReg', (78, 85))	('inhibitors', 'Var', (64, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('cisplatin-based chemotherapy regimens', 'MPA', (98, 135))	('mTOR', 'Gene', (59, 63))
193240	33488678	Passenger mutations can become driver mutations (and vice versa) under changing environmental conditions and selection pressures, increasing the complexity of intratumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('Passenger mutations', 'Var', (0, 19))
193260	33488678	The OR2C3 mutation relevance score in TCGA-BC-A10X is evidently high (OR2C3 and k = TCGA-BC-A10X) and is ranked 1st.	('TCGA-BC-A10X', 'Var', (38, 50))	('A10X', 'Mutation', 'p.A10X', (92, 96))	('OR2C3', 'Gene', '81472', (4, 9))	('OR2C3', 'Gene', '81472', (70, 75))	('OR2C3', 'Gene', (4, 9))	('A10X', 'Mutation', 'p.A10X', (46, 50))	('OR2C3', 'Gene', (70, 75))
193273	33488678	In general, considering the weights for the different types of mutations (Weighted_MinNetRank) had a better performance than other six methods (MinNetRank, Mean, Maximum, NetICS, DawnRank, and Freq) in all six cancer datasets (TCGA-LIHC, TCGA-STAD, TCGA-BLCA, TCGA-LUAD, TCGA-SKCM, and LIRI-LIHC).	('mutations', 'Var', (63, 72))	('TCGA-SKCM', 'Disease', (271, 280))	('TCGA-LUAD', 'Disease', (260, 269))	('TCGA-LIHC', 'Disease', (227, 236))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('TCGA-STAD', 'Disease', (238, 247))	('TCGA-BLCA', 'Disease', (249, 258))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
193296	33488678	TP53 was one of the most frequent alterations and potential prognostic markers in human cancers.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('alterations', 'Var', (34, 45))	('human', 'Species', '9606', (82, 87))
193320	33488678	Besides mutation data, other events, such as miRNA differential expression, epigenetic changes, copy number variation, and structure variation, could also contribute to cancer progression.	('cancer', 'Disease', (169, 175))	('structure', 'MPA', (123, 132))	('copy number variation', 'Var', (96, 117))	('miRNA differential expression', 'MPA', (45, 74))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('epigenetic changes', 'Var', (76, 94))	('contribute', 'Reg', (155, 165))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
193337	33488678	Although synonymous mutations do not alter amino acids, some deleterious synonymous mutations play important roles in cancer.	('cancer', 'Disease', (118, 124))	('roles', 'Reg', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('synonymous mutations', 'Var', (73, 93))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('play', 'Reg', (94, 98))
193353	33397444	Overall, mutations of ZFP36 family genes (ZFP36, ZFP36L1, and ZFP36L2) are identified in 26.7% of cases, which display a high mutational load.	('ZFP36', 'Gene', (42, 47))	('ZFP36', 'Gene', (62, 67))	('ZFP36L2', 'Gene', '678', (62, 69))	('ZFP36', 'Gene', (49, 54))	('ZFP36', 'Gene', '7538', (42, 47))	('mutations', 'Var', (9, 18))	('ZFP36', 'Gene', '7538', (62, 67))	('ZFP36', 'Gene', '7538', (49, 54))	('ZFP36L1', 'Gene', (49, 56))	('ZFP36', 'Gene', (22, 27))	('ZFP36L2', 'Gene', (62, 69))	('identified', 'Reg', (75, 85))	('ZFP36', 'Gene', '7538', (22, 27))	('ZFP36L1', 'Gene', '677', (49, 56))
193356	33397444	Our study delineates for the first time the key role for convergence between genetic and epigenetic alterations in shaping clinicopathological and immune upper tract urothelial carcinoma features.	('upper tract urothelial carcinoma', 'Disease', (154, 186))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (154, 186))	('epigenetic alterations', 'Var', (89, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))
193363	33397444	Recent studies using whole-exome sequencing and/or targeted sequencing of UTUC samples identified recurrent mutations of genes known to be altered in bladder carcinomas, although with different frequencies (e.g., HRAS).	('bladder carcinomas', 'Disease', 'MESH:D001749', (150, 168))	('HRAS', 'Gene', (213, 217))	('mutations', 'Var', (108, 117))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (150, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (150, 168))	('bladder carcinomas', 'Disease', (150, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (158, 168))	('HRAS', 'Gene', '3265', (213, 217))
193368	33397444	To fill this knowledge gap, we decided to investigate the putative contribution of both genetic and epigenetic alterations in dictating muscle invasiveness, a key predictor of poor outcome in UTUC patients.	('epigenetic alterations', 'Var', (100, 122))	('muscle invasiveness', 'Disease', (136, 155))	('patients', 'Species', '9606', (197, 205))	('muscle invasiveness', 'Disease', 'MESH:D009362', (136, 155))
193369	33397444	We identified different key findings, including the discovery of novel mutations affecting the zinc-finger RNA-binding protein ZFP36L1 in 20% of cases, a rate by far the highest among cancer subtypes profiled to date.	('cancer', 'Disease', (184, 190))	('ZFP36L1', 'Gene', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('RNA', 'cellular_component', 'GO:0005562', ('107', '110'))	('mutations', 'Var', (71, 80))	('ZFP36L1', 'Gene', '677', (127, 134))	('RNA-binding', 'molecular_function', 'GO:0003723', ('107', '118'))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))
193370	33397444	In addition, we identified two methylome clusters, EpiC-low and EpiC-high, associated with distinct clinicopathological and genetic tumor features, as well as patient survival.	('cluster', 'Species', '100569', (41, 48))	('EpiC-high', 'Var', (64, 73))	('genetic tumor', 'Disease', 'MESH:D030342', (124, 137))	('genetic tumor', 'Disease', (124, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('patient', 'Species', '9606', (159, 166))	('associated', 'Reg', (75, 85))
193371	33397444	While the EpiC-low cluster was hypermethylated, immune-inflamed, enriched in MI cases, and harbored a high rate of somatic mutations of SWI/SNF genes, the EpiC-high cluster was hypomethylated, immune-desert, enriched for NMI cases, and harbored a high rate of FGFR3 mutations.	('FGFR', 'molecular_function', 'GO:0005007', ('260', '264'))	('mutations', 'Var', (123, 132))	('FGFR3', 'Gene', (260, 265))	('mutations', 'Var', (266, 275))	('cluster', 'Species', '100569', (19, 26))	('FGFR3', 'Gene', '2261', (260, 265))	('SWI/SNF', 'Gene', (136, 143))	('cluster', 'Species', '100569', (165, 172))
193377	33397444	Mutations of FGFR3, KDM6A, and ZFP36L1 alterations were all verified by Sanger sequencing.	('KDM6A', 'Gene', (20, 25))	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('FGFR3', 'Gene', (13, 18))	('KDM6A', 'Gene', '7403', (20, 25))	('ZFP36L1', 'Gene', (31, 38))	('Mutations', 'Var', (0, 9))	('ZFP36L1', 'Gene', '677', (31, 38))	('FGFR3', 'Gene', '2261', (13, 18))
193379	33397444	Mutations of FGFR3 and KMT2C co-occur mutually (log2 odd ratio = 3.1, P = 0.04; Fig.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('KMT2C', 'Gene', (23, 28))	('KMT2C', 'Gene', '58508', (23, 28))	('FGFR3', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('FGFR3', 'Gene', '2261', (13, 18))
193380	33397444	In addition, we observed a mutual co-occurrence of mutations affecting ZFP36L1 with both KDM6A (log2 odd ratio = 3.1; P = 0.03) and STAG2 (log2 odd ratio = 3.29, P = 0.04; Additional file 1: Table S5).	('ZFP36L1', 'Gene', (71, 78))	('mutations', 'Var', (51, 60))	('STAG2', 'Gene', (132, 137))	('ZFP36L1', 'Gene', '677', (71, 78))	('KDM6A', 'Gene', '7403', (89, 94))	('STAG2', 'Gene', '10735', (132, 137))	('co-occurrence', 'Reg', (34, 47))	('KDM6A', 'Gene', (89, 94))
193381	33397444	Mutations of MLL2 (P = 0.04), ARID1A (P = 0.01), and GANAB (P = 0.02) showed significant association with a higher mutation load, as well as a tendency for ZFP36L1 (P = 0.06).	('ARID1A', 'Gene', '8289', (30, 36))	('mutation load', 'MPA', (115, 128))	('ARID1A', 'Gene', (30, 36))	('ZFP36L1', 'Gene', '677', (156, 163))	('MLL2', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('MLL2', 'Gene', '8085', (13, 17))	('GANAB', 'Gene', '23193', (53, 58))	('GANAB', 'Gene', (53, 58))	('ZFP36L1', 'Gene', (156, 163))
193382	33397444	Among genes with mutations arising in > 10% of samples, only FGFR3 mutations were significantly associated with improved overall survival (OS) (P = 0.005) and progression-free survival (PFS) at distant sites (P = 0.007).	('FGFR3', 'Gene', (61, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('61', '65'))	('mutations', 'Var', (67, 76))	('overall', 'MPA', (121, 128))	('progression-free survival', 'CPA', (159, 184))	('FGFR3', 'Gene', '2261', (61, 66))	('improved', 'PosReg', (112, 120))
193383	33397444	We then looked for an association between gene mutations and muscle-invasive status; as expected, we found that FGFR3 mutations were enriched in NMI as compared to MI tumors (73% vs 27%; P = 0.027, FDR = 0.2); conversely, ARID1A mutations were enriched in MI tumors (33% vs 0%; P = 0.042, FDR = 0.2; Additional file 1: Table S6).	('MI tumors', 'Disease', (164, 173))	('MI tumors', 'Disease', 'MESH:D009369', (256, 265))	('FGFR3', 'Gene', (112, 117))	('MI tumors', 'Disease', 'MESH:D009369', (164, 173))	('mutations', 'Var', (229, 238))	('mutations', 'Var', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('FGFR', 'molecular_function', 'GO:0005007', ('112', '116'))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('NMI', 'Disease', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('ARID1A', 'Gene', '8289', (222, 228))	('FGFR3', 'Gene', '2261', (112, 117))	('MI tumors', 'Disease', (256, 265))	('ARID1A', 'Gene', (222, 228))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
193387	33397444	We also observed mutual exclusivity of 8q22.3 gain with FGFR3 mutations (P = 0.03), as well as mutual occurrence with TP53 mutations (P = 0.02) (Additional file 2: Fig.	('FGFR', 'molecular_function', 'GO:0005007', ('56', '60'))	('FGFR3', 'Gene', '2261', (56, 61))	('mutations', 'Var', (62, 71))	('TP53', 'Gene', '7157', (118, 122))	('FGFR3', 'Gene', (56, 61))	('TP53', 'Gene', (118, 122))	('gain', 'PosReg', (46, 50))	('8q22.3', 'Gene', (39, 45))
193389	33397444	To compare mutational frequency regarding NMI, we retrieved mutation data of 24 NMI-BLCA from the Hurst cohort and compared it with our NMI-UTUCs (n = 15), and we found KMT2C (P = 0.08) was more likely to mutate in NMI-UTUCs (n = 15) whereas PIK3CA mutations were significantly enriched in NMI-BLCAs (P = 0.0001) (Additional file 2: Fig.	('MI-BLCA', 'Disease', (81, 88))	('mutate', 'Var', (205, 211))	('MI-BLCA', 'Disease', (291, 298))	('PIK3CA', 'Gene', '5290', (242, 248))	('KMT2C', 'Gene', '58508', (169, 174))	('KMT2C', 'Gene', (169, 174))	('MI-BLCA', 'Disease', 'MESH:D009203', (81, 88))	('MI-BLCA', 'Disease', 'MESH:D009203', (291, 298))	('PIK3CA', 'Gene', (242, 248))
193391	33397444	We found that MI-UTUC showed significantly more mutations of GANAB (P = 0.021), CRIPAK (P = 0.022), and ZFP36L1 (P = 0.1) (Additional file 2: Fig.	('CRIPAK', 'Gene', '285464', (80, 86))	('GANAB', 'Gene', (61, 66))	('CRIPAK', 'Gene', (80, 86))	('ZFP36L1', 'Gene', (104, 111))	('GANAB', 'Gene', '23193', (61, 66))	('ZFP36L1', 'Gene', '677', (104, 111))	('mutations', 'Var', (48, 57))
193392	33397444	As ZFP36L1 mutations have not been previously reported to be altered in UTUC, we thus investigated their significance.	('mutations', 'Var', (11, 20))	('ZFP36L1', 'Gene', (3, 10))	('ZFP36L1', 'Gene', '677', (3, 10))
193393	33397444	Strikingly, six out of eight ZFP36L1 mutations were frameshift insertions or deletions, and two were a non-synonymous mutation predicted to be deleterious by Poly2phen and SIFT (Fig.	('ZFP36L1', 'Gene', (29, 36))	('mutations', 'Var', (37, 46))	('Poly2phen', 'Chemical', '-', (158, 167))	('ZFP36L1', 'Gene', '677', (29, 36))
193394	33397444	When we explored mutations of other members of the ZFP36 family, we identified one additional UTUC case with a ZFP36L2 stop-gain mutation (E249X) and another with a deleterious ZFP36 (p.P253A) mutation, both already existing in COSMIC (Fig.	('ZFP36L2', 'Gene', (111, 118))	('E249X', 'SUBSTITUTION', 'None', (139, 144))	('p.P253A', 'Var', (184, 191))	('ZFP36', 'Gene', (111, 116))	('E249X', 'Var', (139, 144))	('ZFP36', 'Gene', (51, 56))	('ZFP36L2', 'Gene', '678', (111, 118))	('ZFP36', 'Gene', '7538', (51, 56))	('p.P253A', 'SUBSTITUTION', 'None', (184, 191))	('ZFP36', 'Gene', (177, 182))	('ZFP36', 'Gene', '7538', (111, 116))	('ZFP36', 'Gene', '7538', (177, 182))
193395	33397444	Notably, ZFP36L2 E249X was identified as a hotspot for mutations in the bladder TCGA, consolidating our findings about the relevance of this mutation in urothelium carcinogenesis (Additional file 2: Fig.	('TCGA', 'Gene', (80, 84))	('ZFP36L2', 'Gene', (9, 16))	('mutations', 'Var', (55, 64))	('carcinogenesis', 'Disease', 'MESH:D063646', (164, 178))	('bladder TCGA', 'Gene', (72, 84))	('ZFP36L2', 'Gene', '678', (9, 16))	('carcinogenesis', 'Disease', (164, 178))	('E249X', 'SUBSTITUTION', 'None', (17, 22))	('E249X', 'Var', (17, 22))
193397	33397444	Thus, overall mutations of ZFP36 family genes represent 26.7% (n = 8/30) among all UTUC cases.	('ZFP36', 'Gene', (27, 32))	('UTUC', 'Disease', (83, 87))	('mutations', 'Var', (14, 23))	('ZFP36', 'Gene', '7538', (27, 32))
193398	33397444	Mutations of ZFP36 family genes were not associated with clinicopathological tumor features and patient overall survival (not shown).	('ZFP36', 'Gene', (13, 18))	('associated', 'Reg', (41, 51))	('ZFP36', 'Gene', '7538', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('patient', 'Species', '9606', (96, 103))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
193399	33397444	We then decided to analyze the frequency of ZFP36L1 mutations in 10,967 cancer samples related to 32 different histopathological cancer subtypes analyzed by TGCA.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('ZFP36L1', 'Gene', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ZFP36L1', 'Gene', '677', (44, 51))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
193401	33397444	When we combined mutations of ZFP36L2 and ZFP36 to ZFP36L1, the frequency of ZFP36 gene family mutations reached 3% (n = 297) in all TCGA cohorts, with the highest frequencies observed in bladder cancers (Additional file 2: Fig.	('ZFP36L2', 'Gene', (30, 37))	('bladder cancers', 'Disease', 'MESH:D001749', (188, 203))	('ZFP36L1', 'Gene', (51, 58))	('bladder cancers', 'Disease', (188, 203))	('mutations', 'Var', (17, 26))	('ZFP36', 'Gene', '7538', (77, 82))	('ZFP36', 'Gene', '7538', (30, 35))	('ZFP36', 'Gene', (42, 47))	('ZFP36', 'Gene', (51, 56))	('ZFP36L2', 'Gene', '678', (30, 37))	('mutations', 'Var', (95, 104))	('ZFP36L1', 'Gene', '677', (51, 58))	('ZFP36', 'Gene', '7538', (42, 47))	('ZFP36', 'Gene', '7538', (51, 56))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('bladder cancers', 'Phenotype', 'HP:0009725', (188, 203))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('bladder cancer', 'Phenotype', 'HP:0009725', (188, 202))	('ZFP36', 'Gene', (77, 82))	('ZFP36', 'Gene', (30, 35))
193402	33397444	Strikingly, ZFP36L1 mutations were consistently altered in three independent studies exploring the genetic landscape of bladder carcinomas (TCGA, DFCI, and BGI), with frequencies ranging from 6 to 8.5% (Fig.	('bladder carcinomas', 'Disease', 'MESH:D001749', (120, 138))	('DFCI', 'Chemical', '-', (146, 150))	('altered', 'Reg', (48, 55))	('ZFP36L1', 'Gene', '677', (12, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (120, 138))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (120, 137))	('ZFP36L1', 'Gene', (12, 19))	('bladder carcinomas', 'Disease', (120, 138))	('mutations', 'Var', (20, 29))
193403	33397444	The frequency of ZFP36 gene family mutations ranged between 9.1 and 10%, among the three bladder carcinoma cohorts (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('bladder carcinoma', 'Disease', (89, 106))	('ZFP36', 'Gene', (17, 22))	('bladder carcinoma', 'Disease', 'MESH:D001749', (89, 106))	('ZFP36', 'Gene', '7538', (17, 22))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (89, 106))	('mutations', 'Var', (35, 44))
193404	33397444	2e); notably, mutations of ZFP36L1 and ZFP36L2 were mutually co-occurring (P = 0.02; FDR = 0.06).	('ZFP36L2', 'Gene', (39, 46))	('ZFP36L1', 'Gene', (27, 34))	('ZFP36L2', 'Gene', '678', (39, 46))	('ZFP36L1', 'Gene', '677', (27, 34))	('mutations', 'Var', (14, 23))
193405	33397444	UTUC samples with ZFP36 gene family mutations harbored a higher mutational load as compared to others (P = 0.008; Fig.	('mutational load', 'MPA', (64, 79))	('higher', 'PosReg', (57, 63))	('ZFP36', 'Gene', (18, 23))	('ZFP36', 'Gene', '7538', (18, 23))	('mutations', 'Var', (36, 45))
193408	33397444	Finally, a pooled analysis of 562 patients in three bladder cohorts (TCGA, DFCI, and BGI) showed that bladder carcinomas with ZFP36 gene family mutations were associated with better overall survival as compared to others (P = 0.01; Fig.	('better', 'PosReg', (175, 181))	('ZFP36', 'Gene', '7538', (126, 131))	('overall', 'MPA', (182, 189))	('bladder carcinomas', 'Disease', 'MESH:D001749', (102, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (102, 120))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (102, 119))	('patients', 'Species', '9606', (34, 42))	('bladder carcinomas', 'Disease', (102, 120))	('mutations', 'Var', (144, 153))	('DFCI', 'Chemical', '-', (75, 79))	('ZFP36', 'Gene', (126, 131))
193411	33397444	Light microscopy images revealed disruption of the cell to cell junctions and clear change to spindle-shaped morphology in the cells with ZFP36L1 knockdown (Additional file 2: Fig.	('knockdown', 'Var', (146, 155))	('spindle-shaped morphology', 'CPA', (94, 119))	('disruption', 'Reg', (33, 43))	('cell to cell junctions', 'CPA', (51, 73))	('spindle', 'cellular_component', 'GO:0005819', ('94', '101'))	('ZFP36L1', 'Gene', (138, 145))	('change', 'Reg', (84, 90))	('ZFP36L1', 'Gene', '677', (138, 145))
193418	33397444	As mutation signatures of APOBEC cytidine deaminase were associated with high rates of somatic mutations, and likely increased tumor-infiltrating lymphocytes (TILs), we asked whether either these three clusters or signature 13 was associated with TILs, inferred from DNA methylation (MeTIL) analysis for samples for which DNA methylation and WES were available.	('cluster', 'Species', '100569', (202, 209))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('DNA methylation', 'biological_process', 'GO:0006306', ('322', '337'))	('DNA', 'cellular_component', 'GO:0005574', ('267', '270'))	('APOBEC cytidine deaminase', 'Gene', (26, 51))	('tumor', 'Disease', (127, 132))	('DNA methylation', 'biological_process', 'GO:0006306', ('267', '282'))	('DNA', 'cellular_component', 'GO:0005574', ('322', '325'))	('MeTIL', 'Chemical', '-', (284, 289))	('APOBEC', 'cellular_component', 'GO:0030895', ('26', '32'))	('mutation', 'Var', (3, 11))	('TILs', 'Disease', (247, 251))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('somatic mutations', 'MPA', (87, 104))	('associated', 'Reg', (57, 67))
193419	33397444	Notably, UTUC tumors with FGFR3 mutation showed a significantly lower MeTIL score as compared to others (P = 7.8 x 10-5; Additional file 2: Fig.	('MeTIL', 'Chemical', '-', (70, 75))	('FGFR3', 'Gene', (26, 31))	('lower', 'NegReg', (64, 69))	('UTUC tumors', 'Disease', 'MESH:D009369', (9, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('MeTIL score', 'MPA', (70, 81))	('UTUC tumors', 'Disease', (9, 20))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('FGFR3', 'Gene', '2261', (26, 31))	('mutation', 'Var', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
193421	33397444	The immune infiltration derived by FGFR3 mutation was independent from muscle invasiveness status (P = 0.008 for MI; P = 0.024 for NMI).	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR3', 'Gene', '2261', (35, 40))	('mutation', 'Var', (41, 49))	('muscle invasiveness', 'Disease', (71, 90))	('muscle invasiveness', 'Disease', 'MESH:D009362', (71, 90))	('FGFR3', 'Gene', (35, 40))
193429	33397444	None of the stromal enrich or basal squamous harbored FGFR3 mutations (Fig.	('FGFR', 'molecular_function', 'GO:0005007', ('54', '58'))	('mutations', 'Var', (60, 69))	('FGFR3', 'Gene', '2261', (54, 59))	('FGFR3', 'Gene', (54, 59))
193433	33397444	FGFR3 mutations and/or fusions were associated with significantly lower immune and stromal scores (P = 0.016 for immune scores; P = 0.003 for stromal scores; Fig.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (0, 5))	('lower', 'NegReg', (66, 71))	('fusions', 'Var', (23, 30))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
193443	33397444	Notably, the EpiC-low UTUC subtype harbored a significantly lower MeTIL score as compared to the MeTIL high subtype (P = 0.003) (Fig.	('MeTIL', 'Chemical', '-', (66, 71))	('EpiC-low', 'Var', (13, 21))	('MeTIL', 'Chemical', '-', (97, 102))	('MeTIL score', 'MPA', (66, 77))	('lower', 'NegReg', (60, 65))
193444	33397444	5e, f), while samples classified as EpiC-low were enriched for FGFR3 mutations (90% vs 28%, P = 0.004, FDR = 0.044; Fig.	('mutations', 'Var', (69, 78))	('FGFR3', 'Gene', '2261', (63, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('FGFR3', 'Gene', (63, 68))
193448	33397444	No association with survival was identified for other clinicopathological tumor variables, which highlights the prognostic value of epi-clusters in UTUC.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('epi-clusters', 'Var', (132, 144))	('tumor', 'Disease', (74, 79))	('cluster', 'Species', '100569', (136, 143))
193451	33397444	One UTUC cluster was FGFR3-enriched (n = 15/24) and the other was FGFR3 wild-type (n = 0/11) (P = 0.0008), consistent with the notion that FGFR3 mutation might be associated with distinct epigenome alterations.	('FGFR3', 'Gene', '2261', (21, 26))	('cluster', 'Species', '100569', (9, 16))	('FGFR3', 'Gene', '2261', (66, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('FGFR3', 'Gene', (21, 26))	('associated', 'Reg', (163, 173))	('FGFR3', 'Gene', '2261', (139, 144))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('FGFR3', 'Gene', (66, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('139', '143'))	('FGFR3', 'Gene', (139, 144))	('mutation', 'Var', (145, 153))
193453	33397444	Overall, 84,717 (10.1%) out of 836,691 EPIC probes were differentially methylated (Deltabeta value >= 0.2 or <= - 0.2, FDR < 0.05), the majority being hypomethylated in FGFR3-mutated tumors (n = 82,991; 97.8%).	('FGFR', 'molecular_function', 'GO:0005007', ('169', '173'))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('FGFR3', 'Gene', (169, 174))	('FGFR3', 'Gene', '2261', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', (183, 189))	('hypomethylated', 'Var', (151, 165))
193454	33397444	The hypomethylated probes were mildly enriched in enhancers (3.8% vs 3.2%) (P < 0.001) and DNAse hypersensitive sites (63.7% vs 57.4%) (P < 0.001) (Additional file 2: Fig.	('hypersensitive', 'Disease', 'MESH:D004342', (97, 111))	('hypomethylated', 'Var', (4, 18))	('hypersensitive', 'Disease', (97, 111))	('enhancers', 'PosReg', (50, 59))
193457	33397444	To answer the question whether FGFR3 somatic mutations can modulate DNA methylation in urothelial carcinomas, we thus decided to analyze the DNA methylation landscape of 20 bladder cancer cell lines.	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('mutations', 'Var', (45, 54))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (87, 108))	('bladder cancer', 'Disease', (173, 187))	('bladder cancer', 'Disease', 'MESH:D001749', (173, 187))	('FGFR3', 'Gene', '2261', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('DNA methylation', 'biological_process', 'GO:0006306', ('68', '83'))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('bladder cancer', 'Phenotype', 'HP:0009725', (173, 187))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('DNA methylation', 'biological_process', 'GO:0006306', ('141', '156'))	('urothelial carcinomas', 'Disease', (87, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('FGFR3', 'Gene', (31, 36))	('modulate', 'Reg', (59, 67))
193458	33397444	Notably, supervised clustering using the 14,209 hypermethylated probes derived from UTUC EpiC-high vs EpiC-low identified two subgroups tightly associated with FGFR3 and SWI/SNF gene mutations (Fig.	('FGFR3', 'Gene', (160, 165))	('cluster', 'Species', '100569', (20, 27))	('mutations', 'Var', (183, 192))	('associated', 'Reg', (144, 154))	('FGFR3', 'Gene', '2261', (160, 165))	('SWI/SNF', 'Gene', (170, 177))	('FGFR', 'molecular_function', 'GO:0005007', ('160', '164'))
193459	33397444	Notably, all but one cell line (DSH1) in the C2 (75%) cluster harbored FGFR3 fusions with no SWI/SNF gene mutations.	('FGFR3', 'Gene', (71, 76))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('fusions', 'Var', (77, 84))	('cluster', 'Species', '100569', (54, 61))	('FGFR3', 'Gene', '2261', (71, 76))
193460	33397444	Conversely, only 2 out of 16 cell lines (12.5%) in the C1 cluster had FGFR3 mutations; interestingly, FGFR3 mutation is non-functional in J82 cell lines (no expression of FGFR3) and co-occurred with SMARCA4 mutation in the 639V cell line.	('cluster', 'Species', '100569', (58, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('SMARCA4', 'Gene', (199, 206))	('FGFR3', 'Gene', '2261', (70, 75))	('FGFR3', 'Gene', (171, 176))	('FGFR', 'molecular_function', 'GO:0005007', ('70', '74'))	('FGFR3', 'Gene', (102, 107))	('SMARCA4', 'Gene', '6597', (199, 206))	('J82', 'CellLine', 'CVCL:0359', (138, 141))	('FGFR3', 'Gene', (70, 75))	('FGFR', 'molecular_function', 'GO:0005007', ('171', '175'))	('non-functional', 'MPA', (120, 134))	('mutation', 'Var', (108, 116))	('FGFR3', 'Gene', '2261', (171, 176))	('FGFR3', 'Gene', '2261', (102, 107))
193464	33397444	Notably, ACTL6B, a member of SWI/SNF, was frequently methylated (20% in tumors vs 0% in normal samples).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('ACTL6B', 'Gene', (9, 15))	('methylated', 'Var', (53, 63))	('ACTL6B', 'Gene', '51412', (9, 15))
193471	33397444	Additionally, BLCA-C2 was enriched for FGFR3 mutations (Additional file 1: Table S14), along with focal FGFR3 amplification and higher expression of FGFR3 (Fig.	('mutations', 'Var', (45, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('39', '43'))	('FGFR', 'molecular_function', 'GO:0005007', ('149', '153'))	('FGFR3', 'Gene', '2261', (104, 109))	('FGFR3', 'Gene', '2261', (149, 154))	('FGFR', 'molecular_function', 'GO:0005007', ('104', '108'))	('FGFR3', 'Gene', '2261', (39, 44))	('expression', 'MPA', (135, 145))	('FGFR3', 'Gene', (104, 109))	('FGFR3', 'Gene', (149, 154))	('higher', 'PosReg', (128, 134))	('FGFR3', 'Gene', (39, 44))
193481	33397444	Additionally, 6971 methylation probes and four copy number alterations made contributions to the clustering process (Additional file 2: Fig.	('cluster', 'Species', '100569', (97, 104))	('methylation probes', 'Var', (19, 37))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('made contributions', 'Reg', (71, 89))
193482	33397444	Notably, 8q22.3 contains genes for which amplification was recently shown to define aggressive bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('aggressive bladder cancer', 'Disease', (84, 109))	('amplification', 'Var', (41, 54))	('aggressive bladder cancer', 'Disease', 'MESH:D001749', (84, 109))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))
193484	33397444	While the former one was hypomethylated, immune-depleted, and enriched for FGFR3 mutations, the latter one was hypermethylated, immune-infiltrated, and tightly associated with somatic mutations of SWI/SNF genes.	('FGFR3', 'Gene', (75, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('75', '79'))	('SWI/SNF', 'Gene', (197, 204))	('mutations', 'Var', (81, 90))	('FGFR3', 'Gene', '2261', (75, 80))	('associated', 'Reg', (160, 170))
193485	33397444	Notably, we observed similar findings in bladder carcinoma cell lines, suggesting that FGFR3 alterations (i.e., fusions, mutations) might alter the methylome via direct or indirect mechanisms.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('bladder carcinoma', 'Disease', 'MESH:D001749', (41, 58))	('mutations', 'Var', (121, 130))	('FGFR3', 'Gene', '2261', (87, 92))	('methylome', 'MPA', (148, 157))	('alterations', 'Var', (93, 104))	('bladder carcinoma', 'Disease', (41, 58))	('fusions', 'Var', (112, 119))	('alter', 'Reg', (138, 143))	('FGFR3', 'Gene', (87, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (41, 58))
193486	33397444	In addition to other mutations known to be altered in UTUC, we discovered for the first time a high rate of mutations of the ZFP36L1 gene.	('ZFP36L1', 'Gene', (125, 132))	('ZFP36L1', 'Gene', '677', (125, 132))	('mutations', 'Var', (108, 117))
193487	33397444	If we consider mutations affecting all ZFP36 family genes, those were present in more than one quarter among UTUC cases.	('present', 'Reg', (70, 77))	('ZFP36', 'Gene', '7538', (39, 44))	('mutations', 'Var', (15, 24))	('ZFP36', 'Gene', (39, 44))
193491	33397444	Thus, ZFP36L1 mutations might lead to an increase in cell migration, bolstering tumor progression.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('increase', 'PosReg', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ZFP36L1', 'Gene', (6, 13))	('tumor', 'Disease', (80, 85))	('cell migration', 'biological_process', 'GO:0016477', ('53', '67'))	('cell migration', 'CPA', (53, 67))	('bolstering', 'PosReg', (69, 79))	('ZFP36L1', 'Gene', '677', (6, 13))	('mutations', 'Var', (14, 23))
193492	33397444	In addition, UTUC cases harboring ZFP36 family gene mutations displayed higher tumor mutational loads, an observation which we validated in the TCGA bladder carcinoma dataset.	('mutations', 'Var', (52, 61))	('ZFP36', 'Gene', (34, 39))	('tumor', 'Disease', (79, 84))	('ZFP36', 'Gene', '7538', (34, 39))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (149, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('bladder carcinoma', 'Disease', 'MESH:D001749', (149, 166))	('higher', 'PosReg', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('bladder carcinoma', 'Disease', (149, 166))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
193494	33397444	Previous studies investigated mutations of UTUC and identified a small proportion of cases with germline mutations in MMR genes, with the majority of tumors occurring sporadically.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('investigated', 'Reg', (17, 29))	('MMR genes', 'Gene', (118, 127))	('UTUC', 'Gene', (43, 47))	('mutations', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('MMR', 'biological_process', 'GO:0006298', ('118', '121'))	('germline mutations', 'Var', (96, 114))
193495	33397444	Consistent with these recent findings, none of our sporadic UTUC has a mutator phenotype, and the majority of cases have luminal papillary-enriched transcriptome signatures, although caution might be considered in interpreting the results, as almost half of the cases assessed had FGFR3 mutations and were NMI tumors.	('NMI tumors', 'Disease', (306, 316))	('FGFR3', 'Gene', (281, 286))	('FGFR', 'molecular_function', 'GO:0005007', ('281', '285'))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('luminal', 'Chemical', 'MESH:D010634', (121, 128))	('mutations', 'Var', (287, 296))	('tumors', 'Phenotype', 'HP:0002664', (310, 316))	('FGFR3', 'Gene', '2261', (281, 286))	('NMI tumors', 'Disease', 'MESH:D009369', (306, 316))
193499	33397444	Another observation that also deserves to be discussed is the link between immunity and SWI/SNF genetic tumor alterations which we showed to be associated with higher TILs in UTUC.	('alterations', 'Var', (110, 121))	('SNF genetic tumor', 'Disease', (92, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('associated', 'Reg', (144, 154))	('SNF genetic tumor', 'Disease', 'MESH:D030342', (92, 109))
193500	33397444	In addition, bladder cell lines without FGFR3 alterations and which harbored SWI/SNF gene mutations showed higher interferon-gamma stimulation signature.	('interferon-gamma', 'Gene', (114, 130))	('mutations', 'Var', (90, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('FGFR3', 'Gene', (40, 45))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('114', '130'))	('SWI/SNF', 'Gene', (77, 84))	('FGFR3', 'Gene', '2261', (40, 45))	('higher', 'PosReg', (107, 113))	('interferon-gamma', 'Gene', '3458', (114, 130))
193501	33397444	Further studies are needed to clarify these findings in UTUC, given that the link between mutations in SWI/SNF genes and immunity is contradictory in different cancer subtypes.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('mutations', 'Var', (90, 99))	('cancer', 'Disease', (160, 166))	('SWI/SNF', 'Gene', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
193502	33397444	In colorectal cancer, a positive correlation was found between oncogenic BRAF mutations and hypermethylation of multiple promoter CpG islands, known as CpG island methylator phenotype.	('BRAF', 'Gene', '673', (73, 77))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (78, 87))	('colorectal cancer', 'Disease', (3, 20))	('hypermethylation', 'Var', (92, 108))	('BRAF', 'Gene', (73, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
193503	33397444	A high level of mutations of SWI/SNF genes in FGFR3 wild-type UTUC tumors might explain their CpG island hypermethylation, as SWI/SNF genes have been shown to antagonize the polycomb repressive complex 2 (PRC2).	('UTUC tumors', 'Disease', (62, 73))	('antagonize', 'NegReg', (159, 169))	('SWI/SNF', 'Gene', (126, 133))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('mutations', 'Var', (16, 25))	('FGFR3', 'Gene', '2261', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('SWI/SNF', 'Gene', (29, 36))	('UTUC tumors', 'Disease', 'MESH:D009369', (62, 73))	('FGFR3', 'Gene', (46, 51))
193504	33397444	From a therapeutic standpoint, our data suggest that EpiC-Low UTUC might benefit from the combination of FGFR3 inhibitors with PD-1/PD-L1 inhibitors as a targeted therapeutic strategy to modulate the T cell-depleted phenotype, consistent with the results of a recent study.	('FGFR3', 'Gene', (105, 110))	('modulate', 'Reg', (187, 195))	('inhibitors', 'Var', (111, 121))	('PD-L1', 'Gene', (132, 137))	('PD-L1', 'Gene', '29126', (132, 137))	('FGFR3', 'Gene', '2261', (105, 110))	('combination', 'Interaction', (90, 101))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))	('T cell-depleted phenotype', 'CPA', (200, 225))
193505	33397444	Indeed, erdafitinib was granted accelerated approval by the FDA in relapsed/refractory metastatic bladder cancer on the basis of phase 2 trial results, showing a response rate of 40% in 90 patients with tumors that harbored actionable FGFR alterations.	('alterations', 'Var', (240, 251))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('FGFR', 'molecular_function', 'GO:0005007', ('235', '239'))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('erdafitinib', 'Chemical', 'MESH:C000604580', (8, 19))	('patients', 'Species', '9606', (189, 197))	('FGFR', 'Gene', (235, 239))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
193506	33397444	For the remaining tumors with SWI/SNF mutations, EZH2 inhibition with and without cisplatin might represent an effective option, as it has been recently demonstrated in bladder cancer cells and xenografts, through a mechanism that activates a natural killer (NK) cell-based immune response.	('bladder cancer', 'Disease', 'MESH:D001749', (169, 183))	('activates', 'PosReg', (231, 240))	('EZH2', 'Gene', '2146', (49, 53))	('bladder cancer', 'Disease', (169, 183))	('immune response', 'biological_process', 'GO:0006955', ('274', '289'))	('EZH2', 'Gene', (49, 53))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('bladder cancer', 'Phenotype', 'HP:0009725', (169, 183))	('mutations', 'Var', (38, 47))	('SWI/SNF', 'Gene', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
193507	33397444	Our study is the first to propose two distinct routes of UTUC carcinogenesis through a crosstalk between genetic and epigenetic alterations.	('UTUC carcinogenesis', 'Disease', (57, 76))	('UTUC carcinogenesis', 'Disease', 'MESH:D063646', (57, 76))	('epigenetic alterations', 'Var', (117, 139))	('crosstalk', 'Reg', (87, 96))
193520	33397444	In addition, FGFR3 hotspot mutations (S249C and Y373C) were investigated in the remaining samples not analyzed by WES (n = 5).	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('S249C', 'Var', (38, 43))	('FGFR3', 'Gene', (13, 18))	('S249C', 'SUBSTITUTION', 'None', (38, 43))	('Y373C', 'SUBSTITUTION', 'None', (48, 53))	('FGFR3', 'Gene', '2261', (13, 18))	('Y373C', 'Var', (48, 53))
193555	33397444	We further curated the mutation data by removing ARID1A but attaching SWI/SNF pathway mutation.	('ARID1A', 'Gene', '8289', (49, 55))	('SWI/SNF', 'Gene', (70, 77))	('ARID1A', 'Gene', (49, 55))	('mutation', 'Var', (86, 94))
193561	33397444	For transfection, 4 mul of 5 nM of Human ZFP36L1 (#L-011816-00-0005) siRNA smart pool or non-silencing pool siRNA (Cont siRNA) (#L-011816-00-0005) (Dharmacon) was diluted in 100 mul of OptiMEM media.	('#L-011816-00-0005', 'Var', (128, 145))	('OptiMEM media', 'Chemical', '-', (185, 198))	('ZFP36L1', 'Gene', (41, 48))	('Human', 'Species', '9606', (35, 40))	('#L-011816-00-0005', 'Var', (50, 67))	('ZFP36L1', 'Gene', '677', (41, 48))
193595	25633079	Over the last decade, multiple molecular alterations in this pathway have been implicated in many different cancers .	('cancers', 'Disease', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('implicated', 'Reg', (79, 89))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('alterations', 'Var', (41, 52))
193598	25633079	The largest analysis from the Cancer Genome Atlas (TCGA) network, which included a cohort of 131 chemotherapy-naive high grade muscle invasive UC patients (T2-T4a, Nx, Mx), reported mutations and copy number alterations (CNAs) within this pathway in 42% of tumors.	('Cancer Genome Atlas', 'Disease', (30, 49))	('copy number alterations', 'Var', (196, 219))	('Cancer', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Disease', (257, 263))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (30, 49))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('patients', 'Species', '9606', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('mutations', 'Var', (182, 191))
193603	25633079	The TCGA analysis of non-metastatic bladder cancer patients found PIK3CA activating point mutations in 20% of the tumors, mainly in a hotspot area in the helical domain near E545.	('E545', 'Var', (174, 178))	('activating point', 'PosReg', (73, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (36, 50))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('bladder cancer', 'Disease', 'MESH:D001749', (36, 50))	('PIK3CA', 'Gene', (66, 72))	('bladder cancer', 'Disease', (36, 50))	('tumors', 'Disease', (114, 120))	('patients', 'Species', '9606', (51, 59))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('PIK3CA', 'Gene', '5290', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
193604	25633079	This leads to an amino acid substitution at position 545 (glutamic acid {E} to a lysine {K}) in PIK3CA, thereby increasing catalytic activity and downstream signaling.	('glutamic acid', 'Chemical', 'MESH:D018698', (58, 71))	('catalytic activity', 'molecular_function', 'GO:0003824', ('123', '141'))	('increasing', 'PosReg', (112, 122))	('amino acid', 'Var', (17, 27))	('catalytic activity', 'MPA', (123, 141))	('PIK3CA', 'Gene', (96, 102))	('downstream signaling', 'MPA', (146, 166))	('lysine', 'Chemical', 'MESH:D008239', (81, 87))	('PIK3CA', 'Gene', '5290', (96, 102))	('leads to', 'Reg', (5, 13))	('signaling', 'biological_process', 'GO:0023052', ('157', '166'))
193605	25633079	Previous analyses had also found similar frequencies and the same spectrum of PIK3CA mutations in bladder cancer.	('PIK3CA', 'Gene', (78, 84))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('PIK3CA', 'Gene', '5290', (78, 84))	('mutations', 'Var', (85, 94))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
193606	25633079	assessing the frequency of mutations in PIK3CA pathway in bladder cancer, reported 52% mutations in E545k and 13% mutations in H1047R compared to 33% and 46% respectively in non-bladder cancers according to COSMIC study.	('non-bladder cancers', 'Disease', (174, 193))	('bladder cancer', 'Phenotype', 'HP:0009725', (178, 192))	('PIK3CA', 'Gene', (40, 46))	('H1047R', 'Mutation', 'rs121913279', (127, 133))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('PIK3CA', 'Gene', '5290', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('non-bladder cancers', 'Disease', 'MESH:D001749', (174, 193))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('bladder cancer', 'Disease', (58, 72))	('bladder cancer', 'Disease', 'MESH:D001749', (178, 192))	('H1047R', 'Var', (127, 133))	('E545k', 'Var', (100, 105))	('bladder cancers', 'Phenotype', 'HP:0009725', (178, 193))	('mutations', 'Reg', (87, 96))
193608	25633079	PIK3CA alterations also are suggested to have a prognostic significance.	('PIK3CA', 'Gene', '5290', (0, 6))	('alterations', 'Var', (7, 18))	('PIK3CA', 'Gene', (0, 6))
193609	25633079	They co-occur with FGFR3 mutations in 26% of papillary urothelial neoplasms of uncertain malignant potential.	('papillary urothelial neoplasms', 'Disease', (45, 75))	('mutations', 'Var', (25, 34))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))	('FGFR3', 'Gene', '2261', (19, 24))	('FGFR3', 'Gene', (19, 24))	('neoplasms', 'Phenotype', 'HP:0002664', (66, 75))	('co-occur', 'Reg', (5, 13))	('papillary urothelial neoplasms', 'Disease', 'MESH:D002291', (45, 75))
193610	25633079	Tumors bearing PIK3CA mutations tend to have lower recurrence rates whereas FGFR3 mutant PIK3CA wild type tumors have higher recurrence rates.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (15, 21))	('PIK3CA', 'Gene', '5290', (89, 95))	('FGFR3', 'Gene', '2261', (76, 81))	('type tumors', 'Disease', (101, 112))	('lower', 'NegReg', (45, 50))	('Tumors', 'Disease', (0, 6))	('recurrence rates', 'MPA', (51, 67))	('type tumors', 'Disease', 'MESH:D009369', (101, 112))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (22, 31))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))	('FGFR3', 'Gene', (76, 81))	('PIK3CA', 'Gene', (15, 21))	('mutant', 'Var', (82, 88))
193611	25633079	Mutations in PIK3R1, which is a negative regulator of PIK3CA, have also been reported in UC, although the functional implications of these mutations are unclear at this time.	('PIK3R1', 'Gene', '5295', (13, 19))	('PIK3R1', 'Gene', (13, 19))	('PIK3CA', 'Gene', '5290', (54, 60))	('Mutations', 'Var', (0, 9))	('reported', 'Reg', (77, 85))	('PIK3CA', 'Gene', (54, 60))
193613	25633079	The trial is enrolling metastatic transitional cell UC patients with alterations in the PI3K pathway.	('alterations', 'Var', (69, 80))	('metastatic transitional cell UC', 'Disease', (23, 54))	('PI3K pathway', 'Pathway', (88, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('88', '92'))	('patients', 'Species', '9606', (55, 63))
193614	25633079	Preliminary results from another phase I study of PI3K inhibitor GSK2126458 in 170 patients with advanced solid cancer have shown objective responses (1 of 3 UC patients bearing PIK3CA mutations), although responses were also observed in wild-type patients (2 of 15 UC patients).	('GSK2126458', 'Chemical', 'MESH:C561454', (65, 75))	('cancer', 'Disease', (112, 118))	('PIK3CA', 'Gene', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('patients', 'Species', '9606', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('GSK', 'molecular_function', 'GO:0050321', ('65', '68'))	('PI3K', 'molecular_function', 'GO:0016303', ('50', '54'))	('patients', 'Species', '9606', (161, 169))	('GSK2126458', 'Var', (65, 75))	('PIK3CA', 'Gene', '5290', (178, 184))	('mutations', 'Var', (185, 194))	('patients', 'Species', '9606', (248, 256))	('patients', 'Species', '9606', (269, 277))
193621	25633079	Recently, PTEN loss has also been shown to lead to PI3K inhibitor resistance in other cellular contexts; it was reported that PI3K inhibitor refractory lesions in a breast cancer patient had PTEN loss whereas responding lesions had no PTEN alterations.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('PTEN', 'Gene', '5728', (10, 14))	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('PI3K', 'Var', (126, 130))	('breast cancer', 'Disease', (165, 178))	('PTEN loss', 'Disease', (10, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('PTEN', 'Gene', (191, 195))	('patient', 'Species', '9606', (179, 186))	('PTEN', 'Gene', '5728', (191, 195))	('PTEN loss', 'Disease', 'MESH:D006223', (191, 200))	('PTEN', 'Gene', (235, 239))	('PTEN', 'Gene', '5728', (235, 239))	('PI3K', 'molecular_function', 'GO:0016303', ('126', '130'))	('PTEN loss', 'Disease', 'MESH:D006223', (10, 19))	('PTEN loss', 'Disease', (191, 200))	('PTEN', 'Gene', (10, 14))
193623	25633079	It has been proposed that AKT activation is not directly related to PTEN loss or PIK3CA-activating mutations and therefore alternative activating AKT mutations are expected to be discovered.	('PTEN loss', 'Disease', (68, 77))	('PIK3CA', 'Gene', (81, 87))	('AKT', 'Gene', '207', (146, 149))	('PIK3CA', 'Gene', '5290', (81, 87))	('AKT', 'Gene', '207', (26, 29))	('activation', 'PosReg', (30, 40))	('AKT', 'Gene', (146, 149))	('mutations', 'Var', (99, 108))	('PTEN loss', 'Disease', 'MESH:D006223', (68, 77))	('AKT', 'Gene', (26, 29))
193624	25633079	AKT1 (E17K) mutations have been reported in 2.7% of bladder tumors.	('bladder tumors', 'Phenotype', 'HP:0009725', (52, 66))	('AKT1', 'Gene', '207', (0, 4))	('bladder tumor', 'Phenotype', 'HP:0009725', (52, 65))	('bladder tumors', 'Disease', (52, 66))	('AKT1', 'Gene', (0, 4))	('mutations', 'Var', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('reported', 'Reg', (32, 40))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('bladder tumors', 'Disease', 'MESH:D001749', (52, 66))	('E17K', 'Mutation', 'rs121434592', (6, 10))
193627	25633079	The TCGA analysis also reported AKT1 alterations (amplification and homozygous deletion) in 6%, AKT1 mutation in 2%, and AKT3 overexpression in 10% of the samples independent of copy number.	('AKT1', 'Gene', '207', (96, 100))	('AKT3', 'Gene', (121, 125))	('AKT1', 'Gene', (96, 100))	('overexpression', 'PosReg', (126, 140))	('AKT3', 'Gene', '10000', (121, 125))	('AKT1', 'Gene', '207', (32, 36))	('AKT1', 'Gene', (32, 36))	('alterations', 'Reg', (37, 48))	('mutation', 'Var', (101, 109))
193629	25633079	A recent genomic analysis of 35 stage IV UC's identified TSC1 mutations in 6% of the cohort.	('TSC1', 'Gene', '7248', (57, 61))	('TSC1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
193630	25633079	Most of the mutations in the bladder cancer cohort of TCGA were found to be truncating, resulting in loss of function.	('bladder cancer', 'Disease', 'MESH:D001749', (29, 43))	('bladder cancer', 'Disease', (29, 43))	('of function', 'MPA', (106, 117))	('loss', 'NegReg', (101, 105))	('mutations', 'Var', (12, 21))	('TCGA', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('bladder cancer', 'Phenotype', 'HP:0009725', (29, 43))
193631	25633079	Preclinical studies have shown that in TSC1 mutant bladder cancers, combined mTOR/hsp90 inhibition is a promising strategy.	('TSC1', 'Gene', '7248', (39, 43))	('mutant', 'Var', (44, 50))	('bladder cancers', 'Phenotype', 'HP:0009725', (51, 66))	('hsp90', 'Gene', '3320', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('TSC1', 'Gene', (39, 43))	('mTOR', 'Gene', '2475', (77, 81))	('bladder cancers', 'Disease', 'MESH:D001749', (51, 66))	('mTOR', 'Gene', (77, 81))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('bladder cancers', 'Disease', (51, 66))	('hsp90', 'Gene', (82, 87))
193632	25633079	TSC mutations are also shown to be a marker of sensitivity to mTOR inhibition.	('mutations', 'Var', (4, 13))	('mTOR', 'Gene', '2475', (62, 66))	('TSC', 'Gene', (0, 3))	('mTOR', 'Gene', (62, 66))
193634	25633079	Subsequent genomic analysis of other patients on the same trial showed that everolimus responders carried more TSC1 mutations (non-sense or missense) as compared to non-responders who had wild type TSC1.	('TSC1', 'Gene', (111, 115))	('TSC1', 'Gene', '7248', (198, 202))	('missense', 'Var', (140, 148))	('patients', 'Species', '9606', (37, 45))	('TSC1', 'Gene', (198, 202))	('non-sense', 'Var', (127, 136))	('TSC1', 'Gene', '7248', (111, 115))	('everolimus', 'Chemical', 'MESH:D000068338', (76, 86))
193639	25633079	Subsequent whole genome sequencing of the patient who showed near complete response to everolimus in the study had non-synonymous mutations in TSC, lending biomarker credibility to this regulator of mTOR (as noted above).	('mTOR', 'Gene', (199, 203))	('everolimus', 'Chemical', 'MESH:D000068338', (87, 97))	('TSC', 'Gene', (143, 146))	('non-synonymous mutations', 'Var', (115, 139))	('patient', 'Species', '9606', (42, 49))	('mTOR', 'Gene', '2475', (199, 203))
193643	25633079	It is encoded by the ERBB2 gene on chromosome 17 and alterations in this gene have been reported in various cancers, most notably breast cancer (14.9%) and uterine tumors (10.4%).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('alterations', 'Var', (53, 64))	('ERBB2', 'Gene', '2064', (21, 26))	('uterine tumors', 'Phenotype', 'HP:0010784', (156, 170))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('reported', 'Reg', (88, 96))	('chromosome', 'cellular_component', 'GO:0005694', ('35', '45'))	('ERBB2', 'Gene', (21, 26))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('cancers', 'Disease', (108, 115))
193645	25633079	According to recent TCGA data, molecular alterations of ERBB2(HER2) gene have been found in 13% of UC with overexpression in 7% suggesting a potential role of HER2 targeted therapy in selected UC.	('HER2', 'Gene', (159, 163))	('HER2', 'Gene', '2064', (62, 66))	('molecular alterations', 'Var', (31, 52))	('HER2', 'Gene', '2064', (159, 163))	('ERBB2', 'Gene', '2064', (56, 61))	('ERBB2', 'Gene', (56, 61))	('found', 'Reg', (83, 88))	('HER2', 'Gene', (62, 66))
193656	25633079	TCGA bladder study has also identified recurrent missense mutations in ERBB2 and ERBB3 (11%) genes.	('ERBB3', 'Gene', (81, 86))	('ERBB2', 'Gene', '2064', (71, 76))	('ERBB2', 'Gene', (71, 76))	('missense mutations', 'Var', (49, 67))	('ERBB3', 'Gene', '2065', (81, 86))
193657	25633079	The frequency of ERBB2 mutations in the bladder cohort of TCGA was in fact more than identified in the breast cancer TCGA cohort.	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('ERBB2', 'Gene', '2064', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('mutations', 'Var', (23, 32))	('ERBB2', 'Gene', (17, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))
193658	25633079	It has already been shown in inflammatory breast cancer patients that lapatinib is effective for ERBB2 mutated, non amplified tumors.	('patients', 'Species', '9606', (56, 64))	('mutated', 'Var', (103, 110))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('lapatinib', 'Chemical', 'MESH:D000077341', (70, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('ERBB2', 'Gene', (97, 102))	('ERBB2', 'Gene', '2064', (97, 102))
193659	25633079	Based on the same concept, a phase II trial testing Neratinib, a dual EFGR and HER2 inhibitor, is recruiting HER2 mutated solid tumor patients and includes a bladder cancer cohort.	('HER2', 'Gene', '2064', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Neratinib', 'Chemical', 'MESH:C487932', (52, 61))	('bladder cancer', 'Phenotype', 'HP:0009725', (158, 172))	('HER2', 'Gene', (109, 113))	('mutated', 'Var', (114, 121))	('HER2', 'Gene', '2064', (109, 113))	('patients', 'Species', '9606', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('bladder cancer', 'Disease', 'MESH:D001749', (158, 172))	('bladder cancer', 'Disease', (158, 172))	('tumor', 'Disease', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('HER2', 'Gene', (79, 83))
193671	25633079	Both trials did not require the presence of EGFR alterations as a criterion for enrollment.	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))	('alterations', 'Var', (49, 60))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))
193679	25633079	FGFR3 was found to be mutated with a high frequency in up to 84% of pTa tumors and 21% of T1 tumors .	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('pTa tumors', 'Disease', 'MESH:D009369', (68, 78))	('pTa', 'molecular_function', 'GO:0008959', ('68', '71'))	('FGFR3', 'Gene', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('mutated', 'Var', (22, 29))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('pTa tumors', 'Disease', (68, 78))	('FGFR3', 'Gene', '2261', (0, 5))
193680	25633079	As compared to non-muscle invasive tumors, genomic analysis in 35 stage IV UC's revealed FGFR3 alterations in only 11% tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('FGFR3', 'Gene', (89, 94))	('invasive tumors', 'Disease', (26, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('alterations', 'Var', (95, 106))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('invasive tumors', 'Disease', 'MESH:D009369', (26, 41))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('FGFR3', 'Gene', '2261', (89, 94))
193681	25633079	Another analysis done in 97 high grade UC samples(containing 85% muscle-invasive tumors)using array comparative genomic hybridization (for CNA's), mass spectroscopy-based genotyping and Sanger sequencing (for mutation profiling), identified FGFR3 molecular alterations in 15.5% samples with mutations in 13.4% of the cases and amplification in 1%.	('FGFR3', 'Gene', '2261', (241, 246))	('invasive tumors', 'Disease', 'MESH:D009369', (72, 87))	('FGFR3', 'Gene', (241, 246))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (291, 300))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('FGFR', 'molecular_function', 'GO:0005007', ('241', '245'))	('invasive tumors', 'Disease', (72, 87))
193683	25633079	Out of 127 muscle invasive UC samples, FGFR3 was altered in 19% of cases, with mutations in 12.6%, overexpression in 3.1 %, fusions in 2.4% and deletion in 0.8%.	('FGFR', 'molecular_function', 'GO:0005007', ('39', '43'))	('altered', 'Reg', (49, 56))	('overexpression', 'PosReg', (99, 113))	('mutations', 'Var', (79, 88))	('deletion', 'Var', (144, 152))	('FGFR3', 'Gene', '2261', (39, 44))	('fusions', 'Var', (124, 131))	('FGFR3', 'Gene', (39, 44))
193684	25633079	In addition to mutations, chromosomal translocation is another mechanism of FGFR3 activation in bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('FGFR3', 'Gene', (76, 81))	('FGFR3', 'Gene', '2261', (76, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (96, 110))	('activation', 'PosReg', (82, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))	('bladder cancer', 'Disease', 'MESH:D001749', (96, 110))	('bladder cancer', 'Disease', (96, 110))	('chromosomal translocation', 'Var', (26, 51))
193689	25633079	FGFR3 mutations are attractive therapeutic targets for both muscle invasive and superficial UC in preclinical models.	('muscle invasive', 'Disease', (60, 75))	('superficial UC', 'Disease', (80, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
193690	25633079	FGFR inhibition has cytostatic and cytotoxic effects in FGFR-dependent bladder cancer cells.A study of three small molecule FGFR3 inhibitors (PD173074, TKI-258 and SU5402) tested on a panel of 13 bladder cancer cell lines demonstrated a correlation between response and FGFR3 expression levels in each cell line.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', (270, 275))	('PD173074', 'Var', (142, 150))	('FGFR3', 'Gene', '2261', (270, 275))	('SU5402', 'Chemical', 'MESH:C105686', (164, 170))	('bladder cancer', 'Disease', 'MESH:D001749', (71, 85))	('FGFR', 'molecular_function', 'GO:0005007', ('270', '274'))	('FGFR', 'molecular_function', 'GO:0005007', ('124', '128'))	('bladder cancer', 'Disease', (71, 85))	('FGFR3', 'Gene', (124, 129))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))	('FGFR', 'molecular_function', 'GO:0005007', ('56', '60'))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('FGFR3', 'Gene', '2261', (124, 129))	('bladder cancer', 'Disease', 'MESH:D001749', (196, 210))	('bladder cancer', 'Disease', (196, 210))	('bladder cancer', 'Phenotype', 'HP:0009725', (196, 210))	('PD173074', 'Chemical', 'MESH:C115711', (142, 150))	('dependent bladder', 'Phenotype', 'HP:0100645', (61, 78))
193692	25633079	There is an ongoing phase II trial of dovitinib, a small molecule inhibitor which inhibits FGFR3 in histologically confirmed non muscle invasive (Ta, T1,Tis stage) bladder cancer harboring FGFR mutation or overexpression that is refractory to BCG therapy.	('FGFR3', 'Gene', (91, 96))	('mutation', 'Var', (194, 202))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('bladder cancer', 'Phenotype', 'HP:0009725', (164, 178))	('FGFR', 'molecular_function', 'GO:0005007', ('189', '193'))	('non muscle invasive', 'Disease', (125, 144))	('BCG', 'Species', '33892', (243, 246))	('FGFR', 'Gene', (189, 193))	('dovitinib', 'Chemical', 'MESH:C500007', (38, 47))	('overexpression', 'PosReg', (206, 220))	('bladder cancer', 'Disease', 'MESH:D001749', (164, 178))	('bladder cancer', 'Disease', (164, 178))	('FGFR3', 'Gene', '2261', (91, 96))	('inhibits', 'NegReg', (82, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('91', '95'))
193694	25633079	A phase I study testing selective pan FGFR inhibitor, BGJ398, was found to be safe and showed clinical activity in solid tumors with FGFR genetic alteration especially UC.	('BGJ398', 'Gene', (54, 60))	('FGFR', 'Gene', (133, 137))	('solid tumors', 'Disease', 'MESH:D009369', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('solid tumors', 'Disease', (115, 127))	('FGFR', 'molecular_function', 'GO:0005007', ('133', '137'))	('BGJ398', 'Chemical', 'MESH:C568950', (54, 60))	('genetic alteration', 'Var', (138, 156))
193695	25633079	Similarly another pan FGFR inhibitor, JNJ-42756493, has been shown to have a tolerable safety profile and anti-tumor activity with one of the patient harboring FGFR3-TACC3 translocation showing confirmed PR suggesting that patients withFGFR3 fusions may be more sensitive to these newer inhibitors.	('FGFR3', 'Gene', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('FGFR3', 'Gene', (236, 241))	('JNJ-42756493', 'Var', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('TACC3', 'Gene', '10460', (166, 171))	('tumor', 'Disease', (111, 116))	('TACC3', 'Gene', (166, 171))	('patient', 'Species', '9606', (223, 230))	('FGFR3', 'Gene', '2261', (160, 165))	('patient', 'Species', '9606', (142, 149))	('FGFR', 'molecular_function', 'GO:0005007', ('160', '164'))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('patients', 'Species', '9606', (223, 231))	('FGFR3', 'Gene', '2261', (236, 241))
193697	25633079	For instance: FGFR mutant cancer cell lines resistant to anti-FGFR therapy activate EGFR signaling as a compensatory mechanism.	('activate', 'PosReg', (75, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('FGFR', 'Gene', (14, 18))	('EGFR', 'Gene', '1956', (84, 88))	('mutant', 'Var', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('EGFR', 'Gene', (84, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))
193702	25633079	HSP27 is encoded by HSBP1 gene and reported in the TCGA analysis to be amplified in 1.6% of samples HSP27 knockdown inhibits bladder tumor growth, and has shown evidence of enhanced antitumor activity with taxane therapy.	('HSP27', 'Gene', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (186, 191))	('HSBP1', 'Gene', '3281', (20, 25))	('bladder tumor', 'Disease', (125, 138))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('bladder tumor', 'Disease', 'MESH:D001749', (125, 138))	('taxane', 'Chemical', 'MESH:C080625', (206, 212))	('knockdown', 'Var', (106, 115))	('HSP27', 'Gene', (0, 5))	('inhibits', 'NegReg', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('HSP27', 'Gene', '3315', (100, 105))	('tumor', 'Disease', (133, 138))	('enhanced', 'PosReg', (173, 181))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('bladder tumor', 'Phenotype', 'HP:0009725', (125, 138))	('HSBP1', 'Gene', (20, 25))	('HSP27', 'Gene', '3315', (0, 5))
193706	25633079	Another member of this group of proteins, HSP 70-2 expression is also associated with early spread and progression of urothelial carcinoma of bladder and inhibition of HSP 70-2 significantly suppressed the progression of tumor in an in vivo mouse xenograft study.	('suppressed', 'NegReg', (191, 201))	('mouse', 'Species', '10090', (241, 246))	('inhibition', 'Var', (154, 164))	('urothelial carcinoma of bladder', 'Disease', 'MESH:D001749', (118, 149))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('associated with', 'Reg', (70, 85))	('HSP 70-2', 'Gene', (42, 50))	('urothelial carcinoma of bladder', 'Disease', (118, 149))	('HSP 70-2', 'Gene', (168, 176))	('HSP 70-2', 'Gene', '15512', (168, 176))	('urothelial carcinoma of bladder', 'Phenotype', 'HP:0006740', (118, 149))	('HSP 70-2', 'Gene', '15512', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
193709	25633079	This was confirmed by the TCGA study of 131 bladder carcinoma patients, which showed mutations/CNAs of histone modifying genes in 89% of samples.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('bladder carcinoma', 'Disease', (44, 61))	('mutations/CNAs', 'Var', (85, 99))	('bladder carcinoma', 'Disease', 'MESH:D001749', (44, 61))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (44, 61))	('patients', 'Species', '9606', (62, 70))
193710	25633079	Most notably the CREBBP gene which encodes a histone acetyltransferase demonstrated mutations in 12% and CNAs in 14 % of cases.	('mutations', 'Var', (84, 93))	('CNAs', 'Gene', (105, 109))	('CREBBP', 'Gene', (17, 23))	('CREBBP', 'Gene', '1387', (17, 23))
193711	25633079	The methyltransferaseMLL2 showed a mutation rate of 27 % and a 3% CNAs rate, Similarly, KDM6A which encodes for a demethylating protein showed mutations in 24 % and CNAs in 3 % of cases.The majority of these molecular alterations were inactivating resulting in loss of function.	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('KDM6A', 'Gene', '7403', (88, 93))	('inactivating', 'Var', (235, 247))	('loss of function', 'NegReg', (261, 277))	('KDM6A', 'Gene', (88, 93))
193712	25633079	The components of SWI/SNF nucleosomes complex were altered in 64% samples with the most frequent alterations seen in ARID1A (25% mutations and 3% CNAs)  Targeting epigenetic regulation in UC can be achieved using DNA methyltransferase inhibitors(DNMTi) and histone deacetylase inhibitors (HDACi).	('altered', 'Reg', (51, 58))	('HDAC', 'Gene', (289, 293))	('DNMTi', 'Chemical', '-', (246, 251))	('mutations', 'Var', (129, 138))	('HDAC', 'Gene', '9734', (289, 293))	('histone deacetylase', 'Gene', '9734', (257, 276))	('regulation', 'biological_process', 'GO:0065007', ('174', '184'))	('ARID1A', 'Gene', '8289', (117, 123))	('ARID1A', 'Gene', (117, 123))	('DNA', 'cellular_component', 'GO:0005574', ('213', '216'))	('histone deacetylase', 'Gene', (257, 276))	('epigenetic regulation', 'MPA', (163, 184))
193723	25633079	Treatment of histone acetyl-transferase mutated bladder cancers with HDACi's represents an appealing approach.	('bladder cancers', 'Disease', (48, 63))	('HDAC', 'Gene', (69, 73))	('HDAC', 'Gene', '9734', (69, 73))	('bladder cancers', 'Phenotype', 'HP:0009725', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('histone', 'Protein', (13, 20))	('bladder cancers', 'Disease', 'MESH:D001749', (48, 63))	('mutated', 'Var', (40, 47))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
193737	25633079	In this study MPDL3280A (anti PD-L1) was found to be safe and half of the patients had rapid ongoing responses.	('patients', 'Species', '9606', (74, 82))	('MPDL3280A', 'Var', (14, 23))	('PD-L1', 'Gene', '29126', (30, 35))	('PD-L1', 'Gene', (30, 35))
193738	25633079	The FDA has already granted Breakthrough Therapy Designation to MPDL3280A in bladder cancer.	('MPDL3280A', 'Var', (64, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('bladder cancer', 'Disease', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))
193757	25633079	An ongoing clinical trial is evaluating the correlation of carboplatin-DNA monoadduct formation and ERCC1 expression with clinical responses to carboplatin-based chemotherapy  Overexpression of anti-apoptotic proteins such as BCL-2 has been associated with platinum resistance in UC cell lines, siRNA knockdown restored platinum sensitivity .	('restored', 'PosReg', (311, 319))	('platinum', 'Chemical', 'MESH:D010984', (320, 328))	('platinum sensitivity', 'MPA', (320, 340))	('carboplatin', 'Chemical', 'MESH:D016190', (144, 155))	('BCL-2', 'molecular_function', 'GO:0015283', ('226', '231'))	('carboplatin', 'Chemical', 'MESH:D016190', (59, 70))	('BCL-2', 'Gene', (226, 231))	('knockdown', 'Var', (301, 310))	('associated', 'Reg', (241, 251))	('ERCC1', 'Gene', '2067', (100, 105))	('ERCC1', 'Gene', (100, 105))	('formation', 'biological_process', 'GO:0009058', ('86', '95'))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('platinum resistance', 'Disease', (257, 276))	('platinum', 'Chemical', 'MESH:D010984', (257, 265))	('BCL-2', 'Gene', '596', (226, 231))
193763	25633079	Some of these alterations are already validated molecular targets in UC and other cancer types.	('alterations', 'Var', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (82, 88))
193985	26395176	We found that UC cases with parafibromin positivity had less of a tendency to show muscularis propria invasion and were more commonly located in the lower urinary system.	('parafibromin', 'Gene', (28, 40))	('muscularis propria', 'Phenotype', 'HP:0030936', (83, 101))	('muscularis propria invasion', 'CPA', (83, 110))	('positivity', 'Var', (41, 51))	('parafibromin', 'Gene', '79577', (28, 40))
193992	26395176	Mutations of this protein lead to autosomal dominant hyperparathyroidism-jaw tumor syndrome with parathyroid adenoma or carcinoma, mandibular or maxillary fibro-osseous tumors, and renal neoplastic and non-neoplastic abnormalities such as Wilms' tumor, hamartoma, or cystic renal disease.	('renal neoplastic', 'Disease', (181, 197))	('renal disease', 'Phenotype', 'HP:0000112', (274, 287))	('hamartoma', 'Disease', (253, 262))	('renal neoplastic and non-neoplastic abnormalities', 'Phenotype', 'HP:0009726', (181, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('parathyroid adenoma or carcinoma', 'Disease', (97, 129))	('autosomal dominant hyperparathyroidism', 'Phenotype', 'HP:0008200', (34, 72))	('renal neoplastic', 'Disease', 'MESH:D007680', (181, 197))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (239, 251))	('mandibular', 'Disease', (131, 141))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('cystic renal disease', 'Disease', 'MESH:D052177', (267, 287))	('jaw tumor', 'Phenotype', 'HP:0030792', (73, 82))	('fibro-osseous tumors', 'Disease', (155, 175))	('lead to', 'Reg', (26, 33))	('autosomal dominant hyperparathyroidism-jaw tumor syndrome', 'Disease', 'MESH:C563273', (34, 91))	('non-neoplastic abnormalities', 'Disease', (202, 230))	('parathyroid adenoma', 'Phenotype', 'HP:0002897', (97, 116))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('non-neoplastic abnormalities', 'Disease', 'MESH:C580335', (202, 230))	('cystic renal disease', 'Disease', (267, 287))	('hamartoma', 'Disease', 'MESH:D006222', (253, 262))	("Wilms' tumor", 'Disease', (239, 251))	("Wilms' tumor", 'Disease', 'MESH:D009396', (239, 251))	('neoplastic abnormalities', 'Phenotype', 'HP:0002664', (206, 230))	('fibro-osseous tumors', 'Disease', 'MESH:D009810', (155, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cystic renal disease', 'Phenotype', 'HP:0000107', (267, 287))	('parathyroid adenoma or carcinoma', 'Disease', 'MESH:D010282', (97, 129))	('hamartoma', 'Phenotype', 'HP:0010566', (253, 262))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (53, 72))
194089	21159190	Both CDKN2A and CDKN2B losses have been well documented in UC, with a CDKN2A deletion often associated with worsened outcomes.	('CDKN2B', 'Gene', (16, 22))	('CDKN2A', 'Gene', (5, 11))	('deletion', 'Var', (77, 85))	('losses', 'NegReg', (23, 29))	('CDKN2B', 'Gene', '1030', (16, 22))	('CDKN2A', 'Gene', '1029', (5, 11))	('CDKN2A', 'Gene', (70, 76))	('associated', 'Reg', (92, 102))	('CDKN2A', 'Gene', '1029', (70, 76))
194092	21159190	In our subsequent data analyses (Figure 1B), we noticed that two bUCs (bU28 and bU29) and two rUCs (rU173 and rU409) displayed patterns distinct from those of other samples in their respective classes.	('rU409', 'Var', (110, 115))	('bU28', 'Chemical', '-', (71, 75))	('bU29', 'Var', (80, 84))	('bU29', 'Chemical', '-', (80, 84))	('rU173', 'Var', (100, 105))	('bU28', 'Var', (71, 75))
194095	21159190	Indeed, a careful retrospective review of the samples revealed that bU28 had approximately 50% stroma admixed, while bU29 had a lesser (but still significant) amount.	('stroma admixed', 'CPA', (95, 109))	('bU29', 'Var', (117, 121))	('bU28', 'Chemical', '-', (68, 72))	('bU29', 'Chemical', '-', (117, 121))	('bU28', 'Var', (68, 72))
194143	33603337	Of note there are two versions of EV, the hybridoma (AGS-22M6E) and the Chinese Hamster Ovary (CHO or AGS-22CE) version, both of which were proven to induce cell death in vitro.	('Chinese Hamster', 'Species', '10029', (72, 87))	('cell death', 'CPA', (157, 167))	('AGS-22M6E', 'Var', (53, 62))	('cell death', 'biological_process', 'GO:0008219', ('157', '167'))	('CHO', 'molecular_function', 'GO:0043848', ('95', '98'))	('CHO', 'CellLine', 'CVCL:0213', (95, 98))	('induce', 'Reg', (150, 156))
194178	33603337	A total of 7% of patients discontinued treatment with EV + pembrolizumab due to AEs (lipase increase, multi-organ failure).	('multi-organ failure', 'Disease', (102, 121))	('multi-organ failure', 'Disease', 'MESH:D009102', (102, 121))	('increase', 'PosReg', (92, 100))	('patients', 'Species', '9606', (17, 25))	('EV +', 'Var', (54, 58))	('pembrolizumab', 'Chemical', 'MESH:C582435', (59, 72))
194218	33603337	According to NCCN guidelines, erdafitinib which is FDA-approved for the treatment of mUC patients with actionable FGFR3/FGFR2 alterations is recommended as second-line therapy after CPI or third-line therapy after platinum-based chemotherapy and CPI, with EV recommendation as a preferred subsequent-line systemic therapy option.	('erdafitinib', 'Chemical', 'MESH:C000604580', (30, 41))	('FGFR2', 'Gene', (120, 125))	('platinum', 'Chemical', 'MESH:D010984', (214, 222))	('FGFR3', 'Gene', '2261', (114, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('114', '118'))	('CPI', 'Chemical', '-', (246, 249))	('patients', 'Species', '9606', (89, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('120', '124'))	('FGFR2', 'Gene', '2263', (120, 125))	('alterations', 'Var', (126, 137))	('FGFR3', 'Gene', (114, 119))	('CPI', 'Chemical', '-', (182, 185))
194220	33603337	FGFR alteration detection might be useful, in patients with progressive disease eligible for third-line therapy: for a patient with an FGFR2/3 alteration the choice could be based on possible TRAEs and their impact on patients' life.	('patient', 'Species', '9606', (46, 53))	('patient', 'Species', '9606', (119, 126))	('patients', 'Species', '9606', (46, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('patient', 'Species', '9606', (218, 225))	('patients', 'Species', '9606', (218, 226))	('FGFR2/3', 'Gene', (135, 142))	('alteration', 'Var', (143, 153))	('FGFR', 'molecular_function', 'GO:0005007', ('135', '139'))	('FGFR2/3', 'Gene', '2263;2261', (135, 142))
194228	32064261	Although COME of gene mutations in pan-cancer have been well explored, little is known about the COME of DNA methylation in pan-cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('mutations', 'Var', (22, 31))	('DNA methylation', 'biological_process', 'GO:0006306', ('105', '120'))	('cancer', 'Disease', (128, 134))
194234	32064261	Taken together, we identified millions of COME events of DNA methylation in pan-cancer and detected functional epigenetic COME events that could separate tumor patients into different subtypes, which may benefit the diagnosis and prognosis of pan-cancer.	('patients', 'Species', '9606', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('DNA methylation', 'Var', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('DNA methylation', 'biological_process', 'GO:0006306', ('57', '72'))	('cancer', 'Disease', (247, 253))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('benefit', 'PosReg', (204, 211))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('cancer', 'Disease', (80, 86))	('tumor', 'Disease', (154, 159))
194235	32064261	An increasing number of studies have indicated that aberrant DNAm plays an important role in diverse diseases, especially cancers.	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('aberrant DNAm', 'Var', (52, 65))
194236	32064261	For example, the hypermethylation of CpG island in promoter region of tumor suppressor genes have been observed in pediatric acute myeloid leukemia, bladder and adult brain tumors as well as hepatocellular carcinoma, which may lead to proliferative advantages and aggressive phenotypes during tumorigenesis.	('bladder', 'Disease', (149, 156))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('hepatocellular carcinoma', 'Disease', (191, 215))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('acute myeloid leukemia', 'Disease', (125, 147))	('observed', 'Reg', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('brain tumors', 'Phenotype', 'HP:0030692', (167, 179))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('brain tumors', 'Disease', 'MESH:D001932', (167, 179))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('hypermethylation', 'Var', (17, 33))	('hypermethylation of CpG island', 'biological_process', 'GO:0044027', ('17', '47'))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (125, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (191, 215))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (125, 147))	('brain tumors', 'Disease', (167, 179))	('bladder', 'Disease', 'MESH:D001745', (149, 156))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (131, 147))	('proliferative', 'CPA', (235, 248))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', (293, 298))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (191, 215))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
194240	32064261	Co-methylation has been reported as a new indicator for discovering functional associations between gene pairs in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('methylation', 'biological_process', 'GO:0032259', ('3', '14'))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))	('Co-methylation', 'Var', (0, 14))
194246	32064261	Our results suggest that the COME events of DNA methylation could play important roles in tumorigenesis and may benefit the prognosis of different cancers.	('prognosis', 'CPA', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('DNA methylation', 'biological_process', 'GO:0006306', ('44', '59'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('DNA', 'Gene', (44, 47))	('methylation', 'Var', (48, 59))	('benefit', 'PosReg', (112, 119))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('play', 'Reg', (66, 70))
194267	32064261	Moreover, aberrant methylation of hub gene AGR2 was reported to be associated with ovarian cancer, while MT3 was a putative tumor suppressor gene in pediatric acute myeloid leukemia.	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('hub', 'Gene', '1993', (34, 37))	('tumor', 'Disease', (124, 129))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('124', '140'))	('aberrant methylation', 'Var', (10, 30))	('ovarian cancer', 'Disease', (83, 97))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (159, 181))	('tumor suppressor', 'biological_process', 'GO:0051726', ('124', '140'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('acute myeloid leukemia', 'Disease', (159, 181))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (165, 181))	('MT3', 'Gene', '4504', (105, 108))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (159, 181))	('leukemia', 'Phenotype', 'HP:0001909', (173, 181))	('AGR2', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('associated', 'Reg', (67, 77))	('AGR2', 'Gene', '10551', (43, 47))	('ovarian cancer', 'Disease', 'MESH:D010051', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('hub', 'Gene', (34, 37))	('MT3', 'Gene', (105, 108))
194273	32064261	Aberrant DNA methylation of some of those top 10 genes with the highest degree has been reported to be associated with neoplasms, such as HHIPL1, GABRB2, FOXF1 and RSPO4 (: Figure 2E).	('GABRB2', 'Gene', (146, 152))	('neoplasms', 'Disease', 'MESH:D009369', (119, 128))	('Aberrant', 'Var', (0, 8))	('associated', 'Reg', (103, 113))	('RSPO4', 'Gene', '343637', (164, 169))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('neoplasms', 'Phenotype', 'HP:0002664', (119, 128))	('FOXF1', 'Gene', (154, 159))	('GABRB2', 'Gene', '2561', (146, 152))	('FOXF1', 'Gene', '2294', (154, 159))	('HHIPL1', 'Gene', (138, 144))	('HHIPL1', 'Gene', '84439', (138, 144))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('neoplasm', 'Phenotype', 'HP:0002664', (119, 127))	('RSPO4', 'Gene', (164, 169))	('neoplasms', 'Disease', (119, 128))
194276	32064261	To further explore the associations between aberrant DNA methylation of zinc fingers gene family and neoplasms, we found that those genes were significantly enriched in regulation of transcription, DNA binding transcription factor activity, RNA polymerase II regulatory region sequence-specific DNA binding, Neuroactive ligand-receptor interaction, and so on (Supplementary Table S3).	('neoplasms', 'Phenotype', 'HP:0002664', (101, 110))	('transcription', 'biological_process', 'GO:0006351', ('210', '223'))	('DNA', 'cellular_component', 'GO:0005574', ('295', '298'))	('binding', 'Interaction', (299, 306))	('neoplasm', 'Phenotype', 'HP:0002664', (101, 109))	('transcription', 'MPA', (183, 196))	('DNA methylation', 'biological_process', 'GO:0006306', ('53', '68'))	('ligand', 'molecular_function', 'GO:0005488', ('320', '326'))	('regulation', 'MPA', (169, 179))	('neoplasms', 'Disease', 'MESH:D009369', (101, 110))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('DNA binding transcription factor activity', 'molecular_function', 'GO:0003700', ('198', '239'))	('regulation', 'biological_process', 'GO:0065007', ('169', '179'))	('DNA', 'cellular_component', 'GO:0005574', ('198', '201'))	('neoplasms', 'Disease', (101, 110))	('RNA', 'cellular_component', 'GO:0005562', ('241', '244'))	('transcription', 'biological_process', 'GO:0006351', ('183', '196'))	('aberrant', 'Var', (44, 52))	('interaction', 'Interaction', (336, 347))	('RNA polymerase II regulatory region sequence-specific DNA binding', 'molecular_function', 'GO:0000977', ('241', '306'))
194303	32064261	Hypermethylation of the CpG sites on GRM6 (glutamate metabotropic receptor 6) was reported to be a hallmark of CIMP in clear cell renal cell carcinomas.	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (119, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('glutamate metabotropic receptor 6', 'Gene', '2916', (43, 76))	('clear cell renal cell carcinomas', 'Disease', (119, 151))	('Hypermethylation', 'Var', (0, 16))	('clear cell renal cell carcinomas', 'Disease', 'MESH:D002292', (119, 151))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (130, 151))	('GRM6', 'Gene', '2916', (37, 41))	('glutamate metabotropic receptor 6', 'Gene', (43, 76))	('GRM6', 'Gene', (37, 41))
194304	32064261	In contrast, cluster C7 was associated with the poorest prognosis and co-methylation of GRB7-SLC45A4 was enriched in this group (p-value <0.001, hypergeometric test).	('poorest', 'NegReg', (48, 55))	('methylation', 'biological_process', 'GO:0032259', ('73', '84'))	('co-methylation', 'Var', (70, 84))	('SLC45A4', 'Gene', (93, 100))	('cluster C7', 'Disease', (13, 23))	('GRB7', 'Gene', '2886', (88, 92))	('GRB7', 'Gene', (88, 92))	('cluster C7', 'Disease', 'MESH:C566443', (13, 23))	('SLC45A4', 'Gene', '57210', (93, 100))
194307	32064261	The result shows that patients with co-methylation of CRMP1-GRM6 have better outcomes (p-value <0.0001, log-rank test, Figure 6C), whereas patients with co-methylation of GRB7-SLC45A4 exhibit significantly poorer prognosis (p-value <0.0001, log-rank test, Figure 6D).	('patients', 'Species', '9606', (139, 147))	('outcomes', 'MPA', (77, 85))	('SLC45A4', 'Gene', (176, 183))	('CRMP1', 'Gene', (54, 59))	('CRMP1', 'Gene', '1400', (54, 59))	('patients', 'Species', '9606', (22, 30))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('better', 'PosReg', (70, 76))	('GRM6', 'Gene', '2916', (60, 64))	('methylation', 'biological_process', 'GO:0032259', ('156', '167'))	('co-methylation', 'Var', (36, 50))	('GRM6', 'Gene', (60, 64))	('GRB7', 'Gene', '2886', (171, 175))	('SLC45A4', 'Gene', '57210', (176, 183))	('GRB7', 'Gene', (171, 175))
194310	32064261	Although several studies have reported the epigenetic silencing of the zinc finger gene family, we are the first to identify functional epigenetic modules of the zinc finger gene family in six cancer types by integrating gene expression and DNA methylation data in the context of COME networks.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('DNA methylation', 'biological_process', 'GO:0006306', ('241', '256'))	('epigenetic', 'Var', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('gene expression', 'biological_process', 'GO:0010467', ('221', '236'))	('DNA', 'cellular_component', 'GO:0005574', ('241', '244'))
194311	32064261	Methylation was reported to be the main mechanism for downregulation of tumor cell growth suppressor ZNF677 in non-small cell lung cancers (NSCLCs) and the methylation of ZNF677 could be used in the prognosis of NSCLCs.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('non-small cell lung cancers', 'Disease', (111, 138))	('NSCLCs', 'Disease', 'MESH:D002289', (140, 146))	('ZNF677', 'Gene', (171, 177))	('NSCLCs', 'Disease', 'MESH:D002289', (212, 218))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (111, 138))	('ZNF677', 'Gene', '342926', (101, 107))	('ZNF677', 'Gene', (101, 107))	('downregulation', 'NegReg', (54, 68))	('Methylation', 'Var', (0, 11))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (115, 138))	('tumor', 'Disease', (72, 77))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (111, 138))	('NSCLCs', 'Disease', (140, 146))	('NSCLCs', 'Disease', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('methylation', 'biological_process', 'GO:0032259', ('156', '167'))	('cell growth', 'biological_process', 'GO:0016049', ('78', '89'))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancers', 'Phenotype', 'HP:0100526', (126, 138))	('ZNF677', 'Gene', '342926', (171, 177))
194354	31766561	Conversely, patients with high TLE2 expression displayed more favorable OS (n = 29 with high expression, n = 31 with low expression; median survival, 15 vs. 9 months, and p = 0.0236) and DSS (n = 29 with high expression, n = 31 with low expression; median survival, 31 vs. 13 months, and p = 0.2083) than patients with low expression (Figure 1c,d).	('patients', 'Species', '9606', (12, 20))	('TLE2', 'Gene', (31, 35))	('high', 'Var', (26, 30))	('DSS', 'CPA', (187, 190))	('patients', 'Species', '9606', (305, 313))	('TLE2', 'Gene', '7089', (31, 35))
194373	31766561	The majority of copy-number alteration signatures for ANLN were gains and amplifications rather than deletions (number 173 vs. 25, 42.51% vs. 6.14%, median expression 10.54 vs. 9.45, and p = 0.0002, Figure 3a).	('amplifications', 'Var', (74, 88))	('ANLN', 'Gene', (54, 58))	('ANLN', 'Gene', '54443', (54, 58))
194374	31766561	For TLE2, most samples showed deletion variations rather than amplifications (number 143 vs. 54, 35.14% vs. 13.27%, median expression 9.63 vs. 9.77, and p = 0.0394, Figure 3b).	('TLE2', 'Gene', (4, 8))	('TLE2', 'Gene', '7089', (4, 8))	('deletion variations', 'Var', (30, 49))
194375	31766561	Significantly higher expression of ANLN was observed in the subgroup with gain compared to diploid (median expression 10.54 vs. 9.88, and p < 0.0001) and deletion (median expression 10.54 vs. 9.45, and p < 0.0001, Figure 3c).	('expression', 'MPA', (21, 31))	('ANLN', 'Gene', (35, 39))	('gain', 'PosReg', (74, 78))	('deletion', 'Var', (154, 162))	('ANLN', 'Gene', '54443', (35, 39))	('higher', 'PosReg', (14, 20))
194376	31766561	There were no significant differences in TLE2 expression in the subgroups with deletion compared to diploid (median expression 9.63 vs. 9.98, and p = 0.1458) or gain (median expression 9.63 vs. 9.73, and p = 0.9190, Figure 3d).	('TLE2', 'Gene', '7089', (41, 45))	('TLE2', 'Gene', (41, 45))	('deletion', 'Var', (79, 87))
194379	31766561	Furthermore, higher rates of deletion were seen in the TLE2 low expression subgroup than in the TLE2 high expression subgroup (n = 102, 41.46% vs. n = 40, 25.97%).	('TLE2', 'Gene', (55, 59))	('deletion', 'Var', (29, 37))	('low', 'NegReg', (60, 63))	('TLE2', 'Gene', '7089', (96, 100))	('TLE2', 'Gene', '7089', (55, 59))	('TLE2', 'Gene', (96, 100))
194403	31766561	Previous research has established that knockdown of ANLN could significantly inhibit the proliferation of bladder cancer both in vitro and in vivo.	('proliferation', 'CPA', (89, 102))	('inhibit', 'NegReg', (77, 84))	('knockdown', 'Var', (39, 48))	('ANLN', 'Gene', (52, 56))	('bladder cancer', 'Disease', 'MESH:D001749', (106, 120))	('bladder cancer', 'Disease', (106, 120))	('ANLN', 'Gene', '54443', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('bladder cancer', 'Phenotype', 'HP:0009725', (106, 120))
194404	31766561	Furthermore, knockdown of ANLN strongly suppressed the migration and invasion ability of J82 and 5637 bladder cancer cell lines.	('ANLN', 'Gene', '54443', (26, 30))	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('suppressed', 'NegReg', (40, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('bladder cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('invasion ability', 'CPA', (69, 85))	('knockdown', 'Var', (13, 22))	('ANLN', 'Gene', (26, 30))
194418	31766561	It is already known that the proliferation markers MKI67 and RACGAP1 have a significant importance in BLCA.	('MKI67', 'Var', (51, 56))	('RACGAP1', 'Gene', (61, 68))	('RACGAP1', 'Gene', '29127', (61, 68))	('BLCA', 'Disease', (102, 106))
194425	31766561	Gain-of-function mutations in CTNNB1 are detected in numerous human cancers; therefore, it is necessary to explore the role of Wnt/beta-catenin regulated genes in BLCA.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('CTNNB1', 'Gene', (30, 36))	('beta-catenin', 'Gene', (131, 143))	('human', 'Species', '9606', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('Gain-of-function', 'PosReg', (0, 16))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('CTNNB1', 'Gene', '1499', (30, 36))	('beta-catenin', 'Gene', '1499', (131, 143))	('mutations', 'Var', (17, 26))
194430	31766561	Interestingly, the splice variants of ANLN and TLE2 showed different expression levels, with ANLN-201 (ENST00000265748.6), ANLN-202 (ENST00000396068.6), ANLN-210 (ENST00000457743.1), ANLN-212 (ENST00000491782.1), TLE2-201 (ENST00000262953.10), TLE2-202 (ENST00000426948.6), TLE2-204 (ENST00000455444.6), and TLE2-215 (ENST00000590101.5) highly expressed compared with other transcripts.	('ANLN', 'Gene', '54443', (123, 127))	('ANLN', 'Gene', (38, 42))	('TLE2', 'Gene', (308, 312))	('TLE2', 'Gene', (47, 51))	('ANLN', 'Gene', (93, 97))	('TLE2', 'Gene', (213, 217))	('TLE2', 'Gene', (244, 248))	('ANLN', 'Gene', (123, 127))	('TLE2', 'Gene', '7089', (308, 312))	('TLE2', 'Gene', (274, 278))	('TLE2', 'Gene', '7089', (47, 51))	('ANLN', 'Gene', '54443', (183, 187))	('TLE2', 'Gene', '7089', (213, 217))	('TLE2', 'Gene', '7089', (244, 248))	('highly', 'PosReg', (337, 343))	('ANLN', 'Gene', '54443', (153, 157))	('ENST00000396068.6', 'Var', (133, 150))	('ENST00000590101.5', 'Var', (318, 335))	('ENST00000265748.6', 'Var', (103, 120))	('TLE2', 'Gene', '7089', (274, 278))	('ANLN', 'Gene', (183, 187))	('ENST00000262953.10', 'Var', (223, 241))	('ANLN', 'Gene', (153, 157))	('ENST00000426948.6', 'Var', (254, 271))	('ANLN', 'Gene', '54443', (38, 42))	('ENST00000455444.6', 'Var', (284, 301))	('ANLN', 'Gene', '54443', (93, 97))
194444	31766561	The differences of ANLN and TLE2 expression were not significant in the high KRT5 and KRT20 group maybe due the fact that only KRT5 and KRT20 were used for subtype association.	('ANLN', 'Gene', '54443', (19, 23))	('KRT5', 'Gene', (77, 81))	('KRT20', 'Gene', '54474', (86, 91))	('KRT5', 'Gene', (127, 131))	('KRT20', 'Gene', (136, 141))	('KRT5', 'Gene', '3852', (77, 81))	('ANLN', 'Gene', (19, 23))	('KRT20', 'Gene', (86, 91))	('KRT5', 'Gene', '3852', (127, 131))	('TLE2', 'Gene', '7089', (28, 32))	('KRT20', 'Gene', '54474', (136, 141))	('TLE2', 'Gene', (28, 32))	('high', 'Var', (72, 76))
194468	31766561	The cut-off values (2-DeltaDeltaCT value) of the high (>=0.047466) and low (<0.047466) ANLN expression groups, as well as the high (>=0.616383) and low (<0.616383) TLE2 expression groups were determined by receiver operating characteristic (ROC) curve analysis in the Mannheim cohort.	('>=0.047466', 'Var', (55, 65))	('ANLN', 'Gene', (87, 91))	('>=0.616383', 'Var', (132, 142))	('ANLN', 'Gene', '54443', (87, 91))	('TLE2', 'Gene', '7089', (164, 168))	('<0.616383', 'Var', (153, 162))	('TLE2', 'Gene', (164, 168))	('<0.047466', 'Var', (76, 85))
194469	31766561	Similarly, in the TCGA cohort, the cut-off value (log2 value) of high (>=10.695 in the whole group and >=10.8268 in the basal subgroup) and low (<10.695 in the whole group and <10.8268 in the basal subgroup) ANLN expression group, as well as high (>=4.97 in the whole group and >=10.3605 in the luminal subgroup) and low (<4.97 in the whole group and <10.3605 in the luminal subgroup) TLE2 expression group was determined by ROC curve analysis.	('ANLN', 'Gene', '54443', (208, 212))	('>=10.8268', 'Var', (103, 112))	('<10.695', 'Var', (145, 152))	('TLE2', 'Gene', '7089', (385, 389))	('<10.8268', 'Var', (176, 184))	('ANLN', 'Gene', (208, 212))	('TLE2', 'Gene', (385, 389))	('>=10.695', 'Var', (71, 79))
194501	30315148	B7-H1 can inhibit proliferation of T cells and is a negative stimulus in the process of activation of T cells through suppressing the secretion of some cytokines, for example, interferon-gamma (IFN-gamma), interleukin-10 (IL-10), IL-14, and IL-2.	('IL-14', 'Gene', (230, 235))	('B7-H1', 'Var', (0, 5))	('IL-2', 'molecular_function', 'GO:0005134', ('241', '245'))	('secretion', 'MPA', (134, 143))	('IL-10', 'Gene', (222, 227))	('IL-2', 'Gene', '16183', (241, 245))	('IL-2', 'Gene', (241, 245))	('interleukin-10', 'Gene', '16153', (206, 220))	('IL-14', 'Gene', '109658', (230, 235))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('176', '192'))	('interleukin-10', 'Gene', (206, 220))	('IFN-gamma', 'Gene', '15978', (194, 203))	('IL-14', 'molecular_function', 'GO:0005145', ('230', '235'))	('secretion', 'biological_process', 'GO:0046903', ('134', '143'))	('IFN-gamma', 'Gene', (194, 203))	('interferon-gamma', 'Gene', '15978', (176, 192))	('IL-10', 'Gene', '16153', (222, 227))	('interferon-gamma', 'Gene', (176, 192))	('proliferation', 'CPA', (18, 31))	('suppressing', 'NegReg', (118, 129))	('inhibit', 'NegReg', (10, 17))	('IL-10', 'molecular_function', 'GO:0005141', ('222', '227'))
194510	30315148	Patients with high B7H1 expression show shorter survival than those with low B7H1 expression.	('survival', 'MPA', (48, 56))	('B7H1', 'Gene', '29126', (19, 23))	('B7H1', 'Gene', (19, 23))	('B7H1', 'Gene', '29126', (77, 81))	('B7H1', 'Gene', (77, 81))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (40, 47))
194549	30315148	The average survival time in patients with positive expression of B7H1 was 45 months, but it was 65 months in patients with negative expression of B7H1.	('patients', 'Species', '9606', (29, 37))	('B7H1', 'Gene', (147, 151))	('B7H1', 'Gene', '29126', (147, 151))	('positive expression', 'Var', (43, 62))	('B7H1', 'Gene', '29126', (66, 70))	('B7H1', 'Gene', (66, 70))	('patients', 'Species', '9606', (110, 118))
194554	30315148	Furthermore, the levels of B7H1 were associated with the postoperative prognosis.	('levels', 'Var', (17, 23))	('associated', 'Reg', (37, 47))	('B7H1', 'Gene', (27, 31))	('B7H1', 'Gene', '29126', (27, 31))
194555	30315148	The occurrence and development of bladder cancer is a multi-step and multi-stage process involving the activation of oncogenes, inactivation of tumor-suppressor genes, and many signaling pathways.	('signaling', 'biological_process', 'GO:0023052', ('177', '186'))	('tumor', 'Disease', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('144', '160'))	('bladder cancer', 'Disease', 'MESH:D001749', (34, 48))	('inactivation', 'Var', (128, 140))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('144', '160'))	('bladder cancer', 'Disease', (34, 48))	('activation', 'PosReg', (103, 113))	('signaling pathways', 'Pathway', (177, 195))	('oncogenes', 'Gene', (117, 126))
194572	30315148	Our study also showed higher levels of B7H1 and lower survival in positive cases than in negative cases (Figure 3).	('higher', 'PosReg', (22, 28))	('B7H1', 'Gene', '29126', (39, 43))	('levels', 'MPA', (29, 35))	('lower', 'NegReg', (48, 53))	('B7H1', 'Gene', (39, 43))	('survival', 'MPA', (54, 62))	('positive', 'Var', (66, 74))
194595	22125450	In November 1989, the Medical Research Council Advanced Bladder Cancer Working Party and the Genitourinary Group of the European Organisation for Research and Treatment of Cancer (EORTC) initiated an international study which randomized 976 patients with clinical T2 grade 3, T3-4a, N0-Nx tumors who were undergoing either cystectomy or definitive radiation therapy to receive 3 cycles of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) or no chemotherapy.	('methotrexate', 'Chemical', 'MESH:D008727', (412, 424))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Bladder Cancer Working Party', 'Disease', (56, 84))	('Cancer', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('T3-4a', 'Var', (276, 281))	('Cancer', 'Disease', 'MESH:D009369', (172, 178))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('CMV', 'Chemical', '-', (443, 446))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('EORTC', 'Chemical', '-', (180, 185))	('cisplatin', 'Chemical', 'MESH:D002945', (401, 410))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (56, 70))	('patients', 'Species', '9606', (241, 249))	('Cancer', 'Disease', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('Bladder Cancer Working Party', 'Disease', 'MESH:D001749', (56, 84))	('Cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumors', 'Disease', (289, 295))	('vinblastine', 'Chemical', 'MESH:D014747', (430, 441))
194604	22125450	The Nordic Urothelial Cancer Group combined the results of two trials to evaluate cisplatin-based combination neoadjuvant chemotherapy on 620 patients with T1 grade 3, T2-T4aNx bladder tumors.	('Nordic Urothelial Cancer', 'Disease', 'MESH:D014523', (4, 28))	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('bladder tumors', 'Disease', 'MESH:D001749', (177, 191))	('bladder tumors', 'Phenotype', 'HP:0009725', (177, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('bladder tumors', 'Disease', (177, 191))	('Nordic Urothelial Cancer', 'Disease', (4, 28))	('T2-T4aNx', 'Var', (168, 176))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('patients', 'Species', '9606', (142, 150))
194641	22125450	An Italian group randomized 194 patients with pT2 grade 3, pT3-4, N0-2 UCB to adjuvant GC versus chemotherapy at relapse and did not show a significant difference in DFS and OS.	('UCB', 'Chemical', '-', (71, 74))	('patients', 'Species', '9606', (32, 40))	('pT3', 'Gene', '7694', (59, 62))	('GC', 'Chemical', '-', (87, 89))	('pT3', 'Gene', (59, 62))	('OS', 'Chemical', '-', (174, 176))	('N0-2', 'Var', (66, 70))
194770	32757302	Bruton tyrosine kinase (BTK) inhibition may suppress myeloid-derived suppressor cells (MDSCs) and improve T-cell activation.	('Bruton tyrosine kinase', 'Gene', '695', (0, 22))	('improve', 'PosReg', (98, 105))	('myeloid-derived suppressor cells', 'CPA', (53, 85))	('T-cell activation', 'biological_process', 'GO:0042110', ('106', '123'))	('suppress', 'NegReg', (44, 52))	('BTK', 'Gene', (24, 27))	('T-cell activation', 'CPA', (106, 123))	('BTK', 'Gene', '695', (24, 27))	('Bruton tyrosine kinase', 'Gene', (0, 22))	('inhibition', 'Var', (29, 39))
194786	32757302	5 ,  6 ,  7 ,  8  In the Keynote 045 study, a phase 3 trial that randomized platinum-refractory patients with mUC to receive either pembrolizumab, a PD-1 inhibitor, or chemotherapy, pembrolizumab improved median overall survival (OS; 10.3 vs 7.4 months; hazard ratio, 0.73; 95% confidence interval [CI], 0.59-0.91; P = .002) 4  and was established as a preferred immunotherapy regimen for the second-line treatment of platinum-refractory mUC.	('pembrolizumab', 'Var', (182, 195))	('platinum', 'Chemical', 'MESH:D010984', (76, 84))	('pembrolizumab', 'Chemical', 'MESH:C582435', (132, 145))	('platinum', 'Chemical', 'MESH:D010984', (418, 426))	('pembrolizumab', 'Chemical', 'MESH:C582435', (182, 195))	('overall survival', 'MPA', (212, 228))	('patients', 'Species', '9606', (96, 104))	('improved', 'PosReg', (196, 204))
194792	32757302	Bruton tyrosine kinase (BTK) has been shown as a mechanism for MDSC growth in the tumor microenvironment, 14  and this suggests a role for BTK inhibition in lowering MDSCs and, therefore, reducing T-cell suppression.	('Bruton tyrosine kinase', 'Gene', '695', (0, 22))	('BTK', 'Gene', (139, 142))	('MDSCs', 'MPA', (166, 171))	('BTK', 'Gene', '695', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('T-cell suppression', 'CPA', (197, 215))	('inhibition', 'Var', (143, 153))	('lowering', 'NegReg', (157, 165))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BTK', 'Gene', (24, 27))	('tumor', 'Disease', (82, 87))	('BTK', 'Gene', '695', (24, 27))	('Bruton tyrosine kinase', 'Gene', (0, 22))
194793	32757302	15 ,  16 ,  17   Interestingly, studies examining circulating MDSCs in patients treated with PD-1 inhibition have shown that alterations in the myeloid cell compartment correlate with clinical outcomes.	('patients', 'Species', '9606', (71, 79))	('inhibition', 'Var', (98, 108))	('PD-1', 'Gene', (93, 97))
194799	32757302	Because of the important hypothesis that BTK inhibition would inhibit suppressive myeloid cells, a key exploratory endpoint was the characterization of peripheral MDSCs at the baseline and during treatment.	('suppressive myeloid cells', 'CPA', (70, 95))	('BTK', 'Gene', (41, 44))	('inhibition', 'Var', (45, 55))	('inhibit', 'NegReg', (62, 69))	('BTK', 'Gene', '695', (41, 44))
194816	32757302	We also report here a key exploratory objective of immune profiling for changes in peripheral MDSCs based on the hypothesis that BTK inhibition would lower the MDSC population.	('lower', 'NegReg', (150, 155))	('BTK', 'Gene', (129, 132))	('inhibition', 'Var', (133, 143))	('BTK', 'Gene', '695', (129, 132))	('MDSC population', 'CPA', (160, 175))
194881	32757302	27  Hypothetically, if BTK inhibition potentiates immune-mediated damage in the liver, then future studies of combination BTK and PD-1 inhibition should specifically monitor for hepatic dysfunction.	('hepatic dysfunction', 'Phenotype', 'HP:0001410', (178, 197))	('BTK', 'Gene', (23, 26))	('hepatic dysfunction', 'Disease', 'MESH:D008107', (178, 197))	('immune-mediated damage', 'MPA', (50, 72))	('BTK', 'Gene', '695', (23, 26))	('BTK', 'Gene', (122, 125))	('inhibition', 'Var', (27, 37))	('BTK', 'Gene', '695', (122, 125))	('potentiates', 'PosReg', (38, 49))	('hepatic dysfunction', 'Disease', (178, 197))
194885	32757302	5 ,  6 ,  7 ,  8  In this study, PD-L1 positivity, defined by a CPS > 1, was not predictive for a treatment response.	('PD-L1', 'Gene', (33, 38))	('CPS > 1', 'Gene', '1373', (64, 71))	('positivity', 'Var', (39, 49))	('CPS > 1', 'Gene', (64, 71))
194889	32757302	Specifically, PD-L1-positive monocytic MDSCs decreased on treatment with PD-L1-targeting therapy (atezolizumab or avelumab), and PD-1-expressing monocytic and immature MDSCs decreased on treatment with PD-1-targeting therapy (pembrolizumab).	('decreased', 'NegReg', (174, 183))	('PD-L1-targeting', 'Var', (73, 88))	('decreased', 'NegReg', (45, 54))	('pembrolizumab', 'Chemical', 'MESH:C582435', (226, 239))	('atezolizumab', 'Chemical', 'MESH:C000594389', (98, 110))
194899	32757302	CD39 positivity was confirmed on this post hoc biomarker analysis, and further research is needed to understand its clinical utility.	('positivity', 'Var', (5, 15))	('CD39', 'Gene', (0, 4))	('CD39', 'Gene', '953', (0, 4))
194915	32208524	Infigratinib in Upper Tract Urothelial Carcinoma Versus Urothelial Carcinoma of the Bladder and Its Association With Comprehensive Genomic Profiling and/or Cell-Free DNA Results Infigratinib (BGJ398) is a potent and selective fibroblast grown factor receptor 1 to 3 (FGFR1-3) inhibitor with significant activity in patients with advanced or metastatic urothelial carcinoma bearing FGFR3 alterations.	('activity', 'MPA', (303, 311))	('Infigratinib', 'Chemical', 'MESH:C568950', (178, 190))	('Urothelial Carcinoma Versus Urothelial Carcinoma', 'Disease', (28, 76))	('FGFR3', 'Gene', (381, 386))	('FGFR3', 'Gene', '2261', (381, 386))	('carcinoma', 'Phenotype', 'HP:0030731', (363, 372))	('patients', 'Species', '9606', (315, 323))	('Urothelial Carcinoma of the Bladder', 'Phenotype', 'HP:0006740', (56, 91))	('advanced', 'Disease', (329, 337))	('Carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('DNA', 'cellular_component', 'GO:0005574', ('166', '169'))	('Urothelial Carcinoma Versus Urothelial Carcinoma', 'Disease', 'MESH:D014523', (28, 76))	('Infigratinib', 'Chemical', 'MESH:C568950', (0, 12))	('FGFR', 'molecular_function', 'GO:0005007', ('267', '271'))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (352, 372))	('FGFR1-3', 'Gene', '2260;2263;2261', (267, 274))	('BGJ398', 'Chemical', 'MESH:C568950', (192, 198))	('urothelial carcinoma', 'Disease', (352, 372))	('FGFR', 'molecular_function', 'GO:0005007', ('381', '385'))	('FGFR1-3', 'Gene', (267, 274))	('alterations', 'Var', (387, 398))	('Carcinoma', 'Phenotype', 'HP:0030731', (39, 48))
194917	32208524	Eligible patients had metastatic urothelial carcinoma with activating FGFR3 mutations and/or fusions.	('patients', 'Species', '9606', (9, 17))	('fusions', 'Var', (93, 100))	('mutations', 'Var', (76, 85))	('FGFR', 'molecular_function', 'GO:0005007', ('70', '74'))	('FGFR3', 'Gene', '2261', (70, 75))	('activating', 'PosReg', (59, 69))	('urothelial carcinoma', 'Disease', (33, 53))	('FGFR3', 'Gene', (70, 75))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (33, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))
194924	32208524	Notable differences in genomic alterations between patients with UTUC and those with UCB included higher frequencies of FGFR3-TACC3 fusions (12.5% vs 6.8%) and FGFR3 R248C mutations (50% vs 11.9%), and a lower frequency of FGFR3 S249C mutations (37.5% vs 59.3%).	('FGFR3', 'Gene', (160, 165))	('FGFR3', 'Gene', '2261', (223, 228))	('FGFR3', 'Gene', '2261', (160, 165))	('S249C', 'Mutation', 'rs121913483', (229, 234))	('fusions', 'Var', (132, 139))	('patients', 'Species', '9606', (51, 59))	('FGFR', 'molecular_function', 'GO:0005007', ('160', '164'))	('FGFR', 'molecular_function', 'GO:0005007', ('223', '227'))	('R248C', 'Var', (166, 171))	('UCB', 'Phenotype', 'HP:0006740', (85, 88))	('R248C', 'Mutation', 'rs121913482', (166, 171))	('UTUC', 'Chemical', '-', (65, 69))	('TACC3', 'Gene', '10460', (126, 131))	('TACC3', 'Gene', (126, 131))	('FGFR3', 'Gene', (120, 125))	('higher', 'PosReg', (98, 104))	('FGFR3', 'Gene', (223, 228))	('FGFR', 'molecular_function', 'GO:0005007', ('120', '124'))	('FGFR3', 'Gene', '2261', (120, 125))	('S249C', 'Var', (229, 234))
194930	32208524	In one study of 295 patients with stage III to IV UC who were assessed using comprehensive genomic profiling (CGP), mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), fibroblast growth factor receptor 3 (FGFR3), and phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) were noted in 34%, 21%, and 20% of patients, respectively.	('patients', 'Species', '9606', (323, 331))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('129', '162'))	('FGFR3', 'Gene', '2261', (213, 218))	('PIK3CA', 'Gene', '5290', (280, 286))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('176', '200'))	('fibroblast growth factor receptor 3', 'Gene', (176, 211))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (129, 165))	('CDKN2A', 'Gene', (167, 173))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (129, 165))	('CDKN2A', 'Gene', '1029', (167, 173))	('noted', 'Reg', (293, 298))	('FGFR3', 'Gene', (213, 218))	('FGFR', 'molecular_function', 'GO:0005007', ('213', '217'))	('mutations', 'Var', (116, 125))	('patients', 'Species', '9606', (20, 28))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('146', '162'))	('fibroblast growth factor receptor 3', 'Gene', '2261', (176, 211))	('PIK3CA', 'Gene', (280, 286))
194932	32208524	A composite analysis of the ImVigor210 and CheckMate 275 studies evaluating atezolizumab and nivolumab, respectively, in patients with mUC demonstrated no difference in response among patients harboring FGFR3 mutations.	('nivolumab', 'Chemical', 'MESH:D000077594', (93, 102))	('FGFR3', 'Gene', '2261', (203, 208))	('patients', 'Species', '9606', (184, 192))	('FGFR3', 'Gene', (203, 208))	('mutations', 'Var', (209, 218))	('atezolizumab', 'Chemical', 'MESH:C000594389', (76, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('203', '207'))	('patients', 'Species', '9606', (121, 129))
194938	32208524	Most notably, their results suggested alterations in FGFR3 in approximately 74% of cases, with 94% of low-grade UTUCs harboring FGFR3 alterations.	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('FGFR3', 'Gene', (128, 133))	('UTUC', 'Chemical', '-', (112, 116))	('FGFR3', 'Gene', '2261', (128, 133))	('FGFR3', 'Gene', '2261', (53, 58))	('alterations', 'Var', (134, 145))	('FGFR', 'molecular_function', 'GO:0005007', ('128', '132'))	('alterations', 'Var', (38, 49))	('FGFR3', 'Gene', (53, 58))
194943	32208524	We previously reported data related to infigratinib (BGJ398), a potent and selective FGFR1-3 tyrosine kinase inhibitor, in 67 patients with mUC bearing alterations in FGFR3.	('FGFR3', 'Gene', (167, 172))	('alterations', 'Var', (152, 163))	('FGFR1-3', 'Gene', (85, 92))	('FGFR1-3', 'Gene', '2260;2263;2261', (85, 92))	('BGJ398', 'Chemical', 'MESH:C568950', (53, 59))	('patients', 'Species', '9606', (126, 134))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('102', '118'))	('FGFR3', 'Gene', '2261', (167, 172))	('infigratinib', 'Chemical', 'MESH:C568950', (39, 51))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('BGJ398', 'Gene', (53, 59))	('FGFR', 'molecular_function', 'GO:0005007', ('167', '171'))
194947	32208524	Adult patients with mUC who had received prior platinum-based chemotherapy or were deemed intolerant of or ineligible for platinum-based chemotherapy were screened for FGFR3 alterations using comprehensive genomic profiling of 324 genes in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (Foundation Medicine, Cambridge, Massachusetts).	('FGFR3', 'Gene', '2261', (168, 173))	('FGFR3', 'Gene', (168, 173))	('FGFR', 'molecular_function', 'GO:0005007', ('168', '172'))	('patients', 'Species', '9606', (6, 14))	('alterations', 'Var', (174, 185))	('platinum', 'Chemical', 'MESH:D010984', (122, 130))	('platinum', 'Chemical', 'MESH:D010984', (47, 55))
194949	32208524	Patients possessing somatic alterations in FGFR3 with suspected functional significance were eligible for the current study.	('alterations', 'Var', (28, 39))	('FGFR3', 'Gene', (43, 48))	('Patients', 'Species', '9606', (0, 8))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('FGFR3', 'Gene', '2261', (43, 48))
194952	32208524	All patients enrolled provided separate consent for screening for FGFR3 alterations (unless genomic testing was performed as per standard of care) and for therapy with infigratinib.	('alterations', 'Var', (72, 83))	('infigratinib', 'Chemical', 'MESH:C568950', (168, 180))	('FGFR3', 'Gene', '2261', (66, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('FGFR3', 'Gene', (66, 71))	('patients', 'Species', '9606', (4, 12))
194958	32208524	The functional significance of mutations in FGFR3 was determined through interrogation of the Catalogue Of Somatic Mutations In Cancer (COSMIC) database (https://cancer.sanger.ac.uk/cosmic) and review of the published literature.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('mutations', 'Var', (31, 40))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('cancer', 'Disease', (162, 168))	('FGFR3', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Cancer', 'Disease', (128, 134))	('FGFR3', 'Gene', '2261', (44, 49))	('Cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Cancer', 'Disease', 'MESH:D009369', (128, 134))
194959	32208524	Ultimately, these included mutations in exon 7 (R248C and S249C); exon 10 (G372C, A393E, and Y375C); exon 15 (K652M/T and K652E/Q); and FGFR3 fusions, including but not limited to the FGFR3-TACC fusion.	('A393E', 'Mutation', 'rs28931615', (82, 87))	('K652E', 'SUBSTITUTION', 'None', (122, 127))	('A393E', 'Var', (82, 87))	('FGFR', 'molecular_function', 'GO:0005007', ('184', '188'))	('K652M', 'SUBSTITUTION', 'None', (110, 115))	('Y375C', 'Mutation', 'rs121913485', (93, 98))	('R248C', 'Var', (48, 53))	('K652E', 'Var', (122, 127))	('S249C', 'Var', (58, 63))	('R248C', 'Mutation', 'rs121913482', (48, 53))	('G372C', 'Var', (75, 80))	('FGFR3', 'Gene', (184, 189))	('K652M', 'Var', (110, 115))	('FGFR3', 'Gene', (136, 141))	('FGFR3', 'Gene', '2261', (184, 189))	('FGFR', 'molecular_function', 'GO:0005007', ('136', '140'))	('S249C', 'Mutation', 'rs121913483', (58, 63))	('G372C', 'Mutation', 'rs121913479', (75, 80))	('Y375C', 'Var', (93, 98))	('FGFR3', 'Gene', '2261', (136, 141))
194983	32208524	These included a smaller collection of FGFR3 alterations among patients with UTUC and significant differences in the frequency of FGFR3 R248C mutations (50% vs 12%) and FGFR3 S249C mutations (38% vs 59%) in patients in the UTUC cohort compared with the UCB cohort, respectively (Fig.	('R248C', 'Mutation', 'rs121913482', (136, 141))	('patients', 'Species', '9606', (207, 215))	('UCB', 'Phenotype', 'HP:0006740', (253, 256))	('S249C', 'Var', (175, 180))	('FGFR', 'molecular_function', 'GO:0005007', ('130', '134'))	('FGFR', 'molecular_function', 'GO:0005007', ('39', '43'))	('FGFR', 'molecular_function', 'GO:0005007', ('169', '173'))	('S249C', 'Mutation', 'rs121913483', (175, 180))	('FGFR3', 'Gene', (130, 135))	('R248C mutations', 'Var', (136, 151))	('UTUC', 'Chemical', '-', (77, 81))	('FGFR3', 'Gene', '2261', (169, 174))	('FGFR3', 'Gene', '2261', (39, 44))	('UTUC', 'Chemical', '-', (223, 227))	('patients', 'Species', '9606', (63, 71))	('FGFR3', 'Gene', (169, 174))	('FGFR3', 'Gene', '2261', (130, 135))	('FGFR3', 'Gene', (39, 44))
194984	32208524	Oncoplots demonstrated a less complex genomic profile with an increased number of known or likely deleterious mutations and copy number alterations in tissue from patients with UCB versus those with UTUC (Fig.	('UCB', 'Disease', (177, 180))	('patients', 'Species', '9606', (163, 171))	('mutations', 'Var', (110, 119))	('copy number alterations', 'Var', (124, 147))	('UTUC', 'Chemical', '-', (199, 203))	('UCB', 'Phenotype', 'HP:0006740', (177, 180))
194985	32208524	Amplification of genes involved in FGFR signaling, including the FGFR3 ligands FGF3, FGF4, and FGF19 on chromosome 11 and the FGFR adaptor protein FRS2, was more common in patients with UCB (10 of 39 patients; 26%) compared with those with UTUC (1 of 7 patients; 14%).	('FGF19', 'Gene', (95, 100))	('FGF19', 'Gene', '9965', (95, 100))	('UCB', 'Phenotype', 'HP:0006740', (186, 189))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('patients', 'Species', '9606', (253, 261))	('FGF4', 'Gene', (85, 89))	('FRS2', 'Gene', '10818', (147, 151))	('FGFR', 'molecular_function', 'GO:0005007', ('126', '130'))	('FGF3', 'Gene', (79, 83))	('patients', 'Species', '9606', (172, 180))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('FGF3', 'Gene', '2248', (79, 83))	('UCB', 'Disease', (186, 189))	('FGFR3', 'Gene', (65, 70))	('common', 'Reg', (162, 168))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('FGF4', 'Gene', '2249', (85, 89))	('UTUC', 'Chemical', '-', (240, 244))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))	('FGFR3', 'Gene', '2261', (65, 70))	('Amplification', 'Var', (0, 13))	('patients', 'Species', '9606', (200, 208))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FRS2', 'Gene', (147, 151))
194986	32208524	In addition, mutations in the telomerase reverse transcriptase (TERT) promoter that are known to activate gene transcription were more common in patients with UCB (29 of 39 patients; 74%) compared with those with UTUC (3 of 7 patients; 43%).	('patients', 'Species', '9606', (145, 153))	('TERT', 'Gene', (64, 68))	('transcriptase', 'molecular_function', 'GO:0003968', ('49', '62'))	('TERT', 'Gene', '7015', (64, 68))	('transcriptase', 'molecular_function', 'GO:0003899', ('49', '62'))	('UTUC', 'Chemical', '-', (213, 217))	('patients', 'Species', '9606', (173, 181))	('common', 'Reg', (135, 141))	('transcriptase', 'molecular_function', 'GO:0034062', ('49', '62'))	('UCB', 'Phenotype', 'HP:0006740', (159, 162))	('patients', 'Species', '9606', (226, 234))	('transcription', 'biological_process', 'GO:0006351', ('111', '124'))	('telomerase reverse transcriptase', 'Gene', (30, 62))	('mutations', 'Var', (13, 22))	('telomerase reverse transcriptase', 'Gene', '7015', (30, 62))	('UCB', 'Disease', (159, 162))
194987	32208524	Only one patient with UTUC was found to have a high mutation load; however, this patient likely was deficient in mismatch repair due to a frameshift mutation in mutS homolog 2 (MSH2).	('MSH2', 'Gene', '4436', (177, 181))	('frameshift mutation', 'Var', (138, 157))	('patient', 'Species', '9606', (81, 88))	('mismatch repair', 'biological_process', 'GO:0006298', ('113', '128'))	('UTUC', 'Chemical', '-', (22, 26))	('mismatch repair', 'MPA', (113, 128))	('mutS homolog 2', 'Gene', '4436', (161, 175))	('deficient', 'NegReg', (100, 109))	('patient', 'Species', '9606', (9, 16))	('mutS homolog 2', 'Gene', (161, 175))	('MSH2', 'Gene', (177, 181))
194989	32208524	FGFR3 alterations were concordant in 30 of 38 patients (79%) for whom both tumor tissue and cfDNA samples were available at screening.	('alterations', 'Var', (6, 17))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('patients', 'Species', '9606', (46, 54))	('FGFR3', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('FGFR3', 'Gene', '2261', (0, 5))
194990	32208524	As identified in tissue, oncoplots of cfDNA data alluded to a less complex genomic profile and increased mutation in UTUC (Fig.	('mutation', 'Var', (105, 113))	('less complex genomic profile', 'MPA', (62, 90))	('UTUC', 'Gene', (117, 121))	('increased', 'PosReg', (95, 104))	('UTUC', 'Chemical', '-', (117, 121))
194991	32208524	The one patient with UTUC with a high number of point mutations in the cfDNA was likely to be deficient in mismatch repair caused by a frameshift mutation in MSH2.	('mismatch repair', 'biological_process', 'GO:0006298', ('107', '122'))	('mismatch repair', 'MPA', (107, 122))	('MSH2', 'Gene', (158, 162))	('frameshift mutation', 'Var', (135, 154))	('MSH2', 'Gene', '4436', (158, 162))	('UTUC', 'Chemical', '-', (21, 25))	('deficient', 'NegReg', (94, 103))	('cfDNA', 'Gene', (71, 76))	('patient', 'Species', '9606', (8, 15))	('point mutations', 'Var', (48, 63))
194993	32208524	In a cohort already selected for FGFR3 alterations, the data from the current study have suggested that infigratinib may have greater activity in patients with UTUC compared with those with UCB, with DCRs of 100% and 59%, respectively.	('DCR', 'Chemical', '-', (200, 203))	('greater', 'PosReg', (126, 133))	('UTUC', 'Chemical', '-', (160, 164))	('infigratinib', 'Chemical', 'MESH:C568950', (104, 116))	('UTUC', 'Disease', (160, 164))	('FGFR3', 'Gene', '2261', (33, 38))	('alterations', 'Var', (39, 50))	('activity', 'MPA', (134, 142))	('patients', 'Species', '9606', (146, 154))	('FGFR3', 'Gene', (33, 38))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('UCB', 'Phenotype', 'HP:0006740', (190, 193))
195000	32208524	Erdafitinib recently received US Food and Drug Administration accelerated approval for the treatment of patients with locally advanced or mUC with susceptible FGFR3 or FGFR2 genetic alterations who have developed disease progression during or after at least 1 line of prior platinum-based chemotherapy.	('FGFR2', 'Gene', (168, 173))	('FGFR2', 'Gene', '2263', (168, 173))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (0, 11))	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('FGFR3', 'Gene', '2261', (159, 164))	('platinum', 'Chemical', 'MESH:D010984', (274, 282))	('FGFR', 'molecular_function', 'GO:0005007', ('168', '172'))	('FGFR3', 'Gene', (159, 164))	('genetic alterations', 'Var', (174, 193))	('patients', 'Species', '9606', (104, 112))
195004	32208524	Another small molecule, rogaratinib, was tested in a cohort of patients with mUC with either increased FGFR1 to FGFR3 messenger RNA expression or FGFR3 mutation.	('FGFR', 'molecular_function', 'GO:0005007', ('146', '150'))	('increased FGFR1', 'Phenotype', 'HP:0030269', (93, 108))	('FGFR', 'molecular_function', 'GO:0005007', ('103', '107'))	('FGFR3', 'Gene', (112, 117))	('FGFR3', 'Gene', '2261', (146, 151))	('increased', 'PosReg', (93, 102))	('messenger RNA expression', 'MPA', (118, 142))	('FGFR', 'molecular_function', 'GO:0005007', ('112', '116'))	('FGFR1', 'Gene', (103, 108))	('FGFR3', 'Gene', (146, 151))	('patients', 'Species', '9606', (63, 71))	('RNA', 'cellular_component', 'GO:0005562', ('128', '131'))	('FGFR3', 'Gene', '2261', (112, 117))	('FGFR1', 'Gene', '2260', (103, 108))	('mutation', 'Var', (152, 160))
195010	32208524	A different distribution of FGFR3 alterations was observed, with FGFR3 mutations in patients with UTUC restricted to the extracellular immunoglobulin-like domain whereas activating mutations in patients with UCB also were identified in the transmembrane region and kinase domain.	('FGFR3', 'Gene', '2261', (65, 70))	('UCB', 'Phenotype', 'HP:0006740', (208, 211))	('patients', 'Species', '9606', (194, 202))	('FGFR3', 'Gene', '2261', (28, 33))	('patients', 'Species', '9606', (84, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('FGFR3', 'Gene', (65, 70))	('extracellular', 'cellular_component', 'GO:0005576', ('121', '134'))	('UTUC', 'Chemical', '-', (98, 102))	('mutations', 'Var', (71, 80))	('FGFR3', 'Gene', (28, 33))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('135', '149'))	('transmembrane', 'cellular_component', 'GO:0044214', ('240', '253'))	('transmembrane', 'cellular_component', 'GO:0016021', ('240', '253'))
195011	32208524	Similar to the tissue-based genomic profiling in the current study, pretreatment cfDNA analysis demonstrated an increase in mutations and gain and/or loss of gene copy that are known to alter protein function among patients with UCB versus those with UTUC.	('patients', 'Species', '9606', (215, 223))	('UTUC', 'Chemical', '-', (251, 255))	('mutations', 'Var', (124, 133))	('gain', 'PosReg', (138, 142))	('protein function', 'MPA', (192, 208))	('gene', 'Gene', (158, 162))	('increase', 'PosReg', (112, 120))	('loss', 'NegReg', (150, 154))	('protein', 'cellular_component', 'GO:0003675', ('192', '199'))	('alter', 'Reg', (186, 191))	('UCB', 'Phenotype', 'HP:0006740', (229, 232))
195016	32208524	Although the study reported that approximately 91% of patients had detectable alterations, it is interesting that the vast majority were mutations in TP53, giving rise to the possibility that these results could be affected by clonal hematopoiesis.	('TP53', 'Gene', (150, 154))	('hematopoiesis', 'Disease', (234, 247))	('patients', 'Species', '9606', (54, 62))	('hematopoiesis', 'Disease', 'MESH:C536227', (234, 247))	('mutations', 'Var', (137, 146))	('hematopoiesis', 'biological_process', 'GO:0030097', ('234', '247'))	('TP53', 'Gene', '7157', (150, 154))
195017	32208524	In the current study, FGFR3 alterations were found to be concordant in nearly 80% of patients with both tumor tissue and cfDNA samples available at screening, suggesting that blood-based cfDNA may play an important role in the detection of FGFR3 alterations among patients with UC in the future.	('FGFR3', 'Gene', '2261', (240, 245))	('FGFR3', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('alterations', 'Var', (28, 39))	('FGFR3', 'Gene', (240, 245))	('tumor', 'Disease', (104, 109))	('alterations', 'Var', (246, 257))	('patients', 'Species', '9606', (85, 93))	('patients', 'Species', '9606', (264, 272))	('FGFR', 'molecular_function', 'GO:0005007', ('240', '244'))	('FGFR3', 'Gene', '2261', (22, 27))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
195020	32208524	Currently, the reverse transcriptase-polymerase chain reaction-based companion diagnostic for erdafitinib only detects mutations and select fusions.	('erdafitinib', 'Chemical', 'MESH:C000604580', (94, 105))	('transcriptase', 'molecular_function', 'GO:0003899', ('23', '36'))	('transcriptase', 'molecular_function', 'GO:0003968', ('23', '36'))	('fusions', 'Var', (140, 147))	('mutations', 'Var', (119, 128))	('transcriptase', 'molecular_function', 'GO:0034062', ('23', '36'))
195026	32208524	The nature of the mutations noted in UTUC appears to differ from that of mutations in UCB, with the caveat of the small sample size, a higher rate of FGFR3 S249C mutations, and a smaller repertoire of mutations observed in the current study.	('S249C', 'Mutation', 'rs121913483', (156, 161))	('FGFR3', 'Gene', (150, 155))	('UTUC', 'Chemical', '-', (37, 41))	('S249C mutations', 'Var', (156, 171))	('UCB', 'Phenotype', 'HP:0006740', (86, 89))	('FGFR', 'molecular_function', 'GO:0005007', ('150', '154'))	('FGFR3', 'Gene', '2261', (150, 155))
195057	28487808	This disorder results from the deletion of chromosome 15q12 which inactivates the UBE3A gene.	('UBE3A', 'Gene', '7337', (82, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('UBE3A', 'Gene', (82, 87))	('results from', 'Reg', (14, 26))	('deletion', 'Var', (31, 39))	('inactivates', 'NegReg', (66, 77))
195076	28487808	One study documented that in one low grade noninvasive papillary urothelial carcinoma there were deletions of chromosome regions 7q, 9q, and 15q.	('papillary urothelial carcinoma', 'Disease', 'MESH:D002291', (55, 85))	('papillary urothelial carcinoma', 'Disease', (55, 85))	('men', 'Species', '9606', (14, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (55, 85))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('deletions', 'Var', (97, 106))
195077	28487808	This deletion in chromosome 15q could potentially be a link to Angelman syndrome or Prader Willi syndrome as chromosome 15q11-13 is involved in this imprinting disorder; however, this link has not been associated as of yet with bladder cancer.	('deletion', 'Var', (5, 13))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('Prader Willi syndrome', 'Disease', 'MESH:D011218', (84, 105))	('bladder cancer', 'Disease', 'MESH:D001749', (228, 242))	('bladder cancer', 'Disease', (228, 242))	('Prader Willi syndrome', 'Disease', (84, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (228, 242))	('Angelman syndrome', 'Disease', (63, 80))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('Angelman syndrome', 'Disease', 'MESH:D017204', (63, 80))	('link', 'Reg', (55, 59))
195141	24752337	Expression of p53 and/or p16 is very common in urinary bladder adenocarcinoma.	('urinary bladder adenocarcinoma', 'Disease', (47, 77))	('urinary bladder adenocarcinoma', 'Disease', 'MESH:D001749', (47, 77))	('p16', 'Gene', (25, 28))	('common', 'Reg', (37, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (55, 77))	('p16', 'Gene', '1029', (25, 28))	('p53', 'Var', (14, 17))
195142	24752337	These findings implicate a high likelihood that alterations in these cell cycle proteins contribute to the pathogenesis of these tumors.	('tumors', 'Disease', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('alterations', 'Var', (48, 59))	('contribute', 'Reg', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cell cycle', 'biological_process', 'GO:0007049', ('69', '79'))	('pathogenesis', 'biological_process', 'GO:0009405', ('107', '119'))
195154	24752337	In addition, urothelial tumors with alterations in p53 have been shown to portend a less favorable prognosis, and they are associated with decreased survival.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('p53', 'Gene', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('urothelial tumors', 'Disease', 'MESH:D001749', (13, 30))	('alterations', 'Var', (36, 47))	('decreased', 'NegReg', (139, 148))	('urothelial tumors', 'Disease', (13, 30))	('survival', 'CPA', (149, 157))
195155	24752337	A single study investigating the expression of cell cycle markers in primary bladder adenocarcinoma showed a high frequency of p53 alteration in these tumors.	('bladder adenocarcinoma', 'Disease', (77, 99))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('bladder adenocarcinoma', 'Disease', 'MESH:D001749', (77, 99))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('cell cycle', 'biological_process', 'GO:0007049', ('47', '57'))	('alteration', 'Var', (131, 141))	('p53', 'Gene', (127, 130))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (77, 99))
195159	24752337	In some organ systems, such as in the uterine cervix and upper aerodigestive tract, expression of p16 is valuable as a surrogate marker for human papillomavirus (HPV) infection.	('expression', 'Var', (84, 94))	('human', 'Species', '9606', (140, 145))	('p16', 'Gene', (98, 101))	('p16', 'Gene', '1029', (98, 101))	('uterine cervix', 'Phenotype', 'HP:0030160', (38, 52))	('papillomavirus (HPV) infection', 'Disease', 'MESH:D030361', (146, 176))
195184	24752337	Though nearly all cases lacked uninvolved urothelium for comparison, one case did show nondiffuse staining for p53 in the urothelium of a weaker intensity than seen in the tumor; no staining was seen for p16 ( Figure 2B-C ).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('p16', 'Gene', '1029', (204, 207))	('p16', 'Gene', (204, 207))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('p53', 'Var', (111, 114))
195189	24752337	In primary urinary bladder adenocarcinomas, expression of p16 and/or p53 is frequently present.	('p16', 'Gene', (58, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('present', 'Reg', (87, 94))	('p16', 'Gene', '1029', (58, 61))	('urinary bladder adenocarcinomas', 'Disease', (11, 42))	('p53', 'Var', (69, 72))	('urinary bladder adenocarcinomas', 'Disease', 'MESH:D001749', (11, 42))	('bladder adenocarcinoma', 'Phenotype', 'HP:0002862', (19, 41))
195193	24752337	The expression of these two cell cycle regulators in these tumors is similar to the frequency reported for other types of urothelial carcinoma and likely implies that mutations in genes regulating these proteins are involved in the development or progression of both conventional urothelial and adenocarcinoma of bladder tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('urothelial and adenocarcinoma of bladder tumors', 'Disease', 'MESH:D001749', (280, 327))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (122, 142))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('involved', 'Reg', (216, 224))	('tumors', 'Disease', 'MESH:D009369', (321, 327))	('mutations', 'Var', (167, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (321, 327))	('urothelial carcinoma', 'Disease', (122, 142))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('bladder tumors', 'Phenotype', 'HP:0009725', (313, 327))	('cell cycle', 'biological_process', 'GO:0007049', ('28', '38'))	('tumors', 'Disease', (321, 327))
195194	24752337	Alterations in p53 have been studied in a number of human malignancies.	('Alterations', 'Var', (0, 11))	('human', 'Species', '9606', (52, 57))	('malignancies', 'Disease', 'MESH:D009369', (58, 70))	('p53', 'Gene', (15, 18))	('malignancies', 'Disease', (58, 70))
195195	24752337	Alteration in p53 has been well studied in urothelial carcinoma.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (43, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('p53', 'Gene', (14, 17))	('Alteration', 'Var', (0, 10))	('urothelial carcinoma', 'Disease', (43, 63))
195197	24752337	Tumors with p53 alteration are associated with chemoresistance.	('associated', 'Reg', (31, 41))	('p53', 'Gene', (12, 15))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('chemoresistance', 'CPA', (47, 62))	('alteration', 'Var', (16, 26))
195198	24752337	Furthermore, studies examining p53 in mouse models have shown that deficiencies in p53, in concert with Rb1 alteration, were necessary, but not sufficient, for initiation of urothelial tumorigenesis.	('tumor', 'Disease', (185, 190))	('mouse', 'Species', '10090', (38, 43))	('p53', 'Gene', (83, 86))	('urothelial', 'Disease', (174, 184))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('deficiencies', 'Var', (67, 79))
195201	24752337	As both Rb1 and p16 are tumor suppressor genes, alterations in one or both proteins disrupt the cellular mechanisms available to halt tumor proliferation.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Rb1', 'Gene', (8, 11))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('alterations', 'Var', (48, 59))	('tumor', 'Disease', (24, 29))	('p16', 'Gene', '1029', (16, 19))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('disrupt', 'NegReg', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('p16', 'Gene', (16, 19))	('cellular mechanisms', 'CPA', (96, 115))	('tumor', 'Disease', (134, 139))
195202	24752337	A functional loss of Rb1 has been described to cause a positive feedback loop with p16 leading to accumulation of the protein (hence, immunohistochemical overexpression) without ability to halt the cell cycle; essentially negating its "tumor suppressor" ability.	('accumulation', 'PosReg', (98, 110))	('p16', 'Gene', '1029', (83, 86))	('cause', 'Reg', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('loss', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('p16', 'Gene', (83, 86))	('Rb1', 'Gene', (21, 24))	('negating', 'NegReg', (222, 230))	('positive feedback loop', 'MPA', (55, 77))	('cell cycle', 'biological_process', 'GO:0007049', ('198', '208'))	('tumor', 'Disease', (236, 241))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
195203	24752337	Alterations of Rb1 and subsequent overexpression of p16 have been described in a number of non-HPV driven tumors, as well.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('p16', 'Gene', '1029', (52, 55))	('described', 'Reg', (66, 75))	('tumors', 'Disease', (106, 112))	('Alterations', 'Var', (0, 11))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('Rb1', 'Gene', (15, 18))	('overexpression', 'PosReg', (34, 48))	('p16', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('HPV', 'Species', '10566', (95, 98))
195204	24752337	Overexpression of Rb1 and p16 are associated with a poor prognosis in the setting of nonsmall cell lung carcinoma.	('p16', 'Gene', (26, 29))	('Rb1', 'Gene', (18, 21))	('nonsmall cell lung carcinoma', 'Disease', (85, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('nonsmall cell lung carcinoma', 'Phenotype', 'HP:0030358', (85, 113))	('p16', 'Gene', '1029', (26, 29))	('nonsmall cell lung carcinoma', 'Disease', 'MESH:D002289', (85, 113))	('Overexpression', 'Var', (0, 14))
195205	24752337	Therefore, alterations in Rb1 or p16 may lead to overexpression via immunohistochemistry, with or without HPV infection.	('alterations', 'Var', (11, 22))	('p16', 'Gene', (33, 36))	('HPV infection', 'Disease', (106, 119))	('Rb1', 'Gene', (26, 29))	('HPV infection', 'Disease', 'MESH:D030361', (106, 119))	('p16', 'Gene', '1029', (33, 36))	('lead to', 'Reg', (41, 48))	('overexpression', 'MPA', (49, 63))
195226	24752337	Considering these findings, it is likely that alterations in these cell cycle proteins contribute to the biological mechanisms driving these tumors.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cell cycle', 'biological_process', 'GO:0007049', ('67', '77'))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('alterations', 'Var', (46, 57))
195274	33104528	The aim of this work was to develop an accurate stratification in predicting the prognosis and directing the treatment of BLCA patients based on small nucleolar RNAs (snoRNAs).	('snoRNA', 'Gene', '85390', (167, 173))	('patients', 'Species', '9606', (127, 135))	('snoRNA', 'Gene', (167, 173))	('small nucleolar', 'Var', (145, 160))
195341	33104528	Aberrant DNA methylation can provide reliable biomarkers in the prediction of clinical outcomes of common urological cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Aberrant', 'Var', (0, 8))	('urological cancers', 'Disease', (106, 124))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('urological cancers', 'Disease', 'MESH:D014571', (106, 124))	('DNA', 'Protein', (9, 12))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))
195346	33104528	Aberrant snoRNAs expression was found in many cancers, and the expression level was correlated with diagnosis, classification of subtypes, and patient survival.	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('snoRNA', 'Gene', '85390', (9, 15))	('patient', 'Species', '9606', (143, 150))	('Aberrant', 'Var', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('found', 'Reg', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('snoRNA', 'Gene', (9, 15))
195412	29343907	CTLA-4 inhibitors do have considerable potential toxicities and have not been evaluated yet in NMIBC but have demonstrated activity in metastatic urothelial carcinoma.	('toxicities', 'Disease', (49, 59))	('urothelial carcinoma', 'Disease', (146, 166))	('CTLA-4', 'Gene', (0, 6))	('NMIBC', 'Chemical', '-', (95, 100))	('inhibitors', 'Var', (7, 17))	('toxicities', 'Disease', 'MESH:D064420', (49, 59))	('CTLA-4', 'Gene', '1493', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (146, 166))	('activity', 'MPA', (123, 131))
195413	29343907	Another immune checkpoint being explored for checkpoint inhibition immunotherapy is MPDL3280A, an anti-programmed death-ligand 1 (PD-L1) monoclonal antibody that inhibits the interaction between PD-L1 and its receptor, PD-1 on T-cells.	('interaction', 'Interaction', (175, 186))	('programmed death-ligand 1', 'Gene', '574058', (103, 128))	('ligand', 'molecular_function', 'GO:0005488', ('120', '126'))	('programmed death-ligand 1', 'Gene', (103, 128))	('antibody', 'cellular_component', 'GO:0042571', ('148', '156'))	('inhibits', 'NegReg', (162, 170))	('PD-L1', 'Gene', (195, 200))	('antibody', 'cellular_component', 'GO:0019815', ('148', '156'))	('MPDL3280A', 'Var', (84, 93))	('antibody', 'cellular_component', 'GO:0019814', ('148', '156'))	('antibody', 'molecular_function', 'GO:0003823', ('148', '156'))
195417	29343907	MPDL3280A has shown remarkable clinical activity against metastatic urothelial bladder cancer and was not associated with any Grade 4 or 5 adverse events in a recent Phase 1 clinical trial.	('MPDL3280A', 'Var', (0, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (79, 93))	('urothelial bladder cancer', 'Disease', (68, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (68, 93))
195441	29343907	A current Phase Ib/II trial is investigating safety, tolerability, and cancer recurrence rates up to 13 weeks in patients with high-grade Ta, T1, or Tis NMIBC treated with ALT-801 and IV gemcitabine.	('NMIBC', 'Chemical', '-', (153, 158))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('patients', 'Species', '9606', (113, 121))	('ALT', 'molecular_function', 'GO:0004021', ('172', '175'))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('gemcitabine', 'Chemical', 'MESH:C056507', (187, 198))	('high-grade', 'Var', (127, 137))
195449	29343907	Preliminary results of the 78 patients enrolled reported that RFS rates for BCG and low-dose HS-410, BCG, and high-dose HS-410, and BCG and placebo were 65.4%, 65.45%, and 76.9%, respectively.	('BCG', 'Species', '33892', (76, 79))	('BCG', 'Species', '33892', (132, 135))	('HS-410', 'Chemical', '-', (93, 99))	('HS-410', 'Var', (120, 126))	('BCG', 'Species', '33892', (101, 104))	('HS-410', 'Chemical', '-', (120, 126))	('patients', 'Species', '9606', (30, 38))	('HS-410', 'Gene', (93, 99))	('RFS', 'MPA', (62, 65))
195477	29343907	The efficacy of enzalutamide in preventing bladder cancer recurrence in patients with both AR+ or AR- NMIBC will be evaluated by looking at recurrence rate over a 12-month period in an ongoing Phase 2 study.	('AR-', 'Var', (98, 101))	('bladder cancer', 'Disease', 'MESH:D001749', (43, 57))	('NMIBC', 'Chemical', '-', (102, 107))	('bladder cancer', 'Disease', (43, 57))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (43, 68))	('enzalutamide', 'Chemical', 'MESH:C540278', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('bladder cancer', 'Phenotype', 'HP:0009725', (43, 57))	('patients', 'Species', '9606', (72, 80))
195479	29343907	However, it has also been shown to be cytotoxic through inhibition of glutathione S-transferase and Wnt/beta-catenin signaling, and dysregulation of which has been implicated in various tumors including bladder cancer.	('inhibition', 'NegReg', (56, 66))	('Wnt/beta-catenin signaling', 'MPA', (100, 126))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('glutathione S-transferase', 'Enzyme', (70, 95))	('bladder cancer', 'Phenotype', 'HP:0009725', (203, 217))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('implicated', 'Reg', (164, 174))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('bladder cancer', 'Disease', 'MESH:D001749', (203, 217))	('bladder cancer', 'Disease', (203, 217))	('dysregulation', 'Var', (132, 145))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))
195490	29343907	In a rodent NMIBC model, ALT-803+ BCG was shown to reduce tumor burden (by 46%), produce a local cytokine response (IL-1alpha, IL-1 beta, and RANTES), activate NK cells, and reduce angiogenesis (by 76%) when compared to the control group.	('ALT-803+ BCG', 'Var', (25, 37))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('NMIBC', 'Chemical', '-', (12, 17))	('activate', 'PosReg', (151, 159))	('reduce', 'NegReg', (174, 180))	('angiogenesis', 'biological_process', 'GO:0001525', ('181', '193'))	('NK cells', 'CPA', (160, 168))	('IL-1', 'molecular_function', 'GO:0005149', ('116', '120'))	('produce', 'Reg', (81, 88))	('ALT', 'molecular_function', 'GO:0004021', ('25', '28'))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('reduce', 'NegReg', (51, 57))	('angiogenesis', 'CPA', (181, 193))	('BCG', 'Species', '33892', (34, 37))	('IL-1', 'molecular_function', 'GO:0005149', ('127', '131'))
195520	29343907	Preclinical synergistic local (radiosensitizing immunotherapy) and distant antitumor activity were shown with the combination of irradiation and anti-PD-L1.	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('anti-PD-L1', 'Var', (145, 155))	('tumor', 'Disease', (79, 84))
195565	23055747	Denosumab (XGEVA; Amgen, Thousand Oaks, CA), a fully human monoclonal antibody that binds to and neutralizes RANKL, inhibits osteoclast function, prevents generalized bone resorption and local bone destruction, and has become a therapeutic option for preventing or delaying first on-study skeletal-related events in various malignancies.	('local bone destruction', 'CPA', (187, 209))	('generalized bone resorption', 'CPA', (155, 182))	('antibody', 'cellular_component', 'GO:0019814', ('70', '78'))	('neutralizes', 'Var', (97, 108))	('XGEVA', 'Chemical', 'MESH:D000069448', (11, 16))	('bone destruction', 'Phenotype', 'HP:0002797', (193, 209))	('antibody', 'molecular_function', 'GO:0003823', ('70', '78'))	('inhibits', 'NegReg', (116, 124))	('prevents', 'NegReg', (146, 154))	('antibody', 'cellular_component', 'GO:0042571', ('70', '78'))	('human', 'Species', '9606', (53, 58))	('malignancies', 'Disease', 'MESH:D009369', (324, 336))	('osteoclast function', 'CPA', (125, 144))	('malignancies', 'Disease', (324, 336))	('RANKL', 'Gene', (109, 114))	('Denosumab', 'Chemical', 'MESH:D000069448', (0, 9))	('antibody', 'cellular_component', 'GO:0019815', ('70', '78'))	('binds', 'Interaction', (84, 89))	('bone resorption', 'Phenotype', 'HP:0002797', (167, 182))	('bone resorption', 'biological_process', 'GO:0045453', ('167', '182'))
195578	23055747	Denosumab (XGEVA; Amgen, Thousand Oaks, CA), a novel agent targeting bone resorption, is a fully human monoclonal antibody that binds to and neutralizes RANKL, thereby inhibiting osteoclast function and preventing generalized bone resorption and local bone destruction.	('human', 'Species', '9606', (97, 102))	('antibody', 'cellular_component', 'GO:0019814', ('114', '122'))	('osteoclast function', 'CPA', (179, 198))	('bone resorption', 'Phenotype', 'HP:0002797', (69, 84))	('XGEVA', 'Chemical', 'MESH:D000069448', (11, 16))	('bone resorption', 'biological_process', 'GO:0045453', ('69', '84'))	('preventing', 'NegReg', (203, 213))	('RANKL', 'Gene', (153, 158))	('antibody', 'molecular_function', 'GO:0003823', ('114', '122'))	('neutralizes', 'Var', (141, 152))	('bone resorption', 'Phenotype', 'HP:0002797', (226, 241))	('antibody', 'cellular_component', 'GO:0042571', ('114', '122'))	('bone resorption', 'biological_process', 'GO:0045453', ('226', '241'))	('inhibiting', 'NegReg', (168, 178))	('local bone destruction', 'CPA', (246, 268))	('generalized bone resorption', 'CPA', (214, 241))	('bone destruction', 'Phenotype', 'HP:0002797', (252, 268))	('antibody', 'cellular_component', 'GO:0019815', ('114', '122'))	('Denosumab', 'Chemical', 'MESH:D000069448', (0, 9))
195644	23055747	We evaluated the significance of OPG gene polymorphisms in prostate cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('OPG gene', 'Gene', (33, 41))	('polymorphisms', 'Var', (42, 55))	('prostate cancer', 'Disease', (59, 74))
195646	23055747	In addition, the analysis of metastatic prostate cancer patients (stage D) revealed that the T allele of the OPG 950 T/C polymorphism was an independent risk factor, predicting short survival compared to the C allele, according to Cox proportional hazard regression analysis (P = 0.031).	('patients', 'Species', '9606', (56, 64))	('950 T/C', 'Mutation', 'rs2073617', (113, 120))	('metastatic prostate cancer', 'Disease', 'MESH:D011471', (29, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('polymorphism', 'Var', (121, 133))	('OPG 950', 'Gene', (109, 116))	('short survival', 'MPA', (177, 191))	('metastatic prostate cancer', 'Disease', (29, 55))	('T allele', 'Var', (93, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (40, 55))	('T/C polymorphism', 'Var', (117, 133))
195647	23055747	The C allele of the 950 T/C polymorphism was associated with high bone marrow density, suggesting that OPG can function effectively to prevent the RANK/RANKL osteolytic signal.	('prevent', 'NegReg', (135, 142))	('osteolytic', 'Disease', 'MESH:D030981', (158, 168))	('RANK', 'Gene', (147, 151))	('polymorphism', 'Var', (28, 40))	('RANK', 'Gene', '8792', (147, 151))	('RANK', 'Gene', (152, 156))	('bone marrow density', 'CPA', (66, 85))	('osteolytic', 'Disease', (158, 168))	('950 T/C', 'Mutation', 'rs2073617', (20, 27))	('RANK', 'Gene', '8792', (152, 156))
195658	23055747	In a retrospective subset analysis of 74 patients with RCC enrolled in a multicenter, randomized, placebo-controlled study, zoledronic acid was found to significantly reduce the proportion of patients with an SRE (37% vs 74% for placebo; P = 0.015).	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('SRE', 'Disease', (209, 212))	('reduce', 'NegReg', (167, 173))	('zoledronic', 'Var', (124, 134))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (124, 139))	('patients', 'Species', '9606', (192, 200))	('patients', 'Species', '9606', (41, 49))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
195664	23055747	Compared to patients receiving placebo, those receiving zoledronic acid had a lower mean incidence of SREs (2.1 vs 0.95, respectively), and zoledronic acid prolonged the median time to first SRE compared to placebo (16 vs 8 weeks, respectively).	('SREs', 'Disease', (102, 106))	('zoledronic acid', 'Var', (140, 155))	('patients', 'Species', '9606', (12, 20))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (56, 71))	('prolonged', 'PosReg', (156, 165))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (140, 155))
195700	23055747	In the third study, which was double-blind, randomized, and placebo-controlled, men with nonmetastatic castration-resistant prostate cancer at high risk of bone metastasis were enrolled at 319 centers in 30 countries; 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo).	('denosumab', 'Var', (280, 289))	('prostate cancer', 'Disease', 'MESH:D011471', (124, 139))	('men', 'Species', '9606', (80, 83))	('prostate cancer', 'Phenotype', 'HP:0012125', (124, 139))	('men', 'Species', '9606', (263, 266))	('denosumab', 'Chemical', 'MESH:D000069448', (280, 289))	('patients', 'Species', '9606', (223, 231))	('prostate cancer', 'Disease', (124, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
195754	19544456	After three 5-minute washes with FACS buffer, cell suspensions were further incubated with phycoerythrin-conjugated goat anti-mouse IgM (#406507, 2.5 mug/ml; BioLegend, San Diego, CA, http://www.biolegend.com) and fluorescein isothiocyanate (FITC)-conjugated antibodies against mouse H-2Dk and H-2Kb/H-2Db major histocompatibility antigens (mMHC1, #110305 and #114605, 1:20 dilution; BioLegend) for 40 minutes on ice, protected from light.	('mouse', 'Species', '10090', (126, 131))	('#114605', 'Var', (360, 367))	('FITC', 'Chemical', 'MESH:D016650', (242, 246))	('H-2Dk', 'CellLine', 'CVCL:9801', (284, 289))	('mouse', 'Species', '10090', (278, 283))	('goat', 'Species', '9925', (116, 120))	('mug', 'molecular_function', 'GO:0043739', ('150', '153'))	('mMHC1', 'Gene', (341, 346))	('#110305', 'Var', (348, 355))
195764	19544456	The expression values for 67LR bright tumor cell population are presented as a fold expression in relation to 67LR dim tumor cell population; the actual values were calculated using the 2-DeltaDeltaCT equation, where DeltaDeltaCT = [CTTarget - CTHPRT](67LR bright) - [CTTarget - CTHPRT](67LR dim).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', (119, 124))	('HPRT', 'Gene', '3251', (246, 250))	('HPRT', 'Gene', '3251', (281, 285))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('HPRT', 'Gene', (246, 250))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('HPRT', 'Gene', (281, 285))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('DeltaDeltaCT', 'Var', (217, 229))
195798	19544456	Compared to bulk or the control-sorted SW780 cells, 67LR bright cells were approximately 5- to 10-fold more potent at initiating new tumors in vivo (Fig.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('67LR', 'Var', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('initiating', 'Reg', (118, 128))	('SW780', 'CellLine', 'CVCL:1728', (39, 44))
195876	32613817	Diverse immunohistochemical (e.g., keratin and fibroblast growth factor receptor 3 (FGFR3) expression pattern) and molecular (e.g., gene alterations, FGFR3 mutations) markers have been suggested to predict recurrence, but conflicting results have been reported.	('gene alterations', 'Var', (132, 148))	('mutations', 'Var', (156, 165))	('FGFR3', 'Gene', (150, 155))	('fibroblast growth factor receptor 3', 'Gene', '2261', (47, 82))	('FGFR3', 'Gene', '2261', (84, 89))	('FGFR', 'molecular_function', 'GO:0005007', ('84', '88'))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('47', '71'))	('fibroblast growth factor receptor 3', 'Gene', (47, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('150', '154'))	('FGFR3', 'Gene', '2261', (150, 155))	('FGFR3', 'Gene', (84, 89))
195961	32613817	Similarly, as in normal urothelium, DSA did not labelled the apical PM of the papillary carcinomas, while some regions of the cytoplasm of superficial and intermediate urothelial cells were strongly labelled by DSA (Figure 4 J-L).	('papillary carcinomas', 'Disease', (78, 98))	('cytoplasm', 'cellular_component', 'GO:0005737', ('126', '135'))	('DSA', 'Chemical', '-', (211, 214))	('DSA', 'Chemical', '-', (36, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('DSA', 'Var', (211, 214))	('papillary carcinomas', 'Disease', 'MESH:D002291', (78, 98))
196051	32300500	Urothelial carcinoma with squamous differentiation comprises approximately 60% of UC variants, whereas UC with glandular differentiation comprises approximately 10% of all UC.	('Urothelial carcinoma', 'Disease', 'MESH:D014523', (0, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('Urothelial carcinoma', 'Disease', (0, 20))	('variants', 'Var', (85, 93))
196069	32300500	Moreover, histological variants play a major role in tailoring therapeutic approaches to cT1 disease and predicting response to neoadjuvant chemotherapy.	('variants', 'Var', (23, 31))	('cT1', 'Gene', (89, 92))	('cT1', 'Gene', '1489', (89, 92))
196080	32149116	Although its exact mechanism remains obscure, many studies have shown that the tumorigenesis and progression of bladder cancer are closely related to chromosomal anomalies, epigenetic changes, and genetic polymorphism, and genetic changes are obviously involved in its initiation and prognosis.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('epigenetic changes', 'Var', (173, 191))	('involved', 'Reg', (253, 261))	('related', 'Reg', (139, 146))	('tumor', 'Disease', (79, 84))	('genetic polymorphism', 'Var', (197, 217))	('bladder cancer', 'Disease', 'MESH:D001749', (112, 126))	('bladder cancer', 'Disease', (112, 126))	('chromosomal anomalies', 'Disease', 'MESH:D002869', (150, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))	('chromosomal anomalies', 'Disease', (150, 171))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('progression', 'CPA', (97, 108))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
196130	32149116	Furthermore, high COMP expression plays a crucial role in regulating cellular metabolism by blocking intracellular Ca2+ signaling and thus blocking the apoptosis process of the cells.	('intracellular Ca2+ signaling', 'MPA', (101, 129))	('intracellular', 'cellular_component', 'GO:0005622', ('101', '114'))	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('cellular metabolism', 'biological_process', 'GO:0044237', ('69', '88'))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('cellular metabolism', 'MPA', (69, 88))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('blocking', 'NegReg', (139, 147))	('high COMP', 'Var', (13, 22))	('Ca2+', 'Chemical', 'MESH:D000069285', (115, 119))	('blocking', 'NegReg', (92, 100))	('apoptosis process of the cells', 'CPA', (152, 182))
196131	32149116	Previous studies have shown that COMP expression in breast cancer cells is significantly associated with poor prognosis.	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('COMP expression', 'Var', (33, 48))
196133	32149116	DSG1, a member of the desmoglein protein subfamily, plays a crucial role in cell adhesion, whose dysfunction promotes the process of epithelial-mesenchymal transition (EMT) and thus the invasion and metastasis of cancer cells.	('invasion', 'CPA', (186, 194))	('DSG1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('epithelial-mesenchymal transition', 'CPA', (133, 166))	('desmoglein', 'Gene', '1828', (22, 32))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('DSG1', 'Gene', '1828', (0, 4))	('cell adhesion', 'biological_process', 'GO:0007155', ('76', '89'))	('desmoglein', 'Gene', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('133', '166'))	('dysfunction', 'Var', (97, 108))	('cancer', 'Disease', (213, 219))	('EMT', 'biological_process', 'GO:0001837', ('168', '171'))	('promotes', 'PosReg', (109, 117))
196135	32149116	One of the basic challenges in cancer is to detect the regulators of gene expression changes in tumorigenesis and the correlation between that and prognosis.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('gene expression', 'biological_process', 'GO:0010467', ('69', '84'))	('tumor', 'Disease', (96, 101))	('changes', 'Var', (85, 92))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Disease', (31, 37))
196141	32149116	Additionally, we analyzed the correlation between mainly identified DEGs (TNFAIP6, CTSE, COMP, and DSG1) and immune cell infiltration, whose result proved that the identified DEGs modulated the immune microenvironment by influencing the infiltration level of various immune cells.	('modulated', 'Reg', (180, 189))	('CTSE', 'Gene', '1510', (83, 87))	('infiltration level of various immune cells', 'MPA', (237, 279))	('CTSE', 'Gene', (83, 87))	('DEGs', 'Var', (175, 179))	('TNFAIP6', 'Gene', (74, 81))	('influencing', 'Reg', (221, 232))	('TNFAIP6', 'Gene', '7130', (74, 81))	('DSG1', 'Gene', '1828', (99, 103))	('DSG1', 'Gene', (99, 103))
196157	31030505	The UroVysion test is based on multicolor fluorescence in situ hybridization (FISH) and is able to detect aneuploidy of chromosomes 3, 7, and 17, and the deletion of the 9p21 locus (Halling et al., 2000).	('9p21', 'Gene', (170, 174))	('aneuploidy', 'Disease', 'MESH:D000782', (106, 116))	('aneuploidy', 'Disease', (106, 116))	('deletion', 'Var', (154, 162))
196172	31030505	The analysis revealed that high grade tumor tended to be an independent predictor of UroVysion FISH positivity (odds ratio [OR] = 6.18; 95% confidence interval [CI], 0.80-47.70, p=0.080).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('high grade', 'Var', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('UroVysion FISH positivity', 'Disease', (85, 110))
196177	31030505	Moreover, Ho et al., (2013) reported that UroVysion FISH has a high specificity (83.4%) for the patients with hematuria and it facilitates conservation of health resources and minimizes trauma by deferring cystoscopic or ureteroscopic examinations.	('Ho', 'Chemical', 'MESH:D006695', (10, 12))	('facilitates', 'PosReg', (127, 138))	('UroVysion', 'Var', (42, 51))	('hematuria', 'Phenotype', 'HP:0000790', (110, 119))	('trauma', 'Disease', (186, 192))	('hematuria', 'Disease', (110, 119))	('patients', 'Species', '9606', (96, 104))	('trauma', 'Disease', 'MESH:D014947', (186, 192))	('hematuria', 'Disease', 'MESH:D006417', (110, 119))
196187	30237752	In this study, we used bioinformatics approaches to identify gene alteration that contribute to colon cancer progression via analysis of TCGA RNA sequencing data and other publicly GEO microarray data.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colon cancer', 'Phenotype', 'HP:0003003', (96, 108))	('colon cancer', 'Disease', 'MESH:D015179', (96, 108))	('contribute', 'Reg', (82, 92))	('alteration', 'Var', (66, 76))	('RNA', 'cellular_component', 'GO:0005562', ('142', '145'))	('colon cancer', 'Disease', (96, 108))
196191	30237752	High VCAN levels also predict shorter overall survival of colon cancer patients.	('VCAN', 'Gene', '1462', (5, 9))	('overall', 'MPA', (38, 45))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (71, 79))	('colon cancer', 'Phenotype', 'HP:0003003', (58, 70))	('VCAN', 'Gene', (5, 9))	('colon cancer', 'Disease', 'MESH:D015179', (58, 70))	('shorter', 'NegReg', (30, 37))	('colon cancer', 'Disease', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
196192	30237752	Furthermore, in vitro assays of silencing VCAN inhibit HCT116 cell proliferation and invasion.	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('VCAN', 'Gene', (42, 46))	('HCT116 cell proliferation', 'CPA', (55, 80))	('silencing', 'Var', (32, 41))	('inhibit', 'NegReg', (47, 54))	('invasion', 'CPA', (85, 93))	('HCT116', 'CellLine', 'CVCL:0291', (55, 61))	('VCAN', 'Gene', '1462', (42, 46))
196205	30237752	Mutations in this gene are the cause of Wagner syndrome type 1.	('Wagner syndrome', 'Disease', 'MESH:C536075', (40, 55))	('Mutations', 'Var', (0, 9))	('Wagner syndrome', 'Disease', (40, 55))	('cause', 'Reg', (31, 36))
196217	30237752	Colony formation assays were performed to detect HCT-116 cells cloning Capability after HCT-116 cells transfected with si-VCAN or si-NC.	('si-NC', 'Var', (130, 135))	('VCAN', 'Gene', (122, 126))	('VCAN', 'Gene', '1462', (122, 126))	('HCT-116', 'CellLine', 'CVCL:0291', (88, 95))	('formation', 'biological_process', 'GO:0009058', ('7', '16'))	('HCT-116', 'CellLine', 'CVCL:0291', (49, 56))
196235	30237752	Quantitative RT-PCR and Western blot analysis to quantitatively measure the effect of VCAN knockdown.	('VCAN', 'Gene', (86, 90))	('VCAN', 'Gene', '1462', (86, 90))	('knockdown', 'Var', (91, 100))
196237	30237752	Transwell migration assays showed that knockdown of VCAN dramatically decreased cell migration (Fig.	('knockdown', 'Var', (39, 48))	('decreased', 'NegReg', (70, 79))	('cell migration', 'CPA', (80, 94))	('VCAN', 'Gene', (52, 56))	('VCAN', 'Gene', '1462', (52, 56))	('cell migration', 'biological_process', 'GO:0016477', ('80', '94'))
196238	30237752	Furthermore, Colony formation assays showed that knockdown of VCAN inhibited cell proliferation in vitro.	('knockdown', 'Var', (49, 58))	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('inhibited', 'NegReg', (67, 76))	('VCAN', 'Gene', (62, 66))	('cell proliferation in vitro', 'CPA', (77, 104))	('VCAN', 'Gene', '1462', (62, 66))	('formation', 'biological_process', 'GO:0009058', ('20', '29'))
196244	30237752	reported miR-135a-5p could affect the proliferation, invasion and migration of thyroid carcinoma cells by targeting VCAN.	('VCAN', 'Gene', (116, 120))	('proliferation', 'CPA', (38, 51))	('migration', 'CPA', (66, 75))	('invasion', 'CPA', (53, 61))	('VCAN', 'Gene', '1462', (116, 120))	('targeting', 'Reg', (106, 115))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (79, 96))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (79, 96))	('miR-135a-5p', 'Var', (9, 20))	('affect', 'Reg', (27, 33))	('thyroid carcinoma', 'Disease', (79, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
196250	30237752	A loss-of-function study revealed that colony formation assays showed that knockdown of VCAN inhibited cell proliferation in vitro.	('cell proliferation in vitro', 'CPA', (103, 130))	('VCAN', 'Gene', '1462', (88, 92))	('knockdown', 'Var', (75, 84))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('formation', 'biological_process', 'GO:0009058', ('46', '55'))	('inhibited', 'NegReg', (93, 102))	('VCAN', 'Gene', (88, 92))
196251	30237752	Transwell migration assays showed that knockdown of VCAN dramatically decreased cell migration.	('knockdown', 'Var', (39, 48))	('decreased', 'NegReg', (70, 79))	('cell migration', 'CPA', (80, 94))	('VCAN', 'Gene', (52, 56))	('VCAN', 'Gene', '1462', (52, 56))	('cell migration', 'biological_process', 'GO:0016477', ('80', '94'))
196260	28600503	Knockdown of ANLN in J82 and 5637 cells using small interfering RNA significantly inhibited cell proliferation, migration, and invasion ability.	('invasion ability', 'CPA', (127, 143))	('small interfering', 'Var', (46, 63))	('inhibited', 'NegReg', (82, 91))	('J82', 'CellLine', 'CVCL:0359', (21, 24))	('RNA', 'Gene', (64, 67))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('migration', 'CPA', (112, 121))	('cell proliferation', 'CPA', (92, 110))	('RNA', 'cellular_component', 'GO:0005562', ('64', '67'))
196261	28600503	Moreover, knockdown of ANLN resulted in G2/M phase arrest and decreased expression of cyclin B1 and D1.	('G2/M phase arrest', 'CPA', (40, 57))	('decreased', 'NegReg', (62, 71))	('cyclin', 'molecular_function', 'GO:0016538', ('86', '92'))	('M phase', 'biological_process', 'GO:0000279', ('43', '50'))	('expression', 'MPA', (72, 82))	('cyclin B1 and D1', 'Gene', '891;595', (86, 102))	('knockdown', 'Var', (10, 19))	('ANLN', 'Gene', (23, 27))
196272	28600503	Dysregulated ANLN expression has been found in a wide variety of human cancers, i.e.	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('Dysregulated', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('found', 'Reg', (38, 43))	('ANLN', 'Protein', (13, 17))
196279	28600503	Taken together, our data suggested that ANLN was a novel and promising prognostic biomarker for BLCA that may aid in the risk stratification.	('BLCA', 'Disease', (96, 100))	('ANLN', 'Var', (40, 44))	('BLCA', 'Chemical', '-', (96, 100))
196282	28600503	1c, several aberrant pathways were closely associated with carcinogenesis, e.g.	('carcinogenesis', 'Disease', (59, 73))	('carcinogenesis', 'Disease', 'MESH:D063646', (59, 73))	('associated', 'Reg', (43, 53))	('aberrant', 'Var', (12, 20))
196287	28600503	Thirdly, after data-mining and literature search, ANLN was not previously reported to be associated with BLCA.	('ANLN', 'Var', (50, 54))	('associated', 'Reg', (89, 99))	('BLCA', 'Chemical', '-', (105, 109))	('BLCA', 'Disease', (105, 109))
196297	28600503	With a median follow-up of 27.9 months, patients with high ANLN expression in tumor showed significantly poorer CSS (median, 22.4 vs. 37.3 months, p = 0.001), PFS (median, 19.7 vs. 27.9 months, p = 0.001) and RFS (median, 17.1 vs. 25.2 months, p = 0.011) compared with patients with low expression (Fig.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('patients', 'Species', '9606', (40, 48))	('CSS', 'MPA', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('PFS', 'MPA', (159, 162))	('RFS', 'MPA', (209, 212))	('CSS', 'Chemical', '-', (112, 115))	('tumor', 'Disease', (78, 83))	('high ANLN expression', 'Var', (54, 74))	('poorer', 'NegReg', (105, 111))	('patients', 'Species', '9606', (269, 277))
196301	28600503	In MIBC cohort, patients with high ANLN expression had a significantly reduced CSS (p = 0.012) and PFS (p = 0.018), while the RFS (p = 0.144) did not reach the level of statistical significance (Supplementary Fig.	('CSS', 'Chemical', '-', (79, 82))	('PFS', 'CPA', (99, 102))	('CSS', 'CPA', (79, 82))	('patients', 'Species', '9606', (16, 24))	('MIBC', 'Chemical', '-', (3, 7))	('reduced', 'NegReg', (71, 78))	('high ANLN expression', 'Var', (30, 50))
196302	28600503	Regarding NMIBC cohort, patients with high ANLN expression showed a tendential correlation with poorer CSS, PFS and RFS, but none of these parameters reached the level of statistical significance (Supplementary Fig.	('PFS', 'Disease', (108, 111))	('CSS', 'Chemical', '-', (103, 106))	('high ANLN expression', 'Var', (38, 58))	('RFS', 'Disease', (116, 119))	('MIBC', 'Chemical', '-', (11, 15))	('patients', 'Species', '9606', (24, 32))	('CSS', 'Disease', (103, 106))	('poorer', 'Disease', (96, 102))
196304	28600503	Regarding the GSE31684 dataset from NCBI-GEO, patients with ANLN mRNA expression above 75% (n = 23) showed tendentially reduced CSS compared with ANLN below 25% (n = 23, median 10.8 vs. 65.3 months, p = 0.321, Fig.	('patients', 'Species', '9606', (46, 54))	('CSS', 'Chemical', '-', (128, 131))	('CSS', 'CPA', (128, 131))	('ANLN', 'Var', (60, 64))	('reduced', 'NegReg', (120, 127))
196305	28600503	To explore the functions of ANLN in BLCA, we used small interference RNA (siRNA) induced knockdown of ANLN expression in 5637 and J82 cells, which had relative higher ANLN expression among several BLCA cell lines (Supplementary Fig.	('ANLN', 'Gene', (102, 106))	('J82', 'CellLine', 'CVCL:0359', (130, 133))	('higher', 'PosReg', (160, 166))	('expression', 'MPA', (172, 182))	('BLCA', 'Chemical', '-', (36, 40))	('RNA', 'cellular_component', 'GO:0005562', ('69', '72'))	('ANLN', 'MPA', (167, 171))	('BLCA', 'Chemical', '-', (197, 201))	('knockdown', 'Var', (89, 98))
196306	28600503	4A, knockdown of ANLN could significantly inhibit the proliferation of J82 and 5637 cells.	('ANLN', 'Gene', (17, 21))	('proliferation', 'CPA', (54, 67))	('inhibit', 'NegReg', (42, 49))	('knockdown', 'Var', (4, 13))	('J82', 'CellLine', 'CVCL:0359', (71, 74))
196307	28600503	This finding was further confirmed by using in vivo subcutaneous and orthotopic nude mouse models, in which the tumor growth rate was significantly decreased after ANLN knockdown in J82 cells by using lentivirus-mediated gene transfer method (Figs 4B,C and S2).	('J82', 'CellLine', 'CVCL:0359', (182, 185))	('mouse', 'Species', '10090', (85, 90))	('knockdown', 'Var', (169, 178))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('decreased', 'NegReg', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('ANLN knockdown', 'Var', (164, 178))	('tumor', 'Disease', (112, 117))
196309	28600503	The result of the scratch/wound-healing assay showed that ANLN knockdown reduced migration ability of J82 and 5637 cells (Fig.	('J82', 'CellLine', 'CVCL:0359', (102, 105))	('migration ability', 'CPA', (81, 98))	('ANLN', 'Gene', (58, 62))	('wound-healing', 'biological_process', 'GO:0042060', ('26', '39'))	('reduced', 'NegReg', (73, 80))	('knockdown', 'Var', (63, 72))
196310	28600503	Furthermore, cell invasion ability of J82 and 5637 cells, as monitored by matrigel invasion assay, was also significantly alleviated after knockdown of ANLN in J82 and 5637 cells (Fig.	('matrigel invasion assay', 'CPA', (74, 97))	('ANLN', 'Var', (152, 156))	('J82', 'CellLine', 'CVCL:0359', (38, 41))	('knockdown', 'Var', (139, 148))	('cell invasion ability', 'CPA', (13, 34))	('alleviated', 'NegReg', (122, 132))	('J82', 'CellLine', 'CVCL:0359', (160, 163))
196321	28600503	Compared with control cells, multinucleated cancer cells were observed at higher frequency after ANLN knockdown (Fig.	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('knockdown', 'Var', (102, 111))
196332	28600503	found that ANLN expression showed a tumor progression-related pattern in breast, ovarian, kidney, colorectal, hepatic, lung, endometrial and pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (141, 158))	('lung', 'Disease', (119, 123))	('endometrial', 'Disease', (125, 136))	('colorectal', 'Disease', (98, 108))	('ANLN expression', 'Var', (11, 26))	('pancreatic cancer', 'Disease', (141, 158))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('breast', 'Disease', (73, 79))	('pancreatic cancer', 'Disease', 'MESH:D010190', (141, 158))	('endometrial', 'Disease', 'MESH:D014591', (125, 136))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('kidney', 'Disease', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ovarian', 'Disease', (81, 88))	('hepatic', 'Disease', (110, 117))	('tumor', 'Disease', (36, 41))
196333	28600503	These observations were supported by several recent reports, which showed that elevated ANLN expression was associated with poorer overall survival of colorectal cancer, breast cancer, lung cancer and upper urinary tract urothelial carcinoma.	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('colorectal cancer', 'Phenotype', 'HP:0003003', (151, 168))	('upper urinary tract urothelial carcinoma', 'Disease', (201, 241))	('overall survival', 'MPA', (131, 147))	('ANLN', 'Var', (88, 92))	('colorectal cancer', 'Disease', (151, 168))	('upper urinary tract urothelial carcinoma', 'Disease', 'MESH:D014552', (201, 241))	('lung cancer', 'Disease', (185, 196))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('poorer', 'NegReg', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('colorectal cancer', 'Disease', 'MESH:D015179', (151, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))
196334	28600503	These observations indicated that ANLN expression was significant clinically relevant and might play an essential role in the pathogenesis of cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('pathogenesis', 'biological_process', 'GO:0009405', ('126', '138'))	('play', 'Reg', (96, 100))	('ANLN', 'Var', (34, 38))	('cancer', 'Disease', (142, 148))
196339	28600503	Through functional studies, we found that knockdown of ANLN could significantly inhibit the proliferation of BLCA both in vitro and in vivo.	('proliferation of BLCA', 'CPA', (92, 113))	('inhibit', 'NegReg', (80, 87))	('ANLN', 'Gene', (55, 59))	('BLCA', 'Chemical', '-', (109, 113))	('knockdown', 'Var', (42, 51))
196340	28600503	Furthermore, knockdown of ANLN strongly suppressed the migration and invasion ability of J82 and 5637 cells; GO analysis after ANLN knockdown also revealed that differentially expressed genes were mostly enriched in migration and locomotion in biological process.	('locomotion', 'biological_process', 'GO:0040011', ('230', '240'))	('suppressed', 'NegReg', (40, 50))	('biological process', 'biological_process', 'GO:0008150', ('244', '262'))	('ANLN', 'Gene', (26, 30))	('migration and invasion ability of J82 and 5637 cells', 'CPA', (55, 107))	('knockdown', 'Var', (13, 22))	('J82', 'CellLine', 'CVCL:0359', (89, 92))
196347	28600503	Previous studies suggested that ANLN functions might be important in nuclear physiology, and dysregulation of ANLN might perturb the nuclei division in cancer.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('nuclei division', 'CPA', (133, 148))	('ANLN', 'Gene', (110, 114))	('perturb', 'NegReg', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('dysregulation', 'Var', (93, 106))
196348	28600503	reported that ANLN localization defect could induce formation of binucleate cells in cardiomyocyte cells and breast cancer cells, respectively.	('formation', 'biological_process', 'GO:0009058', ('52', '61'))	('ANLN', 'Protein', (14, 18))	('breast cancer', 'Disease', (109, 122))	('induce', 'Reg', (45, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('formation of binucleate cells in cardiomyocyte', 'CPA', (52, 98))	('localization', 'biological_process', 'GO:0051179', ('19', '31'))	('defect', 'Var', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
196349	28600503	Moreover, we found cell cycle was arrested at G2/M phase in J82 and 5637 cells after ANLN knockdown, and less ANLN protein gathered around the nucleus to promote nucleus division in immunofluorescence analysis.	('knockdown', 'Var', (90, 99))	('promote', 'PosReg', (154, 161))	('M phase', 'biological_process', 'GO:0000279', ('49', '56'))	('nucleus', 'cellular_component', 'GO:0005634', ('162', '169'))	('cell cycle', 'CPA', (19, 29))	('protein', 'Protein', (115, 122))	('nucleus', 'cellular_component', 'GO:0005634', ('143', '150'))	('cell cycle', 'biological_process', 'GO:0007049', ('19', '29'))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('J82', 'CellLine', 'CVCL:0359', (60, 63))	('nucleus division', 'CPA', (162, 178))
196350	28600503	Western-blot analysis suggested that the expression of cyclin B1 and D1 were decreased after ANLN knockdown, which could contribute to the G2/M cell cycle arrest.	('expression', 'MPA', (41, 51))	('knockdown', 'Var', (98, 107))	('G2/M cell cycle arrest', 'CPA', (139, 161))	('ANLN', 'Gene', (93, 97))	('contribute', 'Reg', (121, 131))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('144', '161'))	('cyclin B1 and D1', 'Gene', '891;595', (55, 71))	('cyclin', 'molecular_function', 'GO:0016538', ('55', '61'))	('decreased', 'NegReg', (77, 86))
196353	28600503	investigated the function of CENPF in hepatocellular carcinoma cells, and their results suggested that CENPF knockdown resulted in the cell cycle arrest at G2/M checkpoint by down-regulating cell cycle proteins cyclin B1.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (38, 62))	('cell cycle arrest at G2/M checkpoint', 'CPA', (135, 171))	('hepatocellular carcinoma', 'Disease', (38, 62))	('CENPF', 'Gene', '1063', (29, 34))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (38, 62))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('156', '171'))	('cell cycle', 'biological_process', 'GO:0007049', ('191', '201'))	('CENPF', 'Gene', (103, 108))	('knockdown', 'Var', (109, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('CENPF', 'Gene', '1063', (103, 108))	('cyclin', 'molecular_function', 'GO:0016538', ('211', '217'))	('down-regulating', 'NegReg', (175, 190))	('cyclin B1', 'Gene', (211, 220))	('cyclin B1', 'Gene', '891', (211, 220))	('CENPF', 'Gene', (29, 34))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('135', '152'))
196368	28600503	Primary antibodies were as follows: anti-ANLN (1:100), anti-F-actin (1:100, Abcam, ab130935).	('F-actin', 'Gene', '40444', (60, 67))	('F-actin', 'Gene', (60, 67))	('F-actin', 'cellular_component', 'GO:0031941', ('60', '67'))	('anti-ANLN', 'Var', (36, 45))
196375	28600503	Cells (3 x 104) were seeded in the upper compartment in serum-free medium 24 hours after siRNA transfection, and the lower chamber was filled with medium containing 15% fetal bovine serum.	('bovine', 'Species', '9913', (175, 181))	('siRNA', 'Gene', (89, 94))	('transfection', 'Var', (95, 107))
196387	25629698	The expression of eleven microRNAs (miR-10a, miR-21, miR-96, miR-135, miR-141, miR-182, miR-200b, miR-205, miR-429, miR-520b, miR-1244) formerly shown to be upregulated in urothelial bladder cancer were studied in corresponding normal and cancerous tissue samples of patients undergoing nephroureterectomy for UUTUC.	('miR-200b', 'Gene', (88, 96))	('miR-205', 'Gene', (98, 105))	('upregulated', 'PosReg', (157, 168))	('miR-135', 'Var', (61, 68))	('miR-520b', 'Gene', '574473', (116, 124))	('miR-10a', 'Gene', '406902', (36, 43))	('miR-182', 'Gene', (79, 86))	('miR-429', 'Gene', (107, 114))	('cancerous', 'Disease', 'MESH:D009369', (239, 248))	('miR-182', 'Gene', '406958', (79, 86))	('miR-135', 'Chemical', '-', (61, 68))	('patients', 'Species', '9606', (267, 275))	('miR-21', 'Gene', (45, 51))	('miR-1244', 'Gene', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('bladder cancer', 'Phenotype', 'HP:0009725', (183, 197))	('miR-200b', 'Gene', '406984', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('miR-10a', 'Gene', (36, 43))	('miR-141', 'Gene', '406933', (70, 77))	('cancerous', 'Disease', (239, 248))	('miR-96', 'Gene', (53, 59))	('miR-429', 'Gene', '554210', (107, 114))	('miR-205', 'Gene', '406988', (98, 105))	('miR-1244', 'Gene', '100302285', (126, 134))	('miR-141', 'Gene', (70, 77))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (172, 197))	('miR-96', 'Gene', '407053', (53, 59))	('miR-520b', 'Gene', (116, 124))	('urothelial bladder cancer', 'Disease', (172, 197))	('miR-21', 'Gene', '406991', (45, 51))
196389	25629698	MicroRNA expression allowed differentiation of normal and cancerous tissue: miR-21, miR-96, miR-135, miR-141, miR-182, miR-205, miR-429 and miR-520b were significantly overexpressed.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('miR-141', 'Gene', (101, 108))	('cancerous', 'Disease', 'MESH:D009369', (58, 67))	('miR-135', 'Var', (92, 99))	('miR-520b', 'Gene', '574473', (140, 148))	('miR-182', 'Gene', (110, 117))	('miR-135', 'Chemical', '-', (92, 99))	('miR-182', 'Gene', '406958', (110, 117))	('miR-205', 'Gene', (119, 126))	('miR-21', 'Gene', (76, 82))	('cancerous', 'Disease', (58, 67))	('miR-429', 'Gene', (128, 135))	('overexpressed', 'PosReg', (168, 181))	('miR-96', 'Gene', (84, 90))	('miR-96', 'Gene', '407053', (84, 90))	('miR-141', 'Gene', '406933', (101, 108))	('miR-205', 'Gene', '406988', (119, 126))	('miR-429', 'Gene', '554210', (128, 135))	('miR-520b', 'Gene', (140, 148))	('miR-21', 'Gene', '406991', (76, 82))
196404	25629698	In order to investigate the role of microRNAs as non-invasive biomarkers in patients with UUTUC, the expression of eleven microRNAs (miR-10a, miR-21, miR-96, miR-135, miR-141, miR-182, miR-200b, miR-205, miR-429, miR-520b, miR-1244) earlier shown to be upregulated in urothelial cancer of the bladder, was analyzed in corresponding normal ureter and UUTUC tissue.	('miR-182', 'Gene', '406958', (176, 183))	('upregulated', 'PosReg', (253, 264))	('miR-21', 'Gene', (142, 148))	('urothelial cancer of the bladder', 'Disease', 'MESH:D001749', (268, 300))	('miR-1244', 'Gene', (223, 231))	('miR-200b', 'Gene', '406984', (185, 193))	('miR-10a', 'Gene', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('miR-429', 'Gene', '554210', (204, 211))	('miR-96', 'Gene', (150, 156))	('miR-1244', 'Gene', '100302285', (223, 231))	('miR-141', 'Gene', '406933', (167, 174))	('miR-205', 'Gene', '406988', (195, 202))	('patients', 'Species', '9606', (76, 84))	('miR-135', 'Var', (158, 165))	('urothelial cancer of the bladder', 'Disease', (268, 300))	('miR-141', 'Gene', (167, 174))	('miR-96', 'Gene', '407053', (150, 156))	('miR-520b', 'Gene', (213, 221))	('miR-135', 'Chemical', '-', (158, 165))	('miR-21', 'Gene', '406991', (142, 148))	('cancer of the bladder', 'Phenotype', 'HP:0009725', (279, 300))	('miR-200b', 'Gene', (185, 193))	('miR-205', 'Gene', (195, 202))	('miR-520b', 'Gene', '574473', (213, 221))	('miR-10a', 'Gene', '406902', (133, 140))	('miR-182', 'Gene', (176, 183))	('miR-429', 'Gene', (204, 211))
196427	25629698	We observed a significant overexpression of miR-21, miR-96, miR-135, miR-141, miR-182, miR-205, miR-429, miR-520b (all p<0.001) in UUTUC; the microRNAs miR-10a (p = 0.012) and miR-200b (p = 0.006) showed a distinct trend towards upregulation, whereas miR-1244 (p = 0.600) was similar in normal and malignant tissue.	('miR-200b', 'Gene', (176, 184))	('miR-135', 'Var', (60, 67))	('miR-21', 'Gene', '406991', (44, 50))	('miR-520b', 'Gene', (105, 113))	('miR-135', 'Chemical', '-', (60, 67))	('miR-520b', 'Gene', '574473', (105, 113))	('miR-182', 'Gene', (78, 85))	('upregulation', 'PosReg', (229, 241))	('miR-1244', 'Gene', (251, 259))	('miR-182', 'Gene', '406958', (78, 85))	('miR-429', 'Gene', (96, 103))	('miR-200b', 'Gene', '406984', (176, 184))	('miR-205', 'Gene', (87, 94))	('miR-21', 'Gene', (44, 50))	('overexpression', 'PosReg', (26, 40))	('miR-10a', 'Gene', '406902', (152, 159))	('miR-1244', 'Gene', '100302285', (251, 259))	('miR-96', 'Gene', (52, 58))	('miR-141', 'Gene', '406933', (69, 76))	('miR-429', 'Gene', '554210', (96, 103))	('miR-96', 'Gene', '407053', (52, 58))	('miR-141', 'Gene', (69, 76))	('miR-205', 'Gene', '406988', (87, 94))	('miR-10a', 'Gene', (152, 159))
196433	25629698	miR-182 (p = 0.083), miR-21 (p = 0.532) and miR-135 (p = 0.261) were similar in UUTUC patients and controls.	('miR-135', 'Var', (44, 51))	('miR-21', 'Gene', (21, 27))	('miR-182', 'Gene', (0, 7))	('miR-21', 'Gene', '406991', (21, 27))	('miR-182', 'Gene', '406958', (0, 7))	('miR-135', 'Chemical', '-', (44, 51))	('patients', 'Species', '9606', (86, 94))
196439	25629698	Especially miR-21, miR-96, miR-135, miR-141, miR-182, miR-205, miR-429 and miR-520b were distinctly overexpressed in UUTUC.	('miR-205', 'Gene', (54, 61))	('miR-141', 'Gene', (36, 43))	('overexpressed', 'PosReg', (100, 113))	('miR-21', 'Gene', (11, 17))	('miR-205', 'Gene', '406988', (54, 61))	('miR-520b', 'Gene', '574473', (75, 83))	('miR-96', 'Gene', (19, 25))	('miR-182', 'Gene', (45, 52))	('miR-96', 'Gene', '407053', (19, 25))	('miR-429', 'Gene', '554210', (63, 70))	('miR-135', 'Chemical', '-', (27, 34))	('miR-141', 'Gene', '406933', (36, 43))	('miR-429', 'Gene', (63, 70))	('miR-520b', 'Gene', (75, 83))	('miR-135', 'Var', (27, 34))	('miR-182', 'Gene', '406958', (45, 52))	('miR-21', 'Gene', '406991', (11, 17))
196454	25629698	Tumor grade and stage are usually correlated in urothelial cancer, and thus one would expect significant correlations with stage (miR-205) or grade (miR-10a, miR-135), respectively.	('miR-135', 'Chemical', '-', (158, 165))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('miR-10a', 'Gene', '406902', (149, 156))	('miR-205', 'Gene', (130, 137))	('correlations', 'Reg', (105, 117))	('miR-135', 'Var', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('miR-205', 'Gene', '406988', (130, 137))	('urothelial cancer', 'Disease', (48, 65))	('miR-10a', 'Gene', (149, 156))	('urothelial cancer', 'Disease', 'MESH:D014523', (48, 65))
196465	25629698	The sample size in our study was only moderate (47 cancer vs. 36 normal tissues; and 44 UUTUC vs. 34 control serum samples), but the relative rarity of UUTUC compared to bladder cancer or renal cell carcinoma make the analysis of large cohorts difficult.	('bladder cancer', 'Disease', 'MESH:D001749', (170, 184))	('bladder cancer', 'Disease', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('UUTUC', 'Var', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('renal cell carcinoma', 'Disease', (188, 208))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('bladder cancer', 'Phenotype', 'HP:0009725', (170, 184))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (188, 208))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (188, 208))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
196540	33588785	The overall concordance for genomic alterations in ctDNA and matched tumor tissue was 42.97% (0-100%).	('tumor', 'Disease', (69, 74))	('genomic alterations', 'Var', (28, 47))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
196564	33588785	After duplicate removal and local realignment, we applied Genome Analysis Toolkit (GATK) to identify single nucleotide variation (SNV), insertion and deletion (inDel).	('kit', 'Gene', (78, 81))	('single nucleotide variation', 'Var', (101, 128))	('kit', 'Gene', '3815', (78, 81))	('deletion', 'Var', (150, 158))
196574	33588785	After excluding the variants identified as benign or likely benign according to the American College of Medical Genetics and Genomics (ACMG) guideline, 244 germline variants were identified, and 75.89% (85/112) of patients in our cohort harbored at least one germline alteration (Supplemental Table 3).	('harbored', 'Reg', (237, 245))	('variants', 'Var', (20, 28))	('patients', 'Species', '9606', (214, 222))
196575	33588785	However, only two patients (1.85%) had variants that could be classified as pathogenic or likely pathogenic (ERCC4 p.Lys481fs and BRCA2 p.Thr3030fs).	('p.Thr3030fs', 'Mutation', 'rs886040818', (136, 147))	('ERCC4', 'Gene', (109, 114))	('p.Thr3030fs', 'Var', (136, 147))	('p.Lys481fs', 'Mutation', 'p.K481fsX', (115, 125))	('ERCC4', 'Gene', '2072', (109, 114))	('BRCA2', 'Gene', (130, 135))	('patients', 'Species', '9606', (18, 26))	('p.Lys481fs', 'Var', (115, 125))	('BRCA2', 'Gene', '675', (130, 135))
196576	33588785	The patient harbored a deleterious BRCA2 germline variant was also concurrent with prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (83, 98))	('germline', 'Var', (41, 49))	('BRCA2', 'Gene', '675', (35, 40))	('patient', 'Species', '9606', (4, 11))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('concurrent', 'Reg', (67, 77))	('prostate cancer', 'Disease', (83, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('BRCA2', 'Gene', (35, 40))
196579	33588785	The prevalence of alterations in FGFR4, KDM5C, TERT, PDGFRB, FLT3, FLCN, MSH6, FLT1 were higher in the 81 UCB cases in our cohort, compared with the TCGA cohort (Fig.	('TERT', 'Gene', (47, 51))	('TERT', 'Gene', '7015', (47, 51))	('KDM5C', 'Gene', (40, 45))	('PDGFRB', 'Gene', '5159', (53, 59))	('FGFR4', 'Gene', '2264', (33, 38))	('PDGFRB', 'Gene', (53, 59))	('FLT3', 'Gene', (61, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('FLT1', 'Gene', (79, 83))	('FLT3', 'Gene', '2322', (61, 65))	('FLT1', 'Gene', '2321', (79, 83))	('FGFR4', 'Gene', (33, 38))	('alterations', 'Var', (18, 29))	('FLCN', 'Gene', '201163', (67, 71))	('UCB', 'Disease', (106, 109))	('KDM5C', 'Gene', '8242', (40, 45))	('FLCN', 'Gene', (67, 71))	('MSH6', 'Gene', (73, 77))	('MSH6', 'Gene', '2956', (73, 77))	('higher', 'PosReg', (89, 95))
196581	33588785	On the contrary, the prevalence of FGFR3 alteration in the MSKCC cohort was three times higher than that in our cohort (48.24% versus 16.13%, p < 0.001).	('higher', 'PosReg', (88, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR3', 'Gene', '2261', (35, 40))	('alteration', 'Var', (41, 51))	('FGFR3', 'Gene', (35, 40))	('MSKCC', 'Disease', (59, 64))
196582	33588785	The genomic features of UCB and UTUC were similar, while KMT2D (34.57% vs 64.52%, p < 0.01), HRAS (3.7% vs 19.35%, p < 0.01) and CDKN2A (2.47% vs 12.9%, p < 0.05) were significantly more mutated in UTUC than in UCB (Fig.	('HRAS', 'Gene', '3265', (93, 97))	('KMT2D', 'Gene', (57, 62))	('KMT2D', 'Gene', '8085', (57, 62))	('mutated', 'Var', (187, 194))	('CDKN2A', 'Gene', (129, 135))	('UTUC', 'Disease', (198, 202))	('HRAS', 'Gene', (93, 97))	('CDKN2A', 'Gene', '1029', (129, 135))
196584	33588785	Although 28.57% (32/112) UC cases in our cohort had at least one somatic alteration in FGFR genes (including FGFR1, FGFR2, FGFR3 and FGFR4), only 11 cases contained alternations that could be annotated as gain of function (Fig.	('FGFR3', 'Gene', '2261', (123, 128))	('FGFR', 'molecular_function', 'GO:0005007', ('116', '120'))	('FGFR1', 'Gene', (109, 114))	('FGFR', 'molecular_function', 'GO:0005007', ('109', '113'))	('FGFR2', 'Gene', '2263', (116, 121))	('FGFR3', 'Gene', (123, 128))	('FGFR1', 'Gene', '2260', (109, 114))	('FGFR4', 'Gene', '2264', (133, 138))	('FGFR4', 'Gene', (133, 138))	('FGFR', 'molecular_function', 'GO:0005007', ('133', '137'))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('FGFR2', 'Gene', (116, 121))	('FGFR', 'molecular_function', 'GO:0005007', ('123', '127'))	('alteration', 'Var', (73, 83))	('gain of function', 'PosReg', (205, 221))	('FGFR genes', 'Gene', (87, 97))
196586	33588785	Hotspot variants, including FGFR3-p.Ser249Cys, p.Arg248Cys and p.Tyr373Cys were present in six samples, while FGFR3-TACC3 fusion was only identified in two patients.	('p.Arg248Cys', 'Var', (47, 58))	('patients', 'Species', '9606', (156, 164))	('TACC3', 'Gene', (116, 121))	('p.Ser249Cys', 'Mutation', 'rs121913483', (34, 45))	('FGFR3', 'Gene', '2261', (28, 33))	('FGFR', 'molecular_function', 'GO:0005007', ('110', '114'))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('Ser', 'cellular_component', 'GO:0005790', ('36', '39'))	('p.Arg248Cys', 'Mutation', 'rs121913482', (47, 58))	('FGFR3', 'Gene', '2261', (110, 115))	('FGFR3', 'Gene', (28, 33))	('p.Tyr373Cys', 'Mutation', 'rs121913485', (63, 74))	('TACC3', 'Gene', '10460', (116, 121))	('FGFR3', 'Gene', (110, 115))	('p.Tyr373Cys', 'Var', (63, 74))
196587	33588785	Three novel variants (defined as unreported in literature or SNP databases and without ExAC frequency), including p.His349Asn, p.Val166Met and p.Thr755Lys of FGFR3 were identified, though their functions were still unknown (Fig.	('p.Val166Met', 'Mutation', 'rs1219348193', (127, 138))	('p.Thr755Lys', 'Mutation', 'p.T755K', (143, 154))	('p.Thr755Lys', 'Var', (143, 154))	('p.Val166Met', 'Var', (127, 138))	('p.His349Asn', 'Mutation', 'p.H349N', (114, 125))	('FGFR', 'molecular_function', 'GO:0005007', ('158', '162'))	('FGFR3', 'Gene', (158, 163))	('p.His349Asn', 'Var', (114, 125))	('FGFR3', 'Gene', '2261', (158, 163))
196588	33588785	Nine patients (8.04%) were identified with FGFR2 alterations, of which only three alterations could be defined as oncogenic, including one p.Asn549Lys, one p.Lys659Met and one copy number gain (32.87 copies).	('p.Asn549Lys', 'Mutation', 'rs121913476', (139, 150))	('alterations', 'Var', (49, 60))	('patients', 'Species', '9606', (5, 13))	('p.Lys659Met', 'Var', (156, 167))	('p.Lys659Met', 'Mutation', 'p.K659M', (156, 167))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('FGFR2', 'Gene', (43, 48))	('FGFR2', 'Gene', '2263', (43, 48))	('p.Asn549Lys', 'Var', (139, 150))
196590	33588785	Four novel variants with unknown function, including p.Gly305Arg, p.Tyr207Phe, p.Met803Leu and p.Gln683Ter in FGFR2 were identified in this study.	('p.Met803Leu', 'Mutation', 'p.M803L', (79, 90))	('Ter', 'cellular_component', 'GO:0097047', ('103', '106'))	('FGFR2', 'Gene', (110, 115))	('FGFR2', 'Gene', '2263', (110, 115))	('FGFR', 'molecular_function', 'GO:0005007', ('110', '114'))	('p.Gln683Ter', 'Mutation', 'p.Q683X', (95, 106))	('p.Gly305Arg', 'Mutation', 'p.G305R', (53, 64))	('p.Tyr207Phe', 'Mutation', 'p.Y207F', (66, 77))	('p.Gln683Ter', 'Var', (95, 106))	('p.Tyr207Phe', 'Var', (66, 77))	('p.Met803Leu', 'Var', (79, 90))	('p.Gly305Arg', 'Var', (53, 64))
196592	33588785	Eight patients (all were bladder cancer) carried nonsynonymous single nucleotide variants with unknown function in FGFR4.	('carried', 'Reg', (41, 48))	('FGFR', 'molecular_function', 'GO:0005007', ('115', '119'))	('FGFR4', 'Gene', '2264', (115, 120))	('FGFR4', 'Gene', (115, 120))	('bladder cancer', 'Phenotype', 'HP:0009725', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('patients', 'Species', '9606', (6, 14))	('nonsynonymous single nucleotide variants', 'Var', (49, 89))	('bladder cancer', 'Disease', 'MESH:D001749', (25, 39))	('bladder cancer', 'Disease', (25, 39))
196595	33588785	Notably, one patient had an activated EGFR exon 20 insertion (EGFR-p.Val769_Asp770insAspAsnPro) and copy number gain.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('EGFR', 'Gene', '1956', (62, 66))	('patient', 'Species', '9606', (13, 20))	('EGFR', 'Gene', (38, 42))	('EGFR', 'Gene', (62, 66))	('p.Val769_Asp770insAspAsnPro', 'Var', (67, 94))	('p.Val769_Asp770insAspAsnPro', 'INSERTION', 'None', (67, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('copy number', 'Var', (100, 111))	('gain', 'PosReg', (112, 116))
196597	33588785	Two of the five identified ERBB3 alterations were in the furin-like cysteine rich region (amino acid 182-332) and oncogenic.	('ERBB3', 'Gene', '2065', (27, 32))	('ERBB3', 'Gene', (27, 32))	('alterations', 'Var', (33, 44))	('amino acid', 'Var', (90, 100))	('furin', 'Gene', '5045', (57, 62))	('cysteine', 'Chemical', 'MESH:D003545', (68, 76))	('furin', 'Gene', (57, 62))
196600	33588785	The most frequently mutated DDR genes were BRCA2 (10.71%), ATM (9.82%), ERCC2 (8.93%), BRCA1 (7.14%) and BRIP1 (6.25%), respectively (Fig.	('ERCC2', 'Gene', '2068', (72, 77))	('BRCA1', 'Gene', '672', (87, 92))	('ERCC2', 'Gene', (72, 77))	('DDR genes', 'Gene', (28, 37))	('BRIP1', 'Gene', (105, 110))	('BRCA1', 'Gene', (87, 92))	('BRCA2', 'Gene', (43, 48))	('BRCA2', 'Gene', '675', (43, 48))	('ATM', 'Gene', (59, 62))	('BRIP1', 'Gene', '83990', (105, 110))	('mutated', 'Var', (20, 27))	('ATM', 'Gene', '472', (59, 62))
196601	33588785	Among patients who carried DDR gene alterations, only 16 of them (14.29%) had at least one known or likely deleterious somatic DDR alterations (Fig.	('patients', 'Species', '9606', (6, 14))	('alterations', 'Var', (36, 47))	('DDR gene', 'Gene', (27, 35))
196602	33588785	4c), and the most frequently mutated DDR genes with known or likely deleterious variants were ATM (n = 7, 31.82%) and BRCA2 (n = 5, 22.73%).	('ATM', 'Gene', '472', (94, 97))	('BRCA2', 'Gene', (118, 123))	('DDR genes', 'Gene', (37, 46))	('variants', 'Var', (80, 88))	('BRCA2', 'Gene', '675', (118, 123))	('ATM', 'Gene', (94, 97))
196604	33588785	The majority of these MMR gene alterations were unknown of function, and only four alterations in MSH2 and MLH1 could be annotated as loss of function.	('MMR gene', 'Gene', (22, 30))	('alterations', 'Var', (31, 42))	('MSH2', 'Gene', (98, 102))	('MSH2', 'Gene', '4436', (98, 102))	('MMR', 'biological_process', 'GO:0006298', ('22', '25'))	('MLH1', 'Gene', '4292', (107, 111))	('MLH1', 'Gene', (107, 111))
196606	33588785	The cfDNA abundance and ctDNA fraction was calculated according to the method described by Annala Matti, et al.. Only three patients' matched samples were collected with an interval time of more than 1 month (7 months for P074, 18 months for P084 and 34 months for P110, respectively).	('P084', 'Var', (242, 246))	('P074', 'Var', (222, 226))	('patients', 'Species', '9606', (124, 132))
196609	33588785	Conversely, in Patient 20, ctDNA analysis revealed oncogenic mutations in PIK3CA, TP53, ARID1A and KDM6A with allele fractions beyond 3%, but no corresponding valid alteration was found in the matched tissue sample (Fig.	('TP53', 'Gene', (82, 86))	('PIK3CA', 'Gene', '5290', (74, 80))	('KDM6A', 'Gene', '7403', (99, 104))	('ARID1A', 'Gene', (88, 94))	('mutations', 'Var', (61, 70))	('Patient', 'Species', '9606', (15, 22))	('TP53', 'Gene', '7157', (82, 86))	('ARID1A', 'Gene', '8289', (88, 94))	('KDM6A', 'Gene', (99, 104))	('PIK3CA', 'Gene', (74, 80))
196610	33588785	By comparison of blood and matched tumor tissue, the overall concordances for genomic alterations and altered genes identified in matched samples were 42.97% (0-100%) and 46.83% (0-100%), respectively (Table 2).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('genomic alterations', 'Var', (78, 97))
196612	33588785	Specifically, 11 of them (25.58%) were oncogenic mutations and 3 (6.98%) could be identified as actionable, including a PIK3CA activated hot-spot, a PTEN frameshift and a KDM6A frameshift mutation.	('PIK3CA', 'Gene', (120, 126))	('PTEN', 'Gene', (149, 153))	('KDM6A', 'Gene', '7403', (171, 176))	('PTEN', 'Gene', '5728', (149, 153))	('PIK3CA', 'Gene', '5290', (120, 126))	('frameshift', 'Var', (154, 164))	('frameshift mutation', 'Var', (177, 196))	('KDM6A', 'Gene', (171, 176))
196615	33588785	However, because of more possibility of aristolochic acid exposure, many Chinese UC patients, especially UTUC, tend to have chronic kidney disease as well, which made them unfit for platinum treatment.	('chronic kidney disease', 'Disease', (124, 146))	('platinum', 'Chemical', 'MESH:D010984', (182, 190))	('patients', 'Species', '9606', (84, 92))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (124, 146))	('chronic kidney disease', 'Disease', 'MESH:D051436', (124, 146))	('kidney disease', 'Phenotype', 'HP:0000112', (132, 146))	('aristolochic acid', 'Chemical', 'MESH:C000228', (40, 57))	('aristolochic acid', 'Var', (40, 57))
196618	33588785	Currently, activating mutations in FGFR2 and FGFR3 genes were actionable with highest level of evidence in UC, especially for UTUC, as erdafitinib (a FGFR inhibitor) was proved to have a 40% objective response rate in previously treated locally advanced and unresectable or metastatic UC with FGFR2/3 alterations.	('FGFR2/3', 'Gene', '2263;2261', (293, 300))	('FGFR2/3', 'Gene', (293, 300))	('FGFR3', 'Gene', '2261', (45, 50))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGFR2', 'Gene', (35, 40))	('FGFR2', 'Gene', '2263', (35, 40))	('FGFR2', 'Gene', (293, 298))	('FGFR2', 'Gene', '2263', (293, 298))	('FGFR', 'molecular_function', 'GO:0005007', ('150', '154'))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('mutations', 'Var', (22, 31))	('FGFR3', 'Gene', (45, 50))	('erdafitinib', 'Chemical', 'MESH:C000604580', (135, 146))	('locally advanced', 'Disease', (237, 253))	('FGFR', 'molecular_function', 'GO:0005007', ('293', '297'))	('metastatic UC', 'Disease', (274, 287))
196619	33588785	We identified FGFRs alterations in 26.85% of UC patients, which was close to the corresponding ratio reported in the TCGA database.	('alterations', 'Var', (20, 31))	('patients', 'Species', '9606', (48, 56))	('FGFRs', 'Gene', (14, 19))
196620	33588785	Although they may be associated with increased sensitivity to FGFR inhibitors, UC patients with FGFR alterations were reported to have a lower response rate to the ICIs therapy because of the suppressed infiltration of immune cells in the tumor microenvironment.	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('alterations', 'Var', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('lower', 'NegReg', (137, 142))	('FGFR', 'Gene', (96, 100))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('response', 'MPA', (143, 151))	('tumor', 'Disease', (239, 244))	('infiltration', 'CPA', (203, 215))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))
196621	33588785	Alterations in ERBB pathway, especially ERBB2/HER2 in UC, raised increasing research interest recently, as 12.4 and 11% UCB patients were reported to have ERBB2 overexpressing (as shown by positive HER2 immunohistochemistry staining) or activating mutations, respectively.	('overexpressing', 'PosReg', (161, 175))	('Alterations', 'Var', (0, 11))	('patients', 'Species', '9606', (124, 132))	('ERBB', 'Gene', (155, 159))	('ERBB2', 'Gene', (40, 45))	('HER2', 'Gene', '2064', (46, 50))	('ERBB', 'Gene', '1956', (155, 159))	('HER2', 'Gene', '2064', (198, 202))	('ERBB', 'Gene', (40, 44))	('ERBB2', 'Gene', '2064', (40, 45))	('activating', 'MPA', (237, 247))	('ERBB', 'Gene', '1956', (40, 44))	('ERBB2', 'Gene', (155, 160))	('ERBB', 'Gene', (15, 19))	('HER2', 'Gene', (46, 50))	('HER2', 'Gene', (198, 202))	('ERBB', 'Gene', '1956', (15, 19))	('UCB', 'Disease', (120, 123))	('ERBB2', 'Gene', '2064', (155, 160))
196623	33588785	An interesting correlation between ERBB2 gene mutations and a higher probability in response to platinum-based neoadjuvant chemotherapy was found in 61 muscle-invasive UCB.	('response to platinum', 'biological_process', 'GO:0070541', ('84', '104'))	('mutations', 'Var', (46, 55))	('muscle-invasive UCB', 'Disease', (152, 171))	('ERBB2', 'Gene', (35, 40))	('ERBB2', 'Gene', '2064', (35, 40))	('platinum', 'Chemical', 'MESH:D010984', (96, 104))
196625	33588785	Other anti-HER2 therapies, such as tyrosine kinase inhibitors, antibodies and antibody-drug conjugate, had been under development for UC patients with abnormal ERBB2.	('ERBB2', 'Gene', '2064', (160, 165))	('antibody', 'cellular_component', 'GO:0019814', ('78', '86'))	('antibody', 'molecular_function', 'GO:0003823', ('78', '86'))	('ERBB2', 'Gene', (160, 165))	('patients', 'Species', '9606', (137, 145))	('antibody', 'cellular_component', 'GO:0019815', ('78', '86'))	('antibody', 'cellular_component', 'GO:0042571', ('78', '86'))	('HER2', 'Gene', (11, 15))	('abnormal', 'Var', (151, 159))	('HER2', 'Gene', '2064', (11, 15))
196626	33588785	DDR alterations had been reported to be associated with a higher response rate and increased clinical benefit for immune checkpoint inhibitors (ICIs), platinum-based neoadjuvant therapy and first-line chemotherapy in UC patients.	('alterations', 'Var', (4, 15))	('DDR', 'Gene', (0, 3))	('patients', 'Species', '9606', (220, 228))	('platinum', 'Chemical', 'MESH:D010984', (151, 159))	('response', 'MPA', (65, 73))
196629	33588785	In addition to ICIs, tumors with deleterious DDR gene mutations, especially BRCA1/2 genes, were also associated with higher sensitivities to poly (ADP ribose) polymerase inhibitors (PARPi) in pan-cancers.	('DDR gene', 'Gene', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('BRCA1/2', 'Gene', (76, 83))	('mutations', 'Var', (54, 63))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('BRCA1/2', 'Gene', '672;675', (76, 83))	('cancers', 'Disease', (196, 203))	('higher', 'PosReg', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
196631	33588785	The prevalence of germline mutations of cancer susceptibility genes in patients with sporadic UC was conflicting.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('patients', 'Species', '9606', (71, 79))	('germline', 'Var', (18, 26))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
196632	33588785	Although previous studies established that UC was rarely associated with cancer susceptibility genes alterations, the latest research found that 14% of 586 unselected UC patients carried pathogenic or likely pathogenic germline variants, and 11.26% (66/586) had deleterious variants in the DNA repair pathway.	('patients', 'Species', '9606', (170, 178))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('pathogenic', 'Reg', (187, 197))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('DNA repair pathway', 'Pathway', (290, 308))	('variants', 'Var', (274, 282))	('DNA', 'cellular_component', 'GO:0005574', ('290', '293'))	('DNA repair', 'biological_process', 'GO:0006281', ('290', '300'))
196634	33588785	In our cohort, only 1.79% of patients had pathogenic or likely pathogenic germline variants, which may represent a low prevalence of cancer susceptibility genes in Chinese UC patients compared to the corresponding Caucasian patients.	('patients', 'Species', '9606', (29, 37))	('variants', 'Var', (83, 91))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('patients', 'Species', '9606', (175, 183))	('patients', 'Species', '9606', (224, 232))	('pathogenic', 'Reg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('pathogenic', 'Reg', (63, 73))
196636	33588785	Previously, ERCC4 gene mutations were identified in Fanconi anemia, skin-photosensitive nucleotide excision repair (NER)-deficient disorder xeroderma pigmentosum, and XFE progeroid syndrome.	('ERCC4', 'Gene', (12, 17))	('identified', 'Reg', (38, 48))	('ERCC4', 'Gene', '2072', (12, 17))	('skin-photosensitive', 'Phenotype', 'HP:0000992', (68, 87))	('Fanconi anemia', 'Disease', 'MESH:D005199', (52, 66))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('88', '114'))	('deficient disorder xeroderma pigmentosum', 'Disease', (121, 161))	('mutations', 'Var', (23, 32))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (52, 66))	('NER', 'biological_process', 'GO:0006289', ('116', '119'))	('anemia', 'Phenotype', 'HP:0001903', (60, 66))	('XFE progeroid syndrome', 'Disease', (167, 189))	('Fanconi anemia', 'Disease', (52, 66))	('deficient disorder xeroderma pigmentosum', 'Disease', 'MESH:D014983', (121, 161))
196638	33588785	Our study is the first to report germline mutations in ERCC4.	('ERCC4', 'Gene', '2072', (55, 60))	('germline', 'Var', (33, 41))	('ERCC4', 'Gene', (55, 60))
196640	33588785	In the present research, no germline variant in mismatch repair pathway was found, potentially due to the different genetic backgrounds between Chinese and Western UC patients, limited UTUC patients enrolled and technology limitations (such as lack of detecion in MLH1 promoter hypermethylation and large rearrangements).	('patients', 'Species', '9606', (190, 198))	('patients', 'Species', '9606', (167, 175))	('MLH1', 'Gene', '4292', (264, 268))	('MLH1', 'Gene', (264, 268))	('rearrangements', 'Var', (305, 319))	('mismatch repair', 'biological_process', 'GO:0006298', ('48', '63'))
196666	33221763	Alterations in lncRNA expression and mutations are closely associated with tumorigenesis, tumor progression and metastasis, highlighting the emerging roles of lncRNAs as novel biomarkers and therapeutic targets for cancer.	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('Alterations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('metastasis', 'CPA', (112, 122))	('associated', 'Reg', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('lncRNA', 'Gene', (15, 21))	('expression', 'MPA', (22, 32))	('tumor', 'Disease', (75, 80))
196680	33221763	Higher expression of MIR181A2HG (HR: 0.77 [95%CI 0.67-0.88], p<0.001), AC114730.3 (HR: 0.82 [95%CI 0.69-0.97], p=0.017) and LINC00892 (HR: 0.76 [95%CI 0.67-0.87], p<0.001) tended to predict increased survival, while higher expression of PTPRD-AS1 (HR: 1.13 [95%CI 1.01-1.27], p=0.036), LINC01013 (HR: 1.17 [95%CI 1.02-1.34], p=0.022), MRPL23-AS1 (HR: 1.12 [95%CI 1.03-1.22], p=0.007), LINC01395 (HR: 1.20 [95%CI 1.06-1.36], p=0.003) and AC002454.1 (HR: 1.13 [95%CI 1.00-1.28], p=0.046) tended to predict decreased survival.	('MIR181A2HG', 'Gene', (21, 31))	('LINC01013', 'Gene', '100507254', (286, 295))	('LINC01395', 'Gene', (385, 394))	('AS1', 'Gene', (243, 246))	('LINC01013', 'Gene', (286, 295))	('AS1', 'Gene', '5729', (342, 345))	('LINC00892', 'Gene', (124, 133))	('LINC00892', 'Gene', '100128420', (124, 133))	('MRPL23', 'Gene', (335, 341))	('AC114730.3', 'Var', (71, 81))	('survival', 'MPA', (514, 522))	('PTPRD-AS1', 'Gene', '101929407', (237, 246))	('AC002454.1', 'Var', (437, 447))	('MRPL23', 'Gene', '6150', (335, 341))	('MIR181A2HG', 'Gene', '100379345', (21, 31))	('LINC01395', 'Gene', '101929557', (385, 394))	('increased', 'PosReg', (190, 199))	('AS1', 'Gene', '5729', (243, 246))	('AS1', 'Gene', (342, 345))	('PTPRD-AS1', 'Gene', (237, 246))	('survival', 'CPA', (200, 208))	('decreased', 'NegReg', (504, 513))
196683	33221763	Moreover, MIR181A2HG, AC114730.3 and LINC00892 were highly expressed in the low-risk group, while PTPRD-AS1, LINC01013, MRPL23-AS1, LINC01395 and AC002454.1 were highly expressed in the high-risk group (Figure 3C).	('LINC00892', 'Gene', (37, 46))	('AC114730.3', 'Var', (22, 32))	('AS1', 'Gene', '5729', (104, 107))	('PTPRD-AS1', 'Gene', '101929407', (98, 107))	('PTPRD-AS1', 'Gene', (98, 107))	('LINC00892', 'Gene', '100128420', (37, 46))	('MIR181A2HG', 'Gene', '100379345', (10, 20))	('LINC01013', 'Gene', '100507254', (109, 118))	('LINC01395', 'Gene', (132, 141))	('MRPL23', 'Gene', (120, 126))	('AS1', 'Gene', (104, 107))	('AS1', 'Gene', (127, 130))	('AS1', 'Gene', '5729', (127, 130))	('LINC01395', 'Gene', '101929557', (132, 141))	('MRPL23', 'Gene', '6150', (120, 126))	('MIR181A2HG', 'Gene', (10, 20))	('LINC01013', 'Gene', (109, 118))
196697	33221763	In the high-risk group, the proportions of CD8 T cells (0.1105 vs 0.1371, p=0.014) and regulatory T cells (0.0207 vs 0.0384, p<0.001) were decreased, while the proportions of M0 macrophages (0.0764 vs 0.040, p=0.009), M2 macrophages (0.2323 vs 0.1880, p=0.002) and neutrophils (0.0075 vs 0.0031, p=0.009) were increased compared with those in the low-risk group (Figure 8C).	('CD8', 'Gene', (43, 46))	('0.0207', 'Var', (107, 113))	('increased', 'PosReg', (310, 319))	('age', 'Gene', '5973', (228, 231))	('CD8', 'Gene', '925', (43, 46))	('neutrophils', 'CPA', (265, 276))	('decreased', 'NegReg', (139, 148))	('age', 'Gene', (185, 188))	('age', 'Gene', '5973', (185, 188))	('age', 'Gene', (228, 231))	('regulatory T cells', 'CPA', (87, 105))
196698	33221763	Among these cells, low CD8 T cell infiltration was associated with low OS (Figure 8D, p=0.011) while high macrophage M2 cell infiltration was associated with low OS (Figure 8E, p=0.046).	('CD8', 'Gene', (23, 26))	('age', 'Gene', (113, 116))	('CD8', 'Gene', '925', (23, 26))	('low OS', 'Disease', (67, 73))	('low', 'Var', (19, 22))	('age', 'Gene', '5973', (113, 116))	('low CD8 T cell infiltration', 'Phenotype', 'HP:0005415', (19, 46))
196704	33221763	TMB was also a predictive biomarker for immunotherapy, and a high TMB suggested a high response rate to immunotherapy.	('TMB', 'Chemical', '-', (0, 3))	('TMB', 'Gene', (66, 69))	('high', 'Var', (61, 65))	('TMB', 'Chemical', '-', (66, 69))
196730	33221763	High TMB and neoantigen load were associated with a high response to ICIs.	('High', 'Var', (0, 4))	('TMB', 'Chemical', '-', (5, 8))	('neoantigen load', 'Var', (13, 28))
196768	32351666	Radical cystectomy (RC) is recommended in T2-T4aN0M0 and high-risk non-muscle invasive bladder cancer.	('invasive bladder', 'Phenotype', 'HP:0100645', (78, 94))	('muscle invasive bladder cancer', 'Disease', (71, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('men', 'Species', '9606', (32, 35))	('-muscle invasive bladder cancer', 'Phenotype', 'HP:0006740', (70, 101))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (67, 94))	('T2-T4aN0M0', 'Var', (42, 52))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (71, 101))
196822	32351666	Another reason for the gender disparity is that BC is usually the result of environmental carcinogens, whereas UTUC is often the result of genetic problems such as microsatellite instability.	('UTUC', 'Chemical', '-', (111, 115))	('result', 'Reg', (129, 135))	('men', 'Species', '9606', (83, 86))	('result', 'Reg', (66, 72))	('microsatellite instability', 'Var', (164, 190))	('BC', 'Phenotype', 'HP:0009725', (48, 50))
196828	32351666	Genetic variability in both malignancies might play a fundamental role in different outcomes, which have to be elucidated by continued research.	('Genetic variability', 'Var', (0, 19))	('malignancies', 'Disease', 'MESH:D009369', (28, 40))	('play', 'Reg', (47, 51))	('malignancies', 'Disease', (28, 40))	('men', 'Species', '9606', (59, 62))
196830	32351666	A meta-analysis showed that UTUC had specific etiologies (e.g., Balkan nephropathy and phenacetin abuse) and genetic hereditary nonpolyposis colorectal cancer risk factors, microsatellite instability, and epigenetic hypermethylation compared with BC.	('genetic hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (109, 158))	('genetic hereditary nonpolyposis colorectal cancer', 'Disease', (109, 158))	('epigenetic hypermethylation', 'Var', (205, 232))	('phenacetin', 'Chemical', 'MESH:D010615', (87, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('microsatellite instability', 'Var', (173, 199))	('Balkan nephropathy', 'Disease', 'MESH:D007674', (64, 82))	('Balkan nephropathy', 'Disease', (64, 82))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('BC', 'Phenotype', 'HP:0009725', (247, 249))	('nephropathy', 'Phenotype', 'HP:0000112', (71, 82))	('UTUC', 'Chemical', '-', (28, 32))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (117, 158))
196833	32351666	Another research also reported that high MSI indicates a better prognosis, especially in patients younger than 71 years with stage T2-T3N0M0.	('MSI', 'Gene', '5928', (41, 44))	('MSI', 'Gene', (41, 44))	('patients', 'Species', '9606', (89, 97))	('high', 'Var', (36, 40))
196861	32158343	High expression of ISL1 is also associated with the depth of tumour invasion, lymph node metastasis, the histological grade of the tumour and poor survival in gastric cancer patients.	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('ISL1', 'Gene', (19, 23))	('tumour', 'Disease', (61, 67))	('poor survival', 'CPA', (142, 155))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('associated', 'Reg', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('gastric cancer', 'Disease', 'MESH:D013274', (159, 173))	('tumour', 'Disease', (131, 137))	('High', 'Var', (0, 4))	('lymph node metastasis', 'CPA', (78, 99))	('ISL1', 'Gene', '3670', (19, 23))	('gastric cancer', 'Phenotype', 'HP:0012126', (159, 173))	('tumour invasion', 'Disease', 'MESH:D009361', (61, 76))	('tumour invasion', 'Disease', (61, 76))	('patients', 'Species', '9606', (174, 182))	('gastric cancer', 'Disease', (159, 173))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
196908	32158343	However, there was a significant association between the expression of LHX5 with the tumour grade (low/high grade) of urothelial carcinoma of the bladder.	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('LHX5', 'Gene', (71, 75))	('expression', 'Var', (57, 67))	('tumour', 'Disease', (85, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (118, 153))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (118, 153))	('significant association', 'Reg', (21, 44))	('urothelial carcinoma of the bladder', 'Disease', (118, 153))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
196921	32158343	A recent study by Kitchen et al., in 2015 also showed that ISL1 was highly methylated in high-grade tumours as compared to lower or intermediate grade tumours.	('methylated', 'Var', (75, 85))	('tumours', 'Disease', (100, 107))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('ISL1', 'Gene', '3670', (59, 63))	('tumours', 'Phenotype', 'HP:0002664', (151, 158))	('tumours', 'Disease', 'MESH:D009369', (151, 158))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('tumours', 'Disease', 'MESH:D009369', (100, 107))	('ISL1', 'Gene', (59, 63))	('tumours', 'Disease', (151, 158))
196952	31212967	For example, it has been revealed that copy number variations (CNVs) can act as an important driving force in several cancers; such genomic variations can alter gene expression, and thus, affect the corresponding biological functions.	('gene expression', 'biological_process', 'GO:0010467', ('161', '176'))	('cancers', 'Disease', (118, 125))	('variations', 'Var', (140, 150))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('copy number variations', 'Var', (39, 61))	('biological functions', 'MPA', (213, 233))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('gene expression', 'MPA', (161, 176))	('alter', 'Reg', (155, 160))	('affect', 'Reg', (188, 194))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
196953	31212967	In bladder cancer cells, abnormal DNA methylation levels have been shown to be associated with the disorder of certain gene functions, and thus, contribute to the progression of bladder cancer.	('associated', 'Reg', (79, 89))	('abnormal', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (178, 192))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('gene functions', 'MPA', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('disorder', 'MPA', (99, 107))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('bladder cancer', 'Disease', 'MESH:D001749', (178, 192))	('bladder cancer', 'Disease', (178, 192))	('bladder cancer', 'Disease', (3, 17))	('DNA methylation', 'biological_process', 'GO:0006306', ('34', '49'))	('DNA methylation levels', 'MPA', (34, 56))	('contribute to', 'Reg', (145, 158))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))
196954	31212967	For instance, the hypermethylation in the promoters of ITIH5 and RBBP8 can facilitate the progression of bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('hypermethylation', 'Var', (18, 34))	('RBBP8', 'Gene', '5932', (65, 70))	('RBBP8', 'Gene', (65, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (105, 119))	('bladder cancer', 'Disease', (105, 119))	('ITIH5', 'Gene', '80760', (55, 60))	('facilitate', 'PosReg', (75, 85))	('ITIH5', 'Gene', (55, 60))	('progression', 'CPA', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
196961	31212967	In addition, we identified the important functional gene modules that are the most correlated with tumor staging and observed that they display significantly distinct association patterns with other independently measured genomic profiles, such as copy number variations and somatic mutations.	('tumor', 'Disease', (99, 104))	('correlated', 'Reg', (83, 93))	('association', 'Interaction', (167, 178))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('copy number variations', 'Var', (248, 270))
196984	31212967	In this integrative analysis, the response variable was the tumor stage (stage I/II = 3, stage III = 2, stage IV = 1), while the predictor variables included the average expression values (z-score normalized) of protective and hazardous genes, the frequency of copy number amplifications and deletions (z-score normalized), the risk score of DNA methylation, age, and gender (Male = 0, Female = 1).	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('expression', 'MPA', (170, 180))	('deletions', 'Var', (292, 301))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('DNA methylation', 'biological_process', 'GO:0006306', ('342', '357'))	('DNA', 'cellular_component', 'GO:0005574', ('342', '345'))	('tumor', 'Disease', (60, 65))	('copy number amplifications', 'Var', (261, 287))
197005	31212967	Taken together, the above analysis results indicated that the alteration in the expression of the identified survival-related genes were closely related to the progression of bladder cancer, which also evidently reflected the heterogeneity of their co-expression patterns.	('related', 'Reg', (145, 152))	('bladder cancer', 'Phenotype', 'HP:0009725', (175, 189))	('bladder cancer', 'Disease', 'MESH:D001749', (175, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('expression', 'MPA', (80, 90))	('bladder cancer', 'Disease', (175, 189))	('survival-related', 'Gene', (109, 125))	('alteration', 'Var', (62, 72))	('survival-related', 'Gene', '54897', (109, 125))
197019	31212967	The comparison showed that individual stages of bladder cancer displayed significantly different CNV frequencies, and both amplification and deletion increased remarkably along with the progression of bladder cancer (Figure 5A).	('bladder cancer', 'Disease', (48, 62))	('deletion', 'Var', (141, 149))	('bladder cancer', 'Disease', 'MESH:D001749', (201, 215))	('amplification', 'MPA', (123, 136))	('bladder cancer', 'Disease', (201, 215))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))	('increased', 'PosReg', (150, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (201, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
197021	31212967	These results implied that copy number abnormality of these survival-related genes directly reflected their obvious genomic instability and their influence on gene expression during the progression of bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (201, 215))	('gene expression', 'biological_process', 'GO:0010467', ('159', '174'))	('bladder cancer', 'Disease', (201, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('copy number abnormality', 'Var', (27, 50))	('influence', 'Reg', (146, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (201, 215))	('survival-related', 'Gene', (60, 76))	('survival-related', 'Gene', '54897', (60, 76))
197026	31212967	The above results indicated that amplification and deletion of chromosomal segments can display patterns in different stage-specific gene modules during the evolution of bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (170, 184))	('bladder cancer', 'Disease', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('amplification', 'Var', (33, 46))	('patterns', 'Reg', (96, 104))	('bladder cancer', 'Phenotype', 'HP:0009725', (170, 184))	('deletion', 'Var', (51, 59))
197027	31212967	As an important epigenetic regulation factor, DNA methylation has a profound and broad impact on the progression of bladder cancer.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('bladder cancer', 'Phenotype', 'HP:0009725', (116, 130))	('bladder cancer', 'Disease', 'MESH:D001749', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('bladder cancer', 'Disease', (116, 130))	('regulation', 'biological_process', 'GO:0065007', ('27', '37'))	('DNA methylation', 'biological_process', 'GO:0006306', ('46', '61'))	('impact', 'Reg', (87, 93))	('methylation', 'Var', (50, 61))
197028	31212967	Abnormal DNA methylations in cancer cells is often associated with the dysregulation of gene expression, and thus, affect the relevant cellular physiological functions.	('cancer', 'Disease', (29, 35))	('gene expression', 'biological_process', 'GO:0010467', ('88', '103'))	('dysregulation of gene expression', 'MPA', (71, 103))	('affect', 'Reg', (115, 121))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('associated', 'Reg', (51, 61))	('Abnormal DNA methylations', 'Var', (0, 25))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cellular physiological functions', 'MPA', (135, 167))
197041	31212967	Therefore, we profiled the genomic features of somatic mutations in the survival-related genes (see Materials and Methods).	('survival-related', 'Gene', (72, 88))	('survival-related', 'Gene', '54897', (72, 88))	('mutations', 'Var', (55, 64))
197044	31212967	As shown in the oncoprints in Figure 7A, a considerable fraction of genes in these four pathways were mutated in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (113, 127))	('bladder cancer', 'Disease', (113, 127))	('mutated', 'Var', (102, 109))
197045	31212967	More specifically, 70% of the MAPK pathway, 71% of the PI3K/AKT pathway, 55% of the Rap1 pathway, and 50% of the Ras pathway had mutated genes with the frequency >1% in all samples.	('Rap1', 'Gene', (84, 88))	('Ras pathway', 'Pathway', (113, 124))	('MAPK', 'molecular_function', 'GO:0004707', ('30', '34'))	('AKT', 'Gene', '207', (60, 63))	('PI3K', 'molecular_function', 'GO:0016303', ('55', '59'))	('Rap1', 'Gene', '5906', (84, 88))	('mutated genes', 'Var', (129, 142))	('AKT', 'Gene', (60, 63))	('MAPK pathway', 'Pathway', (30, 42))
197046	31212967	Our observation that these four pathways were associated with the relatively high mutation frequencies was consistent with the previous finding that mutations in the gene members of vital signaling pathways often have potential influence on the physiological function of tumor cells.	('influence', 'Reg', (228, 237))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('mutations', 'Var', (149, 158))	('mutation', 'Var', (82, 90))	('physiological function', 'MPA', (245, 267))	('tumor', 'Disease', (271, 276))	('signaling', 'biological_process', 'GO:0023052', ('188', '197'))	('tumor', 'Disease', 'MESH:D009369', (271, 276))
197048	31212967	We found that different tumor stages of BLCA patients shared a large fraction (437 genes) of mutated genes among the 1078 genes (Figure 7B).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutated', 'Var', (93, 100))	('tumor', 'Disease', (24, 29))	('patients', 'Species', '9606', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
197050	31212967	More importantly, we observed significant difference for all or stage-specific samples in the mutation frequencies between the two modules (corresponding to the blue and turquoise modules shown in Figure 4), that were the most positively and negatively correlated with tumor stages, respectively.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumor', 'Disease', (269, 274))	('negatively', 'NegReg', (242, 252))	('correlated', 'Reg', (253, 263))	('mutation', 'Var', (94, 102))
197083	31212967	In general, the cooperation among essential genes may affect the fates of cancer cells to a greater extent than the behaviors of individual genes, and thus, are more conductive to the corresponding disease phenotypes.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('affect', 'Reg', (54, 60))	('cooperation', 'Var', (16, 27))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
197097	29620666	Multivariate logistic regression model identified NLR >= 2.16 (odds ratio [OR] = 2.914; P < .001) and PLR >= 128.46 (OR = 2.761; P < .001) as independent predictors of UCB.	('UCB', 'Chemical', '-', (168, 171))	('UCB', 'Disease', (168, 171))	('UCB', 'Phenotype', 'HP:0006740', (168, 171))	('PLR', 'Var', (102, 105))
197144	29620666	The area under the ROC curve for pretreatment RDW were 0.572 (P = .037, cut-off = 0.135), 0.697 for MLR (P < .001, cut-off = 0.26), 0.725 for NLR (P < .001, cut-off = 2.16), and 0.706 for PLR (P < .001, cut-off = 128.46).	('0.697', 'Var', (90, 95))	('0.706', 'Var', (178, 183))	('0.725', 'Var', (132, 137))	('men', 'Species', '9606', (41, 44))
197147	29620666	Patients with NLR >= 2.16 were 2.914 times more likely to be diagnosed with UCB than those with NLR < 2.16.	('Patients', 'Species', '9606', (0, 8))	('UCB', 'Phenotype', 'HP:0006740', (76, 79))	('NLR >= 2.16', 'Var', (14, 25))	('UCB', 'Chemical', '-', (76, 79))	('UCB', 'Disease', (76, 79))
197151	29620666	High NLR was associated with larger tumor size when compared to patients with lower NLR but no significant association with high tumor grade.	('high tumor', 'Disease', (124, 134))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('high tumor', 'Disease', 'MESH:D009369', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (36, 41))
197180	29620666	Some investigators reported that pretreatment LMR was significantly correlated with survival in bladder cancer patients after RC and could be an independent prognostic factor for UCB patients underwent RC.	('survival', 'Disease', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('correlated with', 'Reg', (68, 83))	('UCB', 'Chemical', '-', (179, 182))	('bladder cancer', 'Phenotype', 'HP:0009725', (96, 110))	('LMR', 'Var', (46, 49))	('UCB', 'Phenotype', 'HP:0006740', (179, 182))	('bladder cancer', 'Disease', 'MESH:D001749', (96, 110))	('bladder cancer', 'Disease', (96, 110))	('men', 'Species', '9606', (41, 44))	('patients', 'Species', '9606', (183, 191))	('patients', 'Species', '9606', (111, 119))
197194	29620666	Our results indicated that NLR >= 2.16 was associated with decreased Hb and ALB levels, thus revealing that high NLR was an important factor in UCB.	('decreased', 'NegReg', (59, 68))	('ALB', 'Gene', '213', (76, 79))	('UCB', 'Chemical', '-', (144, 147))	('ALB', 'Gene', (76, 79))	('UCB', 'Phenotype', 'HP:0006740', (144, 147))	('NLR', 'Var', (27, 30))
197196	29620666	Moreover, patients with NLR >= 2.16 tended to be diagnosed with higher TNM stage and tumor size.	('tumor', 'Disease', (85, 90))	('NLR', 'Var', (24, 27))	('higher', 'PosReg', (64, 70))	('TNM stage', 'CPA', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('patients', 'Species', '9606', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
197197	29620666	Thus, the pretreatment high NLR may be an indicator of increased inflammation and immune responses in UCB.	('immune responses', 'CPA', (82, 98))	('inflammation', 'Disease', (65, 77))	('high', 'Var', (23, 27))	('men', 'Species', '9606', (18, 21))	('UCB', 'Phenotype', 'HP:0006740', (102, 105))	('UCB', 'Chemical', '-', (102, 105))	('increased', 'PosReg', (55, 64))	('NLR', 'Gene', (28, 31))	('UCB', 'Disease', (102, 105))	('inflammation', 'biological_process', 'GO:0006954', ('65', '77'))	('inflammation', 'Disease', 'MESH:D007249', (65, 77))
197202	29620666	In addition, patients with high PLR exhibited decreased ALB, Hb, and RBC.	('ALB', 'Gene', '213', (56, 59))	('patients', 'Species', '9606', (13, 21))	('decreased ALB', 'Phenotype', 'HP:0003282', (46, 59))	('ALB', 'Gene', (56, 59))	('RBC', 'CPA', (69, 72))	('decreased', 'NegReg', (46, 55))	('high PLR', 'Var', (27, 35))
197236	29620666	Writing - review & editing: L. Mo, L. Qin, X. Li, X. Shi, Y. Luo.	(': L.', 'Var', (26, 30))	('Qin', 'Gene', (38, 41))	('Qin', 'Gene', '2290', (38, 41))
197245	20837119	These studies suggest that environmental exposure to As+3 or Cd+2 can alter cell-cell and cell-matrix interactions in normal urothelial cells through a reduction in the expression of SPARC.	('Cd+2', 'Var', (61, 65))	('expression', 'MPA', (169, 179))	('alter', 'Reg', (70, 75))	('SPARC', 'Gene', (183, 188))	('As+3', 'Chemical', '-', (53, 57))	('reduction', 'NegReg', (152, 161))
57588	20837119	This cell line has been used to show that both Cd+2 and As+3 can cause the malignant transformation of human urothelial cells.	('Cd+2', 'Var', (47, 51))	('human', 'Species', '9606', (103, 108))	('cause', 'Reg', (65, 70))	('As+3', 'Chemical', '-', (56, 60))	('malignant transformation of human urothelial cells', 'CPA', (75, 125))	('As+3', 'Var', (56, 60))
197260	20837119	The first goal of the present study was to show that SPARC expression is altered when UROtsa cells are exposed to, or malignantly transformed, by As+3 or Cd+2.	('altered', 'Reg', (73, 80))	('SPARC expression', 'MPA', (53, 69))	('Cd+2', 'Var', (154, 158))	('As+3', 'Chemical', '-', (146, 150))
197287	20837119	Preliminary experiments were performed to determine the conditions of exposure to Cd+2 and As+3 that were near to, but below, a level that produced cell death in confluent cultures of the parental UROtsa cells over a 10 day period of exposure.	('cell death', 'CPA', (148, 158))	('As+3', 'Chemical', '-', (91, 95))	('cell death', 'biological_process', 'GO:0008219', ('148', '158'))	('Cd+2', 'Var', (82, 86))	('produced', 'Reg', (139, 147))
197301	20837119	This analysis demonstrated that none of the cell lines, parental or transformed, treated with MS-275 or 5-AZC expressed increased levels of SPARC mRNA compared to the untreated controls (Figure 2).	('SPARC mRNA', 'MPA', (140, 150))	('5-AZC', 'Chemical', 'MESH:D000077209', (104, 109))	('MS-275', 'Var', (94, 100))	('5-AZC', 'Var', (104, 109))	('increased', 'PosReg', (120, 129))	('MS-275', 'Chemical', 'MESH:C118739', (94, 100))
197325	20837119	The present study is the first to show that the heavy metals, Cd+2 and As+3, may down-regulate the expression of SPARC during the development and progression of bladder cancer.	('As+3', 'Chemical', '-', (71, 75))	('expression', 'MPA', (99, 109))	('down-regulate', 'NegReg', (81, 94))	('SPARC', 'Gene', (113, 118))	('bladder cancer', 'Phenotype', 'HP:0009725', (161, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('bladder cancer', 'Disease', 'MESH:D001749', (161, 175))	('Cd+2', 'Var', (62, 66))	('bladder cancer', 'Disease', (161, 175))
197326	20837119	The present study shows that SPARC is also expressed in the parental UROtsa cells and that SPARC expression is reduced to the limit of detection when the cells are malignantly transformed by both Cd+2 and As+3.	('Cd+2', 'Var', (196, 200))	('As+3', 'Chemical', '-', (205, 209))	('expression', 'MPA', (97, 107))	('reduced', 'NegReg', (111, 118))
197340	20837119	It was also determined that acute exposure of the parental UROtsa cells to both Cd+2 and As+3 resulted in a reduction in the expression of SPARC mRNA and protein.	('As+3', 'Chemical', '-', (89, 93))	('expression', 'MPA', (125, 135))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('SPARC', 'Protein', (139, 144))	('Cd+2', 'Var', (80, 84))	('reduction', 'NegReg', (108, 117))
197341	20837119	To our knowledge, this is the first indication that exposure to Cd+2 or As+3 might cause a reduction in the expression of SPARC in human cells.	('Cd+2', 'Var', (64, 68))	('SPARC', 'Gene', (122, 127))	('human', 'Species', '9606', (131, 136))	('reduction', 'NegReg', (91, 100))	('As+3', 'Var', (72, 76))	('expression', 'MPA', (108, 118))	('As+3', 'Chemical', '-', (72, 76))
197342	20837119	The possibility that SPARC expression might be influenced by histone modification or DNA methylation was suggested by studies showing aberrant methylation of the SPARC gene in human lung and ovarian cancers (; Suzuki et al., 2005).	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('methylation', 'Var', (143, 154))	('methylation', 'biological_process', 'GO:0032259', ('143', '154'))	('human', 'Species', '9606', (176, 181))	('influenced', 'Reg', (47, 57))	('lung and ovarian cancers', 'Disease', 'MESH:D010051', (182, 206))	('histone modification', 'biological_process', 'GO:0016570', ('61', '81'))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('DNA methylation', 'biological_process', 'GO:0006306', ('85', '100'))	('SPARC', 'Gene', (162, 167))	('ovarian cancers', 'Phenotype', 'HP:0100615', (191, 206))
197343	20837119	The finding that both Cd+2 and As+3 had similar effects on SPARC expression before and following malignant transformation suggests a similar mechanism of action once the agents are fully elaborated inside the cell.	('effects', 'Reg', (48, 55))	('SPARC expression', 'MPA', (59, 75))	('As+3', 'Chemical', '-', (31, 35))	('Cd+2', 'Var', (22, 26))
197411	33936226	According to some related research, HER2 expression in metastasizing urothelial neoplasm is relatively frequent, homogeneous in each tumor component, and predicts poor prognosis.	('HER2', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('HER2', 'Gene', '2064', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('metastasizing urothelial neoplasm', 'Disease', (55, 88))	('metastasizing urothelial neoplasm', 'Disease', 'MESH:D009362', (55, 88))	('tumor', 'Disease', (133, 138))	('neoplasm', 'Phenotype', 'HP:0002664', (80, 88))	('predicts', 'Reg', (154, 162))	('expression', 'Var', (41, 51))
197427	32493345	38.9% of all patients experienced any types of recurrence, and the estimated 5-year recurrence-free survival rate was lower in the AAN group (37.1% vs. 63.7%, p = 0.001).	('recurrence-free', 'CPA', (84, 99))	('patients', 'Species', '9606', (13, 21))	('AAN', 'Chemical', '-', (131, 134))	('lower', 'NegReg', (118, 123))	('AAN', 'Var', (131, 134))
197432	32493345	According to the recent EAU Guidelines, several studies have demonstrated a carcinogenic potential of aristolochic acid (AA) contained in Aristolochia fangchi and Aristolochia clematis.	('aristolochic', 'MPA', (102, 114))	('Aristolochia', 'Var', (138, 150))	('Aristolochia fangchi', 'Species', '425107', (138, 158))	('Aristolochia', 'Species', '425107', (138, 150))	('Aristolochia', 'Species', '425107', (163, 175))	('carcinogenic', 'Disease', 'MESH:D063646', (76, 88))	('EAU', 'Chemical', '-', (24, 27))	('carcinogenic', 'Disease', (76, 88))	('aristolochic acid', 'Chemical', 'MESH:C000228', (102, 119))
197433	32493345	Aristolochic acid is implicated in multiple cancer types, sometimes with very high mutational burdens, especially in UTUCs.	('Aristolochic acid', 'Chemical', 'MESH:C000228', (0, 17))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('Aristolochic', 'Var', (0, 12))	('implicated', 'Reg', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
197455	32493345	End-stage renal disease was equally more common in the AAN group than in non-AAN group (p < 0.001).	('AAN', 'Chemical', '-', (55, 58))	('renal disease', 'Disease', (10, 23))	('renal disease', 'Disease', 'MESH:D007674', (10, 23))	('AAN', 'Var', (55, 58))	('renal disease', 'Phenotype', 'HP:0000112', (10, 23))	('AAN', 'Chemical', '-', (77, 80))	('End-stage renal disease', 'Phenotype', 'HP:0003774', (0, 23))
197472	32493345	Currently, the main carcinogenic mechanism of AA is as follows: A:T to T:A transversions occurring in the 5'-CpApG-3' trinucleotide context of the TP53 gene is considered to be the signature mutation of AA.	('TP53', 'Gene', (147, 151))	('transversions', 'Var', (75, 88))	('carcinogenic', 'Disease', 'MESH:D063646', (20, 32))	('carcinogenic', 'Disease', (20, 32))	('TP53', 'Gene', '7157', (147, 151))
197493	32493345	One study showed that patients with AAN were more likely to develop lower-stage and lower-grade UTUC in the Balkans, suggesting the reduced potential for malignancy.	('lower-grade', 'NegReg', (84, 95))	('lower-stage', 'CPA', (68, 79))	('patients', 'Species', '9606', (22, 30))	('AAN', 'Chemical', '-', (36, 39))	('develop', 'PosReg', (60, 67))	('malignancy', 'Disease', 'MESH:D009369', (154, 164))	('malignancy', 'Disease', (154, 164))	('AAN', 'Var', (36, 39))
197497	32493345	The estimated 5-year overall survival rate was slightly lower, and death from other diseases was higher in the AAN group.	('death', 'Disease', 'MESH:D003643', (67, 72))	('death', 'Disease', (67, 72))	('higher', 'PosReg', (97, 103))	('overall survival', 'CPA', (21, 37))	('lower', 'NegReg', (56, 61))	('AAN', 'Chemical', '-', (111, 114))	('AAN', 'Var', (111, 114))
197502	32493345	Our results showed that the estimated 5-year recurrence-free survival rate was significantly lower, and the intravesical and contralateral recurrence rate was higher in the AAN group than in the non-AAN group.	('AAN', 'Chemical', '-', (199, 202))	('recurrence-free survival', 'CPA', (45, 69))	('lower', 'NegReg', (93, 98))	('AAN', 'Chemical', '-', (173, 176))	('AAN', 'Var', (173, 176))	('higher', 'PosReg', (159, 165))
197508	32493345	Jelakovic's molecular epidemiologic study reported that AL-DNA adducts and TP53 mutational signature can persist for years after exposure to AA.	('mutational', 'Var', (80, 90))	('AL', 'Chemical', 'MESH:D000535', (56, 58))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
197513	32493345	Gene sequencing should be done to identify whether these patients have A:T-to-T:A transversions in TP53.	('TP53', 'Gene', '7157', (99, 103))	('transversions', 'Var', (82, 95))	('TP53', 'Gene', (99, 103))	('patients', 'Species', '9606', (57, 65))
197573	31798344	Another work showed the prognostic value of PLR for worse OS (HR = 1.38, 95% CI 1.19-1.62, p < 0.001) and poor RFS or PFS (HR = 1.55, 95% CI 1.27-1.88, p < 0.001) in patients with cholangiocarcinoma.	('RFS', 'Disease', 'MESH:D005198', (111, 114))	('worse OS', 'Disease', (52, 60))	('poor', 'NegReg', (106, 110))	('cholangiocarcinoma', 'Disease', (180, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('PLR', 'Var', (44, 47))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (180, 198))	('RFS', 'Disease', (111, 114))	('PFS', 'MPA', (118, 121))	('patients', 'Species', '9606', (166, 174))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (180, 198))
197589	33161227	A pan-cancer analysis of HER2 index revealed transcriptional pattern for precise selection of HER2-targeted therapy The prevalence of HER2 alterations in pan-cancer indicates a broader range of application of HER2-targeted therapies; however, biomarkers for such therapies are still insufficient and limited to breast cancer and gastric cancer.	('breast cancer', 'Disease', 'MESH:D001943', (311, 324))	('cancer', 'Disease', (318, 324))	('breast cancer', 'Disease', (311, 324))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (337, 343))	('gastric cancer', 'Phenotype', 'HP:0012126', (329, 343))	('alterations', 'Var', (139, 150))	('cancer', 'Disease', (158, 164))	('HER2', 'Gene', (25, 29))	('HER2', 'Gene', (209, 213))	('HER2', 'Gene', '2064', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('HER2', 'Gene', '2064', (94, 98))	('gastric cancer', 'Disease', (329, 343))	('cancer', 'Disease', (337, 343))	('cancer', 'Disease', (6, 12))	('HER2', 'Gene', '2064', (209, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (311, 324))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('gastric cancer', 'Disease', 'MESH:D013274', (329, 343))	('HER2', 'Gene', (134, 138))	('HER2', 'Gene', '2064', (25, 29))	('HER2', 'Gene', (94, 98))
197593	33161227	Increased HER2 somatic copy number alterations (SCNAs) could be divided into two patterns, focal- or arm-level.	('HER2', 'Gene', (10, 14))	('somatic', 'Var', (15, 22))	('HER2', 'Gene', '2064', (10, 14))
197599	33161227	Therapies targeting human epidermal growth factor receptor 2 (HER2) have been routinely applied to patients of breast cancer and gastric cancer harboring HER2 alterations; such applications could be broader given the prevalence of aberrant HER2 status in multi-omics level in pan-cancer.	('cancer', 'Disease', (280, 286))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('26', '49'))	('gastric cancer', 'Disease', 'MESH:D013274', (129, 143))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('human epidermal growth factor receptor 2', 'Gene', (20, 60))	('cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('breast cancer', 'Disease', (111, 124))	('aberrant', 'Var', (231, 239))	('HER2', 'Gene', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('HER2', 'Gene', (240, 244))	('HER2', 'Gene', (154, 158))	('gastric cancer', 'Phenotype', 'HP:0012126', (129, 143))	('HER2', 'Gene', '2064', (62, 66))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('alterations', 'Var', (159, 170))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('patients', 'Species', '9606', (99, 107))	('human epidermal growth factor receptor 2', 'Gene', '2064', (20, 60))	('gastric cancer', 'Disease', (129, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('HER2', 'Gene', '2064', (240, 244))	('HER2', 'Gene', '2064', (154, 158))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
197608	33161227	Since aberrant HER2 status of multiple levels have been identified in a wide range of other tumors, including uterine cancer, gastroesophageal junction cancer, biliary tract cancer, colorectal cancer, non-small-cell lung cancer and bladder cancer, its application may be far beyond than the current.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('colorectal cancer', 'Phenotype', 'HP:0003003', (182, 199))	('bladder cancer', 'Disease', 'MESH:D001749', (232, 246))	('cancer', 'Disease', (193, 199))	('bladder cancer', 'Disease', (232, 246))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (160, 180))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('non-small-cell lung cancer', 'Disease', (201, 227))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (201, 227))	('cancer', 'Disease', (240, 246))	('bladder cancer', 'Phenotype', 'HP:0009725', (232, 246))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('biliary tract cancer', 'Disease', 'MESH:D001661', (160, 180))	('cancer', 'Disease', (152, 158))	('identified', 'Reg', (56, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('cancer', 'Disease', (174, 180))	('HER2', 'Gene', '2064', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('gastroesophageal junction cancer', 'Disease', 'MESH:D009369', (126, 158))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (205, 227))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumors', 'Disease', (92, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (182, 199))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('uterine cancer', 'Phenotype', 'HP:0010784', (110, 124))	('cancer', 'Disease', (221, 227))	('aberrant', 'Var', (6, 14))	('colorectal cancer', 'Disease', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (201, 227))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('biliary tract cancer', 'Disease', (160, 180))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('HER2', 'Gene', (15, 19))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('gastroesophageal junction cancer', 'Disease', (126, 158))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
197620	33161227	Samples harbored mutations in ERBB2 were labeled as "mutation", while the rest were labeled as "wild".	('ERBB2', 'Gene', (30, 35))	('mutations', 'Var', (17, 26))	('ERBB2', 'Gene', '2064', (30, 35))
197623	33161227	Five cohorts "GSE81002", "GSE22358", "GSE20194", "GSE50948", and "GSE55348" were utilized to validate the performance of HER2 index in separating HER2-enriched subtype from other samples of BRCA.	('HER2', 'Gene', '2064', (121, 125))	('HER2', 'Gene', '2064', (146, 150))	('HER2', 'Gene', (121, 125))	('BRCA', 'Phenotype', 'HP:0003002', (190, 194))	('BRCA', 'Gene', '672', (190, 194))	('BRCA', 'Gene', (190, 194))	('GSE55348', 'Var', (66, 74))	('HER2', 'Gene', (146, 150))
197656	33161227	We investigated HER2 status of 11020 tumor samples from the TCGA database, encompassing 33 cancer types in aspect of copy number variation (CNV), single nucleotide variant (SNV), mRNA, reverse phase protein and phospho-protein array data (RPPA).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('HER2', 'Gene', (16, 20))	('HER2', 'Gene', '2064', (16, 20))	('tumor', 'Disease', (37, 42))	('mRNA', 'MPA', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('single nucleotide variant', 'Var', (146, 171))	('protein', 'cellular_component', 'GO:0003675', ('219', '226'))	('protein', 'cellular_component', 'GO:0003675', ('199', '206'))
197672	33161227	HER2 is an oncogene targeted by somatic copy-number alterations (SCNAs) to drive cancer growth.	('drive', 'PosReg', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('copy-number alterations', 'Var', (40, 63))
197687	33161227	Focal-amplification at the HER2 gene is associated with overexpressed HER2 mRNA, whereas arm-level gain had little influence on HER2 mRNA expression (Figure S5).	('HER2', 'Gene', (128, 132))	('HER2', 'Gene', (70, 74))	('HER2', 'Gene', '2064', (128, 132))	('HER2', 'Gene', '2064', (70, 74))	('overexpressed', 'PosReg', (56, 69))	('Focal-amplification', 'Var', (0, 19))	('HER2', 'Gene', (27, 31))	('HER2', 'Gene', '2064', (27, 31))
197700	33161227	Luminal B was associated with elevated cell proliferation, in which cell cycle mitotic, G2-M transition, P53 pathway etc.	('P53', 'Gene', (105, 108))	('Luminal B', 'Var', (0, 9))	('P53', 'Gene', '7157', (105, 108))	('Luminal', 'Chemical', 'MESH:D010634', (0, 7))	('cell cycle mitotic', 'CPA', (68, 86))	('G2-M transition', 'CPA', (88, 103))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('cell cycle', 'biological_process', 'GO:0007049', ('68', '78'))	('elevated', 'PosReg', (30, 38))	('cell proliferation', 'CPA', (39, 57))	('mitotic, G2-M transition', 'biological_process', 'GO:0000086', ('79', '103'))
197731	33161227	Considering that ERBB3 and EGFR are also targeted by these pan-HER inhibitors, we additionally acquired the genome-scale CRISPR knockout results of HER2 gene across pan-cancer cell lines from depmap (Methods) and assessed the association between HER2 index and HER2-dependency score.	('EGFR', 'Gene', '1956', (27, 31))	('HER2', 'Gene', (148, 152))	('EGFR', 'Gene', (27, 31))	('cancer', 'Disease', (169, 175))	('ERBB3', 'Gene', '2065', (17, 22))	('HER2', 'Gene', '2064', (261, 265))	('HER2', 'Gene', '2064', (148, 152))	('ERBB3', 'Gene', (17, 22))	('HER2', 'Gene', (246, 250))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('HER2', 'Gene', '2064', (246, 250))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('knockout', 'Var', (128, 136))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('HER2', 'Gene', (261, 265))
197747	33161227	As for transcription level, the majority of HER2-aberrant tumors with high HER2 index displayed a HER2 transcription level below the cutoff (log10(HER2 mRNA cutoff) = 1.74).	('HER2-aberrant tumors', 'Disease', (44, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('transcription', 'biological_process', 'GO:0006351', ('103', '116'))	('below', 'NegReg', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('transcription', 'biological_process', 'GO:0006351', ('7', '20'))	('HER2-aberrant tumors', 'Disease', 'MESH:D002869', (44, 64))	('HER2', 'Gene', (44, 48))	('HER2', 'Gene', (75, 79))	('HER2', 'Gene', (98, 102))	('HER2', 'Gene', '2064', (147, 151))	('HER2', 'Gene', '2064', (44, 48))	('HER2', 'Gene', (147, 151))	('HER2', 'Gene', '2064', (75, 79))	('HER2', 'Gene', '2064', (98, 102))	('high', 'Var', (70, 74))
197748	33161227	HNSC with high HER2 index had a significantly elevated HER2 protein and phosphor-protein level despite few HER2 amplifications and mRNA overexpression, coinciding with the landscape of HER2 status displayed in the total of HNSC samples (Fig.	('HER2', 'Gene', '2064', (107, 111))	('elevated', 'PosReg', (46, 54))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('HER2', 'Gene', (15, 19))	('HER2', 'Gene', '2064', (15, 19))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('high', 'Var', (10, 14))	('HER2', 'Gene', (185, 189))	('HER2', 'Gene', (55, 59))	('HER2', 'Gene', '2064', (185, 189))	('HER2', 'Gene', (107, 111))	('HER2', 'Gene', '2064', (55, 59))
197771	33161227	HER2 mutation has been suggested as an alternative mechanism for activating HER2 signaling, and functional analysis have revealed several recurrent HER2 mutations that are likely to be driver alterations.	('HER2', 'Gene', (148, 152))	('HER2', 'Gene', (76, 80))	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('HER2', 'Gene', '2064', (148, 152))	('mutations', 'Var', (153, 162))	('HER2', 'Gene', '2064', (76, 80))	('activating', 'PosReg', (65, 75))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
197772	33161227	We found that HER2 mutations were also common in pan-cancer, but they are mainly independent from HER2-amplification.	('HER2', 'Gene', '2064', (14, 18))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (19, 28))	('common', 'Reg', (39, 45))	('HER2', 'Gene', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('HER2', 'Gene', '2064', (98, 102))	('HER2', 'Gene', (14, 18))
197774	33161227	There is a small fraction of tumors having both HER2 amplification and mutation, however, whether they are same with purely HER2-amplified tumors remains uncertain.	('HER2', 'Gene', '2064', (48, 52))	('HER2', 'Gene', '2064', (124, 128))	('mutation', 'Var', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumors', 'Disease', (29, 35))	('HER2', 'Gene', (48, 52))	('HER2', 'Gene', (124, 128))
197775	33161227	Since oncogenic potentials have been identified in HER2 mutations, amplifications and changes in HER2 protein and variations in different cancers, thus identifying the significance of each alteration in the context of each cancer is needed in the future.	('HER2', 'Gene', (97, 101))	('cancer', 'Disease', (138, 144))	('mutations', 'Var', (56, 65))	('HER2', 'Gene', '2064', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('HER2', 'Gene', (51, 55))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Disease', (223, 229))	('HER2', 'Gene', '2064', (51, 55))	('cancers', 'Disease', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('protein', 'Protein', (102, 109))
197781	33161227	Besides, we found different frequencies of Chr17q22-23 amplification between gynecologic tumors and gastrointestinal tumors.	('tumors', 'Disease', (89, 95))	('amplification', 'Var', (55, 68))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Disease', (117, 123))	('gastrointestinal tumors', 'Disease', (100, 123))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (100, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('Chr17q22-23', 'Gene', (43, 54))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (100, 123))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
197812	33161227	In recent years, emerging trials exploring the potential efficacy of HER2 targeted therapy in colorectal tumors, non-small cell lung cancer and bladder cancer with HER2 alterations (amplification,overexpression and mutations) exhibited variable responses, some of which are impressive.	('colorectal tumors', 'Disease', (94, 111))	('HER2', 'Gene', (164, 168))	('bladder cancer', 'Disease', 'MESH:D001749', (144, 158))	('bladder cancer', 'Disease', (144, 158))	('bladder cancer', 'Phenotype', 'HP:0009725', (144, 158))	('alterations', 'Var', (169, 180))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('mutations', 'Var', (215, 224))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('HER2', 'Gene', '2064', (69, 73))	('colorectal tumors', 'Disease', 'MESH:D015179', (94, 111))	('HER2', 'Gene', '2064', (164, 168))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (117, 139))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (113, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('lung cancer', 'Disease', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('HER2', 'Gene', (69, 73))
197814	33161227	It is still unknown whether and what kind of HER2 alterations are relevant oncogenic drivers in pan-cancer tumor types, such as in NSCLC.	('cancer tumor', 'Disease', (100, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('NSCLC', 'Disease', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('alterations', 'Var', (50, 61))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('cancer tumor', 'Disease', 'MESH:D009369', (100, 112))	('HER2', 'Gene', (45, 49))	('HER2', 'Gene', '2064', (45, 49))
197818	33161227	The findings above suggested that therapeutics for HER2 may have potential value in a certain population of gastrointestinal tumors, HNSC, NSCLC, BLCA, CESC and UCEC identified by transcriptional pattern and HER2 alterations.	('CESC', 'Disease', (152, 156))	('HER2', 'Gene', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('HER2', 'Gene', '2064', (208, 212))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('NSCLC', 'Disease', (139, 144))	('UCEC', 'Disease', (161, 165))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (108, 131))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('HER2', 'Gene', (51, 55))	('alterations', 'Var', (213, 224))	('BLCA', 'Disease', (146, 150))	('gastrointestinal tumors', 'Disease', (108, 131))	('HNSC', 'Disease', (133, 137))	('HER2', 'Gene', '2064', (51, 55))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (108, 131))
197819	33161227	Additionally, the discordance between high index and absence of HER2 amplifications and overexpression in some samples may be explained by activating HER2 mutations as in NSCLC or alternative pathway activated in HER2-enriched expression pattern, such as KRAS mutation or AR signaling.	('HER2', 'Gene', '2064', (150, 154))	('KRAS', 'Gene', '3845', (255, 259))	('mutations', 'Var', (155, 164))	('signaling', 'biological_process', 'GO:0023052', ('275', '284'))	('HER2', 'Gene', (64, 68))	('KRAS', 'Gene', (255, 259))	('alternative pathway', 'Pathway', (180, 199))	('HER2', 'Gene', (213, 217))	('HER2', 'Gene', (150, 154))	('HER2', 'Gene', '2064', (64, 68))	('activating', 'PosReg', (139, 149))	('NSCLC', 'Disease', (171, 176))	('HER2', 'Gene', '2064', (213, 217))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
197828	33161227	Assessed by the combination of HER2 index and HER2 alterations, a certain population of gastrointestinal tumors, HNSC, NSCLC, BLCA, CESC and UCEC were identified which may benefit from therapeutics for HER2 target, of which BLCA.3 and HNSC.Basal are promising subtypes.	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (88, 111))	('gastrointestinal tumors', 'Disease', (88, 111))	('alterations', 'Var', (51, 62))	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('HER2', 'Gene', (46, 50))	('HER2', 'Gene', '2064', (31, 35))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (88, 111))	('HER2', 'Gene', '2064', (46, 50))	('HER2', 'Gene', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('HER2', 'Gene', '2064', (202, 206))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('NSCLC', 'Disease', (119, 124))	('HER2', 'Gene', (31, 35))
197882	32882873	Kaplan-Meier analysis of samples between these two clusters showed that in most cancer types (LGG, SKCM, LUAD, KIRC, KIRP, KICH, PRAD, PAAD, LIHC, THCA, BLCA), cluster red is significantly associated with poor disease-free survival (p < 0.05, Figure S2).	('KICH', 'Disease', (123, 127))	('poor', 'NegReg', (205, 209))	('KICH', 'Disease', 'None', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cluster red', 'Var', (160, 171))	('disease-free survival', 'CPA', (210, 231))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
197899	32882873	For the anti-PD1-treated melanoma, the immune score specific to SKCM was calculated using the patient transcriptomic data from these studies.	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('patient', 'Species', '9606', (94, 101))	('melanoma', 'Disease', (25, 33))	('anti-PD1-treated', 'Var', (8, 24))
197901	32882873	Patients with complete response (CR) or partial response (PR) from these studies had a higher cancer-specific immune score compared to patients with stable disease (SD) or progressive disease (PD) that did not respond (Figure 5a-e).	('patients', 'Species', '9606', (135, 143))	('partial response', 'Var', (40, 56))	('higher', 'PosReg', (87, 93))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
197928	32882873	The genes associated with good prognosis were not often shared between the cancer types; however, pathway enrichment of the genes associated with only good prognosis in cancers showed that enrichment of interferon response was commonly associated with good prognosis in multiple cancer types.	('cancer', 'Disease', (169, 175))	('cancers', 'Disease', (169, 176))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('interferon', 'MPA', (203, 213))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('associated', 'Reg', (236, 246))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('good', 'Disease', (252, 256))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('enrichment', 'Var', (189, 199))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
197946	32882873	Patient transcriptomic and clinical data for bladder urothelial carcinoma treated with anti-programmed death ligand 1 (PDL1) were collected from the IMvigor clinical trial data.	('bladder urothelial carcinoma', 'Disease', (45, 73))	('ligand', 'molecular_function', 'GO:0005488', ('109', '115'))	('PDL1', 'Gene', (119, 123))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (45, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('anti-programmed', 'Var', (87, 102))	('Patient', 'Species', '9606', (0, 7))	('PDL1', 'Gene', '29126', (119, 123))
197966	32882873	Figure S3: Kaplan-Meier analysis of disease-free survival of cancer samples stratified by high (>median, red line) or low (<median, blue line) immune scores specific for each of the 20 cancer types shows that high immune scores are significantly associated with better disease-free survival in all cancer types.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('better', 'PosReg', (262, 268))	('high', 'Var', (209, 213))	('cancer', 'Disease', (298, 304))	('disease-free survival', 'CPA', (269, 290))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
197996	30602056	Because of the importance of the amino acid metabolism pathway of cancer cell proliferation, drugs targeting amino acid metabolism may reduce bladder cancer growth.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('bladder cancer', 'Disease', 'MESH:D001749', (142, 156))	('bladder cancer', 'Disease', (142, 156))	('metabolism', 'biological_process', 'GO:0008152', ('120', '130'))	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('reduce bladder', 'Phenotype', 'HP:0005343', (135, 149))	('metabolism', 'biological_process', 'GO:0008152', ('44', '54'))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (142, 156))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('drugs', 'Var', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('reduce', 'NegReg', (135, 141))	('cancer', 'Disease', (66, 72))
198005	30602056	We successfully identified novel disparity genes which predicted poor survival in AA BLCA patients.	('disparity', 'Var', (33, 42))	('BLCA', 'Disease', 'MESH:D001749', (85, 89))	('patients', 'Species', '9606', (90, 98))	('BLCA', 'Disease', (85, 89))
198040	30602056	Kaplan-Meier survival analysis of KDM2A and P3H2 showed that high expression was associated with poor survival in AA but did not show an association with survival among the EA patients (Figure 5C-D).	('patients', 'Species', '9606', (176, 184))	('KDM2A', 'Gene', '22992', (34, 39))	('high', 'Var', (61, 65))	('KDM2A', 'Gene', (34, 39))	('P3H2', 'Gene', (44, 48))	('EA', 'Chemical', '-', (173, 175))	('P3H2', 'Gene', '55214', (44, 48))	('P3H', 'molecular_function', 'GO:0033763', ('44', '47'))	('poor', 'NegReg', (97, 101))
198041	30602056	AA patients with low expression of ME3 also showed an increased risk of mortality (Figure 5E).	('low expression', 'Var', (17, 31))	('patients', 'Species', '9606', (3, 11))	('ME3', 'Gene', (35, 38))	('mortality', 'CPA', (72, 81))	('ME3', 'Gene', '10873', (35, 38))
198044	30602056	Dysregulation of metabolic pathways is a hallmark of cancer development and progression, and altered metabolites in body fluids are direct indicators of deregulated metabolic pathways.	('hallmark of cancer', 'Disease', (41, 59))	('Dysregulation', 'Var', (0, 13))	('altered', 'Reg', (93, 100))	('hallmark of cancer', 'Disease', 'MESH:D009369', (41, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('metabolic pathways', 'Pathway', (17, 35))
198048	30602056	The elevated levels of methyl arginine, methyl histidine, methyl alanine, methyl nicotinamide, serine, and glycine indicate dysregulation of the one-carbon metabolism in AA with BLCA.	('methyl alanine', 'Chemical', '-', (58, 72))	('glycine', 'Chemical', 'MESH:D005998', (107, 114))	('one-carbon metabolism', 'MPA', (145, 166))	('methyl histidine', 'Chemical', 'MESH:D008762', (40, 56))	('carbon', 'Chemical', 'MESH:D002244', (149, 155))	('methyl alanine', 'MPA', (58, 72))	('elevated', 'PosReg', (4, 12))	('methyl nicotinamide', 'Chemical', '-', (74, 93))	('levels', 'MPA', (13, 19))	('methyl arginine', 'Chemical', '-', (23, 38))	('serine', 'MPA', (95, 101))	('methyl histidine', 'MPA', (40, 56))	('one-carbon metabolism', 'biological_process', 'GO:0006730', ('145', '166'))	('BLCA', 'Disease', (178, 182))	('methyl nicotinamide', 'MPA', (74, 93))	('serine', 'Chemical', 'MESH:D012694', (95, 101))	('glycine', 'MPA', (107, 114))	('BLCA', 'Disease', 'MESH:D001749', (178, 182))	('dysregulation', 'Var', (124, 137))	('methyl arginine', 'MPA', (23, 38))
198110	30122958	Hence, PD-L1 single-nucleotide polymorphisms (SNPs) that are easier in standardization, such as rs4143815 and rs2282055, are explored to further select responders.	('rs2282055', 'Var', (110, 119))	('rs4143815', 'Var', (96, 105))	('rs2282055', 'Mutation', 'rs2282055', (110, 119))	('rs4143815', 'Mutation', 'rs4143815', (96, 105))	('PD-L1', 'Gene', (7, 12))	('PD-L1', 'Gene', '29126', (7, 12))
198111	30122958	The second biomarker is microsatellite instability (MSI) or deficient mismatch repair (dMMR), which is recently approved for application as a biomarker predictive of response to anti-PD-1/PD-L1 drug negligible of tumor type.	('tumor', 'Disease', (213, 218))	('PD-L1', 'Gene', '29126', (188, 193))	('deficient', 'Var', (60, 69))	('MSI', 'Disease', 'None', (52, 55))	('dMMR', 'Chemical', '-', (87, 91))	('PD-1', 'Gene', (183, 187))	('PD-L1', 'Gene', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('PD-1', 'Gene', '5133', (183, 187))	('mismatch repair', 'biological_process', 'GO:0006298', ('70', '85'))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('MSI', 'Disease', (52, 55))	('microsatellite instability', 'MPA', (24, 50))
198113	30122958	Polymerase epsilon (POLE) mutation appears as a positive biomarker for patients with a microsatellite stable (MSS) phenotype, while mutations such as Janus Kinase 1 (JAK1) and JAK2 appear to be negative biomarkers for patients with an MSI phenotype, requiring validation by clinical trials.	('POLE', 'Gene', (20, 24))	('JAK2', 'Gene', (176, 180))	('Janus Kinase 1', 'Gene', (150, 164))	('MSI', 'Disease', (235, 238))	('mutation', 'Var', (26, 34))	('JAK1', 'Gene', '3716', (166, 170))	('patients', 'Species', '9606', (218, 226))	('patients', 'Species', '9606', (71, 79))	('JAK', 'molecular_function', 'GO:0004713', ('176', '179'))	('JAK', 'molecular_function', 'GO:0004713', ('166', '169'))	('JAK2', 'Gene', '3717', (176, 180))	('microsatellite stable', 'MPA', (87, 108))	('MSI', 'Disease', 'None', (235, 238))	('MSS', 'Disease', 'MESH:D013132', (110, 113))	('Janus Kinase 1', 'Gene', '3716', (150, 164))	('MSS', 'Disease', (110, 113))	('JAK1', 'Gene', (166, 170))
198115	30122958	Many kinds of genomic aberrations such as copy number amplification of the genes PD-L1 and JAK2 can result in high expression of PD-L1 protein and poor prognosis.	('JAK2', 'Gene', '3717', (91, 95))	('result in', 'Reg', (100, 109))	('PD-L1', 'Gene', (129, 134))	('copy number amplification', 'Var', (42, 67))	('PD-L1', 'Gene', (81, 86))	('PD-L1', 'Gene', '29126', (129, 134))	('JAK2', 'Gene', (91, 95))	('expression', 'MPA', (115, 125))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('PD-L1', 'Gene', '29126', (81, 86))	('protein', 'Protein', (135, 142))	('high', 'PosReg', (110, 114))	('JAK', 'molecular_function', 'GO:0004713', ('91', '94'))
198134	30122958	For example, rs4143815 C.G in 3'UTR of PD-L1 was associated with a decreased PD-L1 expression in NSCLC patients.	('PD-L1', 'Gene', (39, 44))	('decreased PD', 'Phenotype', 'HP:0032198', (67, 79))	('NSCLC', 'Disease', (97, 102))	('PD-L1', 'Gene', (77, 82))	('PD-L1', 'Gene', '29126', (39, 44))	('rs4143815', 'Mutation', 'rs4143815', (13, 22))	('PD-L1', 'Gene', '29126', (77, 82))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('expression', 'MPA', (83, 93))	('patients', 'Species', '9606', (103, 111))	('decreased', 'NegReg', (67, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('rs4143815 C.G', 'Var', (13, 26))
198138	30122958	Strikingly, the ORR and the median progression-free survival (PFS) time for the C/C, C/G genotypes of PD-L1 rs4143815 are better than the G/G genotype (Table 3).	('ORR', 'MPA', (16, 19))	('PD-L1', 'Gene', (102, 107))	('rs4143815', 'Var', (108, 117))	('rs4143815', 'Mutation', 'rs4143815', (108, 117))	('PD-L1', 'Gene', '29126', (102, 107))
198139	30122958	Similarly, a better clinical response is observed in the G/G, G/T genotypes of intronic PD-L1 rs2282055 compared with the T/T genotype (Table 3).	('G/G', 'Var', (57, 60))	('rs2282055', 'Var', (94, 103))	('PD-L1', 'Gene', (88, 93))	('better', 'PosReg', (13, 19))	('PD-L1', 'Gene', '29126', (88, 93))	('rs2282055', 'Mutation', 'rs2282055', (94, 103))	('clinical response', 'CPA', (20, 37))	('G/T', 'Var', (62, 65))
198146	30122958	As the mismatch repair system is of pivotal importance in detecting and cutting off mismatches during DNA replication, MSI leads to an endogenous antitumor response that is counterbalanced by the expression of PD-1 or PD-L1.	('mismatches', 'Var', (84, 94))	('PD-L1', 'Gene', (218, 223))	('MSI', 'Disease', (119, 122))	('PD-1', 'Gene', (210, 214))	('PD-1', 'Gene', '5133', (210, 214))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('PD-L1', 'Gene', '29126', (218, 223))	('DNA replication', 'biological_process', 'GO:0006260', ('102', '117'))	('mismatch repair', 'biological_process', 'GO:0006298', ('7', '22'))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('leads to', 'Reg', (123, 131))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))	('MSI', 'Disease', 'None', (119, 122))
198159	30122958	The limitations of MSI in drug response prediction have triggered the discovery of some new biomarkers by screening the tumors, including POLE mutations as a positive biomarker in MSS phenotype and JAK1/2 mutations as negative biomarkers in MSI phenotype (Table 1).	('MSI', 'Disease', (19, 22))	('tumors', 'Disease', (120, 126))	('MSS', 'Disease', (180, 183))	('MSI', 'Disease', 'None', (241, 244))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('MSI', 'Disease', (241, 244))	('JAK1/2', 'Gene', '3716;3717', (198, 204))	('JAK', 'molecular_function', 'GO:0004713', ('198', '201'))	('JAK1/2', 'Gene', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('MSS', 'Disease', 'MESH:D013132', (180, 183))	('MSI', 'Disease', 'None', (19, 22))	('mutations', 'Var', (143, 152))
198160	30122958	First, mutations in POLE have provided hopes for patients with an MSS phenotype.	('POLE', 'Gene', (20, 24))	('MSS', 'Disease', 'MESH:D013132', (66, 69))	('MSS', 'Disease', (66, 69))	('patients', 'Species', '9606', (49, 57))	('mutations', 'Var', (7, 16))
198161	30122958	Mutations in POLE contribute to an MSS phenotype, but still predict effective response to pembrolizumab in patients with colorectal cancer.	('pembrolizumab', 'Chemical', 'MESH:C582435', (90, 103))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('response', 'MPA', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Mutations', 'Var', (0, 9))	('predict', 'Reg', (60, 67))	('MSS', 'Disease', 'MESH:D013132', (35, 38))	('MSS', 'Disease', (35, 38))	('colorectal cancer', 'Disease', (121, 138))	('POLE', 'Gene', (13, 17))	('patients', 'Species', '9606', (107, 115))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))
198163	30122958	Larger clinical trials testing drug response in patients with mutated POLE and MSS are required, including a study of pembrolizumab for patients with advanced cancer (NCT02693535), a Phase II study evaluating avelumab for patients with endometrial cancer (NCT02912572) as well as a Phase II study assessing azacitidine in combination with durvalumab for patients with colorectal carcinoma (NCT 02811497;ongoing trial).	('patients', 'Species', '9606', (222, 230))	('durvalumab', 'Chemical', 'MESH:C000613593', (339, 349))	('NCT02912572', 'Var', (256, 267))	('MSS', 'Disease', (79, 82))	('patients', 'Species', '9606', (354, 362))	('endometrial cancer', 'Phenotype', 'HP:0012114', (236, 254))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (248, 254))	('avelumab', 'Chemical', 'MESH:C000609138', (209, 217))	('azacitidine', 'Chemical', 'MESH:D001374', (307, 318))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('MSS', 'Disease', 'MESH:D013132', (79, 82))	('endometrial cancer', 'Disease', (236, 254))	('endometrial cancer', 'Disease', 'MESH:D016889', (236, 254))	('colorectal carcinoma', 'Disease', (368, 388))	('carcinoma', 'Phenotype', 'HP:0030731', (379, 388))	('pembrolizumab', 'Chemical', 'MESH:C582435', (118, 131))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (368, 388))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('patients', 'Species', '9606', (136, 144))	('patients', 'Species', '9606', (48, 56))	('mutated', 'Var', (62, 69))
198166	30122958	So that loss-of-function mutations of JAK1 and JAK2 can abolish interferon-gamma signaling.	('JAK', 'molecular_function', 'GO:0004713', ('38', '41'))	('mutations', 'Var', (25, 34))	('JAK2', 'Gene', '3717', (47, 51))	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('interferon-gamma', 'Gene', '3458', (64, 80))	('abolish', 'NegReg', (56, 63))	('JAK2', 'Gene', (47, 51))	('JAK', 'molecular_function', 'GO:0004713', ('47', '50'))	('interferon-gamma', 'Gene', (64, 80))	('JAK1', 'Gene', (38, 42))	('loss-of-function', 'NegReg', (8, 24))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('64', '80'))	('JAK1', 'Gene', '3716', (38, 42))
198167	30122958	It has been reported in case reports that JAK1 and JAK2 mutations are involved in primary resistance to pembrolizumab in dMMR colon cancer.	('mutations', 'Var', (56, 65))	('pembrolizumab', 'Chemical', 'MESH:C582435', (104, 117))	('JAK2', 'Gene', '3717', (51, 55))	('JAK', 'molecular_function', 'GO:0004713', ('51', '54'))	('colon cancer', 'Phenotype', 'HP:0003003', (126, 138))	('primary resistance to pembrolizumab', 'MPA', (82, 117))	('colon cancer', 'Disease', 'MESH:D015179', (126, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('JAK', 'molecular_function', 'GO:0004713', ('42', '45'))	('JAK2', 'Gene', (51, 55))	('JAK1', 'Gene', (42, 46))	('involved', 'Reg', (70, 78))	('dMMR', 'Chemical', '-', (121, 125))	('colon cancer', 'Disease', (126, 138))	('JAK1', 'Gene', '3716', (42, 46))
198170	30122958	Mutations in tumor biopsies have long been plausible biomarkers for drug response prediction.	('tumor', 'Disease', (13, 18))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
198172	30122958	With tumors not mutated for JAK1 or JAK2, patients with melanoma still show resistance to pembrolizumab therapy due to newly occurred JAK1 and JAK2 mutations during the treatment.	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('JAK2', 'Gene', '3717', (143, 147))	('pembrolizumab', 'Chemical', 'MESH:C582435', (90, 103))	('JAK1', 'Gene', '3716', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('JAK2', 'Gene', (143, 147))	('JAK1', 'Gene', (134, 138))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('JAK2', 'Gene', '3717', (36, 40))	('JAK', 'molecular_function', 'GO:0004713', ('36', '39'))	('mutations', 'Var', (148, 157))	('patients', 'Species', '9606', (42, 50))	('JAK1', 'Gene', (28, 32))	('tumors', 'Disease', (5, 11))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('JAK2', 'Gene', (36, 40))	('JAK', 'molecular_function', 'GO:0004713', ('134', '137'))	('JAK', 'molecular_function', 'GO:0004713', ('143', '146'))	('JAK1', 'Gene', '3716', (134, 138))	('JAK', 'molecular_function', 'GO:0004713', ('28', '31'))
198173	30122958	Similarly, a truncated B2M mutation can result in defective antigen presentation and was reported to be linked to acquired resistance to pembrolizumab.	('B2M', 'Gene', (23, 26))	('antigen presentation', 'MPA', (60, 80))	('B2M', 'Gene', '567', (23, 26))	('truncated', 'Var', (13, 22))	('linked', 'Reg', (104, 110))	('antigen presentation', 'biological_process', 'GO:0019882', ('60', '80'))	('pembrolizumab', 'Chemical', 'MESH:C582435', (137, 150))	('defective', 'NegReg', (50, 59))
198210	30122958	Therefore, the ratio of Ki67+ CD8 T cells to pretreatment tumor burden at 6 weeks post pembrolizumab treatment was used as the "reinvigoration score" instead.	('CD8', 'Gene', (30, 33))	('tumor', 'Disease', (58, 63))	('pembrolizumab', 'Chemical', 'MESH:C582435', (87, 100))	('CD8', 'Gene', '925', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Ki67', 'Chemical', '-', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Ki67+', 'Var', (24, 29))
198219	30122958	In a chronic virus-infected mouse model of prostate cancer, the de novo methylation in loci such as IFN-gamma, Myc, Tcf7, Ccr7, Tbx21, and Eomesodermin makes activated CD8 T cells fully exhausted and restricts T cell expansion and clonal diversity.	('Tbx21', 'Gene', '57765', (128, 133))	('T cell expansion', 'CPA', (210, 226))	('Tcf7', 'Gene', (116, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (43, 58))	('Myc', 'Gene', (111, 114))	('prostate cancer', 'Phenotype', 'HP:0012125', (43, 58))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('CD8', 'Gene', (168, 171))	('prostate cancer', 'Disease', (43, 58))	('cell expansion', 'biological_process', 'GO:0016049', ('212', '226'))	('Myc', 'Gene', '17869', (111, 114))	('mouse', 'Species', '10090', (28, 33))	('clonal diversity', 'CPA', (231, 247))	('Tbx21', 'Gene', (128, 133))	('Tcf7', 'Gene', '21414', (116, 120))	('Ccr', 'molecular_function', 'GO:0043880', ('122', '125'))	('Ccr7', 'Gene', '12775', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Ccr7', 'Gene', (122, 126))	('CD8', 'Gene', '925', (168, 171))	('methylation', 'Var', (72, 83))	('restricts', 'NegReg', (200, 209))
198231	30122958	First, regarding tumor characteristics, biomarkers before the initiation of the treatment were centered on PD-L1 expression or MSI, including PD-L1 SNPs such as rs4143815 and rs2282055 compensative for PD-L1 expression, POLE mutations responsive in the MSS phenotype, and JAK1 and JAK2 mutations negative in the MSI phenotype.	('PD-L1', 'Gene', '29126', (202, 207))	('JAK2', 'Gene', (281, 285))	('PD-L1', 'Gene', (142, 147))	('rs2282055', 'Mutation', 'rs2282055', (175, 184))	('mutations', 'Var', (286, 295))	('PD-L1', 'Gene', '29126', (142, 147))	('MSS', 'Disease', (253, 256))	('rs4143815', 'Mutation', 'rs4143815', (161, 170))	('JAK', 'molecular_function', 'GO:0004713', ('272', '275'))	('JAK', 'molecular_function', 'GO:0004713', ('281', '284'))	('MSI', 'Disease', 'None', (312, 315))	('JAK1', 'Gene', '3716', (272, 276))	('tumor', 'Disease', (17, 22))	('MSS', 'Disease', 'MESH:D013132', (253, 256))	('MSI', 'Disease', (312, 315))	('rs2282055', 'Var', (175, 184))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('PD-L1', 'Gene', (107, 112))	('MSI', 'Disease', 'None', (127, 130))	('rs4143815', 'Var', (161, 170))	('PD-L1', 'Gene', '29126', (107, 112))	('JAK2', 'Gene', '3717', (281, 285))	('MSI', 'Disease', (127, 130))	('JAK1', 'Gene', (272, 276))	('PD-L1', 'Gene', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
198232	30122958	Biomarkers in tumor biopsies can also monitor PD-1/PD-L1 blockade, including newly occurred JAK1, JAK2, and B2M mutations that lead to resistance, and PD-L1 upregulation that indicates responsiveness.	('PD-L1', 'Gene', '29126', (51, 56))	('JAK1', 'Gene', '3716', (92, 96))	('JAK2', 'Gene', (98, 102))	('mutations', 'Var', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('upregulation', 'PosReg', (157, 169))	('PD-L1', 'Gene', (151, 156))	('PD-L1', 'Gene', '29126', (151, 156))	('JAK1', 'Gene', (92, 96))	('B2M', 'Gene', (108, 111))	('PD-1', 'Gene', (46, 50))	('PD-1', 'Gene', '5133', (46, 50))	('JAK', 'molecular_function', 'GO:0004713', ('98', '101'))	('resistance', 'MPA', (135, 145))	('tumor', 'Disease', (14, 19))	('JAK2', 'Gene', '3717', (98, 102))	('lead to', 'Reg', (127, 134))	('JAK', 'molecular_function', 'GO:0004713', ('92', '95'))	('B2M', 'Gene', '567', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('PD-L1', 'Gene', (51, 56))
198255	29135410	When p53 becomes damaged, tumor suppression is severely compromised, potentiating the formation of tumors.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Disease', (99, 104))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('formation', 'biological_process', 'GO:0009058', ('86', '95'))	('p53', 'Gene', (5, 8))	('tumor', 'Disease', (26, 31))	('p53', 'Gene', '7157', (5, 8))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('damaged', 'Var', (17, 24))	('potentiating', 'PosReg', (69, 81))	('tumors', 'Disease', (99, 105))
198266	29135410	Overexpression of cyclin A and E and dysregulation of CDK-cyclin complexes can promote tumor cell growth and mediate the pathogenesis of cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cyclin', 'Gene', (18, 24))	('dysregulation', 'Var', (37, 50))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cyclin', 'molecular_function', 'GO:0016538', ('58', '64'))	('cell growth', 'biological_process', 'GO:0016049', ('93', '104'))	('cyclin A and E', 'Gene', '890', (18, 32))	('tumor', 'Disease', (87, 92))	('cyclin', 'Gene', '5111', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('promote', 'PosReg', (79, 86))	('CDK', 'molecular_function', 'GO:0004693', ('54', '57'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cyclin', 'Gene', (58, 64))	('cyclin', 'Gene', '5111', (18, 24))	('pathogenesis', 'biological_process', 'GO:0009405', ('121', '133'))	('cyclin', 'molecular_function', 'GO:0016538', ('18', '24'))
198267	29135410	In addition, high expression of cyclins A and E is associated with a poor prognosis in several types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('high', 'Var', (13, 17))	('cyclins A and E', 'Gene', '890', (32, 47))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
198268	29135410	studied 340 patients with localized disease and found that expression of cyclin A was associated with worse metastasis-free survival (MFS) in the univariate but not multivariate analysis.	('worse', 'NegReg', (102, 107))	('patients', 'Species', '9606', (12, 20))	('localized disease', 'Disease', (26, 43))	('localized disease', 'Disease', 'MESH:D012594', (26, 43))	('cyclin', 'molecular_function', 'GO:0016538', ('73', '79'))	('metastasis-free survival', 'CPA', (108, 132))	('cyclin A', 'Gene', (73, 81))	('expression', 'Var', (59, 69))	('cyclin A', 'Gene', '890', (73, 81))
198289	29135410	Thus, Ki67 can be used as a marker of bladder recurrence after RNU, anticipating intravesical therapies.	('Ki67', 'Chemical', '-', (6, 10))	('RNU', 'Chemical', '-', (63, 66))	('Ki67', 'Var', (6, 10))	('bladder recurrence', 'Disease', (38, 56))
198292	29135410	Overexpression of Ki67 was significantly associated with higher pT stage, lympho-vascular invasion, sessile tumor architecture, tumor necrosis, concomitant carcinoma in situ, and regional lymph node metastasis.	('carcinoma', 'Disease', 'MESH:D002277', (156, 165))	('associated', 'Reg', (41, 51))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (156, 173))	('sessile tumor', 'Disease', 'MESH:D009369', (100, 113))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('lympho-vascular invasion', 'CPA', (74, 98))	('Ki67', 'Chemical', '-', (18, 22))	('Overexpression', 'Var', (0, 14))	('necrosis', 'biological_process', 'GO:0008220', ('134', '142'))	('necrosis', 'biological_process', 'GO:0070265', ('134', '142'))	('necrosis', 'biological_process', 'GO:0019835', ('134', '142'))	('sessile tumor', 'Disease', (100, 113))	('necrosis', 'biological_process', 'GO:0001906', ('134', '142'))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('carcinoma', 'Disease', (156, 165))	('tumor necrosis', 'Disease', 'MESH:D009336', (128, 142))	('necrosis', 'biological_process', 'GO:0008219', ('134', '142'))	('regional lymph node metastasis', 'CPA', (179, 209))	('higher pT stage', 'CPA', (57, 72))	('tumor necrosis', 'Disease', (128, 142))	('Ki67', 'Gene', (18, 22))
198293	29135410	By multivariate analysis, Ki67 was an independent predictor of DFS and CSS.	('Ki67', 'Var', (26, 30))	('Ki67', 'Chemical', '-', (26, 30))	('CSS', 'Gene', '55907', (71, 74))	('CSS', 'Gene', (71, 74))	('DFS', 'Disease', (63, 66))
198297	29135410	Amplification or overexpression of HER-2 stimulates the phophoinositide-3 kinase (PI3K)/AKT pathway and is associated with the development and progression of certain aggressive types of cancer.	('Amplification', 'Var', (0, 13))	('HER-2', 'Gene', (35, 40))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('AKT', 'Gene', '207', (88, 91))	('stimulates', 'PosReg', (41, 51))	('overexpression', 'PosReg', (17, 31))	('associated with', 'Reg', (107, 122))	('AKT', 'Gene', (88, 91))	('HER-2', 'Gene', '2064', (35, 40))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
198298	29135410	In breast cancer, HER-2 amplification is found in nearly 25% to 30% of tumors and correlates with disease recurrence and poor survival.	('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))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('amplification', 'Var', (24, 37))	('HER-2', 'Gene', '2064', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('HER-2', 'Gene', (18, 23))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
198302	29135410	However, patients with overexpression and amplification of HER-2 were more likely to have higher-grade and -stage disease.	('patients', 'Species', '9606', (9, 17))	('overexpression', 'Var', (23, 37))	('HER-2', 'Gene', '2064', (59, 64))	('amplification', 'Var', (42, 55))	('HER-2', 'Gene', (59, 64))
198306	29135410	investigated HER-2 status in 171 UTUC patients who underwent RNU and found that overexpression and amplification of HER-2 was associated with early bladder cancer recurrence.	('overexpression', 'PosReg', (80, 94))	('bladder cancer', 'Disease', 'MESH:D001749', (148, 162))	('bladder cancer', 'Disease', (148, 162))	('associated with', 'Reg', (126, 141))	('patients', 'Species', '9606', (38, 46))	('HER-2', 'Gene', '2064', (13, 18))	('HER-2', 'Gene', (116, 121))	('HER-2', 'Gene', '2064', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('amplification', 'Var', (99, 112))	('HER-2', 'Gene', (13, 18))	('RNU', 'Chemical', '-', (61, 64))	('bladder cancer', 'Phenotype', 'HP:0009725', (148, 162))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (148, 173))
198311	29135410	The activation of EGFR stimulates its intrinsic intracellular protein tyrosine kinase activity and initiates several signal transduction cascades, leading to DNA synthesis and cell proliferation.	('protein tyrosine kinase activity', 'molecular_function', 'GO:0004713', ('62', '94'))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'molecular_function', 'GO:0005006', ('18', '22'))	('activation', 'Var', (4, 14))	('stimulates', 'PosReg', (23, 33))	('cell proliferation', 'biological_process', 'GO:0008283', ('176', '194'))	('EGFR', 'Gene', (18, 22))	('DNA synthesis', 'MPA', (158, 171))	('DNA', 'cellular_component', 'GO:0005574', ('158', '161'))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('158', '171'))	('cell proliferation', 'CPA', (176, 194))	('leading to', 'Reg', (147, 157))	('initiates', 'Reg', (99, 108))	('signal transduction', 'biological_process', 'GO:0007165', ('117', '136'))	('intracellular', 'cellular_component', 'GO:0005622', ('48', '61'))
198312	29135410	Mutations that affect EGFR overexpression or upregulation correlate with several cancers, including UCB.	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('UCB', 'Phenotype', 'HP:0006740', (100, 103))	('Mutations', 'Var', (0, 9))	('EGFR', 'Gene', '1956', (22, 26))	('UCB', 'Disease', (100, 103))	('upregulation', 'PosReg', (45, 57))	('overexpression', 'PosReg', (27, 41))	('EGFR', 'Gene', (22, 26))
198316	29135410	EGFR staining was associated with higher tumor stage and grade, and its intensity correlated with metastatic disease in the univariate but not multivariate analysis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('metastatic disease', 'Disease', (98, 116))	('EGFR', 'Gene', (0, 4))	('tumor', 'Disease', (41, 46))	('staining', 'Var', (5, 13))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('EGFR', 'Gene', '1956', (0, 4))	('grade', 'CPA', (57, 62))
198317	29135410	recently analyzed 320 UTUC patients and found that EGFR positivity was an independent risk factor for bladder cancer recurrence after RNU.	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('EGFR', 'Gene', (51, 55))	('positivity', 'Var', (56, 66))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('bladder cancer', 'Disease', (102, 116))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (102, 127))	('patients', 'Species', '9606', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('RNU', 'Chemical', '-', (134, 137))	('EGFR', 'Gene', '1956', (51, 55))
198339	29135410	By multivariate analysis, high VASH1 density was an independent predictor of tumor recurrence and CSS.	('VASH1', 'Gene', (31, 36))	('high', 'Var', (26, 30))	('VASH1', 'Gene', '22846', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('CSS', 'Gene', '55907', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CSS', 'Gene', (98, 101))	('tumor', 'Disease', (77, 82))
198346	29135410	In survival analyses, negativity for 4N1K was a predictor of DFS and CSS in the univariate but not multivariate analysis.	('4N1K', 'Protein', (37, 41))	('DFS', 'Disease', (61, 64))	('negativity', 'Var', (22, 32))	('CSS', 'Gene', '55907', (69, 72))	('CSS', 'Gene', (69, 72))
198349	29135410	In general, FGFR3 mutations are associated with low-risk tumors that rarely progress and usually have a good prognosis in bladder cancer patients.	('FGFR3', 'Gene', (12, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (122, 136))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))	('patients', 'Species', '9606', (137, 145))	('bladder cancer', 'Disease', 'MESH:D001749', (122, 136))	('bladder cancer', 'Disease', (122, 136))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('FGFR3', 'Gene', '2261', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('mutations', 'Var', (18, 27))
198350	29135410	reported that FGFR3 mutations occurred at the same frequencies in UTUC and bladder tumors in 280 patients (117 bladder tumors and 163 upper tract tumors) with a median follow-up of 56 months.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('bladder tumors', 'Disease', (111, 125))	('FGFR3', 'Gene', (14, 19))	('upper tract tumors', 'Disease', 'MESH:D012141', (134, 152))	('bladder tumors', 'Phenotype', 'HP:0009725', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('FGFR3', 'Gene', '2261', (14, 19))	('bladder tumors', 'Disease', 'MESH:D001749', (75, 89))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('bladder tumors', 'Disease', (75, 89))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('bladder tumors', 'Disease', 'MESH:D001749', (111, 125))	('upper tract tumors', 'Disease', (134, 152))	('mutations', 'Var', (20, 29))	('patients', 'Species', '9606', (97, 105))	('UTUC', 'Disease', (66, 70))	('bladder tumors', 'Phenotype', 'HP:0009725', (75, 89))
198351	29135410	They also claimed that FGFR3 mutations correlated with low-stage tumors and better survival in patients with UTUC and UCB.	('FGFR3', 'Gene', (23, 28))	('low-stage tumors', 'Disease', 'MESH:D009800', (55, 71))	('low-stage tumors', 'Disease', (55, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('patients', 'Species', '9606', (95, 103))	('mutations', 'Var', (29, 38))	('survival', 'CPA', (83, 91))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('better', 'PosReg', (76, 82))	('FGFR3', 'Gene', '2261', (23, 28))	('UCB', 'Phenotype', 'HP:0006740', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
198352	29135410	Burger and colleagues found that FGFR3 mutations were linked to a favorable stage and grade in 172 UTUC patients and benefited the survival rate-24.1% versus 54.2% cancer-related deaths occurred in the mutated group.	('deaths', 'Disease', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('survival', 'MPA', (131, 139))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('mutations', 'Var', (39, 48))	('FGFR3', 'Gene', '2261', (33, 38))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('benefited', 'PosReg', (117, 126))	('patients', 'Species', '9606', (104, 112))	('FGFR3', 'Gene', (33, 38))	('deaths', 'Disease', 'MESH:D003643', (179, 185))
198386	29135410	N-cadherin positivity was seen in 43% of patients and was associated with features of aggressive disease (advanced tumor stage, lymph node metastases, and sessile architecture) and disease recurrence but not CSS or OS in the univariate analysis.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CSS', 'Gene', '55907', (208, 211))	('associated', 'Reg', (58, 68))	('metastases', 'Disease', (139, 149))	('positivity', 'Var', (11, 21))	('N-cadherin', 'Gene', (0, 10))	('tumor', 'Disease', (115, 120))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('patients', 'Species', '9606', (41, 49))	('CSS', 'Gene', (208, 211))	('N-cadherin', 'Gene', '1000', (0, 10))	('metastases', 'Disease', 'MESH:D009362', (139, 149))	('aggressive disease', 'Disease', 'MESH:D001523', (86, 104))	('OS', 'Chemical', '-', (215, 217))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('aggressive disease', 'Disease', (86, 104))
198392	29135410	measured alpha, beta, and gamma-catenin levels in 70 tumors samples from UTUC patients by immunohistochemistry and correlated them with outcomes- in the multivariate analysis, abnormal beta-catenin expression was an independent prognostic factor of tumor progression and CSS.	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('beta-catenin', 'Gene', '1499', (185, 197))	('patients', 'Species', '9606', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('CSS', 'Gene', '55907', (271, 274))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('abnormal', 'Var', (176, 184))	('tumor', 'Disease', (249, 254))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))	('expression', 'MPA', (198, 208))	('CSS', 'Gene', (271, 274))	('tumors', 'Disease', (53, 59))	('beta-catenin', 'Gene', (185, 197))
198406	29135410	Inhibition of apoptosis and apoptotic pathways can result in tumorigenesis and cancer progression, because it allows tumor cells to survive longer and resist harmful stressors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', (117, 122))	('apoptosis', 'Pathway', (14, 23))	('apoptotic pathways', 'Pathway', (28, 46))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Inhibition of apoptosis', 'biological_process', 'GO:0043066', ('0', '23'))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('tumor', 'Disease', (61, 66))	('result in', 'Reg', (51, 60))
198410	29135410	In the univariate analysis, altered survivin correlated significantly with DFS and CSS but did not achieve independent predictive status by multivariate analysis.	('DFS', 'Disease', (75, 78))	('altered', 'Var', (28, 35))	('CSS', 'Gene', (83, 86))	('survivin', 'Protein', (36, 44))	('CSS', 'Gene', '55907', (83, 86))
198415	29135410	In the survival analysis, altered caspase-3 expression was significantly associated with an increased probability of disease recurrence and CSS.	('caspase-3', 'Gene', '836', (34, 43))	('expression', 'MPA', (44, 54))	('disease recurrence', 'CPA', (117, 135))	('associated', 'Reg', (73, 83))	('CSS', 'Gene', '55907', (140, 143))	('altered', 'Var', (26, 33))	('caspase-3', 'Gene', (34, 43))	('CSS', 'Gene', (140, 143))
198420	29135410	This group observed that patients with high bcl-xl levels had a significantly lower 5-year CSS rate (53%) than those with low expression (77%).	('high', 'Var', (39, 43))	('CSS', 'Gene', '55907', (91, 94))	('CSS', 'Gene', (91, 94))	('bcl-xl', 'MPA', (44, 50))	('patients', 'Species', '9606', (25, 33))	('lower', 'NegReg', (78, 83))
198428	29135410	One pathway was associated with non-muscle-invasive bladder cancer and comprised disruption to PI3K-AKT-mTOR signaling and alterations in FGFR3 and the oncogene HRAS.	('HRAS', 'Gene', (161, 165))	('FGFR3', 'Gene', '2261', (138, 143))	('HRAS', 'Gene', '3265', (161, 165))	('invasive bladder', 'Phenotype', 'HP:0100645', (43, 59))	('AKT', 'Gene', (100, 103))	('signaling', 'biological_process', 'GO:0023052', ('109', '118'))	('PI3K', 'molecular_function', 'GO:0016303', ('95', '99'))	('FGFR3', 'Gene', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('disruption', 'Reg', (81, 91))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('associated', 'Reg', (16, 26))	('AKT', 'Gene', '207', (100, 103))	('alterations', 'Var', (123, 134))	('bladder cancer', 'Disease', (52, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('138', '142'))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))
198440	28848661	Comprehensive molecular characterisation of muscle-invasive urothelial carcinoma and variant histological subtypes has led to the identification of recurrent driver mutations that are distinct in these aggressive subgroups of bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('muscle-invasive urothelial carcinoma', 'Disease', (44, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('bladder cancer', 'Disease', 'MESH:D001749', (226, 240))	('bladder cancer', 'Disease', (226, 240))	('muscle-invasive urothelial carcinoma', 'Disease', 'MESH:D009217', (44, 80))	('mutations', 'Var', (165, 174))	('bladder cancer', 'Phenotype', 'HP:0009725', (226, 240))
198459	28848661	Although nodal involvement has been shown to be a strong predictor of loco-regional and distant relapses, as judged by the 29% compared with 12% local relapse rates in patients with pN+ and pN0 disease, respectively, from SWOG 8710, the optimal management of pelvic nodes remains debatable to date.	('loco-regional', 'CPA', (70, 83))	('patients', 'Species', '9606', (168, 176))	('pN+', 'Var', (182, 185))
198460	28848661	Of note, variant subtype MIBCs are also thought to be at risk of nodal metastasis, with reported rates of as high as 40% in some series.	('MIBCs', 'Gene', (25, 30))	('variant', 'Var', (9, 16))	('MIBCs', 'Chemical', '-', (25, 30))	('nodal metastasis', 'CPA', (65, 81))
198465	28848661	In variant bladder cancers, the implications of improved pelvic control are harder to discern, given the subtle differences in modes of tumour dissemination between the different variant histologies.	('bladder cancers', 'Phenotype', 'HP:0009725', (11, 26))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('tumour dissemination', 'Disease', (136, 156))	('bladder cancers', 'Disease', 'MESH:D001749', (11, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (11, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumour dissemination', 'Disease', 'MESH:D009103', (136, 156))	('variant', 'Var', (3, 10))	('bladder cancers', 'Disease', (11, 26))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
198474	28848661	On this note, biomarkers such as mutations in ERCC1 and other DNA repair genes have been reported to predict for sensitivity to cisplatin-based chemotherapy, and thus would be useful tools to identify patients suitable for neoadjuvant chemotherapy a priori.	('patients', 'Species', '9606', (201, 209))	('predict', 'Reg', (101, 108))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('mutations', 'Var', (33, 42))	('sensitivity to cisplatin-based chemotherapy', 'MPA', (113, 156))	('ERCC1', 'Gene', '2067', (46, 51))	('ERCC1', 'Gene', (46, 51))	('DNA repair', 'biological_process', 'GO:0006281', ('62', '72'))
198476	28848661	Arguably, there is limited evidence on the efficacy of adjuvant pelvic radiotherapy, but based on the findings of few randomised trials and retrospective series, it would seem that the primary advantage of adjuvant radiotherapy relates to improved local control, and possibly disease-free survival (table 1).Notably, Zaghloul et al investigated the role of adjuvant radiotherapy to the cystectomy bed and nodal basins, albeit using a variety of fractionation schedules, in patients with pT3-T4 MIBC, and observed substantial gains in local control rates amounting to 37%-43% compared with patients who underwent RC alone.	('patients', 'Species', '9606', (589, 597))	('MIBC', 'Chemical', '-', (494, 498))	('pT3-T4 MIBC', 'Var', (487, 498))	('patients', 'Species', '9606', (473, 481))	('RC', 'Chemical', '-', (612, 614))	('local', 'MPA', (534, 539))	('gains', 'PosReg', (525, 530))
198490	28848661	For the coverage of at-risk nodal regions, while a CTV encompassing the iliac (common, external, and internal iliac) and obturator lymph nodes would sufficiently treat 76% of patients with >=pT3-status and negative margin disease, expansion of the CTV to include the presacral lymph nodes would increase the likelihood of pelvic control by a further 3%.	('pelvic control', 'CPA', (322, 336))	('patients', 'Species', '9606', (175, 183))	('>=pT3-status', 'Var', (189, 201))	('increase', 'PosReg', (295, 303))
198492	28848661	Patients with mixed urothelial carcinoma and variant histologies are allowed in this study, which affirms the impression that variant histological subtype bladder cancers are more clinically aggressive.	('subtype bladder cancers', 'Disease', (147, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('bladder cancers', 'Phenotype', 'HP:0009725', (155, 170))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (20, 40))	('subtype bladder cancers', 'Disease', 'MESH:D001749', (147, 170))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('bladder cancer', 'Phenotype', 'HP:0009725', (155, 169))	('Patients', 'Species', '9606', (0, 8))	('urothelial carcinoma', 'Disease', (20, 40))	('variant', 'Var', (126, 133))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))
198497	28848661	The Cancer Genome Atlas (TCGA) consortium first reported in 131 chemotherapy-naive bladder tumours, high frequencies of recurrent driver mutations (>10%), which included genes involved in cell cycle (eg, CDKN1A, CDKN2A, RB1), chromatin remodelling (ARID1A, KDM6A) and kinase signalling (PIK3CA, EGFR, FGFR3) pathways.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('cell cycle', 'biological_process', 'GO:0007049', ('188', '198'))	('FGFR3', 'Gene', (301, 306))	('KDM6A', 'Gene', (257, 262))	('PIK3CA', 'Gene', '5290', (287, 293))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('CDKN2A', 'Gene', '1029', (212, 218))	('FGFR3', 'Gene', '2261', (301, 306))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('bladder tumours', 'Disease', (83, 98))	('ARID1A', 'Gene', (249, 255))	('RB1', 'Gene', (220, 223))	('bladder tumour', 'Phenotype', 'HP:0009725', (83, 97))	('PIK3CA', 'Gene', (287, 293))	('ARID1A', 'Gene', '8289', (249, 255))	('EGFR', 'Gene', (295, 299))	('signalling', 'biological_process', 'GO:0023052', ('275', '285'))	('EGFR', 'molecular_function', 'GO:0005006', ('295', '299'))	('FGFR', 'molecular_function', 'GO:0005007', ('301', '305'))	('RB1', 'Gene', '5925', (220, 223))	('bladder tumours', 'Disease', 'MESH:D001749', (83, 98))	('KDM6A', 'Gene', '7403', (257, 262))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('226', '247'))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('CDKN1A', 'Gene', '1026', (204, 210))	('CDKN1A', 'Gene', (204, 210))	('mutations', 'Var', (137, 146))	('CDKN2A', 'Gene', (212, 218))	('chromatin', 'cellular_component', 'GO:0000785', ('226', '235'))	('Cancer Genome Atlas', 'Disease', (4, 23))	('EGFR', 'Gene', '1956', (295, 299))
198499	28848661	Crucially, more than two-thirds of the profiled mutations in the tumours could be matched to targeted therapeutics, thus justifying the clinical relevance of these molecular studies.	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('mutations', 'Var', (48, 57))	('tumours', 'Disease', (65, 72))
198500	28848661	In the same vein, two other translational studies that specifically focused on patients with advanced disease confirmed the findings of TCGA, but added observations of an enrichment of ERBB2 mutations in micropapillary variants, and novel mutations in the gene UNC5C.	('papillary', 'Disease', 'MESH:D002291', (209, 218))	('mutations', 'Reg', (239, 248))	('ERBB2', 'Gene', '2064', (185, 190))	('UNC5C', 'Gene', (261, 266))	('mutations', 'Var', (191, 200))	('ERBB2', 'Gene', (185, 190))	('UNC5C', 'Gene', '8633', (261, 266))	('patients', 'Species', '9606', (79, 87))	('papillary', 'Disease', (209, 218))
198501	28848661	Moreover, Yap et al observed that somatic mutations in the DNA repair genes (ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) also predicted for better relapse-free survival, which is in agreement with previous studies showing the link between mutated ERCC2 and an enhanced response to cisplatin in urothelial carcinoma.	('better', 'PosReg', (140, 146))	('BRCA2', 'Gene', (114, 119))	('Yap', 'Gene', (10, 13))	('urothelial carcinoma', 'Disease', (294, 314))	('ATM', 'Gene', '472', (77, 80))	('ERCC2', 'Gene', '2068', (82, 87))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('ERCC2', 'Gene', (247, 252))	('BRCA2', 'Gene', '675', (114, 119))	('response to cisplatin', 'biological_process', 'GO:0072718', ('269', '290'))	('ERCC2', 'Gene', '2068', (247, 252))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (294, 314))	('FANCD2', 'Gene', (89, 95))	('BRCA1', 'Gene', '672', (104, 109))	('ATM', 'Gene', (77, 80))	('BRCA1', 'Gene', (104, 109))	('relapse-free survival', 'CPA', (147, 168))	('FANCD2', 'Gene', '2177', (89, 95))	('Yap', 'Gene', '10413', (10, 13))	('PALB2', 'Gene', (97, 102))	('predicted', 'Reg', (126, 135))	('enhanced', 'PosReg', (260, 268))	('ERCC2', 'Gene', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('mutated', 'Var', (239, 246))	('cisplatin', 'Chemical', 'MESH:D002945', (281, 290))	('mutations', 'Var', (42, 51))	('DNA repair', 'biological_process', 'GO:0006281', ('59', '69'))	('PALB2', 'Gene', '79728', (97, 102))
198502	28848661	Pertaining to variant histologies, which were excluded from the TCGA study, a more recent report highlighted the high prevalence (>80%) of recurrent loss-of-function mutations in the CDH1 gene in plasmacytoid tumours.	('tumours', 'Phenotype', 'HP:0002664', (209, 216))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('mutations', 'Var', (166, 175))	('CDH1', 'Gene', (183, 187))	('CDH1', 'Gene', '999', (183, 187))	('tumours', 'Disease', 'MESH:D009369', (209, 216))	('tumours', 'Disease', (209, 216))	('loss-of-function', 'NegReg', (149, 165))
198506	28848661	An intuitive approach could be the following: foremost, identifying at-risk individuals based on the clinical model proposed by Christodouleas et al,  with an added layer of molecular stratification in patients with 'low-risk' urothelial carcinoma and variant histologies whose tumours are enriched for driver mutations in the ERBB2, CDH1 and DNA repair genes; next, depending on their germline or tumour MRE11 functional status, patients would be assigned to either adjuvant radiotherapy (radiosensitive) or basket novel targeted therapeutics trials (non-radiosensitive; figure 2).	('urothelial carcinoma', 'Disease', 'MESH:D014526', (227, 247))	('ERBB2', 'Gene', '2064', (327, 332))	('mutations', 'Var', (310, 319))	('DNA repair genes', 'Gene', (343, 359))	('DNA repair', 'biological_process', 'GO:0006281', ('343', '353'))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('patients', 'Species', '9606', (202, 210))	('DNA', 'cellular_component', 'GO:0005574', ('343', '346'))	('tumours', 'Disease', (278, 285))	('tumour', 'Phenotype', 'HP:0002664', (398, 404))	('CDH1', 'Gene', '999', (334, 338))	('tumour', 'Phenotype', 'HP:0002664', (278, 284))	('tumour', 'Disease', 'MESH:D009369', (278, 284))	('tumour', 'Disease', 'MESH:D009369', (398, 404))	('tumour', 'Disease', (398, 404))	('tumours', 'Phenotype', 'HP:0002664', (278, 285))	('patients', 'Species', '9606', (430, 438))	('tumour', 'Disease', (278, 284))	('MRE11', 'Gene', (405, 410))	('tumours', 'Disease', 'MESH:D009369', (278, 285))	('urothelial carcinoma', 'Disease', (227, 247))	('CDH1', 'Gene', (334, 338))	('MRE11', 'Gene', '4361', (405, 410))	('ERBB2', 'Gene', (327, 332))
198511	28848661	Alternatively, genomic and transcriptomic profiling have also revealed novel molecular targets in advanced and variant bladder cancers, which could also pave the way for synergistic therapeutic combinations of small molecular inhibitors and radiotherapy.	('variant', 'Var', (111, 118))	('bladder cancers', 'Disease', 'MESH:D001749', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('bladder cancer', 'Phenotype', 'HP:0009725', (119, 133))	('bladder cancers', 'Disease', (119, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('bladder cancers', 'Phenotype', 'HP:0009725', (119, 134))
198537	27467953	Recently, in patients with metastatic urothelial carcinoma, inhibition of the immune checkpoint inhibitor PDL-1 using anti-PD-L1 antibody MPDL3280A was associated with a response rate of approximately 30% in unselected patients, and a favorable tolerability profile.	('PDL-1', 'Gene', '29126', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('inhibition', 'Var', (60, 70))	('antibody', 'cellular_component', 'GO:0019814', ('129', '137'))	('patients', 'Species', '9606', (13, 21))	('PDL-1', 'Gene', (106, 111))	('antibody', 'molecular_function', 'GO:0003823', ('129', '137'))	('MPDL3280A', 'Var', (138, 147))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (38, 58))	('patients', 'Species', '9606', (219, 227))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (138, 147))	('antibody', 'cellular_component', 'GO:0042571', ('129', '137'))	('urothelial carcinoma', 'Disease', (38, 58))	('antibody', 'cellular_component', 'GO:0019815', ('129', '137'))
198620	26376852	Definitive pathological analysis rendered pT2N0M0 high-grade urothelial carcinoma (TNM 2009) with free surgical borders, associated with prostatic adenocarcinoma Gleason score 7 (3 + 4), grade 4 involving 20 % of both prostatic lobes.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('prostatic lobes', 'Disease', 'MESH:D011472', (218, 233))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (61, 81))	('prostatic lobes', 'Disease', (218, 233))	('pT2N0M0', 'Var', (42, 49))	('prostatic adenocarcinoma Gleason', 'Disease', 'MESH:D011471', (137, 169))	('urothelial carcinoma', 'Disease', (61, 81))	('prostatic adenocarcinoma Gleason', 'Disease', (137, 169))
198643	26376852	Although 18F-FDG/PET-CT has been shown to improve baseline staging in the nodal staging of bladder cancer, controversy stills exists in relation to the widespread use of PET/CT in clinical practice.	('18F-FDG/PET-CT', 'Var', (9, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('bladder cancer', 'Disease', (91, 105))	('improve', 'PosReg', (42, 49))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('18F-FDG', 'Chemical', 'MESH:D019788', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('baseline staging', 'MPA', (50, 66))
198656	26376852	18F-FDG PET/CT 18F-fludeoxyglucose-positron emission tomography/computed tomography CT computed tomography MIBC muscle-invasive bladder cancer	('bladder cancer', 'Disease', 'MESH:D001749', (128, 142))	('bladder cancer', 'Disease', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('invasive bladder', 'Phenotype', 'HP:0100645', (119, 135))	('MIBC', 'Var', (107, 111))	('18F-FDG', 'Chemical', 'MESH:D019788', (0, 7))	('MIBC', 'Chemical', '-', (107, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('18F-fludeoxyglucose', 'Chemical', '-', (15, 34))
198663	24908363	HA-1077 dramatically suppressed the expression of ROCK-I and ROCK-II, but did not affect RhoA activity.	('ROCK-I', 'Gene', '6093', (50, 56))	('RhoA', 'Gene', '387', (89, 93))	('ROCK-I', 'Gene', (61, 67))	('ROCK-I', 'Gene', (50, 56))	('ROCK-I', 'Gene', '6093', (61, 67))	('suppressed', 'NegReg', (21, 31))	('ROCK-II', 'Gene', '9475', (61, 68))	('HA-1077', 'Var', (0, 7))	('ROCK-II', 'Gene', (61, 68))	('HA-1077', 'Chemical', 'MESH:C049347', (0, 7))	('RhoA', 'Gene', (89, 93))	('expression', 'MPA', (36, 46))
198685	24908363	It has been reported that HA-1077 is effective for the treatment of cardiovascular disease, including coronary and cerebral vasospasm, arteriosclerosis/stenosis, ischemia/reperfusion injury, systemic hypertension, pulmonary hypertension, stroke, and heart failure.	('arteriosclerosis', 'Disease', (135, 151))	('hypertension', 'Disease', 'MESH:D006973', (224, 236))	('pulmonary hypertension', 'Disease', 'MESH:D006976', (214, 236))	('heart failure', 'Phenotype', 'HP:0001635', (250, 263))	('pulmonary hypertension', 'Disease', (214, 236))	('heart failure', 'Disease', 'MESH:D006333', (250, 263))	('stroke', 'Phenotype', 'HP:0001297', (238, 244))	('hypertension', 'Disease', 'MESH:D006973', (200, 212))	('hypertension', 'Disease', (224, 236))	('ischemia', 'Disease', (162, 170))	('hypertension', 'Disease', (200, 212))	('stroke', 'Disease', 'MESH:D020521', (238, 244))	('HA-1077', 'Var', (26, 33))	('arteriosclerosis', 'Phenotype', 'HP:0002634', (135, 151))	('cerebral vasospasm', 'Disease', (115, 133))	('vasospasm', 'Phenotype', 'HP:0025637', (124, 133))	('hypertension', 'Phenotype', 'HP:0000822', (224, 236))	('stroke', 'Disease', (238, 244))	('heart failure', 'Disease', (250, 263))	('systemic hypertension', 'Phenotype', 'HP:0000822', (191, 212))	('hypertension', 'Phenotype', 'HP:0000822', (200, 212))	('ischemia', 'Disease', 'MESH:D007511', (162, 170))	('HA-1077', 'Chemical', 'MESH:C049347', (26, 33))	('cerebral vasospasm', 'Disease', 'MESH:D020301', (115, 133))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (68, 90))	('cardiovascular disease', 'Disease', 'MESH:D002318', (68, 90))	('arteriosclerosis', 'Disease', 'MESH:D001161', (135, 151))	('cardiovascular disease', 'Disease', (68, 90))
198687	24908363	HA-1077 has been recognized as a promising agent for preventing recurrent vasospasm of cerebral arteries after aneurysmal subarachnoid hemorrhage and its use is covered by the Japanese national health insurance system.	('vasospasm of cerebral arteries', 'Disease', 'MESH:D020301', (74, 104))	('vasospasm', 'Phenotype', 'HP:0025637', (74, 83))	('HA-1077', 'Var', (0, 7))	('aneurysmal subarachnoid hemorrhage', 'Disease', 'MESH:D013345', (111, 145))	('vasospasm of cerebral arteries', 'Disease', (74, 104))	('HA-1077', 'Chemical', 'MESH:C049347', (0, 7))	('aneurysmal subarachnoid hemorrhage', 'Disease', (111, 145))	('subarachnoid hemorrhage', 'Phenotype', 'HP:0002138', (122, 145))
198688	24908363	Because it inhibits the Rho/ROCK pathway, we investigated whether HA-1077 could block the proliferation and migration of bladder cancer cell lines or induce apoptosis of these cells.	('bladder cancer', 'Disease', (121, 135))	('induce', 'PosReg', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('apoptosis', 'CPA', (157, 166))	('apoptosis', 'biological_process', 'GO:0006915', ('157', '166'))	('proliferation', 'CPA', (90, 103))	('inhibits', 'NegReg', (11, 19))	('HA-1077', 'Var', (66, 73))	('block', 'NegReg', (80, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (121, 135))	('Rho/ROCK pathway', 'Pathway', (24, 40))	('HA-1077', 'Chemical', 'MESH:C049347', (66, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('157', '166'))	('bladder cancer', 'Disease', 'MESH:D001749', (121, 135))
198698	24908363	The in vitro antiproliferative effect of HA-1077 was evaluated after incubation of cells in the presence of HA-1077 with or without lysophosphatidic acid (LPA) and geranylgeraniol (GGOH), which is an intermediate of the mevalonate pathway.	('GGOH', 'Chemical', '-', (181, 185))	('LPA', 'Chemical', 'MESH:C032881', (155, 158))	('mevalonate', 'Chemical', 'MESH:D008798', (220, 230))	('lysophosphatidic acid', 'Chemical', 'MESH:C032881', (132, 153))	('HA-1077', 'Var', (108, 115))	('antiproliferative effect', 'CPA', (13, 37))	('HA-1077', 'Chemical', 'MESH:C049347', (41, 48))	('HA-1077', 'Chemical', 'MESH:C049347', (108, 115))	('geranylgeraniol', 'Chemical', 'MESH:C017338', (164, 179))
198724	24908363	Cell proliferation was inhibited by HA-1077 in a dose-dependent manner (Figure 1).In clonogenic assay, HA-1077 made significantly less number of colonies compared to control cultures (Figure 1B).	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('clonogenic assay', 'CPA', (85, 101))	('HA-1077', 'Chemical', 'MESH:C049347', (36, 43))	('less', 'NegReg', (130, 134))	('HA-1077', 'Var', (103, 110))	('HA-1077', 'Chemical', 'MESH:C049347', (103, 110))
198728	24908363	HA-1077 dramatically decreased the expression of ROCK-I and ROCK-II, and this decrease was not reversed by addition of LPA and GGOH.	('ROCK-I', 'Gene', (60, 66))	('ROCK-I', 'Gene', '6093', (60, 66))	('decreased', 'NegReg', (21, 30))	('ROCK-II', 'Gene', '9475', (60, 67))	('expression', 'MPA', (35, 45))	('HA-1077', 'Var', (0, 7))	('LPA', 'Chemical', 'MESH:C032881', (119, 122))	('ROCK-II', 'Gene', (60, 67))	('ROCK-I', 'Gene', (49, 55))	('GGOH', 'Chemical', '-', (127, 131))	('ROCK-I', 'Gene', '6093', (49, 55))	('HA-1077', 'Chemical', 'MESH:C049347', (0, 7))
198729	24908363	In contrast, HA-1077 did not reduce RhoA activity, while LPA and GGOH increased RhoA activity despite the addition of HA-1077.	('HA-1077', 'Chemical', 'MESH:C049347', (118, 125))	('GGOH', 'Chemical', '-', (65, 69))	('RhoA', 'Gene', (80, 84))	('RhoA', 'Gene', (36, 40))	('increased', 'PosReg', (70, 79))	('RhoA', 'Gene', '387', (80, 84))	('RhoA', 'Gene', '387', (36, 40))	('LPA', 'Chemical', 'MESH:C032881', (57, 60))	('HA-1077', 'Chemical', 'MESH:C049347', (13, 20))	('HA-1077', 'Var', (118, 125))
198732	24908363	Cell proliferation was inhibited by HA-1077 in a dose-dependent manner, both when HA-1077 was added alone and when it was added in combination with LPA and GGOH (Figures 4A and 5A).	('HA-1077', 'Var', (36, 43))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('HA-1077', 'Var', (82, 89))	('inhibited', 'NegReg', (23, 32))	('LPA', 'Chemical', 'MESH:C032881', (148, 151))	('HA-1077', 'Chemical', 'MESH:C049347', (36, 43))	('GGOH', 'Chemical', '-', (156, 160))	('HA-1077', 'Chemical', 'MESH:C049347', (82, 89))	('Cell proliferation', 'CPA', (0, 18))
198735	24908363	Addition of HA-1077 to cultured cells led to marked induction of apoptosis in a dose-dependent manner compared with control cultures, and this effect was seen for both HA-1077 alone and HA-1077 combined with LPA and GGOH (Figures 6A, B).	('HA-1077', 'Var', (186, 193))	('HA-1077', 'Chemical', 'MESH:C049347', (12, 19))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('52', '74'))	('HA-1077', 'Chemical', 'MESH:C049347', (186, 193))	('LPA', 'Chemical', 'MESH:C032881', (208, 211))	('apoptosis', 'CPA', (65, 74))	('HA-1077', 'Chemical', 'MESH:C049347', (168, 175))	('GGOH', 'Chemical', '-', (216, 220))	('HA-1077', 'Var', (12, 19))
198739	24908363	Cell migration was suppressed by HA-1077 in a dose-dependent manner, both in cultures with HA-1077 alone and in cultures with HA-1077 plus LPA and GGOH (Figures 7A and 8A).	('HA-1077', 'Var', (91, 98))	('HA-1077', 'Var', (33, 40))	('Cell migration', 'biological_process', 'GO:0016477', ('0', '14'))	('Cell migration', 'CPA', (0, 14))	('suppressed', 'NegReg', (19, 29))	('HA-1077', 'Chemical', 'MESH:C049347', (91, 98))	('HA-1077', 'Var', (126, 133))	('HA-1077', 'Chemical', 'MESH:C049347', (33, 40))	('LPA', 'Chemical', 'MESH:C032881', (139, 142))	('HA-1077', 'Chemical', 'MESH:C049347', (126, 133))	('GGOH', 'Chemical', '-', (147, 151))
198741	24908363	The dose-dependent down-regulation of the expression of these proteins by HA-1077 is likely to occur in parallel to the reduction in the number of migrating cells.	('regulation', 'biological_process', 'GO:0065007', ('24', '34'))	('HA-1077', 'Var', (74, 81))	('expression', 'MPA', (42, 52))	('down-regulation', 'NegReg', (19, 34))	('reduction', 'NegReg', (120, 129))	('HA-1077', 'Chemical', 'MESH:C049347', (74, 81))	('number of migrating cells', 'CPA', (137, 162))
198742	24908363	Regarding changes of protein expression, the difference of ROCK-I and ROCK-II expression between cultures with HA-1077 alone and cultures with HA-1077 plus LPA and GGOH gradually decreased at higher concentrations of HA-1077 (Figures 7C, D and 8C, D).	('decreased', 'NegReg', (179, 188))	('HA-1077', 'Chemical', 'MESH:C049347', (111, 118))	('HA-1077', 'Var', (217, 224))	('LPA', 'Chemical', 'MESH:C032881', (156, 159))	('HA-1077', 'Var', (143, 150))	('GGOH', 'Chemical', '-', (164, 168))	('HA-1077', 'Chemical', 'MESH:C049347', (217, 224))	('ROCK-I', 'Gene', (59, 65))	('ROCK-I', 'Gene', (70, 76))	('HA-1077', 'Chemical', 'MESH:C049347', (143, 150))	('ROCK-I', 'Gene', '6093', (70, 76))	('ROCK-I', 'Gene', '6093', (59, 65))	('ROCK-II', 'Gene', '9475', (70, 77))	('HA-1077', 'Var', (111, 118))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('ROCK-II', 'Gene', (70, 77))
198750	24908363	The dose-dependent suppressive effect of HA-1077 on cell proliferation was accompanied by a marked decrease of ROCK-I and ROCK-II protein expression, while there was only a slight decrease of RhoA activity.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('ROCK-I', 'Gene', (122, 128))	('ROCK-I', 'Gene', '6093', (122, 128))	('suppressive', 'NegReg', (19, 30))	('cell proliferation', 'CPA', (52, 70))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('HA-1077', 'Var', (41, 48))	('ROCK-I', 'Gene', (111, 117))	('decrease', 'NegReg', (99, 107))	('ROCK-II', 'Gene', '9475', (122, 129))	('ROCK-I', 'Gene', '6093', (111, 117))	('RhoA', 'Gene', (192, 196))	('HA-1077', 'Chemical', 'MESH:C049347', (41, 48))	('RhoA', 'Gene', '387', (192, 196))	('ROCK-II', 'Gene', (122, 129))
198752	24908363	On the other hand, RhoA activity was significantly higher in cultures with HA-1077 plus LPA and GGOH at each HA-1077 concentration, but the difference in the level of ROCK-I and ROCK-II protein expression between cultures with HA-1077 alone and cultures with HA-1077 plus LPA and GGOH gradually decreased at higher HA-1077 concentrations.	('ROCK-II', 'Gene', '9475', (178, 185))	('GGOH', 'Chemical', '-', (280, 284))	('HA-1077', 'Var', (75, 82))	('GGOH', 'Chemical', '-', (96, 100))	('ROCK-I', 'Gene', (178, 184))	('HA-1077', 'Chemical', 'MESH:C049347', (315, 322))	('HA-1077', 'Chemical', 'MESH:C049347', (109, 116))	('ROCK-I', 'Gene', '6093', (178, 184))	('protein', 'cellular_component', 'GO:0003675', ('186', '193'))	('ROCK-I', 'Gene', (167, 173))	('LPA', 'Chemical', 'MESH:C032881', (272, 275))	('ROCK-I', 'Gene', '6093', (167, 173))	('HA-1077', 'Chemical', 'MESH:C049347', (259, 266))	('LPA', 'Chemical', 'MESH:C032881', (88, 91))	('HA-1077', 'Chemical', 'MESH:C049347', (75, 82))	('RhoA', 'Gene', (19, 23))	('higher', 'PosReg', (51, 57))	('HA-1077', 'Chemical', 'MESH:C049347', (227, 234))	('RhoA', 'Gene', '387', (19, 23))	('ROCK-II', 'Gene', (178, 185))
198753	24908363	These findings suggest that HA-1077 may selectively inhibit urothelial tumor cell proliferation via suppression of ROCK, but not by acting on RhoA.	('inhibit', 'NegReg', (52, 59))	('RhoA', 'Gene', (142, 146))	('urothelial tumor', 'Disease', (60, 76))	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('suppression', 'NegReg', (100, 111))	('RhoA', 'Gene', '387', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('ROCK', 'Protein', (115, 119))	('HA-1077', 'Var', (28, 35))	('HA-1077', 'Chemical', 'MESH:C049347', (28, 35))	('urothelial tumor', 'Disease', 'MESH:D001749', (60, 76))
198755	24908363	We found that bladder cancer cells were less able to form colonies in response to exposure to HA-1077 compared to those without any treatment.	('less', 'NegReg', (40, 44))	('HA-1077', 'Chemical', 'MESH:C049347', (94, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (14, 28))	('HA-1077', 'Var', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('bladder cancer', 'Disease', 'MESH:D001749', (14, 28))	('bladder cancer', 'Disease', (14, 28))
198756	24908363	These results suggested that HA-1077 inhibits the proliferation of bladder cancer cells at a certain rate.	('HA-1077', 'Var', (29, 36))	('HA-1077', 'Chemical', 'MESH:C049347', (29, 36))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('proliferation', 'CPA', (50, 63))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('inhibits', 'NegReg', (37, 45))
198758	24908363	This suggested that the pro-apoptotic effect of HA-1077 was more effective suppression of ROCK at higher concentrations of HA-1077.	('HA-1077', 'Chemical', 'MESH:C049347', (48, 55))	('ROCK', 'MPA', (90, 94))	('HA-1077', 'Var', (123, 130))	('suppression', 'NegReg', (75, 86))	('HA-1077', 'Chemical', 'MESH:C049347', (123, 130))
198760	24908363	Cell migration was suppressed by HA-1077 in a dose-dependent manner, while this suppressive effect of HA-1077 was inhibited by addition of LPA and GGOH.	('HA-1077', 'Var', (33, 40))	('Cell migration', 'biological_process', 'GO:0016477', ('0', '14'))	('Cell migration', 'CPA', (0, 14))	('suppressed', 'NegReg', (19, 29))	('HA-1077', 'Chemical', 'MESH:C049347', (33, 40))	('HA-1077', 'Var', (102, 109))	('LPA', 'Chemical', 'MESH:C032881', (139, 142))	('HA-1077', 'Chemical', 'MESH:C049347', (102, 109))	('GGOH', 'Chemical', '-', (147, 151))
198761	24908363	Western blotting analysis of the cells from the underside of each filter showed that RhoA activity and ROCK-I and ROCK-II expression were significantly decreased by HA-1077 in a dose-dependent manner.	('ROCK-II', 'Gene', '9475', (114, 121))	('expression', 'MPA', (122, 132))	('ROCK-II', 'Gene', (114, 121))	('decreased', 'NegReg', (152, 161))	('HA-1077', 'Var', (165, 172))	('RhoA', 'Gene', (85, 89))	('ROCK-I', 'Gene', (103, 109))	('ROCK-I', 'Gene', '6093', (103, 109))	('ROCK-I', 'Gene', '6093', (114, 120))	('ROCK-I', 'Gene', (114, 120))	('RhoA', 'Gene', '387', (85, 89))	('HA-1077', 'Chemical', 'MESH:C049347', (165, 172))
198762	24908363	This dose-dependent inhibition of these proteins by HA-1077 is likely to occur in parallel with a reduction in the number of migrating cells, since RhoA activity was higher in cultures with HA-1077 plus LPA and GGOH at each HA-1077 concentration, while expression of ROCK-I and ROCK-II did not increase.	('LPA', 'Chemical', 'MESH:C032881', (203, 206))	('higher', 'PosReg', (166, 172))	('ROCK-I', 'Gene', (267, 273))	('RhoA', 'Gene', (148, 152))	('ROCK-I', 'Gene', '6093', (267, 273))	('ROCK-II', 'Gene', '9475', (278, 285))	('HA-1077', 'Chemical', 'MESH:C049347', (52, 59))	('HA-1077', 'Chemical', 'MESH:C049347', (190, 197))	('ROCK-I', 'Gene', (278, 284))	('ROCK-II', 'Gene', (278, 285))	('RhoA', 'Gene', '387', (148, 152))	('GGOH', 'Chemical', '-', (211, 215))	('ROCK-I', 'Gene', '6093', (278, 284))	('HA-1077', 'Var', (52, 59))	('HA-1077', 'Chemical', 'MESH:C049347', (224, 231))	('HA-1077', 'Var', (190, 197))
198767	24908363	These findings indicate that HA-1077 may selectively inhibit bladder cancer cell proliferation and migration via suppression of ROCK, but not by blocking RhoA activity.	('inhibit', 'NegReg', (53, 60))	('HA-1077', 'Var', (29, 36))	('HA-1077', 'Chemical', 'MESH:C049347', (29, 36))	('bladder cancer', 'Disease', 'MESH:D001749', (61, 75))	('ROCK', 'Protein', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('bladder cancer', 'Phenotype', 'HP:0009725', (61, 75))	('bladder cancer', 'Disease', (61, 75))	('RhoA', 'Gene', (154, 158))	('migration', 'CPA', (99, 108))	('suppression', 'NegReg', (113, 124))	('RhoA', 'Gene', '387', (154, 158))
198772	24908363	In the present study, we found that the expression of both ROCK-I and ROCK-II protein was decreased by HA-1077.	('expression', 'MPA', (40, 50))	('decreased', 'NegReg', (90, 99))	('ROCK-I', 'Gene', (70, 76))	('ROCK-I', 'Gene', (59, 65))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('HA-1077', 'Var', (103, 110))	('ROCK-II', 'Gene', '9475', (70, 77))	('ROCK-I', 'Gene', '6093', (59, 65))	('ROCK-I', 'Gene', '6093', (70, 76))	('HA-1077', 'Chemical', 'MESH:C049347', (103, 110))	('ROCK-II', 'Gene', (70, 77))
198773	24908363	However, since HA-1077 and Y-27632 are not highly selective for ROCK-I and ROCK-II, when ROCK-I and ROCK-II were suppressed by HA-1077, downstream molecules such as the myosin binding subunit of the myosin light chain (MLC) phosphatase (MYPT)-1 and LIN-11, Isl1, and MEC-3 domain kinase (LIMK) might compensate for ROCK inhibition.	('myosin light chain', 'Gene', (199, 217))	('suppressed', 'NegReg', (113, 123))	('ROCK-II', 'Gene', '9475', (75, 82))	('Y-27632', 'Chemical', 'MESH:C108830', (27, 34))	('myosin binding subunit', 'Gene', (169, 191))	('ROCK-I', 'Gene', (100, 106))	('ROCK-I', 'Gene', '6093', (100, 106))	('HA-1077', 'Chemical', 'MESH:C049347', (127, 134))	('myosin light chain', 'Gene', '397666', (199, 217))	('ROCK-I', 'Gene', (75, 81))	('ROCK-I', 'Gene', '6093', (75, 81))	('HA-1077', 'Chemical', 'MESH:C049347', (15, 22))	('phosphatase', 'molecular_function', 'GO:0016791', ('224', '235'))	('LIMK', 'Gene', '3984', (288, 292))	('Isl1', 'Gene', (257, 261))	('ROCK-I', 'Gene', (89, 95))	('ROCK-I', 'Gene', '6093', (89, 95))	('myosin binding subunit', 'Gene', '4659', (169, 191))	('myosin binding', 'molecular_function', 'GO:0017022', ('169', '183'))	('MYPT)-1', 'Gene', '4659', (237, 244))	('LIMK', 'Gene', (288, 292))	('ROCK-I', 'Gene', (64, 70))	('ROCK-II', 'Gene', (100, 107))	('ROCK-I', 'Gene', '6093', (64, 70))	('HA-1077', 'Var', (127, 134))	('ROCK-II', 'Gene', (75, 82))	('ROCK-II', 'Gene', '9475', (100, 107))	('Isl1', 'Gene', '3670', (257, 261))
198774	24908363	p140mDia is a mammalian homologue of Drosophila diaphanous that controls actin polymerization.	('p140mDia', 'Var', (0, 8))	('actin polymerization', 'biological_process', 'GO:0030041', ('73', '93'))	('mammalian', 'Species', '9606', (14, 23))	('actin polymerization', 'MPA', (73, 93))	('controls', 'Reg', (64, 72))	('Drosophila', 'Species', '7227', (37, 47))
198782	24908363	Mutation and/or dysregulation of these AGC protein kinases contributes to the pathogenesis of human cancer.	('pathogenesis', 'biological_process', 'GO:0009405', ('78', '90'))	('protein kinases', 'Enzyme', (43, 58))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Mutation', 'Var', (0, 8))	('contributes', 'Reg', (59, 70))	('human', 'Species', '9606', (94, 99))	('GC', 'Chemical', '-', (40, 42))	('AGC', 'Gene', (39, 42))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('dysregulation', 'Var', (16, 29))
198783	24908363	reported that HA-1077 suppresses neovascularization and tumor growth, in association with reduced expression of VEGF, matrix metalloproteinase (MMP)-2, and MMP-9, as well as attenuating the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and DNA binding activity of activator proteins (a key downstream transcriptional factor for ERK1/2) in malignant glioma cells, indicating that the anti-angiogenic effect of HA-1077 may be due to the combined inhibition of ROCK and the mitogen-activated protein kinase kinase (MEK)/ERK pathway.	('matrix metalloproteinase (MMP)-2', 'Gene', '4313', (118, 150))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('HA-1077', 'Chemical', 'MESH:C049347', (437, 444))	('reduced', 'NegReg', (90, 97))	('anti-angiogenic effect', 'CPA', (411, 433))	('ERK', 'Gene', '5594', (256, 259))	('attenuating', 'NegReg', (174, 185))	('neovascularization', 'CPA', (33, 51))	('MEK', 'Gene', (540, 543))	('ERK1/2', 'Gene', (256, 262))	('HA-1077', 'Var', (14, 21))	('ERK1/2', 'Gene', '5595;5594', (256, 262))	('MMP)-2', 'molecular_function', 'GO:0004228', ('144', '150'))	('ERK1', 'molecular_function', 'GO:0004707', ('256', '260'))	('expression', 'Var', (98, 108))	('phosphorylation', 'biological_process', 'GO:0016310', ('190', '205'))	('ERK1', 'molecular_function', 'GO:0004707', ('356', '360'))	('MMP-9', 'Gene', '4318', (156, 161))	('ERK', 'Gene', (256, 259))	('mitogen-activated protein kinase kinase', 'Gene', '5609', (499, 538))	('ERK1/2', 'Gene', (356, 362))	('MMP-9', 'Gene', (156, 161))	('DNA binding', 'molecular_function', 'GO:0003677', ('268', '279'))	('phosphorylation', 'MPA', (190, 205))	('HA-1077', 'Chemical', 'MESH:C049347', (14, 21))	('ERK1/2', 'Gene', '5595;5594', (356, 362))	('VEGF', 'Gene', '7422', (112, 116))	('inhibition', 'NegReg', (472, 482))	('ERK', 'Gene', '5594', (545, 548))	('extracellular signal-regulated kinase 1 and 2', 'Gene', '5594', (209, 254))	('tumor', 'Disease', (56, 61))	('glioma', 'Phenotype', 'HP:0009733', (377, 383))	('protein', 'cellular_component', 'GO:0003675', ('517', '524'))	('VEGF', 'Gene', (112, 116))	('mitogen-activated protein kinase kinase', 'Gene', (499, 538))	('ERK', 'molecular_function', 'GO:0004707', ('545', '548'))	('MMP-9', 'molecular_function', 'GO:0004229', ('156', '161'))	('ERK', 'Gene', '5594', (356, 359))	('HA-1077', 'Var', (437, 444))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('suppresses', 'NegReg', (22, 32))	('ERK', 'Gene', (545, 548))	('malignant glioma', 'Disease', (367, 383))	('malignant glioma', 'Disease', 'MESH:D005910', (367, 383))	('ERK', 'Gene', (356, 359))	('DNA', 'cellular_component', 'GO:0005574', ('268', '271'))	('MEK', 'Gene', '5609', (540, 543))	('extracellular', 'cellular_component', 'GO:0005576', ('209', '222'))
198785	24908363	The present findings indicate that HA-1077 prevents the proliferation and migration of bladder cancer cells and also induces apoptosis by inhibiting ROCK, suggesting that ROCK may be an attractive molecular target agent for anticancer therapy.	('proliferation', 'CPA', (56, 69))	('apoptosis', 'CPA', (125, 134))	('bladder cancer', 'Disease', 'MESH:D001749', (87, 101))	('bladder cancer', 'Disease', (87, 101))	('ROCK', 'MPA', (149, 153))	('cancer', 'Disease', (95, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('induces', 'Reg', (117, 124))	('HA-1077', 'Var', (35, 42))	('inhibiting', 'NegReg', (138, 148))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (228, 234))	('prevents', 'NegReg', (43, 51))	('apoptosis', 'biological_process', 'GO:0097194', ('125', '134'))	('apoptosis', 'biological_process', 'GO:0006915', ('125', '134'))	('migration', 'CPA', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('HA-1077', 'Chemical', 'MESH:C049347', (35, 42))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
198788	24908363	In order to directly address these issues, we should compare the effectiveness of HA-1077 and its vehicle control in vivo by developing a mouse model of human bladder cancer in the future.	('bladder cancer', 'Disease', 'MESH:D001749', (159, 173))	('HA-1077', 'Var', (82, 89))	('bladder cancer', 'Disease', (159, 173))	('mouse', 'Species', '10090', (138, 143))	('HA-1077', 'Chemical', 'MESH:C049347', (82, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (159, 173))	('human', 'Species', '9606', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
198794	24908363	Treatment with HA-1077 caused a decrease in the growth and migration of bladder cancer cells, while apoptosis showed a significant increase.	('HA-1077', 'Var', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('increase', 'PosReg', (131, 139))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('HA-1077', 'Chemical', 'MESH:C049347', (15, 22))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('bladder cancer', 'Disease', 'MESH:D001749', (72, 86))	('decrease', 'NegReg', (32, 40))	('apoptosis', 'CPA', (100, 109))	('bladder cancer', 'Disease', (72, 86))
198796	24908363	These findings indicate that HA-1077 prevents the proliferation and migration of bladder cancer cells and also induces apoptosis by inhibiting ROCK, suggesting that ROCK may be a molecular target for the treatment of cancer.	('apoptosis', 'CPA', (119, 128))	('bladder cancer', 'Disease', 'MESH:D001749', (81, 95))	('bladder cancer', 'Disease', (81, 95))	('cancer', 'Disease', (89, 95))	('induces', 'Reg', (111, 118))	('inhibiting', 'NegReg', (132, 142))	('bladder cancer', 'Phenotype', 'HP:0009725', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('HA-1077', 'Var', (29, 36))	('prevents', 'NegReg', (37, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('119', '128'))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('apoptosis', 'biological_process', 'GO:0006915', ('119', '128'))	('HA-1077', 'Chemical', 'MESH:C049347', (29, 36))	('proliferation', 'CPA', (50, 63))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('migration', 'CPA', (68, 77))	('ROCK', 'MPA', (143, 147))	('cancer', 'Disease', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
198811	24497693	Immunohistochemisty showed the cells strongly positive for pankeratin (CK AE1/AE3) [Figure 4] and high molecular weight keratin (34BE12), which confirmed their epithelial nature.	('34BE12', 'Var', (129, 135))	('AE3', 'Gene', '6508', (78, 81))	('positive', 'Reg', (46, 54))	('AE1', 'Gene', '6521', (74, 77))	('AE3', 'Gene', (78, 81))	('AE1', 'Gene', (74, 77))
198817	24497693	Ki 67, a proliferation marker, is usually high, whereas it is less than 10% in benign lesions such as inverted papilloma and cystitis glandularis.	('cystitis glandularis', 'Disease', (125, 145))	('inverted papilloma', 'Disease', 'MESH:D018308', (102, 120))	('Ki 67', 'Var', (0, 5))	('cystitis glandularis', 'Disease', 'MESH:D003556', (125, 145))	('papilloma', 'Phenotype', 'HP:0012740', (111, 120))	('inverted papilloma', 'Disease', (102, 120))
198830	29050347	In the controlled trials, although the difference was not significant, the pCR rate in the dd-MVAC group has a trend of increase (odds ratio (OR) 1.52; 95% confidence interval (CI) 0.78-2.98, P = 0.22) compared with classic MVAC group.	('dd-MVAC', 'Chemical', '-', (91, 98))	('dd-MVAC', 'Var', (91, 98))	('MVAC', 'Chemical', '-', (94, 98))	('pCR', 'Disease', (75, 78))	('increase', 'PosReg', (120, 128))	('MVAC', 'Chemical', '-', (224, 228))
198833	29050347	Compared with the classic MVAC group, dd-MVAC was associated with significantly decreased risks of all-grade adverse events (AEs) such as anemia (OR 0.457, 95% CI 0.249-0.840, p = 0.012), febrile neutropenia (OR 0.398 95% CI 0.233-0.681, p = 0.001), and neutropenia (OR 0.373, 95% CI 0.201-0.691, p = 0.002).	('anemia', 'Disease', 'MESH:D000740', (138, 144))	('neutropenia', 'Disease', (254, 265))	('febrile neutropenia', 'Disease', (188, 207))	('AEs', 'Chemical', '-', (125, 128))	('febrile neutropenia', 'Disease', 'MESH:D009503', (188, 207))	('neutropenia', 'Disease', 'MESH:D009503', (196, 207))	('neutropenia', 'Disease', 'MESH:D009503', (254, 265))	('MVAC', 'Chemical', '-', (41, 45))	('anemia', 'Phenotype', 'HP:0001903', (138, 144))	('neutropenia', 'Phenotype', 'HP:0001875', (196, 207))	('decreased', 'NegReg', (80, 89))	('neutropenia', 'Disease', (196, 207))	('neutropenia', 'Phenotype', 'HP:0001875', (254, 265))	('MVAC', 'Chemical', '-', (26, 30))	('dd-MVAC', 'Var', (38, 45))	('dd-MVAC', 'Chemical', '-', (38, 45))	('anemia', 'Disease', (138, 144))
198851	29050347	No significant difference was detected in the odds of achieving a pCR with dd-MVAC versus classic MVAC (odds ratio 1.52, 95% CI 0.78-2.98, P = 0.22, I2 = 55%, random-effects model) (Figure 3A).	('dd-MVAC', 'Chemical', '-', (75, 82))	('pCR', 'Disease', (66, 69))	('dd-MVAC', 'Var', (75, 82))	('MVAC', 'Chemical', '-', (78, 82))	('MVAC', 'Chemical', '-', (98, 102))
198852	29050347	In addition, there was no significant improvement in terms of ORR between the dd-MVAC group compared with classic MVAC group, with an odds ratio of 0.98 (95% CI 0.48-1.99, p = 0.96, I2 = 60%, random-effects model) (Figure 3B).	('men', 'Species', '9606', (45, 48))	('dd-MVAC', 'Chemical', '-', (78, 85))	('ORR', 'MPA', (62, 65))	('dd-MVAC', 'Var', (78, 85))	('MVAC', 'Chemical', '-', (114, 118))	('MVAC', 'Chemical', '-', (81, 85))
198853	29050347	As for long-term survival, a significantly improved OS was noted with dd-MVAC treatment when compared with classic MVAC treatment (hazard ratios (HR) 0.77, 95% CI 0.61-0.97, p = 0.03, I2 = 0%, fixed-effects model) (Figure 3C).	('MVAC', 'Chemical', '-', (73, 77))	('OS', 'Chemical', '-', (52, 54))	('MVAC', 'Chemical', '-', (115, 119))	('men', 'Species', '9606', (83, 86))	('men', 'Species', '9606', (125, 128))	('dd-MVAC', 'Chemical', '-', (70, 77))	('improved', 'PosReg', (43, 51))	('dd-MVAC treatment', 'Var', (70, 87))
198860	29050347	The results showed that compared with the classic MVAC group, dd-MVAC was associated with decreased risks of anemia (OR 0.457, 95% CI 0.249-0.840, p = 0.012, I2 = 0.000, fixed-effects model), febrile neutropenia (OR 0.398 95% CI 0.233-0.681, p = 0.001, I2 = 29.370%, fixed-effects model), and neutropenia (OR 0.373, 95% CI 0.201-0.691, p = 0.002, I2 = 0.000, fixed-effects model).	('MVAC', 'Chemical', '-', (65, 69))	('neutropenia', 'Disease', (200, 211))	('febrile neutropenia', 'Disease', (192, 211))	('febrile neutropenia', 'Disease', 'MESH:D009503', (192, 211))	('neutropenia', 'Disease', (293, 304))	('MVAC', 'Chemical', '-', (50, 54))	('anemia', 'Disease', 'MESH:D000740', (109, 115))	('anemia', 'Disease', (109, 115))	('decreased', 'NegReg', (90, 99))	('dd-MVAC', 'Chemical', '-', (62, 69))	('neutropenia', 'Disease', 'MESH:D009503', (200, 211))	('dd-MVAC', 'Var', (62, 69))	('neutropenia', 'Disease', 'MESH:D009503', (293, 304))	('neutropenia', 'Phenotype', 'HP:0001875', (200, 211))	('anemia', 'Phenotype', 'HP:0001903', (109, 115))	('neutropenia', 'Phenotype', 'HP:0001875', (293, 304))
198867	29050347	In our study, we assumed that the pCR rate and OS tended to increase in the dose-dense group, and no statistical difference might largely rely on the limited sample size.	('pCR', 'Disease', (34, 37))	('dose-dense', 'Var', (76, 86))	('OS', 'Chemical', '-', (47, 49))	('increase', 'PosReg', (60, 68))
198870	29050347	Concomitantly, the toxicity data demonstrated that dd-MVAC was associated with a better tolerability than classic MVAC.	('MVAC', 'Chemical', '-', (114, 118))	('MVAC', 'Chemical', '-', (54, 58))	('tolerability', 'MPA', (88, 100))	('dd-MVAC', 'Chemical', '-', (51, 58))	('dd-MVAC', 'Var', (51, 58))	('toxicity', 'Disease', 'MESH:D064420', (19, 27))	('toxicity', 'Disease', (19, 27))
198977	25431734	reported that treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKi) is promising for ocular metastasis of non-small-cell lung cancer harboring an EGFR mutation.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('EGFR', 'Gene', '1956', (89, 93))	('EGFR', 'Gene', (89, 93))	('EGFR', 'molecular_function', 'GO:0005006', ('177', '181'))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('71', '87'))	('EGFR', 'Gene', '1956', (177, 181))	('mutation', 'Var', (182, 190))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('29', '52'))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('EGFR', 'Gene', (177, 181))	('lung cancer', 'Disease', (152, 163))
199003	23110004	The tumor cells were positive for cytokeratin (CK) 7 and P504S but negative for CK 20, p63 and prostatic-specific antigen (PSA) (Fig.	('tumor', 'Disease', (4, 9))	('P504S', 'Mutation', 'p.P504S', (57, 62))	('prostatic-specific antigen (PSA)', 'Gene', '9520', (95, 127))	('positive', 'Reg', (21, 29))	('P504S', 'Var', (57, 62))	('prostatic-specific antigen (PSA', 'Gene', (95, 126))	('p63', 'Gene', (87, 90))	('cytokeratin', 'Protein', (34, 45))	('CK 20', 'Gene', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('p63', 'Gene', '8626', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CK 20', 'Gene', '54474', (80, 85))
199023	23110004	In addition, other study showed that CCAs were positive for P504S but negative for p63 and these findings are not compatible with urothelial origin tumors.	('P504S', 'Mutation', 'p.P504S', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('positive', 'Reg', (47, 55))	('p63', 'Gene', (83, 86))	('CCAs', 'Disease', (37, 41))	('P504S', 'Var', (60, 65))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('p63', 'Gene', '8626', (83, 86))
199024	23110004	P504S is also called alpha-methylacyl-CoA racemase, an enzyme involved in beta-oxidation of branched-chain fatty acids in the mitochondria and peroxisomes.	('alpha-methylacyl-CoA racemase', 'Gene', '23600', (21, 50))	('alpha-methylacyl-CoA racemase', 'Gene', (21, 50))	('P504S', 'Mutation', 'p.P504S', (0, 5))	('P504S', 'Var', (0, 5))	('mitochondria', 'cellular_component', 'GO:0005739', ('126', '138'))	('branched-chain fatty acids', 'Chemical', '-', (92, 118))
199026	23110004	In the current case, the tumor cells were also negative for CK 20 and p63 but positive for P504S.	('positive', 'Reg', (78, 86))	('negative', 'NegReg', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('P504S', 'Mutation', 'p.P504S', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (25, 30))	('P504S', 'Var', (91, 96))	('p63', 'Gene', (70, 73))	('CK 20', 'Gene', '54474', (60, 65))	('CK 20', 'Gene', (60, 65))	('p63', 'Gene', '8626', (70, 73))
199028	23110004	Nephrogenic adenoma shows histologic and immunohostochemical resemblances those being P504S positive and p63 negative.	('p63', 'Gene', '8626', (105, 108))	('Nephrogenic adenoma', 'Disease', 'MESH:D000236', (0, 19))	('P504S positive', 'Var', (86, 100))	('Nephrogenic adenoma', 'Disease', (0, 19))	('P504S', 'Mutation', 'p.P504S', (86, 91))	('p63', 'Gene', (105, 108))